PMID- 15009772
TI  - Transcatheter closure of ruptured sinus of valsalva aneurysm.
AB  - Percutaneous transcatheter closure of ruptured sinus of valsalva aneurysm was
      attempted in eight patients between January 1995 and March 2003 as an alternative
      strategy to surgery as this technique at present is an accepted therapeutic
      modality for various intracardiac defects. The age range was 14-35 years, all
      were male, seven in symptomatic class III and one in class IV on medical
      treatment. Two-dimensional and color Doppler echocardiography revealed rupture of
      an aneurysm of right coronary sinus into right ventricle in five and noncoronary
      sinus into right atrium in three and none had associated ventricular septal
      defect. The echo estimated size of the defect was 7-12 mm. On cardiac
      catheterization left ventricular end-diastolic pressure ranged from 20 to 40 mmHg
      and the calculated Qp/Qs ratio was 2-3.5. In all patients the defect was crossed
      retrogradely from the aortic side and over an arterio-venous wire loop after
      balloon sizing, devices were successfully deployed by antegrade venous approach
      (Rashkind umbrella device in two and Amplatzer occluders in six, which included
      Amplatzer duct occluder in five and Amplatzer septal occluder in one). One
      patient who had residual shunt developed hemolysis on the next day and was taken
      up for reintervention. That patient continued to have intermittent hemolysis and
      was sent for surgical repair. On follow-up (2-96 months), there was no device
      embolization, infective endocarditis, and aortic regurgitation. One patient died
      of progressive congestive heart failure while other six are asymptomatic. These
      data highlight that transcatheter closure is feasible and effective, especially
      safe with the available Amplatzer devices. Definitely, it has the advantage of
      obviating open heart surgery but complete occlusion is mandatory to prevent
      hemolysis and infective endocarditis.

PMID- 15009773
TI  - An unusual case of an accessory coronary artery to pulmonary artery fistula:
      successful closure with transcatheter coil embolization.
AB  - Coronary artery fistulae (CAF) are rare congenital anomalies. Surgical ligation
      is the standard treatment for symptomatic CAF, but is associated with higher
      morbidity. In a select group of patients, transcatheter coil embolization (TCE)
      is a reasonable alternative to standard surgical treatment. In this article, we
      present a unique (not previously reported) case of a tortuous accessory anomalous
      right coronary artery to pulmonary artery fistula with coronary steal phenomenon.
      TCE of highly tortuous fistulae can be technically difficult and are usually
      referred for surgery. In this case report we describe how utilization of adult
      coronary interventional wires and balloon catheters may help overcome some of the
      technical difficulties encountered with catheter-based closure of CAF.

PMID- 15009774
TI  - Teaching the teachers: national survey of faculty development in departments of
      medicine of U.S. teaching hospitals.
AB  - OBJECTIVE: To determine the prevalence, topics, methods, and intensity of ongoing
      faculty development (FD) in teaching skills. DESIGN: Mailed survey. PARTICIPANTS:
      Two hundred and seventy-seven of the 386 (72%) U.S. teaching hospitals with
      internal medicine residency programs. MEASUREMENTS: Prevalence and
      characteristics of ongoing FD. RESULTS: One hundred and eight teaching hospitals
      (39%) reported ongoing FD. Hospitals with a primary medical school affiliation
      (university hospitals) were more likely to have ongoing FD than non-university
      hospitals. For non-university hospitals, funding from the Health Resources
      Services Administration and >50 house staff were associated with ongoing FD. For
      university hospitals, >100 department of medicine faculty was associated. Ongoing
      programs included a mean of 10.4 topics (standard deviation, 5.4). Most offered
      half-day workshops (80%), but 22% offered > or =1-month programs. Evaluations
      were predominantly limited to postcourse evaluations forms. Only 14% of the
      hospitals with ongoing FD (5% of all hospitals) had "advanced" programs, defined
      as offering > or =10 topics, lasting >2 days, and using > or =3 experiential
      teaching methods. These were significantly more likely to be university hospitals
      and to offer salary support and/or protected time to their FD instructors.
      Generalists and hospital-based faculty were more likely to receive training than
      subspecialist and community-based faculty. Factors facilitating participation in
      FD activities were supervisor attitudes, FD expertise, and institutional culture.
      CONCLUSIONS: A minority of U.S. teaching hospitals offer ongoing faculty
      development in teaching skills. Continued progress will likely require increased
      institutional commitment, improved evaluations, and adequate resources,
      particularly FD instructors and funding.

PMID- 15009775
TI  - Health literacy and use of outpatient physician services by Medicare managed care
      enrollees.
AB  - OBJECTIVE: To determine whether inadequate functional health literacy adversely
      affects use of physician outpatient services. DESIGN: Cohort study. SETTING:
      Community. PARTICIPANTS: New Medicare managed care enrollees age 65 or older in 4
      U.S. cities (N = 3,260). MEASUREMENTS AND MAIN RESULTS: We measured functional
      health literacy using the Short Test of Functional Health Literacy in Adults.
      Administrative data were used to determine the time to first physician visit and
      the total number of visits during the 12 months after enrollment. The time until
      first visit, the proportion without any visit, and adjusted mean visits during
      the year after enrollment were unrelated to health literacy in crude and
      multivariate analyses. Participants with inadequate and marginal health literacy
      were more likely to have an emergency department (ED) visit than those with
      adequate health literacy (30.4%, 27.6%, and 21.8%, respectively; P =.01 and P
      <.001, respectively). In multivariate analysis, the adjusted relative risk of
      having 2 or more ED visits was 1.44 (95% confidence interval, 1.01 to 2.02) for
      enrollees with marginal health literacy and 1.34 (1.00 to 1.79) for those with
      inadequate health literacy compared to participants with adequate health
      literacy. CONCLUSIONS: Inadequate health literacy was not independently
      associated with the mean number of visits or the time to a first visit. This
      suggests that inadequate literacy is not a major barrier to accessing outpatient
      health care. Nevertheless, the higher rates of ED use by persons with low
      literacy may be caused by real or perceived barriers to using their usual source
      of outpatient care.

PMID- 15009776
TI  - The effect of English language proficiency on length of stay and in-hospital
      mortality.
AB  - BACKGROUND: In ambulatory care settings, patients with limited English
      proficiency receive lower quality of care. Limited information is available
      describing outcomes for inpatients. OBJECTIVE: To investigate the effect of
      English proficiency on length of stay (LOS) and in-hospital mortality. DESIGN:
      Retrospective analysis of administrative data at 3 tertiary care teaching
      hospitals (University Health Network) in Toronto, Canada. PARTICIPANTS:
      Consecutive inpatient admissions from April 1993 to December 1999 were analyzed
      for LOS differences first by looking at 23 medical and surgical conditions
      (59,547 records) and then by a meta-analysis of 220 case mix groups (189,119
      records). We performed a similar analysis for in-hospital mortality.
      MEASUREMENTS: LOS and odds of in-hospital death for limited English-proficient
      (LEP) patients relative to English-proficient (EP) patients. RESULTS: LEP
      patients stayed in hospital longer for 7 of 23 conditions (unstable coronary
      syndromes and chest pain, coronary artery bypass grafting, stroke, craniotomy
      procedures, diabetes mellitus, major intestinal and rectal procedures, and
      elective hip replacement), with LOS differences ranging from approximately 0.7 to
      4.3 days. A meta-analysis using all admission data demonstrated that LEP patients
      stayed 6% (approximately 0.5 days) longer overall than EP patients (95%
      confidence interval, 0.04 to 0.07). LEP patients were not at increased risk of in
      hospital death (relative odds, 1.0; 95% confidence interval, 0.9 to 1.1).
      CONCLUSIONS: Patients with limited English proficiency have longer hospital stays
      for some medical and surgical conditions. Limited English proficiency does not
      affect in-hospital mortality. The effect of communication barriers on outcomes of
      care in the inpatient setting requires further exploration, particularly for
      selected conditions in which length of stay is significantly prolonged.

PMID- 15009777
TI  - Exploring neighborhood-level variation in asthma and other respiratory diseases:
      the contribution of neighborhood social context.
AB  - OBJECTIVE: We explore differences in the prevalence of asthma and other
      respiratory diseases at the neighborhood level. In addition to traditional
      metrics of neighborhood structure (e.g., concentrated disadvantage, residential
      stability), we incorporate residents' evaluations of neighborhood context. We
      examine the extent to which indicators such as disorder (observable signs of
      physical and social decay) and collective efficacy (trust and shared expectations
      for beneficial community action) account for differences in the prevalence of
      asthma and other respiratory diseases. METHODS: We examine 338 Chicago
      neighborhoods, combining 3 data sources from the 1990s: 1) the Metropolitan
      Chicago Information Center Metro Survey; 2) the Decennial Census; and 3) the
      Project on Human Development in Chicago Neighborhoods Community Survey. We use a
      multilevel statistical approach to disentangle neighborhood- from individual
      level effects. MEASUREMENTS: A survey-based response to whether a physician has
      diagnosed asthma, bronchitis, emphysema, or other breathing problems. RESULTS:
      Findings indicate that individual- and neighborhood-level factors are associated
      with asthma/breathing problems. At the individual level, female gender, smoking,
      and a weight problem are positively associated with asthma/breathing problems,
      while Latino ethnicity is protective. At the neighborhood level, collective
      efficacy is protective against asthma/breathing problems. Residential stability
      is positively associated only when levels of collective efficacy are controlled.
      CONCLUSIONS: Neighborhood context, particularly collective efficacy, may be an
      underlying factor that reduces vulnerability to asthma and other respiratory
      diseases. Collective efficacy may enhance the ability to garner health-relevant
      resources, eliminate environmental hazards that trigger asthma, and promote
      communication among residents which, in turn, enables dissemination of
      information relevant to respiratory ailments.

PMID- 15009778
TI  - Assessing symptoms and peak expiratory flow rate as predictors of asthma
      exacerbations.
AB  - OBJECTIVE: To investigate peak expiratory flow rate (PEFR) and quality of life
      scores for their ability to predict exacerbations of asthma. PARTICIPANTS AND
      METHODS: We identified adults who received oral or inhaled asthma medications
      from 36 community drugstores. We administered the McMaster Asthma Quality of Life
      Questionnaire (AQLQ) and measured PEFR, defining "red zone" (highest risk) as a
      PEFR < 50% of each patient's expected value based on gender, age, and height. We
      identified asthma exacerbations (breathing-related emergency department visits
      and hospitalizations) within 4 and 12 months after enrollment and used
      proportional hazards regression to assess the ability of PEFR and AQLQ scores to
      predict exacerbations, controlling for clinical and demographic factors. RESULTS:
      A red zone PEFR was a significant univariable predictor of exacerbations within
      12 months (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.1 to 3.0; P
      =.027). However, neither a red zone PEFR, the raw PEFR, or percent of predicted
      maximal PEFR were significantly predictive when controlling for AQLQ scores,
      clinical characteristics, or demographic data (P >.2). However, the 4 subscales
      of the AQLQ were each significant univariable and multivariable predictors of
      asthma exacerbations. For example, the overall AQLQ scale had a multivariable HR
      of 0.63 (95% CI, 0.46 to 0.87; P =.005) for exacerbations occurring within 4
      months and 0.66 (95% CI, 0.54 to 0.82; P <.001) within 12 months. CONCLUSIONS:
      PEFR added no predictive information to that contained in AQLQ scores and
      clinical and demographic data. These results support the National Institutes of
      Health asthma guidelines' recommendation for routinely assessing symptoms but not
      PEFR.

PMID- 15009779
TI  - The frequency of Pap smear screening in the United States.
AB  - BACKGROUND: U.S. professional medical societies and the national health systems
      of all other industrialized nations recommend that most women need not undergo
      Papanicolaou (Pap) smear screening annually. There are no data, however,
      regarding the frequency at which women actually undergo screening. OBJECTIVE: To
      describe the frequency of cervical cancer screening in the United States. DESIGN:
      National Health Interview Survey, a cross-sectional population-based telephone
      survey conducted by the National Center for Health Statistics. PARTICIPANTS:
      Representative sample of U.S. women age 21 and older who denied a history of
      cancer (N = 16,467). MEASUREMENTS: Pap smear screening frequency, categorized as
      no regular screening or screening at 1 of 3 discrete screening intervals (every
      year, every 2 years, or every 3 years) based on each woman's reported number of
      Pap smears in the previous 6 years. RESULTS: The vast majority (93%) of American
      women report having had at least one Pap smear in their lifetime. Among women
      with no history of abnormal smears, 55% undergo Pap smear screening annually, 17%
      report a 2-year screening interval, 16% report being screened every 3 years, and
      11% are not being screened regularly. Even the very elderly report frequent
      screening-38% of women age 75 to 84 and 20% of women age 85 and older reported
      annual Pap smears. Overall, 20% of women reported having had at least one
      abnormal Pap smear. Among these women, rates of frequent Pap smear screening are
      considerably higher-80% undergo annual screening, with only a modest decline in
      screening frequency with increasing age. CONCLUSIONS: The majority of American
      women report being screened for cervical cancer more frequently than recommended.
      Lengthening the screening interval would not only reduce the volume of specimens
      that cytotechnologists are required to read, but would also reduce the follow-up
      testing after abnormal smears.

PMID- 15009780
TI  - A national survey of U.S. internists' experiences with ethical dilemmas and
      ethics consultation.
AB  - OBJECTIVE: To identify the ethical dilemmas that internists encounter, the
      strategies they use to address them, and the usefulness of ethics consultation.
      DESIGN: National telephone survey. SETTING: Doctors' offices. PARTICIPANTS:
      General internists, oncologists, and critical care/pulmonologists (N = 344, 64%
      response rate). MEASUREMENTS: Types of ethical dilemmas recently encountered and
      likelihood of requesting ethics consultation; satisfaction with resolution of
      ethical dilemmas with and without ethics consultation. RESULTS: Internists most
      commonly reported dilemmas regarding end-of-life decision making, patient
      autonomy, justice, and conflict resolution. General internists, oncologists, and
      critical care specialists reported participating in an average of 1.4, 1.3, and
      4.1 consultations in the preceding 2 years, respectively (P <.0001). Physicians
      with the least ethics training had the least access to and participated in the
      fewest ethics consultations; 19% reported consultation was unavailable at their
      predominant practice site. Dilemmas about end-of-life decisions and patient
      autonomy were often referred for consultation, while dilemmas about justice, such
      as lack of insurance or limited resources, were rarely referred. While most
      physicians thought consultations yielded information that would be useful in
      dealing with future ethical dilemmas (72%), some hesitated to seek ethics
      consultation because they believed it was too time consuming (29%), might make
      the situation worse (15%), or that consultants were unqualified (11%).
      CONCLUSIONS: While most internists recall recent ethical dilemmas in their
      practices, those with the least preparation and experience have the least access
      to ethics consultation. Health care organizations should emphasize ethics
      educational activities to prepare physicians for handling ethical dilemmas on
      their own and should improve the accessibility and responsiveness of ethics
      consultation when needed.

PMID- 15009781
TI  - Faculty self-reported experience with racial and ethnic discrimination in
      academic medicine.
AB  - BACKGROUND: Despite the need to recruit and retain minority faculty in academic
      medicine, little is known about the experiences of minority faculty, in
      particular their self-reported experience of racial and ethnic discrimination at
      their institutions. OBJECTIVE: To determine the frequency of self-reported
      experience of racial/ethnic discrimination among faculty of U.S. medical schools,
      as well as associations with outcomes, such as career satisfaction, academic
      rank, and number of peer-reviewed publications. DESIGN: A 177-item self
      administered mailed survey of U.S. medical school faculty. SETTING: Twenty-four
      randomly selected medical schools in the contiguous United States. PARTICIPANTS:
      A random sample of 1,979 full-time faculty, stratified by medical school,
      specialty, graduation cohort, and gender. MEASUREMENTS: Frequency of self
      reported experiences of racial/ethnic bias and discrimination. RESULTS: The
      response rate was 60%. Of 1,833 faculty eligible, 82% were non-Hispanic white,
      10% underrepresented minority (URM), and 8% non-underrepresented minority (NURM).
      URM and NURM faculty were substantially more likely than majority faculty to
      perceive racial/ethnic bias in their academic environment (odds ratio [OR], 5.4;
      P <.01 and OR, 2.6; P <.01, respectively). Nearly half (48%) of URM and 26% of
      NURM reported experiencing racial/ethnic discrimination by a superior or
      colleague. Faculty with such reported experiences had lower career satisfaction
      scores than other faculty (P <.01). However, they received comparable salaries,
      published comparable numbers of papers, and were similarly likely to have
      attained senior rank (full or associate professor). CONCLUSIONS: Many minority
      faculty report experiencing racial/ethnic bias in academic medicine and have
      lower career satisfaction than other faculty. Despite this, minority faculty who
      reported experiencing racial/ethnic discrimination achieved academic productivity
      similar to that of other faculty.

PMID- 15009782
TI  - Hospitalists and an innovative emergency department admission process.
AB  - After treatment in an emergency department (ED), patients often wait several
      hours for hospital admission, resulting in dissatisfaction and increased wait
      times for both admitted and other ED patients. We implemented a new direct
      admission system based on telephone consultation between ED physicians and in
      house hospitalists. We studied this system, measuring admission times, length of
      stay, and mortality. Postintervention, admission times averaged 18 minutes for
      transfer to the ward compared to 2.5 hours preintervention, while pre- and
      postintervention length of stay and mortality rates remained similar.

PMID- 15009783
TI  - Impact of federal safety advisories on health food store advice.
AB  - In early 2002, the FDA and Health Canada issued federal advisories that people
      should discontinue taking the herbal antianxiolitic kava kava, until further
      information regarding safety and potential for liver damage were determined. We
      conducted a field study 2 months following the advisories in Toronto, Canada to
      determine whether kava kava continued to be recommended to consumers at retail
      health food stores. Eight participants asked employees at all stores what was
      recommended for anxiety and whether the products were safe. Twenty-two of 34
      stores recommended kava kava, 9 of which mentioned safety concerns. Physicians
      should be aware that federal advisories may not affect sales of unsafe products.

PMID- 15009784
TI  - Reconsidering the family history in primary care.
AB  - OBJECTIVE: The purpose of this paper is to review the role of the family history
      in predictive genetic testing, describe how family history taking is practiced in
      adult primary care, identify the current barriers to appropriate application of
      the family history, and outline the requirements for a new family history tool
      for primary care. DESIGN: We reviewed current perspectives on the family history,
      identifying key references in the medical literature and web-based family history
      tools through discussions with multiple content experts in clinical genetics,
      family medicine, and internal medicine. We conducted a Medline query using the
      search terms family history and primary care to identify references from the past
      10 years. To illustrate the usefulness of family history information, we
      calculated the predictive value of family history and genetic information for
      familial adenomatous polyposis using current references and standard formulas. We
      identified paper and web-based family history tools through discussions with
      content experts. We also conducted a search on the World Wide Web to identify
      resources for electronic medical record and family history. RESULTS: The family
      history is the most important tool for diagnosis and risk assessment in medical
      genetics, and promises to serve as a critical element in the use of predictive
      genetic testing in primary care. Traditional medical education about family
      history has often been unsophisticated and use of family history in adult primary
      care has been limited, compounded by multiple substantive barriers. Although
      there are numerous paper and computer-based aides for taking the family history,
      none currently meets all the needs of adult primary care. CONCLUSIONS: The
      patient's family history remains a critical element in risk assessment for many
      conditions, but substantive barriers impede application in primary care practice,
      and evidence for its contribution to improved health outcomes is limited in this
      setting. Short of radical changes in reimbursement, new tools will be required to
      aid primary care physicians in the efficient collection and application of
      patient family history in the era of genetic testing.

PMID- 15009785
TI  - Contextualizing medical decisions to individualize care: lessons from the
      qualitative sciences.
AB  - Clinical decision making can be described as answering one question: "What is the
      best next thing for this patient at this time?" In addition to incorporating
      clinical information, research evidence, and patient preferences, the process
      requires considering contextual factors that are unique to each patient and
      relevant to their care. The failure to do so, thereby compromising that care, can
      be called a "contextual error." Although proponents of evidence-based clinical
      decision making and many scholars of the medical interview emphasize the
      importance of individualizing care, no operational definition is provided for the
      concept, nor is any methodology proposed for the interpretation of clinically
      relevant patient-specific variables. By conceptualizing the physician-patient
      encounter as a participant-observer case study with an N of 1, this essay
      describes how existing approaches to studying social systems can provide
      clinicians with a systematic approach to individualizing their clinical decision
      making.

PMID- 15009786
TI  - Embedding faculty development in teaching hospitals: moving beyond the status
      quo.

PMID- 15009787
TI  - Literacy and language: disentangling measures of access, utilization, and
      quality.

PMID- 15009789
TI  - Racial and ethnic differences in patient perceptions of bias and cultural
      competence in health care.
AB  - OBJECTIVES: To determine: 1) whether racial and ethnic differences exist in
      patients' perceptions of primary care provider (PCP) and general health care
      system-related bias and cultural competence; and 2) whether these differences are
      explained by patient demographics, source of care, or patient-provider
      communication variables. DESIGN: Cross-sectional telephone survey. SETTING: The
      Commonwealth Fund 2001 Health Care Quality Survey. SUBJECTS: A total of 6,299
      white, African-American, Hispanic, and Asian adults. MEASUREMENTS AND MAIN
      RESULTS: Interviews were conducted using random-digit dialing; oversampling
      respondents from communities with high racial/ethnic minority concentrations; and
      yielding a 54.3% response rate. Main outcomes address respondents' perceptions of
      their PCPs' and health care system-related bias and cultural competence; adjusted
      probabilities (Pr) are reported for each ethnic group. Most racial/ethnic
      differences in perceptions of PCP bias and cultural competence were explained by
      demographics, source of care, and patient-physician communication variables. In
      contrast, racial/ethnic differences in patient perceptions of health care system
      wide bias and cultural competence persisted even after controlling for
      confounders: African Americans, Hispanics, and Asians remained more likely than
      whites (P <.001) to perceive that: 1) they would have received better medical
      care if they belonged to a different race/ethnic group (Pr 0.13, Pr 0.08, Pr
      0.08, and Pr 0.01, respectively); and 2) medical staff judged them unfairly or
      treated them with disrespect based on race/ethnicity (Pr 0.06, Pr 0.04, Pr 0.06,
      and Pr 0.01, respectively) and how well they speak English (Pr 0.09, Pr 0.06, Pr
      0.06, and Pr 0.03, respectively). CONCLUSION: While demographics, source of care,
      and patient-physician communication explain most racial and ethnic differences in
      patient perceptions of PCP cultural competence, differences in perceptions of
      health care system-wide bias and cultural competence are not fully explained by
      such factors. Future research should include closer examination of the sources of
      cultural bias in the US medical system.

PMID- 15009790
TI  - Asian Americans' reports of their health care experiences. Results of a national
      survey.
AB  - OBJECTIVE: To examine how Asian race/ethnicity affects patients' health care
      experiences and satisfaction with care. DESIGN: Telephone interview using random
      digit dialing, stratified to over-sample adults living in areas with
      disproportionately large numbers of minorities. PARTICIPANTS AND SETTING: White
      (N = 3,205) and Asian-American (N = 521) respondents, weighted to represent all
      such adults living in the continental U.S. in telephone households. MEASUREMENTS:
      Reports of health care experiences and trust in the doctor at the last visit, and
      overall satisfaction with care and desire to change doctors in the last 2 years.
      MAIN RESULTS: Asian Americans were less likely than whites to report that their
      doctors ever talked to them about lifestyle or mental health issues (P < or
      =.01). They were more likely to report that their regular doctors did not
      understand their background and values (P < or =.01). When asked about the last
      visit, they were more likely to report that their doctors did not listen, spend
      as much time, or involve them in decisions about care as much as they wanted (all
      P < or =.0001). In multivariable analyses, Asian Americans were less likely than
      whites to report that they were very satisfied with care (odds ratio [OR], 0.64,
      95% confidence interval [CI], 0.42 to 0.99). However, they were not significantly
      less likely than whites to trust their doctors (OR, 0.79, 95% CI, 0.52 to 1.20),
      or to change doctors (OR, 0.93, 95% CI, 0.56 to 1.56). CONCLUSIONS: In a national
      survey, Asian Americans were less likely to receive counseling and less likely to
      report positive interactions with their doctors than white respondents. More
      research is needed to determine the reasons for these differences.

PMID- 15009791
TI  - Disparities in care for depression among primary care patients.
AB  - CONTEXT: Ethnic minorities traditionally receive less care for depression than do
      white populations; we examine ethnic minority care for depression in a large
      cross-national primary care sample. DESIGN: This is a cross-sectional study of
      identification and treatment of depression among diverse primary care patients,
      using self-report of symptoms and care. SUBJECTS: One thousand four hundred and
      ninety-eight depressed primary care patients participating in four large studies
      of quality improvement for depression care are examined at baseline. RESULTS:
      Primary care providers recommend depression treatments for Latino and African
      American patients as frequently as they do for white patients. However, Latino
      and African-American patients are less likely to take antidepressant medications
      (adjusted odds ratio [OR], 0.30; 95% confidence interval [CI], 0.21 to 0.42 and
      adjusted OR, 0.56; 95% CI, 0.36 to 0.87, respectively) and Latinos are less
      likely to obtain specialty mental health care (adjusted OR, 0.50; 95% CI, 0.36 to
      0.75). CONCLUSIONS: Primary care providers are now able to recognize depression
      and recommend treatment for Latino and African-American patients, with this care
      recommended at equal rates to that of white patients. However, Latino and African
      American patients remain less likely to obtain appropriate care, such as
      antidepressant medications or specialty care. New approaches to improving access
      to appropriate care for Latino and African-American primary care patients are
      needed.

PMID- 15009792
TI  - Differences in Medicare expenditures during the last 3 years of life.
AB  - OBJECTIVE: To examine age, gender, race, and area income differences in Medicare
      expenditures in the 3 years before death. DESIGN: Cross-sectional study.
      PARTICIPANTS: A random sample of aged Medicare beneficiaries who died 1996 to
      1999, N = 241,047. MEASURES: We estimate differences in mean Medicare
      expenditures by year before death and by age, gender, race, and area income,
      adjusting for comorbidities and Medicaid enrollment. RESULTS: Expenditures for
      blacks are lower in the second and third years before death and are not
      significantly different from whites in the last year of life (LYOL) (y3 = 70%, P
      <.0001; y2 = 82%, P <.0001; LYOL = 119%, P =.098). Differences in expenditures
      between decedents with area incomes over $35,000 compared to under $20,000
      attenuate by the LYOL (y3 = 116%, P <.0001; y2 = 107%, P <.0001; LYOL = 96%, P
      <.0001). Expenditure patterns for women versus men vary by age. Among the younger
      cohorts (68 to 74 and 75 to 79), expenditures are higher for women in all 3 years
      before death. This difference attenuates among older cohorts; in the oldest
      cohort (90+), expenditures for men exceed those for women by 11% in the LYOL (P
      <.0001). Older beneficiaries have higher expenditures in the second and third
      years before death but lower expenditures in the LYOL. On average, the youngest
      cohort expended $8,017 more in the LYOL relative to the oldest cohort, whereas in
      the third year before death, the oldest cohort's expenditures were $5,270 more
      than those for the youngest cohort (P <.0001). CONCLUSIONS: Age-associated
      differences in aggregate Medicare payments for end-of-life care are more
      substantial than other differences. The fact that other differences attenuate in
      the LYOL may reflect having overcome barriers to health care, or reflect an
      effective ceiling on the opportunities to provide services for persons with
      overwhelming illness.

PMID- 15009793
TI  - Health plan effects on patient assessments of Medicaid managed care among
      racial/ethnic minorities.
AB  - OBJECTIVE: To examine the extent to which racial/ethnic differences in Consumer
      Assessment of Health Plans Study (CAHPS) ratings and reports of Medicaid managed
      care can be attributed to differential treatment by the same health plans (within
      plan differences) as opposed to racial/ethnic minorities being disproportionately
      enrolled in plans with lower quality of care (between-plan differences). DESIGN:
      Data are from the National CAHPS Benchmarking Database (NCBD) 3.0. Data were
      analyzed using linear regression models to determine the overall effects, within
      plan effects, and between-plan effects of race/ethnicity and language on patient
      assessments of care. Standard errors were adjusted for nonresponse weights and
      the clustered nature of the data. PATIENTS/PARTICIPANTS: A total of 49,327 adults
      enrolled in Medicaid managed care plans in 14 states from 1999 to 2000. MAIN
      RESULTS: Non-English speakers reported worse experiences compared to those of
      whites, while Asian non-English speakers had the lowest scores for most reports
      and ratings of care. An analysis of between-plan effects showed that African
      Americans, Hispanic-Spanish speakers, American Indian/Whites, and White-Other
      language were more likely than White-English speakers to be clustered in worse
      plans as rated by consumers. However, the majority of the observed racial/ethnic
      differences in CAHPS reports and ratings of care are attributable to within-plan
      effects. The ratio of between to within variance of racial/ethnic effects ranged
      from 0.07 (provider communication) to 0.42 (health plan rating). CONCLUSIONS: The
      observed racial/ethnic differences in CAHPS ratings and reports of care are more
      a result of different experiences with care for people enrolled in the same plans
      than a result of racial/ethnic minorities being enrolled in plans with worse
      experiences. Health care organizations should engage in quality improvement
      activities to address the observed racial/ethnic disparities in assessments of
      care.

PMID- 15009794
TI  - Race/ethnicity and the receipt of watchful waiting for the initial management of
      prostate cancer.
AB  - INTRODUCTION: Several recent studies have noted that African Americans
      disproportionately receive "watchful waiting" for the initial management of their
      prostate cancer. To determine whether racial/ethnic differences in the receipt of
      watchful waiting are explained by differences in clinical presentation and life
      expectancy at the time of diagnosis, we examined Surveillance, Epidemiology, and
      End Results (SEER)-Medicare data for men diagnosed with prostate cancer in 1994
      to 1996. METHODS: Race/ethnicity, comorbidity, stage, grade, age, and expected
      lifespan and their association with the receipt of watchful waiting were examined
      in multivariate logistic regression analyses. Race-stratified logistic regression
      analyses were also used to examine racial/ethnic variation in the association of
      clinical and demographic factors with the receipt of watchful waiting among
      African-American, Hispanic, and non-Hispanic white men. RESULTS: African-American
      (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.3 to 1.6) and Hispanic men
      (OR, 1.3; 95% CI, 1.1 to 1.5) were significantly more likely than non-Hispanic
      white men to receive watchful waiting in a multivariate model adjusted for age,
      comorbidity, stage, grade, and life expectancy. Advanced stage and grade, lower
      life expectancy, older age, and high comorbidity indices were also significantly
      associated with an increase in the odds of receipt of watchful waiting in
      multivariate analyses. In general, the association between the receipt of
      watchful waiting and the clinical characteristics (i.e., stage, grade, and age)
      were similar for the three racial/ethnic groups. In race-stratified logistic
      regression analyses, life expectancy was associated with an increase in the odds
      of receiving watchful waiting but results were statistically significant for
      whites only. There was also a statistically significant increase in the odds of
      receiving watchful waiting for African-American and white men with high
      comorbidity indices but not Hispanic men. The odds of receiving watchful waiting
      were also higher for African-American and Hispanic men who resided in census
      tracts where a large percentage of residents had not completed high school than
      for white men who resided in similar census tracts. CONCLUSION: The
      disproportionate receipt of watchful waiting among African Americans and
      Hispanics is not completely explained by racial/ethnic variation in clinical
      characteristics or life expectancy as measured in this study. These data suggest
      that there are other factors that contribute to racial/ethnic differences in
      receipt of watchful waiting that warrant investigation.

PMID- 15009795
TI  - Barriers to colorectal cancer screening in Latino and Vietnamese Americans.
      Compared with non-Latino white Americans.
AB  - OBJECTIVE: To identify current colorectal cancer (CRC) screening practices and
      barriers to screening in the Latino, Vietnamese, and non-Latino white
      populations. METHODS: We conducted a telephone survey of Latino, non-Latino
      white, and Vietnamese individuals living in San Jose, California. We asked about
      demographics, CRC screening practices, intentions to be screened, and barriers
      and facilitators to screening. RESULTS: Seven hundred and seventy-five
      individuals (40% white, 29.2% Latino, and 30.8% Vietnamese) completed the survey
      (Response Rate 50%). Overall, 23% of respondents reported receipt of fecal occult
      blood test (FOBT) in the past year, 28% reported sigmoidoscopy (SIG) in the past
      5 years, and 27% reported colonoscopy (COL) in the past 10 years. Screening rates
      were generally lower in Latinos and Vietnamese. Vietnamese were less likely than
      whites to have had SIG in the past 5 years (odds ratio [OR], 0.26; 95% confidence
      interval [CI], 0.09 to 0.72), but ethnicity was not an independent predictor of
      FOBT or COL. Only 22% of Vietnamese would find endoscopic tests uncomfortable
      compared with 79% of whites (P <.05). While 21% of Latinos would find performing
      an FOBT embarrassing, only 8% of whites and 3% of Vietnamese felt this way (P
      <.05). Vietnamese were more likely than whites to plan to have SIG in the next 5
      years (OR, 2.24; 95% CI, 1.15 to 4.38), but ethnicity was not associated with
      planning to have FOBT or COL. CONCLUSIONS: Rates of CRC screening are lower in
      ethnic minority populations than in whites. Differences in attitudes and
      perceived barriers suggest that culturally tailored interventions to increase CRC
      screening will be useful in these populations

PMID- 15009796
TI  - Physician language ability and cultural competence. An exploratory study of
      communication with Spanish-speaking patients.
AB  - OBJECTIVE: We studied physician-patient dyads to determine how physician self
      rated Spanish-language ability and cultural competence affect Spanish-speaking
      patients' reports of interpersonal processes of care. SETTING/PARTICIPANTS:
      Questionnaire study of 116 Spanish-speaking patients with diabetes and 48 primary
      care physicians (PCPs) at a public hospital with interpreter services. MEASURES:
      Primary care physicians rated their Spanish ability on a 5-point scale and
      cultural competence by rating: 1) their understanding of the health-related
      cultural beliefs of their Spanish-speaking patients; and 2) their effectiveness
      with Latino patients, each on a 4-point scale. We assessed patients' experiences
      using the interpersonal processes of care (IPC) in diverse populations
      instrument. Primary care physician responses were dichotomized, as were IPC scale
      scores (optimal vs nonoptimal). We analyzed the relationship between language and
      two cultural competence items and IPC, and a summary scale and IPC, using
      multivariate models to adjust for known confounders of communication. RESULTS:
      Greater language fluency was strongly associated with optimal IPC scores in the
      domain of elicitation of and responsiveness to patients, problems and concerns
      [Adjusted Odds Ratio [AOR], 5.25; 95% confidence interval [CI], 1.59 to 17.27].
      Higher score on a language-culture summary scale was associated with three IPC
      domains - elicitation/responsiveness (AOR, 6.34; 95% CI, 2.1 to 19.3),
      explanation of condition (AOR, 2.7; 95% CI, 1.0 to 7.34), and patient empowerment
      (AOR, 3.13; 95% CI, 1.2 to 8.19)-and not associated with two more-technical
      communication domains. CONCLUSION: Physician self-rated language ability and
      cultural competence are independently associated with patients' reports of
      interpersonal process of care in patient-centered domains. Our study provides
      empiric support for the importance of language and cultural competence in the
      primary care of Spanish-speaking patients.

PMID- 15009797
TI  - The language divide. The importance of training in the use of interpreters for
      outpatient practice.
AB  - PURPOSE: Provision of interpreter services for non-English-speaking patients is a
      federal requirement. We surveyed clinicians to describe their experience using
      interpreters. SUBJECTS AND METHODS: In this cross-sectional study we surveyed
      clinicians in three academic outpatient settings in San Francisco (N = 194)
      regarding their most recent patient encounter which involved an interpreter.
      Questions about the visit included type of interpreter, satisfaction with content
      of clinical encounter, potential problems, and frequency of need. Previous
      training in interpreter use, languages spoken, and demographics were also asked.
      Questionnaires were self-administered in approximately 10 minutes. RESULTS: Of
      194 questionnaires mailed, 158 were completed (81% response rate) and 67% were
      from resident physicians. Most respondents (78%) were very satisfied or satisfied
      with the medical care they provided, 85% felt satisfied with their ability to
      diagnose a disease and treat a disease, but only 45% were satisfied with their
      ability to empower the patient with knowledge about their disease, treatment, or
      medication. Even though 71% felt they were able to make a personal connection
      with their patient, only 33% felt they had learned about another culture as a
      result of the encounter. Clinicians reported difficulties eliciting exact
      symptoms (70%), explaining treatments (44%), and eliciting treatment preferences
      (51%). Clinicians perceived that lack of knowledge of a patient's culture
      hindered their ability to provide quality medical care and only 18% felt they
      were unable to establish trust or rapport. Previous training in interpreter use
      was associated with increased use of professional interpreters (odds ratio [OR],
      3.2; 95% confidence interval [CI], 1.4 to 7.5) and increased satisfaction with
      medical care provided (OR, 2.6; 95% CI, 1.1 to 6.6). CONCLUSIONS: Clinicians
      reported communication difficulties affecting their ability to understand
      symptoms and treat disease, as well as their ability to empower patients
      regarding their healthcare. Training in the use of interpreters may improve
      communication and clinical care, and thus health outcomes.

PMID- 15009799
TI  - Assessing the nation's progress toward elimination of disparities in health care.
AB  - The Agency for Healthcare Research and Quality submitted the first annual
      National Healthcare Disparities Report to Congress in December, 2003. This first
      report will provide a snapshot of the state of racial, ethnic, and socioeconomic
      disparities in access and quality of care in America. It examines disparities in
      the general population and within the Agency's priority populations. While
      focused on extant data, the first report will form the foundation for future
      versions, which examines causes of disparities and shape solutions to the
      problem. As patient advocates and agents of change, primary care physicians play
      a critical role in efforts to eliminate disparities in health care. Continuing
      participation by primary care physicians in the development and refinement of the
      National Healthcare Disparities Report is essential.

PMID- 15009798
TI  - Disparities in screening mammography. Current status, interventions and
      implications.
AB  - OBJECTIVE: This paper describes trends in screening mammography utilization over
      the past decade and assesses the remaining disparities in mammography use among
      medically underserved women. We also describe the barriers to mammography and
      report effective interventions to enhance utilization. DESIGN: We reviewed
      medline and other databases as well as relevant bibliographies. MAIN RESULTS: The
      United States has dramatically improved its use of screening mammography over the
      past decade, with increased rates observed in every demographic group.
      Disparities in screening mammography are decreasing among medically underserved
      populations but still persist among racial/ethnic minorities and low-income
      women. Additionally, uninsured women and those with no usual care have the lowest
      rates of reported mammogram use. However, despite apparent increases in mammogram
      utilization, there is growing evidence that limitations in the national survey
      databases lead to overestimations of mammogram use, particularly among low-income
      racial and ethnic minorities. CONCLUSIONS: The United States may be farther from
      its national goals of screening mammography, particularly among underserved
      women, than current data suggests. We should continue to support those
      interventions that increase mammography use among the medically underserved by
      addressing the barriers such as cost, language and acculturation limitations,
      deficits in knowledge and cultural beliefs, literacy and health system barriers
      such as insurance and having a source regular of medical care. Addressing
      disparities in the diagnostic and cancer treatment process should also be a
      priority in order to affect significant change in health outcomes among the
      underserved.

PMID- 15009800
TI  - The challenges of understanding and eliminating racial and ethnic disparities in
      health.

PMID- 15009802
TI  - Treatment options for post-transplant lymphoproliferative disorder and other
      Epstein-Barr virus-associated malignancies.
AB  - Epstein-Barr virus (EBV) is associated with a range of malignancies that largely
      arise from a defect in EBV-specific cytotoxic T lymphocyte (CTL) immunity and
      function. Much work has focused on the reconstitution of CTL immunity to EBV in
      transplant patients, in whom immunosuppression modalities render them susceptible
      to post-transplant lymphoproliferative disease (PTLD). Adoptive transfer of
      autologous CTLs is effective at both preventing and curing PTLD in solid organ
      transplant recipients and can produce a long-term memory response and protection
      against recurring disease. In this review, the benefits and restrictions of
      administering EBV-specific CTLs for the treatment of PTLD are discussed and
      compared with emerging therapies including the generation of allogeneic human
      leukocyte antigen-matched CTL banks and the anti-CD20 monoclonal antibody
      therapy, MabThera. Furthermore, studies involving other EBV-associated disorders
      have described the potential benefit of adoptive transfer of EBV-specific CTLs
      for Hodgkin's disease, nasopharyngeal carcinoma, chronic active EBV infection,
      and Burkitt's lymphoma. The challenges of tailor-making therapies for individual
      diseases and EBV antigen expression latencies are highlighted, in addition to
      considering vaccination strategies for optimal treatment.

PMID- 15009803
TI  - Differentiation between African populations is evidenced by the diversity of
      alleles and haplotypes of HLA class I loci.
AB  - The allelic and haplotypic diversity of the HLA-A, HLA-B, and HLA-C loci was
      investigated in 852 subjects from five sub-Saharan populations from Kenya (Nandi
      and Luo), Mali (Dogon), Uganda, and Zambia. Distributions of genotypes at all
      loci and in all populations fit Hardy-Weinberg equilibrium expectations. There
      was not a single allele predominant at any of the loci in these populations, with
      the exception of A*3002 [allele frequency (AF) = 0.233] in Zambians and Cw*1601
      (AF = 0.283) in Malians. This distribution was consistent with balancing
      selection for all class I loci in all populations, which was evidenced by the
      homozygosity F statistic that was less than that expected under neutrality. Only
      in the A locus in Zambians and the C locus in Malians, the AF distribution was
      very close to neutrality expectations. There were six instances in which there
      were significant deviations of allele distributions from neutrality in the
      direction of balancing selection. All allelic lineages from each of the class I
      loci were found in all the African populations. Several alleles of these loci
      have intermediate frequencies (AF = 0.020-0.150) and seem to appear only in the
      African populations. Most of these alleles are widely distributed in the African
      continent and their origin may predate the separation of linguistic groups. In
      contrast to native American and other populations, the African populations do not
      seem to show extensive allelic diversification within lineages, with the
      exception of the groups of alleles A*02, A*30, B*57, and B*58. The alleles of
      human leukocyte antigen (HLA)-B are in strong linkage disequilibrium (LD) with
      alleles of the C locus, and the sets of B/C haplotypes are found in several
      populations. The associations between A alleles with C-blocks are weaker, and
      only a few A/B/C haplotypes (A*0201-B*4501-Cw*1601; A*2301-B*1503-Cw*0202; A*7401
      B* 1503-Cw*0202; A*2902-B*4201-Cw*1701; A*3001-B*4201-Cw*1701; and A*3601-B*5301
      Cw*0401) are found in multiple populations with intermediate frequencies
      [haplotype frequency (HF) = 0.010-0.100]. The strength of the LD associations
      between alleles of HLA-A and HLA-B loci and those of HLA-B and HLA-C loci was on
      average of the same or higher magnitude as those observed in other non-African
      populations for the same pairs of loci. Comparison of the genetic distances
      measured by the distribution of alleles at the HLA class I loci in the sub
      Saharan populations included in this and other studies indicate that the Luo
      population from western Kenya has the closest distance with virtually all sub
      Saharan population so far studied for HLA-A, a finding consistent with the
      putative origin of modern humans in East Africa. In all African populations, the
      genetic distances between each other are greater than those observed between
      European populations. The remarkable current allelic and haplotypic diversity in
      the HLA system as well as their variable distribution in different sub-Saharan
      populations is probably the result of evolutionary forces and environments that
      have acted on each individual population or in their ancestors. In this regard,
      the genetic diversity of the HLA system in African populations poses practical
      challenges for the design of T-cell vaccines and for the transplantation medical
      community to find HLA-matched unrelated donors for patients in need of an
      allogeneic transplant.

PMID- 15009804
TI  - Common ancestral origin of pemphigus vulgaris in Jews and Spaniards: a study
      using microsatellite markers.
AB  - Pemphigus is a group of autoimmune blistering diseases of the skin and mucous
      membranes. The association of pemphigus with human leukocyte antigen (HLA) is
      widely accepted. It was described in many ethnic groups and in most countries of
      the world. Studies showed that the associated HLA haplotype in Jewish pemphigus
      vulgaris (PV) patients is HLA-B38, DRB1*0402, and DQB1*0302; or HLA-B35,
      DRB1*0402, and DQB1*0302. Similar associations with class II genes were found in
      Spanish non-Jewish PV patients. As Jews lived in Spain for hundreds of years and
      many converted to Christianity, the presence of the same HLA haplotype in the
      Jewish and Spanish PV suggests that they may share the same founder.
      Microsatellite markers which span the entire major histocompatibility complex
      (MHC) locus were used as genetic probes. They were utilized to dissect the MHC
      region in the search for possible common haplotypes, besides HLA, which may
      provide an answer to this question. It was found that in both cohorts, in
      addition to HLA class II genes, there are probably genes in the class I region
      which are associated with PV. Alleles belonging to the associated markers were
      used to construct haplotypes and to estimate genetic distances. The distance
      between the two PV cohorts is relatively short, but the distance between the
      Jewish patients and the Jewish controls is greater compared to the distance
      between Spanish patients and Spanish controls. In both PV populations, the same
      microsatellite haplotypes in addition to a common class II haplotype were found,
      suggesting that both patient populations originated from the same genetic stock
      and, therefore, share the same ancestral disease gene.

PMID- 15009805
TI  - Biochemical characterization of recombinant and circulating human Spalpha.
AB  - Human Spalpha is a soluble protein expressed by macrophages present in lymphoid
      tissues (spleen, lymph node, thymus, and bone marrow), for which little
      functional and structural information is available. It belongs to the group B of
      the scavenger receptor cysteine-rich superfamily (SRCR-SF) that includes the
      lymphocyte surface receptors CD5 and CD6 among others. Spalpha is able to bind to
      different cells of the immune system (monocytes and lymphocytes), which suggests
      that it may play an important role in the regulation of this system. To study
      Spalpha, an episomal mammalian expression system (pCEP-Pu/HEK 293-EBNA) was used
      to produce a recombinant form (rSpalpha) that was utilized for biochemical
      studies and for the generation of specific hybridomas. Four monoclonal antibodies
      were selected for their reactivity against rSpalpha by Western blot,
      immunoprecipitation, and enzyme-linked immunosorbent assays. The monoclonal
      antibodies recognized three different epitopes on Spalpha. The monoclonal
      antibodies revealed the existence of two Spalpha isoforms of 38 and 40 kDa,
      resulting from different sialic acid content. They also showed that Spalpha is a
      relatively abundant serum protein (60 micro g/ml) that mostly circulates in
      association with other serum proteins. Accordingly, rSpalpha allowed affinity
      chromatography isolation of polyclonal and monoclonal immunoglobulin M (IgM).
      These data indicate that Spalpha is a circulating protein that may play a role in
      the homeostasis of IgM antibodies.

PMID- 15009806
TI  - Molecular studies of anti-HLA-A2 using light-chain shuffling: a structural model
      for HLA antibody binding.
AB  - Human leukocyte antigen (HLA) A2 is one of the most immunodominant HLA antigens.
      Through a process of light-chain variable domain (VL) shuffling, we analyzed the
      VL domains' role in anti-HLA-A2/A28-binding site diversity. This was achieved by
      combining a VH3-30-encoded HLA-A2/A28-specific heavy-chain variable domain with
      10(4) non-immune VL domains. Twelve HLA-A2/A28-specific antibodies were
      subsequently identified. VL gene analysis demonstrated an absence of Vlambda
      domains and that all have VkappaI-encoded light chains. The affinities correlated
      with the VkappaI gene present, with the seven highest affinity antibodies using
      Vkappa domains encoded by the O18 gene segment. A 300-fold difference in affinity
      was observed between the 12 antibodies, and homology modeling demonstrated a
      correlation between electrostatic surface potential of the antigen-binding site
      and affinity for HLA. Overlap between the T-cell receptor-binding site and that
      of the antibodies was indicated by inhibition of cytotoxic T-lymphocyte killing
      of peptide-pulsed target cells. A model of antibody binding to HLA-A2 suggested
      contact with both alpha helices of the HLA molecule, such that the antigen
      binding site spans the peptide-binding groove. These data increase the
      understanding of antibody recognition of HLA and may facilitate the production of
      clonotypic antibodies with peptide-specific binding.

PMID- 15009807
TI  - Molecular polymorphism of ABO blood group gene in Austronesian and non
      Austronesian populations in Oceania.
AB  - A number of archeological, linguistic, and genetic studies have been carried out
      on the peopling of the Pacific, while the origin of Polynesians or the Lapita
      people is still open to debate. The Lapita people are believed to have populated
      the Bismarck Archipelago more than 3600 years ago. However, their Melanesian
      descendants still living in the Bismarck Archipelago have not been genetically
      clarified yet. To address this question, polymorphism of the ABO blood group gene
      was investigated in the following three populations who are considered to be
      almost free from recent admixtures: (i) Balopa islanders as Austronesian (AN)
      speaking Melanesians living in the northwestern end of the Bismarck Archipelago;
      (ii) Gidra as non-Austronesian (NAN)-speaking Melanesians in southwestern
      lowlands of Papua New Guinea; and (iii) Tongan living in Ha'apai island as AN
      speaking Polynesians. Interestingly, there were marked differences in allele
      frequencies of ABO*A101 and ABO*A102 among the three populations. The allele
      frequencies of ABO*A101 and ABO*A102 were 7.9 and 19.3% in Balopa, 23.2 and 0.0%
      in Gidra, and 2.9 and 25.0% in Tongan. Both phylogenetic and correspondence
      analyses suggested that Balopa was more close to Tongan than to Gidra and that
      Balopa was genetically placed between Tongan and Asian populations. Our results
      imply that Balopa may be Melanesian descendants of the Lapita people who
      populated the Bismarck Archipelago.

PMID- 15009808
TI  - Association of polymorphic MHC microsatellites with GVHD, survival, and leukemia
      relapse in unrelated hematopoietic stem cell transplant donor/recipient pairs
      matched at five HLA loci.
AB  - In order to determine whether matching/mismatching for microsatellite
      polymorphism provides useful information on acute graft-vs-host disease (GVHD),
      survival, and leukemia relapse in hematopoietic stem cell (HSC) transplantation,
      we genotyped for polymorphisms at 13 microsatellite loci within the major
      histocompatibility complex (MHC) of 100 unrelated HSC transplant donor-recipient
      pairs who were matched at five classical human leukocyte antigen (HLA) loci. A
      high percentage of allele matching was obtained for five microsatellite loci,
      DQCARII (96%), MICA (93%), MIB (89%), C1-3-1 (93%), and D6S510 (97%), that are
      localized within 100 kb of the HLA-DR, HLA-DQ, HLA-B, HLA-C, or HLA-A locus. In
      contrast, the other eight microsatellites are located farther away from the HLA
      classical loci and have much lower percentages of allele matching [e.g. tumor
      necrosis factor a (TNFa) (73%), TNFd (74%), D6S273 (64%), C3-2-11 (46%), C5-3-1
      (50%), C5-4-5 (63%), C5-2-7 (68%), and D6S265 (81%)]. Therefore, there were at
      least eight microsatellite markers with relatively high percentages of mismatches
      in the donor/recipient pairs with acute or chronic GVHD, poor graft survival, and
      leukemia relapse. However, there were no statistically significant associations
      between mismatched donor-recipient pairs at the 13 microsatellite loci and acute
      or chronic GVHD, graft survival, and leukemia relapse. Nevertheless, allele
      matching at the microsatellite TNFd locus near the TNFa gene was found by the
      Fisher's exact double-sided test to be significantly associated with decreased
      survival in the grade III/IV acute GVHD group. Overall, these results suggest
      that the matching of microsatellite polymorphisms within the HLA region,
      especially the ones farthest from the classical HLA loci, was not useful
      indicator for the outcome of HSC transplantation from unrelated donors. In this
      regard, the future determination of the genome-wide microsatellite genotypes in
      HLA-matched donor-recipient pairs, outside the MHC, may be a better possibility
      for identifying minor histocompatibility genes in linkage disequilibria with
      microsatellites as potential predictive markers for the occurrence of acute GVHD
      and survival rate in HSC transplantation.

PMID- 15009809
TI  - Soluble HLA class I and HLA-DR plasma levels in patients with anterior uveitis.
AB  - Anterior uveitis (AU) is an autoimmune disease frequently associated with HLA-B27
      antigen. Because of the immune regulatory properties of soluble human leukocyte
      antigen (sHLA) molecules, we quantified sHLA class I (sHLA-I) and sHLA-DR plasma
      levels in HLA-typed AU patients (n = 60). Randomly selected healthy individuals
      (n = 128) and HLA-B27 antigen-positive individuals (n = 24) with HLA phenotype
      frequencies similar to the HLA-B27 antigen-positive AU patients served as control
      panels. As expected, HLA-B27 phenotype was significantly increased in AU patients
      (n = 60), compared to healthy controls. Mean sHLA-I levels in AU patients were
      slightly higher than in randomly selected healthy controls. Regarding AU
      subgroups, elevated sHLA-I levels were only found in HLA-B27 antigen-negative
      patients. Compared to controls, sHLA-DR levels were significantly increased in AU
      patients and the subgroups of HLA-B27 antigen-negative and -positive patients but
      not Fuchs' heterochromic cyclitis (FHC). AU patients negative for HLA-B27 antigen
      with a chronic course had higher sHLA-DR levels than those with an acute course.
      The presence of associated systemic diseases in AU patients was related to
      elevated sHLA-DR levels. Secretion of sHLA-DR in blood differs among the various
      forms of AU. Systemic immune activation was present in AU but not in FHC.

PMID- 15009810
TI  - Identification of HLA-B*56 variant (B*560502) in the Korean population.
AB  - We report here a new HLA-B*56 allele, B*560502, identified by sequencing-based
      typing in the Korean population. HLA-B*560502 differs from B*560501 by a single
      nucleotide at position 141 in exon 2 (T(r)C). This single nucleotide substitution
      may not result in an amino acid difference in the alpha1 domain at residue 23.
      The putative haplotype involving B*560502 may be A*24-DRB1*1201-DQA1*0503
      DQB1*0304-DPB1*0202.

PMID- 15009811
TI  - Sequence-based typing confirmed a novel B*40 allele, B*4046, which was identified
      through sequence-specific oligonucleotide hybridization routine typing.
AB  - In this paper, we report the identification of a new human leucocyte antigen-B
      (HLA-B) allele in a sample which has participated in a search for unrelated bone
      marrow donors which was initiated by the Aktion Knochenmarkspende Bayern. This
      novel allele officially designed B*4046 was detected by different low-resolution
      sequence-specific oligonucleotide typings not matching to known allele
      combinations in a female Caucasoid individual. Confirming the presence of a novel
      allele by sequence-based typing, the closest-related allele B*400103 differs from
      the new B*4046 allele by three mutations. This results in an amino acid
      substitution from threonine to alanine in B*4046 at codon 65, while codon 68
      remains conserved and codon 69 "AAG" lysine is replaced by "GAG" glutamic acid in
      B*4046.

PMID- 15009812
TI  - What I learnt from studying epilepsy: epileptology and myself.
AB  - My life work with epilepsy has allowed me to learn a great deal. As an old
      soldier, I would like to give an account of some important milestones in my
      lifetime learning. The first factor that linked me to epilepsy was listening to a
      lecture delivered by Dr Yushi Uchimura on 'The pathogenesis of Ammon's horn
      sclerosis' at a conference of the Japanese Society of Neurology (now Japanese
      Society of Psychiatry and Neurology) in 1928 when I was a 4th year medical
      student at Tokyo University. The following year, I started to study under Dr
      Uchimura at the Department of Psychiatry, Hokkaido University School of Medicine.
      Another factor that linked me to clinical care and research of epilepsy as a
      psychiatrist was my encounter with the two volumes of 'Selected Writing of John
      Hughlings Jackson' edited by J. Taylor. Jackson's greatest asset and contribution
      to modern epileptology include (i) the discovery of 'Jacksonian epilepsy', (ii)
      'conceptual revolution of epilepsy' by recognizing transient mental disorders as
      seizures, (iii) modern definition of epilepsy by defining epileptic seizures as
      discharges in the gray matter, and (iv) discovery of 'new epilepsy' (now temporal
      lobe epilepsy). In 1940, I reported clinical courses indistinguishable from
      schizophrenia in epilepsy cases. Through my studies, I disputed the then
      prevailing interpretation of this condition as epilepsy complicating
      schizophrenia, and proved that these cases were in fact epileptic mental
      disorders caused by epilepsy. Many patients with epilepsy require medical care as
      well as rehabilitation and welfare support. We need to further promote the
      facilities for rehabilitation and employment in the community for persons with
      epilepsy, such as co-operatives and welfare worksites. The issues that
      epileptology and epilepsy face in the 21st century is to realize the goals of
      liberating epilepsy from social stigma and protecting all the citizen's rights
      for persons with epilepsy.

PMID- 15009813
TI  - Natural disaster and mental health in Asia.
AB  - The purpose of the present article was to review the literature on disaster
      mental health in relation to natural disasters such as earthquakes, volcanic
      eruptions, typhoons and cyclones throughout Asia. Articles reviewed show that
      disaster psychiatry in Asia is beginning to emerge from and leave behind the
      stigma attached to mental health. The emergence of the acceptance of disaster
      mental health throughout Asia can be attributed in part to the acceptance of the
      notion of post-traumatic stress disorder (PTSD). This has allowed greater
      involvement of mental health professionals in providing ongoing support to
      survivors of natural disasters as well as providing greater opportunities for
      further research. Also, articles reviewed in the present paper commonly suggested
      the need for using standardized diagnostic tools for PTSD to appropriately
      interpret the discrepancy of results among studies. The importance of post
      disaster support services and cultural differences is highlighted.

PMID- 15009814
TI  - Schizophrenia and narcolepsy: a review with a case report.
AB  - Several reports emphasize the importance of differentiating between psychosis in
      schizophrenia and the psychotic form of narcolepsy. The failure to identify
      narcolepsy leads to the labeling of patients as refractory to standard treatments
      for schizophrenia and retards consideration of intervention for narcolepsy in
      which psychosis can improve with psychostimulant treatment. Psychosis in patients
      with narcolepsy can occur in three ways: (i) as the psychotic form of narcolepsy
      with hypnagogic and hypnopompic hallucinations; (ii) as a result of
      psychostimulant use in a patient with narcolepsy; and (iii) as the concurrent
      psychosis of schizophrenia in a patient with narcolepsy. The present case report
      describes a difficult-to-treat patient who likely had concurrent schizophrenia
      and narcolepsy. It then summarizes the literature related to the treatment of the
      three types of patients with psychosis associated with narcolepsy.

PMID- 15009815
TI  - Behavior patterns of patients with hebephrenic schizophrenia when they attempt
      academic study.
AB  - Direct assistance with academic study was given to 16 subjects who had
      hebephrenic schizophrenia (HS) and problems with school attendance, with the aim
      of helping the subjects to reaching their desired level of academic achievement.
      The subjects exhibited nine behavior patterns when they reached an impasse in
      their study: (i) difficulty understanding the degree of importance; (ii)
      difficulty integrating multiple concepts; (iii) difficulty understanding abstract
      concepts; (iv) difficulty developing an overview; (v) difficulty with applied
      problems; (vi) attempting to achieve complete understanding; (vii) becoming
      labile prior to exams; (viii) excess cramming leading to breakdown; and (ix)
      extreme reactions. These patterns were compared with those of 10 healthy junior
      high school students (normal group). In the HS group, patterns (i-v) were seen in
      at least a moderate degree in all subjects, but were significantly stronger than
      in the normal group and, even with study advice, improvement was temporary. Wide
      individual variations were seen in patterns (vi-ix) in the HS group, but again
      they were significantly stronger than in the normal group. The behavior patterns
      were influenced by the prospects of academic success, and were more prominent in
      subjects with higher expectations. Cognitive dysfunction was the root cause of
      these behavior patterns, with the additional involvement of psychological
      factors.

PMID- 15009816
TI  - Efficacy and pharmacokinetics of fluvoxamine maleate in patients with mild
      depression undergoing hemodialysis.
AB  - Seven Japanese patients on maintenance hemodialysis who were comorbid with mild
      depression were medicated with 50 mg/day fluvoxamine maleate for 28 days.
      Effectiveness was obtained in four out of seven patients (57%). The plasma
      fluvoxamine concentrations were examined in three patients. The plasma fuvoxamine
      concentration decreased by 22% by hemodialysis. There is a tendency for the
      dialyzed rate of fluvoxamine to become lower if the plasma albumin concentration
      is higher. The half-life of fluvoxamine was possibly shortened more in the
      patient with hypoalbuminaemia. The plasma fluvoxamine concentration reached a
      steady state 8 days after the start of medication and thereafter. The time
      required to reach steady state was lengthened when compared with the results in
      normal Japanese volunteers.

PMID- 15009817
TI  - Clonidine effects on all-night human sleep: opposite action of low- and medium
      dose clonidine on human NREM-REM sleep proportion.
AB  - Norepinephrine (NE) is considered to play a permissive role in the occurrence of
      rapid eye movement (REM) sleep. Clonidine is an NE alpha-2-receptor agonist,
      which has been considered to act mainly on the autoreceptors of presynaptic
      noradrenergic neurons to reduce their release of NE. However, previous studies of
      clonidine effects on REM sleep have produced controversial results and the
      effects of clonidine remain uncertain. To clarify the pharmacological effects of
      clonidine on human sleep, the sleep electroencephalograms (EEG) recorded from 15
      young normal subjects after a single administration of either a low (25 micro g)
      or medium (150 micro g) dose of clonidine were examined, and fast Fourier
      transformation (FFT) spectral analyses of the C3-A2 EEG were performed. Low-dose
      clonidine significantly increased the amount of REM sleep and decreased the
      amount of non-REM (NREM) sleep during the second one-third of the drug nights
      compared to the corresponding hours of baseline night recordings. In contrast,
      medium-dose clonidine significantly decreased REM and increased NREM on drug
      nights compared to baseline nights in the entire night. The opposite actions of
      low and medium doses of clonidine on NREM-REM proportion may indicate that low
      dose clonidine mainly affects the alpha-2-receptors on locus coeruleus-NE neurons
      presynaptically, reducing the release of NE, whereas medium-dose clonidine acts
      more post-synaptically.

PMID- 15009818
TI  - Role of imaginary companion in promoting the psychotherapeutic process.
AB  - An imaginary companion (IC) has been considered to be a transitory phenomenon
      sometimes seen in the normal developmental process of children. In recent years,
      however, it has been observed that ICs are related to various disorders, and
      their clinical significance is again attracting notice. Although an IC may in
      certain ways aggravate the patient's symptoms and regression, an IC may also
      serve to advance the therapy, for example by indicating the location of the
      patient's troubles, or acting as an intermediary between the therapist and
      patient. In cases of dissociative (conversion) disorders, it is generally
      difficult for patients to verbalize their troubles, but the present patients
      gained insight into themselves by closely examining their ICs. Imaginary
      companions are not simply entities incidental to the disorder, and by
      incorporating them into the therapeutic strategy as a presence supporting the
      patient's growth, it is possible that the psychotherapy may proceed more
      smoothly.

PMID- 15009819
TI  - Reliability and validity of the Japanese edition of the Defense Style
      Questionnaire 40.
AB  - Defense styles have a close relationship with ego development and
      psychopathology. The purpose of the present paper was to examine the reliability
      and validity of the Japanese edition of the Defense Style Questionnaire (DSQ-40;
      Andrews et al. 1993). Six hundred and six Japanese university students (348
      female) completed the DSQ-40 and Maudsley Personality Inventory (MPI). The
      neurotic tendency had positive correlations with immature and neurotic defense
      styles and a negative correlation with the mature defense style. The extroversion
      tendency had positive correlations with the mature and neurotic defense styles
      and a negative correlation with the immature defense style. There was a
      significant test-retest correlation for all items of the DSQ-40 (n = 284). The
      results show that the Japanese version of the DSQ-40 had concurrent validity with
      the MPI and a test-retest reliability of 2 months, although there was some doubt
      about the validity of the factor structure of the DSQ-40. Therefore, the DSQ-40
      is a useful scale in Japan to measure ego development and ego function through
      defense styles.

PMID- 15009820
TI  - Catatonic features noted in patients with post-partum mental illness.
AB  - The purpose of the present study was to investigate the prevalence, distribution
      of psychiatric diagnoses, and treatment responses of patients with post-partum
      mental illness at an emergency unit at Chang Gung Memorial Hospital at Kaohsiung
      in Taiwan. During a 1 year period a total of 636 Taiwanese women received
      psychiatric consultation on their visits to the emergency room. Fifteen of these
      were noted to have post-partum mental illnesses. All subjects were followed up
      for a minimum of 3-6 months. The prevalence of patients with post-partum mental
      illness at an emergency unit at Chang Gung Memorial Hospital at Kaohsiung was
      2.4% (15/636). The distribution of psychiatric diagnoses according to Diagnostic
      and Statistical Manual of Mental Disorders (4th edn; DSM-IV) criteria included
      eight cases of major depressive disorders (53.3%), three cases of bipolar I
      disorder (20%), three cases of schizophrenia (20%), and one case of psychotic
      disorder due to a general medical condition (6.7%). Four subjects manifested
      catatonic features. Of these four, three had complete remission in catatonic
      symptoms after receiving intramuscular injection of lorazepam. The fourth subject
      died of multiple medical diseases. The treatment results suggest that most of the
      clinical presentations in patients with post-partum mental illness could be
      relieved by antipsychotics, mood stabilizers or antidepressants. In addition, it
      was found that intramuscular injection of lorazepam was also effective in
      patients with catatonic features and post-partum depression or psychosis.

PMID- 15009821
TI  - Open label study of the effect of amantadine on weight gain induced by
      olanzapine.
AB  - The purpose of the present paper was to investigate the effects of the dopamine
      agonist amantadine in those patients with weight gain induced by olanzapine. An
      open trial was conducted in those patients who gained >3 kg in weight induced by
      olanzapine use. All subjects were evaluated by weight, body mass index (BMI), the
      Brief Psychiatric Rating Scale (BPRS), and the Extrapyramidal Symptom Rating
      Scale (ESRS) before and after the use of amantadine in addition to olanzapine.
      Twenty-five of 30 enrolled patients completed the present study. Mean bodyweight
      and BMI was increased by 6.44 +/- 4.42 kg and 5.04 +/- 3.47 kg/m2 significantly
      with olanzapine alone (P < 0.001). When amantadine and olanzapine were used
      together, the average weight and BMI decreased by 1.07 +/- 3.19 kg and 0.84 +/-
      2.5 kg/m2, but did not have statistical significance. The average values of BPRS
      showed a significant decrease (P < 0.001). No significant changes were present in
      ESRS. Amantadine did not have an effect on weight gain induced by olanzapine.
      Randomized placebo-controlled prospective studies are needed.

PMID- 15009822
TI  - Correlation between scores on Continuous Performance Test and plasma
      concentration for schizophrenic patients on risperidone.
AB  - The purpose of the present paper was to evaluate the relationship between plasma
      antipsychotics concentration and cognitive task performance. This may provide
      valuable information for rational dosage titration. Literature on the
      relationship between plasma risperidone (RIS) concentration and performance on
      the Continuous Performance Test (CPT) remains scarce. Ten patients (four male,
      six female) were given RIS for more than 1 year. Steady-state plasma
      concentrations of the parent drug RIS and its active metabolite, 9-hydroxy
      risperidone (9-OH-RIS), were measured using specific liquid chromatography-tandem
      mass spectrometry assay. Psychopathology, side-effects of extrapyramidal symptoms
      (EPS) and CPT were also assessed. A negative correlation was found between CPT
      performance and the plasma RIS, 9-OH-RIS and its active moiety (RIS + 9-OH-RIS)
      concentrations. Both RIS and 9-OH-RIS have an impact on the CPT performance of
      schizophrenic patients. Optimal active moiety plasma concentration for best
      cognitive performance needs further study.

PMID- 15009823
TI  - Coping behavior in patients with panic disorder.
AB  - The purpose of the present paper was to investigate the role of coping behavior
      in patients with panic disorder (PD). This was done by evaluating three items of
      coping behavior (seeking of social support, wishful thinking and avoidance) in
      the Ways of Coping Checklist. The subjects consisted of 30 patients with PD (26
      with agoraphobia). Coping behavior and the severity of PD was investigated at
      baseline and at 24 months (the final outcome). At baseline there were no gender
      differences in coping behavior. The severity of panic attacks significantly
      correlated with that of agoraphobia. The baseline severity of PD (panic attacks
      and agoraphobia) did not correlate with coping behavior. At the outcome
      assessment there was no significant correlation between the severity of panic
      attack and coping behavior. The severity of agoraphobia at final outcome and the
      coping behavior (seeking of social support) at baseline were significantly
      correlated. In the group that had remission in agoraphobia (the good outcome
      group), the severity of agoraphobia at baseline was significantly lower and the
      seeking of social support coping behavior was significantly higher than that of
      the poor outcome group. No significant difference in panic attack severity was
      noted between the good and poor outcome groups. Discriminant analysis revealed
      that seeking of social support coping behavior was a significant discriminant
      factor of agoraphobia. Although these are preliminary data, special coping
      behavior might be related to improvement of agoraphobia in patients with PD.

PMID- 15009824
TI  - Sleep characteristics of menopausal insomnia: a polysomnographic study.
AB  - Although menopausal insomnia is of clinical significance, the essential features
      of this form of disrupted sleep are poorly understood. The aim of the present
      study was to identify the sleep characteristics of menopausal insomnia by using
      overnight polysomnography (PSG). Twenty-one subjects with menopausal insomnia
      (MI) and 13 sex- and age-matched normal control (NC) subjects without sleep
      complaints took part in the present study. All MI and NC subjects underwent PSG
      on two consecutive nights. In comparison with NC, MI subjects had non-specific
      findings such as significantly shorter total sleep time, longer sleep latency,
      higher wake time after sleep onset, and lower sleep efficiency. As for rapid eye
      movement (REM) sleep variables, MI subjects had significantly shorter total REM
      sleep time, fewer numbers of REM sleep periods, longer REM latency, and higher
      REM density than did the NC subjects. As for the time course of REM density, REM
      density during the first 3 h period of nocturnal sleep was significantly higher
      for MI than for NC subjects. Unlike NC subjects, REM density for MI subjects did
      not tend to rise progressively during nocturnal sleep. The MI subjects had
      objective evidence of disrupted sleep and the most striking characteristics of
      this dysfunction were observed in REM sleep variables. The sleep characteristics
      of MI subjects were found to differ in REM sleep variables from those of patients
      with major depression (except for REM density). Menopausal insomnia patients
      appear to be similar to patients with generalized anxiety disorder accompanied by
      severe sleep disruption. These data lend support to the clinical distinction
      between menopausal insomnia and insomnia associated with major psychiatric
      disorders.

PMID- 15009825
TI  - Premenstrual symptoms and premenstrual exacerbation in patients with psychiatric
      disorders.
AB  - The aim of the present study was to examine the frequencies of premenstrual
      syndrome (PMS) and premenstrual exacerbation (PME) of a number of psychiatric
      disorders in Chinese subjects. Premenstrual syndrome was assessed using a symptom
      checklist based on International Classification of Diseases (10th revision; ICD
      10) criteria. Premenstrual exacerbation was defined as premenstrual worsening of
      pre-existing generalized anxiety disorder (GAD), major depressive disorder or
      dysthymic disorder (depressive disorders, DD), panic disorder (PD), or
      schizophrenia (SCH). Fifty outpatients were randomly sampled for each diagnostic
      group. Diagnosis was performed by psychiatrists using the structured Mini
      International Neuropsychiatric Interview (MINI), and the frequencies of PMS and
      PME were compared for the different diagnostic groups. The PMS symptoms were
      reported by 78%, 80%, 68%, and 52% of GAD, DD, PD, and SCH patients,
      respectively, with 52%, 52%, 36%, and 20% fulfilling the definition of PME. No
      significant statistical relationships between diagnostic entities and family
      history of PMS, years of education, or age were demonstrated, but number of PMS
      symptoms was associated with severity of PME. No significant relationships were
      demonstrated between PME and marital status, parity, years of education, age, or
      family history of PMS. The results showed that high PME rates were noted for a
      sample of Chinese women with mental disorders, especially those with depressive
      and anxiety disorders.

PMID- 15009826
TI  - Habitual self-mutilation in Japan.
AB  - The purpose of the present study was to clarify the relationship between bulimic
      behavior, dissociative phenomenon and sexual/physical abuse histories in Japanese
      subjects with habitual self-mutilation. Subjects consisted of 34 female
      outpatients who had cut their wrists or arms on more than 10 occasions. Two age
      matched groups, which consisted of 31 general psychiatric outpatients and 26 non
      clinical volunteers, served as controls. They were assessed with the Beck
      Depression Inventory-II, Bulimia Investigatory Test of Edinburgh, Adolescent
      Dissociative Experience Scale, and an original self-reporting questionnaire
      concerning various problematic behaviors and sexual/physical abuse histories. The
      habitual self-mutilation and the two control groups were compared. The habitual
      self-mutilation group had significantly higher scores on the Beck Depression
      Inventory-II, Bulimia Investigatory Test of Edinburgh, and Adolescent
      Dissociative Experience Scale than either of the two control groups (P < 0.001).
      Furthermore, the habitual self-mutilation group more frequently had a history of
      illicit psychoactive drug use (P = 0.001), shoplifting (P < 0.001), suicide
      attempts (P < 0.001), overdosing with medicine (P < 0.001), sexual abuse (P =
      0.011), and childhood physical abuse (P = 0.001) than the general psychiatric
      controls. These results are consistent with those in Western studies. Habitual
      self-mutilation is likely to coexist with depression, bulimia, and dissociation.
      Such patients frequently have clinical features similar to those of 'multi
      impulsive bulimia'. Evidence supports the association between habitual self
      mutilation and sexual/childhood physical abuse in Japan.

PMID- 15009828
TI  - Psychiatric comorbidity and gender differences of persons incarcerated for
      methamphetamine abuse in Taiwan.
AB  - Methamphetamine (MAP) abuse has been common in Taiwan for the past decade. The
      purpose of the present study was to investigate MAP abuse in Taiwan, with
      specific attention to psychiatric comorbidity and gender differences. A total of
      325 MAP abuse subjects (180 male, 145 female) from a detention center in Taipei
      were assessed with the Diagnostic Interview for Genetic Studies. The following
      were studied: drug use behavior, treatment-seeking behavior, lifetime prevalence
      of mood disorders, MAP psychosis, alcohol use disorders, pathological gambling
      and antisocial personality. The MAP-abuse subjects in Taiwan had high psychiatric
      morbidity and low access to mental health services. There also exist certain
      differences in the prevalence of psychiatric illnesses and treatment-seeking
      behavior between male and female subjects. Compared with their male counterparts,
      more female subjects reported experience of mental disturbance and experience of
      psychiatric treatment. The female subjects more commonly reported suicidal
      behaviors than the male subjects.

PMID- 15009827
TI  - Transmission disequilibrium test and haplotype analysis of the NOTCH4 gene in
      Japanese patients with schizophrenia.
AB  - A recent study reported that the NOTCH4 gene was highly associated with
      schizophrenia in the British population. To confirm this association for another
      population, a case-control study was conducted and a transmission disequilibrium
      test (TDT) analysis was performed on a group of Japanese subjects (235 pairs of
      schizophrenia patients and controls, and 78 trios consisting of probands and
      their parents) using two single nucleotide polymorphisms and three microsatellite
      markers for the NOTCH4 gene. Haplotype analysis was also studied in case-control
      and family based data sets. In all markers except for (CTG)n (P = 0.012, before
      correction for multiple testing), no differences were found in the case-control
      study. The TDT analysis also revealed only a weak transmission disequilibrium in
      (TTAT)n (genotype-wise P = 0.012). The finding of the present study could not
      support the original findings that the NOTCH4 gene itself is associated with
      susceptibility to schizophrenia.

PMID- 15009829
TI  - Economic slump and suicide method: preliminary study in Kobe.
AB  - During the recent half decade, Japan's suicide rate at approximately 25 deaths
      per 100 000 people has been one of the highest rates in the world. From the
      perspective of suicide prevention by restricting access to suicidal means, the
      aim of the present study was to examine what kind of suicidal method increased
      during prolonged economic slump. During 21 years (1981-2001), for all suicide
      victims (5161 cases) the gender, age, and suicide methods were investigated. The
      yearly full unemployment rate was also used as a representative socioeconomic
      factor during the same periods in Japan using government statistics, and the
      relationship between methods of suicide and full unemployment rate was
      investigated. Pearson's correlation suggested that there was a significant
      correlation only for hanging rate (r = 0.736, P < 0.001), but not for the
      percentages of other methods of suicide. This finding that unemployed persons may
      have a susceptibility towards certain suicide methods could help in the
      prevention of suicides. Mental health in Japan should be given more attention,
      especially for the working population, and social programs offering help should
      be considered widely.

PMID- 15009830
TI  - Comparison of high-functioning atypical autism and childhood autism by Childhood
      Autism Rating Scale-Tokyo version.
AB  - To assess autistic symptom differences between high-functioning atypical autism
      (atypical symptomatology) (HAA; IQ >/= 70) and childhood autism (HCA), 53 HAA
      children (mean: 6.0 +/- 0.5 years) were compared with 21 HCA children (mean: 8.2
      +/- 1.1 years) on the Childhood Autism Rating Scale-Tokyo version (CARS-TV).
      Because IQ on the Japanese version of the Stanford-Binet and CARS-TV total scores
      differed significantly between HAA and HCA, analysis of covariance was conducted
      with IQ and CARS-TV total scores controlled for. In two items of CARS-TV
      (relationship with people and general impressions) the HAA children were
      significantly less abnormal than the HCA children. Affect tended to be
      significantly milder in HAA than HCA. Anxiety reaction was significantly more
      abnormal in HAA than HCA. These findings may be useful to distinguish between HAA
      and HCA.

PMID- 15009831
TI  - Abnormal somatosensory evoked potentials in two patients with conversion
      disorder.
AB  - On clinical grounds, somatosensory evoked potentials (SEP) and motor evoked
      potentials (MEP) are currently used to discriminate between hysterical and
      neurological conditions. The present paper reports on two patients with severe
      gait disturbance who had the near-total absence of SEP responses on the scalp
      during the symptomatic period, which normalized after recovery. These findings,
      along with others, may shed light on the brain correlates of conversion
      phenomena.

PMID- 15009832
TI  - Efficacy of milnacipran for depressive symptoms in schizophrenia spectrum
      disorders.

PMID- 15009833
TI  - Interpretation of pediatric allograft endomyocardial biopsies: a new approach.

PMID- 15009834
TI  - The protocol renal allograft biopsy: has its time come?

PMID- 15009835
TI  - Is there a difference between Hodgkin's disease and a Hodgkin's-like post
      transplant lymphoproliferative disorder, and why should that be of any interest?

PMID- 15009836
TI  - The use of rituximab, anti-CD20 monoclonal antibody, in pediatric
      transplantation.
AB  - Rituximab, chimeric anti-human CD-20, is approved for treatment of B-cell
      lymphoma in adults. It is being used experimentally in other various immune
      related disease such as immune thrombocytopenic purpura, myasthenia gravis, and
      rheumatoid arthritis. In transplant recipients it is used for treatment of post
      transplant lymphoproliferative disease, and prevention and treatment of acute
      rejection. There are few data on its use in children. This paper reviews the use
      of rituximab in these disease states and provides hypotheses for its mode of
      action.

PMID- 15009837
TI  - The yield of surveillance endomyocardial biopsies as a screen for cellular
      rejection in pediatric heart transplant patients.
AB  - Endomyocardial biopsy is commonly used to screen for cellular rejection in
      pediatric heart transplant patients. The yield of EMBs when combined with newly
      developed immunohistochemical techniques and modern immunosuppression in
      pediatric heart transplant patients is unknown. After OHT, surveillance biopsies
      were performed on a routine basis on all pediatric patients. EMBs were also
      performed on symptomatic OHT patients suspected to have rejection. All positive
      results (greater than ISHLT grade 1B) were confirmed with immunohistochemical
      staining. A retrospective review of consecutive EMBs performed in this
      institution from January 1995 to January 2003 was performed. The
      echocardiographic results, clinical history and treatment changes at the time of
      every biopsy were also catalogued. Of the 1093 EMB results from 136 pediatric
      heart transplant grafts (127 patients, 64 male) reviewed, 825 biopsies were
      performed on patients managed with tacrolimus and 268 were performed on patients
      managed with cyclosporine. The patients managed with tacrolimus had an incidence
      of 0.85% (7/825) for significant rejection (greater than ISHLT grade 1B
      rejection) vs. an incidence of 4.1% (11/268) for the patients on cyclosporine (p
      < 0.0005). In the asymptomatic tacrolimus patients, only two screening biopsies
      (0.26%) manifest significant rejection, and both of these were performed within
      the first month after transplantation. Of the symptomatic tacrolimus patients,
      9.1% (n = 5) had findings on biopsy consistent with significant cellular
      rejection. There were 25 patients with grade 1B rejection. Twenty-two of these
      patients were not treated, and all cases of grade 1B rejection resolved without
      clinical sequelae. For pediatric patients more than 30 days after OHT, EMB has
      failed to reveal significant episodes of cellular rejection in asymptomatic
      patients managed with tacrolimus.

PMID- 15009838
TI  - Surveillance biopsies are superior to functional studies for the diagnosis of
      acute and chronic renal allograft pathology in children.
AB  - In this report of our 3-yr protocol biopsy program, we describe the evolution of
      acute rejection (AR) and chronic renal allograft nephropathy (CAN) in a cohort of
      21 children treated with antibody induction, tacrolimus, mycophenolate mofetil,
      and prednisone. The aims of this study were to compare the pathogenicity of
      clinical acute rejection (CAR) and subclinical acute rejection (SAR), and to
      determine whether functional studies accurately represent acute and chronic renal
      allograft pathology in pediatric recipients with disproportionately large grafts.
      Using concurrent biopsies, we evaluated: (i) the utility of changes in the
      baseline sCr (DeltasCr) to predict both the onset of AR and the response to
      immunosuppressive therapy; and (ii) the relationship of the calculated creatinine
      clearance and the presence of pathologic proteinuria to the severity of CAN. We
      performed 112 biopsies: 11 donor, 73 protocol, 16 acute graft dysfunction and 12
      1-month follow-up AR therapy. CAR and SAR were similar in incidence, timing and
      histologic severity. Progression of CAN was associated with the first episode of
      CAR (p < 0.02) and the cumulative number of episodes of CAR (p < 0.01), SAR (p <
      0.05), CAR plus SAR (p < 0.002) and borderline SAR (B-SAR) (p < 0.006). One-month
      post-treatment DeltasCrs could not distinguish 1-month follow-up biopsies with
      histologically confirmed worsened or unchanged AR from those with improved
      histology (35.2 +/- 74.8% vs. 23.8 +/- 24.9%, p = NS). These findings led to the
      addition of anti-lymphocyte antibody therapy in five of 10 (50%) cases. Despite
      100% 3-yr actuarial graft survival and excellent function (GFR = 111 +/- 36
      mL/min/1.73 m(2)), 18 of 21 (86%) patients had grade I CAN or greater chronic
      histology at a mean +/- sd follow-up period of 18.2 +/- 13.1 months. Thirteen of
      21 (62%) patients progressed to grade I CAN at 5.2 +/- 3.6 months and five (38%)
      of these patients progressed to grade II CAN at 17.8 +/- 11.3 months. Schwartz
      GFR did not differ between patients with or without CAN (108 +/- 38 mL/min/1.73
      m(2) vs. 127 +/- 8 mL/min/1.73 m(2), p = NS). In biopsies with CAN and no
      associated AR, neither the Banff chronic tubulointerstitial (Banff ci) score nor
      the Banff chronic grade correlated with the GFR. Proteinuria was not associated
      with CAN. Clinical AR and SAR are similar histologic lesions with a capacity for
      CAN progression. In pediatric renal transplant recipients, longitudinal protocol
      biopsies are superior to functional studies for the diagnosis and post
      therapeutic monitoring of AR and for the surveillance of CAN.

PMID- 15009839
TI  - A single center clinical experience in intensive care management of 104 pediatric
      renal transplantations between 1998 and 2002.
AB  - Only a few publications about the treatment in the intensive care unit (ICU)
      after pediatric renal transplantation have been published yet. As there are no
      guidelines, we hereby describe the results and recommendations of our transplant
      unit. A total of 104 renal transplantations have been performed in 96 children at
      our center since 1998. The age of the children has ranged from 6 months to 18 yr
      and their body weight from 6 kg to 110 kg. A special fluid management was
      performed in order to avoid hypotension and hypoperfusion of the graft. Systolic
      arterial pressure was kept at elevated levels above 100 mmHg during the first day
      after transplantation. The children remained on the respirator for 4-8 h after
      transplantation. Anticoagulation was performed using low dose heparin because of
      the size mismatch of the anastomosed vessels. The mean time in the ICU for the
      pediatric patients aged <3 yr was 2 days and for children older than 3 yr was 1
      day. The main complications after renal transplantation in the ICU were disorders
      of electrolytes, acute renal failure because of a non-functioning graft (12%),
      bleeding from the anastomoses (4%), arterial or venous thrombosis (1%), arterial
      hypertension and pulmonary edema, defined as radiographic evidence (1%). In case
      of non-function peritoneal- or hemodialysis were performed in the ICU. Young
      children were more frequently affected than older children. From 1998-2002 one
      patient died during the ICU time. The 3 yr graft survival rate was 90%. To sum
      up, children undergoing renal transplantation should be treated in a specialized
      unit postoperatively to avoid early non-functioning of the graft and extrarenal
      complications. General guidelines for postoperative care should be established.

PMID- 15009840
TI  - Neuroradiologic findings in children with renal transplantation under 5 years of
      age.
AB  - Chronic renal failure (CRF) is known to have adverse effects on the
      neurodevelopmental outcome of affected children. Some of these effects can be
      ameliorated by transplantation (TX). The cause and nature of the underlying brain
      injury is not known. We performed a brain magnetic resonance imaging (MRI) study
      on a group of children after TX to look for brain abnormalities and, if possible,
      to draw conclusions about their origin. Thirty-three children who received a
      renal allograft before 5 yr of age were studied. The most common diagnosis was
      the congenital nephrotic syndrome of Finnish type (29 patients). The male/female
      ratio was 22/11, the age range 6-11 yr. Pre-TX CT studies of 26 patients were
      available for comparison. The patient files were studied for relevant clinical
      history, including pre- and perinatal events, infections, hypertension,
      hypertensive crises, hypovolemic states and medical emergencies. These risk
      factors were correlated with the MRI findings. Eighteen patients (54%) had
      ischemic lesions in the vascular border zones. Mild lesions were seen in 10
      patients, moderate in six and severe in two patients. Other findings were rare,
      including infarcts in the main vascular territories and basal ganglia, and
      central and cortical atrophy. The pre-TX CT's revealed border zone infarcts in
      six patients. Hemodynamic crises were reported in 14 patients and correlated well
      with border zone infarcts. The age at TX was greater and the duration of dialysis
      longer in those with border zone infarcts than in those without. Low gestational
      age, perinatal complications, and septic infections were not statistically
      significant risk factors. Because of the lack on serial imaging studies we do not
      know the exact timing of these brain infarcts. The good correlation to pre-TX
      hemodynamic crises seems, however, to indicate that most of these lesions could
      be prevented by careful clinical monitoring and early TX.

PMID- 15009841
TI  - The use of art therapy to detect depression and post-traumatic stress disorder in
      pediatric and young adult renal transplant recipients.
AB  - Pediatric and young adult renal transplant recipients may experience feelings of
      depression and emotional trauma. A study was conducted to (1) determine the
      prevalence of depression and emotional trauma and (2) assess the utility of the
      Formal Elements of Art Therapy Scale (FEATS). Sixty-four renal transplant
      recipients, 6-21 yr of age, were evaluated using self-report measures (CDI and
      Davidson) and art-based assessments. Subject art was analyzed by art therapists
      using seven of the 14 elements of the (FEATS), to assess depression. Unlike CDI
      and Davidson self-report testing, all patients were able to complete the art
      based directives. When self-report measures and art-based assessments were
      combined, 36% of the study population had testing results consistent with
      depression and/or post-traumatic stress. The FEATS assessments identified a
      subset of patients who were not identified using the self-report measures. There
      was a correlation between CDI and Davidson scores (p < 0.0001), Davidson scores
      correlated with hospital days (p = 0.05), and FEATS correlated with height Z
      score (p = 0.04) and donor type (p = 0.01). Patients who required psychological
      interventions including antidepressant therapy, psychological counseling and
      psychiatric hospitalization during the year after the study were identified as
      depressed. Sensitivity for FEATS and CDI were 22 and 50% respectively. The
      results suggest that while art therapy may be of utility in the identification of
      pediatric and young adult transplant recipients who are suffering from
      depression, FEATS analysis appears to lack sufficient sensitivity to warrant its
      use in this population. Study of other quantitative art-based assessment
      techniques may be warranted.

PMID- 15009842
TI  - Trial of metronidazole vs. azithromycin for treatment of cyclosporine-induced
      gingival overgrowth.
AB  - Gingival overgrowth usually characterized by increased cellular growth of
      gingival fibroblasts appears to be multifactorial. In patients receiving CyA for
      more than 3 months, the incidence can approach 70% and can be attributed to
      pharmaceutical immunosuppression. Case reports have reported regression of
      overgrowth with both metronidazole and azithromycin. The goal of this study was
      to determine the efficacy of metronidazole and azithromycin in reducing CyA
      induced gingival overgrowth. Twenty-five patients were included in this double
      blinded randomized study. All patients were receiving CyA as medically indicated
      and diagnosed with gingival overgrowth by a dentist. Patients were randomized to
      receive either 5-days of azithromycin or 7-days of metronidazole given at
      baseline only. The extent of gingival overgrowth was measured at 0, 2, 4, 6, 12,
      and 24 wk. Fourteen patients at CCF and 11 patients at CCHMC were studied.
      Repeated measures anova was performed to assess differences within and between
      groups. Gingival overgrowth at baseline was not statistically different between
      groups. The mean degree of gingival overgrowth after treatment was different
      across all time intervals (p = 0.0049) showing azithromycin to be more effective
      than metronidazole. Therapy with azithromycin offers an effective alternative to
      the management of CyA-induced gingival overgrowth.

PMID- 15009843
TI  - Living related small bowel transplantation in children: 3-dimensional computed
      tomography donor evaluation.
AB  - The evaluation of the small bowel vascular anatomy of living small bowel donors
      (LSBD) is usually performed with conventional angiography (CA). Recently, angio
      computed tomography (CT) has become a valid study of the vascular anatomy for
      kidney and liver living donors. We studied the applicability of angio CT with 3-D
      reconstruction (3-D-ACT) in the evaluation of LSBD. Potential LSBDs for pediatric
      transplant underwent both CA and 3-D-ACT to evaluate the anatomy of the distal
      branches of the superior mesenteric artery and vein. Angio-CT was performed with
      General Electric Lightspeed Scanner. The 3-D reconstruction was performed on the
      TeraRecon workstation. Adverse reactions, contrast dosage, test duration,
      invasiveness, hospital-stay, patient discomforts and accuracy were evaluated.
      Four potential donors (four female; mean age: 30.5 yr; mean BMI: 28.4) underwent
      both tests. Adverse reactions correlated to contrast agent used (90 mL CA, 150 mL
      3-D-ACT) were not reported. CA required a hospitalization of 6 h as opposed to
      immediate discharge after the 3-D-ACT. The CA required the placement of
      transfemoral catheter and therefore greater patient discomfort than with 3-D-ACT.
      The 3-D-ACT arterial images were rated as equivalent to CA, however, 3-D-ACT
      venous images were rated better than the CA in all cases. CT-angiography with 3-D
      reconstruction is an acceptable method for vascular evaluation. When compared
      with routine angiography, it is less invasive, better tolerated and faster, but
      does require a significantly greater volume of venous contrast. 3-D-ACT also
      offers a better evaluation of the venous phase, and thus may become the test of
      choice to evaluate the vascular anatomies of LSBD candidates.

PMID- 15009844
TI  - Bronchiectasis in children after renal or liver transplantation: a report of five
      cases.
AB  - More effective immunosuppressive treatment in children following organ
      transplantation has significantly improved the survival of the grafts. Therefore,
      quality of life, long-term prognosis and adverse drug reactions have become more
      important. One of the main complications of immunosuppressive drugs is infections
      of the respiratory tract, but irreversible damage to the airways has not been
      described after renal or liver transplantation. Five children following
      transplantation of kidney or liver were referred to the Paediatric Pulmonology
      department because of chronic respiratory complaints. Pulmonary function tests
      and HRCT scan were performed as routine patient care. Four children with a renal
      transplant and one with a liver transplant showed chronic bronchitis and moderate
      to severe airways obstruction. HRCT showed bronchiectasis in all of them. We
      speculate that the immunosuppressive treatment (in)directly contributes to
      irreversible airway damage. We recommend including follow-up of lung function in
      the post-transplantation protocol and considering bronchiectasis in case of
      respiratory symptoms, to try preventing further damage to the lung.

PMID- 15009845
TI  - Pediatric transplantation of the kidney, liver and heart: summary report.
AB  - The following is a summary report of an extensive review of the literature from
      1966 to 2001 on growth and development in children receiving kidney, liver and
      heart transplants. The literature was assessed for relevancy to current clinical
      practice and for reliability and generalizability of the inferences based on the
      study design, controls, sample size, age distribution, confounding factors, use
      of standardized instruments, and consistency with other findings. While studies
      on growth are included in the review, the main emphasis is on research in
      cognitive and psychosocial development since these areas have been far less
      thoroughly studied and contain various methodological deficiencies. On the basis
      of the literature review both general methodological recommendations and specific
      recommendations for future research studies are made. Access to the full is
      provided on the World Wide Web at http://light.emmes.com/pedstransplantation/.

PMID- 15009846
TI  - Hodgkin's lymphoma after post-transplant lymphoproliferative disease in a renal
      transplant recipient.
AB  - Lymphoid malignancies such as post-transplant lymphoproliferative disease (PTLD)
      are a major complication of solid organ transplantation. Hodgkin's lymphoma (HL)
      is not part of the typical spectrum of PTLD, but has rarely been reported as a
      separate complication. We report a case of HL occurring after previous PTLD in a
      renal transplant recipient. A 9-yr-old girl with end-stage autosomal recessive
      polycystic kidney disease received a cadaveric renal transplant at 1 yr of age.
      She developed polymorphic PTLD localized to the bone marrow at 6 yr post
      transplant. She was treated with reduction of immunosuppression and alpha
      interferon. No chemotherapy or anti-B cell antibody was administered. The PTLD
      resolved and kidney graft function remained stable. At 9 yr post-transplant, she
      presented again with fever of 2 wk duration, associated with enlarged lymph nodes
      at multiple sites. A lymph node biopsy revealed the presence of classic Reed
      Sternberg cells positive for CD15, CD30 and EB RNA. She was treated with standard
      combination chemotherapy for HL with COPP/ABV. All immunosuppressive agents were
      discontinued except for low dose prednisone. The patient had an excellent
      response, with resolution of her lymphadenopathy and maintenance of stable graft
      function. RS like cells have been reported in the setting of PTLD, but these
      cells possess an activated B cell phenotype, are EBV negative and CD15 negative.
      True HL following PTLD has been reported in only three previous cases, with good
      response to standard chemotherapy in each.

PMID- 15009847
TI  - Complete necrosis of allograft ureter after cadaveric renal transplantation.
AB  - Complete necrosis of a transplant ureter is a rare complication that needs to be
      considered early in cases of severe graft dysfunction if successful surgical
      intervention and restoration of graft function is to be achieved. We report on
      two cases of this complication occurring in children and discuss the surgical
      management. Surgical exploration of grafts where there is an early sudden decline
      in function is imperative as routine imaging will not exclude this potentially
      treatable problem.

PMID- 15009850
TI  - Atrial fibrillation and the graying of America.

PMID- 15009851
TI  - Influence of age on atrial fibrillation inducibility.
AB  - The prevalence of AF is known to increase in the elderly. Some
      electrophysiological changes were reported in these patients, but the effects of
      age on AF inducibility and other electrophysiological signs associated with
      atrial vulnerability are unknown. The purpose of the study was to evaluate the
      effects of age on atrial vulnerability and AF induction. The study consisted of
      734 patients (age 16-85 years, mean 61 +/- 15 years) without spontaneous AF who
      were admitted for electrophysiological study. Study was indicated for dizziness
      or ventricular tachyarrhythmia. Programmed atrial stimulation was systematically
      performed. One and two extrastimuli were delivered in sinus rhythm and atrial
      driven rhythms (600, 400 ms). Univariate and multivariate analysis of several
      clinical and electrophysiological data were performed. AF inducibility, defined
      as the induction of an AF lasting > 1 minute, was paradoxically and significantly
      decreased in elderly (> 70 years) patients compared to younger patients (< 70
      years) (P < 0.01). AF inducibility was present in 40% of 62 patients < 40 years,
      39% of 99 patients age 40-50 years, 37% of 130 patients age 50-60 years, 38% of
      222 patients age 60-70 years, and only 28% of 221 patients > 70 years. There was
      no significant correlation with the sex, the presence of dizziness, the presence
      or not of an underlying heart disease, the left ventricular ejection fraction,
      and the presence of salvos of atrial premature beats on 24-hour Holter
      monitoring. There was a significant correlation with a longer atrial effective
      refractory period in the elderly (226 +/- 41 ms) than in younger patients (208 +/
      31 ms) (P < 0.001). Other electrophysiological parameters of atrial
      vulnerability did not change significantly. Increased atrial refractory period
      and age >70 years were independent factors of decreased AF inducibility.
      Programmed atrial stimulation should be interpreted cautiously before the age of
      70 years. AF induction is facilitated by the presence of a short atrial
      refractory period in these patients. Surprisingly, AF inducibility decreases in
      patients > 70 years because their atrial refractory period increases. Therefore,
      increased AF prevalence in these patients should be explained by
      nonelectrophysiological causes.

PMID- 15009852
TI  - Application of radiofrequency energy in surgical and interventional procedures:
      are there interactions with ICDs?
AB  - During surgical and interventional procedures, interference may occur between
      ICDs and electrical cautery or with the application of RF energy. This may lead
      to the false induction of ICD therapies or could even result in device
      malfunction, which represents a potential perioperative hazard for the patient.
      This study analyzed the intraoperative interactions in 45 consecutive ICD
      patients in reference to different surgical and interventional procedures. A
      total of 33 surgical operations (general surgery [n = 14], urologic [n = 5],
      abdominal [n = 10], gynecological [n = 2], thoracic [n = 1], neurosurgical [n =
      1]) and 12 interventional therapies (RF catheter ablation [n = 10], endoscopic
      papillotomy [n = 2]) were performed. The ICD devices were all located in left
      pectoral position and consisted of 25 single and 20 dual chamber defibrillators.
      During the procedure, tachyarrhythmia detection (VF 296 +/- 20 ms, VT 376 +/- 49
      ms) of the devices was maintained active (monitoring mode), only ICD therapies
      were inactivated. The indifferent electrode of the electrical cauter/RF generator
      was placed in standard positions (right/left mid-femoral position [n = 27/8],
      thoracic spine area [n = 10]). After the procedure, the ICD memory was checked
      for detections and for changes in the programming. There was no oversensing,
      reprogramming, or damage of any defibrillator caused by RF energy. Despite the
      lack of undesired interactions, ICDs should be inactivated preoperatively to
      assure maximum patient safety. However, should inactivation not be possible, or
      the achievement uncertain, electromagnetic interference is highly unlikely.

PMID- 15009853
TI  - Heart rate variability and diastolic heart failure.
AB  - Diastolic heart failure accounts for up to 40% of patients with congestive heart
      failure (CHF), and is associated with a better prognosis as compared to patients
      with systolic dysfunction. Nevertheless, patients with diastolic dysfunction have
      a significantly higher mortality as compared to the normal population. Reduced
      heart rate variability (HRV), a marker of autonomic dysfunction, is associated
      with increased mortality in patients with systolic heart failure. We therefore
      sought to determine to what extent HRV is altered in a population of patients
      with diastolic heart failure. Twenty-four hour ambulatory (Holter) recordings
      were performed in 19 consecutive patients with diastolic heart failure, in 9
      patients with systolic heart failure, as well as in 9 healthy volunteers (normal
      controls). Time and frequency domain HRV variables were obtained for all three
      groups of patients. Both Time and Frequency domain variables were found to be
      reduced in both heart failure groups compared to normal controls. When compared
      with each other, patients with diastolic function had relatively higher values of
      HRV variables, compared to those with systolic dysfunction (SDNN, Total power,
      ULF power, all P <or= 0.05). Patients with diastolic dysfunction have reduced
      HRV, suggesting a disturbed sympathetic-parasympathetic balance. Nevertheless,
      values for HRV are not as profoundly reduced as in patients with systolic
      dysfunction. The relative preservation of sympathetic-parasympathetic balance may
      explain the better prognosis in this patient population.

PMID- 15009854
TI  - Evaluation of safety and efficacy of pacemaker and defibrillator implantation by
      axillary incision in pediatric patients.
AB  - We successfully implanted 11 pacemakers, 6 defibrillators, and 1 biventricular
      pacemaker in 18 pediatric patients (15 female; 4 to 15 years, average age: 9)
      using the retropectoral transvenous approach with a hidden axillary incision. The
      average follow-up period was 24 months (range 49 months). Eight patients had
      congenital structural heart conditions (d-transposition of great arteries S/P
      Mustard operation, d-transposition of great arteries S/P arterial switch
      operation, truncus arteriosus, right ventricular diverticula, ventricular septal
      defect, hypertrophic cardiomyopathy). Four patients had acquired heart conditions
      (dilated cardiomyopathy, myocarditis). Excellent sensing and pacing thresholds
      were achieved in all attempted implantations. There was no pneumothorax. There
      was one lead dislodgement. One lead fracture distant from the subclavian vein
      occurred 4 months after implantation. Implantation of pacemakers and
      defibrillators via axillary incisions can be safe and effective in pediatric
      patients. This approach avoids skin erosion when implanting large devices such as
      defibrillators or biventricular devices in small patients with limited muscle
      mass while achieving superior aesthetic results. The axillary or extrathoracic
      venous entry site avoids subclavian crush syndrome.

PMID- 15009855
TI  - QRS duration and shortening to predict clinical response to cardiac
      resynchronization therapy in patients with end-stage heart failure.
AB  - Despite current selection criteria (NYHA Class III-IV, LVEF < 35%, QRS > 120 ms
      with LBBB), 30% of patients do not benefit from cardiac resynchronization therapy
      (CRT). The use of QRS duration as selection criteria for CRT has not been
      evaluated systematically yet. Accordingly, the value of QRS duration at baseline
      (and reduction in QRS duration after CRT) to predict responders was studied.
      Patients were evaluated at baseline and after 6 months of CRT for NYHA Class,
      quality of life score, and 6-minute walk test. QRS duration was evaluated before,
      directly after implantation, and after 6 months of CRT. Sixty-one patients were
      included; 45 (74%) patients were classified as responders (improvement of NYHA
      Class, 6-minute walking distance and quality of life score) and 16 (26%) as
      nonresponders. QRS duration at baseline was similar between the two groups: 179
      +/- 30 ms versus 171 +/- 32 ms, NS. Directly after implantation, QRS duration was
      reduced from 179 +/- 30 ms to 150 +/- 26 ms (P < 0.01) in responders;
      nonresponders did not exhibit this reduction (171 +/- 32 ms vs 160 +/- 26 ms,
      NS). After 6 months of CRT, QRS shortening was only observed in responders (from
      179 +/- 30 ms to 159 +/- 25 ms, P < 0.01). ROC curve analysis showed that a
      reduction in QRS duration > 10 ms had a high sensitivity (73%) with low
      specificity (44%); conversely, a > 50 ms reduction in QRS duration was highly
      specific (88%) but not sensitive (18%) to predict response to CRT. No optimal
      cutoff value could be defined. QRS duration at baseline is not predictive for
      response to CRT; responders exhibit a significant reduction in QRS duration after
      CRT, but individual response varies highly, not allowing adequate selection of
      responders.

PMID- 15009856
TI  - Permanent left atrial pacing: a 2-year follow-up of coronary sinus leads.
AB  - Left atrial pacing is feasible via the coronary sinus. However, long-term
      characteristics of coronary sinus pacing parameters are largely undefined as yet.
      This study assessed the feasibility and long-term pacing parameters of coronary
      sinus pacing. Twenty four patients (13 men, 11 women) with a history of
      paroxysmal AF refractory to drug therapy underwent biatrial pacemaker
      implantation. Leads were sited in the high right atrium or right atrial appendage
      and in either proximal (PCS) or distal coronary sinus (DCS). Pacemaker parameters
      were measured at implant, 24 hours postimplant, 1 month, 3 months, and at 3
      monthly intervals over a period of 2 years. Threshold, impedance, and energy
      requirements (E = Threshold2/impedance x pulse width) were measured. There was
      one lead displacement from the PCS within 24 hours postimplant. There were no
      other acute or chronic complications. The energy values at implant and at 2 years
      were 0.49 +/- 0.47 and 2.18 +/- 1.69 mJ for the PCS leads and 0.94 +/- 1.47 and
      1.27 +/- 0.75 mJ for the DCS leads. P values were >0.05 at all points and
      suggested no significant difference between the two sites over the long-term.
      Chronic coronary sinus pacing is a safe and feasible technique. There was no
      significant difference in energy parameters for leads positioned in the proximal
      or distal coronary sites. The trends seen at both sites for chronic changes in
      pacing characteristics are analogous to those described for endocardial leads at
      other sites.

PMID- 15009857
TI  - Electroanatomic mapping of the right atrium with a right atrial basket catheter
      and three-dimensional intracardiac echocardiography.
AB  - The ablation of arrhythmias progresses towards an approach based upon application
      of linear lesions between nonconducting anatomic/electrical areas. Hence the
      identification of detailed anatomy together with electrical behavior becomes
      increasingly important. This study aims to achieve true electroanatomic mapping
      by the use of three-dimensional intracardiac imaging of the right atrium combined
      with use of a right atrial basket to obtain detailed electrical information. We
      studied nine patients, seven requiring atrial flutter ablation. A 9 Fr, 9 MHZ
      intracardiac echo catheter was pulled back from SVC to IVC using respiratory and
      ECG gating. The images, recorded on a Clearview ultrasound machine, were
      reconstructed using commercially available software. The intracardiac basket was
      placed into the atrium using the markers and fluoroscopy to allow orientation.
      Isochronal maps were obtained from the basket in sinus rhythm, pacing from
      different sites within the atrium and in atrial flutter. Isochronal maps were
      constructed and superimposed on the ICE image. The maps with pacing were
      consistent with that which was expected, confirming the validity of this
      approach. We were able to visualize changes in activation sequence following the
      placement of bidirectional isthmus block. True electroanatomic mapping is
      possible by the use of three-dimensional ICE reconstruction of the right atrium
      with electrical activation obtained from an intracardiac basket. This has
      significance for anatomically based arrhythmia ablations such as the ablation of
      atrial flutter, atrial fibrillation, with transcatheter MAZE procedures and
      pulmonary vein isolation. Further developments in software will allow such maps
      to be produced simultaneously with greater rapidity.

PMID- 15009858
TI  - Dofetilide effects on the inhibition by trains of subthreshold conditioning
      stimuli.
AB  - We investigated the electrophysiological actions of dofetilide upon the
      ventricular myocardium to determine whether the drug modifies the inhibitory
      effects of subthreshold stimuli trains upon ventricular refractoriness. In nine
      Langendorff perfused rabbit hearts, ventricular epicardial electrodes were used
      to determine the following parameters at baseline and during dofetilide perfusion
      (0.5 micromolar): effective (ERP) and functional (FRP) refractory periods,
      conduction velocity (CV), wavelength (WL), and ERP prolongation (inhibitory
      effect) induced by subthreshold stimuli trains (STr) at pulse frequencies of 100,
      300, and 600 Hz. Dofetilide significantly prolongs ventricular refractoriness and
      WL: ERP increment (Dofetilide-baseline, 300 ms cycle length) = 33 +/- 20 ms (24
      +/- 12%, P < 0.01); FRP increment = 37 +/- 19 ms (23%+/- 10%, P < 0.01); WL
      increment = 4.1 +/- 3.2 cm (27%+/- 20%, P < 0.01), without modifying CV. These
      effects are diminished upon increasing the stimulation frequency: ERP increment
      (Dofetilide-baseline, 150 ms cycle length) = 18 +/- 10 ms (18%+/- 12%, P < 0.05);
      FRP increment = 15 +/- 4 ms (14%+/- 5%, P < 0.01); WL increment = 1.9 +/- 1.7 cm
      (18%+/- 10%, P < 0.01). The STr significantly prolong ERP, and the increments
      obtained at baseline and during dofetilide perfusion are similar. In both cases
      the inhibitory effect is slight for STr of 100 Hz (baseline = 5 +/- 3 ms,
      dofetilide = 6 +/- 5 ms, with nonsignificant (ns) differences between them) and
      highly manifest for STr of 300 Hz (baseline = 76 +/- 33 ms, dofetilide = 87 +/-
      32 ms, ns) and 600 Hz (baseline = 109 +/- 39 ms, dofetilide = 89 +/- 34 ms, ns).
      Dofetilide prolongs ventricular refractoriness and WL, exerting a reverse
      frequency dependent effect without modifying CV. The inhibitory effect of STr is
      greater when their pulse frequency is increased, and its magnitude is similar
      under the influence of dofetilide. During dofetilide perfusion the inhibitory
      effect of STr adds to the ERP prolongation induced by the drug.

PMID- 15009859
TI  - A perspective on atrioventricular delay optimization in patients with a dual
      chamber pacemaker.
AB  - Atrioventricular delay (AVD) is critical in patients with DDD pacemakers (PM).
      Echo/Doppler evaluation of AVD providing the longest left ventricular filling
      time (FT) or the highest cardiac output (CO) is used for AVD optimization.
      Recently myocardial performance index (MPI) has been shown to improve by
      optimizing AVD. The aim was to compare the CO, FT, MPI derived optimal AVD, and
      to analyze systolic and diastolic performance at every optimal AVD. Twenty-five
      patients, 16 men 68 +/- 11 years, ejection fraction >or= 50%, with a DDD PM for
      third-degree AV block, without other major cardiomyopathies, underwent
      echo/Doppler AVD optimization. CO, FT, and MPI derived optimal AVDs were
      identified as the AVDs providing the highest CO, the longest FT, and the minimum
      MPI, respectively. Isovolumic contraction and relaxation time (ICT, IRT),
      ejection time (ET), ICT/ET, and IRT/ET ratios were also evaluated at every
      optimal AVD. CO, FT, and MPI derived optimal AVDs were significantly different
      (148 +/- 36 ms, 116 +/- 34 ms, and 127 +/- 33 ms, respectively). ICT/ET was
      similar at CO, FT, and MPI derived optimal AVD (0.22 +/- 0.10, 0.23 +/- 0.11, and
      0.21 +/- 0.10, respectively). IRT/ET ratio was similar at FT and MPI derived
      optimal AVDs (0.34 +/- 0.15 and 0.33 +/- 0.15, respectively) and significantly
      shorter (P < 0.02) than at CO derived optimal AVD (0.40 +/- 0.15). Different
      methods indicate different optimal AVDs. However analysis of systolic and
      diastolic performance shows that different AVDs result in similar systolic or
      diastolic performance. At MPI optimized AVD, a high CO combined with the most
      advantageous conditions of both isovolumic contraction and relaxation phases is
      achieved.

PMID- 15009860
TI  - Sequential biventricular pacing: evaluation of safety and efficacy.
AB  - The study evaluated the clinical safety, performance, and efficacy of sequential
      biventricular pacing in the InSync III (Model 8042) biventricular stimulator in a
      multicenter, prospective 3-month study and assessed the proper functioning of
      features aiming at improving biventricular AV therapy delivery. The system was
      successfully implanted in 189 (95.9%) of 198 patients with symptomatic systolic
      heart failure and a prolonged QRS complex duration. Patients significantly
      improved their 6-minute hall walk distance (baseline 339 +/- 92 vs 3-month 422 +/
      127 meter, P < 0.001) and NYHA class (baseline 3.1 +/- 0.5 vs 3-month 1.9 +/-
      0.7, P < 0.001). Echocardiographic optimization of sequential biventricular
      pacing showed an improvement in stroke volume compared to simultaneous
      stimulation (sequential 68 +/- 24 mL vs simultaneous 56 +/- 23 mL, P < 0.001) at
      baseline and at 3 months. In 88% (30/34) of the patients these improvements were
      seen within a small range of V-V delays of +/-20 ms and in 94% (32/34) within V-V
      delays of +/-40 ms. In contrast, programming beyond this range reduced stroke
      volume below that during simultaneous biventricular pacing. The device functioned
      as expected. LV lead dislodgement was observed in 12 patients and phrenic nerve
      stimulation required lead repositioning in 2 patients. Eight patients died during
      the study. Patient survival at 3 and 6 months was 97 +/- 2% and 94 +/- 2%,
      respectively. Cause of death was cardiac (n = 7), heart failure related (n = 3),
      arrhythmia related (n = 2), and unknown (n = 2). In conclusion, this sequential
      biventricular pacemaker was safe and efficacious.

PMID- 15009861
TI  - Addition of a defibrillation electrode in the low right atrium to a right
      ventricular lead does not reduce ventricular defibrillation thresholds.
AB  - Transvenous unipolar active can defibrillation systems have proven to be
      effective in treating ventricular tachyarrhythmias. However, a further reduction
      of ventricular defibrillation thresholds (V-DFT) would increase the longevity,
      reduce the size of pulse generators, and help to avoid additional leads in
      patients with inacceptable high V-DFTs. In a finite difference computer model,
      the extension of the right ventricular (RV) defibrillation coil into the low
      right atrium led to a 40% reduction of unipolar V-DFT. To evaluate this finding,
      we conducted a prospective, randomized study in 11 patients receiving an ICD.
      Extension of the RV electrode was simulated by adding a second coil placed in the
      low right atrium with the same polarity. Using a binary search protocol, V-DFT
      was determined with and without the additional electrode in each patient. Total
      shock impedance was significantly lower in the two coil (low RA) configuration,
      compared to the single coil (RV) configuration. Corresponding values were 49.9 +/
      6.7 Ohm and 61.1 +/- 9.3 Ohm, respectively (P < 0.01, paired t-test). However,
      there was no reduction, but even a nonsignificant increase in V-DFTs. Mean V-DFT
      in the RV configuration was 12.0 +/- 5.6 J and 16.3 +/- 7.8 J in the low RA
      configuration (P = 0.09, paired t-test). Despite a reduction in total impedance,
      the addition of a defibrillation coil in the low right atrium does not reduce
      ventricular defibrillation thresholds.

PMID- 15009862
TI  - Development of atrial fibrillation in patients with atrioventricular block after
      atrioventricular synchronized pacing.
AB  - Many studies have evidenced an increased incidence of AF in patients receiving
      single chamber ventricular pacing (VVI) when compared with those undergoing an
      atrial-based system (AAI or DDD). However, the difference in incidence of AF
      between two atrial-based systems (VDD, DDD) in patients with AV block was still
      controversial. This study was conducted to compare the development of AF between
      different modes of pacemakers (VDD and DDD) in patients with symptomatic AV
      block. A retrospective review was conducted of the detailed records of all
      consecutive patients who received permanent pacemakers due to symptomatic
      bradycardia from March 1995 to March 2000. The occurrence of AF was documented
      when there was presence of AF in the free-run or 12-lead ECG, any ECG strips, or
      persistent AF on 24-hour Holter ECG during the follow-up. The study included 152
      patients (44 women, 108 men; mean age 73). The patients were divided into two
      groups: VDD (n = 100) and DDD (n = 52). The mean follow-up was 48.9 +/- 22.9
      months. The incidence of AF was 7.9%. A higher incidence of AF was noted in the
      DDD group (15.4%) when compared with the VDD group (4.0%, P = 0.023). The
      incidence of development of AF in patients with AV block was higher in those
      receiving DDD cardiac pacing when compared with those who received the VDD
      system. The authors suggest that VDD pacing may be a better choice than the DDD
      system for patients with AV block, but without clinical evidence of sinus node
      dysfunction, and if an atrial lead is required, it should be placed close to the
      Bachmann's bundle.

PMID- 15009863
TI  - Pacemaker and implantable cardioverter defibrillator implantation without
      reversal of warfarin therapy.
AB  - The study evaluated all patients undergoing permanent pacemaker and ICD
      implantation over a 4-year period to determine if anticoagulated patients
      required normalization of coagulation factors in the periprocedural period. The
      study included 1,025 (597 men, 428 women, age 24-100 years, mean 72 years)
      consecutive patients who underwent device implantation using mostly a
      percutaneous subclavian approach. The procedures were performed without reversal
      of anticoagulation in 470 patients with INRs >or= 1.5 at the time of the
      procedure (mean INR 2.6 +/- 1.0, range 1.5-7.5). The complication rate in the
      anticoagulated group was similar to those in patients with a normal INR. Routine
      normalization of coagulation factors prior to pacemaker/ICD placement may not be
      necessary.

PMID- 15009864
TI  - The subpectoral pacemaker implant: it isn't what it seems!
AB  - The traditional pulse generator implantation site lies subcutaneous on the fascia
      of the pectoralis major muscle. This article describes a subpectoral pocket
      approach, which on anatomic investigation is actually "intrapectoral" and offers
      a much improved cosmetic result with the potential advantage of less erosion. In
      the authors' experience with over 1000 initial pacemaker implants and pulse
      generator replacements, the potential concerns of neurovascular and muscular
      damage have not been realized. There has been no pulse generator damage from the
      ribs, serious loculated hematomas, or unusual postoperative or chronic pain. From
      experience with pulse generator recalls, the replacement procedure has not been
      significantly more difficult than with the subcutaneous approach. The
      intrapectoral approach has now become the authors' routine in patients without
      significant adipose tissue overlying the pectoralis major muscle.

PMID- 15009865
TI  - Incidence of postdischarge symptomatic paroxysmal atrial fibrillation in patients
      who underwent coronary artery bypass graft: long-term follow-up.
AB  - The aim of this retrospective study was to determine the incidence of symptomatic
      AF of patients who had undergone coronary artery bypass grafting (CABG) during
      long-term follow-up. The study population included 305 post-CABG patients who
      were regularly followed in the outpatient clinic. Paroxysmal AF (PAF) was defined
      as an episode of symptomatic AF when symptoms were prolonged enough for the
      patient to request medical care. Perioperative AF occurred in 88 (28.9%)
      patients. Postdischarge symptomatic PAF occurred in 25 (8.2%) patients with an
      annual incidence of 2% during a mean follow-up of 48 +/- 30 months. Eighteen
      (20.4%) patients also experienced perioperative AF with an annual incidence of
      5.1%, while only 7 (3.2%) of 217 patients, without perioperative AF, had
      postdischarge AF (P < 0.0003). During long-term follow-up, postdischarge AF has a
      low incidence and prophylactic antiarrhythmic therapy is not recommended. The
      method of follow-up and retrospective analysis may understate PAF and even miss
      some symptomatic episodes. Perioperative AF is a predictor of symptomatic late
      PAF recurrences, particularly in patients with reduced left ventricular function.

PMID- 15009866
TI  - Effects of pretreatment with intravenous flecainide on efficacy of external
      cardioversion of persistent atrial fibrillation.
AB  - Electrical cardioversion is the most effective and safe method to restore sinus
      rhythm in patients with persistent AF. However, at least 25% of electrical
      cardioversions are unsuccessful. The aim of the present study was to evaluate, in
      a prospective, randomized and double-blind study, the efficacy of a pretreatment
      with intravenous flecainide in patients who underwent electrical cardioversion.
      Fifty-four consecutive patients with persistent AF, mean arrhythmia duration 8
      (mean 3-18) weeks, were randomized in two groups. In the first group (n = 26),
      patients received flecainide (2 mg/kg as a 30-minute IV infusion) before
      electrical cardioversion. In the second group (n = 28), 100 mL IV infusion of 5%
      glucose was administered 30 minutes before electrical cardioversion. The study
      evaluated the (1). acute efficacy of electrical cardioversion, (2). mean and
      maximal energy required, (3). mean number of shocks needed, and (4). incidence of
      complications. The two groups were similar in terms of age, sex, mean AF
      duration, left ventricular systolic function, atrial dimension, and
      cardiovascular risk factors. Seventy-seven percent of patients recovered sinus
      rhythm with electrical cardioversion. No statistical difference was noted between
      the two groups: flecainide 19/26 (73%) versus placebo 23/28 (82%). No significant
      differences were found concerning mean or maximal energy and number of shocks
      required. No major complications were observed. After a 30-day follow-up, 54% of
      patients maintained sinus rhythm with no difference between the two groups.
      Pretreatment with intravenous flecainide before electrical cardioversion is not
      useful in reducing technical failure of cardioversion, however, flecainide does
      not diminish the effectiveness of electrical cardioversion.

PMID- 15009867
TI  - Feasibility of implantable cardioverter defibrillator use in elderly patients: a
      case series of octogenarians.
AB  - This article addresses the feasibility and safety of ICD therapy in patients >80
      years of age. Recent trials have expanded the indication for ICD implantation to
      include an increasing number and variety of patients. The feasibility of ICD
      implantation in elderly patients has not been adequately studied. A prospectively
      collected single center ICD database was analyzed to assess the safety and
      feasibility of ICD implantation in elderly patients. Patients were divided based
      on age into two groups (group 1: 70-79 years of age, n = 183; group 2: >or=80
      years of age, n = 29). The two groups were similar in gender distribution, NYHA
      class, and indication for implantation. The actuarial survival was not
      significantly different between groups 1 and 2 (P > 0.05; primary endpoint), with
      a 1-year survival of 91% and 93% in groups 1 and 2, respectively, (P = NS). The
      complication rates at the time of ICD implantation were similar in groups 1 and 2
      (6.6% and 13.1%, respectively, P = 0.16). Age alone may not be sufficient
      criteria to exclude ICD implantation. The current consensus guidelines for ICD
      implantation appear to be generalizable to treating octogenarians who are
      otherwise medically fit.

PMID- 15009868
TI  - Atrial flutter: historical notes--part 1.

PMID- 15009869
TI  - Ventricular rate control during atrial fibrillation and AV node modifications:
      past, present, and future.
AB  - Atrial fibrillation (AF) is the most common arrhythmia. Currently there are two
      broad strategic treatment options for AF: rhythm control and rate control. For
      rhythm control, the treatment is directed toward restoring and maintaining the
      sinus rhythm. For rate control, the intention is to slow ventricular rate while
      allowing AF to continue. In both cases anticoagulation therapy is recommended.
      The results of currently available clinical trials demonstrated clearly that rate
      control is not inferior to rhythm control. Thus, rate control is an acceptable
      primary therapy for many AF patients. The rate control can be achieved
      essentially by depressing or modifying the filtering properties of the
      atrioventricular (AV) node. This can be attained by medications that depress the
      impulse transmission within the AV node, by anatomic modification of the AV
      communications, as well as by autonomic manipulations that produce AV node
      negative dromotropic effect. We are reviewing current clinical and newer
      experimental modalities aimed at enhancing the lifesaving function of this
      remarkable nodal structure.

PMID- 15009870
TI  - A tachycardia with changing bundle branch block patterns: what is the mechanism.

PMID- 15009872
TI  - An alternate site for pacemaker placement when standard locations are not
      available.
AB  - In patients with no standard sites available for venous access and pulse
      generator location, the authors found that tunneling the leads from the jugular
      vein under the clavicle and placing this pulse generator beneath the latissimus
      dorsi muscle was a satisfactory alternative.

PMID- 15009873
TI  - Radiofrequency catheter ablation of an accessory pathway in a patient with Wolff
      Parkinson-White and Kartagener's syndrome.
AB  - We report a case of a manifest left free wall accessory pathway in a patient with
      Kartagener's syndrome and recurrent episodes of orthodromic atrioventricular
      reentrant tachycardia. To the best of our knowledge, it is the first report of
      Wolff-Parkinson-White syndrome associated with Kartagener's syndrome. Situs
      inversus and mirror image dextrocardia occurred with no additional detectable
      cardiac structural abnormalities. Diagnostic and therapeutic electrophysiological
      study was carried out via transaortic approach and a left-to-right reversal of
      monoplane fluoroscopic image.

PMID- 15009874
TI  - Malfunction of the automatic slope adjustment of the QT sensor in patients with
      normal QT intervals.
AB  - DDDR pacemakers with QT driven sensor algorithms may be susceptible to
      inappropriate pacemaker tachycardia when implanted into patients who have a
      relatively extended cardiac repolarization. The inability to detect and measure
      the QT interval at near maximum sensor rate, results in an inappropriate
      adjustment of the automatic QT slope. Triggering pacemaker induced tachycardia.

PMID- 15009875
TI  - Arrhythmogenic right ventricular cardiomyopathy with left ventricular involvement
      and aortic dissection.
AB  - Ten years ago, a 59-year-old patient presented with ventricular fibrillations.
      The resting ECG showed findings typical for ARVC. Echocardiography and
      ventriculography confirmed the diagnosis of ARVC showing a dilated right
      ventricle with aneurysms. MRI showed additional fatty replacement of the LV.
      Furthermore, the diagnosis of a chronic aortic dissection was established. Two
      years after ICD implantation, the patient died of progressive right heart
      failure. On autopsy, most of the RV and parts of the LV were replaced by fatty
      tissue, and the media of the aorta showed degenerative changes. A pathogenetic
      link between the two diseases remains speculative at this time.

PMID- 15009876
TI  - Percutaneous extraction of a severed and frayed permanent pacing lead.
AB  - From the point of view of established practice, redundant permanent pacing leads
      have been abandoned or extracted using various catheter-based procedures. An
      unusual complication was caused by failed surgical lead extraction resulting in
      electrode severing and wire unbraiding with subsequent induction of electric
      interaction between the metallic, noninsulated part of the lead fragment and the
      defibrillating electrode. This interaction was sensed and detected by the ICD
      system. A modified catheter-based extraction procedure is described.

PMID- 15009877
TI  - Inappropriate ICD therapy due to proarrhythmic ICD shocks and hyperpolarization.
AB  - A 50-year-old man with an ischemic cardiomyopathy underwent ICD implantation for
      inducible ventricular fibrillation (VF). Sixteen months later he experienced
      inappropriate ICD therapy due to atrial fibrillation with a rapid ventricular
      response. The initial shock resulted in the initiation of VF (proarrhythmia) and
      the patient received an additional shock converting his rhythm to an
      idioventricular rhythm with a cycle length of 490 ms (122 beats/min). Due to lead
      hyperpolarization, the device oversensed ventricular events and the patient
      subsequently received additional shocks.

PMID- 15009878
TI  - Aortic perforation by active-fixation atrial pacing lead.
AB  - This report describes perforation of the aorta related to the implantation of an
      active-fixation atrial pacing lead, a previously undocumented complication of
      pacemaker implantation. The complication was related to excessive tissue
      penetration by the screw at the tip of the lead or perforation of the lead body
      by the positioning stylet during manipulation whereupon the stylet traversed the
      atrial wall and aortic wall. Perforation of the aorta should be part of the
      differential diagnosis of cardiac tamponade after pacemaker implantation.

PMID- 15009880
TI  - The evolution of the implantable cardioverter defibrillator.

PMID- 15009882
TI  - The bacterial Sm-like protein Hfq: a key player in RNA transactions.
AB  - The conserved RNA-binding protein Hfq, originally discovered in Escherichia coli
      as a host factor for Qbeta replicase, has emerged as a pleiotropic regulator that
      modulates the stability or the translation of an increasing number of mRNAs.
      During the past 5 years, Hfq-mediated control has been an area of increasing
      focus because the protein has been linked to the action of many versatile RNA
      based regulators that use basepairing interactions to regulate the expression of
      target mRNAs. The recent findings that Hfq assists in bimolecular RNA-RNA
      interactions and is similar structurally and functionally to eukaryotic Sm
      proteins have further fueled interest in this important post-transcriptional
      regulator. Here, we summarize the history of Hfq and highlight results that have
      led to an important gain in insight into the physiology, biochemistry and
      evolution of Hfq and its homologues.

PMID- 15009883
TI  - Genome plasticity in Streptomyces: identification of 1 Mb TIRs in the S.
      coelicolor A3(2) chromosome.
AB  - The chromosomes of several widely used laboratory derivatives of Streptomyces
      coelicolor A3(2) were found to have 1.06 Mb inverted repeat sequences at their
      termini (i.e. long-terminal inverted repeats; L-TIRs), which are 50 times the
      length of the 22 kb TIRs of the sequenced S. coelicolor strain M145. The L-TIRs
      include 1005 annotated genes and increase the overall chromosome size to 9.7 Mb.
      The 1.06 Mb L-TIRs are the longest reported thus far for an actinomycete, and are
      proposed to represent the chromosomal state of the original soil isolate of S.
      coelicolor A3(2). S. coelicolor A3(2), M600 and J1501 possess L-TIRs, whereas
      approximately half the examined early mutants of A3(2) generated by ultraviolet
      (UV) or X-ray mutagenesis have truncated their TIRs to the 22 kb length. UV
      radiation was found to stimulate L-TIR truncation. Two copies of a transposase
      gene (SCO0020) flank 1.04 Mb of DNA in the right L-TIR, and recombination between
      them appears to generate strains containing short TIRs. This TIR reduction
      mechanism may represent a general strategy by which transposable elements can
      modulate the structure of chromosome ends. The presence of L-TIRs in certain S.
      coelicolor strains represents a major chromosomal alteration in strains
      previously thought to be genetically similar.

PMID- 15009884
TI  - The principal sigma factor sigA mediates enhanced growth of Mycobacterium
      tuberculosis in vivo.
AB  - The ability of Mycobacterium tuberculosis to grow in macrophages is central to
      its pathogenicity. We found previously that the widespread 210 strain of M.
      tuberculosis grew more rapidly than other strains in human macrophages. Because
      principal sigma factors influence virulence in some bacteria, we analysed mRNA
      expression of the principal sigma factor, sigA, in M. tuberculosis isolates
      during growth in human macrophages. Isolates of the 210 strain had higher sigA
      mRNA levels and higher intracellular growth rates, compared with other clinical
      strains and the laboratory strain H37Rv. SigA was also upregulated in the 210
      isolate TB294 during growth in macrophages, compared with growth in broth. In
      contrast, H37Rv sigA mRNA levels did not change under these conditions.
      Overexpression of sigA enhanced growth of recombinant M. tuberculosis in
      macrophages and in lungs of mice after aerosol infection, whereas recombinant
      strains expressing antisense transcripts to sigA showed decreased growth in both
      models. In the presence of superoxide, sense sigA transformants showed greater
      resistance than vector controls, and the antisense sigA transformant did not
      grow. We conclude that M. tuberculosis sigA modulates the expression of genes
      that contribute to virulence, enhancing growth in human macrophages and during
      the early phases of pulmonary infection in vivo. This effect may be mediated in
      part by increased resistance to reactive oxygen intermediates.

PMID- 15009885
TI  - Localization and activity of multidrug resistance protein 1 in the secretory
      pathway of Leishmania parasites.
AB  - Upregulation of the multidrug resistance protein 1 (LeMDR1) in the protozoan
      parasite, Leishmania enriettii, confers resistance to hydrophobic drugs such as
      vinblastine, but increases the sensitivity of these parasites to the
      mitochondrial drug, rhodamine 123. In order to investigate the mechanism of
      action of LeMDR1, the subcellular localization of green fluorescent protein (GFP)
      tagged versions of LeMDR1 and the fate of the traceable-fluorescent LeMDR1
      substrate calcein AM were examined in both Leishmania mexicana and L. enriettii
      LeMDR1 -/- and overexpressing cell lines. The LeMDR1-GFP chimera was localized by
      fluorescence microscopy to a number of secretory and endocytic compartments,
      including the Golgi apparatus, endoplasmic reticulum (ER) and a multivesicular
      tubule (MVT)-lysosome. Pulse-chase labelling experiments with calcein AM
      suggested that the Golgi and ER pools, but not the MVT-lysosome pool, of LeMDR1
      were active in pumping calcein AM out of the cell. Cells labelled with calcein AM
      under conditions that slow vesicular transport (low temperature and stationary
      growth) inhibited export and resulted in the accumulation of fluorescent calcein
      in both the Golgi and the mitochondria. We propose that LeMDR1 substrates are
      pumped into secretory compartments and exported from the parasite by exocytosis.
      Accumulation of MDR substrates in the ER can result in alternative transport to
      the mitochondrion, explaining the reciprocal sensitivity of drug-resistant
      Leishmania to vinblastine and rhodamine 123.

PMID- 15009886
TI  - Loss of the mono-allelic control of the VSG expression sites during the
      development of Trypanosoma brucei in the bloodstream.
AB  - Transcription of the variant surface glycoprotein (VSG) gene of Trypanosoma
      brucei occurs in a single of multiple polycistronic expression sites (ESs).
      Analysis of RNA from proliferative long slender (LS) bloodstream forms
      demonstrated that initiation of transcription occurs in different ESs, but
      inefficient RNA processing and elongation is linked to RNA polymerase arrest in
      all except one unit at a time. The pattern of ES transcripts was analysed during
      the transformation of dividing LS forms into quiescent short stumpy (SS) forms.
      The results demonstrated that the mono-allelic control allowing preferential RNA
      production from a given ES stops during this process. Accordingly, the steady
      state ES transcripts, particularly the VSG mRNA, were strongly reduced. However,
      transcripts from the beginning of different ESs were still synthesized, and in
      vitro run-on transcription analysis indicated that RNA polymerase was still fully
      associated with the promoter-proximal half of the 'active' ES. Analysis of
      transcripts from two central tandem genes confirmed the existence of a residual
      decreasing transcriptional gradient in the 'active' ES of SS forms. Thus, in
      these forms the RNA polymerase of the ES is inactivated in situ. This
      inactivation is accompanied by a strong overall reduction of nuclear DNA
      transcription. Although cAMP is involved in the LS to SS transformation, no
      direct effect of cAMP was observed on the VSG ES control.

PMID- 15009887
TI  - Re-replication from non-sequesterable origins generates three-nucleoid cells
      which divide asymmetrically.
AB  - In rapidly growing Escherichia coli cells replication cycles overlap and
      initiation occurs at multiple replication origins (oriCs). All origins within a
      cell are initiated essentially in synchrony and only once per cell cycle.
      Immediate re-initiation of new origins is avoided by sequestration, a mechanism
      dependent on the SeqA protein and Dam methylation of GATC sites in oriC. Here,
      GATC sites in oriC were changed to GTTC. This reduced the sequestration to
      essentially the level found in SeqA-less cells. The mutant origins underwent re
      initiation, showing that the GATC sites in oriC are required for sequestration.
      Each re-initiation eventually gave rise to a cell containing an extra nucleoid.
      The three-nucleoid cells displayed one asymmetrically placed FtsZ-ring and
      divided into a two-nucleoid cell and a one-nucleoid cell. The three nucleoid
      cells thus divided into three daughters by two consecutive divisions. The results
      show that extra rounds of replication cause extra daughter cells to be formed
      prematurely. The fairly normal mutant growth rate and size distribution show,
      however, that premature rounds of replication, chromosome segregation, and cell
      division are flexibly accommodated by the existing cell cycle controls.

PMID- 15009888
TI  - Auto, a surface associated autolysin of Listeria monocytogenes required for entry
      into eukaryotic cells and virulence.
AB  - Listeria monocytogenes is an opportunistic food-borne human and animal pathogen.
      Several surface proteins expressed by this intracellular pathogen are critical
      for the infectious process. By in silico analysis we compared the surface protein
      repertories of L. monocytogenes and of the non-pathogenic species Listeria
      innocua and identified a gene encoding a surface protein of L. monocytogenes
      absent in L. innocua. This gene that we named aut encodes a protein (Auto) of 572
      amino acids containing a signal sequence, a N-terminal autolysin domain and a C
      terminal cell wall-anchoring domain made up of four GW modules. We show here that
      the aut gene is expressed independently of the virulence gene regulator PrfA and
      encodes a surface protein with an autolytic activity. We provide evidence that
      Auto is required for entry of L. monocytogenes into cultured non-phagocytic
      eukaryotic cells. The low invasiveness of an aut deletion mutant correlates with
      its reduced virulence following intravenous inoculation of mice and oral
      infection of guinea pigs. During infection, the autolytic activity of Auto may
      also be critical. Auto appears thus as a novel type of L. monocytogenes virulence
      factor.

PMID- 15009890
TI  - The bacterial condensin/cohesin-like protein complex acts in DNA repair and
      regulation of gene expression.
AB  - Structural maintenance of chromosome (SMC) and the SMC-interacting kleisin
      protein families have key functions in the chromosome organization of most
      organisms. Here, we report that the Bacillus subtilis kleisin, ScpA, can form a
      ternary complex with the SMC and ScpB proteins in a yeast tri-hybrid assay,
      supporting the notion of a bacterial cohesin/condensin-like complex. Furthermore,
      ScpA interacts in two-hybrid assays with the AddAB complex, essential for
      recombinational repair, with DegS, a two-component sensor kinase, as well as with
      other potential transcription regulators. Point mutations in scpA allowing growth
      under conditions not permissive for the spcA null and not affecting chromosome
      condensation were isolated. Among these mutations, some affected DNA repair and
      gene regulation, thus separating ScpA functions in these two pathways from its
      functions in chromosome condensation and segregation. Some separation-of-function
      mutations in scpA caused a deficiency in the repair of mitomycin C DNA lesions
      that was suppressed by increasing the intracellular dosage of the interacting
      AddAB complex. Another mutation in scpA deregulated the expression of genes
      encoding degradative enzymes that are known to be controlled by the interacting
      DegS kinase. We propose that the SMC-ScpA-ScpB complex could: (i) recruit the
      AddAB helicase/nuclease to act in post-replicative repair; and (ii) form a
      complex with the DegS sensor kinase that inhibits its kinase activity. Moreover,
      our results indicate that the role of cohesin and condensin complexes in DNA
      repair and gene regulation is evolutionary conserved.

PMID- 15009889
TI  - SCP1, a 356,023 bp linear plasmid adapted to the ecology and developmental
      biology of its host, Streptomyces coelicolor A3(2).
AB  - The sequencing of the entire genetic complement of Streptomyces coelicolor A3(2)
      has been completed with the determination of the 365,023 bp sequence of the
      linear plasmid SCP1. Remarkably, the functional distribution of SCP1 genes
      somewhat resembles that of the chromosome: predicted gene products/functions
      include ECF sigma factors, antibiotic biosynthesis, a gamma-butyrolactone
      signalling system, members of the actinomycete-specific Wbl class of regulatory
      proteins and 14 secreted proteins. Some of these genes are among the 18 that
      contain a TTA codon, making them targets for the developmentally important tRNA
      encoded by the bldA gene. RNA analysis and gene fusions showed that one of the
      TTA-containing genes is part of a large bldA-dependent operon, the gene products
      of which include three proteins isolated from the spore surface by detergent
      washing (SapC, D and E), and several probable metabolic enzymes. SCP1 shows much
      evidence of recombinational interactions with other replicons and transposable
      elements during its history. For example, it has two sets of partitioning genes
      (which may explain why an integrated copy of SCP1 partially suppressed the
      defective partitioning of a parAB-deleted chromosome during sporulation). SCP1
      carries a cluster of probable transfer determinants and genes encoding likely DNA
      polymerase III subunits, but it lacks an obvious candidate gene for the terminal
      protein associated with its ends. This may be related to atypical features of its
      end sequences.

PMID- 15009891
TI  - The D,D-carboxypeptidase PBP3 organizes the division process of Streptococcus
      pneumoniae.
AB  - Bacterial division requires the co-ordination of membrane invagination, driven by
      the constriction of the FtsZ-ring, and concomitant cell wall synthesis, performed
      by the high-molecular-weight penicillin-binding proteins (HMW PBPs). Using
      immunofluorescence techniques, we show in Streptococcus pneumoniae that this co
      ordination requires PBP3, a D,D-carboxypeptidase that degrades the substrate of
      the HMW PBPs. In a mutant deprived of PBP3, the apparent rings of HMW PBPs and
      that of FtsZ are no longer co-localized. In wild-type cells, PBP3 is absent at
      the future division site and present over the rest of the cell surface, implying
      that the localization of the HMW PBPs at mid-cell depends on the availability of
      their substrate. FtsW, a putative translocase of the substrate of the PBPs, forms
      an apparent ring that is co-localized with the septal HMW PBPs throughout the
      cell cycle of wild-type cells. In particular, the constriction of the FtsW-ring
      occurs after that of the FtsZ-ring, with the same delay as the constriction of
      the septal PBP-rings. However, in the absence of PBP3, FtsW remains co-localized
      with FtsZ in contrast to the HMW PBPs. Our work reveals an unexpected complexity
      in the relationships between the division proteins. The consequences of the
      absence of PBP3 indicate that the peptidoglycan composition is central to the co
      ordination of the division process.

PMID- 15009892
TI  - The Sup35 domains required for maintenance of weak, strong or undifferentiated
      yeast [PSI+] prions.
AB  - The Sup35 protein can exist in a non-infectious form or in various infectious
      forms called [PSI+] prion variants (or prion strains). Each of the different
      [PSI+] prion variants converts non-infectious Sup35 molecules into that prion
      variant's infectious form. One definition of a 'prion domain' is the minimal
      fragment of a prion protein that is necessary and sufficient to maintain the
      prion form. We now demonstrate that the Sup35 N region (residues 1-123), which is
      frequently referred to as the 'prion domain', is insufficient to maintain the
      weak or strong [PSI+] variants per se, but appears to maintain them in an
      'undifferentiated' [PSI+] state that can differentiate into weak or strong [PSI+]
      variants when transferred to the full-length Sup35 protein. In contrast, Sup35
      residues 1-137 are necessary and sufficient to faithfully maintain weak or strong
      [PSI+] variants. This implicates Sup35 residues 124-137 in the variant-specific
      maintenance of the weak or strong [PSI+] forms. Structure predictions indicate
      that the residues in the 124-137 region form an alpha-helix and that the 1-123
      region may have beta structure. In view of these findings, we discuss a plausible
      molecular basis for the [PSI+] prion variants as well as the inherent
      difficulties in defining a 'prion domain'.

PMID- 15009893
TI  - A two-component system that controls the expression of pneumococcal surface
      antigen A (PsaA) and regulates virulence and resistance to oxidative stress in
      Streptococcus pneumoniae.
AB  - Recent genomic-based studies have identified 13 two-component signal transduction
      systems (TCS) in Streptococcus pneumoniae. Bacterial TCSs are important for
      regulating expression of bacterial genes, including those which are important to
      the virulence of pathogenic bacteria. We have used virulence assays together with
      microarray analysis to investigate the importance of pneumococcal TCS04 in the
      virulence and gene regulation of this pathogen. Deletion mutants of the response
      regulator of TCS04, rr04, were examined in three independent pneumococcal strains
      representing three different pneumococcal serotypes. Analysis of the virulence of
      the three strains enabled us to identify a serotype-specific attenuation of
      virulence due to deletion of rr04. Microarray comparison of the transcriptional
      profiles of the wild-type strains with the rr04 mutants allowed us to determine
      which transcriptional changes were occurring in the rr04 mutants. Virulence
      associated changes were demonstrated in the attenuated strain with significant
      downregulation of a previously determined virulence locus, psaB, psaC and psaA.

PMID- 15009894
TI  - The H2-sensing complex of Ralstonia eutropha: interaction between a regulatory
      [NiFe] hydrogenase and a histidine protein kinase.
AB  - Two [NiFe] hydrogenases enable the proteobacterium Ralstonia eutropha H16 to grow
      on molecular hydrogen as the sole energy source. A third [NiFe] hydrogenase (RH)
      acts as an H2 sensor in a multiple component signal transduction chain that
      controls hydrogenase gene transcription. The RH forms a dimeric heterodimer
      (HoxBC)2 in which HoxC contains the H2-sensing active site and HoxB the electron
      transferring components including an organic, not yet identified redox cofactor.
      This oligomer forms a tight complex with the histidine protein kinase HoxJ. Both
      the sensor and the kinase were analysed by mutagenesis for functional domains
      that are instrumental in H2 signal transmission. A mutant deleted for a C
      terminal peptide of 55 amino acids in HoxB lost its H2-sensing ability but still
      catalysed H2 oxidation. The mutant protein failed to form the dimeric heterodimer
      and a complex with HoxJ. The organic redox cofactor was no longer detectable in
      the truncated sensor. H2 sensing was also abolished by deletion of the PAS domain
      of HoxJ, indicating that this domain is involved in signal transduction. A
      truncated version of HoxJ consisting of only the input domain of the kinase was
      still capable of forming a complex with the RH. Mass determination of the
      purified HoxJ protein revealed that the kinase forms a homotetramer. The unique
      oligomeric structure of the H2-sensing complex with respect to its regulatory
      function is discussed.

PMID- 15009895
TI  - Characterizing spontaneous induction of Stx encoding phages using a selectable
      reporter system.
AB  - Shiga toxin (Stx) genes in Stx producing Escherichia coli (STEC) are encoded in
      prophages of the lambda family, such as H-19B. The subpopulation of STEC lysogens
      with induced prophages has been postulated to contribute significantly to Stx
      production and release. To study induced STEC, we developed a selectable in vivo
      expression technology, SIVET, a reporter system adapted from the RIVET system.
      The SIVET lysogen has a defective H-19B prophage encoding the TnpR resolvase gene
      downstream of the phage PR promoter and a cat gene with an inserted tet gene
      flanked by targets for the TnpR resolvase. Expression of resolvase results in
      excision of tet, restoring a functional cat gene; induced lysogens survive and
      are chloramphenicol resistant. Using SIVET we show that: (i) approximately 0.005%
      of the H-19B lysogens are spontaneously induced per generation during growth in
      LB. (ii) Variations in cellular physiology (e.g. RecA protein) rather than in
      levels of expressed repressor explain why members of a lysogen population are
      spontaneously induced. (iii) A greater fraction of lysogens with stx encoding
      prophages are induced compared to lysogens with non-Stx encoding prophages,
      suggesting increased sensitivity to inducing signal(s) has been selected in Stx
      encoding prophages. (iv) Only a small fraction of the lysogens in a culture
      spontaneously induce and when the lysogen carries two lambdoid prophages with
      different repressor/operators, 933W and H-19B, usually both prophages in the same
      cell are induced.

PMID- 15009896
TI  - Overproduction of the Lon protease triggers inhibition of translation in
      Escherichia coli: involvement of the yefM-yoeB toxin-antitoxin system.
AB  - In Escherichia coli, the Lon ATP-dependent protease is responsible for
      degradation of several regulatory proteins and for the elimination of abnormal
      proteins. Previous studies have shown that the overproduction of Lon is lethal.
      Here, we showed that Lon overproduction specifically inhibits translation through
      at least two different pathways. We have identified one of the pathways as being
      the chromosomal yefM-yoeB toxin-antitoxin system. The existence of a second
      pathway is demonstrated by the observation that the deletion of the yefM-yoeB
      system did not completely suppress lethality and translation inhibition. We also
      showed that the YoeB toxin induces cleavage of translated mRNAs and that Lon
      overproduction specifically activates YoeB-dependent mRNAs cleavage. Indeed, none
      of the other identified chromosomal toxin-antitoxin systems (relBE, mazEF, chpB
      and dinJ-yafQ) was involved in Lon-dependent lethality, translation inhibition
      and mRNA cleavage even though the RelB and MazE antitoxins are known to be Lon
      substrates. Based on our results and other studies, translation inhibition
      appears to be the key element that triggers chromosomal toxin-antitoxin systems.
      We propose that under Lon overproduction conditions, translation inhibition is
      mediated by Lon degradation of a component of the YoeB-independent pathway, in
      turn activating the YoeB toxin by preventing synthesis of its unstable YefM
      antidote.

PMID- 15009897
TI  - Switching the polarity of a bacteriophage integration system.
AB  - During lysogenic growth many temperate bacteriophage genomes are integrated into
      the host's chromosome and efficient integration and excision are therefore an
      essential part of the phage life cycle. The Streptomyces phage phiC31 encodes an
      integrase related to the resolvase/invertases and is evolutionarily and
      mechanistically distinct from the integrase of phage lambda. We show that during
      phiC31 integration the polarity of the recombination sites, attB and attP, is
      dependent on the sequences of the two base pairs (bp) where crossover occurs. A
      loss or switch in polarity of the recombination sites can occur by mutation of
      this dinucleotide, leading to incorrectly joined products. The properties of the
      mutant sites implies that phiC31 integrase interacts symmetrically with the
      substrates, which during synapsis can align apparently freely in either of two
      alternative forms that lead to correct or incorrect joining of products. Analysis
      of the topologies of the reaction products provided evidence that integrase can
      synapse and activate strand exchange even when recombinant products cannot form
      due to mismatches at the crossover site. The topologies of the recombination
      products are complex and indicative of multiple pathways to product formation.
      The efficiency of integration of a phiC31 derivative, KC859, into an attB site
      with switched polarity was assayed in vivo and shown to be no different from
      integration into a wild-type attB. Thus neither the host nor KC859 express a
      factor that influences the alignment of the recombination sites at synapsis.

PMID- 15009898
TI  - Large-scale identification of essential Salmonella genes by trapping lethal
      insertions.
AB  - A novel screening approach based on insertion-duplication mutagenesis (IDM) was
      established to efficiently screen for essential genes of Salmonella enterica
      serovar Typhimurium under laboratory conditions. Small, randomly generated
      genomic fragments were cloned into a conditionally replicating vector, and the
      resulting library of single Salmonella clones was grown under permissive
      conditions. Upon switching to non-permissive temperature, discrimination between
      lethal and non-lethal insertions following homologous recombination allowed the
      trapping of genes with essential functions. Further characterization of a total
      of 498 fragments resulting in such lethal knockout revealed 145 known essential
      genes and 112 functionally characterized or hypothetical genes not yet shown to
      encode essential genes, among them three Salmonella-specific genes. The
      essentiality was demonstrated for a prioritised set of 15 putative indispensable
      genes by creating conditional lethal phenotypes. The results of this large-scale
      screening indicate that in rich media, the class of Salmonella genes
      indispensable for growth is composed of approximately 490 genes.

PMID- 15009899
TI  - Induction of the sufA operon encoding Fe-S assembly proteins by superoxide
      generators and hydrogen peroxide: involvement of OxyR, IHF and an unidentified
      oxidant-responsive factor.
AB  - A promoter (sufAp), inducible by various oxidants, directs transcription of the
      sufABCDSE operon encoding an alternative Fe-S cluster assembly system in
      Escherichia coli. Superoxide generators and H2O2 induced expression of sufA-lacZ
      even in DeltasoxRS and DeltaoxyR mutants, suggesting participation of an
      additional regulator(s) in oxidant induction of the sufA operon. Through deletion
      and linker scanning mutagenesis, we found three cis-acting oxidant-responsive
      elements (OREs). ORE-I lies between -236 and -197 nucleotides from the
      transcription start site, overlapping extensively with the OxyR binding site
      reported previously. ORE-II (-156 to -127) was found to be the site of IHF
      action. ORE-III (-56 to -35) had no predictable binding sites for known
      regulators. Gel mobility shift assays with a 50 bp DNA probe containing ORE-III
      revealed the presence of an ORE-III-specific factor that binds only when cells
      are treated with oxidants. S1 mapping analysis revealed that phenazine
      methosulphate (PMS) and H2O2 induced sufA expression by more than 40-fold. In a
      DeltaoxyR mutant, sufA was still induced more than 10-fold. Fur, a ferric uptake
      regulator that negatively regulates this operon in response to iron availability,
      did not mediate the oxidant induction. Deletion of the suf operon caused cells to
      be more sensitive to superoxide-generating agents without affecting sensitivity
      to H2O2. From these results, we propose that the oxidant induction of the sufA
      operon is mediated through OxyR, IHF, plus an unidentified oxidant-responsive
      factor, and that the suf gene products are needed to defend cells against
      oxidative stress caused by superoxide generators.

PMID- 15009900
TI  - Regulation and differential expression of gdhA encoding NADP-specific glutamate
      dehydrogenase in Neisseria meningitidis clinical isolates.
AB  - Meningococcal gdhA, encoding the NADP-specific l-glutamate dehydrogenase (NADP
      GDH), is essential for systemic infection in an infant rat model. In this paper,
      a limited transcriptional analysis detected differences in gdhA expression among
      clinical isolates. In strains expressing high levels of gdhA mRNA, two promoters,
      gdhA P1 and gdhA P2, initiated transcription of gdhA. In contrast, in strains
      expressing low mRNA levels, gdhA P2 was not active because of weak expression of
      gdhR, an associated regulatory gene. Gene knock-out and complementation of a gdhR
      defective mutant confirmed that GdhR is a positive regulator for gdhA P2. Trans
      activation of gdhA P2 was maximal in complex medium during late logarithmic
      growth phase and in chemical defined medium (MCDA) when glucose (MCDA-glucose)
      instead of lactate (MCDA-lactate) was used as a carbon source in the presence of
      glutamate. gdhR knock-out mutants lost both growth phase and carbon source
      regulation, and exhibited a growth defect more severe in MCDA-glucose than in
      MCDA-lactate. DNA-protein interaction studies demonstrated that 2-oxoglutarate, a
      product of the catabolic reaction of the NADP-GDH and an intermediate of the
      tricarboxylic acid (TCA) cycle, inhibits binding of GdhR to gdhA P2.

PMID- 15009901
TI  - IHF is the limiting host factor in transposition of Pseudomonas putida transposon
      Tn4652 in stationary phase.
AB  - Transpositional activity of mobile elements is not constant. Conditional
      regulation of host factors involved in transposition may severely change the
      activity of mobile elements. We have demonstrated previously that transposition
      of Tn4652 in Pseudomonas putida is a stationary phase-specific event, which
      requires functional sigma S (Ilves et al., 2001, J Bacteriol 183: 5445-5448). We
      hypothesized that integration host factor (IHF), the concentration of which is
      increased in starving P. putida, might contribute to the transposition of Tn4652
      as well. Here, we demonstrate that transposition of Tn4652 in stationary phase P.
      putida is essentially limited by the amount of IHF. No transposition of Tn4652
      occurs in a P. putida ihfA-defective strain. Moreover, overexpression of IHF
      results in significant enhancement of transposition compared with the wild-type
      strain. This indicates that the amount of IHF is a bottleneck in Tn4652
      transposition. Gel mobility shift and DNase I footprinting studies revealed that
      IHF is necessary for the binding of transposase to both transposon ends. In
      vitro, transposase can bind to inverted repeats of transposon only after the
      binding of IHF. The results obtained in this study indicate that, besides sigma
      S, IHF is another host factor that is implicated in the elevation of
      transposition in stationary phase.

PMID- 15009902
TI  - The large resolvase TnpX is the only transposon-encoded protein required for
      transposition of the Tn4451/3 family of integrative mobilizable elements.
AB  - Chloramphenicol resistance in Clostridium perfringens and Clostridium difficile
      is often encoded by catP genes located within the 6.3 kb integrative mobilizable
      elements Tn4451 and Tn4453 respectively. This family of transposons is capable of
      being mobilized into a recipient cell in the presence of another conjugative
      element. Transposition is mediated by the large resolvase TnpX, which excises the
      element to produce a circular molecule that is the integrative intermediate. In
      this study, in vivo deletion analysis of the transposon-encoded tnpV and tnpY
      genes showed that they are not essential for excision or integration of this
      group of elements. Similar studies on tnpW suggested either that this gene is not
      essential for these functions or that TnpW does not function when provided in
      trans. Development and use of an in vivo insertion assay showed that TnpX is the
      only transposon-encoded protein required for the integration reaction.
      Subsequently, a TnpXLEH6 protein was purified and shown to catalyse excision in
      vitro in the absence of any other protein and preferentially to excise a
      supercoiled DNA substrate. In summary, these studies have shown that TnpX is the
      only transposon protein required in vivo and in vitro for the excision process
      and that, like excision, integration also occurs by a serine recombinase-mediated
      site-specific recombination mechanism.

PMID- 15009903
TI  - Proteolytic degradation of Escherichia coli transcription activators SoxS and
      MarA as the mechanism for reversing the induction of the superoxide (SoxRS) and
      multiple antibiotic resistance (Mar) regulons.
AB  - In Escherichia coli, the SoxRS regulon confers resistance to redox-cycling
      compounds, and the Mar regulon provides a defence against multiple antibiotics.
      The response regulators, SoxS and MarA, are synthesized de novo in response to
      their inducing signals and directly activate transcription of a common set of
      target genes. Although the mechanisms of transcription activation by SoxS and
      MarA have been well studied, little is known about how the systems are shut-off
      once the inducing stress has subsided, except that de novo synthesis of the
      regulators is known to cease almost immediately. Here, we induced the SoxRS
      regulon and determined that, upon removal of the inducer, expression of the
      regulon's genes quickly returns to the preinduced level. This rapid shut-off
      indicates that the system is reset by an active process. We found that SoxS is
      unstable and infer that SoxS degradation is responsible for the rapid return of
      the system to the ground state upon removal of the inducing signal. We also found
      that MarA is unstable and that the instability of both proteins is intrinsic and
      unregulated. We used null mutations of protease genes to identify the proteases
      involved in the degradation of SoxS and MarA. Among single protease mutations,
      only lon mutations increased the half-life of SoxS and MarA. In addition, SoxS
      appeared to be nearly completely stable in a lon ftsH double mutant. Using
      hexahistidine tags placed at the respective ends of the activators, we found that
      access to the amino-terminus is essential for the proteolytic degradation.

PMID- 15009904
TI  - Post-transcriptional regulation of bacterial motility by aconitase proteins.
AB  - Escherichia coli and Bacillus subtilis aconitases can act as iron and oxidative
      stress-responsive post-transcriptional regulators. Here, it is shown that a
      Salmonella enterica serovar Typhimurium LT2 acnB mutant exhibits impaired binding
      to the surface of J774 macrophage-like cells. Proteomic analyses were used to
      investigate further the binding defect of the acnB mutant. These revealed that
      the levels of the flagellum protein FliC were much lower for the acnB mutant.
      This strain was correspondingly less motile and possessed fewer flagella than
      either the parental strain or the acnA and acnAB mutants. The acnB lesion did not
      alter fliC transcription, nor did apo-AcnB select the fliC transcript from a
      library of S. enterica transcripts; thus, the effect of AcnB on FliC is indirect.
      Evidence is presented to show that apo-AcnB regulates FliC synthesis via
      interaction with the ftsH transcript to decrease the intracellular levels of
      FtsH. The lower levels of FtsH protease activity then influence sigma32, DnaK
      and, ultimately, FliC production.

PMID- 15009908
TI  - Lymphocyte homing in xenotransplanted human thyroid tissue can be inhibited by
      LFA-1 and ICAM-1 antibodies.
AB  - OBJECTIVES: Homing of lymphocytes is an important factor with respect to the
      initiation of the autoimmune process in Graves' disease (GD). As previously
      shown, human lymphocytes, particularly of intrathyroidal origin, derived from
      patients with GD, are able to migrate into normal xenotransplanted thyroid tissue
      and induce functional and histological changes. The aim of this study was to
      investigate the effect of LFA-1 and ICAM-1 antibodies on the homing of
      lymphocytes of different origin into xenografted human thyroid tissue. METHODS:
      Eighty-five nude mice bearing 8-week-old xenografts of normal human thyroid
      tissue were treated twice with anti-CD 54 (anti-ICAM-1), anti-CD 11a (anti-LFA
      1), a combination of both, or, serving as controls, iso-antibodies without
      specific binding capacity or saline. Thereafter, intrathyroidal (ITL) or
      peripheral blood lymphocytes (PBL) obtained from 4 patients with GD or saline
      were injected into the animals (i.v., 0.2 mL, 10(6) cells). After 48 hours the
      mice were sacrificed and transplants as well as mice thyroids were examined by
      immunohistochemical staining with Ki67, CD3, HLA-II (DAKO, Hamburg), IgG, CD44,
      ICAM-1, and VCAM-1 (Immunotech, Hamburg). RESULTS: Pretreatment with anti-ICAM-1
      and anti-LFA-1 decreased lymphocyte homing (CD3-staining), and expression of HLA
      II, IgG, CD44, and VCAM-1 in the transplants. CONCLUSION: Our data show that
      [ICAM-1/LFA-1 stimulated (induced)] lymphocyte homing and subsequently thyrocyte
      proliferation are inhibited by ICAM-1 and LFA-1 antibodies in xenotransplanted
      thyroid tissue. This suggests that ICAM1 and LFA-1 play an important role in the
      early steps of autoimmune thyroid disease. The inhibition/suppression of ICAM-1
      and LFA-1 interaction by respective antibodies, as demonstrated in the present
      study, may provide a new concept for prophylaxis and therapy.

PMID- 15009906
TI  - Association of the functional V158M catechol-O-methyl-transferase polymorphism
      with panic disorder in women.
AB  - Panic disorder is an anxiety disorder with an estimated heritability of up to
      48%. Pharmacological and genetic studies suggest that genes coding for proteins
      involved in the catecholaminergic system might be relevant for the pathogenesis
      of the disease. In the present study, we genotyped a single nucleotide
      polymorphism (472G/A=V158M) in the coding region of the catechol-O-methyl
      transferase (COMT) gene in 115 patients with panic disorder and age- and sex
      matched controls. Association analysis revealed a significant excess of the more
      active COMT allele (472G=V158) in patients with panic disorder (p=0.04),
      particularly in female patients (p=0.01), but not in male patients (p=1.0). The
      assessment of a possible interaction of the COMT polymorphism with a previously
      reported functional 30-bp VNTR in the monoamine oxidase A promoter (MAOALPR) in
      female patients did not yield significant results. Our data support a role of the
      472G/A (V158M) COMT polymorphism or a nearby locus in the pathogenesis of panic
      disorder in women.

PMID- 15009909
TI  - Maspin expression is directly associated with biological aggressiveness of
      thyroid carcinoma.
AB  - Maspin belongs to the serpin superfamily and has been identified as a tumor
      suppressor because it inhibits cell motility, invasion, and angiogenesis.
      However, its physiological activity in carcinoma tissues seems to differ
      according to the origin of the carcinoma. In this study, we investigated maspin
      expression in thyroid neoplasms originating in follicular cells by means of
      immunohistochemistry. Neither normal follicular cells nor stromal cells expressed
      maspin. Follicular adenomas were all negative for maspin, but 12.5% of follicular
      carcinomas and 30.5% of papillary carcinomas were positive for it. However, the
      staining pattern was only focal in all positive specimens except for one and
      maspin-expressing cells were present mainly at the edge of carcinoma nests.
      Widely invasive follicular carcinomas tended to be more frequently positive for
      maspin than minimally invasive ones. In papillary carcinoma, maspin expression
      was directly linked to stage, tumor size, and extrathyroidal invasion. Papillary
      and follicular carcinomas involving lesions with solid, trabecular, or scirrhous
      growth patterns (poorly differentiated carcinoma as designated by Sakamoto et
      al.) expressed maspin in significantly higher incidence than those with pure
      papillary or follicular patterns. Furthermore, 48.2% of anaplastic
      (undifferentiated) carcinomas diffusely expressed maspin, and the rest were
      completely negative. These findings indicate that, in contrast to other
      carcinomas, maspin expression is directly associated with the biological
      aggressiveness of thyroid carcinoma. Further studies regarding the function of
      maspin in this carcinoma are required.

PMID- 15009910
TI  - Cloning of the 5'-flanking region of mouse sodium/iodide symporter and
      identification of a thyroid-specific and TSH-responsive enhancer.
AB  - The sodium/iodide symporter (NIS) mediates active iodide uptake into thyroid
      follicular cells and is important for the diagnosis and radioiodide treatment of
      thyroid cancers. In order to better investigate the transcriptional regulation of
      the NIS gene, we cloned the 3.2 kb 5'-flanking region of the mouse NIS (mNIS)
      gene in this study. The cloned 5'-flanking region of mNIS shares 68% identity
      with that of rat NIS (rNIS), yet has little similarity to that of human NIS
      (hNIS). Based on sequence homology to rNIS, the putative mNIS transcriptional
      start site is mapped to -97 nt relative to the ATG site. The minimal promoter of
      mNIS is located within 650 bp of the 5'-flanking region as determined by the
      transient expression analysis of promoter-reporter constructs. The mNIS upstream
      enhancer (mNUE) was identified based on sequence homology to rNUE. The mNUE is
      localized to the region between -3042 and -2809 nt relative to the ATG site and
      shares 94.4% identity with rat NUE (rNUE), while only 67.8% identity with human
      NUE (hNUE). It contains two Pax-8 binding sites and a Tax/CREB binding site. The
      mNUE is also demonstrated to confer thyroid-specific and TSH-responsive
      transcriptional activity. The high degree of homology in the 5'-flanking region
      between mNIS and rNIS suggests that mNIS and rNIS share similar mechanisms for
      transcriptional regulation.

PMID- 15009911
TI  - Prevalence, clinical and ultrasonographic characteristics of thyroid
      incidentalomas.
AB  - High-resolution ultrasonography (US) has made possible the detection of
      asymptomatic small thyroid nodules. Thyroid incidentalomas have created a
      clinical dilemma as to how to properly manage such incidental findings. We
      investigated the prevalence, the clinical and US characteristics, and optimal
      diagnostic approach to incidentally detected benign and malignant thyroid nodules
      < 1.5 cm. Retrospective review was done on 1475 patients who had visited Samsung
      Medical Center, Soul Korea from January 1999 to December 2000. The prevalence of
      thyroid incidentalomas was 13.4%. The malignancy rate within thyroid
      incidentalomas was 28.8%. There were no significant differences in age, nodule
      size and number, thyroid function test, and Tc99m thyroid scan between benign and
      malignant incidentalomas. US characteristics of solid echostructure, irregular
      margin, and calcification showed meaningful diagnostic value in detecting
      malignancy in thyroid incidentalomas (p < 0.05). Most malignant incidentalomas
      were low stage. In conclusion, occult thyroid cancers are a fairly common
      finding. There were no significant differences in clinical and laboratory
      parameters between benign and malignant thyroid nodules <1.5 cm; however, US
      findings can be used in the decision of optimal management strategies.

PMID- 15009912
TI  - Fine needle aspiration of the thyroid: a cytohistologic correlation and study of
      discrepant cases.
AB  - OBJECTIVE: Fine needle aspiration (FNA) is a reliable method in the initial
      assessment of thyroid nodules. The purpose of this study was to evaluate the
      causes for discordance between the interpretation on FNA and the pathologic
      findings in the resected thyroid. METHODS: A computer search of all thyroidectomy
      specimens with previous FNA from January 1998 to December 2001 was obtained from
      the files of the Lauren V. Ackerman laboratory of surgical pathology, Barnes
      Jewish Hospital. Excluded from the study were those FNAs performed for suspected
      and confirmed metastatic disease to the thyroid as well as those cases
      unavailable for review. A total of 45 FNA cases were identified with cytologic
      and histologic discrepancies. RESULTS: Of the 1253 individual thyroid FNA
      performed during the study period, 255 patients (20%) subsequently had an open
      surgical procedure on the thyroid. Of those who underwent surgery, 196 cases
      (77%) were concordant, whereas 45 patients (18%) were discordant, and 14 cases
      were excluded due to unavailability of slides for review (for example, returned
      consult slides). The causes of the 45 discordant cases were: 20 cases (44%) were
      unsatisfactory for diagnosis, 14 cases (31%) were due to interpretation error
      (false positive), and 11 cases (24%) were due to sampling error (false negative).
      CONCLUSIONS: The most common causes of our discrepant cases are those whose FNA
      diagnosis was interpreted as "unsatisfactory for diagnosis," in 20 (7.8%) of 255
      surgical cases. The false negative rate due to sampling error in 11 (4%) of 255
      cases was mainly due to the presence of microscopic papillary thyroid carcinoma
      (PTC); the false positive rate was due to interpretation error in 14 (6%) of 255
      cases, and those were explained by the occurrence of overlapping cytologic
      features among adenomatous nodules, follicular neoplasms, the follicular variant
      of PTC, and Hashimoto's thyroiditis.

PMID- 15009913
TI  - Management of cystic or predominantly cystic thyroid nodules: the role of
      ultrasound-guided fine-needle aspiration biopsy.
AB  - OBJECTIVE: Conventional fine-needle aspiration biopsy (FNAB) for cystic thyroid
      nodules (CTNs) has a high rate of nondiagnostic and false-negative results.
      Ultrasound-guided FNAB (UG-FNAB) permits direct sampling of the wall and/or the
      solid portion of CTNs, increasing the possibility of a representative sample. In
      this study we evaluated the role of UG-FNAB in CTNs management. METHODS: Five
      hundred-seventy-five UG-FNAB of CTNs were performed. Thyroidectomy was carried
      out in 119 of these cases. The medical records of these 119 patients were
      reviewed and form the basis of this report. RESULTS: The nondiagnostic smear rate
      was 9.2%. Cytological diagnosis was benign nodule in 42 cases, predominantly
      follicular lesion in 50 cases, and suspicious or malignant lesion in 16 cases.
      The final pathology revealed a benign nodule in 98 cases (82.4%) and a carcinoma
      in 21 (17.6%). The overall accuracy of UG-FNAB was 88.0%. No significant
      differences were found in age, sex, lesion size, or echographic pattern (p = NS)
      comparing patients with benign CTNs to patients with malignant CTNs. CONCLUSION:
      UG-FNAB has a low rate of nondiagnostic smears and a high overall accuracy in
      CTNs. All CTNs should undergo UG-FNAB to select patients for surgery, since the
      malignancy rate is not negligible and no clinical parameter can reliably predict
      it.

PMID- 15009914
TI  - The elimination of iodine deficiency in the Czech Republic: the steps toward
      success.
AB  - The Czech Republic has a long history of iodine deficiency. Salt iodization was
      introduced in 1947, followed by a progressive correction of iodine deficiency.
      The present study reports the changes in the status of iodine nutrition and of
      thyroid function in the country from 1994 to 2002. The study included 29612
      individuals, aged 0 to 98 years, including 5263 individuals randomly selected
      from the general population and 24349 individuals who attended the Institute of
      Endocrinology of Prague (hospital population). Urinary iodine was determined in
      all individuals. Measurements of serum thyrotropin (TSH), free thyroxine (FT4),
      free triiodothyronine (FT3), and thyroglobulin (Tg), were taken in 8544 to 19060
      individuals. The iodine content of table salt was measured in 1130 samples. The
      median urinary iodine in the general and hospital populations were not
      significantly different. They progressively increased with time, starting from
      values indicating mild iodine deficiency (88-95 microg/L) prior to 1997, reaching
      the critical threshold of 100 microg/L in 1998, and optimal values between 120
      140 microg/L since 2000. There was only a low and not significant positive
      correlation between the iodine content of salt and the urinary iodine. In
      contrast, urinary iodine showed marked seasonal changes, with the highest values
      during winter, when livestock were supplemented by mineral tablets containing
      iodine. Variables exploring thyroid function were all situated within the normal
      range in adults but another study (results not reported) has shown the
      persistence of slightly elevated TSH in neonates. The correction of iodine
      deficiency was not accompanied by unfavorable side effects. In conclusion, the
      Czech Republic has achieved sustainable elimination of iodine deficiency. Salt
      iodization has been a determining, but not the only, factor responsible for the
      success. Iodine supplementation of livestock and increased consumption of milk
      rich in iodine have probably played a determining role. Neonatal thyroid
      screening could constitute the major monitoring tool in order to insure
      sustainable elimination of iodine deficiency in the Czech Republic.

PMID- 15009915
TI  - Two-week low iodine diet is necessary for adequate outpatient preparation for
      radioiodine rhTSH scanning in patients taking levothyroxine.
AB  - We evaluated a self-managed, outpatient, low iodine diet (LID) (<50 microg/day)
      designed to decrease total body iodine (TBI) in preparation for radioiodine
      (131I) scans. However, levothyroxine (LT4) ingestion is a significant source of
      dietary iodine in recombinant human TSH (rhTSH)-stimulated studies. Measuring
      urine iodine to creatinine ratios (I/Cr), a reflection of TBI, we evaluated the
      LID for 7-day and 14-day periods to determine the efficacy of our LID to deplete
      TBI, with and without LT4. Patients following the LID for 14 days (n = 28)
      without LT4 attained the goal of an iodine deficient state (I/Cr <50 microg/g) in
      78% of cases, establishing the diet's efficacy in significantly reducing TBI. In
      patients taking LT4, 7 days of the LID was insufficient to attain this goal of
      true iodine deficiency. However, a 14 day LID while taking LT4 resulted in 21% of
      patients being iodine deficient. For diagnostic purposes, a 7 day LID period (n =
      21) suboptimally but adequately (I/Cr <100 microg/g) prepared 41% of the
      patients, whereas 14 days on the diet (n = 24) adequately prepared 71% of the
      patients taking LT4. Our simple, self-managed, outpatient, LID effectively makes
      patients iodine deficient. Though less efficacious when taking LT4, this LID
      adequately reduces TBI for rhTSH-stimulated 131I uptake scans when followed for
      14 days.

PMID- 15009916
TI  - Differentiated thyroid carcinoma: the new UICC 6th edition TNM classification
      system in a retrospective analysis of 169 patients.
AB  - AIM: To compare the new, 6th edition, UICC TNM staging system with the former
      edition, we updated TNM staging in patients with differentiated thyroid
      carcinoma. METHODS: The new and old TNM classification systems for differentiated
      thyroid carcinoma were applied in a retrospective analysis of 169 patients who
      underwent therapy with radioiodine (131I) from 1975 through 2002 at the
      Department of Nuclear Medicine, Frankfurt. RESULTS: According to the new staging
      system, 83 patients (49%) were classified as T1 compared to 54 patients (32%)
      based on the former edition; 32 patients (19%) as T2 compared to 61 (36%)
      patients formerly. In 44 patients with minimal extrathyroid extension, formerly
      classified T4, the new TNM staging changed to T3, and no patient was classified
      T4. The one year relapse-free survival fraction under the former edition staging
      was 100% for T1 and 92.2% for T2, compared to 96.8% for new edition T1 and 93.3%
      for T2. CONCLUSION: The new TNM classification causes a significant change in
      staging. New T1 classified tumors had a slightly worse relapse-free survival
      fraction compared with the old T1 carcinomas. For patients treated at our
      department, the altered criteria for classifying extrathyroid extensions have had
      only a minor impact on disease management.

PMID- 15009917
TI  - Regression of a large goiter in a patient with resistance to thyroid hormone by
      every other day treatment with triiodothyronine.
AB  - Resistance to thyroid hormone (RTH) is a syndrome of reduced responsiveness to
      thyroid hormone caused, in the majority of cases, by mutation in the thyroid
      hormone receptor (TR) beta gene. Partial compensation through increase synthesis
      and secretion of thyroid hormone is mediated through TSH and results in thyroid
      gland enlargement. Goiters are of variable size but are recalcitrant to surgical
      treatment, and tend to recur. We describe a 17-year-old girl with a very large
      goiter cosmetically unacceptable to the patient. She was the index case of a
      large Azorean family harbouring the TRbeta mutation R243Q. Complete goiter
      regression was achieved without significant side effects by administration of L
      T3 every other day. The required dose of 250 microg suppressing TSH to values
      below 0.1 mU/L was derived by titration. Supraphysiological doses of L-T3 can be
      given safely as long-term treatment of goiter in patients RTH.

PMID- 15009918
TI  - Thyroid hemiagenesis associated with Graves' disease and Graves' ophthalmopathy:
      case report.
AB  - Failure of embryologic development of a lobe of the thyroid gland is a rare
      anomaly. Usually, this condition is diagnosed when there are some other
      pathologic conditions in the gland and is often found when a patient presents
      with a thyroid nodule, which in reality is compensatory hypertrophy of the side
      that is present, therefore appearing as a nodule. A variety of pathological
      conditions occur in the remaining thyroid tissue in association with this rare
      anomaly such as adenoma, carcinoma, subacute thyroiditis, colloid nodule, Graves'
      disease, simple goiter, and Hashimoto thyroiditis. Association of Graves' disease
      with ophthalmopathy and thyroid hemiagenesis is quite rare and very few cases are
      reported in the literature. We report a 29-year-old female presented as Graves'
      disease and Graves' ophthalmopathy with left lobe hemiagenesis of the thyroid
      gland.

PMID- 15009919
TI  - Images in thyroidology. Nervus laryngeus inferior non recurrens and lusorial
      artery.

PMID- 15009920
TI  - Images in thyroidology. Graves' disease unmasking ectopic thyroid tissue.

PMID- 15009921
TI  - Some thoughts about fine needle aspirations of thyroid nodules.

PMID- 15009922
TI  - Activating mutations of the TSH receptor.

PMID- 15009925
TI  - Chitin mineralization.
AB  - The polysaccharide chitin is found in nature as a major component of the organic
      fraction of several biocomposites in which an organic matrix is associated with
      an inorganic fraction. The relationship between the mineral phase and the organic
      phase implies a high level of molecular recognition. Chitin in mineralized
      biological systems is present in different polymorphs and has a crucial role in
      the hierarchical control of the biomineralization processes; the nacre of the
      mollusk shell is a representative example. Biologically inspired synthesis has
      been used for the production of mineral-chitin composites. Their actual and
      future applications move from the medical field as bone repair (chitin-calcium
      phosphate composites) to the industrial field as catalyst (silica chitin
      structure replica).

PMID- 15009926
TI  - Tissue engineering of fish skin: behavior of fish cells on poly(ethylene glycol
      terephthalate)/poly(butylene terephthalate) copolymers in relation to the
      composition of the polymer substrate as an initial step in constructing a
      robotic/living tissue hybrid.
AB  - This study presents the development of a biosynthetic fish skin to be used on
      aquatic robots that can emulate fish. Smoothness of the external surface is
      desired in improving high propulsive efficiency and maneuvering agility of
      autonomous underwater vehicles such as the RoboTuna (Triantafyllou, M., and
      Triantafyllou, G. Sci. Am. 272, 64, 1995). An initial step was to determine the
      seeding density and select a polymer for the scaffolds. The attachment and
      proliferation of chinook salmon embryo (CHSE-214) and brown bullhead (BB) cells
      were studied on different compositions of a poly(ethylene glycol terephthalate)
      (PEGT) and poly(butylene terephthalate) (PBT) copolymer (Polyactive). Polymer
      films were used, cast of three different compositions of PEGT/PBT (weight ratios
      of 55/45, 60/40, and 70/30) and two different molecular masses of PEGT (300 and
      1000 Da). When a 55 wt% and a 300-Da molecular mass form of PEGT was used,
      maximum attachment and proliferation of CHSE-214 and BB cells were achieved.
      Histological studies and immunostaining indicate the presence of collagen and
      cytokeratins in the extracellular matrix formed after 14 days of culture. Porous
      scaffolds of PEGT/PBT copolymers were also used for three-dimensional tissue
      engineering of fish skin, using BB cells. Overall, our results indicate that fish
      cells can attach, proliferate, and express fish skin components on dense and
      porous Polyactive scaffolds.

PMID- 15009927
TI  - Cryopreservation of collagen-based tissue equivalents. II. Improved freezing in
      the presence of cryoprotective agents.
AB  - In Part I of this study we determined an optimal cooling rate for
      cryopreservation of collagen-based tissue equivalents (TEs) that preserves both
      the postthaw cell viability and mechanical properties, but results in tissue
      contraction and an overall loss of opacity. The empirically determined optimal
      cooling rate (5 degrees C/min) was obtained in a freezing medium consisting
      solely of phosphate-buffered saline (PBS) at physiological concentration (1x). In
      the present study we report the effect of freezing on TEs in the presence of PBS
      and two cryoprotective agents (CPAs) (glycerol and dimethyl sulfoxide [Me(2)SO]),
      at two different concentrations (0.5 and 1.0 M), to two different end
      temperatures (-80 and -160 degrees C), at a cooling rate of 5 degrees C/min. The
      controlled rate freezing experiments, postthaw cell viability, and mechanical
      property measurements were performed as described in Part I of this study. In
      addition to studying the effect of CPAs on the postthaw properties of TEs, we
      also investigated (1). the effect of freezing TEs attached to the substrate (as
      opposed to detached and floating in medium) to determine differences when
      freezing TEs subject to static mechanical stress via a mechanical constraint to
      contraction; (2). the effect of freezing glutaraldehyde-fixed TEs to determine
      differences in freezing-mediated damage to the microstructure; and (3). the
      effect of freezing more mature TEs that were incubated for 4 weeks in growth
      factor-supplemented medium as opposed to 2 weeks in basal medium. All TEs frozen
      at 5 degrees C/min to -80 degrees C in the presence of 0.5 M glycerol or Me(2)SO
      in PBS were found to be optimally cryopreserved in terms of maintaining opacity
      and structure as well as cell viability and mechanical properties as compared
      with unfrozen TEs. The postthaw mechanical properties were adversely affected by
      freezing to the lower end temperature of -160 degrees C in the presence of CPAs,
      with the samples frozen in the 1.0 M concentration of CPAs exhibiting a total
      loss of structural integrity on thawing. Furthermore, TEs frozen attached to the
      substrate showed decreased opacity and significant contraction as compared with
      TEs frozen detached from the substrate, as did cross-linked samples frozen
      without CPA.

PMID- 15009928
TI  - In vivo bone tissue engineering using mesenchymal stem cells on a novel
      electrospun nanofibrous scaffold.
AB  - The objective of this study was to assess bone formation from mesenchymal stem
      cells (MSCs) on a novel nanofibrous scaffold in a rat model. A highly porous,
      degradable poly(epsilon-caprolactone) (PCL) scaffold with an extracellular matrix
      like topography was produced by electrostatic fiber spinning. MSCs derived from
      the bone marrow of neonatal rats were cultured, expanded, and seeded on the
      scaffolds. The cell-polymer constructs were cultured with osteogenic supplements
      in a rotating bioreactor for 4 weeks, and subsequently implanted in the omenta of
      rats for 4 weeks. The constructs were explanted and characterized by histology,
      immunohistochemistry, and scanning electron microscopy. The constructs maintained
      the size and shape of the original scaffolds. Morphologically, the constructs
      were rigid and had a bone-like appearance. Cells and extracellular matrix (ECM)
      formation were observed throughout the constructs. In addition, mineralization
      and type I collagen were also detected. This study establishes the ability to
      develop bone grafts on electrospun nanofibrous scaffolds in a well-vascularized
      site using MSCs.

PMID- 15009929
TI  - Preliminary development of a novel resorbable synthetic polymer fiber scaffold
      for anterior cruciate ligament reconstruction.
AB  - We are developing novel resorbable fiber-based scaffolds for reconstruction of
      the anterior cruciate ligament (ACL). For the first time, we report fabrication
      of fibers from poly(DTE carbonate) polymer. Poly(L-lactic acid) fibers were also
      fabricated for comparison purposes. The study was performed in three phases. In
      phase I, first-generation fibers were found to promote tissue ingrowth in a
      subcutaneous model. In phase II, second-generation fibers were fabricated from
      poly(DTE carbonate) and poly(L-lactic acid), with diameters of 79 and 72 microm,
      ultimate tensile strengths of 230 and 299 MPa, moduli of 3.1 and 4.9 GPa, and
      molecular weights of 65000 and 170000, respectively. These fibers were evaluated
      on the basis of molecular weight retention, strength retention, and
      cytocompatibility. After 30 weeks of incubation in phosphate-buffered saline,
      poly(DTE carbonate) and poly(L-lactic acid) fibers had 87 and 7% strength
      retention, respectively. Similar trends were observed for molecular weight loss.
      Fibroblasts attached and proliferated equally well on both scaffold types in
      vitro. Finally, in phase III, a prototype ACL reconstruction device was
      fabricated from poly(DTE carbonate) fibers with strength values comparable to
      those of the normal ACL (57 MPa). Collectively, these data suggest that poly(DTE
      carbonate) fibers are potentially useful for development of resorbable scaffolds
      for ACL reconstruction.

PMID- 15009930
TI  - Immobilization of biomacromolecules onto aminolyzed poly(L-lactic acid) toward
      acceleration of endothelium regeneration.
AB  - By reaction of poly(L-lactic acid) (PLLA) membrane with 1,6-hexanediamine, free
      amino groups were introduced onto a PLLA surface, through which biocompatible
      macromolecules such as gelatin, chitosan, or collagen were covalently immobilized
      by employing glutaraldehyde as a coupling agent. The existence of free amino
      groups on the aminolyzed PLLA surface was verified quantitatively by the
      ninhydrin analysis method, which revealed that surface NH(2) density increased
      with 1,6-hexanediamine concentration or aminolyzing time. Scanning force
      microscopy measurements detected an increase in surface roughness after
      aminolysis. The culture of human umbilical vein endothelial cells (HUVECs) in
      vitro proved that the cell proliferation rate and cell activity of both
      aminolyzed and biomacromolecule-immobilized PLLAs were improved compared with
      control PLLA. Scanning electron microscopy observation showed more spreading and
      flat cell morphology after HUVECs were cultured for 4 days on either aminolyzed
      or biomacromolecule-immobilized PLLA membranes. Confluent cell layers were
      observed on the modified PLLA. Measurement of von Willebrand factor secreted by
      these HUVECs confirmed that endothelium function was maintained. Therefore,
      aminolysis and biomacromolecule immobilization are promising ways to accelerate
      endothelium regeneration, which is crucial for blood vessel tissue engineering.

PMID- 15009931
TI  - Locally enhanced angiogenesis promotes transplanted cell survival.
AB  - A developing therapy for complete or partial loss of function in various tissues
      and organs involves transplanting an appropriate cell population, capable of
      compensating for the existing deficiencies. Clinical application of this type of
      strategy is currently limited by the death or dedifferentiation of the
      transplanted cells after delivery to the recipient. A delay in thorough
      vascularization of the implant area creates an environment low in oxygen and
      other nutrients, and likely contributes to the initial death of transplanted
      cells. We have addressed this problem by sustained delivery of vascular
      endothelial growth factor (VEGF), an initiator of angiogenesis, from a porous
      polymer matrix utilized simultaneously for cell delivery. As expected from
      previous studies, VEGF delivered from these constructs elicited an enhanced
      angiogenic response over a 2-week period when implanted subcutaneously in SCID
      mice. Hepatocytes implanted using VEGF-containing matrices demonstrated
      significantly greater survival after 1 week in vivo as compared with cells
      implanted on matrices without growth factor. The results of this study therefore
      indicate that enhancing vascularization in the location of transplanted cells
      promotes their survival. In addition, this delivery system may be used in future
      studies to directly promote cell survival and function by also providing growth
      factors specific to the transplanted cells.

PMID- 15009932
TI  - In vitro and in vivo degradation of mineralized collagen-based composite
      scaffold: nanohydroxyapatite/collagen/poly(L-lactide).
AB  - The objective of this article was to investigate the in vitro and in vivo
      biodegradation of a novel biomimetic bone scaffold composite,
      nanohydroxyapatite/collagen/poly(L-lactide), that could be used for bone tissue
      engineering. For evaluation of in vitro degradation specimens were immersed into
      1% trypsin/phosphate-buffered saline solution at 37 degrees C. In vivo evaluation
      involved the implantation of samples into the posterolateral lumbar spine of
      rabbits, and the retrieved specimens were analyzed by Fourier transform-infrared
      spectroscopy. The results demonstrated that weight loss increased continuously in
      vitro with a reduction in mass of 19.6% after 4 weeks. During the experimental
      period in vitro, the relative rate of reduction of the three components in this
      material was shown to differ greatly: collagen decreased the fastest, from 40% by
      weight to 20% in the composite; hydroxyapatite content increased from 45 to 60%;
      and PLA changed little. The pore structure was maintained throughout the whole
      experimental period in vitro; however, the thickness of the walls of the pores
      decreased and the surface of the walls increased in roughness. In vivo, the ratio
      of collagen to hydroxyapatite appeared to be slightly higher near the transverse
      process than in the central part of the intertransverse process. This finding may
      have been due to new bone matrix formation extending from the transverse to the
      intertransverse process.

PMID- 15009933
TI  - Osteogenic differentiation of human bone marrow stromal cells on partially
      demineralized bone scaffolds in vitro.
AB  - Tissue engineering has been used to enhance the utility of biomaterials for
      clinical bone repair by the incorporation of an osteogenic cell source into a
      scaffold followed by the in vitro promotion of osteogenic differentiation before
      host implantation. In this study, three-dimensional, partially demineralized bone
      scaffolds were investigated for their ability to support osteogenic
      differentiation of human bone marrow stromal cells (BMSCs) in vitro. Dynamic cell
      seeding resulted in homogeneous cell attachment and infiltration within the
      matrix and produced significantly higher seeding efficiencies when compared with
      a conventional static seeding method. Dynamically seeded scaffolds were cultured
      for 7 and 14 days in the presence of dexamethasone and evaluated on biochemical,
      molecular, and morphological levels for osteogenic differentiation. Significant
      elevation in alkaline phosphatase activity was observed versus controls over the
      14-day culture, with a transient peak indicative of early mineralization on day
      7. On the basis of RT-PCR, dexamethasone-treated samples showed elevations in
      alkaline phosphatase and osteocalcin expression levels at 7 and 14 days over
      nontreated controls, while bone sialoprotein was produced only in the presence of
      dexamethasone at 14 days. Scanning electron microscopy evaluation of
      dexamethasone-treated samples at 14 days revealed primarily cuboidal cells
      indicative of mature osteoblasts, in contrast to nontreated controls displaying a
      majority of cells with a fibroblastic cell morphology. These results demonstrate
      that partially demineralized bone can be successfully used with human BMSCs to
      support osteogenic differentiation in vitro. This osseous biomaterial may offer
      new potential benefits as a tool for clinical bone replacement.

PMID- 15009934
TI  - Osteoclastogenesis on tissue-engineered bone.
AB  - Bone remodeling plays an important role in bone function. To date, bone tissue
      engineering research has focused primarily on bone formation from osteoblasts.
      This study demonstrates that osteoclastogenesis can occur on a mineralized
      polymer scaffold. Porcine bone marrow-derived mesenchymal stem cells (pMSCs) and
      hematopoietic cells were isolated from the bone marrow of Yucatan minipigs (n =
      3) and cultured separately. pMSCs were differentiated into osteoblasts, seeded on
      porous poly(D,L-lactic-co-glycolic acid) foams, and cultured in a rotating oxygen
      permeable bioreactor system. Once the cell-polymer constructs had started to
      mineralize, the hematopoietic cells were added and cocultured to include
      osteoclastogenesis. The cultured constructs were evaluated by histochemical and
      microscopic examination. Our results show that osteoblasts and osteoclasts were
      successfully differentiated from bone marrow on the scaffolds. This is the first
      demonstration of osteoclast formation on mineralized polymer surfaces.

PMID- 15009935
TI  - Bone morphogenetic protein 2 incorporated into biomimetic coatings retains its
      biological activity.
AB  - We have previously shown that proteins can be incorporated into the latticework
      of calcium phosphate layers when biomimetically coprecipitated with the inorganic
      components, upon the surfaces of titanium-alloy implants. In the present study,
      we wished to ascertain whether recombinant human bone morphogenetic protein 2
      (rhBMP-2) thus incorporated retained its bioactivity as an osteoinductive agent.
      Titanium alloy implants were coated biomimetically with a layer of calcium
      phosphate in the presence of different concentrations of rhBMP-2 (0.1-10
      microg/mL). rhBMP-2 was successfully incorporated into the crystal latticework,
      as revealed by protein blot staining. rhBMP-2 was taken up by the calcium
      phosphate coatings in a dose-dependent manner, as determined by ELISA. Rat bone
      marrow stromal cells were grown directly on these coatings for 8 days. Their
      osteogenicity was then assessed quantitatively by monitoring alkaline phosphatase
      activity. This parameter increased as a function of rhBMP-2 concentrations within
      the coating medium. rhBMP-2 incorporated into calcium phosphate coatings was more
      potent in stimulating the alkaline phosphatase activity of the adhering cell
      layer than was the freely suspended drug in stimulating that of cell layers grown
      on a plastic substratum. This system may be of osteoinductive value in orthopedic
      and dental implant surgery.

PMID- 15009936
TI  - Multiplication of human chondrocytes with low seeding densities accelerates cell
      yield without losing redifferentiation capacity.
AB  - To treat a cartilage defect with tissue-engineering techniques, multiplication of
      donor cells is essential. However, during this multiplication in monolayer
      expansion culture chondrocytes will lose their phenotype and produce matrix of
      inferior quality (dedifferentiation). Dedifferentiation occurs more extensively
      with low seeding densities and passaging. To obtain cartilage of good quality it
      is important that the multiplicated cells regain their cartilaginous phenotype
      (redifferentiation capacity). A "gold standard" for the multiplication of
      chondrocytes in monolayer, with respect to seeding density and passaging, is
      lacking. In numerous available studies, various cell densities have been used,
      making comparison of the results of these studies difficult. Therefore, we
      performed a comparative study to gain insight concerning the effect of seeding
      density and passaging on the capacity of cells to redifferentiate. From the
      resulting data we deduced the seeding density in monolayer culture for which cell
      expansion is both sufficient and fast, while the cells retain a capacity to
      redifferentiate. As a guideline we calculated that, at minimum, 20-fold
      multiplication is needed to fill an average cartilage defect of 4 cm(2) with the
      amount of donor chondrocytes we obtained. For this study we used isolated ear
      chondrocytes from five children. Four different seeding densities in monolayer
      culture were used, ranging from 3500 to 30000 cells/cm(2). The cells were
      cultured for four passages. The capacity of the expanded chondrocytes to
      redifferentiate (redifferentiation capacity) was studied after an additional 3
      week culture in alginate beads and was assessed by glycosaminoglycan production
      and immunohistochemical stainings for collagen type I, collagen type II, elastin,
      and a fibroblast marker (11-fibrau). In general, we found that both passaging and
      decreasing seeding density yielded an increase in expanded chondrocytes, but at
      the same time decreased the dedifferentiation capacity. In further analyzing our
      data according to the proposed guidelines we found that with lower seeding
      densities sufficient multiplication (20 times) was reached in less time and with
      less passaging than at higher seeding densities. Importantly, the
      redifferentiation capacity of these chondrocytes was preserved. It was equal to
      or even surpassed that of chondrocytes multiplied 20 times at higher seeding
      densities, which required more time and more passages in monolayer culture. Thus,
      for cartilage tissue-engineering purposes we propose that expansion culture with
      low seeding densities is preferable.

PMID- 15009937
TI  - Effect of passage number and collagen type on the proliferative, biosynthetic,
      and contractile activity of adult canine articular chondrocytes in type I and II
      collagen-glycosaminoglycan matrices in vitro.
AB  - One tissue-engineering approach being investigated for the treatment of defects
      in articular cartilage involves the implantation of autologous chondrocyte-seeded
      absorbable scaffolds. The present study evaluated the effects of passage number
      (freshly isolated and passages 1 and 2) and collagen type on the proliferative,
      biosynthetic, and contractile activity of adult canine articular chondrocytes
      grown in type I and II collagen-glycosaminoglycan (GAG) matrices that were cross
      linked by dehydrothermal/carbodiimide treatment. P0, P1, and P2 cells seeded in
      the type II matrices continued to proliferate over a 4-week period, but
      thereafter the P0 and P1 cells continued to increase in number and the P2 cells
      decreased. At 4 weeks the DNA contents of the type I and II matrices seeded with
      P1 and P2 cells were comparable, and higher than the values for matrices seeded
      with freshly isolated chondrocytes. The rates of protein and GAG synthesis by the
      P1 and P2 cells were comparable, and higher than the rates for the P0
      chondrocytes, after 1 week, and the rates were generally higher in the type II
      than in the type I collagen scaffolds. Western blot analysis demonstrated the
      presence of newly synthesized type II collagen in type II matrices in which P1
      and P2 cells were grown. The cross-linking treatment imparted a sufficient degree
      of mechanical stiffness to both types of matrices to resist cell-mediated
      contraction. This study demonstrated that adult articular chondrocytes expanded
      in number through two passages in monolayer culture can be expected to provide
      behavior comparable to or better than freshly isolated cells with respect to
      proliferation and biosynthesis through 4 weeks of culture in collagen-GAG
      matrices, and these cells retain the capability to synthesize type II collagen.
      The results of this investigation further commend the use of a type II collagen
      GAG matrix, based on the higher biosynthetic rates of the cells grown in the
      matrices, for the preparation of chondrocyte-seeded scaffolds for articular
      cartilage tissue engineering.

PMID- 15009938
TI  - Fibrochondrogenesis of free intraarticular small intestinal submucosa scaffolds.
AB  - Naturally occurring biomaterials, such as small intestine submucosa (SIS), are
      attractive as potential scaffolds for engineering various tissue types. The aim
      of this study was to determine whether acellular SIS scaffolds can support cell
      attachment and ingrowth in a diarthroadial joint without significant
      intraarticular hemorrhage. Disks of porcine SIS were arthoscopically implanted
      freely within a randomized knee joint of 21 dogs and harvested 1, 2, 3, and 6
      weeks postoperatively. Harvested disks were assessed for gross and histologic
      appearance, cellular infiltration, and immunoreactivity of collagenase and
      collagen types I and II. Knee synovium and synovial fluid were also evaluated.
      All disks were thickened and opacified at harvest. Eleven disks (52%) had adhered
      to intraarticular tissues and cellular infiltration into the disks was positively
      correlated with tissue adherence. Further, tissue adherence was positively
      correlated with duration of intraarticular implantation. Five disks (24%)
      contained focal areas of homogeneous extracellular matrix. A trend toward more
      collagenase immunoreactivity was noted in the 3-week disks. Collagen type I was
      present in remaining SIS and extracellular matrix associated with infiltrated
      cells. Placed freely within a joint, acellular SIS disks underwent cellular and
      extracellular matrix modification resulting in fibrocartilage-like tissue.
      Utilization of SIS as a scaffold for intraarticular tissue-engineering
      applications is supported as cytoconductivity, appropriate residence time, and
      absence of untoward effects of implantation are desirable criteria for a tissue
      engineering biomaterial.

PMID- 15009939
TI  - Expansion of the number of human auricular chondrocytes: recycling of culture
      media containing floating cells.
AB  - To grow a complete human size auricle by utilizing the principles of tissue
      engineering, a large number of chondrocytes is required for initial implantation.
      The number of chondrocytes can be increased by repeated passaging or by
      incubation with different growth factors, both of which can promote
      dedifferentiation. New methods of chondrocyte expansion over a relatively brief
      time period for potential practical application are required. In this study
      auricular chondrocytes were obtained from patients and cultured in vitro. Two
      groups of cells were created. Group A chondrocyte number was increased by
      repeated passaging. Group B cells were grown from floating culture medium and
      their number was increased both by passaging and by repeated recycling of the
      culture medium. Chondrocytes from both groups were implanted in nude mice for 8
      weeks to generate tissue-engineered cartilage. Flow cytometry studies performed
      on both groups confirmed the presence of two distinct populations of structures
      as the source of chondrocytes from the recycled medium. Repeated recycling of the
      culture medium demonstrates a promising method to increase the number of
      chondrocytes in vitro for clinical application.

PMID- 15009940
TI  - Serum-free growth medium sustains commitment of human articular chondrocyte
      through maintenance of Sox9 expression.
AB  - Human articular cartilage heals poorly in adults and current surgical procedures
      do not provide long-term repair. Cell therapy and tissue engineering could become
      the treatment of choice, but suffer a major limitation as chondrocytes in vitro
      lose the differentiated phenotype. In vivo, the chondrogenic lineage is specified
      by transcription factor Sox9. Thus, cell-based therapy could be successful if
      Sox9 expression and chondrogenic commitment of the expanded cells were preserved.
      To achieve this goal, we developed a serum-free medium that supports cell
      proliferation and preserves the differentiation potential. Indeed, expression of
      Sox9 is maintained when the conventionally used serum is substituted for by this
      defined supplement. Spontaneous cartilage formation after expansion in serum-free
      medium is obtained in vitro in a high-density pellet culture and confirmed in
      vivo in a functional assay in immunodeficient mice. By contrast, cells grown in
      serum lose the expression of Sox9 and fail to reform cartilage both in vitro and
      in vivo unless they are rescued by chondrogenic inducers such as transforming
      growth factor beta(1) and dexamethasone. Our data emphasize the importance of the
      microenvironment in modulating commitment, plasticity, and phenotype of
      chondrocytes, and provide an experimental system to study their physiological or
      pathological metabolism in a controlled context.

PMID- 15009941
TI  - Addition of cultured Schwann cells to tendon autografts and freeze-thawed muscle
      grafts improves peripheral nerve regeneration.
AB  - The effects of addition of Schwann cells on peripheral nerve regeneration through
      a novel graft material-the tendon autograft-and a conventional freeze-thawed
      muscle graft, were studied in the rat sciatic nerve. Adult Schwann cell cultures
      were established from predegenerated nerves. The Schwann cells were added to the
      autologous grafts by coculture (tendon autograft) or injection (freeze-thawed
      muscle graft). Both graft types supported adherence of the added Schwann cells.
      Addition of cultured Schwann cells to the two different graft models improved
      regeneration by increasing the rate of axonal outgrowth as compared with similar
      grafts without added cells.

PMID- 15009942
TI  - Influence of flow conditions and matrix coatings on growth and differentiation of
      three-dimensionally cultured rat hepatocytes.
AB  - Maintenance of liver-specific function of hepatocytes in culture is still
      difficult. Improved culture conditions may enhance the cell growth and function
      of cultured cells. We investigated the effect of three-dimensional culture under
      flow conditions, and the influence of surface modifications in hepatocyte
      cultures. Hepatocytes were harvested from Lewis rats. Cells were cultured on
      three-dimensional polymeric poly-lactic-co-glycolic acid (PLGA) matrices in
      static culture, or in a pulsatile flow-bioreactor system. Different surface
      modifications of matrices were investigated: coating with collagen I, collagen
      IV, laminin, or fibronectin; or uncoated matrix. Hepatocyte numbers, DNA content,
      and albumin secretion rate were assessed over the observation period. Culture
      under flow condition significantly enhanced cell numbers. An additional
      improvement of this effect was observed, when matrix coating was used. Cellular
      function also showed a significant increase (4- to 5-fold) under flow conditions
      when compared with static culture. Our data showed that culture under flow
      conditions improves cell number, and strongly enhances cellular function. Matrix
      modification by coating with extracellular matrix showed overall an additive
      stimulatory effect. Our conclusion is that combining three-dimensional culture
      under flow conditions and using matrix modification significantly improves
      culture conditions and is therefore attractive for the development of successful
      culture systems for hepatocytes.

PMID- 15009943
TI  - Engineering of multilayered urinary tissue in vitro.
AB  - Regeneration of the urinary conduit, using engineered autologous material, could
      have many clinical implications. The urinary system is composed of a three
      layered wall consisting of different cell types. In this study we investigated
      the possibility to coculture these components in vitro into a continuous sheet
      for total autologous regeneration. To address this issue, human urothelial cells,
      fibroblasts, and smooth muscle cells were isolated separately and expanded in
      vitro. Cells were then cocultured by seeding them in layers in a "sandwich
      model." After coculturing the material was investigated histologically and with
      immunoassays. The different cells could be cocultured after being isolated and
      expanded separately in vitro. The cells formed a continuous sheet that could be
      enzymatically detached and that sustained mechanical handling. The morphology of
      different cell layers and the reaction to immunostaining indicated their
      preserved individual phenotype. In conclusion, we showed that human urothelial
      cells, fibroblasts, and smooth muscle cells can be expanded in vitro and
      cocultured to form a continuous cellular sheet consisting of three distinct
      layers of different types of cells. This could provide the surgeon with
      autologous tissue for urogenital reconstructive purposes.

PMID- 15009944
TI  - Bladder regeneration with cell-seeded small intestinal submucosa.
AB  - This study was performed to determine the regenerative properties of smooth
      muscle cells (SMCs) and urothelial cells (UCs) seeded on small intestinal
      submucosa (SIS), utilizing a nude mouse model. Human bladder SMCs and UCs were
      seeded on SIS in a layered coculture fashion. Cell-seeded SIS grafts (1 x 1
      cm(2)) were maintained in a CO(2) incubator for 14 days and subsequently folded
      with the seeded cells facing the lumenal side and implanted subcutaneously into
      the flanks of nude mice (n = 20). Unseeded SIS grafts were implanted into the
      contralateral flanks of the mice to serve as controls. Grafts were harvested at
      4, 8, and 12 weeks after implantation. By 12 weeks, layered urothelium with a
      central lumen was noted with early smooth muscle bundle formation peripherally.
      At each time point, the regenerated SMCs stained positive for alpha-smooth muscle
      actin, and the UCs stained positive for cytokeratin AE1/AE3. The control group
      demonstrated no evidence of organized bladder regeneration. This study
      demonstrates the potential for cell-seeded SIS to induce organized bladder
      regeneration in vivo. This also provides the basis for additional work utilizing
      seeded SIS grafts for bladder augmentation.

PMID- 15009945
TI  - Genetic modification of smooth muscle cells to control phenotype and function in
      vascular tissue engineering.
AB  - Rat smooth muscle cells (SMCs) stably transfected with the gene for the phenotype
      regulating protein cyclic guanosine monophosphate-dependent protein kinase (PKG)
      were used as a cell source in the preparation of three-dimensional (3D) collagen
      type I vascular constructs. PKG-transfected cells expressed severalfold higher
      levels of the contractile protein smooth muscle alpha-actin (SMA), relative to
      untransfected SMCs, both in monolayer culture and in 3D gels. The proliferation
      rate of PKG-transfected cells was lower than that of untransfected cells in both
      culture geometries. Three-dimensional collagen constructs made with PKG
      transfected cells compacted to a similar degree as those made with untransfected
      cells, and this compaction could be augmented by biochemical stimulation with
      platelet-derived growth factor BB (PDGF) or transforming growth factor beta(1)
      (TGF). Application of cyclic mechanical strain to tubular collagen gels seeded
      with PKG-transfected cells resulted in a higher degree of gel compaction and
      circumferential matrix alignment, relative to statically grown controls, but cell
      proliferation and SMA expression were not affected. These results show that
      genetic modification of SMCs can be used as a tool to control cell function in
      vascular tissue engineering, and that the function of such cells can be further
      modulated by application of biochemical and mechanical stimulation.

PMID- 15009946
TI  - Design of artificial myocardial microtissues.
AB  - Cultivation technologies promoting organization of mammalian cells in three
      dimensions are essential for gene-function analyses as well as drug testing and
      represent the first step toward the design of tissue replacements and
      bioartificial organs. Embedded in a three-dimensional environment, cells are
      expected to develop tissue-like higher order intercellular structures (cell-cell
      contacts, extracellular matrix) that orchestrate cellular functions including
      proliferation, differentiation, apoptosis, and angiogenesis with unmatched
      quality. We have refined the hanging drop cultivation technology to pioneer
      beating heart microtissues derived from pure primary rat and mouse cardiomyocyte
      cultures as well as mixed populations reflecting the cell type composition of
      rodent hearts. Phenotypic characterization combined with detailed analysis of
      muscle-specific cell traits, extracellular matrix components, as well as
      endogenous vascular endothelial growth factor (VEGF) expression profiles of heart
      microtissues revealed (1). a linear cell number-microtissue size correlation,
      (2). intermicrotissue superstructures, (3). retention of key cardiomyocyte
      specific cell qualities, (4). a sophisticated extracellular matrix, and (5). a
      high degree of self-organization exemplified by the tendency of muscle structures
      to assemble at the periphery of these myocardial spheroids. Furthermore (6).
      myocardial spheroids support endogenous VEGF expression in a size-dependent
      manner that will likely promote vascularization of heart microtissues produced
      from defined cell mixtures as well as support connection to the host vascular
      system after implantation. As cardiomyocytes are known to be refractory to
      current transfection technologies we have designed lentivirus-based transduction
      strategies to lead the way for genetic engineering of myocardial microtissues in
      a clinical setting.

PMID- 15009947
TI  - Three-dimensional in vitro model of adipogenesis: comparison of culture
      conditions.
AB  - In vivo and in vitro studies have demonstrated both promise and current
      limitations in tissue engineering of fat. Herein, we report the establishment of
      a well-defined three-dimensional (3-D) in vitro model useful for systematic
      investigations of 3-D adipogenesis. Polyglycolic acid fiber meshes were
      dynamically seeded with 3T3-L1 preadipocytes; subsequently, cell-polymer
      constructs were hormonally induced and cultivation under three different
      conditions was evaluated. Regarding tissue coherence and intracellular lipid
      content, culture of cell-polymer constructs either dynamically in well plates or
      in stirred bioreactors yielded similar results, which were distinctly improved
      compared with static conditions in well plates. At the protein and mRNA levels,
      significantly increased expression of genes characteristic for a mature adipose
      phenotype was demonstrated for constructs dynamically cultured in well plates, as
      compared with static conditions. Furthermore, investigation of lipolysis under
      stimulating and inhibiting conditions demonstrated functionality of the
      dynamically differentiated constructs. Using dynamic culture conditions, the
      presented in vitro model system is suggested as a valuable tool serving both fat
      tissue engineering and basic research by facilitating investigations of tissue
      inherent features not possible under conventional 2-D culture conditions.

PMID- 15009948
TI  - Bone tissue engineering for spine fusion: an experimental study on ectopic and
      orthotopic implants in rats.
AB  - Alternatives to the use of autologous bone as a bone graft in spine surgery are
      needed. The purpose of this study was to examine tissue-engineered bone
      constructs in comparison with control scaffolds without cells in a posterior
      spinal implantation model in rats. Syngeneic bone marrow cells were cultured in
      the presence of bone differentiation factors and seeded on porous hydroxyapatite
      particles. Seven rats underwent a posterior surgical approach, in which scaffolds
      with (five rats) or without cells (two rats) were placed on both sides of the
      lumbar spine. In addition, separate scaffolds were inserted intramuscularly and
      subcutaneously during the surgical procedure. After 4 weeks, all rats were killed
      and examined radiographically, by manual palpation of the excised spine and
      histologically for signs of bone formation or spine fusion. All rats that
      received cell-seeded scaffolds showed newly formed bone in all three locations,
      whereas none of the locations in the control rats showed bone formation. The
      results of this study support the concept of developing tissue-engineering
      techniques in posterior spine fusion as an alternative to autologous bone.

PMID- 15009949
TI  - Design and application of a test system for viscoelastic characterization of
      collagen gels.
AB  - Characterization and control of the mechanical properties of the extracellular
      matrix are critical to the interpretation of results of in vitro studies of
      cultured tissues and cells and for the design of functional engineered
      constructs. In this work a viscoelastic tensile test system and custom culture
      chambers were developed and characterized. The system allowed quantification of
      strain as well as the stresses developed during cyclic viscoelastic material
      testing. Finite element analysis of the culture chambers indicated that the
      tensile strains near the actuated ends of the gel were greater than the strains
      experienced by material in the center of the culture chambers. However, the
      strain was uniformly distributed over the central substance of the gel,
      validating the assumption that a homogeneous strain state existed in the central
      region of the chamber. Viscoelastic testing was performed on collagen gels that
      were created with three different collagen concentrations. Results demonstrated
      that there was a significant increase in the dynamic stiffness of the gels with
      increasing equilibrium strain, collagen concentration, and frequency of applied
      strain. With increasing strain rate, the phase angle, representing the energy
      dissipated, dropped initially and then increased at higher rates. Mechanical
      testing of gels at different time intervals up to 7 days after polymerization
      demonstrated that the material properties remained stable when appropriate
      environmental conditions were maintained. The ability to characterize the
      viscoelastic properties of gels after different periods of culture will allow the
      quantification of alterations in gel material properties due to changes in cell
      cytoskeletal organization, cell-matrix interactions, and cellular activity on the
      matrix. Further, the test device provides a means to apply controlled mechanical
      loading to growing gel cultures. Finally, the results of this study will provide
      guidance to the design of further experiments on this substrate.

PMID- 15009950
TI  - Effects of enhanced O(2) transport on hepatocytes packed within a bioartificial
      liver device.
AB  - The functional performance of an extracorporeal bioartificial liver (BAL) device
      requires that suitable nutrient pathways exist to support the hepatocytes packed
      within it. Consequently the limited transport distance of the nutrient oxygen is
      a limiting factor in the scale-up of many BAL designs. In this study the porosity
      of a collagen extracellular matrix is increased to evaluate how enhanced O(2)
      transport alters the viability and functional performance of gel-entrapped
      hepatocytes packed within a BAL. Our results indicate that the porous collagen
      increases the number of viable hepatocytes that can be supported by a single O(2)
      source. Furthermore, the results illustrate that, compared with normal collagen,
      porous collagen extends the O(2) transport distance such that hepatocytes located
      at larger distances from the O(2) source of the BAL can be supported. Finally,
      the function results reveal that hepatocytes within the porous collagen
      experience significantly improved function over the control cultures. Hence our
      results demonstrate that enhancing O(2) transport through the extracellular
      matrix of densely packed BAL designs is one way to significantly improve the
      functionality of these devices.

PMID- 15009951
TI  - Geometric control of fibroblast growth on proton beam-micromachined scaffolds.
AB  - Circular three-dimensional (3D) micropatterns with grooves and ridges of various
      sizes on the circumference of the structure were micromachined in
      polymethylmethacrylate, using proton beam micromachining. Fibroblasts were seeded
      in the center smooth nonpatterned surface of the circle. The circumference
      grooves could retard the outward spreading of cells after they became confluent
      in the central smooth surface. The fibroblasts eventually migrated across the
      grooves and ridges several days later. Wider and deeper grooves were more
      effective in retarding fibroblast spreading. Our results indicate that groove
      structures in cellular dimensions can effectively retard fibroblasts invasion.
      Proton beam micromachining, which has the unique advantage of being the only
      technique capable of manufacturing direct-write precise 3D microstructure at
      cellular dimensions, has great potential in generating 3D microscaffolds for
      studying cell behavior in a 3D microenvironment, which is important for tissue
      engineering.

PMID- 15009952
TI  - A novel tubular scaffold for cardiovascular tissue engineering.
AB  - We have developed a counter rotating cone extrusion device to produce the next
      generation of three-dimensional collagen scaffold for tissue engineering. The
      device can produce a continuously varying fibril angle from the lumen to the
      outside of a 5-mm-diameter collagen tube, similar to the pattern of heart muscle
      cells in the intact heart. Our scaffold is a novel, oriented, type I collagen,
      tubular scaffold. We selected collagen because we believe there are important
      signals from the collagen both geometrically and biochemically that elicit the in
      vivo -like phenotypic response from the cardiomyocytes. We have shown that
      cardiomyocytes can be cultured in these tubes and resemble an in vivo phenotype.
      This new model system will provide important information leading to the design
      and construction of a functional, biologically based assist device.

PMID- 15009953
TI  - Tissue factory: conceptual design of a modular system for the in vitro generation
      of functional tissues.
AB  - Tissue factory is a modular system designed to generate artificial tissues under
      optimal perfusion culture conditions. The microenvironment within the culture
      containers can be fine-tuned to meet the physiological needs of individual
      tissues, so that the generation of differentiated three-dimensional tissue
      constructs becomes possible. An optimal physiological environment is created by
      modulating a liquid phase as well as an artificial interstitium surrounding the
      growing construct. An innovative construction principle allows production of
      tissue culture containers, gas exchangers, and gas expanders at minimal material
      expenditure. Therefore it will be possible for the first time to produce sterile
      one-way perfusion culture modules for the generation of artificial tissues. The
      modules can be used separately as well as in a combined module. The system is
      designed to provide a possible platform for the standardized production of
      artificial tissues for future applications in biomedicine.

PMID- 15009954
TI  - Gene delivery in bone tissue engineering: progress and prospects using viral and
      nonviral strategies.
AB  - Bone tissue loss as a consequence of the natural aging process or as a result of
      trauma and degenerative disease has led to the need for procedures to generate
      cartilage and bone for a variety of orthopedic applications. The ability to
      transfer genes into multipotential mesenchymal stem cells, while still in its
      infancy, offers considerable therapeutic hope in a variety of musculoskeletal
      disorders. However, the choice of gene delivery method is key. This review
      examines the various techniques and methods currently available to enable gene
      transfer into a target population from viral methods (transduction) to nonviral
      (transfection) methods and the limitations associated with each method. The
      potential applications and current understanding of each method are presented.
      Given the demographic challenge of an aging population, the ultimate goal remains
      the development of simple, safe, and reproducible strategies for gene delivery
      that will address the pressing orthopedic clinical imperatives of many.

PMID- 15009955
TI  - Tissue engineering: the end of the beginning.
AB  - This study was undertaken to assess the impact of current economic conditions and
      recent disappointing product launches on the field of tissue engineering. Data
      were collected on all firms known to be active in the field, analyzed, and
      compared with analogous data collected in 1995, 1998, and 2000. As of December
      31, 2002, more than 2600 full-time equivalents (FTEs) in 15 countries and 89
      firms were engaged in tissue-engineering research and development. Annual
      spending was US dollars 487 million, down about 20% since 2000-a reasonable
      performance in the face of a stagnant economy and difficult capital markets.
      Individual sectors proved far more volatile. Activity in skin, cartilage, and
      other structural applications declined by more than 50% with a loss of 800 FTEs.
      This downsizing was somewhat counterbalanced by a 42% increase in stem cell
      firms, which added more than 300 employees. Consistent with general
      disenchantment with technology sector equities, capital value of publicly traded
      tissue-engineering corporations has decreased by almost 90% from US dollars 2.5
      billion at the end of 2000 to US dollars 300 million at the end of 2002. The
      United States' fraction of the total workforce declined from 80% in 2000 to 54%
      in 2002. By the close of 2002, twenty tissue-engineered products had entered Food
      and Drug Administration clinical trials. Four were approved but none of these are
      yet commercially successful. Six other applications were either abandoned or
      failed to achieve product approval. Ten products were still in clinical trials,
      some of which were investigator sponsored, and most of which were at the phase
      I/phase II stage. The field has yet to produce a profitable product despite an
      aggregate research and development investment exceeding US dollars 4.5 billion.
      Tissue engineering is clearly having difficulty transitioning from a development
      stage industry to one with a successful product portfolio. This is often the case
      for breakthrough medical technologies.

PMID- 15009956
TI  - [Experimental study of the effects of mild hypothermia on the acute myocardial
      infarction size in the rabbits with coronary artery reperfusion].
AB  - OBJECTIVE: To study the effect of mild hypothermia on the acute myocardial
      infarction size in the rabbits with coronary artery reperfusion. METHODS:
      fourteen rabbits were randomly divided into two groups: mild hypothermia group
      and control group. Each group underwent 45 minutes of left anterior descending
      coronary artery occlusion and 2 hours of reperfusion. Core temperatures were
      measured with thermistor. The mild hypothermia group received ice cooling around
      the body and the core temperature was dropped to 32-35 centigrade after occluded
      for 30 minutes, while the control group's body temperature were kept above 38
      centigrade. The myocardial area at risk and the infarct area were determined with
      Evan's blue dye and triphenyl tetrazolium chloride (TTC). RESULTS: The total
      elevated amplitude of ST segment in chest leads V1, V3 and V5 in the mild
      hypothermia group was (25.8+/-8.5) mV, it was lower than that in the control
      group (37.7+/-6.5) Mv (P=0.021). The changes of serum MB isoenzyme of creatine
      kinase (CK-MB) activities in mild hypothermia group was (2646.9+/-1227.3) U/L, it
      was significantly lower than that in the control group (4787.8+/-1934.2)
      U/L(P=0.045). The weight of infarct myocardium of the mild hypothermia group was
      (0.23+/-0.05)g, it was lower than that in the control group (0.42+/-0.16)g
      (P=0.020). Myocardial infarct size as a percentage of the risk zone (0.214+/
      0.044 vs. 0.357+/-0.066, P=0.001) and of the left ventricle weight (0.041+/-0.010
      vs. 0.071+/-0.027, P=0.029) were smaller than those in the control group. The
      ratio of the survived myocardial area over the risk zone in the mild hypothermia
      group was significantly higher than that in the control group (0.786+/-0.044 vs.
      0.643+/-0.066, P<0.001). CONCLUSION: Mild hypothermia may reduce infarct size in
      the rabbits with transient acute myocardial infarction, and increase survived
      myocardium in the risk zone.

PMID- 15009957
TI  - [Effects of Ca2+ antagonist on cardiomyocytic apoptosis after experimental
      myocardial infarction].
AB  - OBJECTIVE: To explore the effects of Ca(2+) antagonist on apoptosis of
      cardiomyocytes after myocardial ischemia. METHODS: The model of myocardial
      infarction was made by ligating left coronary artery in SD rats. In experimental
      group, the rats were administrated with Adalat through oral cavity (1 mg/kg)
      before operation and through peritoneal cavity (0.4 mg/kg 3 hours after
      operation. In ischemic control group the rats were injected with placebo and in
      normal control group the rats were treated with sham operation (no ligating left
      coronary artery) and placebo. The rats were killed 6 hours after operation, with
      their left ventricular function had been measured. Apoptotic myocardial cells
      were detected by terminal deoxynucleotidyl transferase mediated dUTP nick end
      labeling (TUNEL) method, Fas and Bcl-2 proteins by the ABC immunohistochemistry
      method. Apoptosis indexes were calculated under high magnification field of
      microscopy. RESULTS: The systolic pressure, end-diastolic pressure and dp/dt of
      left ventricle in experiment group were not significant different from those in
      the ischemic control group, they were 76.7+/-7.5/8.0+/-6.1 mm Hg vs. 74.9+/
      11.1/11.6+/-8.3 mm Hg (P>0.05) and (777.3+/-128.6)mm Hg/s vs. (761.8+/-136.4)mm
      Hg/s (P>0.05) respectively; but those in both the experimental group and the
      ischemic control group were lower than those in the normal control group, they
      were 94.9+/-7.5/2.8+/-3.2 mm Hg (P<0.001) and (1131.5+/-112.8)mm Hg/s(P<0.001).
      There were a lot of positive myocytes with TUNEL stain in the ischemic region of
      left ventricle in both the experimental and the ischemic control group, apoptosis
      index in the experimental group was lower than that in the ischemic control group
      (0.201+/-0.053 vs. 0.261+/-0.045, P<0.05). The positive myocytes of Fas and Bcl-2
      protein appeared in the region surrounding ischemic myocytes. There were no
      positive myocytes with the three types of stain in normal control group.
      CONCLUSION: Ischemia could induce apoptosis of myocytes and expression of Fas and
      Bcl-2 gene; Ca(2+) antagonist could protect myocytes from apoptosis.

PMID- 15009958
TI  - [Clinical significance of soluble selectins and matrix metalloproteinases-9 in
      patients after successful cardiopulmonary resuscitation].
AB  - OBJECTIVE: To investigate whether patients after successful cardiopulmonary
      resuscitation (CPR) exist elevated levels of soluble P-and E-selectin (sP
      selectin, sE-selectin), matrix metalloproteinases-9 (MMP-9) and to evaluate the
      clinical significance of changes in these cytokine levels. METHODS: Plasma levels
      of sP-and sE-selectin, MMP-9 of 82 patients who survived >or=48 hours after CPR
      were determined on the second day after successful CPR. They were classified into
      different groups according to whether causing systemic inflammatory response
      syndrome (SIRS) and developing sepsis. Sixty-five non-critically ill patients
      were served as control group. RESULTS: Incidence of SIRS was 68.3% (56/82 cases)
      after successful CPR. Plasma levels of sP-selectin were higher in patients with
      SIRS compared with those in patients without SIRS or control group (all P<0.01).
      Plasma levels of sE-selectin and MMP-9 were not significantly different between
      patients with SIRS and without SIRS (all P>0.05), but were higher in both patient
      groups than those in the control group (all P<0.01) 43.9% of the patients
      developed sepsis within 1 week after CPR. Plasma levels of sP-selectin were
      higher in patients developing sepsis than those in patients without sepsis
      (P<0.05), but plasma levels of sE-selectin and MMP-9 were not significantly
      different between two groups (all P>0.05). Plasma levels of sE-selectin and MMP-9
      were higher in nonsurvivors than those in survivors (both P<0.01), but plasma
      levels of sP-selectin were not significantly different between two groups (all
      P>0.05). CONCLUSION: SIRS is a frequent but unspecific finding after CPR with
      only minor impact on outcome. Determination of sP-and sE-selectin, MMP-9 early
      after CPR might help to identify patients at a high risk for sepsis or an
      adverse, respectively.

PMID- 15009959
TI  - [Effect of beta3-adrenoreceptors agonist on beta3-adrenoreceptors expression and
      myocyte apoptosis in a rat model of heart failure].
AB  - OBJECTIVE: To evaluate the effects of beta(3)-adrenoreceptor (AR) agonist (BRL
      37344) on the expression of beta(3)-AR in a isoproterenol (ISO)-induced heart
      failure (HF) rat model and to investigate the influence on the levels of beta(3)
      AR in failing heart. METHODS: The rats were randomly divided into four groups: I
      group (control group, n=10); II group (normal with BRL group, n=10); III group
      (HF group, n=30); IV group (HF with BRL group, n=35).II and IV groups received
      BRL 0.4 nmol.kg-1.min-1 through caudal vein for 10 minutes twice a week. I and
      III groups received saline at the same time. The measure included hemodynamics,
      the expression of beta3-AR in left ventricular myocytes by the techniques of
      immunohistochemistry, beta3-AR proteins by western blot, expression levels of
      beta3-AR mRNA in myocardium by reverse transcription- polymerase chain reaction
      (RT-PCR) and the levels of apoptotic cells with a terminal deoxynucleotidyl
      transferase mediated dUTP-biotin nick end labeling(TUNEL) kit. RESULTS:
      (1)Hemodynamic: The tendency of left ventricular end systolic pressure (PES),
      maximal rates of rise of ventricular pressure(dp/dtmax), maximal rates of decline
      of ventricular pressure (dp/dtmin) in II, III and IV groups were lower (P<0.01),
      time constant of left ventricular relaxation (Tc) and left ventricular end
      diastolic pressure (PED) were higher than those of the I group (all P<0.01).
      There was no difference between I and II group except PED (P<0.05). Compared with
      III group, PES, dp/dtmax, dp/dtmin in IV group were dramatically decline
      (P<0.05): Tc, PED were markedly increased (Tc P<0.05, PED P<0.01). (2)The levels
      of beta3-AR mRNA and beta3-AR proteins were higher in III and IV groups when
      compared with I and II groups. There was no difference between I and II group. IV
      group's levels were higher than III group's. (3)The apoptotic rates in III group
      and IV group were significantly higher than those in I and II group (all P<0.01).
      When compared with III group's apoptotic cell rate, IV group's was higher
      (P<0.01). CONCLUSION: The levels of beta(3)-AR mRNA and proteins show an increase
      in failing heart compared with nonfailing heart. The effect of beta(3)-AR agonist
      aggravate markedly cardiac function and stimulate cardiac myocytes apoptosis in
      failing heart. If the levels of beta(3)-AR were too high, they might contribute
      to the loss of cardiac function and be the foundation of the functional
      degradation of HF.

PMID- 15009960
TI  - [Clinical features and treatment of cardiogenic shock complicated with acute
      myocardial infarction].
AB  - OBJECTIVE: To identify the clinical features and the outcome of patients with
      cardiogenic shock complicating acute myocardial infarction (AMI). METHODS: One
      hundred and eight consecutive patients with AMI were included in this
      retrospective analysis. The characteristics, management, and outcome of patients
      with AMI were compared between patients with cardiogenic shock (group A, n=11)
      and without cardiogenic shock (group B, n=9). RESULTS: There was no difference in
      the age and other characteristics including proportion of women, diabetics, prior
      myocardial infarction and the position of myocardial infarction. The levels of
      peak creatine kinase and troponin I were (31979.7+/-22271.1)nmol x s(-1) x L(-1)
      and (90.7+/-61.1) microg/L respectively in group A, they were higher than those
      in group B (17795.2+/-14979.7)nmol.s-1.L-1 and (39.9+/-52.1) microg/L,
      respectively (both P<0.05). The left ventricular ejection fraction was
      significantly lower in group A than that in group B (0.46+/-0.12 vs. 0.55+/-0.12,
      P<0.05). Patients in group A had a higher proportion of pump failure, arrhythmia
      and pneumonia (64% vs. 14%, P<0.001; 55% vs. 21 %, P<0.05; and 46% vs. 12%,
      P<0.01, respectively) than those in group B. In addition, in group A patients
      often underwent thrombolysis of urokinase, coronary angiography and intra-aortic
      balloon counterpulsation (46% vs. 18%, 73% vs. 26% and 36% vs. 4%, all P<0.05,
      respectively). There was no difference in in-hospital mortality between group A
      and group B (0 vs. 4%, P>0.05). CONCLUSION: Shock patients more likely have pump
      failure, arrhythmia, and pneumonia and more often underwent intra-aortic balloon
      counterpulsation. If cardiogenic shock complicating AMI is managed with rapid
      evaluation and prompt initiation of supportive measures and definitive therapy,
      outcomes can be improved.

PMID- 15009962
TI  - [Therapeutic assessment between the thrombolysis in 6 hours and delayed
      thrombolysis after onset of acute myocardial infarction].
AB  - OBJECTIVE: To explore the effect of different starting time of thrombolysis on
      acute myocardial infarction (AMI). METHODS: Ninety-five patients of AMI were
      divided into prompt thrombolysis group (less then 6 h, 46 patients) and delayed
      thrombolysis group (6-12 hours, 49 patients), according to the different starting
      time of treating AMI. The incidences of reopening and side-effect, as well as
      mortality were compared between two groups. RESULTS: The reopening rate and
      mortality in prompt thrombolysis group were 76% and 4%, respectively. The
      reopening rate and mortality in delayed thrombolysis group were 49% and 12%,
      respectively. Compared the prompt thrombolysis group with the delayed
      thrombolysis group, there was a significance discrepancy (both P<0.01). The side
      effect rate had not significant discrepancy (15% vs. 16%, P>0.05). CONCLUSION:
      The clinical reopening rate of the thrombolysis is higher in patients with
      thrombolysis less than 6 hours, the mortality is lower. The thrombolytic
      treatment should be prompt for patients adapting thrombolysis.

PMID- 15009961
TI  - [Study on changes of neuron apoptosis after focal cerebral ischemia/reperfusion
      in the aged rats].
AB  - OBJECTIVE: To study ultrastructured change and neuron apoptosis after focal
      cerebral ischemia/reperfusion (I/R) in the aged rats. METHODS: The aged SD rats
      (20-21 months) and the young (4-5 months) were subjected to 3 hours of middle
      cerebral artery occulsion with the intraluminal filament technique, followed by
      reperfusion for 3 hours, 6 hours, 12 hours, 24 hours, 72 hours. The
      ultrastructure of brain, infarct zone and neuron apoptosis were observed.
      RESULTS: The cerebral infarct zone increased in the aged rats with ischemia for 3
      hours and I/R for 12 hours compared with those in the young. The brain injury was
      obviously deteriorated with I/R time longer, which was serious in the aged than
      that in the young. The neuron apoptosis increase with I/R time longer, and showed
      earlier and lasted longer in the aged. CONCLUSION: The cerebral injury is serious
      and neuron apoptosis increase shows early and lasts longer.

PMID- 15009964
TI  - [Effects of adenosine preconditioning on cardiac myocyte apoptosis and expression
      of nuclear factor-kappaB in ischemia/reperfusion rats].
AB  - OBJECTIVE: To investigate the effect of adenosine preconditioning on cardiac
      myocyte apoptosis and the expression of nuclear factor-kappaB (NF-kappaB)during
      myocardial ischemia/reperfusion (I/R) in rats. METHODS: A model of I/R injury
      (I/R group) and pretreatment with adenosine (AP group) was reproduced in rats.
      The morphologic features of apoptosis were identified histochemically by TdT
      mediated dUTP nick end (TUNEL) staining. Expression of NF-kappaB in apoptosis
      myocardiac cells was observed by immunohistochemical stain and image analysis.
      RESULTS: The percentage of cardiac myocyte apptosis and the expression of NF
      kappaB in AP group were (2635.0+/-316.0)% and (33.21+/-16.91)%, they were
      significantly lower than those in I/R group (5013.0+/-503.7) % and (59.30+/
      10.36) % respectively  (P<0.05 or P<0.01), but higher than those in control group
      (68.7+/-50.3) % and (10.98+/-4.65)% respectively (both P<0.01). CONCLUSION:
      Adenosine preconditioning can pretect from myocardial I/R injury and relieve
      cardiac myocyte apoptosis and expression of NF-kappaB.

PMID- 15009965
TI  - [Relationship between polymorphisms of cystathionine beta-synthase gene and
      stroke].
AB  - OBJECTIVE: To determine whether the T27796C mutation in cystathionine beta
      synthase (CBS) gene is associated with stroke in Chinese. METHODS: The T27796C
      mutation in CBS gene of 59 cases with stroke and 65 health controls were detected
      by polymerase chain reaction-restriction fragment length polymorphisms (PCR
      RFLP). RESULTS: As this investigation shown, the frequencies of two alleles of
      T27796C mutation were followed: C was 56.8%, T was 43.2% in cases and C was
      51.5%, T was 48.5% in controls. T27796C mutation had no obvious relativity to the
      stroke (P>0.05). There was no significant difference in frequency of alleles of
      this mutation between cases and controls (CC: 35.6% vs. 24.6%; CT: 42.4% vs.
      53.8%; TT: 22.0% vs. 21.5%; all P>0.05). There was not obvious difference in
      frequency of alleles of this mutation between hemorrhagic patients and ischemic
      stroke patients (all P>0.05). CONCLUSION: T27796C mutation in CBS is not
      obviously correlated with stroke and this mutation is not associated with
      categories of stroke.

PMID- 15009967
TI  - [Clinical significance of plasma free 15-F2t-isoprostane concentration during
      coronary artery bypasses graft surgery].
AB  - OBJECTIVE: To analyse retrospectively the variation of plasma 15-F2t-isoprostane
      concentration during cardiac surgery and the relation with early myocardial
      dysfunction following normothemic cardiac surgery. METHODS: Thirty patients
      scheduled for coronary artery bypass graft surgery using normothermic
      cardiopulmonary bypass (CPB) and warm intermittent blood, crystalloid
      cardioplegia were enrolled. Patients were divided into two groups treated with
      (group II) or without (group I) positive inotropic drugs. Central venous blood
      was sampled at baseline, 30 minutes after global myocardial ischemia, 10, 30 and
      120 minutes after aortic declamping (reperfusion). Plasma free 15-F2t-isoprostane
      was measured with enzyme immunoassay (EIA) using a highly specific rabbit 15-F2t
      isoprostane antibody. Cardiac index (CI) was monitored intraoperatively and up to
      6 hours following surgery. RESULTS: Plasma free 15-F2t-isoprostane increased
      significantly during ischemia, remained elevating at 10 minutes after reperfusion
      (P<0.05 vs. baseline) and began to decline at 30 minutes after reperfusion in the
      whole population. 15-F2t-isoprostane underwent exponential decay and returned to
      baseline at 30 minutes after reperfusion in group I that did not need any
      postoperative inotropic support. In contrast, 15-F2t-isoprostane further
      increased upon reperfusion and remained significantly higher than baseline at 30
      minutes after reperfusion (P<0.05) in group II that needed two or more inotropes
      to maintain CI greater than 2.2 L x min(-1) x m(-2). Postoperative CI was
      significantly inversely correlated with the percentage change in plasma free 15
      F2t-isoprostane concentration from 10 to 30 minutes after reperfusion (r=-0.95,
      P<0.01). CONCLUSION: It shows a close relationship between free plasma
      concentrations of 15-F2t-isoprostane and early postoperative cardiac function
      following coronary artery bypass graft surgery.

PMID- 15009968
TI  - [Study on the reperfusion rate of acute myocardial infarction affected by
      inspiring nitric oxide and resolving thrombus intravenously before admission].
AB  - OBJECTIVE: To observe the reperfusion rate of acute myocardial infarction (AMI)
      affected by inspiring nitric oxide (NO) and resolving thrombus through veins.
      METHODS: Sixty cases with AMI were randomly divided into test group (n=30) and
      control groups (n=30). Patients in test group were cured with NO (20+/-1)mg/L
      inspiration for 30 minutes at once before admission and urokinase (150x10(4) U)
      adding 0.9% sodium chloride intravenously injected within 30 minutes, while
      patients in control were treated with urokinase as the same method of the test
      group. RESULTS: The reperfusion and non-reperfusion patients were 25 and 5 cases
      in test group, and they were 19 and 11 cases in control group. The reperfusion
      rate of AMI in test group was significantly higher than that in control group
      83.3% vs. 63.3% (P<0.05). No peak periods of lactate dehydrogenase (LDH) and
      creatine phosphokinase (CPK) appeared in test group, and the difference was
      significant compared to the control group (P<0.05). CONCLUSION: NO inspiration
      before urokinase is an effective method to treat AMI and advance the reperfusion
      rate.

PMID- 15009970
TI  - [Evaluation of operation and anesthesia on hemodynamic variables in patients
      undergoing elective abdominal surgery by noninvasive thoracic bioimpedance
      technique].
AB  - OBJECTIVE: To analyse and discuss the effects of elective abdominal operation and
      anaesthesia on patients' cardiac output via noninvasive thoracic bioimpedance
      technique. METHODS: Noninvasive monitoring system HeMo-601 was applied to detect
      the hemodynamic variables of 32 elective abdominal surgery patients. The clinical
      data of cardiac output (CO), cardiac index (CI), cardiac working per minute (CW),
      left ventricular end-diastolic pressure (LVEDP), stroke volume (SV), cardiac
      stroke working (SW) and heart rate (HR) were analysed at 1 hour before operation,
      4-6 hours after operation and 24 hours after operation, respectively. RESULTS: No
      significant differences were found in CO, CI, CW and LVEDP between various time
      points and preoperation (all P>0.05). SV and SW at 4-6 hours after operation were
      significant lower than those before operation (all P<0.05). Whereas, SV and SW at
      24 hours after operation were no significant differences compared with those
      before operation (all P>0.05). As compared with preoperation, HR at 4-6 hours
      after operation was significantly faster (P<0.05). However, there was no
      significant difference in HR between 24 hours after operation and preoperation
      (P>0.05). CONCLUSION: The reductions in SV and SW at 4-6 hours after operation
      might be a result of anaesthesia that could weaken the contraction of heart. The
      presence of rapidness of HR at 4-6 hours after operation might be a compensatory
      mechanism for the decreases in SV and SW. Therefore, optimizing adequate infusion
      by the greatest extent during and after operation is very crucial for the
      maintenance of CO, CI and tissue perfusion.

PMID- 15009971
TI  - [Changes of blood-cerebrospinal fluid barrier in rabbits with diabetic
      ketoacidosis].
AB  - OBJECTIVE: To explore the mechanism of the changes of blood-cerebrospinal fluid
      barrier in rabbits with diabetic ketoacidosis (DKA). METHODS: The New Zealand
      rabbits were injected with 150 mg/kg streptozotion and alloxan monohydrate each
      (model group, n=6) intravenously, or equal volume of normal saline (control
      group, n=6). After 72 hours, blood sugar and uric ketone were detected. All of
      animals were injected with Evans blue (EB). After 6 hours, arterial blood gases
      were measured and animals were killed. Absorbency of EB of brain tissue was
      detected. All brains of animals were examined with light and electron microscopy.
      Marker of blood-cerebrospinal fluid barrier, cytochemical stains of alkaline
      phosphatase (ALPase) was operated by ultrastructure. The inducible nitric oxide
      synthase (iNOS) in brain tissue was detected by immunohistochemical method.
      RESULTS: The models of DKA were established after 72 hours of injecting
      streptozotion and alloxan monohydrate. Absorbency of EB of model group rabbits
      was slightly increased, but had no significant difference compared with controls
      (P>0.05). The brain edema, damages of vessel endothelium and necrosis of neuron
      were observed through histological and ultrastructure examination in model group.
      ALPase activity of model group was evidently decreased in brain blood vessel
      endothelium in comparison with controls. Compared to controls, the iNOS activity
      of model group was increased and its positive cells were aggregated on blood
      vessel of brain membrane. CONCLUSION: By streptozotion and alloxan monohydrate
      inducing DKA models, NO could induce blood-cerebrospinal fluid barrier damages
      and result in brain edema.

PMID- 15009972
TI  - [Study on the clinical value of serum cardiac troponin T in early diagnosing of
      acute non-Q-wave myocardial infarction and prognostic evaluation].
AB  - OBJECTIVE: To investigate the value of serum cardiac troponin T (cTnT) in
      diagnosing earlier acute non-Q-wave myocardial infarction (NQMI) and judging the
      prognosis. METHODS: Seventy-four NQMI patients and 118 Q-wave myocardial
      infarction (QMI) patients were studied. Serum cTnT and MB isoenzyme of creatine
      kinase (CK-MB) levels were monitored on fixed time. On the 15th day of
      hospitalization, 99 mTc-MIBI myocardial single photon emission computed
      tomography (SPECT) was performed to assess the infarct size index. Clinical
      informations of the two groups such as cardiac dysfunction, re-infarction, fatal
      cadiac arrhythmia, sudden death were collected. RESULTS: The time for serum cTnT
      beginning to rise was earlier than CK-MB. Its peak time value was paralled to
      that of CK-MB, and cTnT elevation lasted longer than CK-MB. Serum cTnT and CK-MB
      peak value showed positive correlation with the infarct size index (both P<0.01).
      The peak values of cTnT and CK-MB in NQMI group were lower than those in QMI
      group, and the infarct size was smaller than QMI group (all P<0.05). The
      frequencies of cardiac events were significantly raised in both groups when there
      was a high level of serum cTnT. But the proportion in NQMI group was less than
      those in QMI group (P<0.05). The cardiac events in NQMI group were less than that
      in QMI group (P<0.05). CONCLUSION: Serum cTnT is an effective marker for
      diagnosing earlier NQMI, detecting myocardial damage, estimating infarct size and
      prognosis in the nearly future.

PMID- 15009980
TI  - [Surgical treatment for double outlet of the right ventricle].
AB  - OBJECTIVE: To summarize the experience and results of surgical treatment for
      double outlet of the right ventricle (DORV). METHODS: From May 1985 to December
      2001, 41 patients with DORV with age ranging from 10 months to 21 (mean age 10 +/
      6) years underwent surgical treatment. There were 26 male and 15 female
      patients. 14 patients underwent the classical Rastelli procedure (an
      intraventricular tunnel and a extra cardiac conduit repair); intraventricular
      tunnel and relive right ventricle outflow tract directly with and with out
      pericardial patch in 11; and modified Rastelli procedure in 11; total
      cavopulmonary connection (TCPC) in 2; Bidirection cavopulmnary connection in 2;
      Arterial switch operation in 1. All patients underwent the procedure by
      cardiopulmonary bypass. RESULTS: There were 1 early death, 40 patients were
      discharged without any complication. Thirty-six patients were followed up from 5
      months to 17 years. Reoperation in 3, because of residual ventricular septal
      defect in 1 and left ventricle outflow tract stenosis in 2. All patients were
      asymptomatic and did well in ordinary life. The cardiac function were in NYHA
      class I in 34 and class II in 2. The outcome was satisfactory. CONCLUSIONS:
      Biventricular repair can be achieved in most patients with DORV with satisfactory
      early and late results, and the late survival was exciting. In complex DORV, a
      right heart bypass procedure is related to a lower surgical mortality.

PMID- 15009981
TI  - [A study of correlation between early postoperative relapse with lymph node
      micrometastasis in patients with N0 esophageal cancer].
AB  - OBJECTIVE: To explore the correlation between early postoperative tumor relapse
      with lymph node micrometastasis in the patients with pN(0) esophageal cancer.
      METHODS: Using reverse transcriptase-polymerase chain reaction (RT-PCR), one
      hundred and sixty-six regional lymph nodes obtained from forty-three patients
      with esophagus cancer without invasion of the tumor confirmed by histopathologic
      analysis (pN(0)) were studied for further detecting mRNA of Mucin1 (MUC1) gene
      and determining nodal micrometastasis. All the patients underwent radical
      resection and regional lymph node dissection. Patients were followed up for one
      year to detect early tumor relapse. Difference in relapse was compared by chi(2)
      test. RESULTS: MUC1 mRNA expression was identified for twenty-six lymph nodes
      (15.7%), in eighteen patients (42%) who were diagnosed as having nodal
      micrometastasis. TNM staging for these patients was up-regulated from stages I
      II(A) to stages II(B)-III. Relapse disease was found in nine patients with lymph
      nodes micrometastasis and three patients without nodal micrometastasis (P <
      0.05). CONCLUSION: Early tumor relapse after radical surgery in the patients with
      pN(0) esophageal cancer might be correlated with nodal micrometastasis.

PMID- 15009983
TI  - [Surgical treatment of apical chest tumor in 27 patients].
AB  - OBJECTIVE: To explore the "hemi-clamshell" approach to the resection of the
      apical chest tumors, and to evaluate its advantages of operative safety and
      completeness. METHODS: We conducted a retrospective review of the records of 27
      patients undergoing resection of the primary apical chest tumors from January
      1995 to January 2001. Tumor type included NSCLC, sarcoma, neurofibromatosis,
      esophageal carcinoma. Data collected included clinical presentation, tumor type
      and involvement, type of resection, complication, and survival. RESULTS: A
      clinical operation for gross-total resection of tumors and invaded structures was
      performed on six patients by means of a successful anterior approach. Among other
      21 patients on whom a clinical operation was performed by posterior approach,
      only 13 patients obtained gross-total resection. There were significant
      difference between the two groups (P < 0.01). The mean duration for follow-up was
      29 months, and the overall median survival was 21 months. Median survival in
      patients undergoing gross-total resection was 29 months, and this is
      significantly better than in incomplete resection group (P < 0.01). CONCLUSIONS:
      The anterior "hemi-clamshell" approach is a successful technique for the exposure
      and resection of these tumors and invaded structures. Release of symptoms and
      long-term survival is acceptable if complete resection can be performed.

PMID- 15009984
TI  - [Infection after cardiac transplantation: prevention and management].
AB  - OBJECTIVE: To explore and sum up the characteristics of infection after cardiac
      transplantation and to discuss the prophylaxis and management. METHOD: From May
      2000 to April 2003, 36 patients received orthotopic heart transplantation, the
      clinical data were observed and analyzed. RESULTS: Infection occurred in 2 (6%)
      cases, both belonged to lung infection caused by human cytomegalovirus. The 2
      cases were cured by ganciclovir intravenously. CONCLUSION: Good prophylactic
      method may decrease post cardiac transplantation infection significantly. It is
      very important to early diagnose and treat infection.

PMID- 15009985
TI  - [The effect of anterior spinal release on severe adolescent idiopathic
      scoliosis].
AB  - OBJECTIVE: To explore the effect of anterior spinal release on severe scoliosis.
      METHODS: Twenty-six cases of severe scoliosis were retrospectively reviewed from
      January 1998 to December 2001. There were 7 males and 19 females with an average
      age of 15 years (ranging from 10 to 21 years). Twenty-four cases were classified
      according to King classification for adolescent idiopathic scoliosis, including
      King type I 4 cases, type II 9 cases, type III 5 cases, King IV 4 cases, King V 2
      cases; another two cases were thoracolumbar curve. The major curves were averaged
      respectively 89.8 degrees, 66.5 degrees, 67.7 degrees, 61.2 degrees on standing,
      traction, bending and fulcrum film before operation. The distance of apex
      vertebrae deviated from sacral midline was 39.7 mm before operation. RESULTS: Six
      cases received anterior spinal release with posterior correction by one stage, 20
      cases by two stages. The cases with two stage operation increased the spinal
      flexibility about 17.8 degrees after anterior release. The major curve was 52.6
      degrees on average, and the distance of apex vertebrae deviated from sacral
      midline was 9.9 mm after operation. The major curve was 54.9 degrees on average,
      loss the correction 6.4% during follow-up. There was no complication related to
      the operation in this group. CONCLUSIONS: The anterior spinal release alone has
      little effect on severe scoliosis with flexibility less than 20% preoperation.
      The curve can be corrected to a great degree by anterior osteotomy for spine.

PMID- 15009986
TI  - [Surgical treatment of shotgun injuries of the sciatic nerve].
AB  - OBJECTIVE: To explore the clinical characteristics and the effect of surgical
      therapy for shotgun injuries of the sciatic nerve. METHODS: From 1996 to 2000, 19
      sciatic nerve injuries resulted from shotgun were observed. Among 19 cases of
      shotgun sciatic nerve wounds, the gluteal wound was in 2 cases, thigh wound in 15
      cases, and knee wound in 2 cases. The firing distance was between 0.5-9 m.
      According to Shermen classification of shotgun injury, 4 cases belonged to type I
      injury, 11 cases type II, 4 cases type III. The time from injury to admission was
      between 2 months-14 months except 1 patient who underwent emergency operation 4
      hours after injury, and 1 patient was treated with debridement and epineurial
      neurorrhaphy, 7 cases with nerve trunk grafting, 6 cases with nerve cable
      grafting, 4 cases with neurolysis, 1 case with arthrodesis of ankle. RESULTS:
      Nineteen cases were followed-up for 0.8-3.5 years (mean, 19 months). The
      excellent and good nerve functional recovery was found in 52.6% according to
      MCRR. CONCLUSIONS: Shotgun injuries of the sciatic nerve are very severe and
      complicated, and injuries in most patients were usually complicated by open
      fracture, vascular injury, soft-tissue loss and infection; the character of nerve
      injury was classified as 4-5 degree according to Sunderland Standard, nerve
      transfer is effective in the treatment of shotgun injuries of the sciatic nerve,
      but outcome is poor; the recovery of the sciatic nerve should be observed
      continually after injury; selecting correct initial treatment after injury,
      strict minimally invasive surgical procedure, physical therapy and reasonable
      preoperative and postoperative medication can improve the surgical results.

PMID- 15009987
TI  - [Cell membrane phospholipid variation and protein kinase C expression effects on
      hepatic metastasis of large intestinal carcinoma].
AB  - OBJECTIVE: To study cell membrane phospholipid variation and protein kinase C
      (PKC) isoenzyme expression and their effects on hepatic metastasis of large
      intestinal carcinoma. METHODS: High function liquid chromatography was used to
      separate and detect cell membrane phospholipids of phosphatidylinosital (PI),
      phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine
      (PC) in primary foci, paratumor intestine mucosa and hepatic metastasis of large
      intestinal carcinomas. And mRNA expression levels of PKC-alpha, -beta II, -delta,
      -epsilon, -lambda, -zeta isoenzymes were detected using QRT-PCR technique.
      RESULTS: Fifty-eight cases of colorectal cancer were examined. CONTENTS: of PI,
      PC and PE in primary foci and hepatic metastasis were higher than those in
      paratumor mucosa. PE content in hepatic metastasis was much higher than that in
      primary foci (t = 98.88, P < 0.01). But PI and PC contents had no significant
      differences between primary and hepatic metastasis (t = 1.73, 1.36, P > 0.05).
      PKC-beta II, -delta, -epsilon, -lambda, -zeta expression were enhanced in primary
      foci and hepatic metastasis, but PKC-alpha level decreased in comparison with
      paratumor mucosa. And PKC-delta, -epsilon, -lambda, -zeta levels in hepatic
      metastasis were higher than those in primary foci (t = 4.31, P < 0.05). PI and PC
      had positive correlations with PKC-beta II expression. PE had positive
      correlations with PKC-delta, -epsilon, -lambda, -zeta, but a negative correlation
      with PKC-alpha. CONCLUSIONS: The increases of PI and PC and PKC-alpha/PKC-beta II
      ratio change are related with colorectal cancer genesis. High content of PE and
      enhanced expression of PKC-delta, -epsilon, -lambda, -zeta isoenzymes and
      decreased PKC-alpha level improved hepatic metastasis of large intestinal
      carcinoma.

PMID- 15009988
TI  - [In situ nucleic acid detection of HBV X gene in extrahepatic biliary tract
      carcinomas and its clinicopathological significance].
AB  - OBJECTIVE: To detect the expression of HBV X gene (HBx mRNA) in extrahepatic
      biliary tract carcinomas and the adjacent non-cancerous tissues, and to analyzed
      the relationship between HBV infection and incidence of biliary tract carcinomas,
      thereby to elucidate the possible role of HBx in the carcinogenesis of biliary
      tract. METHODS: The plasmid pSPX46 was digested by appropriate restriction
      enzyme. HBx fragment was obtained through gel extraction kit. The digoxigenin
      labeled DNA probes for HBx mRNA were prepared by a random prime technique. The
      expression of HBx mRNA was detected in formalin-fixed- paraffin-embedded
      specimens from 71 cases of biliary tract carcinomas and 39 specimens of non
      cancerous tissues adjacent to cancer by in situ hybridization. The correlations
      between HBx mRNA expression and clinicopathological parameters were statistically
      analysed in 71 cases of biliary duct carcinomas. RESULTS: Forty-three of 71
      malignant specimens had detectable HBx mRNA expression with a positive rate being
      61%. Only 7 of 39 specimens of non-cancerous tissues adjacent to cancer had weak
      HBx mRNA expression, with a positive rate being 18%, and all these positive
      signals were found in the hyperplastic biliary epithelium. No significant
      correlation was found between HBx mRNA expression and clinicopathological
      parameters, but a strong positive correlation was found between HBx mRNA and
      protein expression. CONCLUSION: There is a high frequency of HBx mRNA expression
      in extrahepatic biliary tract carcinomas. HBV infection and its gene integration
      might play a role to certain extent in the development of biliary tract
      carcinomas.

PMID- 15009989
TI  - [Ureteroscopic holmium: YAG laser lithotripsy for managing urinary tract
      calculi].
AB  - OBJECTIVE: To evaluate the effectiveness and safety of ureteroscopic holmium: YAG
      laser lithotripsy for managing ureteral calculi. METHODS: Ureteroscopic holmium:
      YAG laser lithotripsy was used in 168 ureteral calculi (proximal 27 cases, middle
      33 cases, distal 108 cases). Transurethral cystoscopic holmium: YAG laser
      lithotripsy in 12 bladder calculi. RESULTS: Four to six weeks after operation,
      The stone-free rate was 93% (25/27) in the proximal ureteral calculi, 94% (31/33)
      in the middle ureteral calculi, 94% (102/108) in the distal ureteral calculi,
      respectively. The complication rate was 5% (8 cases). the stone-free rate of
      bladder calculi was 100% (12/12), no complication. CONCLUSION: Ureteroscopic
      holmium: YAG laser lithotripsy is a highly effective and safe treatment modality
      for managing ureteral calculi.

PMID- 15009991
TI  - [Adrenal incidentalomas: report of 126 cases].
AB  - OBJECTIVE: To evaluate the diagnosis and treatment of adrenal incidentalomas.
      METHODS: One hundred and twenty-six patients were analyzed, in which 98 patients
      underwent operation. RESULTS: Of all types of the adrenal incidentalomas, 52
      (41.3%) of them were adenomas and they were the most often; 43 (34.1%) of them
      were hypersecretory adrenal tumors, most of them were pheochromocytomas and Conn
      adenomas; all nonhypersecretory adrenal adenomas were under 6 cm, and all adrenal
      carcinomas were above 6 cm. CONCLUSIONS: It is important to search for
      hypersecretory adrenal tumors and to detect malignant adrenal tumors. To
      nonhypersecretory adrenal adenomas, the sizes of tumors are the most important
      indexes in determining weather the tumors are benign or malignant and weather the
      tumors need to be treated with operation or not.

PMID- 15009990
TI  - [Study of three-dimensional reconstruction of digitized virtual hepatic images].
AB  - OBJECTIVE: To study the methods of three-dimensional reconstruction of digitized
      virtual hepatic. METHODS: Images of DSCF 2511-2520 were taken from the database
      of digitized Virtual Chinese Human female No. 1 (VCH-F1). Method of insertion
      value algorithm of three-dimensional reconstruction was used to make three
      dimensional block diagram. In ordering to auto-judge the position of hepatic
      solid and hepatic ducts, these images were shown with different colors according
      to the character of color and location of every spot. RESULTS: Stereo image of
      hepatic solid could be shown satisfactorily. Every shape of stereo image and the
      structure of hepatic duct could be shown by revolving the three-dimensional image
      with different direction. CONCLUSIONS: The image of hepatic database of digitized
      Virtual Chinese female No. 1 was exact. The three-dimensional image of the liver
      and hepatic duct made by insertion value algorithm of three-dimensional
      reconstruction were distinct, and it was a ideal method of three-dimensional
      reconstruction.

PMID- 15009992
TI  - [Experimental investigation of non-heart-beating donor in the rat lung
      transplantation].
AB  - OBJECTIVE: To explore the impact of different warm ischemia time on structure and
      function of the non-heart-beating donor lung and to find out the feasibility of
      non-heart-beating donor in rat lung transplantation. METHODS: Sixty Sprague
      Dawley rats were randomly divided into 3 groups: heart-beating donor (HBD) group,
      non-heart-beating donor (NHBD) with 30 minutes of warm ischemia time (WIT) group
      and NHBD with 60 minutes of WIT group. Each group has 10 pairs (the donors and
      the recipients). The donor lungs of group HBD were flushed with low potassium
      dextran (LPD) solution at 4 degrees C after asystolia while the lungs of group
      NHBD-30 and group NHBD-60 remained ventilated at the room temperature for 30 and
      60 minutes after asystolia and then were flushed with LPD solution. All the donor
      lungs remained inflated when they were stored in LPD solution at 4 degrees C for
      4 hours. The recipient rat underwent left thoracotomy, and then orthotopic left
      lung transplantation. Followed by a right thoracotomy, the right pulmonary hilum
      were ligated with one-hour reperfusion and ventilation. RESULTS: All the
      recipients in group HBD and group NHBD-30 survived the observation period of one
      hour with excellent gas exchange, whereas 4 of recipients in group NHBD-60
      survived for 10 minutes after the ligation of right pulmonary hilum and 3 for 20
      minutes. The pulmonary compliance, ultrastructure, energy metabolite and other
      markers revealed no significant differences between group HBD and group NHBD-30
      (P > 0.05). But the differences between group NHBD-60 and other two groups were
      significant (P < 0.05). CONCLUSIONS: The adoption of non-heart-beating donor
      could be a safe and effective method to expand the lung donor pool. The NHBD lung
      with 30 minutes of WIT may be suitable for lung transplantation in rat.

PMID- 15009993
TI  - [HBx gene facilitates the proliferation activity of hepatoma cells in vitro and
      in vivo].
AB  - OBJECTIVE: To investigate the effects of HBx gene on proliferation activity of
      hepatoma cells in vitro and in vivo. METHODS: The plasmid pHA-HBx carrying HBx
      gene was transfected into HepG(2) cells, and the positive clones were screened
      and identified with G418 and RT-PCR, respectively. The growth curve and
      population doubling time were calculated, and the cell cycle was analyzed by flow
      cytometry (FCM). The proliferation activity of transformed cells was measured
      with (3)H-TdR incorporation rate and nude mice model in vitro and in vivo.
      RESULTS: The result of RT-PCR indicated that HBx gene was integrated into the
      genome DNA of HepG(2) cells and transcripted. The growth curve and population
      doubling time showed a high proliferation activity of transformed cells. The
      amount of cells at stage S and G(2)/M were significantly higher, and cells at
      stage G(0)/G(1) were lower than those in control group. The tumors developed from
      transfected cells grew much quicker than those developed from HepG(2) cells in
      nude mice model. CONCLUSION: HBx gene can facilitate the proliferation of
      hepatoma cells both in vitro and in vivo.

PMID- 15009994
TI  - [The experimental study of histomorphology and biomechanical of cortical strut
      allograft in proximal femoral].
AB  - OBJECTIVE: To explore the deep-frozen allograft strut in the rabbits for the sake
      of finding some evidence to support the clinical practice of cortical strut
      allograft. METHODS: Fifty deep-frozen allograft struts were implanted on the
      lateral side of the femur in 50 male New Zealand white rabbits. These rabbits
      were randomly divided into 5 groups. The specimen were retrieved at 2, 4, 8, 16,
      24 weeks after surgeries. In each group histomorphology and biomechanic
      properties were studied. RESULTS: From the X ray photography the edge of the
      strut would turn blunt at the 4th week, union could be found at the 8th week, the
      inner side of the strut could be absorbed at the 24th week. In the early stage
      when the strut was implanted in the rabbit, the capillary would be found to grow
      into the cortical strut from the interior side of it. Then the capillaries were
      found to converge at the 16th week. This phenomenon is correspondent with the
      resorption of the dead bone and formation of the new bone. There are few
      neoformated capillaries on the lateral side of the strut. From the decalcificied
      section, allograft struts were found to unit to the host at 4 to 8th week.
      Osteoclast and the new bone formation could be seen at the 8th week, and 3% of
      the total area of what had been the allograft was replaced by the new bone at
      that time, 12% was replaced at the 16th week, 21% at the 24th week. There are few
      resorption or neoformated bone at the lateral side of the strut. The
      biomechanical property indicated that the strength of the strut decreased at the
      early time, and only 38% of its original strength remained at 16 weeks.
      CONCLUSIONS: The cortical allograft strut can unit to the host by the callus. The
      capillaries invading into the allograft from the interior side, new bone is
      formed from the interior side. The biomechanical strength of the strut decreased
      at early stage.

PMID- 15009995
TI  - [Preliminary study on in vitro tendon engineering using tenocytes and
      polyglycolic acids].
AB  - OBJECTIVE: To find out the feasibility of tendon engineering in vitro using
      expanded tenocytes and polyglycolic acids (PGA). METHODS: Tenocytes were isolated
      using tissue explant method and expanded in vitro. Tenocytes (20 x 10(6)) at the
      second passage were collected and then seeded onto PGA unwoven fibers to form a
      cell-scaffold construct in a shape of tendon. The constructs were cultured in
      DMEM with 20% FBS for 1 week. The cell-scaffold constructs were then cultured
      under constant tension generated by a U-shaped spring (n = 5), which served as
      experimental group, or cultured without tension (n = 4), which served as control
      group 1. PGA fibers alone were cultured (n = 3), which served as control group 2.
      Small fragments at the end of the constructs were harvested at 2, 4 and 6 weeks
      respectively for histological and immunohistochemistry (IHC) analysis. Six-week
      samples were also evaluated by transmission electron microscope (TEM) and
      mechanical test. RESULTS: No obvious difference was observed among the three
      groups at 2 weeks grossly and histologically as the constructs remained to be
      mainly undegraded PGA fibers. By 4 weeks, a neo-tendon was formed in the
      experimental group and control group 1 grossly, and histology and IHC revealed
      the formation of collagen fibers. In contrast, PGA fibers alone in control group
      2 were mostly degraded. At 6 weeks, tendons of control group 1 were much thicker
      [(2.55 +/- 0.18) mm in diameter] than those of experimental group [(1.44 +/-
      0.13) mm in diameter]. Periodical striae were observed in collagen fibers of
      experimental group and control group 1 by TEM. However, histology of tendons in
      experimental group revealed longitudinally aliened collagen fibers, which
      resembled the structure of normal tendon more closely than that of control group
      1 tendons. Furthermore, the maximum tensile stress (N/mm(2)) of experimental
      group (1.107 +/- 0.327) was greater than that of control group 1 (0.294 +/-
      0.138) (P < 0.05). CONCLUSION: It is possible to use an engineering to construct
      tendon tissue in vitro. Periodical strain generated by bioreactor may be the
      optimal mechanical stimulation, which is currently under investigation.

PMID- 15010007
TI  - Number needed to treat to gain one controlled hypertensive.

PMID- 15010008
TI  - Causes for hyperinsulinemia in obesity.

PMID- 15010009
TI  - Nitric oxide, oxidative excess, and vascular complications of diabetes mellitus.
AB  - The prevalence of diabetes mellitus is rising worldwide and has reached epidemic
      dimensions. Diabetes mellitus places patients at high cardiovascular risk. High
      blood glucose levels, altered insulin signaling, reactive oxygen species (ROS),
      inflammation, and protein kinase C activation might lead to a decrease in nitric
      oxide (NO) bioavailability. Diminished NO and enhanced oxidative stress play a
      central role in several pathophysiologic pathways, leading to vascular damage,
      such as endothelial dysfunction, vascular inflammation, atherosclerotic plaque
      formation and vulnerability, and promotion of a prothrombotic state. Possible
      sources of oxidative excess in diabetes are reduced nicotinamide adenine
      dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, uncoupled NO synthase,
      and the mitochondria. Advances in understanding the pathophysiologic mechanisms
      leading to vascular damage in diabetes will result in discovery of new
      therapeutic targets, which should help reduce cardiovascular risk in these
      patients.

PMID- 15010010
TI  - Hypertension in diabetes: the role of the vasculature.
AB  - This review is focused on the interplay between two major factors affecting the
      vascular tree in diabetes, insulin resistance, and hyperglycemia. The
      implications for vascular function, structure, and the interaction between
      vascular cells and other tissues by which they are affected under these
      conditions are reviewed.

PMID- 15010011
TI  - The tissue renin-angiotensin-aldosterone system in diabetes mellitus.
AB  - Diabetes is associated with an inordinate burden of cardiovascular and renal
      disease, which is expected to accelerate during the next few decades. The
      relationship between the renin-angiotensin system (RAS) and diabetic
      macrovascular and microvascular disease is well established. The contribution of
      the tissue RAS in disease pathogenesis has recently been the focus of much
      interest, and has prompted investigators to explore the use of high-dose RAS
      inhibition with monotherapy or combination therapy to provide a more complete
      blockade of the actions of angiotensin II, beyond lowering blood pressure. There
      is now evidence to support this approach to maximize cardiovascular and renal
      protection. Optimal dosing strategies remain uncertain, but tissue specificity
      does not appear to be important if the doses of angiotensin-converting enzyme-I
      and angiotensin-receptor binders are high enough. The purpose of this review is
      to highlight our current understanding of the role of the tissue RAS in the
      pathogenesis of diabetic end-organ damage and ongoing strategies to interfere
      pharmacologically.

PMID- 15010012
TI  - Metabolic issues in the Antihypertensive and Lipid-Lowering Heart Attack Trial
      Study.
AB  - Based on the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
      Attack (ALLHAT) Trial, the Seventh Joint National Committee on Prevention,
      Detection, Evaluation and Treatment of High Blood Pressure (JNC-7) states that
      "thiazide-type diuretics should be used as initial therapy for most patients with
      hypertension." In the ALLHAT study, although there was no difference in the
      primary outcome for fatal heart attack and nonfatal myocardial infarction between
      all treatment groups, the manuscript endorses thiazide-type diuretics as first
      choice, based on their cardioprotective effects and low cost. It is well known
      that thiazide-type diuretics cause hypokalemia, glucose intolerance, and
      diabetes, although the ALLHAT study showed a significant 43% to 65% higher risk
      of new-onset diabetes with chlorthalidone compared with amlodipine (30%) and
      lisinopril (18%). The investigators justified the fact that the greater incidence
      of diabetes did not translate into more cardiovascular events. Such a conclusion
      ignores that the morbidity and mortality from diabetes manifests over decades and
      not the mere 2- to 6-year time frame examined in the ALLHAT study. It would
      appear that the strong endorsement of thiazide-type diuretics as first-line
      therapy by the JNC-7 will lead to a higher incidence of diabetes in these
      patients.

PMID- 15010013
TI  - Mineralocorticoid-receptor blockade in hypertensive patients during angiotensin
      converting enzyme inhibition: effects on left ventricular mass.

PMID- 15010014
TI  - Acute candesartan cilexetil therapy in stroke survivors.

PMID- 15010015
TI  - Vascular angiotensin II actions mediated by angiotensin II type 2 receptors.
AB  - Angiotensin II (Ang II) is the major effector peptide of the renin-angiotensin
      system and acts at two major receptors known as Ang II type 1 receptor (AT(1)R)
      and Ang II type 2 receptor (AT(2)R). Increasingly, there is evidence suggesting
      that the AT(2)R counter-regulates the excitatory effects of AT(1)R stimulation.
      In this review, we have focused on pharmacodynamic and trophic components of
      AT(2)R with respect to vascular function, and put the current status of vascular
      AT(2)R research in the context of a potential role for this ATR subtype in the
      therapeutic effects of AT(1)R antagonists.

PMID- 15010016
TI  - Newly recognized physiologic and pathophysiologic actions of the angiotensin
      converting enzyme.
AB  - Despite several decades of research into the renin-angiotensin system, new
      aspects of this endocrine system are elucidated every few years, expanding its
      role not only in hypertension but also in diabetes, oncology, and cardiology. In
      this review, we describe newly recognized physiologic actions of the angiotensin
      converting enzyme (ACE). These include the role of local versus systemic ACE in
      maintaining blood pressure, the physiology of bradykinin accumulation during ACE
      inactivation, and the role of alternate "non-angiotensin" substrates and
      potential non-enzymatic properties of ACE.

PMID- 15010017
TI  - Renin/prorenin-receptor biochemistry and functional significance.
AB  - The renin-angiotensin system (RAS) has become increasingly complex. New
      components have been identified, and additional roles for angiotensin peptides
      and their receptors are being uncovered. A functional (pro)renin receptor has
      been cloned that acts as (pro)renin cofactor on cell surface, enhancing the
      efficiency of angiotensinogen cleavage by (pro)renin and unmasking prorenin
      catalytic activity. Binding of (pro)renin to the receptor mediates (pro)renin
      cellular effects by activating mitogen-activating protein (MAP) kinases,
      extracellular signal-regulated kinases (ERK)1/2. Immunofluorescence studies have
      localized the receptor on mesangial and vascular smooth muscle cells in human
      heart and kidney. This suggests that the renin receptor might represent a means
      to capture (pro)renin from the circulation and to concentrate (pro)renin at the
      interface between smooth muscle and endothelial cells. In this article, we review
      the biochemical characteristics of this receptor and of other renin-binding
      proteins, and discuss their physiologic significance.

PMID- 15010019
TI  - Improved blood pressure control with nocturnal hemodialysis: review of clinical
      observations and physiologic mechanisms.
AB  - Nocturnal hemodialysis (NHD) involves nightly (5-6 sessions per week), long (8
      hour) home hemodialysis treatments. NHD therapy has recently attracted
      considerable attention owing to certain clear cardiovascular advantages with this
      method over conventional hemodialysis. In this article, we review the clinical
      reports of improved blood pressure control and normalization of left ventricular
      geometry associated with NHD therapy. Recent mechanistic studies exploring the
      reversal of the uremic hemodynamic state with NHD are also reviewed. The
      implication of these hemodynamic changes for the prospective renal transplant
      candidate are discussed.

PMID- 15010018
TI  - Nephron endowment and blood pressure: what do we really know?
AB  - It has been hypothesized that a reduced number of nephrons at birth contributes
      to the development of essential hypertension. Nephron number in normal human
      kidneys has been shown to vary up to eightfold. Therefore, a significant
      proportion of the population appears to be at risk for developing hypertension.
      Furthermore, nephron deficits might explain why some racial groups have a higher
      incidence of hypertension and end-stage renal disease than others. Animal studies
      have demonstrated that maternal limitations in nutrient supply, both gross and
      nutrient-specific; exposure to elevated levels of hormones or toxins; and genetic
      factors can lead to permanent deficits in nephron number and, when examined,
      elevated blood pressure. In this review, maternal and genetic factors influencing
      nephron endowment and the implications of nephron deficit for hypertension and
      renal disease in humans are discussed.

PMID- 15010020
TI  - Hypertensive renal damage: insights from animal models and clinical relevance.
AB  - Investigations using chronic blood pressure (BP) radiotelemetry in conscious
      animals have provided substantial insights into the pathophysiology of
      hypertensive renal damage. Normal renal autoregulation protects the renal
      microvasculature from significant injury in most patients with primary
      hypertension, unless BP exceeds a certain threshold, when malignant
      nephrosclerosis develops. However, if autoregulation is impaired, as in chronic
      renal disease and/or diabetes models, the threshold for renal damage is lowered
      and glomerulosclerosis (GS) increases linearly with increasing BP. Modest BP
      reductions are predicted to prevent malignant nephrosclerosis, but prevention of
      GS in patients with diabetes and chronic renal disease requires that BP be
      lowered well into the normotensive range, as recognized in the currently
      recommended BP goals. When BP load is accurately assessed in these experimental
      models, renal protection is proportional to the achieved BP reductions, and there
      is little evidence of BP-independent protection, even with agents that block the
      renin-angiotensin system (RAS). Recent clinical data also suggest that achieving
      lower BP targets might be vastly more important than the choice of therapeutic
      regimens. Nevertheless, because aggressive diuretic use is usually necessary to
      achieve such BP goals, RAS blockade should be included as initial therapy both
      for antihypertensive synergy and to minimize the potassium and magnesium
      depletion associated with diuretics.

PMID- 15010022
TI  - Recurrent Pyogenic Cholangitis.
AB  - Recurrent pyogenic cholangitis is a condition that most commonly affects patients
      of East Asian descent. It is characterized by recurrent bouts of cholangitis.
      Work-up with ultrasound, computed tomography, and more specifically magnetic
      resonance cholangiopancreatography and endoscopic retrograde
      cholangiopancreatography (ERCP), reveals areas of biliary dilatation and
      stricturing, most commonly affecting the left hepatic ducts. Initial treatment
      includes supportive medical therapy with intravenous fluids and electrolytes,
      correction of coagulopathy if present, and antibiotics. Once stabilized, patients
      should receive urgent biliary decompression. This may be achieved using ERCP or
      percutaneous transhepatic cholangiogram (PTC). ERCP is excellent at decompressing
      more distal obstruction, whereas PTC provides reliable drainage of peripherally
      obstructed bile ducts. If disease is anatomically limited, surgical resection
      with excision of the extrahepatic bile ducts and involved intrahepatic segments
      (usually left lobe) should be performed. Otherwise, repeated radiographic and
      endoscopic procedures will be necessary to treat recurrent cholangitis. Liver
      transplant may be an option for patients with diffuse disease.

PMID- 15010023
TI  - Prevention or Surgical Treatment of Gallstones in Patients Undergoing Gastric
      Bypass Surgery for Obesity.
AB  - It is well known that obesity is a risk for gallstone formation and biliary
      sludge. Additionally, it has been clearly shown that rapid weight loss following
      bariatric surgery is a risk factor for cholesterol cholelithiasis. Multiple
      serious complications from gallstones such as cholecystitis, cholangitis,
      gallstone pancreatitis, and cholecystenteric fistulae may occur. Thus, it is
      necessary to employ medical or surgical methods to prevent or treat gallstones in
      this group. Therapy should be individualized. Although there is a high incidence
      of gallstones in this group, only a minority of individuals will develop
      symptomatic disease. When used in patients who are compliant, ursodeoxycholic
      acid therapy can be effective to prevent gallstone formation during rapid weight
      loss. The cost effectiveness of routine ursodeoxycholic acid therapy compared
      with the potential costs of complicated gallstone disease needs to be further
      investigated. Combined cholecystectomy with Roux-en-Y gastric bypass surgery is a
      safe and appropriate therapeutic option in those with preoperatively known
      gallstones, biliary sludge, and prior episodes of cholecystitis. However, routine
      cholecystectomy at the time of gastric bypass surgery is not warranted for all
      patients because of the increased time of operation and postoperative
      hospitalization, as well as all the potential complications after
      cholecystectomy. The approach of routine cholecystectomy in this setting subjects
      many patients to an unnecessary procedure because the majority will not develop
      symptoms or complications of gallstones. Furthermore, cholecystectomy is
      technically easier to perform after weight loss occurs.

PMID- 15010021
TI  - Surveillance and Treatment of Periampullary and Duodenal Adenomas in Familial
      Adenomatous Polyposis.
AB  - Patients with familial adenomatous polyposis (FAP) have a cumulative lifetime
      risk of over 90% for developing duodenal adenomas, which are the precursor
      lesions for duodenal adenocarcinoma. Consequently, these patients have a 5% to
      10% lifetime risk of periampullary or duodenal adenocarcinoma, making this the
      leading cause of cancer death in FAP patients who have had prophylactic
      colectomies. The increased relative risk of duodenal carcinoma in FAP patients
      and the poor outcomes associated with the treatment of advanced duodenal cancer
      have led to the development of prevention strategies for this cancer in the
      setting of FAP. It is generally accepted that surveillance for duodenal adenomas
      and adenocarcinomas should be included in the management of patients with FAP,
      although there are few data from clinical trials that demonstrate the
      effectiveness of surveillance strategies or chemoprevention for the prevention of
      death from duodenal cancer. Prospective case series have shown that endoscopic
      surveillance with endoscopic or surgical treatment of high-risk lesions in the
      duodenal or periampullary region can be performed with successful removal of the
      at-risk lesion(s). Surveillance should begin at about 21 years of age and should
      be performed using both an end-viewing and a side-viewing upper endoscope. An
      interval of 3 to 5 years between examinations appears to be adequate if no
      polyposis is evident. Once polyposis develops, an interval of 1 to 3 years
      between screenings for mild polyposis is appropriate. Patients with denser
      polyposis or larger adenomas are recommended to undergo examination every 6 to 12
      months because of their increased risk of developing duodenal adenocarcinoma.
      Nonsteroidal anti-inflammatory drug therapy with sulindac, a nonselective
      cyclooxygenase (COX) inhibitor, or celecoxib, a COX-2 selective inhibitor, may be
      of benefit after the development of duodenal polyposis by inducing the regression
      or stabilization of the polyposis, although there is limited evidence from
      randomized, controlled trials to support its routine use. Almost all cases of
      adenocarcinoma occur in patients with advanced polyposis (Spigelman stage IV
      disease), and approximately 33% of this group will go on to develop
      adenocarcinoma if left untreated. The most definitive procedure for reducing the
      risk of adenocarcinoma is surgical resection of the ampulla and/or duodenum.
      Pancreaticoduodenectomy or pancreas-sparing duodenectomy are appropriate surgical
      therapies that are believed to substantially reduce the risk of developing
      periampullary adenocarcinoma. However, these procedures are associated with
      significant morbidity and mortality, including the risk of inducing desmoid tumor
      formation in FAP patients.

PMID- 15010024
TI  - Biliary Sludge: When Should It Not be Ignored?
AB  - Biliary sludge is usually seen on transabdominal sonography as low-level echoes
      that layer in the dependent portion of the gallbladder without acoustic
      shadowing. Synonyms for biliary sludge include microlithiasis, biliary sand or
      sediment, pseudolithiasis, and microcrystalline disease. In most patients,
      biliary sludge is composed of calcium bilirubinate and cholesterol monohydrate
      crystals. A variety of predisposing factors are associated with biliary sludge
      formation. In most of these patients, removal of the risk factor can lead to
      resolution of sludge. In asymptomatic patients, biliary sludge can be managed
      expectantly. In patients who develop biliary-type pain, cholecystitis,
      cholangitis, or pancreatitis, the treatment of choice is cholecystectomy for
      those who can tolerate surgery. In patients who are not operative candidates,
      endoscopic sphincterotomy can prevent further episodes of cholangitis and
      pancreatitis, whereas medical therapy with ursodeoxycholic acid can prevent
      sludge formation and recurrent acute pancreatitis.

PMID- 15010025
TI  - AIDS Cholangiopathy.
AB  - AIDS is an advanced disease with systemic and infectious complications that can
      be fatal. When a patient with AIDS presents with right upper quadrant or
      midepigastric pain, cholestasis, and symptoms of cholangitis, AIDS cholangiopathy
      should be suspected and appropriate diagnostic and therapeutic interventions
      should be initiated. Opportunistic infections such as Cryptosporidium and
      cytomegalovirus are the most common cause of AIDS cholangiopathy. Four distinct
      cholangiographic abnormalities have been demonstrated by endoscopic retrograde
      cholangiopancreatography, the most common being papillary stenosis with
      sclerosing cholangitis. Antimicrobial therapy is often ineffective. Highly active
      antiretroviral therapy may enhance immune function and offers the best medical
      therapy to clear the opportunistic infections. Ursodeoxycholic acid has a limited
      benefit in patients with sclerosing cholangitis and cholestasis. Endoscopic
      sphincterotomy has been shown to relieve pain and biliary obstruction in patients
      with papillary stenosis. Balloon dilation of strictures and stent placement
      decompress the biliary system and may be helpful. Cholecystectomy is recommended
      to treat acalculous cholecystitis, and celiac plexus block may be offered to
      patients with terminal disease and intractable abdominal pain.

PMID- 15010026
TI  - Treatment of Functional Dyspepsia.
AB  - Functional dyspepsia is a common chronic condition. It can have a major impact on
      quality of life and remains a large burden on healthcare resources. Its
      underlying mechanisms are not fully understood and therapies are mainly
      empirical. In this review, we summarize the best evidence on available
      therapeutic interventions in functional dyspepsia. Helicobacter pylori
      eradication, for those infected, is likely a safe and cost-effective strategy but
      benefits only a minority. Antisecretory agents such as proton-pump inhibitors and
      histamine-2 receptor antagonists have shown some benefit and are recommended as
      the first-line option in the absence of H. pylori infection. There is a lack of
      strong evidence of benefit from prokinetic agents, and cisapride, the most
      studied agent, is largely unavailable. Antidepressants need to be adequately
      tested in functional dyspepsia, but both psychotherapy and hypnotherapy
      interventions have shown promising results. Herbal therapies need further study
      in these patients. 5-Hydroxytryptamine3 (5-HT(3)) and 5-HT(4) receptor
      antagonists, and cholecystokinin type A and neurokinin receptor antagonists
      remain promising emerging therapies.

PMID- 15010027
TI  - Marginal Zone B-cell Lymphoma (MALT Lymphoma).
AB  - The preferred terminology for mucosa-associated lymphoid tissue (MALT) lymphoma
      of the stomach (variously referred to as MALT lymphoma, MALToma, low-grade
      MALToma, or pseudolymphoma) is marginal zone B-cell lymphoma (MZBL). MZBL, the
      hallmark of which is the lymphoepithelial lesion, develops as a consequence of
      Helicobacter pylori infection in susceptible individuals. In general, MZBL is
      slow growing, can remain localized for years, and has an excellent prognosis.
      Staging involves endoscopy with biopsy, computed tomography scanning, and
      endoscopic ultrasound. In patients with limited disease, eradication of H. pylori
      leads to remission. In patients who fail eradication therapy or have more
      extensive disease, surgery, chemotherapy, and radiation alone and in various
      combinations have been used successfully.

PMID- 15010028
TI  - Treatment of Gastroparesis.
AB  - Gastroparesis is a condition of impaired gastric motility that can be chronic and
      result in decreased quality of life and complete disability. Once the diagnosis
      of gastroparesis is established, the clinician's attention should immediately
      focus on restoring nutritional status, providing symptomatic relief from nausea
      and vomiting, and improving gastric motility. Combination therapy is the rule
      rather than the exception, and most patients require multiple prokinetic and
      antiemetic modalities for adequate symptom relief. Currently available
      medications are often inadequate to achieve therapeutic goals, and newer
      modalities, such as gastric electrical stimulation, which has been shown to
      decrease symptoms and improve quality of life, should be employed at a low
      threshold. Several novel therapeutic options are under investigation and may also
      become part of the routine treatment of gastroparesis.

PMID- 15010030
TI  - How far reaching is pediatric adolescent gynecology? Just ask the Surgeon
      General.

PMID- 15010029
TI  - Gastric Adenocarcinoma.
AB  - Adenocarcinoma of the stomach is advanced enough in some patients to preclude
      curative treatment, but many gastric cancer patients have what appears to be
      localized disease that is amenable to surgical resection, which is the only truly
      effective treatment. Long-term results of what appear to be "curative resections"
      are relatively poor, however, and new management tools such as sentinel lymph
      node biopsy, recently promising adjunctive therapies (such as radiochemotherapy),
      and the organization of the order of treatment combinations do require further
      study with an eye to improving outcomes. However, there appears to be little hope
      for a dramatic improvement in treatment results from these innovations for
      patients with established gastric cancer. Fortunately, gastric cancer in the
      United States has gone from being the number one cause of cancer death in our
      population 50 years ago to that of being the number eight cause of cancer death
      at this time. This intriguing major decrease in the incidence of this disease
      must be considered secondary to one or more changes in our own environment that
      we hope will be exploitable in the future. As with cancers of all types and in
      all sites, a prevention strategy may prove more effective than the treatment
      strategies that are outlined here. The management strategies outlined are
      hopefully only temporary ones until we are able to develop a better handle on
      primary prevention.

PMID- 15010031
TI  - Healthcare for adolescents in juvenile facilities: increasing needs for
      adolescent females.
AB  - In 1999, 2.4 million youth between the ages of 10 and 17 were arrested. On any
      given day that year, 133,000 juveniles were detained in long-term detention
      facilities. Since 1990, there has been a wide disparity in the number of minority
      youth in the juvenile justice system. In 1999, 41% of youth in this system were
      African American. Additionally, there has been growth in the percent of arrests
      of females (29% in 1999) and adolescents younger than 15 years of age (32%).

PMID- 15010032
TI  - Interstitial cystitis in adolescents and children: a review.

PMID- 15010033
TI  - Unusual vulvar ulcerations in young adolescent females.
AB  - STUDY OBJECTIVE: To review a series of young female patients who presented to the
      Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio, from July of
      1996 to November of 2001 with new, unexplained vulvar ulcerations, in order to
      elucidate common factors. DESIGN: Retrospective case series. SETTING: Cincinnati
      Children's Hospital Medical Center and its satellite offices. PARTICIPANTS:
      Female patients who have never been sexually active or abused who presented with
      the diagnosis of vulvar ulcerations. INTERVENTIONS: None. MAIN OUTCOME MEASURES:
      Description of clinical features. RESULTS: Nine patients who developed vulvar
      ulcerations and denied sexual contact or sexual abuse were identified. Eight of
      nine were premenarchal. All nine had negative Herpes Simplex Virus (HSV) cultures
      from the lesions, and three had negative HSV serology. Negative Epstein Barr
      virus (EBV) tests were documented in six patients. Lesions were recurrent in
      three patients. The diagnosis of Behcet's disease was considered in three
      patients. The remaining six patients had systemic complaints consistent with a
      viral syndrome at the time of the vulvar ulcerations, but no definite etiology
      could be documented. CONCLUSION: The rare finding of a vulvar ulcer in a sexually
      inexperienced patient can result in a diagnostic dilemma in the absence of signs
      of systemic illness such as Crohn's disease, Behcet's syndrome or EBV infection.
      These ulcers could be a local manifestation of a non-sexually transmitted
      systemic viral infection that has yet to be identified. The occurrence in
      premenarchal females suggests the possibility of mediating hormonal factors.

PMID- 15010035
TI  - Evaluation of the adolescent with chronic abdominal or pelvic pain.

PMID- 15010034
TI  - Bone mineral density in adolescent females using depot medroxyprogesterone
      acetate.
AB  - STUDY OBJECTIVE: To examine bone mineral density (BMD) on a semi-annual basis
      among control subjects and adolescent females receiving depot medroxyprogesterone
      acetate (DMPA) injection or oral contraceptives. DESIGN: Non-randomized
      prospective study. SETTING: Teenage pregnancy prevention intervention clinic.
      PARTICIPANTS: Adolescent females who were new users of DMPA injection (N=58, age
      12-21) or the oral contraceptive pill (N=71, age 11-19) and normal menstruating
      girls (N=19, age 15-18). INTERVENTIONS: Baseline and 6-monthly measures of lumbar
      vertebral BMD using dual-energy X-ray absorptiometry over a 2-year period. MAIN
      OUTCOME MEASURES: comparison of percent change on BMD over time between DMPA
      users, pill users, and normal menstruating girls. RESULTS: There was no
      difference on group characteristics at baseline except for the ethnicity between
      the controls and the DMPA group. There was a statistically significant decrease
      in BMD between DMPA users and controls at 6 months (-3.02% change, P=0.014) 12
      months (-3.38% change, P=0.001) 18 months (-4.81% change, P<0.001) and 24 months
      (-6.81% change, P=0.010). There was no statistical difference between pill users
      and controls. CONCLUSION: There is a relationship between DMPA use and a decrease
      in BMD compared to normal menstruating controls that seems to persist up to 24
      months.

PMID- 15010036
TI  - Paradoxical adolescent reproductive decisions.
AB  - OBJECTIVE: To determine why teenagers who say they do not plan to parent if they
      become pregnant fail to use contraceptives consistently enough to avoid
      conceiving by default. METHODS: A racially diverse group of 333 inadequately
      contracepting, nulligravida teens, 45 (13.5%) of whom did not plan to parent if
      they became pregnant was studied. Participants completed scales assessing
      traditional teen pregnancy risk factors, deterrents to contraceptive use,
      expectations about the effect of pregnancy, the desire to remain non-pregnant,
      and sexual behavior. RESULTS: Teens who said they would not parent if pregnant
      were less apt to report boyfriends who wanted them to conceive (RR=0.7; 95%
      CI=0.5-0.9) and deterrents to contraceptive use (RRs around: 0.6; 95% CI: 0.3
      0.9) and more apt to anticipate that childbearing would negatively impact their
      lives (RR: 1.9; 95% CI: 1.6-2.2), to want to remain non-pregnant (RR: 2.2; 95%
      CI: 1.8-2.4), and to have used contraception at last sexual intercourse (RR: 1.8;
      95% CI: 1.3-2.4). In the group that did not intend to parent the only difference
      between those who had and had not used contraception at last intercourse was
      their willingness to plan for sexual activity (OR: 4.6; 95% CI: 1.3-16.7).
      CONCLUSION: This study suggests that further progress toward preventing unwanted
      teen pregnancies might be made by dispelling the notion that for young, unmarried
      women, unplanned sexual intercourse is preferable to planned sexual intercourse.

PMID- 15010037
TI  - Pimecrolimus for the treatment of vulvar lichen sclerosus in a premenarchal girl.
AB  - BACKGROUND: Lichen sclerosus is a chronic cutaneous disorder with a predilection
      for the vulva. Lichen sclerosus affects more than one in 900 girls. Superpotent
      corticosteroids like clobetasol propionate are the most effective treatment for
      vulvar lichen sclerosus. However, recurrence after stopping steroids is very
      high. As repeated courses of corticosteroids are frequently needed, there are
      concerns about potential side effects. Therefore, a treatment regimen that does
      not rely on corticosteroids may be beneficial. As lichen sclerosus is a T
      lymphocyte mediated disorder, it has been suggested that pimecrolimus, a topical
      T-lymphocyte inhibitor, may be safe and effective for the treatment of lichen
      sclerosus in children. CASE REPORT: A 10-year-old girl with lichen sclerosus was
      initially treated with clobetasol. Remission was achieved, but 3 months later she
      had a recurrence. Subsequent treatment with clobetasol led to a breakdown of her
      peri-anal skin with a superimposed infection. She was then treated with
      pimecrolimus and remission was achieved. She has had no recurrence of active
      lichen sclerosus and has less burning with pimecrolimus than with clobetasol.
      CONCLUSION: Pimecrolimus may be an effective treatment of vulvar lichen
      sclerosus. Pimecrolimus has been shown to be very safe in the pediatric
      population for the treatment of mild to moderate eczema, without causing dermal
      atrophy, tachyphylaxis, striae, rebound flares, or hypothalamic-pituitary axis
      suppression. As the recurrence rate of active lichen sclerosus in prepubertal
      girls treated with topical corticosteroids is high, and the majority of
      prepubertal girls with lichen sclerosus continue to have disease after menarche,
      a treatment regimen that does not rely on corticosteroids may be beneficial.

PMID- 15010039
TI  - Vulvar intraepithelial neoplasia in adolescents with abnormal Pap smear results:
      a series report.
AB  - OBJECTIVE: The objective of this study was to determine the prevalence of vulvar
      intraepithelial neoplasia (VIN) in adolescents presenting for cervical colposcopy
      in an adolescent gynecology office. MATERIALS AND METHODS: We conducted a
      retrospective chart review from 1999 to 2002 of the concomitant diagnosis of
      cervical intraepithelial neoplasia and VIN in our private general pediatric and
      adolescent practice in patients younger than 22 years of age who underwent
      cervical colposcopy as well as evaluation of the vulva secondary to gross and
      microscopic visualized lesions. RESULTS: Sixty-one patients underwent colposcopy
      for abnormal Pap smears; we found a 10% overall prevalence of vulvar
      intraepithelial neoplasia. Forty-four percent (n=27) underwent concomitant
      evaluation of the vulva; from these, 22% (n=6) fulfilled the characteristics of
      vulvar and cervical intraepithelial neoplasia. CONCLUSION: In the presence of
      cervical cytology abnormalities, VIN may be more common than recognized and
      careful screening is definitely warranted.

PMID- 15010038
TI  - Impact of new diagnostic criteria on the prevalence and incidence of pelvic
      inflammatory disease.
AB  - STUDY OBJECTIVE: The Centers for Disease Control and Prevention (CDC) recently
      changed the recommended criteria for the clinical diagnosis of pelvic
      inflammatory disease (PID). The purpose of this study was to assess the impact of
      this change on the frequency with which we made a diagnosis of PID. DESIGN:
      prospective cohort study. SETTING: juvenile detention center. PARTICIPANTS:
      adolescent females. INTERVENTIONS: We used the new diagnostic criteria to
      determine the prevalence and incidence of PID. We then compared these values to
      those in a previous study of a similar cohort of youth who were evaluated with
      the CDC's old, more stringent clinical criteria. MAIN OUTCOME MEASURES:
      Prevalence and incidence of PID. INCIDENCE MEASURES: Incidence density and
      cumulative incidence, using the Kaplan-Meier method. Results between studies were
      compared using prevalence and incidence ratios. RESULTS: In sexually active
      adolescents (N=315), the prevalence of PID (95% confidence interval) at admission
      was 8.6% (5.7-12.2%). During the first 31 days of incarceration, the cumulative
      incidence was 7.9% (5.0-12.3%) and the incidence density was 11.1 cases/100
      person-months (6.5-16.4). Comparison of these results with those of our previous
      study that used old diagnostic criteria yielded a prevalence ratio of 2.0 (1.0
      4.2), a risk ratio (comparing cumulative incidence) of 3.6, and a rate ratio
      (comparing incidence density) of 3.4 (1.2-11.2). All differences were
      statistically significant (P<0.05). CONCLUSION: The new diagnostic criteria for
      PID doubled the prevalence and more than tripled the incidence of this disease in
      this high risk population of incarcerated adolescents.

PMID- 15010040
TI  - A case of poorly differentiated Sertoli-Leydig tumor of the ovary.

PMID- 15010041
TI  - Screening for dating violence: should we screen or not?

PMID- 15010042
TI  - Vulvar disorders in prepubertal children.

PMID- 15010043
TI  - Management quandary. Menorrhagia in a teenager: Von Willebrand disease type 1.

PMID- 15010045
TI  - The continuing challenge of teen pregnancy.

PMID- 15010044
TI  - "Quick Start", an innovative approach to the combination oral contraceptive pill
      in adolescents. Is it time to make the switch?

PMID- 15010049
TI  - Pre-departure counselling and an email contact service for patients with epilepsy
      faring abroad for long periods of time.
AB  - The fate and management of 50 patients with epilepsy is described whilst they
      undertook varied gap year experiences in various countries. Despite initial
      apprehension on my part almost all had no change in their epilepsy (or had actual
      improvement) and it turned out to be a positive experience for all. With the
      ready availability of email it is suggested that the home clinic keeps in touch
      with gap year students whilst they are away and provides them with basic
      information and an assessment before they go, information which they can then
      take with them.

PMID- 15010050
TI  - Efficacy and tolerability of levetiracetam in children aged 10 years and younger:
      a clinical experience.
AB  - Levetiracetam is a new anti-epileptic drug that is currently not licensed for use
      in children. Studies in adults suggest that it may be a useful adjunctive
      treatment both in partial onset and generalised epilepsy. A retrospective case
      notes review of 26 children age 10 years and under with refractory epilepsy was
      undertaken to evaluate the efficacy and safety of the drug. The drug appeared to
      be most effective in children with partial onset seizures and least effective in
      those with myoclonic seizures. Sixty-one percent of patients showed a good
      response to levetiracetam with at least a 50% reduction in seizure frequency with
      two of these 26 children with previously refractory epilepsy becoming seizure
      free. Levetiracetam was also found to be well-tolerated with very few reported
      side-effects.

PMID- 15010052
TI  - Intentional seizure interruption may decrease the seizure frequency in drug
      resistant temporal lobe epilepsy.
AB  - We investigated the nature of preictal subjective phenomena and whether they had
      any effect on the seizure frequency in 95 adult patients with medial temporal
      lobe epilepsy. Seventy-three (77%) patients indicated that they experienced
      seizure-provoking factors. Ten patients (11%) had prodromas independent of auras,
      while auras occurred in 89%. Forty-four patients (46%) reported that that they
      had tried to stop their seizures in the presence of prodroma or aura and this
      action had resulted in success at least once. Twenty-one patients (22%) regularly
      tried to stop their seizures because this effort was often successful according
      to their interpretation. Patients who reported that they could frequently inhibit
      their seizures had 1.8 +/- 1.6 seizures/month, a significantly lower mean seizure
      frequency than those 74 patients who did not do it regularly (4.6 +/- 4.8
      seizures/month, P<0.001). Patients who reported regular experience in inhibiting
      intentionally their seizures more often had affective (P=0.05) and vertiginous
      auras (P<0.01) as well as isolated auras (P<0.05). Patients who experienced
      provoking factors showed the same seizure frequency as those who did not. Our
      results suggest that intentional seizure inhibition had an impact on the severity
      of drug-resistant epilepsy.

PMID- 15010051
TI  - Recent onset pseudoseizures--clues to aetiology.
AB  - PURPOSE: To examine associations of potentially aetiological significance for the
      development of pseudoseizures by comparing patients with recent onset
      pseudoseizures with patients with recent onset epilepsy. METHODS: A prospective
      study of consecutive patients with recent onset pseudoseizures and epilepsy
      presenting to two Swedish hospitals. Demographic characteristics, somatic
      symptoms, depression severity, personality disorder, potential childhood
      aetiological factors and recent life events were elicited from clinical data and
      a research interview, which included a structured clinical interview for DSM-IV,
      a measure of perceived parental care and a life events inventory. RESULTS: Twenty
      patients with pseudoseizures of duration less than 12 months (mean 5.4 months)
      were compared with 20 patients with recent onset epilepsy. There was no
      statistically significant difference in the rate of current psychiatric disorder.
      Patients with recent onset pseudoseizures were however more likely to have a
      borderline personality disorder (P<0.05), and to recollect less parental warmth
      and more paternal rejection (P=0.0001) in childhood. They had no more life events
      in the 3 months prior to onset but did report more when the whole year before
      onset was assessed (P<0.001). CONCLUSIONS: Perceived childhood neglect,
      borderline personality, and an excess of life events over the preceding year is
      associated with pseudoseizures of recent onset more than with epilepsy. The study
      was limited by the small sample size making type two errors likely. However, by
      selecting both cases and controls with recent onset symptoms, the potential bias
      of differing illness durations and complicating factors of chronicity that have
      affected previous studies was avoided.

PMID- 15010053
TI  - Did St Birgitta suffer from epilepsy? A neuropathography.
AB  - Several famous religious personalities have been discussed as possibly having had
      epilepsy. Partial epileptic fits can be accompanied by religious experiences. The
      Swedish St Birgitta of Vadstena is focused on from this perspective as the
      exterior of the skull thought to belong to her has a prominent tuberculum with a
      corresponding interior indentation possibly indicating the previous existence of
      a meningioma, a well known cause of epilepsy. This article scrutinises arguments
      for and against the possibility of epileptic features in the revelations of the
      saint, as well as in her life story.

PMID- 15010054
TI  - Efficacy and tolerability of levetiracetam in patients with therapy-resistant
      epilepsy and learning disabilities.
AB  - INTRODUCTION: The purpose was to evaluate the effects of levetiracetam (LEV) in
      routine therapy in learning disabled patients with therapy-resistant epilepsy.
      METHODS: In an open observational add-on study design, 46 patients (residents of
      the Bethel Epilepsy Centre) with severe therapy-resistant epilepsy and different
      degrees of learning disabilities, who were treated with LEV between its
      introduction in Autumn 2000 and February 2002, were evaluated retrospectively.
      Information on monthly seizure frequencies, seizure severity and psychiatric
      status was extracted from the current patient case records. A 3 months baseline
      and a 3 months LEV treatment period (after 3 months of titration) were compared.
      Responders were defined as having a 50% reduction in seizure frequency and being
      evaluated as good or very good in an ad hoc global clinical efficacy scale. When
      only one criterion was positive, a careful individual decision was made based on
      the impact on the patients' daily activities. RESULTS: The responder rate was
      41.3% (34.8 for 50% seizure reduction). It was higher in focal and multifocal
      epilepsy as compared to symptomatic generalised epilepsy/Lennox Gastaut Syndrome
      (P<0.05). Antiepileptic response occurred in doses between 500 and 4000 mg/day.
      Changes in seizure severity were rare. Nine patients experienced positive
      psychotropic effects (mostly improved vigilance and mood); six of these patients
      had antiepileptic effects as well. Twelve patients had adverse effects, mostly
      mild; in three cases, however, more severe effects led to discontinuation.
      CONCLUSIONS: LEV is an effective and generally well-tolerated drug for this
      patient group, especially in focal and multifocal epilepsy.

PMID- 15010055
TI  - Vagus nerve stimulation for refractory idiopathic generalised epilepsy.
AB  - We reviewed our experience with vagus nerve stimulation (VNS) in 165 patients
      with medically refractory epilepsy (138 partial epilepsy (PE), 13 symptomatic
      generalised epilepsy (SGE), 14 idiopathic generalised epilepsy (IGE)). Average
      duration of VNS therapy was 21.6 months. A 50% or greater reduction in seizure
      frequency was achieved in 47.1% of the PE group, 46.1% of the SGE group, and
      57.1% of the IGE group. A 50% or greater reduction in seizure frequency and
      reduced antiepileptic drug (AED) regimen were achieved in: PE (9.4%), SGE (7.7%),
      and IGE (35.7%). These preliminary results suggest that VNS is an effective
      therapy for some patients with medically refractory IGE.

PMID- 15010056
TI  - Tooth-brushing epilepsy with ictal orgasms.
AB  - We report a 41-year-old woman with complex reflex epilepsy in which seizures were
      induced exclusively by the act of tooth brushing. All the attacks occurred with a
      specific sensation of sexual arousal and orgasm-like euphoria that were followed
      by a period of impairment of consciousness. Ictal EEG demonstrated two events of
      epileptic seizure that were provoked after tooth brushing for 38 and 14 seconds,
      respectively. The interictal EEG showed epileptiform discharges over the right
      anterior temporal region and interictal single photon emission computed
      tomography (SPECT) scan showed relative hypoperfusion in the uncus of right
      temporal lobe. Brain magnetic resonance imaging (MRI) revealed right hippocampal
      atrophy. We suggest that tooth-brushing epilepsy, especially with sexual ictal
      manifestations, may provide insight into the cerebral pathophysiology at the
      right temporolimbic structure.

PMID- 15010057
TI  - Epileptic nystagmus in a patient with nonconvulsive status epilepticus.
AB  - Epileptic nystagmus (EN) is a rare form of rhythmic eye oscillations occurring
      during seizure activity. Not only convulsive states, but also nonconvulsive
      status may represent with EN and this phenomenon may be the only motor
      manifestation of seizure activity. Epileptic activation of a cortical saccade
      region may be distinguished from activation of a cortical pursuit region
      clinically as activation of pursuit regions results in nystagmus slow phases that
      bring the eyes across the midline. Horizontal EN results most commonly from
      seizure activity involving the occipital cortex. In this report, horizontal EN in
      a patient with nonconvulsive status epilepticus (NCSE) is described with
      clinical, radiological and electrophysiological findings that occur probably due
      to posterior leukoencephalopathy syndrome.

PMID- 15010058
TI  - Carbamazepine-induced IgG1 and IgG2 deficiency associated with B cell maturation
      defect.
AB  - This paper presents the first case of asymptomatic IgG1 and IgG2 deficiency
      induced by carbamazepine (CBZ). The patient has remained asymptomatic since CBZ
      was started because IgM reduced only transiently, IgA decreased but remained
      within the normal range, and the specific antibodies to organisms having capsular
      polysaccharide antigens were not defective in this case. Analysis of membrane
      surface immunoglobulin (sIg) on B lymphocytes indicated that the maturation of B
      cells was defective from sIgM+ cells to sIgG+ cells. There have been no previous
      reports of IgG deficiency induced by CBZ due to this mechanism. Immunoglobulins
      should be carefully examined in patients treated with CBZ, particularly after its
      initiation.

PMID- 15010059
TI  - Epilepsia partialis continua in cat scratch disease.
AB  - Cat scratch disease (CSD) is a world-wide, diffuse, non-epidemic infection caused
      by the Gram-negative bacillus Bartonella henselae. The occurrence of
      encephalopathy represents an infrequent and atypical complication, whose
      manifestations include ischemic strokes, transverse myelitis and epileptic
      seizures. Status epilepticus has been described as the most frequent emergency in
      CSD encephalopathy. In this report, we describe a case of CSD complicated by an
      epilepsia partialis continua (EPC) manifested as rhythmic movements of the flexor
      muscles of the left hand. Although CSD is a benign, self-limited disease and a
      complete neurological recovery usually occurs, in the present case the EPC
      resulted in a partial epilepsy. Magnetic resonance imaging (MRI), single photon
      emission computed tomography (SPECT) and back-averaged EEG data recorded during
      myoclonic activity document this CSD complication.

PMID- 15010060
TI  - Status epilepticus and seizures induced by iopamidol myelography.
AB  - PURPOSE: To report that iopamidol myelography can induce status epilepticus (SE)
      in patients carrying the diagnosis of symptomatic epilepsy and to estimate the
      incidence of seizures in patients undergoing iopamidol myelography. METHODS: We
      retrospectively identified all patients with seizures/SE associated with 1350
      iopamidol myelographies during the last 5 years at our institution. The impact of
      cervical versus lumbar myelography was analysed. RESULTS: Induced by iopamidol
      myelography two non-epileptic patients suffered from first generalised tonic
      clonic seizures and a 67-year-old women with symptomatic epilepsy after a remote
      ischemic stroke developed a generalised tonic-clonic seizure evolving into a
      dialeptic and right nystagmus SE (i.e. complex focal status) of 5-hour duration.
      The incidence of seizures in non-epileptic patients was 0.15%. The incidence of
      seizure induction for lumbar myelography was lower than for myelographies that
      included the cervical subarachnoid space. CONCLUSIONS: Iopamidol myelography
      (especially if cervical) is associated with a risk of seizures in non-epileptic
      individuals and can induce SE in patients with epilepsy. Patients should be
      informed about the risk of seizure induction.

PMID- 15010061
TI  - A retrospective analysis of patients with febrile seizures followed by epilepsy.

PMID- 15010062
TI  - Cancer registries contribute to quality improvements in clinical care for all
      European cancer patients.

PMID- 15010063
TI  - Colorectal cancer screening in Europe: first things first.

PMID- 15010064
TI  - Cumulative incidence and risk factors of mitoxantrone-induced cardiotoxicity in
      children: a systematic review.
AB  - Mitoxantrone is believed to maintain anthracycline antitumour activity but be
      associated with a reduced cardiotoxicity. The aim of this study was to evaluate
      the evidence for the cumulative incidence of and risk factors for mitoxantrone
      induced cardiotoxicity (M-CT) in children treated for childhood cancers. After an
      extensive literature search, 17 studies were included. The cumulative incidence
      varied between 0 and 6.7% in the 16 studies evaluating symptomatic M-CT and
      between 0 and 80% in the 11 studies evaluating asymptomatic M-CT. Risk factors
      for developing M-CT remain unclear. All studies had serious methodological
      limitations. In conclusion, children treated with mitoxantrone are at risk of
      developing M-CT, but due to the low quality of the current evidence, the exact
      cumulative incidence and risk factors for M-CT remain unclear. It is too early to
      conclude that in children mitoxantrone is less cardiotoxic than anthracyclines.
      More well-designed studies are needed to reliably evaluate the incidence of M-CT
      and its associated risk factors.

PMID- 15010065
TI  - Guidelines for the management of women at increased familial risk of breast
      cancer.
AB  - The Guidelines were prepared by an international expert panel on behalf of the
      Association of Breast Surgery. The majority of women who have a relative with
      breast cancer are not themselves at significantly increased risk. The Guidelines
      propose a management strategy, including genetic assessment, chemo-prevention,
      risk reducing surgery and radiological screening, based on risk assessment of the
      individual. The Guidelines are based on evidence where available, or on consensus
      statements from surgeons, radiologists, geneticists and clinical psychologists.

PMID- 15010066
TI  - Glufosfamide administered by 1-hour infusion as a second-line treatment for
      advanced non-small cell lung cancer; a phase II trial of the EORTC-New Drug
      Development Group.
AB  - The activity of glufosfamide (beta-D-glucosylisophosphoramide mustard) was tested
      in a multicentre phase II clinical trial in patients with advanced non-small cell
      lung cancer (NSCLC) who had received one prior line of platinum-based
      chemotherapy. Patients were treated with 5000 mg/m(2) glufosfamide by a 1-h
      intravenous (i.v.) infusion every 3 weeks following registration at the European
      Organisation for Research and Treatment of Cancer (EORTC) Data Center. Patients
      were randomised between hydration and no hydration to evaluate the
      nephroprotective effects of forced diuresis. Patients experiencing >/= 35
      micromol/l increase of serum creatinine compared with baseline values were taken
      off the treatment. The Response evaluation criteria in solid tumours (RECIST)
      criteria were applied for the response assessment. Blood sampling was performed
      for a pharmacokinetic analysis. 39 patients from seven institutions were
      registered and a median of three cycles was given (range 0-6) cycles; 20 patients
      were randomised to the hydration arm. Haematological toxicity was mild, but
      treatment-related metabolic and electrolytic abnormalities and increases of serum
      creatinine occurred in several patients. Hydration did not have any significant
      influence on the plasma pharmacokinetics of glufosfamide and did not show any
      nephroprotective effect. Only one confirmed partial remission was observed
      (response rate 3%; 95% (Confidence Interval (CI) 0-14) and 18 cases with stable
      disease (49%) were recorded as assessed by an independent panel. Median survival
      of all patients treated was 5.8 months (95% CI 4.2-7.9). In conclusion,
      glufosfamide administered by a 1-h infusion every 3 weeks has modest activity in
      advanced NSCLC patients after one prior platinum-based chemotherapy.

PMID- 15010067
TI  - Age-specific detriments to quality of life among breast cancer patients one year
      after diagnosis.
AB  - The aim of our study was to identify any differences in the quality of life (QOL)
      of breast cancer survivors one year after diagnosis when the acute treatment
      effects should not longer be apparent. QOL was assessed in a population-based
      cohort of 387 women with breast cancer from Saarland (Germany) using the European
      Organisation for Research and Treatment of Cancer Quality of Life Questionnaire
      Core 30 (EORTC-QLC30). Functional and symptom QOL-scores were compared with
      published reference data from the general population. Breast cancer survivors and
      women from the general population reported similar scores of global health/QOL.
      However, major deficits among women with breast cancer were found, for emotional,
      social, role and cognitive functioning. Age-specific comparisons between breast
      cancer patients and the reference population revealed that these deficits are
      predominantly found in younger age groups. The overall QOL of life of breast
      cancer survivors one year after diagnosis is comparable to women from the general
      population. However, some differences exist that seem to predominantly affect
      younger women who show a poorer QOL in certain domains.

PMID- 15010068
TI  - Real-time pharmacokinetics guiding clinical decisions; phase I study of a weekly
      schedule of liposome encapsulated paclitaxel in patients with solid tumours.
AB  - The purpose of this weekly schedule phase I study of liposome encapsulated
      paclitaxel (LEP) was to define the maximum-tolerated dose (MTD), the recommended
      dose (RD), the dose-limiting toxicities (DLTs), the pharmacokinetic profiles, and
      to evaluate preliminarily antitumour effects in patients with refractory solid
      malignancies. LEP was administered as an intravenous (i.v.) infusion over 45 min
      once every week for 6 out of 8 weeks. Fourteen patients were treated at doses
      ranging from 90 to 150 mg/m(2)/week. In one patient, DLT was observed at the dose
      level of 150 mg/m(2)/week, who received less than 70% of the intended cumulative
      dose. No cumulative toxicities were observed. Stabilisation of disease for 8
      weeks was documented in two patients. The whole blood clearance of total
      paclitaxel was similar for LEP (15.3+/-8.98 l/h/m(2)) and Taxol (17.5+/-3.43
      l/h/m(2)), and the extraliposomal to total drug ratio increased rapidly to unity
      at later sampling time points. The trial was discontinued upon completion of
      enrolment of the 150 mg/m(2)/week cohort because an assessment of the
      pharmacokinetics and clinical data suggested that LEP was unlikely to have any
      advantages over Taxol. It is concluded that this formulation of LEP is unlikely
      to provide improvements over the taxanes currently in clinical use.

PMID- 15010069
TI  - Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to
      imatinib in patients with advanced gastrointestinal stromal tumours entered on
      phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group.
AB  - Previous studies have shown that activating mutations of c-KIT/PDGFRA, potential
      therapeutic targets for imatinib mesylate, are implicated in the pathophysiology
      of gastrointestinal stromal tumours (GISTs). In this study, GISTs from 37
      patients enrolled in an European Organisation for Research and Treatment of
      Cancer (EORTC) phase I/II clinical study of imatinib were examined for mutations
      of c-KIT/PDGFRA in order to explore whether the mutational status of the tumour
      predicts the clinical response to therapy. Mutations were screened by denaturing
      high-pressure liquid chromatography (DHPLC) and characterised by bi-directional
      DNA sequencing. Activating mutations of c-KIT or PDGFRA were found in 29 (78%)
      and 2 (6%) GISTs, respectively. Most c-KIT mutations involved exon 11 (n=24;
      83%), all but one being an in-frame deletion; no isolated point mutations were
      found. The other c-KIT mutations included exon 9 AY 502-503 duplication (n=4;
      14%) and exon 13 Lys-->Glu(642) missense mutation (n=1; 3%). Two tumours with no
      detectable c-KIT mutations demonstrated PDGFRA Asp-->Glu(842) amino acid
      substitutions. Patients with GISTs harbouring exon 11 mutations were more likely
      to achieve a partial response (PR) on imatinib therapy (83%) than all of the
      others (23%). The overall survival and progression-free survival rates for the
      entire group at 106 weeks were 78.3% and 46.9%, respectively. Based on a Kaplan
      Meier analysis, patients with GISTs harbouring c-KIT mutations had longer median
      survival times and were less likely to progress than the other patients. These
      findings indicate that the mutational status of the c-KIT/PDGFRA oncoproteins
      could be useful to predict the clinical response of patients imatinib therapy.

PMID- 15010070
TI  - Long-term survivors of ovarian malignancies after cisplatin-based chemotherapy;
      cardiovascular risk factors and signs of vascular damage.
AB  - Male germ cell tumour patients treated with cisplatin-based chemotherapy
      frequently develop cardiovascular risk factors and disease, but sparse
      information is available about long-term complications of this type of
      chemotherapy in women. We investigated the prevalence of cardiovascular risk
      factors and vascular damage in 21 women (median age 39 years; range 26-57 years)
      with an epithelial or germ cell tumour of the ovary cured by cisplatin-based
      chemotherapy after a median follow-up of 14 years (range 3-21 years).
      Hypercholesterolaemia was present in 62%, obesity in 24%, hypertension in 14%,
      insulin resistance in 14%, and microalbuminuria in 24% of patients.
      Microalbuminuria was more frequent in long-term cancer survivors than in a female
      background population with a similar age (23.8 versus 3.2%; P<0.05). A
      substantial portion of young female patients cured by cisplatin-based
      chemotherapy are likely to develop cardiovascular risk factors and signs of
      endothelial damage at an early stage.

PMID- 15010071
TI  - Microalbuminuria, decreased fibrinolysis, and inflammation as early signs of
      atherosclerosis in long-term survivors of disseminated testicular cancer.
AB  - Testicular cancer patients have an increased risk for coronary artery disease
      more than ten years after cisplatin-based chemotherapy. We investigated whether
      vascular changes, including endothelial dysfunction, are present earlier. Ninety
      chemotherapy-treated testicular cancer patients (median follow-up of seven years)
      were compared with 44 patients after orchidectomy only and 47 healthy men.
      Microalbuminuria was present in 10 (12%) chemotherapy patients, one stage I
      patient and none of the controls. Chemotherapy patients had higher levels of
      fibrinogen, C-reactive protein (hs-CRP), von Willebrand factor (vWF), plasminogen
      activator inhibitor (PAI-1), and tissue-type plasminogen activator (t-PA).
      Chemotherapy patients with elevated PAI-1 (25/90) showed clustering of
      cardiovascular risk factors resembling the metabolic syndrome. In conclusion,
      cured testicular cancer patients showed a high prevalence of microalbuminuria and
      increased plasma levels of endothelial and inflammatory marker proteins, which
      might progress to more severe endothelial dysfunction and overt atherosclerosis.

PMID- 15010072
TI  - FLT3 inhibitors: a paradigm for the development of targeted therapeutics for
      paediatric cancer.
AB  - The area of molecularly-targeted cancer therapeutics is generating tremendous
      interest and excitement. While clinical investigation of these agents has been
      largely limited to adults, clinical trials for paediatric cancer patients with
      many of these agents are now underway. This paper reviews the current status of
      molecularly-targeted therapies for paediatric malignancies, with special
      attention given to one class of agents, inhibitors of the FLT3 receptor tyrosine
      kinase. FLT3 is expressed and activated in many human leukemias, including a
      significant percentage of pediatric AML and infant and childhood ALL, especially
      in the setting of MLL gene rearrangement. Activating mutations of FLT3 portend a
      poor prognosis in pediatric AML. Activated FLT3 can be effectively and
      selectively targeted by small molecule inhibitors, and these agents have shown
      promise in early phase clinical trials in adults with AML. Limited preclinical
      data with FLT3 inhibitors in MLL-rearranged ALL have also been reported.
      Challenges and future directions for the use of FLT3 inhibitors and other
      targeted agents in paediatric cancer are discussed.

PMID- 15010074
TI  - Pathology review for paediatric non-Hodgkin's lymphoma patients in Japan; a
      report from the Japan association of childhood leukaemia study (JACLS).
AB  - A central pathology review system with an immunophenotyping laboratory was
      established in Japan to support the clinical trial, the Japan Association of
      Childhood Leukaemia Study (JACLS) NHL-98, for patients with paediatric non
      Hodgkin's lymphoma (NHL). Pathology samples from 155 clinically-suspected NHL
      cases were evaluated centrally initially using the Revised European-American
      Lymphoma (REAL) classification in a rapid review (within 2 weeks after
      surgery/biopsy) and then later at the consensus review (once a year). The samples
      were subsequently re-classified according to the new World Health Organisation
      (WHO) classification. After the pathology review, 96 (62%) patients were eligible
      for the study, and 58 of them (60%) had extra-nodal primaries. These NHL cases
      included B-cell lymphomas (precursor B-cell, 11; Burkitt, 18; diffuse large B
      cell, 18; not otherwise specified, 3) and T/Natural Killer (NK)-cell lymphomas
      (precursor T-cell, 23; anaplastic large cell, 20; others, 3). There was excellent
      concordance in making the diagnoses (95/96, 99%) and typing (93/96, 97%) of NHL
      between the rapid and consensus reviews. Five cases, initially diagnosed as
      diffuse large B-cell lymphoma by the review, were re-classified as Burkitt
      lymphoma according to the immunocytochemical criteria by the WHO classification.
      A total of 59 (38%) cases were excluded from the study: they were Hodgkin
      lymphoma (7), leukaemias (11), reactive lymphoid hyperplasia (20), necrotizing
      lymphadenitis (7), no consensus diagnosis (1), insufficient materials (2), and
      others (11). This is the first report of the central pathology review from the
      paediatric NHL group study in Japan. Because various diseases, either neoplastic
      or reactive, mimicked NHL, clinically and histopathologically, the central
      pathology review system was critical and essential for patient enrollment and
      protocol assignment in our clinical trial. Through the two-step review system,
      highly reliable data were generated to support this study.

PMID- 15010075
TI  - Colorectal cancer survival trends in Norway 1958-1997.
AB  - The purpose of this study was to examine the pattern of survival for colorectal
      adenocarcinoma (CRC), and to investigate the prognostic factors for the disease.
      In the analysis, 50993 cases of CRC aged 40-84 years, diagnosed between 1958 and
      1997 in Norway, were included. Esteve's relative survival method was used,
      together with a time trend analysis, conducted by least-squares linear
      regression. Cox proportional hazards regression analysis was used to examine
      cause-specific mortality. Five-year relative CRC survival has increased by an
      estimated 3% per 5-year diagnostic period. In 1958-1962, relative survival was
      about 40% for both males and females, and increased to 56 and 60%, respectively,
      in 1993-1997. Rectal cancer had a higher cause-specific mortality (RR 1.26, 95%
      CI 1.22-1.30) than proximal colon (reference) and distal colon (RR 0.97, 95% CI
      0.93-1.00 cancers), while females had a lower cause-specific mortality than males
      (RR 0.88, 95% CI 0.86-0.90). The increase in the relative survival rate in Norway
      is probably due to improved treatments and advanced diagnostics. Norway has a
      higher CRC survival rate than the EUROCARE average.

PMID- 15010076
TI  - Improvements in survival for women with breast cancer in Scotland between 1987
      and 1993: impact of earlier diagnosis and changes in treatment.
AB  - We investigated changes in survival, and their causes, in women with early breast
      cancer diagnosed in Scotland. The Scottish Cancer Registry identified 1617 and
      2077 such women, without metastases at diagnosis who underwent surgery as part of
      their primary treatment, diagnosed in 1987 and 1993, respectively. There was a
      statistically significant 11% improvement in 8-year survival between 1987 and
      1993. Survival improved across almost all clinical/pathological, treatment and
      health care delivery/deprivation categories; improvement was not limited to those
      women diagnosed through the screening programme. In a multivariate model,
      improved survival appeared to be explained largely by screening and
      clinical/pathological prognostic factors. Deprivation also had an adverse effect
      on survival; however, the geographical variation in survival observed for women
      diagnosed in 1987 was not apparent by 1993. We did not demonstrate a significant
      independent effect of surgical caseload on survival. We conclude that survival
      has increased partly as a consequence of screening and earlier diagnosis, but
      also due to improvements in the organisation and delivery of care.

PMID- 15010079
TI  - Comment on "The relative contributions of screen-detected in-situ and invasive
      breast carcinomas in reducing mortality from the disease" by S.W. Duffy, L.
      Tabar, B. Vitak et al.

PMID- 15010078
TI  - Differential expression of retinoic acid receptor beta (RARbeta) and the AP-1
      transcription factor in normal, premalignant and malignant human laryngeal
      tissues.
AB  - The anticancer effects of retinoids are mainly mediated by their nuclear
      receptors. Recent studies have demonstrated that retinoic acid receptor beta
      (RARbeta) plays a pivotal role from the early stages of laryngeal carcinogenesis;
      however, the exact mechanism of this detrimental effect has not yet been
      elucidated. One of the best-documented actions of retinoid receptors is the
      transrepression of activator protein-1 (AP-1) transcription factor activity,
      although this complex interplay has not been clarified. The present report is the
      first systematic morphological evaluation of the cross-talk of RARbeta and AP-1
      transcription factor in a large series of human laryngeal tissues containing
      normal epithelium, premalignant lesions (hyperplasia and/or dysplasia) and
      squamous cell carcinoma. Immunohistochemical methodology was performed on
      formalin-fixed, paraffin-embedded sections by using a panel of monoclonal and
      polyclonal antibodies against RARbeta and the AP-1 components c-Jun, p-c-Jun
      (phosphorylated, active c-Jun) and c-Fos proteins. Their expression was screened
      and compared in 154 patients with various laryngeal histological entities.
      Nuclear expression of RARbeta, c-Jun, p-c-Jun and c-Fos was detected in 81
      (89.2%), 48 (52.8%), 66 (72.6%) and 73 (80.3%), respectively, out of 91 specimens
      with normal-appearing laryngeal epithelium; in 86 (87.8%), 94 (95.9%), 94 (95.9%)
      and 94 (95.9%), respectively, out of 98 specimens with hyperplastic laryngeal
      epithelium; in 58 (56.8%), 92 (90.2%), 96 (94.1%) and 96 (94.1%), respectively,
      out of 102 specimens with dysplastic laryngeal epithelium; in 10 (22.3%), 41
      (91.2%), 44 (97.8%) and 41 (91.2%), respectively, out of 45 specimens with well
      differentiated squamous cell carcinoma; in 13 (30.3%), 37 (86%), 39 (90.7%) and
      41 (95.3%), respectively, out of 43 specimens with moderately-differentiated
      squamous cell carcinoma; and in 8 (66.7%), 10 (83.3%), 12 (100%) and 12 (100%),
      respectively, out of 12 specimens with poorly-differentiated squamous cell
      laryngeal carcinoma. Statistical analysis and correlation of the intensity of
      nuclear immunostaining of the studied proteins among the various histological
      entities revealed statistically significant results. The progressive upregulation
      of the AP-1 transcription factor constituents and downregulation of the RARbeta
      protein detected from the onset of laryngeal tumorigenesis suggests an important
      role for the immediate-early AP-1/RARbeta on/off "switch" in the process of
      laryngeal carcinogenesis.

PMID- 15010077
TI  - Family history of benign thyroid disease and cancer and risk of thyroid cancer.
AB  - In a population-based study of 313 case-control pairs in Kuwait, we evaluated
      whether a family history of benign thyroid disease (BTD) and thyroid or other
      cancers was associated with an increased risk of thyroid cancer, the second most
      common neoplasm among women in this and several other Arab countries in the Gulf
      region. Family history of BTD was reported by 78 (24.9%) cases and 40 (12.8%)
      controls in 132 and 57 relatives, respectively. There was an approximately 2-fold
      increased risk of thyroid cancer in individuals who had a mother (Odds Ratio
      (OR)=2.3; 95% Confidence Intervals (95% CI): 1.1-5.1), sister(s) (OR=2.6; 95% CI:
      1.3-5.3) or aunt(s) (OR=2.1; 95% CI: 0.9-5.3) with BTD; there was also a
      significant trend in increasing risk with an increasing number of affected female
      relatives (P<0.0001). Stratification by age at diagnosis of the case showed that
      individuals aged </= 35 years, who had an affected first- or second/third-degree
      relative(s), had an approximately 3-fold increased risk of the cancer. Family
      history of thyroid cancer was reported by 9 (2.9%) cases in 13 relatives (11
      females, 2 males) and by 3 controls in 3 relatives (all females) (OR=3.0; 95% CI:
      0.8-11.1). The OR for all hormone-related cancers combined was 1.5 (95% CI: 0.8
      2.6). There was no clear association with family history of breast or any other
      common cancer. Our data suggest that a family history of BTD is associated with
      an increased risk of thyroid cancer, and point to the role of familial
      susceptibility to BTD and thyroid cancer in the Kuwaiti population.

PMID- 15010081
TI  - Modification of SAS macros for a more efficient analysis of relative survival
      rates.

PMID- 15010082
TI  - Neuropsychological and emotional changes during simulated microgravity: effects
      of triiodothyronine alendronate, and testosterone.
AB  - INTRODUCTION: We present the results of a two-experiment study designed to
      evaluate the neurocognitive and psychological effects of six-degree head-down
      bedrest and pharmacologic interventions (3,5,3'-triiodothyronine; T3) implemented
      to enhance the muscle and bone atrophy associated with simulated microgravity.
      Subsequently, the effects of countermeasures (alendronate and testosterone)
      administered to retard or reverse these T3 plus bedrest enhanced atrophic
      changes, were evaluated. Each participant was tested weekly for 5 weeks during
      Bedrest or non-bedrest (Up) conditions with the Neurobehavioral Evaluation System
      2 (NES2), the Symptom Check List 90 Revised (SCL-90-R), and the Coping Responses
      Inventory (CRI). Resultant data were subjected to repeated measures, between
      groups analysis of variance testing for all 82 neurocognitive and psychological
      test measures. RESULTS: In Experiment 1, participants in the Placebo-Bedrest
      condition performed better on several neurocognitive measures compared to
      participants in the T3-Up condition. However, participants in the Placebo-Bedrest
      condition also reported more confusion. In Experiment 2 (countermeasure trials),
      superior coordination was observed for participants in the Testosterone-T3
      condition over those in the Alendronate-T3 condition, but just the opposite for
      reaction time. Also, testosterone and to a lesser degree, alendronate, were
      associated with less self-reported emotional distress than T3 plus bedrest alone.
      CONCLUSION: Triiodothyronine, alendronate, and testosterone each influence
      participant response to simulated microgravity. Between group differences for
      significant findings were substantial and averaged 1.62 standard deviations.
      Although the observed neurocognitive effects likely pose no immediate danger for
      research participants, the significantly greater level of self-reported
      psychological symptoms by T3-Placebo and Placebo-Bedrest treated participants is
      of clinical importance.

PMID- 15010083
TI  - Neuropsychological functioning following bilateral subthalamic nucleus
      stimulation in Parkinson's disease.
AB  - The cognitive effects of subthalamic nucleus (STN) stimulation in Parkinson's
      disease (PD) have been examined. However, there are no reported studies that
      evaluate, by incorporating a disease control group, whether neuropsychological
      performance in surgical patients changes beyond the variability of the assessment
      measures. To examine this issue, 17 PD patients were tested before and after
      bilateral STN stimulator implantation, both on and off stimulation. Eleven
      matched PD controls were administered the same repeatable neuropsychological test
      battery twice. Relative to changes seen in the controls, the surgery for
      electrode placement mildly adversely affected attention and language functions.
      STN stimulation, per se, had little effect on cognition. The STN DBS procedure as
      a whole resulted in a mild decline in delayed verbal recall and language
      functions. There were no surgery, stimulation, or procedure effects on depression
      scale scores. In contrast to these group findings, one DBS patient demonstrated
      significant cognitive decline following surgery.

PMID- 15010084
TI  - The public's misconception about traumatic brain injury: a follow up survey.
AB  - Two prior surveys from rural Louisiana, Canada, and New York [Arch. Clin.
      Neuropsychol. 3 (1988) 331; Arch. Clin. Neuropsychol. 8 (1993) 461] revealed that
      a high portion of the population endorses misconceptions about the sequelae of
      traumatic brain injury (TBI). The purpose of this study was to assess the
      public's perceptions of head trauma in an urban setting in the Northeast region
      of the country and to compare those results with surveys from other geographical
      areas conducted 8 and 13 years ago. This study also examined the prevalence of
      perceptions about TBI that may be relevant to personal injury litigation with TBI
      plaintiffs. Data were collected at an office of the Department of Motor Vehicles
      from persons conducting business there. Participants (n = 179) voluntarily
      completed a 19-item survey covering several facets of brain injury. This sample
      endorsed misconceptions at a level consistent with previous studies, indicating a
      comparable lack of knowledge about moderate to severe TBI. With regard to mild
      TBI, however, our sample generally endorsed fewer misconceptions than previous
      samples. The public also holds perceptions of TBI that may be relevant to
      personal injury litigation involving TBI plaintiffs.

PMID- 15010085
TI  - The Penn Conditional Exclusion Test: a new measure of executive-function with
      alternate forms of repeat administration.
AB  - Studies of change in neuropsychological function over time in both healthy and
      diseased populations have been hindered by the absence of alternate forms of most
      commonly used neuropsychological tests. The Penn Conditional Exclusion Test
      (PCET) was developed as a new cognitive instrument to assess "executive"
      functioning with four alternate forms. In Study 1, the PCET was administered in
      counterbalanced order to 80 healthy young adults to establish equivalent test
      difficulty. Results revealed that the four versions were related on categories
      achieved, total number of errors and total number of trials. In Study 2, the PCET
      was administered to 25 healthy adults of a wide age range with a battery of
      computerized neuropsychological tests to assess construct validity. Convergent
      validity was confirmed by positive correlations between the PCET and a measure of
      abstraction. Divergent validity was established through low, nonsignificant
      correlations between the PCET and measures of facial emotion recognition, word
      and face memory, visuospatial function, and verbal reasoning.

PMID- 15010086
TI  - Trail Making Test A and B: normative data stratified by age and education.
AB  - Normative data for the Trail Making Test (TMT) A and B are presented for 911
      community-dwelling individuals aged 18-89 years. Performance on the TMT decreased
      with increasing age and lower levels of education. Based on these results, the
      norms were stratified for both age (11 groups) and education (2 levels). The
      current norms represent a more comprehensive set of norms than previously
      available and will increase the ability of neuropsychologists to determine more
      precisely the degree to which scores on the TMT reflect impaired performance for
      varying ages and education.

PMID- 15010087
TI  - Social processing deficits in agenesis of the corpus callosum: narratives from
      the Thematic Appreciation Test.
AB  - Clinical observations suggest that individuals with agenesis of the corpus
      callosum (ACC) and normal IQ may have deficits in social intelligence. This study
      analyzed responses by normally intelligent individuals with ACC to pictures from
      the Thematic Apperception Test. A rating system was developed to assess three
      elements of story-generation: story logic, social understanding, and common
      content. Six individuals with ACC (five complete and one partial; IQs > 85) were
      compared to eight controls matched for sex, age, and IQ. Based on independent
      rankings of story protocols by two raters, the five individuals with complete ACC
      were found to be significantly impaired on all three criteria. The one individual
      with partial ACC performed better than the majority of controls in all three
      domains. Results demonstrated that individuals with complete ACC are impaired in
      understanding socially complex scenes and generating appropriate narratives.
      Absence of the anterior corpus callosum appears to be important for this deficit.

PMID- 15010088
TI  - A proposed method to estimate premorbid intelligence utilizing group achievement
      measures from school records.
AB  - Estimating premorbid cognitive functioning is an important part of any
      neuropsychological evaluation. This estimate is the benchmark against which
      current cognitive functioning is compared to establish the existence, degree, and
      rate of cognitive decline. Typically methods used to estimate premorbid cognitive
      functioning are based on; (1) demographic information, (2) combined current test
      performance with demographics, and (3) current reading (word recognition)
      ability. These approaches each have drawbacks including difficulty estimating
      premorbid abilities of people close to the extremes of intellectual functioning
      (i.e., estimating the premorbid ability of individuals in the gifted or
      borderline intellectual ranges). The current study reviewed the existing data
      comparing commonly used group administered achievement and college board tests
      with the Wechsler IQ tests. It is proposed that clinicians may predict premorbid
      cognitive functioning by applying the well-known predicted-difference method to
      estimate IQ from group administered achievement test scores. The correlations
      between group administered achievement and college board tests with the Wechsler
      IQ tests are reviewed and the descriptive statistics of selected group
      administered achievement and college board tests are presented.

PMID- 15010090
TI  - Metamemory in multiple sclerosis: exploring affective and executive contributors.
AB  - Although previous reports have examined metamemory in various neurological
      groups, no study to date has examined various affective and cognitive
      contributors to metamemory collectively in a sample of multiple sclerosis (MS)
      patients. In the present study, 48 MS patients completed the Memory Functioning
      Questionnaire (MFQ) and were administered measures assessing depression,
      depressive attitudes, and executive functioning. Correlational analyses indicated
      that certain aspects of metamemory in MS were associated with both affective and
      executive variables. Structural equation modeling (SEM) analyses of three a
      priori models revealed the best fit with one model proposing that greater
      executive dysfunction and depression were associated with increased self-reported
      memory complaints, but via the mediating influence of depressive attitudes.
      Although our results suggest some objective basis for metamemory complaints in MS
      (i.e., executive dysfunction), they also suggest that these complaints may be
      exacerbated by the potentially reversible influences of depression and depressive
      attitudes. Treatment of depression and depressive attitudes in MS may result in
      MS patients having more accurate perceptions of their actual memory abilities
      that, in turn, may lead to improvements in their quality of life.

PMID- 15010089
TI  - Cognitive functioning and length of abstinence in polysubstance dependent men.
AB  - To date, there are few large-scale studies that have examined the relationship
      between duration of abstinence and cognitive functioning in polysubstance
      dependent individuals. Existing large-scale studies of polysubstance abusers have
      reported only minimal recovery of cognitive functioning with abstinence [Arch.
      Gen. Psychiatry 35 (1978) 1063]. The goal of this study is to test whether length
      of abstinence (1 day and 14 months) is related to cognitive ability in a large
      cross-sectional sample of men recovering from dependence on at least two drugs (N
      = 207). A series of Poisson and linear regressions were run to test whether
      length of abstinence is associated with neuropsychological performance while
      controlling for demographic variables, raw Vocabulary score, drug use, and
      dependency. The primary finding is that increasing length of abstinence was not
      statistically associated with superior neuropsychological ability. This suggests
      that the abuse of multiple substances potentially produces long-lasting
      neuropsychological impairment with minimal recovery of functioning over a 1-year
      period.

PMID- 15010091
TI  - The Trail Making Test as an initial screening procedure for neuropsychological
      impairment in older children.
AB  - This study was designed to explore the possibility of using a brief
      neuropsychological test for broad-band initial screening of children with
      academic problems who might have neuropsychological deficits that should be more
      completely evaluated. Part B of the Trail Making Test was selected as the
      instrument for investigation. Three groups of children, aged 9-14 years, were
      composed for this study to represent (1) children with diagnosed brain damage or
      disease, (2) children who were medically normal but who were of serious concern
      to parents and teachers because of inadequate academic progress, and (3) a normal
      control group. The Brain-Damaged group required more than three times the number
      of seconds needed by the controls to complete the test, and the group with
      academic difficulties required more than twice the time of the controls. Using
      the limits set by the distributions of the Brain-Damaged and control groups, it
      was possible to identify a cutoff point that may be used for preliminary
      identification of children with academic difficulties who might benefit from
      further neuropsychological evaluation. The results of this study stand in need of
      cross-validation and, obviously, much additional outcome research is necessary to
      evaluate the efficacy and validity of the findings for screening purposes.

PMID- 15010092
TI  - A comprehensive analysis of verbal fluency deficit in geriatric schizophrenia.
AB  - Deficits in verbal fluency are common in schizophrenia and may provide keys to
      some of the abnormalities in the semantic system in schizophrenia. While a number
      of studies have outlined the severity and implications of verbal fluency deficits
      in younger schizophrenia patients, these findings have not yet been extended to
      older patients with schizophrenia. In this study, 392 older (age >/= 50) patients
      with schizophrenia were administered phonological and semantic (i.e., category)
      fluency examinations, as well as tests of learning, memory, language, and praxic
      skills, and rated for clinical symptoms and functional status. When compared to
      normative standards, 82% of the patients were impaired in semantic fluency and
      83% were impaired in phonological fluency. Both semantic and phonological fluency
      impairment were significantly correlated with other cognitive variables, total
      scores on the functional status measure, and with the social and self-care
      subscales. Scores were uncorrelated with the severity of psychosis, but were
      correlated with the severity of negative symptoms. Furthermore, the severity of
      poverty of speech (a clinical measure of verbal underproductivity) was moderate
      in magnitude and failed to enter as a predictor of verbal fluency, indicating
      that impaired fluency scores are not simply an artifact of general
      underproductivity or mutism. The findings support conclusions from studies with
      younger schizophrenia patients that suggest that verbal fluency impairment is a
      consequence of a disorganized semantic system. Verbal fluency impairment remains
      common and functionally relevant in schizophrenia patients in late life.

PMID- 15010093
TI  - Use of the Progressive Figures Test in evaluating brain-damaged children,
      children with academic problems, and normal controls.
AB  - This study explores the use of the Progressive Figures Test as an instrument for
      broad initial screening of children in the 6- through 8-year age range with
      respect to the possible need for more definitive neuropsychological evaluation.
      Considering earlier results obtained in comparison of brain-damaged and control
      children [Clinical Neuropsychology: Current Applications, Hemisphere Publishing
      Corp., Washington, DC, 1974, p. 53; Proceedings of the Conference on Minimal
      Brain Dysfunction, New York Academy of Sciences, New York, 1973, p. 65], the
      Progressive Figures Test seemed potentially useful as a first step in determining
      whether a comprehensive neuropsychological evaluation is indicated. In this
      investigation, three groups were studied: (1) children with definitive evidence
      of brain damage or disease who, when compared with normal controls, help to
      establish the limits of neuropsychological functioning, (2) a group of children
      who had normal neurological examinations but also had academic problems of
      significant concern to both parents and teachers, and (3) a normal control group.
      Statistically significant differences were present in comparing each pair of
      groups, with the brain-damaged children performing most poorly and the controls
      performing best. Score distributions for the three groups make it possible to
      identify a score-range that represented a borderline or "gray" area and to
      suggest a cutting score that identified children whose academic problems might
      have a neurological basis and for whom additional neuropsychological evaluation
      appeared to be indicated.

PMID- 15010094
TI  - Planning versus speed: an experimental examination of what Planned Codes of the
      Cognitive Assessment System measures.
AB  - This study provided validity evidence that the Cognitive Assessment System,
      Planned Codes subtest measures planning rather than speed. Each of 156 children
      completed Planned Codes using two different sets of directions. The first set of
      directions allowed each child to use strategies to complete Planned Codes. The
      second set of directions allowed the child only to use speed to complete Planned
      Codes. The results of the study indicated significantly higher scores (t = 11.5,
      P < .0001) when the child was allowed to use strategies (mean = 34.1, S.D. = 9.2)
      compared to the same child's score when speed (mean = 25.6, S.D. = 7.5) alone was
      used to complete Planned Codes. A partial correlation, with age effects removed,
      between the scores each child earned under the two conditions was very low (r =
      .23, P < .01). Calculation of the magnitude of difference between the two groups
      yielded an effect size of 1.0. The results of this study provided validity
      support that the Cognitive Assessment System Planned Codes subtest measures
      planning.

PMID- 15010095
TI  - Concordance between the CVLT and the WMS-III word lists test.
AB  - The California Verbal Learning Test (CVLT) and the Word Lists Test (WLT) from the
      Wechsler Memory Scale-III are widely used tests of verbal learning and memory. To
      examine concordance between these popular tests, we administered both to a
      diagnostically diverse group of 25 patients. As expected, measures from the two
      tests were highly correlated, although level of concordance was not as high as
      might be expected. When diagnostic outcomes were discordant for free recall
      measures, the CVLT indicated impairment more often than did the WLT.

PMID- 15010096
TI  - Withdrawal symptoms during chronic transdermal fentanyl administration managed
      with oral methadone.

PMID- 15010097
TI  - Use of thioridazine in palliative care patients with troublesome sweating.

PMID- 15010098
TI  - A comparison of five pain assessment scales for nursing home residents with
      varying degrees of cognitive impairment.
AB  - The aim of the study was to compare five different pain assessment scales for use
      with people with different levels of cognitive impairment who resided in nursing
      homes. The verbal rating scale, horizontal numeric rating scale, Faces pictorial
      scale, color analogue scale and mechanical visual analogue scale were presented
      in random order to 113 residents. Cognitive impairment was assessed using the
      Mini-Mental State Examination. The use of the verbal rating scale was the most
      successful with this group, completed by 80.5% overall, and 36% of those with
      severe cognitive impairment. Repeated explanation improved completion rates for
      all the scales. Consistency between scores on the five scales was good for those
      with none to moderate cognitive impairment and poor for those severely impaired.
      This study showed no difference in pain scores according to cognitive status.

PMID- 15010099
TI  - Terminal cancer patients' wishes and influencing factors toward the provision of
      artificial nutrition and hydration in Taiwan.
AB  - Identifying the concerns of terminal cancer patients and respecting their wishes
      is important in clinical decision-making concerning the provision of artificial
      nutrition and hydration (ANH). The aim of this study was to discover terminal
      cancer patients' wishes and determine influencing factors toward the provision of
      ANH. One hundred and ninety-seven patients with terminal cancer, admitted to a
      palliative care unit in Taiwan over a two-year period, completed a questionnaire
      interview, which included demographic characteristics, knowledge and attitudes on
      ANH, the health locus of control, subjective norms, and the wishes to use ANH.
      One hundred and fifty-four patients (78.2%) used ANH in the past month. A
      knowledge test on issues related to ANH showed the rates of accurate responses
      were ranked as: peripheral intravenous route can only provide hydration (48.7%),
      excessive artificial nutrition may increase the proliferation of cancer cells
      (32%), ANH can prolong life expectancy for all patients (17.3%), and ANH can
      prevent all patients from starving to death (5.6%). The strongest attitude of
      patients toward the potential benefit of ANH was "it can provide the body need
      with nutrition and hydration when inability to eat or drink occurs." Otherwise,
      the strongest attitude toward the potential burdens of ANH was "gastrostomy makes
      the illness worse." One hundred and twenty-two of 197 patients (62.9%) expressed
      their wishes to have ANH. The results of logistic regression analysis showed that
      the experience of using a nasogastric tube and intravenous fluids, and subjective
      norms were the most significant variables related to the wishes of patients to
      use ANH (odds ratio [OR]=11.11, 95% confidence interval [CI]=3.20-38.64; OR=2.51,
      95% CI=1.22-5.15, OR=1.30, 95% CI=1.05--1.60, respectively). However, the use of
      artificial nutrition was negatively affected by the knowledge of ANH (OR=0.53,
      95% CI=0.37-0.84). In conclusion, Taiwanese patients with terminal cancer have
      insufficient knowledge about AHN and still believe in the benefits of ANH,
      especially in avoiding dehydration or starvation. The findings of this study
      indicate the importance of medical professional training and decision-making in
      the initial consideration of using ANH. By improving the knowledge about ANH
      among patients, more appropriate decisions can be achieved.

PMID- 15010100
TI  - Coping with long-term pain after a stroke.
AB  - The aim of this qualitative study was to describe pain, coping strategies, and
      experienced outcome of coping with long-term pain conditions after a stroke.
      Forty-three participants were interviewed: 15 with central post-stroke pain
      (CPSP), 18 with nociceptive pain, and 10 with tension-type headache. Analysis of
      the data was by content analysis. Pain-related problems described were
      incomprehensibility regarding the pain, disturbed sleep, fatigue, diminished
      capacity, mood changes, and stress in relationships. Different coping strategies
      were used; the most common were making the pain comprehensible, planning of
      activities, taking medications, communicating, and distractions. Changing body
      position, making comparison, and enduring the pain were common in central or
      nociceptive pain, rest and relaxation in tension-type headache. Communicating
      their pain gave a feeling of perplexity and resignation. Satisfaction was
      reported in the cases of consideration shown by others. Pain after a stroke
      requires specialized knowledge in order to understand the patient's experiences
      and to enhance coping.

PMID- 15010101
TI  - Development of a symptom assessment instrument for chronic hemodialysis patients:
      the Dialysis Symptom Index.
AB  - Little is known about the prevalence, severity, or impact of symptoms in
      hemodialysis patients because of the lack of a validated symptom assessment
      instrument. We systematically developed an index to assess physical and emotional
      symptom burden in this patient population. We employed four steps in the
      generation of this index: a review of dialysis quality-of-life instruments, three
      focus groups, experts' content validity assessment, and test-retest reliability
      measurement. Seventy-five symptoms were identified. Of these, 46 appeared in > or
      = 4 of the instruments/focus groups and were considered for inclusion. Twelve
      were grouped into other symptom constructs and experts judged four of the
      remaining items not to be pertinent, leaving 30 items in the new index. Overall
      kappa statistic was 0.48+/-0.22. These steps allowed the systematic development
      of a 30-item symptom assessment index for hemodialysis patients. Additional
      reliability and validity testing is needed prior to its widespread use.

PMID- 15010102
TI  - Existential pain--an entity, a provocation, or a challenge?
AB  - "Existential pain" is a widely used but ill-defined concept. Therefore the aim of
      this study was to let hospital chaplains (n=173), physicians in palliative care
      (n=115), and pain specialists (n=113) respond to the question: "How would you
      define the concept existential pain?" A combined qualitative and quantitative
      content analysis of the answers was conducted. In many cases, existential pain
      was described as suffering with no clear connection to physical pain. Chaplains
      stressed significantly more often the guilt issues, as well as various religious
      questions (P<0.001). Palliative physicians (actually seeing dying persons)
      stressed more often existential pain as being related to annihilation and
      impending separation (P<0.01), while pain specialists (seeing chronic patients)
      more often emphasized that "living is painful" (P<0.01). Thirty-two percent (32%)
      of the physicians stated that existential suffering can be expressed as physical
      pain and provided many case histories. Thus, "existential pain" is mostly used as
      a metaphor for suffering, but also is seen as a clinically important factor that
      may reinforce existing physical pain or even be the primary cause of pain, in
      good agreement with the current definition of pain disorder or somatization
      disorder.

PMID- 15010103
TI  - Self-discrepancy in chronic low back pain: relation to pain, depression, and
      psychological distress.
AB  - Self-discrepancies occur when patients' evaluations of their actual self differ
      from their views of who they ideally would like to be (ideal self) or feel they
      ought to be (ought self), or from patients' perceptions of how significant others
      wish they could be (ideal-other self) or ought to be (ought-other self). These
      self-discrepancies may be related to psychological functioning and adjustment to
      pain. This study sought to: 1) determine the reliability of self-discrepancy
      assessments in patients; 2) determine whether each of the four types of self
      discrepancies (actual self vs. ideal self, actual self vs. ought self, actual
      self vs. ideal-other self and actual self vs. ought-other self) measure a
      distinct type of self-discrepancy; and, 3) examine the relationship of self
      discrepancies to pain intensity, depression, and psychological distress in 93
      chronic low back pain patients. A semi-structured questionnaire assessed self
      discrepancies. Standardized measures were used to assess pain intensity,
      depression, and psychological distress. Results showed that self-discrepancies
      can be reliably assessed in patients with persistent pain. Furthermore, data
      analyses showed that patients who had large ought-other self-discrepancies
      reported more severe pain and higher levels of psychological distress. Patients
      who had large ideal self-discrepancies reported higher levels of depression and
      psychological distress. Taken together, these findings suggest that self
      discrepancy can be reliably assessed in patients with persistent pain and
      demonstrate that self-discrepancies are related in meaningful ways to measures of
      pain, depression, and psychological distress in chronic low back pain patients.

PMID- 15010105
TI  - MRI diffusion tensor reconstruction with PROPELLER data acquisition.
AB  - MRI diffusion imaging is effective in measuring the diffusion tensor in brain,
      cardiac, liver, and spinal tissue. Diffusion tensor tomography MRI (DTT MRI)
      method is based on reconstructing the diffusion tensor field from measurements of
      projections of the tensor field. Projections are obtained by appropriate
      application of rotated diffusion gradients. In the present paper, the potential
      of a novel data acquisition scheme, PROPELLER (Periodically Rotated Overlapping
      ParallEL Lines with Enhanced Reconstruction), is examined in combination with DTT
      MRI for its capability and sufficiency for diffusion imaging. An iterative
      reconstruction algorithm is used to reconstruct the diffusion tensor field from
      rotated diffusion weighted blades by appropriate rotated diffusion gradients. DTT
      MRI with PROPELLER data acquisition shows significant potential to reduce the
      number of weighted measurements, avoid ambiguity in reconstructing diffusion
      tensor parameters, increase signal-to-noise ratio, and decrease the influence of
      signal distortion.

PMID- 15010104
TI  - Urine drug testing in pain medicine.
AB  - The use of urine drug testing (UDT) has increased over recent years. UDT results
      have traditionally been used in legal proceedings under supervision of a medical
      review officer (MRO). In this context, testing has been required by statute or
      regulation and so is typically not in the "donor's" interest. Physicians,
      however, can use UDT to assist in monitoring their patient's treatment plan. By
      using UDT in a patient-centered fashion, both patient and physician interests are
      maintained. The MRO-based model of testing in the clinical setting can lead to
      mistrust and a deterioration of the doctor-patient relationship. Clinical testing
      can enhance the doctor-patient relationship when the results are used to improve
      communication. A patient-centered model of UDT should be used to improve quality
      of care. This article discusses why urine is the biological specimen of choice
      for drug testing; who, when and why to test; testing methods; and, most
      importantly, interpretation of results.

PMID- 15010106
TI  - MR digital subtraction angiography with three-dimensional data acquisition in the
      diagnosis of brain tumors: preliminary experience.
AB  - MR digital subtraction angiography (DSA) visualizes intracranial vasculature
      using a rapid T1-weighted sequence and a bolus injection of gadolinium. Although
      two-dimensional sequences are most frequently used, we applied a three
      dimensional technique in combination with a fast method of k-space filling to
      improve both the temporal and spatial resolutions. In this preliminary study, we
      assessed the feasibility of using this technique for the diagnosis of brain
      tumors in 21 patients by reviewing the obtained images and, in 10 patients,
      comparing the images with conventional angiograms. MR DSA visualized a tumor
      stain in 11 patients, a tumor mass effect in 9, and tumor-related vessels in 5.
      In 9 of the 10 patients for whom conventional angiograms were available, the two
      kinds of angiograms corresponded well. Three-dimensional MR DSA using our
      technique is a useful adjunct to conventional MR imaging for the visualization of
      tumor hemodynamics and, in some cases, tumor-related vessels and mass effects.

PMID- 15010107
TI  - Delayed contrast enhancement of MRI in hypertrophic cardiomyopathy.
AB  - Fibrotic lesions in the myocardium exhibit delayed contrast enhancement (DCE) on
      MR images. On the other hand, plexiform fibrosis is observed in hypertrophic
      cardiomyopathy (HCM), indicating an association of this condition with the
      pathogenesis of heart failure and arrhythmia. To examine the occurrence and
      extent of DCE and its relation to cardiac function and arrhythmia in HCM, we
      studied 59 patients with HCM who had undergone MRI. The relationship of DCE to
      cardiac function and arrhythmia was further investigated. DCE occurred in 45
      (76.3%) of the 59 patients with HCM, with a high frequency of localization in
      regions, where the right ventricle is attached. As for the relationship of DCE to
      cardiac function, a significant decrease (P=0.007) in cardiac function was
      observed in the group in which 4 or more segments exhibited DCE, compared with
      the group in which DCE was observed in 3 or less segments. Regarding the
      relationship of DCE to arrhythmia, both the occurrence of DCE and the extent of
      DCE were significantly larger (p<0.05, p=0.026, respectively) in the group with
      VT. These results indicate that DCE may save to identify severe cases of HCM on
      the basis of cardiac function, arrhythmia, and pathophysiological aspects.

PMID- 15010108
TI  - Optimized distortion correction of epi-based statistical parametrical maps for
      stereotactic neurosurgery.
AB  - A new approach is presented for unwarping geometrical distortions in echo planar
      imaging (EPI)-based statistical parametrical maps (SPM). With the developed
      method, a substantial reduction of geometrical distortions in the order of 5-15
      mm down to a residue of approximately 1-2 mm was possible, thus allowing reliable
      activation localization and, hence, interpretation after fusion with undistorted
      conventional anatomic images. The unwarping procedure is an optimized combination
      of two distortion correction methods, the "inhomogeneity mapping" and the
      coregistration approach. Local and global distortions, the first one object
      dependent, the second one caused by imperfect gradient waveforms, are reduced.
      With several examples of patients and volunteers, the applicability for
      stereotactic neurosurgery is demonstrated.

PMID- 15010109
TI  - Sodium 3-D MRI of the human torso using a volume coil.
AB  - Sodium MR imaging is considered to provide clinically important information about
      the human body that is not achievable by hydrogen-based approaches. However, due
      to the low natural abundance in biological tissues, sodium signals usually lead
      to low spatial resolution, low SNR, and long acquisition times compared to
      conventional 1H imaging, even using well-adapted surface coils. For our study, a
      volume coil was designed with nearly homogeneous excitation/receive
      characteristics and a suitable geometry fitting the human torso. A sufficient
      penetration throughout the entire thorax, abdomen, or pelvis is provided allowing
      for sodium imaging of the kidneys, the liver with gall bladder, or the
      myocardium. All measurements were performed on a 1.5 T whole body scanner using a
      spoiled 3-D gradient echo sequence. Imaging parameters TE, TR, and readout
      bandwidth were optimized for sensitive recording of the sodium component with
      slow transverse relaxation. Nonselective RF excitation pulses with a duration of
      2.5 ms and rectangular shape were applied to avoid SAR problems. Narrow receiver
      bandwidth and excitation near the Ernst angle provided clinically practicable
      examinations with measuring times of less than 15 min at a spatial resolution of
      8 x 8 x 8 mm3. Under these conditions, SNR of 11 for the kidneys and vertebral
      disks, 9 for the spinal canal, and 6 for the liver was achieved. A special 3-D
      spin echo sequence was used to determine T2, times which resulted to 15.3 +/- 1.1
      ms for liver, 27.7 +/- 7.2 ms for kidneys, and 24.0 +/- 4.7 ms for the content of
      the spinal canal.

PMID- 15010110
TI  - Off-resonance binomial preparatory pulse technique for high sensitivity MRI of
      H2O17.
AB  - H2O17 is a freely diffusible tracer and naturally occurring isotope of O16
      detectable by MRI and has been shown to be useful for assessing cerebral
      perfusion in animal studies using direct and indirect MR detection techniques.
      However, earlier MR techniques are either not sensitive to changes in small
      concentrations of tissue H2O17 or are not practical for use on clinical scanners.
      In this work, a novel method for detecting H2O17 with high sensitivity has been
      proposed that uses a short, intense, binomial preparatory spin lock pulse with
      resonance offsets for high sensitive rapid, multislice imaging of tissue H2O17.
      Two sets of phantom experiments were performed on the 1.5 T and repeated on 3.0 T
      to assess the feasibility of the proposed technique. The phantom was constructed
      using ovalbumin and doped with 0.4 atom% and 1.0 atom% H2O17. After obtaining
      initial parameters, the proposed technique was validated in an anesthetized
      primate model that was injected with 1.8 cc of 40 atom% H2O17. Phantom
      experiments showed that the proposed technique was able to detect H2O17 with
      relatively high sensitivity and high B1 amplitude (and small offsets) preparatory
      pulses produced similar results as low B1 amplitude (and larger offsets). Primate
      brain study showed a 42.97% difference in mean signal intensity between pre- and
      post-H2O17 injection. The proposed technique was successfully implemented on a
      clinical scanner and was able to detect H2O17 with relatively high sensitivity.
      Primate study has shown that such a technique can be successfully used for human
      imaging applications to investigate and assess cerebral perfusion.

PMID- 15010111
TI  - Comparison of methods for detecting nondeterministic BOLD fluctuation in fMRI.
AB  - Functional MR imaging (fMRI) has been used in detecting neuronal activation and
      intrinsic blood flow fluctuations in the brain cortex. This article is aimed for
      comparing the methods for analyzing the nondeterministic flow fluctuations. Fast
      Fourier Transformation (FFT), cross correlation (CC), spatial principal component
      analysis (sPCA), and independent component analysis (sICA) were compared. 15
      subjects were imaged at 1.5 T. Three quantitative measures were compared: (1) The
      number of subjects with identifiable fluctuation, (2) the volume, and (3) mean
      correlation coefficient (MCC) of the detected voxels. The focusing on cortical
      structures and the overall usability were qualitatively assessed. sICA was
      spatially most accurate but time consuming, robust, and detected voxels with high
      temporal synchrony. The CC and FFT were fast suiting primary screening. The CC
      detected highest temporal synchrony but the subjective detection for reference
      vector produced excess variance of the detected volumes. The FFT and sPCA were
      not spatially accurate and did not detect adequate temporal synchrony of the
      voxels.

PMID- 15010113
TI  - Measuring optical properties of an eye lens using magnetic resonance imaging.
AB  - We compare the focal lengths of porcine lenses measured optically and by using a
      novel MRI technique. The geometric properties of the lenses were also measured
      and compared. The MRI technique exploits the dependence of both the lens
      refractive index and relaxation rates on the local protein concentration. By
      measuring the refractive index and corresponding values of R2 (=1/T2) for samples
      of lens homogenates with different protein concentrations, the dependence of
      refractive index on R2 was determined empirically. R2 maps, constructed from
      monoexponential fits to multiecho images of a slice through the lens containing
      the optical axis, were converted to refractive index maps using this
      relationship. A simulated ray trace through the refractive index map provided an
      estimate of lens focal length that was compared to a direct optical measurement
      of focal length using a laser ray-tracing method. It was found that the mean
      focal lengths estimated from the two techniques agreed within experimental
      uncertainty. The refractive index profile along the optical axis was found to be
      well described by a simple function of the form n=n0 + n1 x ra where r is the
      (normalized) lens radius.

PMID- 15010112
TI  - Event-related fMRI with painful electrical stimulation of the trigeminal nerve.
AB  - Several functional brain imaging studies of pain using positron emission
      tomography (PET) and functional magnetic resonance imaging (fMRI) have shown that
      painful stimulation causes activation of different brain areas. The aim of the
      present study was to develop and implement painful stimulation of the trigeminal
      nerve, which can be applied with event-related paradigms by using MRI. Twelve
      healthy, right-handed volunteers were examined. Painful electrical stimulation of
      the first trigeminal branch was performed. In an event-related setting with a 1.5
      T clinical scanner with EPI capability, the following fMRI parameters were used:
      20 slices, 3 mm thickness, isotropic voxel, 306 measurements with 54 randomized
      events. Statistical postprocessing was performed with SPM99. Activation of the
      ipsi- and contralateral secondary somatosensory cortex (SII), and the
      contralateral insular cortex was observed as well as a contralateral thalamic
      activation (T=4.45, extension 15 voxels). Six of the 12 volunteers revealed also
      activation of the cingulate cortex. The investigation demonstrates that painful
      stimulation of the trigeminal nerve activates the contralateral insular cortex,
      SII, and thalamus, as well as the ipsilateral SII. In contrast to other studies,
      the cingulate cortex was only activated inconsistently.

PMID- 15010114
TI  - Signal characteristics of FLAIR related to water content: comparison with
      conventional spin echo imaging in infarcted rat brain.
AB  - To examine the correlation between tissue water content and signal intensity on
      fluid-attenuated inversion recovery (FLAIR) images, we analyzed infarcted rat
      brain, verified the results by theoretical simulation, and compared them with
      conventional spin-echo images. We produced brain infarction with cavitation in
      five rats by middle cerebral artery occlusion. After in vivo MRI, histologic
      sections of the MRI plane were obtained. We measured the signal intensity of
      regions on FLAIR and spin-echo images, and measured the area of cavitation on
      histologic sections. We plotted curves of cavity percentage to signal intensity.
      Theoretical values were calculated using a two-compartment model. On the curve of
      cavity area to signal intensity, the signal on FLAIR images peaked in tissues
      with 20% to 30% area of cavitation. On the theoretical curve, the signal on FLAIR
      images peaked at 90% tissue water content. These results seem to be
      characteristic of FLAIR.

PMID- 15010115
TI  - F-18-FDG uptake is a reliable predictory of functional recovery of akinetic but
      viable infarct regions as defined by magnetic resonance imaging before and after
      revascularization.
AB  - Identification of akinetic but viable myocardium is important for the selection
      of patients for coronary revascularization. In order to assess predictive values
      of end-diastolic wall thickness and dobutamine induced wall thickening obtained
      by magnetic resonance imaging (MRI) and [18F]Fluorodeoxyglucose uptake assessed
      by positron emission tomography (F-18-FDG-PET), these parameters were compared to
      recovery of left ventricular function after successful revascularization. Forty
      patients with chronic myocardial infarction and regional a- or dyskinesia by
      ventriculography underwent rest- and dobutamine-MRI studies (10 microg
      dobutamine/kg body weight/min) and F-18-FDG-PET. Viability of the infarct region
      was considered to be present if; 1) end-diastolic wall thickness was > or =5.5
      mm; 2) dobutamine induced wall thickening > or =2 mm could be measured; and 3)
      normalized F-18-FDG-uptake was > or =50% in > or =50% of akinetic segments.
      Preserved end-diastolic wall thickness was found in 32/40 patients, functional
      improvement during dobutamine infusion in 26/40 patients and preserved F-18-FDG
      uptake in 29/40 patients. After revascularization regional left ventricular
      function improved in 25/40 patients. Positive and negative predictive values and
      diagnostic accuracy were 78%, 100%, and 83% for preserved end-diastolic wall
      thickness, 92%, 93%, and 93% for dobutamine inducible contraction reserve and
      86%, 100%, and 90% for preserved F-18-FDG-uptake. Quantitative assessment of
      dobutamine induced systolic wall thickening by MRI and F-18-FDG-uptake by PET are
      highly accurate techniques for the identification of viable myocardium and
      prediction of functional recovery after successful revascularization. Preserved
      end-diastolic wall thickness results in an overestimation of viable myocardium
      compared to functional improvement, but wall thickness <5.5 mm excludes recovery
      of regional function.

PMID- 15010116
TI  - Influence of age and osteoporosis on calcaneus trabecular bone structure: a
      preliminary in vivo MRI study by quantitative texture analysis.
AB  - Recent developments in high-resolution MR imaging techniques have opened up new
      perspectives for structural characterization of trabecular bone by non-invasive
      methods. In this study, 3-D MR imaging was performed on 17 healthy volunteers and
      6 osteoporotic patients. Two different MR sequences were used to evaluate the
      impact on MR acquisition on texture analysis results. Images were analyzed with
      four automated methods of texture analysis (grey level histogram, cooccurrence,
      runlength and gradient matrices) enabling quantitative analysis of grey level
      intensity and distribution within three different regions of interest (ROI).
      Texture analysis is not very frequently used since the interpretation of the
      large number of calculated parameters is difficult. We applied multiparametric
      data analyses such as principal component analysis (CFA) and hierarchical
      ascending classification (HAC) to determine the relevant parameters to
      differentiate between three sets of images (healthy young volunteers, healthy
      postmenopaused and osteoporotic patients). The results suggest that relevant
      texture information (depending on the ROI localization in the calcaneus) can be
      extracted from calcaneus MR images to evaluate osteoporosis and age effects on
      trabecular bone structure if strictly the same acquisition sequences are used for
      all patients' examination.

PMID- 15010117
TI  - Sacroiliitis in patients with ankylosing spondylitis: association of MR findings
      with disease activity.
AB  - The purpose of this study was to determine whether MR findings can correlate
      disease activity as measured by laboratory markers in ankylosing spondylitis. MR
      images in 19 patients with ankylosing spondylitis were retrospectively analyzed
      for cartilage abnormality, periarticular erosion, synovial enhancement, and bone
      marrow edema. Each MR finding was correlated with laboratory inflammatory markers
      (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) and the sum
      of ESR + CRP. Synovial enhancement showed a significant correlation with ESR
      (r=0.58; p<0.01) and increased activity at bone scan (r=0.74; p<0.005), whereas
      there was no significant correlation with CRP. A significant correlation was
      found between ESR + CRP and synovial enhancement (r=0.54; p<0.05). Synovial
      enhancement was more common when ESR + CRP was greater than 30 (p<0.05). In
      conclusion, synovial enhancement at MR imaging could correlate disease activity
      as measured by laboratory inflammatory markers in ankylosing spondylitis.

PMID- 15010119
TI  - Extraction and validation of correlation lengths from interstitial velocity
      fields using diffusion-weighted MRI.
AB  - Magnetic Resonance Imaging methods sensitive to individual molecular
      displacements (q-space MRI) provide a convenient means of measuring dispersion in
      complex interstitial spaces. Pressure-driven flow experiments through a water
      saturated packed bed phantom have been conducted to prove the feasibility of
      using q-space MRI to measure the coherence length associated with the
      interstitial velocity field. The method involves measuring the dependence of the
      apparent dispersion coefficient on the distance along the mean flow by repeating
      a small number of pulsed-gradient stimulated-echo experiments with increasing
      gradient pulse separation times. Assuming homogeneous interstitial flow
      statistics inside the averaging volume, an integral spatial scale characterizing
      the Eulerian velocity auto-correlation coefficient is extracted via a stochastic
      convective model. The validity of the a priori statistical description of
      interstitial flow is verified by comparing with an independent MRI measurement of
      the Eulerian velocity field using phase contrast methods in the same phantom with
      pore-level resolution. The integral length scale obtained via q-space MRI agrees
      with the mean pore size in the present as well as in similar phantoms found in
      the literature. This method has direct applicability in the quantification of the
      interstitial morphology of fluid-saturated porous media with resolution
      independent of voxel size, assuming "perfectly reflecting pore walls" (no surface
      relaxation) and no contribution to the MR signal from outside the pore space.

PMID- 15010120
TI  - The Elgin marvel: using magnetic resonance imaging to look at a moldic fossil
      from the Permian of Elgin, Scotland, UK.
AB  - The successful use of magnetic resonance imaging (MRI) of a moldic fossil
      dicynodont from the Permian aeolian Hopeman Sandstone Formation of Elgin,
      Scotland, UK, provides paleontologists with a nondestructive technique for
      examining fossils preserved in this fashion. For large moldic fossils, medical
      scanners such as the Phillips Gyroscan MRI, provide adequate resolution for gross
      morphologic determination. The 3-D rendered images using software such as Philips
      Easivision allows the fossil to be examined and dissected without causing any
      physical damage to the original material. From the scans it is also possible to
      produce 3-D stereolithographs for a more tactile manipulation of the renderings.

PMID- 15010118
TI  - Unsupervised feature dimension reduction for classification of MR spectra.
AB  - We present an unsupervised feature dimension reduction method for the
      classification of magnetic resonance spectra. The technique preserves spectral
      information, important for disease profiling. We propose to use this technique as
      a preprocessing step for computationally demanding wrapper-based feature subset
      selection. We show that the classification accuracy on an independent test set
      can be sustained while achieving considerable feature reduction. Our method is
      applicable to other classification techniques, such as neural networks, support
      vector machines, etc.

PMID- 15010121
TI  - Renal replacement lipomatosis: MR findings in one case.
AB  - Replacement lipomatosis of the kidney is the result of severe atrophy or
      destruction of the renal parenchyma, often caused by calculous disease with
      secondary marked proliferation of renal sinus, renal hilus, and perirenal fatty
      tissue. Different diagnostic tools have been used to define this entity, with
      ultrasonography (US), i.v. pyelography (IVP) and computed tomography (CT) used
      most commonly. We report MR urography and MR appearance of replacement
      lipomatosis in a 38-year-old man. We think that it combines the advantages of
      IVP, US and CT.

PMID- 15010124
TI  - Lactic acid triggers, in vitro, thiomersal to degrade protein in the presence of
      PLGA microspheres.
AB  - Microspheres of polymers like poly(lactic-co-glycolic acid) (PLGA) have been
      studied as a vehicle for controlled release vaccines. They require materials and
      processes that might change the protein antigenicity. Lactic acid is produced
      during microsphere degradation that occurs in tandem with protein liberation. In
      addition, most of the proteins that have been used in microencapsulation studies
      contain Thimerosal((R))(TM) and this can introduce another undesirable effect for
      their stability. We demonstrated in vitro that the thiosalycilic acid (TSA),
      produced after the reduction of TM by lactic acid, reduces the S-S bridge of the
      previously incubated diphtheric toxoid (Dtxd). This reduction is immediately
      followed by blocking the two -SH formed by the same TSA molecules. In the light
      of these conclusions it is necessary now, to reinterpret the in vitro protein
      degradation-stabilization data in the presence of PLGA microspheres, mainly for
      those proteins which contain S-S. We propose that all the PLGA microspheres
      microencapsulation studies and protein structural considerations should be done
      in the absence of TM as preservative.

PMID- 15010122
TI  - MRI findings of intraosseous lipoma: case report.
AB  - Intraosseous lipoma is one of the rarest benign bone tumors and usually presents
      in the fourth to fifth decades. Except for minor symptoms, they are usually
      asymptomatic. Metaphysis of long bones, especially proximal parts of femur and
      fibula, are involved in most cases. We present intraosseous lipoma to discuss the
      benefits of MRI and contrast-enhanced MRI findings for differential diagnosis.

PMID- 15010123
TI  - A case of fat necrosis after breast quadrantectomy in which preoperative
      diagnosis was enabled by MRI with fat suppression technique.
AB  - A 63-year-old woman was found to have a left breast mass after quadrantectomy and
      radiation for bilateral breast cancer on postoperative cyclic examination.
      Intramammary recurrence could not be excluded by physical examination,
      mammography, or ultrasound examination. MR imaging with fat suppression technique
      revealed an oil-containing lesion, indicating fat necrosis. It was confirmed
      histologically that the mass-forming lesion included no cancer tissue. MR imaging
      with fat suppression technique appears to be a promising method for
      identification of postoperative mass lesions of the breast.

PMID- 15010125
TI  - Mechanistic studies of flux variability of neutral and ionic permeants during
      constant current dc iontophoresis with human epidermal membrane.
AB  - Although constant current iontophoresis is supposed to provide constant
      transdermal transport, significant flux variability and/or time-dependent flux
      drifts are observed during iontophoresis with human skin in vitro and human
      studies in vivo. The objectives of the present study were to determine (a) the
      causes of flux variability in constant current dc transdermal iontophoresis and
      (b) the relationships of flux variabilities among permeants of different
      physicochemical properties. Changes in the human epidermal membrane (HEM)
      effective pore size and/or electroosmosis during constant current dc
      iontophoresis were examined. Tetraethylammonium ion (TEA), urea, and mannitol
      were the model permeants. For the neutral permeants, the results in the present
      study showed a significant increase of fluxes with time in a given experiment and
      large HEM sample-to-sample variability. Although both effective pore size and
      pore charge density variations contributed to the time-dependent flux drifts
      observed in electroosmotic transport, the significant flux drifts observed were
      found to be primarily a result of the time-dependent increase in effective pore
      charge density. For the ionic permeant, the observed flux variability was smaller
      than that of the neutral permeants and was believed to be primarily due to
      effective pore size alteration in HEM during iontophoresis as suggested in a
      previous study. The different extents of flux variability observed between
      neutral and ionic permeants are consistent with the different iontophoretically
      enhanced transport mechanisms for the neutral and ionic permeants (i.e.
      electroosmosis and electrophoresis, respectively). The results of the present
      study also demonstrate that flux variability of two neutral permeants are inter
      related, so the flux of one neutral permeant can be predicted if the permeability
      coefficient of the other neutral permeant is known.

PMID- 15010126
TI  - Controlled release of atenolol from the ethylene-vinyl acetate matrix.
AB  - The present study was carried out to evaluate the possibility of using the
      polymer EVA membrane as an EVA matrix system for transdermal delivery of
      atenolol. The effects of drug concentration, temperature, and plasticizers on
      drug release were studied from the atenolol-EVA matrix. The release rate of drug
      from the EVA matrix increased with increased temperature and drug loading doses.
      The flux of atenolol versus the reciprocal of the loading dose yielded a straight
      line. The release of atenolol from the EVA matrix follows a diffusion-controlled
      model, where the quantity released per unit area is proportional to the square
      root of time. Among the plasticizers used such as alkyl citrates and phthalates,
      tributyl citrate (TBC) showed the best enhancing effects. Enhancement factor of
      TBC was 1.51 from the EVA matrix at 37 degrees C. The controlled release of
      atenolol system could be developed using the EVA polymer including the
      plasticizer.

PMID- 15010127
TI  - Preparation and characterization of solid lipid nanoparticles containing peptide.
AB  - Solid lipid nanoparticles (SLN) are an alternative colloidal carrier system for
      controlled drug delivery. However, only a few have been studied regarding the
      incorporation of peptides into SLN, due to the hydrophilic peptide not easy to
      enter the lipophilic matrix of SLN. In the present report, peptide-loaded solid
      lipid nanoparticles were prepared by a novel solvent diffusion method in an
      aqueous system. The model peptide gonadorelin was incorporated to study the
      entrapment efficiency, size, zeta potential (charge) and drug delivery
      characterization. Gonadorelin and monostearin were dissolved in acetone and
      ethanol at 50 degrees C in water bath, the resultant organic solution was poured
      into an aqueous containing 1% polyvinyl alcohol (PVA) under mechanical agitation.
      The peptide-loaded solid lipid nanoparticles were quickly produced and separated
      by centrifugation. The average volume diameter of gonadorelin-loaded SLN is 421.7
      nm and the zeta potential of SLN is -21.1 mV dispersed in distilled water. Up to
      69.4% of gonadorelin can be incorporated. In vitro release of gonadorelin from
      SLN is slow. In the test solution of a 0.1N hydrochloric acid for 2h and then
      transferred in a pH 6.8 phosphate buffer (simulative gastrointestinal fluid), the
      drug-release behavior from SLN suspension exhibited a biphasic pattern. After
      burst drug-release at the first 6h at a percentage of 24.4% of loaded
      gonadorelin, a distinctly prolonged release over a monitored period of 12 days
      was observed and nearly 3.81% of drug was released in each day. In the test
      solution of a pH 6.8 phosphate buffer (simulative intestinal fluid), the drug
      release rate from SLN was similar to that in the simulative gastrointestinal
      fluid. Further, a novel preparation method in the present research for peptide
      loaded SLN was established. These results also demonstrate the principle
      suitability of SLN as a prolonged release formulation for hydrophilic peptide
      drugs.

PMID- 15010128
TI  - Effect of chitosan and of N-carboxymethylchitosan on intraocular penetration of
      topically applied ofloxacin.
AB  - The effects of chitosan hydrochloride (Ch-HCl) and of N-carboxymethylchitosan
      (CMCh), formulated in ophthalmic solutions, on the ocular pharmacokinetics of
      ofloxacin were studied in rabbits. The carboxymethylation of a chitosan of high
      molecular mass (1460 kDa) and deacetylation degree (89.9%) introduced 0.84 N
      carboxymethyl groups per repeating unit. Aqueous solutions containing 1% (w/v) of
      either polymer showed a pseudoplastic rheologic behaviour, and, when instilled in
      rabbit eyes, produced no irritation. The kinetics of drug disappearance from tear
      fluid and the profiles of drug concentration in the aqueous humour versus time
      were determined and interpreted in the light of a pharmacokinetic model and of
      drug-polymer binding. Ch-HCl significantly enhanced intraocular drug penetration
      with respect to an isoviscous drug solution containing poly(vinyl alcohol) and to
      commercial ofloxacin eyedrops. This effect, which resulted in about 190% increase
      of the peak concentration in the aqueous, was ascribed to an increased corneal
      permeability. The polyanionic CMCh failed to enhance intraocular drug
      penetration. It nevertheless increased precorneal drug retention in virtue of its
      viscosity and of ofloxacin binding. Consequently, the residence time at
      concentrations higher than the MIC90 and the bioavailability of the antibiotic in
      the aqueous were increased by about 150 and 240%, respectively, with respect to
      the reference vehicle.

PMID- 15010129
TI  - Optimisation of aciclovir poly(D,L-lactide-co-glycolide) microspheres for
      intravitreal administration using a factorial design study.
AB  - The purpose of this work was to obtain an optimised long-term aciclovir PLGA
      microspheres formulation for intravitreal administration to minimise, as much as
      possible, the dose of microspheres to be administered with a suitable particle
      size for its injection through a 27G needle in a single dose. Microspheres were
      prepared by the solvent evaporation method. To obtain the optimum formulation a
      two-factor five-level central rotatable composite 2(2) + star design was
      employed. The independent variables were aciclovir and gelatin (added to the
      external phase of the emulsion). The dependent variables were the yield of
      production (%), the encapsulation efficiency (%), the initial burst release (%),
      the cumulative amount released from 1 to 14 days and the amount of aciclovir at
      the end of the release assay (microg aciclovir/mg microspheres). The best
      formulation according to the studied variables was (0,0), prepared with 80 mg of
      aciclovir and 80 mg of gelatin. This formulation showed good yield of production
      (70.14 +/- 3.72 %) and encapsulation efficiency ( 70.77 +/- 2.62 %), and released
      the drug at a constant rate for 63 days with a mean release constant of 1.73 +/-
      0.08 microg/day per mg microspheres. The selected formulation reduces a 40% the
      dose of microspheres to be administered through a 27G needle with respect to
      previous studies.

PMID- 15010130
TI  - Haemolytic properties of some water-soluble para-sulphonato-calix-[n]-arenes.
AB  - In this paper, we describe the haemolytic effect of parent para-sulphonato-calix
      [n]-arenes and their derivatives bearing one pendant group at the lower rim of
      calix-arene towards human erythrocytes. A maximum of 30% of haemolysis has been
      observed for para-sulphonato-calix-[8]-arene for a concentration of 200 mM
      representing 300 g of calix-arene per liter of human blood, para-sulphonato-calix
      [4]-arene and para-sulphonato-calix-[6]-arene show much lower haemolytic effects,
      0.5 and 8%, respectively at 200 mM concentration. Coupling of a methoxy
      carboxylate function at the phenolic group reduces haemolytic effects in all
      cases. The presence of an ethoxy-amine function increases the haemolytic
      behaviour for the calix-[4]-arene and calix-[6]-arene systems, but reduces the
      effect for the calix-[8]-arene derivatives.

PMID- 15010131
TI  - Evaluation of cytotoxicity of oils used in coenzyme Q10 Self-emulsifying Drug
      Delivery Systems (SEDDS).
AB  - The objective of the present study was to develop a suitable method for
      evaluation of cytotoxicity of the oils used in Self-Emulsified Drug Delivery
      Systems (SEDDS) using Coenzyme Q10 (Co Q10) as a model compound. For this
      purpose, three methods of sample preparation were tested, namely (i) suspensions,
      (ii) homogenization, and (iii) nanoemulsions of oils in Dulbecco's Modified
      Eagle's Media (DMEM). Studies were carried out by incubating the sample or
      control with Caco-2 cells grown on transwell insert systems as well as in flat
      bottom 96-well plates. The cell viability was assessed by using WST-1 and
      propidium iodide reagents while the monolayer integrity was assessed by mannitol
      permeability and Trans Epithelial Electrical Resistance (TEER). The cytotoxicity
      of oils was found to be dependent on the method of sample preparation;
      nanoemulsions being the least cytotoxic. In conclusion, nanoemulsification is a
      useful tool for cytotoxicity evaluation of substances, which exhibit poor
      aqueous/dimethyl sulfoxide (DMSO) solubility.

PMID- 15010132
TI  - A nanometer lipid emulsion, lipid nano-sphere (LNS), as a parenteral drug carrier
      for passive drug targeting.
AB  - We attempted to develop an artificial lipoprotein-like particle, lipid nano
      sphere (LNS), incorporating dexamethasone palmitate (DMP). LNS is 25-50 nm in
      diameter and is composed of soybean oil and egg lecithin. Potential drug carriers
      were compared with a conventional fat emulsion for intravenous nutrition, lipid
      microsphere (LM, d=200-300 nm), which is already used clinically. LM easily
      entered reticuloendothelial systems, such as the liver, and was rapidly cleared
      from the circulation. However, LNS showed much higher plasma levels of DMP after
      intravenous administration to rats and recovered more than 80% of the injected
      dose in the perfusate in single-pass rat liver perfusion. The calculated volume
      for the distribution of the lipid emulsion within the liver showed that LNS
      underwent fenestration and was distributed into the Disse space in the liver.
      Because of the lower uptake of LNS particles by the liver, LNS showed good
      recovery from the liver and prolonged the plasma half-life of DMP after
      intravenous injection. In addition, higher efficiency in the targeting of DMP
      into inflammation sites and higher anti-inflammatory efficacy were observed in
      LNS. Thus, LNS easily and selectively passed through the leaky capillary wall by
      passive diffusion depending on the plasma concentration. Nanometer-sized lipid
      emulsion particles, LNS, seem to be a promising carrier system for passive drug
      targeting of lipophilic drugs.

PMID- 15010133
TI  - Effects of sodium tetraborate and boric acid on nonisothermal mannitol
      crystallization in frozen solutions and freeze-dried solids.
AB  - The purpose of the present study was to elucidate the effects of sodium
      tetraborate (borax) and boric acid on the crystallization of mannitol in frozen
      aqueous solutions and freeze-dried solids. Thermal analysis of frozen solutions
      showed that sodium tetraborate inhibits mannitol crystallization at sodium
      tetraborate/mannitol molar concentration ratios of approximately 0.05, which is
      much lower than the other co-solutes studied (boric acid, sucrose, sodium
      phosphate buffer). Inhibition of the mannitol crystallization in frozen solutions
      resulted in highly amorphous mannitol in the freeze-dried solids. Mannitol
      remained in an amorphous state in some of the combination freeze-dried solids,
      even at elevated temperatures. Changes in the thermal transition temperatures
      (glass transition temperature of maximally freeze-concentrated solute ( T'g) and
      glass transition temperature of freeze-dried solid (Tg)) suggested reduced
      mannitol molecular mobility with increases in the sodium tetraborate ratio.
      Fourier-transform infrared spectroscopy (FT-IR) analysis of the bovine serum
      albumin secondary structure showed apparent protein structure-stabilizing effects
      of the amorphous mannitol and sodium tetraborate combination during the freeze
      drying process. The mannitol and sodium tetraborate combination also protected
      lactate dehydrogenase (LDH) from inactivation during freeze-drying. We conclude
      that the complex formation and the accompanying reduction in molecular mobility
      make sodium tetraborate an effective mannitol crystallization inhibitor in frozen
      solutions and freeze-dried solids.

PMID- 15010134
TI  - All-trans-retinoic acid release from core-shell type nanoparticles of
      poly(epsilon-caprolactone)/poly(ethylene glycol) diblock copolymer.
AB  - Poly(epsilon-caprolactone)/poly(ethylene glycol) (abbreviated as CE) diblock
      copolymers were synthesized to make core-shell type nanoparticles for all-trans
      retinoic acid (atRA). Fluorescence spectroscopy showed that critical association
      concentration (CAC) value decreased at higher MW of CE diblock copolymer. Drug
      loading characteristics were studied under various experimental conditions. Drug
      contents and loading efficiency increased as the MW of poly(epsilon-caprolactone)
      (PCL) block of CE and initial drug feeding amount increased. Solvent used and
      preparation method also affected drug contents and loading efficiency. According
      to 1H NMR using CDCl3 and D2O, specific peaks of the PCL block and drug appearing
      in CDCl3, disappeared at D2O, suggesting hydrophobic core with hydrophilic shell
      formed in water. atRA release was faster at smaller MW of copolymer and lower
      drug contents. Nanoparticles prepared in DMF showed faster release rate compared
      with those prepared in THF or acetone. Cytotoxicity of atRA against U87MG, U251MG
      and U343MG cell lines were increased by nanoencapsulation while empty
      nanoparticles of CE diblock copolymer were not significantly affected.

PMID- 15010135
TI  - Poly(N-isopropylacrylamide) copolymers for constant temperature controlled drug
      delivery.
AB  - In the course of the development of a new drug delivery concept, four
      thermosensitive copolymers of poly(N-isopropylacrylamide) (PNIPAAm), with phase
      transition temperature slightly higher than 37 degrees C, were synthesised and
      used as time-controlled drug delivery agents. For this purpose, compression
      coated tablets coated with the thermosensitive copolymers and containing Na2SO4
      were prepared and in vitro dissolution tests were performed at constant
      physiological temperature, the lag time before drug release being controlled by
      the amount of Na2SO4 incorporated into the form. Due to the salting out effect,
      the lag time was increased by up to 80-90% for PNIPAAm-co-NVA and PNIPAAm-co-MVA
      coated tablets.

PMID- 15010136
TI  - Assay of amoxicillin sustained release from matrix tablets containing different
      proportions of Carbopol 971P NF.
AB  - The sustained release of amoxicillin is desired because of its short biological
      half-life. Particularly to treat Helicobacter pylori infections, the sustained
      release is desired to be confined to the upper gastrointestinal tract. In vitro
      dissolution of amoxicillin has been evaluated utilizing a direct UV-absorption
      method. However, UV-absorption has been reported as not useful to determine
      amoxicillin in acidic dissolution test medium. To clarify the suitability of the
      assay method, the stability and dissolution behavior of amoxicillin sustained
      release tablets was determined by HPLC, iodometric titration and UV-absorption.
      Stability of amoxicillin studied under dissolution test conditions of pH 1.2, 37
      degrees C and 50 rpm and determined by HPLC and titration showed considerable
      degradation of amoxicillin. On the other hand, the UV-absorption increased
      progressively as amoxicillin degradation proceeded. Amoxicillin release curves
      determined by different analytical methods show different release profiles, which
      can be corrected for amoxicillin degradation and change in the UV-absorption to
      produce similar dissolution results. Release curves determined by UV-absorption
      and obtained from tablets containing 1017 mg amoxicillin trihydrate and Carbopol
      971P NF in a range from 180 to 680 mg showed increasing values of the exponent
      indicative of the release mechanism (n) and decreasing release constant values
      (k) as the matrix polymer content increased. The release constant (k) and the
      exponent (n) were found to be logarithmically related.

PMID- 15010137
TI  - Amylose formulations for drug delivery to the colon: a comparison of two
      fermentation models to assess colonic targeting performance in vitro.
AB  - The purpose of this study was to develop an enzyme-based fermentation system for
      the in vitro assessment of colonic digestion of amylose films and coatings, and
      to compare its performance with a conventional fermentation model inoculated with
      human faecal bacteria. Amylose and ethylcellulose were mixed in different ratios
      and cast as isolated films, as well as spray coated onto drug-(5-aminosalicylic
      acid) loaded pellets. Four commercial amylase enzymes were individually screened
      for their ability to digest amylose cast films. The enzyme from the bacterium
      Bacillus licheniformis was found to be the most active against this substrate.
      Digestion of mixed amylose and ethylcellulose films was also observed, with the
      extent of digestion being proportional to the quantity of amylose present in the
      film. In terms of product performance, drug release from coated pellets was
      accelerated in the presence of the enzyme. The results with the enzyme system
      were comparable to those obtained from a faecal-based fermentation model, thereby
      suggesting that such a system has practical potential for in vitro screening of
      putative amylose formulations for colonic drug delivery.

PMID- 15010138
TI  - The influence of enaminones on the transport and oral bioavailability of P
      glycoprotein substrate therapeutic agents.
AB  - OBJECTIVE: The enaminones have shown high P-gp affinity and may act as P-gp
      modulators. This study investigated the potential inhibition of the enaminones on
      paclitaxel efflux in vitro compared to cyclosporin A, a known P-gp inhibitor, and
      the effectiveness of select enaminones on paclitaxel oral absorption in rats.
      METHODS: Caco-2 transport of [14C]paclitaxel was evaluated in presence of various
      enaminones at 10(-5)M. Concentration-effect (10(-10)M to 10(-4)M) profiles for
      the enaminones, DM27 and/or DM40, with paclitaxel and cyclosporin A were
      determined. Male Sprague-Dawley (250-275 g) rats were orally administered either
      [14C]paclitaxel (30 microCi/kg) or [14C]paclitaxel/DM27 (7 mg/kg) and blood
      samples were collected. Paclitaxel brain concentrations were measured. RESULTS:
      Papp(A-B) of [14C]paclitaxel, with DM27 and DM40 at 10(-5)M, was significantly (P
      < 0.05) higher versus control. DM27 produced a 360% and a 139% increase in Papp(A
      B)Paclitaxel and Papp(A-B)Cyclosporin, respectively. DM40 displayed a 131%
      increase in Papp(A-B)Paclitaxel whereas cyclosporin A produced a 213% increase in
      Papp(A-B)Paclitaxel. Rats in the DM27 group displayed large Vdss/F values (23.35
      liters/kg versus 14.62 liters/kg) and lower AUC (5.47 microg/ml min versus 8.74
      microg/ml min) versus control. However, significantly higher levels (2.25-fold)
      of paclitaxel were observed in the brains of the DM27 group. CONCLUSION: This
      study presents the enaminones as promising P-gp inhibitors with comparable
      potency to other P-gp inhibitors. Furthermore, the enaminones may improve
      conventional therapy when used in combination with P-gp substrate drugs.

PMID- 15010139
TI  - Influence of magnesium glutamate on stability of penicillin G aqueous solution.
AB  - Differential scanning microcalorimetry (DSC) has been used to determine the
      influence of magnesium glutamate on the stability of penicillin G in aqueous
      solution. The degradation of penicillin is accompanied by an evolution of heat
      and has been observed as an irreversible, scan rate dependent, broad exothermic
      transition. The increase of the transition temperature Tm and enthalpy change
      DeltaH with increasing magnesium glutamate concentration indicates the increase
      of penicillin G stability. The kinetic parameters describing the penicillin
      decomposition process, obtained for a reaction following a first-order course,
      suggest maximum penicillin G stability if about two molecules of salt per one
      penicillin molecule are present in solution.

PMID- 15010140
TI  - Applications of NIR spectroscopy to monitoring and analyzing the solid state
      during industrial crystallization processes.
AB  - Fiber-optic near infrared (NIR) spectroscopy was used to investigate several key
      features of the polymorphic transitions observed during the crystallization and
      the filtration of SaC, an Active Pharmaceutical Ingredient (API) produced by
      Sanofi-Synthelabo. Using few samples, the spectroscopic data were calibrated to
      provide measurements of the polymorphic composition of the solid product which is
      likely to appear in two crystalline forms or in the amorphous state. Both
      qualitative and quantitative methods were successfully evaluated to characterize
      the API. The NIR spectroscopy measurement was then applied to investigate the
      kinetic behavior of the phase transition phenomena against various operating
      conditions. From the viewpoint of industrial process development several
      applications are presented. The effects of temperature and seed crystal habits on
      the rate of transition of filtration cakes are briefly investigated; and a study
      of the effect of residual water in the solvent on the transition occurring during
      filtration is more deeply analyzed. The experimental results demonstrate that
      highly valuable information can be provided by the NIR spectroscopy measurements,
      when one aims at understanding more deeply and optimizing the consequences of
      various and complex phenomena involved during the solid processing chain.

PMID- 15010141
TI  - Predicting the physical state of spray dried composites: salbutamol
      sulphate/lactose and salbutamol sulphate/polyethylene glycol co-spray dried
      systems.
AB  - The effect of spray drying salbutamol sulphate, salbutamol sulphate/lactose and
      salbutamol sulphate/polyethylene glycol (PEG) solutions was investigated. Co
      spray drying salbutamol sulphate with lactose, which is amorphous when spray
      dried alone, resulted in amorphous composites. Co-spray drying salbutamol
      sulphate with PEG 4000 and PEG 20,000, which do not form amorphous systems when
      spray dried alone, resulted in systems of varying crystallinity, the
      crystallinity depending on the weight ratio of polymer to drug. Examination of
      the physical properties of these salbutamol sulphate co-spray dried systems and
      those of bendroflumethiazide/PEG and lactose/PEG composites suggested that the
      formation and physical stability of amorphous composites prepared by spray drying
      is dependent on whether the glass transition temperature, Tg, of one of the two
      components is high enough to result in a Tg of the composite sufficiently high
      that the Kauzmann temperature of the mix is greater than the temperature of
      storage. The modified Gordon-Taylor equation proved to be useful in predicting
      the likelihood that a two-component composite will be amorphous on spray drying.
      Furthermore, the Gordon-Taylor equation was also useful in predicting the likely
      physical stability of amorphous two component composites and predicted that even
      polymers with apparently low Tgs, such as PEGs, may be stabilised in an amorphous
      composite by a suitable additive having a sufficiently high Tg.

PMID- 15010142
TI  - Twin screw granulation as a simple and efficient tool for continuous wet
      granulation.
AB  - The modification of a twin screw extruder for continuous wet granulation was
      investigated. Modification of the extruder setup as well as the screw design
      allowed the continuous wet granulation of alpha-lactose monohydrate without the
      need of a wet sieving step. The robustness of twin screw granulation was
      evaluated by studying the influence of processing parameters and formulation
      variables on the process performance and on the properties of alpha-lactose
      monohydrate granules and tablets. The process reproducibility during long term
      production was evaluated. Screw speed (200-450 rpm) and total input rate (5.5-9.5
      kg/h) had no significant influence on the granule properties, while the water
      concentration during granulation influenced the process as well as the granule
      properties. At a water concentration (calculated on wet granule basis) of 5.5
      8.5%, continuous twin screw granulation of alpha-lactose monohydrate 200 M was
      feasible and the granules obtained had good properties. PVP addition mainly
      affected tablet properties. Tablets made from granules containing 2.5% PVP had a
      tensile strength above 0.94 MPa, a friability below 1% and a disintegration time
      ranging between 495 and 576 s. Tablets containing hydrochlorothiazide complied
      with the dissolution requirements as 60% was released after 5 and 15 min from
      tablets without PVP and with 2.5% PVP, respectively. No problems were observed
      during continuous twin screw granulation over a period of 8h and the granule and
      tablet properties were reproducible throughout the process. These results
      indicated that twin screw granulation is an efficient tool for continuous wet
      granulation.

PMID- 15010143
TI  - Determining the relative physical stability of anhydrous and hydrous crystal
      forms of GW2016.
AB  - The slurry equilibration method used to determine the relative physical stability
      of polymorphs is extended to a crystal system of an anhydrate and hydrate. The
      method involves preparation of organic/aqueous slurries of known water activity
      containing mixtures of the anhydrate and hydrate forms. The slurries equilibrate
      to the lowest free energy form, from which the relative physical stability is
      determined as a function of relative humidity. The method is particularly
      valuable when one or more of the crystal forms is kinetically stable, since
      solvent-mediated transformation accelerates the conversion process. Results are
      provided for GW2016 anhydrate and monohydrate crystal forms, for which it was
      determined that interconversion occurs between 7 and 15% relative humidity.

PMID- 15010144
TI  - The release of cefazolin and gentamicin from biodegradable PLA/PGA beads.
AB  - Infection has been one of the most common causes of problems and complications
      after the operation despite the advance in surgical techniques and the
      availability of newly developed antibiotics. Local antibiotic delivery beads for
      treatment of various surgical infections had been studied recently especially in
      osteomyelitis. This current paper used cefazolin sodium and gentamicin sulfate
      combined with biodegradable polymers (50:50 poly(DL-lactide):co-glycolide) as
      antibiotic beads for a long-term drug release. To manufacture an antibiotic bead,
      polylactide-polyglycolide copolymers were mixed with the antibiotics. The mixture
      was compressed and sintered at 55 degrees C to form beads of different sizes. The
      beads were placed in 3 ml of phosphate buffered saline and incubated at 37
      degrees C. An elution method combined with a bacterial inhibitory test was
      employed to characterize the release rate of the antibiotics over a 30-day
      period. The results suggested that the biodegradable beads released high
      concentrations of antibiotic (well above the minimum inhibitory concentration) in
      vitro for the period of time needed to treat bone infection; i.e. 2-4 weeks. This
      provides advantages as a first line choice of long-term antibiotics for patients
      with osteomyelitis and various infections such as thoracic, abdominal, and pelvic
      infections, as well as for the prophylaxis of these infections.

PMID- 15010145
TI  - The estimation of glutaminyl deamidation and aspartyl cleavage rates in glucagon.
AB  - The major hydrolytic degradation pathways of glucagon under acidic conditions are
      cleavage at Asp-9, Asp-15, and Asp-21, and deamidation at Gln-3, Gln-20, Gln-24,
      and Asn-28. The rate constants for these pathways were determined in the pH range
      1-2.4 at 60 degrees C by kinetic data analysis of substrate and degradation
      product concentration-time profiles. Deamidation kinetics were determined using
      penta-peptide fragments of glucagon containing the labile amide residue. The
      accurate determination of the cleavage rate constants was confounded by the
      complexity of the degradation scheme of glucagon. Peptide cleavage kinetics were
      determined by degradation of glucagon and its cleavage fragments under identical
      conditions and the use of area-under-the-curve (AUC) and nonlinear regression
      methods of analysis. Glucagon degradation was first-order with respect to time
      and concentration in the range of 31-00 microM. Glutaminyl deamidation rate
      constants were first-order with respect to hydronium ion concentration and were
      similar for all three residues indicating a lack of sequence effects. The rate
      constants for Asp cleavage were not first-order with respect to hydronium ion
      concentration and cleavage at Asp-21 was slower than cleavage at Asp-9 and Asp-15
      over the studied pH range.

PMID- 15010146
TI  - Neonatal thrombosis and its treatment.
AB  - Thromboembolic disease (TE) has been described as the new epidemic of tertiary
      paediatrics, and no where is this more evident than in the neonatal population.
      As survival of premature and sick newborns has improved, the frequency of
      complications associated with intensive supportive therapy and monitoring has
      increased. Clinically significant thrombosis is emerging as one of the more
      common complications associated with improved neonatal outcome. The long-term
      implications of neonatal thrombosis are only just being realised. This systematic
      review will consider the epidemiology, diagnostic strategies, and outcome for
      both arterial and venous TE in neonates. The role of inherited thrombophilic
      abnormalities, and the evidence for anticoagulation therapy will also be
      considered. The lack of high level evidence in determining optimum therapy is
      obvious. Further research regarding diagnostic strategies, and optimal therapies
      is urgently needed.

PMID- 15010147
TI  - Haemophilia and the newborn.
AB  - Haemophilia A and B are the most common of the inherited bleeding disorders.
      Haemophilia in the newborn presents a number of challenges in terms of both
      diagnosis and management which reflect features unique to this age group. In the
      presence of a family history of haemophilia optimal management requires close co
      operation between three individual specialist groups - obstetricians,
      haematologists and neonatologists, who each have an important role to play in
      ensuring a safe outcome for these infants. More problematic is where a family
      history is absent or has not been adequately elucidated in which case the
      diagnosis of haemophilia in the neonate will be unsuspected. Diagnostic
      difficulties may then arise due to failure to recognise the presence of abnormal
      bleeding, which is often different from that typically observed in older children
      with haemophilia. In addition, diagnostic investigations are complicated by
      physiological differences in the neonatal haemostatic system. Although major
      bleeding is relatively uncommon, the incidence of intracranial haemorrhage is
      higher during the first few days of life than at any other stage in childhood,
      which relates to the trauma of delivery. Controversy, however, remains on optimal
      strategies for both prevention and management of this potentially devastating
      complication.

PMID- 15010148
TI  - Central venous catheters in children with haemophilia.
AB  - Infections, thrombosis and technical problems are the most frequent complications
      when using implantable central venous access devices in patients with
      haemophilia. There seem to be two major experiences concerning infections in non
      inhibitor patients, one is approx. 0.2 infections per 1000 days and the other
      approx. 1.0(0.7-1.6)/1000 days. Infections are more frequent in inhibitor
      patients and one can expect approx. one infection per 6-12 months of use. The
      figures are low for clinically apparent thrombosis in the larger series on
      record, but routine venograms were not done in most of these series. In studies
      where this has been done, a high frequency of abnormalities on venograms have
      been seen in some but not in others. The final decision to use a central line has
      to be a compromise between the medical goal, the patient's bleeding tendency, the
      social situation and the expected risk of complications at the particular
      haemophilia center. Some of the complications may be reduced by adequate aseptic
      measures both during implantation and in the subsequent use and clear basic
      routines for surveillance of the systems and repeated education of the users.

PMID- 15010149
TI  - Prophylactic factor replacement in hemophilia.
AB  - Prophylaxis, the regular infusion of coagulation factor concentrates to severe
      hemophiliacs, has been an evolving therapeutic tool of management for the past
      three decades. Multiple clinical trials have and continue to be conducted in the
      field of prophylaxis in an attempt to determine ideal regimens of prophylaxis,
      its benefits, its risks and costs, and to address still unanswered questions; who
      to place on prophylaxis, when to start prophylaxis, when (if ever) to stop
      prophylaxis, etc. We present a detailed review and discussion of the evolution of
      prophylaxis as a tool in managing patients with hemophilia and we address the
      major issues and still unanswered questions.

PMID- 15010150
TI  - Cytogenetics in acute leukemia.
AB  - Cytogenetic analyses in acute myeloid leukemia (AML) and acute lymphoblastic
      leukemia (ALL) have revealed a great number of non-random chromosome
      abnormalities. In many instances, molecular studies of these abnormalities
      identified specific genes implicated in the process of leukemogenesis. The more
      common chromosome aberrations have been associated with specific laboratory and
      clinical characteristics, and are now being used as diagnostic and prognostic
      markers guiding the clinician in selecting the most effective therapies. Specific
      chromosome aberrations and their molecular counterparts have been included in the
      World Health Organization classification of hematologic malignancies, and
      together with morphology, immunophenotype and clinical features are used to
      define distinct disease entities. However, the prognostic importance of less
      frequent recurrent aberrations in AML and ALL, both primary and secondary, is
      still to be determined. This review summarizes current views on clinical
      relevance of major cytogenetic findings in adult AML and ALL.

PMID- 15010151
TI  - Novel therapies for chronic lymphocytic leukemia.
AB  - New therapies for chronic lymphocytic leukemia (CLL) are moving away from non
      specific cytotoxic to more targeted approaches. The monoclonal antibody
      alemtuzumab induces responses in 33% to 43% of patients with relapsed or
      refractory disease, with 2-5% CR. Side effects include infusional reactions as
      well as immunosuppressive effects. Rituximab has limited activity in relapsed
      refractory patients, but response rates are comparable to follicular non
      Hodgkin's lymphoma in untreated patients. Other antibodies in early phases of
      development include anti-CD23 [IDEC-152], anti-CD22 [epratuzumab], Hu1D10
      [apolizumab], and anti-CD80 [anti-B7, IDEC-114]. Other agents that are being
      studied include denileukin diftitox fusion protein (Ontak), and bcl-2 antisense
      [G3139, Genasense]. The mechanism of action of the new drugs and their role in
      CLL, as well as the emergence of new prognostic markers are discussed.

PMID- 15010152
TI  - Tubular repair of the median or ulnar nerve in the human forearm: a 5-year follow
      up.
AB  - The long-term outcome from silicone tube nerve repair was compared with the
      outcome from routine microsurgical repair in a clinical randomized prospective
      study, comprising 30 patients with median or ulnar nerve injuries in the distal
      forearm. Postoperatively, the patients underwent neurophysiological and clinical
      assessments of sensory and motor function regularly over a 5-year period. After 5
      years there was no significant difference in outcome between the two techniques
      except that cold intolerance was significantly less severe with the tubular
      technique. In the total group there was ongoing improvement of functional
      sensibility throughout the 5 years after repair. It is concluded that tubular
      repair of the median and ulnar nerves is at least as good as routine
      microsurgical repair, and results in less cold intolerance.

PMID- 15010153
TI  - Thenar flap for severe finger tip injuries in children.
AB  - Twelve children aged between 18 months and 11 years old who had sustained a
      severe fingertip amputation with total or subtotal pulp loss were treated with a
      distal-based thenar flap. The injuries were palmar oblique amputations or
      avulsion injuries involving the pulp and the nail bed. The pedicles of the thenar
      flaps were divided after 18 to 25 days and none suffered any necrosis. At the
      final follow-up, no interphalangeal joint contractures were found, the average
      two point discrimination was 5mm, the thenar scar was asymptomatic and the
      subcutaneous tissue of the thenar flap was providing sufficient bulk to produce a
      rounded contour, like a normal fingertip. The thenar flap is a useful technique
      for use with severe fingertip injuries when local flaps cannot provide enough
      soft tissue and replantation is not possible.

PMID- 15010154
TI  - A randomized controlled trial of knifelight and open carpal tunnel release.
AB  - A randomized controlled trial was done to compare the results of carpal tunnel
      decompression using the standard open approach and the Knifelight technique.
      Twenty-six patients with bilateral carpal tunnel syndrome requiring operation
      were selected for the study and the operative technique was randomized for the
      first hand. Six weeks later, the second hand was operated upon using the
      alternate technique. There was little difference between the two techniques with
      regard to time taken to return to work, return of grip strength, symptom relief,
      complications, incidence of pillar pain and patient preference. However, the
      incidence of scar tenderness was significantly lower with the Knifelight
      technique.

PMID- 15010155
TI  - Minimally invasive fixation versus conservative treatment of undisplaced scaphoid
      fractures: a cost-effectiveness study.
AB  - This study compares the direct and indirect costs of conservative and minimally
      invasive treatment for undisplaced scaphoid fractures. Costs data concerning
      groups of non-operated and operated patients were analysed. Direct costs were
      higher in operated patients. Although highly variable, indirect costs were
      significantly smaller in operated patients and the total costs were higher in non
      operated patients. In conclusion, operative treatment of scaphoid fractures is
      initially more expensive than conservative treatment but markedly decreases the
      work compensation costs.

PMID- 15010156
TI  - The indications for toe transfer after "minor" finger injuries.
AB  - Toe-to-hand transfer is widely considered to be unjustified for "minor" finger
      injuries. In this invited personal view article the indications for toe-to-hand
      transfer for finger amputation and neurocutaneous and major pulp defects are
      discussed, and a classification of multidigital injury that has both prognostic
      and decision-making value is presented. In the author's opinion a toe transfer
      should always be considered as an option when reconstructing "minor" finger
      injuries, as it can reproduce significant long-term benefit to the hand and the
      patient's sense of well being. The procedure should be carried out in the acute
      period, not only because it is technically easier and better for hand function,
      but above all because the surgeon can save structures that will be lost if the
      transfer is delayed.

PMID- 15010157
TI  - Tension band wiring of unstable transverse fractures of the proximal and middle
      phalanges of the hand.
AB  - Twenty-three isolated, unstable and closed transverse middle and proximal
      phalangeal shaft fractures in 23 patients were treated by tension band wiring.
      The tension band was applied with two transverse Kirschner wires that did not
      cross the fracture line. All of the fractures united and achieved satisfactory
      functional outcomes. No patient required either physiotherapy or tenolysis or
      capsulotomy surgery.

PMID- 15010158
TI  - Open reduction and screw fixation of mallet fractures.
AB  - Twelve patients with mallet fractures treated by open reduction and internal
      fixation with small screws were reviewed at an average of 31 months after
      surgery. The indication for surgery was a fracture involving more than one-third
      of the distal phalanx articular surface or with subluxation of the distal
      interphalangeal joint. Loss of reduction occurred in one patient and in another
      one screw loosened slightly without loss of reduction. There were no nail
      deformities, infections, or secondary procedures. The mean range of motion was
      from 6 degrees (range, 0-30 degrees ) (extensor lag) to 70 degrees (range, 60-90
      degrees ) flexion. Ten patients had no evidence of degenerative changes, one had
      minor joint space narrowing and one had significant deformity. Open reduction and
      screw fixation with small screws can lead to satisfactory outcome in appropriate
      patients.

PMID- 15010159
TI  - Acquired localized subcutaneous cavernous vascular malformations of the hand.
AB  - A series of 15 patients with acquired localized subcutaneous cavernous (venous)
      vascular malformations of the hand is reported. There were nine women and six
      men. The malformation was first noted at a mean age of 24 years (range, 16-40
      years). Six patients had solitary lesions and nine had multiple lesions. A
      painful mass was the most common presenting symptom. Calcification within the
      malformation was noted radiologically in one-third of the patients. Patients were
      managed with simple excision of the symptomatic lesions with no recurrence.

PMID- 15010160
TI  - A comparison of two indices for ulnar translation and carpal height in the
      rheumatoid wrist.
AB  - The indices for ulnar translation described by Chamay et al. (1983, Annales de
      Chirurgie de la Main, Vol. 2, pp. 5-17), and Bouman et al. (1994, Journal of Hand
      Surgery Vol. 19B, pp. 325-329), and for carpal height described by Youm et al.
      (1978, Journal of Bone and Joint Surgery, Vol. 40A, pp. 423-431) and Bouman et
      al. (1994) were compared in pre- and postoperative wrist X-rays of 91 patients
      with rheumatoid arthritis undergoing radiolunate arthrodesis. Both indices
      described by Bouman had a higher applicability and sensitivity than the Chamay
      and Youm indices and are recommended for use with the rheumatoid wrist. However
      false-negative values may result when the Bouman index for ulnar translation is
      used to follow up radiolunate arthrodesis.

PMID- 15010161
TI  - Radiographic changes after resection of the distal ulna in rheumatoid arthritis.
AB  - Progressive ulnar translocation of the carpus and problems with the ulnar stump
      have been reported after resection of the distal ulna in rheumatoid arthritis
      (RA). However this has only occasionally been quantitatively assessed. In this
      study 24 wrists in 21 patients with RA were followed up for an average of 100
      months after resection of the distal ulna. An additional 24 wrists in 14 non
      operated RA patients were followed up for 92 months. In a retrospective
      radiographic analysis we demonstrate similar increases in ulnar translocation and
      ulnar-carpal distances in both groups.

PMID- 15010162
TI  - Tissue reaction to titanium debris following Swanson arthroplasty in the hand: a
      report of two cases.
AB  - Silicone abrasion particles are known to cause inflammatory changes following
      Swanson arthroplasty. Titanium grommets were introduced to protect the implants
      from wear and abrasion. Two cases with histological evidence of symptomatic
      titanium particulate tissue inflammation following Swanson joint replacement with
      grommets are presented.

PMID- 15010163
TI  - The towel test: a useful technique for the clinical and electromyographic
      evaluation of obstetric brachial plexus palsy.
AB  - The towel test consists of covering an infant's face with a towel and seeing if
      he/she can remove it with either arm. In this study it has been used to aid the
      clinical and electromyographic assessment of 21 infants with obstetric brachial
      plexus palsy. At 2 to 3 months, none of the 21 infants succeeded in removing the
      towel, either with their normal or affected arm. At 6 months, all the infants
      succeeded in removing the towel with their normal arm, but 11 could not with
      their affected arm, and the same was observed at a further assessment at 9
      months. The towel test is a reliable technique for evaluating children with
      obstetric brachial plexus injuries.

PMID- 15010164
TI  - Dash and Boston questionnaire assessment of carpal tunnel syndrome outcome: what
      is the responsiveness of an outcome questionnaire?
AB  - This prospective study evaluates if the Disabilities of the Arm, Shoulder and
      Hand (DASH) questionnaire is an adequately responsive outcome measure in carpal
      tunnel syndrome by comparing it with the disease-specific Boston questionnaire
      (BQ). To measure responsiveness (sensitivity to clinical change), 57 patients
      with a clinical diagnosis of carpal tunnel syndrome completed the DASH and BQ
      preoperatively and again 3 months after open carpal tunnel decompression. A
      second group of 31 patients completed the questionnaires in the outpatient clinic
      and again 2 weeks later to assess test-retest reliability. The time to complete
      all questionnaires was recorded. Responsiveness of the DASH is comparable with
      the BQ with standardized response means of 0.66, 1.07 and 0.62 for the DASH, BQ
      symptoms and BQ-function, respectively. Test-retest data show both questionnaires
      are reliable. Mean times to complete questionnaires were 6.8minutes (DASH) and
      5.6minutes (BQ). This study concludes that the DASH questionnaire is a reliable,
      responsive and practical outcome instrument in carpal tunnel syndrome.

PMID- 15010166
TI  - Tumoral calcinosis infiltrating the biceps brachii tendon - excision and
      reconstruction with allograft: a case report.
AB  - Two patients with limited elbow motion due to tumoral calcinosis underwent
      resection of calcified masses around the elbow joints. This necessilated removal
      of the distal two thirds and three fourths of the biceps muscles. The resulting
      defects were reconstructed with homologous Achilles tendon grafts. Both patients
      regained M4 muscle power and no recurrences were observed.

PMID- 15010165
TI  - Assessment of mRNA levels for matrix molecules and TGF- beta1 in rabbit flexor
      and peroneus tendons reveals regional differences in steady-state expression.
AB  - This study analysed the differences on a molecular level between two segments of
      the deep flexor tendon, and compared the intrasynovial flexor tendon with the
      tendon sheath and the extrasynovial peroneus tendon in a rabbit model. The
      TRIspin method of RNA extraction was combined with the reverse transcription
      polymerase chain reaction to assess mRNA levels in the tissue segments.
      Significant differences were detected for all genes studied. mRNA levels for
      aggrecan, biglycan and collagen III were significantly higher in the
      fibrocartilaginous proximal segment of the flexor tendon. Collagen I was higher
      in the flexor tendon than the sheath and the peroneus tendon, and TGF-beta1 was
      significantly lower in the peroneus tendon. This study demonstrates differences
      at the mRNA level between different segments of tendon, indicating that the
      tendon tissue may be adapted to its environment.

PMID- 15010167
TI  - Radiographic optimization of the Eaton classification.
AB  - Thumb basal arthritis is evaluated using the Eaton classification. However, the
      shape and orientation of the trapezium do not allow easy visualization of this
      bone. The purpose of this study was to determine if the intra- and interobserver
      reliability of the Eaton classification could be improved using a combination of
      X-rays. Six hand surgeons independently evaluated 40 sets of X-rays. First, the X
      rays were staged using the posterior-anterior and lateral views of the wrist, and
      then using just the Bett's (Gedda's) view. Subsequently, all three views were
      evaluated together. The process was repeated at least 1 week later. Intra- and
      interobserver reliability was measured using kappa statistics. Results show a
      trend toward increased reliability when the three views are used. Agreement
      between the stages using the posterior-anterior and lateral X-rays and the Bett's
      view was only fair. With three views, intraobserver reproducibility is good while
      interobserver reliability is moderate.

PMID- 15010168
TI  - Repair of distal biceps tendon ruptures using a suture anchor and an anterior
      approach.
AB  - In a prospective study, eight consecutive patients with nine ruptures of the
      distal biceps tendon underwent repair through a single incision. All patients
      were satisfied with their clinical results and had full ranges of elbow and
      forearm motion. There were no radial nerve injuries and no radio-ulnar
      synostoses. Isokinetic testing, after correction for dominance, demonstrated a 6%
      strength deficit, but 7% higher endurance in the repaired extremity for the
      flexion-concentric test, and no strength deficit and 13% higher endurance for
      supination. The improved endurance is probably explained by initial reduced
      effort due to apprehension which minimized subsequent fatigue.

PMID- 15010169
TI  - The crepe bandage as an alternative to the Esmarch bandage for upper limb
      exsanguination: a volumetric comparison study.
AB  - A study was carried out to compare the effectiveness of upper limb exsanguination
      using the Esmarch bandage, a crepe bandage and the Rhys-Davies exsanguinator.
      Upper limb volume changes were measured in ten volunteers using a water
      displacement method. The crepe bandage produced a mean volume reduction of 59 ml
      (range, 39-94), which was very similar to the Esmarch bandage, which achieved 63
      ml (range, 42-101). This difference is negligible in practical terms. Both
      bandages were more effective than the Rhys-Davies exsanguinator, which reduced
      the volume by a mean of 28 ml (range, 11-54). It is our opinion that the use of
      the Esmarch bandage in hand surgery is unnecessary and recommend the crepe
      bandage as a safer alternative.

PMID- 15010170
TI  - Evaluation of a novel tourniquet device for bloodless surgery of the hand.
AB  - This study evaluates a new device (S-MART ) for exsanguination and occlusion of
      the blood flow to the arm for hand surgery. The device consists of a silicone
      ring wrapped within a sterile stockinette and pull straps. It is applied by
      placing it on the patient's fingers and rolling it up the limb to the desired
      occlusion site by pulling on the straps. The time for placement and removal of
      the device was measured during trigger release and carpal tunnel surgery and the
      quality of exsanguination was evaluated. The device could be placed and removed
      quickly and provided an excellent bloodless field. At follow-up examination no
      signs or symptoms were seen at the site of the S-MART occlusion and no
      complications were observed in any patient.

PMID- 15010171
TI  - Mycetoma of the hand caused by Gordona terrae: a case report.

PMID- 15010172
TI  - A simple tendon retrieval method.
AB  - This report describes a simple technique of retrieving retracted proximal flexor
      tendon ends in Zone II injuries. This technique utilizes steel wires that are
      readily available in any hand set in the operating room. We have found that this
      is a consistently successful and atraumatic technique.

PMID- 15010174
TI  - Letter to the editor.

PMID- 15010173
TI  - Letters to the editor.

PMID- 15010175
TI  - Exposure to binge food in bulimia nervosa: finger pulse amplitude as a potential
      measure of urge to eat and predictor of food intake.
AB  - The conditioning model of binge eating states that cues such as the sight, smell
      and taste of binge food prepare the binger's body for the intake of large amounts
      of food. The bodily preparations are supposed to be felt as an almost
      irresistible urge to binge. In the present study, the validity of the model was
      tested. Clinical binge eaters (bulimia nervosa patients) and healthy control
      participants were exposed to their most favourite food and physiological
      responding was measured. As predicted, the exposure increased physiological
      responding and led to more intense urge to eat, but no significant differences
      between the bulimics and the normal controls were found. For both groups,
      increased urge to eat appeared to be related to finger pulse amplitude (FPA), and
      both the FPA and the self-reported urge to eat predicted increased caloric intake
      during a subsequent taste test. It is concluded that changes in FPA might reflect
      classically conditioned bodily responses that prepare for eating.

PMID- 15010176
TI  - Sensitivity to reward: implications for overeating and overweight.
AB  - Sensitivity to reward (STR)-a personality trait firmly rooted in the neurobiology
      of the mesolimbic dopamine system-has been strongly implicated in the risk for
      addiction. This construct describes the ability to derive pleasure or reward from
      natural reinforcers like food, and from pharmacologic rewards like addictive
      drugs. Recently experts in the field of addiction research have acknowledged that
      psychomotor stimulant drugs are no longer at the heart of all addictions, and
      that brain circuits can also be deranged with natural rewards like food. The
      present study tested a model in which STR was expected to relate positively to
      overeating, which in turn would be associated with higher body weight in woman
      aged 25-45 years. As predicted, STR was correlated positively with measures of
      emotional overeating. Also, overweight woman were significantly more sensitive to
      reward than those of normal weight. Interestingly, however, the obese woman (Body
      Mass Index>30) were more anhedonic than the overweight woman (Body Mass
      Index>25<30). These findings are discussed in the context of neuroadaptations to
      overactivity of brain reward circuits. Results also indicate that STR may serve
      as a risk factor for overeating and overweight, especially in cultures such as
      ours where palatable, calorically-dense food is plentiful.

PMID- 15010177
TI  - Binge-type eating induced by limited access in rats does not require energy
      restriction on the previous day.
AB  - This study was designed to determine if a limited access feeding protocol would
      induce binge-type eating when energy intake on the day before the binge was not
      reduced. Rats were assigned to four groups; all groups had continuous access to
      chow and water throughout the 4 wk study. In addition, access to optional
      shortening was provided as follows: (1) Control (C): no access to shortening, (2)
      Regular Shortening Access-7 (RSA7): 2-h access everyday, (3) Regular Shortening
      Access-3 (RSA3): 2-h access every Monday, Wednesday, and Friday, (4) Irregular
      Shortening Access (ISA): 2-h access on various days, such that the number of
      shortening access (binge) sessions equaled that of RSA3, but the last three
      sessions were each separated by 4 days. On the days prior to the last two binge
      sessions, RSA3 consumed significantly less energy than any other group (p < 0.05)
      but ISA intakes equaled those of Control and RSA7. During the last two binge
      sessions, intakes of RSA3 and ISA did not differ, and both groups consumed
      significantly more than RSA7 or Control (p < 0.05) These results demonstrate that
      binge-type eating can be induced by limiting access to an optional fatty food,
      and does not depend upon undereating on the previous day.

PMID- 15010178
TI  - Effects of added glutamate on liking for novel food flavors.
AB  - Adding glutamate to foods increases their umami quality, their acceptability and
      their consumption. The functional significance of this palatability is unclear.
      Other highly palatable substances, e.g. sugar and fats, also increase liking for
      novel flavors with which they are repeatedly paired, especially when ingested.
      This is thought to reflect the rewarding effects of sugar and fat energy, post
      ingestion. To determine if a liking for novel flavors can also be conditioned
      using glutamate, 44 subjects rated 10 ml samples of three novel soups for liking
      and familiarity, both before and after seven daily exposures to each of two soup
      flavors-one with added monosodium l-glutamate (MSG) (0.5% w/w; MSG+) and one
      without (MSG-). During exposure, subjects received either a 250 ml bowl of soup
      (Consume group) or a 10 ml sample (Taste group). There were no significant
      differences as a function of samples or groups, despite some trends for changes
      in liking to be higher in the consumed MSG+ condition. In a second experiment, 69
      subjects were divided into three groups (Consume MSG+; Consume MSG-; Taste MSG+)
      in which they received nine exposures to one novel soup flavor. The Consume MSG+
      group showed a significantly greater increase in liking than either the Consume
      MSG- or the Taste MSG+ groups, which did not differ. Changes in familiarity
      ratings reflected amount consumed, not MSG content. Pairing glutamate with a
      novel flavor can condition liking for that flavor. While post-ingestive effects
      of glutamate may be rewarding, flavor conditioning cannot be ruled out.

PMID- 15010179
TI  - Mental health and food habits among employed women and men.
AB  - The aim of this study was to examine the association between mental health and
      recommended food habits among employed middle-aged women and men. A mail survey
      including data on mental health and intake of food items was collected from 40 to
      60-year-old women (n=4991) and men (n=1252) employed by the City of Helsinki. The
      participants' current mental health status was assessed by the General Health
      Questionnaire 12-item version and categorised into 'poor' (score 3-12) and
      'normal' mental health (score 0-2). Multivariable logistic regression analyses
      were conducted using this categorisation as an independent variable to predict
      recommended food habits among women and men. All analyses first adjusted for age
      and lifetime mental diagnosis, secondly socio-economic status variables, and
      thirdly health behaviours. Women having poor mental health were less likely than
      their healthier counterparts to report consuming fresh vegetables, fresh fruits,
      low-fat milk and low-fat cheese on a daily basis, and cereals or porridge at
      least five times a week. Men having poor mental health reported consuming less
      frequently fresh fruits and dark bread. Except for cereals and dark bread, these
      results remained statistically significant in the fully adjusted model. The
      results suggest that poor mental health is associated with unhealthy food habits.

PMID- 15010180
TI  - Explaining fruit and vegetable consumption: the theory of planned behaviour and
      misconception of personal intake levels.
AB  - The influence of individuals' misconceptions in assessing fruit and vegetable
      consumption on the ability of the theory of planned behaviour to explain variance
      in the consumption of these foods was studied. Dutch women (mean age 41, n=159)
      completed a questionnaire assessing the theory's constructs with regard to the
      daily consumption of at least two pieces of fruit and 200 gram of vegetables.
      Consumption was assessed using a self-rated measure and more objectively with a
      food-frequency questionnaire. Both measures were combined to classify
      participants according to the accuracy of their self-assessed intake levels
      ('realists' vs. 'overestimators'). The model explained variation in objective
      fruit and vegetable intake much better among realists (R2 = 45% for fruits and
      39% for vegetables) than among overestimators (R2 = 18% and 5%, respectively).
      Perceived behavioural control was the strongest predictor of intentions and
      behaviour. When plasma vitamin C and carotenoid concentrations were used as
      objective indicators for fruit and vegetable intake, the explanatory value of the
      model was lower, but again more variance was explained among realists than among
      overestimators. We conclude that awareness of personal behaviour should be taken
      into account when applying the theory of planned behaviour to explain dietary
      behaviours as well as to design health education interventions.

PMID- 15010181
TI  - Differential effects of active and passive stress on food intake in restrained
      and unrestrained eaters.
AB  - This study examined the effects of active (AC) and passive coping (PC) stress
      tasks on food intake in female restrained (n = 20) and unrestrained eaters (n =
      20) Participants completed a reaction time task (AC), a cold-pressor test (PC),
      and a relaxation control condition separated by 1-week intervals. Food intake was
      assessed after each task. Self-reported anxiety, heart rate and blood pressure
      (BP) were measured before and after each task. Restraint was measured using the
      Dutch Eating Behaviour Questionnaire. Significant increases in BP were evident in
      the AC task only. Stress tasks produced significant increases in self-rated
      anxiety. Restrained eaters consumed more than unrestrained following the reaction
      time task, while the opposite was observed following relaxation. The findings of
      this study show that disinhibited eating of restrained eaters can be triggered by
      the distracting effects of a cognitively demanding task and may be independent of
      anxiety experienced.

PMID- 15010182
TI  - Nutritional knowledge and concerns about meat of elderly French people in the
      aftermath of the crisis over BSE and foot-and-mouth.
AB  - The aim of this study was to compare elderly people with young adults in France
      for nutritional knowledge and concerns about meat in the aftermath of the rises
      with bovine spongiform encephalopathy and foot-and-mouth disease. Between March
      and April 2001, 99 healthy elderly people and 93 younger adults living in France
      were interviewed. Most of the elderly and young participants knew that meat
      contains proteins but were unaware of the role of proteins in body metabolism.
      The elderly knew that meat also contains iron and vitamins and is necessary for
      growth and for physical activity. However, elderly people had little awareness of
      the importance of consuming meat and were convinced that they had to reduce meat
      consumption because of their lower physical activity. On the other hand, they
      knew more than younger adults about animal diseases and were less worried about
      'mad cow disease'. Thus, although the elderly people were confident about the
      safety of meat and recognised its nutritional properties, they did not consider
      it to be an essential food.

PMID- 15010183
TI  - Wake-promoting agents with different mechanisms of action: comparison of effects
      of modafinil and amphetamine on food intake and cardiovascular activity.
AB  - Despite efforts to achieve a desirable weight, two-thirds of the population has
      an elevated body weight. Medications are useful in supporting weight loss, but
      produce adverse effects. This study compared the effects of amphetamine and
      modafinil on food intake and cardiovascular activity in healthy men and women.
      Participants (n = 11) completed 11 sessions. In random order, participants
      received placebo on five separate sessions and single oral doses of modafinil
      (1.75, 3.5, or 7.0 mg/kg) and amphetamine (0.035, 0.07, 0.14 mg/kg). Free time
      between hourly performance testing intervals gave participants the opportunity to
      eat. Like amphetamine, modafinil reduced the amount of food consumed and
      decreased energy intake, without altering the proportion of macronutrients
      consumed. Although both medications significantly increase heart rate and blood
      pressure at higher doses, the dose of modafinil that was efficacious in
      decreasing food intake did not significantly increase heart rate. Modafinil may
      be well suited for the treatment of obesity, although further studies with
      repeated dosing in overweight populations are warranted. Modafinil may have less
      adverse health consequences than some anorectic agents and greater treatment
      efficacy.

PMID- 15010184
TI  - Cross-cultural validity of the food-related lifestyles instrument (FRL) within
      Western Europe.
AB  - The food-related lifestyle instrument (FRL) was tested for its validity across
      food cultures in Western Europe. First, responses from samples of 1000 or more
      consumers from each of Denmark, France, Germany, Spain and the UK were compared
      using multi-sample confirmatory factor analysis with structured means. The
      loadings, covariances and variances of the factors were invariant across
      countries, although item intercepts and error variances were not. In the second
      part of the analysis, replication samples (also Ns of 1000 or more) from France,
      Germany and the UK were examined for intra-cultural stability using the same
      statistical models. The factorial structure was completely invariant over time in
      three of five FRL domains, and subject to only minor variations in the other two
      domains. In the third part of the analysis, a revised version of the FRL was
      tested for cross-cultural validity, using consumer samples of 1000 each from
      France and the UK. This version of the FRL was also cross-culturally valid in
      factor loadings, covariances and variances, but still subject to variation
      between countries in item intercepts and error variances.

PMID- 15010185
TI  - Effects of food unit size and energy density on intake in humans.
AB  - The effects of food unit size (FU) and energy density (ED) on food consumption
      were explored in 20 adults using a within subjects 2 x 2 design study. The four
      food treatment combinations were provided in the laboratory in random order on
      four non-consecutive days. The foods differed in FU (small food unit (SFU) or
      customary food unit (CFU)) and energy density, by manipulating fat content (low
      (LED) or high (HED)). Appetitive responses and total grams and kilocalories
      consumed were monitored. Hunger, fullness, desire to eat and prospective
      consumption ratings were not significantly different between treatments. Gram
      weight of food consumed was constant across all treatments. Energy intake of HED
      foods was greater than LED foods independent of food unit size for breakfast
      (F(1,17) = 11.77, p < 0.001), lunch (F(1,17) = 4.70, p < 0.05) and the 24 h
      period (F(1,17) = 8.99, p < 0.001) but only tended to be increased at dinner. In
      summary, appetitive sensations were not markedly altered by food unit size or
      energy density. The daily gram weight of food consumed and appetitive ratings
      were relatively consistent across treatments resulting in higher energy intake
      with HED foods.

PMID- 15010186
TI  - Effect of television advertisements for foods on food consumption in children.
AB  - The impact of television (TV) advertisements (commercials) on children's eating
      behaviour and health is of critical interest. In a preliminary study we examined
      lean, over weight and obese children's ability to recognise eight food and eight
      non-food related adverts in a repeated measures design. Their consumption of
      sweet and savoury, high and low fat snack foods were measured after both
      sessions. Whilst there was no significant difference in the number of non-food
      adverts recognised between the lean and obese children, the obese children did
      recognise significantly more of the food adverts. The ability to recognise the
      food adverts significantly correlated with the amount of food eaten after
      exposure to them. The overall snack food intake of the obese and overweight
      children was significantly higher than the lean children in the control (non-food
      advert) condition. The consumption of all the food offered increased post food
      advert with the exception of the low-fat savoury snack. These data demonstrate
      obese children's heightened alertness to food related cues. Moreover, exposure to
      such cues induce increased food intake in all children. As suggested the
      relationship between TV viewing and childhood obesity appears not merely a matter
      of excessive sedentary activity. Exposure to food adverts promotes consumption.

PMID- 15010187
TI  - Influence of social norms and palatability on amount consumed and food choice.
AB  - In two parallel studies, we examined the effect of social influence and
      palatability on amount consumed and on food choice. In Experiment 1, which looked
      at amount consumed, participants were provided with either palatable or
      unpalatable food; they were also given information about how much previous
      participants had eaten (large or small amounts) or were given no information. In
      the case of palatable food, participants ate more when led to believe that prior
      participants had eaten a great deal than when led to believe that prior
      participants had eaten small amounts or when provided with no information. This
      social-influence effect was not present when participants received unpalatable
      food. In Experiment 2, which looked at food choice, some participants learned
      that prior participants had chosen the palatable food, others learned that prior
      participants had chosen the unpalatable food, while still others received no
      information about prior participants' choices. The social-influence manipulation
      had no effect on participants' food choices; nearly all of them chose the
      palatable food. The results were discussed in the context of Churchfield's (1995)
      distinction between judgments about matters of fact and judgments about
      preferences. The results were also used to illustrate the importance of
      palatability as a determinant of eating behavior.

PMID- 15010188
TI  - Letrozole-induced polycystic ovaries in the rat: a new model for cystic ovarian
      disease.
AB  - BACKGROUND: Our objective was to develop a new animal model for the study of
      polycystic ovaries by using the non-steroidal aromatase inhibitor, letrozole.
      METHODS: Thirty four rats were divided into four groups, including a control
      group of 10 rats that received vehicle only (1% aqueous solution of
      carboxmethlycellulose [CMC]) once daily orally (p.o.) and three treatment groups
      of eight rats each that were administered letrozole at concentrations of 0.1 or
      0.5 or 1 mg/kg p.o. dissolved in 1% CMC (2 mL/kg) once daily. The treatment
      period was 21 days. During this period, vaginal smears were collected daily for
      estrus cycle determination. On the day subsequent to last letrozole dose
      administration, rats were killed; uteri and ovaries were then excised and
      weighed. Serum hormone levels and histologic changes in ovaries were examined.
      RESULTS: When compared to control group, ovaries from study groups showed high
      incidence of subcapsular ovarian cyst and capsular thickening together with
      incomplete luteinization and decreased number of corpora lutea. Letrozole
      treatment brought about dose-dependent suppression of uterine weight despite
      having no significant effect on ovarian weight. Although serum estradiol and
      progesterone levels were reduced in a dose-dependent manner, testosterone levels
      were elevated as were levels of luteinizing hormone (LH). Serum follicle
      stimulating hormone (FSH) levels were markedly increased at higher doses of
      letrozole (0.5 and 1.0 mg/kg), contrary to low dose of letrozole (0.1 mg/kg) at
      which slight decrease was observed. CONCLUSIONS: Despite the fact that this is
      not a fully convincing model for the study of polycystic ovaries or of polycystic
      ovary syndrome (PCOS) as a whole, this animal model in several ways is similar to
      the human polycystic ovary syndrome.

PMID- 15010189
TI  - Sodium caseinate induces expression and secretion of murine multipotent myeloid
      cell line 32D macrophage colony-stimulating factor.
AB  - BACKGROUND: Evidence that sodium caseinate (CasNa) is capable of inhibiting
      proliferation of hematopoietic precursor cell line 32D and inducing its
      differentiation into macrophage cells has recently been published. Taking into
      consideration that hematopoiesis is regulated by growth factors and that
      macrophage colony-stimulating factor (M-CSF) is a well-known growth factor that
      induces differentiation of macrophages, in this work we evaluated whether CasNa
      is capable of inducing expression and secretion of M-CSF in 32D cells. METHODS:
      We cultured 32D cells in presence and absence of CasNa and compared their
      proliferation and viability. RNA was extracted from cell lysates to evaluate
      expression of the gene for M-CSF and its receptor. Cultured conditioned media was
      used to evaluate presence of M-CSF. RESULTS: Our results showed that CasNa
      inhibited proliferation of 32D cells and that conditioned media (CM) of these
      cultures contained M-CSF-like activity. Presence of M-CSF in CM was detected by
      inhibiting M-CSF activity with anti-M-CSF and presence of this growth factor was
      confirmed by ELISA assay. We also provided evidence that CasNa induced expression
      of mRNA for M-CSF in 32D cells as well as increased expression of mRNA for its
      receptor. CONCLUSIONS: CasNa inhibits proliferation of 32D cells and induces
      expression of the gene for M-CSF and that of its receptor. It also induces
      secretion of the bioactive form of M-CSF.

PMID- 15010190
TI  - Regeneration of beta-cells and neogenesis from small ducts or acinar cells
      promote recovery of endocrine pancreatic function in alloxan-treated rats.
AB  - BACKGROUND: We previously showed by using biochemical parameters that male
      Sprague-Dawley rats receiving a single intraperitoneal (i.p.) administration of
      alloxan (120 mg/kg body weight) with no further treatment recovered endocrine
      pancreatic function after 12 days. METHODS: Male Sprague-Dawley rats received an
      i.p. injection of alloxan (120 mg/kg body wt), were killed at 3, 6, 9, or 12 days
      (n=7), and their capacity to recover endocrine function was evaluated by means of
      a) biochemical parameters, which included glucose, triglyceride, and total
      cholesterol measurements and b) nuclear incorporation of 5'-bromodeoxyuridine
      (BrdU) by beta and acinar cells as well as presence of neogenesis from either
      ductal or acinar cells using double-staining BrdU-insulin immunohistochemical
      technique. RESULTS: Three days after receiving a single i.p. administration of
      alloxan, rats showed increase in serum glucose, triglyceride, and total
      cholesterol concentrations, reaching levels of 542.4+/-63.1, 907.6+/-154.9, and
      106.0+/-2.7 mg/dL (mean+/-standard deviation [SD]), respectively. At this time,
      increase in beta-cell replication was also observed, although this reached
      maximum by day 6 (p <0.001). Replication was also present in acinar cells, but
      these cells showed their maximum at day 3 (p <0.001) and subsequently decreased,
      as did beta-cells, almost steadily to normal values by day 12. Neogenesis of beta
      cells was observed mainly as transdifferentiation from acinar cells at day 3 and
      from ductal cells at day 6, after which it tended to be normal. CONCLUSIONS: Male
      Sprague-Dawley rats receiving a single i.p. alloxan dose tended to normalize
      their endocrine function by day 12 after alloxan administration. This process
      included both regeneration and neogenesis of pancreatic beta-cells from either
      ductal or acinar cells.

PMID- 15010191
TI  - Follicular fluid antibodies to Chlamydia trachomatis and human heat shock protein
      60 kDa and infertility in women.
AB  - BACKGROUND: The objective of this study was to establish the relationship between
      presence of anti-Chlamydia trachomatis and anti-HSP60 antibodies in serum and
      follicular fluid of infertile women. METHODS: Serum IgG and follicular fluid IgA
      to Chlamydia trachomatis and human heat shock protein 60 (HSP60) were determined
      in 41 women undergoing in vitro fertilization (IVF). RESULTS: A significant
      association was found between presence of bacterial antibodies in serum and IgA
      anti-HSP60 in follicular fluid. CONCLUSIONS: Chlamydia trachomatis infection
      might be triggering an autoimmune process that could negatively affect the
      success of IVF.

PMID- 15010192
TI  - Invasive Haemophilus influenzae type b infections in children in Paraguay.
AB  - BACKGROUND: In Paraguay, as in most Latin American countries, data on the
      epidemiology and clinical characteristics of Haemophilus influenzae type b (Hib)
      diseases are scarce and incomplete. METHODS: To address this issue, we performed
      a retrospective analysis of 102 patients admitted to the Instituto de Medicina
      Tropical, a referral hospital in Asuncion, Paraguay, between January 1991 and
      September 1995 with diagnosis of invasive Hib infection. This study included
      patients 15 years of age and under-identified with positive cultures for Hib in
      blood, cerebrospinal fluid, or other sterile body fluids. RESULTS: Eighty three
      (81%) patients presented with meningitis as principal focus of infection with
      median age of 9 months. Forty five (54%) patients with Hib meningitis were <12
      months of age and 20 (24% of total cases) were <6 months of age. Overall
      mortality rate of meningitis was 13%. Of 11 patients who died, 10 (91%) were <12
      months of age (p <0.02). Risk for mortality was correlated with presence of coma
      during admission (p <0.007) and CSF glucose level of <10 mg/dL (p <0.05). Severe
      sequelae such as bilateral hearing loss, hydrocephalus, and mental retardation
      were observed in 39% (28/72) of surviving patients, of whom 18 (51%) patients
      were <12 months of age (p <0.02). Thirty percent of isolated strains of Hib were
      resistant to ampicillin, 20% were resistant to chloramphenicol, and 10% to both
      drugs. CONCLUSIONS: This information provides evidence concerning the importance
      of continued support for Hib vaccine supplies in immunization programs in
      countries with limited resources such as Paraguay.

PMID- 15010193
TI  - Glycemic control, oxidative stress, and lipid profile in children with type 1
      diabetes mellitus.
AB  - BACKGROUND: In diabetes mellitus, persistence of hyperglycemia was reported to
      cause increased production of oxidative parameters including malondialdehyde
      (MDA). In the present study, the effect of glycemic control on oxidative stress
      and the lipid profile of pediatric type 1 diabetes mellitus (DM) patients were
      investigated. METHODS: Serum total cholesterol, HDL cholesterol, VLDL
      cholesterol, apolipoprotein A, apolipoprotein B, lipoprotein a, HbA(1c), and MDA
      levels were assessed in 96 children with type 1 DM. Study cases were evaluated in
      two groups in view of their mean HbA(1c) values, as metabolically well controlled
      (HbA(1c) < or =8%) and poorly controlled (HbA(1c) >8%) patients with DM. Fifty
      healthy children were included as normal controls. RESULTS: Total cholesterol,
      LDL cholesterol, apolipoprotein A, apolipoprotein B, and MDA levels of total
      diabetic patients were significantly (p<0.05) higher than those of the control
      group. Serum MDA levels and MDA/LDL cholesterol index were significantly
      increased in metabolically poorly controlled in relation to metabolically well
      controlled DM patients and were similar in metabolically well-controlled DM
      patients with relation to control group and in metabolically poorly controlled
      patients with relation to control group. CONCLUSIONS: In the present study,
      increased levels of MDA, MDA/LDL index, and dyslipoproteinemia showed that
      especially metabolically poorly controlled DM children are at high risk of
      atherosclerosis and vascular complications of DM and that there is a significant
      relationship between the lipid profile and oxidative stress. Thus, it may be
      appropriate to evaluate MDA in addition to routine laboratory assessments in
      evaluation of type 1 DM pediatric patients.

PMID- 15010194
TI  - Platelet aggregation in children with acute lymphoblastic leukemia during
      induction of remission therapy.
AB  - BACKGROUND: Development of thromboembolytic events is a major complication during
      induction of remission therapy (IRT) for acute lymphoblastic leukemia (ALL) of
      childhood. Increased in vitro platelet aggregation in response to drugs employed
      at this stage has been documented. To investigate the presence of an in vivo
      platelet agonist effect, we studied changes in aggregation patterns of patients
      with ALL receiving IRT. METHODS: Platelets from 22 children with a new diagnosis
      of ALL were obtained during IRT once the platelet count reached >100 x 10(9)/L.
      Platelets were stimulated with adenosine diphosphate (ADP), collagen, ristocetin,
      and epinephrine. Platelet responses were evaluated by optical aggregometry.
      RESULTS: Percentages of platelet aggregation in ALL patients were as follows:
      ADP, 89+/-22; collagen, 90+/-24; ristocetin, 84+/-26, and epinephrine, 81+/-20.
      Percentages in healthy individuals were ADP: 98+/-12; collagen: 105+/-10;
      ristocetin: 100+/-15, and epinephrine, 98+/-8. CONCLUSIONS: Platelet aggregation
      with classical agonists was diminished during IRT for ALL of childhood, although
      it remained within the normal lower limit for age. Considerable heterogeneity in
      platelet reactivity existed, probably reflecting the presence of several
      pharmacologically altered platelet subpopulations. No apparent clinical
      correlation of aggregometric changes was documented.

PMID- 15010195
TI  - Agreement between HbA1c measured by DCA 2000 and by HPLC: effects of fetal
      hemoglobin concentrations.
AB  - BACKGROUND: In subjects with type 1 diabetes, persisting elevations of fetal
      hemoglobin (HbF) have been demonstrated. This study evaluated whether HbF levels
      typically seen in type 1 diabetes (up to 3%) interfere with glycohemoglobin
      determinations using a common immunologic method (DCA 2000). METHODS: HbA(1c) was
      measured by high-performance liquid chromatography (HPLC) using a Diamat analyzer
      in 90 type 1 diabetics with parallel determinations of HbF. Results were compared
      with HbA(1c) concentrations obtained using DCA 2000. RESULTS: Reproducibility was
      good for both methods with coefficients of variation <5% and correlation between
      the two methods was good (r(2)=0.939, p<0.0001). Mean difference between the two
      methods was small (0.007%). Limits of agreement varied between -0.92% and +0.93%
      (95% confidence interval [95% CI]) and constant bias (intercept: 0.73 95% CI 0.28
      1.18) as well as a proportional bias (slope: 0.92 95% CI 0.87-0.97) were
      detected. At low concentrations of HbF, the DCA 2000 immunologic method tended to
      underestimate and at higher concentrations tended to overestimate HbA(1c) when
      compared with Diamat. Stepwise linear regression with HbA(1c) (DCA 2000) as
      dependent variable included HbA(1c) (Diamat) and HbF in the model (r(2)=0.946,
      p<0.0001), explaining 94.6% of the variability of HbA(1c) (DCA 2000). Partial
      correlation coefficient between HbA(1c) (DCA 2000) and HbF corrected for HbA(1c)
      (Diamat) was 0.337 (p=0.0012). CONCLUSIONS: DCA 2000 allowed measurements of
      HbA(1c) rapidly and with precision adequate for clinical purposes. However,
      agreement with Diamat results was comparatively weak with both constant as well
      as proportional biases. The 95% limits of agreement between Diamat and DCA 2000
      fell within a range that significantly limited traceability between these two
      methods; therefore, the two methods should not be used interchangeably. Small but
      persistent elevations of HbF concentrations were identified as a significant
      cofactor, which may be relevant for limited traceability between the two methods.

PMID- 15010196
TI  - Technetium-99m-Sestamibi SPECT myocardial perfusion imaging in patients with
      complete left bundle branch block.
AB  - BACKGROUND: Diagnosis of coronary artery disease (CAD) in patients with left
      bundle branch block (LBBB) is considered a challenge in cardiology due to low
      accuracy of noninvasive methods such as basal and exercise stress test. Recently,
      myocardial perfusion imaging showed attainment of higher sensitivity and
      specificity. Scintigraphy with thallium-201 has been widely used in these
      patients. Few have used technetium-99m-Sestamibi and single photon emission
      computed tomography (SPECT). The aim of the study was to assess the diagnostic
      value of Tc-99m Sestamibi SPECT myocardial perfusion imaging in patients with
      complete LBBB. METHODS: We studied 57 consecutive patients with complete LBBB
      using Tc-99m-Sestamibi SPECT and treadmill or dipyridamole stress to evaluate
      CAD. Eighteen patients also underwent coronary angiography. Perfusion defects
      were classified as fixed or reversible. RESULTS: Prevalence of resting perfusion
      abnormalities in anterior, septal, and apical regions was 51, 56, and 19%,
      respectively. Sensitivity for detecting >50% left anterior descending artery
      (LAD) stenosis was 67 and 56% for anterior or septal defects, and 56% for
      specificity. Apical perfusion abnormality showed 21% sensitivity and 89%
      specificity. Among six patients with reversibility and who underwent coronary
      angiography, all had >50% LAD stenosis. CONCLUSIONS: With Tc-99m-MIBI SPECT
      imaging, prevalence of anteroseptal perfusion abnormalities was >50% in patients
      with LBBB. The test has moderate sensitivity and specificity for LAD disease.
      Absence of apical defect is specific for excluding LAD disease. Reversible
      changes in anteroseptal wall should be considered as an indicator of ischemia in
      this territory.

PMID- 15010197
TI  - A comparison of three rating scales for measuring subjective phenomena in
      clinical research. II. Use of experimentally controlled visual stimuli.
AB  - BACKGROUND: In a previous study of three types of global scales we found that
      verbal rating scales were particularly reliable for rating auditory stimuli. We
      now wanted to check the performance of the scales for rating experimentally
      controlled visual stimuli. METHODS: We used a prospective, experimentally
      controlled, clinimetric study, which was conducted at the Department of
      Psychiatry of the Autonomous University of Puebla Medical School in the state
      capital city of Puebla, Mexico. A total of 20 fifth-year medical students
      participated in the study. Visual stimuli consisted of 15 cards with five
      different intensities on the gray-to-black scale, administered randomly in three
      sessions to each subject. With regard to main outcome measurement, validity and
      consistency indices were determined for visual analog scale (VAS), numerical
      rating score (NRS), and verbal rating scale (VRS) to rate visual stimuli.
      RESULTS: For validity, correlation coefficients between scales and reference
      standard were high, especially in VRS (r=0.902). For consistency, VRS had highest
      kappa value (k(w)=0.71) for interobserver variability. CONCLUSIONS: Three
      instruments could be hierarchically ranked for their indices of validity and
      consistency. Being more consistent than VAS and NRS, VRS merits more frequent
      usage in clinical research.

PMID- 15010198
TI  - Multiple myeloma in Mexico: a 20-year experience at a single institution.
AB  - BACKGROUND: In a 20-year period at a single institution, 66 cases of multiple
      myeloma (MM) were identified. The disease was less frequent in Mexico because in
      a multicenter study it represented 4.2% of all hematologic malignancies, whereas
      during this experience it was found to represent 7.7%. These figures contrast
      with those reported in Caucasians-10-15%. METHODS: There were two patients <40
      years of age; median age was 66 years. Bone pain was present in 54%, fatigue in
      66%, and weight loss in 47%. Anemia was present in 75% of females and in 96% of
      males at diagnosis; median hemoglobin was 10.2 g/dL; abnormal monoclonal spike
      had a median of 2.87 g/dL (range 0-9.9). Four cases (6%) of nonsecretory myelomas
      were identified. Bence Jones proteinuria was present in 51 cases (77%). Forty six
      individuals were followed for >3 months (97-7,054 days, median 2,371 days).
      RESULTS: Their survival (SV) was 51% at 540 days. Patients treated with
      melphalan/prednisone had a median SV of 33 months with a 72-month SV of 30%.
      Patients treated with vincristine/adriamycin/dexamethasone had an SV of 40% at 42
      months, whereas those given high-dose chemotherapy and autologous stem cell
      rescue had an SV of 80% at 22 months. CONCLUSIONS: Clinical features of Mexican
      patients with MM were not significantly different from those reported for other
      populations; best results from treatment were observed in patients administered
      autologous stem cell transplantation.

PMID- 15010199
TI  - Pharmacokinetic study of carbamazepine and its carbamazepine 10,11-epoxide
      metabolite in a group of female epileptic patients under chronic treatment.
AB  - BACKGROUND: Although epileptic crises are equally frequent in women and men,
      several factors cause female epileptics to present a series of gender-specific
      problems. To date, few studies have been published on the kinetics of
      carbamazepine (CBZ) and carbamazepine 10,11-epoxide (CBZ-E) active metabolite in
      a Mexican population, and no information for epileptic women of reproductive age
      is available. The aim of the present work was to study the pharmacokinetic
      behavior of this group of women during steady state. METHODS: Fourteen epileptic
      women under chronic treatment receiving only the anticonvulsant CBZ to control
      their crises were studied. A blood sample was taken before breakfast, before the
      morning dose of 200 mg, and after the dose at 1, 2, 3, 4, 5, and 8 h. Serum was
      separated by centrifugation at 1,350 x g. Serum concentrations of carbamazepine
      (CBZ) and of the metabolite carbamazepine 10,11-epoxide (CBZ-E) were measured by
      HPLC. Pharmacokinetic parameters were calculated by statistical moment method
      after obtaining serum concentrations. RESULTS: Maximum time (T(max)) for CBZ was
      reached at 2.72+/-0.71 h and for CBZ-E, it was 3.60+/-0.79 h. C(max) for CBZ was
      7.30+/-2.30 microg/mL, while C(min) for CBZ was 6.30+/-2.49. Maximum serum values
      for CBZ-E were 1.01+/-0.57, equivalent to 13.80% of CBZ; t(12) value for CBZ and
      CBZ-E was 18.20 and 16.10 h, respectively. AUC values for CBZ and metabolite were
      70.33+/-17.10 microg/L/h and 9.20+/-2.50 microg/L/h, respectively. CBZ and CBZ-E
      clearance did not show differences and were 0.37 mL/kg/min and 0.40 mL/kg/min,
      respectively. Extraction index for serum concentrations of CBZ and CBZ-E
      AUC(CBZ)/AUC(CBZ-E) was 0.13; positive correlation was observed between serum
      concentrations of CBZ and E-CBZ, with r=0.94. CONCLUSIONS: The schedule we
      suggest for therapeutic monitoring of serum concentrations of CBZ in chronic
      treatments is 3 h for maximum peak concentration of C(max) after dose
      administration and for minimum peak concentration, C(min) prior to subsequent
      administration of the dose.

PMID- 15010200
TI  - Predictors of bone mineral density in female workers in Morelos State, Mexico.
AB  - BACKGROUND: Although several studies have identified factors associated with bone
      mineral density (BMD), little research is available on Mexican women. METHODS: A
      cross-sectional study was conducted in 1,622 female workers between 20 and 80
      years of age at the Mexican Social Security Institute (IMSS), an integral part of
      the Mexican health system. It was carried out in Morelos, a Mexican state that
      borders Mexico City. Women were recruited to participate in this study from their
      workplaces. Body mass index (BMI) was measured and BMD was assessed using dual
      energy x-ray absorptiometry of dominant forearm. Predictors of BMD (age,
      reproductive factors, BMI, diet, and physical activity) in pre- and
      postmenopausal women were assessed by questionnaire and analyzed using
      generalized additive models. RESULTS: In premenopausal women, older age, higher
      BMI, younger age at menarche, and greater vitamin D intake were associated with
      higher BMD (R(2)=0.06, null deviance reduction=6.9%). In postmenopausal women,
      determinants of BMD were older age, higher BMI, greater height, later initiation
      of menopause, longer time of use of hormonal replacement therapy (HRT), and
      greater calcium intake from dairy products (R(2)=0.39, null deviance
      reduction=40.7%). CONCLUSIONS: As observed in other populations, age, BMI,
      height, age at menopause, time of use of HRT, and calcium intake derived from
      dairy products in these Mexican women are factors associated with higher forearm
      BMD during postmenopausal period. Age, BMI, age at menarche, and vitamin D are
      associated with higher forearm BMD in premenopausal women. Some of these factors
      are not linearly associated with BMD. This was a limited population study carried
      out in a large group of female healthcare workers whose reproductive and
      lifestyle factors potentially agreed with those of female workers from urban
      areas of Mexico.

PMID- 15010201
TI  - Difference of body mass index stratified by the period of smoking cessation from
      a cross-sectional study.
AB  - BACKGROUND: Smoking cessation is associated with subsequent obesity. This study
      was designed to clarify the duration of weight gain lasted after cessation of
      smoking. METHODS: A total of 2,511 male subjects aged 25-62 years participated in
      an annual health examination at their workplace. The relationship between body
      mass index (BMI) and the period since cessation of smoking was evaluated by
      multiple logistic regression analysis using age, drinking status, and physical
      activity as covariates. RESULTS: Percentages of current and nonsmokers with BMI
      not <25 kg/m(2) were 23.3 and 27.5%, respectively. Percentage of ex-smokers with
      BMI not <25 and with periods of 0-1 year, 2-4 years, 5-7 years, 8-10 years, and
      >10 years since giving up smoking were 37.5, 27.9, 43.2, 29.4, and 29.8%,
      respectively. Among ex-smokers with the previously mentioned periods after giving
      up smoking, odds ratios (ORs) and 95% confidence intervals (95% CIs) of BMI not
      <25 kg/m(2) were 1.58 (0.90-2.76), 1.01 (0.57-1.81), 2.01 (1.08-3.71), 1.10 (0.59
      2.05), and 1.11 (0.75-1.65), respectively. ORs and 95% CIs of BMI with not <25
      kg/m(2) on current smokers were 0.80 (0.66-0.97). CONCLUSIONS: Obesity due to
      smoking cessation was observed in subjects within the period from 5 to 7 years
      after stopping smoking; obesity due to smoking cessation is not a permanent
      phenomenon.

PMID- 15010202
TI  - Rat neurological mutations cerebellar vermis defect and hobble are caused by
      mutations in the netrin-1 receptor gene Unc5h3.
AB  - Rats homozygous for the spontaneous cerebellar vermis defect mutation (cvd) or
      hobble mutation (hob) exhibit cerebellar and midbrain defects, possibly as a
      result of abnormal neuronal migration. Both mutant rats demonstrate laminar
      structure abnormalities in the fused cerebellar hemispheres and ectopic
      cerebellar tissues in the cerebello-pontine junction. Previous genetic studies
      showed that cvd and hob were allelic and suggested that Unc5h3, the causative
      gene of the mouse rostral cerebellar malformation (rcm) mutation, was a strong
      candidate for both cvd and hob. Unc5h3 encodes a receptor mediating the repulsive
      action for Netrin-1 and has an important role during cell migration in the
      developing murine cerebellum. Here, we describe positional candidate cloning of
      cvd and hob, and identified cvd and hob mutations in the rat Unc5h3. The cvd
      mutation is a nucleotide conversion of G to T resulting in a premature
      termination at codon 451 of the UNC5H3 protein. The hob mutation is a 2-bp
      insertion resulting in a frame shift from codon 312 and a premature termination
      at codon 385 of the UNC5H3 protein. Both cvd and hob mutations are predicted to
      lead to truncated UNC5H3 proteins lacking their cytoplasmic region required for
      Netrin-Unc5h3 signaling pathway. Therefore, we conclude that Unc5h3 is causative
      gene of both cvd and hob mutant phenotypes. Rats homozygous for Unc5h3cvd or
      Unc5h3hob are the first mammalian Unc5h3 mutant model other than Unc5h3rcm/rcm
      mice, and will provide a useful tool for further understanding of the biological
      function of Unc5h3.

PMID- 15010203
TI  - Effect of C-type natriuretic peptide (CNP) on water channel aquaporin-4 (AQP4)
      expression in cultured astrocytes.
AB  - Astrocytes play a vital role in volume and ion control in the central nervous
      system. C-type natriuretic peptide (CNP) may be involved in neuronal-glial
      signaling, but its physiological role has not yet been characterized. In our
      study, we found that CNP can regulate the water channel aquaporin-4 (AQP4)
      expression in cultured astrocytes. Using immunocytochemistry and enzyme
      immunoassay, we found that primary neuronal cultures exhibited a high level of
      reactivity to CNP, and that cultured astrocytes exhibited reactivity to cyclic
      GMP after exposure of CNP. Using RT-PCR, immunoblot and immunocytochemistry, we
      detected increased levels of AQP4 mRNA and AQP4 immunoreactivity in the cultured
      astrocytes after they had been exposed to CNP or cyclic GMP. These results
      suggest that CNP, which is mainly produced by the neurons, effects the level of
      AQP4 in the astrocytes. Therefore, CNP may be a regulator of water homeostasis in
      the central nervous system.

PMID- 15010204
TI  - Rescue of NGF-deficient mice I: transgenic expression of NGF in skin rescues mice
      lacking endogenous NGF.
AB  - Mice lacking a functional NGF gene (ngf-/- mice) have less than one third of the
      normal complement of sensory neurons, few sympathetic postganglionic neurons and
      die shortly after birth. We report here that transgenic expression of NGF under
      control of the K14 keratin promoter can rescue some elements of the peripheral
      nervous system and restore normal growth and viability to ngf-/- mice. While
      hybrid transgenic-ngf-/- mice (ngfTKOs) displayed marginal rescue of trigeminal
      ganglion neurons, the percentage of CGRP-positive neurons was restored to normal.
      Restoration of CGRP-positive terminals in skin and spinal cord was also found and
      accompanied by recovery of behavioral responses to noxious stimuli. ngfTKO mice
      displayed a normal number of superior cervical ganglion neurons and recovery of
      sympathetic innervation of skin. These results demonstrate that substitution of a
      functional NGF locus by a transgene directing expression largely to skin can
      result in normal growth and viability. Thus, the most vital functions of NGF are
      not dependent on faithful recapitulation of the normal spatiotemporal pattern of
      gene expression.

PMID- 15010205
TI  - Protein oxidation and the degradation of oxidized proteins in the rat
      oligodendrocyte cell line OLN 93-antioxidative effect of the intracellular spin
      trapping agent PBN.
AB  - Oligodendrocytes are the myelin-producing cells in the central nervous system. It
      was proposed that these cells are much more prone to oxidative damage than to
      other cells of the central nervous system. This fact seems to be due to their
      high iron store and low antioxidative defense mechanisms. Consequently, free
      radical induced damage should lead to an enhanced damage of oligodendrocytes.
      Thus, we chose the oligodendrocyte cell line OLN 93 to measure the stability of
      the protein pool after oxidation and the possibilities of protecting proteins by
      alpha-phenyl-N-tert-butylnitrone (PBN). We were able to demonstrate for the first
      time that OLN 93 cells are able to respond with an increase in overall
      proteolysis when exposed to various oxidants. This increase was the consequence
      of an enhanced protein oxidation. The activity of the 20S proteasome, which is
      thought to be involved in the removal of oxidized proteins, was not effected by
      moderate concentrations of the oxidants. The spin-trap PBN was used as an
      antioxidant and was able to prevent protein oxidation in OLN 93 cells
      effectively. Consequently, we proved that PBN is also able to prevent the
      increase in overall protein oxidation. We were able to demonstrate that OLN 93
      oligodendrocytes react to oxidative stress with an increase in the protein
      turnover directed towards the removal of oxidized proteins. The intracellular
      spin-trap PBN is able to prevent protein oxidation in OLN 93 cells.

PMID- 15010206
TI  - A collection of cDNAs enriched in upper cortical layers of the embryonic mouse
      brain.
AB  - In an attempt to elucidate the molecular basis of neuronal migration and
      corticogenesis, we performed subtractive hybridization of mRNAs from the upper
      cortical layers (layer I and upper cortical plate) against mRNAs from the
      remaining cerebral cortex at E15-E16. We obtained a collection of subtracted cDNA
      clones and analyzed their 3' UTR sequences, 47% of which correspond to EST
      sequences, and may represent novel products. Among the cloned sequences, we
      identified gene products that have not been reported in brain or in the cerebral
      cortex before. We examined the expression pattern of 39 subtracted clones, which
      was enriched in the upper layers of the cerebral cortex at embryonic stages. The
      expression of most clones is developmentally regulated, and especially high in
      embryonic and early postnatal stages. Four of the unknown clones were studied in
      more detail and identified as a new member of the tetraspanin superfamily, a
      putative RNA binding protein, a specific product of the adult dentate gyrus and a
      protein containing a beta-catenin repeat. We thus cloned a collection of
      subtracted cDNAs coding for protein products that may be involved in the
      development of the cerebral cortex.

PMID- 15010207
TI  - mGluR5-dependent increases in immediate early gene expression in the rat striatum
      following acute administration of amphetamine.
AB  - Metabotropic glutamate receptor 5 (mGluR5) is densely expressed in medium-sized
      spiny projection neurons of the rat striatum. Activation of mGluR5 increases
      intracellular Ca2+, resulting in Ca(2+)-dependent cellular responses. Acute
      administration of the psychostimulant amphetamine (AMPH) induces immediate early
      gene (IEG) expression in the striatum, which is considered an important molecular
      event for the development of striatal neuroplasticity related to the addictive
      properties of drugs of abuse. This study investigated the role of mGluR5 in the
      mediation of IEG expression in the rat striatum induced by a single dose of AMPH
      (4 mg/kg, i.p.) in vivo. We found that systemic administration of the mGluR5
      selective antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) at
      a dose of 10 mg/kg, i.p. reduced AMPH-stimulated c-fos mRNA levels in the dorsal
      (caudoputamen) and ventral (nucleus accumbens) striatum as revealed by
      quantitative in situ hybridization. Similar results were observed in the three
      areas of cerebral cortex (cingulate, sensory, and piriform cortex). In contrast
      to c-fos mRNAs, AMPH-stimulated mRNA expression of another IEG, zif/268, was not
      significantly altered by the blockade of mGluR5 with MPEP in the entire striatum
      and the three areas of cortex. Treatment with MPEP alone had no effect on basal
      levels of c-fos and zif/268 mRNAs in the striatal and cortical areas. These
      results indicate that an mGluR5-dependent mechanism selectively contributes to c
      fos expression in the striatum and cortex in response to acute exposure to AMPH.

PMID- 15010208
TI  - Further evidence for the role of cryptochromes in retinohypothalamic
      photoreception/phototransduction.
AB  - Cryptochrome is a blue-light absorbing photopigment that has been proposed to act
      as a photoreceptor for a variety of nonvisual light-responsive tasks. While mouse
      models have suggested an important role for cryptochrome in nonvisual
      photoreception, there are no biochemical data demonstrating the functional
      photoreceptive capability of cryptochrome in mice. There are two models that
      describe the effect of cryptochrome on light responsive events: (1) cryptochrome
      is a photoreceptor or (2) cryptochrome is required for either normal
      phototransduction from the retina to the brain or for normal transcriptional
      regulation in the brain, irrespective of light. To differentiate between these
      two models, we have examined the integrity of the regulatory mechanism of c-fos
      in cryptochromeless cell lines and in the suprachiasmatic nucleus (SCN) of
      cryptochromeless mice. Photoinduction of c-fos mRNA in the SCN can be used as a
      marker for circadian photoreception/phototransduction and it is drastically
      reduced in mice lacking cryptochromes. Our results indicate that light
      independent transcription regulatory system of c-fos is normal in
      cryptochromeless mice and that the reduced c-fos light responsiveness in the
      absence of cryptochromes is due to a loss of photoreceptor function.

PMID- 15010209
TI  - Manganese potentiates lipopolysaccharide-induced expression of NOS2 in C6 glioma
      cells through mitochondrial-dependent activation of nuclear factor kappaB.
AB  - Neuronal injury in manganese neurotoxicity (manganism) is thought to involve
      activation of astroglial cells and subsequent overproduction of nitric oxide (NO)
      by inducible nitric oxide synthase (NOS2). Manganese (Mn) enhances the effects of
      proinflammatory cytokines on expression of NOS2 but the molecular basis for this
      effect has not been established. It was postulated in the present studies that Mn
      enhances expression of NOS2 through the cis-acting factor, nuclear factor kappaB
      (NF-kappaB). Exposure of C6 glioma cells to lipopopolysaccharide (LPS) resulted
      in increased expression of NOS2 and production of NO that was dramatically
      potentiated by Mn and was blocked through overexpression of mutant IkappaBalpha
      (S32/36A). LPS-induced DNA binding of p65/p50 was similarly enhanced by Mn and
      was decreased by mutant IkappaBalpha. Phosphorylation of IkappaBalpha was
      potentiated by Mn and LPS and was not blocked by U0126, a selective inhibitor of
      ERK1/2. Mn decreased mitochondrial membrane potential and increased matrix
      calcium, associated with a rise in intracellular reactive oxygen species (ROS)
      that was attenuated by the mitochondrial-specific antioxidant, MitoQ. Blocking
      mitochondrial ROS also attenuated the enhancing effect of Mn on LPS-induced
      phosphorylation of IkappaBalpha and expression of NOS2, suggesting a link between
      Mn-induced mitochondrial dysfunction and activation of NF-kappaB. Overexpression
      of a dominant-negative mutant of the NF-kappaB-interacting kinase (Nik) prevented
      enhancement of LPS-induced phosphorylation of IkappaBalpha by Mn. These data
      indicate that Mn augments LPS-induced expression of NOS2 in C6 cells by
      increasing mitochondrial ROS and activation of NF-kappaB.

PMID- 15010210
TI  - Leucine toxicity in a neuronal cell model with inhibited branched chain amino
      acid catabolism.
AB  - Individuals with the inborn error of metabolism, maple syrup urine disease
      (MSUD), are identified by newborn screening programs and treated with protein
      modified diets that allow near normal growth and development. However, regardless
      of cause, a protein insult leads to metabolic decompensation, resulting in brain
      cell damage. The mechanism responsible for the damage is not well characterized
      due, in part, to the lack of an appropriate experimental model system with
      impaired branched chain alpha-ketoacid dehydrogenase (BCKD) activity. Here, we
      describe the construction of a rat pheochromocytoma cell (PC12) model harboring a
      doxycycline-controlled BCKD-kinase transgene. When BCKD-kinase is over-expressed
      in these cells, the endogenous BCKD activity is decreased, blocking branched
      chain amino acid (BCAA) catabolism. In cells over-expressing BCKD-kinase,
      addition of 25 mM leucine to the medium results in cell death. This experimental
      cell model accurately mimics the neuronal dysfunction in maple syrup urine
      disease and should facilitate further understanding of the pathophysiology of
      this disease and neuronal cell branched chain amino acid metabolism in general.

PMID- 15010211
TI  - Neurofilament subunits undergo more rapid translocation within retinas than in
      optic axons.
AB  - Axonal transport of neurofilaments (NFs) has long been considered to be regulated
      by phosphorylation, although recent studies have challenged this hypothesis. Our
      prior analyses of axonal transport in optic axons demonstrated two distinct NF
      transport rates that spatially and temporally correlated with changes in NF
      phosphorylation. In our prior studies, we focused on subunits already within
      axons. Re-examination of these data using additional approaches and examining
      additional earlier time points have allowed us to calculate rates at which
      subunits transport out of retinas and into optic axons. NF subunits were
      radiolabeled by intravitreal injection of 35S-methionine. NF axonal transport was
      monitored by following the location of the front of radiolabeled subunits
      immunoprecipitated from retinas and segments of optic axons, which demonstrated
      four distinct transport rates. Subunits within retinas exhibited the fastest
      rate, and underwent a 50% slowing upon exiting the retina and entering optic
      axons. While this slowing could be due to a regional caliber increase and/or
      regional increase in NF phosphorylation within the first segment, prior studies
      indicated that inhibition of phosphatase activities increased NF phosphorylation
      within retinas and slowed NF subunit exit from retinas to a degree similar to
      that normally observed within the first segment of axons, suggesting that
      regional phosphorylation played a major role in slowing of NF transport following
      their exit from the retina. These findings provide additional support for the
      notion that phosphorylation regulates NF axonal transport.

PMID- 15010213
TI  - The dsRNA viruses.
AB  - The dsRNA viruses represent a large, diverse group of pathogens (affecting a very
      wide range of host species), several of which are of medical, veterinary or
      agricultural importance. Many of the icosahedral dsRNA viruses show striking
      structural and functional similarities that reflect the similar problems that
      they face replicating their dsRNA genomes while avoiding the dsRNA activated
      defence mechanisms of their host species. These similarities appear to indicate a
      common if distant ancestry that is not always evident simply by comparison of
      nucleotide or amino acid sequences. To facilitate the identification and
      comparisons of cognate proteins from different species, genera and families of
      dsRNA viruses, a series of tables were originally constructed for the 7th
      International Symposium of dsRNA viruses held in Aruba in 2000. These have now
      been updated and extended (for the 8th Symposium, held in Tuscany 2003) and are
      available from the dsRNA virus website at.

PMID- 15010214
TI  - Orthoreovirus and Aquareovirus core proteins: conserved enzymatic surfaces, but
      not protein-protein interfaces.
AB  - Orthoreoviruses and Aquareoviruses constitute two respective genera in the family
      Reoviridae of double-stranded RNA viruses. Orthoreoviruses infect mammals, birds,
      and reptiles and have a genome comprising 10 RNA segments. Aquareoviruses infect
      fish and have a genome comprising 11 RNA segments. Despite these differences,
      recent structural and nucleotide sequence evidence indicate that the proteins of
      Orthoreoviruses and Aquareoviruses share many similarities. The focus of this
      review is on the structure and function of the Orthoreovirus core proteins
      lambda1, lambda2, lambda3, and sigma2, for which X-ray crystal structures have
      been recently reported. The homologous core proteins in Aquareoviruses are VP3,
      VP1, VP2, and VP6, respectively. By mapping the locations of conserved residues
      onto the Orthoreovirus crystal structures, we have found that enzymatic surfaces
      involved in mRNA synthesis are well conserved between these two groups of
      viruses, whereas several surfaces involved in protein-protein interactions are
      not well conserved. Other evidence indicates that the Orthoreovirus mu2 and
      Aquareovirus VP5 proteins are homologous, suggesting that VP5 is a core protein
      as mu2 is known to be. These findings provide further evidence that
      Orthoreoviruses and Aquareoviruses have diverged from a common ancestor and
      contribute to a growing understanding of the functions of the core proteins in
      viral mRNA synthesis.

PMID- 15010215
TI  - The bluetongue virus core: a nano-scale transcription machine.
AB  - The replication phase of the bluetongue virus (BTV) infection cycle is initiated
      when the virus core is delivered into the cytoplasm of a susceptible host cell.
      The 10 segments of the viral genome remain packaged within the core throughout
      the replication cycle, helping to prevent the activation of host defence
      mechanisms that would be caused by direct contact between the dsRNA and the host
      cell cytoplasm. However, the BTV core is a biochemically active 'nano-scale'
      machine, which can simultaneously and repeatedly transcribe mRNA from each of the
      10 genome segments, which are packaged as a liquid crystal array within a central
      cavity. These mRNAs, which are also capped and methylated within the core, are
      extruded into the cytoplasm through pores at the vertices of the icosahedral
      structure, where they are translated into viral proteins. One copy of each of the
      viral mRNAs is also assembled with these newly synthesised proteins to form
      nascent virus particles, which mature by a process that involves -ve RNA strand
      synthesis on the +ve stand template, thereby reforming dsRNA genome segments
      within progeny virus cores. The structure of the BTV core particle has been
      determined to atomic resolution by X-ray crystallography, revealing the
      organisation and interactions of its major protein components (VP3(T2)-subcore
      shell and VP7(T13) outer core layer) and important features of the packaged
      dsRNA. By soaking crystals of BTV cores with metal ions and substrates/products
      of the transcription reactions prior to analysis by X-ray crystallography, then
      constructing difference maps, it has been possible to identify binding sites and
      entry/exit routes for these ions, substrates and products. This has revealed how
      BTV solves the many logistical problems of multiple and simultaneous
      transcription from the 10 genome segments within the confined space of the core
      particle. The crystal structure of the BTV core has also revealed an outer
      surface festooned with dsRNA. This may represent a further protective strategy
      adopted by the virus to prevent host cell shut-off, by sequestering any dsRNA
      that may be released from damaged particles.

PMID- 15010216
TI  - RNA-dependent RNA polymerases of dsRNA bacteriophages.
AB  - Genome replication and transcription of riboviruses are catalyzed by an RNA
      dependent RNA polymerase (RdRP). RdRPs are normally associated with other virus-
      or/and host-encoded proteins that modulate RNA polymerization activity and
      template specificity. The polymerase complex of double-stranded dsRNA viruses is
      a large icosahedral particle (inner core) containing RdRP as a minor constituent.
      In phi6 and other dsRNA bacteriophages from the Cystoviridae family, the inner
      core is composed of four virus-specific proteins. Of these, protein P2, or Pol
      subunit, has been tentatively identified as RdRP by sequence comparisons, but the
      role of this protein in viral RNA synthesis has not been studied until recently.
      Here, we overview the work on the Pol subunits of phi6 and related viruses from
      the standpoints of function, structure and evolution.

PMID- 15010217
TI  - Nonstructural proteins involved in genome packaging and replication of
      rotaviruses and other members of the Reoviridae.
AB  - Rotaviruses, members of family Reoviridae, are a major cause of acute
      gastroenteritis of infants and young children. The rotavirus genome consists of
      11 segments of double-stranded (ds)RNA and the virion is an icosahedron composed
      of multiple layers of protein. The virion core is formed by a layer of VP2 and
      contains multiple copies of the RNA-dependent RNA polymerase VP1 and the mRNA
      capping enzyme VP3. Double-layered particles (DLPs), representing cores
      surrounded by a layer of VP6, direct the synthesis of viral mRNAs. Rotavirus core
      and DLP-like replication intermediates (RIs) catalyze the synthesis of dsRNA
      from viral template mRNAs coincidentally with the packaging of the mRNAs into the
      pre-capsid structures of RIs. In addition to structural proteins, the
      nonstructural proteins NSP2 and NSP5 are components of RIs with replicase
      activity. NSP2 self assembles into octameric structures that have affinity for
      ssRNA and NTPase and helix-destabilizing activites. Its interaction with
      nucleotides induces a conformational shift in the octamer to a more condensed
      form. Phosphate residues generated by the NTPase activity are believed to be
      transferred from NSP2 to NSP5, leading to the hyperphosphorylation of the latter
      protein. It is suspected that the transfer of the phosphate group to NSP5 allows
      NSP2 to return to its noncondensed state and, thus, to accept another NTP
      molecule. The NSP5-mediated cycling of NSP2 from condensed to noncondensed
      combined with its RNA binding and helix-destabilizing activities are consistent
      with NSP2 functioning as a molecular motor to facilitate the packaging of
      template mRNAs into the pre-capsid structures of RIs. Similarities with the
      bluetongue virus protein NS2 and the reovirus proteins sigmaNS and micro2 suggest
      that they may be functional homologs of rotavirus NSP2 and NSP5.

PMID- 15010218
TI  - Emerging themes in rotavirus cell entry, genome organization, transcription and
      replication.
AB  - Rotaviruses, causative agents of gastroenteritis in young animals and humans, are
      large icosahedral viruses with a complex architecture. The double-stranded RNA
      (dsRNA) genome composed of 11 segments, which codes for 6 structural and 6 non
      structural proteins, is enclosed within three concentric capsid layers. In
      addition to facilitating host-specific interactions, the design of the capsid
      architecture in rotaviruses as in other dsRNA viruses should also be conducive to
      the requirement of transcribing the enclosed genome segments repeatedly and
      simultaneously within the capsid interior. Several non-structural proteins
      facilitate the subsequent processes of genome replication and packaging. Electron
      cryomicroscopy studies of intact virions, recombinant virus-like particles,
      functional complexes, together with recent X-ray crystallographic studies on
      rotavirus proteins have provided structural insights into the capsid
      architecture, genome organization, antibody interaction, cell entry, trypsin
      enhanced infectivity, endogenous transcription and replication. These studies
      underscore contrasting features and unifying themes between rotavirus and other
      dsRNA viruses.

PMID- 15010219
TI  - Packaging, replication and recombination of the segmented genome of bacteriophage
      Phi6 and its relatives.
AB  - The genomes of bacteriophage Phi6 and its relatives are packaged through a
      mechanism that involves the recognition and translocation of the three different
      plus strand transcripts of the segmented dsRNA genomes into preformed polyhedral
      structures called procapsids or inner cores. The packaging requires hydrolysis of
      NTPs and takes place in the order S:M:L. Minus strand synthesis begins after the
      completion of the plus strand packaging. The packaging and replication reactions
      can be studied in vitro with purified components. A model has been presented that
      proposes that the program of serially dependent packaging is determined by the
      conformational changes at the surface of the procapsid due to the amount of RNA
      packaged at each step. The in vitro packaging and replication system has
      facilitated the application of reverse genetics and the study of recombination in
      the family of Cystoviridae.

PMID- 15010220
TI  - Self-assembly of double-stranded RNA bacteriophages.
AB  - Double-stranded RNA viruses infecting bacterial hosts belong to the Cystoviridae
      family. Bacteriophage phi6 is one of the best characterized dsRNA viruses and
      shares structural as well as functional similarities with other well-studied
      eukaryotic dsRNA viruses (e.g. L-A, rotavirus, bluetongue virus, and reovirus).
      The assembly pathway of the enveloped, triple-layered phi6 virion has been well
      documented and can be divided into four distinct steps which are (1) procapsid
      formation, (2) genome encapsidation and replication, (3) nucleocapsid surface
      shell assembly, and (4) envelope formation. In this review, we focus primarily on
      the procapsid and nucleocapsid assembly for which in vitro systems have been
      established. The in vitro assembly systems have been instrumental in revealing
      assembly intermediates and conformational changes that are common to phi6 and
      phi8, two cystoviruses with negligible sequence homology. Two viral enzymes, the
      packaging NTPase (P4) and the RNA-dependent RNA polymerase (P2), were found
      essential for the nucleation step. The nucleation complex contains one or more
      tetramers of the major procapsid protein (P1) and is further stabilized by
      protein P4. Interaction of P1 and P4 during assembly is accompanied by an
      additional folding of their respective polypeptide chains. The in vitro assembled
      procapsids were shown to selectively package and replicate the genomic ssRNA.
      Furthermore, in vitro assembly of infectious nucleocapsids has been achieved in
      the case of phi6. The in vitro studies indicate that the nucleocapsid coat
      protein (P8) assembles around the polymerase complex in a template-assisted
      manner. Implications for the assembly of other dsRNA viruses are also presented.

PMID- 15010221
TI  - Toll-like receptors 2 and 4, and acute phase cytokine gene expression in
      dexamethasone and growth hormone treated dairy calves.
AB  - Cattle are exposed to growth hormone stimulants and to stressors that cause
      cortisol release. Both of these hormones affect immune responses which may reduce
      disease resistance. Toll-like receptors are the pattern recognition molecules of
      pathogens that are on immune cells. They then orchestrate the induction of the
      appropriate acute phase cytokines of the early innate response. The objective of
      this study was to determine changes in toll-like receptors and acute phase
      cytokines following treatment with a synthetic glucocorticoid (dexamethasone) and
      growth hormone (GH). Twenty-eight calves were given the control (Cnt),
      dexamethasone (DEX), GH, or dexamethasone and GH (Both) treatments from 3 until
      56 days of age. Blood was collected by jugular venipuncture on days 14, 28, 42,
      and 56. On day 56, a lung lavage was performed and spleen and thymus tissues
      collected. Total RNA was extracted from blood leukocytes, lung lavage cells,
      spleen and thymus cells. Real-time reverse transcriptase-polymerase chain
      reaction (RT-PCR) was used to quantify interleukin-1 (IL-1), IL-1 receptor
      antagonist (IL-1Ra), tumor necrosis factor (TNF)-alpha, toll-like receptor 2
      (TLR2), and toll-like receptor 4 (TLR4). Blood leukocytes had a time effect for
      IL-1Ra (P < 0.01), with a trend for a treatment effect (P = 0.07) and had a
      treatment by time interaction (P < 0.05). IL-1, TNF, and TLR2 and TLR4 were
      greatest (P < 0.05) for Cnt only at day 14. IL-1 expression of lung lavage cells
      was greatest (P < 0.05) for calves on the Both treatment compared to the other
      three treatments. However, IL-1Ra was not different among the treatments. Toll
      like receptor 2 expression was enhanced with Both compared to either DEX (P <
      0.05) or GH (P < 0.05) and tended to be greater than Cnt expression (P = 0.07).
      Expression of TLR4 tended to be reduced by Both compared to Cnt (P = 0.06). Tumor
      necrosis factor-alpha was greatly enhanced by Both compared to the other three
      treatments (P < 0.05). Spleen cell tended to have different IL-1 expression
      between GH and Both (P < 0.10). Interleukin-1 receptor antagonist and TLR2 and
      TLR4 were not different among treatments. However, TNF-alpha expression was
      enhanced by the DEX treatment alone compared to the GH treatment (P < 0.05), and
      tended (P < 0.10) to be greater than Cnt expression. None of the gene expressions
      were different among treatments for thymus cells. Lung lavage cell expression
      appears to be most susceptible to these hormones while blood leukocyte expression
      was only slightly affected, and thymus cells were not affected at all. These data
      demonstrate that TLR2 and TLR4 and acute phase cytokine expression can be altered
      by stress and growth hormones, which may decrease resistance of those animals to
      disease.

PMID- 15010222
TI  - Use of recombinant modified vaccinia Ankara viral vectors for equine influenza
      vaccination.
AB  - Recombinant modified vaccinia Ankara (MVA) vectors expressing equine influenza
      virus genes were constructed and evaluated for use in equine vaccination. Two
      strains of recombinant MVA, expressing either hemagglutinin (HA) or nucleoprotein
      (NP) genes were constructed. Each influenza virus gene was cloned from
      A/equine/Kentucky/1/81 (Eq/Ky) into an MVA construction plasmid, and was
      introduced to the deletion III locus of the wild type MVA genome by homologous
      recombination. Recombinant viruses were plaque purified, and antigen expression
      was confirmed by immunostaining. Two ponies were primed by vaccination with 50
      microg HA-DNA and two ponies were vaccinated with 50 microg NP-DNA using the
      PowderJect XR research device. Six and 10 weeks later, ponies were immunized with
      2 x 10(9) infectious units of recombinant MVA encoding the homologous influenza
      antigen, equally divided between intramuscular and intradermal sites in the neck.
      A marked rise in influenza virus-specific IgGa and IgGb serum antibody titers was
      detected following administration of MVA boosters with both HA and NP antigens.
      Influenza virus-specific lymphoproliferative responses and IFN-gamma mRNA
      production were also strongly elicited by both antigens. This study demonstrates
      the facility with which recombinant MVA viruses expressing defined pathogen genes
      can be constructed, and provides preliminary evidence of the immunogenicity and
      safety of these vectors in the horse.

PMID- 15010223
TI  - Mapping of B-cell epitopes in the N-terminal repeated peptides of Anaplasma
      marginale major surface protein 1a and characterization of the humoral immune
      response of cattle immunized with recombinant and whole organism antigens.
AB  - Major surface protein (MSP) 1a of the genus type species Anaplasma marginale
      (Rickettsiales: Anaplasmataceae) together with MSP1b forms the MSP1 complex.
      MSP1a has been shown to be involved in adhesion, infection and tick transmission
      of A. marginale, as well as to contribute to protective immunity in cattle. A
      differential antibody response to MSP1a and MSP1b was observed in cattle
      immunized with A. marginale derived from bovine erythrocytes (anti-MSP1a
      response) or cultured tick cells (anti-MSP1b response). In this study, we further
      characterized the MSP1a antibody response of cattle using several immunogens,
      including recombinant MSP1a (rMSP1a) protein, erythrocyte- or tick cell culture
      derived A. marginale, or a combination of tick cell culture-derived A. marginale
      and rMSP1a. The MSP1a antibody response to all these immunogens was directed
      primarily against the N-terminal region of MSP1a that contains tandemly repeated
      peptides, whereas low antibody levels were detected against the C-terminal
      portion. Linear B-cell epitopes of MSP1a were mapped using synthetic peptides
      representing the entire sequence of the protein that were prepared by SPOT
      synthesis technology. Only two peptides in the N-terminal repeats were recognized
      by sera from immunized cattle. These peptides shared the sequence SSAGGQQQESS,
      which is likely to contain the linear B-cell epitope that was recognized by the
      pools of bovine sera. The average differential of antibody titers against MSP1a
      minus those against MSP1b correlated with lower percent reductions in PCV. A
      preferential antibody response to MSP1a was observed in cattle immunized with
      erythrocyte-derived, cell culture-derived plus rMSP1a or rMSP1a alone, and the
      percent reduction PCV was significantly lower in these cattle as compared with
      the other immunization groups. These results provide insight into the bovine
      antibody response against A. marginale and the role of MSP1a in protection of
      cattle against A. marginale infection.

PMID- 15010224
TI  - Biochemical and functional assessment of equine lymphocyte phosphodiesterases and
      protein kinase C.
AB  - Lymphocytes play an important role in allergic inflammation and have been
      implicated in the pathogenesis of equine allergic skin and respiratory disease.
      Targeting intracellular signalling pathways in human lymphocytes has demonstrated
      a role for both phosphodiesterase and protein kinase C in cell activation. The
      aim of this study was to measure total cyclic nucleotide hydrolysing
      phosphodiesterase activity and to identify the phosphodiesterase and protein
      kinase C isoenzymes present in equine lymphocytes. The functional significance of
      these isoenzymes was then investigated by examining their role in peripheral
      blood mononuclear cell proliferation using isoenzyme selective inhibitors. Total
      cyclic adenosine monophosphate hydrolysing phosphodiesterase activity was double
      that of cyclic guanosine monophosphate (30+/-2 pmol/min mg versus 16+/-3 pmol/min
      mg for cyclic adenosine and cyclic guanosine monophosphate phosphodiesterase
      activity, respectively). Evidence for the presence of PDE1, 3, 4 and 5 was
      obtained and PKCalpha, beta, delta, eta, iota, theta and zeta were identified.
      Selective inhibitors of PDE4, PKCdelta and conventional PKCs alpha and beta
      caused significant inhibition of mitogen-induced peripheral blood mononuclear
      cell proliferation. This study demonstrates a functional role for specific
      signalling isoenzymes and suggests that, in the context of allergic inflammation,
      targeting inflammatory cells involved in disease pathogenesis with relevant
      isoenzyme inhibitors may have therapeutic potential.

PMID- 15010225
TI  - Blood lymphocyte subsets in canine idiopathic pericardial effusion.
AB  - The immunophenotype of peripheral blood lymphocytes was investigated in 23 dogs
      diagnosed with idiopathic pericardial effusion in order to provide information
      about a possible role of the immune system in this pathology. Flow cytometric
      analysis showed a significant reduction in nearly all lymphocyte subsets examined
      and a strong, significant (P < 0.001) reduction of the CD4 subset, which gave
      rise to a significantly lower CD4/CD8 ratio. Our data suggest that an imbalance
      in the immune system is present during the course of the disease, preferentially
      affecting the T helper cell response.

PMID- 15010226
TI  - Cloning of bovine MAIL and its mRNA expression in white blood cells of Holstein
      cows.
AB  - Molecule possessing ankyrin-repeats induced by lipopolysaccharide (MAIL) is known
      as an IkappaB protein induced after administration of bacterial
      lipopolysaccharide (LPS) to mice. In the present study, we cloned bovine MAIL
      cDNA and examined its mRNA expression in white blood cells isolated from Holstein
      cows. Bovine MAIL had more than 80% amino acid identities with murine and human
      MAILs, highly conserved ankyrin-repeat motifs and PEST-like sequences. Bovine
      MAIL mRNA was undetectable in isolated peripheral white blood cells, but rapidly
      induced (<1h) after stimulation by LPS and lipid A in vitro in a dose-dependent
      manner. The lipid A-induced MAIL mRNA expression was found in polymorphonuclear
      cells, monocytes/macrophages and total lymphocytes, but not in T-lymphocytes.
      MAIL mRNA was also induced in vivo in peripheral blood leukocytes of cows after
      intramammary injection of Escherichia coli derived from coliform mastitis. Thus,
      bovine MAIL, as rodent MAILs, is induced by inflammatory stimuli in specific
      immune cells in vitro and in vivo, suggesting a role in inflammatory responses to
      bacterial infection in cattle.

PMID- 15010227
TI  - Identification of the feline CD63 homologue using retrovirus-mediated expression
      cloning.
AB  - Recently, we combined a retrovirus-mediated expression cloning with a simple
      screening method using non-adherent cells and panning [Anal. Biochem. 315 (2003)
      138]. In this study, we applied this method to identify the antigen recognized by
      an uncharacterized monoclonal antibody raised against a feline cell line, and
      identified it as the feline homologue of CD63. This simple method is useful for
      characterizing unknown antibodies that recognize cell surface molecules.
      Furthermore, the monoclonal antibody identified as an anti-feline CD63 antibody
      will be useful for studying feline molecular function(s).

PMID- 15010228
TI  - Live Salmonella enterica serovar Typhimurium (S. Typhimurium) elicit dendritic
      cell responses that differ from those induced by killed S. Typhimurium.
AB  - The immune response of bovine monocytes-derived dendritic cells (DC) exposed to
      either live or killed Salmonella enterica serovar Typhimurium was compared. Both
      live and killed bacteria induced changes in morphology with distinctive formation
      of processes and up-regulation of the ability of DC to stimulate allogeneic T
      cell proliferation. Also, both live and killed bacteria up-regulated the
      expression of MHC-I, MHC-II and CD80. However, live bacteria induced greater up
      regulation of the expression of CD40 and CD86 than killed bacteria. Live bacteria
      also induced greater up-regulation of transcription for IL-6, IL-12 and GM-CSF
      than killed bacteria as measured by quantitative RT-PCR. These data suggest that
      blood-monocyte-derived DC may follow distinct maturation pathways following
      exposure to live or killed bacteria. These differences are likely to have
      consequences for the priming of the adaptive immune responses.

PMID- 15010229
TI  - B7+CTLA4+ T cells engage in T-T cell interactions that mediate apoptosis: a model
      for lentivirus-induced T cell depletion.
AB  - Apoptosis in lymph node (LN) T cells of feline immunodeficiency virus (FIV)
      infected cats is associated with cells co-expressing B7.1 and B7.2 costimulatory
      molecules, and their ligand CTLA4. To study the possibility of B7.1/B7.2-CTLA4
      mediated T-T interactions and the predicted induction of T cell apoptosis in
      vitro, costimulatory molecules were up-regulated on CD4+ and CD8+ T cells by
      mitogen stimulation. B7.1 expression on in vitro stimulated CD4+ and CD8+ cells
      increased within 24h; B7.2 and CTLA4 expression increased after 48-72 h.
      Apoptosis, as analyzed by terminal deoxynucleotidyl transferase (transferase nick
      end labeling, TUNEL)-based staining followed by three color flow cytometric
      analysis, correlated to the cells expressing B7 and/or CTLA4. Blocking
      experiments revealed that CD4+ and CD8+ T cell apoptosis could be significantly
      inhibited with anti-B7 antibodies. As FIV infection results in immune activation
      with a T cell phenotype similar to that of the in vitro activated T cells, the
      data support the hypothesis that the chronic expansion of B7+CTLA4+ LN T cells in
      infected cats allows for T-T cell interactions resulting in T cell depletion and
      eventually the development of AIDS.

PMID- 15010230
TI  - Reduced constitutive cytokine transcription in isolated monocytes of clinically
      healthy cats, infected with an FIV strain of low pathogenicity.
AB  - Twenty-five barrier-maintained cats had been experimentally infected for 9.5
      months with an FIV strain of low pathogenicity, FIV Zurich 2. Animals were
      clinically healthy and did not exhibit any haematological changes. FIV proviral
      DNA was demonstrated in peripheral blood lymphocytes of all cats and in monocytes
      of most animals, identifying FIV Zurich 2 as a both lympho- and monocytotropic
      strain. Monocytes were isolated from FIV-infected cats as well as from age
      matched uninfected control cats, short-term cultured and examined for cytokine
      (IL-1beta, IL-6, IL-10, IL-12 p40 and TNF-alpha) transcription by real-time PCR.
      Constitutive transcription of cytokines in monocytes from FIV-infected cats was
      restricted to IL-1beta and, in the majority of samples, TNF-alpha. For all
      cytokines, transcription levels were significantly lower in FIV-infected cats
      than in control cats. Transcription was often least intense in those samples
      where FIV infection of the monocyte fraction was not demonstrated. Results show
      that infection of cats with an FIV strain of low pathogenicity was associated
      with depression of constitutive cytokine transcription in monocytes even if
      clinical and haematological changes were not observed.

PMID- 15010231
TI  - Auditory comprehension: is multiple choice really good enough?
AB  - Auditory comprehension is commonly measured with multiple choice tasks. The
      sensitivity of these tasks in identifying deficits, however, is limited by credit
      given for correct guesses by forced choice. In this study, we compare performance
      on the multiple choice task to an alternative word/picture verification task, in
      122 subjects with acute left hemisphere stroke. As predicted, word/picture
      verification identifies significantly more subjects with deficits in auditory
      comprehension. Furthermore, the pattern of errors in the two tasks is consistent
      with a current distributed model of semantic memory, and inconsistent with
      alternative local models.

PMID- 15010232
TI  - Neural correlates of lexical and sublexical processes in reading.
AB  - The purpose of the present study was to compare the brain regions and systems
      that subserve lexical and sublexical processes in reading. In order to do so,
      three types of tasks were used: (i). silent reading of very high frequency
      regular words (lexical task); (ii). silent reading of nonwords (sublexical task);
      and, (iii). silent reading of very low frequency regular words (sublexical task).
      All three conditions were contrasted with a visual/phonological baseline
      condition. The lexical condition engaged primarily an area at the border of the
      left angular and supramarginal gyri. Activation found in this region suggests
      that this area may be involved in mapping orthographic-to-phonological whole word
      representations. Both sublexical conditions elicited significantly greater
      activation in the left inferior prefrontal gyrus. This region is thought to be
      associated with sublexical processes in reading such as grapheme-to-phoneme
      conversion, phoneme assembly and underlying verbal working memory processes.
      Activation in the left IFG was also associated with left superior and middle
      temporal activation. These areas are thought to be functionally correlated with
      the left IFG and to contribute to a phonologically based form of reading. The
      results as a whole demonstrate that lexical and sublexical processes in reading
      activate different regions within a complex network of brain structures.

PMID- 15010233
TI  - The fragile nature of the speech-perception deficit in dyslexia: natural vs
      synthetic speech.
AB  - A number of studies reported that developmental dyslexics are impaired in speech
      perception, especially for speech signals consisting of rapid auditory
      transitions. These studies mostly made use of a categorical-perception task with
      synthetic-speech samples. In this study, we show that deficits in the perception
      of synthetic speech do not generalise to the perception of more naturally
      sounding speech, even if the same experimental paradigm is used. This contrasts
      with the assumption that dyslexics are impaired in the perception of rapid
      auditory transitions.

PMID- 15010234
TI  - Motor-iconicity of sign language does not alter the neural systems underlying
      tool and action naming.
AB  - Positron emission tomography was used to investigate whether the motor-iconic
      basis of certain forms in American Sign Language (ASL) partially alters the
      neural systems engaged during lexical retrieval. Most ASL nouns denoting tools
      and ASL verbs referring to tool-based actions are produced with a handshape
      representing the human hand holding a tool and with an iconic movement depicting
      canonical tool use, whereas the visual iconicity of animal signs is more
      idiosyncratic and inconsistent across signs. We investigated whether the motor
      iconic relation between a sign and its referent alters the neural substrate for
      lexical retrieval in ASL. Ten deaf native ASL signers viewed photographs of
      tools/utensils or of actions performed with or without an implement and were
      asked to overtly produce the ASL sign for each object or action. The control task
      required subjects to judge the orientation of unknown faces. Compared to the
      control task, naming tools engaged left inferior and middle frontal gyri,
      bilateral parietal lobe, and posterior inferotemporal cortex. Naming actions
      performed with or without a tool engaged left inferior frontal gyrus, bilateral
      parietal lobe, and posterior middle temporal gyrus at the temporo-occipital
      junction (area MT). When motor-iconic verbs were compared with non-iconic verbs,
      no differences in neural activation were found. Overall, the results indicate
      that even when the form of a sign is indistinguishable from a pantomimic gesture,
      the neural systems underlying its production mirror those engaged when hearing
      speakers name tools or tool-based actions with speech.

PMID- 15010235
TI  - Physiological evidence that a masked unrelated intervening item disrupts semantic
      priming: implications for theories of semantic representation and retrieval
      models of semantic priming.
AB  - Event-related potentials were recorded in a paradigm where an unrelated word was
      interposed between two related words. In one condition, the intervening item was
      masked and in another condition it was not. The N400 component indicated that
      priming of the related word was disrupted by the intervening item whether it was
      masked or not. The data are interpreted to be inconsistent with retrieval models
      of priming.

PMID- 15010236
TI  - Meaning construction and integration in children with hydrocephalus.
AB  - Text comprehension processes were investigated in children with hydrocephalus, a
      neurodevelopmental disorder associated with good word decoding, but deficient
      reading comprehension. In Experiment 1, hydrocephalus and control groups were
      similar in processes related to activating word meanings and using context to
      enhance meaning. The hydrocephalus group was poorer at suppressing contextually
      irrelevant meanings. In Experiment 2, the hydrocephalus group had difficulty
      integrating information from an earlier read sentence to understand a new
      sentence as textual distance between the two propositions increased, suggesting
      difficulty in reactivation processes related to comprehension. Results are
      discussed in relation to cognitive and neurocognitive models of comprehension.

PMID- 15010237
TI  - Tense and agreement in German agrammatism.
AB  - This study presents results from sentence-completion and grammaticality-judgment
      tasks with 7 German-speaking agrammatic aphasics and 7 age-matched control
      subjects examining tense and subject-verb agreement marking. For both
      experimental tasks, we found that the aphasics achieved high correctness scores
      for agreement, while tense marking was severely impaired. To account for the
      observed tense-agreement dissociation, we suggest that the functional category
      T(ense)/INFL(ection) is tense-defective in agrammatic aphasia, i.e., it is
      specified for [+/-Realis], but not for [+/-Past]. It will also be argued that
      other accounts, specifically the tree-pruning model, do not explain our findings.

PMID- 15010238
TI  - Bilingual corpus callosum variability.
AB  - Magnetic resonance imaging was used to produce midsagittal images of the corpus
      callosum of 19 right-handed adult male and female subjects. The preliminary
      findings of this study indicate that significant adaptation in the anterior
      midbody of the corpus callosum has occurred to accommodate multiple language
      capacity in bilingual individuals compared to monolingual individuals. The main
      interpretation of this finding is that the precentral gyrus is involved in
      bilingual faculty adaptation assuming a role consistent with the somatotopical
      input to areas dedicated to the mouth, and input to association tracts connecting
      the premotor and supplementary motor cortices. This paper discusses possible
      implications to neuroscientists, second language educators, and their students.

PMID- 15010239
TI  - Semantic short-term memory and its role in sentence processing: a replication.
AB  - Previous studies have shown that an aphasic patient (AB) with a semantic short
      term memory deficit (STM) had difficulties comprehending and producing sentences
      with structures that demanded the simultaneous retention of several individual
      word meanings (Martin & Freedman, 2001a, 2001b; Martin & Romani, 1994; Martin,
      Shelton, & Yaffee, 1994). The present study provides a replication of these
      findings with an additional case (ML) who shows a striking dissociation between
      preserved semantic knowledge and disrupted semantic STM. ML performed poorly on
      comprehension tasks for sentences that required the retention of single word
      meanings across several intervening words. In contrast, he did not show an effect
      of intervening words on processing grammatical relations. ML had difficulty
      producing adjective-noun phrases, though able to produce the individual nouns and
      adjectives. These findings support the contention that there is a semantic
      retention capacity, involved in both comprehension and production, that is
      separate from semantic knowledge representations.

PMID- 15010240
TI  - Levels of processing with free and cued recall and unilateral temporal lobe
      epilepsy.
AB  - This study investigates the role of the temporal lobes in levels-of-processing
      tasks (phonetic and semantic encoding) according to the nature of recall tasks
      (free and cued recall). These tasks were administered to 48 patients with
      unilateral temporal epilepsy (right "RTLE"=24; left "LTLE"=24) and a normal group
      (n=24). The results indicated that LTLE patients were impaired for semantic
      processing (free and cued recall) and for phonetic processing (free and cued
      recall), while for RTLE patients deficits appeared in free recall with semantic
      processing. It is suggested that the left temporal lobe is involved in all
      aspects of verbal memory, and that the right temporal lobe is specialized in
      semantic processing. Moreover, our data seem to indicate that RTLE patients
      present a retrieval processing impairment (semantic condition), whereas the LTLE
      group is characterized by encoding difficulties in the phonetic and semantic
      condition.

PMID- 15010241
TI  - Word order and finiteness in Dutch and English Broca's and Wernicke's aphasia.
AB  - The effect of two linguistic factors in Broca's and Wernicke's aphasia was
      examined using Dutch and English subjects. Three tasks were used to test (1). the
      comprehension and (2). the construction of sentences, where verbs (in Dutch) and
      verb arguments (in Dutch and English) are in canonical versus non-canonical
      position; (3). the production of finite versus infinitive verbs. Proportions of
      errors as well as types of errors made by each aphasic group are similar on the
      sentence comprehension and sentence anagram tasks. On the verb production task
      the performance pattern is, again, the same, but the error types are different.
      The discussion focuses on how the similarities and differences across languages
      and across aphasia types may be interpreted with respect to the underlying
      deficit in Broca's and Wernicke's aphasia.

PMID- 15010242
TI  - Category size effects in semantic and letter fluency in Alzheimer's patients.
AB  - Many studies have found that patients with Alzheimer's disease (AD) perform
      significantly worse than normal controls on verbal fluency tasks. Moreover, some
      studies have found that AD patients' deficits compared to controls are more
      severe for semantic fluency (e.g., vegetables) than for letter fluency (e.g.
      words that begin with F). These studies, however, have not taken category size
      into account. A comparison of AD patients and age-matched controls on three
      semantic and three letter categories revealed that both the size and type of a
      category significantly predicted AD patients' deficits on verbal fluency tasks.
      These results suggest that the verbal fluency of AD patients will be most
      attenuated on large semantic categories.

PMID- 15010243
TI  - The time course for language acquisition in biologically distinct populations:
      evidence from deaf individuals.
AB  - The present study provides evidence that individuals who have different patterns
      of cerebral lateralization and who develop along different maturational time
      courses can attain comparable levels of language proficiency. Right-handed
      individuals with left-handed family members (left-handed familials, LHFs) showed
      a shorter sensitive period for language acquisition than did right-handed
      individuals with only right-handed family members (right-handed familials, RHFs).
      The shorter sensitive period for LHFs may be due to a focus on non-linguistic,
      word-based conceptual information during language acquisition. RHFs may focus on
      grammatical relations during language acquisition, which matures later than
      lexical knowledge. This suggests that there may be different patterns of cerebral
      lateralization for language in all normal populations as a function of familial
      handedness.

PMID- 15010244
TI  - The relationship between perisylvian morphology and verbal short-term memory
      functioning in children with neurodevelopmental disorders.
AB  - Although children with neurodevelopmental disorders frequently present with
      reduced short-term memory functioning, the relationship between perisylvian
      morphology and verbal short-term memory functioning has received limited
      attention. Thus, examining this relationship in children with neurodevelopmental
      disorders was the focus of this exploratory study. Results suggested leftward
      asymmetry in the temporal bank of the planum temporale is related to better
      coding and storage of semantic material. In contrast, parietal bank morphology is
      related to coding and storage of phonological material, and presence of an extra
      gyrus in the parietal region is associated with reduced phonological working
      memory. Data also supported a relationship between pars triangularis morphology
      and verbal short-term memory functioning, but this is not material-specific.

PMID- 15010245
TI  - Investigating hemispheric specialization in a novel face-word Stroop task.
AB  - We examined hemispheric specialization in a lateralized Stroop facial
      identification task. A 2 (presentation side: left or right visual field [LVF or
      RVF])x2 (picture emotion: happy or angry)x3 (emotion of distractor word: happy,
      angry, or blank) factorial design placed the right hemispheric specialization for
      emotional expression processing and the left hemispheric specialization for
      verbal processing in conflict. Faces (from ) and emotion words were briefly
      displayed, and participants responded with keypresses corresponding to the
      picture emotion. As predicted, greater Stroop interference in identification
      accuracy was found with incongruent displays of facial expression in the LVF and
      emotion words in the RVF, and females exhibited less Stroop interference.
      Reaction times were moderated by emotion and visual field.

PMID- 15010246
TI  - Comprehension of sentences with stylistic inversion by French aphasic patients.
AB  - Three French-speaking agrammatic aphasics and three French-speaking Conduction
      aphasics were tested for comprehension of Active, Passive, Cleft-Subject, Cleft
      Object, and Cleft-Object sentences with Stylistic Inversion using an object
      manipulation test. The agrammatic patients consistently reversed thematic roles
      in the latter sentence type, and the Conduction aphasics performed at chance. The
      results are discussed in relationship to existing models of aphasic impairments
      in assigning syntactic structures and using them to determine thematic roles in
      sentences. We conclude that the results for the agrammatic patients demonstrate
      the importance of compensatory mechanisms underlying aphasic comprehension and
      the results in the Conduction aphasics indicate the importance of working memory
      deficits in determining such deficits. The results are also relevant to models of
      normal syntactic structure.

PMID- 15010247
TI  - I'm sitting here feeling aphasic! A study of recurrent perseverative errors
      elicited in unimpaired speakers.
AB  - In this study, the recurrent perseverative errors produced by 44 speakers without
      impairment were examined in picture naming and reading aloud tasks under a fast
      response deadline. The proportion of perseverative relative to non-perseverative
      errors was greater in picture naming, the more error-prone task, than in reading
      aloud. Additionally, although perseverative errors were less likely to be related
      to the target than non-perseverative errors, the overall distribution of
      perseverative and non-perseverative errors in each task was similar. It is
      concluded that the perseverative errors produced by the participants reflected
      both the degree and level at which language processing efficiency was reduced in
      each task. This is consistent with a more recent account of perseveration as a
      result of normally existing persistent activation overcoming weakened activation
      of a target at any level of language processing. These results are compared with
      recent studies of recurrent perseverative errors produced by people with aphasia
      in light of the cognitive neuropsychological assumption that speakers with and
      without impairment utilise a common language processing system.

PMID- 15010248
TI  - Do alternative names block young and older adults' retrieval of proper names?
AB  - This study evaluates whether tip of the tongue experiences (TOTs) are caused by a
      more accessible word which blocks retrieval of the target word, especially for
      older adults. In a "competitor priming" paradigm, young and older adults produced
      the name of a famous character (e.g., Eliza Doolittle) in response to a question
      and subsequently named a picture of a famous actor or actress depicting this
      character (e.g., Audrey Hepburn as Eliza Doolittle). Older adults produced more
      TOTs than young adults, but prior production of a related character name did not
      affect TOTs, although it did reduce incorrect responses. There were no age
      differences in knowledge of films and TV and thus the age-related increase in
      TOTs is not because older adults have more relevant knowledge. The findings are
      compatible with models in which alternate words are a consequence not a cause of
      TOT.

PMID- 15010249
TI  - Word production deficits in schizophrenia.
AB  - Fronto-cerebellar circuitry is implicated in word production. Data suggest that
      the cerebellum is involved in word search, whereas the prefrontal cortex
      underlies the selection of words from among competing alternatives. We explored
      the role of search and selection processes in word production deficits in
      schizophrenia patients. In Experiment 1, patients were impaired in a verb
      generation task under both high and low selection conditions but were more
      impaired in the high selection condition. In Experiment 2, when the difficulty
      level of search and selection conditions was equated in a word stem completion
      task, patients were only impaired in the search condition. Word search deficits
      underlie word production problems in schizophrenia, and may involve fronto
      cerebellar dysfunction.

PMID- 15010250
TI  - Verbal fluency output in children aged 7-16 as a function of the production
      criterion: qualitative analysis of clustering, switching processes, and semantic
      network exploitation.
AB  - Developmental changes in children's verbal fluency were explored in this study.
      One hundred and forty children aged from 7 to 16 completed four verbal fluency
      tasks, each with a different the production criterion (letter, sound, semantic,
      and free). The age differences were analyzed both in terms of number of words
      produced, and clustering, switching, and semantic network exploration. Analysis
      of the number of words produced showed a larger difference between the 7-8- and
      the 9-10-year-olds in semantic than in letter fluency, but this difference
      gradually disappeared with increasing age for semantic fluency while remaining
      constant for letter fluency. In letter fluency production, age modified both the
      number of switches and clusters formed whereas in semantic fluency tasks, only
      cluster size changed with age. Concerning the semantic network exploration
      indicators derived from the supermarket fluency task, the number of categories
      sampled increased from 11 to 12 years, but efficient semantic exploitation
      occurred only after the age of 13-14 years. These results are discussed in terms
      of the development of strategic retrieval components and categorical knowledge.

PMID- 15010251
TI  - Crossed Wernicke's aphasia: a case report.
AB  - Crossed aphasia is a phenomenon in which an individual sustains a lesion in the
      right hemisphere (typically non-language dominant), but who exhibits an aphasic
      syndrome. The authors present a case study of an individual with crossed aphasia
      (CA) in an attempt to provide anecdotal information for four questions posed by :
      (a). Is CA a reversal of the normal cerebral hemisphere pattern of language
      function? (b). Does the presence of aphasia following a right cerebral hemisphere
      lesion indicate that typical right hemisphere functions (e.g., visual perception)
      are intact? (c). How may the aphasia's presentation differ from typical left
      hemisphere aphasias? And (d). is the pattern of improvement following CA similar
      to that of typical left hemisphere aphasias? We longitudinally examined the
      communicative-cognitive performance of an adult man with crossed aphasia of the
      Wernicke's type following a cerebrovascular accident. A 21-week follow-up
      evaluation indicated improvements in his language functioning from our initial
      evaluation, but he continued to exhibit a classic, moderately severe Wernicke's
      aphasia.

PMID- 15010252
TI  - Spared access to idiomatic and literal meanings: a single-case approach.
AB  - The current study examines how patients with aphasia access the meanings of
      idioms during spoken sentence comprehension. In our experiment, we had 4 subjects
      whose native language is German: 2 left-hemisphere damaged patients (Wernicke's
      and global aphasia); 1 right-hemisphere damaged patient; and 1 age-matched
      healthy speaker. Ambiguous two-element German noun compounds carrying an
      idiomatic as well as a literal meaning served as target words. While listening to
      contextually biasing sentences containing the target words, the subjects
      performed a lexical decision task at the offset of each compound. All the
      subjects, including the aphasic patients, accessed the compounds' literal and
      idiomatic meanings simultaneously despite the existence of contextually biasing
      sentences. The data are discussed by taking account of the findings of recent
      studies of lexical semantic processing in aphasia.

PMID- 15010253
TI  - Feature description and categorization of common objects after traumatic brain
      injury: the effects of a multi-trial paradigm.
AB  - This study investigated the ability to describe and categorize common objects
      following brain injury. Thirteen subjects with moderate to severe traumatic brain
      injury (TBI) and 13 noninjured controls participated in this project. The project
      consisted of 3 parts: 1. A spontaneous condition, 2. A training session, and 3.
      An application condition. During the spontaneous condition, subjects were asked
      to describe common objects. Following the spontaneous condition, subjects
      participated in a multi-trial training session to learn 8 perceptual features.
      The protocol concluded with an application condition where subjects were asked to
      apply all 8 features to describe additional objects. Overall, noninjured subjects
      provided more features than the group with TBI. However, subjects with TBI
      benefited from the training session, as they were able to learn more features
      across the repeated trials. Furthermore, both groups performed better during the
      application condition compared to the spontaneous description of objects. The
      results indicate that the multi-trial training session was effective in teaching
      subjects the 8 perceptual features.

PMID- 15010254
TI  - Idiom comprehension in aphasic patients.
AB  - Idiom comprehension was assessed in 10 aphasic patients with semantic deficits by
      means of a string-to-picture matching task. Patients were also submitted to an
      oral explanation of the same idioms, and to a word comprehension task. The
      stimuli of this last task were the words following the verb in the idioms. Idiom
      comprehension was severely impaired, with a bias toward the literal
      interpretation. Very few errors were produced with words, making impossible to
      establish a correlation between comprehension of idioms and of individual words.
      The difficulties in idiom comprehension seemed to be due to the fact that
      patients rely on a literal-first strategy, accessing a figurative interpretation
      only when the linguistic analysis fails to yield acceptable results.

PMID- 15010255
TI  - Eye movements of dyslexic children when reading in a regular orthography.
AB  - Participants were German dyslexic readers (13-year-olds) who-compared to English
      dyslexic readers-suffer mainly from slow laborious reading and less from reading
      errors. The eye movements of eleven dyslexic boys and age-matched controls were
      recorded during reading of text passages and pseudoword lists. For both text and
      pseudoword reading, the dyslexic readers exhibited more and much longer
      fixations, but relatively few regressions. Increased length of words and
      pseudowords led to a greater increase in number of fixations for dyslexic than
      normal readers. Comparisons across studies suggest that the present German
      dyslexic eye movement findings differ from English-based findings by a lower
      frequency of regressions (presumably due to the higher regularity of German) and
      from Italian findings by longer fixation duration (presumably due to the greater
      syllabic complexity of German).

PMID- 15010256
TI  - Speech rate as a sticky switch: a multiple lesion case analysis of mutism and
      hyperlalia.
AB  - Though it has long been known on the basis of clinical associations and
      serendipitous observation that speech rate is related to mood and psychomotor
      baseline, it is less known that speech rate is also related to libido and to
      immune function. We make the case for a bipolar phenomenon of "psychic tonus,"
      encompassing all these dimensions. The elated, agitated, libidinal,
      immunofacilitated, and talkative pole is an "approach" disposition primarily
      activated by the normal left hemisphere-especially, though not exclusively, its
      frontal lobe. The dejected, lethargic, delibidinized, immunosuppressed, and mute
      pole is an "avoidance" disposition primarily activated by the normal right
      hemisphere-especially, though not exclusively, its frontal lobe. In support of
      this proposed model, we present new evidence, via meta-analysis of previously
      published single lesion case reports, of a highly significant association between
      right hemisphere lesions and non-aphasic hyperlalia, and between left hemisphere
      lesions and non-aphasic mutism.

PMID- 15010257
TI  - Neural correlates of bimodal speech and gesture comprehension.
AB  - The present study examined the neural correlates of speech and hand gesture
      comprehension in a naturalistic context. Fifteen participants watched audiovisual
      segments of speech and gesture while event-related potentials (ERPs) were
      recorded to the speech. Gesture influenced the ERPs to the speech. Specifically,
      there was a right-lateralized N400 effect-reflecting semantic integration-when
      gestures mismatched versus matched the speech. In addition, early sensory
      components in bilateral occipital and frontal sites differentiated speech
      accompanied by matching versus non-matching gestures. These results suggest that
      hand gestures may be integrated with speech at early and late stages of language
      processing.

PMID- 15010258
TI  - Angiogenesis and anti-angiogenesis activity of Chinese medicinal herbal extracts.
AB  - The aqueous extracts of 24 herbs traditionally used as curing ischemic heart
      disease in clinic in China were screened for their in vitro angiogenic activity,
      another twenty-four traditionally used as anti-tumor or anti-inflammatory
      remedies in China were screened for their in vitro anti-angiogenic activity. The
      activity of angiogenesis was determined by quantitation of vessels on chick
      embryo chorioallantoic membrane (CAM) model and cell proliferation of cultured
      bovine aortic endothelial cells (BAECs). Among the herbal extracts examined, the
      aqueous extracts of Epimedium sagittatum, Trichosanthes kirilowii and Dalbergia
      odorifera showed the strong angiogenetic activity both in CAM and BAECs models;
      and the aqueous extracts of Berberis paraspecta, Catharanthus roseus, Coptis
      chinensis, Taxus chinensis, Scutellaria baicalensis, Polygonum cuspidatum and
      Scrophularia ningpoensis elicited significant inhibition at a concentration of 1g
      dry herb /ml.

PMID- 15010259
TI  - Human neutrophil-derived elastase induces airway smooth muscle cell
      proliferation.
AB  - Neutrophils and their derived elastase are abundant in chronic inflammatory
      responses of asthma. This study aimed to investigate the mitogenic effect of
      elastase on airway smooth muscle (ASM) cells and the implicated signal
      transduction pathway. Near confluent cultured human ASM cells were treated with
      human neutrophil elastase (HNE, 0.01 to 0.5 microg/ml) or vehicle for 24 hours
      with or without extracellular signal-regulated kinase (ERK) inhibitor (PD98059,
      30 microM), p38 kinase inhibitor (SB203580, 10 microM) or elastase inhibitor II
      (100 microg/ml). The ASM cell numbers were counted by a hemocytometer and DNA
      synthesis was assessed by flowcytometry. Western blots analysis for the
      expression of ERK, p38 and cyclin D1 was determined. HNE dose-dependently
      increased ASM cell numbers and the percentage of cells entering S-phase of cell
      cycle. This response was abolished by neutrophil elastase inhibitors and
      attenuated by PD98059, but not SB203580. HNE increased ERK phosphorylation and
      cyclin D1 expression. Pretreatment with PD98059 significantly inhibited elastase
      induced cyclin D1 activity. The increased ASM cellular gap and cell shape change
      by proteolytic activity of HNE may be contributory to ERK activation and
      therefore cell proliferation. Our results demonstrate that HNE is mitogenic for
      ASM cells by increasing cyclin D1 activity through ERK signaling pathway.

PMID- 15010260
TI  - Effect of beta-alanyl-L-histidinato zinc on the differentiation pathway of human
      periodontal ligament cells.
AB  - We examined the effect of beta-alanyl-L-histidinato zinc (AHZ) on the
      differentiation of human periodontal ligament (HPDL) cells. HPDL cells were
      cultured with alpha-minimum essential medium containing 10% fetal bovine serum
      with or without 10(-4) or 10(-5) M AHZ for up to 10 days. The expression of runt
      related transcription factor-2/core binding factor alpha-1 (RUNX2/Cbfa1), Sox9,
      bone morphogenetic proteins (BMPs), and BMP receptors was measured using
      semiquantitative reverse transcription-polymerase chain reactions.
      Phosphorylation of Smad1 was determined using a Western blot analysis.
      RUNX2/Cbfa1 expression increased markedly in cells cultured with AHZ, while Sox9
      expression increased slightly. BMP-7 expression was much higher than that of
      controls in cultures with AHZ, whereas BMP-2 expression was only slightly higher.
      The expression of BMP receptors increased markedly in cells cultured with AHZ.
      The phosphorylation of Smad1, a signal-transducing molecule for BMP-2 and BMP-7,
      was increased markedly in cultures with AHZ. The results suggest that AHZ diverts
      the differentiation pathway of HPDL cells to the osteoblast lineage via BMP-2 or
      BMP-7.

PMID- 15010261
TI  - Involvement of the 3'-untranslated region of cyclooxygenase-2 gene in its post
      transcriptional regulation through the glucocorticoid receptor.
AB  - Functional roles of the 3'-untranslated region (3'-UTR) of the human
      Cyclooxygenase-2 (COX-2) gene were evaluated by transient transfection using
      luciferase (Luc) reporter vectors into bovine arterial endothelial cells (BAEC).
      Insertion of the 3'-UTR into the downstream of a Luc coding region resulted in
      decreased reporter activity (23%), although insertion into the upstream was no
      effect. The reporter activity of the downstream insertion but not the upstream
      insertion was induced by bacterial lipopolysaccharide (LPS). Moreover, LPS
      selectively stabilized COX-2 mRNA. Next, to evaluate the role of the 3'-UTR
      together with glucocorticoid receptor (GR), a GR-expression vector was
      cotransfected with the reporter vector of the downstream insertion of the 3'-UTR.
      As a result, the LPS-induced reporter activity was suppressed by dexamethasone in
      a dose-dependent manner. These data suggest that the 3'-UTR of the COX-2 gene is
      involved in not only the induction by LPS but also the suppression by DEX of COX
      2 expression at the post-transcriptional level.

PMID- 15010262
TI  - Phenylpropanoid glycosides from Scrophularia scorodonia: in vitro anti
      inflammatory activity.
AB  - Five phenylpropanoid glycosides isolated from Scrophularia scorodonia L.
      (Scrophulariaceae), namely angoroside A (1), angoroside C (2), angoroside D (3),
      acteoside (4) and isoacteoside (5), had been evaluated as potential inhibitors of
      some macrophage functions involved in the inflammatory process. These compounds
      have been tested in two experimental systems: ionophore-stimulated mouse
      peritoneal macrophages and human platelets serve as source of COX-1 and 5-LOX,
      and mouse peritoneal macrophages stimulated with E. coli LPS are the means of
      testing for COX-2, NO and TNF-alpha activity. None of compounds assayed had a
      significant effect on LTC(4)-release from calcium ionophore-stimulated mouse
      peritoneal macrophages. However, the release of PGE(2) by mouse peritoneal
      macrophages stimulated with calcium ionophore was inhibited by most of these
      compounds. In the TXB(2)-release assay, acteoside (4), angoroside A (1) and
      angoroside C (2) showed a significant effect. These five compounds, except
      angoroside C (2) significantly inhibited LPS-induced PGE(2), NO and TNF-alpha in
      a concentration-dependent manner. In LPS-stimulated macrophages, the
      phenylpropanoid glycoside angoroside C (2) only had activity on NO. These results
      indicate that the pharmacology of these compounds may participate in the anti
      inflammatory effect of Scrophularia scorodonia.

PMID- 15010263
TI  - Glucuronidation of haloperidol by rat liver microsomes: involvement of family 2
      UDP-glucuronosyltransferases.
AB  - The purposes of this study were to develop a HPLC method to assay for haloperidol
      glucuronide (HALG); to apply this assay method to the in vitro determination of
      haloperidol (HAL) UDP-glucuronosyltransferase (UGT) enzyme kinetics in rat liver
      microsomes (RLM); and to identify the UGT isoforms catalyzing glucuronidation of
      HAL in rats. Incubation of Brij-activated RLM with HAL and UDP-glucuronic acid
      (UDPGA) in TRIS pH 7.4 buffer resulted in the formation of a single peak in the
      HPLC chromatogram at 270 nm. The identity of this peak was confirmed to be that
      of HALG by 1) beta-glucuronidase hydrolysis; 2) incubation without UDPGA; 3) UV
      spectral analysis; and 4) LC/MS/MS to yield the expected mass of 552.1. Enzyme
      kinetic studies using single enzyme Michaelis-Menton model showed an apparent
      Vmax = 271.9 +/- 10.1 pmoles min(-1) mg protein(-1) and Km = 61 +/- 7.2 microM.
      Glucuronidation activity in homozygous Gunn (j/j) rats was approximately 80% as
      compared to Sprague-Dawley RLM. HALG formation was approximately doubled in PB
      induced RLM. There was no increase in glucuronidation activities in 3MC-induced
      RLM. The Gunn rat and the PB-induced RLM data suggest predominant but not
      exclusive involvement of the UGT2B family in the formation of HALG. Because the
      UGTs exhibit overlapping substrate specificities and most substrates are
      glucuronidated by more than one isoform, inhibition studies with UGT2B1 substrate
      probe testosterone and the UGT2B12 substrate probe borneol were conducted. UGT2B1
      and UGT2B12 exhibited 40% and 90% inhibition of HAL glucuronidation,
      respectively. Thus, UGT2B12 and UGT 2B1 isoforms are responsible for catalyzing
      HAL glucuronidation in rats. Our HPLC assay provides a specific and sensitive
      technique for the measurement of in vitro HAL-UGT activity.

PMID- 15010264
TI  - The effect of desflurane on ameliorating cerebral infarction in rats subjected to
      focal cerebral ischemia-reperfusion injury.
AB  - To obtain more information on the cerebral ischemia and reperfusion injury under
      desflurane anesthesia, we compared the infarct volume and lactate dehydrogenase
      (LDH) activity in rats subjected to focal cerebral ischemia during different
      concentration of desflurane anesthesia. Male Long-Evans rats weighing 270-350 g
      were anesthetized with desflurane in air at 1.0, 1.25 or 1.5 MAC whereas rats in
      the control group received intraperitoneal chloral hydrate (400 mg/kg)
      anesthesia. Cerebral infarction was induced by microsurgical procedures with
      ligation of the right middle cerebral artery (MCA) and clipping of the bilateral
      common carotid arteries (CCA) for 60 minutes. The rats were sacrificed 24 hours
      later, serial brain slices of 2mm thickness were taken and stained for the
      measurement of the infarct area. Cellular damage was evaluated by measuring the
      LDH level in the plasma. Desflurane (1.0, 1.25 or 1.5 MAC by inhalation) and
      chloral hydrate (400 mg/kg; ip.) did not produce any changes in pH, blood gases,
      heart rate or mean arterial blood pressure. In the rats subjected to focal
      cerebral ischemia, the volume of infarction was significantly less in the
      desflurane groups in all three different concentrations than in the chloral
      hydrate group. The changes of LDH activity in plasma also correlated with the
      result of the infarct volume. Our study suggests that desflurane may offer a
      neuroprotective effect such as decreased infarct volume after focal cerebral
      ischemia.

PMID- 15010265
TI  - Potential roles of hepatic heat shock protein 25 and 70i in protection of mice
      against acetaminophen-induced liver injury.
AB  - The aim of the present study was to assess the contribution of the level of
      expression of heat shock protein 25 (HSP25), 60 (HSP60), 70 (HSC70) and 70i
      (HSP70i) in mouse livers after a lethal dose of acetaminophen (APAP) to their
      survival. We examined changes in survival ratio, plasma APAP level and alanine
      aminotransferase (ALT) activity, and hepatic reduced glutathione (GSH), HSP25,
      HSP60, HSC70 and HSP70i levels following treatment of mice with APAP (500 mg/kg,
      p.o.). The plasma APAP level increased rapidly, and reached a maximum 0.5 h after
      APAP treatment. Hepatic GSH decreased rapidly, and was almost completely depleted
      1 h after APAP treatment. Plasma ALT activity, an index of liver injury,
      significantly increased from 3 h onwards after APAP treatment. The survival
      ratios 9 h, 24 h and 48 h after APAP treatment were 96%, 38% and 36%,
      respectively. We found a remarkable difference in the patterns of hepatic HSP25
      and HSP70i induction in mice that survived after APAP treatment. HSP70i levels
      increased from 1 h onwards after APAP treatment in a time-dependent manner, and
      reached a maximum at 9 h. In contrast, HSP25 could be detected just 24 h after
      APAP treatment, and maximal accumulation was observed at 48 h. Other HSPs
      examined were unchanged. Notably, the survival ratio dropped by only 2% after
      HSP25 expression. Recently, a novel role for HSP25 as an anti-inflammatory factor
      was suggested. We have already shown that 48-h treatment with APAP induces severe
      centrilobular necrosis with inflammatory cell infiltration in mouse livers. Taken
      together, the level of expression of hepatic HSP25 may be a crucial determinant
      of the fate of mice exposed to APAP insult.

PMID- 15010266
TI  - Intratracheal double-stranded RNA plus interferon-gamma: a model for analysis of
      the acute phase response to respiratory viral infections.
AB  - Double-stranded (ds)RNA is made as a by-product of viral replication. Synthetic
      dsRNA induces virtually all of the same systemic symptoms as acute viral
      infections, such as fever and malaise. In order to develop a model of respiratory
      viral infections (such as influenza) suitable for use in gene knockout mice
      (where the deleted gene may affect viral replication), we examined C57BL/6 mouse
      body temperature and locomotor activity responses to the synthetic dsRNA
      polyriboinosinic.polyribocytidylic acid (poly[rI.rC]) introduced via the
      intratracheal (IT) route. We compared the IT poly[rI.rC] responses to the well
      characterized intraperitoneal (IP) poly[rI.rC] responses. IT poly[rI.rC] failed
      to induce an acute phase response (APR) in mice, in contrast to IP poly[rI.rC].
      However, addition of interferon (IFN)gamma to the IT poly[rI.rC] inoculum induced
      sustained hypothermia and suppressed locomotor activity responses with similar
      kinetics to those responses seen in acute mouse influenza. We further examined
      cytokine, antiviral, muscarinic M2 receptor and inducible nitric oxide synthase
      gene expression at 5 hr in the lungs of IT challenged mice. These studies
      suggested that priming the lung with IFNgamma could enhance proinflammatory
      (IL1beta, IL6, TNFalpha) cytokine gene expression and suppress interferon gene
      expression compared to IT poly[rI.rC] alone. No differences were detected for the
      other genes examined. While further molecular characterization of the model is
      required, we demonstrate that IT challenge with combined poly[rI.rC] and IFNgamma
      closely simulates the APR to an acute respiratory virus, and may serve as a
      suitable model for analyzing the molecular basis of the viral APR in gene
      knockout mice.

PMID- 15010267
TI  - Diclofenac-induced peripheral antinociception is associated with ATP-sensitive K+
      channels activation.
AB  - In order to investigate to the contribution of K+ channels on the peripheral
      antinociception induced by diclofenac, we evaluated the effect of several K+
      channel blockers, using the rat paw pressure test, in which sensitivity is
      increased by intraplantar injection (2 microg) of prostaglandin E2. Diclofenac
      administered locally into the right hindpaw (25, 50, 100 and 200 microg) elicited
      a dose-dependent antinociceptive effect which was demonstrated to be local, since
      only higher doses produced an effect when injected in the contralateral paw. This
      blockade of PGE2 mechanical hyperalgesia induced by diclofenac (100 microg/paw)
      was antagonized in a dose-dependent manner by intraplantar administration of the
      sulphonylureas glibenclamide (40, 80 and 160 microg) and tolbutamide (80, 160 and
      320 microg), specific blockers of ATP-sensitive K+ channels, and it was observed
      even when the hyperalgesic agent used was carrageenin, while the antinociceptive
      action of indomethacin (200 microg/paw), a typical cyclo-oxygenase inhibitor,
      over carrageenin-induced hyperalgesia was not affected by this treatment.
      Charybdotoxin (2 microg/paw), a blocker of large conductance Ca2+-activated K+
      channels and dequalinium (50 microg/paw), a selective blocker of small
      conductance Ca2+-activated K+ channels, did not modify the effect of diclofenac.
      This effect was also unaffected by intraplantar administration of non-specific
      voltage-dependent K+ channel blockers tetraethylammonium (1700 microg) and 4
      aminopyridine (100 microg) or cesium (500 microg), a non-specific K+ channel
      blocker. The peripheral antinociceptive effect induced by diclofenac was
      antagonized by NG-Nitro L-arginine (NOarg, 50 microg/paw), a NO synthase
      inhibitor and methylene blue (MB, 500 microg/paw), a guanylate cyclase inhibitor,
      and this antagonism was reversed by diazoxide (300 microg/paw), an ATP-sensitive
      K+ channel opener. We also suggest that an endogenous opioid system may not be
      involved since naloxone (50 microg/paw) did not affect diclofenac-induced
      antinociception in the PGE2-induced hyperalgesia model. This study provides
      evidence that the peripheral antinociceptive effect of diclofenac may result from
      activation of ATP-sensitive K+ channels, possible involving stimulation of L
      arginine/NO/cGMP pathway, while Ca2+-activated K+ channels, voltage-dependent K+
      channels as well as endogenous opioids appear not to be involved in the process.

PMID- 15010268
TI  - Adventitial ex vivo gene transfer with autologous vascular smooth muscle cells: a
      superior approach for delivery of therapeutics into the arterial wall?

PMID- 15010269
TI  - Cardiac remodeling: is 8 the heart's lucky number?

PMID- 15010270
TI  - Do the FHC-associated R403 mutations in myosin heavy chain lead to a greater
      energetic cost of contraction?

PMID- 15010271
TI  - Angiogenic effect of prostaglandin I 2 in relation with its effect on PPAR
      nuclear receptors.

PMID- 15010272
TI  - Feline immunodeficiency virus and retrovirus-mediated adventitial ex vivo gene
      transfer to rabbit carotid artery using autologous vascular smooth muscle cells.
AB  - We have developed an ex vivo gene transfer technique to rabbit arterial wall
      using autologous smooth muscle cells (SMCs). SMCs were harvested from rabbit ear
      artery, transduced in vitro with vesicular stomatitis virus G-glycoprotein
      pseudotyped retrovirus or feline immunodeficiency virus (FIV) and returned to the
      adventitial surface of the carotid artery using a periadventitial silicone collar
      or collagen sheet placed around the artery. Beta-galactosidase (lacZ) and human
      apolipoprotein E3 (apoE3) cDNAs were used as transgenes. After retrovirus
      mediated gene transfer of lacZ the selected cells implanted with high efficiency
      and expressed lacZ marker gene at a very high level 7 and 14 days after the
      operation. The level of lacZ expression decreased thereafter but was still
      detectable 12 weeks after the gene transfer, and was exclusively localized to the
      site of cell implantation inside the collar. Utilizing FIV vector expressing
      apoE3, low levels of apoE were measured from serum collected from a low-density
      lipoprotein receptor deficient Watanabe heritable hyperlipidemic rabbits 1 month
      after the gene transfer. The physiological effect of apoE expression was detected
      as transiently elevated serum cholesterol levels. The results indicate that the
      model can be used for high efficiency local gene transfer in arteries, e.g.
      during vascular surgery. The model is also valuable for studying expression,
      stability and safety of new gene transfer vectors and their expression products
      in vivo.

PMID- 15010273
TI  - Alpha8beta1 integrin is upregulated in myofibroblasts of fibrotic and scarring
      myocardium.
AB  - Integrins mediate cell attachment to the extracellular matrix (ECM) regulating
      migration, proliferation, and differentiation. We previously reported the
      presence of alpha8beta1 integrin on cultured cardiac fibroblasts. Extending this
      information, we localized alpha8beta1 integrin in normal rat myocardial tissue,
      and investigated its expression pattern in rats chronically infused with
      angiotensin II (Ang II, 500 ng/kg/min), a well-recognized profibrotic factor.
      Alpha8beta1-integrin expression was analyzed by binding assay, western blotting,
      and immunohistochemistry. In normal myocardium, immunohistochemical staining for
      alpha8 was found in fibroblasts, as well as in the epicardium, endocardium, and
      valves. Vascular smooth muscle cells (VSMCs) of the media of cardiac arteries
      also stained positively. After 14-d-Ang II infusion, staining for fibronectin, as
      well as collagen staining by Sirius red, revealed extensive interstitial and
      perivascular fibrosis. Increased expression of alpha8 integrin in ventricular
      smooth muscle (SM) alpha-actin-positive fibroblasts (myofibroblasts) was also
      recorded. The upregulation of alpha8beta1 integrin was confirmed by binding assay
      and by western blotting. Microscopic scars, a characteristic of reparative
      fibrosis, were invaded by matrix proteins and by strongly alpha8- and SM alpha
      actin-positive myofibroblasts. The results indicate that, in rat adult
      myocardium, alpha8beta1 integrin is expressed in fibroblasts and VSMC. In Ang II
      infused animals, alpha8beta1-integrin expression was enhanced in the left
      ventricle and arteries. The coordinate regulation of alpha8beta1 integrin on
      fibroblasts and ECM proteins raises the possibility that this integrin is
      implicated in the deposition of matrix components leading to fibrosis.

PMID- 15010274
TI  - Human homozygous R403W mutant cardiac myosin presents disproportionate
      enhancement of mechanical and enzymatic properties.
AB  - Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in 11
      genes encoding sarcomeric proteins. Most families present mutations in MYBPC3 and
      MYH7 encoding cardiac myosin-binding protein C and beta-myosin heavy chain. The
      consequences of MYH7 mutations have been extensively studied at the molecular
      level, but controversial results have been obtained with either reduced or
      augmented myosin motor function depending on the type or homogeneity of myosin
      studied. In the present study, we took advantage of the accessibility to an
      explanted heart to analyze for the first time the properties of human homozygous
      mutant myosin. The patient exhibited eccentric hypertrophy with severely impaired
      ejection fraction leading to heart transplantation, and carries a homozygous
      mutation in MYH7 (R403W) and a heterozygous variant in MYBPC3 (V896M). In situ
      analysis of the left ventricular tissue showed myocyte disarray and hypertrophy
      plus interstitial fibrosis. In vitro motility assays showed a small, but
      significant increase in sliding velocity of fluorescent-labeled actin filaments
      over human mutant cardiac myosin-coated surface compared to control (+18%;
      P<0.001). Mutant myosin exhibited a large increase in maximal actin-activated
      ATPase activity (+114%; P<0.05) and Km for actin (+87%; P<0.05) when compared to
      control. These data show disproportionate enhancement of mechanical and enzymatic
      properties of human mutant myosin. This suggests inefficient ATP utilization and
      reduced mechanical efficiency in the myocardial tissue of the patient, which
      could play an important role in the development of FHC phenotype.

PMID- 15010275
TI  - Comparative analysis of the in vivo angiogenic properties of stable prostacyclin
      analogs: a possible role for peroxisome proliferator-activated receptors.
AB  - OBJECTIVE: Until recently, prostacyclin (PGI2) biological activities were thought
      to be exclusively mediated by cell surface receptors named IP. Recent studies
      have instead identified a novel pathway of PGI2 signaling, occurring through
      activation of peroxisome proliferator-activated receptors (PPARs) located in the
      nucleus. The availability of stable PGI2 analogs with different affinity for IP
      receptors and PPARs provides the possibility to test the importance and function
      of this dual pathway in vitro and in vivo. In this study, the in vivo angiogenic
      properties of different PGI2 analogs and the potential relationship between PPAR
      mediated pathways, vascular endothelial growth factor (VEGF), and angiogenesis
      were investigated. METHODS AND RESULTS: By using the murine corneal model of
      angiogenesis, we found that PGI2 analogs able to act on nuclear PPARs, such as
      iloprost and carbaprostacyclin (cPGI), induce angiogenesis in vivo. In contrast,
      cicaprost, a PGI2 analog that only acts on IP receptors, has no in vivo
      angiogenic activity. Interestingly, angiogenesis induced by iloprost and cPGI
      does not differ in extent and morphology from that induced by VEGF and is
      associated with local increment of VEGF mRNA expression and protein levels.
      Finally, iloprost-induced angiogenesis is significantly decreased by systemic
      inhibition of VEGF activity, obtained by gene transfer of a soluble form of the
      VEGF receptor Flt-1. CONCLUSIONS: These data demonstrate that stable PGI2 analogs
      may have angiogenic properties in vivo, depending on their ability to act on
      PPARs. The resulting angiogenic process appears to be mediated by VEGF. These
      findings indicate that important physiological activities in the cardiovascular
      system, such as angiogenesis and VEGF induction, may be modulated by PGI2 through
      specific activation of the PPAR signaling pathway in vivo, with potentially
      important fundamental and clinical implications.

PMID- 15010276
TI  - Role of Ca2+ in determining the rate of tension development and relaxation in rat
      skinned myocardium.
AB  - To clarify the roles of Ca2+ and crossbridge kinetics in determining the cardiac
      contraction profile, we analyzed the rate of tension development following
      nitrophenyl-EGTA photolysis and the rate of relaxation following diazo-2
      photolysis in the absence and presence of phosphate (Pi, 5 mM) in rat skinned
      ventricular trabeculae. The rate of tension development was fitted with a single
      exponential function. The rate constant (kc) increased not only with an increase
      in prephotolysis tension (initial activation level) under the same postphotolysis
      tension (final Ca2+ level), but also with an increase in postphotolysis tension
      under the same prephotolysis tension. Pi increased kc, though decreased both the
      prephotolysis and postphotolysis tension greatly. The rate of relaxation was
      fitted with a double-exponential function. The rate constants of both initial
      rapid phase (kr1), which was higher than kc, and subsequent slow (kr2) relaxation
      were almost independent of either the prephotolysis tension or the postphotolysis
      tension (i.e. the extent of relaxation). Pi increased both kr1 and kr2 by about
      twofold. These results apparently contradicting both the "steric blocking model"
      and the "kinetic model", and can be explained in terms of the changes in number
      of tension-generating crossbridges through the Ca2+-dependent cooperative thin
      filament activation/inactivation associated with the Pi-modulated changes in
      number of tension-generating crossbridges. The thin filament activation kinetics
      seems to be slower than its inactivation.

PMID- 15010277
TI  - Signal-transduction pathways involved in the hypertrophic effect of hsp56 in
      neonatal cardiomyocytes.
AB  - Heat shock protein (hsp) 56 (hsp56) is an immunophilin that acts as a cofactor
      with hsp90 and exhibits both peptidyl-prolyl isomerase activity and chaperone
      activity. Previous studies have shown that the hypertrophic effect of
      cardiotrophin-1 (CT-1) in cardiac cells is dependent on hsp56 induction. CT-1
      activates a number of signal-transduction pathways. Therefore, we sought to
      determine whether these pathways were also important for hsp56-induced
      hypertrophy using overexpression with transiently transfected plasmid vectors in
      rat neonatal cardiomyocytes. Here we show that multiple signalling pathways are
      involved in hsp56-induced hypertrophy, namely the Janus kinase-signal-transducer
      and activator of transcription, extracellular signal-regulated protein kinase and
      PI3-kinase/Akt signalling pathways. Dominant-negative mutants and inhibitors of
      these pathways were able to block the hypertrophy observed as a result of hsp56
      overexpression. However, an inhibitor of the p38 mitogen-activated protein kinase
      (p38 MAPK) pathway was not able to block the hypertrophic effect of hsp56
      overexpression. Furthermore, we show that domains I, II and IV of the hsp56
      protein may be involved in its hypertrophic effect. These studies show for the
      first time that multiple signalling pathways are involved in the hypertrophic
      effect of hsp56 and that overexpression of hsp56 itself is able to activate the
      necessary signalling pathways, which induce hypertrophy.

PMID- 15010278
TI  - Connective tissue growth factor--a novel mediator of angiotensin II-stimulated
      cardiac fibroblast activation in heart failure in rats.
AB  - The pathophysiologic mechanisms of myocardial remodeling in heart failure (HF)
      remain poorly understood. Using differential mRNA display of myocardial tissue
      from rats with ischemic HF vs. controls we identified robust myocardial induction
      of the mRNA encoding connective tissue growth factor (CTGF). The aim of this
      study was to investigate the sites of synthesis and the mechanisms of induction
      of CTGF in failing myocardial tissue. The study demonstrates that myocardial
      expression of CTGF mRNA and protein is substantially elevated in non-ischemic
      tissue from both the left and the right ventricles of rats with experimentally
      induced myocardial infarction (MI). The induction of myocardial CTGF mRNA was
      shown to transcend from early post-infarction HF to chronic HF. In situ
      hybridization and immunohistochemical analysis of myocardial tissue sections
      demonstrated expression of CTGF confined to fibroblasts and endothelial cells of
      non-ischemic myocardial tissue. In subsequent experiments rats subjected to MI
      were randomized to treatment with the AT1 angiotensin receptor antagonist
      losartan (12.5 mg/kg b.i.d. per os) or vehicle. Losartan attenuated ventricular
      hypertrophy, improved hemodynamics, and prevented the induction of myocardial
      CTGF mRNA observed in rats post-MI. To provide the cellular basis of Ang II
      stimulated CTGF mRNA expression, primary cultures of rat myocardial fibroblasts
      were stimulated with Ang II (10(-7) M). Real-time reverse transcription
      polymerase chain reaction and western blot analysis demonstrate that Ang II
      induces rapid, AT1 receptor-mediated elevations of CTGF mRNA and protein in rat
      cardiac fibroblasts. Furthermore, CTGF was shown to stimulate fibroblast
      proliferation in vitro. In conclusion, this study demonstrates that CTGF is a
      myocardial effector of Ang II-induced myocardial remodeling in HF mediated via
      AT1 receptors situated on cardiac fibroblasts.

PMID- 15010279
TI  - Effect of C-reactive protein on chemokine expression in human aortic endothelial
      cells.
AB  - Inflammation plays a pivotal role in atherosclerosis. In addition to being a risk
      marker for cardiovascular disease, much recent data support a role for C-reactive
      protein (CRP) in atherogenesis. Interleukin-8 (IL-8), a member of the CXC
      chemokines promotes monocyte-endothelial cell adhesion and arrest and is abundant
      in atherosclerotic plaques. However, there is a paucity of data examining the
      effect of CRP on IL-8 secretion in human aortic endothelial cells (HAEC). In this
      report, we show that incubation of HAEC with CRP resulted in a time and dose
      dependent increase in IL-8 protein and mRNA via transcription. In contrast to
      human umbilical vein endothelial cells, monocyte-chemoattractant protein-1
      expression in HAEC was not affected by CRP. Furthermore, CRP upregulated NF-kappa
      B activity in HAEC and inhibitors of NF-kappa B significantly reversed the
      upregulation of IL-8 by CRP. Blocking antibodies to IL-8 significantly decreased
      monocyte-endothelial cell adhesion induced by CRP (31%, P<0.01). In conclusion,
      this study makes the novel observation that CRP induces IL-8 synthesis and
      secretion in HAEC via upregulation of NF-kappa B activity.

PMID- 15010280
TI  - NECA and bradykinin at reperfusion reduce infarction in rabbit hearts by
      signaling through PI3K, ERK, and NO.
AB  - The adenosine A1/A2 adenosine agonist 5'-(N-ethylcarboxamido) adenosine (NECA)
      and bradykinin both limit infarction when administered at reperfusion in rabbits.
      This study compares the signal transduction pathways responsible for their anti
      infarct effect. Receptor agonists were administered to isolated rabbit hearts
      starting 25 min after the onset of a 30-min period of ischemia and continued into
      the 2-h reperfusion period. Infarct size was measured. Both NECA and bradykinin
      decreased infarction from 31.5 +/- 2.4% of the risk zone in untreated hearts to
      11.8 +/- 2.0% and 15.4 +/- 2.4%, respectively (P<0.05). Protection from both
      agents was blocked by PD98059, wortmannin, and Nomega-nitro-L-arginine methyl
      ester (L-NAME), thus demonstrating dependence on activation of extracellular
      regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) and stimulation
      of nitric oxide synthase (NOS). Both wortmannin and PD98059 prevented
      phosphorylation of ERK 1/2 in NECA-treated hearts, whereas only wortmannin and
      not PD98059 blocked Akt phosphorylation. These data suggest Akt is upstream of
      ERK 1/2. In addition, 8-(3-chlorostyryl) caffeine blocked NECA's protection
      indicating that A2 adenosine receptors trigger NECA's anti-infarct effect. Of
      note, both bradykinin and acetylcholine (ACh) administered before ischemia to
      trigger preconditioning's cardioprotection use PI3K and NOS in their signaling
      pathway. Curiously, however, ACh, unlike bradykinin, was not protective when
      administered at reperfusion. Hence, both NECA and bradykinin administered at
      reperfusion protect through a common signaling pathway that includes PI3K, NO,
      and ERK.

PMID- 15010281
TI  - Distribution and relative expression levels of calcium channel beta subunits
      within the chambers of the rat heart.
AB  - Calcium channel beta subunits expressed in rat atria and atrial myocytes are
      identified and their expression quantified and compared to beta subunit
      expression in the ventricle. mRNAs encoding all four know beta subunits are
      expressed in atrial myocytes including the following splice variants: beta1a,
      beta2b, beta2c, beta2e and beta4d. The specific beta2 splice variants expressed
      in the atria (beta2b, beta2c, beta2e) differ from those previously reported from
      rat ventricle. Beta2 isoform is the most abundant beta mRNA expressed in the
      heart and the amount of both beta2 subunit mRNA and beta2 subunit protein is
      significantly greater in the ventricles than in the atria. The expression of
      individual beta2 splice variants varies with age and within different chambers of
      the heart. The beta2b splice variant appears in both atria and ventricle in both
      young (4.5 week) and old (16 week) animals, the beta2c isoform is more highly
      expressed in young as compared to old animals and the beta2e splice variant is
      robustly expressed only in 4.5 week ventricle. Beta4 mRNA expression is higher in
      atrial tissue than in ventricles and its expression decreases in older animals.
      In contrast, the abundance of the beta3 mRNA does not significantly change as a
      function of postnatal age. Antisense oligonucleotides targeting sequence common
      to all the beta isoforms as well as that specific for beta2 significantly reduced
      HVA calcium current density in isolated atrial cells confirming that the beta2
      subunits contribute to the regulation of HVA calcium current expression in the
      rat atria. The complexity of beta isoform expression within the heart may provide
      a mechanism for functional fine-tuning of the cardiac HVA current.

PMID- 15010282
TI  - Mitochondrial ROS generation following acetylcholine-induced EGF receptor
      transactivation requires metalloproteinase cleavage of proHB-EGF.
AB  - Acetylcholine (ACh) mimics ischemic preconditioning by a mechanism dependent on
      phosphatidylinositol 3-kinase (PI3-kinase) and reactive oxygen species (ROS). In
      other tissues muscarinic receptors activate a metalloproteinase, which liberates
      surface-associated heparin-binding epidermal growth factor (HB-EGF) and causes
      transactivation of epidermal growth factor receptors (EGFRs) with activation of
      PI3-kinase. We tested whether this pathway is operative in myocardium. Adult
      rabbit cardiomyocytes were incubated in reduced MitoTracker Red, which fluoresces
      after ROS exposure. ACh caused a 36 +/- 6% increase in fluorescence (P<0.001) and
      metalloproteinase inhibitor III (MPI) abolished this increase. Both exogenous EGF
      as well as HB-EGF caused similar increases in the ROS signal (41 +/- 12%, P=0.005
      and 40 +/- 7%, P<0.001, respectively). The ROS burst from HB-EGF was unaffected
      by MPI (37 +/- 6%, P=0.002), confirming that inhibition of metalloproteinase
      activity blocked ACh's effect at a site upstream of EGFR. CRM-197, which inhibits
      HB-EGF activity, also blocked ACh-induced ROS generation, again implicating
      release of HB-EGF as a necessary step for ROS generation. An HB-EGF-neutralizing
      antibody also prevented ACh-induced increase in ROS. In isolated, perfused rabbit
      hearts ACh increased phosphorylation of EGFR by 127.4 +/- 43.7%, and this
      increase was abolished by MPI. Finally, ACh decreased infarct size from 30.1 +/-
      2.9% of the risk zone in control hearts to 13.7 +/- 3.0% (P=0.002), and this
      protection could be abolished by co-treatment with MPI (28.7 +/- 2.6%, P=n.s. vs.
      control). Stimulation of a second Gi-protein-coupled receptor by the delta-opioid
      agonist [D-Ala2, D-Leu5]-enkephalin acetate (DADLE) also protected the heart (9.1
      +/- 2.0% infarction, P<0.005 vs. control), and this protection was similarly
      blocked by MPI (28.9 +/- 2.3% infarction). We conclude that ACh-induced ROS
      generation in myocytes is mediated via transactivation of EGFR through
      metalloproteinase-dependent release of HB-EGF, and that this pathway is also
      operative in the intact heart and is required for ACh's cardioprotection.

PMID- 15010283
TI  - Normalization of renal aquaporin-2 water channel expression by fosinopril,
      valsartan, and combination therapy in congestive heart failure: a new mechanism
      of action.
AB  - This study investigated the effect of fosinopril (Fos), valsartan (Val), and
      combination of both drugs (Fos + Val) on the cardiac and renal expression of
      aquaporin-1 (AQP1) and aquaporin-2 (AQP2) in congestive heart failure (CHF). A
      rat model of CHF was created by ligating the left anterior descending coronary
      artery to induce acute myocardial infarction (AMI). Rats were treated by Fos,
      Val, or Fos + Val for 4 weeks. In renal medulla and cortex, AMI was associated
      with 2.2- and 1.8-fold increase in AQP2 mRNA expression when compared with Sham
      operated rats (medulla: 23.6 +/- 2.8 vs. 52.3 +/- 8.7%; P<0.001; cortex: 19.4 +/-
      3.9 vs. 35.5 +/- 7.1%; P<0.05). All the treatment regimens were able to normalize
      AQP2 transcription in the renal medulla (Fos, 19.9 +/- 4.9%; Val, 22.8 +/- 4.9%;
      Fos + Val, 20.1 +/- 5.1%; P=NS vs. Sham) and in the cortex (Fos, 21.2 +/- 6.7%;
      Val, 20.4 +/- 6.0%; Fos + Val, 18.9 +/- 7.5%; P=NS vs. Sham). Similarly, the AQP2
      protein expression increased by 2.1-fold after CHF (P<0.05), and was normalized
      by the treatment regimens (Sham, 0.57 +/- 0.19%; CHF, 1.22 +/- 0.45%; Fos, 0.39
      +/- 0.36%; Val, 0.46 +/- 0.34%; Fos + Val, 0.36 +/- 0.15%; all P<0.05 vs. CHF).
      These treatment regimens also prevented the increase in body weight as found in
      untreated CHF rats (analysis of variance P<0.05). The renal and cardiac AQP1 gene
      and protein expressions were unaltered in CHF or by medical therapy. There was no
      observed cardiac AQP2 expression in all the study groups. Treatment with Fos,
      Val, or combination therapy was effective in preventing the upregulation of renal
      AQP2 gene and protein expressions in CHF rats caused by AMI.

PMID- 15010285
TI  - Proteasome inhibition induces cytokeratin accumulation in vivo.
AB  - Chronic ethanol ingestion leads to inhibition of proteasomal activity. As a
      consequence, proteins accumulate in liver cells. Cytokeratin accumulation as seen
      in alcoholic hepatitis could lead to the formation of Mallory bodies. In order to
      study the phenomenon of cytokeratin accumulation in liver cells, rats were fed
      ethanol or dextrose for 1 month and some were given the proteasome inhibitor, PS
      341, to augment the inhibitory effect of ethanol feeding. This was done to study
      the involvement of proteasome inhibition in the process of cytokeratin
      accumulation. There was a marked increase in the accumulation of
      polyubiquitinated proteins, and heat shock proteins (hsp) 25 and 70 in the liver
      of rats treated with PS-341. Similarly, cytokeratin-8 (CK-8) levels were markedly
      increased in the liver homogenates of rats fed ethanol when given PS-341. When
      normal mouse cultured hepatocytes were transfected with cytokeratin-18 (CK-18)
      tagged with red fluorescent protein (RFP), CK-18 aggresomes formed because
      proteasome was overloaded. These data provide new evidence that proteasome
      inhibition is involved in cytokeratin accumulation, when aggresomes are formed in
      tissue culture. Accumulation of cytokeratin in this way may ultimately lead to
      Mallory body formation as seen in alcoholic hepatitis.

PMID- 15010286
TI  - Cytotoxic activity of natural killer cells lacking killer-inhibitory receptors
      for self-HLA class I molecules against autologous hematopoietic stem cells in
      healthy individuals.
AB  - Killer-inhibitory receptors (KIR) are receptors for self-HLA class I molecules,
      which are expressed on natural killer (NK) cells and small subsets of T
      lymphocytes. KIR receptors that do not bind to self-HLA class I have been
      implicated in the pathogenesis of pure red-cell aplasia and other autoimmune
      diseases. However, NK cells whose inhibitory receptors lack any apparent self
      ligand can also be found in healthy individuals. We therefore tested whether
      these NK cells are capable of exerting cytotoxic activity against autologous
      CD34(+) hematopoietic precursors. We detected NK cells whose sole inhibitory
      receptors were CD94/NKG2-A and that had no affinity for autologous HLA-C
      molecules. In vitro, such cells were able to kill autologous CD34(+) stem cells
      that expressed MHC class I antigen at a high level in about 50% of the cases of
      HLA-C group 2 donors. Two individual clones derived from this NK subpopulation
      were stimulated by autologous HLA-Cw5/6-positive stem cells, but not by
      allogeneic HLA-Cw7-positive stem cells. Our findings demonstrate the presence of
      potentially autoreactive natural killer cells in otherwise healthy individuals.

PMID- 15010287
TI  - Inducible expression of the signal transduction protein 14-3-3gamma in injured
      arteries and stimulated human vascular smooth muscle cells.
AB  - Although the 14-3-3 family of proteins have been shown to be key signal
      transduction proteins involved in regulation of cellular growth and
      proliferation, little has been reported on their expression in pathophysiological
      states. We hypothesized that expression of one isoform, 14-3-3gamma, would also
      be increased in vascular proliferative diseases. We observed 14-3-3gamma
      expression induced in human coronary artery vasculopathy (CAV) as compared with
      coronary arteries isolated from normal and end-stage heart failure patients. 14-3
      3gamma is acutely expressed in aortic medial smooth muscle cells in experimental
      models of arterial injury including rat cardiac allografts balloon angioplasty
      injured swine coronary arteries. In each case, 14-3-3gamma protein expression is
      induced by 3 days and peaks at 7-10 days post-injury. Expression of this protein
      in cultured human vascular smooth muscle cells (VSMC) is associated with cytokine
      induced VSMC activation, rather than direct injury to the VSMC themselves, and is
      unique among other 14-3-3 family proteins. Potential 14-3-3gamma protein-protein
      interactions are also differentially regulated by cytokine stimulation. This
      study indicates that 14-3-3gamma expression is induced in arterial trauma by
      cytokines, and suggests that this protein may play an important role in
      progression of vascular proliferative diseases.

PMID- 15010288
TI  - Hemodynamic forces regulate mural macrophage infiltration in experimental aortic
      aneurysms.
AB  - Blood flow (BF) and wall shear stress (WSS) influence reactive oxygen species
      production and oxidative stress in abdominal aortic aneurysm (AAA) disease. To
      gain further insight into the mechanisms of hemodynamic influences on AAA
      inflammation, we examined aneurysm macrophage density, chemotaxis and survival
      under varying aortic flow conditions. Rat AAAs were created via porcine
      pancreatic elastase (PPE) infusion. In selected cohorts, AAA flow was increased
      via left common femoral arteriovenous fistula (AVF) creation (HF-AAA) or
      decreased by left common iliac ligation (LF-AAA). WSS was highest in HF-AAA (10.4
      +/- 2.3 dyn/cm(2) vs. 2.4 +/- 0.4 and 0.5 +/- 0.2 for NF- and LF-AAA,
      respectively, P < 0.001) 7 days after PPE infusion, with reduced medial
      macrophage density and increased apoptosis. Adventitial macrophage density was
      not significantly influenced by flow. Monocyte chemoattractant protein-1 (MCP-1)
      and granulocyte-macrophage colony-stimulating factor (GM-CSF) gene expression
      correlated with observed macrophage densities in the media and adventitia.
      Luminal flow conditions regulate AAA inflammation in part via influences on
      medial macrophage density. Hemodynamic forces may modulate AAA inflammation and
      diameter enlargement via direct regulation of intimal macrophage adhesion,
      transmural migration or survival.

PMID- 15010289
TI  - Antibodies to highly conserved peptide sequence of staphylococcal and
      streptococcal superantigens in Kawasaki disease.
AB  - Superantigen-mediated disease such as toxic shock syndrome is seen in patients
      who have a weak antibody response to the antigen toxic shock syndrome toxin 1
      (TSST-1). We hypothesized that there may be deficiency in antibody production to
      staphylococcal and streptococcal toxins in Kawasaki disease (KD) children. A
      peptide was constructed from the homologous portion of the staphylococcal
      enterotoxins (SE) and streptococcal pyrogenic enterotoxins (SPE), and antibodies
      to the peptide were made. The anti-peptide antibody immunoblotted several of the
      SE toxins and SPE toxins. Presence of the peptide antibodies was investigated via
      ELISA in the sera of acute KD (n = 30), convalescent KD (n = 12), control adults
      (n = 10), and children (n = 19). The mean anti-peptide antibodies were
      indistinguishable between control children and KD before treatment with
      immunoglobulin (P = 0.7) but rose significantly after therapy (P < 0.01). The
      adults had significantly higher antibodies than the KD, both acute and late (P <
      0.0001) and the control children (P < 0.0001). Thus, KD patients do not have a
      defective serological response against toxins such as SPE/SE/TSST-1. Normal
      children have significantly lower antitoxin antibody levels to the toxins
      compared to the adults.

PMID- 15010290
TI  - Human S-antigen: peptide determinant recognition in uveitis patients.
AB  - Uveitis is an inflammation of the uveal tract and is one of the major causes of
      visual impairment. Several lines of evidence suggest an important role for
      activated T lymphocytes in the perpetuation of posterior uveitis. In sequel to
      our preliminary observations with human S-antigen, we have further investigated
      the proliferative response of peripheral blood lymphocytes of posterior uveitis
      patients against 20 linear and 9 overlapping peptides of retinal S-antigen. The
      expression of surface markers CD4, CD8, CD29, CD45RA in peripheral blood was
      detected by flow cytometry. We have also assessed the pattern of cytokines
      present in peripheral blood mononuclear cells (PBMCs) using ribonuclease
      protection assay (RPA). Nineteen out of 32 patients' lymphocytes showed
      proliferative response to S-antigen, one or more of its 20 linear and nine
      overlapping synthetic peptides. Six patients showed significant
      lymphoproliferative response against various peptides. The maximum response was
      found to peptides from the 231-270 amino acid region of human S-antigen sequence.
      The percentage of CD29(+) (memory cells) and CD45RA(+) (naive cells) T
      lymphocytes was higher in patients compared to healthy volunteers. There was a
      demonstrable difference in the percentage of CD4(+) and CD8(+) lymphocytes in the
      patients (P <== 0.05) as compared to controls. Higher message for interleukin
      (IL)-5, IL-10, IL-15, IL-9, IL-2, IL-13, and interferon (IFN)-gamma was observed
      in uveitis patients than in healthy individuals. In brief, our study suggests
      that a particular region of S-antigen plays an important role in idiopathic
      uveitis.

PMID- 15010291
TI  - In vivo inhibition of tumor angiogenesis by a soluble VEGFR-2 fragment.
AB  - The interaction of vessel endothelial cell growth factor (VEGF) and its receptors
      (flt-1, FLK-1/KDR) regulates tumor angiogenesis. Therefore, blocking the binding
      of VEGF and the corresponding receptor has become critical for antitumor
      angiogenesis biological therapy. Our study extracted sFLK-1 fragment from embryo
      mouse liver using RT-PCR, recombined it to retrovirus vector, and transfected it
      to tumor cell lines (S180 and B16) by the liposome mediated method, then we
      observed the biological behavior of transgenic cells in vivo. The results are:
      (1) Fragment (1034 bp) was extracted from E9, E11 embryo mouse liver tissue,
      which was identified by sequence analysis. (2) This fragment was cloned to
      retrovirus vector (PLXSN vector), which was further transfected to tumor cells
      lines (S180 and B16). SDS-PAGE indicated the suspension of transgenic cells
      present sVEGFR-2(sFLK-1) fragment; Western blot identified it. (3) In vivo study
      showed that the weight and size of tumor in the group of transgenic cells were
      smaller than in control groups. Microvessel density (MVD) and FLK-1 expression
      were obviously different between transgenic and control groups, but there were no
      differences in VEGF expression between transgenic and control groups. In short,
      the isolated soluble VEGFR2 fragment transfected to tumor cells can be secreted
      to extracellular suspension and can inhibit tumor angiogenesis in vivo.

PMID- 15010292
TI  - FISH analysis of BRCA1 copy number in paraffin-embedded ovarian cancer tissue
      samples.
AB  - We investigated the BRCA1 gene copy number in unselected ovarian malignancies.
      Both additional genes (amplification) as well as deletion (loss of
      heterozygosity, LOH) are often thought to have a role in the initiation or
      progression of cancer. In addition, if there were little change, deletion studies
      might help identify BRCA1 mutation carriers. Forty-seven paraffin-embedded
      ovarian tissue blocks obtained between 1984 and 1997 were used for this study. A
      sample was "deletion-positive" when BRCA1-deleted cells in the tumor area were
      significantly different from the benign area. Twenty-five (53%) cases were found
      to be "deletion-positive". The average age of onset of "deletion-positive"
      patients was 50.8 years and of "deletion-negative" 57.8 years (P < 0.05). There
      was no statistical difference between groups in the staging, histology, or
      prognosis. A Kaplan-Meier study did show a trend towards poorer survival for
      "deletion-positive" patients. FISH permits unique molecular characterization of
      malignancies at a cellular level. Double amplification of HER-2 and c-myc
      predicts poor ovarian cancer survival. There appears to be a definite role for
      BRCA1 deletion in reducing the age of ovarian cancer onset and possibly in
      overall survival. Further FISH studies of this and other patient sets using
      additional molecular markers are needed.

PMID- 15010293
TI  - Correlation between VEGF and HIF-1alpha expression in human oral squamous cell
      carcinoma.
AB  - Understanding the development and progression of oral cancer is critical in the
      quest for successful therapeutic intervention. The hypoxic microenvironment
      present in human oral tumor in vivo may actively influence tumor growth and
      neovascularization. This study correlates expression of both VEGF and HIF-1alpha
      in normal keratinocytes and oral cancer cell lines and determine whether hypoxia
      played a role in VEGF and HIF-1alpha regulation. Three human oral cancer cell
      lines and three normal keratinocytes were exposed to both normoxia and hypoxia
      culture conditions. Northern and Western blot analysis were used to assess VEGF
      and HIF-1alpha expression in the different culture conditions. ELISA assays were
      performed to measure VEGF production in the different cell lines tested. Hypoxia
      upregulated VEGF and HIF-1alpha expression on both normal and oral cancer cell
      lines, with a statistically significant difference between normal and oral cancer
      cell lines. Pattern of hypoxia-induced VEGF mRNA level tightly followed the HIF
      1alpha mRNA expression in the cell lines tested. These results suggest that
      hypoxia regulates both VEGF and HIF-1alpha expression in head and neck carcinoma
      cell lines, thus establishing a biochemical pathway between tumor hypoxia and
      neoangiogenesis in these aggressive neoplasms.

PMID- 15010294
TI  - Study on the practical use of quantitative whole-body auto-radioluminography.
AB  - The practical use of quantitative radioluminography (RLG) using reading system
      BAS 2000 (Fuji Photo Film Ltd., Tokyo, Japan) and STORM 820 (Molecular Dynamics,
      USA) was examined using a chemical matrix as an internal standard, which offers
      the benefits of being preservative, inexpensive, and easy to handle. The results
      were as follows: 1. As the water content is within the range of 65-80% for most
      organs and tissues, we selected a chemical matrix, Tissue-TEK containing 85%
      water, as a base for the preparation of a standard curve. 2. The calibration
      curve prepared using Tissue-Tek as the internal standard was compared with the
      calibration curve using liver paste preparations as the internal standard. The
      results showed good linearity in both cases, with almost no difference in the
      slopes of the two calibration curves. 3. The PSL-BG or MD counts/pixel-BG values
      of the lowest radioactivity concentration measured for small areas of the region
      of interest (ROI) showed large fluctuations with both BAS 2000 and STORM 820, but
      the fluctuation became less than 15% at above 25 mm(2) of ROI. 4. The value of
      dpm/g calculated using the calibration curve prepared from Tissue-Tex internal
      standards showed a very good correlation with the values of dpm/g obtained by
      scraping off the tissue from the remaining block and conducting measurements with
      a liquid scintillation counter.

PMID- 15010295
TI  - Morphometric ultrastructural analysis of satellite cells in denervated rat soleus
      muscle.
AB  - Morphometric analysis of the ultrastructural changes of satellite cells (SCs) of
      rat soleus muscle 7, 14, and 36 days post denervation was performed. Denervation
      caused decrease of surface area cross-section of SCs and their nuclei, volume
      fractions of nucleus and Golgi complex elements and ribosomes number. In
      contrast, the increase of surface area/volume ratio of SCs and nucleus, volume
      fraction and number of endosome/lysosome-like structures, and number of caveolae
      like structures was noticed. Ultrastructural changes of SCs in denervated muscles
      strongly suggest decline of cell activity accompanied by increased processes of
      degradation of material of endo-, and/or egzogenous origin.

PMID- 15010296
TI  - A new allele of the mouse hairless gene interferes with Hox/LacZ transgene
      regulation in hair follicle primordia.
AB  - A new autosomal recessive mouse mutation, causing loss of hair in homozygous mice
      2-3 weeks after birth, arose spontaneously in a colony at the National Institute
      for Medical Research (NIMR), Mill Hill, London in early 1998. Complementation
      analysis confirmed that this mutation was an allele of the hairless gene (hr).
      The gene symbol hr(rhbm) (hairless-rhino-bald Mill Hill) was assigned to reflect
      the source of the colony. Here we show the molecular defect in these mutants,
      which is a substantial deletion at the 3'-end of the hairless gene. Morphological
      and immunological analysis of the new hairless mutation was performed at early
      postnatal stages. In an effort to address the molecular and cellular mechanisms
      of the hairless phenotype, we analysed developmental stages before the
      establishment of alopecia. Using a HoxLacZ reporter line of transgenic mice,
      epidermal placode formation was followed in embryos. Homozygous mutant embryos
      (hr(rhbmh)/hr(rhbmh)), containing the LacZ reporter under the control of a Hoxb4
      gene enhancer, display sharp loss of LacZ staining in epidermal cells
      invaginating to form the embryonic hair follicle placode. In the light of
      targeted mutagenesis data involving a Hox gene in the hair development, we
      discuss the potential implication of the hr(rhbmh) locus in cascades of Hox gene
      regulation during embryogenesis.

PMID- 15010299
TI  - NMR spectroscopic and molecular modeling studies of protein-carbohydrate and
      protein-peptide interactions.
AB  - Investigations of the conformations of carbohydrates, their analogues and their
      molecular mimics are described, with emphasis on structural and functional
      information that can be gained by NMR spectroscopic techniques in combination
      with molecular modeling. The transferred nuclear Overhauser effect (trNOE) has
      been employed to determine the bound conformations of carbohydrates and other
      bioactive molecules in complex with protein receptors. The corresponding
      experiments in the rotating frame (trROE) and selective editing experiments
      (e.g., QUIET-NOESY) are used to eliminate indirect cross-relaxation pathways
      (spin diffusion), thereby minimizing errors in the data used for calculation of
      conformations. Saturation transfer difference NMR experiments reveal detailed
      information about intermolecular contacts between ligand and protein.
      Computational techniques are integrated with NMR-derived information to construct
      structural models of these bioactive molecules and of their complexes with
      proteins. Recent investigations into the nature of molecular mimicry with regard
      to protein-ligand interactions are described, along with applications in
      determining the mode of action of enzyme inhibitors. The results are relevant for
      the design of the next generation of drug and vaccine candidates.

PMID- 15010297
TI  - The secondary dyslipidemia and deranged serum phosphate concentration in thyroid
      disorders.
AB  - Hyperlipidemia is a secondary disorder associated with many metabolic disorders
      including hypothyroidism. The occurrence of dyslipidemia in subclinical
      hypothyroidism is controversial. Hyperphosphatemia may accompany the dyslipidemia
      in some metabolic disorders. Both hyperlipidemia and hyperphosphatemia are
      considered to be risk factors for the coronary heart diseases. In the present
      study, we investigated the occurrence of dyslipidemia and altered serum phosphate
      concentrations in patients with thyroid disorders. The results indicated a
      significantly elevated serum cholesterol and triglyceride concentrations in the
      hypothyroid patients. The dyslipidemia was accompanied with significantly
      elevated serum phosphate level. On the other hand, no significant difference was
      evident in the serum lipid or phosphate concentrations of subclinical hypothyroid
      patients compared to euthyroid subjects. A significantly reduced serum phosphate
      level was shown in hyperthyroid patients with unaltered serum lipid levels.
      Significant correlations were evident between TSH and T(4) levels as independent
      parameters and the serum concentrations of triglyceride, cholesterol and
      phosphate. The results indicate in hypothyroidism that a secondary
      hyperphosphatemia may aggravate myocardial and arterial abnormalities induced by
      the secondary hyperlipidemia, which may need correction.

PMID- 15010300
TI  - Web resources for the carbohydrate chemist.
AB  - Bioinformatics has played a pivotal role in advancing genetics and protein
      sciences. The large amount of information generated by genomics, and now
      proteomics, has been a driving force. By comparison, glycobiology still generates
      small amounts of data. The need to organize our knowledge about carbohydrates is
      however growing constantly and has given rise to an increasing number of public
      databases and freely available tools. This review gives an overview of the
      carbohydrate-oriented resources currently available on the Internet. Many of the
      resources are seldom referred to in the literature and difficult to find, in part
      because of the constant flux of the net itself, but also because many efforts
      have been lead by a single individual. As the World Wide Web has matured the
      number of 'permanent' resources, maintained by organizations rather than
      individuals, has increased. In this paper, we present some of the more useful and
      accessible public tools and databases. There are also a few commercial
      initiatives but these have not been reviewed.

PMID- 15010301
TI  - Evaluation of carbohydrate molecular mechanical force fields by quantum
      mechanical calculations.
AB  - A quantitative evaluation of 20 second-generation carbohydrate force fields was
      carried out using ab initio and density functional methods. Geometry-optimized
      structures (B3LYP/6-31G(d)) and relative energies using augmented correlation
      consistent basis sets were calculated in gas phase for monosaccharide
      carbohydrate benchmark systems. Selected results are: (i). The interaction energy
      of the alpha-d-glucopyranose.H(2)O heterodimer is estimated to be 4.9 kcal/mol,
      using a composite method including terms at highly correlated (CCSD(T)) level.
      Most molecular mechanics force fields are in error in this respect; (ii). The
      (3)E envelope (south) pseudorotational conformer of methyl 5-deoxy-beta-d
      xylofuranoside is 0.66 kcal/mol more stable than the (3)E envelope (north)
      conformer and the alpha-anomer of methyl d-glucopyranoside is 0.82 kcal/mol more
      stable than the beta-anomer; (iii). The relative energies of the (gg, gt and tg)
      rotamers of methyl alpha-d-glucopyranoside and methyl alpha-d-galactopyranoside
      are (0.13, 0.00, 0.15) and (0.64, 0.00, 0.77) kcal/mol, respectively. The results
      of the quantum mechanical calculations are compared with the results of
      calculations using the 20 second-generation carbohydrate force fields. No single
      force field is consistently better than the others for all the test cases. A
      statistical assessment of the performance of the force fields indicates that
      CHEAT(95), CFF, certain versions of Amber and of MM3 have the best overall
      performance, for these gas phase monosaccharide systems.

PMID- 15010302
TI  - Conformational analysis of complex oligosaccharides: the CICADA approach to the
      uromodulin O-glycans.
AB  - Uromodulin is the pregnancy-associated Tamm-Horsfall glycoprotein, with the
      enhanced ability to inhibit T-cell proliferation. Pregnancy-associated structural
      changes mainly occur in the O-glycosylation of this glycoprotein. These include
      up to 12 glycan structures, made up of an unusual core type 2 sequence terminated
      with one, two, or three sialyl Lewis(x) sequences; this type of O-glycans could
      serve as E- and P-selectin ligands. The present work focuses on the most complex
      one; a tetradecamer made up of a type 2 core carrying three sialyl Lewis(x)
      branches. Five different monosaccharides are assembled by 14 glycosidic linkages.
      The conformational behavior of the constituting disaccharide segments was
      evaluated using the flexible residue procedure of the MM3 molecular mechanics
      procedure. For each disaccharide, the adiabatic energy surface, along with the
      local energy minima were established. All these results were used for the
      generation, prior to complete optimization of the tetradecamer. This was followed
      by a complete exploration of conformational hyperspace throughout the use of the
      single coordinate method as implemented in the CICADA program. Despite the
      potential flexibility of the tetradecasaccharide, only four conformational
      families occur, accounting for more than 95% of the total low energy
      conformations. For each family, the molecular properties (electrostatic,
      lipophilicity, and hydrogen potential) were studied. The shape of the
      tetradecasaccharide is best described as a flat ribbon, flanked by three branches
      having terminal sialyl residues. Two of the branches interact through nonbonded
      interactions, bringing further energy stabilization, and limiting the
      conformational flexibility of the sialyl residues. Only one branch maintains the
      original conformational features of sialyl Lewis(x). This O-glycan can be seen as
      a fascinating example of 'dendrimeric' structure, where the spatial arrangement
      of three S-Le(x) epitopes may favor its complementary 'presentations' for the
      interactions with E- and P-selectins.

PMID- 15010303
TI  - The conformations of the O-specific polysaccharides of Shigella dysenteriae type
      4 and Escherichia coli O159 studied with molecular mechanics (MM3) filtered
      systematic search.
AB  - The branched O-antigens of Escherichia coli O159 and Shigella dysenteriae type 4
      are structurally related and are known to show cross-reactivity with antibodies.
      In the present study, conformational analyses were performed on these two O
      antigens using molecular mechanics MM3(96) with filtered systematic search. The
      results show very strong steric restrictions for the trisaccharide at the branch
      point of the E. coli O159 antigen, especially for the beta-d-GlcNAc-(1-->3)-beta
      d-GlcNAc linkage of the main chain. For the type 4 O-antigen the calculations
      show essentially a single conformation with respect to the alpha-d-GlcNAc-(1-->3)
      alpha-d-GlcNAc linkage of the main chain and three different favoured
      conformations for the fucose branch. Consecutive repeating units of the S.
      dysenteriae type 4 and E. coli O159 O-antigens form linear extended chains with
      significant flexibility between the branches. Comparative calculations carried
      out with the SWEET server indicate that our method of filtered systematic search
      is a superior method in the case of branched, constrained oligosaccharides. Based
      on the results of the MM3 calculations, we propose that the common epitope
      explaining the cross-reactivity comprises the fucose branch, the downstream
      GlcNAc and part of the uronic acid.

PMID- 15010304
TI  - Conformational analysis and dynamics of mannobiosides and mannotriosides using
      Monte Carlo/stochastic dynamics simulations.
AB  - The conformation and dynamics of alpha-(1-->2)-mannobioside, alpha-(1-->6)
      mannobioside, and of the trisaccharide alpha-Man-(1-->2)-alpha-Man-(1-->6)-alpha-
      Man-OMe were studied using Monte Carlo/stochastic dynamics (MC/SD) simulations,
      the AMBER* force field, and the GB/SA implicit water solvation model. The results
      are in agreement with available experimental data.

PMID- 15010305
TI  - The heparin-Ca(2+) interaction: the influence of the O-sulfation pattern on
      binding.
AB  - The specific binding of Ca(2+) to synthetic hexasaccharide models of modified
      heparin has been investigated by NMR and molecular modeling and compared with
      previous results on a model of regular heparin. These two models represent the
      regular region of heparin lacking one type of O-sulfate group, either at C-6 of
      glucosamine or at C-2 of iduronate. The NMR experiments show different responses
      to the presence of Ca(2+). In the case of the compound lacking O-sulfate groups
      at C-2, the results are indicative of specific binding similar to that observed
      for the regular heparin, while the model lacking sulfate groups in position 6
      interacts more weakly with Ca(2+). In order to understand the basis of this
      difference, a molecular modeling study based on a rigid body docking approach of
      the interaction of these carbohydrates with Ca(2+) and Na(+) was performed. We
      have found that the results are strongly dependent on the starting orientation of
      the lateral side chains of the charged groups of the carbohydrate, and that the
      best agreement with the experimental results is obtained when the starting
      conformations are taken from previous simulations in the presence of Ca(2+).

PMID- 15010306
TI  - Toward the understanding of the structure and dynamics of protein-carbohydrate
      interactions: molecular dynamics studies of the complexes between hevein and
      oligosaccharidic ligands.
AB  - Herein we study, through all atom molecular dynamics simulations, the complex
      between hevein and two N-acetylated chitin oligomers, namely N,N(')
      diacetylchitobiose and N,N('),N(")-triacetylchitotriose. The results of the
      simulations for two disaccharide complexes and one trisaccharide complex show
      that a carbohydrate oligomer is able to move on the surface of the relatively
      flat binding pocket of hevein, therefore occupying different binding subpockets.
      Statistical analysis methods were also applied in order to define the principal
      overall motions in the complexes, showing how the different ligands in the
      simulations modulate the protein motions. The oligosaccharide binding can be
      considered as defined by a subtle balance between enthalpic (formation of
      intermolecular interactions between the ligand and the receptor) and entropic
      (due mainly to the possibility for the sugar to move on the surface of the
      protein domain) effects, determining multiple binding conformations. This
      structural and dynamical view could parallel the results obtained by regularly
      used restrained MD simulations based on NOE NMR data that provide a well defined
      structure for both the disaccharide and trisaccharide complexes, and agrees with
      the observations for longer oligosaccharide chains.

PMID- 15010308
TI  - Molecular modeling insights into the catalytic mechanism of the retaining
      galactosyltransferase LgtC.
AB  - The bacterial enzyme lipopolysaccharyl alpha-galactosyltransferase C (EC 2.4.1.x,
      LgtC) is involved in the synthesis of lipooligosaccharides displayed on the cell
      surfaces of Neisseria meningitidis. LgtC catalyzes the transfer of a galactosyl
      residue from UDP-Gal to the terminal galactose residue of glycoconjugates with an
      overall retention of stereochemistry at the anomeric center. Several hypothetical
      catalytic mechanisms of the LgtC enzyme were examined herein using DFT quantum
      chemical methods up to the B3LYP/6-311++G**//B3LYP/6-31G* level. The
      computational model used to follow the reaction is based on the crystallographic
      structure of LgtC in complex with both the nucleotide-galactose donor and the
      oligosaccharide-acceptor analogues. The 136 atoms included in this model
      represent fragments of residues critical for the substrate binding and catalysis.
      From our calculations, the preferred pathway is predicted to be a one step
      mechanism with the nucleophilic attack of the acceptor oxygen onto the anomeric
      carbon and the proton transfer to a phosphate oxygen occurring simultaneously.
      This mechanism has an A(N)D(N)A(H)D(H) character, with the unique transition
      state structure in which the attacking galactose group is more closely bound to
      the anomeric carbon than to the UDP leaving group and where the hydrogen bond
      between the nucleophile and the leaving group oxygens facilitates the attack of
      the acceptor O4(') from the same side of the transferred galactose.

PMID- 15010307
TI  - Molecular dynamics simulations of glycosyltransferase LgtC.
AB  - Molecular dynamics simulations have been performed on fully solvated alpha-(1-
      >4)-galactosyltransferase LgtC from Neisseria meningitidis with and without the
      donor substrate UDP-Gal and in the presence of the manganese ion. The analysis of
      the trajectories revealed a limited movement in the loop X (residues 75-80) and a
      larger conformational change in the loop Y (residues 246-251) in the simulation,
      when UDP-Gal was not present. In this case, the loops X and Y open by almost 10A,
      exposing the active site to the solvent. The 'hinge region' responsible for the
      opening is composed of residues 246-247. We have also analyzed the behavior of
      the manganese ion in the simulations. The coordination number is 6 when UDP-Gal
      is present and it increases to 7 when it is absent. In the latter case, three
      water molecules become coordinated to the ion. In both cases, the coordination is
      very stable implying that the manganese ion is tightly bound in the active site
      of the enzyme even if UDP-Gal is not present. Further analysis of the structural
      water molecules location confirmed that the mobility of water molecules in the
      active site and the accessibility of this site for solvent are higher in the
      absence of the substrate.

PMID- 15010309
TI  - Data mining the protein data bank: automatic detection and assignment of
      carbohydrate structures.
AB  - Knowledge of the 3D structure of glycans is a prerequisite for a complete
      understanding of the biological processes glycoproteins are involved in. However,
      due to a lack of standardised nomenclature, carbohydrate compounds are difficult
      to locate within the Protein Data Bank (PDB). Using an algorithm that detects
      carbohydrate structures only requiring element types and atom coordinates, we
      were able to detect 1663 entries containing a total of 5647 carbohydrate chains.
      The majority of chains are found to be N-glycosidically bound. Noncovalently
      bound ligands are also frequent, while O-glycans form a minority. About 30% of
      all carbohydrate containing PDB entries comprise one or several errors. The
      automatic assignment of carbohydrate structures in PDB entries will improve the
      cross-linking of glycobiology resources with genomic and proteomic data
      collections, which will be an important issue of the upcoming glycomics projects.
      By aiding in detection of erroneous annotations and structures, the algorithm
      might also help to increase database quality.

PMID- 15010310
TI  - Dysfunctional mammalian telomeres join with DNA double-strand breaks.
AB  - In addition to joining broken DNA strands, several non-homologous end-joining
      (NHEJ) proteins have a second seemingly antithetical role in constructing
      functional telomeres, the nucleoprotein structures at the termini of linear
      eukaryotic chromosomes that prevent joining between natural chromosome ends.
      Although NHEJ deficiency impairs double-strand break (DSB) repair, it also
      promotes inappropriate chromosomal end fusions that are observed microscopically
      as dicentric chromosomes with telomeric DNA sequence at points of joining. Here,
      we test the proposition that unprotected telomeres can fuse not only to other
      dysfunctional telomeres, but also to ends created by DSBs. Severe combined
      immunodeficiency (scid) is caused by a mutation in the catalytic subunit of DNA
      dependent protein kinase (DNA-PK), an enzyme required for both efficient DSB
      repair and telomeric end-capping. Cells derived from wild-type, Trp53-/-, scid,
      and Trp53-/-/scid mice were exposed to gamma radiation to induce DSBs, and
      chromosomal aberrations were analyzed using a novel cytogenetic technique that
      can detect joining of a telomere to a DSB end. Telomere-DSB fusions were observed
      in both cell lines having the scid mutation, but not in wild-type nor Trp53-/-
      cells. Over a range of 25-340 cGy, half of the visible exchange-type chromosomal
      aberrations in Trp53-/-/scid cells involved telomere-DSB fusions. Our results
      demonstrate that unprotected telomeres are not only sensed as, but also acted
      upon, by the DNA repair machinery as if they were DSB ends. By opening a new
      pathway for misrepair, telomere-DSB fusion decreases the overall fidelity of DSB
      repair. The high frequency of these events in scid cells indicates telomere
      dysfunction makes a strong, and previously unsuspected, contribution to the
      characteristic radiation sensitivity associated with DNA-PK deficiency.

PMID- 15010311
TI  - Loss of ATM sensitizes against O6-methylguanine triggered apoptosis, SCEs and
      chromosomal aberrations.
AB  - A critical pre-cytotoxic and -apoptotic DNA lesion induced by methylating
      carcinogens and chemotherapeutic drugs is O6-methylguanine (O6MeG). The mechanism
      by which O6MeG causes cell death via apoptosis is only partially understood. The
      current model ascribes a role to DNA replication and mismatch repair, which
      converts O6MeG into a critical distal lesion (presumably a DNA double-strand
      break) that is finally responsible for genotoxicity and apoptosis. Here we
      analysed whether the PI3-like kinase ATM is involved in this process. ATM is a
      major player in recognizing and signaling DNA breaks, but most reports are
      limited to ionizing radiation. Comparing mouse ATM knockout fibroblasts (ATM-/-)
      with the corresponding wild-type (ATM+/+) we show that ATM-/- cells are
      hypersensitive to the cytotoxic and apoptosis-inducing effect of N-methyl-N'
      nitro-N-nitrosoguanidine (MNNG). Inhibition of O6-methylguanine-DNA
      methyltransferase (MGMT) activity by O6-benzylguanine enhanced cell killing
      whereas the increase of MGMT activity by transfection with an expression vector
      provoked MNNG resistance. This was more pronounced in ATM-/- than in ATM+/+
      cells, suggesting that O6MeG is responsible, at least in part, for increased MNNG
      sensitivity of ATM-/- cells. Cytogenetic studies showed that MNNG-induced sister
      chromatid exchange frequencies were the same in ATM-/- and ATM+/+ cells in the
      first mitoses following treatment, but higher in ATM-/- cells than in the wild
      type in the second post-treatment mitoses, when MGMT was depleted. Also, a
      significant higher frequency of MNNG-induced chromosomal aberrations was observed
      in ATM-/- than in ATM+/+ cells when analysed at a late recovery time, which is
      consistent with O6MeG being the inducing lesion. In summary, we conclude that ATM
      is not only involved in resistance to ionizing radiation but also to methylating
      agents, playing a role in the repair of secondary DNA damage generated from O6MeG
      lesions. The data also show that ATM is not required for activating the apoptotic
      pathway in response to O6MeG since ATM-/- cells are able to undergo apoptosis
      with high frequency.

PMID- 15010312
TI  - The possible roles of the DNA helicase and C-terminal domains in RECQ5/QE:
      complementation study in yeast.
AB  - DmRECQ5/QE is a member of the RECQ5 subfamily, which shares homology with the
      Escherichia coli RecQ DNA helicase. Although the DNA helicase activity of
      RECQ5/QE has been characterized in vitro, the in vivo function of RECQ5/QE was
      essentially unknown. To investigate the cellular role of RECQ5, the potential of
      RECQ5/QE was evaluated by substitution of the only RecQ-like helicase, Sgs1, in
      budding yeast. RECQ5/QE can complement several phenotypes of sgs1, including the
      synthetic growth defect with srs2, the hypersensitivity to hydroxyurea and methyl
      methanesulfonate, and the elevated frequency of homologous recombination and
      sister chromatid exchange (SCE), but poorly complemented the suppression of slow
      growth in top3. These data suggested that RECQ5/QE exhibits an evolutionarily
      conserved RecQ function in vivo. The RECQ5/QE domain necessary for the yeast
      complementation was determined. The helicase domain and helicase activity were
      required to complement both the sgs1srs2 and sgs1top3 phenotypes. In contrast,
      the C-terminal domain was dispensable for complementing the sgs1srs2 phenotype,
      but was required for the sgs1top3 phenotype. These results suggested that the
      RECQ5/QE helicase activity is important for cellular function and that the C
      terminal domain has a specific function in the absence of Top3.

PMID- 15010313
TI  - Mutations in the Trp53 gene of UV-irradiated Xpc mutant mice suggest a novel Xpc
      dependent DNA repair process.
AB  - Mutational hot spots in the human p53 gene are well established in tumors in the
      human population and are frequently negative prognosticators of the clinical
      outcome. We previously developed a mouse model of skin cancer with mutations in
      the xeroderma pigmentosum group C gene (Xpc). UVB radiation-induced skin cancer
      is significantly enhanced in these mice when they also carry a mutation in one
      copy of the Trp53 gene (Xpc-/-Trp53+/-). Skin tumors in these mice often contain
      inactivating mutations in the remaining Trp53 allele and we have previously
      reported a novel mutational hot spot at a non-dipyrimidine site (ACG) in codon
      122 of the Trp53 gene in the tumors. Here we show that this mutation is not a hot
      spot in Xpa or Csa mutant mice. Furthermore, the mutation in codon T122 can be
      identified in mouse skin DNA from (Xpc-/-Trp53+/-) mice as early as 2 weeks after
      exposure to UVB radiation, well before histological evidence of dysplastic or
      neoplastic changes. Since this mutational hot spot is not at a dipyrimidine site
      and is apparently Xpc-specific, we suggest that some form of non-dipyrimidine
      base damage is normally repaired in a manner that is distinct from conventional
      nucleotide excision repair, but that requires XPC protein.

PMID- 15010314
TI  - The human topoisomerase I damage response plays a role in apoptosis.
AB  - Previous studies have shown that human topoisomerase I cleavage complexes form as
      a response to various DNA damages in vivo, the so called human topoisomerase I
      "damage response". It was suggested that this damage response may play a role in
      DNA repair as well as in apoptosis, but only very few investigations have been
      done and the significance of the damage response still remains unclear. Here we
      demonstrate that human topoisomerase I cleavage complexes induced by high doses
      of UV irradiation are highly stable for up to 48 h. Furthermore, we show that
      human topoisomerase I cleavage complexes correlate with apoptosis. However, at
      low UV doses the cleavage complex level was very low and the complexes were
      repaired. Surprisingly, we found that high levels of stable cleavage complexes
      were not only found in UV-irradiated cells but also in untreated cells that
      underwent apoptosis. A possible role of human topoisomerase I in apoptosis is
      discussed.

PMID- 15010315
TI  - Polymerase zeta dependency of increased adaptive mutation frequencies in
      nucleotide excision repair-deficient yeast strains.
AB  - Reversions of an auxotrophy-causing frameshift allele during prolonged starvation
      of yeast cells were used as a means to elucidate the mechanisms concerned with
      the generation of spontaneous adaptive mutations in cell cycle-arrested cells.
      Whereas about 50% of these reversions were previously shown to depend on the non
      homologous end joining pathway of DNA double-strand break repair, the origin of
      the residual 50% remains unknown. In search for a mechanism for generation of the
      latter fraction of reversions we examined the role of the translesion synthesis
      (TLS) polymerases zeta, eta and Rev1p in cells with wild-type or impaired
      nucleotide excision repair (NER) capacity. The basal level of adaptive mutations
      in the repair-proficient wild type was not influenced by disruptions of the genes
      coding for these three TLS polymerases. Intriguingly, a deficiency in NER by
      disruption of RAD14, RAD16 or RAD26 resulted in a significantly higher frequency
      of adaptive mutation, yet this increase was strictly dependent on an intact REV3
      gene, coding for the catalytic subunit of polymerase zeta. Furthermore, we
      observed that intact REV3 was also required for the occurrence of increased
      frequencies of adaptive mutants in the NER-proficient wild type following UV
      irradiation. While in proliferating cells the translesion synthesis function of
      polymerase zeta is connected to DNA replication, our data suggest that in cell
      cycle-arrested cells this enzyme is able to carry out either TLS or error-prone
      polymerization along an undamaged template in the course of repair processes.
      Such a hitherto unappreciated activity of polymerase zeta in non-replicating
      cells may contribute to the incidence of mutations in evolution, aging and
      cancer.

PMID- 15010316
TI  - Repair of oxidative damage in mitochondrial DNA of Saccharomyces cerevisiae:
      involvement of the MSH1-dependent pathway.
AB  - Mitochondrial DNA (mtDNA) is located close to the respiratory chain, a major
      source of reactive oxygen species (ROS). This proximity makes mtDNA more
      vulnerable than nuclear DNA to damage by ROS. Therefore, the efficient repair of
      oxidative lesions in mtDNA is essential for maintaining the stability of the
      mitochondrial genome. A series of genetic and biochemical studies has indicated
      that eukaryotic cells, including the model organism Saccharomyces cerevisiae, use
      several alternative strategies to prevent mutagenesis induced by endogenous
      oxidative damage to nuclear DNA. However, apart from base excision repair (BER),
      no other pathways involved in the repair of oxidative damage in mtDNA have been
      identified. In this study, we have examined mitochondrial mutagenesis in S.
      cerevisiae cells which lack the activity of the Ogg1 glycosylase, an enzyme
      playing a crucial role in the removal of 8-oxoG, the most abundant oxidative
      lesion of DNA. We show that the overall frequency of the mitochondrial oligomycin
      resistant (Olir) mutants is increased in the ogg1 strain by about one order of
      magnitude compared to that of the wild-type strain. Noteworthy, in the
      mitochondrial oli1 gene, G:C to T:A transversions are generated approximately 50
      fold more frequently in the ogg1 mutant relative to the wild-type strain. We also
      demonstrate that the increased frequency of Olir mutants in the ogg1 strain is
      markedly reduced by the presence of plasmids encoding Msh1p, a homologue of the
      bacterial mismatch protein MutS, which specifically functions in mitochondria.
      This suppression of the mitochondrial mutator phenotype of the ogg1 strain seems
      to be specific, since overexpression of the mutant allele msh1-R813W failed to
      exert this effect. Finally, we also show that the increased frequency of Olir
      mutants arising in an msh1/MSH1 heterozygote grown in glucose-containing medium
      is further enhanced if the cells are cultivated in glycerol-containing medium,
      i.e. under conditions when the respiratory chain is fully active. Taken together,
      these results strongly suggest that MSH1-dependent repair represents a
      significant back-up to mtBER in the repair of oxidative damage in mtDNA.

PMID- 15010318
TI  - Characterization of palindromic loop mismatch repair tracts in mammalian cells.
AB  - Single- and multi-base (loop) mismatches can arise in DNA by replication errors,
      during recombination, and by chemical modification of DNA. Single-base and loop
      mismatches of several nucleotides are efficiently repaired in mammalian cells by
      a nick-directed, MSH2-dependent mechanism. Larger loop mismatches (> or =12
      bases) are repaired by an MSH2-independent mechanism. Prior studies have shown
      that 12- and 14-base palindromic loops are repaired with bias toward loop
      retention, and that repair bias is eliminated when five single-base mismatches
      flank the loop mismatch. Here we show that one single-base mismatch near a 12
      base palindromic loop is sufficient to eliminate loop repair bias in wild-type,
      but not MSH2-defective mammalian cells. We also show that palindromic loop and
      single-base mismatches separated by 12 bases are repaired independently at least
      10% of the time in wild-type cells, and at least 30% of the time in MSH2
      defective cells. Palindromic loop and single-base mismatches separated by two
      bases were never repaired independently. These and other data indicate that loop
      repair tracts are variable in length. All tracts extend at least 2 bases, some
      extend <12 bases, and others >12 bases, on one side of the loop. These properties
      distinguish palindromic loop mismatch repair from the three known excision repair
      pathways: base excision repair which has one to six base tracts, nucleotide
      excision repair which has approximately 30 base tracts, and MSH2-dependent
      mismatch repair, which has tracts that extend for several hundred bases.

PMID- 15010317
TI  - Killing and mutagenic actions of dacarbazine, a chemotherapeutic alkylating
      agent, on human and mouse cells: effects of Mgmt and Mlh1 mutations.
AB  - Among various types of drugs designed for use in cancer chemotherapy, some have
      the potential for alkylation. After metabolic activation, these chemicals attack
      DNA and alkylate their bases, thereby preventing multiplication of rapidly
      growing tumor cells. Some of alkylated bases cause mutations, leading to untoward
      induction of tumors. To search for the rationale to separate lethal and mutagenic
      effects of alkylation drugs, we investigated actions of dacarbazine, a
      monofunctional triazene, on mouse and human cell lines defective in the Mgmt
      and/or the Mlh1 gene, the former encoding a DNA repair methyltransferase and the
      latter a protein involved in mismatch repair and induction of apoptosis. Mgmt
      deficient cells are hypersensitive to the killing action of dacarbazine. On the
      other hand, cells defective in both Mgmt and Mlh1 genes are as resistant to the
      drug as are wild-type cells, in terms of survival, but do have many mutations
      after dacarbazine treatment. Thus, the killing and mutagenic actions of
      dacabazine can be dissociated by manipulating actions of these gene products.

PMID- 15010320
TI  - A second life in science--working after the age of 65.
AB  - I was born in January, 1921 and was fortunate in working for a research
      organization that had no fixed retirement age. I was permitted to continue
      Science as long as there were some resources to support research that had some
      relevance to the organization's goals. A number of projects on which I worked
      were continuations of ones begun before the age of 65 (1986) and several new ones
      were based on both previous interests and ideas and some on new ideas. A number
      of the ideas arose from participation on Committees of the US National Research
      Council. I was able to extend my earlier interests in DNA repair to include
      experiments on the variations in DNA repair among apparently normal humans. In
      collaborations with other researchers we showed that the repair abilities
      following exposures to chemicals or to ionizing or ultraviolet (UV) radiation did
      not follow Poisson distributions. I participated in experiments, using a fish
      model to estimate the wavelength ranges in sunlight responsible for inducing
      melanoma and another fish model to estimate the germ cell mutations that might
      arise from exposures to the heavily ionizing particles in cosmic rays beyond low
      Earth orbit. A transgenic fish model was used to investigate the possibilities of
      using the fish to assay for mutagens in sediments in Long Island Sound. These
      Reflections summarize the atmosphere necessary for a second life and the
      scientific results of this life.

PMID- 15010319
TI  - SMC6 is required for MMS-induced interchromosomal and sister chromatid
      recombinations in Saccharomyces cerevisiae.
AB  - SMC6 (RHC18) in Saccharomyces cerevisiae, which is a homologue of the
      Schizosaccharomyces pombe rad18+ gene and essential for cell viability, encodes a
      structural maintenance of chromosomes (SMC) family protein. In contrast to the
      rest of the SMC family of proteins, Smc1-Smc4, which are the components of
      cohesin or condensin, little is known about Smc6. In this study, we generated
      temperature sensitive (ts) smc6 mutants of budding yeast and characterized their
      properties. One ts-mutant, smc6-56, ceased growth soon after up-shift to a non
      permissive temperature, arrested in the late S and G2/M phase, and gradually lost
      viability. smc6-56 cells at a permissive temperature showed a higher sensitivity
      than wild-type cells to various DNA damaging agents including methyl
      methanesulfonate (MMS). The rad52 smc6-56 double mutant showed a sensitivity to
      MMS similar to that of the rad52 single mutant, indicating that Smc6 is involved
      in a pathway that requires Rad52 to function. Moreover, no induction of
      interchromosomal recombination and sister chromatid recombination was observed in
      smc6-56 cells, which occurred in wild-type cells upon exposure to MMS.

PMID- 15010323
TI  - Derivation, propagation and differentiation of human embryonic stem cells.
AB  - Embryonic stem (ES) cells are in vitro cultivated pluripotent cells derived from
      the inner cell mass (ICM) of the embryonic blastocyst. Attesting to their
      pluripotency, ES cells can be differentiated into representative derivatives of
      all three embryonic germ layers (endoderm, ectoderm and mesoderm) both in vitro
      and in vivo. Although mouse ES cells have been studied for many years, human ES
      cells have only more recently been derived and successfully propagated. Many
      biochemical differences and culture requirements between mouse and human ES cells
      have been described, yet despite these differences the study of murine ES cells
      has provided important insights into methodologies aimed at generating a greater
      and more in depth understanding of human ES cell biology. One common feature of
      both mouse and human ES cells is their capacity to undergo controlled
      differentiation into spheroid structures termed embryoid bodies (EBs). EBs
      recapitulate several aspects of early development, displaying regional-specific
      differentiation programs into derivatives of all three embryonic germ layers. For
      this reason, EB formation has been utilised as an initial step in a wide range of
      studies aimed at differentiating both mouse and human ES cells into a specific
      and desired cell type. Recent reports utilising specific growth factor
      combinations and cell-cell induction systems have provided alternative strategies
      for the directed differentiation of cells into a desired lineage. According to
      each one of these strategies, however, a relatively high cell lineage
      heterogeneity remains, necessitating subsequent purification steps including
      mechanical dissection, selective media or fluorescent or magnetic activated cell
      sorting (FACS and MACS, respectively). In the future, the ability to specifically
      direct differentiation of human ES cells at 100% efficiency into a desired
      lineage will allow us to fully explore the potential of these cells in the
      analysis of early human development, drug discovery, drug testing and repair of
      damaged or diseased tissues via transplantation.

PMID- 15010324
TI  - Mesenchymal stem cells: clinical applications and biological characterization.
AB  - Mesenchymal stem cells (MSCs) have been isolated from bone marrow, periosteum,
      trabecular bone, adipose tissue, synovium, skeletal muscle and deciduous teeth.
      These cells have the capacity to differentiate into cells of connective tissue
      lineages, including bone, fat, cartilage and muscle. A great deal has been
      learned in recent years about the isolation and characterization of MSCs, and
      control of their differentiation. These cells have generated a great deal of
      interest because of their potential use in regenerative medicine and tissue
      engineering and there are some dramatic examples, derived from both pre-clinical
      and clinical studies, that illustrate their therapeutic value. This review
      summarizes recent findings regarding the potential clinical use of MSCs in
      cardiovascular, neural and orthopaedic applications. As new methods are
      developed, there are several aspects to the implanted cell-host interaction that
      need to be addressed before we can fully understand the underlying mechanisms.
      These include the host immune response to implanted cells, the homing mechanisms
      that guide delivered cells to a site of injury and the differentiation in vivo of
      implanted cells under the influence of local signals.

PMID- 15010325
TI  - Circulating mesenchymal stem cells.
AB  - Mesenchymal precursor cells (MPCs) are multipotent cells capable of
      differentiating into various mesenchymal tissues, such as bone, cartilage, fat,
      tendon and muscle. They are present within both mesenchymal tissues and the bone
      marrow (BM). If marrow-derived MPCs are to have a role in repair and fibrosis of
      mesenchymal tissues, transit of these cells through the peripheral blood is to be
      expected. Although there is evidence for the existence of MPCs within the
      peripheral blood, results are debated and are not always reproducible. Variations
      in the methods of cell purification, culture and characterisation may explain the
      inconsistent results obtained in different studies.

PMID- 15010326
TI  - Circulating fibrocytes: collagen-secreting cells of the peripheral blood.
AB  - Since the original description of circulating fibrocytes in 1994, our knowledge
      of this unique cell population has grown steadily. While initially described in
      the context of wound repair, fibrocytes have since been found to participate in
      granuloma formation, antigen presentation, and various fibrosing disorders.
      Fibrocytes produce matrix proteins such as vimentin, collagens I and III, and
      they participate in the remodeling response by secreting matrix
      metalloproteinases. Fibrocytes also are a rich source of inflammatory cytokines,
      growth factors, and chemokines that provide important intercellular signals
      within the context of the local tissue environment. Moreover, fibrocytes express
      the immunological markers typical of an antigen-presenting cell, and they are
      fully functional for the presentation of antigen to naive T cells. Fibrocytes can
      further differentiate, and they may represent a systemic source of the
      contractile myofibroblast that appears in many fibrotic lesions. Clinically,
      there is evidence that patients with hypertrophic scars such as keloids, and
      those affected by scleroderma and other fibrosing disorders have fibrocytes in
      their lesions. Recently, a new disease entity called nephrogenic fibrosing
      dermopathy (NFD) has been described, and the fibrocyte may play an important
      etiopathogenic role in disease development. Nephrogenic fibrosing dermopathy
      occurs in patients with renal insufficiency and leads to thickening and hardening
      of the skin, especially of the extremities. Ongoing research is focusing on the
      molecular signals that influence fibrocyte migration, proliferation, and function
      in the context of normal physiology and pathology.

PMID- 15010327
TI  - Haemopoietic stem cells.
AB  - Considerable effort has been made in recent years in understanding the mechanisms
      that govern stem cell generation, proliferation, self-renewal, commitment and
      lately plasticity. In the development of the haemopoietic system during embryonic
      and fetal life the notion of different pools of stem cells arising from the
      endothelium is gaining consensus. Gene expression profiling of populations of
      stem cells is bringing to light categories of genes important for self-renewal or
      commitment. Besides the role of transcription factors in lineage decision, the
      role of soluble factors and transmembrane proteins, very active at the time of
      embryo development, are taking central stage in the maintenance and in vitro
      expansion of haemopoietic stem cells (HSCs). The hierarchical model of
      haemopoietic development is being questioned with reports of lineage switching
      and plasticity of haemopoietic stem cells to non-haemopoietic cells. Yet the
      understanding of the overall process is still very fragmented and hypothetical.
      This is mainly due to the absence of appropriate markers to enable selection of
      homogeneous stem cell populations and the need to rely on retrospective
      functional assays, able only to determine the overall behaviour of a population
      of cells. This review is intended to be an overview of the haemopoietic system
      and a critical re-visitation of issues such as plasticity and self-renewal
      important for therapeutic applications of haemopoietic stem cells.

PMID- 15010328
TI  - Mesothelial progenitor cells and their potential in tissue engineering.
AB  - The mesothelium consists of a single layer of flattened mesothelial cells that
      lines serosal cavities and the majority of internal organs, playing important
      roles in maintaining normal serosal integrity and function. A mesothelial 'stem'
      cell has not been identified, but evidence from numerous studies suggests that a
      progenitor mesothelial cell exists. Although mesothelial cells are of a
      mesodermal origin, they express characteristics of both epithelial and
      mesenchymal phenotypes. In addition, following injury, new mesothelium
      regenerates via centripetal ingrowth of cells from the wound edge and from a free
      floating population of cells present in the serosal fluid, the origin of which is
      currently unknown. Recent findings have shown that mesothelial cells can undergo
      an epithelial to mesenchymal transition, and transform into myofibroblasts and
      possibly smooth muscle cells, suggesting plasticity in nature. Further evidence
      for a mesothelial progenitor comes from tissue engineering applications where
      mesothelial cells seeded onto tubular constructs have been used to generate
      vascular replacements and grafts to bridge transected nerve fibres. These
      findings suggest that mesothelial cell progenitors are able to switch between
      different cell phenotypes depending on the local environment. However, only by
      performing detailed investigations involving selective cell isolation, clonal
      analysis together with cell labelling and tracking studies, will we begin to
      determine the true existence of a mesothelial stem cell.

PMID- 15010329
TI  - Stem cells in the eye.
AB  - In the adult organism, all tissue renewal and regeneration depends ultimately on
      somatic stem cells, and the eye is no exception. The importance of limbal stem
      cells in the maintenance of the corneal epithelium has long been recognised, and
      such cells are now used clinically for repair of a severely damaged cornea. The
      slow cycling nature of lens epithelial cells and their ability to terminally
      differentiate into fiber cells are suggestive of a stem cell lineage.
      Furthermore, recent studies have identified progenitor cells in the retina and
      ocular vasculature which may have important implications in health and disease.
      Although the recent literature has become flooded with articles discussing
      aspects of stem cells in a variety of tissues our understanding of stem cell
      biology, especially in the eye, remains limited. For instance, there is no
      definitive marker for ocular stem cells despite a number of claims in the
      literature, the patterns of stem cell growth and amplification are poorly
      understood and the microenvironments important for stem cell regulation and
      differentiation pathways are only now being elucidated. A greater understanding
      of ocular stem cell biology is essential if the clinical potential for stem cells
      is to be realised. For instance; How do we treat stem cell deficiencies? How do
      we use stem cells to regenerate damaged retinal tissue? How do we prevent stem
      cell lineages contributing to retinal vascular disease? This review will briefly
      consider the principal stem cells in the mature eye but will focus in depth on
      limbal stem cells and corneal epithelium. It will further discuss their role in
      pathology and their potential for therapeutic intervention.

PMID- 15010330
TI  - Adult stem cell therapy for the heart.
AB  - The purpose of this review is to summarize current data leading to and arising
      from recent clinical application of cellular therapy for acute myocardial infarct
      (heart attack) and congestive heart failure. We specifically focus on use of
      adult stem cells and compare and contrast bone marrow and adipose tissue; two
      different sources from which stem cells can be harvested in substantial numbers
      with limited morbidity. Cellular therapy is the latest in a series of strategies
      applied in an effort to prevent or mitigate the progressive and otherwise
      irreversible loss of cardiac function that frequently follows a heart attack.
      Unlike surgical, pharmacologic, and gene transfer approaches, cellular therapy
      has the potential to restore cardiac function by providing cells capable of
      regenerating damaged myocardium and/or myocardial function. Skeletal muscle
      myoblast expansion and transfer allows delivery of cells with contractile
      function, albeit without any evidence of cardiomyogenesis or electrical coupling
      to remaining healthy myocardium. Delivery of endothelial progenitor cells (EPCs)
      which drive reperfusion of infarct zone tissues is also promising, although this
      mechanism is directed at halting ongoing degeneration rather than initiating a
      regenerative process. By contrast, demonstration of the ability of adult stem
      cells to undergo cardiomyocyte differentiation both in vitro and in vivo suggests
      a potential for regenerative medicine. This potential is being examined in early
      clinical studies.

PMID- 15010331
TI  - Stem cell-based approaches to solving the problem of tissue supply for islet
      transplantation in type 1 diabetes.
AB  - Type 1 diabetes is a debilitating condition, affecting millions worldwide, that
      is characterized by the autoimmune destruction of insulin-producing pancreatic
      islets of Langerhans. Although exogenous insulin administration has traditionally
      been the mode of treatment for this disease, recent advancements in the
      transplantation of donor-derived insulin-producing cells have provided new hope
      for a cure. However, in order for islet transplantation to become a widely used
      technique, an alternative source of cells must be identified to supplement the
      limited supply currently available from cadaveric donor organs. Stem cells
      represent a promising solution to this problem, and current research is being
      aimed at the creation of islet-endocrine tissue from these undifferentiated
      cells. This review presents a summary of the research to date involving stem
      cells and cell replacement therapy for type 1 diabetes. The potential for the
      differentiation of embryonic stem (ES) cells to islet phenotype is discussed, as
      well as the possibility of identifying and exploiting a pancreatic
      progenitor/stem cell from the adult pancreas. The possibility of creating new
      islets from adult stem cells derived from other tissues, or directly form other
      terminally differentiated cell types is also addressed. Finally, a model for the
      isolation and maturation of islets from the neonatal porcine pancreas is
      discussed as evidence for the existence of an islet precursor cell in the
      pancreas.

PMID- 15010332
TI  - A molecular view of stem cell and cancer cell self-renewal.
AB  - With the recent advances in cell biology and molecular genetics, scientists were
      able to isolate and culture tissue-specific stem cells from various sources and
      define their properties. The challenge has now shifted to understanding the
      genetic programs controlling the stem cell state, i.e. self-renewal and
      multipotential. Cracking the molecular codes that govern the stem cell state
      turns out to be a difficult task. This is in part because a single gene may
      exhibit distinct activities when expressed in different cell types. Comprehending
      the cell-context dependent readout of any given gene requires an integrated
      knowledge of the complex cellular machinery, a platform which can be provided by
      the research on stem cells. This review is an attempt to formulate a model for
      the self-renewal machinery operating in stem cells and cancer cells. Insight into
      this issue at the molecular and cellular levels will no doubt facilitate the
      realization of the stem cell potential in both regenerative medicine and
      anticancer therapy.

PMID- 15010333
TI  - Differentiation and migration of long term expanded human neural progenitors in a
      partial lesion model of Parkinson's disease.
AB  - Human neural progenitor cells (HNPCs) can be expanded in large numbers for
      significant periods of time to provide a reliable source of neural cells for
      transplantation in neurodegenerative disorders such as Parkinson's disease (PD).
      In the present study, HNPCs isolated from embryonic cortex were expanded as
      neurospheres in cell culture for 10 months. Just prior to transplantation, a
      proportion of the HNPCs were treated in a "predifferentiation" protocol in
      combination with the neurotropic factor NT4, in order to yield significant
      numbers of neurons. For transplantation, either undifferentiated HNPCs, or
      predifferentiated HNPCs were transplanted into the substantia nigra of a rat
      model of Parkinson's disease. At 12 weeks, there was good survival with
      proliferation of transplanted HNPCs occurring after transplantation but ceasing
      before the animals were sacrificed. Transplants of predifferentiated cells
      contained a higher proportion of neurons. The presence of a lesion in the
      striatum had a significant influence on the migration of transplanted cells from
      the substantia nigra into the striatum. There was no significant behavioural
      recovery or effect of transplanted HNPCs on the loss of dopaminergic cells from
      the host brain. In conclusion, HNPCs may provide a source of cells for use in the
      treatment of Parkinson's disease.

PMID- 15010334
TI  - Direct cell contact influences bone marrow mesenchymal stem cell fate.
AB  - Adult bone marrow-derived mesenchymal stem cells (MSC) can differentiate into
      various cell types of mesenchymal origin, but mechanisms regulating such cellular
      changes are unclear. We have conducted co-culture experiments to examine whether
      mesenchymal stem cell differentiation is influenced by indirect or direct contact
      with differentiated cells. Cultured adult mesenchymal stem cells showed some
      characteristics of synthetic state vascular smooth muscle cells (SMC). When co
      cultured with vascular endothelial cells (EC) without cell contact, they
      exhibited abundant well-organised smooth muscle alpha-actin (alpha-actin)
      filaments. Direct co-culture with endothelial cells resulted in increased smooth
      muscle alpha-actin mRNA and protein, yet also comprehensive disruption of smooth
      muscle alpha-actin filament organisation. In order to assess whether these cell
      contact effects on mesenchymal stem cells were cell type specific, we also
      analysed direct co-cultures of mesenchymal stem cells with dermal fibroblasts.
      However, these experiments were characterised by the appearance of abundant
      spindle-shaped myofibroblast-like cells containing organised smooth muscle alpha
      actin filaments. Thus, direct contact with distinct differentiated cells may be a
      critical determinant of mesenchymal stem cell fate in blood vessels and other
      connective tissues.

PMID- 15010336
TI  - Taurine kinetics assessed using [1,2-13C2]taurine in healthy adult humans.
AB  - To assess the dynamics of taurine metabolism in vivo, two sets of studies were
      carried out in healthy volunteers. First, pilot studies were carried in a single
      human subject to determine the time course of plasma and whole blood isotope
      enrichment over the course of an 8-h, unprimed continuous infusion of [1,2
      (13)C(2)]taurine. Second, five healthy adult males received two tracer infusions
      on separate days and in randomized order: 1) a 6-h continuous infusion of [1,2
      (13)C(2)]taurine (3.1 +/- 0.2 micromol x kg(-1) x h(-1)) and 2) a bolus injection
      of [(13)C(2)]taurine (3.0 +/- 0.1 micromol/kg). Isotope enrichments in plasma and
      whole blood taurine were determined by gas chromatography-mass spectrometry. The
      pilot experiments allowed us to establish that steady-state isotope enrichment
      was reached in plasma and whole blood by the 5th h of tracer infusion. The
      plateau enrichment reached in whole blood was lower than that obtained in plasma
      taurine (P < 0.02). In the second set of studies, the appearance rate (R(a)) of
      plasma taurine, determined from continuous infusion studies was 31.8 +/- 3.1
      micromol x kg(-1) x h(-1). After a bolus injection of tracer, the enrichment
      decay over the subsequent 2 h was best fitted by a two-exponential curve. Taurine
      R(a) was approximately 85% higher when determined using the bolus injection
      technique compared with continuous infusion of tracer. We conclude that 1)
      taurine R(a) into plasma is very low in healthy postabsorptive humans, and, due
      to taurine compartmentation between the extra- and intracellular milieus, may
      represent only interorgan taurine transfer and merely a small fraction of whole
      body taurine turnover; and 2) the bolus injection technique may overestimate
      taurine appearance into plasma. Further studies are warranted to determine
      whether alterations in bile taurine dynamics affect taurine R(a).

PMID- 15010335
TI  - Involvement of micro-calpain (CAPN 1) in muscle cell differentiation.
AB  - Several studies have already demonstrated that micro- and milli-calpains (CAPN 1
      CAPN 2), calcium-dependent intracellular cysteine-proteases are involved in many
      biological phenomenon including muscle growth and development. More particularly,
      recent studies have demonstrated that milli-calpain is implicated in myoblast
      fusion. Moreover, in primary muscle cells, these proteases do not appear
      simultaneously throughout muscle cell differentiation. Because micro- and milli
      calpains do not have the same intracellular localization, it appears likely that
      these two calcium-dependent proteases have different biological roles during
      muscle cell differentiation. The goal of this study is to determine the role of
      micro-calpain. We therefore, have developed a muscle cell line in which micro
      calpain is over-expressed, using the inducible Tet Regulated Expression System.
      The outcome is observed by following the behavior of different proteins,
      considered to be potential substrates of the protease. The present study shows
      important decreases in the expression level of ezrin (68%), vimentin (64%) and
      caveolin 3 (76%) whereas many other cytoskeletal proteins remain remarkably
      stable. Concerning the myogenic transcription factors, only the level of myogenin
      decreased (59%) after the over-expression of micro-calpain. Ultra structural
      studies have shown that the myofibrils formed near the cell periphery are
      normally oriented, lying along the longitudinal axis. This regularity is lost
      progressively towards the cell center where the cytoskeleton presented an
      increasing disorganization. All these results indicate that micro-calpain is
      involved in regulation pathway of myogenesis via at least its action on ezrin,
      vimentin, caveolin 3 and myogenin, a muscle transcription factor.

PMID- 15010337
TI  - Impaired expression and insulin-stimulated phosphorylation of Akt-2 in muscle of
      obese patients with atypical diabetes.
AB  - Although a pharmacological dose of insulin produces a dramatic increase in
      phosphorylation and activity of Akt isoforms 1 and 2 in mammalian skeletal
      muscle, few studies have examined the effect of physiological concentrations of
      insulin on the phosphorylation of Akt-1 and -2 in normal and diabetic tissue.
      This study examined the patterns of insulin-stimulated Akt isoform
      phosphorylation and protein expression in muscle biopsies obtained from obese
      patients with atypical diabetes immediately after a hyperglycemic crisis and
      again after near-normoglycemic remission. In obese patients with new-onset
      diabetes mellitus presenting with hyperglycemic crisis (plasma glucose 30.5 +/-
      4.8 mM), in vitro stimulation of vastus lateralis muscle biopsies with 100
      microU/ml (0.6 nM) insulin increased insulin receptor phosphorylation threefold
      and Akt-1 phosphorylation on Ser(473) twofold, whereas Akt-2 phosphorylation was
      not stimulated. After 10-wk intensive insulin therapy that led to near
      normoglycemic remission and discontinuation of insulin therapy, both Akt-2
      expression and insulin-stimulated Akt-2 Ser(474) phosphorylation doubled.
      Hyperglycemic crisis did not affect insulin-stimulated threonine phosphorylation
      of either Akt-1 or Akt-2. The decreased Akt-2 expression at presentation was
      accompanied by reduced GLUT4 protein expression and increased expression of
      enzymes counterregulatory to insulin action. Thus a physiological concentration
      of insulin stimulated Akt-1 and Akt-2 phosphorylation in human skeletal muscle in
      the absence of hyperglycemia, but Akt-2 expression and stimulation appeared to be
      impaired in muscle of obese patients with atypical diabetes presenting with
      severe hyperglycemia.

PMID- 15010338
TI  - Elevated circulating adiponectin levels in liver cirrhosis are associated with
      reduced liver function and altered hepatic hemodynamics.
AB  - Adiponectin is a novel adipocytokine negatively correlated with parameters of the
      metabolic syndrome, such as body mass index (BMI), body fat mass (BFM), and
      circulating insulin levels. Furthermore, metabolic actions directly on the liver
      have been described. The aim of the present study was to characterize circulating
      adiponectin levels, hepatic turnover, and the association of adiponectin with key
      parameters of hepatic as well as systemic metabolism in cirrhosis, a catabolic
      disease. Circulating adiponectin levels and hepatic turnover were investigated in
      20 patients with advanced cirrhosis. Hepatic hemodynamics [portal pressure, liver
      blood flow, hepatic vascular resistance, indocyanine green (ICG) half-life], body
      composition, resting energy expenditure, hepatic free fatty acids (FFA) and
      glucose turnover, and circulating levels of hormones (catecholamines, insulin,
      glucagon) and proinflammatory cytokines (IL-1beta, TNF-alpha, IL-6) were also
      assessed. Circulating adiponectin increased dependently on the clinical stage in
      cirrhosis compared with controls (15.2 +/- 1.7 vs. 8.2 +/- 1.1 microg/ml,
      respectively, P < 0.01), whereas hepatic extraction decreased. Adiponectin was
      negatively correlated with parameters of hepatic protein synthesis (prothrombin
      time: r = -0.62, P = 0.003; albumin: r = -0.72, P < 0.001) but not with
      transaminases or parameters of lipid metabolism. In addition, circulating
      adiponectin increased with portal pressure (r = 0.67, P = 0.003), hepatic
      vascular resistance (r = 0.60, P = 0.008), and effective hepatic blood flow (ICG
      half-life: r = 0.69, P = 0.001). Adiponectin in cirrhosis was not correlated with
      BMI, BFM, parameters of energy metabolism, insulin levels, hepatic FFA and
      glucose turnover, and circulating proinflammatory cytokines. These results
      demonstrate that 1) adiponectin plasma levels in cirrhosis are significantly
      elevated, 2) the liver is a major source of adiponectin extraction, and 3)
      adiponectin levels in cirrhosis do not correlate with parameters of body
      composition or metabolism but exclusively with reduced liver function and altered
      hepatic hemodynamics.

PMID- 15010339
TI  - Bedside to bench and back again: translational neuroscience research and
      geriatric psychiatry.

PMID- 15010341
TI  - William Carlos Williams.
AB  - Williams Carlos Williams was a physician and a poet. He suffered from multiple
      episodes of major depression, and had post-stroke depressions in later life; yet,
      he remained a productive writer until a few years prior before his death, at age
      80. The structure, style, and content of Williams' writings evolved continually,
      and he received a Pulitzer Prize posthumously for poetry written during his later
      life. The authors discuss factors that seem to be associated with his successful
      coping with mental illness. Williams' life helps challenge the negative
      stereotypes associated with serious mental illness and aging.

PMID- 15010342
TI  - Protein mis-folding emerges as a "drugable" target for discovery of novel
      therapies for neuropsychiatric diseases of aging.

PMID- 15010343
TI  - Assessment of pathological tau proteins in frontotemporal dementias: qualitative
      and quantitative approaches.
AB  - A large group of clinically and neuropathologically heterogeneous frontotemporal
      dementias (FTDs) is distinguished by the accumulation of filamentous tau proteins
      in neuronal and non-neuronal cells, and these disorders are collectively
      designated as tauopathies. Recent advances in the development of new reagents and
      the utilization of new multidisciplinary approaches have made substantial
      progress in the extensive characterization of tau proteins in different
      tauopathies. Until recently, semi-quantitative assessment of specific
      pathological lesions in FTDs was limited to immunohistochemical methods. However,
      it has become increasingly evident that biochemical analyses of pathological tau
      proteins in diseased brains also play a significant role in establishing the
      diagnosis of specific FTD subtypes. In this review, the authors summarize recent
      findings of the unique biochemical tau signatures for a number of specific
      tauopathies. Moreover, the quantitative assessment of abnormal tau proteins
      described here reveals heterogeneity in the biochemical features of tau
      pathologies in FTDs. The identification of highly insoluble tau species that may
      be more prone to physiological clearance, other than those that form paired
      helical filaments, could provide additional insights into the role of tau in
      mechanisms of neurodegeneration in FTDs.

PMID- 15010344
TI  - Clinical, pathological, and biochemical spectrum of Alzheimer disease associated
      with PS-1 mutations.
AB  - Three genes have been implicated in the etiology of early-onset autosomal
      dominant Alzheimer disease (AD): the amyloid precursor protein, the presenilin-1,
      and presenilin-2 genes. Approximately half of autosomal-dominant AD cases are
      associated with mutations in the presenilin-1 (PS-1) gene on the long arm of
      Chromosome 14. Marked allelic heterogeneity characterizes families with PS-1 gene
      mutations; more than 100 different mutations have been found in independent
      families thus far. With the exception of age at onset, the clinical phenotype is
      similar to late-onset AD, although some rare specific phenotypes have been
      described. These mutations lead to enhanced deposition of total Abeta and Abeta42
      (but not Abeta40) in the brain, compared with sporadic AD. There is a
      considerable heterogeneity in the histological profiles among brains from
      patients with different mutations, and although some lead to predominantly
      parenchymal deposition of Abeta in the form of diffuse and cored plaques, others
      show predominantly vascular deposition, with severe amyloid angiopathy. Only some
      mutations are associated with enhanced neurofibrillary tangle formation and
      increased neuronal loss compared with sporadic AD. However, there is an important
      clinical and pathological variability even among family members with the same
      mutation, which suggests the involvement of other genetic or environmental
      factors that modulate the clinical expression of the disease. This represents a
      valuable model for identifying such factors and has potential implications for
      the development of new therapeutic strategies for delaying disease onset.

PMID- 15010345
TI  - Mapping behavioral traits by use of genome-tagged mice.
AB  - OBJECTIVE: Complex trait mapping has been widely used to analyze the genetics of
      behavior. However, the approach has some disadvantages, including poor gene
      localization and low replicability. Genome-tagged mice (GTMs) are sets of
      congenic mouse strains that span the entire mouse genome and are a promising
      reagent for localization of genes contributing to behavior. METHODS: In order to
      map behavioral loci of interest, a GTM was investigated in which the middle
      region of Chromosome 1 from DBA/2J was introgressed onto a C57BL/6J background.
      The GTM was analyzed for behaviors related to sensorimotor gating, anxiety,
      depression, pain sensitivity, and learning and memory. RESULTS: The GTM was found
      to harbor a locus contributing to learning and memory, replicating results from
      complex trait analysis. CONCLUSIONS: The GTMs should be a valuable resource for
      mapping and confirmation of loci contributing to complex behavioral traits in the
      mouse, with ultimate implications for human genomic-based research, as well.

PMID- 15010346
TI  - Evidence for oxidative DNA damage in the hippocampus of elderly patients with
      chronic schizophrenia.
AB  - OBJECTIVE: The authors investigated the idea that some patients with
      schizophrenia exhibit a chronic, deteriorating course without showing frank
      neurodegeneration at postmortem examination. Oxidative damage is one form of
      cellular injury that may cause cellular dysfunction without necessarily leading
      to neuron death. METHODS: Authors obtained postmortem hippocampi from 13 elderly
      non-psychiatric comparison cases and 10 patients with "poor-outcome"
      schizophrenia. The groups were compared for the presence of neuronal 8-hydroxy,
      2' deoxyguanosine (8-OHdG), a robust marker of oxidized DNA, and neuronal Ki-67,
      a marker of cell-cycle activation, as well as neurofibrillary tangles, amyloid
      beta senile plaques, and astrocytosis. RESULTS: The mean proportion of neurons
      exhibiting 8-OHdG immunoreactivity was 10 times higher in schizophrenia than in
      comparison cases. Ki-67 was similarly elevated and was correlated with 8-OHdG in
      the schizophrenia group. There were no significant between-group differences for
      densities of neurofibrillary tangles, amyloid-beta plaques, or astrocytes.
      CONCLUSIONS: Our data provide evidence for oxidative DNA damage and coordinated
      cell-cycle activation in elderly "poor-outcome" schizophrenia. These findings
      could have important implications for cellular metabolism, gene expression, and
      membrane functioning in schizophrenia.

PMID- 15010347
TI  - Familial occurrence of dementia with Lewy bodies.
AB  - OBJECTIVE: The authors investigated the validity of the designation "familial
      dementia with Lewy bodies (DLB)" by evaluating the clinical, neuropathological,
      and genetic characteristics of previously reported families exhibiting both
      familial parkinsonism and dementia. METHODS: Several families, including multiple
      individuals with parkinsonism as well as prominent dementia, were identified
      through a literature search. Selected families had at least one member with
      dementia with autopsy evidence of neocortical and/or limbic Lewy-body (LB)
      pathology. Clinical and neuropathological evidence from reports of families with
      prominent dementia as well as parkinsonism was reviewed to further define
      familial DLB. RESULTS: All selected families had at least one affected individual
      with dementia and autopsy-proven DLB. Therefore, these families might be
      considered examples of familial DLB. Individuals in the first six families
      typically presented with parkinsonian features, whereas cognitive decline did not
      appear until years later. In contrast, in the other six families, affected
      individuals typically presented with cognitive decline, and parkinsonism
      developed later. CONCLUSIONS: Families exist in which one or more persons meet
      both clinical and neuropathological criteria for DLB. They differ as to whether
      the signs of parkinsonism precede or follow signs of dementia. It remains to be
      determined whether this clinical distinction is biologically important.
      Susceptibility to developing LB pathology may be determined by the interaction
      between genetic predisposition and environmental risk factors.

PMID- 15010349
TI  - Genes related to vascular disease (APOE, VLDL-R, DCP-1) and other vascular
      factors in late-life depression.
AB  - OBJECTIVE: The authors asked whether polymorphic variation at three genes related
      to vascular disease, and other vascular disease risk factors, determine late-life
      depression. METHODS: A group of 370 participants, representing 57% of survivors
      of an initial cohort of 1,083 participants in the Medical Research Council
      treatment trial of hypertension in older adults, had been screened for depression
      at baseline and were traced and genotyped for genetic analysis 11 years later.
      Genetic analyses were performed to establish variability at three polymorphisms
      related to vascular disease: APOE encoding for apolipoprotein-E, VLDL-R encoding
      for the VLDL cholesterol-receptor, and DCP-1 encoding for angiotensin-converter
      enzyme. Information on vascular disease and its risk factors (ECG ischemia or
      arrhythmia, body mass index, serum cholesterol, smoking status, and
      systolic/diastolic blood pressure) and cognitive functioning was also available
      from baseline. RESULTS: The authors found no association between the three
      studied polymorphisms and depression. Female gender, higher diastolic blood
      pressure, poorer cognitive functioning, and smoking status at baseline were all
      associated with depression independently of antidepressant and NSAIDs use, age,
      ECG-established vascular disease, and the remaining vascular disease risk factors
      studied. CONCLUSIONS: This study found no association between late-life
      depression and three polymorphisms related to vascular disease. Depression was
      found to independently associated with smoking, female gender, poorer cognitive
      functioning, and higher diastolic blood pressure. Taken together, this study does
      not seem to support the notion of a specific link between the studied vascular
      risk factors or these vascular-related loci and late-life depression.

PMID- 15010348
TI  - Longitudinal progression of subclinical structural brain disease in normal aging.
AB  - OBJECTIVE: The authors describe four types of brain structural change in "normal
      aging:" cortical atrophy, central atrophy, deep white-matter hyperintensities
      (DWMH), and periventricular hyperintensities (PVH). Cross-sectional
      investigations have reported that greater volumes of these forms of "subclinical
      structural brain disease" (SSBD) were found with increasing age. Greater volumes
      were also associated with poorer cognition, even though subjects performed within
      the normal range. The natural history of these forms of SSBD and their functional
      impact are not well established. METHODS: Twenty-nine normal subjects, ages 60
      89, were examined longitudinally by volumetric magnetic resonance imagery, with
      two assessments performed at least 2 years apart; 26 also completed
      neuropsychological testing to evaluate processing speed, executive functions,
      language, and other cognitive functions. Associations between structure and
      function were evaluated with regression models. RESULTS: For most subjects, the
      volumes for signs of all types of SSBD were found to have increased; for many
      subjects, increases were small, and a few showed no change or small decreases.
      PVH and DWMH increases were predicted by baseline cerebrovascular risk factors.
      Cognitive test performance changed little over time for these normal subjects.
      CONCLUSIONS: SSBD volumes increased for most subjects over time, with small
      average increases for most types. Pretreatment cerebrovascular risk factors were
      associated with greater increases of PVH and DWMH, suggesting that progression of
      these types of SSBD may be amenable to intervention.

PMID- 15010350
TI  - Cerebral infarctions and the relationship of depression symptoms to level of
      cognitive functioning in older persons.
AB  - OBJECTIVE: Recent studies report an association between depressive symptoms and
      cognitive impairment in old age. The neurobiologic basis of this association is
      unknown. The authors examined whether cerebral infarcts (present in 55 persons)
      accounted for the association of depressive symptoms with cognitive impairment in
      a group of 153 older Catholic nuns, priests, and brothers (67 with dementia and
      86 without dementia). METHODS: Subjects underwent detailed clinical evaluations
      and brain autopsy at death. RESULTS: Mean values for depressive symptoms during
      the time of participation were associated with level of cognitive functioning
      proximate to death in analyses that controlled for age, sex, education, and
      Alzheimer disease (AD) pathology. The association of depressive symptoms with
      cognitive functioning was essentially unchanged after controlling for cerebral
      infarctions, which suggests that depressive symptoms, cerebral infarctions, and
      AD pathology were independently related to cognitive function. Similar results
      were found in analyses with episodic memory, semantic memory, working memory,
      perceptual speed, and visual-spatial ability. The results did not change in
      analyses examining the volume or location of cerebral infarctions. CONCLUSIONS:
      These data suggest that cerebral infarctions do not account for the association
      of depressive symptoms with level of cognitive functioning. The neurobiologic
      basis for this association remains to be elucidated.

PMID- 15010351
TI  - Dimensions of sexual dysfunction in Parkinson disease.
AB  - OBJECTIVE: The authors sought to better understand the factors related to sexual
      dysfunction in Parkinson disease (PD). METHODS: Twenty-one PD patients and their
      partners received the Derogatis Interview for Sexual Functioning-Self Report
      (DISF-SR). Additional measures assessed disease severity, autonomic dysfunction,
      mood, and social circumstance. RESULTS: Data from 17 male patients demonstrated
      profound impairment in the dimensions of sexual arousal, behavior, orgasm, and
      drive, with most patients scoring below the 1st percentile on these Derogatis
      Interview subscales. All four dimensions showed significant intercorrelations. In
      contrast, 53% of patients scored above the 50th percentile in sexual fantasy.
      Sexual fantasy subscale scores were positively correlated with duration of PD.
      CONCLUSIONS: The usefulness of the DISF-SR in this PD population was limited by
      extremely low scores and strong correlations among the subscales. The increase in
      sexual fantasy with greater PD duration suggests that patients with advancing
      disease remain interested in sex and that sexual dysfunction in PD is clinically
      relevant in this group.

PMID- 15010352
TI  - Efficacy of sertraline for panic disorder in older adults: a preliminary open
      label trial.

PMID- 15010353
TI  - Ten categories of statistical errors: a guide for research in endocrinology and
      metabolism.
AB  - A simple framework is introduced that defines ten categories of statistical
      errors on the basis of type of error, bias or imprecision, and source: sampling,
      measurement, estimation, hypothesis testing, and reporting. Each of these ten
      categories is illustrated with examples pertinent to research and publication in
      the disciplines of endocrinology and metabolism. Some suggested remedies are
      discussed, where appropriate. A review of recent issues of American Journal of
      Physiology: Endocrinology and Metabolism and of Endocrinology finds that very
      small sample sizes may be the most prevalent cause of statistical error in this
      literature.

PMID- 15010354
TI  - Effect of sympathetic denervation on the rate of protein synthesis in rat
      skeletal muscle.
AB  - Rates of protein synthesis were investigated in skeletal muscles from rats
      submitted to chemical and surgical sympathectomy. Three models of sympathetic
      denervation were used: 1) treatment with guanethidine (100 mg.kg(-1).day(-1) sc);
      2) lumbar sympathetic denervation (surgical excision of the second and third
      lumbar ganglia of the sympathetic chain, from which arises the postganglionic
      fibers to the skeletal muscles of rat hindlimb); and 3) adrenodemedullation.
      Protein synthesis was estimated in isolated soleus muscle by the rate of
      incorporation of [(14)C]tyrosine (0.1 mM, 0.05 microCi/ml) into total protein.
      Soleus isolated after 2 and 4 days of chemical sympathectomy or after 3 days of
      lumbar denervation showed a 17-20% statistically significant decrease in in vitro
      rates of protein synthesis. These effects were reverted by addition of 10(-5) M
      isoproterenol or epinephrine in vitro. Neither clenbuterol nor isoproterenol (10(
      7), 10(-6), or 10(-5) M) in vitro affected the rate of protein synthesis in
      soleus from normal rats. On the other hand, clenbuterol or epinephrine (10(-5) M)
      increased by 20% the rate of protein synthesis in soleus muscles from
      adrenodemedullated rats and prevented its decrease in muscles from fasted rats.
      The data suggest that the sympathetic nervous system stimulates protein synthesis
      in oxidative muscles, probably through the activation of beta(2)-adrenoceptors,
      especially in situations of hormonal or nutritional deficiency.

PMID- 15010355
TI  - Rat renal cortical OAT1 and OAT3 exhibit gender differences determined by both
      androgen stimulation and estrogen inhibition.
AB  - In rats, the secretion of p-aminohippurate (PAH) by the kidney is higher in males
      (M) than in females (F). The role of the major renal PAH transporters, OAT1 and
      OAT3, in the generation of these gender differences, as well as the responsible
      hormones and mechanisms, has not been clarified. Here we used various
      immunocytochemical methods to study effects of gender, gonadectomy, and treatment
      with sex hormones on localization and abundance of OAT1 and OAT3 along the rat
      nephron. Both transporters were localized to the basolateral membrane: OAT1 was
      strong in proximal tubule S2 and weak in the S3 segments, whereas OAT3 was
      stained in proximal tubule S1 and S2 segments, thick ascending limb, distal
      tubule, and in principal cells along the collecting duct. Gender differences in
      the expression of both transporters in adult rats (M > F) were observed only in
      the cortical tubules. OAT1 in the cortex was strongly reduced by castration in
      adult M, whereas the treatment of castrated M with testosterone, estradiol, or
      progesterone resulted in its complete restitution, further depression, or partial
      restitution, respectively. In adult F, ovariectomy weakly increased, whereas
      estradiol treatment of ovariectomized F strongly decreased, the expression of
      OAT1. The expression of OAT3 in the M and F cortex largely followed a similar
      pattern, except that ovariectomy and progesterone treatment showed no effect,
      whereas in other tissue zones gender differences were not observed. In
      prepubertal rats, the expression of OAT1 and OAT3 in the kidney cortex was low
      and showed no gender differences. Our data indicate that gender differences in
      the rat renal cortical OAT1 and OAT3 (M > F) appear after puberty and are
      determined by both a stimulatory effect of androgens (and progesterone in the
      case of OAT1) and an inhibitory effect of estrogens.

PMID- 15010356
TI  - Inhibition of nNOS expression in the macula densa by COX-2-derived prostaglandin
      E(2).
AB  - It is well established that cyclooxygenase-2 (COX-2) and the neuronal form of
      nitric oxide synthase (nNOS) are coexpressed in macula densa cells and that the
      expression of both enzymes is stimulated in a number of high-renin states. To
      further explore the role of nNOS and COX-2 in renin secretion, we determined
      plasma renin activity in mice deficient in nNOS or COX-2. Plasma renin activity
      was significantly reduced in nNOS -/- mice on a mixed genetic background and in
      COX-2 -/- mice on either BALB/c or C57/BL6 congenic backgrounds. In additional
      studies, we accumulated evidence to show an inhibitory influence of PGE(2) on
      nNOS expression. In a cultured macula densa cell line, PGE(2) significantly
      reduced nNOS mRNA expression, as quantified by real-time RT-PCR. In COX-2 -/-
      mice, nNOS mRNA expression in the kidney, determined by real-time RT-PCR, was
      upregulated throughout the postnatal periods, ranging from postnatal day (PND) 3
      to PND 60. The induction of nNOS protein expression and NOS activity in COX-2 -/-
      mice was localized to macula densa cells using immunohistochemistry and NADPH
      diaphorase staining methods, respectively. Therefore, these findings reveal that
      the absence of either COX-2 or nNOS is associated with suppressed renin
      secretion. Furthermore, the inhibitory effect of PGE(2) on nNOS mRNA expression
      indicates a novel interaction between NO and prostaglandin-mediated pathways of
      renin regulation.

PMID- 15010358
TI  - Downregulation of hepatic acyl-CoA:diglycerol acyltransferase in chronic renal
      failure.
AB  - Chronic renal failure (CRF) is associated with hypertriglyceridemia and elevated
      plasma VLDL and IDL concentrations. These events can be due to either increased
      production or depressed catabolism of triglyceride-rich lipoproteins. Several
      studies have documented downregulation of lipoprotein lipase, hepatic
      triglyceride lipase, and the VLDL receptor, leading to depressed clearance and
      elevated plasma concentration of triglyceride-rich lipoproteins and their
      remnants in CRF. However, the effect of CRF on the triglyceride biosynthetic
      pathway has not been explored. Diglycerol acyltransferase (DGAT) is a microsomal
      enzyme that joins acyl-CoA to 1,2 diacylglycerol and, as such, constitutes the
      final step in triglyceride biosynthesis. Two distinct forms of DGAT (DGAT-1 and 
      2) have thus far been identified. The present study was undertaken to examine the
      effect of CRF on DGAT gene expression and activity in the liver, which is the
      source of endogenous triglycerides in the circulation. Male Sprague-Dawley rats
      were studied 8 wk after 5/6 nephrectomy (CRF) or sham operation. DGAT-1 and DGAT
      2 mRNA abundance and DGAT activity were quantified. The CRF group showed reduced
      creatinine clearance, elevated plasma triglycerides, and VLDL concentrations.
      This was accompanied by significant reductions in hepatic DGAT-2 mRNA abundance
      (P < 0.01) and total DGAT activity (P < 0.1), pointing to diminished hepatic
      triglyceride production capacity in CRF animals. In conclusion, CRF results in
      significant downregulation of hepatic DGAT gene expression and activity. Given
      the critical role of DGAT in triglyceride biosynthesis, the present study points
      to diminished, not increased, hepatic triglyceride synthetic capacity in CRF
      rats.

PMID- 15010357
TI  - Opioid receptor-like 1 stimulation in the collecting duct induces aquaresis
      through vasopressin-independent aquaporin-2 downregulation.
AB  - Nociceptin, the endogenous ligand of the inhibitory G protein-coupled opioid
      receptor-like 1 receptor, produces aquaresis (i.e., increases the excretion of
      solute-free urine) in rats. However, the mechanism underlying this effect has not
      yet been explained. Using immunohistochemistry, we found the opioid receptor-like
      1 receptor in the rat kidney colocalized with the vasopressin-regulated water
      channel aquaporin-2 in inner medullary collecting ducts. We investigated the
      aquaretic effect of opioid receptor-like 1 receptor stimulation by infusing the
      selective nociceptin analog ZP120C; volume depletion was prevented by computer
      driven, servo-controlled intravenous volume replacement with 50 mM glucose.
      ZP120C induced a marked and sustained aquaresis in normal and congestive heart
      failure rats in the absence of changes in vasopressin plasma concentrations. The
      ZP120C-induced aquaresis was associated with downregulation of the aquaporin-2
      protein level in both rat groups, suggesting that opioid receptor-like 1 receptor
      stimulation produces aquaresis by inhibiting the vasopressin type-2 receptor
      mediated stimulation on collecting duct water reabsorption. However, substantial
      amounts of PKA-mediated serine 256 phosphorylated aquaporin-2 were still present
      after 4 h of ZP120C treatment. Furthermore, neither preincubation with nociceptin
      nor ZP120C inhibited vasopressin-mediated cAMP accumulation in isolated
      collecting ducts. We conclude that renal opioid receptor-like 1 receptor
      stimulation in normal and congestive heart failure rats produces aquaresis by a
      direct renal effect, via aquaporin-2 downregulation, through a mechanism not
      involving inhibition of vasopressin type-2 receptor-mediated cAMP production.

PMID- 15010360
TI  - Inflammation and Cancer II. Role of chronic inflammation and cytokine gene
      polymorphisms in the pathogenesis of gastrointestinal malignancy.
AB  - It is well established that cancer arises in chronically inflamed tissue, and
      this is particularly notable in the gastrointestinal tract. Classic examples
      include Helicobacter pylori-associated gastric cancer, hepatocellular carcinoma,
      and inflammatory bowel disease-associated colorectal cancer. There is growing
      evidence to suggest that this association is not coincidental but may indeed be
      causal. In this review, we discuss the role of chronic inflammation and cytokine
      gene polymorphisms in the pathogenesis of gastrointestinal malignancy and outline
      some of the possible mechanisms involved.

PMID- 15010359
TI  - Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)
      in endothelial cells by nitric oxide deficiency.
AB  - Endothelial cell dysfunction (ECD) is emerging as a common denominator for
      diverse cardiovascular abnormalities associated with inhibition of endothelial
      nitric oxide (NO) synthase (eNOS). Elevated levels of asymmetric dimethylarginine
      (ADMA), a potent eNOS inhibitor, are common in renal failure and may contribute
      to ECD. Through DNA microarray screening of genes modulated in human umbilical
      vein endothelial cells (HUVEC) by N(G)-nitro-l-arginine methyl ester (l-NAME), we
      found a 1.8-fold increase in low-density lipoprotein receptor-1 (LOX-1)
      expression. LOX-1 is a major endothelial receptor for oxidized low-density
      lipoproteins (OxLDL) and is assumed to play a role in the initiation and
      progression of atherosclerosis. Here, we confirmed the upregulation of LOX-1 mRNA
      and protein level by quantitative RT-PCR and Western blot analysis. Increased
      expression of LOX-1 was associated with the accumulation of DiI-labeled OxLDL
      (DiI-OxLDL) in ADMA- and l-NAME-pretreated HUVEC. To evaluate the contribution of
      LOX-1 in ADMA-induced accumulation of OxLDL by HUVEC, we used the competitive
      receptor inhibitor, soluble LOX-1. Treatment of HUVEC with soluble LOX-1 was
      associated with an approximately two- to threefold inhibition of DiI-OxLDL uptake
      in l-NAME- or ADMA-treated HUVEC. In conclusion, ADMA- or l-NAME-induced NO
      deficiency leads to the increased expression of LOX-1 mRNA and protein in HUVEC,
      which in turn results in the accumulation of OxLDL. Competition with LOX-1
      soluble extracellular domain reduces OxLDL accumulation. In summary, elevated
      ADMA levels, i.e., in patients with renal failure, may be responsible for
      endothelial accumulation of OxLDL via upregulated LOX-1 receptor, thus
      contributing to endothelial lipidosis and dysfunction.

PMID- 15010361
TI  - Slowing intestinal transit by PYY depends on serotonergic and opioid pathways.
AB  - Slowing of intestinal transit by fat is abolished by immunoneutralization of
      peptide YY (PYY), demonstrating a key role for this gut peptide. How PYY slows
      intestinal transit is not known. We tested the hypothesis that the slowing of
      intestinal transit by PYY may depend on an ondansetron-sensitive serotonergic
      pathway and a naloxone-sensitive opioid pathway. In a fistulated dog model,
      occluding Foley catheters were used to compartmentalize the small intestine into
      proximal (between fistulas) and distal (beyond midgut fistula) half of gut.
      Buffer (pH 7.0) was perfused into both proximal and distal gut, and PYY was
      delivered intravenously. Ondansetron or naloxone was mixed with buffer and
      delivered into either the proximal or distal half of gut. Intestinal transit was
      measured across the proximal half of the gut. The slowing of intestinal transit
      by PYY was abolished when either ondansetron or naloxone was delivered into the
      proximal, but not the distal gut, to localize the two pathways to the efferent
      limb of the slowing response. In addition, 5-HT slows intestinal transit with
      marker recovery decreased from 76.2 +/- 3.6% (control) to 33.5 +/- 2.4% (5-HT) (P
      < 0.0001) but was reversed by naloxone delivered into the proximal gut with
      marker recovery increased to 79.9 +/- 7.2% (P < 0.0005). We conclude that the
      slowing of intestinal transit by PYY depends on serotonergic neurotransmission
      via an opioid pathway.

PMID- 15010362
TI  - Ischemic preconditioning attenuates ischemia-reperfusion-induced mucosal
      apoptosis by inhibiting the mitochondria-dependent pathway in rat small
      intestine.
AB  - Ischemic preconditioning provides a way of protecting organs from damage
      inflicted with prolonged ischemia-reperfusion. In this study, we investigated the
      mechanism of ischemic preconditioning involved in inhibition of prolonged
      ischemia-reperfusion-induced mucosal apoptosis in rat small intestine. Ischemic
      preconditioning was triggered by a transient occlusion of the superior mesenteric
      artery followed by reperfusion. Ischemia-reperfusion was induced by 60-min
      occlusion of the superior mesenteric artery followed by 60-min reperfusion in the
      small intestine. Ischemia-reperfusion alone induced mucosal apoptosis and
      mitochondrial respiratory dysfunction via promoted reactive oxygen species
      generation, reduced mitochondrial glutathione oxidation, increased mitochondrial
      lipid peroxidation, reduced mitochondrial membrane potential, and enhanced
      release of cytochrome c from mitochondria to activate caspase-9 and caspase-6 in
      the small intestine. Pretreatment with 20-min ischemia followed by 5-min
      reperfusion significantly inhibited the prolonged ischemia-reperfusion-induced
      mucosal apoptosis by 30%. Ischemic preconditioning ameliorated mitochondrial
      respiratory dysfunction by 50%, reduced reactive oxygen species generation by
      38%, and suppressed mitochondrial lipid peroxidation by 36%, resulting in
      improvement of the mitochondrial membrane potential and prevention of cytochrome
      c release as well as caspase-6 activation. Results suggest that ischemic
      preconditioning attenuated ischemia-reperfusion-induced mucosal apoptosis partly
      by inhibiting the reactive oxygen species-mediated mitochondria-dependent pathway
      in the rat small intestine.

PMID- 15010363
TI  - Functional modulation of enterocytes by gram-positive and gram-negative
      microorganisms.
AB  - Clinical studies have suggested that so-called probiotic bacteria may be
      effective as therapy in inflammatory bowel disease. However, the molecular
      mechanisms of their interaction with the intestinal surface remain undefined. The
      influence of whole probiotic bacteria [Escherichia coli Nissle 1917 (EcN);
      probiotic mixture VSL#3 (PM)], bacterial cell lysates, and conditioned media on
      transepithelial resistance (TER), IL-8 secretion, mucin gene expression, and
      tight junction proteins were determined in T84 and HT-29 intestinal epithelial
      cells (IEC). In addition, effects on pathogen (Salmonella dublin)-induced
      alterations were analyzed. EcN as well as debris and cell extracts induced IL-8
      secretion from IEC, whereas no such effect was observed following incubation with
      the PM. The PM and soluble protein(s) released from the PM increased TER,
      prevented pathogen-induced decrease in TER, and were shown to stabilize tight
      junctions. The PM induced expression of mucins in IEC, and these organisms as
      well as EcN diminished S. dublin-induced cell death. Inhibition of MAPKs with PD
      98059 or SB-203580 significantly decreased alterations in IL-8 synthesis and
      mucin expression and affected the regulation of TER. Probiotics and protein(s)
      released by these organisms may functionally modulate the intestinal epithelium
      of the host by different mechanisms, including the competition of whole organisms
      for contact with the epithelial surface as well as stabilization of the
      cytoskeleton and barrier function and the induction of mucin expression. Gram
      negative and gram-positive organisms differ in the mechanisms activated, and a
      combination of organisms might be more effective than the application of a single
      strain.

PMID- 15010364
TI  - Severe deficiency of glycoprotein VI in a patient with gray platelet syndrome.
AB  - We report a novel case of gray platelet syndrome (GPS) where a severe deficiency
      of the platelet collagen receptor, glycoprotein (GP) VI, accompanies classical
      symptoms of a low platelet count and platelets lacking alpha-granules. Dense
      granules were normally present. Platelet aggregation with collagen was severely
      decreased, as was the response to convulxin (Cvx), a GPVI agonist. Quantitative
      analysis of GPVI using fluorescein isothiocyanate (FITC)-Cvx in flow cytometry
      showed its virtual absence on the patient's platelets. The GPVI deficiency was
      confirmed using monoclonal antibodies in Western blotting and in immunogold
      labeling on frozen thin sections where internal pools of GPVI were confirmed for
      normal platelets. The Fc receptor gamma-chain, constitutively associated with
      GPVI in normal platelets, was present in subnormal amounts, and the phospholipase
      C gamma 2-dependent activation pathway appeared to function normally. No
      autoantibodies to GPVI were found in the patient's serum using monoclonal
      antibody immobilization of platelet antigen (MAIPA). Sequencing of coding regions
      of the GPVI gene failed to show abnormalities, and mRNA for GPVI was present in
      the patient's platelets, pointing to a probable acquired defect in GPVI
      expression. Our results may provide a molecular explanation for the subgroup of
      patients with severely deficient collagen-induced platelet aggregation as
      previously described for GPS in the literature.

PMID- 15010365
TI  - Gaucher disease: alendronate disodium improves bone mineral density in adults
      receiving enzyme therapy.
AB  - Symptomatic patients with Gaucher disease (GD) (acid beta-glucosidase [Gcase]
      deficiency) are treated with injectable human recombinant GCase. Treatment
      results in significant decreases in lipid storage in liver, spleen, and bone
      marrow, but the generalized osteopenia and focal bone lesions present in many
      adult patients are refractory to treatment. A double-blind, 2-arm, placebo
      controlled trial of alendronate (40 mg/d) was performed in adults with GD who had
      been treated with enzyme for at least 24 months. Primary therapeutic endpoints
      were improvements in (1) bone mineral density (BMD) and content (BMC) at the
      lumbar spine, and (2) focal lesions in x-rays of long bones assessed by a blinded
      reviewer. There were 34 patients with GD type 1 (age range, 18-50 years)
      receiving enzyme therapy who were randomized for this study. After 18 months,
      DeltaBMD at the lumbar spine was 0.068 +/- 0.21 and 0.015 +/- 0.034 for
      alendronate and placebo groups, respectively (P =.001). Long-bone x-rays showed
      no change in focal lesions or bone deformities in any subject in either arm.
      Alendronate is a useful adjunctive therapy in combination with enzyme replacement
      therapy (ERT) for the treatment of GD-related osteopenia in adults, but it cannot
      be expected to improve focal lesions.

PMID- 15010366
TI  - Utilization of Ig heavy chain variable, diversity, and joining gene segments in
      children with B-lineage acute lymphoblastic leukemia: implications for the
      mechanisms of VDJ recombination and for pathogenesis.
AB  - Sequence analysis of the immunoglobulin heavy chain genes (IgH) has demonstrated
      preferential usage of specific variable (V), diversity (D), and joining (J) genes
      at different stages of B-cell development and in B-cell malignancies, and this
      has provided insight into B-cell maturation and selection. Knowledge of the
      association between rearrangement patterns based on updated databases and
      clinical characteristics of pediatric acute lymphoblastic leukemia (ALL) is
      limited. We analyzed 381 IgH sequences identified at presentation in 317 children
      with B-lineage ALL and assessed the V(H)D(H)J(H) gene utilization profiles. The
      D(H)J(H)-proximal V(H) segments and the D(H)2 gene family were significantly
      overrepresented. Only 21% of V(H)-J(H) joinings were potentially productive, a
      finding associated with a trend toward an increased risk of relapse. These
      results suggest that physical location at the V(H) locus is involved in
      preferential usage of D(H)J(H)-proximal V(H) segments whereas D(H) and J(H)
      segment usage is governed by position-independent molecular mechanisms. Molecular
      pathophysiology appears relevant to clinical outcome in patients who have only
      productive rearrangements, and specific rearrangement patterns are associated
      with differences in the tumor biology of childhood ALL.

PMID- 15010367
TI  - Characterization of hematopoietic progenitor mobilization in protease-deficient
      mice.
AB  - Recent evidence suggests that protease release by neutrophils in the bone marrow
      may contribute to hematopoietic progenitor cell (HPC) mobilization. Matrix
      metalloproteinase-9 (MMP-9), neutrophil elastase (NE), and cathepsin G (CG)
      accumulate in the bone marrow during granulocyte colony-stimulating factor (G
      CSF) treatment, where they are thought to degrade key substrates including
      vascular cell adhesion molecule-1 (VCAM-1) and CXCL12. To test this hypothesis,
      HPC mobilization was characterized in transgenic mice deficient in one or more
      hematopoietic proteases. Surprisingly, HPC mobilization by G-CSF was normal in
      MMP-9-deficient mice, NE x CG-deficient mice, or mice lacking dipeptidyl
      peptidase I, an enzyme required for the functional activation of many
      hematopoietic serine proteases. Moreover, combined inhibition of neutrophil
      serine proteases and metalloproteinases had no significant effect on HPC
      mobilization. VCAM-1 expression on bone marrow stromal cells decreased during G
      CSF treatment of wild-type mice but not NE x CG-deficient mice, indicating that
      VCAM-1 cleavage is not required for efficient HPC mobilization. G-CSF induced a
      significant decrease in CXCL12 alpha protein expression in the bone marrow of Ne
      x CG-deficient mice, indicating that these proteases are not required to down
      regulate CXCL12 expression. Collectively, these data suggest a complex model in
      which both protease-dependent and -independent pathways may contribute to HPC
      mobilization.

PMID- 15010368
TI  - Reconstitution dynamics of plasmacytoid and myeloid dendritic cell precursors
      after allogeneic myeloablative hematopoietic stem cell transplantation.
AB  - Dendritic cells (DCs) are fundamental for immunity. We investigated
      reconstitution of plasmacytoid DC (PDC) and myeloid DC (My-DC) precursors in the
      first 2 months after allogeneic hematopoietic stem cell transplantation (Allo
      HSCT). Circulating DCs were monitored from the earliest phase of hematopoietic
      reconstitution in 43 children given standard therapy to prevent graft-versus-host
      disease (GVHD) and either treated or untreated with granulocyte colony
      stimulating factor (G-CSF) after HSCT. In patients without GVHD, both My-DCs and
      PDCs reached consistently high absolute values during the initial phase. Time of
      engraftment did not differ between My-DCs and PDCs, regardless of administration
      of G-CSF. Treatment with G-CSF (1) accelerated early recovery of My-DC absolute
      numbers; (2) was associated with lower numbers of both My-DCs and PDCs in the
      later phase; and (3) significantly reduced the proportion of interleukin-12 (IL
      12)-secreting cells. In some patients who developed acute GVHD, we found high
      numbers of circulating DC precursors during the early phase of this complication.
      However, treatment with steroids invariably induced rapid decrease of PDCs.
      Altogether, these data provide an evaluation of DC release after Allo-HSCT,
      indicate that postgrafting administration of G-CSF impairs the appearance of IL
      12-producing DCs, and suggest that DC homeostasis may be disrupted at onset of
      GVHD.

PMID- 15010369
TI  - A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the
      cytotoxicity of topoisomerase II poisons used in the treatment of leukemia.
AB  - We report for the first time the use of a selective small-molecule inhibitor of
      DNA repair to potentiate topoisomerase II (topo II) poisons, identifying DNA
      dependent protein kinase (DNA-PK) as a potential target for leukemia therapy.
      Topo II poisons form cleavable complexes that are processed to DNA double-strand
      breaks (DSBs). DNA-PK mediates nonhomologous end joining (NHEJ). Inhibition of
      this DSB repair pathway may sensitize cells to topo II poisons. We investigated
      the effects of a novel DNA-PK inhibitor, NU7026 (2-(morpholin-4-yl)
      benzo[h]chomen-4-one), on the response to topo II poisons using K562 leukemia
      cells. NU7026 (10 microM) potentiated the growth inhibition of idarubicin,
      daunorubicin, doxorubicin, etoposide, amsacrine (mAMSA), and mitroxantrone with
      potentiation factors at 50% growth inhibition ranging from approximately 19 for
      mAMSA to approximately 2 for idarubicin (potentiation of etoposide was confirmed
      by clonogenic assay). In contrast, NU7026 did not potentiate camptothecin or
      cytosine arabinoside (araC). NU7026 did not affect the levels of etoposide
      induced topo IIalpha or beta cleavable complexes. NU7026 alone had no effect on
      cell cycle distribution, but etoposide-induced accumulation in G2/M was increased
      by NU7026. A concentration-dependent increase in etoposide-induced DSB levels was
      increased by NU7026. The mechanism of NU7026 potentiation of topo II poisons
      involves inhibition of NHEJ and a G2/M checkpoint arrest.

PMID- 15010370
TI  - NTAL phosphorylation is a pivotal link between the signaling cascades leading to
      human mast cell degranulation following Kit activation and Fc epsilon RI
      aggregation.
AB  - Aggregation of high-affinity receptors for immunoglobulin E (Fc epsilon RI) on
      the surface of mast cells results in degranulation, a response that is
      potentiated by binding of stem cell factor (SCF) to its receptor Kit. We observed
      that one of the major initial signaling events associated with Fc epsilon RI
      mediated activation of human mast cells (HuMCs) is the rapid tyrosine
      phosphorylation of a protein of 25 to 30 kDa. The phosphorylation of this protein
      was also observed in response to SCF. This protein was identified as non-T-cell
      activation linker (NTAL), an adaptor molecule similar to linker for activated T
      cells (LAT). Unlike the Fc epsilon RI response, SCF induced NTAL phosphorylation
      in the absence of detectable LAT phosphorylation. When SCF and antigen were added
      concurrently, there was a marked synergistic effect on NTAL phosphorylation,
      however, SCF did not enhance the phosphorylation of LAT induced by Fc epsilon RI
      aggregation. Fc epsilon RI- and SCF-mediated NTAL phosphorylation appear to be
      differentially regulated by Src kinases and/or Kit kinase, respectively.
      Diminution of NTAL expression by silencing RNA oligonucleotides in HuMCs resulted
      in a reduction of both Kit- and Fc epsilon RI-mediated degranulation. NTAL, thus,
      appears to be an important link between the signaling pathways that are initiated
      by these receptors, culminating in mast cell degranulation.

PMID- 15010371
TI  - Human B cells that hyperexpress a triad of costimulatory molecules via avipox
      vector infection: an alternative source of efficient antigen-presenting cells.
AB  - Dendritic cells (DCs) are the most potent of the antigen-presenting cells (APCs).
      Preparation of sufficient numbers of mature DCs, however, is both costly and time
      consuming. We have examined here the possibility of using an alternative source
      of APCs that would be easier to obtain, would not require extensive culture, and
      thus would be more applicable to human immunotherapy protocols. We show here that
      freshly isolated human B cells can be efficiently infected by a replication
      defective fowlpox recombinant vector, designated rF-TRICOM (TRIad of
      COstimulatory Molecules), to markedly increase surface expression of the human
      costimulatory molecule B7-1 and moderately increase expression of intercellular
      adhesion molecule-1 (ICAM-1) and leukocyte function-associated antigen-3 (LFA-3).
      Peptide-pulsed rF-TRICOM-infected B cells were highly efficient in activating
      antigen-specific human T cells and shown to be superior to the use of CD40L in
      enhancing APC potency. Moreover, when infection of freshly isolated B cells with
      rF-TRICOM was combined with CD40L, a still further marked enhancement of the
      antigen-presenting potency was observed. Ex vivo-generated antigen-specific T
      cells activated in this manner might be applied to experimental protocols or used
      for adoptive transfer in immunotherapy protocols.

PMID- 15010372
TI  - Acquired Fanconi syndrome is an indolent disorder in the absence of overt
      multiple myeloma.
AB  - Adult-acquired Fanconi syndrome (FS) is a rare complication of monoclonal
      gammopathy. We retrospectively reviewed 32 patients diagnosed with adult-acquired
      FS between April 1968 and June 2002 at Mayo Clinic (Rochester, MN). At diagnosis,
      most patients had monoclonal gammopathy of undetermined significance (MGUS) or
      smoldering multiple myeloma (SMM), with a median creatinine level of 176.8 microM
      (2.0 mg/dL; range, 79.56-327.08 microM [0.9-3.7 mg/dL]) and evidence of
      osteomalacia. During the average 65 months (range, 2-238 months) of follow-up, 5
      patients developed end-stage renal disease (ESRD) and only 1 of 14 patients with
      MGUS transformed to multiple myeloma (MM). Also, 14 deaths occurred, with only 1
      from ESRD but 4 from alkylator-related leukemia or myelodysplastic syndrome.
      Chemotherapy offered little benefit on renal functions of MGUS or SMM patients.
      In conclusion, FS associated with monoclonal gammopathy does not appear to confer
      an additional risk of subsequent evolution to MM. ESRD occurs late in the disease
      process.

PMID- 15010373
TI  - Randomized comparison of low-dose versus high-dose interferon-alfa in chronic
      myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and
      HOVON groups.
AB  - The optimal dose of interferon-alfa (IFN) for chronic myeloid leukemia (CML) is
      unknown. Retrospective analyses suggest that low doses are as effective as high
      doses, with less toxicity and fewer patients abandoning the drug. The Dutch
      Hemato-Oncology Association (HOVON) and British Medical Research Council (MRC)
      cooperative groups jointly performed randomized trials in newly diagnosed CML
      patients, comparing high-dose IFN (5 MIU/m(2) daily) with low-dose (3 MIU, 5
      times a week). Both arms allowed additional hydroxyurea to keep the white blood
      cell count lower than 5 x 10(9)/L. Quality of life data were collected in a
      subset of patients. Between 1993 and 2001, 407 patients were randomized. At a
      median follow-up of 53 months, there were no significant differences in overall
      survival (odds ratio = 1.09, 95% confidence interval, 0.81-1.46), progression
      free survival, and complete hematologic or major cytogenetic responses. Fewer
      patients in the low-dose group abandoned IFN for reasons other than transplant or
      progressive disease (P =.002, 58% vs 72% at 5 years). Quality of life data showed
      comparable results in both arms for most factors. There is no evidence of benefit
      for high-dose IFN compared with low-dose for the treatment of CML. Therefore,
      when IFN is combined with other drugs, low-dose IFN is advised, to minimize
      toxicity and costs.

PMID- 15010374
TI  - TXAS-deleted mice exhibit normal thrombopoiesis, defective hemostasis, and
      resistance to arachidonate-induced death.
AB  - Besides its well-recognized role in hemostasis and thrombosis, thromboxane A(2)
      synthase (TXAS) is proposed to be involved in thrombopoiesis and lymphocyte
      differentiation. To evaluate its various physiologic roles, we generated TXAS
      deleted mice by gene targeting. TXAS(-/-) mice had normal bone marrow
      megakaryocytes, normal blood platelet counts, and normal CD4 and CD8 lymphocyte
      counts in thymus and spleen. Platelets from TXAS(-/-) mice failed to aggregate or
      generate thromboxane B(2) in response to arachidonic acid (AA) but produced
      increased prostaglandin-E(2) (PGE(2)), PGD(2), and PGF(2 alpha). AA infusion
      caused a progressive drop of mean arterial pressure (MAP), cardiac arrest, and
      death in wild-type (WT) mice but did not induce shock in TXAS(-/-) mice or in WT
      and TXAS(-/-) mice treated with antagonist to the thromboxane-prostanoid (TP)
      receptor. The TXAS(-/-) mice were able to maintain normal MAP upon AA insult when
      TP was present but were unable to do so when TP was blocked by an antagonist,
      suggesting a role of endoperoxide accumulation in influencing MAP. We conclude
      that TXAS is not essential for thrombopoiesis and lymphocyte differentiation. Its
      deficiency causes a mild hemostatic defect and protects mice against arachidonate
      induced shock and death. The TXAS-deleted mice will be valuable for investigating
      the roles of arachidonate metabolic shunt in various pathophysiologic processes.

PMID- 15010377
TI  - Geometric uncertainties in radiotherapy.

PMID- 15010375
TI  - Myogenic fusion of human bone marrow stromal cells, but not hematopoietic cells.
AB  - Following marrow transplantation in both patients and animals, cells containing
      donor nuclei have been detected in a variety of nonhematopoietic tissue. Whether
      this phenomenon represents transdifferentiation of marrow-derived cells,
      infiltration of blood cells, or cell fusion is still controversial. In muscle,
      where cell fusion occurs during normal myogenesis, fusion of marrow-derived cells
      with resident myotubes is a likely explanation. We tested 8 subpopulations of
      human bone marrow for their ability to fuse with mouse C2C12 myoblast cells.
      Relatively high fusion efficiency was observed with marrow stromal cells whereas
      hematopoietic cells, including populations enriched for stem cells, progenitor
      cells, and monocytes were refractory to fusion. Mouse myotubes containing human
      nuclei also contained transcripts for human muscle-specific genes. Injection in
      vivo of human stromal cells expressing green fluorescent protein (GFP) into the
      regenerating tibialis anterior muscle of nonobese diabetic-severe combined
      immunodeficient (NOD/SCID) beta 2m(-/-) mice resulted in regenerating mouse
      muscle fibers expressing GFP. These data suggest that marrow-derived cells
      contribute to myogenesis through fusion and that stromal cells are better fusion
      partners than hematopoietic cells.

PMID- 15010378
TI  - Clinical use of intensity-modulated radiotherapy: part I.
AB  - Intensity-modulated radiotherapy (IMRT) is a novel conformal radiotherapy
      technique which is gaining increasing clinical use worldwide. This article aims
      to summarize the published data pertaining to clinical indications of this
      therapy for head and neck, central nervous system, and lung tumours. The main
      indications in head and neck cancer are parotid gland sparing and dose escalation
      to tumours close to organs at risk. For central nervous system tumours, IMRT has
      been used to reduce normal tissue radiation by more conformal dose distributions.
      To date, the majority of reports concern patients treated in the context of
      clinical trials, and for most tumour types longer term follow up of treated
      patients will be required to confirm the clinical benefits of IMRT.

PMID- 15010379
TI  - Radiation protection in humans: extending the concept of as low as reasonably
      achievable (ALARA) from dose to biological damage.

PMID- 15010380
TI  - Technetium-99m sestamibi scintigraphy and helical CT together in patients with
      primary hyperparathyroidism: a prospective clinical study.
AB  - 44 consecutive patients with confirmed primary hyperparathyroidism (HPT)
      undergoing surgery were prospectively enrolled in the study. There were 13
      (29.5%) men and 31 (70.5%) women with an overall median age of 59 years (range 23
      78 years). Prior to successful parathyroidectomy both (99)Tc(m)
      sestamibi/(99)Tc(m)-pertechnetate subtraction scintigraphy (SS) and helical CT
      were performed, and the results of imaging studies were compared against
      intraoperative findings. Final histopathology showed 40 (90.9%) solitary
      parathyroid (PT) adenomata (median size 18 mm, range 8-40 mm), that were in an
      ectopic location in 13 (32.5%) patients. Moreover, 3 (6.8%) patients had
      multiglandular disease (one patient with two PT adenomata, two patients with PT
      hyperplasia), while one (2.3%) patient had a PT carcinoma. The sensitivity and
      positive predictive value were 86.0% and 97.4% for SS, 88.1% and 94.9% for CT,
      and 100% and 97.4% for the combination of SS and CT, respectively. Calcium and
      parathyroid hormone (PTH) serum levels, and the mean size of the removed PT
      glands of patients with false negative results were lower than that of those with
      true positive results, but the difference was not significant. Among patients
      with solitary PT tumours (N=41) the sensitivity was 88.1% and 90.3% for SS and CT
      scan, respectively. In conclusion, our study confirms the usefulness of SS, which
      should be the initial test for patients undergoing parathyroidectomy. However,
      the strategy of performing two tests in each patient with primary HPT could be of
      limited utility when the initial SS is positive.

PMID- 15010381
TI  - Ultrashort echo time (UTE) MRI of the spine in thalassaemia.
AB  - Back pain is common in adult patients with homozygous thalassaemia, and
      degenerative disc disease is increasingly recognised as a cause. Ultrashort echo
      time (UTE) pulse sequences, which are sensitive to the presence of short T(2)
      relaxation components in tissue produced by iron deposition and other processes,
      were used to examine the lower thoracic and lumbar spine in symptomatic patients
      with beta-thalassaemia major or intermedia. Three patients were studied with fat
      suppressed as well as both fat suppressed and long T(2) suppressed UTE (TE=0.08
      ms) pulse sequences. Conventional 2D Fourier transformation T(1) and T(2)
      weighted scans were also performed for comparison. Normal controls showed narrow
      high signal areas in the region of the end-plate and annulus fibrosus. Patients
      showed hyperintense bands adjacent to the vertebral end plate in lower thoracic
      and lumbar spine discs using a UTE sequence with both long T(2) component and fat
      suppression. The extent of the changes was most marked in the patient with the
      most severe degenerative change. In the patient with minimal disease, findings of
      this type were present in discs which did not show evidence of degeneration with
      conventional MR imaging. High signal changes of a type previously not described
      were observed in each patient. The effect may be due to organic iron entering the
      disc and decreasing its T(1) and T(2), but susceptibility effects from iron in
      the vertebral bodies, fibrosis and other causes also need to be considered.

PMID- 15010382
TI  - MRI of neck nodes in non-Hodgkin's lymphoma of the head and neck.
AB  - The aim of this study is to describe the imaging features of neck nodes in non
      Hodgkin's lymphoma (NHL). The MR scans of 61 patients undergoing staging of a
      primary extranodal NHL of the head and neck were reviewed retrospectively. Those
      MR images with nodal disease were assessed for (a) the pattern of nodal disease,
      (b) presence of nodal necrosis and (c) presence of extracapsular neoplastic
      spread (ENS) and nodal matting. The features of the nodal disease were analysed
      in relationship to the sites of the primary NHL (palatine tonsil (PT) n=23, nasal
      cavity (NC) n=24, nasopharynx (NP) n=6, other extralymphatic sites (OES) n=8),
      and histology (natural killer/T-cell (NK/T) n=26, diffuse large cell (DLC) n=24,
      other subtypes (OS) n=11). Nodal disease was present in 26 patients (43%) and
      occurred in NHL of the PT n=16 (70%), NP n=3 (50%), NC n=5 (21%) and OES n=2
      (25%) and in DLC n=15 (63%), NK/T n=6 (23%) and OS n=5 (45%). Nodal disease was
      significantly more frequent in DLC than NK/T lymphomas (p=0.0053). Nodal disease
      spread in a contiguous fashion in 25 (96%) patients with nodes. Necrosis was
      present in 7 of 26 (27%) being present in DLC of the PT in 5, NK/T of the NP in
      one and NK/T of the NC in one. ENS and matting were present in 19 (73%) and 13
      (50%) patients with nodes, respectively. ENS was found in DLC, NK/T, OS, NC, NP,
      PT, OES (11, 4, 4,1, 2, 14, 2, respectively) and matting was found in DLC, NK/T,
      OS, NC, NP, PT, OES (9, 3, 1, 0, 2, 10, 1, respectively). Nodal NHL spreads in a
      contiguous fashion and is most commonly associated with DLC lymphoma of the NP
      and PT in Waldeyer's ring. Extracapsular nodal spread is frequent and found in
      most histological subtypes especially those arising from Waldeyer's ring.
      Necrosis is more common than previously believed.

PMID- 15010383
TI  - Barium enema: use of increased copper filtration to optimize dose and image
      quality.
AB  - The purpose of this study was to determine and validate the optimum copper
      filtration for adult double contrast barium enema examinations. Entrance surface
      dose rates to polymethyl methacrylate slabs and corresponding image intensifier
      input kermas, were measured for various added copper filters. Image contrast was
      assessed using a Leeds TO.10 test object. Copper filter thickness of 0.3 mm was
      chosen, as this reduced entrance surface dose rate by 56%, without substantially
      degrading image contrast due to kV and mA saturation. 20 sets of clinical films
      taken with each of 0.3 mm copper, 0.1 mm copper and no copper were reviewed
      following randomization, by a specialist gastrointestinal radiologist. Each set
      of digital spot and conventional films was allocated a score for each of three
      regions of the bowel, on a scale of 0-3 for perceived barium coating. The Kruskal
      Wallis test showed no significant difference in perceived coating between the
      three groups (Digital spot: sigmoid colon p=0.207, splenic flexure p=0.103,
      hepatic flexure p=0.894. Screen-film: left colon p=0.803, right colon p=0.487,
      transverse colon p=0.905). All examinations but one were classified as
      diagnostic. The remaining one was classified indeterminate, due to poor
      distension of the colon. On adding 0.3 mm copper filtration, the mean dose-area
      product per examination was reduced by 57%, from 17.7 Gy cm(2) to 7.6 Gy cm(2).
      The estimated reduction in effective dose was 11%, from 3.0 mSv to 2.7 mSv. X-ray
      tube loading increased by 30%, but this caused no overheating with our local
      examination protocol and schedule. Additional filtration of 0.3 mm copper for
      adult double contrast barium enemas has now been implemented in routine clinical
      use at our hospital.

PMID- 15010384
TI  - Assessment of a technique for 2D-3D registration of cerebral intra-arterial
      angiography.
AB  - This study assesses the ability of a computer algorithm to perform automated 2D
      3D registrations of digitally subtracted cerebral angiograms. The technique was
      tested on clinical studies of five patients with intracranial aneurysms. The
      automated procedure was compared against a gold standard manual registration, and
      achieved a mean registration accuracy of 1.3 mm (SD 0.6 mm). Two registration
      strategies were tested using coarse (128 x 128 pixel) or fine (256 x 256 pixel)
      images. The mean registration errors proved similar but registration of the lower
      resolution images was 3 times quicker (mean registration times 33 s, SD 13 s for
      low and 150 s SD 48 s for high resolution images). The automated techniques were
      considerably faster than manual registrations but achieved similar accuracy. The
      technique has several potential uses but is particularly applicable to
      endovascular treatment techniques.

PMID- 15010385
TI  - Sparing of the penile bulb and proximal penile structures with intensity
      modulated radiation therapy for prostate cancer.
AB  - Quality of life is an important consideration in the treatment of early prostate
      cancer. Laboratory and clinical data suggest that higher radiation doses
      delivered to the bulb of penis and proximal penile structures correlates with
      higher rates of post-radiation impotence. The goal of this investigation was to
      determine if intensity-modulated radiation therapy (IMRT) spares dose to the
      penile bulb while maintaining coverage of the prostate. 10 consecutive patients
      with clinically organ confined prostate cancer were planned with 3D conformal
      radiation therapy (3D-CRT) or IMRT to give a dose of 74 Gy without specifically
      constraining the plans to spare the penile bulb. All 10 patients were ultimately
      treated with IMRT. Dose-volume histograms were evaluated and the doses to
      prostate, rectum, bladder and penile bulb were compared. IMRT reduced the mean
      penile bulb doses compared with 3D-CRT (33.2 Gy vs 48.9 Gy, p<0.001), the
      percentage of penile bulb receiving over 40 Gy (37.7% vs 67.2%, p<0.001) and the
      dose received by >95% of penile bulb (5.3 Gy vs 11.7 Gy, p=0.003). Maximum penile
      bulb doses were higher with IMRT (81.2 Gy vs 73.1 Gy, p<0.001) although the
      volume of this high dose region was small. Both methods resulted in similar
      coverage of the prostate. The volume of rectum receiving 70 Gy was significantly
      reduced with IMRT (18.4% vs 21.9%, p=0.003) but the volumes of bladder receiving
      70 Gy were similar (p=0.3). IMRT may potentially reduce long term sexual
      morbidity by reducing the dose to the majority of the penile bulb.

PMID- 15010386
TI  - Irradiation of the heart during tangential breast treatment: a study within the
      START trial.
AB  - Radiotherapy to the breast is often given as a component of the treatment for
      women with breast cancer. It has been shown to increase overall survival although
      an increase in cardiac mortality has also been noted. This study was undertaken
      as part of the START trial quality assurance programme to record and evaluate the
      cardiac dose using modern radiotherapy techniques. Departments randomizing
      patients into the START trial and who had CT facilities for planning breast
      patients were invited to take part. 62 patients were included. CT slices were
      taken at the level of the maximum heart depth and on the treatment field central
      axis. Each patient was planned in the normal way and the distributions were
      analysed by the quality assurance team at Mount Vernon Hospital. The maximum
      heart position was found to be inferior to the central axis used for breast
      planning for the majority of patients; mean position 2.3 cm inferior with a mean
      maximum heart depth of 0.55 cm. For 45% of patients the maximum heart dose was
      less than 50% of the prescribed dose. The study showed that the volume of
      irradiated cardiac tissue has decreased compared with earlier studies, and also
      highlighted the need to scan away from the central axis if the dose to cardiac
      tissue is to be assessed.

PMID- 15010387
TI  - Barium paste: useful for primary tumour localization in oral cancer.

PMID- 15010388
TI  - Gadolinium: named after Finland's most famous chemist.

PMID- 15010389
TI  - Intrapancreatic accessory spleen: diagnosis using contrast enhanced ultrasound.
AB  - Intrapancreatic accessory spleen (IPAS) is a mass that can mimick a neoplastic
      mass in the pancreas. As it poses no clinical problem no treatment is required.
      Unfortunately almost all the reported cases of IPAS have been misdiagnosed and
      unnecessary surgery performed. We performed contrast-enhanced ultrasound (CEUS)
      in a patient with IPAS for a research purpose, and confirmed that CEUS is useful
      for diagnosing this entity.

PMID- 15010390
TI  - Focal sparing of fatty liver in segment II associated with aberrant left gastric
      vein.
AB  - We present a patient with aberrant left gastric vein (LGV) that directly enters
      the posterior edge of segment II in the liver. The corresponding area was focally
      spared of fatty liver. We consider that this aberrant LGV contributed to the
      cause of focal sparing. This is the first report of the use of helical CT and
      Doppler ultrasound to depict the aberrant LGV that directly enters the liver.

PMID- 15010391
TI  - Monophasic, solitary tumefactive demyelinating lesion: neuroimaging features and
      neuropathological diagnosis.
AB  - The characteristic clinicoradiological findings of multiple sclerosis and acute
      disseminated encephalomyelitis (ADEM), demonstrating a recurrent progressive
      course in the former and monophasicity in the latter associated with multiple
      discrete white matter lesions with variable enhancement on MRI, are not a
      diagnostic challenge. On the other hand, the less typical radiological
      presentation of a solitary tumefactive demyelinating lesion mimics a neoplasm,
      and often necessitates a biopsy. Nonetheless, histopathological examination is an
      imperfect gold standard and the recognition of certain imaging features may
      facilitate the correct diagnosis.

PMID- 15010393
TI  - Primary rhabdomyosarcoma of the seminal vesicle.
AB  - Sarcomas of the seminal vesicle are very rare and poorly documented; as it is not
      always possible to pinpoint a truly vesicular origin of the pelvic mass due to
      local spread at the time of presentation. The purpose of the article is to
      document and characterize a rhabdomyosarcoma of the seminal vesicle of which to
      the knowledge of the authors there has been no previous report in the English
      literature.

PMID- 15010392
TI  - Spontaneous rupture of a true uterine artery aneurysm: a cause of retroperitoneal
      haematoma.
AB  - We report the first case of spontaneous rupture of a true uterine artery aneurysm
      in a 69-year-old woman presenting with severe abdominal pain, a left iliac fossa
      mass, anaemia and a retroperitoneal haematoma on CT scanning. In this patient,
      the aneurysm was successfully embolised using microcoils. The different imaging
      modalities used for diagnosis and the treatment options are discussed.

PMID- 15010394
TI  - Castleman's disease presenting as an adnexal mass: ultrasound, CT and MRI
      features.

PMID- 15010395
TI  - Female genital tuberculosis: hysterosalpingographic appearances.
AB  - Genital tuberculosis is an important cause of infertility in developing countries
      and hysterosalpingography (HSG) is the initial procedure performed for the
      evaluation. Reviewing 37 cases of female genital tuberculosis, we encountered
      various appearances on HSG. Of 579 HSGs performed over a period of 4 years, 492
      (85%) were performed as part of infertility work up. Genital tuberculosis was
      found in 6.3% of all the patients who underwent HSGs and 7.5% of all patients
      investigated for infertility. The various features of proven tuberculosis cases
      are illustrated in this pictorial review. We briefly discuss the pathology and
      these appearances along with radiopathological correlation.

PMID- 15010396
TI  - An unusual cause of intraluminal gastric radio-opacities.

PMID- 15010397
TI  - Anesthesiology, the birth of pharmacogenetics and Werner Kalow.

PMID- 15010398
TI  - Ischemic preconditioning in the brain.

PMID- 15010399
TI  - Atypical plasma cholinesterase. A personal discovery story: a tale of three
      cities.

PMID- 15010400
TI  - An increased circulating blood volume does not prevent hypotension after
      pheochromocytoma resection.
AB  - PURPOSE: Pulse dye-densitometry, a novel monitor that measures circulating blood
      volume (CBV) and cardiac output (CO), was used in patients with pheochromocytoma
      to determine the relationship between CBV and post resection hypotension.
      METHODS: Case control study. An alpha blocker was administered for approximately
      two weeks, and its effect on the expansion of CBV was quantified. CBV was
      monitored in seven patients admitted for resection of suspected pheochromocytoma
      before preoperative alpha-blocker therapy, after alpha-blocker therapy and three
      times during the operation. Relationships between the CBV and blood pressure
      after resection of the tumour were examined. RESULTS: CBV increased from 72.0 +/-
      10.0 mL.kg(-1) to 83.4 +/- 12.2 mL.kg(-1) after alpha blockade. (P < 0.001). We
      found a significant inverse relationship between the increase in CBV after alpha
      blocker therapy and blood pressure after resection of the tumour. CONCLUSIONS:
      Expansion of the CBV by alpha-blocker therapy was related to lower blood
      pressures after resection of the pheochromocytoma. Expansion of the CBV by an
      alpha blocker may have increased the elastance of blood vessels. Preoperative
      blood volume expansion does not preclude hypotension after tumour resection.
      Although the CBV value itself is not a predictor for hypotension after tumour
      resection, pulse dye-densitometry provides values of CO and CBV simultaneously,
      assisting in the management of volume resuscitation and/or the need for
      catecholamines.

PMID- 15010401
TI  - Controlled-release codeine is equivalent to acetaminophen plus codeine for post
      cholecystectomy analgesia.
AB  - PURPOSE: Following ambulatory surgery, long-acting analgesics may provide
      advantages over short-acting analgesics. This study compared controlled-release
      codeine (CC) and acetaminophen plus codeine (A/C; 300 mg/30 mg) for pain control
      in the 48-hr period following laparoscopic cholecystectomy. METHODS: Eligible
      patients were randomized to CC or A/C in a double-blind, double-dummy parallel
      group study. Unrelieved pain in hospital was treated with fentanyl i.v. bolus.
      Pain [100 mm visual analogue scale (VAS)] was assessed before the first dose of
      medication; at 0.5, one, two, three, and four hours post-dose; at discharge; and
      three times a day for 48 hr. Adverse events were recorded and measures of patient
      satisfaction were assessed at the end of the study. RESULTS: Eighty-four patients
      were enrolled in the study; 42 patients in each group. There were no
      statistically significant differences between CC and A/C treatment. Mean VAS
      baseline pain was similar in both groups (P = 0.49) and there was no significant
      difference in the time to onset of analgesia (P = 0.17). At 0.5 hr, the mean VAS
      pain score was significantly reduced from baseline in both groups (P = 0.0001).
      The VAS pain scores at discharge were reduced 59% and 56% from baseline,
      respectively (P = 0.61). There was no difference between treatments in the
      incidence of adverse events and patients reported similar levels of satisfaction.
      CONCLUSIONS: Controlled-release codeine provides an equivalent onset of
      analgesia, reduction in postoperative pain, and level of patient satisfaction, to
      acetaminophen plus codeine, over 48 hr following cholecystectomy, with the
      advantage of less frequent dosing.

PMID- 15010402
TI  - Desflurane does not accelerate recovery from operations of short duration: a
      practice audit.
AB  - PURPOSE: Desflurane, a newer inhalation anesthetic agent, has been promoted as a
      superior drug because patients will awaken sooner after anesthesia. This has only
      been proven in operations of long duration (i.e., more than one hour). We
      assessed our experience using desflurane in short out-patient surgery with a
      retrospective analysis of a single surgeon's elective laparoscopic
      cholecystectomy patients. METHODS: With Institutional consent, we performed a
      retrospective comparison of the postoperative recovery of patients who received
      desflurane/air/oxygen to historical control patients who received
      isoflurane/N2O/oxygen. RESULTS: Patient preoperative characteristics were similar
      in the two groups. Duration of surgery and the time from the end of surgery to
      patient leaving the operating room for the desflurane and isoflurane/N2O groups
      were (in minutes) 42.7 +/- 13.5 and 9.6 +/- 4.6 vs 47.2 +/- 15.1 and 8.5 +/- 4.1
      respectively (P = NS). Total Aldrete scores upon presentation to the
      postanesthesia care unit (PACU) were 8.1 +/- 1.4 and 7.9 +/- 1.8 for the two
      groups respectively (P = NS). The percentage of patients who arrived in the PACU
      with consciousness scores of 2, 1, 0 for the desflurane and isoflurane/N2O groups
      were 20.4, 75.5, and 4.1 vs 14.6, 73.2 and 12.2 respectively (P = NS). Mean
      length of stay in the PACU for the two groups was 160 +/- 111 and 156 +/- 114 min
      (P = NS). CONCLUSION: Our results show that in short procedures the use of
      desflurane does not necessarily result in faster patient recovery or discharge
      from the PACU.

PMID- 15010403
TI  - Witnessed asystole during spinal anesthesia treated with atropine and
      ondansetron: a case report.
AB  - PURPOSE: To present a case of asystole during spinal anesthesia that responded to
      atropine and ondansetron and to discuss the possible pathophysiology with special
      emphasis on the Bezold-Jarisch reflex and the role of 5-HT3 receptors in
      mediating bradycardia and sympathoinhibition. CLINICAL FEATURES: A 50-yr-old, 97
      kg, healthy male presented for elective left high tibial osteotomy. Spinal
      anesthesia was induced uneventfully at L3-4 with 11.25 mg of hyperbaric 0.75%
      bupivacaine and morphine 0.25 mg. Thirteen minutes after induction, the incision
      site was infiltrated with 20 mL of 0.5% bupivacaine with epinephrine 5 microg.mL(
      1) for intraoperative hemostasis, resulting in an increase in heart rate from 74
      to 90 beats.min(-1). Three minutes after infiltration of the incision site, the
      patient's heart rate dropped to 48 beats.min(-1), accompanied by a blood pressure
      of 107/51 mmHg, SpO2 97%, and a sinus bradycardia on the electrocardiogram. The
      electrocardiographic complexes suddenly disappeared with loss of the pulse
      oximeter waveform. Pre-drawn atropine 0.6 mg i.v. and ondansetron 4 mg i.v. were
      administered within seven seconds of the event. After an asystolic period of 30
      to 40 sec, but before chest compressions were initiated, vital signs returned to
      normal with no other sequelae. CONCLUSION: Exogenous epinephrine may have
      triggered the Bezold-Jarisch reflex and subsequent asystole. It is postulated
      that the combination of atropine and ondansetron may have played a key role in
      resuscitation by blocking the serotonergic and cholinergic receptors in the
      afferent and efferent limbs of this vagally-mediated reflex.

PMID- 15010404
TI  - Acute pain management services have progressed, albeit insufficiently in Canadian
      academic hospitals.
AB  - PURPOSE: Acute pain management services (APMS) evolved in response to the desire
      for improved management of postoperative pain. The management of postoperative
      pain received formal support from international organizations over the past
      decade and by 1993 half of the Canadian university-affiliated teaching hospitals
      had implemented an APMS. The purpose of this survey was to describe APMSs in
      Canadian academic institutions, with specific emphasis on postoperative
      analgesics, new analgesic methods, training and research. METHODS: Between June
      2000 and January 2001, 62 Canadian hospitals affiliated with the 16 Canadian
      university anesthesiology departments were sent a postal questionnaire. RESULTS:
      Fifty of the 62 respondents returned a completed questionnaire representing a
      response rate of 81%. Eighty percent of the hospitals surveyed had at least 200
      beds, 90% (45) had implemented an APMS. Anesthesiology was primarily responsible
      in all 45 hospitals with an APMS. The results presented are based on the 45
      centres with an APMS. CONCLUSION: Since the early 1990s the percent of Canadian
      academic hospitals with an APMS has increased from 53% to 92%. These figures are
      comparable to the United States. Greater collaboration from nursing and pharmacy,
      mandatory training for medical and nursing students and residents, and a
      standardized approach to continuous quality improvement remain necessary.

PMID- 15010406
TI  - Temporary atrial pacing via a triple lumen central venous catheter.

PMID- 15010405
TI  - 3.5% urea-linked gelatin is as effective as 6% HES 200/0.5 for volume management
      in cardiac surgery patients.
AB  - PURPOSE: To compare the efficacy of volume expansion with 3.5% gelatin and 6%
      hydroxyethyl starch 200/0.5 in patients undergoing cardiac surgery. The second
      objective was to compare the two colloids in terms of blood losses and allogeneic
      blood transfusion exposure rate. METHODS: In this open-label controlled study,
      patients were randomly allocated to receive either 3.5% urea-linked gelatin (GEL
      group: n = 55) or 6% hydroxyethyl starch 200/0.5/5.1 (HES group: n = 55) for per-
      (including priming of the bypass machine) and postoperative volume management
      with a maximum dosage of 30 +/- 3 mL.kg(-1).day(-1). Volume replacement was
      guided according to routine per- and postoperative care based on cardiac index,
      mixed venous oxygen saturation, and diuresis. If additional colloid was required,
      4.5% albumin had to be given. The study period comprised per- and postoperative
      investigations up to 18 hr after surgery. RESULTS: All hemodynamic variables were
      comparable in both groups. Total study drug was 25.8 +/- 4.8 mL.kg(-1) in the GEL
      group and 24.5 +/- 6.0 mL.kg(-1) in the HES group. There was no difference in the
      number of patients receiving albumin solution or in the amount of albumin
      administered. Total blood loss was higher in the HES than in the GEL group (11.0
      +/- 7.8 mL.kg(-1) vs 8.7 +/- 4.0 mL.kg(-1); P < 0.05) resulting in a higher need
      for allogeneic blood transfusion (HES: nine patients received 12 units, GEL two
      patients received 3 units; P = 0.026). CONCLUSION: In the conditions of the
      present study, HES was not associated with a better plasma expansion effect than
      GEL. HES could result in a higher need for allogeneic blood transfusion.

PMID- 15010407
TI  - The incidence of gastroesophageal reflux and tracheal aspiration detected with pH
      electrodes is similar with the Laryngeal Mask Airway and Esophageal Tracheal
      Combitube--a pilot study.
AB  - PURPOSE: Aspiration as a result of gastroesophageal reflux (GER) and
      regurgitation remains a serious potential problem in anesthetized patients. The
      incidence of GER with either the Esophageal Tracheal Combitube (ETC) or the
      laryngeal mask airway (LMA) was investigated using tracheal and esophageal pH
      electrodes. METHODS: Following approval by the Institutional Review Board and
      written informed consent, 57 patients of ASA physical status I to III were
      randomly assigned to receive either an LMA (Group I, n = 28) or an ETC (Group II,
      n = 29) during general anesthesia. All patients were paralyzed and received
      positive pressure ventilation. Two monocrystalline antimony catheters were used
      for pH monitoring: one unipolar catheter with a single pH sensor for tracheal pH
      measurements and one bipolar catheter with proximal and distal sensors for
      pharyngeal and esophageal pH measurements, respectively. RESULTS: One episode of
      GER occurred in a patient in Group II, yet there were no pH changes reflected in
      the oropharyngeal or tracheal regions. There were 3/25 (12%) patients in Group I
      vs 1/25 (4%) patients in Group II that met the pH criterion for aspiration (pH
      below 4.0 that lasted at least 15 sec), yet no patient developed any clinical
      signs of aspiration. In all patients, hemodynamic and respiratory variables
      remained stable throughout the period of measurement (data not included).
      CONCLUSION: In this pilot study, the ETC appears comparable to the LMA regarding
      the incidence of GER and tracheal acid aspiration.

PMID- 15010408
TI  - A difficult airway is not more prevalent in patients suffering from spasmodic
      torticollis: a case series.
AB  - PURPOSE: We designed this retrospective study to assess the frequency of
      difficult airway and difficult intubation in patients with spasmodic torticollis
      and compare it to that of the general population. METHODS: After Institutional
      Review Board approval, data were collected from the charts of all the patients
      with spasmodic torticollis who underwent selective peripheral denervation at our
      institution between 1988 and 2001. The intubation grade was determined using the
      Cormack and Lehane laryngoscopic classification. The best laryngeal view was
      recorded. RESULTS: Data from 342 patients were available for analysis. Fourteen
      patients had a difficult airway. In two patients, intubation was difficult with
      three attempts at laryngoscopy in one patient and use of fibreoptic bronchoscopy
      in the other. Twelve (3.5%) patients presented with laryngoscopic grades of III
      or IV. The combined prevalence of laryngoscopic view grade III and IV and
      difficult intubation was 4.4%. CONCLUSIONS: This study assesses the frequency of
      difficult intubation in patients suffering from spasmodic torticollis. When
      compared to the general population, these patients do not appear to have a higher
      frequency of difficult airway or difficult intubation.

PMID- 15010409
TI  - Supplementary cleaning does not remove protein deposits from re-usable laryngeal
      mask devices.
AB  - PURPOSE: To test the hypothesis that supplementary cleaning facilitates removal
      of protein deposits from the laryngeal mask airway (LMA). METHODS: Twenty
      previously used Classic) and Flexible LMAs were hand washed, machine washed,
      dried, autoclaved and then randomly allocated into four groups for supplementary
      cleaning. In Group A, the dorsal surface was immersed in water and the surface
      scrubbed with a high-speed rotating brush. In Group B, the dorsal surface was
      immersed in a plaque removing solution. In Group C, the dorsal surface was
      immersed in a protein removing solution. In Group D (controls), the dorsal
      surface was immersed in water. Before and after supplementary cleaning the LMAs
      were immersed in a protein staining solution, rinsed and a high-resolution
      digital image taken of the dorsal surface. The location and severity of staining
      were scored by two observers blinded to group assignment. RESULTS: Staining was
      similar before and after supplementary cleaning for all groups. Mild, moderate
      and severe staining occurred in 31%, 7% and 2% of zones respectively; 60% were
      unstained. Staining was less common on the cuff than on the backplate and distal
      tube (both: P < 0.00001). Staining was less common on the backplate than on the
      distal tube (P = 0.001). Staining was always present on the mid-portion of the
      backplate or distal tube. CONCLUSION: Supplementary cleaning using a rotating
      brush, plaque or protein removing solution does not facilitate removal of protein
      deposits from re-usable LMAs; however, the infectious risk associated with the
      protein deposits remains to be determined.

PMID- 15010410
TI  - Preconditioning with prolonged oxygen exposure induces ischemic tolerance in the
      brain via oxygen free radical formation.
AB  - PURPOSE: To determine if 100% oxygen (O2) inhalation induces ischemic tolerance
      to focal cerebral ischemia and if the effect is induced via O2 free radical
      formation. METHODS: Experiment 1: 36 rats were randomly assigned to four groups
      (n = 9 each): Group A, control rats inhaled air for 24 hr; Groups B, C and D
      animals inhaled 100% O2 for six hours, 12 hr and 24 hr respectively. Experiment
      2: 32 rats were randomly assigned to four groups (n = 8 each): Groups E and F
      rats received normal saline (5 mL.kg(-1) intraperitoneally) and then inhaled air
      (Group E) or 100% O2 (Group F) for 24 hr; Groups G and H animals received 10%
      dimethylthiourea (500 mg.kg(-1) intraperitoneally) and then inhaled 100% O2
      (Group G) or air (Group H) for 24 hr. Twenty-four hours after the treatments, the
      right middle cerebral artery was occluded in all rats for 120 min. The neurologic
      deficit scores (NDS) and brain infarct volumes were evaluated at 24 hr after
      reperfusion. RESULTS: Experiment 1: the infarct volume and NDS of Group D were
      smaller than in controls (P = 0.004 and 0.042 respectively). The infarct volume
      was reduced by 47% in Group D. There was no statistical difference among Groups
      A, B and C. Experiment 2: the infarct volume and NDS in Group F were less than in
      controls (Group E; P = 0.001 and 0.036 respectively). The infarct volume was
      reduced by 60% in Group F. There was no difference among Groups E, G and H.
      CONCLUSION: Our study demonstrates that preconditioning with 100% O2 for 24 hr
      can induce ischemic tolerance via formation of O2 free radicals in transient
      focal cerebral ischemia in rats.

PMID- 15010411
TI  - Best evidence in critical care medicine: Treatment: Adrenal replacement therapy
      improves survival in patients with septic shock.

PMID- 15010412
TI  - Dying in the ICU: strategies that may improve end-of-life care.
AB  - PURPOSE: Since 10 to 20% of adult patients admitted to the intensive care unit
      (ICU) in Canada die, addressing the needs of dying critically ill patients is of
      paramount importance. The purpose of this article is to suggest some strategies
      to consider to improve the care of patients dying in the ICU. SOURCE: Data
      sources were randomized clinical trials, observational studies and surveys. We
      purposively selected key articles on end-of-life care to highlight eight
      initiatives that have the potential to improve care for dying critically ill
      patients. These initiatives were presented at the International Consensus
      Conference on End-of-Life Care in the ICU on April 24-25, 2003 in Brussels,
      Belgium. PRINCIPAL FINDINGS: We describe eight strategies that, if adopted, may
      positively impact on the end-of-life care of critically ill patients: 1) promote
      social change through professional initiatives; 2) legitimize research in end-of
      life care; 3) determine what dying patients need; 4) determine what families of
      dying patients need; 5) initiate quality improvement locally; 6) use quality
      tools with care; 7) educate future clinicians; and 8) personally engage in end-of
      life care. Most of these strategies have not been subjected to rigorous
      evaluation. CONCLUSION: Adoption of some of these strategies we describe may lead
      to improved end-of-life care in the ICU. Future studies should include more
      formal evaluation of the efficacy of end-of-life interventions to help us ensure
      high quality, clinically relevant, culturally adapted care for all dying
      critically ill patients.

PMID- 15010413
TI  - Cultural considerations for Canadians in the diagnosis of brain death.
AB  - PURPOSE: This articles explores cultural perceptions and values related to brain
      death and organ donation from both a Western and non-Western perspective. SOURCE:
      Anthropological literature review of the historical concept of brain death in
      Canada using Eastern culture as a comparison. PRINCIPAL FINDINGS: Although the
      concept of brain death and concomitant organ donation have become widely
      practiced in Western nations such as Canada, from a cross-cultural point of view
      these concepts and practices can be deeply troubling and may hold profoundly
      different meaning to people new to Canada. CONCLUSIONS: Canada has a deep
      commitment and obligation to respect diversity as reflected in the Canadian
      Charter of Rights and Freedoms. Therefore, healthcare workers have an obligation
      to respect cultural differences. To truly respect cultural differences we must
      first explore our own culturally formulated belief systems and then consider how
      our views may interface with other cultures. Our findings call for a greater
      analysis of the cultural influences on the concept of brain death and organ
      donation as a means of building a better understanding and respect for cultural
      diversity.

PMID- 15010415
TI  - Analgesia in bariatric patients following upper abdominal surgery.

PMID- 15010416
TI  - Ultrasound imaging in pediatric regional anesthesia.

PMID- 15010417
TI  - Lumbo-sacral spine surgery and severe bradycardia.

PMID- 15010418
TI  - The "bouncing sign" may optimize the insertion of the laryngeal tube.

PMID- 15010419
TI  - Difficulty in airway management during sedation of patients affected by
      obstructive sleep apnea.

PMID- 15010421
TI  - Inconsistencies in the ethical declaration of death.

PMID- 15010424
TI  - Quantitative real-time PCR with automated sample preparation for diagnosis and
      monitoring of cytomegalovirus infection in bone marrow transplant patients.
AB  - BACKGROUND: In bone marrow and stem cell transplant patients, the widespread use
      of preemptive cytomegalovirus (CMV) antiviral therapy necessitates faster, more
      precise, and more sensitive quantitative laboratory methods for serial viral load
      monitoring. METHODS: We developed a novel CMV viral load assay using real-time
      PCR of plasma DNA prepared by an automated robotic workstation. Fluorescent
      hybridization probes directed at the glycoprotein B (gB) gene (or EcoRI D region)
      of CMV were used to detect and quantify PCR products. The beta-globin gene was
      amplified in parallel to control for the efficiency of the extraction and PCR
      steps. RESULTS: The assay was linear (R = 0.999) from a lower detection limit of
      125 copies/mL to 5 x 10(9) copies/mL with a PCR efficiency of 1.975 (gB) or 2.02
      (EcoRI D). The viral loads determined by PCRs directed at these two different
      viral targets were no different (n = 53; R = 0.928). The interassay CV was 3.5%,
      and the intraassay CV was 1-4%. Compared with a commercially available
      quantitative competitive PCR assay (Roche MONITOR; R = 0.59), the mean CMV viral
      load by real-time PCR was 3.1 times higher (mean ratio; P = 0.002). The
      diagnostic sensitivity and specificity of the real-time assay were 96% and 100%,
      respectively (n = 147), compared with 74% and 98% for a qualitative PCR assay
      (Roche AMPLICOR). On a subset of samples, the diagnostic sensitivity of viral
      culture was no greater than 50% (n = 44). Of 1115 clinical referral samples from
      252 patients, 10% of the samples and 18% of the patients had low-level CMV
      viremia (median, 500 copies/mL). In this predominantly (85%) bone marrow
      transplant testing cohort, serial CMV viral load results were the predominant
      clinical trigger for the initiation, monitoring, and cessation of preemptive
      antiviral therapy. CONCLUSIONS: The combination of automated DNA preparation and
      semiautomated real-time fluorescent PCR detection allows for a sensitive,
      precise, and accurate high-throughput assay of CMV viral load that can be used as
      the laboratory trigger for preemptive antiviral therapy.

PMID- 15010423
TI  - Analytical and clinical evaluation of the Bayer ADVIA Centaur automated B-type
      natriuretic peptide assay in patients with heart failure: a multisite study.
AB  - BACKGROUND: B-Type natriuretic peptide (BNP) is released from the left ventricle
      of the heart into the circulation in response to ventricular stretching and
      volume overload. Increased BNP concentrations are associated with heart failure
      (HF). METHODS: We evaluated the analytical and clinical performance of the Bayer
      ADVIA Centaur BNP assay. Studies included precision, analytical correlation
      (against the Shionogi ShionoRIA and Biosite Triage BNP assays), BNP results for
      blood collected in plastic tubes containing EDTA vs other collection tubes, high
      dose hook effect, detection limits, and interferences. The clinical performance
      was tested on 2243 blood samples collected from 983 apparently healthy
      individuals, 538 patients with chronic disease but without HF (renal
      insufficiency, chronic obstructive pulmonary disease, diabetes, and
      hypertension), and 722 patients with HF (New York Heart Association classes I
      IV). RESULTS: The ADVIA Centaur assay had total imprecision (CV) of 3.4%, 2.9%,
      and 2.4% at BNP concentrations of 48, 461, and 1768 ng/L, respectively. The
      Passing-Bablok correlations to the ShionoRIA and Triage were as follows: ADVIA
      Centaur = 1.11(ShionoRIA) - 1.19 ng/L (r = 0.98); ADVIA Centaur = 0.78(Triage) +
      5.89 ng/L (r = 0.92), respectively. Of the different blood collection tubes, only
      EDTA plastic tubes (with and without the barrier gel) were acceptable. The lower
      detection limit was 0.5 ng/L, and there were no interferences from common
      analytes, other neuropeptides, or unusual antibodies. BNP exhibited different
      reference intervals according to age and gender. BNP concentrations increased
      progressively as the severity of HF increased. CONCLUSIONS: The ADVIA Centaur is
      the first commercially available BNP assay for use on an automated
      immunochemistry platform. This assay has good analytical and clinical performance
      characteristics for diagnosing HF.

PMID- 15010425
TI  - Partitioning of nongaussian-distributed biochemical reference data into
      subgroups.
AB  - BACKGROUND: The aim of this study was to develop new methods for partitioning
      biochemical reference data, covering in particular nongaussian distributions.
      METHODS: We recently proposed partitioning criteria for gaussian distributions.
      These criteria relate to proportions of the subgroups outside each of the
      reference limits of the combined distribution (proportion criteria) and to
      distances between the subgroup distributions as correlates of these proportions
      (distance criteria). However, distance criteria do not seem to be ideal for
      nongaussian distributions because a generally valid relationship between
      proportions and distances cannot be established for these. RESULTS: Proportion
      criteria appear preferable to distance criteria for two additional reasons: (a)
      The prevalences of the subgroup populations may have a considerable effect on
      stratification, but these are hard to account for by using distance criteria. Two
      methods to handle prevalences are described, the root method and the
      multiplication method. (b) Tied reference values, another complication of the
      partitioning problem, could also be hard to take care of using distance criteria.
      Some solutions to the problems caused by tied reference values are suggested.
      CONCLUSIONS: Partitioning of biochemical reference data should preferably be
      based on proportion criteria; this is particularly true for nongaussian
      distributions. Both of the described complications of the partitioning problem,
      the prevalences of the subgroups and tied reference values, are hard to deal with
      using distance criteria, but the proposed methods make it possible to account for
      them when proportion criteria are applied.

PMID- 15010426
TI  - Simple technique for internal control of real-time amplification assays.
AB  - BACKGROUND: In real-time PCR assays, the most accurate way to identify false
      negative results, e.g., those caused by PCR inhibitors, is to add to samples an
      internal control that will be coamplified with the target (e.g., pathogen) DNA.
      Current internal control procedures, however, which usually involve the
      introduction of a DNA fragment, are complex, time-consuming, and expensive.
      METHODS: Single-stranded oligonucleotides, which contain little more than primer
      and probe binding sites, were used as internal controls in real-time PCR assays.
      Mismatches were included in the probe-binding region of the internal control
      oligonucleotide (ICO) to prevent probe-control hybridization during the
      fluorescence acquisition step of the PCR. Amplified ICOs were detected by melting
      point analysis. ICOs could be added directly to the sample material before DNA
      extraction. RESULTS: To demonstrate the feasibility of the new approach, we
      designed ICOs for the LightCycler hybridization probe assays for Mycobacterium
      tuberculosis complex, hepatitis B virus, herpes simplex virus, and varicella
      zoster virus. In each case, the controls did not interfere with detection of the
      pathogen, but were clearly detectable during a subsequent melting point analysis.
      CONCLUSIONS: A single-stranded oligonucleotide that mimics the target region of
      the pathogen but is clearly distinguishable from the target during melting point
      analysis can serve as a simple, cost-effective internal control for real-time
      amplification assays. Such control oligonucleotides are easy to design and
      inexpensive. A costly second probe system is not necessary. Moreover, the
      internally controlled assay uses only one fluorescence detection channel of the
      instrument, leaving the second channel free for multiplex applications.

PMID- 15010427
TI  - Direct visualization of cystic fibrosis transmembrane regulator mutations in the
      clinical laboratory setting.
AB  - BACKGROUND: The recommendation for population- based cystic fibrosis (CF) carrier
      screening by the American College of Medical Genetics for the 25 most prevalent
      mutations and 6 polymorphisms in the CF transmembrane regulatory gene has greatly
      increased clinical laboratory test volumes. We describe the development and
      technical validation of a DNA chip in a 96-well format to allow for high
      throughput genotype analysis. METHODS: The CF Portrait chip contains an 8 x 8
      array of capture probes and controls to detect all requisite alleles. Single-tube
      multiplex PCR with 15 biotin-labeled primer pairs was used to amplify sequences
      containing all single-nucleotide polymorphisms to be interrogated. Detection of a
      thin-film signal created by hybridization of multiplex PCR-amplified DNA to
      complementary capture probes was performed with an automated image analysis
      instrument, NucleoSight. Allele classification, data formatting, and uploading to
      a laboratory information system were fully automated. RESULTS: The described
      platform correctly classified all mutations and polymorphisms and can screen
      approximately 1300 patient samples in a 10-h shift. Final validation was
      performed by two separate 1000-sample comparisons with Roche CF Gold line probe
      strips and the Applera CF OLA, Ver 3.0. The CF Portrait Biochip made no errors
      during this validation, whereas the Applera assay made seven miscalls of the IVS
      8 5T/7T/9T polymorphism CONCLUSIONS: The CF Portrait platform is an automated,
      high-throughput, DNA chip-based assay capable of accurately classifying all CF
      mutations in the recommended screening panel, including the IVS-8 5T/7T/9T
      polymorphism.

PMID- 15010428
TI  - Human embryos cloned for stem cells: work not seen as leap toward reproductive
      cloning.

PMID- 15010429
TI  - Obesity Is Now on Everyone's Plate.

PMID- 15010430
TI  - Researchers eye "predatory" bacterium for novel antimicrobial strategies.

PMID- 15010434
TI  - Quality of care in Medicaid managed care vs commercial managed care plans.

PMID- 15010435
TI  - Quality of care in Medicaid managed care vs commercial managed care plans.

PMID- 15010436
TI  - Quality of care in Medicaid managed care vs commercial managed care plans.

PMID- 15010437
TI  - Quality of care in Medicaid managed care vs commercial managed care plans.

PMID- 15010438
TI  - Parenteral vs epidural analgesia for postoperative pain.

PMID- 15010439
TI  - Optimal control of glycemia among critically ill patients.

PMID- 15010440
TI  - Coffee consumption and insulin sensitivity.

PMID- 15010441
TI  - Management and outcomes of care of fever in early infancy.
AB  - CONTEXT: Fever in infants challenges clinicians in distinguishing between serious
      conditions, such as bacteremia or bacterial meningitis, and minor illnesses. To
      date, the practice patterns of office-based pediatricians in treating febrile
      infants and the clinical outcomes resulting from their care have not been
      systematically studied. OBJECTIVES: To characterize the management and clinical
      outcomes of fever in infants, develop a clinical prediction model for the
      identification of bacteremia/bacterial meningitis, and compare the accuracy of
      various strategies. DESIGN: Prospective cohort study. SETTING: Offices of 573
      practitioners from the Pediatric Research in Office Settings (PROS) network of
      the American Academy of Pediatrics in 44 states, the District of Columbia, and
      Puerto Rico. PATIENTS: Consecutive sample of 3066 infants aged 3 months or
      younger with temperatures of at least 38 degrees C seen by PROS practitioners
      from February 28, 1995, through April 25, 1998. MAIN OUTCOME MEASURES: Management
      strategies, illness frequency, and rates and accuracy of treating
      bacteremia/bacterial meningitis. RESULTS: The PROS clinicians hospitalized 36% of
      the infants, performed laboratory testing in 75%, and initially treated 57% with
      antibiotics. The majority (64%) were treated exclusively outside of the hospital.
      Bacteremia was detected in 1.8% of infants (2.4% of those tested) and bacterial
      meningitis in 0.5%. Well-appearing infants aged 25 days or older with fever of
      less than 38.6 degrees C had a rate of 0.4% for bacteremia/bacterial meningitis.
      Frequency of other illnesses included urinary tract infection, 5.4%; otitis
      media, 12.2%; upper respiratory tract infection, 25.6%; bronchiolitis, 7.8%; and
      gastroenteritis, 7.2%. Practitioners followed current guidelines in 42% of
      episodes. However, in the initial visit, they treated 61 of the 63 cases of
      bacteremia/bacterial meningitis with antibiotics. Neither current guidelines nor
      the model developed in this study performed with greater accuracy than observed
      practitioner management. CONCLUSIONS: Pediatric clinicians in the United States
      use individualized clinical judgment in treating febrile infants. In this study,
      relying on current clinical guidelines would not have improved care but would
      have resulted in more hospitalizations and laboratory testing.

PMID- 15010442
TI  - Coffee consumption and risk of type 2 diabetes mellitus among middle-aged Finnish
      men and women.
AB  - CONTEXT: Only a few studies of coffee consumption and diabetes mellitus (DM) have
      been reported, even though coffee is the most consumed beverage in the world.
      OBJECTIVE: To determine the relationship between coffee consumption and the
      incidence of type 2 DM among Finnish individuals, who have the highest coffee
      consumption in the world. DESIGN, SETTING, AND PARTICIPANTS: A prospective study
      from combined surveys conducted in 1982, 1987, and 1992 of 6974 Finnish men and
      7655 women aged 35 to 64 years without history of stroke, coronary heart disease,
      or DM at baseline, with 175 682 person-years of follow-up. Coffee consumption and
      other study parameters were determined at baseline using standardized
      measurements. MAIN OUTCOME MEASURES: Hazard ratios (HRs) for the incidence of
      type 2 DM were estimated for different levels of daily coffee consumption.
      RESULTS: During a mean follow-up of 12 years, there were 381 incident cases of
      type 2 DM. After adjustment for confounding factors (age, study year, body mass
      index, systolic blood pressure, education, occupational, commuting and leisure
      time physical activity, alcohol and tea consumption, and smoking), the HRs of DM
      associated with the amount of coffee consumed daily (0-2, 3-4, 5-6, 7-9, > or =10
      cups) were 1.00, 0.71 (95% confidence interval [CI], 0.48-1.05), 0.39 (95% CI,
      0.25-0.60), 0.39 (95% CI, 0.20-0.74), and 0.21 (95% CI, 0.06-0.69) (P for
      trend<.001) in women, and 1.00, 0.73 (95% CI, 0.47-1.13), 0.70 (95% CI, 0.45
      1.05), 0.67 (95% CI, 0.40-1.12), and 0.45 (95% CI, 0.25-0.81) (P for trend =.12)
      in men, respectively. In both sexes combined, the multivariate-adjusted inverse
      association was significant (P for trend <.001) and persisted when stratified by
      younger and older than 50 years; smokers and never smokers; healthy weight,
      overweight, and obese participants; alcohol drinker and nondrinker; and
      participants drinking filtered and nonfiltered coffee. CONCLUSION: Coffee
      drinking has a graded inverse association with the risk of type 2 DM; however,
      the reasons for this risk reduction associated with coffee remain unclear.

PMID- 15010443
TI  - Sex differences in outcomes after cardiac catheterization: effect modification by
      treatment strategy and time.
AB  - CONTEXT: Studies comparing outcomes of cardiac care in women vs men yield various
      results, with some suggesting worse outcomes for women and others suggesting
      equivalent outcomes. OBJECTIVE: To determine whether extent of coronary disease,
      treatment strategy, and follow-up time influence the risk of death in women vs
      men among patients who have had cardiac catheterization. DESIGN, SETTING, AND
      PATIENTS: We studied a large inception cohort by using detailed clinical data
      from a registry of 37 401 patients undergoing cardiac catheterization in Alberta,
      Canada, from 1995-2000, with follow-up through December 31, 2001. MAIN OUTCOME
      MEASURES: The risk of death for women vs men was assessed for all patients
      combined and then in analyses stratified by degree of coronary anatomic risk and
      by treatment strategy (no revascularization, percutaneous coronary intervention
      [PCI], coronary artery bypass graft [CABG] surgery). The latter analysis included
      a graphic assessment of the changing relative risk over time for women vs men.
      RESULTS: Women had higher 1-year mortality than men did (5.6% vs 4.6%; P<.001).
      However, stratified analyses demonstrated that sex differences in risk occurred
      only early after catheterization and were most apparent among patients undergoing
      revascularization. The early risk-adjusted relative risks for women vs men were
      elevated at 3.49 (95% confidence interval [CI], 1.95-6.24) for CABG surgery and
      2.38 (95% CI, 1.48-3.83) for PCI on day 1 after catheterization, with a
      subsequent decrease in relative risk over time to equivalence in risk between
      sexes before 1 year. CONCLUSIONS: Sex-based differences in death rates after
      cardiac catheterization are time- and treatment-specific. This finding may at
      least partially explain the discrepancies in results from earlier studies on sex
      differences in outcomes of cardiac care.

PMID- 15010444
TI  - Caloric restriction and incidence of breast cancer.
AB  - CONTEXT: Restricting caloric intake is one of the most effective ways to extend
      lifespan and to reduce spontaneous tumor occurrence in experimental animals, but
      whether similar associations hold in humans has not been appropriately studied.
      OBJECTIVE: To determine whether caloric restriction in early life reduces the
      risk of invasive breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Retrospective
      cohort study using data from the Swedish Inpatient Registry, the Swedish Cancer
      Registry, the Swedish Death Registry, and the Swedish Fertility Registry.
      Participants were 7303 Swedish women hospitalized for anorexia nervosa prior to
      age 40 years between 1965 and 1998. Women were excluded (n = 31) if they were
      diagnosed with cancer prior to their first discharge from hospitalization for
      anorexia nervosa. MAIN OUTCOME MEASURE: Incidence of invasive breast cancer.
      RESULTS: Compared with the Swedish general population, women hospitalized for
      anorexia nervosa prior to age 40 years had a 53% (95% confidence interval [CI],
      3%-81%) lower incidence of breast cancer; nulliparous women with anorexia nervosa
      had a 23% (95% CI, 79% higher to 75% lower) lower incidence, and parous women
      with anorexia nervosa had a 76% (95% CI, 13%-97%) lower incidence. CONCLUSIONS:
      Severe caloric restriction in humans may confer protection from invasive breast
      cancer. Low caloric intake prior to first birth followed by a subsequent
      pregnancy appears to be associated with an even more pronounced reduction in
      risk.

PMID- 15010445
TI  - Trends in private and public health insurance for adolescents.
AB  - CONTEXT: Previous studies (1984-1995) of adolescent health insurance have shown
      little change in the proportion with coverage. Federally mandated expansions in
      Medicaid were offset by declines in private coverage. Further expansions of
      Medicaid and implementation of the State Children's Health Insurance Program
      (SCHIP) have opened new avenues for increasing coverage rates. OBJECTIVES: To
      assess the current health insurance status of adolescents, the demographic and
      socioeconomic correlates of insurance coverage, and document recent changes in
      public and private coverage rates. DESIGN, SETTING, AND PARTICIPANTS: We analyzed
      data on 12 995 adolescents aged 10 to 18 years, who had been included in the 2002
      National Health Interview Survey. We conducted multivariate analyses to assess
      the independent association of age, sex, race, poverty status, family structure,
      family size, and region on the likelihood of having insurance coverage. Results
      are compared with previously published findings on adolescent health insurance
      coverage spanning 1984 to 1995. MAIN OUTCOME MEASURE: Insurance coverage for
      adolescents. RESULTS: An estimated 12.2% of adolescents were uninsured in 2002,
      which is a decrease from 14.1% in 1995 (P<.003). The decrease occurred entirely
      because of an expansion of public coverage and is concentrated among children in
      poor (<100% of the federal poverty level) and near-poor (100%-199% of the federal
      poverty level) families. A substantial decrease in the differences between poor
      and higher-income groups occurred between 1995 and 2002 due to gains in coverage
      for adolescents in poor and near-poor families and losses in coverage among those
      in middle- and upper-income families (> or =200% of the federal poverty level).
      Specifically, the proportion of adolescents in poor families without coverage
      declined from 27.4% in 1995 to 19.7% in 2002 (P<.001). The proportion of
      adolescents in near-poor families without coverage declined from 24.8% in 1995 to
      19.2% in 2002 (P<.002). In contrast, the proportion of adolescents in middle- and
      higher-income families without insurance increased from 4.1% in 1995 to 6.3% in
      2002 because availability of insurance through the private market declined
      (P<.001). CONCLUSIONS: A modest but significant reduction in the percentage of
      adolescents without insurance has occurred since 1995, largely as a result of
      expansions in public coverage. An even larger reduction in the proportion of
      adolescents without coverage would have occurred, if not for a reduction in
      private coverage for adolescents in middle- and higher-income families.

PMID- 15010446
TI  - Actual causes of death in the United States, 2000.
AB  - CONTEXT: Modifiable behavioral risk factors are leading causes of mortality in
      the United States. Quantifying these will provide insight into the effects of
      recent trends and the implications of missed prevention opportunities.
      OBJECTIVES: To identify and quantify the leading causes of mortality in the
      United States. DESIGN: Comprehensive MEDLINE search of English-language articles
      that identified epidemiological, clinical, and laboratory studies linking risk
      behaviors and mortality. The search was initially restricted to articles
      published during or after 1990, but we later included relevant articles published
      in 1980 to December 31, 2002. Prevalence and relative risk were identified during
      the literature search. We used 2000 mortality data reported to the Centers for
      Disease Control and Prevention to identify the causes and number of deaths. The
      estimates of cause of death were computed by multiplying estimates of the cause
      attributable fraction of preventable deaths with the total mortality data. MAIN
      OUTCOME MEASURES: Actual causes of death. RESULTS: The leading causes of death in
      2000 were tobacco (435 000 deaths; 18.1% of total US deaths), poor diet and
      physical inactivity (365 000 deaths; 15.2%) [corrected], and alcohol consumption
      (85 000 deaths; 3.5%). Other actual causes of death were microbial agents (75
      000), toxic agents (55 000), motor vehicle crashes (43 000), incidents involving
      firearms (29 000), sexual behaviors (20 000), and illicit use of drugs (17 000).
      CONCLUSIONS: These analyses show that smoking remains the leading cause of
      mortality. However, poor diet and physical inactivity may soon overtake tobacco
      as the leading cause of death. These findings, along with escalating health care
      costs and aging population, argue persuasively that the need to establish a more
      preventive orientation in the US health care and public health systems has become
      more urgent.

PMID- 15010447
TI  - Can health care teams improve primary care practice?
AB  - In health care settings, individuals from different disciplines come together to
      care for patients. Although these groups of health care personnel are generally
      called teams, they need to earn true team status by demonstrating teamwork.
      Developing health care teams requires attention to 2 central questions: who is on
      the team and how do team members work together? This article chiefly focuses on
      the second question. Cohesive health care teams have 5 key characteristics: clear
      goals with measurable outcomes, clinical and administrative systems, division of
      labor, training of all team members, and effective communication. Two
      organizations are described that demonstrate these components: a private primary
      care practice in Bangor, Me, and Kaiser Permanente's Georgia region primary care
      sites. Research on patient care teams suggests that teams with greater
      cohesiveness are associated with better clinical outcome measures and higher
      patient satisfaction. In addition, medical settings in which physicians and
      nonphysician professionals work together as teams can demonstrate improved
      patient outcomes. A number of barriers to team formation exist, chiefly related
      to the challenges of human relationships and personalities. Taking small steps
      toward team development may improve the work environment in primary care
      practices.

PMID- 15010448
TI  - A 43-year-old woman with chronic renal insufficiency.

PMID- 15010449
TI  - Update: A 75-year-old man with depression.

PMID- 15010450
TI  - Young, febrile infants: a 30-year odyssey ends where it started.

PMID- 15010451
TI  - The immediate vs the important.

PMID- 15010452
TI  - JAMA patient page. Fever in infants.

PMID- 15010454
TI  - The crystal structure of the family 6 carbohydrate binding module from Cellvibrio
      mixtus endoglucanase 5a in complex with oligosaccharides reveals two distinct
      binding sites with different ligand specificities.
AB  - Glycoside hydrolases that release fixed carbon from the plant cell wall are of
      considerable biological and industrial importance. These hydrolases contain non
      catalytic carbohydrate binding modules (CBMs) that, by bringing the appended
      catalytic domain into intimate association with its insoluble substrate, greatly
      potentiate catalysis. Family 6 CBMs (CBM6) are highly unusual because they
      contain two distinct clefts (cleft A and cleft B) that potentially can function
      as binding sites. Henshaw et al. (Henshaw, J., Bolam, D. N., Pires, V. M. R.,
      Czjzek, M., Henrissat, B., Ferreira, L. M. A., Fontes, C. M. G. A., and Gilbert,
      H. J. (2003) J. Biol. Chem. 279, 21552-21559) show that CmCBM6 contains two
      binding sites that display both similarities and differences in their ligand
      specificity. Here we report the crystal structure of CmCBM6 in complex with a
      variety of ligands that reveals the structural basis for the ligand specificity
      displayed by this protein. In cleft A the two faces of the terminal sugars of
      beta-linked oligosaccharides stack against Trp-92 and Tyr-33, whereas the rest of
      the binding cleft is blocked by Glu-20 and Thr-23, residues that are not present
      in CBM6 proteins that bind to the internal regions of polysaccharides in cleft A.
      Cleft B is solvent-exposed and, therefore, able to bind ligands because the loop,
      which occludes this region in other CBM6 proteins, is much shorter and flexible
      (lacks a conserved proline) in CmCBM6. Subsites 2 and 3 of cleft B accommodate
      cellobiose (Glc-beta-1,4-Glc), subsite 4 will bind only to a beta-1,3-linked
      glucose, whereas subsite 1 can interact with either a beta-1,3- or beta-1,4
      linked glucose. These different specificities of the subsites explain how cleft B
      can accommodate beta-1,4-beta-1,3- or beta-1,3-beta-1,4-linked gluco-configured
      ligands.

PMID- 15010453
TI  - Defective endoplasmic reticulum-resident membrane protein CLN6 affects lysosomal
      degradation of endocytosed arylsulfatase A.
AB  - Variant late infantile neuronal ceroid lipofuscinosis, a lysosomal storage
      disorder characterized by progressive mental deterioration and blindness, is
      caused by mutations in a polytopic membrane protein (CLN6) with unknown
      intracellular localization and function. In this study, transient transfection of
      BHK21 cells with CLN6 cDNA and immunoblot analysis using peptide-specific CLN6
      antibodies demonstrated the expression of a approximately 27-kDa protein that
      does not undergo proteolytic processing. Cross-linking experiments revealed the
      presence of CLN6 dimers. Using double immunofluorescence microscopy, epitope
      tagged CLN6 was shown to be retained in the endoplasmic reticulum (ER) with no
      colocalization with the cis-Golgi or lysosomal markers. The translocation into
      the ER and proper folding were confirmed by the N-linked glycosylation of a
      mutant CLN6 polypeptide. Pulse-chase labeling of fibroblasts from CLN6 patients
      and from sheep (OCL6) and mouse (nclf) models of the disease followed by
      immunoprecipitation of cathepsin D indicated that neither the synthesis, sorting
      nor the proteolytic processing of this lysosomal enzyme was affected in CLN6
      defective cells. However, the degradation of the endocytosed index protein
      arylsulfatase A was strongly reduced in all of the mutant CLN6 cell lines
      compared with controls. These data suggest that defects in the ER-resident CLN6
      protein lead to lysosomal dysfunctions, which may result in lysosomal
      accumulation of storage material.

PMID- 15010455
TI  - The second intracellular loop of the glycine transporter 2 contains crucial
      residues for glycine transport and phorbol ester-induced regulation.
AB  - Na+ and Cl(-)-coupled glycine transporters control the availability of glycine
      neurotransmitter in the synaptic cleft of inhibitory glycinergic pathways. In
      this report, we have investigated the involvement of the second intracellular
      loop of the neuronal glycine transporter 2 (GLYT2) on the protein conformational
      equilibrium and the regulation by 4alpha-phorbol 12 myristate 13-acetate (PMA).
      By substituting several charged (Lys-415, Lys-418, and Lys-422) and polar (Thr
      419 and Ser-420) residues for different amino acids and monitoring plasma
      membrane expression and kinetic behavior, we found that residue Lys-422 is
      crucial for glycine transport. The introduction of a negative charge in 422, and
      to a lower extent in neighboring N-terminal residues, dramatically increases
      transporter voltage dependence as assessed by response to high potassium
      depolarizing conditions. In addition, [2-(trimethylammonium)ethyl]
      methanethiosulfonate accessibility revealed a conformational connection between
      Lys-422 and the glycine binding/permeation site. Finally, we show that the
      mutation of positions Thr-419, Ser-420, and mainly Lys-422 to acidic residues
      abolishes the PMA-induced inhibition of transport activity and the plasma
      membrane transporter internalization. Our results establish a new structural
      basis for the action of PMA on GLYT2 and suggest a complex nature of the PMA
      action on this glycine transporter.

PMID- 15010456
TI  - Caveolar and lipid raft localization of the growth hormone receptor and its
      signaling elements: impact on growth hormone signaling.
AB  - The growth hormone receptor (GHR) is a cell surface receptor that mediates the
      somatogenic and metabolic effects of the growth hormone (GH). GHR signaling is
      transduced via the receptor-associated cytoplasmic tyrosine kinase called Janus
      protein kinase 2 (JAK2). The major intracellular signaling systems activated by
      JAK2 in response to GH include the signal transducer and activator of
      transcription (STAT) 5 and extracellular signal-regulated kinase (ERK)-1 and -2
      pathways. In this report, we investigate the role of cholesterol-rich plasma
      membrane microdomains (caveolae and lipid rafts) in GH signaling. By subcellular
      fractionation of the GH-responsive 3T3-F442A murine preadipocyte, we found
      dramatic enrichment (6.7-fold) of plasma membrane GHR in the caveolae membranes
      (CM). JAK2 was also represented in the CM fraction, but was less enriched (2.5
      fold) than GHR. ERK1/2 and the important ERK pathway upstream small adaptor
      protein, Grb2 (growth factor receptor-bound protein 2), were also enriched in
      caveolae (2.3- and 8.3-fold, respectively), but STAT5 was barely detected in the
      same fraction. Correspondingly, GH-induced tyrosine-phosphorylated GHR, JAK2, and
      ERK1/2 were highly represented in the CM fraction, whereas tyrosine
      phosphorylated STAT5 was enriched in the non-membranous fraction of the post
      nuclear supernatant. Additionally, GH induced further accumulation of GHR, Grb2,
      and SHC proteins in the CM fraction. Interestingly, treatment of the cells with
      the caveolae-disrupting agent, methyl-beta-cyclodextrin (mbetaCD), selectively
      inhibited GH-induced ERK1/2 activation but not STAT5 phosphorylation; repletion
      of cholesterol in mbetaCD-treated cells restored GH-induced ERK activation.
      Comparison of 3T3-F442A cells with the GHR-expressing human IM-9 lymphoblasts
      revealed similar enrichment of GHR in the lipid raft fraction of IM-9 as in the
      CM fraction of 3T3-F442A, but there were dramatic differences in the ERKs and
      Grb2. The IM-9 cell, in which ERKs are not activated by GH, displayed no
      enrichment of ERKs and Grb2 in the lipid raft fraction. Our results suggest that
      localization of GHRs in the CM fraction of the plasma membrane plays important
      roles in signaling.

PMID- 15010457
TI  - Manipulation of alternative splicing by a newly developed inhibitor of Clks.
AB  - The regulation of splice site usage provides a versatile mechanism for
      controlling gene expression and for the generation of proteome diversity, playing
      an essential role in many biological processes. The importance of alternative
      splicing is further illustrated by the increasing number of human diseases that
      have been attributed to mis-splicing events. Appropriate spatial and temporal
      generation of splicing variants demands that alternative splicing be subjected to
      extensive regulation, similar to transcriptional control. The Clk (Cdc2-like
      kinase) family has been implicated in splicing control and consists of at least
      four members. Through extensive screening of a chemical library, we found that a
      benzothiazole compound, TG003, had a potent inhibitory effect on the activity of
      Clk1/Sty. TG003 inhibited SF2/ASF-dependent splicing of beta-globin pre-mRNA in
      vitro by suppression of Clk-mediated phosphorylation. This drug also suppressed
      serine/arginine-rich protein phosphorylation, dissociation of nuclear speckles,
      and Clk1/Sty-dependent alternative splicing in mammalian cells. Consistently,
      administration of TG003 rescued the embryonic defects induced by excessive Clk
      activity in Xenopus. Thus, TG003, a novel inhibitor of Clk family will be a
      valuable tool to dissect the regulatory mechanisms involving serine/arginine-rich
      protein phosphorylation signaling pathways in vivo, and may be applicable for the
      therapeutic manipulation of abnormal splicing.

PMID- 15010458
TI  - A novel human Cl(-) channel family related to Drosophila flightless locus.
AB  - Large conductance chloride (maxi-Cl(-)) currents have been recorded in some
      cells, but there is still little information on the molecular nature of the
      channel underlying this conductance. We report here that tweety, a gene located
      in Drosophila flightless, has a structure similar to those of known channels and
      that human homologues of tweety (hTTYH1-3) are novel maxi-Cl(-) channels. hTTYH3
      mRNA was found to be distributed in excitable tissues. The whole cell current of
      hTTYH3 was large enough to be discriminated from the control but emerged only
      after treatment with ionomycin. Analysis of pore mutants suggested that
      positively charged amino acids contributed to anion selectivity. Like a maxi-Cl(
      ) channel in situ, the hTTYH3 single channel showed 26-picosiemen linear current
      voltage, complex kinetics, 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid
      sensitivity, subconductance, and the permeability order of I(-) > Br(-) > Cl(-).
      Similarly, hTTYH2 encoded an ionomycin-induced maxi-Cl(-) channel, but TTYH1
      encoded a Ca(2+)-independent and swelling-activated maxi-Cl(-) channel.
      Therefore, the hTTYH family encoded maxi-Cl(-) channels of mammals. Further
      studies on the hTTYH family should lead to the elucidation of physiological and
      pathophysiological roles of novel Cl(-) channel molecules.

PMID- 15010460
TI  - Cisplatin-induced post-translational modification of histones H3 and H4.
AB  - The anti-cancer drug cisplatin kills cells by damaging DNA and inducing
      apoptosis. Understanding the detailed mechanisms by which cancer cells respond to
      cisplatin has the potential to improve substantially platinum-based therapy. Post
      translational modification of histones alters chromatin structure, facilitating
      the binding of nuclear factors that mediate DNA repair, transcription, and other
      processes. In the present study, we have investigated the effects of cisplatin
      treatment on histone post-translational modification in cancer cells. We
      discovered that specific phosphorylation of histone H3 at Ser-10, mediated by the
      p38 MAPK pathway, is induced in response to cisplatin treatment. In addition,
      hyperacetylation of histone H4 was caused by drug treatment. These findings
      revealed a link between cisplatin administration and chromosomal structural
      alterations, providing mechanistic information about how cells respond to
      platinum-induced stress.

PMID- 15010459
TI  - The involvement of two cdc2-related kinases (CRKs) in Trypanosoma brucei cell
      cycle regulation and the distinctive stage-specific phenotypes caused by CRK3
      depletion.
AB  - Cyclin-dependent protein kinases are among the key regulators of eukaryotic cell
      cycle progression. Potential functions of the five cdc2-related kinases (CRK) in
      Trypanosoma brucei were analyzed using the RNA interference (RNA(i)) technique.
      In both the procyclic and bloodstream forms of T. brucei, CRK1 is apparently
      involved in controlling the G(1)/S transition, whereas CRK3 plays an important
      role in catalyzing cells across the G(2)/M junction. A knockdown of CRK1 caused
      accumulation of cells in the G(1) phase without apparent phenotypic change,
      whereas depletion of CRK3 enriched cells of both forms in the G(2)/M phase.
      However, two distinctive phenotypes were observed between the CRK3-deficient
      procyclic and bloodstream forms. The procyclic form has a majority of the cells
      containing a single enlarged nucleus plus one kinetoplast. There is also an
      enhanced population of anucleated cells, each containing a single kinetoplast
      known as the zoids (0N1K). The CRK3-depleted bloodstream form has an increased
      number of one nucleus-two kinetoplast cells (1N2K) and a small population
      containing aggregated multiple nuclei and multiple kinetoplasts. Apparently,
      these two forms have different mechanisms in cell cycle regulation. Although the
      procyclic form can be driven into cytokinesis and cell division by kinetoplast
      segregation without a completed mitosis, the bloodstream form cannot enter
      cytokinesis under the same condition. Instead, it keeps going through another
      G(1) phase and enters a new S phase resulting in an aggregate of multiple nuclei
      and multiple kinetoplasts in an undivided cell. The different leakiness in cell
      cycle regulation between two stage-specific forms of an organism provides an
      interesting and useful model for further understanding the evolution of cell
      cycle control among the eukaryotes.

PMID- 15010461
TI  - Dimerization is required for activation of eIF2 kinase Gcn2 in response to
      diverse environmental stress conditions.
AB  - In the yeast Saccharomyces cerevisiae, starvation for amino acids induces
      phosphorylation of the alpha subunit of eukaryotic initiation factor 2alpha by
      Gcn2 protein kinase, leading to elevated translation of GCN4. Gcn4p is a
      transcriptional activator of hundreds of genes involved in remedying nutrient
      deprivation. In addition to a conserved kinase domain, Gcn2p has a regulatory
      region homologous to histidyl tRNA synthetase enzymes that binds uncharged tRNA
      that accumulates during amino acid starvation. Flanking the carboxyl terminus of
      the histidyl-tRNA synthetase-related domain is a region spanning 162 residues
      that participates in the activation of the protein kinase. Gel filtration and
      chemical cross-linking analysis of the recombinant carboxyl-terminal Gcn2 protein
      revealed that this region is a stable homodimer that is highly resistant to high
      concentrations of salt. Residue alterations in three hydrophobic segments and one
      segment with a proposed amphipathic alpha-helix in this Gcn2p carboxyl terminus
      blocked oligomerization, supporting the role of hydrophobic interactions in the
      dimerization interface of Gcn2p. Introduction of residue substitutions that
      impaired dimerization into the full-length protein prevented the ability of Gcn2p
      to phosphorylate its substrate eukaryotic initiation factor-2alpha and induce
      GCN4 translational expression in yeast cells subjected to a variety of stresses
      including amino acid limitation or exposure to rapamycin or high levels of NaCl.
      This latter stress can be overcome by addition of increasing amounts of K+ ions,
      indicating that the Na+/K+ ion balance is central to this stress induction. We
      conclude that dimerization involving hydrophobic segments in the carboxyl
      terminal region is required for activation of Gcn2p in response to a multitude of
      stresses.

PMID- 15010462
TI  - Critical role for hematopoietic cell kinase (Hck)-mediated phosphorylation of
      Gab1 and Gab2 docking proteins in interleukin 6-induced proliferation and
      survival of multiple myeloma cells.
AB  - Interleukin-6 (LI-6) is a known growth and survival factor in multiple myeloma
      via activation of extracellular signal-regulated kinase and phosphatidylinositol
      3-kinase signaling cascade. In this report we show that Grb2-associated binder
      (Gab) family adapter proteins Gab1 and Gab2 are expressed by multiple myeloma
      cells; and that interleukin-6 induces their tyrosine phosphorylation and
      association with downstream signaling molecules. We further demonstrate that
      these events are Src family tyrosine kinase-dependent and specifically identify
      the role of hematopoietic cell kinase (Hck) as a new Gab family adapter protein
      kinase. Conversely, inhibition of Src family tyrosine kinases by the
      pyrazolopyrimidine PP2, as in kinase-inactive Hck mutants, significantly reduces
      IL-6-triggered activation of extracellular signal-regulated kinase and AKT-1,
      leading to significant reduction of multiple myeloma cell proliferation and
      survival. Taken together, these results delineate a key role for Hck-mediated
      phosphorylation of Gab1 and Gab2 docking proteins in IL-6-induced proliferation
      and survival of multiple myeloma cells and identify tyrosine kinases and
      downstream adapter proteins as potential new therapeutic targets in multiple
      myeloma.

PMID- 15010463
TI  - Anthrax lethal toxin rapidly activates caspase-1/ICE and induces extracellular
      release of interleukin (IL)-1beta and IL-18.
AB  - Anthrax lethal toxin (LT), a critical virulence factor for Bacillus anthracis,
      has been demonstrated to cleave and to inactivate mitogen-activated protein
      kinase kinases (MAPKKs) that propagate prosurvival signals in macrophages (1-5).
      Whether this action of anthrax LT leads to the production of proinflammatory
      cytokines by macrophages has been more controversial (6, 7). We now report that
      anthrax LT treatment leads to the specific extracellular release of interleukin
      (IL)-1beta and IL-18 by the murine macrophage cell lines, RAW264.7 and J774A.1.
      Studies of the processing of IL-1beta reveal that the levels of activated/cleaved
      IL-1beta in RAW264.7 and J774.A1 cells are increased following treatment with
      anthrax LT. Enhanced processing of IL-1beta directly correlates with increased
      levels in the activation of its upstream regulator, IL-1beta-converting
      enzyme/Caspase-1 (ICE). The extracellular release of IL-1beta and IL-18 in
      response to anthrax LT is ICE-dependent, as an ICE-specific inhibitor blocks this
      process. These data indicate that ICE, IL-1beta, and IL-18 are downstream
      effectors of anthrax LT in macrophages, providing the basis for new bioassays for
      anthrax LT activity and representing potential therapeutic targets.

PMID- 15010464
TI  - Lysine 43 is trimethylated in subunit C from bovine mitochondrial ATP synthase
      and in storage bodies associated with batten disease.
AB  - The hydrophobic membrane protein, subunit c, has been isolated from ATP synthase
      purified from bovine heart mitochondria. It has also been obtained from lysosomal
      storage bodies associated with ceroid lipofuscinosis from ovine liver and from
      human brain tissue of a victim of Batten disease. It is likely that the lysosomal
      protein has originated from the mitochondrion. These samples have been
      characterized by mass spectrometric methods. Irrespective of its source, subunit
      c has an intact molecular mass of 7650 Da, 42 Da greater than the value
      calculated from the amino acid sequence, and the protein has been modified post
      translationally. In all three samples, the modification is associated with lysine
      43, which lies in a polar loop region linking the two transmembrane alpha-helices
      of the protein. This residue is conserved throughout vertebrate sequences. The
      additional mass arises from trimethylation and not acetylation at the epsilon-N
      position of the residue. These experiments show that the post-translational
      modification of subunit c is not, as has been suggested, an abnormal phenomenon
      associated with the etiology of Batten disease and ceroid lipofucinoses.
      Evidently, it occurs either before or during import of the protein into
      mitochondria or at a mitochondrial location after completion of the import
      process. The function of the trimethyllysine residue in the assembled ATP
      synthase complex is obscure. The residue and the modification are not conserved
      in all ATP synthases, and their role in the assembly and (or) functioning of the
      enzyme appear to be confined to higher organisms.

PMID- 15010465
TI  - Mechanism of stimulation of ribosomal promoters by binding of the +1 and +2
      nucleotides.
AB  - The rate of transcription of Escherichia coli ribosomal RNA promoters is central
      to adjusting the cellular growth rate to nutritional conditions. The +1
      initiating nucleotide and ppGpp are regulatory effectors of these promoters. The
      data herein show that in vitro transcription is also regulated by the +2
      nucleotide. Both the +1 and +2 nucleotides act by driving polymerase into an
      altered conformation rather than by increasing the lifetime of transcription
      complexes. The unique design of the ribosomal promoters may stabilize a distorted
      state of polymerase that is relieved by the binding of the two nucleotides
      required for transcription initiation.

PMID- 15010466
TI  - Immunological characterization of tristetraprolin as a low abundance, inducible,
      stable cytosolic protein.
AB  - Tristetraprolin (TTP) is a zinc finger protein that can bind to AU-rich elements
      within certain mRNAs, resulting in deadenylation and destabilization of those
      mRNAs. Its physiological targets include the mRNAs encoding the cytokines tumor
      necrosis factor alpha (TNF) and granulocyte-macrophage colony-stimulating factor.
      TTP was originally identified on the basis of its massive but transient increase
      in mRNA levels following mitogen stimulation of fibroblasts. It has been
      difficult to reconcile this transient mRNA profile with the presumed continuing
      "need" for TTP protein, for example, to reverse the effects of lipopolysaccharide
      (LPS)-stimulated TNF secretion. To investigate this and other questions
      concerning endogenous TTP protein in cells and tissues, we raised a high titer
      rabbit antiserum against full-length mouse TTP. TTP could be detected on
      immunoblots of mouse cytosolic tissue extracts; it was most highly expressed in
      spleen, but its concentration in that tissue was only about 1.5 nm. TTP could be
      detected readily in splenic macrophages and stromal cells from LPS-injected rats.
      In both LPS-treated RAW 264.7 macrophages and fetal calf serum-treated mouse
      embryonic fibroblasts, TTP protein was stable after induction, with minimal
      degradation occurring for several hours after treatment of the cells with
      cycloheximide. The biosynthesis of TTP was accompanied by large changes in
      electrophoretic mobility consistent with progressive phosphorylation. Confocal
      microscopy revealed that TTP accumulated in a vesicular pattern in the cytosol of
      the LPS-stimulated RAW 264.7 cells, and was occasionally seen in the cytosol of
      unstimulated dividing cells. Gel filtration of the endogenous protein suggested
      that its predominant structure was monomeric. TTP appears to be a low abundance,
      cytosolic protein in unstimulated cells and tissues, but once induced is
      relatively stable, in contrast to its very labile mRNA.

PMID- 15010467
TI  - A single residue modulates tyrosine dephosphorylation, oligomerization, and
      nuclear accumulation of stat transcription factors.
AB  - The NH(2) terminus of Stat proteins forms a versatile protein interaction domain
      that is believed to use discrete surfaces to mediate oligomerization and tyrosine
      dephosphorylation of Stat dimers. Here we show for Stat1 and Stat5a/b that these
      interfaces overlap and need to be reassigned to an unrelated region of the N
      domain. Unexpectedly, our study showed for Stat1 that defective oligomerization
      of DNA-bound dimers was associated with prolonged interferon-induced nuclear
      accumulation. This uncoupling of DNA binding and nuclear retention was explained
      by the concomitant dephosphorylation deficiency that both Stat1 and Stat5a/b have
      in common and that for Stat1 was due to defective dephosphorylation by the
      phosphatase TC45. Furthermore, diminished N-domain-mediated oligomerization
      affected transcriptional activation by both Stat1 and Stat5a/b in a promoter
      specific manner. DNA binding analysis indicated that oligomerization of Stats on
      DNA may be common, irrespective of the presence of multiple canonical binding
      sites. Accordingly, also transcription from promoters with only a single
      discernable gamma-activated sequence site was negatively effected by reduced
      tetramerization. Thus, these results indicate that defective oligomerization
      cannot generally be compensated for by enhanced tyrosine phosphorylation and
      prolonged nuclear accumulation. In addition, these data clarify the role of DNA
      binding in nuclear retention of Stat1.

PMID- 15010468
TI  - The cyclin-dependent kinase inhibitor p27Kip1 is stabilized in G(0) by
      Mirk/dyrk1B kinase.
AB  - Elevated levels of the cyclin-dependent kinase (CDK) inhibitor p27 block the cell
      in G(0)/G(1) until mitogenic signals activate G(1) cyclins and initiate
      proliferation. Post-translational regulation of p27 by different phosphorylation
      events is critical in allowing cells to proceed through the cell cycle. We now
      demonstrate that the arginine-directed kinase, Mirk/dyrk1B, is maximally active
      in G(0) in NIH3T3 cells, when it stabilizes p27 by phosphorylating it at Ser-10.
      The phospho-mimetic mutant p27-S10D was more stable, and the non-phosphorylatable
      mutant p27-S10A was less stable than wild-type when expressed in G(0)-arrested
      cells. Following phosphorylation by Mirk, p27 remains a functional CDK inhibitor,
      capable of binding to CDK2. Mirk did not induce the translocation of p27 from the
      nucleus in G(0), but instead co-localized with nuclear p27. Depletion of Mirk by
      RNA interference decreased the phosphorylation of p27 at Ser-10 and the stability
      of endogenous p27. RNA(i) to Mirk increased cell entry from G(0) into G(1) as
      shown by increased expression of proliferating cell nuclear antigen and decreased
      expression of p27. These data suggest a model in which Mirk increases the amount
      of nuclear p27 by stabilizing it during G(0) when Mirk is most abundant. Mitogen
      stimulation then causes cells to enter G(1), reduces Mirk levels (Deng, X.,
      Ewton, D., Pawlikowski, B., Maimone, M., and Friedman, E. (2003) J. Biol. Chem.
      278, 41347-41354), and initiates the translocation of p27 to the cytoplasm. In
      addition, depletion of Mirk by RNA(i) in postmitotic C2C12 myoblasts decreased
      protein but not mRNA levels of p27, suggesting that stabilization of p27 by Mirk
      also occurs during differentiation.

PMID- 15010469
TI  - Phosphorylation of histone H2A inhibits transcription on chromatin templates.
AB  - The regulation of gene expression via the histone code has, for the most part,
      revealed that histone modifications cause the recruitment of adaptor proteins
      that indirectly regulate the synthesis of RNA. Using purified factors to assemble
      and modify the chromatin and to transcribe the DNA, we investigated whether
      modifications of histones may directly impact the RNA polymerase II transcription
      process. We screened proteins known to modify histones for effects on
      transcription, and we found that the mitogen- and stress-induced kinase, MSK1,
      inhibited RNA synthesis. Inhibition of transcription by MSK1 was most sensitive
      when the template was in chromatin, as naked DNA templates were resistant to the
      effects of MSK1. We found that MSK1 phosphorylated histone H2A on serine 1, and
      mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1.
      Furthermore, we found that acetylation of histone H3 by the p300 and CREB-binding
      protein associated factor, PCAF, suppressed the kinase-dependent inhibition of
      transcription. These results suggest that acetylation of histones may stimulate
      transcription by suppressing an inhibitory phosphorylation by a kinase as MSK1.

PMID- 15010470
TI  - Polypyrimidine tract-binding protein is involved in vivo in repression of a
      composite internal/3' -terminal exon of the Xenopus alpha-tropomyosin Pre-mRNA.
AB  - The Xenopus alpha(fast)-tropomyosin gene contains, at its 3' -end, a composite
      internal/3' -terminal exon (exon 9A9'), which is subjected to three different
      patterns of splicing according to the cell type. Exon 9A9' is included as a
      terminal exon in the myotome and as an internal exon in adult striated muscles,
      whereas it is skipped in nonmuscle cells. We have developed an in vivo model
      based on transient expression of minigenes encompassing the regulated exon 9A9'
      in Xenopus oocytes and embryos. We first show that the different alpha
      tropomyosin minigenes recapitulate the splicing pattern of the endogenous gene
      and constitute valuable tools to seek regulatory sequences involved in exon 9A9'
      usage. A mutational analysis led to the identification of an intronic element
      that is involved in the repression of exon 9A9' in nonmuscle cells. This element
      harbors four polypyrimidine track-binding protein (PTB) binding sites that are
      essential for the repression of exon 9A9'. We show using UV cross-linking and
      immunoprecipitation experiments that Xenopus PTB (XPTB) interacts with these PTB
      binding sites. Finally, we show that depletion of endogenous XPTB in Xenopus
      embryos using a morpholinobased translational inhibition strategy resulted in
      exon 9A9' inclusion in embryonic epidermal cells. These results demonstrate that
      XPTB is required in vivo to repress the terminal exon 9A9' and suggest that PTB
      could be a major actor in the repression of regulated 3' -terminal exon.

PMID- 15010471
TI  - Dynamic control of cystic fibrosis transmembrane conductance regulator Cl(
      )/HCO3(-) selectivity by external Cl(-).
AB  - HCO(3)(-) secretion is a vital activity in cystic fibrosis transmembrane
      conductance regulator (CFTR)-expressing epithelia. However, the role of CFTR in
      this activity is not well understood. Simultaneous measurements of membrane
      potential and pH(i) and/or current in CFTRexpressing Xenopus oocytes revealed
      dynamic control of CFTR Cl(-)/HCO(3)(-) permeability ratio, which is regulated by
      external Cl(-) (Cl(-)(o)). Thus, reducing external Cl(-) from 110 to 0-10 mm
      resulted in the expected increase in membrane potential, but with no
      corresponding OH(-) or HCO(3)(-) influx. Approximately 3-4 min after reducing
      Cl(o)(-) to 0 mm, an abrupt switch in membrane potential occurs that coincided
      with an increased rates of OH(-) and HCO(3)(-) influx. The switch in membrane
      permeability to OH(-)/HCO(3)(-) can also be recorded as a leftward shift in the
      reversal potential. Furthermore, an increased rate of OH(-) influx in response to
      elevating pH(o) to 9.0 was observed only after the switch in membrane potential.
      The time to switch increased to 11 min at Cl(o)(-) of 5 mm. Conversely, re
      addition of external Cl(-) after the switch in membrane potential did not stop
      HCO(3)(-) influx, which continued for about 3.9 min after Cl(-) addition.
      Importantly, addition of external Cl(-) to cells incubated in Cl(-)-free medium
      never resulted in HCO(3)(-) efflux. Voltage and current clamp experiments showed
      that the delayed HCO(3)(-) transport is electrogenic. These results indicate that
      CFTR exists in two conformations, a Cl(-) only and a Cl(-) and OH(-)/HCO(3)(-)
      permeable state. The switch between the states is controlled by external Cl(-).
      Accordingly, a different tryptic pattern of CFTR was found upon digestion in Cl(
      )-containing and Cl(-)-free media. The physiological significance of these
      finding is discussed in the context of HCO(3)(-) secretion by tissues such as the
      pancreas and salivary glands.

PMID- 15010472
TI  - Formation of molecular complexes by N-methyl-D-aspartate receptor subunit NR2B
      and ryanodine receptor 2 in neonatal rat myocard.
AB  - The N-methyl-d-aspartate (NMDA) receptor is a glutamate gated cation channel
      prevalent in the postsynaptic membranes of central nervous system neurons. The
      neurotransmitter receptor complex is thought to represent a tetramer where
      variable NR2 or NR3 polypeptides form heteromeric assemblies with an obligatory
      NR1 subunit. Recently, we showed that cardiac myocytes from perinatal rats
      transiently express the NMDA receptor subunit NR2B, the function of which in
      heart is unknown. To characterize the cardiac NR2B protein, we determined its
      subcellular distribution and specific molecular interaction partners. By
      immunostaining of rat heart tissue slices and acutely dissociated cardiac
      myocytes, the NR2B antigen was localized at the sarcomeric Z-bands. Using
      immunoprecipitation of detergent-solubilized NR2B protein and subsequent analysis
      employing matrix-assisted laser desorption/ionization time of flight mass
      spectrometry, ryanodine receptor 2 was identified as a molecular interaction
      partner of the cardiac NR2B polypeptide. Differences in antibody recognition
      indicate that the cardiac NR2B polypeptide carries a structurally altered C
      terminus as compared with the NR2B variant prevalent in central nervous system.
      Based on its localization and protein interaction, the function of cardiac NR2B
      protein may relate to mechanosensitivity or play a role in the regulation of the
      contractile apparatus of neonatal heart.

PMID- 15010473
TI  - Sites of protein kinase A activation of the human ClC-2 Cl(-) channel.
AB  - Human ClC-2 Cl(-) (hClC-2) channels are activated by protein kinase A (PKA) and
      low extracellular pH(o). Both of these effects are prevented by the PKA
      inhibitor, myristoylated PKI. The aims of the present study were to identify the
      PKA phosphorylation site(s) important for PKA activation of hClC-2 at neutral and
      low pH(o) and to examine the relationship between PKA and low pH(o) activation.
      Recombinant hClC-2 with point mutations of consensus phosphorylation sites was
      prepared and stably expressed in HEK-293 cells. The responses to forskolin plus
      isobutylmethylxanthine at neutral and acidic pH(o) were studied by whole cell
      patch clamp in the presence and absence of phosphatase inhibitors. The double
      phosphorylation site (RRAT655(A) plus RGET691(A)) mutant hClC-2 lost PKA
      activation and low pH(o) activation. Either RRAT or RGET was sufficient for PKA
      activation of hClC-2 at pH(o) 7.4, as long as phosphatase inhibitors (cyclosporin
      A or endothal) were present. At pH(o) 6 only RGET was needed for PKA activation
      of hClC-2. Low pH(o) activation of hClC-2 Cl(-) channel activity was PKA
      dependent, retained in RGET(A) mutant hClC-2, but lost in RRAT(A) mutant hClC-2.
      RRAT655(D) mutant hClC-2 was constitutively active and was further activated by
      PKA at pH(o) 7.4 and 6.0, consistent with the above findings. These results show
      that activation of hClC-2 is differentially regulated by PKA at two sites,
      RRAT655 and RGET691. Either RRAT655 or RGET691 was sufficient for activation at
      pH(o) 7.4. RGET, but not RRAT, was sufficient for activation at pH(o) 6.0.
      However, in the RGET691(D) mutant, there was PKA activation at pH(o) 6.0.

PMID- 15010474
TI  - NADH oxidation by the Na+-translocating NADH:quinone oxidoreductase from Vibrio
      cholerae: functional role of the NqrF subunit.
AB  - The Na(+)-translocating NADH:quinone oxidoreductase from Vibrio cholerae is a six
      subunit enzyme containing four flavins and a single motif for the binding of a Fe
      S cluster on its NqrF subunit. This study reports the production of a soluble
      variant of NqrF (NqrF') and its individual flavin and Fe-S-carrying domains using
      V. cholerae or Escherichia coli as expression hosts. NqrF' and the flavin domain
      each contain 1 mol of FAD/mol of enzyme and exhibit high NADH oxidation activity
      (20,000 micromol min(-1) mg(-1)). EPR, visible absorption, and circular dichroism
      spectroscopy indicate that the Fe-S cluster in NqrF' and its Fe-S domain is
      related to 2Fe ferredoxins of the vertebrate-type. The addition of NADH to NqrF'
      results in the formation of a neutral flavosemiquinone and a partial reduction of
      the Fe-S cluster. The NqrF subunit harbors the active site of NADH oxidation and
      acts as a converter between the hydride donor NADH and subsequent one-electron
      reaction steps in the Na(+)-translocating NADH:quinone oxidoreductase complex.
      The observed electron transfer NADH --> FAD --> [2Fe-2S] in NqrF requires
      positioning of the FAD and the Fe-S cluster in close proximity in accordance with
      a structural model of the subunit.

PMID- 15010475
TI  - Protease-activated receptor 2 in colon cancer: trypsin-induced MAPK
      phosphorylation and cell proliferation are mediated by epidermal growth factor
      receptor transactivation.
AB  - Several lines of evidence suggest that tumor-derived trypsin contributes to the
      growth and invasion of cancer cells. We have recently shown that trypsin is a
      potent growth factor for colon cancer cells through activation of the G protein
      coupled receptor protease-activated receptor 2 (PAR2). Here, we analyzed the
      signaling pathways downstream of PAR2 activation that lead to colon cancer cell
      proliferation in HT-29 cells. Our data are consistent with the following cascade
      of events upon activation of PAR2 by the serine protease trypsin or the specific
      PAR2-activating peptide (AP2): (i) a matrix metalloproteinase-dependent release
      of transforming growth factor (TGF)-alpha, as demonstrated with TGF-alpha
      blocking antibodies and measurement of TGF-alpha in culture medium; (ii) TGF
      alpha-mediated activation of epidermal growth factor receptor (EGF-R) and
      subsequent EGF-R phosphorylation; and (iii) activation of ERK1/2 and subsequent
      cell proliferation. The links between these events are demonstrated by the fact
      that stimulation of cell proliferation and ERK1/2 upon activation of PAR2 is
      reversed by the metalloproteinase inhibitor batimastat, TGF-alpha-neutralizing
      antibodies, EGF-R ligand binding domain-blocking antibodies, and the EGF-R
      tyrosine kinase inhibitors AG1478 and PD168393. Therefore, transactivation of EGF
      R appears to be a major mechanism whereby activation of PAR2 results in colon
      cancer cell growth. By using the Src tyrosine kinase inhibitor PP2, we further
      showed that Src plays a permissive role for PAR2-mediated ERK1/2 activation and
      cell proliferation, probably acting downstream of the EGF-R. These data explain
      how trypsin exerts robust trophic action on colon cancer cells and underline the
      critical role of EGF-R transactivation.

PMID- 15010477
TI  - Passive tools for enhancing muscle-driven motion and locomotion.
AB  - Musculo-skeletal systems and body design in general have evolved to move
      effectively and travel in specific environments. Humans have always aspired to
      reach higher power movement and to locomote safely and fast, even through
      unfamiliar media (air, water, snow, ice). For the last few millennia, human
      ingenuity has led to the invention of a variety of passive tools that help to
      compensate for the limitations in their body design. This Commentary discusses
      many of those tools, ranging from halteres used by athletes in ancient Greece, to
      bows, skis, fins, skates and bicycles, which are characterised by not supplying
      any additional mechanical energy, thus retaining the use of muscular force alone.
      The energy cascade from metabolic fuel to final movement is described, with
      particular emphasis on the steps where some energy saving and/or power
      enhancement is viable. Swimming is used to illustrate the efficiency breakdown in
      complex locomotion, and the advantage of using fins. A novel graphical
      representation of world records in different types of terrestrial and aquatic
      locomotion is presented, which together with a suggested method for estimating
      their metabolic cost (energy per unit distance), will illustrate the success of
      the tools used.

PMID- 15010476
TI  - A subpopulation of platelets responds to thrombin- or SFLLRN-stimulation with
      binding sites for factor IXa.
AB  - Strong agonists cause platelets to expose a procoagulant surface supporting the
      assembly of two important coagulation enzyme complexes. Equilibrium binding has
      determined the density of high affinity saturable factor IXa binding sites to be
      500-600 sites/platelet. We have now used flow cytometry to visualize the binding
      of factor IX and IXa to thrombin- or SFLLRN-activated platelets. Concentrations
      of these agonists that are half-maximal or maximal in kinetic studies resulted in
      only a small subpopulation (4-20%) of platelets binding factor IX or IXa with the
      density of binding sites for factor IX being about half of that for factor IXa,
      consistent with previous equilibrium binding studies. A small subpopulation (5 +/
      1.5%) of platelets stimulated with either agonist also exposed annexin V binding
      sites, and this subpopulation of platelets also bound factor IXa. Annexin V
      decreased factor IXa binding in the presence or absence of factor VIIIa, and
      factor IXa could also decrease annexin V binding on some platelets indicating a
      common binding site in agreement with previous studies. All platelets binding
      factor IXa were positive for glycoprotein IX, at the same glycoprotein IX surface
      density as seen in platelets negative for factor IXa binding. These studies
      refine the results from equilibrium binding studies and suggest that, on average,
      only a small subpopulation (approximately 10%) of PAR 1-stimulated platelets
      expose approximately 6000 factor IXa binding sites/platelet.

PMID- 15010478
TI  - Stick insect locomotion in a complex environment: climbing over large gaps.
AB  - In a complex environment, animals are challenged by various types of obstacles.
      This requires the controller of their walking system to be highly flexible. In
      this study, stick insects were presented with large gaps to cross in order to
      observe how locomotion can be adapted to challenging environmental situations.
      Different approaches were used to investigate the sequence of gap-crossing
      behaviour. A detailed video analysis revealed that gap-crossing behaviour
      resembles modified walking behaviour with additional step types. The walking
      sequence is interrupted by an interval of exploration, in which the insect probes
      the gap space with its antennae and front legs. When reaching the gap, loss of
      contact of an antenna with the ground does not elicit any observable reactions.
      In contrast, an initial front leg step into the gap that often follows antennal
      'non-contact' evokes slowing down of stance velocity. An ablation experiment
      showed that the far edge of the gap is detected by tactile antennal stimulation
      rather than by vision. Initial contact of an antenna or front leg with the far
      edge of the gap represents a 'point of no return', after which gap crossing is
      always successfully completed. Finally, flow chart diagrams of the gap-crossing
      sequence were constructed based on an ethogram of single elements of behaviour.
      Comparing flow charts for two gap sizes revealed differences in the frequency and
      succession of these elements, especially during the first part of the sequence.

PMID- 15010479
TI  - Metabolism of the sub-Antarctic caterpillar Pringleophaga marioni during cooling,
      freezing and thawing.
AB  - Although general models of the processes involved in insect survival of freezing
      exist, there have been few studies directly investigating physiological processes
      during cooling, freezing and thawing, without which these models remain
      hypothetical. Here, we use open-flow respirometry to investigate the metabolism
      of the freeze-tolerant sub-Antarctic caterpillar Pringleophaga marioni Viette
      (Lepidoptera: Tineidae) during cooling, freezing and thawing and to compare
      animals exposed to non-lethal (-5.8 degrees C) and lethal (-6.0 degrees C, after
      which caterpillars are moribund for several days, and -18 degrees C, after which
      caterpillars are completely unresponsive) freezing stress. We found a large
      decrease in metabolic rate (that is not associated with freezing) at -0.6+/-0.1
      degrees C and calculated a Q10 of 2.14 x 10(3) at this breakpoint. This
      breakpoint is coincident with the critical thermal minimum (CTmin) and is
      hypothesised to be a metabolic manifestation of the latter, possibly a failure of
      the Na+/K(+)-ATPase pump. This provides a plausible link between processes at the
      cellular level and observations of the action of the CTmin at tissue and whole
      organism levels. Caterpillars froze at -4.6+/-0.1 degrees C and had detectable
      metabolism when frozen. Post-thaw, metabolic rates were lower than pre-freezing
      measurements. Post-thaw metabolic rates did not differ between temperatures that
      did and did not kill the caterpillars, which suggests that mortality may be a
      result of a breakdown in processes at the organismal, rather than cellular, level
      of organisation.

PMID- 15010480
TI  - Nitric oxide control of the dorsal aorta and the intestinal vein of the
      Australian short-finned eel Anguilla australis.
AB  - This study investigated the mechanisms by which nitric oxide (NO) regulates the
      dorsal aorta and the intestinal vein of the Australian short-finned eel Anguilla
      australis. NADPH diaphorase histochemistry and immunohistochemistry using a
      mammalian endothelial nitric oxide synthase (NOS) antibody could not demonstrate
      NOS in the endothelium of either blood vessel; however, NOS could be readily
      demonstrated in the endothelium of the rat aorta that was used as a control. Both
      blood vessels contained NADPH diaphorase positive nerve fibres and nerve bundles,
      and immunohistochemistry using a neural NOS antibody showed a similar
      distribution of neural NOS immunoreactivity in the perivascular nerves. In vitro
      organ bath physiology showed that a NO/soluble guanylyl cyclase (GC) system is
      present in the dorsal aorta and the intestinal vein, since the soluble GC
      inhibitor oxadiazole quinoxalin-1 (ODQ; 10(-5) mol l(-1)) completely abolished
      the vasodilatory effect of the NO donor, sodium nitroprusside (SNP; 10(-4) mol l(
      1)). In addition, nicotine (3 x 10(-4) mol l(-1)) mediated a vasodilation that
      was not affected by removal of the endothelium. The nicotine-mediated dilation
      was blocked by the NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA; 10(-4) mol l(
      1)), and ODQ (10(-5) mol l(-1)). More specifically, the neural NOS inhibitor,
      N(omega)-propyl-L-arginine (10(-5) mol l(-1)), significantly decreased the
      dilation induced by nicotine (3 x 10(-4) mol l(-1)). Furthermore, indomethacin
      (10(-5) mol l(-1)) did not affect the nicotine-mediated dilation, suggesting that
      prostaglandins are not involved in the response. Finally, the calcium ionophore
      A23187 (3 x 10(-6) mol l(-1)) caused an endothelium-dependent dilation that was
      abolished in the presence of indomethacin. We propose the absence of an
      endothelial NO system in eel vasculature and suggest that neurally derived NO
      contributes to the maintenance of vascular tone in this species. In addition, we
      suggest that prostaglandins may act as endothelially derived relaxing factors in
      A. australis.

PMID- 15010481
TI  - Independent effects of heart-head distance and caudal blood pooling on blood
      pressure regulation in aquatic and terrestrial snakes.
AB  - Changes in orientation in a gravitational field markedly alter the patterns of
      blood pressure and flow in animals, especially tall or long ones such as giraffes
      or snakes. Vertical orientation tends to reduce blood flow and pressure in the
      head for two major reasons. First, the increased vertical blood column above the
      heart creates a gravitational hydrostatic pressure against which the heart must
      work. Second, expansion of dependent vessels in the lower extremities causes
      blood pooling and reduces return of venous blood to the heart, thereby lowering
      flow and pressure. For most animals, it is difficult to separate these two
      effects, but snakes offer the possibility of bending the animal in the region of
      the heart and manipulating the two ends of the body independently. We studied
      baroregulatory responses in terrestrial pythons (Liasis fuscus) and aquatic file
      snakes (Acrochordus arafurae) by tilting only the front or rear parts and then
      the whole animal. Changes in head blood pressure during partial tilts added up to
      the change during full tilt. The vertical distance to the head had twice as much
      influence on head blood pressure than did blood pooling in the pythons and four
      times as much in file snakes. This accounts for the cephalad location of the
      heart in terrestrial species compared with aquatic ones.

PMID- 15010482
TI  - Chemical defense of an opilionid (Acanthopachylus aculeatus).
AB  - The opilionid Acanthopachylus aculeatus was shown to produce a defensive
      secretion containing quinones (2,3-dimethyl-1,4-benzoquinone, 2,5-dimethyl-1,4
      benzoquinone and 2,3,5-trimethyl-1,4-benzoquinone), confirming the findings
      reported nearly a half century ago in a classic study. The mechanism by which the
      opilionid puts the secretion to use is described. When disturbed, the animal
      regurgitates enteric fluid, which it conveys by intercoxal clefts to the
      anterolateral corners of the carapace, where the two gland openings are situated.
      It then injects some of its quinonoid secretion into the fluid, and conveys the
      mixed liquid along the length of its flanks by way of two special channels. Such
      a discharge mechanism may be widespread among opilionids of the family
      Gonyleptidae (suborder Laniatores), to which A. aculeatus belongs. In a bioassay
      based on a scratch reflex in decapitated cockroaches (Periplaneta americana) the
      liquid effluent of A. aculeatus was shown to be potently irritating. Use of the
      effluent was demonstrated to protect the opilionid against ants (Formica
      exsectoides). Wolf spiders (Lycosa ceratiola) were shown to be minimally affected
      by the effluent (they showed little response when the fluid was added to their
      mouthparts as they fed on mealworms, their normal laboratory prey), although they
      proved to be aversive to mere contact with the opiliond itself, and to reject the
      animal without inducing it to discharge. A. aculeatus may therefore contain
      distasteful factors besides its glandular products.

PMID- 15010483
TI  - Structure-function analysis of the cysteine string protein in Drosophila:
      cysteine string, linker and C terminus.
AB  - Cysteine string proteins (CSPs) are conserved secretory vesicle proteins involved
      in regulating neurotransmitter and peptide release. While the function of the J
      domain has been studied in detail, little is known about other conserved regions.
      We have constructed mutant genes coding for proteins with modified cysteine
      string, linker region or C terminus and transformed them into Csp null-mutant
      Drosophila: In the living animal, mutated CSP lacking all cysteines fails to
      associate with membranes, does not concentrate in synaptic terminals, and cannot
      rescue adult temperature-sensitive paralysis and short life span, both prominent
      null mutant phenotypes. A mutant protein with 5 instead of 11 string cysteines
      appears to be normally targeted but cannot rescue paralysis at 37 degrees C. We
      propose that the cysteine string, in addition to its role in targeting, may be
      essential for a function of CSP that is dependent on the number of cysteines in
      the string. A deletion in the linker region or the C terminus does not affect CSP
      targeting, and function in adults is only marginally impaired.

PMID- 15010484
TI  - Mitochondria-rich cell activity in the yolk-sac membrane of tilapia (Oreochromis
      mossambicus) larvae acclimatized to different ambient chloride levels.
AB  - Mitochondria-rich cells (MRCs) in the yolk-sac membrane of tilapia (Oreochromis
      mossambicus) larvae were examined by Na+/K(+)-ATPase immunocytochemistry and
      vital staining for glycoproteins following acclimation to high (7.5-7.9 mmol l(
      1)), normal (0.48-0.52 mmol l(-1)) or low (0.002-0.007 mmol l(-1)) ambient Cl-
      levels. With a combination of concanavalin-A (Con-A)-Texas-Red conjugate staining
      (larvae exposed to the dye in vivo in the water) and a monoclonal antibody raised
      against Na+/K(+)-ATPase, MRCs were easily recognized and presumed to be active
      when Con-A-positive (i.e. with their apical membrane in contact with the water)
      or inactive when Con-A-negative. The proportion of active cells gradually
      increased during a 48-h acclimation to low-Cl- medium but decreased during
      acclimation to high-Cl- medium. Total densities of MRCs did not change when
      ambient chloride levels were altered. Furthermore, in live larvae exposed to
      changes in ambient Cl-, yolk-sac MRCs, vitally stained with DASPEI and
      subsequently traced in time, did not significantly alter turnover. The
      polymorphism of the apical membrane compartment of the MRCs represents structural
      modification of the active MRCs. Yolk-sac pavement cells labeled with the
      membrane marker FM1-43 (fluorescent lipophilic tracer) were shown to cover active
      MRCs in larvae transferred from normal to high ambient Cl- levels, thereby
      inactivating the MRCs.

PMID- 15010485
TI  - Take-off mechanics in hummingbirds (Trochilidae).
AB  - Initiating flight is challenging, and considerable effort has focused on
      understanding the energetics and aerodynamics of take-off for both machines and
      animals. For animal flight, the available evidence suggests that birds maximize
      their initial flight velocity using leg thrust rather than wing flapping. The
      smallest birds, hummingbirds (Order Apodiformes), are unique in their ability to
      perform sustained hovering but have proportionally small hindlimbs that could
      hinder generation of high leg thrust. Understanding the take-off flight of
      hummingbirds can provide novel insight into the take-off mechanics that will be
      required for micro-air vehicles. During take-off by hummingbirds, we measured
      hindlimb forces on a perch mounted with strain gauges and filmed wingbeat
      kinematics with high-speed video. Whereas other birds obtain 80-90% of their
      initial flight velocity using leg thrust, the leg contribution in hummingbirds
      was 59% during autonomous take-off. Unlike other species, hummingbirds beat their
      wings several times as they thrust using their hindlimbs. In a phylogenetic
      context, our results show that reduced body and hindlimb size in hummingbirds
      limits their peak acceleration during leg thrust and, ultimately, their take-off
      velocity. Previously, the influence of motivational state on take-off flight
      performance has not been investigated for any one organism. We studied the full
      range of motivational states by testing performance as the birds took off: (1) to
      initiate flight autonomously, (2) to escape a startling stimulus or (3) to
      aggressively chase a conspecific away from a feeder. Motivation affected
      performance. Escape and aggressive take-off featured decreased hindlimb
      contribution (46% and 47%, respectively) and increased flight velocity. When
      escaping, hummingbirds foreshortened their body movement prior to onset of leg
      thrust and began beating their wings earlier and at higher frequency. Thus,
      hummingbirds are capable of modulating their leg and wingbeat kinetics to
      increase take-off velocity.

PMID- 15010486
TI  - Accumulation and translation of ferritin heavy chain transcripts following anoxia
      exposure in a marine invertebrate.
AB  - Differential screening of a Littorina littorea (the common periwinkle) cDNA
      library identified ferritin heavy chain as an anoxia-induced gene in
      hepatopancreas. Northern blots showed that ferritin heavy chain transcript levels
      were elevated twofold during anoxia exposure, although nuclear run-off assays
      demonstrated that ferritin heavy chain mRNAs were not transcriptionally
      upregulated during anoxia. Polysome analysis indicated that existing ferritin
      transcripts were actively translated during the anoxic period. This result was
      confirmed via western blotting, which demonstrated a twofold increase in ferritin
      heavy chain protein levels during anoxia, with a subsequent decrease to control
      levels during normoxic recovery. Organ culture experiments using hepatopancreas
      slices demonstrated a >50% increase in ferritin heavy chain transcript levels in
      vitro under conditions of anoxia and freezing, as well as after incubation with
      the second messenger cGMP. Taken together, these results suggest that ferritin
      heavy chain is actively regulated during anoxia exposure in the marine snail, L.
      littorea.

PMID- 15010487
TI  - Contribution of eye retraction to swallowing performance in the northern leopard
      frog, Rana pipiens.
AB  - Most anurans retract and close their eyes repeatedly during swallowing. Eye
      retraction may aid swallowing by helping to push food back toward the esophagus,
      but this hypothesis has never been tested. We used behavioral observations,
      cineradiography, electromyography and nerve transection experiments to evaluate
      the contribution of eye retraction to swallowing in the northern leopard frog,
      Rana pipiens. Behavioral observations of frogs feeding on 1.5 cm long crickets
      reveal a high degree of variability in eye retraction and swallowing. Eye
      retraction can occur bilaterally or unilaterally, and both swallowing movements
      and eye retraction can occur separately as well as together. During swallowing,
      cineradiography shows that the eyes and associated musculature retract well into
      the oropharynx and appear to make contact with the prey item. This contact
      appears to help push the prey toward the esophagus, and it may also serve to
      anchor the prey for tongue-based transport. Electromyographic recordings confirm
      strong activity in the retractor bulbi muscles during eye retraction. After
      bilateral denervation of the retractor bulbi, frogs maintain the ability to
      swallow but show a 74% increase in the number of swallows required per cricket
      (from a mean of 2.3 swallows to a mean of 4.0 swallows per cricket). Our results
      indicate that, in Rana pipiens feeding on medium-sized crickets, eye retraction
      is an accessory swallowing mechanism that assists the primary tongue-based
      swallowing mechanism.

PMID- 15010488
TI  - Effect of beta-adrenergic stimulation on the relationship between membrane
      potential, intracellular [Ca2+] and sarcoplasmic reticulum Ca2+ uptake in rainbow
      trout atrial myocytes.
AB  - Long depolarizations cause a steady tonic contraction and induce sarcoplasmic
      reticulum (SR) Ca(2+)-uptake in trout atrial myocytes. Simultaneous measurements
      of cytosolic [Ca2+] ([Ca2+]i) and whole membrane current showed an elevated
      [Ca2+]i throughout the depolarization. Rapid caffeine (Caf) applications at -80
      mV before and after a long depolarization were used to determine SR Ca2+ loading
      and its dependency on membrane potential and [Ca2+]i during depolarization.
      Following a 10 s depolarization, the maximal SR Ca2+ load was 597 micromol l(-1)
      and loading was half-maximal at -12 mV. The beta-adrenergic agonist isoproterenol
      (ISO) did not affect the maximal SR Ca2+ loading but shifted the potential for
      half-maximal loading by -26 mV. Following a 3 s depolarization, the maximal SR
      Ca2+ uptake rate (Vmax) was 418 micromol l(-1) s(-1) in control conditions. ISO
      did not affect Vmax, but significantly lowered the average free Ca2+ transient
      during the depolarization and shifted the K(0.5) for the relationship between SR
      Ca2+ uptake and [Ca2+]i from 1.27 in control to 0.8 micromol l(-1) with ISO.
      Following repetitive 200 ms depolarizations, ISO increased the L-type Ca2+
      current (ICa) amplitude by 91+/-29% and the peak Ca2+ transient by 41+/-10%, and
      decreased the half life of the Ca2+ transient from 151+/-12 to 111+/-6 ms. Using
      the relationship between [Ca2+]i and SR Ca2+ uptake to calculate the total SR
      Ca2+ uptake during a Ca2+ transient elicited by a 200 ms depolarization, a
      significant increase in the SR Ca2+ uptake from 37+/-6 micromol l(-1) in control
      to 68+/-4 micromol l(-1) with ISO was seen. When normalized to the total Ca2+
      transport the contribution of the SR was not significantly different in the
      absence (35+/-6%) or presence of ISO (41+/-4%). Exposure of cells to ISO and low
      extracellular [Ca2+] increased ICa by 67+/-40% (N=5) but significantly reduced SR
      Ca2+ uptake at membrane potentials above -30 mV. Together, these results suggest
      that (i) ISO has a stimulatory effect on the SR Ca2+ pump that may contribute to
      the faster decay of the Ca2+ transient, and (ii) the relative contribution of the
      SR to the Ca2+ removal during relaxation is not altered by ISO in trout atrial
      myocytes.

PMID- 15010489
TI  - Ventilatory compensation of the alkaline tide during digestion in the snake Boa
      constrictor.
AB  - The increased metabolic rate during digestion is associated with changes in
      arterial acid-base parameters that are caused by gastric acid secretion (the
      'alkaline tide'). Net transfer of HCl to the stomach lumen causes an increase in
      plasma HCO3- levels, but arterial pH does not change because of a ventilatory
      compensation that counters the metabolic alkalosis. It seems, therefore, that
      ventilation is controlled to preserve pH and not PCO2 during the postprandial
      period. To investigate this possibility, we determined arterial acid-base
      parameters and the metabolic response to digestion in the snake Boa constrictor,
      where gastric acid secretion was inhibited pharmacologically by oral
      administration of omeprazole. The increase in oxygen consumption of omeprazole
      treated snakes after ingestion of 30% of their own body mass was quantitatively
      similar to the response in untreated snakes, although the peak of the metabolic
      response occurred later (36 h versus 24 h). Untreated control animals exhibited a
      large increase in arterial plasma HCO3- concentration of approximately 12 mmol l(
      1), but arterial pH only increased by 0.12 pH units because of a simultaneous
      increase in arterial PCO2 by about 10 mmHg. Omeprazole virtually abolished the
      changes in arterial pH and plasma HCO3- concentration during digestion and there
      was no increase in arterial PCO2. The increased arterial PCO2 during digestion is
      not caused, therefore, by the increased metabolism during digestion or a lower
      ventilatory responsiveness to ventilatory stimuli during a presumably relaxed
      state in digestion. Furthermore, the constant arterial PCO2, in the absence of an
      alkaline tide, of omeprazole-treated snakes strongly suggests that pH rather than
      PCO2 normally affects chemoreceptor activity and ventilatory drive.

PMID- 15010490
TI  - The occurrence of two types of hemopexin-like protein in medaka and differences
      in their affinity to heme.
AB  - Full-length cDNA clones encoding two types of hemopexin-like protein, mWap65-1
      and mWap65-2, were isolated from the HNI inbred line of medaka Oryzias latipes.
      The deduced amino acid sequence of mWap65-2 resembled mammalian hemopexins more
      closely than that of mWap65-1. Histidine residues required for the high affinity
      of hemopexins for hemes were conserved in mWap65-2, but not in mWap65-1.
      Surprisingly, mWap65-1, but not mWap65-2, showed heme-binding ability as revealed
      by hemin-agarose affinity chromatography, even though mWap65-1 lacked the
      essential histidine residues. Furthermore, RT-PCR analysis of different tissues
      demonstrated that the transcripts of mWap65-2 were restricted to liver, whereas
      those of mWap65-1 were found in various tissues including liver, eye, heart and
      brain. Quantitative RT-PCR revealed that transcripts of mWap65-2 were expressed
      earlier than those of mWap65-1 during ontogeny. However, the accumulated mRNA
      levels of both mWap65-1 and mWap65-2 did not differ significantly in fish
      acclimated to either 10 degrees C or 30 degrees C for 5 weeks. These
      characteristics suggest that the two proteins have different physiological
      functions and that mWap65-2 is not a hemopexin.

PMID- 15010491
TI  - Physiological, biochemical and morphological indicators of osmoregulatory stress
      in 'California' Mozambique tilapia (Oreochromis mossambicus x O. urolepis
      hornorum) exposed to hypersaline water.
AB  - The salinity tolerance of the 'California' Mozambique tilapia (Oreochromis
      mossambicus x O. urolepis hornorum), a current inhabitant of the hypersaline
      Salton Sea in California, USA, was investigated to identify osmoregulatory stress
      indicators for possible use in developing a model of salinity tolerance. Seawater
      acclimated (35 g l(-1)) tilapia hybrids were exposed to salinities from 35-95 g
      l(-1), using gradual and direct transfer protocols, and physiological (plasma
      osmolality, [Na+], [Cl-], oxygen consumption, drinking rate, hematocrit, mean
      cell hemoglobin concentration, and muscle water content), biochemical (Na+, K(+)
      ATPase) and morphological (number of mature, accessory, immature and apoptotic
      chloride cells) indicators of osmoregulatory stress were measured. Tilapia
      tolerated salinities ranging from 35 g l(-1) to 65 g l(-1) with little or no
      change in osmoregulatory status; however, in fish exposed to 75-95 g l(-1)
      salinity, plasma osmolality, [Na+], [Cl-], Na+, K(+)-ATPase, and the number of
      apoptotic chloride cells, all showed increases. The increase in apoptotic
      chloride cells at salinities greater than 55 g l(-1), prior to changes in
      physiological and biochemical parameters, indicates that it may be the most
      sensitive indicator of osmoregulatory stress. Oxygen consumption decreased with
      salinity, indicating a reduction in activity level at high salinity. Finally,
      'California' Mozambique tilapia have a salinity tolerance similar to that of pure
      Mozambique tilapia; however, cellular necrosis at 95 g l(-1) indicates they may
      be unable to withstand extreme salinities for extended periods of time.

PMID- 15010492
TI  - Effect of serotonin on ciliary beating and intracellular calcium concentration in
      identified populations of embryonic ciliary cells.
AB  - Embryos of the pond snail Helisoma trivolvis express three known subtypes of
      ciliary cells on the surface of the embryo early in development: pedal,
      dorsolateral and scattered single ciliary cells (SSCCs). The pedal and
      dorsolateral ciliary cells are innervated by a pair of serotonergic sensory-motor
      neurons and are responsible for generating the earliest whole-animal behavior,
      rotation within the egg capsule. Previous cell culture studies on unidentified
      ciliary cells revealed that serotonin (5-hydroxytryptamine; 5-HT) produces a
      significant increase in the ciliary beat frequency (CBF) in a large proportion of
      ciliary cells. Both Ca2+ influx and a unique isoform of protein kinase C (PKC)
      were implicated in the signal transduction pathway underlying the cilio
      excitatory response to 5-HT. The goal of the present study was to characterize
      the anatomical and physiological differences between the three known populations
      of superficial ciliary cells. The pedal and dorsolateral ciliary cells shared
      common structural characteristics, including flat morphology, dense cilia and
      lateral accessory ciliary rootlets. By contrast, the SSCCs had a cuboidal
      morphology, reduced number of cilia, increased ciliary length and absence of
      lateral accessory rootlets. In cultures containing unidentified ciliary cells,
      the calcium/calmodulin-dependent enzyme inhibitor calmidazolium (2 micromol l(
      1)) blocked the stimulatory effect of 5-HT (100 micromol l(-1)) on CBF. In
      addition, 50% of unidentified cultured cells responded to 5-HT (100 micromol l(
      1)) with an increase in [Ca2+]i. To facilitate the functional analyses of the
      individual populations, we developed a method to culture identified ciliary
      subtypes and characterized their ciliary and calcium responses to 5-HT. In
      cultures containing either pedal or dorsolateral ciliary cells, 5-HT (100
      micromol l(-1)) produced a rapid increase in CBF and a slower increase in [Ca2+]i
      in all cells examined. By contrast, the CBF and [Ca2+]i of SSCCs were not
      affected by 100 micromol l(-1) 5-HT. Immunohistochemistry for two putative 5-HT
      receptors recently cloned from Helisoma revealed that pedal and dorsolateral
      ciliary cells consistently express the 5-HT(1Hel) protein. Intense 5-HT(7Hel)
      immunoreactivity was observed in only a subset of pedal and dorsolateral ciliary
      cells. Cells neighboring the SSCCs, but not the ciliary cells themselves,
      expressed 5-HT(1Hel) and 5-HT(7Hel) immunoreactivity. These data suggest that the
      pedal and dorsolateral ciliary cells, but not the SSCCs are a homogeneous
      physiological subtype that will be useful for elucidating the signal transduction
      mechanisms underlying 5-HT induced cilio-excitation.

PMID- 15010493
TI  - Catching for real and catching for fun in ecological psychology. Focus on
      "Internal models of target motion: expected dynamics overrides measured
      kinematics in timing manual interceptions".

PMID- 15010494
TI  - Homeland defense begins in precentral cortex. Focus on "Sensorimotor integration
      in the precentral gyrus: polysensory neurons and defensive movements".

PMID- 15010496
TI  - Neural correlates of beauty.
AB  - We have used the technique of functional MRI to address the question of whether
      there are brain areas that are specifically engaged when subjects view paintings
      that they consider to be beautiful, regardless of the category of painting (that
      is whether it is a portrait, a landscape, a still life, or an abstract
      composition). Prior to scanning, each subject viewed a large number of paintings
      and classified them into beautiful, neutral, or ugly. They then viewed the same
      paintings in the scanner. The results show that the perception of different
      categories of paintings are associated with distinct and specialized visual areas
      of the brain, that the orbito-frontal cortex is differentially engaged during the
      perception of beautiful and ugly stimuli, regardless of the category of painting,
      and that the perception of stimuli as beautiful or ugly mobilizes the motor
      cortex differentially.

PMID- 15010495
TI  - Developmental changes in pedunculopontine nucleus (PPN) neurons.
AB  - The developmental decrease in rapid-eye-movement (REM) sleep in man occurs
      between birth and after puberty. We hypothesize that if this decrease in REM
      sleep does not occur, lifelong increases in REM sleep drive may ensue. Such
      disorders are characterized by hypervigilance and sensory-gating deficits, such
      as are present in postpubertal onset disorders like schizophrenia, panic attacks
      (a form of anxiety disorder), and depression. The decrease in REM sleep in the
      rat occurs between 10 and 30 days of age. We studied changes in size and
      physiological properties of pedunculopontine nucleus (PPN) cells involved in the
      control of arousal, i.e., waking and REM sleep. During the largest decrease in
      REM sleep (12-21 days), cholinergic PPN neurons doubled in cell area, the
      hypertrophy peaking at 15-16 days, then decreasing in area by 20-21 days.
      Noncholinergic PPN cells did not change in area during this period. We confirmed
      the presence of two populations of PPN neurons based on action potential (AP)
      duration, with the proportion of short-AP-duration cells increasing and long AP
      duration decreasing between 12 and 21 days. Most cholinergic and noncholinergic
      cells had short AP durations. Afterhyperpolarization (AHP) duration became
      segregated into long and short AHP duration after 15 days. Cells with short AP
      duration also had short AHP duration. The proportion of PPN cells with Ih current
      increased gradually, peaking at 15 days, then decreased by 21 days. These changes
      in morphological and physiological properties are discussed in relation to the
      developmental decrease in REM sleep.

PMID- 15010498
TI  - Statistical method for detection of phase-locking episodes in neural
      oscillations.
AB  - In many networks of oscillatory neurons, synaptic interactions can promote the
      entrainment of units into phase-coupled groups. The detection of synchrony in
      experimental data, especially if the data consist of single-trial runs, can be
      problematic when, for example, phase entrainment is of short duration, buried in
      noise, or masked by amplitude fluctuations that are uncorrelated among the
      oscillating units. In the present study, we tackle the problem of detecting
      neural interactions from pairs of oscillatory signals in a narrow frequency band.
      To avoid the interference of amplitude fluctuations in the detection of
      synchrony, we extract a phase variable from the data and utilize statistical
      indices to measure phase locking. We use three different phase-locking indices
      based on coherence, entropy, and mutual information between the phase variables.
      Phase-locking indices are calculated over time using sliding analysis windows. By
      varying the duration of the analysis windows, we were able to inspect the data at
      different levels of temporal resolution and statistical reliability. The
      statistical significance of high index values was evaluated using four different
      surrogate data methods. We determined phase-locking indices using alternative
      methods for generating surrogate data and found that results are sensitive to the
      particular method selected. Surrogate methods that preserve the temporal
      structure of the individual phase time series decrease substantially the number
      of false positives when tested on a pair of independent signals.

PMID- 15010497
TI  - Organization of the intermediate gray layer of the superior colliculus. I.
      Intrinsic vertical connections.
AB  - A pathway from the superficial visual layers to the intermediate premotor layers
      of the superior colliculus has been proposed to mediate visually guided orienting
      movements. In these experiments, we combined photostimulation using "caged"
      glutamate with in vitro whole cell patch-clamp recording to demonstrate this
      pathway in the rat. Photostimulation in the superficial gray and optic layers
      (SGS and SO, respectively) evoked synaptic responses in intermediate gray layer
      (SGI) cells. The responses comprised individual excitatory postsynaptic currents
      (EPSCs) or EPSC clusters. Blockade of these EPSCs by TTX confirmed that they were
      synaptically mediated. Stimulation within a column (approximately 500 microm
      diam) extending superficially from the recorded cell evoked the largest and most
      reliable responses, but off-axis stimuli were effective as well. The EPSCs could
      be evoked by stimuli 1,000 microm off-axis from the postsynaptic neuron. The
      dimensions of this wider region (approximately 2 mm diam) corresponded to those
      of the dendrites of superficial layer wide-field neurons. SGI neurons differed in
      their input from SGS and SO; neurons in the middle of the intermediate layer
      (SGIb) were less likely to respond to visual layer photostimulation than were
      those in sublayers just above and below them. However, focal stimulation within
      SGIa did evoke responses within SGIb, indicating that SGIb neurons may receive
      input from the visual layers indirectly. These results demonstrate a columnar
      pathway that may mediate visually guided orienting movements, but the results
      also reveal spatial attributes of the pathway which imply that it also plays a
      more complex role in visuomotor integration.

PMID- 15010499
TI  - Recursive bayesian decoding of motor cortical signals by particle filtering.
AB  - The population vector (PV) algorithm and optimal linear estimation (OLE) have
      been used to reconstruct movement by combining signals from multiple neurons in
      the motor cortex. While these linear methods are effective, recursive Bayesian
      decoding schemes, which are nonlinear, can be more powerful when probability
      model assumptions are satisfied. We have implemented a recursive Bayesian
      algorithm for reconstructing hand movement from neurons in the motor cortex. The
      algorithm uses a recently developed numerical method known as "particle
      filtering" and follows the same general strategy as that used by Brown et al. to
      reconstruct the path of a foraging rat from hippocampal place cells. We
      investigated the method in a numerical simulation study in which neural firing
      rate was assumed to be positive, but otherwise a linear function of movement
      velocity, and preferred directions were not uniformly distributed. In terms of
      mean-squared error, the approach was approximately 10 times more efficient than
      the PV algorithm and 5 times more efficient than OLE. Thus use of recursive
      Bayesian decoding can achieve the accuracy of the PV algorithm (or OLE) with
      approximately 10 times (or 5 times) fewer neurons. The method was also used to
      reconstruct hand movement in an ellipse-drawing task from 258 cells in the
      ventral premotor cortex. Recursive Bayesian decoding was again more efficient
      than the PV and OLE methods, by factors of roughly seven and three, respectively.

PMID- 15010500
TI  - Amiloride kills malignant glioma cells independent of its inhibition of the
      sodium-hydrogen exchanger.
AB  - Previously, we demonstrated that malignant glioma cell lines have increased
      intracellular pH (pHi) as a result of increased activities of the type I
      sodium/hydrogen exchanger (NHE1). This alkalotic pHi of 7.2 to 7.4 is favorable
      for augmented glycolysis, DNA synthesis, and cell cycle progression. Conversely,
      reductions in pHi have been associated with reduced rates of proliferation in
      transformed cell types. The effects of reducing pHi directly and by NHE1
      inhibition on human malignant glioma cells were systematically compared with
      those on primary rat astrocytes. Neither cariporide, nor direct acidification to
      pHi 6.9 altered the proliferative rates or viabilities of human U87 or U118
      malignant glioma cell lines. However, amiloride significantly impaired glioma
      cell proliferation and viability while not affecting astrocytes at concentrations
      (500 microM) that exceeded its inhibition of NHE1 in glioma cells (IC50 = 17
      microM). Preventing a reduction of pHi did not alter the drug's antiproliferative
      and cytotoxic effects on glioma cells. These findings indicated that amiloride's
      cytotoxic effects on glioma cells are independent of its ability to inhibit NHE1
      or to reduce intracellular pHi. The amiloride derivative 2,4 dichlorobenzamil
      (DCB) inhibits the sodium-calcium exchanger (NCX) and was both antiproliferative
      and cytotoxic to glioma cells at low doses (20 microM). By contrast, KB-R7943 [(2
      [2-[4-nitrobenzyloxy]phenyl]ethyl)-isothioureamethanesulfonate] preferentially
      blocks sodium-dependent calcium influx by NCX (reverse mode) and was nontoxic to
      glioma cells. It is proposed that DCB (20 microM) and amiloride (500 microM)
      impair calcium efflux by NCX, leading to elevations of intracellular calcium that
      initiate a morphologically necrotic, predominantly caspase-independent glioma
      cell death.

PMID- 15010501
TI  - The nitric oxide donor, O2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V
      PYRRO/NO), protects against cadmium-induced hepatotoxicity in mice.
AB  - The nitric oxide (NO) donor, O2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
      (V-PYRRO/NO), is metabolized by P450 enzymes to release NO within the liver and
      is effective in protecting against hepatotoxicity of endotoxin and acetaminophen.
      This study examined the effects of V-PYRRO/NO on cadmium (Cd) hepatotoxicity in
      mice. Mice were given multiple injections of V-PYRRO/NO (10 mg/kg, s.c. at 2-h
      intervals) before and after a hepatotoxic dose of Cd (3.7 mg/kg Cd as CdCl2,
      i.p.). V-PYRRO/NO administration reduced Cd-induced hepatotoxicity as evidenced
      by reduced serum alanine aminotransferase activity, improved pathology, and
      reduced hepatic lipid peroxidation. The protection by V-PYRRO/NO was not mediated
      by altered Cd distribution to the liver or within hepatic subcellular fractions.
      Similar inductions of metallothionein, a metal-binding protein, were observed in
      mice receiving Cd alone or Cd plus V-PYRRO/NO. Real-time reverse transcription
      polymerase chain reaction analysis revealed that V-PYRRO/NO administration
      suppressed the expression of inflammation-related genes such as macrophage
      inflammatory protein-2, CXC chemokine, thrombospondin-1, intracellular adhesion
      molecular-1, and interleukin-6. V-PYRRO/NO also suppressed the expression of
      acute phase protein genes and genes related to cell-death pathways, such as c
      jun/AP-1, nuclear factor-kappaB, early response growth factor-1, heme oxygenase
      1, caspase-3, growth arrest, and DNA-damaging protein-153. In summary, the liver
      selective NO donor, V-PYRRO/NO, protects against Cd hepatotoxicity in mice. This
      protection is not mediated through altered distribution of Cd but may be related
      to reduced hepatic inflammation, reduced acute phase responses, and the
      suppression of cell-death-related components.

PMID- 15010502
TI  - KW-7158 [(2S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10
      dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] enhances A-type K+ currents
      in neurons of the dorsal root ganglion of the adult rat.
AB  - Recent studies revealed that a new compound, KW-7158 [(2S)-(+)-3,3,3-trifluoro-2
      hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9
      yl)propanamide], can depress the excitability of afferent pathways from the
      urinary bladder and reduce bladder overactivity induced by chemical irritation of
      the urinary tract with xylene, an agent that sensitizes capsaicin-sensitive, C
      fiber afferent nerves. In the present experiments, we examined the mechanisms
      that might underlie the depressant effect of KW-7158 on primary afferent neurons
      by studying the actions of the compound on ion channels and firing in dissociated
      dorsal root ganglion (DRG) cells from adult rats using whole cell patch-clamp
      techniques. KW-7158 increased transient, A-type K+ currents at concentrations
      ranging from 50 nM to 1 microM (20-50% increases). Similar effects were seen in
      fast blue identified bladder afferent neurons. Low concentrations of KW-7158
      shortened the action potential duration, produced a 5- to 10-mV
      hyperpolarization, and inhibited repetitive firing induced by either 4-AP (50
      microM) or substance P (0.5 microM) in phasic firing DRG neurons. Above 1 microM,
      KW-7158 elicited a smaller enhancement of A-type K+currents and in high
      concentrations inhibited the currents. Tetraethylammonium (5-60 mM) and verapamil
      (50 microM), which block noninactivating K+ currents, did not prevent the
      facilitatory effects of KW-7158. High concentrations of 4-AP (5 mM) inhibited A
      type K+ currents and prevented the facilitatory effect of KW-7158 on the
      remaining currents. These data suggest that KW-7158 enhances A-type K+ currents
      in DRG neurons. Because A-type K+ channels regulate afferent neuron excitability
      and firing properties, KW-7158 is a promising new compound for treatment of hyper
      reflexic bladder conditions.

PMID- 15010512
TI  - Experimental analysis of the fertilization process.

PMID- 15010513
TI  - Nuclear endosperm development in cereals and Arabidopsis thaliana.

PMID- 15010514
TI  - Pistil factors controlling pollination.

PMID- 15010511
TI  - Analyses of cDNAs from growth and slug stages of Dictyostelium discoideum.
AB  - Dictyostelium is a favored model for studying problems in cell and developmental
      biology. To comprehend the genetic potential and networks that direct growth and
      multicellular development, we are performing a large-scale analysis of
      Dictyostelium cDNAs. Here, we newly determine 7720 nucleotide sequences of cDNAs
      from the multicellular, slug stage (S) and 10 439 from the unicellular,
      vegetative stage (V). The combined 26 954 redundant ESTs were computer assembled
      using the PHRAP program to yield 5381 independent sequences. These 5381 predicted
      genes represent about half of the estimated coding potential of the organism. One
      third of them were classified into 12 functional categories. Although the overall
      classification patterns of the V and S libraries were very similar, stage
      specific genes exist in every category. The majority of V-specific genes function
      in some aspect of protein translation, while such genes are in a minority in the
      S-specific and common populations. Instead, genes for signal transduction and
      multicellular organization are enriched in the population of S-specific genes.
      Genes encoding the enzymes of basic metabolism are mainly found in the common
      gene population. These results therefore suggest major differences between
      growing and developing Dictyostelium cells in the nature of the genes
      transcribed.

PMID- 15010515
TI  - Imprinting and seed development.

PMID- 15010518
TI  - The mouse muscle creatine kinase promoter faithfully drives reporter gene
      expression in transgenic Xenopus laevis.
AB  - Developing Xenopus laevis experience two periods of muscle differentiation, once
      during embryogenesis and again at metamorphosis. During metamorphosis, thyroid
      hormone induces both muscle growth in the limbs and muscle death in the tail. In
      mammals, the muscle creatine kinase (MCK) gene is activated during the
      differentiation from myoblasts to myocytes and has served as both a marker for
      muscle development and to drive transgene expression in transgenic mice.
      Transcriptional control elements are generally highly conserved throughout
      evolution, potentially allowing mouse promoter use in transgenic X. laevis. This
      paper compares endogenous X. laevis MCK gene expression and the mouse MCK (mMCK)
      promoter driving a green fluorescent protein reporter in transgenic X. laevis.
      The mMCK promoter demonstrated strong skeletal muscle-specific transgene
      expression in both the juvenile tadpole and adult frog. Therefore, our results
      clearly demonstrate the functional conservation of regulatory sequences in
      vertebrate muscle gene promoters and illustrate the utility of using X. laevis
      transgenesis for detailed comparative study of mammalian promoter activity in
      vivo.

PMID- 15010517
TI  - The molecular and genetic bases of S-RNase-based self-incompatibility.

PMID- 15010516
TI  - Genetic regulation of fruit development and ripening.

PMID- 15010520
TI  - Successful treatment of Tourette's disorder with amisulpride.

PMID- 15010519
TI  - Lansoprazole-tacrolimus interaction in Japanese transplant recipient with CYP2C19
      polymorphism.
AB  - OBJECTIVE: To report a patient with a high tacrolimus blood concentration after
      lansoprazole administration and assess the potential interaction between
      tacrolimus and lansoprazole. CASE SUMMARY: A 34-year-old Japanese man underwent a
      living-donor kidney transplantation having received tacrolimus, mycophenolate
      mofetil, and prednisolone for immunosuppression. Lansoprazole was administered
      from postoperative day 4 as prophylaxis of ulcers. The trough concentration of
      tacrolimus increased markedly after the introduction of lansoprazole, while
      results of liver function tests were within normal limits. Lansoprazole was
      stopped on day 15 and was replaced with famotidine on day 17. The trough
      concentration of tacrolimus returned to the therapeutic range after
      administration of lansoprazole ceased. Genetic analysis revealed a heterozygous
      mutation at exon 5 of the CYP2C19 gene (CYP2C19*1/*2) in this patient.
      DISCUSSION: Lansoprazole is metabolized by 2 enzymes, CYP2C19 and CYP3A4. Since
      tacrolimus is also metabolized by CYP3A4, the blood concentration of tacrolimus
      in this patient who had a CYP2C19 gene mutation may have been elevated by
      decreased hepatic elimination of lansoprazole. An objective causality assessment
      revealed that this interaction was probable. CONCLUSIONS: Trough concentrations
      of tacrolimus should be monitored closely for optimizing the dosage regimen in
      patients receiving concomitant lansoprazole.

PMID- 15010522
TI  - Effect of infliximab on refractory uveitis in Behcet's disease.

PMID- 15010521
TI  - Codeine phosphate-induced hypersensitivity syndrome.
AB  - OBJECTIVE: To report a case of drug-induced hypersensitivity syndrome related to
      codeine phosphate. CASE SUMMARY: A 19-year-old Japanese man was prescribed
      codeine phosphate 10 mg 3 times daily and several other drugs for cold symptoms.
      About 20 days later, an erythematous, maculopapular rash appeared and progressed
      to erythroderma; a spiking fever also developed. He had splenomegaly and
      generalized lymphadenopathy on admission. Laboratory examinations showed atypical
      lymphocytosis, eosinophilia, and increased liver enzyme values. The platelet
      count slowly decreased after admission. The increased numbers of megakaryocytes
      in bone marrow and platelet-associated immunoglobulin (Ig) G antibodies in serum
      were compatible with a diagnosis of immune thrombocytopenic purpura. A
      significant increase in IgG antibodies to human herpesvirus 6 (HHV6) and
      transient viremia were helpful in diagnosing hypersensitivity syndrome. The
      results of patch tests were positive for codeine phosphate. An objective
      causality assessment revealed that an adverse drug event was probable.
      DISCUSSION: Codeine is an opioid analgesic. Severe adverse cutaneous reactions
      rarely occur. As of March 3, 2004, our case is, to our knowledge, the first
      report of hypersensitivity syndrome attributed to codeine phosphate. Drug-induced
      hypersensitivity syndrome is an acute, potentially life-threatening,
      idiosyncratic adverse reaction caused mainly by aromatic anticonvulsants. It is
      characterized by the triad of fever, skin rash, and internal organ involvement.
      Reactivation of HHV6 is involved in the pathogenesis of this syndrome and may
      have also caused the immune thrombocytopenic purpura in our patient. CONCLUSIONS:
      Codeine phosphate may rarely be associated with hypersensitivity syndrome.
      Clinicians should be aware that the potentially fatal syndrome can be caused by
      various drugs.

PMID- 15010523
TI  - Treatment of recurrent perforating intestinal ulcers with thalidomide in Behcet's
      disease.
AB  - OBJECTIVE: To report the beneficial effects of thalidomide on recurrent
      perforating intestinal ulcers in a patient with Behcet's disease (BD). CASE
      SUMMARY: A 24-year-old Turkish woman with BD was admitted to our hospital because
      of severe abdominal pain and vomiting. She had been receiving colchicine 1.5
      mg/day and azathioprine 150 mg/day for treatment of BD for 2 years. During
      emergency laparatomy, 2 perforating ulcers were detected in the anterior cecum,
      which were treated with debridement and primary repair. She experienced 2 more
      episodes of intestinal perforations during the second and fifth weeks despite
      intense immunosuppressive treatment with methylprednisolone and cyclophosphamide.
      New intestinal perforations were found in the posterolateral cecum and transverse
      colon during the second operation and in the terminal ileum during the third one.
      Thalidomide 100 mg/day was then started, and the symptoms disappeared within 2
      weeks. The woman experienced no other intestinal perforation during the follow-up
      period of 4 months. DISCUSSION: The mode of action of thalidomide in BD is still
      unclear. In BD, various cytokines have been shown to be abnormally expressed and
      neutrophils are overactive. This is a possible mechanism of action with
      thalidomide reducing both tumor necrosis factor and the neutrophil migration.
      CONCLUSIONS: Thalidomide may be an effective alternative treatment for BD
      patients with recurrent and perforating intestinal ulcers despite intense
      immunosuppressive therapy.

PMID- 15010524
TI  - MglA regulates transcription of virulence factors necessary for Francisella
      tularensis intraamoebae and intramacrophage survival.
AB  - Francisella tularensis is able to survive and grow within macrophages, a trait
      that contributes to pathogenesis. Several genes have been identified that are
      important for intramacrophage survival, including mglA and iglC. F. tularensis is
      also able to survive within amoebae. It is shown here that F. tularensis mglA and
      iglC mutant strains are not only defective for survival and replication within
      the macrophage-like cell line J774, but also within Acanthamoebae castellanii.
      Moreover, these strains are highly attenuated for virulence in mice, suggesting
      that a common mechanism underlies intramacrophage and intraamoebae survival and
      virulence. A 2D gel analysis of cell extracts of wild-type and mglA mutant
      strains revealed that at least seven prominent proteins were at low levels in the
      mglA mutant, and one MglA-regulated protein was identified as the IglC protein.
      RT-PCR analysis demonstrated reduced transcription of iglC and several other
      known and suspected virulence genes in the mglA mutant. Thus, MglA regulates the
      transcription of virulence factors of F. tularensis that contribute to
      intramacrophage and intraamoebae survival.

PMID- 15010525
TI  - Isolation of an endotoxin-MD-2 complex that produces Toll-like receptor 4
      dependent cell activation at picomolar concentrations.
AB  - Host proinflammatory responses to minute amounts of endotoxins derived from many
      Gram-negative bacteria require the interaction of lipopolysaccharide-binding
      protein (LBP), CD14, Toll-like receptor 4 (TLR4) and MD-2. Optimal sensitivity to
      endotoxin requires an ordered series of endotoxin-protein and protein-protein
      interactions. At substoichiometric concentrations, LBP facilitates delivery of
      endotoxin aggregates to soluble CD14 (sCD14) to form monomeric endotoxin-sCD14
      complexes. Subsequent interactions of endotoxin-sCD14 with TLR4 and/or MD-2 have
      not been specifically defined. This study reports the purification of a stable,
      monomeric, bioactive endotoxin-MD-2 complex generated by treatment of endotoxin
      sCD14 with recombinant MD-2. Efficient generation of this complex occurred at
      picomolar concentrations of endotoxin and nanogram per milliliter doses of MD-2
      and required presentation of endotoxin to MD-2 as a monomeric endotoxin-CD14
      complex. TLR4-dependent delivery of endotoxin to human embryonic kidney (HEK)
      cells and cell activation at picomolar concentrations of endotoxin occurred with
      the purified endotoxin-MD-2 complex, but not with purified endotoxin aggregates
      with or without LBP and/or sCD14. The presence of excess MD-2 inhibited delivery
      of endotoxin-MD-2 to HEK/TLR4 cells and cell activation. These findings
      demonstrate that TLR4-dependent activation of host cells by picomolar
      concentrations of endotoxin occurs by sequential interaction and transfer of
      endotoxin to LBP, CD14, and MD-2 and simultaneous engagement of endotoxin and
      TLR4 by MD-2.

PMID- 15010526
TI  - Dynamics of HIV-1 recombination in its natural target cells.
AB  - Genetic recombination is believed to assist HIV-1 diversification and escape from
      host immunity and antiviral therapies, yet this process remains largely
      unexamined within the natural target-cell populations. We developed a method for
      measuring HIV-1 recombination directly that employs reporter viruses bearing
      functional enhanced yellow fluorescent protein (YFP) and enhanced cyan
      fluorescent protein (CFP) genes in which recombination produces a modified GFP
      gene and GFP fluorescence in the infected cells. These reporter viruses allow
      simultaneous quantification of the dynamics of HIV-1 infection, coinfection, and
      recombination in cell culture and in animal models by flow-cytometric analysis.
      Multiround infection assays revealed that productive cellular coinfection was
      subject to little functional inhibition. As a result, generation of recombinants
      proceeded according to the square of the infection rate during HIV-1 replication
      in T lymphocytes and within human thymic grafts in severe combined
      immunodeficient (SCID)-hu (Thy/Liv) mice. These results suggest that increases in
      viral load may confer a compounding risk of virus escape by means of
      recombinational diversification. A single round of replication in T lymphocytes
      in culture generated an average of nine recombination events per virus, and
      infection of macrophages led to approximately 30 crossover events, making HIV-1
      up to an order of magnitude more recombinogenic than recognized previously and
      demonstrating that the infected cell exerts a profound influence on the frequency
      of recombination.

PMID- 15010528
TI  - Controlling lentiviruses: single amino acid changes can determine specificity.

PMID- 15010527
TI  - Characterization of severe acute respiratory syndrome-associated coronavirus
      (SARS-CoV) spike glycoprotein-mediated viral entry.
AB  - Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is a rapidly
      emerging pathogen with potentially serious consequences for public health. Here
      we describe conditions that result not only in the efficient expression of the
      SARS-CoV spike (S) protein on the surface of cells, but in its incorporation into
      lentiviral particles that can be used to transduce cells in an S glycoprotein
      dependent manner. We found that although some primate cell lines, including Vero
      E6, 293T and Huh-7 cells, could be efficiently transduced by SARS-CoV S
      glycoprotein pseudoviruses, other cells lines were either resistant or very
      poorly permissive to virus entry. Infection by pseudovirions could be inhibited
      by several lysosomotropic agents, suggesting a requirement for acidification of
      endosomes for efficient S-mediated viral entry. In addition, we were able to
      develop a cell-cell fusion assay that could be used to monitor S glycoprotein
      dependent membrane fusion. Although proteolysis did not enhance the infectivity
      of cell-free pseudovirions, trypsin activation is required for cell-cell fusion.
      Additionally, there was no apparent pH requirement for S glycoprotein-mediated
      cell-cell fusion. Together, these studies describe important tools that can be
      used to study SARS-CoV S glycoprotein structure and function, including
      approaches that can be used to identify inhibitors of the entry of SARS-CoV into
      target cells.

PMID- 15010529
TI  - The neural F-box protein NFB42 mediates the nuclear export of the herpes simplex
      virus type 1 replication initiator protein (UL9 protein) after viral infection.
AB  - The neural F-box 42-kDa protein (NFB42) is a component of the SCF(NFB42) E3
      ubiquitin ligase that is expressed in all major areas of the brain; it is not
      detected in nonneuronal tissues. We previously identified NFB42 as a binding
      partner for the herpes simplex virus 1 (HSV-1) UL9 protein, the viral replication
      initiator, and showed that coexpression of NFB42 and UL9 in human embryonic
      kidney (293T) cells led to a significant decrease in the level of UL9 protein. We
      have now found that HSV-1 infection promotes the shuttling of NFB42 between the
      cytosol and the nucleus in both 293T cells and primary hippocampal neurons,
      permitting NFB42 to bind to the phosphorylated UL9 protein, which is localized in
      the nucleus. This interaction mediates the export of the UL9 protein from the
      nucleus to the cytosol, leading to its ubiquitination and degradation via the 26S
      proteasome. Because the intranuclear localization of the UL9 protein, along with
      other viral and cellular factors, is an essential step in viral DNA replication,
      degradation of the UL9 protein in neurons by means of nuclear export through its
      specific interaction with NFB42 may prevent active replication and promote
      neuronal latency of HSV-1.

PMID- 15010530
TI  - The plant hormone indoleacetic acid induces invasive growth in Saccharomyces
      cerevisiae.
AB  - Fungi must recognize plant-specific signals to initiate subsequent morphogenetic
      events such as filamentation that lead to infection. Here we show that the plant
      hormone indoleacetic acid (IAA) induces adhesion and filamentation of
      Saccharomyces cerevisiae. Genome expression profiling of cells treated with IAA
      identified Yap1, a fungal specific transcription factor, as a key mediator of
      this response. Strains lacking YAP1 (yap1-1) are hypersensitive to growth on IAA
      because they accumulate more IAA than can wild type. Members of a family of
      transporters the amino acid/auxin:proton symport permeases with homology to AUX1,
      a putative IAA transporter from plants, are up-regulated in the yap1-1 mutant.
      Deletion of any one of these transporters makes yap1-1 mutants more resistant to
      IAA by decreasing its uptake. The permease mutants are defective in IAA
      perception and filamentation. The ability of a fungus to perceive a plant hormone
      that causes it to differentiate into an invasive form has important implications
      for plant-pathogen interactions.

PMID- 15010531
TI  - Expression profiling with arrays of randomly disrupted genes in mouse embryonic
      stem cells leads to in vivo functional analysis.
AB  - DNA arrays are capable of profiling the expression patterns of many genes in a
      single experiment. After finding a gene of interest in a DNA array, however,
      labor-intensive gene-targeting experiments sometimes must be performed for the in
      vivo analysis of the gene function. With random gene trapping, on the other hand,
      it is relatively easy to disrupt and retrieve hundreds of genes/gene candidates
      in mouse embryonic stem (ES) cells, but one could overlook potentially important
      gene-disruption events if only the nucleotide sequences and not the expression
      patterns of the trapped DNA segments are analyzed. To combine the benefits of the
      above two experimental systems, we first created approximately 900 genetrapped
      mouse ES cell clones and then constructed arrays of cDNAs derived from the
      disrupted genes. By using these arrays, we identified a novel gene predominantly
      expressed in the mouse brain, and the corresponding ES cell clone was used to
      produced mice homozygous for the disrupted allele of the gene. Detailed analysis
      of the knockout mice revealed that the gene trap vector completely abolished gene
      expression downstream of its integration site. Therefore, identification of a
      gene or novel gene candidate with an interesting expression pattern by using this
      type of DNA array immediately allows the production of knockout mice from an ES
      cell clone with a disrupted allele of the sequence of interest.

PMID- 15010532
TI  - What arthropod brains say about arthropod phylogeny.

PMID- 15010533
TI  - A Fenton reaction at the endoplasmic reticulum is involved in the redox control
      of hypoxia-inducible gene expression.
AB  - It has been proposed that hydroxyl radicals (.OH) generated in a perinuclear iron
      dependent Fenton reaction are involved in O(2)-dependent gene expression. Thus,
      it was the aim of this study to localize the cellular compartment in which the
      Fenton reaction takes place and to determine whether scavenging of.OH can
      modulate hypoxia-inducible factor 1 (HIF-1)-dependent gene expression. The Fenton
      reaction was localized by using the nonfluorescent dihydrorhodamine (DHR) 123
      that is irreversibly oxidized to fluorescent rhodamine 123 while scavenging.OH
      together with gene constructs allowing fluorescent labeling of mitochondria,
      endoplasmic reticulum (ER), Golgi apparatus, peroxisomes, or lysosomes. A 3D two
      photon confocal laser scanning microscopy showed.OH generation in distinct hot
      spots of perinuclear ER pockets. This ER-based Fenton reaction was strictly pO(2)
      dependent. Further colocalization experiments showed that the O(2)-sensitive
      transcription factor HIF-1alpha was present at the ER under normoxia, whereas HIF
      1alpha was present only in the nucleus under hypoxia. Inhibition of the Fenton
      reaction by the.OH scavenger DHR attenuated HIF-prolyl hydroxylase activity and
      interaction with von Hippel-Lindau protein, leading to enhanced HIF-1alpha
      levels, HIF-1alpha transactivation, and activated expression of the HIF-1 target
      genes plasminogen activator inhibitor 1 and heme oxygenase 1. Further,.OH
      scavenging appeared to enhance redox factor 1 (Ref-1) binding and, thus,
      recruitment of p300 to the transactivation domain C because mutation of the Ref-1
      binding site cysteine 800 abolished DHR-induced transactivation. Thus, the
      localized Fenton reaction appears to impact the expression of hypoxia-regulated
      genes by means of HIF-1alpha stabilization and coactivator recruitment.

PMID- 15010534
TI  - Insulin-like growth factor-binding protein 5 (Igfbp5) compromises survival,
      growth, muscle development, and fertility in mice.
AB  - The insulin-like growth factors (IGFs) are essential for development;
      bioavailable IGF is tightly regulated by six related IGF-binding proteins
      (IGFBPs). Igfbp5 is the most conserved and is developmentally up-regulated in key
      lineages and pathologies; in vitro studies suggest that IGFBP-5 functions
      independently of IGF interaction. Genetic ablation of individual Igfbps has
      yielded limited phenotypes because of substantial compensation by remaining
      family members. Therefore, to reveal Igfbp5 actions in vivo, we generated lines
      of transgenic mice that ubiquitously overexpressed Igfbp5 from early development.
      Significantly increased neonatal mortality, reduced female fertility, whole-body
      growth inhibition, and retarded muscle development were observed in Igfbp5
      overexpressing mice. The magnitude of the response in individual transgenic lines
      was positively correlated with Igfbp5 expression. Circulating IGFBP-5
      concentrations increased a maximum of only 4-fold, total and free IGF-I
      concentrations increased up to 2-fold, and IGFBP-5 was detected in high M(r)
      complexes; however, no detectable decrease in the proportion of free IGF-I was
      observed. Thus, despite only modest changes in IGF and IGFBP concentrations, the
      Igfbp5-overexpressing mice displayed a phenotype more extreme than that observed
      for other Igfbp genetic models. Although growth retardation was obvious
      prenatally, maximal inhibition occurred postnatally before the onset of growth
      hormone-dependent growth, regardless of Igfbp5 expression level, revealing a
      period of sensitivity to IGFBP-5 during this important stage of tissue
      programming.

PMID- 15010535
TI  - Transcriptional switch by activating transcription factor 2-derived peptide
      sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity.
AB  - The notorious resistance of melanoma cells to drug treatment can be overcome by
      expression of a 50-aa peptide derived from activating transcription factor 2
      (ATF2(50-100)). Here we demonstrate that ATF2(50-100) induced apoptosis by
      sequestering ATF2 to the cytoplasm, thereby inhibiting its transcriptional
      activities. Furthermore, ATF2(50-100) binds to c-Jun N-terminal kinase (JNK) and
      increases its activity. Mutation within ATF2(50-100) that impairs association
      with JNK and the inhibition of JNK or c-Jun expression by RNA interference (RNAi)
      reduces the degree of ATF2(50-100)-induced apoptosis. In contrast, TAM67, a
      dominant negative of the Jun family of transcription factors, or JunD RNAi
      attenuates sensitization of melanoma cells expressing ATF2(50-100) to apoptosis
      after treatment with anisomycin, which is used as a model drug. Mutations within
      the JNK binding region of ATF2(50-100) or expression of TAM67 or JunD RNAi
      attenuates inhibition of melanoma's tumorigenicity by ATF2(50-100). We conclude
      that inhibition of ATF2 in concert with increased JNK/Jun and JunD activities is
      central for the sensitization of melanoma cells to apoptosis and inhibition of
      their tumorigenicity.

PMID- 15010537
TI  - Identification of the bacterial alarmone guanosine 5'-diphosphate 3'-diphosphate
      (ppGpp) in plants.
AB  - Stringent control mediated by the bacterial alarmone guanosine 5'-diphosphate 3'
      diphosphate (ppGpp) is a key regulatory process governing bacterial gene
      expression. By devising a system to measure ppGpp in plants, we have been able to
      identify ppGpp in the chloroplasts of plant cells. Levels of ppGpp increased
      markedly when plants were subjected to such biotic and abiotic stresses as
      wounding, heat shock, high salinity, acidity, heavy metal, drought, and UV
      irradiation. Abrupt changes from light to dark also caused a substantial
      elevation in ppGpp levels. In vitro, chloroplast RNA polymerase activity was
      inhibited in the presence of ppGpp, demonstrating the existence of a bacteria
      type stringent response in plants. Elevation of ppGpp levels was elicited also by
      treatment with plant hormones jasmonic acid, abscisic acid, and ethylene, but
      these effects were blocked completely by another plant hormone, indole-3-acetic
      acid. On the basis of these findings, we propose that ppGpp plays a critical role
      in systemic plant signaling in response to environmental stresses, contributing
      to the adaptation of plants to environmental changes.

PMID- 15010538
TI  - Responses of human visual cortex to uniform surfaces.
AB  - Surface perception is fundamental to human vision, yet most studies of visual
      cortex have focused on the processing of borders. We therefore investigated the
      responses of human visual cortex to parametric changes in the luminance of
      uniform surfaces by using functional MRI. Early visual areas V1 and V2/V3 showed
      strong and reliable increases in signal for both increments and decrements in
      surface luminance. Responses were significantly larger for decrements than for
      increments, which was fully accounted for by differences in retinal illumination
      arising from asymmetric pupil dynamics. Responses to both sustained and transient
      changes of illumination were transient. Signals in early visual cortex scaled
      linearly with the magnitude of change in retinal illumination, as did subjects'
      subjective ratings of the perceived brightness of the stimuli. Our findings show
      that early visual cortex responds strongly to surfaces and that perception of
      surface brightness is compatible with brain responses at the earliest cortical
      stages of processing.

PMID- 15010539
TI  - Biography of Jan-Ake Gustafsson.

PMID- 15010540
TI  - Biography of Martha L. Ludwig.

PMID- 15010541
TI  - Equilibrium thermal transitions of collagen model peptides.
AB  - The folding of collagen in vitro is very slow and presents difficulties in
      reaching equilibrium, a feature that may have implications for in vivo collagen
      function. Peptides serve as good model systems for examining equilibrium thermal
      transitions in the collagen triple helix. Investigations were carried out to
      ascertain whether a range of synthetic triple-helical peptides of varying
      sequences can reach equilibrium, and whether the triple helix to unfolded monomer
      transition approximates a two-state model. The thermal transitions for all
      peptides studied are fully reversible given sufficient time. Isothermal
      experiments were carried out to obtain relaxation times at different
      temperatures. The slowest relaxation times, on the order of 10-15 h, were
      observed at the beginning of transitions, and were shown to result from self
      association limited by the low concentration of free monomers, rather than cis
      trans isomerization. Although the fit of the CD equilibrium transition curves and
      the concentration dependence of T(m) values support a two-state model, the more
      rigorous comparison of the calorimetric enthalpy to the van't Hoff enthalpy
      indicates the two-state approximation is not ideal. Previous reports of melting
      curves of triple-helical host-guest peptides are shown to be a two-state kinetic
      transition, rather than an equilibrium transition.

PMID- 15010542
TI  - Energy functions for protein design I: efficient and accurate continuum
      electrostatics and solvation.
AB  - Electrostatics and solvation energies are important for defining protein
      stability, structural specificity, and molecular recognition. Because these
      energies are difficult to compute quickly and accurately, they are often ignored
      or modeled very crudely in computational protein design. To address this problem,
      we have developed a simple, fast, and accurate approximation for calculating Born
      radii in the context of protein design calculations. When these approximate Born
      radii are used with the generalized Born continuum dielectric model, energies
      calculated by the 10(6)-fold slower finite difference Poisson-Boltzmann model are
      faithfully reproduced. A similar approach can be used for estimating solvent
      accessible surface areas (SASAs). As an independent test, we show that these
      approximations can be used to accurately predict the experimentally determined
      pK(a)s of >200 ionizable groups from 15 proteins.

PMID- 15010543
TI  - Prediction of functional sites by analysis of sequence and structure
      conservation.
AB  - We present a method for prediction of functional sites in a set of aligned
      protein sequences. The method selects sites which are both well conserved and
      clustered together in space, as inferred from the 3D structures of proteins
      included in the alignment. We tested the method using 86 alignments from the NCBI
      CDD database, where the sites of experimentally determined ligand and/or
      macromolecular interactions are annotated. In agreement with earlier
      investigations, we found that functional site predictions are most successful
      when overall background sequence conservation is low, such that sites under
      evolutionary constraint become apparent. In addition, we found that averaging of
      conservation values across spatially clustered sites improves predictions under
      certain conditions: that is, when overall conservation is relatively high and
      when the site in question involves a large macromolecular binding interface.
      Under these conditions it is better to look for clusters of conserved sites than
      to look for particular conserved sites.

PMID- 15010544
TI  - An improved crystal form of Plasmodium falciparum peptide deformylase.
AB  - An altered version of peptide deformylase from Plasmodium falciparum (PfPDF), the
      organism that causes the most devastating form of malaria, has been
      cocrystallized with a synthesized inhibitor that has submicromolar affinity for
      its target protein. The structure is solved at 2.2 A resolution, an improvement
      over the 2.8 A resolution achieved during the structural determination of
      unliganded PfPDF. This represents the successful outcome of modifying the protein
      construct in order to overcome adverse crystal contacts and other problems
      encountered in the study of unliganded PfPDF. Two molecules of PfPDF are found in
      the asymmetric unit of the current structure. The active site of each monomer of
      PfPDF is occupied by a proteolyzed fragment of the tripeptide-like inhibitor.
      Unexpectedly, each PfPDF subunit is associated with two nearly complete molecules
      of the inhibitor, found at a protein-protein interface. This is the first
      structure of a eukaryotic PDF protein, a potential drug target, in complex with a
      ligand.

PMID- 15010545
TI  - Mimicking the action of folding chaperones in molecular dynamics simulations:
      Application to the refinement of homology-based protein structures.
AB  - A novel method for the refinement of misfolded protein structures is proposed in
      which the properties of the solvent environment are oscillated in order to mimic
      some aspects of the role of molecular chaperones play in protein folding in vivo.
      Specifically, the hydrophobicity of the solvent is cycled by repetitively
      altering the partial charges on solvent molecules (water) during a molecular
      dynamics simulation. During periods when the hydrophobicity of the solvent is
      increased, intramolecular hydrogen bonding and secondary structure formation are
      promoted. During periods of increased solvent polarity, poorly packed regions of
      secondary structures are destabilized, promoting structural rearrangement. By
      cycling between these two extremes, the aim is to minimize the formation of long
      lived intermediates. The approach has been applied to the refinement of
      structural models of three proteins generated by using the ROSETTA procedure for
      ab initio structure prediction. A significant improvement in the deviation of the
      model structures from the corresponding experimental structures was observed.
      Although preliminary, the results indicate computationally mimicking some
      functions of molecular chaperones in molecular dynamics simulations can promote
      the correct formation of secondary structure and thus be of general use in
      protein folding simulations and in the refinement of structural models of small-
      to medium-size proteins.

PMID- 15010546
TI  - Tissue transglutaminase acylation: Proposed role of conserved active site Tyr and
      Trp residues revealed by molecular modeling of peptide substrate binding.
AB  - Transglutaminases (TGases) catalyze the cross-linking of peptides and proteins by
      the formation of gamma-glutamyl-epsilon-lysyl bonds. Given the implication of
      tissue TGase in various physiological disorders, development of specific tissue
      TGase inhibitors is of current interest. To aid in the design of peptide-based
      inhibitors, a better understanding of the mode of binding of model peptide
      substrates to the enzyme is required. Using a combined kinetic/molecular modeling
      approach, we have generated a model for the binding of small acyl-donor peptide
      substrates to tissue TGase from red sea bream. Kinetic analysis of various N
      terminally derivatized Gln-Xaa peptides has demonstrated that many CBz-Gln-Xaa
      peptides are typical in vitro substrates with K(M) values between 1.9 mM and 9.4
      mM, whereas Boc-Gln-Gly is not a substrate, demonstrating the importance of the
      CBz group for recognition. Our binding model of CBz-Gln-Gly on tissue TGase has
      allowed us to propose the following steps in the acylation of tissue TGase.
      First, the active site is opened by displacement of conserved W329. Second, the
      substrate Gln side chain enters the active site and is stabilized by hydrophobic
      interaction with conserved residue W236. Third, a hydrogen bond network is formed
      between the substrate Gln side chain and conserved residues Y515 and the acid
      base catalyst H332 that helps to orient and activate the gamma-carboxamide group
      for nucleophilic attack by the catalytic sulphur atom. Finally, an H-bond with
      Y515 stabilizes the oxyanion formed during the reaction.

PMID- 15010547
TI  - Sites of interaction between SecA and the chaperone SecB, two proteins involved
      in export.
AB  - SecB, a small tetrameric cytosolic chaperone in Escherichia coli, facilitates the
      export of precursor poly-peptides by maintaining them in a nonnative conformation
      and passing them to SecA, which is a peripheral member of the membrane-bound
      translocation apparatus. It has been proposed by several laboratories that as
      SecA interacts with various components along the export pathway, it undergoes
      conformational changes that are crucial to its function. Here we report details
      of molecular interactions between SecA and SecB, which may serve as
      conformational switches. One site of interaction involves the final C-terminal 21
      amino acids of SecA, which are positively charged and contain zinc. The C
      terminus of each subunit of the SecA dimer makes contact with the flat beta-sheet
      that is formed by each dimer of the SecB tetramer. Here we demonstrate that a
      second interaction exists between the extreme C-terminal alpha-helix of SecB and
      a site on SecA, as yet undefined but different from the C terminus of SecA. We
      investigated the energetics of the interactions by titration calorimetry and
      characterized the hydrodynamic properties of complexes stabilized by both
      interactions or each interaction singly using sedimentation velocity
      centrifugation.

PMID- 15010548
TI  - Heme as an optical probe of a conformational transition of ovine recPrP.
AB  - The prion protein occurs as a globular domain and a leading fragment whose
      structure is not well-defined. For the ovine species, all of the tryptophan
      residues are in the initial fragment, while the globular domain is rich in
      tyrosine residues. Using heme as a spectroscopic probe, we have studied the
      recombinant prion protein before and after a temperature-induced conformational
      change. As for most heme proteins, the absorption spectrum of heme-CO displays a
      red shift upon binding to the protein, and both the Y and W fluorescence are
      highly quenched. Flash photolysis kinetics of the PrP-heme-CO complex shows a low
      yield for the bimolecular phase, indicating a pocket around the hemes. By
      comparing the holoprotein and the truncated sequence corresponding to the
      globular domain, the stoichiometry was determined to be five hemes for the
      globular domain and two hemes for the leading fragment. At high temperature, the
      hemes are released; upon cooling, only two hemes bind, and only the tryptophan
      fluorescence is quenched; this would indicate that the globular domain has formed
      a more compact structure, which is inert with respect to the hydrophobic probe.
      The final state of polymerization is perturbed if the synthetic peptide "N3" (PrP
      residues 142-166, which include the first helix) is added to the prion protein
      solution; the temperature cycle no longer reduces the number of heme binding
      sites. This would indicate that the peptide may alter or inhibit the polymer
      formation.

PMID- 15010549
TI  - Monitoring apoptosis with fluorescent Zn2+-indicators.
AB  - Apoptosis, a mechanism of programmed cell death that removes superfluous and
      harmful cells, is important both during development and in tissue homeostasis.
      Although Zn2+ is believed to be critical in apoptosis, the precise details of its
      role have yet to be elucidated. The macrocyclic Zn2+ ligand
      dansylamidoethylcyclen [L1*(HCl)4*(H2O)2], which is found primarily in a
      diprotonated form (H2L1), is cell-permeable and forms a strongly fluorescent 1:1
      Zn2+ complex when Zn2+ entry into cells is facilitated by the Zn2+ ionophore
      pyrithione. H2L1 can be used to readily identify HeLa cells undergoing the early
      stages of etoposide-induced apoptosis because of the increased level of free Zn2+
      that occurs at this time. The selectivity of H2L1 for the detection of apoptotic
      cells was verified by a conventional probe for apoptosis, annexin V-Cy3. Here, we
      describe methods for detecting apoptotic cells with H2L1 and for comparing
      detection of apoptosis with H2L1 to detection with annexin V-Cy3 and Zinquin.

PMID- 15010550
TI  - Rapid depletion of budding yeast proteins by fusion to a heat-inducible degron.
AB  - One effective way to study the biological function of a protein in vivo is to
      inactivate it and see what happens to the cell. For proteins that are dispensable
      for cell viability, the corresponding gene can simply be deleted from its
      chromosomal locus. The study of essential proteins is more challenging, however,
      because the function of the protein must be inactivated conditionally. Here, we
      describe a method that allows the target protein to be depleted rapidly and
      conditionally, so that the immediate effects on the cell can be examined. The
      chromosomal locus of a budding yeast gene is modified so that a "heat-inducible
      degron cassette" is added to the N terminus of the encoded protein, causing it to
      be degraded by a specific ubiquitin-mediated pathway when cells are shifted from
      24 degrees to 37 degrees C. Degradation requires recognition of the degron
      cassette by the evolutionarily conserved Ubr1 protein, which is associated with a
      ubiquitin-conjugating enzyme. To promote rapid and conditional depletion of the
      target protein, we use a yeast strain in which expression of the UBR1 gene can be
      either repressed or strongly induced. Degron strains are constructed by a simple
      "one-step" approach using the polymerase chain reaction.

PMID- 15010552
TI  - Management and treatment of HIV infected pregnant women in Poland.
AB  - Currently, in Poland the number of women infected by human immunodeficiency virus
      (HIV) is still increasing. The majority of them are in the reproductive age. It
      is well known that mother-to-child transmission of HIV can occur during
      pregnancy, delivery and postnatally through breastfeeding. The risk of
      transmission is related to maternal health, obstetric factors and infant
      prematurity. The management of pregnant women infected with HIV in Poland
      involves: recognizing HIV infection early by promoting HIV testing of all
      pregnant women; minimizing the risk of vertical transmission of HIV by using
      maternal antiretroviral therapy during pregnancy and labour, followed by six
      weeks of neonatal zidovudine therapy and performing elective caesarean section.
      Adequate care requires also specialized laboratory monitoring and appropriate
      psychological and social support. Some modifications of standards in routine care
      of pregnant HIV seropositive women are necessary. For HIV infected women more
      attention to pre-conception counselling should also be paid.

PMID- 15010553
TI  - Antenatal and neonatal antiretroviral therapy in HIV-infected women and their
      infants: a review of safety issues.
AB  - Specific interventions to prevent mother-to-child transmission (MTCT) include
      antiretroviral therapy, elective caesarean section and avoidance of
      breastfeeding. Rates of MTCT below 1-2% are now achievable in developed country
      settings. However, although the vast majority of infants born to HIV infected
      mothers are protected from acquisition of infection, most are exposed to
      antiretroviral drugs for which there is only limited information on toxicity.
      Increasing use of complex and potent combinations of antiretroviral drugs in
      pregnancy, particularly during the period of organogenesis, has raised many
      questions relating to pregnancy outcome and safety issues for the exposed
      children, both in the short and longer term. A shorter duration of pregnancy has
      been reported to be associated with taking protease inhibitors in pregnancy,
      particularly prolonged and early use, but this has been an inconsistent finding.
      Risk of congenital abnormalities may be increased with exposure to specific
      antiretroviral drugs, such as efavirenz, and certain combinations of Pneumonia
      Pneumocystis Carinii (PCP) prophylaxis and antiretroviral drugs, but there is no
      evidence of an excess of congenital malformations associated with exposure to
      zidovudine prophylaxis. Although data from observational studies and follow-up of
      children enrolled in clinical trials have not shown uninfected, zidovudine
      exposed children to be at increased risk of adverse events including cancer in
      the short- to medium-term, the possibility that they may be at risk of cancer at
      older ages cannot be excluded. Concerns regarding mitochondrial dysfunction in
      children with foetal/neonatal exposure to zidovudine have arisen following a
      report from France of eight uninfected children with mitochondrial dysfunction,
      of whom two died. However, there is limited additional evidence of clinically
      evident mitochondrial disease in children exposed to antiretroviral therapy in
      utero or neonatally, and the absence of any excess mortality in large
      observational cohort studies of children born to HIV infected women and exposed
      to antiretroviral drugs is reassuring.

PMID- 15010555
TI  - European participation in an international perinatal trial.
AB  - OBJECTIVES: To identify factors affecting recruitment into a randomised trial
      involving HIV infected pregnant women. To compare the population enrolled in a
      Phase III trial to that enrolled during the same period in a parallel
      longitudinal cohort, and to assess the generalisability of the trial results.
      MATERIAL AND METHODS: The PACTG 316 trial was initiated in the USA and
      subsequently extended to Europe. Based on their involvement in an ongoing
      European cohort study, clinicians in 27 antenatal HIV reference centres in Italy,
      Spain, Sweden, UK, Belgium, Germany, Switzerland, Netherlands and Denmark were
      asked to participate. In centres with local, national and American approval,
      eligible women attending antenatal clinics were offered the chance to take part
      in the trial, which aimed to evaluate the additional use of nevirapine during
      labour and neonatally to reduce HIV mother-to-child transmission (MTCT). HIV
      infected women who did not enrol in the trial were enrolled in the European
      Collaborative Study (ECS). Reasons for non-randomisation were recorded. Clinical
      and laboratory information on mother-child pairs were collected according to a
      standard protocol. RESULTS: Between February 1999 and June 2000, 247 women were
      enrolled in the ECS cohort and 118 were randomised in the 316 trial. Reasons for
      non-randomisation included the presence of the placebo arm, randomisation
      procedures and delays in obtaining approval from the various regulatory bodies.
      Women in the trial were younger, and their HIV disease was less advanced than
      those included in the ECS. The MTCT rate in the ECS was higher than in the trial.
      CONCLUSIONS: Differences between women who participated in the trial and those
      who did not had an effect on the absolute vertical transmission rate, but not on
      the relative effectiveness of the intervention assessed within the trial.
      Extrapolation of the trial MTCT rates to the general HIV infected population may
      be inappropriate.

PMID- 15010554
TI  - Clinical and biological disease progression in vertically acquired paediatric HIV
      infection.
AB  - With available interventions in Europe, mother-to-child, or vertical transmission
      of HIV has been reduced from 15-20%, but still occurs in around one or two of
      every 100 pregnancies of HIV infected women. Progression of disease in vertically
      infected children is most rapid in early life and without early treatment about
      one-fifth progress to serious clinical illness or die before one year of age.
      However, those surviving the first few years of life, including the ones with
      previous serious illness are generally clinically well throughout childhood,
      sometimes even without antiretroviral treatment. With the increasingly common use
      of aggressive therapy at an early stage of infection, progression to serious
      disease or death is now rare. Clinical disease progression is closely associated
      with HIV RNA viral load which peaks at around age three months, with a subsequent
      decline thereafter in vertically-infected children. Levels in girls are different
      to those of boys, but the pattern of this difference is not consistent over age.
      Progression of HIV infection is also related to the levels of immunological
      components such as CD4, CD8 and absolute lymphocyte cell counts. Patterns over
      age differ by both gender and race in both infected and uninfected children with
      absolute lymphocyte values and subsets being generally higher for girls and white
      children. Levels in infected children differ markedly to those of uninfected
      children but much of the ranges of measurements are common to both. Early-life
      measurements of CD4 percentage and absolute lymphocyte count independently
      predict rapid progression to serious disease or death during the first year of
      life, while early persistent hepatomegaly or splenomegaly is prognostic of
      serious disease progression thereafter. However, there are no differences in
      progression by gender and race, nor are the prognostic abilities of markers
      altered by gender or race, which would suggest that clinical guidelines need not
      account for such factors. Of the early prognostic indicators, CD4 percentage
      measurement is the most useful and beyond six months of age a CD4 percentage cut
      off of 10% best informs subsequent disease progression risk.

PMID- 15010556
TI  - Effect of antiretroviral therapy on pregnancy outcome in HIV-1 positive women.
AB  - OBJECTIVE: The aim of this study was to assess the effect of antiretroviral
      therapy (ART) on pregnancy outcome. MATERIAL AND METHODS: The study included 102
      HIV-1-infected pregnant women. We investigated maternal and gestational age at
      delivery, time of ART initiation, mode of delivery, birth weight, maternal CD4
      count and HIV-1 viral load at delivery and also drug use during pregnancy. Infant
      HIV-1 status was used to determine the rate of vertical transmission of HIV-1.
      RESULTS: Antiretroviral therapy was given to 81 (79.4%) patients, on zidovudine
      monotherapy there were 35 (34.4%) women, on Highly Active Antiretroviral Therapy
      (HAART) with a protease inhibitor (PI) there were 18 (17.6%) patients and 28
      (27.4%) patients on HAART with no PI regimen. Overall rate of pre-term delivery
      (before 37 weeks of gestation) was estimated as 11.8% (12 out of 102). Premature
      delivery occurred in 16.7% of women on HAART with PI and in 17.9% of women on
      HAART without PI as compared to any case in patients not receiving ART. Combined
      therapy was started before pregnancy or during the first trimester in 62.5% of
      women who delivered prematurely versus 15,6% who gave birth at term. Low birth
      weight (<2500 grams) occurred in 13 of 81 (16%) newborns of treated mothers and
      in 2 of 21 (9.5%) children when mothers did not get any therapy. The highest risk
      of infant low birth weight was associated with receiving HAART containing PI
      (22.2% vs. 13.3% in the group of non-treated women). Vaginal deliveries occurred
      among 67.9% women on HAART without PI and in 76.5% of non-treated women. Elective
      caesarean section was performed in 28.1% of women under monotherapy and in 17.6%
      of non-treated women. Emergency caesarean section was highly prevalent in women
      on HAART without PI (14.2%) compared to non-treated women (5.9%). Rate of mother
      to child HIV-1 transmission among treated women was 8.8% as compared to 25% when
      no ARV therapy during pregnancy was used. No infected infants were born to
      mothers on HAART. Non-treated women had lower CD4 cell count and higher HIV-1
      viral load at delivery. CONCLUSIONS: Pre-term deliveries were highly prevalent
      among women on HAART during pregnancy, especially when therapy was started before
      or in the first trimester of pregnancy. Women receiving HAART with PI were at a
      higher risk of delivering a baby with low birth weight. Antiretroviral therapy
      during pregnancy, together with elective caesarean section, was associated with a
      reduced risk of mother to child transmission of HIV-1.

PMID- 15010557
TI  - Diagnosis and management of children born to HIV infected mothers in Poland.
AB  - OBJECTIVE: The aim of this study was to describe the management of children born
      to HIV positive mothers in Poland. MATERIAL AND METHODS: Between 1987 to 2003,
      218 children of HIV positive mothers were admitted to the Department of
      Children's Infectious Diseases of the Medical University in Warsaw. Currently
      recommended management of newborn infants and the routine schedule of diagnostic
      procedures of children born to HIV positive mothers were discussed. Children, who
      were in the programme of HIV mother to child transmission (MTCT) prophylaxis, are
      followed up from birth. Their psychosomatic development is evaluated. They also
      follow a modified vaccination schedule. RESULTS: From 1994 to 2003 the prevention
      programme of vertical transmission was carried out in 107 children. The risk of
      vertical transmission in this group was 2%. CONCLUSIONS: Children born to HIV
      infected mothers need to be diagnosed, to receive antiretroviral therapy
      initiated at the moment of diagnosis of HIV infection and to be under specialized
      care.

PMID- 15010558
TI  - Cervical disease and cancer in HIV positive women. Recommendations for screening
      and diagnosis.
AB  - Cancer and cervical disease occur more frequently in HIV infected women than in
      HIV negative. HIV infection is associated with an increased prevalence and
      severity of Human Papilloma Virus (HPV) associated cervical intraepithelial
      lesions. Advanced HIV disease is the strongest independent risk factor for cancer
      associated HPV infection. Up to now, there have been limited and controversial
      data on the effect of High Active Antiretroviral Therapy (HAART) on the natural
      history of cervical lesions. The major risk factors associated with cervical
      cancer detection are similar in HIV positive and negative women and include lack
      of screening and prolonged duration of symptoms. HIV positive women should have a
      complete gynaecological examination, including a Pap test, which should be
      performed twice in the first year after the diagnosis of HIV infection. Referral
      for colposcopy and biopsy should be recommended in case of abnormal cytology.

PMID- 15010559
TI  - Vulvar neoplasia in HIV positive women: a review.
AB  - Among genital malignancies, vulvar cancer and its precursor, Vulvar
      Intraepithelial Neoplasia (VIN), is less commonly encountered than cervical
      neoplasia. According to R.W. Jones (2001) vulvar cancer represents about 3-5% of
      all genital neoplasms and its peak of incidence is between 60 and 80 years of
      age. Risk factors for vulvar carcinoma are: smoking and immune depression, which
      expose to a higher risk of vulvar HPV infection caused by high risk strains. In
      recent years, increased prevalence and incidence of high grade VIN and vulvar
      invasive carcinoma in young patients (below 45 years of age) have been reported.
      The main group of affected cases is represented by HIV infected women. Data about
      the severity of immune depression, expressed by CD4 cell count, as an adjunctive
      risk factor for persistence, recurrence or progression, are conflicting and
      scanty. Moreover, information about the effect of Highly Active Antiretroviral
      Therapy (HAART) on the natural history of VIN are inconclusive. So far, a
      thorough examination of the vulvar region, associated with colposcopy and biopsy
      when indicated, should be considered a routine procedure in the gynaecological
      surveillance of HIV positive women.

PMID- 15010560
TI  - Mucosal immune response to Human Papilloma Virus (HPV) infection in HIV positive
      women.
AB  - Mucosal immunity plays a central role in the control of genital human papilloma
      virus (HPV) infection. HIV infection is associated with higher risks of HPV
      induced neoplasias. Prevalence, incidence and evolution of genital HPV lesions
      are correlated with the level of immunodepression. Several changes of the local
      immune response in the genital tract of HIV infected women have been
      demonstrated. The influence of HIV on the production of some immunoregulatory
      cytokines appears of particular interest. The shift from the helper T cells type
      1 (Th1) to the helper T cells type 2 (Th2) immune response, which determines the
      downregulation of the cell-mediated immunity, may explain the frequent loss of
      immunologic control of HPV and its oncological complications

PMID- 15010561
TI  - Non-effective partner notification system: a missed opportunity for the reduction
      of sexually transmitted infections in sub-Saharan Africa.
AB  - It is well know that common sexually transmitted infections (STI) promote
      HIV/AIDS infections in the community. Partner notification is one of the
      recommended strategies used for STI control. Antenatal syphilis screening,
      treatment of syphilis-positive pregnant women and their partner (partners)
      treatment may decrease the number of new syphilis cases, cases of congenital
      syphilis and diminish maternal morbidity and mortality. OBJECTIVE: The aim of the
      study was to assess the adequacy and effectiveness of partner notification and
      treatment system of rapid plasma reagin (RPR) positive patients of antenatal
      clinics (ANC) in Swaziland as an example of a country in sub-Saharan Africa.
      MATERIAL AND METHODS: It was a prospective study of the incidence of syphilis in
      the group of pregnant women attending antenatal clinics (ANC), and a study of the
      results of their partners' notification. The data for this study were collected
      prospectively from routine records of ANC attendees. RESULTS: The positive Rapid
      Plasma Reagin (RPR) test was established in 19% (n = 2034) screened patients. 38%
      out of all RPR-positive patients were not informed of their RPR status. The
      typical syphilis treatment was given in 42% of all RPR-positive pregnant women.
      Only 5% of partners of the RPR-positive pregnant women were traced, checked and
      correctly treated. CONCLUSIONS: The usual way of syphilis screening and partner
      notification in a country like Swaziland is not effective, and there is a need to
      develop other, African-specific methods of syphilis screening and partners'
      notification. Most probably without the effective STI management in Africa the
      battle against HIV/AIDS epidemic will be extremely difficult if not impossible.

PMID- 15010562
TI  - Attitudes among medical students regarding HIV/AIDS.
AB  - OBJECTIVE: To evaluate attitudes and misgivings among the medical faculty's
      students regarding HIV/AIDS. MATERIAL AND METHODS: The 10-item questionnaires was
      distributed among 237 fifth year medical students regarding willingness to take
      care for people living with HIV/AIDS, misgivings contracting HIV, comfortable
      relationship with AIDS patients, attitudes towards HIV infected health care
      workers and support for routine HIV testing. The students filled the
      questionnaire before and after completing the 3-weeks long clinical training.
      RESULTS: Neither willingness to take care nor obligation to treat patients with
      HIV changed significantly during the clinical training. We achieved reduction of
      fear of contracting HIV and an increase in feeling comfortable with HIV infected
      patients. There were no changes in support for HIV testing among patients and
      health care workers. CONCLUSIONS: Medical schools should develop and frequently
      update programmes for continuous training on HIV/AIDS.

PMID- 15010563
TI  - Clinical holistic medicine: applied consciousness-based medicine.
AB  - Consciousness-based medicine is our term for a form of medical treatment that
      works by direct appeal to the consciousness of the patient, in contrast to modern
      biomedical treatment where drugs are used to affect body chemistry. With this
      concept, maybe we are (in a sense) turning back to the "old medicine", where the
      family physician was the all-concerned "old country doctor" who knew the child,
      the siblings, the parents, the family, and the village. In a series of papers on
      clinical holistic medicine, we would like to present the classic art of healing,
      where the physician works mostly with his hands, then show how the modern
      biomedical physician performs with biochemistry, and finally introduce
      consciousness-based medicine. Some of our questions will be: If you improve your
      quality of life, will you also improve your health? Will learning more about
      yourself bring more purpose in your life? Will finding someone to live with in a
      loving and mutually respectful relationship improve your health? Scientists and
      thinkers like Antonovsky, Frankl, Maslow, and Jung have pointed to love as a
      unique way to coherence in life, and thus to biological order and a better
      health. Several scientific studies have also suggested that patients who focus on
      improving their quality of life usually will not follow the general statistics
      for survival, since somehow other factors are at play, which sometimes you will
      find referred to as "exceptional".

PMID- 15010564
TI  - Quality of life: a longitudinal analysis of correlates of morale in old age.
AB  - This paper examines recurrent continuous morale in old age within a statistical
      modelling paradigm. The Anglicised Philadelphia Geriatric Centre Morale Scale was
      used as a small component of a major longitudinal study of old age in rural North
      Wales, U.K. The literature review and cross-sectional analysis of morale in old
      age is published elsewhere. This paper deals with the aspect of the longitudinal
      analysis of morale in old age. The proposed statistical modelling relates
      recurrent morale to a set of explanatory variables that includes subjective as
      well as objective measures. In order to assess the degree to which explanatory
      variables influence morale, an adequate statistical model must handle the
      possibility that substantial variation between respondents will be due to
      unmeasured and potentially unmeasurable variables (residual heterogeneity),
      multicollinearity, and past behaviour effect. These applications are illustrated
      using morale in old age from the North Wales Longitudinal Study Old Age. The
      results suggested a strong presence of heterogeneity effect, i.e., current levels
      of morale appear to be individual specific and independent of its previous
      levels.

PMID- 15010565
TI  - Handgrip strength as a diagnostic tool in work-related upper extremity
      musculoskeletal disorders in women.
AB  - The aim of this study was to determine if handgrip strength might be used as a
      diagnostic tool in musculoskeletal disorders of the upper extremities in women
      working in an industrial environment. The setting was an electronic factory with
      four groups of women (n = 101) in a factory assembling electronic components.
      Handgrip strength was measured using a Jamar hydraulic hand dynamometer. The
      study investigated grip strength in managers-engineers, cable wiring, circuit
      board assembly, integrated circuits women at 90 degrees elbow flexion and 180
      elbow extension. Women seeking or receiving medical care for musculoskeletal
      disorders of the upper extremities or neck showed significant declines (p < 0.01)
      in handgrip strength and these also related to the type of work and the level of
      perceived physical exertion. Women in the managerial-engineering group showed
      fewer musculoskeletal disorders of the upper extremity compared with the other
      groups and also had significantly stronger handgrip. Our findings encourage us to
      recommend hand dynamometer testing as a useful diagnostic tool to determine loss
      of handgrip strength.

PMID- 15010566
TI  - Quality of life: a case report of bullying in the workplace.
AB  - The literature on bullying in the workplace describes the mental and physical ill
      health suffered by the victims and their families as the consequences of the
      bullying. The literature also discusses methods of bullying such as overt and
      covert physical and psychological abuse. The implications are that the
      consequences of abuse go far beyond the intended target; from impact on the
      working environment to individuals' health to economic and financial loss. The
      literature suggests various recommendations to employers and managers to combat
      bullying at work. However, the common assumption within the literature has been
      that the bullying is done by a colleague, a line manager, or middle manager.
      Furthermore, it is often assumed that the executive/vice-chancellor, human
      resources, the trustees, or the governing board are unaware of bullying in their
      workplace. In this article, it is argued that cases of bullying (whether due to
      isolated individuals, competition, rivalry, power, or pure meanness as is
      reported in the literature) can only thrive in a bullying management culture.
      Therefore, debate and policy formulation must be directed at government level in
      the first instance. The case report is intended to raise some relevant issues to
      stimulate a debate and more research in this area.

PMID- 15010567
TI  - Quality of life as medicine III. A qualitative analysis of the effect of a five
      day intervention with existential holistic group therapy or a quality of life
      course as a modern rite of passage.
AB  - Existential group therapy seems to be a very efficient way of inducing the
      holistic state of healing, described in the holistic process theory of healing.
      We have designed a series of four quality of life (QOL) and health courses of 5
      days duration called "Philosophy of Life that Heals--Courses in QOL and Personal
      Development". The four courses are meant to be taken over four consecutive years.
      They contain training in philosophy of life and existential theory as well as
      exercises in holding: awareness, respect, care, acknowledgment, and acceptance.
      The courses teach the participants respect, love, and intimacy; help them to draw
      on their seemingly unlimited hidden resources; and inspire them to take more
      responsibility for their own life. Exercises are accomplished with a partner
      chosen at the course as: (1) a person you like, (2) a person you do not know
      already, or (3) a person to whom you want to give help, support, and holding more
      than you want to get help from him or her. Pilot studies with 5-day quality of
      life interventions that combine training in quality of life philosophy with
      psychotherapy and bodywork have proved effective on patients with chronic pain
      and alcoholism. The present design aims to take this a step further and engage
      the patients in a process of personal growth that will last for years. The aim is
      to lead them to a stabile state of quality of life, health, and ability, from
      where they will not again fall into sickness and unhappiness. The focus of these
      courses is as much on prevention as is it on healing. The existential group
      therapy induces spontaneous healing of body, mind, and soul that seems to be
      highly efficient with hopefully lasting results. Every course is intended to give
      an immediate improvement in the quality of life, so its efficiency can be
      measured with the square curve paradigm. We have studied the participant"s
      accounts from their experience with the courses and have analyzed the remarkably
      large, qualitative changes in the state of being, quality of life, health, and
      consciousness, which many participants experience during the course. The long
      term and preventative effects of the courses have yet to be documented.

PMID- 15010568
TI  - Clinical holistic medicine: classic art of healing or the therapeutic touch.
AB  - Touching is often a forgotten part of medicine. The manual medicine or
      therapeutic touch (TT) is much more powerful than many modern, biomedically
      oriented physicians think. Pain and discomfort can be alleviated just by touching
      the sick area and in this way help the patient to be in better contact with the
      tissue and organs of their body. Lack of presence in the body seems to be
      connected with many symptoms that can be readily reversed simply by sensitive
      touch. When touch is combined with therapeutic work on mind and feelings,
      holistic healing seems to be facilitated and many problems can be solved in a
      direct and easy way in the clinic without drugs. This paper gives examples of the
      strength of manual medicine or therapeutic touch in its most simple form, and
      points to the power of physical contact between physician and his patient in the
      context of the theory and practice of holistic healing. Intimacy seems highly
      beneficial for the process of healing and it is very important to distinguish
      clearly between intimacy and sexuality for the physician and his patent to be
      able to give and receive touch without fear and without holding back emotionally.

PMID- 15010569
TI  - Clinical holistic medicine: holistic pelvic examination and holistic treatment of
      infertility.
AB  - In clinical holistic practice, it is recommended that ample time is spent with
      the gynecological or pelvic examination, especially in cases of women with
      suspected old emotional traumas following early childhood cases of incest or
      sexual abuse. The holistic principles of holding and processing should be
      followed with the purpose of healing the patient, re-establishing the natural
      relationship with the body, sexuality, and reproductive organs. Sexual violations
      are often forcibly repressed. It appears that the tissues that were touched
      during the violation often bear the trauma. It is characteristic of these
      patients that their love lives are often problematic and do not provide the
      necessary support to heal the old wounds in the soul and therapy is therefore
      indicated. When this is concerned with the reproductive organs, it poses
      particular difficulties, as the therapy can easily be experienced as a repetition
      of the original violation, not least due to the risk of projection and
      transference. There is, therefore, a need for a procedure that is familiar to and
      safe for the patient, for all work that involves therapeutic touching of sexual
      organs over and beyond what is standard medical practice. This paper presents one
      case story of earlier child sexual abuse and one case of temporary infertility.
      We have established a procedure of slow or extended pelvic examination, where
      time is spent to make the patient familiar with the examination and accept the
      whole procedure, before the treatment is initiated. The procedure is carried out
      with a nurse, and 3 h are set aside. It includes conversation on the present
      condition and symptoms; concept of boundaries; about how earlier assaults can be
      projected into the present; establishment of the therapeutic room as a safe
      place; exercises on when to say "stop"; therapeutic touch; visualization of the
      pelvic examination step by step beforehand; touching on the outside of the
      clothes with repetition of the "stop" procedure if necessary; pelvic examination
      paying special attention to traumatized (damaged/scarred/blocked) areas with
      feel, acknowledge, and let go of the traumatized areas; postprocessing of
      emotions and traumas with final healing. The patient cannot be healed until
      negative decisions are found and dropped with a tour back to the present, to let
      go of negative sentences and ideas, and a plan for further positive progress.

PMID- 15010570
TI  - European surveillance of travel associated legionnaires' disease.

PMID- 15010571
TI  - Travel associated legionnaires' disease in Europe: 2002.
AB  - Twenty countries reported 676 cases of travel associated legionnaires' disease to
      the EWGLINET surveillance scheme, and 94 clusters were detected. 80.5% of all
      cases were diagnosed by the urinary antigen test. On average there were 20.5 days
      between onset and report of cases, compared with 51.5 days in 1993. Between the
      introduction of the EWGLI investigation guidelines (on 1st July 2002) and the end
      of 2002, 37 six-week investigation reports were accepted as satisfactory and on
      time by the coordinating centre. 274 sites were investigated in total in 2002.
      The travel patterns of the main reporters in EWGLINET influenced the months of
      peak activity, and helped to determine which countries bore the greatest
      investigation burden.

PMID- 15010572
TI  - European Guidelines for Control and Prevention of Travel Associated Legionnaires'
      Disease: the Italian experience.
AB  - In Italy, 35 clusters of travel associated Legionnaires' disease were identified
      from July 2002, when the European Guidelines for Control and Prevention of Travel
      Associated Legionnaires' Disease have been adopted by the EWGLINET network, to
      October 2003. Eight per cent (28.6%) would not have been identified without the
      network. The clusters detected were small, ranging from 2 cases to a maximum of
      6. All clusters involved 5 camping sites and 30 hotels/residences, and an overall
      of 87 patients. The diagnosis was confirmed in 92.0% of the cases and mainly
      performed by urinary antigen detection (84.7%). A clinical isolate was available
      only in one case. Following environmental investigations, samples were collected
      for all the 35 clusters from the water system, and Legionella pneumophila was
      found in 23 occasions (65.7%). In 15 resorts out of 35, investigations were
      already in progress at the time of EWGLI cluster notification, since in Italy
      full environmental investigation is performed even after notification of a single
      case. Control measures were implemented in all accommodation sites at risk and
      one hotel only was closed. In all the 35 clusters, reports were completed and
      sent on time, highlighting that it is possible to comply with the procedures
      requested by the European Guidelines.

PMID- 15010573
TI  - Clusters of travel associated legionnaires' disease in France, September 2001-
      August 2003.
AB  - Clusters of travel associated legionnaires' disease warrant urgent attention, and
      are detected by the French national surveillance system and the European network
      EWGLINET. Between September 2001 and August 2003, 37 clusters were identified in
      French tourist accommodation: 27 hotels and 10 campsites. The number of clinical
      cases per cluster was as follows: 30 clusters of 2 cases (81%), 6 clusters of 3
      cases (16%) and one cluster of 4 cases (3%), a total of 82 cases. The local
      health authorities performed environmental investigations for 36 of the 37
      clusters. Among the 36 clusters investigated, water samples were collected for
      35. At 16 (46%) sites, Legionella pneumophila was found at a level of more than
      103 cfu/litre. In all of the accommodation where risk assessment was found to be
      inadequate- control measures were implemented immediately. Six hotels were closed
      immediately following cluster alerts. Comparison of clinical and environmental
      isolates by pulsed field gel electrophoresis (PFGE) was possible in 3 clusters
      and identical genomic profiles of the isolates were found in all. During this two
      year period of surveillance, we found that on many sites there has been a risk of
      exposure to Legionella. This reinforces the importance of the European
      surveillance network and the timely notifications of all the cases to EWGLINET.

PMID- 15010574
TI  - Legionnaires' disease clusters associated with travel to Spain during the period
      January 2001 to July 2003.
AB  - Epidemiological surveillance and control of travel associated cases of
      legionnaires' disease are necessary tasks for public health and collaboration
      between countries is necessary to do this. Within the framework of the European
      Surveillance Scheme for Travel Associated Legionnaires' Disease (EWGLINET),
      European Guidelines for Control and Prevention of Travel Associated Legionnaires'
      Disease have been produced . This has established the reporting and response
      criteria when cases or clusters appear. In this paper the analysis of the
      information corresponding to the 46 reported clusters related to Spain is
      presented. Data corresponds to the period January 2001 to July 2003.

PMID- 15010575
TI  - Transvascular passage of macromolecules into the peritoneal cavity of normo- and
      hypothermic rats in vivo: active or passive transport?
AB  - During the last decades there has been a debate regarding whether transvascular
      protein transport is an active (transcytosis) or a passive (porous) process. To
      separate cooling-sensitive transcytosis from passive transport processes between
      blood and peritoneal fluid, we induced hypothermia in rats in vivo, reducing
      their body temperature to 19 degrees C. Control rats were kept at 37 degrees C.
      Either human albumin, or IgG, or IgM, or LDL, radiolabeled with (125)I, was given
      intra-arterially together with (51)Cr-EDTA. During tracer administration, a 2
      hour peritoneal dialysis dwell was performed. Clearance of the tracers to
      dialysate, and the permeability-surface area coefficient (PS) for (51)Cr-EDTA and
      glucose were assessed. During cooling, mean arterial blood pressure (MAP) was
      reduced to 40% of control and plasma viscosity increased by 48.5%, while
      peritoneal blood flow was reduced to 10%. At 19 degrees C, clearance of albumin
      to dialysate fell from 9.30 +/- 1.62 (SEM) to 3.13 +/- 0.28 microl/min (p <
      0.05), clearance of IgG from 6.33 +/- 0.42 to 2.54 +/- 0.12 microl/min (p <
      0.05), clearance of IgM from 3.65 +/- 0.33 to 1.10 +/- 0.12 microl/min (p <
      0.05), and clearance of LDL from 3.54 +/- 0.20 to 0.73 +/- 0.06 microl/min (p <
      0.05). The fall in PS for (51)Cr-EDTA was from 0.320 +/- 0.01 to 0.075 +/- 0.003
      ml/min (p < 0.05), and that for glucose from 0.438 +/- 0.02 to 0.105 +/- 0.01
      ml/min (p < 0.05). Tissue cooling reduced large solute transport largely in
      proportion to the cooling-induced reductions of MAP (to 40%), and the concomitant
      increase in viscosity (to 67%), i.e. to approximately 20-30% (0.40 x 0.67) of
      control, though LDL clearance was reduced further. The fall in small solute PS,
      in excess of the viscosity effect, mirrored the fall in peritoneal blood flow
      occurring during hypothermia. In conclusion, the good correlation of predicted to
      calculated changes suggests that the overall transendothelial macromolecular
      passage in vivo occurs passively, and not due to active processes.

PMID- 15010576
TI  - Increased expression of endothelin-converting enzyme-1c isoform in response to
      high glucose levels in endothelial cells.
AB  - Endothelin-1 (ET-1) is both a potent vasoconstrictor and mitogenic factor that
      has been implicated as a cause of the micro- and macrovascular complications of
      diabetes mellitus. The pathway by which the high-glucose environment of diabetes
      mediates increased levels of endothelins has not been completely elucidated but
      appears to involve endothelin-converting enzyme (ECE-1), which converts inactive
      big ET-1 to active ET-1 peptide. To determine the effect of high glucose
      concentrations on the expression of ECE-1, hybrid endothelial cells (EA.hy926)
      and human umbilical vein endothelial cells (HUVEC) were both grown in various
      glucose concentrations. There was a 2-fold increase in ECE-1 immunoreactivity in
      the EA.hy926 cell line growing in medium containing 22.2 versus 5.5 mmol/l
      glucose after 24 h, which rose to greater than 20-fold after 5 days. Similar
      results were seen with HUVEC. Bradykinin or NG-nitro-L-arginine methyl ester did
      not change the effect of high glucose on ECE-1 protein expression. High glucose
      induced a 72 and 41% increase in total protein kinase C (PKC) activity in both
      EA.hy926 cells and HUVEC, respectively, and a 39, 49 and 109% elevation in PKC
      beta1, beta2 and delta expression, respectively, in EA.hy926 cells. The increase
      in ECE-1 expression was inhibited in both cell cultures by GF109203X (5
      micromol/l), a general PKC inhibitor, while addition of 10 nmol/l phorbol
      myristic acid to EA.hy926 cells or HUVEC growing on medium containing 5.5 mmol/l
      glucose increased ECE-1 expression to a level similar to that of cells
      conditioned in high glucose. Human ECE-1 protein exists in four different
      isoforms, termed 1a, 1b, 1c and 1d. Northern blot analysis revealed that only ECE
      1c isoform mRNA levels increased. Immunohistochemical staining of EA.hy926 cells
      grown in high glucose concentrations demonstrated an increase in the ECE-1c
      isoform, which occurred mainly in the plasma membrane. These results showed that
      the PKC pathway may play an important role in the glucose-mediated induction of
      ECE-1 expression. The main isoform to increase in response to high glucose was
      ECE-1c. This enzyme may be one of the factors contributing to the elevated ET-1
      peptide levels observed in diabetes.

PMID- 15010577
TI  - Polyamine synthesis inhibition attenuates vascular smooth muscle cell migration.
AB  - Vascular smooth muscle cell migration, occurring after intimal injury, is a
      substantial clinical problem in atherosclerosis and restenosis after stenting.
      Here we investigate the effects of polyamine synthesis inhibition on vascular
      smooth muscle cell migration after maximal and submaximal growth stimulation with
      PDGF-AB or FCS. Vascular smooth muscle cells were obtained from mouse aorta
      explants. These cells coexpressed smooth muscle alpha-actin, PDGFRalpha and
      PDGFRbeta as demonstrated by immunocytochemistry. Treatment with a high (100
      ng/ml) concentration of PDGF-AB stimulated DNA synthesis 6-fold and markedly
      elevated cell migration. PDGF-AB (100 ng/ml) increased cellular spermidine
      concentration 2-fold, but had no effect on spermine or putrescine levels.
      Treatment with the polyamine synthesis inhibitors CGP48664 (1 microM) and DFMO (5
      mM) prevented the PDGF-AB-induced increase in spermidine and reduced spermine
      concentrations, but had no effect on PDGF-AB-stimulated DNA synthesis or cell
      migration. Cell migration after submaximal stimulation with either PDGF-AB (8
      ng/ml) or FCS (8%) was, however, inhibited by the polyamine synthesis blockers.
      In summary, these data show that polyamine synthesis inhibition attenuates
      vascular smooth muscle cell migration under submaximal growth-stimulating
      conditions, suggesting that polyamines participate in regulation of cell
      migration and that treatment with polyamine synthesis inhibitors might reduce
      vascular smooth muscle cell migration after intimal injury.

PMID- 15010578
TI  - Observations on genital morphology and anatomy of a hybrid male muriqui (genus
      Brachyteles).
AB  - The reproductive anatomy of the muriqui (genus Brachyteles) is poorly known. This
      paper describes the anatomy of the testis, penis and striated penile muscles in a
      young adult (5.25-year-old) captive-born muriqui which died at the Rio Primate
      Center. Two forms of muriqui occur in the Atlantic coastal forests of Brazil, and
      both are endangered. The form which is found north of 21 degrees 00' S latitude
      is classified as B. hypoxanthus by some authorities and is considered to be a
      species separate from B. arachnoides. The male specimen described here was a
      hybrid (the sire was B. arachnoides and the mother B. hypoxanthus). Hybridization
      was associated with absence of spermatozoa in the testis and with degeneration of
      the seminiferous epithelium. The structure of the prominent penis and striated
      penile muscles is discussed in relation to patterns of copulatory behavior and
      the likely occurrence of sperm competition in the muriqui. In addition, the
      occurrence of a baculum (os penis) is confirmed for this genus, and the first
      description of its morphology is provided.

PMID- 15010579
TI  - Microhabitat preference and vertical use of space by patas monkeys (Erythrocebus
      patas) in relation to predation risk and habitat structure.
AB  - Habitat structure can be important in determining habitat preference of animals
      because it is often closely linked to factors that affect survival and
      reproduction, such as food availability and predation risk. Here we examine the
      ways in which microhabitat structure and predation risk affect the habitat
      preference of wild patas monkeys (Erythrocebus patas). Patas monkeys in Kenya are
      typically restricted to Acacia drepanolobium habitat, but within our study
      group's home range, there are two distinct microhabitats, one with taller trees
      ('tall microhabitat') and one with apparently perennially shorter trees ('short
      microhabitat'). Examination of ranging behavior indicates that the patas monkeys
      preferred the tall microhabitat. In the tall microhabitat, focal animals climbed
      into trees that were significantly taller than average, indicating that they
      preferred tall trees. Female patas monkeys spent more time scanning from tall
      trees than from short trees and detected predators only from taller than average
      trees, based on alarm call data. Their use of tall trees may have decreased their
      predation risk by increasing their ability to detect predators. We found no
      evidence of increased food availability or reduced predator presence in the tall
      microhabitat that could contribute to the monkeys' preference for the tall
      microhabitat.

PMID- 15010580
TI  - Differences in aerial and terrestrial visual scanning in captive black tufted-ear
      marmosets (Callithrix penicillata) exposed to a novel environment.
AB  - Aerial and terrestrial visual scanning were investigated in captive black tufted
      ear marmosets, Callithrix penicillata, exposed to a novel environment. Naive
      adult subjects (n=24) were individually exposed to a figure-eight maze during
      seven 30-min trials, 48 h apart. Habituation to the maze was observed, as
      indicated by the significant decrease in locomotion. The frequency of aerial
      scanning, however, remained elevated throughout the 7 trials, while its duration
      rapidly increased to high levels. Frequency and duration of terrestrial scanning
      persisted at constant low rates, differing significantly from aerial scanning.
      Males and females did not differ significantly. The different impact of aerial
      versus terrestrial predators could have a significant influence on vigilant
      behaviour in this species. Thus, visual scanning is an important and highly
      organized antipredation strategy in marmosets.

PMID- 15010581
TI  - Population density of black howlers (Alouatta caraya) in the gallery forests of
      the Argentinean Chaco: a preliminary assessment.

PMID- 15010582
TI  - Social organization of white-headed langurs Trachypithecus leucocephalus in
      Fusui, China.

PMID- 15010583
TI  - Transfer from the natal group is related to presence of immature relatives in
      orphaned male rhesus macaques (Macaca mulatta).

PMID- 15010584
TI  - Three apparent cases of infanticide by males in wild white-faced capuchins (Cebus
      capucinus).

PMID- 15010585
TI  - Urinary testosterone metabolite levels in captive bonobos: relationship with age.

PMID- 15010586
TI  - Fatal attack of a Boa constrictor on a bearded saki (Chiropotes satanas
      utahicki).

PMID- 15010587
TI  - Masturbation observations in Temmnick's red colobus.

PMID- 15010588
TI  - Circulatory and respiratory complications of carbon dioxide insufflation.
AB  - BACKGROUND: Although providing excellent outcome results, laparoscopy also
      induces particular pathophysiological changes in response to pneumoperitoneum.
      Knowledge of the pathophysiology of a CO(2) pneumoperitoneum can help minimize
      complications while profiting from the benefits of laparoscopic surgery without
      concerns about its safety. METHODS: A review of articles on the
      pathophysiological changes and complications of carbon dioxide pneumoperitoneum
      as well as prevention and treatment of these complications was performed using
      the Medline database. RESULTS: The main pathophysiological changes during CO(2)
      pneumoperitoneum refer to the cardiovascular system and are mainly correlated
      with the amount of intra-abdominal pressure in combination with the patient's
      position on the operating table. These changes are well tolerated even in older
      and more debilitated patients, and except for a slight increase in the incidence
      of cardiac arrhythmias, no other significant cardiovascular complications occur.
      Although there are important pulmonary pathophysiological changes, hypercarbia,
      hypoxemia and barotraumas, they would develop rarely since effective ventilation
      monitoring and techniques are applied. The alteration in splanchnic perfusion is
      proportional with the increase in intra-abdominal pressure and duration of
      pneumoperitoneum. CONCLUSION: A moderate-to-low intra-abdominal pressure (<12 mm
      Hg) can help limit the extent of the pathophysiological changes since consecutive
      organ dysfunctions are minimal, transient and do not influence the outcome.

PMID- 15010589
TI  - Localised megacolon complicating neurofibromatosis type 1.

PMID- 15010590
TI  - The evolution of the Proteocephalidea (Platyhelminthes, Eucestoda) based on an
      enlarged molecular phylogeny, with comments on their uterine development.
AB  - We present a molecular phylogeny of the Proteocephalidea based on 28S rDNA
      sequence data that is a follow-up to the paper by Zehnder & Mariaux (1999).
      Twenty-three new sequences, including three outgroups are added in our new data
      set. The Gangesiinae Mola, 1929 and the Acanthotaeniinae Freze, 1963 appear to be
      the most primitive clades. They are followed by a robust clade comprising the
      Palaearctic Proteocephalinae Mola, 1929 from freshwater fishes. The structure of
      the more derived clades, comprising most Neotropical and Nearctic species, is
      less resolved. At the nomenclatural level, we erect a new genus, Glanitaenia n.
      g. for G. osculata (Goeze, 1782) n. comb., previously Proteocephalus osculatus,
      and define an aggregate for the Palaearctic Proteocephalus Weinland, 1858. After
      a re-examination of all of the studied taxa, we identify two types of uterine
      development and show the importance of this character for the systematics of the
      order. Our phylogeny does not support the classical view of a Neotropical origin
      for the Proteocephalidea but rather favours an Old World origin of the group
      either in saurians or Palaearctic Siluriformes.

PMID- 15010591
TI  - Filling the Gondwana gaps: new species and new reports of Beatogordius Heinze,
      1934 (Nematomorpha) from Australia and Madagascar.
AB  - We describe two new species of Beatogordius Heinze, 1934 (Nematomorpha), B.
      australiensis and B. lineatus, from Queensland, Australia. One further species,
      B. abbreviatus (Villot, 1874), which was known from Reunion, is reported from
      Madagascar. These new reports extend the range of Beatogordius from Africa and
      South America to include Madagascar and Australia. Beatogordius was likely
      distributed over the Gondwana continent prior to the separation of continental
      plates in the Mesozoic. This extends the existence of the taxon Nematomorpha,
      which was only known from young brown coal and amber, into the Mesozoic. Adhesive
      warts, structures anterior of the cloacal opening in males of B. abbreviatus,
      were originally described as characteristic structures of Gordionus Muller, 1927,
      but their occurrence in B. abbreviatus and one South American species indicates a
      wider distribution of this character.

PMID- 15010592
TI  - Morphometric variability between and within species of Ligophorus Euzet &
      Suriano, 1977 (Monogenea: Ancyrocephalidae) in the Mediterranean Sea.
AB  - Monogeneans belonging to the genus Ligophorus Euzet & Suriano, 1977 are parasitic
      on the gills of several fish species of the family Mugilidae (mullets). At
      present, 12 species belonging to this genus have been described in the
      Mediterranean Sea and each host species is infected by a number of Ligophorus
      species that are not found on other mullets. A multivariate study using principal
      component and canonical variate analyses was carried out, with the aim of
      investigating the extent of morphometric variability within and between the 12
      Mediterranean species of Ligophorus. Significant intraspecific morphometric
      variation was detected between two allopatric populations of L. angustus Euzet &
      Suriano, 1977 parasitic on Chelon labrosus from Sardinia; however, the existence
      of a new species of Ligophorus needs further evidence. Analysis of interspecific
      variation confirms the validity of the morphological keys used at present for the
      identification of Ligophorus at the species level and provides a picture of the
      relationships between species, indicating that the two species parasitising Mugil
      cephalus, L. chabaudi Euzet & Suriano, 1977 and L. mugilinus (Hargis, 1955) are
      the most differentiated. The hypothesis that strict host-parasite ecological
      relationships may be the result of co-speciation processes is briefly discussed.

PMID- 15010593
TI  - Life-cycles of cestodes of the genus Branchiopodataenia Bondarenko &
      Kontrimavichus, 2004 (Cestoda: Hymenolepididae) from gulls in Chukotka.
AB  - Data are presented on the life-cycles and the postembryonal development of four
      species of Branchiopodataenia Bondarenko & Kontrimavichus, 2004, B.
      anaticapicirra Bondarenko & Kontrimavichus, 2004, B. arctowskii (Jarecka & Ostas,
      1984), B. haldemani (Schiller, 1951) and B. pacifica (Spassky & Jurpalova, 1968),
      which are specific parasites of gulls. The investigation was carried out in
      Chukotka (Chaun Bay) between 1971 and 1981 under natural and experimental
      conditions. Branchiopod crustaceans were exclusive natural and experimental
      intermediate hosts of all of the species studied; this fact provided additional
      evidence for the erection of Branchiopodataenia. The metacestodes exhibit a
      pattern of postembryonal development and a typical larval form, termed a
      'cercocyst', which is a modification of a cysticercoid. This modification of the
      metacestode does not occur in species of Wardium Mayhew, 1925, the genus with
      which species of Branchiopodataenia had previously been affiliated.

PMID- 15010594
TI  - Tormopsolus orientalis Yamaguti, 1934 (Digenea: Acanthocolpidae) from Seriola
      dumerili (Risso) (Perciformes: Carangidae) in the western Mediterranean Sea.
AB  - Tormopsolus orientalis Yamaguti, 1934, is redescribed from Seriola dumerili from
      off Corsica, Majorca and Aguilas, SE Spain. The vitellarium is interrupted at the
      level of the ovary and both testes, and a bipartite seminal vesicle is found in
      many specimens. Oral sucker papillae are always seen. Type-specimens and voucher
      specimens from off Japan, Bermuda, Panama, Curacao and the Great Barrier Reef
      have been compared with the Mediterranean species. Specimens of T. medius Reimer,
      1983, from Mozambique have been studied and this species is synonymised with T.
      orientalis.

PMID- 15010596
TI  - Two new species of Dendromonocotyle Hargis, 1955 (Monogenea: Monocotylidae) from
      the skin of Taeniura meyeni (Dasyatidae) and Aetobatus narinari (Myliobatidae)
      from aquaria in Queensland, Australia.
AB  - Dendromonocotyle pipinna n. sp. (Monogenea: Monocotylidae) is described from the
      dorsal skin surface of Taeniura meyeni Muller & Henle from a public aquarium in
      Mooloolaba, Queensland, Australia. D. torosa n. sp. was found on the dorsal skin
      surface of a heavily infected specimen of Aetobatus narinari (Euphrasen) during a
      post-mortem at the Mooloolaba aquarium and on a specimen of A. narinari kept in
      an aquarium in Cairns. Both of these new Dendromonocotyle species are
      distinguished from each other and others in the genus by the morphology of the
      terminal papillary sclerite and the male copulatory organ.

PMID- 15010595
TI  - Description of the nymph and larva and redescription of the female of Ixodes
      neuquenensis Ringuelet, 1947 (Acari: Ixodidae), a parasite of the endangered
      Neotropical marsupial Dromiciops gliroides Thomas (Microbiotheria:
      Microbiotheriidae).
AB  - The female of Ixodes neuquenensis Ringuelet, 1947 (Acari: Ixodidae) is
      redescribed and the nymph and larva are described from specimens collected from
      the endangered marsupial Dromiciops gliroides Thomas (Microbiotheria:
      Microbiotheriidae) in Argentina. At first sight the female of I. neuquenensis
      resembles a member of the subgenus Ixodes Latreille, 1795. However, the female of
      I. neuquenensis is peculiar in having the combination of two spurs on coxae II-IV
      and a pair of chitinous plaques internal to coxa I. Both the nymph and larva have
      an anterior and posterior process on palpal article I, characteristics of the
      subgenus Ixodiopsis Filippova, 1957 and some representatives of the subgenus
      Pholeoixodes Schulze, 1942. Analysis of 16S mitochondrial rDNA sequences showed
      no strong relationship with any known Ixodes subgenus.

PMID- 15010597
TI  - A new species of Pseudanisakis Layman & Borovkova, 1926 (Nematoda: Ascaridida)
      from Rioraja agassizii and Psammobatis extenta (Rajidae) in Brazilian
      southwestern Atlantic waters.
AB  - Pseudanisakis sulamericana n. sp. is described from the intestines of the rays
      Rioraja agassizii and Psammobatis extenta off the coast of Brazil. It can be
      readily differentiated from the three existing species of the genus. From P.
      tricupola Gibson, 1973, it differs in not having cupolas on the lips, having a
      dentigerous ridge of 90-95 denticles ( vs 65-78) in a continuous subtriangular
      ring around the mouth, and in having an ejaculatory duct which is shorter than
      the spicules. From P. rajae (Yamaguti, 1941), it differs in having a single
      rather than a double row of denticles. It appears most similar to P. baylisi
      Gibson, 1973, but differs from it in having a smaller body-size (7.5-27 vs 16-46
      mm), shorter spicules (1.14-1.90 vs 1.90-3.80 mm) and especially in having much
      more conspicuous denticles on the lips. The present record confirms the presence
      of the genus in subtropical waters.

PMID- 15010599
TI  - Selective transcription and post-transcriptional processing of the heteroplasmic
      mitochondrial orf156 copies in the nucleus-cytoplasm hybrids of wheat.
AB  - Transcript profile and post-transcriptional processing of the mitochondrial
      orf156 were compared among the nucleus-cytoplasm (NC) hybrids of tetraploid and
      hexaploid wheat and their parental lines. These NC hybrids, in which the plasmon
      from the maternal Aegilops squarrosa parent is combined with the nuclear genomes
      of the paternal parents, and their parental lines were previously shown to have
      heteroplasmic copies of the polycistronic transcriptional unit nad3-orf156 in
      different sub-stoichiometries. Despite the heteroplasmic conditions, only single
      transcript types were detected among reverse transcription-PCR products of the
      orf156 mRNA in the respective lines. In the NC hybrids only a major maternal copy
      was transcribed and edited, likewise in the parental lines only single major
      copies were transcribed and edited. RNA gel blot analysis using the orf156 probe
      showed that the NC hybrids had the transcripts similar to the parental lines but
      unlike the maternal line. Primer extension analysis further revealed the orf156
      transcripts with different 5' termini, which most probably resulted from the
      alternative post-transcriptional cleavages of the precursor mRNA. These cleaved
      transcripts were polymorphic not only among the lines but also among four
      different tissues. The cleavages were highly selective and the paternal-type
      cleavages predominated in the NC hybrids, irrespective of the tissues studied.
      This seemingly neutral polymorphisms in wheat could make this system convenient
      for further analysis of mitochondrial gene expression in plants.

PMID- 15010601
TI  - Physcomitrella patens as a model for the study of chloroplast protein transport:
      conserved machineries between vascular and non-vascular plants.
AB  - A single general import pathway in vascular plants mediates the transport of
      precursor proteins across the two membranes of the chloroplast envelope, and at
      least four pathways are responsible for thylakoid protein targeting. While the
      transport systems in the thylakoid are related to bacterial secretion systems,
      the envelope machinery is thought to have arisen with the endosymbiotic event and
      to be derived, at least in part, from proteins present in the original
      endosymbiont. Recently the moss Physcomitrella patens has gained worldwide
      attention for its ability to undergo homologous recombination in the nuclear
      genome at rates unseen in any other land plants. Because of this, we were
      interested to know whether it would be a useful model system for studying
      chloroplast protein transport. We searched the large database of P. patens
      expressed sequence tags for chloroplast transport components and found many
      putative homologues. We obtained full-length sequences for homologues of three
      Toc components from moss. To our knowledge, this is the first sequence
      information for these proteins from non-vascular plants. In addition to
      identifying components of the transport machinery from moss, we isolated plastids
      and tested their activity in protein import assays. Our data indicate that moss
      and pea (Pisum sativum) plastid transport systems are functionally similar. These
      findings identify P. patens as a potentially useful tool for combining genetic
      and biochemical approaches for the study of chloroplast protein targeting.

PMID- 15010602
TI  - Members of the aquaporin family in the developing pea seed coat include
      representatives of the PIP, TIP, and NIP subfamilies.
AB  - Water and nutrients required by developing seeds are mainly supplied by the
      phloem and have to be released from a maternal parenchyma tissue before being
      utilized by the filial tissues of embryo and endosperm. To identify aquaporins
      that could be involved in this process four full-length cDNAs were cloned and
      sequenced from a cDNA library of developing seed coats of pea (Pisum sativum L.).
      The cDNA of PsPIP1-1 appeared to be identical to that of clone 7a/TRG-31, a
      turgor-responsive gene cloned previously from pea roots. PsPIP1-1, PsPIP2-1, and
      PsTIP1-1, or their possible close homologues, were also expressed in cotyledons
      of developing and germinating seeds, and in roots and shoots of seedlings, but
      transcripts of PsNIP-1 were only detected in the seed coat. In mature dry seeds,
      high hybridization signals were observed with the probe for PsPIP1-1, but
      transcripts of PsPIP2-1, PsTIP1-1, and PsNIP-1 were not detected. Functional
      characterization after heterologous expression in Xenopus oocytes showed that
      PsPIP2-1 and PsTIP1-1 are aquaporins whereas PsNIP-1 is an aquaglyceroporin.
      PsNIP-1, like several other NIPs, contains a tryptophan residue corresponding
      with Trp-48 in GlpF (the glycerol facilitator of Escherichia coli) that borders
      the selectivity filter in the permeation channel. It is suggested that PsPIP1-1
      and/or its possible close homologues could play a role in water absorption during
      seed imbibition, and that PsPIP2-1, possibly together with PsPIP1-1, could be
      involved in the release of phloem water from the seed coat symplast, which is
      intimately connected with the release of nutrients for the embryo.

PMID- 15010604
TI  - Mutation of a family 8 glycosyltransferase gene alters cell wall carbohydrate
      composition and causes a humidity-sensitive semi-sterile dwarf phenotype in
      Arabidopsis.
AB  - The genome of Arabidopsis thaliana contains about 400 genes coding for
      glycosyltransferases, many of which are predicted to be involved in the synthesis
      and remodelling of cell wall components. We describe the isolation of a
      transposon-tagged mutant, parvus, which under low humidity conditions exhibits a
      severely dwarfed growth phenotype and failure of anther dehiscence resulting in
      semi-sterility. All aspects of the mutant phenotype were partially rescued by
      growth under high-humidity conditions, but not by the application of growth
      hormones or jasmonic acid. The mutation is caused by insertion of a maize
      Dissociation (Ds) element in a gene coding for a putative Golgi-localized
      glycosyltransferase belonging to family 8. Members of this family, originally
      identified on the basis of similarity to bacterial lipooligosaccharide
      glycosyltransferases, include enzymes known to be involved in the synthesis of
      bacterial and plant cell walls. Cell-wall carbohydrate analyses of the parvus
      mutant indicated reduced levels of rhamnogalacturonan I branching and alterations
      in the abundance of some xyloglucan linkages that may, however, be indirect
      consequences of the mutation.

PMID- 15010605
TI  - Cestrum yellow leaf curling virus (CmYLCV) promoter: a new strong constitutive
      promoter for heterologous gene expression in a wide variety of crops.
AB  - Appropriately regulated gene expression requires a suitable promoter. A number of
      promoters have been isolated and shown to be functional in plants, but only a few
      of them activate transcription of transgenes at high levels constitutively. We
      report here the cloning and characterization of a novel, constitutively expressed
      promoter isolated from Cestrum yellow leaf curling virus (CmYLCV), a double
      stranded DNA plant pararetrovirus belonging to the Caulimoviridae family. The
      CmYLCV promoter is highly active in callus, meristems and vegetative and
      reproductive tissues in Arabidopsis thaliana, Nicotiana tabacum, Lycopersicon
      esculentum, Zea mays and Oryza sativa. Furthermore, the level of expression is
      comparable to, or higher than, that from the CaMV 35S, the 'super-promoter' or
      the maize ubiquitin 1 promoters, three frequently used promoters in agricultural
      biotechnology. The heritable, strong and constitutive activity in both
      monocotyledonous and dicotyledonous plants, combined with the extremely narrow
      CmYLCV host range, makes the CmYLCV promoter an attractive tool for regulating
      transgene expression in a wide variety of plant species.

PMID- 15010606
TI  - Spontaneous mutation frequency in plants obscures the effect of chimeraplasty.
AB  - In this study we tested the performance of chimeraplasts, chimeric RNA/DNA
      oligonucleotides, for the creation of directed changes in chromosomal sequences
      in tobacco and oilseed rape. As target genes for chimeraplasty, the endogenous
      als gene and two transgenes, bar and a fusion between egfp and bar, were used. In
      experiments in which similar numbers of cells were treated with and without
      chimeraplasts, delivery of chimeraplasts did not lead to increased numbers of
      herbicide-resistant or egfp fluorescent calli. Sequence analysis of the target
      genes revealed a range of sequence changes rather than the sequence modification
      intended through chimeraplast design. Importantly, in both the presence and
      absence of chimeraplasts, similar types of changes were obtained at similar
      frequencies. These data suggest that the observed changes at the target codon
      result primarily from spontaneous mutation.

PMID- 15010607
TI  - In vivo phosphorylation of a recombinant peptide substrate of CDPK suggests
      involvement of CDPK in plant stress responses.
AB  - A phage display library displaying random peptides 15 amino acids in length was
      screened for peptides that interact with soybean (Glycine max L.) CDPKalpha, an
      isoform of calcium-dependent protein kinase (EC 2.7.1.37). Interaction of phage
      displaying the peptide RHPTLTRSPTLRNIQ with CDPKalpha was confirmed in an
      independent binding assay. A synthetic peptide corresponding to this sequence
      plus the surrounding amino acids AERHPTLTRSPTLRNIQPPC was synthesized and found
      to be a substrate of CDPK isoforms alpha, beta, and gamma. A second random
      peptide phage display library was constructed that displayed the substrate
      peptide sequence plus an additional 10 random amino acids on its amino-terminal
      side. Nine new peptides were obtained from the screening, all of which were
      phosphorylated by CDPKalpha. Sequence VSPRSFWTTWRHPTLTRSPTLRNIQ appeared twice in
      the screen. Because it agreed well with the consensus phosphorylation site of
      CDPKs, its coding sequence was cloned and stably transformed into tobacco cells.
      The substrate peptide expressed in tobacco was phosphorylated by recombinant
      CDPKalpha in vitro and by endogenous CDPK in vivo. Increased phosphorylation of
      the peptide substrate in response to hydrogen peroxide treatment was observed in
      transgenic tobacco cells. These results show that the peptide substrate expressed
      in tobacco cells can be used as a CDPK activity reporter for in vivo studies.

PMID- 15010608
TI  - Rapid induction of a protein disulfide isomerase and defense-related genes in
      wheat in response to the hemibiotrophic fungal pathogen Mycosphaerella
      graminicola.
AB  - Mycosphaerella graminicola, incitant of septoria tritici blotch, is a widespread
      and significant pathogen of wheat that is not closely related to other fungi
      being developed as genetic models for host-pathogen interactions. Several
      resistance genes in wheat have been identified, yet the molecular mechanisms of
      resistance are unknown. To identify host genes involved in the resistance
      response, expression profiles of the wheat line Tadinia (containing the Stb4 gene
      for resistance) and the susceptible line Yecora Rojo, non-inoculated or
      inoculated with M. graminicola, were compared by differential-display polymerase
      chain reaction (DD-PCR). Among the differentially expressed genes was a protein
      disulfide isomerase (PDI), which is well known as a molecular chaperone and
      component of signal-transduction pathways in animal systems but had not been
      implicated previously in plant defense response. Real-time quantitative reverse
      transcription PCR and northern analysis revealed that PDI was induced within 3 h
      of inoculation with highest induction in the pathogen-treated resistant lines.
      These responses of PDI were similar to the early and strong resistance-related
      responses displayed by the pathogenesis-related (PR) proteins, PR-1, PR-2 and PR
      5. In contrast, a wheat lipoxygenase was down-regulated in the resistant lines at
      time points corresponding with peak induction of the PR genes. Thus, part of the
      resistance mechanism may involve repression of a gene that could otherwise aid
      fungal growth. Wheat responds much more rapidly than believed previously to
      signals produced by M.graminicola. These early responses begin prior to
      penetration of the host and appear to determine the outcome of the host-pathogen
      interaction.

PMID- 15010609
TI  - Arabidopsis MBD proteins show different binding specificities and nuclear
      localization.
AB  - Recent results in animals and plants have shown a strong link between DNA
      methylation, chromatin structure and epigenetic control. In plants DNA
      methylation affects both symmetric and asymmetric cytosines by means of different
      DNA-methyltransferases. In vertebrates these modifications are interpreted by a
      group of proteins (methylated DNA-binding domain proteins, MBDs) able to
      specifically bind methylated CpG. In plants several genes sharing structural
      homology to mammalian MBD have been identified in Arabidopsis and maize, but
      their characterization is still to be completed. Here we present the
      characterization of six different MBDs from Arabidopsis. As judged by semi
      quantitative RT-PCR, their expression proved to be differentially modulated in
      different organs. All the corresponding polypeptides, expressed in Escherichia
      coli as His-tagged recombinant proteins, have been functionally tested on gel
      shift experiments but only two of them (namely MBD5, 6) were able to specifically
      bind methylated CpG oligonucleotides. A third protein, AtMBD11, showed a strong
      affinity for DNA independently from the level of methylation. Moreover we were
      able to differentiate MBD5 and 6, despite their high homology, for their ability
      to recognize methylated asymmetrical sites. The binding specificity of these
      three AtMBD proteins was tested not only on arbitrarily chosen probes but also on
      the Arabidopsis E2F recognition sequence containing a single CpG site.
      Protoplasts transient expression experiments of GFP-fusion proteins showed for
      AtMBD5 and AtMBD6 a heterochromatic localization which was affected by 5
      azacytidine treatment. These data demonstrate that AtMBD5 and AtMBD6 bind
      methylated DNA in vitro and in vivo with different specificity and might
      therefore have different roles in methylation-mediated transcriptional silencing.

PMID- 15010610
TI  - Genome-wide gene expression in an Arabidopsis cell suspension.
AB  - Plant cell suspension cultures are invaluable models for the study of cellular
      processes. Here we develop the recently described Arabidopsis suspension culture
      MM2d as a transcript profiling platform by means of Affymetrix ATH1 microarrays.
      Analysis of gene expression profiles during normal culture growth, during
      synchronous cell cycle re-entry and during synchronous cell cycle progression
      provides a unique integrated view of gene expression responses in a higher-plant
      system. Particularly striking is that expression of over 14 000 genes belonging
      to all defined categories can be reliably detected, suggesting that integrated
      and comparative analysis of data sets derived from transcript profiling of
      cultures is a powerful approach to identify candidate components involved in a
      wide range of biological processes. Combinatorial analysis of independent cell
      cycle synchrony methods allows the identification of genes that are apparently
      cell-cycle-regulated but are most likely responding to the induction of
      synchrony. We thus present an integrated genome-wide view of the transcriptional
      profile of a plant suspension culture and identify a refined set of 1082 cell
      cycle regulated genes largely independent of synchrony method.

PMID- 15010611
TI  - Transcriptome analysis of O3-exposed Arabidopsis reveals that multiple signal
      pathways act mutually antagonistically to induce gene expression.
AB  - To analyze cellular responses to ozone (O3), we performed a large-scale analysis
      of the Arabidopsis transcriptome after plants were exposed to O3 for 12 h. By
      using cDNA macroarray technology, we identified 205 non-redundant expressed
      sequence tags (ESTs) that were regulated by O3. Of these, 157 were induced and 48
      were suppressed by O3. A substantial proportion of these ESTs had predicted
      functions in cell rescue/defense processes. Using these isolated ESTs, we also
      undertook a comprehensive investigation of how three hormones, ethylene (ET),
      jasmonic acid (JA), and salicylic acid (SA), interact to regulate O3-induced
      genes in various genetic backgrounds of Arabidopsis, such as the ET-insensitive
      ein2-1, JA-resistant jar1-1, and SA-insensitive npr1-1. The expression of half of
      the 157 induced genes, especially cell rescue/defense genes, was controlled by ET
      and JA signaling, indicating that O3-induced defense gene expression at this
      stage was mainly regulated by ET and JA. Clustering analysis of the 157 O3
      induced gene expressions revealed that multiple signal pathways act mutually
      antagonistically to induce the expression of these genes, and many cell
      rescue/defense genes induced by ET and JA signal pathways were suppressed by SA
      signaling, suggesting that the SA pathway acts as a strong antagonist to gene
      expression induced by ET and JA signaling.

PMID- 15010612
TI  - Arabidopsis transcript profiling on Affymetrix GeneChip arrays.
AB  - DNA microarrays are becoming a frequently used research tool. Whilst several
      studies have confirmed the reproducibility of analysing the same RNA samples on
      duplicate arrays, there is little analysis of the reproducibility of the results
      of transcript profiling between microarrays carrying different probes to a common
      set of genes. To address this question, we compared the performance and
      reproducibility of two microarrays commonly used in plant research, the
      Affymetrix Arabidopsis AG array containing more than 8000 probe sets and the
      Affymetrix Arabidopsis ATH1 array containing more than 22,000 redesigned probe
      sets. A total of 21 different RNA samples were labelled and hybridized in
      parallel to the two microarray types. Focusing on the overlap of more than 7300
      targets detected with both arrays, we found a high degree of reproducibility.
      Despite the use of different probe sets, both signal and signal log ratio were
      very similar for most genes. However, genes that were called absent or not
      changed by Affymetrix' statistical algorithm implemented in MAS5.0 showed
      considerably less conservation of expression patterns. Moreover, we identified
      about 300 genes that yielded strongly different measurements with the two
      microarrays, emphasizing that RNA profiling data need careful interpretation.
      Overall, this study shows that results obtained with ATH1 and AG arrays are very
      comparable and hence that the analysis is largely independent of probe sets.
      However, the result emphasize the need for appropriate filtering schemes such as
      those based on the present and change calls provided by MAS5.0 rather than
      reliance solely on signal values.

PMID- 15010613
TI  - Evaluation of light regulatory potential of Calvin cycle steps based on large
      scale gene expression profiling data.
AB  - Although large-scale gene expression data have been studied from many
      perspectives, they have not been systematically integrated to infer the
      regulatory potentials of individual genes in specific pathways. Here we report
      the analysis of expression patterns of genes in the Calvin cycle from 95
      Arabidopsis microarray experiments, which revealed a consistent gene regulation
      pattern in most experiments. This identified pattern, likely due to gene
      regulation by light rather than feedback regulations of the metabolite fluxes in
      the Calvin cycle, is remarkably consistent with the rate-limiting roles of the
      enzymes encoded by these genes reported from both experimental and modeling
      approaches. Therefore, the regulatory potential of the genes in a pathway may be
      inferred from their expression patterns. Furthermore, gene expression analysis in
      the context of a known pathway helps to categorize various biological
      perturbations that would not be recognized with the prevailing methods.

PMID- 15010614
TI  - Transcriptome analysis reveals novel features of the molecular events occurring
      in the laticifers of Hevea brasiliensis (para rubber tree).
AB  - Latex of Hevea brasiliensis (Willd. ex A, Juss.) Mull. Arg. (Brazilian rubber
      tree) contains 30-50% (w/w) of natural rubber (cis-1,4-polyisoprene), which is an
      important raw material for many industrial uses. In order to gain insights into
      the molecular events occurring in latex, we analyzed more than 20,000 cDNA-AFLP
      based TDFs (transcription-derived fragments) and 1176 ESTs. The results revealed
      several novel features of the latex transcriptome. First, the repertoire of the
      genes expressed in latex is unique. Only seven gene families accounted for more
      than 51% of the latex transcriptome. Among them, two of the most abundant ESTs
      were the genes encoding rubber particle proteins REF (rubber elongation factor)
      and SRPP (small rubber particle protein), comprising 29% of the total ESTs.
      Unexpectedly, several genes involved in the rubber biosynthesis were expressed at
      low levels in the latex. In fact, genes encoding cis -prenyltransferase (CPT), a
      potential candidate for rubber polymerase, were not present in the EST pool
      because of their low expression level. However, we were able to clone four full
      length cDNAs by screening the same latex cDNA library used in the EST analysis
      and confirmed their enzyme activity in vitro. The second most abundant
      transcripts were defense- or stress-related genes, suggesting that defense is one
      of the functions of laticifers. Finally, the presence of the non-mevalonate
      DXP/MEP pathway for IPP synthesis in latex was noted by up-regulation of the 1
      deoxy-D-xylulose 5-phosphate synthase gene.

PMID- 15010615
TI  - Rootstock effects on gene expression patterns in apple tree scions.
AB  - Like many fruit trees, apple trees (Malus pumila) do not reproduce true-to-type
      from seed. Desirable cultivars are clonally propagated by grafting onto
      rootstocks that can alter the characteristics of the scion. For example, the M.7
      EMLA rootstock is semi-dwarfing and reduces the susceptibility of the scion to
      Erwinia amylovora, the causal agent of fire blight disease. In contrast, the M.9
      T337 rootstock is dwarfing and does not alter fire blight susceptibility of the
      scion. This study represents a comprehensive comparison of gene expression
      patterns in scions of the 'Gala' apple cultivar grafted to either M.7 EMLA or M.9
      T337. Expression was determined by cDNA-AFLP coupled with silver staining of the
      gels. Scions grafted to the M.9 T337 rootstock showed higher expression of a
      number of photosynthesis-related, transcription/translation-related, and cell
      division-related genes, while scions grafted to the M.7 EMLA rootstock showed
      increased stress-related gene expression. The observed differences in gene
      expression showed a remarkable correlation with physiological differences between
      the two graft combinations. The roles that the differentially expressed genes
      might play in tree stature, stress tolerance, photosynthetic activity, fire
      blight resistance, and other differences conferred by the two rootstocks are
      discussed.

PMID- 15010617
TI  - DCL is a plant-specific protein required for plastid ribosomal RNA processing and
      embryo development.
AB  - The defective chloroplast and leaf-mutable (dcl-m) mutation of tomato blocks
      chloroplast differentiation in leaf mesophyll cells and a signaling system that
      appears to be required for morphogenesis of palisade cells during leaf growth. To
      dissect the function of DCL, mutants with stable dcl alleles (dcl-s) were
      generated and examined for their phenotype. DCL/dcl-s plant produce dcl-s/dcl-s
      seeds with embryos arrested at the globular stage of development. The levels of
      several chloroplast- and nuclear-encoded proteins are strongly reduced in dcl-m
      mutant leaf sectors without significant changes in their corresponding mRNAs. The
      4.5S rRNA fails to be processed efficiently, however, suggesting that DCL has a
      direct or indirect function in rRNA processing or correct ribosome assembly.
      Accordingly, chloroplasts in dcl-m sectors are impaired in polysome assembly,
      which can explain the reduced accumulation of chloroplast-encoded proteins. These
      results suggest that DCL is required for chloroplast rRNA processing, and
      emphasize the importance of plastid function during embryogenesis.

PMID- 15010616
TI  - Expression of an Arabidopsis phosphoglycerate mutase homologue is localized to
      apical meristems, regulated by hormones, and induced by sedentary plant-parasitic
      nematodes.
AB  - We previously isolated a partial soybean cDNA clone whose transcript abundance is
      increased upon infection by the sedentary, endoparasitic soybean cyst nematode
      Heterodera glycines. We now isolated the corresponding full-length cDNA and
      determined that the predicted gene product was similar to the group of cofactor
      dependent phosphoglycerate mutase/bisphosphoglycerate mutase enzymes (PGM/bPGM;
      EC 5.4.2.1/5.4.2.4). We designated the corresponding soybean gene GmPGM. PGM and
      bPGM are key catalysts of glycolysis that have been well characterized in animals
      but not plants. Using the GmPGM cDNA sequence, we identified a homologous
      Arabidopsis thaliana gene, which we designated AtPGM. Histochemical GUS analyses
      of transgenic Arabidopsis plants containing the AtPGM promoter ::GUS construct
      revealed that the AtPGM promoter directs GUS expression in uninfected plants only
      to the shoot and root apical meristems. In infected plants, GUS staining also is
      evident in the nematode feeding structures induced by the cyst nematode
      Heterodera schachtii and by the root-knot nematode Meloidogyne incognita.
      Furthermore, we discovered that the AtPGM promoter was down-regulated by abscisic
      acid and hydroxyurea, whereas it was induced by sucrose, oryzalin, and auxin,
      thereby revealing expression characteristics typical of genes with roles in
      meristematic cells. Assessment of the auxin-inducible AUX1 gene promoter (a gene
      coding for a polar auxin transport protein) similarly revealed feeding cell and
      meristem expression, suggesting that auxin may be responsible for the observed
      tissue specificity of the AtPGM promoter. These results provide first insight
      into the possible roles of PGM/bPGM in plant physiology and in plant-pathogen
      interactions.

PMID- 15010619
TI  - Genetic mapping and molecular characterization of the self-incompatibility (S)
      locus in Petunia inflata.
AB  - Gametophytic self-incompatibility (SI) possessed by the Solanaceae is controlled
      by a highly polymorphic locus called the S locus. The S locus contains two linked
      genes, S-RNase, which determines female specificity, and the as yet unidentified
      pollen S gene, which determines male specificity in SI interactions. To identify
      the pollen S gene of Petunia inflata, we had previously used mRNA differential
      display and subtractive hybridization to identify 13 pollen-expressed genes that
      showed S -haplotype-specific RFLP. Here, we carried out recombination analysis of
      1205 F2 plants to determine the genetic distance between each of these S -linked
      genes and S-RNase. Recombination was observed between four of the genes (3.16,
      G211, G212, and G221) and S-RNase, whereas no recombination was observed for the
      other nine genes (3.2, 3.15, A113, A134, A181, A301, G261, X9, and X11). A
      genetic map of the S locus was constructed, with 3.16 and G221 delimiting the
      outer limits. None of the observed crossovers disrupted SI, suggesting that all
      the genes required for SI are contained in the chromosomal region defined by 3.16
      and G221. These results and our preliminary chromosome walking results suggest
      that the S locus is a huge multi-gene complex. Allelic sequence diversity of G221
      and 3.16, as well as of 3.2, 3.15, A113, A134 and G261, was determined by
      comparing two or three alleles of their cDNA and/or genomic sequences. In
      contrast to S-RNase, all these genes showed very low degrees of allelic sequence
      diversity in the coding regions, introns, and flanking regions.

PMID- 15010618
TI  - Isolation, sequence analysis, and expression studies of florally expressed cDNAs
      in Arabidopsis.
AB  - Molecular genetics has identified dozens of genes that regulate flower
      development in Arabidopsis. However, the complexity of flower development
      suggests that many other genes are yet to be uncovered. To identify floral genes
      that are expressed at low levels in the flower, we have sequenced 1587 cDNA
      fragments from a subtractive floral cDNA library. A total of 1222 unique genes
      represented by these ESTs are distributed on all five chromosomes with similar
      frequencies as all predicted genes in the genome. Among these, 17 genes were
      shown to be expressed anywhere for the first time because they were not found in
      previous EST and full-length cDNA datasets. Furthermore, 724 of the genes
      revealed by this library were not definitively shown to be expressed in the
      flower by previous floral EST datasets. In addition, 49 transcriptional
      regulators, 31 protein kinases, 12 zinc-finger proteins and other signaling
      proteins were found to be present in floral buds. Moreover, the EST sequences
      likely extended the transcribed regions of 26 previously annotated genes, and may
      have uncovered several previously unrecognized genes. To obtain additional clues
      about possible gene function, we hybridized cDNA microarray with probes derived
      from wild-type Arabidopsis rosette leaves and floral buds. We estimated that over
      50% of genes were expressed at levels lower than 1/30 of the highest detectable
      signal intensity, indicating that many floral genes are expressed at low levels.
      Furthermore, 97 genes were found to be expressed at a higher level in the flower
      than the leaf by the Significance Analysis of Microarray (SAM) method with a 1.0%
      false discovery rate (FDR). Further RT-PCR analyses of selected genes support the
      microarray results. We suggest that the genes encoding putative regulatory
      proteins and at least some proteins with currently unknown functions might play
      important roles during flowering.

PMID- 15010620
TI  - The elongation defective1 mutant of Arabidopsis is impaired in the gene encoding
      a serine-rich secreted protein.
AB  - Coordinated cell growth and differentiation is crucial for the development of
      higher plants. Using the elongation defective 1-1 (eld1-1) mutant, we cloned the
      ELD1 gene, which encodes a serine-rich protein. Genes homologous to ELD1 can be
      found in plants, including Arabidopsis, rice, and tobacco, but not in other
      organisms. Using reverse genetics, we identified a new allele, eld1-2, which is
      phenotypically indistinguishable from eld1-1, but does not produce a detectable
      ELD1 transcript. The ELD1 gene sequence is the same as that of the KOBITO1
      sequence. However, the kob1 mutants display weak phenotype relative to the two
      eld1 mutants, which are likely null alleles. KOB1 was reported to be a membrane
      protein involved in cellulose synthesis. However, based on ELD1-GFP localization
      in plasmolyzed cells, we found that ELD1 is localized to the cell
      wall/extracellular matrix, rather than the membrane. Thus, ELD1/KOB1 is a
      secreted protein involved in promoting cell growth. To investigate the
      relationship between ELD1 and Arabidopsis genes with high sequence similarity, we
      analyzed the possible subcellular location of their proteins as well as their
      amino acid sequence. The ELD1-related proteins in Arabidopsis were predicted to
      be localized to subcellular compartments different from that of ELD1. Thus, ELD1
      is likely to be functionally distinct from related Arabidopsis genes. These
      results suggest that ELD1 is a single-copy gene which belongs to a small family
      of plant-specific genes with diverse function.

PMID- 15010622
TI  - Prevention of postcoronary artery bypass-related atrial fibrillation by a novel
      anti-inflammatory approach.

PMID- 15010621
TI  - Characterisation of Pt MYB1, an R2R3-MYB from pine xylem.
AB  - A cDNA encoding a member of the R2R3-MYB family of transcription factors was
      cloned from a library constructed from differentiating Pinus taeda (loblolly
      pine) xylem RNA. This MYB family member, Pinus taeda MYB1 (PtMYB1), was most
      abundantly expressed in differentiating xylem, as assessed by both ribonuclease
      protection assays, and by northern blot analysis with poly(A)-enriched RNA.
      Similar to other plant R2R3-MYB family members, recombinant Pt MYB1 protein was
      able to bind to AC elements in electrophoretic mobility shift assays (EMSAs). AC
      elements are DNA motifs rich in adenosine and cytosine that have been implicated
      in the xylem-localised regulation of genes encoding lignin biosynthetic enzymes.
      Pt MYB1 not only bound to AC elements, but was also able to induce AC-element
      dependent shifts in the electrophoretic mobility of a plant promoter that
      contains three AC elements, the minimal PHENYLALANINE AMMONIA-LYASE 2 (PAL2)
      promoter from Phaseolus vulgaris. Transcriptional activation assays conducted
      using yeast showed that Pt MYB1 also activated transcription, and that it did so
      in an AC-element-dependent fashion. Pt MYB1 also activated transcription from the
      minimal PAL2 promoter in plant cells in an AC-element-dependent fashion, as
      revealed by transient transcriptional activation assays with microprojectile
      bombarded tobacco NT-1 cells. Taken together, these finding are consistent with
      the hypothesis that Pt MYB1 may regulate transcription from cis -acting AC
      elements in pine xylem.

PMID- 15010623
TI  - Efficacy of nonsteroidal anti-inflammatory medications for prevention of atrial
      fibrillation following coronary artery bypass graft surgery.
AB  - This study was designed to test whether nonsteroidal anti-inflammatory
      medications could reduce the frequency of atrial fibrillation after coronary
      artery bypass graft surgery. The study was designed as an open-label, randomized
      trial. Patients undergoing first-time coronary artery bypass graft surgery were
      considered eligible. Patients with a history of atrial fibrillation, serum
      creatinine >2.0 mg/dL, on antiarrhythmic treatment, and those undergoing
      concomitant valvular surgery were excluded. The study was conducted in a single,
      university-affiliated community hospital. The researchers' role in the study was
      restricted to randomizing the patients and collecting data. The primary clinical
      care team made all decisions regarding patient care. One hundred patients were
      randomized to two groups: one received 30 mg ketorolac intravenously every 6
      hours until able to take oral medications, at which point the patients were
      switched to 600 mg ibuprofen orally three times a day; the other group received
      conventional treatment. The primary end point of the study was incidence of
      atrial fibrillation in the immediate postoperative period. Atrial fibrillation
      occurred in 14 patients (28.6%) in the conventional treatment group vs. five
      patients (9.8%) in the ibuprofen group (p<0.017). Nonsteroidal anti-inflammatory
      medications were relatively safe and effective in significantly reducing the
      incidence of atrial fibrillation after coronary artery bypass graft surgery.

PMID- 15010624
TI  - The influence of an intense cardiovascular disease risk factor modification
      program.
AB  - In an effort to make intensive lifestyle modification programs more accessible to
      patients with cardiovascular disease, the Ornish Program was offered at eight
      independent medical centers located across the United States. The purpose of this
      study was to determine if one of these independent sites was able to replicate
      outcomes produced by the original Ornish Program. Fifty program participants from
      six different cohorts provided baseline, 3- and 12-month data consisting of blood
      lipids, body fat, blood pressure, anginal pain, quality of life, stress,
      depression, social support, and hostility. A pooled analysis showed significant
      reductions in almost all physiological and psychosocial variables with most
      reductions persisting for at least 12 months. These findings suggest that
      cardiovascular disease patients who choose to participate in an independent,
      intensive lifestyle modification program can experience significant improvements
      in both physiological and psychosocial cardiovascular disease risk factors.

PMID- 15010625
TI  - Heart to Heart: a computerized decision aid for assessment of coronary heart
      disease risk and the impact of risk-reduction interventions for primary
      prevention.
AB  - Heart to Heart is a computer-based decision aid for patients and providers that
      provides personalized, evidence-based information about coronary heart disease
      (CHD) risk and potential risk-reducing interventions. To develop Heart to Heart,
      the authors used Framing-ham risk equations and systematic reviews of risk
      reducing interventions. The Web version was programmed using PHP: Hypertext
      Processor, a Web-based programming language, and has separate interfaces for
      providers and patients. The authors subsequently developed a modified version for
      personal digital assistants. Heart to Heart uses information about a patient's
      CHD risk factors (age, gender, total and high-density lipoprotein cholesterol
      levels, diabetes, smoking, systolic blood pressure, and left ventricular
      hypertrophy) to calculate risk of total CHD events over 5 or 10 years. Patients
      and providers can then examine the effect of introducing one or more risk
      reducing interventions (aspirin, lipid-lowering drug therapy, antihypertensive
      medication, or smoking cessation) on the patient's CHD risk. Future research will
      be directed to determining whether Heart to Heart can improve utilization of
      effective CHD risk-reducing interventions.

PMID- 15010626
TI  - Cholesterol management and the reduction of cardiovascular risk.
AB  - The increasing number of outcomes-based clinical trials addressing cardiovascular
      risk factor reduction using statin therapy has resulted in a substantial revision
      of the management of patients at risk for cardiovascular events. The clinical
      trials involve both primary and secondary preventive care. This review outlines
      the trials addressing primary and secondary prevention, detailing the more
      recently published studies, their place in risk-factor management, and their
      relationship to the National Cholesterol Education Program guidelines. Available
      data in elderly patients are reviewed, as are the adverse effects of the
      different statins and the statin drugs undergoing preliminary trials but not yet
      approved for general clinical use. The underuse of statin therapy is also
      addressed. Conclusions are drawn regarding the appropriate use of statin therapy
      in the contemporary primary and secondary preventive management of patients to
      reduce cardiovascular mortality and morbidity.

PMID- 15010627
TI  - VALIANT and EUROPA.

PMID- 15010628
TI  - Panacea in a pill?

PMID- 15010629
TI  - The bedbugs never left.

PMID- 15010630
TI  - Kaposi's sarcoma: its Janus face.

PMID- 15010631
TI  - Doctor, is it something I ate?

PMID- 15010632
TI  - Women leaders in American dermatology. Interview by Marylou C. Thelmo, E. Dorinda
      Shelley, Gloria F. Graham.
AB  - BACKGROUND: Women leaders in dermatology opened doors that allowed many men and
      women to follow in their footsteps. Their achievements have included presidencies
      of national and state medical organizations, teaching, and research. They changed
      the specialty through words and leadership. OBJECTIVE: This study highlights four
      women who significantly influenced American dermatology. METHODS: We selected
      four female leaders in American dermatology, one of whom is deceased. For the
      other physicians, a questionnaire was sent to two and a telephone interview was
      conducted with one. Other responses were garnered through an autobiography, a
      self-recorded interview, and journal articles. RESULTS: Brief biographies with
      career highlights are presented for Minerva Smith Buerk, MD, founder of the
      Women's Dermatologic Society; Naomi Marilyn Kanof, MD, the first female editor of
      The Journal of Investigative Dermatology; Wilma Fowler Bergfeld, MD, the first
      female president of the American Academy of Dermatology; and Antoinette Foote
      Hood, MD, the first female executive director of the American Board of
      Dermatology.

PMID- 15010633
TI  - Foods, diet, and skin diseases.
AB  - Human skin is continuously exposed to internal and external influences that may
      alter its condition and functioning. As a consequence, the skin may undergo
      alterations leading to immune dysfunction, imbalanced epidermal homeostasis, or
      other skin disorders. New theories are developing that link food intake and
      health. The objective of this review is to evaluate current knowledge about the
      interrelation of food and skin, particularly the effect of nutrients on some
      cutaneous immune disorders and therapeutic actions of nutrients in skin
      disorders.

PMID- 15010635
TI  - Acne.

PMID- 15010634
TI  - Rosac Cream With Sunscreens (sodium sulfacetamide 10% and sulfur 5%).

PMID- 15010636
TI  - Sulfur/sodium sulfacetamide preparations.

PMID- 15010637
TI  - Merkel cell carcinoma of the left temple.

PMID- 15010638
TI  - The introduction of griseofulvin.

PMID- 15010639
TI  - Misconceptions surrounding genetic diseases in developing countries.

PMID- 15010640
TI  - Widespread Kaposi's sarcoma in an HIV-negative man.

PMID- 15010641
TI  - Kaposi's sarcoma mimicking a facial cyst as the presenting sign of human
      immunodeficiency virus.

PMID- 15010642
TI  - Chronic cutaneous herpes simplex in a patient with hypogammaglobulinemia.

PMID- 15010643
TI  - Keep the management of hypertension simple.

PMID- 15010645
TI  - Circadian blood pressure variability as a function of parity in normotensive
      pregnant women.
AB  - Studies based on office blood pressure measurements concluded that parity has
      significant effects on blood pressure during pregnancy. The authors evaluated
      possible differences in the circadian pattern of blood pressure as a function of
      parity in normotensive women systematically studied by ambulatory blood pressure
      monitoring. They analyzed 1400 blood pressure series sampled for 48 consecutive
      hours every 4 weeks from the first obstetric visit (usually within the first
      trimester of pregnancy) until delivery in 234 women. The circadian pattern of
      blood pressure variation for each group (nulliparous vs. multiparous) and
      trimester of gestation was established by population multiple-component analysis.
      A highly statistically significant circadian pattern, described by a model that
      includes components with periods of 24 and 12 hours, was demonstrated for
      systolic and diastolic blood pressure for both groups of pregnant women in all
      trimesters (p<0.001). There was no significant difference in 24-hour mean among
      groups divided by parity at any stage of pregnancy (p>0.315). Data obtained from
      systematic ambulatory monitoring in normotensive pregnant women indicate the lack
      of differences in blood pressure according to parity. Reference thresholds for
      blood pressure in pregnancy could thus be developed as a function of rest
      activity cycle and gestational age only, independent of parity.

PMID- 15010644
TI  - Cardiovascular outcomes using doxazosin vs. chlorthalidone for the treatment of
      hypertension in older adults with and without glucose disorders: a report from
      the ALLHAT study.
AB  - Insulin resistance underlies most glucose disorders in adults and is associated
      with an increased risk of cardiovascular disease. Alpha blockers decrease insulin
      resistance, whereas diuretics increase insulin resistance. The authors studied
      the effects of these two classes of hypertension medications (doxazosin, an a
      blocker, and chlorthalidone, a diuretic) on cardiovascular disease outcomes in
      adults aged >55 years with hypertension and glucose disorders who were
      participants in the Antihypertensive and Lipid Lowering Treatment to Prevent
      Heart Attack Trial (8749 had known diabetes mellitus and 1690 had a newly
      diagnosed glucose disorder [fasting glucose >/=110 mg/dL]). There was no
      difference in either group between the chlorthalidone- and doxazosin-based
      treatments with regard to fatal or nonfatal myocardial infarction or all-cause
      mortality. There was, however, a difference for combined cardiovascular disease
      (myocardial infarction, revascularization procedures, angina, stroke, heart
      failure, and peripheral arterial disease) in favor of the diuretic. This
      difference was due primarily to an increased heart failure risk in those treated
      with doxazosin (relative risk, 1.85; 95% confidence interval, 1.56-2.19) in the
      known diabetes mellitus group and a relative risk of 1.63 (95% confidence
      interval, 1.05-2.55) in those with a newly diagnosed glucose disorder despite
      lower glucose levels on follow-up in those treated with a blockers. The authors
      conclude that treatment of hypertension with doxazosin in adults with glucose
      disorders incurs the same risk of coronary heart disease as treatment with
      chlorthalidone; however, treatment with doxazosin increases the risk of combined
      cardiovascular disease and heart failure despite lower glucose levels.

PMID- 15010646
TI  - Microalbuminuria in type 2 diabetics: an important, overlooked cardiovascular
      risk factor.
AB  - The presence of microalbumin in the urine of persons with type 2 diabetes is
      perhaps the most important early signal heralding the onset of systemic
      vasculopathy and associated target organ damage to the brain, the heart, and the
      kidneys. It is easily measured and, unfortunately, frequently overlooked as a
      screening tool in clinical medicine. If present, it identifies patients at risk
      for early cardiovascular death and progressive renal disease. Microalbuminuria
      also identifies patients who need more rigorous cardiovascular risk management,
      especially more intensive blood pressure control, preferably below 130/80 mm Hg,
      and strict attention to glycemic control and lipid levels. Therapeutic strategies
      to facilitate better blood pressure control and reduce microalbuminuria likely
      will prove to be the most effective way to retard not only the progression of
      renal disease but also cardiovascular disease. Consequently, the identification
      and normalization of urine microalbumin excretion should be an important
      consideration in patients with diabetes.

PMID- 15010647
TI  - Interview with Raymond Gifford, Jr., MD. Interview by Marvin Moser.

PMID- 15010648
TI  - Should hypertensive patients take aspirin? A report from the Food and Drug
      Administration.

PMID- 15010650
TI  - The Cardiovascular Health Study: a national treasure of cardiovascular
      information about the elderly.

PMID- 15010651
TI  - The Cardiovascular Health Study: risk factors, subclinical disease, and clinical
      cardiovascular disease in older adults.

PMID- 15010652
TI  - Congestive heart failure in the elderly: the Cardiovascular Health Study.
AB  - Congestive heart failure in the elderly is recognized as a national public health
      priority; however, clinical diagnosis can be problematic in elderly persons, many
      of whom have a history of heart failure in the presence of normal or only
      minimally decreased ejection fraction. Findings of the Cardiovascular Health
      Study have underscored the common substrate and predictors underlying heart
      failure both with decreased ejection fraction and with normal ejection fraction
      (i.e., diastolic heart failure). Coronary heart disease, systolic blood pressure,
      and C-reactive protein (a measure of inflammation) are predictive of heart
      failure independent of ejection fraction. Left atrial size, arguably a marker of
      the effects of impaired diastolic filling over time, is increased in both
      systolic and diastolic heart failure of the elderly, as is atrial natriuretic
      peptide. The outcome of heart failure in elderly persons is poor both for
      systolic and diastolic heart failure. Moreover, many community-dwelling elderly
      persons have decreased ejection fraction without heart failure. In these persons
      the chance of death is similar to that of participants with diastolic heart
      failure. Since most clinical trials have studied younger patients with
      predominantly systolic heart failure, the appropriate therapy for heart failure
      in elderly persons remains to be determined.

PMID- 15010653
TI  - Traditional and novel risk factors in older adults: cardiovascular risk
      assessment late in life.
AB  - As a population-based, longitudinal study of nearly 6000 older American adults,
      the Cardiovascular Health Study provides an excellent opportunity to assess the
      roles of traditional and novel cardiovascular risk factors in the development of
      coronary heart disease. Cardiovascular Health Study investigators have analyzed
      both traditional risk factors, such as diabetes, hypertension, and smoking, and
      new risk factors, such as hemostatic factors, inflammatory markers, exposure to
      infectious agents, and genetic determinants. These analyses have led to several
      important conclusions. First, older adults without previous cardiovascular events
      have a tremendous burden of subclinical vascular disease, which may change how
      physicians view risk factor modification in this age group. Second, some
      traditional cardiovascular risk factors lose importance as predictors of
      cardiovascular disease among older adults. Third, even modest elevations in
      fasting blood glucose or systolic blood pressure-below the levels used to define
      diabetes or hypertension-may have prognostic implications. Fourth, novel
      cardiovascular risk factors may add further information about cardiovascular
      disease risk in older adults. Promising potential candidates identified in the
      Cardiovascular Health Study include markers of hemostatic activation, fibrinogen,
      factor VIII coagulant activity, C-reactive protein, and exposure to herpes
      simplex virus-1 and possibly chlamydia. Future Cardiovascular Health Study
      investigations will help to clarify which combination of traditional and newer
      risk factors provides the best estimate of cardiovascular risk for older adults.

PMID- 15010655
TI  - What really happens as we grow older?

PMID- 15010654
TI  - Chronic renal insufficiency and cardiovascular events in the elderly: findings
      from the Cardiovascular Health Study.
AB  - In the Cardiovascular Health Study, the authors sought to evaluate the impact of
      chronic renal insufficiency (CRI) on cardiovascular risk status and outcomes in a
      representative sample of community-dwelling elderly adults. Defined as a serum
      creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men, CRI was
      present in 647 (11%) of 5808 participants. At baseline, the prevalence of
      clinical or subclinical cardiovascular disease was 64% in participants with CRI
      and 43% in those without CRI (odds ratio, 2.34; 95% confidence interval, 1.96
      2.80). The incidence of cardiovascular disease events during follow-up was 3% per
      year in participants with creatinine levels <1.10 mg/dL and increased steadily to
      reach 7% per year in those with creatinine > or =1.70 mg/dL. Among the possible
      mediators for the association between CRI and cardiovascular morbidity are
      inflammatory (C-reactive protein, fibrinogen, and interleukin-6) and hemostatic
      (factor VII, factor VIII, plasmin-antiplasmin product, and D-dimer) biomarkers,
      all of which were significantly elevated in Cardiovascular Health Study
      participants with CRI. Future studies should evaluate the contribution of novel
      and traditional cardiovascular risk factors to the cardiovascular risk of elderly
      persons with CRI. The identification of CRI in the elderly and the use of
      cardiovascular prevention therapies represent a major opportunity to reduce their
      burden of cardiovascular morbidity.

PMID- 15010656
TI  - Ethical issues in the management of geriatric cardiac patients.

PMID- 15010658
TI  - Primary health care by midwives: compassionate and competent services for women.

PMID- 15010659
TI  - Cesarean section on demand: round one.

PMID- 15010660
TI  - CEU:Managing menopausal symptoms after the women's health initiative.
AB  - Until the results of the Women's Health Initiative (WHI) were released in July
      2002, hormone replacement therapy (HRT) had been thought to be the most effective
      way to manage unwanted menopausal symptoms and to prevent long-term health
      problems associated with aging. The results of the WHI, showing that HRT is less
      beneficial and associated with more risks than previously thought, has
      complicated the management of unwanted menopausal symptoms. This article
      discusses the effectiveness of HRT and other modalities used to relieve
      menopausal symptoms and discusses how to choose an HRT product to match specific
      menopausal complaints and provide maximum safety.

PMID- 15010661
TI  - Complementary therapies as adjuncts in the treatment of postpartum depression.
AB  - Postpartum depression affects an estimated 13% of women who have recently given
      birth. This article discusses several alternative or complementary therapies that
      may serve as adjuncts in the treatment of postpartum depression. The intent is to
      help practitioners better understand the treatments that are available that their
      clients may be using. Complementary modalities discussed include herbal medicine,
      dietary supplements, massage, aromatherapy, and acupuncture. Evidence supporting
      the use of these modalities is reviewed where available, and a list of resources
      is given in the appendix.

PMID- 15010662
TI  - Supportive counseling before and after elective pregnancy termination.
AB  - Midwives are likely to encounter women seeking care before or after an elective
      abortion. National estimates of abortion rates suggest that 43% of women in the
      United States will have at least one abortion by the time they are 45 years old.
      By not asking women about abortion experiences, providers risk perpetuating
      women's guilt, shame, and silence. This article describes the emotional
      consequences of elective abortion, identifies women at high risk for negative
      reactions, and offers approaches to counseling about the psychosocial effects of
      abortion both before and after the procedure. Through the provision of counseling
      for women who have abortions, providers will be able to assist with coping,
      identify women who might be at greater risk for psychological sequelae, and offer
      referrals to those in need.

PMID- 15010663
TI  - Vaginal birth after cesarean section: a pilot study of outcomes in women
      receiving midwifery care.
AB  - A recent trend discouraging or not offering women a choice to labor after a
      cesarean birth has resulted in higher cesarean birth rates and lower rates of
      vaginal birth after cesarean birth (VBAC). The few studies describing midwifery
      practice have demonstrated favorable outcomes; however, the studies are too small
      to thoroughly evaluate critical outcomes. In this retrospective descriptive
      study, clinical outcome data were obtained from eight midwifery practices. The
      aims were to collect, aggregate, and analyze data from multiple midwifery
      practices and then describe outcomes. Usable data representing 649 trials of
      labor were submitted. Overall, 72% (range 64%-100%) of women gave birth
      vaginally. Mean infant birth weight was 3,501 (SD = 534) g, and the mean Apgar
      scores were 7.99 (SD = 1.4; median 8) at 1 minute and 8.84 (SD = 0.8; median 9)
      at 5 minutes. Only 5.3% (n = 14) of infants were admitted to the neonatal
      intensive care unit. This small retrospective study demonstrates similar outcomes
      to those reported in the current literature. A larger prospective study to
      carefully describe midwifery care outcomes using a common data collection method
      is needed to provide evidence for determining the continuation of VBAC as part of
      midwifery care.

PMID- 15010664
TI  - Fatherhood and the meaning of children: an ethnographic study among Puerto Rican
      partners of adolescent mothers.
AB  - This study of the male partners of adolescent mothers was conducted in a small
      urban city in the northeastern United States where adolescent birth rates remain
      high despite declining national trends. Despite stated opposition to adolescent
      birth, one third of the fathers interviewed planned their pregnancies with their
      partners for more than a year. Because poverty and violence were part of life in
      the community of these fathers, the experience of having children initiated self
      reflection. Men did not value absence from their children's lives, and they
      recognized their own agency in constructing a fatherless reality for their
      children. Thus, having children gave men an opportunity to consider alternative
      possibilities for their lives. This study suggests that despite widespread
      efforts to prevent teenage pregnancy, children born to adolescent mothers provide
      the fathers of these children with an affirming and valued component of self
      identity.

PMID- 15010665
TI  - Mary Breckinridge meets Healthy People 2010: a teaching strategy for visioning
      and building healthy communities.
AB  - In both midwifery and nursing education, it is essential to include innovative
      teaching strategies that address the health of communities. This article presents
      a creative learning activity for midwifery and/or nursing education that
      integrates Mary Breckinridge's historical example with today's national goals for
      building communities. The establishment of the Frontier Nursing Service in 1925
      is an excellent example of the Mobilize, Assess, Plan, Implement, and Track (MAP
      IT) framework for building health communities. Advanced practice nursing and
      midwifery students can use this historical template to implement their ideas for
      building healthy communities today.

PMID- 15010666
TI  - Delayed lactogenesis II: a comparison of four cases.
AB  - Lactogenesis II is the onset of copious milk production (i.e., the milk "coming
      in"), which usually occurs between 30 to 40 hours postpartum. When lactogenesis
      II fails to occur or is delayed, it may be due to a number of underlying hormonal
      or non-hormonal conditions. Of the various hormonal etiologies, many can be
      identified with the aid of a few standard blood tests. Gestational ovarian theca
      lutein cysts may cause delayed lactogenesis II and are fairly easily detected by
      ordering testosterone levels. Although this condition can delay lactogenesis II
      for as long as 31 days, with proper management women affected by these cysts have
      established breastfeeding. Three of the four women reviewed in this article were
      eventually able to produce 100% of their infants' caloric requirements.

PMID- 15010667
TI  - Women's exercise beliefs and behaviors during their pregnancy and postpartum.
AB  - Limited research examines women's beliefs about the value of exercise and their
      actual exercise behaviors during pregnancy and postpartum. A retrospective study
      of 74 postpartum women was conducted to examine women's behavioral, normative,
      and control beliefs about exercising during pregnancy and postpartum and to
      determine their most salient beliefs. In addition, women's prepregnancy,
      pregnancy, and postpartum exercise behavior was examined. We found that 1) the
      most common exercise beliefs during pregnancy were that exercise improves mood
      and physical limitations (e.g., nausea) obstructed exercise participation; 2) the
      most common exercise beliefs during postpartum were that exercise controls weight
      gain and a lack of time obstructed exercise participation; 3) women's
      husband/partner and family members most strongly influenced their pregnancy and
      postpartum exercise behavior; and 4) women exercised more before they were
      pregnant than during pregnancy and postpartum. Researchers and health care
      professionals are encouraged to examine and understand women's beliefs about
      exercising during their pregnancy and postpartum and design their interventions
      accordingly, in an attempt to increase women's exercise behavior during their
      childbearing years.

PMID- 15010668
TI  - Use of phenytoin in pregnancy for epileptic seizure prevention: a case report.
AB  - Epilepsy is the most common neurological disorder in women of reproductive age.
      Phenytoin is one of the most frequently prescribed antiepileptic drugs. Although
      the vast majority of women with epilepsy have normal pregnancy outcomes, certain
      fetal anomalies and pregnancy complications are associated with epilepsy and
      phenytoin use. Appropriate midwifery care of women with epilepsy includes
      consultation and co-management with an obstetrician and a neurologist. The
      clinical course of a woman with epilepsy taking phenytoin is presented.

PMID- 15010669
TI  - Resources for evidence-based practice, March/April 2004.

PMID- 15010670
TI  - Galactagogues.

PMID- 15010671
TI  - Counseling women about elective cesarean section.

PMID- 15010681
TI  - Should I have a cesarean section?

PMID- 15010693
TI  - Abeta(25-35)-induced memory impairment, axonal atrophy, and synaptic loss are
      ameliorated by M1, A metabolite of protopanaxadiol-type saponins.
AB  - We previously screened neurite outgrowth activities of several Ginseng drugs in
      human neuroblastoma, and demonstrated that protopanaxadiol (ppd)-type saponins
      were active constituents. Since ppd-type saponins are known to be completely
      metabolized to 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (M1) by
      intestinal bacteria when taken orally, M1 and ginsenoside Rb1, as a
      representative of ppd-type saponins, were examined for cognitive disorder. In a
      mouse model of Alzheimer's disease (AD) by Abeta(25-35) i.c.v. injection,
      impaired spatial memory was recovered by p.o. administration of ginsenoside Rb1
      or M1. Although the expression levels of phosphorylated NF-H and synaptophysin
      were reduced in the cerebral cortex and the hippocampus of Abeta(25-35)-injected
      mice, their levels in ginsenoside Rb1- and M1-treated mice were almost completely
      recovered up to control levels. Potencies of the effects were not different
      between ginsenoside Rb1 and M1 when given orally, suggesting that most of the
      ginsenoside Rb1 may be metabolized to M1, and M1 is an active principal of ppd
      type saponins for the memory improvement. In cultured rat cortical neurons, M1
      showed extension activity of axons, but not dendrites. The axon-specific
      outgrowth was seen even when neuritic atrophy had already progressed in response
      to administration of Abeta(25-35) as well as in the normal condition. These
      results suggest that M1 has axonal extension activity in degenerated neurons, and
      improve memory disorder and synaptic loss induced by Abeta(25-35). M1 was shown
      to be effective in vitro and in vivo, indicating that Ginseng drugs containing
      ppd-type saponins may reactivate neuronal function in AD by p.o. administration.

PMID- 15010694
TI  - Experimental parkinsonism alters anandamide precursor synthesis, and functional
      deficits are improved by AM404: a modulator of endocannabinoid function.
AB  - Modulation of the endocannabinoid system might be useful in treating Parkinson's
      disease. Here, we show that systemic administration of N-(4-hydroxyphenyl)
      arachidonamide (AM404), a cannabinoid modulator that enhances anandamide (AEA)
      availability in the biophase, exerts antiparkinsonian effects in 6
      hydroxydopamine-lesioned rats. Local injections of AM404 into denervated striata
      reduced parkinsonian motor asymmetries, these effects being associated with the
      reduction of D2 dopamine receptor function together with a positive modulation of
      5-HT(1B) serotonin receptor function. Stimulation of striatal 5-HT(1B) receptors
      alone was observed to ameliorate parkinsonian deficits, supporting the fact that
      AM404 exerts antiparkinsonian effects likely through stimulation of striatal 5
      HT(1B) serotonin receptor function. Hence, modulation of cannabinoid function
      leading to enhancement of AEA in the biophase might be of therapeutic value in
      the control of symptoms of Parkinson's disease. On the other hand, reduced levels
      of N-acyl-transferase (AEA precursor synthesizing enzyme), without changes in
      fatty acid amidohydrolase (AEA degradative enzyme), were detected in denervated
      striata in comparison with intact striata. This finding reveals the presence of a
      homeostatic striatal mechanism emerging after dopaminergic denervation likely
      tending to enhance low dopamine tone.

PMID- 15010695
TI  - Transdermal nicotine maintenance attenuates the subjective and reinforcing
      effects of intravenous nicotine, but not cocaine or caffeine, in cigarette
      smoking stimulant abusers.
AB  - The effects of transdermal nicotine maintenance on the subjective, reinforcing,
      and cardiovascular effects of intravenously administered cocaine, caffeine, and
      nicotine were examined using double-blind procedures in nine volunteers with
      histories of using tobacco, caffeine, and cocaine. Each participant was exposed
      to two chronic drug maintenance phases (21 mg/day nicotine transdermal patch and
      placebo transdermal patch). Within each drug phase, the participant received
      intravenous injections of placebo, cocaine (15 and 30 mg/70 kg), caffeine (200
      and 400 mg/70 kg), and nicotine (1.0 and 2.0 mg/70 kg) in mixed order across
      days. Subjective and cardiovascular data were collected before and repeatedly
      after drug or placebo injection. Reinforcing effects were also assessed after
      each injection with a Drug vs Money Multiple-Choice Form. Intravenous cocaine
      produced robust dose-related increases in subjective and reinforcing effects;
      these effects were not altered by nicotine maintenance. Intravenous caffeine
      produced elevations on several subjective ratings; nicotine maintenance did not
      affect these ratings. Under the placebo maintenance condition, intravenous
      nicotine produced robust dose-related subjective effects, with maximal increases
      similar to the high dose of cocaine; nicotine maintenance significantly decreased
      the subjective and reinforcing effects of intravenous nicotine. The results of
      the present study demonstrate that chronic nicotine maintenance produces
      tolerance to the effects of intravenous nicotine, but does not affect the
      subjective or reinforcing effects of cocaine or caffeine.

PMID- 15010696
TI  - Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working
      Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release.
AB  - Pharmacological manipulation of N-methyl-D-aspartate (NMDA) receptors may be
      critical for the treatment of many neurological and psychiatric disorders.
      Metabotropic glutamate (mGlu5) receptors are abundant in corticolimbic circuitry,
      where they modulate NMDA receptor-mediated signal transduction. Therefore,
      pharmacological manipulation of mGlu5 receptor may provide a treatment strategy
      for cognitive disorders that are associated with NMDA receptor dysfunction. We
      sought to determine whether the recently described molecular and cellular
      interactions between NMDA and mGlu5 receptors coregulate higher order behaviors.
      We examined the interaction of the selective mGlu5 receptor antagonist, 2-methyl
      6-(phenylethynyl)-pyridine (MPEP), and the use-dependent NMDA antagonist MK-801,
      on locomotion, stereotypy, working memory, instrumental learning, and
      corticolimbic dopamine release. MPEP, at 10 mg/kg, but not 3 mg/kg, impaired
      working memory and instrumental learning, transiently increased dopamine release
      in prefrontal cortex and nucleus accumbens, and augmented the effect of MK-801 on
      cortical dopamine release, locomotion, and stereotypy. Pretreatment with 3 mg/kg
      of MPEP enhanced the detrimental effects of MK-801 on cognition. These results
      demonstrate that an mGlu5 receptor antagonist can potentiate the motoric,
      cognitive, and dopaminergic effects of an NMDA receptor antagonist. Thus, mGlu5
      receptors appear to play a major role in regulating NMDA receptor-dependent
      cognitive functions such as learning and working memory. By extension, these
      results suggest that pharmacological potentiation of mGlu5 receptors may
      ameliorate the cognitive and other behavioral abnormalities associated with NMDA
      receptor deficiency.

PMID- 15010697
TI  - Addition of the alpha2-antagonist yohimbine to fluoxetine: effects on rate of
      antidepressant response.
AB  - Electrophysiological studies suggest that alpha2-adrenoceptors profoundly affect
      monoaminergic neurotransmission by enhancing noradrenergic tone and serotonergic
      firing rates. Recent reports suggest that alpha2-antagonism may hasten and
      improve the response to antidepressant medications. To test this hypothesis, a
      randomized double-blind controlled trial was undertaken to determine if the
      combination of an alpha2-antagonist (yohimbine) with a selective serotonin
      reuptake agent (SSRI) (fluoxetine) results in more rapid onset of antidepressant
      action than an SSRI agent alone. In all, 50 subjects with a DSM-IV diagnosis of
      major depressive disorder confirmed by SCID interview were randomly assigned to
      receive either fluoxetine 20 mg plus placebo (F/P) or fluxetine 20 mg plus a
      titrated dose of yohimbine (F/Y). The yohimbine dose was titrated based on blood
      pressure changes over the treatment period, in a blind-preserving manner.
      Hamilton depression scale ratings (HDRS) and clinical global impression (CGI)
      ratings were obtained weekly over a period of 6 weeks. The rate of achieving
      categorical positive responses was significantly more rapid in the F/Y group
      compared to the F/P group using both the HDRS and the CGI scales as outcome
      measures in a survival analysis using a log-rank test (chi2(1) = 5.86, p = 0.016
      and chi2(1) = 5.29, p = 0.021, respectively). At the last observed visit, 18
      (69%) of the 26 F/Y subjects met the response criteria for CGI compared to 10
      (42%) of 24 F/P subjects. Using the HDRS criteria, 17 (65%) of 26 F/Y subject vs
      10 (42%) of 24 F/P subjects were responders. The addition of the alpha2
      antagonist yohimbine to fluoxetine appears to hasten the antidepressant response.
      There is also a trend suggesting an increased percentage of responders to the
      combined treatment at the end of the 6-week trial.

PMID- 15010698
TI  - Cocaine dependence and d2 receptor availability in the functional subdivisions of
      the striatum: relationship with cocaine-seeking behavior.
AB  - Striatal dopamine D2 receptors have been implicated in the neurobiology of
      cocaine addiction. Previous imaging studies showed reduced striatal D2 receptor
      availability in chronic cocaine abusers, and animal studies suggested that low D2
      receptor availability promotes cocaine self-administration. Here, D2 receptor
      availability was assessed with positron emission tomography (PET) and
      [11C]raclopride in the limbic, associative, and sensori-motor subdivisions of the
      striatum in 17 recently detoxified chronic cocaine-dependent (CCD) subjects and
      17 matched healthy control (HC) subjects. In addition, the relationship between
      regional D2 receptor availability and behavioral measures obtained in cocaine
      self-administration sessions was investigated in CCD subjects. [11C]Raclopride
      binding potential was significantly reduced by 15.2% in the limbic striatum,
      15.0% in the associative striatum, and 17.1% in the sensori-motor striatum in CCD
      subjects compared to HC subjects. In CCD subjects, no relationship was detected
      between D2 availability in striatal regions and either the positive effects of
      smoked cocaine or the choice of cocaine over an alternative reinforcer (money)
      following a priming dose of cocaine (a laboratory model of relapse). Thus, this
      study confirms previous reports of a modest decrease in D2 receptor availability
      in CCD subjects, and establishes that this decrease is generalized throughout the
      striatum. However, this study failed to demonstrate a relationship between D2
      receptor availability and cocaine-induced cocaine-taking behavior. Additional
      research is warranted to unravel potential neurobiological traits that might
      confer vulnerability to relapse in detoxified CCD subjects.

PMID- 15010699
TI  - Effects of chronic haloperidol and clozapine treatment on neurogenesis in the
      adult rat hippocampus.
AB  - It has been proposed that the therapeutic benefits of treatment with
      antidepressants and mood stabilizers may arise partially from their ability to
      stimulate neurogenesis. This study was designed to examine the effects of chronic
      antipsychotic treatment on cell proliferation and survival in the adult rat
      hippocampus. Haloperidol (0.05 and 2 mg/kg), clozapine (0.5 and 20 mg/kg), or
      vehicle were administered i.p. for 28 days, followed by bromodeoxyuridine (BrdU,
      200 mg/kg, i.p.), a marker of DNA synthesis. One group of rats was killed 24 h
      following BrdU administration and BrdU-positive cells were quantified to assess
      the effects of drug treatment on cell proliferation. The remaining animals
      continued on antipsychotic medication for an additional 3 weeks following BrdU
      administration to assess the effects of antipsychotics on cell survival. Our
      results show that 24 h following BrdU, a low dose of clozapine (0.5 mg/kg)
      increased the number of BrdU-positive cells in the dentate gyrus (DG) by two
      fold. Neither 20 mg/kg of clozapine nor haloperidol had any effect on cell
      proliferation in DG. Moreover, neither drug at either dose had an effect on the
      number of newly generated neurons surviving in the DG 3 weeks following BrdU
      administration. These preliminary findings suggest that clozapine may influence
      the number of cells which divide, but antipsychotics do not promote the survival
      of the newly generated neurons at 3 weeks after a BrdU injection.

PMID- 15010702
TI  - Preclinical studies of glimepiride.
AB  - The treatment of NIDDM is advancing on a number of fronts, ranging from the
      understanding of the mechanisms of action of existing agents to the development
      of new drugs. Glimepiride, the most recently U.S. approved sulfonylurea, is
      evaluated for its pancreatic and extrapancreatic activities in addition to
      safety, when compared with glibenclamide in preclinical studies. Glimepiride
      uniquely binds to the 65 kDa protein K(ATP) channel in pancreatic islet beta-cell
      membranes and directly stimulates insulin secretion. Glimepiride has a lower
      binding affinity and causes less insulin release than glibenclamide in normal
      dogs and humans. However, in various animal models, glimepiride produces a more
      rapid and pronounced blood glucose-decreasing activity than glibenclamide. In
      vivo studies indicate that glimepiride also significantly reduces HbA1c, blood
      glucose and fasting insulin levels via extrapancreatic activities. These insulin
      mimetic effects are supported by demonstration of stimulated lipogenesis in 3T3
      adipocytes and glycogenesis in rat diaphragm, by more efficient translocation of
      GLTU4 in fat and skeletal muscle tissues, and by activation of key metabolic
      enzymes. The insulin sensitivity effects of glimepiride have been demonstrated in
      vivo by increased glucose disposal rates in euglycemic clamp studies and in vitro
      by increased sensitivity and responsiveness of insulin-induced glucose uptake.
      Moreover, glimepiride might stimulate insulin-mediated glucose utilization in
      hepatocytes. With exercise-induced hypoglycemia, a suppression of endogenous
      insulin secretion was observed for glimepiride only. Data accumulated from in
      vitro and animal studies suggest that glimepiride has the least cardiotoxic
      potential. Its relative activities in multiple cardiovascular studies do not
      correlate with its potency to lower blood glucose levels. Similar cardiovascular
      effects have been seen in human studies. In contrast to the lack of an acute
      action, chronic application of glimepiride to cultured cardiomyocytes was found
      to produce an approximate doubling of the basal glucose uptake rates by an
      insulin-independent pathway most probably involving increased protein expression
      of both GLUT1 and GLUT4. Like glibenclamide, glimepiride possibly has
      antiatherogenic activity by inhibiting platelet aggregation via suppression of
      arachidonic acid metabolism. Our recent studies on rats and humans indicated that
      glimepiride has immunomodulatory activity and this action appears to be related
      to lowering autoimmune responses rather than metabolic action. These studies have
      been extended to include glimepiride involvement with prevention of diabetes in
      BB rats using an islet transplantation model. Finally, sulfonylureas, including
      glimepiride, may be useful for treating and preventing NIDDM.

PMID- 15010700
TI  - Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis.
AB  - Phosphorylation of BCL-2 within an unstructured loop inhibits its antiapoptotic
      effect. We found that phosphorylated BCL-2 predominantly localized to the
      endoplasmic reticulum (ER) and tested whether phosphorylation would control its
      activity at this organelle, where Ca(2+) dynamics serve as a critical control
      point for apoptosis. Phosphorylation greatly inhibits the ability of BCL-2 to
      lower [Ca(2+)](er) and protect against Ca(2+)-dependent death stimuli. Cells
      expressing nonphosphorylatable BCL-2(AAA) exhibited increased leak of Ca(2+) from
      the ER and further diminished steady-state [Ca(2+)](er) stores when compared to
      cells expressing BCL-2(wt). Consequently, when BCL-2 is phosphorylated, Ca(2+)
      discharge from the ER is increased, with a secondary increase in mitochondrial
      Ca(2+) uptake. We also demonstrate that phosphorylation of BCL-2 inhibits its
      binding to proapoptotic family members. This inhibitory mechanism manifested at
      the ER, where phosphorylated BCL-2 was unable to bind proapoptotic members.
      [Ca(2+)](er) proved coordinate with the capacity of BCL-2 to bind proapoptotic
      BH3-only members, further integrating the apoptotic pathway and Ca(2+)
      modulation. Unexpectedly, the regulation of ER Ca(2+) dynamics is a principal
      avenue whereby BCL-2 phosphorylation alters susceptibility to apoptosis.

PMID- 15010701
TI  - Founder mutations among the Dutch.
AB  - Many genetic disorders demonstrate mutations that can be traced to a founder,
      sometimes a person who can be identified. These founder mutations have generated
      considerable interest, because they facilitate studies of prevalence and
      penetrance and can be used to quantify the degree of homogeneity within a
      population. This paper reports on founder mutations among the Dutch and relates
      their occurrence to the history and demography of the Netherlands. International
      migration, regional and religious endogamy, and rapid population growth played
      key roles in shaping the Dutch population. In the first millenniums BC and AD,
      the Netherlands were invaded by Celts, Romans, Huns, and Germans. In more recent
      times, large numbers of Huguenots and Germans migrated into the Netherlands.
      Population growth within the Netherlands was slow until the 19th century, when a
      period of rapid population growth started. Today, the Dutch population numbers 16
      million inhabitants. Several different classes of founder mutations have been
      identified among the Dutch. Some mutations occur among people who represent
      genetic isolates within this country. These include mutations for benign familial
      cholestasis, diabetes mellitus, type I, infantile neuronal ceroid lipofuscinosis,
      L-DOPA responsive dystonia, and triphalangeal thumb. Although not related to a
      specific isolate, other founder mutations were identified only within the
      Netherlands, including those predisposing for hereditary breast-ovarian cancer,
      familial hypercholesterolemia, frontotemporal dementia, hereditary
      paragangliomas, juvenile neuronal ceroid lipofuscinosis, malignant melanoma,
      protein C deficiency, and San Filippo disease. Many of these show a regional
      distribution, suggesting dissemination from a founder. Some mutations that occur
      among the Dutch are shared with other European populations and others have been
      transmitted by Dutch emigres to their descendents in North America and South
      Africa. The occurrence of short chromosomal regions that have remained identical
      by descent has resulted in relatively limited genetic heterogeneity for many
      genetic conditions among the Dutch. These observations demonstrate the
      opportunity for gene discovery for other diseases and traits in the Netherlands.

PMID- 15010703
TI  - Clinical trials with glimepiride.
AB  - Data from 21 placebo-controlled, active-controlled or noncomparative studies
      involving more than 6500 patients, more than 4220 of whom were treated with
      glimepiride, are reviewed. Glimepiride has a rapid onset of action and is
      effective at a single daily dose. It is equally effective as the other second
      generation sulfonylureas at doses of 1-8 mg/day, with doses above 4 mg/day
      reserved for patients with initial HbA(1c) above 8%. Glimepiride (at doses
      yielding the same blood-lowering effect as glyburide and glipizide), has a safety
      profile somewhat superior to that of glyburide, glipizide and gliclazide at a
      lower mg/day dose. Glimepiride also has been shown to be safe and effective in
      combination with insulin. Finally, glimepiride has two pharmacologic properties
      which have theoretical advantages over the other currently available
      sulfonylureas, but which have not as yet been shown to be clinically significant:
      it does not activate the cardiovascular K(ATP) channel and it achieves equivalent
      metabolic control at lower insulin secretion levels than the other sulfonylureas.

PMID- 15010704
TI  - AIDS-related cytomegalovirus retinitis.
AB  - Until recently, chronic daily intravenous infusions of ganciclovir or foscarnet
      were the only available treatment regimens for cytomegalovirus (CMV) retinitis, a
      sight-threatening complication that has historically affected approximately one
      third of all AIDS patients in industrialized countries. In recent years, results
      of many randomized clinical trials of new treatments for AIDS-related CMV
      retinitis have been disseminated. These trials have involved four novel treatment
      modalities (i.e., an oral formulation of ganciclovir, a ganciclovir intraocular
      device, a combined intravenous ganciclovir/foscarnet regimen and a new agent,
      cidofovir) that offer better efficacy and/or less inconvenience than standard
      daily intravenous therapy with either ganciclovir or foscarnet. This review
      summarizes the main points clinicians should know about the available treatments
      for CMV disease.

PMID- 15010705
TI  - Central neurological paraneoplastic syndromes. Part 1. Clinical features,
      pathophysiology and immunopharmacology.
AB  - Neurological paraneoplastic syndromes, sometimes called remote effects of cancer
      on the nervous system, are rare but important and often devastating complications
      of cancer. The immunological theory of causation is supported by many different
      lines of evidence and reasoning which implicate abnormalities of both humoral and
      cellular immunity. The targets of immunologically mediated injury, although
      remote from the tumor, may be hard hit and irreversibly damaged, giving rise to
      discrete syndromes of motor or cognitive impairment. In the CNS, they are
      neuronal nuclei, cerebellar Purkinjie cells and cell surface glutamate receptors.
      Although central paraneoplastic neurological syndromes may occur in children or
      adults, the clinical syndromes and response to treatment differ substantially
      between the two groups. The current therapeutic armamentarium provides a broad
      spectrum of nonselective immunotherapies including noncytotoxic and cytotoxic
      drugs, intravenous immunoglobulins and plasma exchange, some selected for
      induction and others for maintenance. Combination immunotherapies allow steroid
      sparing and targeting of more than one immunologic effector pathway, and deploy
      an advantageous mixture of early- and late-acting drugs. More selective and
      efficacious immunotherapies are needed.

PMID- 15010706
TI  - Drug therapy of inflammatory bowel disease.
AB  - The drugs that are effective in inflammatory bowel disease (IBD) act by
      inhibiting the chronic unregulated intestinal inflammation in these patients. The
      mainstays of the drug therapy of IBD are a variety of formulations of 5
      aminosalicylic acid (5-ASA), the conventional and newer low bioavailability
      glucocorticoids, the nitroimidazole antibiotic metronidazole, and certain
      immunomodulating agents. Increased understanding of the mechanisms of
      inflammation in IBD has permitted the development of effective designer drugs.
      These agents are products of the biotechnology industry and include antibodies to
      tumor necrosis factor (TNF)-alpha, antisense oligonucleotides and recombinant
      human interleukin (IL)-10. In addition, a number of other agents such as nicotine
      and n-3 fatty acids are useful in certain patients. This review first focuses on
      the pharmacology and mechanism of action of these drugs in IBD, followed by an
      approach to the treatment of patients with ulcerative colitis (UC) and Crohns
      disease (CD). The recommendations consider type and activity of IBD and are based
      largely on data from controlled trials and systematic reviews in the IBD
      literature.

PMID- 15010707
TI  - Dry eye syndrome.
AB  - The present review is of dry eye syndrome, an entity caused by various conditions
      that lead to tear film abnormalities. The tear film consists of aqueous, mucin,
      proteins and lipids. Dry eye syndrome may be caused by local ocular disorders or
      systemic diseases. The symptoms include foreign body sensation, redness,
      photophobia and burning sensation. Clinical tests such as the Schirmer test,
      fluorescein staining test and Rose Bengal test are useful diagnostic tools.
      Laboratory tests are important assets in the diagnosis and identification of the
      underlying systemic disease. Biopsy of the accessory salivary gland is important
      in the diagnosis of Sjogren's syndrome. The management of dry eye syndrome
      includes replacing the deficient tear film and prolonging its residence time on
      the ocular surface.

PMID- 15010708
TI  - Male menopause.
AB  - Menopause is the cessation of menses caused by the age-associated decline in
      gonadal hormone secretion in women. Although men do not menstruate, they do have
      an age-associated decline in gonadal hormone secretion. This "male menopause" is
      associated with loss of libido, loss of muscle mass and various other undesirable
      effects. The underlying causes of decreased testosterone production in older men
      may include decreased hypothalamic gonadotropin releasing hormone (GnRH)
      secretion, impaired feedforward effect of luteinizing hormone (LH) on
      testosterone secretion and decreased testosterone release from the Leydig cells.
      When chronic illness is superimposed on healthy aging, there are further
      decrements in testosterone availability. Although a consensus has not been
      reached, various studies suggest that older men may benefit from testosterone
      supplementation. For example, testosterone supplementation to older men seems to
      cause increased muscle protein synthesis, increased muscle strength and decreased
      cholesterol. Nevertheless, if testosterone supplementation is provided,
      clinicians must be vigilant to detect adverse effects such as accelerated growth
      of prostate carcinoma.

PMID- 15010709
TI  - Pharmacology of immunosuppressive drugs.
AB  - Immunosuppressive therapy of solid organ transplantation has become more potent,
      effective and selective since the results of earlier use of prednisone and
      azathioprine post renal transplantation. Calcineurin inhibitors and mycophenolate
      mofetil have been important additions to the effective antirejection
      armamentarium. Today, cyclosporin, tacrolimus, azathioprine, mycophenolate and
      prednisone are all effective immunosuppressive agents and are the cornerstone of
      immunosuppressive protocols used posttransplant. However, the use of these agents
      is hindered by a 20% rate of rejection, lack of selectivity and a high rate of
      major adverse drug reactions which ultimately lead to a decrease in patient and
      graft survival. A number of clinical trials are underway to compare efficacy,
      safety and tolerability of different combination protocols to improve patient and
      allograft survival and decrease adverse drug reactions. Clinical knowledge of the
      pharmacology, pharmacokinetics, pharmacodynamics, adverse drug reactions and
      therapeutic drug monitoring of antirejection agents is essential for designing an
      effective immunosuppressive protocol for individual solid organ transplant
      recipients. The clinical application of pharmacotherapeutic principles into the
      clinical practice will improve both long-term patient and allograft survival
      while minimizing systemic toxicity of immunosuppressive drugs.

PMID- 15010710
TI  - The management of severe chronic pain with a focus on new treatment modalities.
AB  - Pain is the most common reason for consultation with a physician, but because
      pain is not objectively measurable, it is often neglected or underestimated.
      Chronic, severe pain is a major complication of cancer and HIV-1 infection.
      Current therapy typically employs stepwise treatment first with nonopioid
      analgesics, followed by weak and then strong opioids. Nevertheless, treatment can
      be limited both by side effects and by the development of tolerance, and patients
      with neuropathic pain are often resistant to all conventional therapies. Much has
      been learned about the neuroanatomy and physiology of both acute and chronic
      pain. Drugs now being developed, such as alpha(2)-receptor agonists, the N-type
      calcium channel blocker, SNX-111 and NMDA antagonists, take advantage of current
      knowledge of the neurochemistry of pain transduction and target neurotransmitter
      modulation as a means of achieving analgesia. These new drugs and alternative
      administration methods, such as intraspinal drug delivery and preemptive
      analgesia for postoperative pain, should add substantially to the current
      analgesic armamentarium.

PMID- 15010711
TI  - Advances in the diagnosis and treatment of arterial hypertension.
AB  - Hypertension is a major risk factor for the development of serious complications
      affecting the heart, brain, kidneys and the vascular system, leading to death and
      disability on a huge scale globally. This manuscript deals primarily with the
      clinical strategy for the control of hypertension and only refers in passing to
      the population strategy and primary prevention. It also concentrates on essential
      hypertension and does not deal with the diagnosis and management of secondary
      causes of hypertension. Rather, the paper describes the clinical evaluation,
      laboratory investigations and management of the patient with essential
      hypertension. The focus of management is on patients with mild and moderate
      hypertension, without any discussion of the treatment of more severe
      hypertension, malignant hypertension or hypertensive encephalopathy. Accordingly,
      the emphasis is on lifestyle factors important in both prevention and treatment
      of hypertension and on the drug treatment of patients with elevated blood
      pressures in routine clinical practice. The paper does not cover special
      populations or problems such as hypertension of pregnancy or hypertension in
      children.

PMID- 15010712
TI  - Central paraneoplastic neurological syndromes. Part 2. Practical, theoretical and
      mechanistic considerations of treatment with drugs and biologicals.
AB  - New information about paraneoplastic neurological syndromes, or the remote
      effects of cancer, has raised more questions than answers. The underlying
      mechanisms of brain injury remain to be elucidated. A brief review of
      autoimmunity provides a basis for exploring hypotheses of induction of the immune
      system by a tumor in the periphery and its subsequent attack on the brain.
      Onconeural antigens shared by tumors and the brain are the targets of
      immunologically mediated injury. What provokes the immune system to
      inappropriately autoaggress and cause autoimmune disease is unknown, but the
      mechanisms of molecular mimicry or superantigens provide plausible explanations.
      The root of the problem appears to be a failure of immunoregulation on some
      level. The more precisely the immunological defect can be defined, the more
      select the possible therapy. Selective immunotherapies, now available or in
      preclinical and clinical trials, have great therapeutic potential but require
      precise information on the underlying immunological problem. These data will
      provide new directions for immunologic research and therapy in CNS paraneoplastic
      syndromes.

PMID- 15010713
TI  - Epidural and other labor analgesic methods.
AB  - This article focuses on methods of pain relief during labor, reviewing the
      current state of the art including risks and benefits. Regional techniques such
      as epidural or combined spinal/epidural techniques are discussed. A limited
      review of the effects of epidural analgesia on labor and delivery is presented.
      Other pharmacologic methods for labor pain relief are discussed including
      intravenous narcotics, paracervical block and inhalational analgesia. The
      following nonpharmacologic methods are also discussed: hypnosis, supportive care,
      transcutaneous electronic nerve stimulation (TENS), acupuncture/acupressure,
      subcutaneous water blocks and hydrotherapy.

PMID- 15010714
TI  - Lyme neuroborreliosis.
AB  - The series on treatable neuromuscular disorders continues with the present
      article on the peripheral nervous system manifestations of Lyme neuroborreliosis.

PMID- 15010715
TI  - Medical management of Crohn's disease.
AB  - Crohn's disease is a chronic inflammatory bowel disease of unknown etiology.
      Sulfasalazine and the newer 5-aminosalicylates remain the first agents of choice
      to treat mild to moderate disease and often are effective at high doses as
      maintenance therapies. Corticosteroids are often required to treat more moderate
      to severe disease activity, although approximately one-third of patients become
      steroid-dependent after a steroid-induced remission. Corticosteroids have proven
      ineffective in maintaining remission and side effects resulting from prolonged
      exposure preclude their long-term use. Azathioprine and 6-mercaptopurine are
      effective in the setting of steroid dependence and steroid resistance, as well as
      for the treatment of perianal and fistulizing complications unresponsive to
      antibiotics. Crohn's disease commonly recurs following surgical resection, and
      there is expanding evidence that postoperative prophylaxis with certain
      antibiotics (e.g., metronidazole), aminosalicylates or immunomodulators may be
      beneficial in the prevention of disease recurrence following resection.
      Cyclosporin may benefit patients with severe Crohn's disease or refractory
      fistulas. Recent trials of newer immunosuppressive agents commonly employed in
      transplant recipients and ongoing development of a new class of "biologic" agents
      targeting specific sites in the immunoinflammatory cascade, are expanding the
      pharmacological armamentarium available to treat certain patients.

PMID- 15010716
TI  - New aerosol drug delivery systems for the treatment of immune-mediated pulmonary
      diseases.
AB  - In the lung, unchecked immune responses mediated predominantly by T-lymphocytes
      and concurrent inflammation can lead to the development of different pathological
      conditions such as parenchymal disease, interstitial fibrosis, hypersensitivity
      pneumonitis, bronchiolitis obliterans and bronchiolar asthma. Targeted modulation
      of uncontrolled T-cell activation and inhibition of cytokine production within
      different pulmonary compartments is the challenge for the development of novel
      methods for immunotherapeutic intervention. Utilization of aerosol technology for
      pulmonary drug delivery represents new potential opportunities for therapeutic
      application for such immune-mediated pulmonary diseases. For targeted aerosol
      pulmonary drug delivery, continuous-flow jet nebulizers have several advantages
      over metered dose or dry powder inhalers since they are the simplest and most
      effective for aerosol droplet deposition into the peripheral lung tissues. At the
      present, the major limitations for targeted pulmonary immunosuppression through
      effective utilization of nebulizer technology has been the conspicuous lack of
      suitable formulations. The development of liposomal formulations compatible with
      aerosol delivery with jet nebulizers has expanded the potential for more
      effective utilization with an array of potent and effective immunosuppressive
      drugs. For pulmonary therapy, the utilization of liposomes for aerosol delivery
      has many potential advantages, including universal carrier suitability for most
      lipophilic drugs, aqueous compatibility, sustained pulmonary release or depot and
      intracellular delivery. Drug liposomes may also prevent local irritation in the
      lung, and increase potency with reduced systemic toxicity. Successful utilization
      of potent immunosuppressive drugs, like cyclosporin, tacrolimus (FK-506),
      rapamycin, mycophenolate and budesonide, in a variety of immunopathological
      conditions for other indications demonstrates their potential efficacy for the
      treatment of many different immune-mediated pulmonary diseases. The route of
      delivery to the pulmonary tissues can potentially limit adverse effects and
      markedly affect localized immunosuppressive activity in the lung. Combination of
      liposomal formulations with topical aerosol delivery to the central and
      peripheral lung tissues has expanded potential for more effective utilization
      with these lipophilic immunosuppressive (and antiinflammatory) drugs. Synergistic
      combinations can also be developed for localized and sustained delivery of
      therapeutic drug concentrations within the lung to provide multisite
      immunosuppression. Drug liposome aerosol technology represents one readily
      available approach for more effective therapeutic intervention in the lung using
      cyclosporin, FK-506, rapamycin, mycophenolate, budesonide and other lipophilic
      drugs.

PMID- 15010717
TI  - Pseudotumor cerebri and its medical treatment.
AB  - Pseudotumor cerebri is an idiopathic disorder characterized by papilledema and
      elevated intracranial pressure without a mass lesion. Most patients are female
      and young and are either overweight or have a history of recent weight gain.
      Other disease states, such as systemic lupus erythematosus, and drugs, such as
      tetracycline, have also been associated with the development of pseudotumor
      cerebri. The mechanism is unclear, but is likely related to decreased
      cerebrospinal fluid (CSF) resorption. Almost all patients have headache, but the
      greatest morbidity of the disorder is visual loss related to optic disc swelling.
      Common radiographic findings in pseudotumor cerebri include an empty sella,
      dilation of the optic nerve sheaths and elevation of the optic disc. The CSF,
      aside from elevated opening pressure, is normal without evidence of infection or
      inflammation. Treatment of patients with no or mild to moderate visual loss is
      primarily medical, with acetazolamide as the first-line agent. Acetazolamide
      decreases CSF production. Furosemide and corticosteroids are secondary choices.
      Optic nerve surgery is reserved for patients with severe visual loss or
      progression in visual deficits despite medical management.

PMID- 15010718
TI  - Alternatives to lithium therapy in the treatment of acute mania.
AB  - Manic depressive illness is a poorly understood condition whose causes are
      primary (possibly hereditary) as well as secondary. It is difficult to diagnose
      and treat and at the present time, lithium and anticonvulsants remain the
      preferred medications for the acute phase of mania. However, concomitant use of
      benzodiazepines or neuroleptics may be helpful to facilitate early response to
      treatment. Management of lithium refractory patients unresponsive to reasonable
      trials of anticonvulsants may make it necessary for the psychiatrist to use
      electroconvulsive therapy, generally considered a safe and effective alternative.
      Evaluation of concurrent illnesses and recognition of side effects in these
      treatments are also important to optimize results.

PMID- 15010719
TI  - Changes in sexual function secondary to medication effects.
AB  - Over 200 medications have been cited in case reports, prescribing literature or
      controlled studies as possibly impacting sexual function (1). Recognizing and
      treating these side effects is important for patient medication adherence and
      overall quality of care. The following article provides suggestions for
      evaluating the impact of medications on sexual function, as well as possible
      interventions. A table is included which lists medications suspected to cause
      changes in sexual function and the side effects with their relative frequencies.

PMID- 15010720
TI  - Donepezil.
AB  - Donepezil is a highly selective, long-acting acetylcholinesterase inhibitor which
      has been approved in numerous countries for the treatment of Alzheimer's disease.
      Donepezil increases the levels of acetylcholine in the brain of patients with
      Alzheimer's disease and presumably corrects some dysfunction associated with loss
      of cells in the basal forebrain. Several large-scale multinational clinical
      studies have demonstrated drug-related improvements in cognitive performance on
      objective psychometric tests and in ratings by clinicians of patients' function.
      Further studies will be needed to determine the long-term impact of donepezil on
      Alzheimer's disease and related dementias.

PMID- 15010721
TI  - Drug treatment of juvenile arthritis: accepted therapeutic options.
AB  - Juvenile arthritis (JA) is classified into 3 subtypes based primarily on clinical
      characteristics (sign and symptoms) at onset. For all patients with JA, drug
      therapy begins with nonsteroidal antiinflammatory drugs (NSAIDs) from which there
      are a number of pediatric approved compounds to choose. If disease activity
      persists after an adequate NSAID trial, a second-line agent, typically
      methotrexate, is added. In patients with a small number of resistant joints, in
      the absence of other illness manifestations, intraarticular corticosteroids
      (triamcinolone hexacetonide) can be used to induce remission. Some children with
      severe JA, particularly systemic onset disease, will require the addition of
      systemic corticosteroids for symptom control. Further treatment has been less
      well evaluated but includes intravenous immunoglobulin, drug combination
      cytotoxic therapy and biologic agents. The latter will be increasingly studied in
      the pediatric population in the future, but are currently reserved for severely
      unresponsive disease. Management of JA extends beyond drugs, to incorporate
      occupational and physical therapy, appropriate mental health care and a family
      centered strategy that seeks to achieve the highest attainment and quality of
      life for these patients and their families.

PMID- 15010722
TI  - Recent innovations in asthma therapy.
AB  - Guidelines for the diagnosis and management of asthma have been published since
      1990 and already new versions are being published. The recommendations for the
      treatment of asthma were organized around four components of effective asthma
      management: i) use of objective measures of lung function to assess the severity
      of asthma and to monitor the course of therapy, ii) environmental control
      measures to avoid or eliminate factors that precipitate asthma symptoms or
      exacerbations, iii) comprehensive pharmacologic therapy for long-term management
      designed to reverse and prevent the airway inflammation characteristic of asthma
      as well as pharmacologic therapy to manage asthma exacerbations, and iv) patient
      education that fosters a partnership among the patient, family and clinicians.
      Newly released medications include anti-leukotriene (LTs) agents which function
      either by blocking the interaction of LTs with receptors (receptor antagonists)
      or by inhibiting leukotriene synthesis (synthesis inhibitors). Representatives of
      the antagonists discussed here are zafirlukast, pranlukast and montelukast.
      Zafirlukast (20 mg twice daily) improves pulmonary function indices and days
      without symptoms and decreases the asthma exacerbation frequency. Pranlukast, the
      first leukotriene receptor antagonist to be marketed, improves lung function and
      symptoms when 450 mg twice daily is used. A study with montelukast demonstrated
      similar positive results irrespective of the use of concomitant inhaled
      corticosteroid. This indicates that leukotriene receptor antagonists may have
      additive effects to steroid therapy. They may also be a potential alternative to
      inhaled steroids, although more studies need to be performed before defining the
      role of receptor antagonists in the treatment of asthma. Zileuton, a leukotriene
      synthesis inhibitor, has been shown to improve lung function, reduce symptoms and
      reduce use of beta-agonists and asthma exacerbations. These positive effects are
      dose-dependent and liver function abnormalities seem to be a relevant issue
      during zileuton use in some patients. Other compounds that inhibit LTs synthesis
      are in development and, like zileuton, need more tests. Phosphodiesterases (PDE),
      enzymes that break down cAMP and cGMP, have been a target for new compounds
      developed to treat asthma. Inhibition of PDE enzymes increases intracellular cAMP
      or cGMP which then produces bronchodilation. Recent studies have also shown
      antiinflammatory effects by suppressing some PDE isoenzymes, including PDE III
      and PDE IV. These effects were detected by studies in vitro and in animal models.
      Clinical trials are necessary to determine which PDE inhibitors can be useful for
      the treatment of asthma.

PMID- 15010723
TI  - Surgical and nonsurgical invasive treatment of benign prostatic hyperplasia.
AB  - A third era in the surgical treatment of benign prostatic hyperplasia (BPH)
      utilizes less invasive treatment modalities. Transurethral microwave therapy
      (TUMT), transurethral needle ablation of the prostate (TUNA) and a wide variety
      of laser treatments are the most conspicuous new treatment modalities approved or
      awaiting approval. In general, the alternative treatments produce less
      improvement in symptoms and peak urinary flow rates (Q(max)) than open
      prostatectomy or transurethral resection of the prostate (TURP), which remains
      the "gold standard". However, most are promising, particularly because they are
      associated with low morbidity. Long-term outcome has yet to be assessed with any
      of the newer treatments and total costs are difficult to calculate. Most have
      proved safe, are feasible on an outpatient basis and which, provided a low
      retreatment rate, will presumably reduce the socioeconomic costs. Although
      differences are found in outcome, morbidity and costs, none of the newer
      treatments has demonstrated convincing superiority or established a well-defined
      niche. In the future, controlled randomized studies against well-documented
      treatments like TURP or transurethral incision of the prostate (TUIP), focusing
      on long-term outcome, quality of life and socioeconomic costs, are needed.

PMID- 15010724
TI  - The idiopathic hypereosinophilic syndrome: clinical presentation, pathogenesis
      and therapeutic strategies.
AB  - The idiopathic hypereosinophilic syndrome (HES) is a heterogenous disease entity
      characterized by persistent unexplained hypereosinophilia generally complicated
      by end-organ damage. Correct diagnosis and management are important in order to
      prevent long-term complications. Furthermore, it appears that HES represents a
      premalignant state in some patients, and close follow-up is necessary to detect
      early signs of malignant transformation. Previous studies of patient cohorts have
      led to the identification of a subgroup of patients with various clinical and
      biological features of primitive myeloproliferative disease. Patients in this
      subgroup have a clinically more aggressive disease in terms of organ damage and
      eventually develop acute myeloid leukemia. Among the remaining patients, it
      appears that some present an underlying T-cell disorder characterized by
      overproduction of Th2-type cytokines in vivo. Indeed, lymphocytes belonging to
      the Th2 subset are implicated in the maturation, activation and recruitment of
      eosinophils, essentially through the production of IL-5. Such patients appear to
      present a more benign disease at short term; however, they may develop T-cell
      lymphoma years after initial diagnosis. Therapy of HES includes glucocorticoids,
      hydroxyurea and more recently, interferon-alpha. Prednisone is generally
      recommended initially, followed by hydroxyurea in case of treatment failure.
      Until now, interferon-alpha has been reserved for refractory cases of HES. Our
      proposal for a new treatment strategy, based on current understanding of the
      pathogenesis of different subgroups of HES and on the mechanisms of action of the
      proposed therapeutic agents, which will be discussed in detail. Moreover,
      prevention of malignant transformation has become a new subject of concern when
      considering the beneficial effects of drugs.

PMID- 15010725
TI  - Zafirlukast (Accolate).
AB  - Cysteinyl-leukotrienes are important mediators in the pathogenesis of asthma.
      Zafirlukast is a selective and competitive leukotriene receptor antagonist that
      has been developed for the treatment of asthma. It inhibits exercise-induced
      asthma, both the early- and late-phase response after allergen challenge in
      asthmatic subjects, and aspirin-induced asthma in aspirin-sensitive asthmatic
      patients. Published data indicate that zafirlukast 20 mg twice daily causes an
      improvement in lung function (FEV(1) and peak expiratory flow measurements) and
      symptom control, together with a reduction in the use of short-acting beta
      agonist inhaled therapy in patients with mild to moderate asthma. Studies
      presented in abstract form have shown that zafirlukast 20 mg twice daily had
      similar efficacy as sodium cromoglycate aerosol or dry powder inhalation; in one
      of the studies, no advantage of the active drugs was reported over placebo.
      Compared to inhaled beclomethasone dipropionate therapy (200-250 microg b.i.d.),
      improvements in morning peak flow, FEV(1) and daytime symptom score were
      significantly less with zafirlukast 20 mg twice daily than with inhaled steroids.
      A steroid-sparing effect of zafirlukast (20 mg b.i.d.) was not observed in
      studies of 12-20 weeks duration in patients on inhaled steroid therapy. A
      significant improvement in lung function and symptom control was observed on
      addition of zafirlukast 80 mg twice daily in symptomatic patients maintained on
      high-dose inhaled steroid therapy. Meta-analysis of 5 large studies indicate that
      there is a significant reduction in the number of asthma exacerbations compared
      to placebo. Zafirlukast at 20 mg twice daily dosage appears to be well-tolerated
      comparable to placebo. High doses of 80 mg twice daily have been associated with
      reports of elevated liver enzymes. Zafirlukast is a useful addition to existing
      antiasthma therapies. It may be used in combination with inhaled or oral
      corticosteroid therapy. Further investigation of its efficacy and
      antiinflammatory effects will clarify its use as a first-line antiinflammatory
      agent in mild asthma. Zafirlukast is administered orally and may therefore be
      useful in patients poorly compliant with inhaled steroid therapy and with a poor
      inhaler technique.

PMID- 15010726
TI  - Persistence and compliance.

PMID- 15010727
TI  - The good COPD guidelines.

PMID- 15010728
TI  - 2003 Christie Memorial lecture. Occupational asthma--the past 50 years.

PMID- 15010729
TI  - Inhaled corticosteroids in COPD: determinants of use and trends in patient
      persistence with treatment.
AB  - METHODS: The determinants of a new treatment with inhaled corticosteroids and
      secular trends in patient persistence with treatment among chronic obstructive
      pulmonary disease (COPD) patients were investigated. A cohort of 3768 physician
      diagnosed, elderly COPD patients was selected between 1990 and 1996 from the
      health care administrative database of the Regie de l'assurance maladie du
      Quebec. A nested case-control design was used to identify patient and physician
      characteristics that were associated with a new treatment with inhaled
      corticosteroids. Treatment persistence with inhaled corticosteroids was also
      estimated using Kaplan-Meier analysis. In addition to that, changes in treatment
      persistence over time, from 1990 to 1995, were investigated by estimating the
      yearly proportion of patients persisting for less than one year. RESULTS: Within
      the cohort, the yearly percentage of patients filling at least one prescription
      for inhaled corticosteroids was 42.2% in 1990 and increased to 53.1% in 1995
      (P=0.001). Using a conditional logistic regression model, it was found that the
      patients most likely to initiate a treatment with inhaled corticosteroids were
      those who had severe COPD (rate ratio [RR] 1.7; 95% CI 1.4 to 2.0), those who
      were hospitalized for COPD (RR 10.0; 95% CI 5.6 to 17.9), those who consulted a
      respirologist in the previous month (RR 2.3; 95% CI 1.6 to 3.3) or those who
      visited more than three different physicians in the previous three months (RR
      1.6; 95% Cl 1.3 to 1.9). The proportion of patients persisting with inhaled
      corticosteroids for less than one year rose by 19.4%, from 47.6% in 1990 to 67.0%
      in 1995 (P=0.011; test for trend). CONCLUSIONS: The use of inhaled
      corticosteroids increased while patient persistence decreased between 1990 and
      1995. Disease severity, as well as recent consultation to a respirologist and
      multiple visits to a physician, were associated with a strong likelihood of being
      prescribed inhaled corticosteroids. The cost of this practice is far from
      negligible, while their clinical impact is still uncertain.

PMID- 15010730
TI  - Different profile of interleukin-10 production in circulating T cells from atopic
      asthmatics compared with healthy subjects.
AB  - BACKGROUND: Interleukin (IL)-10 is a pleiotropic cytokine released from various
      cells, including T cells. Although IL-10 is suggested to inhibit allergic
      responses, its role in asthma remains uncertain. The purpose of the present study
      was to compare the profile of IL-10 in circulating T cells from stable atopic
      asthmatics, atopic nonasthmatics and healthy controls. METHODS: Peripheral blood
      mononuclear cells were isolated, stained with anti-CD3 and CD4/CD8 antibodies,
      and then processed for intracellular IL-10 detection by flow cytometry. RESULTS:
      A kinetic study in healthy controls showed that stimulation with phorbol 12
      myristate 13-acetate and ionomycin significantly increased the frequencies of IL
      10-producing CD3+, CD4+ and CD8+ cells. Without stimulation, the frequencies of
      IL-10-producing CD3+, CD4+ and CD8+cells were significantly higher in asthmatics
      than in healthy controls, while a similar trend was observed in atopic
      nonasthmatics. Stimulation for 24 h significantly increased IL-10-producing CD3+,
      CD4+ and CD8+cells in healthy controls and atopic nonasthmatics, but not in
      asthmatics. CONCLUSIONS: The frequency of IL-10-producing T cells is increased in
      the circulation of stable atopic asthmatics compared with normal controls. The
      lack of enhancement in their frequency by phorbol 12-myristate 13-acetate and
      ionomycin in asthmatics suggests that the circulating T cells of asthmatic
      subjects are maximally stimulated with regards to IL-10 production;
      alternatively, IL-10 production by T cells from asthmatics may be regulated
      differently than T cells from other subjects.

PMID- 15010731
TI  - A population-based evaluation of a regional asthma education centre.
AB  - BACKGROUND: A population-based, ecological evaluation was conducted to determine
      the impact of a regional asthma education centre on reducing asthma-related
      morbidity and improving the quality of prescribing. METHODS: The number of
      emergency department (ED) visits for respiratory-related illness and the
      prescribing of antiasthmatic medications were monitored during consecutive 18
      month pre- and postintervention periods in two communities with similar health
      care resources. Using defined daily doses, the quality of prescribing was
      assessed by calculating the ratio of inhaled corticosteroids to inhaled, short
      acting beta 2-agonists. RESULTS: The reduction in the rate of respiratory-related
      ED visits in subjects five to 45 years of age was 410 per 10,000 people and 450
      per 10,000 people for the intervention and nonintervention communities,
      respectively. A significant reduction in the rate of ED visits of 698 per 10,000
      people was found for patients aged 35 to 45 years in the intervention community
      (P<0.05). The reduction achieved statistical significance in the nonintervention
      community in younger patients: 557 per 10,000 people and 567 per 10,000 people
      for patients aged five to 14 years and 15 to 24 years, respectively (P<0.05). The
      ratio of inhaled corticosteroids to inhaled beta 2-agonists increased from 0.47
      to 0.78 in the intervention community--a 66% change. However, over the course of
      the preintervention period, the prescribing ratio was already increasing in this
      community. The corresponding ratios were 0.47 and 0.53 in the nonintervention
      community--an increase of 13%. CONCLUSIONS: A conclusive association between the
      establishment of an asthma education centre and changes in health care use or the
      quality of prescribing could not be demonstrated.

PMID- 15010732
TI  - Spirometric findings among school-aged First Nations children on a reserve: a
      pilot study.
AB  - BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are
      increasing concerns for First Nations peoples in Canada. Although hospital
      utilization for asthma and COPD among First Nations peoples has been increasing,
      the prevalence of asthma or wheezing is comparable to national averages.
      OBJECTIVES: A pilot study was conducted to determine the prevalence of impaired
      lung function in school-aged First Nations children. PATIENTS AND METHODS: A
      First Nations community in northern Alberta was selected to participate. Consent
      forms and a school health survey were completed by parents or guardians. Children
      with consent completed spirometry at school, and results were compared with
      predicted values. RESULTS: A total of 36 children participated (response rate
      70.6%). Of these, 19.4% of parents reported that their child had received a
      physician diagnosis of asthma at some point in their life; only 28.6% had a
      parental report of still having asthma. Parents smoked in 73.1% of the children's
      homes. The mean (+/- SD) percentage of forced expiratory volume in 1 s (FEV1)
      over forced vital capacity (FVC) was 82.6%+/-6.9% (94.4%+/-0.08% of predicted).
      Evidence of airflow obstruction was found in 25% of the children. Parental report
      of the child ever having asthma was associated with impaired lung function (OR
      3.20; P=0.033). Children in a home with reported mold exposure were less likely
      to have impaired lung function (OR 0.68; P=0.030). CONCLUSIONS: Many children in
      this study already have established airflow obstruction and may be at increased
      risk for asthma or COPD. Exposure to mold appeared to be protective. Further
      research is needed to evaluate the lung health concerns of this population.

PMID- 15010733
TI  - Atypical presentation of lymphomatoid granulomatosis in a patient with
      longstanding sarcoidosis.
AB  - A patient was recently evaluated who had longstanding sarcoidosis with
      lymphadenopathy and multiple, small lung nodules, and who developed a new, 9 cm
      solitary pulmonary mass in the right lower lobe. After thoracotomy, this lesion
      was ultimately found to be lymphomatoid granulomatosis, a rare
      lymphoproliferative disorder. Radiographic evaluations of patients with this
      disorder characteristically show multiple, bilateral reticulonodular opacities
      that follow the bronchovascular bundles; however, presentation with a solitary,
      large pulmonary mass is rare. The present case illustrates the need for complete
      evaluation of new clinical and radiographic findings in the setting of chronic
      lung disease.

PMID- 15010734
TI  - Rapidly progressive pulmonary fibrosis in a patient treated with danazol for
      idiopathic thrombocytopenic purpura.
AB  - The case of a patient that developed pulmonary fibrosis two months after
      initiation of danazol for treatment of idiopathic thrombocytopenic purpura is
      described. Bilateral pneumothoraxes and pneumomediastinum complicated the rapidly
      fatal pulmonary fibrosis. An association between danazol therapy and the
      development of pulmonary fibrosis is suspected. There is only one other case
      report with this connection in the literature.

PMID- 15010735
TI  - Compete or couple?

PMID- 15010736
TI  - Use of valve surgery in Canada.
AB  - BACKGROUND: To date, although clinical databases have been used to report on
      single centre or regional valve surgery outcomes, neither clinical nor
      administrative data have been used to examine rates of valve surgery use across
      large geographical regions. The objective of the present study was to use
      administrative data to evaluate use of valve surgery over time and across Canada.
      METHODS: All cases of aortic valve replacement (AVR), mitral valve replacement
      (MVR), mitral valve repair (MV repair), combined AVR and coronary artery bypass
      grafting (CABG), and combined MVR/MV repair and CABG between fiscal years 1994/95
      and 1999/2000 were identified using hospital discharge abstract data obtained
      from the Canadian Institute of Health Information. Age- and sex-adjusted rates of
      valve surgery were then calculated by province and by procedure type. RESULTS:
      Rates of valve surgery for all procedure types increased between fiscal years
      1994/95 and 1999/2000 with the exception of MVR, which remained relatively
      constant. Significant variation in rates of valve surgery was found between male
      and female residents. Similar variation was also demonstrated across provinces by
      year and by procedure type. CONCLUSION: There was a trend toward increased use of
      valve surgery over time for most procedures. Variation in rates of valve surgery
      exists across provinces. These results provide a starting point from which to
      track future trends in use and outcomes for these major procedures.

PMID- 15010738
TI  - The investigator's dilemma.

PMID- 15010737
TI  - Outcomes after aortic and mitral valve replacement surgery in Canada: 1994/95 to
      1999/2000.
AB  - BACKGROUND: Although outcomes after coronary artery bypass grafting (CABG) have
      been studied extensively across Canada, using both clinical and administrative
      databases, studies examining outcomes after valve surgery in Canada have been
      restricted to regional investigations using clinical data sources of limited
      scope. The objective of the present study was to report on observed and risk
      adjusted in-hospital mortality rates after aortic valve replacement (AVR) and
      mitral valve replacement (MVR) across Canada between 1994/95 and 1999/2000 using
      administrative data. METHODS: All cases of AVR and MVR (with and without
      concomitant CABG) performed between 1994/95 and 1999/2000 were identified using
      hospital discharge abstract data obtained from the Canadian Institute for Health
      Information. Rates of in-hospital mortality were risk-adjusted using logistic
      regression modelling techniques to account for variations in sociodemographic,
      comorbidity, and disease-specific indicators of average severity of illness
      across years and provinces. Risk-adjusted outcomes were unavailable for the
      province of Quebec. RESULTS: The overall in-hospital mortality rate, excluding
      Quebec, between 1994/95 and 1999/2000 after isolated AVR with or without CABG was
      3.7% and isolated MVR with or without CABG was 5.7%. Although risk-adjusted in
      hospital mortality rates by year were unchanged between 1994/95 and 1999/2000,
      significant interprovincial variation did exist, ranging from 2.6% to 6.8% for
      AVR with or without CABG and 2.5% to 13.0% for MVR with or without CABG.
      CONCLUSION: In-hospital mortality rates after valve surgery have remained stable
      over time. However, significant variation in outcomes was noted between
      provinces. The results of this study provide the first comprehensive account of
      valve surgery outcomes across Canada.

PMID- 15010739
TI  - Detection of myocardial injury after internal cardioversion for atrial
      fibrillation.
AB  - BACKGROUND: Cardiac troponin levels do not rise to marked levels after external
      cardioversion of atrial fibrillation. Subsequent test discharges during
      implantation of cardioverter defibrillators may cause an elevation of cardiac
      troponin levels, but are still controversial. OBJECTIVE: To determine whether the
      biomarkers of cardiac injury increase after internal cardioversion (IC) of atrial
      fibrillation. METHODS: Forty-four patients with chronic atrial fibrillation were
      studied (mean age 59 +/-7 years). Electrode catheters were inserted through the
      femoral vein. One of these was positioned in the lower right atrium. A second
      defibrillation electrode was placed in the coronary sinus and an additional
      catheter was positioned in the right ventricular apex in order to obtain
      satisfactory R wave synchronization and to provide postshock ventricular pacing.
      The shocks were delivered by external defibrillator. Starting with a test shock
      of 1 J intensity, the energy was increased in steps (to maximum 15 J) until
      cardioversion was achieved. At least 1 min was permitted to elapse between
      unsuccessful defibrillation attempts before the next shock was applied. Blood
      samples for serum levels of cardiac troponin T, cardiac troponin I, creatine
      kinase MB and myoglobin were drawn before and 2 h, 4 h, 8 h and 24 h after IC.
      Each level of biomarker was compared with baseline. RESULTS: In 40 of 44
      patients, IC was successful at a mean cardioversion threshold of 7.6+/-3.3 J.
      Although the serum levels of these biomarkers tended to rise, marked elevation
      was not detected in any of samples (P>0.05 for each). There was no correlation
      between the levels of biomarkers and the number and energy of shocks applied. No
      severe complications were observed. CONCLUSIONS: Following uncomplicated IC of
      atrial fibrillation, cardiac biomarkers do not rise to marked levels, which
      indicates that significant myocardial injury does not occur by shocks in the
      usual dosage.

PMID- 15010740
TI  - Two-dimensional echocardiography estimation of right ventricular ejection
      fraction by wall motion score index.
AB  - BACKGROUND: Radionuclide angiography (RNA) and echocardiography (biplane Simpson
      method) are the most accepted methods for right ventricular ejection fraction
      (RVEF) evaluation. The authors tried to determine a new method to measure RVEF
      based on wall motion score index (WMSI). OBJECTIVES: One hundred forty-one
      patients with RV dysfunction had transthoracic echocardiography (TTE) evaluation
      of the right ventricle. In a first group of 54 patients, a correlation between
      RVEF using the biplane Simpson method (four chamber and two chamber [4C+2C]) and
      RV-WMSI was established from a polar map using an eight-segment model to find a
      regression equation. With the second group of 51 subsequent patients, this
      equation (RVEF=73.07-20.7 x WMSI), comparing the RVEF-WMSI with the biplane
      Simpson RVEF (4C+2C), was validated. In a third group of 36 consecutive patients
      with abnormal RV contractility, the RVEF was calculated by RNA and this RVEF was
      correlated to the RV-WMSI. RESULTS: The first group of 54 patients had a
      correlation coefficient of 0.84 between WMSI and RVEF (biplane Simpson method).
      The results from the second group of 51 patients with RVEF derived from the
      estimated regression equation correlated well with the biplane Simpson RVEF
      (r=0.84). The correlation coefficient for these two groups taken together (105
      patients), that is, between WMSI and RVEF (biplane Simpson method), was 0.92. The
      third group of 36 patients with RNA-EF displayed a correlation coefficient of
      0.83 with RV-WMSI. CONCLUSION: This new semiquantitative method for estimating
      RVEF from RV-WMSI is easy to use in routine TTE and shows an excellent
      correlation with the biplane Simpson method and RNA.

PMID- 15010742
TI  - Systematic review of statistical methods used to analyze Seattle Angina
      Questionnaire scores.
AB  - BACKGROUND: The Seattle Angina Questionnaire (SAQ) is being used with increasing
      frequency in clinical research to address the health-related quality of life
      (HRQOL) outcomes of patients with coronary artery disease. The reliability and
      validity of the SAQ as a disease-specific HRQOL questionnaire has been
      established. The purpose of this paper was to systematically identify all studies
      analyzing SAQ scores, and to review the suitability of the statistical methods
      used. METHODS: The literature search included all years from the development of
      the SAQ (1994) to December 2001. Electronic databases were searched using
      'Seattle angina questionnaire' as a key word, text word or medical subject
      heading, as well as combinations of Seattle, angina and questionnaire. The
      Scientific Citation Index was searched to identify any manuscripts that cited the
      developmental articles of the SAQ. Relevant manuscripts were identified as
      studies that used the SAQ as a measurement tool for HRQOL outcome data. RESULTS:
      Of the 62 studies identified, 14 articles used the SAQ as an outcome measurement
      tool. The statistical validity of all but one of the 14 studies was doubtful
      because assumptions required for the use of parametric tests were not addressed
      and there was no mention of the distributions of the SAQ scores. Based on the
      designs of the studies, unsuitable analysis methods were used. CONCLUSIONS: Our
      results demonstrate that investigators may need to increase their attention to
      the distributional characteristics of their HRQOL data and the design of the
      study before applying statistical tests to appropriately analyze SAQ HRQOL data.

PMID- 15010741
TI  - Effectiveness of multidisciplinary patient counselling in reducing cardiovascular
      disease risk factors through nonpharmacological intervention: results from the
      Healthy Heart Program.
AB  - BACKGROUND: The value of lifestyle modification in reducing physiological
      cardiovascular disease (CVD) risk factors remains controversial because changes
      in patient behaviour following CVD prevention counseling have failed to correlate
      with or impact reductions in physiological variables. OBJECTIVES: To determine
      whether nonpharmacological CVD prevention counselling significantly reduces
      behavioural and physiological risk factors, and to examine correlations between
      changes in these variables. METHODS: At baseline, dyslipidemic individuals with
      or at risk of developing CVD completed CVD risk factor questionnaires. At
      baseline and three months, participants submitted dietary logs, self-classified
      their readiness for behaviour change for eight lifestyles, and had their blood
      lipid profiles, weight and height assessed. Following CVD risk factor screening,
      lower and higher risk participants were recommended for multidisciplinary group
      counselling (GC) or group plus individual counselling (GIC), respectively. A
      prospective time series design assessed behavioural and physiological risk factor
      changes. RESULTS: Participants progressed forward (P<0.01) through the stage of
      change continuum for all behaviours. GIC participants progressed to a higher
      average stage of behaviour change for achieving optimal body weight (P<0.01),
      drinking less alcohol (P<0.05) and controlling blood pressure (P<0.05).
      Significant reductions in body mass index (2.1% and 1.9%), total cholesterol
      (7.0% and 5.5%), low density lipoprotein cholesterol (6.2% and 5.4%), total
      cholesterol to high density lipoprotein cholesterol ratio (5.1% and 3.8%) and
      triglyceride levels (10.8% and 8.5%) were observed in GC and GIC participants,
      respectively. Furthermore, significant correlations were observed between
      concurrent changes in lifestyle behaviour and physiological risk factors.
      CONCLUSIONS: Multidisciplinary CVD prevention counseling positively influenced
      participant readiness for lifestyle behaviour change which translated into
      significant reductions in several physiological risk factors.

PMID- 15010743
TI  - Thromboembolic events occur despite sinus rhythm maintenance in patients treated
      for atrial fibrillation: The Canadian Trial of Atrial Fibrillation experience.
AB  - BACKGROUND: Anticoagulation reduces the risk of stroke in patients with atrial
      fibrillation. It is not clear whether patients who revert and are maintained in
      sinus rhythm should continue to receive warfarin. The recommendation is to
      anticoagulate these patients for a minimum of four weeks after cardioversion.
      Whether warfarin should be maintained for a longer period of time is unknown.
      METHODS AND RESULTS: To address this question, data from the Canadian Trial of
      Atrial Fibrillation were reviewed. Among the 403 patients, 81.9% had at least one
      risk factor for stroke, of whom only 60% were on warfarin. Nine thromboembolic
      events occurred in nine patients (2.2%): all had at least one risk factor for
      stroke. Six events occurred in patients who were either not anticoagulated (n=4)
      or for whom the international normalization ratio was subtherapeutic (n=2). Eight
      of the nine patients were in sinus rhythm at the last follow-up visit before and
      at the time of evaluation of the thromboembolic event. CONCLUSIONS:
      Anticoagulants are underused in atrial fibrillation patients at risk of stroke.
      Thromboembolic events are most often associated with suboptimal levels of
      anticoagulation and they occur despite the appearance of sinus rhythm
      maintenance.

PMID- 15010744
TI  - Prevalence and significance of increased intraventricular velocities in healthy
      elderly subjects.
AB  - BACKGROUND: Heart murmurs are common in the elderly and increased intracavitary
      velocities (IIV) within the left ventricle have been reported to be a cause of
      systolic murmur. OBJECTIVE: To assess the prevalence and functional significance
      of IIV in healthy elderly subjects METHODS: Ambulatory healthy elderly subjects
      were recruited from community centres and seniors' apartments. They were screened
      using a structured questionnaire and then underwent a comprehensive history and
      physical examination. Electrocardiogram, echocardiogram and 6-min walk test were
      performed on the same day. RESULTS: Four of the 88 subjects were excluded because
      of significant valvular dysfunction. Ten of the remaining 84 subjects had IIV and
      their demographics were similar to those of the 74 subjects without IIV.
      Echocardiographic parameters including left ventricular size and mass were
      similar between the two groups. Left ventricular mass index was lower in subjects
      with IIV (P=0.02). Both groups had similar 6-min walk results. CONCLUSIONS: In
      the healthy elderly who do not have valvular disease or left ventricular
      hypertrophy, IIV is uncommon and does not appear to have functional significance.

PMID- 15010745
TI  - Measuring continuity of care for cardiac patients: development of a patient self
      report questionnaire.
AB  - BACKGROUND: Continuity of care can be a challenge for cardiac patients, many of
      whom require chronic and complex management from a variety of health care
      personnel in multiple settings. For health services research, measures are needed
      that encompass the multifaceted nature of continuity of care for cardiac
      patients. OBJECTIVE: To assess continuity of care from the patient's perspective,
      a comprehensive self-report instrument of continuity of care for patients with
      congestive heart failure and atrial fibrillation was developed and validated.
      METHODS: Based on published work, patient interviews and provider input, the
      Heart Continuity of Care Questionnaire (HCCQ) was developed to assess various
      aspects of care in the transition from hospital to home. The HCCQ covered a
      variety of content areas relevant to cardiac care. The HCCQ and either the
      Continuity of Care Index (CCI) or the Minnesota Living with Heart Failure
      Questionnaire (MLHFQ) were completed by 83 patients who had been discharged for
      at least six months. RESULTS: Most items had good response rates. The subscales,
      defined a priori, had good reliability (subscales alpha ranged from 0.80 to
      0.93). The HCCQ and its subscales had strong correlations with the CCI but not
      the MLHFQ. The HCCQ subscales demonstrated better known group validity than the
      CCI. CONCLUSIONS: In this preliminary study, the HCCQ appears to be a
      comprehensive, reliable and valid measure of continuity of care from the patient
      perspective. Further studies of the validity, generalizability and use are
      needed.

PMID- 15010746
TI  - Acute myocardial infarction in Alberta: temporal changes in outcomes, 1994 to
      1999.
AB  - BACKGROUND: The current survival trends in patients with acute myocardial
      infarction (AMI) are not known. A population-based study using administrative
      data to examine the short and long term survival of patients after AMI in Alberta
      between 1994 and 1999 was conducted. METHODS: AMI patients were identified from
      hospital discharge data. Temporal changes in the adjusted (age, sex, AMI
      anatomical location and comorbidities) fatality rate were analyzed in 19,928 AMI
      patients. RESULTS: The age- and sex-adjusted incidence of hospitalization for AMI
      in Alberta significantly declined from 169.6 per 100,000 population in 1994 to
      160.8 per 100,000 in 1999 (P=0.03). The risk-adjusted in-hospital case fatality
      rate from all causes was 11.4% (95% CI 10.6% to 12.3%) in 1994 versus 9.2% (8.4%
      to 10.1%) in 1999; the 30-day case fatality rate was 12.6% (11.7% to 13.6%) in
      1994 versus 10.1% (9.1% to 11.0%) in 1999; and the one-year case fatality rate
      was 19.0% (17.8% to 20.1%) in 1994 versus 14.9% (13.8% to 16.0%) in 1999. The
      percentage of hospitalized AMI patients who underwent coronary angiography within
      one year after admission rose from 48.2% in 1994 to 52.4% in 1999; percutaneous
      transluminal coronary angioplasty increased from 25.5% to 35.0% and coronary
      artery bypass surgery increased from 9.7% to 12.6%. Prescriptions for
      pharmacological drugs at discharge increased from 1994 to 1999 among patients
      aged 65 and older: from 29.5% in 1994 to 41.0% in 1999 for beta-blockers, from
      5.2% to 18.7% for lipid lowering agents and from 14.0% to 20.5% for angiotensin
      converting enzyme inhibitors. INTERPRETATION: There was a modest improvement in
      patient survival after AMI between 1994 and 1999. The improvements may be
      associated with increasing use of revascularization and pharmacological therapy
      provided in the management of AMI.

PMID- 15010747
TI  - Safety of glycoprotein IIb/IIIa inhibitors in urgent or emergency coronary artery
      bypass graft surgery.
AB  - Approximately 2% to 4% of patients undergo urgent or emergency coronary artery
      bypass grafting (CABG) for complications of percutaneous coronary intervention
      (PCI) after treatment with glycoprotein (GP) IIb/IIIa inhibitors. The
      pharmacokinetic and pharmacodynamic properties of GP IIb/IIIa inhibitors play a
      large role in determining the safety of their use in the setting of urgent or
      emergency CABG procedures. Emergency or urgent CABG after treatment with the GP
      IIb/IIIa inhibitor, abciximab, may be associated with increased risk of
      hemorrhage and the requirement of platelet transfusions if surgery is performed
      within 12 h of abciximab discontinuation. Eptifibatide is associated with a
      similar risk compared with placebo, even when surgery is performed within 2 h of
      eptifibatide cessation. Limited data for tirofiban show that bleeding is not
      increased when compared with acetylsalicylic acid or heparin. Eptifibatide and
      tirofiban appear to have favourable safety profiles compared with abciximab in
      the setting of emergency or urgent CABG after failed PCI.

PMID- 15010748
TI  - Tricuspid valve disruption and ventricular septal defect secondary to blunt chest
      trauma.
AB  - An unusual case of blunt thoracic injury is presented, highlighting the
      importance of echocardiography in the assessment of patients with suspected
      cardiac trauma.

PMID- 15010749
TI  - Migration of an inferior vena cava filter to the right ventricle and literature
      review.
AB  - Migration of an inferior vena cava (IVC) filter to the heart after placement is
      an extremely rare complication. The case of a 42-year-old man who presented with
      ventricular arrhythmia and tricuspid valve regurgitation, and underwent open
      heart surgery to extract an IVC filter from the right ventricle 12 days after
      infrarenal IVC filter placement, is reported.

PMID- 15010750
TI  - Ethics for editors.

PMID- 15010751
TI  - Chemoselective ligation in glycochemistry.
AB  - This feature article describes chemoselective techniques for the assembly of
      neoglycopeptides and oligosaccharide mimics. Chemoselective ligation, allowing
      the use of aqueous environments and non-protected substrates, provides rapid
      access to complex glycoconjugates. The role of these molecules in recognition,
      signal transduction pathways and other events of fundamental biomedical
      significance is an object of study in the emerging field of chemical glycomics.

PMID- 15010752
TI  - Rechargeable Fe(III/VI) super-iron cathodes.
AB  - This study addresses a fundamental challenge posed by hexavalent iron
      electrochemical irreversibility, which had slowed practical development of
      reversible Fe(VI) cathodes; nanolayers circumvent fundamental passivation
      challenges, and are electrodeposited from solution phase FeO(4)(2-), forming 601
      mAh g(-1) Li, and 485 mAh g(-1) Na, Fe(III/VI) alkaline cathodes, the latter
      exhibiting 100-200 storage cycles at 80% depth of discharge, providing pathways
      towards metal hydride batteries with twice the cathode capacity.

PMID- 15010753
TI  - Sweet success: Ionic liquids derived from non-nutritive sweeteners.
AB  - The anions of the sweeteners saccharin and acesulfame form ionic liquids when
      paired with a variety of organic cations.

PMID- 15010754
TI  - Stereochemical determination of dictyostatin, a novel microtubule-stabilising
      macrolide from the marine sponge Corallistidae sp.
AB  - The relative stereochemistry of the 22-membered marine macrolide dictyostatin, a
      Taxol-like antimitotic agent, was determined based on a combination of extensive
      high field NMR studies, including J-based configuration analysis, and molecular
      modelling.

PMID- 15010755
TI  - Diastereospecific synthesis of phosphinidene-capped cyclodextrins leading to
      "introverted" ligands.
AB  - alpha-Cyclodextrins (alpha-CDs) containing "PPh" units which cap the primary face
      of the CD were obtained in high yield by reaction of Li(2)PPh with A,B- or A,C
      dimesylated and A,B,D,E-tetramesylated precursors; the resulting phosphines are
      diastereomerically pure and constitute valuable precursors for the synthesis of
      metallo-cavitands.

PMID- 15010756
TI  - Reversible formation of DNA G-quadruplex hairpin dimers from stilbenediether
      conjugates.
AB  - Rapid and reversible G-quadruplex hairpin dimer formation is observed for
      bis(oligonucleotide) conjugates possessing stilbenediether (Sd) linkers
      connecting two short poly(G) sequences.

PMID- 15010757
TI  - Self-aggregation of reverse bis peptide conjugate derived from the unstructured
      region of the prion protein.
AB  - A novel bis scaffold containing a pentapeptide PHGGG, derived from the prion
      octarepeat, forms fibrils of nanometric dimensions, thus indicating that certain
      segments in the unstructured region of the prion protein may facilitate an
      initial fibrillation event.

PMID- 15010758
TI  - Supported nickel bromide catalyst for atom transfer radical polymerization (ATRP)
      of methyl methacrylate.
AB  - A new supported catalytic system, i.e. nickel bromide catalyst ligated by
      triphenylphosphine (TPP) ligands immobilized onto crosslinked polystyrene resins
      (PS-TPP) is reported. Per se, this catalyst does not allow any control over the
      polymerization of methyl methacrylate (MMA) initiated by ethyl 2-bromoisobutyrate
      but, in the presence of a given amount of purposely added free TPP, it promotes
      controlled ATRP of MMA. Indeed colorless PMMA chains of low polydispersity
      indices are readily recovered, the molecular weight of which linearly increases
      with monomer conversion and agrees with the expected values. Recycling of the
      supported catalyst is evidenced and does not prevent the polymerization from
      being controlled.

PMID- 15010759
TI  - A design strategy for four-connected coordination frameworks.
AB  - Reactions of tetrahedral Cu(I) and Ag(I) cations with 2,3,4,5-tetra(4
      pyridyl)thiophene allows targeted construction of coordination frameworks with
      zeolite-like, 4(2).8(4), topologies.

PMID- 15010760
TI  - Gauche and staggered forms of diethylamine in solvates of 1,5-dichloro-cis-9,10
      diethynyl-9,10-dihydroanthracene-9,10-diol. A case of conformational
      pseudopolymorphism?
AB  - Diethylamine has been trapped in its less stable gauche conformation in a solvate
      of the title diol; the staggered conformation, which is ca. 4 kJ mol(-1) more
      stable, is found in another solvate of the same host.

PMID- 15010762
TI  - Novel hybrid hetero-sandwich architectures via stoichiometric control of host
      guest self-organization.
AB  - Thiocyanate cadmium and methylviologen hybrid host-guest compounds give two novel
      multiple sandwich architectures with regular or irregular grids of the anionic
      layer in the structures as effected by the molar ratios of starting ingredients,
      and show evidence of charge-transfer to the organic dications.

PMID- 15010761
TI  - A helical array of pendant fullerenes on a helical poly(phenylacetylene) induced
      by non-covalent chiral interactions.
AB  - Novel [60]fullerene-based poly(phenylacetylene)s prepared by the copolymerization
      of achiral phenylacetylenes bearing a C(60) or crown ether pendant form a one
      handed helix upon complexation with L- and D-alanine, yielding a helical array of
      the pendant fullerenes with a predominant screw-sense along the polymer backbone.

PMID- 15010763
TI  - First row wheels, [((t)Bu(3)SiS)MX](12)(M = Co, X = Cl; M = Ni, X = Br), are
      common amongst both simpler and more complex aggregates.
AB  - [((t)Bu(3)SiS)MX[(12) are wheels for first row transition metals (M = Co, X = Cl;
      M = Ni, X = Br), but for nickel, simpler [e.g. [((t)Bu(3)SiS)Ni](2)(mu
      SSi(t)Bu(3))(2)[ and more complicated [e.g. [(mu-SSi(t)Bu(3))Ni](5)(mu(5)-S)]
      structures are by-products.

PMID- 15010764
TI  - Isotopic effects may induce cooperativity in valence tautomeric transition.
AB  - The replacing of CH(2)Cl(2) solvent molecules with their deuterated analogues in
      a Co complex undergoing valence-tautomeric interconversion drastically modifies
      its magnetic properties giving rise to a thermal hysteresis.

PMID- 15010765
TI  - Anion control of ligand self-recognition in a triple helical array.
AB  - Self-assembly of the ligand L(1) with Co(2+) into a dinuclear triple helicate
      [Co(2)(L(1))(3)](4+) produces an anion binding pocket which encapsulates
      perchlorate anions. Furthermore we demonstrate how this ability to bind anions
      can control ligand self-recognition properties.

PMID- 15010766
TI  - Novel iron-decorated carbon nanorods from fullerene soot.
AB  - A novel form of nano-sized carbon rods decorated with monodispersed iron
      particles in a size range of 30-50 nm on their surface is successfully
      synthesized by arcing discharge of composite electrodes made from iron particles
      and fullerene soot; this will be of potential as catalyst for hydrogenation
      reactions.

PMID- 15010767
TI  - How is the CH/pi interaction important for molecular recognition?
AB  - Ab initio calculations illustrate that CH/pi attractions significantly contribute
      to host-guest complexation, but are not always a direct factor in molecular
      recognition.

PMID- 15010768
TI  - Palladium(II)- and platinum(II)-catalyzed addition of stabilized carbon
      nucleophiles to ethylene and propylene.
AB  - PdCl(2)(CH(3)CN)(2) and [PtCl(2)(H(2)C[double bond]CH(2))](2) catalyze the
      addition of beta-dicarbonyl compounds to ethylene and propylene.

PMID- 15010769
TI  - Novel oxygen storage mechanism based on redox of sulfur in lanthanum
      oxysulfate/oxysulfide.
AB  - A sulfur redox cycle between La(2)O(2)SO(4)(S(6+)) and La(2)O(2)S(S(2-)) phases
      was found for the first time to achieve the oxygen storage of 2 mol O(2) mol(-1),
      which is eight times larger than that of the conventional CeO(2)-ZrO(2) system.

PMID- 15010770
TI  - Catalytic reduction of nitro-group terminated monolayers by Ag nanoparticles; a
      novel strategy for site-selective patterning of organic monolayers.
AB  - We have demonstrated that site-selective patterning of organic monolayers can be
      accomplished simply by inducing Ag nanoparticle-mediated catalytic reduction to
      occur on the desired regions of those monolayers.

PMID- 15010771
TI  - Platinum(II)-bis(9-methyladenine) complexes; N1-->N6 migration of Pt(II)vs
      deamination of coordinated methyladenine.
AB  - Stepwise migration of coordinated Pt(II) from the endocyclic N1 site to the
      exocyclic amino group occurs in the bis(9-methyladenine-N1) complex of cis
      Pt(II)(NH(3))(2) in basic solution, whereafter deamination of the 9-methyladenine
      still coordinated at N-1 competes with a second migration step.

PMID- 15010772
TI  - Using Caenorhabditis elegans to probe toxicity of 1-alkyl-3-methylimidazolium
      chloride based ionic liquids.
AB  - Ionic liquids are gaining attention as new solvents within the green chemistry
      community; however this attention has quickly outstripped current environmental
      and toxicological data available. In the present communication, we establish the
      use of Caenorhabditis elegans as a model organism for inexpensively and quickly
      exploring toxicological effects of 1-alkyl-3-methylimidazolium chloride ionic
      liquids.

PMID- 15010773
TI  - Tuning the fluorescence of 1-imino nitroxide pyrene with two chemical inputs:
      mimicking the performance of an "AND" gate.
AB  - The fluorescence of 1-imino nitroxide pyrene can be significantly enhanced only
      under the combined actions of Cys and CF(3)COOH; such spectral change upon the
      actions of two chemical inputs mimics the performance of an "AND" gate.

PMID- 15010774
TI  - Highly diastereoselective synthesis of anti-gamma-N-benzylamino-beta
      hydroxyphosphonates.
AB  - The reduction of gamma-N-benzylamino-beta-ketophosphonates derived from readily
      available amino acids can be carried out stereoselectively with Zn(BH(4))(2) at 
      78 degrees C to produce the anti-gamma-amino-beta-hydroxyphosphonates.

PMID- 15010775
TI  - Superoxide-stable ionic liquids: new and efficient media for electrosynthesis of
      functional siloxanes.
AB  - The electrogeneration of diorganylsilanones from difunctional precursors
      Y(CH(2))(3)(Me)SiX(2) and Ph(2)SiX(2)(Y = NH(2), CF(3), CN; X = Cl, OEt, OMe),
      performed in the presence of hexamethyldisiloxane or hexamethylcyclotrisiloxane
      (D(3)) in the ionic liquids [C(5)H(5)NC(8)F(18)].NTf(2),
      [C(5)H(5)NC(18)H(38)].NTf(2) and Me(3)BuN.NTf(2), which reveal high solubility of
      oxygen and are inert toward superoxide anion, allows functionalized siloxanes to
      be produced selectively in good isolated yields.

PMID- 15010776
TI  - Extended X-ray absorption fine structure (EXAFS) characterisation of the
      hydroformylation of oct-1-ene by dilute Rh-PEt3 catalysts in supercritical carbon
      dioxide.
AB  - Dilute EXAFS characterisation has been used to elucidate species involved during
      the course of the 3 mM Rh-catalysed hydroformylation of oct-1-ene in scCO(2);
      significant metal clustering occurs with a Rh:P ratio of 1:1 but at a 1:3 ratio,
      metal clustering is not detected, with the presence of monomer species only.

PMID- 15010777
TI  - Isolation, dynamic NMR study and X-ray characterisation of a bis sulfonium
      zirconocene-ate dimer.
AB  - The novel dimer [Cp(2)Zr[upper bond start]([minus sign in circle])S([plus sign in
      circle])CH(Ph)CH[double bond]C[upper bond end]PPh(2)](2), the first example of a
      structurally characterised sulfur-bridged binuclear zirconathiolane complex, was
      prepared, characterised by NMR spectroscopy and X-ray crystallography, and some
      aspects of its solution behaviour were studied.

PMID- 15010778
TI  - Modifying zeolite particle morphology and size using water/oil/surfactant
      mixtures as confined domains for zeolite growth.
AB  - Here we report the synthesis of silicalite-1 particles using microemulsions
      wherein the particle size and morphology can be varied.

PMID- 15010779
TI  - Mesoporous silica with Ia3d cubic structure and good thermal stability.
AB  - Ia3d cubic mesoporous silica with unusual thermal stability has been synthesized
      using cetyltrimethylammonium bromide (CTAB) and sugar surfactant dodecyl-beta-D
      maltoside (DM) as co-templates.

PMID- 15010780
TI  - A novel azulene synthesis from the Ramirez ylide involving two different modes of
      its reaction with activated alkynes.
AB  - The Ramirez ylide undergoes electrophilic substitution with
      acetylenedicarboxylates to form Z and E adducts. The latter can react by
      cycloaddition with another equivalent of the alkyne to provide a new route to
      novel tetra-substituted azulenes, which show interesting bond localisation and
      crystal packing effects.

PMID- 15010781
TI  - Unusual chromic and doping behavior of ether substituted polythiophenes.
AB  - Poly[3-(oligoethylene oxide)-4-methylthiophene] is doped by HCl in aqueous
      solution in the absence of oxygen and undergoes dramatic solvatochromism in water
      ethanol mixtures.

PMID- 15010782
TI  - Reduction of nitroaromatics to arylnitrenium ions by vinyl halide cations.
AB  - The title reduction of nitroaromatics ArNO(2) by vinyl halide radical cations
      CH(2)[double bond]CH-X(+*)(X = Cl or Br) to form arylnitrenium ions ArNH(+)
      involves a change in oxidation number of nitrogen from +3 to -1. This novel
      reaction provides a new route for the generation of arylnitrenium ions, a highly
      selective method for the detection of explosives in mixtures, and offers clues to
      the carcinogenic activity of nitroaromatics in vivo.

PMID- 15010783
TI  - A sequential highly stereoselective hydroboration and Suzuki-Miyaura cross
      coupling reaction of fluoroalkylated internal acetylenes: a practical one-pot
      synthesis of fluoroalkylated trisubstituted alkenes.
AB  - The one-pot synthesis of trisubstituted alkenes starting from fluoroalkylated
      internal alkynes was investigated. Hydroboration of the alkynes proceeded in a
      highly regio- and stereoselective manner to give the corresponding vinylboranes
      in excellent yields. Without isolation, treatment of the vinylboranes with
      various aryl halides under the Suzuki-Miyaura cross-coupling conditions gave the
      fluoroalkylated trisubstituted alkenes in high yields with complete retention of
      the olefinic geometry.

PMID- 15010784
TI  - Facile protocol for the highly regioselective and stereodivergent synthesis of
      substituted bishomoallylic alcohols from esters.
AB  - Regio- and diastereoselective preparation of bishomoallylic alcohols was realized
      by a facile four-step protocol including alpha,alpha'-selective zinc-mediated
      bispropargylation of unactivated esters and stereoselective reduction of the
      resulting bishomopropargylic alcohols.

PMID- 15010785
TI  - Phosphabarrelene-rhodium complexes as highly active catalysts for isomerization
      free hydroformylation of internal alkenes.
AB  - A new class of phosphabarrelene-rhodium catalysts is described which allows for
      the first time hydroformylation of internal alkenes with very high activity and
      which proceeds essentially free of alkene isomerization.

PMID- 15010786
TI  - Metal organic chemical vapour deposition (MOCVD) of bone mineral like carbonated
      hydroxyapatite coatings.
AB  - For the first time, the MOCVD technique has been used to deposit carbonated
      hydroxyapatite onto Ti6AL4V substrates using volatile monomeric (liquid)
      complexes [Ca(beta-diketonate)(2)(L)] and P(OEt)(3).

PMID- 15010787
TI  - The synthesis of a di-N-heterocyclic carbene-amido complex of palladium(II).
AB  - A diimidazolium salt incorporating a secondary amine moiety has been used to
      prepare a palladium(II) di-N-heterocyclic carbene amino complex that can be
      deprotonated with NaH to give the first example of a transition metal NHC-amide.

PMID- 15010788
TI  - Living cationic polymerisation of styrene in an ionic liquid.
AB  - For the first time, living cationic polymerisation of styrene has been carried
      out in room temperature ionic liquids under mild reaction conditions and using
      mild acid catalysts (e.g. organoborate acids) to obtain polymers of narrow
      polydispersity.

PMID- 15010789
TI  - Two contrasting ethynyl hydroboration pathways in the formation of a novel tris
      hydroboration product from reaction of dimesitylborane with 2,5
      diethynylpyridine.
AB  - Reaction of 2,5-diethynylpyridine with dimesitylborane, [(Mes)(2)BH](2)(Mes =
      mesityl = 2,4,6-Me(3)C(6)H(2)), gave the unexpected tris-hydroboration product 1
      [(Mes)(2)B]-2-[Z-1-[(Mes)(2)B]ethylidene]-5-[E-[(Mes)(2)B]vinyl]-1,2
      dihydropyridine, which has been structurally characterised by single-crystal X
      ray diffraction.

PMID- 15010790
TI  - Synthesis and structural characterization of an azatitanacyclobutene: the key
      intermediate in the catalytic anti-Markovnikov addition of primary amines to
      [small alpha]-alkynes.
AB  - Reaction of the imidotitanium complexes [Ti(N(t)Bu)(N(2)N(py))(py)](1) and [Ti(N
      2,6-C(6)H(3)(i)Pr(2))(N(2)N(py))(py)](2) with phenyl acetylene and tolyl
      acetylene in toluene gave the corresponding [2+2] cycloaddition products
      [Ti(N(2)N(py))[kappa(2)-N((t)Bu)CH[double bond]CR]](R = Ph:3, Tol:4) and
      [Ti(N(2)N(py))[kappa(2)-N(2,6-C(6)H(3)(i)Pr(2))CH[double bond]CR]](R = Ph:5, Tol:
      6). Complex 6 is the first example of a key intermediate in the anti-Markovnikov
      addition of a primary amine to a terminal acetylene which has been structurally
      characterized by X-ray diffraction.

PMID- 15010791
TI  - Exploration of the pentacyano-cyclo-pentadienide ion, C(5)(CN)(5)(-), as a weakly
      coordinating anion and potential superacid conjugate base. Silylation and
      protonation.
AB  - The reportedly unprotonatable pentacyano-cyclo-pentadienide ion, C(5)(CN)(5)(-),
      can be protonated and silylated at the cyano N atom using electrophilic reagents
      derived from weakly coordinating carborane anions.

PMID- 15010792
TI  - Mixed halo/hydroxy-carborane anions: thermally stable platforms for hydronium ion
      isolation.
AB  - Hydroxylation of the robust, weakly coordinating hexahalo-carborane anion system,
      CB(11)H(6)Br(6)(-1), produces a new class of anion with mixed halo/hydroxyl
      substituents, HCB(11)(OH)(5)Br(6)(-1) which can be used to isolate a number of
      hydronium cation salts including an 'ice tautomer' composed of hydronium cation,
      anion hydroxyl groups and coordinated water molecules.

PMID- 15010793
TI  - Recycling of the homogeneous Co-Jacobsen catalyst through solvent-resistant
      nanofiltration (SRNF).
AB  - The Co-Jacobsen complex, catalysing a hydrolytic kinetic resolution, was recycled
      in a semi-continuous operation using a laboratory prepared polymeric SRNF
      membrane.

PMID- 15010794
TI  - A template-free aqueous route to ZnO nanorod arrays with high optical property.
AB  - A mild template-free aqueous route was successfully established to synthesize
      well-aligned ZnO nanorod arrays, which were proved to exhibit high optical
      property by PL spectra.

PMID- 15010795
TI  - Highly diastereoselective formation of C2-symmetric bis-thioglycoside Pd(II)
      complexes: the role of the exo anomeric effect.
AB  - Treatment of several C(2) symmetric bis-thioglycosides with Pd(CH(3)CN)(2)Cl(2)
      always leads to a single diastereomeric Pd(II) complex as a consequence of the
      exo-anomeric effect.

PMID- 15010796
TI  - Helical supramolecular host with aquapores anchoring alternate molecules of
      helical water chains.
AB  - Unprecedented 1D helical chains of hydrogen bonded water molecules, showing both
      handedness and anchored onto a helical supramolecular host formed from the self
      assembly of a dicopper(II) complex (1) containing pentadentate Schiff base (L)
      and p-hydroxycinnamate in 1.2H(2)O, propagate along the crystallographic 2(1)
      screw axis and the compound shows two endotherms due to loss of water molecules
      at 61.5 and 88.5 degrees C in the differential scanning calorimetry giving an
      overall change of enthalpy value of approximately 36 kJ mol(-1) per water
      molecule.

PMID- 15010797
TI  - Protonic modulation of redox properties in ionisable [2 x 2] grid-like
      metalloarrays.
AB  - The oxidation state of the cobalt centres can be controlled by modification of
      the protonation state in [2 x 2] grid-like arrays based on ionisable
      bis(hydrazone) ligands, allowing conversion of the paramagnetic Co(II)(4) into
      the diamagnetic Co(III)(4) grid.

PMID- 15010798
TI  - A novel mixed-valence complex containing Co(II)(2)Co(III)(2) molecular squares
      with 4,5-imidazoledicarboxylate bridges.
AB  - A heterometallic complex, Na(2)[Co(II)(2)Co(III)(2)(IDC(3-))(4)(bipy)(4)].12H(2)O
      (bipy = 2,2'-bipyridine), in which mixed-valence tetranuclear squares with
      imidazoledicarboxylate (IDC(3-)) linkers are tethered into a unique chain through
      disodium units, is hydrothermally synthesized and structurally and magnetically
      characterized.

PMID- 15010799
TI  - Enantiopure oxazolidinones as chiral acids in the asymmetric protonation of N-Boc
      pyrrole derived enolates.
AB  - The first use of geminally disubstituted oxazolidinones as chiral protonating
      agents is described: these new acids are able to directly protonate an enolate
      generated by the ammonia free partial reduction of an electron deficient pyrrole
      and give up to 68% ee in the pyrroline product.

PMID- 15010800
TI  - A mild and efficient protocol for the conversion of carboxylic acids to olefins
      by a catalytic decarbonylative elimination reaction.
AB  - A new method for the conversion of aliphatic carboxylic acids to olefins under
      unprecedented mild conditions is disclosed, wherein the carboxylic acids are
      converted in situ with pivalic anhydride to the mixed anhydrides, which
      regioselectively add to a PdCl(2)-DPE-Phos catalyst. At a temperature of only 110
      degrees C, smooth decarbonylation and beta-hydride elimination occur, and the
      corresponding olefins along with CO, CO(2) and pivalic acid are liberated.

PMID- 15010802
TI  - Nafion-polyfurfuryl alcohol nanocomposite membranes with low methanol permeation.
AB  - Nafion-polyfurfuryl alcohol nanocomposite membranes with low methanol
      permeability and high proton conductivity were synthesized by in-situ
      polymerisation of furfuryl alcohol inside commercial Nafion membranes.

PMID- 15010801
TI  - Multicomponent redox gradients on photoactive electrode surfaces.
AB  - Redox gradients have been used to tailor the arrangement of photoactive ITO
      electrodes at the molecular level.

PMID- 15010803
TI  - Kinetic resolution of chiral aminoalkenes via asymmetric
      hydroamination/cyclisation using binaphtholate yttrium complexes.
AB  - Chiral binaphtholate yttrium aryl complexes are highly active and
      enantioselective catalysts for the asymmetric hydroamination of aminoalkenes, as
      well as the kinetic resolution of alpha-substituted 1-aminopent-4-enes to give
      trans-2,5-disubstituted pyrrolidines with good enantiomeric excess and high
      k(rel).

PMID- 15010804
TI  - Selective voltammetric detection of dopamine in the presence of ascorbate.
AB  - The selective detection of dopamine in the presence of ascorbate is demonstrated
      based on the voltammetry of dopamine transfer across the interface between two
      immiscible electrolyte solutions (ITIES) facilitated by an organic-phase
      ionophore; ascorbate transfer does not occur, leading to highly selective
      detection of dopamine in the presence of excess ascorbate.

PMID- 15010805
TI  - An efficient synthesis of organic carbonates: atom economic protocol with a new
      catalytic system.
AB  - Selective and solvent free synthesis of unsymmetrical organic carbonates
      catalysed by a reusable MgLa mixed oxide is achieved for the first time via
      direct condensation of an alcohol and diethyl carbonate in economic route with
      excellent yields.

PMID- 15010806
TI  - An ordered array of cadmium clusters assembled in zeolite A.
AB  - We report the assembly of a cubic array of cationic cadmium clusters encapsulated
      in zeolite A, and its characterization through Rietveld analysis of powder
      synchrotron X-ray diffraction data and high resolution transmission electron
      microscopy.

PMID- 15010807
TI  - A pentanuclear yttrium hydroxo cluster as an oxidation catalyst. Catalytic
      oxidation of aldehydes in the presence of air.
AB  - The air- and moisture-stable pentanuclear yttrium cluster H(5)[Y(5)(mu(4)
      O)(mu(3)-O)(4)(mu-eta](2)-Ph(2)acac)(4)(eta](2)-Ph(2)acac)(6)](Ph(2)acac =
      dibenzoylmethanide) has been used as a homogeneous catalyst for the oxidation of
      aldehydes to the corresponding carboxylic acids in the presence of air.

PMID- 15010809
TI  - In situ conversion of a Ru metathesis catalyst to an isomerization catalyst.
AB  - Addition of alcohols and substoichiometric amounts of a base to a metathesis
      reaction induces conversion of the metathesis-active carbene catalyst to an
      isomerization-active hydride species.

PMID- 15010808
TI  - A novel nonanuclear CuII carboxylate-bridged cluster aggregate with an S= 7/2
      ground spin state.
AB  - The Cu(II) aggregate in [Cu(9)(cpida)(6)(MeOH)(6)].6(MeOH)[H(3)cpida = 2
      (carboxyphenyl)iminodiacetic acid] is made up of two weakly ferromagnetically
      coupled carboxylate-bridged Cu(4) units that are antiferromagnetically linked
      through a central Cu(II) to give a Cu(9) core with an S= 7/2 spin ground state.

PMID- 15010810
TI  - Identification of catalyst surface species during asymmetric platinum-catalysed
      hydrogenation in a "supercritical" solvent.
AB  - In situ attenuated total reflection infrared spectroscopy studies during the
      enantioselective hydrogenation of ethyl pyruvate in "supercritical" ethane over a
      chirally modified Pt/Al(2)O(3) catalyst show the preferential adsorption of ethyl
      pyruvate as cis-conformer and indicate a hydrogen bond interaction of this
      species with the co-adsorbed modifier cinchonidine.

PMID- 15010811
TI  - High benzene selectivity of uniform sub-nanometre pores of self-ordered
      mesoporous silicate.
AB  - The high benzene gas selectivity of mesoporous silicate (SBA-15) was observed in
      the sub-nanometre micropore condensation region. The benzene/toluene ratios of
      the adsorbed amount were >100 and >6 in ideal and pseudo-atmospheric
      environments, respectively.

PMID- 15010812
TI  - Evolutionary recombination hotspot around GSDML-GSDM locus is closely linked to
      the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon.
AB  - PPP1R1B-STARD3-TCAP-PNMT-PERLD1-ERBB2-MGC14832-GRB7 locus at human chromosome
      17q12 is frequently amplified in human gastric cancer and breast cancer. Here, we
      compared human GSDML-GSDM locus with rodent genomes by using bioinformatics.
      Rodent ortholog of human GSDML was not identified. Rat Gsdm gene was identified
      within rat genome clone CH230-28N16 (AC119462.4), and was mapped to rat
      chromosome 10q31. Rat Gsdm gene, consisting of 12 exons, encoded a 446-amino-acid
      protein, which showed 86.3% and 32.3% total-amino-acid identities with human GSDM
      and GSDML, respectively. Mouse Gsdm-like 1 (Gsdml1) and Gsdml2 genes were
      identified within mouse genome clone RP23-438D7 (AL591125.20). Gsdml1 and Gsdml2
      genes were found to encode 456- and 443-amino-acid proteins, respectively. Mouse
      2200001G21Rik cDNA (AK008613.1) was a partial cDNA derived from mouse Gsdml2
      gene. Mouse Gsdml1 and Gsdml2 were also more homologous to human GSDM than to
      human GSDML. Mouse Gsdml1, Gsdml2 and Gsdm genes, existing in the tandem
      homologous gene cluster, was mapped to mouse chromosome 11D. Mouse Gsdml1-Gsdml2
      Gsdm gene cluster was predicted to be generated due to triplication of mouse Gsdm
      gene, while GSDML gene was predicted to be generated due to duplication of GSDM
      gene. Evolutionary recombination hotspot around the GSDML-GSDM locus was closely
      linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7
      amplicon. The evolutionary recombination hotspot and oncogenomic recombination
      hotspot might be clustered around the fragile sites within the human genome.

PMID- 15010813
TI  - Single-chain antibodies: A therapeutic modality for cancer gene therapy (review).
AB  - Gene therapy has rapidly evolved into a field that is treating not only inborn
      errors of metabolism, but other diseases associated with poor outcomes such as
      malignancy, where transient gene expression can be therapeutic. Cancer gene
      therapy is a novel form of treatment that exploits differences at the molecular
      level between normal and malignant cells. Current gene therapy approaches that
      are being evaluated include the use of replication competent viruses, mutation
      compensation strategies, improved targeting with tumor specific promoters, and
      the utilization of enhanced infectivity viruses. An additional aspect of gene
      therapy that has gained increased interest in the last several years is the
      utilization of single-chain antibodies (scFv). Specifically, scFv have been
      utilized to target molecular processes associated with carcinogenesis, as well as
      to improve gene transfer efficiency. We will limit our discussion to the role of
      scFv in targeting molecular processes associated with carcinogenesis.

PMID- 15010814
TI  - Microarray profiling of the effects of histone deacetylase inhibitors on gene
      expression in cancer cell lines.
AB  - Chromatin is a highly dynamic environment playing critical roles in the
      regulation of gene expression. Modifications to the proteins which make up the
      nucleosome core have been shown to have profound regulatory effects on gene
      expression. Of these, the best known modification is acetylation of the histone
      tails. Two enzymes regulate these processes, histone deacetylases and histone
      acetyltransferases. Both have been shown to have dysregulated functions in
      certain tumors. Several classes of histone deacetylase inhibitors have been
      isolated and are currently undergoing evaluation as potential therapeutic
      modalities in the treatment of cancer. In this study we examined the effects of
      three such inhibitors on general gene expression in three tumor cell lines
      derived from three separate tumor types using microarray gene profiling. Our
      results show that the patterns of alterations which emerge are similar for each
      cell type.

PMID- 15010815
TI  - Acyclic retinoid in the chemoprevention of hepatocellular carcinoma (review).
AB  - We here review therapeutic application of a synthetic analog of retinoids
      (vitamin A and its derivatives), named acyclic retinoid (AR), towards
      chemoprevention of hepatocellular carcinoma (HCC), and its underlying molecular
      mechanisms. A high incidence of post-therapeutic recurrence has become a major
      determinant of the prognosis of HCC, especially in the patients of hepatitis
      virus-infected cirrhosis. Oral supplementation of AR successfully prevented the
      recurrence of HCC, associated with a disappearance in serum levels of lectin
      reactive alpha-fetoprotein (AFP-L3), a marker of occult cancer clones in the
      liver, suggesting eradication of latent malignant clones from patients' liver.
      This led us a novel concept of 'clonal deletion' with AR as an agent that is
      conceptually similar to cancer chemotherapy. HCC in cirrhotic patients contains
      lower levels of endogenous retinoids and simultaneously is insensitive to
      retinoic acid (RA) because of malfunction of its nuclear receptor, retinoid X
      receptor alpha (RXRalpha). In HCC tissues, RXRalpha is constitutively
      phosphorylated by the action of extracellular signal-regulated kinase (Erk),
      thereby losing its transactivation activity and becoming resistant to degradation
      via ubiquitin/proteasome pathway. This leads to accumulation of phospho
      inactivated RXRalpha, that functions as a dominant negative receptor and
      interferes with transactivation by remaining normal RXRalpha. AR but not natural
      RA prevents phosphorylation of RXRalpha and restores the function of RXRalpha via
      down-regulating Ras/Erk system, making HCC cells sensitive to the endogenous
      ligand, 9-cis-RA. This may link to both caspase-dependent and -independent
      apoptosis of the cancer cells via induction of growth suppressor(s) such as
      p21CIP1 and/or apoptosis inducer(s) including tissue transglutaminase. AR also
      enhances the sensitivity of HCC cells to interferons-alpha and -beta, and thereby
      indirectly promotes apoptosis induced by these interferons. In summary, our
      clinical experience and basic research together provide a strong rationale to use
      AR in the chemoprevention of HCC.

PMID- 15010816
TI  - Expression of p53 protein as a predictor of the response to 5-fluorouracil and
      cisplatin chemotherapy in human gastrointestinal cancer cell lines evaluated with
      apoptosis by use of thin layer collagen gel.
AB  - Apoptosis of the target cells is an important index in the assessment of the
      efficacy of cancer chemotherapy. We previously established a new experimental
      technique in which cancer cells are distributed in thin collagen gel as one or
      two cell layers, and cultured with anti-cancer drugs. The cells are stained with
      fluorescent Hoechst 33258 (Ho) and photographed, then with hematoxylin and eosin
      (H&E) and again photographed. The results show that most cell death patterns can
      be determined by combining observations of Ho and H&E-stained cells without the
      necessity for judging the apoptosis by electron microscopy. 5-fluorouracil (5-FU)
      and cisplatin (CDDP) are important anti-cancer drugs in the treatment of a
      variety of cancers. 5-FU or CDDP alone have shown significant effects in the
      treatment of gastric and colon cancers, and in addition, it has been shown that
      the combination of 5-FU plus CDDP (FP) therapy produces synergism greater than 5
      FU or CDDP alone in gastrointestinal cancer. In this study, we evaluated the
      efficacy and toxicity of FP therapy in the gastric cancer cell lines MKN45,
      MKN28, and KATOIII and the colon cancer cell lines HCT116 and COLO320, and
      examined the relationship between the response to FP therapy and apoptosis.
      Additionally, we performed transfection of normal p53 gene into p53 mutant MKN28
      cells and analyzed the impact of the p53 gene on a sensitivity test. Wild-type
      p53 in MKN45, HCT116, and COLO320 cells underwent significantly (p<0.01) more
      apoptosis than MKN28 and KATOIII cells possessing p53 mutant- and deficient-type,
      respectively, in FP therapy. Transfection of p53 to MKN28 cells resulted in a
      significantly (p<0.01) higher apoptotic index. From these results, we conclude
      that the p53 pathway allows induction of apoptosis in gastrointestinal cancers in
      FP therapy treatment, and that identification of the p53 type of a patient's
      cancer can be used to predict the success of FP therapy.

PMID- 15010817
TI  - Relationship between the expression of extracellular signal-regulated kinase 1/2
      and the dissociation of pancreatic cancer cells: Involvement of ERK1/2 in the
      dissociation status of cancer cells.
AB  - Mitogen-activated protein kinase kinase 2 (MEK2), the upstream kinase of
      extracellular signal-regulated kinase 1/2 (ERK1/2) was previously isolated as
      cancer cell dissociation related factor. In this study, to further clarify the
      regulatory mechanism of cancer cell dissociation, two hamster (PC-1.0 and PC-1)
      and human (Capan-2 and AsPC-1) pancreatic cancer cell lines were analyzed
      immunocytochemically with anti-ERK1, anti-ERK2 and anti-phosphorylated ERK1/2 (p
      ERK1/2) antibodies. U0126 (a MEK1/2 inhibitor) significantly suppressed ERK2 and
      p-ERK1/2 expressions in PC-1.0 and AsPC-1 cells (P<0.05). Cancer cell
      dissociation factor (DF) markedly induced ERK2 and p-ERK1/2 expressions in PC-1
      and Capan-2 cells (P<0.05), and the induced ERK2 and p-ERK1/2 expressions were
      inhibited by subsequent U0126-treatment (P<0.05). Simultaneously, light
      microscopic images showed that DF clearly induced cell dissociation in PC-1 and
      Capan-2 cells, while U0126-treatment induced cell aggregation in these pancreatic
      cancer cells. ERK2 activation is closely involved in cell dissociation of
      pancreatic cancer cells.

PMID- 15010818
TI  - Expression of lipoxygenase in human prostate cancer and growth reduction by its
      inhibitors.
AB  - The metabolism of arachidonic acid by either the cyclooxygenase (COX) or
      lipoxygenase (LOX) pathway generates eicosanoids, which have been implicated in
      the pathogenesis of a variety of human diseases, including cancer. They are
      believed to play important roles in tumor promotion, progression, and metastasis.
      Involvement of LOXs expression and function in tumor growth and metastasis has
      been reported in human tumor cell lines. Expressions of 5- and 12-LOX in prostate
      cancer (PC) patients, prostatic intraepithelial neoplasia (PIN), benign prostatic
      hyperplasia (BPH), and normal prostate (NP) tissues were examined, as well as
      effects of their inhibitors on cell proliferation in 2 PC cell lines (PC3, DU
      145). Expression of 5- and 12-LOX protein was detected by immunohistochemistry.
      Effects of LOX inhibitors on prostate cancer cell growth were examined by MTT
      assay, and Hoechst staining was used to determine whether or not the LOX
      inhibitors induce apoptosis. While 5- and 12-LOX expressions were slightly
      detected in BPH and NP tissues, marked expressions of 5- and 12-lipoxygenase were
      detected in PIN and PC tissues. The LOX inhibitors caused marked reduction of
      prostate cancer cells in a concentration- and time-dependent manner. The LOX
      inhibitors caused marked inhibition of PC cells through apoptosis. LOX is induced
      in prostate cancer, and our results suggest that LOX inhibitors may mediate
      potent antiproliferative effects against prostate cancer cells. Thus, LOX may
      become a new target in treatment of prostate cancer.

PMID- 15010819
TI  - The diagnostic utility of human papillomavirus-testing in combination with
      immunohistochemistry in advanced gynaecologic pelvic tumours: a new diagnostic
      approach.
AB  - Gynaecologic pelvic tumours comprise a range of histological entities that are
      highly variable with respect to their clinical behaviour. The distinction of
      these tumours can be extremely difficult. Accurate identification of the primary
      tumour site has significant impact on the treatment strategy and prognosis. In
      this study we investigated the diagnostic and clinical utility of HPV (Human
      Papillomavirus)-testing in combination with selected immunohistochemical markers
      in advanced pelvic tumours of unknown primary origin. Specimens of eight patients
      who presented with advanced gynaecologic pelvic tumour of unknown primary origin,
      10 unequivocal cervical carcinomas with 10 corresponding metastases and 10
      unequivocal endometrial carcinomas with 4 corresponding metastases were studied.
      All cases were analysed for HPV-infection by PCR. The expression of CEA, vimentin
      (VIM), estrogen receptor (ER) and progesterone receptor (PR) was studied by
      immunohistochemistry. HPV-DNA was exclusively detected in cervical carcinomas and
      their corresponding metastases but in none of the endometrial carcinomas
      (Fisher's exact test p<0.001). Endometrial carcinomas and their metastases were
      generally positive for ER (86%), PR (93%) and VIM (100%) but rarely positive for
      CEA (14%) and HPV (0%). Most cervical carcinomas and their corresponding
      metastases were positive for CEA (79%) and HPV (89%). They rarely expressed ER
      (5%), PR (5%) and VIM (10%). Among the eight patients with unknown primary tumour
      four patients were diagnosed with a cervical carcinoma and four with an
      endometrial carcinoma. In one case we could exclude an ovarian carcinoma.
      Immunohistochemical analysis of selected markers in combination with HPV-testing
      is simple and inexpensive. The detection of HPV-DNA seems to provide the most
      compelling evidence for the primary tumour site, when immunohistochemical
      analysis is less definitive. The proposed diagnostic approach is helpful in the
      identification and management of pelvic tumours of unknown primary origin.

PMID- 15010820
TI  - Down-regulation of matrix-invasive potential of human liver cancer cells by type
      I interferon and a histone deacetylase inhibitor sodium butyrate.
AB  - We have demonstrated anti-proliferation and anti-metastasis effects of both
      interferon-alpha and a histone deacetylase inhibitor, sodium butyrate, on human
      liver cancer cell lines. In this study, invasive ability of human liver cancer
      cell lines through the matrix-coated membrane was examined and inhibitory effect
      of interferon-alpha and sodium butyrate was investigated. Among six human liver
      cancer cell lines, HLE and HLF showed high invasive ability using the Matrigel
      invasion assay. This invasion ability was significantly inhibited by pretreatment
      of the cells with 1000 IU/ml of interferon-alpha or 2 mM of sodium butyrate.
      Gelatin zymography and the matrix metalloproteinase-2 and -9 activity assay
      showed that these two cell lines produce active- and pro-matrix metalloproteinase
      2 and -9, and their activity was significantly reduced by pretreatment with both
      agents. Real-time quantitative reverse transcription-polymerase chain reaction
      showed decrease in matrix metalloproteinase-1 mRNA levels by pretreatment with
      both agents, but mRNA levels of tissue inhibitor of matrix metalloproteinase-1
      and -2 were differently modulated by interferon-alpha and sodium butyrate. These
      results suggest that interferon-alpha and sodium butyrate reduce a chance of
      invasion and metastasis of human liver cancer cells by inhibiting matrix
      metalloproteinase activity, although its inhibitor is differently regulated.

PMID- 15010821
TI  - Microarray analysis of differentially expressed genes associated with human
      ovarian cancer.
AB  - To define the molecular changes associated with ovarian cancer, DNA microarray
      analysis has been adapted to detect differentially expressed genes in human
      normal ovary tissue, borderline, and invasive epithelial ovarian tumors. The
      differential expression of genes in the tumor tissues and normal tissues was
      confirmed by Northern and/or semi-quantitative RT-PCR analysis. Analysis of the
      differential gene-expression profiles of the normal and neoplastic ovary allowed
      us to detect previously unidentified genes in ovarian tissues. We observed up
      regulation of the following genes in ovarian cancer: catechol-O-methyltransferase
      (COMT), the autocrine motility factor neuroleukin (NLK), the transcription
      regulator high mobility group I proteins (HMGI), the tyrosine kinase receptor
      ErbB-3, S100-alpha protein and Acyl-CoA-binding protein (ACBP). The transcription
      factor, chicken ovalbumin up-stream promoter transcription factor II (COUP-TFII),
      was the only gene down-regulated in ovarian cancer. Comparable gene-expression
      profiles were previously reported in breast cancer, suggesting that similar
      molecular events also exist in ovarian cancer. Our microarray analysis showed
      that most differentially expressed genes in ovarian cancer are linked to
      glucose/insulin metabolism, providing a possible molecular link between the
      glucose/insulin signaling pathway and the neoplasms of ovarian cancer.

PMID- 15010822
TI  - Cyclooxygenase-2 pathway correlates with vascular endothelial growth factor
      expression and tumor angiogenesis in hepatitis B virus-associated hepatocellular
      carcinoma.
AB  - Evidence indicates that cyclooxygenase (COX)-2-derived prostaglandins (PGs)
      contribute to tumor growth by inducing angiogenesis. We investigated the role of
      COX-2 in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). COX-2
      and vascular endothelial growth factor (VEGF) expressions were examined by
      immunohistochemistry in 24 HBV-associated HCC. Tumor micro-vessel density (MVD)
      was assessed using CD34 immunohistochemistry. Hep3B HCC cell line, which carries
      integrated HBV genome, was stably transfected with human COX-2 cDNA. COX-2 and
      VEGF expressions were determined by Western blot while PG level was determined by
      ELISA. The effects of PGs on VEGF expression were also investigated. Expression
      of COX-2 and VEGF in HCC cells were observed in 19 (79%) and 16 (67%) cases,
      respectively. Well-differentiated HCC expressed COX-2 more strongly than less
      differentiated HCC (p<0.001). COX-2 expression was found to correlate with VEGF
      expression and MVD (p=0.003 and 0.004, respectively). COX-2 overexpressing Hep3B
      clone had higher VEGF expression as compared to non-COX-2 expressing clone and
      parental cells. Treatment of the COX-2 overexpressing cells with a COX-2
      selective inhibitor, NS-398 (10 microM), decreased PGE2 level and attenuated VEGF
      expression. Addition of PGE2 (10 microM) and the stable analog of PGI2,
      carbaprostacyclin (5 microM), to Hep3B cells also increased VEGF expression. Up
      regulation of COX-2 correlates with VEGF expression and tumor angiogenesis in HBV
      associated HCC. Moreover, COX-2 up-regulates VEGF expression in HCC cells,
      possibly via PGs production. Selective inhibition of COX-2 may block HCC
      associated angiogenesis and thus provides a rational approach for treatment of
      this malignancy.

PMID- 15010823
TI  - Minimal residual disease detection in breast cancer: improved sensitivity using
      cytokeratin 19 and epidermal growth factor receptor RT-PCR.
AB  - Breast cancer cells pose a difficult target for detection due to their lack of
      tumor specific markers. Small numbers of metastatic cells circulate through the
      blood and reach target organs, but current methods are presently not sensitive
      enough to allow for early detection. Our goal is to develop a method for specific
      and sensitive detection for breast cancer tumor cells by using cell enrichment
      coupled to RT-PCR with selective primer pairs. Fifty million normal donor
      mononuclear cells (NDMNC) were spiked with serial dilutions of a breast cancer
      cell line, positively selected for surface expression of the epithelial cell
      adhesion molecule (EPCAM) with anti-Ber-EP4 mAb. Total RNA was isolated and the
      cDNA was transcribed and measured by quantitative PCR for cytokeratin 19 (CK19),
      epidermal growth factor receptor (EGF-R), and beta-2-microglobulin (beta2M)
      transcripts using specific hybridization probes with the LightCycler System. A
      sensitivity of 1 tumor cell in 5 million NDMNC was consistently achieved with a
      metastatic breast cancer cell line with target primer sets for CK19 and EGF-R.
      Less, but appreciable sensitivity was achieved by spiking NDMNC with other breast
      cancer cells. Detection of both gene targets ranged between 1 in 5,000 to 5
      million cells. The method described, a cell enrichment procedure and RT-PCR using
      specific hybridization probes (spanning introns and hybridizing to areas that
      discriminate transcribed pseudogenes), results in increased sensitivity while
      decreasing false positives above those methods previously reported. This general
      approach may have wide applicability to increasing sensitivity of minimal
      residual disease detection in other cancers.

PMID- 15010824
TI  - Protein phosphatase inhibitor-1 mRNA expression correlates with neoplastic
      transformation of epithelial liver cells and progression of hepatocellular
      carcinomas.
AB  - Protein phosphatase inhibitor-1 plays an important role in the regulation of
      glycogen metabolism through inhibition of protein phosphatase-1 activity, and it
      has been implicated in the regulation of cell growth. Using real-time
      quantitative RT-PCR, we studied the mRNA expression of inhibitor-1 in
      hepatocellular carcinomas induced in rats by oral administration of N
      nitrosomorpholine, and in a non-tumorigenic liver cell line (C1I), that stores
      glycogen in excess during early passages. In late passages, glycogen is gradually
      lost concomitant with cell transformation. Our in vitro model included a
      tumorigenic subline of C1I cells that was obtained by chemically-induced
      neoplastic transformation using N-methyl-N'-nitro-N-nitrosoguanidine (C1Ict), and
      does not store glycogen, as well as Morris hepatoma 3924A (MH3924A) cells. We
      found that in hepatocellular carcinomas, in the late glycogen-poor passages
      (C1I(late)), and in the tumorigenic subline (C1Ict) of C1I cells, and in MH3924A
      cells the mRNA expression of inhibitor-1 is significantly increased. This
      increase in expression varied from 15 to 290-fold of that observed in normal
      liver. In contrast, in the early glycogen-storing passage of C1I cells
      (C1I(early)) the level of inhibitor-1 mRNA was found to be slightly less than
      that of normal liver. Inhibitor-1 mRNA levels correlated with the degree of
      differentiation of HCCs. These results indicate that the expression of inhibitor
      1 mRNA is tightly linked to tumor progression and to the process of liver cell
      transformation in vitro and is inversely correlated with the glycogen content of
      the cell.

PMID- 15010825
TI  - Human telomerase reverse transcriptase mRNA is highly expressed in normal breast
      tissues and down-regulated in ductal carcinoma in situ.
AB  - Telomerase is a ribonuclear protein that maintains telomere length in eukaryotic
      cells. Activation of the human telomerase reverse transcriptase (hTERT), the
      catalytic subunit of telomerase, has been implicated in cellular immortalization
      and may play a critical role in carcinogenesis. Prior studies in DCIS have been
      small, and used polymerase chain reaction (PCR)-based methods on heterogeneous
      tissue extracts. In this study, we used in situ hybridization to determine the
      cell type and topographic expression pattern of hTERT mRNA in a large series of
      cased in normal breast ductal-lobular units and ductal carcinoma in situ (DCIS).
      A total of 120 breast samples were evaluated. High level of hTERT mRNA expression
      was observed in both normal breast ductal-lobular units and DCIS, which showed a
      very heterogeneous expression pattern. Overall, hTERT mRNA expression was
      significantly higher in normal cells compared to DCIS (p=0.000). These results
      suggest that hTERT not only plays an important role in breast cancer progression
      but it is also involved in regulating the cellular function of normal breast
      ductal-lobular units. This finding challenges the conventional view that hTERT
      mRNA expression is repressed in somatic cells but activated in neoplastic cells.
      Our results also suggest that telomerase reverse transcriptase mRNA expression
      may play an important role in the homeostasis of normal breast epithelial cells
      and neoplastic cells do not necessarily have increased level of expression of
      hTERT.

PMID- 15010826
TI  - Proteomic profiling in microdissected hepatocellular carcinoma tissue using
      ProteinChip technology.
AB  - At present, the molecular mechanisms of hepatocellular carcinogenesis are not
      well understood. It is known, however, that cancer development and progression
      are accompanied by profound changes at the cellular and subcellular level,
      involving RNA/DNA and protein structure and function. Therefore, high-throughput,
      proteomic techniques targeting these biological molecules may provide novel
      insights into HCC genesis and prognosis. We characterized tissue protein profiles
      from 10 HCC patients using ProteinChip technology (SELDI) which is able to detect
      minute amounts of proteins and moreover to analyze complex protein pattern.
      Therefore, after histopathological examination, proteins from kryostat sections
      of non-tumorous hepatic tissue as well as from central and peripheral tumor areas
      were isolated from complete histological sections or from selected and
      microdissected tissue areas. Analysis on the SAX and WCX ProteinChip Arrays
      revealed 14-26, and 25-29 differentially expressed peaks respectively, which
      characterized non-tumorous and tumor tissue (p< or =0.05). One feature which
      allows differentiation between central tumor and peripheral tumor regions could
      only be detected in microdissected tissue. Using ProteinChip technology in
      combination with tissue microdissection it is possible to investigate complex
      changes at the protein level in hepatocellular cancer associated with tumor
      development and progression.

PMID- 15010827
TI  - Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human
      tumors.
AB  - The protein synthetic machinery is activated by a variety of genetic alterations
      during tumor progression and represents an attractive target for cancer therapy.
      The mammalian target of rapamycin (mTOR) plays an important role in regulating
      protein translation through phosphorylation of p70 S6 kinase 1 (S6K1), a protein
      involved in ribosome biogenesis, and 4E-BP1 (eIF-4E binding protein), a
      translation repressor. It has been shown that mTOR has a direct linkage to the
      phosphatidylinositol-3'-kinase (PI3K)/PTEN-AKT survival pathway. Recent studies
      have demonstrated that mTOR inhibition by rapamycin or its analogues have
      remarkable activity against a wide range of human cancers in vitro and in human
      tumor xenograft models. Phase I clinical evaluations also suggested an anti-tumor
      effect of rapamycin analogue such as CCI-779. The clinical challenge for the
      application of this class of anticancer drug is the ability to prospectively
      identify which tumors will be sensitive to mTOR inhibition. Recent studies have
      identified cellular markers that are associated with the in vitro activity of
      rapamycin or CCI-779. However, there have been no reports on how these cellular
      markers are expressed together in human tumor specimen. In this study, multiple
      components of the PI3K/PTEN-AKT-mTOR pathway were evaluated by
      immunohistochemistry in tissue arrays containing 124 tumors from 8 common tumor
      types. The results show variable expression of all the signaling proteins. For
      example, mTOR expression was low in brain tumors, but high in the rest of tumors.
      High levels of 4E-BP1 were seen in colonic adenocarcinoma and low levels in
      lymphoma. Phospho-AKT (p-AKT) and phospho-S6K1 (p-S6K1) were the only proteins
      that had significantly correlated protein expression (rs=0.51, p<0.001). Since
      low PTEN, high p-AKT and high p-S6K1 expression render tumors sensitive to mTOR
      inhibition in vitro, these criteria were used to model tumor sensitivity.
      Overall, 26% of tumors (32/124) are predicted to be sensitive to mTOR inhibition,
      with variable rates for different tumors (melanoma 0% vs ovarian 41%). This is
      the first report on the PI3K/PTEN-AKT-mTOR pathway in common human tumors and
      evaluation of the coordinated expression of different signaling proteins. This
      study should provide a useful tool for selecting future targeted phase II and III
      clinical trials in the development of this exciting class of agents.

PMID- 15010828
TI  - Immunopharmacological and antitumor effects of second-generation immunomodulatory
      oligonucleotides containing synthetic CpR motifs.
AB  - Bacterial and synthetic DNAs containing CpG dinucleotides in specific sequence
      contexts (CpG DNA) activate the vertebrate immune system and produce potent Th1
      immune responses. Recently, we reported immunomodulatory oligonucleotides (IMOs)
      containing 3'-3'-attached novel structures (immunomers) and synthetic
      immunostimulatory CpR (R=2'-deoxy-7-deazguanosine) dinucleotides show potent
      stimulatory activity with distinct cytokine secretion profiles. In the present
      study, we evaluated in vivo immunopharmacological and antitumor properties of
      second-generation immunomodulatory oligonucleotides (IMOs) either alone or in
      combination with chemotherapeutic agents. Repeated peritumoral administration of
      IMOs at 1 mg/kg to mice bearing established subcutaneous CT26 colon tumor or
      B16.F0 melanoma resulted in complete regression or strong inhibition of tumor
      growth. Direct peritoneal injection of IMOs at 2.5 mg/kg to mice bearing
      peritoneally implanted ascites CT26 or B16.F0 tumors completely eradicated or
      inhibited tumor growth. Treatment of mice bearing beta-gal expressing CT26.CL25
      tumor with IMOs resulted in a significant tumor-specific CTL responses compared
      with treatment with a control non-CpG DNA or PBS. These responses correlated with
      IFN-gamma, but not IL-4 secreted in IMO, treated mice. A 5-fold increase in beta
      gal specific IgG2a antibodies was found in mice, significantly increasing the
      IgG2a/IgG1 ratio. IMOs showed similar antitumor activity in both wt and IL-6
      knockout (ko) C57BL/6 mice but failed to elicit activity in IL-12 ko C57BL/6
      mice. Tumor-free mice from the IMO treatment group rejected the same tumor cell
      rechallenge, suggesting an adaptive immune response against these cells.
      Moreover, naive mice quickly developed specific antitumor response without IMO
      treatment following adoptive transfer of splenocytes obtained from tumor free
      mice from the IMO treated group. Additionally, the co-administration of IMOs with
      chemotherapeutic agents, docetaxel and doxorubicin, resulted in synergistic
      antitumor effects in both B16.F0 melanoma and 4T1 breast carcinoma models. These
      results demonstrate potent antitumor activity of second-generation IMO compounds
      containing a synthetic CpR stimulatory motif in a broad spectrum of tumor models
      through induction of strong Th1 immune responses. IMO treatment resulted in the
      development of tumor-specific memory immune responses. No treatment-related
      toxicity was observed in mice at the doses and treatment schedules studied.

PMID- 15010829
TI  - Dendritic cell-based immunotherapy of cancer with carcinoembryonic antigen
      derived, HLA-A24-restricted CTL epitope: Clinical outcomes of 18 patients with
      metastatic gastrointestinal or lung adenocarcinomas.
AB  - We conducted a clinical study of cancer vaccine therapy with dendritic cells
      (DCs) and HLA-A24-restricted carcinoembryonic antigen (CEA)-derived peptide to
      assess the feasibility and efficacy of such therapy. Eighteen patients with CEA
      expressing metastatic gastrointestinal or lung adenocarcinomas who were positive
      for human leukocyte antigen (HLA)-A24 were enrolled. DCs were generated from the
      patients' autologous monocyte-enriched fractions of granulocyte colony
      stimulating factor-mobilized peripheral blood mononuclear cells in the presence
      of granulocyte/macrophage colony-stimulating factor and interleukin-4. The
      generated DCs were pulsed with CEA-derived, HLA-A24-restricted 9-mer peptide
      (CEA652) and injected into the patients intradermally and subcutaneously every 2
      weeks. Toxicity and clinical and immunological responses were closely monitored
      in each patient. No severe toxicity directly attributable to the treatment was
      observed, and the vaccine was well tolerated. Although no definite tumor
      shrinkage occurred in any patient, long-term stable disease or marked decreases
      in the serum CEA level were observed in some patients after therapy. Most of the
      patients in whom treatment was clinically effective showed a positive skin
      response to CEA652-pulsed DCs (delayed-type hypersensitivity skin test) and a
      positive in vitro CTL response to CEA652 peptide after therapy. We conclude that
      active specific immunotherapy using DCs pulsed with CEA652 is a safe and feasible
      treatment that is clinically effective in some patients with metastatic
      gastrointestinal or lung adenocarcinomas. Our results will hopefully encourage
      further refinement and development of DC-based immunotherapy with HLA-A24
      restricted CEA-derived peptide for refractory solid cancers that express CEA.

PMID- 15010830
TI  - Alphavirus vectors for cancer gene therapy (review).
AB  - Alphaviruses have several characteristics that make them attractive as gene
      therapy vectors such as transient and high-level expression of a heterologous
      gene. Alphavirus vectors, Semliki Forest virus (SFV), Sindbis virus (SIN) and
      Venezuelan equine encephalitis virus (VEE) have been developed as gene expression
      vectors. Alphaviruses are positive-strand RNA viruses that can mediate efficient
      cytoplasmic gene expression in mammalian cells. The alphavirus RNA replication
      machinery has been engineered for high level heterologous gene expression. Since
      an RNA virus vector cannot integrate into chromosomal DNA, concerns about cell
      transformation are reduced. Alphavirus vectors demonstrate promise for the safe
      tumor-killing and tumor-specific immune responses. Recombinant alphavirus RNA
      replicons may facilitate gene therapy of cancer.

PMID- 15010831
TI  - Expression and alternative splicing pattern of human telomerase reverse
      transcriptase in human lung cancer cells.
AB  - Telomerase activity is generally considered to be necessary for cancer cells to
      avoid senescence. The expression of human telomerase reverse transcriptase
      (hTERT) is believed to be a rate-limiting step in telomerase activation.
      Recently, it has been proposed that the alternative splicing of hTERT is also
      involved in regulation of telomerase activity. However, the regulatory mechanism
      of telomerase in cancer cells has not been thoroughly investigated. To clarify it
      in lung cancer cells, we measured the expression of the hTERT transcript,
      analyzed its alternative splicing by RT-PCR, and compared it with telomerase
      activity and telomere length. The expression of the hTERT transcript was
      positively correlated with telomerase activity in lung cancer cells. Cancer cells
      with high telomerase activity contained 4 splicing variants of hTERT, and the
      full-length variant was 31.3-54.2% of the total transcripts. Cells of the TKB-20
      cell line, which has extremely low telomerase activity, showed a different
      splicing pattern of hTERT in addition to low expression. The functional full
      length variant was scarcely detected in TKB-20 cells, suggesting that the
      telomerase activity was repressed by alternative splicing of hTERT. Telomere
      length was not necessarily correlated with telomerase activity or hTERT
      expression in lung cancer cells. Cells of the TKB-4 cell line that also showed
      relatively low telomerase activity (as TKB-20 cells) had long telomeres. In
      conclusion, hTERT expression is regulated at both the transcriptional and post
      transcriptional levels in lung cancer cells, and the alternative splicing of
      hTERT is involved in the control of telomerase activity.

PMID- 15010832
TI  - STAT3 and MAPK in human lung cancer tissues and suppression of oncogenic growth
      by JAB and dominant negative STAT3.
AB  - To search for the signaling events in lung carcinoma relevant to its
      tumorigenesis, we investigated the phosphorylation of MAPK and STAT3 in human
      lung carcinoma tissues and their paired normal tissues. Although relative amounts
      of MAPK levels differed among the cases examined, no clear difference in MAPK
      levels was observed between tumor tissues and their paired normal tissues. Of 79
      cases examined, only 7 cases (8.9%) showed tumor-specific phosphorylation of
      MAPK, whereas 41 cases (52%) showed more than 2-fold lower levels of MAPK
      phosphorylation in tumor tissues. In contrast to MAPK, 42 cases (53%) showed
      tumor-specific increase in STAT3 expression. In addition, 15 cases (19%) showed
      tumor-specific increase of STAT3 phosphorylation and 51 cases (65%) had STAT3
      phosphorylation proportional to its expression. Moreover, exogenous expression of
      either JAB or dominant negative STAT3 in lung carcinoma cell lines led to the
      suppression of STAT3 phosphorylation and the drastic reduction of anchorage-
      independent growth of the cells. Taken together, our results suggest that JAK
      STAT3 signaling has a pivotal role for oncogenic growth of lung carcinoma cells.

PMID- 15010834
TI  - Non-small cell lung cancer as a target disease for herpes simplex type 1
      thymidine kinase-ganciclovir gene therapy.
AB  - Lung cancer is a group of diseases that are difficult to cure and new treatment
      modalities, like gene therapy are actively tested to find alternatives for
      currently used strategies. Herpes simplex virus thymidine kinase/ganciclovir (HSV
      TK/GCV) method is one of the most frequently utilized forms of gene therapy and
      it has been tested on lung cancer, but no systematic study with comparison of
      different lung cancer types has been published. In this study, we examined in
      vitro and in vivo how good targets non-small cell lung cancer (NSCLC) cell lines
      representing adenocarcinoma, squamous cell lung cancer and large cell lung cancer
      are for adenovirus-mediated HSV-TK/GCV gene therapy. By using an adenovirus
      vector carrying a fusion gene of HSV-TK and green fluorescent protein (GFP), we
      found that: a) adenoviruses were efficient gene transfer vehicles for all types
      of NSCLCs; b) all adenocarcinoma and large cell lung cancer cells were good
      targets for HSV-TK/GCV therapy, whereas one of the squamous cell carcinoma cell
      lines was not responsive to the treatment; c) bystander effect played a major
      role in the success of this gene therapy form; d) subcutaneous tumors
      representing all three NSCLC types were efficiently treated with adenovirus
      mediated HSV-TK/GCV gene therapy. In summary, this form of gene therapy appeared
      to be efficient treatment for human NSCLC and these results warrant further
      studies with primary lung cancer cells and orthotopic lung tumor models.

PMID- 15010833
TI  - Influence of p53 and p21Waf1 expression on G2/M phase arrest of colorectal
      carcinoma HCT116 cells to proteasome inhibitors.
AB  - Ubiquitin-mediated protein degradation in vertebrates has been implicated in cell
      cycle control. In this report we explored the effects of proteasome inhibitors
      (MG132, lactacystin and ALLN) on cell cycle distribution. Colorectal carcinoma
      HCT116 cells were treated with proteasome inhibitor MG132. The results showed
      that MG132 inhibited cell proliferation in a dose-dependent manner. MG132
      arrested HCT116 cells at G2/M phase, which was associated with drug-induced
      blockade of p53 degradation and/or induction of p53-related gene expression along
      with the accumulation of cyclin B, cyclin A and p21. MG132 treated HCT116 (wild
      type) had a similar cell cycle distribution as the MG132 treated HCT116 (p53-/-)
      and HCT116 (p21-/-) cells, suggesting that p53 and p21 may not be essential for
      MG132-induced G2/M phase arrest. The release experiments from nocodazole-induced
      mitotic phase cells indicated that MG132 inhibits the proliferation of HCT116
      cells via arrest in the G2 phase. In addition, when HCT116 cells were exposed to
      combination of sodium butyrate and MG132 enhanced cell growth inhibition and
      induction of apoptosis were observed.

PMID- 15010835
TI  - Wild-type p53 gene transfer into mutated p53 HT29 cells improves sensitivity to
      photodynamic therapy via induction of apoptosis.
AB  - Photodynamic therapy (PDT) is an effective local cancer treatment that induces
      cytotoxicity through the intracellular generation of reactive oxygen species. It
      is generally thought that p53 regulates chemotherapy and radiation therapy
      responsiveness via apoptosis induction control. The current study investigated
      whether cellular sensitivity to PDT is increased when a wild-type (wt) p53 status
      is restored by gene transfer in the established HT9blk Ala273-mutant p53 human
      colon cancer cell line. The photosensitizer accumulation was similar in both cell
      lines, and survival measurements using MTT test and clonogenic assays
      demonstrated that wt p53 transfected cells (HT29A4) were significantly more
      sensitive to chlorin e6-mediated PDT. P53 protein expression and its
      functionality as a transcription factor demonstrated through the induction of
      mdm2 transactivation, were not found to be directly involved in this differential
      photosensitivity. However, induction of caspase 3 activation (2.6-fold), leading
      to significant apoptosis induction 24-h after PDT was observed in HT29A4 cells.
      These results suggest that the introduction of wt p53 in HT29A4 potentiates the
      cell sensitivity to PDT through the induction of apoptosis in relation to p53
      mutational status, but independently of p53 expression level and transcriptional
      activity.

PMID- 15010836
TI  - Locoregional immunotherapy of malignant ascites from gastric cancer using DTH
      oriented doses of the streptococcal preparation OK-432: Treatment of Th1
      dysfunction in the ascites microenvironment.
AB  - Locoregional administration of the streptococcal preparation OK-432 is effective
      in treating malignant ascites from gastric cancer. In order to enhance the
      efficacy, we conducted a pilot study of locoregional immunotherapy for malignant
      ascites using host-oriented doses of OK-432. Moreover, action mechanisms of OK
      432 were further explored in view of the T-helper type 1 (Th1)-Th2 concept.
      Gastric cancer patients with cytologically determined malignant ascites were
      locoregionally administered with OK-432. The dose of OK-432 was selected
      according to the delayed-type hypersensitivity (DTH) reaction levels to OK-432.
      Cytokine production profiles of ascites cells were determined using whole ascites
      assay by stimulation with OK-432. IL-10 mRNA expression was analyzed using RT
      PCR. It was found that a positive clinical response was observed in 37 of the 51
      (73%) patients with the DTH-oriented approach, showing a significantly higher
      efficacy than traditional dosage methods using empirical doses (31/58, 53%)
      (p=0.0487). The DTH-oriented administration of OK-432 produced adverse effects
      such as fever elevation (p<0.0001) and abdominal pain (p=0.0013) to a
      significantly lesser extent compared with the traditional treatment. Analysis of
      the action mechanism of OK-432 revealed that the DTH reaction in responders (19+/
      6 mm) was stronger than that in non-responders (6+/-4 mm) (p<0.0001). Tumor
      necrosis factor (TNF)-alpha production of ascites cells was also higher in
      responders (3943+/-1247 pg/ml) than in non-responders (1217+/-939 pg/ml)
      (p=0.0002). There was a significant positive correlation (p=0.0085) between the
      levels of DTH reaction and TNF-alpha production of ascites cells, but not of
      blood cells. Responders appeared to polarize on the Th1 axis when clinical
      responses were plotted on Th1-Th2 dimensions according to the cytokine production
      profiles of TNF-alpha, IFN-gamma, IL-4 and IL-6 of ascites cells. In vitro
      culture with IL-2 of ascites cells after OK-432 administration demonstrated an
      almost clonal expansion of CD4+ lymphocytes, which produced TNF-alpha and IFN
      gamma, but did not produce IL-4 or IL-6. IL-10 mRNA expression was detectable in
      ascites cells from non-responders before treatment. These results suggest that
      the DTH-oriented locoregional administration of OK-432 may be both effective and
      less toxic in treating malignant ascites from gastric cancer, showing a
      possibility of the tailored immunotherapy for malignant ascites. Th1 dysfunction
      exists in the microenvironment of malignant ascites from gastric cancer, in which
      IL-10 may, in part, play a role. The up-regulation of Th1 responses by OK-432 may
      result in positive clinical responses. The DTH reaction to OK-432 may be a useful
      tool not only for predicting clinical response but also for selecting the optimal
      dose of OK-432.

PMID- 15010837
TI  - HER2/neu-derived peptides recognized by both cellular and humoral immune systems
      in HLA-A2+ cancer patients.
AB  - HER2/neu is one of the most appropriate target antigens for anti-cancer therapy
      because of its expression in various types of epithelial cancer. HER2/neu can
      also be a target for both cellular and humoral immune responses. In this study,
      we attempted to identify HER2/neu-derived peptides, which are able to be
      recognized by both humoral and cellular immune systems in HLA-A2+ cancer
      patients. Among 12 HER2/neu-derived peptides having the HLA-A2 binding motifs,
      immunoglobulin G reactive to each of 7 HER2/neu peptides was detected in the
      plasma of >50% of cancer patients. Among these 7 peptides, 3 including HER2/neu
      444-452, HER2/neu 466-474, and HER2/neu 484-492, effectively induced peptide
      specific and HLA-A2-restricted cytotoxic T lymphocyte activity from peripheral
      blood mononuclear cells of cancer patients, regardless of different HLA-A2
      subtypes. Experiments using blocking antibodies and cold inhibition targets
      revealed that the cytotoxicity against HER2/neu-expressing HLA-A2+ tumor cells
      was peptide-specific and CD8+ T cell-dependent. Overall, these results indicate
      that these 3 HER2/neu-derived peptides are efficiently recognized by both the
      humoral and cellular immune systems, and therefore could be useful for peptide
      based immunotherapy for HLA-A2+ patients with various types of epithelial cancer.

PMID- 15010838
TI  - Conventional and array-based comparative genomic hybridization analyses of novel
      cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix.
AB  - We established 2 novel human cell lines (GCCOT-1, GCCRK) from glassy cell
      carcinoma. Both cell lines showed dual tendencies of glandular and squamous
      differentiation, and thus possess the characteristics resembling reserve cells,
      the putative origin of most carcinomas arising from the uterine cervix. HPV type
      18 DNA including E6-E7, which is commonly found in cell types other than squamous
      cell carcinoma of uterine cervix, was detected in both cell lines. We analyzed
      gene copy number alterations of the 2 cell lines using conventional comparative
      genomic hybridization (CGH) coupled with array-based CGH. Among the putative
      oncogenes demonstrating copy number gain in both cell lines, FGR(SRC2) at 1p36.2
      1 and LAMC2 at 1q25-31 have not been reported to show amplification in previous
      analyses of conventional cervical cell lines. These oncogenes are thus speculated
      to be directly associated with oncogenesis of glassy cell carcinoma. On the other
      hand, among the putative suppressor genes demonstrating copy number loss in both
      cell lines, the 9q region, ATM at 11q22.3, and CYLD at 16q12-13 have not been
      reported to show loss in conventional cervical cancer cell lines. These sites are
      speculated to be important as tumor suppressors directly associated with
      oncogenesis of glassy cell carcinoma. This study suggests for the first time that
      together with the presence of HPV type 18, alterations at the above sites are
      closely associated with oncogenesis of glassy cell carcinoma, a special type of
      carcinoma in the uterine cervix.

PMID- 15010839
TI  - Identification of differentially expressed genes in colorectal adenoma compared
      to normal tissue by suppression subtractive hybridization.
AB  - Altered gene expression that results in unrestricted growth and loss of
      differentiation is a hallmark of neoplastic cells. The goal of the present study
      was to determine early changes in gene expression profiles during colorectal
      carcinogenesis with emphasis on those genes whose expression is upregulated in
      adenoma tissue compared to adjacent normal colon. Using the suppression
      subtractive hybridization (SSH) approach on enriched colonic crypts we identified
      14 candidate genes showing increased expression levels in the original adenoma
      sample. Subsequent dot blot, Northern blot, standard and real-time RT-PCR
      analysis confirmed increased transcript levels of ten genes in various subsets of
      colorectal adenoma and cancer samples. SERPINB5 and a yet uncharacterized HERV-H
      sequence showed the highest expression in adenoma and tumor samples without
      significant expression in the corresponding normal tissue. These genes might
      represent promising new candidates for colorectal cancer early detection.

PMID- 15010840
TI  - Induction by hypoxia combined with low glucose or low bicarbonate and high
      posttranslational stability upon reoxygenation contribute to carbonic anhydrase
      IX expression in cancer cells.
AB  - Hypoxia is an important factor of tumor microenvironment that significantly
      influences behaviour of tumor cells via activation of genes whose products are
      involved in adaptation to hypoxic stress, such as vascular endothelial growth
      factor (VEGF) and glucose transporter (GLUT-1). Carbonic anhydrase IX (CA IX) is
      one of the most strongly hypoxia-inducible proteins with potential value as an
      intrinsic marker of hypoxia. However, intratumoral distribution of CA IX only
      partially overlaps with distribution of VEGF and GLUT-1 indicating that
      regulation of CA IX differs from the regulation of other hypoxic markers.
      Therefore, we analysed CA IX expression in response to hypoxia combined with
      other stresses, and determined the stability of CA IX protein upon reoxygenation
      using HeLa cells as a model. We found that both hypoxia-induced transcription and
      CA IX protein level are further increased by reduced glucose or bicarbonate
      concentrations. Post-translational stability of CA IX was assessed by monitoring
      the quantity of biotinylated protein extracted at different time points from the
      cells labelled immediately after shift to reoxygenation. CA IX protein half-life
      in reoxygenated cells was 38 h and was independent of the duration of the
      foregoing hypoxia. This finding has potential implications for interpretation of
      clinical data as it suggests that CA IX expression may detect not only actually
      hypoxic tumor regions, but also the regions affected by hypoxia and adverse
      microenvironmental stresses before biopsy or tumor removal.

PMID- 15010841
TI  - Detection of (NAD(P)H:Quinone oxidoreductase-1, EC 1.6.99.2) 609C-->T and 465C-
      >T polymorphisms in formalin-fixed, paraffin-embedded human tumour tissue using
      PCR-RFLP.
AB  - NQO1 is a cytosolic flavoprotein that plays a dual role in the detoxification of
      potentially carcinogenic compounds and the bioreductive activation of quinone
      based anticancer drugs. Two polymorphic variants of NQO1 exist (NQO1*2 and
      NQO1*3) which cause significant phenotypic reductions in NQO1 protein content and
      activity. Current methods for detecting NQO1 polymorphisms commonly use PCR-RFLP
      techniques and have exclusively used DNA isolated from fresh tissues. This study
      describes a method that is suitable for analysing NQO1 polymorphisms in genomic
      DNA isolated from formalin-fixed paraffin-embedded tissue. The method utilises
      two rounds of PCR amplification using a nested primer strategy that generates
      specific PCR products followed by RFLP analysis using either Hinf1 (for NQO1*2)
      or Msp1 (for NQO1*3). Whilst existing methods proved unsatisfactory (low product
      yield and poor specificity), the nested primer strategy produced good quality PCR
      products suitable for RFLP analysis and genotyping of NQO1*2 and NQO1*3 in
      archival tissue samples. The ability to utilise the vast archives of human tissue
      held by pathology laboratories would be of considerable benefit as retrospective
      studies comparing NQO1 genotype status, patient history and treatment outcomes
      could be conducted.

PMID- 15010842
TI  - Imprinting status of DLK1 gene in brain tumors and lymphomas.
AB  - DLK1 and GTL2 are reciprocally imprinted genes on human chromosome 14q32. DLK1
      encodes a transmembrane protein that is a paternally expressed gene. The
      maternally expressed GTL2 allele encodes a non-translated RNA. Many of features
      of DLK1/GTL2 are remarkably similar to those of the prototypical IGF2/H19
      reciprocally imprinted gene pair. Imprinting status of IGF2 has been studied in
      many types of tumors, and loss of imprinting (LOI) leads to biallelic expression
      of IGF2 in most of these tumors. The imprinting status of DLK1 has seldom been
      investigated in clinical tumor samples. We examined whether DLK1 was imprinted in
      brain tumors and lymphomas by analyzing a single nucleotide polymorphism (SNP),
      rs1802710. Analysis of 47 brain tumors and 55 lymphomas found that 23 and 29 of
      them were heterozygous for rs1802710, respectively. Monoallelic expression of
      DLK1 was detected in the heterozygous samples. These data show that imprinting of
      DLK1 is maintained in brain tumors and lymphomas, even though the DLK1 gene is
      very analogous to the IGF2 gene in its DNA structure and regulation. Also, the
      high frequency of heterozygosity (about 50%) showed that the polymorphic site
      that we chose is a good genomic marker for imprinting studies of the DLK1 gene in
      additional tumor types.

PMID- 15010844
TI  - Induction of the early response protein EGR-1 in human tumour cells after
      ionizing radiation is correlated with a reduction of repair of lethal lesions and
      an increase of repair of sublethal lesions.
AB  - The role of EGR-1 in potentially lethal damage repair (PLDR) was studied.
      Induction of the early response protein EGR-1 and survival after ionizing
      radiation of two human tumour cell lines after culturing for 48 h in serum
      deprived medium was investigated. The glioblastoma cell line (Gli-6) and a lung
      carcinoma cell line (SW-1573) were selected as these cell lines differ
      considerably in the degree of PLD repair after radiation. In both cell lines
      induction of EGR-1 protein was observed between 30-120 min after treatment with
      10 Gy in serum-deprived cultures. In cells growing in medium with normal serum no
      induction of EGR-1 was observed. No difference in EGR-1 expression levels between
      the two cell lines was detected. Linear-Quadratic analysis of the survival curves
      showed a much larger difference between the values of alpha after immediate and
      delayed plated cells of the cultures in normal serum as compared to cells
      cultured in serum-deprived medium. The cells cultured in serum-deprived medium
      showed much larger difference between the values of beta. This indicates that
      induction of EGR-1 is correlated with a reduction of repair of lethal lesions
      (PLDRalpha) and with an increase of repair of sublethal lesions (PLDRbeta).

PMID- 15010845
TI  - Identification and characterization of human GUKH2 gene in silico.
AB  - Drosophila Guanylate-kinase holder (Gukh) is an adaptor molecule bridging Discs
      large (Dlg) and Scribble (Scrib), which are implicated in the establishment and
      maintenance of epithelial polarity. Here, we searched for human homologs of
      Drosophila gukh by using bioinformatics, and identified GUKH1 and GUKH2 genes.
      GUKH1 was identical to Nance-Horan syndrome (NHS) gene, while GUKH2 was a novel
      gene. FLJ35425 (AK092744.1), DKFZp686P1949 (BX647246.1) and KIAA1357 (AB037778.1)
      cDNAs were derived from human GUKH2 gene. Nucleotide sequence of GUKH2 cDNA was
      determined by assembling 5'-part of FLJ35425 cDNA and entire region of
      DKFZp686P1949 cDNA. Human GUKH2 gene consists of 8 exons. Exon 5 (132 bp) of
      GUKH2 gene was spliced out in GUKH2 cDNA due to alternative splicing. GUKH2-REPS1
      locus at human chromosome 6q24.1 and GUKH1-REPS2 locus at human chromosome
      Xp22.22-p22.13 are paralogous regions within the human genome. Mouse Gukh2 and
      zebrafish gukh2 genes were also identified. N-terminal part of human GUKH2, mouse
      Gukh2 and zebrafish gukh2 proteins were completely divergent from human GUKH1
      protein. Human GUKH2 and GUKH1, consisting of eight GUKH homology (GKH1-GKH8)
      domains and Proline-rich domain, showed 28.5% total-amino-acid identity. GKH1,
      GKH4, GKH5, GKH7 and GKH8 domains were conserved among human GUKH1, human GUKH2
      and Drosophila Gukh. Because human homologs of Drosophila dlg (DLG1-DLG7) as well
      as human homologs of Drosophila scrib (SCRIB, ERBB2IP and Densin-180) are cancer
      associated genes, human homologs of Drosophila gukh (GUKH1 and GUKH2) are
      predicted cancer-associated genes.

PMID- 15010843
TI  - Modulation of Janus kinase 2 by cisplatin in cancer cells.
AB  - Constitutive activation of Janus kinases (JAKs) is frequently detected in various
      human cancers. The activation of JAKs results in the phosphorylation and
      activation of signal transducers and activators of transcription (STATs). The
      constitutive activation of JAK/STAT pathway may play an important role in growth
      and survival of human cancer cells. In this study, we examined whether a
      chemotherapeutic agent cisplatin could inhibit the JAK/STAT pathway. In ovarian
      cancer and sarcoma cells that express constitutively active JAK2, cisplatin
      significantly inhibited tyrosine phosphorylation and kinase activity of JAK2 in a
      dose- and time-dependent manner. Meanwhile, cisplatin also inhibited Stat3
      tyrosine phosphorylation and down-regulated BcL-XL anti-apoptotic protein in the
      cancer cells tested. In leukemia cells expressing high level of TEL-JAK2 fusion
      protein, cisplatin dramatically inhibited tyrosine phosphorylation of TEL-JAK2 as
      well. Furthermore, our results have shown that down-regulation of JAK2 by
      cisplatin might be through modulation of a tyrosine phosphatase SHP-1 but not
      SOCS family members. Taken together, our observations demonstrated that cisplatin
      down-regulated the JAK/STAT pathway through de-phosphorylation of JAK/STAT in
      cancer cells.

PMID- 15010846
TI  - Mutations in DNA mismatch repair genes: implications for DNA damage signaling and
      drug sensitivity (review).
AB  - The DNA mismatch repair (MMR) system functions in the elimination of biosynthetic
      errors that arise during DNA replication, in DNA damage surveillance, and in the
      prevention of recombination between non-identical sequences. It therefore
      substantially contributes to the maintenance of genome integrity. It is thus not
      surprising that loss of MMR function may lead to cancer. Inherited defects due to
      germline mutations in the MMR genes underlie the hereditary non-polyposis colon
      cancer (HNPCC) syndrome in humans, and epigenetic silencing of the hMLH1 gene
      accounts for sporadic cancers, including those of the endometrium and ovaries.
      Another hallmark of MMR is its capacity to elicit DNA damage-induced cell death.
      Although this might seem to make MMR a useful target for anticancer agents, it
      has become clear that tumor cells with defective MMR display reduced sensitivity
      to the cytotoxic effect of DNA damaging agents such as alkylating agents and
      cisplatin. This is of clinical relevance, as these agents provide MMR-deficient
      tumor cells a growth advantage. This effect is exacerbated by the potential of
      some agents to cause the de novo generation of MMR-resistant variants. Thus, the
      discovery of antitumor agents that retain sensitivity against or specifically
      target MMR-deficient tumor cells, and the development of strategies to overcome
      MMR-related drug resistance assumes clinical importance. Efforts have been taken
      in the past years to come to a better understanding of the molecular mechanisms
      of MMR, including those underlying MMR-related tumorigenesis, those determining
      the substrate-specificity of MMR-dependent damage recognition, and those linking
      damage recognition to cell death responses. This information is also expected to
      contribute to the establishment of diagnostic methods to screen for MMR gene
      mutations in tumors and to the development of strategies which enable the
      oncologists to apply appropriate and specific regimens for tumor treatment.

PMID- 15010847
TI  - The microrevolution: applications and impacts of microarray technology on
      molecular biology and medicine (review).
AB  - Microarray is a technique that provides a global analysis of gene expression at
      the level of transcription. Genetic and epigenetic changes underlie neoplastic
      transformation, cardiovascular disease, some psychiatric illnesses, and a growing
      list of disease pathogeneses and therapeutic responses. The profile of genes
      expressed by different cells (gene up- and downregulation under different
      conditions) determines their phenotype, and thus provides insights into the
      molecular basis for health and disease. Microarray technology combines standard
      molecular techniques with high-throughput screening to monitor the expression of
      up to 38,500 genes. A single experiment can assay gene expression across the
      entire genome under experimental or clinical conditions. Microarray therefore
      extends wide bridges between basic science and clinical medicine. This review
      describes the principles behind transcriptional profiling, experimental designs,
      and data analyses in the context of basic and clinical sciences. In addition, we
      survey the Microrevolutionized field of clinical cancer research by reviewing the
      most recent and innovative microarray studies of breast carcinoma.

PMID- 15010849
TI  - Tissue engineering with chondrocytes and function of the extracellular matrix
      (Review).
AB  - Tissue engineering represents a promising method for the construction of
      autologous chondrogenic grafts for reconstructive surgery. The destruction or
      malformation of organs such as nasal cartilage, pinna and trachea in otorhinology
      head and neck surgery can be caused by both: primary disease or treatment
      modalities. A large part of modern medical practice is aimed to repair, replace,
      maintain or enhance the function of damaged or diseased tissues and organs.
      Replacement or repair is by either artificial implants or transplantation of
      tissues. Such interventions are hindered by factors such as rejection by the
      immune system, limited blood supply or morbidity of the donor site.
      Reconstruction of an injured face using plastic surgery is a prime example of
      when the limitations of materials, science and reconstructive techniques become
      apparent. This review aims to briefly outline the use of chondrocytes for tissue
      engineering with special regard to the function of the extracellular matrix for
      the signalling between the chondrocytes.

PMID- 15010848
TI  - Interleukin-2 activated microglia engulf tumor infiltrating T cells in the
      central nervous system.
AB  - Interleukin-2 (IL-2) has been utilized to treat cancer patient. However, recent
      studies disclosed that IL-2 induces T cell death. To clarify IL-2 induced T cell
      apoptosis at tumor sites in the central nervous system (CNS), we utilized an
      intracranial implantation of IL-2 cDNA transduced murine tumor cells and examined
      freshly recovered tumor infiltrating T lymphocytes (TIL) with a magnetic beads
      separation method. CD8(+) TIL recovered from the IL-2 therapy model had three
      times more apoptosis than a control group, tumor weights at day 12 decreased
      (0.016 versus 0.041 g/mouse) and the number of TIL per gram of tumor tissue
      increase more than six times by IL-2 therapy (5.69x10(6) versus 33.7x10(7) cells
      per mouse). In addition, both activation marker expressions (CD25 and CD69) and
      cytokine message levels (interferon gamma, and tumor necrosis factor alpha) on
      CD8(+) TIL decrease in the IL-2 therapy model. Moreover, we detected higher
      CD8beta message levels in purified tumors associated with F4/80(+) cells from the
      IL-2 model than the control by a one-step RT-PCR method. Finally, we observed
      many CD8beta(+) TIL surrounded by numerous infiltrating F4/80(+) cells in the
      tumor tissues of the IL-2 therapy model by immuno-fluorescence microscopic
      analysis. Our data show that IL-2 sensitization of apoptosis induction for CD8(+)
      TIL occurred and the apoptotic T cells were eliminated by F4/80(+) microglia in
      the CNS. Moreover, this is the first report describing in situ elimination of TIL
      by F4/80(+) phagocytic cells in the CNS.

PMID- 15010850
TI  - Deletion of the kinase domain in death-associated protein kinase attenuates renal
      tubular cell apoptosis in chronic obstructive uropathy.
AB  - Death-associated protein kinase (DAPK) is a Ca2+/calmodulin-dependent
      serine/threonine kinase that has been implicated as a positive mediator of
      apoptosis. However, little is known about the involvement of DAPK in the
      apoptosis associated with several pathological states, except for cancer. Here,
      DAPK-mutant mice were used in order to examine the role of DAPK in renal cell
      apoptosis in chronic obstructive uropathy (COU) created by unilateral ureteral
      ligation. These mice express mutant DAPK with a deletion of 74 amino acids from
      the catalytic kinase domain. Obstructed kidneys in wild-type and mutant mice were
      examined for both DAPK protein levels and renal cell apoptosis during the course
      of COU. Obstructed kidneys in wild-type and mutant mice showed a marked increase
      in the DAPK and mutant DAPK protein levels, respectively, at day 14 after
      ureteric ligation. The obstructed kidneys in DAPK-mutant mice displayed a
      significant attenuation of tubular cell apoptosis, compared with wild-type mice.
      In contrast, no significant difference in interstitial cell apoptosis was
      observed between the obstructed kidneys from wild-type and mutant mice. Thus,
      these results indicate that the part of the kinase domain deleted by the gene
      targeting is crucial for the execution of tubular cell apoptosis, but is not
      essential for interstitial cell apoptosis in a COU model in mice.

PMID- 15010851
TI  - The peptide nucleic acids, efficient tools for molecular diagnosis (Review).
AB  - Peptide nucleic acids (PNAs) are synthetic analogs of DNA that hybridize with
      complementary DNAs or RNAs with high affinity and specificity, essentially
      because of an uncharged and flexible polyamide backbone. Originally conceived as
      ligand for the recognition of double stranded DNA, the unique physico-chemical
      properties of PNAs have led to the development of a variety of research and
      diagnostic assays. Initially used as antisense and antigene reagents, the more
      recent applications of PNA have involved their use as molecular hybridization
      probes. Thus, sensitive and robust PNA-dependent methods have been designed for
      developing anti-cancer drugs, modulating PCR reactions, detecting genomic
      mutation or labelling chromosomes in situ.

PMID- 15010852
TI  - Efficient and faithful in vitro translation of natural and synthetic mRNA with
      human ribosomes.
AB  - Efficient systems for in vitro translation are of importance for biochemical and
      gene expression studies as well as for biotechnological developments. We
      optimized a cell-free translation system using subcellular fractions from human
      placenta and high quality placental tRNAs isolated using a simple and fast
      procedure. The postmitochondrial fraction or a reconstituted system containing
      soluble proteins plus polysomes were able to efficiently translate endogenous and
      exogenous mRNAs. Optima for ions, enzymes, tRNA and energy mix components were
      determined for a poly(U)-directed poly(Phe) synthesis test. The use of homologous
      tRNAPhe, omission of commercial creatine kinase, and addition of 3.5 mM
      spermidine at near physiological magnesium concentration (2.5 mM), were the most
      significant improvements. Under optimal conditions, poly(Phe) synthesis proceeded
      at a maximal initial rate of 1.2 Phe/80S/min at 37 degrees C, while natural mRNA
      translation by S-30 started at a near in vivo estimated rate of 0.3-0.5 amino
      acid/80S/sec. Furthermore, natural mRNA directed the synthesis of a family of
      polypeptides closely resembling the pattern of cytoplasmic proteins in both,
      molecular weight and relative amounts. This efficient and faithful system is of
      interest for biochemical studies of the human translational machinery, as well as
      a basis for screening new drugs affecting protein synthesis in pathogenic
      microorganisms.

PMID- 15010853
TI  - Arginine and Leucine regulate p70 S6 kinase and 4E-BP1 in intestinal epithelial
      cells.
AB  - Amino acids, especially branched-chain amino acids such as l-Leucine, have been
      revealed to regulate activation of p70 S6 kinase and phosphorylation of 4E-BP1
      through mTOR signaling pathway. In this study, we showed that a cationic amino
      acid, l-Arginine, also activated this signaling pathway in a rapamycin-sensitive
      manner in rat intestinal epithelial cells, and this l-Arginine-induced amino acid
      signal transduction involved the cationic amino acid transport system. The manner
      of l-Arginine- and l-Leucine-induced activation of p70 S6 kinase depended on the
      stimulation time and the concentration of each amino acid, which suggested that
      the mechanism of this amino acid signal acceptance might be saturable. l-Arginine
      and l-Leucine induced activation of p70 S6 kinase and phosphorylation of 4E-BP1
      in a rapamycin-sensitive manner, which suggested the involvement of mTOR
      signaling pathway in these effects. l-Arginine-induced activation of p70 S6
      kinase was inhibited by NG-Methyl-L-Arginine (NMMA) and L-N5-(1-Iminoethyl)
      Ornithine (NIO), inhibitors of nitric oxide synthase (NOS) which also block
      cationic amino acid transporters, system y(+). However, l-Leucine-induced
      activation of p70 S6 kinase was not affected with treatment of NOS inhibitors. In
      conclusion, l-Arginine regulates p70 S6 kinase activity and phosphorylation of 4E
      BP1 through mTOR signaling pathway, which involves system y(+), cationic amino
      acid transporters.

PMID- 15010854
TI  - A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer
      cells.
AB  - TAS-102 is a new oral anti-tumor drug preparation, composed of a 1:0.5 mixture
      (on a molar basis) of alpha,alpha,alpha-tri-fluorothymidine (FTD) and thymidine
      phosphorylase inhibitor (TPI). TAS-102 is currently undergoing clinical trials,
      and has been demonstrated to have at least 2 mechanisms; inhibition of
      thymidylate synthase (TS) and incorporation into DNA. 5-FU is widely used in the
      treatment of solid tumor, but the inherent or acquired resistance of certain
      tumors to 5-FU therapy is a major clinical problem. In the present study, we
      investigated FTD in vitro and in vivo comparing with 5-FU and using FU-resistant
      cells. There was no relationship between FTD and 5-FU growth inhibition effect in
      vitro. A different sensitivity pattern was observed by the log-mean graph. We
      next investigated the anti-tumor activity of TAS-102 in a FU-resistant xenograft
      model. Comparative efficacy was observed between FU-resistant cell and its parent
      cell. We also studied the influence of TAS-102 on liver metastasis in a mouse
      model of human colorectal cancer, because liver metastasis of colorectal cancer
      is associated with patient survival. Human cancer DNA was detected by PCR, and
      TAS-102 markedly inhibited the number of liver metastasis. A novel angiogenic
      factor, platelet-derived endothelial cell growth factor (PD-ECGF), was shown to
      be identical to a previously characterized intracellular enzyme, thymidine
      phosphorylase, TAS-102 can be expected to have not only anti-tumor cytocidal
      effects but also antiangiogenesis activity and may inhibit liver metastasis. Our
      findings suggested that TAS-102 is a promising candidate for clinical use and can
      be expected to decrease minimal residual disease.

PMID- 15010855
TI  - Up-regulation of the adrenomedullin system mediates hypotension and
      hypoaldosteronism induced by simulated microgravity.
AB  - We recently demonstrated that prolonged simulated microgravity (SMG) induced
      hypotension and hypoaldosteronism in rats, and gathered preliminary evidence for
      an involvement of circulating adrenomedullin (AM). Thus, we aimed to investigate
      whether short-term SMG elicits the same effects, and whether up-regulation of
      adrenal AM system plays a relevant role. Rats were exposed for 8 days to SMG in
      the form of hindlimb unweighting, and then, along with control animals, were
      given an intraperitoneal injection of AM22-52 and/or angiotensin-II (Ang-II) (100
      nmoles/kg) or the saline vehicle. Systolic blood pressure (SBP) was measured by
      tail-cuff sphygmomanometry. The adrenal expression of AM was assayed by
      semiquantitative RT-PCR. The plasma concentrations of aldosterone (PAC) and AM,
      and adrenal AM content were measured by RIA. Short-term SMG induced significant
      decreases in SBP and PAC. Conversely, both the plasma and adrenal levels of AM,
      and adrenal AM mRNA were enhanced in SMG-exposed animals. The SMG-induced
      hypotension and hypoaldosteronism were reversed by AM22-52, an AM-receptor
      antagonist, thereby demonstrating a causal link between these effects and the up
      regulation of AM system. SMG hampered SBP and PAC responses to Ang-II; the co
      administration of AM22-52 restored these responses. These findings accord well
      with the known ability of AM to counteract the effects of Ang-II on both blood
      vessels and adrenocortical cells. Taken together, our findings allow us to
      conclude that up-regulation of the adrenal AM system i) occurs early and takes
      part in the adaptative changes occurring during SMG conditions; and ii) may
      account for both hypotension and hypoaldosteronism on returning to the
      normogravitational environment.

PMID- 15010856
TI  - Lipidic inhibitors of human N-myristoyltransferase.
AB  - This study was undertaken in order to identify compounds which inhibit the
      activity of human myristoyl-CoA:protein N-myristoyltransferase (hNMT). In
      particular, the structural features of such molecules which contribute to enzyme
      inhibition were investigated. Two groups of compounds, namely myristic acid and
      analogs 1-13 and derivatives of myristoyl-CoA 14-19 were evaluated. All compounds
      were examined using cAMP-dependent protein kinase derived peptide substrate. The
      IC(50) values were <1 micro M, between 1 and 100 micro M or >100 micro M in
      eight, four and seven compounds, respectively. Of the six myristoyl-CoA analogs,
      five had IC(50) values in the 0.06-0.59 micro M range. These molecules were
      examined using three additional substrates viz pp60src, MARCKS and M2 gene
      segment of reovirus type 3 which led to results similar to those obtained with
      the cAMP-dependent protein kinase substrate. On the other hand, evaluation of
      myristic acid and four related compounds revealed some differences in hNMT
      inhibiting properties among the substrates. From the results obtained, the
      possible manner whereby potent inhibitors interact with the enzyme was formulated
      thus enabling the design of further analogs as candidate inhibitors of hNMT.

PMID- 15010858
TI  - Cloning of the Cav 1.3 (alpha1D) L-type Ca2+ channel from mouse and its
      expression in the liver.
AB  - Dihydropyridine (DHP) type Ca2+ channel blocker (CCB) is effective in treatment
      of hepatitis in man. L-type Ca2+ channel is a target of DHP-CCB, and basic
      studies suggest that L-type Ca2+ channel alpha1D-subunit (Cav 1.3) seems to be a
      target of drug development for the treatment of hepatitis. Mouse hepatitis model
      is useful to study the effect of DHP-CCB on hepatitis. In order to use mouse
      hepatitis model to screen DHP-CCB specific for Cav 1.3, Cav 1.3 expressed in the
      mouse liver should have enough structural homology with that of human Cav 1.3.
      cDNA of the Cav 1.3 was cloned from mouse brain by reverse transcription
      polymerase chain reaction. The primary structure of the mouse Cav 1.3 comprises
      an open reading frame of 6540 bp encoding 2180 amino acids. Liver transcript
      lacked 60 and 45 bases from 1497 to 1556, and from 3949 to 3993 of the sequence,
      respectively, due to results of an alternative splicing. The present results
      indicated that mouse Cav 1.3 exhibited 96% homology with human Cav 1.3 and was
      expressed in the liver. Thus, mouse hepatitis model seemed to be useful to screen
      DHP-CCB specific for Cav 1.3.

PMID- 15010857
TI  - Staurosporine-induced apoptosis in Chang liver cells is associated with down
      regulation of Bcl-2 and Bcl-XL.
AB  - A potent inhibitor of serine/threonine kinases, staurosporine exerts
      antiproliferative and apoptotic effects in many cancer cells, although the exact
      mechanism of its action is still unclear. This study examines the effects of
      staurosporine on Chang liver cells, an immortalized non-tumor cell line, in
      comparison with those caused in HuH-6 and HepG2 cells, two human hepatoma cell
      lines. Our results provide evidence that staurosporine promotes apoptosis in
      Chang liver cells as observed by flow cytometric analysis and acridine
      orange/ethidium bromide staining. The effect appeared already after 8 h of
      treatment and increased with treatment time and dose. After 48 h of exposure to
      200 nM staurosporine clear apoptotic signs were observed in about 50% of the
      cells. Western blotting analysis showed that in Chang liver cells staurosporine
      induced a marked decrease in the levels of the antiapoptotic factors Bcl-2 (-75%)
      and Bcl-XL (-50%). Staurosporine also caused loss of mitochondrial transmembrane
      potential, release of cytochrome c from mitochondria and activation of caspase-3.
      The involvement of caspases in staurosporine-induced cell death was also
      suggested by the observation that the addition of z-VAD-fmk, a general inhibitor
      of caspases, suppressed apoptosis. In HuH-6 and HepG2 cells treatment with
      staurosporine induced the arrest of cells in G2/M phase of cell cycle. This
      effect was not modified by z-VAD-fmk and was not accompanied by the appearance of
      biochemical signs of apoptosis. We conclude that staurosporine induced apoptosis
      in Chang liver cells by a mitochondria-caspase-dependent pathway which was
      closely correlated with a decrease in Bcl-2 and Bcl-XL levels, while in HuH-6 and
      HepG2 hepatoma cells the drug caused only an antiproliferative effect.

PMID- 15010859
TI  - Clostridium butyricum, a probiotic derivative, suppresses dextran sulfate sodium
      induced experimental colitis in rats.
AB  - Recent studies have suggested that probiotics or short chain fatty acids (SCFAs)
      exert a therapeutic effect on inflammatory bowel disease (IBD) patients. In a
      previous study, we demonstrated that Clostridium butyricum produces high levels
      of SCFAs in culture. In addition, a yogurt-based additive effectively masked,
      completely eliminating the unpleasant odor derived from the SCFAs. We recently
      reported that the oral administration of both high and low dose diets (50% w/w
      for 17 days and 5% w/w for 16 months, respectively) of the Clostridium butyricum
      derivative did not cause pathological abnormalities in rats. In the present
      study, we evaluated the effects of this product against dextran sulfate sodium
      (DSS)-induced experimental colitis in rats. Five-week-old male Wistar Hannover
      GALAS rats were given a mixture of a standard diet containing 3% (w/w) of DSS for
      8 days. In the derivative-fed group, Clostridium butyricum derivative (20% w/w)
      with 0.1% (w/w) additive was also added to their diet. The control-fed group was
      given tap water (20% w/w) with 0.1% (w/w) additive. After 8 days, a laparotomy
      was performed, and macroscopic and microscopic inflammation scoring was
      determined. The Clostridium butyricum derivative effectively prevented bloody
      diarrhea. In addition, mucosal damage to the derivative-fed group was
      significantly reduced macroscopically compared to that of the control-fed group.
      The potential clinical efficacy of the Clostridium butyricum derivative in IBD
      patients is also discussed.

PMID- 15010860
TI  - Delayed angiogenesis in aging rats and therapeutic effect of adenoviral gene
      transfer of VEGF.
AB  - We have studied an age-related impairment in angiogenesis and evaluated the
      effect of overexpressing VEGF in this situation. Polyvinyl alcohol sponges were
      implanted subcutaneously into aged (24-month), adult (12-month), and young (2
      month) rats. Blood vessel ingrowth and proliferative activity in the sponges were
      assessed by histology with immunostaining for von Willebrand's factor and
      proliferating cell nuclear antigen (PCNA), respectively. The percentage of total
      sponge area filled with ingrowing fibrovascular tissue was minimal in aged rats,
      intermediate in adult rats and highest in young rats. A similar pattern was
      observed for the total blood vessel numbers in the sponges from old to young
      animals. The percentage of total sponge endothelial cells (ECs) showing
      proliferative activity (PCNA positive) was lowest in the aged animals,
      intermediate in the adult rats and highest in the young rats. To further explore
      the mechanism of impaired angiogenesis in aged animals, we investigated and found
      a reduced level of endogenous VEGF protein expression in 12-month-old rats
      compared to that in 2-month-old rats. VEGF121 gene transfer significantly
      enhanced blood vessel and fibrovascular tissue ingrowth in adult/aged rats.
      Adenoviral-VEGF gene transfer also significantly stimulated EC proliferation in
      aged and adult rats. However, identical treatment failed to further stimulate the
      already more robust angiogenesis in young animals. The different angiogenic
      response in adult vs. young rats was not due to differences in gene transfer
      efficiency, since similar levels of human VEGF121 protein was detected in adult
      and young rats. Our results indicate that the decreased angiogenic response with
      aging is associated with reduced EC proliferation and reduced endogenous VEGF
      production. Adenoviral-VEGF121 gene transfer is effective in augmenting
      angiogenesis, particularly in older animals.

PMID- 15010861
TI  - Human papillomavirus DNA status after loop excision for cervical intraepithelial
      neoplasia grade III - A prospective study.
AB  - The aims of the study were to investigate the relationship between human
      papillomavirus (HPV) DNA status and recurrence of cervical intraepithelial
      neoplasia (CIN) after loop excision (LEEP/LLETZ). Women (n=161) who underwent
      loop excision for CIN III and who were followed up prospectively for at least 4
      years were the study cohort. Cervical smear cytology and testing for HPV DNA was
      performed at 3, 6 and 12 months prospectively and thereafter at intervals of 6-12
      months, using the PCR method with a consensus primer targeting the L1 region.
      There has been no recurrence in 141 (81.6%) out of 161 subjects, while squamous
      intra-epithelial lesions (SIL) of low or high grade on cytology and CIN grade I
      III on histology have been detected in 20 subjects. Prior to loop excision, HPV
      DNA was detected in 17 subjects who developed recurrence (9 had type 16, 2 each
      had types 18 and 52, and 1 each had types 31, 51, 58, and unknown). Within 3
      months postoperatively, 12 (70.7%) subjects became negative for HPV, but 2
      remained positive for the same type (1 each had types 16, 18), along with high
      grade SIL on cytology, and CIN III on histology within 6 months, so repeat loop
      excision was performed. On the other hand, cytological findings were normalized
      in all transiently infected subjects within 18-36 months. Our results suggest
      that loop excision has improved HPV infection in many cases of CIN III and the
      persistent infection with a high-risk type of HPV is a predictor of the
      recurrence of CIN grade III.

PMID- 15010862
TI  - Normal p21Ras/MAP kinase pathway expression and function in PBMC from patients
      with polycystic ovary disease.
AB  - Polycystic ovary disease (PCOD) is associated with insulin resistance and
      increased prevalence of type II diabetes mellitus (T2DM). The p21Ras/MAP kinase
      is a major intracellular signaling pathway mediating insulin signaling in insulin
      responsive tissues. The expression, regulation and function of the p21Ras/MAP
      kinase pathway in PCOD patients were examined. Peripheral blood mononuclear cells
      (PBMC) were isolated from ten patients with PCOD and ten controls. The expression
      of p21Ras and its regulatory proteins; hSOS1 and p120GAP were studied. The basal
      and phytohemaglutinin (PHA) or insulin stimulated phosphorylation of MAP kinase
      was determined. Expression of p21Ras, and its regulatory proteins hSOS1 and
      p120GAP were similar in PCOD patients and controls. Basal, PHA and insulin
      stimulated phosphorylation of MAP kinase, were also comparable in the two groups
      as well as their PBMC proliferative response. These data indicate that the
      expression and overall function of the p21Ras/MAP kinase pathway remain intact in
      non-diabetic patients with PCOD.

PMID- 15010863
TI  - IL2-dependent phosphorylation of 40S ribosomal protein S6 is controlled by PI
      3K/mTOR signalling in CTLL2 cells.
AB  - Growth factors and hormones activate global and selective protein translation by
      phosphorylation and therefore activation of p70 S6 kinase through a wortmannin
      sensitive phosphoinositide-3 kinase (PI-3K) antiapoptotic pathway and a rapamycin
      sensitive signalling pathway of mTOR. Here we demonstrate that the
      phosphorylation of 40S ribosomal protein S6, a physiological substrate p70 S6
      kinase, was highly increased by growth-stimulation of the cytolytic T cells
      (CTLL2) with interleukin 2 (IL2), which was accompanied with the increased
      phosphorylation of p70 S6K. The activity of p70 S6K and phosphorylation of the S6
      protein was completely blocked by rapamycin and significantly decreased upon
      treatment of the cells with wortmannin, indicating an involvement of the PI-3K
      pathway in concert with the signalling pathway of mTOR in IL2-dependent phos
      phorylation of ribosomal protein S6. The phosphorylation and activity of PKB/Akt
      in IL2-stimulated CTLL2 cells were rapamycin-insensitive and reduced upon
      wortmannin treatment of the cells, confirming a requirement for PI-3K for Akt
      activity. The data support the hypothesis that Akt may act downstream to PI-3K
      and upstream to mTOR in an IL2-mediated signal transduction pathway that controls
      phosphorylation of the regulatory protein S6 in CTLL2 cells.

PMID- 15010864
TI  - Identification and characterization of PDZRN3 and PDZRN4 genes in silico.
AB  - NUMB and NUMBL are implicated in cell fate determination through the inhibition
      of Notch signaling. LNX, binding to NUMB and CXADR (CAR), functions as E3
      ubiquitin ligase at least for NUMB. LNX is the paralog of PDZRN1 (PDZ domain
      containing RING finger 1). Here, we identified two novel homologs of LNX and
      PDZRN1 by using bioinformatics, which were designated PDZRN3 (LNX3 or SEMCAP3)
      and PDZRN4 (LNX4 or SAMCAP3L), respectively. KIAA1095 cDNA (AB029018) was the
      representative PDZRN3 cDNA. Complete coding sequence of PDZRN4 cDNA was
      determined by assembling nucleotide sequences of ESTs (BF059062 and AW297403),
      FLJ33777 cDNA (AK091096) and IMAGE5767589 cDNA (BC040922). PDZRN4 gene,
      consisting of 11 exons, was found to encode two isoforms with N-terminal
      divergence (PDZRN4 and PDZRN4S) due to an alternative promoter. PDZRN3-CNTN3
      locus at human chromosome 3p13-p12.3 and PDZRN4-CNTN1 locus at human chromosome
      12q12 were paralogous regions within the human genome. PDZRN3 (1066 aa) and
      PDZRN4 (1036 aa) showed 59.9% total-amino-acid identity. Two bipartite nuclear
      localization signals (NLS) were located within the C-terminal region of PDZRN3
      and PDZRN4. PR34H1 and PR34H2 domains were identified as the regions conserved
      among PDZRN3, PDZRN4 and Drosophila CG1783. PDZRN3 and PDZRN4 consist of RING,
      two PDZ, PR34H1, PR34H2 domains and two NLS, while PDZRN1 and LNX consist of RING
      and four PDZ domains. PDZRN family proteins were classified into the LNX-PDZRN1
      subfamily and the PDZRN3-PDZRN4 subfamily. This is the first report on the PDZRN3
      and PDZRN4 genes.

PMID- 15010865
TI  - Identification and characterization of human FHOD3 gene in silico.
AB  - Formin homology proteins are actin regulators with scaffold function, which are
      implicated in organogenesis, normal tissue homeostasis, and cancer-cell invasion.
      FHOD1/FHOS, GRID2IP, Fmn1 and Fmn2 are non-FDD-type Formin homology proteins,
      while FMNL1, FMNL2/FHOD2, FMNL3, DAAM1, DAAM2, DIAPH1, DIAPH2 and DIAPH3 are FDD
      type Formin homology proteins. Here, we identified and characterized FHOD3 (also
      known as FHOS2), a novel gene homologous to FHOD1, by using bioinformatics.
      Because FLJ46173, FLJ22297, KIAA1695 and FLJ34580 were partial FHOD3 cDNAs,
      complete coding sequence of FHOD3 cDNA was determined by assembling nucleotide
      sequences of FLJ46173 and FLJ22297. FHOD3 gene at human chromosome 18q12.2 was
      found consisting of at least 25 exons. Exon 11 of FHOD3 gene was spliced out in
      KIAA1695 cDNA and BF116064 EST, while exon 13 of FHOD3 gene was spliced out in
      FLJ46173 cDNA. FHOD3 gene encodes at least three isoforms due to alternative
      splicing of the exon skipping type. FHOD3 and FHOD1 showed 52.1% total-amino-acid
      identity. Drosophila CG32030 showed 43.9% total-amino-acid identity with human
      FHOD3, and 39.1% total-amino-acid identity with human FHOD1. FHDHN domain (codon
      1-327 of FHOD3) and FHDHC domain (codon 1377-1421 of FHOD3) were identified as
      the N-terminal conserved region and the juxta C-terminal conserved region,
      respectively. Human FHOD3, FHOD1 and Drosophila CG32030 were found to share the
      conserved domain structure consisting of FHDHN, FH1, FH2, and FHDHC domains. This
      is the first report on the FHOD3 gene as well as on the novel FHDHN and FHDHC
      domains.

PMID- 15010866
TI  - Hierarchy of carcinoma cell responses to apigenin: gap junctional coupling versus
      proliferation.
AB  - We discriminated the role of gap junctional communication and phenotypic
      constitution of tumour cells in determining their responsiveness to apigenin.
      Effects of apigenin on intercellular communication and proliferation of two lines
      of carcinoma cells, uncoupled HeLa cells and their coupled Cx43-transfected
      counterparts, were analysed and compared with the responses of highly coupled
      BICR/M1Rk cells. Dye transfer analyses demonstrated that apigenin decreases the
      degree of coupling in Cx43-coupled populations of HeLa cells but does not affect
      BICR/M1Rk cells. Similarly, no communication enhancement was observed in
      originally uncoupled HeLa cell populations. A G2-specific growth arrest
      paralleled by the induction of apoptosis was observed which was more pronounced
      and correlated with higher number of apoptotic events in coupled HeLa Cx43
      transfectants than in parental cell line. On the other hand, apoptosis was not
      observed in highly coupled BICR/M1Rk cells, instead, these cells were only
      transiently blocked in G2 which might be a result of their ability to metabolise
      apigenin. These data demonstrate a hierarchy of systems determining cellular
      sensitivity to apigenin. Gap junctional coupling does not influence the quality
      of cell cycle-related responses to apigenin but modulates their magnitude. This
      modulating effect of gap junctional coupling depends, however, on a cellular
      context determined by specific cell phenotype and can be overcome by tissue
      specific compensatory mechanisms.

PMID- 15010867
TI  - Fluorescence in situ hybridization detects frequent chromosome 9 deletions and
      aneuploidy in histologically normal urothelium of bladder cancer patients.
AB  - Investigation of early urothelial lesions is essential to gain insight into the
      development of bladder cancer. In order to evaluate if deletions of chromosome
      arms 9p and 9q are preceding histomorphological changes in the urothelium,
      histologically normal urothelial samples of patients with previous and/or
      simultaneous (pre)malignant urothelial lesions were investigated. Dual colour
      fluorescence in situ hybridization (FISH) was performed on 96 histologically
      inconspicuous urothelial biopsies from 41 patients. Centromeric probes for
      chromosomes 9 and 17 were combined with gene locus specific probes for 9p21
      (p16/CDKI2), 9q22 (FACC) and 17p (p53). Deletions of chromosome 9 (defined as
      presence of only one copy of centromere 9 or fewer gene-specific than centromeric
      signals in at least 40% of evaluated cells) were found in 21% of the samples
      (18/87). Deletions of chromosome 9p were present in 16% of cases (14/89), whereas
      deletions of chromosome 9q were encountered in 10% of specimens (9/93). A
      hemizygous deletion of p53 was found only once. Polysomy in more than 10% of
      cells was encountered in 16% of cases for both chromosome 9 and chromosome 17.
      Non-diploidy (defined as polysomy of both chromosomes) was found in 6% of samples
      (5/80). In summary, chromosome 9 deletions are frequently found in histologically
      normal urothelium of patients with bladder cancer, although less frequently than
      in hyperplasias and dysplasias. These findings support the hypothesis of multi
      focal development of bladder cancer from histologically inconspicuous but already
      genetically altered urothelium. FISH analysis of chromosome 9 regions could
      provide a useful tool to detect potentially premalignant lesions in the follow-up
      care of patients with bladder cancer.

PMID- 15010868
TI  - Expression of ERalpha, ERbeta and Ki-67 in primary tumors and lymph node
      metastases in breast cancer.
AB  - The success of current hormonal therapies used in breast cancer patients often
      depends on estrogen receptor (ER) status. The simultaneous pathological
      assessment of primary breast tumors (PTs) and metastases to regional lymph nodes
      (MRLNs) could improve the effectiveness of this treatment, but is rarely
      performed. Consequently, we studied by immunohistochemistry the expression of
      ERalpha (ERalpha), ERbeta (ERbeta), and the proliferation marker (Ki-67) in PTs
      and matching MRLNs. The expression of each ERalpha, ERbeta, and Ki-67 positively
      correlated between PTs and MRLNs (r=0.751, p<0.0001; r=0.391, p<0.03; and
      r=0.707, p<0.0001, respectively). A negative correlation between the expression
      of ERalpha and Ki-67 was found in PTs (r=-0.678, p<0.001) and MRLNs (r=-0.501,
      p<0.005). A negative correlation between ERalpha and Ki-67 was also observed in
      PTs vs. MRLNs (r=-0.619, p<0.0001). Moreover, the expression of ERalpha and Ki-67
      was not associated with nodal status, contrary to ERbeta expression, which
      correlated with negative axillary node status. The results indicated that the
      associations among ERalpha, ERbeta, and Ki-67 are maintained in PTs and MRLNs.
      Thus, simultaneous assessment of selected markers in PT and MRLN might help in
      understanding the mechanisms of breast cancer progression as well as result in
      the development of new principles for diagnosis and individual therapy planning
      of estrogen dependent cancer.

PMID- 15010869
TI  - Primary amyloidosis of the breast associated with invasive breast cancer.
AB  - Amyloidosis is usually a systemic disorder. A localised form can involve the
      breast and may mimic breast cancer. We report a case of primary amyloid deposit
      confirmed by immunohistochemistry, occurring in a patient with early breast
      cancer and review other cases of breast involvement with various types of
      amyloid.

PMID- 15010870
TI  - Fluorescence and ultrastructural localization of actin distribution patterns in
      the nucleus of HL-60 and K-562 cell lines treated with cytostatic drugs.
AB  - Actin has been studied extensively for decades, but so far its well-defined role
      has been found localized to the cytoplasm. The present study characterizes the
      distribution pattern of actin in the nucleus of HL-60 and K-562 cell lines
      treated with etoposide and doxorubicin. F-actin labeled with TRITC-phalloidin was
      found in the nucleus in both cell lines independently of the cytostatic drugs
      used. Using confocal microscopy F-actin is seen in the center of the nucleus
      showed labeling of the nucleoli by phalloidin. There are also distinct tracts of
      F-actin seen from nucleoli to the nuclear envelope in some sections. HL-60 cells
      treated with 200 micro M etoposide and 5, 10 micro M doxorubicin showed cells
      with characteristic features of apoptosis at the ultrastructural level. Intense
      immunogold labeling for actin was seen in nucleus of HL-60 cells with compaction
      and margination of chromatin. In K-562 cells more intense labeling was often
      found in the cytoplasm of the cells. Positive labeling for actin was not found
      after control incubations. F-actin is present in the nucleus and there is
      labeling of nucleoli by phalloidin. The observation at the ultrastructural level
      suggests that actin can be involved in chromatin reorganization during the
      process of apoptosis. Increase of labeling at the ultrastructural level in the
      nucleus of HL-60 cells in relation with compaction and margination of nuclear
      chromatin might also suggest translocation of actin from cytoplasm to the nucleus
      in connection with chromatin reorganization.

PMID- 15010871
TI  - In vitro and in vivo induction of human LoVo cells into apoptotic process by non
      invasive microwave treatment: a potentially novel approach for physical therapy
      of human colorectal cancer.
AB  - The human LoVo and WI-38 cells were exposed to high power non-invasive
      microwaves. The apoptotic effect of the microwaves on the cells was examined with
      TUNEL, DNA fragmentation and flow cytometry. The human colon cancer LoVo cells
      showed pathological change of apoptosis but the normal human WI-38 cells showed
      no detectable apoptotic response. Exposure of the mice bearing tumor tissue to
      microwave resulted in a significant regression of the tumor tissue in the animal
      models. We demonstrate that the LoVo cells can be induced into apoptosis by
      microwave treatment both in in vitro and in vivo. The data described in this
      communication implies the possibility that microwave therapy may become a novel
      approach in human colorectal cancer treatment.

PMID- 15010872
TI  - CFR-1 receptor as target for tumor-specific apoptosis induced by the natural
      human monoclonal antibody PAM-1.
AB  - The human monoclonal antibody PAM-1 was isolated from a patient with stomach
      cancer. The germ-line coded IgM antibody identifies a recently described 130 kDa
      variant of CFR-1 (cysteine-rich fibroblast growth factor receptor 1). This CFR
      1/PAM-1 receptor is post-transcriptionally modified and over-expressed on human
      epithelial tumors and carcinoma pre-cancer lesions such as H. pylori induced
      gastritis, intestinal metaplasia and dysplasia of the stomach, ulcerative colitis
      related dysplasia and adenomas of the colon, Barrett metaplasia and dysplasia of
      the esophagus, squamous cell metaplasia and dysplasia of the lung and cervical
      intraepithelial neoplasia. Furthermore, the expression of CFR-1/PAM-1 correlates
      with the proliferation rate and increases with the grade of malignancy. This
      study demonstrates that the human monoclonal antibody PAM-1 inhibits cell growth
      and induces apoptosis, in vitro and in vivo. Both, the unique tumor-specific
      expression of the CFR-1/PAM-1 receptor and the growth inhibitory effect of the
      PAM-1 antibody makes this combination a good diagnostic and therapeutic tool for
      all kinds of epithelial cancers and precursor lesions.

PMID- 15010873
TI  - Analysis of cellular localization of SART3 tumor antigen by a newly established
      monoclonal antibody: heterotopic expression of SART3 on the surface of B-lineage
      leukemic cells.
AB  - SART3 has been identified as a tumor antigen recognized by cytotoxic T
      lymphocytes. Subcellular localization of SART3 is still controversial, although
      it has been studied extensively. In this study, we established an anti-SART3
      monoclonal antibody (mAb) to analyze the subcellular localization of SART3 in
      tumor specimens. Immunohistochemical analysis demonstrated that SART3 was
      preferentially expressed in the nucleus of cancer cells. Flow cytometric analysis
      indicated that SART3 was not expressed on the cell surface of tumor cells, except
      for B-lineage cells. SART3 was detected on the cell surface of several B-lineage
      leukemic cells with different maturation stages, but not on normal peripheral
      blood B cells. These results suggest that heterotopically expressed SART3 is a
      tumor-associated antigen rather than a differentiation antigen on B-lineage
      cells.

PMID- 15010874
TI  - Endothelin-1, Endothelin-A- and Endothelin-B-receptor expression in preinvasive
      and invasive breast disease.
AB  - Endothelin-1 (ET-1) is overexpressed in breast carcinomas and influences via its
      receptors (ETAR and ETBR) transformation, differentiation and growth processes in
      the human breast, but little is known about the ET expression in breast cancer
      precursors. On this basis we evaluated the expression of ET-1, ETAR and ETBR in a
      series of breast carcinomas, ductal (DCIS) and lobular carcinoma in situ (LCIS)
      and normal breast tissue by immunohistochemical (IH) methods. IH staining of ET
      1, ETAR and ETBR was performed in 88 invasive breast carcinomas, with adjacent
      carcinoma in situ and concomitant normal breast tissue. Moderate or strong
      cytoplasmic immunostaining was observed for ET-1 in 33.3%, for ETAR in 45.3% and
      for ETBR in 55.7% of invasive breast carcinomas. Comparative analysis of invasive
      cancer (CA), concomitant carcinoma in situ (CIS) and normal breast epithelium
      (NBE) revealed a stepwise increase of ET-1 and ETAR expression in the sequence
      NBE < CIS < CA. ETBR expression tended to be slightly higher in CIS than in CA
      (NBE versus CIS and NBE versus CA, for ETAR and ETBR, p<0.001, respectively; NBE
      versus CA for ET-1, p=0.035). Our data suggest that the expression of ET-1, ETAR
      and ETBR correlates with the acquisition of malignant potential and may be used
      as a prognostic indicator of aggressive behaviour and invasive potential of
      premalignant breast lesions.

PMID- 15010875
TI  - Expression of Smac/DIABLO is a novel prognostic marker in lung cancer.
AB  - Recently Smac/DIABLO (second mitochondria-derived activator of caspase) has been
      identified as a proapoptotic protein that inhibits IAPs (inhibitors of apoptosis
      proteins). Smac is expressed ubiquitously in many organs, including the lung.
      Here we evaluated the expression of Smac mRNA with real-time reverse
      transcription PCR in 88 primary lung cancers and matched normal tissues. Smac
      mRNA expression in tumor tissues was significantly lower than that in normal
      tissues (p<0.0001). In squamous cell carcinomas, Smac mRNA expression was
      significantly lower than that in adenocarcinomas (p=0.0072). Smac mRNA expression
      in T2-T4 tumors was significantly lower than that in T1 tumors (p=0.0006). The
      expression of Smac in the tumors of smokers was lower than that in the tumors of
      non-smokers (p=0.0011). The prognosis of patients with a tumor exhibiting a low
      expression of Smac mRNA was worse than that in those with a tumor exhibiting high
      Smac mRNA expression (log-rank test, p=0.047). These results indicate that Smac
      expression may play a role in the carcinogenesis, progression, and prognosis of
      primary lung cancer.

PMID- 15010876
TI  - Influence of the site of human gallbladder xenograft (Mz-ChA-1) on angiogenesis
      at the distant site.
AB  - We reported that orthotopic xenograft of human gallbladder cancer (Mz-ChA-2)
      produced a greater amount of endogenous angiogenic inhibitory factors, however,
      only TGFbeta1 suppressed angiogenesis and tumor growth at the distant site
      (intracranium). The aim of this study was to confirm the validity of our previous
      findings that the site of the primary tumor would influence the angiogenesis in
      the distant site in a different xenograft of human gallbladder cancer (Mz-ChA-1).
      The growth rates, histology of the ectopic (flank) and orthotopic (gallbladder)
      xenografts, the plasma level of TGFbeta1, micro-circulation and angiogenesis in
      the distant site (intracranium) were estimated by size-measurement, hematoxylin
      and eosin staining, ELISA, intravital fluorescence microscopic observation and
      cranial window gel assay for angiogenesis. All experiments were performed in
      severe combined immunodeficient (SCID) mice. Orthotopic tumors grew faster and
      were less necrotic than ectopic tumors. Angiogenesis, vessel diameters, vessel
      density and leukocyte-rolling count in the distant site were significantly
      decreased in orthotopic tumor-bearing mice compared to those in either ectopic or
      no tumor-bearing mice. The plasma level of TGFbeta1 was significantly elevated in
      mice bearing orthotopic tumor as compared with ectopic and no tumor-bearing mice.
      Angiogenesis at the distant site was inhibited by the orthotopic xenograft of Mz
      ChA-1 by the greatest amount of TGFbeta1 production. The results of the present
      study together with our previous study imply that the primary tumor
      microenvironment is conducive to the angiogenesis at a distant site by the
      production of the endogenous angiogenesis inhibitor TGFbeta1.

PMID- 15010877
TI  - Angiogenesis of AFP producing gastric carcinoma: correlation with frequent liver
      metastasis and its inhibition by anti-AFP antibody.
AB  - We studied roles of angiogenesis in patients with alpha-fetoprotein (AFP)
      producing gastric carcinoma (APGC), which is well known to have a poor prognosis
      and frequent liver metastases. Immunohistochemical analyses were conducted using
      antibodies against alpha-fetoprotein, factor VIII (endothelial cells) and
      vascular endothelial growth factor (VEGF). Archival specimens of APGC (n=25) and
      non-APGC (n=68) were studied. Expressions of vessel density and VEGF were
      significantly higher in APGC than those in non-APGC (p<0.001). There is a
      correlation among the AFP expression, the vessel density and the VEGF expression
      in APGC (p<0.001). Next, we studied the effects of anti-AFP antibody on APGC
      xenotransplanted in nude mice. There is significant inhibition of tumor growth in
      the treatment groups compared to the control groups in 2 APGC lines (p<0.01).
      There were also significant differences in serum AFP and VEGF levels between
      treatment groups and non-treatment groups in 2 APGC lines, but not in a non-APGC
      line. Moreover, vessel densities of the treatment groups were significantly lower
      than those of the control groups in the two lines. These findings thus suggest
      that the biological behavior of APGC is angiogenesis-dependent. Down-regulation
      of angiogenesis by anti-AFP antibody suggest that AFP itself may up-regulate
      angiogenesis, and the treatment by antibody could have anti-angiogenic effects,
      inhibiting metastasis, especially liver metastasis in APGC.

PMID- 15010878
TI  - Gallbladder cancers rarely overexpress HER-2/neu, demonstrated by Hercep test.
AB  - c-erbB-2, proto-oncogene is amplified and overexpressed in a number of human
      adenocarcinomas. Overexpression of c-erbB-2 is indicated as a worse prognostic
      factor and associated with neoplastic progression in various organs. To
      investigate the therapeutic effect of Trastuzumab in gallbladder cancer, we
      studied HER-2/neu expression in 43 primary tumors, 12 metastatic lymph nodes and
      two liver metastasis, using the Hercep test. Among primary tumors, strong (3+)
      immunohistochemical intensity was found in two cases (4.7%), weak (2+) in two
      (4.7%) and negative (1+) (2.3%) in one case. This positivity rate was distinctly
      lower than those in previous reports. There was no tendency between
      clinicopathologic characteristics and HER-2 positivity in the primary
      gallbladder. Among 12 metastatic lymph nodes, only one specimen showed 2+
      positivity where the primary lesion revealed 3+ intensity of HER-2. In two liver
      metastatic lesions, the expression of HER-2 was not found. Our study implied that
      Trastzumab may not contribute to improvement in treatment of gallbladder cancer.
      However, there may be a therapeutic possibility for cases with lymph node
      recurrence overexpressing c-erbB-2.

PMID- 15010879
TI  - Glycerol enhances CDDP-induced growth inhibition of thyroid anaplastic carcinoma
      tumor carrying mutated p53 gene.
AB  - To increase the chemo-sensitivity of anaplastic thyroid carcinoma, we examined
      the effects of glycerol on the tumor growth after CDDP treatment. The cultured
      cells of an anaplastic thyroid carcinoma cell line (8305c) carrying a mutated p53
      gene (mp53) were transplanted into the thighs of nude mice. Tumor growth was
      evaluated until 24 days after intraperitoneal injection of CDDP and/or pre
      injection of glycerol to the tumor. We treated the mice with half the tumor
      volume of glycerol (1.2 M) and/or CDDP at 6 mg/kg (BW) either of which hardly
      inhibited tumor growth by itself. When we treated the mice with the combination
      of glycerol and CDDP at these concentrations, however, a clear delay of the tumor
      growth was observed. We also immunohistochemically analyzed the effects of
      glycerol on the induction of caspase-3 activity and apoptosis. Cells positive for
      cleavage to active caspase-3 and 85 kDa PARP, and apoptosis were hardly observed
      in the tumors when they were treated with glycerol or CDDP alone. In contrast,
      when they were treated with CDDP combined with glycerol, such positive cells were
      significantly increased. It has been shown that glycerol synergistically enhanced
      the effects of CDDP as a tumor suppressive agent through the induction of caspase
      3-mediated apoptosis in 8305c tumors. Therefore, glycerol might be useful for
      chemotherapy in patients with mp53 cancer cells.

PMID- 15010880
TI  - Comparative study of primary mammary small cell carcinoma, carcinoma with
      endocrine features and invasive ductal carcinoma.
AB  - Mammary small cell carcinoma (SmCC) is a very rare neoplasm with a poor prognosis
      compared with other invasive carcinomas. We studied the histological and
      immunohistochemical profiles of two cases of mammary SmCC, and compared them with
      those of five cases of carcinoma with endocrine features (CEF) and five cases of
      invasive ductal carcinoma (IDC), to elucidate the correct diagnosis of mammary
      SmCC. Immunohistochemical analysis was performed with antibodies against
      cytokeratins (CKAE1/AE3, CK34betaE12, CKCAM5.2, CK7, CK8, CK19, CK20), epithelial
      membrane antigen (EMA), vimentin, CD10, neural cell adhesion molecule (NCAM;
      CD56), neuron-specific enolase (NSE), chromogranin A, S-100 protein, carcino
      embryonic antigen (CEA), E-cadherin, N-cadherin, thyroid transcription factor-1
      (TTF-1), p53, estrogen (ER), progesterone (PR), HER2/neu, bcl-2, synaptophysin,
      calcitonin and Leu7. SmCCs were diffusely and strongly positive for NCAM in
      comparison with CEFs and IDCs. SmCCs were negative for vimentin, whereas CEFs and
      IDCs were positive. Neuro-endocrine carcinomas, including SmCCs and CEFs, were
      diffusely and strongly positive for NSE, compared with IDCs. Moreover,
      neuroendocrine carcinomas were negative for CK34betaE12, CK20 and CD10, whereas
      IDCs were positive. Our study suggests that NCAM and vimentin are useful markers
      for the diagnosis of mammary SmCC. CK34betaE12, NSE, CD10, CK20 and chromogranin
      A appear to be useful for differentiating neuroendocrine carcinoma from IDCs.

PMID- 15010881
TI  - Combinatorial treatment of ovarian cancer cells with harringtonine and cisplatin
      results in increased cisplatin-DNA adducts.
AB  - The current studies represent the first step in assessing the utility of
      harringtonine in combination with cisplatin as an improved approach for treating
      ovarian cancer. Three ovarian cancer cell lines, platinum-sensitive A2780, and
      platinum-resistant A2780/CP70 and OvCar-3, were exposed to their respective
      IC(50) dose of cisplatin for 1 h with or without a 24-h pretreatment with
      harringtonine. The level of platinum-DNA adducts was determined by atomic
      absorption spectrometry (AAS). These studies show for the first time that
      harringtonine pretreatment significantly increased the amount of platinum-DNA
      adducts in all ovarian cancer cell lines by 2-4 fold, immediately following 1-h
      exposure to cisplatin. Moreover, the level of cisplatin-DNA adducts in
      harringtonine-pretreated cells remained elevated by 3-4.7-fold for at least 6 h
      after cisplatin was removed, relative to cells only exposed to cisplatin. In all
      three cell lines the removal (repair) of platinum-DNA adducts was not
      significantly altered by harringtonine. In addition, the extent to which
      harringtonine altered the expression of select DNA damage response genes (p53,
      P16, ERCC1 and XPB) was determined using RT-PCR and Southern hybridization in
      A2780 and A2780/CP70 cells. The expression of ERCC1 and XPB RNAs were only
      modestly altered by harringtonine, consistent with a lack of effect of
      harringtonine on repair of cisplatin-DNA damage. However, harringtonine altered
      expression of p53 and P16 RNAs in both cell lines, although the down-regulation
      of p53 and P16 RNAs by harringtonine were more pronounced in A2780 cells. The
      novel observation that harringtonine augments platinum-DNA adducts in both
      platinum-sensitive and -resistant ovarian cancer cells indicates this combination
      of drugs may have utility in treating ovarian cancer and may be especially useful
      in managing platinum-resistant cancers. Additional studies are required to
      determine which sequence of these drugs is most beneficial, as well as the
      mechanism by which harringtonine increases cisplatin-DNA damage in ovarian cancer
      cells.

PMID- 15010882
TI  - Associations between polymorphisms in the thymidylate synthase gene, the
      expression of thymidylate synthase mRNA and the microsatellite instability
      phenotype of colorectal cancer.
AB  - Microsatellite instability (MSI) is a characteristic feature of up to 15% of
      colorectal cancers (CRC) and is associated with better response to adjuvant
      chemotherapy with 5-fluorouracil (5-FU). In this study we have investigated the
      association between the MSI status and the mRNA expression as well as the
      polymorphisms of the cellular target of 5-FU therapy, thymidylate synthase.
      Polymorphisms in the 3'- and the 5'-UTR of the TS gene were determined by a PCR
      assay in 53 colorectal cancer tissues. TS mRNA was quantified by real-time RT
      PCR. Data were correlated with the MSI phenotype. There was neither a significant
      correlation between the polymorphisms in the TS gene and the MSI phenotype nor
      between the mRNA expression and MSI status. CRC with a 3R/3R or 2R/3R genotype
      showed a significantly higher TS mRNA expression than those with 2R/2R genotype
      (p=0.001 and p=0.026, respectively). No association was seen between the
      polymorphism of the 3'-UTR and mRNA expression. From our results, we conclude
      that there is no association between MSI status and TS expression. Samples
      containing the 3R/3R or 2R/3R genotype of TS seem to have higher mRNA levels
      perhaps due to a higher mRNA stability. Polymorphic variants of the 3'-UTR do not
      influence the TS mRNA level. Genotyping of the 5'-UTR and quantitation of TS mRNA
      levels might serve as predictors for the response to 5-FU based chemotherapy.

PMID- 15010883
TI  - Loss of hMSH2 expression in primary breast cancer with p53 alterations.
AB  - Inactivation of DNA mismatch repair genes (MRG) is a recently described pathway
      of cancer development and progression resulting in genetic instability. Germline
      mutations in MRG have been studied predominantly in patients with hereditary non
      polyposis colorectal cancer (HNPCC) where it is associated with microsatellite
      instability (MSI). The expression of MRG in primary breast cancer is still
      largely unexplored. The hMSH2 MRG encodes a protein that recognizes and binds to
      mismatch sequences of DNA. We investigated the relation-ship between hMSH2
      expression and clinicopathological and biological characteristics, including p53
      and p185 expression, in 44 primary invasive breast cancers. hMSH2 was not
      expressed in 11 cases (25%). Interestingly, p53 (p=0.05), p185 and steroidal
      receptor expression (p=0.07) were more frequent in tumors without hMSH2
      expression. Furthermore, in 30 of 44 cases we analyzed hMSH2 expression in
      relation to MSI at 9 dinucleotide loci, and found that MRG expression was not
      significantly related to MSI. The presence of hMSH2 and p53 alterations in the
      same tumor suggests that the two oncoproteins act through a common mutational
      pathway, whereas the absence of a correlation between hMSH2 and MSI suggests that
      oncogenetic mechanisms of progression in primary breast cancer differ from those
      in HNPCC.

PMID- 15010884
TI  - Wikyungtang inhibits proliferation of A549 human lung cancer cells via inducing
      apoptosis and suppressing cyclooxygenase-2 activity.
AB  - Wikyungtang, an oriental herbal formulation, has been known to exert anti
      inflammatory and anti-tumoral activity. However, its molecular mechanism of
      action is not understood. The purpose of the present study was to examine the
      effect of the water extract of Wikyungtang (WKT) on the growth of A549 human lung
      cancer cells. Treatment with WKT resulted in a dose-dependent growth inhibition
      coupled with the characteristic morphological features of apoptosis. Apoptosis
      inducing concentrations of WKT induced caspase-3 and caspase-9 activation
      accompanied by proteolytic degradation of poly(ADP-ribose)-polymerase and
      phospholipase C-gamma1. In addition, WKT-induced apoptosis in A549 cells was
      associated with a decreased expression of the anti-apototic Bcl-XL expression.
      WKT treatment also inhibited the expression of cyclooxygenase (COX)-2 and the
      accumulation of prostaglandin E2 without significant changes in the levels of COX
      1. Taken together, these findings provide important new insights into the
      possible molecular mechanisms of the anti-cancer activity of WKT.

PMID- 15010885
TI  - Enhancement of carcinostatic activity of omega-hydroxy fatty acids by their
      esterification through increased uptake into tumor cells.
AB  - Diverse omega-hydroxy fatty acids (omegaHFAs) and their derivatives were examined
      for their ability to diminish the cell viability of Ehrlich ascites tumor cells
      by the mitochondrial dehydrogenase-based WST-1 assay and trypan blue dye
      exclusion assay. Of the diverse omegaHFAs, hydroxyhexadecanoic acid (omegaH16:0)
      was appreciably carcinostatic, and hydroxypentadecanoic acid (omegaH15:0) or
      hydroxypentadecenoic acid (omegaH15:1) was weakly carcinostatic at a dose of 100
      micro M, whereas hydroxydodecanoic acid (omegaH12:0) and hydroxyhexadecenoic acid
      (omegaH16:1) acid were scarcely carcinostatic at the same dose. In contrast their
      sodium salt derivatives except omegaH16:0 were not carcinostatic. Enhancement of
      the carcinostatic activity was markedly exerted by ethylesterization of omegaHFAs
      with the saturated fatty moiety such as omegaH16:0 and omegaH15:0, whereas
      ethylesters of the unsaturated omegaHFAs such as omegaH15:1 and omegaH16:1 were
      weakly carcinostatic. Thus intramolecular introduction of a double bond was shown
      to weaken the carcinostatic activity in case of either omegaHFAs or their
      ethylester, being in contrast to the conventional knowledge concerning the
      enhancement of carcinostatic activities of non-hydroxy fatty acids appendant with
      more double bonds. The intracellular uptake amount of each omegaHFA as quantified
      by gas chromatography was the following order: omegaH16:0 ethylester (10.1
      pg/cell) > omegaH15:0 ethylester (6.4 pg/cell) > omegaH16:0 (3.4 pg/cell) >
      omegaH15:0 (2.8 pg/cell), which accords with the order of carcinostatic
      activities of four saturated omegaHFAs in contrast to discord between both the
      orders for unsaturated omegaHFAs which could be scarcely detected as the intact
      form within cells. The results indicate that enhancement of carcinostatic
      activity of omegaH16:0 by ethylesterization was attributed to an appreciable
      correlation between intracellular uptake amounts and carcinostatic activities for
      diverse omegaHFAs with saturated fatty moiety, being not true for unsaturated
      omegaHFAs.

PMID- 15010886
TI  - Expression of VEGF and brain specific angiogenesis inhibitor-1 in glioblastoma:
      prognostic significance.
AB  - Brain specific angiogenesis inhibitor (BAI)-1 is a novel p53-inducible anti
      angiogenic molecule. We examined the expression of BAI-1 in glial tumors and its
      association with patient survival. The expression of BAI-1 was evaluated in 20
      brain tumors (meningiomas, pituitary adenomas, hemangiopericytomas,
      hemangioblastomas), 2 normal brain samples, 5 benign gliomas, and 26
      glioblastomas. In the 26 glioblastoma tumors, we also evaluated the expression of
      VEGF, p53, p53 mutations, and MIB-1 to determine their association with survival.
      BAI-1 mRNA was expressed in all benign gliomas, normal brain, and 9 out of 26
      glioblastomas, but not in the other tumors. Low VEGF and aberrant high expression
      of p53 were associated with a favorable outcome in univariate survival analysis,
      but they were not independent factors in multivariate analysis. For the treatment
      response, BAI-1 expression was associated with better response to radiation
      therapy (p=0.014). When we divided the patients into groups according to the
      expression patterns of BAI-1 and VEGF mRNA, the median survival of 9 patients
      with high VEGF expression and no expression of BAI-1 was just 6 months, while the
      median survival of the other 17 patients was 14 months (p=0.013). Glioblastomas
      with no BAI-1 and high VEGF mRNA expression are more often associated with poor
      clinical outcome. These findings suggest that the balance between the angiogenic
      and anti-angiogenic factors is important in the progression of glioblastoma and
      its response to treatment.

PMID- 15010887
TI  - Human PinX1, a potent telomerase inhibitor, is not involved in human
      gastrointestinal tract carcinoma.
AB  - PinX1 was isolated as a Pin2/TRF1 binding protein that also binds to the
      telomerase catalytic subunit hTERT. The gene is a potent telomerase inhibitor and
      a putative tumor suppressor since it inhibits telomerase activity and affects
      tumorigenicity in nude mice. This study investigated aberrations of PinX1 gene in
      gastrointestinal tract carcinomas (GITCs). We examined mutations, mRNA expression
      and promoter methylation of PinX1 gene in 15 GITC cell lines, and 20 patients
      with primary GITC. We found a missense mutation at codon 254 (AGC/TGC) in a colon
      and an esophageal carcinoma cell line, and in cancerous and matching normal
      tissues of 2 patients with primary GITC (10%). It might be a benign polymorphism.
      No hyper-methylation was found in the promoter region and the treatment by 5-Aza
      2'-deoxycytidine did not affect PinX1 mRNA expression level in any of the cell
      lines. It was concluded that the human PinX1 does not affect tumorigenesis of
      human GITC.

PMID- 15010888
TI  - Activin A inhibits growth-inhibitory signals by TGF-beta1 in differentiated human
      endometrial adenocarcinoma cells.
AB  - Although human endometrial adenocarcinoma tissues express high levels of activin
      A, the pathophysiological functions of endometrial activin A remain unclear.
      Human endometrial cancer cells express both activin receptor and TGF-beta
      receptor, and TGF-beta1 utilizes the same intracellular signaling molecules as
      activin A. Using three differentiated human endometrial adenocarcinoma cell
      lines, we investigated whether there are interactions between TGF-beta1- and
      activin A-mediated signaling. Flow cytometric analysis revealed cell surface
      expression of two types of TGF-beta receptor subunits and four types of activin
      receptor subunits. TGF-beta1 inhibited cell proliferation in three endometrial
      adenocarcinoma cell lines. Activin A did not affect the growth of the three
      endometrial cell lines, and pre-incubation with activin A dose-dependently
      reduced TGF-beta1-mediated inhibition of cell growth. These results suggest that
      in endometrial adenocarcinoma cells, the intracellular signals underlying TGF
      beta1-mediated inhibition of growth can themselves be inhibited by activin A.
      Therefore, the increased expression of activin A may be involved in
      carcinogenesis by reducing TGF-beta-mediated signals inhibiting cell growth in
      human endometrial adenocarcinoma tissues.

PMID- 15010889
TI  - Possible distinct molecular carcinogenic pathways for bladder cancer in Ukraine,
      before and after the Chernobyl disaster.
AB  - After the Chernobyl accident in 1986, the incidence of urinary bladder cancers in
      the Ukraine increased gradually from 26.2 to 43.3 per 100,000 people between 1986
      and 2001. In the areas of low level but persistent cesium-137 (137Cs) radio
      contamination, a unique atypical radiation-related urinary bladder cystitis named
      'Chernobyl cystitis', a possible pre-neoplastic condition in humans, has been
      detected. We have previously documented high incidences of bladder lesions,
      including severe dysplasias and/or carcinoma in situ, in association with this
      cystitis and correlating with oxidative DNA damage. To further investigate the
      molecular mechanisms underlying bladder carcinogenesis with this specific
      etiology, mutation analysis of p53 gene (exon 5-8) was performed for 11 and 18
      paraffin-embedded bladder cancers in Ukrainians, respectively collected before
      and after the Chernobyl disaster. DNAs were extracted and subjected to nested PCR
      single-strand conformational polymorphism analysis followed by direct DNA
      sequencing, as well as p53 immunohistochemistry (IHC). The incidences of p53 gene
      mutation were 54.5 and 16.7% for before and after the Chernobyl disaster,
      respectively, the difference being statistically significant. Also a tendency for
      higher p53 IHC score was apparent in the earlier group of lesions. No significant
      difference was noted for the proportions of historical types. These results point
      to possible distinct molecular carcinogenic pathways of bladder cancer formation,
      before and after the Chernobyl disaster, on the basis of variation in p53 gene
      alteration.

PMID- 15010890
TI  - Dietary boron intake and prostate cancer risk.
AB  - Boron affects human steroid hormone levels. Circulating testosterone and
      estradiol levels have been proposed to modify prostate cancer risk. However, the
      association between dietary boron intake and the risk of prostate cancer has not
      been evaluated by any epidemiological study. We explored the association between
      dietary boron intake and the risk of prostate cancer in the USA. Our analysis was
      based on data from the third National Health and Nutrition Examination Survey
      (NHANES III). Cross-sectional case-control study design was employed by comparing
      boron intake of 95 prostate cancer cases with that of 8,720 male controls. After
      controlling for age, race, education, smoking, body mass index, dietary caloric
      intake, and alcohol consumption, increased dietary boron intake was associated
      with a decreased risk of prostate cancer with a dose-response pattern. The
      adjusted odds ratio was 0.46 (95% confidence interval: 0.21-0.98) for the highest
      quartile of boron intake comparing to the lowest quartile (P for trend = 0.0525).
      The observed association should be interpreted with caution because of the small
      case sample size and the nature of the cross-sectional study design, but deserve
      further investigation.

PMID- 15010891
TI  - In vitro exposure to paclitaxel modulates integrin expression by human T
      lymphocytes and inhibits T cell adhesion to breast carcinoma cells.
AB  - Paclitaxel (Taxol) is a drug that is commonly used in the treatment of metastatic
      breast cancer. In this study, we investigated the effect of prior exposure to
      submaximal cytotoxic concentrations (EC(25) and EC(50)) of paclitaxel on the
      subsequent ability of human Jurkat T lymphocytes to adhere to monolayers of MDA
      MB-435 human breast carcinoma cells. Jurkat T cells that survived culture for 24
      h in the presence of paclitaxel (0.1 or 3 micro g/ml) exhibited a diminished
      ability to adhere to MDA-MB-435 breast cancer cell monolayers. Flow cytometric
      analysis of paclitaxel-treated Jurkat T cells revealed reduced surface expression
      of alphaL, alpha4, alpha5, and beta7 integrins, but normal beta1 integrin
      expression. These data suggest that paclitaxel interferes with the expression of
      alphaLbeta2 (LFA-1), alpha4beta1 (VLA-4), alpha5beta1 (VLA-5), and alpha4beta7
      (LPAM-1) adhesion molecules by surviving T cells. Blocking experiments with
      antibodies against alphaL, alpha4, alpha5, beta1, and beta7 integrins revealed
      that adhesion of Jurkat T cells to MDA-MB-435 breast cancer cell monolayers was
      dependent upon alphaL, alpha4, and beta7 but not alpha5 or beta1 integrins. We
      conclude that prior exposure to paclitaxel caused a reduction in Jurkat T cell
      adhesion to MDA-MB-435 breast carcinoma cells by preventing optimal alphaLbeta2
      and alpha4beta7 interactions with their corresponding ligands on tumor cells. A
      similar effect by paclitaxel on T lymphocytes of breast cancer patients may
      compromise cell-mediated anti-tumor immune responses.

PMID- 15010892
TI  - Breast cancer after curative chemotherapy in non-Hodgkin's lymphoma: examination
      of the role of drug resistance and retrospective comparison to the outcome of de
      novo breast cancer.
AB  - We examined the outcome of patients who developed breast cancer after curative
      chemotherapy (CHOP) for aggressive non-Hodgkin's lymphoma (NHL) in comparison to
      the outcome of a retrospectively selected matched-pair group of patients with de
      novo breast cancer, and evaluated the role of drug resistance-related protein
      (MDR, MRP, LRP) expression in breast cancer tissue. Twenty-two patients presented
      with breast cancer (BC) in complete remission after CHOP for NHL. The median age
      was 62 (49-70) years, each had high/intermediate grade B-cell NHL treated with 6
      courses of CHOP, and were in complete remission. These patients were compared to
      a matched-pair group of de novo BC patients selected from our database over the
      same time period. Breast cancer tissue was stained by immunohistochemistry for
      drug resistance proteins LRP, MRP, and MDR. Breast cancer developed after a
      median of 26 (9-49) months of NHL diagnosis; breast tumor grades 1-2 were seen in
      12, and grade 3 in 10 patients; 15 were negative and 7 weakly positive for
      estrogen and progesterone receptors. Twelve patients were stage IIIA/B, and 10
      stage IV and were treated with conventional chemotherapy regimens. All progressed
      early in liver (n=13), brain (n=9), lung (n=6), bone (n=8), lymph nodes (n=7) and
      soft tissue (n=5), and received second-line chemotherapy with mitomycin-C +
      vinblastine or taxanes. The overall survival was 11.8 (6-26) months (p<0.01).
      Time from NHL to breast cancer development was 19 (14-27) months in patients with
      positive drug resistance proteins (group A), and 37 (26-56) months in patients
      with 1 or 2 positive resistance proteins (group B) (p<0.001). In patients with
      stage IIIA/B disease, there was no difference between the examined and control
      matched-pair group in median TTP, but there was in overall survival (OS) (23 vs
      36 months, p=0.029). In advanced disease, there were more responders in the
      control vs the examined group (p=0.07). Patients in the control matched-pair
      group had more prolonged OS when compared to group A patients who developed BC in
      <24 months from NHL to BC (p=0.017). We conclude that breast cancer developing
      shortly after a complete response in NHL, is an aggressive disease variant with
      minimal potential for response to conventional chemotherapy. Analysis of drug
      resistance mechanisms concerning MDR, MRP and LRP indicates that most of these
      patients have BC that overexpress these proteins leading to the suggestion that
      these mechanisms might be a part of the aggressive disease phenotype and
      partially explain the poor outcome.

PMID- 15010893
TI  - Assessment of breast cancer vascularisation by Doppler ultrasound as a prognostic
      factor of survival.
AB  - Tumor growth and metastasis in breast cancer are correlated to neoangiogenesis,
      which became a potential candidate as a prognostic factor in this tumor type.
      Several studies have used immunohistochemical staining to count microvessel
      density as a marker of neoangiogenesis. This hospital-based retrospective pilot
      study measured vascularisation of early breast cancer by Doppler ultrasound and
      determined its value as a prognostic factor of overall survival in 147 women. The
      number of tumor related arteries were detected by color-coded Doppler ultrasound.
      We identified < or =10 tumor arteries and >10 tumor arteries in 117 and 30 women,
      respectively. Only weak correlation was found between the number of tumor
      arteries and established clinicopathological parameters such as tumor size
      (r=0.25) and lymph node involvement (r=0.13). In an univariate analysis, the
      strongest predictors of overall survival were number of tumor arteries [relative
      risk (RR) 4.60 (1.96-10.78)], positive axillary lymph nodes [RR 4.48 (1.59
      12.60)] and angioinvasion [RR 4.26 (1.93-9.37)]. These three parameters were also
      found to be independent predictors of overall survival in a multivariate analysis
      [RR 3.21 (1.13-9.10) for positive lymph nodes; RR 2.69 (1.33-5.41) for number of
      tumor arteries; RR 2.84 (1.27-6.34) for angioinvasion]. Tumor vascularisation
      detected by Doppler ultrasound appears to be an independent predictor of overall
      survival in women with early breast cancer.

PMID- 15010894
TI  - Gastric cancer treatment: a systematic review.
AB  - Gastric cancer remains one of the leading causes of cancer related deaths
      worldwide. The overall 5-year survival rate in the United States and most of the
      Western World ranges from 5 to 15%. The only potentially curative treatment for
      localized gastric cancer is complete surgical resection. Meta-analyses of
      adjuvant systemic chemotherapy in gastric cancer have shown at best marginal
      benefits, neoadjuvant chemotherapy and chemoradiotherapy are also feasible and
      are the subject of several ongoing studies. In metastatic disease, chemotherapy
      confers benefit when compared with best supportive care alone. This review will
      focus on the several treatment modalities available for gastric cancer patients:
      surgery, adjuvant, neoadjuvant and palliative chemotherapy as well as new target
      agents.

PMID- 15010895
TI  - Single nucleotide polymorphisms in breast cancer.
AB  - A limited number of genes have been identified that explain heritable risks of
      breast cancer (BC). We searched for low-penetrant genes in an association study
      using two populations: 223 Finnish unselected patients and 172 Polish familial
      cases, both with locally collected healthy controls. Candidate genes included DNA
      repair genes, methylenetetrahydrofolate reductase (MTHFR) and cyclin D1 genes.
      The frequencies for single nucleotide polymorphisms (SNPs) were measured in the
      following genes: NBS1, XPC, XPD, XRCC1, XRCC3, MTHFR, and cyclin D1. Odds ratios
      (ORs) were calculated to the wild-type genotype. The positive findings in the
      Finnish series were repeated in the Polish series. Significant findings among
      Finns were associations to XPC exon 15, XPD exon 10 and XRCC3 exon 7, the latter
      of borderline significance. None of these results could be repeated in the Polish
      series. The XPC result among Finns was probably an artifact of the control group
      deviating from the Hardy-Weinberg Equilibrium (HWE). The attempt to repeat the
      result for the XPD polymorphism among Poles was probably not valid because the
      control group deviated from the HWE. We conclude that within statistical power of
      the present study, none of the tested polymorphisms associated with BC, with the
      probable exception of XPD.

PMID- 15010896
TI  - Analysis of tumor suppressor p53 status in head and neck squamous cell carcinoma.
AB  - Head and neck cancer belongs to the most common types of cancer in both males and
      females with a mortality rate of approximately 50%. More than 90% of head and
      neck cancers are squamous cell carcinoma (HNSCC). Carcinogenesis of this disease
      involves activation of proto-oncogenes and inactivation of tumor suppressor
      genes. Among them, aberrations of p53 tumor suppressor gene are common events.
      The aim of this study was to assess the frequency of the tumor suppressor p53
      aberrations in Czech population by using a functional test in yeast (FASAY) and
      by two immunochemical methods. We compared results of the methods and assessed
      the relationship between the presence of p53 aberration and some clinico
      pathological parameters. The following observations were made: i) the accumulated
      p53 protein was detected in 33 of 50 tested samples (66%) by immunohistochemical
      analysis and in 27 of 49 tested samples (55.1%) by immunoblotting; ii) the
      presence of p53 mutation was detected in 36 of 50 tested samples (72%); iii) 6 of
      36 p53 mutations detected by FASAY were temperature sensitive (16.7%); iv) 2
      independent p53 mutations were found in at least 2 of the 36 positive cases; v)
      no statistically significant relationship was found between p53 aberration and
      overall survival.

PMID- 15010897
TI  - Apoptotic and growth regulatory genes as mutational targets in mismatch repair
      deficient endometrioid adenocarcinomas of young patients.
AB  - Among multiple genetic pathways involved in endometrial cancer (EC), the mutator
      pathway is characterized by defective mismatch repair (MMR) causing
      microsatellite instability (MSI+). Inactivation of MMR genes allows elevation of
      mutation rates in key target genes involved in important cellular pathways,
      providing a selective growth advantage. Our aim was to investigate apoptotic and
      growth regulatory target genes in young endometrioid adenocarcinoma patients and
      their association with stepwise neoplastic progression through distinct stages of
      hyperplasia and cancer. Screening of 184 ECs revealed 38 microsatellite high (MSI
      H), 10 microsatellite low (MSI-L) and 136 microsatellite stable (MSS) tumors. We
      observed somatic frameshift mutations in the coding region repeats of the target
      genes in 12/38 MSI-H tumors (T) and in 3/8 of available associated hyperplasias
      (HY). Mutations were detected in FAS (T=1, HY=1), BAX (T=6, HY=1), CASP5 (T=2)
      and IGFIIR (T=3, HY=1) genes. None of the MSI-L or MSS tumors showed alterations
      in these coding repeats. Increased mutation frequency in apoptotic and growth
      regulatory genes demonstrated a significant relationship with advancing tumor
      grade (p=0.02) by Fisher's exact test. Furthermore, a significant trend was found
      by Bartholomew's test (P<0.05) for the apoptotic pathway and close to significant
      (p approximately 0.06) for the overall mutation status for both pathways
      combined. Our results suggest that genes implicated in apoptosis may serve as
      targets in the progression of MSI+ EC in young patients.

PMID- 15010898
TI  - Timing of goal-directed hitting: impact requirements change the information
      movement coupling.
AB  - In hitting, performers are found to adapt to the approach speed of the ball, i.e.
      they tend to initiate their movement at a shorter time before contact for faster
      approaching balls. A change in movement time is always accompanied by a change in
      movement velocity when the movement trajectory is kept constant. Hence, a fast
      approaching ball might induce high impact velocity that is in conflict with low
      impact constraints, such as propelling the ball towards a near goal. In this
      study we investigated the capacities of participants to perform one-dimensional
      hitting movements in the frontal plane to balls approaching on a head-on
      collision course. The temporal precision (i.e. ball approach speed: 1, 1.5, and 2
      m/s) and impact requirements (i.e. No-Goal, Near-Goal, and Far-Goal) were
      manipulated to examine the influence of task constraints on the temporal
      regulation of a stroke. The results showed that timing and speed were
      significantly affected by ball approach speed when the hit was not directed to a
      goal. In contrast, no speed-coupling and a constant time-to-impact strategy were
      found when impact velocity was constrained (i.e. aiming for a near goal). We were
      particularly interested in the nature and relation of information sources and
      timing patterns of movement initiation. Therefore, the relation between the time
      evolution of three optical sources related to the approach of the ball and the
      observed patterns of swing onset were evaluated quantitatively. The analyses
      revealed that a viable explanation for the two observed qualitatively different
      onset patterns of the swing is a regulation based on the absolute rate of
      expansion or a co-varying variable. The flexible adaptation of timing to impact
      constraints may be realized by an adjustment of the critical region of this
      optical variable.

PMID- 15010900
TI  - Structure of colloidal complexes obtained from neutral/poly-electrolyte
      copolymers and oppositely charged surfactants.
AB  - We report on the phase behavior and scattering properties of colloidal complexes
      made from block copolymers and surfactants. The copolymer is poly(sodium
      acrylate)-b-poly(acrylamide), hereafter abbreviated as PANa-PAM, with molecular
      weight 5000 g/mol for the first block and 30000 g/mol for the second. In aqueous
      solutions and neutral pH, poly(sodium acrylate) is a weak polyelectrolyte,
      whereas poly(acrylamide) is neutral and in good-solvent conditions. The
      surfactant is dodecyltrimethylammonium bromide (DTAB) and is of opposite charge
      with respect to the polyelectrolyte block. Combining dynamical light scattering
      and small-angle neutron scattering, we show that in aqueous solutions PANa-PAM
      diblocks and DTAB associate into colloidal complexes. For surfactant-to-polymer
      charge ratios Z lower than a threshold (Z(C) approximately 0.3), the complexes
      are single surfactant micelles decorated by few copolymers. Above the threshold,
      the colloidal complexes reveal an original core-shell microstructure. We have
      found that the core of typical radius 100-200 A is constituted from densely
      packed surfactant micelles connected by the polyelectrolyte blocks. The outer
      part of the colloidal complex is a corona and is made from the neutral
      poly(acrylamide) chains. Typical hydrodynamic sizes for the whole aggregate are
      around 1000 A. The aggregation numbers expressed in terms of numbers of micelles
      and copolymers per complex are determined and found to be comprised between 100
      400, depending on the charge ratio Z and on the total concentration. We have also
      shown that the sizes of the complexes depend on the exact procedure of the sample
      preparation. We propose that the driving mechanism for the complex formation is
      similar to that involved in the phase separation of
      homopolyelectrolyte/surfactant systems. With copolymers, the presence of the
      neutral blocks prevents the macroscopic phase separation from occurring.

PMID- 15010899
TI  - Calcium-antagonizing activity of S-petasin, a hypotensive sesquiterpene from
      Petasites formosanus, on inotropic and chronotropic responses in isolated rat
      atria and cardiac myocytes.
AB  - Petasites formosanus, an indigenous species of Petasites, has been used to treat
      cardiovascular diseases such as hypertension for years. We have suggested
      recently that S-petasin, a major sesquiterpene from P. formosanus, inhibits
      vascular smooth muscle contraction through inhibition of voltage-dependent Ca(2+)
      channels, a phenomenon possibly responsible for the hypotensive effect of P.
      formosanus. This study was designed to examine the chronotropic and inotropic
      actions of S-petasin in the heart in vivo and in vitro. Administration of S
      petasin (0.1-1.5 mg/kg i.v.) in anesthetized rats reduced heart rate dose
      dependently. This response was consistent with significant suppression of both
      contractile amplitude and spontaneous firing rate of isolated atria, responses
      that were not antagonized by atropine (1 microM). Mechanical evaluation in
      isolated ventricular myocytes showed that S-petasin (0.1 to 100 microM) depressed
      peak myocyte contraction and intracellular Ca(2+) transients concentration
      dependently. The duration of myocyte contraction was not affected. Whole-cell
      voltage clamp analysis revealed that S-petasin inhibited the L-type Ca(2+)
      current ( I(Ca,L)) concentration-dependently and shifted the steady-state
      inactivation curve of I(Ca,L) to more negative potentials. However, a receptor
      binding assay failed to identify any significant interaction between S-petasin
      (0.1-300 microM) and the dihydropyridine binding sites of L-type voltage
      dependent Ca(2+) channels. Taken together, these data show that the negative
      chronotropic and inotropic properties of S-petasin that can be ascribed mainly to
      I(Ca,L) inhibition, but not to blockade of dihydropyridine binding sites of L
      type Ca(2+) channel or to muscarinic receptor activation.

PMID- 15010901
TI  - Monte Carlo simulations of star-branched polyelectrolyte micelles.
AB  - The concentration profiles of monomers and counterions in star-branched
      polyelectrolyte micelles are calculated through Monte Carlo simulations, using
      the freely jointed chain model. We have investigated the onset of different
      regimes corresponding to the spherical and Manning condensation of counterions as
      a function of the strength of the Coulomb coupling. The Monte Carlo results are
      in fair agreement with the predictions of Self-Consistent-Field analytical
      models. We have simulated a real system of diblock copolymer micelles of (sodium
      polystyrene-sulfonate)(NaPSS)-(polyethylene-propylene)(PEP) with f = 54
      hydrophilic branches of N = 251 monomers at room temperature in salt-free
      solution. The calculated form factor compares nicely with our neutron scattering
      data.

PMID- 15010902
TI  - Viscosity minimum in bimodal concentrated suspensions under shear.
AB  - We study a model of concentrated suspensions under shear in two dimensions.
      Interactions between suspended particles are dominated by direct-contact
      viscoelastic forces and the particles are neutrally bouyant. The bimodal
      suspensions consist of a variable proportion between large and small droplets,
      with a fixed global suspended fraction. Going beyond the assumptions of the
      classical theory of Farris (R.J. Farris, Trans. Soc. Rheol. 12, 281 (1968)), we
      discuss a shear viscosity minimum, as a function of the small-to-large-particle
      ratio, in shear geometries imposed by external body forces and boundaries. Within
      a linear-response scheme, we find the dependence of the viscosity minimum on the
      imposed shear and the microscopic drop friction parameters. We also discuss the
      viscosity minimum under dynamically imposed shear applied by boundaries. We find
      a reduction of macroscopic viscosity with the increase of the microscopic
      friction parameters that is understood using a simple two-drop model. Our
      simulation results are qualitatively consistent with recent experiments in
      concentrated bimodal emulsions with a highly viscous or rigid suspended
      component.

PMID- 15010903
TI  - Nonlinear optical characterization of cluster dynamic in water in oil
      microemulsion by a pump probe laser beam technique.
AB  - We present a new pump probe laser beams configuration for the nonlinear optical
      characterization of microemulsions. We detect the variation of the on-axis
      optical intensity of the probe beam as generated by the concentration profile
      induced in an optically thin film of microemulsion by the pump beam. A
      mathematical model has been introduced to describe the phenomenon. The technique
      allows the determination of both Kerr-like optical nonlinearity and time
      constants and, therefore, it gives information both on cluster dimension and
      their shape. We discuss its application to WAD (water/AOT/decane, where AOT
      denotes sodium-bis-di-ethyl-sulfosuccinate) with the application of a strong
      electric field of optical source. Comparison between theoretical predictions and
      experimental results confirms the presence of giant optical nonlinearity in the
      absence of turbidity divergence. Chainlike shape of clusters, of the kind already
      reported with the application of strong electric field, could justify this
      result.

PMID- 15010904
TI  - Colloidal interactions in two-dimensional nematics.
AB  - The interaction between two disks immersed in a 2D nematic is investigated i)
      analytically using the tensor order parameter formalism for the nematic
      configuration around isolated disks and ii) numerically using finite-element
      methods with adaptive meshing to minimize the corresponding Landau-de Gennes free
      energy. For strong homeotropic anchoring, each disk generates a pair of defects
      with one-half topological charge responsible for the 2D quadrupolar interaction
      between the disks at large distances. At short distance, the position of the
      defects may change, leading to unexpected complex interactions with the
      quadrupolar repulsive interactions becoming attractive. This short-range
      attraction in all directions is still anisotropic. As the distance between the
      disks decreases, their preferred relative orientation with respect to the far
      field nematic director changes from oblique to perpendicular.

PMID- 15010905
TI  - Scale-dependent rigidity of polymer-ornamented membranes.
AB  - We study the fluctuation spectrum of fluid membranes carrying grafted polymers.
      Contrary to usual descriptions, we find that the modifications induced by the
      polymers cannot be reduced to the renormalization of the membrane bending
      rigidity. Instead we show that the ornamented membrane exhibits a scale-dependent
      elastic modulus that we evaluate. In ornamented lamellar stacks, we further
      compute the polymer contribution to the Caille parameter characterizing the power
      law singularities of the Bragg peaks.

PMID- 15010906
TI  - Adsorption of a semiflexible wormlike chain.
AB  - Adsorption of ideal polymers with stiff backbone onto a flat surface is
      considered theoretically. Both scaling approach and quantitative theory are
      developed. We predict a self-similar monomer concentration profile c(x)
      approximately x(-4/3) near the surface (when the distance to the surface x is
      much smaller than the chain persistence length l /2). The typical conformation of
      a weakly adsorbed chain can be viewed as a sequence of alternating flat (2
      dimensional) trains of wormlike short loops (flat blobs) and coil-like (3
      dimensional) loops forming a triple-layer structure: contact layer (x < Delta) of
      adsorbed fragments virtually laid on the surface, proximal layer (Delta < x < l)
      of flat blobs, and more dilute distal corona layer (x > l). Here Delta defines
      the range of monomer/surface attraction, Delta << l. The adsorption transition is
      continuous. However, its relative width Delta(T) is divided by T* is small (T(*)
      is the adsorption temperature, Delta T is the relevant temperature interval):
      Delta(T) is divided by T* approximately (Delta is divided by l)(4/3), i.e. a
      discontinuous transition in the limit Delta/ l --> 0.

PMID- 15010907
TI  - Thermal undulations of quasi-spherical vesicles stabilized by gravity.
AB  - The classical treatment of quasi-spherical vesicle undulations has, in the
      present work, been reviewed and extended to systems, which are affected by a
      gravitational field caused by a density difference across the membrane. The
      effects have been studied by the use of perturbation theory leading to
      corrections to the mean shape and the fluctuation correlation matrix. These
      corrections have been included in an analytical expression for the flicker
      spectrum to probe how the experimentally accessible spectrum changes with
      gravity. The results are represented in terms of the gravitational parameter,
      g(0) = Delta(rho)g R(4)/kappa. The contributions from gravity are in most
      experimental situations small and thus negligible, but for values of g(0) above a
      certain limit, the perturbational corrections must be included. Expressions for
      the relative error on the flicker spectrum have been worked out, so that it is
      possible to define the regime where gravity is negligible. An upper limit of g(0)
      has also been identified, where the error in all modes of the flicker spectrum is
      significant due to distortion of the mean shape.

PMID- 15010908
TI  - Dilational rheology of monolayers of a miscible polymer blend: from good- to poor
      solvent conditions.
AB  - The viscoelastic moduli (elasticity and dilational viscosity) of monolayers of
      PVAc + P4HS has been studied over a broad frequency range (0.1 mHz-200 kHz) using
      a combination of relaxation and capillary-waves techniques. The analysis of the
      surface pressure, the elasticity and the viscosity on the semidilute regime show
      that the air-water interface is a good solvent for the monolayers of PVAc-rich
      blends, and a poor (near-Theta) solvent for the monolayers of P4HS-rich blends.
      The solvent quality changes continuously over a broad concentration range. The
      results of viscoelastic moduli show that there is a broad relaxation process in
      the low-frequency range (omega < 1 Hz). While for PVAc-rich monolayers this
      relaxation process follows the reptation-like behavior described by Noskov, for
      P4HS-rich monolayers the model does not describe the amplitudes of the different
      relaxation modes. For PVAc-rich monolayers two processes are clearly
      distinguished at higher frequencies: one centered at around 500 Hz and another
      one at around 40 kHz. However, for P4HS-rich monolayers only one broad relaxation
      mode is found below 1 kHz. The crossover from one type of behavior to the other
      one takes place in a very narrow blend-composition range, and is not clearly
      related to the crossover from good- to poor-solvent condition.

PMID- 15010909
TI  - Electrically induced flows in the vicinity of a dielectric stripe on a conducting
      plane.
AB  - We report a theoretical and experimental study of the hydrodynamic flow induced
      by an a.c. electric field in the vicinity of a dielectric stripe deposited on a
      conducting plate. In the theoretical part, we model the stripe as a small change
      of the surface capacitance of the plate, and a perturbative approach is used to
      perform the calculations. This approach predicts an outwards rectified electro
      osmotic slip along the surface that generates two steady counter-rotating rolls,
      the size of which decreases with the frequency. In the experimental section, we
      use tracers to determine the structure of the flow and investigate its dependence
      on the frequency and the amplitude of the applied voltage. The structure and
      amplitude of the observed flow compares satisfactorily with the theoretical
      analysis. This could guide the design of surface-controlled flows and help to
      understand the collective behavior of colloids near electrodes.

PMID- 15010910
TI  - Euclidean random matrices, the glass transition and the boson peak.
AB  - In this paper I will describe some results that have been recently obtained in
      the study of random Euclidean matrices, i.e. matrices that are functions of
      random points in Euclidean space. In the case of translation invariant matrices
      one generically finds a phase transition between a phonon phase and a saddle
      phase. If we apply these considerations to the study of the Hessian of the
      Hamiltonian of the particles of a fluid, we find that this phonon-saddle
      transition corresponds to the dynamical phase transition in glasses, that has
      been studied in the framework of the mode coupling approximation. The boson peak
      observed in glasses at low temperature is a remanent of this transition.

PMID- 15010911
TI  - Probability distribution of inherent states in models of granular media and
      glasses.
AB  - The present paper develops a Statistical Mechanics approach to the inherent
      states of glassy systems and granular materials by following the original ideas
      proposed by Edwards for granular media. We consider three lattice models (a
      diluted spin glass, a system of hard spheres under gravity and a hard-spheres
      binary mixture under gravity) introduced to describe glassy and granular systems.
      They are evolved using a "tap dynamics" analogous to that of experiments on
      granular media. We show that the asymptotic states reached in such a dynamics are
      not dependent on the particular sample history and are characterized by a few
      thermodynamical parameters. We assume that under stationarity these systems are
      distributed in their inherent states satisfying the principle of maximum entropy.
      This leads to a generalized Gibbs distribution characterized by new
      "thermodynamical" parameters, called "configurational temperatures" (related to
      Edwards compactivity for granular materials). Finally, we show by Monte Carlo
      calculations that the average of macroscopic quantities over the tap dynamics and
      over such distribution indeed coincide. In particular, in the diluted spin glass
      and in the system of hard spheres under gravity, the asymptotic states reached by
      the system are found to be described by a single "configurational temperature".
      Whereas in the hard-spheres binary mixture under gravity the asymptotic states
      reached by the system are found to be described by two thermodynamic parameters,
      coinciding with the two configurational temperatures which characterize the
      distribution among the inherent states when the principle of maximum entropy is
      satisfied under the constraint that the energies of the two species are
      independently fixed.

PMID- 15010912
TI  - Topological jamming and the glass transition in a frustrated system.
AB  - The relationship between extended structures, glassy dynamics and an underlying
      critical point is examined in the context of a lattice model of fluctuating
      lines. Monte Carlo simulations are used to construct an effective, coarse-grained
      dynamics for the "order parameter" near the critical point. Analysis of the
      effective dynamics reveals that the critical point is associated with diverging
      barriers leading to the observed Vogel-Fulcher divergence of the relaxation
      times. A direct connection is established between the presence of extended
      structures and the activated dynamics.

PMID- 15010913
TI  - Water and its energy landscape.
AB  - We present an overview of the recent studies on the properties of the potential
      energy surface for a simple model of water. We emphasize the relations between
      PES properties and dynamics in supercooled states for the model and discuss
      possible future application of the PES studies.

PMID- 15010914
TI  - Pressure amorphization through displacive disorder.
AB  - After classifying amorphous materials according to their topology, we review a
      recently proposed theory of pressure amorphization (PA) that arises from some
      degree of displacive disorder while retaining a crystalline topology. That theory
      is based on the notion that one or more branches of the phonon spectrum become
      soft and flat with increasing pressure and is illustrated by a simple model that
      possesses the range of features displayed by many of the materials which undergo
      PA with displacive disorder. We report the results of Langevin simulations of the
      simple model which show how the probability of amorphization increases with the
      number of unit cells in the system and support our theory. We comment on how to
      generalize the model for the study of real systems.

PMID- 15010915
TI  - On the microscopic foundations of elasticity.
AB  - The modeling of the elastic properties of disordered or nanoscale solids requires
      the foundations of the theory of elasticity to be revisited, as one explores
      scales at which this theory may no longer hold. The only cases for which
      microscopically based derivations of elasticity are documented are (nearly)
      uniformly strained lattices. A microscopic approach to elasticity is proposed. As
      a first step, microscopically exact expressions for the displacement, strain and
      stress fields are derived. Conditions under which linear elastic constitutive
      relations hold are studied theoretically and numerically. It turns out that
      standard continuum elasticity is not self-evident, and applies only above certain
      spatial scales, which depend on details of the considered system and boundary
      conditions. Possible relevance to granular materials is briefly discussed.

PMID- 15010916
TI  - Stress fluctuations and macroscopic stick-slip in granular materials.
AB  - This paper deals with the quasi-static regime of deformation of granular matter.
      It investigates the size of the Representative Elementary Volume (REV), which is
      the minimum packing size above which the macroscopic mechanical behaviour of
      granular materials can be defined from averaging. The first part uses typical
      results from recent literature and finds that the minimum REV contains in general
      10 grains; this result holds true either for most experiments or for Discrete
      Element Method (DEM) simulation. This appears to be quite small. However, the
      second part gives a counterexample, which has been found when investigating
      uniaxial compression of glass spheres which exhibit stick-slip; we show in this
      case that the minimum REV becomes 10(7) grains. This makes the system not
      computable by DEM. Moreover, similarity between the Richter law of seism and the
      exponential statistics of stick-slip is stressed.

PMID- 15010917
TI  - Restructuring of force networks.
AB  - The compaction of granular packings or soils is a collective process which for
      higher densities becomes increasingly slower reaching glassy behaviour. We
      present a study of this problem from various points of view, in particular we
      will represent the evolving force network that percolates through the system by
      an inverse fiber rupture model.

PMID- 15010918
TI  - Thermodynamics and effective temperatures in sheared granular matter and
      emulsions.
AB  - Recent theories postulate that the non-equilibrium behavior of systems
      experiencing jamming or structural arrest could be described by equilibrium
      thermodynamic concepts. If a thermodynamic framework can describe the behavior of
      systems far from equilibrium, then an effective temperature with a true
      thermodynamic meaning exists as a key parameter in characterizing the material's
      properties. In order to examine the validity of the thermodynamics for jammed
      systems, we perform a numerical experiment with a realistic granular matter model
      specially conceived to be reproducible in the laboratory. The results strongly
      support the thermodynamic picture.

PMID- 15010919
TI  - On the slow dynamics of density fluctuations near the colloidal glass transition.
AB  - Slow dynamics of density fluctuations near the colloidal glass transition is
      discussed from a new viewpoint by numerically solving a nonlinear stochastic
      diffusion equation for the density fluctuations recently proposed by one of the
      present authors (MT). The effects of spatial heterogeneities on the dynamics of
      density fluctuations are then investigated in an equilibrium system. The spatial
      heterogeneities are generated by the nonlinear density fluctuations, while in a
      nonequilibrium system they are described by a nonlinear deterministic equation
      for the average number density. The dynamics of equilibrium density fluctuations
      is thus shown to be quite different from that of nonequilibrium ones, leading to
      a logarithmic decay followed by less distinct alpha- and beta-relaxation
      processes.

PMID- 15010920
TI  - Complex dynamics in gelling systems.
AB  - We study the viscoelastic properties and the relaxation process in a gelling
      system by means of a minimal statistical-mechanics model. The model is based on
      percolation and bond fluctuation dynamics. The values for the critical exponents
      of the viscosity and elasticity agree with a part of the experimental
      observations and of the theoretical predictions. The obtained relaxation patterns
      well reproduce the behaviour observed in different gelling systems.

PMID- 15010921
TI  - Observation of a re-entrant kinetic glass transition in a micellar system with
      temperature-dependent attractive interaction.
AB  - We detect in a tri-block co-polymer micellar system an ergodic-to-nonergodic-to
      ergodic transition, as a function of temperature, in a range of concentrations,
      by photon correlation measurements. The shear viscosity is also shown to jump two
      order of magnitude at these transition temperatures. Surprisingly, the structure
      factor as measured by small angle neutron scattering shows a marked narrowing at
      the structural arrest state. Rationalization of these results with the existence
      of an attractive branch in the phase diagram of an attractive colloid system
      predicted by mode coupling theory is made.

PMID- 15010922
TI  - Anomalous dynamical light scattering in soft glassy gels.
AB  - We compute the dynamical structure factor S( q,tau) of an elastic medium where
      force dipoles appear at random in space and in time, due to "micro-collapses" of
      the structure. Various regimes are found, depending on the wave vector q and the
      collapse time theta. In an early time regime, the logarithm of the structure
      factor behaves as (q tau)(3/2), as predicted in (L. Cipelletti et al., Phys. Rev
      Lett. 84, 2275 (2000)) using heuristic arguments. However, in an intermediate
      time regime we rather obtain a (q tau)(5/4) behaviour. Finally, the asymptotic
      long-time regime is found to behave as q(3/2)tau. We also give a plausible
      scenario for aging, in terms of a strain-dependent energy barrier for micro
      collapses. The relaxation time is found to grow with the age t(w), quasi
      exponentially at first, and then as t(w)(4/5) with logarithmic corrections.

PMID- 15010923
TI  - Scaling concepts for polymer brushes and their test with computer simulation.
AB  - After a brief review of the scaling concepts for static and dynamic properties of
      polymer brushes in good solvents and Theta solvents, the Monte Carlo evidence is
      discussed. It is shown that under typical conditions the diameter of the last
      blob is of the order of 10-20% of the brush height, and therefore pronounced
      deviations from the self-consistent field predictions occur. In bad solvents,
      lateral microphase separation occurs leading to an irregular pattern of
      "dimples". Particularly interesting is the response of brushes to shear
      deformation, and the interaction between two interpenetrating brushes. Recent
      attempts to understand the resulting shear forces via molecular-dynamics
      simulations are briefly described, and an outlook on related experiments is
      given.

PMID- 15010924
TI  - Nonlinear dielectric response of antiferroelectric liquid crystals in the smectic
      C alpha* phase.
AB  - Nonlinear dielectric response of antiferroelectric liquid crystals has been
      studied in the smectic C(alpha)* (SmC(alpha)*) phase. The linear dielectric
      spectrum shows a single relaxation of Debye type and its relaxation frequency is
      as high as one hundred kHz. The profile of the third-order nonlinear dielectric
      spectrum varies in complex fashion with temperature. In the vicinity of the SmA
      SmC(alpha)* phase transition, experimentally obtained nonlinear spectra are well
      described by those calculated with phenomenological theory of Landau type. The
      soft mode of the SmC(alpha)* phase shows critical slowing-down near the
      transition temperature. In the lower-temperature region of the SmC(alpha)* phase,
      the contribution from the soft mode of the SmC(alpha)* phase reduces and the
      other relaxation mode with Debye-type spectrum appears at several hundred Hz in
      the nonlinear spectrum. The appearance of this low-frequency mode suggests that
      the cooperative fluctuation of directors over long range exists in the
      SmC(alpha)* phase.

PMID- 15010925
TI  - Catching the PEG-induced attractive interaction between proteins.
AB  - We present the experimental and theoretical background of a method to
      characterize the protein-protein attractive potential induced by one of the
      mostly used crystallizing agents in the protein-field, the poly(ethylene glycol)
      (PEG). This attractive interaction is commonly called, in colloid physics, the
      depletion interaction. Small-Angle X-ray Scattering experiments and numerical
      treatments based on liquid-state theories were performed on urate oxidase-PEG
      mixtures with two different PEGs (3350 Da and 8000 Da). A "two-component"
      approach was used in which the polymer-polymer, the protein-polymer and the
      protein-protein pair potentials were determined. The resulting effective protein
      protein potential was characterized. This potential is the sum of the free
      polymer protein-protein potential and of the PEG-induced depletion potential. The
      depletion potential was found to be hardly dependent upon the protein
      concentration but strongly function of the polymer size and concentration. Our
      results were also compared with two models, which give an analytic expression for
      the depletion potential.

PMID- 15010926
TI  - Surface effects in thin films of antiferroelectric smectic liquid crystals in
      terms of the short-pitch long-pitch competition model.
AB  - A theoretical model based on the competition between short-pitch and long-pitch
      types of helical order is developed for thin films of antiferroelectric smectic
      liquid crystals. In the case of the "bookshelf" structure of the film and non
      polar surfaces, subsurface perturbations of the ordering are found out
      analytically. Corresponding contributions to the free energies of the different
      phases are analysed. The possibility of sufficient influence of the boundaries on
      phase sequences is predicted even in the case of weak surface anchoring. A
      consistent explanation of the controversial experimental information is given;
      further ways of experimental justification of the model assumptions are
      discussed.

PMID- 15010927
TI  - Nucleation and growth of cavities in soft viscoelastic layers under tensile
      stress.
AB  - The process of growth of an individual cavity in a viscoelastic adhesive layer
      has been investigated experimentally. The formation of cavities was caused by the
      application of a negative pressure on a very confined layer with a flat-ended
      probe. The cavities appeared in the bulk of the adhesive layer and were observed
      for a range of values of applied stress approximately ten times higher than the
      shear modulus of the adhesive layer. Depending on the loading rate, the shape of
      the growing cavity changed from a flat disc to a more spherical shape.
      Furthermore, the growth rate of the cavity radius was consistent with a constant
      strain rate at the edge of the cavity, which suggests a constant level of stress
      at the edge of the cavity.

PMID- 15010928
TI  - Radial distribution function of rod-like polyelectrolytes.
AB  - We study the effect of electrostatic interactions on the distribution function of
      the end-to-end distance of a single polyelectrolyte chain in the rod-like limit.
      The extent to which the radial distribution function of a polyelectrolyte is
      reproduced by that of a wormlike chain with an adjusted effective persistence
      length is investigated. Strong evidence is found for a universal scaling formula
      connecting the effective persistence length of a polyelectrolyte with the
      strength of the electrostatic interaction and the Debye screening length.

PMID- 15010929
TI  - Nanorheology: An investigation of the boundary condition at hydrophobic and
      hydrophilic interfaces.
AB  - It has been shown that the flow of a simple liquid over a solid surface can
      violate the so-called no-slip boundary condition. We investigate the flow of
      polar liquids, water and glycerol, on a hydrophilic Pyrex surface and a
      hydrophobic surface made of a Self-Assembled Monolayer of OTS
      (octadecyltrichlorosilane) on Pyrex. We use a Dynamic Surface Force Apparatus
      (DSFA) which allows one to study the flow of a liquid film confined between two
      surfaces with a nanometer resolution. No-slip boundary conditions are found for
      both fluids on hydrophilic surfaces only. Significant slip is found on the
      hydrophobic surfaces, with a typical length of one hundred nanometers.

PMID- 15010930
TI  - Aggregation of particles settling in shear-thinning fluids. Part 2. Three
      particle aggregation.
AB  - We have experimentally studied the coaxial settling of three identical non
      Brownian spheres in a shear-thinning fluid at small Reynolds numbers. While
      settling, the particles create corridors of reduced viscosity in their wake and,
      if they are initially close enough to one another, they can form stable clusters.
      By analogy with previous results obtained on two-particle interaction in the
      first part of this work, we show that the particle velocities can be
      satisfactorily described using a first-order expression and assuming that the
      reduced viscosity remains constant. We report systematic experiments performed at
      different initial separation distances between particles and the use of our
      simple model allows the prediction of the settling behaviour and in particular
      the conditions for clusters formation. We thus show that particle aggregation can
      occur even for large initial distances between particles and within times that
      are small compared to the time scales in Newtonian fluids.

PMID- 15010931
TI  - Polymer collapse in the presence of hydrodynamic interactions.
AB  - We investigate numerically the dynamical behaviour of a polymer chain collapsing
      in a dilute solution. The rate of collapse is measured with and without the
      presence of hydrodynamic interactions. We find that hydrodynamic interactions
      both accelerate polymer collapse and alter the folding pathway.

PMID- 15010932
TI  - The secondary structure of RNA under tension.
AB  - We study the force-induced unfolding of random disordered RNA or single-stranded
      DNA polymers. The system undergoes a second-order phase transition from a
      collapsed globular phase at low forces to an extensive necklace phase with a
      macroscopic end-to-end distance at high forces. At low temperatures, the sequence
      inhomogeneities modify the critical behaviour. We provide numerical evidence for
      the universality of the critical exponents which, by extrapolation of the scaling
      laws to zero force, contain useful information on the ground-state (f = 0)
      properties. This provides a good method for quantitative studies of scaling
      exponents characterizing the collapsed globule. In order to get rid of the
      blurring effect of thermal fluctuations, we restrict ourselves to the ground
      state at fixed external force. We analyze the statistics of rearrangements, in
      particular below the critical force, and point out its implications for force
      extension experiments on single molecules.

PMID- 15010933
TI  - Non-uniformities in polymer/liquid crystal mixtures I. Interfacial tension.
AB  - We theoretically study interfacial properties between two coexisting phases in
      mixtures of a flexible polymer and a low-molecular-weight liquid crystal. By
      numerically solving Euler equations for compositional and orientational order
      parameter fields, we calculate the order parameter profiles and interfacial
      tensions for nematic-isotropic and isotropic-isotropic phase equilibria. We find
      that the order parameter profiles are non-monotonic at some temperatures. The
      nematic-isotropic interfacial tension increases with decreasing temperature and
      is approximately proportional to (T - T(NI))(n) at temperatures below the nematic
      isotropic transition temperature (T(NI)) of the pure nematogen. The value of the
      exponent n is strongly affected by the existence of a triple point.

PMID- 15010934
TI  - Non-uniformities in polymer/liquid crystal mixtures II. Nematic nucleation.
AB  - We theoretically model the nucleation of nematic droplets during phase ordering
      in mixtures of a flexible polymer and a low-molecular-weight liquid crystal. By
      appealing to classical nucleation theory (CNT), we calculate the energy barrier
      to nucleation and the size of a critical nucleus. We study the influence of a
      metastable intermediate phase on the nucleation of the nematic. Below a triple
      point in the phase diagram, there are two distinct mechanisms for the formation
      of a nematic nucleus: 1) direct nucleation from the isotropic phase and 2)
      nucleation via a precursor metastable isotropic phase. We calculate the crossover
      concentration as a function of temperature, delineating the regions of the phase
      diagram in which each mechanism prevails. In the latter case, the presence of a
      hidden metastable isotropic-isotropic binodal may either promote or delay the
      nucleation of a nematic phase.

PMID- 15010935
TI  - Fouling dynamics in suspension flows.
AB  - A particle suspension flowing in a channel in which fouling layers are allowed to
      form on the channel walls is investigated by numerical simulation. A two
      dimensional phase diagram with at least four different behaviors is constructed.
      The fouling is modeled by attachment during collision with the deposits and by
      detachment caused by large enough hydrodynamic drag. For fixed total number of
      particles and small Reynolds numbers, the relevant parameters governing the
      fouling dynamics are the solid volume fraction of the suspension and the
      detachment drag force threshold. Below a critical curve in this 2D phase space
      only transient fouling takes place when the suspension is accelerated from rest
      by a pressure gradient. Above the fouling transition line, persistent fouling
      layers are formed via ballistic deposition for low and via homogeneous deposition
      for large solid volume fractions. Close to the fouling transition line, the flow
      path between the deposited layers meanders, while necking appears for increasing
      distance from the transition. Finally, another transition to a fully blocked flow
      path takes place. As determined by the estimated amount of deposited particles at
      saturation, both transitions seem to be discontinuous. Large fluctuations and
      long saturation times are typical of the dynamics of the system.

PMID- 15010936
TI  - Hole nucleation in thin diblock copolymer films.
AB  - This paper reports an experimental study of a homogeneous nucleation process in
      the direct space, using an atomic-force microscope. Nucleated patterns are holes
      in a thin diblock copolymer film. The formation of nuclei from the metastable
      majority phase is followed either by the dissolution or by the growth of the
      hole. It is also preceded by the unexpected presence of a bump at the free
      surface. From the study of the nucleus surface topography at different stages of
      the evolution, we infer a description of the nucleation mechanism at a molecular
      level. It involves the existence of ordered metastable states characterized by
      the presence of compressed internal layers, the formation of pores in the center
      of the film, and the existence of interfacial flows across these pores. The
      presence of compressed internal layers was directly demonstrated using Neutron
      Reflectivity experiments, Our scheme is also consistent with all existing
      experimental data. After hole nucleation, we identify two distinct growth
      regimes: the first one is individual and the second one is interactive.

PMID- 15010937
TI  - Stripe patterns in the magnetic reorientation of a glass-forming nematic liquid
      crystal.
AB  - We study spontaneous pattern formation in a glass-forming nematic liquid crystal
      during the magnetically induced dynamic Freedericksz transition. Pattern growth
      rates and wavelengths as functions of the magnetic field are extracted from
      optical transmission textures of thin planar cells. The characteristics of the
      observed stripe pattern can be related to viscoelastic parameters of the nematic
      by means of a linear stability analysis of director fluctuation modes. The
      viscous properties of the material allow to vary the time scales of the
      experiment with temperature by orders of magnitude, leaving the spatial structure
      of the pattern essentially unchanged. We find that the ratios of shear and
      rotational viscosity coefficients relevant for the pattern wavelength selection
      remain constant in the temperature range investigated, whereas their absolute
      values change by almost two orders.

PMID- 15010938
TI  - Effects of properties of the surfactant on its aggregate behavior.
AB  - The effects of the solvent-surfactant interaction, chain length and stiffness of
      surfactants on the formation of aggregates and the aggregation degree of
      surfactants in the two-dimension solution have been investigated using
      discontinuous molecular-dynamics simulations. When the tail-water repulsion
      increases or the head-water attraction decreases, the aggregation degree
      increases. Increasing the chain length and raising the stiffness of surfactants
      lead to the increment of the aggregation degree.

PMID- 15010939
TI  - pH-dependent color change of colloidal dispersions of gold nanoclusters: effect
      of stabilizer.
AB  - Gold nanoclusters protected by 3-mercaptopropionic acid (MPA-Au nanoclusters)
      were prepared by citrate-reduction of hydrogen tetrachloroaurate(III) in the
      presence of sodium 3-mercaptopropionate. Color of the dispersions of MPA-Au
      nanoclusters changed from red to purple by addition of hydrochloric acid and
      returned from purple to red by addition of an aqueous sodium hydroxide solution.
      This reversible response can be attributed to synchronized changes between
      dispersion and ordering of MPA-Au nanoclusters, determined by transmission
      electron microscopy. Gold nanoclusters protected by poly(acrylic acid) (PAA-Au
      nanoclusters) were prepared by UV irradiation of an aqueous solution of hydrogen
      tetrachloroaurate(III) in the presence of poly(sodium acrylate). The pH-dependent
      spectral change observed for MPA-Au was not observed for PAA-Au. UV-Vis
      absorption spectra of colloidal dispersions of PAA-Au nanoclusters after addition
      of hydrochloric acid and an aqueous sodium hydroxide solution were in good
      agreement with each other, suggesting the stability of PAA-Au nanoclusters to pH
      change.

PMID- 15010940
TI  - Adhesion between an elastic body and a randomly rough hard surface.
AB  - I have developed a theory of adhesion between an elastic solid and a hard
      randomly rough substrate. The theory takes into account that partial contact may
      occur between the solids on all length scales. I present numerical results for
      the case where the substrate surface is self-affine fractal. When the fractal
      dimension is close to 2, complete contact typically occurs in the macro-asperity
      contact areas, while when the fractal dimension is larger than 2.5, the area of
      (apparent) contact decreases continuously when the magnification is increased. An
      important result is that even when the surface roughness is so high that no
      adhesion can be detected in a pull-off experiment, the area of real contact (when
      adhesion is included) may still be several times larger than when the adhesion is
      neglected. Since it is the area of real contact which determines the sliding
      friction force, the adhesion interaction may strongly affect the friction force
      even when no adhesion can be detected in a pull-off experiment.

PMID- 15010941
TI  - Phase transitions in lyotropic nematic gels.
AB  - In this paper, we discuss the equilibrium phases and collapse transitions of a
      lyotropic nematic gel immersed in an isotropic solvent. A nematic gel consists of
      a cross-linked polymer network with rod-like molecules embedded in it. Upon
      decreasing the quality of the solvent, we find that a lyotropic nematic gel
      undergoes a discontinuous volume change accompanied by an isotropic-nematic
      transition. We also present phase diagrams that these systems may exhibit. In
      particular, we show that coexistence of two isotropic phases, of two nematic
      phases, or of an isotropic and a nematic phase can occur.

PMID- 15010942
TI  - Smectic-A edge dislocations in a very thin cell.
AB  - We study stable "bookshelf" smectic-A structures within a very thin plane
      parallel cell of thickness L in which the mismatch between surface preferred
      (d(s)) and intrinsic (d(0)) smectic layer thicknesses occurs. The Landau-Ginzburg
      approach based on a complex smectic order parameter is used. For a weak enough
      smectic positional anchoring strength W smectic layers adopt the modified
      bookshelf profile. In a thick enough cell with increasing W a lattice of edge
      dislocations is continuously formed at the confining surfaces and then depinned
      from them. The structure with dislocations is formed when the condition
      d(0)/(zeta(s)/d(0)/d(s)-1/) approximately 2 is fulfilled, where zeta(s) is the
      positional surface anchoring extrapolation length. If the cell is thin enough the
      dislocations formed at opposite cell plates annihilate and consequently the
      smectic layers adopt a locked bookshelf structure. This transition is
      discontinuous and takes place when d(0)/(L/d(0)/d(s)-1/) approximately 5 is
      realized. To observe these transitions in a cell of thickness L approximately
      1microm the conditions W approximately 10(-6) J/ m(2) and /d(0)/d(s) - 1/
      approximately 5 x 10(-4) have to be fulfilled. All the three qualitatively
      different structures coexist at the triple point.

PMID- 15010943
TI  - Vertical water distribution during the drying of polymer films cast from aqueous
      emulsions.
AB  - We present a systematic study of the vertical uniformity of water distribution
      during the drying of waterborne colloidal films, testing the predictions of a
      Peclet number Pe defined for this system. Pe indicates the relative contributions
      of water evaporation and Brownian diffusion in determining the concentration
      profile in the vertical direction ( i.e. normal to the substrate). When Pe < 1,
      the water concentration in films cast from an alkyd emulsion is found via
      magnetic-resonance profiling to be uniform with depth, which is consistent with
      expectations. When Pe > 1, a gradient in the water concentration develops, with
      less water near the interface with air. The water profiles reveal that the alkyd
      particles do not coalesce immediately upon contact in close-packing. At later
      times, a concentrated surface layer develops, but particles are not coalesced in
      this layer to form a continuous "skin", but rather the structure is likely to be
      that of a biliquid foam.

PMID- 15010944
TI  - Brownian motion of particles embedded in a solution of giant micelles.
AB  - We have measured the mean-square displacement of colloidal particles embedded in
      a semi-dilute solution of worm-like micelles, using diffusing wave spectroscopy.
      This allowed us to describe their rheological properties over a very wide time
      range. At very short times, the particles diffuse freely in the solvent, and
      then, they experience the characteristic relaxation times of the living chains.
      We deduced directly, from the mean-square displacement of the particles, the
      mechanical properties of the micellar solution, not only in the high-frequency
      regime, but also in the low-frequency range, in which we compared our results
      with direct mechanical measurements, and found good agreement.

PMID- 15010945
TI  - Roughness and dynamics of a contact line of a viscous fluid on a disordered
      substrate.
AB  - We have studied the roughness and the dynamics of the contact line of a viscous
      liquid on a disordered substrate. We have used photolithographic techniques to
      obtain a controlled disorder with a correlation length xi = 10microm. Liquids
      with different viscosity were used: water and aqueous glycerol solution. We have
      found that the roughness W of the contact line depends neither on the viscosity
      nor on the velocity v of the contact line for v in the range 0.2-20microm/s. W is
      found to scale with the length L of the line as L(zeta) with a roughness exponent
      zeta = 0.51+/-0.03. This value is similar to the one obtained with superfluid
      helium. In the present experiment, we have checked that the motion of the contact
      line is actually overdamped, so that the phenomenological equation first proposed
      by Ertas and Kardar should be relevant. However, our measurement of zeta is in
      disagreement with the predicted value zeta = 0.39. We have also analyzed the
      avalanche-like motion of the contact line. We find that the size distribution
      does not follow a power law dependence.

PMID- 15010946
TI  - Experimental study of cracking induced by desiccation in 1-dimensional systems.
AB  - We designed a simple experiment to study both the dynamical and statistical
      properties of cracking that occurs in a one-dimensional system composed of wet
      clay (or similar material) exposed to shrinkage induced by desiccation. We study
      both the dynamical formation of cracks and the statistical characteristics of the
      final cracks pattern. We observe that the drying rate has a strong influence on
      the way cracks appear and grow. We find that the final crack width is related to
      the order of apparition of the cracks. We discuss the statistical distributions
      of cracks width and separation between two adjacent cracks. We also study the
      correlations between these two quantities. Our results are compared to the
      predictions of existing models. Finally, a comparison with another kind of clay
      is made.

PMID- 15010947
TI  - Dynamical precursor of nematic order in a dense fluid of hard ellipsoids of
      revolution.
AB  - We investigate hard ellipsoids of revolution in a parameter regime where no long
      range nematic order is present but already finite-size domains are formed which
      show orientational order. Domain formation leads to a substantial slowing down of
      a collective rotational mode which separates well from the usual microscopic
      frequency regime. A dynamic coupling of this particular mode into all other modes
      provides a general mechanism which explains an excess peak in spectra of
      molecular fluids. Using molecular dynamics simulation on up to 4096 particles and
      on solving the molecular mode coupling equation we investigate dynamic properties
      of the peak and prove its orientational origin.

PMID- 15010948
TI  - Dewetting of solid-supported multilamellar lipid layers.
AB  - Thin multilamellar assemblies of neutral lipid bilayers deposited on silicon
      substrates are shown to be unstable upon hydration. We analyze the stability of
      these systems taking into account a reduction of the fluctuation-related
      components of the bilayer interaction potential. The sizes of the patterns
      observed are consistent with a spinodal dewetting process.

PMID- 15010949
TI  - Thermophysical properties of fluorinated acrylate homopolymers: mixing and phase
      separation.
AB  - The thermophysical properties of fluorinated acrylate homopolymers are
      investigated by differential scanning calorimetry (DSC) and optical microscopy
      and discussed in terms of relative lengths of the fluorinated chain and the
      hydrocarbon spacer between the acrylate moiety and the fluorinated chain. These
      compounds exhibit an intrinsic microphase-separation (Isotropic+Isotropic
      morphology) occurring between the fluorinated chains and the acrylate polymer
      backbone. It is shown that the enthalpy of mixing is a function of the length of
      the lateral fluorocarbon chains. The thermophysical behaviour of these materials
      may be regarded as demixed systems exhibiting an Upper Critical Solution
      Temperature. The photopolymerization process of one of the monomer is studied by
      isothermal photocalorimetry. High acrylate double-bond conversion and fast curing
      rates were obtained thus demonstrating the promising use of these materials for
      coating and film processing applications using UV-curing techniques.

PMID- 15010950
TI  - Branched crystal morphology of linear polyethylene crystallized in a two
      dimensional diffusion-controlled growth field.
AB  - The branched crystal morphology of linear polyethylene formed at various
      temperatures from thin films has been studied by atomic-force microscopy (AFM),
      transmission electron microscopy (TEM), electron diffraction (ED) pattern and
      polymer decoration technique. Two types of branched patterns, i.e. dendrite and
      seaweed patterns, have been visualized. The fractal dimension d(f) = 1.65 of both
      dendrite and some of seaweed patterns was obtained by using the box-counting
      method, although most of the seaweed patterns are compact. Selected-area ED
      patterns indicate that the fold stems tilt about 34.5( degrees ) around the b
      axis and polymer decoration patterns show that the chain folding direction and
      regularity in two (200) regions are quite different from each other. Because of
      chain tilting, branched crystals show three striking features: 1) the lamella
      like branches show two (200) regions with different thickness; 2) the crystals
      usually bend towards the thin region; 3) the thick region grows faster by
      developing branches, thus branches usually occur outside the thick region. The
      branched patterns show a characteristic width w, which gives a linear
      relationship with the crystallization temperature on a semilogarithmic plot.

PMID- 15010951
TI  - The distribution of counterions around synthetic rod-like polyelectrolytes in
      solution: a study by small-angle X-ray scattering and by anomalous small-angle X
      ray scattering.
AB  - An investigation of the radial distribution of the counterions of a synthetic
      rodlike polyelectrolyte in aqueous solution is presented. The cationic
      polyelectrolyte used here has a poly(p-phenylene) backbone. For typical molecular
      weights the macroion comprises approximately one persistence length (ca. 20 nm)
      and effects of finite stiffness may be disregarded. Each repeating unit bears
      four charges which leads to a charge parameter of xi = 6.65. The distribution of
      the iodide counterions around this highly charged macroion is studied by small
      angle X-ray scattering (SAXS) in dilute aqueous solution. These investigations
      are supplemented by measurements using anomalous small-angle X-ray scattering
      (ASAXS) that furnishes additional information about the contrast of the macroion.
      Data taken at high scattering angles give indication for contributions caused by
      the longitudinal fluctuations of the counterions. After correction for this
      effect the experimental results are compared to intensities calculated by use of
      the Poisson-Boltzmann (PB)-cell model. It is found that the PB-cell model
      describes the corrected data at intermediate and high scattering angles.
      Deviations at low scattering angle are attributed to the mutual interaction of
      the rod-like polyelectrolyte that can be described in terms of an effective
      structure factor. Data taken at lowest scattering angles point to a weak
      attraction between the rod-like macroions.

PMID- 15010952
TI  - SAXS investigation on aggregation phenomena in supercritical CO2.
AB  - Synchrotron Small-Angle X-Ray scattering (SAXS) measurements on aggregate
      formation of a Polyvinyl acetate- b-Perfluoro octyl acrylate (PVAc- b-PFOA) block
      copolymer in supercritical CO(2) are here reported. Experiments were carried out
      for a series of different thermodynamic conditions, changing the solvent density
      by profiling both the pressure at constant temperature and the temperature at
      constant pressure. This block copolymer and in general fluorocarbon-hydrocarbon
      di-blocks form aggregates depending on the value of CO(2) density. A sharp
      transition between monomers dissolved as random coils and micelles characterized
      by a solvophilic shell and a solvophobic core occurs when the CO(2) density
      reaches a critical value. Results of critical micellization density (CMD) derived
      from pressure and temperature ramps experiment along with the comparison with
      previous SANS results are here reported to give additional experimental support
      to the solvent density-driven aggregation process.

PMID- 15010953
TI  - Application of the Sherman-Morisson formula to scattering problems by multi
      component systems.
AB  - The scattering matrix for multi-component systems is recalculated using the
      extended form of the Sherman-Morisson formula. The matrix elements are given
      explicitly in closed form. The Gibbs-Duhem relation separates the density and
      composition contributions.

PMID- 15010954
TI  - Adsorption of polyampholytes on charged surfaces.
AB  - We have studied the adsorption of neutral polyampholytes on model charged
      surfaces that have been characterized by contact angle and streaming current
      measurements. The loop size distributions of adsorbed polymer chains have been
      obtained using atomic-force microscopy (AFM) and compared to recent theoretical
      predictions. We find a qualitative agreement with theory; the higher the surface
      charge, the smaller the number of monomers in the adsorbed layer. We propose an
      original scenario for the adsorption of polyampholytes on surfaces covered with
      both neutral long-chain and charged short-chain thiols.

PMID- 15010955
TI  - Rheological aging and rejuvenation in solid friction contacts.
AB  - We study the low-velocity (0.1-100 microm s(-1)) frictional properties of
      interfaces between a rough glassy polymer and smooth silanized glass, a
      configuration which gives direct access to the rheology of the adhesive joints in
      which shear localizes. We show that these joints exhibit the full phenomenology
      expected for confined quasi-2D soft glasses: they strengthen logarithmically when
      aging at rest, and weaken (rejuvenate) when sliding. Rejuvenation is found to
      saturate at large velocities. Moreover, aging at rest is shown to be strongly
      accelerated when waiting under finite stress below the static threshold.

PMID- 15010956
TI  - Equilibrium charge distribution on annealed polyelectrolytes.
AB  - Monte Carlo simulations are used to study the non-uniform equilibrium charge
      distribution along a single annealed polyelectrolyte chain under theta solvent
      conditions and with added salt. Within a range of the order of the Debye length
      charge accumulates at chain ends while a slight charge depletion appears in the
      central part of the chain. The simulation results are compared with theoretical
      predictions recently given by Castelnovo et al. In the parameter range where the
      theory can be applied we find almost perfect quantitative agreement.

PMID- 15010957
TI  - Acoustic instabilities in thin polymer films.
AB  - The spatial confinement of a fluctuation spectrum leads to forces at the
      confining boundaries. While electromagnetic (EM) fluctuations lead to the well
      known dispersion forces, the acoustic analogy has widely been neglected. We show
      that the strength of the forces resulting from confined acoustic modes may be of
      the same order of magnitude as van der Waals forces. Additionally, the predicted
      scaling behavior is identical to the non-retarded case of the EM fluctuations.
      Our results suggest that dewetting experiments using polymer films are strongly
      influenced by the acoustic dispersion forces.

PMID- 15010958
TI  - Special issue on properties of thin polymer films.

PMID- 15010959
TI  - Influence of surface ordering on the wetting of structured liquids.
AB  - The substrate is shown to induce substantial ordering in diblock copolymer thin
      films above the bulk order-disorder transition (ODT) where, thermodynamically, a
      phase mixed state is favored. Initially, uniform films reorganize to form a
      hierarchy of transient surface patterns and stable film thicknesses that depend
      on the initial film thickness and on the substrate. Self-consistent field
      calculations of the free energy of the system for different situations, depending
      on the relative tendency for the different block components to be attracted to
      the substrate and/or free surface, provide an explanation of the formation of the
      stable film thicknesses. A continuum picture proposed earlier by Brochard et al.
      provides an explanation of the wetting characteristics of this system. In some
      cases the ordering destabilizes the film so that dewetting occurs (wetting
      autophobicity), whereas in other cases the surface ordering results in a kinetic
      stabilization of a film that would otherwise dewet.

PMID- 15010960
TI  - Surface visco-elastic moduli of a Langmuir film of a polystyrene-polydimethyl
      siloxane block copolymer at the air-ethyl benzoate interface.
AB  - Surface quasi-elastic light scattering has been applied to a spread film of a
      block copolymer of polystyrene and polydimethyl siloxane. The influence of
      surface concentration (surface pressure) at a fixed surface wave number has been
      explored. The capillary wave frequency and damping showed a similar dependence on
      the surface concentration as values obtained earlier, but due to a more
      appropriate analysis of the correlation functions, surface visco-elastic moduli
      obtained were distinctly different. By correlating the values obtained with the
      variations in solvated polystyrene layer thickness from neutron reflectometry,
      the maximum in dilational modulus was shown to occur at the same nominal surface
      concentration where the layer begins to stretch and take on brush-like behaviour.
      This same surface concentration is where the relaxation time of the spread film
      also has a maximum value, the relaxation time being calculated using the standard
      linear model of visco-elasticity, which was found to fit the frequency dependence
      of the surface tension and dilational moduli at the resonant nominal surface
      concentration of 3.1 mg m(-2).

PMID- 15010961
TI  - Film thickness effects on the distribution of high-molecular-weight
      heterotelechelic polymers.
AB  - High-molecular-weight heterotelechelic deuteriopolystyrene, NDPSF, possessing an
      amine functional group at one end of the chain and a fluorocarbon group at the
      other was tethered to a silicon substrate by its amine functional group. These
      layers were coated with an unfunctionalised polystyrene matrix, HPS, such that
      the total film thickness covered a range from 2.2 to 9 times the radius of
      gyration of NDPSF. The detailed distribution of the polymers after annealing for
      times much greater than the reptation period of either of the components, was
      obtained using neutron reflectometry. No evidence for bridging of the two
      interfaces was found for the thicker films, but the finite concentration of the
      NDPSF polymer observed for the thinnest films may be due to bridging since the
      energy gain of the fluorocarbon end is just greater than the loss due to
      configurational entropy losses. A linear increase in the ellipsometric thickness
      of the excess of NDPSF at the substrate was discovered and we attribute this to
      the NDPSF slowly being leached out of the layer initially at the substrate
      followed by diffusion into the bulk of the film. The concentration profiles
      obtained are consistent with hindered relaxation of the large NDPSF molecules,
      when they are tethered at the substrate or at the vacuum surface.

PMID- 15010962
TI  - Using adhesion to probe viscoelasticity of polymer film surfaces: a quartz
      crystal microbalance study.
AB  - We have used a quartz crystal microbalance to monitor the adhesion of small
      particles to the surface of polystyrene films. This technique is shown to provide
      a signature of viscoelastic relaxation processes at the polymer surface. For M(n)
      values less than 10(4) and greater than 10(5), this signature occurs at a
      temperature approximately 12.5 K above the measured bulk glass transition
      temperature, T(g). For intermediate values of M(n) however, the relaxation
      signature occurs at temperatures as low as 7 K above the bulk T(g). This
      observation suggests a slight decrease in the T(g) value near the polymer
      surface. A model incorporating the effects of enrichment of polymer chain ends at
      the free surface was considered and found to provide a quantitative description
      of the data.

PMID- 15010963
TI  - The timescale of spinodal dewetting at a polymer/polymer interface.
AB  - We investigate the dynamics of spinodal dewetting in liquid-liquid polymer
      systems. Dewetting of poly(methyl-methacrylate) (PMMA) thin films on polystyrene
      (PS) "substrates" is followed in situ using neutron reflectivity. By following
      the development of roughness at the PS/PMMA interface and the PMMA surface we
      extract characteristic growth times for the dewetting process. These
      characteristic growth times are measured as a function of the molecular weight of
      the two polymers. By also carrying out experiments in the regime where the
      dynamics are independent of the PS molecular weight, we are able to use dewetting
      to probe the scaling of the PMMA thin film viscosity with temperature and
      molecular weight. We find that this scaling reflects bulk behaviour. However,
      absolute values are low compared to bulk viscosities, which we suggest may be due
      in part to slippage at the polymer/polymer interface.

PMID- 15010964
TI  - Molecular dynamics in thin films of isotactic poly(methyl methacrylate).
AB  - The molecular dynamics in thin films (18 nm-137 nm) of isotactic poly(methyl
      methacrylate) (i-PMMA) of two molecular weights embedded between aluminium
      electrodes are measured by means of dielectric spectroscopy in the frequency
      range from 50 mHz to 10 MHz at temperatures between 273 K and 392 K. The observed
      dynamics is characterized by two relaxation processes: the dynamic glass
      transition (alpha-relaxation) and a (local) secondary beta-relaxation. While the
      latter does not depend on the dimensions of the sample, the dynamic glass
      transition becomes faster (<or=2 decades) with decreasing film thickness. This
      results in a shift of the glass transition temperature T(g) to lower values
      compared to the bulk. With decreasing film thickness a broadening of the
      relaxation time distribution and a decrease of the dielectric strength is
      observed for the alpha-relaxation. This enables to deduce a model based on
      immobilized boundary layers and on a region displaying a dynamics faster than in
      the bulk. Additionally, T(g) was determined by temperature-dependent
      ellipsometric measurements of the thickness of films prepared on silica. These
      measurements yield a gradual increase of T(g) with decreasing film thickness. The
      findings concerning the different thickness dependences of T(g) are explained by
      changes of the interaction between the polymer and the substrates. A quantitative
      analysis of the T(g) shifts incorporates recently developed models to describe
      the glass transition in thin polymer films.

PMID- 15010965
TI  - Confinement and processing effects on glass transition temperature and physical
      aging in ultrathin polymer films: novel fluorescence measurements.
AB  - Fluorescence intensity measurements of chromophore-doped or -labeled polymers
      have been used for the first time to determine the effects of decreasing film
      thickness on glass transition temperature, T(g), the relative strength of the
      glass transition, and the relative rate of physical aging below T(g) in
      supported, ultrathin polymer films. The temperature dependence of fluorescence
      intensity measured in the glassy state of thin and ultrathin films of pyrene
      doped polystyrene (PS), poly(isobutyl methacrylate) (PiBMA), and poly(2
      vinylpyridine) (P2VP) differs from that in the rubbery state with a transition at
      T(g). Positive deviations from bulk T(g) are observed in ultrathin PiBMA and P2VP
      films on silica substrates while substantial negative deviations from bulk T(g)
      are observed in ultrathin PS films on silica substrates. The relative difference
      in the temperature dependences of fluorescence intensity in the rubbery and
      glassy states is usually reduced with decreasing film thickness, indicating that
      the strength of the glass transition is reduced in thinner films. The temperature
      dependence of fluorescence intensity also provides useful information on effects
      of processing history as well as on the degree of polymer-substrate interaction.
      In addition, when used as a polymer label, a mobility-sensitive rotor chromophore
      is demonstrated to be useful in measuring relative rates of physical aging in
      films as thin as 10 nm.

PMID- 15010966
TI  - Confinement-induced differences between dielectric normal modes and segmental
      modes of an ion-conducting polymer.
AB  - Dielectric measurement in the range 0.1 Hz to 1 MHz were used to study the
      motions of polymers and ions in an ion-conducting polymer, polypropylene oxide
      containing small quantities (on the order of 1%) of lithium ions (LiClO(4)),
      confined as a sandwich of uniform thickness between parallel insulating mica
      surfaces. In the dielectric loss spectrum, we observed three peaks; they
      originated from the normal mode of the polymer, segmental mode of the polymer,
      and ion motions. With decreasing film thickness, the peak frequencies
      corresponding to the normal mode and ion motion shifted to lower frequencies,
      indicating retardation due to confinement above 30 nm. This was accompanied by
      diminished intensity of the dielectric normal-mode relaxation, suggesting that
      confinement diminished the fluctuations of the end-to-end vector of the chain
      dipole in the direction between the confining surfaces. On the contrary, the
      segmental mode was not affected at that thickness. Finally, significant
      retardation of the segmental mode was observed only for the thinnest film (14
      nm). The different dynamical modes of the polymer (segmental and slowest normal
      modes) respond with different thickness and temperature dependence to
      confinement.

PMID- 15010967
TI  - Static and dynamic properties of supercooled thin polymer films.
AB  - The dynamic and static properties of a supercooled (non-entangled) polymer melt
      are investigated via molecular-dynamics (MD) simulations. The system is confined
      between two completely smooth and purely repulsive walls. The wall-to-wall
      separation (film thickness), D, is varied from about 3 to about 14 times the bulk
      radius of gyration. Despite the geometric confinement, the supercooled films
      exhibit many qualitative features which were also observed in the bulk and could
      be analyzed in terms of mode-coupling theory (MCT). Examples are the two-step
      relaxation of the incoherent intermediate scattering function, the time
      temperature superposition property of the late time alpha-process and the space
      time factorization of the scattering function on the intermediate time scale of
      the MCT beta-process. An analysis of the temperature dependence of the alpha
      relaxation time suggests that the critical temperature, T(c), of MCT decreases
      with D. If the confinement is not too strong ( D>or=10monomer diameter), the
      static structure factor of the film coincides with that of the bulk when compared
      for the same distance, T - T(c)( D), to the critical temperature. This suggests
      that T - T(c)( D) is an important temperature scale of our model both in the bulk
      and in the films.

PMID- 15010968
TI  - The origins of fast segmental dynamics in 2 nm thin confined polymer films.
AB  - Molecular-Dynamics computer simulations were used to study 2 nm wide polystyrene
      films confined in slit pores, defined by inorganic crystalline surfaces. The
      simulated systems mimic experimentally studied hybrid materials, where
      polystyrene is intercalated between mica-type, atomically smooth, crystalline
      layers. A comparison between the experimental findings and the simulation results
      aims at revealing the molecular origins of the macroscopically observed behavior,
      and thus provide insight about polymers in severe/nanoscopic confinements, as
      well as polymers in the immediate vicinity of solid surfaces. Pronounced dynamic
      inhomogeneities are found across the 2 nm thin film, with fast relaxing moieties
      located in low local density regions throughout the film. The origins of this
      behavior are traced to the confinement-induced density inhomogeneities, which are
      stabilized over extended time scales by the solid surfaces.

PMID- 15010969
TI  - Effects of entanglement concentration on Tg and local segmental motions.
AB  - The process of spin-coating to fabricate thin polymer films with high molecular
      weight can produce samples with entanglement concentrations that are far below
      the equilibrium value. It is not clear whether or not such low entanglement
      concentrations are responsible for the depression of the glass temperature in
      thin polymer films. In this work, we measure the calorimetric glass temperature
      and viscoelastic response of polystyrenes with molecular weights ranging from
      3x10(3) to 43.7x10(6) g/mol, for both bulk material and for samples freeze-dried
      from dilute solution. We conclude that the reduction of the glass temperature
      observed in thin polymer films cannot be due to the reduced entanglement
      concentration in the samples.

PMID- 15010970
TI  - Enthalpy recovery of a glass-forming liquid constrained in a nanoporous matrix:
      negative pressure effects.
AB  - The T(g) of organic liquids confined to nanoporous matrices and that of thin
      polymer films can decrease dramatically from the bulk value. One possible
      explanation for this phenomenon is the development of hydrostatic tension during
      vitrification under confinement that results in a concomitant increase in the
      free volume. Here we present experimental evidence and modeling results for ortho
      terphenyl (o-TP) confined in pores as small as 11.6 nm that indicate that,
      although there is an important hydrostatic tension in the liquid in the pores, it
      does not develop until near the reduced T(g) of the constrained material --well
      below the bulk T(g). Enthalpy recovery for the o-TP in the nanopores exhibits
      accelerated physical aging relative to the bulk, as well as a leveling off of the
      fictive temperature at equilibrium values greater than the aging temperature. An
      adaptation of the structural recovery model that incorporates vitrification under
      isochoric conditions is able to provide a quantitative explanation for the
      apparently anomalous aging observed in nanopore confined liquids and in thin
      polymeric films. The results strongly support the existence of an intrinsic size
      effect as the cause of the reduced T(g).

PMID- 15010971
TI  - Some relevant parameters affecting the glass transition of supported ultra-thin
      polymer films.
AB  - We have measured, the thickness dependence of the glass transition temperature
      T(g)( h), using ellipsometry at variable temperature, for poly(methyl
      methacrylate) (PMMA) of various tacticity in confined geometry. We report that
      several factors significantly affect T(g)( h): i) polymer microstructure
      (stereoregularity of PMMA) related to local dynamics; ii) interfacial
      interactions; iii) conformation of the polymer chains. These results raise many
      fundamental questions on the origin of the thickness-dependent glass transition.
      Why and how do the interactions with the substrate significantly affect T(g)( h)?
      Does T(g)( h) depend on the modifications of conformational parameters of the
      chains (their entropy)? What is the correlation between local dynamics and T(g)(
      h) in thin films? The aim of this paper is to summarise these open questions,
      which should stimulate further investigations in the thin polymer film scientific
      community.

PMID- 15010972
TI  - Mobility in thin polymer films ranging from local segmental motion, Rouse modes
      to whole chain motion: a coupling model consideration.
AB  - Large increases of mobility of local segmental relaxation observed in polymer
      films as the film thickness is decreased, as evidenced by decreases of the glass
      temperature, are not found for relaxation mechanisms that have longer length
      scales including the Rouse relaxation modes and the diffusion of entire polymer
      chains. We show that the coupling model predictions, when extended to consider
      polymer thin films, are consistent with a large increase of the mobility of the
      local segmental motions and the lack of such a change for the Rouse modes and the
      diffusion of entire polymer chains. There are two effects that can reduce the
      coupling parameter of the local segmental relaxation in thin films. One is the
      chain orientation that is induced parallel to the surface when the film thickness
      h becomes smaller than the end-to-end distance of the chains and the other is a
      finite-size effect when h is no longer large compared to the cooperative length
      scale. Extremely thin ( approximately 1.5 nm) films obtained by intercalating a
      polymer into layered silicates have thickness significantly less than the
      cooperative length scale near the bulk polymer glass transition temperature. As a
      result, the coupling parameter of the local segmental relaxation in such thin
      films is reduced almost to zero. With this plausible assumption, we show the
      coupling model can explain quantitatively the large decrease of the local
      segmental relaxation time found experimentally.

PMID- 15010973
TI  - Polymer thin films and surfaces: possible effects of capillary waves.
AB  - It is discussed how the proximity of a free surface or mobile interface may
      affect the strain relaxation behavior in a viscoelastic material, such as a
      polymer melt. The eigenmodes of a viscoelastic film are thus derived, and applied
      in an attempt to explain the experimentally observed substantial shift of the
      glass transition temperature of sufficiently thin polymer films with respect to
      the bulk. Based on the idea that the polymer freezes due to memory effects in the
      material, and exploiting results from mode-coupling theory, the experimental
      findings of several independent groups can be accounted for quantitatively, with
      the elastic modulus at the glass transition temperature as the only fitting
      parameter. The model is finally applied discussing the possibility of polymer
      surface melting. A surface molten layer is predicted to exist, with a thickness
      diverging as the inverse of the reduced temperature. A simple model of thin
      polymer film freezing emerges which accounts for all features observed
      experimentally so far.

PMID- 15010976
TI  - Are changes in morphology clear indicators for the glass transition in thin
      polymer films? Tentative ideas.
AB  - I present some tentative ideas on the possibility of plastic deformation which
      might be relevant in ultra-thin polymer films at temperatures close but below the
      glass transition temperature. Several possible sources for sufficiently strong
      forces are discussed. The relevance of such forces in experiments aiming at
      determining thin-film properties like the glass transition temperature, thermal
      expansion or surface morphology is discussed.

PMID- 15010977
TI  - The glass transition and contact mechanical experiments on polymer surfaces.

PMID- 15010978
TI  - A decade of dynamics in thin films of polystyrene: where are we now?

PMID- 15010979
TI  - The electrostatic persistence length of polymers beyond the OSF limit.
AB  - We use large-scale Monte Carlo simulations to test scaling theories for the
      electrostatic persistence length l(e) of isolated, uniformly charged polymers
      with Debye-Huckel intrachain interactions in the limit where the screening length
      kappa(-1) exceeds the intrinsic persistence length of the chains. Our simulations
      cover a significantly larger part of the parameter space than previous studies.
      We observe no significant deviations from the prediction l(e) proportional to
      kappa(-2) by Khokhlov and Khachaturian which is based on applying the Odijk
      Skolnick-Fixman theories of electrostatic bending rigidity and electrostatically
      excluded volume to the stretched de Gennes-Pincus-Velasco-Brochard
      polyelectrolyte blob chain. A linear or sublinear dependence of the persistence
      length on the screening length can be ruled out. We show that previous results
      pointing into this direction are due to a combination of excluded-volume and
      finite chain length effects. The paper emphasizes the role of scaling arguments
      in the development of useful representations for experimental and simulation
      data.

PMID- 15010980
TI  - Theoretical and finite-element investigation of the mechanical response of
      spinodal structures.
AB  - In recent years there have been major advances in our understanding of the
      mechanisms of phase separation in polymer and copolymer blends, to the extent
      that good control of phase-separated morphology is a real possibility. Many
      groups are studying the computational simulation of polymer phase separation. In
      the light of this, we are exploring methods which will give insight into the
      mechanical response of multiphase polymers. We present preliminary results from a
      process which allows the production of a two-dimensional finite-element mesh from
      the contouring of simulated composition data. We examine the stretching of two
      phase structures obtained from a simulation of linear Cahn-Hilliard spinodal
      phase separation. In the simulations, we assume one phase to be hard, and the
      other soft, such that the shear modulus ratio G is large (>or= 10(3)). We
      indicate the effect of varying composition on the material modulus and on the
      distribution of strains through the stretched material. We also examine in some
      detail the symmetric structures obtained at 50% composition, in which both phases
      are at a percolation threshold. Inspired by simulation results for the
      deformation of these structures, we construct a "scaling" theory, which
      reproduces the main features of the deformation. Of particular interest is the
      emergence of a lengthscale, below which the deformation is non-affine. This
      length is proportional to G(1/4), and hence is still quite small for all
      reasonable values of this ratio. The same theory predicts that the effective
      composite modulus scales also as G(1/4), , which is supported by the simulations.

PMID- 15010981
TI  - Simulations of counterions at charged plates.
AB  - Using Monte Carlo simulations, we study the counterion distribution close to
      planar charged walls in two geometries: i) when only one charged wall is present
      and the counterions are confined to one half-space, and ii) when the counterions
      are confined between two equally charged walls. In both cases the surface charge
      is smeared out and the dielectric constant is the same everywhere. We obtain the
      counterion density profile and compare it with both the Poisson-Boltzmann theory
      (asymptotically exact in the limit of weak coupling, i.e. low surface charge,
      high temperature and low counterion valence) and the strong-coupling theory
      (valid in the opposite limit of high surface charge, low temperature and high
      counterion valence) and with previously calculated correction terms to both
      theories for different values of the coupling parameter, thereby establishing the
      domain of validity of the asymptotic limits. Gaussian corrections to the leading
      Poisson-Boltzmann behavior (obtained via a systematic loop expansion) in general
      perform quite poorly: At coupling strengths low enough so that the Gaussian (or
      one-loop) correction does describe the numerical deviations from the Poisson
      Boltzmann result correctly, the leading Poisson-Boltzmann term by itself matches
      the data within high accuracy. This reflects the slow convergence of the loop
      expansion. For a single charged plane, the counterion pair correlation function
      indicates a behavioral change from a three-dimensional, weakly correlated
      counterion distribution (at low coupling) to a two-dimensional, strongly
      correlated counterion distribution (at high coupling), which is paralleled by the
      specific-heat capacity which displays a rounded hump at intermediate coupling
      strengths. For the case of counterions confined between two equally charged
      walls, we analyze the inter-wall pressure and establish the complete phase
      diagram, featuring attraction between the walls for large enough coupling
      strength and at intermediate wall separation. Depending on the thermodynamic
      ensemble, the phase diagram exhibits a discontinuous transition where the inter
      wall distance jumps to infinity (in the absence of a chemical potential coupling
      to the inter-wall distance, as for charged lamellae in excess solvent) or a
      critical point where two coexisting states with different inter-wall distance
      become indistinguishable (in the presence of a chemical potential, as for charged
      lamellae with a finite fixed solvent fraction). The attractive pressure decays
      with the inter-wall distance as an inverse cube, similar to analytic predictions,
      although the amplitude differs by an order of magnitude from previous theoretical
      results. Finally, we discuss in detail our simulation methods and compare the
      finite-size scaling behavior of different boundary conditions (periodic, minimal
      image and open).

PMID- 15010982
TI  - Adhesion of membranes with competing specific and generic interactions.
AB  - Biomimetic membranes in contact with a planar substrate or a second membrane are
      studied theoretically. The membranes contain specific adhesion molecules
      (stickers) which are attracted by the second surface. In the absence of stickers,
      the trans-interaction between the membrane and the second surface is assumed to
      be repulsive at short separations. It is shown that the interplay of specific
      attractive and generic repulsive interactions can lead to the formation of a
      potential barrier. This barrier induces a line tension between bound and unbound
      membrane segments which results in lateral phase separation during adhesion. The
      mechanism for adhesion-induced phase separation is rather general, as is
      demonstrated by considering two distinct cases involving: i) stickers with a
      linear attractive potential, and ii) stickers with a short-ranged square-well
      potential. In both cases, membrane fluctuations reduce the potential barrier and,
      therefore, decrease the tendency of phase separation.

PMID- 15010983
TI  - Defects in a TGBA phase: a theoretical approach.
AB  - Following our experimental observations of disclination lines in freely suspended
      droplets and free-standing films (Yu.A. Nastishin et al., Eur. Phys. J. E 5 353
      (2001)), topological defects of the twist grain boundary (TGBA) phase are
      considered according to two aspects: topological and energetical. There are two
      classes of line defects, disclinations (as in the cholesteric (N*) phase and the
      liquid vortices phase (NL*), relating to the directors tripod symmetries) and
      dispirations (relating to the translation-rotation symmetries); there are no
      topological point defects. Differences between N*, NL* and TGBA disclinations are
      physical, not topological. The absence of focal conic domains in the TGBA phase
      is an immediate consequence of the materialization of the helical axis (along the
      chi-director); the same feature, coupled to the trend to parallelism of the
      smectic layers, accounts for the predominance of lambda-lines. Finally, the
      presence of defects akin to developable domains is explained in the frame of the
      least curvature model, that requires the introduction of a third type of defects:
      the densities of edge dislocations of the smectic layers.

PMID- 15010984
TI  - Peeling model for cell detachment.
AB  - In many experimental situations, the adhesion of cells to solid substrates is due
      to non-covalent chemical bonds. It is the thesis of this paper that many
      phenomena occurring in cell detachment experiments, such as in I (E. Decave, G.
      Garriver, Y. Brechet, B. Fourcade, F. Bruckert, Biophys. J. 82, 2383 (2002)),
      result from the static and dynamic properties of the adhesive bridges at the
      extreme margin of the cell. This region defines the adhesive belt where the
      distribution of connected bonds crosses over to zero where the membrane leaves
      the substrate. The theoretical model we introduce in this paper discusses the
      threshold force together with the peeling velocity in the same theoretical
      framework. In this one-dimensional model, the threshold force results from a non
      homogeneous distribution of anchor proteins along the membrane so that the
      adhesive belt increases its capacity to resist motion with increasing the
      external force. Analyzing the kinetics of the the contact line motion, we derive
      the characteristic relationship speed versus external force and we describe the
      non-equilibrium state of the adhesive belt as a function of the speed. We discuss
      our model in view of the experimental results obtained with D. discoideum for
      hydrodynamic shear experiments. Our results could be also confronted to single
      cell observations.

PMID- 15010993
TI  - [Andropathology and transplantation pathology. Invitation to the 88th Annual
      meeting of the German Pathology Society in Rostock on June 2-5 2004].

PMID- 15010994
TI  - [Rostock--light of the north. Venue of the 88th Annual Meeting of the German
      Pathology Society on june 2-5 2004].

PMID- 15010995
TI  - [Morphological findings after stent implantation in the carotid artery].
AB  - This report describes the pathological-anatomical and immunohistochemical
      findings of carotid arteries after incorporation of self-expanding metal stents.
      Ten stent specimens were examined. All specimens displayed variable expression
      patterns of chronic low-grade foreign body reactions in the vicinity of the
      incorporated stent struts as characterized by the appearance of CD68-positive
      macrophages and mainly CD3- and CD45-R0-positive T lymphocytes. Overwhelming
      proliferations in relation to intimal hyperplasia can be regarded as the main
      cause of stent-associated vascular restenosis. After a period of 6 months the
      expression of factor VIII-positive neoendothelial cells on the luminal surface
      can be detected in individual cases. Reactions of the vascular wall depend on the
      state of the underlying atherosclerotic lesions prior to stenting. In cases of
      predominantly atheromatous soft plaques, the typical reaction pattern triggered
      by the metallic foreign body pressed into vessel tissue can be absent. In
      summary, the morphological findings show a chronic tissue reaction in response to
      stent incorporation. In addition, individually differing reaction patterns
      ranging from discrete inflammatory changes to massive stenoses were identified
      and documented.

PMID- 15010996
TI  - [Chronic circumferential aortic dissection with intimo-intimal intussusception].
AB  - A circumferential aortic dissection with so-called intimo-intimal intussusception
      is a very rare complication of a dissecting aneurysm, in which the sock-like
      intimal flap is upended in the true lumen by the blood stream. The few cases
      reported thus far are based on radiological or intraoperative findings in acute
      dissections. The present postmortem study documents the very rare case of long
      term survival of a chronic circumferential dissection with intimo-intimal
      intussusception.

PMID- 15010997
TI  - [Inflammatory aortic aneurysm after vascular-prosthetic treatment. Morphological
      findings after years of incorporation].
AB  - Until now the causal and formal pathogenesis of the inflammatory aortic aneurysm
      is poorly known. This report shows the pathological- anatomical findings of
      surgical and autoptical preparations, on the one hand 78 months and on the other
      hand 82 months, after vascular-prosthetical treatment of inflammatory aneurysms
      in the abdominal and thoracal part of the aorta. By morphological studies it was
      possible to reveal, the over years existing disease, the typical picture of
      inflammatory aneurysm, focal destruction of the genuine aortic wall and partial
      substitution by inflammatory-fibrous, less qualitative granulation tissue. Even 6
      1/2 years past the implantation of the Dacron-prosthesis, there is still no
      complete ingrown. In addition to the known findings of the transprosthetical
      organization with a variable development of the outer connective-tissued coat and
      neointima, the incorporated granulation-tissue was overlapped by a strong
      inflammation according to the basic disease. In several parts of the inflammatory
      destructed aortic wall, there is still no fixed incorporation of the prosthesis
      after 7 years, so that "hypermobile-prosthetic-parts" can be found as a result.

PMID- 15010999
TI  - [Cardio-pulmonary vascular system. Three-dimensional quantitative evaluation by
      microcomputed tomography].
AB  - In recent years microcomputed tomography (microCT) has become more and more
      important in basic research. Now commercial microCT scanners are available. Thus,
      it is very likely that this new, accurate and promising method for three
      dimensional and non-destructive quantitative evaluation of intact tissues
      including vessels will be applied more frequently. The review provides a survey
      of the basic technology of microCT and its current use for high resolution three
      dimensional morphometric and functional analysis within the cardio-pulmonary
      vascular system.

PMID- 15010998
TI  - [Therapy-related changes of angiogenesis in Philadelphia chromosome positive
      chronic myelogenous leukemia].
AB  - To elucidate the effect of first-line treatment with interferon (IFN),
      hydroxyurea (HU) and the tyrosine kinase inhibitor imatinib (STI571) on
      angiogenesis, we studied bone marrow (BM) biopsies in 104 patients with chronic
      myelogenous leukemia (CML) and 138 patients before and after allogeneic BM
      transplantation (BMT). After immunostaining (CD34) and morphometric analysis in
      comparison with a control group, CML specimens showed an increased vascularity
      and conspicuous morphological abnormalities of microvessels. A close relationship
      between microvessels and fiber density was detectable in initial biopsies and
      also in repeatedly performed examinations following therapy. Monotherapy by
      imatinib and HU generated a significant reduction of microvessels and reticulin
      fibers in contrast to changes after IFN administration or combination regimens of
      IFN and HU. A persistence of numerical and structural anomalies of vasculature
      was observable even several months after BMT. These anomalies shed some light on
      disturbances of the stroma compartment after myeloablative therapy. The
      relationship between BM vascularity and fibers is probably dependent on
      concomitant changes of megakaryopoiesis as the source of various mediators
      involved in the development of myelofibrosis and neo-angiogenesis acting within a
      complex functional network.

PMID- 15011000
TI  - [Angiotensin converting enzyme (ACE, CD143) in the regular pulmonary
      vasculature].
AB  - Angiotensin I converting enzyme (ACE, CD143) is an endothelial transmembrane Zn2+
      dipeptidylpeptidase. By formation of angiotensin II and degrading bradykinin it
      acts as a vasoconstrictor. We examined endothelial ACE expression in human
      pulmonary vessels in specimens from 20 female and 19 male patients (age: 34-76
      years) by immunohistochemistry. In all specimens, capillary endothelial cells
      showed the strongest expression, followed by those in arterioles and arteries.
      Venules and veins showed next to no staining. The differences in staining
      intensities were significant ( P<0.001). Sex affected neither the expression
      intensity nor the expression pattern. Summarizing, we demonstrate the existence
      of a vessel-type specific ACE expression pattern for pulmonary vessels. The
      nearly exclusive endothelial ACE expression in capillaries and arterial vessels
      points to ACE as an immunohistochemical marker for these vessels in normal lung
      tissue.

PMID- 15011001
TI  - [Paleopathological skeleton findings. Macroscopical and radiographical studies of
      364 individuals from a medieval graveyard].
AB  - Paleopathological examinations can give an idea of diseases and living conditions
      in ancient populations. An archaeological collection of 364 late medieval/early
      modern skeletons from the thirteenth to eighteenth centuries, excavated from a
      church cemetery in the Rostock town center, was examined palaeopathologically.
      The type and frequency of certain diseases within this north German urban
      population are described. The majority of the skeletons were from adults with a
      remarkably low percentage of children. Skeletal malformations (e.g. gap
      formations of the spinal column) were not abnormally represented. With the
      exception of single individuals, metabolic disorders or unusual infectious
      diseases could not be diagnosed. Degenerative diseases often found at the joints
      and the spinal column showed substantially lower prevalences in comparison with
      reference rural populations. Individual cases of benign and rare malignant
      neoplasms could be documented. Traumatic injuries as well as dental pathological
      changes were rare. In summary it can be concluded that the individuals buried
      here belonged to a better social class within the medieval population of Rostock.

PMID- 15011003
TI  - De-mixing dynamics of a binary liquid system in a controlled-pore glass. A
      neutron spin-echo spectroscopy and small angle neutron scattering study.
AB  - The temperature-induced microphase separation of the binary liquid system iso
      butyric acid+heavy water (iBA + D(2)O) in a mesoporous silica glass (CPG-10-75)
      of nominal pore width 7.5 nm was investigated by neutron spin-echo spectroscopy
      (NSE) and neutron small-angle scattering (SANS). Two mixtures of different
      composition were studied at different scattering angles at temperatures above and
      below the bulk phase transition temperature. The phase separation in the pore
      space is found to occur at a lower temperature than the bulk transition and
      extends over a significant temperature range. The effective diffusion coefficient
      derived from NSE at low scattering angles is found to decrease by one order of
      magnitude from 70 degrees C to 20 degrees C. This observation is attributed to
      the growing size of concentration fluctuations having a cut-off at ca. 8 nm,
      which corresponds to the mean pore size. The dynamics of the concentration
      fluctuations appears to be strongly influenced by the confinement in the pores,
      as it differs strongly from the bulk behaviour. These results are consistent with
      the preliminary results of the SANS study.

PMID- 15011002
TI  - [Secondary malignant melanoma of the gallbladder. A contribution to the
      differential diagnosis of pigmented lesions of the gallbladder].
AB  - The history of gallbladder involvement by a malignant melanoma in a 65-year-old
      woman is reported. The gallbladder, clinically resected for cholecystitis,
      harboured a polypoid dark pigmented tumour. The tumour was identified as a
      malignant melanoma immunohistochemically by positive reactions for gp100 (HMB45),
      melan A, and MiTF. Clinically, the patient was treated for cutaneous malignant
      melanoma by local excision 10 years earlier. The literature of pigmented lesions
      of the gallbladder is reviewed. In conclusion, the most important differential
      diagnosis of pigmented lesions of the gallbladder is the secondary gallbladder
      melanoma.

PMID- 15011004
TI  - Collective dynamics near a phase transition in confined fluids.
AB  - We performed molecular dynamics simulations in the microcanonical ensemble (MEMD)
      for a "simple" fluid confined between two solid substrates. From the calculation
      of the intermediate scattering function F(k( parallel ),t) and through the memory
      function formalism, we extract material ( i.e. transport and thermodynamics)
      coefficients in the vicinity of the liquid-gas phase transition. Our results show
      that approaching the limit of stability ( i.e. the spinodal), the dynamics of the
      system changes markedly.

PMID- 15011005
TI  - Confined phonons in glasses. A study by nuclear inelastic absorption and Raman
      scattering.
AB  - We have applied nuclear inelastic absorption (NIA) to the molecular glass former
      dibutyl phthalate/ferrocene, both in bulk and in nanoporous matrices having pore
      sizes of 50 and 25 A. The quantity g(E)/E(2), where g(E) is the vibrational
      density of states (VDOS) of the iron atoms, exhibits a pronounced maximum around
      2 meV. Confinement in pores leads to a suppression of the VDOS below 1.5 meV,
      independent of the pore size. The influence of local interactions at the pore
      wall was assessed using Raman scattering. Our observations are discussed in the
      light of experimental and theoretical results on nanoparticles and for the Boson
      peak.

PMID- 15011006
TI  - Solid state polymorphism of liquid crystals in confined geometries.
AB  - Solid polymorphism of 4-alkyl-4'-cyanobiphenyl (nCB) was studied so far as a
      function of thermal history. In this paper we show that metastable solid phases
      of 4-octyl-4'-cyanobiphenyl (8CB) are also formed when the mesogens are confined
      in porous silica matrices and we study their structure by neutron diffraction and
      by Raman spectroscopy. Three metastable solid states are identified: one
      crystalline phase K', two frozen-in smectic-like phases K(s) and K'(s). We
      discuss the relation between the structure of the metastable solid phases and
      that of the mesomorph phases.

PMID- 15011007
TI  - Nematic ordering of suspension of charged anisotropic colloids detected by
      multinuclear quadrupolar spectra and 1H PGSE-NMR measurements.
AB  - The structure of aqueous dispersion of charged anisotropic nano-composites
      (synthetic Laponite clays) have been studied by NMR and numerical simulations
      based on a multi-scale statistical analysis have been used to interpret the
      mobility of the confined water molecule diffusing within dense Laponite aqueous
      dispersions (29-52% w/w) prepared by uniaxial compression. Firstly, the lineshape
      detected by NMR quadrupolar spectroscopy of the counterions ((23)Na or (7)Li)
      exhibits a large residual splitting Delta nu which is the fingerprint of the
      macroscopic nematic ordering of the anisotropic particles. Secondly, these
      results are also confirmed by the anisotropy of the self-diffusion tensor of the
      water molecule measured by (1)H Pulsed Gradient Spin Echo NMR. This self
      diffusion anisotropy increases with the suspension density. Thirdly, the multi
      scale statistical analysis of the water mobility bridges the gap between the time
      scale (ps) accessible by Molecular Dynamics simulations and the time-scale
      (micros) accessible by Brownian Dynamics, leading to macroscopic behaviour
      comparable with PGSE-NMR data measurements.

PMID- 15011008
TI  - Structure and properties of confined sodium nitrite.
AB  - The temperature evolution of the structure of NaNO(2) nanocomposite ferroelectric
      material in a porous glass with 7 nm pores was studied by neutron diffraction in
      temperature region from room temperature up to the melting, i.e. in the ferro-
      and paraelectric phases. It is demonstrated that in the ferroelectric phase the
      structure is consistent with the structure of the bulk, but above the
      ferroelectric phase transition (and up to approximately 513 K) a volume premelted
      state is formed, manifesting itself in a growth of amplitudes of ion thermal
      vibrations, a steep increase of elementary cell volume and "softening" of
      lattice. For the first time the temperature dependence of order parameter eta for
      confined sodium nitrite is determined. eta (T) follows a power law with
      T(C)=425.6+/- 2.1 K and beta= 0.31+/- 0.04, which is essentially different from
      that for bulk NaNO(2). Our obtained data are in a good agreement with the results
      of earlier dielectric and neutron diffraction measurements.

PMID- 15011009
TI  - Molecular mobility of confined phases in model mesoporous (MCM-41) and
      microporous (AlPO(4)-5 zeolite) host materials.
AB  - The considered host materials are well suited to confine quasi-(1d) molecular
      phases, seeing that their porosities are composed of parallel unconnected
      cylindrical pores. For such a simple geometry, confinement effects can be simply
      described by a single parameter, the pore diameter phi. Our study concerns medium
      and ultra confinement ranges ( 40 A >or= O >or= 7.3 A). The primary effect of
      such confinements is the decrease of the molecular interactions within the
      confined phase. As a consequence, we have observed strong triple point depressure
      Delta T(3t) effects for hydrogen and water confined phases in MCM-41 samples. In
      the limit case of (1d) phase (the neopentane/AlPO(4)-5 system) it seems that a
      molecular mobility is observed even at very low temperature T=5 K. The secondary
      confinement effect is an increase of the interactions between the host inner
      surface and the confined molecular assembly induced by the pore diameter
      decreasing. Such host material influence gives rise, for medium range confinement
      to the physisorption of a curved solid film on the inner surface before the
      capillary phase condensation (hydrogen/MCM-41 (24 A)) and for ultra confinement
      to the solidification of the confined phase when the molecular species are
      commensurate with the inner surface sites (methane/AlPO(4)-5).

PMID- 15011010
TI  - Gas adsorption in mcm-41 porous silicas dynamic measurements using SANS.
AB  - The isothermal gas adsorption of two hexane isomers (n-hexane and cyclohexane) in
      the mesopores of MCM-41 silica have been investigated by small angle neutron
      scattering (SANS). This has been achieved by performing SANS measurements under
      contrast matching conditions for the silica matrix and condensed hydrocarbon
      confined in the mesopores. Insight into the kinetics of adsorption have been
      derived from changes in the intensity of the (100) diffraction peak associated
      with the ordered hexagonal mesoporous structure of the MCM-41 silica.

PMID- 15011011
TI  - Gas diffusion in zeolite beds: PFG NMR evidence for different tortuosity factors
      in the Knudsen and bulk regimes.
AB  - Self-diffusion of ethane in beds of zeolite NaX is studied using Pulsed Field
      Gradient (PFG) NMR. The ethane diffusivities were measured for displacements,
      which are orders of magnitude larger than the size of individual crystals. These
      diffusivities were compared with those, calculated using simple gas kinetic
      theory. The results of the comparison indicate that for the same bed of NaX
      crystals the apparent tortuosity factor in the Knudsen regime ( i.e. when
      molecule-solid collisions dominate) is significantly larger than that in the bulk
      regime ( i.e. when molecule-molecule collisions dominate). This finding is
      attributed to the more pronounced geometrical trapping by the pore structure of
      the zeolite bed in the Knudsen than in the bulk regime.

PMID- 15011012
TI  - Inversion and suppression of an oxygen bulk phase transition in confined
      geometry.
AB  - By means of susceptibility experiments on oxygen confined to the pores of a
      Gelsil substrate we investigated the bulk gamma- beta transition. At low
      fillings, the transformation is completely suppressed. At higher but still
      incomplete filling we observe a partial transformation from gamma to beta on
      cooling and a subsequent inverted transition on heating, i.e. the transformation
      of gamma-phase material into the beta-phase upon heating. At 100% filling this
      inversion disappears. We discuss our results on the basis of geometric
      considerations.

PMID- 15011013
TI  - Methyl group dynamics in a confined glass.
AB  - We present a neutron scattering investigation on methyl group dynamics in glassy
      toluene confined in mesoporous silicates of different pore sizes. The
      experimental results have been analysed in terms of a barrier distribution model,
      such a distribution following from the structural disorder in the glassy state.
      Confinement results in a strong decreasing of the average rotational barrier in
      comparison to the bulk state. We have roughly separated the distribution for the
      confined state in a bulk-like and a surface-like contribution, corresponding to
      rotors at a distance from the pore wall respectively larger and smaller than the
      spatial range of the interactions which contribute to the rotational potential
      for the methyl groups. We have estimated a distance of 7 A as a lower limit of
      the interaction range, beyond the typical nearest-neighbour distance between
      centers-of-mass (4.7 A).

PMID- 15011014
TI  - Aging and memory effects in a clathrate.
AB  - The out-of-equilibrium low-frequency complex susceptibility of the orientational
      glass methanol(73%)-beta-hydroquinone-clathrate is studied using temperature-stop
      protocols in aging experiments. Although the material does not have a sharp glass
      transition aging effects including rejuvenation and memory similar to the effects
      in spin glasses are found at low temperatures.

PMID- 15011015
TI  - Dynamics of water in molecular sieves by dielectric spectroscopy.
AB  - We present recent dielectric data on the dynamics of water confined in molecular
      sieves with pore sizes 5 and 10 A. The dielectric measurements in the frequency
      and temperature ranges 10(-2)-10(6) Hz and 120-300 K show three relaxation
      processes for both samples. In the case of the 10 A pore the slowest process
      shows an Arrhenius temperature dependence at low temperatures (<220 K), while at
      high temperatures the relaxation appears to follow a more Vogel-Fulcher-Tammann
      (VFT) like behaviour. The relaxation time for this process is 100 s at about 170
      K. The second slowest process is at low temperatures very similar to the main
      process of (bulk-like) water in a fully hydrated clay, but also this process
      seems to exhibit some kind of dynamical transition, in this case at T
      approximately 185 K. All the three processes in the 5 A pore exhibit Arrhenius
      temperature dependence, and two of them are considerably slower than the main
      relaxation in the hydrated clay. Thus, dynamics of bulk-like water is only
      observed in the 10 A molecular sieves, and most of the water molecules in both 5
      and 10 A pores have considerably slower dielectric relaxation than has been
      observed for water confined in clay, most likely due to strong interactions with
      the considerably more hydrophilic inner surfaces of molecular sieves.

PMID- 15011016
TI  - A FT-IR absorption analysis of vibrational properties of water encaged in NaA
      zeolites: evidence of a "structure maker" role of zeolitic surface.
AB  - We performed, in the O-H stretching region, Fourier-transform Infrared (FT-IR)
      Absorption measurements for investigating the vibrational dynamics on water
      confined in NaA zeolite, vs. temperature and for different hydration percentages.
      The spectral substructure of the O-H stretching band is explained postulating the
      existence of three major components centred at approximately 3290 cm(-1)
      (omega(1)), approximately 3470 cm(-1) (omega(2)), approximately 3590 cm(-1)
      (omega(3)), with different dynamical properties traced over the full T-range
      investigated.

PMID- 15011017
TI  - Dynamics of supercooled water in mesoporous silica matrix MCM-48-S.
AB  - Using three different quasielastic neutron spectrometers with widely different
      resolutions, we have been able to study the microscopic translational and
      rotational dynamics of water, in a mesoporous silica matrix MCM-48-S, from T=300
      K to 220 K, with a single consistent model. We formulated our fitting routine
      using the relaxing cage model. Thus, from the fit of the experimental data, we
      extracted the fraction of water bound to the surface of the pore, the
      characteristic relaxation times of the long-time translational and rotational
      decays, the stretch exponent describing the shape of the relaxation processes,
      and the power exponent determining the Q-dependence of the translational
      relaxation time. A tremendous slowing down of the rotational relaxation time, as
      compared to the translational one, has been observed.

PMID- 15011018
TI  - Structure and dynamics of water confined in silica hydrogels: X-ray scattering
      and dielectric spectroscopy studies.
AB  - We have used a sol-gel technique to obtain optically transparent hydrogels in
      which water is confined within a 3D silica matrix. In this work we report X-ray
      scattering and dielectric spectroscopy measurements on samples having different
      aging times and compare them with previously obtained results with near-infrared
      (NIR) absorption spectroscopy. X-ray scattering at room temperature enables to
      characterize the structure and size of the matrix pores and the non-uniform
      distribution of water inside the hydrogel. Broad band dielectric spectroscopy in
      the temperature range 130-280 K enables to study water dynamics. In aged
      hydrogels two relaxations are clearly evident and show characteristic temperature
      dependence. The faster relaxation has an Arrhenius behavior in the whole
      temperature range investigated with an activation enthalpy of approximately 50
      kJ/mol; it is attributed to water molecules strongly interacting with the silica
      matrix. The slower relaxation has a markedly non-Arrhenius behavior which can be
      fitted with a Vogel-Fulcher-Tamman (VFT) relation with critical temperature of
      approximately 100 K and activation enthalpies of 35 and 95 kJ/mol at 300 and 170
      K respectively; it is attributed to water molecules within the pores that do not
      interact strongly with the matrix and behave collectively. The VFT temperature
      dependence of the dielectric relaxation time suggests that this water does not
      crystallize, in agreement with previous results from NIR spectroscopy.

PMID- 15011019
TI  - Confinement effect on thermodynamic and structural properties of water in
      hydrophilic mesoporous silica.
AB  - The adsorption of water on porous silica surfaces at 300 K, has been
      qualitatively reproduced by Grand Canonical Monte Carlo simulations (GCMC)
      without any adjustment of adsorbate/substrate potential parameter. The simulated
      adsorption isotherm and isosteric differential enthalpy of adsorption compare
      well to experimental data for Vycor, showing the ability of the model in
      describing hydrophilic properties of silica surfaces. The analysis of fluid
      structure in the mesoporous glass gives detailed insights into confinement and
      disorder effects on water adsorbed on the hydrophilic surface of a porous glass.
      It is shown that hydrophilic properties are not simply related to surface
      hydroxyl density but are also related to local structure of the silica surface.

PMID- 15011020
TI  - Evidence of shear-dependent boundary slip in Newtonian liquids.
AB  - The flow of Newtonian fluids was studied by directly measuring the hydrodynamic
      drainage force acting on a sphere approaching a flat surface. Our force
      measurements provide clear evidence of boundary slip and show that the degree of
      boundary slip is a function of the liquid viscosity and the shear rate. A shear
      dependent boundary slippage was also observed in experiments with a polymer
      (PDMS). The liquids wetted the bounding surfaces either partially or completely.
      Our results have important consequences for the design of microfluidic devices,
      and in technological processes, such as lubrication and permeability of
      microporous media.

PMID- 15011021
TI  - Anisotropic diffusion of single molecules in thin liquid films.
AB  - Single molecule wide field imaging is applied to study the diffusion in ultrathin
      liquid films on solid surfaces. The results show a broad distribution of
      diffusion coefficients. This is tentatively ascribed to an anisotropy of the
      diffusion coefficient perpendicular to the surface and a slow exchange of
      molecules between regions of different diffusion coefficients. We have evidence,
      that these changes as well as the slow motion perpendicular to the surface are
      related to the molecular layering of the liquid close to the surface.

PMID- 15011023
TI  - Influence of the glass transition on solvent loss from spin-cast glassy polymer
      thin films.
AB  - The interdependence of solvent loss and vitrification in spin-cast poly(methyl
      methacrylate) thin films is explored. Fast measurements of decreases in film
      thickness, achieved with ellipsometry, indicate that the rate of solvent
      (toluene) loss decreases sharply when the solvent volume fraction phi(solv) falls
      below about 0.15 and the film vitrifies. Ellipsometry and microgravimetry show
      that solvent is lost from a glassy thin film (150 nm thick) over of a period of
      more than ten hours, which is much longer than would be required if it was
      limited by diffusion in the glass. These results support the recently-proposed
      idea that the compression of the glass creates an energy barrier that slows down
      solvent loss.

PMID- 15011022
TI  - Ion crater healing and variable temperature ellipsometry as complementary probes
      for the glass transition in thin polymer films.
AB  - Poly(methyl methacrylate) (PMMA) thin films of various tacticity and thickness
      were bombarded at grazing angles by 20 MeV Au ions at different temperatures. The
      shape of the tracks was investigated by scanning force microscopy (SFM) after
      annealing for various time at different temperatures and constant quenching rate.
      The thickness dependent glass transition temperature, T(g)(h), was estimated from
      the temperature of relaxation of ion-caused nanodeformations in the films.
      T(g)(h) obtained from the thermal healing of the holes and hillocks is found in
      good agreement with the one determined by variable temperature ellipsometry for
      PMMA film thickness of 80 nm and corresponds to the T(g) of each bulk PMMA
      stereoisomer. Below this thickness, some significant divergences are observed
      between the T(g) measured by the two techniques. We propose that the healing of
      ion crater hillock and the kink in the thermal expansion arise from the different
      nature of chains motions which are perturbed to different extents according to
      the main polymer chain preferential orientation in the thin film. This can be
      tentatively interpreted by a so-called "anisotropic" character of the glass
      transition.

PMID- 15011024
TI  - First inelastic neutron scattering studies on thin free standing polymer films.
AB  - Glass transition studies in free standing polymer films have revealed values of
      the transition temperature, T(g), which were substantially reduced below the bulk
      for sufficiently thin films. Here we report on the preparation of two stacks of
      free standing polystyrene films: 70 films with a thickness of h approximately 107
      nm and 140 films with h approximately 55 nm with equivalent total sample
      thicknesses of approximately 7.5 microm. We have performed the first measurements
      on such samples using inelastic neutron scattering, and demonstrate that
      inelastic neutron scattering experiments, performed on the time-of-flight
      spectrometer IN6 and the backscattering spectrometer IN16 at the Institut Laue
      Langevin, are feasible.

PMID- 15011025
TI  - Thickness dependence of the dynamics in thin films of isotactic poly
      (methylmethacrylate).
AB  - The film thickness dependence of both the glass transition temperature (T(g)) and
      the 1 kHz alpha relaxation were studied for thin films of isotactic Poly
      (methylmethacrylate) (i-PMMA) supported on aluminium substrates. Films in the
      thickness range 7-200 nm were studied. The ellipsometrically determined T(g) was
      found to show reductions for films thinner than 60 nm, with the largest observed
      reduction being 12 K for a 7 nm thick film. Measurements of the T(g) were also
      performed on i-PMMA films supported on silicon substrates. Dielectric studies of
      the temperature dependent 1 kHz alpha relaxation peak, showed that the position
      (T(alpha)) and shape of the peak have no film thickness dependence. This was
      shown to hold for films with one free surface and films with a 30 nm thermally
      evaporated capping layer. Capping the films was shown to have no effect on the
      thickness dependence of either T(g) or T(alpha). The implications of these
      results are discussed further and the different film thickness dependencies of
      T(g) and T(alpha) are discussed. This is done within the framework of the Vogel
      Fulcher-Tamann (VFT) theory of glass forming materials and also in the context of
      the existence of a dynamic correlation length xi.

PMID- 15011026
TI  - Glass transition temperature of freely-standing films of atactic poly(methyl
      methacrylate).
AB  - We have used ellipsometry to measure the glass transition temperature T(g) of
      high molecular weight (M(w)=790 x 10(3)), freely-standing films of atactic
      poly(methyl methacrylate) (a-PMMA), as well as films of the same polymer
      supported on two different substrates: the native oxide layer of silicon (Si) and
      gold-covered Si. We observe linear reductions in T(g) with decreasing film
      thickness h for the freely-standing PMMA films with 30 nm < h<100 nm, which is
      qualitatively similar to previous results obtained for freely-standing
      polystyrene (PS) films. However the magnitude of the T(g) reductions for PMMA is
      much less than for freely-standing films of PS of comparable molecular weight and
      thickness. We also find that for films supported on either substrate, with
      thicknesses as small as 30 nm, the T(g) values do not deviate substantially from
      the value measured for thick films.

PMID- 15011027
TI  - Dielectric relaxations in ultrathin isotactic PMMA films and PS-PMMA-PS trilayer
      films.
AB  - The local and cooperative dynamics of supported ultrathin films ( L = 6.4 - 120
      nm) of isotactic poly(methyl methacrylate) (i-PMMA, Mn = 118 x 10(3) g/mol) was
      studied using dielectric relaxation spectroscopy for a wide range of frequencies
      (0.1 Hz to 10(6) Hz) and temperatures (250 - 423 K). To assess the influence of
      the PMMA film surfaces on the glass transition dynamics, two different sample
      geometries were employed: a single layer PMMA film with the film surfaces in
      direct contact with aluminum films which act as attractive, hard boundaries; and
      a stacked polystyrene-PMMA-polystyrene trilayer film which contains diffuse PMMA
      PS interfaces. For single layer films of i-PMMA, a decrease of the glass
      transition temperature T(g) by up to 10 K was observed for a film thickness L <
      25 nm (comparable to R(EE)), indicated by a decrease of the peak temperature
      T(alpha) in the loss epsilon(")(T) at low and high frequencies and by a decrease
      in the temperature corresponding to the maximum in the apparent activation energy
      E(a)(T) of the alpha-process. In contrast, measurements of i-PMMA sandwiched
      between PS-layers revealed a slight (up to 5 K) increase in T(g) for PMMA film
      thickness values less than 30 nm. The slowing down of the glass transition
      dynamics for the thinnest PMMA films is consistent with an increased contribution
      from the less mobile PMMA-PS interdiffusion regions.

PMID- 15011028
TI  - Dielectric relaxation studies of poly(propylene glycol) confined in vermiculite
      clay.
AB  - The molecular dynamics of oligomeric poly(propylene glycol) (PPG) liquids
      (M(w)=1200, 2000 and 4000 g/mol) confined in a two-dimensional layer-structured
      Na-vermiculite clay has been studied by broadband dielectric spectroscopy. In
      addition to the alpha-relaxation, the normal mode relaxation process was studied
      for all samples both in bulk and confinement. For the normal mode process the
      relaxation rate in the clay is drastically shifted to lower frequencies compared
      to that of the bulk material in contrast to the alpha-process whose relaxation
      time is only slightly affected by the confinement. Also the temperature
      dependence of the relaxation time for the normal mode process is strongly
      affected by the confinement. Moreover, in the clay the intensity of the normal
      mode is stronger than that of the alpha-process, in contrast to the bulk samples
      where the opposite is observed.

PMID- 15011029
TI  - Some remarks on the chain segment dynamics in confined polymers.
AB  - Recently, the chain dynamics of molten polymers in confined geometries has been
      investigated, using NMR. Some of these experiments have been performed on
      poydimethylsiloxane (PDMS) confined in planar nanolayers involving non-adsorbant
      solid surfaces. Here the data obtained on various PDMS systems are compared. The
      common property to these systems is that the local dynamics is anisotropic and
      the chain segments are undergoing uniaxial fluctuations around the normal n to
      the layers. Our data clearly show that the sign of the degree of orientational
      order S ( i.e. the direction of the fluctuations around n) and the broadening of
      the order distribution P( S) both result from the relative influence of the
      impenetrable interfaces and anchoring junctions on the segment behaviour.

PMID- 15011030
TI  - Segmental order and dynamics of polymer chains confined in block copolymer
      lamellar mesophases: NMR and dielectric relaxation studies.
AB  - The PDMS lamellar sublayers of a poly(styrene)-poly(dimethylsiloxane) diblock (PS
      PDMS) and PS-PDMS-PS triblocks are investigated by NMR and dielectric
      spectroscopy. Some segments of the confined PDMS chains display anisotropic
      orientational fluctuations along the interfaces with the PS glassy blocks,
      whereas the others display fluctuations rather parallel to the lamellae normal.
      This coexistence results from a competitive ordering effect induced by the glassy
      interfaces and the chain-end anchoring junctions. The distribution of PDMS
      relaxation times within the sublayers is also examined: in particular, a slowing
      down of the segmental motions, together with a broadening of this distribution,
      are detected.

PMID- 15011031
TI  - Self-confined polymer dynamics in miscible binary blends.
AB  - The segmental dynamics of PVME within the single-phase state of
      poly(styrene)/poly(vinyl methyl ether) blends (PS/PVME) was examined by
      dielectric spectroscopy. A particular attention has been given to the high PS
      concentration regime. In this latter, rather localized, weakly cooperative
      motions of the PVME segments are detected at low temperatures, in addition of the
      secondary relaxation processes. This feature is attributed to confinement effects
      induced by the PS chains on the PVME.

PMID- 15011032
TI  - Characterization of porous structure through the dynamical properties of ions
      confined in sulfonated polyimide ionomers films.
AB  - The structure of sulfonated PolyImide (sPI) ionomer membrane has been
      investigated via the transport properties of ions confined inside. Transport
      coefficients of N(CH(3))(4)(+) and Na(+) ions have been determined by several
      techniques in order to get a range of time/space scale as wide as possible: a
      method using radiotracers, conductivity, pulsed field gradient NMR and NMR
      quadrupolar relaxation rates determination. For N(CH(3))(4)(+), the self
      diffusion has been measured in the direction of membrane plan (parallel) and in
      the perpendicular direction (transverse), whereas for Na(+) only transverse self
      diffusion has been measured. The conductivity of both ions has been measured in
      the transverse direction. The results show a anisotropic and multiscale structure
      with a separation phase between hydrophilic and hydrophobic domains that is not
      well-defined.

PMID- 15011033
TI  - Molecular dynamics simulations of a mixed DOPC/DOPG bilayer.
AB  - We have constructed a mixed dioleoylphosphatidylcholine (DOPC) and
      dioleoylphosphatidylglycerol bilayer (DOPG) bilayer utilizing MD simulations. The
      aim was to develop an explicit molecular model of biological membranes as a
      complementary technique to neutron diffraction studies that are well established
      within the group. A monolayer was constructed by taking a previously customized
      PDB file of each molecule and arranging them in a seven rows of ten molecules and
      duplicated and rotated to form a bilayer. The 140-molecule bilayer contained 98
      DOPC molecules and 42 DOPG molecules, in a 7:3 ratio in favour of DOPC. Sodium
      counter ions were placed near the phosphate moiety of DOPG to counteract the
      negative charge of DOPG. This was representative of the lipid ratio in a sample
      used for neutron diffraction. The MD package GROMACS was used for confining the
      bilayer in a triclinic box, adding Simple Polar Charge water molecules, energy
      minimization (EM). The bilayer/solvent system was subjected to EM using the
      steepest descent method to nullify bad contacts and reduce the potential energy
      of the system. Subsequent MD simulation using an initial NVT (constant number of
      particles, volume and temperature) for a 20 ps MD run followed by a NPT (constant
      number of particles, pressure and temperature) was performed. Structural
      parameters including volume of lipid, area of lipid, order parameter of the fatty
      acyl carbons and electron density profiles generated by the MD simulation were
      verified with values obtained from experimental data of DOPC, as there are no
      comparable experimental data available for the mixed bilayer.

PMID- 15011034
TI  - Effect of polymer tacticity on the molecular structure of
      polyelectrolyte/surfactant stoichiometric complexes in solutions and gels.
AB  - The molecular structure of polystyrene sulphonate/CTAB stoichiometric complexes
      has been examined by means of small-angle neutron scattering in solutions and in
      the gel state for two different tacticities of the polystyrene moiety, namely
      atactic polystyrene and isotactic polystyrene. It is found that tacticity has no
      influence on the molecular structure in solution, while it plays a role in the
      gel state. The neutron scattering curves are interpreted with different helical
      models. The thermal properties of the gels are discussed in the light of the
      neutron scattering outcomes.

PMID- 15011035
TI  - Comparing simulation and experiment of a 2D granular Couette shear device.
AB  - We present experiments along with molecular-dynamics (MD) simulations of a two
      dimensional (2D) granular material in a Couette cell undergoing slow shearing.
      The grains are disks confined between an inner, rotating wheel and a fixed outer
      ring. The simulation results are compared to experimental studies and
      quantitative agreement is found. Tracking the positions and orientations of
      individual particles allows us to obtain density distributions, velocity and
      particle rotation rates for the system. The key issue of this paper is to show
      the extent to which quantitative agreement between an experiment and MD
      simulations is possible. Besides many differences in model details and the
      experiment, the qualitative features are nicely reproduced. We discuss the
      quantitative agreement/disagreement, give possible reasons, and outline further
      research perspectives.

PMID- 15011036
TI  - Conformational fluctuations of a tethered polymer in uniform flow.
AB  - The decay of correlations in the conformational fluctuations of a tethered
      polymer subjected to a uniform flow is analyzed in terms of relaxation times and
      associated normal modes. These quantities are calculated numerically from
      Brownian dynamics simulations of several bead spring polymer models. In this way,
      the influence of different effects like a finite extensibility of the springs and
      excluded-volume as well as hydrodynamic interactions between the beads on the
      decay of fluctuations is identified. Moreover, by comparison of the simulation
      results to analytically tractable blob models with corresponding assumptions, the
      capability of the tensile-blob picture to predict relaxation times and modes is
      assessed. For excluded-volume and hydrodynamic interactions a crossover to Rouse
      like behavior occurs when the flow velocity and hence the polymer deformation
      exceeds a certain value. For finitely extensible springs, in contrast, the
      relaxation times decrease monotonically with increasing polymer deformation. This
      latter behavior differs from assumptions often used in rheological modeling by
      dumbbells and is not captured by the blob model.

PMID- 15011037
TI  - Frequency dispersion of sound propagation in Rouse polymer melts via generalized
      dynamic random phase approximation.
AB  - An extended generalization of the dynamic random phase approximation (DRPA) for L
      component polymer systems is presented. Unlike the original version of the DRPA,
      which relates the (LxL) matrices of the collective density-density time
      correlation functions and the corresponding susceptibilities of concentrated
      polymer systems to those of the tracer macromolecules and so-called broken-links
      system (BLS), our generalized DRPA solves this problem for the (5xL) x (5xL)
      matrices of the coupled susceptibilities and time correlation functions of the
      component number, kinetic energy and flux densities. The presented technique is
      used to study propagation of sound and dynamic form-factor in disentangled
      (Rouse) monodisperse homopolymer melt. The calculated ultrasonic velocity and
      absorption coefficient reveal substantial frequency dispersion. The relaxation
      time tau is proportional to the degree of polymerization N, which is N times less
      than the Rouse time and evidences strong dynamic screening because of interchain
      interaction. We discuss also some peculiarities of the Brillouin scattering in
      polymer melts. Besides, a new convenient expression for the dynamic structure
      function of the single Rouse chain in (q,p) representation is found.

PMID- 15011038
TI  - Stripe instability in thin films of smectic liquid-crystal polymers.
AB  - Two-dimensional nanostripes are formed in thin films of side-chain liquid
      crystalline polymer films when the material enters the smectic phase. The
      structure is investigated using transmission electron microscopy. Electron
      diffraction patterns show that the chain molecules are mostly aligned in the film
      plane and the average molecular director is parallel to the direction of the
      stripes. We discuss factors affecting the stripe amplitude and periodicity, such
      as the film thickness and the temperature of annealing in the nematic phase, and
      suggest a possible mechanism for their formation. We propose that an equilibrium
      instability occurs due to a competition between the layer-aligning effect of the
      substrate and the planar director alignment, forcing smectic layers perpendicular
      to the film surface. The stripes decorate the overall patterns of nematic
      director in the polymer film and provide a means of high-resolution imaging for
      observation of textures and disclinations.

PMID- 15011039
TI  - The crossover from 2D to 3D percolation: theory and numerical simulations.
AB  - We describe here the crossover between 2D and 3D percolation, which we do on
      cubic and square lattices. As in all problems of critical phenomena, the
      quantities of interest can be expressed as power laws of /p-pc(h)/, where pc(h)
      and h are the percolation threshold and the thickness of the film, respectively.
      When these quantities are considered on the scale of the thickness h of the
      films, the corresponding numerical prefactors are of order one. However, for many
      problems, the scale of interest is the elementary one. The corresponding
      expressions contain then prefactors in power of h which we calculate. For
      instance, we show that the mass distribution n(m) of the clusters is given by a
      master function of h(-D+1/sigma2nu3)/p-pc(h)/1/sigma2(m), where h is the
      thickness of the film and D, nu3, sigma2 are tabulated 2D and 3D critical
      exponents. We consider also the size R2( m) of the clusters as a function of
      their mass m, for which we provide both scaling laws and numerical data.
      Therefore, any property corresponding to a given moment of mass and size can be
      obtained from our results. These results might be useful for describing transport
      properties, such as electric conductivity, or the mechanical properties of thin
      films made of disordered materials.

PMID- 15011040
TI  - Hydrodynamic instabilities in ferronematics.
AB  - In the hydrodynamic description of ferronematics there are various dynamic
      magnetic-field effects, linear in the field strength, that are negligible in
      usual nematics, but can play a role in ferronematics. Here, we investigate
      theoretically the influence of these new terms on the thermal convection
      (Rayleigh-Benard) and the viscous fingering (Saffman-Taylor) instability in
      ferronematics in the presence of a strong magnetic field. We find that the
      instabilities are qualitatively changed due to the occurrence of a finite
      vorticity component--a feature that is known from simple liquids in the case of a
      superimposed mechanical rotation. We suggest to use the additional effects (cross
      flow within convection rolls, oblique rolls, rotating fingers) for measuring the
      phenomenological coefficients involved.

PMID- 15011041
TI  - The effect of thermal fluctuations on Schulman area elasticity.
AB  - We study the elastic properties of a two-dimensional fluctuating surface whose
      area density is allowed to deviate from its optimal (Schulman) value. The
      behavior of such a surface is determined by an interplay between the area
      dependent elastic energy, the curvature elasticity, and the entropy. We identify
      three different elastic regimes depending on the ratio Ap/As between the
      projected (frame) and the saturated areas. We show that thermal fluctuations
      modify the elastic energy of stretched surfaces (Ap/As>1), and dominate the
      elastic energy of compressed surfaces (Ap/As<1). When Ap approximately As the
      elastic energy is not much affected by the fluctuations; the frame area at which
      the surface tension vanishes becomes smaller than As and the area elasticity
      modulus increases.

PMID- 15011042
TI  - Role of the external pressure on the dewetting of soft interfaces.
AB  - We consider dewetting at soft interfaces, e.g., a rubber ball squeezed in a fluid
      against a flat hard substrate. We show that the applied squeezing pressure, which
      was not taken into account in earlier studies of the dewetting transition, may
      have a big effect on the squeeze-out dynamics.

PMID- 15011043
TI  - Irreversible adsorption from dilute polymer solutions.
AB  - We study irreversible polymer adsorption from dilute solutions theoretically.
      Universal features of the resultant non-equilibrium layers are predicted. Two
      broad cases are considered, distinguished by the magnitude of the local monomer
      surface sticking rate Q: chemisorption (very small Q) and physisorption (large
      Q). Early stages of layer formation entail single-chain adsorption. While single
      chain physisorption times tau ads are typically micro- to milli-seconds, for
      chemisorbing chains of N units we find experimentally accessible times tau ads=Q(
      1)N(3/5), ranging from seconds to hours. We establish 3 chemisorption
      universality classes, determined by a critical contact exponent: zipping,
      accelerated zipping and homogeneous collapse. For dilute solutions, the mechanism
      is accelerated zipping: zipping propagates outwards from the first attachment,
      accelerated by occasional formation of large loops which nucleate further
      zipping. This leads to a transient distribution omega(s) approximately s(-7/5) of
      loop lengths s up to a maximum size smax approximately (Qt)(5/3) after time t. By
      times of order tau ads the entire chain is adsorbed. The outcome of the single
      chain adsorption episode is a monolayer of fully collapsed chains. Having only a
      few vacant sites to adsorb onto, late-arriving chains form a diffuse outer layer.
      In a simple picture we find for both chemisorption and physisorption a final loop
      distribution Omega(s) approximately s(-11/5) and density profile c(z)
      approximately z(-4/3) whose forms are the same as for equilibrium layers. In
      contrast to equilibrium layers, however, the statistical properties of a given
      chain depend on its adsorption time; the outer layer contains many classes of
      chain, each characterized by a different fraction of adsorbed monomers f.
      Consistent with strong physisorption experiments, we find the f values follow a
      distribution P(f) approximately f(-4/5).

PMID- 15011044
TI  - Miscible displacement of non-Newtonian fluids in a vertical tube.
AB  - The influence of rheology on the miscible displacement of a viscous fluid by a
      less viscous, Newtonian one in a vertical tube is studied experimentally as a
      function of the flow velocity. For Newtonian displaced fluids the transient
      residual film thickness hri is nearly 38% of the tube radius at large viscosity
      ratios between the two fluids in agreement with experimental and numerical
      results from the literature. For shear-thinning fluids with a zero yield stress
      (mostly xanthan-water solutions), hri decreases down to 28-30% of the radius for
      the most concentrated solutions. For fluids with a non-zero yield stress, hri
      further decreases down to 24-25% of the radius. The orders of magnitude of these
      values can be obtained through numerical simulations (commercial code) for the
      various types of fluids. Instabilities of the film at its boundary develop
      downstream and lead to a reduction of the final thickness of the film at longer
      times: this reduction is larger for lower viscosity ratios and larger velocities.

PMID- 15011045
TI  - Mobile polymer connectors.
AB  - We study the junction between two solid objects, formed by polymer connectors
      which are supposed to freely explore the two grafting surfaces. We focus on the
      sphere-plane and sphere-sphere geometries. Because the chains are mobile, they
      are able to adapt both the local grafting density and their conformation to the
      position of the surfaces. Using a scaling approach, we show that, in chemical
      equilibrium, local grafting density is non-monotonic, and the junction can be
      divided into two different regions: the center, where connectors are compressed
      and exert a repulsive force between the objects (high excluded-volume
      interactions) and an external corona, where chains are stretched and attract the
      two objects. The relative importance of these regions varies for different
      separations and depends on surface geometries. When an external force is applied,
      this spatially inhomogeneous constraint exerted by the junction leads to specific
      force-distance profiles, which differ from profiles in the case of fixed
      connectors. An effective interaction potential and the adhesion energy are
      computed, showing a strong dependence on the geometry of surfaces.

PMID- 15011046
TI  - Modelling thin-film dewetting on structured substrates and templates: bifurcation
      analysis and numerical simulations.
AB  - We study the dewetting process of a thin liquid film on a chemically patterned
      solid substrate (template) by means of a thin-film evolution equation
      incorporating a space-dependent disjoining pressure. Dewetting of a thin film on
      a homogeneous substrate leads to fluid patterns with a typical length scale, that
      increases monotonously in time (coarsening). Conditions are identified for the
      amplitude and periodicity of the heterogeneity that allow to transfer the
      template pattern onto the liquid structure ("pinning") emerging from the
      dewetting process. A bifurcation and stability analysis of the possible liquid
      ridge solutions on a periodically striped substrate reveal parameter ranges where
      pinning or coarsening ultimately prevail. We obtain an extended parameter range
      of multistability of the pinning and coarsening morphologies. In this regime, the
      selected pattern depends sensitively on the initial conditions and potential
      finite perturbations (noise) in the system as we illustrate with numerical
      integrations in time. Finally, we discuss the instability to transversal modes
      leading to a decay of the ridges into rows of drops and show that it may diminish
      the size of the parameter range where the pinning of the thin film to the
      template is successful.

PMID- 15011047
TI  - Some general features of limited coalescence in solid-stabilized emulsions.
AB  - We produce direct and inverse emulsions stabilized by solid mineral particles. If
      the total amount of particles is initially insufficient to fully cover the oil
      water interfaces, the emulsion droplets coalesce such that the total interfacial
      area between oil and water is progressively reduced. Since it is likely that the
      particles are irreversibly adsorbed, the degree of surface coverage by them
      increases until coalescence is halted. We follow the rate of droplet coalescence
      from the initial fragmented state to the saturated situation. Unlike surfactant
      stabilized emulsions, the coalescence frequency depends on time and particle
      concentration. Both the transient and final droplet size distributions are
      relatively narrow and we obtain a linear relation between the inverse average
      droplet diameter and the total amount of solid particles, with a slope that
      depends on the mixing intensity. The phenomenology is independent of the mixing
      type and of the droplet volume fraction allowing the fabrication of both direct
      and inverse emulsion with average droplet sizes ranging from micron to
      millimetre.

PMID- 15011048
TI  - Deformable tetrahedratic phases: the effects of external fields and flows.
AB  - We discuss changes in the symmetry and physical properties of an isotropic phase
      which has initially tetrahedral symmetry characterized by four unit vectors. In
      its undeformed state, these four vectors are at the tetrahedral angle (109.47
      degrees) to each other. We find that this optically isotropic phase becomes
      uniaxial under the influence of an external electric field, E, resulting in a
      phase with C3v symmetry. For an applied simple shear flow, the system becomes
      biaxial and a time-dependent state with C1 symmetry arises. We discuss to what
      extent deformations induced by external forces and flows on this optically
      isotropic phase, which we call a "deformable tetrahedratic phase", are consistent
      with observations at the isotropic-B7 transition found recently in compounds
      composed of banana-shaped molecules and suggest a number of experiments to test
      the conclusions of this model.

PMID- 15011049
TI  - Conducting polymers as driving electrodes for Polymer-Dispersed Liquid-Crystals
      display devices: on the electro-optical efficiency.
AB  - Intrinsically conducting polymer (ICP) thin films are used as driving electrodes
      for Polymer-Dispersed Liquid-Crystals (PDLC) display devices. In order to
      investigate the electro-optical efficiency of these organic electrodes, three
      different kinds of conducting polymers, i.e. polyaniline doped with 10
      camphorsulfonic acid (PANI(HCSA)), polypyrrole doped with dodecylbenzenesulfonic
      acid (PPY(DBSA)), and polyethylenedioxythiophene doped with polystyrenesulfonate
      (PEDOT(PSS)), were prepared or purchased, and coated either on glass or plastic
      substrates. Optical absorption studies in the UV-Vis range of the conducting
      polymer-coated substrates were first performed showing the presence of conducting
      species for the three types of polymers. The electrical characteristics of the
      resulting films were measured with the four-probes technique. PANI(HCSA) exhibits
      a higher conductivity sigma approximately 122 S x cm(-1) (RS=1.2x10(3) Omega x (
      1)) compared to PPY(DBSA) sigma approximately 2.6 S x cm(-1) (RS=150.7x10(3)
      Omega x (-1)), and PEDOT(PSS) sigma approximately 1.6 S x cm(-1) (RS=637.3x10(3)
      Omega x (-1)). It is also shown that for a given conducting polymer, its
      electrical conductivity decreases when a plastic substrate is used. These
      observations have been related to significant morphological changes observed by
      scanning electron microscopy (SEM). A mixture of Norland Optical Adhesive 65 and
      nematic liquid-crystal E7 in the weight ratio (35:65) was used as precursor of
      the PDLC material. Better electro-optical responses (transmission properties,
      drive voltages and switching times) of PDLC films were obtained for devices
      prepared with (PPY(DBSA))-based electrodes. The electro-optical performances of
      the PDLC display devices also depend on the nature of the ICP substrate used.

PMID- 15011050
TI  - Variational charge renormalization in charged systems.
AB  - We apply general variational techniques to the problem of the counterion
      distribution around highly charged objects where strong condensation of
      counterions takes place. Within a field-theoretic formulation using a fluctuating
      electrostatic potential, the concept of surface-charge renormalization is
      recovered within a simple one-parameter variational procedure. As a test, we
      reproduce the Poisson-Boltzmann surface potential for a single-charged planar
      surface both in the weak-charge and strong-charge regime. We then apply our
      techniques to non-planar geometries where closed-form solutions of the non-linear
      Poisson-Boltzmann equation are not available. In the cylindrical case, the
      Manning charge renormalization result is obtained in the limit of vanishing salt
      concentration. However, for intermediate salt concentrations a slow crossover to
      the non-charged-renormalized regime (at high salt) is found with a quasi-power
      law behavior which helps to understand conflicting experimental and theoretical
      results for the electrostatic persistence length of polyelectrolytes. In the
      spherical geometry charge renormalization is only found at intermediate salt
      concentrations, in agreement with previous numerical results.

PMID- 15011051
TI  - Depletion effect on partial organization of atactic polymer chain segments in
      microcells.
AB  - Glass transition for atactic poly(methyl methacrylate) (a-PMMA) prepared in nano
      cells by microemulsion polymerization was measured at a faster heating rate after
      slow cooling of the sample from a temperature above Tg. An additional enthalpy
      relaxation and glass transition were observed at higher temperatures for the a
      PMMA sample due to the partial organization of the chain segments which occurred
      during microemulsion polymerization. The re-precipitated a-PMMA did not show any
      self-organization under the same thermal conditions, although there are no
      changes in molecular weight or tacticity of the polymer chains. A depletion
      interaction phenomenon was understood to provide entropic force for the self
      organization of polymer chains inside the walls of the microemulsion cells.

PMID- 15011052
TI  - Characteristic variations in the effect of diluents on polymer crystallization
      and melting observed for a sample of poly(ethylene-co-octene).
AB  - Melting points in mixtures of a crystallizable polymer with a low-molar-mass
      diluent depend on both, the diluent fraction and the crystal thickness. A
      differentiation of the two factors can be achieved by temperature-dependent SAXS
      experiments. A corresponding study, complemented by DSC, dilatometry, microscopy
      and AFM-imaging, was carried out for mixtures of a poly(ethylene-co-octene) with
      n-C16H34, c-C16H32 and methyl-anthracene, respectively. All diluents lead for a
      constant crystal thickness to melting point depressions in agreement with
      Raoult's law. On the other hand, the effect of the diluents on the thickness of
      the crystals formed at a fixed crystallization temperature varies. While in the
      presence of the two alkanes thicker crystals form, no effect arises for the
      methyl-anthracene--as was previously found for the octene-co-units. We consider
      these observations as a further support for our view that polymer crystallization
      follows a multi-stage route which includes a passage through an intermediate
      mesomorphic phase. Under such conditions crystal thicknesses would only be
      affected if the diluent is still present in the mesomorphic phase and stay
      invariant if the diluent molecules are already rejected when this intermediate
      phase forms.

PMID- 15011053
TI  - Dispersive flow of disks through a two-dimensional Galton board.
AB  - We report here an experimental and numerical study of the flow properties of
      disks driven by gravity through a hexagonal lattice of obstacles, i.e. a Galton
      board. During the fall, particles experience dissipative collisions that scatter
      them in random directions. A driven-diffusion regime can be achieved under
      certain conditions. A characteristic length of the motion and its dependence on
      geometrical parameters of the system is analyzed in the steady regime. The
      influence of collective effects on the dispersion process is investigated by
      comparison between single- and many-particle flows. The characterization of the
      dynamics and the diffusive properties of the flow in a system like a Galton board
      can be expanded to other granular systems, particularly static solid particle
      mixers and will give some insight in understanding granular mixing.

PMID- 15011054
TI  - Elastic interaction between "hard" or "soft" pointwise inclusions on biological
      membranes.
AB  - We calculate the induced elastic interaction between pointwise membrane
      inclusions that locally interact up to quadratic order with the membrane
      curvature tensor. For isotropic inclusions, we recover the usual interaction
      proportional to the inverse fourth power of the separation, however with a
      prefactor showing a non-trivial dependence on the rigidity Gamma of the quadratic
      potential. In the large-Gamma limit, corresponding to "hard" inclusions, we
      recover the standard prefactor first obtained by Goulian et al. (Europhys. Lett.
      22, 145 (1993)). In the small-Gamma limit, corresponding to "soft" inclusions, we
      recover the recent result of Marchenko and Misbah (Eur. Phys. J. E 8, 477
      (2002)). This shows that the latter result bears no fundamental discrepancy with
      previous works, but simply corresponds to the limit of soft inclusions. We
      discuss how the same inclusion can be depicted as hard or soft according to the
      degree of coarse-graining of the pointwise description. Finally, we argue that
      conical transmembrane proteins should be fundamentally considered as hard
      inclusions.

PMID- 15011055
TI  - Monodisperse dry granular flows on inclined planes: role of roughness.
AB  - Recent studies have pointed out the importance of the basal friction on the
      dynamics of granular flows. We present experimental results on the influence of
      the roughness of the inclined plane on the dynamics of a monodisperse dry
      granular flow. We found experimentally that there exists a maximum of the
      friction for a given relative roughness. This maximum is shown to be independent
      of the slope angle. This behavior is observed for four planes with different bump
      sizes (given by the size of the beads glued on the plane) from 200 microm to 2
      mm. The relative roughness corresponding to the maximum of the friction can be
      predicted with a geometrical model of stability of one single bead on the plane.
      The main parameters are the size of the bumps and the size of the flowing beads.
      In order to obtain a higher precision, the model also takes into account the
      spacing between the bumps of the rough plane. Experimental results and model are
      in good agreement for all the planes we studied. Other parameters, like the
      sphericity of the beads, or irregularities in the thickness of the layer of glued
      particles, are shown to be of influence on the friction.

PMID- 15011056
TI  - Interrupted shear of granular media.
AB  - The response of a granular material during a stop-and-go shear experiment is
      investigated using an annular shear cell and silicagel powders of different
      particle sizes. The experimental results are examined on the basis of the
      Dieterich-Rice-Ruina model for solid friction. In addition to making this analogy
      with solid friction, we describe a new instability that is observed when
      restarting shear, where the powder bed is found to slip and compact for short
      hold times but only dilates for long hold times. The minimum hold time to restore
      a non-slip behaviour has been investigated for different size particles and
      normal loadings. The observed dependencies show analogies between this behaviour
      and the sliding rearrangements seen above the stick-slip threshold.

PMID- 15011057
TI  - Structure and polarity of 8CB films evaporated onto solid substrates.
AB  - Brewster-angle reflection ellipsometry and surface optical second harmonic
      generation were used to study the growth of 4'-n-octyl-4-cyanobiphenyl (8CB)
      films evaporated in air onto polymeric and quartz glass substrates. The layer-by
      layer growth of the films terminates after formation of two distinctive
      interfacial layers. Both of these two layers are polar and tilted. In the first
      layer the molecules lie nearly flat on the surface, while in the second layer
      they point on average about 50 degrees toward the surface normal. The dipole
      moment of the second layer has a lower magnitude and an opposite direction with
      respect to the dipole moment of the first layer.

PMID- 15011058
TI  - Bubbles under stress.
AB  - We present an experimental and theoretical investigation of a system composed of
      two soap bubbles strained between two parallel solid surfaces. The two-bubble
      cluster can be found in several configurations. The existence and stability of
      each of these states is studied as a function of the distance between the two
      facing surfaces. The change of this distance can induce a transition from one
      configuration to another; we observe that most transitions are subcritical,
      showing that the system is often trapped in states where the minimum of free
      energy is only local. The hysteretic transitions are responsible for the
      dissipation of elastic energy. The existence of more than one stable states for
      given boundaries conditions combined with the absence of thermalization means
      that the history of the system has to be taken into account and that there is no
      unique stress-strain relation. In the present system, because of its simplicity,
      a complete quantitative analysis of these general processes is obtained. The
      presented results may contribute to a better understanding of the dynamics of
      more complex systems such as foams or granular materials where similar processes
      are at work.

PMID- 15011059
TI  - Crystallization kinetics and crystal morphology in thin poly(ethylene oxide)
      films.
AB  - We present a detailed study of the kinetics of crystallization for thin films of
      poly(ethylene oxide) (PEO). Measurements of the growth rate have been carried out
      using optical-microscopy techniques on films of monodisperse PEO. Films with
      thicknesses from 13 nm to approximately 2 microm were crystallized isothermally
      at temperatures approximately 20 degrees C below the melting point. A remarkable
      non-monotonic slowing-down of the crystal growth is observed for films with
      thickness less than approximately 400 nm. The changes in the growth rate from
      bulk-like values is significant and corresponds to a factor of 40 decrease for
      the thinnest films studied. The morphologies of isothermally crystallized samples
      are studied using atomic-force microscopy. We find that a morphology, similar to
      diffusion-controlled growth (dendritic growth and densely branched growth), is
      observed for films with h<150 nm. In addition, changes in the morphology occur
      for thicknesses consistent with changes in the growth rate as a function of film
      thickness.

PMID- 15011060
TI  - Azimuthal anchoring energy at the interface between a nematic liquid crystal and
      a PTFE substrate.
AB  - The azimuthal anchoring energy of the nematic liquid crystal 4-pentyl-4'
      cyanobiphenil (5CB) on a poly(tetrafluoroethylene) (teflon, PTFE) film is
      measured for the first time. The PTFE film is deposed using the Wittmann and
      Smith technique which consists on rubbing a bar of this polymer against a glass
      substrate at a controlled temperature and pressure. Measurements of the azimuthal
      anchoring energy are made with a reflectometric technique which provides high
      accuracy and sensitivity. The dependence of the azimuthal anchoring energy on
      temperature and on the rubbing pressure is investigated. The extrapolation length
      remains virtually constant in the whole temperature range of the nematic phase
      except for an increase of 25% close to the clearing temperature. The azimuthal
      anchoring energy is somewhat strong and increases with increasing the deposition
      pressure of PTFE. The observation of a relevant pre-transitional anisotropy of
      the reflection coefficients in the isotropic phase proves that the surface
      interactions favor an excess of orientational order. Ageing of the anchoring
      energy and gliding of the easy axis are experimentally observed. Both these
      phenomena suggest the presence of an anisotropic adsorbed layer of nematic
      molecules on the PTFE film.

PMID- 15011061
TI  - Persistence length for a model semirigid polyelectrolyte as seen by small angle
      neutron scattering: a relevant variation of the lower bound with ionic strength.
AB  - In a SANS experiment, we have directly determined for the first time the
      conformation of hyaluronan, a model semirigid polyelectrolyte. At high ionic
      strength, this is completely possible, where the scattered intensity crosses over
      (when decreasing q) from a q(-1) rod variation to a q(-2) and, where fitting to
      the "wormlike" chain model gives the backbone, intrinsic, persistence length: L0
      = 86.5 A. At low ionic strength, we can safely check that the measured
      persistence length appears increased by at least the amount predicted by Odijk
      for the electrostatic contribution, L(e) (approximately kappa(-2), square of the
      Debye screening length). However, the intensity at the lowest q is not only due
      to the single chain, since it crosses over from a q(-1) to a q(-4) variation,
      characteristic of polymer associations.

PMID- 15011062
TI  - Statistics of copolymer sequences obtained by polymeranalogous reactions of
      homopolymer globules.
AB  - For the first time the macrokinetics of polymeranalogous reaction in a
      homopolymer globule is considered theoretically. Using mathematical apparatus of
      the theory of markovian stochastic processes we examined the statistical
      characteristics of the chemical structure of the emerging copolymers. It is shown
      that when the reaction is kinetically-controlled the sequence distribution of
      monomeric units in copolymer chains follows Bernoullian statistics. In the
      opposite regime, when the reaction is diffusion-controlled it is proved that the
      resulting primary structure is described by the Levy flight distribution. Such
      copolymers with nonmarkovian character of the alteration of units in
      macromolecules can not be synthesized in the bulk or in concentrated solutions by
      means of standard synthetic polymerization procedures.

PMID- 15011063
TI  - Controlling wettability by light: illuminating the molecular mechanism.
AB  - The functionalisation of a surface with an organic monolayer containing
      photoactive moieties such as the azobenzene chromophore opens an elegant route
      for controlling its wettability by light. In this paper we investigate the
      microscopic origin of the macroscopic change in wettability upon photo-induced
      cis-trans isomerization of a copolymeric diphenyl-diazene Langmuir-Blodgett
      monolayer. Polarised UV-Vis and FTIR spectroscopy have been used to monitor the
      orientational order of various functional groups, Atomic Force Microscopy and
      Imaging Ellipsometry is employed for the quantification of the surface roughness
      and morphology, contact angle and surface potential measurements are carried out
      for a characterisation of the polar ordering. The data analysis is further
      supported by semi-empirical and ab-initio calculations of the molecular dipole
      moments and the normal IR-modes of the fluorinated chromophore. The combination
      of all these techniques provides a detailed molecular picture. The data suggest
      that changes in the projection of the dipole moment onto the surface normal
      caused by isomerization of the azobenzene are responsible for the observed
      changes in the surface energy. This knowledge allowed us to predict guidelines
      for the synthesis of molecules in order to maximize the wetting contrast upon
      photo-irradiation.

PMID- 15011064
TI  - Measuring a colloidal particle's interaction with a flat surface under
      nonequilibrium conditions. Total internal reflection microscopy with absolute
      position information.
AB  - A new and general approach is proposed to analyze the dynamics of a colloidal
      particle interacting with a nearby wall. This analysis can be used to determine
      the acting forces even when the system is non-stationary. As an illustration, we
      use total internal reflection microscopy to investigate the forces acting on a
      polystyrene sulfate latex particle as it is receding from a charged glass
      surface.

PMID- 15011065
TI  - Segment-sphere size ratio influence on the stability of a polymer-colloid
      mixture.
AB  - The influence of the sphere to segment size ratio on the effective depletion
      layer thickness around a sphere and the resulting phase behaviour of a colloid
      polymer mixture is considered. An analytical expression for the excluded volume
      between an ideal freely jointed chain and a sphere [L. Lue, J. Colloid Interface
      Sci. 202, 558 (1998)] allows the effect of polymer characteristics (chain length,
      segment/sphere size ratio) on the depletion interaction in polymer-colloid
      mixtures to be calculated. For both small and intermediate polymer-to-colloid
      size ratios the respectively gas-solid and gas-liquid coexistence curves shift to
      larger polymer coil volume fractions as the relative segment size increases. It
      is further demonstrated that the conditions for optimal (protein) crystallization
      are affected when the segment to sphere size is altered.

PMID- 15011066
TI  - Switching of banana liquid crystal mesophases under field.
AB  - Taking advantage of the great number of bent-core or "banana" compounds
      synthesized and studied in the laboratory, we describe their behaviour under the
      application of an external electric field. If the field were a static one, we
      would work within the frame of an equilibrium phase diagram in a (field E,
      temperature T) space where some phases would be simple dielectrics and others
      ferroelectric ones with a macroscopic polarization, either spontaneous or induced
      by the field. In this paper, we deal with the basic responses of "banana" liquid
      crystals under the application of a low frequency (1 to 100 Hz) AC field. Firstly
      square-wave voltages allow us to locate the phase boundary between dielectric (at
      lower field) and ferroelectric phases (higher field) at a given temperature and
      field threshold. Then we apply slowly varying AC voltages with shapes like
      triangle or "triple-plateau" to check out the stability of the induced
      ferroelectric phase versus field removal. Three behaviours are encountered, the
      unstable one (short lifetime of the high-field ferroelectric phase) where the
      macroscopic polarization is destroyed and then rebuilt in the opposite direction
      during each half period and usually called "antiferroelectric"; the stable one
      (long lifetime) with a polarization that rotates at constant modulus which is
      labeled as "ferroelectric" and a new one where the macroscopic polarization is
      proportional to the applied field, we named this behaviour as
      "superparaelectric". Let us stress that these observations apply to the
      ferroelectric phases of the (E, T) phase diagram not to the zero field (0,T)
      phases observed in the usual phase characterization experiments except for an
      eventual spontaneous ferroelectric phase.

PMID- 15011067
TI  - Small-angle neutron scattering studies of aqueous solutions of short-chain
      amphiphiles.
AB  - We present small angle neutron scattering measurements on binary aqueous
      solutions of some short-chain amphiphiles (diols, triols, glycols and diglycols)
      at room temperature. The spectra were analysed in terms of the Teubner-Strey
      phenomenological formula which allows to obtain a measure for the amphiphilicity
      strength of each system (amphiphilicity factor fa). In some systems, however,
      other models, valid for micellar solutions, give also a good representation of
      the spectra. As a result, we find that, independently of the type of hydrophilic
      group side (oxydrilic or oxirane), these systems cover the entire accessible
      amphiphilicity scale ( -1 < fa < 1). Some disordered systems (fa > 1) presumably
      are able to form micelle-like aggregates.

PMID- 15011068
TI  - Rectangular to hexagonal columnar phase transition exhibited by a biforked
      mesogen.
AB  - We present the structural study of a biforked compound exhibiting a Colr-Colh
      phase transition. This study was performed by means of DSC, optical microscopy, X
      ray diffraction, dilatometry and molecular modelling. The molecular packing
      within the two columnar mesophases of this compound is discussed. For the first
      time, it is shown that the clusters of adjacent molecules which form the
      elementary section of a column are tilted with respect to the columnar axis in
      the rectangular mesophase. From the whole set of experimental data, the number of
      molecules in a columnar section is found to be about 5 in the rectangular
      mesophase, and 4 in the hexagonal one. The transition between the two columnar
      mesophases is discussed with respect to its slow kinetics.

PMID- 15011069
TI  - Slow nucleic acid unzipping kinetics from sequence-defined barriers.
AB  - Recent experiments on unzipping of RNA helix-loop structures by force have shown
      that approximately 40-base molecules can undergo kinetic transitions between two
      well-defined "open" and "closed" states, on a timescale approximately 1 sec
      [Liphardt et al., Science 297, 733-737 (2001)]. Using a simple dynamical model,
      we show that these phenomena result from the slow kinetics of crossing large free
      energy barriers which separate the open and closed conformations. The dependence
      of barriers on sequence along the helix, and on the size of the loop(s) is
      analyzed. Some DNA and RNA sequences that could show dynamics on different time
      scales, or three(or more)-state unzipping, are proposed. Our dynamical model is
      also applied to the unzipping of long (kilo-basepair) DNA molecules at constant
      force.

PMID- 15011070
TI  - Orientational phase transition and the solvation force in a nematic liquid
      crystal confined between inhomogeneous substrates.
AB  - A nematic liquid crystal confined between two identical flat solid substrates,
      with an alternating stripe pattern of planar and homeotropic anchoring, is
      studied in the framework of the Frank-Oseen theory. By means of numerical
      minimization of the free energy functional we study the effect of the sample
      thickness D on the location of the phase transition between a uniform alignment,
      either planar or homeotropic, and a distorted nematic texture. The solvation
      force f due to distortions of the nematic director is also studied. It is found
      that f is always attractive, and for D small compared to the periodicity of the
      surface structure it exhibits two distinct asymptotic behaviors: f approximately 
      D(-1/2) or f approximately -D(-1), depending on the relation between D and the
      extrapolation lengths.

PMID- 15011071
TI  - On the connection of Joule-Thompson's coefficient with dissipation properties of
      filtrating media.
AB  - In the paper is shown that the Joule-Thompson's coefficient may be connected with
      dissipation properties of filtrating liquid or gas. The calculations are based on
      the classical Boltzmann's kinetic equation. The connection between Joule
      Thompson's coefficient and the viscosity of liquid is found.

PMID- 15011072
TI  - Vesicles in haptotaxis with hydrodynamical dissipation.
AB  - We analyze the problem of vesicle migration in haptotaxis (a motion directed by
      an adhesion gradient), though most of the reasoning applies to chemotaxis as well
      as to a variety of driving forces. A brief account has been published on this
      topic. We present an extensive analysis of this problem and provide a basic
      discussion of most of the relevant processes of migration. The problem allows for
      an arbitrary shape evolution which is compatible with the full hydrodynamical
      flow in the Stokes limit. The problem is solved within the boundary integral
      formulation based on the Oseen tensor. For the sake of simplicity we confine
      ourselves to 2D flows in the numerical analysis. There are basically two regimes
      (i) the tense regime where the vesicle behaves as a "droplet" with an effective
      contact angle. In that case the migration velocity is given by the Stokes law.
      (ii) The flask regime where the vesicle has a significant (on the scale of the
      vesicle size) contact curvature. In that case we obtain a new migration law which
      substantially differs from the Stokes law. We develop general arguments in order
      to extract analytical laws of migration. These are in good agreement with the
      full numerical analysis. Finally we mention several important future issues and
      open questions.

PMID- 15011073
TI  - Osmotic force resisting chain insertion in a colloidal suspension.
AB  - We consider the problem of inserting a stiff chain into a colloidal suspension of
      particles that interact with it through excluded volume forces. The free energy
      of insertion is associated with the work of creating a cavity devoid of colloid
      and sufficiently large to accommodate the chain. The corresponding work per unit
      length is the force that resists the entry of the chain into the colloidal
      suspension. In the case of a hard sphere fluid, this work can be calculated
      straightforwardly within the scaled particle theory; for solutions of flexible
      polymers, on the other hand, we employ simple scaling arguments. The forces
      computed in these ways are shown, for nanometer chain and colloid diameters, to
      be of the order of tens of pN for solution volume fractions of a few tenths.
      These magnitudes are argued to be important for biophysical processes such as the
      ejection of DNA from viral capsids into the cell cytoplasm.

PMID- 15011074
TI  - Complex nanostructured materials from segmented copolymers prepared by ATRP.
AB  - The development of new controlled/living radical polymerization processes, such
      as Atom Transfer Radical Polymerization (ATRP) and other techniques such as
      nitroxide mediated polymerization and degenerative transfer processes, including
      RAFT, opened the way to the use of radical polymerization for the synthesis of
      well-defined, complex functional nanostructures. The development of such
      nanostructures is primarily dependent on self-assembly of well-defined segmented
      copolymers. This article describes the fundamentals of ATRP, relevant to the
      synthesis of such systems. The self-assembly of block copolymers prepared by ATRP
      is illustrated by three examples. In the first, block copolymers of poly(butyl
      acrylate) with polyacrylonitrile phase separate, leading to spherical,
      cylindrical or lamellar morphologies, depending on the block copolymer
      composition. At a higher temperature, polyacrylonitrile block converts to
      nanostructured carbon clusters, whereas poly(butyl acrylate) block serves as a
      sacrificial block, aiding the development of designed nanostructures. In the
      second example, conductive nanoribbons of poly(n-hexylthiophene) surrounded by a
      matrix of organic polymers are formed from block copolymers prepared by ATRP. The
      third example describes an inorganic-organic hybrid system consisting of hard
      nanocolloidal silica particles (approximately 20 nm) grafted by ATRP with well
      defined polystyrene-poly(benzyl acrylate) block copolymer chains (approximately
      1000 chains per particle). Silica cores in this system are surrounded by a rigid
      polystyrene inner shell and softer polyacrylate outer shell.

PMID- 15011075
TI  - Block copolymers with amino acid sequences: Molecular chimeras of polypeptides
      and synthetic polymers.

PMID- 15011077
TI  - Control of amphiphilic block copolymer morphologies using solution conditions.
AB  - It is well known that the morphology of block copolymer aggregates depends on
      polymer properties such as the molecular weight, the relative block length, and
      the chemical nature of the repeat unit. Recently, we have shown that if
      aggregates are allowed to self-assemble in solution, then in addition to the
      above factors, a high degree of control over the aggregate architecture can be
      achieved by adjusting the solution conditions. Factors such as the water content
      in the solvent mixture, the solvent nature and composition, the presence of
      additives (ions, surfactants, and homopolymer) and the polymer concentration were
      successfully employed to control the aggregate shape and size. In this paper, we
      review a series of studies performed in our group to show how solution properties
      can control the architecture of aggregates prepared from a given copolymer. The
      control mechanism is explained in terms of the effect of each property on the
      forces that govern the formation of any given morphology, namely the core-chain
      stretching, corona-chain repulsion and interfacial tension.

PMID- 15011076
TI  - From supramolecular polymersomes to stimuli-responsive nano-capsules based on
      poly(diene-b-peptide) diblock copolymers.
AB  - This paper discusses the self-assembly of block copolymers into vesicular
      morphology. After a brief state of art of the field, a system based on an
      amphiphilic poly(butadiene)- b-poly(-L-glutamic acid) (PB- b-PGA) diblock
      copolymer in aqueous solution is discussed in detail. The aggregation behavior of
      this block copolymer has been investigated by means of fluorescence spectroscopy,
      dynamic (DLS) and static (SLS) light scattering as well as transmission electron
      microscopy (TEM). The diblock copolymer was found to form well-defined vesicles
      in water. The size of these so-called polymersomes or peptosomes could be
      reversibly manipulated as a function of both pH and ion strength. Depending on
      the pH of the aqueous solution, the hydrodynamic radii of these vesicles were
      found to vary from 100 nm to 150 nm. By cross-linking the 1,2-vinyl double bonds
      present in the polybutadiene block, the ability to transform a transient
      supramolecular self-organized aggregate into a permanent "shape-persistent
      stimuli-responsive nanoparticle" has been demonstrated.

PMID- 15011078
TI  - Phase behavior and structure of an ABC triblock copolymer dissolved in selective
      solvent.
AB  - A mean-field lattice theory is applied to predict the self-assembly into ordered
      structures of an ABC triblock copolymer in selective solvent. More specifically,
      the composition-temperature phase diagram has been constructed for the system
      (C)14(PO)12(EO)17/water, where C stands for methylene, PO for propylene oxide and
      EO for ethylene oxide. The model predicts thermotropic phase transitions between
      the ordered hexagonal, lamellar, reverse hexagonal, and reverse cubic phases, as
      well as the disordered phase. The thermotropic behavior is a result of the
      temperature dependence of water interaction with EO- and PO-segments. The
      lyotropic effect (caused by changing the solvent concentration) on the formation
      of different structures has been found weak. The structure in the ordered phases
      is described by analyzing the species volume fraction profiles and the end
      segment and junction distributions. A "triple-layer" structure has been found for
      each of the ordered phases, with each layer rich in C-, PO-, and EO-segments,
      respectively. The blocks forming the layers are not stretched. The dependence of
      the domain spacing on polymer volume fraction and temperature is also considered.

PMID- 15011079
TI  - Association behavior of polyisoprenes having cholesterol and phosphatidylcholine
      analogous end groups.
AB  - Linear polyisoprenes having dimethylamine end groups were prepared by high vacuum
      anionic polymerization techniques using 3-dimethylaminopropyllithium as the
      initiator. The amine group was reacted with 2-cholesteryl-2-oxo-1,3,2
      dioxaphospholane to provide polymer chains having end zwitterionic groups
      chemically connected with cholesterol. The association behavior of these end
      functionalized polymers was studied in cyclohexane by low angle laser light
      scattering, dynamic light scattering, and viscometry. The aggregation numbers, Nw
      were found to decrease by increasing the molecular weight of the precursor
      polymer, due to excluded volume repulsions. The ability of cholesterol to form
      liquid crystal mesophases facilitated the association process leading to higher
      Nw values. The hydrodynamic behavior of the aggregates was similar to that of
      star polymers. The dependence of the Nw values on the molecular weight of the
      base polymer, the polydispersity of the associates and the absence of critical
      micelle concentration, cmc are compatible with the linear head-packing model.

PMID- 15011080
TI  - pH effects in the formation of interpolymer complexes between poly(N
      vinylpyrrolidone) and poly(acrylic acid) in aqueous solutions.
AB  - The critical pH values for hydrogen-bonded interpolymer complexes of poly(N
      vinylpyrrolidone) and poly(acrylic acid) in aqueous solutions were determined.
      The effect of polymer concentrations, molecular weights and addition of inorganic
      salts (NaCl and KCl) on the complexation was studied.

PMID- 15011081
TI  - One-dimensional optical reflectors based on self-organization of polymeric comb
      shaped supramolecules.
AB  - We demonstrate that complexation of dodecylbenzenesulphonic acid, DBSA, to a
      diblock copolymer of polystyrene- block-poly(4-vinylpyridine), PS- block-P4VP,
      leads to polymeric supramolecules PS- block-P4VP(DBSA)y (y = 1.0, 1.5, and 2.0),
      which self-organize with a particularly large lamellar periodicity in excess of
      1000 A. The structures consist of alternating PS and P4VP(DBSA)y layers, where
      the latter contains smaller internal structure, probably lamellar. The DBSA side
      chains are bonded to the pyridines by protonation and hydrogen bonding and they
      effectively plasticize the material. In this way relatively well-developed
      structures are obtained even without annealing or macroscopic alignment.
      Transmission and reflectance measurements show that a relatively narrow and
      incomplete bandgap exists for supramolecules of high molecular weight block
      copolymer at ca. 460 nm.

PMID- 15011082
TI  - Controlled polystyrene brushes grown on AFM tip.
AB  - We report here the first successful growth of Polystyrene brushes directly from
      the apex of a conventional AFM tip using a Langmuir-Blodgett deposition technique
      associated with a controlled free radical polymerization. The efficiency of the
      grafting together with the possibility to form multi-layers are checked through
      AFM force measurements between a bare or functionalized tip and a silicon wafer
      in water or xylene.

PMID- 15011083
TI  - Polymer chemists/polymer physicists: a constructive partnership.

PMID- 15011084
TI  - The polymer mat: arrested rebound of a compressed polymer layer.
AB  - Compression of an adsorbed polymer layer distorts its relaxed structure. Surface
      force measurements from different laboratories show that the return to this
      relaxed structure after the compression is released can require tens of minutes
      and that the recovery time can grow rapidly with molecular weight. We argue that
      the arrested state of the free layer before relaxation can be described as a
      Guiselin brush structure (O. Guiselin, Europhys. Lett. 17, 225 (1992)), in which
      the monomer density falls off only weakly with distance from the surface. This
      brush structure predicts an exponential falloff of the force at large distance
      with a decay length that varies as the initial compression distance to the 6/5
      power. This exponential falloff is consistent with surface force measurements. We
      propose a relaxation mechanism that accounts for the increase in relaxation time
      with chain length.

PMID- 15011086
TI  - About the role of non-equilibrium effects for polymers at surfaces.

PMID- 15011087
TI  - Perspective: kinetic and mechanical properties of adsorbed polymer layers.

PMID- 15011089
TI  - UV isomerisation in nematic elastomers as a route to photo-mechanical transducer.
AB  - The macroscopic shape of liquid-crystalline elastomers strongly depends on the
      order parameter of the mesogenic groups. This order can be manipulated if photo
      isomerisable groups, e.g. containing N=N bonds, are introduced into the material.
      We have explored the large photo-mechanical response of such an azobenzene
      containing nematic elastomer at different temperatures, using force and optical
      birefringence measurements, and focusing on fundamental aspects of population
      dynamics and the related speed and repeatability of the response. The
      characteristic time of "on" and "off" regimes strongly depends on temperature,
      but is generally found to be very long. We were able to verify that the
      macroscopic relaxation of the elastomer is determined by the nematic order
      dynamics and not, for instance, by the polymer network relaxation.

PMID- 15011090
TI  - Hydrodynamic interaction of AFM cantilevers with solid walls: an investigation
      based on AFM noise analysis.
AB  - The noise power spectrum of the thermally activated motion of an AFM cantilever
      has been analyzed with respect to viscoelastic and hydrodynamic coupling between
      the cantilever and a substrate surface. Spheres with radii between 5 and 25
      microm were glued to the cantilever to provide a well-defined geometry. The
      cantilever is modeled as a harmonic resonator with a frequency-dependent complex
      drag coefficient xi(omega). The variation of the drag coefficient xi(omega) with
      the tip-sample distance, D, and the sphere radius, R, can be expressed as a
      function of the single dimensionless parameter D/ R. However, this scaling breaks
      down close to the surface. There are two sources of a frequency dependence of
      xi(omega), which are viscoelastic memory and hydrodynamics. Viscoelastic
      relaxation is observed when the surface is covered with a soft polymer layer. In
      the absence of such a soft layer one still finds a frequency dependence of
      xi(omega) which is caused by hydrodynamics. At large substrate-cantilever
      distances, the drag coefficient increases with frequency because of inertial
      effects. At small distances, on the other hand, the drag coefficient decreases
      with increasing frequency, which is explained by the reflection of shear waves
      from the substrate surface. In liquids, inertial effects can be important when
      performing dynamic AFM experiments.

PMID- 15011091
TI  - How do smectic liquid crystals of different molecular length mix in thin films?
AB  - We present a model for the structure of binary mixtures of smectic compounds in
      freely suspended films of 2-7 layers. The compounds are the hexyl (6AB) and
      dodecyl (10AB) homologues of p, p'-dialkylazoxybenzene that differ by about 40%
      in molecular length. X-ray reflectivity indicates that no demixing occurs between
      6AB and 10AB molecules, while also there is no indication found of increased
      roughness at the film surfaces. However, the surface layers are somewhat expanded
      compared to the interior layers. This can be explained by backfolding of the
      dodecyl end chains of 10AB molecules at the surface via two gauche kinks, which
      ensures dense packing. This model is supported by surface tension measurements
      that indicate an increased amount of alkyl groups at the surfaces.

PMID- 15011092
TI  - Lower bounds for the surface energy of two-dimensional foams.
AB  - Amongst the two-dimensional cellular patterns that fill a plane, dry foams at
      stable equilibrium typify a particular subset for which the total perimeter P of
      cell boundaries ( i.e., films between bubbles) has a local minimum. For a given
      set of bubble areas Ai (i=1,..., N), P can be written in the form P=R(SigmaN(i=1)
      square root Ai)/2, where R is topology dependent. We seek the set of areas Ai and
      the cluster topology that minimise R, and propose lower bounds for R that set
      lower bounds for the surface energy of i) individual bubbles, with circular edges
      meeting at 2pi/3 angles at vertices (Plateau cells), and ii) infinite periodic
      bubble clusters.

PMID- 15011093
TI  - Instabilities of cylindrical bubble clusters.
AB  - Small bubbles in an experimental two-dimensional foam between glass plates
      regularly undergo a three-dimensional instability as the small bubbles shrink
      under diffusion or equivalently as the plate separation increases, and end up on
      one of the plates. The most recent experiments of Cox, Weaire, and Vaz are
      accompanied by Surface Evolver computer simulations and rough theoretical
      calculations. We show how a recent second variation formula may be used to
      perform exact theoretical calculations for infinitesimal perturbations for such a
      system, and verify results with Surface Evolver simulations.

PMID- 15011094
TI  - Surface-induced smectic-ordering effect in thin nematic liquid-crystal cell.
AB  - The influence of the surface-induced smectic A (SmA) phase on the threshold
      field, for homeotropic alignment of polar liquid crystals is discussed from the
      energy point of view. It is shown that the Freedericksz critical field, for 4-n
      octyl-4'-cyanobiphenyl (8CB), in a very thin cell near the second-order nematic
      SmA phase transition, exhibits an anomalous increase with decreasing of
      temperature.

PMID- 15011095
TI  - Statistics of a hydrophobic chain near a hydrophobic boundary.
AB  - We study the behavior of a hydrophobic chain near a hydrophobic boundary in two
      dimensions, adapting the decorated lattice model of Berkema and Widom (G.T.
      Barkema, B. Widom, J. Chem. Phys. 113, 2349 (2000)) to obtain effective,
      temperature-dependent intrachain and chain-boundary interactions. We use these
      interactions to construct two model Hamiltonians. The resulting partition
      functions may be integrated numerically. Our results compare favorably with
      preliminary Monte Carlo computations, using the same effective interactions. At
      relatively low temperatures and at high temperatures, we find that the chain is
      randomly configured in the ambient water, and detached from the wall, whereas at
      intermediate temperatures it adsorbs onto the wall in a stretched or partially
      folded state, again depending upon the temperature, and the energy of solvation.

PMID- 15011096
TI  - Numerical study of the flow around a cylinder using multi-particle collision
      dynamics.
AB  - A novel mesoscopic simulation technique--multi-particle collision dynamics--which
      has been suggested very recently, is used to study the two-dimensional flow
      around a square and a circular cylinder. The method is described and new proper
      boundary conditions are proposed to deal with wall collisions. The flow is
      analyzed in a wide range of Reynolds numbers in order to cover both the steady
      and unsteady regimes, resulting in symmetric steady vortices and periodic vortex
      shedding, respectively. The numerical results for integral flow parameters, such
      as the recirculation length, the drag and lift coefficients, the Strouhal number,
      as well as the spatial dependence of the velocity field, are compared with
      previous numerical and experimental studies. The qualitative and quantitative
      agreement is very good, validating the method as a promising technique to
      describe the hydrodynamic effects of solvent on embedded particles.

PMID- 15011097
TI  - Drying processes in the presence of temperature gradients--pore-scale modelling.
AB  - The influence of temperature gradients on the drying of water-saturated porous
      networks has been studied. We have focussed on the influence of the temperature
      on the drying process via the equilibrium vapor density rhoe, because this is the
      most sensitive parameter with respect to variations of the temperature T. We have
      used a 2D model which accounts for both capillary and buoyancy forces. Invasion
      events by air or water are handled by standard rules of invasion percolation in a
      gradient (IPG). Vapor fluxes are calculated by solving a discretized version of
      the Laplace equation. In the model the temperature T varies linearly from the
      open side T0 to the closed side TL. The temperature gradients strongly influence
      the cluster evolution during the process, because they facilitate vapor transport
      through wet regions. When T0<TL, the movement of the front is inhibited and dry
      patches develop after a certain time at the closed side. When T0>TL, the front
      movement is enhanced and the air ingress in the wet region behind the front is
      inhibited. The behavior of 3D systems differs from that of 2D systems, because
      the point where air percolates the system and the point where the water network
      breaks up in isolated clusters do not coincide. Before the latter fragmentation
      point the temperature will mainly influence the drying rates. After this point
      also the water distribution becomes sensitive to the temperature profile.

PMID- 15011098
TI  - Fat oxidation in obesity: druggable or risky enterprise?
AB  - Two potential approaches for the treatment of obesity are presented, in which
      modulation of a target increases fatty acid oxidation. These two methods, which
      are here referred to as 'pull' and 'push' routes, involve creating a demand for
      fuel by uncoupling oxidation from ATP production ('pulling'), or shuttling fatty
      acyl CoA into the mitochondria by an afferent mechanism ('pushing'). Proof-of
      principle studies in humans are required to assess the use of these approaches in
      weight loss maintenance.

PMID- 15011099
TI  - Growth factor treatment of neurodegenerative disorders: new developments pave the
      way for clinical success.
AB  - Neurotrophic factors have received significant attention in recent years for
      their potential use in the treatment of neurodegenerative and other nervous
      system disorders. However, the first attempts to apply factors such as nerve
      growth factor, glial-derived neurotrophic factor and ciliary neurotrophic factor
      failed to demonstrate any significant benefits in the clinic, despite a wealth of
      positive preclinical data. Recent advances in our understanding of the biology of
      neurotrophic factors in combination with the development of several new and
      improved delivery methods, for example, genetically engineered cells and viral
      vectors, have revitalized the interest in these potential nervous system protein
      therapeutics, and influenced the design of new clinical trials.

PMID- 15011100
TI  - Current and emerging therapies for type 2 diabetes.
AB  - Diabetes affects approximately 150 million people worldwide, of which
      approximately 90% are type 2 diabetics. This article reviews the current and
      emerging therapies for type 2 diabetes and examines how these therapies affect
      the etiology and progression of the disease. Although current therapies can only
      at best delay the progression of type 2 diabetes, it is feasible to prevent pre
      diabetics from developing the costly disease. Public awareness of the risk
      factors for and the symptoms of diabetes are crucial for its prevention and
      control.

PMID- 15011101
TI  - Diflomotecan. Ipsen.

PMID- 15011102
TI  - 99mTc-Hynic-Annexin V. North American Scientific.

PMID- 15011103
TI  - [What are the expectations in a Working Group for Quality on behalf of a
      scientific society?].

PMID- 15011104
TI  - [Possibilities in improving patients's turn-over coordination in the OR of an
      University Hospital].
AB  - An efficient Operating Room (OR) management might increase the cost-effectiveness
      of an OR. For this purpose, we have evaluated the coordination and the times of
      the solitary processes that are involved in the patient turnover. The mean time
      between skin suture of the preceding patient and incision of the following
      patient (SI-time) was, depending on the type of operation, between 44 and 78
      minutes. Mean empty-room time (ERT) was 7 minutes. SI-times depended on various
      factors, including the times necessary to discharge the preceding patient from
      the OR and the times necessary for induction of anesthesia or for preparation of
      the OR. Altogether, our data provide evidence for the fact, that optimisation of
      the patients turnover can decrease SI-times between 10-15 minutes. Although this
      period appears too short to reliably allow an additional scheduled operation
      during regular working hours, an improved coordination may result in reduced
      overtimes of the OR-staff and thus should increase staff satisfaction.

PMID- 15011105
TI  - [A multidisciplinary mModule for oncological documentation within a hospital
      information system].
AB  - The follow-up documentation of oncological patients in Germany is inadequate in
      many cases: it is usually limited to a minimal dataset mandated by the
      epidemiological tumor registers; it is carried out in a paper-based fashion and
      rarely in a multi-disciplinary context. Parallel documentation efforts can result
      in redundant or erroneous data and excess work. The introduction of hospital
      information systems (HIS) allows the implementation of digital oncological
      documentation systems integrated in surrounding clinical workflows that can
      provide access to existing data sources as well as data entry and presentation
      across departmental boundaries. This concept enables the integration of tumor
      documentation, quality assurance and process optimization within HIS. Feasibility
      requirements include a high flexibility and adaptability of the underlying HIS to
      reach a seamless integration of oncological documentation forms within routine
      clinical workflows. This paper presents the conceptual design and implementation
      of a modular oncological documentation system at the Muenster University Hospital
      that is capable of integrating the documentation requirements of multiple
      departments within the hospital.

PMID- 15011106
TI  - [Utility of the questionnaire for quality of life EORTC-QLQ-C30 in psycho
      oncological outcome research].
AB  - Aim of this paper is to examine the utility and validity of the questionnaire for
      quality of life EORTC-QLQ-C30 (European Organization for Research and Treatment
      of Cancer). Data were collected within the scope of a study for evaluation of
      individual psycho-oncological support for inpatients with colorectal cancer
      undergoing surgery. The study was sponsored by the German Cancer Aid. The design
      was a prospective randomized controlled trial. After informed consent, patients
      were randomized in one of two groups: patients in the experimental group received
      individualized psychotherapeutic support during the hospital stay; those in the
      control group received a daily program of classical music. All patients were
      assessed one day before surgical treatment, ten days and three months after
      surgery. Instruments were questionnaires for quality of life and state anxiety.
      106 patients met the inclusion criteria. Results show insufficient discriminative
      power (high significant bivariate correlations between most EORTC scales,
      Kendalls tau-b) and insufficient construct validity (high and significant
      bivariate correlations between most EORTC scales and state anxiety, Kendalls tau
      b) of the EORTC scales. The scores of "cognitive functioning" and some symptom
      scales show an insufficient scatter. The illustration of situational influences
      and therefore an insufficient illustration of effects of specific interventions
      are connected with a high sensitivity of the scales and a tendency to extreme
      sores. The psycho-oncological intervention shows a significant stress reducing
      effect on the specific EORTC-scale "Emotional Functioning" and on State Anxiety
      (STAI). The testing of utility and validity of the EORTC-Questionnaire shows that
      they are insufficient and therefore the benefit for evaluation of specific
      intervention procedures is restricted.

PMID- 15011107
TI  - [Injuries of carotid arteries].
AB  - Carotid artery injuries reveal as a specific and relatively small group of
      vascular trauma. Hemorrhage from vessels of this diameter and flow (10 % of
      cardiac output) has predominantly a fatal end or shows severe neurological
      sequelae. Cut and stab wounds represent the majority of carotid injuries, often
      associated with venous damage. Blunt trauma and fractures of the skull basis are
      uncommon causes. We present 43 cases of carotid injuries operated upon as
      emergency service (in the majority outside of our hospital). The number of
      postoperative surgical and neurological complications was moderate.

PMID- 15011108
TI  - [Analysis of vascular complications in intra-venous drug addicts after puncture
      of femoral vessels].
AB  - BACKGROUND: Intravenous drug abuse is a global social and health care problem.
      Vascular complications following intravascular inguinal self-injection of
      addictive drugs are rarely seen. An efficient therapeutic concept is needed
      because, besides the risk of vascular injuries, infections ranging up to systemic
      inflammatory response syndrome or sepsis might occur. METHODS: This was a single
      center retrospective analysis of vascular complications in drug addicts from 1994
      to 2002 in an university hospital. A systematic literature review in MEDLINE was
      performed with the following key words: 1 vascular, 2 complications, 3 drugs, 4
      addicts, 5 mycotic aneurysms. RESULTS: 10 patients with a long lasting history of
      i. v. drug abuse (median: 16.1 years, range: 10-28 years) and vascular
      complications were included in this study. The mean age was 40.2 years (range 32
      50 years). 5 patients showed pain and tumescence of the inguinal region at the
      time of admission. 7/10 patients had a poor general health and nutritional
      status. 2 patients had a hepatitis-B- and C-infection, 7 patients were hepatitis
      C Ag positive. All patients were HIV negative. 1 patient had an older deep venous
      leg thrombosis that was treated conservatively. In six cases, we saw an
      intraoperative arterial bleeding; in five cases pseudoaneurysms. The patients
      were treated with 5 venous interpositions, 4 venous patch plastics, 1 end-to-end
      anastomosis and 2 prosthetic grafts. 3 thrombectomies were performed. One time we
      performed a ligation of the pseudoaneurysm without reconstruction. Six
      reconstructions were covered with a biological seal. One thigh amputation was
      necessary; no patient died. In 2 patients with severe problems, we performed 11
      operative revisions. The systematic literature review in MEDLINE showed no
      evidenced based therapy regimen. CONCLUSION: We favour the resection of the
      aneurysm including a radical debridement of the wound with secondary wound
      healing. In the case of an isolated aneurysm of the arteria femoralis
      superficialis or the arteria profunda femoris, a ligation or excision without
      reconstruction is possible with a low risk of postoperative complications. A
      reconstruction with autologous material is necessary in the case of aneurysms of
      the common femoral artery or its bifurcation. The reconstructed vessel should be
      covered with a biological seal, e. g. omentum majus. If there is no autologous
      material available for the reconstruction, we recommend the ligation without
      reconstruction, because the results after implantation of artificial vascular
      prostheses are not satisfying.

PMID- 15011110
TI  - [The unstable patient with pelvic fracture].
AB  - For the hemodynamically unstable patient with pelvic fracture a target focussed
      and rapid diagnostic and therapy is mandatory. After hemorrhage control at crash
      site the direct transport in a trauma center follows. Primary therapy in the
      emergency room sometimes includes stabilization by a pelvic clamp or an external
      fixator. If the patient is still hemodynamically unstable the life threatening
      bleeding is packed. After that simple internal osteosynthesis is allowed. The
      presented article shows the possible options of the therapy. The main message is:
      hemorrhage control is not possible without stabilization of the pelvic ring.

PMID- 15011109
TI  - [Reconstruction of extensive soft tissue loss by transplantation of dermal and
      epidermal equivalents].
AB  - AIM: The opportunities of autologous dermal and epidermal grafting as starting
      point for non-invasive reconstruction of extensive soft tissue defects will be
      demonstrated and discussed. METHODS: Skin biopsies for cell cultivation were
      taken from patients with extensive acute soft tissue defects of different origin.
      Cultured autologous fibroblasts grown on three dimensional biocompatible
      scaffolds made up of benzyl ester of hyaluronan were transplanted as "neo-dermis"
      on debrided and conditioned wound sites. After incorporation of the dermal
      equivalents grafting of subconfluent proliferative keratinocytes on hyaluronan
      based laser perforated membranes was performed. Ten days later a 0.2 mm thin, 1 :
      6 meshed autograft to create definite biomechanical stability was overlaid.
      RESULTS: Grafting of in vitro cultured autologous fibroblasts revealed a good
      vascularized dermal tissue substitute. After keratinocyte-transfer formation of
      thin epithelium was visible. Final closure of the defects with aesthetic and
      normo-elastic tissue properties was achieved after thin mesh-grafting.
      CONCLUSIONS: Preliminary results seem to be very promising. Clinical follow-up as
      well as histological and immunohistochemical outcome in the treatment of five
      extensive soft-tissue defects are discussed. As in all fields of tissue
      engineering, long-tem studies and cost-benefit analyses are required.

PMID- 15011112
TI  - [Long-term results of surgical therapy of epicondylitis humeri radialis using the
      technique described by Mittelmeier].
AB  - INTRODUCTION: Tennis elbow is one of the most common stress induced pathological
      findings in patients consulting an orthopaedic surgeon. In refractory cases
      operation is indicated after conservative treatment. Several operative techniques
      have been published. We prefer the technique described by Mittelmeier. Aim of
      this study is to show long- term results of operative therapy of the tennis elbow
      using this technique. PATIENTS AND METHOD: Between 1.1.1980 and 31.12.1992 we
      performed 115 outpatient operations for epicondylitis humeri radialis using the
      technique described by Mittelmeier. After a mean follow-up of 15,3 years we could
      examine 98 patients according to the score of Roles and Maudsley. RESULTS: We
      found excellent results in 47 %, good results in 43 % and fair results in 10 % of
      the evaluated cases. All patients had a benefit concerning the operation. There
      was one infection as a serious complication which led to revision. CONCLUSION: In
      epicondylitis humeri radialis surgical therapy according to Mittelmeier leads to
      good long-term results and can be recommended for persistent radial
      epicondylitis.

PMID- 15011111
TI  - [The angle stable locking-proximal-humerus-plate (LPHP) for proximal humeral
      fractures using a small anterior-lateral-deltoid-splitting-approach - technique
      and first results].
AB  - The Locking-Proximal-Humerus-Plate (LPHP) was slided from proximally to distally
      through a small anterior-lateral-deltoid-splitting-approach following a closed
      reduction. Additional tension band wiring for the rotator cuff was fixed at the
      plate after screw insertion. The prospective study included 35 patients (age
      median: 63 years, range: 33-92; male: 13, female: 22) from 08/01-05/02. The
      follow-up period was set to 3 months postoperatively, whereas 29 patients were
      able to attend. The patient-group with 2-part fractures (n = 8) showed an average
      Constant score of 77.6 points (+/- 10.7, "good"), the patients with 3-part
      fractures (n = 16) an average score of 75.1 points (+/- 14.4, "good") and the
      patients with 4-part fractures (n = 5) an average score of 64.8 points (+/- 10.
      4, "moderate"). Specific, approach-related problems were not observed. Almost all
      fractures revealed bony union during the first 3 months and only one loss of
      reduction was found. A screw loosening in 2 cases and a break of the plate in 3
      cases were seen as implant related problems, and furthermore in 5 cases the
      screws placed in the humeral head were too long. Only one early re-osteosynthesis
      with the same plate was necessary due to an initial non-correct reposition. As
      demonstrated by these good short-term results, this technique seems to be a
      suitable procedure for displaced humeral head fractures.

PMID- 15011113
TI  - [Plantar fibromatosis: therapy by total plantarfasciectomy].
AB  - Morbus Ledderhose is a rare fibromatous disease of the plantar fascia. Clinical
      features include palpable solitary or multiple nodules and cords, mainly
      affecting the medial part of the plantar fascia. When clinical symptoms occur,
      conservative options include stretching, orthotics, nonsteroidal antirheumatic
      drugs, local cortisone-injections and physiotherapy. Operative treatment is
      indicated in case of persistent pain or if conservative measures fail. The
      standard procedure includes a partial fasciectomy of the plantar aponeurosis.
      There is a high recurrence rate with an increased risk of complications and more
      aggressive ingrowth into anatomical structures after partial resection. Therefore
      we recommend a complete fasciectomy not only in recurrent disease, but also as
      the primary procedure of choice.

PMID- 15011114
TI  - [Transrectal ultrasound-assisted gun-biopsy in the diagnostic of presacral
      recurrent rectal carcinoma].
AB  - Suspected extraluminal recurrence of rectal carcinoma after surgical treatment
      represents a frequent diagnostic challenge. Clinical history and examination as
      well as tomographic imaging often do not equivocally settle this tissue. Glucose
      PET is an expensive, not universally available test. Early diagnosis is required
      for both successful operative reintervention aiming at cure and indication to
      palliative therapy. We performed gun-biopsy of presacral space-occupying lesions
      in three patients, choosing the ultrasound-guided transrectal approach in three
      of them. Extraluminal recurrence was proven in one patient. In another patient,
      anastomotic recurrence was proven by endoscopic biopsy and presacral recurrence
      ruled out before reoperation. In the third patient, no tumour tissue was found in
      the samples, as confirmed by his clinical course and by another biopsy after one
      year. By providing a sufficient amount of tissue for histological examination,
      ultrasound-guided gun-biopsy allows definite diagnosis in presacral space
      occupying lesions and hence represents an important expansion of the diagnostic
      repertoire in the follow-up of rectal cancer.

PMID- 15011115
TI  - [Visualization of a solitary myeloma of the sternum by ultrasonography].
AB  - We report on a 32-year-old patient with a 9 month history of pain of the mid
      third of his sternum. The laboratory results as well as other diagnostical
      methods (MRI and bone scintigraphy) were negative. The ultrasound examination
      revealed an interruption of the corticalis reflex beneath the sternal
      synchondrosis of a length of 4 cm. Under suspicion of an osteolysis we performed
      an open biopsy. The histological analysis made the diagnosis of a solitary
      myeloma. Therefore ultrasonography is able to depict tumerous infiltrations of
      the sternum if the anterior corticalis is involved and allows therapeutical
      consequences.

PMID- 15011116
TI  - [Lung herniation after a single cough].
AB  - We present the case of an overweight male patient with a lung hernia caused by a
      single massive coughing attack. The diagnosis could only be verified by CT-scans.
      Following a conservative therapeutic approach, surgical intervention was
      necessary. Lung hernias are easy to detect using radiological diagnostic.
      Standard X-ray examinations where a subcutaneous air mass can be seen have
      become, since the inauguration of computed tomography, second line tests. Large
      traumatic lung hernias should be treated surgically. Spontaneous and especially
      cervical hernias should be handled conservatively and only must be surgically
      treated when complications or a progression in size should be observed.

PMID- 15011118
TI  - Further experience with the medial circumflex femoral(GRACILIS) perforator free
      flap.
AB  - The microsurgical transfer of the medial groin skin territory previously required
      this to be part of a transverse-oriented gracilis musculocutaneous free flap. As
      the concept of muscle perforator flaps has evolved, avoidance of muscle bulk
      and/or retention of muscle function here is also possible with the careful
      intramuscular dissection of the gracilis musculocutaneous perforators back to the
      usual medial circumflex femoral source vessel. This so-called medial circumflex
      femoral (GRACILIS) [MCF (GRACILIS)] perforator free flap has been successfully
      used seven times in six patients with minimal complications. The MCF (GRACILIS)
      muscle perforator flap may well represent the ideal skin flap: no muscle function
      is sacrificed; a reliable skin territory of large size is available; the dominant
      vascular pedicle is consistent in location; the flap may be harvested with the
      patient in a supine position; a combined conjoint flap including the gracilis
      muscle is optional; closure of the donor site leaves a medial groin scar that can
      be readily concealed; and flap dissection in this region is already very familiar
      to most microsurgeons.

PMID- 15011117
TI  - [Verrucous carcinoma of the esophagus - a rare entity].
AB  - Verrucous carcinoma of the esophagus is a very rare entity. It has a high
      mortality. Treatment is different. 14 cases are reported. With this 15th case we
      report on a 66-year-old female with a verrucous carcinoma of the esophagus and
      surgical treatment after 4 times of recurrence and unsuccessful endoscopic
      resection of the tumor. The patient received transthoracic removal of the distal
      esophagus and interposition of the stomach. The patient recovered completely and
      was discharged from hospital after 18 days. Considering this case therapeutic
      options will be discussed.

PMID- 15011119
TI  - Aesthetic refinements in reconstructive microsurgery of the lower leg.
AB  - Even if a surgical procedure is performed for reconstructive and functional
      reasons, a plastic surgeon must be responsible for the visible result of the work
      and for the social reintegration of the patient; therefore, the aesthetic
      appearance of a microsurgically reconstructed lower leg must be considered. Based
      on the experience of 124 free-tissue transfers to the lower leg performed in 112
      patients between January 1994 and March 2001 (110 [88.7 percent] were transferred
      successfully), three cases are presented. Considerations concerning flap
      selection and technical refinements in designing and tailoring microvascular
      flaps to improve the quality of reconstruction, also according to the aesthetic
      appearance, are discussed.

PMID- 15011120
TI  - Thoracoumbilical flap: experience with 33 cases.
AB  - From August 1996 to June 2000, 33 free thoracoumbilical flaps were transferred to
      reconstruct a variety of soft-tissue defects. The size of the flaps ranged from
      10 to 40 cm in length and 8 to 25 cm in width. The blood supply to the skin
      island came from the largest periumbilical perforator of the deep inferior
      epigastric vessels. The main indications were complex extremity trauma or soft
      tissue tumor resection with extensive skin loss, either acute or postprimary. The
      overall success rate was 100 percent (33/33). The donor area was closed directly
      in 10- to 12-cm-wide flaps, leaving an inconspicuous scar. Larger flaps required
      skin grafting. After a 2-year follow-up, all flaps have healed uneventfully and
      donor abdominal morbidity is minimal.

PMID- 15011121
TI  - One-stage reconstruction of both the biceps brachii and triceps brachii tendons
      using a free anterolateral thigh flap with a fascial flap.
AB  - An avulsed elbow with severe degloving and crush injury was reconstructed in a 66
      year-old man. The biceps brachii was completely transected, and the triceps
      brachii tendon was partly transected. In addition, the skin around the elbow had
      become totally necrotic. Four weeks after the injury, a free anterolateral thigh
      flap with a fascial flap was transplanted to reconstruct both the biceps brachii
      and triceps brachii tendons simultaneously. Six months after the initial injury,
      the range of elbow motion had recovered to almost the same level as that before
      injury.

PMID- 15011122
TI  - The gracilis free muscle flap is more than just a "graceful" flap for lower-leg
      reconstruction.
AB  - In 60 consecutive cases, a gracilis free muscle flap was used to reconstruct
      defects in the lower extremity. Although the harvest of the gracilis free flap is
      straightforward, the flap is not frequently considered as a valid option for
      reconstruction because of its "gracile" shape. Hence, it is not considered
      voluminous enough to cover defects of significant size in the lower leg. However,
      once the epimysium is separated, the muscle flap spreads out and covers a large
      surface area, large enough to reconstruct wide rectangular wounds or extended
      spindleshaped defects. Especially in young patients, the volume of the gracilis
      muscle is much larger than expected from its descriptive but misleading name.
      Often it is precisely this patient population that gets involved in motorcycle
      accidents or traumas caused by contact sports. For the treatment of Gustilo type
      III open tibia fractures with moderately large-sized soft-tissue defects and for
      chronic lower leg defects with osteomyelitis, the gracilis muscle flap is an
      excellent choice. Fifty-nine out of the 60 flaps in long-term follow-up
      (minimally 3 years) fully healed. The pedicle can be more than 7 cm in length
      when the final dissection under the long adductor muscle is carried up to the
      origin at the deep femoral vessels. The functional and aesthetic outcomes at the
      donor site at the inner thigh are minimal, compared to alternative transfers for
      such defects, while the reconstructive features of the gracilis muscle flap are
      excellent.

PMID- 15011123
TI  - Radiation-induced brachial plexopathy: review. Complication without a cure.
AB  - Radiation-induced brachial plexopathy, especially the chronic and progressive
      form, has become an increasingly rare entity in patients receiving radiation
      therapy to the chest wall and axilla. However, for the patients affected by this
      pathologic process, the chronic pain, decline in function, and absence of a
      satisfactory treatment are a continuing challenge to the reconstructive
      peripheral nerve surgeon. The authors have undertaken a review of the relevant
      literature addressing radiation-induced brachial plexopathy, and here present a
      summary of the current understanding of the pathophysiology, diagnosis, and
      treatment of this disorder.

PMID- 15011124
TI  - Combined application of human amniotic membrane wrapping and hyaluronic acid
      injection in epineurectomized rat sciatic nerve.
AB  - The purpose of this study was to investigate the effects of combined application
      of human amniotic membrane wrapping and hyaluronic acid injection on peripheral
      nerve scarring in an adult rat model. After circumferential epineurectomies of
      right sciatic nerves were performed in each of 72 rats, nerves were randomly
      divided into three groups: (1) nothing was done additional to epineurectomy; (2)
      the epineurectomized segment was wrapped with human amniotic membrane; and (3)
      the epineurectomized segment was wrapped with human amniotic membrane and
      hyaluronic acid was injected inside. The extent of adhesions and perineurial scar
      thickness was macroscopically and histologically evaluated at 4 and 12 weeks. The
      least adhesion and perineurial scar tissue were observed in nerves treated with
      human amniotic membrane wrapping and hyaluronic acid injection. This combination
      appears to be safe and effective in preventing perineurial scar formation after
      peripheral nerve surgery in rats.

PMID- 15011125
TI  - Functional, electrophysiologic, and morphometric evaluation of nerve regeneration
      from coaptation on regenerated nerve fibers: experimental study in rabbits.
AB  - The importance of a sufficient number of nerve fibers at a proximal coaptation
      site is indisputable for the successful repair of nerves; however, the quality of
      nerve fibers required at this site has yet to be defined. The present study deals
      with the question of whether it is necessary to trim nerves back to unaffected
      neuronal tissue or whether the coaptation on recently regenerated nerve fibers,
      commonly believed to produce a poor quality of repair can, in fact, produce
      adequate nerve regeneration. Twenty New Zealand White rabbits received a
      standardized crush lesion on the peroneal nerves of both hind legs. Four weeks
      later, the nerves of the left hind legs (n = 20) were transected 10 mm distal to
      the previous crush lesion and coapted to the freshly regenerated nerve fibers.
      For comparison, on 10 right hind legs, the nerves were transected at the site of
      previous crushing (Group A, superimposition) or 10 mm proximal to the site of
      crushing on unscathed nerve fibers (Group B). Eleven weeks later, the quality of
      nerve regeneration was assessed by the toe-spreading reflex, electrophysiologic
      data, muscle weight, and histomorphologic evaluation. In the animals of Group A,
      the quality of nerve regeneration following coaptation on the regrown axons did
      not differ in any of the examined parameters from the quality of nerve fibers
      outgrown from the site of the superimposed lesion. Both lesions led to a
      completely functional reinnervation. Also in Group B, nerve action potential
      recording and histologic data on both sides did not reveal a significant
      difference between the number and maturation of nerve fibers equidistant from the
      suture site, shortly before muscle entrance. With this coaptation model, it could
      be demonstrated in the peroneal nerve of rabbits, that coaptation to recently
      regenerated nerve fibers leads to a significant functional regeneration.

PMID- 15011126
TI  - Interposed autologous nerve segment stimulates nerve regeneration in peripheral
      nerve allografts in a rat model.
AB  - The ability of autologous nerve segments interposed between allografts, to
      increase the total nerve-gap distance, was studied. Sciatic nerve allografts were
      carried out in a rat model. A 15-mm nerve gap was repaired with a 25-mm nerve
      graft (interposed group: allo-auto-allograft; control group: allo-allo
      allograft). Cyclosporin was given for 12 weeks. Nerve regeneration was evaluated
      using the weight of the anterior tibial muscle and histologic, morphometric and
      immunohistochemical analyses at 12, 13, 14, 15, 16, 20, and 24 weeks. Nerve
      regeneration in the interposed group was statistically significantly better than
      that in the control group. The authors concluded that a nerve allograft with
      interposed autograft may enhance nerve regeneration in this model, because of the
      migration of host-derived Schwann cells into the graft from not only the proximal
      and distal host nerve stumps, but also the interposed autograft.

PMID- 15011127
TI  - Ischemic preconditioning-induced microvascular protection at a distance.
AB  - Ischemic preconditioning-induced microcirculatory protection appears to be a
      systemic rather than a local phenomenon. This protection induced by remote
      ischemic preconditioning (RIPC) may be attributed to a humoral rather than a
      neuronal mechanism. An innervated (Inn, Groups 1 and 4) or denervated (Den,
      Groups 2 and 3) and vascular isolated right cremaster of the rat was prepared.
      Left femoral vessels were clamped (Groups 1, 2, and 4) for 45 min or unclamped
      (Group 3) as a control. After 2 hr of reperfusion in the left lower extremity, 4
      hr of ischemia in the right cremaster was applied in Groups 1, 2, and 3. However,
      in Group 4, 4 hr of ischemia in the cremaster muscle was instituted before
      reperfusion of the left femoral artery was begun. Microcirculatory responses,
      including terminal arteriole diameter, capillary perfusion, and endothelium
      function were evaluated. Four groups (six rats per group) were designed: Group 1:
      RIPC (Inn); Group 2: RIPC (Den); Group 3: sham RIPC (Den); and Group 4: fake RIPC
      (Inn). Ischemia of 45 min followed by 2 hr of reperfusion in the left lower
      extremity of the rat induced a significant microvascular protection against
      subsequent 4-hr ischemia in both innervated and denervated cremasters. This
      microvascular protection at a distance was lost in sham RIPC and in fake RIPC
      groups. The results demonstrated that remote protection induced by ischemic
      preconditioning is a systemic phenomenon and due to a humoral mechanism.

PMID- 15011128
TI  - Improved early muscle recovery using FK506 in a rat nerve-repair model.
AB  - The authors hypothesized that FK506 improves maximal muscle force (P (0))
      recovery during early muscle reinnervation. Rat peroneal nerve was unilaterally
      cut and repaired. Rats received subcutaneous injections of vehicle (controls) or
      FK506 at 1 mg/kg (FK506-1MG) or 5 mg/kg (FK506-5MG) for 3 weeks. Extensor
      digitorum longus (EDL) isometric muscle P (0) was measured bilaterally 4 weeks
      postoperatively. FK506 treatment adversely affected body mass. With body mass as
      a covariate, the P (0) for denervated-reinnervated muscle in the FK506-5MG group
      was statistically significantly higher by 34 percent and 32 percent, compared
      with controls and FK506-1MG groups. There was no group difference for the
      contralateral, nerve-intact EDL muscle P (0), when loss of body mass was
      considered. NCAM immunohistologic data showed significantly better reinnervation
      of the denervated muscle in a dose-dependent fashion. Thus, FK506 treatment at
      high dose improves early recovery of force in denervated-reinnervated muscle,
      following nerve repair, when loss of body mass is considered.

PMID- 15011129
TI  - [Efficacy and safety of treatment of acute ischemic stroke with glycoprotein
      IIb/IIIa receptor blocker in routine clinical practice].
AB  - BACKGROUND: Platelet aggregation plays an important pathophysiological role in
      the incidence of myocardial infarction and ischemic stroke. The expression of
      glycoprotein IIb/IIIa receptors on the surface of activated platelets is the
      final common pathway of platelet aggregation. PATIENTS AND METHODS: Encouraged by
      the favorable outcome in acute coronary syndromes and by preliminary results,
      which substantiate the efficacy and safety of GP IIa/III antagonists (GP) in
      ischemic stroke, we treated 21 cases/20 patients (13 male, 7 female, age 39-79
      y.) and conducted a retrospective study using a clinical graduation scale
      (Modified Rankin Scale MRS). Patients received tirofiban (n = 18) or eptifibatide
      (n = 3) in the usual cardiological dose 3 h (0.5-8 h) after beginning of symptoms
      together with "full dose " heparin (n = 8) or "low dose" heparin (n = 12) in the
      acute phase, with aspirin 100 mg (n = 4), Clopidrogel 75 mg (n = 5), aspirin +
      clopidogrel (n = 4) in the chronic phase. All patients had a cranial CT, 95% an
      echocardiography and Doppler sonography of the carotid artery system and some
      cranial MRI (43%). RESULTS: There was no significant clinical deterioration. All
      except one patient showed a rapid and impressive improvement during the first 24
      h after initiation of treatment (median MRS pre/post 3/1). CONCLUSION: The
      results with GP in acute ischemic stroke are promising and further studies should
      be initiated using especially tirofiban, but with monitoring by cerebral
      diffusion-weighted MRI before and after treatment.

PMID- 15011130
TI  - [Mediastinal tumour in children misdiagnosed as bronchial asthma].
AB  - HISTORY: Three school children (2 girls and 1 boy, aged 9-15 years) complained
      about exercise-induced shortness of breath and stridor. The children were treated
      with inhalation steroids, one of them with systemic steroids, without a
      significant effect. INVESTIGATIONS: Because of lack of treatment response a chest
      X-ray was done. In all cases a mediastinal mass was visible. No radiological
      signs of an obstructive pulmonary disease was demonstrated. In none of the three
      cases did a pulmonary function tests demonstrate an obstructive pulmonary
      disease. DIAGNOSIS, TREATMENT, AND COURSE: Bone marrow aspiration in one girl
      showed an acute lymphoblastic leukemia of T-cell immunophenotype with a large
      mediastinal lymphoma. Lymph node biopsy in the boy demonstrated a nodular
      sclerosing subtype of Hodgkin's disease. In the other girl a ganglioneuroma was
      found. CONCLUSION: In children and adolescents a chest radiograph and pulmonary
      function tests should be performed if history and clinical signs are suggestive
      of bronchial asthma, before a specific inhalative or systemic treatment is
      started.

PMID- 15011131
TI  - [Multifocal nodular fatty infiltration of the liver associated with porphyria and
      haemochromatosis].
AB  - HISTORY AND CLINICAL FINDINGS: A 64-year-old woman suffered from severe fatigue.
      She was admitted to our outpatient unit for a diagnostic evaluation of multiple
      liver lesions as well as an adrenal gland tumor. Diabetes mellitus was diagnosed
      22 years ago. Clinical evaluation revealed a mild obesity and a facial
      hypertrichosis. INVESTIGATIONS: Apart from elevated liver enzymes, serum ferritin
      and transferrin saturation were increased. Suspected haemochromatosis was
      verified by genetic analyses. Analyses of a 24 hours urine sample revealed
      typical constellation of a chronic hepatic porphyria. The liver lesions were
      diagnosed as multifocal fatty infiltrations using computer tomography. The
      patient refused a liver biopsy. The tumor of the adrenal gland represented an
      adenoma without endocrine activity. TREATMENT AND COURSE: Repeated phlebotomies
      were performed for the treatment of haemochromatosis. In the following serum
      ferritin returned to normal and liver enzymes as well as hyperporphyriuria
      decreased markedly. Diabetes was better controlled due to decrease of insulin
      requirements, too. CONCLUSION: This case report highlights the association of
      hereditary haemochromatosis and chronic hepatic porphyria, which presumably cause
      multifocal nodal fatty infiltration of the liver. Iron overload is likely the
      underlying cause, which represents the target for treatment options.

PMID- 15011132
TI  - [Carbamazepine].

PMID- 15011133
TI  - [Hereditary neuroendocrine gastroenteropancreatic tumors and multiple endocrine
      neoplasia type 1. I. Diagnosis].

PMID- 15011134
TI  - [Innovative therapeutic options for psoriatic arthritis: TNFalpha inhibitors].

PMID- 15011135
TI  - [Mastopathy, breast cancer and iodolactone].

PMID- 15011136
TI  - [How would a volume dose be transported in renal insufficiency?].

PMID- 15011137
TI  - Gene flow between cassava, Manihot esculenta Crantz, and wild relatives.
AB  - Controlled and natural hybridization between cassava and wild relatives does
      occur. Barriers within the genus appear to be weak due to recent evolution of the
      group. All Manihot species examined cytogenetically have a chromosome number of
      2n = 36. However, they behave meiotically as diploids. The weak interspecific
      barriers have led to an extremely heterozygous gene pool that may begin a
      sequence of hybridization followed by speciation. Introgression from cassava into
      a number of wild species (M. neusana, M. alutacea, M. reptans and M. anomala) has
      been detected by both morphological marker genes and molecular techniques. Winged
      fruit, setaceous bracteoles, and wide leaf sinus were dominant genes that came
      from cassava and appeared in the hybrids. The characteristic protein bands of
      cassava were recognized in the hybrid seed protein electrophoresis.

PMID- 15011138
TI  - Oxidative stress in Lactococcus lactis.
AB  - Lactococcus lactis, the most extensively characterized lactic acid bacterium, is
      a mesophilic- and microaerophilic-fermenting microorganism widely used for the
      production of fermented food products. During industrial processes, L. lactis is
      often exposed to multiple environmental stresses (low and high temperature, low
      pH, high osmotic pressure, nutrient starvation and oxidation) that can cause loss
      or reduction of bacterial viability, reproducibility, as well as organoleptic
      and/or fermentative qualities. Among these stress factors, oxidation can be
      considered one of the most deleterious to the cell, causing cellular damage at
      both molecular and metabolic levels. During the last two decades, considerable
      efforts have been made to improve our knowledge of oxidative stress in L. lactis.
      Many genes involved with both oxidative stress resistance and control mechanisms
      have been identified; functionally they seem to overlap. The finding of new
      genes, and a better understanding of the molecular mechanisms of stress
      resistance in L. lactis and other lactic acid bacterium, will lead to the
      construction and isolation of stress-resistant strains. Such strains could be
      exploited for both traditional and probiotic uses.

PMID- 15011139
TI  - Genetic polymorphism at spinocerebellar ataxia 1 and 2 loci in Brazil.
AB  - Dynamic mutation involves the expansion of a tandem arrayed DNA sequence that is
      polymorphic in the population. This mechanism is associated with
      neurological/neuromuscular disorders and the pathology depends on the extension
      of the repeated tract, with a specific threshold for each disease. We made a PCR
      based characterization of allelic polymorphism of SCA1 and SCA2 loci in a sample
      of 200 pairs of chromosomes in a population in Rio de Janeiro and found 23
      different alleles at the SCA1 locus, varying from 10 to 39 CAG repeats (mean 27.7
      +/- 3.3, mode 28) and 10 different alleles ranging from 19 to 29 CAG (mean 22.1
      +/- 1.0, mode 22) at the SCA2 locus. The level of heterozygosis was 53% (SCA1)
      and 8% (SCA2).

PMID- 15011140
TI  - Evolution without speciation but with selection: LUCA, the Last Universal Common
      Ancestor in Gilbert's RNA world.
AB  - This is not an attempt to analyze the Last Universal Common Ancestor (LUCA) to
      understand the origin of living systems. We do not know what came before
      Gilberts' RNA world. Our analysis starts with the RNA world and with genes
      (biological replicators alla Dawkings) made up of RNA proteins with enzymatic
      catalytic functions within units that are not yet modern cells. We offer a
      scenario where cellular entities are very simple and without individuality; they
      are only simple primary units of selection (the first level of selection) in
      which replicators compete in the most Darwinian manner, totally deprived of
      cooperation and interactions among genes. The information processing system of
      this RNA world is inaccurate and inefficient when compared to that found in
      organisms that came later. Among the "genes" and the entities that harbor them,
      high mutation rate was the most prevalent source of variability and the only
      inheritance was through lateral gene transfer of mobile elements. There were no
      chromosomes or any other genomic organization. As millions of years accumulated,
      complex and organized biological structures and processes evolved thanks to the
      variability mustered up mostly by lateral gene transfers and mutations. With
      micro- and mini-satellites, lateral gene transfers became indispensable devices
      of selection to mold variability. Competition and Darwinian selection gave way to
      a new transition in evolution, one I consider ineluctable, in which cooperation
      among interactive genes prevailed for the sake of higher fitness.
      Compartmentalization constituted a major transition in evolution that spurted new
      types of genome organization. Minichromosomes is one of these; cellular membranes
      and cytoplasmic structures completed the picture of the primitive cell. However,
      the much talked about phylogenetic tree does not exit in that ancient LUCA. The
      tree has no organism at its base; only clusters of genes evoke a fragile
      beginning for the increasingly complex cell types that were to emerge later.

PMID- 15011141
TI  - Putative pyrophosphate phosphofructose 1-kinase genes identified in sugar cane
      may be getting energy from pyrophosphate.
AB  - Pyrophosphate-dependent phosphofructokinase (PPi-PFK) has been detected in
      several types of plant cells, but the gene has not been reported in sugar cane.
      Using Citrus paradisi PPi-PFK gene (AF095520 and AF095521) sequences to search
      the sugar cane EST database, we have identified both the alpha and beta subunits
      of this enzyme. The deduced amino acid sequences showed 76 and 80% similarity
      with the corresponding alpha and beta subunits of C. paradisi. A high degree of
      similarity was also observed among the PFK b subunits when the alignment of the
      sugar cane sequences was compared to those of Ricinus communis and Solanum
      tuberosum. It appears that alpha and beta are two distinct subunits; they were
      found at different concentrations in several sugar cane tissues. It remains to be
      determined if the different gene expression levels have some physiological
      importance and how they affect sucrose synthesis, export, and storage in
      vacuoles. A comparison between the amino acid sequences of b PFKs from a variety
      of organisms allowed us to identify the two critical Asp residues typical of this
      enzyme's activity site and the other binding sites; these residues are tightly
      conserved in all members of this protein family. Apparently, there are catalytic
      residues on the b subunit of the pyrophosphate-dependent enzyme.

PMID- 15011142
TI  - Preferred amino acids and thermostability.
AB  - Most organisms grow at temperatures from 20 to 50 degrees C, but some
      prokaryotes, including Archaea and Bacteria, are capable of withstanding higher
      temperatures, from 60 to >100 degrees C. Their biomolecules, especially proteins,
      must be sufficiently stable to function under these extreme conditions; however,
      the basis for thermostability remains elusive. We investigated the preferential
      usage of certain groupings of amino acids and codons in thermally adapted
      organisms, by comparative proteome analysis, using 28 complete genomes from 18
      mesophiles (M), 4 thermophiles (T), and 6 hyperthermophiles (HT). Whenever the
      percent of glutamate (E) and lysine (K) increased in the HT proteomes, the
      percent of glutamine (Q) and histidine (H) decreased, so that the E + K/Q + H
      ratio was >4.5; it was <2.5 in the M proteomes, and 3.2 to 4.6 in T. The E + K/Q
      + H ratios for chaperonins, potentially thermostable proteins, were higher than
      their proteome ratios, whereas for DNA ligases, which are not necessarily
      thermostable, they followed the proteome ratios. Analysis of codon usage revealed
      that HT had more AGR codons for Arg than they did CGN codons, which were more
      common in mesophiles. The E + K/Q + H ratio may provide a useful marker for
      distinguishing HT, T and M prokaryotes, and the high percentage of the amino acid
      couple E + K, consistently associated with a low percentage of the pair Q + H,
      could contribute to protein thermostability. The preponderance of AGR codons for
      Arg is a signature of all HT so far analyzed. The E + K/Q + H ratio and the codon
      bias for Arg are apparently not related to phylogeny. HT members of the Bacteria
      show the same values as the HT members of the Archaea; the values for T organisms
      are related to their lifestyle (intermediate temperature) and not to their domain
      (Archaea) and the values for M are similar in Eukarya, Bacteria and Archaea.

PMID- 15011143
TI  - Behavioral genetics of Drosophila ananassae.
AB  - Drosophila ananassae has a unique status among Drosophila species because of
      certain peculiarities in its genetic behavior. The most unusual feature of this
      species is its relatively high frequency of spontaneous male recombination. The
      results of studies on non-sexual behavior, such as phototactic responses,
      eclosion rhythm, and preferences for oviposition and pupation sites, lead us to
      suggest that this behavior is under polygenic control, with a substantial amount
      of additive genetic variation. Sexual isolation has been reported in D. ananassae
      with the degree of such isolation being stronger in isofemale lines than in
      natural populations. The significant variations seen in the mating propensity of
      several isofemale strains, inversion karyotypes and wild type strains, the
      diminishing effects of certain mutations on the sexual activity of males, and the
      positive responses to selection for high and low mating propensity point to a
      genetic control of sexual behavior in D. ananassae. Males contribute more to
      variation and thus are more subject to intrasexual selection than females. There
      is a positive correlation between sternopleural bristle number, mating propensity
      and fertility in D. ananassae. This correlation between morphometric traits and
      mating success suggests that larger flies are more successful in mating than
      smaller ones. There is also evidence for adaptive plasticity and a trade-off
      between longevity and productivity in D. ananassae. Rare, specific courtship song
      parameters that provide males with a mating advantage have also been reported in
      different geographic strains of D. ananassae. The remating behavior of males and
      females, sperm displacement, and the bi-directional selection for female remating
      speed indicate that post-mating behavior in this species may also be under
      genetic control. The occurrence of size assortative mating further indicates that
      there is size-dependent sexual selection in D. ananassae.

PMID- 15011144
TI  - Occupational genotoxicity risk evaluation through the comet assay and the
      micronucleus test.
AB  - The micronucleus (MN) test and the alkaline single cell gel or comet assay were
      applied to exfoliated cells of the buccal mucous in order to evaluate the
      genotoxic risk associated with occupational exposure of 10 storage battery
      renovation workers, and 10 car painters, with age matched controls, in Pelotas,
      RS, in southern Brazil. In the MN test, 2000 exfoliated buccal cells were
      analyzed for each individual, while 100 cells were examined in the comet assay.
      In the comet test, both comet tail length and a damage index were calculated.
      Highly significant effects of occupational exposure were found with both the MN
      test and the comet assay (P<0.001). The comet assay was found to be rapid, of
      simple visualization, and it is a sensitive technique for measuring and analyzing
      DNA damage in human cells.

PMID- 15011146
TI  - [The ontogeny of self awareness. How the cognitive brain is constructed].
AB  - INTRODUCTION: We understand the term ontogenesis to mean the process that begins
      from the moment the ovule is fertilised up to the second year of postnatal life,
      which is a process that plays a key role in the organisation of the central
      nervous system. DEVELOPMENT: In this paper we describe the stages of
      micromaturation (glial cell proliferation, neuronal migration, synaptogenesis,
      selective apoptosis and general myelination) and the theories of neuronal
      plasticity are also explained. CONCLUSIONS: The best known ontogenic process is
      the acquisition of motor maturity, while other areas such as the social and
      cognitive dimensions are less well known, and this would explain how autistic
      spectrum disorders remain undetected in the early stages. The somatogram is a
      valuable tool in the process of maturing that constitutes the foundation for
      understanding how the cognitive brain is constructed.

PMID- 15011147
TI  - [The neuropaediatric and pathogenic clinical bases of autistic spectrum
      disorder].
AB  - INTRODUCTION: The dimension of the autistic spectrum embraces a considerable
      degree of clinical complexity which is, in turn, an expression of the numerous
      systems involved in the functioning of the central nervous system. Every day
      different biological factors are revealed which put in doubt other factors that,
      in a more objective way, appear to be involved in a particular aetiology.
      DEVELOPMENT AND CONCLUSIONS: It is clear that exactly what causes autistic
      spectrum disorder is still unknown and it may be useful to analyse cases with a
      known aetiology and correlate them with other similar cases, as it is likely to
      be this association between findings and studies in the future that will probably
      enable us to better define the bases and the underlying causes of the complex and
      manifold origin of the autistic spectrum. This will enable a more efficient
      therapeutic approach to be developed, which, when all is said and done, is what
      is primarily sought in the management of children with autistic spectrum
      disorder.

PMID- 15011148
TI  - [Diagnostic yield in studies of autism. The contribution made by neuroimaging,
      metabolic tests and genetic studies].
AB  - AIMS: We reviewed the literature on the diagnostic yield of the different medical
      tests carried out on autistic patients in order to determine the aetiology of the
      process. DEVELOPMENT: Although it is generally said that a causation of the
      process can be determined in 10 30% of cases, the actual diagnostic yield of
      autism when a routine diagnosis is applied is between 2 and 7%. The diagnostic
      yield of radiology, metabolic studies and genetic studies was analysed. Genetic
      tests are the ones that offer the highest efficiency, and carrying out a
      karyotype and molecular study of fragile X chromosome syndrome is indicated in
      all patients with mental retardation associated to autism. The next most
      efficient are metabolic studies, which become particularly important mainly in
      populations where no screening has previously been conducted for metabolic
      disorders. CONCLUSIONS: Despite their being capable of showing up a large number
      of disorders, neuroimaging studies are unspecific and the diagnostic yield of
      radiological studies is very low when they are conducted on a routine basis.

PMID- 15011149
TI  - [Primary versus secondary stereotypic movements].
AB  - Stereotypic movements are repetitive patterns of movements whose physiopathology
      and relations to other neurobehavioural disorders are still only poorly
      understood. In this paper our aim is to distinguish between primary stereotypic
      movements, which are the sole manifestation of an anomaly, while the
      complementary examinations, except for those involving molecular genetics, are
      normal; associated stereotypic movements, when they meet primary disorder
      criteria but there are other coexisting independent neurological signs, that is
      to say, they are neither the cause nor the consequence of the movement disorder;
      and secondary stereotypic movements, when they are the consequence of a lesion or
      acquired neurological dysfunction. Examples of primary stereotypic movements
      include episodes of parasomnia, such as head rocking, in subjects who are
      otherwise normal, and stereotypic movements due to emotional disorders, severe
      environmental deprivation or in institutionalised infants. Examples of associated
      stereotypic movements are those observed in Rett syndrome, in subjects with
      sensory defects or with mental retardation due to a variety of causes. And as
      instances of secondary stereotypic movements we have those that can be seen in
      infinite like syndrome caused by congenital cerebellar lesions. The purpose of
      the classification is to lay the foundations for the identification of new
      syndromes, which would without a doubt facilitate research into their
      physiopathology, their aetiology and the possible therapeutic attitude to be
      adopted.

PMID- 15011150
TI  - [Metabolic imaging by positron emission tomography using [18F] fluorodeoxiglucose
      in developmental disorders].
AB  - INTRODUCTION: Developmental disorders are a common pathological condition in
      Neuropaediatrics and do not usually present characteristic anatomical alterations
      in the different neuroanatomical imaging tests that can be employed, such as
      computerised axial tomography or magnetic resonance (MR). Positron emission
      tomography (PET) using [18F] fluorodeoxiglucose (PET FDG), one of the battery of
      imaging tests currently available, enables us to obtain data about brain activity
      in a non invasive manner. PATIENTS AND METHODS: A group of 39 patients with
      developmental disorders from the Hospital del Mar was analysed. They were
      submitted to PET FDG brain metabolism tests and in some cases hybrid PET MR
      images were also obtained; findings were then correlated against the clinical
      progression of the patients. RESULTS AND CONCLUSIONS: The alterations that were
      observed showed predominantly bilateral thalamic, mesial temporal and orbital
      frontal hypometabolism. This alteration of the limbic system, which has no
      correlation with anatomical damage, can be a predictor of the clinical
      progression and of the confirmation of the presence of alterations in the brain
      functions in this type of patients.

PMID- 15011151
TI  - [A magnetoencephalographic study of generalised developmental disorders. A new
      proposal for their classification].
AB  - INTRODUCTION: Autistic spectrum disorders (ASD) is a term that is not included in
      DSM IV or in ICD 10, which are the diagnostic tools most commonly used by
      clinical professionals but can offer problems in research when it comes to
      finding homogenous groups. DEVELOPMENT: From a neuropaediatric point of view,
      there is a need for a classification of the generalised disorders affecting
      development and for this purpose we used Wing's triad, which defines the
      continuum of the autistic spectrum, and the information provided by
      magnetoencephalography (MEG) as grouping elements. Specific generalised
      developmental disorders were taken as being those syndromes that partially
      expressed some autistic trait, but with their own personality so that they could
      be considered to be a specific disorder. ASD were classified as being primary,
      cryptogenic or secondary. The primary disorders, in turn, express a continuum
      that ranges from Savant syndrome to Asperger's syndrome and the different degrees
      of early infantile autism. MEG is a functional neuroimaging technique that has
      enabled us to back up this classification.

PMID- 15011152
TI  - [The characteristics of non-verbal learning disorder].
AB  - INTRODUCTION: Non verbal learning disorder (NLD) appears to be the consequence of
      an alteration in the cognitive functions linked to the right hemisphere. It is
      characterised by the coexistence of difficulties in carrying out social skills,
      poor academic achievement, low visuospatial skills and motor clumsiness.
      DEVELOPMENT: In this paper, information from the medical literature and the
      authors' own experience are taken as the basis to describe the most relevant
      clinical manifestations and the cognitive behavioural profile presented by
      children with NLD. Bearing in mind the similarity between NLD and Asperger's
      syndrome, we have also attempted to highlight the differences between the two
      developmental disorders.

PMID- 15011153
TI  - [Early development: some data about autism and language disorders].
AB  - INTRODUCTION: The early development of children who have been diagnosed as
      suffering from autism and children with specific language disorder (SLD) is still
      an area of research that receives little attention. There is a need for
      descriptive patterns of the early stages in the development of the two groups
      that foster the formation of reliable early diagnoses. Aims. In this study we
      attempt to determine the incidence of different symptoms in the first two years
      in the life of children who were later diagnosed as suffering from autism or SLD
      and to confirm or refute the data that suggests a pattern of onset of the
      disorder that differs from one group to the other. PATIENTS AND METHODS: We
      compare the data concerning the development of a sample made up of 42 children
      with autism and 41 children with SLD, which was carried out by means of a
      retrospective analysis of the information obtained from the families in the
      evaluation and diagnosis processes that were conducted in our centre. More
      specifically, we compare information about the following variables: family
      history, parents' age at the time of pregnancy, parents' profession, position at
      birth and incidence by sex, information about prenatal, perinatal and postnatal
      aspects, eating and sleeping problems, the presence or absence of signs of
      passivity, traces of alarm during the first year, age of the child when the first
      suspicions appeared, symptoms or difficulties that are described, data linked to
      medical neurological explorations carried out and data related to motor
      development. RESULTS: Although there are numerous similarities in many of the
      variables studied in both groups, it seems that the earlier onset of symptoms,
      passivity and the absence of pointing behaviour are more frequent in the group
      with autism than in children with SLD. The latter present a specific difficulty
      in language, tantrums and poorer motor competencies. CONCLUSIONS: At present
      there is no single symptom in early development that is exclusive to any of the
      disorders described above, although it is possible to determine some significant
      differences between the two groups. There is also a need to conduct more studies
      in the same line as this one that take into account the patterns of early
      development of other the autistic spectrum disorders.

PMID- 15011154
TI  - [Educational implications of the cognitive impairment in developmental dyslexia].
AB  - AIMS: In this study we review the main theories put forward to account for
      developmental dyslexia, as well as the intervention procedures deriving from
      these theories that enjoy the most empirical support. DEVELOPMENT: Developmental
      dyslexia is a complex disorder that reflects cognitive impairment related to
      neurobiological anomalies, although researchers still do not agree on fundamental
      aspects regarding its aetiology. There are at present a number of different
      theories that can be grouped in two antagonistic lines of work. On the one hand,
      one of them considers that the exclusive and direct cause of dyslexia is a
      specific cognitive disorder. On the other hand, however, there are several
      theories that consider the impairments experienced by dyslexic patients to be
      part of a wide range of tasks and processes that are secondary to an underlying
      primary deficit. As a consequence of the progress made in the characterisation of
      dyslexia, an unprecedented effort has been made in recent decades in the
      development of intervention programmes and in the analysis of their
      effectiveness. CONCLUSIONS: Research into the explanation for dyslexia finds
      itself faced with the challenge of determining whether the different cognitive
      problems identified in dyslexic patients represent different cognitive routes
      towards the same dyslexic phenotype, whether they correspond to different types
      of dyslexia or whether they refer to the sum of the problems resulting from
      different comorbid conditions. Until this issue is resolved, as educators, we
      must carry out more comprehensive evaluations in order to determine the profile
      of the difficulties that are experienced in each particular case and to be able
      to tailor the interventions employed in this enigmatic problem.

PMID- 15011155
TI  - [Cognitive aspects in girls with fragile X syndrome].
AB  - INTRODUCTION AND AIMS: Fragile X syndrome (FXS) is the first cause of
      intellective dysfunction due to hereditary reasons, but above all it is a
      multisystemic pathology, in which the cognitive behavioural phenotype is going to
      mark the child's entire school and social life. An early diagnosis is fundamental
      for proper genetic counselling and for the pedagogical approach. In girls, this
      diagnosis is hindered by a poorer knowledge of the semiology and because of the
      variability of the symptoms. Recognising the most significant clinical signs that
      suggest a diagnosis during early childhood is fundamental. DEVELOPMENT: An
      analysis of the literature offered us very few reports of girls affected by FXS
      and most of them are to be found in publications about genetics. There is often
      no clear separation between adulthood and childhood or between permutation and
      complete mutation, and extreme shyness and low self esteem are the most commonly
      reported data. Intellective capacity is normal in 40% of those affected by
      complete mutation; the pragmatic aspects of language and difficulties at school
      that can take on symptoms of non verbal learning disorder are the most
      significant data at school age; the incidence that the number of CGG repetitions,
      the degree of methylation and the FMR protein rate can have on both the
      symptomatology and the intensity with which they appear do not offer any
      homogeneous data; the attitude of the school and familial environment is a factor
      that has recently been considered to be of great importance in the maintenance or
      improvement of behavioural aspects. CONCLUSIONS: Although the discovery of the
      FMR1 gene provided us with a greater understanding of the symptomatology of FXS
      in girls, the scarcer knowledge available about its manifestations means that we
      can find ourselves before the problem of possibly mistaking it for learning
      disorders. The greater variability of its clinical symptoms and the shortage of
      studies that have appeared in publications on paediatrics and neuropaediatrics
      may be the underlying reason behind this lack of knowledge. Spanish language
      publications practically ignore cases of girls with FXS.

PMID- 15011156
TI  - [Functional neuronal plasticity].
AB  - INTRODUCTION: Thanks to the contributions made by neuroscientific research and
      the clinical evidence regarding the functional recovery of the central nervous
      system in the different motor, cognitive, linguistic and sensory spheres, we now
      know more about how the brain is built and its modifications. This recovery is
      possible due to the plasticity of the brain, its capacity to reorganise itself
      and to modify functions in order to adapt to both external and internal changes.
      This capacity is inherent to brain cells and allows cortical circuits to be
      repaired, integrates other cortical areas to carry out modified functions and
      responds to different disorders. It depends on genetic, neuronal and
      neurochemical factors and its limits can be manipulated through clinical and
      pharmacological intervention. DEVELOPMENT: The brain's capacity to adapt itself
      to changes is crucial in the development of the nervous system and has important
      repercussions on learning. The neuroanatomical, neurochemical and functional
      changes that take place during the reorganisation made possible by plasticity
      will facilitate the recovery acquisition of the functions involved (adaptive
      plasticity) and may hinder the development of others (maladaptive plasticity).
      This variability of the possible responses is related to the chronology of the
      lesion, the site that is affected, the state of the substrata that can take on
      the function and the type of function that is altered. The mechanisms responsible
      for facilitating this plasticity are different at any given time (fast and late
      plasticity), depending on the function that is altered, with expansion of the
      somatotopic representations in the motor cortex adjacent to the damage,
      interhemispherical transfer of language or crossed plasticity in the auditory or
      visual function. The neuropsychological pathology can appear linked to the lesion
      or secondary to a maladaptive plasticity. CONCLUSIONS: Advancing in our knowledge
      of the intrinsic mechanisms of brain plasticity and synaptic regulation will lead
      us to understand the recovery of damaged or lost functions in the brains of
      children with special needs, and thus allow us to implement favourable clinical
      and pharmacological interventions.

PMID- 15011157
TI  - [The evaluation of pragmatic difficulties. A case study].
AB  - INTRODUCTION: Pragmatic skills are defined as the speaker's appropriate use of
      language to communicate in different contexts and with different interlocutors.
      Within the field of disorders affecting language and communication, research into
      this issue became particularly important when, in 1983, Rapin and Allen put
      forward the term semantic pragmatic disorder to describe the communicative
      behaviour of children who presented traits such as pathological talkativeness,
      deficient access to vocabulary and discourse comprehension, atypical choice of
      terms and inappropriate conversational skills. This pioneering proposal has led
      to a development from both a terminological perspective and as regards the entity
      itself and the differential validity of the disorder. DEVELOPMENT: In this work,
      our aim is to bring together the main procedures used to evaluate pragmatic
      skills in children; this will be illustrated with examples taken from our own
      clinical practice and experience involving children belonging to different
      clinical groups. These procedures include getting people who play significant
      roles in the child's life to answer scales and surveys, the use of standardised
      instruments and other tasks, and finally the qualitative analysis of their
      discourse and conversation.

PMID- 15011158
TI  - [Neurocognitive abilities in schoolchildren with periventricular leukomalacia.
      Preliminary results in 15 patients].
AB  - INTRODUCTION: Apart from chronic motor disorder and the possible sensory deficits
      (visual, propioception) associated to periventricular leukomalacia (PVL),
      disorders involving the integration of higher functions due to bilateral injury
      to the occipital parietal junction are relatively common. AIMS: Our aim was to
      further our knowledge of the neuropsychological characteristics of this non
      progressive cerebral motor disorder. Patients and methods. We analysed a sample
      of 15 patients with spastic diplegia due to PVL who did not present mental
      retardation (verbal IQ> 75 and mean verbal IQ= 91, WISC R) in order to evaluate
      their visual gnosis praxis, verbal and visual memory, psycholinguistic and
      attentional capabilities. RESULTS: Disorders involving visuospatial integration
      and visual constructive memory are frequent. Long term verbal memory is poor (in
      fact in some cases it is clearly deficient), but can be improved with associative
      learning. They do not present any difficulties regarding attention and some
      subjects display deficiencies in the pragmatic use of language. This research is
      still underway and the findings presented here are preliminary. CONCLUSIONS: The
      neuropsychological profile of the diplegic children who were studied shares the
      characteristics of non verbal learning disorder. The declarative memory disorder
      observed in several of the subjects in our sample, who were all born premature
      and below weight, can be accounted for by a bihippocampal pathology or by a
      dysexecutive disorder.

PMID- 15011159
TI  - [Intervention in children with pragmatic language and communication disorders].
AB  - AIMS: In this paper we analyse the educational and therapeutic needs of children
      who present pragmatic disorders in language and communication. DEVELOPMENT:
      Pragmatic disorders in language and communication stand apart from the other
      disorders affecting the remaining aspects of language development. Their less
      specific nature goes beyond the purely linguistic domain and involves wide areas
      of the patient's affective and social development. CONCLUSIONS: Not only is it
      necessary to adapt the general model of speech therapy intervention, but also to
      include it within a set of pedagogical (based on the framework of school itself)
      and psychological measures (in early care and family guidance services).

PMID- 15011160
TI  - [Unusual forms of clinical presentation of attention deficit hyperactivity
      disorder].
AB  - INTRODUCTION AND DEVELOPMENT: Attention deficit hyperactivity disorder (ADHD) is
      one of the most frequently observed processes in our Neuropaediatric unit, and in
      recent years has become one of the leading reason for visits, together with
      headaches. On occasions, the diagnosis that should be made, in accordance with
      the criteria included in the DSM IV, is more difficult because initially they are
      patients who visit because of some other problem that becomes the centre of our
      clinical attention. Headaches, in our experience, are the main reason for
      visiting in these cases. A careful review of the patient's history and a physical
      examination, together with their observation during the interview, lead us to
      suspect a genuine case of ADHD underlying the problem that presents with other
      non specific symptoms. These patients are mainly boys and, less frequently, girls
      who see how the chances of academic and social failure increase and then become
      worried to such an extent that they start suffering from important tension type
      headaches. Concentrating the study and the therapy on just solving the problem of
      the headaches sometimes gives rise to therapeutic failure, which occasionally
      goes on for months. Other symptoms, such as tics, unspecific dizziness, pains in
      the abdomen and visual disorders, can also be the reason that brings ADHD
      patients to visit. CONCLUSIONS: When faced with these symptoms we should always
      bear in mind (mainly in the case of headaches) the possibility referred to above
      and special care must be taken not to diagnose ADHD in excess, and always base
      our judgment on objective proof that meets the criteria required for its
      diagnosis. Therapy based on pharmacological treatment and a suitable
      psychopedagogical intervention solves the problem in these cases and
      significantly reduces the symptomatology that led to the visit.

PMID- 15011161
TI  - [Graphic skills in attention deficit hyperactivity disorder].
AB  - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is the most
      frequent neuropsychiatric disorder in childhood and its prevalence rate is
      between 3 5%. SUBJECTS AND METHODS: We describe a study of 601 children aged
      between 8 and 9 in the 3rd and 4th years of primary education from 17 public
      schools in the area around Badajoz. The results of the Conners rating scale (CRS)
      and the drawings of the familial figure done to explore the following variables
      were analysed and compared: dominant or valued figure, number of colours used,
      number of anatomical elements (nose, mouth, etc.) and the complements included in
      the key figure (rings, skirts, etc.). RESULTS: Of all the schoolchildren who drew
      the picture in the classroom (n = 601), useful information was obtained from the
      CRS by teachers in 562 cases. 5% presented clinical traits of hyperactivity (HA);
      2.5% met attention deficit (AD) criteria; 10% presented behavioural disorders
      (BD), and 7.5% showed signs of combined ADHD. Prevalence rate by sexes: ratio 3:1
      (male: female) for AD; 5.5:1 for HA; 4:1 for BD. Drawing of the family (main
      variables): dominant figure: father (48%); mean size: 7.258 cm (range: 2.00 16.50
      cm; SD: 2.57). Number of colours employed: 6.53 (SD: 2.90). A difference of two
      colours was observed for children with AD and HA (p = 0.011 and p =.0001,
      respectively). CONCLUSIONS: When this pattern is compared with the results from
      children with ADHD, a clear graphic deviation is observed in the model of the
      drawing of the familial figure.

PMID- 15011163
TI  - [Nocturnal polysomnographic study in children with attention deficit
      hyperactivity disorder].
AB  - INTRODUCTION: The main symptoms of attention deficit hyperactivity disorder
      (ADHD) are attention deficit, hyperactivity and impulsivity. Its prevalence lies
      between 3 and 5% in schoolchildren. Children with ADHD can present a high
      prevalence rate of comorbidity. A timely diagnosis and treatment can modify the
      educational and psychosocial development of most of these children. A number of
      subjective reports (especially from parents) describe sleep disorders. The
      objective verification of these disorders and the exact nature of the sleep
      problems are still to be determined and the purpose of this study is to deal with
      these issues. PATIENTS AND METHODS: We studied a sample of 48 children (9 females
      and 39 males) with a mean age of 8 (SD: 2.59) who met DSM IV criteria. They were
      submitted to a general exploration as well as a neurological exploration,
      including their patient record, and then they were evaluated using the DSM IV,
      which was carried out by parents and teachers (in order to evaluate two different
      environments), and a nocturnal polysomnographic study. In the sample there were
      26 children with predominant attention deficit type ADHD (ADHD/AD); 4 children
      with predominant hyperactivity impulsivity type ADHD (ADHD/H); and 18 children
      with combined type ADHD (ADHD/C). RESULTS: The most frequently diagnosed subtype
      is the attention deficit subtype. The sleep architecture of children with ADHD
      presents the most consistent differences as compared to normal children in an
      increase in the percentage of phase 3 of sleep and, consequently, an increase in
      the percentage of slow sleep. Epileptiform type paroxysms were observed in 16.7%
      of the children who presented symptoms of ADHD. The number of epileptiform
      paroxysms is more usual in the attention deficit subtype. CONCLUSIONS: The
      increase in phase 3 may be related to the alterations in noradrenaline and
      dopamine transmission present in children who suffer from ADHD. Some children
      with ADHD can have a region of the brain with intense epileptic activity, which
      does not trigger epileptic seizures but gives rise to behavioural disorders,
      learning disorders and language problems.

PMID- 15011162
TI  - [Cognitive flexibility, an additional symptom of attention deficit hyperactivity
      disorder. Is it a therapeutically predictive element?].
AB  - INTRODUCTION: Cognitive flexibility is a capability acquired during infancy that
      can be evaluated from the age of 8 onwards. This executive function can affect
      patients with dorsolateral frontal lesions. Involvement of this function in some
      children with attention deficit hyperactivity disorder (ADHD) would point to an
      additional disorder. AIMS: The objective of this study was to report on the
      involvement of cognitive flexibility in patients with ADHD from the age of 8
      years onwards, to establish a correlation with the progressive phenomenon in its
      development, and to relate the findings from the study of cognitive flexibility
      with those of the attentional function. PATIENTS AND METHODS: A group of 50
      children diagnosed as suffering from ADHD (8 21 years old) and 50 normal children
      were evaluated. The same subjects were submitted to a study of their attentional
      functions, their inhibitory control mechanisms as well as their cognitive
      flexibility. RESULTS: At least 38% of the patients studied showed involvement of
      cognitive flexibility. No statistically significant relation was observed when
      data were linked to the age variable, which could point to the absence of the
      maturation factor, unlike the results observed in the case of sustained
      attention. Patients with poor cognitive flexibility also present disorders
      involving attentional discrimination, the control of impulses and interference
      control. CONCLUSIONS: The group with cognitive rigidity as a symptom added to the
      attentional disorder could correspond to a complex subtype that does not respond
      so successfully to stimulants. Consequently, cognitive flexibility studies could
      reflect an indicator for selecting the type of pharmacological treatment to be
      employed.

PMID- 15011164
TI  - [Grammatical complexity and cohesion mechanisms in the communicative pragmatics
      of children with attention deficit hyperactivity disorder].
AB  - AIMS: The purpose of this study was to compare the grammatical structures and
      cohesion used in the narrative sequencing of real events by children with and
      without attention deficit hyperactivity disorder. SUBJECTS AND METHODS: A total
      of 27 children, between the ages of seven and eight, took part in the study; 15
      of them had the combined subtype of ADHD and 12 participated as a control group.
      To obtain the narration the children were asked to talk about two real events
      they had experienced: 'What happened the last time you went to the doctor's?' and
      'Have you ever been bitten by an insect?' An analysis of their narrations allowed
      us to obtain the following variables: the total number of communication units,
      their average length, the syntactic complexity index, the rate of lexical
      diversity, the lexical type referential cohesion procedures, the deictic and
      anaphoric grammatical procedures, the conjunctive procedures, discourse markers,
      changes of subject matter and dysfluency. RESULTS: Results show that there are
      significant differences between the two groups in the narrative cohesion
      indicators used, the group of normal children being those that were favoured by
      these differences. The most striking pragmatic peculiarities were difficulties in
      the use of conversational markers and the changes in the subject being discussed.
      CONCLUSIONS: The narratives of children with attention deficit hyperactivity
      disorder are more difficult to understand, which means that the listener has to
      adopt a more active role in order to make up for the missing information and has
      to infer a great deal more. This is an aspect that can have social implications
      and may make communication more difficult, especially with their peers, since
      these usually make less effort to understand the conversations than adults do.

PMID- 15011165
TI  - [New therapeutic options in the treatment of attention deficit/hyperactivity
      disorder].
AB  - INTRODUCTION: The most frequently used pharmacological treatment for attention
      deficit/hyperactivity disorder (ADHD) over the last few decades has been
      methylphenidate. Although methylphenidate is still one of the first choices in
      the treatment of ADHD, new alternatives have appeared with the intention of
      improving on some of its drawbacks. DEVELOPMENT: The work being carried out on
      the development of drugs that may be an alternative to methylphenidate is centred
      on two main lines. On the one hand, preparations have been developed that allow
      the sustained release of methylphenidate by means of the SODAS and OROS
      techniques and these have allowed us to obtain methylphenidate preparations that
      only require a single daily dose. As an alternative to stimulants, other drugs
      have been studied that act by means of different mechanisms and which have proved
      to be quite effective in ADHD. Another recent arrival has been atomoxetine, a new
      drug with a noradrenergic action that was designed specifically for the treatment
      of ADHD. In this paper, we describe the neuropharmacological bases of these
      drugs, and the mechanisms of action and possible indications of each of them are
      also discussed.

PMID- 15011166
TI  - [Tourette syndrome: an analysis of its comorbidity and specific treatment].
AB  - INTRODUCTION AND METHOD: Tic disorders can be severe enough to be incapacitating,
      but in most cases the observation of tics should alert the clinician to the
      possible presence of other conditions that may be more impairing even if less
      directly observable. The comorbid diagnoses that are best documented are
      obsessive compulsive disorder and attention deficit/hyperactivity disorder
      (ADHD). CONCLUSIONS: Treatment of Tourette syndrome combined with ADHD is often
      challenging. Alpha 2 agonists, such as guanfacine, or non stimulant options such
      as atomoxetine, where available, are worth considering, although many individuals
      with Tourette syndrome and ADHD can be successfully treated with judicious doses
      of stimulant medications.

PMID- 15011167
TI  - [The neuroanatomy of attention deficit/hyperactivity disorder].
AB  - Neuroimaging techniques are increasingly being applied to the study of attention
      deficit/hyperactivity disorder (ADHD). This review focuses on magnetic resonance
      imaging studies of the brain anatomy of ADHD, which have now been conducted for
      over a decade. Most studies have focused on frontal striatal regions and have
      tended to find smaller volumes in children with ADHD relative to controls.
      Recently published analyses with the largest sample of patients and controls
      found that ADHD is associated with a statistically significant global reduction
      in brain volume in both boys and girls of 3 4%, which is confirmed in a meta
      analysis of this global measure. Specific regional differences have been found in
      many studies in the basal ganglia with the most prominent differences being found
      in the cerebellum.

PMID- 15011168
TI  - [Experimental bases for evaluating attention in attention deficit hyperactivity
      disorder].
AB  - INTRODUCTION: The experimental evaluation of the time variable in attention
      enables us to distinguish between what can be considered as its normal and its
      pathological behaviour. It has proved to be useful in evaluating the population
      suffering from attention disorders (attention deficit hyperactivity disorder,
      frontal lesions, etc.) as a means of defining the extent to which the patient is
      affected by the disorder and also in designing a training programme for later
      use. DEVELOPMENT: The most notable attentional paradigms are attentional blink
      (AB), repetition blindness, change detection, psychological refractory period,
      task switching, and negative and positive priming. Patients with ADHD showed a
      poor capacity for identification of target stimuli (T1) in attentional blink
      tests; they also displayed a significantly higher attentional blink than that
      observed in the control group, especially for time intervals between 300 and 600
      ms after the first target letter (T1). CONCLUSIONS: Attention is a complex,
      dynamic concept derived from the interaction of different neuroanatomical
      systems. There are several different theories to explain disorders affecting the
      attentional skills. One of the explanations comes into being as a result of
      linking sustained attentional disorder with impulsiveness and hyperactive
      behaviour. Another is related to selective attention disorders. This distinction
      allows us to discern the involvement of two systems that will give rise to
      different clinical symptoms and hence the presence of attentional subtypes. Thus,
      for example, it is possible to find a first group with disorders affecting
      attention, impulsiveness and disinhibition, and a second group with slow
      reactions and in a state of confusion and/or inattention as regards the events
      taking place around them (but they do not have impulsiveness or disinhibition).

PMID- 15011169
TI  - [The neurofunctional foundation of cognitive rigidity in attention deficit
      hyperactivity disorder: some preliminary findings].
AB  - INTRODUCTION: It has been proposed that there is an impairment in cognitive
      flexibility in children with attention deficit hyperactivity disorder (ADHD). The
      Wisconsin card sorting test (WCST) is the most widely used neuropsychological
      test for assessing this process. Previous studies have reported the presence of a
      subgroup of children with ADHD which has a low cognitive flexibility. In addition
      this subgroup showed a high resistance to the treatment with stimulant
      medication. OBJECTIVES: The aim of this study was to examine whether there were
      different patterns of brain magnetic activity in different subgroups of ADHD,
      during the performance of a cognitive flexibility task, such as WCST. PATIENTS
      AND METHODS: We recruited a sample of 18 children, divided into three groups
      according to DSM IV R diagnostic criteria. Here we present preliminary data based
      on a subsample of nine children. Brain magnetic activity was registered while the
      children performed the WCST by means of Magnetoencephalography (MEG). This is a
      non invasive neuroimaging technique with a high spatio temporal resolution.
      RESULTS: Preliminary results showed that ADHD mixed group had a higher rate of
      perseverative responses. In addition, a different pattern of brain magnetic
      activity was noted in this group, showing less activation in anterior cingulate
      cortex and dorsolateral prefrontal cortex in the left hemisphere during the first
      400 ms. CONCLUSIONS: MEG seems to be an useful tool to describe the brain network
      that subserves cognitive flexibility in different groups of children. It could
      have important repercussions in the classification of ADHD, both
      neuropsychologically and pharmacologically.

PMID- 15011170
TI  - [Psychopedagogical management of attention deficit hyperactivity disorder with
      the model of executive function training].
AB  - Different therapeutic models have been presented with which to treat the
      condition of attention deficit hyperactivity disorder (ADHD) and the scientific
      literature speaks of the benefits linked to multimodal approaches. The National
      Institute of Mental Health report grants combined treatments an essential role.
      Throughout the literature authors agree that the executive functions are
      intrinsically related to the functions of the frontal lobe. We consider executive
      function training (EFT) to be another resource available within the different
      approaches used to treat ADHD and which is oriented towards developing and
      reinforcing the neuropsychological functions so as to give rise to new cognitive
      resources. Working memory is responsible for storage for a minimum amount of time
      while the information needed to resolve higher cognitive processes is
      manipulated. Some authors consider executive dysfunction to be a distinguishing
      element of ADHD. This type of dysfunction would make it more difficult for the
      higher cognitive processes to be carried out and is therefore a disorder that
      conditions the problems observed in the formal academic learning processes. The
      EFT programme consists of specific work modules and is aimed at favouring the
      appearance, development and operation of the affected functions.

PMID- 15011171
TI  - [Further contributions to the knowledge about attention deficit hyperactivity
      disorder. From research to practice].
AB  - INTRODUCTION AND DEVELOPMENT: This work is a compendium of the research conducted
      in recent years by a team from the University of Valencia on attention deficit
      hyperactivity disorder (ADHD). It describes three large areas of study: the
      progress made in the differential characterisation of the subtypes of ADHD, as
      well as its comorbidity profiles, the discriminative capacity of
      neuropsychological tasks in the evaluation of children with ADHD, and the
      analysis of how effective multicomponent and multicontextual interventions are in
      children with ADHD. CONCLUSIONS: The joint analysis of the findings from these
      studies establishes a series of reflections and guidelines that undoubtedly offer
      benefits both in delimiting the distinct subtypes of ADHD and in improving
      intervention procedures.

PMID- 15011172
TI  - Overview.

PMID- 15011173
TI  - The Dialysis Outcome and Quality Initiative (DOQI) recommendations.
AB  - National surveys have demonstrated that the US End Stage Renal Disease (ESRD)
      program has witnessed an increasing number of patients each and every year with a
      corresponding increase in cost. However, when compared to the data from the ESRD
      program of other countries, we find that these US patients have a low rate of
      autogenous arteriovenous access (AVA) placement and increased use of
      nonautogenous (or prosthetic) AVA. Some of the impetus for this can be attributed
      to (1) the lack of adequate or easily identifiable superficial veins in patients
      starting on hemodialysis with a history of multiple venipuncture or obesity, (2)
      earlier access rates of nonautogenous AVA as compared to autogenous AVA, (3) the
      relative ease of placement of nonautogenous AVA, and (4) a prior payment
      differential in favor of nonautogenous AVA placement that has since been
      abolished. However, by virtue of the increased number of procedures required to
      maintain nonautogenous AVA patency when compared to that of autogenous AVA
      patency, hemodialysis access failure has become the most frequent cause of
      hospitalization among ESRD patients. To further investigate this issue, the
      National Kidney Foundation Dialysis Outcome and Quality Initiative (DOQI)
      organized multidisciplinary work groups who reviewed 3325 articles concerning
      various issues of ESRD over a 2-year period. They suggested that autogenous AVA
      have the best longer-term patency rates and require the fewest interventions as
      compared to other access types. In order to improve overall patency rates and
      help contain angioaccess costs, these DOQI recommendations were published in 1997
      and updated in 2000. While there is evidence that the guidelines are slowly being
      adopted, there remains much room for improvement in their implementation.

PMID- 15011174
TI  - Strategies of arteriovenous dialysis access.
AB  - Surgical management of the patient who requires hemodialysis access, while
      continuing to demand more attention from the vascular surgeon, suffers from
      discrepancies of approach and strategy. With the increase in incidence of
      dialysis dependent renal failure among our population, many have attempted to
      present a uniform, logical strategy with which the vascular surgeon can most
      effectively treat the hemodialysis patient in the long term. Most notably, the
      multidisciplinary Dialysis Outcomes Quality Initiative (DOQI) guidelines present
      the surgeon with a rough outline of hemodialysis access insertion strategy, and
      it has become nationally recognized as an acceptable summary of treatment
      strategy and goals. The decision as to the most appropriate surgical access to
      offer a patient depends on immediate need for hemodialysis, history and physical
      examination findings, and suitability of available veins in the extremity. While
      percutaneous, catheter based access affords the luxury of immediate access, these
      devices suffer from several complicating factors, such as infection, and damage
      to large, proximal veins. For long-term access, the autogenous access, while
      perhaps less successful in the immediate short term, is always the preferred
      access type given its favorable longevity. The surgeons should focus on sites
      distally on the extremity, reserving proximal sites for potential future access
      insertions should the primary access fail. In the absence of suitable vein,
      prosthetic access may be considered. When both the upper and lower aspects of
      both upper extremities have been exhausted, the surgeon should consider access
      insertion elsewhere, such as the lower extremity.

PMID- 15011175
TI  - Alternative graft materials for hemodialysis access.
AB  - Since the initial description of the arteriovenous (AV) fistula, autogenous
      access has been the procedure of choice for chronic hemodialysis. Recently
      established National Kidney Foundation Dialysis Outcome and Quality Initiative
      guidelines have validated the superiority of arteriovenous fistulas over AV
      grafts but have also addressed the fact that a significant percentage of the
      growing dialysis population does not have veins suitable for primary AV fistulas.
      Recent advances in forearm, upper arm, and femoral venous transpositions have
      facilitated the performance of increased numbers of autogenous access procedures.
      Nevertheless, substantial numbers of patients on chronic hemodialysis require
      prosthetic AV grafts. Since early reports describing hemodialysis access using
      expanded polytetrafluoroethylene, surgical results with prosthetic graft
      materials have remained suboptimal. Modifications in polytetrafluoroethylene
      grafts and the recent development of alternative graft materials for hemodialysis
      access have yielded encouraging early results in efforts to improve patency of AV
      grafts. We will review currently available graft materials and recent
      developments in an ongoing effort to improve the results with prosthetic and
      biologic hemodialysis access conduits.

PMID- 15011176
TI  - Medical factors affecting patency of arteriovenous access.
AB  - Arteriovenous access failure is multifactorial in nature with contributions from
      both medical and surgical etiologies. Medical causes of arteriovenous access
      failure are rare, and therefore infrequently identified as a major contributing
      source of malfunction. Although they account for only 10-15% of all cases of
      access failure, their importance should not be underestimated, especially in
      cases where a surgical source cannot be identified. Most medical causes are
      derived from Virchow's triad of endothelial cell injury, stasis, and
      hypercoaguability. Endothelial cell injury occurs through oxidative stress,
      activated platelets, increased levels of circulating tumor necrosis factor-alpha,
      and preexisting intimal hyperplasia. Stasis can occur through prolonged access
      compression, hypotension, or hypoalbuminemia. Finally, patients with renal
      failure requiring hemodialysis are frequently at increased risk for
      hypercoaguable states, except for situations of platelet dysfunction, and
      therefore access failure. Potential treatments include identifying and removing
      the offending source, as well as innovative, new medications to prevent their
      reoccurrence. Treatment is aimed at improving quality of life, as well as
      decreasing morbidity and hospital admissions in this difficult patient
      population.

PMID- 15011177
TI  - Management of thrombosed dialysis access: thrombectomy versus thrombolysis.
AB  - More than 250,000 patients per year with end stage renal disease are maintained
      on long-term hemodialysis. Because of this large population, hemodialysis access
      procedures now account for a large percentage of operative interventions in the
      United States. Prosthetic arteriovenous access thrombosis is a frequent
      complication that occurs at a rate of 0.5 to 0.8 episodes per year and is a major
      source of hospital admissions, increasing hospital costs, patient morbidity, and
      physician frustration. Thrombosed grafts often require rescue procedures to
      extend the life of the graft and make the most use of the limited available
      access sites. Such salvage procedures of thrombosed prosthetic dialysis shunts
      may be performed with either conventional surgical or endovascular techniques.
      Many techniques for declotting have been used, including open surgical
      thrombectomy, percutaneous pharmacologic or mechanical thrombectomy, and
      pharmacomechanical techniques. Despite the various treatment options, no
      individual declotting modality has proven itself superior. Long-term patencies
      after a single revascularization procedure are meager, with a median of less than
      90 days. This article will review prosthetic hemodialysis access graft declotting
      mechanisms and supporting literature.

PMID- 15011178
TI  - Management of hemodialysis access infections.
AB  - Management of hemodialysis (HD) access infection is one of the most challenging
      and most common problems faced by surgeons, interventional radiologists, and
      nephrologists. The goal to eradicate infection is often at odds with the need to
      maintain access. Patients on HD are immunocompromised and typically have
      significant comorbid conditions placing them at high risk for the occurrence of
      access infection. Infection is most common with central-vein catheter access,
      followed by prosthetic arteriovenous grafts (AVG) and is rare with autogenous
      fistulas. The diagnosis is usually evident on physical exam, but it is not
      uncommon for these patients to present with atypical symptoms and lack of
      clinical findings. Although Staphylococcal species are the most common organism
      to cause infection, early empiric antimicrobial therapy should also include
      coverage for Gram-negative organisms. Management of central-vein catheter
      infection includes removal and delayed replacement or, in patients with mild
      clinical symptoms, catheter exchange over a guide wire. Our management of AVG
      infection includes total graft excision when patients present with sepsis or the
      entire graft is bathed in pus, subtotal graft excision when all of the graft is
      removed except a small oversewn cuff of prosthetic material on an underlying
      patent artery, and partial graft excision when only a limited infected portion of
      the graft is removed and a new graft is rerouted in adjacent sterile tissue to
      maintain patency of the original graft. This strategy has proven to be highly
      successful in the management of these complicated cases.

PMID- 15011179
TI  - Management of steal syndrome resulting from dialysis access.
AB  - Ischemic steal secondary to a hemodialysis arteriovenous (AV) access occurs in
      approximately 10% of cases. The pathophysiological basis of this condition is a
      marked decrease or reversal of flow in the arterial segment distal to the AV
      fistula or AV graft, induced by the low resistance of the fistula outflow.
      Clinically it can manifest with either mild symptoms (coolness, paresthesia, and
      absence of distal pulses), or severe symptoms (rest pain, severe paresthesia,
      paralysis, cyanosis, and gangrene) immediately after construction of the AV
      access or later after its inception. Diagnosis is based on clinical
      manifestations, aided by the vascular laboratory and angiography. Mild cases can
      be observed closely, most of them will reverse in a few weeks. In order to
      prevent permanent sequela, severe cases require immediate intervention. Several
      surgical treatments have been used: access ligation, banding, elongation, distal
      arterial ligation, and distal revascularization-interval ligation. Best results,
      with maintenance of access function and reversal of symptoms, have been obtained
      with the distal revascularization-interval ligation procedure.

PMID- 15011180
TI  - Venous hypertension associated with arteriovenous hemodialysis access.
AB  - Venous hypertension is a significant problem for the patient on chronic
      hemodialysis. This condition can result in impairment of arteriovenous access
      function, disabling upper extremity edema with bluish discoloration and
      pigmentation of the skin, and, in advanced cases, ulceration of the finger tips
      and neuralgias. Venous hypertension usually results from central vein stenosis or
      valvular incompetence in the arteriovenous access outflow vein. A high index of
      suspicion is required to identify patients at risk for venous hypertension. A
      history of ipsilateral central venous catheter placement, or physical signs such
      as visible distended shoulder venous collaterals, and upper extremity edema are
      suggestive. Diagnosis is confirmed with Duplex ultrasound or contrast venography.
      The primary goal of diagnosis and therapy of venous hypertension is symptomatic
      relief while maintaining the functionality of the access. Treatment includes
      percutaneous catheter-based and open surgical techniques. Open surgical
      techniques, while more invasive, remain the gold standard as long-term patency
      after angioplasty, with or without covered stents, remains unproven.

PMID- 15011181
TI  - What is new in the preoperative evaluation of arteriovenous access operation?
AB  - It is widely recognized that autogenous arteriovenous access is the preferred
      dialysis access of choice because of improved patency and low infection rate. It
      has been shown recently that preoperative ultrasound study to identify available
      venous conduits can increase the utilization of autogenous arteriovenous access.
      The article examines the clinical evidence to support this rationale and reviews
      the available portable ultrasound devices that enable surgeons to perform
      ultrasound examination in patients undergoing dialysis access operation.

PMID- 15011184
TI  - In consideration of BSN-to-PhD programs.

PMID- 15011185
TI  - Communication and malpractice lawsuits.

PMID- 15011186
TI  - Patient safety: Developing policies for engagement in the prevention of harm to
      patients.

PMID- 15011187
TI  - Raising $4 million in 4 months.

PMID- 15011188
TI  - The scholarship of teaching: implications for nursing faculty.
AB  - Nursing educators are faced with the dilemma of addressing the scholarship of
      teaching for promotion and tenure decisions. This article defines the scholarship
      of teaching and explores the history of the concept. Implications of the
      relevance of the topic for nursing faculty with suggestions for documenting the
      scholarship of teaching are discussed.

PMID- 15011189
TI  - Reliability of assessment of critical thinking.
AB  - Although clinical critical thinking skills and behaviors are among the most
      highly sought characteristics of BSN graduates, they remain among the most
      difficult to teach and assess. Three reasons for this difficulty have been (1)
      lack of agreement among nurse educators as to the definition of critical
      thinking, (2) low correlation between clinical critical thinking and existing
      standardized tests of critical thinking, and (3) poor reliability in scoring
      other evidences of critical thinking, such as essays. This article first
      describes a procedure for teaching critical thinking that is based on a consensus
      definition of 17 dimensions of critical thinking in clinical nursing practice.
      This procedure is easily taught to nurse educators and can be flexibly and
      inexpensively incorporated into any undergraduate nursing curriculum. We then
      show that students' understanding and use of these dimensions can be assessed
      with high reliability (coefficient alpha between 0.7 and 0.8) and with great time
      efficiency for both teachers and students. By using this procedure iteratively
      across semesters, students can develop portfolios demonstrating attainment of
      competence in clinical critical thinking, and educators can obtain important
      summary evaluations of the degree to which their graduates have succeeded in this
      important area of their education.

PMID- 15011190
TI  - Adult student satisfaction in traditional and accelerated RN-to-BSN programs.
AB  - The pressures and complexities that the registered nurse (RN) encounters in
      today's health care system have motivated many RNs to return to college to obtain
      their baccalaureate degrees. Competition among institutions of higher education
      has led faculty to develop and offer more nontraditional delivery models of
      nursing education. In developing these new models of educational delivery, it is
      important for faculty to determine what items of education are essential to adult
      learners. A survey was conducted to assess two delivery formats, traditional and
      accelerated, for a bachelor of science in nursing (BSN) program for RNs. The goal
      of the research was to determine what items of education are essential to
      students and whether one group of students was more satisfied with one delivery
      system over the other. Items of importance and the concomitant level of
      satisfaction were surveyed by using an adult students' priorities scale. The
      survey was distributed to 53 RN students. The results demonstrated that the
      students in the accelerated format were more satisfied with the institution,
      program, and services than the students in the traditional format.

PMID- 15011191
TI  - International exchange program: findings from Taiwanese graduate nursing
      students.
AB  - This study explored Taiwanese graduate nursing students' transcultural
      experiences in the United States during an international exchange program. A
      qualitative method with content analysis was used to analyze journal entries on
      perceptions of American culture, American nursing, and reflections on personal
      and professional growth written by nine graduate nursing students from Taiwan.
      The mean age of the participants was 32 (range, 29-45). Taiwanese nursing
      students perceived American culture as full of hospitality and patriotism,
      valuing human rights and social welfare, and favoring direct and expressive
      affection. American nursing was viewed as a combination of independence,
      confidence, autonomy, and knowledge, with caring being the core element, fostered
      by an environment conducive to patient care. In personal and professional growth,
      three themes surfaced: reinforcement of holistic care, nursing without borders,
      and lifelong learning and changing. American culture and nursing were perceived
      by Taiwanese students as a paradigm of Western culture valuing individual rights,
      autonomy, and independence. A caring and supportive patient care environment was
      a positive perception of American nursing; it was the desired practice standard
      that was lacking in these students' homeland. Overall, the exchange program was
      thought by these students to foster their personal and professional growth.

PMID- 15011192
TI  - Matching standards and needs in doctoral education in nursing.
AB  - The debate about the number and type of doctoral degrees required in nursing has
      recurred with regularity throughout the history of nursing. National discussions
      about the shortcomings and relevance of the PhD within general higher education
      circles are described. Applicability of these concerns to nursing education is
      discussed. In the midst of this national debate, new nursing doctoral degrees are
      being proposed and implemented. Emergence of these new degrees has caused many to
      worry about replicating at the highest degree level the current confusion about
      nursing preparation at the entry level. A classification of doctoral degrees in
      nursing is proposed along with a call for standardization of degrees.

PMID- 15011193
TI  - Patient-centered advance care planning in special patient populations: a pilot
      study.
AB  - The purpose of this study was to assess the feasibility of a patient-centered
      advance care planning (PC-ACP) approach to patients with chronic illnesses and
      their surrogates with respect to promotion of shared decision-making outcomes
      congruence between patient and surrogate, patient's decisional conflict, and
      knowledge of advance care planning. An experimental design was used. The settings
      were the heart failure, renal dialysis, and cardiovascular surgery clinics at
      Gundersen Lutheran Medical Center in La Crosse, WI. Twenty-seven patient
      surrogate pairs participated. A 1-hour PC-ACP interview was provided to the
      experimental group. Only usual care was delivered to participants in the control
      group. Comparison of the composite scores of a Statement of Treatment Preferences
      indicated that congruence in decision-making for future medical treatment in
      patient-surrogate pairs in the treatment group was significantly higher than in
      the control group. Greater satisfaction with the decision-making process and less
      decisional conflict were demonstrated in the treatment group. The PC-ACP
      interview can be effective in promoting shared decision-making between patients
      and their surrogates and in producing greater satisfaction with the process of
      decision-making and less decisional conflict.

PMID- 15011194
TI  - Faculty encounters with uncivil nursing students: an overview.
AB  - The critical incident technique (CIT) was used to explore faculty experiences
      with uncivil nursing students. Twenty-one nursing faculty with various years of
      experience in teaching were interviewed to ascertain what they considered
      critical incidents of uncivil encounters with nursing students and what effect
      those encounters had on them. Thirty-six encounters were described by the
      faculty. Of the 36 encounters, 33 occurred with individual students and 3
      occurred with groups of students. Twenty-three encounters occurred in the context
      of poor student performance requiring constructive criticism or resulting in
      course failure. A battlefield metaphor is used to describe the incidents, their
      antecedents, and their consequences. The encounters were precipitated by a period
      of escalating tensions and effort by the faculty to diffuse the situation. The
      faculty were surprised and caught off guard by the encounters, which ranged in
      severity from mild to highly aggressive. The faculty often perceived significant
      threats to well-being of self, loved ones, job security, and/or possessions. The
      aftermath of the encounters included physical and emotional tolls on faculty,
      decreased self-esteem and loss of confidence in teaching ability, significant
      time expenditures, and negative consequences to the educational process. Three of
      the faculty left teaching in part due to encounters with students.

PMID- 15011195
TI  - Ethical and legal issues of conducting nursing research via the Internet.
AB  - In February 2001, President Clinton's Information Technology Advisory Commission
      reported that information technology has the potential to advance biomedical
      research. As nursing research via the Internet expands, important ethical and
      legal issues need to be addressed. The purpose of this article is to report one
      researcher's journey in attempting to conduct ethical and legal nursing research
      via the Internet. The ethical and legal issues needing attention are discussed.
      Potential guidelines are provided for researchers wanting to use Internet
      technology.

PMID- 15011199
TI  - Asymptomatic food hypersensitivity prevalence in patients with eczematous
      external otitis.
AB  - PURPOSE: The purpose of our study was to investigate the association between food
      hypersensitivity and eczematous external otitis. MATERIALS AND METHODS: In this
      cross-sectional study, 27 patients with eczematous external otitis and 16 healthy
      volunteer were included. The existence of food hypersensitivity was defined by
      positive epicutaneous prick test and specific immunoglobulin E (IgE) antibodies.
      RESULTS: Food allergy test was positive in 13 (48.1%) out of 27 cases with
      eczematous external otitis, and it was positive in 2 (12.5%) out of 16 cases in
      control group. The difference between 2 groups was statistically significant (P
      =.02). Specific IgE seropositivity (51.9%) was high in the patients with
      eczematous external otitis compared with the control group (12.5%) (P =.02).
      CONCLUSIONS: Food hypersensitivity may be a factor, which should be considered in
      eczematous external otitis patients. Patients suffering from eczematous external
      otitis symptoms should be evaluated for food hypersensitivity.

PMID- 15011200
TI  - Chronic rhinosinusitis and adenoid hypertrophy in children.
AB  - PURPOSE: The purpose of this study was to investigate the relationship between
      adenoid microbiology, adenoid size, and maxillary sinus microbiology in children
      with both chronic rhinosinusitis and adenoid hypertrophy. METHODS: The children
      with both chronic rhinosinusitis and adenoid hypertrophy were admitted to this
      prospective study. The study included 30 children. The diagnosis of chronic
      rhinosinusitis was based on clinical and radiologic examinations. Adenoid
      hypertrophy was classified as medium and large based on the preoperative flexible
      fiberoptic endoscopy and nasal endoscopy during surgery. Maxillary sinus
      aspiration and adenoidectomy was performed in all patients. Sinus aspirate and
      adenoid tissue specimens were cultured. The correlation of culture results was
      investigated. The relationship between adenoid size and maxillary sinus culture
      results was analyzed by using chi-square test. RESULTS: Adenoid sizes were medium
      in 12 (40%) and large in 18 (60%) cases. Bacterial growth was found on 14 of 30
      (47%) sinus aspirate, and all adenoid specimen cultures showed bacterial growth
      (100%). There was no statistical correlation between cultures obtained from the
      adenoid tissue with those from the maxillary sinus. The relationship between
      adenoid size and maxillary sinus culture results was not found statistically
      significant (chi(2) = 0.96, P = 1.0). CONCLUSION: The reason that there was no
      correlation between cultures obtained from the adenoid tissue with those from the
      maxillary sinus is that it seems possible that the adenoids act as a barrier
      causing mechanical obstruction rather than a nidus for chronic sinus infection.
      However, there is no relationship between adenoid size and maxillary sinus
      culture positivity. Medium adenoids causing partial obstruction may lead to
      changes in the microenvironment and may start bacterial growth in children with
      positive maxillary culture. Further investigation is needed to explain the
      association between adenoid hypertrophy and rhinosinusitis. Adenoidectomy helps
      to resolve the symptoms of chronic rhinosinusitis in the children with both
      chronic rhinosinusitis and adenoid hypertrophy.

PMID- 15011201
TI  - Incidence of occult thyroid carcinoma metastases in lateral cervical cysts.
AB  - PURPOSE: To establish the incidence of thyroid carcinoma metastasis in adult
      patients presenting with apparently benign cervical cysts. The authors report
      their experience with four cases of papillary thyroid carcinoma who present with
      a lateral cervical cystic mass and no palpable disease in the thyroid gland.
      MATERIALS AND METHODS: A retrospective review of patients undergoing surgery for
      solitary cervical cysts in our clinic from 1994 to 2002 was performed. Patients
      with a clinically obvious primary malignancy, age less than 16 years were
      excluded from the study. RESULTS: Thirty-seven patients were identified. A
      diagnosis of benign cervical cyst was shown by histological examination of the
      resected specimen in 32 patients (86.4%), with a mean age of 34 years (range, 16
      59 years). A diagnosis of squamous cell carcinoma metastasis arising from an
      occult tonsillary primary was confirmed histologically in one patient (2.7%).
      Papillary thyroid carcinoma metastasis was confirmed by histological examination
      of the resected specimen in 4 patients (10.8 %), with a mean age of 29 years
      (range, 18-37 years). Diagnostic studies performed included ultrasound, computed
      tomography scan, fine-needle aspiration (FNA), and excisional biopsy. FNA was
      found to be helpful in only one of the 3 cases with papillary thyroid carcinoma
      metastasis. Final histopathological examination exhibited primary focus in the
      thyroid gland in all 4 patients, with a mean size of 0.5 cm (range, 0.3-0.8 cm).
      CONCLUSION: Our data indicate that nearly 1 out of every 10 lateral cervical
      cysts in young adult patients represents lymphatic metastases from occult thyroid
      carcinoma. An excisional biopsy for definitive diagnosis should be undertaken
      without prolonged delay, even if FNA does not reveal malignancy.

PMID- 15011202
TI  - Current treatment practices in obstructive sleep apnea and snoring.
AB  - PURPOSE: To determine current management strategies of otolaryngologists involved
      in the treatment of sleep-disordered breathing. MATERIALS AND METHODS: Survey of
      practitioners regarding their workup and treatment of patients suspected of
      obstructive sleep apnea. RESULTS: Of 305 respondents, 280 actively treated
      patients with obstructive sleep apnea or snoring, form the basis for this study.
      Respondents were from assorted practice settings, from a diverse geographic
      background, and varied length of time in practice. Although 48% see more than 3
      new outpatients a week for snoring or obstructive sleep apnea, only 46% routinely
      ask their patients about sleep problems, and 49 % fail to ask all of their
      patients with sleep apnea about sleep-related automobile accidents. Although most
      regularly use nasopharyngoscopy, a significant proportion seldom uses the Muller
      maneuver. Most tend to rely predominantly on whole-night polysomnography, rather
      than split night or home testing. Half of respondents offer their patients with
      simple snoring more than 1 method of treatment. Although many different surgical
      procedures are offered by most, only 28% of respondents offer patients any
      procedure aimed at airway obstruction at the base of tongue level. CONCLUSIONS:
      Otolaryngologists, with their unique expertise in airway management, need to be
      more vigilant for patients with sleep-disordered breathing. The hypopharynx fails
      to be frequently addressed by the respondents and could lead to inadequate
      treatment of obstructive sleep apnea. Further research should seek to develop an
      evidence-based standard of care such that this disorder might be most effectively
      managed in the future.

PMID- 15011203
TI  - Nasopharyngeal carcinoma with skull base invasion: a necessity of staging
      subdivision.
AB  - PURPOSE: To investigate prognostic values of nasopharyngeal carcinoma (NPC) with
      skull base invasion for optimal management, according to its extent of
      involvement. METHODS: From January 1985 through December 2000, 119 patients with
      histologically proven NPC were analyzed retrospectively with review of their
      computed tomography/magnetic resonance imaging and medical records. All patients
      underwent sequential chemoradiotherapy except 2 cases, which were treated
      concurrently. The mean duration of follow-up was 61 months (range 8-179).
      Potential prognostic factors were evaluated by univariate and multivariate
      analyses by the Kaplan-Meier method and the Cox model, with a particular emphasis
      on the extent of skull base invasion. RESULTS: Skull base invasion was found in
      46 (38.6%) of 119 patients. Cranial nerve palsy and intracranial extension was
      discovered in 34 (28.6%) and 23 (19.3%) of these patients, respectively. The sole
      erosion of the skull base was not found to be a poor prognostic factor. Patients
      with involvement of both anterior (I-VIII) and posterior (IX-XII) cranial nerves
      had a worse prognosis than those with involvement of either anterior or posterior
      cranial nerves (P = 0.0219). The presence of intracranial extension was the worst
      prognostic factor in NPC with skull base invasion (P = 0.0269). The advanced neck
      stage and histology did not affect the prognosis of NPC in the presence of skull
      base invasion. CONCLUSION: Our results show that NPC with skull base invasion
      should be divided into the groups with, simple skull base erosion, minimal
      involvement of either anterior or posterior cranial nerves, multiple involvements
      of both cranial nerves, and intracranial extension.

PMID- 15011204
TI  - Treatment variations on the Epley maneuver for benign paroxysmal positional
      vertigo.
AB  - PURPOSE: To determine if using more head rotation during the Epley maneuver or
      specific posttreatment instructions for sleeping position would affect treatment
      effectiveness, compared with the usual maneuver without extra instructions.
      MATERIALS AND METHODS: Patients with unilateral benign paroxysmal positional
      vertigo of the posterior semicircular canal were randomized to a standard Epley
      maneuver group, a group that received an additional 45 degrees head rotation
      during the maneuver (Augmented Epley), and a group that received instructions
      about sleeping position after treatment. RESULTS: Posttests from 1 week to 6
      months showed no differences in vertigo intensity or frequency or responses to
      the Dix-Hallpike maneuver. All groups showed significant decreases in vertigo and
      Dix-Hallpike responses. Some subjects in each group had abnormal pretreatment
      scores on computerized dynamic posturography. Those subjects in the Augmented
      Epley group who had abnormal pretreatment posturography scores had significantly
      better posttreatment scores than those subjects in the Home Instruction group who
      had abnormal pretreatment scores. All subjects with abnormal responses, however,
      showed improvement. CONCLUSIONS: Although clinicians continue to give patients
      home instructions and to use additional head rotation during the maneuver, these
      variations are not essential for achieving improvement in symptoms.

PMID- 15011205
TI  - Management of acoustic schwannoma.
AB  - PURPOSE: To discuss the optimal management for patients with acoustic schwannoma.
      MATERIALS AND METHODS: Review of the pertinent literature. RESULTS: Microsurgery,
      stereotactic radiosurgery, and fractionated radiotherapy result in cure rates
      that approximate 90% at 5 years. Depending on tumor extent and surgical approach,
      the morbidity of microsurgery may exceed that of stereotactic radiosurgery and
      fractionated radiotherapy. Patients with useful hearing before treatment may have
      a higher likelihood of hearing preservation after radiotherapy compared with
      radiosurgery. CONCLUSION: Both microsurgery and radiosurgery are good options for
      patients with tumors less than 3 cm. Depending on tumor extent and the surgical
      approach, the morbidity of microsurgery may exceed that of radiosurgery. Patients
      with useful hearing may have a higher likelihood of hearing preservation after
      radiotherapy. Microsurgery is preferred for patients in whom the disease
      progresses after initial irradiation and in patients with tumors larger than 3
      cm.

PMID- 15011206
TI  - Sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid: a case
      report and review of the literature.
AB  - We present the clinical and histopathologic findings of a 38-year-old woman
      recently diagnosed with sclerosing mucoepidermoid carcinoma with eosinophilia of
      the thyroid (SMECE). This case is of particular interest because of its extremely
      aggressive clinical course. After total thyroidectomy, there was extensive
      bilateral thyroid lobe involvement with extension into perithyroidal soft tissues
      and the modified radical neck dissection contained 35 of 35 positive lymph nodes.
      This patient underwent 2 further surgeries; the first was a second right neck and
      supraclavicular surgery for lymph node metastases in which 8 of 11 were positive,
      followed a few months later by posterior neck surgery in which multiple lymph
      nodes were positive. Tumor was also documented by histological review from a
      right axillary lymph node. Imaging evidence of tumor in the lungs and liver was
      also present. Establishing the correct diagnosis of SMECE involves an awareness
      of the cyto- and histomorphologic features of this rare malignancy. As evidence
      that the biologic behavior of this neoplasm may well be more aggressive than
      previously considered, we briefly present the clinical and biologic course of
      this patient's neoplasm and a review of the literature.

PMID- 15011207
TI  - Metastatic renal cell carcinoma to the nasal cavity.

PMID- 15011209
TI  - Bilateral spontaneous cerebrospinal fluid otorrhea.
AB  - We present a rare case of bilateral cerebrospinal fluid (CSF) otorrhea via
      multiple bony defects in the left tegmen and a single defect with the herniated
      brain tissue on the right side. Initially, the patient complained of left hearing
      loss and fullness and was diagnosed with serous otitis media. After myringotomy,
      the pulsating watery discharge suggested CSF otorrhea. Five months after surgical
      repair of the left side, right-side CSF leakage occurred. The right side was
      repaired surgically, and the patient recovered without incident. From our
      findings and a review of the literature, we postulate that bilateral CSF otorrhea
      resulted mainly from the thinness of the tegmen because of well-pneumatized
      mastoid air cells and the weakness of the dura after chronic inflammatory
      changes. In case of spontaneous CSF otorrhea, the roof of tegmen should be
      assessed bilaterally with care using radiologic examinations so as not to
      overlook a subclinical condition on the contralateral side.

PMID- 15011208
TI  - Anterolateral and lateral skull-base approaches for treatment of neoplastic
      diseases.
AB  - PURPOSE: Neoplasms affecting the anterolateral and lateral skull base have
      different sites of origin and histology, and its resection is technically
      difficult. The purpose of this study was to describe the surgical outcome and
      overall and disease-free survival of patients who had anterolateral and lateral
      skull base procedures for treatment of neoplasms with and without adjuvant
      therapy. MATERIALS AND METHODS: A retrospective study was performed on 26
      patients who underwent anterolateral or lateral skull-base procedures through
      subcranial approaches such as maxillectomy with ethmoidectomy, osteoplastic
      maxillotomy, transmandibular, infratemporal, and transtemporal/infratemporal
      techniques for treatment of neoplastic diseases. Twenty-one cases were
      malignancies, with no evidence of metastasis. These approaches were combined
      frequently with a transbasal, pterional, subtemporal, or temporo-occipital
      craniotomy. Survival and disease-free intervals were evaluated with the Kaplan
      Meier product limit method. RESULTS: Nine cases were maxillary antrum
      malignancies with extension to the middle fossa and/or infratemporal fossa, 7
      with nasopharyngeal neoplasms, 3 malignant lesions in the infratemporal fossa,
      and 3 with auditory canal carcinomas. The rest had miscellaneous diagnosis. Major
      morbidity occurred in 15% of cases. Perioperative mortality was 0. From 21 cases
      with malignancies, 4 had recurrences and the overall survival was 78% at 36
      months of follow-up. CONCLUSION: Anterolateral and lateral skull-base surgery is
      done with low morbidity and no operative mortality. The oncologic results are
      better than those reported in the literature probably because of a stringent
      selection of cases, although a longer follow-up period is required.

PMID- 15011210
TI  - Central granular cell odontogenic tumor: immunohistochemistry and ultrastructure.
AB  - Central granular cell odontogenic tumors are rare, with only 30 cases having been
      reported. The tumors usually occur in the mandibular molar area and are seen as
      localized painless swellings in patients older than 40 years. We report an
      additional case that occurred in the posterior mandible of an elderly black
      woman. All reported cases of this tumor are benign, and cure is effected by
      localized surgical excision. Ultrastructurally, the cells contain numerous
      lysosomes and phagocytic vacuoles. Immunohistochemically, the granular cells were
      positive for vimentin, CD68, muramidase, carcinogenic embryonic antigen, and bcl
      2. These features support a mesenchymal origin with a possible histiocytic
      lineage for the granular cells. Awareness of the occurrence of this neoplasm is
      important to promote detection and differentiation from other intraoral granular
      cell lesions.

PMID- 15011215
TI  - Disagreement in the interpretation of electrocardiographic ST segment elevation:
      a source of error for emergency physicians?
AB  - Evaluation of the electrocardiogram (ECG) is a complex, subjective process with
      the potential for interobserver disagreement. The objective of this study was to
      determine the ECG patterns with discrepant interpretations, the rates of
      disagreement in the determination of both the presence of ST segment elevation
      (STE) and morphology. ECGs were reviewed in a retrospective fashion by attending
      EPs for STE and waveform morphology. Those ECGs that were interpreted in a
      discrepant fashion were then analyzed to detect patterns of disagreement. ECGs
      from 599 patients were reviewed. Two hundred eleven patients (35.2% of the total
      patient population surveyed) had STE as determined by at least one attending EP;
      40 (19% of the STE population) patients had STE determined by 1 EP, 21 (10% of
      the STE population) patients by 2 EPs, and 150 (71% of the STE population)
      patients by 3 EPs. The STE of 61 (28.9%) ECGs were interpreted in a discrepant
      fashion. The average STE was 1.31 mm per lead for ECGs with disagreement and 2.93
      mm per lead for ECGs with agreement (P<.05). ECGs with reciprocal ST depression
      were more likely to have agreement with regard to the STE (P<.05). Fourteen ECGs
      (8.2% of 171 ECGs with STE determined by at least 2 EPs) had ST segment
      morphology interpreted in a discrepant fashion. Disagreement in the determination
      of electrocardiographic ST segment elevation by EPs occurs frequently and is
      related to the amount of STE present on the ECG. Electrocardiographic patterns
      responsible for this interpretive disagreement of ST segment elevation can
      represent an unfortunate but potentially predictable source of error in emergency
      medical care.

PMID- 15011216
TI  - Initial clinical evaluation of cardiac systolic murmurs in the ED by
      noncardiologists.
AB  - It is not exactly known how ED physicians perform in evaluating cardiac systolic
      murmurs. In 203 consecutive medical ED patients with systolic murmur, we compared
      the initial clinical evaluation, including auscultation, with transthoracic
      echocardiography. Of the 203 patients, 132 (65%) had innocent murmurs and 71
      patients (35%) had valvular heart disease. Sensitivity and specificity of the
      initial clinical routine evaluation in diagnosing echocardiographic valvular
      heart disease were 82% (70%-86%) and 69% (60%-76%), respectively. Independent
      significant positive predictors of valvular heart disease were grade >2/6
      systolic murmur (odds ratio [OR], 8.3; confidence interval [CI], 3.5-19.7,
      P<.001) and pathologic electrocardiogram (ECG) (OR, 8.4; CI, 3.2-22, P<.001.
      Patients younger than 50 years with a systolic murmur graded < or =2/6 had
      innocent murmurs in 98%. The initial clinical evaluation, including auscultation,
      by experienced ED physicians in internal medicine distinguishes well between
      innocent murmurs and valvular heart disease in medical patients with cardiac
      systolic murmurs.

PMID- 15011217
TI  - Can the bispectral index monitor the sedation adequacy of intubated ED adults?
AB  - The Bispectral Index Monitor (BIS) is validated as a measure of sedation depth
      during general anesthesia, but its value otherwise remains unclear. We
      hypothesized that BIS scores would correlate with standard subjective measures of
      assessing sedation in intubated adult ED patients and that BIS would predict
      inadequate sedation. Sedation was assessed by recording clinical features and by
      having treating physicians complete a visual analog scale (VAS; rated "not
      sedated" to "completely sedated") at 10, 30, and 60 minutes after intubation.
      Measurements of BIS were later paired with sedation assessments. Despite being
      statistically significant (p=.002), the correlation between BIS and VAS in our
      147 paired readings was fair (Pearson's rho=-0.37) and displayed wide
      variability. Receiver operating characteristic curve analysis of BIS demonstrated
      no discriminatory power in predicting sedation adequacy (area under curve 0.53).
      BIS is not associated with and did not predict standard measures of sedation
      adequacy in intubated adults.

PMID- 15011218
TI  - ED evaluation of infants after an apparent life-threatening event.
AB  - The objective of this study was to determine the rate of positive ED diagnostic
      evaluations and significant interventions during the hospitalization of infants
      after an apparent life-threatening event (ALTE). The study was performed at a
      single, tertiary care children's hospital. Patients under 6 months of age were
      identified for a potential ALTE from the ED chief complaint log. The charts of
      patients meeting the definition of an ALTE were abstracted for data pertaining to
      the patient's history, physical examination, ED diagnostic evaluation, and
      admission. The yield of the ED diagnostic evaluation and hospitalization was
      noted. A positive ED evaluation was defined as a diagnostic intervention that
      resulted in a specific treatment for a defined condition. Significant medical
      interventions were derived from a validated instrument assessing the risk of
      admission for pediatric patients presenting to an ED. Such interventions
      included, but were not limited to, parenteral antibiotics for documented
      infections, supplemental oxygen, endotracheal intubation, airway suctioning, and
      intensive-care unit admission. Over a 5-year period with 253,408 patient visits,
      523 patents met the initial search criteria for a potential ALTE. From this
      group, 483 charts were reviewed (92.4%) and 150 patients met the definition for
      an ALTE. The mean age of the patients was 61.7 days and 115 (76.7%) were
      admitted. Of the patients with an ALTE, 122 patients had ED diagnostic tests
      performed and three had a positive result (2.5%; 95% confidence interval [CI];
      0.5-7.0). The rate of significant medical interventions among admitted patients
      was 7.% (9 of 115, 95% CI, 3.6-14.3). No patients with a positive ED diagnostic
      evaluation were discharged from the ED. Risk factors for significant medical
      interventions included prematurity, a positive medical history, and age >60 days.
      The overall rate of either positive ED diagnostic evaluations or significant
      medical interventions during hospitalizations of infants after an ALTE is low. A
      majority of these patients can be best managed with a limited ED diagnostic
      evaluation and a period of observation.

PMID- 15011219
TI  - A neural network model analysis to identify victims of intimate partner violence.
AB  - The objective of this study was to determine if a neural network model can
      identify victims of intimate partner violence (IPV). A custom neural network
      model was constructed and trained using the 1995 ED databases at Truman Medical
      Center of all female visits. The input vector developed was an array of 100
      binary elements containing, in coded form, the patient's age, day of week,
      primary diagnosis (excluding 995.81), disposition, race, time, and E-code. The
      trained network was then presented with a series of 19,830 female patients from
      the 1996 ED database to determine if it could discriminate cases from control
      subjects. The neural network identified 231 of 297 known IPV victims (sensitivity
      78%) in the 1996 database. It also categorized 2234 false-positive patients out
      of 19,533 IPV-negative patients (specificity 89%). A computer-based neural
      network model, when supplied with information commonly available in the ED
      medical record, can identify victims of IPV.

PMID- 15011220
TI  - The influence of urban, suburban, or rural locale on survival from refractory
      prehospital cardiac arrest.
AB  - There are many variables that can have an effect on survival in cardiopulmonary
      arrest. This study examined the effect of urban, suburban, or rural location on
      the outcome of prehospital cardiac arrest as a secondary end point in a study
      evaluating the effect of bicarbonate on survival. The proportion of survivors
      within a type of EMS provider system as well as response times were compared.
      This prospective, randomized, double-blind clinical intervention trial enrolled
      874 prehospital cardiopulmonary arrest patients encountered by prehospital urban,
      suburban, and rural regional EMS area. Population density (patients per square
      mile) calculation allowed classification into urban (>2000/mi2), suburban
      (>400/mi2), and rural (0-399/mi2) systems. This group underwent standard advanced
      cardiac life support (ACLS) intervention with or without early empiric
      administration of bicarbonate in a 1-mEq/kg dose. A group of demographic,
      diagnostic, and therapeutic variables were analyzed for their effect on survival.
      Times were measured from collapse until onset of medical intervention and
      survival measured as the presence of ED vital signs on arrival. Data analysis
      used chi-squared with Pearson correlation for survivorship and Student t test
      comparisons for response times. The overall survival rate was approximately 13.9%
      (110 of 793), ranging from 9% rural, 14% for suburban, and 23% for urban sites
      for 372 patients (P=.007). Survival differences were associated with
      classification of arrest locale in this sample-best for urban, suburban, followed
      by rural sites. There was no difference in time to bystander cardiopulmonary
      resuscitation, but medical response time (basic life support) was decreased for
      suburban or urban sites, and intervention (ACLS) and transport times were
      decreased for suburban sites alone. Although response times were differentiated
      by location, they were not necessarily predictive of survival. Factors other than
      response time such as patient population or resuscitation skill could influence
      survival from cardiac arrest occurring in diverse prehospital service areas.

PMID- 15011221
TI  - Accuracy of emergency medical information on the web.
AB  - A large amount of EM information can be found on the Internet, but the accuracy
      of this information has not been determined. This study compares the "gold
      standards" of EM information on four common emergencies with top healthcare web
      sites. The study also examines the relationship of web sites' credentials and
      certification on content. Checklists were developed for four emergency medical
      topics: influenza, febrile child, chest pain, and stroke from the "gold
      standards" promoted by the American Stroke Association, the American Heart
      Association, the National Heart, Lung and Blood Institute, and the American
      College of Emergency Physicians. Information found at the 20 most visited health
      information web sites were compared with the "gold standards." Completeness of
      the information, certification, and credentials were used to judge the accuracy
      of the web sites. Inaccurate or incorrect information from these web sites were
      noted. Correlations between the site's credentials and its content were also
      measured. This study, conducted from January 18, 2002, to January 31, 2002,
      excluded eight of the top 20 health web sites because they did not cater to the
      lay public. MEDLINEplus was the most complete web site with 74.8% of the items
      noted contained in the web site; MayoClinic.com had 54.5% and Medscape had 50.9%.
      Half of the web sites fell between 35% and 50%, including WebMD at 46.9%,
      InteliHealth at 45.5%, HealthWorld Online at 44.8%, Yahoo! Health at 41.3%,
      AllHealth.com at 40.6%, and Health.excite.com at 36.4%. Healthcentral.com at 35%,
      Drkoop.com at 35%, and AskDrWeil at 26.8% were the bottom three sites.
      Information on stroke was the most complete overall in 11 of 12 web sites. Four
      web sites contained questionable or concerning information. No correlation was
      found between possession of certification and the completeness of content
      (Pearson correlation -0.264 with a two-tailed significance of .406). Despite
      recent efforts to improve web site content through certification, few web sites
      contained a significant amount of EM information on all four topics investigated.
      In fact, some of the information provided on these health information web sites
      has the potential to be dangerous. Thus, most web sites are not good sources of
      reference for the public to find out what to do in the case of a medical
      emergency.

PMID- 15011222
TI  - Pain management after discharge from the ED.
AB  - Pain is an important but understudied and often overlooked aspect of emergency
      medical care. This study examined the management of pain after discharged of
      patients from the emergency department (ED). We hypothesized that pain management
      after discharge would be adequate, and that patients would use their medications
      as prescribed. We surveyed 144 patients by telephone after they had been treated
      in the ED for common orthopedic complaints. We used a standardized questionnaire
      to assess prescription-filling practices, side effects of medications,
      interventions by other health-care professionals, and adequacy of pain relief.
      Most patients discharged from the ED with a prescription for medication were
      satisfied with their pain relief (77%). Of those who did not fill their
      prescription, only 67% were satisfied. Although 26% of the patients reported side
      effects, most were minor. Thirteen percent of patients with prescribed
      medications did not fill their prescriptions. Of patients for whom narcotic
      analgesics were prescribed, 7% drove vehicles while taking these medications. The
      patients in the study were quite satisfied with their pain control. Most filled
      their prescriptions and did so in a timely manner. Those who did not fill
      prescriptions for medications reported the least satisfaction with pain control.

PMID- 15011223
TI  - Genital trauma associated with forced digital penetration.
AB  - Clinicians may not perform a medical-legal examination in cases in which a sexual
      assault was attempted but no penile-vaginal contact occurred. This retrospective
      study was conducted to document the frequency and type of genital injuries in
      women in whom forced digital penetration was the only reported type of assault.
      Study patients were consecutive female patients presenting to an urban sexual
      assault clinic during a 3-year study period. The clinic is associated with a
      university-affiliated urban hospital and is staffed by registered nurses trained
      to perform forensic examinations using colposcopy with nuclear staining. Case
      files of 941 patients were reviewed; 6% (53) reported only digital-vaginal
      contact. Genital injuries were documented in 81% of the patients (mean number of
      genital injuries, 2.4). Fifty-six percent of the injuries occurred at four sites:
      fossa navicularis, labia minora, cervix, and posterior fourchette. The most
      common type of injury was erythema (34%) followed by superficial tears (29%) and
      abrasions (21%). Colposcopy with nuclear staining was useful in detecting these
      injuries--and can provide valuable legal information in sexual assault victims
      reporting only digital-vaginal penetration.

PMID- 15011224
TI  - Unusual causes of hyperammonemia in the ED.
AB  - Plasma ammonia measurement is a simple yet important screening in the ED for
      patients with unexplained stupor or delirium. Acute hyperammonemia is a medical
      emergency for which immediate steps must be taken to minimize permanent brain
      damage. Although the most common causes of hyperammonemia are severe abnormal
      liver function, the absence of liver disease in some cases has been observed.
      This brief report describes four hyperammonemia cases with normal liver function
      in the ED. On careful history and speculated examinations, ornithine
      carbamoyltransferase (OTC) deficiency, hematologic malignancy, and the side
      effects of valproic acid and 5-fluorouracil (5-FU) were considered. Therapy was
      first aimed at correcting the hyperammonemia. Once a specific diagnosis was
      reached, protein restriction, essential amino acid supplementation, efficient
      chemotherapy, and valproic acid and 5-FU level discontinuance were instituted. In
      this report, the clinical presentation, pathogenesis, and diagnostic workup for
      various hyperammonemia causes are discussed. Every EP should understand that the
      clinical symptoms for hyperammonemia and prognosis are related to early
      diagnosis.

PMID- 15011225
TI  - Presentation variability of acute urolithiasis in school-aged children.
AB  - Urolithiasis is not a frequent diagnosis in school-aged children. The clinical
      presentation can lack many of the clinical clues such as flank pain that are seen
      in older patients. We present four cases demonstrating this potential diagnostic
      dilemma.

PMID- 15011226
TI  - A rapid quantitative turbimetric d-dimer assay has high sensitivity for detection
      of pulmonary embolism in the ED.
AB  - Many rapid d-dimer assays are commercially available with wide ranges of reported
      sensitivities, often based on small sample sizes. This has limited their intended
      use as rapid and inexpensive tests to evaluate pulmonary embolism in the low-risk
      patient. We sought to determine the sensitivity of the STA-Liatest D-Di d-dimer
      assay in our ED. We performed a retrospective analysis of 103 patients seen in
      our ED with the admitting diagnosis of known or suspected pulmonary embolism.
      These charts were assessed to establish if a d-dimer assay was performed within
      24 hours. These charts were then reviewed to determine what diagnostic studies
      were performed and what final diagnosis was reached. Of the 103 charts
      identified, 55 had d-dimer assays performed within 24 hours. Of those, 38 were
      diagnosed with pulmonary embolism; none had negative d-dimer assays (<400 ng/mL).
      Using the exact method, the sensitivity of this assay was calculated to be 100%
      with a 95% confidence interval (CI) of 91.4% to 100%. Our results suggest that
      the STA-Liatest D-Di d-dimer assay could have an adequate sensitivity to be used
      to rule out pulmonary embolism in low-risk patients. Further prospective studies
      with larger sample sizes are required to validate this observation.

PMID- 15011227
TI  - EPs do not accept the strategy of "lumbar puncture first" in subarachnoid
      hemorrhage.
AB  - It has been proposed that the workup of suspected subarachnoid hemorrhage should
      begin with lumbar puncture (LP) rather than computed tomography (CT) scan. We
      investigated whether EPs would in fact advocate this strategy in an index
      hypothetical case and in variations of the index case. An eight-question survey
      was distributed to EM physicians attending national continuing medical education
      meetings. Questions included whether the responders would advocate "LP first" in
      the following scenarios: (1) the index case in which the patient's symptoms had
      been present for more than 12 hours, other diagnoses were very unlikely, the
      patient was fully insured, and CT scan was available immediately; (2) a case in
      which the patient is not insured; (3) a case in which the respondent is the
      patient; and (4) a case in which there is a delay in obtaining a CT scan. Two
      hundred forty-one of 275 surveys were completed for a response rate of 88%. Given
      the index scenario, only 22.8% of the respondents would advise patients to have
      an LP first versus 17.9% if they themselves were the patient (P=.11). Compared
      with the index scenario, 34.0% of respondents would advise LP first if their
      patient did not have insurance (P<.0001); a majority, 57.1%, would advise LP
      first if the CT were delayed (P<.0001). The "LP first" strategy for workup of
      subarachnoid hemorrhage was rejected by most EM physicians except when the CT
      scan would entail delay. Compared with the index case, an added number of
      physicians would advocate this strategy if the patient was uninsured. The ethical
      implication of advocating a strategy because of financial concerns and that most
      physicians would not favor for themselves or their patients merits attention.

PMID- 15011228
TI  - Cases in electrocardiography.

PMID- 15011229
TI  - Electrocardiographic ST-segment elevation: a source of error or burden for EPs
      [corrected]?

PMID- 15011230
TI  - Cognitive impairment in elderly ED patients.

PMID- 15011232
TI  - Nitrous oxide "whippit" abuse presenting as clinical B12 deficiency and ataxia.

PMID- 15011233
TI  - Descending necrotizing mediastinitis from upper respiratory infection.

PMID- 15011234
TI  - Delayed absorption and postdialysis rebound in a case of acute methanol
      poisoning.

PMID- 15011235
TI  - Hyperleukocytosis presenting as myocardial ischemia, altered sensorium, and
      metabolic acidosis.

PMID- 15011236
TI  - Injury incidence during the 2001 World Police and Fire Games.

PMID- 15011237
TI  - Vomiting gravel.

PMID- 15011238
TI  - Rate-related bundle branch block: an uncommon wide complex tachycardia.

PMID- 15011239
TI  - Ocular injuries related to airbag use.

PMID- 15011240
TI  - A case of Guillain-Barre syndrome presenting as ataxia.

PMID- 15011241
TI  - Multiple organ dysfunction syndrome associated with Salmonella typhi infection.

PMID- 15011245
TI  - 1H magnetic resonance spectroscopy of invasive cervical cancer: an in vivo study
      with ex vivo corroboration.
AB  - The objective of this study was to establish in vivo (1)H-magnetic resonance (MR)
      spectroscopic appearances of cervical cancer using an endovaginal receiver coil
      and corroborate findings with magic angle spinning (MAS) MR spectroscopy of
      tissue samples. Fifty-three women (14 controls and 39 with cervical cancer)
      underwent endovaginal coil MR imaging at 1.5 T with T(1)- and T(2)-weighted scans
      sagittal and transverse to the cervix. Localized (1)H MR spectra (PRESS
      technique, TR 1600 ms, TE 135 ms) were accumulated in all controls and 29 cancer
      patients whose tumour filled > 50% of a single 3.4 cm(3) voxel. Peaks from
      triglyceride-CH(2) and -CH(3) were defined as present and in-phase (with the
      choline resonance), present but out-of-phase, or not present. Peak areas of
      choline-containing compounds were standardized to the area of unsuppressed tissue
      water resonance. Comparisons in observed resonances between groups were made
      using Fisher's exact test (qualitative data) and a t-test (quantitative data).
      Biopsies from these women analysed using MAS-MR spectroscopy and normalized to
      the intensity of an external standard of silicone rubber were similarly compared.
      Adequate water suppression permitted spectral analysis in 11 controls and 27
      cancer patients. In-phase triglyceride-CH(2) resonances (1.3 ppm) were observed
      in 74% of tumours but in no control women (p < 0.001). No differences were
      observed in the presence of a 2 ppm resonance, choline-containing compounds or
      creatine in cancer compared with control women. However, ex vivo analysis showed
      significant differences not only in -CH(2), but also in -CH(3), a 2 ppm
      resonance, choline-containing compounds and creatine between tissues from control
      women and cancer tissue (p < 0.001, = 0.001, = 0.036, < 0.001 and = 0.004
      respectively). On in vivo (1)H-MR spectroscopy, the presence of positive
      triglyceride-CH(2) resonances can be used to detect and confirm the presence of
      cervical cancer. However, technical improvements are required before routine
      clinical use.

PMID- 15011246
TI  - Identification of MRI and 1H MRSI parameters that may predict survival for
      patients with malignant gliomas.
AB  - Although MR imaging (MRI) and MR spectroscopic imaging (MRSI) have been applied
      in the diagnosis and treatment planning for brain tumors, their prognostic
      significance has not yet been determined. The goal of this study was to identify
      pre-treatment MRI and MRSI parameters for patients with malignant glioma that may
      be useful in predicting survival. Two populations of patients with newly
      diagnosed malignant glioma were examined with MRI and three-dimensional proton
      ((1)H) MRSI. Thirty-nine patients (22 grade 3 and 17 glioblastoma multiforme,
      GBM) were studied prior to surgery, and 33 GBM patients were studied after
      surgery but prior to treatment with radiation and chemotherapy. Signal
      intensities of choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), and
      lactate/lipid (LL) were estimated from the spectra. Recursive partitioning
      methods were applied to parameters that included age, histological grade, MRI and
      MRSI variables to generate survival trees. Patients were grouped into high and
      low risk categories and the corresponding Kaplan-Meier curves were plotted for
      comparison between groups. The parameters that were selected by recursive
      partitioning as being predictive of poor outcome were older age, larger contrast
      enhancement, higher Cho-to-Cr, higher Cho-to-NAA, higher LL and lower Cr-to-NAA
      abnormalities. The survival functions were significantly different between the
      sub-groups of patients obtained from the survival tree for both pre-surgery and
      post-surgery data. The results of this study suggest that pre-treatment MRI and
      three-dimensional (1)H-MRSI provide information that predicts outcome for
      patients with malignant gliomas and have drawn attention to variables that should
      be examined prospectively in future studies using these techniques.

PMID- 15011247
TI  - Magnetic resonance angiography of collateral vessels in a murine femoral artery
      ligation model.
AB  - The in vivo detection of growing collateral vessels following arterial occlusion
      is difficult in small animals. We have addressed the feasibility of performing
      high resolution time-of-flight angiograms to monitor the growth of collateral
      vessels after femoral artery occlusion in mice. We will also present a low-pass
      quadrature birdcage coil construction with a sufficient signal-to-noise ratio to
      produce high resolution. After a 4-month recovery period a C57BL/6 mouse with a
      surgical occlusion of the right femoral artery was used to assess the image
      quality and time requirements to produce magnetic resonance angiograms sufficient
      to assess collateral artery development using a two-dimensional gradient echo
      sequence. At a resolution of 100 x 100 x 100 microm and a matrix size of 256 x
      128 x 256 for a 2.56 cm isometric volume, three scans were performed with one,
      two and four repetitions resulting in signal-to-noise ratios for the femoral
      artery proximal to the ligation site of 58, 126 and 194, respectively. Five
      C57BL/6 mice were additionally measured 4 weeks after occlusion using two
      repetitions and the visual collateral vessels were assessed for number and
      location: 2.0 +/- 1.2 in quadriceps muscle, 0.6 +/- 0.5 in adductor (deep
      adductor vessel), 0.0 +/- 0.0 in adductor (surface adductor vessels). The results
      showed a significant difference, two-sided t-test, p < 0.05, in number of vessels
      in all the locations. We have shown that this method can be utilized to elucidate
      the contribution of collateral vessels to arterial flow.

PMID- 15011248
TI  - MRI detects early hindlimb muscle atrophy in Gly93Ala superoxide dismutase-1
      (G93A SOD1) transgenic mice, an animal model of familial amyotrophic lateral
      sclerosis.
AB  - MRI has been used to measure hindlimb muscle volume in female and male transgenic
      mice overexpressing the Gly93Ala (G93A) mutant human superoxide dismutase 1
      (SOD1), a widely used model of familial amyotrophic lateral sclerosis (FALS),
      over the first 4 months of life. Significant decreases in the hindlimb muscle
      volume of the female G93A SOD1 mice were evident from 11 weeks of age, before
      other overt pathology appeared. By 15 weeks volume had decreased by 37% compared
      with 7 weeks, from 0.84+/-0.04 cm(3) (mean+/-standard deviation, n = 6) to 0.54+/
      0.07 cm(3), (p < 0.05), despite an increase in body weight of ca. 12% (from 16.2
      +/- 1.4 to 18.1 +/- 0.7 g). Female wild-type volume increased by ca. 30% whilst
      the body weight increased by 15%. Muscle wasteage was less (0.82+/-0.1 to 0.65+/
      0.02 cm(3), p < 0.05, n = 6) in male G93A SOD1 mice between 8 and 16 weeks of
      age, against a body weight increase trend from 20.7 +/- 0.4 to 21.6 +/- 0.5 g, (p
      > 0.05). Wild-type male muscle volume did not change significantly over this
      period, with an increase in body weight of 20%. Longitudinal MRI hindlimb muscle
      volume measurements may provide a straightforward, rapid, non-invasive and
      sensitive, way of monitoring outcome of experimental ALS treatments.

PMID- 15011250
TI  - Pattern recognition strategies for molecular surfaces: III. Binding site
      prediction with a neural network.
AB  - An algorithm for the identification of possible binding sites of biomolecules,
      which are represented as regions of the molecular surface, is introduced. The
      algorithm is based on the segmentation of the molecular surface into overlapping
      patches as described in the first article of this series.1 The properties of
      these patches (calculated on the basis of physical and chemical properties) are
      used for the analysis of the molecular surfaces of 7821 proteins and protein
      complexes. Special attention is drawn to known protein binding sites. A binding
      site identification algorithm is realized on the basis of the calculated data
      using a neural network strategy. The neural network is able to classify surface
      patches as protein-protein, protein-DNA, protein-ligand, or nonbinding sites. To
      show the capability of the algorithm, results of the surface analysis and the
      predictions are presented and discussed with representative examples.

PMID- 15011249
TI  - Effects of temperature on intracellular sodium, pH and cellular energy status in
      RIF-1 tumor cells.
AB  - Most perfused tumor cell experiments are performed at 37 degrees C, the normal
      healthy body temperature. However, the temperature of subcutaneously implanted
      tumors in small animals is generally 29-33 degrees C when the rectal temperature
      of the animal is maintained at 37 degrees C. We have investigated the acute
      effects of increasing the temperature of perfused radiation-induced-fibrosarcoma
      (RIF-1) tumor cells from 33 to 37 degrees C (30 min) on intracellular sodium
      (Na(i)+) , intracellular pH (pH(i)), and bioenergetic status. Heating the cells
      by 4 degrees C produced a reversible increase in Na(i)+, slight acidification and
      no change in nucleotide triphosphate to inorganic phosphate ratio (NTP/P(i)) as
      measured by shift-reagent-aided (23)Na and (31)P NMR spectroscopy. In the
      presence of 3 microM 5-(N-ethyl-N-isopropyl) amiloride (EIPA), a potent and
      specific inhibitor of Na(+)/H(+) antiporter, the increase in Na(i)+ during the
      heating was completely abolished suggesting that the heat induced increase in
      Na(i)+ was caused by an increase in Na(+)/H(+) antiporter activity. However, the
      changes in pH(i) with the heating were identical with or without EIPA, indicating
      that pH(i) is controlled by other ion exchange mechanisms in addition to
      Na(+)/H(+) antiporter. NTP/P(i) was significantly higher in presence of EIPA for
      some time points during the heating suggesting that both NTP production and
      consumption rates may be altered during the heating. These results indicate that
      a slight increase in temperature from 33 to 37 degrees C induces significant
      changes in Na(+) physiology largely because of activation of Na(+)/H(+)
      antiporter but other ion exchange mechanisms are also involved in maintaining
      pH(i) in the RIF-1 tumor cells. Thus, care must be taken in choosing the
      temperature for perfused cell studies.

PMID- 15011252
TI  - Car-Parrinello simulations with a real space method.
AB  - An approach for Car-Parrinello type molecular dynamics simulations using real
      space discretized wave functions is presented. The implementation uses a higher
      order finite difference approximation for the Laplacian in the kinetic energy
      operator and in the Poisson equation for the evaluation of the Hartree energy.
      Norm conserving pseudopotentials are employed to replace the nucleus-core
      interactions. Both nuclei and wave functions are propagated with a second-order
      Verlet propagator with a timestep comparable to standard plane wave
      implementations. The orthonormality constraints are fulfilled via Lagrange
      multipliers. Both periodic and nonperiodic boundary conditions can directly be
      imposed within the real space approach. In order to maintain energy conservation
      both forces on the nuclei and the wave functions must be sufficiently accurate.
      It is shown that the spurious energy dependence on the nuclear positions with
      respect to the grid points, which is an inevitable artifact of the
      discretization, is mirrored in the nuclear forces, and does not affect energy
      conservation. In contrast to the plane wave methodology, the Hartree energy is
      calculated via an iterative solution of the Poisson equation. As a result, the
      quality of the forces on the wave function crucially depends on its convergence,
      as well as on the accuracy of the approximation for the boundary values in
      nonperiodic calculations. The influence of these factors on the energy
      conservation is investigated. It is shown that Car-Parrinello simulations can be
      performed with real space wave functions, given a proper prescription to
      calculate the Hartree potential is used.

PMID- 15011251
TI  - Performance of SuSi: a method for generating atomistic models of amorphous
      polymers based on a random search of energy minima.
AB  - The performance of a recently developed method to generate representative
      atomistic models of amorphous polymers has been investigated. This method, which
      is denoted SuSi, can be defined as a random generator of energy minima. The
      effects produced by different parameters used to define the size of the system
      and the characteristics of the generation algorithm have been examined.
      Calculations have been performed on poly(L,D-lactic) acid (rho = 1.25 g/cm3) and
      nylon 6 (rho = 1.084 g/cm(3)), which are important commercial polymers.

PMID- 15011253
TI  - Hydrogen bonding and solvent effects on the lowest 1(n, pi*) excitations of
      triazines in water.
AB  - Our method for estimating solvent effects on electronic spectra in media with
      strong solute-solvent interactions is applied here to calculate the absorption
      and fluorescence solvatochromatic shifts of dilute triazines in water. First, the
      ab initio CASSCF method is used to estimate the gas-phase electronic excitation
      properties and state charge distributions; second, Monte Carlo simulations are
      performed to elucidate liquid structures around the ground and excited state
      solute; finally, the solvent shift is evaluated based on the gas-phase charge
      distributions and the explicit solvent structures. For the dilute triazine
      solutions, simulations predict one linear (different) hydrogen bond attached to
      each nitrogen atom. Upon the first (1)(n, pi*)electronic excitation one hydrogen
      bond is completely broken. For the absorption and fluorescence spectra, our
      calculations demonstrated that the specific solvent-solute interaction, in any
      electronic state, plays a critical role in the determination of solvent shifts.

PMID- 15011254
TI  - Intramolecular interaction energies in model alanine and glycine tetrapeptides.
      Evaluation of anisotropy, polarization, and correlation effects. A parallel ab
      initio HF/MP2, DFT, and polarizable molecular mechanics study.
AB  - An extension of the SIBFA polarizable molecular mechanics procedure to flexible
      oligopeptides is reported. The procedure is evaluated by computing the relative
      conformational energies, deltaE(conf), of the alanine tetrapeptide in 10
      representative conformations, which were originally derived by Beachy et al. (J
      Am Chem Soc 1997, 119, 5908) to benchmark molecular mechanics procedures with
      respect to ab initio computations. In the present study, a particular emphasis is
      on the separable nature of the components of the energy and the particular impact
      of the polarization energy component on deltaE(conf). We perform comparisons with
      respect to single-point HF, DFT, LMP2, and MP2 computations done at the SIBFA
      derived energy minima. Such comparisons are made first for the 10 conformers
      derived from phi/psi torsional angle energy-minimization (the rigid rotor
      approach), and, in a second step, after allowing additional relaxation of the
      C(alpha) centered valence angles. In both series of energy-minimization, the
      SIBFA deltaE(conf) compared best with the LMP2 results using the 6-311G** basis
      set, the rms being 1.3 kcal/mol. In the absence of the polarization component,
      the rms is 3.5 kcal/mol. In both series of minimizations, the magnitudes of
      deltaE(conf), computed as differences with respect to the most stable conformer
      taken as energy zero, decrease along the series: HF > DFT > LMP2 > SIBFA > MP2,
      indicative of increasing stabilization of the most highly folded conformers.

PMID- 15011255
TI  - Continuous medium theory for nonequilibrium solvation: II. Interaction energy
      between solute charge and reaction field and single-sphere model for spectral
      shift.
AB  - On the basis of continuous medium theory, a model for evaluation of spectral
      shifts in solution has been developed in this work. The interaction energy
      between solute dipole and reaction field and the self-energy of the reaction
      field have been formulated through derivations. Applying the interaction energy
      expression together with the point dipole approximation to the case of spherical
      cavity produces new formulations of spectral shifts. The same expression of
      electrostatic free energy of the nonequilibrium state is achieved by integrating
      the change of the electrostatic free energy for a charging process. Moreover,
      generalized formulations evaluating spectral shifts have been established in the
      charge-potential notation, and the reduction of them to the point dipole case
      consistently leads to the same formulations of spectral shifts as those by
      interaction energy approach. Mutual supports provide convincing evidences for the
      reliability of the present results. In this work, attentions are particularly
      paid to the conclusion of zero self-energy of the reaction field, which is
      different from the previous theory. Reasoning and arguments are given on this
      point. From the present derivations, it is concluded that the spectral shifts of
      light absorption and emission were theoretically exaggerated in the past, in
      particular, by a factor of 2 for the spectral shift sum.

PMID- 15011256
TI  - Development and evaluation of a generic evolutionary method for protein-ligand
      docking.
AB  - We have developed a generic evolutionary method with an empirical scoring
      function for the protein-ligand docking, which is a problem of paramount
      importance in structure-based drug design. This approach, referred to as the
      GEMDOCK (Generic Evolutionary Method for molecular DOCKing), combines both
      continuous and discrete search mechanisms. We tested our approach on seven
      protein-ligand complexes, and the docked lowest energy structures have root-mean
      square derivations ranging from 0.32 to 0.99 A with respect to the corresponding
      crystal ligand structures. In addition, we evaluated GEMDOCK on crossdocking
      experiments, in which some complexes with an identical protein used for docking
      all crystallized ligands of these complexes. GEMDOCK yielded 98% docked
      structures with RMSD below 2.0 A when the ligands were docked into foreign
      protein structures. We have reported the validation and analysis of our approach
      on various search spaces and scoring functions. Experimental results show that
      our approach is robust, and the empirical scoring function is simple and fast to
      recognize compounds. We found that if GEMDOCK used the RMSD scoring function,
      then the prediction accuracy was 100% and the docked structures had RMSD below
      0.1 A for each test system. These results suggest that GEMDOCK is a useful tool,
      and may systematically improve the forms and parameters of a scoring function,
      which is one of major bottlenecks for molecular recognition.

PMID- 15011257
TI  - Ligand-protein docking using a quantum stochastic tunneling optimization method.
AB  - A novel hybrid optimization method called quantum stochastic tunneling has been
      recently introduced. Here, we report its implementation within a new docking
      program called EasyDock and a validation with the CCDC/Astex data set of ligand
      protein complexes using the PLP score to represent the ligand-protein potential
      energy surface and ScreenScore to score the ligand-protein binding energies. When
      taking the top energy-ranked ligand binding mode pose, we were able to predict
      the correct crystallographic ligand binding mode in up to 75% of the cases. By
      using this novel optimization method run times for typical docking simulations
      are significantly shortened.

PMID- 15011258
TI  - SPICKER: a clustering approach to identify near-native protein folds.
AB  - We have developed SPICKER, a simple and efficient strategy to identify near
      native folds by clustering protein structures generated during computer
      simulations. In general, the most populated clusters tend to be closer to the
      native conformation than the lowest energy structures. To assess the generality
      of the approach, we applied SPICKER to 1489 representative benchmark proteins
      </=200 residues that cover the PDB at the level of 35% sequence identity; each
      contains up to 280,000 structure decoys generated using the recently developed
      TASSER (Threading ASSembly Refinement) algorithm. The best of the top five
      identified folds has a root-mean-square deviation from native (RMSD) in the top
      1.4% of all decoys. For 78% of the proteins, the difference in RMSD from native
      to the identified models and RMSD from native to the absolutely best individual
      decoy is below 1 A; the majority belong to the targets with converged
      conformational distributions. Although native fold identification from divergent
      decoy structures remains a challenge, our overall results show significant
      improvement over our previous clustering algorithms.

PMID- 15011259
TI  - A new hierarchical parallelization scheme: generalized distributed data interface
      (GDDI), and an application to the fragment molecular orbital method (FMO).
AB  - A two-level hierarchical scheme, generalized distributed data interface (GDDI),
      implemented into GAMESS is presented. Parallelization is accomplished first at
      the upper level by assigning computational tasks to groups. Then each group does
      parallelization at the lower level, by dividing its task into smaller work loads.
      The types of computations that can be used with this scheme are limited to those
      for which nearly independent tasks and subtasks can be assigned. Typical examples
      implemented, tested, and analyzed in this work are numeric derivatives and the
      fragment molecular orbital method (FMO) that is used to compute large molecules
      quantum mechanically by dividing them into fragments. Numeric derivatives can be
      used for algorithms based on them, such as geometry optimizations, saddle-point
      searches, frequency analyses, etc. This new hierarchical scheme is found to be a
      flexible tool easily utilizing network topology and delivering excellent
      performance even on slow networks. In one of the typical tests, on 16 nodes the
      scalability of GDDI is 1.7 times better than that of the standard parallelization
      scheme DDI and on 128 nodes GDDI is 93 times faster than DDI (on a multihub Fast
      Ethernet network). FMO delivered scalability of 80-90% on 128 nodes, depending on
      the molecular system (water clusters and a protein). A numerical gradient
      calculation for a water cluster achieved a scalability of 70% on 128 nodes. It is
      expected that GDDI will become a preferred tool on massively parallel computers
      for appropriate computational tasks.

PMID- 15011260
TI  - Modification of the Wiener index 4.
AB  - A novel topological index W(F) is defined by the matrices X, W, and L as W(F) =
      XWL. Where L is a column vector expressing the characteristic of vertices in the
      molecule; X is a row vector expressing the bonding characteristics between
      adjacent atoms; W is a reciprocal distance matrix. The topological index W(F),
      based on the distance-related matrix of a molecular graph, is used to code the
      structural environment of each atom type in a molecular graph. The good QSPR/QSAR
      models have been obtained for the properties such as standard formation enthalpy
      of inorganic compounds and methyl halides, retention indices of gas
      chromatography of multiple bond-containing hydrocarbons, aqueous solubility, and
      octanol/water partition of benzene halides. These models indicate that the idea
      of using multiple matrices to define the modified Wiener index is valid and
      successful.

PMID- 15011261
TI  - The calculation of the vibrational frequencies of crystalline compounds and its
      implementation in the CRYSTAL code.
AB  - The problem of numerical accuracy in the calculation of vibrational frequencies
      of crystalline compounds from the hessian matrix is discussed with reference to
      alpha-quartz (SiO(2)) as a case study and to the specific implementation in the
      CRYSTAL code. The Hessian matrix is obtained by numerical differentiation of the
      analytical gradient of the energy with respect to the atomic positions. The
      process of calculating vibrational frequencies involves two steps: the
      determination of the equilibrium geometry, and the calculation of the frequencies
      themselves. The parameters controlling the truncation of the Coulomb and exchange
      series in Hartree-Fock, the quality of the grid used for the numerical
      integration of the Exchange-correlation potential in Density Functional Theory,
      the SCF convergence criteria, the parameters controlling the convergence of the
      optimization process as well as those controlling the accuracy of the numerical
      calculation of the Hessian matrix can influence the obtained vibrational
      frequencies to some extent. The effect of all these parameters is discussed and
      documented. It is concluded that with relatively economical computational
      conditions the uncertainty related to these parameters is smaller than 2-4 cm(
      1). In the case of the Local Density Approximation scheme, comparison is possible
      with recent calculations performed with a Density Functional Perturbation Theory
      method and a plane-wave basis set.

PMID- 15011262
TI  - Expression of gap junction connexin36 in adult rat retinal ganglion cells.
AB  - Electrophysiological and ultrastructural studies have demonstrated that gap
      junctions connect diverse types of neurons in the central nervous system,
      permitting direct electrical and metabolic coupling. A member of gap junction
      channel subunit connexin36 (Cx36), is probed for the location of cell-to-cell
      communication in the mammalian retina, where gap junction networks of major
      classes of neurons are present. We present an analysis of the expression and
      localization of Cx36 protein in adult Wistar rat retina, using a newly generated
      polyclonal antibody against a sequence in the predicted cytoplasmic loop of the
      Cx36 amino acid alignment, deduced from the cDNA sequence. The affinity-purified
      antibody, recognizing a single 36-kDa protein, consistently labeled discrete
      puncta of subcellular structures likely to be associated with gap junctions in
      the inner plexiform layer, and also cytoplasm within somata and dendrites of
      retinal amacrine and ganglion cells, following examination with various fixation
      protocols and double labeling immuno-fluorescence. These results provide that
      prominent cell-to-cell communication appears in mature excitatory neurons such as
      retinal ganglion cells, in addition to inhibitory amacrine cells, mediated by gap
      junctions in the adult retina.

PMID- 15011263
TI  - An integrative theory of brain and mind: the inner sensibilities.
AB  - This work advances the theory of the integrated functional organic unity of the
      combined brain and mind, with explicit inclusion of conscious awareness and
      associated partial autonomy, and outlines its main foundations and qualities.
      This view: a--indicates new perspectives regarding the foundations of the mind
      body question; b--brings the mentoexperiential realm and its qualities into
      cooperative communication with neurobiological realms; c--offers fresh ground for
      considering the mentoexperiential in broader biological frameworks such as
      evolutionary theory; and d--provides a Neuroscientific framework for a full range
      of specific mentoexperiential qualities.

PMID- 15011264
TI  - On the mathematical integration of the nervous tissue based on the S-propagator
      formalism.
AB  - The integration of physiological functions in living organisms corresponds to the
      reconstruction of a biological system from its components. This calls for a sound
      theoretical framework based on the rigorous definition of the elementary
      physiological function within the context of multiple levels of biological
      organization. One of the main problems encountered in the neurosciences is that
      of extending the current theory of automata, as used in the study of artificial
      neural networks, to real neural networks. The difficulty arises because the
      theory of automata fails to take into account the various levels of biological
      organization involved in nervous activity. This article recalls the main elements
      of G. A. Chauvet's novel n-level field theory, i.e., the properties of non
      symmetry and non-locality of functional interactions, and the S-propagator
      formalism that governs the propagation of a functional interaction across the
      different levels of the structural organization of a biological system. The
      neural field equations derived from this theory allow the inclusion of multiple
      organizational levels of a biological system into the analysis by incorporating
      specific local models into a global non-local model. The main advantage of the
      method presented here is the simplification obtained by breaking down the
      physiological function into its components according to the time scales and space
      scales of operation. Moreover, the method takes into account the non-locality of
      the functional interaction, assuming it to be propagated at finite velocity in a
      continuous and hierarchical space. Finally, this approach allows the systematic
      study of physiological functions within a single theoretical framework, the
      complexity of which could be progressively increased by integrating specific
      local models as new findings become available.

PMID- 15011265
TI  - Dendritic integration in a recurrent network.
AB  - Classical nonlinear cable theory is appropriate for the unmyelinated axonal
      membrane because voltage-dependent ion channels are densly distributed, but
      dendrites with a sparse density distribution of voltage-dependent ion channels
      show "weakly" excitable membrane properties. Therefore, a model for "weakly"
      active dendrites is presented by introducing voltage-dependent ion channels at
      discrete locations along the dendritic cable. This provides an alternative
      representation for the investigation of regenerative potentials in dendrites in
      order to explore how active dendrites influence synaptic integration. As an
      example, we consider a two-neuron recurrent network of biophysically distinct
      conductance-based model neurons with discrete clusters of persistent sodium
      channels. Analytical solutions, expressed in terms of a Volterra series expansion
      for the voltage in response to a suprathreshold input current at the soma of one
      neuron, are obtained to investigate dendritic spikes, and the effect of
      backpropagation on distal dendritic spike-like potentials.

PMID- 15011266
TI  - Early integrative processes physiologically observed in dentate gyrus during an
      olfactory associative training in rat.
AB  - Modifications of synaptic efficacy in the dentate gyrus were investigated during
      an olfactory associative task. A group of rats was trained to discriminate
      between a patterned electrical stimulation of the lateral olfactory tract, used
      as an artificial cue, associated with a water reward, and a natural odor
      associated with a flash of light. Monosynaptic field potential responses evoked
      by single electrical stimuli to the lateral perforant path were recorded in the
      granular layer of the ipsilateral dentate gyrus prior to and just after each
      training session. An early increase in this response was observed just after the
      first learning session but disappeared 24 hours later. Inversely, a synaptic
      depression developed across sessions, becoming significant at the onset of a last
      (fifth) session. When a group of naive animals was pseudo-conditioned, no
      increase was observed and the synaptic depression was noted since the onset of
      the second session. In a group of rats similarly trained for only one session,
      and in which EPSPs were recorded throughout the 24 hours that followed, it was
      demonstrated that the increase lasted at least two hours, while the significant
      synaptic depression started after the fourth hour. These results are consistent
      with the early involvement of the dentate gyrus in learning the association
      between the cues and their respective rewards. These early integrative processes
      physiologically observed in dentate gyrus suggest early hippocampal processing
      before dentate gyrus reactivation via entorhinal cortex which will allow long
      term memory storage in cortical areas once the meaning of the olfactory cues is
      learned.

PMID- 15011267
TI  - Savant-like skills exposed in normal people by suppressing the left fronto
      temporal lobe.
AB  - The astonishing skills of savants have been suggested to be latent in everyone,
      but are not normally accessible without a rare form of brain impairment. We
      attempted to simulate such brain impairment in healthy people by directing low
      frequency magnetic pulses into the left fronto-temporal lobe. Significant
      stylistic changes in drawing were facilitated by the magnetic pulses in four of
      our 11 participants. Some of these "facilitated" participants also displayed
      enhanced proofreading ability. Our conclusions are derived from 11 right-handed
      male university students, eight of whom underwent placebo stimulation. We
      examined performance before, during and after exposure to the stimulation.

PMID- 15011268
TI  - Closing an open-loop control system: vestibular substitution through the tongue.
AB  - The human postural coordination mechanism is an example of a complex closed-loop
      control system based on multisensory integration [9,10,13,14]. In models of this
      process, sensory data from vestibular, visual, tactile and proprioceptive systems
      are integrated as linearly additive inputs that drive multiple sensory-motor
      loops to provide effective coordination of body movement, posture and alignment
      [5-8, 10, 11]. In the absence of normal vestibular (such as from a toxic drug
      reaction) and other inputs, unstable posture occurs. This instability may be the
      result of noise in a functionally open-loop control system [9]. Nonetheless,
      after sensory loss the brain can utilize tactile information from a sensory
      substitution system for functional compensation [1-4, 12]. Here we have
      demonstrated that head-body postural coordination can be restored by means of
      vestibular substitution using a head-mounted accelerometer and a brain-machine
      interface that employs a unique pattern of electrotactile stimulation on the
      tongue. Moreover, postural stability persists for a period of time after removing
      the vestibular substitution, after which the open-loop instability reappears.

PMID- 15011269
TI  - Age related alterations in the complexity of respiratory patterns.
AB  - The objective of this study is to investigate the relative contributions of
      maturation to the dynamic behavior of respiration during ontogeny in the neonate.
      The phrenic neurogram, an output of the respiratory network, was recorded during
      eupnea at three postnatal ages (3-7, 12-19, and 26-31 days) in decerebrate
      piglets. The inter-breath interval (IBI) time series were reconstructed from
      phrenic neurograms for each piglet and analyzed using the approximate entropy
      (ApEn) method. The mean values of the approximate entropy were high during the
      first seven days of the postnatal age [1.02 +/- 0.02 (standard error)] and
      decreased for the 12-19 days (0.67 +/- 0.008) and increased during subsequent
      maturation [the 26-31 days age group (0.92 +/- 0.015)]. The mean approximate
      entropy values for the 3-7 days age group was significantly different from those
      of the 12-19 days age groups (p < 0.05) using the nonparametric statistical test.
      The complexity values for the 3-7 days age group were slightly higher than those
      of the 26-31 days age group, but these differences were not statistically
      significant (p > 0.05). Therefore, these findings suggest that a decrease in the
      complexity values is unique to the 12-19 days age groups. This could be due to a
      reduction in the number of dendritic terminals per cell for the 12-19 days age
      groups. The results of these preliminary experiments also indicate that the
      behavior of the respiratory pattern generator in the neonate fluctuates during
      the early maturation period.

PMID- 15011270
TI  - A basal ganglia inspired model of action selection evaluated in a robotic
      survival task.
AB  - The basal ganglia system has been proposed as a possible neural substrate for
      action selection in the vertebrate brain. We describe a robotic implementation of
      a model of the basal ganglia and demonstrate the capacity of this system to
      generate adaptive switching between several acts when embedded in a robot that
      has to "survive" in a laboratory environment. A comparison between this brain
      inspired selection mechanism and classical "winner-takes-all" selection
      highlights some adaptive properties specific to the model, such as avoidance of
      dithering and energy-saving. These properties derive, in part, from the capacity
      of simulated basal ganglia-thalamo-cortical loops to generate appropriate
      "behavioral persistence".

PMID- 15011271
TI  - Applying database technology to clinical and basic research bioinformatics
      projects.
AB  - This paper describes the application of database technology to medical
      information with the goal of providing medical and clinical researchers with the
      tools necessary to plan bioinformatics projects. Commercial database management
      systems were utilized, standard database design practices were applied, a user
      interface was created, data entered, and the development of analysis tools,
      including data mining technologies is underway. Databases were constructed based
      on animal and cell culture models of diabetes and clinical data. Bioinformatics
      is a useful tool in both basic research and clinical settings. The advantages of
      relational databases and an approach to managing bioinformatics projects are
      discussed.

PMID- 15011273
TI  - Estimating distributed coding efficiency in orthogonal models of facial
      processing.
AB  - Orthogonal facial processing models attempt to mimic the local decomposition
      performed in the visual cortex by simple cell receptive fields. The purpose of
      this study was to investigate how the neurophysiological validity of orthogonal
      models of facial processing could be improved by implementing a "whitening"
      filter, based on current knowledge of similar filtering that occurs in the
      retina. By using a metric known as the "distributed coding efficiency index"
      (DCE), this study demonstrates that an orthogonal facial processing model
      significantly increased coding efficiency when a low-pass, zero-phase whitening
      filter was applied. The extent to which orthogonal decomposition of filtered data
      represents a realistic V1 model is discussed.

PMID- 15011272
TI  - Short-term autonomic control of cardiovascular function: a mini-review with the
      help of mathematical models.
AB  - In this work the main aspects of the short-term regulation of the cardiovascular
      system are reviewed and critically discussed, laying special emphasis on the role
      of the autonomic neural mechanisms involved, on their mutual interrelationships
      and complex integration. All these aspects are summarized with the help of
      mathematical models developed by the authors in past years. The main
      characteristics of the uncontrolled system (i.e., the heart and vessels) and of
      the efferent neural branches (sympathetic and vagal) working on it are first
      described. Then, the afferent pathways which participate in feedback mechanisms
      (baroreceptors, chemoreceptors, lung-stretch receptors, direct CNS response), and
      the feedforward mechanisms anticipating cardiovascular requirements are
      introduced, and their role discussed with reference to various cardiovascular
      perturbations (hemorrhage or posture changes, hypoxia, asphyxia, dynamic
      exercise). Analysis of physiological data via mathematical equations, and results
      of computer simulations, emphasize the great complexity, richness and variability
      of the autonomic cardiovascular control, including redundant mechanisms and
      antagonistic requirements. The use of mathematical models is essential to capture
      this richness, and to summarize apparent contradictory data into a coherent and
      comprehensive theoretical setting.

PMID- 15011274
TI  - The wave packet: an action potential for the 21st century.
AB  - Sensing and perceiving involve enormous numbers of widely distributed dendritic
      and action potentials in cortex, before, during and after stimulus arrival but
      with differing spatiotemporal patterns. Stimulus-activated receptors drive
      cortical neurons directly (olfactory) or indirectly through thalamocortical
      relays. The driven activity induces hemisphere-wide, self-organized patterns of
      neural activity called wave packets. Three levels of brain function are
      hypothesized to mediate transition from sensation and perception. Microscopic
      activity expressed by action potentials is sensory. Macroscopic activity of the
      whole forebrain expressed by behavior is perceptual. Mesoscopic activity bridges
      the gap by the formation of wave packets. They form when sensory input
      destabilizes the primary receiving areas by local state transitions. The sensory
      driven action potentials condense into mesoscopic wave packets like molecules
      forming raindrops from vapor. The condensation disks sustain 2D spatial patterns
      of phase and amplitude of carrier waves in the beta and gamma EEG. The AM
      patterns correlate not with features but with the context and value of sensory
      stimuli for the subjects, in a word, their meaning. The wave packets from all
      sensory areas are broadly transmitted through the forebrain. They induce the
      formation of macroscopic patterns that coalesce like scintillating pools over
      much and perhaps all of each hemisphere. The prediction is made for clinical
      testing that wave packets are precursor to states of awareness. They are not by
      themselves accessible to experience, as may be the macroscopic states initiated
      by global state transitions.

PMID- 15011275
TI  - Two species of gamma oscillations in the olfactory bulb: dependence on behavioral
      state and synaptic interactions.
AB  - Gamma oscillations (40-100 Hz), originally seen in the olfactory bulb (OB), have
      long been a defining characteristic of sensory coding in the olfactory system.
      This study proposes that gamma oscillations are of two types, associated with
      different behavioral features and synaptic origins within the OB. Local field
      potentials were recorded from rat and mouse OBs during various behavioral periods
      (immobility, alert motionlessness, exploration and odor discrimination). High
      frequency gamma activity (65-100 Hz) is shown to be correlated with the sniff
      cycle, initiated at the peak of inhalation and is called type 1 gamma. It is
      prominent during exploratory behavior, but also present during resting and
      trained odor discrimination. Low frequency gamma activity (35-65 Hz), called type
      2 gamma, is not strongly correlated with the sniff cycle, is inhibited by the
      sniff onset and is prominent during alert immobility. Rest and alert immobility
      are characterized by alternating type 1 and type 2 gamma rhythms, while
      exploratory sniffing and odor discrimination show a dramatic decrease in type 2
      gamma with a broadband increase in the power of type 1 gamma. Periods of alert
      immobility prior to odor discrimination in trained animals show dominance of type
      2 gamma, with episodes lasting up to 0.5 second. Data from mice with selective
      deletion of granule cell inhibition in the OB show a selective loss of type 2
      gamma with type 1 gamma dramatically enhanced during exploratory behavior,
      suggesting that mutual inhibition between granule cells or centrifugal inhibitory
      input drives type 2 gamma, and that the excitatory-inhibitory connections between
      mitral and granule cells likely drive type 1 gamma. Gamma activity is not a
      single type of oscillation, and the largest amplitude gamma bursts are often
      those associated with an attentive cognitive state rather than odor sniffing.

PMID- 15011276
TI  - The global effects of stroke on the human electroencephalogram.
AB  - The scaling properties of the fluctuations of EEG time series are used in an
      investigation of acute stroke in humans. We use detrended fluctuation analysis to
      characterize the fluctuations in 10-second time series in terms of two
      dimensionless scaling exponents. The statistics of these scaling exponents across
      129 scalp sites define measures which may be used to distinguish normal subjects
      from those with acute cerebral ischemia. By their nature, these statistics
      emphasize the global properties of EEG dynamics. Simulation of a focal anomaly
      which accurately reproduces the mean scaling exponents for stroke subjects
      contradicts the data for the variances, which we take as evidence that the effect
      of stroke on EEG is global.

PMID- 15011277
TI  - A model for emergent complex order in small neural networks.
AB  - A new neural network model is introduced in this paper. The aim of the proposed
      Sierpinski neural networks is to provide a simple and biologically plausible
      neural network architecture that produces emergent complex spatio-temporal
      patterns through the activity of the output neurons of the network and is able to
      perform computational tasks. Such networks may play an important role in the
      analysis and understanding of complex dynamic activity observed at various levels
      of biological neural systems. The proposed Sierpinski neural networks are
      described in detail and their functioning is analyzed. We discuss about emerging
      neural activity patterns and their interpretations, neuro-computation with such
      emerging activity patterns, and also possible implications for computational
      neuroscience.

PMID- 15011278
TI  - Dimension change, coarse grained coding and pattern recognition in spatio
      temporal nonlinear systems.
AB  - Several research programs employing spatio-temporal recurrent dynamics and
      changes in dimensionality have extended the dialog on neural computation and
      coding beyond classical frameworks such as feed forward and attractor neural
      networks and feature detectors. Some have emphasized spiking networks, while
      others emphasize oscillations and synchronization as the locus of computation and
      coding. In this paper, the formalism of locally connected homogeneous coupled map
      lattices is described. Its deployment in an extended version of the dynamical
      recognizer framework is described, and is compared with density coding,
      computational mechanics, and liquid state machine frameworks for neural
      computation. A population coding strategy based on coarse graining the continuous
      valued distribution of all sites in the lattice is developed and examined as a
      form of dimension reduction. Results on recognition of 3-D objects are reported.
      In order to better understand the dynamics supporting recognition, measures
      suggested by these other research programs and computational frameworks were
      examined. Dynamics trajectories from object recognition trials were examined for
      correlation with recognition rates and measures of the distance of the
      representation space statistics between the target objects and noise initial
      conditions, and the intrinsic separation between different objects in the set to
      be classified were performed. These results raise questions about the efficacy of
      density coding as an explanation for the results, and on the validity of recent
      criticisms that chaotic systems cannot satisfy separation requirements required
      for real time computation.

PMID- 15011279
TI  - On the formation of persistent states in neuronal network models of feature
      selectivity.
AB  - We study the existence and stability of localized activity states in neuronal
      network models of feature selectivity with either a ring or spherical topology.
      We find that the neural field has mono-stable, bi-stable, and tri-stable regimes
      depending on the parameters of the weighting function. In the case of homogeneous
      inputs, these localized activity states are marginally stable with respect to
      rotations. The response of a stable equilibrium to an inhomogeneous input is also
      determined.

PMID- 15011280
TI  - Basic principles of the KIV model and its application to the navigation problem.
AB  - EEG measurements indicate the presence of common-mode, coherent oscillations
      shared by multiple cortical areas. In previous studies the KIII model has been
      introduced, which interprets the experimental observations as nonlinear,
      spatially distributed dynamical oscillations of locally coupled neural
      populations. KIII can account for the fast and robust classification and pattern
      recognition in sensory cortices. In order to describe selection of action,
      planning, and spatial orientation functions, in this paper we expand KIII into
      the KIV model. KIV approximates the operation of the corticostriatal-hippocampal
      system. KIV consists of three KI, eight KII and three KIII components, including
      sensory and cortical systems, as well as the hippocampus, amygdala, and the
      septum. KIV implements various types of dynamic neural activities. The neural
      activity patterns determine the emergence of global spatial encoding to implement
      the orientation function of a simulated animal. Our results indicate the
      mechanisms, which we believe support the generation of cognitive maps in the
      hippocampus based on the sensory input-based destabilization of cortical spatio
      temporal patterns. In this paper, we describe the conceptual design of the KIV
      model. We outline the biological background and motivation of the basic
      principles that are applied to design the KIV computational model. We use the KIV
      model to explain how the hippocampal neural circuitry functions are constructed
      and controlled by the corticostriatal-hippocampal loops, supplemented with
      specific subcortical units. In the second part, we implement these principles
      using the example of the hippocampal formation as a KIII unit. We demonstrate the
      learning and navigation principles using the Evolving Multi-module Mobile Agent
      (EMMA) in 2D software environment.

PMID- 15011281
TI  - Neuroinformatics: the integration of shared databases and tools towards
      integrative neuroscience.
AB  - There is significant interest amongst neuroscientists in sharing neuroscience
      data and analytical tools. The exchange of neuroscience data and tools between
      groups affords the opportunity to differently re-analyze previously collected
      data, encourage new neuroscience interpretations and foster otherwise uninitiated
      collaborations, and provide a framework for the further development of
      theoretically based models of brain function. Data sharing will ultimately reduce
      experimental and analytical error. Many small Internet accessible database
      initiatives have been developed and specialized analytical software and modeling
      tools are distributed within different fields of neuroscience. However, in
      addition large-scale international collaborations are required which involve new
      mechanisms of coordination and funding. Provided sufficient government support is
      given to such international initiatives, sharing of neuroscience data and tools
      can play a pivotal role in human brain research and lead to innovations in
      neuroscience, informatics and treatment of brain disorders. These innovations
      will enable application of theoretical modeling techniques to enhance our
      understanding of the integrative aspects of neuroscience. This article, authored
      by a multinational working group on neuroinformatics established by the
      Organization for Economic Co-operation and Development (OECD), articulates some
      of the challenges and lessons learned to date in efforts to achieve international
      collaborative neuroscience.

PMID- 15011282
TI  - Controller-regulator model of the central nervous system.
AB  - In the central nervous system, activities of numerous neurons are integrated to
      constitute a number of major functional blocks, each characterized by unique
      structural and functional features. Five controller systems are centers of
      reflexes, compound movements and innate behaviors in the brainstem and spinal
      cord and those of the sensory/motor and executive/cognitive functions in the
      cerebral neocortex. Four regulator systems are the sleep-wakefulness centers in
      the brainstem, cerebellum, basal ganglia and limbic system. This article
      describes characteristic features of these nine systems based on current
      knowledge of neuroscience, and attempts to account for several important aspects
      of the central nervous system (hierarchy, top-down operation, internal model and
      will) by compounding these component functions.

PMID- 15011283
TI  - Towards an integrative theory of cognition.
AB  - A framework is outlined for connecting brain imaging activity with the underlying
      biophysical properties of neural networks, and their mechanisms of action and
      organizing principles. The main thrust of the framework is a dynamic theory of
      semantics based on functional integration of biophysical neural networks. It
      asserts that higher-brain function arises from both synaptic and extrasynaptic
      integration in the neuropil where information on environmental changes are
      represented dynamically through a discourse of semantics. Consequently,
      integrative neural modeling is shown to be an important methodology for analyzing
      the response activities of functional imaging studies in elucidating the
      relationship between brain and structure, function and behavior.

PMID- 15011284
TI  - On the mathematical integration of the nervous tissue based on the S-propagator
      formalism: II. Numerical simulations for molecular-dependent activity.
AB  - In a previous article (G. A. Chauvet, 2002), presenting a theoretical approach
      for integrating physiological functions in nervous tissue, we showed that a
      specific hierarchical representation, incorporating the novel concepts of non
      symmetry and non-locality, and an appropriate formalism (the S-propagator
      formalism) could provide a good description of a living system in general, and
      the nervous system in particular. We now show that, in the framework of this
      theory, in spite of the complexity inherent to nervous tissue and the great
      number of elementary mechanisms involved, the numerical resolution of the global
      non-local system allows us to envisage simulations that would otherwise be
      impossible to realize. Here, the study is limited to one physiological function,
      i.e., the spatiotemporal variation of membrane potential in neuronal tissue. We
      demonstrate that the role of the kinetic constants at the molecular level is in
      agreement with the observed activity of the neuronal network. The method also
      reveals the critical role of the maximum density of synapses along the dendritic
      tree in the behavior of the network. This illustrates the great advantage of the
      theoretical approach in studying separately any other complementary coupled
      function without having to modify the computational methods used here. The
      application of this method to the spatiotemporal variation of synaptic efficacy,
      which is the basis of the learning and memory function, will be treated in a
      forthcoming paper.

PMID- 15011285
TI  - Investigating shape and function relationship in retinal ganglion cells.
AB  - This article addresses the investigation of the relationship between neural shape
      and function in cat retinal ganglion cells in terms of representative
      morphological features. More specifically, a series of geometrical measures is
      extracted from two-dimensional images of these cells, and pattern recognition
      methods are applied in order to quantify the differentiation between the two
      classes (i.e., alpha, beta). The morphological measures cover several of the more
      meaningful geometrical features of neuronal cells, including: (a) the
      distribution of angles along the cell contours considering several smoothing
      degrees; (b) the overall interaction between the cell arborization and the
      surrounding space, quantified in terms of the multiscale fractal dimension; and
      (c) the distribution of width and extent of the dendritic processes. Several
      combinations of such morphological measures are assessed with respect to the
      separability of the classes. The obtained results indicate that the methods based
      on statistic relation between segment length and segment diameter, and the method
      of multiscale angle entropy not only successfully encapsulated a large amount of
      experimental data into relatively compact patterns but also marked off various
      ganglion cells into befit groups. On the other hand, the method of neuron
      classification based on fractal dimension resulted relatively less effective for
      class separation.

PMID- 15011286
TI  - Neuronal integrative analysis of the "Dumbbell" model for passive neurons.
AB  - We analyze the so called "Dumbbell" model of Jackson (J. Neurophysiol. 69 (1993)
      pp. 464) for a single neuron consisting of a patch-clamped cell body attached to
      dendritic cable of finite length terminating in an oblique derivative ("natural
      termination") boundary condition representing a dendritic swelling or a natural
      ending sealed by a continuous surface of the cell membrane. The model is solved
      analytically via the Green's function method. Large and small time asymptotic
      behavior of the membrane potential is developed when there is a somatic voltage
      clamp imposed. We discuss the difference in the voltage distribution if a sealed
      end (Neumann) termination is used instead of the natural termination boundary
      condition. If the access resistance is large the differences between the
      potentials corresponding to the two boundary conditions are small at the soma,
      but can vary significantly near the dendritic termination. This discrepancy is
      amplified at the soma if there is a synaptic stimulus introduced between the soma
      and dendritic tip.

PMID- 15011287
TI  - MGMA is your advocate.

PMID- 15011288
TI  - What counts. Facts, figures, findings.

PMID- 15011289
TI  - What do you do to help staff improve performance?

PMID- 15011290
TI  - Terminated! A medical group CEO's tale of dismissal.

PMID- 15011291
TI  - President proposes budget changes affecting group practice.

PMID- 15011293
TI  - Streamlining health plan processes. How one practice embraced Web-based
      connectivity.

PMID- 15011292
TI  - You get what you pay for.

PMID- 15011294
TI  - 'Doctor, you have mail'.

PMID- 15011295
TI  - Them ol' retention blues may be culture shock.

PMID- 15011296
TI  - Talking trash. Options for the storage and disposal of medical records.

PMID- 15011297
TI  - How a hippo came to work in an Alaska medical practice. An innovative approach to
      HIPAA compliance.

PMID- 15011298
TI  - Keep it simple, stupid. Administrative complexity raises costs, frustrates
      patients and hampers care.
AB  - The administrative complexity of the U.S. health care system places an enormous
      wedge between our scientific capability and our performance in serving people
      promptly, affordably and inclusively. Those adverse effects have eroded public
      trust in health care and threaten the availability of physicians and other health
      workers to provide care for a growing and aging population. The author details
      the problem--and offers a solution.

PMID- 15011299
TI  - Big problem, many people, one goal. Improving patient financial services
      performance.
AB  - A multispecialty organization, faced with growing patient complaints about its
      billing services, developed a large-scale plan to make the billing process more
      effective and efficient--a service recovery program. Strong organizational
      support, leadership commitment and vision, thorough planning and follow-through,
      and dedicated staff drove the project to surpass expectations.

PMID- 15011300
TI  - Know when to hold 'em, fold 'em. A tool to project expected provider pay from
      contracts.
AB  - The authors present a method to approximate costs of multiple individual
      practices. The formula approximates costs, builds in an acceptable profit margin
      and encourages productivity. In addition to developing a rational, analytic
      approach to pricing, they describe how they convinced the organization's
      physicians that its managers negotiated fair fees for them and that they would
      maintain their incomes if the organization achieved a predetermined level of
      fees.

PMID- 15011301
TI  - [Intraocular lymphoma--a clinical study of 14 patients with non-Hodgkin's
      lymphoma].
AB  - AIM: To evaluate the course of clinical picture of intraocular lymphoma,
      possibilities of examination of this disease and the association with general
      symptoms of the non-Hodgkin lymphoma (NHL) in patients with manifestations of
      uveitis. PATIENTS AND METHODS: A retrospective study in 14 patients followed in
      the period of 1996-2001 in the Center for Diagnostics and Therapy of Uveitis,
      Ocular Clinic of General Faculty Hospital and 1st Medical Faculty, Charles
      University in Prague. RESULTS: The group included 7 women and 7 men at the
      average age of 57.3 years (18-82) with clinical picture of uveitis. The time
      period from the first symptoms to the diagnosis of NHL was 5-38 months (mean,
      14.6 month). In two patients the diagnosis of systemic NHL preceded ocular
      symptoms, in four other patients the diagnosis of systemic or central nervous
      system NHL (CNS NHL) was established during ocular manifestations of uveitis.
      Intraocular lymphoma was the only first manifestation of CNS NHL in six patients
      for the period of 9-34 months (mean, 15.2). Two patients have been so far
      affected by primary intraocular lymphoma (PIL) for 8 and 14 months respectively,
      and presently do not display any signs of systemic or CNS NHL. Clinical signs of
      intraocular inflammation of both eyes were encountered in 71.4% of patients.
      Vitritis (85.7%) and tumor infiltration of retina (65.3%) were the most frequent
      manifestations of NHL. Intraocular NHL was diagnosed on the basis of cytological
      examination of samples of intraocular fluids in 8 patients (57.1%). In four
      patients radiotherapy was applied onto 5 eyes and in 5 patients radiotherapy of
      CNS was used. Nine patients were treated with chemotherapy. 50% of patients died
      until the end of 2001, the survival from the establishment of diagnosis was 20.6
      months on the average. CONCLUSIONS: Intraocular lymphoma should be considered as
      the eye and life-threatening disease. Cytological examination of intraocular
      fluids in patients with uveitis who do not respond to the therapy with steroids
      in the usual way may give more precision and shorten the establishment of
      diagnosis in this masquerade syndrome. Early diagnosis and therapy may improve
      the prognosis of NHL.

PMID- 15011302
TI  - [Thygeson's keratitis--clinical characteristics and therapy].
AB  - PURPOSE: The evaluation of clinical manifestations and therapeutical modalities
      Thygeson's keratitis (Thygeson's superficial punctate keratitis-TSPK) in a group
      of patients with long follow-up in the Cornea and Immunology Clinic of the
      Department of Ophthalmology, General Teching Hospital, Charles University in
      Prague. PATIENTS AND METHODS: The group of 7 patients (13 eyes) at the mean age
      of 20.7 years (9-39) with clinical diagnosis of TSPK was evaluated
      retrospectively. The course of the disease, symptoms and signs of the disease,
      efficacy of the therapy and primary established diagnosis were evaluated.
      RESULTS: The average onset of the disease was 12.5 years (6-27) and the average
      duration was 6 years (2-10). TSPK was bilateral in six patients, while unilateral
      the disease was only in one patient. The clinical picture was characterized by
      recurrent episodes of photophobia, tearing and burning and foreign body sensation
      in the eyes. The examination revealed whitish fine granular asterisk-form or
      dendriform intraepithelial opacities, sometimes slightly above the niveau of the
      surrounding epithelium. In the acute phase the corneal epithelium above the
      lesions was disrupted. Subjective symptoms and sometime also the objective
      findings diminished after local corticosteroids administration. The most common
      primary diagnoses the TSPK patients were treated for herpetic keratitis.
      CONCLUSION: TSPK is a rare, relapsing corneal disease with the onset mostly in
      the first and third decade of life. TSPK is mostly bilateral, but may be also
      unilateral and findings are asymmetrical in almost all cases. Relapses frequently
      occur in connection with physical or psychological stress. Concerning the
      permanent damage to the cornea and potential to decrease visual acuity TSPK can
      be considered as a benign and during several years self-limited disease.
      Subjective symptoms however may significantly deteriorate patient's quality of
      life. Local treatment with corticosteroids diminishes subjective symptoms, number
      and duration of relapses but does not cure the disease. The disease is often
      misdiagnosed and treated incorrectly.

PMID- 15011303
TI  - [Comparison of ultrasound and optic biometry with respect to ocular refraction
      after cataract surgery].
AB  - In the prospective study of 56 patients with cataract (67 eyes) the authors
      compared axial length biometry) regarding to postoperative refraction of the
      eyes. Dioptric power of the intraocular lens (IOL) was determined by SRK II.
      formula. The difference between predicted and actual postoperative refraction in
      the spherical equivalent were compared 3 months postoperatively. Axial length
      measured by ultrasound differed significantly from the axial length measured by
      optical biometry (p = 0.016). Dioptric power of IOL calculated according to the
      axial length measured by ultrasound was significantly different from the dioptric
      power of IOL calculated according to the axial length measured by optical
      biometry (p = 0.003). The difference between predicted and actual postoperative
      refraction was not statistically significant (p = 0.384) even if we considered
      both type of measurement. In conclusion, we found partial coherence
      interferometry was an accurate and reproducible method for measurement of axial
      length of the eye before cataract surgery. In the cases of advanced dense
      cataracts backup of ultrasonic biometry is still necessary.

PMID- 15011304
TI  - [Implantation of multifocal intraocular lenses].
AB  - The authors refer to the first experience in implantation of multifocal
      intraocular lens (MIOL) AMO ARRAY (model SA 40 N) produced by Allergan to a group
      of 35 patients (69 eyes). The proportion of men in the group was 42.9%, women
      being 57.1%. The mean age of the group was 50.9 +/- 4.3 year, range 36-71 years.
      The implantation of this type of intraocular lens was made due to a refractory
      intervention on a clear lens in 84.0% eyes and operation on cataract in 16.0%.
      The study was aimed at evaluation of the results of visual acuity for short and
      long distances, resulting refraction after the operation, the occurrence of side
      visual phenomena and their tolerance by the patient, necessary supplementary
      eyeglass correction especially in patients after refraction lensectomy.
      Uncorrected visual acuity for long distances 0.7 or better was in 75.9% of
      patients. Sixty one % of patients with MIOL in both eyes do not require glasses
      for vision into short distances (No 1-3).

PMID- 15011306
TI  - [Argon laser photocoagulation in the therapy of the wet form of age-related
      macular degeneration].
AB  - The authors evaluate the results of argon laser therapy of extrafoveal and
      juxtafoveal subretinal neovascular membranes in the wet form of age-related
      macular degeneration. Their experience is evaluated in the group of 24 eyes of 23
      patients during the period of observation lasting from 6 to 42 months. It became
      obvious that in the group of 24 eyes with extrafoveal and juxtafoveal subretinal
      neovascular membrane the laser photocoagulation cured up the condition in 17 eyes
      (71%), whereas the therapy failed in 7 eyes (29%). Vision improved in 7 eyes
      (29%), retained stabilized in 10 eyes (42%), but deteriorated in 7 eyes (29%).
      Among 11 eyes with extrafoveal subretinal neovascular membrane the authors
      reached improvement in 10 eyes (90.9%), the therapy failed with one eye (9.1%),
      the vision improved in 6 eyes (55%), remained stabilized in 4 eyes (36%), but
      deteriorated in one eye (9%). In 13 eyes with juxtafoveal subretinal neovascular
      membrane 7 eyes were cured up (54%), the therapy failed in 6 eyes (46%), vision
      improved in one eye (8%), remained stabilized in 6 eyes (46%), but deteriorated
      in 6 eyes (46%). Based on the results obtained it has become obvious that laser
      photocoagulation is a useful method for the therapy of extrafoveal and
      juxtafoveal subretinal nasovascular membranes in te age-related macular
      degeneration. Better prognosis has been shown in the extrafoveal subretinal
      neovascular membrane.

PMID- 15011305
TI  - [Results of long term treatment of essential blepharospasm and facial hemispasm
      with botulinum toxin A].
AB  - Botulotoxin A (BT) was administered to 51 patients (40 patients with essential
      blepharospasm, 11 patients with facial hemispasm) 299 times since December 1993
      till January 2002. Total doses of 20-48 U of the preparation BOTOX (Allergan
      Inc.) were administered bilaterally in essential blepharospasm, doses of 12-24 U
      were administered unilaterally in facial hemispasm. The mean duration of
      therapeutic effect evaluated by the patient was 12.2 weeks (3-28 weeks) in the
      blepharospasm group and 13.8 weeks (7-35 weeks) in the hemispasm group. No
      general side effects were noted. Local complications in the blepharospasm group
      were observed in 8.83% (ptosis in 5.62%) and those in the facial hemispasm in
      8.16% (ptosis in 2.04%) from the total number of BT administration in the
      respective groups. The therapeutic effect during the long-term administration was
      decreasing and required increasing doses of BT by more than 10%, as observed in 9
      patients with essential blepharospasm (22.5%). The mean increase of BT dose
      required to maintain sufficient therapeutic effect was by 32% (14-66%). Two
      patients with the longest 8-year period of observation have not required
      increasing dosages above 16 U unilaterally over the last 5 years. The treatment
      with BT-A exerted the same effects in most cases even during long-term therapy
      lasting several years. The need to increase the doses of the administered BT was
      more frequent during the first two years of the treatment. Locally administered
      botulotoxin A is a safe and efficient remedy for the therapy of essential
      blepharospasm and facial hemispasm, the efficiency being unchanged in more than
      80% of patients.

PMID- 15011307
TI  - [Photorefractive keratectomy in hypermetropia].
AB  - AIM: To evaluate the results in patients with hypermetropia having undergone
      photoreactive keratectomy (PRK). GROUP AND METHODS: The authors present a
      retrospective analysis of the results in 40 eyes operated on PRK in the period of
      September 1997 to November 2002 at the Eye Clinic of the Faculty Hospital in
      Hradec Kralove. The mean preoperation spherical refraction was 2.90 +/- 0.98
      dioptry (D), the mean astigmatism being -0.82 +/- 0.78 D, visual uncorrected
      visual acuity (NZO) 0.37 +/- 0.37, the mean corrected visual acuity (KZO) 1.28 +/
      0.27). RESULTS: One year after the operation on 31 eyes, the resulting mean
      spherical refraction was 0.76 +/- 1.10 D, the mean astigmatism being -1.01 +/-
      0.80 D, NZO 0.77 +/- 0.18, KZO 0.99 +/- 0.21, NZO 6/12 and better was detected in
      94% of surgically treated eyes. CONCLUSION: The PRK method has been found
      sufficiently effective for the correction of low and medium hypermetropia.

PMID- 15011308
TI  - [Topical H1 antihistaminics in the therapy of acute conjunctival allergic
      reactions].
AB  - AIM: To determine, whether the immediately originated allergic reaction of
      conjunctivas may be treated with local H1 antihistaminic drugs in a monotherapy
      (Allergodil gtt, Emadine gtt). GROUP AND METHODS: The group included 30 patients
      at the age of 17 to 40 years at the mean age of 33.2 years, where chemosis and
      hyperemia of bulbar conjunctiva originated suddenly as well as edema of eyelids.
      The reported subjective symptoms were itching, burning sensation in the eyes,
      lacrimation, and the feeling of pressure under the eyelid. Local treatment with
      azelastin (Allergodil gtt. oph., Pliva), was applied in 15 patients, the other 15
      patients were treated locally with emedastin (Emadine gtt. oph., Alcon) at the
      dose of one drop twice daily into the conjunctival sac of both eyes. The time of
      onset of the therapeutic effect and the disappearance of subjective symptoms and
      objective signs were observed. RESULTS: The disappearance of subjective symptoms
      after the start of therapy developed within 20 minutes after Allergodil gtt and
      within 5 minutes after Emadin. Subjective complaints disappeared in the range of
      86-100% after Allergodil gtt and in the range of 90-100% after Emadin gtt. A
      substantial diminution or even complete disappearance of objective symptoms
      developed in 74-80% cases after the treatment with Allergodil gtt and in 80-87%
      subjects after Emadin gtt. CONCLUSION: The investigated local H1 antihistaminic
      drugs proved to be effective in monotherapy of acute phase of allergic
      conjunctivitis. The drugs influence subjective complaints faster and more
      efficiently than the objective signs. The therapy of objective manifestations
      requires longer period of time for the effect to develop.

PMID- 15011309
TI  - [Jaroslav Jezek and his eyes. 25 September 1906--1 January 1942].

PMID- 15011310
TI  - [Simple solutions often remain long undiscovered...].

PMID- 15011311
TI  - [Definition and diagnostic criteria for vascular dementia].

PMID- 15011312
TI  - [Epidemiology of vascular dementia].

PMID- 15011313
TI  - [Vascular dementia--sign, symptoms and laboratory findings].

PMID- 15011314
TI  - [Vascular dementia--a diagnosis and diacrisis of similar disorders].

PMID- 15011315
TI  - [Vascular dementia: classification and neuropathology].

PMID- 15011317
TI  - [Alzheimer's disease: concept and diagnostic criteria].

PMID- 15011316
TI  - [Treatment of vascular dementia].

PMID- 15011318
TI  - [Genetic risk factors for Alzheimer's disease].

PMID- 15011319
TI  - [Life environmental factors in sporadic Alzheimer's disease].

PMID- 15011320
TI  - [Vascular factor of Alzheimer disease].

PMID- 15011321
TI  - [Clinical aspects of Alzheimer's disease].

PMID- 15011322
TI  - [Alzheimer disease: criteria and differential diagnosis].

PMID- 15011323
TI  - [Non-pharmacological therapy for Alzheimer's disease].

PMID- 15011324
TI  - [Drugs for the treatment of Alzheimer's disease].

PMID- 15011326
TI  - [Familial Alzheimer's disease by beta-amyloid protein precursor (beta APP)
      mutations].

PMID- 15011325
TI  - [Prognosis in Alzheimer's disease].

PMID- 15011327
TI  - [Alzheimer's disease due to presenilin mutations].

PMID- 15011328
TI  - [Parkinson's disease, familial Parkinson's disease].

PMID- 15011329
TI  - [Huntington disease].

PMID- 15011330
TI  - [Progressive supranuclear palsy].

PMID- 15011331
TI  - [Corticobasal degeneration].

PMID- 15011332
TI  - [Parkinsonism-dementia complex on Guam].

PMID- 15011333
TI  - [Dementia with Lewy bodies].

PMID- 15011334
TI  - [Cognitive impairment in patients with multiple system atrophy].

PMID- 15011335
TI  - [Dentatorubral-pallidoluysian atrophy].

PMID- 15011336
TI  - [Amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam].

PMID- 15011337
TI  - [Amyotrophic lateral sclerosis-parkinsonism-dementia complex of the Kii peninsula
      of Japan].

PMID- 15011338
TI  - [Frontal lobe degeneration, a clinical syndrome].

PMID- 15011339
TI  - [Pick's disease].

PMID- 15011340
TI  - [Presenile dementia with motor neuron disease].

PMID- 15011341
TI  - [Progressive non-fluent aphasia].

PMID- 15011342
TI  - [Semantic dementia].

PMID- 15011343
TI  - [Progressive prosopagnosia associated with selective right temporal lobe
      atrophy].

PMID- 15011344
TI  - [Pick complex].

PMID- 15011345
TI  - [Diffuse neurofibrillary tangles with calcification].

PMID- 15011346
TI  - [Limbic neurofibrillary tangle dementia].

PMID- 15011347
TI  - [Argyrophilic grain disease].

PMID- 15011348
TI  - [Progressive subcortical gliosis].

PMID- 15011349
TI  - [Thalamic degeneration].

PMID- 15011350
TI  - [The coexistence of vascular dementia and Alzheimer's disease].

PMID- 15011351
TI  - [General aspects of dementia due to physical illness].

PMID- 15011352
TI  - [Viral infections of the central nervous system].

PMID- 15011353
TI  - [HIV infection, acquired immunodeficiency syndrome (AIDS)].

PMID- 15011354
TI  - [Dementia due to bacterial, fungal and protozoal neuro-infections].

PMID- 15011355
TI  - [Neurosyphilis].

PMID- 15011356
TI  - [Lyme disease].

PMID- 15011357
TI  - [Whipple disease].

PMID- 15011359
TI  - [Iatrogenic Creutzfeldt-Jakob disease].

PMID- 15011358
TI  - [Creutzfeldt-Jakob disease].

PMID- 15011360
TI  - [Variant Creutzfeldt-Jakob disease].

PMID- 15011361
TI  - [Kuru].

PMID- 15011362
TI  - [Inherited Creutzfeldt-Jakob disease].

PMID- 15011363
TI  - [Gerstmann-Straussler-Scheinker syndrome].

PMID- 15011364
TI  - [Fatal familial insomnia].

PMID- 15011365
TI  - [Chronic subdural hematoma].

PMID- 15011366
TI  - [Acute epidural hematoma].

PMID- 15011367
TI  - [Dementia due to traumatic brain injury].

PMID- 15011368
TI  - [Idiopathic normal pressure hydrocephalus--regarding the guideline in progress].

PMID- 15011369
TI  - [Brain tumor].

PMID- 15011371
TI  - [Concentric sclerosis].

PMID- 15011370
TI  - [Multiple sclerosis and cognitive impairment].

PMID- 15011372
TI  - [Progressive multifocal leukoencephalopathy].

PMID- 15011373
TI  - [Disseminated necrotizing leukoencephalopathy].

PMID- 15011374
TI  - [Radiation leukoencephalopathy].

PMID- 15011375
TI  - [Acute disseminated encephalomyelitis (ADEM)].

PMID- 15011376
TI  - [Central pontine myelinolysis].

PMID- 15011377
TI  - [Binswanger's disease].

PMID- 15011378
TI  - [Cerebral autosomal dominant arteriopathy with subcortical infarcts and
      leukoencephalopathy (CADASIL)].

PMID- 15011379
TI  - [Paraneoplastic limbic encephalitis].

PMID- 15011380
TI  - [Hypopituitarism].

PMID- 15011381
TI  - [Hypothyroidism].

PMID- 15011382
TI  - [Dementia in parathyroid disease].

PMID- 15011383
TI  - [Adrenocortical hypofunction].

PMID- 15011384
TI  - [Insulinoma].

PMID- 15011385
TI  - [Vitamin B1].

PMID- 15011386
TI  - [Dementia associated with vitamin B12 deficiency].

PMID- 15011387
TI  - [Folic acid deficiency].

PMID- 15011388
TI  - [Nicotinic acid].

PMID- 15011389
TI  - [Vitamin E].

PMID- 15011390
TI  - [Metabolic disorder (diabetes mellitus, hypoglycemia, hyperglycemia, insulin
      resistance)].

PMID- 15011391
TI  - [Hypoxic encephalopathy].

PMID- 15011393
TI  - [Lysosomal diseases [metachromatic leukodystrophy (adult), Krabbe's disease
      (adult)]].

PMID- 15011392
TI  - [X-linked adrenoleukodystrophy (ALD)].

PMID- 15011395
TI  - [Dementia symptoms by electrolyte imbalance].

PMID- 15011394
TI  - [Wilson disease].

PMID- 15011396
TI  - [Hepatic encephalopathy].

PMID- 15011397
TI  - [Chronic portal-systemic encephalopathy].

PMID- 15011398
TI  - [Chronic acquired hepatocerebral degeneration].

PMID- 15011399
TI  - [Uremic encephalopathy, dialysis encephalopathy].

PMID- 15011400
TI  - [Systemic lupus erythematosus].

PMID- 15011401
TI  - [Dementia due to cerebral vasculitis].

PMID- 15011402
TI  - [Dementia due to sarcoidosis].

PMID- 15011403
TI  - [Dementia due to Behcet's disease].

PMID- 15011404
TI  - [Dementia due to celiac disease].

PMID- 15011405
TI  - [Cognitive impairment induced by sedatives/hypnotics].

PMID- 15011406
TI  - [Dementia induced by antianxiety drugs].

PMID- 15011407
TI  - [Dementia induced by antipsychotic drugs].

PMID- 15011408
TI  - [Drug induced dementia--anti-parkinsonian drugs].

PMID- 15011409
TI  - [Cognitive impairment of antiepileptic medication].

PMID- 15011410
TI  - [Preventive effects of anti-inflammatory drugs(non steroidal anti-inflammatory
      drugs) on Alzheimer disease].

PMID- 15011411
TI  - [Delirium induced by antimicrobial agents].

PMID- 15011412
TI  - [Dementia induced by antineoplastic agents].

PMID- 15011413
TI  - [Dementia induced by cardiokinetic and anti-hypertensive drugs].

PMID- 15011414
TI  - [Neuropsychiatric complications associated with digestive system agents].

PMID- 15011416
TI  - [Neuropsychiatric symptoms in carbon monoxide poisoning].

PMID- 15011415
TI  - [Neuropsychiatric disorders induced by exposure to metals].

PMID- 15011417
TI  - [Alcoholic dementia].

PMID- 15011419
TI  - [Comparison of 8 mg and 10 mg hyperbaric bupivacaine during spinal anesthesia for
      cesarean section in Japanese parturients].
AB  - BACKGROUND: Hypotension after spinal anesthesia for cesarean section is common
      and may result in serious complications despite the use of uterine displacement
      and volume preloading. Adequate amount of hyperbaric bupivacaine for Japanese
      parturients whose frames are generally smaller than those of Caucasian
      counterparts have not yet been examined. We compared the analgesic efficacy and
      the incidence of hypotension with 8 mg versus 10 mg hyperbaric bupivacaine during
      spinal anesthesia for cesarean section in Japanese parturients. METHODS: Thirty
      six parturients were randomly divided into two groups, one receiving 8 mg (n =
      19) and the other receiving 10 mg (n = 17) hyperbaric bupivacaine. Sensory block
      level and the incidence of hypotension were evaluated from the time of injection
      to delivery. Hypotension was defined as a decrease in systolic blood pressure
      below 100 mmHg and to less than 80% of the baseline value. RESULTS: 15 minutes
      after spinal injection, the difference in sensory block level was not
      significant. Ten minutes after the spinal anesthesia, in 79% of 8 mg group and in
      88% of 10 mg group, sensory block level reached T 4. Hypotension occurred in 19
      parturients (7 in 8 mg group and 12 in 10 mg group). The incidence of hypotension
      was significantly lower in 8 mg group (37%) than in 10 mg group (71%). There were
      no significant differences either in neonatal Apgar scores or umbilical blood gas
      pH. CONCLUSIONS: Injection of 8 mg hyperbaric bupivacaine is preferable than 10
      mg in spinal anesthesia for cesarean section to obtain adequate analgesic
      efficacy and to avoid maternal hypotension.

PMID- 15011418
TI  - [Effects of olprinone hydrochloride after coronary artery bypass grafting].
AB  - BACKGROUND: We have examined the effect of olprinone hydrochloride on
      hemodynamics and peripheral circulation after cardiopulmonary bypass (CPB) in 56
      patients who underwent coronary artery bypass grfting. METHODS: The subjects were
      randomly classified into 2 groups: B-group of 25 patients who received bolus plus
      continuous administration of olprinone hydrochloride and control group without
      administration of olprinone hydrochloride (C-group) of 31 patients. In the B
      group, after de-clamping of the aortic occlusion, olprinone hydrochloride 15
      micrograms.kg-1 bolus was administered and followed by continuous administration
      at 0.1 microgram.kg-1.min-1. RESULTS: We excluded six cases in C-group in whom it
      was not possible to maintain blood pressure without olprinone hydrochloride. In
      the B-group, peripheral temperature was kept significantly higher and blood
      lactic acid value was kept significantly lower until 6 hours after the operation
      compared with C-group. In the B-group, cardiac index was kept significantly
      higher for a long period of time, and dosage of concomitantly used catecholamine
      could be significantly reduced. CONCLUSIONS: Olprinone increased CI and decreased
      SVRI, and it led to easy weaning from CPB, providing excellent hemodynamics after
      CABG. These results suggest that olprinone hydrochloride 15 micrograms.kg-1 bolus
      plus 0.1 microgram.kg-1.min-1 continuous administration may be effective for
      improvement of hemodynamics and peripheral circulation after CPB.

PMID- 15011420
TI  - [The proper size of bronchial tube for pediatric differential lung ventilation
      using laryngeal mask airway].
AB  - BACKGROUND: Since the double lumen tube (DLT) for pediatric use is not
      commercially available, we have developed the method of differential lung
      ventilation using the laryngeal mask airway (LMA) and the cuffed-bronchial tube
      (BT) made with two conventional cuffed-tracheal tubes (Intermediate,
      Mallinckrodt). METHODS: The proper inner diameters (IDs) of the BT were
      determined with the following condition; the inner cross-sectional area of BT is
      less than the outer cross-section area of BT in the trachea, or equal to it. The
      proper BT lengths were derived from the equation; the distance from LMA to swivel
      connecter + tracheal distance + cuff portion length of BT tip in main bronchus
      +3.5 cm. RESULTS: The proper IDs of BT are 2 size smaller than those of proposed
      tracheal tube at the age of 5 yr or below, and 3 size smaller (max ID = 5.0 mm)
      at the ages over 6 yr. CONCLUSIONS: Our method using the BT' (ID 3 mm, length 29
      cm) with LMA size 2 could be applied to the patient aged less than 2 yr, weighing
      over 10 kg, and the non-cuffed BT (ID 2.5 mm, length 27.5 mm) through LMA size
      1.5 could be used to those weighing over 5 kg.

PMID- 15011421
TI  - [Successful anesthetic management of patients with poor ventricular function
      using the phosphodiesterase III inhibitor, olprinone, during major cardiovascular
      procedures].
AB  - We administered olprinone, a newly developed phosphodiesterase III inhibitor,
      commencing before induction of general anesthesia to patients with poor
      ventricular function during major cardiovascular procedures. Case 1 patient
      underwent off-pump CABG for acute myocardial infarction. Although he was in a
      shock state, olprinone improved the contractility of viable myocardium, increased
      the cardiac index, and decreased the pulmonary artery pressure. Case 2 patient
      underwent off-pump CABG for unstable angina. Olprinone significantly increased
      the cardiac index and the mixed venous oxygen saturation. Case 3 patient
      underwent graft replacement for rupture of a dissected descending aorta. Although
      he showed ischemic cardiomyopathy with diffuse hypokinetic left ventricle,
      olprinone drastically improved the contractility of the heart. Olprinone was very
      effective for improving ventricular dysfunction; its institution prior to
      induction of anesthesia made successful anesthetic management possible without
      resorting to a mechanical assist device like the intra-aortic balloon pump.

PMID- 15011422
TI  - [Retrospective analysis of postoperative nausea and vomiting after craniotomy].
AB  - BACKGROUND: Postoperative nausea and vomiting are important complications after
      craniotomy. METHODS: One hundred and seventy eight patients who had undergone
      brain tumor resection at Nara Medical University were retrospectively divided to
      one of two groups; with or without PONV within 24 hours postoperatively.
      Variables compared between the groups include gender, age, weight, height, site
      of surgery (supratentorial versus infratentorial craniotomy), size of brain
      tumor, type of anesthesia (inhalation versus intravenous anesthesia with nitrous
      oxide), intraoperative fentanyl dose, duration of surgery as well as anesthesia,
      and intraoperative posture. RESULTS: PONV occurred in 87 patients (49%). The
      incidence of PONV in patients undergoing infratentorial craniotomy was
      significantly higher than that in patients undergoing supratentorial craniotomy
      (75% vs 45%, P = 0.0011). There were no significant associations between PONV and
      other variables analyzed. CONCLUSIONS: These results indicate that the incidence
      of PONV after brain tumor resection is high and infratentorial surgery is a risk
      factor for PONV. Strategies for the prevention of PONV after craniotomy are
      required.

PMID- 15011423
TI  - [Anesthetic management of the surgical patients with complete left bundle branch
      block].
AB  - For last ten years twenty three cases of anesthesia were performed in twenty
      surgical patients with complete left bundle branch block (CLBBB) ranging in ages
      from 58 to 82 years. The CLBBB in these patients included 16 cases of permanent
      block, 6 cases of transient block and one case of alternative block. Two of these
      patients had no past history of heart disease, but the remaining patients had
      hypertension, ischemic heart disease, cardiomegaly, cardiac hypertrophy or
      others. Transient episodes of CLBBB were detected on the preoperative
      examination, on arrival at operating room or after the emergence from anesthesia
      at a recovery room, and some of which were provoked by elevated blood pressure or
      increased heart rate. A transient CLBBB in the patient changed to permanent CLBBB
      two years later. Complete atrioventricular (A-V) block appeared suddenly in the
      patient with alternative CLBBB four months after the surgery. Complete A-V block
      did not develop during anesthesia and surgery in our patients with CLBBB.
      Therefore we consider a routine prophylactic temporary pacemaker is not necessary
      during anesthesia and surgery in patients with asymptomatic CLBBB. However, a
      temporary pacemaker equipment should be at hand in case of complete A-V block.
      Appropriate perioperative management of circulatory system is important for the
      patients with CLBBB because most of these patients have underlying heart disease.

PMID- 15011424
TI  - [Comparison of analgesics used during balanced anesthesia on the incidence of
      PONV].
AB  - BACKGROUND: When we make reference to the quality of anesthesia, we consider
      three points, early emergence, postoperative pain relief, and postoperative
      nausea and vomiting (PONV). Among these, PONV is comparatively neglected. Many
      analgesics used during anesthesia may cause PONV. METHODS: The incidence of PONV
      was assessed in 100 surgical patients who had received balanced anesthesia.
      Anesthesia was induced with propofol, ketamine, midazolam and buprenorphine
      (Group P), or butorphanol (Group T), and vecuronium was given to facilitate
      tracheal intubation. The patients received balanced anesthesia with infusion of
      propofol, ketamine, vecuronium, and either buprenorphine (Group P) or butorphanol
      (Group T), with nitrous oxide. PONV was recorded for 24 hours postoperatively.
      RESULTS: Incidences of nausea were 27.1% in Group P and 15.8% in Group T (NS).
      Incidences of vomiting were 12.5% in Group P and 5.3% in Group T (NS). However, a
      high incidence of PONV was found in female (42.2%) vs. male (6.2%) (P < 0.01) and
      in over 25 BMI group (34.5%) vs. under 25 BMI group (15.5%) (P < 0.05).
      CONCLUSIONS: The type of analgesics used during balanced anesthesia is not
      important for development of PONV, but patient's factors, such as gender and BMI,
      are more closely associated with PONV.

PMID- 15011425
TI  - [Anesthetic management of elderly patients aged 90 years or older].
AB  - The authors experienced 55 cases of anesthetic management in 52 elderly surgical
      patients, 14 men and 38 women, aged 90 to 101 years with an average of 92.1 +/-
      2.1 years for the past ten years. Surgical procedures included 38 cases of
      orthopedic, 14 cases of general surgical and 3 cases of ophthalmic operations.
      Thirteen cases out of them were emergency. General, epidural, spinal, and local
      anesthesia were applied in 34 cases, 18 cases, 2 cases, and one case out of these
      elderly patients, respectively. These general anesthesia consisted of total
      intravenous anesthesia with propopol, fentanyl and ketamine in 27 cases,
      sevoflurane with nitrous oxide in 4 cases, isoflurane with nitrous oxide or air
      in 2 cases, and thiopental anesthesia in one case. The elderly patients had past
      history of heart disease, dementia, hypertension, cerebral infarction/hemorrhage,
      diabetes mellitus and others. Their preoperative examinations revealed anemia,
      hypoproteinemia, renal hypofunction, serum electrolytes imbalance, and others.
      Vasopessors were given to 42% of the patients during anesthesia and surgery.
      Their postoperative complications included myocardial infarction, paroxysmal
      atrial fibrillation, hypotension following anemia, transient hemiparesis,
      delirium and so on. Two patients developed myocardial infarction postoperatively
      and died thereafter. The authors suggest that appropriate anesthetic management
      for elderly patients aged 90 years or older requires proper preoperative
      evaluation, sufficient vigilance of hemodynamics with direct arterial pressure
      measurement, reliable preparation of medical agents, and awareness of impairment
      of circulatory function and others by aging.

PMID- 15011426
TI  - [Evaluation of a lockable combined spinal-epidural device for use with needle
      through-needle technique].
AB  - BACKGROUND: Recently, a new combined spinal-epidural (CSE) device has been
      introduced which allows the spinal needle to be extended a maximum of 15 mm
      beyond the Tuohy needle and locked onto the epidural needle after dural puncture.
      The aim of this study was to compare this lockable CSE device with the
      conventional CSE device, which allows the spinal needle to be extended 9 mm
      beyond the Tuohy needle, and to measure the length of the protrusion of the
      spinal needle beyond the Tuohy needle (top-to-top distance: TTD). METHODS: We
      studied sixty patients scheduled to undergo elective gynecological surgery and
      cesarean section. Patients were divided into three groups: patients in Group I (n
      = 20) using the conventional CSE device in gynecological surgery; patients in
      Group II (n = 20) using the lockable CSE device in gynecological surgery; and
      patients in Group III (n = 20) using the lockable CSE device in cesarean section.
      RESULTS: The success rate of spinal anesthesia with needle-through-needle
      technique was higher with the lockable CSE device (100%) than with the
      conventional CSE device (75%). The TTD was 7.9 +/- 1.8 (SD) cm in non-pregnant
      group (Group II) and 8.7 +/- 1.5 cm in pregnant group (Group III). This
      difference was not statistically significant. In the lockable CSE device groups
      (Group II and III), 10 patients (25%) had a TTD of 10 mm or more. CONCLUSIONS:
      The lockable CSE device improves the success rate of spinal anesthesia in needle
      through-needle CSE anesthesia.

PMID- 15011427
TI  - [Total intravenous anesthesia with propofol, ketamine, and fentanyl (PFK) for a
      patient with mitochondrial myopathy].
AB  - Anesthetic management for a patient with mitochondrial myopathy is described. A
      57 year-old-female underwent laparoscopic cholecystectomy for cholelithiasis. The
      patient had been diagnosed as having mitochondrial myopathy from muscle biopsy.
      Anesthesia was managed with total intravenous anesthesia with propofol, fentanyl,
      and ketamine. Her reaction to vecuronium bromide was within normal limits
      evaluated with a neuromuscular activity parameter, train-of-four ratio. No
      serious acidosis, hyperlactemia, hypothermia, nor prolonged recovery from the
      anesthesia was observed. As inhaled anesthetics may be contraindicated for
      mitochondrial myopathy, and nitrous oxide for laparoscopic surgery is relative
      contraindication, total intravenous anesthesia with muscle relaxant titration is
      appropriate for laparoscopic surgery for patients with mitochondrial myopathy.

PMID- 15011428
TI  - [Anesthetic management for a patient with platypnea-orthodeoxia syndrome].
AB  - We experienced anesthetic management for a patient with platypnea-orthodeoxia
      syndrome. This syndrome is relatively uncommon and accompanies dyspnea and
      hypoxemia on changing to a sitting or standing from recumbent position. A 75-year
      old man with the syndrome underwent atrial septal defect closure on
      cardiopulmonary bypass. General anesthesia was induced and maintained with
      midazolam, propofol, fentanyl and vecuronium bromide. During the induction, Spo2
      decreased suddenly from 100% to 70%, Spo2, however, recovered to 97% immediately
      after changing to Trendelenburg position. The perioperative and postoperative
      course was uneventful, except for hypoxemia during induction. Although the exact
      mechanisms of platypneaorthodeoxia remains to be solved, right-to-left shunt by
      an anatomical abnormality and by change of the atrial septum is considered one of
      the hypoxic mechanisms. We suggest that it is necessary to prevent right-to-left
      shunt and hypoxemia in anesthetic management of a patient with
      platypneaorthodeoxia syndrome.

PMID- 15011429
TI  - [A successful weaning from mechanical ventilation by diaphragmatic plication for
      unilateral diaphragmatic paralysis].
AB  - A patient with unilateral diaphragmatic paralysis (UDP) after cardiac surgery,
      commonly extubated without any troubles, encounters a serious fetal respiratory
      complication in a rare case. We had a case of a 68-year-old man under long term
      mechanical ventilation (MV) because of UDP and phrenic nerve injuries after the
      replacement of the ascending aorta. After this operation he suffered from
      mediastinal infection and needed MV for a few days. Thereafter, he was extubated
      successfully and returned to the ward, but his chest X-p showed right
      diaphragmatic elevation. Two days after returning to the ward, he developed
      dyspnea and tachypnea and received MV for two months. We decided to perform
      diaphragmatic plication (DP) because of long term MV and difficulty in
      respiratory weaning. The patient was successfully weaned from MV on the 4th
      postoperative day of the right DP. Pulmonary function test was improved
      dramatically. In a case of long term MV due to UDP, DP can be one of effective
      treatments.

PMID- 15011430
TI  - [A case of acute respiratory distress syndrome (ARDS) caused by splenic
      infarction].
AB  - Acute respiratory distress syndrome (ARDS) is the most severe lung injury caused
      by many pathologic states. We treated a patient who suffered from ARDS caused by
      splenic infarction. A 75-year-old patient had a gastric cancer with multiple lung
      and liver metastasis. During anti-cancer therapy, she developed a high fever
      (above 39 degrees C) and a chest and an abdominal CT scan revealed splenic
      infarction. Hypoxia progressed gradually and she was transferred to ICU with
      tracheal intubation. Mechanical ventilation was performed according to open lung
      strategy, but she did not recover. On ICU day 3, the bilateral infiltration
      shadow on her chest X-ray was pointed out, and she had a low central venous
      pressure. We diagnosed her ARDS. The administration of methylprednisolone was
      started according to Meduri's report. Hypoxia was improved gradually and on ICU
      day 7, she was weaned from mechanical ventilation, and extubated. On ICU day 8,
      she was returned to her ward without ventilatory support.

PMID- 15011431
TI  - [Short-term bed rest as a cause of deep vein thrombosis in a patient with a huge
      abdominal tumor].
AB  - A 43-year-old female with a huge myoma uteri was scheduled for a simple total
      hysterectomy. However, there was massive penetration of the tumor into the
      retroperitoneum, and her first operation failed because we had no advance
      information on its posterior aspect. Angiography was done to obtain this
      information. She rested on bed until the day after the first operation and
      angiography. MRI, performed again due to early growing tumor, revealed deep vein
      thrombi in the left iliac vein to the left femoral vein which the last MRI had
      not shown. Therefore, just before the second operation a temporary vena-cava
      filter was inserted, to prevent acute pulmonary thromboembolism. The operation
      was performed without incident. The filter captured some thrombi, and these were
      resolved by urokinase postoperatively. No symptomatic pulmonary thromboembolism
      was recognized during the perioperative period. The postoperative course was
      uneventful.

PMID- 15011432
TI  - [A case of ventilatory difficulty during the use of the laryngeal mask airway].
AB  - A 67-year-old male patient with chronic tympanitis was scheduled for elective
      tympanoplasty. Propofol and fentanyl were used for induction and the patient was
      ventilated with sevoflurane, oxygen and nitrous oxide for general anesthesia.
      After about 10 minutes following anesthetic induction, the lungs suddenly could
      not be ventilated through the laryngeal mask airway, and then it was impossible
      to insert an endotracheal tube. The surgery was discontinued for the safety of
      the patient, in spite of the recovery of ventilation with a facemask. It is
      suspected that the ventilatory difficulty was caused by the following reasons;
      first, the laryngeal mask airway was shifted by change of the body position,
      second, the mask tip was inserted at the inlet of the larynx because the internal
      cuff pressure had risen with nitrous oxide.

PMID- 15011433
TI  - [A sheared off and sequestered epidural catheter: a case report].
AB  - This is a report of a retained epidural catheter segment after placement of 20-G
      polyethylene catheter (Hakko Medical) through 17-G Tuohy needle and 25-G spinal
      needle (Top Company) for a patient receiving combined spinal-epidural anesthesia.
      Retained catheter fragment (approximately 10.6 cm) was removed easily with small
      incision under local anesthesia. Electron microscopic findings of the catheter
      showed that the catheter might have been traumatized by the Tuohy needle through
      which the catheter was placed or by the spinal needle for intrathecal anesthesia,
      resulting in having been sheared off.

PMID- 15011434
TI  - [New study on the history of anesthesiology--(10). Prof. K. Shimizu and the
      Foundation of Japanese Society of Anesthesiology].
AB  - In August 1950, Japanese-American Joint Conference of Medical Educators was held
      in Tokyo and Dr Meyer Saklad of Rhode Island Hospital delivered his lectures on
      anesthesia. Prof. Shimizu of the Tokyo University who had just come back from the
      United States was asked to translate Dr Saklad's lectures. Dr Hideo Yamamura was
      compulsorily asked to attend the conference on behalf of the surgeons at the
      first Department of Surgery of the Tokyo University. With this conference as a
      trigger, many surgeons developed deep interests in anesthesia, particularly
      endotracheal anesthesia. This was followed by a rapid increase in anesthetic
      papers in surgical meetings. To solve this problem, an independent society for
      anesthesiology was established in May 1st, 1954. Prof. Shimizu played a dominant
      role in the foundation of Japan Society of Anesthesiology.

PMID- 15011435
TI  - [DNA chip, expression profile, and SNP analyses applied for clinical
      gastroenterology].

PMID- 15011436
TI  - [Innate immunity and gastrointestinal diseases].

PMID- 15011437
TI  - [Acquired immunity in gastrointestinal diseases].

PMID- 15011438
TI  - [Immunological aspect of liver and liver diseases].

PMID- 15011439
TI  - [Evaluation of endoscopic sphincter of Oddi manometry in patients with
      biliopancreatic diseases].
AB  - Diagnostic ability of endoscopic sphincter of oddi manometry for 112 patients
      with biliopancreatic diseases (including 12 patients of normal) was evaluated.
      The presence of abnormal high pressure was recognized in 50% of suspected
      sphincter of oddi dysfunction (SOD). 56% of cholecystolithiasis, 67% of
      cholecystocholedocholithiasis and 50% of pancreatic stones. Many patients with
      abdominal pain of suspected SOD or stones of biliopancreatic ducts were
      considered to have possibility of the complication of papillary stenosis. It was
      thought that endoscopic sphincter of oddi manometry was a useful method of
      confirming the presence of SOD.

PMID- 15011440
TI  - [A case of intestinal spirochaetosis due to Brachyspira aalbolgi].

PMID- 15011441
TI  - [A case of Castleman disease arising from lesser sac].

PMID- 15011442
TI  - [A case of focal fatty liver with aberrant gastric venous drainage after
      gastrectomy].

PMID- 15011443
TI  - [A case of AFP producing pancreatic acinar cell carcinoma diagnosed by EUS FNA
      and treated by intraarterial injection chemotherapy].

PMID- 15011444
TI  - [A case of angiosarcoma with generalized metastasis].

PMID- 15011445
TI  - [A case of mediastinal pancreatic pseudocysts which ruptured into the pleural
      cavity and emerged pancreatic pleural effusion].

PMID- 15011446
TI  - [Stress ultrasonography].

PMID- 15011447
TI  - [Blood transfusion monitoring, quality control at the patient's beside].

PMID- 15011449
TI  - [Cardiac insufficiency and patient participation].

PMID- 15011448
TI  - [Prevention of infectious risks in a cardiology unit].

PMID- 15011450
TI  - [Dietetic management of coronary patients].

PMID- 15011451
TI  - [Teaching function and evaluation of student training].

PMID- 15011453
TI  - Case managers, utilization reviewers team for cost savings of $3.6 million.

PMID- 15011452
TI  - [William Harvey, the secret of blood].

PMID- 15011454
TI  - Type of data plotted determines which control chart to use.

PMID- 15011456
TI  - Integrated CM system will make your job easier.

PMID- 15011455
TI  - ED is hotbed for lawsuits; address risky conditions.

PMID- 15011457
TI  - [Hemorrhagic fever with renal syndrome in Croatia--still a real disease].

PMID- 15011458
TI  - [The biggest epidemic of hemorrhagic fever with renal syndrome in Croatia].
AB  - INTRODUCTION: The largest outbreak of hemorrhagic fever with renal syndrome
      (HFRS) to date occurred in Croatia in the year 2002. The epidemic started in
      winter, lasted throughout spring to summer months, ending not earlier than
      November. AIM: The aim of this study was to investigate and analyze the basic
      epidemiologic and clinical features of HFRS in Croatia by uniform and
      standardized prospective-retrospective analysis of all patients affected by the
      epidemic. PATIENTS AND METHODS: When the epidemic started, a patient
      questionnaire with questions on the basic demographic data, site of infection and
      other epidemiologic characteristics, clinical symptoms, disease severity and
      laboratory results was designed. Data on 401 patient with a clinical diagnosis of
      HFRS were collected. The etiologic diagnosis of the disease was confirmed by
      ELISA, and in some patients by indirect immunofluorescence test (IFT). The
      results were analyzed using a descriptive statistical method. RESULTS: HFRS was
      clinically diagnosed in 401 patients from all over Croatia. A total of 320
      (79.8%) cases were reported to the Epidemiology Service of the National Institute
      of Public Health. The majority of patients (n = 128) were registered in June.
      Males were three times more affected than females. Apart from its long duration,
      this epidemic was characteristic for the involvement of general population, with
      only a small number of the affected from the potential risk groups (forestry
      workers 28, soldiers 14, farmers 18). The epidemic spread almost throughout
      inland Coratia. At least 44 patients were infected in the Plitvice Lakes area, 32
      in Slunj, 27 on Sljeme, 24 in Velika, and at least 19 in the area of Kutjevo. The
      youngest patient was aged 4 and the oldest 80 years. The majority of patients
      were treated in Zagreb (University Hospital for Infectious Diseases--110, Zagreb
      University Hospital Center--3), followed by Karlovac (71 inpatients and 39
      outpatients), Pozega (n = 79), and Rijeka (n = 37). Serologic analysis (ELISA
      method) detected Puumala virus in 161 and Dobrava virus in only 17 patients. The
      disease was confirmed by immunofluorescence method in 53 patients (mostly in
      Kariovac). During the 2002 outbreak, HFRS clinically manifested mostly in a
      milder form with general symptoms and transitory renal insufficiency, while
      hemorrhages were rarely recorded. According to our disease severity score, a mild
      form of the disease was recorded in 65%, moderately severe in 28%, severe in 5%
      and extremely severe form in 2% of the patients. One patient died. Two thirds of
      the patients were hospitalized during the febrile stage of the disease. All
      patients had fever, whereas headache and pain in the lumbar region were recorded
      in more than 90% of cases, polyuria in 75%, oliguira and vomiting in
      approximately 50%, respiratory symptoms in 35%, and hemorrhages (mostly on the
      skin and mucous membranes), vision disturbances, conjunctivitis and diarrhea in
      approximately 25% of patients. ESR was elevated in 64% and CRP in 93% of
      patients. Leukocytosis was recorded in 25% and thrombocytopenia in 70% of
      patients. Increased values of urea and creatinine and signs of liver damage were
      recorded in approximately 50% of the patients. CONCLUSION: The largest outbreak
      of HFRS occurred in Croatia in 2002, with more than 400 diseased throughout
      Croatia. This epidemic confirmed our previous assumption that the whole Croatia,
      apart from its narrow coastline area and islands, is a natural focus of HFRS with
      different causative types of hantaviruses. Efforts should be made to conduct a
      comprehensive ecologic and mammologic study on hantaviruses and their biologic
      characteristics in these areas.

PMID- 15011459
TI  - [Clinical and epidemiologic characteristics of hemorrhagic fever with renal
      syndrome in patients treated at the Dr. Fran Mihaljevic Clinic for Infectious
      Diseases in Zagreb].
AB  - AIM: The aim of the study was to examine and analyze the main epidemiologic and
      clinical data of 94 patients with hemorrhagic fever with renal syndrome (HFRS)
      hospitalized at the University Hospital for Infectious Diseases in Zagreb during
      the HFRS outbreak in Croatia in 2002. PATIENTS AND METHODS: A total of 110
      patients with clinical diagnosis HFRS were treated at the University Hospital for
      Infectious Diseases in Zagreb. In 110 of HFRS suspected patients, the clinical
      diagnosis was verified serologically in 94 patients and they were included in the
      retrospective study. In 93 patients the diagnosis was confirmed by enzyme-linked
      immunosorbent assay (ELISA), and in one patient by indirect immunofluorescence
      assay (IFA). Results were analyzed by the use of descriptive statistics. RESULTS:
      Puumala (PUU) virus infection was verified in 80 (85.1%), Dobrava (DOB) infection
      in 8 (8.5%) and cross-reactive antibodies to both PUU and DOB viruses in 5 (5.3%)
      HFRS patients. In one patient who was confirmed by IFA the hantavirus serotype
      causing HFRS could not be determined. The localities of the presumed HFRS patient
      exposure to hantaviruses were mostly in the Zagreb area. Most patients were aged
      21-50 (83.0%) and male (76.6%). The majority of HFRS cases occurred between May
      and August (75.5%). A high proportion of HFRS cases were found in the general
      population from Zagreb and its surroundings (78.7%). The majority of patients
      were hospitalized in the febrile stage of the disease (70.2%). The main symptoms
      were: fever (100%), headache (88.3%) and backache (87.2%). Oliguria was recorded
      in 56.4% and, anuria in 7.5% of patients, however, only three (3.2%) patients
      required hemodialysis. Six patients developed hemorrhagic manifestations,
      especially petechiae on the skin and mucosa. One patient in the convalescent
      stage had subarachnoidal bleeding. Six patients had pathologic
      electroencephalogram (EEG) findings and two developed epileptic seizures. Lumbar
      puncture was performed in 12 patients without inflammatory changes in the
      cerebrospinal fluid. Pathologic ECG findings were recorded in 30/79 (38.0%)
      patients, primarily including mild and translent disturbances such as sinus
      tachycardia, sinus bradycardia, nonspecific alteration of the final complex and
      incomplete right bundle branch block. Conventional chest radiography revealed
      abnormal findings in 23/84 (27.4%) patients. The abnormalities consisted of
      interstitial infiltrates and/or pleural effusions and atelectasis. The patients
      were divided into 4 groups according to the disease severity: mild in 74 (78.7%),
      moderate in 15 (16.0%), severe in 4 (4.2%), and very severe in one (1.1%)
      patient. The latter developed multiorgan failure and died. CONCLUSION: The
      largest outbreak of HFRS to date was recorded in Croatia in 2002. Ninety-four
      patients with clinical and serologically verified HFRS were treated at the Dr.
      Fran Mihaljevic University Hospital for Infectious Disease, Zagreb. The majority
      of patients were hospitalized between May and August. Most patients had mild form
      of the disease primarily caused by PUU virus.

PMID- 15011460
TI  - [Grading the severity of disease in patients with Puumala or Dobrava virus
      infections from 1995 to 2000 in Croatia].
AB  - AIM: The aim of our study was to evaluate the proposed Croatian scale for grading
      the disease severity in patients with hemorrhagic fever with renal syndrome
      (HFRS). The aim was also to determine whether the infection with Dobrava virus
      (DOBV) in Croatia was associated with a more severe illness than the infection
      with Puumala virus (PUUV). PATIENTS AND METHODS: To evaluate the scale, case
      records of 62 HFRS patients hospitalized at the University Hospital for
      Infectious Diseases in Zagreb from 1995 till 2000 were reviewed. ELISA IgM and
      IgG tests were used for the detection of specific IgM and IgG antibodies to PUUV
      or DOBV. DISCUSSION: HFRS caused by hantaviruses is a zoonotic disease spread
      worldwide, posing a major public health problem of global dimensions. Recent
      epidemiologic studies show that almost all parts of Croatia are endemic regions
      for two hantaviruses, Puumala and Dobrava. The disease severity ranges from
      subclinical infection to severe illness with fatal outcome. Clinical picture is
      predominated by fever, myalgia, vomiting, hemorrhagic manifestation, visual
      impairment and kidney affection. There is still a lack of knowledge concerning
      all the parameters involved in the disease severity. Besides the type of virus
      and genetic material, host genes are also associated with the variable clinical
      course. HLA alleles B8, DR3, and DQ2 are strongly associated with severe outcome
      of PUUV infection, white HLA B27 allele is associated with a mild course. Whether
      similar genetic factors also operate in DOBV infection remains to be determined.
      Recently, a Croatian scale for grading the disease severity was proposed. The
      disease severity is graded by a scoring system (points attributed to specific
      clinical symptoms and laboratory findings) as 1--mild, 2--moderate, 3--severe,
      and 4--very severe. We found 60% of HFRS patients to be infected with PUUV and
      40% with DOBV. In our study, 65% of patients infected with PUUV had mild, and 24%
      moderate disease. Severe and very severe disease was recorded in 11% of PUUV
      infected patients. In contrast, only 44% of patients infected with DOBV had mild
      disease, whereas 40% of patients showed a moderate clinical picture. Severe and
      very severe clinical picture was recorded in 16% of patients with DOBV infection.
      Statistical analysis showed a significant number of pa (p < 0.01) with PUUV
      infection to have mild disease, whereas a significant number of HFRS patients
      infected with DOBV had moderate (p < 0.01) and severe or very severe (p < 0.01)
      disease. CONCLUSION: Our results clearly indicate that in Croatia DOBV infection
      is associated with a more severe disease than PUUV infection. However, we
      confirmed previous findings that even PUUV infection could lead to a severe
      disease. Our initial experience in the evaluation of the proposed grading scale
      for disease severity demonstrated the proposed Croatian scale to be a useful tool
      in grading disease severity in patients infected with PUUV or DOBV. Moreover, the
      proposed scale may also prove highly useful for the prognostic purpose.

PMID- 15011461
TI  - [An epidemic of hemorrhagic fever with renal syndrome at the therapeutic
      community for treatment of psychoactive drug dependence in Ivanovac].
AB  - GOAL: The outbreak of hemorrhagic fever with renal syndrome (HFRS) at the
      Ivanovac Drug Therapeutic Community near Nova Gradiska was analyzed. The major
      epidemiologic, clinical and serologic findings are presented. PATIENTS AND
      METHODS: During the HFRS outbreak, serum samples were obtained from 31 men from
      the Community and analyzed by ELISA IgM and IgG tests for Puumala (PUUV) and
      Dobrava (DOBV) viruses. The main epidemiologic and clinical data were analyzed.
      RESULTS: At the beginning of March 2002, a-30-year-old male from the Community
      developed severe clinical picture of HFRS with fulminant systemic hemorrhage,
      acute renal failure and consecutive death. IgM antibodies to DOBV were detected.
      HFRS was serologically confirmed in 15 subjects in total. All others were
      infected with PUUV. During the mild and dry winter, the Community members cut
      bushes, collected trash, branches and dry leaves near the beech-wood forest
      border to prepare that part of the field as a garden. They observed a number of
      rodents, their nests and holes. Most of the patients developed mild to moderate
      clinical picture with fever, headache, backache, myalgia, abdominal pain, melena,
      oliguria, polyuria, epistaxis, and conjunctival injection. Hepatitis B (HBV)
      and/or C (HCV) infection was recorded in 58.1% of Community members.
      Interestingly, 86.7% of the HFRS patients were HBV and/or HCV positive.
      CONCLUSIONS: This is the first HFRS outbreak described among drug addicts in
      Europe, mostly caused by PUUV. Further studies are needed to identify additional
      risk factors that may contribute to hantavirus infection among drug addicts in
      HFRS endemic regions in Croatia as well as in Europe.

PMID- 15011462
TI  - [Is permanent renal function damage possible after hemorrhagic fever with renal
      syndrome?].
AB  - AIM: To investigate the possibility of permanent renal function impairment and
      other organ lesions following hemorrhagic fever with renal syndrome (HFRS).
      METHODS: Data on 30/37 patients infected with HFRS, treated at the Department of
      Infectious Diseases, Split University Hospital, in 1995 were retrospectively
      analyzed. The data were collected three to six years following the appearance of
      HFRS. In 1998, 30/37 patients presented for control checkup, when their history
      data were collected, along with physical examination, hematology and biochemistry
      tests, and urinalysis. Creatinine clearance and sodium, potassium, chlorine,
      phosphorus, beta 2-microglobulin and N-acetyl-beta-D glucosaminase in 24-h urine
      were determined. In native urine, erythrocyturia was observed, with 10
      erythrocytes per field were considered pathologic result. During the 1998-2001
      period, renal scintigraphy by means of technetium labeled diethylene
      triaminopentacetic acid (99mTC DTPA) was performed in 13/30 patients. RESULTS: Of
      subjective discomforts, 29/30 (96.7%) patients reported lumbar pain. Elevated
      blood pressure was found in 9/30 (30.0%), erythrocyturia in 4/30 (13.3%) and
      hepatic lesion in 4/30 (13.3%) patients. Decreased creatinine clearance values (<
      1.2 ml/s) were found in 4 and increased values (> 2.35 ml/s) in 10 patients.
      Increased sodium in 24-h urine was recorded in 10/23 and increased beta 2
      microglobulin in 6/23 (26%) patients. Proteinuria exceeding 150 mg/day was
      detected in 11/23 (47.8%) patients. Scintigraphy of the kidneys demonstrated
      reduced glomerular filtration (< 100 ml/min/1.72 m2) in 3/13 patients. Prolonged
      mean times (> 5 minutes) of radiopharmaceutical passage through the renal
      parenchymae were found in 7/13 (53.8%) patients. DISCUSSION: Studies performed in
      30 patients three years after they had recovered from HFRS revealed changes
      suggesting a mild to moderate impairment of the renal function. Hypertension
      found in 9/30 patients was a significant finding, considering the fact that all
      subjects were soldiers, thus having undergone through examinations to prove them
      completely healthy prior to joining army. Hypertension results were consistent
      with those reported from the USA. Although erythrocyturia points to urinary tract
      damage, its glomerular or postglomerular origin was not examined. Decreased
      creatinine clearance found in 4/23 patients suggested functional renal
      impairment. Increased natriuresis found in 10/23 patients implied tubular damage,
      i.e. reduced ability of tubular cells for sodium reabsorption from primary urine.
      Non-selective albuminuria detected in 11/23 patients indicated permanent lesion
      of the glomerular basal membrane. Increased beta 2-microglobulin found in 6/23
      patients indicated that the lysosomal enzyme level was elevated only in the acute
      stage of the disease, but may have been an indicator of permanent lesion. No
      description of post-HFRS scintigraphic lesion of the kidneys was found in the
      literature. A decreased value of glomerular filtration, found in three patients,
      and especially the prolonged mean time of glomerular micropharmaceutical passage
      in 7/13 (53.8%) patients may have suggested glomerular damage. However, the
      possible reason may have also been a reduced passage of glomerular filtrate
      through the damaged lower parts of the nephrons. Transaminase increase during the
      acute stage of HFRS suggested the possible liver infection, maybe even hantavirus
      replication in hepatocytes. Even though biopsy confirmed the histologic picture
      of chronic hepatitis in one patient, the question remains whether it could have
      been caused by hantavirus. CONCLUSION: Studies performed in 30 patients with a
      history of HFRS revealed renal function impairment, along with hypertension and
      damage to the liver parenchyma in some patients. The results obtained showed that
      the HFRS infection in Croatia may have entailed chronic sequels. To confirm this
      hypothesis, additional studies including a control group of hantavirus negative
      persons are needed.

PMID- 15011463
TI  - [Leptospirosis and hemorrhagic fever with renal syndrome in northwestern
      Croatia].
AB  - Leptospirosis is a worldwide spread zoonosis, therefore being also present in
      northwest Croatia. It has been recently discovered that hemorrhagic fever with
      renal syndrome (HFRS) is present throughout Croatia, not just in the previously
      well known epidemic foci. Because of the similar clinical presentation and
      epidemiology of the two diseases, it is important to know the exact etiology of
      the current disease. The aim of this study was to determine the presentation of
      HFRS in northwest Croatia and possible coinfection in patients with
      leptospirosis. PATIENTS AND METHODS: During the 1988-2000 period, 42 patients
      with leptospirosis from northwest Croatia were analyzed. Leptospiral infection
      was confirmed in all 42 patients by microagglutination test. Serology for
      hantaviruses was done by ELISA test in a few patients with leptospirosis and
      severe renal failure. RESULTS: In the majority of patients (37/42: 88%) acute
      renal failure was mild or moderate, with creatinine values below 500 mol/l.
      However, 12% of the patients developed severe acute renal failure, with
      creatinine values over 500 mol/l. The main therapeutic regime in all patients
      with leptospiral infection included body fluid replacement (electrolyte and
      glucose infusions) and antibiotic therapy. In patients with severe acute renal
      failure, it was necessary to introduce hemodialysis treatment. There was no fatal
      outcome in our patients. Over the last few years, antibody titers to hantaviruses
      were assessed by ELISA testing in five patients with leptospiral infection and
      severe form of acute renal failure, confirming HFRS persistence in northwest
      Croatia Testing for specific antibodies to hantaviruses has been suggested in all
      patients with leptospirosis and in whole Croatia, especially in northwest
      Croatia.

PMID- 15011465
TI  - [Serologic diagnosis of hemorrhagic fever with renal syndrome in Bosnia and
      Herzegovina in 2002].
AB  - AIM: Results of the serologic confirmation of hemorrhagic fever with renal
      syndrome (HFRS) in patients with clinical picture and overt symptoms of the
      disease from particular areas in Bosnia and Herzegovina during 2002 are
      presented. METHODS: A total of 146 sera from 100 clinically suspected patients
      were tested. The sera were tested for the presence of specific IgM antibodies to
      Hantaan and Puumala antigens by Elisa IgM "capture" test, and for the presence of
      specific antibodies to Hantaan, Puumala and Dobrava antigens by Elisa IgG test.
      DISCUSSION: Most of the positive IgM reactions were recorded as cross reactions
      to Hantaan and Puumala antigens, and most of the positive IgG reactions as cross
      reactions to Hantaan and Dobrava antigens. The finding of antibodies in the sera
      of patients from Europe that react with Hantaan antigen are not associated with
      the infection with Hantaan, but with the infection with viruses that are
      genetically related with Hantaan. To date, HFRS caused by Puumala and Dobrava
      viruses has been verified in Bosnia and Herzegovina. CONCLUSION: Using Elisa IgM
      "capture" test, acute hantavirus infection was serologically confirmed in 38% of
      clinically suspected patients with manifested symptoms from different areas of
      Bosnia and Herzegovina in 2002. The distribution of human hantavirus infection in
      Bosnia and Herzegovina was confirmed by the presence of specific hantavirus
      antibodies in patient sera.

PMID- 15011466
TI  - [Hemorrhagic fever with renal syndrome in Croatia--historical review].
AB  - Hemorrhagic fever with renal syndrome (HFRS) has been known from ancient times as
      a disease with many names, which raised great interest during the Korean war
      (1951-1954), occurring as a large epidemic (Korean hemorrhagic fever). Therefore,
      the subsequently discovered causative agent was named after the Hantaan River
      which runs along the 38th parallel and divides North Korea from South Korea. A
      similar disease was described in 1934 in Scandinavian countries (epidemic
      nephrosonephritis or nephropathy). During the Second World War, the disease was
      also registered as wartime nephritis in several European south-eastern countries.
      Since 1982, similar clinical manifestations of the disease, differently named in
      various parts of the world, have been assigned one unique name--hemorrhagic fever
      with renal syndrome, as recommended by the World Health Organization. In Croatia,
      the first patient with HFRS was diagnosed in 1952 and the paper describing the
      case was published in 1954 (Radosevic and Mohacek). Since then, the disease has
      been regularly occurring in our country, especially in sporadic form, with only
      two smaller epidemics recorded until 1995. The first epidemic with 14 forestry
      workers involved occurred in 1967 at the Plitvice Lakes, and the second with the
      same number of soldiers in 1989 around the Pieso-Airport near Zagreb.
      Simultaneously, in 1967 and 1989 two large-scale epidemics of HFRS occurred in
      Bosnia and Herzegovina with 144 cases each. Until the first large epidemic of
      HFRS in Croatia during the Croatian War in 1995, occurring at several localities
      (Mala Kapela, Dinara mountain, west Slavonia), it was considered that there were
      only several natural foci of the disease in Croatia (around Ogulin and Slunj,
      Plitvice Lakes, Zagreb surroundings). A total of 125 cases were reported to the
      Croatian National Institute of Public Health in 1995. Fifty patients, 45 of them
      soldiers, were hospitalized at Dr. Fran Mihaljevic University Hospital for
      infectious Diseases in Zagreb. In the same year, the largest epidemic also
      occurred in Bosnia and Herzegovina with more than 300 cases. During the almost 50
      year experience in HFRS surveillance, we have noticed two different clinical
      manifestations of the disease. The milder type of illness without hemorrhage is
      more common than the severe type with hemorrhages and extensive renal
      insufficiency. After the virus discovery and introduction of serologic testing,
      two causative agents have been detected during the 1970s and 1980s--Vranica and
      Fojnica, that were later serotyped as Puumala and Dobrava viruses.

PMID- 15011464
TI  - [Puumala and Dobrava viruses in the northeastern and central regions of Bosnia].
AB  - Bosnia and Herzegovina has been known as a highly endemic region for Hantavirus
      infections for more than 50 years. Previous studies have shown that at least two
      different hantaviruses, the murine Dobrava (DOB) and avricoline Puumala (PUU)
      viruses, each carried by a different rodent species, have been circulating in the
      area. However, there is little information on rodent population density
      fluctuations in Bosnia over the past years as well as on the ratio of Puumala to
      Dobrava infection in humans. THE AIMS:  THE AIMS OF OUR STUDY WERE: to identify
      the rodent species which may serve as hantavirus reservoirs in the north-east and
      central Bosnia; to assess the geographical distribution, density and population
      dynamics of rodent species in the area; to assess the influence of climatic
      conditions on the size of rodent population; and to determine the ratio of
      Puumala to Dobrava infection in humans. METHODS: The epidemiologic and epizootic
      study in the north-east and central Bosnia was conducted during the 8-year period
      (1995-2003). The average yearly and monthly temperatures, air humidity and
      precipitation during the study period were analyzed. A total of 381 small rodents
      were caught during the epidemic years (1995 and 2002), and in-between the
      epidemic periods (1999 and 2000). The animals were caught by live-traps and
      identified by morphometric methods. The density of animals was estimated by
      counting the number of holes per 1000 m2. Sera of 311 patients with clinical
      signs and symptoms of hemorrhagic fever with renal syndrome (HFRS) were tested
      for the presence of antibodies reactive to the Dobrava, Puumala and Seoul viruses
      by using indirect immunofluorescence test (IIF), and IgG and IgM ELIS. Sera of 84
      patients were tested using only IIF, and 227 sera were tested by IIF and -capture
      IgM ELIS tests. RESULTS: During the epidemic years, the average monthly
      temperatures in February were by 4.3 times higher than the average temperatures
      during the nonepidemic years, which may have influenced the early reproduction of
      rodents and development of "mouse years". The rodents were identified as:
      Apodemus flavicollis (n = 139), Apodemus sylvaticus (n = 89), Apodemus agrarius
      (n = 4), Clethrionomys glareolus (n = 117), Sorex araneus (n = 5), Pytimus
      subterraneus (n = 23), Mus musculus (n = 1), Mycrotus arvalis (n = 1) and Rattus
      norvegicus (n = 2). Clethrionomys glareolus was predominant in the regions with
      the altitude higher than 1160 meters and Apodemus species in the regions with the
      altitude lower than 670 meters. The rodent population density changes seasonally
      and cyclically. During the epidemic years, the rodent population density was
      marked as very high, whereas during the nonepidemic years it was designated from
      low to moderate. Well-known natural hosts of Hantaviruses (A. flavicolis and C.
      glareolus) are most widely spread species of small rodents, and the increase in
      their population is closely related with outbreaks of epidemics of HVBS-a.
      Puumala virus caused HVBS-a in 49.84% (155/311); Dobrava virus in 23.15% (72/311)
      of cases, whereas Hantaviruses serotype was not identified in 27.00% (84/311) of
      cases. Infections caused by Puumala virus were more frequent than the infections
      caused by Dobrava virus during both epidemic and nonepidemic periods. The
      proportion of humans infected with Puumala and Dobrava viruses correlated with
      the number of natural hosts of Hantaviruses in the areas of HVBS outbreaks. The
      study of the prevalence of hantavirus antibodies in the populations of rodents
      and humans, which had been under way, should elucidate these relationships.

PMID- 15011467
TI  - [Clinical picture of hemorrhagic fever with renal syndrome in Croatia].
AB  - Among many viral hemorrhagic fevers, only hemorrhagic fever with renal syndrome
      (HFRS) occurs in Croatia. HFRS is a natural focus zoonosis with sudden onset,
      characterized by high fever and other clinical symptoms, renal insufficiency and
      hemorrhages. In Croatia, HFRS is caused by two types of hantaviruses--Puumala
      (PUU) and Dobrava (DOB). The basic pathologic and patophysiologic disorder in
      HFRS is capillary damage (vasculitis). Incubation of HFRS has not been precisely
      determined, it is most frequently around two weeks. The disease onset is usually
      abrupt. At the beginning, general symptoms include high fever and myalgias,
      especially in the lumbar region, and abdominal pain, as well as strong headaches,
      malaise and nausea, and often vomiting or diarrhea. In half of the patients
      respiratory symptoms occur. Later on, some patients may experience hypotension,
      oliguria and other signs of renal failure, and apart from petechial, severe
      hemorrhages may also occur in other organs. During typical clinical presentation
      of the disease, some characteristic symptoms are clearly distinguished in
      particular stages of the disease. Therefore, the course of HFRS is usually
      divided into five distinct stages (febrile, hypotensive, oliguric, polyuric and
      convalescent). Such a course of the disease is more commonly present in case of
      DOB virus than PUU virus infection. The febrile stage with sudden onset usually
      lasts from 3 to 7 days, when thrombocytopenia and hemoconcentration, as well as
      albuminuria and hematuria are almost always recorded. The hypotensive stage lasts
      from one to 2 days on an average and is characterized by lower blood pressure and
      signs of renal failure. The oliguric stage usually starts at the beginning of the
      second week of the disease, when extensive hemorrhage may occur and urea and
      creatinine reach their highest values. The oliguric stage is followed by the
      polyuric stage which can last for up to two weeks, and is characterized by
      excretion of a large quantity of urine of low specific gravity (up to 15 liters
      during 24 hours). The convalescence (convalescent stage) is slower, may last for
      several weeks or months, but usually resolves without complications. During the
      infection caused by PUU virus, the course of disease is usually milder with only
      two stages. The first one is febrile, followed by the second stage with renal
      symptoms, and rare and mild hemorrhagic manifestations. This type of disease is
      mostly encountered during epidemics. The mortality in severe cases of the disease
      (DOB virus) is 5% to 10%, whereas in PUU virus infection it is less than 1%.

PMID- 15011468
TI  - [What is new in the epidemiologic characteristics of hemorrhagic fever with renal
      syndrome in Croatia?].
AB  - AIM: The aim was to describe epidemiologic characteristics of hemorrhagic fever
      with renal syndrome in Croatia. METHODS: We analyzed published data from
      obligatory infectious disease reports and notification of deaths due to
      infectious diseases, data on the hemorrhagic fever with renal syndrome epidemics
      in Croatia, and our own data. RESULTS AND DISCUSSION: During the 1987-2002
      period, 555 cases of hemorrhagic fever with renal syndrome were recorded in
      Croatia, 160 (28.8%) of them in soldiers. The mortality rate was up to 15.4%
      (mean 1.1%) (6/555). The highest number of cases (317) were recorded during 2002.
      The epidemic started in winter. The highest number of cases were recorded in June
      and July, i.e., during the warm season characterized by an increased activity of
      both animals acting as infection reservoirs and humans as hosts. The epidemic
      spread almost throughout Croatia. The known natural foci of hemorrhagic fever
      with renal syndrome are Plitvice and Slunj areas, Dinara mountain, Velika and
      Mala Kapela mountains, Zagreb area (Velika Gorica and Jastrebarsko), Gorski kotar
      area (Ogulin, Delnice), west Slavonia, and Novska area. The disease has not been
      recorded in the littoral area and on Adriatic Islands. The disease was also
      recorded in the neighboring countries of Slovenia, Bosnia and Herzegovina, Serbia
      and Montenegro. The identified causative agents include Dobrava and Puumala
      viruses of the genus Hantavirus, whereas the rodents Clethrionomys glareolus,
      Apodemus flavicollis, Apodemus agrarius and Apodemus sylvaticus serve as the main
      reservoirs of the infection in Croatia. Typical biotopes of the infection in
      Croatia are deciduous woods. CONCLUSION: The 2002 epidemic confirms the
      presumption that almost all continental part of Croatia contains natural foci of
      hemorrhagic fever with renal syndrome.

PMID- 15011469
TI  - [Immunopathogenesis of hemorrhagic fever with renal syndrome and hantavirus
      pulmonary syndrome].
AB  - Hantaviruses (HTV) cause two serious human diseases: hemorrhagic fever with renal
      syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), posing a considerable
      public health problem worldwide. Immunopathogenesis has been suggested to be
      involved in both HFRS and HPS. A common feature of hantavirus diseases is an
      increased microvascular bed permeability, suggesting that vascular endothelium is
      a prime target of virus infection. Although HTV infect numerous cell lines and
      primary cells, it was considered that they do cause no cytopathic effect.
      Recently, we found HTV to cause a cytopathic effect and apoptosis in 293 HEK
      cells. Monocytes/macrophages also represent the important target cells, which may
      also have an important role in the spread of HTV from the primary site of
      infection. Both endothelial cells and monocytes/macrophages may act as a rich
      source of cytokines/chemokines during the infection with HTV and additionally
      contribute to the HFRS/HPS immunopathogenesis. The main reservoirs of HTV are
      small rodents which are infected but do not have manifest disease. However, some
      studies show that T-lymphocytes may play an important role in rodent resistance
      to infection with HTV. Some clinical studies indicate the important role of pro
      inflammatory cytokines in the immunopathogenesis of HFRS/HPS. The efficient anti
      hantaviral cell-immune response in patients is mainly due to the generation of
      cytotoxic T-lymphocytes. Our study also pointed to a decrease in the percentage
      of total naive (CD45RA) cells and an increase in the percentage of memory cells
      (CD45RO). Specific IgM antibodies appear at the very beginning of the diseases
      followed by an increase in specific IgG. Additionally, IgE antibodies have been
      suggested to play a role in HFRS immunopathogenesis. Immune complexes have been
      detected in the sera, on the surface of red blood cells and platelets, in urine,
      glomerull and dermal capillaries of HFRS patients. They may be responsible for
      increased capillary permeability, vascular injury, platelet lysis and kidney
      damage. The immunopathologic disorders accompanying HFRS/HPS are complex. As
      there is no appropriate animal model to investigate HFRS/HPS immunopathogenesis,
      we mostly rely on in vitro and rare clinical studies. Additional efforts in the
      research of immunopathogenesis caused by HTV, may contribute to better
      understanding of HFRS/HPS characteristics and course of disease, and improve the
      treatment and prevention.

PMID- 15011470
TI  - [Ocular changes in hemorrhagic fever with renal syndrome].
AB  - Hemorrhagic fever with renal syndrome (HFRS) is a rodent-originating zoonotic
      disease caused by Puumala and Dobrava viruses, which belong to the genus
      Hantavirus. The most prominent ocular change in HFRS is transient myopia, which
      lasts for up to one week and is due to a forward movement of the ocular anterior
      diaphragm and thickening of the lens. Other ophthalmic manifestations of HFRS are
      eyelid edema, conjunctival injection with or without hemorrhages, chemosis,
      anterior uveitis, retinal edema with or without hemorrhages, and photophobia.
      Acute glaucoma attacks, which are rare, could be explained by the increased
      intraocular pressure (IOP) due to edema and hemorrhage in the ciliary body,
      causing anterolateral rotation, relaxation of the zonules, and anterior movement
      of the lens. They are treated with mydriatic-cycloplegic and corticosteroid eye
      drops and with furosemide. However, there are also controversial reports on
      decreased IOP during the acute phase of HFRS. Despite the fact that ocular
      symptoms in HFRS are common generally they do not require any medical therapy and
      the recovery of the patients is complete.

PMID- 15011471
TI  - [Small rodents in the forest ecosystem as infectious disease reservoirs].
AB  - Due to numerousness of populations and width of ecologic valence, small rodents
      are important parts of almost any forest ecosystem. The represent an important
      animal group, which connects primary makers with higher trophic levels. They
      transmit various infectious diseases dangerous for the health of people and
      domestic and wild animals (trichinosis, leptospirosis, tick encephalitis, Lyme
      disease, hemorrhagic fever with renal syndrome, etc.). The following species of
      small rodents live in forest ecosystems of Croatia: Chletrionomys glareolus
      Schreib., Arvicola terrestris L, M. subterraneus de Sel., M. arvalis Pall., M.
      agrestis L, M. multiplex Fat., Apodemus agrarius Pall., A. sylvaticus L. and A.
      flavicollis Melch. Small rodents transmit causative agents of diseases in active
      (excretion products) of passive (ectoparasites and endoparasites) ways. Their
      multiplication potential is quite high. Transmission of certain disease sometimes
      takes place extremely fast due to the high number of rodents, their high
      movability and distribution, and the fact that they easily get in touch with men
      and domestic and wild animals. The number of population of each species is
      directly influenced by abiotic and biotic factors and changes during one year and
      in a several year period. In a year when the influence of ecologic factors is
      favorable, it is presumed that the number of these rodents will significantly
      increase, by which the danger of their damaging effect also increases. The
      following factors influence the increase of a small rodent population: number and
      physiologic condition of the population, meteorologic conditions, habitat, food
      sources, natural enemies, and diseases. The occurrence of an epidemic is closely
      connected to the number and infectivity of causative agents. Regular control of
      the number of rodent population and their infectivity can help in planning
      preventive epidemiologic and sanitary measures to preclude the occurrence of
      epidemics and individual cases of disease among animals and humans who come in
      contact with forest (forest workers, holiday makers, hikers, soldiers, tourists,
      etc.).

PMID- 15011472
TI  - [Ultrasound findings on abdominal organs in the acute phase of hemorrhagic fever
      with renal syndrome].
AB  - INTRODUCTION: There are significant changes in small blood vessels with increased
      permeability, edema of abdominal organs and ascites in the acute phase of
      hemorrhagic fever with renal syndrome (HFRS). We analyzed ultrasound changes of
      abdominal organs in patients with serologically verified HFRS, in order to assess
      the value of this method in the diagnosis of acute renal failure (ARF). METHODS:
      The study included 14 sporadic patients with ARF and suspicion of HFRS, treated
      in 2002. Ultrasonography of the liver, gallbladder, pancreas, spleen, kidneys,
      prostate and retroperitoneum was performed on a Toshiba 220 SSA. RESULTS:
      Parenchymal edema with increased echogenicity, sinus narrowing and enlargement of
      both kidneys were found in all 14 (100%) patients. Hepatosplenomegaly was found
      in seven (50%), ascites in four (28.6%), and pleural effusion in two (14.3%)
      patients. Increased thickness of the bladder wall was found in two (14.3%),
      gallbladder enlargement in one (7%), and edema of the pancreas in one (7%)
      patient. CONCLUSION: Ultrasound examination has a very important role in the
      diagnosis and follow-up of changes in the parenchymal organs in the acute acute
      phase of the disease.

PMID- 15011473
TI  - [Thrombotic thrombocytopenic purpura and hemorrhagic fever with renal syndrome:
      possible dilemma in differential diagnosis].
AB  - Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are
      classical diseases characterized by thrombocytopenia and microangiopathic
      hemolytic anemia. Microangiopathic hemolytic anemia is also a part of clinical
      picture in patients with hemorrhagic fever with renal syndrome (HFRS). Some
      overlap in other elements of clinical picture between TTP and HFRS is possible,
      which could pose difficulties in differential diagnosis. Early treatment of
      patients with TTP is essential and significantly improves the outcome, whereas
      the treatment of HFRS is mainly supportive. In the last ten years, we treated 13
      patients with TTP and 17 patients with HFRS. Two patients with HFRS were
      initially treated as TTP because it was not possible to exclude TTP on the basis
      of clinical picture. Further clinical course and serologic tests excluded TTP and
      suggested HFRS. CONCLUSION: Sometimes it is difficult to distinguish HFRS from
      TTP because thrombocytopenia and microangiopathic hemolytic anemia are present in
      both diseases and overlaps in other parts of clinical picture are possible. The
      serious consequences of delay in the efficacious treatment of patients with TTP
      could also influence the physicians' decisions.

PMID- 15011474
TI  - [Hemorrhagic fever with renal syndrome: imported or native disease in the Zadar
      region].
AB  - AIM: The aim of the study is to warn of the need of clinical hemorrhagic fever
      with renal syndrome (HFRS) recognition and determination, and of the risk of its
      spread from a new focus of this natural zoonosis near Zadar (north Dalmatia),
      i.e., in the northern part (Lika) of the Zadar County. METHOD: Clinical and
      epidemiologic characteristics of HFRS were analyzed in four patients. Patient
      sera were analyzed for Puumala (PUU) and Hantaan (HTN) viruses by
      immunofluorescence test (IFT) and immunoenzyme test (ELISA). RESULTS:
      Epidemiologic studies confirmed the source of infection to be out of the area in
      three patients, whereas in one patient it was near Zadar area. Mild symptoms
      pointed to the disease. Pathologic findings showed pathologic leukocyte values
      (leukocytosis), two- to four-fold alanine aminotransferase, aspartate
      aminotransferase and creatinine increase in serum, proteinuria and
      erythrocyturia. A significant PUU antibody titer was found by serum IF and ELISA.
      CONCLUSION: The occurrence of HFRS in the Zadar area was confirmed by clinical
      description and laboratory evidence. The newly identified focus was in the
      vicinity of this area could imply a risk for the disease epidemic in the Zadar
      area.

PMID- 15011475
TI  - The evidence-based medicine heresy.

PMID- 15011476
TI  - What makes a leader?

PMID- 15011477
TI  - Diagnosing and treating strep throat.

PMID- 15011478
TI  - How to code for observation services.

PMID- 15011479
TI  - Physicians' reimbursement claims face greater scrutiny.

PMID- 15011480
TI  - The outcomes of open-access scheduling.

PMID- 15011481
TI  - The Stark truth about the Stark law: Part II.

PMID- 15011482
TI  - Making evidence-based medicine doable in everyday practice.

PMID- 15011484
TI  - A primer on wireless networks.

PMID- 15011485
TI  - The fine art of refusal.

PMID- 15011483
TI  - Diagnosing pulmonary embolism.

PMID- 15011487
TI  - The challenges of leadership.

PMID- 15011488
TI  - The Africa chronicle.

PMID- 15011489
TI  - Transformative learning.

PMID- 15011490
TI  - Needlestick injuries. Protective legislation is group's aim.

PMID- 15011491
TI  - Helping children make better food, lifestyle choices.

PMID- 15011492
TI  - Influenza vaccination choices.

PMID- 15011493
TI  - Nurses' perceptions of rehabilitation certification.

PMID- 15011495
TI  - Adverse events. Focus on patient safety.

PMID- 15011494
TI  - Collaboration. Parents on the healthcare team.

PMID- 15011496
TI  - An eye on development.

PMID- 15011497
TI  - Stroke unit decreases patient LOS with care, culture changes.

PMID- 15011498
TI  - Cleveland Clinic system doubles use of i.v. tPA.
AB  - Doubling the use of intravenous tissue plasminogen activator and reducing the
      frequency of brain hemorrhagic complications by more than half has earned the
      Cleveland Clinic Health System the Ernest A. Codman Award for 2003.

PMID- 15011500
TI  - Reduced telephone tag results in 60% fewer patient complaints, more efficiency.
AB  - If you are seeking to improve the performance of your health care organization,
      you don't have to look any farther than the plastic box sitting on your desk with
      all the buttons--the telephone. Improving the flow of patient calls through your
      organization can dramatically boost efficiency, lower labor costs, and increase
      both patient and staff satisfaction.

PMID- 15011499
TI  - Tough love approach helps physician practice transition to EMR.
AB  - Many physician practices could benefit by making the switch from paper charts to
      an electronic medical record. Faster access to information, less time spent
      filing and retrieving charts, and fewer hours spent updating the records are some
      of the potential performance improvements. But physicians often balk at the
      thought of learning how to use a new system.

PMID- 15011501
TI  - [A strategy for treating the anxious patient].
AB  - The article describes the different ways of dealing with dental fear. First the
      importance of preventive dentistry is pointed out. Subsequently the potential of
      behaviour therapy for both children and adults is discussed. Relaxation therapy
      and hypnosis are considered next. From the pharmacological point of view the
      indications and use of oral and intravenous sedation are explained. One more
      option to achieve sedation is nitrous oxide inhalation. As a last resort we have
      general anaesthesia. Indications and procedures are outlined.

PMID- 15011502
TI  - [Medical history in relation to dental anxiety in adults].
AB  - Fear in adults has a clearly endogenous component. Specific fear anamnesis
      questionnaires are available to gauge the fear of dental treatment. On the basis
      of a literature review the different questionnaires and their usefulness are
      being discussed.

PMID- 15011503
TI  - [Medical history in relation to dental anxiety in children].
AB  - Fear in children is of clearly exogenous origin. Negative experiences will cause
      fear by direct conditioning. The influence of an important other person can be
      the root of fear by indirect conditioning. Antecedent factors and intermediary
      variables associated with fear are described. Usefulness and indications of the
      different questionnaires for children are specified.

PMID- 15011504
TI  - [Pharmacologic sedation in dentistry: an overview].
AB  - The primary purpose of pharmacological fear management is to reduce or block the
      anxiety reflex. Conscious sedation is a viable tool for both dentist and patient
      to overcome anxiety without having to turn to general anesthesia. This article
      reviews the current use of oral sedatives in dentistry, taking into account their
      availability and pointing out advantages and disadvantages in daily practice.
      Rapid onset and short half-life benzodiazepines can be considered the gold
      standard, always taking into account possible adverse effects. Moreover this
      article provides the different guidelines of international organizations such as
      AAPD, EAPD and EFAAD regarding the educational requirements dentists should meet
      to deliver safe and effective pharmacologic oral sedation.

PMID- 15011505
TI  - [Sedation with nitrous oxide in daily practice].
AB  - Conscious sedation is recommended, together with behaviour management techniques,
      to facilitate treatment of dental fear or dental phobia patients. In this article
      the authors focus on inhalation sedation by means of nitrous oxide. The
      procedures and indications are explained and illustrated with clinical cases. On
      the strength of the literature and their own experience the authors reach the
      conclusion that Inhalation sedation is a kind of pharmacological behaviour
      management and an important additional tool to increase patient cooperation.
      Inhalation sedation can only be performed by trained practitioners under
      internationally accepted safety conditions. Inhalation sedation has a future in
      Belgium providing the appropriate law is adapted. This technique deserves a place
      in the dental curriculum.

PMID- 15011506
TI  - Ties that bind.

PMID- 15011507
TI  - Missing link.

PMID- 15011508
TI  - Home grown.

PMID- 15011509
TI  - The HSJ interview: Denise Platt share options. Interview by Mary-Louise Harding.

PMID- 15011510
TI  - Healthcare funding.

PMID- 15011511
TI  - Clinical management. Where medicine meets management. Kidney complaint.
AB  - The renal NSF sets a 10-year modernization plan for dialysis and transplantation.
      The shortage of haemodialysis facilities are blamed for UK end-stage renal
      failure death rates being 36 per cent higher than in other European countries.
      Critics have targeted the NSF's lack of hard-hitting targets.

PMID- 15011512
TI  - Bed management. Pillow talk.

PMID- 15011513
TI  - Mental health. Ever ready.

PMID- 15011514
TI  - Law. Statute of liberty.

PMID- 15011515
TI  - HSJ people. Hard graft.

PMID- 15011516
TI  - The English patients.

PMID- 15011517
TI  - Learning curve.

PMID- 15011518
TI  - In for the skill.

PMID- 15011519
TI  - School of thought.

PMID- 15011520
TI  - Fellow the leader.

PMID- 15011521
TI  - Cage of reason.

PMID- 15011522
TI  - The source of the problem.

PMID- 15011523
TI  - Nasal mist an alternative to traditional flu shot.

PMID- 15011524
TI  - Boring basics. The magic potion for success.

PMID- 15011525
TI  - Tooth color correction. First things first.

PMID- 15011526
TI  - Achieving natural posterior anatomy with Ormocer technology.

PMID- 15011528
TI  - Mandibular overdentures retained with porous-surfaced implants.

PMID- 15011527
TI  - Aesthetic posterior crowns with minimal tooth reduction.

PMID- 15011529
TI  - New study: the value of emotional intelligence in dentistry.

PMID- 15011530
TI  - Partnering for success. Doctor/technician communication.

PMID- 15011531
TI  - A simple and elegant impression technique.

PMID- 15011532
TI  - Single-visit endodontics, Part 1. Are we there yet?

PMID- 15011533
TI  - The safety and effectiveness of dental Er:YAG lasers. A literature review with
      specific reference to bone.

PMID- 15011534
TI  - Soft-tissue root coverage. Clinical rationale and case report.

PMID- 15011536
TI  - On-hold time. Taking a look at an often-overlooked marketing opportunity.

PMID- 15011535
TI  - Evaluation and management of TMDs, Part 1. History, epidemiology, classification,
      anatomy, and patient evaluation.
AB  - The study of temporomandibular disorders has undergone many changes throughout
      its history. Focus on the structure and function of the TMJ continues to improve
      our understanding of these complex disorders. A more standardized classification
      system allows practitioners and researchers to discuss findings in a common
      language. With improved patient evaluation techniques, the clinician can
      establish a proper working differential diagnosis and begin focusing attention on
      treatment planning.

PMID- 15011537
TI  - Dentistry for sale. What makes a patient buy into a treatment plan?

PMID- 15011538
TI  - Ten backup tasks for your computers.

PMID- 15011539
TI  - Study links childhood incidence of sexual abuse with dental fears.

PMID- 15011540
TI  - Terrifying, troublesome, or terrific? Secrets to perfect pediatric patients.

PMID- 15011541
TI  - Hand hygiene; bring on the alcohol rubs.

PMID- 15011542
TI  - Simplifying diastema closure in the anterior region.

PMID- 15011543
TI  - An innovative, heat-accelerated, in-office whitening technique for nonvital
      teeth.

PMID- 15011544
TI  - The use of the Nd:YAG dental laser as an adjunct to aesthetic restorative
      treatment.

PMID- 15011545
TI  - Interpreting endodontic radiographs. Take a trip to a Japanese rock garden.

PMID- 15011546
TI  - Periodontal surgery. Resection to regeneration.

PMID- 15011547
TI  - Materials and techniques for restoring teeth with severe caries or fractures.

PMID- 15011549
TI  - Living your big dream. Considering a professional coach to assist you and your
      practice.

PMID- 15011548
TI  - Informed consent. The patient's rights.

PMID- 15011550
TI  - Internet safety precautions.

PMID- 15011551
TI  - [Abstracts of the 1st meeting of the Society of Cell Biology. St Petersburg,
      Russia, October 14-16, 2003].

PMID- 15011552
TI  - [Abstracts of the International Symposium on the Problem of Meiosis. St.
      Petersburg, Russia, October 17, 2003].

PMID- 15011553
TI  - Nurse convicted of killing six pts.: limitations bars suit.

PMID- 15011554
TI  - Going before disciplinary board without counsel is unwise. Case on point: Slone
      Vasquez v. Kentucky Board Of Nursing, 2003 WL 22976179 S.W.3d-KY.

PMID- 15011555
TI  - AR: failure to follow protocol for no bowel sounds: nurse terminated for good
      cause denied UI benefit.

PMID- 15011556
TI  - CA: CNA convicted of illegal possession of firearm: denial of application to
      renew CNA license upheld.

PMID- 15011557
TI  - Foreign object left in bypass pt.: why wasn't dr. responsible? Case on point:
      Breaux v. Thurston, 2003 WL 23028311 So.2d-AL.

PMID- 15011558
TI  - Reliable caries reversal: another paradigm shift?

PMID- 15011559
TI  - Treating the "whole patient" builds the practice.

PMID- 15011560
TI  - Selection and use of masks.

PMID- 15011561
TI  - New directions in dentistry.
AB  - Dentistry is growing and serving the public better than ever before. In this
      article, the various divisions of dentistry have been considered, observing the
      current state of the art in each one and making predictions about the changes
      that are coming in the near future.

PMID- 15011562
TI  - Interdisciplinary dentistry. An aesthetic outcome.

PMID- 15011563
TI  - A strategy for correcting poor anterior aesthetics. A case study.

PMID- 15011564
TI  - Long-lasting restorations using compatible dual-cured materials.

PMID- 15011565
TI  - Digital image management and manipulation in the dental office.

PMID- 15011566
TI  - See tomorrow today.

PMID- 15011567
TI  - Early orthodontics. 5 new steps to better care.

PMID- 15011569
TI  - Prerestorative periodontal plastic surgery. Creating the gingival framework for
      the ideal smile.

PMID- 15011568
TI  - Rotary nickel titanium instrumentation. A literature review.

PMID- 15011570
TI  - The tobacco-using patient and the dental office.

PMID- 15011571
TI  - Dealing with dental malpractice, Part 1.

PMID- 15011572
TI  - Hiring practices ... not so fast!

PMID- 15011573
TI  - The human side of technology. A team-wide look at the implementation "game".

PMID- 15011574
TI  - [Antiretroviral therapy 2003. The current status].
AB  - In the year 2003, the basis of antiretroviral treatment comprising nucleoside and
      nucleotide reverse transcriptase inhibitors (NRTI, NNRTI, NtRTI) and protease
      inhibitors (PI) will be extended to include entry inhibitors (EI). A
      representative of this class of drugs, enfurvitide (T20), is about to receive
      official approval. In the meantime, initial data on long-term treatment with
      tenofovir, which has been available in Germany since February 2002, have become
      available. Further medications are in the pipe-line of clinical development, for
      example, the NRTI emtricitabine (FTC) and the Pis amdoxovir and Atazanavir.
      Results from studies employing immunomodulatory approaches have so far proved
      disappointing. In contrast, a number of smaller studies on vaccination have
      provided promising data. Recommendations for antiretroviral treatment of HIV
      infection were updated in the summer of 2002.

PMID- 15011575
TI  - [Treatment compliance as a priority in HIV control. "Once daily" suits life
      style].

PMID- 15011576
TI  - [A "once daily" drug that with proven effectiveness. Efavirenz has successful
      outcome also in direct comparisons].

PMID- 15011577
TI  - [Highly effective drug without modifying the lipid profile. Atazanavir, the
      protease inhibitor for "once daily" administration].

PMID- 15011578
TI  - [Entry inhibitors. Ring-free for a new principle of action].
AB  - Entry-inhibitors represent a new option in antiretroviral therapy. They prevent
      infection of HIV target-cells. According to their mechanism of action they can be
      divided into three groups: attachment-inhibitors, corezeptor-antagonists and
      fusion-inhibitors. The fusion-inhibitor T-20 (Enfuvirtide) will be the first
      substance to be licensed in 2003. It has been shown that entry-inhibition is a
      realistic goal for clinical use. Until now T-20 was mainly added to an optimized
      background regimen in intensively pretreated patients. To achieve the best
      efficacy a combination of substances with only slight preexisting resistance
      seems to be favorable. Further efforts in providing orally applicable drugs with
      little potential for developing resistance and with synergistic effects are
      required.

PMID- 15011579
TI  - [Viral hepatitis B/C and HIV. Therapy of double infections].
AB  - In patients with HIV coinfection, chronic hepatitis B was initially treated with
      interferon alpha, but the long-term results were disappointing. Currently,
      pegylated interferon is being investigated in an ongoing study. The nucleoside
      analogues lamivudine and adefovir may well become established as alternatives to
      interferon alpha. Treatment of hepatitis C in HIV coinfection with interferon
      alpha plus ribavirin also proved less efficacious compared to HCV-monoinfection.
      Initial preliminary results of studies on pegylated interferon alpha indicate an
      advantage over conventional interferon. Under treatment for hepatitis metabolic
      acidosis and hepatic decompensation may occur--in particular with didanosine
      and/or stavudine--and these substances may therefore be avoided as antiretroviral
      therapy in dual infection with hepatitis and HIV.

PMID- 15011580
TI  - [Counteracting the sigma. Lipodystrophy decreases prognosis and quality of life].

PMID- 15011581
TI  - [Lipodystrophy syndrome. Therapeutic progress is still pending].
AB  - A common problem seen with the long-term use of highly active antiretroviral
      therapy (HAART) is the HIV-associated lipodystrophy syndrome. Clinical signs
      include a loss of peripheral subcutaneous fatty tissue, an increase in visceral
      or local fat, and altered glucose and lipid metabolism. The physical changes
      frequently impair quality of life, and the patient's adherence to treatment
      regimens. Metabolic changes may possibly represent cardiovascular risks with
      incalculable consequences over the long term. Although the lipodystrophy syndrome
      was first described in 1998. It still lacks a definition. So far, therapeutic
      strategies have remained ineffective or have had only limited success. Proposed
      treatments include general recommendations (diet, physical exercise, etc.),
      changing the antiretroviral therapy, and treatment with metabolically active
      medication.

PMID- 15011582
TI  - [Opportunistic diseases. Risk can be estimated].
AB  - The role of opportunistic diseases in daily clinical routine is once again
      expanding. The signs of a change in the trend towards increasing incidence
      observed in the year 2000 have unfortunately been confirmed. The risk of
      contracting an opportunistic infection can be estimated with the aid of the CD4
      cell count and the viral burden. CM viremia can also be employed as a predictor
      if highly active antiretroviral therapy (HAART) fails to cure cytomegaly. In the
      age of HAART, the spectrum of diseases resulting in hospitalization of HIV
      patients has undergone a change. A notable increase has been observed in
      hospitalizations for toxic side effects of medication, respiratory infections and
      liver diseases, in particular hepatitis. Following the introduction of HAART, the
      mortality rate of HIV-infected patients dramatically decreased, but the results
      of an American study show that, since 1999. It is on the increase again.

PMID- 15011583
TI  - [Ensuring high adherence. Clever combination assures therapeutic success].

PMID- 15011585
TI  - [Potent new protease inhibitor. Boostered protease inhibitors--a separate class
      of drugs].

PMID- 15011584
TI  - [Long-term tolerance. Preventing lipoatrophy].

PMID- 15011586
TI  - [No selection of mutations. 908 raises genetic resistance barrier].

PMID- 15011587
TI  - [Immune reconstituted inflammatory syndrome. Pitfalls of antiretroviral therapy].
AB  - The pandemic HIV infection, the more frequent use of immunosuppressive treatment,
      and the improved long-term prognosis of immunocompromised patients due to better
      supporting therapies have resulted in an increase in the prevalence of
      immunodeficiencies. Highly active antiretroviral therapy (HAART) can improve
      immunocompetence in HIV patients, even when the immunodeficiency is far advanced.
      This has resulted in an impressive and lasting lowering of the morbidity and
      mortality associated with HIV infection. However, immune reconstitution may
      exacerbate subclinical opportunistic infections or autoimmune diseases, or result
      in an unexpected, paradoxical aggravation of intercurrent inflammatory diseases.
      The atypical inflammatory conditions have a number of synonymous names: immune
      restoration disease (IRD), immune reconstitution syndrome (IRS), or immune
      reconstitution inflammatory syndrome (IRIS). In the light of specific
      differential therapeutic consequences, it is important to distinguish the
      clinical presentation from that of corresponding opportunistic infections.
      However, diagnostic and therapeutic standards for IRIS have not yet been worked
      out. The present overview also points to possible diagnostic pitfalls, and makes
      suggestions for a possible classification of the condition and the therapeutic
      options.

PMID- 15011588
TI  - [Justified hope after 4 years. Initial therapy still without resistance].

PMID- 15011589
TI  - [Results of a large randomized study: after switch to LPV/r quality of life
      improved].

PMID- 15011590
TI  - [Immunologic control of HIV-1 infection. Fantasy or soon reality?].
AB  - The human immunodeficiency virus-1 (HIV-1) preferentially infects CD4+ cells,
      leading to their destruction. In contrast to other viral infections, the immune
      system is unable to keep the HIV infection under permanent control in most cases.
      This failure ultimatively results in immunodeficiency with occurrence of AIDS
      defining diseases. In recent years, highly active antiretroviral therapy (HAART)
      has become available, and the number of AIDS cases and deaths have decreased
      dramatically. However, limitations of HAART become more apparent, demanding
      greater emphasis on search for alternative approaches. Stimulation and modulation
      of the immune response to HIV are new and promising strategies. A prerequisite,
      however, is the knowledge about immunologic defense mechanisms against HIV. In
      this article, the major factors of innate and acquired immune responses to HIV
      are described.

PMID- 15011591
TI  - [Initial retroviral drug with new mechanism of action. Peptide T-20 enriches
      therapeutic arsenal].

PMID- 15011592
TI  - [A light meal at the same time is enough. Advantages of natural enhancement of
      nelfinavir].

PMID- 15011593
TI  - [HIV resistance. More the rule than an exception].
AB  - Resistance-associated mutations of the HIV genome are one major reason for
      failure of highly, active antiretroviral therapy. The accumulation of resistance
      is demonstrated by data from the HCUS-study, where resistant virus strains were
      isolated in about 50%. More than 60% of the patients showed therapy failure in
      this survey, and resistance was found in almost 80% of these. Mutations in the
      HIV genome were also described in treatment-naive patients. In the German
      Seroconverter Study the rate of resistance was 12%, in a multicenter study in
      Nordrhein-Westfalen resistant isolates were found in 14% of chronically infected
      cases. The wide distribution of HIV resistance in treated and untreated patients
      is an important problem in the management of HIV-infection. It requires a
      rational application of resistance testing. International studies are under way
      to further characterize the relevance of the phenomenon of HIV resistance.

PMID- 15011594
TI  - [First nucleotide analog with noteworthy safety profile. Tenofovir effective in
      all stages of the infection].

PMID- 15011595
TI  - [Resistance in a new light. About mutations and their interactions].

PMID- 15011596
TI  - [Neurologic complications of HIV infection in the HAART era. Rapid and efficient
      diagnosis].
AB  - Despite the undisputable therapeutic success of highly active antiretroviral
      therapy (HAART), neurological complications of HIV-infection are still an
      unresolved problem. Most important are the directly HIV-associated complications,
      which comprise HIV-associated encephalopathy, myelopathy as well as peripheral
      neuropathies and muscle diseases. Among the nowadays relevant opportunistic
      infections are toxoplasma encephalitis and JC-virus related progressive
      multifocal leukencephalopathy, finally neurological complications are provoked by
      so called immune reconstitution phenomena. This reviews' aim is to provide a
      diagnostic manual leading to appropriate therapy by effective diagnostic
      procedures.

PMID- 15011597
TI  - [Psychiatric diseases and HIV infection. These patients are dually stigmatized].
AB  - Psychiatric disease is a frequent complication of HIV-infection. Schizophrenic
      psychosis, major depression, affective disorders, phobia and drug addiction occur
      among others. Furthermore, highly active antiretroviral therapy (HAART) can
      provoke psychiatric illness in HIV-infected patients. Intrapersonnel and
      psychosocial factors of this systemic manifestation are described, additionally,
      diagnostic and therapeutic problems are presented in detail.

PMID- 15011598
TI  - [Nevirapine has gained acceptance. Good antiretroviral effect--favorable lipid
      profile].

PMID- 15011600
TI  - [Pharmaco-economic aspects of HIV therapy. Savings with HAART].

PMID- 15011599
TI  - [Non-peptide protease inhibitor in phase III study. Tipranavir--control of
      multidrug resistant viruses].

PMID- 15011601
TI  - [No standard: drug holidays in HAART. Continuous or interval treatment?].

PMID- 15011602
TI  - [HIV infection + tumor. Fewer cases of Kaposi tumor, but greater lymphoma
      incidence].

PMID- 15011603
TI  - [Lipid profile and body fat--significant "side effect" of antiretroviral therapy.
      Tenofovir: favorable profile of adverse effects].

PMID- 15011604
TI  - [CROI highlights of D:A:D Study (Data Collection on Adverse Events of Anti-HIV
      Drugs Study) and 2NN Study. Stepping into the grease pot].

PMID- 15011605
TI  - [Managing side effects. Individualized dosage makes indinavir more tolerable].

PMID- 15011606
TI  - ["Once daily" drugs simplify therapy. Rp. HAART once daily].

PMID- 15011608
TI  - ERISA preemption remains on the front burner.

PMID- 15011607
TI  - ["Double boosting" passes the test. LPV/r plus SQV in complicated salvage
      situation].

PMID- 15011609
TI  - Claim based on fraudulently obtained consent restored. Petzelt v. Tewes.

PMID- 15011610
TI  - Toolkit teaches youth about AIDS prevention.

PMID- 15011611
TI  - ACLU identifies HIV/AIDS discriminatory practices in U.S.

PMID- 15011612
TI  - Challenges remain in preventing mother-to-child HIV transmission.

PMID- 15011613
TI  - Political asylum. Court denies asylum for critic of Ethiopian AIDS policies.

PMID- 15011614
TI  - Prisons. Food preparation by HIV-positive inmates not unconstitutional.

PMID- 15011615
TI  - Legal assistance. ACLU issues brochure on civil rights of those with HIV/AIDS.

PMID- 15011616
TI  - HHS issues national reports on quality of health care services.

PMID- 15011618
TI  - Stiff sentence upheld for inmate who bit deputy.

PMID- 15011617
TI  - Discrimination. HIV bias not a factor in bus driver's penalty for nondisclosure.

PMID- 15011619
TI  - Reduced sentence for offender with AIDS denied on appeal.

PMID- 15011620
TI  - Prisons. HIV-positive female sexual offender ordered released.

PMID- 15011621
TI  - Transfer of fluids necessary to mandate HIV testing of offender.

PMID- 15011622
TI  - AIDS fundraiser cleared in wrongful-death suit.

PMID- 15011623
TI  - Discrimination. AIDS legal group pushes for Philadelphia HIV education.

PMID- 15011624
TI  - New data from the CDC confirm HIV is on the rise.
AB  - The CDC has unveiled data showing that new HIV diagnoses have increased 5%
      between 1999 and 2002, and says the statistics likely reflect an increase in HIV
      cases and not simply increased HIV testing. The recent report offers the
      strongest evidence to date that the nation's prevention efforts are beginning to
      fail.

PMID- 15011625
TI  - CAFTA will harm HIV care, according to critics. Final agreement helps drug
      companies, they say.
AB  - Negotiations on the Central American Free Trade Agreement will result in more
      deaths from AIDS in the Central American nations participating in the agreement,
      charge several organizations that work to provide health care to poor
      populations. The reason is that the United States pushed for new intellectual
      property rules that will obstruct access to medicine by increasing medicine
      prices and delaying or blocking generic competition, they contend.

PMID- 15011626
TI  - Study: HIV diagnosis won't stop unprotected sex. Study shows prevention efforts
      are hindered.
AB  - Research of an inner-city New York City population has showed that many of the
      people, particularly women, diagnosed with HIV infection continued to engage in
      unprotected sex after their diagnosis and prevention education. The study also
      found that 25% of those infected with HIV had a new sexually transmitted disease
      diagnosis, and 15% used injection drugs.

PMID- 15011627
TI  - Study confirms the link between MSM and web. San Francisco officials use on-line
      interventions.
AB  - When the number of early syphilis cases in San Francisco increased from 41 in
      1998 to 495 in 2002, and more than two-thirds of these cases also were HIV
      positive, health department officials decided that new prevention interventions
      were needed. The syphilis outbreak also was notable in how it mainly involved men
      who have sex with men (MSM) by 2002. In 1998, only 22% of the early syphilis
      cases involved MSM, whereas in 2002, 88% involved MSM. Investigators with the San
      Francisco Department of Public Health discovered that a significant majority of
      the MSM syphilis cases listed the Internet as venue for meeting sexual partners.

PMID- 15011628
TI  - Review mortality trends to reveal emerging picture. Mortality increased for some
      complications.

PMID- 15011629
TI  - FDA notifications. UCB Pharma and FDA issue advisory letter.

PMID- 15011630
TI  - Epidemics in Asia, Eastern Europe worsen global picture. UNAIDS reports no good
      news in sight.
AB  - New HIV infections worldwide topped 5 million in 2003, and 3 million people died
      of AIDS globally, catapulting the epidemic to its most bleak year yet. And
      despite talk about expanding treatment and prevention services to Africans, few
      are getting it.

PMID- 15011631
TI  - China private partnership offers some new hope. SARS outbreak opened doors for
      HIV prevention.
AB  - Until recently, there have been multiple barriers to initiating HIV prevention
      and education programs in China. That might be changing thanks to an unlikely
      scenario. Criticism of the way China dealt with SARS could result in more
      attention to HIV.

PMID- 15011632
TI  - PACHA town hall meeting discusses Bush AIDS plan.

PMID- 15011633
TI  - U.S. specialists analyze challenges facing China's response to AIDS.

PMID- 15011634
TI  - Court: offender forfeited challenge to HIV testing.

PMID- 15011635
TI  - Housing. Sale of Harlem residential HIV/AIDS facility approved.

PMID- 15011636
TI  - Probable cause must be shown to order HIV testing.

PMID- 15011637
TI  - Prisons. Appeals court: poor health not only consideration for parole.

PMID- 15011638
TI  - Sentencing. Peril posed by HIV can be used to enhance prison term.

PMID- 15011639
TI  - Sentencing. Life sentence for offender with AIDS not in state's interest.

PMID- 15011640
TI  - Grants. NIAA seeks researchers to examine alcohol, HIV-AIDS links.

PMID- 15011641
TI  - Advocacy in America.

PMID- 15011642
TI  - Open letter from ATAC to Abbott's CEO, Miles White.

PMID- 15011643
TI  - T-1249 development suspended.

PMID- 15011644
TI  - Gene genie. Can gene therapy deliver a better fusion blocker?

PMID- 15011645
TI  - Learning to ask for what you need.

PMID- 15011646
TI  - Seeking a definition of advocacy.

PMID- 15011648
TI  - Dodging bullets. The problem with PowerPoint.

PMID- 15011647
TI  - News from the bench.

PMID- 15011649
TI  - Groundswell.

PMID- 15011650
TI  - Funding long-term care by applying the trade-off principle to public and private
      insurance.
AB  - The uncertain need for long-term care (LTC) services is a risk that is best
      protected by insurance. However, current LTC funding in the United States relies
      heavily on personal payment and public welfare and only lightly on social
      insurance and private insurance. This method is akin to sitting on a two-legged
      stool, which is likely to be unstable. This brief describes a "three-legged"
      funding model where social insurance would provide basic LTC protection that
      would be supplemented by private insurance and personal payment. The model would
      mobilize public and private resources more effectively by linking LTC insurance
      to social security, private life insurance, and other financial products.

PMID- 15011651
TI  - The role of the patient and the family in deciding to forgoing life-support:
      Eastern and Western perspectives.

PMID- 15011652
TI  - Balancing autonomy with paternalism for psychiatric patients? Ambiguities in
      personal choice and adcance directivesments [sic].

PMID- 15011653
TI  - Bioethics: a philosophical basis for moral decisions.

PMID- 15011654
TI  - The ethical and epistemic issues in inferior treatment in clinical research.

PMID- 15011655
TI  - New technology ethic.

PMID- 15011656
TI  - Euthanasia, and the meaning of death and dying: a Confucian inspiration for
      today's medical ethics.

PMID- 15011657
TI  - Is informed consent not applicable in China? Intellectual flaws of the "cultural
      difference argument".

PMID- 15011658
TI  - Professional responsibilities versus right of self-decision.

PMID- 15011659
TI  - Medical technologies vs human dignity: commodification of the human body and the
      moral cost.

PMID- 15011660
TI  - The human genome and the human control of natural evolution.
AB  - Recent advances in research on the Human Genome are provoking many critical
      problems in the global policy regarding the future status of human beings as well
      as in that of the whole life system on the earth, and consequently, these
      advances provoke the serious bioethical and philosophical questions. Firstly, how
      can we comprehend that we are going to have the complete technology to manipulate
      the system of the human genome and other non-human genomes? Though no science and
      technology can be complete, we will, I believe, take possession of an almost
      complete gene technology in the early stage of the next Century. Gene technology
      will soon fall into the hands of human beings instead of rendering in the
      province of God. Secondly, which gene technologies will we actually realize and
      utilize in the early stages of the 21st Century? Most probably, we will adopt
      these technologies to health care to treat some apparent bodily diseases, for
      instance, cancer, hemophilia, ADA deficiency, and so forth, and sooner or later
      we will adopt gene therapy to germ lines, which, in the long run, suggests the
      possibility of a future "artificial evolution" instead of the "natural evolution"
      of the past. Thirdly, how is the new concept of "artificial evolution" justified
      ethically? I believe this kind of manmade evolution is the only way for human
      beings to survive into the future global environment. There cannot be any serious
      ethical objection against the idea of artificial evolution. Fourthly, what is the
      background philosophy for the concept of "artificial evolution"? I will discuss
      the nature of modern European humanism with individual dignity and fundamental
      human rights which has led the philosophy of modern culture and modern society,
      and I will conclude by suggesting that we should abolish an essential part of
      modern humanism and newly devise some alternative philosophy to fit the new
      Millennium.

PMID- 15011661
TI  - Common moral priorities and cultural diversities.

PMID- 15011662
TI  - "Bioethics--meetings and conflicts with a man".

PMID- 15011663
TI  - Call for a righteous justice: a Christian bioethics for the poor.

PMID- 15011664
TI  - Health care: a calling or just another profession?

PMID- 15011665
TI  - Job-based health insurance in the balance: employer views of coverage in the
      workplace.

PMID- 15011666
TI  - Midterm results of beating heart surgery in 1-vessel disease: minimally invasive
      direct coronary artery bypass versus off-pump coronary artery bypass with full
      sternotomy.
AB  - BACKGROUND: Off-pump cardiac surgery is becoming an established method of
      surgical revascularization. However, performing anastomoses on a beating heart
      can be challenging, especially through small incisions. We compared our midterm
      results in patients with 1 vessel disease using full sternotomy (OPCAB) or a left
      anterior minithoracotomy (MIDCAB). METHODS: At our institution between December
      1996 and December 1998, 102 patients (OPCAB, n = 45, MIDCAB, n = 57); age, 61 +/-
      11 years; 69% men with 1-vessel disease of the left anterior descending coronary
      artery (LAD) underwent off-pump myocardial revascularization through the left
      internal thoracic artery (LITA). In the OPCAB group 17 (37.8%) of the patients
      received an additional vein graft to a diagonal branch. OPCAB was generally
      preferred in obese or high-risk patients or patients with a long LITA-LAD
      distance (>7 cm) on an electron beam computed tomography of the chest. RESULTS:
      Operative mortality was 0. Time of surgery (169 +/- 48 versus 197 +/- 45 minutes)
      and coronary artery occlusion time (19 +/- 7 versus 23 +/- 6 minutes) were
      significantly lower (P = .004 and P = .009) in the OPCAB group. MIDCAB surgery
      was related to a higher incidence of occluded (4 versus 0; P = .039) or stenosed
      (7 versus 2; P = .06) anastomoses and necessity for immediate reintervention (9
      versus 0; P = .023). During a mean follow-up period of 5.2 years, MIDCAB patients
      (6 MIDCAB patients versus 1 OPCAB patient) tended to need more coronary
      interventions and develop more recurrent angina (23 MIDCAB versus 12 OPCAB
      patients). Two OPCAB patients died during the follow-up period. CONCLUSIONS: Our
      initial experience in beating heart surgery demonstrated that MIDCAB is
      technically more challenging than OPCAB. MIDCAB procedures should therefore be
      performed by experienced surgeons on selected patients. Midterm results after
      OPCAB procedures tend to a lower rate of adverse cardiac events.

PMID- 15011667
TI  - The new genetic technologies: why a theological perspective is necessary.
AB  - Secular bioethics poses questions that can be recognized as important, though it
      lacks the resources to answer them. Secular bioethics may retain the sense that
      there should be moral limits to the use of germline genetic engineering, but it
      lacks the basis to justify limits in principle. The contemporary practice of
      bioethics arose in the United States to fill a moral vacuum created by (1) the
      marginalization of medical ethics through the deprofessionalization of medicine,
      (2) the secularization of American society, and (3) an increased reliance on
      individual decision-making. The result is an ethics at the core of secular
      bioethics severed from a sense of ultimate purpose or direction for humans or the
      cosmos. This ethics and its bioethics are marked by (1) moral fragmentation and
      pluralism and (2) a loss of ultimate orientation. This bioethics can at best
      require (1) the prudent maximization of benefits over harms, (2) the condemnation
      of malevolent acts, and (3) the use of persons only with their consent. However,
      there fails to be a basis for a common view of benefit or of harm. Within this
      impoverished moral context, human biological nature can only appear to be a
      contingent outcome of spontaneous mutations, selective pressure, the constraints
      of physical laws, and random catastrophes. Such a bioethics, deprived of ultimate
      orientation, can provide no ground in principle for forbidding cloning, germline
      genetic engineering, or the fundamental recasting of human nature. Absent a
      theological point of orientation, medicine and the genetic technology are left
      with more power than ever but no clear moral sense of how to use that power.

PMID- 15011668
TI  - Bioethics and the challenges of the 21st century.
AB  - Bioethics is both a field of academic research and practical activity. It is
      understood as a body of scholarship directed to a better understanding of moral
      problems associated with health care and the biomedical sciences. As Romanian
      Orthodox experience the transformation of their culture through importing Western
      science and technology, they must critically assess the moral presuppositions
      that come attached to these forces. An authentic Orthodox Christian approach to
      health care and the biomedical sciences, as well as to bioethics, must develop a
      critical maturity. The challenge of Orthodox Christians in Romania is to join
      with Orthodox elsewhere in articulating an authentically Orthodox Christian
      bioethics.

PMID- 15011669
TI  - The involuntary civil commitment of mentally ill persons in the United States and
      Romania: a comparative analysis.
AB  - The law and policy relating to the civil commitment of mentally ill persons in
      the United States and Romania are currently undergoing significant changes. While
      many jurisdictions in the United States are moving towards increasing emphasis on
      various forms of outpatient civil commitment, Romania is contemplating a
      restructuring of its commitment procedures to conform to international principles
      of human rights and to resemble more closely the United States model of
      commitment and care. A comparison of the procedures and standards for the
      involuntary civil commitment of mentally ill persons under each system is,
      consequently, timely. This article begins with a discussion of how mental illness
      is defined and identified clinically in a cross-cultural context. The article
      then examines the legal meaning of mental illness in the civil context in the
      United States and Romania, focusing on the implications of these meanings for the
      civil commitment of persons deemed to be mentally ill. Current models, standards,
      and procedures for the civil commitment of persons deemed to be mentally ill are
      described, using schizophrenia as a case example. The article concludes with an
      analysis of the strengths and weaknesses of each system and the arguments that
      provide the basis for the current reform efforts.

PMID- 15011670
TI  - Creating conducive conditions for informed consent.

PMID- 15011671
TI  - The right to a dignified death--need for debate.

PMID- 15011672
TI  - Euthanasia.

PMID- 15011673
TI  - Understanding voluntary euthanasia: a personal perspective.

PMID- 15011674
TI  - Medical decisions as seen by philosophers.

PMID- 15011675
TI  - Should doctors strike work?

PMID- 15011676
TI  - Resident doctors on strike.

PMID- 15011677
TI  - Organs for sale.

PMID- 15011678
TI  - Hospital ethics committee.

PMID- 15011679
TI  - Handbook on medical ethics: medical ethics and the practitioner.

PMID- 15011680
TI  - Prenatal diagnostics: an offer you can't refuse?

PMID- 15011681
TI  - [Guidelines for Clinical Pathology/Laboratory Medicine of Cardiology of the
      Brazilian Society of Cardiology].

PMID- 15011683
TI  - Handbook of medical ethics: ethics in biomedical research.

PMID- 15011682
TI  - Medical ethics in the context of the National Mental Health Programme.

PMID- 15011684
TI  - The right to die.

PMID- 15011685
TI  - Medical ethics in India: ancient and modern (II).

PMID- 15011686
TI  - Idiopathic intracranial hypertension: The presence and morphology of sinovenous
      stenosis.

PMID- 15011687
TI  - A statewide evaluation of services provided to rape survivors.
AB  - This article presents the descriptive results of a statewide evaluation of
      hotline, advocacy, and counseling services provided to sexual assault victims in
      Illinois. Collaborative efforts of a multidisciplinary research team and sexual
      assault service providers resulted in victim-sensitive evaluation measures and
      data that reflect, for the first time, the collective impact of services on rape
      victims across the state of Illinois. Results of the evaluation suggest that,
      overall, services provided to rape victims provided support, increased
      information and knowledge, and helped victims to understand options and make
      decisions. The evaluation approach is notable for its collaborative nature and
      its sensitivity to rape victims during help-seeking and delivery; however, due to
      the high levels of distress common among rape survivors, some evaluation methods
      may not be appropriate for crisis intervention services such as hotline or
      advocacy. Implications for future evaluation research and policy are noted.

PMID- 15011688
TI  - A handicap for U.S. businesses.

PMID- 15011689
TI  - Accrediting telemedicine.

PMID- 15011690
TI  - Need nurses? Money matters.

PMID- 15011691
TI  - On: Miscarriages of psychoanalytic treatment with suicidal patients.

PMID- 15011692
TI  - On: Verdi's Rigoletto: the dialectic interplay of the psychic positions in
      seemingly 'mindless' violence.

PMID- 15011693
TI  - On: The idea of a moral philosophy: the impact of psychoanalysis on philosophy in
      Britain.

PMID- 15011694
TI  - Anger management.

PMID- 15011695
TI  - A patient walks into a bar... .

PMID- 15011696
TI  - Reorganisational and educational demands of psychoanalytic training today: our
      long and marasmic night of one century. Rejoinder.

PMID- 15011698
TI  - The moral implications of motherhood by hire.

PMID- 15011697
TI  - Institutional responses to boundary violations: the case of Masud Khan.

PMID- 15011699
TI  - Clinical trials: some ethical issues.

PMID- 15011700
TI  - Clinical trials: the pitfalls of interpretation.

PMID- 15011701
TI  - Ethics of contraceptive research: some issues.

PMID- 15011702
TI  - Sex-selection by IVF: the freedom to choose.

PMID- 15011704
TI  - Disclosure of confidential medical information.

PMID- 15011703
TI  - Sex-selection by IVF: detrimental to Indian women.

PMID- 15011705
TI  - The new genetics and ethics: Sixth Shri. B.V. Narayana Reddy Memorial Lecture,
      Indian Institute of World Culture, Bangalore.

PMID- 15011706
TI  - [Isokinetic or conventional physiotherapy in LBP rehabilitation].

PMID- 15011707
TI  - The debate on human cloning and legislative morality: notes on eugenics for an
      age of affluence.

PMID- 15011708
TI  - Health departments remain ill-prepared to respond to public health emergencies.

PMID- 15011709
TI  - Science policy and the law: reproductive and therapeutic cloning.

PMID- 15011710
TI  - To clone or not to clone.

PMID- 15011711
TI  - Why human reproductive cloning should not in all cases be prohibited.

PMID- 15011712
TI  - Popular cloning versus scientific cloning in ethical debate.

PMID- 15011713
TI  - Views of cloning from a physician's perspective.

PMID- 15011714
TI  - Cloning and harm to offspring.

PMID- 15011715
TI  - Primary lymphoma of bone: report of one case.

PMID- 15011716
TI  - The right to die: but who says? An agonizing quarrel between parents and husband.

PMID- 15011717
TI  - Progestins initiate adverse events of menopausal estrogen therapy.
AB  - OBJECTIVE: Recent report, particularly the Women's Health Initiative,
      demonstrated that hormone therapy with combined estrogen plus progestin increased
      the incidence of heart attacks, stroke, blood clots, breast cancer and dementia
      in women over 65 years old. We investigated the role of synthetic progestins in
      initiating the adverse events associated with estrogen therapy. METHODS: We used
      a fluorescence imaging technique, which allows video microscopic recordings of
      blood flow, blood vessel morphology and activities of various blood cells in a
      live animal. The acute peripheral and cerebrovascular responses were measured
      following intraperitoneal (5 or 10 mg) or intravenous (10 or 100 microg)
      administration of progesterone, synthetic progestins (medroxyprogesterone acetate
      and norethindrone) or estrogens (conjugated equine estrogens and 17 beta
      estradiol). RESULTS: In both peripheral and cerebral vasculature, synthetic
      progestins caused endothelial disruption, accumulation of monocytes in the vessel
      wall, platelet activation and clot formation, which are early events in
      atherosclerosis, inflammation and thrombosis. Natural progesterone or estrogens
      did not show such toxicity. CONCLUSION: The risk associate with combined estrogen
      plus progestin therapy may be a consequence of vascular actions of progestins.
      Using progestins with minimal vascular toxicity may lead to safer estrogen
      preparations for menopausal women.

PMID- 15011718
TI  - The Dutch story.

PMID- 15011719
TI  - [Process leading to the final negotiation of the WHO framework convention on
      tobacco control and the future direction for its implementation].

PMID- 15011720
TI  - The metamorphosis of a CNS entrepreneurial business.

PMID- 15011721
TI  - [Clinico-pathological conference. Penicillium marneffei infection].

PMID- 15011722
TI  - [Clinico-pathological conference. Paracoccidioidomycosis].

PMID- 15011723
TI  - [Clinico-pathological conference. Pulmonary actinomycosis].

PMID- 15011724
TI  - [Clinico-pathological conference. Pulmonary aspergillosis with an infiltrating
      image rapidly spreading in the pulmonary field prior to surgery].

PMID- 15011725
TI  - [Magnetic resonance: Nobel Prize of Medicine this year].

PMID- 15011726
TI  - [Impact of gastrointestinal symptoms on health related quality of life in
      patients with type 2 diabetes mellitus].
AB  - INTRODUCTION: A recent study has shown that health related quality of life
      (HRQOL) in patients with diabetes mellitus (DM) is affected by the presence of
      gastrointestinal symptoms (GI). It is unknown if this is reproducible among Latin
      patients with DM. OBJECTIVE: To determine the impact of GI symptoms on HRQOL of
      Latin patients with type 2 DM. METHODS: Between March and June 2001, consecutive
      patients with type 2 DM from a referral center were studied, excluding those with
      a history of DM related chronic complications or using insulin. A Bowel Symptom
      Questionnaire identified 47 patients with GI symptoms (A) and they were compared
      with 46 consecutive patients without GI symptoms (B). All patients answered the
      HRQOL questionnaire, SF-36 Spanish-Mexico. Results of the SF-36 were expressed in
      means +/- SD and analyzed by ANOVA and Bonferroni. A p < 0.05 was considered
      significant. RESULTS: The frequency of GI symptoms in A were: 41.6%
      gastroesophageal reflux, 14.6% dyspepsia, 21.3% IBS, 20.8% fecal incontinence and
      2.2% combinations. Compared to A, B showed lower scores in all the SF-36 scales
      (Physical function: p = 0.001, role limitations-physical: p = 0.003, bodily pain:
      p = 0.001, general health: p = 0.016, energy/fatigue: p = 0.003, social
      functioning: p = 0.013, emotional well-being: p = 0.004) except in role
      limitations-emotional. Also A had lower scores in the physical component summary
      (p = 0.001) but no difference in the mental component. CONCLUSIONS: In Latin
      patients with type 2 DM the presence of GI symptoms has a negative impact mainly
      on the physical components of HRQOL, compared to those without GI symptoms.

PMID- 15011727
TI  - [Increasing trend of antimicrobial drug-resistance in organisms causing
      bacteremia at a tertiary-care hospital: 1995 to 2000].
AB  - We described the trends of drug-resistant organisms isolated in blood cultures
      from patients detected in a teaching hospital from 1995 to 2000. We found an
      increase in the number of clinical isolates of Pseudomonas aeruginosa, Klebsiella
      pneumoniae, Enterobacter spp, Serratia spp, Staphylococcus aureus, S. epidermidis
      and Enterococcus spp, resistant to antibiotics commonly used to treat infections
      caused by these organisms. The frequency of gram-negative bacilli resistant to
      third-generation cephalosporins and quinolones increased during the period of
      study, and in 2000 more than 20% of the isolates were resistant. In contrast, the
      frequency of resistance to aminoglycosides and carbapenems was less than 20%. The
      frequency of resistant staphylococci increased exuberantly fifty fold to
      quinolones and five fold to oxacillin during the study period, therefore in 2000,
      26.1% of S. aureus isolates and 61% of S. epidermidis were resistant to
      oxacillin. The frequency of resistant enterococci also increased, and in 2000,
      50% were resistant to ampicillin, and 37.5% to gentamicin. The increase of drug
      resistant organisms isolated in blood had a direct impact in the empirical
      treatment of severely infected patients in our hospital. It is important to
      continuously supervise antibiotic use, and to adopt more strict control measures
      to decrease the frequency of infections caused by drug resistant organisms.

PMID- 15011729
TI  - Rigid rectosigmoidoscopy: still a well-tolerated diagnostic tool.
AB  - BACKGROUND: Although rigid rectosigmoidoscopy has been gradually replaced by the
      use of flexible rectosigmoidoscopy in recent years, it remains an effective,
      economic and widely available diagnostic tool. The aim of this study was to
      determine the type and magnitude of symptoms during rigid rectosigmodoscopy.
      METHODS: Prospective evaluation of patients who underwent diagnostic rigid
      rectosigmoidoscopy. The main complaints were recorded, and their magnitude
      quantified using a visual analogue scale. RESULTS: A total of 134 patients (mean
      age = 48 years) were examined. The prone jackknife position was used in 54% of
      them and left lateral decubitus in 46%. A complete (full length) examination was
      achieved in 68%. There were no complications. Sixty percent of patients referred
      complaints: pain (33%), discomfort by rectal preparation (13%), uncomfortable
      defecation desire (8%), and discomfort by the position (4%). Median values
      determined by visual analogue scale for pain, discomfort by rectal preparation,
      uncomfortable positioning and overall discomfort were graded as 3.3, 3.3, 2.1 and
      2, respectively. There was an association between higher magnitude of pain and
      overall discomfort with female gender, left lateral decubitus position, and full
      length exploration (p < 0.05). CONCLUSION: A high percentage of patients have
      symptoms during rigid rectosigmoidoscopy but the study is usually well tolerated
      due the low magnitude of pain and discomfort and remains a very cost-effective
      study.

PMID- 15011728
TI  - [Diagnostic evaluation of cardiovascular autonomic function in patients with
      diabetes mellitus].
AB  - Cardiovascular autonomic neuropathy is a common complication of diabetes
      mellitus. There are several diagnostic methods currently used. New techniques are
      described. The purpose of this review paper is to describe and analyze the
      clinical relevance of all this methods and propose an algorithm for the diagnosis
      of the cardiovascular autonomic neuropathy at daily medical practice.

PMID- 15011730
TI  - [Diagnosis and treatment of gout in Mexico City. Results from a physicians
      survey].
AB  - The diagnosis and proper treatment for gout were described decades ago but these
      guides are not always realized in all the patients. OBJECTIVES: To evaluate by a
      mail survey sent to general physicians (GP), internal medicine physicians (IM),
      orthopedists (OP) and rheumatologists (RP) from Mexico city, the way they
      diagnose and treat gouty patients. SUBJECTS AND METHODS: The survey was anonymous
      and included 20 questions, it was sent by mail to 1,836 physicians (640 GP, 640
      OP, 423 IM and 133 RP) living in Mexico city. RESULTS: The response was 6.8% OP,
      10.4% IM, 10.8% GP and 41.4% RP. Eighty two to 95% of them attend gouty patients.
      Diclofenac was the drug most frequently used as the treatment for acute attacks,
      although a high frequency of glucocorticoids and allopurinol prescription for
      acute gout attacks was detected (28% OP and 49% GP respectively). Allopurinol is
      the drug more frequently used for the chronic treatment, it is also used for
      asymptomatic hyperuricemia by 43-84% of the physicians. Twenty five percent do
      not adjust initial allopurinol doses to glomerular filtration rate. The
      prophylactic treatment is used in only some cases and the dietetic restrictions
      were variable. Some points regarding the treatment of these patients are not
      according those recommended in the literature. CONCLUSIONS: We need to increase
      the knowledge between physicians about gout diagnosis and proper treatment. The
      adequate treatment is in most of the cases safe, cheap and effective.

PMID- 15011731
TI  - [Response to thymectomy in patients with thymoma].
AB  - INTRODUCTION: Approximately 10% of patients with myasthenia gravis also have
      thymomas. The objective of this study was to describe the evolution after the
      thymectomy in 10 cases of myasthenia gravis associated with thymomas. METHODS:
      The study was based in a cohort of 132 patients with the diagnosis of myasthenia
      gravis, that underwent thymectomy between 1987 and 1997, and had at least three
      years of follow-up. We found 10 cases (7%) of thymomas. We analyzed the following
      variables: sex, age, associated diseases, disease evolution, Osserman, dose of
      edrophonium before surgery, steroid use before surgery, types of thymectomy,
      Osserman after surgery, pathology findings, and evolution. We used descriptive
      statistics according to the measurement level of the variables. RESULTS: Four
      (40%) were women and 6 (60%) were men. The antibodies against the acetylcholine
      receptor were tested in only 5 (50%) patients, and in all of them they were
      positive. 4 (40%) patients had complications after the thymectomy, being 2 (20%)
      of them myasthenic crisis, one (10%) pneumonia and another (10%) hemorrhage in
      the surgical wound. Six (60%) cases had malignant thymomas and 4 (40%) were
      benign. In the follow-up, 4 (40%) patients had a good clinical response of
      myasthenia gravis and 6 (60%) had no changes. CONCLUSION: The response to
      thymectomy was not as good as the response of the vast majority of patients with
      myasthenia gravis without thymomas. We found a high frequency of malignant
      thymomas in our patients.

PMID- 15011732
TI  - [Combined fixed doses therapy in systemic hypertension].
AB  - OBJECTIVE: A single blind clinical trial was conducted to assess the concept that
      initial treatment in stage I and II of hypertension with fixed doses of two
      antihypertensives that have different modes of action and additive effects, in a
      24-week period with bisoprolol (B), an cardioselective beta blocker, that does
      not have intrinsic sympathomimetic activity, associated to hydrochlorothiazide
      (HCTZ). MATERIAL AND METHODS: Thirty-one patients (22 females and 9 male) were
      included, with an age range between 20 and to 70 years (mean 52.45 +/- 12.10).
      After a two-weeks wash out period and a similar placebo phase, patients were
      assigned to receive a once-daily dosing of B 5 mg and 6.25 mg of HCTZ, during
      eight-weeks. Those patients that did not reduce their blood pressure below 90 mm
      Hg received a double dose of the beta blocker until the end of the study.
      RESULTS: After twenty-fourth weeks period of the study, the mean
      systolic/diastolic blood pressures reduction was 23.9/20.1 mm Hg, compared to
      basal levels (p < 0.001). The adverse effects were rare. No clinically
      significant changes from baseline in laboratory parameters were observed.
      CONCLUSION: This study demonstrates that fixed doses combination therapy with
      B/HCTZ (5 mg plus 6.25 mg) is effective and well tolerated, with a sustained
      hypotensive effect. Combined therapy with fixed doses, is an alternative in the
      initial treatment of mild to moderate hypertension.

PMID- 15011733
TI  - [Construction and validation of a clinical diagnostic-therapeutic guide for the
      hospitable management of patients with type 2 diabetes mellitus].
AB  - OBJECTIVE: To develop and validate a diagnostic-therapeutic guideline (DTG) for
      the management of hospitalized diabetic patients, and apply it to a sample of
      medical files. MATERIAL AND METHODS: The DTG was constructed and then validated
      by a consensus of internist physicians, afterwards it was applied to a sample of
      97 randomly selected medical files of diabetic patients discharged from a
      internal medicine service. Hospitalization time, studies requested, average
      glycemia, glycemic prior to the discharge, time for to achieve glycemic control
      and mortality were compared at different percentages of the DTG's application.
      The results were analyzed by U of Mann-Whitney and ANOVA of Kruskal-Wallis.
      RESULTS: The intra-class correlation coefficient among the physicians for the
      guide validation was 0.94, with minimal modifications of content and format. The
      time, in hours, to achieve glycemic control was minor with a higher application
      percentage of the complete guide, p < 0.001, and also of the therapeutic domain,
      p = 0.05. The last glycemic prior to the discharge was lower with a higher
      application than 75% of the diagnostic domain, p < 0.001. A higher application
      percentage of the entire guide was found in living subjects more than in deceased
      subjects, p = 0.001, and also of the therapeutic domain, p = 0.008, and of the
      diagnostic domain p = 0.05. CONCLUSIONS: A higher level of application of the DTG
      is associated with a shorter time to achieve glycemic control, lower glycemic
      prior to the discharge and lower mortality.

PMID- 15011734
TI  - Changes in compulsion and anxiety symptoms with nicotine transdermal patches in
      non-smoking obsessive-compulsive disorder patients.
AB  - OBJECTIVE: Some of the obsessive-compulsive disorder (OCD) symptoms can be
      elicited in rats by the administration of quinpirole (D2/D3 dopaminergic
      agonist). Nicotine administration blocked some aspect of checking behavior in
      that model. The main goal of this study was to determine if the clinical
      manifestations of OCD non smoking patients change with the administration of
      transdermal nicotine patches. MATERIAL AND METHODS: Eleven patients were studied
      (6 female and 5 males), average age 29.7 +/- 5.5 years. All of them were OCD
      according to DSM-IV criteria. Clinical scorings were done with Yale-Brown
      Obsessive Compulsive Scale (Y-BOCS), Beck Depression Inventory (BDI) and Beck
      Anxiety Inventory (BAI). Nicotine (17.5 mg/day) or placebo transdermal patches
      were randomly administered for five continuous days. RESULTS: Nicotine
      administration reduced the total Y-BOCS and the compulsive score of that scale,
      but did not reduce obsessions. Also anxiety was reduced as was shown by the BAI
      scores, when patients were on nicotine patches, no changes were observed in BDI.
      CONCLUSIONS: The present results replicated the animal findings about reduction
      in compulsive behavior after nicotine administration. Also suggest that nicotine
      depending on the dysfunction of the different neurotransmitter systems may
      produce different behavior or cognitive effects, also that even nicotine showed
      some beneficial effect in OCD patients, the low rate of nicotine smoking in this
      type of patients, may show other mechanisms than may protect to smoke in some
      psychiatric patients.

PMID- 15011735
TI  - [Comparative analysis of the influence of food and cimetidine in plasma levels of
      praziquantel].
AB  - Praziquantel (PZQ) is an effective drug for treatment of neurocysticercosis. The
      drug shows an extensive first-pass effect and therefore plasma levels are low. In
      order to increase plasma and CSF levels of PZQ other alternatives have been
      investigated such as the use of PZQ jointly with cimetidine or food. With the
      pharmacokinetic parameters obtained in these studies, in the present work
      computer simulations were made in order to predict plasma concentrations of PZQ
      administration with cimetidine or with meals under the two treatments currently
      used: ultrashort scheme (three dose of 25 mg/kg given at 2-hours intervals) and
      the traditional scheme (50 mg/kg/day divided in three dose given at 8-hours
      intervals for 15 days). The results of our simulations showed that the
      combination of PZQ with a high carbohydrate diet could be an adequate alternative
      for clinical therapy. Furthermore a clinical study was performed in 18 patients
      with neurocysticercosis, which received the ultrashort scheme in fasting state,
      with cimetidine or with a high carbohydrate diet. The efficacy of the treatment
      was evaluated by the percentage of disappearance of the lesions and plasma levels
      obtained in each group. The results showed that a high carbohydrate diet
      increases plasma levels of PZQ. The results of the clinical study, together with
      our simulations indicate that the treatment of PZQ with a high carbohydrate diet
      was an adequate clinical alternative and showed improvement of the effectiveness
      of PZQ therapy.

PMID- 15011736
TI  - Apolipoprotein(a) phenotypes and lipoprotein(a) in type 1 diabetes mellitus
      patients and their first-degree relatives.
AB  - The coronary artery disease is associated with more than threefold-increased risk
      in diabetes mellitus. Lipoprotein(a) and apo(a), a specific protein of this
      lipoprotein are risk factors for atherosclerosis. However, the association of
      apo(a) size with the lipoprotein(a) levels in patients with type 1 diabetes
      mellitus still controversial. OBJECTIVE: We investigated the apo(a) polymorphism
      and its association with lipoprotein(a) levels in children with type 1 diabetes
      mellitus and their non diabetic first-degree relatives. METHODS: This cross
      sectional study included 25 type 1 diabetic patients aged 1 to 17 years, one non
      diabetic sibling of each patient and both parents. Glucose, lipids, lipoproteins,
      apoAI, apoB, lipoprotein(a) plasma concentration as well as apo(a) phenotypes
      were determined. RESULTS: Median plasma lipoprotein(a) concentrations were 8.3,
      8.2, 4.2, and 9.3 mg/dL in type 1 diabetes mellitus, siblings, fathers and
      mothers respectively (p ns). The prevalence of plasma lipoprotein(a) excess (> 30
      mg/dL) was not significantly higher in type 1 diabetes mellitus patients than in
      their non diabetic siblings, or in their parents. Lipoprotein(a) levels and
      apo(a) distribution were similar in all groups (p ns) and those of parents
      correlated directly with the lipoprotein(a) and phenotypes of their offspring.
      CONCLUSIONS: Lipoprotein(a) levels and apo(a) size were similar in type 1
      diabetes mellitus cases and their first degree relatives and the associations
      between them were similar too, suggesting that Lp(a) does not appear to explain
      increased risk of atherosclerosis in patients with this disease.

PMID- 15011737
TI  - [Assay validation for determining nitrites and nitrates in biological fluids].
AB  - INTRODUCTION: Nitric oxide is an important modulator of numerous physiological
      and pathophysiological processes. An indirect form to detect NO production has
      been the quantification of its stable end products, nitrites and nitrates (NO2- +
      NO3-). These metabolites can be detected with a commercial kit, but it is
      somewhat expensive and not accessible to some laboratories in our country.
      OBJECTIVE: To validate an easy, accessible and less expensive assay for detecting
      nitrates and nitrites in biological fluids. MATERIAL AND METHODS: In this study
      we determined nitrates and nitrites by reducing nitrates enzymatically with
      nitrate reductase, followed by nitrites quantification using the Griess reagent.
      To validate the assay, NO3- concentration was evaluated in aliquots with known
      amounts of sodium nitrate, also NO2- + NO3- concentrations were detected in
      plasma containing known amounts of sodium nitrate, finally NO2- + NO3- levels
      were evaluated in plasma (n = 17) and ascites (n = 11) samples of cirrhotic
      patients. In samples of patients, NO2- + NO3- levels were also detected by using
      a commercial kit. RESULTS: The assay that we describe here detects nitrates in
      the range between 25 to 400 microM/L and nitrites between 25 to 100 microM/L.
      When specific concentrations of nitrates were added to plasma samples, the
      recovery percentage in most cases was greater than 95%. In plasma samples of
      cirrhotic patients, average concentrations of NO2- + NO3- was 44.6 +/- 22.4
      microM (mean +/- SD), similar to that found using the commercial kit, 40.9 +/-
      18.3 microM/L (p = 0.107). In ascitis samples, similar results using both methods
      were seen, 64.5 +/- 42.0 vs. 58.2 +/- 39.3 microM/L (p = 0.172) respectively.
      CONCLUSIONS: Our results suggest that the method described here could be
      considered as an alternative instead of commercial kits to determine NO2- + NO3-
      in plasma and ascites samples. In addition, this assay results more attractive
      because, it does not, require special equipment, it is very accessible to most
      laboratories, it may be use to assay one or more samples at any given time, but
      the most important advantage, is its cost effectiveness; thus each sample
      determination is about one fifth of the cost using the commercial kit.

PMID- 15011738
TI  - Nicotine dependence and psychiatric disorders.
AB  - Nicotine addiction is the single largest preventable cause of morbidity and
      mortality in the Western World. Smoking is not any more just a bad habit, but a
      substance addiction problem. The pharmacological aspects of nicotine show that
      this substance has a broad distribution in the different body compartnents, due
      mainly to its lipophilic characteristic. There are nicotinic receptors as members
      of cholinergic receptors' family. They are located in neuromuscular junction and
      in the central nervous system (CNS). Although they are similar, pentameric
      structure with an ionic channel to sodium, there are some differences in the
      protein chains characteristics. Repeated administration of nicotine in rats,
      results in the sensitization phenomenon, which produces increase in the
      behavioral locomotor activity response. It has been found that most
      psychostimulants-induced behavioral sensitization through a nicotine receptor
      activation. Nicotine receptors in CNS are located mainly in presynaptic membrane
      and in that way they regulated the release of several neurotransmitters, among
      them acetylcholine, dopamine, serotonin, and norepinephrine. In some activities
      like sleep-wake cycle, nicotine receptors have a functional significance.
      Nicotine receptor stimulation promotes wake time, reduces both, total sleep time
      and rapid eye movement sleep (REMS). About nicotine dependence, this substance
      full fills all the criteria for dependence and withdrawal syndrome. There are
      some people that have more vulnerability for to become nicotine dependent, those
      are psychiatric patients. Among them schizophrenia, major depression, anxiety
      disorders and attention deficit disorder, represent the best example in this
      area. Nicotine may have some beneficial effects, among them are some
      neuroprotective effects in disorders like Parkinson's disease, and Gilles de la
      Tourette' syndrome. Also there are several evidences that support the role of
      nicotine in cognitive improvement functions like attention, concentration, and
      memory. Finally there are several strategies to deal with nicotine dependence,
      Nicotine Replacement Therapy (NRT), which are nicotine chewing-gum, transdermal
      nicotine patches, and nicotine inhalators device. Also some antidepressants like
      bupropion has shown to be effective in smoking cessation treatment. To know more
      about nicotine phenomenon would be important, because that will allow a more
      mature perspective about the damage and beneficial effects of that substance.

PMID- 15011739
TI  - [Stem cells from postnatal tissues. Expectations regarding their possible
      clinical use].

PMID- 15011740
TI  - [Immunogenetics of chronic ulcerative colitis].
AB  - Genetic factors have a definitive role in the etiology of ulcerative colitis
      (UC). The mode of inheritance suggests a polygenic disease with the penetrance of
      the genetic factors being strongly influenced by environmental factors. Several
      studies have been reported associations between UC and the polymorphism of genes
      that are located in the major histocompatibility complex (MHC) on the short arm
      of chromosome 6. The human leukocyte antigen (HLA) class II genes are candidates
      for a role in the pathogenesis of UC, because their products play a central role
      in the immune response. The MHC region contains numerous immune related genes,
      and it has now become clear that different alleles of the MHC genes are strongly
      linked. Association studies have suggested a role for HLA-DR alleles in disease
      susceptibility to UC. Thus, HLA-DRB1*0103, DRB1*1502 and DRB1*12 were found to be
      positively associated with UC. On the other hand, the tumor necrosis factor alpha
      (TNF-alpha) gene encodes a proinflammatory cytokine that is found in increased
      concentrations in the mucosa of patients with inflammatory bowel disease. The
      regulation of TNF expression is in part genetically determined because the
      polymorphisms -238, -308, -863, -857, and -1031 found in the promoter region are
      associated with increased TNF production. Recent data suggests that TNF
      polymorphism may be more important in determining susceptibility to UC and these
      TNF markers could predict response to infusion with chimeric anti-TNF antibody.

PMID- 15011741
TI  - [Phage display applications in clinical diagnosis].
AB  - To date, the phage display methodology is a great choice in clinical diagnostic
      field. Using phage display is possible design and choose peptides and proteins
      that are expressed on filamentous phage surface. So, these extremely reactive and
      specific biomolecules can be used in several diagnostic tests. The advantages of
      phage display over other methodologies have been shown because of its successful
      results in biomedical and clinical research. The more important reaches of phage
      display in clinical diagnostic and the way that has been applied to different
      diseases will be described in this review.

PMID- 15011742
TI  - [The surgery and its teaching in Mexico. Historical review 1325-2000].
AB  - OBJECTIVE: To relate the outstanding events in the surgical teaching in Mexico
      since 1325 to 2000. DESIGN: Historic review. SETTING: Third level health care
      hospital. RESULTS: The teaching of surgical procedures has been pretty much alike
      in many cultures around the world, even though this did not happened at the same
      time in all places; a very good example of this are surgical teachings in ancient
      Egypt, Greece and Mexico separated by 4,300 and 1,900 years respectively whose
      surgical methods and its teaching are quite similar. Afterwards the influence of
      Spanish, French, German and American medical cultures developed faster and
      efficient changes with the main objective of obtain every time better surgeons.

PMID- 15011743
TI  - [More about interest conflicts].

PMID- 15011744
TI  - [Commentary about electrocardiographic alterations in myasthenia gravis].

PMID- 15011745
TI  - Correlation of ionizing irradiation-induced late pulmonary fibrosis with long
      term bone marrow culture fibroblast progenitor cell biology in mice homozygous
      deletion recombinant negative for endothelial cell adhesion molecules.
AB  - Ionizing irradiation damage to the lung is associated with an acute inflammatory
      reaction, followed by a latent period and then late effects including
      predominantly pulmonary fibrosis. The cells mediating fibrosis have recently been
      shown to derive from the bone marrow hematopoietic microenvironment. Initiation
      of late pulmonary irradiation lung damage has been correlated with up-regulation
      of VCAM-1 and ICAM-1 in pulmonary endothelial cells, followed by infiltration of
      macrophages and bone marrow-derived fibroblasts forming the fibrotic lesions of
      organizing alveolitis/fibrosis. To determine whether the absence of expression of
      VCAM-1, ICAM-1, or other adhesion molecules known to be relevant to inflammatory
      cell attachment to lung endothelial cells was associated with a decrease in
      irradiation-induced lung fibrosis, homozygous deletion recombinant knockout mice
      lacking each of several adhesion molecules were tested compared to littermates
      for survival and development of organizing alveolitis following 20 Gy irradiation
      to both lungs. Bone marrow culture longevity has been shown to be a parameter,
      which correlates with both hematopoietic stem cell reserve and the integrity of
      fibroblast progenitors of the supportive hematopoietic microenvironment;
      radiation lung survival data were correlated to longevity of hematopoiesis in
      long-term bone marrow cultures established from tibia and femur bone marrow of
      the same mice. Homozygous deletion recombinant negative mice including VCAM-1-/-,
      ICAM-1-/-, E-Selectin-/-, or L-Selectin-/- were irradiated to 20 Gy to both lungs
      and followed for survival and percent organizing alveolitis at time of death
      compared to each normal littermate. A significant increase in survival (median
      190 days) was detected with L-Selectin-/- compared to littermate control mice
      (median 140 days) or other groups. Long-term bone marrow cultures from L-Selectin
      /- mice showed no detectable difference in marrow fibroblasts or hematopoietic
      cell biology compared to normal littermates; however, E-Selectin-/- mouse long
      term bone marrow cultures showed an increase in total cumulative cell production
      (1.7 x 10(8) cells per flask) compared to bone marrow cultures from normal
      littermates (1.8 x 10(6) cells per flask) or other groups. As additional
      controls, transgenic Sod2 mouse long-term bone marrow cultures and those from
      HPV16, E6 and E7 cytokeratin 14 transgenic mice were also tested. No detectable
      difference in hematopoiesis was noted in these cultures compared to littermates.
      The results suggest a complex pattern of involvement of endothelial specific
      adhesion molecules and marrow fibroblasts in the cell biologic events associated
      with late irradiation pulmonary fibrosis.

PMID- 15011746
TI  - Plasma vascular endothelial growth factor (VEGF) measured in seventy dogs with
      spontaneously occurring tumours.
AB  - BACKGROUND: Vascular endothelial growth factor (VEGF) acts specifically on
      endothelial cells mediating tumour neovascularisation and initiating tumour
      growth and metastasis. In humans, high VEGF levels are correlated with poorer
      prognosis but in dogs minimal information on plasma VEGF is available. Therefore,
      we analysed plasma VEGF in a variety of spontaneous canine tumours. MATERIALS AND
      METHODS: Plasma from seventy dogs with various spontaneous tumours was taken
      prior to radiation therapy. A human VEGF ELISA was used for analysis. RESULTS:
      Mean plasma VEGF was 7.2+/-7.8 pg/ml. Mean plasma VEGF level varied among
      different tumour types with the highest level in oral melanomas (12.4 pg/ml). In
      patients with sarcomas of soft tissue or bone origin, plasma VEGF levels
      increased significantly with decreasing haemoglobin concentration (p =0.013).
      CONCLUSION: Canine plasma VEGF levels depend on tumour histology, with higher
      levels found in more aggressive tumours. The negative correlation between plasma
      VEGF and haemoglobin (hb) is most probably due to tissue hypoxia seen in anaemic
      animals.

PMID- 15011747
TI  - The inhibition of N-acetyltransferase activity and gene expression in human
      bladder cancer cells (T24) by shikonin.
AB  - Shikonin has the potential to prevent, or be used in the treatment of, bladder
      transitional cell carcinoma induced by arylamines. We evaluated its effectiveness
      by measuring the amount of acetylated 2-aminofluorene (AF), AF-DNA adducts,
      changes of NAT mRNA and the amount of NAT enzyme. T24 human bladder cancer cells
      were incubated with 30 microM AF with different concentrations of shikonin for
      various times. T24 cells treated with shikonin (16 microM) were then harvested
      and used in 2 experiments: 1). T24 cells were incubated with 22.5 microM AF and
      shikonin (0, 16 microM) (co-treatment) for 6, 12, 18, 24 and 48 h. 2). T24 cells
      were incubated with various concentrations of AF and shikonin (0, 16 microM) for
      24 h. AF and AAF were measured by HPLC. Then in the prepared human T24 cell
      cytosols different concentrations of AF and shikonin were added to measure the
      kinetic constants of NAT. Next, AF-DNA adducts in human T24 cells with or without
      treatment with shikonin were detected and measured. The final two steps included
      measuring the NAT Ag-Ab complex after treatment with and without shikonin and
      evaluating the effect of shikonin on the NAT genes. Higher concentrations of
      shikonin induced decreasing AF acetylation. We found that the longer the culture
      period, the greater the difference in AF acetylation in the same shikonin
      concentrations. It was also noted that increase in AAF was proportional to
      incubation time. In the presence of 16 microM of shikonin, N-acetylation of AF
      decreased by up to 72-84%. Shikonin decreased the amount of AAF production in
      human T24 cells in all examined AF doses. Both Km and Vmax values in the
      cytosolic NAT decreased after the addition of shikonin to the cytosol. Finally,
      shikonin decreased the amount of AAF production and AF-DNA adducts formation in
      human 724 cells in all examined AF doses. The percentage of cells stained by
      antibody was significantly different after treatment with shikonin, especially
      with the higher shikonin concentrations. The NAT1 mRNA level and the NAT1/beta
      actin ratio decreased significantly with higher concentrations (16-24 microM) of
      shikonin. Shikonin affected NAT activity, gene expression (NAT1 mRNA), AF-DNA
      adducts formation and formation of NAT Ag-Ab in human bladder tumor T24 cells.
      Therefore, shikonin should be considered as a candidate agent for the prevention
      or treatment of transitional cell carcinoma.

PMID- 15011748
TI  - The 500-base-pair fragment of the putative gene RvD1-Rv2031c is also present in
      the genome of Mycobacterium tuberculosis.
AB  - BACKGROUND: It has been proposed that differentiation between M. bovis and M.
      tuberculosis is possible by using a PCR assay for the 500bp fragment present only
      in the M. bovis genome. MATERIALS AND METHODS: Forty clinical samples and 16
      clinical isolates from the Department of Microbiology, as well as 4 clinical
      isolates obtained from another laboratory, were tested for the purpose of this
      study. As controls we tested 2 M. bovis (M. bovis BCG Pasteur TMC1011 and M.
      bovis BCG Copenhagen), 1 H37Rv M. tuberculosis strain, 2 M. avium (ATCC15765 and
      ATCC1975, respectively) and 1 M. paratuberculosis (ATCC19698) strains. RESULTS:
      None of the mtp40- negative clinical isolates amplified the 500bp fragment,
      whereas 4 out of 17 mtp40-positive clinical isolates scored positive for the
      500bp fragment. All clinical isolates scored positive for IS6110, mtp40, the pncA
      and oxyR PCR's. All but one of the clinical isolates amplified the 500bp
      fragment. Sequence analysis of the pncA and oxyR PCR products revealed the
      presence of nucleotide C at position 169 and G at position 285 respectively,
      suggesting M. tuberculosis as the causative agent. CONCLUSION: Our data suggest
      that the 500bp PCR fragment is present not only in M. bovis but also in M.
      tuberculosis.

PMID- 15011749
TI  - Insulin-like growth factor binding protein 1 (IGFBP-1) in vaginal fluid in
      pregnancy.
AB  - OBJECTIVE: To examine vaginal insulin-like growth factor binding protein 1 (IGFBP
      1) as a marker of preterm delivery, amniotic fluid leakage or vaginal infection.
      MATERIALS AND METHODS: The material consisted of a nested case-control study (67
      with idiopathic preterm delivery and 406 randomly selected women with term
      deliveries) from a prospective cohort of 2,846 women. RESULTS: Vaginal npIGFBP-1
      was weakly associated with preterm delivery. Elevated npIGFBP-1 gave an increased
      risk of preterm delivery (OR 2.8 [1.4-6. 7]). Elevated IGFBP-1 provided a
      sensitivity of 13% at a false-positive rate of 4.4% in a low-risk population.
      When adjusting for other covariates associated with preterm delivery the
      association between npIGFBP-1 and preterm delivery disappeared; there was an
      interaction between alcohol consumption and npIGFBP-1. CONCLUSION: The current
      study found vaginal npIGFBP-1 to be weakly associated with gestational age at
      delivery. However, in this study the association may potentially be explained by
      alcohol consumption.

PMID- 15011750
TI  - Glucocorticoid receptor function suppresses insulin-like growth factor 1 activity
      in human KLE endometrial-like cells.
AB  - We analysed the glucocorticoid receptor (GR) regulation on the expression of
      insulin-like growth factor 1 (IGF-1), type I IGF receptor (IGF-1.R), IGF-binding
      protein 3 (IGFBP-3), urokinase-type plasminogen activator (uPA) and uPA receptor
      (uPA.R) mRNA in human KLE endometrial-like cells. We documented that KLE cells
      express IGF-1, IGF-1.R, uPA and IGFBP-3 mRNA, however not uPA.R mRNA. Exogenous
      administration of dexamethasone inhibited the proliferation of KLE cells without
      inducing apoptosis. The inhibition of dexamethasone on KLE cell proliferation was
      neutralized by exogenous administration of IGF-1. Furthermore, dexamethasone
      suppressed the expression of IGF-1 mRNA and IGF-1.R mRNA as well as the IGF-1
      bioavailability in KLE cell culture media, but it did not alter the expression of
      uPA mRNA and IGFBP-3 mRNA in KLE cells. Since the peritoneal fluid of women with
      endometriosis is known to contain IGF-1, which stimulates the proliferation and
      inhibits the apoptosis of endometrial-like cells, it is conceivable that GR
      mediated down-regulation of IGF-1 bioavailability may be of clinical relevance
      for endometriosis.

PMID- 15011751
TI  - The effect of alcohol and gemfibrozil co-administration in Wistar rats.
AB  - INTRODUCTION: The ingestion of alcohol (Alc) as well as gemfibrozil (Gem), a
      fibrate drug used to treat hypertriglyceridaemia, may occur on a long-term basis
      in humans. Since both Alc and Gem can disturb liver function, we assessed the
      effects of administering Alc together with Gem in Wistar rats. MATERIALS AND
      METHODS: Male Wistar rats were randomized and divided into 4 groups of 10 each.
      They were fed (once a day) via a stomach tube with: i) 2 ml of polyethylene
      glycol (Peg); group Peg, ii) 2 ml of Peg + 2 ml of 25% v/v pure Alc in water;
      group Alc + Peg, iii) 2 ml of Gem solution in Peg (3.4 mg/100 g body weight);
      group Gem +Peg, iv) 2 ml of Gem solution in Peg 2 + 2 ml of Alc; group Gem +Alc
      +Peg. Another 13 male Wistar rats were only fed a standard laboratory diet
      (control group). After 8 weeks, blood samples were drawn and the livers removed.
      Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline
      phosphatase (AP), total cholesterol (TC) and triglycerides (TG) were measured.
      Liver histopathology was also assessed. RESULTS: All tube-fed groups had higher
      body mass index compared to controls (p<0.001). The control group had lower AP
      compared to Gem+Peg and Gem +Alc+Peg groups (p=0.005 and p=0.018, respectively).
      The Peg group had lower AP compared to G+Peg (p=0.041). All tube-fed groups had
      lower ALT compared to controls (p<0.001). The TC levels were lower in tube-fed
      groups with Gem (Gem +Peg and Gem+Alc +Peg) compared to controls (p=0.002 and
      p=0.039, respectively). Among the tube-fed groups, the TC level was lower in Gem
      +Peg compared to Peg and Alc+Peg groups (p=0.047 and p=0.01, respectively). No
      differences were found among tube-fed groups and control rats in blood AST and
      TG. Liver histopathology was similar in all groups and within the normal range.
      CONCLUSION: A moderate amount of Alc daily together with Gem is safe in rats. Peg
      administration in Wistar rats protects from the Alc-induced TG and AST rises.

PMID- 15011753
TI  - Comparison of metastatic behavior of parental and metastatic pancreatic cancer
      cell lines in Syrian golden hamsters.
AB  - The major cause of death in patients with pancreatic cancer is metastatic
      disease. In fact, at the time of diagnosis, patients usually have locally
      advanced or metastatic disease involving lymph nodes, liver, lungs or peritoneum.
      Therefore, for a better understanding of the tumoral behavior to design
      prevention or treatment strategies, in vivo models are important. We report here
      the results of the metastatic behavior of parental and metastatic cell lines in a
      hamster pancreatic cancer model when implanted orthotopically (OIH,OIM) or into
      the liver (LIH,LIM). Metastatic sites and survival were studied. Survival ranged
      from 72 to 105 days. The OIH group showed spontaneous metastases to lymph nodes.
      The second target organ was the lung. Liver metastases appeared earlier in the
      OIM group than OIH. LIH showed only metastases to the pancreas while the LIM
      group showed metastases to pancreas, vas deferens and testis. This study suggests
      that the metastatic behavior of parental and metastatic cell lines is different.
      Thus, this should be considered in the planning of clinical or surgical treatment
      against pancreatic cancer.

PMID- 15011752
TI  - Anti-obesity effects of three major components of green tea, catechins, caffeine
      and theanine, in mice.
AB  - To elucidate the anti-obesity effects of three major components of green tea,
      catechins, caffeine and theanine, female ICR mice were fed on diets containing 2%
      green tea powder and diets containing 0.3% catechins, 0.05% caffeine and 0.03%
      theanine, which correspond, respectively, to their concentrations in a 2% green
      tea powder diet, singly and in combination for 16 weeks. Body weight and food
      intake were determined monthly during this period, kidneys, adrenals, liver,
      spleen, brain, pituitary and intraperitoneal adipose tissues (IPAT) were weighed
      and lipid levels in the serum and liver were measured at the end of this period.
      The body weight increase and weight of IPAT were significantly reduced by the
      diets containing green tea, caffeine, theanine, caffeine + catechins, caffeine +
      theanine and caffeine + catechins + theanine. Noticeably, the IPAT weight
      decreased by 76.8% in the caffeine + catechins compared to the control group.
      Serum concentrations of triglycerides (TG) and non-esterified fatty acids (NEFA)
      were decreased by green tea, catechins and theanine. Moreover, caffeine +
      catechins, caffeine + theanine and caffeine + catechins + theanine also decreased
      NEFA in the serum. The TG level in the liver was significantly reduced by
      catechins and catechins + theanine in comparison with the control. These results
      indicated that at least caffeine and theanine were responsible for the
      suppressive effect of green tea powder (GTP) on body weight increase and fat
      accumulation. Moreover, it was shown that catechins and caffeine were synergistic
      in anti-obesity activities.

PMID- 15011754
TI  - Etiological agents of lower respiratory tract infections in Japanese children.
AB  - To investigate the etiology of pediatric community-acquired pneumonia and
      bronchitis, we conducted a prospective, population-based study covering the total
      population < 15 years of age in 16 municipalities in Hokkaido, Japan, during the
      period of April 2000 to March 2001. Chest radiographs were available for all
      cases (n = 921; 398 as pneumonia and 523 as bronchitis) and paired sera for
      serologic assays were available for more than half of the cases. The following
      specimens were also collected: nasopharyngeal swabs for viral, bacteriological,
      mycoplasmal and chlamydial studies, blood for serology and blood culture. The
      children were then followed-up on days 3, 7 and 14. Specific infecting organisms
      were identified in a total of 853 (92.6%) out of 921 patients (398 cases of
      pneumonia and 523 cases of bronchitis) including 205 with mixed infection as
      follows: Mycoplasma pneumoniae, 252 (274%) patients; respiratory syncytial (RS)
      virus, 188 (20.4%); influenza A virus, 110 (11.9%); Streptococcus pneumoniae, 95
      (10.3%); Haemophilus influenzae, 90 (9.8%); Haemophilus parainfluenzae, 35
      (3.8%); Staphylococcus aureus, 29 (3.1%); adenovirus, 27 (2.9%); Moraxella
      catarrhalis, 12 (1.3%); Pseudomonas aeruginosa , 7 (0.8%); Chlamydia pneumoniae,
      6 (0.7%); and other agents, 2 (0.2%). Mycoplasma infections were seen even in
      patients less than 5 years and RS and influenza A virus infections in patients
      more than 5 years of age. The importance of M. pneumoniae and RS virus in the
      etiology of lower respiratory infections in Japanese children was confirmed.

PMID- 15011755
TI  - Inhibition of proteasome activity by various fruits and vegetables is associated
      with cancer cell death.
AB  - There is a large amount of scientific evidence showing that fruits and vegetables
      lower the risk of cancer. However, the responsible molecular mechanisms remain
      poorly understood. Our previous studies have demonstrated that inhibition of
      proteasomal chymotrypsin-like activity is associated with cancer cell apoptosis,
      which may also be the major mechanism responsible for the anticancer effects of
      green tea polyphenols. In the current study, we tested the hypothesis that some
      fruits and vegetables inhibit tumor cell proteasome activity and that this
      inhibition contributes to their cancer-preventative activities. We report that
      the extracts of apple and grape are more potent than onion, tomato and celery in:
      (i) inhibiting the proteasomal chymotrypsin-like activity in leukemia Jurkat T
      cell extract; (ii) accumulating the polyubiquitinated proteins in intact Jurkat T
      cells; (iii) inducing activation of caspase-3/-7 and cleavage of poly(ADP-ribose)
      polymerase in intact Jurkat T cells; and (iv) inducing the appearance of
      spherical cells preferentially in prostate cancer PC-3 over the normal NIH 3T3
      cell line. We also found that strawberry extract had some effect on Jurkat T cell
      extract and the prostate PC-3 cell line but not on intact Jurkat T cells. Our
      findings suggest that the proteasome is a cancer-related molecular target for, at
      least, the extracts of apple, grape and onion, and that the inhibition of
      proteasome activity by these fruits or vegetable may contribute to their cancer
      preventative effects, although other molecular mechanisms may also be involved.

PMID- 15011756
TI  - Antigen presentation by dendritic cells and their significance in antineoplastic
      immunotherapy.
AB  - Dendritic cells (DCs) are present in essentially every mammalian tissue, where
      they operate at the interface of innate and acquired immunity by recognizing
      pathogens and presenting pathogen-derived peptides to T lymphocytes. According to
      the research group of Shortman, experimental results suggest a "dual" DC
      differentiation model, demonstrating the existence of both myeloid-derived (with
      characteristic IF: CD11b+, CD11c+, CD8alpha- and DEC205+) and lymphoid-derived
      DCs (showing CD11b- CD11c-, CD8alpha+ and DEC205+ IF). DCs, including
      interdigitating cells (IDCs) and Langerhans cells (LCs), are characterized by
      dendritic morphology, high migratory mobility and are the most effective,
      "professional" cells for antigen presentation in primary immune responses. Most
      of the DCs express immunocytochemically detectable antigens like: S-100, CD1a,
      CD40 receptor, adhesion molecules (ICAM-1 or CD54, LFA-1 and LFA-3), integrins
      (CD11a, CD11c and CD18), CD45, CD54, co-stimulatory molecules (B7-1 or CD80, B7-2
      or CD86), F418, MHC class I and II and DEC-205, multilectin receptor,
      immunostimulatory cytokine (IL-12) and, of course, Fc and complement receptors.
      Following recognition and uptake of antigens, mature dendritic cells (DCs)
      migrate to the T lymphocyte rich area of draining lymph nodes, display an array
      of antigen-derived peptides on the surface of major histocompatibility complex
      (MHC) molecules and acquire the cellular specialization to select and activate
      naive antigen-specific T lymphocytes. Immunotherapeutic ideas are based on the
      ability of the mammalian immune system to recognize neoplastically transformed
      cells. Immunotherapy of human neoplasms has always represented a very attractive
      fourth-modality therapeutic approach, especially in light of the many
      shortcomings of conventional surgical, radiation and chemotherapies in the
      management of neoplastically transformed cells. The cancer vaccine approach to
      therapy is based on the notion that the immune system could possibly mount a
      rejection strength response against the neoplastic cell conglomerate. The
      efficiency of DCs for T lymphocyte stimulation moved a number of research groups
      to develop DC- based immunotherapy approaches. The failure of cancer vaccines may
      be attributed to the relationship between host and neoplasm: through a natural
      selection process, the host facilitates the selective enrichment of clones with
      highly aggressive neoplastically transformed cells, being in various stages of
      differentiation and only during certain stages express neoplastic cell specific
      molecules.

PMID- 15011757
TI  - CMS disease management project underway in four states.

PMID- 15011759
TI  - Pricing data rule revised to 10 years.

PMID- 15011758
TI  - Drug importation raises issues for pharmacists.

PMID- 15011760
TI  - New drug and biological product approvals, 2003.

PMID- 15011761
TI  - New Medicare law adds 150 million dollars to OPPS.

PMID- 15011762
TI  - Collaborative drug therapy management services and reimbursement in a family
      medicine clinic.
AB  - PURPOSE: The legislative and regulatory issues surrounding the reimbursement of
      pharmacists for cognitive services are reviewed and billing practices for a
      pharmacist-physician collaborative drug therapy management service (DTMS) in a
      family medicine clinic are examined. A case study is offered to illustrate the
      real-world application of these practices. SUMMARY: As regimens of prescription
      medications have become more complex and the potential for adverse drug reactions
      and interactions has increased, the need for individualized optimal drug therapy
      and drug-therapy experts has grown. Pharmacists, who are professionally trained
      to be an integral part of the medical team, are well prepared to ensure optimal
      drug therapy and medication safety for patients. Consequently, collaboration
      between physicians and pharmacists can lead to improved patient care and reduced
      medication errors. The following 10 steps are recommended for establishing a
      successful collaborative DTMS: (1) establish a working relationship with
      physician colleagues, (2) assess the needs of your patients, (3) draft
      collaborative DTMS protocols and agreements, (4) apply for credentialing status
      within your health organization, (5) consult the billing office staff at the
      clinic, (6) design a clinic-encounter form, (7) identify and train support
      personnel, (8) allocate resources, (9) advertise the DTMS, and (10) evaluate and
      improve your service. CONCLUSION: Establishing a DTMS presents many challenges
      and obstacles, but they should not lead to discouragement. Rather, pharmacists
      should be diligent and continue to explore ways in which they could provide
      optimal medication therapy to patients through appropriate channels that also
      facilitate reimbursement.

PMID- 15011763
TI  - Treatment of priapism in pediatric patients with sickle cell disease.
AB  - PURPOSE: The available treatment options for priapism in pediatric (1-21 years of
      age) patients with sickle cell disease (SCD) are reviewed. SUMMARY: Priapism is a
      complication of SCD that receives little attention, yet it is a particularly
      bothersome issue for many pediatric patients. Numerous therapeutic options have
      been attempted, including diethylstilbestrol, gonadotropin-releasing hormone
      analogues, various adrenergic agonists, and hydroxyurea. Few agents have actually
      been examined in a controlled clinical trial, making it difficult for
      practitioners to treat this complication. It is our recommendation that treatment
      should be conservative initially, with the patient being encouraged to urinate,
      exercise, increase his fluid intake, and take oral analgesics. If the episode of
      priapism persists beyond 2 hours, the patient should report to the emergency
      department for i.v. hydration and analgesics. If the episode persists beyond 4
      hours, intracavernosal aspiration and instillation of an alpha-agonist should be
      performed and repeated as needed. If the priapism remains for longer than 12
      hours, surgery should be considered for shunt placement. CONCLUSION: There is
      little evidence available regarding the definitive treatment of priapism, which
      affects a large number of pediatric patients with SCD. It is quite clear that
      more research is needed to determine what the best treatment options are for
      patients with this condition. Health care providers should educate their patients
      with SCD about the condition. Education, combined with more research of treatment
      options, may help patients avoid the damaging social, psychological, and medical
      implications of this bothersome and often embarrassing complication of SCD.

PMID- 15011764
TI  - Randomized trial of pharmacist interventions to improve depression care and
      outcomes in primary care.
AB  - PURPOSE: The impact of pharmacist interventions on the care and outcomes of
      patients with depression in a primary care setting was evaluated. METHODS:
      Patients diagnosed with a new episode of depression and started on anti
      depressant medications were randomized to enhanced care (EC) or usual care (UC)
      for one year. EC consisted of a pharmacist collaborating with primary care
      providers to facilitate patient education, the initiation and adjustment of
      antidepressant dosages, the monitoring of patient adherence to the regimen, the
      management of adverse reactions, and the prevention of relapse. The patients in
      the UC group served as controls. Outcomes were measured by the Hopkins Symptom
      Checklist, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,
      criteria for major depression, health-related quality of life, medication
      adherence, patient satisfaction, and use of depression-related health care
      services. An intent-to-treat analysis was used. RESULTS: Seventy-four patients
      were randomized to EC or UC. At baseline, the EC group included more patients
      diagnosed with major depression than did the UC group (p = 0.04). All analyses
      were adjusted for this difference. In both groups, mean scores significantly
      improved from baseline for symptoms of depression and quality of life at three
      months and were maintained for one year. There were no statistically significant
      differences between treatment groups in depression symptoms, quality of life,
      medication adherence, provider visits, or patient satisfaction. CONCLUSION:
      Frequent telephone contacts and interventions by pharmacists and UC in a primary
      care setting resulted in similar rates of adherence to antidepressant regimens
      and improvements in the outcomes of depression at one year.

PMID- 15011765
TI  - Variation in medication understanding among the elderly.
AB  - PURPOSE: Types of medication misunderstanding among community-dwelling elderly
      people were studied. METHODS: Community-dwelling people who were at least 65
      years of age and who volunteered to participate in a medication-review program
      were recruited for the study. A structured interview including a background
      interview, attitudinal questions, and questions related to dosage, frequency,
      timing, and what to do if a dose was missed was conducted. RESULTS: A total of
      375 people were included in the study. Of these, 232 (62%) showed perfect
      understanding of their medication regimens. Twenty-eight (7.5%) of the subjects
      with less than perfect understanding misunderstood a limited aspect of their
      regimens across multiple medications, most frequently what to do if a dose was
      missed. These subjects had the least complex regimens, could name their
      medications and describe their purpose, and rated themselves as having few
      medical problems. Their lack of knowledge was not attributed to cognitive
      problems. Twenty-seven subjects (7%) did not know multiple aspects of at least
      one medication and appeared to be at high risk for nonadherence. These
      individuals had the most complex regimens, had difficulty naming and explaining
      the purpose of their medications, and rated themselves as less adherent. Eighty
      eight subjects (23.5%) demonstrated mixed problems with understanding; they did
      not show a defined pattern attributable to cognitive or noncognitive factors.
      CONCLUSION: A majority of people over the age of 65 years had good understanding
      of the drugs they were taking.

PMID- 15011766
TI  - Evaluation of personal digital assistant software for drug interactions.
AB  - PURPOSE: The accuracy, comprehensiveness, and ease of use of drug interaction
      software used with personal digital assistants (PDAs) were studied. METHODS: Each
      program was assessed for accuracy using 40 clinically important and 40 clinically
      unimportant drug interaction pairs. Accuracy was scored through the summation of
      software sensitivity, specificity, and positive and negative predictive values.
      The comprehensiveness of each program was determined by the number of components
      in the drug interaction monograph. Time needed to identify the management of five
      important drug interactions defined each program's ease of use. The aggregate
      scores for accuracy, comprehensiveness, and ease of use were calculated. RESULTS:
      Scoring 777 and 756 out of a possible 800 points, iFacts and Lexi-lnteract,
      respectively, provided the most competent, complete, use-friendly compendia for
      assessment of drug interactions. Mosby's Drug Consult and Mobile Micromedex
      ranked third and fourth, scoring 688 and 655 points, respectively, while
      ePocrates Rx v. 6.0 rated seventh, with a score of 559. All drug interaction
      resources suffer from limitations in the quality or relevance of evidence for the
      interaction, an absence of identifiable patient and medication risk factors, and
      a lack of standardization in assigning significance to the interaction.
      Consequently, clinicians must interpret the importance of the interaction based
      on all available evidence. Discussion of such evidence was available for only
      iFacts and Lexi-Interact. CONCLUSION: Both iFacts and Lexi-Interact excelled as
      PDA pharmacopoeia for assessing drug interactions. However, clinicians should
      understand the limitations of all current drug interaction resources and exercise
      vigilance in prevention and recognition of interactions relevant to their
      patients.

PMID- 15011767
TI  - Development of educational materials for congestive-heart-failure patients.

PMID- 15011768
TI  - Prevalence of edema in patients receiving combination therapy with insulin and
      thiazolidinedione.

PMID- 15011769
TI  - Stability of zidovudine with oxytocin in a simulated Y-site injection.

PMID- 15011770
TI  - Building a better drug database.

PMID- 15011771
TI  - Clinical inertia: errors of omission in drug therapy.

PMID- 15011772
TI  - Job satisfaction of pharmacists at a large medical center.

PMID- 15011773
TI  - Skin reaction to subcutaneous phytonadione injections.

PMID- 15011774
TI  - Web alert. Molecular, viral and cell-based vaccines for disease prevention and
      therapy.

PMID- 15011775
TI  - Immunotherapy in anticancer responses.

PMID- 15011776
TI  - Predictive power of preclinical studies in animals for the immunogenicity of
      recombinant therapeutic proteins in humans.
AB  - Despite advances at the level of gene sequence (eg, humanized versus murine
      antibodies), expression systems (eg, mammalian versus prokaryotic) and post
      expression modification (eg, 'PEGylation'), clinical immunogenicity of
      therapeutic proteins remains a concern. Although animals are routinely and
      effectively used to evaluate pharmacological activity and to support a claim of
      safety for recombinant proteins, their usefulness for predicting clinical
      immunogenicity is more questionable. This review argues that recombinant proteins
      can be grouped into immunogenic classes; for some of these classes, for example,
      bacterial proteins, immunogenicity in animals is often predictive for humans, but
      for others, for example, fully human proteins, even data from non-human primates
      can have little predictive value. We will attempt to make the case that for a
      variety of immunological and practical constraints, animal studies, even those
      conducted in non-human primates, have limited predictive power for immunogenicity
      in humans, and tend to over-predict clinical immunogenicity.

PMID- 15011777
TI  - Cancer vaccines: a critical review on clinical impact.
AB  - Developing cancer vaccines to treat solid tumors is not an easy task. As solid
      tumors develop, the immune system places cancer cells under selective pressure;
      it detects those that are more 'antigenically different', selecting those cells
      that are not recognized by the immune system and are therefore resistant to
      immune surveillance. Resistant cells survive, and in turn their clones will
      spread to distant sites. This phenomenon, called 'immune editing', is not novel,
      but is quite similar in principle to the selective pressure induced by
      chemotherapy and hormone therapy, and is molecularly based on the clonal
      heterogeneity and molecular instability present in most solid tumors. This
      explains, at least in part, why many cancer vaccines work in animal models but
      not in a clinical setting. The aim of this article is to review the most commonly
      used cancer vaccine strategies and to evaluate the evidence supporting their
      efficacy. This is not as easy at it may sound, as each research group involved in
      cancer vaccine development uses different technologies, targets different
      antigens, combines different carriers and adjuvants to obtain an immune response,
      and immunizes patients with different administration schedules. The final picture
      is somewhat confusing, and comparison of different vaccine strategies is almost
      impossible. Most of the vaccines are still experimental, far from being approved
      by regulatory authorities, and their clinical utility is almost negligible.

PMID- 15011778
TI  - Induction of protective therapy for autoimmune diseases by targeted DNA vaccines
      encoding pro-inflammatory cytokines and chemokines.
AB  - T-cell-mediated autoimmune diseases such as multiple sclerosis, rheumatoid
      arthritis or type 1 diabetes result from an aggressive attack of self-components
      by autoimmune T-cells. Pro-inflammatory mediators, particularly cytokines and
      chemokines, direct the homing and effectorfunction of these cells. It has
      recently been demonstrated that the immune system, which can attack self
      components, also generates 'beneficial' autoimmunity against pro-inflammatory
      mediators. During the course of an autoimmune condition, and to a much lesser
      extent in response to microbial inflammation, the immune system produces auto
      antibodies to pro-inflammatory mediators. This reduces the harm from these
      diseases. We also discovered that targeted DNA vaccines could effectively amplify
      these responses to provide protective immunity. The underlying mechanism is
      partially understood. At the site of immunization, the relevant gene product is
      produced and then presented by dendritic cells/macrophages, which undergo
      activation due to an interaction of plasmid CpG with toll-like receptor 9 on the
      dendritic cell. This then activates CD4+ T-cells, which help the production of T
      cell-dependent antibodies against the gene product of the vaccines. These
      antibodies neutralize their target product and suppress inflammation. This review
      explores this interesting concept and its therapeutic implications.

PMID- 15011779
TI  - Development of novel vaccines using DNA shuffling and screening strategies.
AB  - DNA shuffling and screening technologies recombine and evolve genes in vitro to
      rapidly obtain molecules with improved biological activity and fitness. In this
      way, genes from related strains are bred like plants or livestock and their
      successive progeny are selected. These technologies have also been called
      molecular breeding-directed molecular evolution. Recent developments in
      bioinformatics-assisted computer programs have facilitated the design, synthesis
      and analysis of DNA shuffled libraries of chimeric molecules. New applications in
      vaccine development are among the key features of DNA shuffling and screening
      technologies because genes from several strains or antigenic variants of
      pathogens can be recombined to create novel molecules capable of inducing immune
      responses that protect against infections by multiple strains of pathogens. In
      addition, molecules such as co-stimulatory molecules and cytokines have been
      evolved to have improved T-cell proliferation and cytokine production compared
      with the wild-type human molecules. These molecules can be used to immunomodulate
      vaccine responsiveness and have multiple applications in infectious diseases,
      cancer, allergy and autoimmunity. Moreover, DNA shuffling and screening
      technologies can facilitate process development of vaccine manufacturing through
      increased expression of recombinant polypeptides and viruses. Therefore, DNA
      shuffling and screening technologies can overcome some of the challenges that
      vaccine development currently faces.

PMID- 15011780
TI  - Therapeutic cancer vaccines.
AB  - Therapeutic vaccination against cancer-associated antigens represents an
      attractive option for cancer therapy in view of the comparatively low toxicity
      and, so far, excellent safety profile of this treatment. Nevertheless, it is now
      recognized that the vaccination strategies used for prophylactic vaccinations
      against infectious diseases cannot necessarily be used for therapeutic cancer
      vaccination. Cancer patients are usually immunosuppressed, and most cancer
      associated antigens are self antigens. Therefore, various immunostimulation
      techniques are under investigation in an effort to bolster immune systems and to
      overcome immune tolerance to self antigens. Various strategies to stimulate
      antigen presentation, T-cell reactivity and innate immune activity are under
      investigation. Similarly, strategies to produce an immunological 'danger signal'
      at the site of the tumor itself are under evaluation, as it is recognized that
      while tumor-specific T-cells can be activated at the site of vaccination, they
      require appropriate signals to be attracted to a tumor. The detection, evaluation
      and quantification of specific immune responses generated by vaccination with
      cancer-associated antigens is another important area of therapeutic cancer
      vaccine evaluation receiving much attention and novel strategies. Multiple
      clinical trials have been undertaken to evaluate therapeutic vaccines in
      patients. Aggressive protocols such as those combining specific stimulation of T
      cells and chemotherapy or strategies to block immune regulation are having some
      success.

PMID- 15011781
TI  - Hematopoietic stem cell transplant as a platform for tumor immunotherapy.
AB  - Blood or marrow transplantation (BMT) has been utilized as a cancer therapy with
      varying levels of success. While it has been an important option for many
      hematological malignancies, it has met with less success in solid tumors. More
      recently, new combinations of therapies with BMT have been developed to enhance
      the efficacy of this therapy and to expand the number of target tumors. This
      review highlights current uses of BMT, rationales for experimental approaches
      using BMT alone or as a part of a combination therapy, and reviews some of the
      novel therapies that have been developed in tumor immunotherapy with BMT, in
      addition to the implications for translation.

PMID- 15011782
TI  - Molecular targets for anti-angiogenic therapy.
AB  - Tumor-induced angiogenic blood vessels (tumor neovasculature) permit tumor
      survival, growth and metastasis. Compelling evidence supports the notion that the
      tumor neovasculature expresses specific molecular markers that are absent in the
      parental quiescent preformed blood vessels and can be exploited for molecular
      therapeutics. Therefore, the clinical success of selective killing of tumor
      neovasculature depends upon the identification of antigens that are specifically
      expressed by the tumor neovasculature, but not by preformed quiescent blood
      vessels. Many laboratories have identified, discovered and characterized the
      cellular and molecular components necessary to tumor-induced angiogenesis. This
      has led to the understanding of requisite interactions between endothelium,
      angiogenic cytokines, stromal cells, the supporting extracellular matrix
      molecules and proteases that accompany these processes. Notably, in the last ten
      years the signaling pathways mediated by angiopoietin, basic fibroblast growth
      factor and vascular endothelial growth factor, and in particular how they may
      promote formation tumor neovasculature, have been investigated in vitro and in
      vivo expeditiously. An in-depth understanding of tumor neovasculature-specific
      antigen clearly holds promises in the development of novel therapeutic strategies
      to treat aggressive cancers. A precision-based molecular therapy would be one
      that destroys the tumor neovasculature selectively, avoids toxicity and leaves
      parental vessels unharmed.

PMID- 15011783
TI  - Role of anti-CTLA-4 therapies in the treatment of cancer.
AB  - Studies in the field of T-cell receptor (TCR)/antigen (Ag) recognition have led
      to the discovery of a unique receptor/ligand system that, in collaboration with
      TCR/Ag engagement, underlies the molecular basis of T-cell activation and
      proliferation. Such a process has been termed co-stimulation, which serves to
      either upregulate or downregulate T-cell signaling following TCR ligation. As
      neoplasia represents a pathogenic process whereby a sustained T-cell response may
      be desirable, intensive efforts to prolong endogenous tumor-induced T-cell
      activity in vivo have been investigated. One innovative approach has been to
      block a crucial inhibitory arm of the co-stimulatory pathway using monoclonal
      antibodies against the CTLA-4 molecule expressed by Ag-primed, activated T-cells.
      In both preclinical models and clinical settings, such a therapeutic intervention
      has been found to be effective in promoting antitumor T-cell responses and, in
      some patients, clinical regression has been concomitant with autoreactivity.
      Thus, CTLA-4 blockade, perhaps in conjunction with other oncological modalities,
      may comprise important therapeutic paradigms to facilitate long-lasting
      antineoplastic immunity.

PMID- 15011784
TI  - Fashioning regulatory dendritic cells: what is currently in vogue?
AB  - Dendritic cells (DCs) are uniquely well-equipped antigen-presenting cells with
      remarkable plasticity, whose differentiation and function can be manipulated in
      vitro and in vivo. With increased understanding of their immunoregulatory
      properties, strategies to enhance DC tolerogenicity have emerged. Carefully
      fashioned DCs, the result of biological, pharmacological or genetic modification,
      hold promise as new cell-based therapies of organ allograft rejection and
      autoimmune diseases.

PMID- 15011785
TI  - Peptide vaccines in immunocontraception.
AB  - Vaccines have been used successfully to treat and eradicate infectious diseases;
      this has encouraged a major drive towards development of contraceptive vaccines
      (immunocontraception) as an additional method against rising human and animal
      populations. Despite three decades worth of research in this field, there are no
      licensed human contraceptive vaccines and less than ten for use in animals. The
      development of peptide antifertility vaccines has had a substantial impact on
      improving safety and specificity of immunogens, but has resulted in efficacy
      problems. Innovative strategies have been developed to overcome these problems.

PMID- 15011786
TI  - Technology evaluation: cT84.66, City of Hope.
AB  - Chimeric T84.66 (cT84.66) is a high affinity anti-carcinoembryonic antigen (CEA)
      immunoglobulin G1, that is being developed by City of Hope for the potential
      treatment of CEA-expressing malignancies.

PMID- 15011787
TI  - Technology evaluation: Matuzumab, Merck KGaA.
AB  - Merck KGaA is developing matuzumab, a fully humanized epidermal growth factor
      receptor (EGFR)-specific monoclonal antibody, as a potential treatment for EGFR
      bearing tumors. Matuzumab is currently undergoing phase II clinical trials for
      gastric, cervical, pancreatic and ovarian cancers.

PMID- 15011789
TI  - The new Health Savings Account.

PMID- 15011790
TI  - Do we consider gender differences in how we manage our patients?

PMID- 15011788
TI  - Technology evaluation: Canvaxin, John Wayne Cancer Institute/CancerVax.
AB  - CancerVax and the John Wayne Cancer Institute are co-developing Biotechnology
      Tumor antigen Canvaxin, a vaccine containing over 20 tumor antigens, for the
      potential treatment of melanoma and colon cancer. Canvaxin is currently
      undergoing phase III clinical trials for melanoma and a phase II trial for colon
      cancer.

PMID- 15011792
TI  - Hometown girl.

PMID- 15011791
TI  - A silent killer.

PMID- 15011793
TI  - Carcinomatous optic neuropathy.
AB  - A man with advanced malignant disease presented complaining of vision changes in
      the left eye. Examination revealed an afferent pupillary defect and visual field
      defect in that eye. Imaging indicated carcinomatous disease of the left optic
      nerve, and a diagnosis of carcinomatous optic neuropathy was made.

PMID- 15011794
TI  - Office-based management of diabetes: two-year trial of primary care quality
      improvement.
AB  - BACKGROUND AND OBJECTIVES: The goals of this study were to learn different
      approaches to improve the quality of care for the diabetic patients of the family
      practice setting FMC. METHODS: Participants of the study were 34 adult diabetic
      patients (Type 1 or 2) seen in the University of Arkansas of Medical Sciences'
      Family Medical Center by either family practice residents or faculty. Each CQI
      innovation was introduced in a stepwise fashion. The study team used a
      biopsychosocial, economic and environmental model of care to impact each
      dimension of ambulatory care. Not all cycles included all patients in the study,
      but patients and physicians received multiple interventions designed to improve
      hypertension control. RESULTS: The project intended to assess the feasibility of
      introducing a "package" of approaches to improve the outpatient management of
      diabetes rather than assess whether a specific innovation was efficacious.
      Improvement in blood pressure control, increased referral for eye exams, improved
      prescribing and/or use of aspirin and improved patient satisfaction with care
      were noted. CONCLUSION: The study demonstrated that the biopsychosocial and
      economic dimensions of the patients' diabetes must be addressed to achieve
      optimal care and that many approaches to improving outcomes can feasibly be
      introduced in a family practice setting.

PMID- 15011795
TI  - Pediatric overweight: a management guide for Arkansas medical providers.

PMID- 15011796
TI  - Do you give your 401 (k) plan an annual physical?

PMID- 15011797
TI  - What winners reveal about good journalism.

PMID- 15011798
TI  - Today I offer a challenge to you.

PMID- 15011799
TI  - Advances in caries diagnostics and the changing face of dental practice.
AB  - Advances in scientific understanding of disease processes and diagnostic
      technology will lead to changes in the ways caries is managed. These changes will
      include new relationships with patients that will call for greater skills in the
      behavioral sciences. Specifically, there will be a need for greater understanding
      of the biopsychosocial and the socio-cultural bases of disease and health care
      behavior and enhanced communication skills. The need to understand and respond to
      demographic forces-especially those that involve population groups at increased
      risk-and to work collaboratively with medicine will also assume greater
      significance.

PMID- 15011801
TI  - In search of the secrets of Methuselah: implications for dentistry in the third
      millennium.
AB  - Aging is the progressive deterioration of bodily functions over time. Age has
      been prolonged as more individuals avoid early death and as the mature years are
      extended. The potential exists for even further extensions of age through genomic
      advances. Although it is currently unclear how this might happen, the benefits of
      research in genetics might extend oral health-related life issues through a
      multiprong approach.

PMID- 15011800
TI  - On translating new biologic-based interventions into dental practice.
AB  - Prudent change is a professional responsibility. Four forces will influence the
      incorporation of the new biology into dental practice--and their individual
      application in various settings will lead to a range of practice characteristics.
      These forces include our vision of what it means to be a professional, health
      consequences of the new biology, infrastructure features, and incentive
      structures.

PMID- 15011802
TI  - The new dental biology--threat or opportunity?
AB  - A clinician argues that the new biology is a threat or an opportunity depending
      on the perspective practitioners take. New approaches should be seen as
      extensions of the services dentists can provide patients rather than
      restrictions. Different parts of the new biology will become available in the
      office at different times, and will be implemented by general practitioners or
      specialists, depending on their character. Important innovations in diagnosis and
      prevention are emerging currently. New relationships with medicine will be forged
      rather than dentistry becoming part of medicine. Innovations in dental education
      and continuing education will accelerate the coming changes.

PMID- 15011803
TI  - National Institute for Dental and Craniofacial Research. Strategic Plan--2003
      2008.

PMID- 15011804
TI  - Rights access and justice in oral health care: justice toward underserved patient
      populations--the elderly.
AB  - Recent data indicate that health utilization, calculated on the basis of visits
      to physicians, specialists, surgery rates, and hospitalization stays, increases
      with age. Yet, visits to the dentist decrease with age. Although dentistry has
      made dramatic improvements in the provision of oral health care over the past
      half-century, access-limited populations including older adults are burdened with
      the poorest levels of oral health. Many factors contribute to the oral health
      problems faced by elders. Also, because of its marginalization from general
      health and public health care delivery systems, oral health does not garner
      meaningful consideration as a social good. Needs associated with oral health
      cannot be met without a rethinking of concepts that define oral health and
      recognition of its impact on general health and quality of life. Determining the
      extent to which elders endure an undeserved or unreasonable burden of illness and
      disability is an important first step toward understanding the meaning of
      "justice" in the context of caring for elders. A clearer understanding of justice
      allows the oral health community to begin to recognize appropriate levels of
      responsibility to address the issue of just and respectful caring for this
      vulnerable population.

PMID- 15011805
TI  - Standards.
AB  - We use standards to raise the general quality level and to identify and encourage
      those who lag behind. Standards agreed by professional organizations are the
      best. There are differences between licensure and certification in the mechanisms
      for creating standards, the level at which standards are set, how data are
      gathered, and the types of decisions they support. There is also a danger that
      standards can by hijacked for commercial purposes.

PMID- 15011806
TI  - A prescription for protecting the doctor-patient relationship.
AB  - The relationship between patients and their physicians is fundamental to high
      quality care, yet this relationship is under stress in the current healthcare
      environment. Health plans have instituted a variety of policies to contain costs,
      not fully appreciating the adverse effect these decisions have on the doctor
      patient interaction. Legislators have responded to the public's concern about
      managed care with "patient protection" bills that fail to address the fundamental
      causes of tension between doctors and patients. This paper presents a model
      describing how the need to contain costs affects the doctor-patient interaction
      and proposes a prescription for protecting the relationship. The model highlights
      how the healthcare environment affects patients' and physicians' expectations
      before a medical visit, the nature of their interaction during a visit, and
      patients' health outcomes. This prescription for protecting the doctor-patient
      relationship contains 4 key ingredients: (1) definition and promulgation of
      evidence-based standards for the doctor-patient relationship; (2) joint doctor
      patient advocacy on behalf of the relationship; (3) positive incentives for
      exemplary doctor-patient relationships; and (4) expanded training and assessment
      of physicians' communication skills, both in general and related to discussing
      cost containment with patients. These measures will help restore the essential
      element of superb healthcare: a strong doctor-patient relationship.

PMID- 15011807
TI  - Medical and self-care practices reported by women with urinary incontinence.
AB  - OBJECTIVES: To determine the extent to which women with incontinence have been
      identified by physicians, the coping and treatment strategies that incontinent
      women use, and the factors associated with treatment strategy utilization. STUDY
      DESIGN: A 2-stage, nationwide, cross-sectional survey. METHODS: Survey
      participants were adult women from representative US households in NFO WorldGroup
      survey panels. Of 2310 incontinent women who received the second-stage detailed
      questionnaire, 1970 (85%) responded. Descriptive analyses were performed to
      determine the impact of incontinence, the proportion of respondents who had
      talked to a physician about incontinence, the responses of physicians to these
      incontinent women, and coping strategies used. We conducted logistic regressions
      to determine factors associated with treatment strategy utilization. RESULTS:
      Almost half of incontinent women considered their incontinence moderately to
      extremely bothersome, yet only 56% of the moderately to extremely bothered women
      had ever talked to a physician about incontinence. In 85% of all cases, the
      incontinent woman, rather than the physician, raised the issue of incontinence.
      Coping strategies women reported ever trying included limiting fluid intake (38%)
      and physical activity (21%). Kegel exercises and prescription medications were
      used currently by 20% and 6% of this population, respectively. CONCLUSIONS: Among
      women of all ages, only about half of women bothered by incontinence have ever
      talked to a physician about it, and many incontinent women rely on strategies to
      avoid or conceal incontinence. A better understanding of the current use of
      coping and treatment strategies as well as the interaction between women and
      physicians regarding incontinence may help to inform efforts to optimize
      management of incontinence for women bothered by incontinence symptoms.

PMID- 15011808
TI  - Examining healthcare disparities in a disease management population.
AB  - OBJECTIVES: To examine whether racial disparities in healthcare exist in a heart
      failure population and to estimate the impact of disease management (DM) on any
      identified disparities. STUDY DESIGN: Before-after cohort study. PATIENTS AND
      METHODS: A total of 2619 high-risk heart failure patients (2129 whites and 490
      blacks) who participated in a DM program for at least 90 days between July 2001
      and July 2003 were examined. Analysis was stratified by sex and age (< 65 years
      and > or = 65 years). Functional status as measured by the New York Heart
      Association (NYHA) classification system and mental and physical quality of life
      (QOL) as measured by the 8-Item Short-Form Health Survey were used to assess
      disparities between races. RESULTS: At baseline, 33.7% of black versus 44.3% of
      white older women and 32.6% of black versus 48.5% of white older men were at NYHA
      level I or II (P < .01 and P = .005, respectively). At the most current
      measurement, the differences between the cohorts disappeared. Results were
      similar for the younger male, but not the younger female, cohort. The only QOL
      disparities at baseline were in favor of blacks. Both races had significant
      increases in mean mental and physical QOL scores (P < .001) after involvement in
      the DM program. CONCLUSIONS: Disparities in QOL were not observed between blacks
      and whites at baseline or over the course of the study. Disparities in functional
      status at baseline disappeared over time, implying that DM may help reduce
      disparities and maintain equity in healthcare outcomes.

PMID- 15011809
TI  - Risk classification of Medicare HMO enrollee cost levels using a decision-tree
      approach.
AB  - OBJECTIVE: To determine whether classification tree techniques used on survey
      data collected at enrollment from older adults in a Medicare HMO could predict
      the likelihood of an individual being in a low, medium, high, or very high cost
      group in the subsequent year. METHODS: Data from comprehensive health risk
      assessment (HRA) screening of 11 744 new enrollees (age > or = 65 years)
      continuously enrolled in a Medicare HMO for at least 24 months between 1997 and
      2002 were combined with complete healthcare service utilization data for each
      enrollee in the postenrollment period to create cost groups. An original
      clinically devised algorithm and a Classification and Regression Tree (CART) that
      used the HRA data were compared with respect to their ability to correctly place
      an individual within the cost groups over 12 months of enrollment. RESULTS: The
      variables that best classified enrollees into 12-month cost groups included
      quality of life, age, and preenrollment health services. Classification was best
      for CART: a sensitivity of 39.8% and a specificity of 83% was achieved for very
      high cost enrollees. Compared with the clinical algorithm, CART also utilized
      only one third as many predictor variables to define risk categories. CONCLUSION:
      Brief self-report survey data collected at enrollment can be modeled to provide
      moderate sensitivity in predicting very high costs in the postenrollment year.
      The ease of applicability of software to create empirically derived profiles of
      high-cost enrollees precludes the need to rely on clinically devised algorithms
      to identify enrollees at risk for very high costs.

PMID- 15011810
TI  - Does patient cost sharing matter? Its impact on recommended versus controversial
      cancer screening services.
AB  - OBJECTIVES: To examine whether there are differential impacts of patient cost
      sharing and health plan organizational characteristics on the use of a
      recommended cancer screening service (mammography) versus a controversial cancer
      screening service (prostate cancer screening [PCS]). STUDY DESIGN: Observational
      cohort using the 1996 Medical Expenditure Panel Survey. PATIENTS AND METHODS: A
      nationally representative sample of privately insured individuals was examined.
      Outcome measures were the receipt of mammography and PCS. Logistic regression was
      used to assess the impact of patient cost sharing and health plan organizational
      characteristics on the receipt of mammography and PCS, controlling for other
      covariates. RESULTS: Patient cost sharing and gatekeeper requirements were strong
      predictors of PCS but were statistically insignificant predictors of mammography.
      Men in health plans with a copayment over dollar 10 (odds ratio [OR] = 0.38, 95%
      confidence interval [CI] = 0.19-0.78) or with deductibles over dollar 250 (OR =
      0.38, 95% CI = 0.23-0.62) were significantly less likely to receive PCS than men
      in plans with no or lower copayments and deductibles. Men in gatekeeper plans
      were less likely to receive PCS than those without gatekeepers (OR = 0.48, 95% CI
      = 0.29-0.81). CONCLUSIONS: We found the impact of cost sharing on utilization is
      different between mammography and PCS. Prostate cancer screening utilization
      appears to respond to financial incentives while mammography utilization does
      not. The use of copayments, deductibles, and gatekeepers may discourage
      controversial services but may not have an adverse effect on more recommended
      services. These findings have implications for the design of insurance benefits
      and plan organizational structure.

PMID- 15011811
TI  - "Hopelessly entangled in Nordic pre-suppositions": Catholic participation in the
      American Eugenics Society in the 1920s.
AB  - While American Catholics stand out as some of the few voices of cultural
      opposition to the eugenics movement in the United States, Catholics and
      eugenicists actively engaged in conversational exchanges during the late 1920s.
      In association with the Committee on Cooperation with Clergymen of the American
      Eugenics Society, John A. Ryan and John Montgomery Cooper engaged in a process
      that Sander Gilman and Nancy Leys Stepan call "recontextualization," whereby they
      challenged the social and scientific basis for eugenics policy initiatives while
      constantly urging American eugenicists to rid their movement of racial and class
      prejudice. In the process, they participated in a revealing debate on immigration
      restriction, charity, racial hierarchies, feminism, birth control, and
      sterilization that points to both the instances of convergence and divergence of
      Catholic and eugenic visions for the national community.

PMID- 15011813
TI  - Rethinking mental retardation: education and eugenics in Connecticut, 1818-1917.
AB  - This case study of mental retardation in Connecticut during 1818-1917 questions
      the existing model of interpretation. The discovery of mental retardation in
      Connecticut did not emanate from social fear over those who were different,
      difficult, or dangerous. Nor did state government initiate the
      institutionalization of the feeble-minded. Instead, Dr. Henry M. Knight, who
      founded the private Connecticut School for Imbeciles in 1858, was motivated by
      antebellum religious benevolence. His altruism was additionally motivated by
      cultural concerns to shape behavior according to middle-class, Protestant norms.
      By the end of the century, his son and successor Dr. George H. Knight departed
      from his father's emphasis on education and assimilation to embrace eugenics and
      segregation of the mentally retarded. Connecticut's pioneering marital ban (1895)
      and sterilization law (1909) were, however, virtually ineffective. Instead, the
      state sponsored in 1917 a large-scale custodial facility that sought to isolate
      the feeble-minded, whom reformers now portrayed as a menace to society. In sum,
      the Knights show a clear departure in policy between the first and second
      generation of administrators.

PMID- 15011812
TI  - The history of gold therapy for tuberculosis.
AB  - This is a historical study of the popularization of a medical therapy contrary to
      pertinent experimental findings. Presumably this circumstance reflects the
      desperation about tuberculosis: highly prevalent, highly fatal, and lacking any
      etiologically directed therapy. Gold compounds were introduced, based initially
      on the reputation of Robert Koch, who had found gold cyanide effective against M.
      tuberculosis in cultures, but not in experimentally infected animals. Treatment
      of pulmonary tuberculosis with these compounds was popularized, particularly by
      Danish physicians, in the mid-1920s, despite consistently negative experimental
      results, based on Paul Ehrlich's theories of antimicrobial drug effects.
      Difficulties in the design of interpretable clinical studies were soon recognized
      but also generally ignored, thus permitting data to be interpreted as favorable
      to antituberculous gold therapy. Eventually toxicity was considered to outweigh
      the alleged therapeutic benefit of all gold compounds. This resulted in their
      discard shortly before the introduction of streptomycin therapy.

PMID- 15011814
TI  - The history of masturbation: an essay review.

PMID- 15011815
TI  - Comments on P. W. J. Bartrip's article "Irving John Selikoff and the strange case
      of the missing medical degrees" (Vol. 58, January 2003, 3-33).

PMID- 15011816
TI  - Irving John Selikoff and the strange case of the missing medical degrees.

PMID- 15011817
TI  - Venous-drainage-guided selective hepatectomy: a novel approach to liver surgery.
AB  - Selective hepatectomy under the guidance of hepatic venous drainage has not yet
      been developed because hepatic venous occlusion alone produces no visible
      congested area. Now that this area can be identified by simultaneous occlusion of
      the hepatic vein and artery, venous-drainage-guided selective hepatectomy is
      considered feasible. Because the congested area becomes dysfunctional or atrophic
      due to the absence of portal blood supply, it can be regarded as a first
      candidate for preventive resection in livers that may bear latent tumors. We
      report here a novel approach to selective hepatectomy. Segment 4 hepatectomy and
      ventral hemisectorectomy of segments 5+8, with middle hepatic vein resection, was
      undertaken in a patient with hepatocellular carcinoma. After hepatic dissection
      between segments 2+3 and 4, the root of the middle hepatic vein was isolated.
      Test clamping of the middle hepatic vein and proper hepatic artery demonstrated a
      discolored area. Hepatic dissection was performed along the discolored border
      towards the hepatic hilum, exposing the right anterior portal pedicle with
      division of the ventral branches. The middle hepatic vein was finally divided.
      Selective hepatectomy was successfully performed without transfusion or
      complications. Venous-drainage-guided selective hepatectomy is feasible with
      acceptable perioperative results.

PMID- 15011818
TI  - Early ligation of the inferior pancreaticoduodenal artery to reduce blood loss
      during pancreaticoduodenectomy.
AB  - When performing a pancreaticoduodenectomy, a considerable amount of congested
      blood is lost, especially during the period when the pancreatic head area is
      being isolated from the superior mesenteric vessels. Following Kocher's maneuver,
      a 4-cm dissection was continued along the right margin of the superior mesenteric
      artery. The root of the inferior pancreaticoduodenal artery was disclosed and
      ligated prior to the following resection procedures. The early ligation of the
      inferior pangreaticoduodenal artery decreased blood loss (from 194+/-24 mL to
      86+/-50 mL) during the period when the pancreatic head area was isolated from the
      superior mesenteric vessels. This approach was feasible in reducing blood loss
      presumably related to blood congestion.

PMID- 15011819
TI  - Living organ donation: is there still place for altruism?
AB  - Living organ donation for transplantation, the ultimate action of altruism, is
      nowadays the object of extended discussion in many levels. The international
      trend is to find the best and finest way to support and reward this action. A lot
      of proposals have been suggested, some of them, however, could turn the whole
      action into a procedure of trade. In this paper, the present status and the
      international trend in living organ donation are discussed; furthermore, the role
      of information, education and religion in the individual acceptance of "being a
      living donor" is evaluated. The experience of the transplantation center and the
      hospital volume as important factors for the medical management of the donor are
      also taken into consideration. Our purpose is to emphasize the mean and origins
      of living organ donation, which must be a well-balanced decision after detailed
      information, an educational procedure or a religious-based encouragement.
      Monetary incentives can have only short-term results in increasing the number of
      donors; they can also increase the exploitation of poor people and, in the long
      run, destroy the concept of donation, dissuading the altruistic donors.

PMID- 15011820
TI  - Complications of laparoscopic cholecystectomy and their management.
AB  - BACKGROUND/AIMS: Of all the complications of laparoscopic cholectecystomy, bile
      duct injury and bile leak are the most serious complications. The purpose of this
      study is to present our data of incidence of the complications and our experience
      in the management of complications during and after laparoscopic cholecystectomy.
      METHODOLOGY: Retrospective study was performed on 348 patients, 102 males and 246
      females with mean age of 52 years who underwent laparoscopic cholecystectomies
      during the period from 1 January 1996 to 31 December 1998 in the Department of
      Surgery, Rajavithi Hospital, Bangkok, Thailand. All complications were diagnosed
      and their management was recorded. RESULTS: The complications included common
      bile duct injury in one case (0.29%) then we converted to exploratory laparotomy
      with cholecystectomy and Roux-en-Y choledochojejunostomy. One case that had
      cystic stump leakage (0.29%) and retained common bile duct stones was diagnosed
      later, we corrected by endoscopic retrograde cholangiopancreatography & ES,
      removed stones and placed a stent. One case had port wound infection (0.29%)
      which we treated by drainage and antibiotics. All of these had satisfactory
      results. CONCLUSIONS: The complications of laparoscopic cholecystectomy can be
      prevented by adequate surgical experiences, carefulness and case selection. The
      results of their management also depend on the facilities and cooperation with
      the endoscopists.

PMID- 15011821
TI  - Bile duct injuries during laparoscopic cholecystectomy: an audit of 1522 cases.
AB  - BACKGROUND/AIMS: Bile duct injuries during laparoscopic cholecystectomy are
      serious complications. The incidence of this complication increases compared with
      open cholecystectomy. The aim of this paper has been to audit the incidence and
      nature of bile duct injuries during laparoscopic cholecystectomy in a single
      center. METHODOLOGY: From January 1991 to September 2000, all laparoscopic
      cholecystectomy attempts performed in Rajavithi Hospital were analyzed. RESULTS:
      Of the 1522 procedures performed, there were 9 (0.59%) cases of bile duct
      injuries. These involved the common hepatic duct (n=3) and the common bile duct
      (n=6). The underlying gallbladder pathology included chronic cholecystitis (n=6),
      Mirizzi's syndrome (n=2), and acute cholecystitis (n=1). Transection of the duct
      accounted for the majority of the injuries. Six bile duct injuries were
      identified at the time of operation. These were primarily repaired by direct
      suture (n=1) or by a biliary-enteric anastomosis (n=5). In the remaining three
      patients, the diagnosis was delayed. Two patients presented with a large amount
      of bile from the drain after surgery and one patient presented with jaundice.
      These were repaired by direct suture over a T tube (n=1) or biliary-enteric
      anastomosis (n=2). One patient developed recurrent cholangitis following biliary
      enteric anastomosis after delayed diagnosis. CONCLUSIONS: The experience of a
      0.59% incidence of bile duct injury is comparable to the best results from most
      large series in the West. Inflammation/adhesion at Calot's triangle is an
      important associated factor for injury. Injuries identified and repaired at the
      time of the first operation afford good results.

PMID- 15011822
TI  - Diagnostic role of serum interleukin 6 and CA 19-9 in patients with
      cholangiocarcinoma.
AB  - BACKGROUND/AIMS: Cholangiocarcinoma is particularly common in Northeastern
      Thailand where the liver fluke, O. viverrini, is endemic. Currently there is no
      sensitive and specific tumor marker for the diagnosis of this cancer. The aim of
      this study was to investigate the accuracy of carbohydrate antigen 19-9 and
      interleukin-6 in the diagnosis of cholangiocarcinoma. The first marker represents
      the commonly used serum marker in cholangiocarcinoma and the second marker is a
      multi-functional cytokine associated with cancer development. METHODOLOGY: The
      serum concentrations of carbohydrate antigen 19-9 and interleukin-6 were
      simultaneously determined in 45 patients with cholangiocarcinoma, 15 with
      hepatocellular carcinoma, 15 with metastatic liver cancers, 10 with benign
      biliary disease and 10 healthy controls. RESULTS: The sensitivity of carbohydrate
      antigen 19-9 value (> or = 37 U/mL) in diagnosing cholangiocarcinoma was 64.4%,
      while its specificity was 100% and 56.7% when compared with benign biliary
      disease and other liver cancers, respectively. The sensitivity and specificity of
      detectable interleukin-6 (> or = 0.18 ng/mL) for differentiating between
      cholangiocarcinoma and benign biliary disease was 71.1% and 90%, respectively,
      whereas the specificity for differentiating cholangiocarcinoma from other liver
      cancers was 26.7%. When higher concentrations of either carbohydrate antigen 19-9
      (> or = 100 U/mL) or interleukin-6 (> or = 50 pg/mL) were used as the cut-off
      points, they provided additional diagnostic sensitivity and accuracy in
      differentiating between cholangiocarcinoma and other liver cancers to 80% and
      76%, respectively. CONCLUSIONS: The combined assays of both serum carbohydrate
      antigen 19-9 and interleukin-6 could be useful in diagnosing cholangiocarcinoma,
      particularly in populations where this cancer is prevalent.

PMID- 15011823
TI  - Outcome of transcatheter oily chemoembolization in patients with hepatocellular
      carcinoma.
AB  - BACKGROUND/AIMS: From July 1989 to June 1999, eighty-one patients with
      hepatocellular carcinoma, 63 males and 18 females, aged 18 to 82 years, were
      treated with transcatheter oily chemoembolization (TOCE) with an emulsion
      comprising 10 mL lipiodol and 20 mg mitomycin-C and final embolization with
      gelfoam particles. METHODOLOGY: Management began with angiography to identify
      tumor vascularity followed by TOCE via hepatic artery as peripheral as possible.
      Initial angiography prior to TOCE revealed both hepatic and extrahepatic
      collaterals in 11 patients with tumors larger than 10 cm. Following initial TOCE,
      48 patients developed intrahepatic collaterals. The remaining 22 patients
      developed extrahepatic collaterals after 4 sessions of TOCE over a period of
      about 5 months. Following TOCE, all patients were followed monthly for residual
      or recurrent tumor. If residual or recurrent tumor was found, TOCE would be
      repeated at 6-week intervals. The survival of the patients was retrospectively
      analyzed with respect to the type of hepatic collaterals and completeness of TOCE
      of extrahepatic collaterals. RESULTS: The results of the analysis show that the
      survival times were significantly shorter in patients with both hepatic and
      extrahepatic collaterals than patients with either extrahepatic collaterals or
      intrahepatic collaterals; their respective median values (ranges) in months were
      8 (4-24), 12.8 (3-48) and 12.5 (13-36). The significant differences in survival
      times were apparently due to differences in tumor size and stage of disease;
      their respective tumor sizes (means +/- SD, cm) were 13.6+/-3.9, 9.4+/-4.3 and
      10.0+/-3.9. Patients with extrahepatic collaterals and patients with intrahepatic
      collaterals had similar tumor sizes and survival times. In patients with
      extrahepatic collaterals, complete TOCE resulted in longer survival time, albeit
      not statistically significant, than incomplete TOCE. CONCLUSIONS: outcome of TOCE
      in patients with hepatocellular carcinoma is dependent on tumor size, the stage
      of disease and completeness of TOCE of extrahepatic collateral vessels.

PMID- 15011824
TI  - Anti-p53 antibodies and p53 protein expression in cholangiocarcinoma.
AB  - BACKGROUND/AIMS: Mutations of p53 are found in the majority of human
      malignancies. The accumulated mutant p53 can be detected in tumor sections by
      immunohistochemical methods. The abnormal accumulation of the defective p53
      protein can induce the host to develop anti-p53 antibodies in sera of cancer
      patients. This study aimed to investigate the presence of anti-p53 antibodies in
      sera of patients with cholangiocarcinoma and to evaluate the correlation between
      such antibodies and p53 protein accumulation. METHODOLOGY: The presence of serum
      anti-p53 antibodies in 49 patients with cholangiocarcinoma was determined by
      ELISA kit (Pharma Cell, France). Immunohistochemical detection of p53 protein
      expression was examined in available tissue samples of 36 patients. RESULTS:
      Serum anti-p53 antibodies were detected in 6 of 49 patients with
      cholangiocarcinoma (12.2%). Immunostaining of p53 was found in 15 of 36 patients
      (41.6%) and 4 of these 15 patients (26.7%) were positive for anti-p53 antibodies.
      The association between anti-p53 antibodies and p53 protein expression was
      statistically significant (P=0.023). No correlation was found between the
      presence of anti-p53 antibodies and sex, age, histological grade, site and stage
      of tumor (P>0.05). CONCLUSIONS: The majority of serum anti-p53 antibodies
      detected in cholangiocarcinoma were specifically associated with the accumulation
      of p53 protein in tumor tissues. However, antibody generation against the p53
      protein is a relatively uncommon event in cholangiocarcinoma.

PMID- 15011825
TI  - Distributing pattern of the bile duct of the caudate lobe on computed tomography
      with drip infusion cholangiography and its surgical significance.
AB  - BACKGROUND/AIMS: It is important to recognize the distribution of the bile ducts
      in the caudate lobe of the liver for the hepato-biliary surgery. To map the
      spatial relationship between the bile ducts and the liver parenchyma under
      physiological conditions, we performed an anatomical analysis of them using
      computed tomography combined with drip infusion cholangiography (DIC-CT).
      METHODOLOGY: We identified the bile ducts in the caudate lobe, which was divided
      into the Spiegel lobe, paracaval portion, and caudate process, with DIC-CT. We
      then investigated their number and confluence pattern in 132 patients without any
      abnormality in the hilar bile ducts. RESULTS: The mean number of the bile ducts
      in the caudate lobe was 2.68 per liver. In the Spiegel lobe, the branches drained
      into the left hepatic duct system in about 83%. The confluence of the paracaval
      branch was the left hepatic duct, right hepatic duct, and posterior segmental
      branch, all with the same frequency of approximately 30%. Almost all of the
      caudate process branches (92.4%) drained into the posterior segmental branch.
      CONCLUSIONS: DIC-CT is a useful method for the anatomical analysis of the
      intrahepatic bile ducts under physiological conditions, and we obtained novel and
      important findings for surgery.

PMID- 15011826
TI  - Diagnosis of gallstone ileus by serial computed tomography.
AB  - An unusual case of choledocholithiasis followed by gallstone ileus documented by
      serial computed tomography is reported. A 91-year-old woman underwent gastrostomy
      because she repeatedly developed aspiration pneumonia, and a common bile duct
      stone was detected. She and her family refused surgery once symptoms resolved.
      One year later, she presented with increasing, intermittent abdominal pain and
      nausea. Abdominal computed tomography revealed a common bile duct stone with
      inflammatory changes, but the patient still refused surgery. Three months later,
      she was admitted with abdominal pain and vomiting. On admission, plain abdominal
      radiographs demonstrated proximal small bowel obstruction. A long ileus tube was
      inserted through the gastric fistula. Two days after admission, gallstone ileus
      was diagnosed on abdominal computed tomography based on the presence of
      pneumobilia, disappearance of the common bile duct stone, fluid-filled bowel
      loops, and the discovery of an impacted stone in the small bowel. Ten and 15 days
      after admission, repeated computed tomography demonstrated the impacted stone in
      the terminal ileum. Seventeen days after admission, a laparotomy was performed,
      and a 5x3-cm gallstone was removed through an ileotomy.

PMID- 15011827
TI  - Cystic duct remnant and the 'post-cholecystectomy syndrome'.
AB  - Post-cholecystectomy syndrome refers to a wide spectrum of conditions that pose a
      challenging diagnostic dilemma. Cystic duct remnant, defined as a residual duct
      greater than 1 cm in length, may, in the presence of stones, cause post
      cholecystectomy syndrome. In this report, 4 patients with post-cholecystectomy
      syndrome due to cystic duct remnant are described. All underwent laparoscopic
      cholecystectomy and one was converted to open. The patients presented with pain
      10 months to 9 years post-cholecystectomy and investigations demonstrated cystic
      duct remnant. All patients underwent successful resection with resolution of
      symptoms. In this era of laparoscopic surgery, where surgery favors a long cystic
      duct remnant, we should be aware of cystic duct stones as a possible cause of
      postcholecystectomy syndrome. This report highlights magnetic resonance
      cholangiopancreatography as the optimal method for evaluating the biliary tract
      in these cases.

PMID- 15011829
TI  - Diagnosis and management of cholangiocarcinomas: a comprehensive review.
AB  - First described by Maximilian deStoll in 1777, cholangiocarcinoma remains to be a
      diagnostic and therapeutic challenge. The incidence of cholangiocarcinoma is of
      2000-3000 cases a year in the US but much higher in Southeast Asia and Eastern
      Europe. Sclerosing cholangitis, ulcerative colitis, liver fluke infestations,
      hepatolithiasis, thorotrast exposure, choledochal cysts are associated with an
      increased risk. Recently, substantial progress has been achieved in the
      understanding of the cellular and molecular mechanisms playing a role in biliary
      carcinogenesis including oncogenes and tumor suppressor genes. Surgery alone can
      be a curative treatment in only a fraction of patients with a 5-year survival
      rate of 0-39%. The role of radiotherapy including intensification with
      intraoperative radiation therapy, brachytherapy or conformal external beam
      radiation therapy has not been proven. Experience with chemotherapy is not
      widespread in cholangiocarcinoma. Chemotherapy trials have mostly included small
      numbers of patients and there have been no large prospective randomized trials.
      Observed objective response rates have been between 0% and 40% with no complete
      remissions. Further studies are required to find out the impact of chemotherapy
      in the management of cholangiocarcinoma and search for newer agents with novel
      mechanisms of action that can be more active in cholangiocarcinoma should
      continue. Meanwhile prevention and early diagnosis of cholangiocarcinoma is
      essential. Efforts should also continue to discover means to detect high-risk
      patients with less invasive methods.

PMID- 15011828
TI  - A traumatic neuroma of the bile duct: a case report.
AB  - Traumatic neuroma of the bile duct is not a true neoplasm, but a reactive
      proliferation of pericholangial nerve tissue induced by injury. A 60-year-old
      Japanese man was admitted to investigate obstructive jaundice. He had undergone
      cholecystectomy and common bile duct exploration 17 years previously.
      Ultrasonography and computed tomography showed a pneumobilia with dilatation of
      the intrahepatic biliary ducts. Endoscopic retrograde cholangiography and spiral
      computed tomography cholangiography revealed biliary stenosis in the hepatic
      hilus with dilatation of the intrahepatic biliary ducts. Celiac angiography and
      arterial portography showed neither tumor stains nor signs of vessel invasion. At
      surgery, the confluent portion of the intrahepatic biliary ducts in the hepatic
      hilus was hardly palpable and deformed, but frozen-section microscopic
      examination confirmed that no malignant cells were present. Anastomosis of the
      right and left extrahepatic bile duct to the jejunum, reconstructed by Roux-en-Y
      hepaticojejunostomy, was performed. Histological examination revealed a nodule
      composed of a haphazard proliferation of nerve fascicles in the fibromuscular
      layer of the bile duct which were positively stained for S-100 protein. The
      pathological diagnosis was traumatic neuroma of the bile duct. Thus, the
      possibility of traumatic neuroma should be considered in the differential
      diagnosis of patients with late-onset jaundice after biliary tract surgery.

PMID- 15011830
TI  - Venous pressure measurements in the superior and inferior vena cava: the
      influence of intra-abdominal pressure.
AB  - BACKGROUND/AIMS: To investigate the relationship of pressure in the inferior vena
      cava (Pivc) with a) pressure in the superior vena cava (Psvc), b) intra-abdominal
      pressure as measured in the urinary bladder (Pcyst). METHODOLOGY: A prospective
      study of 38 mechanically ventilated patients. Simultaneous measurements of Psvc,
      Pivc and Pcyst (151 sets of measurements) were performed. Measurements were
      divided in: Group A (Pcyst < 10 mmHg), group B (10 mmHg < or = Pcyst < 15 mmHg),
      group C (Pcyst > or = 15 mmHg). Statistical analysis was performed with paired t
      test, Pearson correlation. Results are expressed in mean +/- SEM. RESULTS: In
      Groups A and B, Psvc and Pivc were not significantly different and they were
      highly correlated (10.8+/-0.5 mmHg vs. 10.9+/-0.5 mmHg, r=0.93 for Group A and
      14.4+/-0.7 mmHg vs. 14.7+/-0.6 mmHg, r=0.87 for Group B). Pcyst was significantly
      lower than Pivc in both groups. In Group C, Pivc was significantly higher than
      Psvc (18.9+/-0.7 mmHg vs. 16.4+/-0.7 mmHg). There was no significant difference
      between Pivc and Pcyst (19.2+/-0.6 mmHg). Pivc significantly correlated with
      Pcyst (r=0.78) and Psvc (r=0.7). A. When Pcyst > Psvc, Pivc was higher than Psvc
      (p<0.01). With Pcyst < 15 mmHg, no significant difference was found between Pcyst
      and Pivc and they were correlated (r=0.766, p<0.05). Pressures in the superior
      and inferior vena cava were also correlated (r=0.764, p<0.05). With Pcyst > or =
      15 mmHg, Pivc was lower than Pcyst (p<0.01). It correlated highly with Pcyst
      (r=0.85, p<0.01) and less strongly with Psvc (r=0.701, p<0.01). B. When Pcyst <
      or = Psvc, no difference between Pivc and Psvc was observed. With Pcyst < 15
      mmHg, Pivc was higher than Pcyst (p<0.01) and highly correlated with Psvc
      (r=0.932, p<0.01). Pivc also correlated with Pcyst (r=0.69, p<0.01). With Pcyst >
      or = 15 mmHg, Pivc was higher than Pcyst (p<0.01) and correlated with Psvc
      (r=0.74, p<0.01) and Pcyst (r=0.789, p<0.01). CONCLUSIONS: Although Psvc and Pivc
      are interchangeable in the absence of an increased Pcyst, when Pcyst is high,
      measurements of Pivc are misleading. A Pcyst > Psvc results in a "waterfall"
      effect, and Pivc does not accurately reflect Psvc any more.

PMID- 15011831
TI  - Re-appearance of power Doppler signals in the tumor nodules of hepatocellular
      carcinoma after transarterial embolization reflects residual viable tumor cells:
      histological confirmation.
AB  - BACKGROUND/AIMS: A recent advance in ultrasonography is the use of power Doppler
      for detecting low-velocity angle-independent blood flow at the microvascular
      level. The present study was prospectively performed to elucidate the
      relationship between the power Doppler signals of hepatocellular carcinoma after
      transarterial embolization and histological confirmation of viable tumor cells.
      METHODOLOGY: The observance of hepatocellular carcinoma-related Doppler signals
      in 48 patients with 67 nodules was examined after transarterial embolization, and
      its correlation with the presence of viable tumor cells using ultrasound-guided
      biopsy specimens was analyzed. RESULTS: Power Doppler signals disappeared in 54
      out of 67 nodules (80%) one day after transarterial embolization, but the signals
      re-appeared in 55-53% of the specimens at 4-7 days and 10-14 days after
      treatment. Viable tumor cells were histologically proven in 27 of 34 nodules
      (79%) presenting power Doppler signals, while only 5 of the 22 nodules (23%)
      negative for Doppler signals confined viable tumor cells (P<0.001). Univariate
      and multivariate analysis showed that the detection of power Doppler signals
      after transarterial embolization was related to the size of the tumor and the
      presence of viable tumor cells (both, P<0.001). CONCLUSIONS: These results
      indicate that the presence of power Doppler signals may reflect the presence of
      viable tumor cells after transarterial embolization, leading to the need for
      further treatment of hepatocellular carcinoma nodules.

PMID- 15011832
TI  - New frontiers in the management of advanced hepatocellular carcinoma. "A new look
      to an old problem".
AB  - BACKGROUND/AIMS: To evaluate the benefits of two-stage liver surgery with main
      portal branch ligation and transection combined with transarterial targeting
      locoregional neo and adjuvant immunochemotherapy in patients suffering from
      hepatocellular carcinoma. METHODOLOGY: 43 consecutive patients underwent two
      stage liver surgery for advanced hepatocellular carcinoma. First we performed
      ligation and transection of the main portal vein branch corresponding to the
      liver lobe occupied by the tumor. Subsequently we introduced an arterial jet port
      catheter towards the hepatic artery via the gastroduodenal artery. After
      locoregional transarterial targeting immunochemotherapy regimen the patient
      underwent a second laparotomy for hemihepatectomy. Following surgery,
      locoregional transarterial targeting immunochemotherapy was given to all patients
      via the arterial port of the gastroduodenal artery as an adjuvant treatment.
      RESULTS: Mean survival was 41 months. There were no operative deaths.
      CONCLUSIONS: Two-stage liver surgery and transarterial targeting locoregional
      immunochemotherapy is the favorable option of treatment for advanced
      hepatocellular carcinoma. It not only results in an increase in the overall
      survival of these patients, but also increases the rate of resectability of these
      tumors by the hepatobiliary surgeon.

PMID- 15011834
TI  - Scintigraphic sign of functional biliary obstruction is pathognomic for sphincter
      of Oddi dysfunction.
AB  - BACKGROUND/AIMS: Quantitative hepatobiliary scintigraphy (QHBS) is a valuable
      method for the detection of a low-grade biliary obstruction in patients with
      suspected sphincter of Oddi (SO) dysfunction (SOD), though the relatively low
      specificity of this noninvasive test has been criticized. The aim of the present
      study was a critical assessment of the diagnostic value of glyceryl trinitrate
      augmented QHBS in patients with suspected SOD. METHODOLOGY: Glyceryl trinitrate
      augmented QHBS and endoscopic retrograde cholangiopancreatography (ERCP) was
      performed on 27 cholecystectomized patients with suspected SOD. RESULTS: In 14
      patients the ERCP depicted organic causes of biliary obstruction
      (choledocholithasis, juxtapapillary diverticulum, Vater papilla adenoma and
      common bile duct stenosis). In 12 of the 13 patients with inconclusive ERCP,
      endoscopic SO manometry demonstrated an elevated SO basal pressure. In patients
      with manometrically confirmed SOD, glyceryl trinitrate administration
      significantly increased the radioactive bile transit into the duodenum and
      normalized the QHBS parameters. In contrast, the 14 patients with an organic
      biliary obstruction glyceryl trinitrate administration had no effect on the
      transpapillary bile flow. CONCLUSIONS: In conclusion, glyceryl trinitrate
      augmented QHBS is a specific method in the diagnosis of SOD, proving the
      functional reversibility of the biliary obstruction.

PMID- 15011833
TI  - Adenovirus expressing mutant p27kip1 enhanced apoptosis against
      cholangiocarcinoma than adenovirus-p27kip1 wild type.
AB  - BACKGROUND/AIMS: The prognosis of cholangiocarcinoma is extremely poor despite
      the aggressive multidisciplinary cancer therapies that have been used clinically.
      Thus, it is imperative to develop new and effective treatments, such as gene
      therapy in order to treat this disease. p53 is the most common target for cancer
      gene therapy treatment. However, cholangiocarcinoma has a low frequency of p53
      mutation, which makes this protein a poor candidate for gene therapy in this
      disease and another suitable gene therapy target must be found. p27kip1 is a
      universal cyclin-dependent kinase (CDK) inhibitor that blocks cell cycle
      progression and inhibits proliferation. Our previous reports have demonstrated
      the role of p27kip1 in the induction of apoptosis using a recombinant adenoviral
      vector expressing p27kip1 (Adp27) in several different human cancer cells.
      p27kip1 is regulated by two mechanisms composed of a ubiquitin-proteasome system
      and proteolytic processing system that requires the phosphorylation of p27kip1 on
      Thr-187 by the cyclinE/Cdk2 complex followed by proteolytic degradation.
      METHODOLOGY: In this study, we focused our aim on the degradation of p27kip1
      protein mediated by a recombinant adenoviral expressing a mutant p27kip1 (Adp27
      mt), which has a mutation of Thr-187/Pro-188 (ACGCCC) to Met-187/Ile-188
      (ATGATC). RESULTS: We observed that the mutated p27kip1 markedly inhibited
      ubiquitination and the subsequent degradation of p27kip1 when compared to wild
      type p27kip1. Consequently, we found that mutated p27kip1 induced a stronger
      induction of apoptosis and cell growth inhibition than wild type p27kip1 in
      cholangiocarcinoma cell lines TFK-1 and HuCCT-1. Furthermore, we demonstrated
      that Adp27-mt mainly caused G2/M arrest in the cell cycle progression and a
      decreased cyclinB1 and Cdc2 protein where as Adp27-wt mediated a G1/S arrest at
      48 hours after infection. CONCLUSIONS: In this study, we showed that adenoviral
      vector expression of mutant p27kip1 protein inhibited degradation by the
      ubiquitin-proteasome system and strongly induced apoptosis and cell growth
      inhibition compared to wild type p27kip1. Thus recombinant adenovirus expressing
      mutant p27kip1 may be potentially useful for gene therapy against
      cholangiocarcinoma.

PMID- 15011835
TI  - Surgical outcome of 483 patients with early gastric cancer: prognosis,
      postoperative morbidity and mortality, and gastric remnant cancer.
AB  - BACKGROUND/AIMS: The aim of this retrospective study was to evaluate the
      characteristics, treatment, postoperative morbidity, mortality, and prognosis of
      early gastric cancer patients as well as the incidence of gastric remnant cancer
      after curative surgery based on an analysis of the surgical results of Nippon
      Medical School Hospital over the past 10 years (1991-2000). METHODOLOGY: Out of
      1057 patients with gastric cancer (all stages), 483 patients (301 males and 182
      females; mean age 60.9 years) underwent surgery for early gastric cancer. Early
      gastric cancer, defined as that invading the m or sm layer regardless of lymph
      node metastasis, was classified according to the Japanese Classification of
      Gastric Carcinoma. The survival rate was calculated using the Kaplan-Meier
      method. RESULTS: The stages of the 483 patients were as follows: stage Ia
      patients, 443 cases; stage Ib, 29 cases; stage II, 7 cases; and stage IV, 4
      cases. The overall 5- and 10-year survival rates were 95.9% and 95.9% for stage
      Ia, 82.9% and 80.2% for stage Ib, 73.2% and 68.6% for stage II and 0% for stage
      IV, respectively. No difference was observed in the 5- and 10-year survival rates
      between patients with D1 and D2 dissections in cases without lymph node
      metastasis. In patients with n1 positive sm cancer, however, the 5-year survival
      rate of the patients who underwent D2 dissection was 91.0% while that of those
      who underwent D1 dissection was 80.0% (P<0.05). The incidences of postoperative
      morbidity from various cancers included 4.2% from surgical site infections, 1.6%
      from anastomotic dehiscence, 1.6% from intestinal obstructions, and 3.9% from
      respiratory and/or heart dysfunction. Three patients (0.6%) died of multiple
      organ failure. Five patients who had undergone gastrectomy for early gastric
      cancer were diagnosed as having early cancer in the gastric remnant during a
      periodic follow-up endoscopy and underwent regastrectomy. CONCLUSIONS: The
      prognosis of early gastric cancer is usually excellent, and the morbidity and
      mortality rates are satisfactory. D2 lymph node dissection is necessary in
      patients with n1 positive sm cancer. Periodic follow-up endoscopies in
      gastrectomized patients may be useful for the early detection of gastric remnant
      cancer.

PMID- 15011836
TI  - Spleen-preserving distal pancreatectomy for intraductal papillary-mucinous tumor
      (IPMT).
AB  - BACKGROUND/AIMS: Recently, the significance of preserving the spleen has received
      a lot of attention. Since our first trial and success of spleen-preserving distal
      pancreatectomy with conservation of the splenic artery and vein for chronic
      pancreatitis, this procedure has been more frequently performed and reported. In
      this study, we introduce the technique and indications for the procedure for
      intraductal papillary mucinous tumor of the pancreas. METHODOLOGY: Nine patients
      underwent spleen-preserving distal pancreatectomy with conservation of the
      splenic artery and vein. We performed this procedure in two patients with
      intraductal papillary mucinous tumor. The splenic vein is identified behind the
      pancreas and within the thin connective tissue membrane. The connective tissue
      membrane is cut longitudinally above the splenic vein. An important technique is
      to remove the splenic vein from the pancreas from the body of the pancreas toward
      the spleen. There are many branches from the splenic vein on both sides, and
      these branches should be carefully ligated and cut. The pancreas is removed from
      the splenic artery from the spleen toward the head of the pancreas. This
      procedure is much easier than removing the pancreas from the vein. RESULTS: The
      postoperative course was uneventful in all nine cases, but one, in which
      pancreatic fistula continued for more than several weeks. The mean and standard
      deviation of the operative blood loss, the duration of the operation and the
      postoperative hospital stay in seven cases, excluding two cases, in which either
      Puestow's procedure or simultaneous subtotal esophagectomy was performed, were
      413+/-385 mL, 298+/-55 min, and 39+/-15 days, respectively. Severe complications
      were not found in any of the nine cases. The two patients with intraductal
      papillary mucinous tumor have been followed as outpatients without any
      recurrence. CONCLUSIONS: Spleen-preserving distal pancreatectomy with
      conservation of the splenic artery and vein is easy and safe, and should be
      performed for some of the patients with intraductal papillary mucinous tumor of
      the pancreas.

PMID- 15011837
TI  - REG I as a marker for human pancreatic acinoductular cells.
AB  - BACKGROUND/AIMS: Several studies have suggested that pancreatic exocrine cells
      are able to differentiate into endocrine cells. REG I has been shown to be
      crucial for induction of ductal epithelial cells to differentiate into insulin
      producing cells. To date, however, there has been no study which examined the
      expression of REG I along with other differentiation markers in patients with
      chronic pancreatitis. METHODOLOGY: Six cases with chronic pancreatitis and the
      pancreata from the age-matched autopsy cases of unrelated diseases (n=2) were
      included in this study and examined by immunostaining methods using antibodies
      against human REG I protein, trypsin, insulin, chromogranin A, cytokeratin 19 and
      Ki-67. RESULTS: In chronic pancreatitis, REG I was found in acinar and
      acinoductular cells and the latter were also characterized by cytokeratin 19
      positivity. The acinoductular cells showed the budding of REG I-positive cells
      which were also trypsin- and chromogranin A-positive. MIB-1 antibody against Ki
      67 was found negative in the ductal, acinoductular and islet cells reflecting low
      proliferation in these cells. CONCLUSIONS: The current study revealed that
      acinoductular cells characterized by dual expression of REG I and cytokeratin 19
      also express insulin, chromogranin A and trypsin and therefore supports the
      hypothesis that transdifferentiation of fully differentiated (acinar) cells may
      be the main source of islet neogenesis in patients with chronic pancreatitis.
      However, low proliferation rate in these cells limits the regeneration capacity
      of the pancreatic tissue in these cases. The present results of double staining
      of REG I with cytokeratin 19, chromogranin A and insulin in the acinoductular
      cells indicate that REG I may be used as a marker for these cells.

PMID- 15011838
TI  - The usefulness of intraoperative needle decompression of the colon during radical
      gastrectomy--a prospective and randomized trial.
AB  - BACKGROUND/AIMS: Intraoperative colonic distension is associated with
      postoperative ileus, which contributes to delayed hospital discharge. A
      randomized and prospective study was conducted, to evaluate the usefulness of
      intraoperative needle decompression of the colon during radical gastrectomy for
      gastric cancer. METHODOLOGY: Fifty patients that had received subtotal or total
      gastrectomy for gastric cancer were randomly assigned to either a non
      decompression (n=27) or a decompression group (n=23). Prior to the main
      procedure, the transverse or right colon was pulled up, and a 19-gauge disposable
      needle connected to suction was introduced to the colon through the taenia site
      of anterior wall. Gas collected in the colon was aspirated out. The time to the
      first postoperative passage of flatus or feces was measured precisely to evaluate
      the restoration of bowel function. Additional measures of outcome were the
      operation time, the complication rate, and hospital stay. RESULTS: Demographic
      details, pathologic features, operation time, complication rate and hospital stay
      were not different between the two groups. A collapsed colon was required for
      good surgical exposure and easy manipulation. No unexpected complication related
      to this procedure was found. The first flatus was 6.8 hours sooner in the
      decompression group than in the non-decompression, though this result was not
      statistically significant. CONCLUSIONS: This technique is a simple and safe
      procedure for intraoperative colon decompression during radical gastrectomy.

PMID- 15011839
TI  - Lower limb compartment syndrome associated with Lloyd-Davies/lithotomy position
      in colorectal surgery.
AB  - Lower limb compartment syndrome is a rare complication of surgical patients
      submitted to operation in the lithotomy/Lloyd-Davies position. The diagnosis and
      treatment of this feared complication should be promptly instituted otherwise the
      patient may have serious neuromuscular impairment, limb loss or even fatal
      outcome. Furthermore, rabdomyolysis and myoglobinuria may lead to acute renal
      failure. Among the factors involved in the development of this syndrome are
      prolonged operation time, elevation of the lower limbs, Trendelenburg position,
      metabolic acidosis and perioperative hypotension. The authors illustrate this
      rare and deadly complication after an abdominal perineal resection for a low
      rectal cancer in an otherwise healthy patient. Early fasciotomies of all three
      compartments of both legs led to complete functional recovery of both limbs and
      avoided more serious complications. The authors emphasize the importance of early
      recognition of this syndrome as well as immediate or even prophylactic
      intervention to avoid most common sequelae. Moreover, they point out some
      preventive measures that can be observed to lower the incidence of this condition
      in patients exposed for a long period to this position during colorectal or
      urological operations.

PMID- 15011840
TI  - Exceptional bilateral adrenalectomy after secondaries from colorectal cancer.
AB  - We report a very uncommon case of bilateral adrenal metastasis treated at our
      institution. The patient was 65 years old, with a history of low anterior
      resection for colorectal cancer in 2001. One year later, he was diagnosed with
      bilateral adrenal metastasis, based on the results of abdominal computed
      tomography-scan. A bilateral adrenalectomy extended to distal pancreatectomy and
      splenectomy was performed. Postoperative course was uneventful. He is alive and
      free of disease 12 months after adrenalectomy. We conclude adrenal metastasis
      from colorectal cancer should be managed surgically, even if they are bilateral.

PMID- 15011842
TI  - Mucosa-associated lymphoid tissue-type lymphoproliferative lesion of the common
      bile duct.
AB  - Only a few cases of primary lymphoma of the common bile duct have been reported
      up to now. Here, we report a mucosa-associated lymphoid tissue (MALT)-type
      lymphoproliferative lesion of the common bile duct with some considerations about
      MALT lymphoma and benign lymphoproliferation. The patient, a 71-year-old woman,
      was admitted to our hospital because of progressive epigastric pain. Abdominal
      ultrasonography, magnetic resonance cholangiopancreatography, endoscopic
      retrograde cholangiopancreatography, and abdominal computed tomography showed a
      non-specific finding of stenosis of the common bile duct due to thickening of the
      wall. Angiography provided little diagnostic information. Bile duct carcinoma was
      diagnosed and pylorus-preserving pancreaticoduodenectomy was performed.
      Histological examination revealed that the common bile duct was occupied by full
      thickness proliferation of lymphoplasma cells with many reactive lymph follicles.
      The histological features were somewhat consistent with those of MALT lymphoma.
      However, we could not determine the clonal proliferation of lymphoplasma cells in
      either immunohistochemical immunoglobulin light chain restriction of the plasma
      cells or in polymerase chain reaction based immunoglobulin heavy chain gene
      rearrangement. The present case may be categorized as a borderline lesion close
      to benign lymphoproliferation. To the best of our knowledge, there have been no
      reports of cases similar to the present case.

PMID- 15011843
TI  - Evaluation of genetic mutations of tumor suppresser genes in colorectal cancer
      patients.
AB  - BACKGROUND/AIMS: The mutation of tumor suppresser genes of colorectal cancer was
      evaluated to clarify its significance in the clinical management of colorectal
      cancer patients. METHODOLOGY: Polymerase chain reaction amplification was
      performed to investigate the loss of heterozygosity (LOH) of the DCC (deleted-in
      colorectal-carcinoma) gene and p53 gene in 76 colorectal cancers. RESULTS: Thirty
      five of 76 tumors showed LOH at the p53 locus. LOH at the DCC locus was observed
      in 30 of 76 tumors. Tumors with DCC LOH had a significantly higher rate of p53
      LOH. DCC LOH was associated with both liver metastasis and lymph node metastasis.
      Moreover, younger patients and patients with a well-differentiated adenocarcinoma
      had a higher risk of liver and lymph node metastasis when the tumor had DCC LOH.
      The association between liver or lymph node metastasis and clinicopathological
      factors was stronger in tumors with smaller size and negative serosal invasion.
      CONCLUSIONS: The careful exploration of the liver and regional lymph nodes is
      advocated when the tumor has a DCC alteration, even at an early stage of the
      disease and especially in younger patients and patients with a well
      differentiated carcinoma. The assessment of DCC LOH may be useful for selecting
      patients for extensive surgical intervention or adjuvant chemotherapy.

PMID- 15011841
TI  - Sarcomatoid carcinoma of common bile duct: a case report.
AB  - Sarcomatoid carcinomas (carcinosarcomas) are rare lesions in the hepatobiliary
      pancreatic system. We present an extremely rare case of sarcomatoid carcinoma of
      the common bile duct. The tumor showed a biphasic pattern of intermixed
      carcinomatous (adenocarcinoma) and sarcomatoid elements (spindle and giant
      cells). By immunohistochemical staining, cytokeratin and vimentin were
      demonstrated in the sarcomatoid component. The proliferative activity and the
      oncoproteins expressed by the tumor were investigated by the PCNA, Ki-67, p53 and
      Bcl-2 in different tumor fields. Overall, the intensities of PCNA and p53 were
      moderate in the sarcomatoid component, but mild in the carcinomatous component.
      However, Ki-67 and Bcl-2 were both negative in the carcinomatous and sarcomatoid
      components. The possible histogenensis of sarcomatoid carcinoma of the common
      bile duct is discussed. We report upon an additional extremely rare case of
      sarcomatoid carcinoma arising in the common bile duct together with its
      immunohistochemical characteristics, and give details of its proliferative
      activity and oncoprotein expression.

PMID- 15011844
TI  - Colorectal cancers under 45 years of age.
AB  - BACKGROUND/AIMS: The aim of this study was to evaluate patients with colorectal
      cancer under the age of 45 and compare with colorectal cancer patients over the
      age of 45 treated in our surgical clinic. METHODOLOGY: At the Surgical Department
      of the Medical Faculty of Uludag University between 1986-2000 (15 years), 680
      cases with colorectal cancer diagnosis were operated on. One hundred and thirty
      six (20%) of these cases who were under the age of 45 were retrospectively
      evaluated and compared with other patients. RESULTS: The family history of ten of
      those patients was positive. The most common referring symptoms were rectal
      bleeding (61.7%), and weight loss (29.4%). Tumor was localized at right colon in
      19%, at left colon in 6.6%, at the sigmoid and the rectum in 74%. Nine of those
      cases (6.6%) were operated emergently, the rest (93.3%) were operated electively.
      One hundred and eighteen of the cases (86.7%) were resectable and 61 cases
      (44.8%) were showing distant metastases during the operations. CONCLUSIONS: As a
      conclusion, in Turkey, young age group colorectal cancers are 4-5 times more
      common than in Western communities. Because of the high probability of colorectal
      cancers, considering the possibility of colorectal cancer and taking a careful
      family history will help to catch the case at an earlier stage and will improve
      the chance of cure.

PMID- 15011845
TI  - Polyps with different grades of dysplasia and their distribution in the
      colorectum.
AB  - BACKGROUND/AIMS: To determine the role of adenomatous polyps in the development
      of colorectal cancers, we examined the relationship between the distribution and
      polyps with different grades of dysplasia (low, high), or/and cancers in the
      colorectum. METHODOLOGY: The distribution of 527 polyps with low-grade dysplasia
      was compared with that of 121 polyps with high-grade dysplasia, and 10 colorectal
      cancer lesions with adenomatous polyps in 361 patients who underwent total
      colonoscopy. RESULTS: The distribution rate of polyps at the distal colon and
      rectum into polyps with high-grade dysplasia significantly increased in
      comparison to that into polyps with low-grade dysplasia, respectively (p<0.002).
      The percentage of polyps with high-grade dysplasia measuring >1 cm significantly
      increased in comparison to that with low-grade dysplasia measuring >1 cm
      (p<0.00001). In patients with both adenomatous polyps and colorectal cancers, the
      polyps with high-grade dysplasia at the distal sites of cancerous lesions
      increased significantly more than at the proximal sites of cancerous lesions
      (p<0.05). Polyps with high-grade dysplasia have malignant potentials to
      intermediate between polyps with low-grade dysplasia and colorectal cancers in
      our study. CONCLUSIONS: The different distributions of different grades thus
      suggested that polyps with different grades of dysplasia at various colorectal
      sites were found to have different malignant potentials for cancer development.

PMID- 15011846
TI  - Adjuvant hepatic arterial infusion chemotherapy after curative resection for
      Dukes C colorectal cancer: a pilot study.
AB  - BACKGROUND/AIMS: The aim of this study was to evaluate the effect and the
      toxicity of prophylactic adjuvant hepatic arterial infusion chemotherapy (HAIC)
      on liver metastases and on overall survival of Dukes C colorectal cancer
      patients. METHODOLOGY: Ninety patients in whom Dukes C colorectal cancer was
      diagnosed and were treated with curative resection between 1993 and 1997
      underwent HAIC. The HAIC regimen consisted of a 24-hour continuous infusion of
      1500 mg of 5-fluorouracil, administered once a week for 8 weeks, utilizing a
      portable infusion drug delivery system to ambulatory patients. Patients to whom 7
      g or more of 5-fluorouracil could be given were included in the HAIC group, which
      resulted in 70 of the 90 patients being in this group. The HAIC group overall
      survival and liver recurrence rates were compared with those of 62 non-treated
      cases of Dukes C, which formed the non-HAIC control group. RESULTS: There were no
      serious toxic effects in this study. Significant differences were seen in the
      cumulative overall 5-year survival (HAIC group, 84.1%; non-HAIC group, 65.2%;
      p=0.0369). The cumulative 5-year liver metastasis-free rate was 92.7% in the HAIC
      group and 78.6% in the non-HAIC group (p=0.0649). In cases of distal lymph node
      metastasis, a risk factor for liver metastasis, the cumulative 5-year liver
      metastasis-free rate in the HAIC group (91.7%) was significantly higher than that
      in the non-HAIC group (58.6%; p=0.0268). CONCLUSIONS: HAIC effectively prevents
      metachronous liver metastasis, especially in patients with pre-existing distal
      lymph node metastases, and improves the prognosis of advanced colorectal cancer.

PMID- 15011848
TI  - Gadolinium enhanced endorectal coil and air enema magnetic resonance imaging as a
      useful tool in the preoperative examination of patients with rectal carcinoma.
AB  - BACKGROUND/AIMS: In the present study, we attempted to evaluate the usefulness of
      gadolinium enhanced endorectal coil and air enema magnetic resonance imaging with
      slice adjustments in patients with rectal carcinoma. METHODOLOGY: The subjects
      were patients with rectal cancer from June 1997 to September 1999 who were
      examined with a 1.5 Tesla magnetic resonance device. Buscopan was administered
      both intravenously and intramuscularly to reduce motion artifacts. Imaging
      sequences were obtained for T1 weighed, T2 weighed and T2 fat-saturated images.
      Slice thickness was 5 mm and interslice gap 3 mm. Endorectal coil insertion and
      air enema technique were performed with slice adjustments. Images were
      interpreted according to the criteria of the TNM classification. Lymph node
      metastasis was diagnosed as positive when the lymph nodes exceeded 5 mm in
      diameter. Histological and magnetic resonance findings were compared, and
      diagnostic accuracy was calculated. RESULTS: Fifty-four consecutive patients were
      included in this study (37 male, 17 female). There were 10 early cases and 44
      advanced cases of rectal cancer. Images with an endorectal coil were obtained in
      4 patients. Fifty patients underwent air enema technique. The depth of tumor
      invasion was accurately diagnosed in all 4 patients undergoing endorectal coil
      examination. On air enema study, magnetic resonance imaging correctly staged the
      depth of invasion in 41 of 50 patients (82.0%). Overstaging was seen in 8 of 50
      patients (16%), however, only one patient (2.0%) was understaged. Overall
      accuracy, overstaging and understaging rates were 83.3% (45/54), 14.8% (8/54),
      and 1.8% (1/54), respectively. On endorectal coil study, accurate diagnosis of
      lymph node metastasis was obtained in 3 of 4 (75.0%) patients. On air enema
      study, an accurate diagnosis of lymph node metastasis was obtained in 36 of 50
      (72.0%) patients, yielding 75.0% sensitivity and 73.1% specificity. Overall
      magnetic resonance imaging findings of lymph node metastasis resulted in 72.2%
      (39/54) diagnostic accuracy, yielding sensitivity of 75.0% (18/24) and
      specificity of 73.3% (22/30). CONCLUSIONS: We conclude that gadolinium enhanced
      endorectal coil and air enema magnetic resonance imaging is promising for
      preoperative evaluation of patients with rectal carcinoma.

PMID- 15011847
TI  - The effect of tegafur and uracil combination on colonic anastomotic strength: an
      experimental study on rats.
AB  - BACKGROUND/AIMS: Some patients are candidates for neo-adjuvant use of Tegafur, a
      prodrug of 5-fluorouracil, and Uracil combination (UFT). The purpose of this
      study is to assess the effect of preoperative UFT use on the strength of colonic
      anastomosis. METHODOLOGY: Forty Wistar albino rats were randomly divided into a
      control (group 1, n=10) and three study (Group 2, 3 and 4, 10 animals in each
      group) groups. Animals in control and study groups were given saline or UFT which
      included 50 mg/kg of Tegafur via an oral-gastric tube for 28 days. A segmental
      colonic resection and end-to-end anastomosis was performed on all animals 1, 1, 7
      and 14 days after the treatments had ended in groups 1, 2, 3 and 4, respectively.
      On postoperative day 7 the animals were killed and bursting pressure and breaking
      strength were measured. RESULTS: Three animals in the treatment groups died
      during the preoperative period, and one in the control group died after surgery.
      The animals in groups 2 and 3 had lesser bursting pressures than the control
      group (p<0.001), but no statistical difference was observed in bursting pressures
      of the control group and group 4 (p>0.05). The breaking strengths of each group
      were statistically different from the other groups (p<0.001 for each comparison).
      CONCLUSIONS: UFT use during the preoperative period affected the anastomosis
      strength in this animal experiment. Current study suggests that an operation
      should not be performed during the 14 days after UFT use has ended.

PMID- 15011849
TI  - EIA versus RIA in detecting carcinoembryonic antigen level of patients with
      metastatic colorectal cancer.
AB  - BACKGROUND/AIMS: Little literature exists comparing the differences between
      enzyme immunoassay (EIA) and radioimmunoassay (RIA) in the detection of serum
      carcinoembryonic antigen (CEA) levels of patients with metastatic colorectal
      cancer. Because EIA has the advantage of avoiding the use of radioisotopes, the
      potential of using EIA instead of RIA in detecting CEA of patients with
      colorectal cancer is of interest to us. METHODOLOGY: Between March and August
      2001, a total of 120 blood specimens, including 60 specimens from patients with
      metastatic colorectal cancer and another 60 from patients with non-malignant
      diseases, were examined in this study. Serum CEA levels were examined by EIA and
      RIA methods in parallel. The CEA-EIA tests were done using EIA kits manufactured
      by Abbott Laboratories at Illinois in the United States. Comparison was done with
      the conventional CEA-RIA tests using RIA kits manufactured by CIS laboratory at
      France. The blood samples were sent to Veterans General Hospital-Taipei for EIA
      and RIA determination. The cut-off value for CEA was set at 5.0 ng/mL. RESULTS:
      The correlation between the Abbott-EIA and the CIS-RIA methods in detecting serum
      CEA levels was high. The results give a correlation coefficient of 0.992 with a
      linear regression line y=0.975 x + 0.215 (p<0.0001). Agreement in the Abbott-EIA
      and CIS-RIA tests in diagnosis was observed in 113 patients (94%), including 53
      positive (>5 ng/mL) and 60 negative (<5 ng/mL) in both tests. The sensitivity was
      similar in both assays (83% vs. 80%) at a cut-off level of 5 ng/mL. The ability
      to discriminate between colorectal cancer and non-malignant diseases was good in
      both assays (p<0.001). The specificity and positive predictive value were
      slightly higher with the Abbott-EIA method compared with CIS-RIA assay (92% vs.
      83% and 91% vs. 83%, respectively). The Abbott-EIA method achieved a similar
      diagnostic accuracy to CIS-RIA method (88% vs. 82%). CONCLUSIONS: These data
      suggest that the Abbott-EIA has similar diagnostic power to CIS-RIA in the
      measurement of CEA levels of patients with metastatic colorectal cancer, with an
      additional advantage of avoiding the use of radioisotopes. We believe that ELA
      has the potential to replace RIA in the measurement of CEA in clinical practice.

PMID- 15011850
TI  - Clinical and pathological prognostic indicators with colorectal mucinous
      carcinomas.
AB  - BACKGROUND/AIMS: Colorectal mucinous carcinomas are considered to have a worse
      prognosis than typical adenocarcinomas. To evaluate the prognostic relevance of a
      series of clinical and pathological variables, patients with colorectal mucinous
      carcinomas were studied retrospectively. METHODOLOGY: Ninety-eight patients who
      underwent surgery for colorectal mucinous carcinomas were included in this study.
      We firstly examined whether signet-ring cell carcinomas exhibited worse prognosis
      than the other mucinous carcinomas. Prognostic factors were then analyzed by both
      univariate and multivariate analysis for 70 patients who underwent complete
      resection. RESULTS: The overall five-year survival rate was 44%. Amount of signet
      ring cells was a non-significant indicator of poor prognosis. For the cases whose
      cancers were completely resected, four parameters (liver metastasis, lymph node
      involvement, vessel involvement, spread beyond the bowel wall) were significantly
      related to prognosis on univariate analysis. With the multivariate analysis,
      liver metastasis and spread beyond the bowel wall were independent variables.
      CONCLUSIONS: This study reaffirmed the importance of liver metastasis and spread
      beyond the bowel wall for prediction of prognosis with colorectal mucinous
      carcinomas for cases who undergo complete resection. In addition, the presence of
      signet-ring cells is a non-significant indicator of a poor prognosis.

PMID- 15011851
TI  - Distributions in CEA doubling time differ in patients with recurrent colorectal
      carcinomas.
AB  - BACKGROUND/AIMS: Serum carcinoembryonic antigen (CEA) is often measured during
      follow-up of patients surgically treated for colorectal cancer. We determined
      characteristic findings in serum CEA concentrations or CEA doubling time (DT)
      depending on the different tumor distributions in colorectal cancer patients.
      METHODOLOGY: Serum CEA levels were measured monthly until the patients expired in
      32 colorectal cancers after operations. CEA DT was based on semilogarithmic plots
      of time courses of CEA concentrations. RESULTS: In cases who were preoperatively
      CEA positive, the maximum serum CEA levels for proximal colon, distal colon and
      rectal cancers were 384.8+/-586.1 ng/mL, 1395.7+/-1954.6 ng/mL and 1343.4+/
      1478.3 ng/mL, respectively. The maximum serum CEA level in cases of the proximal
      colon in preoperative CEA positive patients was lower than that in cases of
      distal colon or rectum. The average CEA DT on the proximal colon, distal colon
      and rectal cancers was 71.62+/-43.77 days, 31.07+/-15.98 days and 73.97+/-36.66
      days, respectively. The CEA DT with distal colon cancers was also significantly
      shorter than that with proximal colon or rectal cancers (p<0.05, p<0.02). The CEA
      DT for lung metastasis was significantly longer than that for liver metastasis,
      locally or lymph node metastasis or multiple metastases (p<0.02, p<0.02,
      p<0.001). CONCLUSIONS: CEA DT serves to predict life expectancy for patients with
      recurrent colorectal cancers with different tumor distributions. We propose that
      precise measurements of serum CEA are needed so as not to overlook recurrent
      tumors. Detailed follow-up after operations is necessary for such patients, that
      CEA DT was noted in case of distal colon cancers.

PMID- 15011852
TI  - Laparoscopy-assisted surgery for colorectal neoplasm is justifiable regardless of
      advanced age.
AB  - BACKGROUND/AIMS: Laparoscopy-assisted surgery has been applied in patients with
      colorectal disease and resulted in favorable outcome compared with open surgery.
      However, it is not reported exclusively in terms of the curative mean in the
      geriatric patients with colorectal neoplasm yet. The aim of this study was to
      confirm the pros and cons of laparoscopy-assisted surgery for colorectal neoplasm
      in geriatric patients. METHODOLOGY: Seventy-four patients with colorectal
      neoplasm underwent laparoscopic surgery and all their charts were retrospectively
      reviewed. Fourteen patients were 75 years of age or older and compared with the
      remaining non-aged 60 patients in STUDY 1, and also compared with 46 aged
      patients who underwent open surgery in STUDY 2. RESULTS: In STUDY 1, the compiled
      total frequency of preoperative concomitant disease was significantly higher in
      the LAS-aged group. In STUDY 2, the mean operative time of the laparoscopic group
      was significantly longer than that of the open group. Mean estimated blood loss
      of the laparoscopic group was significantly smaller than that in the open group.
      Postoperative oral resumption and duration of hospital stay tended to be shorter
      in the laparoscopic group than in the open group. CONCLUSIONS: Laparoscopy
      assisted surgery is a satisfactory treatment for colorectal neoplasm, even in
      geriatric patients.

PMID- 15011853
TI  - Colon cancer complicated by vascular and intestinal anomaly.
AB  - We present a case of colon cancer in a patient with an anomalous mesenteric
      artery, a middle mesenteric artery, associated with intestinal nonrotation. At
      surgery for such a rare case, an exact grasp of the feeding artery, the draining
      vein, and the lymphatic flow of the tumor is necessary to perform appropriate
      bowel resection and oncological nodal dissection. Selective angiography and
      preoperative endoscopic submucosal injection of India ink near the tumor were
      thought to be essential for surgical decision-making.

PMID- 15011854
TI  - The prognostic factors after radical esophagectomy for esophageal cancer with
      positive preoperative CEA.
AB  - BACKGROUND/AIMS: We investigated in this paper the clinicopathological factors
      that affect the prognosis of esophageal cancer with preoperative positive CEA.
      METHODOLOGY: Out of 252 patients with thoracic esophageal cancer who received
      curative resection in our department, we selected 33 cases with esophageal cancer
      that had positive serum CEA level preoperatively. We analyzed the
      clinicopathological factors which affect the prognosis in these CEA positive
      cases. RESULTS: There were no differences in preoperative CEA levels according to
      the variant clinicopathological factors. The number of lymph nodes metastasis,
      depth of tumor involvement, lymphatic invasion, and preoperative SCC antigen
      level were the significant factors influencing survival. But, only preoperative
      SCC antigen level was independent and a significant prognostic factor on
      multivariant analysis. CONCLUSIONS: While sensitivities of SCC antigen and CEA
      are low in esophageal cancer, the cases having positive value in both CEA and SCC
      antigen preoperatively have high recurrence rates after radical esophagectomy.

PMID- 15011855
TI  - Resection of an esophageal metastasis from a renal cell carcinoma.
AB  - Surgery for patients with isolated metastases from renal cell carcinoma has been
      shown to improve survival. Isolated esophageal metastases are very uncommon among
      patients with renal cell carcinoma and there are no reports addressing the
      outcome of their resection. A 60-year-old woman who had previous history of renal
      cell carcinoma was admitted to the hospital with progressive dysphagia.
      Esophagography and endoscopy showed an esophageal tumor and biopsies were
      consistent with adenocarcinoma. No other site with tumor was identified on CT
      scan. Resected specimen showed metastasis from renal cell carcinoma and the
      patient survived for an 11-month period. Although resection of metastatic renal
      cell carcinoma has been shown to improve long-term survival, the presence of
      esophageal metastases can be considered an adverse prognostic factor.

PMID- 15011856
TI  - Argon plasma coagulation versus injection sclerotherapy in peptic ulcer
      hemorrhage--a prospective, controlled study.
AB  - BACKGROUND/AIMS: In Slovenia, the annual incidence of peptic ulcer hemorrhage is
      118/100,000 inhabitants, with mortality up to 14%. Interventional endoscopy has
      largely reduced mortality in these patients. This study aims to evaluate the
      efficacy and safety of argon plasma coagulation and injection sclerotherapy in
      bleeding peptic ulcer. METHODOLOGY: A prospective, controlled study which
      includes 100 patients with peptic ulcer hemorrhage (male 63, female 37, av.age
      57.1 years, SD+/-16, span 26-80; gastric ulcer 50 patients, duodenal ulcer 50
      patients) in the period between 1.01.1999 and 15.05.2000 treated in our
      institution. The bleeding activity was determined according to the Forrest
      classification. Fifty patients were randomized to receive argon plasma
      coagulation (ARCO 2000 ES unit, group A) and in fifty patients injection
      sclerotherapy (sclerosing with diluted adrenalin 1:10,000 plus polidocanol 1%,
      group B) was performed. The groups did not differ with respect to age, sex, site,
      severity of bleeding, use of NSAID and additional diseases. RESULTS: Clinically
      and endoscopically diagnosed rebleeding occured in 7/50 patients (14%) in group A
      and in 9/50 patients (18%) in group B; p=0.78. The majority of rebleeding occured
      within 48 hours after endoscopic hemostasis, group A 4-/7 (57.1%), group B 7/9
      (77.7%), p = 0.74. Repeated endoscopic hemostasis did not prove successful in 8
      patients (group A 3/50, 6%, group B 5/50, 10%), p=0.71. Seven patients were
      treated operatively. The total mortality rate was 9% (9/100 patients, group A
      4/50, 8%, group B 5/50, 10%), p>0.05. Only one patient died due to peptic ulcer
      hemorrhage, other 8 patients died due to concomitant diseases. CONCLUSIONS: Argon
      plasma coagulation seems to be an effective and safe alternative to other
      hemostatic modalities in peptic ulcer hemorrhage.

PMID- 15011857
TI  - Intestinal ischemia-reperfusion injury augments intestinal mucosal injury and
      bacterial translocation in jaundiced rats.
AB  - BACKGROUND/AIMS: The aim of this study was to evaluate local effects and degree
      of bacterial translocation related with intestinal ischemia-reperfusion injury in
      a rat obstructive jaundice model. METHODOLOGY: Thirty adult Sprague-Dawley rats
      (200-250 g) were divided into three groups; including Group 1 (jaundice group),
      Group 2 (jaundice-ischemia group) and Group 3 (ischemia group). All rats had 2
      laparotomies. After experimental interventions, tissue samples for translocation;
      liver and ileum samples for histopathological examination, 25 cm of small
      intestine for mucosal myeloperoxidase and malondialdehyde levels and blood
      samples for biochemical analysis were obtained. RESULTS: Jaundiced rats had
      increased liver enzyme levels and total and direct bilirubin levels (p<0.05).
      Intestinal mucosal myeloperoxidase and malondialdehyde levels were found to be
      high in intestinal ischemia-reperfusion groups (p<0.05). Intestinal mucosal
      damage was more severe in rats with intestinal ischemia-reperfusion after bile
      duct ligation (p<0.05). Degree of bacterial translocation was also found to be
      significantly high in these rats (p<0.05). CONCLUSIONS: Intestinal mucosa is
      disturbed more severely in obstructive jaundice with the development of ischemia
      and reperfusion. Development of intestinal ischemia-reperfusion in obstructive
      jaundice increases bacterial translocation.

PMID- 15011858
TI  - Effect of Helicobacter pylori eradication on bulbitis and duodenal gastric
      metaplasia.
AB  - BACKGROUND/AIMS: Duodenal gastric metaplasia seems to be linked to infection by
      Helicobacter pylori, to the extent of acid secretion and to bulbitis. An
      investigation was made of the relationship between bulbitis and duodenal gastric
      metaplasia, or whether bulbitis can arise along with duodenal gastric metaplasia
      after Helicobacter pylori eradication in an average of six years. METHODOLOGY: We
      compared 22 patients with duodenal ulcers [male/female 16/6; (mean age+/-SD) 55+/
      12 years] Helicobacter pylori-negative after eradication, with 23 Helicobacter
      pylori-positive patients free from active duodenal ulcers [male/female 17/6;
      (mean age+/-SD) 59+/-12 years]. RESULTS: The bulbitis score was found to be lower
      in the Helicobacter pylori-negative than in the Helicobacter pylori-positive
      group (p=0.02). The duodenal gastric metaplasia score in the Helicobacter pylori
      negative was higher than in the Helicobacter pylori-positive group (p=0.001). We
      failed to find any relationship between the presence of bulbitis and duodenal
      gastric metaplasia. We found a non-significant inverse correlation between the
      presence of duodenal gastric metaplasia and chronic body gastritis (p=0.07).
      CONCLUSIONS: Bulbitis and duodenal gastric metaplasia may depend on different
      causal factors not related to Helicobacter pylori infection. The extension of
      duodenal gastric metaplasia with time following recovery from peptic ulcer
      disease may represent a mucosal protection factor against acid.

PMID- 15011859
TI  - The repeated hepatectomy for frequent recurrence of hepatic metastasis from
      gastrointestinal stromal tumor of the stomach.
AB  - Although in recent years hepatic resection has become a safe procedure, there are
      few data on repeat liver resection for hepatic metastases from gastrointestinal
      stromal tumor. A 60-year-old Japanese man underwent partial gastrectomy and
      extended right hepatectomy for gastrointestinal stromal tumor of the stomach with
      liver metastasis. However, liver metastasis recurred at the interval of less than
      1 year. Therefore, the patient underwent a total of six liver resections. The
      liver resections comprised four R0, one R1 and one R2 resection. To our
      knowledge, six times for liver resection performed on one patient is a maximum.
      This patient survived 43 months after the first surgery. Despite frequent
      recurrence of hepatic metastasis from gastrointestinal stromal tumor, repeated
      hepatectomy provides a survival benefit if complete removal of all tumorous
      masses appears possible.

PMID- 15011860
TI  - Carcinoma of gastric stump causing afferent loop obstruction and acute
      pancreatitis.
AB  - We report a case of a 79-year-old man who had undergone partial gastrectomy with
      Billroth-II (B-II) anastomosis 42 years ago for benign peptic ulcer. He presented
      with abdominal pain, distention and acute pancreatitis.
      Esophagogastroduodenoscopy showed a malignant mass obstructing the afferent
      stoma; surgical resection was performed. Pathogenesis of acute pancreatitis in
      this case and the problem of gastric stump carcinoma are discussed.

PMID- 15011861
TI  - Allelic imbalance at 1p36 in the pathogenesis of human hepatocellular carcinoma.
AB  - BACKGROUND/AIMS: It has been well accepted that there is an allelic imbalance at
      a subtelomeric region of chromosome 1p in various human malignancies including
      hepatocellular carcinoma. We conducted a detailed deletion mapping study at 1p36
      loci in 65 hepatocellular carcinomas as an initial step towards positional
      cloning of the target gene. METHODOLOGY: We performed a fine-scale deletion
      mapping using 10 highly polymorphic microsatellite markers along the telomeric
      region of 1p (1p32-p36.3) and compared the clinicopathologic features with
      allelic imbalance of 1p36 loci. RESULTS: Allelic imbalance occurred in at least
      one locus on 1p in 32 (49.2%) of the 65 cases. Consequently, it was confirmed
      that a common region of overlaps was restricted to 1p36 and it was further
      clearly demonstrated that there were at least three independent regions in 1p36
      (1p36.1, p36.2'36.3 and p36.3). An apparent trend towards significance has been
      demonstrated between allelic imbalance at 1p36 loci and tumors with classifcation
      T1-T2 (p<0.01). CONCLUSIONS: The present study demonstrated that the shortest
      region of overlap was confined within 1p36 chromosomal sub-band in human
      hepatocellular carcinoma, which might be involved in an early step of
      hepatocarcinogenesis, and it encourages future studies to identify the putative
      tumor suppressor gene(s) at 1p36.

PMID- 15011862
TI  - Impact of previous multiple portoenterostomies on living donor liver
      transplantation for biliary atresia.
AB  - BACKGROUND/AIMS: The present study examined the impact of portoenterostomy on the
      morbidity and mortality of patients who later underwent living donor liver
      transplantation for biliary atresia. METHODOLOGY: Sixty-one consecutive patients
      from January 1996 to May 2001 were analyzed. They were divided into two groups
      according to the number of previous portoenterostomies: once (group A, n=26) and
      twice or more (group B, n=35). Preoperative status, mortality, morbidity,
      hospital duration and survival were examined and compared between the groups.
      RESULTS: Preoperative parameters regarding liver function and urgency status were
      comparable between the groups. The operation duration tended to be longer in
      group B than in group A (p=0.07). The blood loss and transfusion volumes in group
      B were greater than those in group A (p=0.03 for both comparisons). Vascular
      complications tended to be more frequent in group B patients. However, this
      difference was not significant (12% vs. 29%, p=0.06). The duration of
      hospitalization was longer in group B (p=0.04). Survival rates were comparable
      between the groups. CONCLUSIONS: Our surgical results suggest that multiple
      previous portoenterostomies might have negative short-term effects in patients
      who undergo living donor liver transplantation for biliary atresia.

PMID- 15011863
TI  - The efficacy of endoscopic ligation for the prevention of variceal rebleeding in
      cirrhotic patients according to the hepatocellular function.
AB  - BACKGROUND/AIMS: Endoscopic variceal ligation is considered the leading therapy
      for the prevention of variceal rebleeding in cirrhotic patients. However, the
      efficacy of this method in cirrhotic patients with poor hepatocellular function
      is not well-known yet. The aim of this study is to compare the efficacy of
      endoscopic variceal ligation for the eradication of esophageal varices,
      rebleeding and mortality rates, based on hepatocellular function, as graded by
      Child-Pugh. METHODOLOGY: Between June 1996 and December 2001, 163 consecutive
      cirrhotic patients were submitted to band ligation at our Department. Of these
      cases, 128 patients with previous variceal bleeding (mean age = 50.7 years; 90
      males and 38 females) were followed-up. 55 patients were graded as Child A, 49 as
      Child B and 24 as Child C. RESULTS: The mean follow-up period for all groups was
      17.3 months. Varices were eradicated in 82.7% (86 of 104 cases) of Child A/B
      cirrhotic patients and in 54.2% (13 of 24 cases) of Child C cases (p=0.0061).
      Eradication was achieved after a mean of 3.7 sessions, and no difference was
      observed among the groups. Varices recurred in 38.4% (38 of 99 cases) of the
      patients, presenting no difference among the different Child classes. However,
      there was a trend to a higher rebleeding rate among patients with variceal
      recurrence (21% vs. 8.2%, p=0.075). Rebleeding occurred in 20.2% (21 of 104
      cases) of Child A/B cirrhotics and in 41.7% (10 of 24 cases) of Child C patients
      (p=0.001 log-rank test). The mortality rate was 13.5% (14 of 104 cases) among
      Child A/B patients and 37.5% (9 of 24 cases) among Child C cases (p=0.0135).
      CONCLUSIONS: Endoscopic variceal ligation is an effective method for the
      prevention of rebleeding in patients with better liver function. Child C patients
      had a poor response to treatment. These patients, in a statistically significant
      fashion, had a worse eradication rate and greater rebleeding and mortality rates
      than Child A/B patients.

PMID- 15011864
TI  - Radiation therapy for the locoregional lymph node metastases from hepatocellular
      carcinoma, phase I clinical trial.
AB  - BACKGROUND/AIMS: The patients with lymph node metastasis from hepatocellular
      carcinoma may survive only a few months. These patients are not suitable for
      transcatheter arterial chemoembolization, percutaneous ethanol injection and
      surgical resection. External beam radiation therapy (EBRT) could provide a useful
      treatment, but only 4 hepatocellular carcinoma cases with abdominal lymph nodes
      involvement were treated with EBRT in the two reports over the last 10 years. In
      this paper, we report 29 hepatocellular carcinoma patients with abdominal lymph
      node metastasis who received EBRT over a period of 5 years. METHODOLOGY: Of 29
      patients, 20 were pathologically confirmed to have hepatocellular carcinoma and 9
      patients were clinically diagnosed to have hepatocellular carcinoma. All of the
      patients had proven abdominal lymph node metastasis by enhanced abdominal
      computer tomography scan due to clinical follow-up or abdominal symptoms. EBRT
      was not the initial treatment in all. The patients received locoregional lymph
      nodes irradiation. The tumor dose ranged from 30 to 60 Grays (Gy) in daily 2.0-Gy
      fractions (Fx), 5 times a week. RESULTS: It is of interest to note that an
      objective regression (complete response and partial response) rate was 100%. The
      clinical symptoms were relieved. The median survival time was 8 (4-28) months.
      The overall 1-year and 2-year survival rates were 43.5% and 10.5%, respectively.
      The median survival time consistently decreased as the lymph node involvement
      increase follows the natural flow of lymph. CONCLUSIONS: Lymph node metastasis
      from hepatocellular carcinoma is sensitive to EBRT, although EBRT is palliative
      in intent, it is useful in the treatment with 50 Gy/25 Fx for those patients.

PMID- 15011865
TI  - Polyamine metabolism and recurrence after resection for hepatocellular carcinoma.
AB  - BACKGROUND/AIMS: Ornithine decarboxylase activity, a rate-limiting enzyme in
      polyamine biosynthesis, is correlated with the degree of malignancy of
      hepatocellular carcinoma. We investigated the relationship between polyamine
      metabolism in hepatocellular carcinoma tissues and the recurrence after resection
      of hepatocellular carcinoma. METHODOLOGY: The subjects were 49 patients who
      underwent liver resection for hepatocellular carcinoma. The relationship between
      ornithine decarboxylase activity and polyamine concentration in hepatocellular
      carcinoma tissues and the pathologic findings or recurrence after the operation
      was studied. RESULTS: The prevalences of moderately or poorly differentiated
      hepatocellular carcinoma, portal invasion, and intrahepatic metastasis were
      higher in patients with a high ornithine decarboxylase activity (> or = 100 pmol
      putrescine/h/mg protein) than in patients with a low ornithine decarboxylase
      activity (< 100 pmol putrescine/h/mg protein). The tumor-free survival rate was
      significantly lower in patients with a high ornithine decarboxylase activity than
      in patients with a low ornithine decarboxylase activity (p=0.0394). The tumor
      free survival rate was significantly lower in patients with a high spermidine
      concentration (> or = 80 nmol/mg protein) than in patients with a low spermidine
      concentration (< 80 nmol/mg protein, p = 0.0454). CONCLUSIONS: A high ornithine
      decarboxylase activity and a high spermidine concentration of hepatocellular
      carcinoma were risk factors for recurrence after resection of hepatocellular
      carcinoma.

PMID- 15011866
TI  - Tc-99m MIBI liver imaging for hepatocellular carcinoma: correlation with P
      glycoprotein-multidrug-resistance gene expression.
AB  - BACKGROUND/AIMS: Technetium-99m methoxyisobutyl isonitrile (MIBI) has been shown
      to be useful in identifying several types of tumors, such as breast, lung and
      thyroid cancers. There are only a few reports in the literature regarding Tc-99m
      MIBI uptake in hepatocellular carcinoma, and the results are conflicting. The aim
      of this study was to investigate the relationship between Tc-99m MIBI
      accumulation in patients with hepatocellular carcinoma and the gene expression of
      P-glycoprotein-multidrug-resistance. METHODOLOGY: Twenty-two patients with
      hepatocellular carcinoma were enrolled in this study. Tc-99m MIBI imaging was
      performed 10 minutes after intravenous injection of 20 mCi Tc-99m MIBI. All
      patients had liver biopsy or surgery within 1 week of MIBI imaging.
      Immunohistochemical study of the biopsy or resected hepatocellular carcinoma
      specimens was performed using the anti-human P-glycoprotein antibody. RESULTS: On
      Tc-99m MIBI imaging, 20 of 22 (90.9%) patients with hepatocellular carcinoma
      showed negative Tc-99m MIBI uptake in tumor lesions, whereas only 2 patients
      showed positive Tc-99m MIBI uptake in tumor lesions. P-glycoprotein expression
      was observed in 13 of 20 (65%) patients with negative Tc-99m MIBI uptake, but in
      the 2 patients who showed positive Tc-99m MIBI uptake in tumor lesions, P
      glycoprotein expression was negative. CONCLUSIONS: Tc-99m MIBI SPECT is a useful
      noninvasive method for predicting the expression of P-glycoprotein-multidrug
      resistance gene in hepatocellular carcinoma patients.

PMID- 15011867
TI  - Long-term results of central inferior (S4a+S5) hepatic subsegmentectomy and
      pancreatoduodenectomy combined with extended lymphadenectomy for gallbladder
      carcinoma with subserous or mild liver invasion (pT2-3) and nodal involvement: a
      preliminary report.
AB  - BACKGROUND/AIMS: Gallbladder carcinoma, especially advanced cancer that has
      invaded the subserosal or deeper layers, has a poor prognosis. Recently, radical
      operations combining resection of the liver and pancreas with extended lymph node
      dissection have been introduced to improve the prognosis of advanced gallbladder
      carcinoma. We have introduced central inferior (Couinaud's subsegments 4a and 5;
      S4a+S5) hepatic subsegmentectomy and pancreatoduodenectomy combined with extended
      lymphadenectomy for gallbladder carcinoma demonstrating subserous or mild liver
      invasion (pathological tumor stage pT2-3) and nodal involvement. METHODOLOGY:
      Morbidity, mortality, clinicopathological features, and long-term outcome were
      analyzed retrospectively for seven consecutive patients who underwent this
      radical operation. RESULTS: The postoperative morbidity rate was 57.1% and there
      was no surgical mortality. All patients had lymph node involvement: two had pN1
      disease and five had pN2 disease. All patients underwent curative resection. Only
      one patient developed gallbladder carcinoma recurrence after resection and it
      involved the paraaortic lymph nodes. Five patients, three of whom displayed pN2
      disease, survived longer than 5 years postoperatively with no evidence of
      disease. CONCLUSIONS: S4a+S5 hepatic subsegmentectomy and pancreatoduodenectomy
      combined with extended lymphadenectomy improve the long-term survival of
      gallbladder carcinoma with pT2-3 and nodal involvement. The presence of pN2
      disease is not a contraindication for surgery. Further study is necessary to
      evaluate the usefulness of this radical procedure, especially as a standard
      operation.

PMID- 15011868
TI  - Hepatic resection for hepatocellular carcinoma in elderly patients.
AB  - BACKGROUND/AIMS: We present the clinical features and outcome of 34 patients with
      hepatocellular carcinoma older than 70 years of age who underwent hepatic
      resection (elderly-HCC). Nowadays, hepatic surgeons unavoidably have to perform
      hepatic resection on elderly patients with hepatocellular carcinoma due to
      increasing life expectancy. However, the outcome of hepatic resection on elderly
      patients with hepatocellular carcinoma varies in each series, and the exact role
      of surgery in the management of hepatocellular carcinoma in the elderly remains
      to be clarified. METHODOLOGY: From 1986 to 1998, the clinical features of 34
      surgically treated cases of elderly-HCC were reviewed. Factors that may influence
      the outcome were also analyzed. Clinical features and outcome of 398 patients
      with hepatocellular carcinoma younger than 70 years old (younger-HCC) were also
      summarized for comparison. RESULTS: Of 432 surgically resected hepatocellular
      carcinomas, 34 (7.9%) were elderly-HCC. More underlying diabetes mellitus
      association, higher hepatitis C infection, and lower hepatitis B infection were
      observed in the elderly-HCC group. More blood loss, larger tumor size, less
      capsule formation, and more recurrence were significantly prominent in the
      patients in the younger-HCC group compared with the elderly-HCC group. The
      patients in the elderly-HCC group had a favorable disease-free survival rate
      compared with the younger-HCC group, although not statistically significant. The
      1- and 5-year survival rates of elderly-HCC patients were 85.3% and 39.6%,
      respectively. No significant difference in survival or mortality rate was found
      between elderly-HCC and younger-HCC groups. CONCLUSIONS: We present the clinical
      features and outcomes of 34 elderly patients with hepatocellular carcinoma who
      underwent hepatic resection. The results seem to indicate that hepatic resection
      is safe and feasible in the elderly with hepatocellular carcinoma with or without
      cirrhosis. The prognosis after hepatic resection is as comparable as that of the
      younger patients with hepatocellular carcinoma.

PMID- 15011869
TI  - Correlation between tumor size and mode of spread in mass-forming intrahepatic
      cholangiocarcinoma.
AB  - BACKGROUND/AIMS: Mode of spread of intrahepatic cholangiocarcinoma of the mass
      forming type (MF-ICC) has not been assessed according to tumor size. METHODOLOGY:
      We retrospectively evaluated 17 cases of resected MF-ICCs. Tumor size was
      categorized as follows: < 45 mm (n=4), 45-79 mm (n=7), and > or = 80 mm (n=6).
      The correlation of tumor size with presence or absence of histological invasion
      to the portal vein (vp), hepatic vein (vv), intrahepatic metastasis (im), and
      lymphatic vessel or perineural space (ly/pn) was evaluated. Clinical outcomes of
      13 patients who underwent curative resection were also investigated. RESULTS: The
      positive rates of vp, vv, im, and ly/pn were calculated as 25, 0, 0, and 0% in
      the < 45-mm group; 86, 29, 86, and 71% in the 45-79-mm group; and 100, 50, 83,
      and 83% in the > or = 80-mm group, respectively. Of 13 patients who underwent
      curative resection, 6 of 9 in the > 45-mm group were found to have recurrent
      diseases in the liver remnant, lymph node, and the lung, whereas one of 4
      patients in the < 40-mm group developed peritoneal recurrence. CONCLUSIONS:
      Systematic hepatectomy without lymphadenectomy might be appropriate for MF-ICC
      smaller than 45 mm in diameter.

PMID- 15011871
TI  - Long-term prognosis after arterio-portal embolization for hepatocellular
      carcinoma.
AB  - BACKGROUND/AIMS: Resection is the treatment of choice for hepatocellular
      carcinoma. However, relatively few patients with hepatocellular carcinoma are
      surgical candidates. The efficacy of a radiologic hepatectomy, achieved by
      combined embolization of the arterial and portal tumor blood supply, was
      determined and compared to surgical hepatectomy in a retrospective analysis.
      METHODOLOGY: The records of 32 patients treated for hepatocellular carcinoma
      between 1989 and 1992 were reviewed. The outcome in 15 patients treated with
      combined selective segmental portal vein embolization and hepatic artery
      embolization without hepatectomy (Embolization group) was compared with the
      outcome in 17 patients who under went curative hepatic resection (Resection
      group). The recurrence-free and cumulative survival rates were compared in the
      two groups. RESULTS: Except for a greater number of men in the Resection Group
      (p=0.03), the demographics and clinical characteristics of the two groups were
      similar at baseline. There was no patient who died within 30 days of treatment.
      The recurrence-free survival rates after embolization and resection were 20.8 and
      23.4% at 5 years, respectively. The corresponding cumulative survival rates were
      23.2 and 51.3%. CONCLUSIONS: Combined embolization without hepatectomy may be a
      viable alternative to curative hepatectomy for selected patients with
      hepatocellular carcinoma.

PMID- 15011870
TI  - Serum concentration of transforming growth factor (TGF)-beta 1 does not predict
      advanced liver fibrosis in children with chronic hepatitis B.
AB  - BACKGROUND/AIMS: The aim of the study was to evaluate if measurement of TGF-beta1
      has clinical usefulness as a marker of liver fibrosis using ROC analysis and to
      assess its serum concentration during IFN alpha treatment. METHODOLOGY: Fibrosis
      stage and inflammation grade were assessed according to Batts and Ludwig and
      Ishak et al. before and 12 months after the end of IFN alpha treatment of 30
      children with chronic hepatitis B. TGF-beta1 was measured by means of the
      quantitative sandwich enzyme immunoassay technique using recombinant human TGF
      beta soluble receptor type II as a solid phase pre-coated onto a microplate (R&D
      System Inc., Minneapolis, USA). RESULTS: There was no significant correlation
      between serum TGF-beta1 level and the stage of liver fibrosis. However TGF-beta1
      levels in patients before IFN alpha therapy were significantly higher than in
      controls. IFN alpha treatment did not improve histological fibrosis during 18
      months of observation and it did not cause any significant changes in serum TGF
      beta1 levels although there was a tendency to decrease its level during therapy
      and follow-up. CONCLUSIONS: Serum concentration of TGF-beta1 does not predict
      advanced liver fibrosis in children with chronic hepatitis B.

PMID- 15011872
TI  - Early recurrence of hepatocellular carcinoma after living donor liver
      transplantation.
AB  - Milan criteria are standards for considering the indications of liver
      transplantation for hepatocellular carcinoma. A 57-year-old man underwent living
      donor liver transplantation for hepatitis B-related liver cirrhosis and
      hepatocellular carcinoma. Hepatocellular carcinoma had been treated with
      percutaneous microwave coagulation therapy and transarterial chemoembolization.
      Resected specimens revealed a solitary necrotic tumor 5 cm in diameter, which
      satisfied the Milan criteria. Although the patient survived the operation, he
      suffered from tumor recurrence in the graft and lung 2 months afterward. Adjuvant
      chemotherapy had no effect and the patient expired 7 months after
      transplantation. The present results indicate that a tumor satisfying the Milan
      criteria does not necessarily guarantee long-term survival after transplantation.

PMID- 15011873
TI  - Surgical treatment in a patient with multiple implanted intraperitoneal
      metastases after resection of ruptured large hepatocellular carcinoma.
AB  - We report a case with multiple disseminated intraperitoneal metastases caused by
      the rupture of large hepatocellular carcinoma. A 52-year-old man was admitted due
      to sudden abdominal pain with progressive abdominal distention. Computed
      tomography showed a 5x7-cm low-attenuation mass in the right hepatic lobe and
      hemoperitoneum was demonstrated. He was taken for emergency hepatic angiography
      and hepatic arterial chemoembolization was done. Ten days after embolization,
      right lobectomy was performed successfully. Microscopic examination confirmed
      hepatocellular carcinoma. After 4 months, follow-up computed tomography showed a
      2-cm-sized irregular-shaped mass at the right great omentum. A second surgery for
      omentectomy with mass excision was performed. Three months later, splenectomy and
      segmental resection of the colon was performed. Five months later, metastatic
      lymph node was detected around the head of the pancreas. Mass excision was then
      performed. Microscopically, all resected tumors were confirmed as metastatic
      hepatocellular carcinoma. The patient underwent resection of multiple
      intraperitoneal metastases three times for 1 year after resection of ruptured
      hepatocellular carcinoma and is currently disease free for 15 months. Hepatic
      resection is the treatment of choice for ruptured hepatocellular carcinoma but
      dissemination of tumor cells in the peritoneal cavity should be kept in mind.
      Even if intraperitoneal metastases develop, long-term survival could be possible
      with aggressive surgical treatment.

PMID- 15011874
TI  - Cholestatic hepatitis due to hepatitis C virus after a living donor liver
      transplantation.
AB  - Recurrence of hepatitis C virus after liver transplantation is common and
      cholestatic hepatitis occurs in approximately 10% of the patients and leads to
      accelerated graft failure and death. A 47-year-old man underwent living donor
      liver transplantation for hepatitis C-related liver cirrhosis. Preemptive
      antiviral therapy was started using interferon-alpha2b (6 MU x 3 per week) and
      ribavirin (600 mg per day) two months after living donor liver transplantation.
      The response to the combined therapy was not satisfactory. He developed liver
      failure and expired 11 months after the transplantation. The present results
      indicate that a rapid development of graft failure can occur in spite of
      preemptive antiviral therapy after living donor liver transplantation.

PMID- 15011875
TI  - Resection of liver metastasis from extrahepatic bile duct carcinoma previously
      treated by pancreatoduodenectomy.
AB  - No English report of a 5-year survivor with liver metastasis from periampullary
      carcinoma has been published to date. Here, we report a 52-year-old woman with
      liver metastasis previously treated with pylorus-preserving pancreatoduodenectomy
      for extrahepatic bile duct carcinoma, who underwent hepatectomy and has survived
      for more than 5 years without recurrence after the procedure. This outcome
      suggests that hepatic resection is effective for selected patients with liver
      metastasis from extrahepatic bile duct carcinoma previously treated by
      pancreatoduodenectomy. When a patient has a solitary metastasis of the liver with
      no other evidence of recurrence, surgical resection of the liver metastasis
      should be considered a valid option.

PMID- 15011876
TI  - Central pontine myelinolysis after living donor liver transplantation.
AB  - There are few reports of central pontine myelinolysis after living donor liver
      transplantation. A 59-year-old male received a right liver graft from his
      daughter for hepatitis B-related liver cirrhosis. Methylprednisolone and
      tracrolimus were used for immunosuppression. Dysarthria and dysphasia were noted
      on the second postoperative day. Brain magnetic resonance image taken on the 9th
      postoperative day revealed a hyperintense area at the center of his pons in T2
      weighted images. The symptoms improved spontaneously 1 month after the operation.
      Central pontine myelinolysis should be included in the differential diagnosis
      when neurologic manifestations are observed after living donor liver
      transplantation.

PMID- 15011877
TI  - Does neoplastic gastrin expression remodel the embryonal pattern of the protein?
      A study in human pancreas.
AB  - BACKGROUND/AIMS: To determine the immunoreactivity of gastrin during the
      development of the human fetal pancreas and ductal pancreatic adenocarcinoma,
      given that, gastrin positive cells were demonstrated either into its embryonic
      anlage or into pancreatic cancer. METHODOLOGY: Tissue sections from 15 pancreatic
      fetal specimens, and an equal number of ductal adenocarcinoma specimens, were
      assessed using immunohistochemical methods for gastrin. RESULTS: The density of
      positive cells in the primitive exocrine ductal walls and outgrowing buds was
      significantly higher than the relevant density in the neoplastic pancreatic
      tissue of mixed (ductal endocrine) and pure ductal type (p1=0.017, p2<0.0001,
      p3<0.0001 and p4=0.019, respectively). The above values were estimated from 20-22
      weeks of gestation. There was no significant difference in the density of
      positive cells in the islet cell epithelium from 25-30 weeks, and the neoplastic
      tissue of mixed (p5=0.24) and pure ductal type (p6=0.55). CONCLUSIONS: The
      immunostaining for gastrin identifies a subgroup of pancreatic ductal
      adenocarcinomas with a neuroendocrine component (initially considered as pure
      ductal tumors), and mixed ductal-endocrine tumors. This pattern of expression in
      neoplasms recapitulates the normal pattern during the embryonal development of
      the organ, and may be important for the development of new therapeutic approaches
      with eventual clinical utility.

PMID- 15011878
TI  - Severe lactic acidosis and thiamine deficiency during total parenteral nutrition-
      case report.
AB  - We encountered a case of total parenteral nutrition-associated lactic acidosis
      that did not respond to sodium bicarbonate or other conventional emergency
      treatments. He was characterized by minimal food intake before surgery, delayed
      gastric emptying after pylorus-preserving pancreatoduodenectomy due to pancreas
      head cancer and long-term total parenteral nutrition without food intake and
      vitamin supplements after surgery. After thiamine administration, the patient
      very quickly recovered with dramatic reestablishment of the acid-base balance. We
      emphasize the need to supplement total parenteral nutrition with thiamine
      containing vitamins for the patients whose food intake does not meet nutritional
      requirements and to intravenously replenish using high-dose thiamine
      simultaneously with the manifestation of signs and symptoms of severe lactic
      acidosis with unknown cause. In conclusion, thiamine deficiency should be
      included in the differential diagnosis of lactic acidosis for the patients who
      received total parenteral nutrition without food intake and vitamin supplements.

PMID- 15011879
TI  - Inferior head resection of the pancreas for noninvasive intraductal papillary
      mucinous adenocarcinoma.
AB  - We report inferior head resection of the pancreas for noninvasive intraductal
      papillary mucinous cancer. A 77-year-old man was admitted to our hospital
      complaining of epigastric pain. Contrast-enhanced computed tomographic scan and
      magnetic resonance imaging showed a multilocular cystic tumor 3.5 cm in diameter
      in the head of the pancreas. We performed inferior head resection of the pancreas
      with partial resection of the duct of Santorini. The duodenum, the common bile
      duct, and most of the duct of Santorini were preserved. He is presently alive and
      well without any evidence of recurrent disease 49 months after the operation.
      Partial pancreatic resection has the advantage of preserving pancreatic
      parenchyma. Inferior head resection of the pancreas would play an important role
      in surgical management of low-grade malignant neoplasm.

PMID- 15011880
TI  - A case of retroperitoneal lymphoma presenting as pancreatic tumor.
AB  - We describe a case of non-Hodgkin's lymphoma arising in the peripancreatic
      retroperitoneal lymph node and extending into the pancreatic parenchyma.
      Abdominal ultrasonogram and computed tomography of the abdomen showed an mass in
      the head of pancreas with absence of extrapancreatic disease and no direct tumor
      extension to the portal vein or superior mesenteric artery. Laparotomy
      demonstrated a large pancreatic mass with no obstruction of common bile duct or
      encasement of portal vein and superior mesenteric artery and a
      pancreaticoduodenectomy was performed. He received chemotherapy with
      cyclophosphamide, doxorubicin, vincristine and prednisone. The patient is alive
      and in remission with a follow-up time of 24 months.

PMID- 15011881
TI  - Spleen volume and platelet number changes after living donor liver
      transplantation in adults.
AB  - BACKGROUND/AIMS: The purpose of the present study was to examine the changes of
      spleen volume and platelet numbers after living donor liver transplantation in
      adults. METHODOLOGY: The spleen volume was measured by computed tomography
      preoperatively and 1, 6, and 12 months in 19 patients after liver
      transplantation. The platelet numbers were followed on the same time schedule.
      RESULTS: The preoperative average spleen volume was 451+/-276 mL, which decreased
      gradually after liver transplantation. The preoperative averaged platelet number
      was 15.4+/-9.0x10(4)/mL, which did not change significantly during the
      observation period. CONCLUSIONS: The changes in spleen volume in the present
      study were consistent with the previous data, suggesting that living donor liver
      transplantation effectively reduced hypersplenism for adult patients.

PMID- 15011883
TI  - Endoscopic resection with a two-channel videoendoscope for gastric carcinoid
      tumors.
AB  - BACKGROUND/AIMS: Endoscopic resection has been used to treat hypergastrinemia
      associated early carcinoid tumors of the stomach. However, indications for
      endoscopic treatment of these tumors have not been established. Moreover,
      endoscopic resection of these tumors is often difficult with conventional
      polypectomy, because these tumors are often located in the submucosal layer. To
      completely remove these tumors, we used a two-channel videoendoscope with which
      both grasping forceps and a polypectomy snare could be used simultaneously.
      METHODOLOGY: At Osaka Medical Center for Cancer and Cardiovascular Diseases,
      eight carcinoid tumors in six patients were removed with a two-channel
      videoendoscope. Reports of early carcinoid tumor in Japanese literature were
      reviewed to analyze the relationship between lymph node metastasis and the size
      and depth of involvement of these tumors. RESULTS: Six carcinoid tumors were
      completely removed "en bloc", but two tumors were incompletely removed. In these
      two patients, submucosal tumor invasion was observed on the excision line. To
      completely remove these tumors, the oral side, but not the top, of the tumor
      should be strongly grasped and pulled toward the center of the lumen as far as
      possible by the grasping forceps, which had been passed through the snare loop.
      Endoscopic follow-up studies showed no local recurrence in any patients with and
      without complete tumor resection during the average observation period of 30
      months. A review of histological reports in Japanese literature showed that lymph
      node metastasis did not occur when the tumors were less than 10 mm in diameter,
      and could be completely removed by an endoscope. CONCLUSIONS: Endoscopic
      resection with a two-channel videoendoscope is a useful and safe method for
      resection of small carcinoid tumors of the stomach.

PMID- 15011882
TI  - Tumor cell proliferation in early gastric cancer: biological and clinical
      behavior.
AB  - BACKGROUND/AIMS: Recently, early gastric cancers without lymph node metastasis
      have successfully been removed through a simple endoscopic resection. Tumor cell
      proliferation may be related to the malignant potential of early gastric cancer.
      The purpose of this study is to prospectively investigate the relationship
      between the incorporation rate of bromodeoxyuridine (BrdU) into the DNA of
      dividing cells, and the main biological and clinical early gastric cancer
      characteristics. METHODOLOGY: Multiple tumor specimens were taken from 27 early
      gastric cancers and analyzed through anti-BrdU monoclonal antibody. Tumor BrdU
      labeling index (LI=% positive cells over 2,000 tumor cells) was determined. Early
      gastric cancers were evaluated in tumor size, mucosal and submucosal involvement,
      histologic type and grading, lymphatic and venous invasion, and nodal metastasis.
      RESULTS: BrdU LI was significantly higher in patients with submucosal neoplastic
      invasion, Pen A Kodama type, tumor vessel invasion and lymph node involvement.
      Early gastric cancer patients with over 22% BrdU LI showed a significantly higher
      incidence of submucosal invasion, lymphatic-venous involvement and a reduced
      survival when compared to patients with medium (12-22%) or low BrdU LI (<12%).
      CONCLUSIONS: Our results suggest that BrdU LI may be considered a useful
      indicator of early gastric cancer aggressiveness.

PMID- 15011884
TI  - Quantitative analysis of p53 expression and cell proliferation in gastric
      carcinomas. An immunohistochemical study.
AB  - BACKGROUND/AIMS: Adenocarcinoma of the stomach is still among the leading
      malignancies in human morbidity and mortality statistics in spite of endoscopic
      screening of the high-risk patients. Investigation of prognostic factors of
      gastric cancer disease seems to be still very important. The authors present a
      clinicopathological study based on the analysis of 49 gastric carcinomas.
      METHODOLOGY: P53 overexpression and proliferation activity of the cells were
      examined by immunohistological method with peroxidase-antiperoxidase technique.
      The percentage of the positive cells was calculated after counting of 300 tumor
      cells in each case. The rate of the labeled cells was related to different
      pathological characteristics of the carcinomas i.e., TNM stage of the tumor,
      histological subtypes of Ming's as well as Lauren's and Goseki's classification
      respectively, grade of differentiation and lymph node status. RESULTS: According
      to the above-mentioned parameters, p53 overexpression was significantly higher in
      carcinomas of the cardiac region than in those of the distal parts of the
      stomach. These findings are consistent with results published in the literature:
      cell proliferation rate alone is not an independent prognostic factor, but the
      degree of cell proliferation activity and p53 expression are changing usually
      parallel with each other and with other prognostic markers as well. CONCLUSIONS:
      The assessment of p53 activity and cell proliferation rate in gastric carcinoma
      is of prognostic value especially if evaluated together with other clinical and
      histopathological characteristics. The examination of these markers is useful in
      detecting early gastric cancer, in selecting high-risk patients and in planning
      proper individual treatment.

PMID- 15011885
TI  - Prevention by bovine milk against Helicobacter pylori-associated atrophic
      gastritis through its adherence inhibition.
AB  - BACKGROUND/AIMS: The effects of Helicobacter pylori infection on the development
      of atrophic gastritis and intestinal metaplasia in relation to lifestyle and diet
      and the effect of the bovine milk on H. pylori adherence to gastric antral mucosa
      were investigated. METHODOLOGY: H. pylori infection was investigated in 63
      patients without endoscopic evidence of gastroduodenal disease. Presence of H.
      pylori infection was assessed by culture and histologic examination of antral and
      corpus biopsy samples. Grades of atrophic gastritis and intestinal metaplasia
      were judged with chromoendoscopy (Congo red-methylene blue test). Adherence of H.
      pylori was evaluated with scanning electron microscopic examination of antral
      mucosa in Mongolian gerbils. RESULTS: Cross-sectional analysis of lifestyle and
      diet showed that a high intake of bovine milk was significantly related to
      prevention of H. pylori infection and the developments of atrophic gastritis and
      intestinal metaplasia. H. pylori adherence to the gastric mucosa was inhibited by
      bovine milk in a dose-dependent manner. CONCLUSIONS: Bovine milk prevents the
      development of atrophic gastritis and intestinal metaplasia through its defense
      mechanisms against the attachment of H. pylori to the gastric mucosa.

PMID- 15011886
TI  - Systemic humoral anti-Helicobacter pylori immune response in patients with
      gastric malignancies and benign gastroduodenal disease.
AB  - BACKGROUND/AIMS: Helicobacter pylori elicits a strong local and systemic humoral
      immune response, but it is not able to eliminate bacteria. Immune response may be
      important for the course of infection that may lead to different gastroduodenal
      disease. In order to investigate differences in systemic humoral immune response
      between patients with different gastroduodenal diseases, we conducted clinical
      and serological studies. METHODOLOGY: From 1999 to 2001 we enrolled 80 patients
      with dyspeptic symptoms: 26 with gastritis, 12 with duodenal ulcer, 29 with
      gastric cancer and 13 with gastric lymphoma. In all patients during diagnostic
      work-up we performed ELISA test with Helicobacter pylori-specific IgG and IgA. We
      investigated difference in stimulation of different immunoglobulin classes in
      patients with different gastroduodenal diseases, particularly benign and
      malignant. We estimated significance of differences with Mann-Whitney and Fisher
      exact probability test. RESULTS: All patients enrolled in the study were
      seropositive. Patients with gastritis had statistically significant higher level
      of IgG than patients with gastric cancer (p=0.0001), and gastric lymphoma
      (p=0.006). Patients with duodenal ulcer had statistically significant higher
      level of IgG than patients with gastric cancer (p=0.02), and gastric lymphoma
      (p=0.046). IgA level was significantly higher in patients with gastritis than in
      patients with gastric cancer (p=0.03). IgA>IgG ratio was significantly more
      frequent in patients with gastric cancer and gastric lymphoma than in patients
      with gastritis and duodenal ulcer (p=0.0002). CONCLUSIONS: Result of our study
      suggested that Helicobacter pylori elicits different systemic humoral immune
      response in patients with gastritis and duodenal ulcer than in patients with
      gastric cancer and gastric lymphoma at least in intensity of stimulation of
      different immunoglobulin classes.

PMID- 15011887
TI  - Clinical interpretation of the histological typing of gastric cancer using
      endoscopic forceps biopsy.
AB  - BACKGROUND/AIMS: Histological typing of gastric cancer is important for
      determining the treatment strategy and predicting the prognosis. We compared the
      histological types obtained by endoscopic forceps biopsy with the finally
      determined histological types of surgically resected specimens to investigate the
      reliability of histologically typing gastric cancer by biopsy. METHODOLOGY:
      Agreement between the biopsy typing and the final histological typing based on
      the predominant histology of the resected tumor was studied in 115 consecutive
      gastric cancers. RESULTS: The overall agreement rate of histological typing of
      gastric cancer was 75.7%. In patients with early gastric cancer, the agreement
      rate was a high 82.5% and the final histological type was usually predicted. In
      patients with advanced gastric cancer, the agreement rate was 72.0%, which was
      significantly lower than for early gastric cancer (p<0.05). The agreement rate
      for advanced differentiated cancer was also significantly lower than that for
      early cancer (63.6% vs. 90.0%) (p<0.05). CONCLUSIONS: The reliability of using
      histological typing by biopsy to set the indications for endoscopic treatment and
      for preoperative prediction of the prognosis is expected to be good for
      differentiated early gastric cancer, but it might not be adequate for advanced
      cancer or undifferentiated cancer.

PMID- 15011888
TI  - Combined S-1 and cisplatin preoperative chemotherapy for patients with advanced
      gastric cancer: report of five cases.
AB  - BACKGROUND/AIMS: A high response rate with acceptable toxicities is required in
      the setting of neoadjuvant chemotherapy. Five cases (3 stage IV, 2 stage IIIb) of
      advanced gastric cancer were successfully treated by neoadjuvant chemotherapy
      consisting of a combination of S-1 and cisplatin. METHODOLOGY: All 5 patients
      were men younger than age 60, with no severe complications. S-1 was administered
      orally (80 mg/m2/day) twice daily for 21 consecutive days, and cisplatin (60
      mg/m2) was infused over 2 hours on day 8 with hydration. This schedule was
      repeated every 5 weeks. After each cycle, the clinical response evaluation was
      performed with endoscopy, barium meal, and spiral CT scan. Surgery was carried
      out about 3 weeks after chemotherapy. RESULTS: All patients were responders
      (100%) after one or two cycles. However, there was no patient with either
      complete response, or down-staging. Toxicities, according to the WHO criteria,
      were very mild and none required treatment. Postoperatively one patient died of
      aspiration pneumonia unrelated to the chemotherapy. The others were discharged
      within 3 weeks after operation without complications. CONCLUSIONS: S-1 plus
      cisplatin seems safe and effective as neoadjuvant chemotherapy in advanced
      gastric cancer patients.

PMID- 15011889
TI  - Postoperative morbidity/mortality and survival rates after total gastrectomy,
      with splenectomy/pancreaticosplenectomy for patients with advanced gastric
      cancer.
AB  - BACKGROUND/AIMS: Indications for splenectomy in patients with proximal and middle
      gastric cancer remain controversial. We investigated characteristic findings in
      patients with lymph node metastasis to the splenic hilus and the indication of
      splenectomy with total gastectomy for T2 and T3 advanced gastric cancer.
      METHODOLOGY: Two hundred and forty-one Japanese patients underwent curative
      operations for T2 and T3 advanced gastric cancer. RESULTS: The mortality rates
      were similar, but the morbidity rate for patients who underwent
      pancreaticosplenectomy was higher than for patients who underwent either total
      gastrectomy alone or with splenectomy (p<0.007). The rates in cases of lymph node
      metastasis at the depth of tumor invasion within the subserosa and serosa (T3)
      were 1.7% and 17.5%, respectively (p<0.003). Lymph node metastasis to the splenic
      hilus was also evident in patients with T3 or T2 advanced gastric cancer with
      multiple lymph nodes metastasis (more than 7 nodes). The 10-year survival rates
      for patients who underwent total gastrectomy alone, with splenectomy, and with
      pancreaticosplenectomy in T3 advanced gastric cancers were 25%, 42% and 32%,
      respectively (p=0.184). CONCLUSIONS: Based on these data, the addition of distal
      pancreaticosplenectomy to total gastrectomy in patients with T2 and T3 advanced
      gastric cancer increased the risk of complications. Nevertheless, we recommend
      that total gastrectomy with splenectomy should be done for patients with T3
      advanced gastric cancers [and T2 advanced gastric cancer with multiple lymph
      nodes metastasis (more than 7 nodes)], recognizing the lymph node metastasis to
      the splenic hilus.

PMID- 15011890
TI  - Lack of benefit of treating Helicobacter pylori infection in patients with
      functional dyspepsia. Randomized one-year follow-up study.
AB  - BACKGROUND/AIMS: To assess whether H. pylori therapy is significantly better than
      control therapy in patients with functional dyspepsia, and to assess whether
      curing the infection relieves symptoms of dyspepsia. METHODOLOGY: We
      prospectively included consecutive H. pylori-positive patients in whom a
      gastroscopy was carried out and who were diagnosed of functional dyspepsia. At
      endoscopy, biopsies were obtained (histology and rapid urease test), and a 13C
      urea breath test was carried out. Patients were randomly assigned to 10 days of
      treatment with either eradication therapy (omeprazole, amoxicillin and
      clarithromycin) or with ranitidine. No antisecretory therapy was prescribed
      thereafter. Breath test was repeated four weeks after completing eradication
      treatment. A validated five-point Likert scale was used to measure severity of
      symptoms, both at the beginning of the study and 6 and 12 months after treatment.
      RESULTS: Fifty patients were included in the study. Sixteen patients were
      randomized to ranitidine and 34 to eradication treatment. The two groups were
      well balanced for base-line characteristics. One patient in each treatment arm
      was lost to follow-up at 12 months. Differences between ranitidine and
      eradication groups were not demonstrated in any of the symptom comparisons,
      either initially or at 12 months. The rates of treatment success for each symptom
      were similar in both groups. H. pylori was eradicated in 76% of the patients
      receiving antibiotics. Differences between groups of patients with eradication
      success and failure were not demonstrated in any of the symptom comparisons,
      either initially or at 12 months. Among the groups given eradication regimen, the
      rates of treatment success for each symptom were similar in the group with H.
      pylori eradication success and failure. CONCLUSIONS: H. pylori eradication is not
      likely to play a major role in the treatment of symptoms in patients with
      functional dyspepsia.

PMID- 15011891
TI  - Helicobacter pylori infection as a risk factor for gastric ulceration.
AB  - BACKGROUND/AIMS: Recent reports have shown that Helicobacter pylori infection is
      closely related to pathogenesis of gastric ulcers. But there have been no reports
      on the prospective follow-up study of the patients with H. pylori infection to
      determine whether H. pylori infection puts patients at high risk of developing
      gastric ulcers. METHODOLOGY: Fifty-two patients with H. pylori infection and 34
      patients without H. pylori infection, who were found endoscopically not to have
      localized lesions in the esophagus, stomach, or duodenum, underwent endoscopy
      follow-ups during the average observation period of 52 months. During each
      endoscopy, biopsy specimens were obtained from the antrum and the middle corpus.
      The grade of atrophy and intestinal metaplasia in the biopsy specimens were
      assessed histologically in accordance with the guidelines of the Updated Sydney
      System. RESULTS: Gastric ulcers developed in 8 (15%) of 52 patients with H.
      pylori infection, but not in patients without H. pylori infection: the difference
      was statistically significant (P<0.05). The development and the location of
      gastric ulcers was correlated to the development or progression of mucosal
      atrophy. In 8 (38%) of 21 patients in whom mucosal atrophy developed or
      progressed, gastric ulcers developed, but no ulcers developed in 31 patients
      without development or progression of gastric mucosal atrophy. Gastric ulcers
      developed in the gastric mucosa in which atrophy developed or progressed.
      CONCLUSIONS: H. pylori infection increases the risk for development of gastric
      ulcers and gastric ulcers developed through the progression of H. pylori
      associated gastric mucosal atrophy.

PMID- 15011892
TI  - Improvement of complete blood count in patients with iron deficiency anemia and
      Helicobacter pylori infection after the eradication of Helicobacter pylori.
AB  - BACKGROUND/AIMS: Recent reports support the possible association between Hp
      infection and iron deficiency anemia. In the present study, the effects of the
      eradication therapy on iron deficiency anemia were investigated. METHODOLOGY:
      Fourteen women with iron deficiency anemia were enrolled (mean age: 36.4 years;
      range: 20-52 years old). None of the patients received iron supplementation.
      Several examinations including upper and lower gastrointestinal endoscopy were
      performed to reveal any gastrointestinal bleeding sites in all patients. Gastric
      biopsies during endoscopy were taken from the subjects except one whose serum
      anti-Hp IgG was positive. After diagnosing the Hp infection by means of
      microbiology, histology and Gram stain, a combination therapy consisting of
      lansoprosol, clarithromycin and amoxicillin was administered to each patient.
      Hematologic examinations and the body iron status were evaluated periodically,
      following the eradication therapy. RESULTS: Endoscopic findings were as follows:
      Seven patients with antral gastritis, two patients with pangastritis, whereas
      five patients were found to be endoscopically normal. None of the subjects were
      found to have gastrointestinal bleeding of any type. Serum hemoglobin, iron and
      transferrin saturations of the patients were found to be increased at 20-24 weeks
      of follow-up after the eradication therapy. Serum ferritin levels were not found
      to be increased. CONCLUSIONS: Hp infection may be involved in cases of iron
      deficiency anemia of unknown origin, and the eradication of the infection may
      improve blood parameters other than serum ferritin levels.

PMID- 15011893
TI  - Poor responders to intravenous omeprazole in patients with peptic ulcer bleeding.
AB  - BACKGROUND/AIMS: Although proton pump inhibitors are highly effective in raising
      intragastric pH, there still remains a small group of patients who resist acid
      suppression. A high dose of omeprazole has been shown to reduce rebleeding rate
      in patients with bleeding peptic ulcers after endoscopic therapy. The primary
      objective of this study was to assess the incidence of peptic ulcer bleeding
      patients who were resistant to intravenous omeprazole. The secondary objective
      was to evaluate the relationship between intragastric pH and rebleeding rate in
      studied patients after successful endoscopic therapy. METHODOLOGY: Between Oct.
      1996 and Aug. 1999, 88 bleeding peptic ulcer patients who had obtained initial
      hemostasis with endoscopic therapy were enrolled in this study. In these
      patients, 40 mg of omeprazole was given as intravenous bolus followed by 40 mg
      intravenously every 6 h for 3 days. Thereafter, omeprazole was given 20 mg orally
      once daily for 2 months. The intragastric pH was recorded for 24 hours after the
      first dose of omeprazole. The occurrence of rebleeding was observed for 14 days.
      RESULTS: The mean intragastric pH value of these 88 patients was 6.07, (95% CI:
      5.91-6.23). Four patients (5%) were found to have omeprazole resistance (pH <
      4.0, 50% of the time). By the 3rd days after entering the study, more patients
      with a mean pH < 6 rebled (5/25 vs. 3/63, p<0.05). CONCLUSIONS: About five
      percent of patients with peptic ulcer bleeding respond poorly to intravenous
      omeprazole. Rebleeding rate is higher in patients with a mean intragastric pH of
      less than 6.

PMID- 15011895
TI  - Doctors are most likely adults to be involved in auto accidents.

PMID- 15011894
TI  - Genes and gastric cancer.
AB  - Gastric cancer remains quite a common malignancy and counts among the most
      important causes of cancer-related death worldwide. Although the pathogenesis is
      multifactorial, familial aggregation in a significant proportion of cases
      suggests the importance of genetic predisposition. The association between the E
      cadherin/CDH1 gene germline mutations and the development of diffuse gastric
      cancer was the first evidence for a molecular basis of gastric cancer in
      predisposed families and led many authorities in the world to produce guidelines
      regarding the management of such families members. The recent advances in
      genetics resulted in the discovery of numerous genetic events occurring during
      the course of gastric carcinogenesis (activation of oncogenes, silencing of tumor
      suppressor genes, mutations in DNA-repairing genes) and contributed to a better
      understanding in pathogenesis. Many genetic changes described have been found to
      affect tumor's biological behavior. In this article the authors attempt a review
      of all the molecular alterations in gastric cancer described in the literature
      and their impact on the management of patients with an inherited predisposition
      to gastric cancer. The promising role of gene therapy in the treatment of gastric
      cancer in the near future is also commented on.

PMID- 15011896
TI  - Acute coronary syndrome and crystal methamphetamine use: a case series.
AB  - "Ice" is a form of methamphetamine commonly used as a recreational drug in Hawaii
      and the Philippines, but seldom encountered in the continental United States. It
      differs in appearance from methamphetamine tablets, but otherwise has exactly the
      same molecules, only arranged in a crystalline structure. A sizeable body of in
      vitro, animal, and autopsy data suggest a linkage between methamphetamine use and
      myocardial pathology. In this report, we describe a series of eight patients who
      developed unstable angina or acute myocardial infarction in association with
      smoking crystal methamphetamine. The findings, to a large extent, resemble those
      with cocaine-associated acute coronary syndromes. Given the widespread abuse of
      methamphetamine among young age groups, the recognition and primary prevention of
      cardiovascular toxic effects is of mounting socioeconomic importance.

PMID- 15011897
TI  - 5-azacitidine: An alternative treatment of myelodysplastic syndromes in patient
      with refractory response to hematopoietic growth factor, a case report and review
      of literatures.
AB  - Myelodysplastic Syndrome (MDS) comprises a heterogeneous group of clonal
      hemopathies derived from an abnormality affecting a multipotent hematopoietic
      stem cell and characterized by maturation defects resulting in ineffective
      hematopoiesis. It most frequently occurs in elderly patients. Despite trials
      testing numerous agents in patients with MDS, no single drug has yet emerged as
      the accepted standard of treatment. Most MDS patients, due to their age and co
      morbidity, are not eligible for allogeneic hematopoietic stem cell
      transplantation; the only established curative regimen. The effect of available
      lineage-specific growth factors is limited to improvement of single lineages and
      has not resulting in the survival benefit. Treatment with low dose Ara-C is
      disappointing in regard to response rate or duration. No benefit has been
      demonstrated in differentiation inducers such as retinoids and Vitamin D3 as
      single agents. We report a case of a patient with transfusion dependent MDS who
      was not a candidate for allogeneic stem cell transplantation or cytotoxic
      chemotherapy, who also failed to response to erythropoietin support but had a
      favorable response to 5-azacitidine. His blood transfusion requirement reduced
      significantly, and was correlated with the remarkable improvement of the
      pancytopenia, particularly anemia and thrombocytopenia after receiving the
      investigational therapy with 5-azacitidine. In summary, 5-azacitidine appears to
      be a promising alternative therapy for patient with refractory anemia secondary
      to MDS.

PMID- 15011898
TI  - When persistence wears thin.

PMID- 15011899
TI  - Perception of tuberculosis in the Democratic Republic of Congo: wali ya nkumu in
      the Mai Ndombe district.
AB  - To implement effective tuberculosis (TB) control programs, we must first
      understand the health culture in a given region. The authors organized eight
      focus group sessions in the Mai Ndombe district in the Democratic Republic of
      Congo to study the underlying attitudes toward TB and to describe the TB context
      with special reference to gender differences. They then analyzed the focus group
      data using a grounded theory design. TB is called "the disease of distance" and
      is described as a person invading people. Isolation and stigmatization are the
      methods being used to protect society from the TB threat. The authors observed no
      gender differences in the collected data.

PMID- 15011900
TI  - Intercultural residential care in New Zealand.
AB  - Along with other Organization for Economic Cooperation and Development (OECD)
      countries, New Zealand's society is aging such that an increase in the number of
      older people requiring residential care is predicted. What cannot be foreseen is
      how culturally defined health beliefs affect the care given to older people in
      residential care. In this article, the authors describe and discuss the
      culturally based health beliefs of some Pacific Islands caregivers and
      predominately European (Pakeha) older people resident at one long-term care
      facility in Auckland, New Zealand. The delivery of care is influenced by
      culturally related beliefs about "being old." Racism is evident in residential
      care, and the authors discuss the reactions of caregivers, residents, and
      management. This research extends the discussion of caregiving and receiving in
      to the cross-cultural setting, and the findings highlight a number of elements in
      cultural differences between carer and cared-for that might affect care practices
      at the residential facility studied.

PMID- 15011901
TI  - Traditions in transition: young people's risk for HIV in Chiang Mai, Thailand.
AB  - Thailand is in the midst of a social and sexual transition that is affecting
      gender roles, sexual behavior, and, hence, risk for HIV. The continuation of past
      traditions, such as men having sex with commercial sex workers, coupled with an
      increasing acceptance of noncommercial premarital sex among young people, is
      fueling the AIDS epidemic. To examine young people's potential risk for HIV, the
      author investigated their perspectives on sexual behavior and sexual networking,
      the continued acceptance of premarital sex with commercial sex workers, and
      perception of risk for HIV in Chiang Mai. This study suggests that a changing
      social environment and the response to the AIDS epidemic have resulted in new
      patterns of sexual behavior that might trigger the dissemination of HIV into a
      broader network.

PMID- 15011902
TI  - The cultural context of suicide stigma in Taiwan.
AB  - In the ethnographic study on which this article is based, the authors investigate
      experiences after a suicide attempt from the perspective of patients and their
      family members in Taiwan. Thirty-four patients and 49 family members or
      colleagues participated in interviews from the point of patients' hospitalization
      to their return to the community. The postsuicide stigma suffered by patients and
      their families was based on such cultural themes as Suicide is bu-hsiao (non
      filial piety), Suicide results in an inability to transmigrate the soul, and
      Suicide is inherited. Patients, family members, and colleagues cope with the
      stigma through explaining suicide as due to "bad luck" or "a kan-huo (hot energy)
      problem," or by insisting that it was "not a true suicide." These findings
      suggest that health professionals can move closer to patients and their families
      and suggest appropriate health care policy through understanding the patient's
      and the family's explanation of suicide experiences.

PMID- 15011903
TI  - Kanadier Mennonites: a case study examining research challenges among religious
      groups.
AB  - In this article, the authors address the research issues experienced in carrying
      out a study with the Kanadier Mennonites, members of the Anabaptist religious
      group who support a lifestyle that demonstrates separation from mainstream
      society. The authors provide a brief description of the Kanadiers along with the
      purpose of the research and a synopsis of the sample. They focus primarily on
      discussing the methodological challenges in approaching this group. In addition,
      they place emphasis on addressing the research questions in ways that are
      respectful and nonintrusive. They discuss the lessons learned from the study
      within the context of qualitative cross-cultural research.

PMID- 15011904
TI  - Recruiting participants from a community of Bangladeshi immigrants for a study of
      spousal abuse: an appropriate cultural approach.
AB  - In this article, the authors describe a recruitment strategy used to enroll
      female Bangladeshi immigrants into a study of spousal abuse, crucial in the
      process of identifying abuse in this community. The researchers used a
      qualitative method involving a three-staged process designed for sampling and
      recruiting for focus groups and in-depth interviews. The Bangladeshi women
      declined participation in either of these qualitative genres, but the modified
      and adapted strategies proved effective in recruiting participants from the
      tightly knit immigrant community. Key to the success of the effort was the
      involvement of a Bangladeshi investigator, unspecified time to establish rapport
      with key informants and representatives of the larger community, and maintaining
      contact with the target population after completion of the project.

PMID- 15011905
TI  - Benefits and drawbacks of employment: perspectives of people with mental illness.
AB  - In this article, the author presents the perspectives of people with mental
      illness about the benefits and drawbacks of employment, what factors influence
      these, and how they affect consumers' decisions and actions. Forty-one consumers
      of mental health services participated in 76 in-depth interviews and two focus
      groups. The author coded data inductively and analyzed them using grounded theory
      method. The results demonstrate that the benefits and drawbacks of employment are
      experienced in six domains. Individuals' perceptions of benefits and drawbacks
      are influenced by individual and contextual factors, are dynamic over time, and
      are instrumental in determining their employment-related actions. The findings
      suggest several areas for future exploration with a view to improving policy and
      practice in employment for people with mental illness.

PMID- 15011906
TI  - The experiences of close relatives living with a person with serious chronic
      illness.
AB  - Living with serious chronic illness has a directly threatening effect on the life
      course of healthy relatives. The aim of this study was to elucidate the meaning
      of close relatives' experiences of living with a person with serious, chronic
      illness. Using a narrative approach, the authors interviewed 13 spouses and 1
      daughter about the meaning of their experiences. They used a phenomenological
      hermeneutic method to interpret the interview text. The structural analysis
      revealed three major themes: A Shrinking Life, Forced to Take Responsibility, and
      Struggling to Keep Going. Close relatives in this study seemed to be living lives
      characterized by a reduced sense of individual freedom and an increased sense of
      responsibility for the care of the ill person. It means struggling to obtain the
      strength to manage their duty and an inner sense of community and of solidarity.
      The authors interpret the findings in the light of the works of philosophers who
      have described ethical demands and natural love between people.

PMID- 15011907
TI  - Communicating professional identity in medical socialization: considering the
      ideological discourse of morning report.
AB  - In this study, the authors investigate how medical ideology and physician
      professional identity are socially constructed during morning report, a formal
      teaching conference considered to be a cornerstone of medical education. Analysis
      of transcripts from 20 meetings reveals physician identity is developed through
      ideological discourse that produces and reproduces systems of domination that
      privilege scientific medicine and marginalize humanistic approaches. Findings
      indicate how, in a socialization context uniquely focused on discourse,
      communication functions to construct a professional identity grounded in the
      principles of the biomedical model. Although medical residents deviate from
      traditional ideology by articulating the voice of the lifeworld, faculty
      physicians counter these moves by asserting the voice of medicine. The authors
      draw conclusions regarding identity formation and the socialization practices of
      medical education.

PMID- 15011908
TI  - After methods, the story: from incongruity to truth in qualitative research.
AB  - Writing is the integral part of research when a story is crafted. This story
      makes whatever claim the research will have on readers, and social scientists
      have increasingly recognized the need to take their storytelling seriously.
      Discussion of several contemporary ethnographies offers practical advice on
      writing by asking how the authors tell such good stories. Advice begins with how
      to catch readers' attention and moves to issues of telling the truth in
      postmodern times.

PMID- 15011909
TI  - Does no good deed go unpunished? Notes to a young surgeon.

PMID- 15011910
TI  - Nonsentinel lymph node status after positive sentinel lymph node biopsy in early
      breast cancer.
AB  - Axillary dissection is the current standard of care for patients with breast
      cancer who are diagnosed with metastasis to axillary sentinel lymph nodes (SLNs).
      Recently, that concept has come under increasing scrutiny because not all women
      with a positive SLN will need further dissection. The purpose of this study was
      to look at nonsentinel lymph node status in patients with breast cancer and
      axillary SLN metastasis in an effort to determine tumor variables that can guide
      further treatment if there are additional axillary nodes involved. A
      retrospective chart review was performed on patients with breast cancer who
      underwent SLN biopsy between July 1998 and April 2003. Chi2 analysis, Student t
      test, and multivariate analysis were used to determine the significance of tumor
      size, grade, location, estrogen receptor (ER) and progestrone receptor (PR)
      receptor status, angiolymphatic invasion, stage, and number and size of SLNs in
      predicting the status of nonsentinel lymph nodes. During the study interval, 116
      patients were identified who underwent SLN biopsy and 34 (29.3%) had positive
      SLNs. All of these patients underwent complete axillary node dissection and 11
      patients (32.3%) had non-SLN metastasis. The presence of palpable breast mass (P
      = 0.03), tumor size (P = 0.04), angiolymphatic invasion (P = 0.03), and
      extracapsular extension of SLN metastasis (P = 0.001) were the variables that
      predicted non-SLN involvement. Micrometastasis was inversely related to non-SLN
      involvement. In patients with breast cancer and SLN metastasis, the presence of a
      palpable breast mass, tumor size, angiolymphatic invasion, and extracapsular node
      extension increase the likelihood of identifying additional node metastasis on
      subsequent axillary dissection.

PMID- 15011911
TI  - Mucin secreting cystic lesions of the pancreas: treatment by enucleation.
AB  - Ninety per cent of pancreatic cysts are inflammatory pseudocysts. The other 10
      per cent are congenital or neoplastic and include congenital true cysts,
      retention cysts, lymphoepithelial cysts, the mucinous cystadenoma, mucinous
      cystadenocarcinoma, and serous microcystic cystadenomas and the more recently
      described intraductal papillary mucin-secreting neoplasms. The advent of
      computerized tomographic scanning, endoscopic retrograde cholangiopancreatography
      (ERCP), and endoscopic ultrasonography (EUS) has brought many of these lesions to
      light when they are minimally symptomatic or are incidentally found while
      investigating unrelated problems. If there is any suspicion of actual or
      potentially malignant disease, then total excision of the lesion with part of or
      the entire pancreas is indicated to achieve a likely cure, as survival is better
      than for the more common ductal adenocarcinomas. There are few reliable
      preoperative studies to distinguish accurately the etiology and prognosis of this
      spectrum of cystic lesions, and usually the actual diagnosis is made only at the
      time of operation or histopathologic examination after the cystic lesion has been
      biopsied or excised. If a cyst is confirmed to be totally benign, as in the
      congenital true cyst, lymphoepithelial cyst, or a benign mucinous cyst, they may
      lend themselves to nonoperative observation or excision without sacrifice of
      pancreatic parenchyma. However, many mucin-producing cystic lesions may evolve
      into a dysplastic or invasive malignant lesion requiring more aggressive
      resective treatment, and it is important not to miss that diagnosis early when
      cure is still possible. This report presents four benign mucin-secreting cysts
      treated by local excision. All four were in the head of the pancreas and
      communicated with the main pancreatic duct and lacked ovarian-type stroma, thus
      categorizing them as side-branch intraductal papillary mucinous neoplasms. These
      lesions were able to be easily dissected out of the pancreas with only one
      patient developing a transient pancreatic fistula. Intraoperative and final
      histopathology confirmed the benign status, and these patients have remained
      disease free 3 to 5 years postoperatively. A review of benign tumors reported to
      have been treated by cyst enucleation in the literature confirms the rationale of
      this approach in highly selected lesions.

PMID- 15011912
TI  - Post-parathyroidectomy hypocalcemia: incidence, risk factors, and management.
AB  - The purpose of this study was to evaluate the incidence and severity of
      hypocalcemia after parathyroidectomy and delineate its risk factors. Data was
      retrieved from a prospective database. Patients with postoperative hypocalcemia
      were identified and risk factors were investigated including primary versus renal
      hyperparathyroidism (HPT), preoperative calcium, parathyroid hormone (PTH) and
      alkaline phosphatase levels, gland weight, pathology, extent of surgery, and
      reoperative surgery. Of the 162 patients who underwent parathyroidectomy, 84
      (52%) were hypocalcemic postoperatively: 55 (42%) of 132 patients with primary
      and 29 (97%) of 30 patients with renal HPT (P = 0.0001). Patients with renal HPT
      had more profound hypocalcemia with a mean +/- SD calcium of 7.34 mg/dL +/- 1.07
      versus 7.76 mg/dL +/- 0.59 for patients with primary HPT (P < 0.05). Symptoms
      were present in 28 (51%) of 55 patients with primary and 13 (45%) of 29 patients
      with renal HPT. Only three (2%) patients with primary compared to 29 (97%) with
      renal HPT were treated with intravenous calcium. The average length of stay for
      hypocalcemic patients was 0.7 days for primary HPT versus 4.7 days for renal HPT
      (P < 0.0005). Patients with primary HPT who underwent subtotal parathyroidectomy
      had significantly lower postoperative calcium levels (7.95 mg/dL +/- 0.64) than
      patients who had a single or double adenoma removed (8.49 mg/dL +/- 0.79) (P =
      0.036). No other factor was predictive of postoperative hypocalcemia. Patients
      with renal HPT develop profound postoperative hypocalcemia requiring intravenous
      calcium and vitamin D therapy. Hypocalcemia in patients with primary HPT develop
      less severe hypocalcemia that is amenable to outpatient oral calcium therapy and
      should be routinely initiated following subtotal parathyroidectomy.

PMID- 15011913
TI  - Personal experience with the Whipple operation: outcomes and lessons learned.
AB  - Pancreaticoduodenectomy (PD) has evolved into a safe procedure in major high
      volume medical centers. This retrospective outcome review is from a database of
      134 consecutive PDs from 1985 through 2002; all of whom underwent resection in a
      community hospital with a general surgery residency. All resections were
      performed by senior residents under the supervision of the same attending surgeon
      (V.L.H.). Follow-up was 100 per cent. There were 117 (88%) pyloric-sparing
      pancreaticoduodenectomies (PSPD) and 17 (12%) standard Whipple (SW) operations.
      Mean age for patients was 60 years with a range 29 to 84 years. There were 62
      female and 72 male patients. Resections performed were periampullary
      malignancies, 83.6 per cent; benign neoplasm, 3.7 per cent; and non-neoplastic
      disease, 12.7 per cent. For the pancreatic anastomoses, 84 (63%) were
      pancreaticogastrostomies (PGs) and 50 (37%) were pancreaticojejunostomies (PJs).
      Mortality was 3.7 per cent, and 60 major complications occurred in 38 patients
      (28%) which included pancreatic fistula, 5.2 per cent; bile leak, 0.7 per cent;
      other anastomotic leaks, 1.5 per cent; intra-abdominal abscesses, 8.2 per cent;
      intra-abdominal bleeding, 3.0 per cent; upper gastrointestinal bleeding, 3.7 per
      cent; bowel ischemia, 1.5 per cent; and delayed gastric emptying (DGE), 17.9 per
      cent. Reoperation was required in only five patients (3.7%). There were no
      complications in 96 patients (72%) with an average hospital stay of 9.0 days.
      Long-term complications were peptic ulcer disease, liver abscess, hepatic stones,
      pancreatic insufficiency, and radiation jejunal strictures. Long-term survival
      was achieved in periampullary malignancies including pancreatic with excellent
      functional status.

PMID- 15011914
TI  - Residents' working hours in a consortium-wide surgical education program.
AB  - Traditional work schedules of surgical residents have been cited as a factor that
      negatively influences education and the quality of patient care. Demands by
      federal and state legislators as well as the general public have forced a re
      evaluation of the issue. Long working hours and resulting sleep deprivation
      affect the lives of residents profoundly, but the question remains does it lower
      the quality of medical care? The justification for the long hours is that they
      are vital to medical education, but residents are so drained by their schedules
      that they are rarely in the best state of mind to learn from their experiences.
      Under the scrutiny of the Resident Review Committee (RRC), many programs and
      institutions have been cited in the recent past in violation of resident working
      hour requirements. As a result, many institutions have implemented reforms,
      thereby reducing the number of citations they received. In spite of having the
      highest number of citations, the field of general surgery has failed to show any
      improvement. The Oakland Health Education Programme Center for Medical Education
      (OHEP), a consortium of 16 teaching hospitals in the State of Michigan, set out
      to review the components of general surgery residency training in order to be
      able to make recommendations that might assist program directors in making
      appropriate changes where necessary to enhance resident education and the quality
      of patient care as well as to meet the personal demands of residents.
      Questionnaires on residents' attitudes concerning their working hours and
      possible reforms were sent to all general surgery residency programs in the OHEP
      consortium. The questionnaire consisted of 25 questions divided into three major
      sections: the first section encompassed demographic information including current
      work hours and on-call schedules. The second section consisted of questions
      relating to attitudes toward work hours and the options for change. The third
      section consisted of questions that viewed the perceived effects of limited work
      hours. From the seven participating hospitals with surgery residency programs in
      OHEP, 92 residents responded to our survey. The majority of residents were in the
      first 3 years of postgraduate training. The mean age of residents was 30 years
      old. Sixty-four per cent of respondents were male, and 18 per cent were female.
      Residents reported an average of 56 with a range of 0 to 110 hours on call.
      Variations in the number of hours had to do with the various rotations residents
      were on, in that during certain elective rotations, residents were not assigned
      to any call. The on-call schedule varied; alternate nights were reported by 11
      per cent, every third night by 33 per cent, and every fourth night or more by 53
      per cent. The majority of surgical residents did express the need for reform and
      did not feel that reforms would affect the quality of resident education.
      However, residents did not want to lengthen residency training beyond the 5
      years. The results of our study indicates that the majority of residents in
      general surgery programs in Michigan perceive a need for reform of work
      schedules. Surgical educators may have underestimated this need in the past. Most
      residents thought that long hours impaired their educational experience and at
      times compromised their clinical care.

PMID- 15011915
TI  - Inguinal hernia recurrence following preperitoneal Kugel patch repair.
AB  - Three hundred eighty-six preperitoneal inguinal herniorrhaphies using a
      polypropylene Kugel patch (Davol) were performed in 355 consecutive patients by
      six surgeons. Variables for recurrence evaluated included age, gender, hernia
      type, whether the Kugel patch was placed for a primary or recurrent hernia, and
      the experience of the surgeon. Of 336 patients with long-term follow-up available
      (18 months to 63 months, median 42 months) 28 recurrences developed 1 to 48
      months (mean 16 months) after 366 Kugel patch repairs (7.7%). Recurrence was
      highest (27.8%) in the subset of patients who had a Kugel patch placed for
      recurrent inguinal hernias (P < 0.05). Patients with direct primary hernias
      involving the entire floor had a recurrence rate of 22.7 per cent (P < 0.05).
      Patient age and gender had no bearing on recurrence. Surgeon experience did play
      a role, as the recurrence rate was 18.2 per cent during each surgeon's first 36
      cases and 2.9 per cent thereafter (P < 0.0005). Surgeons using a preperitoneal
      Kugel patch for inguinal herniorraphy had a recurrence rate that was unacceptably
      high. The technique may not be suitable for repair of recurrent inguinal hernias
      or primary large direct inguinal hernias. Surgeons in this study saw a learning
      curve of 36 cases.

PMID- 15011916
TI  - Open abdomen management of intra-abdominal sepsis.
AB  - Despite surgical advances, antimicrobial therapy, and intensive care, the
      morbidity and mortality of intra-abdominal sepsis remains high. The primary
      purpose of this study was to determine whether open abdomen management of intra
      abdominal sepsis reduces intensive care unit (ICU) and hospital mortality. The
      records of 81 consecutive patients with open abdomen management for intra
      abdominal sepsis admitted to the surgical ICU from January 1998 to April 2002
      were retrospectively reviewed. Outcomes were compared to a historical control
      group with primary abdominal closure, also admitted to the surgical ICU with
      intra-abdominal sepsis and matched for sex, age, source of sepsis, and APACHE III
      score. ICU mortality for the open abdomen group was 25 per cent versus 17 per
      cent for the control group. Hospital mortality was 33 per cent and 25 per cent
      for the open abdomen patients and historical controls, respectively. Both ICU and
      hospital length of stay were significantly longer for the open abdomen group. An
      overall fistula rate of 14.8 per cent was demonstrated in the open abdomen
      patients. A significant difference in overall ICU and hospital mortality was not
      demonstrated between patients treated with open abdomen management and historical
      controls. A prospective randomized study accounting for extent of sepsis may
      define a role for open abdomen management in selected subgroups of patients.

PMID- 15011917
TI  - Inhibition of heme oxygenase-1 in microvascular lung pericytes diminishes at high
      concentrations of an inflammatory mediator.
AB  - Post-traumatic inflammation and sepsis induce changes in the lung
      microvasculature causing increased permeability. Pericytes, contractile cells
      positioned abluminally to endothelial cells, play a role in regulating this
      response. An in vitro model of microvascular lung pericytes (MLP) was used to
      investigate the effect of inhibiting heme oxygenase-1 (HO-1), a stress-induced
      enzyme, in the presence of varying levels of lipopolysaccharide (LPS), a mediator
      in the initiation of inflammation, on pericyte contractility. Rat MLP were
      cultured on collagen gel matrices. Cells were exposed to three concentrations of
      LPS in the presence of zinc protoporphyrin IX (ZnPP-9), a known inhibitor of HO
      1. After 24 hours, the surface area of the collagen disks was quantified, thereby
      measuring pericyte contraction. ZnPP-9 caused a significant attenuation of the
      LPS-induced relaxation of the pericytes (P < or = 0.003). The effects of ZnPP-9,
      however, depended on the concentration of LPS to which the pericytes were
      exposed. Greater concentrations of LPS decrease the attenuating power of ZnPP-9.
      The inhibition of HO-1 diminished MLP relaxation triggered by LPS. The effect of
      ZnPP-9, however, is dependent on the concentration of LPS to which the MLP are
      exposed, indicating its saturation. ZnPP-9 may antagonize the microvascular
      response to trauma.

PMID- 15011918
TI  - Early and late complications following laparoscopic adjustable gastric banding.
AB  - There is limited U.S. data on short- and long-term complications of laparoscopic
      adjustable gastric banding (LAGB) as a treatment option for morbid obesity.
      Hereafter, we present our experience with the first 154 consecutive LAGBs
      performed at Loyola University Medical Center. Inpatient and outpatient charts
      were reviewed retrospectively for all patients undergoing LAGB between November
      2001 and February 2003 for perioperative morbidity and mortality and repeat
      operations. Thirty-seven men (24%) and 117 women (76%) underwent LAGB in a 16
      month period. There was one (0.6%) death from postoperative myocardial infarction
      (MI) and one (0.6%) pulmonary embolism. Six (3.9%) patients required readmission
      to the hospital for dehydration. During a mean follow-up of 33 weeks (range, 4-69
      weeks), 14 (9%) patients required repeat operations. There were five (3.2%) band
      slippages and one (0.6%) gastric erosion. Three bands were removed
      laparoscopically. Three slippages were revised laparoscopically. One patient
      underwent laparoscopic cholecystectomy. Seven patients (4.5%) required port
      revisions for catheter disconnection (4), leak at port site (2), or flipped port
      (1). LAGB is a safe operative approach for the management of morbid obesity. The
      incidence of postoperative complications can be minimal with application of a
      standardized technique. LAGB should be strongly considered for morbidly obese
      patients who have failed nonoperative management.

PMID- 15011919
TI  - Hand-sewn versus stapled intestinal anastomoses in a chronically steroid-treated
      porcine model.
AB  - Chronic steroid treatment is known to delay wound healing; however, there are no
      trials examining stapled intestinal anastomoses in subjects chronically treated
      with steroids. The current study compares mechanically stapled to manually
      sutured intestinal anastomoses in a steroid-treated porcine model. Twenty adult
      male pigs were treated with daily prednisolone (0.5 mg/kg IM) for 14 days. The
      pigs were divided between hand-sewn and stapled groups. All pigs underwent a
      laparotomy with construction of a jejunojejunostomy, an ileocecostomy, and a
      colocolostomy. Pigs were sacrificed on postoperative day 4. Bursting pressure,
      collagen content, and inflammatory scores were used to evaluate each anastomosis.
      Bursting pressure was greater for the hand-sewn group at the jejunojejunostomies
      only (1.52 vs 0.79 psi; P < 0.001). The collagen content and microscopic
      inflammatory scores were not significantly different at any location. The mean
      gross inflammatory score was greater for the hand-sewn colocolostomies only (5.20
      vs 4.00; P < 0.01). Stapled ileocecostomies and colocolostomies appear to heal as
      well as hand-sewn anastomoses. This may not be true of the jejunojejunostomies as
      evidenced by the decreased bursting pressures. These data may provide evidence in
      support of the use of stapled anastomoses in steroid-treated patients.

PMID- 15011921
TI  - Surgeon-directed ultrasound for trauma is a predictor of intra-abdominal injury
      in children.
AB  - This study investigated the efficacy of surgeon-directed focused assessment with
      sonography for trauma (FAST) in conjunction with physical exam (PEx) as a
      predictor of intra-abdominal injury in children. Injured children (ages < or =
      17) presenting to a level I trauma center with abdominal trauma were evaluated in
      the emergency department (ED) by the trauma team of surgical attendings and
      residents. PEx and FAST were performed immediately upon arrival to the ED and
      results compared to CT, the standard exam for presence of intra-abdominal injury.
      Data was collected prospectively from July 1, 2000, until April 30, 2002. One
      hundred and twenty injured children underwent evaluation of abdominal trauma with
      PEx, FAST, and abdominal CT. Two patients had false-negative CT scans. Bayesian
      analysis was applied to the results of the remaining 118 patients. FAST compared
      with CT findings revealed sensitivity 70 per cent, specificity 100 per cent,
      positive predictive value 100 per cent, and negative predictive value 92 per
      cent. FAST results were combined with PEx findings such that either suggestive of
      intra-abdominal injury was regarded as a "positive exam." Sensitivity was 100 per
      cent, specificity 74 per cent, positive predictive value 53 per cent, and
      negative predictive value 100 per cent. Surgeon-directed FAST with consideration
      of PEx is a predictor of intra-abdominal injury in children.

PMID- 15011920
TI  - Predictors of mortality in patients with traumatic diaphragmatic rupture and
      associated thoracic and/or abdominal injuries.
AB  - This is a retrospective review of 731 patients sustaining diaphragmatic trauma
      over a 22 year period (1980-2002) at an urban level I trauma center. Patients had
      an average injury severity score (ISS) of 22 +/- 12. The mortality rate (MR) was
      23 per cent (168/731). There were a total of 460 left-sided diaphragmatic
      injuries (L-TDR), 263 right-sided diaphragmatic injuries (R-TDR), and 8 bilateral
      diaphragmatic injuries (B-TDR). There were no significant differences in
      mortality with L-TDR versus R-TDR. Shotgun wounds had the highest MR (42%) (P =
      0.0028). Emergency thoracotomies were performed in 31 per cent (225) with a 62
      per cent (140) MR. Bilateral thoracotomies had a significantly higher MR of 85
      per cent (33/39) compared to the 58 per cent (107/186) for unilateral
      thoracotomies (P = 0.0028). Multivariate analysis revealed the most significant
      independent predictors of mortality to be the revised trauma score, transfusion
      of pRBCs > 10 units, and need for thoracotomy (P < 0.0001). The infection rate
      was 41 per cent. Multivariate analysis revealed blunt trauma, blood transfusions,
      ISS, and pancreatic injury as the most significant independent predictors of
      infection (P < 0.001). The initial physiologic presentation of the patient and
      the severity of hemorrhagic shock are the primary determinants for survival.
      Prompt identification of associated injuries with rapid control of bleeding is
      paramount to survival.

PMID- 15011922
TI  - Neoadjuvant therapy and biliary decompression lower biliary and pancreatic juice
      vascular endothelial growth factor levels in patients with periampullary
      adenocarcinoma.
AB  - Increased expression of vascular endothelial growth factor (VEGF) by pancreatic
      cancer correlates with poor survival. The significance of VEGF in biliary and
      pancreatic secretions in periampullary cancers is unknown. Bile and pancreatic
      juice samples were collected from patients undergoing pancreaticoduodenectomy
      (PD). All samples were frozen at -70 degrees C until subsequent analysis for VEGF
      concentration using enzyme-linked immunoabsorbent assay (ELISA). Plasma VEGF
      levels in pancreatic cancer patients were <10 pg/mL. The biliary VEGF
      concentration for patients with malignancy was significantly elevated compared to
      benign disease (P = 0.05). There was no difference in pancreatic VEGF
      concentrations between benign and malignant disease. Cancer patients undergoing
      preoperative chemoradiation (CRT) had lower biliary and pancreatic VEGF
      concentrations than those who did not. Preoperative biliary drainage (BD) was
      associated with decreased VEGF concentrations in bile (3500 pg/mL vs 7740 pg/mL,
      P = 0.027). Patients undergoing both CRT and BD had diminished biliary and
      pancreatic VEGF concentrations compared to those who had neither. This was
      statistically significant for pancreatic VEGF concentrations (917 pg/mL vs 4723
      pg/mL, P = 0.044). VEGF is highly concentrated in bile and pancreatic juice
      compared to plasma. Preoperative CRT and BD significantly reduce these levels in
      patients with periampullary cancers. Antiangiogenic therapy aimed at interrupting
      the VEGF pathway appears to be a logical target in periampullary cancer.

PMID- 15011923
TI  - Major depression due to primary hyperparathyroidism: a frequent and correctable
      disorder.
AB  - While primary hyperparathyroidism (primary HPT) is recognized as a correctable
      cause of nephrolithiasis and osteoporosis, its role as an organic cause of major
      depression is less clear. The rate of major depression in primary HPT, response
      of symptoms to parathyroidectomy, and potential cost benefits were reviewed. From
      August 1994 to September 2002, 360 patients underwent parathyroidectomy for
      primary HPT. Thirty-five patients met Diagnostic and Statistical Manual of Mental
      Disorders IV-Text Revision (DSM IV-TR) criteria for major depression.
      Postoperatively, a modified form of the Outcomes Institutes Health Status
      Questionnaire 2.0 was used to evaluate patient mood and continued need for
      antidepressant medication (ADM). Cost analysis of ADM use was performed. Thirty
      five of 360 patients (10%) with primary HPT met criteria for major depression.
      Thirteen of 35 (37%) required ADM preoperatively. Postoperatively, 29/35 (83%)
      patients responded to a phone survey: 90 per cent stated depression no longer
      impacted their ability to work or activities of daily living; 52 per cent
      reported an improved quality of life; 27 per cent discontinued preoperative ADM;
      and 27 per cent reduced their ADM dose. Reduction in ADM resulted in a savings of
      dollars 700 to dollars 3000 per patient per year. Major depression occurs in 10
      per cent of patients undergoing parathyroidectomy for primary HPT.
      Parathyroidectomy reduces symptoms of major depression, improves quality of life,
      and can eliminate or reduce the need for antidepressant medication in up to 54
      per cent of patients.

PMID- 15011924
TI  - Comparison of standard carotid endarterectomy with Dacron patch angioplasty
      versus eversion carotid endarterectomy during a 4-year period.
AB  - Currently, the two primary approaches to carotid endarterectomy for extracranial
      carotid stenosis are carotid endarterectomy with patch angioplasty and eversion
      carotid endarterectomy. In a retrospective study over a 4-year period from 1998
      to 2002, we had an opportunity to compare the two approaches as two surgeons
      utilized carotid endarterectomy with Dacron patch angioplasty and two other
      surgeons utilized eversion carotid endarterectomy. During the 4-year period, 189
      carotid endarterectomies were performed, 125 with Dacron patch angioplasty (CE-P)
      and 64 with eversion (EE) endarterectomy. There were no significant differences
      in age of the patients, operative indication, or associated risk factors between
      the two groups. Perioperative outcome measurement in the CE-P versus EE included
      stroke or transient ischemic attack, 1.6 per cent versus 1.56 per cent, cranial
      nerve injury, 2.4 per cent versus 3.13 per cent; death, 0.8 per cent versus 0 per
      cent; need for operative conversion or revision, 2.4 per cent versus 7.81 per
      cent, respectively. Only the need for operative conversion or revision reached
      significant difference (P < 0.05), although the need decreased to 4 per cent for
      the last 50 EE cases. Recurrent stenosis of 50 per cent to 79 per cent was 4.88
      per cent versus 3.13 per cent and >80 per cent was 0.81 per cent versus 0 per
      cent in the CE-P versus EE group over a follow up of 16.3 months and 17.0 months,
      respectively. We conclude that both CE-P and EE are equally efficacious operative
      approaches to extracranial carotid occlusive disease.

PMID- 15011925
TI  - Harnessing the full power of the federal government to promote good health.

PMID- 15011926
TI  - Reaching out to promote physical activity in Australia: a statewide randomized
      controlled trial of a stage-targeted intervention.
AB  - PURPOSE: This study examined the broader use of a print-media intervention, which
      was previously shown to be effective at promoting physical activity to
      participants recruited from a regional Australian community, as a strategy
      suitable for a more diverse statewide population sample. METHODS: Participants
      were randomly selected adults who responded to a telephone interview conducted by
      the New South Wales Health Department and consented to participate in a
      randomized controlled trial. Consenters were allocated to either intervention (n
      = 361) or control (n = 358) conditions. The intervention, a personalized letter
      plus stage-targeted booklets, was sent 1 week postbaseline. Data were collected
      via telephone interview at baseline and 2 and 8 months and were analyzed using
      repeated measures analysis of variance (ANOVA) and chi2 statistics. RESULTS: The
      groups were similar at baseline (mean age 43 +/- 3 years; 64% women). Process
      evaluation showed high intervention recall (76% at 2 months) and high follow-up
      response rates (> 85% at 8 months) were achieved. Nonsignificant increases in
      physical activity were observed (F1,719 = 2.18, p = .14). DISCUSSION: A single
      mailing of stage-targeted print materials was not effective in promoting
      increases in physical activity among participants selected from the statewide
      population. Future research could examine how the effectiveness of print media
      might be enhanced, possibly by using supplementary media, community-based
      prompts, or other incentives.

PMID- 15011927
TI  - Lifestyle physical activity for individuals with spinal cord injury: a pilot
      study.
AB  - PURPOSE: To evaluate the acceptability and feasibility of a lifestyle physical
      activity program for people with spinal cord injury (SCI). METHODS: Sixteen
      nonexercising adult volunteers with SCI participated in a single group pre-post
      test of the "Be Active in Life Program" comprising stage-matched educational
      materials, home visit by a nurse, construction of a personal plan to increase
      activity, and four follow-up phone calls. Program acceptability, stage of change,
      barriers to health-promoting activities, abilities for health practices, health,
      depression, and muscle strength were rated. Physical activity was monitored using
      actigraphy and a self-report record. RESULTS: Participants rated the program
      positively, although some preferred a structured exercise approach. Eighty-one
      percent of participants progressed in stage of change and 60% increased physical
      activity. There were significant changes in motivational barriers, exercise self
      efficacy, self-rated health, and muscle strength. DISCUSSION: Lifestyle physical
      activity is feasible and acceptable and could be effective in promoting greater
      physical activity among people with SCI.

PMID- 15011928
TI  - Efficacy of a video for teaching patients about prostate cancer screening and
      treatment.
AB  - PURPOSE: To test the effectiveness of a video to teach patients about prostate
      cancer screening and treatment in a clinic setting. METHODS: A staged, two-group,
      pretest-posttest quasi-experimental design was used. Questionnaires were
      completed before and after a routine doctor's appointment in a Veteran's
      Administration clinic. The experimental group (n = 52) viewed the video, and the
      control group (n = 52) received usual care only. The two groups were similar in
      age, education, race, and quality of life. RESULTS: Knowledge increased
      significantly from pretest to posttest for the experimental group, but not for
      the control group (p < .001). More patients in the experimental group changed
      their preference for prostate-specific antigen (PSA) screening (31% experimental
      vs. 2% control, p = .002), indicating the patients were impacted by the
      information presented. Viewing the video did not stimulate increased discussion
      with the physician or lengthen appointment time. CONCLUSION: The video was
      effective in improving knowledge about a complex topic and changing some
      patients' preference for PSA testing without frightening or confusing patients.

PMID- 15011929
TI  - Self exposure to secondhand smoke among prenatal smokers, abstainers, and
      nonsmokers.
AB  - PURPOSE: Prenatal smoking cessation will not eliminate health risks if women
      continue to be exposed to passive smoking. This study compared the risks of
      secondhand smoke (SHS) exposure for low-income prenatal nonsmokers, abstainers,
      and smokers. METHODS: A questionnaire was administered to 225 pregnant women.
      Exposure to six sources of SHS was compared across smoking groups using chi
      square and multivariate logistic regression. RESULTS: In adjusted analyses,
      patterns of SHS exposure were consistent. Abstainers were at lower risk of
      exposure than smokers for all sources except for having a partner who smoked.
      Abstainers were at higher risk of exposure than nonsmokers for most sources. For
      example, 11.7% of nonsmokers were exposed to < 4 hours of SHS daily compared with
      33.3% of abstainers (adjusted odds ratio = .32, 95% confidence interval = .12
      .88). Mean number of exposures for nonsmokers, abstainers, and smokers were 1.4,
      2.7, and 4.2, respectively (p < .001). DISCUSSION: Interventions need to address
      the full range of health risks posed by cigarette smoke exposure during
      pregnancy.

PMID- 15011930
TI  - Changes in cognitive measures in a randomized controlled trial of a health
      promotion program for couples targeting diet and physical activity.
AB  - PURPOSE: To examine cognitive responses to a 4-month health promotion program
      targeting diet and physical activity in recently cohabiting couples. DESIGN: A
      three-group randomized controlled trial: no intervention (Controls), interactive
      group sessions and mail-outs (Interactive), and one group session followed by
      mail-outs (Mail). SETTING: Australian research studies unit. SUBJECTS: Seventy
      eight of 137 couples cohabiting for < 2 years, recruited by advertising,
      completed the study. MEASURES: Stages of change; health beliefs; self-efficacy;
      and perceived barriers to change evaluated by questionnaires at baseline,
      postintervention, and 1-year follow-up. Data were analyzed using mixed models,
      factor analysis, and linear regression. RESULTS: In the Mail group, the perceived
      importance of barriers to dietary change decreased by 19% at postintervention and
      16% at 1-year follow-up; dietary self-efficacy increased by 9% and 3%,
      respectively. In the Interactive group, the perceived importance of barriers to
      dietary change decreased by 26% and 20%, and dietary self-efficacy increased by
      14% and 12%, respectively. Similar trends for physical activity were not
      statistically significant. However, changes in self-efficacy and perceived
      barriers to change significantly predicted dietary and physical activity
      behaviors. A preponderance of higher socio-economic groups and the proportion of
      drop-out may have biased results. CONCLUSIONS: Health promotion using partners'
      support and targeting diet and physical activity improves associated cognitive
      variables in couples. Most improvements were greater and more sustained with
      interactive group sessions.

PMID- 15011931
TI  - Increasing stair use in a worksite through environmental changes.
AB  - PURPOSE: This study assessed the impact on stair use of four sequential
      environmental interventions: (1) installing new carpet and painting the walls,
      (2) adding framed art-work on stair landings, (3) displaying motivational signs
      throughout the building, and (4) adding a stereo system and playing various types
      of music in the stairwell. METHODS: We conducted a longitudinal study with no
      comparison group to evaluate the impact of environmental changes on stairway use.
      The setting was the main stairwell in the Centers for Disease Control and
      Prevention's (CDC) Rhodes Building in Atlanta, Georgia. Proximity sensors were
      installed in each stairwell entry to monitor traffic. The subjects were 554
      permanent CDC employees and 110 temporary employees. Changes in stairwell use by
      intervention were evaluated. RESULTS: Both motivational signs and music
      significantly increased stair use by 8.9% over baseline (p < .05). The increase
      in sign use occurred in the first 3 months of the intervention, whereas the
      increase in music occurred after the first 3 months. DISCUSSION: These data
      suggest that physical improvements to a stairwell, signage that encourages stair
      use, and music may increase physical activity among building occupants.

PMID- 15011932
TI  - Estimating risk reduction required to break even in a health promotion program.
AB  - PURPOSE: To illustrate a formula to estimate the amount of risk reduction
      required to break even on a corporate health promotion program. DESIGN: A case
      study design was implemented. Base year (2001) health risk and medical
      expenditure data from the company, along with published information on the
      relationships between employee demographics, health risks, and medical
      expenditures, were used to forecast demographics, risks, and expenditures for
      2002 through 2011 and estimate the required amount of risk reduction. SETTING:
      Motorola. SUBJECTS: 52,124 domestic employees. MEASURES: Demographics included
      age, gender, race, and job type. Health risks for 2001 were measured via health
      risk appraisal. Risks were noted as either high or low and related to
      exercise/eating habits, body weight, blood pressure, blood sugar levels,
      cholesterol levels, depression, stress, smoking/drinking habits, and seat belt
      use. Medical claims for 2001 were used to calculate medical expenditures per
      employee. RESULTS: Assuming a dollar 282 per employee program cost, Motorola
      employees would need to reduce their lifestyle-related health risks by 1.08% to
      1.42% per year to break even on health promotion programming, depending upon the
      discount rate. Higher or lower program investments would change the risk
      reduction percentages. CONCLUSION: Employers can use information from published
      studies, along with their own data, to estimate the amount of risk reduction
      required to break even on their health promotion programs.

PMID- 15011933
TI  - The database at age seventeen: vision, evolution, and potential.

PMID- 15011934
TI  - Review of the studies cited in the DataBase section of the American Journal of
      Health Promotion.
AB  - PURPOSE OF THE REVIEW: To analyze the characteristics of the articles reviewed in
      the DataBase section of the American Journal of Health Promotion and to summarize
      this review in tabular format. DATA SOURCES: All 350 entries in the American
      Journal of Health Promotion DataBase section beginning with issue 1:3 (Winter
      1987) through issue 17:3 (January/February 2003) were included in this review.
      STUDY INCLUSION AND EXCLUSION CRITERIA: Every study summarized in the DataBase
      section was included. Five duplicate sets of entries existed in the DataBase
      section. One entry from each set was excluded based upon author consensus. Thus,
      this review includes 345 unique entries. DATA EXTRACTION METHODS: All data
      reported in the DataBase section (e.g., sample sizes, measurement tools, study
      duration), as well as additional data derived directly from the studies (i.e.,
      cross-sectional versus longitudinal study design, unit of analysis, and study
      topic) were entered in SPSS 11.5 for PC (SPSS, Inc, Chicago, Illinois). DATA
      SYNTHESIS: Data were synthesized to identify the frequency of entry by research
      question, research design and internal validity rating, unit of analysis,
      measurement tool(s), and health topics addressed. MAJOR CONCLUSIONS: The majority
      of articles included in the DataBase received the highest research design rating,
      had robust sample sizes, and were of a meaningful duration. Additionally, a wide
      variety of topics were addressed. Overall, these strengths indicate that a solid
      foundation of research has been established on many of the most critical issues
      facing the health promotion field.

PMID- 15011935
TI  - Building program participation: strategies for recruitment and retention in
      worksite health promotion programs.
AB  - Building program participation is vital for all health promotion programs. There
      are a large variety of strategies that have been used to enhance recruitment and
      retention in worksite health promotion programs. Many of these strategies are
      examined and their significance in the design and operation of health promotion
      programs in worksite settings is reviewed.

PMID- 15011936
TI  - Guidelines for health promotion in worksite settings.

PMID- 15011937
TI  - HIV/AIDS among African-Americans: how far have we come in eradicating a known
      killer?

PMID- 15011938
TI  - Views of African-American nurses about tobacco cessation and prevention.
AB  - African-Americans experience a disproportionate share of tobacco-related diseases
      and death and have not received equal access to tobacco cessation and prevention
      services. The purpose of this study was to describe views of African-American
      nurses about tobacco control. This was a survey of a convenience sample of
      attendees of the 2002 annual meeting of the National Black Nurses Association.
      One hundred and sixty three (N=163) nurses participated in the survey. Eighty-one
      percent (81%) of these nurses reported that they should be involved in tobacco
      control efforts; 92% indicated nurses should help patients stop smoking; 63%
      encountered patients who smoked at least every week, but only 11% of these nurses
      actually provided counseling for smoking cessation. The majority (89%) of these
      respondents also noted that nurses needed additional training in tobacco control.
      African-American nurses can address the significant tobacco-induced health
      disparities experienced by African-Americans by helping to prevent tobacco use
      and helping patients stop smoking. The findings of this study support the
      critical need for nursing education in tobacco control.

PMID- 15011939
TI  - Knowledge, attitudes, perceptions and practices of African-American women toward
      menopausal health.
AB  - The purpose of this study was to describe and compare the knowledge, attitudes,
      perceptions and health practices related to menopausal health among African
      American women (N= 106) from diverse SES levels, between 40 to 65 years of age.
      The mean age was 49 years of age, 60.7% were college graduates, 45.8% were
      married, 85% employed full-time and 88% had medical insurance. Two-thirds rated
      their health as good, and half believed their health was better than other women.
      Most women (58%) use hormone replacement therapy (HRT) or would consider using
      HRT. In general women were knowledgeable about the process of menopause. Among
      this diverse group of women there were significant differences (p<.05) in use of
      HRT and health promotion behaviors. Most women (48.5%) sought information from
      printed materials. Women and their physicians should be encouraged to discuss
      menopausal health. Culturally appropriate materials should be provided in all
      women's health settings, through media and places where women gather including
      churches, beauty parlors, community centers.

PMID- 15011940
TI  - Quality of care in African-American communities and the nursing shortage.
AB  - The National Black Nurses Foundation commissioned a research project to determine
      the effect of the nursing shortage on African-American communities. The W.K.
      Kellogg Foundation funded the project as part of a multiphase project aimed at
      identifying issues related to the nursing shortage among ethnic people of color
      communities and developing policy recommendations around the supply of nurses to
      serve those communities. The study was conducted over a six-month period by the
      nursing research investigative team at Cedars-Sinai Medical Center and Burns and
      Allen Research Institute in Los Angeles, California. One hundred (N=100) nurse
      leaders from communities across the United States participated in the research.
      Each leader completed a questionnaire regarding the existence of the nursing
      shortage in their community and the effect of the shortage on access to services,
      clinical quality and the retention and recruitment of nurses. Leaders were
      queried on nurse vacancy and turnover within their communities, incidence of
      adverse events and the ability of institutions to meet the demands for nursing
      and health services in their communities. Forty-five percent of the organizations
      in the study were reported to be single facilities and 55% consisted of
      integrated health systems. Respondents identified five major issues resulting
      from nurse vacancies in their communities: closure of acute care beds or clinical
      services, delays in providing treatment to patients, inability to retain nurses
      due to increased workload and decreased nurse satisfaction, diminished capacity
      to address chronic health problems in their communities and increased incidence
      of adverse patient events. African-American nurse leaders reported higher rates
      of nurse vacancy and turnover; higher incidence of adverse events and greater
      difficulty providing access to health care than was reported in the literature.
      Nurse vacancy and turnover rates are higher than reported national averages. The
      study suggests the need for further research at the community level in addition
      to acute care settings to ameliorate the potential adverse effects of nursing
      work force shortages on the health of African-American communities. Further
      research examining the effectiveness of interventions at increasing the supply,
      improving the retention of nurses at all levels and the effect of increased
      supply and the utilization of nurses in African-American communities should be
      conducted. The study reported in this edition of the Journal of the National
      Black Nurses Association is the first in a series of reports on the nursing
      shortage and its effect on access to care, the recruitment and retention of
      ethnic nurses in the pipeline and leadership and policy strategies required to
      assure the availability of a qualified work force to meet current and future
      health care demand.

PMID- 15011941
TI  - Determinants of HIV and AIDS among young African-American men who have sex with
      men: a public health perspective.
AB  - This study was an examination of community, age, race and ethnicity. Individual
      behavior and health promotion was critically examined within the context of (HIV)
      Human Immunodeficiency Virus and AIDS (Acquired Immuno Deficiency Syndrome) among
      young African-American men who have sex with men. Examples from the literature
      provided empirical illustrations of how these concepts have been defined
      conceptually and measured with respect to HIV/AIDS; particularly among this
      population from a public health perspective. Additionally, a conceptual model
      depicting the interplay of these concepts was reviewed and is provided and
      discussed to shed further light on the conceptual link between these concepts and
      healthy behaviors among sexually active African-American young men who have sex
      with men. The concepts are discussed in an integrative format throughout the
      paper within the backdrop of the proposed model for understanding the wave of
      HIV/AIDS within this subculture from a public health nursing perspective.

PMID- 15011942
TI  - Complementary and alternative medicine instruction in nursing curricula.
AB  - With an ever-increasing number of consumers reportedly using non-conventional
      methods of disease management, nurses have now been recognized as key providers
      in education on complimentary and alternative medicine (CAM). The risk of herb
      drug interactions secondary to consumer use of alternative medicines further
      increases the need for nurses to assume the role of patient educators in the area
      of CAM. Many nurses, however, feel rather ill-prepared to properly care for
      patients using CAM due to inadequate instruction on the subject matter during
      their training. Many nursing educators have now moved to address such concerns by
      considering including education on CAM therapies in the nursing school
      curriculum. This study evaluated CAM education in US nursing schools to gain a
      perspective on how nursing students are currently being trained. A survey
      questioning CAM education was administered to 148 nursing schools and collected
      over a 3-month period. The results indicate that nearly half of the responding
      schools offered some form of education on CAM in their curriculum with electives
      being the primary form of instruction. Teaching methodologies on CAM instruction
      in the curriculum included group discussion on CAM topics, lectures, and review
      of case studies. The majority of faculty respondents in this study held Ph.D.
      degrees followed by instructors holding a MS, DNS, and/or MSN degree.

PMID- 15011944
TI  - Issues in revising research instruments for use with Southern populations.
AB  - Researchers are in the initial stages of developing instruments that give insight
      into culture. Through these efforts nurses are gaining a more complete picture of
      the client's perspective on health and response to illness. Little emphasis has
      been given in the literature to adapting instruments for use with English
      speaking American sub-cultures. In this manuscript, a process used to revise
      instruments to capture elements of beliefs about managing uncertainty during
      treatment for cancer by Southern White and African-American men and women is
      presented. Bridging the gap in cultural knowledge between the investigators and
      study population is explored. Issues of instrument reliability and construct
      validity are addressed.

PMID- 15011943
TI  - Partnering in the cultivation of the next generation of ethnic minority nurse
      scientists: responding to a compelling national agenda.
AB  - Health disparities continue to exist between communities of color and the poor
      and the health of the nation as a whole. Highly competent and culturally
      sensitive nurse researchers are needed to contribute to the elimination of
      disparities. There is however, an inadequate supply of nurse researchers of color
      and an insufficient number of students in the pipeline aspiring to careers as
      nurse researchers. The purpose of this article is to analyze a partnership model
      between nursing programs in a Historically Black Colleges/Universities (HBCU)
      with an evolving research presence and an Ivy League university with an research
      extensive environment. After four years of collaborating, minority undergraduate
      students have an increased interest in nursing research and the problems of
      health disparities, conduct original pilot studies, produce and deliver scholarly
      papers based on their pilots, publish in referred journals with their mentors,
      engage in networking with accomplished nurse researchers and leaders, and
      demonstrate increased enrollment and interest in graduate study. Faculties at
      both institutions exhibit enhanced competencies in the design and conduct of
      research related to eliminating disparities and in strengthening their respective
      research environments. The model demonstrates that the career trajectory of
      minority nursing students and the research capacity of faculty can be influenced
      through the deliberate application of elements of the model.

PMID- 15011945
TI  - Maternal and child health project in Nigeria.
AB  - Maternal deaths in developing countries are rooted in womens powerlessness and
      their unequal access to employment, finance, education, basic health care, and
      other resources. Nigeria is Africa's most populous country, and it is an oil
      producing country, but Nigeria has one of the worst maternal mortality rates in
      Africa. These deaths were linked to deficiencies in access to health care
      including poor quality of health services, socio-cultural factors, and access
      issues related to the poor status of women. To address these problems, a
      participatory approach was used to bring Christian women from various
      denominations in Eastern Nigeria together. With technical assistance from a
      research unit in a university in Eastern Nigeria, the women were able to
      implement a Safe Motherhood project starting from needs assessment to program
      evaluation. Lessons learned from this program approach are discussed.

PMID- 15011946
TI  - Controlling influenza by inhibiting the virus's neuraminidase.
AB  - Despite the fact that influenza is a disease which affects millions of people,
      sometimes with fatal consequences. there has not, until recently, been any drug
      effective against all strains. Vaccines may be relatively or totally ineffective,
      so drugs are needed. Random screening of many thousands of compounds by
      pharmaceutical companies has resulted in only two compounds, amantadine and
      rimantidine, which target the M2 ion channel on the virus. These drugs have major
      disadvantages. Knowledge of the crystal structure of influenza virus
      neuraminidase, on the other hand, has allowed the rational design of four "plug
      drugs" which bind to the active site of flu neuraminidase and stop replication of
      the virus. Two of these compounds. Relenza and Tamiflu, are now being used
      worldwide and, although effective when used properly, suffer from problems of
      delivery. They need to be given very soon after infection to be effective, they
      only inhibit the influenza virus and none of the other respiratory agents which
      cause flu-like symptoms, and they are very expensive.

PMID- 15011947
TI  - Structure-based approaches to the development of novel anti-malarials.
AB  - Malaria remains a major disease of mankind, and resistance to existing
      therapeutics is rapidly emerging. Limited financial investment to develop new
      therapeutics requires the careful selection of well-defined targets from the
      causative parasite, Plasmodium falciparum. In these circumstances, protein
      crystallography can provide valuable structural detail to facilitate both the
      selection of suitable targets and the development of compounds to provide novel
      drug candidates. This review summarises the current involvement of
      crystallographic studies in anti-malarial drug development programmes. Protein
      crystallography is increasingly central to the exploitation of a number of
      potential Plasmodial targets. including the aspartic acid proteases (plasmepsins)
      and cysteine proteases (falcipains) involved in haem degradation within the
      parasite food vacuole. Lead compounds are being identified from collections
      previously synthesised against homologous human enzymes. Plasmodium have an
      unusual dependence on the glycolytic pathway relative to their human hosts, and
      this is reflected in subtle structural differences identified in the crystal
      structures of a number of parasite glycolytic enzymes including aldolase and
      lactate dehydrogenase. Other enzymes from a range of biosynthetic pathways have
      also been targeted in crystallographic studies. These include dihydrofolate
      reductase, the target of existing anti-folate therapeutics, and enoyl reductase
      from the fatty acid biosynthesis pathway which is already the target of effective
      bacteriocides. Crystal structures of these drug-enzyme complexes not only allow
      visualisation and improvement of inhibitor-protein contacts, but in the former
      case have also been used to probe the molecular basis of emerging anti-malarial
      drug resistance. Crystallography is similarly proving valuable as a tool to
      facilitate the development of inhibitors of purine salvage, isoprenoid synthesis
      and utilisation, and protein processing mechanisms.

PMID- 15011948
TI  - Perspectives for drug intervention in amyloid diseases.
AB  - Amyloid fibres are stable, persistent and highly ordered aggregates of mis-folded
      protein that accumulate in tissues and are a prominent feature of the pathology
      of a wide range of human diseases. The presumed role of amyloid as a causative
      factor of tissue damage is based largely on 'guilt by association'. However,
      growing understanding of the nature of amyloid, its formation by a nucleated
      growth mechanism from destabilised and partially unfolded precursors and its
      persistence at sites of deposition has provided the foundation for the
      development of approaches to inhibit amyloid formation and enable its clearance.
      In spite of intensive study, our understanding of the detailed structure of
      amyloid itself remains incomplete although 'crossed-beta' structure is clearly a
      common constituent. On the other hand detailed structural understanding of
      transthyretin, beta-secretase and serum amyloid P component is contributing to
      the design of small molecule compounds to target amyloid. Thyroxin mimetics
      stabilise the native tetrameric protein structure, beta-secretase inhibitors will
      limit the production of the amyloidogenic Abeta1-42 polypeptide. Compounds that
      crosslink serum amyloid P component rapidly deplete the plasma and amyloid-bound
      pool of this protein. The efficacy of these compounds as drugs to prevent
      formation or enable removal of amyloid will provide a stringent test of the
      'amyloid hypothesis' of disease.

PMID- 15011949
TI  - Towards understanding the structure-function relationship of human amyloid
      disease.
AB  - Immunoglobulin light chain (LC) proteins exhibit the greatest sequence
      variability of all proteins associated with amyloid disease. The hallmark event
      in amyloidogenesis is a change in the secondary and/or tertiary structure of a
      normal, soluble protein, that fosters self-aggregation and fibril formation. The
      structural heterogeneity of light chain proteins has hampered understanding of
      the precise mechanisms involved in fibril formation. The development of effective
      therapeutics will be benefited by a fundamental understanding of mechanisms and
      structural prerequisites which govern amyloidogenesis. This review focuses on
      light chain (AL) amyloidosis resulting from the aggregation of kappa and lambda
      LCs. Specifically the thermodynamic and structural data of several WT and mutant
      amyloidogenic LCs have been carefully examined. Moreover, we discuss the
      importance of hydrophobic and ionic interactions on amyloidosis by comparing
      several available three-dimensional structures of amyloidogenic and highly
      homologous non-amyloidogenic proteins that can be destabilized to become
      amyloidogenic by site specific mutations.

PMID- 15011950
TI  - Prospects for atomic resolution and neutron crystallography in drug design.
AB  - The number of protein crystal structures being refined to atomic resolution is
      increasing each year as well as the size of proteins being studied. There are
      currently 346 structures in the protein data bank which have been refined to or
      beyond atomic resolution. The benefits of atomic resolution X-ray data are
      discussed along with a number of structural examples of biomedically relevant
      proteins. The complementary role of neutron diffraction will also be discussed.

PMID- 15011951
TI  - The tumour specific pro-apoptotic factor apoptin (Vp3) from chicken anaemia
      virus.
AB  - Cancer is a growing problem for human health world-wide. Dramatic breakthroughs
      have increased our understanding of the molecular mechanisms involved in the
      process of tumorigenesis, allowing us to develop more refined anti-cancer
      treatments, expanding the repertoire of available anti-cancer drugs, and
      increasing the efficiency of their delivery to malignant cells. Nevertheless,
      even with improved understanding of the complex origins of cancer cells, there is
      a dearth of efficient and above all specific anti-cancer treatments. Apoptin
      (viral protein 3 - VP3), a gene product derived from the Chicken Anaemia Virus
      (CAV) represents a novel anti-cancer tool. It appears to have innate tumour
      specific p53-independent, Bcl-2-enhanced pro-apoptotic activity, and hence may be
      of great utility in the endeavour to achieve specific and efficient elimination
      of cancer cells, particularly in cases of drug resistance through Bcl-2
      overexpression/loss of p53 function etc. This review will examine the unique
      aspects of apoptin's properties, and in particular, its ability to localise
      specifically in the nucleus of transformed but not normal cells. The latter
      ability, importantly, appears to be integrally related to its tumour-specific pro
      apoptotic action.

PMID- 15011952
TI  - DNA polymerases as targets of anticancer nucleosides.
AB  - DNA polymerase is one of the most important target molecules of antitumor agents,
      especially for antimetabolite nucleosides that include 1-beta-D
      arabinofuranosylcytosine (araC) and 2'-deoxy-2',2'-difluorocytidine
      (gemcitabine). There are several subtypes of mammalian DNA polymerases and their
      localization and function have been clarified. DNA polymerase alpha, delta and
      epsilon have been implicated to be responsible for DNA replication, whereas DNA
      polymerase beta, delta and epsilon have been suggested to work in DNA repair. DNA
      polymerase gamma is encoded in the nucleus but localizes in the mitochondria, and
      is responsible for the mitochondrial DNA replication. Recently, several antiviral
      nucleoside analogs were reported to inhibit DNA polymerase gamma after
      intracellular phosphorylation and cause severe chronic toxicity. 1-(2-Deoxy-2
      fluoro-4-thio-beta-D-arabinofuranosyl)cytosine (4'-thio-FAC), an antimetabolite
      similar to araC and gemcitabine, is recently shown by us to be a very promising
      agent because of its potent antitumor activity by oral administration to mice. We
      tested for the inhibitory activities of the triphosphates of 4'-thio-FAC and
      gemcitabine against DNA polymerase alpha, beta and gamma. The triphosphates of 4'
      thio-FAC (4'-thio-FACTP) exhibited the potent inhibitory action against DNA
      polymerase alpha, whereas it showed moderate inhibition against DNA polymerase
      beta and little inhibition against DNA polymerase gamma. The triphosphate of
      gemcitabine (dFdCTP) did not show potent inhibition against these three DNA
      polymerases. Thus, the effect on ribonucleotide reductase was suggested to be
      more responsible for the antitumor action of gemcitabine. The differences in the
      mechanisms of action against DNA polymerases between these drugs and other
      nucleosides were also discussed.

PMID- 15011953
TI  - Neurokinin peptides and neurokinin receptors as potential therapeutic
      intervention targets of basal ganglia in the prevention and treatment of
      Parkinson's disease.
AB  - Parkinson's disease (PD) is a serious motor disorder and it is the second most
      common brain degenerative disease in human. PD is known to be caused by
      degeneration of dopamine neurons in the substantia nigra but the cause of cell
      death is largely unknown. Mammalian neurokinins [NKs] are a group of
      neuropeptides that include substance P (SP; neurokinin-1, NK-1), substance K (SK;
      NK-2; neurokinin A), and neuromedin K (NK; NK-3; neurokinin B). Their biological
      effects as neurotransmitters, neuromodulators, or neurotrophic-like factors are
      mediated by three distinct neurokinin receptors, namely SP receptor (SPR: NK-1
      receptor, NK-1R), SKR (NK-2R), and NKR (NK-3R). Several lines of evidence have
      indicated that neurokinins are implicated in the pathogenesis of PD. First,
      decreases of SP level and SP-immunoreactivity have been found in nigral and
      striatal tissues of animals with PD and postmortem PD patients. Second, NKs exert
      neuroprotective effects on neurons. In addition, NK receptors, namely NK-1 and NK
      3 receptors, are abundantly localized in dopaminergic and cholinergic neurons of
      the basal ganglia, indicating that these neurons are under the physiological
      regulation of NKs. Moreover, modulation in motor activity occurred in 1-methyl-4
      phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, PD animal model, after
      systemic administration of NK receptor agonists. NKs and NK receptors, therefore,
      might be important molecules that are associated with functions and survival of
      neurons in the basal ganglia, in particular the dopamine neurons. Further studies
      should be devoted to elucidate the functional roles of NK systems in (a) the
      neuropathogenesis and neuroprotection during the course of PD, (b) the efficacy
      of NK receptor drugs towards PD, and (c) potential therapeutic intervention that
      targets at the prevention or treatment of PD.

PMID- 15011954
TI  - The histopathology of spondyloarthropathy.
AB  - An extensive histopathological analysis of diseased tissues and organs is a
      crucial step in our understanding of how specific molecular and cellular events
      described in vitro or in animal models might by relevant to the clinical
      presentation of a specific disease in humans. Although in spondyloarthropathy
      (SpA) such an approach is hampered by the fact that some target tissues are not
      readily accessible for biopsy sampling (the sacroiliac joint, the axial skeleton,
      the enthesis, and the eye), numerous histological studies of the synovial
      membrane of the peripheral joint, the gut, and the skin have contributed to new
      insights into the cellular and molecular base of SpA. Firstly, the peripheral
      synovitis is characterized by an extensive hypervascularity and the presence of
      specific macrophage and T cell subsets. Secondly, the fact that the same subsets
      of macrophages and T cells can be identified in the gut mucosa, even before
      histological inflammation is present, point to a role for early immune
      alterations of the gut in the development of the disease. Thirdly, macrophages
      and macrophage-derived cytokines such as the pro-inflammatory TNFalpha and the
      anti-inflammatory IL-10 appear to be crucial mediators of the tissue
      inflammation. Therefore, neovascularization, recirculation of inflammatory cells
      between gut and synovium, and macrophage-derived cytokines are all potential
      targets for immunotherapy. As a proof of concept, anti-TNFalpha treatment has
      been demonstrated to have an impressive clinical effect as well as a major impact
      on the histological tissue inflammation. Further research should benefit from the
      combination of classical histopathology with newer molecular techniques
      (genomics, proteomics) to unravel the molecular and cellular base of the
      different disease presentations and should aim to translate these basic findings
      into clinical applications such as histopathological differential diagnosis and
      follow-up of targeted therapies.

PMID- 15011955
TI  - Genetic susceptibility to ankylosing spondylitis.
AB  - Ankylosing spondylitis is a highly heritable, common rheumatic condition,
      primarily affecting the axial skeleton. The association with HLA-B27 has been
      demonstrated worldwide, and evidence for a role of HLA-B27 in disease comes from
      linkage and association studies in humans, and transgenic animal models. However,
      twin studies indicate that HLA-B27 contributes only 16% of the total genetic risk
      for disease. Furthermore, there is compelling evidence that non-B27 genes, both
      within and outwith the major histocompatability complex, are involved in disease
      aetiology. In this post-genomic era we have the tools to help elicit the genetic
      basis of disease. This review describes methods for genetic investigation of
      ankylosing spondylitis, and summarises the status of current research in this
      exciting area.

PMID- 15011956
TI  - The immunobiology of HLA-B27: variations on a theme.
AB  - In the thirty years since the initial discovery of a striking association between
      HLA-B27 and susceptibility to ankylosing spondylitis, numerous hypotheses have
      been proposed to explain the role of this molecule in the pathogenesis of
      spondyloarthropathies. In the past few years the focus has shifted from one
      centered largely on the physiological peptide-presenting function of HLA-B27, to
      include ideas based on aberrant aspects of its immunobiology. This has been
      driven in part by results from animal models of HLA-B27-associated disease where
      CD8+ T cells do not appear to be playing a major role in pathogenesis. In
      addition, the HLA-B27 heavy chain is unusual in that it has a tendency to misfold
      in the endoplasmic reticulum and to form disulfide linked heavy chain dimers that
      can be expressed on the cell surface. Although the data suggest misfolding and
      cell surface dimerization are fundamentally different processes, it appears that
      certain structural features of the heavy chain are common to both. Potential
      links between these aberrant characteristics of HLA-B27 and inflammatory disease
      are discussed in this and other reviews in this issue. Herein we consider how
      protein misfolding affects cell function through the activation of an 'unfolded
      protein response' and/or an 'ER overload response', and the potential impact on
      the immune system. Despite significant advances in the treatment of
      spondyloarthropathies over the past few years, a better understanding of
      pathogenesis is likely to improve outcome by identifying ways to provide greater
      and more sustained clinical responses.

PMID- 15011957
TI  - Animal models of HLA-B27-associated diseases.
AB  - The HLA-B27 molecule is strongly associated with the spondyloarthropathies (SpA),
      a group of inflammatory conditions affecting the skeleton, the skin and several
      mucosae. The mechanism of this association remains unknown, largely because the
      HLA-B27 molecule displays normal function. A disease that closely mimicks SpA
      arises spontaneously in HLA-B27 transgenic rats. This disease is dependent on the
      presence of a normal bacterial flora and implicates the immune system. The
      presence of both CD4+ T cells and antigen presenting cells (APCs) expressing high
      levels of HLA-B27, seems of critical importance in its pathogenesis, whereas CD8+
      T cells are dispensable. The T cell stimulatory function of APCs is disturbed by
      the HLA-B27 molecule. This disease could result from a failure of tolerance,
      related in part to high level of B27 expression in professional APCs and to the
      immune response to gut bacteria. In contrast, HLA-B27 transgenic mice have
      usually remained healthy. However, two types of inflammatory conditions affecting
      the skeleton, which arise in mice of susceptible background after exposure to a
      conventional bacterial flora, are increased by an HLA-B27 transgene. The first is
      ANKENT, a spontaneous ankylosing enthesitis that affects ankle and/or tarsal
      joints of ageing mice; the second is a spontaneous arthritis of hindpaws
      developing in mice lacking endogenous mbeta2m. As in rats, the absence of CD8+ T
      cells in the latter model, argues against the "arthritogenic peptide" hypothesis.
      In these mbeta2m0 mice, B27 free heavy chain could be implicated in the
      pathogenesis of arthritis by presenting extracellular peptides to CD4+ T cells.

PMID- 15011958
TI  - Non-antigen presenting effects of HLA-B27.
AB  - Spondyloarthropathies (SpA) are a group of chronic rheumatic diseases, which show
      a strong asoociation with human leukocyte antigen (HLA)-B27. Although the
      association between HLA-B27 and the susceptibility to SpA was discovered thirty
      years ago, the exact mechanism by which HLA-B27 predisposes to disease
      development remains unclear. The classical role of MHC class I molecules is to
      present peptides for CD8+ T cells. Therefore, it has been proposed that the
      antigen presenting function of HLA-B27 is somehow altered in the patients
      developing SpA. However, despite extensive research, the attempts to create a
      comprehensive theory that would explain the role of HLA-B27 as an antigen
      presenting molecule in the development of SpA have been unsuccessful. Reactive
      arthritis (ReA) belongs to the group of SpA. It is a joint inflammation
      developing after certain bacterial infections e.g. Salmonella, Yersinia, and
      Chlamydia. Several unrelated observations indicate that HLA-B27 modulates the
      interaction between ReA-triggering bacteria and host cell. These findings suggest
      that HLA-B27 may possess functions, which are unrelated to antigen presentation.
      In this paper, we summarize these findings and discuss their potential impact in
      the development of SpA.

PMID- 15011959
TI  - The recognition of abnormal forms of HLA-B27 by CD4+ T cells.
AB  - The MHC class I molecule, HLA-B27 can be expressed as a number of non
      conventional forms, in addition to conventional HLA-B27 heterodimers presenting
      peptide. This has lead to new avenues of research to explain the association of
      this molecule with SpA. Surprisingly, HLA-B27 transgenic animal models implicated
      CD4+ T cells, which conventionally interact with MHC class II molecules, not MHC
      class I molecules, in the pathogenesis of SpA. One hypothesis to explain these
      finding is that non-conventional forms of HLA-B27, specifically HLA-B27
      homodimers, might mimic MHC class II molecules and be recognised by CD4+ T cells.
      We investigated whether CD4+ T cells from AS patients can interact with HLA-B27,
      discovering that indeed CD4+ T cells can interact with various forms of HLA-B27.
      Here we discuss how such interactions between HLA-B27 and CD4+ T cells could
      occur in vivo and potential contributions of such interactions to the
      pathogenesis of SpA.

PMID- 15011961
TI  - Epidemiological characteristics of an outbreak of severe acute respiratory
      syndrome in Dongcheng District of Beijing from March to May 2003.
AB  - OBJECTIVE: To describe epidemiologic features of an outbreak of severe acute
      respiratory syndrome (SARS) in Dongcheng District, Beijing occurred in a period
      between March and May 2003. METHODS: Data of SARS cases notified from Dongcheng
      District Center for Disease Control and Prevention(CDC)and supplemented by other
      channels were collected. Clinicians and officials of local hospitals were
      interviewed in groups and medical records of fatal cases of SARS were reviewed to
      verify the diagnosis. Stored serum specimens of the patients were detected for
      IgG antibody against SARS Co-V by enzyme-linked immunosorbent assay (ELISA). All
      the data were input into dataset files by Microsoft Excel-2000 software and
      analyzed with SPSS version 10.0 software. RESULTS: Outbreak of SARS in Dongcheng
      District started on March 14, 2003 with a peak in mid- and late April, and
      dropped in early May. A total of 572 reported cases were collected during this
      period in Dongcheng District, Beijing, and 99 of them were excluded from SARS,
      because of diagnosis of common cold, regular pneumonia, measles and rubella, etc.
      Actually, 473 SARS cases, which included 390 (82.5%) probable cases and 83
      (17.5%) suspect cases, were analyzed. About 90% of the probable cases were
      positive for IgG antibody. Attack rate of SARS in permanent residents of
      Dongcheng District was 28.3 per 100 000. Forty-one of them died, with a case
      fatality rate of 8.7%. Persons were all susceptible to infection of SARS Co-V,
      with the highest proportion at ages of 20-50 years, which accounted for 68.7% of
      the total cases. Average age of the patients at their onset was 40.7 years. No
      gender difference in SARS cases was found. Number of SARS cases in health-care
      workers (HCWs) accounted for 18.0% and that in retired workers accounted for
      15.4% of the total cases. Cases occurred in all 10 sub-districts of Dongcheng,
      with the highest in Beixinqiao and Andingmen Sub-districts. Totally, 230 of the
      572 notified cases (40.2%) were hospitalized at local hospitals under the
      jurisdiction of Dongcheng District. Eighteen of 85 cases of SARS occurred in HCWs
      of local hospitals, accounting for 4.5% of the total number of HCWs working at
      wards caring for SARS patients or fever clinics. There were 34.7% of SARS cases
      without any histories of contact before the onset of the disease. Familial
      aggregation phenomena were observed in 41.8% of the cases and 18.1% of
      households. And 7.4% (attack rate) of those exposed to SARS cases suffered from
      the illness during the periods of quarantine. CONCLUSIONS: SARS appeared to be
      infectious in origin and caused outbreak in Dongcheng District, Beijing
      introduced by an imported case traveling from Hong Kong in a period between March
      and May 2003. People are all susceptible to infection of SARS Co-V, which mainly
      threatens the young adults and the middle-aged, as well as HCWs and the retired
      workers. The main mode of transmission is direct exposure to SARS patients in a
      near distance at hospitals or families via droplets spread. Prevention and
      control of SARS should be focused on early isolation of patients and quarantine
      for close contacts. Current available measures to prevent and control SARS are
      proved to be effective.

PMID- 15011960
TI  - Recognition of classical and heavy chain forms of HLA-B27 by leukocyte receptors.
AB  - As an MHC class I protein, the disease association of HLA-B27 with inflammatory
      arthritis has been widely assumed to imply a role for the T cell antigen receptor
      (TCR) in disease. However, in addition to their classical antigen-presenting
      role, HLA class I proteins are recognised by members of the killer immunoglobulin
      receptor (KIR) and leukocyte immunoglobulin-like receptor (LILR/ILT/LIR)
      families. Unusual properties of HLA-B27 include an ability of free heavy chains
      (FHC) to reach the cell surface in the absence of beta2m and to maintain their
      peptide-binding groove in vitro. This review describes immunomodulatory receptors
      that recognise HLA class I, and the recognition of HLA-B27 in both the classical
      beta2m-associated and beta2m-independent forms by members of the KIR and LILR
      families. Alternative recognition of different forms of HLA-B27 by leukocyte
      receptors could influence the function of cells from both innate and adaptive
      immune systems, and may indicate a role for various leukocyte populations in HLA
      B27-associated inflammatory disease.

PMID- 15011962
TI  - Influences of quinclorac on culturable microorganisms and soil respiration in
      flooded paddy soil.
AB  - OBJECTIVE: To investigate the potential effects of herbicide quinclorac (3,7
      dichloro-8-quinoline-carboxylic) on the culturable microorganisms in flooded
      paddy soil. METHODS: Total soil aerobic bacteria, actinomycetes and fungi were
      counted by a 10-fold serial dilution plate technique. Numbers of anaerobic
      fermentative bacteria (AFB), denitrifying bacteria (DNB) and hydrogen-producing
      acetogenic bacteria (HPAB) were numerated by three-tube anaerobic most-probable
      number (MPN) methods with anaerobic liquid enrichment media. The number of
      methanogenic bacteria (MB) and nitrogen-fixing bacteria (NFB) was determined by
      the rolling tube method in triplicate. Soil respiration was monitored by a 102G
      type gas chromatography with a stainless steel column filled with GDX-104 and a
      thermal conductivity detector. RESULTS: Quinclorac concentration was an important
      factor affecting the populations of various culturable microorganisms. There were
      some significant differences in the aerobic heterotrophic bacteria. AFB and DNB
      between soils were supplemented with quinclorac and non-quinclorac at the early
      stage of incubation, but none of them was persistent. The number of fungi and DNB
      was increased in soil samples treated by lower than 1.33 micro x g(-1) dried
      soil, while the CFU of fungi and HPAB was inhibited in soil samples treated by
      higher than 1.33 microg x g(-1) dried soil. The population of actinomycete
      declined in negative proportion to the concentrations of quinclorac applied after
      4 days. However, application of quinclorac greatly stimulated the growth of AFB
      and NFB. MB was more sensitive to quinclorac than the others, and the three soil
      samples with concentrations higher than 1 microg x g(-1) dried soil declined
      significantly to less than 40% of that in the control, but the number of samples
      with lower concentrations of quinclorac was nearly equal to that in the control
      at the end of experiments. CONCLUSION: Quinclorac is safe to the soil
      microorganisms when applied at normal concentrations (0.67 microg x g(-1)).

PMID- 15011963
TI  - Effects of aging and advanced glycation on gene expression in cerebrum and spleen
      of mice.
AB  - OBJECTIVE: To analyze the effects of aging or advanced glycation on gene
      expression in the cerebrum and spleen of female C57BL/6J mice. METHODS: The gene
      expression profile was determined by using cDNA expression arrays containing 588
      cDNA. RESULTS: Aging and advanced glycation resulted in differential gene
      expression patterns of cerebrum and spleen compared with young mice. Among the 80
      genes detected in cerebrum, 43 exhibited a change in mRNA ratios with aging or
      treatment. Thirty-four changes (79%) were common in aged and D-galactose treated
      mice, whereas the cerebrum from aged and AGE-lysine treated mice showed common
      changes in expression of 38 genes (88%). Of the 86 genes detected in spleen, 29
      (34%) displayed an age-related decrease in expression, whereas 3 (3%) displayed
      an increase in expression levels with aging. Eighteen genes from the detectable
      genes exhibited expression changes in both cerebrum and spleen of mice.
      CONCLUSIONS: The gene expression profiles of D-galactose and AGE-lysine treated
      mice resemble those of aged mice. Use of cDNA hybridization arrays may provide a
      promising tool to explore the mechanism of aging at a molecular level.

PMID- 15011964
TI  - Diet rich in saturated fat decreases the ratio of thromboxane/prostacyclin in
      healthy men.
AB  - OBJECTIVE: To investigate the effect of dietary saturated fat (SFA) from animal
      sources on the urine excretion 11-dehydro thromboxane B2 (TXB2) and 6-keto
      prostaglandin F 1alpha (PGF 1alpha) in 27 healthy free-living male subjects aged
      30 to 55 years. METHODS: It was a randomized crossover design. Each volunteer was
      randomly assigned to one of the two diets (high fat and low fat) for a period of
      4 weeks, after which each subject resumed his usual diet for 2 weeks as a 'wash
      out period', before being assigned to the other diet for an additional 4 weeks.
      RESULTS: Serum proportion of 20:4n-6 was 5% lower in the high fat (6.2% of total
      fatty acid) than in the low fat diet (6.5% of total fatty acid), which was
      associated with a significantly decreased ratio of the urinary excretion 11
      dehydro TXB2 to 6-keto PGF 1alpha (P < 0.05). However, there was no significant
      fall in the absolute urinary excretion of 11-dehydro TXB2. CONCLUSIONS: Diet rich
      in SFA from animal sources may influence TXA2 formation via effect on tissue
      proportion of 20:4n-6.

PMID- 15011965
TI  - Effect of antibiotic treatment on toxin production by Alexandrium tamarense.
AB  - OBJECTIVE: Impact of the presence of bacteria associated with a marine
      dinoflagellate, Alexandrium tamarense CI01, on the growth and toxin production of
      the algae in batch culture was investigated. METHODS: Pronounced changes in the
      activities of the algal culture were observed when the culture was treated with
      different doses of a mixture of penicillin and streptomycin. RESULTS: In the
      presence of antibiotics at the initial concentration of 100 u/mL in culture
      medium, both algal growth and toxin yield increased markedly. When the
      concentration of antibiotics was increased to 500 u/mL, the microalgal growth was
      inhibited, but resumed in a few days to eventually reach the same level of growth
      and toxin production as at the lower dose of the antibiotics. When the
      antibiotics were present at a concentration of 1 000 u/mL, the algal growth was
      inhibited permanently. CONCLUSIONS: The results indicate that antibiotics can
      enhance algal growth and toxin production not only through their inhibition of
      the growth and hence competition for nutrients, but also through their effects on
      the physiology of the algae.

PMID- 15011966
TI  - Effects of red palm oil on serum lipids and plasma carotenoids level in Chinese
      male adults.
AB  - OBJECTIVE: Effects of red palm oil on major plasma carotenoids, tocopherol,
      retinol and serum lipids were evaluated when used in Chinese diet. METHODS: Red
      palm oil group (RPO) composed of 20 male subjects(aged 18-32) and soybean oil
      group (SBO) composed of 22 male subjects (aged 18-32). Dietary fat provided about
      28% of total calories, and the test oil accounted for about 60% of total dietary
      fat. In the 3 weeks of pretest period, diets were prepared with soybean oil, and
      then in the next 6 weeks subjects in each group consumed the diet prepared by
      test oil. RESULTS: Plasma alpha-carotene, beta-carotene and lycopene
      concentration of RPO group significantly increased at the time of interim (21
      days) and of the end (42 days) (P < 0.05), and alpha-tocopherol concentration
      significantly increased at the time of the end (42 days) in this study. Though
      Chinese plasma retinol level was relatively low when compared with that of
      Westerners, red palm oil diet showed no significant effect on adult Chinese
      plasma retinol level. Serum concentration of total cholesterol, triglyceride,
      high density lipoprotein cholesterol, apolipoprotein AI and apolipoprotein B of
      all subjects showed no significant changes in RPO group during the study.
      CONCLUSIONS: The data in our study suggest that red palm oil is a good source of
      carotenoids and vitamin E when used in Chinese diet preparation, and it can
      significantly increase plasma concentration of alpha-carotene, beta-carotene,
      lycopene and alpha-tocopherol.

PMID- 15011967
TI  - Bladder cancer and arsenic exposure: differences in the two populations enrolled
      in a study in southwest Taiwan.
AB  - OBJECTIVE: Analyses of bladder cancer mortality in the Black Foot Disease (BFD)
      endemic area of southwest Taiwan conducted by Morales et al. showed a
      discontinuity in risk at 400 microg/L arsenic in the drinking water in a
      stratified analysis and no discontinuity in a continuous analysis. As the
      continuous analysis presentation had been used by both the NRC and the EPA to
      assess the carcinogenic risk from arsenic ingestion, an explanation of the
      discontinuity was sought. METHODS: Review of 40 years of published health studies
      of the BFD-endemic area of SW Taiwan showed that earlier publications had limited
      their cancer associations with arsenic levels in artesian well waters and that
      the reports of Morales et al., NRC, and EPA failed to do so. Underlying data for
      the Morales et al. study were obtained from the appendix to the NRC report.
      Bladder cancer mortality rates were calculated from case counts and person-years
      of observation for each study village. Villages were categorized by water source
      according to the descriptions from the underlying study. Graphic and regression
      analyses were conducted of the bladder cancer mortality rates using exposure as a
      continuous variable and simultaneously stratifying by water source. RESULTS: The
      median village well arsenic levels ranged from 350 to 934 microg/L for villages
      solely dependent on artesian well water and from 10 to 717 microg/L for villages
      not solely dependent on artesian well water. Bladder cancer mortality rates were
      found to be dependent upon the arsenic level only for those villages that were
      solely dependent on artesian well water for their water source. Bladder cancer
      mortality rates were found to be independent of arsenic level for villages with
      non-artesian well water sources. CONCLUSIONS: The data indicate that arsenic
      exposure levels do not explain the bladder cancer mortality risk in SW Taiwan
      among villages not dependent upon artesian well water. The association for
      villages dependent upon artesian well water may be explained either by arsenic
      acting as a high-dose carcinogen or in artesian well water as a co-carcinogen
      with some other aspect of artesian well water (possibly humic acid). Arsenic
      exposure level alone appears to be an insufficient exposure measure to describe
      the risk of bladder cancer mortality in the BFD-endemic area. Risk analyses that
      fail to take water source into account are likely to misrepresent the risk
      characterization, particularly at low arsenic levels.

PMID- 15011968
TI  - Exacerbation of soft tissue lesions in lead exposed virus infected mice.
AB  - OBJECTIVE: To investigate the effect of Lead (Pb) acetate exposure on Semliki
      forest virus (SFV) pathogenesis in mice. METHODS: Different doses (62.5, 125, 250
      and 500 mg/Kg body weight) of Pb dissolved in normal saline were given to mice by
      oral intubation in a sub-acute (28 days) and sub-chronic (90 days) regimen
      followed by SFV infection. Morbidity, mortality, clinical symptoms, mean survival
      time (MST), changes in body and organ weight, accumulation of lead in soft
      tissues, virus titre in brain and histopathological alterations were compared
      between lead exposed and infected groups. RESULTS: Early appearance of virus
      symptoms, increased mortality, decreased MST, enhanced SFV titre and greater
      tissue damage were observed in lead exposed-SFV-infected mice. CONCLUSION: Pre
      exposure to lead increases the susceptibility of mice towards SFV infection.
      Further studies are suggested in view of the persistence of lead in the
      environment and the possibility of infection by microbial pathogens.

PMID- 15011969
TI  - Forecasting loss of ecosystem service value using a BP network: a case study of
      the impact of the South-to-north Water Transfer Project on the ecological
      environmental in Xiangfan, Hubei Province, China.
AB  - OBJECTIVE: To recognize and assess the impact of the South-to-north Water
      Transfer Project (SNWTP) on the ecological environment of Xiangfan, Hubei
      Province, situated in the water-out area, and develop sound scientific
      countermeasures. METHODS: A three-layer BP network was built to simulate topology
      and process of the eco-economy system of Xiangfan. Historical data of ecological
      environmental factors and socio-economic factors as inputs, and corresponding
      historical data of ecosystem service value (ESV) and GDP as target outputs, were
      presented to train and test the network. When predicted input data after 2001
      were presented to trained network as generalization sets, ESVs and GDPs of 2002,
      2003, 2004... till 2050 were simulated as output in succession. RESULTS: Up to
      2050, the area would have suffered an accumulative total ESV loss of RMB104.9
      billion, which accounted for 37.36% of the present ESV. The coinstantaneous GDP
      would change asynchronously with ESV, it would go through an up-to-down process
      and finally lose RMB89.3 billion, which accounted for 18.71% of 2001.
      CONCLUSIONS: The simulation indicates that ESV loss means damage to the
      capability of socio-economic sustainable development, and suggests that
      artificial neural networks (ANNs) provide a feasible and effective method and
      have an important potential in ESV modeling.

PMID- 15011970
TI  - Risk factors of learning disabilities in Chinese children in Wuhan.
AB  - OBJECTIVE: To investigate prevalence rate of learning disabilities (LD) in
      Chinese children, and to explore related risk factors, and to provide theoretical
      basis for preventing such disabilities. METHODS: One thousand and one hundred
      fifty one children were randomly selected in primary schools. According to
      criteria set by ICD-10, 118 children diagnosed as LD were classified into the
      study group. Four hundred and ninety one children were classified into the normal
      control group. Five hundred and forty two children were classified into the
      excellent control group. The study instruments included PRS (The pupil rating
      scale revised screening for learning disabilities), Conners' children behavior
      check-list taken by parents and YG-WR character check-list. RESULTS: The
      prevalence rate of LD in Chinese children was 10.3%. Significant differences were
      observed between LD and normally learning children, and between the LD group and
      the excellent group, in terms of scores of Conners' behavior check-list (P <
      0.05). The study further showed that individual differences in character between
      the LD group and the control groups still existed even after controlling
      individual differences in age, IQ, and gender. Some possible causal explanations
      contributing to LD were improper teaching by parents, low educational level of
      the parents, and children's characteristics and social relationships. CONCLUSION:
      These data underscore the fact that LD is a serious national public health
      problem in China. LD is resulted from a number of factors. Good studying and
      living environments should be created for LD children.

PMID- 15011971
TI  - Microbial degradation of aniline by bacterial consortium.
AB  - OBJECTIVE: To investigate the characteristics of microbial degradation of aniline
      by a stable bacterial consortium. METHODS: The bacterial consortium was isolated
      from activated sludge treating chemical wastewater using aniline as the sole
      source of carbon and nitrogen by enrichment and isolation technique. The biomass
      was measured as optical density (OD) at 510 nm using a spectrophotometer. Aniline
      concentrations were determined by spectrophotometer. The intermediates of aniline
      degradation were identified by GC/MS method. RESULTS: The bacterial consortium
      could grow at a range of aniline concentrations between 50 and 500 mg/L. The
      optimal pH and temperature for aniline degradation were determined to be 7.0 and
      30, respectively. The presence of NH4NO3 as an additional nitrogen source (100
      500 mg/L) had no adverse effect on bacterial growth and aniline degradation. The
      presence of heavy metal ions, such as Co2+, Zn2+, Ni2+, Mn2+ and Cu2+ had an
      inhibitory effect on aniline degradation. CONCLUSIONS: The isolated bacterial
      consortium can degrade aniline up to 500 mg/L effectively and tolerate some heavy
      metal ions that commonly exist in chemical wastewater. It has a potential to be
      applied in the practical treatment of aniline-containing wastewater.

PMID- 15011972
TI  - Enforcement of CLIA and billing regulations.

PMID- 15011973
TI  - Preparing a digital video examination of urinary sediments.

PMID- 15011974
TI  - Human papillomavirus detection: verification with cervical cytology.
AB  - OBJECTIVE: Thirteen specific types of human papillomavirus (HPV), classified as
      high-risk for the development of cervical cancer, have been reported in 99.7% of
      all cervical cancers. For this reason, and because of the reported lack of
      sensitivity of the Papanicolaou (Pap) smear for detecting HPV, some experts
      believe that the use of papillomavirus DNA testing may replace cytology for
      routine gynecological screening. Our goal was to validate a commercial assay, the
      Digene Hybrid Capture-2 for the detection of human papillomavirus by comparing
      the results to cytological detection of cervical abnormalities. DESIGN: Cytology
      results of concurrent liquid-based Papanicolaou smears were compared to the
      Hybrid Capture-2 results. Correlation was assessed and discordant cytology
      results were reviewed. SETTING: Louisiana State University Health Sciences Center
      at Shreveport, Department of Pathology, HPV Diagnostic Laboratory. PATIENTS: All
      liquid cytology specimens submitted for HPV testing between November 1, 2000 and
      April 1, 2001. RESULTS: Of the 291 cases tested by Hybrid Capture-2, 12% and 28%
      were positive with the low-risk and high-risk probes, respectively, and 265 had
      concurrent cytology results. Fourteen specimens testing positive only with the
      low-risk probe were not included in this comparison. Thus, the results for 251 of
      the 291 (86%) specimens tested for human papillomavirus DNA were compared to the
      original cytology report. Overall concordance between Hybrid Capture-2 and the
      original smear cytology result was 78%. Slide review reduced the number of
      discordant specimens from 22% to 12%. CONCLUSION: Based upon these data, we find
      the HPV assay to be useful as a routine screen for Human papillomavirus.

PMID- 15011975
TI  - Using cooperative learning in clinical laboratory science education.
AB  - OBJECTIVE: To compare performance of students instructed by cooperative learning
      (CL) activities with those taught by lecture. A secondary objective was to assess
      students' perceptions about their ability to work in teams before and after their
      exposure to these instructional approaches. DESIGN/SETTING/PARTICIPANTS: CL was
      incorporated into the immunology/serology course of a university-based clinical
      laboratory science (CLS) program. Twenty-two students participated in a 4-week
      study and were randomly assigned to one of two study groups. INTERVENTION: One
      group received the course material by CL activities, and the other group was
      exposed to the material through lecture. MAIN OUTCOMES MEASURE: Mean examination
      scores for CL and lecture groups were compared using an independent samples t
      test. Teamwork knowledge, skills, and attitude (KSA) assessment rated students'
      perceptions of their ability to work in a team environment pre and post tests
      were compared using a 2 x 2 repeated measures ANOVA. RESULTS: No significant
      difference was found between mean examination scores of students who acquired
      their knowledge by CL activities (85.09%) and those taught by lecture (82.18%).
      Teamwork KSA means scores pre and post tests (22.5, 22.6 CL; 22.7, 21.6 lecture)
      were not significantly different. CONCLUSION: Results suggest that the
      incorporation of CL activities did not reduce the students' academic performance
      or self-perceptions of their ability to work in teams. The use of CL in the
      classroom, student laboratory, or clinical setting may help prepare students for
      the role they will be expected to perform as laboratory professionals.

PMID- 15011976
TI  - Standardized test scores as an admission requirement.
AB  - OBJECTIVE: The usefulness of standardized test scores as an admission requirement
      for the University of Washington Medical Technology Program (UWMTP) was
      evaluated. Scores from the Allied Health Professions Admissions Test (AHPAT) were
      used. DESIGN: Student data (n = 183) were analyzed and evaluated statistically
      using Pearson correlation and Cox proportional hazards regression analyses.
      Sensitivity and specificity for several admissions criteria were calculated.
      SETTING: The UWMTP is a 2 + 2 medical technology program (MTP) located in a large
      public university. PARTICIPANTS: Student records for classes of 1993 through 2000
      were reviewed. Eligibility for inclusion was based on completeness of student
      record. MAIN OUTCOME MEASURES: Several admission criteria were analyzed for their
      ability to predict success in the UWMTP and on the ASCP Board of Registry (BOR)
      certification examination, and for their sensitivity and specificity. RESULTS:
      Pearson correlations for the AHPAT total score were r = 0.402 with the MTP GPA
      and r = 0.414 with the BOR exam. Cox proportional hazards regression analysis
      defined the decreased likelihood of failure for each unit increase in the test
      score. For the MTP GPA, the risk decrease was 0.8% for the AHPAT total and 2.8%
      for the Biology subtest. For the BOR exam, the risk decrease was 0.8% for the
      AHPAT total and 2.8% for the Verbal subtest. The admissions criteria selected
      based on specificity (26.7%) and maximum sensitivity (100%) was one in which the
      student must achieve at least two of the following three scores: AHPAT total > or
      = 150, Biology subtest score > or = 10, Verbal subtest score > or = 5.
      CONCLUSIONS: Scores on a standardized test can be used to predict success in a
      MTP and on the ASCP BOR exam.

PMID- 15011977
TI  - Yersinia pestis: still a plague in the 21st century.
AB  - Yersinia pestis, the causative agent of plague, is an aerobic, non-motile, gram
      negative bacillus belonging to the family Enterobacteriacea. It is a zoonotic
      infection transmitted to humans via the bite of a flea. Three clinical forms of
      human plague exist: bubonic, pneumonic, and septicemic. Many important virulence
      factors associated with this organism are responsible for its extreme
      pathogenicity and high mortality rates. The bubonic form of plague is usually not
      transmitted human to human but the pneumonic form is--through inhalation of
      contaminated aerosol droplets. The pneumonic plague would be the form most likely
      implicated in the event of an intentional attack. Inhalation of aerosols can
      cause devastating consequences resulting in many casualties. Unless antibiotics
      are administered within 24 hours of the initial symptoms, death is inevitable.
      Its potential for use as a biological weapon is of major concern to public health
      officials.

PMID- 15011978
TI  - Botulin toxin: a weapon in terrorism.
AB  - Clostridium botulinum, the causative agent of botulism is an anaerobic, spore
      forming gram-positive bacillus. C. botulinum causes three types of botulism;
      foodborne botulism, wound botulism, and infant botulism. Most strains of the
      bacterium produce a potent, muscle-paralyzing neurotoxin. Respiratory failure
      secondary to paralysis of the respiratory muscles can lead to death unless
      appropriate therapy is promptly initiated. Due to the severity and potency of
      this neurotoxin, its importance as a biological weapon is of major concern to
      public health officials.

PMID- 15011979
TI  - Francisella tularensis: possible agent in bioterrorism.
AB  - Francisella tularensis, the causative agent of tularemia, is a highly infectious
      gram-negative coccobacillus. Due to its high infectivity it is of major concern
      to public health officials as a possible biological weapon. Although accidental
      exposure can occur through arthropod bites, handling infected animals, or
      breathing in aerosols, cases are usually isolated and contained. In the event of
      an intentional exposure such as in a bioterrorist attack, inhalation of aerosols
      can result in devastating consequences with much causality. Although a vaccine is
      available, sufficient quantities may not be readily accessible in an actual
      attack. Therefore, it is very important for both medical professionals and public
      health officials to be prepared to contain and control the situation should it
      actually occur.

PMID- 15011981
TI  - The role of cardiac troponin in the recent redefinition of acute myocardial
      infarction.

PMID- 15011980
TI  - Update on selected markers used in risk assessment for vascular disease.
AB  - CVD remains the greatest health risk in the U.S.. Assessment of laboratory data
      in establishing risk and treatment modalities has come to the forefront in
      patient primary care. Guidelines published in the ATP III document by the NCEP
      have incorporated lower limits of lipids and included a number of risk factors
      and conditions, such as the metabolic syndrome associated with insulin
      resistance, as a means for earlier detection and intervention in CVD. Endothelial
      dysfunction and the associated inflammatory process, including soluble plasma
      markers, have lead to the addition of hs-CRP as an adjunct to other laboratory
      indicators of CVD. The precise mechanisms and interrelationships between these
      factors and atherosclerosis have yielded some confusing data, along with
      investigations of a number of associated substances and conditions. An emerging
      theme is the body's response to injury and stress; a lack of metabolic balance.
      While currently outside the domain of routine laboratory testing, future CVD risk
      assessment may include the metabolic by-products generated by chronic external
      pressures, including genetic predisposition or alterations associated with
      socioeconomic factors. Further studies are needed to better understand the
      significance each plays in assessing the individual's development and CVD risk.

PMID- 15011982
TI  - B-type natriuretic peptide and congestive heart failure.

PMID- 15011983
TI  - Modes of transmission for West Nile virus.

PMID- 15011984
TI  - ATV riders should follow manufacturers rules.

PMID- 15011985
TI  - With rights and privileges go responsibilities.

PMID- 15011986
TI  - ATV safety legislation must become a reality.

PMID- 15011987
TI  - ATV-related deaths in West Virginia: 1990-2003.
AB  - During the 14-year period from 1990-2003, West Virginia experienced 220 deaths
      related to All Terrain Vehicles (ATVs). Death rates in West Virginia however,
      were significantly higher than the national rate or those of any of the its five
      surrounding states. About 25% of the West Virginia deaths occurred in children
      less than 18 years of age. Ninety-five percent of the victims were not wearing
      helmets and 15% were passengers. Nearly one-third of the ATV crashes occurred on
      public roads, streets, and highways--surfaces on which ATVs are not designed nor
      recommended to be used. The cost of ATV-related deaths is estimated to be over
      dollar 100 million annually. The number of non-fatal injuries resulting from ATV
      crashes is difficult to ascertain because of a lack of a centralized and
      standardized state-based surveillance mechanism. The 44 states that have some
      level of ATV safety requirements have a collective death rate half that of
      states, like West Virginia, who do not have ATV safety requirements. Due to the
      continuing public health burden caused by ATV deaths and injuries, as well as
      their associated costs, it is important that West Virginia policymakers pass
      strong ATV safety legislation during the current session.

PMID- 15011988
TI  - Iatrogenic pseudoaneurysms: comparison of treatment modalities, including duplex
      guided thrombin injection.
AB  - The purpose of our study was to review the results of the three treatment
      modalities currently used at Charleston Area Medical Center (CAMC) for iatrogenic
      pseudoaneuryms. Retrospective records were reviewed of patients treated for
      pseudoaneurysms (PSA) from July 1, 2001 to June 30, 2002. In the 12-month period,
      69 psedoaneurysms were treated with either ultrasound-guided compression (UGC),
      duplex-guided thrombin injection, or open operative repair. Twenty-seven of 47
      femoral pseudoaneurysms (57%) were successfully treated with UGC. Twenty-six of
      27 femoral pseudoaneurysms (96%) were succcessfully treated with DGTI, including
      nine after failed UGC. Seventeen patients were taken to the OR, 11 after failure
      of UGC and one patient after failure of both UGC and DGTI. Mean time for
      successful compression was 27 minutes. Mean operative time was 48 minutes and
      mean operative blood loss was 267cc. We conclude that ultrasound-guided thrombin
      injection should become the initial treatment of choice with operative therapy
      reserved for failed injection therapy.

PMID- 15011989
TI  - Bilateral testicular microlithiasis with a unilateral testicular germ cell tumor:
      a case report.
AB  - There is an important association between testicular microlithiasis and germ cell
      tumors. Ultrasound findings of 1-3 mm echogenic foci within the testicular
      parenchyma may be noted. Testicular microlithiasis in the general population
      without germ cell tumors or cryptorchidism has been estimated between 0.05 and
      0.6%. However, findings of microlithiasis in concordance with germ cell tumors
      can be as high as 40%. We present the case report of a man with bilateral
      testicular microlithiasis and a unilateral germ cell tumor. Discussion of the
      relationship between these two conditions is also reviewed.

PMID- 15011990
TI  - Vasopressin--finding a place in critical care?

PMID- 15011991
TI  - Shifts and drifts in critical care: learning together in order to work together.

PMID- 15011992
TI  - Nutritional intake in the critically ill: improving practice through research.
AB  - Enteral feeding is the preferred method of nutritional support in the critically
      ill; however, evidence suggests that many critically ill patients do not meet
      their nutritional goals. The implementation of enteral feeding protocols has
      improved nutritional delivery, although protocols can be widely variable.
      Similarly, enteral feeding related nursing practice is also inconsistent within
      and between intensive care units (ICUs). These variations in enteral feeding
      practice can be linked to the shortage of reliable and valid research into the
      many issues associated with the effective delivery of enteral nutrition. In the
      absence of a strong research tradition and practice, rituals are embraced and
      rarely challenged, further contributing to the wide variations in enteral feeding
      practice. Of particular importance are practice issues related to the
      commencement of enteral feeding and the assessment of feeding tolerance. This
      article seeks to review the literature related to commencing enteral feeding,
      with particular reference to the suitability of enteral nutrition, methods of
      enteral feeding and adjustment of enteral feeding rates. Issues relating to
      feeding intolerance, including the assessment of gastric residual volume and the
      development of diarrhoea, will also be explored.

PMID- 15011993
TI  - Ten Australian ICU nurses' perceptions of organisational restructuring.
AB  - The Australian healthcare system underwent radical reform in the 1990s as
      economic rationalist policies were embraced. As a result, there was significant
      organisational restructuring within hospitals. Traditional indicators, such as
      nursing absenteeism and attrition, increase during times of organisational
      change. Despite this, nurses' views of healthcare reform are under-represented in
      the literature and little is known about the impact of organisational
      restructuring on perceived performance. This study investigated the perceived
      impact of organisational restructuring on a group of intensive care unit (ICU)
      nurses' workplace performance. It employed a qualitative approach to collect data
      from a purposive sample of clinical nurses. The primary method of data collection
      was semi-structured interviews. Content analysis generated three categories of
      data. Participants identified constant pressure, inadequate communication and
      organisational components of restructuring within the hospital as issues that had
      a significant impact on their workplace performance. They perceived
      organisational restructuring was poorly communicated, and this resulted in an
      environment of constant pressure. Organisational components of restructuring
      included the subcategories of specialised service provision and an alternative
      administrative structure that had both positive and negative ramifications for
      performance. To date, there has been little investigation of nurses' perceptions
      of organisational restructure or the impact this type of change has in the
      clinical domain. Participants in this study believed reorganisation was
      detrimental to quality care delivery in intensive care, as a result of fiscal
      constraint, inadequate communication and pressure that influenced their workplace
      performance.

PMID- 15011994
TI  - The impact of a liaison nurse on ICU nurses' perceptions of discharge planning.
AB  - The objective of the study was to examine the impact of a discharge liaison nurse
      on intensive care unit (ICU) nurses' perceptions of discharge planning. The
      discharge liaison nurse coordinated the discharge of patients from ICU to the
      ward, assisted with hospital discharge, provided clinical teaching and support to
      both ICU and ward nurses and supported patients and families during
      hospitalisation. A block intervention design was used. All ICU nurses within one
      Australian teaching hospital were surveyed prior to and following the
      implementation of the discharge liaison nurse. Measures included the perceptions
      of discharge planning scale and the general perceived self-efficacy scale.
      Following implementation of the liaison nurse, less nurses perceived that
      discharge planning in the ICU was premature (chi2(2, n=117)=7.759, p=0.021) and
      that ICU nurses lack an understanding of the discharge planning process (chi2(2,
      n=118)=15.557, p<0.001). Discharge planning was more frequently seen as the
      responsibility of the bedside nurse (chi2(2, n=115) =15.270, p<0.005) but there
      was greater recognition of discharge planning as a time consuming process
      (chi2(2, n=117)=8.560, p=0.015). Self efficacy in relation to discharge planning
      did not change over time. Some support was found for the role of the discharge
      liaison nurse in promoting attitudinal change towards discharge planning in the
      ICU. Future research is needed to investigate the processes by which the liaison
      nurse fosters attitudinal change and to document the actual discharge planning
      practices undertaken in ICU.

PMID- 15011995
TI  - Chest x-ray quiz. Atelectasis.

PMID- 15011996
TI  - The challenges of pain measurement in critically ill young children: a
      comprehensive review.
AB  - This article addresses the issues in measuring pain in critically ill children,
      provides a comprehensive review of the pain measures for children aged between 0
      and 3 years, and discusses their applicability to this group of children. When
      children are critically ill, pain can only exacerbate the stress response that
      already exists, to the extent that homeostasis cannot be maintained. Severity of
      illness is thus likely to affect physiologic and behavioural pain responses that
      would normally be demonstrated in healthy children. The problem of
      differentiating pain from other constructs adds to the complexity of assessing
      pain in non-verbal children. A pain measure to be useful clinically must be
      adapted to the developmental age of the target population. Search of electronic
      databases and other electronic sources was supplemented by hand review of
      relevant journals to identify published and unpublished pain measures for use in
      children aged between 0 and 3 years. Twenty eight pain measures were identified
      in the literature; 11 for neonates only, 11 for children aged between 0 and 3
      years, and six for children more than 12 months. These measures vary in relation
      to their psychometric properties, clinical utility and the context in which the
      study was performed. These measures may not be suitable for the critically ill
      young child, because the items included were derived from observations of healthy
      or moderately sick children, and may not reflect pain behaviour in those who are
      critically ill. It is therefore recommended to develop new pain scales for this
      population of compromised children.

PMID- 15011997
TI  - Family presence during resuscitation.

PMID- 15011998
TI  - HIV/AIDS care and treatment in sub-Saharan Africa.
AB  - Antiretroviral (ARV) drugs have become the cornerstone of care and treatment for
      AIDS in North America, Brazil, and Europe. Twenty years into the epidemic, and
      more than 10 years after the introduction of ARV's, effective global treatment of
      AIDS, particularly in sub-Saharan Africa where the epidemic is most concentrated,
      is an extraordinary challenge. Guidelines and experience in anti-microbial
      prophylaxis, prescription and monitoring of ARV's in resource-rich countries
      should inform the efforts to scale-up AIDS care and treatment in Africa. Here, we
      review the considerable experience of ARV treatment acquired largely in the
      Americas and Europe, and the fledgling clinical trials and observational studies
      in Africa. Implementation of safe, effective, and equitable access to ARV's in
      Africa should be cognizant of the guidelines for ARV treatment in the Northern
      countries. Careful observation and operational research to accrue more African
      data, and evaluate regional and local solutions to this daunting challenge, will
      identify new approaches to scaling-up of ARV treatment.

PMID- 15011999
TI  - The clades of HIV: their origins and clinical significance.
AB  - It is over 20 years since the identification of HIV as the causative agent of
      AIDS. Despite the innovation and perseverance of biomedical researchers, HIV has
      cumulatively infected over 60 million individuals and caused the deaths of over
      28 million, the majority in the developing world. There is perhaps no greater
      need in medical science than the development of more effective treatments for HIV
      and, ultimately, a protective vaccine. The spread of an extraordinary range of
      variants of HIV has implications for diagnosis and therapy. As the availability
      of antiretrovirals increases, data on the clinical response to treatment for non
      B subtype infections has increasing relevance. Efficient targeting of the extreme
      genetic diversity of HIV-1, and an understanding of the processes underlying
      this, represents one of the major challenges in the control of this ongoing
      pandemic.

PMID- 15012000
TI  - HIV-1 gp41: mediator of fusion and target for inhibition.
AB  - The bipartite envelope glycoprotein (Env) of the human immunodeficiency virus
      type 1 (HIV-1) performs two essential functions for initiating virus infection.
      The gp120 surface subunit of Env binds cell receptors to attach virus to target
      cells and regulate viral entry. The gp41 transmembrane subunit fuses host-cell
      and viral membranes to deliver the viral core into the cell cytoplasm. The two
      subunits derive from a polyprotein precursor, gp160. Cleavage of gp160 in the
      biosynthetic pathway creates mature Env consisting of the noncovalently
      associated gp120/gp41 that is primed for viral entry. While performing distinct
      operations in HIV entry, the activities of the gp120 and gp41 subunits must be
      highly coordinated in order to lead to successful infection. This review
      highlights structure-function relationships in Env, with a focus on the heptad
      repeat regions in the ectodomain of gp41. The mechanism of Env-mediated membrane
      fusion and ways to interfere with this process using inhibitors and antibodies
      that target gp41 are discussed.

PMID- 15012001
TI  - Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8): key aspects of epidemiology
      and pathogenesis.
AB  - The search for a transmissible infectious agent as the cause of Kaposi's sarcoma
      lead to the discovery in 1994 of Kaposi's sarcoma-associated herpesvirus (KSHV),
      also known as human herpesvirus type 8 (HHV8). KSHV is the only human gamma2
      herpesvirus (rhadinovirus) known so far, and is also associated with two other
      AIDS-related lymphoproliferative disorders: primary effusion lymphoma (PEL) and
      the plasma-cell variant of multicentric Castleman's disease (MCD). This review
      addresses key aspects of KSHV epidemiology, life cycle and pathogenesis,
      including the role played by key latent and lytic KSHV genes.

PMID- 15012002
TI  - Mechanisms involved in non-progressive HIV disease.
AB  - HIV disease is a culmination of a complex interplay between both viral and host
      factors. As the underlying biological and molecular mechanisms involved in
      determining disease status are not fully understood, the relationship between the
      two can be better extrapolated using long-term non-progressing individuals who
      harbor the virus but clinically show some form of immunologic control over it.
      Only a fraction of individuals comprising less than 1% of the total HIV-infected
      population show no clinical sign of infection for an extended period of time.
      Continued immunologic characterization of such non-progressing individuals will
      lead to the delineation of anti-HIV mechanisms and development of
      immunotherapeutic modulators for controlling HIV. In this article, we present
      recent progress made in non-progressive HIV disease, and summarize the vast array
      of literature on factors and mechanisms which determine the effectiveness of
      viral and antiviral responses in maintaining a non-progressive state of HIV
      infection.

PMID- 15012004
TI  - Nobel Prize in Physiology or Medicine 2003 awarded to Paul Lauterbur and Peter
      Mansfield for discoveries concerning magnetic resonance imaging.

PMID- 15012003
TI  - The mucosal immune system and HIV-1 infection.
AB  - Recent progress in HIV-1 and SIV pathogenesis has revealed that mucosal tissues,
      primarily the gastrointestinal tract, are major sites for early viral replication
      and CD4+ T-cell destruction, and may be the major viral reservoir, even in
      patients receiving HAART. This is likely attributable to the fact that the
      majority of mucosal CD4+ T-cells co-expressing chemokine receptors requited for
      HIV-1 entry, reside in mucosal tissues. Furthermore, the intestinal mucosal
      immune system is continuously bombarded by dietary antigens, resulting in
      continual lymphocyte activation, dissemination, and homing of these activated
      lymphocytes (including CCR5+CD4+ T-cells) throughout mucosal tissues. Thus, the
      intestinal immune system represents a very large target for HIV-infection, which
      is continually generating newly activated CD4+ T-cells that are the preferred
      target of infection. Thus, HIV-1 appears uniquely adapted to persist and thrive
      in the mucosal-tissue environment. The selective loss of intestinal CD4+ T-cells
      from immune-effector sites is also likely to explain, at least in part, the
      preponderance of opportunistic infections at mucosal sites. It is increasingly
      evident that effective therapies and vaccines must be directed towards
      eliminating HIV-1 in mucosal tissue reservoirs, protecting mucosal CD4+ T-cells
      and stimulating effective mucosal immune responses.

PMID- 15012005
TI  - In vivo molecular and genomic imaging: new challenges for imaging physics.
AB  - The emerging and rapidly growing field of molecular and genomic imaging is
      providing new opportunities to directly visualize the biology of living
      organisms. By combining our growing knowledge regarding the role of specific
      genes and proteins in human health and disease, with novel ways to target these
      entities in a manner that produces an externally detectable signal, it is
      becoming increasingly possible to visualize and quantify specific biological
      processes in a non-invasive manner. All the major imaging modalities are
      contributing to this new field, each with its unique mechanisms for generating
      contrast and trade-offs in spatial resolution, temporal resolution and
      sensitivity with respect to the biological process of interest. Much of the
      development in molecular imaging is currently being carried out in animal models
      of disease, but as the field matures and with the development of more
      individualized medicine and the molecular targeting of new therapeutics, clinical
      translation is inevitable and will likely forever change our approach to
      diagnostic imaging. This review provides an introduction to the field of
      molecular imaging for readers who are not experts in the biological sciences and
      discusses the opportunities to apply a broad range of imaging technologies to
      better understand the biology of human health and disease. It also provides a
      brief review of the imaging technology (particularly for x-ray, nuclear and
      optical imaging) that is being developed to support this new field.

PMID- 15012006
TI  - The use of chloroaluminium phthalocyanine tetrasulfonate (AlPcTS) for time
      delayed fluorescence imaging.
AB  - Phthalocyanine derivatives are currently under investigation for use in
      photodynamic therapy, which is a promising cancer treatment. These materials,
      which display preferential uptake in cancerous cells, also exhibit high
      fluorescence yields and can be used for tumour detection. Problems with steady
      state fluorescence techniques such as excitation scatter and background
      autofluorescence can be eliminated by using time-resolved imaging techniques
      without the need for filters. A tissue phantom was assembled to test a
      constructed time-gated imaging system by drilling 36 wells of varying diameter
      and depth (10 mm to 1 mm) into a block of polymethyl methacrylate (PMMA). The
      system was used to record images of chloroaluminium phthalocyanine tetrasulfonate
      (AlPcTS) at differing concentrations in neat aqueous solvent and cell suspensions
      within the wells. A mixture of Intralipid (to mimic tissue scatter) and Evan's
      blue (to mimic tissue absorption) of depths ranging from 1 mm to 10 mm was placed
      on top of the PMMA block. The ensuing images were analysed using signal-to-noise
      ratios and contrast-detail curves. The results indicate that the time-gated
      imaging system can prevent background excitation scatter from distorting the
      fluorescence signal from a longer-lived photosensitizer without the need for
      filters.

PMID- 15012007
TI  - Acoustic rhinometry measurements in stepped-tube models of the nasal cavity.
AB  - Stepped-tube models with a constriction in the anterior section were used to
      evaluate the effects that nasal valve passage area and nasal cavity shape have on
      acoustic rhinometry (AR) measurements. The AR-determined cross-sectional areas
      beyond a constriction of small passage area were consistently underestimated, and
      the corresponding area-distance curves showed pronounced oscillations. Also, the
      AR technique did not accurately reproduce abrupt changes in passage area. The
      results suggest that, regardless of the particular shape of the nasal cavity
      model, AR does not provide reliable information about cross-sectional areas
      posterior to a severe constriction. The experimental results are discussed in
      terms of theoretically calculated acoustic input impedance for the models
      studied, the physical limitations of AR, and assumptions made in AR algorithms.
      The study demonstrated that energy losses and sound wave attenuation due to air
      viscosity do not significantly affect AR measurements. It was also shown that
      passage area beyond a severe constriction is underestimated because the barrier
      created by the constriction reflects most of the incident sound power. The
      results also indicate that the oscillations in area-distance curves are due to
      low-frequency acoustic resonances in the nasal cavity model.

PMID- 15012008
TI  - Benchmark of PENELOPE code for low-energy photon transport: dose comparisons with
      MCNP4 and EGS4.
AB  - The expanding clinical use of low-energy photon emitting 125I and 103Pd seeds in
      recent years has led to renewed interest in their dosimetric properties. Numerous
      papers pointed out that higher accuracy could be obtained in Monte Carlo
      simulations by utilizing newer libraries for the low-energy photon cross
      sections, such as XCOM and EPDL97. The recently developed PENELOPE 2001 Monte
      Carlo code is user friendly and incorporates photon cross-section data from the
      EPDL97. The code has been verified for clinical dosimetry of high-energy electron
      and photon beams, but has not yet been tested at low energies. In the present
      work, we have benchmarked the PENELOPE code for 10-150 keV photons. We computed
      radial dose distributions from 0 to 10 cm in water at photon energies of 10-150
      keV using both PENELOPE and MCNP4C with either DLC-146 or DLC-200 cross-section
      libraries, assuming a point source located at the centre of a 30 cm diameter and
      20 cm length cylinder. Throughout the energy range of simulated photons (except
      for 10 keV), PENELOPE agreed within statistical uncertainties (at worst +/- 5%)
      with MCNP/DLC-146 in the entire region of 1-10 cm and with published EGS4 data up
      to 5 cm. The dose at 1 cm (or dose rate constant) of PENELOPE agreed with
      MCNP/DLC-146 and EGS4 data within approximately +/- 2% in the range of 20-150
      keV, while MCNP/DLC-200 produced values up to 9% lower in the range of 20-100 keV
      than PENELOPE or the other codes. However, the differences among the four
      datasets became negligible above 100 keV.

PMID- 15012009
TI  - 'Tongue-and-groove' effect in intensity modulated radiotherapy with static
      multileaf collimator fields.
AB  - The 'tongue-and-groove problem' in step-and-shoot delivery of intensity modulated
      radiotherapy is investigated. A 'tongue-and-groove' index (TGI) is introduced to
      quantify the 'tongue-and-groove' effect in step-and-shoot delivery. Four
      different types of leaf sequencing methods are compared. The sliding window
      method and the reducing level method use the same number of field segments to
      deliver the same intensity map, but the TGI is much less for the reducing level
      method. The leaf synchronization method of Van Santvoort and Heijmen fails in
      step-and-shoot delivery, but a new method inspired by the method of Van Santvoort
      and Heijmen is shown to eliminate 'tongue-and-groove' underdosage completely.

PMID- 15012010
TI  - Optimization of tumour control probability for heterogeneous tumours in
      fractionated radiotherapy treatment protocols.
AB  - We find the dose distribution that maximizes the tumour control probability (TCP)
      for a fixed mean tumour dose per fraction. We consider a heterogeneous tumour
      volume having a radiation response characterized by the linear quadratic model
      with heterogeneous radiosensitivity and repopulation rate that may vary in time.
      Using variational calculus methods a general solution is obtained. We demonstrate
      the spatial dependence of the optimal dose distribution by explicitly evaluating
      the solution for different functional forms of the tumour properties. For
      homogeneous radiosensitivity and growth rate, we find that the dose distribution
      that maximizes TCP is homogeneous when the clonogen cell density is homogeneous,
      while for a heterogeneous initial tumour density we find that the first dose
      fraction is inhomogeneous, which homogenizes the clonogen cell density, and
      subsequent dose fractions are homogeneous. When the tumour properties have
      explicit spatial dependence, we show that the spatial variation of the optimized
      dose distribution is insensitive to the functional form. However, the dose
      distribution and tumour clonogen density are sensitive to the value of the
      repopulation rate. The optimized dose distribution yields a higher TCP than a
      typical clinical dose distribution or a homogeneous dose distribution.

PMID- 15012011
TI  - Prediction of respiratory tumour motion for real-time image-guided radiotherapy.
AB  - Image guidance in radiotherapy and extracranial radiosurgery offers the potential
      for precise radiation dose delivery to a moving tumour. Recent work has
      demonstrated how to locate and track the position of a tumour in real-time using
      diagnostic x-ray imaging to find implanted radio-opaque markers. However, the
      delivery of a treatment plan through gating or beam tracking requires adequate
      consideration of treatment system latencies, including image acquisition, image
      processing, communication delays, control system processing, inductance within
      the motor, mechanical damping, etc. Furthermore, the imaging dose given over long
      radiosurgery procedures or multiple radiotherapy fractions may not be
      insignificant, which means that we must reduce the sampling rate of the imaging
      system. This study evaluates various predictive models for reducing tumour
      localization errors when a real-time tumour-tracking system targets a moving
      tumour at a slow imaging rate and with large system latencies. We consider 14
      lung tumour cases where the peak-to-peak motion is greater than 8 mm, and compare
      the localization error using linear prediction, neural network prediction and
      Kalman filtering, against a system which uses no prediction. To evaluate
      prediction accuracy for use in beam tracking, we compute the root mean squared
      error between predicted and actual 3D motion. We found that by using prediction,
      root mean squared error is improved for all latencies and all imaging rates
      evaluated. To evaluate prediction accuracy for use in gated treatment, we present
      a new metric that compares a gating control signal based on predicted motion
      against the best possible gating control signal. We found that using prediction
      improves gated treatment accuracy for systems that have latencies of 200 ms or
      greater, and for systems that have imaging rates of 10 Hz or slower.

PMID- 15012012
TI  - An ultrasound-driven needle-insertion robot for percutaneous cholecystostomy.
AB  - A real-time ultrasound-guided needle-insertion medical robot for percutaneous
      cholecystostomy has been developed. Image-guided interventions have become widely
      accepted because they are consistent with minimal invasiveness. However, organ or
      abnormality displacement due to involuntary patient motion may undesirably affect
      the intervention. The proposed instrument uses intraoperative images and modifies
      the needle path in real time by using a novel ultrasonic image segmentation
      technique. In phantom and volunteer experiments, the needle path updating time
      was 130 and 301 ms per cycle, respectively. In animal experiments, the needle
      could be placed accurately in the target.

PMID- 15012013
TI  - Synergistic effect of hyperosmotic agents of dimethyl sulfoxide and glycerol on
      optical clearing of gastric tissue studied with near infrared spectroscopy.
AB  - In an effort to find an effective concentration that could minimize the side
      effect for clinical applications, and to understand the potential synergistic
      effect of hyperosmotic agents on optical clearing of gastric tissues, porcine
      stomach tissues (pyloric mucosa) applied with a mixed solution of glycerol and
      dimethyl sulfoxide (DMSO) are investigated with near infrared reflectance
      spectroscopy. Five chemical solutions, containing 80% glycerol, 50% DMSO, 50%
      glycerol with 10% DMSO, 20% DMSO and 30% DMSO, respectively, are prepared and
      studied; all of which show significant improvement in light transmittance, and
      thus reduction of the light scattering of tissue. It is found that, among the
      solutions investigated, 50% glycerol with 30% DMSO achieves the best clearing
      effect on the improvement of light penetration. Light transmittance is increased
      approximately 29% and diffuse reflectance decreased approximately 31% at 30 min
      after the topical application of 50% glycerol with 30% DMSO. This solution shows
      significantly stronger effect than 80% glycerol on optical clearing even though
      they have the same osmolarity. 80% glycerol leads to 23% increase of light
      transmittance and 24% decrease of diffuse reflectance. The mixed solution of 50%
      glycerol and 20% DMSO has less osmolarity than the solution of 80% glycerol, but
      they achieve a similar degree of optical clearing. In other words, the clearing
      effect of glycerol is enhanced by adding DMSO into it. It is suggested that
      membrane penetration and carrier effect of DMSO probably accounts for this
      synergistic effect.

PMID- 15012014
TI  - Measurement of bone mineral density via light scattering.
AB  - In this study we have investigated the potential of optical techniques to monitor
      changes in bone mineral density (BMD) via changes in scattering coefficient. For
      each of five bone samples, diffuse reflection and transmission coefficients were
      measured over the wavelength range 520-960 nm using an integrating sphere and CCD
      spectrometer. These were converted into optical absorption and scattering
      coefficients using a Monte Carlo inversion procedure. Measurements were made on
      samples immersed in formic acid solution for different lengths of time in order
      to investigate the effect of reduction in BMD on the optical properties. After
      full demineralization, the optical scattering coefficient fell by a factor 4.
      From the observed degree of fluctuation of the measurements, we estimate that BMD
      could be measured with an accuracy of 7% if optical scattering can be measured
      with an accuracy of 10%. We also report preliminary measurements of bone
      scattering using optical coherence tomography (OCT). An inter-side variability of
      3% is obtained on dry samples with and without overlying periosteum. These
      results suggest that minimally invasive techniques for measuring optical
      scattering, such as OCT, may have a role in monitoring regional changes in BMD.
      This could be an important advance in our understanding of bone remodelling and
      its relationship to osteoarthritis. Both the integrating sphere and OCT
      measurements also suggest that light transport in bone is spatially anisotropic.
      OCT was used to assess probability of obtaining results in vivo.

PMID- 15012015
TI  - Optimal leaf sequencing with elimination of tongue-and-groove underdosage.
AB  - The individual leaves of a multileaf collimator (MLC) have a tongue-and-groove or
      stepped-edge design to minimize leakage radiation between adjacent leaves. This
      design element has a drawback in that it creates areas of underdosages in
      intensity-modulated photon beams unless a leaf trajectory is specifically
      designed such that for any two adjacent leaf pairs, the direct exposure under the
      tongue-and-groove is equal to the lower of the direct exposures of the leaf
      pairs. In this work, we present a systematic study of the optimization of a leaf
      sequencing algorithm for segmental multileaf collimator beam delivery that
      completely eliminates areas of underdosages due to tongue-and-groove or stepped
      edge design of the MLC. Simultaneous elimination of tongue-and-groove effect and
      leaf interdigitation is also studied. This is an extension of our previous work
      (Kamath et al 2003a Phys. Med. Biol. 48 307) in which we described a leaf
      sequencing algorithm that is optimal for monitor unit (MU) efficiency under most
      common leaf movement constraints that include minimum leaf separation. Compared
      to our previously published algorithm (without constraints), the new algorithms
      increase the number of sub-fields by approximately 21% and 25%, respectively, but
      are optimal in MU efficiency for unidirectional schedules.

PMID- 15012016
TI  - The use of molecular sieves to produce point sources of radioactivity.
AB  - We have used commercially available molecular sieves (zeolites) to adsorb
      radioactivity onto small (approximately 2.1 mm diameter) beads for use in various
      applications in nuclear medicine. Soaking the beads in [99mTc]-NaTcO4 solution of
      approximately 3 GBq ml(-1) for 1-2 min can produce point sources containing 3-6
      MBq total. Radioactive uptake was strongly dependent on bead size. We have
      employed the sources for gamma camera uniformity and as point source markers for
      interactive identification of anatomical landmarks. Due to their small size (<<
      system spatial resolution), relatively high uptake and negligible scattering
      contribution they provide excellent devices with which to measure spatial
      resolution, detector uniformity and energy resolution. The molecular sieves are
      inexpensive and readily usable with both single photon and positron emitting
      radionuclides.

PMID- 15012017
TI  - Mediterranean diet and cardiovascular epidemiology.

PMID- 15012018
TI  - The emerging role of Mediterranean diets in cardiovascular epidemiology:
      monounsaturated fats, olive oil, red wine or the whole pattern?

PMID- 15012019
TI  - Change in cardiovascular risk factors in France, 1985-1997.
AB  - The change in the main cardiovascular risk factors in France was assessed using
      the MONICA population surveys conducted in the Urban Community of Lille, Bas-Rhin
      and Haute-Garonne. Trends in obesity, tobacco smoking, hypertension,
      hypercholesterolaemia and self-reported diabetes were established for the first
      (1985-1988) and the last (1995-1997) survey. The results indicate that the
      prevalence of overweight and obesity remained stable in both genders; tobacco
      smoking decreased in men but increased in women. Prevalence of hypertension
      decreased, and preventive measures improved in both genders. Prevalence of
      hypercholesterolaemia remained stable, and preventive measures improved only in
      men. Prevalence of self-reported diabetes increased solely in women, and
      preventive measures improved in both genders. However, in 1995-1997 still 40% of
      the treated hypertensive and 30% of the treated hypercholesterolaemic subjects
      were not adequately controlled. We conclude that prevalence and prevention of the
      main cardiovascular risk factors have evolved favourably in France, but the
      management of hypercholesterolaemia and hypertension can still be improved.

PMID- 15012020
TI  - Prevalence of obesity in south-east Spain and its relation with social and health
      factors.
AB  - Recent studies have confirmed important regional differences in the prevalence of
      obesity, as well as a tendency for this prevalence to increase. Determination of
      the social factors involved in obesity may be very useful to design intervention
      and prevention strategies. This transverse study was undertaken in Pizarra
      (Malaga, Spain) from a random sample of the population between 18 and 65 years of
      age (n = 1226). All participants were interviewed and given a physical
      examination. Standardized anthropometrical measurements were made, and a baseline
      blood sample was taken after an oral glucose tolerance test. The overall
      prevalence of obesity (BMI > 30 kg/m2) was 28.8%. This figure increased
      continuously from 10% in the group aged 18-25 years to above 50% in the groups
      aged over 55 years. This prevalence is higher than that reported in most other
      studies in Spain. The obese persons ate differently, at least from a qualitative
      viewpoint, probably more saturated fats and fewer unsaturated fats, and had a
      different behaviour concerning alcohol and smoking. Marital status was related
      with the rate of obesity, and the close relation between the level of education
      and the risk of obesity was confirmed (OR = 3.8 for being obese and having no
      education compared to having university studies). The most important consequence
      of the study was that all these factors are potentially modifiable and
      preventable. An increased level of general education in the population may well
      contribute decisively to a reduction in the prevalence of obesity.

PMID- 15012021
TI  - Markers of fetal growth and serum levels of insulin-like growth factor (IGF) I, 
      II and IGF binding protein 3 in adults.
AB  - Fetal growth has been linked with increased risk of cancer and cardiovascular
      disease later in life. The insulin-like growth factor (IGF) axis has recently
      been proposed as a predictor of risk of subsequent cancer and cardiovascular
      disease. However, only few data are available on the possible association between
      fetal growth and levels of IGFs later in life. We examined the association
      between markers of fetal growth, i.e. birth weight, birth length and Ponderal
      Index, from birth records and serum IGF-I, IGF-II, and IGF binding protein 3
      (IGFBP-3) levels in 545 middle-aged Danish men and women. We fitted separate
      multivariate models including birth weight, birth length, Ponderal Index and
      serum IGF-I, IGF-II, and IGFBP-3, respectively. After adjustment for age, alcohol
      intake, smoking, diabetes mellitus, systolic and diastolic blood pressure, serum
      total cholesterol and current height and weight, we found negative associations
      between birth weight and Ponderal Index, respectively, and serum IGF-II in men,
      i.e. the mean regression coefficients were -49.41 (95% CI: -87.06-11.77)
      (microg/l)/kg and -3.49 (95% CI: -6.73-0.25) (microg/l)/(kg/m3), respectively.
      Furthermore, in men birth weight was negatively associated with the (IGF-I + IGF
      II)/IGFBP-3 and IGF-II/IGFBP-3 ratios, which are believed to be indicators of
      bioavailable IGF and IGF-II, respectively. However, no other associations were
      found in any of the models. Between 1 and 16% of the variance in serum IGF-I, IGF
      II, and IGFBP-3, respectively, could be explained by the statistical models used
      in the analyses. We found very little support to the hypothesis of an association
      between fetal growth and the IGF axis throughout life.

PMID- 15012022
TI  - Case-control study on cancer risk associated to residence in the neighbourhood of
      a petrochemical plant.
AB  - The aim of the present study is to investigate cancer mortality and residence in
      the neighbourhood of the petrochemical plant located in Brindisi, South-eastern
      Italy. Cases were all subjects resident in Brindisi and in three neighbouring
      municipalities who died in the study area in 1996-1997 from lung cancer, pleural
      neoplasm, bladder cancer and lymphohematopoietic malignancies. Controls were
      subjects resident in the same area and deceased in 1996-1997 for any cause except
      those listed for the cases. Next of kin's of all study subjects were visited by
      an interviewer who collected anamnestic information. The main residence of each
      subject, defined as the longest held residence with exclusion of the last 10
      years, was reported on a digitalized map of the study area (MapInfo). The study
      included 144 cases and 176 controls; response rate was 98%. Residence within 2 km
      from the centre of the petrochemical plant was associated with a 3 fold increase
      of the Odds ratios (OR) for lung cancer, which did not reach statistical
      significance. Living close to the petrochemical plant was associated with
      moderate increases of OR for bladder cancer and lymphohematopoietic neoplasms
      which did not reach statistical significance. In conclusion the present study has
      shown moderate increases in risk for lung, bladder and lymphohematopoietic
      neoplasms in the population resident within 2 km from the centre of the
      petrochemical plant in Brindisi. These figures were confirmed after adjusting for
      smoking habit, occupation and school level. Random misclassification may have
      somehow resulted in risk underestimation.

PMID- 15012023
TI  - Haematological malignancies in childhood in Croatia: investigating the theories
      of depleted uranium, chemical plant damage and 'population mixing'.
AB  - Some of potential causes proposed to explain the reported increase of
      haematological malignancies in childhood during or after the war period in
      several countries include depleted uranium, chemical pollution and population
      mixing theory. The aim of this study was to define the population of Croatian
      children aged 0-14 years who were potentially exposed to each of those risks
      during the war and to investigate any possible association between the exposure
      and the incidence of haematological malignancies. The authors analyzed the data
      reported by the Cancer Registry of Croatia during the pre-war period (1986-1990),
      war period (1991-1995) and post-war period (1996-1999). In the group of 10
      counties potentially exposed to depleted uranium and two counties where chemical
      war damage occurred, no significant difference in incidence of the studied
      haematological malignancies was noted in comparison to pre-war period. The
      incidence of lymphatic leukaemia significantly increased in four counties where
      population mixing had occurred during the war period, supporting the 'mixing
      theory'. In those counties, the incidence of Hodgkin's lymphoma decreased during
      and after the war. In Croatia as a whole, decreases in incidence of myeloid
      leukaemias during war and non-Hodgkin lymphoma after the war were noted.

PMID- 15012024
TI  - Blood borne viral infections among Danish health care workers--frequent blood
      exposure but low prevalence of infection.
AB  - Denmark is a country with low prevalence and incidence of blood borne viral
      infections. Among health care workers (HCWs) vaccination for hepatitis B is only
      offered to high-risk groups. The aims of this cross sectional survey were to
      determine the prevalence of hepatitis B, -C, and human immunodeficiency virus
      (HIV) among the staff at a Danish University hospital and to correlate this with
      risk factors for transmission. Additionally, we wanted to examine the current
      frequency of blood exposure, reporting habits and hepatitis B vaccination status
      in the staff. Of 1439 eligible hospital staffs included, 960 (67%) were HCWs. The
      overall human immunodeficiency virus (HIV)-, hepatitis C Virus (HCV)- and
      hepatitis B Virus (HBV)-prevalence was 0% (0/1439), 0.14% (2/1439) and 1.6%
      (23/1439), respectively. Twenty-three percent of HCWs were vaccinated against
      HBV. Age, blood transfusion and stay in endemic areas were associated
      independently to HBV infection as opposed to job-category, duration of
      employment, HBV vaccination status and blood exposure. Based on a 4-week recall
      period, the incidence of percutaneous blood exposure was 1.5/person-year. In
      conclusion the HIV and hepatitis prevalence was low despite frequent blood
      exposure and the principal risk factors were unrelated to work. Danish HCWs do
      not seem to be at increased risk of hepatitis B even though universal HBV
      vaccination has not been implemented.

PMID- 15012025
TI  - Seroprevalence of pertussis antibody among health care personnel in Spain.
AB  - Pertussis in healthcare workers is of particular concern, as they can be in
      contact with infected patients and may transmit the infection to susceptible
      patients, co-workers and other contacts. This study was carried out to examine
      the prevalence of pertussis antibodies in hospital personnel. A total of 487
      healthcare workers > or = 25 years in age and students (19-24 years) in hospital
      training were recruited. The overall prevalence of pertussis antibody determined
      by ELISA was 51.7%. No significant differences on prevalence by age group (19-24,
      25-34, 35-44 and > or = 45 years) and occupation (student, physician, nursing
      personnel and non-healthcare occupations) were found. In Spain, health care
      personnel in a general hospital will not have a significantly higher risk of
      serologically detectable contact with B. pertussis. Fifty percent of physicians
      and nursing personnel working in hospital were seronegative for pertussis
      antibody. A high percentage of these subjects will be susceptible to infection.

PMID- 15012026
TI  - Prevalence of HCV infection among health care workers in a hospital in central
      Italy.
AB  - Health care workers are at risk of acquiring transmissible diseases.
      Controversial results have been reported about HCV. The aims of the present study
      are to assess the prevalence of HCV in health care workers in Pistoia General
      Hospital (central Italy) and to compare prevalence with other groups,
      particularly with a sample of the general population. Serum samples collected
      from 511 health care employees engaged in direct clinical task and 222 clerical
      and nurse school attendees have been tested by ELISA and confirmed by RIBA. Total
      seroprevalence was 3.8%:4.7% in the first group; 1.8% in the second group. The
      data showed a slight increase in prevalence by age and not by length of stay in
      the health care workers' group. Comparison of HCV prevalence with blood donors
      from the province of Pistoia and the general population from Sersale (Catanzaro,
      southern Italy), restricted to under-40 subjects, indicates an increasing trend
      in this order: Blood donors, general population, clerical and nursing school
      attendees, health care workers' group with the highest value (3.4%). A cohort
      study is needed to evaluate pattern of HCV seroconversion.

PMID- 15012027
TI  - Detection of antibodies to tick salivary antigens among patients from a region of
      Spain.
AB  - With a view to determine which tick species bite humans most frequently in the
      province of Soria (Spain) and to know whether these species act as vectors of
      Rickettsia conorii and/or Borrelia burgdorferi, we analysed the presence of
      antibodies against salivary proteins of several tick species and of antibodies
      against R. conorii and B. burgdorferi sensu lato in 102 samples of serum. The
      sera were collected from 63 patients who were treated for tick bites at the
      health services of the Soria Health Area. Thirty-nine percent of the patients
      displayed antibodies against Dermacentor marginatus; 21% against Ixodes ricinus,
      and 6% against Rhipicephalus sanguineus. IgM antibodies against R. conorii were
      found in 15 patients, but none of the patients included in the study displayed
      IgG/IgM Abs against B. burgdorferi sensu lato. In 30% of the patients bitten by
      I. ricinus and in 24% bitten by D. marginatus, antibodies against R. conorii were
      found. None of the patients who had been bitten by R. sanguineus expressed
      antibodies against this pathogen. The results obtained here suggest that D.
      marginatus and I. ricinus are the main vectors of the spotted fever group
      rickettsiae in our environment and that the role of R. sanguineus in the
      transmission of these rickettsiae is debatable.

PMID- 15012029
TI  - Only superficial spreading melanoma is causing the melanoma epidemics?
AB  - Population-based data from the Tuscany Cancer Registry including 1836 malignant
      melanoma diagnosed during 1985-1999 were analysed according to the morphological
      type. Only superficial spreading melanoma (1017 cases) showed a striking increase
      in incidence during the period. This was true both for thin and thick tumours. A
      differential effect of sun exposure in melanoma development according to
      morphological type deserve to be investigated.

PMID- 15012028
TI  - Is there a change in cytomegalovirus seroepidemiology in Spain?
AB  - The aim of this paper is to compare the seroprevalence of cytomegalovirus (CMV)
      in women in the Autonomous Region of Madrid (ARM) obtained in two different years
      (1993 and 1999), according to age and seroprevalence of a virus transmitted by
      the faecal-oral route (hepatitis A virus, HAV) and another virus of respiratory
      transmission (varicella zoster virus, VZV). A total of 1813 serum samples were
      studied, taken from females aged 2-40 in two different serosurveys which were
      representative of the general population in the ARM. Of these, 933 were taken in
      1993, and 880 in 1999. In each survey the samples were distributed over six
      groups, according to age group (2-5, 6-10, 11-15, 16-20, 21-30 and 31-40 years).
      CMV- and VZV-specific IgG was tested by indirect ELISA (Dade-Behring, Germany);
      and HAV-IgG by ImX (Abbott, USA) in the 1993 samples, or by Vidas (BioMerieux,
      France) in the case of those taken in 1999. A significant age-related rise in CMV
      seroprevalence was observed in both serosurveys. The seroprevalence obtained was
      lower in all age groups in 1999 than in 1993. The differences were statistically
      significant in two age groups: 6-10 years old (43.7 vs. 56.7%) and 31-40 years
      old (79.1 vs. 90.3%). In the younger age groups concurrent seroprevalence of CMV
      and VZV was significant lower in 1999. In older age groups a significant decrease
      in concurrent seroprevalence of both CMV and HAV was also seen. Agreement between
      serological results for CMV-HAV, CMV-VZV and HAV-VVZ during the two time periods
      and in every age group was poor or fair (kappa index < or = 0.2 or between 0.21
      and 0.4) in all age groups. To conclude, a change in CMV epidemiology seems to be
      taking place in Madrid. The increase in the proportion of CMV seronegative women
      of childbearing age may have some impact on the incidence of congenital diseases
      related to vertical transmission of CMV. Apparently, such a change, among
      children, could be related to a lower close contact transmission rate (as in
      VZV), and among adults to improvements in standards of public health (as in HAV).
      However, due to the poor or fair agreement between serological results for CMV
      HAV, CMV-VZV and HAV-VVZ, other independent factors may affect the fall in CMV
      seroprevalence.

PMID- 15012030
TI  - External fixation use in arthrodesis of the foot and ankle.
AB  - The use of external fixation in foot and ankle arthrodesis can be beneficial. Its
      advantages, disadvantages, and indications were reviewed in this article.
      External fixation offers the surgeon an opportunity to treat complex foot and
      ankle deformities, trauma, chronic infections, pseudoarthroses, soft tissue
      contractures, and limb length discrepancies in ways that were unavailable before
      its advent. The Ilizarov technique requires considerable experience and patient
      compliance for the best postoperative outcome. An understanding of
      musculoskeletal physiology and the biomechanics of bone and soft tissue are
      essential for the competent application of external fixators in general and
      Ilizarov frames in particular. The surgeon should be aware of all the surgical
      options before the application of an external complex apparatus.

PMID- 15012031
TI  - Techniques of digital arthrodesis: revisiting the old and discovering the new.
AB  - Digital surgery is commonplace for foot and ankle surgeons. The techniques of
      arthrodesis are more exacting and complex than techniques of arthroplasty. They
      are generally performed in cases of more severe deformity or underlying
      biomechanical abnormalities, which strongly influence the development and
      propagation of the deformity. When performed properly in a patient with good
      compliance, the results are consistently good and rewarding to patients and
      surgeons. Attention to detail cannot be overemphasized in managing digital
      deformities. Failure to do so is likely to result in a less than satisfactory
      outcome for physician and patient. Traditional techniques are proven effective
      approaches. Meticulous attention to detail and precise execution of the procedure
      will minimize complications. The exact role of newer implants for fusion is yet
      to be determined. Further short-term and long-term experience will determine
      their role in foot surgery.

PMID- 15012032
TI  - Hallux IPJ fusion.
AB  - Surgical arthrodesis of the hallux interphalangeal joint can be used as an
      isolated procedure to address painful or deformed joints or in conjunction with
      other procedures to create a better functioning first ray. This type of
      arthrodesis may be necessary in neuropathic patients to prevent ulcerations or
      amputations. Several etiologies exist that result in a deformity about the hallux
      IPJ, some can be pain-free, others may be extremely debilitating to a patient.
      Many different surgical approaches have been described and used when performing a
      hallux IPJ arthrodesis. Developing your own technique enables you to understand
      what works for you and your patients and allows you to determine the most
      effective way to achieve arthrodesis. The goal is to prevent painful nonunions
      and address the underlying deformity. It is also important to understand that a
      successful arthrodesis in a patient who has a neurological disorder is the only
      way to prevent recurring deformities secondary to the underlying disease process.
      The ability to properly work-up and surgically address deformities of the hallux
      interphalangeal joint is necessary for those who perform lower extremity surgery.

PMID- 15012033
TI  - First metatarsophalangeal joint arthrodesis.
AB  - First MTP joint arthrodesis continues to be a time-honored, effective, and
      valuable procedure as a primary or secondary surgery for various pathologies
      afflicting the first ray segment. Though commonly thought of as a salvage
      procedure, it has proven beneficial in the management of primary hallux limitus
      and rigidus, geriatric hallux valgus deformity, severe arthritis of any etiology,
      and conditions in which joint instability or deformity are not readily
      correctable by more traditional approaches. Since its initial description in the
      1800s, the procedure has continued to be popular among orthopedic and podiatric
      surgeons. Success of the procedure is highly dependent on the position of fusion.
      Though surgeons are often fascinated and at times obsessed with a particular
      fixation technique, it cannot be over-emphasized that this takes a back seat to
      the importance of achieving proper position to meet the needs of an individual
      patient. Unlike joint resection or implant arthroplasty procedures, which
      commonly leave the hallux lacking stability and propulsion, first MPJ fusion has
      been shown to be effective during weight bearing and propulsion. The success
      enjoyed by the senior author continues to reinforce that motion is not necessary
      at the first MTP joint for good, pain-free function.

PMID- 15012034
TI  - Lapidus bunionectomy: arthrodesis of the first metatarsocunieform joint.
AB  - Fusion of the first metatarsocunieform (MC) joint allows for correction of the
      first metatarsal in three planes, including adduction, plantarflexion, and
      rotation. It also allows for decreased jamming of the great toe joint and
      increased medial column stability. As knowledge about other medial column
      procedures grows, fusion of the first MC joint will continue to grow in
      popularity. It is an excellent procedure for hallux limitus and also for
      metatarsus primus elevatus cases.

PMID- 15012035
TI  - Lisfranc arthrodesis.
AB  - Fracture-dislocation of the tarsometatarsal joint is a major injury and can be
      associated with a chronic disability. The incidence is low, but the long-term
      results can be a devastating problem to the patient. This article reviews the
      anatomy, mechanism of injury, classifications, diagnostic procedures, treatment,
      and long-term results of a fracture-dislocation to the tarsometatarsal joint
      complex.

PMID- 15012036
TI  - Lateral column fusions.
AB  - There is a considerable amount of literature on the treatment of the medial
      column. The lateral column is sometimes as difficult and can also pose
      biomechanical challenges. The distinction of medial or lateral column pain is
      dependent on the patient's foot type. The senior author has observed that lateral
      column pain is much more prevalent in a neutral to supinated foot. Chronic pain
      and end-stage arthrosis of the lateral column joints can be treated successfully
      with the approaches discussed. As the Achilles tendon is important in medial
      column collapse, its contribution to lateral column pathology should also be
      considered.

PMID- 15012037
TI  - Naviculocuneiform arthrodesis.
AB  - NC arthrodesis is a useful procedure to alleviate pain secondary to arthritis or
      collapse of the medial longitudinal arch. Fusion of this joint provides
      stabilization of the medial column and is often used in conjunction with other
      flatfoot-correcting procedures to restore normal function to the foot. Because
      the NC joint is the center of the lever arm of the foot and is therefore subject
      to bending-moment stress, concomitant gastrocnemius recession or tendo-Achillis
      lengthening is recommended.

PMID- 15012038
TI  - [Macroscopic findings for the exclusion of a forensic relevant soil embedded
      resting period in skeletal remains--an approach based upon literature].
AB  - A reliable determination of the post mortem interval (PMI) in human bones has
      neither been found by morphological nor by intensive analyses of other kinds. In
      most cases of legal medicine practice the question of PMI is restricted to a
      forensically relevant resting period. In a survey based upon literature, all
      osteological signs of decomposition, which have not been described for a soil
      embedded resting period of under 50 years, were collected. 21 research reports
      could be found, describing macroscopic findings on soil-embedded human bones with
      known PMI. All in all, 1295 individuals were examined in these investigations. A
      censorious review of the summarized results found in literature reveals that the
      following findings have never been seen in a PMI of 50 years or less. Outer
      appearance: macroscopically no adipocere, deep incisions of the outer compact
      layer, extensive defects of the bone surface, intense brownish-black lawn of
      microorganisms, fraying of the outer lamellar system, lifting of the cortical
      area, torsion of the tissue, attached brushit, bone manually breakable. On
      freshly sawn cross sections: lack of adipocere, brushit in the marrow area,
      reduced or lack of UV-fluorescence.

PMID- 15012039
TI  - [Injury potential of soft-air pistols].
AB  - Report on a case in which an 8-year-old girl was injured on the left anterior
      thoracic wall by two shots fired by her 14-year-old cousin from a soft-air pistol
      (replica of mod. 17 make Glock, cal. 6 mm, solid plastic bullets); the
      projectiles caused two skin lesions, both reaching into the subcutis. The results
      of our own shooting tests with 2 different soft-air pistols and the injuries seen
      in our case confirm that soft-air pistols may cause penetrating soft-tissue
      injuries when fired from a short distance.

PMID- 15012041
TI  - [Reconstruction of a real car-pedestrian-accident. Part I: Generating an
      individual digital topographic image of the victim].
AB  - The aim of forensic biomechanics is the reconstruction of traumatic events based
      on the pathological findings in the victim's morphology, the accident traces and
      the car damages. The use of forensic documentation tools (e.g.
      Streifenlichttopometrie) enables 3-dimensional and proportional accurate
      documentation of the victim's body, of its injuries and of the car damages with
      submillimeter precision. The generated topographic image serves as input for a
      multi-body system model of the victim. It allows further to determine exactly the
      contact points between car and victim for a computer simulated dynamical
      reconstruction of the impact situation. In the case of an accident involving a
      car and a pedestrian the generation and application of computer aided 3
      dimensional reconstruction models are shown.

PMID- 15012040
TI  - [Comparative investigations on the uptake of basic substances into the human
      keratinocyte cell line HaCaT--a model for the uptake of xenobiotics into the
      keratinocytes of the hair follicle].
AB  - The human cell line HaCaT was used to study drug uptake by keratinocytes as an in
      vitro model to elucidate drug incorporation into anagen hair follicle. The basic
      drugs under investigation were taken up very rapidly resulting in a concentration
      plateau in the keratinocytes which was dependent on the drug concentration in the
      cell culture medium. The results obtained for HaCaT clearly demonstrated the
      existence of a partition-equilibrium between the extracellular and intracellular
      drug concentrations. Only small amounts of the offered drugs were taken up and
      remarkable differences were observed showing a decreasing uptake for imipramine >
      haloperidol > cocaine/benzoylecgonine. Total protein content in the culture
      medium was 3.5 +/- 0.3 mg/mL and the protein binding of the drugs to the foetal
      serum proteins was found to be negligible in the experiments. Overall, the in
      vitro findings were consistent with previous observations for in vivo drug
      incorporation into hair. In particular, an explanation was found for the
      correlation between the AUC-value and hair concentration observed in animal
      studies as well as for the generally low drug concentrations in non-pigmented
      hair.

PMID- 15012042
TI  - [Reconstruction of a real car-pedestrian-accident. Part 2: Modelling and
      simulation].
AB  - A real pedestrian-car-crash was reconstructed by use of a multi-body simulation.
      The main aspect was the use of an individual body surface for the human body
      model and the car. The simulation allowed a plausible reconstruction of the
      accident. A good correlation of the contact-pairs in the model and the real
      forensic data was achieved by variation of the hypothetical szenario.

PMID- 15012043
TI  - Reversal of liver fibrosis and cirrhosis--an emerging reality.

PMID- 15012044
TI  - Perioperative optimisation.

PMID- 15012045
TI  - Physician opinions on the implementation of the SIGN guideline for heart failure.
AB  - BACKGROUND AND AIMS: To assess physician opinion of and attitudes to, the
      Scottish Intercollegiate Guideline Network (SIGN) guideline for chronic heart
      failure (CHF) due to left ventricular systolic dysfunction. METHODS AND RESULTS:
      A questionnaire examining physicians' attitudes and their use of the SIGN
      guideline for CHF was distributed to 158 physicians in two teaching hospitals
      within one NHS trust. 65% of recipients responded. More cardiologists had read
      the guideline compared to non-cardiologists (91 vs 56%, p < 0.05). The majority
      of cardiologists and non-cardiologists agreed that it was applicable to their
      patients (92 vs 79%, p > 0.1) and that implementation may reduce hospital
      admissions (65 vs 59%, p > 0.5). In general, compliance was thought to be a
      problem in only a minority of patients in both groups for angiotensin converting
      enzyme inhibitors (8 vs 19%), diuretics (12 vs 29%) and digoxin (17 vs 19%, all p
      > 0.1). Beta-blocker compliance was identified as a problem by both groups (50 vs
      53%, P > 0.5) while fewer cardiologists reported compliance as a problem with
      spironolactone (4 vs 25%, p < 0.05). More cardiologists felt that there was a
      need for a community based CHF nurse specialist (100 vs 57%, p < 0.001), and that
      this strategy would reduce hospital admissions (92 vs 57%, p < 0.01).
      CONCLUSIONS: Differences exist between cardiologist and non-cardiologist
      physicians' awareness of the SIGN guideline for CHE. Furthermore, we have shown
      differences in reported implementation of the guideline and perceived
      difficulties with specific drug therapies. This is in spite of high levels of
      agreement in both groups with the treatment suggested by the guideline and the
      anticipated benefits resulting from its implementation.

PMID- 15012046
TI  - Exercise during haemodialysis: West of Scotland pilot study.
AB  - BACKGROUND: Exercise during dialysis (EDD) in End-Stage Renal Disease (ESRD) has
      been documented as an effective intervention to improving a patient's aerobic
      capacity. AIMS: This pilot study aimed to confirm physiological improvements, to
      establish its safety and practicality and to form guidelines for a long-term
      study, leading to the integration of EDD in ESRD therapy. METHODS: A total of 17
      patients on hospital haemodialysis were recruited: ten exercisers (age 42.4 +/-
      12.6) and six controls (age 41.0 +/- 8.3). Both groups were initially tested for
      estimated VO(2max), heart rate, blood pressure, leg extension peak torque,
      anxiety and depression levels, as well as biochemical and haematological values.
      The exercisers then underwent cycling ergometer exercise sessions during
      dialysis, twice weekly, for a total of 12 sessions. Both groups were re-tested
      after this period. RESULTS: All test and exercise sessions were completed without
      complication. Compliance was high with only 1 exerciser failing to complete all
      12 sessions. The exercisers showed a statistically significant increase (p <
      0.05) in EDD workrates (44.3 to 52.1 watts) during the 12 sessions and a
      reduction in anxiety (p < 0.05). Statistical analysis showed no other significant
      changes in either group after the 6-week period. CONCLUSION: This pilot study has
      confirmed that aerobic EDD is feasible and well accepted by patients on hospital
      haemodialysis. EDD reduced anxiety scores and showed a trend for an improved
      level of aerobic fitness.

PMID- 15012047
TI  - Childhood asthma in the Highlands of Scotland--morbidity and school absence.
AB  - BACKGROUND: The prevalence of childhood asthma in Scotland is one of the highest
      in the world. The morbidity secondary to allergic diseases is significant in
      terms of costs to the nation and effects on the family including the child. AIMS:
      The aims of this study were to describe the prevalence of asthma, eczema and hay
      fever in the Highlands of Scotland and in the Shetland Isles and to examine
      factors in relation to quality of life and social deprivation. METHOD: A total
      population survey of 12 year old children using a parent completed questionnaire.
      RESULTS: 86.3% (2658/3080) returned questionnaires. Of the 2549 questionnaires
      analysed, 476 (18.7%) reported asthma ever, 362 (14.2%) wheeze in last 12 months,
      508 (19.9%) reported hay fever ever and 555 (21.8%) reported eczema ever. Of the
      children reporting asthma or wheeze, 35.4% (229/647) had missed school because of
      asthma or wheeze, 38.0% (246/647) had missed physical education. 62.5% (354/566)
      of subjects with wheeze ever reported sleep disturbance. Deprivation measured by
      DEPCAT scores was associated with maternal smoking and bronchitis in the child
      but not with allergic diseases. CONCLUSION: Compared with previous studies, the
      prevalence of asthma was unchanged but eczema has increased in Highland
      adolescents. Allergic disease has a significant impact on school attendance and
      physical activity. Deprivation was associated with maternal smoking and
      bronchitis in the child but not with allergic diseases. The impact of allergic
      diseases in rural areas may be different from urban areas.

PMID- 15012048
TI  - An audit of neonatal respiratory morbidity following elective caesarean section
      at term.
AB  - Studies have suggested that a reduction in neonatal respiratory morbidity may be
      achieved by delaying elective caesarean section until 39 weeks gestation. In 1997
      staff at the Glasgow Royal Maternity Hospital were concerned at the level of
      neonatal respiratory morbidity following elective caesarean section. AIMS: To
      determine the extent of neonatal respiratory morbidity following elective
      caesarean section at term. Then to present the findings, make recommendations and
      perform a repeat analysis. METHODS: A retrospective analysis of all elective
      caesarean sections at term between October 1996 and October 1997 was performed.
      Labour ward, operating theatre and SCBU records were examined, followed by
      maternal and infant case note review. The gestational age at the time of
      caesarean section and any neonatal respiratory morbidity was recorded. The
      results were subsequently presented at a perinatal morbidity meeting and a
      recommendation made to delay elective sections until 39 weeks gestation. The
      audit was repeated between June 1999 and June 2000. RESULTS: The first cycle of
      the audit showed significantly lower rates of neonatal admissions with advancing
      gestation (p < 0.001). There was also a reduction in the number of infants
      requiring oxygen (p = 0.001), the number of infants requiring intensive care
      admission (p = 0.001) and ventilation (p = 0.003) with advancing gestation. In
      the second cycle of the audit there was a significant decrease in the number of
      elective caesarean sections performed prior to 39 weeks gestation (51% vs. 26%)
      (p < 0.0001). There were fewer neonatal admissions with respiratory morbidity
      between the two phases of the audit (26/292 vs. 18/327) (RR = 0.62, 95% CI 0.34
      1.1). There was also a reduction in the number of infants requiring oxygen (RR =
      0.5, 95% CI 0.23-1.06) the number of infants requiring intensive care admission
      (RR = 0.45, 95% CI 0.15-1.29) and the number of infants requiring ventilation (RR
      = 0.38, 95% CI 0.1-1.47). CONCLUSION: A reduction in neonatal respiratory
      morbidity can be achieved by delaying elective caesarean section until 39 weeks
      gestation.

PMID- 15012050
TI  - Chiral metallacyclophanes: self-assembly, characterization, and application in
      asymmetric catalysis.
AB  - [structure: see text] A family of chiral metallacyclophanes has been readily
      assembled based on robust Pt-acetylide linkage and characterized by a variety of
      spectroscopic techniques and X-ray crystallography. The steric congestion around
      the chiral dihydroxy groups in rigid metallacyclophane 4 prevents their reactions
      with Ti(O(i)()Pr)(4) to form active catalysts for enantioselective diethylzinc
      additions to aromatic aldehydes. In contrast, chiral dihydroxy groups in more
      flexible unclosed metallacyclophane 5 are effective ligands for enantioselective
      catalytic diethylzinc additions to aromatic aldehydes.

PMID- 15012049
TI  - Routine unselected access to day case electrical cardioversion of persistent
      atrial fibrillation: anticoagulant preparation is the key factor.
AB  - OBJECTIVES: To determine the routine efficacy of a day case cardioversion system
      operating in a remote geographical area with an unselected case referral base and
      a proportion of direct GP access. DESIGN: Prospective analysis of all admitted
      cases in a 13 week period. PARTICIPANTS: 47 consecutive patients admitted for 49
      planned episodes of electrical cardioversion. MEASUREMENTS: Pre procedural
      investigations and preparation, immediate and three-month outcome of rhythm
      following ECV. RESULTS: We found a predominant use by the cardiac unit despite
      working within a general medical service unit suggesting low case selection from
      non-cardiac sources. We suspected and confirmed a high rate of point of care
      treatment cancellation. Poor management of anticoagulation was the dominant
      reason for canceling planned treatment. Procedural preparation in terms of anti
      arrhythmic drug therapy and investigations seemed well preserved. CONCLUSION: New
      strategies for initiating and sustaining adequate outpatient warfarin therapy are
      needed to allow such systems to operate efficiently.

PMID- 15012051
TI  - Synthesis and structure of m-terphenyl-based cyclophanes with nitrogen intra
      annular functional groups.
AB  - [structure: see text] Herein we describe an efficient synthesis of cyclophanes
      comprised of intra-annular nitrogen functional groups through a template-promoted
      cyclization by ring-closing metathesis (RCM). The synthesis proceeds through
      condensation of meta-styryl anilines with acenaphthenequinone to form the
      templates, followed by RCM with Grubb's second-generation catalyst to afford
      cyclophanes with internal alpha-diimine functionality. Prolonged hydrogenation
      efficiently removes the template to provide a macrocycle containing the diamine
      functionality.

PMID- 15012052
TI  - Novel dolabellane-type diterpene alkaloids with lipid metabolism promoting
      activities from the seeds of Nigella sativa.
AB  - [structure: see text] Four new dolabellane-type diterpene alkaloids, nigellamines
      A(1) (1), A(2) (2), B(1) (3), and B(2) (4), were isolated from the seeds of
      Nigella sativa. Their absolute stereostructures were determined on the basis of
      chemical and physicochemical evidence. Nigellamines A(1) (1), B(1) (3), and B(2)
      (4) were found to show potent lipid metabolism promoting activity in primary
      cultured mouse hepatocytes, and their activities were equivalent to that of a
      PPAR-alpha agonist, clofibrate.

PMID- 15012053
TI  - A remarkably long-lived benzyl carbanion.
AB  - [structure: see text] The photochemistry of ketoprofen, a widely used
      nonsteroidal antiinflammatory drug (NSAID) has been the subject of several
      studies as a result of its known phototoxicity. Photolysis of ketoprofen leads to
      3-ethylbenzophenone, a process that is mediated by a short-lived carbanion. We
      have found that under carefully controlled conditions in THF, the lifetime of the
      carbanion can be extended to several hours, thus providing a powerful tool for
      studying the mechanism of its formation and subsequent reactions.

PMID- 15012055
TI  - First direct observation of reactive carbenes in the cavities of cation-exchanged
      Y zeolites.
AB  - [reaction: see text] Herein we report the first direct observation of reactive
      carbenes within the cavities of cation-exchanged Y zeolites. Chloro(phenyl)- and
      bromo(phenyl)carbenes were generated upon laser photolysis of 3-halo-3
      phenyldiazirines incorporated within dry zeolites and the absolute reactivity of
      the carbenes was investigated as a function of counterbalancing cation and
      coincorporated quenchers in order to elucidate the behavior of these
      intermediates within zeolites. Product analysis performed upon thermolysis of the
      diazirine in Y zeolites yielded products that were identified as those derived
      from the carbene.

PMID- 15012054
TI  - Cause of hydration/dehydration in condensed organic materials: synthesis of
      hydrophobic pores.
AB  - [reaction: see text] The unique solid-state hydration/dehydration properties of
      the diacid (+/-)-1e in comparison with other homologues of the same family are
      studied. Hydrophobic enhancement, which is a consequence of the loss of water
      molecules from (+/-)-1e chains, is a property that can be exploited to achieve
      organic condensed systems for nonpolar molecules by interstitial van der Waals
      confinement.

PMID- 15012056
TI  - Synthesis of [323]-p-octiphenyls: orthogonal functionalization along a rigid-rod
      scaffold for refined supramolecular architecture.
AB  - [structure: see text] The synthesis of p-octiphenyls carrying orthogonal tert
      butyl esters in the peripheral positions 1(2), 2(2), 3(3), 6(2), 7(3), and 8(2)
      and either p-methoxybenzyl or benzyl ester substituents in the central positions
      4(2) and 5(3) is described. Resolution-enhanced HSQC/HMBC two-dimensional NMR
      spectroscopy is implemented as an attractive method for the complete
      characterization of complex p-oligophenyl scaffolds.

PMID- 15012057
TI  - Single-site modifications and their effect on the folding stability of m
      phenylene ethynylene oligomers.
AB  - [reaction: see text] The folded structure of a m-phenylene ethynylene oligomer is
      tolerant to single-site modifications to both the backbone sequence and end
      groups. The helical structure is reinforced by multiple noncovalent interactions,
      allowing the oligomer sequence to be customized without a significant change in
      stability in most cases. The small changes that are observed are consistent with
      the expected behavior of pi-stacked systems and demonstrate subtle control over
      folding through single-site modifications.

PMID- 15012058
TI  - A new nucleophilic addition/ring-closure sequence. Enantioselective synthesis of
      3-deoxy-8-oxatropanes.
AB  - [reaction: see text] A study of new nucleophilic addition/ring-closure (NARC)
      sequences has resulted in the development of a stereoselective synthetic route to
      3-deoxy-8-oxatropanes. The new sequences consisted of either a syn or anti aldol
      addition, employing an omega-alkenoyl sultam, followed by two-step bicyclic ring
      construction involving, consecutively, ring-closing metathesis and intramolecular
      oxymercuration.

PMID- 15012060
TI  - Conrotatory ring-opening reactions of cyclopropyl anions in monocyclic and
      tricyclic systems.
AB  - [reaction: see text] Only conrotatory transition structures were located by
      B3LYP6-311++G(3df, 2p) computations for the electrocyclic ring opening of
      cyclopropyl anions having different substituents (H, Me, CN). The transition
      structure for the similarly substituted cyclopropyl anion fused to a bicyclic
      system exhibits the same features, in apparent contradiction with the observed
      product. A reaction path where the direction of twist changes after the
      transition state provides an explanation alternative to those proposed in recent
      reports.

PMID- 15012059
TI  - S-linked ganglioside analogues for use in conjugate vaccines.
AB  - [structure: see text] Glycosidase resistant thioglycoside precursors of the
      melanoma-associated ganglioside GM(2) have been synthesized starting from
      lactose. Syntheses of several analogues of ganglioside GM(3) and a positional
      isomer have been developed. These compounds contain thio-linked sialic acid
      residues and a modified ceramide aglycon functionalized for coupling to proteins,
      surfaces, or matrices. The hydrolytic stability of these oligosaccharides
      enhances the immunogenicity of the corresponding conjugate vaccines by ensuring
      their integrity in the acidic compartments of antigen processing cells.

PMID- 15012061
TI  - The Woodward-Hoffmann-De Puy rule revisited.
AB  - [structure: see text] An estimate of the kinetic advantage, in the gas phase and
      in MeOH, of one of the two allowed disrotatory movements in the electrocyclic
      ring opening of cyclopropyl derivatives has been theoretically obtained at the
      B3LYP/6-311++G level. Confirming the Woodward-Hoffmann-DePuy rule, the
      torquoselectivity of this process is attributed to charge donation from the
      dissociating C-C bond to the antibonding orbital of the breaking C-Br bond.
      Substituents do not modify the inherent torquoselectivity.

PMID- 15012062
TI  - Improved photostability and fluorescence properties through polyfluorination of a
      cyanine dye.
AB  - [structure: see text] A polyfluorinated cyanine dye has been synthesized and
      characterized. Compared with the nonfluorinated analogue, the dye exhibits
      significantly reduced aggregation in aqueous media, enhanced fluorescence quantum
      yield, greater resistance to photobleaching upon direct irradiation, and reduced
      reactivity toward singlet oxygen. All of these properties are favorable for use
      of cyanine dyes as fluorescent labels and point toward fluorination as a general
      strategy for improving performance in imaging applications.

PMID- 15012063
TI  - A general and mild Ullmann-type synthesis of diaryl ethers.
AB  - [reaction: see text] An efficient method for the synthesis of diaryl ethers under
      particularly mild conditions is described. Inexpensive ligands were found to
      greatly accelerate the Ullmann-type coupling of aryl bromides or iodides with
      phenols. A series of diaryl ethers were obtained with excellent yields in
      acetonitrile in the presence of Cs(2)CO(3) and catalytic copper(I) oxide. The
      reaction tolerates substrates with unfavorable substitution patterns, such as
      sterically hindered coupling partners or electron-rich aryl halides.

PMID- 15012064
TI  - Six- versus five-membered ring formation in radical cyclizations of 7-bromo
      substituted hexahydroindolinones.
AB  - [reaction: see text] Radical cyclization of N-allyl-7-bromo-3a-methyl
      hexahydroindol-2-one affords a six-membered ring product that prevails over the
      isomeric five-membered compound. The former product is generated through two
      reaction pathways: (a) 6-endo-trig ring closure and (b) rearrangement of an
      intermediate methylenecyclopentyl radical obtained by 5-exo-trig cyclization.

PMID- 15012065
TI  - Reactivity of beta-lactamido N-sulfonyl radicals.
AB  - [reaction: see text] A new class of N-substituted radical has been studied.
      Obtained from the corresponding chlorides, beta-lactamido N-sulfonyl radicals
      were allylated and added onto electron-rich olefins. It has been shown that the
      radicals do not undergo desulfonylation and are electrophilic in nature.

PMID- 15012066
TI  - Heck vinylation of aryl iodides by a silica sol-gel entrapped Pd(II) catalyst and
      its combination with a photocyclization process.
AB  - [reaction: see text] Silica sol-gel encaged PdCl(2)(PPh(3))(2) is a recyclable
      catalyst for the Heck vinylation of aryl iodides. It is possible to couple the
      Heck reaction with photocyclization in a one-pot process.

PMID- 15012067
TI  - New method for the synthesis of diversely functionalized imidazoles from N
      acylated alpha-aminonitriles.
AB  - [reaction: see text] A new general method for the synthesis of medicinally
      important diversely functionalized imidazoles from N-acylated alpha-aminonitriles
      has been developed. N-Acylated alpha-aminonitriles were reacted with
      triphenylphosphine and carbon tetrahalide to afford 2,4-disubstituted 5-halo-1H
      imidazoles in good yield. This new methodology was applied for the synthesis of 2
      butyl-4-chloro-5-hydroxymethylimidazole. These halo-imidazoles can be directly
      converted to 2,4,5-trisubstituted imidazoles through palladium-catalyzed coupling
      reactions.

PMID- 15012068
TI  - A highly regio- and stereoselective carbocupration of fluoroalkylated internal
      alkynes: a short total synthesis of the antiestrogenic drug panomifene.
AB  - [reaction: see text] A highly regio- and stereoselective carbometalation reaction
      of fluoroalkylated internal alkynes with organocopper reagents is described. This
      reaction is utilized successfully in the short, stereoselective total synthesis
      of the antiestrogenic drug panomifene.

PMID- 15012069
TI  - Effects of alternative side chain pairings and reverse turn sequences on
      antiparallel sheet structure in beta-peptide hairpins.
AB  - [structure: see text] We describe a series of beta-peptide hexamers that allow us
      to explore relationships between sequence and hairpin folding. Different reverse
      turn segments are compared at the central two positions, and the outer residues
      allow a variety of interstrand side chain-side chain pairings. NMR analysis in
      methanol demonstrates that several reverse turn and side chain pairing
      arrangements are compatible with antiparallel beta-peptide sheet structure;
      however, none of the beta-peptides folds in water.

PMID- 15012070
TI  - Stereoselective synthesis of the ABC ring system of norzoanthamine.
AB  - [reaction: see text] An efficient synthesis of enone 4, representing the ABC ring
      motif of norzoanthamine, is presented. The crucial C22 quaternary center was
      introduced via a stereoselective methylation of enone 8. The trans-anti-trans
      relative configuration of the ABC framework of 4 was installed via a sequence of
      reactions that included a hydroboration and a modified Robinson annulation.

PMID- 15012072
TI  - Proposal for the metallacycle pathway during the cyclopropanation catalyzed by
      cobalt-Schiff base complexes.
AB  - [reaction: see text] The density functional study of the cobalt(II) complex
      catalyzed cyclopropanation revealed that the cobalt(II)-Schiff base complex
      without an ethylene bridge would be flexible enough to transform into the cis
      beta conformer while approaching the olefin; consequently, the metallacycle
      pathway would be preferred, while the ethylene bridge would stabilize the planar
      conformer to allow reaction via the concerted mechanism.

PMID- 15012073
TI  - No-D NMR (no-deuterium proton NMR) spectroscopy: a simple yet powerful method for
      analyzing reaction and reagent solutions.
AB  - [reaction: see text] The title technique is a convenient and powerful method for
      directly monitoring or assaying any reaction mixture or reagent solution.
      Examples of some common processes (Fischer esterification, lithiation,
      butyllithium/THF compatibility, olefin metathesis, and a quantification assay),
      each interrogated in its native solvent, are presented. The spectral data are
      easy to acquire, and the information content makes a compelling case for routine
      use of No-D NMR spectroscopy.

PMID- 15012071
TI  - Counterion-directed regioselective acetylation of octyl beta-D-glucopyranoside.
AB  - [reaction: see text] The DMAP-catalyzed acetylation of octyl beta-D
      glucopyranoside with a series of acetylating agents has been investigated. The
      nature of the counterion of the catalytic DMAP-acetyl complex dramatically
      influences the outcome of the reaction, indicating that the deprotonation of the
      transition state is controlling the reaction. Noncovalent interactions of the
      acetate ion with the substrate seem to direct the acetylation toward secondary
      hydroxyl groups.

PMID- 15012074
TI  - Stereoselective formation of tri- and tetracycles by samarium diiodide-induced
      cyclizations of naphthyl-substituted ketones.
AB  - [reaction: see text] Samarium diiodide promotes smooth reductive cyclizations of
      gamma-naphthyl-substituted ketones to afford tri- and tetracyclic compounds in
      high yields and with excellent stereoselectivities. Cyclic ketones furnish
      steroid-like compounds with "unnatural" cis/cis annulation of rings B/C/D. The
      remaining styrene-type double bond of ring B allows further stereoselective
      reactions. Cases with matched and mismatched relative configuration could be
      identified leading to dramatic differences in the ring closure ability.

PMID- 15012075
TI  - Enantioselective total synthesis of eurylene, 14-deacetyl eurylene, and their 11
      epimers: the relation between ionophoric nature and cytotoxicity.
AB  - [structure: see text] Enantioselective synthesis of eurylene, 14-deacetyl
      eurylene, and their 11-epimers was achieved. The characteristic structural
      feature of these compounds is two tetrahydrofuran (THF) rings substituted in
      different stereochemistry. The synthetic approach involves nonstereoselective THF
      ring formation to afford both segments from a common precursor. We also
      investigated their ionophoric nature and cytotoxicity. The complexation of these
      compounds with K(+) might be related to their cytotoxic activity.

PMID- 15012076
TI  - A formal total synthesis of (+/-)-halichlorine and (+/-)-pinnaic acid.
AB  - [reaction: see text] A stereocontrolled approach for the preparation of the
      Danishefsky intermediates has been developed starting with the azaspirobicyclic
      ketone as a common precursor, representing a formal total synthesis of (+/-)
      halichlorine and (+/-)-pinnaic acid. This approach involves the construction of
      the 1,7-disubstituted 6-azaspiro[4.5]decane with the proper stereochemistry
      established by olefin hydrogenation followed by C-methylation of the
      spirotricyclic lactam and the subsequent processes involving lactam ring-opening
      using methyl triflate and RCM to form the azaspirotricyclic quinolizidine
      skeleton.

PMID- 15012077
TI  - Reactions of alpha,alpha'-dihydroxy ketones with phosgene. Structural
      requirements for spiro epoxy carbonate formation.
AB  - [reaction: see text] Apha,alpha'-dihydroxy ketones having two OH groups that can
      come into close proximity react with phosgene in the presence of DMAP to produce
      1,3-dioxane-2,5-diones. When covalent bonding in this manner is prohibited,
      alternate reaction pathways can in principle be adopted. Of these, the generation
      of spiro epoxy carbonates is shown to be feasible in three examples. In other
      cases, the alpha-ketol rearrangement precedes diacylation.

PMID- 15012079
TI  - First total synthesis of trans- and cis-resorcylide: remarkable hydrogen-bond
      controlled, stereospecific ring-closing metathesis.
AB  - [reaction: see text] Stereospecific synthesis of the pair of natural macrolides,
      trans- and cis-resorcylide, was performed using ring-closing metathesis on dienes
      3 and 4, which lack or feature an intramolecular H-bond, respectively. An
      effective Stille carbonylative coupling of benzyl chlorides 11 and 15 was
      employed for their preparation. The influence of intramolecular H-bonding on the
      interconversions of resorcylides was also studied.

PMID- 15012078
TI  - Unique reactions of glycosyl iodides with oxa- and thiocycloalkane acceptors.
AB  - [reaction: see text] Glucosyl-, galactosyl-, and mannosyl iodides efficiently
      react with strained oxacycloalkane acceptors to afford O-glycosides with high
      beta-selectivity. The mechanism of ring opening was investigated by reacting
      mannosyl iodides with pure enantiomers of propylene oxide and styrene oxide.
      Competition experiments between three- and five-membered oxacycloalkanes were
      also investigated. Finally, beta-thiomannosides were synthesized from
      thiocycloalkane acceptors.

PMID- 15012080
TI  - Carbene fragmentation in the bicyclo[3.1.0]hexyl system: disconnecting the
      trishomocyclopropenyl cation.
AB  - [structure: see text] Fragmentation of cis-3-bicyclo[3.1.0]hexyloxychlorocarbene
      (4) affords cis- and trans-3-bicyclo[3.1.0]hexyl chlorides, cis- and trans-2
      bicyclo[3.1.0]hexyl chlorides, and 2-bicylo[3.1.0]hexene. The promiscuity of
      product formation, taken together with kinetics and labeling studies, suggests
      that the fragmentation of 4 proceeds via a 3-bicyclo[3.1.0]hexyl cation-chloride
      ion pair but largely bypasses a trishomocyclopropenyl cation intermediate.

PMID- 15012081
TI  - Microwave-assisted amination from aryl triflates without base and catalyst.
AB  - [reaction: see text] Aryl triflates are effectively converted to the
      corresponding anilines under microwave irradiation in 1-methyl-2-pyridone (NMP)
      without base and catalyst. Aryl triflates substituted with both electron-poor and
      electron-rich groups give good to excellent yields. It is noteworthy that the
      halogenated aryl triflates can chemoselectively react with amines to afford
      halogenated anilines.

PMID- 15012082
TI  - Synthesis and metalation of a chiral, pyridine-strapped, cyclic
      bis(benzimidazole) ligand.
AB  - [reaction: see text] Synthesis of a chiral, strapped, cyclic bis(benzimidazole)
      ligand is reported. This compound forms a stable, Jahn-Teller-distorted,
      octahedral Cu(II) complex in which the elongated axis is positioned within the
      main macrocycle. The C(2)-symmetric bis(benzimidazole) core adopts a highly
      ruffled conformation with the ortho-substituted benzene rings located anti
      relative to the pyridine-bearing strap.

PMID- 15012083
TI  - A new synthetic route to nucleosides: dissymmetric construction of a cyclopentene
      system by double [3,3]-sigmatropic rearrangement and double ring-closing
      metathesis.
AB  - [reaction: see text] The dissymmetric synthesis of a carbocyclic nucleoside was
      achieved by a novel double [3,3]-sigmatropic rearrangement/double ring-closing
      metathesis strategy with a high stereoselectivity.

PMID- 15012084
TI  - Alpha,omega-bis(quinquethienyl)alkanes as a pi-dimer model of polythiophene.
AB  - [structure: see text] A series of the title dimeric quinquethiophenes linked with
      a di- to hexamethylene spacer was synthesized and examined as a pi-dimer model of
      polythiophene. Upon two-electron oxidation with iron(III) chloride in
      dichloromethane, they readily form intramolecular pi-dimer species, except for
      the dimethylene-linked dimer that cannot be bent into a pi-stacked structure.

PMID- 15012085
TI  - Microwave-promoted three-component coupling of aldehyde, alkyne, and amine via C
      H activation catalyzed by copper in water.
AB  - [reaction: see text] An efficient three-component coupling of aldehyde, alkyne,
      and amine to generate propargylamines has been effected under microwave
      irradiation in water using only CuI catalyst without the noble metal cocatalyst.
      This method has proved to be applicable to a wide range of substrates. In
      addition, the preliminary experiment using (S)-proline methyl ester as a chiral
      source demonstrated that it could be developed to be a direct and highly
      diastereoselective method for construction of chiral propargylamines.

PMID- 15012086
TI  - Azomethine ylides from tin-substituted cyclic carbinol amides: a new route to
      highly substituted pyrrolizidines.
AB  - [reaction: see text] Addition of organolithium and organomagnesium reagents to N
      (tri-n-butylstannylmethyl)phthalimides yields N-(tri-n-butylstannylmethyl) cyclic
      carbinol amides, which form azomethine ylides upon treatment with HF.pyridine.
      This novel route to azomethine ylides allows rapid access to highly
      functionalized pyrrolizidines (1,2,3,9b-tetrahydropyrrolo[2,1-a]isoindol-5-ones).

PMID- 15012087
TI  - Diastereoselective aldol reaction of N,N-dibenzyl-alpha-amino aldehydes with
      ketones catalyzed by proline.
AB  - [reaction: see text] L-proline-catalyzed direct aldol reaction of L-amino acid
      derived N,N-dibenzyl amino aldehydes with acetone, cyclopentanone, or
      hydroxyacetone provides gamma-amino-beta-hydroxy- or gamma-amino-alpha,beta
      dihydroxy-ketones with moderate to excellent yields and diastereoselectivities.

PMID- 15012088
TI  - An efficient synthesis of 3-substituted 3H-pyrimidin-4-ones.
AB  - [reaction: see text] A novel and practical synthesis of 3-substituted 3H
      pyrimidin-4-ones is described. The key step involves the cyclization of enamide
      esters, derived from readily available beta-keto esters, with trimethylaluminum
      and various primary amines.

PMID- 15012089
TI  - Synthesis of a Val-Pro diaminodiol dipeptide isostere by epoxyamine cyclization.
AB  - [reaction: see text] The stereoselective synthesis of a novel proline-containing
      dipeptide isostere is described. Starting from l-valine, three new contiguous
      stereocenters are generated by asymmetric induction and epoxide chemistry, while
      the pyrrolidine ring of proline is introduced in the final step via
      intramolecular ring opening of the amino acid derived epoxyamine. Proline
      containing peptidomimetics are potentially attractive as selective inhibitors of
      proline-specific enzymes, such as PPIases and retroviral proteases, and as
      analogues of bioactive peptides.

PMID- 15012090
TI  - Extractive phase vanishing reactions with dichloromethane, perfluorohexanes, and
      dibromoethane: slow addition in a test tube.
AB  - [reaction: see text] Partition coefficient measurements and experiments with a
      dye show that a new fluorous "phase vanishing reaction" described by Jana and
      Verkade occurs by an extractive mechanism. This mechanism is contrasted with the
      original diffusive phase-vanishing reactions introduced by Ryu and co-workers.

PMID- 15012091
TI  - Quantum mechanical calculations of NMR J coupling values in the determination of
      relative configuration in organic compounds.
AB  - [structure: see text] An approach relying on quantum mechanical calculations of
      proton-proton and proton-carbon J coupling values is proposed as a tool for
      assigning the relative configuration on chiral organic compounds. The method is
      suitable for carbon frameworks containing several adjacent stereogenic centers
      and may allow significant advances in the extensive use of spin-spin couplings in
      structural elucidation.

PMID- 15012092
TI  - Photoinduced electron-transfer bicyclopropenyl-benzene rearrangements of
      2,2',3,3'-tetraphenylbicyclopropenyls: a new mechanism via Dewar benzene.
AB  - [reaction: see text] The 9,10-dicyanoanthracene-sensitized photoreaction of 1
      methyl- and 1,1'-dimethyl-2,2',3,3'-tetraphenylbicyclopropenyl gives the
      corresponding benzene and Dewar benzene derivatives, indicating that their
      photoinduced electron-transfer bicyclopropenyl-benzene rearrangements proceed via
      Dewar benzenes.

PMID- 15012093
TI  - Appending a tris-imidazole ligand with a Tyr 244 mimic on the distal face of
      bromoacetamidoporphyrin.
AB  - [structure: see text] Bromoacetamidoporphyrin is a convenient synthon for the
      attachment of distal superstructures at room temperature in good yields. New
      models are presented that contain a tris-imidazole distal ligand set bound to the
      porphyrin in either a binary or trinary fashion. More importantly, one distal
      imidazole is cross-linked to a phenol mimicking Tyr(244), making this model the
      closest structural analogue yet reported of the metal free cytochrome c oxidase
      (CcO) active site.

PMID- 15012094
TI  - Synthesis of 3-iodoindoles by electrophilic cyclization of N,N-dialkyl-2-(1
      alkynyl)anilines.
AB  - [reaction: see text] A wide variety of N-alkyl-3-iodoindoles are readily prepared
      under very mild reaction conditions by the palladium/copper-catalyzed cross
      coupling of N,N-dialkyl-o-iodoanilines and terminal alkynes, followed by
      electrophilic cyclization by I(2)(). Alkyl-, aryl-, and vinylic-substituted
      alkynes all undergo iodocyclization in excellent yields.

PMID- 15012095
TI  - Total synthesis of the proposed structure for spirofungin B: a reassignment of
      the stereochemistry.
AB  - [structure: see text] The total synthesis of the proposed structure for
      spirofungin B (2) is described. The data for the synthetic material did not
      compare with that for the natural product leading to the conclusion that the
      structure 2 assigned for spirofungin B is incorrect. Analysis of the NMR data
      reported for spirofungins A and B as well as related spiroketals allowed for the
      reassignment of the stereochemistry of spirofungin B to be that corresponding to
      15-epi-spirofungin A (27).

PMID- 15012096
TI  - Efficient, stereoselective synthesis of trans-2,5-disubstituted morpholines.
AB  - [reaction: see text] Enantio- and diastereoselective syntheses of trans-2,5
      disubstituted morpholine derivatives are described. The routes are initiated by
      the reaction of enantiopure epoxides (2) with amino alcohols (3) and address the
      problem of regioselective hydroxyl activation-ring closure of the resulting amino
      diol adducts for (amino alcohol-derived) alkyl substituents of different steric
      demands.

PMID- 15012098
TI  - Synthesis of long-chain polyketide fragments by reaction of 1,3-dioxy-1,3-dienes
      with allylsilanes: umpolung with sulfur dioxide.
AB  - [reaction: see text] In the presence of a Lewis or protic acid and at low
      temperature, 1,3-dioxy-1,3-dienes add to sulfur dioxide generating zwitterionic
      intermediates that can react with carbon nucleophiles such as allylsilanes. After
      a retro-ene elimination of SO(2), valuable polyketide precursors are obtained.

PMID- 15012097
TI  - Berkeleydione and berkeleytrione, new bioactive metabolites from an acid mine
      organism.
AB  - [structure: see text] Two novel hybrid polyketide-terpenoid metabolites were
      isolated from a Penicillium sp. growing in the Berkeley Pit Lake of Butte,
      Montana. Their structures were deduced by spectroscopic analysis and confirmed by
      single-crystal X-ray analysis on berkeleydione (1). Both compounds inhibited
      matrix metalloproteinase-3 and caspase-1, and berkeleydione showed activity
      toward non-small-cell lung cancer in NCI's human cell line antitumor screen.

PMID- 15012099
TI  - Synthesis of 2,2'-bipyrroles and 2,2'-thienylpyrroles from donor-acceptor
      cyclopropanes and 2-cyanoheteroles.
AB  - [reaction: see text] Two new series of 2,2'-bipyrroles and 2,2'-thienylpyrroles
      have been prepared by trimethylsilyl trifluoromethanesulfonate (TMSOTf)-mediated
      reaction of donor-acceptor cyclopropanes with 2-cyanopyrroles and 2
      cyanothiophene, respectively. This method opens the door toward a wide variety of
      unsymmetrical bipyrroles and thienylpyrroles.

PMID- 15012100
TI  - Stanna-Brook rearrangement of carboxylic acid derivatives. Synthetic utility and
      mechanistic studies.
AB  - [reaction: see text] The reaction of R(3)SnLi with carboxylic acid derivatives
      proceeds through a novel, very fast stanna-Brook rearrangement that generates
      alpha-alkoxyorganolithium compounds as intermediates. The outcome of these
      reactions depends on the nature of the carboxyl derivatives. Reaction of R(3)SnLi
      with ester derivatives gives rise to coupled products through a novel C-C bond
      formation reaction. Experimental evidence of the detailed reaction mechanism is
      provided.

PMID- 15012101
TI  - BINOL-Salen-catalyzed highly enantioselective alkyne additions to aromatic
      aldehydes.
AB  - [structure: see text] The BINOL-Salen compound (-)-1 can catalyze the addition of
      both aryl- and alkylalkynes to aromatic aldehydes at room temperature with high
      enantioselectivity (86-97% ee). The conditions for this catalytic process are
      both mild and simple. Unlike most other BINOL-based catalysts, using ligand (-)-1
      not only avoids heating or cooling but also does not require the addition of
      Ti(O(i)Pr)(4).

PMID- 15012103
TI  - A catalysis-based selection for peroxidase antibodies with increased activity.
AB  - A biotin-tyramine conjugate (1) was found to covalently cross-link with
      peroxidase antibody 7G12 upon the catalytic oxidation of the tyramine moiety in
      the presence of hydrogen peroxide (H2O2). On the basis of this observation, a
      novel strategy was developed to select mutants of 7G12 Fab with enhanced
      peroxidase activity from a library of phage displayed antibodies. In such a
      selection, tyramine is oxidized by hydrogen peroxide in a process catalyzed by
      peroxidase antibodies displayed on phage. Antibodies with higher peroxidase
      activity are preferentially labeled with biotin through irreversible adduct
      formation between oxidized biotin-linked tyramine molecules and phenolic side
      chains of the antibody. The corresponding phage particles can then be selected
      via biotin-streptavidin interactions. Using this strategy, phage displayed
      libraries of antibody 7G12 were selected for higher peroxidase activity. As a
      result, mutations of antibody 7G12 that led to 10 to 20-fold increases in the
      peroxidase activity (kcat/Km) were identified, suggesting the validity of this
      method for the evolution of peroxidase antibodies based directly on catalytic
      turnover.

PMID- 15012104
TI  - Core structure of amyloid fibril proposed from IR-microscope linear dichroism.
AB  - A new approach for studying a peptide conformation of amyloid fibril has been
      developed. It is based on infrared linear dichroism analysis using an IR
      microscope for aligned amyloid fibril. The polarization directions of amide I and
      II bands were perpendicular similarly for beta2-microglobulin and its #21-31
      peptide. Furthermore, this approach has shown that the #21-31 peptide consists of
      two C=O bonds in the beta-sheet that makes 0 degrees with the fibril axis, three
      C=O bonds in the beta-sheet inclined by 27 degrees with respect to the fibril
      axis, four residues in the random coil by 47 degrees , and two residues in
      possible beta-bulge structure by 32 degrees . Plausible structures of the amyloid
      core in the fibril are proposed by taking account of these results.

PMID- 15012105
TI  - Ultrasensitive electrical biosensing of proteins and DNA: carbon-nanotube derived
      amplification of the recognition and transduction events.
AB  - A new strategy for dramatically amplifying enzyme-linked electrical detection of
      proteins and DNA using carbon nanotubes (CNTs) for carrying numerous enzyme
      tracers and accumulating the enzymatically liberated product on CNT-modified
      transducer is described. Such a CNT-derived double-step amplification pathway (of
      both the recognition and transduction events) allows the detection of DNA and
      proteins down to 1.3 and 160 zmol, respectively, in 25-50 muL samples and
      indicates great promise for PCR-free DNA analysis. The new protocol is
      illustrated for monitoring sandwich hybridization and antibody-antigen
      interactions in connection with alkaline-phosphatase tracers. The DNA-linking of
      CNTs and particles holds promise also for assembling hybrid nanostructures
      relevant to molecular electronic devices.

PMID- 15012106
TI  - Design and synthesis of 3d-4f metal-based zeolite-type materials with a 3D
      nanotubular structure encapsulated "water" pipe.
AB  - A nanotubular 3D heterometallic zeolitic polymer, {[Yb(PDA)3Mn1.5(H2O)3].1.5H2O}n
      (2), was designed and synthesized by simply tuning the amount of coordinated
      water on the Mn ion in the molecular ladder polymer {[Yb(PDA)3Mn1.5(H2O)6].6H2O}n
      (1). 1 and 2 were structurally and magnetically characterized. The water
      molecules capsulated within the nanotube were arrayed into an unprecedented
      "water" pipe. The robust 2 retained intact networks after the removal of guest
      water trapped in the nanotubes and even after methanol replaced guest water.

PMID- 15012107
TI  - Mineralomimetic sodalite- and muscovite-type coordination frameworks. Dynamic
      crystal-to-crystal interconversion processes sensitive to ion pair recognition.
AB  - A flexible sodalite-type metal organic framework [Cu(pyrimidine-2-olate)2]n (1R)
      is obtained in a self-assembly process involving Cu2+ ions and pyrimidine-2-olate
      ligands. 1R suffers a series of sequential and reversible structural changes upon
      solid-liquid sorption processes of metal nitrates. The 1C-to-1O transformation
      occurs only with large cations.

PMID- 15012108
TI  - Surface amplification of invasive cleavage products.
AB  - A major focus of current efforts in genomics is to elucidate the genetic
      variations extent within the human population, and to study the effects of these
      variations upon the human system. The most common type of genetic variations are
      the single nucleotide polymorphisms (SNPs), which occur every 500-1000 nt in the
      genome. Large-scale population association studies to study the biological or
      medical significance of such variations may require the analysis of hundreds of
      thousands of SNPs on thousands of individuals. We are pursuing development of an
      approach to large-scale SNP analysis that combines the specificity of invasive
      cleavage reactions with the parallelism of high density DNA arrays. A surface
      immobilized probe oligonucleotide is specifically cleaved in the presence of a
      complementary target sequence in unamplified human genomic DNA, yielding a 5'
      phosphate group. High sensitivity detection of this reaction product on the
      surface is achieved by the use of rolling circle amplification, with an
      approximate concentration detection limit of 10 fM target DNA. This combination
      of very specific surface cleavage and highly sensitive surface detection will
      make possible the rapid and parallel analysis of genetic variations across large
      populations.

PMID- 15012109
TI  - S K-edge X-ray absorption spectroscopic investigation of the Ni-containing
      superoxide dismutase active site: new structural insight into the mechanism.
AB  - Superoxide dismutases protect cells from the toxic effects of reactive oxygen
      species derived from superoxide. Nickel-containing superoxide dismutases (NiSOD),
      found in Streptomyces species and in cyanobacteria, are distinct from Mn-, Fe-,
      or Cu/Zn-containing SODs in amino acid sequence and metal ligand environment.
      Sulfur K-edge X-ray absorption spectroscopic investigations were carried out for
      a series of mono- and binuclear Ni model compounds with varying sulfur ligation,
      and for oxidized and reduced NiSOD to elucidate the types of Ni-S interactions
      found in the two oxidation states. The S K-edge XAS spectra clearly indicate the
      presence of Ni(III)-bound terminal thiolate in the oxidized enzyme and the
      absence of such coordination to Ni(II) in the peroxide-reduced enzyme. This
      striking change in the S ligation for Ni with redox suggests that, upon peroxide
      reduction, an electron is transferred to the Ni(III) site and the terminal
      thiolate becomes protonated, providing an efficient mechanism for proton-coupled
      electron transfer.

PMID- 15012110
TI  - pH-Dependent chemoselective synthesis of alpha-amino acids. Reductive amination
      of alpha-keto acids with ammonia catalyzed by acid-stable iridium hydride
      complexes in water.
AB  - An acid-stable hydride complex [Cp*IrIII(bpy)H]+ {1, Cp* = eta5-C5Me5, bpy = 2,2'
      bipyridine} serves as the active catalyst for the highly chemoselective synthesis
      of alpha-amino acids by reductive amination of alpha-keto acids with aqueous NH3
      and HCOO- in water at pH 5-8. pH-dependent catalytic 15N- and 2H-double-labeling
      has also been accomplished by using 15NH3 and DCOONa, which are ideal amine and
      hydride ion sources, respectively.

PMID- 15012111
TI  - Rational design of a supra C-1027: kinetically stabilized analogue of the
      antitumor enediyne chromoprotein.
AB  - C-1027, an extremely potent antitumor agent, is composed of a highly reactive
      chromophore and an apoprotein. While the chromophore causes DNA cleavage, the
      apoprotein functions as its carrier. Despite these ideal properties as an
      anticancer agent, C-1027 slowly self-decomposes through chromophore-mediated
      abstraction of hydrogens from the apoprotein. In this paper, we report the design
      and preparation of an engineered C-1027 apoprotein that decelerates this self
      decomposition pathway. Our design is based on the kinetic isotope effect, and
      deuterium is incorporated instead of protium into the hydrogen-abstraction site.
      The deuterated supra C-1027 was found to have a 4-fold longer lifetime than the
      natural C-1027.

PMID- 15012112
TI  - The origin of sticking between a hydroperoxy radical and a water surface.
AB  - An understanding of how gas-phase radicals in the earth's atmosphere become
      incorporated with liquid-phase cloud droplets is a vital part of understanding
      the chemical budgeting of these highly reactive species. Recent studies have
      suggested that hydroperoxy radicals (HO2) have an affinity for binding to a water
      surface. The calculations presented here are used to extricate the components of
      the attractive contribution of the intermolecular interactions that are
      responsible for the unusually strong binding between the hydroperoxy radical and
      a water surface. The analyses reveal that, for the binding of an HO2 radical to a
      water surface, the two water molecules nearest the radical are the most relevant
      to the bonding and the addition of other water molecules has little affect on the
      bonding between the radical and the two nearest waters. These results suggest
      that, once the HO2 is bound to the surface, the binding is a relatively local
      phenomenon. Identifying the properties responsible for the strong attraction is
      an important result that can be used to identify other radical systems whose
      chemistry might be impacted by the presence of water.

PMID- 15012113
TI  - Synthesis of gold nanoparticles modified with ionic liquid based on the
      imidazolium cation.
AB  - The synthesis and processing of nanoparticles consisting of metallic nanocrystal
      cores and organic monolayer shells promise interesting technological
      applications. Here, we report the synthesis of gold nanoparticles modified with
      ionic liquids based on the imidazolium cation. Aggregation-induced color changes
      of the gold nanoparticles in an aqueous solution were used as an optical sensor
      for anions via anion exchange of ionic liquid moiety. We also demonstrated the
      phase transfer of the gold nanoparticles from aqueous media to ionic liquid.

PMID- 15012115
TI  - Reductively activated nitrous oxide reductase reacts directly with substrate.
AB  - In the terminal step of bacterial denitrification, N2O is converted to N2 at the
      mu4-sulfide bridged tetranuclear CuZ center of nitrous oxide reductase. The
      enzyme can be activated by reduced methyl viologen, with up to a 15-fold increase
      in specific activity. The reductively activated nitrous oxide reductase from
      Achromobacter cycloclastes was isolated and characterized by visible absorption
      and EPR spectroscopy, and both methods showed that the CuZ center can attain a
      [4Cu(I)] oxidation state. When N2O was added to the activated, reductant-free
      enzyme, distinct spectral changes were observed, indicating that this state of
      the enzyme interacts with substrate. This was further supported by the detection
      of 15N-labeled product in the absence of steady-state turnover conditions. A new
      absorption band around 970 nm appeared following reaction of activated nitrous
      oxide reductase with N2O, which may represent a catalytic intermediate state of
      the enzyme.

PMID- 15012114
TI  - Pseudospecificity of the acidic patch of plastocyanin for the interaction with
      cytochrome f.
AB  - The ionic strength dependence of the physiological electron-transfer reaction of
      plastocyanins (PCus) from a range of sources with a eukaryotic cytochrome f (cyt
      f) has been studied. The presence of an acidic patch on the surface of PCu is key
      to this interaction in higher plants, but minor modifications in this surface
      region have a limited effect. Surprisingly, a similarly small influence results
      from the repositioning of the acidic patch (as in the fern PCu). The only
      requirement of a plant PCu to ensure efficient interaction with its cyt f is the
      presence of acidic residues on the periphery of the protein's hydrophobic patch.

PMID- 15012116
TI  - Fluorescent polymeric AND logic gate with temperature and pH as inputs.
AB  - We illustrate a general polymeric design of fluorescent logic gates, for example,
      AND, using temperature and pH as inputs.

PMID- 15012118
TI  - Deuterium-labeling studies establishing stereochemistry at the oxypalladation
      step in Wacker-type oxidative cyclization of an o-allylphenol.
AB  - The stereochemical pathway (syn or anti) of the oxypalladation step was studied
      in the palladium(II)-catalyzed Wacker-type cyclization of stereospecifically
      deuterated 6-(2-hydroxyphenyl)-3-deuteriocyclohexenes, cis-3-d-1 and trans-3-d-1,
      giving dihydrobenzofuran derivatives. The stereochemistry was determined to be
      syn in the reaction catalyzed by a dicationic palladium(II) catalyst generated
      from Pd(MeCN)4(BF4)2 and (S,S)-ip-boxax in the presence of benzoquinone in
      methanol, while it is mainly anti in the reaction catalyzed by PdCl2(MeCN)2 in
      the presence of a chloride ion.

PMID- 15012117
TI  - Dissociation behavior of doubly-charged tryptic peptides: correlation of gas
      phase cleavage abundance with ramachandran plots.
AB  - Analysis of fragmentation patterns from 5654 unique doubly charged tryptic
      peptides is obtained. Great variability of average relative abundance of bond
      cleavage is found between different amino acid combinations. There exist
      similarities as well as differences between b and y ions. Strong enhancement or
      suppression of cleavage gives insight into possible chemical interactions at
      reactive conformations formed by preferred phi-psi angles.

PMID- 15012119
TI  - Surface-to-surface bridges formed by reversibly assembled polymers.
AB  - Self-assembled polymers whose main chains are defined by reversible DNA base
      pairing form bridges between the tip of an atomic force microscope and substrate.
      The forces associated with the rupture of these assemblies are independent of
      polymer bridge length, and they resemble those expected for the isolated
      associations defining the polymer bridges. The assembly is reversible and is
      inhibited by a competitive, nonpolymerizing oligonucleotide. Noncomplementary
      polymer brush layers do not bridge, and therefore, the forces result from
      specific molecular recognition events. The length distribution of the bridges
      differs greatly from that of the polymers in solution, and thus the bridging is
      responsive to the spatial constraints of the environment.

PMID- 15012121
TI  - Platinum participation in the hydrogenation of phenylacetylene by
      Ru5(CO)15(C)[Pt(PBu(t)3)].
AB  - The hydride and PhC2H complexes, Ru5(CO)14(mu6-C)[Pt(PBut3)](mu-H)2, 2, and
      Ru5(CO)13(mu5-C)(PhC2H)[Pt(PBut3)], 3, were obtained from the reactions of
      Ru5(CO)15(C)[Pt(PBut3)], 1, with hydrogen and PhC2H, respectively. Styrene was
      formed catalytically when hydrogen and PhC2H were allowed to react with 3 in
      combination, and the complex Ru5(CO)12(mu5-C)[PtPBut3](PhC2H)(mu-H)2, 4,
      containing both hydrides and a PhC2H ligand was formed. The catalysis is promoted
      by the presence of the platinum atom in the complexes.

PMID- 15012120
TI  - Selective pairing of polyfluorinated DNA bases.
AB  - Novel selective non-hydrogen-bonding DNA base pairs utilizing fluorinated
      nucleoside analogues have been investigated. Melting studies of DNA duplexes
      containing 2,3,4,5-tetrafluorobenzene and 4,5,6,7-tetrafluoroindole bases on
      opposite strands show greater stabilization of the duplex compared with
      nonfluorinated hydrocarbon controls. Overall, these hydrophobic analogues are
      destabilizing compared with natural base pairs but are stabilizing compared with
      natural base mismatches. Such selective pairing may be due to solvent avoidance
      of these hydrophobic structures, burying their surfaces within the duplex. Our
      findings suggest that polyfluoroaromatic bases might be employed as a new,
      selective base-pairing system orthogonal to the natural genetic system.

PMID- 15012122
TI  - [Ni2O(L-Asp)(H2O)2)].4H2)O: a homochiral 1D helical chain hybrid compound with
      extended Ni-O-Ni bonding.
AB  - The hydrothermally synthesized 1D homochiral nickel aspartate oxide [Ni2O(l
      Asp)(H2O)2].4H2O is based on infinite helical chains of edge- and corner-sharing
      nickel octahedra. It represents the first example of a chiral one-dimensional
      compound with an extended helical TM-O-TM subnetwork synthesized as an optically
      pure product. Its structure was determined ab initio by real-space methods from
      laboratory powder diffraction data.

PMID- 15012123
TI  - Thermal splitting of Bis-Cu(II) octaphyrin(1.1.1.1.1.1.1.1) into two Cu(II)
      porphyrins.
AB  - When heated, bis-Cu(II) octaphyrin(1.1.1.1.1.1.1.1) is quantitatively split into
      two Cu(II) porphyrins both in solution and film states, which is accompanied by
      large absorption spectral changes.

PMID- 15012124
TI  - Highly diastereoselective heterogeneously catalyzed hydrogenation of enamines for
      the synthesis of chiral beta-amino acid derivatives.
AB  - Pure (Z)-enamines readily prepared from beta-ketoesters and amides using (S)
      phenylglycine amide were hydrogenated with very high diastereoselectivities (up
      to 200:1) using heterogeneous catalysis. Hydrogenolytic cleavage of the (S)
      phenylglycine amide afforded the corresponding chiral beta-aminoesters and
      amides. The high geometrical purity of the (Z)-enamine and a simple activation
      procedure for the PtO2 catalyst are essential in achieving high selectivity.

PMID- 15012126
TI  - Toward single-site, immobilized molecular catalysts: site-isolated Ti ethylene
      polymerization catalysts supported on porous silica.
AB  - A new, general patterning methodology that may allow for the preparation of site
      isolated organometallic catalysts on a silica surface is reported. The technique
      is demonstrated with Group 4 polymerization catalysts. The catalysts synthesized
      via the patterning method have up to a 10-fold increase in activity as compared
      to materials prepared by traditional techniques. In addition to supporting Group
      4 polymerization catalysts, the patterned aminosilica is a possible support for
      other metal complexes, allowing for the synthesis of a wide array of immobilized
      single-site organometallic catalysts.

PMID- 15012125
TI  - Branched phospha[7]triangulanes.
AB  - A highly strained, thermally stable (up to 150 degrees C) branched
      phospha[7]triangulane was synthesized from the second-generation
      bicyclopropylidene and transient phosphinidene [Ph-P=W(CO)5], followed by
      demetalation in refluxing xylene. Bulkier transient CuCl-alkene-complexed
      phosphinidene gave 2-phosphabicyclo-[3.2.0]hept-1(5)-ene as an additional
      product. The "outer sphere" spirocyclopropanes provide a stabilizing factor for
      both of these novel compounds.

PMID- 15012127
TI  - Investigation of the origin of tensile stress-induced rate enhancements in the
      photochemical degradation of polymers.
AB  - To investigate the effect of tensile stress on the photochemical degradation
      efficiencies of polymers, a modified PVC polymer with Cp(CO)3Mo-Mo(CO)3Cp (Cp =
      eta5-C5H5) units along the backbone was synthesized. The polymer is
      photochemically reactive because the Mo-Mo bonds are photolyzed with visible
      light and the resulting radicals are captured with Cl atoms from along the
      polymer backbone. Of most importance from a mechanistic standpoint, the
      photochemical degradation reaction occurs in the absence of oxygen, which
      eliminates the kinetically complicating effect of rate-limiting oxygen diffusion.
      Tensile stress initially caused the quantum yield of polymer degradation to
      increase, but, after a certain point, additional stress caused a decrease in the
      quantum yield. This dependence of quantum efficiency on stress is consistent with
      a hypothesis in which stress affects the ability of the photochemically generated
      radicals to recombine. At low to moderate stress, the effect of stress is to
      increase the separation of the radicals (by recoil), thus decreasing their
      recombination probability. As the stress increases, however, segments of
      different chains align, which induces a higher degree of orientation and
      crystallinity in the polymer, which in turn makes diffusion more difficult. The
      efficiency of degradation is predicted to decrease accordingly because of
      decreased radical and/or trap mobility in the ordered polymer. Infrared and X-ray
      data are presented, showing that the degree of orientation and crystallinity in
      the polymer does indeed increase with increasing stress.

PMID- 15012129
TI  - Room-temperature Ni0-catalyzed cross-coupling reactions of aryl arenesulfonates
      with arylboronic acids.
AB  - Room-temperature Ni(0)-catalyzed cross-coupling reactions of aryl arenesulfonates
      with arylboronic acids are described. The Ni(0) catalyst, derived from Ni(COD)2
      and PCy3, proved to be a general one for the Suzuki-Miyaura cross-coupling of a
      variety of aryl arenesulfonates. The mild reaction condition, the readily
      availability of the catalyst, and excellent coupling yields make aryl
      arenesulfonates potentially useful substrates in organic synthesis.

PMID- 15012128
TI  - Energy transfer between singlet (1Delta(g)) and triplet (3Sigma(g)-) molecular
      oxygen in aqueous solution.
AB  - We clearly demonstrate the occurrence of energy transfer between 18O2 (1Deltag)
      and 16O2 in the ground state (3Sigmag-) with subsequent conversion of the latter
      species into its singlet excited state (1Deltag) in aqueous solution. This was
      inferred from the results of incubation experiments involving DHPN18O2 as a
      chemical generator of 18O2 (1Deltag) and the water-soluble disodium salt of
      anthracene (EAS) used as a chemical trap of singlet oxygen. The products of the
      reaction were accurately analyzed by HPLC-ESI-MS.

PMID- 15012130
TI  - Fabrication of Ru and Ru-based functionalized nanotubes.
AB  - Ru and Ru-Pt nanotubes were synthesized by a pressure-filter-template technique,
      and, furthermore, Ru-Pt-core/Nafion-sheath composite nanotubes were fabricated by
      a dip-and-dry method, showing high catalytic activity toward methanol oxidation
      at 25 degrees C.

PMID- 15012131
TI  - Enantioselective molecular recognition between beta-sheets.
AB  - This communication asks whether homochiral or heterochiral interaction is
      preferred between enantiomeric beta-sheets and finds that homochiral pairing is
      strongly preferred. Interactions between beta-sheets occur widely among proteins
      through pairing of the hydrogen-bonding edges. Although the hydrogen-bonding
      edges of both l- and d-beta-sheets put forth the same pattern of hydrogen-bond
      donor and acceptor groups, the side chains point in opposite directions.
      Homochiral pairing of beta-sheets generates structures in which the pleats and
      side chains of adjacent beta-strands are parallel to each other, while
      heterochiral pairing of beta-sheets generates structures in which the pleats and
      side chains are antiparallel. To test which pairing is preferred, we have
      prepared and studied the interactions of beta-sheets 1a-d, which comprise all l
      amino acids, and beta-sheets 2a-c, which comprise all d-amino acids. Previous
      studies in our laboratory have established that these compounds form well-defined
      dimers in organic solvents. In the current study, 1H NMR experiments establish
      that when the l-beta-sheets (1) are mixed with the enantiomeric d-beta-sheets
      (2), homochiral beta-sheet dimers predominate, and only small quantities of
      heterochiral beta-sheet dimers form. Ratios of homochiral and heterochiral dimers
      ranging from 95.8:4.2 to 98.5:1.5 are measured in CDCl3 at 253 K, which
      correspond to statistically corrected free-energy differences of 3.1-4.2 kcal/mol
      (0.6-0.8 kcal/mol per interacting residue). Possible explanations for the high
      enantioselectivity of molecular recognition between beta-sheets include favorable
      nonbonded contacts between the adjacent beta-strands of the homochiral beta
      sheets and poor fit of the heterochiral beta-strands, which should twist in
      opposite directions.

PMID- 15012132
TI  - Polyelectrolyte multilayer as matrix for electrochemical deposition of gold
      clusters: toward super-hydrophobic surface.
AB  - This communication describes the use of polyelectrolyte multilayer as a preformed
      matrix in electrochemical deposition to adjust the morphology of gold clusters,
      and only the surface covered with dendritic gold clusters shows a super
      hydrophobic property, with the contact angle above 150 degrees and the tilt angle
      less than 1.5 degrees , after the surface further chemisorbed with a self
      assembled monolayer of n-dodecanethiol.

PMID- 15012134
TI  - The fluoro analogue of Wilkinson's catalyst and unexpected Ph-Cl activation.
AB  - The fluoro analogue of Wilkinson's catalyst, [(Ph3P)3RhF] (1), was synthesized
      and fully characterized. Both solution behavior and solid-state geometry
      parameters of 1 were found to be surprisingly similar to those of Wilkinson's
      catalyst. Unlike Wilkinson's catalyst however, 1 exhibited most unusual
      reactivity toward the notoriously inert C-Cl bond of nonactivated chloroarenes.
      The novel Ph-Cl activation with 1 includes fluorine transfer from the metal to a
      phosphine ligand and evidently phenyl transfer from the phosphine to Rh to
      produce an electron-rich sigma-phenylrhodium intermediate.

PMID- 15012133
TI  - Carotenoid and pheophytin on semiconductor surface: self-assembly and
      photoinduced electron transfer.
AB  - Self-assembling of a carotenoid and pheophytin a into a supramolecular system was
      observed on the surface of nanocrystalline TiO2, and the photoinduced electron
      transfer reactions within the system were studied by means of femtosecond
      transient absorption and laser flash photolysis techniques. Excitation of the
      pheophytin moiety results in ultrafast electron transfer from carotenoid to the
      excited pheophytin, creating a long-lived charge-separated state. Two decay
      pathways of the formed pheophytin a anion radical are proposed. The first is a
      direct back electron recombination forming a carotenoid triplet state on the
      nanosecond time scale, while the other is suggested to occur via electron
      injection to the TiO2 nanoparticle. These results demonstrate that a self
      assembled carotenoid-pheophytin system leads to an efficient reductive quenching
      of the pheophytin moiety, suggesting that a similar mechanism can operate also in
      natural photosynthetic systems. Moreover, the formation of a long-lived charge
      separated state indicates that such self-assembling strategy may be also
      considered for novel dye-sensitized solar cell constructions and other artificial
      systems aiming to mimic the electron-transfer chain in natural photosynthesis.

PMID- 15012135
TI  - Metallophosphites as umpolung catalysts: the enantioselective cross silyl benzoin
      reaction.
AB  - Carbonyl polarity reversal (umpolung) has been realized employing
      metallophosphites as catalysts. As a result, nonenzymatic asymmetric cross silyl
      benzoin reactions have been achieved, giving optically active silyl ether
      protected benzoin adducts. The reaction is general with respect to aryl, alkyl,
      and heterocyclic substrates with good to excellent yields and good to excellent
      enantioselectivities.

PMID- 15012136
TI  - Substrate affinities for membrane transport proteins determined by 13C cross
      polarization magic-angle spinning nuclear magnetic resonance spectroscopy.
AB  - We have devised methods in which cross-polarization magic-angle spinning (CP-MAS)
      solid-state NMR is exploited to measure rigorous parameters for binding of (13)C
      labeled substrates to membrane transport proteins. The methods were applied to
      two proteins from Escherichia coli: a nucleoside transporter, NupC, and a
      glucuronide transporter, GusB. A substantial signal for the binding of methyl [1
      (13)C]-beta-d-glucuronide to GusB overexpressed in native membranes was achieved
      with a sample that contained as little as 20 nmol of GusB protein. The data were
      fitted to yield a K(D) value of 4.17 mM for the labeled ligand and 0.42 mM for an
      unlabeled ligand, p-nitrophenyl beta-d-glucuronide, which displaced the labeled
      compound. CP-MAS was also used to measure binding of [1'-(13)C]uridine to
      overexpressed NupC. The spectrum of NupC-enriched membranes containing [1'
      (13)C]uridine exhibited a large peak from substrate bound to undefined sites
      other than the transport site, which obscured the signal from substrate bound to
      NupC. In a novel application of a cross-polarization/polarization-inversion
      (CPPI) NMR experiment, the signal from undefined binding was eliminated by use of
      appropriate inversion pulse lengths. By use of CPPI in a titration experiment, a
      K(D) value of 2.6 mM was determined for uridine bound to NupC. These approaches
      are broadly applicable to quantifying binding of substrates, inhibitors, drugs,
      and antibiotics to numerous membrane proteins.

PMID- 15012138
TI  - The biosynthesis of the thiazole phosphate moiety of thiamin (vitamin B1): the
      early steps catalyzed by thiazole synthase.
AB  - Thiazole synthase (ThiG) catalyzes an Amadori-type rearrangement of 1-deoxy-d
      xylulose-5-phosphate (DXP) via an imine intermediate. In support of this, we have
      demonstrated enzyme-catalyzed exchange of the C2 carbonyl of DXP. Borohydride
      reduction of the enzyme DXP imine followed by top-down mass spectrometric
      analysis localized the imine to lysine 96. On the basis of these observations, a
      new mechanism for the biosynthesis of the thiazole phosphate moiety of thiamin
      pyrophosphate in Bacillus subtilis is proposed. This mechanism involves the
      generation of a ketone at C3 of DXP by an Amadori-type rearrangement of the imine
      followed by nucleophillic addition of the sulfur carrier protein (ThiS
      thiocarboxylate) to this carbonyl group.

PMID- 15012137
TI  - C-terminal domain of the membrane copper transporter Ctr1 from Saccharomyces
      cerevisiae binds four Cu(I) ions as a cuprous-thiolate polynuclear cluster: sub
      femtomolar Cu(I) affinity of three proteins involved in copper trafficking.
AB  - The cytosolic C-terminal domain of the membrane copper transporter Ctr1 from the
      yeast Saccharomyces cerevisiae, Ctr1c, was expressed in E. coli as an oxygen
      sensitive soluble protein with no significant secondary structure. Visible-UV
      spectroscopy demonstrated that Ctr1c bound four Cu(I) ions, structurally
      identified as a Cu(I)(4)(micro-S-Cys)(6) cluster by Xray absorption spectroscopy.
      This was the only metalated form detected by electrospray ionization mass
      spectrometry. An average dissociation constant K(D) = (K(1)K(2)K(3)K(4))(1/4) =
      10(-)(19) for binding of Cu(I) to Ctr1c was estimated via competition with the
      ligand bathocuproine disulfonate bcs (beta(2) = 10(19.8)). Equivalent experiments
      for the yeast chaperone Atx1 and an N-terminal domain of the yeast Golgi pump
      Ccc2, which both bind a single Cu(I) ion, provided similar K(D) values. The
      estimates of K(D) were supported by independent estimates of the equilibrium
      constants K(ex) for exchange of Cu(I) between pairs of these three proteins. It
      is apparent that, in vitro, the three proteins buffer "free" Cu(I) concentrations
      in a narrow range around 10(-)(19) M. The results provide quantitative support
      for the proposals that, in yeast, (a) "free" copper concentrations are very low
      in the cytosol and (b) the Cu(I) trafficking gradient is shallow along the
      putative Ctrlc --> Atx1 --> Ccc2n metabolic pathway. In addition, both Ctr1c and
      its copper-responsive transcription factor Mac1 contain similar clusters which
      may be important in signaling copper status in yeast.

PMID- 15012140
TI  - Elaboration of diaryl ketones into naphthalenes fused on two or four sides: a
      naphthoannulation procedure.
AB  - Transition metal-catalyzed double ring closures of 1,1-diaryl-2,2
      diethynylethylenes yield polycyclic aromatic hydrocarbons and heterocycles that
      contain a newly formed naphthalene ring system embedded in a larger polycyclic
      network. The diynes required for this procedure are readily synthesized from
      diaryl ketones by the Corey-Fuchs olefination and subsequent Sonogashira coupling
      with trimethylsilylacetylene followed by desilylation. This procedure provides
      easy access to new compounds such as 3,11-di-tert-butyl[4]helicene and 1,8,9
      perinaphthothioxanthene. Double naphthoannulation of 9,10-anthraquinone by this
      procedure closes four new benzene rings in a single operation to give coronene,
      although the yield in this case is presently low.

PMID- 15012139
TI  - Physicochemical properties of mixed micellar aggregates containing CCK peptides
      and Gd complexes designed as tumor specific contrast agents in MRI.
AB  - New amphiphilic molecules containing a bioactive peptide or a claw moiety have
      been prepared in order to obtain mixed micelles as target-specific contrast
      agents in magnetic resonance imaging. The first molecule, C(18)H(37)CONH(AdOO)(2)
      G-CCK8 (C18CCK8), contains a C18 hydrophobic moiety bound to the C-terminal
      cholecystokinin octapeptide amide (CCK 26-33 or CCK8). The second amphiphilic
      compound, C(18)H(37)CONHLys(DTPAGlu)CONH(2) (C18DTPAGlu) or its gadolinium
      complex, (C18DTPAGlu(Gd)), contains the same C18 hydrophobic moiety bound,
      through a lysine residue, to the DTPAGlu chelating agent. The mixed aggregates as
      well as the pure C18DTPAGlu aggregate, in the presence and absence of Gd, have
      been fully characterized by surface tension measurements, FT-PGSE-NMR,
      fluorescence quenching, and small-angle neutron scattering measurements. The
      structural characterization of the mixed aggregates C18DTPAGlu(Gd)-C18CCK8
      indicates a spherical arrangement of the micelles with an external shell of
      approximately 21 A and an inner core of approximately 20 A. Both the DTPAGlu(Gd)
      complexes and the CCK8 peptides point toward the external surface. The measured
      values for relaxivity in saline medium at 20 MHz proton Larmor frequency and 25
      degrees C are 18.7 mM(-)(1) s(-)(1). These values show a large enhancement in
      comparison with the isolated DTPAGlu(Gd) complex.

PMID- 15012141
TI  - Reaction of ketones with lithium hexamethyldisilazide: competitive enolizations
      and 1,2-additions.
AB  - Reaction of 2-methylcyclohexanone with lithium hexamethyldisilazide (LiHMDS,
      TMS(2)NLi) displays highly solvent-dependent chemoselectivity. LiHMDS in
      THF/toluene effect enolization. Rate studies using in situ IR spectroscopy are
      consistent with a THF concentration-dependent monomer-based pathway. LiHMDS in
      pyrrolidine/toluene affords exclusively 1,2-addition of the pyrrolidine fragment
      to form an alpha-amino alkoxide-LiHMDS mixed dimer shown to be a pair of
      conformers by using (6)Li, (15)N, and (13)C NMR spectroscopies. Rate studies are
      consistent with a monomer-based transition structure
      [(TMS(2)NLi)(ketone)(pyrrolidine)(3)](). The partitioning between enolization and
      1,2-addition is kinetically controlled.

PMID- 15012142
TI  - Water-catalyzed dehalogenation reactions of isobromoform and its reaction
      products.
AB  - A combined experimental and theoretical study of the photochemistry of CHBr(3) in
      pure water and in acetonitrile/water mixed solvents is reported that elucidates
      the reactions and mechanisms responsible for the photochemical conversion of the
      halogen atoms in CHBr(3) into three bromide ions in water solution. Ultraviolet
      excitation at 240 nm of CHBr(3) (9 x 10(-)(5) M) in water resulted in almost
      complete conversion into 3HBr leaving groups and CO (major product) and HCOOH
      (minor product) molecules. Picosecond time-resolved resonance Raman (ps-TR(3))
      experiments and ab initio calculations indicate that the water-catalyzed O-H
      insertion/HBr elimination reaction of isobromoform and subsequent reactions of
      its products are responsible for the production of the final products observed
      following ultraviolet excitation of CHBr(3) in water. These results have
      important implications for the phase-dependent behavior of polyhalomethane
      photochemistry and chemistry in water-solvated environments as compared to gas
      phase reactions. The dissociation reaction of HBr into H(+) and Br(-) ions is the
      driving force for several O-H insertion and HBr elimination reactions and allows
      O-H and C-H bonds to be cleaved more easily than in the absence of water
      molecules. This water-catalysis by solvation of a leaving group and its
      dissociation into ions (e.g., H(+) and Br(-) in the examples investigated here)
      may occur for a wide range of chemical reactions taking place in water-solvated
      environments.

PMID- 15012143
TI  - Aromaticity of four-membered-ring 6pi-electron systems: N2S2 and Li2C4H4.
AB  - N(2)S(2) is a four-membered-ring system with 6pi electrons. While earlier
      proposals considered N(2)S(2) to be aromatic, recent electronic structure
      calculations claimed that N(2)S(2) is a singlet diradical. Our careful
      reexamination does not support this assertion. N(2)S(2) is closed shell and
      aromatic since it satisfies all three generally accepted criteria for
      aromaticity: energetic (stability), structural (planarity with equal bond
      lengths), and magnetic (negative nucleus-independent chemical shift due to the pi
      electrons). These characteristics as well as the electronic structure of N(2)S(2)
      are compared with those for an isoelectronic pi system, Li(2)C(4)H(4), motivated
      by theoretical and recent experimental investigations that confirmed its
      aromaticity. However, N(2)S(2) and Li(2)C(4)H(4) are both essentially 2pi
      electron aromatic systems with a formal N-S (C-C) bond order of 1.25 even though
      they both have 6pi electrons. This is because four of the six pi electrons occupy
      the nonbonding pi HOMOs and only two electrons participate effectively in the
      aromatic stabilization. However, wave function analysis shows relatively large
      LUMO occupation numbers; this antibonding effect can be said to reduce the
      aromatic character by approximately 7% and 4% for N(2)S(2) and Li(2)C(4)H(4),
      respectively.

PMID- 15012144
TI  - Nanosized molecular propellers by cyclodehydrogenation of polyphenylene
      dendrimers.
AB  - In a polymer analogous approach, large dendritic oligophenylenes containing
      benzene and tetraphenylmethane cores are transformed via oxidative
      cyclodehydrogenation to novel propeller-shaped molecules with large polycyclic
      aromatic hydrocarbon units as "blades". Structure analysis is performed by a
      combination of MALDI-TOF mass spectrometry, UV/vis, fluorescence, and Raman
      spectroscopy using solid-state sample preparation methods. These methods are also
      utilized to determine the degree of the cyclodehydrogenation reaction.

PMID- 15012145
TI  - Backbone-rigidified oligo(m-phenylene ethynylenes).
AB  - Oligo(m-phenylene ethynylenes) (oligo(m-PE)) with backbones rigidified by
      intramolecular hydrogen bonds were found to fold into well-defined conformations.
      The localized intramolecular hydrogen bond involves a donor and an acceptor from
      two adjacent benzene rings, respectively, which enforces globally folded
      conformations on these oligomers. Oligomers with two to seven residues have been
      synthesized and characterized. The persistence of the intramolecular hydrogen
      bonds and the corresponding curved conformations were established by ab initio
      and molecular mechanics calculations, 1D and 2D (1)H NMR spectroscopy, and UV
      spectroscopy. Pentamer 5, hexamer 6, and heptamer 7 adopt well-defined helical
      conformations. Such a backbone-based conformational programming should lead to
      molecules whose conformations are resilient toward structural variation of the
      side groups. These m-PE oligomers have provided a new approach for achieving
      folded unnatural oligomers under conditions that are otherwise unfavorable for
      previously described, solvent-driven folding of m-PE foldamers. Stably folded
      structures based on the design principle described here can be developed and may
      find important applications.

PMID- 15012146
TI  - Crystal structures and spectroscopic characterization of radical cations and
      dications of oligothiophenes stabilized by annelation with bicyclo[2.2.2]octene
      units: sterically segregated cationic oligothiophenes.
AB  - The remarkably stable SbF(6)(-) salts of the radical cations of bithiophene 1(2T)
      and terthiophene 1(3T), completely surrounded by bicyclo[2.2.2]octene (BCO)
      units, were obtained by one-electron oxidation of the neutral precursors with
      NO(+)SbF(6)(-), and their solid-state structures were determined by X-ray
      crystallography. In these radical cations, the presence of quinoidal character
      was apparent, as shown by the increased planarity and by comparison of the bond
      lengths with those of the neutral precursors. The shortest intermolecular pi-pi
      distances in the crystal structure of 1(2T)(*)(+)SbF(6)(-) (distance between two
      sp(2) carbon atoms, 4.89 A) and 1(3T)(*)(+)SbF(6)(-) (distance between an sp(2)
      carbon and a sulfur atom, 3.58 A) were found to be longer than the sums of the
      van der Waals radii of the corresponding atoms. In accord with this, no apparent
      change was observed in ESR and UV-vis-NIR spectra of solutions of 1(2T)(*)(+) and
      1(3T)(*)(+) upon lowering the temperature, indicating that the pi- (or sigma-)
      dimer formation is inhibited in solution as well as in the solid state. The
      dications 1(2T)(2+) and 1(3T)(2+) were generated with the stronger oxidant SbF(5)
      in CH(2)Cl(2) at -40 degrees C and characterized by NMR spectroscopy. In the (1)H
      NMR spectra, two conformers were observed for each dication of both 1(2T)(2+)
      (transoid (t) and cisoid (c)) and 1(3T)(2+) (t,t and c,t) at room temperature due
      to the high rotational barrier around the inter-ring bond(s) between thiophene
      rings, which was caused by the enhanced double bond character of these bonds
      following two-electron oxidation. This is supported by DFT calculations (B3LYP/6
      31G(d)), which predicted the rotational barriers in the dications of
      unsubstituted bithiophene and terthiophene to be 27.6 and 22.9 kcal mol(-)(1),
      respectively. In the case of quaterthiophene and sexithiophene surrounded by BCO
      frameworks 1(4T) and 1(6T), oxidation with even one molar equivalent of
      NO(+)SbF(6)(-) afforded the dication salts 1(4T)(2+)2SbF(6)(-) and
      1(6T)(2+)2SbF(6)(-), which were isolated as stable single crystals and allowed
      the X-ray crystallography. In their crystal structures, the cationic pi-systems
      became planar again due to the great contribution of quinoidal resonance
      structures, and the pi-systems, which were arrayed in a parallel geometry, were
      also segregated by the steric effect of BCO units. The degree and tendency of
      changes in the bond lengths of thiophene rings of 1(4T)(2+) and 1(6T)(2+) as
      compared with neutral precursors were similar to those of 1(2T)(*)(+)SbF(6)(-)
      and 1(3T)(*)(+)SbF(6)(-), respectively, implying that the contribution of
      quinoidal character is modulated by the amount of positive charge per thiophene
      unit.

PMID- 15012147
TI  - Polymorphism in NaSbO3: structure and bonding in metal oxides.
AB  - A new polymorph of NaSbO(3) has been synthesized at 10.5 GPa and 1150 degrees C
      in a uniaxial split sphere anvil type press (USSA-2000) and recovered back to
      ambient conditions. The high-pressure form of NaSbO(3) adopts an orthorhombically
      distorted perovskite structure, isostructural with CaTiO(3), GdFeO(3), and
      NaTaO(3). The space group is Pnma, and the unit cell dimensions are a =
      5.43835(6) A, b = 7.66195(8) A, c = 5.38201(5) A. It is a white insulator with an
      optical band gap of 3.4 eV. This compound represents the first ternary perovskite
      prepared containing Sb(5+) on the octahedral site. The octahedral tilting
      distortion in this compound is much larger than expected from ionic radii
      considerations. The distortion is driven by a second-order Jahn-Teller distortion
      originating on oxygen that can be traced back to strong Sb-O covalent bonding. A
      conflict arises between the strong covalent bonding interactions at oxygen that
      favor a large octahedral tilting distortion and the repulsive Na-O interactions
      that oppose excessive octahedral tilting. This conflict destabilizes the
      perovskite topology, thereby stabilizing the ilmenite polymorph under ambient
      conditions. Analysis of ionic and covalent bonding explains why ASbO(3) and
      ABiO(3) compositions frequently adopt structures that violate Pauling's rules.

PMID- 15012148
TI  - Synthetic creatinine receptor: imprinting of a Lewis acidic zinc(II)cyclen
      binding site to shape its molecular recognition selectivity.
AB  - Molecularly imprinted polymers (MIPs) from polymerizable Lewis acidic
      zinc(II)cyclen complexes and ethylene glycol dimethyl acrylate have been
      prepared. For the imprinting process the template molecule creatinine is
      reversibly coordinated to the zinc atom. The high strength of this interaction
      allows analyte binding to the MIP from aqueous solution with high affinity. Its
      pH dependence is used for controlled guest release with nearly quantitative
      analyte recovery rate. The binding capacity and selectivity profile of the MIP
      remains constant through several pH controlled binding and release cycles. MIPs
      missing a suitable metal binding site showed no significant affinity for thymine
      or creatinine. Flavin adsorbs nonspecifically to all polymers. The imprinting
      process reverses the binding selectivity of zinc(II)cyclen for creatinine and
      thymine from 1:34 in homogeneous solution to 3.5:1 in the MIP. Scatchard plot
      analysis of creatinine binding isotherms reveals uniform binding of the imprint,
      with fits indicating a one-site model; however, similar analysis for thymine
      indicate high and low affinity sites. This corresponds to unrestricted
      coordination sites freely accessible for thymine, e.g., at the polymer surface,
      and misshaped imprinted sites, which still can accommodate thymine. More than 50%
      of all binding sites exclusively bind creatinine and are not accessible to
      thymine. The binding properties of a copolymer of polymerizable zinc(II)cyclen
      and ethylene glycol dimethyl acrylate missing the creatinine template, which
      match the binding selectivity of the complex in solution, confirm that the origin
      of altered selectivities is the imprinting process. With binding ability at
      physiological pH, the MIPs are applicable for tasks in medicinal diagnostics or
      biotechnology. Imprinted zinc(II)cyclen complexes provide, like a metalloenzyme
      binding motif, high binding affinity by reversible coordination while the
      surrounding macromolecule determines binding selectivity.

PMID- 15012149
TI  - Diamond and diamond-like carbon from a preceramic polymer.
AB  - The synthesis of poly(hydridocarbyne), one of a class of carbon-based random
      network polymers and a structural isomer of polyacetlyene, is reported. The
      network backbone of this polymer is primarily composed of tetrahedrally
      hybridized carbon atoms, each bearing one hydride substituent and linked via
      three carbon-carbon single bonds into a three-dimensional random network of fused
      rings. This atomic-level carbon network backbone confers unusual properties on
      the polymer, including facile thermal decomposition to form diamond or diamond
      like carbon high-quality films at atmospheric pressure, by direct deposition or
      by chemical vapor deposition (CVD), without the use of hydrogen or any other
      reagent.

PMID- 15012150
TI  - Synthesis and characterization of hypoelectronic rhenaboranes. Analysis of the
      geometric and electronic structures of species following neither borane nor metal
      cluster electron-counting paradigms.
AB  - The reaction of (CpReH(2))(2)B(4)H(4) with monoborane leads to the sequential
      formation of (CpRe)(2)B(n)()H(n)() (n = 7-10, 1-4). These species adopt closed
      deltahedra with the same total connectivities as the closo-borane anions
      [B(n)()H(n)()](2)(-), n = 9-12, but with flattened geometries rather than
      spherical shapes. These rhenaborane clusters are characterized by high metal
      coordination numbers, Re-Re cross-cluster distances within the Re-Re single bond
      range, and formal cluster electron counts three skeletal electron pairs short of
      that required for a canonical closo-structure of the same nuclearity. An open
      cluster, (CpReH)(2)B(7)H(9) (5), is isolated that bears the same structural
      relationship to arachno-B(9)H(15) as 1-4 bear to the closo-borane anions.
      Chloroborane permits the isolation of (CpReH)(2)B(5)Cl(5) (6), an isoelectronic
      chloro-analogue of known open (CpWH(2))(2)B(5)H(5) and (CpRe)(2)B(6)H(4)Cl(2)
      (7), a triple-decker complex containing a planar, six-membered 1,2-B(6)H(4)Cl(2)
      ring. Both are putative five- and six-boron intermediates in the formation of 1.
      Electronic structure calculations (extended Huckel and density functional theory)
      yield geometries in agreement with the structure determinations, large HOMO-LUMO
      gaps in accord with the high stabilities, and (11)B chemical shifts accurately
      reflecting the observed shifts. Analyses of the bonding in 1-4 reveal that the
      CpRe.CpRe interaction generates fragment orbitals that are able to contribute the
      "missing" three skeletal electron pairs required for skeletal bonding. The
      necessity of a Re.Re interaction for strong cluster bonding requires a borane
      fragment shape change to accommodate it, thereby explaining the noncanonical
      geometries. Application of the debor principle of borane chemistry to the shapes
      of 1-4 readily rationalizes the observed geometries of 5 and 6. This evidence of
      the scope of transition metal fragment control of borane geometry suggests the
      existence of a large class of metallaboranes with structures not found in known
      borane or metal clusters.

PMID- 15012151
TI  - Engineering of layer-by-layer coated capsules with the prospect of materials for
      efficient and directed electron transfer.
AB  - Intermolecular electron transfer is investigated in a dye-doped polyelectrolyte
      (PE) multilayer film. Hollow PE capsules, with a mean diameter of 2 microm, were
      prepared by stepwise adsorption of a pyrene (PY)-labeled polyanion and various
      polycations onto charged colloids and subsequent dissolution of the colloidal
      core. The high concentration of dye molecules within the capsule wall and the
      control of the medium polarity on a nanometer length scale are proposed to
      facilitate light-induced charge separation over distances of a few nanometers. In
      particular, a PY-labeled poly(styrene sulfonate) (PSS-PY) has been synthesized
      and used as polyanion for the polyelectrolyte capsule preparation. A polarity
      gradient across the wall of the PE shells is assumed to be achieved by adsorbing
      diverse polycations at different film positions. The high effective film area
      followed by high optical density of the PE capsule solution enables time-resolved
      optical spectroscopy. Using pulsed excited state absorption (ESA) the transient
      absorption peaks of the radical anion and cation state of pyrene were measured,
      respectively. In the presence of additional electron donor (or acceptor)
      molecules in the capsule solution the pyrene anion (cation) is observed in the
      ESA spectra, while both transient states are seen if no additional molecules are
      present. These results are interpreted as an electron transfer from pyrene to the
      donor (acceptor) molecule or between two pyrene molecules. An asymmetry of the
      electron donor and electron acceptor efficiency was observed when multilayer
      shells were used that are supposed to carry an internal polarity gradient.

PMID- 15012152
TI  - Understanding the high activity of a nanostructured catalyst obtained by a
      deposit of Pd on Ni: first principle calculations.
AB  - The catalytic activity of a 4 monolayer deposit of Pd on a Ni(110) surface toward
      the hydrogenation of ethylene is investigated by using gradient-corrected
      periodic density functional calculations. The Pd/Ni(110) surface is strongly
      nanostructured, due to the anisotropic stress induced by the Ni(110) substrate on
      the Pd layer. A kinetic analysis, based on the investigation of the optimal
      reaction pathway for the hydrogenation of ethylene to ethane, is presented,
      allowing a comparison between Pd/Ni(110) and pure Pd(110) surfaces. The
      calculated activation energies allow one to reproduce the experimental result,
      which shows that the Pd/Ni(110) surface is about 30 times more active than the
      pure Pd(110) surface. This marked increase of the catalytic activity is a
      consequence of the specific nanostructure of the Pd/Ni(110) surface. By examining
      the structure of the adsorbed species and of the transition states and by
      analyzing the electronic properties, we show that this rate increase can be
      associated to the fact that the ethylene adsorption energy in the first
      hydrogenation step and the ethyl-hydrogen coadsorption energy in the second step
      are both much lower on Pd/Ni(110) than on pure Pd(110).

PMID- 15012153
TI  - On the mechanism of the cis-trans isomerization in the lowest electronic states
      of azobenzene: S0, S1, and T1.
AB  - In this paper, we identify the most efficient decay and isomerization route of
      the S(1), T(1), and S(0) states of azobenzene. By use of quantum chemical
      methods, we have searched for the transition states (TS) on the S(1) potential
      energy surface and for the S(0)/S(1) conical intersections (CIs) that are closer
      to the minimum energy path on the S(1). We found only one TS, at 60 degrees of
      CNNC torsion from the E isomer, which requires an activation energy of only 2
      kcal/mol. The lowest energy CIs, lying also 2 kcal/mol above the S(1) minimum,
      were found on the torsion pathway for CNNC angles in the range 95-90 degrees. The
      lowest CI along the inversion path was found ca. 25 kcal/mol higher than the S(1)
      minimum and was characterized by a highly asymmetric molecular structure with one
      NNC angle of 174 degrees. These results indicate that the S(1) state decay
      involves mainly the torsion route and that the inversion mechanism may play a
      role only if the molecule is excited with an excess energy of at least 25
      kcal/mol with respect to the S(1) minimum of the E isomer. We have calculated the
      spin-orbit couplings between S(0) and T(1) at several geometries along the CNNC
      torsion coordinate. These spin-orbit couplings were about 20-30 cm(-)(1) for all
      the geometries considered. Since the potential energy curves of S(0) and T(1)
      cross in the region of twisted CNNC angle, these couplings are large enough to
      ensure that the T(1) lifetime is very short ( approximately 10 ps) and that
      thermal isomerization can proceed via the nonadiabatic torsion route involving
      the S(0)-T(1)-S(0) crossing with preexponential factor and activation energy in
      agreement with the values obtained from kinetic measures.

PMID- 15012154
TI  - Weak C-H...O and C-H...F-C hydrogen bonds in the oxirane-trifluoromethane dimer.
AB  - The oxirane-trifluoromethane dimer generated in a supersonic expansion has been
      characterized by Fourier transform microwave spectroscopy. The rotational spectra
      of the parent species and of its two (13)C isotopomers in combination with ab
      initio calculations have been used to establish a C(s)() geometry for the dimer
      with the two monomers bound by one C-H.O and two C-H.F-C hydrogen bonds. An
      overall bonding energy of about 6.7 kJ/mol has been derived from the centrifugal
      distortion analysis. The lengths of the C-H.O and C-H.F hydrogen bonds, r(O.H)
      and r(F.H), are 2.37 and 2.68 A, respectively. The C-H.F-C interactions give rise
      to the HCF(3) internal rotation motion barrier of 0.55(1) kJ/mol, which causes
      the A-E splittings observed in the rotational spectra. The analysis of the
      structural and energetic features of the C-H.O and C-H.F-C interactions allows us
      to classify them as weak hydrogen bonds. Ab initio calculations predict these
      weak interactions to produce blue shifts in the C-H vibrational frequencies and
      shortenings of the C-H lengths.

PMID- 15012155
TI  - Deuterium NMR used to indicate a common mechanism for the biosynthesis of
      ricinoleic acid by Ricinus communis and Claviceps purpurea.
AB  - Previous studies have shown that ricinoleic acid from castor bean oil of Ricinus
      communis is synthesized by the direct hydroxyl substitution of oleate, while it
      has been proposed that ricinoleate is formed by hydration of linoleate in the
      ergot fungus Claviceps purpurea. The mechanism of the enzymes specific to
      ricinoleate synthesis has not yet been established, but hydroxylation and
      desaturation of fatty acids in plants apparently involve closely related
      mechanisms. As mechanistic differences in the enzymes involved in the
      biosynthesis of natural products can lead to different isotopic distributions in
      the product, we could expect ricinoleate isolated from castor or ergot oil to
      show distinct (2)H distribution patterns. To obtain information concerning the
      substrate and isotope effects that occur during the biosynthesis of ricinoleate,
      the site-specific natural deuterium distributions in methyl ricinoleate isolated
      from castor oil and in methyl ricinoleate and methyl linoleate isolated from
      ergot oils have been measured by quantitative (2)H NMR. First, the deuterium
      profiles for methyl ricinoleate from the plant and fungus are equivalent. Second,
      the deuterium profile for methyl linoleate from ergot is incompatible with this
      chemical species being the precursor of methyl ricinoleate. Hence, it is apparent
      that 12-hydroxylation in C. purpurea is consistent with the biosynthetic
      mechanisms proposed for R. communis and is compatible with the general
      fundamental mechanistic similarities between hydroxylation and desaturation
      previously proposed for plant fatty acid biosynthesis.

PMID- 15012156
TI  - Selective deposition of native cell membranes on biocompatible micropatterns.
AB  - We establish two methods to deposit native biomembranes (human erythrocyte
      membranes and sarcoplasmic reticulum membranes) selectively onto biocompatible
      microtemplates. The first method utilizes UV photolithography to micropattern the
      regenerated cellulose, while the second uses the "stamping" of protein barriers
      onto homogeneous cellulose supports. The relatively simple methods established
      here allow for the position selective spreading of three-dimensional native cells
      into two-dimensional films, retaining the orientation and lateral density of
      transmembrane proteins in their native state.

PMID- 15012157
TI  - Investigation of noncovalent interactions in deprotonated peptides: structural
      and energetic competition between aggregation and hydration.
AB  - Noncovalent peptide-peptide and peptide-water interactions in small model systems
      were examined using an electrospray mass spectrometer equipped with a high
      pressure drift cell. The results of these aggregation and hydration experiments
      were interpreted with the aid of molecular mechanics (MM) and density functional
      theory (DFT) calculations. The systems investigated include bare deprotonated
      monomers and dimers [P(1,2)-H](-) and hydrated deprotonated monomers and dimers
      [P(1,2)-H](-).(H(2)O)(n)() for the peptides dialanine (P = AA) and diglycine (P =
      GG). Mass spectra indicated that both peptides AA and GG form exclusively dimer
      ions in the electrospray process. Monomeric ions were generated by high-energy
      injection of the dimers into the drift cell. Temperature-dependent hydration
      equilibrium experiments carried out in the drift cell yielded water binding
      energies ranging from 11.7 (first water molecule) to 7.1 kcal/mol (fourth water)
      for [AA-H](-) and 11.0 to 7.4 kcal/mol for [GG-H](-). The first water molecule
      adding to the dimer ions [AA-H](-).(AA) and [GG-H](-).(GG) is bound by 8.4 and
      7.5 kcal/mol, respectively. The hydration mass spectra for the monomers and
      dimers provide a means to compare the ability of water and a neutral peptide to
      solvate a deprotonated peptide [P-H](-). The data indicate that a similar degree
      of solvation is achieved by four water molecules, [P-H](-).(H(2)O)(4), or one
      neutral peptide, [P-H](-).(P). Temperature-dependent kinetics experiments yielded
      activation energies for dissociation of the dimers [AA-H](-).(AA) and [GG-H](
      ).(GG) of 34.9 and 32.2 kcal/mol, respectively. MM and DFT calculations carried
      out for the dialanine system indicated that the dimer binding energy is 24.3
      kcal/mol, when the [AA-H](-) and AA products are relaxed to their global minimum
      structures. However, a value of 38.9 kcal/mol is obtained if [AA-H](-) and AA
      dissociate but retain the structures of the moieties in the dimer, suggesting the
      transition state occurs early in the dissociation process. Similar results were
      found for the diglycine dimer.

PMID- 15012158
TI  - Charge transport properties in discotic liquid crystals: a quantum-chemical
      insight into structure-property relationships.
AB  - We describe at the quantum-chemical level the main parameters that control charge
      transport at the molecular scale in discotic liquid crystals. The focus is on
      stacks made of triphenylene, hexaazatriphenylene, hexaazatrinaphthylene, and
      hexabenzocoronene molecules and derivatives thereof. It is found that a subtle
      interplay between the chemical structure of the molecules and their relative
      positions within the stacks determines the charge transport properties; the
      molecular features required to promote high charge mobilities in discotic
      materials are established on the basis of the calculated structure-property
      relationships. We predict a significant increase in the charge mobility when
      going from triphenylene to hexaazatrinaphthylene; this finding has been confirmed
      by measurements carried out with the pulse-radiolysis time-resolved microwave
      conductivity technique.

PMID- 15012159
TI  - Hydrogen bond geometries from electron paramagnetic resonance and electron
      nuclear double resonance parameters: density functional study of quinone radical
      anion-solvent interactions.
AB  - Density functional theory was used to study the impact of hydrogen bonding on the
      p-benzosemiquinone radical anion BQ(*-) in coordination with water or alcohol
      molecules. After complete geometry optimizations, (1)H, (13)C, and (17)O
      hyperfine as well as (2)H nuclear quadrupole coupling constants and the g-tensor
      were computed. The suitability of different model systems with one, two, four,
      and 20 water molecules was tested; best agreement between theory and experiment
      could be obtained for the largest model system. Q-band pulse (2)H electron
      nuclear double resonance (ENDOR) experiments were performed on BQ(*-) in D(2)O.
      They compare very well with the spectra simulated by use of the theoretical
      values from density functional theory. For BQ(*-) in coordination with four water
      or alcohol molecules, rather similar hydrogen-bond lengths between 1.75 and 1.78
      A were calculated. Thus, the computed electron paramagnetic resonance (EPR)
      parameters are hardly distinguishable for the different solvents, in agreement
      with experimental findings. Furthermore, the distance dependence of the EPR
      parameters on the hydrogen-bond length was studied. The nuclear quadrupole and
      the dipolar hyperfine coupling constants of the bridging hydrogens show the
      expected dependencies on the H-bond length R(O.H). A correlation was obtained for
      the g-tensor. It is shown that the point-dipole model is suitable for the
      estimation of hydrogen-bond lengths from anisotropic hyperfine coupling constants
      of the bridging (1)H nuclei for H-bond lengths larger than approximately 1.7 A.
      Furthermore, the estimation of H-bond lengths from (2)H nuclear quadrupole
      coupling constants of bridging deuterium nuclei by empirical relations is
      discussed.

PMID- 15012160
TI  - Determination of an ensemble of structures representing the denatured state of
      the bovine acyl-coenzyme a binding protein.
AB  - The denatured state of a protein contains important information about the
      determinants of the folding process. By combining site-directed spin-labeling NMR
      experiments and restrained computer simulations, we have determined ensembles of
      conformations that represent the denatured state of the bovine acyl-coenzyme A
      binding protein (ACBP) at three different concentrations of guanidine
      hydrochloride. As the experimentally determined distance information corresponds
      to weighted averages over a broad ensemble of structures, we applied the
      experimental restraints to a system of noninteracting replicas of the protein by
      using a Monte Carlo sampling scheme. This procedure permits us to sample
      ensembles of conformations that are compatible with the experimental data and
      thus to obtain information regarding the distribution of structures in the
      denatured state. Our results show that the denatured state of ACBP is highly
      heterogeneous. The high sensitivity of the computational method that we present,
      however, enabled us to identify long-range interactions between two regions,
      located near the N- and C-termini, that include both native and non-native
      elements. The preferential formation of these contacts suggests that the sequence
      dependent patterns of helical propensity and hydrophobicity are important
      determinants of the structure in the denatured state of ACBP.

PMID- 15012161
TI  - Reaction intermediates in acid catalysis by zeolites: prediction of the relative
      tendency to form alkoxides or carbocations as a function of hydrocarbon nature
      and active site structure.
AB  - The mechanism of protonation of ethene, propene, and isobutylene adsorbed on
      seven different Bronsted acid sites of mordenite has been studied at the ONIOM
      (B3PW91/6-31G(d,p):MNDO) theoretical level to assess the influence of olefin size
      and local geometry of the active site on the species and energies involved. The
      activation energies for olefin protonation are determined by short- and medium
      range electrostatic effects and reflect the order of stability of primary,
      secondary, and tertiary carbenium ions. On the other hand, the stability of
      covalent alkoxides depends linearly on the AlO(b)Si angle value in the complex,
      which in turn is determined by the corresponding value in the deprotonated
      zeolite. It is also shown that the mechanism of protonation of isobutylene is
      different from that of ethene and propene and involves a free tert-butyl
      carbenium ion as a true reaction intermediate. Whether this carbenium ion is
      converted into a covalent alkoxide depends on the T position on which the Al is
      located. All these findings allow us to predict, on the basis of the position and
      local geometry of the Bronsted acid site, whether the reaction intermediates of
      olefin protonation will be covalent alkoxides or free carbenium ions.

PMID- 15012162
TI  - Peroxovanadate imidazole complexes as catalysts for olefin epoxidation: density
      functional study of dynamics, 51V NMR chemical shifts, and mechanism.
AB  - A density functional study of [VO(O(2))(2)(Im)](-) (1, Im = imidazole) is
      presented, calling special attention to effects of dynamics and solvation on the
      (51)V chemical shift. According to Car-Parrinello molecular dynamics simulations,
      rotation of the Im ligand can be fast in the gas phase, but is more hindered in
      aqueous solution. In the latter, bonding between Im and V is reinforced, and
      dynamic averaging of GIAO-B3LYP magnetic shieldings affords a gas-to-liquid shift
      of ca. -100 ppm for delta((51)V). A complete catalytic cycle has been
      characterized for olefin epoxidation mediated by 1, using H(2)O(2) as oxidant.
      The rate-determining step is indicated to be initial oxygen atom transfer from 1
      to the substrate via a spiro-like transition state. Substituent effects on this
      barrier are examined, and a significant decrease (by 2-6 kcal/mol) is revealed
      upon removal of the Im proton or upon complexation with a H-bond acceptor.
      Implications for the mechanism of the oxidative chemistry of vanadium-dependent
      haloperoxidases and requirements for prospective biomimetic analogues are
      discussed.

PMID- 15012163
TI  - Mechanism of ferromagnetic coupling in copper(II)-gadolinium(III) complexes.
AB  - This paper offers the first series of state-of-the-art quantum chemical
      calculations (CASSCF, CASPT2, MS-CASPT2) and analytical models for the well-known
      problem of quasi-general ferromagnetic coupling in copper-gadolinium complexes. A
      system chosen from the chemical report of Costes et al. was taken as prototype.
      At the CASSCF level, calculated results for the experimental structure reproduced
      the magnetic coupling constant well (J(calcd)( )()= +7.67 cm(-)(1) vs J(exp)(
      )()= +7.0 cm(-)(1)). For more insight, the study molecule was further idealized
      by geometry optimization to C(2)(v)() symmetry. Systematic ab initio computation
      experiments were designed and performed. Owing to specific problems related to
      the non-aufbau ground configuration of the [CuL-Gd] complexes, the calculations
      were conducted in a nonstandard manner. We found that the qualitative mechanism
      of Kahn, assigned to the electron jump from 3d of Cu(II) to 5d shell of Gd(III),
      can be presented effectively as the cause of the phenomenon, if CASPT2 MOs are
      taken as magnetic orbitals. We showed that the ferromagnetic coupling is also
      matched and magnified by spin polarization effects over the ligand, in line with
      the early assumption of Gatteschi. To be distinguished from the initial
      hypothesis of Gatteschi, which assumed the role of 6s AO of Gd(III), we found
      that one 5d-type AO is actually involved in the polarization scheme. In fact, the
      Gatteschi and Kahn mechanisms are not mutually contradictory, but are even
      interconvertible with appropriate changes of the magnetic orbitals. Within
      C(2)(v)() symmetry of complexes, the ferromagnetic coupling can be qualitatively
      regarded as the preponderant influence of interaction channels exhibiting orbital
      orthogonality (four 3d-4f contacts) over the nonorthogonal ones (two 3d-4f
      contacts). The effective preponderance from ferromagnetic pathways is supported
      by CASPT2 results. One may explain the generality of Cu(II)-Gd(III) ferromagnetic
      coupling as being correlated with the large occurrence of approximate pseudo
      C(2)(v)() geometry of complexes. The observed orbital regularity is lost in lower
      symmetries. Thus, the antiferromagnetic exceptions occur when the molecular
      asymmetry is advanced (e.g., owing to strong chemical nonequivalence of the donor
      atoms).

PMID- 15012164
TI  - Theoretical study of the Cp2Zr-catalyzed hydrosilylation of ethylene. Reaction
      mechanism including new sigma-bond activation.
AB  - The Cp(2)Zr-catalyzed hydrosilylation of ethylene was theoretically investigated
      with DFT and MP2-MP4(SDQ) methods, to clarify the reaction mechanism and the
      characteristic features of this reaction. Although ethylene insertion into the Zr
      SiH(3) bond of Cp(2)Zr(H)(SiH(3)) needs a very large activation barrier of 41.0
      (42.3) kcal/mol, ethylene is easily inserted into the Zr-H bond with a very small
      activation barrier of 2.1 (2.8) kcal/mol, where the activation barrier and the
      energy of reaction calculated with the DFT(B3LYP) method are given and in
      parentheses are those values which have been corrected for the zero-point energy,
      hereafter. Not only this ethylene insertion reaction but also the coupling
      reaction between Cp(2)Zr(C(2)H(4)) and SiH(4) easily takes place to afford
      Cp(2)Zr(H)(CH(2)CH(2)SiH(3)) and Cp(2)Zr(CH(2)CH(3))(SiH(3)) with activation
      barriers of 0.3 (0.7) and 5.0 (5.4) kcal/mol, respectively. This coupling
      reaction involves a new type of Si-H sigma-bond activation which is similar to
      metathesis. The important interaction in the coupling reaction is the bonding
      overlap between the d(pi)-pi bonding orbital of Cp(2)Zr(C(2)H(4)) and the Si-H
      sigma orbital. The final step is neither direct C-H nor Si-C reductive
      elimination, because both reductive eliminations occur with a very large
      activation barrier and significantly large endothermicity. This is because the d
      orbital of Cp(2)Zr is at a high energy. On the other hand, ethylene-assisted C-H
      reductive elimination easily occurs with a small activation barrier, 5.0 (7.5)
      kcal/mol, and considerably large exothermicity, -10.6 (-7.1) kcal/mol. Also,
      ethylene-assisted Si-C reductive elimination and metatheses of
      Cp(2)Zr(H)(CH(2)CH(2)SiH(3)) and Cp(2)Zr(CH(2)CH(3))(SiH(3)) with SiH(4) take
      place with moderate activation barriers, 26.5 (30.7), 18.4 (20.5), and 28.3
      (31.5) kcal/mol, respectively. From these results, it is clearly concluded that
      the most favorable catalytic cycle of the Cp(2)Zr-catalyzed hydrosilylation of
      ethylene consists of the coupling reaction of Cp(2)Zr(C(2)H(4)) with SiH(4)
      followed by the ethylene-assisted C-H reductive elimination.

PMID- 15012165
TI  - Optical and electrical properties of three-dimensional interlinked gold
      nanoparticle assemblies.
AB  - The optical and electrical properties of 11-20 nm thick films composed of
      approximately 4 nm gold nanoparticles (Au-NPs) interlinked by six organic dithiol
      or bis-dithiocarbamate derivatives were compared to investigate how these
      properties depend on the core of the linker molecule (benzene or cyclohexane) and
      its metal-binding substituents (thiol or dithiocarbamate). Films prepared with
      the thiol-terminated linker molecules, (1,4-bis(mercaptomethyl)benzene, 1,4
      bis(mercaptomethyl)cyclohexane, 1,4-bis(mercaptoacetamido)benzene, and 1,4
      bis(mercaptoacetamido)cyclohexane), exhibit thermally activated charge transport.
      The activation energies lie between 59 and 71 meV. These films show distinct
      plasmon absorption bands with maxima between 554 and 589 nm. In contrast, the
      film prepared with 1,4-cyclohexane-bis(dithiocarbamate) has a significantly red
      shifted plasmon band ( approximately 626 nm) and a pronounced absorbance in the
      near infrared. The activation energy for charge transport is only 14 meV. These
      differences are explained in terms of the formation of a resonant state at the
      interface due to overlap of the molecular orbital and metal wave function,
      leading to an apparent increase in NP diameter. The film prepared with 1,4
      phenylene-bis(dithiocarbamate) exhibits metallic properties, indicating the full
      extension of the electron wave function between interlinked NPs. In all cases,
      the replacement of the benzene ring with a cyclohexane ring in the center of the
      linker molecule leads to a 1 order of magnitude decrease in conductivity. A
      linear relationship is obtained when the logarithm of conductivity is plotted as
      a function of the number of nonconjugated bonds in the linker molecules. This
      suggests that nonresonant tunneling along the nonconjugated parts of the molecule
      governs the electron tunneling decay constant (beta(N)(-)(CON)), while the
      contribution from the conjugated parts of the molecule is weak (corresponding to
      resonant tunneling). The obtained value for beta(N)(-)(CON) is approximately 1.0
      (per non-conjugated bond) and independent of the nanoparticle-binding group.
      Hence, the molecules can be viewed as consisting of serial connections of
      electrically insulating (nonconjugated) and conductive (conjugated) parts.

PMID- 15012166
TI  - Highly sensitive fluorescence probes for nitric oxide based on boron
      dipyrromethene chromophore-rational design of potentially useful bioimaging
      fluorescence probe.
AB  - Boron dipyrromethene (BODIPY) is known to have a high quantum yield (phi) of
      fluorescence in aqueous solution but has not been utilized much for biological
      applications, compared to fluorescein. We developed 8-(3,4-diaminophenyl)-2,6
      bis(2-carboxyethyl)-4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s
      indacene (DAMBO-P(H)), based on the BODIPY chromophore, as a highly sensitive
      fluorescence probe for nitric oxide (NO). DAMBO-P(H) had a low phi value of
      0.002, whereas its triazole derivative (DAMBO-P(H)-T), the product of the
      reaction of DAMBO-P(H) with NO, fluoresced strongly (phi = 0.74). The change of
      the fluorescence intensity was found to be controlled by an intramolecular
      photoinduced electron transfer (PeT) mechanism. The strategy for development of
      DAMBO-P(H) was as follows: (1) in order to design a highly sensitive probe of NO,
      the reactivity of o-phenylenediamine derivatives as NO-reactive moieties was
      examined using 4,5-diaminofluorescein (DAF-2, a widely used NO fluorescence
      probe), (2) in order to avoid pH-dependency of the fluorescence intensity, the
      PeT process was controlled by modulating the spectroscopic and electrochemical
      properties of BODIPY chromophores according to the Rehm-Weller equation based on
      measurement of excitation energies of chromophores, ground-state reduction
      potentials of PeT acceptors (BODIPYs), and calculation of the HOMO energy level
      of the PeT donor (o-phenylenediamine moiety) at the B3LYP/6-31G level, (3) in
      order to avoid quenching of fluorescence by stacking of the probes and to obtain
      probes suitable for biological applications, hydrophilic functional groups were
      introduced. This strategy should be applicable for the rational design of other
      novel and potentially useful bioimaging fluorescence probes.

PMID- 15012168
TI  - Epidemiology and management of diverticular disease of the colon.
AB  - Colonic diverticula are protrusions of the mucosa through the outer muscular
      layers, which are usually abnormally thickened, to form narrow necked pouches.
      Diverticular disease of the colon covers a wide clinical spectrum: from an
      incidental finding to symptomatic uncomplicated disease to diverticulitis. A
      quarter of patients with diverticulitis will develop potentially life-threatening
      complications including perforation, fistulae, obstruction or stricture. In
      Western countries diverticular disease predominantly affects the left colon, its
      prevalence increases with age and its causation has been linked to a low dietary
      fibre intake. Right-sided diverticular disease is more commonly seen in Asian
      populations and affects younger patients. Its pathogenesis and relationship to
      left-sided diverticular disease remains unclear. Diverticular disease of the
      colon is a significant cause of morbidity and mortality in the Western world and
      its frequency has increased throughout the whole of the 20th century. Since it is
      a disease of the elderly, and with an aging population, it can be expected to
      occupy an increasing portion of the surgical and gastroenterological workload. It
      is uncertain what symptoms uncomplicated diverticular disease gives rise to:
      there is an overlap with irritable bowel syndrome. Diagnosis is primarily by
      barium enema and colonoscopy, but more sophisticated imaging procedures such as
      computed tomography (CT) are increasingly being used to assess and treat
      complications such as abscess or fistula, or to provide alternative diagnoses if
      diverticulosis is not confirmed. Initial therapy for uncomplicated diverticulitis
      is supportive, including monitoring, bowel rest and antibacterials. CT is used to
      guide percutaneous drainage of abscesses to avoid surgery or allow it to be
      performed as an elective procedure. Surgery is indicated for complications of
      acute diverticulitis, including failure of medical treatment, gross perforation,
      and abscess formation that cannot be resolved by percutaneous drainage.
      Complications of chronic diverticulitis (fistula formation, stricture and
      obstruction) are also usually treated surgically. However, the indications for,
      and the timing and staging of operations for diverticular disease are often
      difficult decisions requiring sound clinical judgement. Factors such as the
      number of episodes of inflammation, the age of the patient, and his/her overall
      medical condition play a role in determining whether or not a patient should
      undergo surgical resection. Laparoscopic surgery may be associated with less
      pain, less morbidity and shorter hospital stays, but its exact role is yet to be
      defined. Diverticular disease of the colon is the most common cause of acute
      lower gastrointestinal haemorrhage, which can be massive. Although the majority
      of patients stop bleeding spontaneously, angiographic and surgical treatment may
      be required, while the place of endoscopic haemostasis remains to be established.

PMID- 15012169
TI  - Anaesthesia in elderly patients with neurodegenerative disorders: special
      considerations.
AB  - Neurodegenerative diseases are increasingly common in elderly patients, who
      present a particular anaesthetic challenge. The majority of people over the age
      of 70 years have some degree of cerebral atrophy. The pathogenesis of
      neurodegenerative diseases is due to alterations in the transport, degradation
      and aggregation of proteins. Alterations in physiology that occur with advancing
      age affect both the pharmacokinetics and pharmacodynamics of drugs used in the
      elderly. Changes in pharmacokinetics result in either increased or reduced drug
      concentrations depending on the variable contributions of absorption, metabolism
      and elimination. The distribution of a drug depends on its protein binding,
      cardiac output and blood volume, which are all altered in the elderly. Metabolism
      and excretion of drugs are also affected due to changes in hepatic and renal mass
      and blood flow in the elderly. A number of drugs are used in neurodegenerative
      disorders including antidepressants, benzodiazepines, antipsychotics,
      acetylcholinesterase inhibitors and levodopa. Polypharmacy is a common problem,
      which can lead to adverse drug interactions and an exacerbation of dementia.
      Levodopa, bromocriptine and tricyclic antidepressants are known to cause
      orthostatic hypotension in patients with neurodegenerative disease. Elderly
      patients are liable to excessive sedation from benzodiazepines in both the pre-
      and postoperative period; therefore these drugs should be prescribed in low
      doses. For induction of general anaesthesia propofol is a suitable agent in
      patients with neurodegenerative disease due to its rapid metabolism, but may not
      be suitable in patients with Parkinson's disease as it can induce spontaneous
      involuntary movements. Volatile inhalational agents should be administered
      carefully in the elderly, as they are more sensitive to the depressant cerebral
      and cardiovascular effects. Levodopa should be avoided in conjunction with
      halothane, which sensitises the heart to catecholamines. Co-administration of
      monoamine oxidase inhibitors and opioids should be avoided as it can cause
      agitation, muscular rigidity, sweating and hyperpyrexia. If an anticholinergic
      agent is required, then glycopyrronium bromide is the drug of choice in this
      group of patients, as it does not cross the blood brain barrier. Patients should
      continue to take their usual medications in hospital and do not let the change in
      routine alter the times at which treatments are administered. This is
      particularly relevant to the timing of levodopa in Parkinson's disease, as missed
      treatment can be detrimental. Regional anaesthesia may, however, have significant
      advantages in patients with Parkinson's disease, who can continue to take oral
      levodopa preoperatively, during surgery, if required, and early in the
      postoperative period. Anti-emetic drugs such as phenothiazines, butyrophenones
      and metoclopramide should be used carefully in the postoperative period in these
      patients as their antidopaminergic effects may induce or exacerbate parkinsonian
      effects.

PMID- 15012171
TI  - Pioglitazone is effective therapy for elderly patients with type 2 diabetes
      mellitus.
AB  - BACKGROUND: Pioglitazone as monotherapy and in combination with sulfonylurea,
      metformin, or insulin has consistently demonstrated improved glycaemic and lipid
      parameters in patients with type 2 diabetes mellitus. OBJECTIVE: We performed a
      subanalysis to examine the effect of pioglitazone on glycaemia and lipids in
      patients <65 and > or =65 years of age in two double-blind, placebo-controlled
      monotherapy studies and in three separate multi-centre trials. METHOD: In Study
      1, 197 patients were randomised to receive pioglitazone 30 mg/day or placebo for
      16 weeks. Study 2 was a forced dose-titration trial in patients randomised to
      receive pioglitazone 7.5/15/30 mg/day, pioglitazone 15/30/45 mg/day, or placebo
      daily for 26 weeks. Each of the lower dosages was given for at least 4 weeks and
      the highest dosage for 16 weeks. The three combination studies evaluated efficacy
      of pioglitazone 30 or 45 mg/day over a 24-week period in combination with
      sulfonylureas, metformin, or insulin. RESULTS: In both placebo-controlled
      monotherapy studies, at 16 weeks, and at maximum pioglitazone dosage, 0.53-0.55%
      and 0.57-1.27% mean reductions from baseline in glycosylated haemoglobin
      (HbA(1c)) were seen in patients aged <65 (n = 225) and > or =65 (n = 45) years,
      respectively. There were statistically significant differences between the
      placebo and pioglitazone groups in each age cohort. Similar effects were observed
      in fasting plasma glucose (FPG) levels, with 2.03-2.59 mmol/L and 3.20-4.44
      mmol/L mean reductions from baseline, respectively, which were significantly
      different from the changes in the placebo group, but there was no difference
      between pioglitazone groups. At treatment endpoint in combination trials,
      pioglitazone added to sulfonylurea produced a mean decrease in HbA(1c) of 0.78
      1.61%, and 1.64-1.96% in patients aged <65 (n = 557) and > or =65 (n = 115)
      years, respectively. Pioglitazone added to metformin produced a mean decrease in
      HbA(1c) of 0.78-1.03% and 0.78-0.98% in patients aged <65 (n = 686) and > or =65
      (n = 112) years, respectively. Pioglitazone added to insulin produced a mean
      decrease in HbA(1c) of 1.13-1.37% and 1.39-1.66% in patients aged <65 (n = 500)
      and > or =65 (n = 156) years, respectively. In patients aged > or =65 years,
      hypoglycaemia was observed in 1 of 14 patients and in 0 of 13 patients in the two
      monotherapy studies. In the combination studies, the incidence of hypoglycaemia
      among patients aged > or =65 years was as follows: 26.7-28.8% combined with
      sulfonylurea; 0-4.4% combined with metformin; and 53.4-56.4% combined with
      insulin. CONCLUSION: Pioglitazone monotherapy, or added to a sulfonylurea,
      metformin, or insulin demonstrated no significant differences in effectiveness
      while exhibiting similar adverse events in patients aged > or =65 years compared
      with patients aged <65 years. Well-controlled randomised clinical trials are
      recommended to confirm the impact of pioglitazone therapy on the glycaemic and
      lipid control in elderly patients with type 2 diabetes.

PMID- 15012173
TI  - [Are the current dispensation systems appropriate in a pediatric setting?].

PMID- 15012172
TI  - Prescription of anti-oedema agents and short-term mortality in older patients
      with acute ischaemic stroke.
AB  - BACKGROUND AND OBJECTIVE: In Western countries, stroke is the third most common
      cause of death and one of the main causes of disability in individuals aged over
      65 years. Mortality at 1 month after stroke is still high, at around 25-30%.
      Despite the widespread use of anti-oedema agents in clinical practice, there are
      only a few studies that have investigated the effect of these drugs on stroke
      outcome. In this study we evaluated the effect of intravenously administered
      glycerol or mannitol individually and in combination with corticosteroids, on
      short-term mortality (30 days). The sample included patients aged over 65 years
      who were admitted to hospital for acute ischaemic stroke. STUDY DESIGN: This was
      a retrospective cohort study. The odds ratio, estimated by means of multivariate
      logistic regression method, was used to compare short-term mortality risk across
      treatment groups after adjusting for possible confounders. METHODS: This study
      included 442 consecutive patients aged over 65 years with severe ischaemic stroke
      who were admitted to either the University School of Internal Medicine (Ferrara)
      or the Geriatric Department (Perugia), Italy, over a 4-year period (1996-2000).
      All patients underwent a computed tomography (CT) scan of the brain within 72
      hours of admission. Stroke type was classified according to the system used by
      the Oxfordshire Community Stroke Project. The data recorded included: (i)
      clinical features of stroke; (ii) detailed medical history, including vascular
      risk factors (arterial hypertension, diabetes mellitus, atrial fibrillation,
      coronary heart disease, congestive heart failure, alcohol abuse, smoking,
      previous transient ischaemic attacks or stroke); (iii) 12-lead ECG; and (iv)
      routine blood analysis and urine tests. RESULTS: No reduction in short-term
      mortality risk was observed in patients treated with intravenous (IV) glycerol.
      However, an increase in short-term mortality risk was observed in the patients
      who were concurrently treated with IV corticosteroids. Similarly, treatment with
      mannitol did not reduce the risk of short-term mortality; however, concurrent
      treatment with IV corticosteroids did not show a significant rise in short-term
      mortality risk. When treatment with IV glycerol and mannitol was considered
      together, the treatment did not decrease short-term mortality risk, while
      concurrent therapy with corticosteroids was associated with an increase in short
      term mortality risk. CONCLUSION: This study does not support the use of IV
      osmotic agents such as glycerol or mannitol in the prevention of short-term
      mortality in older patients with acute ischaemic stroke. Furthermore, our data
      suggest a possible harmful effect of IV corticosteroids on short-term mortality
      risk.

PMID- 15012170
TI  - Acute cough in the elderly: aetiology, diagnosis and therapy.
AB  - Although the frequency of physician consultations and the sale of over-the
      counter remedies establish the high prevalence of acute cough in the elderly,
      epidemiological studies have tended to be imprecise. However, respiratory tract
      infections in nose, larynx and/or bronchi, either viral or bacterial or both, are
      by far the commonest cause of acute cough. These are especially frequent and
      hazardous in the elderly, and community living and institutionalisation may
      aggravate this problem. A variety of viruses and bacteria have been incriminated,
      with rhinovirus, influenza and respiratory syncytial viruses, and Streptococcus
      pneumoniae, Haemophilus influenza and Bordetella pertussis being especially
      important. Viral infections can readily lead to community-acquired pneumonia.
      Successful diagnosis should point to successful treatment, and in this respect
      clinical examination and patient history are paramount, supplemented by chest X
      ray, viral and bacterial culture and serological testing. Depending on the
      results of these tests, specific antibacterial therapy may be called for,
      although there is dispute as to the merits of antibacterial therapy in cases of
      uncertain diagnosis. Prevention and prophylaxis for influenza and S. pneumoniae
      infections are now commendably routine in the elderly, especially those in
      communities. Treatment, as well as the use of antibacterials, may also be
      directed against the inflammatory and infective processes in the airways. Non
      specific antitussive therapy is common and usually highly desirable to prevent
      the adverse effects of repeated coughing. There have been few advances in
      antitussive therapy in recent years, opioids and dextromethorphan being the most
      commonly used agents; they act centrally on the brainstem, but also have a large
      placebo effect. However they work, they are much appreciated by patients and
      their partners. Moreover, striking advances in our understanding of the
      peripheral sensory and central nervous pathways of the cough reflex in recent
      years should soon lead to a new and more specific choice of agents to inhibit
      cough.

PMID- 15012174
TI  - [Cyclosporin pharmacokinetic modeling in renal transplant patients].
AB  - AIM: To characterize the pharmacokinetic behavior of oral cyclosporin (CsA) in
      renal transplant patient, based on through blood concentration (C0) value, and to
      develop and to evaluate a Bayesian method for the individualized adjustment of
      CsA daily dose (DD). METHODS: Sixty-seven renal allograft recipients (42 men and
      25 women) who had been treated with CsA (Sandimmun Neoral) associated with
      mycophenolate mofetil (2g daily) and prednisone (0,5-1 mg/kg daily) were randomly
      divided into two groups. Group A (N=48) was used to characterize CsA
      pharmacokinetic behavior and Group B (N=19) to evaluate Bayesian predictive
      performance for the model developed. We evaluated different structural models
      using non linear mixed effects modeling implemented in the NONMEN computer
      program in order to quantify the relationship between DD and C0. Accuracy and
      precision were evaluated by the mean standardized prediction error and its
      standard deviation. RESULTS: The Michaelis-Menten model was found to be optimum
      for quantifying the relationship between DD and C0. This model includes time
      dependent parameters such as the Michaelis-Menten constant (Km) and daily maximum
      dose (Dmax) as well as first order autoregressive terms DD and C0 included in the
      structural model in an additive way. In the final model, the Dmax parameter is
      affected by plasmatic urea values and shows a half-life stabilization time of
      90.90 days (95% CI: 52.60 to 250 days). Plasmatic urea values of 50 mg/dL are
      related to an initial Dmax value of 3 mg/kg daily (95% CI: 1.81 to 4.19 mg/kg
      daily) which decreases exponentially throughout the post-transplant period until
      it reaches a constant value of 2.16 mg/kg daily (95% CI: 1.41 to 2.91 mg/kg
      daily) In the same way, the Km parameter presents a central tendency value of
      93.60 ng/mL (95% CI: 28.60 to 158.60 ng/mL) and the half-life necessary for its
      stabilization is 12.70 days (95% CI: 9.80 to 17.90 days). The residual
      variability of the model is 8.2%. The mean value of standardized prediction
      errors for populations and its standard deviation, as well as its confidence
      intervals of 95%, confirm the appropriate accuracy and precision of both a priori
      and a posteriori predictions with this model. Also, it reached between 70 and
      100% a posteriori sequential predictions with prediction errors below 10%.
      CONCLUSION: The characterization of the pharmacokinetic behavior of CsA requires
      us to consider parameters such as Dmax and Km as non lineal functions of time,
      while the first order autoregressive terms DD and C0 must also be incorporated
      into the model.

PMID- 15012175
TI  - [Erythropoietin: a study of its use in oncohematology].
AB  - OBJECTIVE: To assess the effectiveness of erythropoietin (EPO) in a Clinical
      Oncohematology Unit within a general hospital, and to propose a therapeutic
      algorithm with EPO based on recommendations by ASCO. MATERIAL AND METHODS: A
      descriptive, retrospective study was carried out on patients who required support
      treatment with EPO while in the Oncohematology Unit during the year 2001. Data
      were collected by reviewing patient medical records. An effective treatment was
      defined as an increase in baseline hemoglobin (Hb) equal to or higher than 2 g/dL
      over 4-8 weeks, with no transfusion requirements or decreased transfusion needs.
      Baseline Hb values, their distribution per diagnosis, and the involvement of
      platinum-containing chemotherapy regimens were analyzed. RESULTS: Of the 353
      patients in chemotherapy, 87% corresponded to oncologic diagnoses while the rest
      had hematological neoplasms. A total of 54 patients were assessed, with 83% of
      these corresponding to the oncologic area. Oncologic diagnoses that most required
      the use of EPO included: head-neck 53%, genitourinary 39%, and lung 39%. Overall
      effectiveness was 57% (60% in oncology and 44% in hematology). The Hb value
      leading to initial prescription (baseline Hb) was always below 10 g/dL for the
      hematology area, whereas most oncology patients exhibited higher levels at
      therapy onset. CONCLUSIONS: 1. Its percentage of failure: 40% for oncology and
      56% for hematology patients, together with its high cost, shows that a further
      search for predictive factors is warranted in order to more precisely select
      individuals who may benefit from this therapy. 2. The percentage of oncology
      patients with baseline Hb <10 is only 29%. Baseline Hb values for treatment onset
      and peak Hb values for therapy discontinuation should be agreed upon. Treatment
      initiation when Hb values fall below 10 g/dL would be a reasonable option, and a
      decision to use EPO above 10 g/dL should be made in patients with less severe
      anemia (10-12 g/dL) only if clinical circumstances render it advisable. 3. Use
      protocols must include clear concept definitions for treatment, and for primary
      and secondary prophylaxis, which will help in the establishment of therapeutic
      algorithms.

PMID- 15012176
TI  - [A pharmacoeconomic study of in-hospital treatment against community-acquired
      pneumonia].
AB  - INTRODUCTION: A computer-driven unit-dose drug-dispensing system allows for
      improved knowledge on pharmaceutical costs per DRG and clinical department,
      between-hospital pharmacoeconomic studies to be carried out, as well as deviation
      analysis. METHODS: A retrospective, cost-minimization study was undertaken to
      both analyze and compare prescriptions for a number of antibiotics and
      bronchodilators, and their costs in both 89 and 90 DRGs, as well as their cost
      per hospital stay in patients admitted to the Internal Medicine Departments of
      two hospitals in Areas 6 (HUPH) and 9 (SVO) in CAM (Autonomous Community of
      Madrid). A statistical analysis was performed using the Kolmogorov-Smirnov test,
      Student 's "t" test, Mann-Whitney test, and least squares method. RESULTS AND
      CONCLUSIONS: Patient samples are similar, with no significant differences
      existing in clinical status at admission or in cure percentage. Also, no
      significant differences exist in antibiotic use, except for clarithromycin and
      ceftriaxone, which were more commonly used at SVO (P = 0.001 and P = 0.003,
      respectively), and levofloxacin, which was more commonly prescribed at HUPH (P <
      0.001). For identical results measured by using the cure index and mean stay, the
      cost of antibiotic therapy was significantly higher at HUPH (113.57 euro) versus
      SVO (78.32 euro), which related to a wider use of levofloxacin; while no
      statistical relation to clinical status was found that warranted its choice. No
      differences were seen in bronchoinhaler use which, together with antibiotics,
      represent 82.6% of cost at HUPH and 72% at SVO.

PMID- 15012177
TI  - [Pharmacy Department standard procedures for clinical trial development].
AB  - INTRODUCTION: Regulations on good clinical practice in the execution of clinical
      trials require the establishment and compliance of normalised working procedures
      by the hospital Pharmacy Department. These procedures must indicate precisely
      each one of the processes involved in their development, e.g. the reception,
      custody, storage, preparation and dispensing of research samples. OBJECTIVE: The
      aim of the present study is to analyse the information included in clinical trial
      protocols involved in the circulation of drug samples during the research stage
      and, based on the results obtained, to develop normalised working procedures for
      our hospital Pharmacy Department in order to carry out these clinical trials.
      MATERIAL AND METHODS: Eleven items were defined in order to describe key
      processes involved in identification, storage, receipt, preparation,
      dispensation, administration, maintenance and return of research samples, as well
      as those related to the beginning and end or closing of a clinical trial.
      Information included in 39 clinical trial protocols that had been sent to the
      Hospital Ethics Committee for evaluation between January and August of 2002 and
      was analysed in terms of the items previously defined. RESULTS: 46% of the
      protocols included data from the monitor or person representing the sponsor. 64%
      adequately described conservation and storage conditions of the research samples;
      but in 39% of the studied cases external labelling descriptions did not comply
      with legislation. Only 15% of the cases included clear instructions on research
      sample reception and its acknowledgement. 25.6% reported correct handling and/or
      preparation instructions for research samples with parenteral administration.
      Sample dispensation procedures were correctly described in no more than 5.1% of
      the protocols analyzed. 41% included information for patients, relatives or
      nurses on administration and handling of research samples, but none of them
      included specific information pamphlets or three-page leaflets. Procedures for
      either returning research samples to the sponsor or for their maintenance and
      replacement were not specified in the 71.8 and 100% of the cases, respectively.
      Likewise, trial ending or closing dates as well as procedures that must be
      followed by the Hospital Pharmacy Department during these processes were not
      stated in 89.7% of the protocols. Finally, only 30.8% of the cases explicitly
      cite the hospital Pharmacy Department. CONCLUSION: These results support and
      justify the need to improve clinical trial protocols in order for them to be
      performed in a secure, effective and efficient way. Besides, they have been the
      starting point to devise the normalised working procedures of the hospital
      Pharmacy Department for the development of the clinical trials.

PMID- 15012178
TI  - [Primary pulmonary hypertension and its management].
AB  - Primary pulmonary hypertension (PPH) is a disease of un-known etiology that is
      characterized by an increase in pulmonary arterial pressure. Traditionally its
      treatment has been based on the administration of the vasodilator therapy with
      calcium channel blockers. At present there are some treatments which not only
      correct the vasoconstriction but also other pathogenic PPH associated effects,
      such a vascular remodelling and the thrombosis. These treatments include: a)
      analogs of prostacyclin with different administration routes; b) endothelin
      receptor antagonists; and c) drugs that affect the metabolic pathway of nitric
      oxide. These pharmacological advances have reduced the number of pulmonary
      transplants in the patients with HPP, which is the last therapeutic alternative.

PMID- 15012179
TI  - [Cross-hypersensitivity syndrome between antiepileptic drugs: report of a case].
AB  - Antiepileptic hypersensitivity syndrome (SHA) is a rare (1/1.000 to 1/10.000 in
      new exposures) but potentially life-threatening syndrome that occurs after
      exposure to an anticonvulsant, most commonly the aromatic ones such as phenytoin,
      carbamazepine or phenobarbital. Clinical features of this syndrome include
      cutaneous reactions, fever, lymphadenopaties, eosinophilia and internal organ
      involvement (mainly liver, but also kidney, CNS, heart or lung). We present a
      case report of a 61-year-old woman treated with phenobarbital who developed a
      cutaneous eruption attributed to this drug. Treatment was changed to phenytoin
      and after 17 days the patient developed cutaneous rash, eosinophilia and an
      increase in transaminase levels. The high rate of cross-sensitivity between
      aromatic anticonvulsants (40-80%) suggests a link between a hypersensitivity
      reaction to phenytoin and the previous reaction to phenobarbital.

PMID- 15012181
TI  - [Elaboration of potassium permanganate, 1 in 10,000].

PMID- 15012180
TI  - [Pharmacobezoar in a patient operated on for pyloric stenosis].
AB  - Bezoars are concretions made up of a variety of partially digested materials seen
      in several portions of the gastrointestinal tract; they may result in
      gastrointestinal obstruction. Bezoar types described in the scientific literature
      include bezoars resulting from drugs. Their development is usually associated
      with some predisposing risk factor. The case of a patient is described, who was
      admitted to the hospitals Emergency Department because of a clinical event
      suggesting a gastrointestinal bleeding episode. After admission, endoscopy
      demonstrated the presence of a bezoar whose components included a great number of
      Adalat Oros tablets. A review of the drugs that induced bezoar formation is made,
      and associated risk factors, formation mechanisms, bezoar appearance, and
      treatments used are all described.

PMID- 15012182
TI  - [Dispensation of drugs at home? Some commentaries on the decision of the
      Constitutional Court on the Galician Law of Pharmaceutical Arrangement].

PMID- 15012183
TI  - [Drug safety. Notes about surveillance].

PMID- 15012184
TI  - FIFTY YEARS OF PLANT SCIENCE: Was There Really No Place for A Woman?

PMID- 15012185
TI  - BIOTIN METABOLISM IN PLANTS.
AB  - Biotin is an essential cofactor for a small number of enzymes involved mainly in
      the transfer of CO2 during HCO-3-dependent carboxylation reactions. This review
      highlights progress in plant biotin research by focusing on the four major areas
      of recent investigation: the structure, enzymology, and localization of two
      important biotinylated proteins (methylcrotonoyl-CoA carboxylase involved in the
      catabolism of leucine and noncyclic isoprenoids; acetyl-CoA carboxylase isoforms
      involved in a number of biosynthetic pathways); the biosynthesis of biotin; the
      biotinylation of biotin-dependent carboxylases, including the characterization of
      biotin holocarboxylase synthetase isoforms; and the detailed characterization of
      a novel, seed-specific biotinylated protein. A central challenge for plant biotin
      research is to determine in molecular terms how plant cells regulate the flow of
      biotin to sustain the biotinylation of biotin-dependent carboxylases during
      biosynthetic reactions.

PMID- 15012186
TI  - SUGAR-INDUCED SIGNAL TRANSDUCTION IN PLANTS.
AB  - Sugars have important signaling functions throughout all stages of the plant's
      life cycle. This review presents our current understanding of the different
      mechanisms of sugar sensing and sugar-induced signal transduction, including the
      experimental approaches used. In plants separate sensing systems are present for
      hexose and sucrose. Hexokinase-dependent and -independent hexose sensing systems
      can further be distinguished. There has been progress in understanding the signal
      transduction cascade by analyzing the function of the SNF1 kinase complex and the
      regulatory PRL1 protein. The role of sugar signaling in seed development and in
      seed germination is discussed, especially with respect to the various mechanisms
      by which sugar signaling controls gene expression. Finally, recent literature on
      interacting signal transduction cascades is discussed, with particular emphasis
      on the ethylene and ABA signal transduction pathways.

PMID- 15012187
TI  - THE CHLOROPLAST ATP SYNTHASE: A Rotary Enzyme?
AB  - The chloroplast adenosine triphosphate (ATP) synthase is located in the thylakoid
      membrane and synthesizes ATP from adenosine diphosphate and inorganic phosphate
      at the expense of the electrochemical proton gradient formed by light-dependent
      electron flow. The structure, activities, and mechanism of the chloroplast ATP
      synthase are discussed. Emphasis is given to the inherent structural asymmetry of
      the ATP synthase and to the implication of this asymmetry to the mechanism of ATP
      synthesis and hydrolysis. A critical evaluation of the evidence in support of and
      against the notion that one part of the enzyme rotates with respect to other
      parts during catalytic turnover is presented. It is concluded that although
      rotation can occur, whether it is required for activity of the ATP synthase has
      not been established unequivocally.

PMID- 15012188
TI  - NONPHOTOSYNTHETIC METABOLISM IN PLASTIDS.
AB  - Nonphotosynthetic plastids are important sites for the biosynthesis of starch,
      fatty acids, and the assimilation of nitrogen into amino acids in a wide range of
      plant tissues. Unlike chloroplasts, all the metabolites for these processes have
      to be imported, or generated by oxidative metabolism within the organelle. The
      aim of this review is to summarize our present understanding of the anabolic
      pathways involved, the requirement for import of precursors from the cytosol, the
      provision of energy for biosynthesis, and the interaction between pathways that
      share common intermediates. We emphasize the temporal and developmental
      regulation of events, and the variation in mechanisms employed by different
      species that produce the same end products.

PMID- 15012189
TI  - PATHWAYS AND REGULATION OF SULFUR METABOLISM REVEALED THROUGH MOLECULAR AND
      GENETIC STUDIES.
AB  - Sulfur is essential for life. Its oxidation state is in constant flux as it
      circulates through the global sulfur cycle. Plants play a key role in the cycle
      since they are primary producers of organic sulfur compounds. They are able to
      couple photosynthesis to the reduction of sulfate, assimilation into cysteine,
      and further metabolism into methionine, glutathione, and many other compounds.
      The activity of the sulfur assimilation pathway responds dynamically to changes
      in sulfur supply and to environmental conditions that alter the need for reduced
      sulfur. Molecular genetic analysis has allowed many of the enzymes and regulatory
      mechanisms involved in the process to be defined. This review focuses on recent
      advances in the field of plant sulfur metabolism. It also emphasizes areas about
      which little is known, including transport and recycling/degradation of sulfur
      compounds.

PMID- 15012190
TI  - (TRANS)GENE SILENCING IN PLANTS: How Many Mechanisms?
AB  - Epigenetic silencing of transgenes and endogenous genes can occur at the
      transcriptional level (TGS) or at the posttranscriptional level (PTGS). Because
      they can be induced by transgenes and viruses, TGS and PTGS probably reflect
      alternative (although not exclusive) responses to two important stress factors
      that the plant's genome has to face: the stable integration of additional DNA
      into chromosomes and the extrachromosomal replication of a viral genome. TGS,
      which results from the impairment of transcription initiation through methylation
      and/or chromatin condensation, could derive from the mechanisms by which
      transposed copies of mobile elements and T-DNA insertions are tamed. PTGS, which
      results from the degradation of mRNA when aberrant sense, antisense, or double
      stranded forms of RNA are produced, could derive from the process of recovery by
      which cells eliminate pathogens (RNA viruses) or their undesirable products (RNA
      encoded by DNA viruses). Mechanisms involving DNA-DNA, DNA-RNA, or RNA-RNA
      interactions are discussed to explain the various pathways for triggering
      (trans)gene silencing in plants.

PMID- 15012191
TI  - CEREAL CHROMOSOME STRUCTURE, EVOLUTION, AND PAIRING.
AB  - The determination of the order of genes along cereal chromosomes indicates that
      the cereals can be described as a single genetic system. Such a framework
      provides an opportunity to combine data generated from the studies on different
      cereals, enables chromosome evolution to be traced, and sheds light on key
      structures involved in cereal chromosome pairing. Centromeric and telomeric
      regions have been highlighted as important in these processes.

PMID- 15012192
TI  - AGROBACTERIUM AND PLANT GENES INVOLVED IN T-DNA TRANSFER AND INTEGRATION.
AB  - The phytopathogenic bacterium Agrobacterium tumefaciens genetically transforms
      plants by transferring a portion of the resident Ti-plasmid, the T-DNA, to the
      plant. Accompanying the T-DNA into the plant cell is a number of virulence (Vir)
      proteins. These proteins may aid in T-DNA transfer, nuclear targeting, and
      integration into the plant genome. Other virulence proteins on the bacterial
      surface form a pilus through which the T-DNA and the transferred proteins may
      translocate. Although the roles of these virulence proteins within the bacterium
      are relatively well understood, less is known about their roles in the plant
      cell. In addition, the role of plant-encoded proteins in the transformation
      process is virtually unknown. In this article, I review what is currently known
      about the functions of virulence and plant proteins in several aspects of the
      Agrobacterium transformation process.

PMID- 15012193
TI  - SIGNALING TO THE ACTIN CYTOSKELETON IN PLANTS.
AB  - Plants have developed finely tuned, cellular mechanisms to respond to a variety
      of intrinsic and extrinsic stimuli. In several examples, these responses
      necessitate rearrangements of the cytoplasm that are coordinated by a network of
      actin microfilaments and microtubules, dynamic polymers collectively known as the
      cytoskeleton. This review focuses on five different cellular responses in which
      the actin cytoskeleton redistributes following extracellular stimulation: pollen
      tube tip growth and the self-incompatibility response; root hair responses to
      bacterial nodulation factors; light-mediated plastid positioning; nonhost
      resistance to fungal attack; and guard cell shape and turgor changes. For each of
      these systems, there is reasonable knowledge about what signals induce the plant
      response and the function(s) of the actin rearrangement. This review aims to
      build beyond a description of cytoskeletal changes and look at specific actin
      binding proteins that have been implicated as effectors of each response, as
      sites of action for second messengers, and as fundamental coordinators of actin
      dynamics.

PMID- 15012194
TI  - CYTOSKELETAL PERSPECTIVES ON ROOT GROWTH AND MORPHOGENESIS.
AB  - Growth and development of all plant cells and organs relies on a fully functional
      cytoskeleton comprised principally of microtubules and microfilaments. These two
      polymeric macromolecules, because of their location within the cell, confer
      structure upon, and convey information to, the peripheral regions of the
      cytoplasm where much of cellular growth is controlled and the formation of
      cellular identity takes place. Other ancillary molecules, such as motor proteins,
      are also important in assisting the cytoskeleton to participate in this front
      line work of cellular development. Roots provide not only a ready source of cells
      for fundamental analyses of the cytoskeleton, but the formative zone at their
      apices also provides a locale whereby experimental studies can be made of how the
      cytoskeleton permits cells to communicate between themselves and to cooperate
      with growth-regulating information supplied from the apoplasm.

PMID- 15012195
TI  - THE GREAT ESCAPE: Phloem Transport and Unloading of Macromolecules1.
AB  - The phloem of higher plants translocates a diverse range of macromolecules
      including proteins, RNAs, and pathogens. This review considers the origin and
      destination of such macromolecules. A survey of the literature reveals that the
      majority of phloem-mobile macromolecules are synthesized within companion cells
      and enter the sieve elements through the branched plasmodesmata that connect
      these cells. Examples of systemic macromolecules that originate outside the
      companion cell are rare and are restricted to viral and subviral pathogens and
      putative RNA gene-silencing signals, all of which involve a relay system in which
      the macromolecule is amplified in each successive cell along the pathway to
      companion cells. Evidence is presented that xenobiotic macromolecules may enter
      the sieve element by a default pathway as they do not possess the necessary
      signals for retention in the sieve element-companion cell complex. Several sink
      tissues possess plasmodesmata with a high-molecular-size exclusion limit,
      potentially allowing the nonspecific escape of a wide range of small (<50-kDa)
      macromolecules from the phloem. Larger macromolecules and systemic mRNAs appear
      to require facilitated transport through sink plasmodesmata. The fate of phloem
      mobile macromolecules is considered in relation to current models of long
      distance signaling in plants.

PMID- 15012196
TI  - DEVELOPMENT OF SYMMETRY IN PLANTS.
AB  - Plant development involves specification and elaboration of axes of asymmetry.
      The apical-basal and inside-outside axes arise in embryogenesis, and are probably
      oriented maternally. They are maintained during growth post-germination and
      interact to establish novel axes of asymmetry in flowers and lateral organs (such
      as leaves). Whereas the genetic control of axis elaboration is now partially
      understood in embryos, floral meristems, and organs, the underlying mechanisms of
      axis specification remain largely obscure. Less functionally significant aspects
      of plant asymmetry (e.g. the handedness of spiral phyllotaxy) may originate in
      random events and therefore have no genetic control.

PMID- 15012197
TI  - PLANT THIOREDOXIN SYSTEMS REVISITED.
AB  - Thioredoxins, the ubiquitous small proteins with a redox active disulfide bridge,
      are important regulatory elements in plant metabolism. Initially recognized as
      regulatory proteins in the reversible light activation of key photosynthetic
      enzymes, they have subsequently been found in the cytoplasm and in mitochondria.
      The various plant thioredoxins are different in structure and function. Depending
      on their intracellular location they are reduced enzymatically by an NADP
      dependent or by a ferredoxin (light)-dependent reductase and transmit the
      regulatory signal to selected target enzymes through disulfide/dithiol
      interchange reactions. In this review we summarize recent developments that have
      provided new insights into the structures of several components and into the
      mechanism of action of the thioredoxin systems in plants.

PMID- 15012198
TI  - SELENIUM IN HIGHER PLANTS.
AB  - Plants vary considerably in their physiological response to selenium (Se). Some
      plant species growing on seleniferous soils are Se tolerant and accumulate very
      high concentrations of Se (Se accumulators), but most plants are Se
      nonaccumulators and are Se-sensitive. This review summarizes knowledge of the
      physiology and biochemistry of both types of plants, particularly with regard to
      Se uptake and transport, biochemical pathways of assimilation, volatilization and
      incorporation into proteins, and mechanisms of toxicity and tolerance. Molecular
      approaches are providing new insights into the role of sulfate transporters and
      sulfur assimilation enzymes in selenate uptake and metabolism, as well as the
      question of Se essentiality in plants. Recent advances in our understanding of
      the plant's ability to metabolize Se into volatile Se forms (phytovolatilization)
      are discussed, along with the application of phytoremediation for the cleanup of
      Se contaminated environments.

PMID- 15012199
TI  - PLANT CELLULAR AND MOLECULAR RESPONSES TO HIGH SALINITY.
AB  - Plant responses to salinity stress are reviewed with emphasis on molecular
      mechanisms of signal transduction and on the physiological consequences of
      altered gene expression that affect biochemical reactions downstream of stress
      sensing. We make extensive use of comparisons with model organisms, halophytic
      plants, and yeast, which provide a paradigm for many responses to salinity
      exhibited by stress-sensitive plants. Among biochemical responses, we emphasize
      osmolyte biosynthesis and function, water flux control, and membrane transport of
      ions for maintenance and re-establishment of homeostasis. The advances in
      understanding the effectiveness of stress responses, and distinctions between
      pathology and adaptive advantage, are increasingly based on transgenic plant and
      mutant analyses, in particular the analysis of Arabidopsis mutants defective in
      elements of stress signal transduction pathways. We summarize evidence for plant
      stress signaling systems, some of which have components analogous to those that
      regulate osmotic stress responses of yeast. There is evidence also of signaling
      cascades that are not known to exist in the unicellular eukaryote, some that
      presumably function in intercellular coordination or regulation of effector genes
      in a cell-/tissue-specific context required for tolerance of plants. A complex
      set of stress-responsive transcription factors is emerging. The imminent
      availability of genomic DNA sequences and global and cell-specific transcript
      expression data, combined with determinant identification based on gain- and loss
      of-function molecular genetics, will provide the infrastructure for functional
      physiological dissection of salt tolerance determinants in an organismal context.
      Furthermore, protein interaction analysis and evaluation of allelism, additivity,
      and epistasis allow determination of ordered relationships between stress
      signaling components. Finally, genetic activation and suppression screens will
      lead inevitably to an understanding of the interrelationships of the multiple
      signaling systems that control stress-adaptive responses in plants.

PMID- 15012200
TI  - GROWTH RETARDANTS: Effects on Gibberellin Biosynthesis and Other Metabolic
      Pathways.
AB  - Plant growth retardants are applied in agronomic and horticultural crops to
      reduce unwanted longitudinal shoot growth without lowering plant productivity.
      Most growth retardants act by inhibiting gibberellin (GA) biosynthesis. To date,
      four different types of such inhibitors are known: (a) Onium compounds, such as
      chlormequat chloride, mepiquat chloride, chlorphonium, and AMO-1618, which block
      the cyclases copalyl-diphosphate synthase and ent-kaurene synthase involved in
      the early steps of GA metabolism. (b) Compounds with an N-containing heterocycle,
      e.g. ancymidol, flurprimidol, tetcyclacis, paclobutrazol, uniconazole-P, and
      inabenfide. These retardants block cytochrome P450-dependent monooxygenases,
      thereby inhibiting oxidation of ent-kaurene into ent-kaurenoic acid. (c)
      Structural mimics of 2-oxoglutaric acid, which is the co-substrate of
      dioxygenases that catalyze late steps of GA formation. Acylcyclohexanediones,
      e.g. prohexadione-Ca and trinexapac-ethyl and daminozide, block particularly 3ss
      hydroxylation, thereby inhibiting the formation of highly active GAs from
      inactive precursors, and (d) 16,17-Dihydro-GA5 and related structures act most
      likely by mimicking the GA precursor substrate of the same dioxygenases. Enzymes,
      similar to the ones involved in GA biosynthesis, are also of importance in the
      formation of abscisic acid, ethylene, sterols, flavonoids, and other plant
      constituents. Changes in the levels of these compounds found after treatment with
      growth retardants can mostly be explained by side activities on such enzymes.

PMID- 15012201
TI  - EDUCATOR AND EDITOR.

PMID- 15012202
TI  - PHOSPHATE TRANSLOCATORS IN PLASTIDS.
AB  - During photosynthesis, energy from solar radiation is used to convert atmospheric
      carbon dioxide into intermediates that are used within and outside the
      chloroplast for a multitude of metabolic pathways. The daily fixed carbon is
      exported from the chloroplasts as triose phosphates and 3-phosphoglycerate. In
      contrast, nongreen plastids rely on the import of carbon, mainly hexose
      phosphates. Most organelles require the import of phosphoenolpyruvate as an
      immediate substrate for carbon to enter the shikimate pathway, leading to a
      variety of important secondary compounds. The envelope membrane of plastids
      contains specific translocators that are involved in these transport processes.
      Elucidation of the molecular structure of some of these translocators during the
      past few years has provided new insights in the functioning of particular
      translocators. This review focuses on the characterization of different classes
      of phosphate translocators in plastids that mediate the transport of the
      phosphorylated compounds in exchange with inorganic phosphate.

PMID- 15012203
TI  - THE 1-DEOXY-D-XYLULOSE-5-PHOSPHATE PATHWAY OF ISOPRENOID BIOSYNTHESIS IN PLANTS.
AB  - In plants the biosynthesis of prenyllipids and isoprenoids proceeds via two
      independent pathways: (a) the cytosolic classical acetate/mevalonate pathway for
      the biosynthesis of sterols, sesquiterpenes, triterpenoids; and (b) the
      alternative, non-mevalonate 1-deoxy-d-xylulose-5-phosphate (DOXP) pathway for the
      biosynthesis of plastidic isoprenoids, such as carotenoids, phytol (a side-chain
      of chlorophylls), plastoquinone-9, isoprene, mono-, and diterpenes. Both pathways
      form the active C5-unit isopentenyl diphosphate (IPP) as the precursor from which
      all other isoprenoids are formed via head-to-tail addition. This review
      summarizes current knowledge of the novel 1-deoxy-d-xylulose-5-phosphate (DOXP)
      pathway for isopentenyl diphosphate biosynthesis, apparently located in plastids.
      The DOXP pathway of IPP formation starts from D-glyceraldehyde-3-phosphate (GA-3
      P) and pyruvate, with DOXP-synthase as the starting enzyme. This pathway provides
      new insight into the regulation of chloroplast metabolism.

PMID- 15012204
TI  - CHLOROPHYLL DEGRADATION.
AB  - Although the loss of green color in senescent leaves and ripening fruits is a
      spectacular natural phenomenon, research on chlorophyll breakdown has been
      largely neglected until recently. This review summarizes knowledge about the fate
      of chlorophyll in degreening tissues that has been gained during the past few
      years. Structures of end- and intermediary products of degradation as well as the
      biochemistry of the porphyrin-cleaving reaction have been elucidated. The
      intracellular localization of the catabolic pathway is particularly important in
      the regulation of chlorophyll breakdown. None of the genes encoding the related
      catabolic enzymes has so far been isolated, which makes chlorophyll degradation
      an area of opportunity for future research.

PMID- 15012205
TI  - PLANT PROTEIN SERINE/THREONINE KINASES: Classification and Functions.
AB  - The first plant protein kinase sequences were reported as recently as 1989, but
      by mid-1998 there were more than 500, including 175 in Arabidopsis thaliana
      alone. Despite this impressive pace of discovery, progress in understanding the
      detailed functions of protein kinases in plants has been slower. Protein
      serine/threonine kinases from A. thaliana can be divided into around a dozen
      major groups based on their sequence relationships. For each of these groups,
      studies on animal and fungal homologs are briefly reviewed, and direct studies of
      their physiological functions in plants are then discussed in more detail. The
      network of protein-serine/threonine kinases in plant cells appears to act as a
      "central processor unit" (cpu), accepting input information from receptors that
      sense environmental conditions, phytohormones, and other external factors, and
      converting it into appropriate outputs such as changes in metabolism, gene
      expression, and cell growth and division.

PMID- 15012206
TI  - IMPROVING THE NUTRIENT COMPOSITION OF PLANTS TO ENHANCE HUMAN NUTRITION AND
      HEALTH1.
AB  - Plant foods contain almost all of the mineral and organic nutrients established
      as essential for human nutrition, as well as a number of unique organic
      phytochemicals that have been linked to the promotion of good health. Because the
      concentrations of many of these dietary constituents are often low in edible
      plant sources, research is under way to understand the physiological,
      biochemical, and molecular mechanisms that contribute to their transport,
      synthesis and accumulation in plants. This knowledge can be used to develop
      strategies with which to manipulate crop plants, and thereby improve their
      nutritional quality. Improvement strategies will differ between various
      nutrients, but generalizations can be made for mineral or organic nutrients. This
      review focuses on the plant nutritional physiology and biochemistry of two
      essential human nutrients, iron and vitamin E, to provide examples of the type of
      information that is needed, and the strategies that can be used, to improve the
      mineral or organic nutrient composition of plants.

PMID- 15012207
TI  - GAMETOPHYTE DEVELOPMENT IN FERNS.
AB  - The fern gametophyte has interested plant biologists for the past century because
      its structure and development is simple and amenable to investigation. Past
      studies have described many aspects of its development, including germination of
      the spore, patterns of cell division and differentiation, photomorphogenic or
      light-regulated responses, sex determination and differentiation of gametangia,
      hormone and pheromone responses, and fertilization. Several genes that are
      predicted to regulate some of these processes have been recently cloned, making
      it possible to analyze how these processes are controlled at a molecular level.
      The emergence of the fern Ceratopteris richardii as a model organism for readily
      identifying and characterizing mutations that affect key developmental processes
      in gametophytes makes it a powerful tool for dissecting the molecular mechanisms
      underlying these processes. If advances in gene cloning techniques and
      transformation are forthcoming in Ceratopteris, it is likely that the study of
      developmental processes in ferns will significantly contribute to our
      understanding of plant development and evolution beyond that which can be learned
      solely from studying angiosperms.

PMID- 15012208
TI  - C4 GENE EXPRESSION.
AB  - C4 plants, including maize, Flaveria, amaranth, sorghum, and an amphibious sedge
      Eleocharis vivipara, have been employed to elucidate the molecular mechanisms and
      signaling pathways that control C4 photosynthesis gene expression. Current
      evidence suggests that pre-existing genes were recruited for the C4 pathway after
      acquiring potent and surprisingly diverse regulatory elements. This review
      emphasizes recent advances in our understanding of the creation of C4 genes, the
      activities of the C4 gene promoters consisting of synergistic and combinatorial
      enhancers and silencers, the use of 5' and 3' untranslated regions for
      transcriptional and posttranscriptional regulations, and the function of novel
      transcription factors. The research has also revealed new insights into unique or
      universal mechanisms underlying cell-type specificity, coordinate nuclear
      chloroplast actions, hormonal, metabolic, stress and light responses, and the
      control of enzymatic activities by phosphorylation and reductive processes.

PMID- 15012209
TI  - GENETIC ANALYSIS OF HORMONE SIGNALING.
AB  - Phytohormones influence many diverse developmental processes ranging from seed
      germination to root, shoot, and flower formation. Recently, mutational analysis
      using the model plant Arabidopsis thaliana has been instrumental in determining
      the individual components of specific hormone signal transduction pathways.
      Moreover, epistasis and suppressor studies are beginning to explain how these
      genes and their products relate to one another. While no hormone transduction
      pathway is completely understood, the genes identified to date suggest that
      simple molecular rules can be established to explain how plant hormone signals
      are transduced. This review describes some of the shared characteristics of plant
      hormone signal transduction pathways and the properties for informational
      transfer common to many of the genes that specify the transduction of the signal.

PMID- 15012210
TI  - CELLULOSE BIOSYNTHESIS: Exciting Times for A Difficult Field of Study.
AB  - The past few decades have witnessed exciting progress in studies on the
      biosynthesis of cellulose. In the bacterium Acetobacter xylinum, discovery of the
      activator of the cellulose synthase, cyclic diguanylic acid, opened the way for
      obtaining high rates of in vitro synthesis of cellulose. This, in turn, led to
      purification of the cellulose synthase and for the cloning of genes that encode
      the catalytic subunit and other proteins that bind the activator and regulate its
      synthesis and degradation, or that control secretion and crystallization of the
      microfibrils. In higher plants, a family of genes has been discovered that show
      interesting similarities and differences from the gene in bacteria that encodes
      the catalytic subunit of the synthase. Genetic evidence now supports the concept
      that members of this family encode the catalytic subunit in these organisms, with
      various members showing tissue-specific expression. Although the cellulose
      synthase has not yet been purified to homogeneity from plants, recent progress in
      this area suggests that this will soon be accomplished.

PMID- 15012211
TI  - NITRATE REDUCTASE STRUCTURE, FUNCTION AND REGULATION: Bridging the Gap between
      Biochemistry and Physiology.
AB  - Nitrate reductase (NR; EC 1.6.6.1-3) catalyzes NAD(P)H reduction of nitrate to
      nitrite. NR serves plants, algae, and fungi as a central point for integration of
      metabolism by governing flux of reduced nitrogen by several regulatory
      mechanisms. The NR monomer is composed of a ~100-kD polypeptide and one each of
      FAD, heme-iron, and molybdenum-molybdopterin (Mo-MPT). NR has eight sequence
      segments: (a) N-terminal "acidic" region; (b) Mo-MPT domain with nitrate-reducing
      active site; (c) interface domain; (d) Hinge 1 containing serine phosphorylated
      in reversible activity regulation with inhibition by 14-3-3 binding protein; (e)
      cytochrome b domain; (f) Hinge 2; (g) FAD domain; and (h) NAD(P)H domain. The
      cytochrome b reductase fragment contains the active site where NAD(P)H transfers
      electrons to FAD. A complete three-dimensional dimeric NR structure model was
      built from structures of sulfite oxidase and cytochrome b reductase. Key active
      site residues have been investigated. NR structure, function, and regulation are
      now becoming understood.

PMID- 15012212
TI  - CRASSULACEAN ACID METABOLISM: Molecular Genetics.
AB  - Crassulacean acid metabolism (CAM) is an adaptation of photosynthesis to limited
      availability of water or CO2. CAM is characterized by nocturnal CO2 fixation via
      the cytosolic enzyme PEP carboxylase (PEPC), formation of PEP by glycolysis,
      malic acid accumulation in the vacuole, daytime decarboxylation of malate and CO2
      re-assimilation via ribulose-1,5-bisphosphate carboxylase (RUBISCO), and
      regeneration of storage carbohydrates from pyruvate and/or PEP by
      gluconeogenesis. Within this basic framework, the pathway exhibits an
      extraordinary range of metabolic plasticity governed by environmental,
      developmental, tissue-specific, hormonal, and circadian cues. Characterization of
      genes encoding key CAM enzymes has shown that a combination of transcriptional,
      posttranscriptional, translational, and posttranslational regulatory events
      govern the expression of the pathway. Recently, this information has improved our
      ability to dissect the regulatory and signaling events that mediate the
      expression and operation of the pathway. Molecular analysis and sequence
      information have also provided new ways of assessing the evolutionary origins of
      CAM. Genetic and physiological analysis of transgenic plants currently under
      development will improve our further understanding of the molecular genetics of
      CAM.

PMID- 15012213
TI  - PHOTOPROTECTION REVISITED: Genetic and Molecular Approaches.
AB  - The involvement of excited and highly reactive intermediates in oxygenic
      photosynthesis poses unique problems for algae and plants in terms of potential
      oxidative damage to the photosynthetic apparatus. Photoprotective processes
      prevent or minimize generation of oxidizing molecules, scavenge reactive oxygen
      species efficiently, and repair damage that inevitably occurs. This review
      summarizes several photoprotective mechanisms operating within chloroplasts of
      plants and green algae. The recent use of genetic and molecular biological
      approaches is providing new insights into photoprotection, especially with
      respect to thermal dissipation of excess absorbed light energy, alternative
      electron transport pathways, chloroplast antioxidant systems, and repair of
      photosystem II.

PMID- 15012214
TI  - MOLECULAR AND CELLULAR ASPECTS OF THE ARBUSCULAR MYCORRHIZAL SYMBIOSIS.
AB  - Arbuscular mycorrhizae are symbiotic associations formed between a wide range of
      plant species including angiosperms, gymnosperms, pteridophytes, and some
      bryophytes, and a limited range of fungi belonging to a single order, the
      Glomales. The symbiosis develops in the plant roots where the fungus colonizes
      the apoplast and cells of the cortex to access carbon supplied by the plant. The
      fungal contribution to the symbiosis is complex, but a major aspect includes the
      transfer of mineral nutrients, particularly phosphate from the soil to the plant.
      Development of this highly compatible association requires the coordinate
      molecular and cellular differentiation of both symbionts to form specialized
      interfaces over which bi-directional nutrient transfer occurs. Recent insights
      into the molecular events underlying these aspects of the symbiosis are
      discussed.

PMID- 15012215
TI  - LEAF DEVELOPMENT IN ANGIOSPERMS.
AB  - Leaves are produced in succession on the shoot apical meristem (SAM) of a plant.
      The three landmark stages in leaf morphogenesis include initiation, acquisition
      of suborgan identities, and tissue differentiation. The expression of various
      genes relative to these steps in leaf morphogenesis is described. KNOTTED-like
      homeobox (KNOX) genes, FLO/LFY, and floral homeotic genes may be involved in
      generation of leaf shape and complexity. The differences between compound leaves
      and simple leaves in gene expression characteristics and morphogenetic patterns
      are discussed.

PMID- 15012216
TI  - THE PRESSURE PROBE: A Versatile Tool in Plant Cell Physiology.
AB  - This review discusses how the pressure probe has evolved from an instrument for
      measuring cell turgor and other water relations parameters into a device for
      sampling the contents of individual higher plant cells in situ in the living
      plant. Together with a suite of microanalytical techniques it has permitted the
      mapping of water and solute relations at the resolution of single cells and has
      the potential to link quantitatively the traditionally separate areas of water
      relations and metabolism. The development of the probe is outlined and its
      modification to measure root pressure and xylem tension described. The deployment
      of the pressure probe to determine and map turgor, hydraulic conductivity,
      reflection coefficient, cell rheological properties, solute concentrations and
      enzyme activities at the resolution of single cells is discussed. The controversy
      surrounding the interpretation of results obtained with the xylem-pressure probe
      is included. Possible further developments of the probe and applications of
      single cell sampling are suggested.

PMID- 15012217
TI  - THE SHIKIMATE PATHWAY.
AB  - The shikimate pathway links metabolism of carbohydrates to biosynthesis of
      aromatic compounds. In a sequence of seven metabolic steps, phosphoenolpyruvate
      and erythrose 4-phosphate are converted to chorismate, the precursor of the
      aromatic amino acids and many aromatic secondary metabolites. All pathway
      intermediates can also be considered branch point compounds that may serve as
      substrates for other metabolic pathways. The shikimate pathway is found only in
      microorganisms and plants, never in animals. All enzymes of this pathway have
      been obtained in pure form from prokaryotic and eukaryotic sources and their
      respective DNAs have been characterized from several organisms. The cDNAs of
      higher plants encode proteins with amino terminal signal sequences for plastid
      import, suggesting that plastids are the exclusive locale for chorismate
      biosynthesis. In microorganisms, the shikimate pathway is regulated by feedback
      inhibition and by repression of the first enzyme. In higher plants, no
      physiological feedback inhibitor has been identified, suggesting that pathway
      regulation may occur exclusively at the genetic level. This difference between
      microorganisms and plants is reflected in the unusually large variation in the
      primary structures of the respective first enzymes. Several of the pathway
      enzymes occur in isoenzymic forms whose expression varies with changing
      environmental conditions and, within the plant, from organ to organ. The
      penultimate enzyme of the pathway is the sole target for the herbicide
      glyphosate. Glyphosate-tolerant transgenic plants are at the core of novel weed
      control systems for several crop plants.

PMID- 15012218
TI  - ASYMMETRIC CELL DIVISION IN PLANTS.
AB  - Asymmetric cell divisions generate cells with different fates. In plants, where
      cells do not move relative to another cell, the specification and orientation of
      these divisions is an important mechanism to generate the overall cellular
      pattern during development. This review summarizes our knowledge of selected
      cases of asymmetric cell division in plants, in the context of recent insights
      into mechanisms underlying this process in bacteria, algae, yeast, and animals.

PMID- 15012219
TI  - CO2 CONCENTRATING MECHANISMS IN PHOTOSYNTHETIC MICROORGANISMS.
AB  - Many microorganisms possess inducible mechanisms that concentrate CO2 at the
      carboxylation site, compensating for the relatively low affinity of Rubisco for
      its substrate, and allowing acclimation to a wide range of CO2 concentrations.
      The organization of the carboxysomes in prokaryotes and of the pyrenoids in
      eukaryotes, and the presence of membrane mechanisms for inorganic carbon (Ci)
      transport, are central to the concentrating mechanism. The presence of multiple
      Ci transporting systems in cyanobacteria has been indicated. Certain genes
      involved in structural organization, Ci transport and the energization of the
      latter have been identified. Massive Ci fluxes associated with the CO2
      concentrating mechanism have wide-reaching ecological and geochemical
      implications.

PMID- 15012220
TI  - PLANT COLD ACCLIMATION: Freezing Tolerance Genes and Regulatory Mechanisms.
AB  - Many plants increase in freezing tolerance upon exposure to low nonfreezing
      temperatures, a phenomenon known as cold acclimation. In this review, recent
      advances in determining the nature and function of genes with roles in freezing
      tolerance and the mechanisms involved in low temperature gene regulation and
      signal transduction are described. One of the important conclusions to emerge
      from these studies is that cold acclimation includes the expression of certain
      cold-induced genes that function to stabilize membranes against freeze-induced
      injury. In addition, a family of Arabidopsis transcription factors, the CBF/DREB1
      proteins, have been identified that control the expression of a regulon of cold
      induced genes that increase plant freezing tolerance. These results along with
      many of the others summarized here further our understanding of the basic
      mechanisms that plants have evolved to survive freezing temperatures. In
      addition, the findings have potential practical applications as freezing
      temperatures are a major factor limiting the geographical locations suitable for
      growing crop and horticultural plants and periodically account for significant
      losses in plant productivity.

PMID- 15012221
TI  - THE WATER-WATER CYCLE IN CHLOROPLASTS: Scavenging of Active Oxygens and
      Dissipation of Excess Photons.
AB  - Photoreduction of dioxygen in photosystem I (PSI) of chloroplasts generates
      superoxide radicals as the primary product. In intact chloroplasts, the
      superoxide and the hydrogen peroxide produced via the disproportionation of
      superoxide are so rapidly scavenged at the site of their generation that the
      active oxygens do not inactivate the PSI complex, the stromal enzymes, or the
      scavenging system itself. The overall reaction for scavenging of active oxygens
      is the photoreduction of dioxygen to water via superoxide and hydrogen peroxide
      in PSI by the electrons derived from water in PSII, and the water-water cycle is
      proposed for these sequences. An overview is given of the molecular mechanism of
      the water-water cycle and microcompartmentalization of the enzymes participating
      in it. Whenever the water-water cycle operates properly for scavenging of active
      oxygens in chloroplasts, it also effectively dissipates excess excitation energy
      under environmental stress. The dual functions of the water-water cycle for
      protection from photoinihibition are discussed.

PMID- 15012222
TI  - SILICON.
AB  - Silicon is present in plants in amounts equivalent to those of such macronutrient
      elements as calcium, magnesium, and phosphorus, and in grasses often at higher
      levels than any other inorganic constituent. Yet except for certain algae,
      including prominently the diatoms, and the Equisetaceae (horsetails or scouring
      rushes), it is not considered an essential element for plants. As a result it is
      routinely omitted from formulations of culture solutions and considered a
      nonentity in much of plant physiological research. But silicon-deprived plants
      grown in conventional nutrient solutions to which silicon has not been added are
      in many ways experimental artifacts. They are often structurally weaker than
      silicon-replete plants, abnormal in growth, development, viability, and
      reproduction, more susceptible to such abiotic stresses as metal toxicities, and
      easier prey to disease organisms and to herbivores ranging from phytophagous
      insects to mammals. Many of these same conditions afflict plants in silicon-poor
      soils-and there are such. Taken together, the evidence is overwhelming that
      silicon should be included among the elements having a major bearing on plant
      life.

PMID- 15012223
TI  - PHOSPHATE ACQUISITION.
AB  - Phosphorus is one of the major plant nutrients that is least available in the
      soil. Consequently, plants have developed numerous morphological, physiological,
      biochemical, and molecular adaptations to acquire phosphate (Pi). Enhanced
      ability to acquire Pi and altered gene expression are the hallmarks of plant
      adaptation to Pi deficiency. The intricate mechanisms involved in maintaining Pi
      homeostasis reflect the complexity of Pi acquisition and translocation in plants.
      Recent discoveries of multiple Pi transporters have opened up opportunities to
      study the molecular basis of Pi acquisition by plants. An increasing number of
      genes are now known to be activated under Pi starvation. Some of these genes may
      be involved in Pi acquisition, transfer, and signal transduction during Pi
      stress. This review provides an overview of plant adaptations leading to enhanced
      Pi acquisition, with special emphasis on recent developments in the molecular
      biology of Pi acquisition.

PMID- 15012224
TI  - ROOTS IN SOIL: Unearthing the Complexities of Roots and Their Rhizospheres.
AB  - The root system of a plant is as complicated as the shoot in its diversity, in
      its reactions with the matrix of substances, and with the myriad organisms that
      surround it. Laboratory studies blind us to the complexity found by careful study
      of roots in soil. This complexity is illustrated in the much-studied corn root
      system, covering the changes along the framework roots: the surface tissues and
      their interactions with the soil, the water-conducting xylem, whose gradual
      elaboration dictates the water status of the root. A conspicuous manifestation of
      the changes is the rhizosheath, whose microflora differs from that on the mature
      bare zones. The multitude of fine roots is the most active part of the system in
      acquiring water and nutrients, with its own multitude of root tips, sites of
      intense chemical activity, that strongly modify the soil they contact, mobilize
      reluctant ions, immobilize toxic ions, coat the soil particles with mucilage, and
      select the microflora.

PMID- 15012225
TI  - GENETIC ANALYSIS OF OVULE DEVELOPMENT.
AB  - Ovules are the direct precursors of seeds and thus play central roles in sexual
      plant reproduction and human nutrition. Extensive classical studies have
      elucidated the evolutionary trends and developmental processes responsible for
      the current wide variety of ovule morphologies. Recently, ovules have been
      perceived as an attractive system for the study of genetic regulation of plant
      development. More than a dozen regulatory genes have now been identified through
      isolation of ovule mutants. Characterization of these mutants shows that some
      aspects of ovule development follow independent pathways, while other processes
      are interdependent. Some of these mutants have ovules resembling those of
      putative ancestors of angiosperms and may help in understanding plant evolution.
      Clones of several of the regulatory genes have been used to determine expression
      patterns and putative biochemical functions of the gene products. Newly
      constructed models of genetic regulation of ovule development provide a framework
      for interpretation of future discoveries.

PMID- 15012226
TI  - POSTTRANSLATIONAL ASSEMBLY OF PHOTOSYNTHETIC METALLOPROTEINS.
AB  - The assembly of chloroplast metalloproteins requires biochemical catalysis.
      Assembly factors involved in the biosynthesis of metalloproteins might be
      required to synthesize, chaperone, or transport the cofactor; modify or chaperone
      the apoprotein; or catalyze cofactor-protein association. Genetic and biochemical
      approaches have been applied to the study of the assembly of chloroplast iron
      sulfur centers, cytochromes, plastocyanin, and the manganese center of
      photosystem II. These have led to the discovery of NifS-homologues and cysteine
      desulfhydrase for iron-sulfur center assembly, six loci (CCS1-CCS5, ccsA) for c
      type cytochrome assembly, four loci for cytochrome b6 assembly (CCB1-CCB4), the
      CtpA protease, which is involved in pre-D1 processing, and the PCY2 locus, which
      is involved in holoplastocyanin accumulation. New assembly factors are likely to
      be discovered via the study of assembly-defective mutants of Arabidopsis,
      cyanobacteria, Chlamydomonas, maize, and via the functional analysis of candidate
      cofactor metabolizing components identified in the genome databases.

PMID- 15012227
TI  - BIOSYNTHESIS AND FUNCTION OF THE SULFOLIPID SULFOQUINOVOSYL DIACYLGLYCEROL.
AB  - The sulfolipid sulfoquinovosyl diacylglycerol is an abundant sulfur-containing
      nonphosphorous glycerolipid that is specifically associated with photosynthetic
      membranes of higher plants, mosses, ferns, algae, and most photosynthetic
      bacteria. The characteristic structural feature of sulfoquinovosyl diacylglycerol
      is the unique head group constituent sulfoquinovose, a derivative of glucose in
      which the 6-hydroxyl is replaced by a sulfonate group. While there is growing
      evidence for the final assembly of the sulfolipid by the transfer of the
      sulfoquinovosyl moiety from UDP-sulfoquinovose to the sn-3 position of
      diacylglycerol, very little is known about the biosynthesis of the precursor UDP
      sulfoquinovose. Recently, a number of mutants deficient in sulfolipid
      biosynthesis and the corresponding sqd genes have become available from different
      organisms. These provide novel tools to analyze sulfolipid biosynthesis by a
      combination of molecular and biochemical approaches. Furthermore, the analysis of
      sulfolipid-deficient mutants has provided novel insights into the function of
      sulfoquinovosyl diacylglycerol in photosynthetic membranes.

PMID- 15012228
TI  - SPLICE SITE SELECTION IN PLANT PRE-mRNA SPLICING.
AB  - The purpose of this review is to highlight the unique and common features of
      splice site selection in plants compared with the better understood yeast and
      vertebrate systems. A key question in plant splicing is the role of AU sequences
      and how and at what stage they are involved in spliceosome assembly. Clearly,
      intronic U- or AU-rich and exonic GC- and AG-rich elements can influence splice
      site selection and splicing efficiency and are likely to bind proteins. It is
      becoming clear that splicing of a particular intron depends on a fine balance in
      the "strength" of the multiple intron signals involved in splice site selection.
      Individual introns contain varying strengths of signals and what is critical to
      splicing of one intron may be of less importance to the splicing of another.
      Thus, small changes to signals may severely disrupt splicing or have little or no
      effect depending on the overall sequence context of a specific intron/exon
      organization.

PMID- 15012229
TI  - PROTEIN TARGETING TO THE THYLAKOID MEMBRANE.
AB  - The assembly of the photosynthetic apparatus at the thylakoid begins with the
      targeting of proteins from their site of synthesis in the cytoplasm or stroma to
      the thylakoid membrane. Plastid-encoded proteins are targeted directly to the
      thylakoid during or after synthesis on plastid ribosomes. Nuclear-encoded
      proteins undergo a two-step targeting process requiring posttranslational import
      into the organelle from the cytoplasm and subsequent targeting to the thylakoid
      membrane. Recent investigations have revealed a single general import machinery
      at the envelope that mediates the direct transport of preproteins from the
      cytoplasm to the stroma. In contrast, at least four distinct pathways exist for
      the targeting of proteins to the thylakoid membrane. At least two of these
      systems are homologous to translocation systems that operate in bacteria and at
      the endoplasmic reticulum, indicating that elements of the targeting mechanisms
      have been conserved from the original prokaryotic endosymbiont.

PMID- 15012230
TI  - PLANT TRANSCRIPTION FACTOR STUDIES.
AB  - Major advances have been made in understanding the role of transcription factors
      in gene expression in yeast, Drosophila, and man. Transcription factor
      modification, synergistic events, protein-protein interactions, and chromatin
      structure have been successfully integrated into transcription factor studies in
      these organisms. While many putative transcription factors have been isolated
      from plants, most of them are only poorly characterized. This review summarizes
      examples where molecular biological techniques have been successfully employed to
      study plant transcription factors. The functional analysis of transcription
      factors is described as well as techniques for studying the interactions of
      transcription factors with other proteins and with DNA.

PMID- 15012231
TI  - LESSONS FROM SEQUENCING OF THE GENOME OF A UNICELLULAR CYANOBACTERIUM,
      SYNECHOCYSTIS SP. PCC6803.
AB  - The nucleotide sequence of the entire genome of the unicellular cyanobacterium,
      Synechocystis sp. PCC6803, has been determined. The length of the circular genome
      was 3,573,480 bp, and a total of 3168 protein-coding genes were assigned to the
      genome by a computer-assisted analysis. The functions of approximately 45% of the
      genes were deduced based on sequence similarity to known genes. Here are
      distinctive features of genetic information carried by the cyanobacteria, which
      have a phylogenetic relationship to both bacteria and plants.

PMID- 15012232
TI  - ELABORATION OF BODY PLAN AND PHASE CHANGE DURING DEVELOPMENT OF ACETABULARIA: How
      Is the Complex Architecture of a Giant Unicell Built?
AB  - While uninucleate and unicellular, Acetabularia acetabulum establishes and
      maintains functionally and morphologically distinct body regions and executes
      phase changes like those in vascular plants. Centimeters tall at maturity, this
      species has allowed unusual experimental approaches. Amputations revealed fates
      of nucleate and enucleate portions from both wild type and mutants. Historically,
      graft chimeras between nucleate and enucleate portions suggested that
      morphological instructions were supplied by the nucleus but resided in the
      cytoplasm and could be expressed interspecifically. Recently, graft chimeras
      enabled rescue of mutants arrested in vegetative phase. Since the 1930s, when
      Acetabularia provided the first evidence for the existence of mRNAs, a dogma has
      arisen that it uses long-lived mRNAs to effect morphogenesis. While the evidence
      favors translational control, the postulated mRNAs have not been identified, and
      the mechanism of morphogenesis remains unknown. Amenable to biochemistry,
      physiology, and both classical and molecular genetics, Acetabularia may
      contribute yet new insights into plant development and morphogenesis.

PMID- 15012233
TI  - ABSCISIC ACID SIGNAL TRANSDUCTION.
AB  - The plant hormone abscisic acid (ABA) plays a major role in seed maturation and
      germination, as well as in adaptation to abiotic environmental stresses. ABA
      promotes stomatal closure by rapidly altering ion fluxes in guard cells. Other
      ABA actions involve modifications of gene expression, and the analysis of ABA
      responsive promoters has revealed a diversity of potential cis-acting regulatory
      elements. The nature of the ABA receptor(s) remains unknown. In contrast,
      combined biophysical, genetic, and molecular approaches have led to considerable
      progress in the characterization of more downstream signaling elements. In
      particular, substantial evidence points to the importance of reversible protein
      phosphorylation and modifications of cytosolic calcium levels and pH as
      intermediates in ABA signal transduction. Exciting advances are being made in
      reassembling individual components into minimal ABA signaling cascades at the
      single-cell level.

PMID- 15012234
TI  - DNA METHYLATION IN PLANTS.
AB  - Methylation of cytosine residues in DNA provides a mechanism of gene control.
      There are two classes of methyltransferase in Arabidopsis; one has a carboxy
      terminal methyltransferase domain fused to an amino-terminal regulatory domain
      and is similar to mammalian methyltransferases. The second class apparently lacks
      an amino-terminal domain and is less well conserved. Methylcytosine can occur at
      any cytosine residue, but it is likely that clonal transmission of methylation
      patterns only occurs for cytosines in strand-symmetrical sequences CpG and CpNpG.
      In plants, as in mammals, DNA methylation has dual roles in defense against
      invading DNA and transposable elements and in gene regulation. Although
      originally reported as having no phenotypic consequence, reduced DNA methylation
      disrupts normal plant development.

PMID- 15012235
TI  - ASCORBATE AND GLUTATHIONE: Keeping Active Oxygen Under Control.
AB  - To cope with environmental fluctuations and to prevent invasion by pathogens,
      plant metabolism must be flexible and dynamic. Active oxygen species, whose
      formation is accelerated under stress conditions, must be rapidly processed if
      oxidative damage is to be averted. The lifetime of active oxygen species within
      the cellular environment is determined by the antioxidative system, which
      provides crucial protection against oxidative damage. The antioxidative system
      comprises numerous enzymes and compounds of low molecular weight. While research
      into the former has benefited greatly from advances in molecular technology, the
      pathways by which the latter are synthesized have received comparatively little
      attention. The present review emphasizes the roles of ascorbate and glutathione
      in plant metabolism and stress tolerance. We provide a detailed account of
      current knowledge of the biosynthesis, compartmentation, and transport of these
      two important antioxidants, with emphasis on the unique insights and advances
      gained by molecular exploration.

PMID- 15012236
TI  - PLANT CELL WALL PROTEINS.
AB  - The nature of cell wall proteins is as varied as the many functions of plant cell
      walls. With the exception of glycine-rich proteins, all are glycosylated and
      contain hydroxyproline (Hyp). Again excepting glycine-rich proteins, they also
      contain highly repetitive sequences that can be shared between them. The majority
      of cell wall proteins are cross-linked into the wall and probably have structural
      functions, although they may also participate in morphogenesis. On the other
      hand, arabinogalactan proteins are readily soluble and possibly play a major role
      in cell-cell interactions during development. The interactions of these proteins
      between themselves and with other wall components is still unknown, as is how
      wall components are assembled. The possible functions of cell wall proteins are
      suggested based on repetitive sequence, localization in the plant body, and the
      general morphogenetic pattern in plants.

PMID- 15012237
TI  - MOLECULAR-GENETIC ANALYSIS OF PLANT CYTOCHROME P450-DEPENDENT MONOOXYGENASES.
AB  - Cytochrome P450-dependent monooxygenases are a large group of heme-containing
      enzymes, most of which catalyze NADPH- and O2-dependent hydroxylation reactions.
      The cloning of plant P450s has been hampered because these membrane-localized
      proteins are typically present in low abundance and are often unstable to
      purification. Since the cloning of the first plant P450 gene in 1990, there has
      been an explosion in the rate at which genes encoding plant P450s have been
      identified. These successes have largely been the result of advances in
      purification techniques, as well as the application of alternative methods such
      as mutant- and PCR-based cloning strategies. The availability of these cloned
      genes has made possible the analysis of P450 gene regulation and may soon reveal
      aspects of the evolution of P450s in plants. This new knowledge will
      significantly improve our understanding of many metabolic pathways and may permit
      their manipulation in the near future.

PMID- 15012238
TI  - GENETIC CONTROL OF FLOWERING TIME IN ARABIDOPSIS.
AB  - The timing of the transition from vegetative to reproductive development is of
      great fundamental and applied interest but is still poorly understood. Recently,
      molecular-genetic approaches have been used to dissect this process in
      Arabidopsis. The genetic variation present among a large number of mutants with
      an early- or late-flowering phenotype, affecting the control of both
      environmental and endogenous factors that influence the transition to flowering,
      is described. The genetic, molecular, and physiological analyses have led to
      identification of different components involved, such as elements of
      photoperception and the circadian rhythm. Furthermore, elements involved in the
      signal transduction pathways to flowering have been identified by the cloning of
      some floral induction genes and their target genes.

PMID- 15012239
TI  - MEIOTIC CHROMOSOME ORGANIZATION AND SEGREGATION IN PLANTS.
AB  - During meiosis, homologous chromosomes are brought together to be recombined and
      segregated into separate haploid gametes. This requires two cell divisions, an
      elaborate prophase with five substages, and specialized mechanisms that regulate
      the association of sister chromatids. This review focuses on plant chromosomes
      and chromosome-associated structures, such as recombination nodules and
      kinetochores, that ensure accurate meiotic chromosome segregation.

PMID- 15012240
TI  - PHOTOSYNTHETIC CYTOCHROMES c IN CYANOBACTERIA, ALGAE, AND PLANTS.
AB  - The cytochromes that function in photosynthesis in cyanobacteria, algae, and
      higher plants have, like the other photosynthetic catalysts, been largely
      conserved in their structure and function during evolution. Cyanobacteria and
      algae contain cytochrome c6, which is not found in higher plants and which may
      enhance survival in their planktonic mode of life. Cyanobacteria and algae
      contain another cytochrome, low-potential c549, which is not found in higher
      plants. This cytochrome has a structural role in PSII and may contribute to
      anaerobic survival. There is a third unique cytochrome, cytochrome M, in the
      planktonic photosynthesizers, and its function is unknown. New evidence is
      appearing to indicate evolution of cytochrome interaction mechanisms during the
      evolution of photosynthesis. The ease of cytochrome gene manipulation in
      cyanobacteria and in Chlamydomonas reinhardtii now provides great advantages in
      understanding of photosynthesis. The solution of tertiary and quaternary
      structures of cytochromes and cytochrome complexes will provide structural and
      functional detail at atomic resolution.

PMID- 15012241
TI  - BRASSINOSTEROIDS: Essential Regulators of Plant Growth and Development.
AB  - Brassinosteroids (BRs) are growth-promoting natural products found at low levels
      in pollen, seeds, and young vegetative tissues throughout the plant kingdom.
      Detailed studies of BR biosynthesis and metabolism, coupled with the recent
      identification of BR-insensitive and BR-deficient mutants, has greatly expanded
      our view of steroids as signals controlling plant growth and development. This
      review examines the microchemical and molecular genetic analyses that have
      provided convincing evidence for an essential role of BRs in diverse
      developmental programs, including cell expansion, vascular differentiation,
      etiolation, and reproductive development. Recent advances relevant to the
      molecular mechanisms of BR-regulated gene expression and BR signal transduction
      are also discussed.

PMID- 15012242
TI  - NUCLEAR CONTROL OF PLASTID AND MITOCHONDRIAL DEVELOPMENT IN HIGHER PLANTS.
AB  - The nucleus must coordinate organelle biogenesis and function on a cell and
      tissue-specific basis throughout plant development. The vast majority of plastid
      and mitochondrial proteins and components involved in organelle biogenesis are
      encoded by nuclear genes. Molecular characterization of nuclear mutants has
      illuminated chloroplast development and function. Fewer mutants exist that affect
      mitochondria, but molecular and biochemical approaches have contributed to a
      greater understanding of this organelle. Similarities between organelles and
      prokaryotic regulatory molecules have been found, supporting the prokaryotic
      origin of chloroplasts and mitochondria. A striking characteristic for both
      mitochondria and chloroplast is that most regulation is posttranscriptional.

PMID- 15012243
TI  - BORON IN PLANT STRUCTURE AND FUNCTION.
AB  - New and exciting developments in boron research in the past few years greatly
      contributed to better understanding of the role of boron in plants. Purification
      and identification of the first boron-polyol transport molecules resolved much of
      the controversy about boron phloem mobility. Isolation and characterization of
      the boron-polysaccharide complex from cell walls provided the first direct
      evidence for boron crosslinking of pectin polymers. Inhibition and recovery of
      proton release upon boron withdrawal and restitution in plant culture medium
      demonstrated boron involvement in membrane processes. Rapid boron-induced changes
      in membrane function could be attributed to boron-complexing membrane
      constituents. Boron may affect metabolic pathways by binding apoplastic proteins
      to cis-hydroxyl groups of cell walls and membranes, and by interfering with
      manganese-dependent enzymatic reactions. In addition, boron has been implicated
      in counteracting toxic effects of aluminum on root growth of dicotyledonous
      plants. Molecular investigations of boron nutrition have been initiated by the
      discovery of a novel mutant of Arabidopsis thaliana with an altered requirement
      for boron.

PMID- 15012244
TI  - HORMONE-INDUCED SIGNALING DURING MOSS DEVELOPMENT.
AB  - Understanding how a cell responds to hormonal signals with a new program of
      cellular differentiation and organization is an important focus of research in
      developmental biology. In Funaria hygrometrica and Physcomitrella patens, two
      related species of moss, cytokinin induces the development of a bud during the
      transition from filamentous to meristematic growth. Within hours of cytokinin
      perception, a single-celled initial responds with changes in patterns of cell
      expansion, elongation, and division to begin the process of bud assembly. Bud
      assembly in moss provides an excellent model for the study of hormone-induced
      organogenesis because it is a relatively simple, well-defined process. Since buds
      form in a nonrandom pattern on cells that are not embedded in other tissues, it
      is possible to predict which cells will respond and where the ensuing changes
      will take place. In addition, bud assembly is amenable to biochemical, cellular,
      and molecular biological analyses. This review examines our current understanding
      of cytokinin-induced bud assembly and the potential underlying mechanisms,
      reviews the state of genetic analyses in moss, and sets goals for future research
      with this organism.

PMID- 15012245
TI  - EVOLUTION OF LIGHT-REGULATED PLANT PROMOTERS.
AB  - In this review, we address the phylogenetic and structural relationships between
      light-responsive promoter regions from a range of plant genes, that could explain
      both their common dependence on specific photoreceptor-associated transduction
      pathways and their functional versatility. The well-known multipartite light
      responsive elements (LREs) of flowering plants share sequences very similar to
      motifs in the promoters of orthologous genes from conifers, ferns, and mosses,
      whose genes are expressed in absence of light. Therefore, composite LREs have
      apparently evolved from cis-regulatory units involved in other promoter
      functions, a notion with significant implications to our understanding of the
      structural and functional organization of angiosperm LREs.

PMID- 15012246
TI  - GENES AND ENZYMES OF CAROTENOID BIOSYNTHESIS IN PLANTS.
AB  - Carotenoids are integral and essential components of the photosynthetic membranes
      in all plants. Within the past few years, genes encoding nearly all of the
      enzymes required for the biosynthesis of these indispensable pigments have been
      identified. This review focuses on recent findings as to the structure and
      function of these genes and the enzymes they encode. Three topics of current
      interest are also discussed: the source of isopentenyl pyrophosphate for
      carotenoid biosynthesis, the progress and possibilities of metabolic engineering
      of plants to alter carotenoid content and composition, and the compartmentation
      and association of the carotenogenic enzymes. A speculative schematic model of
      carotenogenic enzyme complexes is presented to help frame and provoke insightful
      questions leading to future experimentation.

PMID- 15012247
TI  - RECENT ADVANCES IN UNDERSTANDING LIGNIN BIOSYNTHESIS.
AB  - After a long period of little change, the basic concepts of lignin biosynthesis
      have been challenged by new results from genetic modification of lignin content
      and composition. New techniques for making directed genetic changes in plants, as
      well as improvements in the analytical techniques used to determine lignin
      content and composition in plant cell walls, have been used in experimental tests
      of the accepted lignin biosynthetic pathway. The lignins obtained from
      genetically modified plants have shown unexpected properties, and these findings
      have extended the known range of variation in lignin content and composition.
      These results argue that the accepted lignin biosynthetic pathway is either
      incomplete or incorrect, or both; and also suggest that plants may have a high
      level of metabolic plasticity in the formation of lignins. If this is so, the
      properties of novel lignins could be of significant scientific and practical
      interest.

PMID- 15012248
TI  - DESATURATION AND RELATED MODIFICATIONS OF FATTY ACIDS1.
AB  - Desaturation of a fatty acid first involves the enzymatic removal of a hydrogen
      from a methylene group in an acyl chain, a highly energy-demanding step that
      requires an activated oxygen intermediate. Two types of desaturases have been
      identified, one soluble and the other membrane-bound, that have different
      consensus motifs. Database searching for these motifs reveals that these enzymes
      belong to two distinct multifunctional classes, each of which includes
      desaturases, hydroxylases, and epoxidases that act on fatty acids or other
      substrates. The soluble class has a consensus motif consisting of carboxylates
      and histidines that coordinate an active site diiron cluster. The integral
      membrane class contains a different consensus motif composed of histidines.
      Biochemical and structural similarities between the integral membrane enzymes
      suggest that this class also uses a diiron cluster for catalysis. Soluble and
      membrane enzymes have been successfully re-engineered for substrate specificity
      and reaction outcome. It is anticipated that rational design of these enzymes
      will result in new and desired activities that may form the basis for improved
      oil crops.

PMID- 15012249
TI  - PHYTOREMEDIATION.
AB  - Contaminated soils and waters pose a major environmental and human health
      problem, which may be partially solved by the emerging phytoremediation
      technology. This cost-effective plant-based approach to remediation takes
      advantage of the remarkable ability of plants to concentrate elements and
      compounds from the environment and to metabolize various molecules in their
      tissues. Toxic heavy metals and organic pollutants are the major targets for
      phytoremediation. In recent years, knowledge of the physiological and molecular
      mechanisms of phytoremediation began to emerge together with biological and
      engineering strategies designed to optimize and improve phytoremediation. In
      addition, several field trials confirmed the feasibility of using plants for
      environmental cleanup. This review concentrates on the most developed subsets of
      phytoremediation technology and on the biological mechanisms that make
      phytoremediation work.

PMID- 15012250
TI  - MOLECULAR BIOLOGY OF CATION TRANSPORT IN PLANTS.
AB  - This review summarizes current knowledge about genes whose products function in
      the transport of various cationic macronutrients (K, Ca) and micronutrients (Cu,
      Fe, Mn, and Zn) in plants. Such genes have been identified on the basis of
      function, via complementation of yeast mutants, or on the basis of sequence
      similarity, via database analysis, degenerate PCR, or low stringency
      hybridization. Not surprisingly, many of these genes belong to previously
      described transporter families, including those encoding Shaker-type K+ channels,
      P-type ATPases, and Nramp proteins. ZIP, a novel cation transporter family first
      identified in plants, also seems to be ubiquitous; members of this family are
      found in protozoa, yeast, nematodes, and humans. Emerging information on where in
      the plant each transporter functions and how each is controlled in response to
      nutrient availability may allow creation of food crops with enhanced mineral
      content as well as crops that bioaccumulate or exclude toxic metals.

PMID- 15012251
TI  - CALMODULIN AND CALMODULIN-BINDING PROTEINS IN PLANTS.
AB  - Calmodulin is a small Ca2+-binding protein that acts to transduce second
      messenger signals into a wide array of cellular responses. Plant calmodulins
      share many structural and functional features with their homologs from animals
      and yeast, but the expression of multiple protein isoforms appears to be a
      distinctive feature of higher plants. Calmodulin acts by binding to short peptide
      sequences within target proteins, thereby inducing structural changes, which
      alters their activities in response to changes in intracellular Ca2+
      concentration. The spectrum of plant calmodulin-binding proteins shares some
      overlap with that found in animals, but a growing number of calmodulin-regulated
      proteins in plants appear to be unique. Ca2+-binding and enzymatic activation
      properties of calmodulin are discussed emphasizing the functional linkages
      between these processes and the diverse pathways that are dependent on Ca2+
      signaling.

PMID- 15012252
TI  - FROM VACUOLAR GS-X PUMPS TO MULTISPECIFIC ABC TRANSPORTERS.
AB  - While the concept of H+-coupling has dominated studies of energy-dependent
      organic solute transport in plants for over two decades, recent studies have
      demonstrated the existence of a group of organic solute transporters, belonging
      to the ATP-binding cassette (ABC) superfamily, that are directly energized by
      MgATP rather than by a transmembrane H+-electrochemical potential difference.
      Originally identified in microbial and animal cells, the ABC superfamily is one
      of the largest and most widespread protein families known. Competent in the
      transport of a broad range of substances including sugars, peptides, alkaloids,
      inorganic anions, and lipids, all ABC transporters are constituted of one or two
      copies each of an integral membrane sector and cytosolically oriented ATP-binding
      domain. To date, two major subclasses, the multidrug resistance-associated
      proteins (MRPs) and multidrug resistance proteins (MDRs) (so named because of the
      phenotypes conferred by their animal prototypes), have been identified
      molecularly in plants. However, only the MRPs have been defined functionally.
      This review therefore focuses on the functional capabilities, energetics,
      organization, and regulation of the plant MRPs. Otherwise known as GS-X pumps, or
      glutathione-conjugate or multispecific organic anion Mg2+-ATPases, the MRPs are
      considered to participate in the transport of exogenous and endogenous
      amphipathic anions and glutathionated compounds from the cytosol into the
      vacuole. Encoded by a multigene family and possessing a unique domain
      organization, the types of processes that likely converge and depend on plant
      MRPs include herbicide detoxification, cell pigmentation, the alleviation of
      oxidative damage, and the storage of antimicrobial compounds. Additional
      functional capabilities might include channel regulation or activity, and/or the
      transport of heavy metal chelates. The identification of the MRPs, in particular,
      and the demonstration of a central role for ABC transporters, in general, in
      plant function not only provide fresh insights into the molecular basis of energy
      dependent solute transport but also offer the prospect for manipulating and
      investigating many fundamental processes that have hitherto evaded analysis at
      the transport level.

PMID- 15012253
TI  - THEMES IN PLANT DEVELOPMENT.

PMID- 15012254
TI  - THE C2 OXIDATIVE PHOTOSYNTHETIC CARBON CYCLE.
AB  - The C2 oxidative photosynthetic carbon cycle plus the C3 reductive photosynthetic
      carbon cycle coexist. Both are initiated by Rubisco, use about equal amounts of
      energy, must regenerate RuBP, and result in exchanges of CO2 and O2 to establish
      rates of net photosynthesis, CO2 and O2 compensation points, and the ratio of CO2
      and O2 in the atmosphere. These concepts evolved from research on O2 inhibition,
      glycolate metabolism, leaf peroxisomes, photorespiration, 18O2/16O2 exchange, CO2
      concentrating processes, and a requirement for the oxygenase activity of Rubisco.
      Nearly 80 years of research on these topics are unified under the one process of
      photosynthetic carbon metabolism and its self-regulation.

PMID- 15012255
TI  - TRANSPORT OF PROTEINS AND NUCLEIC ACIDS THROUGH PLASMODESMATA.
AB  - Despite a potentially key role in cell-to-cell communication, plant intercellular
      connections-the plasmodesmata-have long been a biological "black box." Little is
      known about their protein composition, regulatory mechanisms, or transport
      pathways. However, recent studies have shed some light on plasmodesmal function.
      These connections have been shown to actively traffic proteins and protein
      nucleic acid complexes between plant cells. This review describes these transport
      processes-specifically, cell-to-cell movement of plant viruses as well as
      endogenous cellular proteins-and discusses their possible mechanism(s). For
      comparison and to provide a broader perspective on the plasmodesmal transport
      process, the current model for nuclear import, the only other known example of
      transport of large proteins and protein-nucleic acid complexes through a membrane
      pore, is summarized. Finally, the function of plasmodesmata as communication
      boundaries within plant tissue is discussed.

PMID- 15012256
TI  - AUXIN BIOSYNTHESIS.
AB  - Indole-3-acetic acid (IAA) is the most abundant naturally occurring auxin. Plants
      produce active IAA both by de novo synthesis and by releasing IAA from
      conjugates. This review emphasizes recent genetic experiments and complementary
      biochemical analyses that are beginning to unravel the complexities of IAA
      biosynthesis in plants. Multiple pathways exist for de novo IAA synthesis in
      plants, and a number of plant enzymes can liberate IAA from conjugates. This
      multiplicity has contributed to the current situation in which no pathway of IAA
      biosynthesis in plants has been unequivocally established. Genetic and
      biochemical experiments have demonstrated both tryptophan-dependent and
      tryptophan-independent routes of IAA biosynthesis. The recent application of
      precise and sensitive methods for quantitation of IAA and its metabolites to
      plant mutants disrupted in various aspects of IAA regulation is beginning to
      elucidate the multiple pathways that control IAA levels in the plant.

PMID- 15012257
TI  - THE SYNTHESIS OF THE STARCH GRANULE.
AB  - This review describes and discusses the implications of recent discoveries about
      how starch polymers are synthesized and organized to form a starch granule. Three
      issues are highlighted. 1. The role and importance of ADPglucose
      pyrophosphorylase in the generation of ADPglucose as the substrate for polymer
      synthesis. 2. The contributions of isoforms of starch-branching enzyme, starch
      synthase, and debranching enzyme to the synthesis and ordered packing of
      amylopectin molecules. 3. The requirements for and regulation of the synthesis of
      amylose.

PMID- 15012258
TI  - CHEMICAL CONTROL OF GENE EXPRESSION.
AB  - Promoters that respond to otherwise inactive chemicals will enhance the tools
      available for analyzing gene function in vivo and for altering defined traits of
      plants at will. Approaches to provide such tools have yielded plant promoters
      that respond to compounds activating defense genes. In addition, the transfer of
      regulatory elements from prokaryotes, insects, and mammals has opened new avenues
      to construct chemically inducible promoters that respond to signals normally not
      recognized by plants. This review describes results and applications of these two
      approaches.

PMID- 15012259
TI  - REGULATION OF FATTY ACID SYNTHESIS.
AB  - All plant cells produce fatty acids from acetyl-CoA by a common pathway localized
      in plastids. Although the biochemistry of this pathway is now well understood,
      much less is known about how plants control the very different amounts and types
      of lipids produced in different tissues. Thus, a central challenge for plant
      lipid research is to provide a molecular understanding of how plants regulate the
      major differences in lipid metabolism found, for example, in mesophyll,
      epidermal, or developing seed cells. Acetyl-CoA carboxylase (ACCase) is one
      control point that regulates rates of fatty acid synthesis. However, the
      biochemical modulators that act on ACCase and the factors that in turn control
      these modulators are poorly understood. In addition, little is known about how
      the expression of genes involved in fatty acid synthesis is controlled. This
      review evaluates current knowledge of regulation of plant fatty metabolism and
      attempts to identify the major unanswered questions.

PMID- 15012260
TI  - MOLECULAR GENETIC ANALYSIS OF TRICHOME DEVELOPMENT IN ARABIDOPSIS.
AB  - Two basic questions in developmental biology are: How does a cell know when it
      should or should not differentiate, and once a cell is committed to
      differentiate, how is that process controlled? The first process regulates the
      arrangement or pattern of the various cell types, whereas the second makes cells
      functionally distinct. Together, these two processes define plant morphogenesis.
      Trichome development in Arabidopsis provides an excellent model to analyze these
      questions. First, trichome development in Arabidopsis is a relatively simple
      process. A single epidermal cell differentiates into a unicellular trichome.
      Second, this differentiation occurs in a nonrandom pattern on the plant surface.
      Finally, the process is amenable to genetic analysis because many mutations that
      affect trichome differentiation do not alter other aspects of plant development.
      Thus far, more than 20 genes affecting trichome development have been identified.
      This review examines the current state of our understanding of these genes.

PMID- 15012261
TI  - FLUORESCENCE MICROSCOPY OF LIVING PLANT CELLS.
AB  - Since its inception, light microscopy has shown the elegance and subtlety with
      which function is expressed in the form of the cells, tissues, and organs of the
      plant. Recently, light microscopy has seen a resurgence in use fueled by advances
      in microscope design and computer-based image analysis. The structural resolution
      afforded by static, fixed samples is being increasingly supplemented by
      approaches using fluorescent analogs and selective fluorescent indicators, which
      visualize the dynamic processes in living, functioning cells. This review
      describes some of these approaches and discusses how they are taking us a step
      closer to viewing the intricate complexity with which plants organize and
      regulate their functions down to the subcellular level.

PMID- 15012262
TI  - PHLOEM UNLOADING: Sieve Element Unloading and Post-Sieve Element Transport.
AB  - The transport events from the sieve elements to the sites of utilization within
      the recipient sink cells contribute to phloem unloading. The phenomenon links
      sink metabolism and/or compartmentation with phloem transport to, and
      partitioning between, sinks. The nature of the linkage depends upon the cellular
      pathway and mechanism of unloading. The common unloading pathway is symplasmic,
      with an apoplasmic step at or beyond the sieve element boundary reserved for
      specialized situations. Plasmodesmal conductivity exerts the primary control over
      symplasmic transport that occurs by diffusion with bulk flow anticipated to be of
      increasing significance as import rate rises. In the case of an apoplasmic step,
      efflux across the plasma membranes of the vascular cells occurs by simple
      diffusion, whereas efflux from nonvascular cells of developing seeds is
      facilitated and, in some cases, energy coupled. Accumulation of sugars from the
      sink apoplasm universally occurs by a plasma membrane-bound sugar/proton symport
      mechanism.

PMID- 15012263
TI  - OXYGEN DEFICIENCY AND ROOT METABOLISM: Injury and Acclimation Under Hypoxia and
      Anoxia.
AB  - Oxygen deficiency in the rooting zone occurs with poor drainage after rain or
      irrigation, causing depressed growth and yield of dryland species, in contrast
      with native wetland vegetation that tolerates such conditions. This review
      examines how roots are injured by O2 deficiency and how metabolism changes during
      acclimation to low concentrations of O2. In the root apical meristem, cell
      survival is important for the future development; metabolic changes under anoxia
      help maintain cell survival by generating ATP anaerobically and minimizing the
      cytoplasmic acidosis associated with cell death. Behind the apex, where cells are
      fully expanded, ethylene-dependent death and lysis occurs under hypoxia to form
      continuous, gas-filled channels (aerenchyma) conveying O2 from the leaves. This
      selective sacrifice of cells may resemble programmed cell death and is distinct
      from cell death caused by anoxia. Evidence concerning alternative possible
      mechanisms of anoxia tolerance and avoidance is presented.

PMID- 15012264
TI  - THE OXIDATIVE BURST IN PLANT DISEASE RESISTANCE.
AB  - Rapid generation of superoxide and accumulation of H2O2 is a characteristic early
      feature of the hypersensitive response following perception of pathogen
      avirulence signals. Emerging data indicate that the oxidative burst reflects
      activation of a membrane-bound NADPH oxidase closely resembling that operating in
      activated neutrophils. The oxidants are not only direct protective agents, but
      H2O2 also functions as a substrate for oxidative cross-linking in the cell wall,
      as a threshold trigger for hypersensitive cell death, and as a diffusible signal
      for induction of cellular protectant genes in surrounding cells. Activation of
      the oxidative burst is a central component of a highly amplified and integrated
      signal system, also involving salicylic acid and perturbations of cytosolic Ca2+,
      which underlies the expression of disease-resistance mechanisms.

PMID- 15012265
TI  - PLANT TRANSFORMATION: Problems and Strategies for Practical Application.
AB  - Plant transformation is now a core research tool in plant biology and a practical
      tool for cultivar improvement. There are verified methods for stable introduction
      of novel genes into the nuclear genomes of over 120 diverse plant species. This
      review examines the criteria to verify plant transformation; the biological and
      practical requirements for transformation systems; the integration of tissue
      culture, gene transfer, selection, and transgene expression strategies to achieve
      transformation in recalcitrant species; and other constraints to plant
      transformation including regulatory environment, public perceptions, intellectual
      property, and economics. Because the costs of screening populations showing
      diverse genetic changes can far exceed the costs of transformation, it is
      important to distinguish absolute and useful transformation efficiencies. The
      major technical challenge facing plant transformation biology is the development
      of methods and constructs to produce a high proportion of plants showing
      predictable transgene expression without collateral genetic damage. This will
      require answers to a series of biological and technical questions, some of which
      are defined.

PMID- 15012266
TI  - CYANOBACTERIAL CIRCADIAN RHYTHMS.
AB  - Evidence from a number of laboratories over the past 12 years has established
      that cyanobacteria, a group of photosynthetic eubacteria, possess a circadian
      pacemaker that controls metabolic and genetic functions. The cyanobacterial
      circadian clock exhibits the three intrinsic properties that have come to define
      the clocks of eukaryotes: The timekeeping mechanism controls rhythms that show a
      period of about 24 h in the absence of external signals, the phase of the rhythms
      can be reset by light/dark cues, and the period is relatively insensitive to
      temperature. The promise of cyanobacteria as simple models for elucidating the
      biological clock mechanism is being fulfilled, as mutants affected in period,
      rhythm generation, and rhythm amplitude, isolated through the use of real time
      reporters of gene expression, have implicated genes involved in these aspects of
      the clock.

PMID- 15012267
TI  - BIOSYNTHESIS AND ACTION OF JASMONATES IN PLANTS.
AB  - Jasmonic acid and its derivatives can modulate aspects of fruit ripening,
      production of viable pollen, root growth, tendril coiling, and plant resistance
      to insects and pathogens. Jasmonate activates genes involved in pathogen and
      insect resistance, and genes encoding vegetative storage proteins, but represses
      genes encoding proteins involved in photosynthesis. Jasmonic acid is derived from
      linolenic acid, and most of the enzymes in the biosynthetic pathway have been
      extensively characterized. Modulation of lipoxygenase and allene oxide synthase
      gene expression in transgenic plants raises new questions about the
      compartmentation of the biosynthetic pathway and its regulation. The activation
      of jasmonic acid biosynthesis by cell wall elicitors, the peptide systemin, and
      other compounds will be related to the function of jasmonates in plants.
      Jasmonate modulates gene expression at the level of translation, RNA processing,
      and transcription. Promoter elements that mediate responses to jasmonate have
      been isolated. This review covers recent advances in our understanding of how
      jasmonate biosynthesis is regulated and relates this information to knowledge of
      jasmonate modulated gene expression.

PMID- 15012268
TI  - PLANT IN VITRO TRANSCRIPTION SYSTEMS.
AB  - In vitro transcription systems provide a powerful tool for detailed analysis of
      transcription reactions including initiation, elongation, and termination.
      Despite problems inherent to plant cells, efforts have been made to develop plant
      in vitro transcription systems in the past decade. These efforts have finally
      culminated in the development of reliable in vitro systems from suspension-cell
      cultures of both monocot and dicot plants. These systems can be useful in
      elucidating the specific mechanisms involved in the process of plant
      transcription and thus can potentially open a new era of transcription studies in
      plants.

PMID- 15012269
TI  - AQUAPORINS AND WATER PERMEABILITY OF PLANT MEMBRANES.
AB  - The mechanisms of plant membrane water permeability have remained elusive until
      the recent discovery in both vacuolar and plasma membranes of a class of water
      channel proteins named aquaporins. Similar to their animal counterparts, plant
      aquaporins have six membrane-spanning domains and belong to the MIP superfamily
      of transmembrane channel proteins. Their very high efficiency and selectivity in
      transporting water molecules have been mostly characterized using heterologous
      expression in Xenopus oocytes. However, techniques set up to measure the osmotic
      water permeability of plant membranes such as transcellular osmosis, pressure
      probe measurements, or stopped-flow spectrophotometry are now being used to
      analyze the function of plant aquaporins in their native membranes. Multiple
      mechanisms, at the transcriptional and posttranslational levels, control the
      expression and activity of the numerous aquaporin isoforms found in plants. These
      studies suggest a general role for aquaporins in regulating transmembrane water
      transport during the growth, development, and stress responses of plants. Future
      research will investigate the integrated function of aquaporins in long-distance
      water transport and cellular osmoregulation.

PMID- 15012270
TI  - GIBBERELLIN BIOSYNTHESIS: Enzymes, Genes and Their Regulation.
AB  - The recent impressive progress in research on gibberellin (GA) biosynthesis has
      resulted primarily from cloning of genes encoding biosynthetic enzymes and
      studies with GA-deficient and GA-insensitive mutants. Highlights include the
      cloning of ent-copalyl diphosphate synthase and ent-kaurene synthase (formally
      ent-kaurene synthases A and B) and the demonstration that the former is targeted
      to the plastid; the finding that the Dwarf-3 gene of maize encodes a cytochrome
      P450, although of unknown function; and the cloning of GA 20-oxidase and 3beta
      hydroxylase genes. The availability of cDNA and genomic clones for these enzymes
      is enabling the mechanisms by which GA concentrations are regulated by
      environmental and endogenous factors to be studied at the molecular level. For
      example, it has been shown that transcript levels for GA 20-oxidase and 3beta
      hydroxylase are subject to feedback regulation by GA action and, in the case of
      the GA 20-oxidase, are regulated by light. Also discussed is other new
      information, particularly from mutants, that has added to our understanding of
      the biosynthetic pathway, the enzymes, and their regulation and tissue
      localization.

PMID- 15012271
TI  - POLLEN GERMINATION AND TUBE GROWTH.
AB  - Many aspects of Angiosperm pollen germination and tube growth are discussed
      including mechanisms of dehydration and rehydration, in vitro germination, pollen
      coat compounds, the dynamic involvement of cytoskeletal elements (actin,
      microtubules), calcium ion fluxes, extracellular matrix elements (stylar
      arabinogalactan proteins), and control mechanisms of gene expression in
      dehydrating and germinating pollen. We focus on the recent developments in pollen
      biology that help us understand how the male gamete survives and accomplishes its
      successful delivery to the ovule of the sperm to effect sexual reproduction.

PMID- 15012272
TI  - METABOLITE TRANSPORT ACROSS SYMBIOTIC MEMBRANES OF LEGUME NODULES.
AB  - Infection of legume roots or stems with soil bacteria of the Rhizobiaceae results
      in the formation of nodules that become symbiotic nitrogen-fixing organs. Within
      the infected cells of these nodules, bacteria are enveloped in a membrane of
      plant origin, called the peribacteroid membrane (PBM), and divide and
      differentiate to form nitrogen-fixing bacteroids. The organelle-like structure
      comprised of PBM and bacteroids is termed the symbiosome, and is the basic
      nitrogen-fixing unit of the nodule. The major exchange of nutrients between the
      symbiotic partners is reduced carbon from the plant, to fuel nitrogenase activity
      in the bacteroid, and fixed nitrogen from the bacteroid, which is assimilated in
      the plant cytoplasm. However, many other metabolites are also exchanged. The
      metabolic interaction between the plant and the bacteroids is regulated by a
      series of transporters and channels on the PBM and the bacteroid membrane, and
      these form the focus of this review.

PMID- 15012273
TI  - PROGRAMMED CELL DEATH IN PLANT-PATHOGEN INTERACTIONS.
AB  - Plants cope with pathogen attacks by using mechanisms of resistance that rely
      both on preformed protective defenses and on inducible defenses. The latter are
      the most well studied, and progress is being made in determining which induced
      responses are responsible for limiting pathogen growth. Many plant-pathogen
      interactions are accompanied by plant cell death. Recent evidence suggests that
      this cell death is often programmed and results from an active process on the
      part of the host. The review considers the roles and possible mechanisms of plant
      cell death in response to pathogens.

PMID- 15012274
TI  - POLLINATION REGULATION OF FLOWER DEVELOPMENT.
AB  - Pollination regulates a syndrome of developmental responses that contributes to
      successful sexual reproduction in higher plants. Pollination-regulated
      developmental events collectively prepare the flower for fertilization and
      embryogenesis while bringing about the loss of floral organs that have completed
      their function in pollen dispersal and reception. Components of this process
      include changes in flower pigmentation, senescence and abscission of floral
      organs, growth and development of the ovary, and, in certain cases, pollination
      also triggers ovule and female gametophyte development in anticipation of
      fertilization. Pollination-regulated development is initiated by the primary
      pollination event at the stigma surface, but because developmental processes
      occur in distal floral organs, the activity of interorgan signals that amplify
      and transmit the primary pollination signal to floral organs is implicated.
      Interorgan signaling and signal amplification involves the regulation of ethylene
      biosynthetic gene expression and interorgan transport of hormones and their
      precursors. The coordination of pollination- regulated flower development
      including gametophyte, embryo, and ovary development; pollination signaling; the
      molecular regulation of ethylene biosynthesis; and interorgan communication are
      presented.

PMID- 15012275
TI  - PLANT DISEASE RESISTANCE GENES.
AB  - In "gene-for-gene" interactions between plants and their pathogens,
      incompatibility (no disease) requires a dominant or semidominant resistance (R)
      gene in the plant, and a corresponding avirulence (Avr) gene in the pathogen.
      Many plant/pathogen interactions are of this type. R genes are presumed to (a)
      enable plants to detect Avr-gene-specified pathogen molecules, (b) initiate
      signal transduction to activate defenses, and (c) have the capacity to evolve new
      R gene specificities rapidly. Isolation of R genes has revealed four main classes
      of R gene sequences whose products appear to activate a similar range of defense
      mechanisms. Discovery of the structure of R genes and R gene loci provides
      insight into R gene function and evolution, and should lead to novel strategies
      for disease control.

PMID- 15012276
TI  - MORE EFFICIENT PLANTS: A Consequence of Rising Atmospheric CO2?
AB  - The primary effect of the response of plants to rising atmospheric CO2 (Ca) is to
      increase resource use efficiency. Elevated Ca reduces stomatal conductance and
      transpiration and improves water use efficiency, and at the same time it
      stimulates higher rates of photosynthesis and increases light-use efficiency.
      Acclimation of photosynthesis during long-term exposure to elevated Ca reduces
      key enzymes of the photosynthetic carbon reduction cycle, and this increases
      nutrient use efficiency. Improved soil-water balance, increased carbon uptake in
      the shade, greater carbon to nitrogen ratio, and reduced nutrient quality for
      insect and animal grazers are all possibilities that have been observed in field
      studies of the effects of elevated Ca. These effects have major consequences for
      agriculture and native ecosystems in a world of rising atmospheric Ca and climate
      change.

PMID- 15012277
TI  - STRUCTURE AND MEMBRANE ORGANIZATION OF PHOTOSYSTEM II IN GREEN PLANTS.
AB  - Photosystem II (PSII) is the pigment protein complex embedded in the thylakoid
      membrane of higher plants, algae, and cyanobacteria that uses solar energy to
      drive the photosynthetic water-splitting reaction. This chapter reviews the
      primary, secondary, tertiary, and quaternary structures of PSII as well as the
      function of its constituent subunits. The understanding of in vivo organization
      of PSII is based in part on freeze-etched and freeze-fracture images of thylakoid
      membranes. These images show a resolution of about 40-50 A and so provide
      information mainly on the localization, heterogeneity, dimensions, and shapes of
      membrane-embedded PSII complexes. Higher resolution of about 15-40 A has been
      obtained from single particle images of isolated PSII complexes of defined and
      differing subunit composition and from electron crystallography of 2-D crystals.
      Observations are discussed in terms of the oligomeric state and subunit
      organization of PSII and its antenna components.

PMID- 15012279
TI  - ALTERNATIVE OXIDASE: From Gene to Function.
AB  - Plants, some fungi, and protists contain a cyanide-resistant, alternative
      mitochondrial respiratory pathway. This pathway branches at the ubiquinone pool
      and consists of an alternative oxidase encoded by the nuclear gene Aox1.
      Alternative pathway respiration is only linked to proton translocation at Complex
      1 (NADH dehydrogenase). Alternative oxidase expression is influenced by stress
      stimuli-cold, oxidative stress, pathogen attack-and by factors constricting
      electron flow through the cytochrome pathway of respiration. Control is exerted
      at the levels of gene expression and in response to the availability of carbon
      and reducing potential. Posttranslational control involves reversible covalent
      modification of the alternative oxidase and activation by specific carbon
      metabolites. This dynamic system of coarse and fine control may function to
      balance upstream respiratory carbon metabolism and downstream electron transport
      when these coupled processes become imbalanced as a result of changes in the
      supply of, or demand for, carbon, reducing power, and ATP.

PMID- 15012278
TI  - GENETICS OF ANGIOSPERM SHOOT APICAL MERISTEM DEVELOPMENT.
AB  - Recent progress has been made in the genetic dissection of angiosperm shoot
      apical meristem (SAM) structure and function. Genes required for proper SAM
      development have been identified in a variety of species through the isolation of
      mutants. In addition, genes with expression patterns indicating they play a role
      in SAM function have been identified molecularly. The processes of SAM formation,
      self-renewal, and pattern formation within the SAM are examined with an emphasis
      on the contributions of recent classical and molecular genetic experiments to our
      understanding of this basic problem in plant developmental biology.

PMID- 15012280
TI  - REFLECTIONS OF A BIO-ORGANIC CHEMIST.
AB  - The chapter provides a personal and anecdotal account of the author's attempts to
      keep the horizons of advancing science in sight. It sketches his background to
      entering science and chronicles various episodes across fifty years in research.
      Milestones are noted on the author's journey from his structural studies on
      colchicine, griseofulvin, and gibberellic acid to the isolation, analysis,
      biosynthesis, and molecular biology of plant gibberellins. The author discusses
      his personal and professional interactions with plant physiologists and plant
      biochemists over the years. Philosophical observations are offered on some of the
      attributes important to conducting research and on changing attitudes toward
      research.

PMID- 15012281
TI  - HOMOLOGY-DEPENDENT GENE SILENCING IN PLANTS.
AB  - Homology-dependent gene silencing phenomena in plants have received considerable
      attention, especially when it was discovered that the presence of homologous
      sequences not only affected the stability of transgene expression, but that the
      activity of endogenous genes could be altered after insertion of homologous
      transgenes into the genome. Homology-mediated inactivation most likely comprises
      at least two different molecular mechanisms that induce gene silencing at the
      transcriptional or posttranscriptional level, respectively. In this review we
      discuss different mechanistic models for plant-specific inactivation mechanisms
      and their relationship with repeat-specific silencing phenomena in other species.

PMID- 15012282
TI  - 14-3-3 PROTEINS AND SIGNAL TRANSDUCTION.
AB  - Perhaps in keeping with their enigmatic name, 14-3-3 proteins offer a seemingly
      bewildering array of opportunities for interaction with signal transduction
      pathways. In each organism there are many isoforms that can form both homo- and
      heterodimers, and many biochemical activities have been attributed to the 14-3-3
      group. The potential for diversity-and also confusion-is high. The mammalian
      literature on 14-3-3 proteins provides an appropriate context to appreciate the
      potential roles of 14-3-3s in plant signal transduction pathways. In addition,
      functional and structural themes emerge when 14-3-3s are examined and compiled in
      ways that draw attention to their participation in protein phosphorylation and
      protein-protein interactions. These themes allow examination of plant 14-3-3s
      from two perspectives: the ways in which plant 14-3- 3s contribute to and extend
      ideas already described in animals, and the ways that plant 14-3-3s present
      unique contributions to the field. The crystal structure of an animal 14-3- 3 has
      been solved. When considered with the evolutionary stability of large segments of
      the 14-3-3 protein, the structure illuminates several aspects of 14-3-3 function.
      However, diversity in other regions of the 14-3-3s and their presence as
      multigene families offer many opportunities for cell-specific specialization of
      individual functions.

PMID- 15012283
TI  - DNA DAMAGE AND REPAIR IN PLANTS.
AB  - The biological impact of any DNA damaging agent is a combined function of the
      chemical nature of the induced lesions and the efficiency and accuracy of their
      repair. Although much has been learned from microbes and mammals about both the
      repair of DNA damage and the biological effects of the persistence of these
      lesions, much remains to be learned about the mechanism and tissue-specificity of
      repair in plants. This review focuses on recent work on the induction and repair
      of DNA damage in higher plants, with special emphasis on UV-induced DNA damage
      products.

PMID- 15012284
TI  - PLANT PROTEIN PHOSPHATASES.
AB  - Posttranslational modification of proteins by phosphorylation is a universal
      mechanism for regulating diverse biological functions. Recognition that many
      cellular proteins are reversibly phosphorylated in response to external stimuli
      or intracellular signals has generated an ongoing interest in identifying and
      characterizing plant protein kinases and protein phosphatases that modulate the
      phosphorylation status of proteins. This review discusses recent advances in our
      understanding of the structure, regulation, and function of plant protein
      phosphatases. Three major classes of enzymes have been reported in plants that
      are homologues of the mammalian type-1, -2A, and -2C protein serine/threonine
      phosphatases. Molecular genetic and biochemical studies reveal a role for some of
      these enzymes in signal transduction, cell cycle progression, and hormonal
      regulation. Studies also point to the presence of additional phosphatases in
      plants that are unrelated to these major classes.

PMID- 15012285
TI  - THE FUNCTIONS AND REGULATION OF GLUTATHIONE S-TRANSFERASES IN PLANTS.
AB  - Glutathione S-transferases (GSTs) play roles in both normal cellular metabolism
      as well as in the detoxification of a wide variety of xenobiotic compounds, and
      they have been intensively studied with regard to herbicide detoxification in
      plants. A newly discovered plant GST subclass has been implicated in numerous
      stress responses, including those arising from pathogen attack, oxidative stress,
      and heavy-metal toxicity. In addition, plant GSTs play a role in the cellular
      response to auxins and during the normal metabolism of plant secondary products
      like anthocyanins and cinnamic acid. This review presents the current knowledge
      about the functions of GSTs in regard to both herbicides and endogenous
      substrates. The catalytic mechanism of GST activity as well as the fate of
      glutathione S-conjugates are reviewed. Finally, a summary of what is known about
      the gene structure and regulation of plant GSTs is presented.

PMID- 15012286
TI  - PHYSIOLOGY OF ION TRANSPORT ACROSS THE TONOPLAST OF HIGHER PLANTS.
AB  - The vacuole of plant cells plays an important role in the homeostasis of the
      cell. It is involved in the regulation of cytoplasmic pH, sequestration of toxic
      ions and xenobiotics, regulation of cell turgor, storage of amino acids, sugars
      and CO2 in the form of malate, and possibly as a source for elevating cytoplasmic
      calcium. All these activities are driven by two primary active transport
      mechanisms present in the vacuolar membrane (tonoplast). These two mechanisms
      employ high-energy metabolites to pump protons into the vacuole, establishing a
      proton electrochemical potential that mediates the transport of a diverse range
      of solutes. Within the past few years, great advances at the molecular and
      functional levels have been made on the characterization and identification of
      these mechanisms. The aim of this review is to summarize these studies in the
      context of the physiology of the plant cell.

PMID- 15012287
TI  - THE ORGANIZATION AND REGULATION OF PLANT GLYCOLYSIS.
AB  - This review discusses the organization and regulation of the glycolytic pathway
      in plants and compares and contrasts plant and nonplant glycolysis. Plant
      glycolysis exists both in the cytosol and plastid, and the parallel reactions are
      catalyzed by distinct nuclear-encoded isozymes. Cytosolic glycolysis is a complex
      network containing alternative enzymatic reactions. Two alternate cytosolic
      reactions enhance the pathway's ATP yield through the use of pyrophosphate in
      place of ATP. The cytosolic glycolytic network may provide an essential metabolic
      flexibility that facilitates plant development and acclimation to environmental
      stress. The regulation of plant glycolytic flux is assessed, with a focus on the
      fine control of enzymes involved in the metabolism of fructose-6-phosphate and
      phosphoenolpyruvate. Plant and nonplant glycolysis are regulated from the "bottom
      up" and "top down," respectively. Research on tissue- and developmental-specific
      isozymes of plant glycolytic enzymes is summarized. Potential pitfalls associated
      with studies of glycolytic enzymes are considered. Some glycolytic enzymes may be
      multifunctional proteins involved in processes other than carbohydrate
      metabolism.

PMID- 15012288
TI  - LIGHT CONTROL OF SEEDLING DEVELOPMENT.
AB  - Light control of plant development is most dramatically illustrated by seedling
      development. Seedling development patterns under light (photomorphogenesis) are
      distinct from those in darkness (skotomorphogenesis or etiolation) with respect
      to gene expression, cellular and subcellular differentiation, and organ
      morphology. A complex network of molecular interactions couples the regulatory
      photoreceptors to developmental decisions. Rapid progress in defining the roles
      of individual photoreceptors and the downstream regulators mediating light
      control of seedling development has been achieved in recent years, predominantly
      because of molecular genetic studies in Arabidopsis thaliana and other species.
      This review summarizes those important recent advances and highlights the working
      models underlying the light control of cellular development. We focus mainly on
      seedling morphogenesis in Arabidopsis but include complementary findings from
      other species.

PMID- 15012289
TI  - DIOXYGENASES: Molecular Structure and Role in Plant Metabolism.
AB  - Dioxygenases are nonheme iron-containing enzymes important in the biosynthesis of
      plant signaling compounds such as abscisic acid, gibberellins, and ethylene and
      also of secondary metabolites, notably flavonoids and alkaloids. Plant
      dioxygenases fall into two classes: lipoxygenases and 2-oxoacid-dependent
      dioxygenases. The latter catalyze hydroxylation, epoxidation, and desaturation
      reactions; some enzymes catalyze more than one type of reaction in successive
      steps in a biosynthetic pathway. This review highlights recent discoveries on
      both enzyme groups, particularly in relation to gibberellin biosynthesis, in vivo
      activity of 1-aminocyclopropane-1-carboxylate oxidase, and molecular
      structure/function relationships. Similarities between the roles of
      monooxygenases and dioxygenases are also discussed.

PMID- 15012290
TI  - PHOSPHOENOLPYRUVATE CARBOXYLASE: A Ubiquitous, Highly Regulated Enzyme in Plants.
AB  - Since plant phosphoenolpyruvate carboxylase (PEPC) was last reviewed in the
      Annual Review of Plant Physiology over a decade ago (O'Leary 1982), significant
      advances have been made in our knowledge of this oligomeric, cytosolic enzyme.
      This review highlights this exciting progress in plant PEPC research by focusing
      on the three major areas of recent investigation: the enzymology of the protein;
      its posttranslational regulation by reversible protein phosphorylation and
      opposing metabolite effectors; and the structure, expression, and molecular
      evolution of the nuclear PEPC genes. It is hoped that the next ten years will be
      equally enlightening, especially with respect to the three-dimensional structure
      of the plant enzyme, the molecular analysis of its highly regulated protein
      Ser/Thr kinase, and the elucidation of its associated signal-transduction
      pathways in various plant cell types.

PMID- 15012291
TI  - XYLOGENESIS: INITIATION, PROGRESSION, AND CELL DEATH.
AB  - Xylem cells develop from procambial or cambial initials in situ, and they can
      also be induced from parenchyma cells by wound stress and/or a combination of
      phytohormones in vitro. Recent molecular and biochemical studies have identified
      some of the genes and proteins involved in xylem differentiation, which have led
      to an understanding of xylem differentiation based on comparisons of events in
      situ and in vitro. As a result, differentiation into tracheary elements (TEs) has
      been divided into two processes. The "early" process involves the origination and
      development of procambial initials in situ. In vitro, the early process of
      transdifferentiation involves the dedifferentiation of cells and subsequent
      differentiation of dedifferentiated cells into TE precursor cells. The "late"
      process, observed both in situ and in vitro, involves a variety of events
      specific to TE formation, most of which have been observed in association with
      secondary wall thickenings and programmed cell death. In this review, I summarize
      these events, including coordinated expression of genes that are involved in
      secondary wall formation.

PMID- 15012292
TI  - COMPARTMENTATION OF PROTEINS IN THE ENDOMEMBRANE SYSTEM OF PLANT CELLS.
AB  - This review focuses on four interrelated processes in the plant endomembrane
      system: compartmentation of proteins in subdomains of the endoplasmic reticulum,
      mechanisms that determine whether storage proteins are retained within the ER
      lumen or transported out, the origin and function of biochemically distinct
      vacuoles or prevacuolar organelles, and the cellular processes by which proteins
      are sorted to vacuolar compartments. We postulate that ER-localized protein
      bodies are formed by a series of orderly events of protein synthesis, protein
      concentration, and protein assembly in subdomains of the ER. Protein
      concentration, which facilitates protein-to-protein interactions and subsequent
      protein assembly, may be achieved by the interactions with chaperones and by the
      localization of storage protein mRNAs. We also describe recent developments on
      the coexistence of two biochemically distinguishable vacuolar compartments, the
      possible direct role of the ER in vacuole biogenesis, and proposed mechanisms for
      transport of proteins from the ER or Golgi apparatus to the vacuole.

PMID- 15012293
TI  - WHAT CHIMERAS CAN TELL US ABOUT PLANT DEVELOPMENT.
AB  - The generation and analysis of plant chimeras and other genetic mosaics have been
      used to deduce patterns of cell division and cell fate during plant development
      and to demonstrate the existence of clonally distinct cell lineages in the shoot
      meristems of higher plants. Cells derived from these lineages do not have fixed
      developmental fates but rely on positional information to determine their
      patterns of division and differentiation. Chimeras with cells that differ
      genetically for specific developmental processes have been experimentally
      generated by a variety of methods. This review focuses on studies of
      intercellular interactions during plant development as well as of the
      coordination of cells during meristem function and organogenesis. Recent
      experiments combining mosaic analysis with molecular analysis of developmental
      mutants have begun to shed light on the nature of the signals involved in these
      processes and the mechanisms by which they are transmitted and received among
      cells.

PMID- 15012294
TI  - THE MOLECULAR BASIS OF DEHYDRATION TOLERANCE IN PLANTS.
AB  - Molecular studies of drought stress in plants use a variety of strategies and
      include different species subjected to a wide range of water deficits. Initial
      research has by necessity been largely descriptive, and relevant genes have been
      identified either by reference to physiological evidence or by differential
      screening. A large number of genes with a potential role in drought tolerance
      have been described, and major themes in the molecular response have been
      established. Particular areas of importance are sugar metabolism and late
      embryogenesis-abundant (LEA) proteins. Studies have begun to examine mechanisms
      that control the gene expression, and putative regulatory pathways have been
      established. Recent attempts to understand gene function have utilized transgenic
      plants. These efforts are of clear agronomic importance.

PMID- 15012295
TI  - BIOCHEMISTRY AND MOLECULAR BIOLOGY OF WAX PRODUCTION IN PLANTS.
AB  - The aerial surfaces of plants are covered with a wax layer that is primarily a
      waterproof barrier but that also provides protection against environmental
      stresses. The ubiquitous presence of cuticular wax is testimony to its essential
      function. Genetic and environmental factors influence wax quantity and
      composition, which suggests that it is an actively regulated process. The basic
      biochemistry of wax production has been elucidated over the past three decades;
      however, we still know very little about its regulation. This review presents a
      discussion along with new perspectives on the regulatory aspects of wax
      biosynthesis. Among the topics discussed are the partitioning of fatty acid
      precursors into wax biosynthesis and the elongation of fatty acids with
      particular emphasis on the nature of the acyl primer, and the role of ATP in
      fatty acid elongation. The recent cloning of wax biosynthetic genes and the
      transport of wax to plant surfaces are also discussed.

PMID- 15012296
TI  - ROLE AND REGULATION OF SUCROSE-PHOSPHATE SYNTHASE IN HIGHER PLANTS.
AB  - Sucrose-phosphate synthase (SPS; E.C. 2.4.1.14) is the plant enzyme thought to
      play a major role in sucrose biosynthesis. In photosynthetic and
      nonphotosynthetic tissues, SPS is regulated by metabolites and by reversible
      protein phosphorylation. In leaves, phosphorylation modulates SPS activity in
      response to light/dark signals and end-product accumulation. SPS is
      phosphorylated on multiple seryl residues in vivo, and the major regulatory
      phosphorylation site involved is Ser158 in spinach leaves and Ser162 in maize
      leaves. Regulation of the enzymatic activity of SPS appears to involve calcium,
      metabolites, and novel "coarse" control of the protein phosphatase that activates
      SPS. Activation of SPS also occurs during osmotic stress of leaf tissue in
      darkness, which may function to facilitate sucrose formation for osmoregulation.
      Manipulation of SPS expression in vivo confirms the role of this enzyme in the
      control of sucrose biosynthesis.

PMID- 15012297
TI  - STRUCTURE AND BIOGENESIS OF THE CELL WALLS OF GRASSES.
AB  - The chemical structures of the primary cell walls of the grasses and their
      progenitors differ from those of all other flowering plant species. They vary in
      the complex glycans that interlace and cross-link the cellulose microfibrils to
      form a strong framework, in the nature of the gel matrix surrounding this
      framework, and in the types of aromatic substances and structural proteins that
      covalently cross-link the primary and secondary walls and lock cells into shape.
      This review focuses on the chemistry of the unique polysaccharides, aromatic
      substances, and proteins of the grasses and how these structural elements are
      synthesized and assembled into dynamic and functional cell walls. Despite wide
      differences in wall composition, the developmental physiology of grasses is
      similar to that of all flowering plants. Grass cells respond similarly to
      environmental cues and growth regulators, exhibit the same alterations in
      physical properties of the wall to allow cell growth, and possess similar
      patterns of wall biogenesis during the development of specific cell and tissue
      types. Possible unifying mechanisms of growth are suggested to explain how
      grasses perform the same wall functions as other plants but with different
      constituents and architecture.

PMID- 15012298
TI  - SOME NEW STRUCTURAL ASPECTS AND OLD CONTROVERSIES CONCERNING THE CYTOCHROME b6f
      COMPLEX OF OXYGENIC PHOTOSYNTHESIS.
AB  - The cytochrome b6f complex functions in oxygenic photosynthetic membranes as the
      redox link between the photosynthetic reaction center complexes II and I and also
      functions in proton translocation. It is an ideal integral membrane protein
      complex in which to study structure and function because of the existence of a
      large amount of primary sequence data, purified complex, the emergence of
      structures, and the ability of flash kinetic spectroscopy to assay function in a
      readily accessible ms-100 mus time domain. The redox active polypeptides are
      cytochromes f and b6 (organelle encoded) and the Rieske iron-sulfur protein
      (nuclear encoded) in a mol wt = 210,000 dimeric complex that is believed to
      contain 22-24 transmembrane helices. The high resolution structure of the lumen
      side domain of cytochrome f shows it to be an elongate (75 A long) mostly beta
      strand, two-domain protein, with the N-terminal alpha-amino group as orthogonal
      heme ligand and an internal linear 11-A bound water chain. An unusual electron
      transfer event, the oxidant-induced reduction of a significant fraction of the p
      (lumen)-side cytochrome b heme by plastosemiquinone indicates that the electron
      transfer pathway in the b6f complex can be described by a version of the Q-cycle
      mechanism, originally proposed to describe similar processes in the mitochondrial
      and bacterial bc1 complexes.

PMID- 15012299
TI  - CARBOHYDRATE-MODULATED GENE EXPRESSION IN PLANTS.
AB  - Plant gene responses to changing carbohydrate status can vary markedly. Some
      genes are induced, some are repressed, and others are minimally affected. As in
      microorganisms, sugar-sensitive plant genes are part of an ancient system of
      cellular adjustment to critical nutrient availability. However, in multicellular
      plants, sugar-regulated expression also provides a mechanism for control of
      resource distribution among tissues and organs. Carbohydrate depletion
      upregulates genes for photosynthesis, remobilization, and export, while
      decreasing mRNAs for storage and utilization. Abundant sugar levels exert
      opposite effects through a combination of gene repression and induction. Long
      term changes in metabolic activity, resource partitioning, and plant form result.
      Sensitivity of carbohydrate-responsive gene expression to environmental and
      developmental signals further enhances its potential to aid acclimation. The
      review addresses the above from molecular to whole-plant levels and considers
      emerging models for sensing and transducing carbohydrate signals to responsive
      genes.

PMID- 15012300
TI  - CHILLING SENSITIVITY IN PLANTS AND CYANOBACTERIA: The Crucial Contribution of
      Membrane Lipids.
AB  - The contribution of membrane lipids, particularly the level of unsaturation of
      fatty acids, to chilling sensitivity of plants has been intensively discussed for
      many years. We have demonstrated that the chilling sensitivity can be manipulated
      by modulating levels of unsaturation of fatty acids of membrane lipids by the
      action of acyl-lipid desaturases and glycerol-3-phosphate acyltransferase. This
      review covers recent studies on genetic manipulation of these enzymes in
      transgenic tobacco and cyanobacteria with special emphasis on the crucial
      importance of the unsaturation of membrane lipids in protecting the
      photosynthetic machinery from photoinhibition under cold conditions. Furthermore,
      we review the molecular mechanism of temperature-induced desaturation of fatty
      acids and introduce our hypothesis that changes in the membrane fluidity is the
      initial event of the expression of desaturase genes.

PMID- 15012301
TI  - THE MOLECULAR-GENETICS OF NITROGEN ASSIMILATION INTO AMINO ACIDS IN HIGHER
      PLANTS.
AB  - Nitrogen assimilation is a vital process controlling plant growth and
      development. Inorganic nitrogen is assimilated into the amino acids glutamine,
      glutamate, asparagine, and aspartate, which serve as important nitrogen carriers
      in plants. The enzymes glutamine synthetase (GS), glutamate synthase (GOGAT),
      glutamate dehydrogenase (GDH), aspartate aminotransferase (AspAT), and asparagine
      synthetase (AS) are responsible for the biosynthesis of these nitrogen-carrying
      amino acids. Biochemical studies have revealed the existence of multiple
      isoenzymes for each of these enzymes. Recent molecular analyses demonstrate that
      each enzyme is encoded by a gene family wherein individual members encode
      distinct isoenzymes that are differentially regulated by environmental stimuli,
      metabolic control, developmental control, and tissue/cell-type specificity. We
      review the recent progress in using molecular-genetic approaches to delineate the
      regulatory mechanisms controlling nitrogen assimilation into amino acids and to
      define the physiological role of each isoenzyme involved in this metabolic
      pathway.

PMID- 15012302
TI  - MEMBRANE TRANSPORT CARRIERS.
AB  - Plant and fungal membrane proteins catalyzing the transmembrane translocation of
      small molecules without directly using ATP or acting as channels are discussed in
      this review. Facilitators, ion-cotransporters, and exchange translocators mainly
      for sugars, amino acids, and ions that have been cloned and characterized from
      Saccharomyces cerevisiae and from various plant sources have been tabulated. The
      membrane topology and structure of the most extensively studied carriers (lac
      permease of Escherichia coli, Glut1 of man, HUP1 of Chlorella) are discussed in
      detail as well as the kinetic analysis of specific Na+ and H+ cotransporters.
      Finally, the knowledge concerning regulatory phenomena of carriers-mainly of S.
      cerevisiae-is summarized.

PMID- 15012303
TI  - LIPID-TRANSFER PROTEINS IN PLANTS.
AB  - Lipid-transfer proteins (LTP) are basic, 9-kDa proteins present in high amounts
      (as much as 4% of the total soluble proteinss) in higher plants. LTPs can enhance
      the in vitro transfer of phospholipids between membranes and can bind acyl
      chains. On the basis of these properties, LTPs were thought to participate in
      membrane biogenesis and regulation of the intracellular fatty acid pools.
      However, the isolation of several cDNAs and genes revealed the presence of a
      signal peptide indicating that LTPs could enter the secretory pathway. They were
      found to be secreted and located in the cell wall. Thus, novel roles were
      suggested for plant LTPs: participation in cutin formation, embryogenesis,
      defense reactions against phytopathogens, symbiosis, and the adaptation of plants
      to various environmental conditions. The validity of these suggestions needs to
      be determined, in the hope that they will elucidate the role of this puzzling
      family of plant proteins.

PMID- 15012304
TI  - REGULATION OF LIGHT HARVESTING IN GREEN PLANTS.
AB  - When plants are exposed to light intensities in excess of those that can be
      utilized in photosynthetic electron transport, nonphotochemical dissipation of
      excitation energy is induced as a mechanism for photoprotection of photosystem
      II. The features of this process are reviewed, particularly with respect to the
      molecular mechanisms involved. It is shown how the dynamic properties of the
      proteins and pigments of the chlorophyll a/b light-harvesting complexes of
      photosystem II first enable the level of excitation energy to be sensed via the
      thylakoid proton gradient and subsequently allow excess energy to be dissipated
      as heat by formation of a nonphotochemical quencher. The nature of this quencher
      is discussed, together with a consideration of how the variation in capacity for
      energy dissipation depends on specific features of the composition of the light
      harvesting system. Finally, the prospects for future progress in understanding
      the regulation of light harvesting are assessed.

PMID- 15012305
TI  - THE CHLOROPHYLL-CAROTENOID PROTEINS OF OXYGENIC PHOTOSYNTHESIS.
AB  - The chlorophyll-carotenoid binding proteins responsible for absorption and
      conversion of light energy in oxygen-evolving photosynthetic organisms belong to
      two extended families: the Chl a binding core complexes common to cyanobacteria
      and all chloroplasts, and the nuclear-encoded light-harvesting antenna complexes
      of eukaryotic photosynthesizers (Chl a/b, Chl a/c, and Chl a proteins). There is
      a general consensus on polypeptide and pigment composition for higher plant
      pigment proteins. These are reviewed and compared with pigment proteins of
      chlorophyte, rhodophyte, and chromophyte algae. Major advances have been the
      determination of the structures of LHCII (major Chl a/b complex of higher
      plants), cyanobacterial Photosystem I, and the peridinen-Chl a protein of
      dinoflagellates to atomic resolution. Better isolation methods, improved
      transformation procedures, and the availability of molecular structure models are
      starting to provide insights into the pathways of energy transfer and the
      macromolecular organization of thylakoid membranes.

PMID- 15012306
TI  - Adaptations in scale insects.
AB  - Many unusual features of scale insects (Hemiptera: Coccoidea) can be explained as
      historical legacy. Developmental specializations in ancestral coccoids resulted
      in a neotenous adult female and a drastic metamorphosis of the male. Subsequent
      evolution led to numerous, often convergently derived, adaptations to parasitic
      life on higher plants. The sedentary lifestyle of female scale insects has
      favored the evolution of appendage reduction or loss, gross changes in body
      shape, and protective wax secretions, tests, and other scale covers.
      Morphological peculiarities of adult males relate to flight or to mating with
      concealed females. Scale insects have diverse egg-protecting methods, a range of
      chromosome behaviors (including several methods of sex determination), marked
      sexual dimorphism [even sometimes in first-instar nymphs (crawlers)], and more
      rarely sexual dichronism. Crawlers have evolved as the main agents of dispersal.
      The biotic interactions of scale insects include diverse endosymbioses with
      microorganisms, sometimes morphological and behavioral adaptations for obligate
      association with ants, and often highly specific host-plant associations that may
      lead to demic adaptation or the evolution of complex galls.

PMID- 15012307
TI  - Ecology and evolution of galling thrips and their allies.
AB  - About 300 species of thrips belonging to 57 genera are known to form galls. Galls
      are caused by feeding, usually by one or more adults, on actively growing plant
      tissue. Most thrips genera with galling capabilities exploit multiple plant
      families, but there are several possible cases of thrips tracking the speciations
      of their host-plants. Gall morphology in thrips reflects insect phylogenetic
      relationships rather than those of plants. Galling species and their nongalling
      allies on Acacia in Australia exhibit a range of complex social behavior,
      including soldier castes, pleometrosis (i.e. joint colony founding), group
      foraging, and group defense, that is directly related to the nature of their
      domiciles. Galling thrips, by virtue of their haplodiploid genetic system and
      their ecological relationships with plants and natural enemies, are useful for
      analyzing a wide range of ecological, evolutionary, and behavioral questions.

PMID- 15012308
TI  - Diptera as parasitoids.
AB  - Parasitoids in the insect order Diptera include an estimated 16,000 species, or
      approximately 20% of the total number of species with this life-style.
      Parasitoids in this order are exceedingly diverse in both their habits and
      evolutionary origins, which makes them an underutilized but highly suitable group
      for quantitative studies of character convergence and adaptive radiation. This
      review focuses on several aspects of the bionomics of dipteran parasitoids that
      have received little comprehensive treatment, including processes associated with
      host location and attack, patterns of host use, and the evolutionary and
      ecological consequences of host-parasitoid interactions. Throughout the review we
      contrast the patterns found within the parasitic Diptera against those found in
      the better studied parasitic Hymenoptera. We conclude that more intensive study
      of dipteran parasitoids is required before we can understand the general
      conditions that favor the evolution of insect parasitoids and the truly
      magnifying themes of their behavior and ecology.

PMID- 15012309
TI  - Wild hosts of Pentatomids: ecological significance and role in their pest status
      on crops.
AB  - Phytophagous stink bugs (Heteroptera: Pentatomidae) are important pests of many
      crops, feeding mostly on seeds and immature fruits. During feeding they introduce
      their stylets to remove the cells' contents. The resulting damage includes drop
      and/or malformation of seeds and fruits. As stink bugs are generally polyphagous,
      they feed on cultivated and uncultivated plants; consequently, wild host plants
      play an important role in the increase in population levels of agricultural pest
      species. These plants are important food resources for development of nymphs and
      reproduction of adults. Because these bugs are multivoltine and feed in general
      on temporarily restricted food plants, host-switching from food plants of nymphs
      to those of adults is common and has varying effects on adult performance
      depending on the quality of the foods involved. Although polyphagous, local
      populations of many pentatomid species may show specific feeding habits,
      restricting their host range to fewer plant species. The knowledge of host plant
      sequences, including cultivated and uncultivated hosts, and the use of wild hosts
      as trap plants will improve management of pest species. Finally, future research
      should focus on determining which plants are preferably used by stink bugs, how
      they affect insect performance, at what rate populations increase on these
      plants, and how effective natural enemies are at this time.

PMID- 15012310
TI  - Behavioral manipulation methods for insect pest-management.
AB  - We discuss methods using stimuli to manipulate behavior of a pest for the purpose
      of protecting a valued resource. The methods are divided into two categories:
      those that manipulate behavior over a long distance, e.g. volatile chemicals,
      visual, and auditory stimuli, and those that manipulate behavior at a short
      distance (<1 cm), e.g. involatile chemicals. Particular emphasis is placed on
      methods that have been developed through studies of pest behavior and on
      combining stimuli to increase efficacy. Future prospects for behavioral
      manipulation methods in pest management are discussed.

PMID- 15012311
TI  - Visual acuity in insects.
AB  - The acuity of compound eyes is determined by interommatidial angles, optical
      quality, and rhabdom dimensions. It is also affected by light levels and speed of
      movement. In insects, interommatidial angles vary from tens of degrees in
      Apterygota, to as little as 0.24 degrees in dragonflies. Resolution better than
      this is not attainable in compound eyes of realistic size. The smaller the
      interommatidial angle the greater the distance at which objects--prey, predators,
      or foliage--can be resolved. Insects with different lifestyles have contrasting
      patterns of interommatidial angle distribution, related to forward flight,
      capture on the wing, and predation on horizontal surfaces.

PMID- 15012312
TI  - Interactions among Scolytid bark beetles, their associated fungi, and live host
      conifers.
AB  - Scolytid bark beetles that colonize living conifers are frequently associated
      with specific fungi that are carried in specialized structures or on the body
      surface. These fungi are introduced into the tree during the attack process. The
      continuing association suggests that there is mutual benefit to the fitness of
      both beetles and fungi. The fungal species may benefit from the association with
      the beetles by transport to new host trees. Beetle species may benefit from the
      association with fungi by feeding on the fungi, or by the fungi contributing to
      the death of the host trees through mycelial penetration of host tissue, toxin
      release, interactions with preformed and induced conifer defenses, or the
      combined action of both beetles and fungi during colonization. Extensive research
      has been directed towards characterizing the interactions of beetle-fungal
      complexes with live host conifers and determining the ecological advantages for
      maintaining the associations. However, differences among systems and how species
      interact under different population and environmental conditions make it
      difficult to generalize about the importance of the separate biological
      components in successful host colonization.

PMID- 15012313
TI  - Physiology and ecology of dispersal polymorphism in insects.
AB  - Studies of dispersal polymorphism in insects have played a pivotal role in
      advancing our understanding of population dynamics, life history evolution, and
      the physiological basis of adaptation. Comparative data on wing-dimorphic insects
      provide the most definitive evidence to date that habitat persistence selects for
      reduced dispersal capability. The increased fecundity of flightless females
      documents that a fitness trade-off exists between flight capability and
      reproduction. However, only recently have studies of nutrient consumption and
      allocation provided unequivocal evidence that this fitness trade-off results from
      a trade-off of internal resources. Recent studies involving wing-dimorphic
      insects document that flight capability imposes reproductive penalties in males
      as well as females. Direct information on hormone titers and their regulation
      implicates juvenile hormone and ecdysone in the control of wing-morph
      determination. However, detailed information is available for only one species,
      and the physiological regulation of wing-morph production remains poorly
      understood. Establishing a link between the ecological factors that influence
      dispersal and the proximate physiological mechanisms regulating dispersal ability
      in the same taxon remains as a key challenge for future research.

PMID- 15012314
TI  - Evolution of arthropod silks.
AB  - Silks belong to the class of molecules called structural proteins. The ability to
      produce silk proteins has evolved multiple times in the arthropods, and silk
      secreting glands have evolved via two different pathways. The comparative data
      and phylogenetic analyses in this review suggest that the silk-secreting systems
      of spiders and insects are homologous and linked to the crural gland (origin of
      systemic pathway to silk production) and cuticular secretions (origin of
      surficial pathway to silk production) of an onychophoran-like ancestor. The
      evolution of silk secreting organs via a surficial pathway is possible in adult
      and larval hexapods, regardless of their developmental mode. Silk secretion via a
      systemic pathway is possible in either adult or larval hexapods, but only larval
      insects have dedicated silk producing glands. Spiders, however, have evolved silk
      producing systems via both systemic pathway and surficial pathways, and a single
      individual retains both throughout its lifespan. Early in the evolution of
      spiders, silk glands were undifferentiated, suggesting that the number of silk
      secreting glands of any individual was related to the spider's energetic need to
      produce large quantities of protein. However, the complex silk-producing systems
      that characterize the aerial web-building spiders and the diverse types of
      proteins they produce suggest that their silks reflect the diverse and increasing
      number of ways in which spiders use them. Because the muscular and innervated
      spinnerets and spigots of spiders allow them to control fiber functional
      properties, silk proteins represent an avenue through which animal behavior may
      directly affect the molecular properties of a protein.

PMID- 15012315
TI  - Insects as teaching tools in primary and secondary education.
AB  - Insects offer a vast array of teaching opportunities for precollege students.
      Here we address the basics teachers need in order to use insects successfully in
      their curricula. We identify exemplary resources in the printed North American
      literature and point out potentially productive places for teachers and students
      to search for ideas and materials. We review the roles of entomology in the
      educational framework, highlight favorite classroom arthropods and less well
      known examples, and guide readers to entomological resources. Tips to help
      teachers identify, rear, and maintain classroom insects and find equipment and
      supplies are included. The review concludes with a plea for greater classroom and
      curricular involvement by those in the entomological profession.

PMID- 15012316
TI  - Life-styles of Phytoseiid mites and their roles in biological control.
AB  - This review categorizes the diversity of life-styles in the Phytoseiidae, based
      primarily on food habits and related biological and morphological traits. The
      life-styles proposed are as follows: Type I, specialized predators of Tetranychus
      species represented by the Phytoseiulus species; Type II, selective predators of
      tetranychid mites (most frequently associated with species that produce dense
      webbing) represented by Galendromus, some Neoseiulus, and a few Typhlodromus
      species; Type III, generalist predators represented by some Neoseiulus species
      and most Typhlodromus and Amblyseius species, as well as species in all other
      genera about which information is available; Type IV, specialized pollen
      feeders/generalist predators represented by Euseius species. Consideration is
      given to the relative importance of each of these types in biological control and
      pest management programs.

PMID- 15012317
TI  - Photoperiodic time measurement and related physiological mechanisms in insects
      and mites.
AB  - For over 60 years, many species of insects and mites have been known to respond
      in an adaptive way to seasonal changes in daylength. Responses to photoperiod
      allow them to survive periods of unfavorable environmental conditions. Since the
      early 1950s, light-sensitive and temperature-compensated circadian clocks have
      also been known to regulate the timing of many events (behavioral, physiological,
      biochemical) in all eukaryotic organisms, including insects and mites. Over the
      past 30 years, considerable effort has been directed at elucidation of the nature
      of the clock mechanism that underlies photoperiodism. Mathematical models using a
      number of insect systems have been developed that attempt to causally relate the
      circadian clock to photoperiodic time measurement. Although some experimental
      evidence supports these circadian-based models, some insects and mites appear to
      utilize a non-periodic hourglass timer as the photoperiodic clock. Future work in
      this field would benefit by following the approach that has proven to be very
      successful in identifying genes and gene products that regulate circadian
      rhythmicity in Drosophila melanogaster.

PMID- 15012318
TI  - Host plant influences on sex pheromone behavior of phytophagous insects.
AB  - The sexual behavior of phytophagous insects is often integrated in a variety of
      ways with their host plants. This integration may be manifested as effects or
      influences of host plants on insect physiology and behavior, including sex
      pheromone communication, that reflect strategies by insects to optimize mating
      and reproduction. Certain insects sequester or otherwise acquire host plant
      compounds and use them as sex pheromones or sex pheromone precursors. Other
      insects produce or release sex pheromones in response to particular host plant
      cues. Chemicals from host plants often synergize or otherwise enhance insect
      responses to sex pheromones. By these means, host plants may be used by insects
      to regulate or mediate sexual communication. For many species of insects, host
      plant influences on insect sex pheromone communication may be important aspects
      of the formation of feeding and mating aggregations, of insect strategies to
      locate both hosts and mates, of behavioral reproductive isolation among sibling
      species, and of the regulation of reproduction to coincide with the availability
      of food and oviposition sites. Knowledge of these relationships is critical to
      understanding many different areas of the behavioral ecology of plant-feeding
      insects.

PMID- 15012319
TI  - Migratory ecology of the black cutworm.
AB  - The long-range migration of insects in general is briefly discussed here and
      serves as an introduction for in-depth inquiry into the migratory ecology of
      Agrotis ipsilon, the black cutworm. Zoogeography, pest status and injury, and
      seasonal occurrence of the species are reviewed. Circumstantial evidence of long
      range movement of A. ipsilon moths within both hemispheres is presented, followed
      by experimental evidence of long-range movement of A. ipsilon moths in China and
      North America. Based upon experimental evidence published by several
      investigators, a theory is proposed of the existence of a thermal range (0-36
      degrees C) for A. ipsilon pupae that acts as the precursor for adult (moth)
      migration. This theory should help explain the circumstantial and empirical
      evidence gathered upon the annual appearance and disappearance of this species
      over large geographic areas.

PMID- 15012320
TI  - Phylogeny of Trichoptera.
AB  - The vitality of the phylogenetic dialogue in trichopterology, especially since
      1967, is evidenced by the high quality and large number of published phylogenetic
      inferences concerning caddisflies and the continuing spirited exchange of
      opinions about some differences among those ideas. Monophyly for Trichoptera
      seems well argued. Monophyly for suborder Annulipalpia sensu stricto also is
      widely acknowledged, as is monophyly for suborder Integripalpia sensu stricto.
      Various postulated relationships of Hydrobiosidae, Rhyacophilidae,
      Glossosomatidae, and Hydroptilidae (="Spicipalpia") are less convincing.
      Phylogenies for several groups of families within Annulipalpia and Integripalpia
      have been proposed and relationships within at least 126 intrafamilial taxa also
      have been inferred.

PMID- 15012321
TI  - Behavior and ecological genetics of wind-borne migration by insects.
AB  - Wind-borne migration, in which migrants ascend to altitudes at which they are
      transported downwind, has evolved independently in several insect orders. The use
      of a range of observational techniques, including ground and air-borne radars,
      has provided new insights into how the migrants' behavior can influence the
      distance traveled and the degree of dispersal during migration. Simultaneously in
      recent years, advances in our knowledge of the genetics of migratory potential
      have provided a basis for understanding how the stochastic effects of the winds
      on destinations and the pattern of habitat distribution in space and time
      maintain variation in these traits in populations of wind-borne migrants. This
      variation, in turn, is an essential factor in the ability of these insects, many
      of which are important pests, to track often unpredictable changes in the spatial
      distribution of suitable habitats.

PMID- 15012322
TI  - Peritrophic matrix structure and function.
AB  - Formed of proteins, glycoproteins, and chitin microfibrils in a proteoglycan
      matrix, the peritrophic matrix (PM) separates the food from the midgut epithelium
      in most but not all insects. A PM occurs in two forms. A type I PM is delaminated
      from the entire midgut epithelium and, in some cases, may only be formed in
      response to feeding and the type of meal ingested. A type II PM is produced by a
      specialized region of the anterior midgut called the cardia and forms a
      continuous sleeve (or sleeves) that is always present. As it is positioned
      between food and midgut epithelium, the PM plays key roles in the intestinal
      biology of the insect. The PM may protect the midgut epithelium from mechanical
      damage and insult from pathogens and toxins; it must act as a semipermeable
      membrane regulating passage of molecules between the different midgut
      compartments; and it may separate the midgut lumen into different,
      physiologically significant compartments.

PMID- 15012323
TI  - Biology of Wolbachia.
AB  - Wolbachia are a common and widespread group of bacteria found in reproductive
      tissues of arthropods. These bacteria are transmitted through the cytoplasm of
      eggs and have evolved various mechanisms for manipulating reproduction of their
      hosts, including induction of reproductive incompatibility, parthenogenesis, and
      feminization. Wolbachia are also transmitted horizontally between arthropod
      species. Significant recent advances have been made in the study of these
      interesting microorganisms. In this paper, Wolbachia biology is reviewed,
      including their phylogeny and distribution, mechanisms of action, population
      biology and evolution, and biological control implications. Potential directions
      for future research are also discussed.

PMID- 15012324
TI  - Insect pests of beans in Africa: their ecology and management.
AB  - Damage by insect pests, inter alia, is considered the limiting factor of bean
      production in Africa. This paper reviews the current status of insect pests of
      beans, focusing on their ecology and management, as well as the potential for
      integrated pest management (IPM) approaches in subsistence farming conditions,
      under which most beans are grown in Africa. Although numerous insect pests attack
      all parts of beans, bean stem maggots and bruchids are the most important field
      and storage pests, respectively. Foliage beetles, flower thrips, pollen beetles,
      pod borers, pod bugs, and sap suckers such as aphids also inflict significant
      damage. Control of bean pests in Africa is achieved through the use of a
      traditional IPM approach that consists of appropriate sowing dates, optimum plant
      density, varietal mixtures, intercropping, good crop husbandry, and locally
      available materials. Research should focus on low-input IPM approaches that
      encompass farmers' current practices, host-plant resistance, and natural
      biological control.

PMID- 15012325
TI  - Ecology of insect communities in nontidal wetlands.
AB  - Published research about wetland insects has proliferated, and a conceptual
      foundation about how wetland insect populations and communities are regulated is
      being built. Here we review and synthesize this new body of work. Our review
      begins with a summary of insect communities found in diverse wetland types,
      marshes, forested floodplains, and peatlands. Next, we critically discuss
      research on the population and community ecology of wetland insects, including
      the importance of colonization strategies and insect interactions with the
      physical environment, plants, predators, and competitors. Results from many of
      the experimental studies that we review indicate that some commonly held beliefs
      about wetland insect ecology require significant reevaluation. We then discuss
      the importance of wetland insect ecology for some applied concerns such as
      efforts to manage wetland insect resources as waterfowl food and development of
      ecologically sound strategies to control pest mosquitoes. We conclude with a
      discussion of wetland conservation, emphasizing insect aspects.

PMID- 15012326
TI  - Living on leaves: mites, tomenta, and leaf domatia.
AB  - Structures on the surfaces of leaves strongly affect phylloplane mites. Glandular
      trichomes defend against some plant parasites but can also mire predators.
      However, leaves with tomenta of nonglandular trichomes are often inhabited by
      large populations of predatory mites. Tufts of hairs and other minute structures
      in the vein axils are called leaf domatia. Comparative observations and
      experimental data demonstrate that leaves with domatia have enhanced levels of
      predatory mites. By accumulating predatory mites, leaf domatia act as a kind of
      constitutive defense against herbivores. Mites benefit from leaf domatia by
      securing a safe place for oviposition and molting. Like several other plant
      structures, leaf domatia are the manifestation of a long-term and mutually
      beneficial interaction between plants and arthropods.

PMID- 15012327
TI  - The role of macroinvertebrates in stream ecosystem function.
AB  - This review focuses on some of the roles of macroinvertebrate functional groups,
      i.e. grazers, shredders, gatherers, filterers, and predators, in stream-ecosystem
      processes. Many stream-dwelling insects exploit the physical characteristics of
      streams to obtain their foods. As consumers at intermediate trophic levels,
      macroinvertebrates are influenced by both bottom-up and top-down forces in
      streams and serve as the conduits by which these effects are propagated.
      Macroinvertebrates can have can important influence on nutrient cycles, primary
      productivity, decomposition, and translocation of materials. Interactions among
      macroinvertebrates and their food resources vary among functional groups.
      Macroinvertebrates constitute an important source of food for numerous fish, and
      unless outside energy subsidies are greater than in-stream food resources for
      fish, effective fisheries management must account for fish-invertebrate linkages
      and macroinvertebrate linkages with resources and habitats. Macroinvertebrates
      also serve as valuable indicators of stream degradation. The many roles performed
      by stream-dwelling macroinvertebrates underscore the importance of their
      conservation.

PMID- 15012328
TI  - Sexual selection in relation to pest-management strategies.
AB  - The application of principles derived from the sexual selection literature can
      assist attempts to subvert the normal mating behavior of pests. Sexual selection
      encompasses both intermale competition for access to females and female choice of
      mates. It can operate during long-range attraction and short-range courtship, as
      well as after copulation. We review the major aspects of sexual selection and
      illustrate their application to pheromonal and SIT pest-management programs.
      Pheromones are important both in long-range attraction and in close-range mate
      choice; parapheromones may be very useful in pest management because of their
      influence on male mating success. Sexual selection theory provides a scheme for
      studying the normal mating behavior of a pest species and thus determining which
      attributes of the mass-reared sterile males are critical to their success with
      wild females. We hope that our review will suggest novel ways of attacking pests
      as well as encourage behavioral ecologists to study pest species.

PMID- 15012329
TI  - Ecology and behavior of ground beetles (Coleoptera: Carabidae).
AB  - The ground beetles from the speciose beetle family Carabidae and, since their
      emergence in the Tertiary, have populated all habitats except deserts. Our
      knowledge about carabids is biased toward species living in north-temperate
      regions. Most carabids are predatory, consume a wide range of food types, and
      experience food shortages in the field. Feeding on both plant and animal material
      and scavenging are probably more significant than currently acknowledged. The
      most important mortality sources are abiotic factors and predators; pathogens and
      parasites can be important for some developmental stages. Although competition
      among larvae and adults does occur, the importance of competition as a community
      organization is not proven. Carabids are abundant in agricultural fields all over
      the world and may be important natural enemies of agricultural pests.

PMID- 15012330
TI  - Floral resource utilization by solitary bees (Hymenoptera: Apoidea) and
      exploitation of their stored foods by natural enemies.
AB  - Bees are phytophagous insects that exhibit recurrent ecological specializations
      related to factors generally different from those discussed for other
      phytophagous insects. Pollen specialists have undergone extensive radiations, and
      specialization is not always a derived state. Floral host associations are
      conserved in some bee lineages. In others, various species specialize on
      different host plants that are phenotypically similar in presenting predictably
      abundant floral resources. The nesting of solitary bees in localized areas
      influences the intensity of interactions with enemies and competitors. Abiotic
      factors do not always explain the intraspecific variation in the spatial
      distribution of solitary bees. Foods stored by bees attract many natural enemies,
      which may shape diverse facets of nesting and foraging behavior. Parasitism has
      evolved repeatedly in some, but not all, bee lineages. Available evidence
      suggests that cleptoparasitic lineages are most speciose in temperate zones.
      Female parasites frequently have a suite of characters that can be described as a
      masculinized feminine form. The evolution of resource specialization (including
      parasitism) in bees presents excellent opportunities to investigate phenotypic
      mechanisms responsible for evolutionary change.

PMID- 15012331
TI  - Predatory behavior of jumping spiders.
AB  - Salticids, the largest family of spiders, have unique eyes, acute vision, and
      elaborate vision-mediated predatory behavior, which is more pronounced than in
      any other spider group. Diverse predatory strategies have evolved, including
      araneophagy, aggressive mimicry, myrmicophagy, and prey-specific prey-catching
      behavior. Salticids are also distinctive for development of behavioral
      flexibility, including conditional predatory strategies, the use of trial-and
      error to solve predatory problems, and the undertaking of detours to reach prey.
      Predatory behavior of araneophagic salticids has undergone local adaptation to
      local prey, and there is evidence of predator-prey coevolution. Trade-offs
      between mating and predatory strategies appear to be important in ant-mimicking
      and araneophagic species.

PMID- 15012332
TI  - Geographic structure of insect populations: gene flow, phylogeography, and their
      uses.
AB  - Geographic structure of populations is a fundamental component of ecology and
      evolution that combines both demographic and genetic processes, such as gene flow
      and migration, genetic drift, selection, and population extinction. Recent
      advances in both molecular biology and theory have revolutionized the field and
      have not only expanded the availability of data but also facilitated the
      accessibility and interpretation of current data. These new techniques allow
      analysis of genetic similarity among populations to be coupled with
      phylogeography and the distribution of genotypes within and among populations
      relative to the history of those genotypes. The numerous case studies described
      herein illustrate the growing impact of geographic structure on insect science,
      as well as the importance of insect model systems for understanding general
      concepts in ecology and evolution.

PMID- 15012333
TI  - Semiochemical parsimony in the Arthropoda.
AB  - A wide variety of arthropods have adapted their own semiochemicals to subserve
      multiple functions in diverse contexts. Semiochemicals, the pheromones and
      allomones, have been detected in arthropod species in six orders, and it has been
      clearly established that these compounds are used with great parsimony. The
      versatility of these invertebrates in using these natural products for an
      incredible diversity of functions emphasizes the significance of semiochemicals
      in the evolutionary biology of Arthropoda. Multifunctional pheromones have proved
      to be especially characteristic of the queens of eusocial species. Compounds such
      as the queen substance of the honey bee, Apis mellifera, possess unrelated primer
      and releaser functions for the workers and act as a sex attractant for drones.
      Females of other hymenopterous species exploit the secretions of sting-associated
      glands as sex pheromones, whereas a variety of nonhymenopterous species have
      adapted components in diverse defensive secretions to function as sex pheromones.
      The alarm pheromones of many arthropods are also used as defensive allomones,
      activity inhibitors, cryptic alarm pheromones, aggregative attractants, robbing
      agents, digging agents, trail pheromones, and antimicrobial agents. Defensive
      allomones also possess some of these parsimonious roles; in addition, however,
      some of these compounds possess highly distinctive roles, such as functioning as
      lethal attractants for prey, or, in he aquatic milieu, cuticular wetting agents.
      Clearly, the availability of a variety of pheromones and allomones has enabled
      arthropods to evolve an elegant semiochemical parsimony with which to exploit the
      biological milieu.

PMID- 15012334
TI  - Biological control with Trichogramma: advances, successes, and potential of their
      use.
AB  - Major contributions to the release of Trichogramma for biological control of
      lepidopterous pests have been made in the past 20 years. Most trials have used
      only five species of Trichogramma against two pests; Ostrinia in corn is
      considered the most universally feasible. All Trichogramma programs must address
      the following four aspects to be successful commercially. Selection of the
      appropriate population is based on inter- and intraspecific variation, as well as
      on current definitions of parasitoid quality. Mass rearing is comprised of both
      host and parasitoid components, although major emphasis is now on developing
      artificial systems. Effective distribution of Trichogramma requires supportive
      extension and advanced technology. Strategies for use in the field vary according
      to the approach desired (inundative or inoculative), the timing, frequency and
      rate of release, and the multiple factors that affect release, such as the
      weather, crop, host, predation, pesticides, and dispersal. The past difficulty in
      assessing the efficacy of Trichogramma should be improved with new guidelines for
      standardizing terminology and measurements.

PMID- 15012335
TI  - The role of nourishment in oogenesis.
AB  - Oogenesis in insects is typically a nutrient-limited process, triggered only if
      sufficient nourishment is available. This nourishment can be acquired during the
      larval or adult stage, depending on the insect. Timing of food intake will have
      major effects on mechanisms of hormonal control. When nourishment for eggs is
      taken primarily by adults, insufficient nutrition inhibits egg development
      through mechanisms such as inhibition of corpora allata, as seen in Orthoptera
      and Blattaria. In adult Diptera, lack of protein inhibits release of brain
      factors that produce reproductive competency or ovarian stimulation. Lepidoptera
      have been characterized as lacking substantial regulation of oogenesis because
      egg development is underway at emergence. Many species for which ecological data
      are available do not mobilize reserves carried over from the larval stage until
      they feed as adults. The endocrine mechanisms underlying these systems are poorly
      understood. In many insects, mating and activity can affect nutritional state and
      therefore oogenesis. Mating can stimulate oogenesis through mobilization of
      reserves or through nutritional contributions by males to females. Activity,
      especially flight, and oogenesis can compete for energy. The flight apparatus,
      especially the muscle, can also compete with oogenesis for protein. Social
      insects exhibit extreme specializations in oogenesis; females range in fertility
      from completely sterile to hyperfecund. Food flow within colonies is a major
      factor regulating fecundity. Finally, maternal nourishment is not needed for
      oogenesis in parasitoids and pseudoplacental viviparous insects, which produce
      eggs with little or no yolk. Virtually nothing is known about the endocrine
      regulation of oogenesis on these insects.

PMID- 15012336
TI  - Tympanal hearing in insects.
AB  - Specialized hearing organs, known as tympanal organs, have evolved in at least
      seven different orders of insects. Tympanal organs are usually defined by the
      presence of a tympanal membrane (or eardrum). They are backed by an air-filled
      space or cavity and are innervated by a chordotonal sensory organ. In some
      insects, however, a recognizable tympanal membrane may not be easily identified
      by visual inspection, yet may possess tympanal hearing organs. In insects that
      possess them, tympanal hearing organs may mediate the detection of predators,
      prey, and potential mates and rivals. Unlike the ears of vertebrates, which are
      localized to cranial segments, the ears of insects may be found in a bewildering
      variety of locations on their bodies, depending on the species. The embryological
      and evolutionary origins of tympanal organs are related to ancestral states as
      proprioceptive chordotonal organs.

PMID- 15012337
TI  - Bacillus sphaericus toxins: molecular biology and mode of action.
AB  - Bacillus sphaericus is a spore-forming aerobic bacterium, several strains of
      which are pathogenic for mosquito larvae. During sporulation, the most active
      strains produce a crystal toxin with a high degree of larvicidal activity. The
      toxin is composed of two proteins of 51.4 and 41.9 kDa, which are encoded by
      highly conserved chromosomal genes. After B. sphaericus is ingested, these
      proteins are released in the larva's midgut, and, in susceptible mosquito
      species, bind to a specific receptor present on midgut brush-border membranes.
      The resulting damages to the midgut cells leads to the mosquitoes' death. During
      vegetative growth, some B. sphaericus strains also synthesize mosquito larvicidal
      proteins of 100 and 30.8 kDa (Mtx toxins), the mode of action of which is still
      unknown. The mechanism of acquisition of the recessive mosquito resistance to the
      crystal toxin varies with selection conditions.

PMID- 15012338
TI  - Sexual receptivity in insects.
AB  - Sexual receptivity is female behavior that allows or helps a male to fertilize
      her eggs; through this behavior, females play an active role in reproduction.
      Multiple signals may be used for receptivity or unreceptivity. Insect species
      exhibit three ontogenetic patterns of receptivity: cyclic, in which females
      alternately become receptive and unreceptive; brief, in which females mate during
      on short developmental period; and continuous. Primary (initial) receptivity may
      be stimulated or inhibited by diet, ovarian development, or juvenile hormone. In
      species with cyclic receptivity, remating may be inhibited by copulation itself,
      the presence of eggs, sperm stored in spermathecae, or seminal factors--usually
      peptides--secreted by the male accessory glands. In many species, there is
      substantial genetic variation for both primary receptivity and speed of remating.
      Several single-gene mutations reduce female receptivity; most of these mutations
      also impair sensory functioning.

PMID- 15012369
TI  - Mites in forest canopies: filling the size distribution shortfall?
AB  - Although often unobserved or ignored, mites usually exceed all other arthropods
      in abundance in forest canopies. Second in species richness only to canopy
      insects, the arboreal acarofauna is composed of multiple lineages of predators,
      scavengers, grazers, animal associates, and plant parasites that each have
      radiated extensively in canopy habitats. The canopy fauna is largely
      complementary to the mite fauna of the forest floor, suggesting that estimates of
      more than one million living species of mites are not extreme. Most mites are
      less than a millimeter in length as adults, and canopy mites tend to be smaller
      than species from other habitats. Even among mites, however, very small species
      are relatively rare, and diversity increases with decreasing size only to the
      penultimate size class (0.316-1 mm). This pattern may be explained by declines in
      microhabitat diversity or host specificity as the limit of body size in a group
      of organisms is approached.

PMID- 15012370
TI  - Insect pests of pigeonpea and their management.
AB  - Pigeonpea (Cajanus cajan) is an important crop in semi-arid tropical and
      subtropical farming systems, providing high quality vegetable protein, animal
      feed, and firewood. Insect pests feeding on flowers, pods, and seeds are the most
      important biotic constraint affecting pigeonpea yields. This review summarizes
      the biology and ecology of the three most important groups of pests: flower- and
      pod-feeding Lepidoptera, pod-sucking Hemiptera, and seed-feeding Diptera and
      Hymenoptera. Recent research investigating the complex interactions among
      pigeonpea, its key pests, and their natural enemies is also reviewed. These
      relationships have implications on the pest status of individual species and on
      possible control strategies. Pigeonpea pest management research has focused until
      recently on the identification and development of resistant cultivars and on
      chemical control. Future research must focus on environmentally sound pest
      management strategies that are compatible with the needs and limitations of
      pigeonpea farmers. Several priority areas for research are suggested.

PMID- 15012371
TI  - The role of stingless bees in crop pollination.
AB  - Stingless bees (Apidae: Meliponini) are common visitors to flowering plants in
      the tropics, but evidence for their importance and effectiveness as crop
      pollinators is lacking for most plant species. They are known to visit the
      flowers of approximately 90 crop species. They were confirmed to be effective and
      important pollinators of 9 species. They may make a contribution to the
      pollination of approximately 60 other species, but there is insufficient
      information to determine their overall effectiveness or importance. They have
      been recorded from another 20 crops, but other evidence suggests that they do not
      have an important role because these plants are pollinated by other means. The
      strengths and limitations of stingless bees as crop pollinators are discussed.
      Aspects of their biology that impact on their potential for crop pollination are
      reviewed, including generalized flower visiting behavior of colonies, floral
      constancy of individual bees, flight range, and the importance of natural
      vegetation for maintaining local populations.

PMID- 15012372
TI  - Bionomics of the Anthocoridae.
AB  - The family Anthocoridae (Hemiptera:Heteroptera) contains between 400 and 600
      species distributed worldwide, chiefly on the continents but also on oceanic
      islands. They are small (1.4-4.5 mm) and common to a wide variety of habitats.
      Many are found in cryptic habitats such as galls, several widespread genera are
      surface feeders on small arthropods (Anthocoris, Orius, and Tetraphleps), and
      others can be found in ant nests and, especially, under bark. Wing polymorphism
      is common in this family, often associated with the cryptic habit. Most known
      species are predaceous, though some take plant food as well (e.g. Orius
      insidiosus, Orius pallidicornis). A few of these are believed to be entirely
      phytophagous (Paratriphleps laeviusculus). Their small size and often generalized
      feeding habits have resulted in about 30 introduced species, mostly accidental. A
      few have been introduced deliberately as biological control agents (Anthocoris
      spp., Montandoniola moraguesi, O. insidiosus, Orius tristicolor, and Tetraphleps
      spp.). Most nonindigenous species seem to have been distributed as a result of
      human activities, especially commerce. The predaceous habits of many Anthocoridae
      have attracted the attention of researchers who work in agroecosystems.
      Integrated pest management programs often include these predators, which has
      given us greater knowledge about these species than those found in natural
      ecosystems. Exciting discoveries about the attractiveness to these bugs of
      certain volatile plant and arthropod compounds are opening new areas of
      investigation into their chemical ecology. The reactions of these tiny predators
      will surely become better understood as a result.

PMID- 15012373
TI  - Adaptive strategies of edaphic arthropods.
AB  - For those arthropod species adapted for living below the soil surface, the soil
      is a refuge from the biotic and abiotic perturbations existing above ground.
      Convergent morphological, physiological, and behavioral adaptations of epedaphic,
      euedaphic, and hemiedaphic arthropods to selective aspects of subterranean
      existence are examined in light of overlapping ecological niches. The abiotic
      impact of the soil environment and its relationship to arthropod evolution,
      radiation, and ecology are discussed as well. Specific areas addressed include
      the invasion of land by marine arthropods, the impact of morphology on arthropod
      mobility, osmoregulatory/respiratory systems, and defensive strategies.

PMID- 15012374
TI  - Assessment of the application of baculoviruses for control of Lepidoptera.
AB  - Baculoviruses, among other insect viruses, are regarded as safe and selective
      bioinsecticides, restricted to invertebrates. They have been used worldwide
      against many insect pests, mainly Lepidoptera. Their application as microbial
      pesticides, however, has not met their potential to control pests in crops,
      forests, and pastures, with the exception of the nuclear polyhedrosis virus of
      the soybean caterpillar (Anticarsia gemmatalis), which is used on approximately 1
      million ha annually in Brazil. Problems that have limited expansion of
      baculovirus use include narrow host range, slow killing speed, technical and
      economical difficulties for in vitro commercial production, timing of application
      based on frequent host population monitoring, variability of field efficacy due
      to climatic conditions, and farmers' attitudes toward pest control, which have
      been based on application of fast-killing chemical insecticides. Farmer education
      regarding use of biological insecticides and their characteristics is considered
      one of the major actions necessary for increased use of baculoviruses. Strategies
      to counteract some of the limitations of baculoviruses, especially their slow
      killing activity, have been investigated and are promising. These include the use
      of chemical or biological substances added to virus formulations and genetic
      engineering of the viruses themselves to express insect toxins or hormones. Such
      strategies can enhance viral activity and increase speed of kill as well as
      reduce larval feeding activity. The use of baculoviruses against Lepidoptera is
      reviewed, with the utilization of the nuclear polyhedrosis virus of A. gemmatalis
      in Brazil serving as a case-study.

PMID- 15012375
TI  - Hyperparasitism: multitrophic ecology and behavior.
AB  - Hyperparasitoids are secondary insect parasitoids that develop at the expense of
      a primary parasitoid, thereby representing a highly evolved fourth trophic level.
      This review evaluates multitrophic relationships and hyperparasitoid ecology.
      First, hyperparasitoid communities of various taxa of phytophagous and predacious
      insects are described. Second, specific patterns of hyperparasitoid community
      organization and hyperparasitoid ecology are described in detail, using the aphid
      parasitoid-hyperparasitoid food web as a model system. Aphid hyperparasitoid
      communities consist of ecto- and endohyperparasitoids, with ectohyperparasitoids
      being less host specific than endohyperparasitoids. Lifetime fecundity and
      intrinsic rate of increase of hyperparasitoids are generally lower than those of
      their primary hosts. Aphid ectohyperparasitoids search randomly for hosts and do
      not use specific cues, whereas endohyperparasitoids gain information that
      originates from host plants or hosts for long-range search. Interactions with
      adult primary parasitoids do not influence hyperparasitoid searches, but aphid
      attending ants typically prevent successful hyperparasitoid foraging. Impact of
      hyperparasitism on biological control is reviewed.

PMID- 15012376
TI  - Density-dependent physiological phase in insects.
AB  - Insects respond to crowding in a variety of ways that are usually exemplified by
      rapid changes in behavior and culminate in enduring long-term morphological
      and/or chromatic responses. A common feature of both short-term and long-term
      effects is that they are graded, dependent not only on density but also on the
      duration and on phase history of the maternal generation. Because of their
      exoskeletons, which are persistent for the duration of each instar and endure
      throughout adult life, overt changes in morphology or coloration are restricted
      to the molting period and shortly afterward, when cuticular hardening and
      pigmentation are expressed. Changes in internal organs or metabolism elicited by
      population density, being independent of integumental constraints, are not
      restricted to the molting period, but the temporal difference between internal
      and external responses is not of fundamental significance. Intraspecific
      responses to the presence of sibling insects are of apparent ecological
      significance and often involve directional movement and/or migration. They are
      mediated via the sensory system, involve signal transduction, and elicit
      downstream biochemical and physiological changes.

PMID- 15012377
TI  - Mate choice in tree crickets and their kin.
AB  - Mate choice theory has become a major field of research in behavioral ecology.
      Tree crickets provide excellent opportunities for studying the diversity and
      variability of mate choice. The evidence for female mate choice in tree crickets
      is reviewed, and broad comparisons with other orthopteran groups are made. The
      evidence shows that female choice may occur during several different stages of
      mating and may target several different criteria. Song preferences are perhaps
      dominated by stabilizing preferences for the cues of species recognition, but
      there is a growing body of evidence for directional preferences based on sensory
      biases or mate quality. Mate rejection during courtship and forms of
      postcopulatory choice may favor males, based both on phenotypic quality and on
      the amount of nutritious courtship gifts they provide, and may differ with the
      value of mating incentives. Understanding the balance and trade-offs between
      different forms of mate choice may help in understanding their evolutionary
      causes.

PMID- 15012378
TI  - Congruence and controversy: toward a higher-level phylogeny of Diptera.
AB  - The order Diptera (true flies) is one of the most species-rich and ecologically
      diverse clades of insects. The order probably arose in the Permian, and the main
      lineages of flies were present in the Triassic. A novel recent proposal suggests
      that Strepsiptera are the sister-order to Diptera. Within Diptera, evidence is
      convincing for the monophyly of Culicomorpha, Blephariceromorpha, and
      Tipulomorpha but weak for the monophyly of the other basal infraorders and for
      the relationships among them. The lower Diptera (Nematocera) is paraphyletic with
      respect to Brachycera, and morphological evidence suggests the sister-group of
      Brachycera lies in the Psychodomorpha. Recent analyses suggest Tipulomorpha are
      closer to the base of Brachycera than to the base of Diptera. Brachycera are
      undoubtedly monophyletic, but relationships between the basal lineages of this
      group are poorly understood. The monophyly of Stratiomyomorpha, Xylophagomorpha,
      Tabanomorpha, and Muscomorpha is well supported. Eremoneura, and its constituent
      clades Empidoidea and Cyclorrhapha, are monophyletic. The sister-group of
      Eremoneura is likely to be part or all of Asiloidea. Several viewpoints on the
      homology of the male genitalia of eremoneuran flies are discussed. Phylogenetic
      analyses suggest that lower Cyclorrhapha (Aschiza) are paraphyletic; however,
      schizophoran monophyly is well supported. The monophyly of Acalyptratae is not
      well-founded and the relationships between acalyptrate superfamilies remain
      obscure. Recent advances document the monophyly of the families of Calyptratae
      and the relationships among them. Areas critical to future advances in
      understanding dipteran phylogeny include the relationships among the basal
      infraorders of Diptera and Brachycera and the relationships between the
      superfamilies of acalyptrates. Progress in dipteran phylogenetics will accelerate
      with the exploration of novel data sources and the formulation of hypotheses in
      an explicitly quantitative framework.

PMID- 15012379
TI  - Management of plant viral diseases through chemical control of insect vectors.
AB  - In this article we consider the role of epidemiological factors and transmission
      processes of insect-vectored viruses on the effectiveness of insecticides in a
      disease management program. We also discuss the use of insecticides within the
      broader framework of the chemical environment surrounding vectors, and how
      chemical-induced alterations in the behavior of vectors can influence
      transmission. Our analysis confirms the belief of Heathcote, who stated in 1973,
      that "no one method of control is likely to keep crops entirely free from virus
      infection and as many preventative measures should be taken as are economically
      justified."

PMID- 15012380
TI  - Influence of the larval host plant on reproductive strategies of cerambycid
      beetles.
AB  - This investigation into the natural history and behavior of 81 species of
      cerambycid beetles suggests that reproductive behavior is correlated with the
      condition of the larval host: Adults of species whose larvae attack living trees
      tend to show behavioral differences from those that attack dying or dead hosts.
      Behavioral differences among species that are associated with larval host
      condition include: (a) choice of adult food source and whether adults feed at
      all; (b) mechanisms of mate location and the role of long-range pheromones; (c)
      vagility and dispersal behaviors of adults; (d) location of the mating site; and
      (e) duration of copulation.

PMID- 15012381
TI  - Risk-spreading and bet-hedging in insect population biology.
AB  - In evolutionary ecology, risk-spreading (i.e. bet-hedging) is the idea that
      unpredictably variable environments favor genotypes with lower variance in
      fitness at the cost of lower arithmetic mean fitness. Variance in fitness can be
      reduced by physiology or behavior that spreads risk of encountering an
      unfavorable environment over time or space. Such risk-spreading can be achieved
      by a single phenotype that avoids risks (conservative risk-spreading) or by
      phenotypic variation expressed by a single genotype (diversified risk-spreading).
      Across these categories, three types of risk-spreading can be usefully
      distinguished: temporal, metapopulation, and within-generation. Theory suggests
      that temporal and metapopulation risk-spreading may work under a broad range of
      population sizes, but within-generation risk-spreading appears to work only when
      populations are small. Although genetic polymorphisms have sometimes been treated
      as risk-spreading, the underlying mechanisms are different, and they often
      require different conditions for their evolution and thus are better treated
      separately. I review the types of evidence that could be used to test for risk
      spreading and discuss evidence for risk-spreading in facultative diapause,
      migration polyphenism, spatial distribution of oviposition, egg size, and other
      miscellaneous traits. Although risk-spreading theory is voluminous and well
      developed in some ways, rarely has it been used to generate detailed, testable
      hypotheses about the evolution of risk-spreading. Furthermore, although there is
      evidence for risk-spreading, particularly in facultative diapause, I have been
      unable to find any definitive tests with unequivocal results showing that risk
      spreading has been a major factor in the evolution of insect behaviors or life
      histories. To advance our understanding of risk-spreading in the wild, we need
      (a) explicit empirical models that predict levels of diversifying risk-spreading
      for several insect populations in several environments that vary in uncertainty,
      and (b) tests of these models using measurements of phenotypes and their
      fitnesses over several generations in each environment.

PMID- 15012382
TI  - Nutrition and culture of entomophagous insects.
AB  - This article reviews the current state of knowledge concerning the nutrition of
      entomophagous insects and other arthropods. Early nutritional investigations
      focused principally on the basic dietary and nutritional requirements for
      beneficial insects. Based on these findings, the first attempts were made to
      develop mass culture methods and to formulate artificial diets that would allow
      rearing of parasitoids and predators in the absence of host or prey, as well as
      the latter's food sources. Although limited success was achieved, these studies
      established the nutritional foundation for later advances. Recently, attention
      has focused on the interaction between nutrition, physiology, behavior, and
      ecology of the different life stages of entomophagous species within a unified
      concept of nutritional ecology. This approach has resulted in more comprehensive
      understanding of nutrition, which in turn has facilitated the continuous
      artificial culture of several parasites and predators. Additional studies have
      confirmed the importance of supplemental feeding of the adult stages of
      beneficial insects for maximizing reproduction and longevity. Applications of
      nutritional ecology to biological control are discussed.

PMID- 15012383
TI  - Nutritional interactions in insect-microbial symbioses: aphids and their
      symbiotic bacteria Buchnera.
AB  - Most aphids possess intracellular bacteria of the genus Buchnera. The bacteria
      are transmitted vertically via the aphid ovary, and the association is obligate
      for both partners: Bacteria-free aphids grow poorly and produce few or no
      offspring, and Buchnera are both unknown apart from aphids and apparently
      unculturable. The symbiosis has a nutritional basis. Specifically, bacterial
      provisioning of essential amino acids has been demonstrated. Nitrogen recycling,
      however, is not quantitatively important to the nutrition of aphid species
      studied, and there is strong evidence against bacterial involvement in the lipid
      and sterol nutrition of aphids. Buchnera have been implicated in various non
      nutritional functions. Of these, just one has strong experimental support:
      promotion of aphid transmission of circulative viruses. It is argued that strong
      parallels may exist between the nutritional interactions (including the
      underlying mechanisms) in the aphid-Buchnera association and other insect
      symbioses with intracellular microorganisms.

PMID- 15012384
TI  - Chemical ecology of phytophagous scarab beetles.
AB  - Sex pheromones have been characterized only for species in the subfamilies
      Rutelinae and Melolonthinae; aggregation pheromones have been identified for two
      species in the Dynastinae. Melolonthines utilize mainly amino acid derivatives
      and terpenoid compounds, but sex pheromones of rutelines are fatty acid
      derivatives. Various other species utilize japonilure-type lactones that are
      produced by desaturation of fatty acids, followed by hydroxylation, chain
      shortening, and cyclization. In marked contrast to melolonthine sex pheromone
      glands that are everted from the abdominal tip, ruteline sex pheromone glands
      consist of epithelial cells that line the inner surfaces of the pygidium and two
      apical sternites. Some species that are geographically and/or seasonally isolated
      utilize the same sex pheromone system, but chirality plays an important role in
      the isolation of the communication channels of two ruteline species, where one
      enantiomer is utilized as sex pheromone and the other is a behavioral antagonist.
      Olfactory receptor neurons (ORNs) are specifically tuned to these enantiomeric
      pheromones. It is unlikely that the specificity of these ORNs is achieved only by
      odorant-binding proteins. Pheromone-degrading enzymes are present in scarab
      beetle antennae and show considerable substrate specificity.

PMID- 15012385
TI  - Life on the edge: insect ecology in arctic environments.
AB  - The restricted Arctic insect fauna is usually explained by a lack of
      recolonization since the last glacial period, inadequate supply of suitable
      resources, or insufficient adaptation to such a harsh environment. These
      hypotheses and others that attempt to explain the latitudinal gradient of species
      distributions and abundance are reviewed. Arctic habitats available to insects
      are strongly heterogeneous, requiring a similarly diverse array of adaptive
      responses, characteristic of those species that have colonized and survived in
      such a stressful climate. Important adaptations in morphology (size, wings),
      behavior (activity patterns, thermoregulation), life cycles, and ecophysiology
      (cold hardiness, anaerobiosis, desiccation resistance) are discussed. The current
      focus of global climate change research on polar regions is identified,
      particularly the opportunity to study fundamental ecological processes and
      spatial dynamics in the relatively simple Arctic ecosystems.

PMID- 15012386
TI  - Fire and insects in northern and boreal forest ecosystems of North America.
AB  - Fire and insects are natural disturbance agents in many forest ecosystems, often
      interacting to affect succession, nutrient cycling, and forest species
      composition. We review literature pertaining to effects of fire-insect
      interactions on ecological succession, use of prescribed fire for insect pest
      control, and effects of fire on insect diversity from northern and boreal forests
      in North America. Fire suppression policies implemented in the early 1900s have
      resulted in profound changes in forest species composition and structure.
      Associated with these changes was an increased vulnerability of forest stands to
      damage during outbreaks of defoliating insects. Information about the roles that
      both fire and insects play in many northern forests is needed to increase our
      understanding of the ecology of these systems and to develop sound management
      policies.

PMID- 15012387
TI  - Indirect sperm transfer in arthropods: behavioral and evolutionary trends.
AB  - Arachnids, myriapods, and wingless hexapods exhibit a fascinating diversity of
      sperm transfer behaviors. Modes of sperm transfer can be categorized by the
      degree of contact between male and female during transfer, with direct transfer
      (copulation) involving the greatest contact, paired-indirect transfer an
      intermediate degree, and dissociated transfer the least. Internal fertilization,
      spermatophores, and copulation are sometimes assumed to have evolved after
      invasion of land, but all have evolved many times in the marine habitat.
      Behaviors associated with indirect sperm transfer include those having close
      parallels with direct transfer (provision of nuptial gifts) as well as unique
      phenomena (spermatophore trampling by rival males). The morphology and physiology
      of indirectly transferred spermatophores have been shaped by environmental
      factors (e.g. humidity) as well as biological ones (e.g. clutch size of females),
      and they may provide useful phylogenetic characters. Unanswered questions about
      indirect transfer include the following: Are females of dissociated species able
      to choose their partners? What determines size and number of spermatophores? Do
      speciation rates differ between taxa with direct versus indirect transfer?

PMID- 15012389
TI  - Insect performance on experimentally stressed woody plants: a meta-analysis.
AB  - In this review, we test the hypothesis that abiotic stress increases the
      suitability of plants as food for herbivores. We conducted a meta-analysis that
      included 70 experimental studies in which insect performance was measured on
      woody plants subjected to water stress, pollution, and/or shading. Overall, plant
      stress had no significant effect on insect growth rate, fecundity, survival, or
      colonization density. We found great variation, however, in the magnitude and
      direction of insect responses among studies, most of which was related to insect
      feeding guild. In general, boring and sucking insects performed better on
      stressed plants, whereas plant stress adversely affected gall-makers and chewing
      insects. Reduction in performance of chewers was greater on stressed slow-growing
      plants than on stressed fast growers. Reproductive potential of sucking insects
      was increased by pollution but reduced by water stress. In some cases where
      sample sizes were small or the treatment periods short, apparent differences in
      insect responses to stress were probably artifacts due to inappropriate
      experimental design.

PMID- 15012388
TI  - Biology of the Mantispidae.
AB  - Members of the Neuropteran family Mantispidae, subfamily Mantispinae, are
      predators in the egg sacs of spiders, draining egg contents through a
      piercing/sucking tube formed by modified mandibles and maxillae. First-instar
      mantispids use two strategies to locate spider eggs: Larvae may burrow directly
      through the silk of egg sacs they find, or they may board and be carried by
      female spiders prior to sac production, entering the sac as it is being
      constructed. Mantispids that board spiders usually adopt positions on or near the
      pedicel; some species may enter the spider's book lungs. Larvae maintain
      themselves aboard spiders by feeding on spider blood. Transfers of larvae from
      spider to spider are possible during spider mating or cannibalism. All of the
      major groups of hunting spiders are attacked by spider-boarding mantispids; the
      egg sacs of web-building species are also entered by egg-sac penetrators.

PMID- 15012390
TI  - The biology of nonfrugivorous tephritid fruit flies.
AB  - This review is the first comprehensive treatment of the biology of nonfrugivorous
      fruit flies of the family Tephritidae. Feeding habits of destructive and useful
      species, morphology of immature stages, and hypotheses regarding structural
      homology and the evolutionary biology of nonfrugivorous tephritids are reviewed,
      including zoogeography and theories involving resource heterogeneity, guild
      structure, resource partitioning, resource utilization, facultative niche
      exploitation, extrinsic and intrinsic factors, host associations, seasonal
      distribution and phenology, aggregative and circumnatal life history strategies,
      voltinism, diapause, aestivation, oviposition site, clutch size, and
      supernumerary oviposition.

PMID- 15012391
TI  - Biodiversity of stream insects: variation at local, basin, and regional scales.
AB  - We review the major conceptual developments that have occurred over the last 50
      years concerning the factors that influence insect biodiversity in streams and
      examine how well empirical descriptions and theory match. Stream insects appear
      to respond to both spatial and temporal variation in physical heterogeneity. At
      all spatial scales, the data largely support the idea that physical complexity
      promotes biological richness, although exceptions to this relationship were
      found. These exceptions may be related to how we measure habitat complexity at
      finer spatial scales and to factors that influence regional richness, such as
      biogeographic history, at broader spatial scales. However, the degree to which
      local stream insect assemblages are influenced by regional processes is largely
      unknown.

PMID- 15012392
TI  - Predaceous Coccinellidae in biological control.
AB  - Coccinellids have been widely used in biological control for over a century, and
      the methods for using these predators have remained virtually unchanged. The
      causes for the relatively low rates of establishment of coccinellids in
      importation biological control have not been examined for most species.
      Augmentative releases of several coccinellid species are well documented and
      effective; however, ineffective species continue to be used because of ease of
      collection. For most agricultural systems, conservation techniques for
      coccinellids are lacking, even though they are abundant in these habitats.
      Evaluation techniques are available, but quantitative assessments of the efficacy
      of coccinellids have not been done for most species in most agricultural crops.
      Greater emphasis is needed on evaluation, predator specificity, understanding
      colonization of new environments, and assessment of community-level interactions
      to maximize the use of coccinellids in biological control.

PMID- 15012393
TI  - Reproductive caste determination in eusocial wasps (Hymenoptera: Vespidae).
AB  - Wasps (Vespidae) exhibit a range of social complexity, from solitary living to
      eusocial colonies, and thus are exemplary for studies of the evolutionary origin
      and maintenance of social behavior in animals. Integral to the definition of
      eusociality is the presence of reproductive castes, group members that differ
      qualitatively in their ability to reproduce in a social setting. Behavioral and
      morphological evidence suggests that caste determination, the developmental
      process by which differences in fecundity are established, occurs to a large
      extent before adult emergence (pre-imaginally) in many species of Vespidae, in
      both basal and advanced taxa within the clade (Vespinae+Polistinae), which
      includes most eusocial species. Pre-imaginal determination has been documented in
      many taxa (e.g. independent-founding Polistinae) where it was not thought to
      occur. Correlative and experimental studies indicate that differences in
      nutrition during larval development are often the basis of pre-imaginal caste
      determination. Pre-imaginal caste determination has important implications for
      the roles of subfertility and manipulation by nest mates in the evolution of
      eusocial behavior.

PMID- 15012394
TI  - Manipulating natural enemies by plant variety selection and modification: a
      realistic strategy?
AB  - The host plants of arthropod pests may affect parasitoids and predators directly
      or indirectly, through multitrophic interactions. Direct plant effects may
      involve simple mechanisms such as reduced parasitoid searching efficiency caused
      by trichomes. Multitrophic effects often involve complex interactions that are
      not well understood, and their impact on natural enemies and biological control
      are difficult to predict. Knowledge of the direct and multitrophic effects
      creates opportunities to increase the effectiveness of natural enemies by
      incorporating natural enemy-enhancing traits into crop plants. The strategy may
      have potential for both generalist and specialist natural enemies, but the
      enemies' behavior and other factors will affect the results. Although combining
      natural enemies and plant resistance may slow the adaptation of some insect
      pests, it may speed up adaptations of others. A better understanding of
      plant/pest/natural enemy evolution is necessary to predict how to combine natural
      enemies and plant resistance for the best long-term results.

PMID- 15012395
TI  - Biological control of weeds.
AB  - Classical biological control, i.e. the introduction and release of exotic
      insects, mites, or pathogens to give permanent control, is the predominant method
      in weed biocontrol. Inundative releases of predators and integrated pest
      management are less widely used. The United States, Australia, South Africa,
      Canada, and New Zealand use biocontrol the most. Weeds in natural ecosystems are
      increasingly becoming targets for biocontrol. Discussion continues on agent
      selection, but host-specificity testing is well developed and reliable. Post
      release evaluation of impact is increasing, both on the target weed and on non
      target plants. Control of aquatic weeds has been a notable success. Alien plant
      problems are increasing worldwide, and biocontrol offers the only safe, economic,
      and environmentally sustainable solution.

PMID- 15012396
TI  - Ecology and management of hazelnut pests.
AB  - Insect and mite pests cause serious damage to the hazelnut crop worldwide. The
      control strategies used against these pests include application of insecticides,
      classical and augmentative biological control, utilization of resistant
      varieties, and use of Bacillus thuringiensis-based preparations. In the United
      States, extensive research has been directed toward elucidating ecological
      interactions among different pests and natural enemies and understanding the role
      of abiotic factors in pest population dynamics. Differences exist worldwide
      regarding the understanding of pests and natural enemy biologies and, to a
      limited extent, control practices. An integrated pest management approach based
      on utilizing effective sampling and monitoring techniques and a near complete
      reliance on biological control and "soft" pesticides, including insect growth
      regulators, is currently under development both in North America and
      Europe/Turkey. Hazelnuts are on the verge of becoming one of the first crops in
      the United States that could possibly be produced commercially without the use of
      any broad-spectrum organic insecticides.

PMID- 15012397
TI  - Ecological considerations for the environmental impact evaluation of recombinant
      baculovirus insecticides.
AB  - The history of baculoviruses in insect control and the current status of
      recombinant baculovirus (recBV) insecticides in the laboratory and the field are
      briefly outlined. A conceptual model for impact evaluation is described that
      distinguishes between scientific impact evaluation and regulatory risk
      assessment. Its components are identified and reviewed in the light of existing
      ecological theory and experimental study under the categories of impact
      identification, exposure identification, and impact evaluation. Impact
      identification aims to identify species and populations sensitive to direct or
      indirect impacts by a recBV. Exposure identification examines how susceptible
      populations may be exposed to a recBV. Impact evaluation combines these data to
      predict the potential for recBV impacts in the environment.

PMID- 15012398
TI  - Spatial heterogeneity and insect adaptation to toxins.
AB  - Behavioral responses of insect herbivores to toxins are examined in managed and
      natural systems with reference to two important but largely ignored factors:
      heterogeneity in toxin distributions and the nature of the relationship between
      behavioral responses and physiological adaptation to the same toxins.
      Heterogeneous toxin distributions, which provide the opportunity for behavioral
      responses, are ubiquitous in managed and natural systems. Insect herbivores have
      evolved a wide variety of behavioral responses to such toxins. The nature of
      behavioral responses reflects toxin apparency, mode of action, and the extent to
      which sublethal effects influence behavior. The interaction between these
      behavioral responses to heterogeneously distributed toxins and physiological
      mechanisms of tolerance has influenced the evolution of insecticide resistance in
      managed systems and the evolution of plant defensive strategies in natural
      systems. An understanding of this interaction could lead to more evolutionarily
      stable methods of crop protection.

PMID- 15012399
TI  - The ecology and behavior of burying beetles.
AB  - Burying beetles conceal small vertebrate carcasses underground and prepare them
      for consumption by their young. This review places their complex social behavior
      in an ecological context that focuses on the evolution of biparental care and
      communal breeding. Both males and females provide extensive parental care, and
      the major benefit of male assistance is to help defend the brood and carcass from
      competitors. As intensity and type of competition vary, so do the effectiveness
      and duration of male care. In many species, a single brood may be reared on large
      carcasses by more than one male and/or female. Limited reproductive
      opportunities, the greater effectiveness of groups in preventing the probability
      of brood failure (especially that caused by competing flies), and the
      superabundance of food on large carcasses have contributed to the evolution of
      this cooperative behavior.

PMID- 15012400
TI  - Evolution and ecology of spider coloration.
AB  - Genetic color variation provides a tangible link between the external phenotype
      of an organism and its underlying genetic determination and thus furnishes a
      tractable system with which to explore fundamental evolutionary phenomena. Here
      we examine the basis of color variation in spiders and its evolutionary and
      ecological implications. Reversible color changes, resulting from several
      mechanisms, are surprisingly widespread in the group and must be distinguished
      from true genetic variation for color to be used as an evolutionary tool. Genetic
      polymorphism occurs in a large number of families and is frequently sex limited:
      Sex linkage has not yet been demonstrated, nor have the forces promoting sex
      limitation been elucidated. It is argued that the production of color is
      metabolically costly and is principally maintained by the action of sight-hunting
      predators. Key avenues for future research are suggested.

PMID- 15012401
TI  - Biology and use of the whitefly parasitoid Encarsia formosa.
AB  - Encarsia formosa is a parasitoid used worldwide for the biological control of
      whiteflies on vegetables and ornamental plants grown in greenhouses. Because of
      outstanding success in controlling Trialeurodes vaporariorum on tomatoes, the
      biology and behavior of this wasp have been intensively studied to identify
      attributes that contribute to successful biological control and how best to
      manipulate augmentative releases into greenhouses to suppress whitefly population
      growth. In this article, we review the biology of adult and immature E. formosa,
      population dynamics of whitefly-parasitoid interactions, and commercial use in
      greenhouses. Deficits in knowledge of aspects of E. formosa's biology and use are
      noted.

PMID- 15012402
TI  - Sustainability of transgenic insecticidal cultivars: integrating pest genetics
      and ecology.
AB  - This review examines potential impacts of transgenic cultivars on insect
      population dynamics and evolution. Experience with classically bred, insecticidal
      cultivars has demonstrated that a solid understanding of both the target insect's
      ecology and the cultivar's performance under varied field conditions will be
      essential for predicting area-wide effects of transgenic cultivars on pest and
      natural enemy dynamics. This experience has also demonstrated the evolutionary
      capacity of pests for adaptive response to insecticidal traits in crops.
      Biochemical and genetic studies of insect adaptation to the Bacillus
      thuringiensis (Bt) toxins expressed by currently marketed transgenic cultivars
      indicate a high risk for rapid adaptation if these cultivars are misused.
      Theoretical and practical issues involved in implementing strategies to delay
      pest adaptation to insecticidal cultivars are reviewed. Emphasis is placed on
      examining the "high dose"/refuge strategy that has become the goal of industry
      and regulatory authorities.

PMID- 15012404
TI  - Nonadiabatic transitions: what we learned from old masters and how much we owe
      them.
AB  - This chapter discusses the impact of two-state models of nonadiabatic coupling by
      Landau, Zener, Stuckelberg, Rosen, and Teller on the current theory of
      nonadiabatic interaction. In particular, the idea of analytical continuation of
      classical dynamical variables into complex-valued phase space and time is
      emphasized. The development of the basic models over the past 30 years has
      provided us with a useful means of investigating the nonadiabatic molecular
      dynamics; this is illustrated by the references to our earlier and most recent
      work.

PMID- 15012405
TI  - Experiments on the dynamics of molecular processes: a chronicle of fifty years.
AB  - This paper reviews the way in which, in the Italy of the years immediately after
      World War II, interest in the dynamics of molecular processes was awakened. The
      narrative begins with the work of a small number of chemists and physicists who,
      in the initial stage, interacted closely. In the course of the years, their
      interests diverged and younger people joined the newly formed groups. Even now,
      after half a century, a common approach can still to be seen regarding how to
      attack problems and perform experiments. Experimental work is discussed, bringing
      out the common viewpoint of fields as diverse as mass spectrometry, isotope
      effects, chemical kinetics, molecular beams, molecule-molecule interactions,
      molecule-ion interactions, molecule-surface interactions, and plasma chemistry.

PMID- 15012406
TI  - Nonlinear kinetics and new approaches to complex reaction mechanisms.
AB  - This paper reviews recent developments in the field of nonlinear chemical
      kinetics. Five topics are dealt with: (a) new approaches to complex reaction
      mechanisms, stoichiometric network analysis, classification of chemical
      oscillators and formulation of their mechanisms by deduction from experiments,
      and correlation metric construction of reaction pathways from measurements; (b)
      thermodynamic and stochastic theory of nonequilibrium processes, the eikonal
      approximation, the evaluation of stochastic potentials, experimental tests of the
      thermodynamic and stochastic theory of relative stability, and fluctuation
      dissipation relations in nonequilibrium chemical systems; (c) chemical kinetics
      and cellular automata and lattice gas automata; (d) theoretical approaches and
      experimental studies of stochastic resonance in chemical kinetics; and (e) rate
      processes in disordered systems, stochastic Liouville equations, stretched
      exponential relaxation in disordered systems, and universality classes for rate
      processes in systems with static or dynamic disorder.

PMID- 15012407
TI  - Reactions of transition metal clusters with small molecules.
AB  - Atoms and small molecules react with transition metal clusters in ways that are
      analogous to the physisorption and chemisorption reactions observed on the
      corresponding extended metal surface. However, often underlying these
      similarities are size-dependent variations in the reaction mechanisms and rates,
      the interpretation of which requires a detailed understanding of the structures
      of both the bare metal cluster substrates and the cluster-molecule complexes.
      Although polyatomic transition metal clusters cannot be characterized by the
      traditional methods of molecular spectroscopy, the combination of other physical
      and chemical probes can provide qualitative and semiquantitative structural
      information. These techniques, when combined with equilibrium geometries
      calculated using ab initio or semiempirical methods, provide a detailed picture
      of the structural origin of metal cluster reactivity and its variation with size.

PMID- 15012408
TI  - The photophysics of silver halide imaging materials.
AB  - Experimental and computational studies of photophysical processes in silver
      halide imaging materials are presented. Recent investigations that have refined
      our understanding of carrier recombination paths, exciton behavior, quantum
      confinement effects, and the structure and function of small surface silver
      clusters are detailed. The theory and mechanism of electron and hole injection
      from photoexcited surface-adsorbed dye molecules are outlined. The carrier
      trapping properties and subsequent photophysics of transition-metal dopant
      complexes are presented. Particular emphasis is given to the role of relaxation
      processes in electron and hole trapping events.

PMID- 15012409
TI  - Ionic effects beyond Poisson-Boltzmann theory.
AB  - Polyelectrolytes are electrolytes asymmetric both in charge and size. Their
      properties in solution are dominated by Coulombic forces, and without a detailed
      understanding of these interactions, no interpretation of experimental data is
      possible. This paper is a review of recent developments in the theory of highly
      asymmetric electrolytes of spherical shape resembling surfactant micelles. Three
      different models are discussed: (a) the cell model, which is focused on the small
      ion-macroion interaction; (b) the model that treats the solution as an effective
      one-component fluid of macroions; and (c) the isotropic model, where the solution
      is represented as a mixture of charged spheres. Traditionally, the electrostatic
      interactions are accounted for via the solution of the Poisson-Boltzmann
      equation. This theory, however, ignores the fluctuations around the most probable
      distribution and may yield poor results for systems with multivalent ions. This
      paper focuses on developments beyond the Poisson-Boltzmann theory; the results of
      computer simulations and integral equation theories represent the major part of
      the review.

PMID- 15012410
TI  - Time-dependent quantum methods for large systems.
AB  - This review focuses on time-dependent methods suitable for simulating the quantum
      dynamics of processes in large clusters and condensed-phase environments. A
      number of mean field, quantum-classical, and quantum statistical approximations
      that avoid the conventional exponential scaling with the number of degrees of
      freedom are reviewed. In addition, rigorous semiclassical and path integral
      approaches are described that are feasible in certain physical situations. Select
      chemical applications illustrating the capabilities of these methods are
      discussed.

PMID- 15012411
TI  - Photothermal applications of lasers: study of fast and ultrafast photothermal
      phenomena at metal-liquid interfaces.
AB  - Recent studies on fast (<10 ns) and ultrafast (<10 ps) photothermal and
      photoacoustic phenomena occurring at solid-liquid interfaces are discussed,
      including related topics, with emphasis placed on interfaces between aqueous
      solutions and metals under electrochemical potential control. Details of
      transient reflecting grating measurements for metal-liquid interfaces are
      considered as they relate to mesoscopic interface structures and nano
      environments. Dependencies of fast photothermal phenomena on the electrochemical
      potential and types of anions in the solutions are shown. Ultrafast photothermal
      phenomena observed by transient reflectivity measurements are considered in
      connection with interface femtochemistry and hot electron reactions. Technical
      progress in measuring fast and ultrafast photothermal phenomena is reviewed for
      solid-liquid interfaces, including colloidal solutions.

PMID- 15012412
TI  - Density functional theory of biologically relevant metal centers.
AB  - Recent applications of density functional theory to biologically relevant metal
      centers are reviewed. The emphasis is on reaction mechanisms, structures, and
      modeling. The accuracy of different functionals is discussed for standard
      benchmark tests of first- and second-row molecules and for transition metal
      systems. Modeling aspects of the protein metal complexes are discussed regarding
      both the size of the model being treated quantum mechanically and the treatment
      of the protein surrounding it. To illustrate the effects, structures computed
      without the effects of the protein are compared with experimental structures from
      enzymes, and results from simple dielectric models of the protein for electron
      transfer processes are described. The choice of spin state is discussed for
      multimetal complexes. Examples of mechanisms studied recently by density
      functional theory are described, such as O2 and methane activation in methane
      monooxygenase and O2 formation in photosystem II.

PMID- 15012413
TI  - Ultrafast spectroscopy of shock waves in molecular materials.
AB  - Recent progress in combining the techniques of time-resolved molecular
      spectroscopy with shock compression science is reviewed. Shock wave spectroscopy
      probes the response of molecules to high-speed, large-amplitude mechanical
      transients and is an important way of studying physical chemical phenomena that
      involve large-amplitude displacements. A brief discussion of the continuum model
      for shock compression and a molecular model for the shock front is presented.
      Methods for generating and detecting shock effects are reviewed. Several
      applications of shock spectroscopy are reviewed, including high explosives, the
      nanoshock technique that uses ultrafast lasers, and shock compression of
      biological molecules.

PMID- 15012414
TI  - Applications of impulsive stimulated scattering in the Earth and planetary
      sciences.
AB  - The elastic, thermodynamic, and transport properties of crystals and fluids at
      high temperature and pressure play a central role in the earth and planetary
      sciences as well as in a variety of technologies. These properties also
      constitute a principal experimental constraint on the description of
      intermolecular interactions at short distances. Aspects of "impulsive stimulated
      scattering," when adapted to measurements in the diamond-anvil high-pressure
      cell, provide an approach to the determination of a subset of equilibrium and
      dynamic properties at high density.

PMID- 15012415
TI  - Nuclear spin conversion in polyatomic molecules.
AB  - Except for ortho- and para-H2, little is known about nuclear spin isomers (or
      spin modifications) of molecules. The main reason is the lack of practical
      enrichment techniques. Recently, a few enrichment methods were developed, which
      opened up new possibilities in the field. These methods are briefly reviewed.
      Substantial progress in the field has been made by the introduction of light
      induced drift as a gas-phase separation tool. This is illustrated by extensive
      data on CH3F, which reveal that the gas-phase ortho-para conversion is governed
      by intramolecular mixing of the nuclear spin states. The role of direct ortho
      para transitions is small. Various aspects of the conversion were investigated in
      detail: pressure and collision partner dependence, isotope effect, and
      temperature dependence. The most decisive information on the spin conversion
      mechanism is derived from the observation of level-crossing resonances in an
      electric field and the quantum Zeno effect induced by collisions.

PMID- 15012416
TI  - Crossed-beam studies of reaction dynamics.
AB  - This article reviews recent progress in our understanding of gas-phase neutral
      reaction dynamics as made possible by improvements in the crossed molecular beam
      scattering technique for measuring reactive differential cross sections. A
      selection of crossed-beam studies on systems that play a fundamental role in our
      basic understanding of reaction phenomena are discussed to illustrate the
      capabilities of the experimental method. The examples include benchmark atom
      diatom abstraction and insertion reactions, and four-atom radical reactions for
      which state-to-state, state-resolved, or state-averaged differential cross
      sections have recently been measured. The results are discussed in the light of
      the latest related theoretical developments regarding the treatment of potential
      energy surfaces and the dynamics of the systems. Recent results on crossed-beam
      studies of chemically relevant reactions of carbon, nitrogen, and oxygen atoms
      are also reviewed, and the latest developments in the technique are noted.

PMID- 15012417
TI  - Simulation of phase transitions in fluids.
AB  - This review provides a discussion of recent techniques for simulation of phase
      equilibria of complex fluids. Monte Carlo methods are emphasized over molecular
      dynamics methods. We describe recent developments, such as the use of expanded
      ensemble, tempering, or histogram reweighting techniques. Our discussion of such
      developments is aimed at a general audience and is intended to provide an
      overview of the main advantages and limitations of each particular technique.
      References are provided to allow interested readers to identify and trace back
      most recent applications of a particular simulation technique. We conclude with
      general guidelines regarding selection of suitable simulation methods for
      particular problems and systems of interest.

PMID- 15012418
TI  - Controlled molecular adsorption on silicon: laying a foundation for molecular
      devices.
AB  - This review is about understanding and controlling organic molecular adsorption
      on silicon. The goal is to provide a microscopic picture of structure and bonding
      in covalently attached molecule-silicon surface systems. The bias here is that an
      unprecedented, detailed understanding of adsorbate-surface structures is required
      in order to gain the control necessary to incorporate organic function into
      existing technologies or, eventually, to make new molecule-scale devices. A
      discussion of recent studies of adsorbate structure is presented. This includes
      simple alkenes, polyenes, benzene, and carene adsorbed on Si(100). Also included
      is a discussion of wet chemical procedures for forming alkyl and alkoxy
      covalently functionalized silicon. These discussions are presented together with
      comments on the related issues of adsorption dynamics and nano-scale manipulation
      in an effort to point the way toward principles and procedures that will allow
      the hybrid properties of organic molecules and surfaces to be harnessed.

PMID- 15012419
TI  - HCP<=>CPH isomerization: caught in the act.
AB  - In this overview we discuss the vibrational spectrum of phosphaethyne, HCP, in
      its electronic ground state, as revealed by complementary experimental and
      theoretical examinations. The main focus is the evolution of specific spectral
      patterns from the bottom of the potential well up to excitation energies of
      approximately 25,000 cm(-1), where large-amplitude, isomerization-type motion
      from H-CP to CP-H is prominent. Distinct structural and dynamical changes, caused
      by an abrupt transformation from essentially HC bonding to mainly PH bonding, set
      in around 13,000 cm(-1). They reflect saddle-node bifurcations in the classical
      phase space--a phenomenon well known in the nonlinear dynamics literature--and
      result in characteristic patterns in the spectrum and the quantum-number
      dependence of the vibrational fine-structure constants. Two polar opposites are
      employed to elucidate the spectral patterns: the exact solution of the
      Schrodinger equation, using an accurate potential energy surface and an effective
      or resonance Hamiltonian (expressed in a harmonic oscillator basis set and block
      diagonalized into polyads), which is defined by parameters adjusted to fit either
      the measured or the calculated vibrational energies. The combination of both
      approaches--together with classical mechanics and semiclassical analyses-
      provides a detailed spectroscopic picture of the breaking of one bond and the
      formation of a new one.

PMID- 15012420
TI  - The fast protein folding problem.
AB  - During protein folding, many of the events leading to secondary and tertiary
      structure occur in milliseconds or faster. Modern nuclear magnetic resonance and
      laser detection techniques, coupled with fast initiation of the folding reaction,
      are probing these events in great detail. Theory, ranging from analytical models
      to molecular dynamics calculations, is beginning to match up with experiment. As
      a result, timescales, from such elementary steps as the addition of a residue to
      a helix to strange kinetics of collapsing protein backbones, can now be measured
      and interpreted.

PMID- 15012421
TI  - Constructing multidimensional molecular potential energy surfaces from ab initio
      data.
AB  - This paper describes the reproducing kernel Hilbert space (RKHS) method for
      constructing accurate, smooth, and efficient global potential energy surface
      (PES) representations for polyatomic systems using high-level ab initio data. The
      RKHS method provides a rigorous and effective framework for smooth multivariate
      interpolation of arbitrarily scattered data points and also for incorporating
      various physical requirements onto the PESs. Smoothness, permutation symmetry,
      and the asymptotic properties of polyatomic systems can be incorporated into the
      construction of reproducing kernels to render globally accurate PESs. Tensor
      products of one-dimensional generalized-spline-reproducing kernels are amenable
      to a fast algorithm, which makes a single evaluation of RKHS PESs essentially
      independent of the number of interpolated ab initio data points. This efficient
      implementation enables the study of the detailed dynamics of polyatomic systems
      based on high-quality RKHS PESs.

PMID- 15012422
TI  - Chemical applications of neutron scattering.
AB  - Neutron scattering represents a versatile technique for chemists, as it explores
      the structure and dynamics of materials at the atomic scale. This review gives an
      outline of the neutron scattering formalism and describes diffraction and
      inelastic and quasielastic scattering techniques. Applications to chemistry are
      illustrated by examples from recent work on crystalline and liquid organic
      materials, including heterogeneous systems, bulk polymers and polymer solutions.
      There is particular emphasis on systems where hydrogen bonding plays a
      significant role. With more powerful sources and improved instrumentation in
      prospect, there is considerable potential for future extension of these methods
      to increasingly complex materials.

PMID- 15012423
TI  - Spectroscopy of atoms and molecules in liquid helium.
AB  - Laser ablation of in situ metals has recently made it possible to immerse a large
      number of different metal atoms and ions and small clusters of metal atoms in
      liquid helium (He) and thus study their absorption and emission spectra in the
      visible region. Atoms and molecules are readily picked up by large (N > or = 103
      atoms) He droplets, and their spectra are sensitively detected through the use of
      either beam depletion following absorption or laser-induced fluorescence. Within
      the past three years, a wide variety of molecules, ranging from OCS to large
      organic molecules such as amino acids and a number of van der Waals complexes and
      even large metal clusters, have been embedded in He droplets and studied either
      in infrared or in the visible region. These results are discussed here in detail,
      and the evidence for the effect of superfluidity on the spectral features is
      reviewed.

PMID- 15012424
TI  - Structure and transformation: Large molecular clusters as models of condensed
      matter.
AB  - This paper reviews investigations of homogeneous nucleation in phase transitions
      in large molecular clusters. The principal techniques brought to bear are
      electron diffraction analyses of transformations in clusters formed by
      condensation of vapor in supersonic expansions and computer simulations of
      spontaneous phase changes in clusters. Results obtained to date are contrasted
      with those of larger systems and interpreted in terms of nucleation theory. The
      review also refers to some unresolved aspects of nucleation theory.

PMID- 15012425
TI  - The shuttle glow phenomenon.
AB  - Spacecraft in low earth orbit exhibit an unusual phenomenon: Surfaces facing the
      atmospheric wind produce a bright orange glow. This phenomenon was first noticed
      on the space shuttle but has since been verified as occurring on all spacecraft.
      The intensity of the glow depends on atmospheric density, on the angle between
      the velocity vector and the spacecraft surface, and on the temperature of the
      surface. This review summarizes the observations as well as the current
      explanation for the glow, namely its being due to NO2* formed in surface-aided
      recombination between O and NO. Laboratory measurements and surface studies
      related to the phenomenon are briefly discussed.

PMID- 15012426
TI  - Ultrafast solvation dynamics explored by femtosecond photon echo spectroscopies.
AB  - Chemical reaction and optical dynamics in the liquid phase are strongly affected
      by specific solute-solvent interactions. The dynamical part of this coupling
      leads to energy fluctuations. The associated energy gap dynamics can be probed by
      using various nonlinear optical spectroscopies. We discuss various forms of
      photon echo--time-integrated, time-gated, and heterodyne-detected photon echo--as
      well as Fourier transform spectral interferometry. It is shown that for solutions
      of the dye molecule DTTCI, a system-bath correlation function can be acquired
      that provides a quantitative description of all (non)linear spectroscopic
      experiments. The deduced correlation function is projected onto the multimode
      Brownian oscillator model, which allows for a physical interpretation of the
      multiple-time correlation function and a determination of the spectral density
      relevant to the solvation process. The following applications of photon echo to
      condensed phase dynamics are discussed: enhanced vibrational mode suppression,
      Liouville pathways interference, and dynamical Stokes shift. Recent results of
      echo-peak shift experiments on the hydrated electron are also presented. The
      review concludes that photon echo should be useful as a novel tool to explore
      transition state dynamics.

PMID- 15012427
TI  - Chemical reaction dynamics beyond the Born-Oppenheimer approximation.
AB  - To predict the branching between energetically allowed product channels, chemists
      often rely on statistical transition state theories or exact quantum scattering
      calculations on a single adiabatic potential energy surface. The potential energy
      surface gives the energetic barriers to each chemical reaction and allows
      prediction of the reaction rates. Yet, chemical reactions evolve on a single
      potential energy surface only if, in simple terms, the electronic wavefunction
      can evolve from the reactant electronic configuration to the product electronic
      configuration on a time scale that is fast compared to the nuclear dynamics
      through the transition state. The experiments reviewed here investigate how the
      breakdown of the Born-Oppenheimer approximation at a barrier along an adiabatic
      reaction coordinate can alter the dynamics of and the expected branching between
      molecular dissociation pathways. The work reviewed focuses on three questions
      that have come to the forefront with recent theory and experiments: Which classes
      of chemical reactions evidence dramatic nonadiabatic behavior that influences the
      branching between energetically allowed reaction pathways? How do the
      intramolecular distance and orientation between the electronic orbitals involved
      influence the nonadiabaticity in the reaction? How can the detailed nuclear
      dynamics mediate the effective nonadiabatic coupling encountered in a chemical
      reaction?

PMID- 15012428
TI  - Explosives detection: a challenge for physical chemistry.
AB  - The detection of explosives, energetic materials, and their associated compounds
      for security screening, demining, detection of unexploded ordnance, and pollution
      monitoring is an active area of research. A wide variety of detection methods and
      an even wider range of physical chemistry issues are involved in this very
      challenging area. This review focuses on techniques such as optical and mass
      spectrometry and chromatography for detection of trace amounts of explosives with
      short response times. We also review techniques for detecting the decomposition
      fragments of these materials. Molecular data for explosive compounds are reviewed
      where available.

PMID- 15012429
TI  - The construction and interpretation of MCSCF wavefunctions.
AB  - The multiconfiguration self-consistent field (MCSCF) method offers the most
      general approach to the computation of chemical reactions and multiple electronic
      states. This review discusses the design of MCSCF wavefunctions for treating
      these problems and the interpretation of the resulting orbitals and
      configurations. In particular, localized orbitals are convenient both for
      selection of the appropriate active space and for understanding the computed
      results. The computational procedures for optimizing these wavefunctions and the
      techniques for recovery of dynamical correlation energy are reviewed.

PMID- 15012430
TI  - Molecular electronic spectral broadening in liquids and glasses.
AB  - The magnitudes, time scales, and underlying mechanisms responsible for broadening
      the electronic spectra of molecules in liquid solutions and glasses are reviewed.
      The emphasis is on experimental results from hole-burning, single-molecule,
      photon echo, and resonance Raman and fluorescence studies. The influence of the
      time scale of the measurement in distinguishing between homogeneous broadening
      (electronic dephasing) and inhomogeneous broadening is discussed, and the role of
      coupling of solvent phonons to the solute's electronic transition is stressed.

PMID- 15012431
TI  - Scanning tunneling and atomic force microscopy probes of self-assembled,
      physisorbed monolayers: peeking at the peaks.
AB  - The imaging and control of self-assembled, physisorbed monolayers have been the
      subject of numerous scanning tunneling microscopy and atomic force microscopy
      investigations. The successful interpretation of the structures observed in
      scanning probe images of molecules self-assembled at liquid-solid and gas-solid
      interfaces has benefited greatly from recent experimental and theoretical work.
      These studies are converging on a general tunneling mechanism that accounts for
      the images of weakly bound, insulating adsorbates. Experiments in which the
      dynamical behavior of these monolayers has been monitored as a function of time
      both statically and after the introduction of an external perturbation are
      described, and novel studies of the selective control of monolayer structure that
      make use of internal and external electric fields, photons, and solvent
      coadsorption are reviewed.

PMID- 15012432
TI  - Nanocrystal superlattices.
AB  - Ordered arrays, or superlattices, of metallic, insulating, or semiconducting
      quantum dots, represent an exciting new class of materials. These superlattices
      are often referred to as artificial solids, in which the nanocrystals take the
      place of atoms in traditional solids, and the packing arrangement of the
      nanocrystals determines the unit cell parameters of the superstructure. In this
      review, we discuss various approaches toward assembling nanocrystal superlattices
      and we discuss their physical properties.

PMID- 15012433
TI  - Computational approach to the physical chemistry of fullerenes and their
      derivatives.
AB  - A critical review is presented of results obtained with different computational
      methods (mainly ab initio) on C60, C70, and specific fullerene derivatives, also
      in comparison with experimental data. From the discussion of diverse systems, the
      (often underestimated) complexity of their physical and chemical behavior
      emerges, and hence the importance of an accurate description and the need for a
      careful inspection of the experimental data, with which comparison is often
      intrinsically difficult. The ambition of this review is to help establish a basis
      not only for a nonsuperficial reading of the existing literature, but also for a
      constructive approach with computations to the challenge posed by recent
      promising applications of fullerenes in nanotechnology, optoelectronics, and
      biology.

PMID- 15012434
TI  - Optical studies of single molecules at room temperature.
AB  - Recent developments in optical studies of single molecules at room temperature
      are reviewed, with an emphasis on the underlying principles and the potential of
      single-molecule experiments. Examples of single-molecule studies are given,
      including photophysics and photochemistry pertinent to single-molecule
      measurements, spectral fluctuations, Raman spectroscopy, diffusional motions,
      conformational dynamics, fluorescence resonant energy transfer, exciton dynamics,
      and enzymatic turnovers. These studies illustrate the information obtainable with
      the single-molecule approach that is hidden in ensemble-averaged measurements.

PMID- 15012435
TI  - High resolution spectroscopy in the gas phase: even large molecules have well
      defined shapes.
AB  - A review of recent high-resolution microwave, infrared, and optical spectroscopy
      experiments demonstrates that remarkable progress has been made in the past 20
      years in determining the equilibrium geometries of large polyatomic molecules and
      their clusters in the gas phase, and how these geometries change when the photon
      is absorbed. A special focus is on the dynamical information that can be obtained
      from such studies, particularly of electronically excited states.

PMID- 15012436
TI  - Interfaces and thin films as seen by bound electromagnetic waves.
AB  - This contribution summarizes the use of plasmon surface polaritons and guided
      optical waves for the characterization of interfaces and thin organic films.
      After a short introduction to the theoretical background of evanescent wave
      optics, examples are given that show how this interfacial "light" can be employed
      to monitor thin coatings at a solid/air or solid/liquid interface. Examples are
      given for a very sensitive thickness determination of samples ranging from self
      assembled monolayers, to multilayer assemblies prepared by the
      Langmuir/Blodgett/Kuhn technique or by the alternate polyelectrolyte deposition.
      These are complemented by the demonstration of the potential of the technique to
      also monitor time-dependent processes in a kinetic mode. Here, we put an emphasis
      on the combination set-up of surface plasmon optics with electrochemical
      techniques, allowing for the on-line characterization of various surface
      functionalization strategies, e.g. for (bio-) sensor purposes.

PMID- 15012437
TI  - Molecules in optical, electric, and magnetic fields: a personal perspective.
AB  - Physical chemistry and theoretical chemistry have advanced over the past 50 years
      from being largely qualitative to having a mature status based firmly on the
      principles of quantum and statistical mechanics. My interest in the chemical
      elements and their compounds has prompted me to learn more about the nature of
      matter through the measurement and interpretation of optical, electric, and
      magnetic properties of molecules. In addition to holding intrinsic interest, such
      properties tell us about charge and current distributions and form the basis of
      electro-optics, magneto-optics, and nonlinear optics. They also help us
      understand the nature and strength of long-range intermolecular forces, the
      hydrogen bond, and molecular biology-topics that are apparently forever young.

PMID- 15012438
TI  - In my time: scenes of scientific life.
AB  - A narrative account of the ingredients in the making of a young scientist, his
      wartime science in England, and subsequent career in France, where, starting in
      molecular electronic spectroscopy, he has grown older and has expanded his
      horizons to address problems of astrophysical, nonlinear optical, and biological
      interest, using, with the aid of many good scientists, a variety of techniques,
      mainly of optical and mass spectroscopies and with synchrotron radiation as an
      important excitation source. He has plans to continue.

PMID- 15012439
TI  - The physical and chemical properties of ultrathin oxide films.
AB  - Thin oxide films (from one to tens of monolayers) of SiO2, MgO, NiO, Al2O3,
      FexOy, and TiO2 supported on refractory metal substrates have been prepared by
      depositing the oxide metal precursor in a background of oxygen (ca 1 x 10(-5)
      Torr). The thinness of these oxide samples facilitates investigation by an array
      of surface techniques, many of which are precluded when applied to the
      corresponding bulk oxide. Layered and mixed binary oxides have been prepared by
      sequential synthesis of dissimilar oxide layers or co-deposition of two different
      oxides. Recent work has shown that the underlying oxide substrate can markedly
      influence the electronic and chemical properties of the overlayer oxide. The
      structural, electronic, and chemical properties of these ultrathin oxide films
      have been probed using Auger electron spectroscopy (AES), X-ray photoelectron
      spectroscopy (XPS), electron energy loss spectroscopy (ELS), ion-scattering
      spectroscopy (ISS), high-resolution electron energy loss spectroscopy (HREELS),
      infrared reflectance absorption spectroscopy (IRAS), temperature-programmed
      desorption (TPD), scanning tunneling microscopy (STM), and scanning tunneling
      spectroscopy (STS).

PMID- 15012440
TI  - Spectroscopy of metal ion complexes: gas-phase models for solvation.
AB  - Weakly bound metal ion complexes are produced in molecular beams and studied with
      mass-selected laser photodissociation spectroscopy. The metal ions Mg+ and Ca+
      are the focus of these studies because they have a single valence electron and
      strong atomic resonance lines in convenient wavelength regions. Weakly bound
      complexes of these ions with rare-gas atoms and small molecules are prepared with
      laser vaporization in a pulsed nozzle cluster source. The vibrationally and
      rotationally resolved electronic spectra obtained for these complexes help to
      determine the complexes' structures and bonding energetics. Observations from
      these studies have provided many new insights into the fundamental interactions
      in electrostatic bonding.

PMID- 15012441
TI  - State-resolved collision-induced electronic transitions.
AB  - Laser and molecular beam techniques have enabled researchers to determine the
      rovibrational levels populated in collision-induced electronic transitions from
      specified initial levels of several diatomic molecules. As exemplified by the N2+
      and CN-rare-gas systems, such measurements, in combination with theoretical
      calculations of cross sections for these state-to-state collisional processes,
      provide a means to understand in detail the dynamics of these electronic
      quenching and energy transfer processes. The present article reviews state-to
      state studies of collision-induced electronic transitions. The various collision
      systems studied provide examples of both perturbation-assisted "gateways" between
      the initial and final electronic states and perturbation-independent transitions
      enabled by nonadiabatic mixing induced by the collision partner.

PMID- 15012442
TI  - Kinetics in solids.
AB  - The kinetics of solid state reactions generally cannot be assumed to follow
      simple rate laws that are applicable to gas-phase reactions. Nevertheless, a
      widely practiced method for extracting Arrhenius parameters from thermal analysis
      experiments involves force fitting of experimental data to simple reaction-order
      kinetic models. This method can produce significant errors in predicted rates
      outside the experimental range of temperatures, and it is of limited utility for
      drawing mechanistic conclusions about reactions. In this review, we discuss how
      an alternative "model-free" approach to kinetic analysis, which is based on the
      isoconversional method, can overcome some of these limitations.

PMID- 15012443
TI  - Dissociative recombination with ion storage rings.
AB  - The development of heavy-ion storage-cooler rings for atomic physics has made it
      possible to produce high-quality beams of molecular ions that are internally
      cold. The stored molecular-ion beam is immersed in a cold electron bath, which
      gives a beam of low divergence and small cross-sectional area. The electron
      cooler also serves as a target for electron-molecular ion collision experiments.
      This allows the study of dissociative recombination of cold molecules with
      respect to cross sections, branching ratios, and angular distributions at an
      unprecedented luminosity.

PMID- 15012444
TI  - Single-molecule spectroscopy.
AB  - Recent experimental and theoretical studies concerning single-molecule
      spectroscopy in solids are discussed. Pure quantum effects--such as photon
      bunching, antibunching, and spectral jumps--and more classical phenomena--such as
      near-field excitation, saturation, ac/dc Stark shifts, spectral diffusion, two
      photon excitation, and customary spectroscopic analysis--are considered. The
      emphasis of this review is on physical results and their interpretation. This is
      preceded by a general introduction, where fundamentals of single-molecule
      spectroscopy are explained.

PMID- 15012445
TI  - Ab initio dynamics of surface chemistry.
AB  - We review the young field of ab initio molecular dynamics applied to molecule
      surface reactions. The techniques of ab initio molecular dynamics include methods
      that use an analytic potential energy function fit to ab initio data and those
      that are fully ab initio. In this review, we focus on the insights provided by ab
      initio-based molecular dynamics that are currently unavailable from experimental
      studies and discuss current techniques and limitations. As an example of how
      different aspects of a problem can be tackled with state-of-the-art theoretical
      tools, we consider the well-studied case of H2 desorption and adsorption from the
      Si(100)-2 x 1 surface.

PMID- 15012446
TI  - Two-photon-induced fluorescence.
AB  - Nonresonant two-photon electronic spectroscopy of polyatomic molecules is
      reviewed for the period since 1979. Emphasis is placed on studies that expose
      patterns in the two-photon fluorescence (also ionization, optoacoustic)
      excitation spectra of aromatic hydrocarbons and the effect of vibrations and
      substitution, particularly within the framework of pseudoparity rules. A section
      is devoted to biological molecules and the emerging use of two-photon-induced
      fluorescence anisotropy. Relevant theoretical results are discussed, with
      emphasis on quantum chemical predictions of vibronic coupling and substituent
      effects on two-photon absorptivity and tensor properties of individual molecules.
      This chapter includes higher-order spectroscopy, and a limited number of three-
      and four-photon studies are discussed.

PMID- 15012447
TI  - Theoretical studies of chemical dynamics: overview of some fundamental
      mechanisms.
AB  - Recent remarkable progress in theoretical studies of (a) quantum dynamics of
      chemical reactions, (b) characteristics and dynamics of superexcited states of
      molecules, (c) nonadiabatic transitions at potential curve crossings, and (d)
      multidimensional tunneling is reviewed briefly. Underlying common basic concepts
      and fundamental mechanisms such as adiabaticity and nonadiabatic transition are
      extracted and discussed in order to facilitate a comprehensive understanding of
      chemical dynamics. Not only the basic theoretical methodologies but also the
      intriguing dynamical aspects of each subject are explained as simply as possible.

PMID- 15012448
TI  - Time-resolved dynamics of proton transfer in proteinous systems.
AB  - The dynamics of proton dissociation from an acidic moiety and its subsequent
      dispersion in the bulk is regulated by the physical chemical properties of the
      solvent. The solvent has to provide a potential well to accommodate the
      discharged proton, screen it from the negative charge of the conjugated base, and
      provide an efficient mode for the diffusion of the proton to the bulk. On
      measuring the dynamics of proton dissociation in the time-resolved domain, the
      kinetic analysis of the reaction can quantitate the properties of the immediate
      environment. In this review we implement the kinetic analysis for evaluating the
      properties of small cavities in proteins and the diffusion of protons within
      narrow channels. On the basis of this analysis,we discuss how the clustering of
      proton-binding sites on a surface can endow the surface with enhanced capacity to
      attract protons and to funnel them toward a specific site.

PMID- 15012449
TI  - Subfemtosecond processes in strong laser fields.
AB  - Strong field atomic and molecular interactions can be understood by following
      electronic dynamics inside the laser cycle. This quasistatic perspective
      introduces the subfemtosecond time scale into strong-field dynamics through time
      dependent Born-Oppenheimer surfaces. We discuss both theoretical and experimental
      results in atomic and molecular ionization and dissociation with applications to
      femtochemistry. An all-optical Coulomb explosion method for determining time
      dependent molecular structure and properties is demonstrated. The concept of time
      dependent Born-Oppenheimer surfaces is used to study molecular dissociation and
      exchange reactions in infrared fields.

PMID- 15012450
TI  - Structural information from methyl internal rotation spectroscopy.
AB  - The fundamental quantum mechanics, group theory, and spectroscopy of methyl
      torsional structure accompanying electronic transitions is presented. The origin
      of barriers to internal rotation and the interaction of the methyl with the pi
      system via hyperconjugation are discussed. Because of the relationship between
      the methyl barrier and the pi system, measurement of the CH3 properties provides
      structural information about the molecule. In para'-substituted p-methyl-t
      stilbenes, barriers in the S1 state show a strong dependence on the substituent,
      substituent conformation, and involvement of the substituent in hydrogen bonding
      interaction. The methyl torsional barrier reflects these changes despite the
      distance of the substitution site, 10 atoms away.

PMID- 15012451
TI  - Active control of the dynamics of atoms and molecules.
AB  - There has been much progress in the control of chemical reactions since methods
      of active control were first proposed by Brumer & Shapiro and by Tannor & Rice
      ten years ago. This chapter reviews both theoretical and experimental advances in
      the field. Control schemes based on quantum mechanical interference between
      competing paths and the manipulation of wave packets with tailored laser pulses
      are discussed. The theory of optimal control, the limitations of control theory
      applied to many-body dynamics, and the effects of constraints on the trajectory
      of the controlled observable are presented. Experimental progress in controlling
      the population of specific quantum states, in manipulating the dynamics of bound
      wave packets, and in the control of chemical reactions are reviewed, and current
      problems in the field are summarized.

PMID- 15012452
TI  - OH-H2 entrance channel complexes.
AB  - The entrance channel to the OH+H2-->H2O+H hydrogen abstraction reaction has been
      investigated from several different experimental approaches and complementary
      theoretical calculations. Weakly bound complexes between the hydroxyl radical and
      molecular hydrogen have been stabilized within a shallow well in the entrance
      channel and characterized via electronic spectroscopy on the OH A2Sigma+-X2Pi
      transition. Laser-induced fluorescence and fluorescence depletion experiments
      have revealed the binding energy of H2/D2 with ground state OH X2Pi radicals, the
      intermolecular energy levels supported by the OH A2Sigma+ (v'=0,1)+H2/D2
      potential, and the OH-H2/D2 excited state dissociation limit. The OH X2Pi + H2
      potentials have also been examined through inelastic scattering measurements on
      Lambda-doublet state-selected OH with normal or para-H2. Finally, photodetachment
      of an electron from the H3O- anion enabled the neutral reaction to be probed in
      conformations sampled by the two isomeric forms of the anion.

PMID- 15012453
TI  - Molecules in high Rydberg states.
AB  - The unusual properties of high molecular Rydberg states with principal quantum
      number n>>100 have enabled the development of new research tools for the study of
      molecules and ions in the gas phase. These tools range from spectroscopic
      techniques such as zero kinetic energy (ZEKE) photoelectron spectroscopy and mass
      analyzed threshold ionization (MATI) spectroscopy to techniques that are suited
      to the investigation of photodissociation processes, bimolecular reactions, and
      state-selected ion-molecule reactions. This review summarizes recent progress in
      the understanding of the properties of high molecular Rydberg states and gives an
      overview of recent chemical applications of these states.

PMID- 15012454
TI  - Femtosecond dynamics of electrons on surfaces and at interfaces.
AB  - Two-photon photoemission is a promising new technique that has been developed for
      the study of electron dynamics at interfaces. A femtosecond laser is used to both
      create an excited electronic distribution at the surface and eject the
      distribution for subsequent energy analysis. Time- and momentum-resolved two
      photon photoemission spectra as a function of layer thickness fully determine the
      conduction band dynamics at the interface. Earlier clean surface studies showed
      how excited electron lifetimes are affected by the crystal band structure and
      vacuum image potential. Recent studies of various insulator/metal interfaces show
      that the dynamics of excess electrons are largely determined by the electron
      affinity of the adsorbate. In general, electron dynamics at the interface are
      influenced by the substrate and adlayer band structures, dielectric screening,
      and polaron formation in the two-dimensional overlayer lattice.

PMID- 15012455
TI  - New EPR methods for investigating photoprocesses with paramagnetic intermediates.
AB  - Some of the significant advances in time-resolved multifrequency electron
      paramagnetic resonance (EPR) methods are reviewed, with the explicit focus on
      studies of light-driven processes and photoreactions in real time. Prominent
      examples are excited state electron transfer reactions with transient charge
      separated radical pairs playing a central role. Paramagnetic intermediates and
      products are key functional states; thus EPR is the method of choice for their
      characterization. Photogenerated spin polarization and coherences as process
      inherent features add the practical advantage of compensation in the trade-off
      between sensitivity and time resolution. Additionally, they provide detailed
      structural and dynamic information on the photoreactive system. Significance and
      specificity of the results achieved for charge separation in photosynthetic
      reaction centers and donor-acceptor model complexes indicate highly promising
      perspectives in photochemical research.

PMID- 15012456
TI  - Microphysics and heterogeneous chemistry of polar stratospheric clouds.
AB  - Liquid and solid particles in polar stratospheric clouds are of central
      importance for the depletion of stratospheric ozone. Surface-catalyzed reactions
      on these particles, and diffusion-controlled processes in the bulk of the
      particles, convert halogens, which derive from compounds of mainly anthropogenic
      origin, from relatively inert reservoir species into forms that efficiently
      destroy ozone. The microphysics of these particles under cold stratospheric
      conditions is still uncertain in many respects, in particular concerning phase
      transitions such as freezing nucleation and deposition nucleation. Furthermore,
      there are indications that the rates of key heterogeneous reactions have not yet
      been established with sufficient accuracy to enable a reliable diagnosis of
      observed ozone losses by means of global models. The present paper reviews the
      current (late 1996) knowledge of the physico-chemistry of polar stratospheric
      clouds and evaluates the remaining uncertainties with respect to their ozone
      depletion potential.

PMID- 15012457
TI  - On knowing a word.
AB  - A person who knows a word knows much more than its meaning and pronunciation. The
      contexts in which a word can be used to express a particular meaning are a
      critical component of word knowledge. The ability to exploit context in order to
      determine meaning and resolve potential ambiguities is not a uniquely linguistic
      ability, but it is dramatically illustrated in the ease with which native
      speakers are able to identify the intended meanings of common polysemous words.

PMID- 15012458
TI  - Conflict in marraige: implications for working with couples.
AB  - The investigation of marital conflict has reached a crossroads. Over 25 years of
      research on marital conflict behavior yields a relatively clear picture of its
      topography, but its relevance for changing the marital relationship remains
      controversial. We can continue to amass observations in a relatively atheoretical
      manner and hope that patterns capable of guiding clinical activity will emerge,
      or we can begin creating a unified theoretical framework to indicate new
      directions for clinical activity and empirical investigation. Before exploring
      the latter option, this chapter reviews briefly the impact of marital conflict on
      mental, physical, and family health and what is known about the nature of
      conflict in marriage. After highlighting some recent theoretically grounded
      advances, we illustrate how conceptualizing marital conflict behavior as goal
      directed provides an integrative theoretical framework for treatment, prevention,
      and marital conflict research.

PMID- 15012459
TI  - Deductive reasoning.
AB  - This chapter describes the main accounts of deductive competence, which explain
      what is computed in carrying out deductions. It argues that people have a modicum
      of competence, which is useful in daily life and a prerequisite for acquiring
      logical expertise. It outlines the three main sorts of theory of deductive
      performance, which explain how people make deductions: They rely on factual
      knowledge, formal rules, or mental models. It reviews recent experimental studies
      of deductive reasoning in order to help readers to assess these theories of
      performance.

PMID- 15012460
TI  - Quantifying the information value of clinical assessments with signal detection
      theory.
AB  - The aim of clinical assessment is to gather data that allow us to reduce
      uncertainty regarding the probabilities of events. This is a Bayesian view of
      assessment that is consistent with the well-known concept of incremental
      validity. Conventional approaches to evaluating the accuracy of assessment
      methods are confounded by the choice of cutting points, by the base rates of the
      events, and by the assessment goal (e.g. nomothetic vs idiographic predictions).
      Clinical assessors need a common metric for quantifying the information value of
      assessment data, independent of the cutting points, base rates, or particular
      application. Signal detection theory (SDT) provides such a metric. We review
      SDT's history, concepts, and methods and provide examples of its application to a
      variety of assessment problems.

PMID- 15012461
TI  - Organizational change and development.
AB  - Recent analyses of organizational change suggest a growing concern with the tempo
      of change, understood as the characteristic rate, rhythm, or pattern of work or
      activity. Episodic change is contrasted with continuous change on the basis of
      implied metaphors of organizing, analytic frameworks, ideal organizations,
      intervention theories, and roles for change agents. Episodic change follows the
      sequence unfreeze-transition-refreeze, whereas continuous change follows the
      sequence freeze-rebalance-unfreeze. Conceptualizations of inertia are seen to
      underlie the choice to view change as episodic or continuous.

PMID- 15012462
TI  - Lifespan psychology: theory and application to intellectual functioning.
AB  - The focus of this review is on theory and research of lifespan (lifespan
      developmental) psychology. The theoretical analysis integrates evolutionary and
      ontogenetic perspectives on cultural and human development across several levels
      of analysis. Specific predictions are advanced dealing with the general
      architecture of lifespan ontogeny, including its directionality and age
      differential allocation of developmental resources into the three major goals of
      developmental adaptation: growth, maintenance, and regulation of loss. Consistent
      with this general lifespan architecture, a meta-theory of development is outlined
      that is based on the orchestrated and adaptive interplay between three processes
      of behavioral regulation: selection, optimization, and compensation. Finally,
      these propositions and predictions about the general nature of lifespan
      development are examined and supported by empirical evidence on the development
      of cognition and intelligence across the life span.

PMID- 15012463
TI  - Survey research.
AB  - For the first time in decades, conventional wisdom about survey methodology is
      being challenged on many fronts. The insights gained can not only help
      psychologists do their research better but also provide useful insights into the
      basics of social interaction and cognition. This chapter reviews some of the many
      recent advances in the literature, including the following: New findings
      challenge a long-standing prejudice against studies with low response rates;
      innovative techniques for pretesting questionnaires offer opportunities for
      improving measurement validity; surprising effects of the verbal labels put on
      rating scale points have been identified, suggesting optimal approaches to scale
      labeling; respondents interpret questions on the basis of the norms of everyday
      conversation, so violations of those conventions introduce error; some
      measurement error thought to have been attributable to social desirability
      response bias now appears to be due to other factors instead, thus encouraging
      different approaches to fixing such problems; and a new theory of satisficing in
      questionnaire responding offers parsimonious explanations for a range of response
      patterns long recognized by psychologists and survey researchers but previously
      not well understood.

PMID- 15012464
TI  - Trust and distrust in organizations: emerging perspectives, enduring questions.
AB  - Scholarly interest in the study of trust and distrust in organizations has grown
      dramatically over the past five years. This interest has been fueled, at least in
      part, by accumulating evidence that trust has a number of important benefits for
      organizations and their members. A primary aim of this review is to assess the
      state of this rapidly growing literature. The review examines recent progress in
      conceptualizing trust and distrust in organizational theory, and also summarizes
      evidence regarding the myriad benefits of trust within organizational systems.
      The review also describes different forms of trust found in organizations, and
      the antecedent conditions that produce them. Although the benefits of trust are
      well-documented, creating and sustaining trust is often difficult. Accordingly,
      the chapter concludes by examining some of the psychological, social, and
      institutional barriers to the production of trust.

PMID- 15012465
TI  - The psychological underpinnings of democracy: A selective review of research on
      political tolerance, interpersonal trust, and social capital.
AB  - This chapter explores two psychological orientations that support democratic
      governance. First, robust democracies require citizens to tolerate others'
      efforts to participate in politics, even if they promote unpopular views.
      Research shows that citizens' political tolerance is influenced strongly by the
      depth of their commitment to democratic values, by their personality, and by the
      degree to which they perceive others as threatening. Cross-national research
      generalizes many of these findings to other countries. Second, robust democracies
      need citizens who will participate in politics. Almond and Verba's cross-national
      research shows that interpersonal trust and other features of political culture
      enhance citizen involvement in politics. Inglehart expanded the political culture
      framework in his work on post-materialism, interpersonal trust, life
      satisfaction, and cognitive mobilization. Recent theories of social capital also
      emphasize the role of generalized interpersonal trust, membership in voluntary
      associations, and norms of reciprocity in enhancing political participation and
      democracy.

PMID- 15012466
TI  - Current issues and emerging theories in animal cognition.
AB  - Comparative cognition is an emerging interdisciplinary field with contributions
      from comparative psychology, cognitive/experimental and developmental psychology,
      animal learning, and ethology, and is poised to move toward greater understanding
      of animal and human information-processing, reasoning, memory, and the
      phylogenetic emergence of mind. This chapter highlights some current issues and
      discusses four areas within comparative cognition that are yielding new
      approaches and hypotheses for studying basic conceptual capacities in nonhuman
      species. These include studies of imitation, tool use, mirror self-recognition,
      and the potential for attribution of mental states by nonhuman animals. Though a
      very old question in psychology, the study of imitation continues to provide new
      avenues for examining the complex relationships among and between the levels of
      imitative behaviors exhibited by many species. Similarly, recent work in animal
      tool use, mirror self-recognition (with all its contentious issues), and recent
      attempts to empirically study the potential for attributional capacities in
      nonhumans, all continue to provide fresh insights and novel paradigms for
      addressing the defining characteristics of these complex phenomena.

PMID- 15012467
TI  - Intergroup contact theory.
AB  - Allport specified four conditions for optimal intergroup contact: equal group
      status within the situation, common goals, intergroup cooperation and authority
      support. Varied research supports the hypothesis, but four problems remain. 1. A
      selection bias limits cross-sectional studies, since prejudiced people avoid
      intergroup contact. Yet research finds that the positive effects of cross-group
      friendship are larger than those of the bias. 2. Writers overburden the
      hypothesis with facilitating, but not essential, conditions. 3. The hypothesis
      fails to address process. The chapter proposes four processes: learning about the
      outgroup, changed behavior, affective ties, and ingroup reappraisal. 4. The
      hypothesis does not specify how the effects generalize to other situations, the
      outgroup or uninvolved outgroups. Acting sequentially, three strategies enhance
      generalization-decategorization, salient categorization, and recategorization.
      Finally, both individual differences and societal norms shape intergroup contact
      effects. The chapter outlines a longitudinal intergroup contact theory. It
      distinguishes between essential and facilitating factors, and emphasizes
      different outcomes for different stages of contact.

PMID- 15012468
TI  - Psychology and the study of marital processes.
AB  - The divorce rate in the United States is extremely high. It is estimated that
      between 50% and 67% of first marriages end in divorce. For second marriages,
      failure rates are even higher. There are strong negative consequences to
      separation and divorce on the mental and physical health of both spouses,
      including increased risk for psychopathology, increased rates of automobile
      accidents, and increased incidence of physical illness, suicide, violence,
      homicide, significant immunosuppression, and mortality from diseases. In
      children, marital distress, conflict, and disruption are associated with
      depression, withdrawal, poor social competence, health problems, poor academic
      performance, and a variety of conduct-related difficulties. Though intervention
      techniques might be expected to reduce these grim statistics, our best scholars
      have concluded that marital therapy is at a practical and theoretical impasse.
      This article discusses the progress of research on the study of marriage.

PMID- 15012469
TI  - Models of the emergence of language.
AB  - Recent work in language acquisition has shown how linguistic form emerges from
      the operation of self-organizing systems. The emergentist framework emphasizes
      ways in which the formal structures of language emerge from the interaction of
      social patterns, patterns implicit in the input, and pressures arising from
      general aspects of the cognitive system. Emergentist models have been developed
      to study the acquisition of auditory and articulatory patterns during infancy and
      the ways in which the learning of the first words emerges from the linkage of
      auditory, articulatory, and conceptual systems. Neural network models have also
      been used to study the learning of inflectional markings and basic syntactic
      patterns. Using both neural network modeling and concepts from the study of
      dynamic systems, it is possible to analyze language learning as the integration
      of emergent dynamic systems.

PMID- 15012470
TI  - Biases in the interpretation and use of research results.
AB  - The latter half of this century has seen an erosion in the perceived legitimacy
      of science as an impartial means of finding truth. Many research topics are the
      subject of highly politicized dispute; indeed, the objectivity of the entire
      discipline of psychology has been called into question. This essay examines
      attempts to use science to study science: specifically, bias in the
      interpretation and use of empirical research findings. I examine theory and
      research on a range of cognitive and motivational mechanisms for bias.
      Interestingly, not all biases are normatively proscribed; biased interpretations
      are defensible under some conditions, so long as those conditions are made
      explicit. I consider a variety of potentially corrective mechanisms, evaluate
      prospects for collective rationality, and compare inquisitorial and adversarial
      models of science.

PMID- 15012471
TI  - Consumer behavior: a quadrennium.
AB  - Consumer behavior continued to attract additional researchers and publication
      outlets from 1993 through 1996. Both general interest and domain-specific
      scholarly contributions are discussed, along with limitations and suggested areas
      for future research. A concluding section observes that the integrity of consumer
      research is unnecessarily compromised by the failure of the major scholarly
      association in the field to develop and adopt a code of researcher ethics.

PMID- 15012472
TI  - Social constructivist perspectives on teaching and learning.
AB  - Social constructivist perspectives focus on the interdependence of social and
      individual processes in the co-construction of knowledge. After the impetus for
      understanding the influence of social and cultural factors on cognition is
      reviewed, mechanisms hypothesized to account for learning from this perspective
      are identified, drawing from Piagetian and Vygotskian accounts. The empirical
      research reviewed illustrates (a) the application of institutional analyses to
      investigate schooling as a cultural process, (b) the application of interpersonal
      analyses to examine how interactions promote cognition and learning, and (c)
      discursive analyses examining and manipulating the patterns and opportunities in
      instructional conversation. The review concludes with a discussion of the
      application of this perspective to selected contemporary issues, including:
      acquiring expertise across domains, assessment, educational equity, and
      educational reform.

PMID- 15012473
TI  - Categorical data analysis.
AB  - This chapter reviews recent developments in the analysis of categorical and
      contingency-table data. The first portion examines developments in model testing
      and selection. The second portion examines work on models for the structure of
      dependence. These include log-linear parameter models, models for latent classes,
      models for missing observations, numerical-scale-based association and
      correlation models (such as correspondence analysis), the treatment of ordered
      categories, and models for marginal distributions.

PMID- 15012474
TI  - Theories linking culture and psychology: universal and community-specific
      processes.
AB  - Psychological theories and research often assume nations are culturally
      homogeneous and stable. But global demographic, political, and economic changes
      and massive immigration have sparked new scholarly and policy interest in
      cultural diversity and change within nations. This chapter reviews
      interdisciplinary advances linking culture and psychological development. These
      challenge and strengthen the external and ecological validity of psychological
      theories and their applications. Seven theoretical perspectives are reviewed:
      individualism-collectivism; ecological systems; cultural-ecological; social
      identity; ecocultural and sociocultural; structure-agency; and multiple worlds.
      Reviews of each theory summarize key constructs and evidence, recent advances,
      links between universal and community-specific research and applications, and
      strengths and limitations. The chapter traces complementarities across theories
      for the case of personal and social identity. It concludes by discussing
      implications for science and policy. By viewing theories as distinct yet
      complementary, researchers and policy makers can forge interdisciplinary,
      international, and intergenerational collaborations on behalf of the culturally
      diverse communities of which we are a part.

PMID- 15012475
TI  - Creative hypothesis generating in psychology: some useful heuristics.
AB  - To correct a common imbalance in methodology courses, focusing almost entirely on
      hypothesis-testing issues to the neglect of hypothesis-generating issues which
      are at least as important, 49 creative heuristics are described, divided into 5
      categories and 14 subcategories. Each of these heuristics has often been used to
      generate hypotheses in psychological research, and each is teachable to students.
      The 49 heuristics range from common sense perceptiveness of the oddity of natural
      occurrences to use of sophisticated quantitative data analyses in ways that
      provoke new insights.

PMID- 15012476
TI  - Human-computer interaction: psychology as a science of design.
AB  - Human-computer interaction (HCI) study is the region of intersection between
      psychology and the social sciences, on the one hand, and computer science and
      technology, on the other. HCI researchers analyze and design specific user
      interface technologies (e.g. pointing devices). They study and improve the
      processes of technology development (e.g. task analysis, design rationale). They
      develop and evaluate new applications of technology (e.g. word processors,
      digital libraries). Throughout the past two decades, HCI has progressively
      integrated its scientific concerns with the engineering goal of improving the
      usability of computer systems and applications, which has resulted in a body of
      technical knowledge and methodology. HCI continues to provide a challenging test
      domain for applying and developing psychological and social theory in the context
      of technology development and use.

PMID- 15012477
TI  - Discourse comprehension.
AB  - The field of discourse processing has dissected many of the levels of
      representation that are constructed when individuals read or listen to connected
      discourse. These levels include the surface code, the propositional textbase, the
      referential situation model, the communication context, and the discourse genre.
      Discourse psychologists have developed models that specify how these levels are
      mentally represented and how they are dynamically built during comprehension.
      This chapter focuses on the meaning representations that are constructed when
      adults read written text, such as literary stories, technical expository text,
      and experimenter-generated "textoids." Recent psychological models have attempted
      to account for the identification of referents of referring expressions (e.g.
      which person in the text does she refer to), the connection of explicit text
      segments, the establishment of local and global coherence, and the encoding of
      knowledge-based inferences.

PMID- 15012478
TI  - Personnel selection.
AB  - This chapter reviews literature from approximately mid-1993 through early 1996 in
      the areas of performance and criteria, validity, statistical and equal
      opportunity issues, selection for work groups, person-organization fit, applicant
      reactions to selection procedures, and research on predictors, including ability,
      personality, assessment centers, interviews, and biodata. The review revolves
      around three themes: (a) attention toward criteria and models of performance, (b)
      interest in personality measures as predictors of job performance, and (c) work
      on the person-organization fit selection model. In our judgment, these themes
      merge when it is recognized that development of performance models that
      differentiate criterion constructs reveal highly interpretable relationships
      between the predictor domain (i.e. ability, personality, and job knowledge) and
      the criterion domain (i.e. technical proficiency, extra-technical proficiency
      constructs such as prosocial organizational behavior, and overall job
      performance). These and related developments are advancing the science of
      personnel selection and should enhance selection practices in the future.

PMID- 15012479
TI  - Organizational behavior in the new organizational era.
AB  - Changes in contemporary firms and their competitive environments translate into a
      new focus in organizational research. This chapter reviews organizational
      behavior research reflecting the shift from corporatist organizations to
      organizing. Key research themes include emerging employment relations, managing
      the performance paradox, goal setting and self-management, discontinuous
      information processing, organization learning, organizational change and
      individual transitions, and the implications of change for work-nonwork
      relations. Research into organizing is building upon and extending many of the
      field's traditional concepts. This chapter suggests that some assumptions of
      organizational behavior research are being superseded by those more responsive to
      the new organizational era.

PMID- 15012480
TI  - Verbal learning and memory: does the modal model still work?
AB  - This chapter focuses on recent research concerning verbal learning and memory. A
      prominent guiding framework for research on this topic over the past three
      decades has been the modal model of memory, which postulates distinct sensory,
      primary, and secondary memory stores. Although this model continues to be
      popular, it has fostered much debate concerning its validity and specifically the
      need for its three separate memory stores. The chapter reviews research
      supporting and research contradicting the modal model, as well as alternative
      modern frameworks. Extensions of the modal model are discussed, including the
      search of associative memory model, the perturbation model, precategorical
      acoustic store, and permastore. Alternative approaches are discussed including
      working memory, conceptual short-term memory, long-term working memory, short
      term activation and attention, processing streams, the feature model,
      distinctiveness, and procedural reinstatement.

PMID- 15012481
TI  - Cross-cultural social and organizational psychology.
AB  - This review considers recent theoretical and empirical developments in cross
      cultural studies within social and organizational psychology. It begins with a
      description of the importance and the difficulties of universalizing
      psychological science. It then continues with an examination of theoretical work
      on both the internal-proximal and the external-distal constraints that mediate
      culture's influence on behavior. Influences on social cognition are documented by
      describing research on self-concept, self-esteem, emotions, attribution
      processes, person perception, interpersonal attraction, and justice. Group
      processes are addressed in the areas of leadership, decision-making, and
      negotiation, and research in organizational psychology is examined with respect
      to work motivation and work behavior. The review concludes that considerable
      improvement is evident in recent cross-cultural research. However, future
      research must include a broader range of cultures and attend more closely to the
      levels at which cultural effects should be analyzed, and cultural samples must be
      unpackaged in more psychologically useful ways.

PMID- 15012482
TI  - Stereotypes.
AB  - The stereotyping literature within psychology has grown considerably over the
      past decade. In large part, this growth can be attributed to progress in
      understanding the individual mechanisms that give rise to stereotypic thinking.
      In the current review, the recent psychological literature on stereotypes is
      reviewed, with particular emphasis given to the cognitive and motivational
      factors that contribute to stereotype formation, maintenance, application, and
      change. In addition, the context-dependent function of stereotypes is
      highlighted, as are the representational issues that various models of
      stereotypes imply.

PMID- 15012483
TI  - Expert and exceptional performance: evidence of maximal adaptation to task
      constraints.
AB  - Expert and exceptional performance are shown to be mediated by cognitive and
      perceptual-motor skills and by domain-specific physiological and anatomical
      adaptations. The highest levels of human performance in different domains can
      only be attained after around ten years of extended, daily amounts of deliberate
      practice activities. Laboratory analyses of expert performance in many domains
      such as chess, medicine, auditing, computer programming, bridge, physics, sports,
      typing, juggling, dance, and music reveal maximal adaptations of experts to
      domain-specific constraints. For example, acquired anticipatory skills circumvent
      general limits on reaction time, and distinctive memory skills allow a domain
      specific expansion of working memory capacity to support planning, reasoning, and
      evaluation. Many of the mechanisms of superior expert performance serve the dual
      purpose of mediating experts' current performance and of allowing continued
      improvement of this performance in response to informative feedback during
      practice activities.

PMID- 15012484
TI  - Teams in organizations: recent research on performance and effectiveness.
AB  - This review examines recent research on groups and teams, giving special emphasis
      to research investigating factors that influence the effectiveness of teams at
      work in organizations. Several performance-relevant factors are considered,
      including group composition, cohesiveness, and motivation, although certain
      topics (e.g. composition) have been more actively researched than others in
      recent years and so are addressed in greater depth. Also actively researched are
      certain types of teams, including flight crews, computer-supported groups, and
      various forms of autonomous work groups. Evidence on basic processes in and the
      performance effectiveness of such groups is reviewed. Also reviewed are findings
      from studies of organizational redesign involving the implementation of teams.
      Findings from these studies provide some of the strongest support for the value
      of teams to organizational effectiveness. The review concludes by briefly
      considering selected open questions and emerging directions in group research.

PMID- 15012485
TI  - Psychology in Canada.
AB  - This chapter reviews how psychology in Canada evolved over half a century to
      become the most popular discipline in universities and a respected health-care
      and helping profession. The organization, journals, and funding of the scientific
      discipline are described. The importance of DO Hebb's research as the stimulus
      and foundation for discipline growth and significant research contributions to
      basic processes is identified. The multicultural mosaic of Canadian society and
      early research on second-language learning are shown to have influenced cross
      cultural and social research. Canadian research contributions to basic processes
      and to the social and health sciences are reviewed. Although late to begin in
      Canada, clinical research and the profession of psychology are shown to have
      substantially developed over the past two decades. With large numbers of quality
      researchers and practitioners, psychology has a bright future in Canada.

PMID- 15012486
TI  - The social structure of schooling.
AB  - The term social structure refers to a relatively enduring pattern of social
      arrangements or interrelations within a particular society, organization, or
      group. This chapter reviews how the social structure of the larger society and
      the organizational structure of schools affect the educational process within
      American schools. The institutional context of schooling is first discussed. The
      ideology of mass education, social stratification, status attainment,
      credentialism, and the emphasis on ability differences are considered. The focus
      then shifts to the organizational structure of schools, beginning with a
      discussion of the external social context for school organization. Attention is
      given to professionalism and bureaucracy, institutional forms of organization,
      decentralized control, and community influences. Finally, the internal structure
      of school organization is considered: teachers' working conditions, status
      differences among students, and curriculum tracking. Throughout, the emphasis is
      on ways in which social structure influences what is taught in school, how it is
      taught, and what is learned.

PMID- 15012487
TI  - Cognitive skill acquisition.
AB  - Cognitive skill acquisition is acquiring the ability to solve problems in
      intellectual tasks, where success is determined more by subjects' knowledge than
      by their physical prowess. This review considers research conducted in the past
      ten years on cognitive skill acquisition. It covers the initial stages of
      acquiring a single principle or rule, the initial stages of acquiring a
      collection of interacting pieces of knowledge, and the final stages of acquiring
      a skill, wherein practice causes increases in speed and accuracy.

PMID- 15012488
TI  - Covariance structure analysis: statistical practice, theory, and directions.
AB  - Although covariance structure analysis is used increasingly to analyze
      nonexperimental data, important statistical requirements for its proper use are
      frequently ignored. Valid conclusions about the adequacy of a model as an
      acceptable representation of data, which are based on goodness-of-fit test
      statistics and standard errors of parameter estimates, rely on the model
      estimation procedure being appropriate for the data. Using analogies to linear
      regression and anova, this review examines conditions under which conclusions
      drawn from various estimation methods will be correct and the consequences of
      ignoring these conditions. A distinction is made between estimation methods that
      are either correctly or incorrectly specified for the distribution of data being
      analyzed, and it is shown that valid conclusions are possible even under
      misspecification. A brief example illustrates the ideas. Internet access is given
      to a computer code for several methods that are not available in programs such as
      EQS or LISREL.

PMID- 15012489
TI  - The motivational impact of temporal focus: thinking about the future and the
      past.
AB  - In this chapter, we consider the degree to which individuals are pulled to behave
      by their conceptions of the future, pushed to act by their recollections of the
      past, or primarily driven by current exigencies. In examining conceptions of the
      future, we discuss how individuals bridge the present and the future, the origin
      of goals, their impact on behavior and cognition, and the motivational
      underpinnings for inferring other people's goals. We then outline four
      theoretical approaches to goal prioritization, the motivational impact of
      proximal vs distal goals, and the distinction between approaching positive vs
      avoiding negative outcomes. Turning to conceptions of the past, we discuss the
      motivational push of the past, the use of the past to select one's goals, the
      impact current goals have on recall and interpretations of the past, and
      individual differences in using the past. We conclude that temporal focus
      provides a meaningful framework for social cognitive approaches to motivation.

PMID- 15012490
TI  - One phytopathologist's growth through ipm to holistic plant health: the key to
      approaching genetic yield potential.
AB  - I relate my becoming a phytopathologist and my very satisfying growth into and
      beyond IPM to holistic plant health, and puzzle over paradigms that have
      prevented our accepting the overwhelming logic of (a) seeking defensible disease
      loss data to justify funding and guide research and management priorities, (b)
      managing genetic diversity to retard pathogen development, (c) conserving genetic
      diversity in situ, and (d) educating and training general practitioner plant
      doctors. These multidisciplinary health care professionals are key to overcoming
      sources of stress that cause major world crops to yield only 15-20% of their
      genetic potential, on average. Thus, plant doctors give hope for approaching
      attainable yield and feeding a hungry world-if, simultaneously, human population
      growth is reduced. The plant health movement has the potential to effect the
      greatest change in world agriculture since the Green Revolution, and the DPH/M to
      become plant agriculture's most important single degree program.

PMID- 15012491
TI  - Katherine Esau, 1898-1997.

PMID- 15012492
TI  - Diversity among xanthomonads pathogenic on pepper and tomato.
AB  - Xanthomonas campestris pv. vesicatoria, causal agent of bacterial spot of tomato
      and pepper, had been considered for nearly 70 years to be a relatively
      homogeneous organism. However, in the past decade this bacterium was determined
      to be composed of two genetically and phenotypically distinct groups. The two
      groups, designated A and B, were distinguished based on amylolytic activity,
      expression of unique protein bands, reaction on differential hosts (tomato races
      T1 and T2), reaction patterns with monoclonal antibodies, DNA restriction
      profiles, and DNA:DNA hybridization. The A and B groups were placed into X.
      axonopodis pv. vesicatoria and X. vesicatoria, respectively. A third group,
      designated C, was pathogenically (race T3) and serologically distinct from A and
      B strains, and formed unique DNA restriction profiles. DNA:DNA hybridization data
      suggest that C is distinct but related to A strains and may represent a
      subspecies of A. A final group, designated D, consisted of X. gardneri, an
      organism identified in Yugoslavia in 1957, and also found in Costa Rica. Group D
      was determined to be genetically distinct from strains within the other two
      groups; it represents a third Xanthomonas species pathogenic on tomato and
      pepper.

PMID- 15012493
TI  - Current concepts of active defense in plants.
AB  - A growing body of evidence indicates that elicitation of primary active defense
      responses results from a recognition event frequently involving protein-protein
      interactions. Most pathogen avirulence determinants eliciting resistance gene
      dependent responses have been shown to be proteins with no apparent enzymic
      activity. Disruption of the tertiary and quaternary structure of these proteins
      abolishes their elicitor activity. Critical to their elicitor activity is their
      display by the pathogen. Resistance genes are proposed to function as receptors
      for the eliciting proteins. The most consistent feature of resistance gene
      products is the presence of potential protein binding domains in the form of
      leucine-rich repeat regions, and there is direct evidence for the physical
      interaction of elicitor proteins and receptor proteins in several cases. Thus in
      many but not all cases the primary recognition event eliciting an active defense
      response during incompatible interactions appears to be a protein-protein
      interaction occurring between a specific pathogen protein and a strategically
      placed receptor protein in the host cell. The interaction of elicitor protein
      with the receptor protein activates a signal transduction pathway leading to
      programmed cell death and an oxidative burst.

PMID- 15012494
TI  - Cypress canker: a pandemic in progress.
AB  - Over the past 70 years a destructive blight of Cupressus macrocarpa and other
      Cupressaceae, caused by Seiridium cardinale, has spread worldwide from
      California, devastating forests, plantations, and ornamental cypresses. The
      epidemic has been particularly severe in the Mediterranean region, on C.
      sempervirens. A similar destructive blight induced by Lepteutypa cupressi, which
      caused serious losses to Monterey cypresses in East Africa in the 1940s, has now
      also spread to distant continents, albeit to a lesser extent. There is yet a
      third wave of canker disease induced by S. unicorne, although this is a milder
      type. This review deals with problems related to identification of the pathogens,
      their taxonomy, pathogenesis and role of fungal toxins, and early screening of
      cypress clones or hybrids for resistance to the pathogens and tolerance to their
      toxins.

PMID- 15012495
TI  - Application of mating type gene technology to problems in fungal biology.
AB  - In ascomycetes, the single mating type locus (MAT) controls sexual development.
      This locus is structurally unusual because the two alternate forms ("alleles")
      are completely dissimilar sequences, encoding different transcription factors,
      yet they occupy the same chromosomal position. Recently developed procedures
      allow efficient cloning of MAT genes from a wide array of filamentous
      ascomycetes, thereby providing MAT-based technology for application to several
      ongoing issues in fungal biology. This article first outlines the basic nature of
      MAT genes, then addresses the following topics: efficient cloning of MAT genes;
      the unusual molecular characteristics of these genes; phylogenetics using MAT;
      the issues of why some fungi are self-sterile, others self-fertile, and yet
      others asexual; the long-standing mystery of possible mating type switching in
      filamentous fungi; and finally the evolutionary origins of pathogenic capability.

PMID- 15012496
TI  - Biology and molecular biology of viruses in the genus Tenuivirus.
AB  - Viruses in the genus Tenuivirus (Tenuiviruses) cause a number of important
      diseases in economically important crop plants including rice and maize.
      Tenuiviruses are transmitted from plant to plant by specific planthopper vectors,
      and their transmission relationship is circulative-propagative. Thus,
      Tenuiviruses have host ranges including plants and animals (planthoppers). Four
      or five characteristic, circular ribonucleoprotein particles (RNPs), each
      containing a single Tenuivirus genomic RNA, can be isolated from Tenuivirus
      infected plants. The genomic RNAs range in size from ca 9.0 kb to 1.3 kb and
      together give a total genome size of ca 18-19 kb. The genomic RNAs are either
      negative-sense or ambisense, and expression of the ambisense RNAs utilizes cap
      snatching during mRNA transcription. The combination of characteristics exhibited
      by Tenuiviruses are quite different than those found for most plant viruses and
      are more similar to vertebrate-infecting viruses in the genus Phlebovirus of the
      Bunyaviridae.

PMID- 15012497
TI  - Developing sustainable systems for nematode management.
AB  - Early researchers identified key concepts and developed tactics for multiple
      option management of nematodes. Although the emphasis on integrated pest
      management over the past three decades has promoted strategies and tactics for
      nematode management, comprehensive studies on the related soil biology-ecology
      are relatively recent. Traditional management tactics include host resistance
      (where available), cultural tactics such as rotation with nonhosts, sanitation
      and avoidance, and destruction of residual crop roots, and the judicious use of
      nematicides. There have been advances in biological control of nematodes, but
      field-scale exploitation of this tactic remains to be realized. New technologies
      and resources are currently becoming central to the development of sustainable
      systems for nematode-pest-crop management: molecular diagnostics for nematode
      identification, genetic engineering for host resistance, and the elucidation and
      application of soil biology for general integrated cropping systems. The latter
      strategy includes the use of nematode-pest antagonistic cover crops, animal
      wastes, and limited tillage practices that favor growth-promoting rhizobacteria,
      earthworms, predatory mites, and other beneficial organisms while suppressing
      parasitic nematodes and other plant pathogens. Certain rhizobacteria may induce
      systemic host resistance to nematodes and, in some instances, to foliage
      pathogens. The systems focusing on soil biology hold great promise for
      sustainable crop-nematode management, but only a few research programs are
      currently involved in this labor-intensive endeavor.

PMID- 15012498
TI  - Homoserine lactone-mediated gene regulation in plant-associated bacteria.
AB  - Many plant-associated bacteria produce and utilize diffusible N-acyl-homoserine
      lactones (AHLs) to regulate the expression of specific bacterial genes and
      operons. AHL-mediated regulation utilizes two genes that encode proteins similar
      to the LuxI/LuxR system originally studied in the marine symbiont Vibrio
      fischeri. The LuxI-type proteins are AHL synthases that assemble the diffusible
      AHL signal. The LuxR-type proteins are AHL-responsive transcriptional regulatory
      proteins. LuxR proteins control the transcription of specific bacterial genes in
      response to the levels of AHL signal. To date, AHL-mediated gene regulation has
      been identified in a broad range of gram-negative bacteria, most of which are
      host-associated. However, it seems unlikely that such a widely conserved
      regulatory mechanism would be limited only to host-microbe interactions. These
      signals probably play central roles in ecological interactions among organisms in
      microbial communities by affecting communication among bacterial populations as
      well as between bacterial populations and their eukaryotic hosts.

PMID- 15012499
TI  - Management of fire blight: a case study in microbial ecology.
AB  - Suppression of the blossom-blight phase of fire blight is a key point in the
      management of this destructive and increasingly important disease of apple and
      pear. For blossom infection to occur, the causal bacterium, Erwinia amylovora,
      needs to increase its population size through an epiphytic phase that occurs on
      stigmatic surfaces. Knowledge of the ecology of the pathogen on stigmas has been
      key to the development of predictive models for infection and optimal timing of
      antibiotic sprays. Other bacterial epiphytes also colonize stigmas where they can
      interact with and suppress epiphytic growth of the pathogen. A commercially
      available bacterial antagonist of E. amylovora (BlightBan, Pseudomonas
      fluorescens A506) can be included in antibiotic spray programs. Integration of
      bacterial antagonists with chemical methods suppresses populations of the
      pathogen and concomitantly, fills the ecological niche provided by the stigma
      with a nonpathogenic, competing microorganism. Further integration of
      biologically based methods with conventional management of blossom blight may be
      achievable by increasing the diversity of applied antagonists, by refining
      predictive models to incorporate antagonist use, and by gaining an improved
      understanding of the interactions that occur among indigenous and applied
      bacterial epiphytes, antibiotics, and the physical environment.

PMID- 15012500
TI  - Recombination in Magnaporthe grisea.
AB  - The heterothallic ascomycete, Magnaporthe grisea, is the blast pathogen of rice
      and about 50 other grasses, and has potential for sexual and asexual
      reproduction. In most populations, data from mating type, fertility assays, and
      genotypic diversity strongly suggest that the pathogen is asexual. However,
      parasexual recombination cannot be ruled out. Chromosome length polymorphisms and
      translocations may prevent successful meiosis in most populations. Pathogens of
      millets and some grasses growing with rice appear to be largely genetically
      isolated, though some gene flow may occur. Sexual fertility has repeatedly been
      reported in rice pathogens from mountainous regions of South and East Asia.
      Several means by which sexual fertility may be lost in an agricultural setting
      are advanced.

PMID- 15012501
TI  - Root-knot nematode resistance genes in tomato and their potential for future use.
AB  - The gene Mi, which confers resistance to several species of root-knot nematode,
      is present in many modern tomato cultivars. Recent cloning of this gene revealed
      that it encodes a member of the plant resistance protein family characterized by
      the presence of a putative nucleotide binding site and a leucine-rich repeat.
      Analysis of transgenic plants revealed the unexpected result that Mi also confers
      resistance to potato aphids. Although highly effective in many conditions, Mi
      fails to confer resistance at high soil temperature, and Mi-virulent nematode
      isolates have been identified in many areas of the world. These findings have
      stimulated efforts to identify new sources of root-knot nematode resistance.
      Resistance genes that differ from Mi in properties and genetic position have been
      identified in Lycopersicon peruvianum. These genes, as well as the cloned Mi
      gene, provide a resource for broadening the base of root-knot nematode resistance
      in tomato and other crops.

PMID- 15012502
TI  - Satellite tobacco mosaic virus.
AB  - Satellite tobacco mosaic virus (STMV) is a small, spherical ssRNA virus common in
      a natural wild plant, Nicotiana glauca or tree tobacco, in southern California
      and is one of the best-studied satellite viruses. It is the only satellite virus
      that has rod-shaped viruses (tobamoviruses) for its helper. In addition to
      describing the general properties of STMV, this review focuses on (a) the
      structural properties of the virus particle including the RNA within the particle
      that is partially double stranded; (b) the genetic diversity within the type
      strain before and after serial passage and between different field isolates; (c)
      the effect of experimental mutation on infectivity, replication, and
      symptomatology; and (d) the genetic changes that occur when the satellite virus
      adapts to different helper tobamoviruses.

PMID- 15012503
TI  - Function of root border cells in plant health: pioneers in the rhizosphere.
AB  - Plants dedicate a large amount of energy to the regulated production of living
      cells programmed to separate from roots into the external environment. This
      unusual process may be worth the cost because it enables the plant to dictate
      which species will share its ecological niche. For example, border cells can
      rapidly attract and stimulate growth in some microorganisms and repel and inhibit
      the growth of others. Such specificity may provide a way to control the dynamics
      of adjacent microbial populations in the soil to foster beneficial associations
      and inhibit pathogenic invasion. Plant genes controlling the delivery of border
      cells and the expression of their unique properties provide tools to genetically
      engineer plants with altered border cell quality and quantity. Such variants are
      being used to test the hypothesis that the function of border cells is to protect
      plant health by controlling the ecology of the root system.

PMID- 15012504
TI  - Genetics and physiology of aflatoxin biosynthesis.
AB  - Aflatoxins are the most thoroughly studied mycotoxins. Elegant early research on
      the biosynthetic scheme of the pathway has allowed a molecular characterization
      of aflatoxin biosynthesis and its regulation. Genetic studies on aflatoxin
      biosynthesis in Aspergillus flavus and A. parasiticus, and sterigmatocystin
      biosynthesis in A. nidulans, led to the cloning of 17 genes responsible for 12
      enzymatic conversions in the AF/ST pathways. Pathway-specific regulation is by a
      Zn(II)2Cys6 DNA-binding protein that regulates the transcription of all pathway
      genes. Less is known about the global factors that regulate aflatoxin
      biosynthesis, but there is a clear link between development and aflatoxin
      biosynthesis. There is also a large body of information on physiological factors
      involved in aflatoxin biosynthesis, but it has been difficult to understand their
      role in the regulation of this pathway. This chapter discusses current knowledge
      on the molecular biology and genetics of the pathway, and provides a summary of
      the physiological factors known to influence aflatoxin formation.

PMID- 15012505
TI  - Type III protein secretion systems in plant and animal pathogenic bacteria.
AB  - Among many interesting and sophisticated mechanisms used by bacterial pathogens
      to subvert eukaryotic hosts is a class of specialized protein secretion systems
      (known as type III protein secretion systems) that deliver bacterial virulence
      proteins directly into the host cell. Recent studies have revealed four important
      features of these secretion systems. First, they are widespread among plant and
      animal bacterial pathogens, and mutations affecting type III protein secretion
      often eliminate bacterial virulence completely. Second, at least eight type III
      secretion components share sequence similarities with those of the flagellar
      assembly machinery and flagellum-like structures are associated with type III
      secretion, raising the possibility that these secretion systems are derived from
      the presumably more ancient flagellar assembly apparatus. Third, type III
      secretion is activated in vivo upon contact with host cells. Fourth, the type III
      secretion mechanism is Sec-independent and the effector proteins may possess mRNA
      based targeting signals. This review highlights the similarities and differences
      among type III secretion systems of selected model plant and animal pathogenic
      bacteria.

PMID- 15012506
TI  - Programmed cell death in plant disease: the purpose and promise of cellular
      suicide.
AB  - The interaction of pathogens with plants leads to a disruption in cellular
      homeostasis, often leading to cell death, in both compatible and incompatible
      relationships. The mechanistic basis of this cellular disruption and consequent
      death is complex and poorly characterized, but it is established that host
      responses to pathogens are dependent on gene expression, involve signal
      transduction, and require energy. Recent data suggest that in animals, a
      genetically regulated, signal transduction-dependent programmed cell death
      process, commonly referred to as apoptosis, is conserved over a wide range of
      phyla. The basic function of apoptosis is to direct the selective elimination of
      certain cells during development, but it also is a master template that is
      involved in host responses to many pathogens. Programmed cell death in plants,
      while widely observed, has not been studied extensively at either the biochemical
      or genetic level. Current data suggest that activation or suppression of
      programmed cell death may underlie diseases in plants as it does in animals. This
      review describes some of the fundamental characteristics of apoptosis in animals
      and points to a number of connections to programmed cell death in plants that may
      lead to both a better understanding of disease processes and novel strategies for
      engineering disease resistance in plants.

PMID- 15012507
TI  - Control of papaya ringspot virus in papaya: a case study.
AB  - The papaya crop is severely affected by papaya ringspot virus (PSRV) worldwide.
      This review focuses on efforts to control the destructiveness of the disease
      caused by PSRV in Hawaii, starting from the use of cross protection to parasite
      derived resistance with transgenic papaya expressing the PSRV coat protein gene.
      A chronology of the research effort is given and related to the development of
      technologies and the pressing need to control PSRV in Hawaii. The development of
      commercial virus-resistant transgenic papaya provides a tangible approach to
      control PSRV in Hawaii. Moreover, the development of transgenic papaya by other
      laboratories and employment of a mechanism of effective technology transfer to
      different countries hold promise for control of PSRV worldwide.

PMID- 15012508
TI  - Root cortex--the final frontier for the biocontrol of root-rot with fungal
      antagonists: a case study on a sterile red fungus.
AB  - Root cortices remain as the last frontier for the biocontrol agents to protect
      the vascular elements from the invader, where the virulent pathogen has breached
      the bulk soil, rhizosphere, and rhizoplane. Root cortices are commonly colonized
      by a variety of soilborne fungi. Many nonmycorrhizal biocontrol fungi that occupy
      the rhizosphere appear to extend their activity into the live cells of the
      cortex. It has been proposed that the occupation of the cortices by biocontrol
      fungi introduced on seed at sowing could extend their activity in time and space.
      The biology and ecology of such fungi with parasitic competency to colonize live
      cortical cells are discussed in relation to a case study involving a sterile
      cortical fungus.

PMID- 15012509
TI  - Systemic resistance induced by rhizosphere bacteria.
AB  - Nonpathogenic rhizobacteria can induce a systemic resistance in plants that is
      phenotypically similar to pathogen-induced systemic acquired resistance (SAR).
      Rhizobacteria-mediated induced systemic resistance (ISR) has been demonstrated
      against fungi, bacteria, and viruses in Arabidopsis, bean, carnation, cucumber,
      radish, tobacco, and tomato under conditions in which the inducing bacteria and
      the challenging pathogen remained spatially separated. Bacterial strains differ
      in their ability to induce resistance in different plant species, and plants show
      variation in the expression of ISR upon induction by specific bacterial strains.
      Bacterial determinants of ISR include lipopolysaccharides, siderophores, and
      salicylic acid (SA). Whereas some of the rhizobacteria induce resistance through
      the SA-dependent SAR pathway, others do not and require jasmonic acid and
      ethylene perception by the plant for ISR to develop. No consistent host plant
      alterations are associated with the induced state, but upon challenge
      inoculation, resistance responses are accelerated and enhanced. ISR is effective
      under field conditions and offers a natural mechanism for biological control of
      plant disease.

PMID- 15012510
TI  - The impact of reduced tillage on soilborne plant pathogens.
AB  - Farmers increasingly leave crop residues on the soil surface rather than
      incorporating them into the soil. This practice helps reduce soil erosion,
      conserve energy, increase soil moisture, and increase crop yields. However, many
      soilborne plant pathogens survive in the previous year's crop residue, making
      diseases more problematic under reduced-tillage conditions. Reduced tillage can
      favor pathogens by such mechanisms as protecting the pathogen's refuge in the
      residue from microbial degradation, lowering soil temperature, increasing soil
      moisture, and leaving soil undisturbed. In order for reduced tillage to become
      more popular, additional controls are needed for pathogens. The four major
      control tactics (disease-control chemicals, biological control, host resistance,
      and cultural controls) can be used to limit damage from diseases. It is highly
      recommended, however, that crop rotation be coupled with reduced tillage. This
      practice controls many diseases and yet allows as much of the crop residue as
      possible to be retained on the soil surface.

PMID- 15012512
TI  - Frank Lamson-Scribner: botanist and pioneer plant pathologist in the United
      States.
AB  - Frank Lamson-Scribner, in 1885, became the first scientist commissioned by the
      United States Department of Agriculture with the responsibility to study diseases
      of economic plants. His innovative approach established the foundation for
      applied plant pathology at the USDA. In an early international cooperative effort
      in plant pathology, he detailed the life history of the grape black rot pathogen.
      His early studies with the Bordeaux mixture introduced the American farmer to the
      modern era of chemical control. Scribner became the botanist and director of the
      University of Tennessee Agricultural Experiment Station. He published the first
      book written on the subject of plant diseases in the United States, and described
      a new nematode disease of potato. He asserted that the practical value of plant
      pathology to farmers would only follow meticulous studies of the life history of
      pathogens.

PMID- 15012511
TI  - Philip Herries Gregory 1907-1986: pioneer aerobiologist, versatile mycologist.
AB  - Philip Gregory pioneered aerobiology as a topic for research, drawing together
      inputs from many disciplines to contribute to better understanding of fungal
      spore dispersal, plant disease epidemiology, and allergy. In childhood, he was
      interested in natural history and meteorology and frequently suffered from
      asthma. Initially, he worked with dermatophytes in Winnipeg, where he was
      influenced by Buller. Returning to Britain, he investigated the epidemiology
      first of flower bulb diseases and then of potato virus diseases, noting the
      occurrence of disease gradients in crops. He developed theories of spore
      dispersal during wartime air-raid duties and published these in his classic paper
      of 1945. The remainder of his career was largely spent obtaining data in support
      of his theories of spore dispersal and disease gradients, on understanding splash
      dispersal, in identifying the cause of farmer's lung disease, and in his
      retirement, in elucidating the epidemiology of black pod disease of cocoa in
      Nigeria.

PMID- 15012513
TI  - Beverly T. Galloway: visionary administrator.
AB  - With a career that began at the University of Missouri in the early 1880s and
      culminated at the USDA in the 1930s, Beverly Galloway devoted his life to
      practical botany and agriculture. He became a driving force in the movement for
      "New Botany" during a period that stressed an experimental approach as well as
      new disciplines such as plant pathology. As administrator and scientist, he was
      arguably the single, most influential figure involved in the early growth and
      development of plant pathology and the plant sciences generally in the USDA. From
      assistant mycologist in the Section of Mycology to Chief of the Bureau of Plant
      Industry to Assistant Secretary of the USDA, Galloway displayed exceptional
      administrative acumen. His administrative and scientific skills were instrumental
      in laying the foundations for the science of plant pathology during its formative
      period in the United States.

PMID- 15012514
TI  - The impact of Ti-plasmid-derived gene vectors on the study of the mechanism of
      action of phytohormones.
AB  - The molecular basis of tumor formation on dicotyledonous plants by Agrobacterium
      relies on the transfer to the plant cell of a unique segment of bacterial DNA,
      the T-DNA. The T-DNA contains genes that are active in the plant cell and encode
      hormone biosynthetic enzymes, or proteins that deregulate the cell's response to
      phytohormones. Study of this process has yielded not only knowledge of how
      alterations in phytohormone homeostasis can affect plant cell growth, but also
      has provided the essential tools to study phytohormone signaling in transgenic
      plants. Furthermore, T-DNA insertion into the plant genome forms the basis of
      gene tagging, a versatile method for isolating genes involved in phytohormone
      signal transduction and action.

PMID- 15012515
TI  - Presentation of heterologous peptides on plant viruses: genetics, structure, and
      function.
AB  - Capsid proteins of a number of plant viruses are permissive to genetic
      modifications in which foreign polypeptides are inserted in exposed loops or at
      their C termini. Plant viruses with these genetic alterations often grow at wild
      type levels, providing gram quantities of modified viruses. Presented
      polypeptides studied most extensively correspond to antigenic epitopes of animal
      viruses and in some cases appropriately altered plant viruses generate
      neutralizing antibodies to the cognate animal virus when the plant virus is used
      as a vaccine. Structure-based analyses of these animal-plant virus chimeras have
      led to rational alterations to the presentation in efforts to increase the
      efficacy of the presented peptide.

PMID- 15012516
TI  - White pine blister rust control in North America: a case history.
AB  - White pine blister rust was introduced into North America at the turn of the
      twentieth century, threatening valuable white pine resources. Measures to
      eliminate, contain, or control this disease constitute the most extensive forest
      disease control effort in time, money, men, and materiel in the history of US
      forestry. The major thrust was protection of pine stands by eliminating currant
      and gooseberry (ribes) alternate hosts from within and around these stands.
      Failures with ribes eradication resulted in application of antibiotic fungicides
      without adequate testing. These failures, coupled with lower dependence on white
      pines and reduced need for a large reserve of men for fire fighting, led to
      sudden termination of the program in 1967. The chronology of events and
      interactions between agencies and personnel responsible for the program provide
      an interesting case history and, it is hoped, valuable lessons for the future.

PMID- 15012517
TI  - The evolutionary biology of Fusarium oxysporum.
AB  - Fusarium oxysporum is an anamorphic species that includes both pathogenic and
      nonpathogenic strains. Plant pathogenic forms cause a wilt disease and are
      grouped into formae speciales based on their host range; some are further
      subdivided into pathogenic races. Many formae speciales are comprised of multiple
      clonal lineages and, in some cases, a pathogenic race is associated with more
      than one clonal lineage, suggesting independent origins. Although some evidence
      suggests one pathogenic race may give rise to another, recent derivation of a
      pathogen from a nonpathogen has not been documented. Most new occurrences of
      Fusarium wilt appear to be the result of a recent introduction rather than an
      independent local origin of the pathotype. Asexual propagation is the dominant
      influence on population structure in F. oxysporum and the absence of sexual
      reproduction is not likely to prevent this pathogen from continuing to inflict
      significant damage on susceptible crop hosts.

PMID- 15012518
TI  - The role of hrp genes during plant-bacterial interactions.
AB  - hrp genes control the ability of phytopathogenic bacteria to cause disease and to
      elicit hypersensitive reactions on resistant plants. Genetic and biochemical
      studies have demonstrated that Hrp proteins are components of Type III secretion
      systems, regulatory proteins, proteinaceous elicitors of the hypersensitive
      reaction, and enzymes needed for synthesis of periplasmic glucans. Significantly,
      Type III secretion systems are involved with the secretion of pathogenicity
      proteins in bacterial pathogens of animals. The transcriptional activation of a
      number of bacterial avirulence (avr) genes is controlled by Hrp regulatory
      proteins, and recent experimental evidence suggests that Avr proteins may be
      transported by Hrp secretion systems. It has also been hypothesized that
      pathogenicity and/or virulence gene products exit bacterial phytopathogens via
      Hrp pathways. Thus, hrp genes may be one of the most important groups of genes
      found in phytopathogenic bacteria in relationship to pathogenicity and host
      range.

PMID- 15012519
TI  - The pinewood nematode: regulation and mitigation.
AB  - In North America, the native pinewood nematode (PWN), Bursaphelenchus xylophilus,
      kills exotic pines. When inadvertently introduced to Japan and other Asian
      countries, PWN became a destructive pest of pines. The PWN has been intercepted
      in pine shipments from North America to Europe, where there is concern that it
      may also kill pines and other conifers. To protect their forests from the PWN and
      other pests, the European Union and other countries now regulate the import of
      all coniferous chips, sawn wood, and logs. Several species of Bursaphelenchus
      have a phoretic relationship with Monochamus spp., which carry them to recently
      felled logs and dead or dying conifers, particularly pines. As a result, species
      of Monochamus, Bursaphelenchus, or both may be found in chips, unseasoned lumber,
      and logs. During the past decade, procedures to disinfest transported unprocessed
      wood have been investigated. These mitigation measures include prevention, host
      selection, and treatment by fumigation, irradiation, chemical dips, and elevated
      temperatures.

PMID- 15012520
TI  - Barley yellow dwarf viruses.
AB  - Barley yellow dwarf viruses represent one of the most economically important and
      ubiquitous groups of plant viruses. This review focuses primarily on four
      research areas in which progress has been most rapid. These include (a) evidence
      supporting reclassification of BYDVs into two genera; (b) elucidation of gene
      function and novel mechanisms controlling gene expression; (c) initial forays
      into understanding the complex interactions between BYDV virions and their aphid
      vectors; and (d) replication of a BYDV satellite RNA. Economic losses,
      symptomatology, and means of control of BYD are also discussed.

PMID- 15012521
TI  - Mechanisms of plant virus evolution.
AB  - Plant viruses utilize several mechanisms to generate the large amount of genetic
      diversity found both within and between species. Plant RNA viruses and
      pararetroviruses probably have highly error prone replication mechanisms, that
      result in numerous mutations and a quasispecies nature. The plant DNA viruses
      also exhibit diversity, but the source of this is less clear. Plant viruses
      frequently use recombination and reassortment as driving forces in evolution,
      and, occasionally, other mechanisms such as gene duplication and overprinting.
      The amount of variation found in different species of plant viruses is remarkably
      different, even though there is no evidence that the mutation rate varies. The
      origin of plant viruses is uncertain, but several possible theories are proposed.
      The relationships between some plant and animal viruses suggests a common origin,
      possibly an insect virus. The propensity for rapid adaptation makes tracing the
      evolutionary history of viruses difficult, and long term control of virus disease
      nearly impossible, but it provides an excellent model system for studying general
      mechanisms of molecular evolution.

PMID- 15012522
TI  - Signal pathways and appressorium morphogenesis.
AB  - Fungal pathogens have evolved elaborate strategies to gain access to plant
      tissues. For many pathogens, following attachment of spores to the leaf surface,
      germ tubes emerge and grow across the surface, often in response to particular
      environmental cues and to a specific location. At an appropriate site, polar
      elongation of the germ tube ceases, the tip attaches to the surface and swells to
      form an appressorium, a uniquely organized infection structure. Following a
      period of maturation, a hypha then emerges at the plant interface and penetrates
      into the plant tissues. This chapter discusses recent developments that provide
      new insight into the molecular mechanism regulating induction and function of
      appressoria. Topics include attachment to the leaf surface; environmental cues
      that signal germ-tube growth and appressorium formation; mechanisms for sensing
      environmental cues; endogenous signaling pathways; and mechanisms of penetration
      from the appressorium.

PMID- 15012523
TI  - Systemic acquired resistance.
AB  - This paper examines induced resistance (SAR) in plants against various insect and
      pathogenic invaders. SAR confers quantitative protection against a broad spectrum
      of microorganisms in a manner comparable to immunization in mammals, although the
      underlying mechanisms differ. Discussed here are the molecular events underlying
      SAR: the mechanisms involved in SAR, including lignification and other structural
      barriers, pathogenesis-related proteins and their expression, and the signals for
      SAR including salicylic acid. Recent findings on the biological role of systemin,
      ethylene, jasmonates, and electrical signals are reviewed. Chemical activators of
      SAR comprise inorganic compounds, natural compounds, and synthetic compounds.
      Plants known to exhibit SAR and induced systemic resistance are listed.

PMID- 15012525
TI  - Structure and evolution of the rp1 complex conferring rust resistance in maize.
AB  - Genetic analyses of the rp1 rust resistance complex of maize have demonstrated
      that recombination plays a central role in the creation of genetic diversity at
      the locus. The generation of rp1 diversity is promoted by a high rate of
      intragenic recombination coupled with a tendency for genes in the complex to
      mispair in meiosis. Among the novel rp1 genes that have been identified include
      genes with novel race-specificities and genes conferring lesion mimic phenotypes.
      Recombinants have also been identified that confer partial resistance which is
      apparently non-race-specific and may be useful in controlling maize rusts in a
      durable manner.

PMID- 15012524
TI  - Advances in the molecular genetic analysis of the flax-flax rust interaction.
AB  - The L6 and M rust-resistance genes, representing two of the five rust-resistance
      gene loci in flax (Linum usitatissimum), have been cloned. The molecular data are
      fully consistent with earlier genetic data: the L locus is a single gene with
      multiple alleles expressing different rust resistance specificities, and the M
      locus is complex, containing an array of about 15 similar genes. Thus, while L6
      and M resistance genes have 86% nucleotide identity, their locus structure is
      very different. These genes encode products belonging to the nucleotide binding
      site-leucine-rich repeat class of disease-resistance proteins. Analysis of
      alleles from the L locus and chimeric genes is providing evidence suggesting that
      important specificity determinants occur in the C-terminal half of the proteins,
      the region containing the leucine-rich repeats. The isolation and
      characterization of the rust (Melampsora lini) avirulence genes that correspond
      to the cloned rust-resistance genes is one of the major challenges remaining to
      the understanding of this system.

PMID- 15012526
TI  - Anticipatory breeding for resistance to rust diseases in wheat.
AB  - Anticipatory resistance breeding is the process of predicting future pathotypes
      and producing resistant germplasm to avert future losses. It is made possible by
      a national pathotype surveillance program and knowledge that new pathotypes arise
      predominantly from mutation in existing pathotypes. This is supported by genetic
      analyses to catalogue the identity and distribution of resistance genes in
      current cultivars. A national germplasm enhancement program ensuring that both
      currently effective and potentially new sources of resistance are available in a
      wide range of adapted genotypes enables rapid cultivar replacement before or soon
      after the occurrence of new pathotypes. The policy of recommending only rust
      resistant cultivars in the more rust-prone areas has resulted in significant
      reductions in pathogen population size and variability. With increased and more
      rapid international human travel and transport, there is an increased threat of
      exotic pathotypes, the effects of which are more difficult to predict. As the
      frequency and magnitude of epidemics decline, public awareness programs will be
      required to achieve and maintain the use of rust resistance by the entire wheat
      industry.

PMID- 15012527
TI  - Microbial population dynamics on leaves.
AB  - Microbial population dynamics on leaves in time and space are a function of
      immigration, emigration, growth, and death. Insight into the relative
      significance of each population process to the generation of specific dynamics
      for individual microorganisms is necessary to understanding the ecology and life
      history strategy of the microorganism and to developing effective control
      strategies. Additionally, information on the significance of within-leaf versus
      extra-leaf processes to the generation of phyllosphere dynamics is important to
      determining the range of spatial scales over which a population should be
      studied. Unfortunately, such information is difficult to obtain due to the lack
      of effective methodologies for distinguishing these processes within phyllosphere
      populations. Future research efforts should focus on the quantification of
      immigration, emigration, growth, and death relative to the population dynamics of
      phyllosphere microorganisms.

PMID- 15012528
TI  - Rationale and perspectives on the development of fungicides.
AB  - Fungicides continue to be essential for the effective control of plant diseases.
      New classes of fungicides with novel modes of action are being developed in the
      1990s. These include the strobilurins, phenylpyrroles, anilinopyrimidines,
      phenoxyquinolines, and compounds that trigger defense mechanisms in the plant.
      For the foreseeable future, new toxophores will be identified through a process
      of random screening, with natural products representing a rich source of
      fungicide leads. Progress is being made in the development of high-throughput
      screens comprised of target enzyme sites or cell-based assays; these techniques
      will improve the probability of discovery. Following the identification of
      suitable leads, biorational design is used to optimize specific properties. In
      vivo glasshouse screens and field trials are expected to remain the dominant
      methods for characterizing new compounds. Low toxicity to humans and wildlife,
      low environmental impact, low residues in food, and compatibility with integrated
      pest management (IPM) programs are increasingly important considerations in the
      selection of fungicides for development.

PMID- 15012529
TI  - Role of plant pathology in integrated pest management.
AB  - Integrated Pest Management (IPM) is a paradigm that is widely adopted by all pest
      control disciplines but whose early definitions and philosophical basis belong to
      entomologists. Plant pathology research and extension work has historically
      emphasized integration of several control strategies and fits both historical and
      modern definitions of IPM. While the term IPM has been used only sparingly in the
      phytopathology literature, the integrated disease management strategies
      emphasized are now considered to be at the forefront of ecologically based or
      biointensive pest management. While IPM is broadly endorsed by crop protection
      disciplines, farmers, other agriculturalists, and consumers, the potential for
      Integrated Pest Management has not been fully realized. Most IPM programs reflect
      a package of tools and decision aids for individual crop insect, weed, nematode,
      and plant disease management. IPM programs that integrate all types of pests with
      the agroecosystem, crop growth and loss models still await the formation of
      interdisciplinary teams focusing on growers needs. Lack of funding for both
      discipline and interdisciplinary developmental research and implementation is
      responsible for the paucity of comprehensive IPM programs for the majority of the
      U.S. crop acreage. This review explores the origins and evolution of the IPM
      paradigm and reviews efforts to achieve the body of knowledge and implementation
      structure to achieve IPM's full potential.

PMID- 15012530
TI  - PLANT PATHOLOGY: a discipline at a crossroads.
AB  - The Department of Plant Pathology at the University of California at Berkeley was
      destroyed as a consequence of a contentious reorganization. The circumstances
      that led to the reorganization provide some insight into the challenges facing
      the discipline of plant pathology. The underlying basis for plant pathology as a
      science is to address problems of plant disease. This requires a balance between
      disciplinary and problem-solving research and a continuum from achieving
      fundamental advances in knowledge to the development and implementation of
      problem-solving approaches. Changes in colleges and universities have placed
      extreme stress on this essential structure. The dilemma that must be addressed is
      how to reestablish the problem-solving continuum where it has been broken and
      strengthen it where it has been weakened. Plants are essential for life, and they
      will always be affected by disease. The understanding and management of these
      diseases is the responsibility and the challenge of plant pathology today and in
      the future.

PMID- 15012531
TI  - Helen Hart, remarkable plant pathologist (1900-1971).
AB  - Helen Hart was a Professor of Plant Pathology at the University of Minnesota from
      1924 until retirement in 1966. Born in Janeville, Wisconsin, she died at Grants
      Pass, Oregon. Her scholarly research concentrated on wheat stem rust to
      understand host pathogen relationships and to develop rust-resistant cultivars.
      She did not teach formal courses but was heavily involved in making seminars a
      vital part of instruction, in teaching languages needed for graduate studies, and
      as an informal advisor for most rust research theses. She had common sense,
      excellent scientific judgment, and sound instincts on personnel matters that
      served the department well. A talented science writer, Hart served as editor of
      hundreds of theses and departmental manuscripts for publication. Her writing and
      editing skills were used as associate editor of Phytopathology for two years and
      as editor-in-chief from 1944-1951. A strong advocate of The American
      Phytopathological Society, Helen Hart served on Council for 12 years and as
      President in 1956. Helen Hart was a great professional scientist who had a far
      reaching impact on plant pathology during the twentieth century.

PMID- 15012532
TI  - Dr. Gotthold Steiner (1886-1961): versatile nematologist.
AB  - Swiss-born Dr. Gotthold Steiner was a pioneer in formulating the discipline of
      nematology. He worked with the American nematologist NA Cobb and together they
      were responsible for acceptance of the concept of nematode phytoparasites.
      Steiner had special expertise in anatomy, morphology, phytonematology, marine
      nematodes, nutrition, mermithids, and selected invertebrate taxa. He authored 191
      scientific papers, established the ubiquitous phytoparasitic genus
      Helicotylenchus, described the pinewood nematode, and did significant work with
      three important economic pests, Ditylenchus dipsaci, Heterodera rostochiensis,
      and H. schachtii. He was responsible for introducing training programs in
      nematology in USDA laboratories.

PMID- 15012533
TI  - The Red Queen Hypothesis and plant/pathogen interactions.
AB  - The Red Queen Hypothesis (RQH) explains how pathogens may maintain sexual
      reproduction in hosts. It assumes that parasites become specialized on common
      host genotypes, reducing their fitness. Such frequency-dependent selection favors
      sexual reproduction in host populations. Necessary conditions are that resistance
      and virulence are genotype specific so that host genotype frequencies respond to
      changes in pathogen genotype frequencies, and vice versa. Empirical evidence on
      the genetic basis of disease, variation in resistance and virulence, and patterns
      of infection in sexual and asexual plants support certain features of the
      hypothesis. However, gene-for-gene interactions are generally not consistent with
      the RQH because they do not result in cycling of gene frequencies, unlike a
      matching allele mechanism. A conclusion of whether the RQH can explain the
      maintenance of sexual reproduction cannot be reached at present. Nevertheless,
      the RQH theory has shed light on many aspects of plant/pathogen interactions
      important for reducing pathogen damage in agricultural systems.

PMID- 15012534
TI  - The role of plant clinics in plant disease diagnosis and education in developing
      countries.
AB  - The scarcity of literature in the realm of plant clinics operating in the
      developing world brought us to the decision to perform a survey in non-OECD
      countries in Africa, Asia and Oceania, Latin America and the Caribbean, and in
      central and southern Europe. Forty-one completed questionnaires that refer to 79
      plant clinics were returned. The best-equipped clinics are operated by the
      international research bodies. By and large, this review shows that considerable
      progress has been achieved in the physical development of plant clinics in
      developing countries and in staffing them with well-trained personnel. Not
      surprisingly, however, many inadequacies and inconsistencies still need to be
      addressed before clinics can fully play their part in providing plant protection
      services to their clients. Success and constraining indicators in the diagnostic
      performance of the clinics are identified. A model of the'ideal plant clinic' is
      suggested.

PMID- 15012535
TI  - DWARF BUNT: politics, identification, and biology.
AB  - Dwarf bunt is a disease of wheat caused by the smut fungus Tilletia controversa
      Kuhn. Winter wheat (Triticum aestivum L.) is the primary host of economic
      significance. Although the total acreage affected by dwarf bunt is small relative
      to total wheat production worldwide, the disease has assumed attention
      disproportionate to its economic impact because it has become a matter of
      contention in world trade in cereals. This review describes the political and
      economic issues underlying the study and identification of T. controversa.

PMID- 15012536
TI  - Fungal transmission of plant viruses.
AB  - Thirty soilborne viruses or virus-like agents are transmitted by five species of
      fungal vectors. Ten polyhedral viruses, of which nine are in the family
      Tombusviridae, are acquired in the in vitro manner and do not occur within the
      resting spores of their vectors, Olpidium brassicae and O. bornovanus. Fungal
      vectors for other viruses in the family should be sought even though
      tombusviruses are reputed to be soil transmitted without a vector. Eighteen rod
      shaped viruses belonging to the furo- and bymovirus groups and to an unclassified
      group are acquired in the in vivo manner and survive within the resting spores of
      their vector, O. brassicae, Polymyxa graminis, P. betae, and Spongospora
      subterranea. The viral coat protein has an essential role in in vitro
      transmission. With in vivo transmission a site in the coat protein-read through
      protein (CP-RT) of beet necrotic yellow vein furovirus determines vector
      transmissibility as does a site in a similar 98-kDa polyprotein of barley mild
      mosaic bymovirus. The mechanisms by which virions move (or are moved) into and
      out of the protoplasm of zoospores or of thalli needs study.

PMID- 15012537
TI  - EPICHLOE SPECIES: fungal symbionts of grasses.
AB  - Epichloe species and their asexual descendants (Acremonium endophytes) are fungal
      symbionts of C3 grasses that span the symbiotic continuum from antagonism to
      mutualism depending on the relative importance, respectively, of horizontal
      transmission of sexual spores versus vertical clonal transmission in healthy
      grass seeds. At least seven sexual Epichloe species are identifiable by mating
      tests, and many asexual genotypes are interspecific hybrids. Benefits conferred
      by the symbionts on host plants include protection from biotic factors and
      abiotic stresses such as drought. Four classes of beneficial alkaloids are
      associated with the symbionts: ergot alkaloids, indolediterpenes (lolitrems),
      peramine, and saturated aminopyrrolizidines (lolines). These alkaloids protect
      host plants from insect and vertebrate herbivores, including livestock. Genetic
      engineering of the fungal symbionts as more suitable biological protectants for
      forage grasses requires identification of fungal genes for alkaloid biosynthesis,
      and DNA-mediated transformation of the fungi.

PMID- 15012538
TI  - Fastidious xylem-limited bacterial plant pathogens.
AB  - Numerous bacteria have been isolated from within plants, and many reported from
      xylem, but only three species of xylem-limited bacteria (XLB) that are fastidious
      in cultural requirements, are plant pathogens, and exclusively occupy xylem, have
      been well characterized. Two XLB, Xylella fastidiosa and Pseudomonas syzygii, are
      transmitted by sucking insects that feed on xylem sap but are not transmitted
      mechanically from plant to plant. In contrast, Clavibacter xyli is mechanically
      transmitted to plants by cutting tools. All of these XLB occupy a highly
      specialized yet diverse ecological niche: the water-conducting systems of an
      extremely wide range of plant hosts. A variety of detection methods are available
      as diagnostic aids; each method has advantages and disadvantages; no single
      method is best for all uses. Molecular and genetic comparisons of strains of XLB
      lag behind progress being made for many other plant-pathogenic bacteria, but such
      studies are needed to answer important questions: (a) How do XLB move from cell
      to cell within plants? (b) What are the physiological and genetic bases of plant
      host specificity for XLB? (c) Why are only xylem-feeding specialists vectors of
      X. fastidiosa (and probably P. syzygii), when many leafhoppers feed regularly
      (but not continuously) on xylem?

PMID- 15012539
TI  - Bacterial avirulence genes.
AB  - Although more than 30 bacterial avirulence genes have been cloned and
      characterized, the function of the gene products in the elictitation of
      resistance is unknown in all cases but one. The product of avrD from Pseudomonas
      syringae pv. glycinea likely functions indirectly to elicit resistance in
      soybean, that is, evidence suggests the gene product is an enzyme involved in
      elicitor production. In most if not all cases, bacterial avirulence gene function
      is dependent on interactions with the hypersensitive response and pathogenicity
      (hrp) genes. Many hrp genes are similar to genes involved in delivery of
      pathogenicity factors in mammalian bacterial pathogens. Thus, analogies between
      mammalian and plant pathogens may provide needed clues to elucidate how virulence
      gene products control induction of resistance.

PMID- 15012540
TI  - Chemoreception in plant parasitic nematodes.
AB  - The role and functioning of the anterior chemosensory organs of plant parasitic
      nematodes is examined, with particular emphasis on the amphids. The morphology of
      the amphids is discussed primarily in the context of the changes in the
      ultrastructure associated with different life stages. The involvement of
      amphidial secretions in chemoreception and the behavioral and
      electrophysiological analyses of nematode responses to semiochemicals are
      discussed with special reference to research on sex pheromones. These research
      techniques, combined with the use of lectins and antibodies, provide information
      on nematode sensilla that may lead to novel control strategies for economically
      important plant parasitic nematodes based on perturbing nematode sensory
      perception to prevent host or mate location.

PMID- 15012541
TI  - Nematode management in sustainable and subsistence agriculture.
AB  - In small-scale, subsistence agriculture in the tropics and the subtropics,
      traditional farming practices have evolved that provide a sustainable means of
      reducing the incidence and damage caused by pests including nematodes. Other
      newer, cultural and low-input practices can also be successfully introduced in
      small-scale farming. In sustainable and subsistence farming systems, nematodes
      and some other pests can be managed by integrating different farming practices
      into four strategies: preventing the introduction and spread of nematodes; using
      direct, nonchemical, cultural and physical control methods; encouraging naturally
      occurring biological control agents; and maintaining or enhancing the
      biodiversity inherent in multiple cropping and multiple cultivar traditional
      farming systems to increase the available resistance or tolerance to nematodes.

PMID- 15012542
TI  - Helper-dependent vector transmission of plant viruses.
AB  - A variety of noncirculatively transmitted viruses have evolved a vector
      transmission strategy that involves, in addition to virions, virus-encoded
      proteins that are not constituents of virions. These "helpers" and the genes
      encoding them have been characterized for viruses in the genera Potyvirus and
      Caulimovirus. Several lines of evidence support the hypothesis that these helpers
      act by mediating retention of virions in regions of the vector's alimentary tract
      from which they subsequently can be egested to initiate an infection. The
      possible advantage this convergently evolved strategy could confer to
      noncirculatively transmitted virus quasispecies is discussed.

PMID- 15012543
TI  - Biology and epidemiology of rice viruses.
AB  - The 15 known viruses that occur in rice are rice black-streaked dwarf, rice
      bunchy stunt, rice dwarf, rice gall dwarf, rice giallume, rice grassy stunt, rice
      hoja blanca, rice necrosis mosaic, rice ragged stunt, rice stripe necrosis, rice
      stripe, rice transitory yellowing, rice tungro bacilliform, rice tungro
      spherical, and rice yellow mottle viruses. This paper describes their
      geographical distribution, relation to vectors, infection cycles, field
      dispersal, and development, and lists recorded outbreaks of the viruses. Many
      rice viruses have become serious problems since rice cultivation has been
      intensified. Double-cropping of rice using improved, photo-insensitive cultivars
      of short growth duration has significantly influenced the incidence of these
      viruses.

PMID- 15012544
TI  - Molecular biology of rice tungro viruses.
AB  - Rice tungro, the most important virus disease of rice in South and Southeast
      Asia, is caused by a complex of two viruses, rice tungro bacilliform virus (RTBV)
      and rice tungro spherical virus (RTSV). RTBV is a plant pararetrovirus with
      bacilliform particles, the structure of which is based on T = 3 icosahedral
      symmetry cut across the threefold axis.The particles encapsidate a circular
      double-stranded DNA of 8 kbp that encodes four proteins. The current information
      on the properties, functions, and expression of these proteins is discussed, as
      is the evidence for replication by reverse transcription. Two major strains of
      RTBV have been recognized, one from the Indian subcontinent and the other from
      Southeast Asia. RTSV particles contain a single-stranded RNA genome of 12 kb that
      encodes a large polyprotein and possibly one or two smaller proteins. The
      properties and processing of the polyprotein are described and the resemblance to
      picornaviruses noted.

PMID- 15012545
TI  - Plant virus gene vectors for transient expression of foreign proteins in plants.
AB  - The development of plant virus gene vectors for expression of foreign genes in
      plants provides attractive biotechnological tools to complement conventional
      breeding and transgenic methodology. The benefits of virus-based transient RNA
      and DNA replicons versus transgenic gene expression include rapid and convenient
      engineering coupled with flexibility for expeditious application in various plant
      species. These characteristics are especially advantageous when very high levels
      of gene expression are desired within a short time, although instability of the
      foreign gene in the viral genome can present some problems. The strategies that
      have been tested for foreign gene expression in various virus-based vectors
      include gene replacement, gene insertion, epitope presentation, use of virus
      controlled gene expression cassettes, and complementation. Recent reports of the
      utilization of virus vectors for foreign gene expression in fundamental research
      and biotechnology applications are discussed.

PMID- 15012546
TI  - Root system regulation of whole plant growth.
AB  - New evidence confirms earlier postulates that root signals to shoots, including
      abscisic acid, nitrate flux, and cytokinins, modify whole plant growth processes
      including leaf expansion, stomatal behavior, and biosynthesis of photosynthetic
      enzymes. Root signals are thought to reflect soil water, nutrient, and mechanical
      attributes, as sensed by roots. Meristematic activities in root tips initiate
      changes in root architecture, modifying the soil volume subject to root uptake,
      and may provide multiple sensory and signaling capabilities. Knowledge of root
      signals regulating whole plant growth processes suggests new analytical and
      experimental tools for integrated analysis of plant phasic development, optimal
      growth, and ecological fitness.

PMID- 15012547
TI  - Ozone and plant health.
AB  - Phytotoxic effects of ozone are described with emphasis on secondary plant
      metabolism. Numerous ozone-induced genes, enzymes and stress metabolites of
      antioxidative and phytopathological defense reactions have been discovered for
      herbaceous plants and forest tree species. Ozone induces reactions normally
      elicited by viral and microbial pathogens. The molecular basis (receptors, signal
      chains) for induction by ozone remains to be elucidated. The induced stress
      reactions seem to change plant predisposition to either enhanced tolerance or
      susceptibility for a second stressor. The following topics are discussed: ozone
      and biotic disease, the role of ozone on field sites and ozone limit values.

PMID- 15012548
TI  - Morphogenesis and mechanisms of penetration by plant pathogenic fungi.
AB  - Infection structures of phytopathogenic fungi are modified hyphae specialized for
      the invasion of plant tissues. Initial events are adhesion to the cuticle and
      directed growth of the germ tube on the plant surface. At the site of
      penetration, appressoria are often formed that may have melanized walls and
      develop high turgor pressure to support the penetration process. The penetration
      hypha accumulates components of the cytoskeleton in the tip and secretes a
      variety of cell wall-degrading enzymes in a highly regulated fashion in order to
      penetrate the cuticle and the plant cell wall. This article reviews recent papers
      on the cytology, physiology, and molecular biology of the penetration process.

PMID- 15012549
TI  - Microbial elicitors and their receptors in plants.
AB  - Elicitors are molecules that stimulate any of a number of defense responses in
      plants. Research over the past decade has focused on the mechanisms by which
      plant cells perceive and transduce these biological signals to activate defense
      responses. Of particular interest has been the identification of specific
      elicitor-binding proteins that might function as physiological receptors in the
      signal transduction cascade. The existence of specific high-affinity binding
      sites has been demonstrated for oligosaccharide, glycopeptide, and peptide
      elicitors, and candidate elicitor-binding proteins have been identified for
      several of them. The properties of these binding sites/proteins are consistent
      with those expected of physiologically important receptors, although experimental
      verification of the role of these binding proteins as receptors has not yet been
      obtained. The purification and characterization of specific elicitor-binding
      proteins is essential for a detailed understanding of the molecular basis for the
      signal exchange between plant hosts and microbial pathogens that leads to
      activation of host defenses.

PMID- 15012550
TI  - Pathogen quiescence in postharvest diseases.
AB  - This chapter examines the quiescence period during different stages of fungal
      attack of postharvest pathogens: quiescence during spore germination and initial
      hyphal development, during and after appressorium formation, and quiescence of
      germinated appressorium and subcuticular hyphae. The different mechanisms for
      quiescence are reviewed: factors affecting quiescence of germinated spores,
      appressoria formation and germination, and fungal colonization. Special emphasis
      is given to mechanisms of quiescence involving fungal colonization: 1. the
      pathogen's nutritional requirements, 2. preformed antifungal compounds, 3. the
      elicitation of phytoalexins and preformed compounds, and 4. the activation of
      factors in fungal pathogenicity.

PMID- 15012551
TI  - Genetics of resistance to wheat leaf rust.
AB  - Leaf rust (caused by Puccinia recondita f. sp. tritici) is the most widespread
      and regularly occurring rust on wheat. Genetic resistance is the most economical
      method of reducing yield losses due to leaf rust. To date, 46 leaf rust
      resistance genes have been designated and mapped in wheat. Resistance gene
      expression is dependent on the genetics of host-parasite interaction, temperature
      conditions, plant developmental stage, and interaction between resistance genes
      with suppressors or other resistance genes in the wheat genomes. Genes expressed
      in seedling plants have not provided long-lasting effective leaf rust resistance.
      Adult-plant resistance genes Lr13 and Lr34 singly and together have provided the
      most durable resistance to leaf rust in wheat throughout the world. Continued
      efforts to isolate, characterize, and map leaf rust resistance genes is essential
      given the ability of the leaf rust fungus to overcome deployed resistance genes.

PMID- 15012552
TI  - Recombination and the multilocus structure of fungal populations.
AB  - This review examines the relationship between recombination and the multilocus
      structure of populations. This discussion of population structure is based on the
      pattern of genetic variation within populations, especially the frequencies of
      multilocus genotypes, which can be used for making inferences about
      recombination. Three questions are addressed: Is population structure consistent
      with a random mating hypothesis? Is there evidence for recombination? How
      frequently does recombination occur?

PMID- 15012553
TI  - QTL mapping and quantitative disease resistance in plants.
AB  - Quantitative trait locus (QTL) mapping is a highly effective approach for
      studying genetically complex forms of plant disease resistance. With QTL mapping,
      the roles of specific resistance loci can be described, race-specificity of
      partial resistance genes can be assessed, and interactions between resistance
      genes, plant development, and the environment can be analyzed. Outstanding
      examples include: quantitative resistance to the rice blast fungus, late blight
      of potato, gray leaf spot of maize, bacterial wilt of tomato, and the soybean
      cyst nematode. These studies provide insights into the number of quantitative
      resistance loci involved in complex disease resistance, epistatic and
      environmental interactions, race-specificity of partial resistance loci,
      interactions between pathogen biology, plant development and biochemistry, and
      the relationship between qualitative and quantitative loci. QTL mapping also
      provides a framework for marker-assisted selection of complex disease resistance
      characters and the positional cloning of partial resistance genes.

PMID- 15012554
TI  - Breeding disease-resistant wheats for tropical highlands and lowlands.
AB  - Wheat is grown on about 10 million ha in the tropical highlands and lowlands of
      the world, where it is an important food source. Many farmers in these areas work
      under subsistence conditions. Wheat diseases in tropical regions can be severe
      and require significant efforts to control. For economic and environmental
      reasons, host plant resistance is the most appropriate and sustainable disease
      control method. We describe highland and lowland tropical wheat regions and
      discuss CIMMYT's breeding strategies, philosophies, and progress in developing
      resistance to the major diseases such as rusts, foliar blights, fusarium scab,
      BYD, and spot blotch. Additionally, we review the role of national wheat research
      programs and beneficial spillovers of our combined breeding efforts to other
      wheat production areas of the world.

PMID- 15012555
TI  - Changing options for the control of deciduous fruit tree diseases.
AB  - The evolution of disease management programs for deciduous fruit trees in the
      United States over the past 50 years has been influenced by factors that include
      public concern over pesticide residues on fruit and in the environment, the
      development of resistance of many important tree pathogens to fungicides and
      bactericides, the loss of fungicide registrations and restrictions on their use
      due to concern for human health and the environment and/or marketing decisions by
      the manufacturers, and changes in cultural practices and marketing objectives.
      These factors have led to wider use of forecasting models and cultural controls,
      the development of resistance management strategies, and the introduction of new
      equipment and methods for pesticide application. These same factors will most
      likely continue to drive the fruit industry to adopt disease management programs
      that rely less on pesticides in the future.

PMID- 15012556
TI  - RESISTANCE TO PHENYLAMIDE FUNGICIDES: a case study with phytophthora infestans
      involving mating type and race structure.
AB  - Phenylamide-resistant isolates of Phytophthora infestans have gradually become an
      important part of populations in many countries. However, fungicide mixtures
      containing a phenylamide component are still an effective strategy for the
      control of late blight in potato and tomato. The proportion of phenylamide
      resistant isolates fluctuates from year to year and within the season. Almost
      concurrent with the appearance of resistant isolates was the discovery of the A2
      mating type of P. infestans in many European countries and in other parts of the
      world. However, no genetic correlation exists between resistance and mating type,
      and the proportion of A2 isolates in European populations remains small.
      Resistance to phenylamides became established in A1 populations before the
      appearance of A2 type. Resistant isolates express equal or greater fitness than
      sensitive isolates, but no correlation was detected between resistance and race
      structure. The continuous changes in P. infestans populations require careful
      adaptation of successful disease control programs.

PMID- 15012557
TI  - STATUS OF CACAO WITCHES' BROOM: biology, epidemiology, and management.
AB  - Origins of Theobroma cacao and Crinipellis perniciosa occurred in the Amazon
      Basin region of South America, and their interaction, the witches' broom disease,
      was first described in the late 1700s. The 100 years of scientific investigations
      of witches' broom of cacao that began in the 1890s developed the present state of
      knowledge of the biology and epidemiology of witches' broom that are discussed.
      Recommended management to reduce the deleterious effects of witches' broom on
      cacao production include the use of phytosanitation (removal of diseased plant
      parts), applications of chemical fungicides, and the use of host resistance. At
      present, there is a paucity of resistant planting materials, and efforts to
      evaluate germplasm for resistance to witches' broom are described. Research
      topics to augment present knowledge about witches' broom of cacao are presented
      with the hope that disease management can be improved.

PMID- 15012558
TI  - Alternative water sources and reuse: what are the public health issues? National
      water-recycling guidelines will address both health and environmental risks.

PMID- 15012559
TI  - Database support for cardiac rehabilitation. RCT evidence for rehabilitation is
      strengthened by an observational cohort study.

PMID- 15012561
TI  - Asthma prevalence: mysterious enigmatic riddle or time-expired illusion? Can we
      solve a riddle by burying an illusion?

PMID- 15012562
TI  - The UK smoking time-warp: roll on 1989! Targets for the prevalence of smoking in
      2010 are embarrassingly modest.

PMID- 15012563
TI  - Attendance rates and outcomes of cardiac rehabilitation in Victoria, 1998.
AB  - OBJECTIVE: To describe the patterns of use of cardiac rehabilitation in Victoria
      and to assess whether the survival benefits predicted in clinical trials have
      been realised in the community. DESIGN: Cohort study based on data linkage.
      PARTICIPANTS: All patients admitted for acute myocardial infarction (AMI),
      coronary artery bypass grafting (CABG) or percutaneous transluminal coronary
      angioplasty (PTCA) in Victoria in 1998 (n = 12821). INTERVENTIONS: Attendance at
      one of 66 participating outpatient cardiac rehabilitation centres in Victoria.
      MAIN OUTCOME MEASURES: Rates of attendance at rehabilitation based on key factors
      such as diagnosis, age, sex, and comorbidity. Five-year survival for attendees
      compared with non-attendees. RESULTS: Rates of participation in rehabilitation
      were 15% for AMI, 37% for CABG, and 14% for PTCA. Rehabilitation attendance rates
      dropped sharply after 70 years of age. Attendees had a 35% improvement in 5-year
      survival (hazard ratio for death associated with rehabilitation attendance, 0.65
      [95% CI, 0.56-0.75]). CONCLUSIONS: Attendance rates at cardiac rehabilitation are
      suboptimal, even though attendance confers a clinically significant difference in
      5-year survival. The elderly, women, and those with comorbid conditions may
      benefit measurably from increased rates of attendance.

PMID- 15012564
TI  - Asthma prevalence in Melbourne schoolchildren: have we reached the peak?
AB  - OBJECTIVE: To determine the change in prevalence of asthma, eczema and allergic
      rhinitis in Australian schoolchildren between 1993 and 2002. DESIGN:
      Questionnaire based survey, using the protocol of the International Study of
      Asthma and Allergy in Childhood. SETTING: Metropolitan Melbourne primary schools
      within a 20 km radius of the GPO in 1993 and 2002. SUBJECTS: All children in
      school years 1 and 2 (ages 6 and 7) attending a random sample of 84 schools in
      1993 and 63 schools in 2002. MAIN OUTCOME MEASURES: Parent-reported symptoms of
      atopic disease; treatment for asthma; country of birth. RESULTS: There was a 26%
      reduction in the 12-month period prevalence of reported wheeze, from 27.2% in
      1993 to 20.0% in 2002. The magnitude of reduction was similar for boys (27%) and
      girls (25%). The 12-month period prevalence of reported eczema increased from
      11.1% in 1993 to 17.2% in 2002, and rhinitis increased from 9.7% to 12.7%. There
      were reductions in the proportion of children attending an emergency department
      for asthma in the previous year (3.6% to 2.3%), the proportion admitted to
      hospital (1.7% to 1.1%) and the proportion taking asthma medication (18.5% to
      13.4%). Of those who reported frequent wheeze, there was an increase in the
      proportion taking regular inhaled steroids (34.5% to 40.9%). CONCLUSION: There
      has been a significant reduction in the prevalence of reported asthma in
      Melbourne schoolchildren, whereas the prevalence of eczema and allergic rhinitis
      has continued to increase.

PMID- 15012565
TI  - An ambulatory stabilisation program for children with newly diagnosed type 1
      diabetes.
AB  - OBJECTIVES: (i) To evaluate the benefits and adverse effects of a Diabetes Day
      Care Program (DDCP); and (ii) to compare outcomes in two cohorts diagnosed before
      and after implementing the DDCP ("pre-DDCP" and "post-DDCP"). DESIGN: Outcomes
      from the pre-DDCP cohort were compared with those of the post-DDCP cohort.
      SETTING: The study was conducted from March 2001 to October 2002 at the
      Children's Hospital at Westmead. PARTICIPANTS: The pre-DDCP cohort comprised all
      children newly diagnosed with type 1 diabetes from March 2000 to November 2000 (n
      = 49). The post-DDCP cohort were those diagnosed from November 2000 to August
      2001 (n = 61). MAIN OUTCOME MEASURES: Length of stay, adverse events, insulin
      requirement and glycohaemoglobin (HbA(1c)) level over the first year after
      diagnosis were ascertained from medical records. Questionnaires to measure
      parents' knowledge of diabetes, emotional adjustment to diabetes, and
      responsibility for and conflict over specific diabetes management tasks were
      completed by parents at 6-monthly intervals. RESULTS: Median length of hospital
      stay decreased from 5.14 days (range, 2-10) to 1.70 days (range, 0-10) (P <
      0.001). There were no differences between the two cohorts in insulin requirement
      at 12 months (pre-DDCP: 0.9 U/kg [95% CI, 0.8-1.0]; post-DDCP: 0.8 U/kg [95% CI,
      0.7-0.9]; P = 0.22), HbA(1c) level at 12 months (pre-DDCP: 8.4% [95% CI, 8.0%
      8.9%]; post-DDCP: 8.2% [95% CI, 7.9%-8.5%]; P = 0.37) and adverse events over the
      first year after diagnosis. Both groups reported similar scores for the parental
      questionnaires. CONCLUSIONS: Ambulatory stabilisation of children with type 1
      diabetes provides similar metabolic outcomes for the child, and comparable levels
      of diabetes knowledge and similar psychosocial outcomes for the family, to
      inpatient stabilisation programs.

PMID- 15012567
TI  - Should patients with severely impaired left ventricular function following
      myocardial infarction receive an implantable defibrillator?

PMID- 15012566
TI  - The decline of the hospital autopsy: a safety and quality issue for healthcare in
      Australia.
AB  - Even with new diagnostic modalities, autopsy remains an important tool for
      quality and safety assurance. A systematic review of reports from 1996 to 2002
      found autopsies detected, on average, 23.5% of clinically missed diagnoses
      involving the principal or underlying cause of death, and 9% of errors that would
      or could have affected the patient's outcome. We surveyed pathology laboratories
      and hospital administrators across Australia, and found a decline in the hospital
      autopsy rate from 21% (210/1000 deaths) in 1992-93 to 12% (118/1000 deaths) in
      2002-03. This decrease is in adult autopsies (66% of all autopsies in 1992-93;
      39% in 2002-03). Perinatal autopsies increased from 29% to 58% of all autopsies
      in this period, mainly due to more examinations of fetuses less than 20 weeks'
      gestation. Factors contributing to this decline may include community attitudes,
      clinicians' reluctance to request autopsy (partly because of administrative
      burdens in making the request), hospital concern about legal action if a
      misdiagnosis is detected, and funding priorities. Reversing this decline will
      require cooperative action at several levels of the healthcare system, and from
      government bodies.

PMID- 15012568
TI  - Subgroup analysis in clinical trials.

PMID- 15012569
TI  - Living with hepatitis C: from self-loathing to advocacy. Compassion for those
      with hepatitis C and accurate information about preventing its transmission will
      also benefit the wider community.

PMID- 15012570
TI  - Cyclospora infection masquerading as coeliac disease.

PMID- 15012572
TI  - Privacy: bad for your health?

PMID- 15012571
TI  - 7: Treatment of osteoporosis: why, whom, when and how to treat. The single most
      important consideration is the individual's absolute risk of fracture.
AB  - All women and men with a history of fragility fractures should be considered for
      treatment of osteoporosis to reduce their risk of future fracture. There is high
      level evidence for the anti-fracture efficacy of treatment in women with
      osteoporosis, particularly if there is prevalent fracture; the evidence is less
      compelling for women with osteopenia, with or without a fracture, and for men.
      The rigorously investigated drugs reported to reduce vertebral fractures are the
      bisphosphonates alendronate and risedronate, the selective oestrogen-receptor
      modulator raloxifene, the anabolic agent parathyroid hormone and, most recently,
      strontium ranelate. Only the two bisphosphonates and hormone replacement therapy
      (HRT) have been reported to reduce hip fractures in community-dwelling women, and
      calcium plus vitamin D and hip protectors have been reported to reduce these
      fractures in elderly people in institutions. HRT is not recommended in women for
      fracture risk reduction alone. Evidence for the anti-fracture efficacy of
      calcitonin, fluoride, anabolic steroids and active vitamin D metabolites is
      insufficient to justify their use; lifestyle changes, while not shown to reduce
      fracture risk, may have a role in maintaining bone strength throughout life.

PMID- 15012573
TI  - A prospective before-and-after trial of a medical emergency team.

PMID- 15012574
TI  - Achieving equity in the Australian healthcare system.

PMID- 15012575
TI  - Lessons from early large-scale adoption of celecoxib and rofecoxib by Australian
      general practitioners.

PMID- 15012577
TI  - Translating evidence into practice.

PMID- 15012576
TI  - What drives the NHS?

PMID- 15012579
TI  - Gaps between best evidence and practice: causes for concern.
AB  - Overseas studies that aim to quantify the evidence base of conventional medical
      care give varying estimates, but many of these studies have potential for bias.
      We do not know how much of the total healthcare Australians receive is based on
      the best available evidence; studies of a number of specific conditions show that
      there are gaps between what is known and what happens in practice. The National
      Institute of Clinical Studies aims to identify and test systemic approaches to
      embed ongoing review and uptake of evidence into routine clinical care.

PMID- 15012578
TI  - Development of strategies to encourage adoption of best evidence into practice in
      Australia: workshop overview.

PMID- 15012580
TI  - Is evidence-based implementation of evidence-based care possible?
AB  - Traditional approaches to disseminating research findings have failed to achieve
      optimal healthcare. In a systematic review of 235 studies of guideline
      dissemination and implementation strategies, we observed the following: there was
      a median 10% improvement across studies, suggesting that it is possible to change
      healthcare provider behaviour and improve quality of care; most dissemination and
      implementation strategies resulted in small to moderate improvements in care;
      multifaceted interventions did not appear more effective than single
      interventions. The interpretation of our systematic review is hindered by the
      lack of a robust theoretical base for understanding healthcare provider and
      organisational behaviour. Future research is required to develop a better
      theoretical base and to evaluate further guideline dissemination and
      implementation strategies.

PMID- 15012581
TI  - Selecting, presenting and delivering clinical guidelines: are there any "magic
      bullets"?
AB  - There are internationally agreed optimal methods for developing clinical practice
      guidelines. The quality of published guidelines varies. A validated assessment
      instrument should be used to identify well developed guidelines that can be used
      with confidence. There are multiple ways of presenting guidelines, including
      computerised systems. Computerisation of guidelines can cover a range of formats,
      from brief prompts through to complex decision-support systems. Integrating
      guidelines into computerised reminder systems has been shown to be effective in
      improving patient care, but there is less evidence to support the effectiveness
      of guidelines integrated into computerised decision-support systems.

PMID- 15012582
TI  - Diffusion of innovation theory for clinical change.
AB  - Maximising the adoption of evidence-based practice has been argued to be a major
      factor in determining healthcare outcomes. However, there are gaps between
      evidence-based recommendations and current care. Bridging the evidence gap will
      not be achieved simply by informing clinicians about the evidence. One
      theoretical approach to understanding how change may be achieved is Rogers'
      diffusion model. He argues that certain characteristics of the innovation itself
      may facilitate its adoption. Other factors influencing acceptance include
      promotion by influential role models, the degree of complexity of the change,
      compatibility with existing values and needs, and the ability to test and modify
      the new procedure before adopting it. The diffusion model may provide valuable
      insights into why some practices change and others do not, as well as guiding
      those who try to effect adoption of best-evidence practice.

PMID- 15012583
TI  - What drives change? Barriers to and incentives for achieving evidence-based
      practice.
AB  - To bridge the gap between scientific evidence and patient care we need an in
      depth understanding of the barriers and incentives to achieving change in
      practice. Various theories and models for change point to a multitude of factors
      that may affect the successful implementation of evidence. However, the evidence
      for their value in the field is still limited. When planning complex changes in
      practice, potential barriers at various levels need to be addressed. Planning
      needs to take into account the nature of the innovation; characteristics of the
      professionals and patients involved; and the social, organisational, economic and
      political context.

PMID- 15012584
TI  - Changing healthcare organisations to change clinical performance.
AB  - We propose the formation of evidence-based clinical practice support units in
      hospitals and clinical research implementation networks. The purpose of these
      initiatives will be to increase the uptake of beneficial forms of care and remove
      harmful or ineffective practices. They will bring together clinicians and other
      professionals to improve clinical care across the healthcare system.

PMID- 15012586
TI  - Adoption of evidence into practice: can change be sustainable?
AB  - Few studies have monitored change in professional practice over time to determine
      the sustainability of change. Research from other behavioural change literature
      shows that initial change is difficult to maintain, with reported relapse rates
      as high as 80%. Interventions most likely to succeed are based on a clear
      understanding of target behaviours and the environmental context. Facilitators
      and barriers are usually multifaceted and occur at a number of interrelated
      levels. The issue targeted for intervention must be clearly defined at the
      outset, so that antecedents, determinants and supporting mechanisms can be
      defined, suggesting points for intervention and strategies for initial and
      sustainable change. The target population's readiness to change is an important
      factor at both an individual and organisational level. In most cases, a
      combination of different interventions will be needed to achieve lasting change.

PMID- 15012585
TI  - Feedback of evidence into practice.
AB  - Concern about risks associated with medical care has led to increasing interest
      in quality improvement processes. Most quality initiatives derive from
      manufacturing, where they have worked well in improving quality by small, steady
      increments. Adaptations of quality processes to the healthcare environment have
      included variations emphasising teamwork; large, ambitious increments in targets;
      and unorthodox approaches. Feedback of clinical information to clinicians is a
      central process in many quality improvement activities. It is important to choose
      feedback data that support the objectives for quality improvement - and not just
      what is expedient. Clinicians need to be better educated about the quality
      improvement process to maintain the quality of their care.

PMID- 15012587
TI  - Solving the information overload problem: a letter from Canada.
AB  - Doctors are inundated with medical information, some inadequately evidence-based,
      much of it captured in clinical practice guidelines (CPGs). The Ontario
      Guidelines Advisory Committee (GAC) selects topic areas, searches for all CPGs on
      the topic, and reviews them using the AGREE Instrument. Based in large part on
      the AGREE score, the GAC summarises one guideline in each topic area and mounts
      it on its website, with links to other information (eg, clinical algorithms)
      where possible. Two topic areas have been selected for implementation--the
      reduction of unnecessary preoperative testing and the rational management of
      acute low back pain. Implementation strategies include performance feedback,
      training of opinion leaders, development of algorithms and reminders, and
      communication through journals and continuing medical education activities.

PMID- 15012589
TI  - Photoperiodic regulation of prolactin secretion: changes in intra-pituitary
      signalling and lactotroph heterogeneity.
AB  - Many mammalian species utilise day-length (photoperiod) to adapt their physiology
      to seasonal changes in environmental conditions, via secretion of pineal
      melatonin. Photoperiodic regulation of prolactin secretion is believed to occur
      via melatonin-mediated changes in the secretion of a putative prolactin
      secretagogue, tuberalin, from the pituitary pars tuberalis. Despite the in vivo
      and in vitro evidence in support of this intra-pituitary signalling mechanism,
      the identity of tuberalin has yet to be elucidated. This paper reviews recent
      advances in the characterisation of tuberalin and the regulation of its
      secretion. Furthermore, the hypothesis that pituitary lactotroph cells display
      heterogeneity in their response to changing photoperiod and tuberalin secretion
      is examined.

PMID- 15012588
TI  - Structural analysis and tissue localization of human C4.4A: a protein homologue
      of the urokinase receptor.
AB  - C4.4A, a structural homologue of the urokinase-type plasminogen activator
      receptor (uPAR), was originally identified as a metastasis-associated membrane
      protein, but little is known about its structural and functional properties.
      Therefore, we expressed, purified and characterized a soluble truncated form of
      human C4.4A, and used this protein to produce specific polyclonal anti-C4.4A
      antibodies. By immunohistochemistry we observed a pronounced surface staining for
      C4.4A in suprabasal keratinocytes of chronic human wounds and found C4.4A
      expression markedly upregulated in migrating keratinocytes during re
      epithelisation of incisional skin wounds. Phorbol-ester-induced hyperplasia of
      mouse skin is also accompanied by a significant induction of C4.4A expression in
      the multilayered, suprabasal keratinocytes. C4.4A contains two Ly-6 (leucocyte
      antigen 6)/uPAR/alpha-neurotoxin modules. Our recombinant human C4.4A is
      extensively modified by post-translational glycosylation, which include 5-6 N
      linked carbohydrates primarily located in or close to its second Ly-6/uPAR/alpha
      neurotoxin module and approximately 15 O-linked carbohydrates clustered in a
      Ser/Thr/Pro-rich region at the C-terminus. A highly protease-sensitive region
      (Tyr200-Arg204) is located between these two clusters of N- and O-linked
      carbohydrates. The natural, glycolipid-anchored C4.4A from amnion membranes of
      human term placenta exhibits similar properties. Using recombinant, soluble C4.4A
      or MCF 7 cells, which express significant amounts of GPI-anchored C4.4A, we find
      no evidence for an interaction between C4.4A and uPA, a property suggested
      previously for rat C4.4A. Collectively these data indicate that C4.4A, although
      being a structural homologue of uPAR, is unlikely to have a functional overlap
      with uPAR.

PMID- 15012590
TI  - Obesity and diabetes in transgenic mice expressing proSAAS.
AB  - ProSAAS is a neuroendocrine peptide precursor that potently inhibits prohormone
      convertase 1 in vitro. To explore the function of proSAAS and its derived
      peptides, transgenic mice were created which express proSAAS using the beta-actin
      promoter. The body weight of transgenic mice was normal until approximately 10-12
      weeks, and then increased 30-50% over wild-type littermates. Adult transgenic
      mice had a fat mass approximately twice that of wild-type mice, and fasting blood
      glucose levels were slightly elevated. In the pituitary, the levels of several
      fully processed peptides in transgenic mice were not reduced compared with wild
      type mice, indicating that the proSAAS transgene did not affect prohormone
      convertase 1 activity in this tissue. Because the inhibitory potency of proSAAS
      derived peptides towards prohormone convertase 1 is much greater in the absence
      of carboxypeptidase E activity, the proSAAS transgene was also expressed in
      carboxypeptidase E-deficient Cpe (fat/fat) mice. Although the transgenic mice
      were born in the expected frequency, 21 of 22 proSAAS transgenic Cpe (fat/fat)
      mice died between 11 and 26 weeks of age, presumably due to greatly elevated
      blood glucose. The levels of several pituitary peptides were significantly
      reduced in the proSAAS transgenic Cpe (fat/fat) mice relative to non-transgenic
      Cpe (fat/fat) mice, suggesting that the transgene inhibited prohormone convertase
      1 in these mice. Taken together, these results are consistent with a role for
      proSAAS-derived peptides as neuropeptides that influence body weight
      independently of their function as inhibitors of prohormone convertase 1.

PMID- 15012591
TI  - Fasting-induced changes in the hypothalamic-pituitary-GH axis in the absence of
      GH expression: lessons from the spontaneous dwarf rat.
AB  - Fasting results in a reciprocal shift in hypothalamic neuropeptide Y (NPY) and GH
      releasing hormone (GHRH) expression in the adult male rat. It is hypothesized
      that the fasting-induced rise in NPY is responsible for the GHRH decline and
      subsequent attenuation of pulsatile GH release. Fasting also leads to a decrease
      in circulating IGF-I, attributed to both reduced GH release and peripheral GH
      resistance. Although pituitary GH output is suppressed in the fasted rat, we
      report herein that pituitary GHRH receptor (GHRH-R) and GH secretagogue receptor
      (GHS-R) mRNA levels are increased, while pituitary expression of the somatostatin
      receptor subtype 2 (sst2) and 5 (sst5) is decreased, as determined by real-time
      reverse transcription (RT)-PCR. A shift in the expression of pituitary receptor
      subtypes to favor GH synthesis and release may be due, at least in part, to a
      decline in GH/IGF-I negative feedback. In order to test this hypothesis, we
      compared hypothalamic and pituitary response to fasting (72 h) in normal male
      rats and rats with isolated GH deficiency (spontaneous dwarf rats (SDR)).
      Circulating GH levels were undetectable in SDR, and IGF-I levels were less than
      10% of normal controls. Fasting stimulated NPY mRNA levels in SDR; however, the
      rise in NPY mRNA levels was not accompanied by a fall in GHRH mRNA, as observed
      in fasted normal rats. In fact, GHRH mRNA levels paradoxically rose in the fasted
      SDR to 135% of fed controls. At the pituitary level, fasting did not alter sst2
      and sst5 mRNA levels in SDR but did stimulate the expression of GHRH-R and GHS-R
      to 165% and 149% of fed controls, respectively. These results demonstrate that
      the fasting-induced changes in pituitary expression of sst2 and sst5, but not
      GHRH-R and GHS-R, are GH/IGF-I dependent. In addition, these results argue
      against the theory that the negative association of NPY and GHRH expression
      observed following fasting represents a simple cause-and-effect relationship and
      suggest that GH, either directly or indirectly, mediates the effects of fasting
      on hypothalamic GHRH expression.

PMID- 15012592
TI  - N-terminal His(7)-modification of glucagon-like peptide-1(7-36) amide generates
      dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity.
AB  - Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and
      beneficial effects for the potential treatment of type 2 diabetes. However, the
      rapid inactivation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a
      short half-life in vivo (less than 2 min) hindering therapeutic development. In
      the present study, a novel His(7)-modified analogue of GLP-1, N-pyroglutamyl-GLP
      1, as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and
      biological activity. Incubation of GLP-1 with either DPP IV or human plasma
      resulted in rapid degradation of native GLP-1 to GLP-1(9-36)amide, while N-acetyl
      GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl
      GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced
      affinities (IC(50) values 32.9 and 6.7 nM, respectively) compared with native GLP
      1 (IC(50) 0.37 nM). Similarly, both analogues stimulated cAMP production with
      EC(50) values of 16.3 and 27 nM respectively compared with GLP-1 (EC(50) 4.7 nM).
      However, N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 exhibited potent insulinotropic
      activity in vitro at 5.6 mM glucose (P<0.05 to P<0.001) similar to native GLP-1.
      Both analogues (25 nM/kg body weight) lowered plasma glucose and increased plasma
      insulin levels when administered in conjunction with glucose (18 nM/kg body
      weight) to adult obese diabetic (ob/ob) mice. N-pyroglutamyl-GLP-1 was
      substantially better at lowering plasma glucose compared with the native peptide,
      while N-acetyl-GLP-1 was significantly more potent at stimulating insulin
      secretion. These studies indicate that N-terminal modification of GLP-1 results
      in DPP IV-resistant and biologically potent forms of GLP-1. The particularly
      powerful antihyperglycaemic action of N-pyroglutamyl-GLP-1 shows potential for
      the treatment of type 2 diabetes.

PMID- 15012593
TI  - Cell signalling of glucagon-like peptide-1 action in rat skeletal muscle.
AB  - Glucagon-like peptide-1 (GLP-1), an incretin with glucose-dependent
      insulinotropic and insulin-independent antidiabetic properties, has insulin-like
      effects on glucose metabolism in extrapancreatic tissues participating in overall
      glucose homeostasis. These effects are exerted through specific receptors not
      associated with cAMP, an inositol phosphoglycan being a possible second
      messenger. In rat hepatocytes, activation of phosphatidylinositol 3-kinase
      (PI3K)/protein kinase B (PKB), protein kinase C (PKC) and protein phosphatase 1
      (PP-1) has been shown to be involved in the GLP-1-induced stimulation of glycogen
      synthase. We have investigated the role of enzymes known or suggested to mediate
      the actions of insulin in the GLP-1-induced increase in glycogen synthase a
      activity in rat skeletal muscle strips. We first explored the effect of GLP-1,
      compared with that of insulin, on the activation of PI3K, PKB, p70s6 kinase
      (p70s6k) and p44/42 mitogen-activated protein kinases (MAPKs) and the action of
      specific inhibitors of these kinases on the insulin- and GLP-1-induced increment
      in glycogen synthase a activity. The study showed that GLP-1, like insulin,
      activated PI3K/PKB, p70s6k and p44/42. Wortmannin (a PI3K inhibitor) reduced the
      stimulatory action of insulin on glycogen synthase a activity and blocked that of
      GLP-1, rapamycin (a 70s6k inhibitor) did not affect the action of GLP-1 but
      abolished that of insulin, PD98059 (MAPK inhibitor) was ineffective on insulin
      but blocked the action of GLP-1, okadaic acid (a PP-2A inhibitor) and tumour
      necrosis factor-alpha (a PP-1 inhibitor) were both ineffective on GLP-1 but
      abolished the action of insulin, and Ro 31-8220 (an inhibitor of some PKC
      isoforms) reduced the effect of GLP-1 while completely preventing that of
      insulin. It was concluded that activation of PI3K/PKB and MAPKs is required for
      the GLP-1-induced increment in glycogen synthase a activity, while PKC, although
      apparently participating, does not seem to play an essential role; unlike in
      insulin signaling, p70s6k, PP-1 and PP-2A do not seem to be needed in the action
      of GLP-1 upon glycogen synthase a activity in rat muscle.

PMID- 15012594
TI  - NO-1886 decreases ectopic lipid deposition and protects pancreatic beta cells in
      diet-induced diabetic swine.
AB  - The synthetic compound NO-1886 (ibrolipim) is a lipoprotein lipase activator that
      has been proven to be highly effective in lowering plasma triglycerides.
      Recently, we found that NO-1886 also reduced plasma free fatty acids and glucose
      in high-fat/high-sucrose diet-induced diabetic rabbits. In the current study, we
      investigated the effects of NO-1886 treatment on ectopic lipid deposition and the
      islet pathology in miniature swine fed a high-fat/high-sucrose diet. Our results
      showed that feeding this diet to miniature swine caused insulin resistance,
      increased lipid deposition in non-adipose tissue, such as in the heart, skeletal
      muscle, liver and pancreas, and also caused pancreatic beta cell damage. However,
      supplementing 1% NO-1886 (200 mg/kg per day) into the high-fat/high-sucrose diet
      decreased ectopic lipid deposition, improved insulin resistance, and alleviated
      the beta cell damage. These results suggest that improvement of lipid disorder,
      non-adipose tissue steatosis and insulin resistance may be very important for the
      protection of beta cell damage. Therefore, NO-1886 is potentially beneficial for
      the treatment of insulin-resistance syndrome.

PMID- 15012595
TI  - Pancreatic islet blood flow during pregnancy in the rat: an increased islet mass
      is associated with decreased islet blood flow.
AB  - Increased blood perfusion of pancreatic islets is seen during various conditions
      of increased demand for insulin secretion. Pregnancy confers an increased need
      for insulin secretion, met by increased islet mass and volume as well as a
      decreased threshold for glucose-induced insulin secretion. In the present study,
      whole pancreatic and islet blood flow were studied with a microsphere technique
      in Wistar rats on days 15, 18 and 20 of pregnancy and days 2 and 7 post-partum.
      There were no changes in total pancreatic blood flow during pregnancy and the
      first post-partum week. Total blood perfusion through islet tissue expressed as
      flow per weight of whole pancreas was higher at day 15 of pregnancy. When islet
      blood flow was expressed per gram of islet tissue there was a decrease at day 18
      of pregnancy. This decrease of islet blood flow was concomitant to a short-lived
      increase of the islet mass at the end of pregnancy. We conclude that upregulation
      of insulin output during late pregnancy does not specifically include increased
      net blood perfusion through the islets. One possible reason for this might be
      lack of synchronization between the proliferation of endocrine cells and
      angiogenesis, resulting in a relative decrease in islet vascular density in the
      islets.

PMID- 15012596
TI  - Octreotide prevents growth factor-induced proliferation of bovine retinal
      endothelial cells under hypoxia.
AB  - Ocular diseases such as proliferative diabetic retinopathy are the major cause of
      blindness in industrialized countries. The main pathologic features of these
      diseases are hypoxia and overproduction of growth factors resulting in pathologic
      proliferation of endothelial cells and new vessel formation. Particularly,
      hypoxia and growth factors, such as VEGF, IGF-1, bFGF and TGF beta(2), show a
      complex interaction in the onset and progression of the diseases. Therefore, to
      date, most therapeutic strategies for proliferative retinopathies have targeted
      proliferation of endothelial cells evoked by growth factors. Recently, a
      synthetic analog of somatostatin, octreotide, has been shown to inhibit the
      proliferation of various cells in vitro, including endothelial cells. In this
      study, we have investigated the proliferative response of bovine retinal
      endothelial cells (BREC) to growth factors under hypoxic conditions and the
      modulation by octreotide. We found a dose-dependent increase of cell
      proliferation with VEGF, IGF-1 and bFGF, and inhibition of hypoxia-induced cell
      proliferation with TGF beta(2). Moreover, growth factor-induced, but not hypoxia
      induced, cell proliferation was attenuated in the presence of octreotide. In
      contrast, TGF beta(2) abolished hypoxia-induced BREC proliferation. Similar to
      octreotide BIM23027, a somatastatin receptor subtype 2 (SSTR2) receptor agonist
      was able to attenuate the growth factor-induced proliferation of BREC expressing
      mRNA and protein for SSTR2. Therefore, we postulate that octreotide exerts its
      effects mainly through binding to the SSTR2. Taken together, our findings point
      to octreotide as a promising candidate for the treatment of eye disorders
      involving growth factor-dependent proliferation of endothelial cells.

PMID- 15012597
TI  - Corticotropin-releasing hormone in the teleost stress response: rapid appearance
      of the peptide in plasma of tilapia (Oreochromis mossambicus).
AB  - High concentrations (up to 600 pg/ml) of corticotropin-releasing hormone (CRH)
      were detected in plasma of the teleost fish Oreochromis mossambicus (tilapia)
      when screening peripheral tissues of tilapia exposed to stress. Notably, the
      plasma CRH response to stressors in tilapia is much more pronounced than that in
      higher vertebrates, such as rats. After characterisation by RIA, by spiking
      plasma with synthetic tilapia CRH and by methanol-acid extraction, it is
      concluded that the immunoreactive (ir) material in plasma represents tilapia
      CRH(1-41). Results indicate that a CRH-binding protein is absent in tilapia
      plasma. Unstressed fish had plasma CRH levels under the limit of detection (<2
      pg/ml), but following capture stress plasma CRH levels (170-300 pg/ml) as well as
      plasma cortisol levels (120 ng/ml) increased rapidly to plateau levels, which
      were reached after approximately 5 min. Tilapia CRH(1-41) tested at
      concentrations between 10(-11) and 10(-7) M in vitro did not stimulate the
      cortisol release from interrenal tissue. Also pretreatment of interrenal tissue
      with 10(-9) M CRH did not sensitise the cortisol-producing cells to a subsequent
      ACTH challenge. Forty-eight hours of net confinement or 48 h of cortisol
      treatment abolished the plasma CRH response and cortisol response to capture
      stress. The rapidity of the plasma CRH response and its inhibition after 48 h of
      stress or cortisol treatment point to release by central nervous tissue.
      Therefore the distribution of glucocorticoid receptors (GRs) in the brain and
      pituitary of tilapia was investigated. Main GR-ir cell clusters were found in the
      medial part (Dm) and posterior part of the dorsal telencephalon, in the preoptic
      region, in the inferior lobe of the hypothalamus and in the cerebellum. We
      conclude from comparison of CRH brain contents of unstressed and stressed fish
      that plasma CRH was released by CRH-ir cells located in the lateral part of the
      ventral telencephalon (Vl), and suggest that the cortisol feedback on CRH release
      by Vl is mainly exerted via the forebrain Dm region. We propose that CRH is
      mobilised during stress to fulfil peripheral functions, such as the regulation of
      circulating leukocytes or of cardiac output, as CRH receptors have been reported
      in these organs for fish species.

PMID- 15012598
TI  - Physiological reactions to fear provocation in dogs.
AB  - Fear is a common behavioral problem in dogs. In this paper, we studied the
      association between behavioral and physiological responses in two potentially
      fear-eliciting situations. The aim was to establish whether it is possible to
      separate dogs of the collie breed that are fearful of floors and gunshots from
      those that are not by studying changes in heart rate and hematocrit, plasma
      cortisol, progesterone, testosterone, vasopressin, and beta-endorphin
      concentrations. Thirteen privately owned male dogs of the collie breed were
      studied during a floor test, using different types of floors, and a subsequent
      gunshot test. Seven of the dogs were identified as being fearful of floors and
      six were declared as fearless. Out of the 13 dogs, seven were fearful of gunshots
      and six were fearless of gunshots. Since fear of floors did not always occur
      concomitantly with fear of gunshots, there were consequently four different
      groups of dogs. The heart rate increased during the floor test in all groups, but
      dogs that were fearful of floors had higher heart rates than dogs that were
      fearless of floors. Dogs that were fearful of gunshots had higher heart rates,
      higher hematocrit levels and higher plasma concentrations of cortisol,
      progesterone, vasopressin, and beta-endorphins during the gunshot test than did
      dogs that were found to be fearless of gunshots. Plasma cortisol and progesterone
      increased drastically during the gunshot test in dogs identified as being fearful
      of gunshots. In fearful dogs, the testosterone concentration increased after
      completion of the floor test and before the gunshot test started, but there were
      no significant differences in testosterone between the groups. Since dogs fearful
      of gunshots had increased levels of several physiological parameters, the results
      demonstrated that this fear is a serious stress for the individual, a fear which
      it is possible to register with physiological variables.

PMID- 15012599
TI  - Cortisol influences the ontogeny of both alpha- and beta-subunits of the cardiac
      sodium channel in fetal sheep.
AB  - During development, the heart has to adapt to changes in shape, size and, at
      birth, to significant changes in arterial pressure. The orderly contraction of
      the heart is dependent on the coordinated expression of ion channels at
      appropriate densities in individual cardiac myocytes. The present study
      demonstrated that the expression of the alpha-subunit of the cardiac sodium
      channel, SCN5a, was high at mid gestation but then decreased until 10 days before
      birth before increasing again. Whereas the beta-subunit, SCN1b, gradually
      increased in expression towards partum, there was no detectable expression of
      SCN3b at any gestational time point. Fetal adrenalectomy prior to the normal
      prepartum surge in cortisol caused a reduction in expression of SCN1b and a 7.0
      kb transcript of SCN5a, but not the major 8.5 kb transcript. Conversely, cortisol
      infusion into immature fetuses precociously increased expression levels of SCN1b
      and the SCN5a 7.0 kb transcript. The results show that cortisol regulates cardiac
      SCN gene expression in fetal sheep during late gestation. These findings could
      have implications for the aetiology of sudden infant death syndrome and for the
      intrauterine programming of adult cardiovascular disease.

PMID- 15012600
TI  - Expression of estrogen receptors and enzymes involved in sex steroid metabolism
      in the rat tibia during sexual maturation.
AB  - Estrogens are essential for bone mass accrual but their role before sexual
      maturation has remained elusive. Using in situ hybridization and
      immunohistochemistry, we investigated the expression of both estrogen receptor
      (ER) alpha and beta mRNA and protein as well as several mRNAs coding for enzymes
      involved in sex steroid metabolism (aromatase, type I and II 17 beta
      hydroxysteroid dehydrogenase (17 beta-HSD), steroid sulfatase (STS) and type I 5
      alpha-reductase) on sections of tibial metaphyses before (1- and 4-week-old),
      during (7-week-old) and after (16-week-old) sexual maturation in female and male
      rats. ER alpha and ER beta mRNA and protein were detected in metaphyseal bone in
      lining cells, osteoblasts, osteoclasts and some osteocytes with no apparent
      differences in expression during development or between the sexes. In contrast,
      aromatase, type I and II 17 beta-HSD and type I 5 alpha-reductase mRNAs were
      first detected in osteoblasts, osteoclasts and occasionally in osteocytes from
      sexual maturation (7-week-old rat) and onwards. Only STS was present before
      sexual maturation. To study the significance of ER alpha and beta expression in
      bone before sexual maturation when circulating sex steroid levels are low, 26-day
      old female and male rats underwent gonadectomy or 17 beta-estradiol (E(2))
      supplementation (0.5 mg/21 days) during 3 weeks. Following gonadectomy,
      trabecular bone volume (TBV) was lower in males (P=0.03) and there was a trend
      towards reduction in females (P=0.057). E(2) supplementation increased tibial TBV
      compared with controls in both genders as assessed by Masson-Goldner staining.
      These data suggest that the presence of ERs in bone cells before sex maturation
      might be of significance for bone mass accrual. Furthermore, based on the mRNA
      expression of the crucial enzymes aromatase and type I 17 beta-HSD, we suggest
      that bone cells in the tibial metaphysis acquire the intrinsic capacity to
      metabolize sex steroids from sexual maturation onwards. This process may
      contribute to the beneficial effects of estrogen on bone mass accrual, possibly
      by intracrinology.

PMID- 15012601
TI  - Changes in the expression of prostaglandin E and F synthases at induced and
      spontaneous labour onset in the sheep.
AB  - The differential production of prostaglandin (PG) F(2 alpha) and PGE(2) within
      the uterine compartment may play a role in controlling myometrial contraction. We
      hypothesized that the enzymes downstream of PG endoperoxide synthase-2 (PGHS-2)
      determine the ratio of PGF(2 alpha) and PGE(2) in the utero-ovarian vein plasma
      and the time of normal and preterm labour onset. The aim of this study was to
      simultaneously determine the expression of PGF and PGE synthases (PGFS and PGES)
      in gestational tissues at spontaneous and induced-preterm labour in sheep.
      Myometrial, endometrial and placental tissue were obtained from ewes in
      dexamethasone-induced preterm labour, age-matched control ewes, and ewes in
      spontaneous term labour for analysis of mRNA expression by real-time PCR. PGFS
      mRNA expression was significantly increased following dexamethasone-induced and
      spontaneous labour onset in placentome (P<0.01) but was unchanged in the
      myometrium and endometrium. In contrast, PGES mRNA expression remained unchanged
      or decreased. PGHS-2 mRNA expression was increased in all tissues examined in
      both dexamethasone-induced and spontaneous labour (P<0.001). Plasma PGE(2) and
      PGF(2 alpha) concentrations rose in both dexamethasone-induced and spontaneous
      labour with the ratio of PGF(2 alpha):PGE(2) increased with labour onset
      (P<0.05). These results are consistent with the hypothesis that the increased
      expression, of PGFS is responsible for the increased PGF(2 alpha):PGE(2) ratio
      and this, together with increased PGHS-2 expression, accounts for myometrial
      activity at labour onset. The findings point to PGFS expression as a key factor
      in regulating the uterotonic process in the sheep.

PMID- 15012602
TI  - The oncostatin M receptor/gp130 ligand murine oncostatin M induces apoptosis in
      adrenocortical Y-1 tumor cells.
AB  - The effects of murine oncostatin M (mOSM) are specifically mediated by the
      heterodimeric oncostatin M receptor (OSMR)/gp130 receptor complex. In the current
      study we demonstrate that murine adrenocortical Y-1 tumor cells express the
      OSMR/gp130 complex. Incubation of Y-1 cells with 1 and 10 ng/ml mOSM induces cell
      death due to specific induction of apoptosis. Western blot analysis of Y-1 cells
      incubated with mOSM for 24 h revealed caspase-3 cleavage and poly(ADP-ribase)
      polymerase (PARP) cleavage. In a proliferation assay system, incubation of Y-1
      cells with 0.01, 0.1, 1 and 10 ng/ml mOSM for 24 h resulted in a decrease in cell
      numbers to 99+/-2%, 84+/-9%, 50+/-7% and 43+/-5% respectively of untreated
      control (defined as 100%). Pretreatment of Y-1 cells with the Jak2 inhibitor
      AG490 (100 microM) rescued Y-1 cells from OSM-induced (10 ng/ml) cell death.
      Similarly, pretreatment of Y-1 cells with the general caspase inhibitor Z-VAD-FMK
      (42 microM) rescued Y-1 cells from OSM-induced (10 ng/ml) cell death. In summary,
      we show that adrenocortical Y-1 tumor cells express the OSMR/gp130 complex and
      that mOSM induces the Jak-STAT signaling cascade in these cells. Murine OSM in a
      dose-dependent manner induces apoptosis in adrenocortical Y-1 tumor cells.
      Apoptosis was demonstrated by caspase-3 cleavage and PARP cleavage. Rescue of Y-1
      cells from mOSM-induced apoptosis by the Jak2 inhibitor, AG490, and the general
      caspase inhibitor, Z-VAD-FMK, demonstrates Jak activation and subsequent caspase
      activation to be essential for mOSM-induced apoptosis in adrenocortical Y-1 tumor
      cells. The putative role of OSM as an immunotherapeutic agent in human
      adrenocortical cancer remains to be elucidated.

PMID- 15012603
TI  - Regulation of estrogen receptor-alpha expression in MCF-7 cells by taxol.
AB  - Results presented in this study demonstrate that treatment of MCF-7 cells with
      taxol resulted in induction of estrogen receptor-alpha (ER alpha) gene
      transcription with a subsequent increase in ER alpha mRNA; this effect was
      promoter specific since taxol did not affect total transcription in MCF-7 cells
      and lacked an effect on transcription of the human acidic ribosomal
      phosphoprotein protein PO, progesterone receptor, and pS2 genes. In contrast to
      the increase in transcription of the ER alpha gene, taxol inhibited translation
      of the ER alpha mRNA. This effect is also transcript specific since taxol did not
      alter total protein synthesis and did not affect the concentration of
      progesterone receptor protein in the cell. The overall result of taxol treatment
      was to decrease the concentration of ER alpha protein in the MCF-7 cells.
      Evidence is presented that the effects of taxol on ER alpha gene transcription
      may be mediated through the induction of p53.

PMID- 15012605
TI  - Parathyroid hormone activates adhesion in bone marrow stromal precursor cells.
AB  - The ability of parathyroid hormone (PTH) to enhance bone formation has recently
      been exploited in the treatment of osteoporosis. However, the underlying
      mechanisms are unknown. Osteoblasts, the bone-forming cells, derive from
      multipotential bone marrow stromal precursors called colony-forming units
      fibroblastic (CFU-F) upon culture ex vivo. Adhesion of such stromal precursors to
      bone is likely to be an early event in the anabolic response of bone to PTH. To
      test this, we measured the number of CFU-F that could be extracted from murine
      bone marrow after administration of an anabolic dose of PTH. We found that a very
      early response is a dramatic reduction, starting within 2 h, in the number of CFU
      F that could be extracted from their bone marrow. We then tested whether PTH has
      the ability to activate adhesion of CFU-F in vitro. For this, bone marrow cells
      were incubated in PTH for varying times. Non-adherent cells were then removed,
      and the adherent cells were incubated in PTH-free medium for 14 days to assess,
      as colony formation, the number of CFU-F that had adhered in the preceding
      period. We found that incubation in PTH caused a substantial increase in the
      number of CFU-F that adhered within 24 h. This increase was abrogated by peptidic
      inhibitors of integrins. The increase did not seem to be mediated through a PTH
      induced increase in interleukin-6, since interleukin-6 had no effect on CFU-F
      numbers when substituted for PTH. Similarly, adhesion was unaffected by
      incubation of bone marrow cells in dibutyryl cyclic AMP, nor by inhibitors or
      donors of nitric oxide. However, activation of CFU-F in vitro by PTH was strongly
      inhibited by indomethacin and mimicked by prostaglandin E(2), and indomethacin
      reversed the PTH-mediated reduction of CFU-F that could be extracted from mouse
      bone marrow. These results suggested that PTH rapidly activates adhesion of CFU-F
      to plastic or bone surfaces. This activation may represent an early event in the
      anabolic response of bone cells to PTH.

PMID- 15012604
TI  - Regulation of estrogen receptor-alpha expression by the tumor suppressor gene p53
      in MCF-7 cells.
AB  - The results presented here demonstrate that p53 upregulates estrogen receptor
      alpha (ER alpha) expression in the human breast cancer cell line MCF-7. Two
      approaches were used to alter the activity of p53 in the cells. In the first
      approach, stable transfectants expressing an antisense p53 were established. In
      the stable clones, expression of antisense p53 resulted in a decrease in the
      expression of ER alpha protein. In the second approach, MCF-7 cells were
      transiently transfected with wild-type p53. Overexpression of p53 increased the
      amount of ER alpha. To determine whether the effects of p53 on the expression of
      ER alpha were due to changes in transcription, deletion mutants of the ER alpha
      promoter were used. This experimental approach demonstrated that p53 up-regulates
      ER alpha gene expression by increasing transcription of the gene through elements
      located upstream of promoter A. Transfection assays using p53 mutants further
      demonstrated that the p53-induced increase in ER alpha gene transcription was not
      dependent on the ability of p53 to bind to DNA but on its ability to interact
      with other proteins.

PMID- 15012606
TI  - Food restriction regulates adipose-specific cytokines in pituitary gland but not
      in hypothalamus.
AB  - White adipose tissue is now recognized as the source of a growing list of novel
      adipocyte-specific factors, or adipokines. These factors regulate energy
      homeostasis, including the response to food deprivation. We hypothesized that the
      brain and pituitary gland would also express adipokines and their regulatory
      factors and subsequently demonstrated that the rodent brain-pituitary system
      expresses mRNA and protein for leptin and resistin. We now report that the
      adipokines FIAF and adiponutrin, as well as the nuclear hormone receptor PPAR
      gamma, are expressed in pituitary, brain and adipose tissue. In pituitary gland,
      24 h of food restriction reduced PPAR gamma expression by 54% whereas both
      adiponutrin and FIAF were increased 1.7 and 2.3 fold, respectively. These changes
      in expression were similar to those observed in fat, except for adiponutrin,
      which by contrast is dramatically reduced 95% by fasting. Furthermore, whereas
      PPAR gamma 2 is the main isoform affected by fasting in adipose tissue, our data
      suggest that only PPAR gamma 1 is present and downregulated by fasting in
      pituitary tissue. In contrast to the sensitivity of pituitary tissue to the
      effects of fasting, no significant change in expression was observed in basal
      hypothalamus for any of the genes studied. Overall, our data suggest that
      pituitary-derived adipokines may play an unexpected role in the neuroendocrine
      regulation of energy homeostasis.

PMID- 15012607
TI  - Insights into the molecular biology of the estrogen receptor define novel
      therapeutic targets for breast cancer.
AB  - Evidence for a role of ovarian factors in the growth of metastatic breast cancer
      was first recognized over 100 years ago. Today, anti-estrogens are central to the
      treatment of breast cancer of all stages. We now understand that the action of
      estrogen is mediated by the estrogen receptors (ER) which are members of the
      nuclear receptor family of ligand-regulated transcription factors. In this
      article we review the molecular mechanisms through which ER activates
      transcription of target genes and through which available anti-estrogens mediate
      their therapeutic effects. We discuss possible mechanisms of failure of treatment
      with current anti-estrogens and how newer anti-estrogens under development
      attempt to address these problems. In addition an expanded view of the molecular
      mechanisms of estrogen action is leading to the development of novel selective ER
      modulators or SERMs.

PMID- 15012608
TI  - Prolonged jaundice and hypothyroidism as the presenting symptoms in a neonate
      with a novel Prop1 gene mutation (Q83X).
AB  - OBJECTIVE: To identify the genetic defect in a neonate presented with prolonged
      jaundice and central hypothyroidism. DESIGN: Central hypothyroidism was detected
      in a neonate initially examined for prolonged jaundice, and levothyroxine therapy
      was initiated. Direct sequencing of the Prop1 gene was carried out and pituitary
      function and morphology were evaluated using hormonal testing and magnetic
      resonance imaging (MRI) respectively. METHODS: Dynamic hormonal testing was
      carried out using established methodologies. Hormones were determined by RIA or
      chemiluminescence immunoassays. Genomic analysis of the Prop1 gene was performed
      by direct sequencing. MRI protocol: sagittal spin echo T2-weighted scans 2500/90
      (TR/TE), plain and contrast-enhanced sagittal and coronal spin echo T1-weighted
      scans 500/20 (TR/TE). RESULTS: Low thyroid hormones (coupled with lack of TSH
      rise), low GH, normal cortisol and normal prolactin values were detected. Direct
      sequencing revealed the presence of two mutations in the Prop1 gene: GA296del and
      Q83X. The Q83X was further confirmed by PvuII restriction digestion and
      represented a novel Prop1 gene mutation, which was not detected in 100 controls
      tested. Pituitary enlargement was detected, with respect to normal-for-age
      controls. CONCLUSIONS: (i) The Q83X mutation extends the spectrum of Prop1 gene
      mutations; (ii) central hypothyroidism in a neonate might constitute the initial
      sign of Prop1 gene defect; (iii) the patient is the youngest individual with
      Prop1 gene defect and pituitary enlargement presented to date; and (iv) early
      detection of Prop1 gene mutations facilitates genetic counseling and ensures
      prompt management of the anticipated hormonal insufficiencies.

PMID- 15012609
TI  - Potent thyrotrophin receptor-blocking antibodies: a cause of transient congenital
      hypothyroidism and delayed thyroid development.
AB  - OBJECTIVE: We describe an infant with surprisingly severe neonatal hypothyroidism
      due to transplacental passage of thyrotrophin receptor (TSH-R)-blocking
      antibodies (TBAb). DESIGN AND METHODS: TBAb were detected using a cell line which
      stably expresses the human TSH-R and a cAMP-responsive luciferase reporter by
      their ability to inhibit TSH-stimulated luciferase expression. Potent TBAb were
      detected in maternal serum and initially in the infant's serum but, in the
      latter, TBAb decreased over time to within the reference range by 3-4 months of
      age, illustrating the transient nature of this condition. RESULTS: The thyroid
      function of this child did not return to normal on withdrawal of thyroxine
      therapy at 16 months of age when he developed transient compensated
      hypothyroidism. CONCLUSIONS: We propose that the presence of potent TBAb in utero
      and in the first weeks of life may have implications for the development of a
      normally sized thyroid gland. We have demonstrated the presence of TBAb in the
      mother's milk and, as far as we are aware, this is the first such report.
      However, the TBAb in the milk probably did not contribute significantly to
      hypothyroidism in the child, given the reducing antibody titre in his
      circulation.

PMID- 15012611
TI  - Diagnostic management of suspected metastatic thyroid carcinoma: clinical value
      of octreotide scintigraphy in patients with negative high-dose radioiodine scans.
AB  - OBJECTIVES: Somatostatin receptor scintigraphy (SRS) with (111)In-octreotide has
      been suggested as a potential tool for the detection of recurrent or metastatic
      differentiated thyroid cancer when no radioiodine uptake can be demonstrated in
      tumour sites. However, there is no consensus concerning the performance and
      clinical impact of this examination in such instances. DESIGN AND METHODS: A
      prospective study was undertaken to evaluate SRS in 43 patients (18 men, 25
      women) with papillary (n=20), follicular (n=9), insular (n=6) and oncocytic (n=8)
      thyroid carcinomas with elevated serum thyroglobulin (Tg) levels and no detected
      radioiodine uptake. RESULTS: Evaluation criteria were interpreted in terms of an
      assumed presence of tumoural tissue. Sensitivity of SRS was 51%, clearly lower
      than that of conventional imaging procedures, and of positron emission tomography
      using [(18)F]-2-fluoro-2-deoxy-d-glucose, performed in a subset of 27 patients.
      In addition, we observed two false-positive foci of uptake of octreotide that
      corresponded to inflammatory pulmonary sites. The sensitivity was higher in
      patients with Tg levels greater than 50 microg/l (76%) for detecting mediastinal
      lesions (93%), and in patients with oncocytic cancer (88%). Finally, SRS changed
      treatment strategy in four patients. CONCLUSION: In differentiated thyroid
      cancer, SRS is a moderately sensitive method for the detection of lesions unable
      to concentrate iodine and appears useful only in patients with very high Tg
      levels or in oncocytic cancer.

PMID- 15012610
TI  - Decreased expression of thyrotropin receptor gene suggests a high-risk subgroup
      for oncocytic adenoma.
AB  - OBJECTIVE: The malignancy of thyroid oncocytic tumours, or oncocytomas, is higher
      than that of follicular tumours. The aim of this study was to investigate the
      role of thyroid-specific genes in oncocytic tumours and papillary carcinomas.
      DESIGN AND METHODS: We compared 29 oncocytic tumours with 12 papillary
      carcinomas. Real-time quantitative PCR was used to measure the expression of
      thyroid-specific differentiation markers (thyrotrophin-stimulation hormone
      receptor (TSHR), thyroglobulin (TG) and Na(+)/I(-) symporter (NIS)),
      transcription factors (thyroid transcription factor-1 (TTF-1) and paired box gene
      8 (PAX8)) and nuclear receptors (peroxisome proliferator-activated receptor
      (PPARgamma1) and thyroid hormone receptor (TRbeta1)) involved in thyroid
      carcinogenesis. RESULTS: TSHR, TTF-1 and TRbeta1 levels were significantly lower
      in oncocytic tumours than in papillary carcinomas, as a result of specific
      biological changes in oncocytic tumours. However, PAX8 and PPARgamma1 did not
      seem to be involved in the process. Applying the criterion of the underexpression
      of the thyroid-specific differentiation markers, TSHR, TG and NIS, we classified
      the oncocytic tumours and papillary carcinomas into three groups. In the first,
      all three markers were underexpressed; in the second, TSHR was normal while TG
      and NIS were underexpressed; and in the third, only NIS was underexpressed. The
      expression patterns revealed that 13 of the 24 oncocytic adenomas underexpressing
      TSHR in our study, as did four of the five oncocytic carcinomas. CONCLUSION:
      Cases of oncocytic adenoma associated with low levels of TSHR could be putative
      oncocytic carcinomas and should therefore receive adequate follow-up [corrected].

PMID- 15012612
TI  - Compliance with follow-up and the informative value of diagnostic whole-body scan
      in patients with differentiated thyroid carcinoma given recombinant human TSH.
AB  - OBJECTIVE: Protocols for monitoring patients with differentiated thyroid cancer
      (DTC) include measurement of serum Tg and, for most patients, whole-body scan
      (WBS) with low radioiodine activities ('diagnostic' WBS). Recently, recombinant
      human thyroid-stimulating hormone (rhTSH) has become available to provide the TSH
      stimulation necessary for these procedures, whilst avoiding thyroid hormone
      withdrawal and hypothyroid complications. In addition, the inclusion of
      diagnostic WBS in DTC follow-up has recently become controversial. We have
      assessed the compliance with withdrawal-aided monitoring and the informative
      value of diagnostic WBS in consecutive tertiary referral center patients. DESIGN:
      Forty-eight patients received rhTSH (0.9 mg) in two consecutive daily injections,
      with radioiodine administration 24 h, diagnostic WBS 48 h, and serum Tg testing
      prior to and 72 h later. METHODS: Compliance with withdrawal-aided monitoring was
      assessed with a questionnaire provided by the referring physician, patient record
      analysis, and patient interview. The informative value of diagnostic WBS was
      assessed by comparing findings against serum Tg measurements in light of physical
      and other radiological examinations. RESULTS: Forty of the forty-eight patients
      were female, the mean age was 43.9 years and the median follow-up from diagnosis
      was 4.5 years (range 1-19 years). Twenty-seven (56%) patients were compliant and
      12 (25%) were non-compliant; compliance was not known in nine. Of 17 patients
      with clinically suspicious or significant findings on any available modality,
      four had uptake outside the thyroid bed on WBS but stimulated Tg <2.5 ng/ml on
      immunometric assay, while five had a negative WBS with serum Tg >2.5 ng/ml.
      CONCLUSIONS: Thyroid hormone withdrawal substantially impairs, and rhTSH
      administration substantially promotes, compliance with DTC monitoring. rhTSH
      aided WBS is informative and should be included in the follow-up of unselected
      patients with DTC.

PMID- 15012614
TI  - Effect of short-term treatment with low dosages of the proton-pump inhibitor
      omeprazole on serum chromogranin A levels in man.
AB  - BACKGROUND: Measurement of chromogranin A (CgA) levels in blood can be used to
      monitor neuroendocrine tumors (NETs). CgA levels may also be elevated in several
      other endocrine and non-endocrine diseases. It is well known that drugs affecting
      acid gastric secretion can increase gastrin. Proton-pump inhibitors are
      extensively used but only a few data have been reported on their effects on CgA
      secretion. DESIGN: The aim of the study was to evaluate the short-term effect of
      low dosages of omeprazole (OM) on CgA levels and to sensitize endocrinologists to
      possible false positive values of CgA in order to prevent expensive diagnostic
      work-up in searching for NETs. SUBJECTS AND METHODS: Thirty-five female and nine
      male in-patients (18-81 years) were studied. Mild or severe hypertension in 20
      patients needed therapy. Endocrine and metabolic diseases were diagnosed in the
      majority of patients. CgA levels were evaluated before and during OM therapy (10
      mg/day, orally). RESULTS: Without OM therapy, CgA levels were 64+/-6 microg/l.
      Elevated baseline CgA levels were found in nine subjects. CgA levels were
      significantly related to age (P<0.001), creatinine levels (P=0.03) and the
      severity of hypertension (P=0.002). On short-term OM therapy (n=42; 18.8+/-2.4
      days; range 5-90 days) a significant (P<0.001) increase in CgA (145+/-22
      microg/l) from baseline (63+/-7 microg/l) levels was found. The average net CgA
      increase on short-term OM therapy was 93+/-20 microg/l. There was a significant
      correlation between baseline CgA levels and CgA increase on short-term OM therapy
      (P=0.004) but not between the increase in CgA and the duration of the therapy.
      CONCLUSIONS: An increase in CgA levels quickly follows the start of low dosages
      of OM. This release is more pronounced when the baseline CgA levels are already
      increased by slight renal insufficiency or severe hypertension. In this common
      clinical situation an intensive work-up for NETs is not justified before
      reassessment of CgA after the withdrawal of OM.

PMID- 15012613
TI  - Central reassessment of GH concentrations measured at local treatment centers in
      children with impaired growth: consequences for patient management.
AB  - OBJECTIVE: GH deficiency is diagnosed in children if serum GH fails to rise above
      a predefined cutoff value in response to at least two stimuli. Diagnostic
      decisions based on this testing are highly variable between centers and depend on
      the GH assays used. Considering the large spectrum of commercially available GH
      assays, we wanted to evaluate the agreement between assays, and to test whether
      assay-related variability of diagnostic decisions could be reduced by
      reassessment of peak GH concentrations in a reference center. DESIGN: We
      reanalysed 699 peak GH serum samples obtained after GH testing of 382 children
      and adolescents from 19 centers using three reference assays and compared these
      results with those obtained with the local assays. A subgroup of 132 patients
      tested with the combination of insulin hypoglycemia test and arginine test was
      evaluated for changes in the assignment to the diagnostic group of GH deficiency.
      RESULTS: The mean difference between methods ranged from 5.4 to 10.3 mU/l, slopes
      of the regression lines from 1.28 to 1.65. Significant non-linearity was detected
      in five of six assay comparisons, indicating that most assay results cannot be
      interconverted by the use of a factor. Overall agreement between reference and
      local assays was only moderate. Significant changes in diagnostic assignment
      occurred when different assays were used on the same patient (P<0.0001-P<0.0023).
      Based on GH remeasurement by one reference assay, 36 of 132 patients were
      categorized differently, with 35 patients changing into the GH-deficient group.
      Similar findings were obtained with the other reference assays. CONCLUSIONS: To
      decrease variability in GH testing related to assays and cutoff values, we
      recommend nationwide reassessment of GH peak sera in reference centers. Decisions
      to treat GH deficiency should incorporate the reference center results.

PMID- 15012615
TI  - Circulating levels of receptor activator of nuclear factor-kappaB
      ligand/osteoprotegerin/macrophage-colony stimulating factor in a presumably
      healthy human population.
AB  - OBJECTIVES: To determine the ranges of variation of circulating receptor
      activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin
      (OPG)/macrophage-colony stimulating factor(M-CSF) and to ascertain their
      potential relationships with age, sex and menopausal status in women, and with
      sex hormones in a population-based healthy cohort. SUBJECTS AND METHODS: Blood
      samples were collected with EDTA after an overnight fast. The plasma levels of
      each of the above biochemical indices were measured by ELISA in a total of 566
      apparently healthy individuals aged 18-75 years. RESULTS: The plasma
      concentrations of cytokine molecules in the entire sample ranged from 674 to 4929
      pg/ml for OPG, from 105 to 4468 pg/ml for soluble RANKL (sRANKL), and from 187 to
      7604 pg/ml for M-CSF. The OPG levels demonstrated a clear positive correlation
      with age in both sexes (r=0.42 and 0.43, P<0.001, for men and women
      respectively). Application of the two-interval mathematical model revealed that
      in females OPG levels were age-independent until age 42, but then showed clear
      and significant correlation with age (r=0.48, P<0.001). As a result, young
      females (before 42 years) had a substantially lower average OPG level, 1377.8+/
      327.68 pg/ml, in comparison with older women, 1666.02+/-397.14 pg/ml. The M-CSF
      correlation with age was significantly greater in women (r=0.29, P<0.001)
      compared with men (r=0.17, P<0.01). Significant negative correlations between
      plasma levels of both OPG and M-CSF with estradiol concentrations were observed
      in women (r=-0.39, P<0.01; r=-0.25, P<0.001 respectively). sRANKL did not
      correlate with either age or sex hormones in either women or men. CONCLUSION: Age
      and sex affect differently the interindividual variation of OPG, RANKL and M-CSF.
      Our observations could form the basis for further research to establish
      provisional reference limits for OPG and RANKL, which are potential markers for
      benign and malignant processes in bone.

PMID- 15012616
TI  - Autoantibodies to human tryptophan hydroxylase and aromatic L-amino acid
      decarboxylase.
AB  - OBJECTIVE: To assess the prevalence of autoantibodies (Abs) to tryptophan
      hydroxylase (TPH) and aromatic l-amino acid decarboxylase (AADC) in patients with
      different autoimmune diseases and to analyse their respective epitopes. DESIGN:
      TPH and AADC Abs were measured in an immunoprecipitation assay using (35)S
      labelled full-length and fragments of TPH and AADC. METHODS: Patients with
      different autoimmune adrenal diseases (n=84), non-adrenal autoimmune diseases
      (n=37), idiopathic vitiligo (n=8) and 56 healthy blood donors were studied.
      RESULTS: Fourteen of twenty-three (61%) of patients with autoimmune polyglandular
      syndrome (APS) type I and 1/34 (3%) of patients with isolated Addison's disease
      (AD) were positive for TPH Abs. None of the patients with APS type II (n=27),
      coeliac disease (n=10), autoimmune thyroid disease (AITD) (n=11), type 1 diabetes
      mellitus (DM) (n=16) or idiopathic vitiligo (n=8) was positive for TPH Abs. AADC
      Abs were detected in 12/23 (52%) patients with APS type I, in 1/29 (3%) patients
      with APS type II and 1/34 (3%) patients with isolated AD. None of the patients
      with coeliac disease, type 1 DM, AITD or idiopathic vitiligo was positive for
      AADC Abs. TPH Abs were found to interact with the C-terminal amino acids (aa) 308
      423, central aa 164-205 and N-terminal aa 1-105 of the TPH molecule. AADC Ab
      binding epitopes were within the C-terminal aa 382-483, the central aa 243-381
      and the N-terminal aa 1-167. CONCLUSIONS: Our study suggests that TPH Abs and
      AADC Abs react with several different epitopes and that different epitopes are
      recognized by different sera. The prevalence of TPH Abs and AADC Abs in patients
      with APS type I in our study is in agreement with previous reports. TPH Abs and
      AADC Abs were found very rarely in patients with other forms of autoimmune
      adrenal disease and were not detected in patients with non-adrenal autoimmune
      diseases.

PMID- 15012617
TI  - Genetic variation in the human vitamin D receptor is associated with muscle
      strength, fat mass and body weight in Swedish women.
AB  - OBJECTIVE: Bone mineral density (BMD) is under strong genetic control and a
      number of candidate genes have been associated with BMD. Both muscle strength and
      body weight are considered to be important predictors of BMD but far less is
      known about the genes affecting muscle strength and fat mass. The purpose of this
      study was to investigate the poly adenosine (A) repeat and the BsmI SNP in the
      vitamin D receptor (VDR) in relation to muscle strength and body composition in
      healthy women. DESIGN: A population-based study of 175 healthy women aged 20-39
      years was used. METHODS: The polymorphic regions in the VDR gene (the poly A
      repeat and the BsmI SNP) were amplified by PCR. Body mass measurements (fat mass,
      lean mass, body weight and body mass index) and muscle strength (quadriceps,
      hamstring and grip strength) were evaluated. RESULTS: Individuals with shorter
      poly A repeat, ss and/or absence of the linked BsmI restriction site (BB) have
      higher hamstring strength (ss vs LL, P=0.02), body weight (ss vs LL, P=0.049) and
      fat mass (ss vs LL, P=0.04) compared with women with a longer poly A repeat (LL)
      and/or the presence of the linked BsmI restriction site (bb). CONCLUSIONS:
      Genetic variation in the VDR is correlated with muscle strength, fat mass and
      body weight in premenopausal women. Further functional studies on the poly A
      microsatellite are needed to elucidate whether this is the functionally relevant
      locus or if the polymorphism is in linkage disequilibrium with a functional
      variant in a closely situated gene further downstream of the VDR 3'UTR.

PMID- 15012618
TI  - Diagnosis of primary aldosteronism: value of different screening parameters and
      influence of antihypertensive medication.
AB  - OBJECTIVE: The aim of this study was to investigate the utility of different
      screening techniques for primary aldosteronism (PA), including serum aldosterone
      (SA), plasma renin activity (PRA) and the SA/PRA ratio in hypertensive patients
      of a tertiary-care centre. Furthermore, the influence of antihypertensive
      medication on SA and the SA/PRA ratio were studied. DESIGN: Clinical records of
      425 hypertensive patients who had SA and PRA measurements over a 27-month period
      were analysed retrospectively. Eighty patients were excluded from further
      analysis because of incomplete data. The remaining 345 patients were classified
      into the following groups: patients with essential hypertension (EH) (n=260,
      75.4%), patients with PA (n=49, 14.2%) and patients with secondary hypertension
      other than PA (n=36, 10.4%). Diagnosis of PA was made in accordance with
      established laboratory criteria (including measurements of SA, PRA, urinary
      excretion of aldosterone and metabolites, imaging techniques and response to
      treatment). RESULTS: Although mean serum potassium values were significantly
      lower (P<0.001) in the PA group compared with the EH group, 61% of PA subjects
      were normokalaemic (3.4-5.2 mmol/l). The SA/PRA ratio alone identified 94% of the
      patients with PA, but was false positive in 30% of the patients with EH. The
      SA/PRA ratio together with SA>150 g/ml increased the diagnostic accuracy, led to
      the correct identification of 84% of the patients with PA, and decreased the
      false-positive rate to 3%. A multivariate binary logistic regression analysis
      based on SA and PRA was performed, which identified PA with 90% sensitivity and
      91% accuracy. The SA(2)/PRA or the SA(3)/PRA ratio was found useful for
      simplification of the regression analysis. Antihypertensive medication influenced
      SA, PRA and the SA/PRA ratio only in EH patients. In EH patients taking beta
      adrenoceptor antagonists PRA tended to be lower, leading to a significantly
      higher SA/PRA ratio and therefore increasing the false-negative rate. CONCLUSION:
      To reduce false-positive results in screening for PA, and thereby avoid
      unnecessary and cost-intensive diagnostic procedures, SA should be taken into
      account in addition to the SA/PRA ratio as a second screening criterion.
      Alternatively, the SA(2)/PRA or the SA(3)/PRA ratio is more accurate screening
      tests than the SA/PRA ratio. Beta-blockers should be avoided whilst screening for
      PA.

PMID- 15012619
TI  - Effect of glucocorticoids on adiponectin: a study in healthy subjects and in
      Cushing's syndrome.
AB  - OBJECTIVE: Glucocorticoids were found to inhibit adiponectin gene expression and
      secretion both in vitro and in animal models. We evaluated first the acute effect
      of i.v. glucocorticoids on adiponectin in normal subjects and secondly plasma
      adiponectin levels in a series of patients with Cushing's syndrome compared with
      controls. DESIGN AND METHODS: Hydrocortisone (25 mg) was administered i.v. to
      five healthy volunteers, with blood samples taken at -15, 0, 30, 60, 120 and 180
      min. Twenty-one patients with Cushing's syndrome were divided in two groups: one
      with 11 obese and the other with 10 non-obese Cushing's patients. Each group was
      compared with controls that were matched for sex, age, body mass index, waist
      circumference, glucose, insulin, lipid levels and blood pressure. RESULTS: In
      normal subjects, hydrocortisone produced a decrease in adiponectin at 30 and 60
      min, compared with placebo (P<0.05). Adiponectin was lower in non-obese Cushing's
      patients than in non-obese controls (P<0.004). In contrast, there was no
      difference in adiponectin levels in obese Cushing's patients and in obese
      controls. Adiponectin was inversely correlated (P<0.05) with homeostasis model
      assessment index in both obese and non-obese Cushing's patients; in non-obese
      Cushing's patients only, adiponectin was inversely correlated with urinary
      cortisol (P<0.05). CONCLUSIONS: Glucocorticoids inhibit adiponectin in man, as
      shown by both exogenous administration to healthy subjects and endogenous
      cortisol hyperproduction. Similar levels of adiponectin in obese Cushing's
      patients and their obese controls indicate that obesity per se may act as a
      predominant factor in masking the relationship between adiponectin and cortisol.

PMID- 15012620
TI  - Circulating vascular endothelial growth factor and active renin concentrations
      and prostaglandin E2 urinary excretion in patients with adrenal tumours.
AB  - OBJECTIVES: The aim of the present study was to determine vascular endothelial
      growth factor (VEGF), prostaglandin E(2) (PGE(2)) and active renin levels in
      patients with hormonally active adrenal tumours. DESIGN: The study was comprised
      of 16 patients with primary aldosteronism, 13 patients with active Cushing's
      syndrome due to adrenal adenomas, 8 patients with adrenal carcinomas, 19 patients
      with phaeochromocytoma and 19 healthy volunteers. METHODS: Active renin in plasma
      was determined by a two-site immunoradiometric assay. VEGF in sera samples and
      PGE(2) in 24-h urine were measured by ELISA. RESULTS: VEGF was significantly
      elevated in all the four groups of patients as compared with the controls. VEGF
      levels in patients with Cushing's syndrome were higher than those in patients
      with primary aldosteronism. Patients with adrenal carcinomas had the highest VEGF
      levels and the differences reached significance as compared with patients with
      primary aldosteronism and phaeochromocytoma. PGE(2) levels were not significantly
      different among groups. Active renin was significantly the lowest in patients
      with primary aldosteronism and significantly the highest in patients with
      phaeochromocytoma compared with the controls. Active renin in patients with
      primary aldosteronism was significantly lower than in those with Cushing's
      syndrome, phaeochromocytoma and adrenal carcinoma. CONCLUSIONS: Our data
      indicated that the mean level of VEGF in patients with all investigated adrenal
      tumours was significantly higher than in healthy controls. The cortisol-producing
      tumours appear to have increased angiogenic potential. Angiogenesis is probably
      associated not only with malignancy but also with functional activity of the
      adrenal tumors.

PMID- 15012621
TI  - A comparison between spironolactone and spironolactone plus finasteride in the
      treatment of hirsutism.
AB  - OBJECTIVE: To compare the clinical efficacy and safety of the combination of
      spironolactone (100 mg/day) plus finasteride (5 mg/day) and spironolactone (100
      mg/day) alone in the treatment of hirsutism. PATIENTS AND MEASUREMENTS: Sixty
      five hirsute women were randomly assigned to one of these two treatment groups.
      Hirsutism score was measured according to the modified Ferriman-Gallwey scoring
      system. Baseline and post-treatment assessments were carried out in each subject
      by an investigator blinded to the therapy. Both groups had similar demographic
      properties at baseline. The serum levels of total and free testosterone,
      dehydroepiandrosterone sulphate and sex hormone-binding globulin were measured at
      the beginning and after 1 year of therapy. Blood chemistry and side-effects were
      evaluated during the study. Hirsutism scores were decreased significantly in both
      groups at the end of the year. RESULTS: The mean percentage change in hirsutism
      scores from baseline in the spironolactone plus finasteride-treated group (51.3%)
      was significantly (P<0.005) higher than in the group treated with spironolactone
      alone (36.6%). Patients from both treatment groups experienced similar side
      effects. CONCLUSIONS: We have concluded that a combination of spironolactone plus
      finasteride is a safe and effective therapy in the treatment of hirsutism.

PMID- 15012622
TI  - The effects of GH and hormone replacement therapy on serum concentrations of
      mannan-binding lectin, surfactant protein D and vitamin D binding protein in
      Turner syndrome.
AB  - OBJECTIVE: Studies in animals and humans indicate that growth hormone (GH) and
      insulin-like growth factor-I (IGF-I) modulate immune function. Recently, it was
      reported that GH therapy increased the level of mannan-binding lectin (MBL) in
      normal patients, and that treatment of acromegalics with pegvisomant decreased
      the levels of MBL. The effect on MBL was thought to be due to a specific action
      of GH, since IGF-I treatment did not affect MBL. Whether it is advantageous or
      not to have high or low levels of MBL is not known. Likewise, it is not clear how
      the modifications induced by GH affect immune function. In the present study we
      examined whether GH or hormone replacement therapy (HRT) in Turner syndrome (TS)
      influence the serum concentrations of MBL and two other proteins partaking in the
      innate immune defence, surfactant protein D (SP-D) and vitamin D binding protein
      (DBP). DESIGN: Study 1: a double-blind crossover study of 12 healthy TS
      adolescents examined during treatment with either placebo or GH for 2 months, and
      compared with a control group. Study 2: triple-blind crossover study of 9 healthy
      TS adolescents randomized to treatment with placebo, GH or GH+17beta-estradiol.
      Study 3: 60 adult TS patients (55 received HRT) compared with 59 age-matched
      controls. Study 4: 27 patients with TS were examined before and during sex
      hormone replacement with 17beta-estradiol and norethisterone and compared with
      age-matched controls (n=24). METHODS: Measurement of MBL, SP-D, DBP, and other
      inflammation markers. RESULTS: Study 1: the levels of MBL (P=0.002) and SP-D
      (P=0.012) increased during GH treatment, whereas no changes were observed in
      comparison with controls. DBP was unchanged by GH, but was significantly higher
      in TS compared with controls (P=0.017). Study 2: treatment with GH increased MBL
      (P=0.045) and SP-D (P=0.05) concentrations in TS, while treatment with GH+17beta
      estradiol did not increase levels further. DBP was unchanged by treatment. Study
      3: levels of MBL, SP-D, and DBP were similar in adult TS and control subjects.
      Study 4: DBP levels decreased in response to HRT, while MBL and SPD levels were
      unchanged. Levels of all three plasma proteins were similar to controls.
      CONCLUSION: We show that treatment with GH significantly increases MBL and SP-D
      concentrations in TS, while HRT marginally decreases DBP. Whether the present
      findings, suggesting a link between the endocrine and the immune system, have
      clinical consequences needs to be studied further.

PMID- 15012623
TI  - High prevalence of autoimmune thyroiditis in patients with polycystic ovary
      syndrome.
AB  - OBJECTIVE: To investigate the prevalence of autoimmune thyroiditis (AIT) in
      patients with polycystic ovary syndrome (PCOS). DESIGN: Over a period of 30
      months, 175 patients with PCOS were recruited to a prospective multicenter study
      to evaluate thyroid function and morphology; 168 age-matched women without PCOS
      were studied as a control group. METHODS: PCOS was defined as a- or
      oligomenorrhea, hyperandrogenism and exclusion of other disturbances of estrogen
      or androgen synthesis. All laboratory parameters were determined with automated
      immunoassays. Thyroid morphology was assessed by ultrasound. RESULTS: PCOS
      patients were characterized by an increased LH/FSH ratio, low progesterone,
      elevated testosterone and a high prevalence of hirsutism (PCOS 83%, control 3%;
      mean hirsutism score 12+/-5 and 3+/-2 respectively), but no differences in
      estrogen levels were found. Thyroid function and thyroid-specific antibody tests
      revealed elevated thyroperoxidase (TPO) or thyroglobulin (TG) antibodies in 14 of
      168 controls (8.3%), and in 47 of 175 patients with PCOS (26.9%; P<0.001). On
      thyroid ultrasound, 42.3% of PCOS patients, but only 6.5% of the controls
      (P<0.001) had a hypoechoic tissue typical of AIT; while thyroid hormone levels
      were normal in all subjects, PCOS patients had a higher mean TSH level (P<0.001)
      and a higher incidence of TSH levels above the upper limit of normal (PCOS 10.9%,
      controls 1.8%; P<0.001). CONCLUSION: This prospective study demonstrates a
      threefold higher prevalence of AIT in patients with PCOS, correlated in part with
      an increased estrogen-to-progesterone ratio and characterized by early
      manifestation of the disease.

PMID- 15012624
TI  - Genomic organization of mouse ZAKI-4 gene that encodes ZAKI-4 alpha and beta
      isoforms, endogenous calcineurin inhibitors, and changes in the expression of
      these isoforms by thyroid hormone in adult mouse brain and heart.
AB  - OBJECTIVE: ZAKI-4 was identified as a thyroid hormone-responsive gene in cultured
      human fibroblasts. A single ZAKI-4 gene encodes two isoforms, ZAKI-4 alpha and
      beta, both inhibiting calcineurin activity. ZAKI-4 alpha and beta differ at their
      N termini, and show distinct distribution profiles in human tissues. The aim of
      this study was to elucidate the organization of the mouse ZAKI-4 gene and to
      determine the effect of thyroid hormone on the expression of ZAKI-4 isoforms in
      vivo. DESIGN: We cloned mouse homologues of human ZAKI-4 alpha and beta cDNA.
      Fluorescence in situ hybridization and bioinformatics analysis were employed to
      determine the gene organization. The effect of thyroid hormone on the expression
      of ZAKI-4 isoforms in mouse brain and heart was also studied. METHODS: Total RNA
      extracted from mouse cerebellum was used to clone ZAKI-4 alpha and beta cDNAs by
      RT-PCR followed by rapid amplification of cDNA ends. Mice were rendered
      hypothyroid by feeding a low iodine diet supplemented with propylthiouracil for 2
      weeks. In one group (hyperthyroid) L-T(3) was injected i.p. for the last 4 days
      whereas another group (hypothyroid) received vehicle only. Non-treated mice were
      controls. RESULTS AND CONCLUSION: Mouse ZAKI-4 alpha and beta cDNAs were highly
      homologous to the human isoforms. The gene was mapped on chromosome 17qC,
      syntenic to human chromosome 6 where the human ZAKI-4 gene is located. As
      observed in human, ZAKI-4 alpha mRNA was expressed only in brain whereas beta
      mRNA was distributed in other tissues as well, such as heart and skeletal muscle.
      ZAKI-4 alpha mRNA was lower in the cerebral cortex of hypothyroid mice. Injection
      of L-T(3) caused an increase in ZAKI-4 beta mRNA in heart; however, expression of
      neither ZAKI-4 alpha nor beta mRNA was influenced by thyroid status in other
      tissues. These results indicate that expression of ZAKI-4 alpha and beta isoforms
      is regulated by thyroid hormone in vivo, and the regulation is isoform- and
      tissue-specific.

PMID- 15012625
TI  - TSH receptor antibodies do not alter the function of gonadotropin receptors
      stably expressed in eukaryotic cells.
AB  - OBJECTIVE: TSH receptor (TSHr) mediates the activating action of TSH on the
      thyroid gland resulting in the growth and proliferation of thyrocytes and thyroid
      hormone production. TSHr is a major autoantigen in Graves' disease (GD) and is
      the target for TSHr antibodies. In GD, thyroid-stimulating antibodies (TSAb) are
      competitive agonists of TSH. In atrophic thyroiditis (AT), thyroid-stimulating
      blocking antibodies (TSHBAb) are TSH antagonists. The TSHr together with the LH
      receptor (LHr) and FSH receptor (FSHr) are G-protein-coupled receptors with
      considerable amino acid homologies in the extracellular domain. We studied the
      cross-reactivity of the antibodies measured in sera from patients with GD or AT
      on the LHr and FSHr function. METHODS: We tested the activity of TSAb and TSHBAb
      in cell lines expressing the LHr and the FSHr. To this purpose a pSVL-FSHr
      construct was transfected in CHO cells and one clone was used. RESULTS: Twenty
      eight sera from patients with GD and four from patients with AT, known to contain
      TSHr antibodies measured with a radioreceptor assay, were selected. TSAb and
      TSHBAb activities were measured in CHO cells expressing the TSHr (CHO-TSHr). TSAb
      and TSHBAb were then tested with the cell lines expressing the LHr and the FSHr
      for their ability to elicit cAMP accumulation or inhibit FSH/LH-induced cAMP
      production. None of the TSAb identified was able to stimulate cAMP increase in
      CHO-LHr or CHO-FSHr. Similarly, none of the TSHBAb was able to block the cAMP
      response induced by FSH or LH in the respective cell lines. CONCLUSIONS: Our
      results confirm the notion of the organ-specific nature of the TSHr antibodies.

PMID- 15012626
TI  - Pax2 mutant mice display increased number and size of islets of Langerhans but no
      change in insulin and glucagon content.
AB  - Pax2 is a paired box transcription factor expressed in a spatially and temporally
      restricted manner and its absence results in major developmental defects of the
      central nervous system, eyes, ears and urogenital system. We recently reported
      that Pax2 is expressed in pancreatic endocrine cell lines and adult islets of
      Langerhans and activates glucagon gene expression. We have shown here that the
      Pax2 gene is expressed during pancreas development as early as embryonic day
      10.5. Its absence, as assessed in Pax2(1Neu) mutant mice, results in a two- to
      threefold increase in the average pancreas volume occupied by the islets in both
      heterozygous and homozygous mutant mice with a gene-dependent dosage effect. This
      increase, which is due to a change in the number of islets per unit pancreas
      volume and in the size of individual islets, is not accompanied by significant
      modification in the insulin or glucagon content of the pancreas, indicating that
      the content of these hormones per cell is decreased. We have concluded that Pax2
      may be implicated in the prenatal determination of the relative proportion of the
      endocrine and exocrine tissues of the pancreas.

PMID- 15012627
TI  - Mechanisms for altered reproductive function in female rats following neonatal
      administration of raloxifene.
AB  - OBJECTIVE: Raloxifene is a non-steroidal selective estrogen receptor modulator
      (SERM) that mimics estrogenic activity on bone density and blood lipid
      concentration without uterotropic actions. Previous data from our laboratory
      indicated that, as is the case for estrogen, neonatal administration of
      raloxifene disturbed normal differentiation of the hypothalamic circuitries
      governing the gonadotropic axis. In contrast, raloxifene did not act in the same
      way as estrogen does on the neuronal systems controlling sexual receptivity in
      the female rat. At present, however, the mechanisms for these organizing effects
      of raloxifene are not completely elucidated. DESIGN AND METHODS: To analyze this
      phenomenon, female rats were injected daily with raloxifene (50, 100, 250 or 500
      microg/rat per day) between days 1 and 5 of age. On day 23, hypothalamic
      gonadotropin-releasing hormone (LHRH) mRNA expression was assessed, and pituitary
      and plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels
      were measured in basal and LHRH-stimulated conditions. In addition, LH and FSH
      responses to ovariectomy were evaluated in raloxifene-treated females. Finally,
      we monitored the ability of neonatal administration of a potent LHRH agonist ([d
      Ala(6),d-Gly(10)]-LHRH ethylamide; 0.01 microg/kg per 12 h on days 1-5) to
      counteract the effects of raloxifene. RESULTS: Our analyses demonstrated that
      prepubertal rats (23-day-old females) treated neonatally with raloxifene showed
      decreased hypothalamic LHRH mRNA expression levels, reduced pituitary content of
      LH and FSH, reduced basal and LHRH-stimulated LH secretion in vivo and in vitro,
      and decreased response to ovariectomy. In addition, adult females treated
      neonatally with raloxifene showed anovulation and reduced serum LH levels; these
      effects were not prevented by the simultaneous administration of a LHRH agonist.
      CONCLUSION: In conclusion, our data demonstrate that neonatal administration of
      raloxifene can disrupt the programming of hypothalamic-pituitary-ovarian axis
      function. Reduced LH secretion, under basal and LHRH-stimulated conditions and
      after ovariectomy, is probably related to decreased LHRH expression, reduced
      pituitary LH content and/or decreased pituitary responsiveness to hypothalamic
      LHRH.

PMID- 15012628
TI  - Circulating levels of ghrelin in human fetuses.

PMID- 15012631
TI  - Guest Editorial: Rethinking research training.

PMID- 15012629
TI  - Asc1p, a WD40-domain containing adaptor protein, is required for the interaction
      of the RNA-binding protein Scp160p with polysomes.
AB  - Scp160p interacts in an mRNA-dependent manner with translating ribosomes via
      multiple RNA-binding heterogeneous nuclear ribonucleoprotein K-homology (KH)
      domains. In the present study, we show by protein-protein cross-linking that
      Scp160p is in close proximity to translation elongation factor 1A and the WD40
      (Trp-Asp 40)-repeat containing protein Asc1p at ribosomes. Analysis of a
      truncation mutant revealed that the C-terminus of Scp160p is essential for
      ribosome binding and that Cys(1067) at the C-terminus of Scp160p is required to
      obtain these cross-links. The interaction of Scp160p with ribosomes depends on
      Asc1p. In fast-growing yeast cells, nearly all Asc1p is tightly bound to
      ribosomes, but it can also be present in a ribosome-free form depending on growth
      conditions. The functional homologue of Asc1p, mammalian RACK1 (receptor of
      activated C kinase), was previously characterized as an adaptor protein bridging
      activated signalling molecules with their substrates. Our results suggest that
      Scp160p connects specific mRNAs, ribosomes and a translation factor with an
      adaptor for signalling molecules. These interactions might regulate the
      translation activity of ribosomes programmed with specific mRNAs.

PMID- 15012630
TI  - Interaction(s) of rotavirus non-structural protein 4 (NSP4) C-terminal peptides
      with model membranes.
AB  - Rotavirus is the major cause of dehydrating gastroenteritis in children and young
      animals. NSP4 (non-structural protein 4), a rotaviral non-structural glycoprotein
      and a peptide NSP4(114-135) (DKLTTREIEQVELLKRIYDKLT), corresponding to NSP4 amino
      acids 114-135, induce diarrhoeal disease in a neonatal mouse model and interact
      with model membranes that mimic caveolae. Correlation of the mechanisms of
      diarrhoea induction and membrane interactions by NSP4 protein and peptide remain
      unclear. Several additional NSP4 peptides were synthesized and their interactions
      with membranes studied by (i) CD, (ii) a filtration-binding assay and (iii) a
      fluorescent molecule leakage assay. Model membranes that varied in lipid
      compositions and radius of curvature were utilized to determine the compositional
      and structural requirements for optimal interaction with the peptides of NSP4.
      Similar to the intact protein and NSP4(114-135), peptides overlapping residues
      114-135 had significantly higher affinities to membranes rich in negatively
      charged lipids, rich in cholesterol and with a high radius of curvature. In the
      leakage assay, small and large unilamellar vesicles loaded with the
      fluorophore/quencher pair 8-aminonaphthalene-1,3,6-trisulphonic acid disodium
      salt/p -xylene-bis-pyridinium bromide were incubated with the NSP4 peptides and
      monitored for membrane disruption by lipid reorganization or by pore formation.
      At a peptide concentration of 15 microM, none of the NSP4 peptides caused
      leakage. These results confirm that NSP4 interacts with caveolae-like membranes
      and the alpha-helical region of NSP4(114-135) comprises a membrane interaction
      domain that does not induce membrane disruption at physiological concentrations.

PMID- 15012633
TI  - Benefits and challenges of nurse prescribing.
AB  - BACKGROUND: Since 1999, all health visitors and district nurses in the United
      Kingdom (UK) have received additional education to permit their registration as
      independent prescribers from a limited list of medicinal products. Little
      research has investigated how more than 20 000 health visitor and district nurse
      prescribers have implemented their new role since the evaluation of the pilot
      sites. AIMS: The aims of the study were to describe prescribing practices of
      health visitors and district nurses, the factors (contextual and professional)
      which enable and facilitate nurse prescribing, and views about the Nurse
      Prescribers' Formulary. METHOD: A mail survey was conducted of all health
      visitors and district nurses working in three trusts in southern England. A 74%
      response rate was achieved (n = 91). FINDINGS: Most respondents prescribed less
      than three times a week, with district nurses prescribing significantly more than
      health visitors (P </= 0.001). Over two-thirds of the sample found nurse
      prescribing at least moderately helpful to their professional role and over four
      fifths reported that they were more than moderately confident nurse prescribers.
      A range of information sources was identified as helpful, regarding both new
      products and for continuing educational needs. Over two-thirds reported that the
      current Nurse Prescribers' Formulary did not cover their prescribing needs, and a
      number of factors were identified as hindering prescribing. Most respondents said
      that their general practitioner/primary care team was at least moderately
      supportive of their prescribing role. LIMITATIONS: The survey was conducted in
      three primary care trusts in southern England, which may be unrepresentative of
      trusts elsewhere in UK. CONCLUSIONS: The level of reported prescribing by health
      visitors and district nurses in this study indicates that they are not acting as
      substitute prescribers for general practitioners of the products in the limited
      formulary. Implementation of a major role change such as nurse prescribing
      requires a number of conditions, including adequate education/preparation, a
      formulary that meets practitioners' needs, and acceptance by the practitioners
      themselves.

PMID- 15012634
TI  - The urban geography of SARS: paradoxes and dilemmas in Toronto's health care.
AB  - BACKGROUND: Severe acute respiratory syndrome (SARS) has impacted heavily on both
      Canada's society and its health care system. Quite unexpectedly, hospitals and
      health care workers became facilitators of disease diffusion. This experience has
      demonstrated the need for a comprehensive disease control strategy. AIMS: The
      aims are threefold. First, to examine the subtle and changing spatial
      characteristics of SARS during the short but critical period of its rapid spread
      in the Greater Toronto Area. Second, to make salient three paradoxes, and their
      associated dilemmas, faced by nurses and other health care professionals
      challenged with caring for the sick and containing the rapid spread of the
      disease. Third, to propose some ways of approaching these dilemmas, as well as
      some broader preventative and mitigating strategies. METHODS: The crosscutting
      concepts of 'clinical uncertainty' and 'flow of human contacts' are used to
      explain disease transmission characteristics and urban spatial diffusion and to
      guide the particular strategies developed. Evidence for the paper comes from
      public health records, governmental and non-governmental health statements and
      the initial epidemiological research on SARS. Direct insights are also gained
      from recent first-hand experiences of Toronto's health care system during the
      crisis. DISCUSSION: The concepts of clinical uncertainty and the flow of human
      contacts provide in-depth insights that complement the findings of large-scale
      epidemiological studies, and help operationalize their general calls for enhanced
      control measures. The comprehensive disease control strategy proposed includes
      the creation of a hospital infrastructure specific to the containment of
      biological threats; an advisory coalition of disease control specialists; the
      development of a biological threat-and-containment simulation laboratory and
      three specific programmes in patient safety, risk assessment and community
      mobilization. CONCLUSION: It is argued that containment alone, while a necessary
      and urgent priority, cannot be seen as an end in itself and might better be
      understood as one possible trajectory within a comprehensive problem-solving
      strategy. The experiences in Toronto may offer insights to other cities and
      countries that currently lack such strategies and hence may be vulnerable to
      similar outbreaks of dangerous infectious diseases.

PMID- 15012635
TI  - Integration of overseas Registered Nurses: evaluation of an adaptation programme.
AB  - BACKGROUND: The growth in overseas nurse recruitment to address staff shortages
      in the United Kingdom (UK) has led to the proliferation of adaptation programmes
      for overseas nurses to gain appropriate experience and enable them register with
      the Nursing and Midwifery Council. This paper reports on selected findings from
      an independent evaluation of an adaptation programme for overseas Registered
      Nurses offered by a large acute National Health Service trust. AIM: This paper
      reports on a study to evaluate the programme with reference to its objectives,
      outcomes and overall success from the perspective of various stakeholders.
      METHODS: A pluralistic evaluation research model was adopted to identify the
      criteria that stakeholders used to judge the success of an adaptation programme,
      and then to use these criteria to judge the programme in question. Data were
      collected by means of focus group and individual in-depth interviews with
      overseas nurses, ward managers, mentors, senior nurse managers and educators over
      a 12 month period and analysed by drawing on the principles of dimensional
      analysis. The criteria for success identified by the various stakeholders
      provided a framework through which the overall success of the initiative could be
      judged. FINDINGS: Five meanings of success were identified: gaining professional
      registration; fitness for practice; reducing the nurse vacancy factor; equality
      of opportunity and promoting an organizational culture that values diversity. Key
      findings relating to each of these are presented. The ease with which nurses
      gained UK registration and integrated into the nursing workforce was influenced
      by the characteristics of the work environment, level of support, and
      organizational context. CONCLUSION: Industrialized nations recruiting from the
      global nursing market need to invest in providing appropriate support to enable
      overseas nurses to adapt to working in a different health care system and social
      and cultural context.

PMID- 15012637
TI  - Health needs of Hong Kong Chinese pregnant adolescents.
AB  - BACKGROUND: The outcomes of adolescent pregnancy have been associated with health
      risks such as obstetric complications and depression, and educational risks such
      as school dropout and reduced employment opportunities. These outcomes arise from
      a range of needs including perceived health needs, which are the focus of this
      paper. AIM: This paper reports a study to identify the perceived needs of Hong
      Kong Chinese adolescents following confirmation of an unintended pregnancy.
      METHODS: An exploratory qualitative approach was used with a purposive sample of
      10 Hong Kong Chinese pregnant adolescents. The study was undertaken during their
      stay in a non-government organization maternal shelter. Semi-structured
      interviews were used to explore adolescents' perceptions of their psychological,
      social and health needs and the extent to which each of these needs was met.
      FINDINGS: Six major categories were identified within the context of need, of
      which three were related to health needs: acceptance of the pregnancy;
      psychological reactions to the pregnancy; and use of contraception and health
      advice. CONCLUSIONS: The findings contribute to an understanding of the perceived
      health needs of Chinese adolescents, in particular those that are culturally
      determined. Implications for nursing practice indicate the significance of
      comprehensive health assessments and health promotion strategies to help
      adolescents increase their knowledge about sexual health and contraception.

PMID- 15012636
TI  - Maternal support during the first year of infancy.
AB  - BACKGROUND: Mental health problems among children and adolescents are becoming
      more visible and some research indicates that they are increasing. Several
      studies suggest that social support counteracts the increasing risk of ill-health
      in families with children. However, there is a lack of studies which focus on the
      support that expectant mothers and parents might need. AIM: The aim of the study
      was to describe mothers' experiences of pregnancy, labour and homecoming, support
      needs, and sources of support in their role as parents. METHODS: One hundred and
      twenty-two mothers participated in the study by answering a questionnaire
      consisting of 37 questions. Data were analysed using descriptive statistics, chi
      square tests and content analysis. FINDINGS: Mothers of infants had a great need
      to talk about their experiences of labour soon afterwards and over the following
      months. Most of the mothers had generally received support from their partners.
      However, in some situations, other people in their networks, and maternity and
      child health services had been more supportive than partners. DISCUSSION: The
      study highlights how important it is for expectant mothers and new mothers to be
      confirmed in their mothering role. Nurses in the maternity and child health
      services have an important task to support people in becoming and being parents,
      with regard to their emotional state. There is a need for more resources within
      these services for establishing parent groups, including groups for fathers. This
      could improve parents' physical, psychological and emotional health, and decrease
      their need for health and social services.

PMID- 15012638
TI  - Lifestyle factors for promoting bone health in older women.
AB  - BACKGROUND: It is accepted practice to recommend a calcium-rich diet, weight
      bearing exercise, cessation of smoking and limited alcohol intake to promote bone
      health. Although one in three women over 50 years old are at risk of
      osteoporosis, the lifestyle practices of older women in Scotland are not well
      documented. AIM: To investigate the lifestyle practices of a group of older women
      who had received lifestyle advice a year previously whilst participating in
      research identifying the individual risk of osteoporosis. METHODS: A mainly
      quantitative approach was taken from the perspective of the empirical-analytical
      paradigm. A descriptive survey research design was used and the primary method of
      data collection was postal questionnaire. Additional qualitative data obtained
      from a telephone interview of a small number of respondents were content
      analysed. FINDINGS: The questionnaire was sent to 320 women. The response rate
      was 92.5% (n = 296). The majority of women were non-smokers, had no alcohol
      problems and were participating in regular weight-bearing exercise. However, most
      had not been taking a calcium-rich diet in the previous year, and only 21.2% (n =
      58) had changed their diet following identification of risk of osteoporosis.
      CONCLUSION: The findings in relation to diet, smoking, exercise and alcohol were
      supported by previous research. We recommend that further research with larger
      samples in the United Kingdom explores the reasons why older women do not have
      adequate calcium intake. A statistically significant finding was that women at
      high risk of osteoporosis were the least likely to have made changes in
      lifestyles. Further research is required to address the information needs and
      lifestyle practices of older women who are at high risk of osteoporosis.

PMID- 15012639
TI  - Living with a terminal illness: patients' priorities.
AB  - BACKGROUND: Our understanding of terminal illness and its consequences has been
      predominantly based on models derived from expert definition, rather than the
      patient's perspective. More recently, quality of life tools have been developed
      to enable patient choice in responses. However, an even broader approach may be
      needed to help identify goals for care for patients who are terminally ill. AIM:
      The aim of this paper is to report on an exploratory, qualitative study exploring
      what people living with terminal illness considered were the areas of priority in
      their lives. METHODS: Ten people living with terminal cancer were interviewed.
      Analysis of the interviews incorporated principles of narrative analysis and
      grounded theory. FINDINGS: Over 30 categories were identified and collated into
      five inter-related themes (personal/intrinsic factors, external/extrinsic
      factors, future issues, perceptions of normality and taking charge) encompassing
      the issues of importance to all participants. Each theme focused on 'life and
      living' in relation to life as it was or would be without illness. Practical
      issues of daily living and the opportunity to address philosophical issues around
      the meaning of life emerged as important areas. The central theme, 'taking
      charge', concerned with people's levels of life engagement, was integrally
      connected to all other themes. CONCLUSIONS: The findings suggest that the way in
      which health professionals manage patients' involvement in matters such as
      symptom relief can impact on existential areas of concern. Understanding
      patients' perspectives in relation to each theme may assist health professionals
      to develop management strategies appropriate to their needs. The findings
      challenge some aspects of traditional 'expert-defined' outcome measures. As this
      was an exploratory study, further work is needed to test and develop the model
      presented.

PMID- 15012640
TI  - Resident-oriented care in nursing homes: effects on nurses.
AB  - BACKGROUND: In a resident-oriented care model the assignment of patients to
      primary nurses takes place. These primary nurses are responsible for the total
      nursing care of their patients and make use of the nursing process. According to
      job demand-control models, these enlarged and enriched jobs can be described in
      terms of autonomy, job demands and social support, and the presence of these work
      characteristics has a positive influence on workers' psychological and
      behavioural outcomes. AIMS: This paper reports a study to investigate the extent
      to which the various features of resident-oriented care were implemented and its
      effects nurses' on work characteristics and on psychological and behavioural
      outcomes in three Dutch nursing homes. METHODS: In a quasi-experimental design,
      experimental and control groups were followed over 22 months, using a pretest and
      two post-tests with questionnaires, interviews and qualitative observations.
      RESULTS: The quantitative data showed significant increases in resident
      assignment, the two variables measuring the nursing process and, in the psycho
      geriatric experimental group, on resident-oriented tasks. The qualitative data
      showed that a partly task-oriented division of labour was still used and that the
      planned delegation of coordination tasks to primary nurses was not fully
      achieved. Effects on work perceptions were limited. After implementation of the
      new system, the experimental group showed an increase in job autonomy.
      CONCLUSIONS: The intervention appeared to be only partly successful. Most of the
      expected results regarding work characteristics and psychological and behavioural
      outcomes did not materialize. Theoretical and methodological reflections are
      presented in the light of these findings.

PMID- 15012641
TI  - Salutogenesis as a framework for child protection: literature review.
AB  - AIM: The aim of this paper is to demonstrate the usefulness of salutogenesis in
      work relating to child protection. METHODS: A systematic review to explore the
      links between parenting, social factors and failure to thrive was carried out
      using 17 CD ROM and online databases using keywords in appropriate medical
      subject headings (MeSH terms) and Boolean operators refined for the studies. The
      salutogenic framework was then used as a way of clarifying what benefit
      particular research findings may have in identifying and using factors which can
      be associated with protection, safety and well being of children. Cross
      referencing the evidence from the systematic review against Antonovsky's
      generalized resistance resources created a salutogenic matrix. FINDINGS: Four
      factors in the systematic review were found crucially important: parent factors;
      parenting factors; child factors; and social factors. However, it is probable
      that these are useful within all child protection research and the evidence
      gathered in particular cases (here failure to thrive) could be plotted against
      each factor. Application of a salutogenic framework to the results was further
      illuminating and has utility for both systematic review methodology and other
      child protection explorations. The matrix created a warp and weft effect that
      identified gaps in current evidence and practice and was able to disentangle some
      of the complexities inherent within failure to thrive situations. By beginning to
      shed understanding on such processes, the concept of salutogenesis added further
      depth and rigour to the analysis. CONCLUSIONS: The concept of salutogenesis is
      widely used in some areas of nursing practice and research, and can also be
      regarded as a theoretical tool that has potential in child care and protection
      research, development and practice. The paper also illustrates the importance of
      a sound theoretical framework in ensuring depth and rigour in analyses of
      literature review findings.

PMID- 15012642
TI  - Psychosocial interventions for people with a milder dementing illness: a
      systematic review.
AB  - INTRODUCTION: Over the last three decades, interest has grown in the use of
      psychosocial interventions for people with dementia. Empirical studies and
      systematic reviews have been undertaken on a range of such interventions to
      examine their effectiveness. However, little account has been taken of the
      appropriateness of psychosocial interventions for people in different stages of
      the illness. This raises important questions about the degree to which the
      research evidence can be generalized for people in the milder and the more severe
      stages of dementia. This systematic review was undertaken therefore to
      investigate the effectiveness of psychosocial interventions for people with a
      milder dementing illness. METHODS: A comprehensive search was undertaken using
      all the major health care databases, as well as various grey literature sources.
      For studies to be included in the review, they must have investigated the effect
      of one or more psychosocial intervention on people with a milder dementing
      illness, employing a controlled trial design, and measuring outcomes such as
      cognitive ability, communication, functional performance and well-being.
      Identified studies were critically appraised, and where suitable for inclusion,
      data were extracted. RESULTS: Four studies met the final inclusion criteria for
      the review, and covered three psychosocial interventions: reality orientation,
      procedural memory stimulation and counselling. No evidence was found for the
      effectiveness of counselling and procedural memory stimulation on the outcome
      measures used. However, some evidence was found that reality orientation is
      effective in improving cognitive ability, with a demonstrable long-term gain
      using follow-up data. CONCLUSIONS: The review provides some evidence for the use
      of reality orientation for people in the milder stages of dementia. However, due
      to the small sample sizes in all the included studies, more research is needed
      into the effectiveness of psychosocial interventions for this client group.
      Implications for nursing practice are discussed, and recommendations for future
      research are set out.

PMID- 15012643
TI  - Coping and stress: a conceptual analysis.
AB  - BACKGROUND: Much work has been done towards the classification of clinical
      concepts in nursing. However, there is a comparative lack of analysis of non
      technical terms, which nevertheless bear closely on professional practice in
      nursing. Within nursing classifications, the term 'coping' functions as an
      element in more complex conceptual structures, the term itself being left
      relatively undefined. The case is similar for the term 'stress'- the set of
      circumstances with which the individual is attempting to cope. AIMS: The aim of
      this paper is to arrive at grounds for consensus over the use and meaning of the
      widely used terms 'stress' and 'coping'. METHODS: A conceptual analysis of the
      terms 'stress' and 'coping' was carried out, looking at etymology, ordinary usage
      and theoretical contingencies, in order to generate paradigmatic cases. A range
      of nursing and non-nursing literature was examined in order to illustrate further
      the range of the terms. CONCLUSIONS: 'Stress' and 'coping' are terms which are
      widely used in nursing; their significance has varied overtime and in the
      literature, and there continues to be lack of clarity over their precise meaning
      and use.

PMID- 15012644
TI  - Evidence of thymic reconstitution after highly active antiretroviral therapy in
      HIV-1 infection.
AB  - OBJECTIVES: We aimed to provide evidence of thymic reconstitution after highly
      active antiretroviral therapy (HAART) in HIV-1 infected patients and to correlate
      this with the restoration of peripheral naive T cells. METHODS: Positron emission
      tomography (PET) enables definitive evidence of thymic activity, indicating
      functional potential. In this case study, a single patient who initiated HAART
      demonstrated reconstitution of the naive T-cell pool and underwent thymic PET
      scans at baseline and 2 and 6 months following initiation of therapy. Two
      patients who failed to demonstrate such reconstitution acted as controls. These
      patients (mean age 27 years) had chronic HIV infection with low CD4 T-cell counts
      (mean 82, range 9-160 cells/microL blood). Increased function of the thymus
      visualized by PET was correlated with phenotypic changes in CD4 and CD8 T cells
      in the periphery measured by flow cytometry, and with numbers of recent thymic
      emigrants measured by quantification of the numbers of T-cell receptor excision
      circles (TRECs) in peripheral cells. RESULTS: In one patient, clear correlations
      could be drawn between visible activity within the thymus, as measured by
      increased [F18]fluorodeoxyglucose (FDG) uptake, and regeneration of naive CD4
      (CD45RA/CD62L) T cells, increased numbers of CD4 T cells, controlled viraemia and
      increased numbers of recent thymic emigrants. A second patient displayed no
      increase in peripheral CD4 count and no increase in thymic activity. The third
      patient elected to stop therapy following the 2-month time point. CONCLUSIONS:
      The use of PET suggests that thymic activity may increase after HAART, indicating
      that the thymus has the potential to be functional even in HIV-1 infected persons
      with low CD4 T-cell counts.

PMID- 15012645
TI  - Differential CD4 T-cell response in HIV-1-infected patients using protease
      inhibitor-based or nevirapine-based highly active antiretroviral therapy.
AB  - OBJECTIVES: To study the dynamics of CD4 T-lymphocyte counts (CD4 counts) after
      the initiation of either protease inhibitor (PI)-based or nevirapine (NVP)-based
      first-line highly active antiretroviral therapy (HAART). DESIGN AND METHODS: A
      retrospective cohort study of 1029 HIV-infected antiretroviral therapy-naive
      patients initiating either PI-based or NVP-based HAART was carried out. Patients
      were censored as soon as they experienced virological failure, or changed their
      original antiretroviral regimen for any reason. RESULTS: In total, 920 and 109
      patients initiated PI- and NVP-based HAART, respectively. The patients in the PI
      group more often had AIDS (15 vs. 6% in the NVP group), had a lower median
      baseline CD4 count (234 vs. 250 cells/microL in the NVP group) and had higher
      median baseline plasma HIV-1 RNA levels (pVL) (5.0 vs. 4.7 log10 HIV-1 RNA
      copies/mL in the NVP group). After 96 weeks of follow-up, the mean increase from
      baseline in CD4 count, adjusted for baseline CD4 count, age, gender and baseline
      pVL, was 310 cells/microL in the PI group and 212 cells/microL in the NVP group
      (P=0.003). This difference was mainly attributable to the patients in the NVP
      group initiating HAART with a baseline CD4 count below 200 cells/microL. There
      were no differences between the PI and NVP groups with respect to the change in
      the number of CD4 cells as a proportion of the total number of lymphocytes.
      CONCLUSION: Patients successfully treated with NVP-based HAART have a smaller
      increase in absolute CD4 cells compared with those treated with PI-based HAART.

PMID- 15012646
TI  - A randomized open-label study of immediate versus delayed polylactic acid
      injections for the cosmetic management of facial lipoatrophy in persons with HIV
      infection.
AB  - BACKGROUND: Polylactic acid (PLA, New-Fill; Medifill, London, UK and Dermic Labs,
      a division of Eventis, Strasbourg, France) injections into the deep dermis
      increase fibroblast numbers and collagen production. The substance is widely used
      in medical applications including cosmetic procedures. METHODS: HIV-positive
      individuals with facial lipoatrophy (based on physician assessment) were
      randomized to immediate (weeks 0, 2 and 4) or delayed (weeks 12, 14 and 16) PLA
      given as three bilateral injections 2 weeks apart into the deep dermis overlying
      the buccal fat pad. Assessments included facial ultrasound, visual analogue
      scales, the Hospital Anxiety and Depression Scale (HADS) and assessment using
      photographs at weeks 0, 12 and 24. RESULTS: All 30 patients completed 24 weeks of
      treatment. The median age of the patients was 41 years, with a mean of 80 months
      of nucleoside reverse transcriptase inhibitor (NRTI) therapy and a mean of 44
      months of prior protease inhibitor (PI) therapy. The median CD4 count was 428-460
      cells/microL, with 47% of patients in the immediate-treatment group and 93% of
      patients in the delayed-treatment groups with <50 HIV-1 RNA copies/mL at
      baseline. No differences in immunological, virological, biochemical,
      haematological or metabolic parameters emerged during the study. Injections were
      well tolerated with only two adverse events (cellulitis and bruising) recorded,
      one of which delayed treatment by 1 week. There were no discontinuations. Patient
      visual analogue assessments, photographic assessments, and anxiety and depression
      scores improved with treatment. At week 12, immediate-treatment patients had
      significantly better visual analogue scores (7 vs. 1, P<0.001) and lower anxiety
      scores (6 vs. 9, P=0.056) than delayed-treatment patients. Benefits on visual
      analogue and HADS scores persisted until week 24. CONCLUSIONS: PLA injections led
      to improvements in patient self-perception, anxiety and depression scores in
      individuals with facial lipoatrophy. Adverse events were uncommon. The benefits
      of PLA persisted for at least 18 weeks beyond the last injection.

PMID- 15012647
TI  - Cardiovascular disease risk factors and antiretroviral therapy in an HIV-positive
      UK population.
AB  - AIM: Although the benefits of antiretroviral therapy (ART) have been dramatic,
      studies have started to report a variety of drug-related side effects and
      toxicities. We sought to characterize the risk factors for cardiovascular disease
      present in an HIV-positive population. METHODS: A total of 394 HIV-positive
      ambulant patients attending the Royal Free Hospital, London, were asked to
      complete a questionnaire. Questions focused on smoking habits and general health.
      RESULTS: In total, 38% of patients were aged >40 years, 37% had a family history
      of heart disease, 3% had diabetes, 14% suffered from raised blood pressure, 20%
      had a body mass index (BMI)>26 kg/m3, 7% had an alcohol consumption above the
      recommended UK limit, and 18% had total cholesterol levels >6.3 mmol/L
      [corrected]. The rate of smoking observed (45%) was much higher than that
      observed amongst the general population in the British Health Survey for England
      (34%). There were significant differences between those receiving and not
      receiving ART. Those on ART tended to be younger (P<0.0001) and less likely to
      smoke cigarettes (P=0.06) or have an alcohol consumption above the recommended
      limit (P=0.08), but were more likely to have diabetes (P=0.05). More patients
      receiving ART reported, and so perceived themselves to have, raised blood fats
      (P<0.0001). This was confirmed when considering blood lipid levels, where those
      on ART had significantly raised total cholesterol levels compared to those not
      currently receiving ART (P<0.0001). CONCLUSION: We have demonstrated an excess of
      cardiovascular risk factors in this cohort. These issues must be addressed if we
      wish to maintain the benefit of treating HIV infection.

PMID- 15012648
TI  - The high cost of medical care for patients who present late (CD4 <200
      cells/microL) with HIV infection.
AB  - OBJECTIVE: To compare the direct costs of medical care in the year following HIV
      diagnosis for patients who present with a CD4 count <200 cells/microL ('late
      presenters') and those who present with a CD4 count >200 cells/microL ('early
      presenters'). METHODS: Direct costs (i.e. drugs, laboratory tests, outpatient
      care, in-patient care, and home care) for the 12 months following HIV diagnosis,
      sociodemographic data and clinical data were collected for all patients
      presenting for HIV care in Southern Alberta, Canada between April 1996 and April
      2001. Mean costs are presented as costs in 2001 Canadian dollars. RESULTS: Thirty
      nine per cent of 241 patients presented with a CD4 count <200 cells/microL. The
      mean costs for late presenters were more than twice as high as those for early
      presenters (i.e. $18,448 vs. $8455, respectively). Late presenters were more
      likely to be older, male and black, and to have a risk activity of men having sex
      with men (MSM) or heterosexual contact (P<0.05). However, the large difference in
      mean costs cannot be attributed to differences in characteristics. When
      characteristics were statistically held constant, the estimated excess cost of
      late presentation was almost unaffected, at $9723 (z=5.6). Repeating the analysis
      using disaggregated costing categories suggested that the difference in total
      costs was largely attributable to differences in HIV-related hospital care costs,
      which were 15 times higher for late presenters. CONCLUSIONS: Direct care costs in
      the year following HIV diagnosis were more than 200% higher for patients who
      presented late. This difference could not be attributed to differences in patient
      characteristics. Most costs were attributable to HIV-related hospital care costs
      and the immediate initiation of antiretroviral therapy. While early diagnosis in
      those at risk for HIV remains medically important, the short-term economic impact
      is also substantial.

PMID- 15012650
TI  - Nevirapine- versus efavirenz-based highly active antiretroviral therapy regimens
      in antiretroviral-naive patients with advanced HIV infection.
AB  - OBJECTIVE: To compare virological and immunological responses to nevirapine (NVP)
      based and efavirenz (EFV)-based highly active antiretroviral therapy (HAART)
      regimens in antiretroviral-naive patients with advanced HIV infection. METHODS: A
      retrospective observational cohort study was conducted on antiretroviral-naive
      HIV-infected patients whose pretreatment CD4 cell counts were less than 100
      cells/microL or whose viral loads were greater than 100,000 HIV-1 RNA copies/mL.
      RESULTS: Baseline characteristics of patients in the NVP (n=24) and EFV (n=29)
      groups were not different. The proportion of patients with viral loads >100,000
      copies/mL was higher in the EFV group. The probability of virological success
      estimated by the Kaplan-Meier method showed that 3- and 6-month success rates
      were 30.8% [95% confidence interval (CI): 16.7-52.2%] and 63.1% (95% CI: 44.7
      81.3%) for the NVP group. The corresponding values were 41.2% (95% CI: 25.8
      61.0%) and 62.9% (95% CI: 45.7-80.1%) for the EFV-based group. The median success
      times of the two groups were about 4 and 3 months (P=0.678), respectively, for
      NVP and EFV. Cox's proportional hazard was used after adjusting for age, previous
      opportunistic infections (OIs), and viral load at baseline, and showed that
      patients who received the NVP-based regimen had about 25% [hazard ratio
      (HR)=0.75, 95% CI: 0.37-1.51] less chance of virological success than patients
      who received the EFV-based regimen (P=0.415). The median times to CD4 > or =100
      cells/microL were 5.6 and 4.4 months for the NVP- and EFV-based regimens,
      respectively (log-rank test, P=0.144). CONCLUSIONS: NVP- and EFV-based HAART
      regimens as initial regimens in patients with advanced HIV infection are
      effective and comparable, in term of virological and immunological responses.
      However, further large-scale randomized controlled clinical trials in this group
      of patients with advanced HIV infection are needed.

PMID- 15012649
TI  - Pharmacokinetics of emtricitabine, didanosine and efavirenz administered once
      daily for the treatment of HIV-infected adults (pharmacokinetic substudy of the
      ANRS 091 trial).
AB  - OBJECTIVE: This study was conducted to investigate the pharmacokinetics of
      emtricitabine (FTC), didanosine (ddI), and efavirenz (EFV) when administered in a
      once-daily combination. METHODS: Nine antiretroviral-naive HIV-infected adults
      who received FTC [200 mg once a day (q.d.)], ddI (400 mg q.d. if > or =60 kg; 250
      mg q.d. if <60 kg) and EFV (600 mg q.d.) were studied. The following
      pharmacokinetic (PK) parameters were determined over 24 h at steady-state after 4
      weeks of treatment: area under the plasma concentration vs. time curve (AUC(0-24
      h)), maximum (Cmax) and minimum (Cmin) plasma concentrations, time to reach Cmax
      (Tmax), and the elimination half-life (t(1/2)). EFV plasma concentrations were
      also measured during follow-up. RESULTS: Median PK parameters for FTC, ddI and
      EFV, respectively, were as follows. AUC(0-24 h): 7.2, 7.0 and 36.4 h x mg/L;
      Cmax: 1.8, 2.6 and 2.5 mg/L; Cmin: 0.04, <0.01 and 1.0 mg/L; Tmax: 1.8, 1.1 and
      2.5 h; t(1/2): 7.4, 2.3, and 23.7 h. EFV plasma concentrations measured 10-13 h
      postdosing were higher during follow-up than during the PK study (2.57 vs. 1.19
      mg/L, P<0.01). CONCLUSION: The simultaneous administration of FTC, ddI and EFV
      did not affect the PK parameters of FTC when compared to historical controls. EFV
      Cmax and Cmin were lower than expected, but the data may have been slightly
      underestimated in this study. High ddI AUC and Cmax were measured in these
      patients, and further studies are warranted to confirm this finding.

PMID- 15012651
TI  - Lung cancer in patients with HIV infection: is it AIDS-related?
AB  - HIV-infected individuals have an increased risk of malignancy, especially non
      Hodgkin's lymphoma and Kaposi's sarcoma. Recently, several workers have noted a
      raised prevalence of lung cancer in HIV-positive subjects. We describe the
      diagnosis and clinical course for four HIV-seropositive patients who presented
      with lung cancer. All of the patients were young and were heavy smokers. They
      were all on highly active antiretroviral therapy (HAART), although the adherence
      varied from poor to excellent. The CD4 cell counts of these patients ranged from
      200 to 686 cells/microL and their viral loads ranged from undetectable to 29,000
      HIV-1 RNA copies/mL. After initial diagnosis of HIV infection between 5 and 13
      years previously, they all presented with advanced lung cancer, with a very short
      clinical course, and all four died within 2-9 months of diagnosis. A comparison
      of the incidence of lung cancer in patients with HIV infection at our centre with
      that in the general population suggests that there is an increased prevalence in
      the HIV-infected patients. We review the literature and discuss whether lung
      cancer in HIV infection is coincidental or related to the primary disease.

PMID- 15012652
TI  - The creation of a large UK-based multicentre cohort of HIV-infected individuals:
      The UK Collaborative HIV Cohort (UK CHIC) Study.
AB  - OBJECTIVES: This paper describes the development of the UK Collaborative HIV
      Cohort (CHIC) Study. The aim of the study is to collate routinely collected data
      on HIV-infected individuals attending one of seven clinical centres in the UK
      since 1 January 1996, with the objectives of describing changes over time in the
      frequency of AIDS-defining illnesses, describing the uptake of and response to
      highly active antiretroviral therapy (HAART), and identifying factors associated
      with virological and immunological responses to HAART. METHODS: By December 2002,
      demographic, clinical and laboratory data had been collected on HIV-positive
      patients seen at six of the seven HIV centres. Missing and inconsistent data had
      been investigated and the datasets audited. Records identified as relating to the
      same patient had been merged, and cross-checks made with UK death registers to
      improve the accuracy of death reporting. RESULTS: The cohort currently contains
      information on 13,833 individuals. Eighty-two per cent of the cohort are male,
      and the median age was 34 years at first follow-up. The main risk factors for HIV
      infection have been determined as sex between men (63%) and sex between men and
      women (24%). Twenty-five per cent of the cohort are known to have developed AIDS,
      and 8% have died. CONCLUSIONS: The UK CHIC Study provides important information
      on the status of individuals infected with HIV in the UK, and provides a means to
      study the response to HAART and to monitor changes in the clinical event and
      death rates that have occurred since the introduction of HAART in the UK.

PMID- 15012653
TI  - Haemodynamic crisis and reversible multiorgan failure caused by HIV post-exposure
      prophylaxis after needle-stick injury in a health care worker.
AB  - We report the case of a 59-year-old nurse from our HIV ward who developed a
      severe haemodynamic crisis with concomitant acute multiorgan failure after
      initiation of a post-exposure prophylaxis (PEP) with zidovudine/lamivudine
      (CombivirTM) and lopinavir/ritonavir (KaletraTM) after a needle-stick injury with
      an HIV-contaminated needle. Although serious and life-threatening adverse effects
      of post-exposure prophylaxis have been documented in several cases, this is the
      first report of a severe acute cardiovascular incident following PEP initiation.

PMID- 15012654
TI  - Treatment of HIV-infected patients with a combination of efavirenz, nevirapine
      and nucleoside reverse transcriptase inhibitors.

PMID- 15012656
TI  - Spatio-temporal imaging of cortical desynchronization in migraine visual aura: a
      magnetoencephalography case study.
AB  - OBJECTIVE: To determine cortical oscillatory changes involved in migraine visual
      aura using magnetoencephalography (MEG). BACKGROUND: Visual aura in the form of
      scintillating scotoma precedes migraine in many cases. The involvement of
      cortical spreading depression within striate and extra-striate cortical areas is
      implicated in the generation of the disturbance, but the details of its
      progression, the effects on cortical oscillations, and the mechanisms of aura
      generation are unclear. METHODS: We used MEG to directly image changes in
      cortical oscillatory power during an episode of scintillating scotoma in a
      patient who experiences aura without subsequent migraine headache. Using the
      synthetic aperture magnetometry method of MEG source imaging, focal changes in
      cortical oscillatory power were observed over a 20-minute period and visualized
      in coregistration with the patient's magnetic resonance image. RESULTS: Alpha
      band desynchronization in both the left extra-striate and temporal cortex
      persisted for the duration of reported visual disturbance, terminating abruptly
      upon disappearance of scintillations. Gamma frequency desynchronization in the
      left temporal lobe continued for 8 to 10 minutes following the reported end of
      aura. CONCLUSIONS: Observations implicate the extra-striate and temporal cortex
      in migraine visual aura and suggest involvement of alpha desynchronization in
      generation of phosphenes and gamma desynchronization in sustained inhibition of
      visual function.

PMID- 15012658
TI  - Factors related to school absenteeism in adolescents with recurrent headache.
AB  - OBJECTIVE: To examine possible risk and protective factors for school absenteeism
      among adolescents referred to a hospital-based behavioral treatment program.
      DESIGN: Data obtained from intake interviews, screening questionnaires, and
      baseline headache diaries of 283 consecutive adolescents referred for behavioral
      treatment of recurrent headache were reviewed for demographics, length of
      headache history, headache type, current headache activity, symptoms of anxiety
      and depression, perceived self-efficacy regarding headache control, school
      performance, participation in extracurricular activities, and school absenteeism.
      The study population was divided into 2 groups at the median number of days
      missed due to headache in the previous 6 months that school was in session.
      Adolescents who missed 2 or less days of school due to headache (low absenteeism)
      were compared with those who missed more than 2 days (high absenteeism). RESULTS:
      Compared with the low absenteeism group, the high absenteeism group had higher
      scores on the Children's Depression Inventory (8.7 +/- 6.5 versus 6.8 +/- 6.2, P
      <.05) and lower academic performance (2.1 +/- 1.0 versus 1.7 +/- 0.8, P <.0001).
      The 2 groups were not statistically different in age, sex, length of headache
      history, type of headache, current headache frequency or intensity scores,
      anxiety scores, self-efficacy ratings, or participation in extracurricular
      activities. CONCLUSIONS: In a referred population, students who missed more
      school due to headache had higher depression scores and lower academic
      performance than students who missed less school. A directional relationship,
      however, cannot be implied from these results. Future studies should investigate
      the complex relationship between recurrent adolescent headache, potential risk or
      protective factors, and school absenteeism.

PMID- 15012657
TI  - Effectiveness of eletriptan in acute migraine: primary care for Excedrin
      nonresponders.
AB  - OBJECTIVE: To evaluate the effectiveness of eletriptan as a treatment for acute
      migraine in patients who were poor responders to Excedrin and had not yet been
      exposed to a triptan. BACKGROUND: Self-medication with over-the-counter drugs,
      such as Excedrin, is the most common treatment for migraine. Guidelines, however,
      recommend that triptans be used as first-line treatment of moderate to severe
      migraine--the severity affecting approximately 80% of migraineurs. Since over-the
      counter medications, such as Excedrin, continue to be used in many patients, it
      is important that clinicians have information on the efficacy of triptans as
      first-line treatment and on treatment of migraineurs who have shown poor response
      to over-the-counter medications. METHODS: One hundred ten patients meeting
      criteria for migraine who were poor responders to Excedrin received open-label
      treatment with a 40-mg dose of eletriptan for one migraine attack. Efficacy
      assessments were made at 1, 2, 4, and 24 hours postdose and consisted of headache
      and pain-free response rates, absence of associated symptoms, and functional
      response. RESULTS: At 1 hour, the headache response rate was 44%; at 2 hours,
      81%. The pain-free response rate at 1 hour was 14% and at 2 hours, 48%. At 2
      hours, relief of baseline-associated symptoms ranged from 74% to 80%. Functional
      response was achieved by 82% of patients by 2 hours, and 68% of patients achieved
      relief of migraine that was sustained across 24 hours with no need for a second
      dose of eletriptan or for rescue medication. Eletriptan was well tolerated with
      adverse events being transient and mild to moderate in intensity. CONCLUSION:
      Previous studies have established the efficacy of eletriptan as a first-line
      treatment for migraine. The results of this open-label trial demonstrate that the
      40-mg dose of eletriptan had a high degree of efficacy and tolerability among
      patients who were poor responders to Excedrin.

PMID- 15012659
TI  - Blood pool scintigraphy of the skull in relation to head-down tilt provocation in
      patients with chronic tension-type headache and controls.
AB  - OBJECTIVE: To investigate the mechanisms behind the increase of chronic tension
      type headache during head-down tilt. BACKGROUND: The pathophysiology of chronic
      tension-type headache is unknown. DESIGN AND METHODS: Ten patients suffering from
      chronic tension-type headache and 10 age- and sex-matched controls were studied
      with respect to pain intensity and alterations in cranial blood volume using
      planar scintigraphy and radiolabeled autologous erythrocytes before, during, and
      after head-down tilt, a procedure known to increase chronic tension-type
      headache. RESULTS: Four of 8 patients with chronic tension-type headache studied
      had increased cerebrospinal fluid pressure. During head-down tilt, the pain
      increased significantly in the group with chronic tension-type headache (P <.001)
      while the procedure did not cause headache in the controls. Blood volume
      significantly increased extracranially and decreased intracranially in both
      groups during head-down tilt. The extracranial nasal blood volume was
      significantly related to the pain experienced by the patients with chronic
      tension-type headache before and during head-down tilt. CONCLUSIONS: Although the
      changes in blood volume and, presumably, the increase of intracranial pressure
      were similar in the patients with chronic tension-type headache and the controls,
      only the patients experienced pain and pain increase during head-down tilt. This
      indicates that the pre-head-down tilt conditions must be different in the 2
      groups and should be related to increased cerebrospinal fluid
      pressure/intracranial venous pressure in patients with chronic tension-type
      headache compared with controls. A difference in central mechanisms may, however,
      also be of importance for the difference in headache provocation in the 2 groups
      during head-down tilt.

PMID- 15012661
TI  - Efficacy and safety of levetiracetam in pediatric migraine.
AB  - BACKGROUND: Headache is a frequent occurrence among children and adolescents.
      Chronic headaches can be severe and disabling, and require prophylactic
      treatment; however, additional data on the use of prophylactic medications for
      migraine in children are needed. OBJECTIVE: To review the efficacy and safety of
      levetiracetam (Keppra) in pediatric patients with a history of recurrent
      headache. DESIGN/METHODS: Data from 19 pediatric patients were retrospectively
      reviewed. The initial dose of levetiracetam was usually 125 or 250 mg twice
      daily, but varied depending upon clinical judgment. RESULTS: Charts of 9 girls
      and 10 boys (mean age, 11.9 years) were reviewed. A variety of medications,
      including triptans, had been used before initiating treatment with levetiracetam.
      Mean headache frequency before treatment was 6.3 per month (standard deviation
      [SD], 3.8; confidence interval [CI], 4.4 to 8.1). Duration of headaches ranged
      from 0.25 to 8 years. Migraine (63.2%) and migraine with aura (15.8%) were the
      most common types of headache reported. Most patients (89.5%) had headaches that
      were severe. After treatment, the mean headache frequency decreased to 1.7 per
      month (SD, 2.7; CI, 0.4 to 3.0), representing a reduction compared with baseline
      (P <.0001). Levetiracetam eliminated headaches in 10 patients (52.6%), and 7
      patients (36.8%) had less severe and less frequent headaches. Levetiracetam did
      not have an effect on headaches in 2 patients (10.5%). Mean duration of treatment
      with levetiracetam was 4.1 months. Doses ranged from 125 to 750 mg twice daily.
      Sixteen patients (84.2%) reported no side effects on levetiracetam. One patient
      experienced asthenia/somnolence and dizziness, and irritable, hyperactive, and
      hostile behavior led to discontinuation of levetiracetam in another patient. A
      third patient experienced irritability and moodiness that attenuated after 1
      month of treatment and did not require discontinuation. CONCLUSIONS: In this
      small retrospective review, levetiracetam was found to be generally well
      tolerated and appears to be a promising candidate for additional evaluation in
      well-controlled clinical trials of pediatric patients with migraine.

PMID- 15012660
TI  - Prophylactic treatment of pediatric migraine.
AB  - BACKGROUND: Migraine occurs in 3% to 5% of young children and up to 18% of
      adolescents. Management requires a tailored regimen of pharmacological and
      behavioral measures that consider the headache burden and disability. Patients
      with frequent or disabling attacks (or both) may warrant preventive agents.
      OBJECTIVE: To investigate the patterns of prophylactic treatment of pediatric
      migraine within one pediatric neurology practice. METHODS: All charts of patients
      diagnosed with headache (International Classification of Diseases [ICD] code
      784.0) and migraine (codes 346.0, 346.1, and 346.2) during January 2001 July 2001
      were retrospectively reviewed to identify diagnosis, demographics, medical
      decision making, rationale for treatment selections, and outcome assessments.
      Migraine was diagnosed according to the 1997 proposed pediatric migraine
      revisions to the International Headache Society. RESULTS: Charts of 250 children
      and adolescents, aged 3.2 to 18 years (mean, 12), were reviewed. One hundred
      twenty-six (50%) were prescribed prophylaxis, along with intermittent analgesic
      agents. Mean age of those provided with daily prophylaxis was 12.4 years (range,
      3.9 to 18), and the mean age of those managed with intermittent therapies was
      11.5 years. Preventive agents included amitriptyline (n = 73), cyproheptadine (n
      = 30), propranolol (n = 8), valproic acid (n = 3), naproxen (n = 3), nimodipine
      (n = 3), imipramine (n = 3), and topiramate (n = 3). Amitriptyline was the most
      commonly prescribed agent (58%). Ten patients initially treated with other agents
      were changed to amitriptyline. Fifteen patients required dosing adjustments, 2
      stopped treatment, and 7 changed to other agents for lack of efficacy. Mean
      headache frequency before treatment was 10.9 per month (range, 4 to 15). After
      treatment, the mean headache frequency decreased to 4.1 per month (range, 0 to
      12), a decrease of 62.4% (n = 54). The overall positive response rate was 89%.
      Cyproheptadine was the second most commonly prescribed agent (mean age, 8.8
      years). Thirty patients were initially treated, 5 later changed to
      cyproheptadine, 6 required dosage changes, 5 changed to other agents for lack of
      efficacy, and 1 stopped treatment. Mean headache frequency before treatment was
      8.4 per month (range, 4 to 15) and following treatment decreased to 3.75 per
      month (range, 0 to 12), a decrease of 55.3%. The overall positive response rate
      was 83%. CONCLUSIONS: Fifty percent of patients with migraine were prescribed
      daily prophylactic medicines, reflecting a referral bias. The most commonly
      prescribed agents were amitriptyline (preferred for the older patients) and
      cyproheptadine (preferred for the younger patients). The overall positive
      response rates were 89% for amitriptyline and 83% for cyproheptadine during a 6
      month follow-up. Headache frequencies were reduced with amitriptyline by 62% and
      with cyproheptadine by 55%. Long-term follow-up of this population is ongoing,
      and prospective studies are needed.

PMID- 15012662
TI  - Cerebral vasospasm and headache during sexual intercourse and masturbatory
      orgasms.
AB  - BACKGROUND: The pathophysiology of the explosive type of headache associated with
      sexual activity is not completely understood. Five reported cases of patients
      with thunderclap headache, precipitated by sexual activity, in association with
      concomitant cerebral arterial narrowing, were found in the literature. METHODS: A
      44-year-old woman with both coital and masturbatory headaches during orgasm
      associated with segmental reversible cerebral artery vasospasm was investigated.
      Cerebral anatomy and eventual spasm was documented by magnetic resonance imaging
      or digital angiography before, during, and after resolution of the orgasmic
      headache-vasospasm clinical manifestation. CONCLUSION: Findings of cerebral
      arterial narrowing, presented by some patients shortly after orgasmic headache
      attacks, support the hypothesis that segmental vasospasm may exert a role in the
      pathogenesis of this uncommon type of headache. The literature is reviewed, and
      possible mechanisms underlying the development of orgasmic headache are
      discussed.

PMID- 15012663
TI  - Outpatient intravenous dihydroergotamine for refractory cluster headache.
AB  - OBJECTIVE: To evaluate the efficacy and safety of outpatient intravenous
      dihydroergotamine (DHE) for treatment of refractory cluster headache. METHOD:
      Medical records were retrospectively reviewed of all patients with cluster
      headache who received outpatient intravenous DHE for treatment of refractory
      cluster headache between January 1992 and May 2000. RESULTS: One hundred four
      treatments were identified in 70 patients. There were 7 dropouts. Of the 97
      completed treatments, 60 were for episodic cluster headache and 37 were for
      chronic cluster headache. Results for all treatments showed complete resolution
      of pain during the intravenous phase at 1 month in 61 (63%) of 97 cases, partial
      resolution in 13 cases (15%), and failure in 23 cases (24%). For the treatment of
      episodic cluster headache, there was complete resolution in 44 (73%) of 60 cases,
      partial resolution in 9 cases (13%), and failure in 7 cases (12%). For treatment
      of chronic cluster headache, there was complete resolution in 17 (46%) of the 37
      cases, partial resolution in 4 cases (11%), and 16 failures (43%). As regards
      side effects and safety, the treatment triggered chest pain suspected of being
      vasospastic angina in 1 patient on day 7 of the treatment, when she was in the
      subcutaneous phase. Two patients dropped out due to fear of the injection, 1
      because of palpitations, 1 because of chest tightness, and 2 others because of
      leg cramps, nausea, and diarrhea. CONCLUSIONS: Outpatient intravenous DHE is a
      safe treatment. It is useful for refractory cluster headache, is more effective
      for the episodic form than the chronic form, and has a rapid onset of action. It
      did not change the evolution of the episodic form, but it did appear to induce
      remission in the chronic form or transform it to the episodic form. We advance a
      hypothesis to explain this.

PMID- 15012664
TI  - SUNCT syndrome in association with persistent Horner syndrome in a Chinese
      patient.
AB  - This is the first case report of a chinese patient with SUNCT (shortlasting,
      unilateral, neuralgiform headache attacks with conjunctival injection and
      tearing) presenting with persistent Horner's syndrome. She had episodic, brief,
      right periorbital pain in association with ipsilateral eye injection, lacrimation
      and rhinorrhea as well as persistent ipsilateral miosis and ptosis. She had
      partial response to a combination of indomethacin and carbamazepine therapy.

PMID- 15012665
TI  - Malignant cough headache.

PMID- 15012666
TI  - Hourglass deformity after botulinum toxin type A injection.
AB  - BACKGROUND: Complications, such as eyelid ptosis, have been attributed to
      botulinum toxin type A. An "hourglass" deformity, which is the consequence of
      temporalis muscle atrophy, has not been reported previously. OBJECTIVE: To report
      a transient muscle deformity of the temporalis muscle caused by botulinum toxin
      type A. METHODS: Patients who underwent injection of 25 units of botulinum toxin
      type A into the temporal muscle, in a fan-shaped fashion, during an ongoing study
      for treatment of migraine were noted to develop temporary depression of the
      temples. Preinjection and postinjection photographs were taken. Patients were
      also sent questionnaires to verify the observed information. RESULTS: Only 26 of
      92 patients who underwent injection of botulinum toxin type A into the temporalis
      muscle subsequently reported depression of the muscle. When examined, all 92
      patients exhibited this deformity ranging from minimal to significant. Patients
      who seemed to have less deformity were those who had excessive soft tissue
      overlying the muscle due to excess weight. CONCLUSION: A newly recognized
      deformity is reported subsequent to the injection of botulinum toxin type A into
      the temporalis muscle. Informing patients of this transient deformity may
      minimize concern following treatment.

PMID- 15012667
TI  - Migraine-associated seizures with recurrent and reversible magnetic resonance
      imaging abnormalities.
AB  - Migraine and epilepsy are highly comorbid, but the nature of their association
      remains unclear. Exceptionally, reversible brain magnetic resonance imaging (MRI)
      abnormalities following migraine and seizures have been reported. There are no
      descriptions, however, of patients with recurrent brain MRI changes. We report a
      patient with repeated episodes of migraine-with-aura-associated seizures
      (migralepsy) and recurrent and reversible brain MRI abnormalities. Location of
      the abnormalities was always consistent with the neurologic deficits. The
      possibility that transient brain MRI abnormalities in a patient with migraine
      with aura followed by seizures may be due to migralepsy should be borne in mind
      to avoid misdiagnosis and potentially aggressive procedures.

PMID- 15012668
TI  - Cost considerations of acute migraine treatment.
AB  - OBJECTIVE: To provide medication price data and cost-reducing strategies for the
      acute treatment of migraine. METHODS: Retail prices for common acute care
      medications were found at http://www.drugstore.com. Cost-reduction tactics were
      obtained from literature searches and clinical experience. RESULTS: Several
      strategies can reduce cost without sacrificing treatment outcome. In mild to
      moderate migraine, low-priced nonsteroidal anti-inflammatory drugs can be used as
      first-line medications due to their proven efficacy and favorable tolerability.
      For patients with more severe migraine, implementing a stratified care approach
      using migraine-specific medications early in acute treatment-is cost-effective
      for most patients. Stratified care not only improves outcome and decreases
      disability, but also reduces cost. Pill splitting and early administration of
      triptans within an attack enhance their value. Supplying rescue medications, such
      as opioids, sedatives, and phenothiazines, can prevent emergency department
      visits. Minimizing multiple dosing of triptans and reducing utilization of
      expensive health care resources are key factors in reducing the cost of effective
      migraine treatment. An important affordability factor for patients with co
      payments is the number of triptan pills per package. Sumatriptan, naratriptan,
      and frovatriptan each contain 9 tablets per package, while most other triptan
      packages contain 6. Current triptan retail prices (per unit) include: Amerge 1
      and 2.5 mg, 17.78 dollars; Axert 6.25 and 12.5 mg, 16.31 dollars; Frova 2.5 mg,
      13.89 dollars; Imitrex 50 mg, 14.96 dollars; Imitrex 100 mg, 14.41 dollars;
      Imitrex Nasal Spray 20 mg, 21.61 dollars; Imitrex SQ 6 mg, 50.26 dollars; Maxalt
      5 and 10 mg, 15 dollars; Maxalt-MLT 5 and 10 mg, 15 dollars; Relpax 40 mg, 13.58
      dollars; Zomig 2.5 mg, 13.67 dollars; Zomig 5 mg, 15.89 dollars; Zomig-ZMT 2.5
      mg, 13.67 dollars; and Zomig-ZMT 5 mg, 15.89 dollars. CONCLUSIONS: Practitioners
      can optimize the use of health care dollars without compromising quality of care
      through awareness of cost-saving treatment strategies, as well as price
      variations among medications.

PMID- 15012669
TI  - Herpes zoster ophthalmicus, ophthalmoplegia, and trauma.

PMID- 15012670
TI  - Meningioma mimicking late-onset migraine with sensory aura.

PMID- 15012671
TI  - Cough headache, indomethacin, and surgery.

PMID- 15012673
TI  - Closure of atrial septal defect and migraine.

PMID- 15012672
TI  - Simplified butalbital withdrawal protocol.

PMID- 15012674
TI  - Chronic infections and migraine.

PMID- 15012675
TI  - Revised estimates for probability of successful outcome of pregnancy after
      sumatriptan exposure.

PMID- 15012683
TI  - Proceedings of the First Korea-Japan Nephrology Forum Treatment of Complications
      in Dialysis Patients. March 21, 2003, Jeju-Island, Korea.

PMID- 15012682
TI  - Abstracts of the 39th Annual Scientific Meeting of the Australian and New Zealand
      Society of Nephrology. August 31- September 3 2003. Perth, Australia.

PMID- 15012684
TI  - Current status of dialytic therapy in Korea.
AB  - The status of dialytic therapy in Korea at the end of 2001 was reported by the
      end-stage renal disease (ESRD) registry committee of Korean Society of
      Nephrology, where data were collected through an internet on-line registry
      program. The number of dialysis centres was 335 and the number of haemodialysis
      machines was 5529. The total number of patients with dialysis was 23,057
      (haemodialysis 17,568, peritoneal dialysis 5489). Prevalence and incidence of
      dialysis patients were 477.5 and 96.4 patients per million population. The most
      common primary cause of end-stage renal diseases was diabetic nephropathy
      (41.5%), hypertensive nephrosclerosis (15.4%), and chronic glomerulonephritis
      (13.6%). Eighty-six percent of haemodialysis patients were on dialysis therapy
      three times a week, the mean urea reduction ratio was 66.7 +/- 8.68% and mean
      Kt/V was 1.250 +/- 0.292 in male patients; 1.526 +/- 0.361 in female patients.
      The technical survival of haemodialysis in 5 years was 30.2% and peritoneal
      dialysis was 13.8%. The common complication of haemodialysis patients was
      hypertension (43.3%), gastrointestinal disease other than peptic ulcer (8.0%),
      congestive heart failure (7.6%), and of peritoneal dialysis patients were also
      hypertension (28.8%), congestive heart failure (5.0%), and peritonitis (4.8%).
      The most common causes of death were cardiac diseases (26.9%), vascular diseases,
      including cerebrovascular accidents (22.7%), and infection (17.8%).

PMID- 15012685
TI  - Development of bioartificial kidneys.
AB  - Bioartificial kidneys, which consist of continuous haemofiltration and
      bioartificial tubules using tubular epithelial cells, have been studied since
      1987. The bioartificial tubules consist of hollow fibre modules and tubular
      epithelial cells grown on the hollow fibre membranes after coating with
      extracellular matrices. The kinds of tubular epithelial cells, extracellular
      matrices and artificial membranes therefore have been investigated and then the
      most appropriate cell and materials have been selected on the basis of the
      development of bioartificial kidneys. Successful seeding to form confluent
      monolayers on the surfaces of hollow fibers is not easy, but this method has
      already been established. Renal assist devices using human renal proximal tubular
      epithelial cells have been used in the treatment of acute renal failure patients
      with endotoxemia by Humes et al., and successful treatment of acute renal failure
      patients with these devices was reported in 2001 and 2002, in which the improved
      mortality rate of those patients was shown. A bioartificial kidney, in which cDNA
      of multidrug resistance protein-1 was transfected into tubular epithelial cells
      that were then grown on the outer surfaces of hollow fibers, was used in the
      experimental treatment of digoxin-intoxicated dogs. Rapidly reduced digoxin
      levels were noted in the plasma of the dogs after treatment. Bioartificial
      kidneys, however, have never been used in the long-term treatment of a
      maintenance dialysis patient, although patients need those kidneys. In order to
      establish long-term treatment with a bioartificial kidney, each haemofilter has
      to function for more than one week without systemic anticoagulation and a
      bioartificial tubule must function for 3-4 weeks.

PMID- 15012686
TI  - Optimization of dialysate sodium in sodium profiling haemodialysis.
AB  - Sodium profiling haemodialysis is a modified method of sodium gradient dialysis
      during which dialysate sodium follows a time-dependent profile. Sodium profiling
      haemodialysis has claimed to reduce intradialytic discomforts such as
      hypotension, muscle cramps, and disequilibrium syndrome. Having the low sodium
      period is an essential part of the sodium profiling haemodialysis to compensate
      for the sodium gain during the high sodium period. In spite of this, however, the
      incidence of interdialytic complications that results from the excessive sodium
      gain has been reported in previous literature. Making the prediction of optimal
      dialysate sodium concentration for isonatric dialysis is practically very
      difficult since too many variables influence the sodium gradient, including the
      initial plasma sodium and tonicity and/or dialysis dynamics that differ from
      patient to patient and from treatment to treatment. As for sodium profiling
      haemodialysis, complexities are added further since details of profile, such as
      type and form of profile, or initial, terminal, or time-distribution of dialysate
      sodium are varied considerably. We have recently reported that the intradialytic
      sodium balance and interdialytic weight gain are directly related to the time
      averaged concentration of dialysate sodium (TACNa). The dialysate sodium can be
      optimized using this concept of TACNa for sodium profiling dialysis. TACNa should
      be approximately 0.5-0.8 mmol/L lower than patient's predialysis serum sodium
      concentrations to achieve a sodium balance neutral dialysis. In that study the
      optimal TACNa, seems to be between 137.8 and 143.5 mmol/L. Such an optimal value
      should be defined for the individual centres based on their profile protocols for
      clinical use. In the future, dialysate sodium should be optimized based on the
      exact prediction of the postdialysis plasma sodium levels.

PMID- 15012687
TI  - Anticoagulation during haemodialysis in patients at high-risk of bleeding.
AB  - Routine haemodialysis is performed with systemic anticoagulation, usually with
      heparin, to prevent thrombosis in the extracorporeal blood circuit. However,
      systemic anticoagulation can produce haemorrhagic complications in patients at
      high risk of bleeding. To minimize the risk of bleeding, a number of alternative
      regimens have been proposed: regional heparinization with protamine reversal;
      minimal heparinization; no heparin with saline flushes; regional anticoagulation
      with citrate; or prostacyclin anticoagulation. Although the incidence of bleeding
      complications has been reduced, each of these methods has its own limitations and
      complications. Among the types of membrane used in dialysers, cellulose membranes
      have been made more biocompatible by attaching N,N-diethyl-aminoehtyl (DEAE)
      groups to cellulose backbone. Positively charged DEAE groups on Hemophan enable
      negative charged heparin to be bound with the membrane. Haemodialysis using
      heparin-bound Hemophan has been reported to be a possible modality for patients
      at risk of bleeding. We designed more simplified heparin binding technique and
      have performed haemodialysis using heparin-bound Hemophan in patients at risk of
      bleeding during the past 7 years. In this review, current strategies to minimize
      bleeding complications and our experience of haemodialysis using heparin-bound
      Hemophan will be discussed.

PMID- 15012688
TI  - Low glucose degradation products dialysis solution modulates the levels of
      surrogate markers of peritoneal inflammation, integrity, and angiogenesis:
      preliminary report.
AB  - The presence of glucose degradation products (GDPs) in peritoneal dialysis (PD)
      fluids has many adverse effects, namely clinically significant abdominal pain or
      discomfort during infusion, inhibition of cell proliferation, impairment of
      inflammatory cell function, cytotoxicity, and the induction of vascular
      endothelial growth factor (VEGF). In a prospective, randomized, controlled trial
      comparing a low GDP PD solution (pH 7.0, two compartment bag: low GDP) to
      conventional PD solution (pH 5.5: high GDP), the overnight dialysate levels of
      the markers of inflammation/wound healing (hyaluronic acid (HA)), mesothelial
      cell mass/membrane integrity (cancer antigen 125 (CA125)), and angiogenesis
      (VEGF) were assessed over a 12-month period. Twenty-six newly commencing
      continuous ambulatory peritoneal dialysis (CAPD) patients were randomly assigned
      to either the Low GDP group (n = 16) or the High GDP group (n = 10). Standard
      peritoneal permeability analysis for membrane transport characteristics and
      dialysis adequacy with nutritional status (serum albumin, nPCR) were evaluated at
      1, 6, and 12 months. In patients treated with high GDP solution, there was
      significant increase in VEGF with time (time = 1 month, 67.2 +/- 10.8; time = 6
      months, 189.8 +/- 90.2; and time = 12 months, 169.3 +/- 83.1 pg/mg of protein; P
      < 0.05). There was no significant change of VEGF with time in the low GDP group.
      Significantly higher concentrations of CA125 (65.5 +/- 10.4 vs. 19.7 +/- 2.6 at 1
      month, P < 0.0001; 66.6 +/- 9.8 vs. 29.7 +/- 5.0 at 6 months, P < 0.01; 68.7 +/-
      10.5 vs. 30.7 +/- 10.0 U/mL at 12 months, P < 0.01) and lower concentrations of
      HA (114.6 +/- 18.8 vs. 254.3 +/- 69.2 at 1 month, P < 0.05; 417.5 +/- 57.2 vs.
      1277.5 +/- 367.9 ng/mg of protein at 12 month, P < 0.05) were observed in the low
      GDP group compared with the high GDP group. In conclusion, continuous therapy
      with the low GDP solution modulates the levels of surrogate markers of peritoneal
      inflammation, integrity and angiogenesis. The results strongly suggest that the
      use of a low GDP solution would be beneficial to maintain the function and
      structural integrity of the peritoneal membrane.

PMID- 15012689
TI  - Sclerosing encapsulating peritonitis as a complication of long-term continuous
      ambulatory peritoneal dialysis in Korea.
AB  - Sclerosing encapsulating peritonitis (SEP) is a rare yet serious complication in
      patients with continuous ambulatory peritoneal dialysis (CAPD). Incidence and
      prevalence of this syndrome have been defined in some large populations and a few
      single-centre experiences, but there is no satisfactory estimate of the
      comparative incidence of dialysis related SEP. The pathogenesis of SEP still
      remains uncertain, but there could be various causative factors. The diagnosis of
      SEP remains based on clinical suspicion confirmed with radiologic and/or
      pathologic findings. The possible variable etiologies and probable distinct
      pathways leading to this syndrome may make a uniform therapeutic approach
      unlikely. To determine the prevalence, etiologic factors, clinical features,
      effect of dialysis duration, and outcome of SEP in Korea, patients undergoing
      CAPD who developed SEP were retrospectively studied in five University Hospital
      dialysis centres with large numbers of CAPD patients in Korea. Out of a total
      3888 CAPD studied patients between January 1981 to December 2002 in those five
      medical centres, 31 cases developed SEP with the overall prevalence 0.8%. There
      were 15 men and 16 women. The mean age of these patients was 44.0 +/- 9.8 years
      old. The mean duration of CAPD before SEP was 70.3 +/- 41.9 months (range 9-144
      months) and 67.8% of patients (21/31) had been on CAPD more than 4 years.
      Peritonitis, including one fungal peritonitis, was the main cause of SEP in 25
      cases (80.6%). Seventy percent of these cases used beta-blocker and the mean
      duration of the usage was 61.7 +/- 47.6 months. Seven cases were surgically
      treated and others were treated conservatively with intermittent total parenteral
      nutrition. The mortality rate was 25.8%. In conclusion, SEP is a serious life
      threatening complication of CAPD, and most cases had long-term peritoneal
      dialysis (PD) duration more than 4 years. To reduce the incidence of SEP, careful
      monitoring may be needed especially in patients with long-term CAPD and
      peritonitis.

PMID- 15012690
TI  - C-reactive protein as a cardiovascular risk factor and its therapeutic
      implications in end-stage renal disease patients.
AB  - We observed the association between a persistent elevation of C-reactive protein
      (CRP) level and the presence of ischemic heart disease in 73 peritoneal dialysis
      (PD) patients. Twenty-six patients showed an elevation of CRP for more than 6
      months. Seventeen (65%) of the 26 patients had positive thallium single photon
      computed tomography (SPECT). Three of 9 patients who had a persistent elevation
      of CRP and negative thallium SPECT had a history of cerebral infarction or
      peripheral vascular disease. Therefore, 77% (20/26) of an elevated CRP level that
      lasted longer than 6 months can be explained by the presence of atherosclerotic
      vascular disease. There are as yet no valid recommendations on how chronic
      inflammation should be handled. We found that aspirin 200 mg daily for 8 weeks
      induce no significant changes of the CRP levels in PD patients (0.22 vs. 0.18
      mg/dL, p > 0.05). However, 62 HD patients were randomly assigned to treatment
      group (simvastatin 20 mg/day) and control group. After 8 weeks medication, hs-CRP
      levels significantly reduced from a median of 0.23 mg/dL to 0.12 mg/dL.

PMID- 15012691
TI  - Current clinical and pathogenetic understanding of beta2-m amyloidosis in long
      term haemodialysis patients.
AB  - As the number of patients undergoing long-term haemodialysis continues to grow,
      beta2-microglubulin (beta2-m) amyloidosis is emerging as an increasingly common
      complication. The frequency of beta2-m amyloid-related osteoarthropathy in
      haemodialysis patients rises steadily with length of survival. We confirmed that
      the prevalence of carpal tunnel syndrome increases with years of dialysis. Up to
      50% of patients had developed this complication after 20 years were affected and
      the percentage was even higher after 25 years. Although retention of beta2-m is a
      necessary requirement for onset of amyloidosis, it is probably not sufficient.
      Using an in vitro model of beta2-m-related amyloid fibril (fAbeta2-m) extension,
      we demonstrated that various amyloid-associated molecules, such as apolipoprotein
      (apo) E and proteoglycans, accelerate beta2-m amyloid fibril formation. General
      categories of therapeutic approaches for amyloidosis include prevention of onset
      or progression, symptomatic therapy (conservative treatment, orthopedic
      procedures, and physiotherapy), and renal transplantation. In association of
      haemodialysis, beta2-m has been removed by high-flux membranes or a beta2-m
      adsorption column. However, proof is lacking that amyloid deposits are decreased
      by long-term use of dialysis techniques to eliminate beta2-m. More effective
      treatment procedures are needed.

PMID- 15012692
TI  - Skeletal resistance to parathyroid hormone as a background abnormality in uremia.
AB  - Skeletal resistance to parathyroid hormone (PTH) is a background abnormality
      underlying uremic bone disease. This abnormality exists even with high PTH. By
      the suppression of PTH, it has become uncovered, presenting as adynamic bone
      disease. Since patients with adynamic bone disease have higher risk of
      hypercalcemia or lumber fracture, mechanisms of this skeletal resistance to PTH
      need to be elucidated for the optimal management of bone turnover and parathyroid
      function in chronic dialysis patients.

PMID- 15012693
TI  - Management of secondary hyperparathyroidism of dialysis patients.
AB  - Hyperphosphatemia, vitamin D deficiency, and resulted hypocalcemia have been
      regarded as classical pathogeneses of secondary hyperparathyroidism. These
      factors have been treated by the administration of phosphorus binder and vitamin
      D derivatives. However, these therapies have not brought about a successful
      result for the prevention and treatment of secondary hyperparathyroidism. The
      reason could be mainly attributed to the hypercalcemia that results from the
      administration of calcium salts as a phosphorus binder and the calcemic action of
      vitamin D. To prevent hypercalcemia, non-calcium containing phosphorus binder
      (sevelamer hydrochloride) and vitamin D analogues, which suppress PTH secretion
      with minimum calcemic action, have been developed. These new vitamin D analogues
      include 19-nor-1-alpha, 25-dihydroxyvitamin D2 (paricalcitol), 1-alpha
      hydroxyvitamin D2 (doxercalciferol), 22oxa-calcitriol (maxacalcitol) and F6
      calcitriol (falecalcitriol). Furthermore, calcimimetics that stimulate calcium
      sensing receptor of parathyroid cells as calcium and suppress PTH secretion are
      now under clinical trial. Percutaneous direct injection therapy of vitamin D,
      vitamin D analogue or calcimimetics into parathyroid gland has also been
      reported. The combination of these new strategies is expected to effectively and
      safely suppresses secondary hyperparathyroidism that has been resistant to
      conventional medical treatments.

PMID- 15012695
TI  - Abstracts of the 9th Asian Pacific Congress of Nephrology.

PMID- 15012696
TI  - Glucocorticoids and the kidney.
AB  - Glucocorticoids are widely used by nephrologists for their immunomodulatory and
      anti-inflammatory effects. The present review considers three aspects of
      glucocorticoids with which nephrologists may be less familiar: (i) renal
      metabolism; (ii) effects on renal haemodynamics; and (iii) effects on blood
      pressure as they relate to the kidney.

PMID- 15012697
TI  - Prevalence of vascular risk factors and vascular disease in predialysis chronic
      renal failure.
AB  - Patients with end-stage renal disease have a high mortality, with the majority of
      deaths due to vascular disease. The prevalence of vascular risk factors and
      vascular disease in predialysis chronic renal failure (CRF) is poorly
      characterized. The aim of the present study was to determine the prevalence of
      vascular risk factors and clinically overt vascular disease in an Australian
      cohort of patients with predialysis CRF. We performed a retrospective chart
      review of outpatients with CRF and noted demographic data, the cause of renal
      failure, the presence or otherwise of vascular risk factors and vascular disease
      and calculated glomerular filtration rate. The prevalence of overt vascular
      disease and modifiable vascular risk factors was calculated. One hundred and
      eighty patients completed the study. Eighty-nine per cent of patients had
      hypertension, 68% had dyslipidaemia, 32% were diabetic and 38% were previous
      smokers. The subgroup with diabetic nephropathy had significantly more risk
      factors (P < 0.001) than other groups. Twenty-seven per cent of the group had
      cardiovascular disease, 22% had cerebrovascular disease, 23% had peripheral
      vascular disease and 9% had renal artery stenosis. Patients with ischaemic
      nephropathy had significantly more vascular disease than other groups (P <
      0.001). Patients with overt vascular disease were older, had a higher number of
      risk factors and a higher calcium phosphate product than those without vascular
      disease. In conclusion, the present study suggests a high prevalence of vascular
      risk factors and vascular disease in predialysis CRF. Early detection provides an
      opportunity for early intervention and may help reduce the development of
      vascular disease, and the associated mortality, once these patients progress to
      dialysis.

PMID- 15012698
TI  - A mechanism for the development of subepithelial deposits in a patient with type
      III membranoproliferative glomerulonephritis.
AB  - We report on a patient with membranoproliferative glomerulonephritis (MPGN) type
      III, whose repeated renal biopsies show evolution from a type I-like pattern to a
      type III pattern of immune complex formation over a 1-year period. Based on the
      development of experimental in situ immune complex glomerulonephritis, we discuss
      possible mechanisms for the formation of subepithelial deposits in type III MPGN
      with reference to an experimental in situ immune complex model of
      glomerulonephritis.

PMID- 15012699
TI  - Homocysteine and cardiovascular disease in renal disease.
AB  - Elevated homocysteine (hyperhomocysteinaemia) in renal patients is a major
      concern for physicians. Although cause and effect between homocysteine and
      cardiovascular disease (CVD) has not been established in either the general
      population or renal patients, there is much evidence that this relationship does
      exist. Purported mechanisms that may explain this effect include increases in
      endothelial injury, smooth muscle cell proliferation, low-density lipoprotein
      oxidation and changes in haemostatic balance. Renal patients have a much greater
      incidence of hyperhomocysteinaemia and this may be explained by decreases in
      either the renal or extrarenal metabolism of the compound. We conclude that data
      from long-term placebo-controlled trials are urgently required to determine
      whether hyperhomocysteinaemia in renal patients is a cause of CVD events and
      requires therapeutic targeting.

PMID- 15012700
TI  - Addition of sertraline to other therapies to reduce dialysis-associated
      hypotension.
AB  - Sertraline has shown promise in the treatment of dialysis-associated hypotension
      (DAH) in a limited number of end-stage renal disease patients. We undertook a
      study to evaluate the effect of adding sertraline to other therapies for patients
      with documented DAH. We also measured the effect of sertraline on intradialytic
      haemodynamics. We used the ultrasound dilution technique (HD01 monitor) to
      measure cardiac output (CO), central blood volume (CBV) and peripheral vascular
      resistance (PVR) in these patients. The study was performed in two phases. Phase
      1 was a control, while the second phase consisted of treatment with sertraline
      (50 mg/day). Cardiac output and central blood volume were measured 30 min
      following the initiation of dialysis and 30 min prior to the termination of
      dialysis. Blood pressure (BP) was monitored during haemodynamic measurements and
      throughout dialysis. Eighteen patients with documented DAH completed the study.
      Cardiac output, CBV and PVR were no different in the sertraline phase as compared
      with the control phase. The declines in systolic BP, diastolic BP and mean
      arterial pressures from pre-haemodialysis (HD) to lowest intradialytic and pre-HD
      to post-HD were not significantly different for the sertraline phase versus the
      control phase. In conclusion, it appears that sertraline has no additive effect
      on intradialytic haemodynamics to improve blood pressure in patients with DAH who
      are under therapy (with sodium modelling, cool dialysate and midodrine).

PMID- 15012701
TI  - Regional citrate anticoagulation during simulated treatments of sustained low
      efficiency diafiltration.
AB  - Renal replacement therapy is frequently required for critically ill patients with
      a high risk of bleeding. Conventional heparinization strategies to prevent
      extracorporeal blood circuit clotting can cause significant haemorrhage in such
      patients because of systemic anticoagulation. Regional citrate anticoagulation
      (RCA) is a well-established technique that minimizes this complication by the
      decalcification of blood in the extracorporeal circuit such that it is incapable
      of clotting. To date, there are no reports on the use of RCA for sustained low
      efficiency dialysis/diafiltration (SLED), a hybrid therapy that involves the use
      of conventional haemodialysis machinery to deliver lower solute clearances over
      prolonged periods of time. In preparation for clinical study, an in vitro
      simulation of SLED was devised (blood substitute flow 250 mL/min, dialysate flow
      200 mL/min, predilution haemofiltration 100 mL/min). Blood substitute was
      decalcified by an infusion of 4% trisodium citrate (TSC) proximally into the
      extracorporeal blood circuit, with partial restoration of calcium homeostasis
      from dialysate containing ionized [Ca2+] at 0.9 mmol/L. This simulation was used
      to establish first the 4% TSC requirement for therapeutic decalcification, and
      second the associated changes in ionized [Ca2+] and [Mg2+] within the blood
      substitute from chelation with citrate and subsequent removal of the resulting
      divalent cation-citrate complex. Serial measurements of blood substitute [Ca2+]
      from strategic points along the extracorporeal circuit showed therapeutic
      decalcification was not achieved with 4% TSC infusion rates up to 400 mL/h, and
      extrapolation of experimental results suggests that 450 mL/h will be required.
      Under these conditions, ionized [Ca2+] and [Mg2+] in the blood substitute venous
      return and would be 0.42 and 0.2 mmol/L, respectively, with 0.35 mmol of citrate
      being returned per minute via the blood substitute venous return. These results
      were modelled for various changes in SLED operating parameters, and discussed in
      detail. An appropriate regimen for 4% TSC infusion and divalent cation
      replacement is proposed for clinical study in the future.

PMID- 15012702
TI  - Increased delivery of haemodialysis assists successful pregnancy outcome in end
      stage renal failure.
AB  - Pregnancy in patients on maintenance dialysis is rare, with few cases of
      successful live births reported in Australian women on dialysis at the time of
      conception. Increasing dialysis delivery may improve outcomes for both mother and
      foetus in this high-risk situation. We report a case of successful pregnancy
      outcome with the application of an intensive dialysis regimen.

PMID- 15012703
TI  - Peritoneoscopic peritoneal dialysis catheter insertion.
AB  - Peritoneal dialysis catheters can be placed under local anaesthesia using a
      peritoneoscope. Although this procedure has been shown to be equal, if not
      superior, to surgical placement in a number of trials, the technique is not
      widely used. The procedure can be performed safely by a nephrologist, as a day
      case, at the convenience of both the patient and the renal service. In the
      present retrospective study, we present 3 years of experience using
      peritoneoscopic catheter insertion in a rural setting.

PMID- 15012704
TI  - Use of cidofovir in polyomavirus BK viral nephropathy in two renal allograft
      recipients.
AB  - Polyomavirus BK viral allograft nephropathy is a potentially reversible cause of
      deteriorating function of kidney allografts. Initial treatment involves reducing
      immunosuppressive medications, with low-dose cidofovir an effective alternative
      in refractory cases. We describe two cases of BK viral allograft nephropathy
      responding to low-dose cidofovir after a reduction in immunosuppressive
      medications failed to clear the virus or stabilize the deterioration in renal
      function. There were no significant side-effects from this treatment in either
      patient.

PMID- 15012707
TI  - Monoclonal antibody against rat podocyte-derived macrophagic cells reacts with
      crescent-forming cells in an experimental model.
AB  - The origin of crescent-forming cells in crescentic glomerulonephritis has not
      been clarified in spite of the application of monoclonal antibodies (mAbs)
      against glomerular epithelial cells or monocytes/macrophages. This study was
      undertaken to characterize the cellular composition of crescents using a new
      marker, mAb OS-3, produced against macrophagic cells derived from podocytes in
      normal rat glomerular culture. Monoclonal antibody OS-3 was confirmed to be
      reactive with some normal epithelial cells of Bowman's capsule. Female Wistar
      Kyoto rats were injected with rabbit antiglomerular basement membrane (GBM) serum
      and killed at 2 h, 1, 3, 7, 14 days and 2 months, respectively. The mAb OS-3
      positive cells were segmentally observed in glomeruli at 3 days, increased at 14
      days, but decreased at 2 months. These cells lacked reactivity with
      antipodocalyxin in double immunofluorescence (IF) staining. In immunoelectron
      microscopy of a glomerulus on day 3 and 7, however, reaction products were
      observed within cells located on the outer surface of the GBM, which were
      considered to be podocyte in terms of its localization. In conclusion, we have
      shown a possibility that damaged podocytes partly constitute crescent-forming
      cells with phenotypic changes, visualized by positive staining with mAb OS-3. We
      propose a novel concept of crescent formation, suggesting that crescents may be
      partly composed of phenotypically changed cells, which could not be detected by
      typical markers for glomerular epithelial cells or monocytes/macrophages.

PMID- 15012708
TI  - Accumulation of cholesterol in the lesions of focal segmental glomerulosclerosis.
AB  - Intraglomerular deposition of low-density lipoprotein (LDL) and oxidized LDL has
      been described in various human glomerular diseases. Yet it is not clear whether
      esterified cholesterol (EC) and unesterified cholesterol (UC) carried in LDL are
      mobilized from deposited LDL particles or accumulate in the diseased human
      glomeruli, particularly in the segmentally sclerotic lesions. To address this
      issue, frozen sections of renal biopsies were first immunostained to localize
      apolipoprotein B (apo B) and then oil red O (ORO) stained to colocalize neutral
      lipids. By using 124 ORO-positive biopsies and nine ORO-negative ones, UC was
      visualized directly with filipin staining, and EC was visualized after its
      enzymatic hydrolysis and staining with filipin. Seventy-seven biopsies (58%)
      showed filipin staining of accumulated EC and/or UC in the glomeruli. Of these,
      11 showed heavy filipin staining for both EC and UC in the segmentally sclerotic
      lesions. In a group with UC deposits in the sclerotic segments, the percentage of
      the glomeruli affected by sclerosis and the intensity of filipin fluorescence for
      UC were significantly higher than biopsies with only mesangial UC deposits. Most
      filipin-positive biopsies showed apo B staining mainly in the mesangium. Yet in
      the sclerotic segments, apo B staining was rarely noted. Accumulated apo B
      stained lipoprotein was not coincident with ORO-stained lipid in the diseased
      glomeruli. These results suggest that both EC and UC accumulate in the sclerotic
      glomerular segments as the glomerular lesions are advanced, and that these EC and
      UC appear to be derived from altered LDL with progressive loss of apo B.

PMID- 15012709
TI  - Urinary nitric oxide levels are increased and correlated with plasma
      concentrations in patients with Behcet's disease: is it a new urinary activity
      marker?
AB  - Nitric oxide (NO) is a free radical and serves many functions within the kidney.
      Excess NO causes glomerular injury. Behcet's disease (BD) is a systemic
      immunoinflammatory vasculitis, affecting every organ in the body including the
      kidneys (subclinic glomerulonephritis). We investigated the role of urinary total
      nitrite levels (end product of NO) in BD and evaluated whether urinary
      concentrations were correlated with its plasma levels or disease activity. Thirty
      six consecutive Behcet's patients (19 men, 17 women; 35.9 years), and 20 age- and
      sex-matched healthy control volunteers (12 men, eight women; 33.2 years) were
      divided into an active (n = 16) and inactive (n = 20) period. Urinary and serum
      NO levels ( micromol/mg urinary creatinine) were higher in BD patients (4.1 +/-
      0.3) than control subjects (1.7 +/- 0.2; P < 0.001). Serum NO levels in Behcet's
      patients and control subjects were 51.3 +/- 9.8 and 21.7 +/- 7.3 micromol/L,
      respectively (P < 0.001). Active patients had higher urinary NO excretion (4.9 +/
      0.3) than inactive patients (3.3 +/- 0.3; P < 0.01). Urinary NO levels were
      correlated with its serum levels (r2 = 0.69, P < 0.001). Higher urinary NO levels
      found in BD may be produced by the kidney as a result of an inflammatory
      stimulation. As excess NO is toxic to the tissues, increased NO levels may play a
      role in mediating subclinic glomerular injury of such patients. However, we could
      not determine the exact site(s) of NO synthesis by the kidney, such as the
      glomeruli, blood vessels and/or the tubular cells. Whatever the source, urinary
      NO levels may be used as a new activity marker in the diagnosis and follow up of
      BD by serial measurements.

PMID- 15012710
TI  - Severe metabolic complications from theophylline intoxication.
AB  - Theophylline is commonly used in the treatment of bronchospastic lung disease. In
      addition to gastrointestinal and cardiac dysfunction, hypokalaemia, lactic and
      ketoacidosis can complicate theophylline overdose. Clinicians frequently fail to
      identify theophylline's role when complications develop. A case of an 80-year-old
      man who developed profound metabolic disturbances while hospitalized is
      presented. The typical causes of these abnormalities were absent, theophylline
      levels were elevated, and the patient recovered after theophylline was held.
      Based on our case and review of the literature, we discuss the reasons why
      theophylline toxicity is under-recognized, and propose mechanisms for the rare
      metabolic abnormalities identified in this case. A high index of suspicion for
      theophylline toxicity should be maintained and it should be considered when
      unexplained acidosis or hypokalaemia occur.

PMID- 15012711
TI  - Antineutrophil cytoplasmic antibody-negative pauci-immune crescentic
      glomerulonephritis associated with rheumatoid arthritis: An unusual case report.
AB  - Clinically relevant renal lesions in rheumatoid arthritis (RA) are not common.
      More often renal involvement is related to complications of therapy than the
      disease itself. The most common forms of primary renal disease in RA are
      membranous glomerulonephropathy and a pure mesangial proliferative
      glomerulonephritis. Some studies have described the association between
      crescentic glomerulonephritis (crescentic GN) and RA, but they were all found to
      be perinuclear antineutrophil cytoplasmic antibody (p-ANCA) positive. However, RA
      associated with ANCA negative pauci-immue crescentic GN has not been reported.
      This is a case report of a 37-year-old female with RA who initially presented
      with general oedema and acute deterioration of renal function. The renal biopsy
      revealed ANCA negative pauci-immune crescentic GN. The patient was treated with
      steroid pulse and plasmapheresis, but not cyclophosphamide because of severe
      urosepsis. Despite the use of aggressive therapy, her renal function was not
      improved and she underwent maintenance haemodialysis thereafter. Because ANCA
      negative crescentic GN may occur in RA patients without frank systemic
      vasculitis, but with severe clinical manifestation, a heightened suspicion for a
      relatively 'silent' crescentic GN would have led to the correct diagnosis and
      appropriate treatment.

PMID- 15012712
TI  - Chronic renal vein thrombosis in a renal allograft.
AB  - Acute renal vein thrombosis in a renal allograft is uncommon and usually occurs
      in the post-transplant period. Chronic renal vein thrombosis can occur
      insidiously many years after transplant without significant deterioration in
      renal allograft function or symptoms.

PMID- 15012713
TI  - Simple estimation of the glomerular filtration rate in sick Thai children.
AB  - The objective of this study was to establish an appropriate formula for the
      estimation of creatinine clearance (CCr) in sick Thai children, and to evaluate
      the accuracy of using the Schwartz formula. Children aged between 0 and 19 years
      with various diseases and varying levels of renal function (but remained stable)
      were studied. Height in centimetres (L) and weight in kilograms (W), time of
      urine collection and urine volume were measured to provide urine flow (mL/min
      (V)) measurements. Body surface area (m2; SA) was also assessed. Quantitative
      urinary and plasma creatinine concentration (UCr and PCr, respectively) were
      determined. Creatinine clearance was calculated by using the following formula:
      UCr x V x 1.73/(PCr x SA). The linear association between CCr and L/PCr derived
      from these data was compared with the Schwartz formula by using bootstrap
      statistics. One-hundred and sixty children were studied. A least squares straight
      line regression through the origin of CCr against L/PCr provided a good fit to
      the data. Our dataset revealed no evidence of an age or sex affect on the
      relationship. Creatinine clearance was estimated by using the following formula:
      0.465 x (L/PCr), in which the calculated 95% confidence interval of the
      coefficient was 0.44-0.49. A comparison of this coefficient with that for the
      Schwartz formula for children aged > or =1 year (0.55), using 1000 bootstrapped
      resamples, showed an incompatibility between the two coefficients (P < 0.00005).
      In conclusion, we suggest estimating CCr in sick Thai children of either sex by
      using a modification of the Schwartz formula in which the coefficient equals
      0.465.

PMID- 15012715
TI  - Osteodystrophy in Indonesian haemodialysis patients.
AB  - A preliminary study of the intact-parathyroid hormone (i-PTH) measurements from
      haemodialysis patients was conducted to determine the prevalence of renal bone
      diseases at the Dr Soetomo Hospital. The objective of this study is to evaluate
      the osteodystrophy renal pattern in haemodialysis patients using i-PTH and
      radiological parameters. The selected populations of 48 (32 males and 16
      females), the mean age 48 +/- 10.3 years, was evaluated to conduct a cross
      sectional study. The calorimetric method was applied to measure serum P and Ca,
      while a radioimmunoassay was used to assay the i-PTH level. Of those 48 patients
      receiving haemodialysis, with a duration ranging from 4 to 432 weeks, 61% had
      hypocalcaemia and 10% had hypercalcaemia. The i-PTH levels below 100 pg/mL
      (normal, 10-65 pg/mL) suggested 'aplastic' bone, and values of 100-200 pg/mL most
      commonly indicated 'normal' bone turnover. The i-PTH levels over 200 pg/mL
      suggested hyperparathyroidism. The results of this study demonstrated that 42% of
      those patients had <100 pg/mL (low turnover bone presumed, no biopsy), 23% had
      100 - <200 pg/mL ('normal' bone turnover) and 35% of them had >200 pg/mL
      ('hyperparathyroidism'). In addition, the radiological study showed that 10% of
      those patients were positive for renal bone diseases. In conclusion, this study
      shows that the common type of renal osteodystrophy was of a low turnover type,
      which was different from the findings in other previous studies. It is postulated
      that this difference is likely to be caused by some factors such as the general
      health condition of the population those patients belong to and, in particular,
      the nutritional status of those patients.

PMID- 15012714
TI  - Prevalence of hepatitis C virus infection and related risk factors among Iranian
      haemodialysis patients.
AB  - Hepatitis C virus (HCV) infection is common among patients undergoing
      haemodialysis, and liver disease is an important cause of morbidity and mortality
      in this population. Management of HCV-related liver disease is a major health
      concern in patients with end-stage renal disease (ESRD) undergoing haemodialysis.
      To investigate the prevalence of HCV infection in patients on haemodialysis and
      its associated risk factors, we conducted a prospective case series study of 838
      patients on haemodialysis in Tehran, Iran. Patients were selected randomly
      (cluster sampling) and all were screened for anti-HCV antibodies, using ELISA 3rd
      generation and confirmed by using RIBA 2nd generation. We found that 111 patients
      (13.2%) were infected. By applying univariate analysis, longer duration on
      haemodialysis (P = 0.000), more weekly dialysis sessions (P = 0.03), history of
      blood transfusion (P = 0.03) and history of previous renal transplantation (P =
      0.01) were found to be associated with a higher rate of HCV infection.
      Multivariate analysis revealed that only length of time on dialysis (P = 0.000)
      and history of blood transfusion (P = 0.02) were significantly associated with
      HCV infection. The more the units transfused, the higher the rate of HCV
      infection. Our results suggest that early transplantation and avoidance of blood
      transfusion, as much as possible, are the two most important practical
      interventions to reduce the HCV exposure rate in our patients on haemodialysis.

PMID- 15012716
TI  - Screening for intracranial aneurysms in autosomal dominant polycystic kidney
      disease.
AB  - Screening patients with autosomal dominant polycystic kidney disease (ADPKD) for
      asymptomatic intracranial aneurysms has been proposed as a method of reducing the
      morbidity and mortality associated with aneurysm rupture. However, recent studies
      have shown lower spontaneous rupture rates of small aneurysms and higher risks of
      significant complications with interventions than previously reported. Risk
      benefit analysis has not demonstrated any benefit of screening ADPKD patients
      without a history of subarachnoid haemorrhage (SAH) for intracranial aneurysms,
      and has suggested that screening might cause harm.

PMID- 15012717
TI  - Angiotensin-converting enzyme polymorphism gene and evolution of nephropathy to
      end-stage renal disease.
AB  - Genetic polymorphisms of the renin-angiotensin system (RAS) have been implicated
      in the pathogenesis of nephropathy and end-stage renal disease (ESRD). The
      association between angiotensin-converting enzyme (ACE) gene polymorphism and
      nephropathy evolution was studied. A random sample of 161 subjects from the
      Nephrology Department (of Hospital de Sant Pau) were divided into two groups: (i)
      117 with end-stage renal disease; (ii) 44 with established nephropathy; and (iii)
      control groups of 129 subjects. The ACE gene polymorphism was performed by using
      polymerase chain reaction. High DD genotype presentation was observed in the two
      groups of subjects with nephropathy (46.12 and 61.37%, respectively vs 35.66% in
      controls; P < 0.0482), and also, a decrease was observed in the II genotype (6.4
      and 4.54%, respectively vs 13.17% in controls, P < 0.0404). Glomerular filtration
      rate (GFR) was evaluated after 44 months of follow up. An important decrease of
      GFR was observed in patients with DD polymorphism versus other genotypes
      (initial, 32.3 +/- 7.9 and at 44 months, 18.35 +/- 3.3 mL/min vs 31.4 +/- 11.9
      and 11.7 +/- 3.2 mL/min; P < 0.039). In a non-longitudinal study of patients in
      ESRD, patients with an ACE-DD genotype had a lower period of time between
      diagnosis of nephropathy and ESRD than patients with other genotypes (10.45 +/-
      9.32 vs 19.5 +/- 8.4 years; P < 0.034). In conclusion, the ACE gene that controls
      RAS response may influence the development and progression of nephropathy to
      ESRD. Patients who develop several types of nephropathy have a higher risk of
      severe evolution if they have a profile of ACE-DD genotype.

PMID- 15012718
TI  - Cardiovascular risk in dialysis patients: a comparison of risk factors and
      cardioprotective therapy between 1996 and 2001.
AB  - Cardiovascular disease (CVD) is the major cause of mortality in dialysis
      patients. Aspirin, beta-blockers, statins, and angiotensin-converting enzyme
      (ACE) inhibitors reduce CVD mortality in the general population, as may
      angiotensin II receptor antagonists. The prevalence of cardiovascular risk
      factors and usage rates of cardioprotective agents in end-stage renal failure are
      unknown. A retrospective, cross-sectional study of dialysis patients was
      performed to compare: (i) prevalence of cardiovascular risk factors (age,
      hypertension, hyperlipidaemia, diabetes mellitus, and smoking); (ii) use of
      cardioprotective agents; and (iii) prevalence of cardiovascular disease between
      the time-points: 1996 (n = 262) versus 2001 (n = 369). We found an increase in
      the risk factors of age (53.6 +/- 14.9 years in 1996 vs 58.4 +/- 14.3 in 2001; P
      < 0.001) and hyperlipidaemia (45 vs 51.8%; P < 0.001) between the two time
      points, with a reduction in the prevalence of smoking (14.5 vs 8.1%; P = 0.016).
      There was no difference in the prevalence of cardiovascular disease (37.4 vs
      40.7%; P = 0.44). Cardioprotective agents were underutilized, with improvement in
      prescribing practice between 1996 and in 2001, especially in the usage of statins
      (21.4 vs 38.7% in 2001; P = 0.019). In conclusion, CVD is the primary cause of
      mortality in our dialysis patients. Although traditional cardiovascular risk
      factors affect the majority of the dialysis population, underutilization of
      cardioprotective agents is common. Proof of efficacy of these agents in this
      population of enormous risk is urgently required.

PMID- 15012719
TI  - Preservation of residual renal function and factors affecting its decline in
      patients on peritoneal dialysis.
AB  - The decline of residual renal function (RRF) in peritoneal dialysis (PD) patients
      was analysed and assessed, and risk factors affecting its decline were
      identified. Residual glomerular filtration rate (GFR) was calculated from
      averaging the urea and creatinine clearance by 24-h urine collection, and
      peritoneal solute removal was evaluated by creatinine clearance calculated from
      24-h effluent collection. Both GFR and peritoneal solute removal were
      chronologically examined in 34 PD patients from the time of initiation, and risk
      factors associated with rapid GFR decline were investigated. The RRF contributed
      to 43.1 +/- 17.6% of total (peritoneal and renal) weekly creatinine clearance at
      1 month after initiation of PD. Residual GFR, however, declined continuously with
      time (-0.19 +/- 0.14 mL/min per month), and the reduction rate was high with a
      higher GFR, higher normalized dietary protein intake, higher urine volume and
      higher urine protein excretion at the initiation of PD. Other factors related to
      the rapid decline of GFR were: being older than 60 years of age, automated
      peritoneal dialysis (APD) rather than continuous ambulatory peritoneal dialysis,
      mean blood pressure higher than 110 mmHg, and serum human atrial natriuretic
      peptide level higher being than 60 pg/dL. These data suggest that while RRF plays
      an important role in the removal of uraemic solute in PD patients, they show a
      significant decrease over 2 years. The factors related to the rapid decline of
      GFR corresponded to older age, modality of PD (APD), higher GFR and higher amount
      of urine protein at initiation, higher dietary protein intake, and inadequate
      control of hypertension and body fluid volume.

PMID- 15012720
TI  - Significance of 8-hydroxy-2'-deoxyguanosine levels in patients with chronic renal
      failure.
AB  - The aim of this study was to determine the significance of 8-hydroxy-2'
      deoxyguanosine (8-OHdG), which is known as a marker of oxidative stress in vivo,
      in patients with chronic renal failure (CRF). Fifty-one non-dialysed CRF patients
      (29 men and 22 women; mean +/- SD age, 57.8 +/- 12.8 years) who were under
      dietary therapy for at least 6 months were enrolled in the study. Both serum and
      urinary 8-OHdG levels were measured by using high-sensitive enzyme-linked
      immunosorbent assay (ELISA) kits. We examined the relationship between 8-OHdG
      levels and clinical indices in patients with CRF. As a result, the serum 8-OHdG
      level was strongly correlated with serum levels of urea nitrogen (UN; r = 0.58; P
      < 0.0001), creatinine (Cr; r = 0.53; P < 0.0001), and beta2-microglobulin (beta2
      MG; r = 0.54; P < 0.0001). Furthermore, the serum 8-OHdG level was inversely
      correlated with creatinine clearance (Ccr; r = -0.54; P < 0.0001). In contrast,
      urinary 8-OHdG level was not correlated with any of the clinical parameters. This
      is the first report of 8-OHdG level determination in patients with CRF. It is
      suggested that serum 8-OHdG level is not sufficient as a marker of oxidative
      damage in patients with CRF, and it should be corrected according to the residual
      renal function to estimate the accurate degree of oxidative stress.

PMID- 15012721
TI  - Fibrogenic stresses activate different mitogen-activated protein kinase pathways
      in renal epithelial, endothelial or fibroblast cell populations.
AB  - Fibrogenic stresses promote progression of renal tubulointerstitial fibrosis,
      disparately affecting survival, proliferation and trans-differentiation of
      intrinsic renal cell populations through ill-defined biomolecular pathways. We
      investigated the effect of fibrogenic stresses on the activation of cell-specific
      mitogen-activated protein kinase (MAPK) in renal fibroblast, epithelial and
      endothelial cell populations. The relative outcomes (cell death, proliferation,
      trans-differentiation) associated with activation or inhibition of extracellular
      regulated protein kinase (ERK) or stress activated/c-Jun N terminal kinase (JNK)
      were analysed in each renal cell population after challenge with oxidative stress
      (1 mmol/L H2O2), transforming growth factor-beta1 (TGF-beta1, 10 ng/mL) or tumour
      necrosis factor-alpha (TNF-alpha, 50 ng/mL) over 0-20 h. Apoptosis increased
      significantly in all cell types after oxidative stress (P < 0.05). In
      fibroblasts, oxidative stress caused the activation of ERK (pERK) but not JNK
      (pJNK). Inhibition of ERK by PD98059 supported its role in a fibroblast death
      pathway. In epithelial and endothelial cells, oxidative stress-induced apoptosis
      was preceded by early induction of pERK, but its inhibition did not support a pro
      apoptotic role. Early ERK activity may be conducive to their survival or promote
      the trans-differentiation of epithelial cells. In epithelial and endothelial
      cells, oxidative stress induced pJNK acutely. Pretreatment with SP600125 (JNK
      inhibitor) verified its pro-apoptotic activity only in epithelial cells.
      Transforming growth factor-beta1 did not significantly alter mitosis or apoptosis
      in any of the cell types, nor did it alter MAPK activity. Tumor necrosis factor
      alpha caused increased apoptosis with no associated change in MAPK activity. Our
      results demonstrate renal cell-specific differences in the activation of ERK and
      JNK following fibrotic insult, which may be useful for targeting excessive
      fibroblast proliferation in chronic fibrosis.

PMID- 15012722
TI  - Ramipril prevents microtubular changes in proximal tubules from streptozotocin
      diabetic rats.
AB  - This study has investigated the microtubular cytoskeleton in rat glomerular and
      proximal tubule cells in experimental diabetes. The effect of treatment with
      ramipril on the relationship between microtubule organization and albuminuria in
      diabetes has also been examined. Diabetes was induced in male Sprague-Dawley rats
      by administration of streptozotocin (50 mg/kg, i.v.). Rats were treated with or
      without ramipril in their drinking water for 12 weeks. Diabetes was characterized
      by an increase in blood glucose level, glomerular filtration rate, and albumin
      excretion rate. Treatment of diabetic rats with ramipril did not affect glycaemic
      control, but reduced systolic blood pressure and prevented the rise in
      albuminuria and glomerular filtration rate. Immunohistochemistry was performed by
      using the ARK Peroxidase method with alpha-tubulin antibody. The regular, grainy
      staining pattern of the microtubules present in the renal proximal tubules from
      control kidneys was altered in diabetic animals, and appeared fragmented and
      striated. This was prevented by treatment with ramipril. Quantitative
      morphometric analysis revealed an increase in the percent proportional staining
      for alpha-tubulin in the proximal tubules of untreated diabetic rats (33.3 +/-
      3.3%, n = 8, P < 0.05 vs control) compared with control rats (11.7 +/- 1.7%, n =
      6), which was reduced by ramipril treatment (26.7 +/- 2.1%, n = 6, P < 0.05 vs
      untreated diabetic). Staining for alpha-tubulin in glomerular cells was unchanged
      in all groups. There was no significant difference in renal alpha-tubulin
      expression among all groups, as determined by real-time reverse transcription
      polymerase chain reaction. These results raise the possibility that diabetes
      induced changes in microtubules in the renal proximal tubules may contribute, in
      part, to the increase in albuminuria observed in diabetes.

PMID- 15012723
TI  - Historical controlled trial of OKT3 versus basiliximab induction therapy in
      simultaneous pancreas-renal transplantation.
AB  - Simultaneous pancreas-kidney (SPK) transplant recipients are at high
      immunological risk of rejection. Antibody induction is beneficial but lymphocyte
      depleting therapy is associated with a high incidence of side-effects. We
      performed a historical controlled trial to compare OKT3 versus anti-CD25 antibody
      (basiliximab) induction therapy with regard to patient, kidney and pancreas
      survival, as well as to examine for any differences in acute rejection, graft
      function, and infective complications. Twenty-eight consecutive SPK transplants
      were performed at the Monash Medical Centre between December 1997 and November
      2001. Anti CD3 monoclonal antibody (OKT3) was used prior to March 2000 (n = 12)
      and basiliximab was used after (n = 16), both in combination with cyclosporin,
      mycophenolate, and prednisolone. A retrospective comparison of outcomes was
      performed. At 6 months, patient (100 vs 100%), kidney (91.7 vs 91.7%) and
      pancreas (75 vs 83.3%) survival were similar in the OKT3 and basiliximab groups,
      respectively. A minority of subjects in each group remained free from rejection
      (42% basiliximab vs 25% on OKT3, P = NS). Renal function was superior in the
      basiliximab group (mean calculated creatinine clearance 79.4 +/- 11.9 vs 54.5 +/-
      15.9 mL/min for basiliximab vs OKT3, P < 0.001). The incidence of major
      opportunistic infection was lower in basiliximab-treated patients (9 vs 50% in
      the OKT3 group, P = 0.033). Basiliximab was associated with similar 6-month
      patient, kidney and pancreas survival, superior renal function and less
      opportunistic infection as compared with OKT3 induction therapy in SPK
      transplants. Basiliximab is at least as effective and is safer than OKT3 for
      induction therapy in SPK transplantation.

PMID- 15012724
TI  - Clinical observations of mycophenolate mofetil therapy in refractory primary
      nephrotic syndrome.
AB  - Mycophenolate mofetil (MMF) is an effective immunosuppressive agent in renal
      transplantation, and preliminary studies suggest that it may also be effective in
      the treatment of lupus nephritis. This study investigated the efficacy and safety
      of MMF therapy in patients with refractory primary nephrotic syndrome in a
      prospective multicentre clinical observation. Nineteen refractory nephrotic
      patients with minimal change disease or mesangial proliferative
      glomerulonephritis were enrolled in this study. Combined MMF and prednisone
      therapy was used for 6 months with an initial MMF dose of 1.0-2.0 g/day and a
      prednisone dose of 20-60 mg/day; both drugs were tapered gradually. It was found
      that all patients achieved clinical remission and 11 of 19 responded within 4
      weeks, and 12 of 19 patients entered complete clinical remission. The prednisone
      dose in those patients who were previously steroid dependent could be
      successfully tapered. During follow up, three patients experienced transient
      increasing of proteinuria associated with infections and recovered without an
      adjustment of therapy. One patient was withdrawn from the study because of a fall
      in haemoglobin levels; other adverse effects did not necessitate withdrawal.
      Follow-up renal biopsies in two patients found no alteration in renal pathology.
      Mycophenolate mofetil is an effective and well-tolerated immunosuppressive agent
      for patients with refractory nephrotic syndrome.

PMID- 15012725
TI  - Even moderate chronic renal failure is associated with impaired acute and long
      term outcome after coronary angioplasty.
AB  - End-stage renal failure requiring maintenance haemodialysis is known to be a
      strong independent predictor of mortality and complications after coronary
      interventions. In contrast, data about the outcome of patients with moderate
      chronic renal failure is very limited and was therefore evaluated in this study
      in patients with coronary angioplasty (PTCA). This was a retrospective case
      control study of 66 patients with moderate chronic renal failure who underwent
      PTCA, and who were matched to 66 PTCA patients with normal renal function and
      followed up by telephone interviews. In hospital, patients with renal failure
      suffered significantly more often from local complications (12.1 vs 0%, P =
      0.004) and acute deterioration of renal function after PTCA (7.6 vs 0%, P =
      0.023) than their matched controls. Angiographic success after PTCA was not
      significantly different (85 vs 83%, n.s.) as was the case with in-hospital
      mortality (6.1 vs 3.0%, n.s.). During follow up (100% complete), 18 patients
      (27.3%) with renal failure had died compared with seven controls (10.6%; OR 3.2,
      P = 0.015). Even if deaths from non-cardiac causes in three patients with renal
      failure were excluded, death after PTCA occurred significantly more often in the
      renal failure group (P = 0.015, log rang test). Multivariate analyses with
      stepwise logistic regression identified impaired left ventricular function (OR
      2.24, 95%CI 1.33-3.77), elevated serum creatinine (OR 2.02, 95%CI 1.24-3.31) and
      smaller height (OR 0.91, 95%CI 0.86-0.98) to be independently associated with
      death. In conclusion, in this matched-pair study, patients with chronic renal
      failure suffered from more in-hospital complications and from markedly increased
      long-term mortality after PTCA.

PMID- 15012726
TI  - Evaluation of parathyroid hyperplasia by ultrasonographic examination in patients
      with end-stage renal failure before and at initiation of dialysis.
AB  - Secondary hyperparathyroidism (2HPT), which is related to renal osteodystrophy
      (ROD), may occur in patients in the comparatively early stage of chronic renal
      failure (CRF). Secondary hyperparathyroidism patients with parathyroid
      hyperplasia showed resistance to vitamin D(3) treatment during long-term
      dialysis. At present, evaluation by ultrasonography is considered to be useful
      for confirming parathyroid hyperplasia. There are no clinical data associated
      with imaging evaluation of 2HPT in CRF patients. In the present study, the
      relationship among clinical and biochemical data, and parathyroid hyperplasia by
      ultrasonography, was evaluated in 12 patients (six males and six females) with
      end-stage renal failure (ESRF) before and at initiation of dialysis. Five
      patients showed an enlargement of parathyroid glands in ultrasonography. Levels
      of serum-intact parathyroid hormone (PTH) in patients with parathyroid
      hyperplasia (positive group) were significantly higher than in those without
      hyperplasia (negative group; 97.6 +/- 36.65 vs 17.4 +/- 4.45 pmol/L; P < 0.05).
      The levels of intact PTH were above 35.0 pmol/L in all five patients with
      hyperplasia. All patients in the positive group had never taken vitamin D(3)
      supplements. Calcium-containing phosphate binders were not prescribed before the
      present study, except in one patient. Parathyroid hyperplasia caused by 2HPT was
      recognized in patients before and at initiation of dialysis in this study. It
      appears that untreated 2HPT in CRF patients may progress to advanced 2HPT in ESRF
      before and/or after the early stage of dialysis. The levels of serum intact PTH
      are useful in predicting parathyroid hyperplasia.

PMID- 15012727
TI  - Depression in chronic haemodialysed patients.
AB  - From April 2000 to April 2001, a total of 108 chronic stable haemodialysed
      patients (34 males aged 57.76 +/- 12.68 years under haemodialysis treatment for
      31.41 +/- 24.71 months and 74 females aged 54.99 +/- 12.87 years under
      haemodialysis for 41.47 +/- 33.47 months) were studied for signs of clinical
      depression. Depression was measured by using 'The Taiwanese Depression
      Questionnaire (TDQ)'. After analysing various possible factors, we chose to study
      three dimensions: affective change, somatic complaint and cognitive disturbance.
      Thirty-six (33.4%) of the patients were found to have TDQ scores above 19; our
      cut-off value. Diabetic patients were also found to have higher depression scores
      and affective change scores than those without diabetes. The elderly suffered
      more from somatic complaints, and patients without jobs also tended to have
      higher depression scores. We compared the nutrition indexes and uraemic toxin
      removal indexes of those with higher depression scores (score > or =19) with
      those with normal scores (score <19), and we found no differences between the two
      groups. We found that an underlying disease and job status were the major
      differences found in the two groups. Therefore, our findings suggest that the
      depression found in our chronic haemodialysed patients was not a result of the
      physical conditions, but a result of psychosocial problems indicating a need for
      psychosocial support for these patients.

PMID- 15012728
TI  - Unruptured intracranial aneurysms in haemodialysis patients.
AB  - While the mortality rate of subarachnoid haemorrhage is very high in
      haemodialysis (HD) patients, the prevalence of unruptured intracranial aneurysms
      in HD patients has not yet been elucidated. We performed cerebral magnetic
      resonance angiography (MRA) on 123 HD patients who did not have symptomatic
      cerebrovascular disease, and on 52 control subjects. On the basis of these
      images, the prevalence of unruptured intracranial aneurysms was evaluated.
      Unruptured aneurysms were found in three HD patients (2.4%). There were no
      aneurysms found in the healthy control group. There was no significant difference
      in the prevalence of unruptured aneurysms between HD patients and healthy
      controls. Therefore, the incidence of intracranial aneurysms is not associated
      with chronic renal failure.

PMID- 15012729
TI  - Mast cells in the kidney.
AB  - Mast cells have become a recent concern in the nephrological world. The
      development of antibodies to mast cell-specific enzymes, tryptase and chymase,
      has facilitated the study of mast cells in the kidney. Now, they are investigated
      immunohistochemically as well as histochemically. There are three types of human
      mast cells, MC(T), which contains exclusively tryptase, MC(TC), which has both
      tryptase and chymase, and MC(C), which contains only chymase. Many
      immunohistochemical studies involving mast cells have been conducted through the
      use of renal biopsy specimens. As a result, human renal diseases including
      various glomerulonephritis and pyelonephritis are found to have increased the
      number of mast cells in the renal cortex, especially in the area of fibrosis. The
      relationship between the number of mast cells and the prognosis of renal diseases
      has been proved to be significantly correlated in many reports. The subtypes of
      mast cells in these diseases are variably present, and no tendency of subtype
      specificity has been found. With the use of electron microscopically, mast cells
      are observed to be in contact with other interstitial cells or to infiltrate into
      tubules. Functionally, human renal mast cells resemble lung mast cells.
      Inhibitory substances for mast cell proliferation have been found in the mouse
      kidney. Compared with the results of human studies, mast cells are not found in
      the interstitum in animal models of renal diseases, except in a few transgenic
      mouse models and magnesium-deficient rats. Little is known about the exact roles
      that mast cells play in the renal interstitium. Future studies will hopefully
      make their characteristics clear.

PMID- 15012730
TI  - Urinary aquaporin-2 levels in healthy volunteers.
AB  - Renal water handling is regulated by the release of arginine vasopressin (AVP)
      and the subsequent insertion of aquaporin 2 (AQP2) in the apical membrane of
      collecting duct cells. This in turn increases the membrane permeability to water
      and the passive reabsorption of water down the concentration gradient present in
      the medulla. Aquaporin 2 can be detected in the urine under conditions of
      antidiuresis. We wish to validate an assay for urinary AQP2. Fourteen volunteers
      participated in studies of water loading and water deprivation followed by the
      administration of 1-deamino-8-D-arginine vasopressin (dDAVP). Urine osmolality
      was measured by vapour pressure osmometry. Urinary AQP2 was measured by using a
      chemiluminescent assay. Baseline correlations between serum AVP levels, urinary
      osmolality and urinary AQP2 levels were not significant. Following the
      administration of dDAVP, a positive correlation between urine osmolality and
      urinary AQP2 was evident (r = 0.762). For specific conditions where renal water
      retention is stimulated via AVP, urinary AQP2 measurements provide a reproducible
      measurement of the renal actions of AVP.

PMID- 15012732
TI  - Effects of bicarbonate buffered dialysate on human peritoneal mesothelial cell
      intracellular calcium homeostasis.
AB  - This study compares the biocompatibility of two bicarbonate-based peritoneal
      dialysis (PD) solutions using the measurement of intracellular free calcium
      (Ca(i)2+)) as a sensitive parameter of cell function in human peritoneal
      mesothelial cells (hPMC). Fura-2-loaded hPMC suspensions were exposed to
      bicarbonate (38 mmol/L) and bicarbonate (25 mmol/L), lactate-buffered PD (15
      mmol/L) solutions at pH 7.4 and compared with Krebs-Ringer physiological saline
      (KRS; pH = 7.4). Resting Ca(i)2+ values and 4br-A23187 (1.0 micro mol/L) induced
      transients were compared in treatment and control groups. In separate studies,
      the effect that low saline pH had on Ca(i)(2+) homeostasis was examined.
      Suspended cells or cells attached to coverslips were bathed in citric acid
      phosphate (McIllvaine's) buffered saline (MBS, pH = 7.4). Cells were acidified
      (pH = 5.3) with citric acid and then challenged with ionophore. Ionophore
      challenge produced a significantly reduced Ca(i)2+ transient response in cells
      exposed to the bicarbonate/lactate fluid compared with bicarbonate or KRS.
      Acidified cell suspensions produced a small monophasic Ca(i)2+ transient rise
      that was short lived. Gradual recovery of MBS to pH 7.4 produced no changes to
      Ca(i)2+ homeostasis of cell monolayers. Ionophore treatment produced a biphasic
      response identical to cells bathed in KRS. This study has demonstrated that short
      term exposure to bicarbonate did not alter Ca(i)2+ homeostasis directly, or
      subsequent modulation of intracellular pH. The MBS system provided a reliable
      method of modifying the external pH during continuous Ca(i)2+ measurement.

PMID- 15012733
TI  - Interferon-gamma induces macrophage migration inhibitory factor synthesis and
      secretion by tubular epithelial cells.
AB  - Macrophage migration inhibitory factor (MIF) promotes macrophage accumulation and
      leucocyte activation during inflammation. Macrophage migration inhibitory factor
      is upregulated in intrinsic renal cells in many types of kidney diseases, and has
      a pathogenic role in rat crescentic nephritis. However, little is known about the
      factors that regulate the production and secretion of MIF in kidney cells. In
      this study, we evaluated whether interferon-gamma (IFN-gamma), a cytokine
      implicated in the development of kidney disease and a potent inducer of MIF
      production in macrophages, could promote MIF synthesis and secretion from renal
      tubular epithelial cells. Northern blot analysis detected constitutive expression
      of MIF mRNA in rat tubular epithelial cells (NRK52E), which increased twofold
      after a 6-h stimulation with IFN-gamma. Macrophage migration inhibitory factor
      protein was found only in the cytoplasm of NRK52E cells. Following IFN-gamma
      stimulation, intracellular MIF in NRK52E cells was rapidly secreted with a
      maximal reduction of 50% after 20 min, which returned to normal levels after 2-4
      h. Rapid secretion of MIF in response to IFN-gamma was also seen in rat mesangial
      cells. These findings indicate that IFN-gamma induces rapid secretion of MIF by
      tubular epithelial cells, and suggest that this may be an important mechanism
      leading to inflammatory cell accumulation and activation during kidney disease.

PMID- 15012731
TI  - Antibiotics induce apoptosis of human peritoneal mesothelial cells.
AB  - The peritoneal mesothelial cell is a critical component of the peritoneal
      membrane. The intraperitoneal use of several antibiotics to treat bacterial
      peritonitis is current clinical practice. Our previous study showed that
      cephalothin (CPL) and cefotaxime (CFT) have cytotoxic effects on human peritoneal
      mesothelial cells (HPMC), however, the exact mechanism of cytotoxicity has not
      been elucidated. In the present study, flow cytometry, TdT-mediated dUTP nick-end
      labelling (TUNEL) staining and electron microscopy were used to detect the
      apoptosis of HPMCs. Immunofluorescent staining was used to evaluate the
      cytochrome c distribution pattern. Western blotting was used to assess apoptotic
      signalling proteins. We found that CPL (0.5 mg/mL) and CFT (1 mg/mL) induced
      apoptosis of HPMCs, whereas cefazolin (0.5 mg/mL) and ceftriaxone (0.5 mg/mL)
      failed to induce apoptosis of HPMCs. While the DNA content of CFT- or CPL-treated
      cells was reduced, as determined by flow cytometry, cefazolin and ceftriaxone had
      no such effect. The CFT- or CPL-treated cells displayed the features of apoptosis
      both under the electron microscope and by using TUNEL staining. However,
      cefazolin and ceftriaxone produced the same result as the medium controls.
      Furthermore, CFT and CPL increased the expression of Bax and p53, and caused the
      translocation of cytochrome c from the mitochondria to the cytoplasm. The HPMC
      treated by CFT but not by CPL induced the cleavage of procaspase-3 to form active
      caspase-3. In conclusion, cefotaxime and cephalothin induce apoptosis of HPMCs in
      vitro. Signal transduction may be through the mitochondrial pathway.

PMID- 15012734
TI  - Reversible acute renal failure associated with hypothyroidism: report of four
      cases with a brief review of literature.
AB  - We present four adult cases of acute renal failure associated with
      hypothyroidism. All patients presented with symptoms suggestive of moderate to
      severe hypothyroidism, such as cold intolerance, constipation, muscle weakness,
      and lower extremity oedema. Initial serum creatinine levels ranged between 115
      and 203 micromol/L (1.3 and 2.3 mg/dL), with creatinine clearances (CrCl) ranging
      between 0.58 and 0.97 mL/s (34.5 and 58 mL/min). After 6-12 weeks of treatment
      with levothyroxin, serum creatinine levels decreased to the range of 80 and 124
      micromol/L (0.9 and 1.4 mg/dL) and CrCl increased to 0.74-1.64 mL/s (44-98
      mL/min). One patient had proteinuria of 800 mg/day, which decreased to the normal
      range (<200 mg/day) after levothyroxin treatment. One patient developed acute
      gouty arthritis before normalization of thyroid-stimulating hormone (TSH), which
      was successfully managed with prednisone therapy. All of our patients had
      increased creatine kinase (CK), ranging between 1000 and 2360 U/L (normal range,
      22-165 U/L), which normalized after 6 weeks of levothyroxin treatment.

PMID- 15012735
TI  - Atorvastatin in dyslipidaemia of the nephrotic syndrome.
AB  - The combined dyslipidaemia that accompanies the nephrotic syndrome increases the
      cardiovascular risk and appears to worsen long-term renal function. Our aim was
      to determine the efficacy and safety of 10 mg atorvastatin in the control of
      dyslipidaemia in these patients. We carried out a prospective, open, 6 month
      study of 10 patients with primary or secondary nephrotic syndrome (proteinuria
      >3.5 g/day, hypoalbuminaemia, oedema and hyperlipidaemia). The changes in lipids
      and plasma lipoproteins were measured, as well as the safety profile
      (transaminases, creatine phosphokinase, fibrinogen and antithrombin III activity)
      and parameters of renal function. The addition of 10 mg atorvastatin daily for 6
      months resulted in a 41% reduction in low density lipoprotein (LDL) cholesterol
      and 31% in triglycerides (both P < 0.05), and a 15% increase in high density
      lipoprotein (HDL) cholesterol (NS). The drug was well tolerated and there was no
      change in the safety profile or deterioration in renal function. In fact, the
      levels of proteinuria fell in all but one patient (6.2 +/- 2.6 vs 4.8 +/- 2.5
      g/24 h; P < 0.05). Atorvastatin, at the above dose, and for the time used proved
      to be a safe drug that effectively reduced dyslipidaemia in patients with
      nephrotic syndrome.

PMID- 15012736
TI  - Role of nitric oxide and prostaglandin E2 in acute renal hypoperfusion.
AB  - Although acute renal ischaemia alters the production of various paracrines, there
      has been little investigation examining the role of intrarenal vasoactive
      substances. In the present study, we investigated the role of intrarenal nitric
      oxide and prostaglandins in modulating the acute renal hypoperfusion-induced
      alterations in renal function. After a 90% clipping of the left renal artery for
      60 min, the clip was released, and the renal haemodynamics and sodium excretion
      were evaluated in both clipped and non-clipped kidneys of anaesthetized dogs.
      Furthermore, the changes in renal contents of nitrate/nitrite (NOx) and
      prostaglandin E2 (PGE2) were assessed by using the renal microdialysis technique.
      The release of the clipping elicited a gradual recovery of renal plasma flow and
      glomerular filtration rate, and a sustained increase in fractional sodium
      excretion (FENa) in the clipped kidney. Renal interstitial NOx was reduced in
      both the cortex (from 8.2 +/- 1.1 to 2.5 +/- 0.3 micromol/L, P < 0.01) and
      medulla (from 10.1 +/- 0.9 to 3.1 +/- 0.2 micromol/L, P < 0.01), but the levels
      gradually elevated after declamping. The treatment with nitro-l-arginine
      methylester only modestly impaired the recovery of renal plasma flow (RPF; at
      hour 4) and glomerular filtration rate (GFR; at hours 3 and 4 after declamping),
      without affecting FENa. Conversely, the renal PGE2 levels increased prominently
      upon the onset of ischaemia (medulla, from 149 +/- 19 to 378 +/- 39 pg/mL, P <
      0.01; cortex, from 107 +/- 13 to 302 +/- 34 pg/mL, P < 0.01). Furthermore, the
      pretreatment with a non-specific cyclo-oxygenase (COX) inhibitor, sulpyrine, and
      a COX-2-specific inhibitor, NS398, prominently inhibited the increases in FENa
      induced by the acute renal arterial clipping in a similar manner. In conclusion,
      in acute renal hypoperfusion, nitric oxide (NO) plays a permissive role in the
      recovery of the renal haemodynamics. In contrast, sustained increases in renal
      PGE2 in both clipped and non-clipped kidneys indicate that the COX-2-mediated
      PGE2 contributes importantly to the failure of the sodium reabsorption in
      response to acute renal hypoperfusion.

PMID- 15012737
TI  - Albumin fragments in normal rat urine are derived from rapidly degraded filtered
      albumin.
AB  - Filtered albumin is excreted as a heterogeneous population of albumin-derived
      molecules resulting from degradation during renal passage. In order to understand
      the dynamics of this degradation process, albumin clearance was studied over a
      short-term (minutes) and a long-term (7 days) by both radioactivity and
      radioimmunoassay. The radiolabelled material in the urine was also analysed
      extensively by using size exclusion chromatography, size selective filtration and
      high performance liquid chromatography. These studies demonstrate that during
      renal passage, albumin degradation to fragments in the size range of 500-10,000
      occurs in a matter of minutes. The fragments are not detected by using
      radioimmunoassay. Steady state excretion rates or fractional clearance of
      radiolabelled albumin occur over a similar time period. Both rates of degradation
      and approach to steady-state clearance, while rapid, were considerably slower
      than the transit time for molecules in the Bowman's capsule and early tubular
      lumen. The results are consistent with an extremely rapid lysosomal uptake of
      filtered albumin, and degradation and regurgitation of the albumin-derived
      peptide fragments into the tubular lumen prior to excretion.

PMID- 15012738
TI  - Comparison of dipyridamole and fosinopril on renal progression in nephrectomized
      rats.
AB  - There is evidence to suggest that antiplatelet aggregation and inhibition of
      angiotensin converting enzyme will attenuate the progression of renal disease. In
      the present study, dipyridamole (DPM; 30 mg/kg per day, p.o.) or fosinopril (FOS;
      20 mg/kg per day, p.o.) was given to rats for 5 weeks starting immediately after
      renal mass reduction (right uninephrectomy and ligation of approximately two
      thirds of the blood supply to the left kidney). Renal mass reduction caused
      increased mean arterial blood pressure, reduced effective renal plasma flow
      (ERPF) and glomerular filtration rate (GFR), azotemia and proteinuria. Neither
      proteinuria nor hypertension was affected by DPM, although renal function
      improved markedly. Rats receiving FOS showed normalization of blood pressure with
      a significant increase in both ERPF and GFR, along with a lower degree of
      proteinuria. A histological examination of the remnant kidney detected the
      presence of vasodilation with a lower degree of podocyte swelling in both
      treatment groups, with a remarkable effect in the FOS group. These data indicate
      that both FOS and DPM attenuate the progression of glomerular disease associated
      with renal mass reduction in rats. However, FOS was more beneficial than DPM
      because it reduced proteinuria and lowered blood pressure.

PMID- 15012739
TI  - Glomerular expression of connective tissue growth factor mRNA in various renal
      diseases.
AB  - Connective tissue growth factor (CTGF) is a cysteine-rich member of a new family
      of growth regulators. It is an important factor in the pathogenesis of mesangial
      matrix accumulation and progressive glomerulosclerosis. The present study was
      designed to elucidate the role of CTGF in diabetic nephropathy (DN),
      immunoglobulin A nephropathy (IgA-N), membranous nephropathy (MN), and minimal
      change nephrotic syndrome (MCNS). We evaluated the expression and localization of
      CTGF mRNA in surgically excised renal tissue samples from 10 patients with DN, 10
      with IgA-N, 10 with MN, 10 with MCNS, and 10 normal human kidney (NHK) tissue
      samples, by using high-resolution in situ hybridization with digoxigenin-labelled
      oligonucleotide. To quantify CTGF mRNA expression, we counted all nuclei, and
      nuclei surrounded by CTGF-positive cytoplasm, in at least 10 randomly selected
      cross-sections of non-sclerotic glomeruli, and expressed the results as a
      percentage of total glomerular cells. In all glomeruli, CTGF mRNA was expressed
      mainly in glomerular intrinsic cells, including glomerular mesangial and
      epithelial cells and some cells of Bowman's capsule. The percentage of cells
      positive for CTGF mRNA was significantly higher in DN and IgA-N than in MN, MCNS
      and NHK. However, there was no significant difference in the percentage of CTGF
      mRNA-positive cells between DN and IgA-N. Our study indicates that CTGF may play
      an important role in the development and progression of glomerulosclerosis in DN
      and IgA-N, which are both accompanied by mesangial matrix expansion and comprise
      two major causes of end-stage renal failure.

PMID- 15012740
TI  - Fibromuscular hyperplasia as a cause of transplant renal artery stenosis.
AB  - There are several causes of transplant renal artery stenosis, resulting in
      hypertension and renal dysfunction. Rarely, fibromuscular hyperplasia may cause
      such a presentation, and this case report discusses the historical, diagnostic
      and management issues pertaining to this rare situation.

PMID- 15012741
TI  - Xanthogranulomatous pyelonephritis with acquired cystic disease of the kidney in
      a haemodialysis patient.
AB  - A 54-year-old-female patient who had received regular haemodialysis therapy for
      12 years was referred to our hospital for evaluation of a left renal mass.
      Imaging examinations revealed acquired cystic disease of the kidney (ACDK) and a
      tumour-like lesion in the left kidney. Because of the preoperative diagnosis of
      the left renal cell carcinoma, the patient underwent a left nephrectomy.
      Pathological examination revealed xanthogranulomatous pyelonephritis. It was
      difficult to distinguish xanthogranulomatous pyelonephritis from renal cell
      carcinoma in our case, because it is very rare for xanthogranulomatous
      pyelonephritis to occur in ACDK.

PMID- 15012742
TI  - Recommendations for the use of icodextrin in peritoneal dialysis patients.
AB  - Icodextrin is a starch-derived, high molecular weight glucose polymer, which has
      been shown to promote sustained ultrafiltration equivalent to that achieved with
      hypertonic (3.86%/4.25%) glucose exchanges during prolonged intraperitoneal
      dwells (up to 16 h). Patients with impaired ultrafiltration, particularly in the
      settings of acute peritonitis, high transporter status and diabetes mellitus,
      appear to derive the greatest benefit from icodextrin with respect to
      augmentation of dialytic fluid removal, amelioration of symptomatic fluid
      retention and possible prolongation of technique survival. Glycaemic control is
      also improved by substituting icodextrin for hypertonic glucose exchanges in
      diabetic patients. Preliminary in vitro and ex vivo studies suggest that
      icodextrin demonstrates greater peritoneal membrane biocompatibility than glucose
      based dialysates, but these findings need to be confirmed by long-term clinical
      studies. This paper reviews the available clinical evidence pertaining to the
      safety and efficacy of icodextrin and makes recommendations for its use in
      peritonal dialysis.

PMID- 15012743
TI  - Incidence of side-effects associated with high-dose ferric gluconate in patients
      with severe chronic renal failure.
AB  - Ferric gluconate complex in sucrose (Ferrlecit) has been associated with less
      side-effects than iron dextran; however, the recommended dose of 62.5-125 mg per
      treatment is only suitable for haemodialysis (HD) patients. We retrospectively
      analysed the incidence of the side-effects associated with a high dose of
      Ferrlecit infusion (20 treatments in 13 patients; 10 treatments of 250 mg/3-4 h,
      and 10 treatments of 500 mg/5 h infusion). The patients were in the age range of
      32-75 years old, seven with chronic renal failure (CRF), and six on dialysis
      treatment. One (10%) of the 10 treatments using a 250 mg dose was complicated
      with severe nausea/vomiting, diarrhoea and a burning sensation in the feet. Three
      (30%) of the 10 treatments using a 500 mg dose were complicated with: chills,
      severe nausea/vomiting, hypotension and syncope in one; severe nausea/vomiting,
      diarrhoea and hypotension in one; and an episode of vomiting in one patient. A
      single treatment with a 250 mg dose resulted in no significant change in
      haematological parameters. A single treatment with a 500 mg dose resulted in a
      significant increase in haemoglobin (Hgb) and haematocrit (Hct), but only a
      rising trend in serum iron,% transferrin saturation and ferritin pre versus 1-2
      months postinfusion. In conclusion, Ferrlecit doses of 250 or 500 mg are
      complicated with significant untoward reactions in 10-30% of patients, in a dose
      dependent fashion.

PMID- 15012744
TI  - Effect of haemodialysis on visual-evoked potential parameters.
AB  - Different papers have emphasized the presence of visual-evoked potential (VEP)
      abnormalities in metabolic disorders. The aim of this study was to perform
      pattern VEP (PVEP) recordings in patients with chronic renal failure just before
      and 24 h after dialysis to test the effect of this procedure on visual pathway
      generated parameters. Twenty-four haemodialysis patients (M/F:14/10; mean age:
      48.8 +/- 14.1 years) were examined. None of them were complaining from visual
      difficulties or from visual loss. The recording sessions were performed just
      before and 24 h after dialysis. The control group consisted from 27 healthy
      subjects matched for age and sex. Eight (33%) patients demonstrated abnormal P100
      latency prolongation in at least one tested eye (six patients in one tested eye,
      two in both eyes) in the recording session just prior to dialytic treatment. In
      the post-treatment session, it was found that the abnormal P100 latencies that
      were present in six patients (75%) before dialysis had returned to normal, while
      in the remaining two (25%), the latency abnormality persisted. No correlation was
      found between VEP parameters and dialysis duration, serum blood urea nitrogen
      (BUN), creatinine, parathyroid hormone and haematocrit levels. However, a
      positive correlation in the intradialytic percentage variation of bodyweight with
      P100 latencies was found. Visual evoked potential is a reliable, simple and non
      invasive technique that can be used for the investigation and follow up of
      subclinical involvement of visual pathways in patients with chronic renal
      failure. Detected abnormalities in some uraemic patients are reversible by using
      dialysis.

PMID- 15012745
TI  - Acute vascular access catheters for haemodialysis: complications limiting
      technique survival.
AB  - The use of acute vascular access catheters (AVACs) has facilitated the delivery
      of haemodialysis to patients lacking functioning access. A review of the
      experience of a tertiary Australian renal treatment centre, consisting of 205
      sequential AVACs in 93 patients, was undertaken over 1 year, to identify issues
      limiting technique survival. Acute vascular access catheters were inserted as
      acute dialysis access for patients with chronic renal failure (CRF; 21%), failed
      grafts or fistulae (18%), acute renal failure (12%), failed chronic ambulatory
      peritoneal dialysis (CAPD; 8%) or failed prior AVACs (37%). The majority of AVACs
      were on the right (74%), and the placement site was simple jugular (69%),
      tunnelled jugular (15%), femoral (12%), or subclavian (4%). During follow up, 198
      of 205 AVACs were removed. The mean AVAC survival was superior (P < 0.0001,
      Fisher's protected least significant difference (PLSD) for tunnelled jugular
      AVACS (62 +/- 46 (SD) days) compared with simple jugular (20 +/- 19), subclavian
      (18 +/- 13) and femoral (7 +/- 6). Causes for AVAC removal were: elective (47%),
      blockage (31%), infection (20%) or cracked catheter (1%). Routine postremoval tip
      cultures grew coagulase negative Staphylococcus (CNS, 46%), negative culture
      (33%), methicillin-resistant Staphylococcus aureus (MRSA; 9%), Staphylococcus
      aureus (9%), Gram-negative rods (1%), Pseudomonas (0.5%) or other uncommon
      organisms (2%). Blood cultures were drawn through the AVAC in the setting of
      suspected bacteraemia in 42 of 198 AVACs. Blood cultures were negative in 40%.
      Positive cultures included Staphylococcus species in 55%: including MRSA (19%),
      Staphylococcus aureus (29%) and CNS (34%). Rare cultures identified Escherichia
      coli (2%) or Serratia (2%). Infection and blockage significantly reduced AVAC
      survival, affecting more than 50% of cases. Approaches to minimize these
      complications are likely to lead to improved clinical outcomes with AVAC use.

PMID- 15012746
TI  - Clinicopathological correlation of intrarenal cytokines and chemokines in IgA
      nephropathy.
AB  - The pathogenetic mechanisms of IgA nephropathy are diverse and are not yet
      clearly elucidated. We believe pro-inflammatory cytokines, Th1/Th2, and
      chemokines would be involved in the pathogenetic pathways and would affect the
      functional and histological consequences of IgA nephropathy. By using
      semiquantitative reverse transcriptase-polymerase chain reactions (RT-PCR), we
      measured the level of intrarenal gene expression of various cytokines and
      chemokines in 61 renal core biopsy specimens confirmed as IgA nephropathy. And,
      by using immunohistochemistry (IHC), the degree of expression and the location of
      various cytokines and chemokines in renal tissues in 29 of the above patients
      were attempted to be determined. In RT-PCR, the gamma-interferon (IFN
      gamma)/interleukin-10 (IL-10) ratio was higher in patients with renal dysfunction
      than in those with normal renal function. The levels of pro-inflammatory cytokine
      gene transcripts (tumor necrosis factor-alpha (TNF-alpha), IL-1beta) were high in
      patients with significant proteinuria. In patients with severe glomerular
      sclerosis, the ratio of IFN-gamma/IL-10 gene transcripts was high. The level of
      IL-10 gene transcript was related to the severity of tubular atrophy and
      interstitial fibrosis. The extent of intrarenal arteriolar lesions correlated
      with the expression of the IL-8 gene transcript. The degree of IgA deposition in
      glomeruli was related to the expression of IL-15 and IL-6. In IHC, TNF-alpha, IFN
      gamma and IL-2 were immunostained dominantly in the mesangial region, but not in
      the tubulointerstitial region. In contrast, positive reactions for IL-10 were
      observed primarily in tubules. Significant reactions for IL-8 were noted in the
      periarteriolar and arteriolar areas. The results of RT-PCR and IHC showed
      positive relationships, but these were not statistically significant. This study
      suggests that pro-inflammatory, Th1/Th2 cytokines and chemokines are involved in
      the specific processes of inflammation and immunological injury in IgA
      nephropathy.

PMID- 15012748
TI  - Role of interleukin-10 in rat mesangioproliferative glomerulonephritis.
AB  - Interleukin-10 (IL-10) has been recognized as a growth factor for rat mesangial
      cells in vitro; however, its role in mesangioproliferative glomerulonephritis is
      unknown. We studied the expression of IL-10 mRNA in the rat anti-Thy-1 model of
      mesangioproliferative glomerulonephritis (experiment 1) and, subsequently, the
      effects of blocking IL-10 during anti-Thy-1 nephritis using the IL-10 inhibitor,
      AS101 (experiment 2). In experiment 1, PCR analysis failed to detect IL-10 mRNA
      in normal rat kidney, however, a clear signal for IL-10 mRNA was evident on day 6
      of anti-Thy-1 nephritis. In situ hybridization showed IL-10 mRNA expression in
      focal glomerular areas in anti-Thy-1 nephritis. Combined in situ hybridization
      and immunohistochemistry showed that glomerular IL-10 mRNA was expressed by both
      macrophages and mesangial cells. In experiment 2, treatment with AS101
      significantly downregulated renal IL-10 gene expression, as demonstrated by
      semiquantitative PCR. However, the induction of glomerular hypercellularity,
      mesangial proliferation (PCNA+ cells), mesangial cell activation (alpha-SMA
      expression) and macrophage accumulation (ED1+ cells) seen in saline-treated anti
      Thy-1 nephritis was unaffected by AS101 treatment. In conclusion, renal IL-10
      gene expression is upregulated during pathological mesangial cell proliferation
      in rats with anti-Thy-1 nephritis. However, the inability of IL-10 suppression
      with AS101 to prevent anti-Thy-1 disease suggests that IL-10 is not essential for
      pathological mesangial cell proliferation.

PMID- 15012747
TI  - Potassium depletion in a healthy north-eastern Thai population: no association
      with tubulo-interstitial injury.
AB  - Potassium depletion prevails among the healthy population of north-east Thailand,
      as well as among patients with certain metabolic disorders such as upper urinary
      tract stones, the sudden unexplained death syndrome, distal renal tubular
      acidosis and hypokalaemic periodic paralysis. However, definite proof of the
      relationship of potassium depletion and these metabolic disorders is lacking. We
      prospectively studied muscle and kidney potassium content including renal tissue
      pathology in three groups of healthy adult Thai subjects who died of vehicular
      accidents. Group 1 (n = 24) were Bangkok city dwellers; groups 2 (n = 10) and 3
      (n = 22) lived in north-eastern Thailand in the metropolitan area and in the
      villages, respectively. The muscle potassium content of group 1 (338.5 +/- 9.6
      mEq/kg dry weight (DW)) were similar to group 2 (307.9 +/- 11.9 mEq/kg DW), but
      was greater than group 3 (295.4 +/- 9.1 mEq/kg DW; P < 0.01). The kidney
      potassium content of group 1 (208.6 +/- 7.8 mEq/kg DW) was significantly higher
      than group 3 (175.9 +/- 6.3 mEq/kg DW, P < 0.05). In group 3, the muscle
      potassium correlated linearly with the kidney potassium (r = 0.455, P = 0.33).
      None of the group 3 patients had renal histopathological change compatible with a
      diagnosis of focal or diffuse interstitial nephritis. This study confirms that
      potassium depletion is common among healthy rural dwellers in north-east
      Thailand. This deficit was probably chronic. However, there was minimal renal
      tubulo-interstitial change.

PMID- 15012749
TI  - Current incidence, treatment patterns and outcome of end-stage renal disease
      among indigenous groups in Australia and New Zealand.
AB  - The changes in rates of treated end-stage renal disease (ESRD) among indigenous
      populations have profound consequences for those individuals affected and for
      health-care providers. By using data from the Australia and New Zealand Dialysis
      and Transplant (ANZDATA) Registry, we examined the current incidence, treatment
      and outcomes of ESRD among indigenous groups in Australia and New Zealand. All
      patients who began renal replacement therapy (RRT) in Australia or New Zealand
      between October 1991 and September 2000 were included. Rates of ESRD, RRT
      modalities, renal transplantation and mortality were the outcomes examined. End
      stage renal disease rates among indigenous groups in Australia and New Zealand
      exceeded non-indigenous rates up to eightfold. The median age of indigenous ESRD
      patients was younger (51 vs 60 years, P < 0.0001), and there was an excess of
      comorbidities, particularly diabetes. For Australian Aboriginal and Torres Strait
      Islanders, and New Zealand Maori patients, mortality rates across all modalities
      of RRT were 70% higher than non-indigenous rates. Indigenous people were less
      likely to receive a renal transplant prior to dialysis treatment, less likely to
      be accepted onto the cadaveric transplant waiting list, and less likely to
      receive a well-matched transplant. The poorer outcomes among Australian
      Aboriginal and Torres Strait Islanders, and New Zealand Maori patients did not
      appear to be explained by the different comorbid conditions or age. Whether the
      outcomes reflect unmeasured differences in disease burden or treatment
      differences is not known. Tackling this problem will involve a spectrum of people
      and approaches, from tertiary care providers and RRT to local staff and
      preventative programs.

PMID- 15012750
TI  - A peritoneal dialysis patient with fatal culture-negative peritonitis.
AB  - Culture-negative peritoneal inflammation accounts for between 5 and 20% of cases
      of peritonitis in peritoneal dialysis patients. Diagnostic yields may be enhanced
      considerably by reculturing dialysate effluents using appropriate collection
      methods and optimal laboratory techniques (including prolonged low-temperature
      and anaerobic incubations). In patients with persistent culture-negative
      peritonitis, consideration should be given to the possibilities of unusual or
      fastidious microorganisms (especially fungi and mycobacteria) and non-infective
      causes (especially drug reactions, malignancy, visceral inflammation and
      retroperitoneal inflammation). In this paper, an illustrative case of persistent
      culture-negative peritonitis is presented followed by a discussion of the
      investigative approach to such patients, with particular emphasis on differential
      diagnosis and the limitations of currently available tests.

PMID- 15012751
TI  - Special issue: analytical methods in phylogeography and genetic structure.

PMID- 15012752
TI  - The incomplete natural history of mitochondria.
AB  - Mitochondrial DNA (mtDNA) has been used to study molecular ecology and
      phylogeography for 25 years. Much important information has been gained in this
      way, but it is time to reflect on the biology of the mitochondrion itself and
      consider opportunities for evolutionary studies of the organelle itself and its
      ecology, biochemistry and physiology. This review has four sections. First, we
      review aspects of the natural history of mitochondria and their DNA to show that
      it is a unique molecule with specific characteristics that differ from nuclear
      DNA. We do not attempt to cover the plethora of differences between mitochondrial
      and nuclear DNA; rather we spotlight differences that can cause significant bias
      when inferring demographic properties of populations and/or the evolutionary
      history of species. We focus on recombination, effective population size and
      mutation rate. Second, we explore some of the difficulties in interpreting
      phylogeographical data from mtDNA data alone and suggest a broader use of
      multiple nuclear markers. We argue that mtDNA is not a sufficient marker for
      phylogeographical studies if the focus of the investigation is the species and
      not the organelle. We focus on the potential bias caused by introgression. Third,
      we show that it is not safe to assume a priori that mtDNA evolves as a strictly
      neutral marker because both direct and indirect selection influence mitochondria.
      We outline some of the statistical tests of neutrality that can, and should, be
      applied to mtDNA sequence data prior to making any global statements concerning
      the history of the organism. We conclude with a critical examination of the
      neglected biology of mitochondria and point out several surprising gaps in the
      state of our knowledge about this important organelle. Here we limelight
      mitochondrial ecology, sexually antagonistic selection, life-history evolution
      including ageing and disease, and the evolution of mitochondrial inheritance.

PMID- 15012753
TI  - The phylogeography of human viruses.
AB  - Viruses, especially those with RNA genomes, represent ideal organisms to study
      the dynamics of microevolutionary change. In particular, their rapid rate of
      nucleotide substitution means that the epidemiological processes that shape their
      diversity act on the same time-scale as mutations are fixed in viral populations.
      Consequently, the branching structure of virus phylogenies provides a unique
      insight into spatial and temporal dynamics. Herein, I describe the key processes
      in virus phylogeography. These are generally associated with the relative rates
      of dispersal among populations and virus-host codivergence (vicariance), and the
      division between acute (short-term) and persistent (long-term) infections. These
      processes will be illustrated by important human viruses - HIV, dengue, rabies,
      polyomavirus JC and human papillomavirus - which display varying spatial and
      temporal structures and virus-host relationships. Key research questions for the
      future will also be established.

PMID- 15012754
TI  - Divergence dates for Malagasy lemurs estimated from multiple gene loci:
      geological and evolutionary context.
AB  - The lemurs of Madagascar are a unique radiation of primates that show an
      extraordinary diversity of lifestyles, morphologies and behaviours. However, very
      little is known about the relative antiquity of lemuriform clades due to the lack
      of terrestrial fossils for the Tertiary of Madagascar. Here, we employ a Bayesian
      method to estimate divergence dates within the lemuriform radiation using several
      unlinked gene loci and multiple fossil calibrations outside the lemuriform clade.
      Two mitochondrial genes (cytochrome oxidase II and cytochrome b), two nuclear
      introns (transthyretin intron 1 and von Willebrand factor gene intron 11) and one
      nuclear exon (interphotoreceptor retinoid binding protein, exon 1) are used in
      separate and combined analyses. The genes differ in taxon sampling and
      evolutionary characteristics but produce congruent date estimates. Credibility
      intervals narrow considerably in combined analyses relative to separate analyses
      due to the increased amount of data. We also test the relative effects of
      multiple vs. single calibration points, finding that, when only single
      calibration points are employed, divergence dates are systematically
      underestimated. For the mitochondrial DNA data set, we investigate the effects of
      sampling density within the mouse lemur radiation (genus Microcebus). When only
      two representative species are included, estimated dates throughout the phylogeny
      are more recent than with the complete-species sample, with basal nodes less
      affected than recent nodes. The difference appears to be due to the manner in
      which priors on node ages are constructed in the two analyses. In nearly all
      analyses, the age of the lemuriform clade is estimated to be approximately 62-65
      Ma, with initial radiation of mouse lemurs and true lemurs (genus Eulemur)
      occurring approximately 8-12 Ma. The antiquity of the mouse lemur radiation is
      surprising given the near uniform morphology among species. Moreover, the
      observation that mouse lemurs and true lemurs are of similar ages suggests
      discrepancies in rates of morphological, behavioural and physiological evolution
      in the two clades, particularly with regard to characteristics of sexual
      signalling. These differences appear to correlate with the nocturnal vs. diurnal
      lifestyles, respectively, of these two primate groups.

PMID- 15012755
TI  - Using molecular markers with high mutation rates to obtain estimates of relative
      population size and to distinguish the effects of gene flow and mutation: a
      demonstration using data from endemic Mauritian skinks.
AB  - We propose a method of analysing genetic data to obtain separate estimates of the
      size (N(p)) and migration rate (m(p)) for the sampled populations, without
      precise prior knowledge of mutation rates at each locus ( micro(L)). The effects
      of migration and mutation can be distinguished because high migration has the
      effect of reducing genetic differentiation across all loci, whereas a high
      mutation rate will only affect the locus in question. The method also takes
      account of any differences between the spectra of immigrant alleles and of new
      mutant alleles. If the genetic data come from a range of population sizes, and
      the loci have a range of mutation rates, it is possible to estimate the relative
      sizes of the different N(p) values, and likewise the m(p) and the micro(L).
      Microsatellite loci may also be particularly appropriate because loci with a high
      mutation rate can reach mutation-drift-migration equilibrium more quickly, and
      because the spectra of mutants arriving in a population can be particularly
      distinct from the immigrants. We demonstrate this principle using a
      microsatellite data set from Mauritian skinks. The method identifies low gene
      flow between a putative new species and populations of its sister species,
      whereas the differentiation of two other populations is attributed to small
      population size. These distinct interpretations were not readily apparent from
      conventional measures of genetic differentiation and gene diversity. When the
      method is evaluated using simulated data sets, it correctly distinguishes low
      gene flow from small population size. Loci that are not at mutation-migration
      drift equilibrium can distort the parameter estimates slightly. We discuss
      strategies for detecting and overcoming this effect.

PMID- 15012756
TI  - Statistical phylogeography: methods of evaluating and minimizing inference
      errors.
AB  - Nested clade phylogeographical analysis (NCPA) has become a common tool in
      intraspecific phylogeography. To evaluate the validity of its inferences, NCPA
      was applied to actual data sets with 150 strong a priori expectations, the
      majority of which had not been analysed previously by NCPA. NCPA did well
      overall, but it sometimes failed to detect an expected event and less commonly
      resulted in a false positive. An examination of these errors suggested some
      alterations in the NCPA inference key, and these modifications reduce the
      incidence of false positives at the cost of a slight reduction in power.
      Moreover, NCPA does equally well in inferring events regardless of the presence
      or absence of other, unrelated events. A reanalysis of some recent computer
      simulations that are seemingly discordant with these results revealed that NCPA
      performed appropriately in these simulated samples and was not prone to a high
      rate of false positives under sampling assumptions that typify real data sets.
      NCPA makes a posteriori use of an explicit inference key for biological
      interpretation after statistical hypothesis testing. Alternatives to NCPA that
      claim that biological inference emerges directly from statistical testing are
      shown in fact to use an a priori inference key, albeit implicitly. It is argued
      that the a priori and a posteriori approaches to intraspecific phylogeography are
      complementary, not contradictory. Finally, cross-validation using multiple DNA
      regions is shown to be a powerful method of minimizing inference errors. A
      likelihood ratio hypothesis testing framework has been developed that allows
      testing of phylogeographical hypotheses, extends NCPA to testing specific
      hypotheses not within the formal inference key (such as the out-of-Africa
      replacement hypothesis of recent human evolution) and integrates intra- and
      interspecific phylogeographical inference.

PMID- 15012757
TI  - Combining demographic, environmental and genetic data to test hypotheses about
      colonization events in metapopulations.
AB  - We describe a method for making inferences about the factors that influence
      colonization processes in natural populations. We consider the general situation
      where we have genetic data from a newly colonized population and also from I
      source populations that may have contributed individuals to the founding group
      that established the new population. The model assumes that p (biotic/abiotic)
      factors, G(1), ... ,G(p) may have influenced some individuals in some of the
      source populations to find a new habitat patch where they could establish a new
      population. The aim of the method is to determine the composition of the founding
      group and to ascertain if the aforementioned factors have indeed played a role in
      the colonization event. We investigate the performance of our method using
      simulated data sets and illustrate its application with data from the grey seal
      Halichoerus grypus. These applications demonstrate that the method can identify
      accurately those factors that are most important for the founding of new
      populations. This is the case even when genetic differentiation among source
      populations is low. The estimates of the contribution that each source population
      makes to the founding groups is somewhat sensitive to the degree of genetic
      differentiation but it is still possible to identify the sources that are the
      main contributors to the founding group, even when genetic differentiation is low
      (F(ST) = 0.01).

PMID- 15012758
TI  - Effect of unsampled populations on the estimation of population sizes and
      migration rates between sampled populations.
AB  - Current estimators of gene flow come in two methods; those that estimate
      parameters assuming that the populations investigated are a small random sample
      of a large number of populations and those that assume that all populations were
      sampled. Maximum likelihood or Bayesian approaches that estimate the migration
      rates and population sizes directly using coalescent theory can easily
      accommodate datasets that contain a population that has no data, a so-called
      'ghost' population. This manipulation allows us to explore the effects of missing
      populations on the estimation of population sizes and migration rates between two
      specific populations. The biases of the inferred population parameters depend on
      the magnitude of the migration rate from the unknown populations. The effects on
      the population sizes are larger than the effects on the migration rates. The more
      immigrants from the unknown populations that are arriving in the sample
      populations the larger the estimated population sizes. Taking into account a
      ghost population improves or at least does not harm the estimation of population
      sizes. Estimates of the scaled migration rate M (migration rate per generation
      divided by the mutation rate per generation) are fairly robust as long as
      migration rates from the unknown populations are not huge. The inclusion of a
      ghost population does not improve the estimation of the migration rate M; when
      the migration rates are estimated as the number of immigrants Nm then a ghost
      population improves the estimates because of its effect on population size
      estimation. It seems that for 'real world' analyses one should carefully choose
      which populations to sample, but there is no need to sample every population in
      the neighbourhood of a population of interest.

PMID- 15012759
TI  - Evaluating the performance of likelihood methods for detecting population
      structure and migration.
AB  - A plethora of statistical models have recently been developed to estimate
      components of population genetic history. Very few of these methods, however,
      have been adequately evaluated for their performance in accurately estimating
      population genetic parameters of interest. In this paper, we continue a research
      program of evaluation of population genetic methods through computer simulation.
      Specifically, we examine the software MIGRATEE-N 1.6.8 and test the accuracy of
      this software to estimate genetic diversity (Theta), migration rates, and
      confidence intervals. We simulated nucleotide sequence data under a neutral
      coalescent model with lengths of 500 bp and 1000 bp, and with three different per
      site Theta values of (0.00025, 0.0025, 0.025) crossed with four different
      migration rates (0.0000025, 0.025, 0.25, 2.5) to construct 1000 evolutionary
      trees per-combination per-sequence-length. We found that while MIGRATEE-N 1.6.8
      performs reasonably well in estimating genetic diversity (Theta), it does poorly
      at estimating migration rates and the confidence intervals associated with them.
      We recommend researchers use this software with caution under conditions similar
      to those used in this evaluation.

PMID- 15012760
TI  - Patterns of DNA sequence diversity and genetic structure after a range expansion:
      lessons from the infinite-island model.
AB  - It has been long recognized that population demographic expansions lead to
      distinctive features in the molecular diversity of populations. However, recent
      simulation results have suggested that a distinction could be made between a pure
      demographic expansion in an unsubdivided population, and a range expansion in a
      subdivided population, both leading to a large increase in the total number of
      the individuals. In order to better characterize the effect of a range expansion,
      I introduce a simple model of instantaneous expansion under an infinite-island
      model, under which I derive the distribution of the number of mutation
      differences between pairs of genes (the mismatch distribution), the
      heterozygosity, the average number of pairwise difference, and the fixation index
      F(ST). These derivations are checked against simulations, and are shown to lead
      to results qualitatively similar to those one would obtain after a range
      expansion in a 2-dimensional stepping-stone model. I then apply these results to
      estimate immigration rates in hunter-gather and post-Neolithic human populations
      from patterns of mitochondrial (mtDNA) diversity. Potential problems with this
      estimation procedure are also discussed.

PMID- 15012761
TI  - Metapopulation models for historical inference.
AB  - The genealogical process for a sample from a metapopulation, in which local
      populations are connected by migration and can undergo extinction and subsequent
      recolonization, is shown to have a relatively simple structure in the limit as
      the number of populations in the metapopulation approaches infinity. The result,
      which is an approximation to the ancestral behaviour of samples from a
      metapopulation with a large number of populations, is the same as that previously
      described for other metapopulation models, namely that the genealogical process
      is closely related to Kingman's unstructured coalescent. The present work
      considers a more general class of models that includes two kinds of extinction
      and recolonization, and the possibility that gamete production precedes
      extinction. In addition, following other recent work, this result for a
      metapopulation divided into many populations is shown to hold both for finite
      population sizes and in the usual diffusion limit, which assumes that population
      sizes are large. Examples illustrate when the usual diffusion limit is
      appropriate and when it is not. Some shortcomings and extensions of the model are
      considered, and the relevance of such models to understanding human history is
      discussed.

PMID- 15012762
TI  - The distribution of the ancestral haplotype in finite stepping-stone models with
      population expansion.
AB  - Recent extensive analyses of human DNA polymorphism reveal that the ancestral
      haplotype at various genetic loci occurs almost exclusively in African samples.
      We develop a coalescence-based simulation method in stepping-stone models with
      population expansion and examine the probability (P(A)) that the ancestral
      haplotype is found in African samples and the probability (Q(A)) that the most
      recent common ancestor of sampled genes occurs in Africa. These probabilities and
      other summary statistics are used to infer the human demographic history. It is
      shown that the high observed P(A) value cannot be explained simply by sampling
      bias. Rather, it suggests that the African population has been more strongly
      subdivided and isolated from each other than the non-African population and that
      there must have been some African populations which were not directly involved in
      the Out-of-Africa expansion in the late Pleistocene.

PMID- 15012763
TI  - Bayesian approaches for the analysis of population genetic structure: an example
      from Platanthera leucophaea (Orchidaceae).
AB  - We describe four extensions to existing Bayesian methods for the analysis of
      genetic structure in populations: (i) use of beta distributions to approximate
      the posterior distribution of f and theta(B); (ii) use of an entropy statistic to
      describe the amount of information about a parameter derived from the data; (iii)
      use of the Deviance Information Criterion (DIC) as a model choice criterion for
      determining whether there is evidence for inbreeding within populations or
      genetic differentiation among populations; and (iv) use of samples from the
      posterior distributions for f and theta(B) derived from different data sets to
      determine whether the estimates are consistent with one another. We illustrate
      each of these extensions by applying them to data derived from previous allozyme
      and random amplified polymorphic DNA surveys of an endangered orchid, Platanthera
      leucophaea, and we conclude that differences in theta(B) from the two data sets
      may represent differences in the underlying mutational processes.

PMID- 15012764
TI  - Moment estimation of population diversity and genetic distance from data on
      recessive markers.
AB  - A moment-based method for estimating a measure of population diversity, theta or
      Wright's FST, is given for dominant markers such as amplified fragment length
      polymorphisms (AFLPs) or RAPDs in noninbred populations. Basic assumptions are
      that there is random mating, Hardy-Weinberg equilibrium, linkage equilibrium, no
      mutation from common ancestor and equally distant populations. It is based on the
      variances between and within populations of genotype frequencies, whereas
      previously moment methods for dominant markers have been indirect in that they
      have been based on first estimating allele frequencies and then using the
      variances of those frequencies. The use of genotype frequencies directly appears
      to be more robust. Approximate sampling errors of the estimates are given.
      Methods are extended to estimate genetic distances and their sampling errors. The
      AFLP data from samples of breeds of pig are used for illustration.

PMID- 15012765
TI  - Using nuclear haplotypes with microsatellites to study gene flow between recently
      separated Cichlid species.
AB  - When populations or species have recently separated they often share genetic
      variation. However, it can be difficult to determine whether shared polymorphisms
      are the result of gene flow, the result of the persistence of variation in both
      populations since the time of common ancestry, or both of these factors. We have
      developed an empirical protocol for using loci that include unique nuclear DNA
      sequence haplotypes together with linked microsatellites or short tandem repeats
      (STRs). These 'HapSTRs' offer the potentially high resolution associated with the
      high mutation rate of STRs, together with the advantages of low homoplasy of
      unique sequence DNA. We also describe a new procedure for estimating the
      likelihood of HapSTR data under an Isolation with Migration model. An example
      using Cichlid fishes from Lake Malawi is described. The analysis suggests that
      the species have been exchanging genes since the time they began to diverge.

PMID- 15012766
TI  - New insights from fine-scale spatial genetic structure analyses in plant
      populations.
AB  - Many empirical studies have assessed fine-scale spatial genetic structure (SGS),
      i.e. the nonrandom spatial distribution of genotypes, within plant populations
      using genetic markers and spatial autocorrelation techniques. These studies
      mostly provided qualitative descriptions of SGS, rendering quantitative
      comparisons among studies difficult. The theory of isolation by distance can
      predict the pattern of SGS under limited gene dispersal, suggesting new
      approaches, based on the relationship between pairwise relatedness coefficients
      and the spatial distance between individuals, to quantify SGS and infer gene
      dispersal parameters. Here we review the theory underlying such methods and
      discuss issues about their application to plant populations, such as the choice
      of the relatedness statistics, the sampling scheme to adopt, the procedure to
      test SGS, and the interpretation of spatial autocorrelograms. We propose to
      quantify SGS by an 'Sp' statistic primarily dependent upon the rate of decrease
      of pairwise kinship coefficients between individuals with the logarithm of the
      distance in two dimensions. Under certain conditions, this statistic estimates
      the reciprocal of the neighbourhood size. Reanalysing data from, mostly,
      published studies, the Sp statistic was assessed for 47 plant species. It was
      found to be significantly related to the mating system (higher in selfing
      species) and to the life form (higher in herbs than trees), as well as to the
      population density (higher under low density). We discuss the necessity for
      comparing SGS with direct estimates of gene dispersal distances, and show how the
      approach presented can be extended to assess (i) the level of biparental
      inbreeding, and (ii) the kurtosis of the gene dispersal distribution.

PMID- 15012767
TI  - Using genetic markers to estimate the pollen dispersal curve.
AB  - Pollen dispersal is a critical process that shapes genetic diversity in natural
      populations of plants. Estimating the pollen dispersal curve can provide insight
      into the evolutionary dynamics of populations and is essential background for
      making predictions about changes induced by perturbations. Specifically, we would
      like to know whether the dispersal curve is exponential, thin-tailed (decreasing
      faster than exponential), or fat-tailed (decreasing slower than the exponential).
      In the latter case, rare events of long-distance dispersal will be much more
      likely. Here we generalize the previously developed TWOGENER method, assuming
      that the pollen dispersal curve belongs to particular one- or two-parameter
      families of dispersal curves and estimating simultaneously the parameters of the
      dispersal curve and the effective density of reproducing individuals in the
      population. We tested this method on simulated data, using an exponential power
      distribution, under thin-tailed, exponential and fat-tailed conditions. We find
      that even if our estimates show some bias and large mean squared error (MSE), we
      are able to estimate correctly the general trend of the curve - thin-tailed or
      fat-tailed - and the effective density. Moreover, the mean distance of dispersal
      can be correctly estimated with low bias and MSE, even if another family of
      dispersal curve is used for the estimation. Finally, we consider three case
      studies based on forest tree species. We find that dispersal is fat-tailed in all
      cases, and that the effective density estimated by our model is below the
      measured density in two of the cases. This latter result may reflect the
      difficulty of estimating two parameters, or it may be a biological consequence of
      variance in reproductive success of males in the population. Both the simulated
      and empirical findings demonstrate the strong potential of TWOGENER for
      evaluating the shape of the dispersal curve and the effective density of the
      population (d(e)).

PMID- 15012768
TI  - Estimating admixture proportions with microsatellites: comparison of methods
      based on simulated data.
AB  - Several methods have been developed to estimate the parental contributions in the
      genetic pool of an admixed population. Some pair-comparisons have been performed
      on real data but, to date, no systematic comparison of a large number of methods
      has been attempted. In this study, we performed a simulated data-based comparison
      of six of the most cited methods in the literature of the last 20 years. Five of
      these methods use allele frequencies and differ in the statistical treatment of
      the data. The last one also considers the degree of molecular divergence by
      estimating the coalescence times. Comparisons are based on the frequency at which
      the method can be applied, the bias and the mean square error of the estimation,
      and the frequency at which the true value is within the confidence interval.
      Eventually, each method was applied to a real data set of variously introgressed
      honeybee populations. In optimal conditions (highly differentiated parental
      populations, recent hybridization event), all methods perform equally well. When
      conditions are not optimal, the methods perform differently, but no method is
      always better or worse than all others. Some guidelines are given for the choice
      of the method.

PMID- 15012769
TI  - Identifying adaptive genetic divergence among populations from genome scans.
AB  - The identification of signatures of natural selection in genomic surveys has
      become an area of intense research, stimulated by the increasing ease with which
      genetic markers can be typed. Loci identified as subject to selection may be
      functionally important, and hence (weak) candidates for involvement in disease
      causation. They can also be useful in determining the adaptive differentiation of
      populations, and exploring hypotheses about speciation. Adaptive differentiation
      has traditionally been identified from differences in allele frequencies among
      different populations, summarised by an estimate of FST. Low outliers relative to
      an appropriate neutral population-genetics model indicate loci subject to
      balancing selection, whereas high outliers suggest adaptive (directional)
      selection. However, the problem of identifying statistically significant
      departures from neutrality is complicated by confounding effects on the
      distribution of FST estimates, and current methods have not yet been tested in
      large-scale simulation experiments. Here, we simulate data from a structured
      population at many unlinked, diallelic loci that are predominantly neutral but
      with some loci subject to adaptive or balancing selection. We develop a
      hierarchical-Bayesian method, implemented via Markov chain Monte Carlo (MCMC),
      and assess its performance in distinguishing the loci simulated under selection
      from the neutral loci. We also compare this performance with that of a
      frequentist method, based on moment-based estimates of FST. We find that both
      methods can identify loci subject to adaptive selection when the selection
      coefficient is at least five times the migration rate. Neither method could
      reliably distinguish loci under balancing selection in our simulations, even when
      the selection coefficient is twenty times the migration rate.

PMID- 15012770
TI  - Asia-Pacific consensus on gastroesophageal reflux disease.

PMID- 15012771
TI  - Report of the Asia-Pacific consensus on the management of gastroesophageal reflux
      disease.
AB  - This report summarizes the conclusions and recommendations of a panel of
      gastroenterologists practising in the Asia-Pacific region. The group recognized
      that although gastroesophageal reflux disease (GERD) is less common and milder in
      endoscopic severity in Asia than in the West, there is nevertheless data to
      suggest an increasing frequency of the disease. During a 2-day workshop, the
      evidence for key issues in the diagnosis and clinical strategies for the
      management of the disease was evaluated, following which the recommendations were
      made and debated. The consensus report was presented at the Asia-Pacific
      Digestive Week 2003 in Singapore for ratification. Upper gastrointestinal (GI)
      endoscopy is the gold standard for the diagnosis of erosive GERD. There is no
      gold standard for the diagnosis of non-erosive GERD (NERD). Diagnosis therefore
      relies on symptoms, a positive 24-h pH study or a response to a course of proton
      pump inhibitor (PPI) treatment. The goals of treatment for GERD are to heal
      esophagitis, relieve symptoms, maintain the patient free of symptoms, improve
      quality of life and prevent complications. The PPI are the most effective medical
      treatment. Following initial treatment, on-demand therapy may be effective in
      some patients with NERD or mild (GI) erosive esophagitis. Anti-reflux surgery by
      a competent surgeon could achieve a similar outcome, although there is an
      operative mortality of 0.1-0.8%. The decision is dependent on the patient's
      preference and the availability of surgical expertise. Currently, endoscopic
      treatment should be performed only in the context of a clinical trial. Treatment
      of patients with typical GERD symptoms without alarm features in primary care
      could begin with PPI for 2 weeks followed by a further 4 weeks before going to on
      demand therapy.

PMID- 15012772
TI  - Non-alcoholic steatohepatitis in the Asia-Pacific region: future shock?
AB  - Clinicians in both the developed and also the newer industrial economies in the
      Asia-Pacific region will encounter non-alcoholic fatty liver disease (NAFLD) with
      increasing frequency. Although the region has been a significant contributor to
      the current state of knowledge, the spectrum of NAFLD, its severity and the
      potential for significant future morbidity and health costs are not widely
      recognized. Lifestyle changes, the epidemic of childhood and adult obesity and
      type 2 diabetes sweeping the Asia-Pacific represent the key substrates for the
      rising prevalence of NAFLD. Physicians in all disciplines need to be aware of
      clinical clues to the presence of NAFLD in the absence of other liver disease and
      in those with chronic viral hepatitis and they should be able to identify subsets
      at risk for liver-related morbidity. Given the scope of the problem, efforts
      should focus primarily on preventing or ameliorating the impact of risk factors;
      the key one is insulin resistance and its associates of diabetes and central
      obesity. Pharmacotherapy may play a role in selected individuals. A regional
      agenda for case definition, future study and public health initiatives is
      urgently required.

PMID- 15012773
TI  - Role of zinc in subclinical hepatic encephalopathy: comparison with somatosensory
      evoked potentials.
AB  - BACKGROUND AND AIM: The purpose of the present paper was to determine the role of
      zinc in subclinical portosystemic encephalopathy (SPSE). METHODS: The serum zinc
      levels were studied for 10 cirrhotic patients who did not suffer SPSE and for 10
      patients who did, and the results compared with those deriving from 10 healthy
      volunteers. The nutritional evaluation included serum prealbumin, albumin, and
      transferrin levels, body mass index (BMI), mid-arm muscle circumference (MAMC),
      and tricep skin-fold (TSF). The occurrence of SPSE was defined as a situation
      when the N20-N65 interpeak latencies of median nerve-stimulated somatosensory
      evoked potentials (SEP) exceeded 2.5 SD of the control mean value. RESULTS:
      Cirrhotic patients suffering SPSE (57.5 +/- 10.5 microg/dL) had lower serum zinc
      levels than those not experiencing SPSE (69.5 +/- 16.6 microg/dL, P = 0.03) and
      controls (77.7 +/- 6.8 microg/dL, P < 0.001). Four of the non-SPSE and nine SPSE
      patients had zinc levels less than the lower normal limit. Cirrhotic patients
      suffering SPSE had lower levels of albumin (2.8 +/- 0.4 g/dL vs 3.8 +/- 0.4 g/dL,
      P < 0.001), prealbumin (9.0 +/- 4.3 mg/dL vs 14.3 +/- 6.0 mg/dL, P = 0.02), and
      transferrin (158 +/- 56 g/L vs 218 +/- 50 g/L, P = 0.01), but a greater total
      bilirubin level (1.2 +/- 1.5 mg/dL vs 0.9 +/- 0.4 mg/dL, P = 0.005) than those
      not suffering SPSE. The serum zinc levels correlated with N20-N65 interpeak
      latencies (P = 0.03), serum albumin (P = 0.006), prealbumin (P < 0.001), and
      total bilirubin (P = 0.02) levels. CONCLUSIONS: The data show that zinc
      deficiency is common in cases of non-alcoholic cirrhosis with SPSE. The early
      assessment of malnutrition and zinc deficiency are important.

PMID- 15012774
TI  - Amplified expression of dominant-negative transforming growth factor-beta type II
      receptor inhibits collagen type I production via reduced Smad-3 activity.
AB  - BACKGROUND AND AIM: As a pleiotropic protein, transforming growth factor (TGF)
      beta induces its effects by binding to its Ser/Thr kinase receptor type II and
      then recruiting and activating receptor type I, which is phosphorylated and
      activates Smads that transduce the signal to the nucleus. METHODS: In this work,
      the authors blocked TGF-beta1 signal transduction pathway via delivery of a
      dominant-negative receptor-II (DeltaCyTbRII)-cDNA lacking Ser/Thr kinase
      intracytoplasmic domain activity. Thus, Cos-1 and hepatic stellate cells were
      cotransfected with pCMV5-DeltaCyTbRII and pAdTrack-green fluorescent protein
      using lipofectamine. RESULTS: Fluorescence microscopy demonstrated an average 10%
      transfection efficiency. Radiolabeled 125I-TGF-beta was bound mostly by cell
      membrane-expressed truncated receptor-II rather than wild-type receptor type II.
      Electrophoretic mobility shift assays were performed using consensus Smad-2 and 
      3 sequences rendering a three-fold decrease in DNA-binding activity, reflecting a
      down-activation in Smad complexes in pCMV5-DeltaCyTbRII-transfected cells, but
      not in mock-transfected cells. The identity of these transcriptional factors was
      confirmed using irrelevant double-stranded oligonucleotides and specific
      antibodies to compete for DNA binding. Also, collagen I mRNA expression showed a
      five-fold decrease, which was reflected at the protein level as a diminished
      collagen type I production in pCMV5-DeltaCyTbRII-transfected Cos-1 cells as
      measured by [3H]proline incorporation and sodium dodecyl sulfate-polyacrylamide
      gel electrophoresis. CONCLUSION: Thus, this could be a useful strategy to
      downregulate or prevent exacerbated synthesis and deposition of extracellular
      matrix in a given fibrotic process.

PMID- 15012775
TI  - Treatment of murine hepatocellular carcinoma using genetically modified cells to
      express interleukin-12.
AB  - BACKGROUND AND AIM: The majority of patients cannot benefit from the conventional
      curative treatments that are currently used for hepatocellular carcinoma (HCC),
      which remains a world health problem. Interleukin (IL)-12 is one of the most
      potent anti-tumor cytokines. The aim of the present study was to examine the anti
      tumor effect and toxicity of intrahepatic delivery of IL-12 using an ex vivo gene
      therapy approach in a murine model of HCC. METHODS: Syngenic fibroblasts or MM45T
      Li HCC tumor cells were genetically modified in vitro to express IL-12 using a
      polycistronic TFG murine IL-12 retroviral vector (TFGmIL-12) coding for both p35
      and p40 murine IL-12 subunits. Hepatocellular carcinoma was generated using
      direct intrahepatic inoculation of the tumor cell line into the left liver lobe
      of BALB/c mice. RESULTS: Direct liver expression of IL-12 by the injected
      genetically modified tumor cells induced a marked inhibition of tumor growth.
      This effect was associated with an early infiltration of macrophages, and
      lymphocytes forming numerous intralobular foci. There was no significant liver
      toxicity, as shown by normal biochemical liver tests. At a later time, the
      intralobular foci were rare and consisted mainly of CD4+ T cells, while CD8+ T
      cells were present in the lobule. Intrahepatic expression of IL-12 did not modify
      circulating or splenic B lymphocytes or natural killer (NK) cells. The inhibition
      of tumor growth was maintained in nude mice even when depleted in NK cells.
      Importantly, in a second model, treatment of established day 7 liver tumors in
      BALB/c mice using direct intra-tumor injection of syngenic fibroblasts that were
      genetically modified to express IL-12 significantly reduced tumor size.
      CONCLUSION: In conclusion, these data provide evidence that experimental HCC can
      be efficiently and safely treated using ex vivo IL-12 gene therapy, which seems
      promising for future clinical studies.

PMID- 15012776
TI  - p16INK4A gene alterations are not a prognostic indicator for survival in patients
      with hepatocellular carcinoma undergoing curative hepatectomy.
AB  - BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is a common malignancy
      worldwide that is highly associated with chronic hepatitis B or C infection and
      cirrhosis. The tumor suppressor gene p16INK4A is an important component of the
      cell cycle and inactivation of the gene has been found in a variety of human
      cancers. The present study was performed to determine genetic and epigenetic
      alterations in the p16INK4A tumor suppressor gene and the effect of these on HCC
      progression. METHODS: The status of p16INK4A was evaluated in 117 HCC tumoral
      nodules and 110 corresponding peritumoral tissues by loss of heterozigosity (LOH)
      at the 9p21-22 region, homozygous deletions, single-strand conformation
      polymorphism-polymerase chain reaction (PCR) mutational analysis and methylation
      specific PCR. RESULTS: The most frequent inactivation mechanism was
      hypermethylation of the promoter region, which was found in 63.2% of the tumor
      samples and in 28.2% of the peritumoral samples. Loss of heterozygosity at the
      9p21 region was detected in 27.3% and 10% of tumor and peritumoral tissues,
      respectively. Homozygous deletions and mutations were less common events in
      hepatocarcinogenesis. The authors found 5.9% of the tumor cases with exon 2
      homozygous deletions and 8.6% with mutations. Two polymorphisms were detected,
      one at codon 148 (GCG --> ACG, Ala --> Thr) in three cases and the other in exon
      3 at 540 bp (34.2% of the samples). No association was found between inactivation
      of p16INK4A and clinicopathological characteristics or prognosis. CONCLUSION:
      p16INK4A is altered frequently and early in HCC, being the predominant mechanism
      of inactivation promoter hypermethylation. The present results suggest that the
      p16INK4A gene plays an important role in the pathogenesis of HCC.

PMID- 15012777
TI  - Role of transfusion-transmitted virus in acute viral hepatitis and fulminant
      hepatic failure of unknown etiology.
AB  - BACKGROUND AND AIM: The role of the newly described transfusion-transmitted virus
      (TTV), a circular single-stranded DNA virus, has been investigated in acute liver
      disease, comprising 36 patients with acute viral hepatitis (AVH) and 25 with
      fulminant hepatic failure (FHF), including 50 volunteer blood donors as controls.
      METHODS: Detection of TTV DNA sequences was carried out by polymerase chain
      reaction (PCR) using primers derived from the UTR(A) region of the TTV genome.
      The clinical course and biochemical profile when infected with TTV alone or
      coinfected with other classical hepatotropic viruses were analyzed. All patients
      were first evaluated for liver function profile and for the presence of various
      hepatotropic viruses using serological tests and PCR in serologically negative
      patients. RESULTS: Transfusion-transmitted virus DNA was detected in 80.6%
      (29/36) of the AVH cases and in 76% (19/25) of the FHF cases, which were
      significantly higher levels (P < 0.05) than the 52% (26/50) observed in volunteer
      blood donors. No significant difference in symptoms, clinical course, liver
      function and risk factor profile between TTV-positive and TTV-negative patients
      could be observed in both AVH and FHF patients. TTV was found to coexist with
      both parenterally and non-parenterally transmitted hepatotropic viruses in
      similar frequency in both AVH and FHF patients. Further, there was no significant
      difference in the mortality rates between TTV-positive and TTV-negative FHF
      patients. Also, there was no difference between patients coinfected by TTV and
      other hepatotropic viruses and those with TTV infection alone. CONCLUSION: Thus,
      it appears that TTV, although it exists in a very high frequency in the Indian
      population, appears to have no significant etiological role in AVH and FHF.

PMID- 15012778
TI  - Biliary excretion of azelnidipine, a calcium antagonist, in rats.
AB  - BACKGROUND AND AIMS: Azelnidipine (CS-905) is a novel dihydropyridine calcium
      antagonist that is known to be excreted in feces. To examine the mechanism of
      biliary excretion of azelnidipine, the authors studied its biliary excretion in
      Eisai hyperbilirubinuria rats (EHBR), multidrug resistance protein (Mrp)2
      deficient rats, and the effect of cholephilic compounds on the biliary excretion
      of azelnidipine in rats. METHODS: Radiolabeled azelnidipine was intravenously
      administered to EHBR and control rats, and the biliary excretion of radiolabeled
      metabolites was studied. Furthermore, the effect of sulfobromophthalein,
      taurocholate and vinblastine on the biliary excretion of azelnidipine metabolites
      was also studied in control rats. RESULTS: The biliary excretion of azelnidipine
      metabolites was delayed in EHBR. The biliary excretion of azelnidipine
      metabolites was inhibited by sulfobromophthalein and vinblastine, but was not
      inhibited by taurocholate or phenothiazine pretreatment. CONCLUSION: These
      findings suggest that the metabolites of azelnidipine are excreted into the bile
      partly by Mrp2 and P-glycoprotein.

PMID- 15012779
TI  - Endoscopic balloon dilatation of benign gastric outlet obstruction.
AB  - BACKGROUND AND AIM: Endoscopic balloon dilatation (EBD) has been used for the
      treatment of gastric outlet obstruction (GOO). There are several reports on the
      utility and success of this non-surgical treatment option in peptic GOO, with
      variable results. However, there are only a few reports documenting the efficacy
      of this method for non-peptic GOO. The authors here report on experience with
      balloon dilatation in peptic and non-peptic GOO over a 3-year period. METHODS:
      Twenty-three patients with benign GOO underwent EBD. Dilatation was carried out
      with through-the-scope balloon dilators after premedication. Dilatation was
      repeated every week and the response was documented on the basis of symptoms and
      endoscopic findings and barium studies. Helicobacter pylori was eradicated in
      patients with peptic GOO, when present. RESULTS: The 23 patients with GOO
      included 11 with peptic ulcer as the etiology, eight with corrosive-induced and
      four with chronic pancreatitis (alcohol three, idiopathic one). Patients with
      peptic GOO required 1-3 sessions (mean 2.0 +/- 0.63) to achieve a diameter of 15
      mm dilatation, with uniformly good response over a mean follow-up period of 14.04
      +/- 9.79 months. Corrosive-induced GOO required a larger number of dilatation
      sessions (2-9, mean 5.63 +/- 2.88), but the response was equally good, with
      follow up of 12-30 months. Patients with pancreatitis-related GOO, however,
      failed to respond despite a mean of 5.50 (+/-0.58) dilatations, and continued to
      have symptoms. All these patients were subjected to surgical bypass. There were
      no major complications such as perforation. CONCLUSIONS: A good response can be
      expected in the majority of patients with peptic and corrosive-related GOO after
      balloon dilatation; however, poor results are noted for chronic pancreatitis
      related GOO.

PMID- 15012780
TI  - Low prevalence of Helicobacter pylori but high prevalence of cytomegalovirus
      associated peptic ulcer disease in AIDS patients: Comparative study of
      symptomatic subjects evaluated by endoscopy and CD4 counts.
AB  - BACKGROUND AND AIMS: The role of Helicobacter pylori infection in gastroduodenal
      lesions might be different between the general population and AIDS patients. The
      aim of the present study was to compare the prevalence of H. pylori and
      cytomegalovirus (CMV) infection in AIDS patients and HIV-negative controls. The
      impact of CD4 lymphocyte counts on H. pylori and CMV infection in the same
      subjects was also assessed. METHODS: One hundred and fifty-six patients (52 HIV
      positive, 104 HIV-negative) with gastrointestinal symptoms were evaluated with
      upper gastrointestinal endoscopy and biopsy. Comparison of the prevalence of H.
      pylori and CMV infection was made by dividing AIDS patients into two groups:
      those with CD4 counts >100/mm3 and those with CD4 counts <100/mm3, and ulcer and
      non-ulcer patients. RESULTS: In comparison with HIV-negative controls, AIDS
      patients had a lower prevalence of H. pylori infection (P < 0.0001) but a higher
      prevalence of CMV infection (P < 0.0001). Cytomegalovirus infection was
      frequently found in AIDS patients with CD4 count <100/mm3, in comparison with
      those with a CD4 count >100/mm3. In AIDS patients, CMV was more frequently
      detected in subjects with peptic ulcers (P = 0.0125). Conversely, the prevalence
      of H. pylori infection in AIDS patients was not different between those with and
      without peptic ulcers. CONCLUSIONS: The low prevalence of H. pylori infection and
      peptic ulcer in AIDS patients suggests a different role of H. pylori infection in
      peptic ulcer or even a different mechanism of peptic ulcerogenesis in HIV
      positive subjects. Cytomegalovirus, rather than H. pylori, may be the main
      causative pathogen of peptic ulcers in AIDS patients.

PMID- 15012781
TI  - Leptin levels in the acute stage of ulcerative colitis.
AB  - BACKGROUND AND AIMS: Leptin, a recently discovered protein, acts as a hormonal
      feedback signal in regulating adipose tissue mass via hypothalamic mechanisms.
      Inflammatory bowel disease is often associated with anorexia and weight loss. The
      aim of the present study was to investigate serum leptin levels during the time
      course of the acute phase of ulcerative colitis (UC) and to evaluate whether
      leptin leads to anorexia and bodyweight loss in these patients. METHODS: Serum
      leptin levels of 29 male patients with acute UC and 17 healthy controls with
      similar age, sex and body mass index (BMI) were measured. Erythrocyte
      sedimentation rate (ESR), BMI, serum albumin and C-reactive protein
      concentrations, and white blood cell counts were determined. RESULTS: A
      significant increase in serum leptin levels was found in patients with acute UC
      when compared with controls (5.89 +/- 2.06 ng/mL and 3.64 +/- 1.69 ng/mL,
      respectively; p = 0.001). There was no correlation between leptin levels and BMI.
      CONCLUSIONS: Our findings in the acute stage of UC suggest that increased serum
      leptin levels may contribute to anorexia and weight loss. However, an
      inappropriate increase in leptin levels is independent of body mass in acute UC,
      and we believe that other factors may be involved in inflammation-induced
      increases in leptin levels.

PMID- 15012782
TI  - Assessment of clinical impact of endoscopic ultrasound on esophageal cancer.
AB  - BACKGROUND AND AIM: Endoscopic ultrasound (EUS) with fine needle aspiration (FNA)
      is the most accurate imaging modality for locoregional staging of esophageal
      cancer. It remains unclear whether this technology impacts on the outcome of
      patients with this malignancy. The aim of the present study was to assess the
      impact of EUS FNA by comparing the clinical outcomes of patients with esophageal
      cancer before and after the introduction of this staging modality in our
      institution. METHODS: Outcomes of patients with de novo non-metastatic esophageal
      cancer seen in 1998 without EUS FNA evaluation (non-EUS control group) were
      compared to patients evaluated in 2000 with EUS FNA (EUS group). RESULTS:
      Outcomes of 60 (non-EUS control group) and 107 (EUS group) patients with non
      metastatic esophageal cancer were compared. Preoperative neoadjuvant therapy was
      administered to 35 patients in the EUS group, all of whom had advanced disease.
      Cox proportional hazards demonstrated EUS FNA to be associated with reduced
      recurrence risk (hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.43
      0.87), P = 0.004, and reduced mortality (HR: 0.66; 95% CI: 0.47-0.90), P = 0.008.
      CONCLUSIONS: The EUS staging of esophageal cancer leads to appropriate use of
      preoperative neoadjuvant therapy in patients with advanced disease. Use of EUS is
      associated with a recurrence-free survival advantage and overall survival
      advantage in patients, thus supporting its routine use in esophageal cancer
      staging.

PMID- 15012783
TI  - Responses of human clasp and sling fibers to neuromimetics.
AB  - BACKGROUND AND AIMS: It has previously been demonstrated that clasp and sling
      fibers at the human gastroesophageal junction respond differently to
      acetylcholine (Ach). The present study was undertaken to investigate the
      differences between the physiological and pharmacological properties of the two
      types of muscle fiber. METHODS: Recordings were made of the isometric tension of
      human sling and clasp fibers in response to Ach, dopamine (DA), phenylephrine
      (Phe), and isoprenaline (Iso). These specimens were obtained from 18 patients who
      were operated on for esophageal cancer. RESULTS: Both Ach and Phe increased the
      tension of the two types of muscle; the values in the Ach group being 3-4-fold
      greater than those in the Phe group, while Iso decreased the tension of both
      types of muscle strip. The tension of the sling fibers was reduced by DA at lower
      concentration, and then increased gradually as the concentration was increased.
      In contrast, the tension of the clasp fibers did not obviously change when the
      concentration of DA was lower, but a slow elevation of tension was seen with the
      increase in DA concentration. CONCLUSIONS: The sensitivities and maximum
      responses to each agent differed between the clasp fibers and sling fibers. This
      suggests that the two kinds of fiber have different roles in establishing tension
      in the lower esophageal sphincter, with implications for the medical and surgical
      treatment of disorders in this region.

PMID- 15012784
TI  - Evaluation of the 13C-triolein breath test for fat malabsorption in adult
      patients with cystic fibrosis.
AB  - BACKGROUND AND AIMS: A simple non-invasive test not requiring the use of
      radioactive isotopes is required to assess fat malabsorption in adult cystic
      fibrosis (CF) patients. Breath tests using substrates labeled with 13C meet these
      conditions. The 14C-triolein breath test is sensitive and specific for measuring
      fat malabsorption, but involves radiation exposure. The aim of this study was to
      examine the utility of a test using a 13C label and to determine whether
      pancreatic replacement therapy would return the test to the values of a normal
      control group. METHODS: 13CO2 recovery was assessed after an overnight fast in
      six adult patients with CF, both with and without pancreatic enzyme replacement
      therapy (PERT) in the usual dose for a light snack, in a randomized order, on
      different days. Studies were also performed in eight healthy volunteers after
      oral ingestion. Subjects drank 50 mL of a liquid meal mixed with 200 microL 13C
      triolein and breath samples were collected by blowing through a straw into
      collection tubes every 30 min for 6 h. The effect of gastric emptying was
      assessed by comparison of oral ingestion with intraduodenal infusion. Intra
      individual variability was assessed in nine volunteers by repeating the breath
      test after drinking the test meal on a separate day. RESULTS: Compared with
      healthy subjects there was virtually no recovery of 13CO2 in CF patients without
      PERT. The median (interquartile range) cumulative percentage dose recovery (cPDR)
      at 6 h was 3% (0-8) in CF patients compared with 28% (22-41) in healthy controls
      (P < 0.01). Fat absorption was normalized (37%) (36-43) after ingestion of PERT.
      Gastric emptying delayed the peak in 13CO2 recovery, but there was no difference
      in the cPDR at 6 h. There was no difference in recovery between days 1 and 2.
      CONCLUSIONS: The 13C-triolein breath test is a simple and reproducible method to
      measure fat malabsorption. The test provides a screening technique for fat
      malabsorption in adult CF patients and may be useful for monitoring the lowest
      effective dose of PERT.

PMID- 15012785
TI  - Comparison of image quality between electronic and mechanical radial scanning
      echoendoscopes in pancreatic diseases.
AB  - BACKGROUND AND AIM: It is common knowledge that endoscopic ultrasonography (EUS)
      can accurately diagnose pancreatic diseases. Echoendoscopes for EUS are roughly
      classified into two categories, the mechanical radial scanning echoendoscope (MR
      ES) and the electronic linear array echoendoscope, both of which have their
      merits and demerits. In 2000, a newly designed echoendoscope, the electronic
      radial scanning echoendoscope (ER-ES), appeared. The aim of the present study was
      to compare B-mode image quality between the ER-ES and the MR-ES in pancreatic
      diseases. METHODS: Patients with pancreatic diseases (30 cystic diseases and 22
      solid diseases) underwent EUS with both ER-ES and MR-ES. The B-mode images
      obtained using both echoendoscopes were graded using a scoring system and
      statistically analyzed. The assessed point for cystic lesions was the existence
      of mechanical-noise-like ring-like artifacts derived using multiple reflections
      ('ring-down'), grating robe and so on, and that for solid lesions was the scale
      of penetration. The authors compared maneuverability, endurance and endoscopic
      images between the two types of echoendoscopes. RESULTS: The ER-ES had a
      significantly higher score than the MR-ES (P < 0.05) in the analysis of both
      cystic and solid diseases. There was no apparent difference as to
      maneuverability, endurance and endoscopic images. CONCLUSION: Ultrasound images
      acquired by ER-ES appear better compared with those acquired by MR-ES.

PMID- 15012786
TI  - Images of interest. Gastrointestinal: gastroduodenal ulceration associated with
      cytomegalovirus.

PMID- 15012787
TI  - Images of interest. Gastrointestinal: sonographic features of celiac disease.

PMID- 15012788
TI  - Images of interest. Hepatobiliary and pancreatic: multiple biliary hamartomas
      (von Meyenburg complex).

PMID- 15012789
TI  - Images of interest. Hepatobiliary and pancreatic: annular pancreas.

PMID- 15012790
TI  - DNA mismatch repair genes and hereditary non-polyposis colorectal cancer.

PMID- 15012791
TI  - Stromal tumor of the pancreas with expression of c-kit protein: report of a case.
AB  - We report on a case of a stromal tumor, similar to a gastrointestinal stromal
      tumor, originating from the pancreas. The patient was a 54-year-old woman, who
      was seen at the Kofu Municipal Hospital because of an abdominal tumor. On
      abdominal computed tomography and splenic arteriography, the tumor was detected
      in the pancreatic tail. The patient underwent distal pancreatectomy with
      splenectomy. Macroscopically, the cut surface of the tumor showed almost
      completely surrounded by the normal pancreatic tissue. Microscopically, the tumor
      composed of spindle-shaped cells that were immunoreactive for vimentin, CD34, and
      c-kit protein. Therefore, the tumor was diagnosed as a stromal tumor of the
      pancreas. The expression of c-kit protein suggests that this pancreatic stromal
      tumor may originate from primitive mesenchymal cells which can be a logical
      candidate for the origin of gastrointestinal stromal tumors and extra
      gastrointestinal stromal tumors.

PMID- 15012792
TI  - Late relapse in chronic hepatitis C after sustained viral response to interferon
      and ribavirin.

PMID- 15012793
TI  - Ethnic disparity in the prevalence of partial villous atrophy and post-infective
      tropical malabsorption.

PMID- 15012794
TI  - Spontaneous fungal peritonitis in a hemochromatotic patient with cirrhosis on
      long-term prophylactic antibiotics.

PMID- 15012795
TI  - Hepatic arterial dot signs in isolated small duct primary sclerosing cholangitis.

PMID- 15012796
TI  - Teratoma in the hepatoduodenal ligament followed by portal hypertension syndrome.

PMID- 15012797
TI  - Steroid-responsive catastrophic antiphospholipid syndrome.

PMID- 15012799
TI  - Emergency embolization of a ruptured pancreaticoduodenal artery aneurysm
      associated with the median arcuate ligament syndrome.

PMID- 15012798
TI  - Focal nodular hyperplasia of the liver in a patient with primary aldosteronism.

PMID- 15012800
TI  - Microbiological monitoring in the biodegradation of sewage sludge and food waste.
AB  - AIM: To study the microbiology of intensive, in-vessel biodegradation of a
      mixture of sewage sludge and vegetable food waste. METHODS AND RESULTS: The
      biodegradation was performed in a closed reactor with the addition of a starter
      culture of Bacillus thermoamylovorans SW25 under conditions of controlled
      aeration, stirring, pH and temperature (60 degrees C). The content of viable
      bacterial cells, determined by flow cytometry, increased from 5 x 108 g-1 of dry
      matter to 61 x 108 g-1 for 6 days of the process and then dropped to the initial
      value at the end of the process. The reductions of organic matter, 16S rRNA of
      methanogens and coenzyme F420 fluorescence during 10 days of the treatment were
      67, 54 and 87% of the initial values, respectively. The biodegradability of the
      organic matter decreased during the 10 days of the treatment from 3.8 to 1.3 mg
      CO2 g-1 of organic matter per day. The treatment of sewage sludge and food waste
      at 60 degrees C did not remove enterobacteria, which are the agents of intestinal
      infections, from the material. The percentage of viable enterobacterial cells,
      determined by fluorescent in situ hybridization (FISH) with Enterobacteriaceae
      specific oligonucleotide probe and flow cytometry, varied from 1 to 14% of the
      viable bacterial cells. CONCLUSIONS: The mixture of sewage sludge and food waste
      can be degraded by the aerobic thermophilic bacteria; the starter culture of
      Bacillus thermoamylovorans SW25 can be used to perform this process; and
      enterobacteria can survive under treatment of sewage sludge and food waste at 60
      degrees C for 13 days. SIGNIFICANCE AND IMPACT OF THE STUDY: The results show
      that FISH with an oligonucleotide probe can be used to study not only the growth
      but also the degradation of biomass. Obtained results could be used to design the
      bioconversion of sewage sludge and food waste into organic fertilizer.

PMID- 15012801
TI  - Characterization of a broad range antimicrobial substance from Bacillus cereus.
AB  - AIMS: The aim of this research was to isolate and characterize an antimicrobial
      substance from the Bacillus cereus type strain ATCC 14579. METHODS AND RESULTS: A
      substance with antimicrobial activity was isolated from B. cereus ATCC 14579. The
      substance was produced during late exponential growth and well into the
      stationary phase with a maximum 9 h after inoculation. The inhibitory substance
      was purified by reverse-phase HPLC and shown to be highly active against closely
      related Bacillus spp. Clinically relevant species such as Staphylococcus aureus
      and Micrococcus luteus were also inhibited. The substance was characterized as a
      bacteriocin-like inhibitory substance (BLIS) with a molecular mass of ca 3.4 kDa.
      The BLIS was very heat stable, and sensitive only to pronase E and proteinase K.
      Antimicrobial activity was stable and high in the pH range of 2.0-9.0, and
      relatively unaffected by organic chemicals. CONCLUSIONS: An antimicrobial
      substance produced by the B. cereus type strain ATCC 14579 was characterized,
      with a wide spectrum of activity and the potential to be applied as a control
      agent against pathogenic bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: The
      present study is the first report of a substance with antimicrobial activity from
      the B. cereus type strain.

PMID- 15012802
TI  - Improvement of human faecal flora-associated mouse model for evaluation of the
      functional foods.
AB  - AIMS: Animal models are required for evaluation of the functional foods such as
      pro/prebiotics exerting effects through the metabolism of the intestinal
      microflora. The object of this study was to establish new human flora-associated
      mice reflecting the environment of the human intestinal tract. METHODS AND
      RESULTS: We inoculated a human faecal suspension into segmented filamentous
      bacteria (SFB) monoassociated mice as a model system. In both human flora (HF)
      and SFB-associated mouse (HF-SFB mouse), intestinal characteristics such as the
      composition of intraepithelial lymphocytes, the expression of major
      histocompatibility complex (MHC) class II molecules and the number of
      immunoglobulin A-producing cells in the mucosa was closer to those of
      conventionally reared mice than was case with human flora-associated mice (HF
      mice) lacking SFB. Several predominant bacterial groups except lactobacilli in
      human flora were found in faeces of HF-SFB mice. Lactobacilli established small
      populations in the gut of HF-SFB mice when administered before inoculation with
      the human flora. Faecal enzymatic activities and organic acid concentration of HF
      SFB mice proportionally reflected those of the donor subject. CONCLUSION: We
      established a new human flora-associated mouse (HF-SFB mouse), in which
      intestinal characteristics are normally developed and their major microbial
      composition reflect the human. SIGNIFICANCE AND IMPACT OF THE STUDY: HF-SFB mice
      are a valuable model for studying pro/prebiotic effects on the human intestine.

PMID- 15012803
TI  - Enhanced recovery and isolation of Campylobacter spp. from water using a novel
      device.
AB  - AIM: To design a special device which can be used with nonselective blood-free
      nutrient agar without enrichment for detection of campylobacters from water.
      METHODS AND RESULTS: The Kapadnis-Baseri device (KB device) was designed and
      evaluated in comparison with the conventional method (C method) for detection of
      Campylobacter spp. from river water samples. The results indicated that the
      recovery of Campylobacter spp. by KB device was relatively more than by C method.
      CONCLUSIONS: To date, the methods for recovery of campylobacters are time
      consuming and involve use of special culture media, which is cost ineffective.
      The KB device is designed based on two important characters of Campylobacter,
      viz. motility and activity at low temperature. With this device we isolated
      Campylobacter spp. from river water on nonselective media without enrichment.
      Thus this device is as effective as the use of antibiotic media for the isolation
      of campylobacters. SIGNIFICANCE AND IMPACT OF THE STUDY: The KB device will be
      useful for isolation of Campylobacter spp. from water and other environmental
      samples, which is less time consuming and inexpensive. Besides, this device
      allows isolation of antibiotic sensitive campylobacters.

PMID- 15012804
TI  - Disruption of the Zymomonas mobilis extracellular sucrase gene (sacC) improves
      levan production.
AB  - AIMS: Disruption of the extracellular Zymomonas mobilis sucrase gene (sacC) to
      improve levan production. METHODS AND RESULTS: A PCR-amplified tetracycline
      resistance cassette was inserted within the cloned sacC gene in pZS2811. The
      recombinant construct was transferred to Z. mobilis by electroporation. The Z.
      mobilis sacC gene, encoding an efficient extracellular sucrase, was inactivated.
      A sacC defective mutant of Z. mobilis, which resulted from homologous
      recombination, was selected and the sacC gene disruption was confirmed by PCR.
      Fermentation trials with this mutant were conducted, and levansucrase activity
      and levan production were measured. In sucrose medium, the sacC mutant strain
      produced threefold higher levansucrase (SacB) than the parent strain. This
      resulted in higher levels of levan production, whilst ethanol production was
      considerably decreased. CONCLUSIONS: Zymomonas mobilis sacC gene encoding an
      extracellular sucrase was inactivated by gene disruption. This sacC mutant strain
      produced higher level of levan in sucrose medium because of the improved
      levansucrase (SacB) than the parent strain. SIGNIFICANCE AND IMPACT OF THE STUDY:
      The Z. mobilis CT2, sacC mutant produces high level of levansucrase (SacB) and
      can be used for the production of levan.

PMID- 15012805
TI  - Genetic characterization and specific detection of beer-spoilage Lactobacillus
      sp. LA2 and related strains.
AB  - AIMS: Lactobacillus sp. LA2 (DSM15502) and related strains (LA2 group) possess
      strong beer-spoilage ability. The 16S rDNA sequence of LA2 strain is virtually
      indistinguishable from that of L. collinoides, generally considered to be nonbeer
      spoilage bacteria. The aim of this study was to identify the genetic marker to
      distinguish between Lactobacillus sp. LA2 group and L. collinoides and to provide
      a rapid means of identifying beer-spoilage strains belonging to Lactobacillus sp.
      LA2 group. METHODS AND RESULTS: The 16-23S rDNA intergenic spacer (ITS) regions
      of Lactobacillus sp. LA2 and L. collinoides JCM1123T were sequenced to identify a
      genetic marker to distinguish between the two groups. As a result, 300 and 500 bp
      ITS regions of Lactobacillus sp. LA2 were found to be almost identical with those
      of L. collinoides JCM1123T. Sequence comparison analysis between Lactobacillus
      sp. LA2 and L. collinoides JCM1123T revealed that the two contiguously located
      nucleotides are absent in both ITS regions of Lactobacillus sp. LA2. Based on the
      sequence difference, we have designed specific PCR primers with a minor
      modification to the primer sequence that can differentiate between beer-spoilage
      Lactobacillus sp. LA2 group and nonbeer-spoilage L. collinoides. CONCLUSIONS: The
      PCR-based method has been developed to identify Lactobacillus sp. LA2 group,
      providing a rapid and sensitive means of determining the beer-spoilage ability of
      detected bacterial strains. SIGNIFICANCE AND IMPACT OF THE STUDY: The
      substitution of one nucleotide, located at the third position to the 3'-end in
      the primer sequence, enhanced the specificity of the PCR method while retaining
      sufficient sensitivity. The nucleotide gap identified in this study appeared to
      serve as a useful genetic marker that can differentiate 12 beer-spoilage
      Lactobacillus sp. LA2 group strains from its close relatives that exhibit no beer
      spoilage ability.

PMID- 15012806
TI  - Assessment of bacterial endospore viability with fluorescent dyes.
AB  - AIM: To validate three fluorescence viability assays designed primarily for
      vegetative cells on pure Bacillus endospores. METHODS AND RESULTS: Purified fresh
      and gamma-irradiated Bacillus endospores (Bacillus cereus, B. coagulans and two
      strains of B. subtilis) were used. The viability assays were: 5-cyano-2,3
      diotolyl tetrazolium chloride (CTC) to test respiratory activity and early
      germination, DiBAC4(3) and Live/Dead BacLight to measure membrane energization
      and permeabilization, respectively. Gamma irradiation treatment completely
      eliminated spore culturability and was used as negative control. The untreated
      spores showed respiratory activity after 1 h of incubation and this was
      characteristic of almost 100% of spores after 24 h. The membrane potential
      assessment gave no answer about spore viability. A lower proportion of untreated
      spores had permeabilized membrane compared with gamma-irradiated spores using
      Live/Dead BacLight (P < 0.02). CONCLUSION: It is possible to use CTC and
      Live/Dead BacLight to rapidly test endospore viability and evaluate the
      proportion of spores in a preparation that could not be recovered with plate
      count. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that fluorescence
      tests could be applied to assess viability in potentially pathogenic Bacillus
      spore preparations within 1 h.

PMID- 15012807
TI  - Anti-Salmonella activity of (2E)-alkenals.
AB  - AIMS: This study investigated the effect of a series of naturally occurring
      aliphatic (2E)-alkenals against Salmonella choleraesuis subsp. choleraesuis ATCC
      35640 and evaluated their antibacterial action. METHOD AND RESULTS: A homologous
      series of aliphatic (2E)-alkenals from C5-C13 were tested for their antibacterial
      activity against Salm. Choleraesuis. The antibacterial action of (2E)-alkenals
      against Salm. choleraesuis increases with increasing carbon chain length. (2E)
      Dodecenal (C12) was the most effective against this food-borne bacterium with
      minimum bactericidal concentration (MBC) of 6.25 microg ml-1 (34 micromol l-1),
      followed by (2E)-undecenal (C11) with an MBC of 12.5 microg ml-1 (77 micromol l
      1). The activity was found to correlate with the hydrophobic alkyl chain length
      from the hydrophilic aldehyde group. The time-kill curve study showed that (2E)
      dodecenal was bactericidal against Salm. choleraesuis at any growth stage.
      CONCLUSIONS: The antibacterial activity of (2E)-alkenals against Salm.
      choleraesuis was found to correlate with the hydrophobic alkyl chain length. The
      conjugated double bond is not essential in eliciting the activity but is
      associated with increasing it. SIGNIFICANCE AND IMPACT OF THE STUDY: Because of
      their easy availability and wide distribution in many edible plants, (2E)
      alkenals can be used as anti-Salmonella agents.

PMID- 15012808
TI  - Adhesive properties of a LamB-like outer-membrane protein and its contribution to
      Aeromonas veronii adhesion.
AB  - AIMS: To identify and characterize nonfimbrial proteins from Aeromonas veronii
      involved in the attachment to epithelial cells in vitro. METHODS AND RESULTS: Two
      Aer. veronii mucin- and lactoferrin-binding proteins with molecular masses of 37
      and 48 kDa were identified by Western blot analysis. According to its N-terminal
      amino acid sequence, the 48-kDa protein was identified as Omp48, an outer
      membrane protein similar to LamB of Escherichia coli. LamB is a well-known porin
      involved in maltose transport across the outer membrane in E. coli. In a
      microtitre plate assay, Omp48 bound to the immobilized extracellular matrix
      proteins collagen and fibronectin, and the mucin- and lactoferrin-binding
      activity was confirmed. Adhesion of Omp48 to mucin, lactoferrin and collagen was
      diminished by preincubation with homologous glycoproteins or other carbohydrates,
      suggesting a putative Omp48 lectin-like binding domain. Anti-Omp48 antiserum
      significantly inhibited the Aer. veronii adhesion to confluent HeLa cell
      monolayers and pretreatment of cells with purified Omp48 elicited competitive
      inhibition of adhesion. Similarly, cross-inhibition of Aer. hydrophila and Aer.
      caviae adhesion was achieved with the same treatments, indicating the existence
      of a conserved surface protein among these species. CONCLUSIONS: Taken together,
      these data indicate that Omp48 is involved in Aer. veronii adhesion to epithelial
      cells and might be an alternative adhesion factor of this micro-organism.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The adhesive potential of Aeromonas spp. is
      correlated with pathogenicity; however, the adhesion mechanism is complex and not
      well understood. This study provides evidence of a putative adhesion factor that
      might be contributing to pathogenicity of Aer. veronii and could be used for
      vaccine development.

PMID- 15012809
TI  - Isolation of Salmonella strains from reptile faeces and comparison of different
      culture media.
AB  - AIMS: To provide information on epidemiology and isolation of Salmonella strains
      from reptiles. METHODS AND RESULTS: Ninety-one samples collected from reptiles of
      the zoo of Rome or belonging to private owners were analysed using a standard
      protocol for isolation of Salmonella from food. Salmonella strains were tested
      for susceptibility to 15 antimicrobics by a disc-agar diffusion method. Forty-six
      samples (50.5%) were positive for Salmonella. Of the 22 strains serotyped, 17
      belonged to Salmonella enterica subsp. I, four to the subsp. IIIa and one strain
      resulted untypeable. Rappaport-Vassiliadis broth (RVB) allowed to recover more
      Salmonella strains when bacterial growth in buffered peptone water (BPW) was
      scarce, while selenite cystine broth (SCB) was more efficient, whereas growth in
      BPW was abundant. The maximum isolation score was obtained by plating onto xylose
      lysine desoxycholate agar (XLD). The strains exhibited resistance at high
      percentages to colistin sulphate (58.7%), sulphamethoxazole (55.5%), streptomycin
      (32.6%), tetracycline (19.6%), ampicillin (17.4%) and nalidixic acid (13.1%).
      CONCLUSIONS: A high prevalence of Salmonella in reptiles was observed. For
      isolation, the choice of the enrichment broth depending on the degree of growth
      in BPW followed by plating onto XLD may be suggested. SIGNIFICANCE AND IMPACT OF
      THE STUDY: This paper provides epidemiological data on the prevalence of
      Salmonella and laboratory protocols useful for isolation of Salmonella from
      faeces of reptiles.

PMID- 15012810
TI  - Impact of essential oils on growth rate, zearalenone and deoxynivalenol
      production by Fusarium graminearum under different temperature and water activity
      conditions in maize grain.
AB  - AIMS: The effect of five essential oils (oregano, cinnamon, lemongrass, clove and
      palmarose) on growth rate, zearalenone (ZEA) and deoxynivalenol (DON) production
      by Fusarium graminearum strains was assessed. METHODS AND RESULTS: The influence
      of the essential oils was tested on irradiated maize at two concentrations (500
      and 1000 mg kg-1), at different water activity (aw) (0.95 and 0.995) and
      temperature (20 and 30 degrees C) levels. At 0.995 aw all essential oils tested
      had an inhibitory effect on growth rate of F. graminearum at both temperatures
      studied. At this aw level, DON production in general was inhibited by all
      essential oils at 30 degrees C and, although palmarose and clove were the only
      essential oils with statistically significant inhibitory effect on ZEA
      production, an inhibitory trend was observed when cinnamon and oregano oils were
      added to maize grain. CONCLUSIONS: Antifungal and antimycotoxigenic activity of
      the essential oils assayed was shown to depend on environmental conditions.
      SIGNIFICANCE AND IMPACT OF THE STUDY: It is apparent that essential oils should
      be considered as alternative preharvest natural fungicides. Further investigation
      on natural maize grain might be useful to study the effectiveness of these
      essential oils in the presence of natural mycoflora of maize grain.

PMID- 15012811
TI  - Analysis of the action of compounds that inhibit the germination of spores of
      Bacillus species.
AB  - AIMS: To determine the mechanism of action of inhibitors of the germination of
      spores of Bacillus species, and where these inhibitors act in the germination
      process. METHODS AND RESULTS: Spores of various Bacillus species are significant
      agents of food spoilage and food-borne disease, and inhibition of spore
      germination is a potential means of reducing such problems. Germination of the
      following spores was studied: (i) wild-type B. subtilis spores; (ii) B. subtilis
      spores with a nutrient receptor variant allowing recognition of a novel
      germinant; (iii) B. subtilis spores with elevated levels of either the variant
      nutrient receptor or its wild-type allele; (iv) B. subtilis spores lacking all
      nutrient receptors and (v) wild-type B. megaterium spores. Spores were germinated
      with a variety of nutrient germinants, Ca2+-dipicolinic acid (DPA) and
      dodecylamine for B. subtilis spores, and KBr for B. megaterium spores. Compounds
      tested as inhibitors of germination included alkyl alcohols, a phenol derivative,
      a fatty acid, ion channel blockers, enzyme inhibitors and several other
      compounds. Assays used to assess rates of spore germination monitored: (i) the
      fall in optical density at 600 nm of spore suspensions; (ii) the release of the
      dormant spore's large depot of DPA; (iii) hydrolysis of the dormant spore's
      peptidoglycan cortex and (iv) generation of CFU from spores that lacked all
      nutrient receptors. The results with B. subtilis spores allowed the assignment of
      inhibitory compounds into two general groups: (i) those that inhibited the action
      of, or response to, one nutrient receptor and (ii) those that blocked the action
      of, or response to, several or all of the nutrient receptors. Some of the
      compounds in groups 1 and 2 also blocked action of at least one cortex lytic
      enzyme, however, this does not appear to be the primary site of their action in
      inhibiting spore germination. The inhibitors had rather different effects on
      germination of B. subtilis spores with nutrients or non-nutrients, consistent
      with previous work indicating that germination of B. subtilis spores by non
      nutrients does not involve the spore's nutrient receptors. In particular, none of
      the compounds tested inhibited spore germination with dodecylamine, and only
      three compounds inhibited Ca2+-DPA germination. In contrast, all compounds had
      very similar effects on the germination of B. megaterium spores with either
      glucose or KBr. The effects of the inhibitors tested on spores of both Bacillus
      species were largely reversible. CONCLUSIONS: This work indicates that inhibitors
      of B. subtilis spore germination fall into two classes: (i) compounds (most alkyl
      alcohols, N-ethylmaleimide, nifedipine, phenols, potassium sorbate) that inhibit
      the action of, or response to, primarily one nutrient receptor and (ii) compounds
      [amiloride, HgCl2, octanoic acid, octanol, phenylmethylsulphonylfluoride (PMSF),
      quinine, tetracaine, tosyl-l-arginine methyl ester, trifluoperazine] that inhibit
      the action of, or response to, several nutrient receptors. Action of these
      inhibitors, is reversible. The similar effects of inhibitors on B. megaterium
      spore germination by glucose or KBr indicate that inorganic salts likely trigger
      germination by activating one or more nutrient receptors. The lack of effect of
      all inhibitors on dodecylamine germination suggests that this compound stimulates
      germination by creating channels in the spore's inner membrane allowing DPA
      release. SIGNIFICANCE AND IMPACT OF THE STUDY: This work provides new insight
      into the steps in spore germination that are inhibited by various chemicals, and
      the mechanism of action of these inhibitors. The work also provides new insights
      into the process of spore germination itself.

PMID- 15012812
TI  - Carbon and nitrogen sources modulate lipase production in the yeast Yarrowia
      lipolytica.
AB  - AIMS: To analyse the influence of nitrogen and carbon sources on extracellular
      lipase production by Yarrowia lipolytica-overproducing mutant in order to
      optimize its production in large-scale bioreactors. METHODS AND RESULTS: The
      level of lipase production and LIP2 induction, measured using an LIP2-LacZ
      reporter gene, were compared for different carbon and nitrogen sources and for
      different concentrations. The localization of the enzyme during growth was also
      determined by Western blotting analysis using a six-histidine-tagged lipase.
      SIGNIFICANCE AND IMPACT OF THE STUDY: Tryptone N1 and oleic acid are the most
      suitable nitrogen and carbon sources for the production of the extracellular
      lipase by the Y. lipolytica mutant. Higher levels of lipase production were
      obtained as the tryptone concentration increased in the culture medium. Such a
      positive correlation was not observed with oleic acid media where the highest
      lipolytic productivities were obtained in the presence of low concentration. We
      also demonstrate that in the presence of oleic acid, lipase is cell-bound during
      the growth phase before being released in the media. CONCLUSIONS: This work
      provides a better understanding of the mechanism controlling LIP2 expression and,
      thus, extracellular lipase production in the yeast Y. lipolytica.

PMID- 15012813
TI  - National survey for Salmonella in pigs, cattle and sheep at slaughter in Great
      Britain (1999-2000).
AB  - AIMS: The objective of these surveys was to estimate the prevalence of faecal
      carriage of Salmonella in healthy pigs, cattle and sheep at slaughter, and of pig
      carcase contamination with Salmonella. These data can be used as a baseline
      against which future change in Salmonella prevalence in these species at
      slaughter can be monitored. METHODS AND RESULTS: In this first randomized
      National Survey for faecal carriage of Salmonella in slaughter pigs, cattle and
      sheep in Great Britain, 2509 pigs, 891 cattle and 973 sheep were sampled in 34
      pig abattoirs and 117 red meat abattoirs in England, Scotland and Wales. Carriage
      of Salmonella in 25 g caecal contents was identified in 578 (23.0% pigs) but in
      only 134 (5.3%) of carcase swabs. The predominant Salmonella serovars found in
      both types of sample were S. Typhimurium (11.1% caeca, 2.1% carcases) and S.
      Derby (6.3% caeca, 1.6% carcases). The main definitive phage types (DT) of S.
      Typhimurium found were DT104 (21.9% of caecal S. Typhimurium isolates), DT193
      (18.7%), untypable strains (17.6%), DT208 (13.3%) and U302 (13.3%). Three
      isolates of S. Enteritidis (PTs 13A and 4) and one enrofloxacin-resistant S.
      Choleraesuis were also isolated. A positive 'meat-juice ELISA' was obtained from
      15.2% of pigs at 40% optical density (O.D.) cut-off level and 35.7% at 10% cut
      off. There was poor correlation between positive ELISA results or carcase
      contamination and the caecal carriage of Salmonella. The ratio of carcase
      contamination to caecal carriage rates was highest in abattoirs from the midland
      region of England and in smaller abattoirs. In cattle and sheep 1 g samples of
      rectal faeces were tested. Two isolates (i.e. 0.2%) were recovered from cattle,
      one each of S. Typhimurium, DT193 and DT12. One sheep sample (0.1%) contained a
      Salmonella, S. Typhimurium DT41. In a small subsidiary validation exercise using
      25 g of rectal faeces from 174 cattle samples, three (1.7%) isolates of
      Salmonella (S. Typhimurium DT104, S. Agama, S. Derby) were found. CONCLUSIONS:
      The carriage rate of Salmonella in prime slaughter cattle and sheep in Great
      Britain was very low compared with pigs. This suggests that future control
      measures should be focused on reduction of Salmonella infection on pig farms and
      minimizing contamination of carcases at slaughter. SIGNIFICANCE AND IMPACT OF THE
      STUDY: This work has set baseline figures for Salmonella carriage in these
      species slaughtered for human consumption in Great Britain. These figures were
      collected in a representative way, which enables them to be used for monitoring
      trends and setting control targets.

PMID- 15012814
TI  - Characterization of faecal enterococci from rabbits for the selection of
      probiotic strains.
AB  - AIMS: To characterize the facultative anaerobic intestinal microbiota of healthy
      rabbits, especially enterococci, for the selection of potential probiotic
      strains. METHODS AND RESULTS: Phenotypic and molecular methods were used to
      identify enterococcal isolates. Results obtained indicated that enterococcal
      microbiota widely varied among individuals both in size and in composition.
      Antibacterial and haemolytic activities, and resistance to acid and bile salts
      were determined. A small group of strains produced bacteriocins active against
      listeriae and indigenous clostridia and therefore they were selected as potential
      probiotics. One such strain, 8G, was assayed for colonization capacity. Results
      obtained suggested that the fate of the introduced strain depended on the
      composition of the enterococcal indigenous microbiota. CONCLUSIONS: Enterococcus
      faecalis and Ent. faecium are the predominant enterococcal species in the gut of
      rabbits. Other species of lactic acid bacteria were not recovered. SIGNIFICANCE
      AND IMPACT OF THE STUDY: The enterococcal intestinal microbiota of healthy
      rabbits has been characterized in detail. Monitoring the fate of an introduced
      probiotic in vivo is required in order to evaluate potential probiotic strains.

PMID- 15012815
TI  - Volumetric productivity improvement for endoglucanase of Trichoderma
      pseudokoingii S-38.
AB  - AIMS: The objective of this study was to design an economically feasible process
      for endoglucanase (EG) production. METHODS AND RESULTS: Trichoderma pseudokoingii
      S-38 EG synthesis was studied. Initially, either glucose at 2.5, 5 or 10 g l-1,
      or cellulose powder (CF11) at 5 g l-1 was used as the sole carbon source. The
      results showed that enzyme synthesis and biomass formation were closely
      correlated, and both were affected by the carbon source. To improve EG volumetric
      product efficiency, a new technique was developed. Glucose and CF11 (2.5 and 5 g
      l-1, respectively) were used as initial carbon source, and glucose was added at
      2.5 g l-1 day-1. EG activity, volumetric and specific EG productivities were 6.17
      IU l-1, 53 IU l-1 h-1 and 114.3 IU (g cell protein)-1 h-1, respectively. Batch
      production in a 2-l laboratory fermenter confirmed the advantage of the
      technique. The product contained 10.86 IU ml-1 EG activity in 88 h. The
      volumetric and specific EG productivities were 123.4 IU l-1 h-1 and 177.8 IU (g
      cell protein)-1 h-1, respectively. CONCLUSIONS: These results suggest that
      optimization of the ratio of glucose to CF11 for balancing the induction and
      growth rate in the production of EG may lead to technical and economical
      benefits. SIGNIFICANCE AND IMPACT OF THE STUDY: A new technique was developed for
      the production of EG which improves both the volumetric product efficiency and
      the specific activity.

PMID- 15012816
TI  - Identification method based on PCR combined with automated ribotyping for
      tracking probiotic Lactobacillus strains colonizing the human gut and vagina.
AB  - AIMS: A molecular methodology based on PCR-associated automated ribotyping was
      developed to specifically detect the Lactobacillus strains of two probiotic
      products (an orally administered lyophilized preparation and vaginal tablets) in
      human faeces and vaginal swabs. METHODS AND RESULTS: The 16S-23S rDNA sequences
      and the ribotype profiles of the probiotic lactobacilli were characterized and
      new species-specific primer sets were designed. The identification of faecal and
      vaginal lactobacilli isolated from subjects administered with the probiotic
      products was performed by using PCR with species-specific primers followed by
      strain-specific automated ribotyping. CONCLUSIONS: The PCR-ribotyping
      identification allowed to study the colonization patterns of the probiotic
      lactobacilli in the human gut and vagina evidencing the strains with the best
      survival capability. SIGNIFICANCE AND IMPACT OF THE STUDY: The proposed molecular
      method represents a powerful tool of strain-specific identification, useful for
      differentiating exogenous from indigenous strains in any microbial ecosystem and
      for rationally choosing probiotic bacteria with the best chance of survival in
      the host.

PMID- 15012817
TI  - Influence of bovine manure as fertilizer on the bacteriological quality of
      organic Iceberg lettuce.
AB  - AIM: To investigate the bacteriological quality, and the occurrence of selected
      pathogenic bacteria from organically grown Iceberg lettuce fertilized with bovine
      manure in the form of compost, firm manure and slurry in a 2-year field trial.
      METHODS AND RESULTS: Samples of soil, fertilizer, fertilized soil, seedlings and
      lettuce were analysed for aerobic plate counts (APC), thermotolerant coliform
      bacteria (TCB), Escherichia coli, E. coli O157:H7, Salmonella spp. and Listeria
      monocytogenes. No difference in bacteriological quality could be shown in lettuce
      at harvest, however, APC varied significantly from year to year in the study. The
      various treatments gave significantly different APC and numbers of TCB isolated
      from fertilized soil. Escherichia coli O157:H7 was isolated from firm manure and
      slurry, and soils fertilized with the respective fertilizers the second year, but
      were not recovered from the lettuce. CONCLUSIONS: No difference in
      bacteriological quality could be detected in lettuce at harvest after application
      of various types of manure-based fertilizers grown under Norwegian conditions.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The results may indicate that the use of
      manure does not have considerable influence on the bacteriological quality of
      organic lettuce. However, others have suggested that there is a risk by using
      manure. There is a need for more research in the field.

PMID- 15012818
TI  - Genetic relatedness among Campylobacter jejuni serotyped isolates of diverse
      origin as determined by numerical analysis of amplified fragment length
      polymorphism (AFLP) profiles.
AB  - AIMS: To use amplified fragment length polymorphism (AFLP) analysis to evaluate
      the genetic relatedness among 254 Campylobacter jejuni reference and field
      strains of diverse origin representing all defined 'Penner' serotypes for this
      species. METHODS AND RESULTS: Field strains (n = 207) from human diarrhoea and
      diverse animal and environmental sources were collected mainly through a National
      surveillance programme in Denmark and serotyped by use of the established
      'Penner' scheme. Genetic relationships among these isolates, and the archetypal
      serotype reference strains, were assessed by numerical analysis of AFLP profiles
      derived from genomic DNA. Extensive genetic diversity was seen among the strains
      examined; however, 43 groups of isolates were identified at the 92% similarity (S
      ) level. Thirteen groups contained isolates from a single host, possibly
      representing genotypes of 'low risk' to human health. The remaining 30 groups
      contained isolates from humans, chickens and associated food products, cattle,
      sheep, turkeys, ostriches and/or dogs. Strains assigned to serotypes 2, 6/7, 11
      and 12 formed major clusters at the 77.6% S-level. Most other serotypes did not
      form homogeneous clusters. CONCLUSIONS: High-resolution genotyping applied to
      strains from a comprehensive range of sources provides evidence for multiple
      sources of sporadic C. jejuni infection. The results suggest that public health
      protection measures should be directed at all foods of animal origin.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The genetic relatedness among all 'Penner'
      serotypes of C. jejuni is assessed by AFLP analysis. In addition, further
      evidence of epidemic and host-specific clones of C. jejuni is provided.

PMID- 15012819
TI  - Quantitative evaluation of antifungal activity of metallic oxide powders (MgO,
      CaO and ZnO) by an indirect conductimetric assay.
AB  - AIMS: To evaluate antifungal activities of MgO, CaO and ZnO powders
      quantitatively by indirect conductimetric assay. METHODS AND RESULTS: Candida
      albicans NBRC1060, Saccharomyces cerevisiae NBRC1950, Aspergillus niger NBRC4067
      and Rhizopus stolonifer NBRC4781 were used as test micro-organisms. The indirect
      conductimetric assay, in which the change in electrical conductivity of an
      alkaline solution (NaOH) is produced by absorption of CO2 from microbial
      metabolism, could offer a simple and rapid evaluation of the antifungal activity
      within 24-48 h. The conductivity curves obtained for MgO, CaO and ZnO were
      analysed using the growth inhibition kinetic model proposed by Takahashi for
      calorimetric evaluation, and the kinetic parameters and minimum inhibitory
      concentration ([I]100) could be determined. MgO and CaO powders exhibited the
      antimicrobial activities against all fungi used in this study and showed little
      differences between types of fungi. However, although ZnO powder inhibited fungal
      growth, the values of [I]100 were over 100 mg ml-1. CONCLUSIONS: Although a
      common method for evaluating antifungal activity requires over 5-7 days, the
      indirect assay could provide a rapid and quantitative evaluation of antifungal
      activity within approx. 2 days, and MgO and CaO were found to have antifungal
      activities. SIGNIFICANCE AND IMPACT OF THE STUDY: The indirect assay can be
      applicable for simple and rapid evaluation of the antimicrobial activity of
      insoluble or slightly soluble materials with high turbidity such as antibacterial
      ceramic powders. Moreover, these materials can be useful for controlling fungi in
      food processing and the environment.

PMID- 15012820
TI  - An Aneurinibacillus sp. strain AM-1 produces a proline-specific aminopeptidase
      useful for collagen degradation.
AB  - AIMS: We have been for a species of thermophilic bacteria that can effectively
      decompose collagen and collagen peptides that tend to be hard-to-degrade proteins
      because of their high content of proline residues. This study focused upon the
      enzymatic degradation of prolyl peptides by thermophilic bacteria. METHODS AND
      RESULTS: A strain, AM-1, producing a proline-specific aminopeptidase was isolated
      using a medium containing gelatin that was taken from soil samples collected at
      Arima Hot Spring located near Kobe, Japan. The strain showed the strongest level
      of hydrolysing activity toward prolyl-p-nitroanilide, and the activity proved to
      be thermostable. Phylogenetic analysis based on 16S rDNA sequences revealed that
      the isolated strain AM-1 was closest to Aneurinibacillus thermoaerophilus
      DSM10154T in its characteristics. Analysis of the purified proline-specific
      aminopeptidase suggested that the enzyme is an aminopeptidase containing metal
      that includes important disulphide bond(s). The strain AM-1 aminopeptidase has
      more similarities with leucyl aminopeptidases, but its activity level differs
      greatly with prolyl peptides. CONCLUSIONS: The proline-specific aminopeptidase
      from strain AM-1 is the first from the genus Aneurinibacillus and may be a new
      type of aminopeptidase for hydrolysing prolyl peptide. This enzyme also
      contributed to the degradation of collagen when used in combination with another
      collagenolytic protease. SIGNIFICANCE AND IMPACT OF THE STUDY: The proline
      specific aminopeptidase obtained from strain AM-1 may be used in the treatment of
      wastewater containing collagen that is encountered in the meat industries, and
      for decreasing bitter peptides in milk products.

PMID- 15012821
TI  - Use of bacteriocin promoters for gene expression in Lactobacillus plantarum C11.
AB  - AIMS: To exploit promoters involved in production of the bacteriocin sakacin P
      for regulated overexpression of genes in Lactobacillus plantarum C11. METHODS AND
      RESULTS: Production of sakacin P by Lact. sakei LTH673 is controlled by a peptide
      based quorum sensing system that drives strong, regulated promoters. One of these
      promoters (PorfX) was used to establish regulated overexpression of genes
      encoding chloramphenicol acetyltransferase from Bacillus pumilus, aminopeptidase
      N from Lactococcus lactis or chitinase B from Serratia marcescens in Lact.
      plantarum C11, a strain that naturally possesses the regulatory machinery that is
      necessary for promoter activation. The expression levels obtained were highly
      dependent on which gene was used and on how the promoter was coupled to this
      gene. The highest expression levels (14% of total cellular protein) were obtained
      with the aminopeptidase N gene translationally fused to the regulated promoter.
      CONCLUSIONS: Sakacin promoters permit regulated expression of a variety of genes
      in Lact. plantarum C11. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows
      the usefulness of regulated bacteriocin promoters for developing new gene
      expression systems for lactic acid bacteria, in particular lactobacilli.

PMID- 15012822
TI  - Functional significance of a periplasmic Mn-superoxide dismutase from Aeromonas
      hydrophila.
AB  - AIMS: A better understanding of the role of superoxide dismutases (SODs) from
      Aeromonas hydrophila and particularly the Mn-SOD which shares a peculiar
      localization within the bacterial periplasm and is only detected during the
      stationary phase of growth. METHODS AND RESULTS: A. hydrophila ATCC 7966 can
      express two distinct SODs: an Fe-SOD and an Mn-SOD. Using insertional
      mutagenesis, an Mn-SOD-deficient mutant was isolated. After growth of this mutant
      under conditions leading to the expression of an Mn-SOD, only the Fe-SOD could be
      detected in nondenaturing PAGE. Study of its response to the oxidative stress
      showed that the Mn-SOD was not implicated in the protection against intracellular
      superoxide but defended the bacterial cells against environmental superoxide.
      CONCLUSIONS: By protecting the bacteria against external superoxide, the role of
      the Mn-SOD from A. hydrophila is equivalent to that of the Cu/Zn-SOD from the
      well-studied Escherichia coli. SIGNIFICANCE AND IMPACT OF THE STUDY: The function
      of this Mn-SOD is in agreement with its periplasmic localization and may confer
      an advantage on the bacteria such as a virulence factor in cases of
      pathogenicity.

PMID- 15012823
TI  - Diversities and similarities in PFGE profiles of Campylobacter jejuni isolated
      from migrating birds and humans.
AB  - AIMS: To genetically sub-type Campylobacter jejuni strains isolated from
      migratory birds, and to compare these with clinical strains collected in the same
      area and corresponding time period, with the aim to increase our knowledge on sub
      types occurring among wild birds and their possible impact on human disease.
      METHODS AND RESULTS: We sub-typed C. jejuni strains from migrating birds (n = 89)
      and humans (n = 47), using macrorestriction profiling by pulsed-field gel
      electrophoresis. Isolates from migrant birds often exhibited sub-types with
      higher levels of similarity to isolates from birds of the same species or feeding
      guild, than to isolates from other groups of birds. Likewise, could the vast
      majority of sub-types found among the migrant bird isolates not be identified
      among sub-types from human cases. Only two bird strains, one from a starling
      (Sturnus vulgaris) and one from a blackbird (Turdus merula), had sub-types that
      were similar to some of the human strain sub-types. CONCLUSIONS: Isolates from
      one bird species, or feeding guild, often exhibited high similarities, indicating
      a common transmission source for individuals, or an association between certain
      sub-types of C. jejuni and certain ecological guilds or phylogenetic groups of
      birds. Sub-types occurring among wild birds were in general distinctively
      different from those observed in patients. The two bird isolates that were
      similar to human strains were isolated from bird species that often live in close
      associations with human settlements. SIGNIFICANCE AND IMPACT OF STUDY: Wild birds
      have often been mentioned as a potential route for transmission of C. jejuni to
      humans. Our study demonstrates that strains isolated from birds most often are
      different from clinical strains, but that some strain similarities occur, notably
      in birds strongly associated with human activities.

PMID- 15012824
TI  - Degradation of 2,4,6-tribromophenol by bacterial cells attached to chalk
      collected from a contaminated aquifer.
AB  - AIM: To investigate the factors governing the adhesion and activity of the 2,4,6
      tribromophenol (TBP) degrading bacterium Achromobacter piechaudii TBPZ-N61 on
      chalk from a contaminated aquifer. METHODS AND RESULTS: Adhesion kinetics of TBPZ
      N61 to grey and white chalk from a polluted fractured chalk aquifer was tested in
      a batch system. Both grey and white chalk contain ca 80% CaCO3, while grey chalk
      contains more organic matter (2.4%) than the white chalk (0.3%) and also contains
      Dolmite and Clinoptilolite. Adhesion of the bacterial cells to the chalk
      particles (<0.2 mm) occurred rapidly (96% of the cells within 15 min). Langmuir
      fitted adhesion isotherms suggest that cells in the stationary phase, which are
      more hydrophobic, adhere to both grey and white chalk more efficiently than cells
      in the logarithmic growth phase. Increasing the pH (from 6.7 to 8.1) caused a
      significant reduction in cell adhesion to the chalk. Activity of attached cells
      was evaluated in both batch and column experiments. Logarithmic cells adhering to
      white and grey chalk were more active in TBP degradation than cells in
      suspension. In column experiments, significant TBP degradation was retained up to
      30 days after a single injection of TBPZ cells. Thereafter, activity was fully
      recovered by amendment of yeast extract. Chalk surfaces that were incubated in
      situ in contaminated groundwater for 20 days still allowed the adhesion and
      activity of TBPZ cells. CONCLUSIONS: Taken together, our results show that
      bacteria adhere efficiently to specific sites on the chalk surfaces, and that
      sustained bacterial activity of the attached cells can be achieved by adding a
      carbon source such as yeast extract which also overcome toxic constituents that
      may occur in some chalk types. SIGNIFICANCE AND IMPACT OF THE STUDY:
      Bioremediation of TBP-contaminated chalk aquifers is made possible by the
      injection of bacterial cultures.

PMID- 15012825
TI  - Application of molecular methods for the differentiation of acetic acid bacteria
      in a red wine fermentation.
AB  - AIMS: To apply rapid and reliable molecular techniques for typing acetic acid
      bacteria and studying their population dynamics during wine-making processes.
      METHODS AND RESULTS: We tested the usefulness of the Enterobacterial Repetitive
      Intergenic Consensus-PCR (ERIC-PCR) and Repetitive Extragenic Palindromic-PCR
      (REP-PCR) techniques with reference strains of most of the species of acetic acid
      bacteria. We obtained exclusive patterns for each strain with the ERIC-PCR
      technique, proving the utility for characterizing below species level. REP-PCR
      technique was not as adequate for this purpose because some strains yielded
      identical fingerprint. One hundred twenty isolates from a commercial red wine
      fermentation were fingerprinted using both techniques. We detected a high degree
      of strain diversity in the first stage of fermentation that decreased throughout
      the process. However, several strains and species were dominant in the alcoholic
      fermentation phases. The identification of different strains or genotypes at the
      species level was carried out by restriction analysis of the 16S ribosomal DNA
      gene. Gluconobacter oxydans dominated the fresh must, while Acetobacter aceti was
      the only isolated species at the end of the process. Gluconacetobacter hansenii
      and G. liquefaciens were also isolated in significant numbers at the beginning of
      fermentation. CONCLUSIONS: ERIC-PCR and REP-PCR techniques proved useful for
      characterizing strains of acetic acid bacteria. SIGNIFICANCE AND IMPACT OF THE
      STUDY: The availability of molecular techniques for a fast and reliable genotypic
      characterization should increase our knowledge of the ecology of acetic acid
      bacteria and determine more accurately their growth behaviour during various
      stages of vinification.

PMID- 15012827
TI  - Intraspecific diversity of the marine fish pathogen Tenacibaculum maritimum as
      determined by randomly amplified polymorphic DNA-PCR.
AB  - AIM: The aim of the present study was to evaluate the intraspecific genetic
      variability within Tenacibaculum maritimum strains isolated from different
      species of marine fish. METHODS AND RESULTS: Twenty-nine strains isolated from
      five different fish species and three reference strains were characterized by
      randomly amplified polymorphic DNA (RAPD) method. Cluster analysis of RAPD-PCR
      profiles showed that the strains, regardless of the oligonucleotide primer
      employed (P2 and P6), were separated into two main groups that strongly
      correlated with the host species and/or O-serotypes described for this pathogen.
      One group composed all strains isolated from sole (Solea senegalensis and S.
      solea) and gilthead seabream (Sparus aurata), and the other compiled the T.
      maritimum isolates from yellowtail (Seriola quinqueradiata), Atlantic salmon
      (Salmo salar) and turbot (Scophthalmus maximus). An important exception was
      observed in the RAPD patterns of the reference strains, which were included in
      different genetic groups depending on the primer employed. CONCLUSIONS: The
      results obtained demonstrated genetic variability within the T. maritimum
      isolated from different marine fish. Such genetic variability proved to be
      strongly associated with the host and/or serogroups described for this pathogen.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The RAPD analysis constitutes a valuable
      molecular technique for epidemiological studies of T. maritimum. Interestingly,
      this is the first report of intraspecific differentiation and characterization of
      T. maritimum strains isolated from cultured fish.

PMID- 15012826
TI  - Molecular monitoring and evaluation of the application of the insect-pathogenic
      fungus Beauveria bassiana in southeast China.
AB  - AIMS: To monitor the fate of inundatively applied strains of Beauveria bassiana
      against Masson's pine caterpillar, Dendrolimus punctatus, in Magushan Forest,
      southeast China, and evaluate the potential environmental risks of biocontrol
      introduction. METHODS AND RESULTS: Filed samplings of mycosed cadavers were
      carried out continuously for more than one year after the inundative applications
      of two exotic B. bassiana strains. By employing four complementary molecular
      markers, the purified cultures from collections were characterized and the two
      released strains Bb17 and Bb13 were recovered with respective frequencies of 9.1
      and 5.2%. The released strains were isolated from nontarget hosts. The genetic
      diversity of the population of B. bassiana in the trial plot changed dynamically
      over time and no single genotype strain dominated throughout the sampling period
      or at different seasons. The indigenous strains were observed to be predominant
      in the local environment. Co-infection and/or genetic recombination might occur
      between strains under natural conditions. CONCLUSION: Field applications of the
      biocontrol agent B. bassiana appear to pose no major risk to the environment.
      There was no evidence of displacement of indigenous strains of B. bassiana.
      SIGNIFICANCE AND IMPACT OF THE STUDY: The results indicate that the introduction
      of exotic B. bassiana strains can persist in local environment and infect
      nontarget insect hosts, highlighting the importance of safety assessment of the
      large-scale application of fungal biocontrol agents.

PMID- 15012828
TI  - Molecular and phenotypic characterization of nonmotile Gram-negative bacteria
      associated with spoilage of freshwater fish.
AB  - AIMS: Characterization of nonmotile bacteria associated with freshwater fish
      spoilage and that phenotypically resembled Psychrobacter spp. METHODS AND
      RESULTS: A population of 44 nonmotile Gram-negative rods could not be assigned to
      the genus Psychrobacter on the basis of a definitive test (transformation assay).
      Conventional and commercial phenotypic systems did not help in identification. A
      second extensive phenotypic analysis using different temperatures and media
      confirmed these isolates as nonmotile although electron microscopic examination
      showed that all but two had one to four polar flagella and other appendages. On
      the basis of numerical taxonomy, this population was divided into six clusters,
      one of them consisting of five fluorescent strains. Sequencing of fluorescent and
      non fluorescent representative strains from each cluster demonstrated that
      strains from five clusters had between 97.8 and 98.8% sequence homology with
      Pseudomonas fragi IFO 3458. This and an unknown strain from deep sea were the
      closest organisms (80.9% sequence homology) to one aflagellated representative
      strain of the remaining cluster. CONCLUSIONS: Oxidase-positive, nonmotile,
      nonfermenter Gram-negative rods isolated from freshwater fish can be wrongly
      ascribed to the genus Psychrobacter. SIGNIFICANCE AND IMPACT OF THE STUDY:
      Molecular methods are necessary for the identification of environmental isolates
      and species with an incomplete phenotypic description. This work emphasizes the
      need for a sound description of Ps. fragi based on molecular and phenotypic
      characterization.

PMID- 15012829
TI  - Comparison of 40 Salmonella enterica serovars injured by thermal, high-pressure
      and irradiation stress.
AB  - AIM: To investigate and compare the inherent resistance of 40 Salmonella serovars
      to heat, irradiation and high-pressure stress. METHODS AND RESULTS: D10 values
      for each of the three stresses were calculated for four serovars, chosen as
      representatives from a catalogue of 40. Based on these results, conditions for
      each stress were defined, which produced, on average, a three-log reduction in
      viability. Heat stress (57 degrees C for 13 min), high-pressure stress (350 MPa
      for 10 min at 20 degrees C) and irradiation stress (1.5 kGy at 20 degrees C) were
      applied to all 40 serovars in the collection. Injury and loss of viability for
      all serovars were determined. CONCLUSIONS: Cluster analysis identified five
      groupings of isolates in terms of resistance to the applied stresses. The
      independent response of each isolate to all three stresses suggests that there is
      no relationship between resistances. SIGNIFICANCE AND IMPACT OF THE STUDY: Each
      serovar is inherently different. For modelling of real-life food preservation
      processing the most resistant isolates for that process should be chosen. The
      results also emphasize the importance of including multiple stress resistant
      strains when food preservation systems apply multiple stresses.

PMID- 15012830
TI  - Calibration of the impedance method for rapid quantitative estimation of
      Escherichia coli in live marine bivalve molluscs.
AB  - AIM: Calibration of impedance measurement was performed vs the Association
      Francoise de Normalisation (AFNOR) MPN method with a view to rapid enumeration of
      Escherichia coli in live marine bivalve molluscs. METHODS AND RESULTS: Linear
      regression models between log10 MPN and detection time (DT) were adjusted for
      several shellfish types, growth media, and impedance instruments (BacTrac and
      Malthus systems). Escherichia coli concentrations could be estimated from DT
      using a single regression line for BacTrac 4100 with M1 medium (R2 = 87.8%) and
      Malthus with M2 medium (R2 = 86.7%), and two regression lines for BacTrac 4110
      with M2 medium (R2 = 86.4 and 88.2%). The uncertainty of the predicted bacterial
      concentration was around +/-0.43 log unit for duplicate sample analysis. The
      impedance signal was attributable to E. coli in 99% of cases. All cultures
      containing E. coli produced an impedance signal with BacTrac 4100 and BacTrac
      4110, whereas 5.6% did not exhibit a signal with Malthus. CONCLUSIONS: Impedance
      measurement is a possible alternative to the MPN method for rapid quantitative
      estimation of E. coli in live bivalve shellfish. SIGNIFICANCE AND IMPACT OF THE
      STUDY: The impedance method reduces analysis handling time considerably and is
      much easier to use than the MPN method. Moreover, results can be obtained within
      5-10 h, allowing rapid intervention to ensure public health protection in case of
      shellfish contamination.

PMID- 15012831
TI  - The role of tumor necrosis factor-alpha and interleukin-1 in the mammalian testis
      and their involvement in testicular torsion and autoimmune orchitis.
AB  - This review will focus the roles of TNF-alpha, IL-1 alpha, and IL-1 beta in the
      mammalian testis and in two testicular pathologies, testicular torsion and
      orchitis. TNF alpha in the testis is produced by round spermatids, pachytene
      spermatocytes, and testicular macrophages. The type 1 TNF receptor has been found
      on Sertoli and Leydig cells and numerous studies suggest a paracrine mode of
      action for TNF alpha in the normal testis. IL-1 alpha has been reported to be
      produced by Sertoli cells, testicular macrophages, and possibly postmeiotic germ
      cells. IL-1 receptors have been reported on Sertoli cells, Leydig cells,
      testicular macrophages, and germ cells suggesting both autocrine and paracrine
      functions. While these proinflammatory cytokines have important roles in normal
      testicular homeostasis, an elevation of their expression can lead to testicular
      dysfunctions. Testicular torsion is a clinical pathology with results in
      testicular ischemia and surgical intervention is often required for reperfusion.
      A pivotal role for IL-1beta in the pathology of testicular torsion has been
      recently described whereby an increase in IL-1beta production after reperfusion
      of the testis is correlated with the activation of the stress-related kinase, c
      jun N-terminal kinase, and ultimately resulting in neutrophil recruitment to the
      testis and germ cell apoptosis. In autoimmune orchitis, on the other hand, TNF
      alpha produced by T-lymphocytes and macrophages of the testis has been implicated
      in the development and progression of the disease. Thus, both proinflammatory
      cytokines, TNF alpha and IL-1, have significant roles in normal testicular
      functions as well as in certain testicular pathologies.

PMID- 15012835
TI  - Longitudinal outcomes of very low birth weight: neuropsychological findings.
AB  - To investigate the effects of very low birth weight (VLBW, &1500 g) on the
      development of neuropsychological skills, we assessed 67 children with birth
      weight <750 g, 64 with birth weight 750-1499 g, and 67 term-born controls. Growth
      modeling of raw scores from mean ages 7-14 years revealed persistent VLBW
      sequelae. Even when adjusting for IQ, the <750 g group scored more poorly than
      the term-born group on measures of language processing, verbal list learning, and
      perceptual-motor and organizational abilities. This group also made slower age
      related progress than the control group on tests of perceptual-motor and
      executive functions. Environmental factors moderated group differences in change
      on other cognitive measures. These results revealed further evidence for slower
      skill development in both VLBW groups relative to controls, as well as"catch-up"
      growth in the 750-1499 g group on some measures. The findings suggest age-related
      changes in the cognitive sequelae of VLBW that depend on the skill assessed, the
      degree of VLBW, and environmental factors.

PMID- 15012836
TI  - The verbal fluency task in the Greek population: normative data, and clustering
      and switching strategies.
AB  - We assessed 300 healthy adults in Greece on measures of semantic and phonemic
      verbal fluency in order to develop norms for the Greek population. We also
      evaluated the strategies that the participants used spontaneously in order to
      maximize word production, namely clustering and switching techniques. Our tasks
      comprised three semantic and three phonemic categories. Consistent with previous
      investigations of English-speaking samples, we found a contribution of
      demographic variables to word fluency. Specifically, level of education
      contributed to total word production, number of switches, and number of
      repetitive responses on both semantic and phonemic tasks, and the average cluster
      size only on the phonemic task. Age contributed to total word production and
      cluster size on the semantic task, and to number of switches on both semantic and
      phonemic tasks. Sex contributed only to total word production on the semantic
      task. In our sample, clustering and switching strategies were related to total
      word production on both tasks, suggesting that these strategies were used
      effectively. We present tables of normative data stratified by age and level of
      education. We have also included detailed guidelines for scoring clusters
      relevant to the Greek population.

PMID- 15012837
TI  - WMS-III performance in epilepsy patients following temporal lobectomy.
AB  - We examined performances on the Wechsler Memory Scale-3rd Edition (WMS-III) among
      patients who underwent temporal lobectomy for the control of medically
      intractable epilepsy. There were 51 right (RTL) and 56 left (LTL) temporal
      lobectomy patients. All patients were left hemisphere speech-dominant. The LTL
      and RTL patients were comparable in terms of general demographic, epilepsy, and
      intellectual/attention factors. Multivariate analyses revealed a significant
      crossover interaction (p <.001), with the RTL group scoring significantly lower
      on the visual than auditory indexes while the LTL group scored significantly
      lower on the auditory than visual memory indexes. Within-group pairwise analyses
      revealed statistically significant auditory versus visual index score comparisons
      (all p <.001) for both surgical groups. Discriminant analysis (p <.001)
      identified Verbal Paired Associates I, Faces I, and Family Pictures II to
      significantly discriminate RTL and LTL patients, with an overall correct
      classification rate of 81.3%. Our findings suggest that the WMS-III is sensitive
      to modality-specific memory performance associated with unilateral temporal
      lobectomy.

PMID- 15012838
TI  - Attentional functioning and white matter integrity among survivors of malignant
      brain tumors of childhood.
AB  - Children surviving treatment for malignant brain tumors commonly have problems
      maintaining their premorbid levels of intellectual development and academic
      achievement. Our group has been especially interested in the effects of treatment
      on normal appearing white matter (NAWM) on MRI and the influence of NAWM volumes
      on neurocognitive functioning. The present study assessed NAWM and attentional
      abilities among 37 long-term survivors of malignant brain tumors, ranging in age
      from 1.7 to 14.8 (Mdn = 6.5) years at diagnosis, who had been treated with
      cranial radiation therapy with or without chemotherapy 2.6 to 15.3 (Mdn = 5.7)
      years earlier. On the Conners' Continuous Performance Test, the Overall Index and
      7 of the other 10 indices were significantly deficient compared to age- and
      gender-corrected normative values. After statistically controlling for the
      effects of age at diagnosis and time elapsed from treatment, 5 of the 8 indices
      were significantly associated with cerebral white matter volumes and/or specific
      regional white matter volumes of the prefrontal/frontal lobe and cingulate gyrus.
      No gender effects were observed. The results of the present study further support
      the contention that NAWM is an important substrate for treatment-induced
      neurocognitive problems among survivors of malignant brain tumors of childhood.

PMID- 15012833
TI  - Sperm specific proteins-potential candidate molecules for fertility control.
AB  - The increase in population growth rate warrants the development of additional
      contraceptive methods that are widely acceptable, free from side effects and less
      expensive. Immunocontraception, and in particular the targeting of antibodies to
      gamete-specific antigens implicated in sperm egg binding and fertilization,
      offers an attractive approach to control fertility. The development of a
      contraceptive vaccine based on sperm antigen represents a promising approach to
      contraception. In mammals, fertilization is completed by the direct interaction
      of sperm and egg, a process mediated primarily by sperm surface proteins. Sperm
      have proteins that are unique, cell specific, immunogenic and accessible to
      antibodies. A few of the sperm specific proteins have been isolated and
      characterized. The antibodies raised against the sperm specific antigens have
      proved to be extremely effective at reducing sperm-egg interaction in vitro;
      fertility trials in sub-human primates would eventually prove the effectiveness
      of the sperm antigens in terms of contraceptive efficacy.

PMID- 15012839
TI  - Awareness of activity limitations and prediction of performance in patients with
      brain injuries and orthopedic disorders.
AB  - The aim of this study was to compare the accuracy of performance predictions in
      experimental tasks with patients' awareness of activity limitations. Participants
      were 24 patients with brain injuries (i.e., traumatic brain injury and
      cerebrovascular disorders) and 22 patients with orthopedic disorders. Prediction
      of performance was examined in a memory task (word list learning) and a motor
      task (finger tapping). Awareness of activity limitations was measured by
      comparing patients' self-ratings and staff ratings in the Patient Competency
      Rating Scale (PCRS). Results for the PCRS showed that patients with orthopedic
      disorders underestimated and patients with brain injuries (i.e., patients with
      TBI) overestimated their level of functioning in the total scale and the
      social/emotional subscale in comparison to staff ratings. Both patient groups
      agreed with staff ratings in physical/basic self-care items. In the predicted
      performance tasks a similar pattern could be observed: None of the groups showed
      an overestimation of performance in the motor task, whereas patients with brain
      injuries overestimated their competency in the memory task. However, the
      agreement between both awareness measures (PCRS, predicted performance) was only
      low, which indicates that they might measure different aspects or levels of self
      awareness.

PMID- 15012841
TI  - Visual attention in long-term survivors of leukemia receiving cranial radiation
      therapy.
AB  - The effect of cranial radiation therapy (CRT) on visual attention was examined in
      long-term survivors of childhood acute lymphoblastic leukemia (ALL) compared to
      peers with no history of ALL (n = 24) using a cued orienting task and a global
      local task. ALL participants treated with CRT (n = 13) demonstrated an increased
      cost in response time with invalid spatial orienting cues and inefficient shifts
      of attention across hierarchical levels. ALL participants treated only with
      chemotherapy (n = 8) showed performance similar to the non-ALL comparison group.
      Participants with exposure to CRT early in life appeared to largely account for
      the attention deficits, and showed particular difficulties with shifting
      attention from the local level of stimuli to the global level. The data are
      consistent with prior reports emphasizing attention deficits following CRT, and
      suggest that attention shifting may be particularly affected by CRT early in
      life.

PMID- 15012840
TI  - Functional and anatomical memory indices in patients with or at risk for
      Alzheimer's disease.
AB  - We investigated the sensitivity of the P300 event-related brain potential (ERP)
      recorded during a memory-demanding task to memory function in subjects with
      dementia of the Alzheimer's type (DAT), those with mild cognitive impairment
      (MCI), and normal elderly controls. We also explored the ability of
      neuropsychological (delayed verbal memory), neuroanatomical (MRI-based
      hippocampal volume), and electrophysiological (memory search P300 amplitude)
      memory measures to distinguish between the three subject groups using
      discriminant function analyses. Fourteen patients with DAT, 16 with MCI, and 15
      age- and education-matched controls were tested. P300 amplitude was reduced in
      DAT subjects at all levels of memory load; however, it did not differ between MCI
      and control subjects. Delayed verbal memory performance best discriminated DAT
      from MCI and control subjects, while delayed verbal memory and hippocampal volume
      best discriminated MCI subjects from controls. These results support the utility
      of neuropsychological and neuroanatomical measures in diagnosing dementia and do
      not support the notion that P300 amplitude is sensitive to mild memory
      dysfunction when measured using the current task.

PMID- 15012843
TI  - The sensitivity of dual-task performance to cognitive status in aging.
AB  - The present study examined dual-task performance in elders with cognitive
      impairments and normal controls. The participants (N = 60; M age = 84.6) were
      recruited from residential facilities and the community. They were assigned to
      one of three groups: (1) cognitive impairment; (2) residential facility control;
      (3) community control. Two different dual-task conditions were comprised of
      simple tests that are presumably processed via separate perceptual modalities: 1
      visual-manual and 1 auditory-verbal. The first condition consisted of a visual
      cancellation test and an auditory digit span. The second condition was comprised
      of an alternate form of the visual cancellation test and letter fluency. MANOVA
      examined the effect of cognitive status (3-level independent variable) on 3
      indices of dual-task performance (letter fluency, digit span, visual
      cancellation). Analyses controlled for age, education and performance on each
      test when performed alone. The results revealed that the cognitive impairment
      group incurred significantly greater dual-task costs compared to both control
      groups. Furthermore, as was evident from discriminant function analyses, the dual
      task measures were very accurate and better than the traditional
      neuropsychological measures at discriminating elders with cognitive impairments
      from normal controls. (JINS, 2004, 10, 230-238.)

PMID- 15012842
TI  - Retrograde amnesia in patients with rupture and surgical repair of anterior
      communicating artery aneurysms.
AB  - The retrograde amnesia of patients with memory loss related to rupture and
      surgical repair of anterior communicating artery (ACoA) aneurysms is compared
      with the retrograde amnesia of temporal amnesic patients and nonamnesic control
      participants. Two tests which focus on popular culture but which differ according
      to extent of news exposure and the cognitive processes necessary for task
      performance were used to measure retrograde memory. ACoA patients demonstrated
      more significant retrograde memory problems than did nonamnesic controls;
      however, the severity and pattern of their memory loss was less severe than that
      seen in association with temporal amnesia. Different factors influenced the
      remote memory loss of respective groups: ACoA patients' problems were related to
      impaired lexical retrieval whereas temporal amnesic patients had problems
      secondary to both retrieval and storage deficits.

PMID- 15012844
TI  - Reduced autonomic responsiveness to gambling task losses in Huntington's disease.
AB  - We examined the possible role of autonomic activity in Huntington's disease (HD)
      during a risky decision making task. Skin conductance responses (SCRs) of 15 HD
      participants and 16 healthy controls were measured while they performed a
      computerized version of the Simulated Gambling Task (SGT). The results replicated
      our previous finding of a performance decrement in HD, and showed that HD was
      associated with an altered pattern of SCRs during the risky decision task.
      Specifically, the healthy controls produced increased SCRs following selections
      from the disadvantageous decks and following losing selections. In contrast, the
      SCRs of the HD group did not differentiate between wins and losses. These
      findings indicate a reduced impact of loss on decision-making processes under
      risky conditions in HD.

PMID- 15012845
TI  - Assessing cognitive outcomes in a rural African population: development of a
      neuropsychological battery in Kilifi District, Kenya.
AB  - The ability to measure neuropsychological outcomes in a comparable manner in
      different cultural groups is important if studies conducted in geographically
      diverse regions are to advance knowledge of disease effects and moderating
      influences. The purpose of this study was to evaluate the application of
      neuropsychological test procedures developed for use in North America and Europe
      to children in a rural region of Kenya. Our specific aim was to determine if
      these methods could be adapted to a non-Western culture in a manner that would
      preserve test reliability and validity. Procedural modifications yielded reliable
      tests that were sensitive to both the sequelae of cerebral malaria and to
      children's social and school backgrounds. Results suggest that adaptations of
      existing tests can be made in such a way as to preserve their utility in
      measuring the cross-cultural sequelae of childhood neurological diseases.

PMID- 15012848
TI  - Neuropsychological deficits in patients with chronic fatigue syndrome.
AB  - The degree of neuropsychological dysfunction across multiple domains was examined
      in individuals suffering from chronic fatigue syndrome (CFS). In this descriptive
      study, a similar series of neuropsychological tests was administered to a group
      of CFS patients and healthy participants. More specifically, CFS patients (n =
      141) who met the 1994 Case Definition criteria were compared to 76 healthy
      control participants on tests of memory, attention (concentration), speed of
      information processing, motor speed, and executive functioning. On the 18
      measures administered, CFS patients scored 1 standard deviation below the healthy
      mean on nine measures and scored 2 standard deviations below the healthy mean on
      four of the measures. Moreover, results indicated that CFS patients were more
      likely than healthy controls to fail (1.6 SD below the healthy mean) at least one
      test in each of the following domains: attention, speed of information
      processing, and motor speed, but not on measures of memory and executive
      functioning. Finally, CFS patients demonstrated a greater total number of tests
      failed across domains.

PMID- 15012846
TI  - Early exposure to lead and neuropsychological outcome in adolescence.
AB  - One hundred and ninety-five participants in the Cincinnati Lead Study were
      neuropsychologically evaluated in mid-adolescence. The neuropsychological
      measures yielded five factors labeled Memory, Learning/IQ, Attention,
      Visuoconstruction, and Fine-Motor. Prenatal, Average Childhood, and 78 month
      blood lead (PbB) levels were used in a series of multiple regression analyses.
      Following rigorous covariate pretesting and adjustment, a significant main effect
      of 78 month PbB on the Fine-Motor factor was found (p <.004). Significant
      interactions were also found between gender and lead exposure parameters for both
      Attention and Visuoconstruction indicating heightened risk in males. Finally, a
      trend toward significance was found for the PbB x SES interaction for
      Learning/IQ, consistent with previous evidence of increased educational and
      cognitive vulnerability for youth from more disadvantaged backgrounds. These
      results provide new evidence from the longest continuing prospective study of the
      remote effects of early lead exposure. They indicate the presence of selective
      neuropsychological effects in this population, and also that males and females
      are not uniformly affected. These results also underscore the complexity of
      models of neurobehavioral development, and the modest predictive power of any
      single determinant.

PMID- 15012847
TI  - Classifying children with heavy prenatal alcohol exposure using measures of
      attention.
AB  - Deficits in attention are a hallmark of the effects of heavy prenatal alcohol
      exposure but although such deficits have been described in the literature, no
      attempt to use measures of attention to classify children with such exposure has
      been described. Thus, the current study attempted to classify children with heavy
      prenatal alcohol exposure (ALC) and non-exposed controls (CON), using four
      measures of attentional functioning: the Freedom from Distractibility index from
      the Wechsler Intelligence Scale for Children-Third Edition (WISC-III), the
      Attention Problems scale from the Child Behavior Checklist (CBCL), and omission
      and commission error scores from the Test of Variables of Attention (TOVA). Data
      from two groups of children were analyzed: children with heavy prenatal alcohol
      exposure and non-exposed controls. Children in the alcohol-exposed group included
      both children with or without fetal alcohol syndrome. Groups were matched on age,
      sex, ethnicity, and social class. Data were analyzed using backward logistic
      regression. The final model included the Freedom from Distractibility index from
      the WISC-III and the Attention Problems scale from the CBCL. The TOVA variables
      were not retained in the final model. Classification accuracy was 91.7% overall.
      Specifically, 93.3% of the alcohol-exposed children and 90% of the control
      children were accurately classified. These data indicate that children with heavy
      prenatal alcohol exposure can be distinguished from non-exposed controls with a
      high degree of accuracy using 2 commonly used measures of attention.

PMID- 15012849
TI  - Neuropsychological and information processing deficits following mild traumatic
      brain injury.
AB  - Neuroradiological and neuropathological investigations have found evidence of
      diffuse brain damage in the frontal and temporal lobes, corpus callosum, and
      fornices in patients who have sustained a mild traumatic brain injury (TBI).
      However, neuropsychological assessments of these patients do not typically target
      many of the subtle information processing deficits that may arise from diffuse
      damage involving the frontotemporal regions of the brain as well as white matter
      pathology, including the corpus callosum. Consequently, we have a limited
      understanding of the deficits that may be attributable to temporary or permanent
      disruptions to these functional pathways. This study assessed a group of mild TBI
      patients (N = 40) and a matched control group (N = 40) on a number of standard
      neuropsychological tests of selective and sustained attention, verbal and non
      verbal fluency, and verbal memory. In addition, reaction time (RT) tasks,
      requiring both the inter- and intra-hemispheric processing of visual and tactile
      information, were used to assess the functional integrity of the tracts that are
      likely to be affected by diffuse damage. In the 1st month after sustaining their
      injury, the mild TBI group demonstrated deficits in attention, non-verbal
      fluency, and verbal memory. They also demonstrated slower visual and tactile RTs,
      with the visual RTs of mild TBI patients being more affected by increased task
      difficulty and the need to transfer information across the corpus callosum, than
      did their matched controls.

PMID- 15012850
TI  - Stroop performance in drug users classified by HIV and hepatitis C virus
      serostatus.

PMID- 15012855
TI  - Nomenclature nightmare.

PMID- 15012851
TI  - Reliability and validity of the Delis-Kaplan Executive Function System: an
      update.

PMID- 15012856
TI  - Knowledge and truth: answers or questions?

PMID- 15012857
TI  - Spider Bites Presenting with Methicillin-Resistant Staphylococcus aureus Soft
      Tissue Infection Require Early Aggressive Treatment.
AB  - BACKGROUND: Occasionally, spider bites result in necrotizing soft tissue
      infections that require aggressive surgical debridement and treatment with
      intravenous antibiotics. With the rise of microbial resistance in the community,
      management with standard gram-positive intravenous antibiotic coverage may be
      ineffective. Our objective was to determine the infectious organisms cultured
      following wide local excision of soft tissue infections caused by spider bites.
      We hypothesized that the majority of isolated organisms would be sensitive to
      penicillin based antibiotics. METHODS: From March 2000 to November 2001, the
      medical records were reviewed of patients who presented to a tertiary care
      hospital with serious soft tissue infections secondary to spider bites that
      required surgical treatment. For each patient, demographics, symptoms, size, time
      to surgical evaluation (TTSE), temperature, white blood cell (WBC) count,
      surgical procedure, and culture data were collected. Data are presented as mean
      +/- SEM. RESULTS: Thirty-eight patients presented with serious soft tissue
      infections secondary to spider bites that required surgical debridement and
      treatment with intravenous antibiotics. Twenty-nine percent (11 of 38) of these
      patients had failed initial outpatient therapy with penicillin-based oral
      antibiotics. The mean TTSE was 5.0 +/- 0.5 days (range = 2-14 days; median = 4.5
      days). The most common presenting symptoms were pain and erythema surrounding the
      bite site. The mean temperature was 98.8 +/- 0.6 degrees F (range = 97.2-102.2
      degrees F; median = 99.2 degrees F). The mean WBC count was 12.6 +/- 0.8 mm3. All
      patients required wide surgical debridement of the infected area. The mean size
      of the excised tissue was 26 +/- 4 cm2 (range = 4-120 cm2; median = 16 cm2).
      Every patient had cultures that grew Staphylococcus aureus. In 86.8% of patients,
      S. aureus was found to be methicillin-resistant (MRSA). All isolated organisms
      were sensitive to trimethoprim-sulfamethoxazole. CONCLUSIONS: In our experience,
      patients who presented with soft tissue infections as result of spider bites
      predominantly had methicillin-resistant S. aureus infections, corresponding to
      the increased incidence of MRSA reported in the community. Therefore, a more
      aggressive approach to the management of spider bites presenting with severe
      cellulitis is warranted. Routine treatment should include aggressive surgical
      debridement, intraoperative wound cultures, the empiric use of antibiotics with
      activity against MRSA, and adjustment of antimicrobial therapy based on culture
      and sensitivity data.

PMID- 15012858
TI  - Vaccinia virus complement control protein increases early bacterial clearance
      during experimental peritonitis.
AB  - BACKGROUND: Complement is one of the first immunological pathways activated in
      peritonitis. It functions to initiate and augment the innate immune response.
      Complement activation has also been shown to contribute to multiple organ failure
      after sepsis. Vaccinia virus complement control protein (VCP) is an
      immunomodulatory protein encoded by vaccinia virus and binds complement
      components C3b and C4b of the complement cascade to inhibit both the classical
      and alternative pathways of complement activation. This study investigates the
      effect of complement inhibition by recombinant (r) VCP on bacterial clearance
      after cecal ligation and puncture (CLP). METHODS: Swiss Webster mice were
      intravenously given either 20 mg/kg rVCP in 0.2 mL of normal saline, or 0.2 mL of
      normal saline alone, at the time of CLP. After 4 and 18 h, samples of peritoneal
      washout, blood, liver, and lung were collected for bacteriology, myeloperoxidase
      (MPO) assay for neutrophil accumulation, differential cell counts, and
      interleukin (IL)12 ELISA. Statistical analysis was by Mann-Whitney U test for
      bacteriology, and analysis of variance (ANOVA) for MPO and IL-12 concentrations.
      RESULTS: Aerobic and anaerobic bacterial levels were significantly lower at 4 h
      after treatment with rVCP (p < 0.05) in peritoneal lavage, blood, and liver
      compared with controls. There were no differences in bacterial levels at 18 h.
      There were no differences in myeloperoxidase concentrations or in the
      differential cell counts between the groups at either 4 or 18 h after CLP. IL-12
      concentrations in serum or peritoneal washout were also not different.
      CONCLUSIONS: rVCP enhances early bacterial clearance in mice after CLP, although
      not through neutrophil recruitment, as MPO concentrations and cell counts were
      not different. rVCP may, however, increase neutrophil function potentially by
      prevention of accumulation of complement factors that inhibit leukocytes. Further
      studies will be needed to elucidate this pathway.

PMID- 15012859
TI  - Monotherapy versus multi-drug therapy for the treatment of perforated
      appendicitis in children.
AB  - BACKGROUND: Children with perforated appendicitis often have a prolonged hospital
      course complicated by surgical site or intra-abdominal infections. Treatment with
      multiple intravenous (IV) antibiotics after appendectomy has been the standard of
      care for these patients. We have recently adopted a protocol using piperacillin
      tazobactam (PT) as a single agent in lieu of the standard multi-drug regimen
      (MD). We hypothesized that PT would be as effective as MD in reducing
      postoperative complications and would result in decreased resource utilization.
      METHODS: We reviewed the medical records of all children admitted to our hospital
      between January 1, 1998 and December 31, 2001 with the diagnosis of perforated
      appendicitis. Patients who underwent operation within the first 24 h of admission
      were divided into two groups based on their antibiotic regimen: PT versus MD.
      Demographic data, duration of presenting symptoms, initial WBC, length of stay,
      and infectious complications were abstracted. Categorical data were compared
      using Chi square analysis; continuous variables were compared using Student's t
      test when the data were normally distributed and the Mann-Whitney U test when the
      data were skewed. RESULTS: There was no difference between the PT (n = 51) and MD
      (n = 43) groups with respect to age, duration of presenting symptoms, initial
      WBC, or length of hospital stay. However, patients in the MD group had a
      significantly higher overall complication rate than those in the PT group (14/43
      vs. 4/51, p = 0.002). Antibiotic-related complications including surgical site
      infections, venous catheter-related infections, intra-abdominal abscesses, and
      drug reactions were also higher in the MD group (10/43 vs. 4/51, p = 0.04). The
      outpatient charges for each patient based on an average of seven days of home
      antibiotics were $2,460 for the PT group and $4,349 for the MD group.
      CONCLUSIONS: Children with perforated appendicitis can be managed effectively
      with a single broad-spectrum antibiotic after appendectomy. Monotherapy is not
      only more efficacious than multi-drug therapy, but may be more cost effective.
      The use of monotherapy for children with perforated appendicitis after adequate
      source control should be considered the treatment of choice.

PMID- 15012860
TI  - Does prior transfusion worsen outcomes from infection in surgical patients?
AB  - BACKGROUND: Controversy continues to exist regarding the immunomodulatory effects
      of cellular blood transfusions in the fields of oncology, transplantation, and
      infectious diseases. Numerous studies have correlated transfusion with hospital
      acquired infection, but the impact of transfusion on infection-related mortality
      has not been addressed. The objective of this study was to determine the effect
      of transfusion on outcomes among infected surgical patients. METHODS: Data on all
      hospital-acquired infectious episodes among surgical intensive care unit and ward
      patients were collected prospectively over 39 months at a single university
      hospital. The relationships between prior transfusion (defined as the receipt of
      allogeneic red blood cells or platelets during the index hospitalization but
      prior to the development of infection) and over 100 variables were examined using
      univariate and multiple logistic regression analysis, with inclusion of a
      propensity score for prior transfusion to attempt to account for treatment
      selection bias. RESULTS: During the study period, 1,228 infectious episodes
      occurred; 641 were associated with the transfusion of packed red blood cells or
      platelets. Univariate analysis revealed that patients with those infectious
      episodes following transfusion had higher Acute Physiology and Chronic Health
      Evaluation II (APACHE II) scores (18.3 +/- 0.3 vs. 10.9 +/- 0.3, p < 0.0001) and
      higher mortality (26.0% vs. 8.9%, p < 0.0001). Those patients who died received a
      greater number of transfusions prior to infection than those who lived (7.7 +/-
      0.8 vs. 4.5 +/- 0.3, p = 0.0002). Multiple logistic regression analysis revealed
      that the propensity score for prior transfusion independently predicted mortality
      (odds ratio 9.45, 95% confidence interval 3.71-24.09, p < 0.001), but that
      neither the presence or absence of transfusion (OR 0.89, 95% CI 0.54-1.46, p =
      0.6) nor the absolute number of units of red blood cells or platelets transfused
      (OR for red blood cells 1.00, 95% CI 0.98-1.02, p = 0.7; OR for platelets 0.97,
      95% CI 0.90-1.05, p = 0.5) independently predicted mortality. CONCLUSIONS: The
      transfusion of packed red blood cells or platelets prior to infection is
      associated with more severe disease among surgical patients, but once corrected
      for treatment selection bias does not appear to worsen outcomes from infection.

PMID- 15012861
TI  - Candidemia: the impact of antifungal prophylaxis in a surgical intensive care
      unit.
AB  - BACKGROUND: Candidemia is fourfold more common in 1990 compared to 1980. In
      addition, a shift to non-albicans species has occurred in some institutions.
      Antifungal prophylaxis (AP) is effective in high-risk patients including
      critically ill surgical patients, but its use has been attributed to a resultant
      shift to non-albicans candida species. We hypothesized that the use of
      fluconazole prophylaxis would lead to a decreased incidence of candidemia but a
      possible increased incidence of resistant species of Candida, especially Candida
      glabrata (CG). METHODS: From 1990 to 2002, all patients with candidemia (C) in
      the surgical intensive care unit (SICU) of a large tertiary care hospital were
      identified and reviewed retrospectively. Antifungal prophylaxis began in 2000 for
      high-risk patients. The periods were separated into PRE (1990-2000), and POST
      prophylaxis (2000-2002). RESULTS: Excluding the year of the trial studying
      prophylaxis, (1998; five cases of C) a total of 83 patients developed candidemia:
      69 PRE (83%) (1.94/1000 patient days) and 14 POST (17%) (0.76/1000 patient days)
      (OR 0.44; 95% CI 0.25, 0.78; p = 0.004). In the PRE period C. albicans (45%) and
      CG (30%) were predominant, whereas in the POST period, CG (9/14, 64%) (p = 0.05),
      and C. albicans (3/14, 21%) were common. Non-albicans species were 38/69 (55%)
      PRE and 11/14 (79%) POST, p = 0.14. Mortality in the group was 43/83 (52%) and
      did not differ PRE/POST or based on treatment. Predictors of SICU mortality
      (model r2 = 0.61) included hospital length of stay (LOS) (OR 1.14, CI 1.04,
      1.25), fever (OR 51.2, CI 2.46, 1064), and broad-spectrum antibiotics (OR 69.7,
      CI 2.08, 2351), whereas post-transplantation status (OR 0.005, CI 0.00, 0.56),
      blood sugar <180 mg/dL (OR 0.03, CI 0.01, 0.81), and fungal prophylaxis (OR 0.03,
      CI 0.01, 0.58) were associated with a decreased risk of mortality. CONCLUSIONS:
      Unfortunately, the mortality of candidemia remains high in SICU patients (52%).
      In the SICU, risk factors for candidemia and mortality are common. However,
      antifungal prophylaxis has significantly decreased the annual incidence of
      candidemia without a statistically significant shift to non-albicans pathogens.

PMID- 15012862
TI  - Risk factors for severe sepsis in secondary peritonitis.
AB  - BACKGROUND: The incidence and risk factors for severe sepsis (SS, organ failure
      associated with infection) in the context of peritonitis are not well
      established; thus, it is not clear which patients require more aggressive
      operative or pharmacologic intervention. We set out to determine risk factors for
      severe sepsis in a large cohort of patients with intra-abdominal infection.
      METHODS: Patients admitted for peritonitis over a four-year interval were
      identified using a Washington State administrative hospital discharge database.
      This cohort was identified by ICD-9 CM diagnoses and diagnosis-related group
      (DRG) assignment. Patients with organ failure were identified by ICD-9 CM
      diagnoses codes using a previously validated classification scheme. Independent
      risk factors for SS were identified using stepwise Poisson regression. RESULTS: A
      total of 11,202 patients with peritonitis were identified, 11% of whom developed
      SS. The crude relative risk of death in patients with SS was 13 (95% CI, 11.1
      15.2) times greater than those without. Severe sepsis was present in 424 (62%) of
      the 686 decedents. Multivariate analysis showed that source of infection, extent
      of peritonitis, increasing age, and pre-existing organ dysfunction were
      independently associated with SS. CONCLUSIONS: Severe sepsis complicates the
      course of 11% of all patients with peritonitis. Risk factor analysis identifies a
      subset of patients at greatest risk for severe sepsis. These are the patients who
      should be targeted for evaluation of novel pharmacologic interventions or more
      aggressive surgical intervention.

PMID- 15012864
TI  - Reclassification of urinary tract infections in critically ill trauma patients: a
      time-dependent analysis.
AB  - BACKGROUND: Successful treatment of urinary tract infections (UTIs) in the trauma
      ICU requires early recognition and timely, appropriate antibiotic therapy. We
      evaluated the incidence and microbiology of UTIs stratified by days post
      admission and risk factors. METHODS: Prospective data were collected on 1,172
      trauma patients admitted to the ICU over a two-year period. Infections were
      classified as Community Acquired (CA, < or = 3 days), Early Nosocomial (EN, 4-6
      days), Mid-Nosocomial (MN, 7-10 days) and Late Nosocomial (LN > 10 days).
      Criteria of the U.S. Centers for Disease Control and Prevention (CDC) were used
      for diagnosis. RESULTS: Two hundred twenty patients (19%) were diagnosed with a
      total of 235 UTIs. Thirtysix patients were diagnosed with multiple UTIs.
      Escherichia coli, Enterococcus sp. and Candida sp. were the most common pathogens
      isolated. One thousand one hundred fifty-one patients had a Foley catheter placed
      (mean duration, 1 +/- 11 days) with a CDC device-related infection rate (no. of
      catheter-associated UTIs/1000 catheter days) of 18. Patients admitted with a CA
      infection were significantly older (p < 0.001) and had a higher mortality rate
      (39% vs. 15%, p = 0.001). Unanticipated pathogens in this group included
      Enterococcus, Candida, and Pseudomonas. Women were more likely to be admitted
      with a CA infection (5% vs. 1%, p < 0.001) or acquire an NI infection (23% vs.
      15%, p < 0.001). Obesity was highly predictive of increased Foley catheter days,
      and thus UTI, by multivariate analysis (p < 0.001). CONCLUSIONS: Escherichia coli
      was the most common pathogen in all nosocomial infection categories. Increased
      age, gender, and obesity, in addition to catheter-days, were significant risk
      factors for UTI in trauma patients. Specific risk factors may predispose patients
      to pathogens that are not ordinarily covered by usually-chosen antibiotic
      therapy.

PMID- 15012863
TI  - Myocardial inflammatory responses to sepsis complicated by previous burn injury.
AB  - BACKGROUND: It is generally accepted that an initial injury such as burn trauma
      alters immune function such that a second insult increases the morbidity and
      mortality over that observed with each individual insult. We have shown
      previously that either burn trauma or sepsis promotes cardiomyocyte secretion of
      TNF-alpha and IL-1beta, cytokines that have been shown to produce myocardial
      contractile dysfunction. This study determined whether a previous burn injury
      (given eight days prior to sepsis) (1) provides a preconditioning phenomenon,
      decreasing inflammatory responses to a second insult or (2) exacerbates
      inflammatory response observed with either injury alone. METHODS: Anesthetized
      Sprague-Dawley rats were given either burn injury over 40% total body surface
      area, sepsis alone (intratracheal S. pneumoniae, 4 x 10(6) colony forming units)
      or sepsis eight days after burn; all rats received lactated Ringer's solution.
      Hearts harvested 24 h after onset of sepsis alone or sepsis plus eight-day burn
      were used to (1) isolate cardiomyocytes (collagenase) or (2) assess contractile
      function (Langendorff). Cardiomyocytes loaded with 2 microg/mL Fura-2AM or sodium
      binding benzofuran isophthalate were used to measure intracellular calcium and
      sodium concentrations (Nikon inverted microscope, Grooney optics, InCyt Im2
      Fluorescence Imaging System). Additional cardiomyocytes were used to measure
      myocyte-secreted TNFalpha, IL-1, IL-6, IL-10 (pg/ml, ELISA). RESULTS: Either burn
      trauma alone or sepsis alone promoted TNF-alpha, IL-1beta, nitric oxide, IL6 and
      IL-10 secretion by cardiomyocytes (p < 0.05). Producing aspiration-related
      pneumonia eight days postburn produced myocardial pro- and anti-inflammatory
      responses and increased myocyte Ca2+/Na+ concentrations to a significantly
      greater degree than the responses observed after either insult alone.
      CONCLUSIONS: A previous burn injury alters myocardial inflammatory responses,
      predisposing the burn-injured subject to exaggerated inflammation, which
      correlates with greater myocardial dysfunction.

PMID- 15012865
TI  - Surgical treatment of spondylodiscitis.
AB  - BACKGROUND: Spondylodiscitis is a rare bacterial infection of the vertebra and
      intervertebral discs with an inflammatory, destructive course. METHODS: To gain
      further information about the management and clinical course of spondylodiscitis,
      we retrospectively reviewed 32 patients in 2002 who had surgical interventions
      between 1992 and 2001. RESULTS: The mean age of patients was 61 years (29-78
      years). The mean hospital stay was 47 days (+/- 5.6 days; 3-121 days), including
      28 days (+/- 8.1 days; 2-112 days) in the ICU. In-hospital mortality was 6%. The
      cervical spine was affected in 20% of patients (6/32), the thoracic spine in 25%
      (8/32), and the lumbosacral spine in 55% (18/32). Abscesses occurred in 63% of
      patients (20/32) and destruction of the vertebral body in 71% (23/32).
      Neurological deficits were present in 17 patients, which improved by surgical
      intervention in 82% of those affected. Thirty-one patients underwent ventral
      resection of the focus, spondylodesis with a bone graft or titanium cage, and
      ventral stabilization with a plate. In 19% of patients (6/32), additional dorsal
      bridging instrumentation was performed. Complete healing was obtained in 94%
      (30/32) patients. At follow-up, 50% of patients (16/32) had no complaints.
      CONCLUSIONS: Spondylodiscitis requires immediate debridement of the focus, with
      decompression and stabilization through a ventral approach, when conservative
      management fails. Otherwise, severe complications occur, such as sepsis,
      vertebral body destruction, abscess, or neurological deficits.

PMID- 15012870
TI  - [Usefulness of PSA and its fractions in the diagnosis of prostate cancer].
AB  - BACKGROUND AND OBJECTIVE: The description of different forms of PSA has opened a
      new strategy in the diagnosis of prostate cancer. The measurement of the ratio
      between free PSA and PSA in the group of patients with a PSA level between 4 and
      10 ng/ml decreases the number of negative biopsies. The aim of our study was to
      compare the diagnostic efficacy of PSA and PSA fractions (free PSA [fPSA] and
      complexed PSA [cPSA]) in the differential diagnosis between Pca and benign
      prostate hyperplasia (BPH). PATIENTS AND METHOD: We measured the serum levels of
      PSA, free PSA and cPSA in 56 patients with Pca and 94 patients with BPH. RESULTS:
      ROC curves were used for the comparison of tests. The biggest area under the
      curve (AUC) was observed for the ratios fPSA/cPSA and fPSA/PSA (0.718 and 0.712,
      respectively). When we compared the AUC between PSA and cPSA, then AUC for cPSA
      was higher than AUC for PSA (0.602 and 0.567, respectively). We observed similar
      results in the group of patients with PSA levels between 4 and 10 ng/ml.
      CONCLUSIONS: The diagnostic accuracy of cPSA is higher than that of PSA.
      Moreover, in the differential diagnosis between prostate cancer and BPH, the use
      of PSA ratios (fPSA/cPSA or fPSA/PSA) increases the diagnostic accuracy obtained
      with the measurement of PSA or cPSA.

PMID- 15012871
TI  - [Usefulness of acute-phase proteins in community-acquired pneumonia].
AB  - BACKGROUND AND OBJECTIVE: We aimed to study the usefulness of acute-phase
      proteins in the evolution and microbial diagnosis of community-acquired pneumonia
      (CAP). PATIENTS AND METHOD: One-year prospective study of CAP. Plasma levels of C
      reactive protein (CRP), erythrocyte sedimentation rate (ESR) and fibrinogen were
      measured on admission in all patients with CAP. RESULTS: 240 cases of CAP were
      included in the study. ESR was higher in patients who developed pleural effusion
      (p = 0.03). A value of ESR > 120 mm/h was associated with a higher likelihood of
      having a CAP complicated with pleural effusion (odds ratio = 3.80; 95% confidence
      interval, 1.37-10.49, p = 0.006). Baseline concentrations of CRP, ESR and
      fibrinogen were higher in patients who developed empyema. CRP and fibrinogen
      levels were significantly higher in patients with Legionella pneumophila
      pneumonia, while pneumococcal pneumonia was associated with a higher ESR value.
      CONCLUSIONS: Some frequently used acute-phase proteins can be useful in the
      prediction of pleural complications and in the approach to the etiological
      diagnosis of CAP.

PMID- 15012872
TI  - [Independent role of C reactive protein to predict major events at one-month and
      at one-year in acute coronary syndrome without ST elevation].
AB  - BACKGROUND AND OBJECTIVE: We intended to determine whether C-reactive protein
      (CRP) provides independent prognostic information after a non-ST elevation acute
      coronary syndrome. PATIENTS AND METHOD: We prospectively studied 630 consecutive
      patients admitted with a diagnosis of non-ST elevation acute coronary syndrome.
      Cut-off values were: troponin I > 1 ng/ml (n = 354; 56%) and CRP > 11 mg/l (n =
      273; 43%). RESULTS: Within a one-year follow-up period, 56 (9%) cardiac deaths,
      85 (13%) myocardial infarctions (MI) and 127 (20%) first major events were
      detected. Patients with increased CRP showed higher rates of death at one-month
      (8% vs 1%), death at one-year (15% vs 4%), myocardial infarction at one-month (8%
      vs 4%), myocardial infarction at one-year (19% vs 9%), major events at one-month
      (15% vs 5%) and major events at one-year (30% vs 13%). In the multivariate
      analysis, once adjusted for baseline and electrocardiogram data and for
      myocardial damage markers, CRP was an independent predictor of death at one-month
      (odds ratio [OR] 4.6) and death at one-year (OR = 2.7), major events at one-month
      (OR = 1.8) and major events at one-year (OR = 1.8). Troponin I predicted MI at
      one-month (OR = 2.5) and MI at one-year (OR = 2.2). CONCLUSIONS: CRP provided
      independent information to predict major events in non-ST elevation acute
      coronary syndromes. Troponin I was a more powerful predictor of MI than PCR. The
      analysis of CRP and myocardial damage markers in the short-term and long-term
      risk stratification seems worthy.

PMID- 15012873
TI  - [Usefulness of oral pilocarpin therapy in the treatment of xerostomia and
      xerophthalmia in patients with primary Sjogren's syndrome].
AB  - BACKGROUND AND OBJECTIVE: We aimed to asses the efficacy of pilocarpine tablets
      as a symptomatic treatment for dry mouth and dry eyes in patients with primary
      Sjogren's syndrome (SS). PATIENTS AND METHOD: We included 40 patients with SS (38
      women and 2 men), mean age 49.2 years (range, 35-68), with severe xerostomia and
      xerophthalmia. Objective tests (salivary scintigraphy, Schirmer's test, break-up
      time, Rose Bengal staining) and subjective tests (symptoms' questionnaire) were
      carried out before starting treatment and 6 months later to evaluate any
      glandular function improvement. RESULTS: All patients initially received 15 mg
      daily of pilocarpine. Twelve (30%) patients received 20 mg daily. Dry mouth
      related symptoms improved in 57.5% of patients and dry eyes-related ones improved
      in 35%. Scintigraphic studies demonstrated an objective improvement of the
      glandular function in 35% patients. Ocular tests showed an improvement in 30%
      cases. CONCLUSIONS: Pilocarpine therapy is useful to improve xerostomia and
      xerophthalmia in SS patients with moderate and severe glandular involvement.
      However, we have not observed a good correlation between subjective improvement
      of symptoms and the objective test results.

PMID- 15012874
TI  - [Measurement of complexed prostatic specific antigen. A new challenge in PSA
      era].

PMID- 15012875
TI  - [Clinical and biological characteristics of a group of 54 pregnant women with
      HELLP syndrome].
AB  - BACKGROUND AND OBJECTIVE: The HELLP syndrome is a rare form of preeclampsia with
      a variable presentation with substantial maternal and perinatal morbidity and
      mortality. The aim of this study was to determine its clinical and biological
      characteristics in our hospital. PATIENTS AND METHOD: An observational study of
      all cases of confirmed HELLP syndrome from 1999 to 2002 was carried out. RESULTS:
      There were 54 cases of HELLP syndrome. Mean maternal age was 30.06 (16-41) years.
      57.4% were primiparous. Mean gestational age at diagnosis of HELLP syndrome was
      31.75 (20-41) weeks. Symptoms and signs were dominated by the digestive ones.
      Hypertension was observed in all cases. 77.8% pregnancies were delivered by
      caesarean section. Mean birth weight was 1674.52 g (150-3800 g). There were 12
      perinatal deaths and one maternal death. CONCLUSIONS: HELLP syndrome is an
      uncommon but potentially serious complication of pregnancy which is associated
      with an increased risk of adverse maternal and fetal outcomes. Management should
      be multidisciplinary and based on strict control by maternal and fetal symptoms.

PMID- 15012876
TI  - [Ethics and smoking].

PMID- 15012877
TI  - [From the accreditation of continuous medical education to the legislation of
      Health Professions in Spain. About the regulation of the Medical practice in
      Spain].

PMID- 15012878
TI  - [Inotropic therapy in heart failure: general aspects and clinical results].
AB  - Classic inotropic agents such as beta-adrenergic agonists and phosphodiesterase
      III inhibitors have beneficial but transitory hemodynamic effects in patients
      with acute and chronic heart failure. In this context, the available data suggest
      that long term inotropic therapy has a negative impact on morbidity and mortality
      in patients with heart failure. For this reason, these agents are mainly used for
      the treatment of refractory episodes of decompensation and they are also used as
      a "bridge" (transplant, revascularization, recovery) or as a palliative measure.
      We present a revision of the general aspects of inotropes including main
      published clinical trials and some findings of its combined use with beta
      blockers. Furthermore, we describe a promising and differential therapeutic
      approach represented by calcium sensitizer agents (levosimendan).

PMID- 15012879
TI  - [Heart failure in the elderly: a frequent cause of readmission].

PMID- 15012880
TI  - [Phencyclidine, PCP or "angel dust": a forgotten drug].

PMID- 15012882
TI  - [Legionella pneumophila in community acquired pneumonia: interpretation of
      microbiological techniques].

PMID- 15012881
TI  - [Neurologic complications in antiphospholipid antibody syndrome: no solved
      question].

PMID- 15012884
TI  - [Recrudescence of tics related with streptococcal infections].

PMID- 15012885
TI  - ["Subjective annotations" in case-histories].

PMID- 15012886
TI  - [Serum vascular endothelial growth factor levels in patients with colorectal
      cancer and its prognostic significance].
AB  - BACKGROUND AND OBJECTIVE: Thirty per cent of patients with histologically node
      negative colorectal cancer die from disseminated disease. Actually disease stage
      is the most useful prognostic parameter although it is not sufficient. Vascular
      endothelial growth factor (VEGF) is an angiogenic cytokine involved in the
      progression of tumors. In our study we tried to know the prognostic significance
      of pre and postoperative serum VEGF levels in patients with colorectal cancer.
      PATIENTS AND METHOD: Cohort study that included 52 patients with colorectal
      cancer surgically treated in our Department from 1998 to 2000. Serum VEGF and CEA
      levels were determined the day before surgery and 30 days after it. RESULTS:
      Preoperative serum VEGF levels (428.5 [38.5] pg/ml) were higher than in control
      patients (p=0.008). Serum VEGF levels fallen significantly after surgery (343
      [31.2] pg/ml; p=0.001). Pre and postoperative serum VEGF levels in poorly
      differentiated neoplasms were higher than in well differentiated ones (p=0.009
      and p=0.008 respectively). Pre and postoperative serum CEA and VEGF levels were
      significantly associated with cancer relapse (p=0.037, p=0.017, p=0.048 and
      p=0.001, respectively). In multivariate analysis only postoperative serum VEGF
      levels were associated with colorectal cancer relapse (p=0.003; HR=1.007; 95% CI,
      1.002-1.012). Pre and postoperative CEA levels (p<0.001 and p=0.001 respectively)
      and postoperative VEGF levels (p=0.001), were associated with mortality. In
      multivariate analysis only tumor stage (p=0.01) and postoperative serum VEGF
      levels (p=0.02) were associated with mortality. Postoperative serum VEGF
      determination and pre and postoperative CEA levels raise specificity and positive
      predictive values to 100% in relation to mortality. CONCLUSIONS: Pre and
      postoperative serum VEGF determination has prognostic significance, regardless of
      tumor stage, in patients with colorectal cancer. In survival methods,
      postoperative VEGF levels >343 pg/ml are significantly with tumor relapse and
      mortality. These results suggest the use of serum VEGF levels as a prognostic and
      monitoring factor besides CEA.

PMID- 15012887
TI  - [Health-related quality of life in the Spanish women through and beyond
      menopause. Development and validation of the Cervantes Scale].
AB  - BACKGROUND AND OBJECTIVE: There are numerous health-related quality of life
      questionnaires but only a few are specific for the menopause. The objective of
      this study was to develop and validate a specific scale, the Cervantes Scale, for
      menopause in Spanish women. SUBJECTS AND METHOD: This cross-sectional study
      included a pilot phase, construction of the questionnaire, validation, and test
      retest reliability. A population-based sample of 2,274 women ponderated by age
      groups and education levels was used in the validation phase. Internal
      consistency was assessed with the Cronbach's alpha analysis. RESULTS: The final
      questionnaire included 31 items ("menopause and health" with 15 items made up of
      vasomotor symptoms, health and aging, "sexuality" with 4 items, "couple
      relationship" with 3 items and "psychical domain" with 9 items). The Cronbach's
      (coefficient of the scale was 0.9092. The correlation coefficient of the test
      retest was r=0.847 (p<.001). The Cervantes Scale is short, easy to administer
      (about 7 minutes), has a minimal score of 0 and a maximal score of 155 (from
      better to worse quality of life) and scores can be compared to reference values
      in younger women and women of the same age. CONCLUSIONS: The Cervantes Scale is
      included in the new generation of instruments of health-related quality of life
      specific for the menopause and is intended to be used in Spanish women aged
      between 45 and 64 years.

PMID- 15012888
TI  - [Evaluation of clinical research studies in a comprehensive cancer center].
AB  - BACKGROUND AND OBJECTIVE: The number of clinical trials in cancer patients has
      experienced an important growth during last years. However, it is difficult to
      find data showing this activity in Spanish Hospitals. This study analyses the
      clinical trials data bases between 1996 and 2002 in a cancer center. MATERIAL AND
      METHODS: We perform a descriptive analysis of data from: selection of protocols,
      origin of proposals, sponsors, investigators, studies performed and published;
      demographic data about patients and phase of the studies in which they have been
      included. RESULTS: Evaluation was undertaken with a standardised protocol review
      assessment. 337 proposals of clinical trials were evaluated during 1996-2002,
      with a decreasing acceptance index (62.5% to 39.18%, respectively), the number of
      proposals has grown from 16 in 1996 to 74 in 2002. The general recruitment index
      was 6.64%. Between 1995-2002, 1479 patients were registered; only 5% were older
      than 75 years. Pharmaceutical Companies sponsored the majority of the studies,
      although Co-operative Groups promote an important number of studies, especially
      in Haematology and Radiotherapy. Thirteen studies performed between 1996-1998 had
      been published, and 3 more are accepted for publication (69.5%). CONCLUSIONS: The
      number of patients included in clinical trials is limited and older patients are
      not well represented in them.

PMID- 15012891
TI  - [Professionalization of biomedical research in Spain: Are we going to miss the
      opportunity?].

PMID- 15012890
TI  - [Cancer of unknown origin].

PMID- 15012889
TI  - [Prognostic and predictive factors of patients with cancer of unknown origin
      treated with a paclitaxel-based chemotherapy].
AB  - BACKGROUND AND OBJECTIVE: Taxane-based combinations appear to be promising for
      the treatment of carcinoma of unknown primary site (CUPS). PATIENTS AND METHOD:
      Patients with CUPS not corresponding to any favourable subset were treated with
      paclitaxel, carboplatin and etoposide. Interaction between various factors with
      survival was analyzed. A regression model was applied to identify factors with
      independent prognostic significance. RESULTS: 48 patients were included and 15
      responses were observed with a median overall survival of 7.4 months. In the
      multivariate analysis, performance status and hypoalbuminemia were negatively
      associated with overall survival. CONCLUSIONS: Some patients can achieve complete
      response and prolonged survival. This treatment cannot be recommended for
      patients with a regular performance status. A better knowledge of prognostic
      factors and a definition of more subgroups with favourable outcome are needed.

PMID- 15012893
TI  - [Elderly and opioid world].

PMID- 15012892
TI  - [Miller-Fisher syndrome: clinical features, associated infections and clinical
      course in 8 cases].
AB  - BACKGROUND AND OBJECTIVE: Miller-Fisher syndrome (MFS) is considered the most
      common variant of Guillain-Barre syndrome (GBS) and is characterized by the
      clinical triad of ophthalmoplegia, ataxia and areflexia. Respiratory involvement
      and relapses are unusual. Patients with MFS usually have a good recovery and no
      residual deficits. We describe the clinical features, associated infections and
      evolution in eight patients with MFS. PATIENTS AND METHOD: Eight cases of MFS and
      sixty-one of GBS were studied between 1994 and 2003. All cases showed the
      clinical triad of MFS without major limb weakness or other signs suggestive of
      CNS involvement. RESULTS: The proportion of MFS with respect to GBS during the
      same period was 13.1%. Four had a positive serology for Epstein-Barr virus,
      Salmonella enteritidis, Chlamydia pneumoniae and Mycoplasma pneumoniae. Our cases
      showed facial palsy (75%), dysphagia (75%), pupillary abnormalities (37.5%) and
      ventilation support (37.5%). Antiganglioside antibodies, determined in three
      cases (4 episodes), were positive [GQ1b (50%) and GD1b (50%)]. In all cases,
      there was a markedly reduced amplitude of the distal sensory as well as frequent
      axonal degeneration signs. The oldest three patients relapsed and required
      ventilation support. CONCLUSIONS: We report for the first time an association
      between S. enteritidis and C. pneumoniae and MFS. Older patients in our series
      suffered a faster disease progression with need of ventilation support. We
      conclude that an older age correlates with poor prognosis and relapses.

PMID- 15012894
TI  - [Pharmacological alternatives to blood transfusion: what is new about?].
AB  - Pharmacological approaches to reduce blood transfusion include the protease
      inhibitor aprotinin, lysine-analogue antifibrinolytics synthetic arginine
      vasopressin derivatives (DDAVP) and recombinant factor VII (rfVIIa). These agents
      are known to prevent the need for blood after major surgery (cardiac, hepatic,
      and orthopaedic). Among the nonhemostatic agents erythropoietin (EPO) may be
      effective to reduce blood requirements in medical and surgical patients.
      Aprotinin is consistently effective in reducing blood transfusion in cardiac and
      hepatic surgical procedures, but there is little data to support its use in
      elective orthopaedic surgery. Antifibrinolytics show no evidence of efficacy in
      cardiac and hepatic surgery and its use is not warranted in orthopaedic surgery.
      Limited data suggest that DDAVP may be effective when a defect in platelet
      function is demonstrated. rFVIIa emerges as a promising haemostatic agent with
      proven benefit to reduce bleeding in haemophiliacs with inhibitors but might also
      be effective in patients with thrombocytopenia and thrombopathy, as well as in
      life-threatening hemorrhage in postsurgical patients. Ongoing studies will
      established its role a possible "universal haemostatic agent". Hematopoietic
      cytokines, such as EPO, may have a place to avoid blood transfusion in a variety
      of clinical conditions, including cancer and critically ill patients.

PMID- 15012895
TI  - [CD44s expression in squamous cell lung carcinomas].

PMID- 15012896
TI  - [Glucocorticoids and immunoglobulins in an acute respiratory distress syndrome
      secondary to varicella pneumoniae].

PMID- 15012898
TI  - [Thoracoepigastric thrombophlebitis secondary to muscular stretching exercises].

PMID- 15012897
TI  - [Treatment of multiresistant Staphylococcus epidermidis meningitis with
      linezolid].

PMID- 15012900
TI  - Arsenic accumulation in livers of pinnipeds, seabirds and sea turtles:
      subcellular distribution and interaction between arsenobetaine and glycine
      betaine.
AB  - Concentrations of total arsenic and individual arsenic compounds were determined
      in liver samples of pinnipeds (northern fur seal Callorhinus ursinus and ringed
      seal Pusa hispida), seabirds (black-footed albatross Diomedea nigripes and black
      tailed gull Larus crassirostris) and sea turtles (hawksbill turtle Eretmochelys
      imbricata and green turtle Chelonia mydas). Among these species, the black-footed
      albatross contained the highest hepatic arsenic concentration (5.8+/-3.7 microg/g
      wet mass). Arsenobetaine was the major arsenic species found in the liver of all
      these higher tropic marine animals. To investigate the cause of high accumulation
      of arsenobetaine, subcellular distribution of arsenic and relationship between
      arsenobetaine and glycine betaine concentrations were examined in the livers of
      these animals. There was no relationship between total arsenic concentration and
      its subcellular distribution in liver tissues. However, a significant negative
      correlation was found between arsenobetaine and glycine betaine concentrations in
      the liver of six species examined. This result may indicate that arsenobetaine is
      accumulated in these marine animals as an osmolyte along with glycine betaine,
      which is a predominant osmolyte in marine animals because the chemical structure
      and properties of arsenobetaine are similar to those of glycine betaine.

PMID- 15012902
TI  - Estrogenic effect of propylparaben (propylhydroxybenzoate) in rainbow trout
      Oncorhynchus mykiss after exposure via food and water.
AB  - The estrogenic effect of propylparaben was investigated in a rainbow trout
      Oncorhynchus mykiss test system. Propylparaben was administered orally to
      sexually immature rainbow trout every second day for up to 10 days in doses
      between 7 and 1830 mg kg(-1) 2 d(-1) and in the water at 50 and 225 microg l(-1)
      for 12 days. Plasma vitellogenin was measured before and during the exposures and
      the concentrations of propylparaben in liver and muscle were determined at the
      end of experiments. Increases in average plasma vitellogenin levels were seen at
      oral exposure to 33 mg propylparabenkg(-1) 2 d(-1); the most sensitive fish
      responded to 7 mg kg(-1). The ED(50) values for increase in vitellogenin
      synthesis were 35, 31 and 22 mg kg(-1) 2 d(-1) at day 3, 6 and 11, respectively.
      Exposure to 225 microg propylparabenl(-1) increased vitellogenin synthesis, but
      exposure to 50 microg l(-1) did not. Propylparaben showed little tendency to
      bioaccumulation in rainbow trout; less than 1 per thousand of the total amount of
      propylparaben administered orally at 1830 mg kg(-1) 2 d(-1) over the 10-d
      experimental period was retained in muscle and liver 24 h after the end of the
      experiment. Exposure to 225 microg propylparabenl(-1) for 12 d led to
      concentrations of 6700 and 870 microg propylparabenkg(-1) liver and muscle,
      respectively. Half lives for propylparaben were 8.6 h in liver and 1.5 h in
      muscle.

PMID- 15012901
TI  - Cytochrome P450 expression and activities in rat, rabbit and bovine tongue.
AB  - Xenobiotic metabolism in the tongue has received little attention in the
      literature. In the present study, we report a comparative analysis of
      constitutive cytochrome P450 (CYP) expression and activities in the tongue. First
      we compared catalytic activities of rabbit, rat and bovine tongue samples using
      the probe substrates 4-nitrophenol, 1-phenylethanol, caffeine and 7
      ethoxycoumarin. Rabbit tongue samples showed the highest activities for all
      substrates. We then compared the activities in rat and rabbit tongue with those
      in the rabbit liver, along with the effects of P450 inhibitors on specific
      activities. Combined, the activity studies indicate that CYP1A1 is active in
      rabbit tongue cells, but CYP1A2, CYP3A6 and CYP2E1 are below limits of detection.
      RT-PCR was also used to compare mRNA levels of 11 different rabbit and six
      different rat P450 isoforms in the tongue to those in the liver of these two
      species. Only CYP2E1, CYP1A1 and CYP4A4 were detected at significant levels in
      the rabbit tongue. None of the six rat isoforms probed were observed in the
      tongue. Although 4-nitrophenol activity was observed in the rabbit tongue
      samples, the kinetic parameter K(m) was inconsistent with the involvement of
      CYP2E1. We suggest that although CYP2E1 is expressed in the tongue, it is rapidly
      degraded in this organ, and the nitrophenol hydroxylation and caffeine
      hydroxylation we observe is the result of activity of CYP1A1.

PMID- 15012903
TI  - Pineal control of immune status and hematological changes in blood and bone
      marrow of male squirrels (Funambulus pennanti) during their reproductively active
      phase.
AB  - In addition to pineal control of reproduction in seasonal breeders, melatonin is
      also known to influence various immune parameters. In the present experiment, we
      assessed the effect of exogenous melatonin treatment on different hematological
      parameters of peripheral blood and bone marrow cells, together with histological
      observations of spleen and thymus blastogenic response and stimulation ratio, and
      hormonal assays (melatonin and testosterone) of Indian palm squirrel (Funambulus
      pennanti) during their reproductively active phase when endogenous melatonin
      levels are low. Daily subcutaneous injection of melatonin (25 microg/100 g body
      mass.) at 17.30-18.00 h to adult male squirrels for 60 consecutive days during
      May-June significantly increased the lymphocyte count of blood and bone marrow
      and the blastogenic response/percent stimulation ratio of spleen and thymus.
      Histological observation showed densely packed thymocytes and splenocytes. During
      this period, peripheral testosterone level was high and melatonin was low
      establishing an inverse relationship as noted earlier for this squirrel. In
      pinealectomized squirrels, decreased total leukocyte count and percent lymphocyte
      count in peripheral blood and bone marrow, along with a decreased cell density in
      spleen and thymus was observed histologically. Further, melatonin treatment of
      pinealectomized squirrels resulted in restoration of the immune parameters in
      line with a normal control level. We suggest that during the reproductively
      active period of male Indian palm squirrels the lymphoid organs were sensitive to
      melatonin; hence, the exogenous melatonin treatment had an immuno-enhancing
      effect.

PMID- 15012904
TI  - Effect of ascorbic acid and acute heat exposure on heat shock protein 70
      expression by young white Leghorn chickens.
AB  - Dietary ascorbic acid (AA) and heat stress (HS) affect heat shock protein 70
      (hsp70) and body temperature (BT) of strain cross white Leghorn chickens. At five
      weeks of age, chicks fed either no supplemental AA (N-AA) or 200 mg/kg AA (AA)
      were subjected to either HS (42 degrees C) or maintained in control (CN, 23
      degrees C) ambient temperature (T(a)) for 1 h. Body temperature (BT) was recorded
      for each bird before collection of heart and liver for hsp70 assay. In the CN AA
      fed groups, neither the lower constitutive hsc70 nor the decreased hsp70 response
      to HS in the heart and liver were sex-dependent. The BT was increased by HS, but
      neither AA nor sex of the bird affected BT response. A diet X T(a) interaction
      revealed that BT of CN AA-fed chickens was lower than in N-AA-fed chickens, but
      BT of HS AA-fed chicks was greater than BT in HS N-AA-fed chickens. The BT and
      hsp70 responses were positively correlated. A lower expression of hsp70 indicated
      less of a stress response in the AA-fed chickens.

PMID- 15012905
TI  - cDNA cloning and expression of bacteria-induced Hdd11 gene from eri-silkworm,
      Samia cynthia ricini.
AB  - A cDNA clone encoding Hdd11 protein, a bacteria-induced protein of unknown
      function, was isolated from fat body of immunized Samia cynthia ricini larvae
      based on suppression subtractive hybridization. The cDNA encodes a 167 amino acid
      residue open reading frame with an 18 residue predicted signal peptide. The
      deduced amino acid sequence showed 54% and 55% identity with Hdd11 proteins from
      Hyphantria cunea and Manduca sexta, respectively. Expression of the gene was
      undetectable in naive larvae when measured by Northern blot hybridization, but
      strongly induced in fat body after injecting bacterial cells or peptidoglycan
      into the larvae. The mRNA expression in the fat body was detected as early as 3 h
      post injection, reached peak levels at 12 h and continued for further 60 h at
      significant levels. The transcript was detected at very low levels in midgut,
      hemocytes and malpighian tubules.

PMID- 15012906
TI  - Comprehensive comparison of the cytotoxic activities of onconase and bovine
      seminal ribonuclease.
AB  - Onconase (ONC) and bovine seminal ribonuclease (BS-RNase) are homologs of bovine
      pancreatic ribonuclease (RNase A). Unlike RNase A, ONC and BS-RNase can evade the
      cytosolic ribonuclease inhibitor protein and are potent cytotoxins. Here, the
      endogenous cytotoxic activities of ONC and BS-RNase are compared in a wide
      variety of assays. Injections of ONC into one or both testes of mice and rats
      evokes a stronger aspermatogenic activity than does the injection of BS-RNase.
      Epididymides exposed to ONC lose mass and all sperm. Testicular tissue is
      gradually colonized by immunite and fibrocytic cells. Yet, Leydig cells are
      always present and functional in the ligamented parts of testicles injected with
      ONC or BS-RNase. ONC is likewise more toxic to mouse embryos than is BS-RNase,
      both in vitro and in vivo. The antiproliferative effect of ONC on human tumor
      cell line ML-2 and lymphocytes in a mixed lymphocyte culture is also more
      pronounced than is that of BS-RNase. The number of granulocyte-macrophage colony
      forming units is repressed almost completely by ONC, whereas a five-fold higher
      dose of BS-RNase does not cause substantial inhibition. In mice, ONC is less
      immunogenic than BS-RNase but more immunogenic than RNase A. Together, these data
      indicate that ONC is a pluripotent cytotoxin, and serves as the benchmark with
      which to gauge the cytotoxicity of other ribonucleases.

PMID- 15012908
TI  - Development of resistance against hexachlorobutadiene in the proximal tubules of
      young male rat.
AB  - Hexachlorobutadiene (HCBD) is a potent nephrotoxin in rodents that can cause
      degeneration, necrosis and regeneration in renal tubular epithelial cells. Its
      toxicity is due to its conjugation by glutathione (GSH) to form glutathione S
      conjugate, by the enzyme glutathione S-transferase and finally to the related
      cysteine-conjugate. This metabolite is then actively taken up by kidney and
      cleared in the renal tubular epithelial cells, rich in beta-lyase, to a reactive
      thiol derivative that covalently binds to the macromolecules. In this study,
      different groups of 28-day male Wistar albino (W/A) rats were dosed daily with 25
      mg/kg HCBD for 2, 3, 4 and 7 days; control group dosed with corn oil. Data showed
      that in the 2- and 3-day treated groups there was substantial necrosis to the
      straight portion of the proximal tubules (pars recta or S3 segment), rich in
      glutamine transaminase K (GTK/beta-lyase). In the 4-day treated group, the renal
      proximal tubules had regenerated and showed a basophilic appearance. In animals
      treated for 7 days, it was observed that the kidney appeared to have returned to
      normal and had become resistant to further doses of HCBD. To define the time for
      the kidney to regain susceptibility to HCBD, 18- and 25-day studies with both low
      (25 mg/kg) and high (100 mg/kg) doses of HCBD (following two initial doses of 25
      mg/kg) were performed. In the 18-day study, histopathological examination of the
      kidneys in animals of this group and also animals in the 25-day study, which
      received two further doses of HCBD, showed that the severity of kidney damage is
      much less than in the 2-day treated animals, a clear indication that the tubular
      cells were still resistant to the low dose of HCBD. Concentration of blood urea
      nitrogen, as a marker of kidney damage, in these two groups also confirmed the
      results. In animals re-exposed to the high dose of HCBD, data showed that the
      susceptibility to HCBD was starting to return.

PMID- 15012907
TI  - Isolation and characterization of raw heparin from dromedary intestine:
      evaluation of a new source of pharmaceutical heparin.
AB  - Heparin, a heterogeneous anionic polysaccharide, is the glycosaminoglycan (GAG)
      used clinically an anticoagulant. This anticoagulant activity is primarily
      derived from its binding to the serine protease inhibitor antithrombin III, a
      potent inhibitor of thrombin (factor IIa) and factor Xa. Heparin is a complex
      natural product and its in vitro synthesis is not yet possible due to the
      difficulty of organizing the many biosynthetic enzymes required for its
      synthesis. The principle natural sources for heparin include porcine intestine
      and bovine lung. These two sources pose concerns for religious and health
      reasons, respectively. To circumvent these concerns, GAG from the intestinal
      tissue of one humped camel was isolated. Chemical characterization of this newly
      isolated GAG and spectroscopic analysis by 1D and 2D 1H-NMR were undertaken.
      Unsaturated disaccharide compositional analysis was performed on the
      enzymatically depolymerized GAG and the molecular weight of the isolated GAG was
      determined by gradient polyacrylamide gel electrophoresis. Anticoagulant activity
      of the newly isolated GAG was tested by using an anti-factor Xa assay. The
      results of these studies suggest that the GAG from one humped camel intestine is
      a mixture of heparin and heparan sulfate and represents an alternative source of
      heparin.

PMID- 15012909
TI  - Chronic oral administration of raw garlic protects against isoproterenol-induced
      myocardial necrosis in rat.
AB  - Wistar albino rats (150-200 g) were fed raw garlic homogenate orally in three
      different doses (125, 250, 500 mg/kg/day) for 30 days. Isoproterenol (85 mg/kg,
      s.c. 2 doses at 24-h interval, animals sacrificed after 24 h of last injection)
      induced myocardial necrosis in control rats and after 30 days of garlic feeding.
      Myocardial oxidative stress was evident following isoproterenol administration by
      reduction in myocardial superoxide dismutase (SOD) and glutathione peroxidase
      (GPx) activities along with a rise in plasma thiobarbituric acid reactive
      substances (TBARS). Myocardial necrosis was evident from the light microscopic
      and ultrastructural changes, along with a rise in plasma lactate dehydrogenase
      (LDH). Significant preservation of myocardial SOD activity was observed in all
      the garlic-fed rats. However, there was no significant change in myocardial
      reduced glutathione level and GPx activity in any of the treated groups.
      Significant reduction in plasma TBARS and LDH levels was observed in the 500
      mg/kg garlic treated group. Isoproterenol-induced myocardial morphological
      changes were least in the 250 and 500 mg/kg garlic treated groups. The results
      suggest that chronic oral administration of raw garlic offered protection against
      isoproterenol-induced myocardial necrosis and associated oxidative stress.

PMID- 15012910
TI  - A bradykinin potentiating peptide from Egyptian cobra venom strongly affects rat
      atrium contractile force and cellular calcium regulation.
AB  - Peptide fractions were isolated from venoms of the Egyptian snake Naja haje haje
      (cobra BPP) and the scorpions Buthus occitanus (BPP(B)) and Leirus
      quenquestriatus (BPP(L)). The pharmacological effects of these peptides were
      bioassayed and showed bradykinin potentiating activities. Amino acid analysis
      revealed that 14 amino acids contribute to the structure of BPP(B) and 16 for
      BPP(L), while cobra BPP was composed of 15 amino acids. Treatment of rat atrial
      preparations with 50 microg/ml of cobra BPP caused a significant reduction
      (P<0.001) in myocardial force. Elevation of extracellular calcium concentration
      from 1.25 to 5 mM antagonized the effect of cobra BPP in a way that restored the
      atrial force development. Na(+)-channel blockers did not change the force
      development at 5 mM Ca(2+). Experiments with (45)Ca revealed that Ca(2+) uptake
      of cobra BPP treated atria was 0.52+/-0.07 microM/g wet mass and the force at the
      end of the uptake period was 55.0+/-2.0%. The corresponding values for non
      treated preparations were 0.56+/-0.04 microM/g and 92.0%+/-3.0%, respectively.
      Our results revealed that cobra BPP did not exhibit any effect on Ca(2+) uptake
      by rat atrial preparations, but strongly affected cellular Ca(2+) regulation.

PMID- 15012911
TI  - A method to reduce loss to follow-up in clinical trials: informed, withdrawal of
      consent.

PMID- 15012912
TI  - Increased regulatory activity of the calcineurin/NFAT pathway in human heart
      failure.
AB  - BACKGROUND: Cardiac hypertrophy may initiate progression to a compromised cardiac
      function. While the clinical consequences of hypertrophy are well understood,
      only little is known about the underlying molecular pathways. As reported from
      animal experiments, the Ca(2+)-calmodulin activated phosphatase calcineurin and
      its downstream transcriptional effector NFAT have been implicated as transducers
      of the hypertrophic response. METHODS AND RESULTS: To study whether the
      calcineurin pathway is activated in human heart failure, we investigated samples
      of human left ventricular myocardium from patients with dilated (idiopathic)
      cardiomyopathy (DCM, NYHA IV, n=8) in comparison with non-failing controls (NF,
      n=8). We not only analyzed the pathway by measuring the calcineurin activity, but
      also by determination of the protein expression of the calcineurin B subunit and
      additional key markers of the calcineurin signaling cascade (NFAT-3, GATA-4).
      Calcineurin enzymatic activity was increased by 80% in human dilated
      cardiomyopathy compared with non-failing human hearts (135.424+/-11.69 and
      83.484+/-1.81 nmol Pi/min per microl). This was in line with increased protein
      expression of calcineurin B in DCM (71.18+9.11 vs. 46.41+/-11.23 densitometric
      units (DU)/microg protein). In order to verify the activated calcineurin pathway
      as described in animal models, we compared the protein expression of NFAT-3 in
      homogenates within nuclear extracts. In nuclear extracts the protein level of
      NFAT-3 was increased in dilated cardiomyopathy compared with non-failing
      myocardium (104.01+/-8.85 vs. 71.47+/-8.79 DU/microg protein). In contrast, in
      homogenates the expression of NFAT-3 was higher in the non-failing tissue
      indicating subcellular redistribution (19.56+/-3.36 vs. 25.84+/-3.16 DU/microg
      protein). The protein expression of GATA-4 was increased in DCM (43.14+/-2.89 vs.
      29.87+/-2.17 DU/microg protein). CONCLUSIONS: In human heart failure (DCM) the
      calcineurin signaling pathway is activated not only by an increased activity of
      calcineurin and expression of GATA-4, but also by the shift from dephosphorylated
      NFAT-3 to the nucleus indicating subcellular redistribution and regulatory
      activation.

PMID- 15012913
TI  - Does angiotensin-converting enzyme gene polymorphism affect blood pressure?
      Findings after 6 years of follow-up in healthy subjects.
AB  - BACKGROUND: There has been an increase in research into the association between
      angiotensin-converting enzyme (ACE) gene deletion polymorphism and cardiovascular
      disease, with conflicting results. The present prospective long-term study was
      conducted to evaluate whether the DD genotype could also be associated with a
      higher prevalence of hypertension in healthy subjects, over 6 years of follow-up.
      METHODS:  POPULATION: 684 healthy volunteers (aged, 25-55 years): normotensive
      and free of cardiovascular diseases, with acceptable echocardiographic window.
      All subjects had to have a normal electrocardiogram (ECG) and echocardiogram
      (ECHO) at entry. STUDY PROTOCOL: All subjects underwent a complete physical
      examination, 12-lead ECG and ECHO, and venous blood samples were drawn for DNA
      analysis and cholesterol. All subjects had a clinical evaluation each year for
      the 6 year duration of the study. RESULTS: All 684 subjects completed 6 years of
      follow-up. We identified three genetically distinct groups. The ACE-DD group
      (n=225, 80F/145M, mean age 43.4+/-7.6 years) had 42 hypertensive subjects
      (18.3%), 5 heart failure (HF) subjects and 6 subjects with acute coronary
      syndromes (ACS). There was no association between family history, smoking habit,
      hypercholesterolemia and events. The ACE-ID group (n=335, 116F/219M, mean age
      43.6+/-7 years) had 16 hypertensive subjects (4.7%) and 3 subjects with ACS. The
      ACE-II group (n=124, 45F/79M, mean age 42.5+/-6.9 years) had 2 hypertensive
      subjects (1.6%) and 1 HF subject. The incidence of hypertension and
      cardiovascular events was significantly higher in the ACE-DD group (53 cases,
      23%) than in the ACE-ID and ACE-II groups (20 and 3 cases, 5.9 and 2.4%,
      respectively), P=0.0001. The higher incidence of hypertension was observed in the
      older age groups (36-45 and 46-55 years) with ACE-DD and ACE-ID genotypes.
      CONCLUSION: Our data suggest that ACE-DD polymorphism is associated with a higher
      incidence of hypertension in baseline healthy subjects, irrespective of other
      risk factors. The higher incidence of hypertension was apparent predominantly in
      the older age groups.

PMID- 15012915
TI  - Association of the angiotensin-converting enzyme gene polymorphism with chronic
      heart failure in Chinese Han patients.
AB  - BACKGROUND: An insertion/deletion (I/D) polymorphism is present in the 16th
      intron of the angiotensin-converting enzyme (ACE) gene and is associated with
      serum and tissue ACE level. Some studies have shown that the DD genotype is
      associated with some cardiovascular diseases; while ACE polymorphism's effect on
      chronic heart failure (CHF) remains uncertain. AIM: To investigate the
      association of the ACE gene I/D polymorphism with CHF in the Chinese Han
      population. METHODS: The genotype was determined by polymerase chain reaction in
      102 normal controls and in 79 patients with CHF. Plasma angiotensin (Ang) levels
      were assessed by radio-immunity assay. Left ventricular end-diastolic diameters
      (LVDD) and left ventricular ejection fractions were assessed by echocardiography.
      RESULTS: The ACE gene polymorphism distribution was similar in patients and
      control subjects. However, ACE gene DD polymorphism was associated with a more
      severe condition, greater LVDD [mm: DD: 71+/-7, ID: 62+/-5, II: 60+/-5, P<0.001
      DD vs. ID, P<0.001 DD vs. II] and higher plasma Ang II level [pg/ml DD: 92+/-19,
      ID: 79+/-21, II: 65+/-17 P<0.05 DD vs. ID, P<0.001 DD vs. II]. CONCLUSION: In
      Chinese Han patients with CHF, ACE gene DD polymorphism might be a marker of a
      more severe condition, and a higher level of activation of the renin-angiotensin
      system.

PMID- 15012914
TI  - Beta-adrenergic receptor blockade and the angiotensin-converting enzyme deletion
      polymorphism in patients with chronic heart failure.
AB  - BACKGROUND: Beta-adrenergic receptor blockade is an established treatment of
      chronic heart failure (HF). Previous studies have suggested a potential
      pharmacogenetic interaction between beta-blocker therapy and the angiotensin
      converting enzyme (ACE) I/D polymorphism in patients with HF. AIMS: We designed
      this study to analyze changes in myocardial function of HF patients in response
      to beta-blocker therapy as a function of the ACE I/D polymorphism. METHODS AND
      RESULTS: We studied 199 consecutive patients with chronic HF not treated with
      beta-blockers. Before initiation of beta-blockers and 3 months after the maximal
      tolerated dose was reached, patients underwent echocardiography, radionuclide
      angiography, and a cardiopulmonary exercise test. We extracted genomic DNA from
      white blood cells and determined the ACE I/D polymorphism. Thirty-five (18%)
      patients had the II genotype, 86 (43%) the ID genotype and 78 (39%) the DD
      genotype. A significant and similar improvement in left ventricular ejection
      fraction (LVEF) was observed in II (from 0.30+/-0.10 to 0.41+/-0.13; P<0.0001),
      ID (from 0.29+/-0.11 to 0.39+/-0.13; P<0.0001) and DD patients (from 0.31+/-0.11
      to 0.40+/-0.13; P<0.0001). Peak Vo(2) before and after beta-blockade was similar
      among the three groups. The proportion of responders to beta-blockers (patients
      without cardiac events during titration who had an increase in LVEF >5% after
      beta-blockers) was similar among the three groups (II: 65.9%%, ID: 60.6%%, DD:
      65.9%; P=NS). During a median follow-up of 933 days, there was no evidence for
      any effect of ACE I/D polymorphism on cardiac survival. CONCLUSIONS: We observed
      no evidence of pharmacogenetic interaction between the ACE I/D polymorphism and
      the effects of beta-blockade on LVEF and other prognostic parameters in patients
      with chronic HF. Our results support the initiation of beta-blockers in HF
      patients with the II or the ID genotype as well as in those with the DD genotype.

PMID- 15012916
TI  - Basal and exercise-induced neuroendocrine activation in patients with heart
      failure and in normal subjects.
AB  - BACKGROUND: Neuroendocrine activation is a pathophysiological response and an
      important prognostic marker in patients with chronic heart failure (CHF).
      Although chronic activation is well described, data on the responsiveness of the
      hormone systems are more limited. Most previous studies have looked at activation
      during maximal exercise, whereas we believe that activation at a submaximal level
      might be more pathophysiologically relevant. AIM: To compare exercise-induced
      neurohormonal activation between CHF patients and normal subjects using the same
      relative and submaximal workload. SUBJECTS: Twenty-three newly-diagnosed CHF
      patients and 18 age- and gender-matched healthy subjects were exercised at two
      workloads, which were calculated to correspond to 50 and 75% of each individual's
      heart rate response. RESULTS: In CHF patients, baseline levels of ANP, BNP, AVP,
      PRA and ET-1 were elevated compared to healthy subjects. Exercise induced an
      increase in ANP, A and NA in both CHF patients and in normal subjects, however
      BNP was only increased in CHF patients and not in normal subjects. CONCLUSION:
      When CHF patients exercise at the same relative and submaximal level as age
      matched healthy subjects, the relative increases in ANP, A and NA were similar,
      however, BNP levels only increased in the CHF group.

PMID- 15012917
TI  - Circulating matrix metalloproteinase-2 is elevated in patients with congestive
      heart failure.
AB  - BACKGROUND AND AIMS: It has been reported that matrix metalloproteinase (MMP)
      protein concentration and activity are upregulated in the failing human heart.
      However, there are few reports describing the role of elevated level of
      circulating MMPs in congestive heart failure (CHF) patients. This study examined
      whether circulating matrix metalloproteinases (MMPs) are also related to the
      pathogenesis of CHF. METHODS: We measured circulating levels of matrix
      metalloproteinase-2 (MMP-2) in 52 patients with CHF (left ventricular ejection
      fraction (LVEF) <50%). The patients were also subdivided into two groups
      according to NYHA functional class; mild CHF (class II, n=43) and severe CHF
      (class III, n=9). RESULTS: The serum level of MMP-2 and MMP-2/TIMP-2 ratio were
      significantly higher in CHF than in controls (P<0.01). Among patient groups,
      serum levels of MMP-2 were significantly higher in patients with severe CHF than
      in patients with mild CHF (P<0.01). Plasma levels of BNP had a significant
      positive correlation with circulating levels of MMP-2 (r=0.78; P<0.01) and MMP
      2/TIMP-2 ratio (r=0.60; P<0.01). CONCLUSIONS: Our data showed that the
      circulating MMP-2 concentration was increased in CHF patients and that the levels
      were related to the plasma levels of BNP in CHF, suggesting that the elevated
      levels are related to developing heart failure syndrome.

PMID- 15012918
TI  - Determinants of platelet responsiveness to nitric oxide in patients with chronic
      heart failure.
AB  - Congestive heart failure (CHF) is associated with oxidative stress. Platelet
      responsiveness to nitric oxide (NO) donors, are impaired in patients with angina
      pectoris, possibly by increasing oxidative stress. We investigated the occurrence
      of platelet resistance to NO in patients, with ischaemic or non-ischaemic
      cardiomyopathy compared with normal subjects. Anti-aggregatory effects of sodium
      nitroprusside (SNP), oxidative stress and whole blood superoxide anion content
      were determined, with correlates of responsiveness to SNP. Inhibition of platelet
      aggregation by SNP was 65.4+/-3.55% in controls and 59.3+/-4.1% in CHF (P=ns)
      despite increased oxidative stress and post-aggregation O2- in CHF patients.
      However, subsets of CHF patients have NO-resistant platelets: this is associated
      with increasing age and/or increased oxidative stress (both p<0.05).

PMID- 15012919
TI  - Diagnostic value of a rapid test for B-type natriuretic peptide in patients
      presenting with acute dyspnoe: effect of age and gender.
AB  - BACKGROUND: B-type natriuretic peptide (BNP) measurements are useful for
      diagnosing congestive heart failure (CHF) in patients presenting to the Emergency
      Department with acute dyspnoe. Whether the diagnostic accuracy of BNP is affected
      by the age and gender of the patients remains unknown. AIMS: To evaluate the
      accuracy of BNP testing for diagnosing CHF in an unselected group of patients
      admitted to the emergency department of a Norwegian teaching hospital with a
      principal complaint of shortness of breath and to assess whether the diagnostic
      accuracy of the test differs according to age and gender. METHODS: BNP levels in
      plasma were determined by a point-of-care device upon arrival in 155 patients
      presenting with acute dyspnoe. The diagnostic 'gold' standard for CHF was
      adjudicated by two independent cardiologists who were blinded to the BNP data.
      RESULTS: By univariate logistic regression analysis, BNP was strongly related to
      a diagnosis of CHF. In a multivariate model BNP provided additional prognostic
      information to patient age and gender, radiographic evidence of pulmonary
      congestion and cardiomegaly, and the presence of pulmonary rales and jugular vein
      distention by physical examination. There was no significant interaction between
      age and BNP or between gender and BNP with regard to the accuracy of diagnosing
      CHF. The area under the receiver-operating characteristics-curve was 0.86 (95%
      confidence interval 0.78-0.93) in women and 0.90 (0.82-0.97) in men. The area
      under the curves were 0.82 (0.73-0.92) and 0.88 (0.80-0.97) for patients (both
      genders) aged > or = 76 and <76 years, respectively. CONCLUSION: Point-of-care
      BNP measurement in the emergency department discriminates well between patients
      with dyspnoe of cardiac and non-cardiac origin regardless of age and gender.

PMID- 15012920
TI  - N-terminal pro-brain natriuretic peptide for discriminating between cardiac and
      non-cardiac dyspnoea.
AB  - AIM: Evaluation of N-terminal pro-brain natriuretic peptide (NT-proBNP) to
      confirm or disprove heart failure in community patients complaining of dyspnoea.
      METHODS AND RESULTS: General practitioners referred 345 consecutive patients
      complaining of dyspnoea to our hospital-based clinic, where a diagnosis was
      established based on a combined programme for heart and lung diseases including
      echocardiography. The level of NT-proBNP in plasma was also measured. The mean
      (S.D.) concentration of NT-proBNP in patients with heart failure was
      significantly higher, 189 (270) pmol/l in patients with heart failure (n=81),
      than in patients with non-cardiac dyspnoea (n=264), 17 (38) pmol/l (P<0.001). In
      patients > or = 50 years NT-proBNP <11 pmol/l for men and <17 pmol/l for women
      excluded heart failure with a negative predictive value of 97% while the positive
      predictive value was 53%, the sensitivity 95% and the specificity 68%. Areas
      under receiver operator characteristic curves for men and women were 0.93 and
      0.90, respectively. CONCLUSION: In a relevant setting of primary care patients
      complaining of dyspnoea, NT-proBNP seems promising for disproval of heart
      failure, and this test may reduce the need for echocardiographic screening with
      50%. However, the discrimination levels of NT-proBNP found in this study may need
      prospective confirmation, before the test can be generally recommended.

PMID- 15012921
TI  - Importance of chronic obstructive pulmonary disease for prognosis and diagnosis
      of congestive heart failure in patients with acute myocardial infarction.
AB  - AIMS: To evaluate the importance of chronic obstructive pulmonary disease for
      prognosis and diagnosis of congestive heart failure in patients with acute
      myocardial infarction. METHOD AND RESULTS: Prospective registration of 6669
      consecutive patients admitted with infarction and screened for a randomised
      controlled trial. A history of COPD was present in 765 (11.5%) patients. Thirty
      day and 5-year survival in patients with chronic obstructive pulmonary disease
      was 86.3 and 42.9%. In patients without pulmonary disease the figures were 87.7
      and 57.5%, respectively, giving a relative risk of 1.49 (1.35-1.65). In
      multivariate analysis the relative risk was 1.15 (1.04-1.28). The prevalence of
      congestive heart failure was 65.9% in patients with chronic obstructive pulmonary
      disease and 52.0% in patients without. This difference was most distinct in
      patients with normal or only slightly decreased left ventricular systolic
      function. In patients without congestive heart failure, chronic obstructive
      pulmonary disease was of prognostic importance [RR=1.44 (1.17-1.78)], but not in
      patients with congestive heart failure [RR=1.09 (0.96-1.23)]. CONCLUSION: Chronic
      obstructive pulmonary disease is a predictor of long-term mortality in patients
      with acute myocardial infarction without congestive heart failure, but is also a
      confounding factor for the diagnosis of congestive heart failure.

PMID- 15012922
TI  - Systematic review of open access echocardiography for primary care.
AB  - Over the last few years there has been a revolution in open access
      echocardiography services due to an increased demand from within secondary care
      and primary care. There have been some concerns expressed by specialists and open
      access echocardiography has not been universally welcomed as a means of offering
      healthcare. Suspected heart failure comprises the majority of primary care
      referrals for open access echocardiography. There is lack of rigorously
      controlled studies to support widespread establishment of open access
      echocardiography services.

PMID- 15012923
TI  - Effect of tissue harmonic imaging and contrast upon between observer and test
      retest reproducibility of left ventricular ejection fraction measurement in
      patients with heart failure.
AB  - AIMS: To investigate the effects of tissue harmonic imaging (THI) and contrast
      chamber opacification (LVO) upon measurement variability and reproducibility of
      echocardiographic left ventricular (LV) volume and ejection fraction (EF)
      measurements in patients with heart failure (HF). BACKGROUND: Echocardiography is
      often used in HF patients to determine LV volumes and EF. However, current echo
      methods are variable and may not be applicable for repeat testing in individual
      patients. THI and LVO have both been shown to improve endocardial visualisation,
      but it remains to be determined whether this results in better measurement
      reproducibility. METHODS: Thirty-one HF patients and 30 control subjects
      underwent echocardiography on two separate days. LV volumes were measured under
      four different imaging conditions: fundamental, THI, LVO and LVO with ECG
      triggered Power Doppler. Chamber opacification, pulmonary transit time (PTT),
      endocardial enhancement, reproducibility and bias were assessed. RESULTS: Chamber
      opacification was inferior and the PTT longer in the HF patients. PTT was related
      to LV volumes, EF, jugular venous pressure and mitral filling pattern. THI
      improved endocardial visualisation, and although LVO improved endocardial
      visualisation in the controls, it offered no benefit over THI in the HF patients.
      LV volumes and EF were different for each method and THI was the least variable
      method for repeat measurements. CONCLUSIONS: THI improved endocardial
      visualisation and was the least variable of the techniques. LVO offered no
      further advantage in patients with HF and thus cannot be routinely advocated and
      since LV volumes and EF were different for each, these methods are neither
      comparable nor interchangeable for follow-up assessments.

PMID- 15012924
TI  - Does aerobic training lead to a more active lifestyle and improved quality of
      life in patients with chronic heart failure?
AB  - BACKGROUND: Due to dyspnea and fatigue, patients with chronic heart failure (CHF)
      are often restricted in the performance of everyday activities, which gradually
      may lead to hypoactivity. AIMS: To assess whether aerobic training leads to a
      more active lifestyle and improved quality of life (QoL) in patients with CHF.
      METHODS: Patients with stable CHF (NYHA II/III; 59 (11) years) were randomly
      assigned to a training group (n=18; 3-month aerobic program above standard
      treatment) or control group (n=16; standard treatment without special advice for
      exercise). Measurements were performed on level of everyday physical activity
      (PA, novel accelerometry-based activity monitor) and QoL, and on several related
      parameters. RESULTS: Training did not result in a more active lifestyle or
      improved QoL, but improved (P<0.05) peak power (17%), 6-min walk distance (10%),
      muscle strength (13-15%) and depression (-1.3 unit). Changes in level of everyday
      PA were related to changes in peak Vo(2) (r=0.58, P=0.01) and knee extension
      strength (r=0.48, P=0.05). CONCLUSIONS: At group level training did not result in
      a more active lifestyle or improved QoL. However, correlations between training
      related changes in parameters suggest that aerobic training has the potential to
      increase levels of everyday PA in CHF.

PMID- 15012925
TI  - Muscle strength as a predictor of long-term survival in severe congestive heart
      failure.
AB  - AIMS: The objective of the study was to test the relationship between isolated
      muscle strength and outcome, and its significance in the context of other
      exercise variables. METHODS AND RESULTS: 122 consecutive patients (LVEF 21+/-7%)
      were enrolled in the study. Isokinetic strength testing of the knee extensor and
      flexor muscles were performed. A subset of 51 patients underwent additional
      upright bicycle testing with gas exchange analysis. The outcome up to 60 months
      was defined by event-free survival (group A, n=59) or death (group B, n=34).
      Patients who had been transplanted were excluded from further analysis. The peak
      strength of the quadriceps muscle was comparable in both groups (N.S.). In
      contrast, the index (value adjusted for weight) did reveal significant
      differences (P<0.04), similar to the peak torque of the knee flexor muscle
      (P<0.04), whose index was even more significant with regard to differences
      (P<0.01). Multivariate analysis including muscle strength variables, pVO2 and
      workload into one model show that the flexor strength index is the only
      independent variable (x2=9 P<0.003). A cut-off point of 68 Nm x 100/kg in the
      strength index of the flexor muscles was used to establish a significant
      difference between groups with regard to outcome (P<0.01). Thus, the isokinetic
      strength of the knee flexor muscles is related to outcome. Moreover, this
      parameter is superior to variables such as peakVO2 and workload.

PMID- 15012926
TI  - Clinical trials update from the American Heart Association meeting: Omega-3 fatty
      acids and arrhythmia risk in patients with an implantable defibrillator, ACTIV in
      CHF, VALIANT, the Hanover autologous bone marrow transplantation study, SPORTIF
      V, ORBIT and PAD and DEFINITE.
AB  - The American Heart Association meeting reported the results of several clinical
      trials of particular interest to those who care for patients with heart failure.
      Omega-3 fatty acids were associated with a trend to increased recurrence of
      ventricular arrhythmias but not mortality in patients with an implantable
      debrillator. The ACTIV in CHF study provides more evidence of a therapeutic role
      for arginine vasopressin antagonists in the treatment of heart failure. The
      VALIANT study provides further evidence to suggest that a combination of
      angiotensin receptor antagonist and ACE inhibitor does not reduce mortality but
      may reduce morbidity in post-MI patients with heart failure or major LV systolic
      dysfunction. A study of autologous bone marrow cell transplantation into
      myocardial scar give gave encouraging results. SPORTIF V showed ximelagation to
      be as effective as warfarin but with improved safety. ORBIT and PAD showed public
      access defibrillators saved lives but questioned their cost effectiveness.
      DEFINITE supported a role for ICDs in patients with non-ischemic cardiomyopathy,
      although cost-effectiveness remains in doubt.

PMID- 15012927
TI  - Aspirin, ACE inhibitors and arterial stiffness.

PMID- 15012928
TI  - Compound decomposition: a new drug discovery tool?

PMID- 15012929
TI  - Advancing applications of microarrays.

PMID- 15012930
TI  - Atomic force microscopy and drug discovery.
AB  - Atomic force microscopy is being used ever more widely in biological imaging,
      because of its unique ability to provide structural information at the single
      molecule level and under near-physiological conditions. Detailed topographic
      images of potential drug targets, such as proteins and DNA, have been produced,
      and the folding of modular proteins has been studied using single-molecule force
      spectroscopy. Recently, atomic force microscopy has been used to examine ligand
      protein and ligand-DNA interactions, and to begin to determine the architecture
      of multi-subunit proteins, including a member of the superfamily of ionotropic
      receptors. Atomic force microscopy is fast becoming a valuable addition to the
      pharmaceutical industry's toolkit.

PMID- 15012932
TI  - Minimizing the immunogenicity of protein therapeutics.
AB  - As is cautioned in many package inserts, 'with all therapeutic proteins, there is
      a potential for immunogenicity'. Immunogenicity problems in humans, which
      currently can be detected only in clinical trials or after product launch, pose a
      significant barrier to the development and acceptance of protein drugs. Recent
      and ongoing research, presented in this review, seeks to address the challenge of
      protein therapeutic immunogenicity by elucidating the mechanisms underlying
      immune recognition of protein therapeutics, establishing preclinical methods for
      assessing immunogenicity and developing strategies for minimizing immune
      responses.

PMID- 15012931
TI  - Anti-cytokine Ab immune therapy: present status and perspectives.
AB  - Allergy, autoimmunity and the pathogenesis of some chronic diseases are dependent
      on host innate and adaptative immune responses. Both responses are associated
      with abnormal cytokine production within pathologic tissues. Over the past two
      decades, the availability of purified cytokines and cytokine antibodies (Abs) has
      prompted a therapeutic approach that aims to supply neutralizing Abs against
      deleterious cytokines, through either passive immunization (administration of
      large quantities of high affinity Abs, prepared ex vivo) or active immunization
      (induction of specific Abs, using immunogenic cytokine derivatives). Both passive
      and active immunization can safely, transiently and effectively be used, as has
      been documented by animal experimentation and confirmed by clinical trials. Novel
      anti-cytokine therapeutic compounds, based on passive Ab immunization, are now
      available to treat rheumatoid arthritis (RA) and have been shown to help control
      neoangiogenesis in cancer patients. Clinical trials using Abs to treat allergic
      disorders are also underway. However, the induction of anti-idiotypic Abs may
      restrict the long-term use of anti-cytokine immunotherapy using allogenic or
      humanized/chimeric Abs. We propose that greater consideration should be given to
      active immunization protocols.

PMID- 15012933
TI  - Molecular resolution of the family Dreissenidae (Mollusca: Bivalvia) with
      emphasis on Ponto-Caspian species, including first report of Mytilopsis
      leucophaeata in the Black Sea basin.
AB  - Considerable uncertainty exists in determination of the phylogeny among extant
      members of the Dreissenidae, especially those inhabiting the Ponto-Caspian basin,
      as multiple systematic revisions based on morphological characteristics have
      failed to resolve relationships within this group of bivalves. In this study we
      use DNA sequence analyses of two mitochondrial gene fragments, 16S rRNA and
      cytochrome c oxidase subunit I (COI), to determine phylogenetic relationships
      among Dreissena rostriformis, D. bugensis, D. polymorpha, D. stankovici, Congeria
      kusceri, and Mytilopsis leucophaeata. Dreissena stankovici was determined to
      represent a sister taxa to D. polymorpha and both are more closely related to
      other extant Dreissena species than Congeria or Mytilopsis. Sequence divergence
      between D. rostriformis and D. bugensis was relatively low (0.3-0.4%), suggesting
      that these two taxa constitute a single species. However, environmental
      differences suggest two races of D. rostriformis, a brackish water race
      (rostriformis) and a freshwater race (bugensis). Spread of bugensis-type
      individuals into habitats in the Caspian Sea that are occupied by rostriformis
      type individuals may create novel hybridization opportunities. Species-specific
      molecular markers also were developed in this study since significant
      intraspecific variation in morphological features complicates dreissenid
      identification. Using two gene fragments (nuclear 28S and 16S), we identified
      restriction fragment length polymorphisms (RFLPs) that distinguish among D.
      rostriformis/bugensis, D. polymorpha, and D. stankovici and revealed the presence
      of a cryptic invader to the Black Sea basin, Mytilopsis leucophaeata. This is the
      first report of this North American native in southern Europe.

PMID- 15012934
TI  - Biogeographic patterns and current distribution of molecular-genetic variation
      among populations of speckled dace, Rhinichthys osculus (Girard).
AB  - We examined genetic diversity within- and among-populations of speckled dace
      (Rhinichthys osculus) in five major drainage systems in the state of Oregon in
      western North America. Analysis of sequence variation in a 670-bp segment of the
      mitochondrial cytochrome b gene revealed deep divergence among basins and high
      genetic diversity within basins. Application of a molecular clock indicated that
      the divergence time among basins reflects vicariant events during the late
      Miocene to early Pliocene. The high levels of genetic diversity observed within
      basins is likely due to large historic population sizes, in particular, within
      the Klamath Basin. Two highly divergent mtDNA lineages were found to co-occur in
      populations in the Klamath Basin. This result may be indicative of a complex
      history of isolation and reconnection in this basin and/or multiple colonization
      events. Based on the observed level of mtDNA divergence these lineages may
      represent two reproductively isolated sympatric taxa. We recommend that major
      basins be regarded as distinct ESUs based on high levels of subdivision, deep
      divergences, and reciprocal monophyly among basins.

PMID- 15012935
TI  - Phylogeny of the Baldratiina (Diptera: Cecidomyiidae) inferred from
      morphological, ecological and molecular data sources, and evolutionary patterns
      in plant-galler relationships.
AB  - The phylogeny of the gall-midge subtribe Baldratiina (Diptera: Cecidomyiidae) was
      reconstructed from molecular (partial sequence of the mitochondrial 12S rDNA),
      morphological and ecological data sets, using 16 representative species of most
      of the genera. The morphological and ecological data were combined in a single
      character matrix and analyzed separately from the molecular data, resulting in an
      eco-morphological cladogram and a molecular cladogram. Attributes of galls and
      host associations were superimposed on the molecular cladogram in order to detect
      possible trends in the evolution of these traits. The cladograms resulting from
      the two independent analyses were statistically incongruent, although both
      provide evidence for the monophyly of the genera Baldratia and Careopalpis and
      the paraphyly of the genera Stefaniola and Izeniola. The results suggest a minor
      impact of the morphological characters traditionally used in the classification
      of the Baldratiina, whereas ecological data had a major impact on the
      phylogenetic inference. Mapping of gall and host attributes on the molecular
      cladogram suggests that multi-chambered stem galls constitute the ancestral state
      in the subtribe, with several subsequent shifts to leaf galls. It is concluded
      that in contrast to other studied groups of gall insects, related baldratiine
      species induce different types of galls, attesting to speciation driven by gall
      type shifts at least as often as host shifts.

PMID- 15012936
TI  - Phylogeny of shorebirds, gulls, and alcids (Aves: Charadrii) from the cytochrome
      b gene: parsimony, Bayesian inference, minimum evolution, and quartet puzzling.
AB  - Charadrii (shorebirds, gulls, and alcids) have exceptional diversity in
      ecological, behavioral, and life-history traits. A phylogenetic framework is
      necessary to fully understand the relationships among these traits. Despite
      several attempts to resolve the phylogeny of the Charadrii, none have
      comprehensively utilized molecular sequence data. Complete and partial cytochrome
      b gene sequences for 86 Charadrii and five Falconides species (as outgroup taxa)
      were obtained from GenBank and aligned. We analyzed the resulting matrices using
      parsimony, Bayesian inference, minimum evolution, and quartet puzzling methods.
      Posterior probabilities, decay indices, and bootstrapping provide strong support
      for four major lineages consisting of gulls, alcids, plovers, and sandpipers,
      respectively. The broad structure of the trees differ significantly from all
      previous hypotheses of Charadrii phylogeny in placing the plovers at the base of
      the tree below the sandpipers in a pectinate sequence towards a large clade of
      gulls and alcids. The parsimony, Bayesian, and minimum evolution models provide
      strong evidence for this phylogenetic hypothesis. This is further corroborated by
      non-tree based measures of support and conflict (Lento plots). The quartet
      puzzling trees are poorly resolved and inconclusive.

PMID- 15012937
TI  - Molecular phylogeny of the livebearing Goodeidae (Cyprinodontiformes).
AB  - The Goodeinae is a speciose group of viviparous freshwater fishes endemic to the
      Mesa Central of Mexico. The current taxonomy of the group is based on morphology
      associated with viviparity and several of the groupings are questionable. We
      sequenced part of the mitochondrial cytochrome c oxidase subunit I (COI) gene
      (627bp) and control region (approximately 430bp aligned) of representatives of 36
      species (all genera) of goodeid fishes in order to establish phylogenetic
      relationships among the taxa. Findings support the monophyly of the Goodeidae,
      the sister-group relationship of the Empetrichthyinae and Goodeinae, and the
      relationship of Profundulus to the Goodeidae. All goodeine genera but Xenotoca
      were recovered as monophyletic. Many of the higher-level relationships within the
      group contradict the findings of previous studies based upon morphology. The rate
      of molecular change in COI (0.9% per Myr), calibrated with the fossil record and
      geological data, suggests an approximate age for the Goodeidae of 16.5Myr. The
      majority of divergence within the Goodeinae appears to have occurred during the
      Miocene, with subsequent cladogenesis in the Pliocene and Pleistocene. Most
      recent speciation appears allopatric. River piracy, particularly involving the
      Rio Ameca basin, has played a significant role in the diversification of the
      Goodeinae.

PMID- 15012938
TI  - Phylogeny and historical biogeography of Agabinae diving beetles (Coleoptera)
      inferred from mitochondrial DNA sequences.
AB  - The Agabinae, with more than 350 species, is one of the most diverse lineages of
      diving beetles (Dytiscidae). Using the mitochondrial genes 16S rRNA and
      cytochrome oxidase I we present a phylogenetic analysis based on 107 species
      drawn mostly from the four main Holarctic genera. Two of these genera (Ilybius
      and Ilybiosoma) are consistently recovered as monophyletic with strong support,
      Platambus is never recovered as monophyletic, and Agabus is found paraphyletic
      with respect to several of the species groups of Platambus. Basal relationships
      among the main lineages are poorly defined, although within each of them
      relationships are in general robust and very consistent across the parameter
      space, and in agreement with previous morphological analyses. In each of the two
      most diverse lineages (Ilybius and Agabus including part of Platambus) there is a
      basal split between Palearctic and Nearctic clades, estimated to have occurred in
      the late Eocene. The Palearctic clade in turn splits into a Western Palearctic
      clade and a clade containing mostly Eastern Palearctic species, and assumed to be
      ancestrally Eastern Palearctic but with numerous transitions to a Holarctic or
      Nearctic distribution. These results suggest an asymmetry in the colonization
      routes, as there are very few cases of transcontinental range expansions
      originating from the Nearctic or the Western Palearctic. According to standard
      clock estimates, we do not find any transcontinental shift during the Pliocene,
      but numerous speciation events within each of the continental or subcontinental
      regions.

PMID- 15012939
TI  - Phylogenetic evidence for an ancient rapid radiation of Caribbean sponge-dwelling
      snapping shrimps (Synalpheus).
AB  - A common challenge in reconstructing phylogenies involves a high frequency of
      short internal branches, which makes basal relationships difficult to resolve.
      Often it is not clear whether this pattern results from insufficient or
      inappropriate data, versus from a rapid evolutionary radiation. The snapping
      shrimp genus Synalpheus, which contains in excess of 100 species and is a
      prominent component of coral-reef faunas worldwide, provides an example. Its
      taxonomy has long been problematic due to the subtlety of diagnostic characters
      and apparently widespread variability within species. Here we use partial mt COI
      and 16S rRNA sequences and morphological characters to reconstruct relationships
      among 31 species in the morphologically well-defined gambarelloides species
      group, a putative clade of obligate sponge associates that is mostly endemic to
      the Caribbean and contains the only known eusocial marine animals. Analysis of
      the combined data produced a single tree with good support for many terminal
      clades and for relationships with outgroups, but poor support for branches near
      the base of the gambarelloides group. Most basal branches are extremely short and
      terminal branches are long, suggesting a relatively ancient, but rapid radiation
      of the gambarelloides group. This hypothesis is supported by significant
      departure from a null model of temporally random cladogenesis. Calibration of
      divergence times among gambarelloides-group species using data from three
      geminate pairs of Synalpheus species separated by the isthmus of Panama suggests
      a major radiation between approximately 5 and 7 Mya, a few My before final
      closure of the Panamanian seaway during a period of spreading carbonate
      environments in the Caribbean; a second, smaller radiation occurred approximately
      4 Mya. This molecular evidence for a rapid radiation among Caribbean marine
      organisms in the late Miocene/early Pliocene is strikingly similar to patterns
      documented from fossil data for several other Caribbean reef-associated
      invertebrate taxa. The similar patterns and timing of cladogenesis evidenced by
      molecular and fossil data for different Caribbean and East Pacific taxa suggests
      that the radiation involved a wide range of organisms, and strengthens the case
      that poor basal resolution in the gambarelloides group of Synalpheus reflects a
      real evolutionary phenomenon. The rapid radiation also helps explain the
      historical difficulty of diagnosing species in Synalpheus.

PMID- 15012940
TI  - Molecular systematics and origin of sociality in mongooses (Herpestidae,
      Carnivora).
AB  - The Herpestidae are small terrestrial carnivores comprising 18 African and Asian
      genera, currently split into two subfamilies, the Herpestinae and the Galidiinae.
      The aim of this work was to resolve intra-familial relationships and to test the
      origin of sociality in the group. For this purpose we analysed sequences of the
      complete cytochrome b gene for 18 species of Herpestidae. The results showed that
      the mongooses were split into three clades: (1) the Malagasy taxa (Galidiinae and
      Cryptoprocta), (2) the true social mongooses and (3) the solitary mongooses, each
      group being also supported by morphological and chromosomal data. Our results
      suggested unexpected phylogenetic relationships: (1) the genus Cynictis is
      included in the solitary mongoose clade, (2) the genera Liberiictis and Mungos
      are sister-group, and (3) the genus Herpestes is polyphyletic. We examined the
      evolution of the sociality in mongooses by combining behavioural traits with the
      cytochrome b data. Some of the behavioural traits provided good synapomorphies
      for characterizing the social species clade, showing the potential benefit of
      using such characters in phylogeny. The mapping of ecological and behavioural
      features resulted in hypothesizing solitary behavior and life in forest as the
      conditions at the base of the mongoose clade.

PMID- 15012941
TI  - Molecular phylogeny and biogeography of the Malagasy and South Asian cichlids
      (Teleostei: Perciformes: Cichlidae).
AB  - Phylogenetic relationships of the Malagasy and South Asian cichlids are
      investigated using nucleotide characters from two mitochondrial genes, a 544 bp
      region of the large ribosomal subunit (16S) and a 649 bp region of cytochrome c
      oxidase subunit I (COI). This is the first molecular analysis to include a
      thorough taxonomic sampling of all Malagasy-South Asian genera, and a near
      complete taxonomic inventory of all valid species. Parsimony analysis of the
      combined data set (1193 aligned nucleotide positions) results in a single,
      completely resolved phylogenetic hypothesis. Results of this analysis, and that
      based on more comprehensive taxonomic sampling across Cichlidae for 16S alone
      (554 bp for 73 taxa), indicate that the Malagasy cichlids are paraphyletic,
      whereas the Malagasy and South Asian cichlids comprise a monophyletic group. In
      both analyses, the African and Neotropical assemblages are monophyletic. The
      Malagasy-South Asian cichlids are not recovered as plesiomorphic members of the
      family in either analysis. Two major clades are recovered within the Malagasy
      South Asian assemblage and given subfamilial rank, Etroplinae, comprising
      Paretroplus (Madagascar) and Etroplus (southern India and Sri Lanka), and
      Ptychochrominae, comprising Ptychochromis, Ptychochromoides, and Oxylapia, all
      endemic Malagasy genera. Placement of the endemic Malagasy genus Paratilapia is
      equivocal depending on the gene fragment(s) analyzed. Inter- and intrageneric
      relationships within Ptychochrominae and Etroplinae are presented and discussed.
      The hypothesis of relationships for Cichlidae based on nucleotide characters from
      16S alone, arguably the most comprehensive and broadly sampled data set across
      all major geographic assemblages to date, is congruent with prevailing hypotheses
      regarding the sequence of Gondwanan fragmentation and a vicariance scenario to
      explain the current distribution of cichlid fishes.

PMID- 15012942
TI  - Phylogenetic analysis of the mitochondrial genes LSU rRNA and COI suggests early
      adaptive differentiation of anal teeth in chrysidine cuckoo wasps (Hymenoptera:
      Chrysididae).
AB  - Cuckoo wasps are a morphologically diverse group of Hymenoptera with parasitoid
      or cleptoparasitic life histories. In the present paper, we explore the
      phylogenetic signal in fragments of the mitochondrial genes LSU rRNA and COI to
      resolve the group's phylogeny. We analyzed sequence data of 33 species
      representing the taxa Cleptinae, Elampini, Parnopini, and Chrysidini. Most of the
      currently recognized relationships of major cuckoo wasp lineages are supported by
      the molecular data. A key difference concerns the phylogenetic position of the
      Euchroeus (=Brugmoia) group within the tribe Chrysidini. It seems likely that an
      erroneous interpretation of morphological characters has led to inappropriate
      rooting of that tribe. We suggest that species of the Euchroeus group be
      interpreted as forming the stem group of the Chrysidini and that the remaining
      genera of that tribe be united in a subordinated taxon. Our results imply that
      the evolution of anal dentition, of significance for breaking into sealed host
      nests otherwise not accessible to cuckoo wasps, already happened at the base of
      the Chrysidini and that an even number of anal teeth arose prior to an odd
      number.

PMID- 15012943
TI  - Phylogenetic relationships of the sweetpotato in Ipomoea series Batatas
      (Convolvulaceae) based on nuclear beta-amylase gene sequences.
AB  - Phylogenetic relationships of 13 accessions and a cultivar representing the
      sweetpotato, Ipomoea batatas (L.) Lam., and its wild progenitors, were
      investigated using the nucleotide sequence variation of a nuclear-encoded beta
      amylase gene. A 1.1-1.3 kb fragment of the gene spanning two exons separated by a
      long intron was PCR-amplified, cloned, and sequenced. Exon sequences proved
      highly conservative, while intron sequences yielded large differences. Intron
      analyses grouped species in a phylogenetic context according to the presence of
      two genome types: A and B. These groups are consistent with results of previous
      analyses, save for the novel placement of I. tiliacea, among the A-genome
      species. Sequences specific to both A and B genome species have been identified.
      Exon sequences indicate that I. ramosissima and I. umbraticola are quite
      different from other A-genome species. Placement of I. littoralis is
      questionable; its intron is similar to other B-genome species, but its exons are
      quite different. Exon evolution indicates that the B-genome has evolved faster
      than the A-genome. Interspecific intron and exon variation indicates I. trifida,
      I. tabascana, and I. batatas form a monophyletic group.

PMID- 15012944
TI  - Phylogeny of "Philoceanus complex" seabird lice (Phthiraptera: Ischnocera)
      inferred from mitochondrial DNA sequences.
AB  - The Philoceanus complex is a large assemblage of lice that parasitise
      procellariiform seabirds (petrels, albatrosses, and their relatives). We obtained
      mitochondrial 12S rRNA and cytochrome oxidase I DNA sequences from 39 species
      from diverse hosts and localities. Resolution of deeper relationships between
      genera was limited, however there is evidence for two major clades, one hosted by
      albatrosses, the other by petrels. Based on our results, the genera hosted by
      albatrosses are excellent candidates for detailed analysis of cospeciation. Our
      results also suggest that a previous estimate of a 5-fold difference in the
      relative rate of sequence evolution in lice and their avian hosts is an artefact
      of limited taxonomic sampling.

PMID- 15012945
TI  - A phylogenetic perspective on larval spine morphology in Leucorrhinia (Odonata:
      Libellulidae) based on ITS1, 5.8S, and ITS2 rDNA sequences.
AB  - Leucorrhinia (Odonata, Anisoptera, Libellulidae) consists of 14-15 species with a
      holarctic distribution. We have combined the morphological characters of a
      previous study with sequence data from the ITS1, 5.8S rDNA, and ITS2 regions of
      the nuclear ribosomal repeat. Cloning was used to investigate the intra
      individual variation and such variation was found in all investigated species.
      Parsimony jackknifing was used to identify supported groups. The effect of
      sequence alignment and gap coding was explored by a modified sensitivity
      analysis. Loss of spines in Leucorrhinia larvae has occurred twice: once in
      Europe and once in North America. The role of spines as a defence against
      predation is discussed in a phylogenetic context.

PMID- 15012946
TI  - Molecular systematics in Aratinga parakeets: species limits and historical
      biogeography in the 'solstitialis' group, and the systematic position of Nandayus
      nenday.
AB  - The parrot genus Aratinga comprises 20 species that can be separated, based on
      morphological characters, in at least three distinct groups. We performed a
      phylogenetic analysis based on mtDNA sequences of individuals belonging to the
      solstitialis group with the objectives of: (1) assessing the genetic differences
      among individuals in order to clarify their specific status; (2) testing the
      monophyly of the group and establishing its phylogenetic position relative to
      other Aratinga species, (3) making inferences about temporal and geographical
      patterns of diversification in the Neotropics. As a result of the analysis, the
      three taxa belonging to the Aratinga solstitialis complex were found to be
      diagnosable phylogenetic species, the monotypic genus Nandayus was found to be
      included in the solstitialis group and the non-monophyly of the genus Aratinga
      was confirmed. Most of the speciation events occurred during the Pliocene and
      Pleistocene and may be related to habitat shifts associated to climate
      oscillation during these periods.

PMID- 15012947
TI  - Radiation and phylogeography in the Japanese macaque, Macaca fuscata.
AB  - The Japanese macaque (Macaca fuscata) presumably differentiated from eastern
      rhesus macaque (Macaca mulatta) populations during the Pleistocene and the two
      species are closely related. In order to analyse speciation and subspeciation
      events in the Japanese macaque and to describe historical and current
      relationships among their populations, we sequenced and analysed a fragment of
      392bp of mitochondrial DNA (mtDNA) control region in 50 individuals belonging to
      six populations of Japanese macaque and compared these sequences with 89 eastern
      rhesus macaque control region sequences from GenBank/EMBL database. There were
      high genetic similarities between both species and only two positions were fixed
      within each species, which supports the inclusion of the Japanese macaque in a
      single species with eastern populations of rhesus macaques. Japanese macaque
      ancestors colonised Japan after the separation of the two species, estimated at
      between 0.31 and 0.88 million years ago (Mya). The star-like phylogeny,
      multimodal mismatch distribution, and lack of correlation between geographic and
      genetic distances are in accordance with a rapid dispersion of macaques
      throughout the archipelago after the arrival into Japan. The species shows low
      genetic variation within populations and high levels of genetic differentiation
      among populations with no mtDNA haplotype shared across populations. Genetic
      distances between Yakushima macaques (Macaca fuscata yakui) and any other
      population of Macaca fuscata fuscata subspecies are comparable to the distances
      between populations of Honshu, Awajishima, and Kyushu, not supporting the
      classification of Yakushima macaques as a different subspecies.

PMID- 15012948
TI  - How do insect nuclear and mitochondrial gene substitution patterns differ?
      Insights from Bayesian analyses of combined datasets.
AB  - We analyzed 12 combined mitochondrial and nuclear gene datasets in seven orders
      of insects using both equal weights parsimony (to evaluate phylogenetic utility)
      and Bayesian methods (to investigate substitution patterns). For the Bayesian
      analyses we used relatively complex models (e.g., general time reversible models
      with rate variation) that allowed us to quantitatively compare relative rates
      among genes and codon positions, patterns of rate variation among genes, and
      substitution patterns within genes. Our analyses indicate that nuclear and
      mitochondrial genes differ in a number of important ways, some of which are
      correlated with phylogenetic utility. First and most obviously, nuclear genes
      generally evolve more slowly than mitochondrial genes (except in one case),
      making them better markers for deep divergences. Second, nuclear genes showed
      universally high values of CI and (generally) contribute more to overall tree
      resolution than mitochondrial genes (as measured by partitioned Bremer support).
      Third, nuclear genes show more homogeneous patterns of among-site rate variation
      (higher values of alpha than mitochondrial genes). Finally, nuclear genes show
      more symmetrical transformation rate matrices than mitochondrial genes. The
      combination of low values of alpha and highly asymmetrical transformation rate
      matrices may explain the overall poor performance of mitochondrial genes when
      compared to nuclear genes in the same analysis. Our analyses indicate that some
      parameters are highly correlated. For example, A/T bias was positively and
      significantly associated with relative rate and CI was positively and
      significantly associated with alpha (the shape of the gamma distribution). These
      results provide important insights into the substitution patterns that might
      characterized high quality genes for phylogenetic analysis: high values of alpha,
      unbiased base composition, and symmetrical transformation rate matrices. We argue
      that insect molecular systematists should increasingly focus on nuclear rather
      than mitochondrial gene datasets because nuclear genes do not suffer from the
      same substitutional biases that characterize mitochondrial genes.

PMID- 15012949
TI  - Nuclear DNA phylogeny of the squirrels (Mammalia: Rodentia) and the evolution of
      arboreality from c-myc and RAG1.
AB  - Although the family Sciuridae is large and well known, phylogenetic analyses are
      scarce. We report on a comprehensive molecular phylogeny for the family. Two
      nuclear genes (c-myc and RAG1) comprising approximately 4500 bp of data (most in
      exons) are applied for the first time to rodent phylogenetics. Parsimony,
      likelihood, and Bayesian analyses of the separate gene regions and combined data
      reveal five major lineages and refute the conventional elevation of the flying
      squirrels (Pteromyinae) to subfamily status. Instead, flying squirrels are
      derived from one of the tree squirrel lineages. C-myc indels corroborate the
      sequence-based topologies. The common ancestor of extant squirrels appears to
      have been arboreal, confirming the fossil evidence. The results also reveal an
      unexpected clade of mostly terrestrial squirrels with African and Holarctic
      centers of diversity. We present a revised classification of squirrels. Our
      results demonstrate the phylogenetic utility of relatively slowly evolving
      nuclear exonic data even for relatively recent clades.

PMID- 15012950
TI  - Phylogenetic analyses of symbiotic nodulation genes support vertical and lateral
      gene co-transfer within the Bradyrhizobium genus.
AB  - Symbiotic nitrogen fixing bacteria-known as rhizobia-harbour a set of nodulation
      (nod) genes that control the synthesis of modified lipo-chitooligosaccharides,
      called Nod factors that are required for legume nodulation. The nodA gene, which
      is essential for symbiosis, is responsible for the attachment of the fatty acid
      group to the oligosaccharide backbone. The nodZ, nolL, and noeI genes are
      involved in specific modifications of Nod factors common to bradyrhizobia, i.e.,
      the transfer of a fucosyl group on the Nod factor core, fucose acetylation and
      fucose methylation, respectively. PCR amplification, sequencing and phylogenetic
      analysis of nodA gene sequences from a collection of diverse Bradyrhizobium
      strains revealed the monophyletic character with the possible exception of
      photosynthetic Bradyrhizobium, despite high sequence diversity. The distribution
      of the nodZ, nolL, and noeI genes in the studied strains, as assessed by gene
      amplification, hybridization or sequencing, was found to correlate with the nodA
      tree topology. Moreover, the nodA, nodZ, and noeI phylogenies were largely
      congruent, but did not closely follow the taxonomy of the strains shown by the
      housekeeping 16S rRNA and dnaK genes. Additionally, the distribution of nodZ,
      noeI, and nolL genes suggested that their presence may be related to the
      requirements of their legume hosts. These data indicated that the spread and
      maintenance of nodulation genes within the Bradyrhizobium genus occurred through
      vertical transmission, although lateral gene transfer also played a significant
      role.

PMID- 15012951
TI  - An empirical test of the treatment of indels during optimization alignment based
      on the phylogeny of the genus Secale (Poaceae).
AB  - The ability of the program POY, implementing optimization alignment, to deal with
      major indels is explored and discussed in connection with a phylogenetic analysis
      of the genus Secale based on partial Adh1 sequences. The Adh1 sequences used span
      exon 2-4. Nearly all variation is found in intron 2 and intron 3, which form the
      basis for the phylogenetic analyses. Both in some ingroup and outgroup taxa
      intron 3 has a major duplication. Previous phylogenetic analyses have repeatedly
      confirmed monophyly of both Secale and Hordeum, the latter being part of the
      outgroup. However, optimization alignment only recovers both genera as
      monophyletic when knowledge of the duplication is incorporated in the analysis.
      The phylogenetic relationships within Secale are not clearly resolved.
      Subspecific taxa of Secale strictum have identical sequences and they are
      confined to a monophyletic group. However, the two subspecific taxa of Secale
      cereale do not form a monophyletic group, and the position of Secale sylvestre is
      uncertain.

PMID- 15012952
TI  - Evolution, biogeography, and the utility of mitochondrial 16s and COI genes in
      phylogenetic analysis of the crab genus Austinixa (Decapoda: Pinnotheridae).
AB  - This study used molecular data (mitochondrial 16s and COI) for the first time to
      explore evolutionary relationships among species of the pinnotherid crab genus
      Austinixa. Low levels of phylogenetic signal were detected for COI. High levels
      of phylogenetic signal were detected for 16s, indicating it is a more useful
      marker for inferring species level phylogenies in Austinixa. Phylogeographic
      patterns among species of Austinixa are consistent with allopatric speciation due
      to numerous climatic and oceanographic fluctuations during the last 5-6 my. In
      addition, all but two species have been derived since the closure of the Isthmus
      of Panama, a pattern consistent with hypotheses that the marine biota of the
      Caribbean and southeastern North America underwent a pulse of biotic turnover
      within the last 2-3 my. Austinixa aidae and Austinixa hardyi had identical 16s
      sequences, and differed by only 2 bp in COI, raising questions about the validity
      of A. hardyi as a distinct species.

PMID- 15012953
TI  - Evolution of preproinsulin gene in birds.
AB  - The coding region of the preproinsulin gene has been cloned and partly sequenced
      in a variety of marine and terrestrial birds (28 species). All genes showed the
      "ancestral" structure with a large intron-2. The size of intron-2 changed
      considerably during the evolution of birds (2.4-4.2kb). The hydrophobicity of
      signal peptides was conserved. Bird C-peptides were predicted to be 28 amino
      acids long, but circulating C-peptides would be only 26 amino acids long, with
      Passer as a possible exception. Bird C-peptides were found to lack the sequences
      identified in mammals as responsible for peptide bioactivity and the structure of
      the central part. In contrast, predicted insulin sequences were highly conserved.
      Only two types of analog were identified: the hypoactive form (GluA8), present
      only in Anseriformes and the hyperactive form (His A8), present in all other
      species. Based on 3'-nucleotide sequence analysis (extending into intron-2),
      birds appeared to be monophyletic. Five groups were clearly identified:
      Paleognathae, Galliformes, Anseriformes, Passeriformes, and Charadriiformes.
      Paleognathae were suggested as the basal group, supporting the traditional view
      of avian evolution. Subsequent branching identified a gallo-anserae group and a
      group containing all other Neognathae. Surprisingly, Columba livia (Columbiforme
      order) clustered with Galliformes. With represented species, Procellariiformes
      and possibly Ciconiiformes, and Pelicaniformes were suggested as paraphyletic, in
      agreement with conclusions from some studies based on mitochondrial DNA
      sequences.

PMID- 15012954
TI  - Historical biogeography at the crossroads of the northern continents: molecular
      phylogenetics of red-backed voles (Rodentia: Arvicolinae).
AB  - Evolutionary relationships of red-backed voles and their relatives were examined
      and used to test biogeographic hypotheses. Sequences of the mitochondrial
      cytochrome b gene were obtained for 25 individuals representing Alticola
      macrotis, Clethrionomys californicus, C. gapperi, C. glareolus, C. rutilus, and
      C. rufocanus. These were combined with 21 partial sequences from GenBank for C.
      regulus, C. rex, C. rufocanus, C. rutilus, Eothenomys imaizumii, E. melanogaster,
      Phaulomys andersoni, and P. smithii. Complete sequences of three species of
      Microtus (M. montanus, M. oeconomus, and M. pennsylvanicus), representative
      species of other arvicoline genera (Myopus, Synaptomys, Arvicola, Ellobius,
      Ondatra, Lemmus, Dicrostonyx, and Phenacomys), and a sigmodontine representative
      (Peromyscus) were included as outgroups. We used maximum parsimony, maximum
      likelihood, distance, and Bayesian based methods and conducted statistical tests
      on proposed hypotheses of phylogenetic relationships and biogeographic histories.
      A close relationship of species representing the genera Alticola, Clethrionomys,
      and Eothenomys was supported (Clethrionomyini); however, the genus Clethrionomys
      was paraphyletic with respect to both Alticola and Eothenomys. Three major clades
      were identified as Asian (Eothenomys andersoni, E. smithii, C. rex, C. regulus,
      and C. rufocanus), Trans-beringian (Alticola macrotis, C. californicus, C.
      gapperi, C. glarelolus, and C. rutilus), and Taiwanese (E. melanogaster). These
      results are consistent with the fossil record which indicates an initial
      diversification in Asia followed by colonization of the Nearctic on at least two
      occasions. The holarctic species, C. rutilus, appears to have either reinvaded
      Asia from North America or colonized North America more recently (late
      Pleistocene) than the two species of Clethrionomys (C. gapperi and C.
      californicus) that are endemic to North America (early to mid-Pleistocene).
      Finally, C. gapperi, appears to be comprised of an eastern and a western species,
      the former with affinities to the Asian C. glareolus and the latter more closely
      related to C. californicus.

PMID- 15012955
TI  - "Lipotyphlan" phylogeny based on the growth hormone receptor gene: a reanalysis.
AB  - From an evolutionary perspective, "insectivores" have been one of the most
      important mammalian groups for over a century. Morphologists have successively
      pruned flying lemurs, elephant shrews, and tree shrews from Insectivora, but have
      retained chrysochlorids, tenrecs, erinaceids, soricids, talpids, and
      solenodontids in crown-group Lipotyphla. With the appearance of large molecular
      data sets, the monophyly of Lipotyphla has proved untenable. Rather, an emerging
      consensus is that Lipotyphla is a diphyletic taxon comprised of two monophyletic
      groups, Afrosoricida and Eulipotyphla. A recent paper by Malia et al. [Mol.
      Phylogenet. Evol. 24 (2002) 91-101] challenged this view and argued that "While
      the data [Growth Hormone Receptor] were unable to support the orders Lipotyphla,
      Eulipotyphla, and Tenrecoidea [= Afrosoricida] this was most likely due to the
      polyphyly of these groups and not to problems associated with the gene itself
      such as saturation or highly divergent sequences em leader " (p. 100). We
      analyzed Malia et al.'s original GHR data set (at both nuclear and protein
      level), an expanded GHR data set that included 49 additional sequences, and a
      concatenated data set that included GHR, BRCA1, vWF, and A2AB for a diverse
      selection of lipotyphlan taxa. Although protein analyses proved inconclusive, all
      analyses at the DNA level clearly show that the statement of Malia et al. is
      erroneous. Indeed, likelihood analyses with GHR and with the concatenated data
      set provide more support for Eulipotyphla and Afrosoricida than for competing
      hypotheses. These results also highlight the potential pitfalls of single-gene
      and parsimony-only analyses.

PMID- 15012956
TI  - A phylogeny of robber flies (Diptera: Asilidae) at the subfamilial level:
      molecular evidence.
AB  - We present the first formal analysis of phylogenetic relationships among the
      Asilidae, based on four genes: 16S rDNA, 18S rDNA, 28S rDNA, and cytochrome
      oxidase II. Twenty-six ingroup taxa representing 11 of the 12 described
      subfamilies were selected to produce a phylogenetic estimate of asilid
      subfamilial relationships via optimization alignment, parsimony, and maximum
      likelihood techniques. Phylogenetic analyses support the monophyly of Asilidae
      with Leptogastrinae as the most basal robber fly lineage.
      Apocleinae+(Asilinae+Ommatiinae) is supported as monophyletic. The laphriinae
      group (Laphriinae+Laphystiinae) and the dasypogoninae-group
      (Dasypogoninae+Stenopogoninae+Stichopogoninae+ Trigonomiminae) are paraphyletic.
      These results suggest that current subfamilial classification only partially
      reflects robber fly phylogeny, indicating the need for further phylogenetic
      investigation of this group.

PMID- 15012957
TI  - Molecular insights into Cumacean family relationships (Crustacea, Cumacea).
AB  - Cumaceans are a diverse order of small, benthic marine crustaceans. Phylogenetic
      hypotheses for the eight currently recognized cumacean families have not been
      formally proposed. However, based on external morphological traits and Linnean
      classification, a few conflicting hypotheses of relatedness have been proposed.
      Family definitions rely on morphological characters that often overlap and
      diagnoses are based on a combination of non-unique characters. Morphological
      analysis does not provide a well-resolved phylogeny. In the present study, we use
      amino acid sequences from the mitochondrial cytochrome oxidase I gene to produce
      a molecular phylogenetic hypothesis for the families of Cumacea. Phylogenetic
      analyses at the amino acid level were performed under Bayesian, likelihood, and
      parsimony methods. Results strongly suggest that families lacking an articulated
      telson form a monophyletic group. This pleotelson clade, composed of the families
      Bodotriidae, Leuconidae, and Nannastacidae, is the most derived within the
      Cumacea. Within this group, the Bodotriidae resolve paraphyletically, with
      Leuconidae and Nannastacidae embedded within it. Comparison of the molecular
      phylogeny with that based on morphology suggests that many "diagnostic"
      characters are homoplasious.

PMID- 15012958
TI  - A DNA investigation into the mysterious disappearance of the Rocky Mountain
      grasshopper, mega-pest of the 1800s.
AB  - The mysterious extinction of the Rocky Mountain Grasshopper, Melanoplus spretus,
      a major pest species on the prairies and plains of the 1800s, is truly a
      remarkable event in the history of agriculture. Recently, we obtained specimens
      of M. spretus from museums and from 400-year-old glacial deposits in Wyoming. We
      report success in obtaining mitochondrial DNA sequences from both sources. This
      permitted us to examine two issues surrounding the species' disappearance. First,
      a long-standing view that M. spretus and the extant species Melanoplus
      sanguinipes are (if not phase transforms of one another) sister taxa, is
      disputed, but cannot be rejected with certainty. Interestingly, there is some
      evidence that suggests there may be a closer affinity with another member of the
      Mexicanus species-group, Melanoplus bruneri. Second, because M. spretus still
      possesses considerable nucleotide diversity (1.15+/-0.19%), a depletion of
      variation cannot be considered a factor contributing to its demise.

PMID- 15012959
TI  - Phylogenetic relationships of nearctic Reticulitermes species (Isoptera:
      Rhinotermitidae) with particular reference to Reticulitermes arenincola Goellner.
AB  - DNA sequence comparisons of the mitochondrial COII, 16S, and 12S rRNA genes were
      used to infer phylogenetic relationships among the six known US Reticulitermes
      species (Reticulitermes flavipes, Reticulitermes arenincola, Reticulitermes
      tibialis, Reticulitermes hageni, Reticulitermes virginicus, and Reticulitermes
      hesperus) and the closely related European species Reticulitermes santonensis.
      The interspecific pairwise sequence divergence, based on uncorrected "p"
      distance, varied up to 10% across the COII, 4.9% across the 16S, and 3% across
      the 12S fragments. Phylogenetic trees were constructed using maximum parsimony,
      likelihood, and distance methods. The combined results suggest several
      phylogenetic relationships including: (i) R. flavipes, R. arenincola, and
      European R. santonensis are possibly conspecific; (ii) R. virginicus and R.
      hageni are closely related species; and (iii) R. tibialis and R. hesperus are
      closely related species. Interestingly, while there is apparent synonymity
      between R. flavipes and R. arenincola by DNA sequence, there are clear
      morphological differences in the soldier caste. This finding suggests a
      combination of molecular and morphological approaches are necessary for accurate
      species identification. These data lend resolution to the complex problem of
      Reticulitermes systematics, and will assist future efforts directed toward
      characterizing species distribution and ecology.

PMID- 15012960
TI  - The phylogenetic position of five genera (Acanthochromis, Azurina, Chrysiptera,
      Dischistodus, and Neopomacentrus) of damselfishes (Perciformes: Pomacentridae).

PMID- 15012961
TI  - Phylogeography of Drosophila subobscura from North Atlantic islands inferred from
      mtDNA A+T rich region sequences.

PMID- 15012962
TI  - How dependable is a non-local molecular clock? A reply to Hausdorf et al. (2003).

PMID- 15012963
TI  - Molecular phylogeny of the extinct cave lion Panthera leo spelaea.
AB  - To reconstruct the phylogenetic position of the extinct cave lion (Panthera leo
      spelaea), we sequenced 1 kb of the mitochondrial cytochrome b gene from two
      Pleistocene cave lion DNA samples (47 and 32 ky B.P.). Phylogenetic analysis
      shows that the ancient sequences form a clade that is most closely related to the
      extant lions from Africa and Asia; at the same time, cave lions appear to be
      highly distinct from their living relatives. Our data show that these cave lion
      sequences represent lineages that were isolated from lions in Africa and Asia
      since their dispersal over Europe about 600 ky B.P., as they are not found among
      our sample of extant populations. The cave lion lineages presented here went
      extinct without mitochondrial descendants on other continents. The high sequence
      divergence in the cytochrome b gene between cave and modern lions is notable.

PMID- 15012964
TI  - Analysis of 18S rRNA gene sequences suggests significant molecular differences
      between Macrodasyida and Chaetonotida (Gastrotricha).
AB  - Partial 18S rRNA gene sequences of four macrodasyid and one chaetonotid
      gastrotrichs were obtained and compared with the available sequences of other
      gastrotrich species and representatives of various metazoan phyla. Contrary to
      the earlier molecular data, the gastrotrich sequences did not comprise a
      monophyletic group but formed two distinct clades, corresponding to the
      Macrodasyida and Chaetonotida, with the basal position occupied by the sequences
      of Tetranchyroderma sp. and Xenotrichula sp., respectively. Depending on the
      taxon sampling and methods of analysis, the two clades were separated by various
      combinations of clades Rotifera, Gnathostomulida, and Platyhelminthes, and never
      formed a clade with Nematoda. Thus, monophyly of the Gastrotricha is not
      confirmed by analysis of the presently available molecular data.

PMID- 15012965
TI  - Complex estimates of evolutionary relationships in Tarentola mauritanica
      (Reptilia: Gekkonidae) derived from mitochondrial DNA sequences.
AB  - Mitochondrial DNA (12S rRNA, 16S rRNA) sequences were analysed within Tarentola
      mauritanica and other selected species of Tarentola. Several highly genetically
      distinct lineages occur in North Africa, revealing phylogroups in southern and
      central Morocco, northern Morocco, Algeria, Tunisia, and Libya. A single
      haplotype characterizes populations across Spain, Portugal, Italy, Menorca,
      Crete, and Tunisia raising the possibility of an anthropogenic introduction
      followed by rapid population expansion throughout southern Europe. T. mauritanica
      is paraphyletic with respect to T. angustimentalis, a Canary islands endemic. The
      high genetic diversity observed across North Africa suggests T. mauritanica may
      represent a species complex.

PMID- 15012966
TI  - Speciation in mountains: phylogeography and phylogeny of the rock lizards genus
      Iberolacerta (Reptilia: Lacertidae).

PMID- 15012967
TI  - Dynamic retrotransposition of ERV-9 LTR and L1 in the beta-globin gene locus
      during primate evolution.

PMID- 15012969
TI  - MtDNA sequencing from zooplankton after long-term preservation in buffered
      formalin.
AB  - Molecular genetic analysis of zooplankton has been slowed by the usual practice
      of preservation and storage of samples in dilute formalin solutions, which are
      not always adequately buffered for pH. We report here the determination of DNA
      sequences for Meganyctiphanes norvegica (Crustacea, Euphausiacea) preserved and
      stored in buffered formalin for up to 25 years. Specifically designed molecular
      protocols for DNA extraction and PCR amplification yielded valid sequence data
      for short (approximately 100-200 bp) regions of the mitochondrial cytochrome b
      (mtCYB) gene for individual euphausiids. Critical aspects of our approach
      include: extended extraction and proteinase-K digestion to maximize DNA yield;
      use of protocols requiring short DNA fragments; design of species-specific PCR
      primers to minimize risks of contamination by exogenous DNA; and comparison with
      published DNA sequences for the same gene and species. We conclude that the yield
      of DNA and the success of subsequent molecular analyses depend primarily on the
      length of time the tissue has been exposed to formalin and the pH of the
      solution. Zooplankton samples intended for molecular analysis should preferably
      be preserved and maintained in ethanol or deep-frozen, but long-term storage in
      buffered formalin does not preclude some types of molecular genetic analysis.

PMID- 15012968
TI  - Molecular systematics of some Indo-Pacific asterinids (Echinodermata,
      Asteroidea): does taxonomy reflect phylogeny?

PMID- 15012970
TI  - The use of composite taxa in supermatrices.

PMID- 15012971
TI  - Antiangiogenic strategies, compounds, and early clinical results in breast
      cancer.
AB  - Angiogenesis is a multi-step process leading to the formation of new blood
      vessels from pre-existing vasculature and it is necessary for primary tumor
      growth, invasiveness and development of metastasis. Experimental and clinical
      data demonstrated that breast cancer is an angiogenesis-dependent disease and
      that the vascular endothelial growth factor (VEGF) family plays a key role it
      being a highly expressed and selective endothelial cell growth factor.
      Preclinical studies have shown that the angiogenic switch occurs early in the
      multistage process of breast cancer development. Targeting the molecular pathways
      involved in tumor progression by biologically-designed treatments is a new
      therapeutic paradigm aimed to reach cancer growth control. A number of possible
      therapeutic targets for antiangiogenic agents have been identified. Here we
      discuss the therapeutic approach based on inhibition of angiogenesis in the
      context of breast cancer with a focus on the early clinical studies on
      antiangiogenic agents in advanced disease.

PMID- 15012972
TI  - Progress in chemoprevention of breast cancer.
AB  - Primary prevention trials have shown that tamoxifen lowers breast cancer
      incidence by 30-40%. Because of the endometrial risk of tamoxifen and the pro
      thrombotic effects of tamoxifen and raloxifene, different strategies are being
      pursued to improve the risk:benefit ratio of breast cancer chemoprevention. Thus,
      raloxifene is being compared with tamoxifen in a phase III trial, while the
      minimal active dose of tamoxifen is being assessed in phase I-II trials. Also,
      the combination of hormone replacement therapy (HRT) and tamoxifen may reduce the
      risks while retaining the benefits of either agent. Anastrozole holds promise as
      a preventive agent based on preliminary results on contralateral breast cancer.
      The identification of women at increased risk for estrogen receptor (ER)-positive
      breast cancer due to hormonal and reproductive factors may maximize the
      therapeutic index of hormonal agents. Finally, new targets that interfere with ER
      negative breast carcinogenesis are being sought as one-third of breast cancers
      will not be preventable by hormonal interventions.

PMID- 15012973
TI  - Progress in the therapy of small cell lung cancer.
AB  - Small cell lung cancer (SCLC) accounts for approximately 14% of all cases of lung
      cancer. Combination chemotherapy is the most effective treatment modality for
      SCLC and recently, several new active drugs have emerged. Combinations of
      platinum agents with CPT-11 or gemcitabine have been successfully compared in
      phase III trials against the cisplatin/etoposide standard. Modest improvements in
      the outcome of patients with SCLC have been noted over the last two decades.
      Thoracic irradiation given concurrently with chemotherapy improves survival
      compared with sequential chemotherapy and radiation, but this approach is
      associated with more toxicity. Moreover, the optimal doses and fractionation of
      thoracic irradiation remain to be determined. Three-dimensional treatment
      planning is under investigation. Prophylactic cranial irradiation (PCI) has
      established a role in the management of patients who have achieved a complete
      response to the initial therapy. Novel molecular targeted therapies are among the
      strategies currently being investigated in SCLC.

PMID- 15012974
TI  - Old and new drugs in systemic therapy of pancreatic cancer.
AB  - BACKGROUND: The incidence of pancreatic cancer nearly equals its death rate
      (97%). Two-year survival is about 10%. Chemotherapy treatment is problematic
      because of the palliative and limited duration of response. MATERIAL AND METHODS:
      The article analyzes the objective response and median survival time (MST) for
      old and new drugs in the treatment of pancreatic cancer. RESULTS: The most
      encouraging results to date come from studies of 5-fluorouracil (5FU) as an
      adjuvant therapy and of gemcitabine in the advanced disease, which is one of the
      most active and best tolerated drugs in recent years. However, with the
      introduction of new drugs or with different old drug associations, interesting
      results are also becoming evident. CONCLUSIONS: New approaches to CT treatment
      are necessary. Patient enrollment into rigorous and well conducted clinical
      trials, either at tumor diagnosis or after tumor recurrence, will generate new
      information regarding investigational therapies and it will offer improved
      therapies for patients with this disease.

PMID- 15012976
TI  - Thoracoscopic surgery in elderly lung cancer patients.
AB  - Age is a recognized risk factor for death after thoracotomy in elderly patients
      with lung cancer. Among other factors, the genesis of this risk is the
      physiologic debilitation that occurs after division of the intrathoracic
      respiratory muscles during thoracotomy, as well as the loss of lung tissue after
      lung resection. Recent advances in video-assisted thoracic surgery (VATS)
      techniques provide an alternative to standard thoracotomy in elderly lung cancer
      patients, resulting in decreased recovery times and fewer perioperative
      complications. Likewise, smaller lung resections (VATS-guided limited wedge
      resection versus lobectomy with thoracotomy) can be adequate oncologic procedures
      in patients with a limited life expectancy but resectable disease. We studied
      these alternative procedures in a cohort of thoracic surgical patients at the
      Brigham and Women's Hospital in Boston, MA. Proposed investigations of the
      psychosocial implications of thoracic surgery in the elderly, irrespective of the
      safety of these maneuvers, are addressed.

PMID- 15012975
TI  - New oral drugs in older patients: a review of idarubicin in elderly patients.
AB  - Idarubicin (IDA) is a structural analogue of daunorubicin with the same mechanism
      of action. Unlike the other currently available anthracyclines, it has a
      significant oral bioavailability, which makes it particularly attractive for the
      treatment of elderly patients. IDA resulted at least as effective as daunorubicin
      for acute nonlymphocytic leukemia and additional data are in analysis as far as
      lymphomas and breast cancer are concerned. Adverse effects are mainly
      hematological, while hair loss, mucositis and cardiotoxicity are less frequently
      reported with IDA than with other anthracyclines. The pharmacokinetics, activity,
      adverse effects and new modalities of oral administration are reviewed.

PMID- 15012978
TI  - Kringle 5 peptide-albumin conjugates with anti-migratory activity.
AB  - Three peptide fragments of the kringle 5 region of plasminogen and their
      respective N- and C-terminus maleimido derivatives conjugated to Cys34 of human
      serum albumin were evaluated in vitro using a human umbilical vein endothelial
      cell (HUVEC) migration assay and a human plasma stability assay. The N-terminus
      maleimido derivative of the 64 to 74 segment of kringle 5 conjugated to human
      serum albumin possessed remarkable anti-migratory activity.

PMID- 15012977
TI  - Effective irreversible alkylating reagents based on the structure of clavulones.
AB  - We describe the design and synthesis of alkylating reagents based on the
      structure of clavulones. They are composed of cross-conjugated dienone system and
      irreversibly reacted with two nucleophiles under mildly basic conditions via beta
      elimination. Hydroxyl derivative 7b showed the highest reactivity toward thiols
      and showed the strongest cytotoxicity in Hela S3 cells among the three
      derivatives having a different protecting group at the tert-hydroxyl group.

PMID- 15012979
TI  - Mass-tag technology for monitoring of protein kinase activity using mass
      spectrometry.
AB  - Monitoring of intracellular protein kinase activity is very important for fields
      involving diagnosis and drug screening. However, current methods, such as
      radiometry using (32)P, or ELISA, are laborious and time-consuming. We have
      developed high-throughput assay system of protein kinase activity using mass
      tagged substrate peptide probes and mass spectrometry. This assay system can
      easily evaluate target kinase activity and will potentially be able to
      simultaneously profile many protein kinase activities.

PMID- 15012980
TI  - A neural network based prediction of octanol-water partition coefficients using
      atomic5 fragmental descriptors.
AB  - An artificial neural network based approach using Atomic5 fragmental descriptors
      has been developed to predict the octanol-water partition coefficient (logP). We
      used a pre-selected set of organic molecules from PHYSPROP database as training
      and test sets for a feedforward neural network. Results demonstrate the
      superiority of our non-linear model over the traditional linear method.

PMID- 15012981
TI  - Miraziridine A: natures blueprint towards protease class-spanning inhibitors.
AB  - The natural product miraziridine A isolated from the marine sponge Theonella aff.
      mirabilis unifies within one molecule three structurally privileged elements: (i)
      (2R,3R)-aziridine-2,3-dicarboxylic acid, (ii) (3S,4S)-4-amino-3-hydroxy-6
      methylheptanoic acid (statine), and (iii) (E)-(S)-4-amino-7-guanidino-hept-2
      enoic acid (vinylogous arginine). The alignment of them realized in the
      tetrapetide allows for a simultaneous inhibition of the proteolytic activity of
      trypsin-like serine proteases, papain-like cysteine proteases, and pepsin-like
      aspartyl proteases. Therefore, this unique compound represents a blueprint for
      the design of protease class-spanning inhibitors.

PMID- 15012982
TI  - Diastereoselective synthesis and configuration-dependent activity of (3
      substituted-cycloalkyl)glycine pyrrolidides and thiazolidides as dipeptidyl
      peptidase IV inhibitors.
AB  - A diastereoselective synthesis was used to prepare a series of (3-substituted
      cyclopentyl and -cyclohexyl)glycine pyrrolidides and thiazolidides. The three
      chiral centers were generated in an unambiguous, stereochemically defined manner.
      Inhibitory activity was dependent on the configuration at each stereocenter and
      on the nature of the 3-substituent. In the cyclopentylglycine pyrrolidide series,
      high potency against dipeptidyl peptidase IV and good selectivity could be
      achieved.

PMID- 15012983
TI  - 3-Amino-2-hydroxyamides and related compounds as inhibitors of methionine
      aminopeptidase-2.
AB  - Substituted 3-amino-2-hydroxyamides and related hydroxyamides and acylhydrazines
      were identified as inhibitors of human methionine aminopeptidase-2 (MetAP2).
      Examination of substituents through parallel synthesis and iterative structure
      based design allowed the identification of potent inhibitors with good
      selectivity against MetAP1. Diacylhydrazine 3t (A-357300) was identified as an
      analogue displaying inhibition of methionine processing and cellular
      proliferation in human microvascular endothelial cells (HMVEC).

PMID- 15012984
TI  - Carbonic anhydrase inhibitors: the first selective, membrane-impermeant
      inhibitors targeting the tumor-associated isozyme IX.
AB  - The inhibition of the tumor-associated transmembrane carbonic anhydrase IX (CA
      IX) isozyme possessing an extracellular active site has been investigated with a
      series of positively-charged, pyridinium derivatives of sulfanilamide,
      homosulfanilamide and 4-aminoethylbenzenesulfonamide. Inhibition data for the
      physiologically relevant isozymes I and II (cytosolic forms) and IV (membrane
      bound) were also provided for comparison. A very interesting inhibition profile
      against CA IX with these sulfonamides has been observed. Several nanomolar
      (K(i)'s in the range of 6-54 nM) CA IX inhibitors have also been detected.
      Because CA IX is a highly active isozyme predominantly expressed in tumor tissues
      with bad prognosis of disease progression, this finding is very promising for the
      potential design of CA IX-specific inhibitors with applications as anti-tumor
      agents. This is the first report of inhibitors that may selectively target CA IX,
      due to their membrane-impermeability and high affinity for this clinically
      relevant isozyme.

PMID- 15012985
TI  - Orally active anti-proliferation agents: novel diphenylamine derivatives as FGF
      R2 autophosphorylation inhibitors.
AB  - (6,7-Disubstituted-quinolin-4-yloxy-phenyl)(4-substituted-phenyl)amine
      derivatives were synthesized and evaluated by a cellular autophosphorylation
      assay for FGF-R2 in the human scirrhous gastric carcinoma cell line, OCUM-2MD3.
      We also performed metabolic stability studies showing that substitutions at the 7
      position of quinoline affect its biological stability. In this study, we achieved
      a remarkable improvement in the solubility and metabolic stability of the
      diphenylamine derivative. The most promising compound 15e showed a significant
      decrease in tumor volume when orally administered.

PMID- 15012986
TI  - Inhibitors of multidrug resistance (MDR) have affinity for MDR substrates.
AB  - Multidrug-resistance (MDR) occurs in many bacterial species and tumour cells. MDR
      functions by membrane proteins which export drugs from cells, resulting in a low
      ineffective concentration of the drug. We have shown by molecular modelling that
      inhibitors of MDR have affinity for substrates of MDR transporters. This affinity
      may facilitate drug entry into cells and a large inhibitor-drug complex may be a
      poorer substrate for the MDR mechanism. This complex would effectively 'cloak'
      the drug rendering it unavailable for efflux.

PMID- 15012987
TI  - Obtaining higher transesterification rates with subtilisin Carlsberg in
      nonaqueous media.
AB  - Three phase partitioning (protein precipitate obtained as an interfacial layer
      between lower aqueous and upper t-butanol phases, formed by the addition of
      ammonium sulphate and t-butanol to the aqueous solution of protein) followed by
      lyophilization in the presence of two-component excipient resulted in 400-480x
      increases in transesterification activity of lyophilized powders of subtilisin
      Carlsberg, depending on the solvent. The three phase partitioned enzyme, 'dried'
      by washing with butanol, gave 3-4x higher rates (depending on the solvent used)
      than the enzyme preparation dried by lyophilization in the presence of two
      component excipient system.

PMID- 15012988
TI  - Mechanism of action of pyridazine analogues on protein tyrosine phosphatase 1B
      (PTP1B).
AB  - The inhibitory effect on PTP1B caused by the addition of pyridazine analogues has
      been investigated. Biophysical techniques, that is, mass spectrometry (MS),
      nuclear magnetic resonance (NMR), and isothermal titration calorimetry (ITC) were
      used for the characterization. Pyridazine analogues cause catalytic oxidation of
      the reducing agent, generating hydrogen peroxide that oxidizes the active site
      cysteine on the enzyme, leading to enzyme inactivation. Two additional compound
      classes show the same effect. We found one common structural feature in these
      molecules that allows the reaction with triplet molecular oxygen to be less
      endothermic. A proposed mechanism for the catalytic redox cycle is described.

PMID- 15012989
TI  - Predicting pharmacophore signals for post-coital antifertility activity of 1
      trifluoromethyl-1,2,2-triphenylethylene derivatives: a statistical approximation
      using E-state index.
AB  - Considering the worth of developing non-steroidal estrogen analogues, the present
      research explores the pharmacophores of 1-trifluoromethyl-1,2,2
      triphenylethylenes (Fig. 1) for post-coital antifertility activity using
      electrotopological state atom (E-state) index. The study shows the efficacy of E
      state index in developing statistically acceptable model, which explains the
      electronic environment and topological states of different atoms in a molecule.
      The exploration concluded that phenyl ring attached to an ethylenic moiety, para
      substitution by nucleophilic group on the phenyl ring and presence of strong
      electronegative group as the 4th substituent on the 1st carbon of the ethylenic
      moiety might be crucial for activity.

PMID- 15012990
TI  - Synthesis and biological evaluation of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) C8
      cyclic amine conjugates.
AB  - We report examples of a series of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD)
      analogues 12-15 prepared from a common functionalized building block 11 that can
      be conveniently synthesized on a large scale and in optically pure form.
      Isoindoline analogue 15 is the most cytotoxic agent in this series, has the
      highest DNA-binding affinity, and shows significant activity in the in vivo
      hollow fibre assay.

PMID- 15012991
TI  - A highly toxic morphine-3-glucuronide derivative.
AB  - By the coupling of octylamine to the uronic acid function of morphine-3
      glucuronide (M3G) a new glycoconjugate (morphine-3-octylglucuronamide, M3GOAM)
      was prepared. When assayed in both rats and mice up to ng/kg (i.p.) doses none of
      the animals survived. The aliphatic octyl chain may be the lethal factor since a
      closely related derivative (M3GNH2), was not toxic and showed similar opioid
      antagonist properties than naloxone.

PMID- 15012993
TI  - A new series of potent oxindole inhibitors of CDK2.
AB  - A novel series of oxindole-type inhibitors of CDK2 that have heteroatom
      substituted alkynyl moieties at their C-4 position is described. These novel 4
      alkynyl-substituted inhibitors have superior potency relative to their parent
      compound in free enzyme and in cell based assays. The crystal structure of CDK2
      in complex with one of these analogues was determined and gives insight to their
      increased potency. The biochemical evaluation of a representative derivative is
      also described.

PMID- 15012992
TI  - Design and synthesis of 3,7-diarylimidazopyridines as inhibitors of the VEGF
      receptor KDR.
AB  - 3,7-Diarylsubstituted imidazopyridines were designed and developed as a new class
      of KDR kinase inhibitors. A variety of imidazopyridines were synthesized and
      potent inhibitors of KDR kinase activity were identified with good aqueous
      solubility.

PMID- 15012994
TI  - Benzimidazolone p38 inhibitors.
AB  - The synthesis and in vitro p38 alpha activity of a novel series of
      benzimidazolone inhibitors is described. The p38 alpha SAR is consistent with a
      mode of binding wherein the benzimidazolone carbonyl serves as the H-bond
      acceptor to Met109 of p38 alpha in a manner analogous to the pyridine nitrogen of
      prototypical pyridylimidazole p38 inhibitors. Potent p38 alpha activity
      comparable to that of several previously reported p38 inhibitors is observed for
      this novel chemotype.

PMID- 15012995
TI  - Epimerisation of lutein to 3'-epilutein in processed foods.
AB  - Lutein can convert to 3'-epilutein and anhydrolutein I in acidic medium as well
      as during different cooking methods. To our knowledge, this is the first
      demonstration of the epimerisation and dehydration of lutein in native samples.
      During different cooking processes the lutein content of the processed vegetables
      and fruits dramatically decreases, thus the bioavailability of processed plant
      food may also decrease. The occurrence of 3'-epilutein in processed food may be
      important regarding the application of synthetic lutein as food additive.

PMID- 15012996
TI  - Regioselective oxidation of 2-amino-3-aroyl-4,5-dialkylthiophenes by DMSO.
AB  - Solutions of 2-amino-3-aroyl-4,5-dialkylthiophenes in DMSO (dimethyl sulfoxide)
      undergo regioselective oxidation of benzylic carbon under mild conditions. We
      describe three examples and propose a mechanism for oxidation.

PMID- 15012997
TI  - Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side
      chains. Part 1: Discovery and SAR study of 4-pyrazolylpiperidine side chains.
AB  - Replacement of the flexible connecting chains between the piperidine moiety and
      an aromatic group in previous CCR5 antagonists with heterocycles, such as
      pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV
      1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted
      nitrogen atom in the heterocycle to be meta to the bond connected to the 4
      position of piperidine. Truncation of a benzyl group to a phenyl group afforded
      compounds with dramatically improved oral bioavailability, albeit with reduced
      activity.

PMID- 15012998
TI  - Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side
      chains. Part 2: Discovery of potent, selective, and orally bioavailable
      compounds.
AB  - Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in
      our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is
      a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1,
      an excellent selectivity profile, and good oral bioavailability in three animal
      species. During this investigation, a new method for the preparation of alpha
      (pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha
      bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This
      allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd
      mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered.

PMID- 15013000
TI  - Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and
      aza-oxindoles.
AB  - The discovery, synthesis, potential binding mode, and in vitro kinase profile of
      3-(3-bromo-4-hydroxy-5-(2'-methoxyphenyl)-benzylidene)-5-bromo-1,3-dihydro
      pyrrolo[2,3-b]pyridin-2-one, 3-[(1-methyl-1H-indol-3-yl)methylene]-1,3-dihydro-2H
      pyrrolo[3,2-b]-pyridin-2-one as potent TrkA inhibitors are discussed.

PMID- 15012999
TI  - Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side
      chains. Part 3: SAR studies on the benzylpyrazole segment.
AB  - Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown
      that both lipophilic and hydrophilic substituents on the phenyl of the benzyl
      group increase antiviral potency. However, improvements in pharmacokinetic
      profiles were generally only observed with more lipophilic substitutions. 4
      Biphenyl (51) performed the best in this regard. Highly lipophilic substituents
      impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy
      substituents provide a good balance of antiviral activity, pharmacokinetic
      parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy
      substituent, are considered the most promising improvements over parent compounds
      9. They demonstrate improved antiviral activity while retaining good
      pharmacokinetic profile and selectivity.

PMID- 15013002
TI  - Lysyl 4-aminobenzoic acid derivatives as potent small molecule mimetics of
      plasminogen kringle 5.
AB  - Kringle 5, a proteolytic fragment of human plasminogen has been shown to potently
      inhibit angiogenesis. The tetrapeptide KLYD derived from kringle 5 has been shown
      to capture many activities of kringle 5 in vitro. Further simplification has been
      achieved by replacement of the two central amino acids with a 4-aminobenzoic acid
      spacer group. Molecules displaying the required recognition groups on this core
      show similar in vitro properties to kringle 5, and are able to displace
      radiolabeled protein from a high affinity binding site on endothelial cells.

PMID- 15013001
TI  - Novel arylsulfonamides possessing sub-picomolar HIV protease activities and
      potent anti-HIV activity against wild-type and drug-resistant viral strains.
AB  - A novel series of P1' chain-extended arylsufonamides was synthesized and
      evaluated for wild-type HIV protease inhibitory activity and in vitro antiviral
      activity against wild type virus and two protease inhibitor-resistant mutant
      viruses. All of the compounds showed dramatic increases in enzyme activity as
      compared to the currently marketed HIV protease inhibitors amprenavir, indinavir,
      and nelfinavir. In addition, significant improvements in antiviral potencies
      against wild type and the two mutant viruses were also realized.

PMID- 15013003
TI  - Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery of
      benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency.
AB  - Optimization of benzimidazole 5-carboxamide derivatives previously identified as
      specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV) has led
      to the discovery of potent analogues that inhibit the enzyme at low-nanomolar
      concentrations. Greater than 800-fold improvement in potency from the original
      lead structure was achieved through the combined effects of conformational
      rigidification, molecular size extension and the identification of previously
      unexploited interactions. Furthermore, these inhibitors retain specificity for
      HCV polymerase relative to other viral and mammalian RNA polymerases.

PMID- 15013004
TI  - Novel inhibitors of fatty acid oxidation as potential metabolic modulators.
AB  - We describe the synthesis of novel inhibitors of fatty acid oxidation as
      potential metabolic modulators for the treatment of stable angina. Replacement of
      the 2H-benzo[d]1,3-dioxolene ring system in our initial lead 3 with different
      benzthiazoles, benzoxazoles and introducing small alkyl substituents into the
      piperazine ring resulted in analogues with enhanced inhibitory activity against 1
      (14)[C]-palmitoyl-CoA oxidation in isolated rat heart mitochondria (6, IC(50)=70
      nM; 25, IC(50)=23 nM).

PMID- 15013005
TI  - Synthesis and evaluation of S-4-(3-thienyl)phenyl-alpha-methylacetic acid.
AB  - Herein we report an efficient procedure to synthesize S-4-(3-thienyl)phenyl-alpha
      methylacetic acid, an enantiomerically pure intermediate of a recently approved
      nonsteroidal antiinflammatory cyclooxygenase inhibitor, atliprofen [methyl RS-4
      (3-thienyl)phenyl-alpha-methylacetate]. The interactions of the active S-isomer
      of the acid were theoretically compared with those of S-ibuprofen through
      molecular docking studies using COX-1 and COX-2 protein structures. The results
      were corroborated by in vitro and in vivo studies.

PMID- 15013006
TI  - Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors
      incorporating substituted biphenyl P4 motifs.
AB  - Anthranilamides 4 and 5 were designed and synthesized as selective and orally
      bioavailable factor Xa inhibitors. Structural modifications aimed at lowering
      their lipophilicity were performed at the central phenyl ring and at the S4
      binding biphenyl region by incorporating water solublizing substituents. The
      resulting compounds (e.g., 7, 8, 14, 30a, and 32b) are highly potent in vitro,
      and show improved activity in human plasma-based thrombin generation assay.

PMID- 15013007
TI  - Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors with
      improved functional activity.
AB  - Compound 2 containing an aminomethylbenzoyl moiety as the S4 binding motif was
      synthesized in order to modulate hydrophlicity of anthranilamide-based factor Xa
      inhibitors with substituted biphenyl P4 groups. Structure-activity relationship
      studies around 2 have led to a series of potent factor Xa inhibitors which are
      highly active in the human plasma-based thrombin generation assay with 2XTG
      values less than 1 microM. Compound 55 shows strong antithrombotic activity in
      our rabbit deep vein thrombosis model, and also exhibits good oral
      bioavailability and a long half life in rats.

PMID- 15013008
TI  - 4-Thio-5-bromo-2'-deoxyuridine: chemical synthesis and therapeutic potential of
      UVA-induced DNA damage.
AB  - 4-Thio-5-bromo-2'-deoxyuridine (3a) is prepared from 5-bromo-2'-deoxyuridine
      (BrdU) and its key properties are explored. The thionucleoside (3a) can react
      readily with monobromobimane and produces high fluorescence. 3a has UV maximum
      absorption at 340 nm and can be incorporated into cellular DNA. The cells
      containing 3a become sensitive to UVA light, offering therapeutic potential for
      UVA-induced cell killing.

PMID- 15013009
TI  - Binding of beta-carbolines at imidazoline I2 receptors: a structure-affinity
      investigation.
AB  - A series of ring-substituted (i.e., methoxy and bromo) 3,4-dihydro- and 1,2,3,4
      tetrahydro-beta-carbolines was examined at I(2) imidazoline receptors, as was the
      effect of ring-opening, ring-expansion, and translocation of the piperidinyl
      nitrogen atom. Several analogues were identified that bind with K(i) <20 nM at
      I(2) sites and with reduced affinity at alpha(2)-adrenergic receptors, and
      1,2,3,4-tetrahydro-gamma-carbolines were identified as a novel class of I(2)
      imidazoline receptor ligand.

PMID- 15013010
TI  - Pyrazino[1,2-a]indoles as novel high-affinity and selective imidazoline I(2)
      receptor ligands.
AB  - 1,2,3,4-Tetrahydropyrazino[1,2-a]indoles are described as a novel class of I(2)
      imidazoline receptor ligands. In particular, 8-methoxy-1,2,3,4
      tetrahydropyrazino[1,2-a]indole (8-OMe THPI; 3c) binds with high affinity at I(2)
      imidazoline receptors (K(i)=6.2 nM) and with exceptional (> or =1000-fold)
      selectivity relative to its affinity for I(1) imidazoline receptors,
      alpha(2)adrenergic receptors, and 5-HT(2A) and 5-HT(2C) serotonin receptors.

PMID- 15013011
TI  - Doxorubicin prodrug on the basis of tert-butyl cephalosporanate sulfones.
AB  - Doxorubicin-cephalosporin prodrug adapted to the development of elastases for the
      liberation of parent drug was synthesized on the basis of cephalosporanate
      sulfone esters.

PMID- 15013012
TI  - Anti-inflammatory flavonoids and pterocarpanoid from Crotalaria pallida and C.
      assamica.
AB  - One new isoflavone, 5,7,4'-trihydroxy-2'-methoxyisoflavone (3) and seven, and
      four known compounds were isolated from the barks of Crotalaria pallida and the
      seeds of C. assamica, respectively. The known compounds, apigenin (1) and 2'
      hydroxygenistein (2), isolated from C. pallida, showed significant concentration
      dependent inhibitory effects on the release of beta-glucuronidase and lysozyme
      from rat neutrophils in response to formyl-Met-Leu-Phe/cytochalasin B (fMLP/CB)
      with IC(50) values of 2.8+/-0.1 and 17.7+/-1.9, and 5.9+/-1.4 and 9.7+/-3.5
      microM, respectively. The known compounds, daidzein (4) and 2'-hydroxydaidzein
      (6), isolated from C. pallida, inhibited of the release of lysozyme and beta
      glucuronidase from rat neutrophils in response to fMLP/CB with IC(50) values of
      26.3+/-5.5 and 13.7+/-2.6 microM, respectively. Compounds 1 and 4 also showed
      significant concentration-dependent inhibitory effects on superoxide anion
      generation in rat neutrophils stimulated with fMLP/CB with IC(50) values of 3.4+/
      0.3 and 25.1+/-5.0 microM, respectively. Compounds 1 and 5, previously isolated
      from C. pallida, showed the inhibition of NO production in lipopolysaccharide
      (LPS)-stimulated RAW 264.7 macrophages and LPS/interferon-gamma (IFN-gamma)
      stimulated N9 microglial cells with IC(50) values of 10.7+/-0.1 and 13.9+/-1.1
      microM, respectively. Flavonoids, suppressed chemical mediators in inflammatory
      cells, may have value in treatment and prevention of central and peripheral
      inflammatory diseases associated with excess production of chemical mediators.

PMID- 15013014
TI  - Cytochrome P450/NADPH-dependent formation of trans epoxides from trans
      arachidonic acids.
AB  - Trans-arachidonic acids (trans-AA) are products of cis-trans isomerization of
      arachidonic acid by nitrogen dioxide radical (NO(2)), and occur in vivo, but
      their metabolism is unknown. We found that hepatic microsomes oxidized trans-AA
      via cytochrome P450/NADPH system to epoxides, which were hydrolyzed by epoxide
      hydrolase to diols (DiHETEs). 14,15-trans-AA produced one erythro diol and three
      threo diols each having one trans double bond.

PMID- 15013013
TI  - Synthesis of angiogenesis-targeted peptide and hydrophobized polyethylene glycol
      conjugate.
AB  - For the purpose of cancer antineovascular therapy, a novel angiogenesis-targeted
      peptide, Ala-Pro-Arg-Pro-Gly, (APRPG) was attached to hydrophobized polyethylene
      glycol (distearoylphosphatidylethanolamine [DSPE]-PEG). DSPE-PEG and the 5-mer
      peptide were condensed with DCC-HOBt method. Liposome modified with this DSPE-PEG
      APRPG conjugate highly accumulated in tumor of tumor-bearing mice.

PMID- 15013015
TI  - 4-Substituted anilides as selective melatonin MT2 receptor agonists.
AB  - A series of 4-substituted anilides with human melatonergic affinity is reported.
      Butyramides 26, 39, 42, 52, 57, and 58 all demonstrated subnanomolar MT(2)
      binding affinity and MT(2) selectivity of at least 70-fold over the MT(1)
      receptor. Compound 26 demonstrated full agonism at the MT(2) receptor.

PMID- 15013017
TI  - Benzodiazepine-based selective inhibitors of mitochondrial F1F0 ATP hydrolase.
AB  - A series of benzodiazepine-based inhibitors of mitochondrial F(1)F(0) ATP
      hydrolase were prepared and evaluated for their ability to selectively inhibit
      the enzyme in the forward direction. Compounds from this series showed excellent
      potency and selectivity for ATP hydrolase versus ATP synthase, suggesting a
      potentially beneficial profile useful for the treatment of ischemic heart
      disease.

PMID- 15013016
TI  - N-[1-Aryl-2-(1-imidazolo)ethyl]-guanidine derivatives as potent inhibitors of the
      bovine mitochondrial F1F0 ATP hydrolase.
AB  - A series of substituted guanidine derivatives were prepared and evaluated as
      potent and selective inhibitors of mitochondrial F(1)F(0) ATP hydrolase. The
      initial thiourethane derived lead molecules possessed intriguing in vitro
      pharmacological profiles, though contained moieties considered non-drug-like.
      Analogue synthesis efforts led to compounds with maintained potency and superior
      physical properties. Small molecules in this series which potently and
      selectivity inhibit ATP hydrolase and not ATP synthase may have utility as
      cardioprotective agents.

PMID- 15013018
TI  - 1,2-Benzothiazine 1,1-dioxide alpha-ketoamide analogues as potent calpain I
      inhibitors.
AB  - A series of potent 1,2-benzothiazine 1,1-dioxide alpha-ketoamide inhibitors of
      calpain I is described.

PMID- 15013019
TI  - The development of potent non-peptidic PTP-1B inhibitors.
AB  - The SAR from our peptide libraries was exploited to design a series of potent
      deoxybenzoin PTP-1B inhibitors. The introduction of an ortho bromo substituent
      next to the difluoromethylphosphonate warhead gave up to 20-fold increase in
      potency compared to the desbromo analogues. In addition, these compounds were
      orally bioavailable and active in the animal models of non-insulin dependent
      diabetes mellitus (NIDDM).

PMID- 15013020
TI  - Structure based design of a series of potent and selective non peptidic PTP-1B
      inhibitors.
AB  - A series of benzotriazole phenyldifluoromethylphosphonic acids were found to be
      potent PTP-1B inhibitors. Molecular modeling on the X-ray crystal structure of
      the lead structure led to the design of potent PTP-1B inhibitors that show
      moderate selectivity against TC-PTP, a very closely related protein tyrosine
      phosphatase.

PMID- 15013021
TI  - Non-peptide alpha v beta 3 antagonists. Part 7: 3-Substituted tetrahydro
      naphthyridine derivatives.
AB  - A series of 3-substituted tetrahydro-[1,8]naphthyridine containing
      alpha(v)beta(3) antagonists was prepared. A comparison of their in vitro IC(50)
      values to the electron properties of the 3-substituents revealed a good linear
      Hammett correlation (rho=-1.96, R(2)=0.959). Electron-withdrawing groups at the 3
      position of the tetrahydro-[1,8]naphthyridine decreased potency while electron
      donating groups enhanced potency.

PMID- 15013023
TI  - A review of compliance, depot intramuscular antipsychotics and the new long
      acting injectable atypical antipsychotic risperidone in schizophrenia.
AB  - BACKGROUND: Several oral atypical antipsychotics are available for schizophrenia
      management. Besides positive and negative symptom control, they may improve
      cognition. Due to their limited availability as oral agents only, benefits are
      limited by noncompliance. METHODS: Using Medline and PsycINFO databases,
      literature was reviewed to address: (1) factors underlying medication
      noncompliance; (2) available evidence on efficacy of depot intramuscular (IM)
      typical antipsychotics; and (3) current knowledge of long-acting atypicals.
      RESULTS: Noncompliance remains high due to illness-, treatment-, and clinician
      related factors. Compared to oral typicals, atypicals may improve compliance,
      even though noncompliance remains high. Depot IM typicals are efficacious
      (reduced relapses and rehospitalizations), but extrapyramidal symptoms are
      problematic. Available data on long-acting atypical risperidone suggest that it
      is safe and efficacious. CONCLUSION: Development of long-acting injectable
      atypical agents is warranted since noncompliance remains high. Future long-acting
      IM atypical trials should include outpatient functioning, and preferably be of
      longer duration to address cost-effectiveness.

PMID- 15013022
TI  - Discovery and SAR development of 2-(phenylamino) imidazolines as prostacyclin
      receptor antagonists [corrected].
AB  - On the basis of screening hits (1a,b), a series of selective, high affinity
      prostacyclin receptor antagonists was developed. The optimized lead compound 25d
      [(4,5-dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxybenzyl)phenyl]amine] had
      analgesic activity in the rat.

PMID- 15013024
TI  - Protective effects of neuronal nitric oxide synthase inhibitor in mouse brain
      against MPTP neurotoxicity: an immunohistological study.
AB  - We recently reported that neuronal nitric oxide synthase (nNOS) inhibitor, 7
      nitroindazole, can protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
      (MPTP) neurotoxicity in mice. It protected against both dopamine depletions and
      tyrosine hydroxylase (TH) positive neuron decreases in the mouse brain. In the
      present study, we further examined whether 7-nitroindazole can also protect
      against the alterations of TH-, microtubule-associated protein 2a,b (MAP2)-,
      glial fibrillary acidic protein (GFAP)-, parvalbumin (PV)-, dopamine transporter
      (DAT)-, nNOS- or endothelial NOS (eNOS)-positive cells, in comparison with
      pargyline as a relatively selective inhibitor of the monoamine oxidase-B (MAO-B).
      The present study showed that nNOS inhibitor as well as MAO-B inhibitor has a
      dose-dependent protective effect against MPTP-induced striatal dopamine and DOPAC
      depletion in mice. Furthermore, the present study revealed that 7-nitroindazole
      and pargyline can protect the alterations of immunohistochemical changes in the
      striatum and substantia nigra after MPTP treatment. These protective effects may
      be, at least in part, produced by the reduction of neuronally derived NO and
      peroxynitrite caused by MPTP. Our results also demonstrate that MPTP can cause
      functional damage of interneurons in the substantia nigra. These results suggest
      the possibility that nNOS inhibitors as well as MAO-B inhibitors may be
      therapeutically useful in neurodegenerative diseases such as Parkinson's disease.
      Thus our present results provide valuable information for the pathogenesis of
      degeneration of the nigrostriatal dopaminergic neuronal pathway.

PMID- 15013025
TI  - Gender in obsessive-compulsive disorder: clinical and genetic findings.
AB  - BACKGROUND: There is increasing recognition that obsessive-compulsive disorder
      (OCD) is not a homogeneous entity. It has been suggested that gender may
      contribute to the clinical and biological heterogeneity of OCD. METHODS: Two
      hundred and twenty patients (n=220; 107 male, 113 female) with DSM-IV OCD (age:
      36.40+/-13.46) underwent structured interviews. A subset of Caucasian subjects
      (n=178), including subjects from the genetically homogeneous Afrikaner population
      (n=81), and of matched control subjects (n=161), was genotyped for polymorphisms
      in genes involved in monoamine function. Clinical and genetic data were
      statistically analyzed across gender. RESULTS: Compared with females, males with
      OCD (1) had an earlier age of onset, and a trend toward having more tics and
      worse outcome, (2) had somewhat differing patterns of OCD symptomatology and axis
      I comorbidity, and (3) in the Caucasian group, were more likely to have the high
      activity T allele of the EcoRV variant of the monoamine oxidase A (MAO-A) gene
      compared to controls, and (4) in the Afrikaner subgroup, were more frequently
      homozygous for the C allele at the G861C variant of the 5HT(1D beta) gene than
      controls. Females with OCD (1) reported more sexual abuse during childhood than
      males, (2) often noted changes in obsessive-compulsive symptoms in the
      premenstrual/menstrual period as well as during/shortly after pregnancy, and with
      menopause, and (3) in the Caucasian subgroup, were more frequently homozygous for
      the low activity C allele of the EcoRV variant of the MAO-A gene compared to
      controls, with this allele also more frequent in female patients than controls.
      CONCLUSION: This study supports the hypothesis that gender contributes to the
      clinical and biological heterogeneity of OCD. A sexually dimorphic pattern of
      genetic susceptibility to OCD may be present. Further work is, however, needed to
      delineate the mechanisms that are responsible for mediating the effects of
      gender.

PMID- 15013026
TI  - Clozapine and olanzapine, but not conventional antipsychotics, increase insulin
      release in vitro.
AB  - This study was undertaken to examine the influence of conventional and atypical
      antipsychotics on insulin release in vitro, using isolated pancreatic islets and
      insulin-secreting INS-1 cells. The effect of the conventional antipsychotics
      haloperidol and zuclopenthixol, and the atypical agents clozapine and olanzapine
      in the concentration of 10(-6) M was investigated on basal and glucose-stimulated
      insulin release. Both clozapine and olanzapine increased basal insulin release,
      whereas zuclopenthixol inhibited glucose-stimulated release and haloperidol had
      no significant effect. In summary, clozapine and olanzapine, in contrast to
      conventional antipsychotics, increase basal insulin release. Interestingly, this
      stimulatory effect on insulin release in vitro may be supported by recent
      clinical findings, showing elevated insulin levels in patients being treated with
      clozapine or olanzapine.

PMID- 15013027
TI  - Alterations in QT dispersion in medicated schizophrenia patients following
      electroconvulsive therapy.
AB  - QT dispersion (QTd) is a measure of interlead variations of the surface 12-lead
      electrocardiogram (ECG). Increased QTd, found in various cardiac diseases,
      reflects cardiac instability and is associated with increased risk for cardiac
      death. Research suggests a link between antipsychotics, ECG abnormalities (QT
      prolongation) and increased sudden cardiac mortality rates. However, QTd analysis
      has been scarcely investigated in schizophrenia patients. We calculated QTd in 20
      medicated psychotic inpatients with schizophrenia, before and 3 days after
      electroconvulsive therapy (ECT), concomitantly with Brief Psychiatric Rating
      Scale (BPRS) assessment. QT interval and the rate-corrected QT (QTc) were
      abnormally prolonged before ECT. However, although QT was significantly
      shortened, QTc showed only a marginal decrease after ECT. QTd, the rate-corrected
      QTd, as well as BPRS, showed a significant decrease after ECT. Further large
      scale studies are warranted to determine if QTd can serve as a marker for
      response to ECT, and if it is a risk factor for sudden cardiac death in
      schizophrenia patients.

PMID- 15013028
TI  - Monosialoganglioside (GM1) attenuates the behavioural effects of long-term
      haloperidol administration in supersensitive rats.
AB  - In the present study we investigated the effects of co-administration of GM(1)
      (15.0 mg/kg, twice daily, for 30 days) and haloperidol (1.0 mg/kg, twice daily,
      for 30 days), as well as the effects of a 5-day treatment with this dose of GM(1)
      after withdrawal from haloperidol in rats. The animals were evaluated in the open
      field test and apomorphine-induced stereotyped behaviour. The results show that
      GM(1) was able to attenuate dopaminergic supersensitivity evaluated by the
      locomotion frequency at 24 and 48 h after the withdrawal from haloperidol. On the
      other hand, rearing frequency was changed neither by haloperidol nor by GM(1.) In
      haloperidol-treated rats immobility time differs from 30 min observation session
      in comparison with the following sessions after the withdrawal from neuroleptic.
      Apomorphine-induced stereotyped behaviour produced a significant increase in
      scores of haloperidol-withdrawn rats. GM(1) did not modify the haloperidol
      effects and did not change the dopamine receptor affinity to apomorphine 100 h
      from abrupt neuroleptic withdrawal.

PMID- 15013029
TI  - Cholesterol in mood and anxiety disorders: review of the literature and new
      hypotheses.
AB  - Cholesterol plays an integral role in the structure and function of the cell
      membrane and may also affect neurotransmission in the central nervous system.
      Previous work has identified abnormalities in serum cholesterol levels in
      patients with mood and anxiety disorders as well as in suicidal patients.
      However, the biological significance of these abnormalities remains to be
      clarified. An understanding of how serum cholesterol relates to the
      pathophysiology of mood disorders may generate biological markers that predict
      treatment response as well as targets for novel therapeutic strategies. In this
      article, we review the literature studying the significance of cholesterol in
      mood and anxiety disorders, with an emphasis on new studies focusing on the
      adverse impact of hypercholesterolemia on the treatment of major depressive
      disorder (MDD). We then propose possible mechanisms that would account for the
      relationship between elevated cholesterol and treatment non-response in MDD.

PMID- 15013031
TI  - Hormonal and temperature responses to flesinoxan in normal volunteers: an
      antagonist study.
AB  - RATIONALE: Flesinoxan is a highly potent and selective 5-HT1A agonist. In a
      recent study, in normal volunteers, flesinoxan induced a significant and dose
      dependent increase in adrenocorticotropic hormone (ACTH), cortisol, prolactin
      (PRL), growth hormone (GH) and a decrease in body temperature. OBJECTIVES: In
      order to better define the role of 5-HT receptor subtypes in response to
      flesinoxan, we assessed the influence of 5-HT1A and 5-HT2 antagonists on hormonal
      and temperature responses to flesinoxan. METHODS: Hormonal and temperature
      responses were studied in 6 volunteers with or without pretreatment with pindolol
      (30 mg p.o.), a 5-HT1A antagonist, or ritanserin (10 mg p.o.), a selective 5-HT2
      antagonist, using a double-blind crossover design. RESULTS: Pindolol
      significantly antagonized ACTH, PRL, GH and temperature responses to flesinoxan
      and ritanserin exhibited similar activity on PRL and ACTH responses. CONCLUSIONS:
      These results show the role of 5-HT1A mechanisms in the PRL, ACTH, GH, and
      temperature responses to flesinoxan, and the role of 5-HT2 mechanisms in PRL and
      ACTH responses. Therefore, they confirm the interest of flesinoxan as a 5-HT
      neuroendocrine probe.

PMID- 15013032
TI  - Reduced anxious behavior in mice lacking the CCK2 receptor gene.
AB  - Cholecystokinin 2 (CCK2) receptors have been implicated as mediators of anxiety
      in standard mouse models such as exploratory behavior both in black and white
      test boxes and in elevated plus-mazes. We investigated the role of the CCK2
      receptor in anxiety by evaluating the behavior of mice lacking the gene for this
      receptor in these standard anxiety models (i.e., exploratory behavior in a black
      and white test box and exploratory behavior in an elevated plus-maze). In the
      black and white test box, mice lacking the CCK2 receptor gene showed
      significantly increased numbers of transitions between the boxes compared to
      control mice. In the elevated plus-maze, mice lacking the CCK2 receptor gene
      displayed significantly more head dips than control mice. These results suggest
      that mice lacking the CCK2 receptor gene are less anxious than normal mice.

PMID- 15013030
TI  - Cell-type specific regulation of calreticulin and Bcl-2 expression by mood
      stabilizer drugs.
AB  - Recent studies in rat brain and cell cultures have demonstrated that expression
      of the peptide-folding chaperone protein calreticulin is increased by valproate
      treatment, while the anti-apoptotic Bcl-2 is increased by both lithium and
      valproate. We asked whether a similar pattern of regulation by these drugs is
      evident in human neuronal and glial cells. One-week treatment with 1 mM valproate
      induced a significant (90%) increase in calreticulin mRNA and protein levels in
      SVG, a glial cell line, but reduced its mRNA levels by 38% in hNT neuronal cells.
      Valproate also markedly increased Bcl-2 mRNA levels by 260%, but only in hNT
      neurons. In contrast, lithium had no significant effect in either cell type.
      Valproate-induced increases in calreticulin may therefore show glial specificity
      in humans, while changes in Bcl-2 levels may be neuron specific. These results
      highlight the cell model dependence of outcomes in molecular studies of mood
      stabilizer effects and the need for caution in interpreting findings in model
      systems.

PMID- 15013034
TI  - Empirical antifungal therapy.
AB  - The number of fungal infections is increasing, particularly in patients with
      cancer, and represent a major problem given the relatively poor response rates,
      especially for aspergillosis, and the high cost. Empirical therapy has become an
      accepted practice as delay in instituting therapy is clearly associated with
      increased morbidity and mortality. In terms of efficacy for the management of
      persistent febrile neutropenic patients, there is no convincing evidence that
      conventional amphotericin B (ampho B) is inferior to any other agent; the lipid
      formulations of ampho B provide similar efficacy with lower toxicity but at a
      much higher cost. Fluconazole is equivalent to ampho B, provided patients at high
      risk of aspergillus infections are excluded. Itraconazole and voriconazole, as
      empirical therapies, are equivalent to conventional ampho B and liposomal ampho
      B, respectively; toxicity is definitely lower and voriconazole is more effective
      at preventing breakthrough fungal infections.

PMID- 15013033
TI  - Interactions between non-barbiturate injectable anesthetics and conventional
      antiepileptic drugs in the maximal electroshock test in mice--an isobolographic
      analysis.
AB  - The aim of this study was the isobolographic evaluation of interactions between
      three non-barbiturate intravenous anesthetics and conventional antiepileptic
      drugs in the maximal electroshock-induced seizures in mice. Electroconvulsions
      were produced by means of an alternating current (ear-clip electrodes, 0.2-s
      stimulus duration, tonic hindlimb extension taken as the endpoint). Adverse
      effects were evaluated in the chimney test (motor performance) and passive
      avoidance task (long-term memory). Plasma levels of antiepileptic drugs were
      measured by immunofluorescence. Obtained results indicate that ketamine acts
      synergistically with valproate and carbamazepine. Also the combinations of
      propofol and valproate or phenobarbital led to synergistic interactions. An
      antagonism was found between etomidate and carbamazepine or phenobarbital. On the
      other hand, interactions between diphenylhydantoin and injectable anesthetics
      proved to be additive. The only exception was the combination of
      diphenylhydantoin and propofol (1:3). Pharmacokinetic phenomena do not seem to
      interfere with the observed interactions, since none of anesthetics influenced
      the free plasma concentrations of antiepileptic drugs. Referring to undesired
      effects, only propofol impaired long-term memory. Although propofol did not
      disturbed motor coordination, it enhanced motor impairment caused by
      carbamazepine and diphenylhydantoin. Results of the present study suggest that
      etomidate needs to be avoided in epileptic patients due to a possibility of
      negative interactions with some antiepileptic drugs and seizure precipitation.

PMID- 15013035
TI  - Oxazolidinones: activity, mode of action, and mechanism of resistance.
AB  - Oxazolidinones are a new group of antibiotics. These synthetic drugs are active
      against a large spectrum of Gram-positive bacteria, including methicillin- and
      vancomycin-resistant staphylococci, vancomycin-resistant enterococci, penicillin
      resistant pneumococci and anaerobes. Oxazolidinones inhibit protein synthesis by
      binding at the P site at the ribosomal 50S subunit. Resistance to other protein
      synthesis inhibitors does not affect oxazolidinone activity, however rare
      development of oxazolidinone resistance cases, associated with 23S rRNA
      alterations during treatment have been reported. Linezolid, the first
      oxazolidinone available, has already taken its place in the clinic for treatment
      of Gram-positive infections. Pharmacokinetic properties as well as its good
      penetration and accumulation in the tissue including bone, lung, vegetations,
      haematoma and cerebrospinal fluid, allow its use for surgical infections.

PMID- 15013036
TI  - Antibiotic therapy for severe bacterial infections: correlation between the
      inhibitory quotient and outcome.
AB  - In severe bacterial infections, treatment failure can occur even when the
      infecting organism has displayed in vitro susceptibility to the antibiotics used.
      Several pharmacokinetic-pharmacodynamic parameters show better correlation with
      therapeutic outcome than susceptibility results. This study was devised to assess
      the relation between the inhibitory quotient (IQ), i.e., the ratio of achievable
      antibiotic concentration at the infection site to the minimum inhibitory
      concentration for the infecting organism, and both clinical and bacteriological
      outcomes in 290 severe bacterial infections. Multivariate analysis showed that
      the IQ was a strong predictor of therapeutic outcome ( P< 0.001-0.002): values <4
      predicted failure, and those >or=6 cure. This simple parameter could be routinely
      used to guide effective antibiotic therapy.

PMID- 15013037
TI  - Five-day moxifloxacin therapy compared with 7-day co-amoxiclav therapy for the
      treatment of acute exacerbation of chronic bronchitis.
AB  - In this randomized, non-blinded study, the efficacy and safety of a 5-day course
      of moxifloxacin (one 400 mg tablet daily) was compared with that of co-amoxiclav
      (one 625 mg tablet every 8h) for 7 days, for the treatment of acute exacerbations
      of chronic bronchitis (AECB). A total of 162 patients with clear signs of an
      acute exacerbation of chronic bronchitis were enrolled. Of these, 153 could be
      studied. Seventy-nine patients were randomized in the moxifloxacin arm and 74 in
      the co-amoxiclav arm of the study. The primary efficacy parameter was clinical
      response at 14 days in the evaluable population. A clinical success was
      classified as resolution or improvement of symptoms. Variables used to assess
      clinical response included wheeze, cough, dyspnoea, sputum volume, rales and
      ronchi. The success rate in the moxifloxacin group was 88.6% (70 of 79) and that
      for co-amoxiclav group was 89.2% (66 of 74). At follow-up (28-35 days post
      treatment), the continued clinical cure rates were 90.0% (63 of 70) for
      moxifloxacin and 89.4% (59 of 66) for co-amoxiclav. No significant differences
      were detected between the two groups. A total of 78 pathogenic bacteria were
      isolated from the sputum samples of the patients, with Moraxella catarrhalis,
      Haemophilus influenzae and Streptococcus pneumoniae being the most frequently
      isolated pathogens. The eradication rate at 14 days in the valid patients was
      similar for both groups, 90.9% (20 of 22) for the moxifloxacin group and 90.0%
      (18 of 20) for the co-amoxiclav group. Both drugs were well tolerated with no
      differences in the drug-related adverse effects or the patients withdrawing
      because of an adverse event. These results and the good spectrum of antibacterial
      activity make moxifloxacin a promising and also safe alternative for the
      empirical treatment of AECB.

PMID- 15013038
TI  - Telephonic back-up improves antibiotic compliance in acute
      tonsillitis/pharyngitis.
AB  - A randomised clinical trial was devised to establish whether telephonic back-up
      added to educational strategy and improved compliance with antibiotic treatment
      in acute tonsillitis/pharyngitis compared with educational strategy only. The
      intervention group was given a telephone call on the fourth day after the start
      of therapy. There were 64 patients in each group (intervention and control). The
      criterion for evaluating the compliance was to count the tablets in a spot-check
      at the patient's house. A tablet count of 80-110% defined good compliance. The
      effect of the intervention was calculated according to the indicators: absolute
      risk reduction (ARR), relative risk reduction (RRR) and number needed to treat
      (NNT). A good compliance percentage was 66.1% (57.7-74.5%) and was significantly
      higher in the intervention group (78.3%) than in the control group (54.1%) (
      P=0.005). Indicators of clinical relevance after the intervention were ARR:
      24.2%; RRR: 52.7%; NNT: 4.13. In conclusion telephonic back-up significantly
      improved the compliance obtained by educational strategy only. It should be used
      in clinical practice.

PMID- 15013039
TI  - Pharmacokinetic interactions of ceftazidime, imipenem and aztreonam with amikacin
      in healthy volunteers.
AB  - The common usage of extended spectrum beta-lactams co-administered with amikacin
      in everyday clinical practice for infections by multidrug-resistant isolates has
      created the need to search for pharmacokinetic interaction. Eighteen healthy
      volunteers were enrolled in the study; six were administered 1g of ceftazidime
      singly intravenously or combined with 0.5 g of amikacin; six received 0.5 g of
      imipenem singly or combined with 0.5 g of amikacin and six 1g of aztreonam singly
      or combined with 0.5 g of amikacin. Blood and urine samples were collected at
      regular time intervals and apparent serum levels were determined by a
      microbiological assay. Co-administration of ceftazidime and amikacin resulted in
      higher C(max) and AUC for amikacin than when administered alone. Co
      administration of imipenem and amikacin resulted in higher C(max) for imipenem
      than when administered alone. The tested interactions did not affect plasma half
      life (t(1/2)) and clearance rate of any antimicrobial compared with its single
      administration. All tested drugs were mainly eliminated by glomerular filtration.
      It is concluded that co-administration of ceftazidime, imipenem or aztreonam with
      amikacin in healthy volunteers might affect C(max) and AUC without influencing
      any other pharmacokinetic parameter. The probable clinical endpoint is that
      giving ceftazidime, imipenem or aztreonam with amikacin might result in a
      transient elevation of beta-lactam serum levels without further affecting the
      complete pharmacokinetic profile of each drug as obtained after administration of
      the drug alone.

PMID- 15013041
TI  - Bacteraemia in Europe--antimicrobial susceptibility data from the MYSTIC
      surveillance programme.
AB  - The in vitro antimicrobial susceptibility of organisms isolated from bacteraemic
      versus non-bacteraemic patients was evaluated using data (1997-2001) from the
      Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Programme.
      Minimum inhibitory concentration values and susceptibility breakpoints of
      meropenem and other broad-spectrum antimicrobials were determined using standard
      methodology. Three thousand one hundred and thirty-six blood culture (BC)
      isolates and 17261 non-BC isolates were obtained from 51 European MYSTIC centres.
      Gram-positive bacteria appeared to be more prevalent in BC isolates compared with
      other sources. Escherichia coli, methicillin-susceptible Staphylococcus aureus
      and Pseudomonas aeruginosa were isolated most frequently. Antimicrobial
      susceptibility of isolates from bacteraemic versus non-bacteraemic patients was
      similar. Meropenem and imipenem were the most active agents against the majority
      of the Gram-positive and Gram-negative organisms. Ceftazidime, gentamicin and
      ciprofloxacin generally exhibited the lowest activities against the most commonly
      isolated organisms. Meropenem was most active against P. aeruginosa and showed
      the highest potency and activity against all extended-spectrum and AmpC beta
      lactamase producers. These results are relevant to the choice of initial,
      empirical therapy for patients with suspected bacteraemia.

PMID- 15013040
TI  - Immunomodulating effect of antimicrobial agents on cytokine production by human
      polymorphonuclear neutrophils.
AB  - It has been previously demonstrated that some antimicrobial agents enhance
      activities of human polymorphonuclear neutrophils (PMNs). The effect on the
      release of cytokines in an inflammatory context from PMNs by these antibiotics
      was evaluated. We studied the effect of the release of some cytokines by human
      PMNs RT-PCR analysis on a clinical strain of Klebsiella pneumoniae by comparing
      the effect with that observed in the presence of co-amoxiclav, sanfetrinem,
      clarithromycin, prulifloxacin and tobramycin. All the drugs tested were capable
      of modulating PMN synthesis in vitro of pro-inflammatory cytokines IL-8, IL
      1beta, TNF-alpha and IL-6, but not that of anti-inflammatory cytokine IL-10. The
      degree of their stimulatory or inhibitory potency varied with the cytokine
      examined.

PMID- 15013042
TI  - Conflicting interpretations of the prevalence of mutations associated with drug
      resistance in antiviral naive HIV-1 patients with acute and chronic infection.
AB  - The routine determination of drug resistance in newly HIV-1 infected individuals
      records a potential increase in transmissions of drug-resistant variants. Plasma
      samples from 38 individuals classified as newly infected (seroconversion time <12
      months) and twenty four individuals with an established infection (seroconversion
      time ranging from 3 to 10 years) were analyzed for the presence of mutations by
      Trugene HIV-1 genotyping assay and Virtual phenotype. Results on the newly
      infected and the chronically infected individuals showed a limited number of
      relevant mutations associated with substantial resistance to reverse
      transcriptase and protease inhibitors. In particular, three patients (4.8%)
      carried viral major mutations (T69D and M41L) associated with resistance to
      reverse transcriptase inhibitors, whereas only one showed the presence of M46L,
      which is correlated with partial resistance to some protease inhibitors. The
      clinical interpretation based on different approaches to monitor resistance
      showed that the Virconet interpretation was less grave than Trugene, suggesting
      that these interpretations need standardization for the currently used sequencing
      methods and that they may be associated with different outcomes when eventually
      are used.

PMID- 15013043
TI  - Measurement of the antibiotic susceptibility of Coxiella burnetii using real time
      PCR.
AB  - The objective of this study was to determine MICs of antibiotics for two
      reference strains of Coxiella burnetii using real time quantitative PCR. The
      method was very sensitive and specific and allowed the evaluation of the doubling
      time of Nine Mile and Q212 strains: 37 and 15 h, respectively. Dose response
      curves of antibiotics were used to determine MICs. Those of doxycycline,
      fluoroquinolone compounds and rifampicin were in the range 1-4 mg/l.
      Telithromycin was the most effective macrolide compound with MICs of 1-2 mg/l.
      The results confirmed previous reports on the accuracy of this new method for the
      determination of the antibiotic susceptibility of C. burnetii and could be used
      for the screening of new drugs.

PMID- 15013044
TI  - Dissemination of CTX-M type beta-lactamases in Enterobacteriaceae isolates in the
      People's Republic of China.
AB  - Previously there have been a number of reports of extended spectrum beta
      lactamase (ESBL) producing isolates of the family Enterobacteriaceae in Asia. We
      first reported the occurrence of bla(CTX-M) in Guangzhou, China, subsequently
      there have been reports of bla(CTX-M) from a number of other south Asian
      countries. Initial surveillance study data suggested that bla(CTX-M) might be
      widely distributed in China. This study examines the type of bla(CTX-M) occurring
      in other major population centres in China. Initial disk diffusion method
      susceptibility testing (NCCLS) selected ESBL producing Escherichia coli and
      Klebsiella pneumoniae isolates from Beijing and near Wuhan, PRC. After screening
      in both China and the UK, 13 isolates producing CTX-M ESBLs were identified and
      studied, 11 also produced TEM-1, and 4 also produced SHV-1. Sequence analysis of
      the bla(CTX-M) containing isolates revealed these isolates contained two
      different bla(CTX-M), three with bla(CTX-M-3) and 10 with bla(CTX-M-14). After
      comparison with other previously published studies in the English language, we
      conclude that the most prevalent bla(CTX-M) so far reported in Asia are bla(CTX-M
      14) and bla(CTX-M-3).

PMID- 15013046
TI  - Validation of commercial dry-form broth microdilution panels and test
      reproducibility for susceptibility testing of dalbavancin, a new very long-acting
      glycopeptide.
AB  - Results from dalbavancin dry-form commercial broth microdilution MIC panels
      (Sensititre, TREK Diagnostics) were compared with reference frozen-form MIC
      values to assure the validity and reproducibility of the extended shelf-life
      product. A collection of 402 organisms from four major organism groups were used
      in the validation trial and 10 strains for reproducibility replicate tests. A
      total of 98.6% commercial dalbavancin MIC results were within +/-1 log(2)
      dilution of reference values (76.2% were identical) and reproducibility trials
      produced identical MIC results in 88.9-92.2% of dalbavancin MIC comparisons.
      These dalbavancin MIC results demonstrated the acceptable accuracy of
      commercially-prepared broth microdilution products for use in subsequent clinical
      trials.

PMID- 15013045
TI  - In vitro activity of gemifloxacin and contemporary oral antimicrobial agents
      against 27247 Gram-positive and Gram-negative aerobic isolates: a global
      surveillance study.
AB  - This study was a multi-centre, multi-country surveillance of 27247 Gram-positive
      and Gram-negative isolates collected from 131 study centres in 44 countries from
      1997 to 2000. MICs of gemifloxacin were compared with penicillin, amoxicillin
      clavulanic acid, cefuroxime, azithromycin, clarithromycin, trimethoprim
      sulphamethoxazole, ciprofloxacin, grepafloxacin and levofloxacin by broth
      microdilution. Penicillin resistance in Streptococcus pneumoniae was extremely
      high in the Middle East (65.6%), Africa (64.0%) and Asia (60.4%) and lower in
      North America (40.3%), Europe (36.9%) and the South Pacific (31.8%). Macrolide
      resistance in S. pneumoniae was highest in Asia (51.7%) but varied widely between
      laboratories in Europe (26.0%), North America (21.6%), the Middle East (13.7%),
      the South Pacific (10.6%) and Africa (10.0%). All the study quinolones were
      highly active against penicillin-resistant and macrolide-resistant S. pneumoniae.
      Overall, gemifloxacin had the lowest MIC(90) at 0.06 mg/l with MICs 4-64-fold
      lower than ciprofloxacin, levofloxacin and grepafloxacin against S. pneumoniae.
      Gemifloxacin MICs were more potent than grepafloxacin > levoflaxacin >
      ciproflaxin against the Gram-positive aerobes and shared comparable Gram-negative
      activity with ciprofloxacin and levofloxacin.

PMID- 15013048
TI  - Efficacy of oral levofloxacin and dirithromycin alone and in combination with
      rifampicin in the treatment of experimental murine Brucella abortus infection.
AB  - The efficacy of levofloxacin and dirithromycin, alone and in combination with
      rifampicin in the treatment of experimental brucellosis was investigated. Seventy
      adult white male mice were infected intraperitoneally with Brucella abortus S544
      standard strain. Four of the animals were sacrificed on the 21st day of
      inoculation for infection control. The remaining 66 mice were randomised into
      treatment and control groups. Following 14 days of treatment the animals were
      sacrificed and spleen cultures were made. The cure rates were 36.4% for
      levofloxacin, 27.3% for dirithromycin, 72.7% for rifampicin, 72.7% for
      levofloxacin + rifampicin and 81.8% for dirithromycin + rifampicin. The results
      of this study indicate that levofloxacin and dirithromycin are ineffective in the
      treatment of experimental murine brucellosis as monotherapy or in combination
      with rifampicin.

PMID- 15013047
TI  - Emergence of resistance to chloramphenicol among vancomycin-resistant
      enterococcal (VRE) bloodstream isolates.
AB  - Therapeutic options for vancomycin-resistant enterococcal (VRE) bloodstream
      infections are extremely limited. Chloramphenicol is effective when VRE isolates
      are susceptible to this agent. However, longitudinal trends in chloramphenicol
      resistant VRE (CR-VRE) are unknown. The possible association between CR-VRE and
      antibiotic use has not been studied. We analyzed the antimicrobial susceptibility
      profiles of all VRE blood isolates from 1991-2000 at our institution. We
      performed a correlational study to examine the relationship between annual
      hospital-wide use of specific antibiotics and antibiotic classes and CR-VRE
      prevalence. During the 10-year study period, the prevalence of CR-VRE increased
      from 0 to 11% ( P< 0.001, trend). CR-VRE prevalence was correlated only with
      chloramphenicol use (P=0.05 ) and quinolone use (P= 0.01 ). If these trends
      continue, dependence on newer, more expensive agents will increase. The
      correlation between both chloramphenicol use and quinolone use and the prevalence
      of CR-VRE suggests that efforts to preserve the utility of chloramphenicol in VRE
      infections may depend on optimizing the use of these agents.

PMID- 15013049
TI  - Recording zone sizes-a rare phenomenon in microbiology laboratories?

PMID- 15013051
TI  - Reduction of intracellular calcium removal rate can explain changes in seizure
      dynamics: studies in neuronal network models.
AB  - Complex partial seizures originating from mesial temporal structures are
      characterized by relatively short durations of organized rhythmic activity (ORA)
      of 5-8 Hz, typically lasting less than 60s. Previous investigations into seizure
      dynamics have revealed that this ORA undergoes a monotonic decline prior to
      seizure evolution into intermittent bursting and subsequent seizure termination.
      Large neural network models of simplified single-compartment neurons were
      employed to address the hypothesis that changes in the free intracellular calcium
      ([Ca2+]i) removal rate during network bursting can result in the alterations of
      rhythmic seizure activity similar to that observed in recordings from humans.
      Both exponential and linear models of decreasing calcium removal rates resulted
      in changes in the predominant frequency of network bursting very similar in
      frequency and time course to those seen in human intracranial recordings. This
      supports the concept that changes in [Ca2+]i removal can explain this important
      network behavior, while not excluding alternative hypotheses. Identifying
      potential mechanisms underlying the dynamic changes seen in epileptogenic
      activity in large neural networks can provide important insights into seizure
      evolution and termination. Model neural network ensembles are attractive systems
      to address these questions that are difficult to investigate in biological
      preparations.

PMID- 15013050
TI  - Evaluation of VPA dose and concentration effects on lamotrigine pharmacokinetics:
      implications for conversion to lamotrigine monotherapy.
AB  - OBJECTIVE: Lamotrigine (LTG) is approved for monotherapy following withdrawal
      from enzyme-inducing antiepileptic drugs. LTG is also frequently used in
      combination with sodium valproate (VPA), and withdrawal to monotherapy in this
      setting is also frequently desirable. Given the known pharmacokinetic interaction
      between these two drugs, clinically relevant questions that should be answered
      include (1) at what dose and/or concentration of VPA does this interaction begin,
      and (2) at what dose of VPA does maximal inhibition occur. METHODS: LTG
      pharmacokinetics was evaluated using single-dose LTG (25 mg) given before and
      following low-dose VPA co-medication (125, 250, 375, 500 mg per day VPA) in
      healthy subjects. Serial blood samples were obtained over 120 h post-dose in
      order to calculate LTG kinetic parameters including area under the concentration
      time curve, apparent oral clearance, elimination half-life and percent inhibition
      of LTG clearance at each dosage level of VPA. Pharmacodynamic modeling was used
      to calculate EC(50) values for this interaction. RESULTS: LTG pharmacokinetic
      parameters were evaluated in adult healthy female & male volunteers. Mean trough
      VPA concentrations at doses of 125, 250, 375 and 500 mg per day were 6.5, 13.9,
      16.1 and 31.9 microg/ml, respectively. Maximal theoretical inhibition of LTG oral
      clearance by VPA is approximately 65%, with an EC50 concentration value of
      approximately 5.6 microg/ml of VPA. Mean inhibition of LTG oral clearance during
      concomitant treatment with VPA 125, 250, 375 and 500 mg per day was 30.8, 51.5,
      52.8 and 50.3%, respectively. CONCLUSIONS: These data suggest that VPA inhibition
      of LTG clearance begins at very low VPA doses and concentrations. Importantly,
      maximal inhibition can be expected at VPA doses of approximately 500 mg per day,
      with the magnitude of inhibition diminishing at doses below this. These data
      provide useful information to develop a dosing algorithm to facilitate conversion
      to LTG monotherapy.

PMID- 15013052
TI  - Effect of valproate on hemostatic function in patients with traumatic brain
      injury.
AB  - OBJECTIVES: To evaluate whether valproate (VPA) resulted in laboratory or
      clinical evidence of a change in bleeding-related measures associated with VPA
      therapy in patients sustaining a traumatic brain injury. METHODS: Fibrinogen,
      platelet count and clot elastic shear modulus using the Thrombelastograph (TEG)
      coagulation analyzer were measured at baseline, 4, 14, 30, and 180 days post
      injury. Clinically significant events, defined as the trigger for requiring a
      transfusion, were identified and evaluated as to possible treatment effects.
      RESULTS: Compared to baseline, the platelet count in the VPA groups was decreased
      on day 4, increased by 100% on day 14, and returned to baseline levels by day 30.
      Fibrinogen was significantly increased by day 4 and returned to baseline by day
      30. The platelet count was correlated with an increase in the maximum amplitude
      or width of the TEG tracing; a measure of strength of the clot, suggesting that
      valproate did not alter the clot strength contributed by platelets. None of the
      clinical events requiring transfusions appeared to be treatment related.
      CONCLUSIONS: No serious hemostatic adverse events occurred in the trauma patients
      receiving VPA or phenytoin that could be attributed to treatment.

PMID- 15013053
TI  - Mechanisms contributing to the exacerbated epileptiform activity in hippocampal
      slices of GABAB1 receptor subunit knockout mice.
AB  - The recently developed GABAB1 receptor subunit knockout (GABAB1 -/-) mouse
      displays complete loss of GABAB receptor function and develops complex
      generalized epilepsies including absence type, audiogenic as well as spontaneous
      generalized seizures with electrographic spike-wave discharge signatures. To gain
      insight into the cellular mechanisms contributing to the generation and
      maintenance of this epileptic phenotype we have compared epileptiform activity
      induced in hippocampal slices obtained from GABAB1 -/- and wild type (GABAB1 +/+)
      littermates. Deletion of the GABAB1 receptor subunit had no effect on a range of
      passive membrane properties of CA3 pyramidale neurones, non-synaptic epileptiform
      field bursting and spreading depression recorded in 6mM K+/Ca2+-free medium, and
      inter-ictal synaptically-induced epileptiform activity induced by 100 microM 4
      aminopyridine (4-AP). In contrast, synaptic epileptiform activity induced by 10
      microM bicuculline, removal of extracellular Mg2+ or addition of 10 microM
      oxotremorine was enhanced in GABAB1 -/- slices. Acute blockade of GABAB receptors
      using a selective antagonist only partly mimicked these effects. It is suggested
      that the exaggerated in vitro epileptiform activity is caused by both acute and
      chronic consequences of the loss of GABAB receptor function in vivo.
      Specifically, enhancement of N-methyl-d-aspartate (NMDA) receptor triggered
      synaptic processes, arising from the loss of the GABAB receptor-mediated
      inhibitory postsynaptic potential (IPSP, together with a possible promotion of
      depolarising IPSPs due to the removal of GABAB autoreceptor function) is likely
      to underlie these effects.

PMID- 15013054
TI  - Recognition memory of serially or simultaneously presented words or figures, of
      epilepsy patients with or without mesial temporal sclerosis.
AB  - Previous studies, examining short-term recognition memory in patients with
      partial seizures as a consequence of mesial temporal sclerosis (MTS) have
      reported inconsistent findings. Dependent on the paradigms used for measuring
      recognition memory, some studies have demonstrated that the mesial temporal
      structures are not critically involved in short-term recognition memory. In
      addition, other studies found a lateralization effect that is consistent with the
      generally accepted association between left temporal lobe lesions and verbal
      memory deficits, and right temporal lobe lesions and non-verbal memory
      impairments. In the present study verbal and non-verbal recognition memory was
      tested in 41 patients with left or right temporal lobe epilepsy with MTS (22
      left; 19 right) versus 44 patients with left or right temporal lobe epilepsy but
      without MTS (28 left; 16 right). Verbal and non-verbal recognition tasks were
      presented in both a serial and simultaneous condition to test a hypothesized
      local/global paradigm. Multiple analyses of variance (MANOVA) showed that
      unilateral MTS has no marked effects on verbal or non-verbal recognition memory
      of patients with seizures. An interaction effect between MTS and the
      lateralization of epileptic activity was found on memory performance: MTS only
      leads to deficits in recognition memory in patients with right-sided epileptiform
      activity. As hypothesized, patients with left temporal lobe abnormalities, have
      specific deficits with recognizing serially presented information.

PMID- 15013055
TI  - Teratogenicity of valproate conjugates with anticonvulsant activity in mice.
AB  - Valproic acid (VPA) is an effective antiepileptic medication, the use of which in
      females of childbearing age is complicated by its ability to induce birth
      defects, including neural tube defects (NTDs), in exposed embryos. In
      experimental settings, VPA reproducibly induces NTDs in laboratory animals such
      as the highly inbred SWV/Fnn mice. In search of new, efficacious derivatives of
      VPA that lack toxicity, the conjugates of VPA with amantadine (VPA-AMA) and N-3
      aminopropyl-2-pyrrolidinone (VPA-PYR) have been synthesized and evaluated for
      their anticonvulsant activity. In the present study, the authors evaluated the
      teratogenicity potential of VPA-AMA and VPA-PYR using a well-established mouse
      model for antiepileptic drug teratogenicity. All tested compounds were injected
      intraperitoneally to pregnant dams on gestational day 8.5, and the fetuses
      examined on day 18.5. At the highest dose tested (3.61 mmol/kg), VPA-PYR was
      maternally lethal, whereas VPA-AMA induced excessive embryonic lethality. At a
      dose of 2.20 mmol/kg, VPA-PYR was not teratogenic to the exposed embryos; VPA-AMA
      induced NTDs in 8.2% of embryos, VPA caused 5.5% NTDs. 0.80 mmol/kg amantadine
      induced NTDs in 2.2% of the exposed fetuses. In conclusion, VPA-AMA has a
      comparable teratogenicity as does VPA, and it is proposed that the teratogenicity
      of VPA-AMA is due to the parent compound. Additional studies are needed to fully
      define and understand the structure-teratogenicity relationships of VPA
      analogues.

PMID- 15013056
TI  - Spikes on the postoperative EEG are related to preoperative spike frequency and
      postoperative seizures.
AB  - PURPOSE: To investigate the factors which influence the persistence of interictal
      epileptiform discharges (IED) after epilepsy surgery. METHODS: In this
      retrospective study we included patients with intractable medial temporal lobe
      epilepsy (MTLE) who underwent presurgical evaluation including high-resolution
      MRI and video-EEG monitoring with seizure registration prior to an anterior
      temporal lobe resection. The postsurgical outcome was assessed by our team 6
      months and 2 years after the surgery. RESULTS: One hundred and forty-seven
      patients fulfilled the inclusion criteria. The mean age of the patients was 31.8
      (range 16-59 years). In 22 patients (15%) interictal epileptiform discharges were
      present on the postoperative routine EEG. We found that both the preoperative
      spike frequency ( P < 0.001 ) and postoperative seizures ( P = 0.04 ) were
      independently associated with the presence of IED on the postoperative routine
      EEG. The preoperative spike frequency was not associated with the postoperative
      outcome. The extent of resection showed no influence on the presence of
      postoperative IED. CONCLUSION: We hypothesize that two factors independently
      influence the presence of postoperative spikes: chronic interictal disturbance
      (represented as preoperative spike frequency) and the acute (postoperative)
      seizures. Our study confirmed that persistent postoperative IED had a prognostic
      value regarding the outcome of the epilepsy surgery.

PMID- 15013058
TI  - Inhibitory function of zinc against excitation of hippocampal glutamatergic
      neurons.
AB  - The function of zinc released from the neuron terminals is poorly understood.
      Here, the action of zinc in excitatory neurotransmission in rat hippocampal CA1
      was studied by using in vivo microdialysis. Glutamate concentration in the
      perfusate was significantly decreased by perfusion with 10-300 microM ZnCl2,
      suggesting that presynaptic release of glutamate is inhibited by zinc in the CA1.
      While gamma-amino butyric acid (GABA) concentration in the perfusate was
      increased by perfusion with zinc. Furthermore, to study the action of zinc in
      postsynaptic response, the response of the CA1 pyramidal cells in the presence of
      50 microM zinc was examined in the entorhinal cortex, which is connected with CA1
      pyramidal cells. Perfusion of the hippocampal CA1 with zinc decreased glutamate
      concentration not only in the CA1, but also in the entorhinal cortex. The
      increase in glutamate concentration in the entorhinal cortex during perfusion of
      the CA1 with 50 microM glutamate was inhibited by the addition of zinc in the
      CA1. Zinc seems to be an inhibitory neuromodulator of glutamate release.

PMID- 15013057
TI  - Somatization, dissociation and general psychopathology in patients with
      psychogenic non-epileptic seizures.
AB  - The etiology of psychogenic non-epileptic seizures (PNES) remains uncertain.
      Previous studies have shown that PNES patients are characterized by high levels
      of somatization, dissociation and general psychopathology but a correlation of
      measures of these features and PNES severity or outcome has never been
      demonstrated, although this would strengthen a possible etiological link. This
      study measured somatization (Screening Test for Somatoform Symptoms-2),
      dissociation (Dissociative Experience Scale, DES), and general psychopathology
      (Symptom Checklist-90-Revised, SCL-90) in 98 patients with PNES and 63 patients
      with epilepsy. All mean scores were raised in the PNES compared to the epilepsy
      group. However, only measures of somatization and general psychopathology
      discriminated between patients with PNES and epilepsy in a logistic regression
      model (even when patient gender was controlled for). In PNES patients, high
      somatization scores correlated with poor outcome and greater seizure severity
      even after correction was made for dissociation and psychopathology. Dissociation
      and psychopathology scores were not independently associated with outcome or
      severity. The results suggest that, as a group, patients with PNES are best
      characterized by their tendency to express psychosocial distress by producing
      unexplained somatic symptoms which are brought to medical attention. Although
      dissociation may be relevant in some individuals it does not appear to be an
      independent factor across the whole PNES patient group.

PMID- 15013059
TI  - Lipopolysaccharide retards development of amygdala kindling but does not affect
      fully-kindled seizures in rats.
AB  - Seizures are common sequel to brain insults in cases such as stroke, trauma and
      infection where there is a certain neuroinflammation. Intracerebroventricular
      (i.c.v.) administration of lipopolysaccharide (LPS) induces an inflammatory state
      in brain that is used as a model of neuroinflammation. We studied the effect of
      LPS (0.25 and 2.5 microg/rat, i.c.v.) on development of electrical kindling of
      the amygdala and on fully-kindled seizures. LPS, at the doses used, had no effect
      on fully-kindled seizures and afterdischarge (AD) duration at 0.5, 2 or 4h after
      administration. However, daily injection of LPS (2.5 microg/rat) retarded
      acquisition of kindled behavioral seizures. This antiepileptogenic effect could
      be due to the release of inflammatory mediators from microglia and the related
      morphological and functional changes in synaptic neurotransmission.

PMID- 15013061
TI  - Dietary influence on the impact of ethinylestradiol-induced alterations in the
      endocrine/reproductive system with perinatal maternal exposure.
AB  - We investigated the effects of two diets, differing in phytoestrogen contents, on
      the phenotypic changes induced in the endocrine/reproductive system by perinatal
      exposure to an estrogen agonist during a critical period for brain sexual
      differentiation in rats. Ethinylestradiol (EE) was mixed at a concentration of
      0.5 ppm into two diets: CRF-1, a standard rodent diet containing soybean-derived
      phytoestrogens; and a soy-free (SF) diet. These diets were provided to maternal
      Sprague-Dawley rats during gestational day 15 to postnatal day 10. Growth
      suppression of offspring was evident with EE especially during the exposure
      period and was slightly enhanced with the SF diet. On the other hand, most of the
      female offspring exposed to EE with CRF-1 showed early onset of vaginal opening,
      strong irregularity in estrous cycle (persistent estrus) and profound
      histopathological alterations, such as multifollicular ovaries, endometrial
      hypertrophy, and diffuse hyperplasia of the anterior pituitary. These EE-induced
      changes were much less pronounced with the SF diet. The results thus demonstrated
      differential effects of perinatal EE depending on the basal diet used, with
      enhancement of typical estrogenic responses in females by potential soybean
      derived factor(s).

PMID- 15013060
TI  - NTP center for the evaluation of risks to human reproduction reports on
      phthalates: addressing the data gaps.
AB  - Between 1998 and 2000 an Expert Panel convened by the National Toxicology
      Program's Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR)
      reviewed information related to the developmental and reproductive toxicity of
      seven phthalate esters; DBP, BBP, DnHP, DEHP, DnOP, DINP, and DIDP. Information
      on exposures was also considered. The objectives were to determine whether any of
      these phthalates posed potential human reproductive risks, and if so, to define
      the circumstances. The Expert Panel also identified some areas of uncertainty.
      These assessments, ultimately published in 2002, concluded that reproductive
      risks were minimal to negligible in most cases although some specific uses were
      considered potentially more problematic. Since the evaluations were completed,
      numerous studies dealing with both hazard characterization and underlying
      mechanism have been carried out. Additionally, exposures of the general
      population have been much better characterized through the use of urinary
      measurements developed by the Centers for Disease Control (CDC). This additional
      information makes several important points. First, calculations based on the
      urinary metabolite measurements indicate that exposures within the general
      population are at levels similar to or lower than the estimates used by the NTP
      CERHR. The demonstration that exposures were not underestimated by the CERHR has
      removed a substantial portion of the uncertainty. Second, new hazard
      characterization studies on several phthalates have established NOAELs similar to
      or higher than those used by the Expert Panel. Thus, these data demonstrate that,
      to the extent that the rodent data are useful for human health risk assessment,
      the no effect levels and dose-response relationships are now more precisely
      defined. In some cases, the no effect levels may be substantially higher than
      those estimated by the Expert Panel. Third, studies of underlying mechanism
      and/or hazard characterization studies in other species suggest that primates may
      be less sensitive than rodents to the reproductive effects of certain phthalates.
      Finally, the two specific situations that the CERHR identified as potentially
      problematic, the exposure of young children to DINP through the use of toys or to
      DEHP from medical devices, have been assessed by the responsible regulatory
      authorities. The Consumer Product Safety Commission concluded that exposure to
      DINP from toys was well below effect levels in animals, and, therefore, there was
      no risk. The Food and Drug Administration estimates of exposures from medical
      devices indicated that for some limited, intensive medical procedures, DEHP
      exposures could be similar to or greater than the NOAELs selected by the NTP
      CERHR. However, the FDA also acknowledged that more recent information indicates
      that the NOAELs identified in rodent studies may be substantially higher than
      values previously proposed by the NTP-CERHR. In summary, much of the uncertainty
      identified by the CERHR has now been addressed, and the overall conclusions that
      levels of concern are minimal to negligible in most situations are much better
      established. The overall objective of this report is to summarize this new
      research and comment on its relevance to the NTP-CERHR assessments.

PMID- 15013062
TI  - Renal toxicity induced by folic acid is associated with the enhancement of male
      reproductive toxicity of di(n-butyl)phthalate in rats.
AB  - Reproductive effects have been observed in experimental animals treated with di(n
      butyl)phthalate (DBP), one of phthalate esters used in soft plastics and a
      variety of consumer products. In this study, we investigated whether testicular
      toxicity of DBP is influenced by diminished renal function. To generate an
      experimental condition reflecting chronic renal disease in man, adult male F344
      rats were given five consecutive weekly subcutaneous injections of folic acid at
      a dose of 300 mg/kg and then a diet containing 1200, 5000, and 20,000 ppm of DBP
      for 4 weeks. These concentrations roughly correspond to 60, 250, and 1000 mg/kg
      per day per rat, respectively. Folic acid clearly induced interstitial nephritis
      accompanied by impairment of renal function. Seminiferous degeneration,
      diminished spermatogenesis and increase in the number of morphologically abnormal
      sperm were more prominent in rats given folic acid and then 20,000 ppm DBP as
      compared to those exposed to DBP alone. These data suggest that DBP-induced male
      reproductive toxicity can be increased by folic acid-induced renal dysfunction.

PMID- 15013063
TI  - Effects of 4-tert-octylphenol given in drinking water for 4 months on the male
      reproductive system of Fischer 344 rats.
AB  - The environmental pollutant 4-tert-octylphenol (OP) is both toxic and estrogenic
      to mammalian cells, and injection of OP into adult male rats has devastating
      effects on their reproductive system. We now report the effects of OP in drinking
      water ( 1 x 10(-5), 1 x 10(-7) or 1 x 10 (-9) M) on the male reproductive system.
      Exposure of adult male rats for 4 months to any tested dose of OP had no
      significant effect on water or food consumption; body weight gain; hematocrit;
      reproductive organ weights; mean serum LH, FSH or testosterone concentrations;
      germ cell yield or relative numbers of different classes of testicular cells; or
      testicular sperm number. In contrast, all doses of OP caused an increase in
      epididymal sperm with tail abnormalities that would interfere with sperm
      motility, and the highest dose decreased epididymal sperm number. Our findings
      raise the possibility that consumption of OP in drinking water may adversely
      influence male reproductive fertility.

PMID- 15013064
TI  - Steroidogenesis in fetal male rats is reduced by DEHP and DINP, but endocrine
      effects of DEHP are not modulated by DEHA in fetal, prepubertal and adult male
      rats.
AB  - The plasticizer di(2-ethylhexyl)phthalate (DEHP) exhibits antiandrogenic effects
      in perinatally exposed male rats. Di(2-ethylhexyl) adipate (DEHA) and diisononyl
      phthalate (DINP) are currently being evaluated as potential substitutes for DEHP,
      but similarities in structure and metabolism of DEHP with DEHA and DINP have led
      to the hypothesis that similarities in action may also exist. Pregnant Wistar
      rats were gavaged during gestation and lactation with vehicle, DEHP (300 or 750
      mg/kg bodyweight per day), DINP (750 mg/kg bodyweight per day), DEHP (750 mg/kg
      bodyweight per day) in combination with DEHA (400 mg/kg bodyweight per day), or
      DEHP (300 mg/kg bodyweight per day) in combination with DINP (750 mg/kg
      bodyweight per day). DINP and DEHP were both shown to reduce testicular
      testosterone production ex vivo and testosterone levels in testes and plasma of
      male fetuses at gestation day 21, indicating a similar mechanism of action for
      DINP and DEHP. Additionally, plasma LH levels in male fetuses were elevated.
      Neonatal anogenital distance was reduced and the number of nipples at postnatal
      day 13 increased in DEHP-exposed male offspring. Serum inhibin B levels were
      significantly reduced in DEHP-exposed prepubertal male offspring, and in a few
      adult males. No modulating effects of DEHA on the endocrine effects of DEHP were
      detected, but a tendency towards an accumulating effect of DEHP and DINP in
      combination on suppression of testosterone synthesis was seen.

PMID- 15013065
TI  - Evaluation of the rodent Hershberger assay using three reference endocrine
      disrupters (androgen and antiandrogens).
AB  - Three chemicals with known endocrine activities have been evaluated in the rat
      Hershberger assay for phase-2 of the international validation exercise within the
      Organization for Economic Cooperation and Development (OECD). The chemicals
      studied included the antiandrogens finasteride (FIN) and procymidone (PRO) and
      the androgen agonist 17alpha-methyltestosterone (MT). Castration of sexually
      immature Sprague-Dawley rats was performed between post-natal days 42 and 46
      whilst dosing of the chemical over 10 days was performed between post-natal days
      53 and 67. Rats were co-treated with testosterone propionate (TP) for the
      antiandrogenic activity evaluation. The endpoints examined for evaluation of the
      androgenic/antiandrogenic activity were changes in sex accessory tissue (SAT)
      weights supplemented with measurement of testosterone and luteinizing hormone
      (LH) levels at sacrifice. Changes in liver, adrenal, kidney and body weights were
      also monitored for general toxicity assessment. Statistically significant changes
      in the SAT weights were detected with the three chemicals tested. Hence, the rat
      Hershberger assay as defined by the OECD was demonstrated sensitive enough for
      the detection of the endocrine disrupting activity of the three reference
      chemicals evaluated.

PMID- 15013066
TI  - Chernobyl: prenatal loss of four hundred male fetuses in the Czech Republic.
AB  - The long-standing higher male birth fraction is considered an indicator of
      reproduction stability and health. In contrast, a decrease in the male birth
      fraction has been reported after prenatal exposure to environmental chemical
      factors. There is generally higher vulnerability of boys to prenatal damage by
      environmental stress. We formulated a hypothesis that the Chernobyl disaster
      might also have had a greater negative impact on male than on female fetuses,
      leading to their selective loss and to a decrease in the male birth fraction. To
      test this hypothesis, we examined demographic data on monthly natality in the
      territory of the Czech Republic from 1950 to 1999. The male birth fraction was
      higher in the Czech Republic each month between 1950 and 1999 except November
      1986, when it was significantly (P< 0.05) reduced. This finding suggests a
      selective negative effect of the Chernobyl accident on male fetuses during the
      3rd month of prenatal development.

PMID- 15013067
TI  - Cytolipotoxicity-induced involution of the female reproductive tract following
      expression of obese (ob/ob) and diabetes (db/db) genotype mutations: progressive,
      hyperlipidemic transformation into adipocytic tissues.
AB  - Both diabetes (db/db) and obese (ob/ob) single gene mutations induce a
      progressive, hyperglycemic-hyperinsulinemic endometabolic environment which
      promotes hypercytolipidemic, utero-ovarian involution in C57BL/KsJ mice. The
      progressive expression of the induced diabetes-obesity syndrome (DOS) results in
      female reproductive sterility and eventual organoatrophy. In order to define the
      intra-cytoplasmic alterations induced by the progressive cytolipidemia on
      cellular vitality, utero-ovarian tissue samples were collected from both control
      (+/?) and littermate-matched ob/ob or db/db C57BL/KsJ mice at either 4 weeks
      (initial-onset DOS phase), 8 weeks (progressive, overt DOS phase), or 16 weeks
      (chronic-DOS phase) of age for cytolipid distribution analysis. All db/db and
      ob/ob mutant groups exhibited phenotypic obesity and systemic hyperglycemia
      hyperinsulinemia relative to age-matched littermate +/? groups. In all db/db and
      ob/ob age groups, a progressive hypercytolipidemia was noted relative to +/?
      groups. When analyzed for lipid channeling, a progressive perinuclear mapping
      pattern of cytolipid distribution was noted. The primary locus of initial db/db
      and ob/ob cytolipid deposition was localized to the baso-polar regions in
      endometrial epithelia samples, or to the interstitium-thecal layer border of
      ovarian follicular compartments, during the initial-onset DOS phase.
      Progressively, intra-cytoplasmic lipid mobilization promoted a consistent
      perinuclear channeling of lipid vacuoles, ultimately isolating nuclear loci from
      the peripherally displaced cytoplasmic organelles within uterine epithelial
      layers. In db/db and ob/ob ovarian tissue samples, a progressive, gradient
      related lipid infiltration of interstitial, thecal and, ultimately, granulosa
      cell layers promoted an enhanced rate of follicular-lipidemic atresia relative to
      +/? groups. In each tissue layer, the cytolipidemia promoted a dramatic
      perinuclear lipid-isolation barrier from intra-cytoplasmic organelle domains.
      With age-related exacerbation of the DOS syndrome, cytoplasmic nuclear-organelle
      displacement and lipoisolation resulted in cellular atresia, promoting the
      eventual utero-ovarian organoatrophy which characterized the chronic-DOS phase in
      db/db and ob/ob C57BL/KsJ mutants. These results indicate that the cytoinvolution
      associated with reproductive tract atrophy in these genetically mutant, diabetic
      obese models is promoted by the disruption of the normal cytoarchitecture of
      utero-ovarian tissue layers induced by the progressive lipid sequestration,
      accumulation and ultimate isolation-induced disruption of intra-cellular
      organelle compartmentalization.

PMID- 15013068
TI  - Pregnancy outcome after first trimester exposure to corticosteroids: a
      prospective controlled study.
AB  - OBJECTIVE: To evaluate the safety of glucocorticosteroids (GCS) in pregnancy.
      STUDY DESIGN: The Israeli Teratogen Information Service (TIS) prospectively
      collected and followed 311 pregnancies counseled regarding systemic use of
      different GCS in the first trimester. The rate of major congenital anomalies was
      compared to that of 790 controls who were counseled for non-teratogenic exposure.
      RESULTS: The rate of major anomalies did not significantly differ between the
      groups [12/262 = 4.6% (GCS), 19/728 = 2.6% (control), [P = 0.116 ]. There was no
      case of oral cleft and no pattern of anomalies among the GCS exposed group.
      Higher rates of miscarriages (11.5% versus 7.0%, P = 0.013) and preterm births
      (22.7% versus 10.8%, P < 0.001 ) were observed among the GCS exposed group
      compared to the controls. GCS exposed infants had a lower median birth weight
      [3080 g versus 3290 g, P < 0.001 ] and were born at an earlier median gestational
      age [39 weeks versus 40, P < 0.001 ] compared to the control. CONCLUSIONS: The
      present study supports that GCS do not represent a major teratogenic risk in
      humans. The study was powered to find a 2.5-fold increase in the overall rate of
      major anomalies.

PMID- 15013069
TI  - Preimplantation exposures of murine embryos to estradiol or methoxychlor change
      postnatal development.
AB  - Long-term effects of in vivo exposures to proestrogen methoxychlor (MXC) or
      estradiol-17beta (E) were studied during early pregnancy (preimplantation) in ICR
      mice. Pregnant dams received either subcutaneous injections of 1 microg of E on
      Day 2 of pregnancy only (vaginal plug = Day 1), or 5.0mg of MXC on Days 2-4 of
      pregnancy in sesame oil. Pregnant control mice were treated with the vehicle
      only. Litter size, postnatal survival, sex ratio at birth, and anogenital
      distance (AGD) in offspring of both sexes were examined, as well as vaginal
      opening in female offspring. High mortality rate was recorded in MXC-exposed
      offspring due to infanticide. Exposures to either E or MXC did not change sex
      ratio at birth, but the litter size was smaller in the former group. On postnatal
      Day 21, male pups exposed to either E or MXC at preimplantation stage exhibited
      shorter AGD than the controls, with the change most pronounced after MXC
      treatments. AGD in female offspring was unaffected after MXC exposures, but E
      treatments produced longer AGD in the females than that recorded in the controls.
      Preimplantation exposures to E or MXC also accelerated sexual maturation as
      significantly more females exhibited precocious vaginal opening at weaning. Our
      study shows that exposures to MXC or E at preimplantation stages cause long term
      alteration of sexual development during weaning in offspring of both sexes. Also,
      MXC treatments retarded both growth and weight of both sexes of offspring, in
      comparison to controls.

PMID- 15013070
TI  - Intrauterine position and postnatal growth in Sprague-Dawley rats and ICR mice.
AB  - In rodents, steroid hormones are thought to be transported between adjacent
      fetuses, and male or female fetuses that develop in utero between female fetuses
      may have higher serum levels of estradiol, and lower serum levels of
      testosterone, relative to siblings of the same sex that develop between two male
      fetuses. The consequence in the variation of postnatal growth, development, and
      function in the intrauterine position, using various parameters such as
      anogenital distance, preputial separation and vaginal opening, estrous cycle,
      locomotor activity, and growth of reproductive organs, were examined in Sprague
      Dawley rats. ICR mice were treated with 17beta-estradiol before copulation and
      during pregnancy to address the interaction with endogenous estradiol during
      pregnancy. In rats, no evidence of effects of prior intrauterine position was
      observed for any of the parameters examined. Mouse fetal exposure via the mother
      to low-dose 17beta-estradiol revealed no changes in the rate of postnatal growth
      in males and females that developed in any intrauterine position in utero. The
      results of this study suggested that the intrauterine position of the
      embryos/fetuses did not affect the postnatal growth of the reproductive organs,
      sexual maturation, or behavior in rats and mice.

PMID- 15013071
TI  - Relationship between hindbrain segmentation, neural crest cell migration and
      branchial arch abnormalities in rat embryos exposed to fluconazole and retinoic
      acid in vitro.
AB  - Fluconazole (FLUCO) and retinoic acid (RA) can perturb morphogenesis of the
      branchial apparatus in rodent embryos exposed in vitro. The aim of the present
      study was to compare the effects induced by in vitro exposure to FLUCO or to RA
      on rhombomere organisation, neural crest cell (NCC) migration and cranial nerve
      differentiation using specific antibodies. For this purpose 9.5 d.p.c. rat
      embryos were exposed to teratogenic concentrations of FLUCO or RA; another group
      was exposed to no-effect concentrations of both agents. Expression of Hox-b1 and
      Krox20 (markers of specific rhombomeres) was altered after FLUCO and RA exposure.
      Furthermore, FLUCO and RA showed a synergistic effect. These results suggest that
      the observed branchial abnormalities are due to anomalous NCC migration related
      to incorrect organisation of specific rhombomeres.

PMID- 15013072
TI  - Tylosin does not affect GnRH-induced LH secretion in rams.
AB  - The aim of this study was to investigate the effect of a therapeutic dose of
      Tylosin (Tylan 50) on gonadotropin releasing hormone (GnRH)-induced luteinizing
      hormone (LH) secretion in sheep. A total of 10 mature rams were divided into two
      groups by balancing body weights (bw) and body condition scores. Five of the rams
      received 10mg/kg Tylosin intramuscularly (i.m., Tylosin group), while the other
      five were given placebo (Control group), for 5 days. On Day 5, all the rams were
      injected intravenously (i.v.) with the GnRH agonist Ovarelin at 0.1 microg/kg bw.
      Blood samples were collected at -30, 0, 30, 60, 90, 120, 150, 180, 210, 240, and
      270 min for measuring LH levels in the plasma. Three days after the cessation of
      Tylosin application (Day 8) the injection of GnRH was repeated at the same dose.
      Although LH secretion appeared to be lower on Day 8 compared to Day 5, there were
      no significant differences between the groups for the mean LH concentrations,
      total LH secretion, peak LH concentrations, timing of LH peak, duration of LH
      secretion, and LH secretions on Days 5 and 8. These results indicate the absence
      of a negative effect of a therapeutic dose of Tylosin on GnRH-induced LH
      secretion in rams.

PMID- 15013073
TI  - Contralateral response of macrophages and astrocytes to injury in the cerebral
      hemisphere of 6-day-old rat following prenatal gamma irradiation.
AB  - Wistar pregnant rats were exposed to a single 1.0 Gy dose of gamma rays on
      gestational days 13, 15, 17 or 19 (E13, E15, E17 and E19, respectively). When
      offsprings of the irradiated females became 6-day-old, they received a mechanical
      injury of the cerebral hemisphere. One or 2 days after the injury, [3H]thymidine
      was injected and the animals were perfused. Brain sections were processed for BSI
      B4 isolectin histochemistry or immunohistochemistry for glial fibrillary acidic
      protein (GFAP) or S-100-beta protein and subjected to autoradiography to
      visualise proliferating and non-proliferating macrophages or proliferating
      astrocytes. Significant changes in the contralateral response to injury related
      to the day of prenatal irradiation could be detected. The response was minimal
      following irradiations performed on E15 and E17. At those stages of prenatal
      development, the majority of cortical neurons with interhemispheric connections
      were formed. Therefore, irradiation-induced reduction of the neurons might
      minimise transfer of pathogenic stimuli to contralateral areas via degenerating
      nerve fibers. Consequently, the degree at which the contralateral glial response
      reflected reactive changes at the lesion site might also be minimal. Results of
      the present study do not show in detail mechanisms underlying the differences in
      the contralateral reactivity to injury. They, however, might be of importance to
      histopathological investigations using animal models of cerebral dysplasia.

PMID- 15013075
TI  - Analysis of age dependent changes of Topoisomerase II alpha and beta in rat
      brain.
AB  - Eukaryotic Topoisomerase II (Topo II) is present in two isoforms alpha and beta.
      The alpha isoform is predominantly localized in proliferative tissue, while beta
      isoform is present in all tissues. In the present study we report the activity
      and protein levels of Topoisomerase II alpha and beta in rat brains of different
      age groups viz.: E11 (Embryo day 11), E18 (Embryo day 18), post-natal day 1,
      young (<10 days), adult (<6 months) and old (>2 years). Topoisomerase II beta
      isoform is found to be the predominant form in brain tissue but Topoisomerase II
      alpha is found in embryos up to post-natal day 1. The studies to examine the
      regional distribution of Topoisomerase II beta in brain showed highest activity
      in cerebellar region and that too only neuronal cell fraction. There was a
      significant age-dependent decline in this activity. Hence, Topoisomerase II beta
      may have some unknown function in cerebellum and the low levels of Topoisomerase
      II beta activity in ageing cerebellum may contribute to the genomic instability
      in cerebellar region of ageing brain.

PMID- 15013074
TI  - Inhibition of Na+, K+-ATPase activity in rat striatum by the metabolites
      accumulated in Lesch-Nyhan disease.
AB  - In the present study, we investigated the in vitro effect of hypoxanthine,
      xanthine and uric acid, metabolites accumulating in tissue of patients with Lesch
      Nyhan disease, on Na(+), K(+)-ATPase activity in striatum of neonate rats.
      Results showed that all compounds significantly inhibited Na(+), K(+)-ATPase
      activity. We also studied the kinetics of the inhibition of Na(+), K(+)-ATPase
      activity caused by hypoxanthine. The apparent K(m) and V(max) of Na(+), K(+)
      ATPase activity for ATP as the substrate and hypoxanthine as the inhibitor were
      0.97 mM and 0.69 nmol inorganic phosphate (Pi) released per min per mg of
      protein, respectively. K(i)-value was 1.9 microM, and the inhibition was of the
      non-competitive type. We also observed that the inhibitory effects of
      hypoxanthine, xanthine and uric acid probably occur through the same mechanism,
      suggesting a common binding site for these oxypurines on Na(+), K(+)-ATPase.
      Therefore, it is conceivable that inhibition of brain Na(+), K(+)-ATPase activity
      may be involved at least in part in the neuronal dysfunction characteristic of
      patients with Lesch-Nyhan disease.

PMID- 15013077
TI  - Development of a polar morphology by identified embryonic motoneurons.
AB  - Motoneuron morphology arises through the coordinated growth of the motor axon and
      dendrites. In the Drosophila embryo the RP motoneurons have a contralaterally
      extended motor axon, ipsilateral dendrites that extend a short distance in the
      ipsilateral connective, and a tuft of short dendrites in the contralateral
      connective. In the present study mechanical and genetic manipulations were
      utilized to test if (i) the ipsilateral dendrites can develop an axon morphology,
      (ii) the presence of the contralateral motor axon suppresses the development of
      an axon-like morphology by the ipsilateral dendrites and (iii) whether
      establishment of a contralateral motor axon can be genetically suppressed. It was
      found that an ipsilateral motor axon could develop-but only at the expense of the
      contralateral motor axon. Axotomy could overturn the normal polarity of the RP
      motoneurons in favor of the development of an ipsilateral motor axon, and this
      reversed morphology was also observed when the motor axon could not extend across
      the midline in the commissureless mutant. These findings show that the RP
      motoneurons have the plasticity for an alternative polarity, but that the
      extension of an ipsilateral axon is normally suppressed by the presence of the
      contralateral axon. The RP motoneurons now represent a genetically amenable in
      vivo system for analyzing the basis of polarity formation in neurons.

PMID- 15013076
TI  - Mosquito repellent (pyrethroid-based) induced dysfunction of blood-brain barrier
      permeability in developing brain.
AB  - Pyrethroid-based mosquito repellents (MR) are commonly used to protect humans
      against mosquito vector. New born babies and children are often exposed to
      pyrethroids for long periods by the use of liquid vaporizers. Occupational and
      experimental studies indicate that pyrethroids can cause clinical, biochemical
      and neurological changes, and that exposure to pyrethroids during organogenesis
      and early developmental period is especially harmful. The neurotoxicity caused by
      MR has aroused concern among public regarding their use. In the present study,
      the effect of exposure of rat pups during early developmental stages to a
      pyrethroid-based MR (allethrin, 3.6% w/v, 8h per day through inhalation) on blood
      brain barrier (BBB) permeability was investigated. Sodium fluororescein (SF) and
      Evan's blue (EB) were used as micromolecular and macromolecular tracers,
      respectively. Exposure during prenatal (gestation days 1-20), postnatal (PND1-30)
      and perinatal (gestation days 1-20 + PND1-30) periods showed significant increase
      in the brain uptake index (BUI) of SF by 54% (P < 0.01), 70% (P < 0.01), 79% (P <
      0.01), respectively. This increase persisted (68%, P < 0.01) even 1 week after
      withdrawal of exposure (as assessed on PND37). EB did not exhibit significant
      change in BBB permeability in any of the group. The results suggest that MR
      inhalation during early prenatal/postnatal/perinatal life may have adverse
      effects on infants leading to central nervous system (CNS) abnormalities, if a
      mechanism operates in humans similar to that in rat pups.

PMID- 15013078
TI  - Connexin 43 expression in glial cells of developing rhombomeres of Xenopus
      laevis.
AB  - Connexin 43 is a gap junctional protein found predominantly in astrocytes. In the
      mammalian nervous system, it appears to play an organizational role during neural
      development. In the current study, conducted on the frog, Xenopus laevis, we
      found that connexin 43 occurs in glial cells during development of rhombomeres
      and that its expression is spatially and temporally regulated. We used neural
      (2G9) and cell proliferation (BrdU) markers to identify the overall organization
      of Xenopus rhombomeres and then tracked expression of connexin 43 and glial
      fibrillary acidic protein, an intermediate filament protein known to mark glia
      during rhombomeric development. 2G9 was expressed in rhombomeric centers
      (ventricular concavities) and outlying neuropil regions, whereas BrdU-labeled
      cells marked boundary regions (ventricular convexities), as early as stage 35/36.
      These labeling patterns persisted through premetamorphic stages of hindbrain
      development. At stage 47, 2G9-labeled profiles were highlighted by the presence
      of connexin 43, and at stage 49/50, connexin 43-labeled profiles, i.e.,
      rhombomeric centers and neuropil, as well as rhombomeric boundaries, not labeled
      by connexin 43, became immunoreactive to glial fibrillary acidic protein. Cells
      of rhombomeric center regions and their processes in the outlying neuropil co
      expressed glial fibrillary acidic protein and connexin 43 at a time that is
      characterized by the emergence of hindbrain auditory neural circuitry. Glial
      fibrillary acidic protein positive glial cells that appeared at rhombomeric
      boundaries never expressed connexin 43, but rather appeared to physically bisect
      ventricular convexities into adjacent rhombomeric regions. Thus, glial cells that
      express connexin 43 in developing rhombomeric centers may be similar to radial
      glia, assisting in formation of neural circuitry, while glial cells that do not
      express connexin 43, situated at rhombomeric boundaries, may be involved in
      demarcating adjacent rhombomeres.

PMID- 15013079
TI  - New insight into the mechanism of hip prosthesis loosening: effect of titanium
      debris size on osteoblast function.
AB  - The incidence of rheumatoid arthritis and osteoarthritis is on the rise due to
      our expanding elderly population. Total joint arthroplasty is the most
      successful, prevalent treatment modality for these and other degenerative hip
      conditions. Despite the wide array of prosthetic devices commercially available,
      hip prostheses share a common problem with a gradual and then accelerating loss
      of bone tissue and bone-implant interface integrity, followed by implant
      instability and loosening. Implant failure is largely the result of inevitable
      wear of the device and generation of wear debris. To provide information for the
      development of improved prosthetic wear characteristics, we examined the effects
      of size-separated titanium particles on bone forming cell populations. We
      demonstrate unequivocally that particle size is a critical factor in the
      function, proliferation, and viability of bone-forming osteoblasts in vitro. In
      addition, we have elucidated the time-dependent distribution of the phagocytosed
      particles within the osteoblast, indicating an accumulation of particles in the
      perinuclear area of the affected cells. The report finds that particle size is a
      critical factor in changes in the bone formation-related functions of osteoblasts
      exposed to simulate wear debris, and that 1.5-4 microm titanium particles have
      the greatest effect on osteoblast proliferation and viability in vitro. The size
      of titanium particles generated through wear of a prosthetic device may be an
      important consideration in the development of superior implant technology.

PMID- 15013080
TI  - The effectiveness of polyethylene versus titanium particles in inducing
      osteolysis in vivo.
AB  - Bearing surface wear and periprosthetic osteolysis due to wear particles are
      among the most common reasons for joint replacement failure. A murine calvarial
      model of wear particle-induced osteolysis has been used to identify different
      biologic factors associated with this problem and to test nonsurgical methods of
      modulating the host response to particulate debris. This model has utilized
      titanium particles, however, in clinical practice the most common source of
      particulate debris is polyethylene particles from bearing surface wear. We now
      report a calvarial model of wear particle-induced osteolysis based on
      commercially available polyethylene particles. We found that compared to sham
      surgery osteoclast recruitment and bone resorption can be induced by introduction
      of the titanium particles or polyethylene particles. However, bone resorption was
      significantly higher with polyethylene particles compared to titanium particles
      (p=0.02). We consider the polyethylene based murine calvarial model of wear
      particle-induced osteolysis a reliable and clinically relevant tool to understand
      the host factors and potential pharmacologic interventions that can influence
      wear debris generated osteolysis. This model might serve as an extension of the
      well-established titanium based bone resorption model.

PMID- 15013081
TI  - Topical, single dose bisphosphonate treatment reduced bone resorption in a rat
      model for prosthetic loosening.
AB  - Fluid pressure, instability or particles have been suggested to cause peri
      prosthetic bone resorption. High intracapsular pressures have been reported in
      hip joints with loose prosthetic components, and oscillating fluid pressure has
      been shown to cause dramatic bone resorption in animal models. Resorption can be
      reduced by systemic bisphosphonate treatment in rat models with oscillating fluid
      pressure, but this has required higher doses than needed to inhibit normal
      remodelling. Bisphosphonates have high affinity to bone mineral. Topical
      application of the drug is therefore feasible. We used a previously described rat
      model where oscillating fluid pressure causes bone resorption. Before
      pressurization, a 1 mg/ml solution of alendronate was applied onto the bone
      surface for 1 min, after which excess bisphosphonate was rinsed away. Bone
      resorption was measured on histological slides as soft tissue area at the
      interface. Rats treated with topical alendronate had soft tissue areas reduced by
      half. Topical bisphosphonate treatment before cementing a joint implant could
      possibly reduce the risk of later loosening.

PMID- 15013083
TI  - Pre-surgery knee joint loading patterns during walking predict the presence and
      severity of anterior knee pain after total knee arthroplasty.
AB  - This study tested if abnormal sagittal knee joint loading patterns after total
      knee arthroplasty (TKA) were present pre-surgery, and if patterns with higher
      external knee flexion moments were related to the presence and severity of post
      surgery anterior knee pain. Gait analysis and clinical evaluation were performed
      on 34 patients (41 arthroplasties) both before and 12-18 months after TKA, and on
      20 healthy age-matched controls at matched velocities. The majority of knees with
      abnormal flexor or extensor sagittal knee joint loading patterns post-surgery (18
      of 26, 69%) also displayed these patterns pre-surgery. Knee joint loading in the
      early mid-stance phase of walking prior to surgery was identified by stepwise
      regression as a significant predictor of the presence (exp(beta)=2.9, CI: 1.2
      6.8, p=0.017) and severity of post-surgery anterior knee pain (R2=0.314,
      p=0.019). Therefore, the frequency and severity of anterior knee pain after TKA
      can be partially explained by retained pre-surgery gait patterns that had higher
      external flexion moments in the early mid-stance phase, which place higher forces
      on the patellofemoral joint.

PMID- 15013082
TI  - Differences in the fretting corrosion of metal-metal and ceramic-metal modular
      junctions of total hip replacements.
AB  - The use of modular interlocking components is a central design feature of total
      joint replacements. In this investigation we hypothesized that clinically
      available ceramic-metal modular connections used in total hip arthroplasty
      release more metal through fretting corrosion than traditional metal-metal
      modular connections. This was investigated using an in vitro comparison of
      ceramic (zirconia, ZrO2) and metal (Co-alloy) femoral-head fretting upon Co-alloy
      stem components. In vitro fretting corrosion testing consisted of potentiodynamic
      monitoring and analysis of metal release from zirconia and Co-alloy 28 mm femoral
      heads with similar surface roughnesses (Ra=0.46 microm) on identical Co-alloy
      stems at 2.2 kN for 1x10(6) cycles at 2 Hz. In contrast to our original
      hypothesis, we found greater metal release (approximately 11-fold increase in Co
      and 3-fold increase in Cr) and potentiodynamic fretting of metal-metal modular
      junctions when compared to ceramic-metal. Potentiodynamic testing demonstrated
      that lower initial voltages (-266<153 mV), greater maximum voltage changes
      (116>56 mV, p<0.05, t-test) and voltage variability (3>0.5 mV, p<0.05, t-test)
      were associated with the open circuit potentials of Co-alloy on Co-alloy
      junctions when compared to zirconia on Co-alloy junctions. In this study of a
      single total hip replacement stem and head design, zirconia heads mated with Co
      alloy stems produced less fretting than Co-alloy heads mated with Co-alloy stems.
      Although further studies are necessary with a variety of implant designs and
      under different experimental conditions, the evidence presented here should, in
      part, alleviate concerns of increases in fretting corrosion at modular junctions
      of ceramic-metal coupled components.

PMID- 15013084
TI  - Knee flexion during stair ambulation is altered in individuals with
      patellofemoral pain.
AB  - Reduced knee flexion is a logical gait adaptation for individuals with
      patellofemoral pain (PFP) to lessen the patellofemoral joint reaction force and
      minimise pain during stair ambulation. This gait adaptation may be related to the
      co-ordination of individual vasti components. PURPOSE: This study investigated
      the amount of stance-phase knee flexion in individuals with (n=48) and without
      (n=18) PFP using a cross-sectional design. The relationship between stance-phase
      knee flexion and onset timing of individual vasti activity was also examined.
      METHOD: Stance-phase knee flexion was measured in 2-dimensions using a PEAK
      movement analysis system during stair ascent and descent. Individuals with PFP
      were separated into those with synchronous onset of the EMG activity of vastus
      medialis obliquus (VMO) and vastus lateralis (VL), and those where the onset of
      VMO EMG activity was delayed relative to the VL. RESULTS: The amount of knee
      flexion at heel-strike and peak was less in the individuals with PFP compared
      with the healthy controls. In addition, there were trends towards individuals
      with PFP who had a delayed EMG onset of VL having reduced knee flexion during
      stair descent compared with PFP individuals with simultaneous vasti onsets and
      the control participants. CONCLUSION: These results indicate that the amount of
      stance-phase knee flexion is lower in individuals with PFP and that this may be
      related to onset timing of the vasti.

PMID- 15013085
TI  - Femoro-tibial and menisco-tibial translation patterns in patients with unilateral
      anterior cruciate ligament deficiency--a potential cause of secondary meniscal
      tears.
AB  - OBJECTIVE: To analyze menisco-tibial and femoro-tibial translation patterns in
      healthy and ACL-deficient knees in different knee flexion angles under muscle
      activity. METHODS: The ACL-deficient and contralateral healthy knees of 10
      patients were examined with an open MRI system at 30 degrees and 90 degrees of
      knee flexion, under isometric contraction of the extensors or flexor muscle
      groups. Translations between the tibia, the femoral condyles and the menisci were
      analyzed by three-dimensional image postprocessing. RESULTS: Posterior
      translation of the femur and menisci relative to the tibia occurred during knee
      flexion (30-90 degrees) in all knees. In ACL-deficient knees, posterior
      translation of the medial femoral condyle (+1.3 +/- 3.8 mm) was significantly
      larger than in healthy knee (-0.9 +/- 2.9 mm; p<0.05), while the translation
      pattern of the menisci was similar (med. meniscus 0.6 +/- 2.3 mm vs. 0.6 +/- 2.7
      mm). Under isometric contraction of the extensors (relative to the flexor muscle
      group), an increased posterior position of the femur and menisci was observed at
      30 degrees knee flexion, but not at 90 degrees. This applied to ACL-deficient and
      healthy knees. CONCLUSIONS: This study shows a significant increase of
      translation of the medial femoral condyle in ACL-deficient knees, whereas menisco
      tibial translation remains almost unchanged. This difference in translation
      patterns indicates that the posterior horn of the medial meniscus might encounter
      shear, potentially explaining the high rate of secondary medial meniscal tears in
      patients with ACL-deficiency.

PMID- 15013086
TI  - A three-dimensional MRI analysis of knee kinematics.
AB  - PURPOSE: To quantify normal, in vivo tibio-femoral knee joint kinematics in
      multiple weight bearing positions using non-invasive, high-resolution MRI and
      discuss the potential of developing future kinematic methods to assess patients
      with abnormal joint pathologies. METHODS: Ten volunteers with clinically normal
      knees pushed inferiorly on the footplate of a weight bearing apparatus inside the
      MR scanner. The volunteers held the weight (133 N) for five scans as the knee
      motion was evaluated from 0 degrees to 60 degrees of flexion. Full extension was
      set as the zero point for all measured parameters. Using 3D reconstructions,
      tibia motion relative to the femur and flexion angle was measured as varus-valgus
      angle, axial rotation, anterior-posterior translation, and medial-lateral
      translation. Medial and lateral compartment tibio-femoral contact areas were
      examined and centroids of the contract areas were calculated. RESULTS: Tibial
      internal rotation averaged 4.8 degrees at 40 degrees of flexion and then
      decreased. Tibial valgus increased by 8 degrees at 60 degrees of flexion. Femoral
      roll back also increased to 18.5 mm average at 60 degrees of flexion, while the
      tibia translated medially 2.5 mm. Medial compartment femoro-tibial contact area
      started at 374 mm2 and decreased to 308 mm2 with flexion of 60 degrees, while
      lateral compartment contact area did not change significantly from 276 mm2.
      CONCLUSIONS: Results correlate with previous studies of knee kinematics while
      providing greater three-dimensional detail. MR imaging allows excellent non
      invasive evaluation of knee joint kinematics with weight bearing. This tool may
      potentially be used for assessing knee kinematics in patients with knee
      pathology.

PMID- 15013088
TI  - The radiographic study in the relationship of the glenohumeral joint.
AB  - Accurate reproduction of anatomic relationship is important in non-constrained
      prosthetic arthroplasty. The accurate lateral glenohumeral offset, which
      indicates a parameter of the lever arm of the deltoid and supraspinatus muscles,
      is one of the most important elements in achieving the efficient shoulder
      functions after prosthetic reconstruction. However, to our knowledge, there has
      been no detailed study on the influence of minute changes in the neck shaft
      angle, within the normal range, on lateral glenohumeral offset. In this study, we
      evaluated the relationship between the neck shaft angle and various geometric
      measurement values in the glenohumeral joint. Radiographs of 471 shoulders
      without osseous lesions in the glenohumeral joint and greater tuberosity were
      reviewed. There were 265 males and 206 females, and a mean age was 53.5 years
      old. The final diagnosis was impingement syndrome in 269 patients, rotator cuff
      tear in 147, and control group in 55 patients. Eight parameters were measured on
      true anteroposterior radiographs. The lateral glenohumeral offset correlated with
      the radius of the curvature of the humeral head and the humeral head diameter.
      The neck shaft angle was not correlated with the offset value. However, when the
      offset value was divided by the humeral head diameter, to eliminate the affection
      of the size of the humeral head toward the offset, a correlation was observed
      with the neck shaft angle. Based on these correlations, we could obtain the
      equation of the lateral glenohumeral offset according to the neck shaft angle.
      Using the equation, when the neck shaft angle is decided, the lateral
      glenohumeral offset can be estimated based on the correlation between the
      parameters, which achieve the efficient shoulder functions after prosthetic
      components. Therefore, inaccurate determination of the neck shaft angle in the
      humeral head component design and selection may induce dysfunction of the
      abductor muscles.

PMID- 15013087
TI  - In situ forces of the anterior and posterior cruciate ligaments in high knee
      flexion: an in vitro investigation.
AB  - The function of the anterior and posterior cruciate ligaments (ACL and PCL) in
      the first 120 degrees of flexion has been reported extensively, but little is
      known of their behavior at higher flexion angles. The aim of this investigation
      was to study the effects of muscle loads on the in situ forces in both ligaments
      at high knee flexion (>120 degrees). Eighteen fresh-frozen human knee specimens
      were tested on a robotic testing system from full extension to 150 degrees of
      flexion in response to quadriceps (400 N), hamstrings (200 N), and combined
      quadriceps and hamstrings (400 N/200 N) loads. The in situ forces in the ACL and
      PCL were measured using the principle of superposition. The force in the ACL
      peaked at 30 degrees of flexion (71.7 +/- 27.9 N in response to the quadriceps
      load, 52.3 +/- 24.4 N in response to the combined muscle load, 32.3 +/- 20.9 N in
      response to the hamstrings load). At 150 degrees, the ACL force was approximately
      30 N in response to the quadriceps load and 20 N in response to the combined
      muscle load and isolated hamstring load. The PCL force peaked at 90 degrees (34.0
      +/- 15.3 N in response to the quadriceps load, 88.6 +/- 23.7 N in response to the
      combined muscle load, 99.8 +/- 24.0 N in response to the hamstrings load) and
      decreased to around 35 N at 150 degrees in response to each of the loads. These
      results demonstrate that the ACL and PCL carried significantly less load at high
      flexion in response to the simulated muscle loads compared to the peak loads they
      carried in response to the same muscle loads at other flexion angles. The data
      could provide a reference point for the investigation of non-weight bearing
      flexion and extension knee exercises in high flexion. Furthermore, these data
      could be useful in designing total knee implants to achieve high flexion.

PMID- 15013089
TI  - The fundamental thumb-tip force vectors produced by the muscles of the thumb.
AB  - A rigorous description of the magnitude and direction of the 3D force vector each
      thumb muscle produces at the thumb-tip is necessary to understand the
      biomechanical consequences to pinch of a variety of paralyses and surgical
      procedures (such as tendon transfers). In this study, we characterized the 3D
      force vector each muscle produces at the thumb-tip, and investigated if these
      thumb-tip force vectors scaled linearly with tendon tension. In 13 cadaver
      specimens, we measured the output 3D thumb-tip force vector produced by each
      tendon acting on the thumb, plus two common tendon transfers, as a function of
      input tendon tension. After fixing the hand to a rigid frame, we mounted the
      thumb by configuring it in standardized key or opposition pinch posture and
      coupling the thumb-tip to a rigidly held 6 degree-of-freedom force/torque sensor.
      Linear actuators applied tension to the distal tendons of the four extrinsic
      thumb muscles, and to six Nylon cords reproducing the lines of action of (i) the
      four intrinsic thumb muscles and (ii) two alternative tendon transfers commonly
      used to restore thumb opposition following low median nerve palsy. Each computer
      controlled linear actuator ramped tendon tension from zero to 1/3 of predicted
      maximal muscle force expected at each tendon, and back to zero, while we measured
      the 3D force vector at the thumb-tip. In test/re-test trials, we saw thumb-tip
      force vectors were quite sensitive to mounting procedure, but also sensitive to
      variations in the seating of joint surfaces. We found that: (i) some thumb-tip
      force vectors act in unexpected directions (e.g., the opponens force vector is
      parallel to the distal phalanx), (ii) the two tendon transfers produced patently
      different force vectors, and (iii) for most muscles, thumb-tip force vectors do
      not scale linearly with tendon tension--likely due to load-dependent viscoelastic
      tendon paths, joint seating and/or bone motion. Our 3D force vector data provide
      the first quantitative reference descriptions of the thumb-tip force vectors
      produced by all thumb muscles and two tendon transfers. We conclude that it may
      not be realistic to assume in biomechanical models that thumb-tip force vectors
      scale linearly with tendon tensions, and that our data suggest the thumb may act
      as a "floating digit" affected by load-dependent trapezium motion.

PMID- 15013090
TI  - Rabbit knee model of post-traumatic joint contractures: the long-term natural
      history of motion loss and myofibroblasts.
AB  - Our objective is to describe the natural history of motion loss with time and
      myofibroblast numbers in a rabbit knee model of post-traumatic joint
      contractures. Twenty-eight skeletally mature New Zealand White female rabbits had
      five-mm-squares of cortical bone removed from the medial and lateral femoral
      condyles of the right knee. A Kirschner wire (K-wire) was used to immobilize the
      knee joint in maximum flexion. A second operation was performed 8 weeks later to
      remove the K-wire. The rabbits were divided into four groups depending on the
      time of remobilization; 0, 8, 16 or 32 weeks. The average flexion contracture of
      the experimental knees in the 0-week and 8-week remobilization groups (38 degrees
      and 33 degrees, respectively) were significantly greater when compared with the
      values of the unoperated contralateral knees (8 degrees). The average flexion
      contractures of the experimental knees in the 16-week and 32-week remobilization
      groups were also greater than the unoperated contralateral knees, although they
      were not statistically significant. The average flexion contractures of the 16
      week and 32-week groups were 19 degrees and 18 degrees, respectively, indicating
      a stabilization of the motion loss. Myofibroblast numbers in the posterior joint
      capsules were elevated 4-5x in the knees with contractures when compared to the
      contralateral knees. The initial decrease in severity followed by stabilization
      of motion loss and the association of motion loss with myofibroblasts mimics the
      human scenario of permanent post-traumatic joint contractures.

PMID- 15013091
TI  - Neurokinin 1-receptors and sensory neuropeptides in tendon insertions at the
      medial and lateral epicondyles of the humerus. Studies on tennis elbow and medial
      epicondylalgia.
AB  - There is no information on the sensory innervation at the flexor muscle origin at
      the medial epicondyle of the humerus and it is not known if substance P receptors
      (Neurokinin 1-receptors, NK1-R) are present in tendon insertions in general. In
      the present investigation, we have studied the muscle origin in patients
      suffering from medial epicondylalgia and tennis elbow. Immunohistochemistry and
      antibodies to substance P (SP) and CGRP as well as the general nerve marker PGP
      9.5 were used. Specific immunoreactions were observed in nerve bundles and as
      free nerve fibers. The immunoreactive structures were partly seen in association
      with some of the blood vessels. The observations constitute a morphological
      correlate for the occurrence of nerve mediated effects in this region. By using
      immunohistochemistry and antibodies to NK1-R, the distribution of this receptor
      was studied at the insertion of the proximal tendon of the extensor carpi
      radialis brevis muscle at the lateral epicondyle. Specific immunoreactions were
      seen as varicose fibers occurring as single fibers or grouped into bundles,
      indicating that SP has effects in the nerves in this region. The results give
      further evidence for a possible neurogenic involvement in the pathophysiology of
      tennis elbow and in medial epicondylalgia.

PMID- 15013092
TI  - Ex vivo static tensile loading inhibits MMP-1 expression in rat tail tendon cells
      through a cytoskeletally based mechanotransduction mechanism.
AB  - To determine the effect of various degrees of ex vivo static tensile loading on
      the expression of collagenase (MMP-1) in tendon cells, rat tail tendons were
      statically loaded in tension at 0.16, 0.77, 1.38 or 2.6 MPa for 24 h. Northern
      blot analysis was used to assay for mRNA expression of MMP-1 in freshly
      harvested, 24 h load deprived, and 24 h statically loaded tendons. Western blot
      analysis was used to assay for pro-MMP-1 and MMP-1 protein expression in fresh
      and 24 h load deprived tendons. Freshly harvested rat tail tendons demonstrated
      no evidence of MMP-1 mRNA expression and no evidence of the pro-MMP-1 or MMP-1
      protein. Ex vivo load deprivation for 24 h resulted in a marked increase in the
      mRNA expression of MMP-1 which coincided with a marked increase of both pro-MMP-1
      and MMP-1 protein expression. When tendons were subjected to ex vivo static
      tensile loading during the 24 h culture period, a significant inhibition of this
      upregulation of MMP-1 mRNA expression was found with increasing load (p<0.05). A
      strong (r2=0.78) and significant (p<0.001) inverse correlation existed between
      the level of static tensile load and the expression of MMP-1. Disruption of the
      actin cytoskeleton with cytochalasin D abolished the inhibitory effect of ex vivo
      static tensile loading on MMP-1 expression. The results of this study suggest
      that up-regulation of MMP-1 expression in tendon cells ex vivo can be inhibited
      by static tensile loading, presumably through a cytoskeletally based
      mechanotransduction pathway.

PMID- 15013093
TI  - Abnormal tenocyte morphology is more prevalent than collagen disruption in
      asymptomatic athletes' patellar tendons.
AB  - This study investigated the prevalence of each of the four features of patellar
      tendinosis in asymptomatic athletic subjects undergoing patellar tendon anterior
      cruciate ligament (ACL) reconstruction. Fifty subjects (39 males and 11 females)
      undergoing ACL reconstruction using a patellar tendon graft were screened for
      previous tendon symptoms, training and playing history and had their patellar
      tendons examined with ultrasound prior to surgery. During surgery, a small piece
      of proximal posterocentral tendon was harvested, fixed and examined under light
      microscopy. Histopathological changes were graded for severity. Results
      demonstrate that 18 tendons were abnormal on light microscopy and 32 were normal.
      There were no differences between subjects with and without pathology in respect
      of training, recovery after surgery and basic anthropometric measures. Three
      tendons were abnormal on ultrasound but only one had proximal and central
      changes. Tendons showed a consistent series of changes. Tenocyte changes were
      found in all but one of the abnormal tendons. In all but one of the tendons with
      increased ground substance there were tenocyte changes, and collagen separation
      was always associated with both tenocyte changes and increased ground substance.
      No tendons demonstrated neovascularization. It appears that cellular changes must
      be present if there is an increase in ground substance, or collagen and vascular
      changes. Further research is required to confirm these findings.

PMID- 15013094
TI  - Dynamic loads are determinants of peak bone mass.
AB  - This study investigated the association between non-invasive measurements of bone
      mass and markers of dynamic and static hip joint loads in subjects expected to be
      at peak bone mass. The bone mineral density (BMD) and bone mineral content (BMC)
      of three proximal femoral sites (neck, greater trochanter, and total) were
      measured by dual energy X-ray absorptiometry, and the peak external joint moments
      at the hip during walking and jogging were calculated from gait analyses of 31
      normal human subjects ranging in age from 30 to 49 years (18 females, 13 males).
      Various multiple regression analyses were performed to determine how much of the
      variance in BMD and BMC was explained by height, body mass, and the peak hip
      joint moments. In total, the models explained up to 40% of the variance in BMD
      and 58% of the variance in BMC. Inclusion of height or body mass did not increase
      the explanatory power of the models for BMD and explained no more than 8% of the
      total variance in BMC once the joint moments from walking were allowed to enter
      the models. These data support the hypothesis that variance in peak bone mass is
      associated with variance in dynamic hip loads largely independent of the effect
      of static factors such as height and body mass.

PMID- 15013095
TI  - Mechanobiological predictions of growth front morphology in developmental hip
      dysplasia.
AB  - Developmental dysplasia of the hip (DDH) is the most common orthopedic problem of
      newborn children. Most clinicians and researchers agree that the primary cause of
      DDH is abnormal mechanical forces on the head of the femur due to limb position,
      pressure from the womb, or ligament laxity. The abnormal mechanical forces result
      in altered growth and bony deformities, in particular large neck-shaft and
      anteversion angles in the proximal femur and a shallow acetabulum. Previous
      studies have suggested that intermittent octahedral shear stress promotes growth
      and ossification, while intermittent hydrostatic compressive stress inhibits
      growth and ossification. We implemented these mechanobiological principles into a
      finite element model to predict the rate of progression of the growth front and
      the formation of coxa valga (large neck-shaft angle) in DDH. Under the assumed
      normal fetal loading conditions the hydrostatic stress was even across the growth
      front, but the octahedral shear stress was higher in the center than at the
      edges. This stress profile promoted growth in the center and a produced a convex
      growth front shape. Under loading conditions of the dysplastic hip, the
      octahedral shear stress was much larger on the medial side than on the lateral
      side, which promoted growth on the medial side and resulted in coxa valga. These
      results indicate that abnormal forces on the prenatal hip might influence total
      bone morphology and the development of DDH. These findings might help in
      understanding the etiology and pathology of other developmental bone deformities.

PMID- 15013096
TI  - Osteoblast-like cell adhesion to bone sialoprotein peptides.
AB  - A number of studies have suggested that biomimetic peptides can be used in the
      design of a new generation of prosthetic implants to promote the successful
      biointegration of the implant materials. In the current study, the in vitro
      bioactivities of several peptides representing RGD (Arg-Gly-Asp)-containing
      sequences of bone sialoprotein (BSP) toward an osteoblast-like cell line (MC3T3
      E1) were examined to provide insight into the molecular basis of BSP's
      interaction with bone cells. BSP residues 283-288, 281-290, 278-293 and 278-302
      were coated on polystyrene surfaces in 96-well non-tissue (untreated) culture
      plates, and their osteoblast adhesive properties compared to intact BSP and
      fibronectin as positive controls. BSP peptides 278-302 and 278-293 were found to
      be the most potent in their adhesive activity, increasing the number of adherent
      cells to 350% of control levels at an added concentration of 1 microM. Since
      these two peptides were equivalent in potency, it is suggested that the region
      294-302 beyond the RGD domain is not necessary for cell binding. In comparison,
      peptides 283-288 and 281-290 were only active at concentrations greater than 200
      microM. 50-70% of the peptide-stimulated adhesion was inhibited by the
      pretreatment of cell suspensions with solution phase RGD, suggesting that a
      portion of the peptides' adhesive effects was specific and integrin-mediated,
      although other non-RGD flanking regions were probably also involved in the
      mechanism of adhesion. Importantly, a modified BSP peptide, in which an aspartic
      acid residue at position 288 of the RGD sequence was replaced by a glutamic acid
      residue to form RGE, was completely inactive as a cell adhesion stimulus at
      concentrations up to 200 microM. Thus, despite the potential role of non-RGD
      flanking regions, an intact RGD tripeptide was essential for all of the adhesive
      activity of the BSP peptides.

PMID- 15013097
TI  - Measurement of changes in trabecular bone at fracture sites using X-ray CT and
      automated image registration and processing.
AB  - Currently, there are no in vivo techniques for quantifying healing within
      fractures involving mainly trabecular bone. Methods for quantitatively assessing
      healing would aid the investigation of new treatment regimes, and might also be
      useful for predicting whether a patient may be undergoing delayed union. Using CT
      and automated image registration, we have developed an image processing technique
      for measuring changes in CT image intensity at fracture sites. The technique
      focuses on quantifying the formation of new mineralised tissue within fracture
      gaps, while ignoring loss of bone mineral due to disuse osteoporosis. Seven
      patients with fractures of the distal radius were examined for 12 weeks following
      fracture. To assess reproducibility of measurements of change in CT intensity at
      the fracture line, measurements were performed on two separate occasions, by each
      of two independent readers. Reproducibility was compared to rates of change over
      time, to determine detectable differences in individual progression. Scans were
      scored qualitatively for features of healing and scores compared to the
      quantitative measurements. The mean (SD) change in CT intensity was +128 (65)
      Hounsfield Units (HU) over the 12 week follow-up. Inter- and intra-observer
      reproducibilities were both similar (+/- 17 HU), 1/7 of the change seen during
      the study. In this small patient cohort, a significant increase in CT intensity
      was seen 2 weeks post-fracture. Large early increases in CT intensity were
      associated with early visual appearance of sclerosis and blurring of the fracture
      line. In this preliminary, prospective study, we have developed a reproducible
      quantitative technique for measuring changes in CT intensity of trabecular bone
      at the fracture line in the distal radius. Further work is required to determine
      whether it can be used to identify, or monitor patients who are undergoing
      delayed fracture repair. The technique appears sensitive for measuring changes
      immediately post-fracture, and could have a role in examining potential effects
      of new therapies in patient cohorts.

PMID- 15013098
TI  - Endochondral ossification in fracture callus during long bone repair: the
      localisation of 'cavity-lining cells' within the cartilage.
AB  - Successful fracture healing typically involves the production of a cartilaginous
      callus, which is eventually remodelled into new bone. The blood vessels in the
      advancing front of endochondral ossification are likely to play an important role
      in the replacement of cartilage with bone within the callus. This was
      investigated by histology and immunohistochemistry techniques carried out on
      rabbit tibial osteotomy tissue. Cavities within the cartilage were identified by
      histology and in many cases, there appeared to be vascular structures within
      them, identified by the immunolocalisation of the transmembrane proteins CD31 and
      CD34. Osteocalcin localisation and Alizarin red histology was carried out to
      identify 'osteoblastic' cells and mineral localisation within the cartilaginous
      callus respectively. However, it was the identification of a population of cells
      lining the cavities within the cartilage that became the main focus of this
      study. These cells were 'osteoblastic' in nature, (positive localisation of
      osteocalcin), and were also positive for the adhesion proteins CD31 and CD34. It
      is thought that these cells play a role in the conversion of cartilage to bone
      during the fracture healing process.

PMID- 15013100
TI  - Neuromuscular electrical stimulation enhances fracture healing: results of an
      animal model.
AB  - Neuromuscular electrical stimulation (NMES) could simulate physiological muscle
      functions known to be associated with the normal bone healing process. The object
      of the present study was to evaluate the effect of NMES on fracture healing,
      using an animal model. Thirty rabbits received unilateral, transverse, mid
      tibial, 3-mm gapped osteotomies that were stabilized with double-bar external
      fixators. The femoral vein was ligated to induce venous stasis. From the fourth
      post-operative day, the study group was treated with 1 h daily of NMES for four
      weeks, while the control group was treated without NMES. For NMES, two surface
      electrodes were used: one above the patellar tendon and another around the
      lateral thigh. Callus area and mineral content at the osteotomy gap were
      measured, biweekly, using computerized tomographic examinations. Biomechanical
      properties of healing were evaluated with a torsion test, eight weeks after the
      index operation. Osteotomies treated with NMES exhibited 31% (p=0.01) higher
      mineral content and 27% (p=0.009) larger callus area than control osteotomies at
      eight weeks. The maximum torque, torsional stiffness, angular displacement at
      maximum torque, and energy required to failure of specimens in the study group
      were 62% (p=0.006), 29% (p=0.03), 34.6% (p=0.008), and 124% (p<0.0001) higher,
      respectively, than those in the control group at eight weeks. The results of the
      present study demonstrated that the use of NMES can enhance callus development
      and mineralization, with the consequent improvement in biomechanical properties
      of the healing bone.

PMID- 15013099
TI  - Bone healing in the rat and dog with nonglycosylated BMP-2 demonstrating low
      solubility in fibrin matrices.
AB  - A novel form of recombinant human bone morphogenetic protein-2 (BMP-2) was
      explored for effective incorporation and long-term retention into fibrin ingrowth
      matrices. The solubility of native BMP-2 is greatly dependent on its
      glycosylation. To enhance retention of BMP-2 in fibrin matrices, a
      nonglycosylated form (nglBMP-2), which is less soluble than the native
      glycosylated protein, was produced recombinantly and evaluated in critical-size
      defects in the rat calvarium (group n=6). When 1 or 20 microg nglBMP-2 was
      incorporated by precipitation within the matrix, 74 +/- 4% and 98 +/- 2% healing
      was observed in the rat calvarium, respectively, as judged radiographically by
      closure of the defect at 3 weeks. More soluble forms of BMP-2, used as controls,
      induced less healing, demonstrating a positive correlation between low
      solubility, retention in vitro, and healing in vivo. Subsequently, the utility of
      nglBMP-2 was explored in a prospective veterinary clinical trial for inter-carpal
      fusion in dogs, replacing the standard-of-care, namely autologous cancellous
      autograft, with nglBMP-2 in fibrin. In a study of 10 sequential canine patients,
      fibrin with 600 microg/ml nglBMP-2 performed better than autograft in the first
      weeks of bone healing and comparably thereafter. Furthermore, a greater fraction
      of animals treated with nglBMP-2 in fibrin demonstrated bone bridging across each
      of the treated joints at both 12 and 17 weeks than in animals treated with
      autograft. These results suggest that evaluation in a human clinical setting of
      nonglycosylated BMP-2 in fibrin matrices might be fruitful.

PMID- 15013101
TI  - Effects of cessation of immunosuppression on skeleton reconstructed by
      vascularized bone allograft in rats.
AB  - In the present study, we investigated the effects of cessation of
      immunosuppression on skeleton reconstructed by vascularized allogenic bone
      transplantation in a rat tibio-fibula graft model. Twelve-week-old male 25 Dark
      Agouti rats with the major histocompatibility antigen (MHC) RT1a were used as
      donors and age-matched male 25 Lewis rats with MHC RT1l were used as recipients.
      Among them, 20 rats were randomly allocated to 8-week cyclosporine A (CsA)
      followed by 8-week CsA vehicle group or continuous 16-week CsA group. The
      remaining 5 rats received CsA for 8 weeks followed by no further treatment for
      next 40 weeks (long-term observation group). In the CsA followed by vehicle group
      as well as the continuous CsA group, the structure of the reconstructed bones was
      maintained, though the transplanted bones in former group were found to be partly
      non-vital. The CsA followed by vehicle group had higher bone mineral density of
      the transplanted bones and stronger strength of the reconstructed bones than the
      continuous CsA group. In the long-term observation group, the structure of the
      reconstructed bones was still maintained and the transplanted bones were almost
      vital. These results suggest that long-term strong immunosuppression may not be
      necessary for successful reconstruction of large bone defect by vascularized bone
      allograft.

PMID- 15013102
TI  - Effects of timing of low-intensity pulsed ultrasound on distraction osteogenesis.
AB  - We investigated the effects of low-intensity pulsed ultrasound (LIPUS; 30 mW/cm2
      spatial and temporal average) on the timing of LIPUS treatment in distraction
      osteogenesis. Lengthening of the right tibia was performed in 75 male Japanese
      white rabbits using unilateral fixators (waiting period, 7 days; distraction
      rate, 1.5 mm/day; distraction period, 7 days). Rabbits were divided into four
      groups according to the timing of the LIPUS treatment. Control group had no
      stimulation. Waiting group was treated with a daily 20-min session of LIPUS
      during a 7-day latency period. Lengthening group was treated during the
      lengthening period. Maturation group was treated for the first 7 days after
      completion of distraction. We evaluated the distraction site by radiography and
      histology every week for 4 weeks. Bone mineral density (BMD) and mechanical
      strength were tested and microfocus X-ray computed tomography was performed on
      specimens 2 weeks after completion of distraction. The lengthening group had
      greater BMD and mechanical strength than the other groups, bone regeneration was
      enhanced more in the maturation group than in the control or waiting groups.
      Histologically, endochondral bone formation in the lengthening and the maturation
      groups occurred earlier than in the control or waiting groups. These results
      suggest the LIPUS effect is mediated via endochondral pathways. We concluded that
      LIPUS stimulates bone formation in distraction osteogenesis and is most effective
      during the lengthening phase.

PMID- 15013103
TI  - Altered Cbfa1 expression and biomineralization in an osteosarcoma cell line.
AB  - Osteoblast differentiation and expression are regulated by Cbfa1 transcription
      factors. Recent evidence suggests that Cbfa1 may also regulate bone
      mineralization. The purpose of this study was to characterize Cbfa1 expression in
      relation to mineralization in rat UMR106-01 osteoblastic cell cultures. UMR106-01
      BSP cultures consistently form bone-like mineral, whereas the UI subclone
      mineralize gradually. BSP and UI cultures were grown for 48 h and then treated
      with beta-glycerophosphate. BSP cultures had alizarin red stained calcifications
      and mineral-like deposits within 24 h of phosphate. Atomic absorption
      spectroscopy measured significantly (P<0.0001) more calcium in the phosphate
      treated BSP cultures than in the UI. Cbfa1 message was detected in the BSP and UI
      cultures, but the Cbfa1 N-terminal isoform was deficient in UI and appeared to be
      up-regulated in the phosphate-treated BSP cultures. Cbfa1 protein levels were
      also reduced in the UI. DNA sequence from the RT-PCR products was utilized to
      design Taqman Real-time RT-PCR reagents. Quantitative Real-time RT-PCR analysis
      showed that Cbfa1 mRNA levels relative to endogenous 18 s rRNA were lower in the
      slower mineralizing UI cultures. Furthermore, the Cbfa1 N-terminal isoform mRNA
      levels were significantly (P<0.001) lower in the slower mineralizing cultures.
      Transfection with Cbfa1 or isoform antisense caused a significant (P<0.001)
      reduction in mineralization. Therefore, Cbfa1 expression may be associated with
      bone-like mineral formation in rat UMR106-01 osteoblastic cell cultures.

PMID- 15013104
TI  - Early osteoblastic differentiation induced by dexamethasone enhances adenoviral
      gene delivery to marrow stromal cells.
AB  - We investigated the implications of induced osteogenic differentiation on gene
      delivery in multipotent rat marrow stromal cells (MSCs). Prior to genetic
      manipulation cells were cultured with or without osteogenic supplements (5x10(-8)
      M dexamethasone, 160 microM l-ascorbic acid 2-phosphate, and 10 mM beta
      glycerophosphate). Comparison of liposome, retroviral, and adenoviral vectors
      demonstrated that all three vectors could mediate gene delivery to primary rat
      MSCs. When these vectors were applied in the absence or presence of osteogenic
      supplements, we found that MSCs differentiated prior to transduction with
      adenovirus type 5 vectors produced a 300% increase in transgene expression
      compared to MSCs that were not exposed to osteogenic supplements. This
      differentiation effect appeared specific to adenoviral mediated gene delivery,
      since there was minimal increase in retroviral gene delivery and no increase in
      liposome gene delivery when MSCs were treated with osteogenic supplements. In
      addition, we also determined this increase in transgene production to occur at a
      higher concentration of dexamethasone (5x10(-8) M) in the culture medium of MSCs
      prior to adenoviral transduction. We found that this increased transgene
      production could be extended to the osteogenic protein, human bone morphogenetic
      protein 2 (hBMP-2). When delivered by an adenoviral vector, hBMP-2 transgene
      production could be increased from 1.4 ng/10(5) cells/3 days to 4.3 ng/10(5)
      cells/3 days by culture of MSCs with osteogenic supplements prior to
      transduction. These results indicate that the utility of MSCs as a therapeutic
      protein delivery mechanism through genetic manipulation can be enhanced by pre
      culture of these cells with dexamethasone.

PMID- 15013105
TI  - Intramembranous ossification mechanism for bone bridge formation at the growth
      plate cartilage injury site.
AB  - Salter's type III and type IV growth plate injuries often induce bone bridge
      formation at the injury site. To understand the cellular mechanisms, this study
      characterized proximal tibial transphyseal injury in rats. Histologically, bony
      bridge trabeculae appeared on day 7, increased on day 10, and became well
      constructed on day 14 with marrow. Prior to and during bone bridging, there was
      no cartilage proteoglycan metachromatic staining and no collagen-X immunostaining
      at the injury site, nor was there any up-regulation of BrdU-labelled chondrocyte
      proliferation at the adjacent physeal cartilage, suggesting no new cartilage
      formation at the injury site. However, infiltration of vimentin-immunopositive
      mesenchymal cells from metaphysis and epiphysis was apparent on day 3, with the
      mesenchymal population being prominent on days 7 and 10 and subsided on day 14.
      Among these infiltrates were osteoprogenitor precursors expressing osteoblast
      differentiation factor (cbf-alpha1) on day 3, along with some cbf-alpha1+
      osteoblast-like cells lining bone trabeculae on days 7 and 10. Some mesenchymal
      cells and trabecula-lining cells were also alkaline phosphatase-immunopositive,
      further suggesting their osteoblast differentiation. From day 7 onwards, some
      trabecula-lining cells became osteocalcin-producing mature osteoblasts. These
      results suggest that bone bridge formation after growth plate injury occurs
      directly via intramembranous ossification through recruitment of marrow-derived
      osteoprogenitor cells.

PMID- 15013106
TI  - Reducing joint destruction due to septic arthrosis using an adenosine2A receptor
      agonist.
AB  - We assessed the efficacy of a new adenosine A2A agonist ATL146e, a potent
      inhibitor of white blood cell chemotaxis, to reduce cartilage damage in the
      treatment of septic arthrosis. A live septic arthrosis model was created using
      Staphylococcus aureus in rabbit knees. Animals were divided into five treatment
      groups: (1) untreated infected control, (2) antibiotics control, and antibiotics
      plus ATL146e for (3) 24, (4) 48, or (5) 72 h and assessed at 1, 4, and 7 days.
      Knees in all ATL146e treated animals exhibited no detectable effusion, and
      histologic examination revealed near normal cartilage and diminished synovial
      inflammatory response. Synovial WBC counts decreased with the addition of ATL146e
      when compared to infected and antibiotic controls. Histologic grading of
      osteochondral specimens demonstrated improved scores for animals treated with
      ATL146e compared to infected (p<0.00004) and antibiotics controls (p<0.05).
      Analysis of glycosaminoglycan content revealed significantly decreased loss of
      articular cartilage following infection in the ATL146e groups when compared to
      infected (p<0.03) and antibiotics controls (p<0.05). Addition of an adenosine A2A
      agonist to antibiotic therapy decreases joint inflammation and articular
      cartilage destruction without compromising bacterial clearance in rabbit knees
      following intraarticular bacterial infection. The use of adenosine agonists
      selective to the A2A receptor to augment conventional treatment of joint sepsis
      may be chondroprotective and ultimately help prevent arthrosis.

PMID- 15013107
TI  - Insulin-like growth factor-I diminishes the activation status and expression of
      the small GTPase Cdc42 in articular chondrocytes.
AB  - Insulin-like growth factor-I (IGF-I) is an important anabolic growth factor in
      the maintenance of articular cartilage phenotypic expression. Chondrocyte
      morphology is also tightly linked to phenotype. The small G-protein Cdc42 plays a
      key role in regulation of cell morphology and phenotypic expression in several
      cell types and, we show here, in articular chondrocytes. The purpose of these
      studies was to investigate possible links between the intracellular signaling
      pathways of IGF-I and Cdc42 in articular chondrocytes. Treatment of chondrocytes
      with IGF-I resulted in a rapid and sustained decrease in the activation state
      (decreased GTP-bound) of Cdc42. Nucleotide exchange and hydrolysis experiments
      suggest that the decreased activation occurs through increased hydrolysis.
      Transient expression of dominant-negative Cdc42(T17N) allowed for enhanced
      expression of normal chondrocyte phenotype as determined by increased mRNA
      expression of collagen type II (Coll II) with decreased matrix metalloproteinase
      3 (MMP-3) expression. The results of these studies suggest a novel link between
      IGF-I and Cdc42 signaling pathways. Further, an additional mechanism for the
      regulation of chondrocyte phenotype is defined through the IGF-I induced down
      regulation of Cdc42 activation.

PMID- 15013108
TI  - The use of debrided human articular cartilage for autologous chondrocyte
      implantation: maintenance of chondrocyte differentiation and proliferation in
      type I collagen gels.
AB  - Autologous chondrocyte implantation (ACI) is the most promising surgical
      treatment for large full thickness knee joint articular cartilage (AC) defects
      where cells from healthy non-weight bearing area AC are multiplied in vitro and
      implanted into such defects. In the routine surgical procedure for symptomatic
      knee full thickness AC defects, damaged AC surrounding the edge and the base of
      such defects is usually debrided and discarded. The purpose of this study was to
      examine if chondrocytes from this 'debrided' AC can proliferate, synthesize a
      cartilage specific matrix and thus can be used for ACI. METHODS: Biopsies were
      retrieved from 12 patients (debrided articular cartilage: DAC, aged 35-61) and
      from two autopsies (normal articular cartilage: NAC, aged 21 and 25).
      Chondrocytes were isolated, seeded at low density in type I collagen gels and as
      monolayer cultures for 4 weeks without passage. RESULTS: After 4 weeks cultures
      in type I collagen gels, cell proliferation from DAC (18.34 +/- 1.95 fold) was
      similar to cells from NAC (11.24 +/- 1.02 fold). Syntheses of proteoglycan and
      collagen in DAC were also similar to NAC. Newly synthesized matrices in gel
      cultures consisted predominantly of type II collagen as shown by immuno-labelling
      and SDS-PAGE followed by fluorography. Chondrocytes from 'debrided human AC'
      cultured at low density in type I collagen gels may be used for the ACI procedure
      as they provide sufficient viable cell numbers for ACI and maintain their
      chondrocyte phenotype as they synthesize a cartilage-like matrix.

PMID- 15013109
TI  - Heart failure with preserved left ventricular systolic function; epidemiology,
      clinical characteristics, and prognosis.
AB  - Recent cross-sectional, population-based echocardiographic studies show that
      about half of all patients with heart failure have preserved left ventricular
      systolic function (HF-PSF). Cohort studies of hospitalized patients show a
      smaller proportion of HF-PSF. Compared to those with reduced systolic function,
      patients with HF-PSF are more often female, older, less likely to have coronary
      artery disease, and more likely to have hypertension. Patients with HF-PSF are
      less symptomatic and receive different pharmacologic therapy than patients with
      reduced systolic function. Morbidity and mortality rates in patients with HF-PSF
      are high but not quite as high as in patients with reduced systolic function.
      Though much has recently been learned about the syndrome of HF-PSF, many
      questions remain to be answered, not least how it should be treated.

PMID- 15013110
TI  - Myocardial perfusion imaging following percutaneous coronary intervention: the
      importance of restenosis, disease progression, and directed reintervention.
AB  - Percutaneous coronary intervention (PCI) has become a mainstay in the treatment
      of patients with coronary artery disease. Currently, more than one million
      coronary angioplasty and stent implantation procedures are performed annually.
      Although increasingly complex lesions and higher risk patients are being
      successfully treated percutaneously, restenosis and disease progression continue
      to cause significant morbidity. Restenosis occurs in approximately one-third of
      patients, one-half of who remain asymptomatic, while disease progression occurs
      at rates approaching 7% per year. Despite technological advances, unadjusted
      mortality rates have actually increased since the mid-1980s, and the current
      annual risk of a major adverse cardiac event following PCI is 5% to 7%. Although
      randomized clinical trials are needed to more definitively show a benefit, when
      performed six or more months following PCI, myocardial perfusion imaging reliably
      identifies patients most at risk of a poor long-term outcome. Directed
      reintervention can have a salutary impact on the prognosis of these patients. In
      view of recent data showing a positive impact of imaging and reintervention in
      patients after PCI, current guidelines should be reassessed.

PMID- 15013111
TI  - Impact of delays to cardiac surgery after failed angioplasty and stenting.
AB  - OBJECTIVES: This study was designed to determine the likelihood of harm in
      patients having additional delays before urgent coronary artery bypass graft
      (UCABG) surgery after percutaneous coronary intervention (PCI). BACKGROUND:
      Patients who have PCI at hospitals without cardiac surgery have additional delays
      to surgery when UCABG is indicated. METHODS: Detailed chart review was performed
      on all patients who had a failed PCI leading to UCABG at a large tertiary care
      hospital. A prespecified set of criteria (hemodynamic instability, coronary
      perforation with significant effusion or tamponade, or severe ischemia) was used
      to identify patients who would have an increased likelihood of harm with
      additional delays to surgery. RESULTS: From 1996 to 2000, 6,582 PCIs were
      performed. There were 45 patients (0.7%) identified to have UCABG. The
      demographic characteristics of the UCABG patients were similar to the rest of the
      patients in the PCI database, except for significantly more type C lesions (45.3%
      vs. 25.0%, p < 0.001) and more urgent cases (66.6% vs. 49.8%, p = 0.03) in
      patients with UCABG. Myocardial infarction occurred in eight patients (17.0%)
      after UCABG, with a mean peak creatine kinase of 2,445 +/- 1,212 IU/l. Death
      during the index hospital admission occurred in two patients. Eleven of the 45
      patients (24.4%) were identified by the prespecified criteria to be at high
      likelihood of harm with additional delays to surgery. The absolute risk of harm
      is approximately one to two patients per 1,000 PCIs. CONCLUSIONS: Approximately
      one in four patients referred for UCABG would be placed at increased risk of harm
      if delays to surgery were encountered.

PMID- 15013112
TI  - Coronary intervention at hospitals without on-site cardiac surgery: are we
      pushing the envelope too far?

PMID- 15013113
TI  - Importance of increasing age on the presentation and outcome of acute coronary
      syndromes in elderly patients.
AB  - OBJECTIVES: The study examined differences in presentation and outcome between
      elderly (> or =70 years) and very elderly (> or =80 years) patients hospitalized
      for acute coronary syndromes (ACS). BACKGROUND: The elderly constitute an
      increasingly important sector of patients with ACS but have been underrepresented
      in many therapeutic trials. METHODS: We compiled a registry of 449 consecutive
      patients, 251 elderly (70 to 79 years) (septuagenarians, group 1) and 198 very
      elderly (> or =80 years) (group 2), to examine outcomes in relation to baseline
      characteristics and treatment. We recorded survival over a period of 24 +/- 4
      months and rehospitalization and symptomatic status at 16 +/- 4 months. RESULTS:
      At index hospitalization, the older cohort (group 2) more often had acute
      myocardial infarction (35% vs. 9.7%, p < 0.0001), heart failure (33.3% vs. 19.4%,
      p < 0.001), and renal dysfunction (21.6% vs. 12.3%, p = 0.01). They were less
      likely to undergo coronary angiography (29.3% vs. 43.8%, p = 0.002), but those
      selected for angiography more often underwent revascularization so that
      revascularization rates were similar (22.7% group 2 vs. 24.3% group 1, p = NS).
      Two-year survival rate was poorer in group 2 (67.4 +/- 3.5% vs. 83.5 +/- 2.5% in
      group 1, p < 0.0001). Repeat rehospitalization was similar (53.0% vs. 48.2%,
      respectively, p = 0.31), but improvement in well-being of survivors was greater
      (60.0% vs. 46.3%, p = 0.01). CONCLUSIONS: The study demonstrated important
      differences between elderly (70 to 79 years) and very elderly (> or =80 years)
      patients hospitalized with ACS. The older cohort was sicker on admission and had
      poorer outcome, but a subgroup selected for angiography and possible intervention
      had two-year outcomes similar to the younger cohort.

PMID- 15013114
TI  - Exercise release of cardiac natriuretic peptides is markedly enhanced when
      patients with coronary artery disease are treated medically by beta-blockers.
AB  - OBJECTIVES: This study sought to identify determinants of the exercise rise in
      plasma levels of cardiac natriuretic peptides (NPs) in patients with coronary
      artery disease (CAD). BACKGROUND: During stress, there is a variable rise in the
      plasma level of NPs, but this rise frequently reaches levels that are known to
      lower the cardiac load and that thus might be beneficial to CAD patients.
      METHODS: Plasma venous concentrations of atrial natriuretic peptide (ANP) and
      brain natriuretic peptide (BNP) were determined at rest and peak exercise in 104
      patients with chronic CAD who were referred to exercise thallium-201 ((201)Tl)
      single-photon emission computed tomography (SPECT) and radionuclide angiography.
      RESULTS: The extent of scarred myocardium by (201)Tl-SPECT and patient age were
      the best independent predictors of NP concentrations at rest, but also of
      increases in NP concentration during exercise (all p < 0.001). Moreover, beta
      blocking treatment was an additional and strong independent predictor of the
      increase in NP concentrations at exercise (p < 0.001 for ANP; p = 0.001 for BNP).
      On average, exercise increases in NP concentrations were more than twice as high
      in patients with (n = 55) than in those without (n = 49) beta-blocker treatment
      (ANP: +49 +/- 63 vs. +22 +/- 25 ng/l, p = 0.01; BNP: +24 +/- 5 vs. +11 +/- 15
      ng/l, p = 0.04), whereas NP concentrations at rest were equivalent in the two
      groups (ANP: 34 +/- 34 vs. 30 +/- 33 ng/l, p = NS; BNP: 85 +/- 152 vs. 57 +/- 101
      ng/l, p = NS). CONCLUSIONS: Patients with chronic CAD exhibit much higher
      exercise releases of ANP and BNP when they are treated with beta-blockers. This
      enhanced secretion of potent vasodilating and natriuretic agents constitutes an
      original therapeutic mechanism for further protecting diseased hearts against
      stress.

PMID- 15013116
TI  - Enhanced coronary flow velocity during intra-aortic balloon pumping assessed by
      transthoracic Doppler echocardiography.
AB  - OBJECTIVES: The study was done to determine potential utility of measuring
      coronary flow velocity (CFV) by transthoracic Doppler echocardiography (TTDE)
      during intra-aortic balloon pumping (IABP). BACKGROUND: Use of IABP has been
      shown to increase CFV assessed by an invasive technique. The CFV in the left
      anterior descending coronary artery (LAD) can be measured by TTDE. METHODS:
      Coronary flow velocity in the distal LAD by TTDE was measured in 40 critically
      ill patients requiring IABP. All patients received emergency coronary
      angiography. Both CFV and pressure data were obtained during 1:2 balloon pumping.
      RESULTS: Adequate diastolic CFV recording was obtained in all patients. The IABP
      decreased systolic pressure and increased diastolic pressure. Average peak
      diastolic flow velocity and diastolic velocity time integral was 19 +/- 11 cm/s
      and 7.7 +/- 4.4 cm with non-augmented beat. These values were increased
      significantly (61 +/- 38%, 59 +/- 35%, p < 0.001) with augmented beat.
      Significant correlation was noted between % diastolic pressure augmentation and %
      increase in diastolic CFV (r = 0.62 to 0.69, p < 0.001). There was no significant
      difference in flow enhancement during IABP, irrespective to the proximal LAD
      stenosis severity (severe stenosis: 73 +/- 70%; intermediate stenosis: 61 +/-
      29%; no significant stenosis: 58 +/- 29%; p = NS, analysis of variance). By
      continuous recording of CFV, the optimal timing of balloon control could be
      adjusted to maximize flow velocity during augmentation. CONCLUSIONS: Use of TTDE
      can be employed in monitoring CFV augmentation during IABP. The IABP produced
      significant distal flow enhancement even in patients with critical proximal
      stenosis. This totally noninvasive approach may help to optimize the benefits of
      IABP for coronary flow augmentation.

PMID- 15013115
TI  - Noninvasive estimation of left ventricular filling pressure by E/e' is a powerful
      predictor of survival after acute myocardial infarction.
AB  - OBJECTIVES: The aim of this study was to assess the prognostic value of a
      noninvasive measure of left ventricular diastolic pressure (LVDP) early after
      acute myocardial infarction (MI). BACKGROUND: The early diastolic velocity of the
      mitral valve annulus (e') reflects the rate of myocardial relaxation. When
      combined with measurement of the early transmitral flow velocity (E), the
      resultant ratio (E/e') correlates well with mean LVDP. In particular, an E/e'
      ratio >15 is an excellent predictor of an elevated mean LVDP. We hypothesized
      that an E/e' ratio >15 would predict poorer survival after acute MI. METHODS:
      Echocardiograms were obtained in 250 unselected patients 1.6 days after admission
      for MI. Patients were followed for a median of 13 months. The end point was all
      cause mortality. RESULTS: Seventy-three patients (29%) had an E/e' >15. This was
      associated with excess mortality (log-rank statistic 21.3, p < 0.0001) and was
      the most powerful independent predictor of survival (risk ratio 4.8, 95%
      confidence interval 2.1 to 10.8, p = 0.0002). The addition of E/e' >15 improved
      the prognostic utility of a model containing clinical variables and conventional
      echocardiographic indexes of left ventricular systolic and diastolic function (p
      = 0.001). CONCLUSIONS: E/e' is a powerful predictor of survival after acute MI.
      An E/e' ratio >15 is superior, in this respect, to other clinical or
      echocardiographic features. Furthermore, it provides prognostic information
      incremental to these parameters.

PMID- 15013118
TI  - Ischemic mitral regurgitation and ventricular remodeling.

PMID- 15013117
TI  - Prevention of ischemic mitral regurgitation does not influence the outcome of
      remodeling after posterolateral myocardial infarction.
AB  - OBJECTIVES: This study was designed to test the hypothesis that ischemic mitral
      regurgitation (IMR) results from, but does not influence, the progression of left
      ventricular (LV) remodeling after posterolateral infarction. BACKGROUND: Surgical
      correction of chronic IMR is being increasingly recommended. METHODS: Three
      groups of sheep had coronary snares placed around the second and third obtuse
      marginal coronary arteries. Occlusion of these vessels in the control group
      resulted in progressive IMR over eight weeks. In a second group, Merseline mesh
      was fitted to cover the exposed LV before infarction. In a third group, a ring
      annuloplasty was placed before infarction to prevent IMR. Remodeling and degree
      of IMR were assessed with echocardiography at baseline and at 30 min and two,
      five, and eight weeks after infarction. RESULTS: Eight weeks after infarction,
      mean IMR grade was significantly higher in control animals than mesh and
      annuloplasty animals. At eight weeks, LV end-systolic volume and end-systolic
      muscle-to-cavity-area ratio (ESMCAR) were significantly better in mesh-treated
      sheep than in control sheep; also, at eight weeks, ESMCAR and akinetic segment
      length were significantly better in mesh-treated sheep than in annuloplasty
      sheep. Ejection fraction was significantly higher in the mesh than the
      annuloplasty group. There was no significant difference in any measure of
      remodeling between the annuloplasty and control groups. CONCLUSIONS: Prophylactic
      ventricular restraint reduces infarct expansion, attenuates adverse remodeling,
      and reduces IMR severity. Prevention of IMR by prophylactic ring annuloplasty
      does not influence remodeling. Ischemic mitral regurgitation is a consequence,
      not a cause, of postinfarction remodeling; infarct expansion is the more
      important therapeutic target.

PMID- 15013119
TI  - Contemporary results of mitral valve repair for infective endocarditis.
AB  - OBJECTIVES: We sought to evaluate the feasibility and immediate and late results
      of mitral valve repair (MVRep) for acute and healed endocarditis. BACKGROUND:
      Improvements in techniques of MVRep have extended its feasibility in complex
      lesions, but experience with endocarditis is limited. METHODS: Among 78 patients
      operated on for mitral endocarditis between 1990 and 1999, 63 underwent MVRep.
      The repair was performed for acute endocarditis in 25 patients (40%) at a median
      of 20 days after the onset of treatment and in 38 patients (60%) for healed
      endocarditis after a median of 11 months. RESULTS: Repair of the mitral valve was
      feasible in 63 patients (81%). This repair involved annuloplasty in 61 patients
      (97%), valve resection in 49 (78%), shortening or transposition of chordae in 29
      (46%), suture of perforation in 18 (29%), a pericardial patch in 12 (19%), and a
      partial mitral homograft in 7 (11%). Associated procedures were aortic valve
      replacement in 11 patients, bypass grafting in 3, and tricuspid repair in 2.
      Early complications were two deaths (3.2%), one re-operation for severe mitral
      regurgitation and one re-operation for subsequent aortic endocarditis. The seven
      year rate of event-free survival was 78 +/- 6% in the global series. Multivariate
      predictors of event-free survival were hypertension (p < 0.006) and intervention
      for acute endocarditis (p < 0.026). Five-year survival rates were 96 +/- 4% after
      MVRep for acute endocarditis and 91 +/- 5% for healed endocarditis. CONCLUSIONS:
      Mitral valve repair is frequently feasible and gives good results in patients
      with infective endocarditis. Patients operated on for acute endocarditis
      experience more events during follow-up than those operated on after healed
      endocarditis but have excellent late survival.

PMID- 15013120
TI  - Dobutamine stress echocardiography for noninvasive assessment and risk
      stratification of patients with rheumatic mitral stenosis.
AB  - OBJECTIVES: We sought to evaluate the impact of dobutamine stress
      echocardiography (DSE) in patients with known rheumatic mitral stenosis (MS) in
      order to assess its safety, feasibility, and prognostic correlation to well-known
      clinical outcomes. BACKGROUND: Noninvasive prognostic assessment of MS still
      represents an unresolved task in patients with clinically challenging disease.
      METHODS: Dobutamine stress echocardiography was performed in 53 patients with MS
      (8 males; age 37.4 +/- 11.3 years) with no major complications. RESULTS: During
      follow-up (60.5 +/- 11.0 months), 29 patients presented with clinical events: 16
      hospitalizations, seven cases of acute pulmonary edema, and six symptomatic
      supraventricular arrhythmias. On multivariate analysis, the diastolic mitral
      valve mean gradient at peak DSE (DSE-MG) was the best predictor of clinical
      events (p < 0.008), especially in patients with moderate disease (p < 0.001). The
      best performance of DSE for the detection of clinical events was obtained at a
      cut-off value of 18 mm Hg DSE-MG (sensitivity 90%, specificity 87%, and accuracy
      90%). The addition of DSE to the conventional cardiology work-up would allow a
      17% increment for the detection of high-risk patients in the entire population
      and a 40% increment in patients with presumed moderate disease. CONCLUSIONS: In
      patients with MS, DSE is a safe and highly feasible stress test. A DSE-MG > or
      =18 mm Hg identifies a subgroup of high-risk patients in whom a more aggressive
      approach may be warranted; on the other hand, patients with a DSE-MG <18 mm Hg
      predicts an uneventful clinical course and may justify a more conservative
      strategy.

PMID- 15013121
TI  - Stress echocardiography in mitral stenosis: when is it useful?

PMID- 15013122
TI  - Impact of tricuspid regurgitation on long-term survival.
AB  - OBJECTIVES: The goal of this study was to examine mortality associated with
      tricuspid regurgitation (TR) after controlling for left ventricular ejection
      fraction (LVEF), right ventricular (RV) dilation and dysfunction, and pulmonary
      artery systolic pressure (PASP). BACKGROUND: Tricuspid regurgitation is a
      frequent echocardiographic finding; however, the association with prognosis is
      unclear. METHODS: We retrospectively identified 5,223 patients (age 66.5 +/- 12.8
      years; predominantly male) undergoing echocardiography at one of three Veterans
      Affairs Medical Center laboratories over a period of four years. Follow-up data
      were available for four years (mean 498 +/- 402 days). Kaplan-Meier and
      proportional hazards methods were used to compare differences in survival among
      TR grades. RESULTS: Mortality increased with increasing severity of TR. The one
      year survival was 91.7% with no TR, 90.3% with mild TR, 78.9% with moderate TR,
      and 63.9% with severe TR. Moderate or greater TR was associated with increased
      mortality regardless of PASP (hazard ratio [HR] 1.31, 95% confidence interval
      [CI] 1.16 to 1.49 for PASP >40 mm Hg; HR 1.32, 95% CI 1.05 to 1.62 for PASP < or
      =40 mm Hg) and LVEF (HR 1.49, 95% CI 1.34 to 1.66 for EF <50%; HR 1.54, 95% CI
      1.37 to 1.71 for EF > or =50%). When adjusted for age, LVEF, inferior vena cava
      size, and RV size and function, survival was worse for patients with moderate (HR
      1.17, 95% CI 0.96 to 1.42) and severe TR (HR 1.31, 95% CI 1.05 to 1.66) than for
      those with no TR. CONCLUSIONS: We conclude that increasing TR severity is
      associated with worse survival in men regardless of LVEF or pulmonary artery
      pressure. Severe TR is associated with a poor prognosis, independent of age,
      biventricular systolic function, RV size, and dilation of the inferior vena cava.

PMID- 15013123
TI  - Noninvasive diagnosis of biopsy-proven cardiac amyloidosis.
AB  - OBJECTIVES: This study analyzed the utility of electrocardiographic (ECG) and
      echocardiographic findings in the diagnosis of amyloidosis proven by
      endomyocardial biopsy. BACKGROUND: Cardiac amyloidosis is associated with
      characteristic ECG and echocardiographic changes, yet each finding alone is
      relatively nonspecific. A combination of noninvasive prognostic parameters would
      be desirable for this tissue-based diagnosis. METHODS: We performed an analysis
      of 196 consecutive patients referred for endomyocardial biopsy because of
      clinical suspicion of cardiac amyloidosis. The diagnosis was confirmed in 58
      patients (29%). The ECGs, echocardiograms, and right heart hemodynamic data were
      reviewed to determine which findings strongly correlate with the diagnosis. These
      findings were then used to build multivariate logistic regression models that
      predict the log-odds of having cardiac amyloidosis. RESULTS: The univariate
      analysis showed that low-voltage and pseudo-infarction patterns on the ECG and
      increased myocardial thickness and speckled-appearing myocardium on the
      echocardiogram were associated with biopsy-proven cardiac amyloidosis (each p <
      0.01). In multivariate logistic regression models, a combination of a low voltage
      and measures of myocardial thickness produced the most statistically useful
      models. For instance, one model showed that if a low voltage was present and
      interventricular septal thickness is >1.98 cm, the diagnosis of cardiac
      amyloidosis could be made with a sensitivity of 72% and a specificity of 91%. In
      this model, the positive predictive and negative predictive values were 79% and
      88%, respectively. CONCLUSIONS: In patients with suspected cardiac amyloidosis, a
      combination of noninvasive parameters-namely, a low voltage and increased
      intraventricular septal thickness-is a useful diagnostic tool.

PMID- 15013124
TI  - Plasma B-type natriuretic peptide levels in systolic heart failure: importance of
      left ventricular diastolic function and right ventricular systolic function.
AB  - OBJECTIVES: This study was designed to characterize the importance of
      echocardiographic indexes, including newer indexes of diastolic function, as
      determinants of plasma B-type natriuretic peptide (BNP) levels in patients with
      systolic heart failure (SHF). BACKGROUND: Plasma BNP levels have utility for
      diagnosing and managing heart failure. However, there is significant
      heterogeneity in BNP levels that is not explained by left ventricular size and
      function alone. METHODS: In 106 patients with symptomatic SHF (left ventricular
      ejection fraction [LVEF] <0.35), we measured plasma BNP levels and performed
      comprehensive echocardiography with assessment of left ventricular diastolic
      function, including color M-mode (CMM) and tissue Doppler imaging (TDI), and of
      right ventricular (RV) function. RESULTS: Median plasma BNP levels were elevated
      and increased with greater severity of diastolic dysfunction. We found
      significant correlations (p < 0.001 for all) between BNP and indexes of
      myocardial relaxation (early diastolic velocity: r = -0.26), compliance
      (deceleration time: r = -0.55), and filling pressure (early transmitral to early
      annular diastolic velocity ratio: r = 0.51; early transmitral flow to the
      velocity of early left ventricular flow propagation ratio: r = 0.41). In
      multivariate analysis, overall diastolic stage, LVEF, RV systolic dysfunction,
      mitral regurgitation (MR) severity, age and creatinine clearance were independent
      predictors of BNP levels (model fit r = 0.8, p < 0.001). CONCLUSIONS: Plasma BNP
      levels are significantly related to newer diastolic indexes measured from TDI and
      CMM in SHF. Heterogeneity of BNP levels in patients with SHF reflects the
      severity of diastolic abnormality, RV dysfunction, and MR in addition to LVEF,
      age, and renal function. These findings may explain the powerful relationship of
      BNP to symptoms and prognosis in SHF.

PMID- 15013125
TI  - Plasma angiopoietin-1, angiopoietin-2, and angiopoietin receptor tie-2 levels in
      congestive heart failure.
AB  - OBJECTIVES: The goal of this research was to test the hypothesis that plasma
      angiopoietin (Ang-1), its soluble receptor tie-2, and Ang-2 levels would be
      abnormal in patients with acute and chronic congestive heart failure (CHF) when
      compared with healthy controls. BACKGROUND: Increased plasma vascular endothelial
      growth factor (VEGF) in CHF is suggestive of excess angiogenesis-possibly driven
      by tissue hypoxia. However, other growth factors also have a major role in
      angiogenesis, such as those of the angiopoietin family (e.g., Ang-1, which exerts
      its activity via its receptor, tie-2, and Ang-2). METHODS: We recruited 39
      patients with acute CHF (mean age 67 +/- 10 years), 40 patients with chronic CHF
      (mean age 63 +/- 9 years), and 17 healthy controls (mean age 67 +/- 7 years), all
      in sinus rhythm. Citrated plasma was analyzed for Ang-1, Ang-2, tie-2, and VEGF
      by enzyme-linked immunosorbent assay. RESULTS: Angiopoietin-2 (p < 0.001), tie-2
      (p < 0.05), and VEGF (p < 0.05) levels were all higher in acute CHF compared with
      controls. The Ang-2 levels were higher in acute CHF compared with chronic CHF (p
      < 0.001), but there were no significant differences in Ang-1 levels between the
      groups. The principal significant correlations were between Ang-2 and tie-2
      (Spearman, r = 0.407; p < 0.0001) and between Ang-2 and ejection fraction (r = 
      0.241, p = 0.043). Although only marginally raised, levels of VEGF correlated
      with both Ang-2 (r = 0.468, p < 0.001) and tie-2 (r = 0.569, p < 0.001).
      CONCLUSIONS: We have demonstrated abnormal levels of Ang-2 and tie-2, but normal
      Ang-1, in both CHF patients. These abnormalities may, alongside VEGF, indicate a
      role for these angiogenic factors in the pathophysiology of CHF.

PMID- 15013126
TI  - Racial variation in the prevalence of atrial fibrillation among patients with
      heart failure: the Epidemiology, Practice, Outcomes, and Costs of Heart Failure
      (EPOCH) study.
AB  - OBJECTIVES: This study was designed to determine the association between race and
      atrial fibrillation (AF) among patients with heart failure (HF). BACKGROUND:
      Atrial fibrillation is known to complicate HF, but whether its prevalence varies
      by race, and the reasons why, are not well understood. METHODS: We identified
      adults hospitalized with confirmed HF within a large integrated healthcare
      delivery system. We obtained information on demographics, comorbidity, vital
      signs, medications, and left ventricular systolic function status. "Atrial
      fibrillation" was defined as AF or atrial flutter documented by electrocardiogram
      or prior physician-assigned diagnoses. We evaluated the independent relationship
      between race and AF using multivariable logistic regression. RESULTS: Among 1,373
      HF patients (223 African Americans, 1,150 Caucasians), the prevalence of AF was
      36.9% (95% confidence interval [CI] 34.3% to 39.5%). Compared with Caucasians,
      African Americans were younger (mean age 67 vs. 74 years, p < 0.001) and more
      likely to have hypertension (86.6% vs. 77.7%, p < 0.01) and prior diagnosed HF
      (79.4% vs. 70.7%, p < 0.01). African Americans had less prior diagnosed coronary
      disease, revascularization, hypothyroidism, or valve replacement. Atrial
      fibrillation was much less prevalent in African Americans (19.7%) than Caucasians
      (38.3%, p < 0.001). After adjustment for risk factors for AF and other potential
      confounders, African Americans had 49% lower odds of AF (adjusted odds ratio
      0.51, 95% CI 0.35 to 0.76). CONCLUSIONS: In a contemporary HF cohort, AF was
      significantly less common among African Americans than among Caucasians. This
      variation was not explained by differences in traditional risk factors for AF, HF
      etiology and severity, and treatment.

PMID- 15013127
TI  - What we're talking about when we talk about race.

PMID- 15013128
TI  - Clinical course of atrial ectopic tachycardia is age-dependent: results and
      treatment in children < 3 or > or =3 years of age.
AB  - OBJECTIVES: We assessed the clinical presentation, natural history, and treatment
      response of atrial ectopic tachycardia (AET) in children <3 years of age (group
      1) compared with those > or =3 years of age (group 2). BACKGROUND: Atrial ectopic
      tachycardia is a common cause of chronic supraventricular tachycardia in children
      and can be resistant to pharmacologic therapy. Radiofrequency ablation (RFA) can
      eliminate AET arising from a single focus. METHODS: A retrospective review
      identified all children at Texas Children's Hospital diagnosed with AET from
      March 1991 to November 2000. Data obtained included clinical presentation,
      echocardiographic evaluation, response to antiarrhythmic therapy, spontaneous
      resolution, and outcomes of radiofrequency and surgical ablation. RESULTS: Sixty
      eight children were identified (22 children <3 years and 46 children > or =3
      years of age). Control of AET with antiarrhythmic therapy was achieved in 91% of
      the younger children but only 37% of the older children (p < 0.001). There was a
      higher rate of spontaneous resolution in the younger group (78%) compared with
      the older group (16%) (p < 0.001). Radiofrequency ablation was performed in 35 of
      the older children, with ultimate success in 74%. Surgical intervention was
      required for six children. CONCLUSIONS: Younger children respond to
      antiarrhythmic therapy and have a high incidence of AET resolution, thus
      warranting a trial of antiarrhythmic therapy. In children > or =3 years, AET is
      unlikely to resolve spontaneously, and antiarrhythmic medications are frequently
      ineffective. Thus, RFA should be considered early in the course of treatment for
      these children; however, surgical intervention may be necessary.

PMID- 15013129
TI  - Glucose-insulin infusion improves cardiac function during fetal tachycardia.
AB  - OBJECTIVES: The aim of this work was to study the effects of substrate deficiency
      and supplementation on cardiac function during fetal tachycardia. BACKGROUND:
      Although sustained fetal tachycardia may lead to cardiac failure and intrauterine
      death, neonatal tachycardia is generally better tolerated. Fetal myocardial
      energy production relies almost solely on glucose as substrate. We hypothesized
      that increased substrate availability by glucose-insulin (GI) infusion would
      improve fetal myocardial responses to tachycardia. METHODS: We used three porcine
      models: 1) an isolated fetal heart model; 2) an in vivo fetal model; and 3) an in
      vivo closed-chest neonatal model. Each animal was randomized to control or GI
      treatment during tachycardia. In model 1, the controls were perfused with
      conventional Krebs-Henseleit solution containing a glucose concentration of 5.5
      mmol/l; the GI hearts received double glucose concentration and added insulin. In
      models 2 and 3, the GI animals received insulin in a 20% glucose solution. All
      hearts were exposed to 90 min of pacing at 250 to 330 beats/min. RESULTS: The
      isolated fetal hearts in the GI group showed no decline in dP/dt(max) during
      pacing, while the controls declined. In the in vivo fetal hearts, dP/dt(max)
      remained unchanged in the GI group and decreased significantly in the control
      group. Myocardial glycogen content was higher in the GI group than in controls.
      Functional indexes remained unchanged among both neonatal groups despite a higher
      glycogen content in the GI group. CONCLUSIONS: Glucose-insulin infusion during
      fetal tachycardia has a beneficial effect on myocardial metabolism and cardiac
      function. These observations may have direct clinical relevance to the management
      of fetal arrhythmia.

PMID- 15013130
TI  - Intravascular ultrasound molecular imaging of atheroma components in vivo.
AB  - OBJECTIVES: Our purpose was to quantitate and confirm specific echogenic
      immunoliposome (ELIP) atheroma component enhancement in vivo. BACKGROUND:
      Targeted ELIPs for ultrasonic detection and staging of active molecular
      components of endothelium and atheroma have been developed. METHODS: In Yucatan
      miniswine, the endothelium was injured from one femoral and one carotid artery,
      and animals were fed a high-cholesterol diet for two months to create various
      stages of atheroma. Arteries were imaged with intravascular ultrasound (IVUS) 5
      and 10 min after ELIP injection (5-mg dose). Anti-intercellular adhesion molecule
      1 (ICAM-1), anti-vascular cell adhesion molecule-1 (VCAM-1), anti-fibrin, anti
      fibrinogen, and anti-tissue factor (TF) conjugated ELIPs were used, and
      immunohistochemistry (IHC) confirmed the presence or absence of molecular
      expression. Two blinded observers determined if each segment was enhanced by
      ELIP. Three-dimensional image reconstruction and videodensitometric analysis
      determined the mean gray-scale (MGS) change of the luminal border. RESULTS: To
      determine endothelial injury component enhancement, anti-fibrinogen ELIP enhanced
      exposed fibrin in all arteries (MGS increased 22 +/- 5%; 6 arteries; 2 animals).
      To determine enhancement of molecular components in atherosclerotic arteries,
      observers detected enhancement 5 min after anti-VCAM, anti-ICAM, anti-TF, anti
      fibrin, and anti-fibrinogen conjugated ELIPs. Furthermore, ELIP enhanced atheroma
      MGS by 39 +/- 18% (n = 8). The IHC staining confirmed the expression of
      respective molecular targets in all enhanced segments. CONCLUSIONS: It was shown
      that ELIPs specifically enhance endothelial injury/atheroma components. This
      allows better characterization of the type and extent of active atheroma
      components and may allow more directed therapy.

PMID- 15013131
TI  - Visualizing coronary atherosclerosis in vivo: thinking big, imaging small.

PMID- 15013132
TI  - The selective peroxisomal proliferator-activated receptor-gamma agonist has an
      additive effect on plaque regression in combination with simvastatin in
      experimental atherosclerosis: in vivo study by high-resolution magnetic resonance
      imaging.
AB  - OBJECTIVES: We sought to investigate the anti-atherogenic effects of a selective
      peroxisomal proliferator-activated receptor-gamma (PPAR-gamma) agonist and
      simvastatin, as well as their combination, over time, in a rabbit model of
      experimental atherosclerosis. BACKGROUND: The PPARs are nuclear transcription
      factors that control a variety of cellular functions, with the potential effects
      required to induce plaque regression and stabilization. METHODS: Atherosclerosis
      was induced in rabbits (n = 37) by the combination of double-balloon injury and a
      nine-month high-cholesterol (HC) diet. The rabbits were randomized into a
      continued HC diet, a normal chow (NC) diet, NC plus simvastatin, NC plus PPAR
      gamma agonist, and NC plus simvastatin plus PPAR-gamma agonist. All rabbits
      underwent magnetic resonance imaging (MRI) at randomization and after six months
      of treatment and were then sacrificed for histopathologic study. RESULTS: All
      groups had a similar vessel wall area by MRI (8.45 +/- 0.65 mm(2), p = NS between
      groups) at randomization. Significant progression was seen in the HC diet group
      (15 +/- 4%, p < 0.01). In the NC and NC plus PPAR-gamma agonist groups,
      progression was abolished (-2.5 +/- 3% and -4.5 +/- 5%, respectively; p = NS).
      The NC plus simvastatin and NC plus simvastatin plus PPAR-gamma agonist groups
      had significant plaque regression (-12 +/- 4% [p < 0.05] and -22 +/- 4% [p <
      0.01], respectively). Regression was independent of plasma lipid levels. All NC
      groups had similar lipid profiles at the end of treatment. Histopathologic
      analysis of the NC groups showed a decreased macrophage content and matrix
      metalloproteinase activity and an increased smooth muscle cell/collagen content
      of lesions. CONCLUSIONS: Our data indicate that normalization of plasma lipid
      levels abolishes progression of atherosclerosis. Simvastatin elicits regression
      of atherosclerotic lesions, and the combination simvastatin plus PPAR-gamma
      agonist has additive regression effects on plaque. This is paralleled by
      structural alterations in plaque composition, which may increase plaque
      stability. These observations support the beneficial effects of statins on
      atherosclerosis and show additional anti-atherogenic benefits of combining a PPAR
      gamma agonist with simvastatin.

PMID- 15013133
TI  - Temporal patterns of gene expression after acute hindlimb ischemia in mice:
      insights into the genomic program for collateral vessel development.
AB  - OBJECTIVES: We sought to understand the genomic program leading to collateral
      vessel formation. BACKGROUND: Recently, technology has advanced to the point that
      it is now possible to elucidate the large array of genes that must be expressed,
      as well as the temporal expression pattern, for the development of functionally
      important collateral vessels. In this investigation, we used deoxyribonucleic
      acid array expression profiling to determine the time course of differential
      expression of 12,000 genes after femoral artery ligation in C57BL/6 mice.
      METHODS: Ribonucleic acid was extracted from the adductor muscle, which showed no
      signs of ischemia. Sampling was at baseline, 6 h, and 1, 3, 7, and 14 days after
      femoral artery ligation or sham operation. RESULTS: Femoral artery ligation
      caused the differential expression (>2-fold) of 783 genes at one or multiple time
      points: 518 were induced and 265 were repressed. Cluster analysis generated four
      temporal patterns: 1) early upregulated (6 to 24 h)-immediate early
      transcriptional factors, angiogenesis, inflammation, and stress-related genes; 2)
      mid-phase upregulated (day 3)-cell cycle and cytoskeletal and inflammatory genes;
      3) late upregulated (days 7 to 14)-angiostatic, anti-inflammatory, and
      extracellular matrix-associated genes; and 4) downregulated-genes involved in
      energy metabolism, water channel, and muscle contraction. Microarray data were
      validated using quantitative reverse transcription polymerase chain reaction.
      CONCLUSIONS: This study documents the large number of genes whose differential
      expression and temporal functional clustering appear to contribute to collateral
      formation. These results can serve as a genomic model for arteriogenesis and as a
      database for developing new therapeutic strategies.

PMID- 15013135
TI  - The year in valvular heart disease.

PMID- 15013134
TI  - Roles of adrenergic and cholinergic stimulation in spontaneous atrial
      fibrillation in dogs.
AB  - OBJECTIVES: We studied the effects of beta-adrenergic and cholinergic stimulation
      and blockade on spontaneous atrial fibrillation (AF) in the intact dog heart.
      BACKGROUND: Paroxysmal AF is often preceded by changes in autonomic tone, but the
      relative roles of adrenergic and cholinergic influences on AF induction are not
      well known. METHODS: Perfusion of catecholamines and acetylcholine (ACh), as well
      as their combination, through the sinus node artery was used to induce AF in 20
      anesthetized open-chest dogs without electrical stimulation of atria. RESULTS:
      Isoproterenol and adrenaline (10 to 100 micromol/l) induced AF in 21% (3 of 14)
      and 17% (1 of 6) of dogs, respectively. Atropine (1 to 2 mg) treatment prevented
      catecholamine-mediated AF, indicating a critical role of cholinergic tone in
      these AF episodes. Acetylcholine (2.8 +/- 0.3 micromol/l) induced AF in all dogs.
      Beta-blockade by propranolol (1 mg/kg) did not prevent ACh-induced AF, but
      increased the threshold ACh concentration for AF induction to 23.5 +/- 3.4
      micromol/l (p < 0.05). Acetylcholine-mediated AF was facilitated by isoproterenol
      (1 to 2 and 10 micromol/l), which decreased the threshold ACh concentration for
      AF induction to 0.5 +/- 0.1 and 0.4 +/- 0.1 micromol/l, respectively (p < 0.05)
      and increased the AF duration (from 25 +/- 7 to 141 +/- 54 and 233 +/- 60 s,
      respectively; p < 0.05). Epicardial mapping of the right atrium (112 unipolar
      electrodes) demonstrated similar activation patterns during arrhythmias induced
      by ACh and catecholamines. CONCLUSIONS: These data indicate that although both
      autonomic systems play a role in AF, cholinergic stimulation is likely the main
      factor for spontaneous AF initiation in this animal model. Adrenergic tone
      modulates the initiation and maintenance of cholinergically mediated AF.

PMID- 15013136
TI  - Is the Hippocrates paradox really a paradox?

PMID- 15013139
TI  - Development and application of a universal method for quantitation of anionic
      constituents in active pharmaceutical ingredients during early development using
      suppressed conductivity ion chromatography.
AB  - A universal method for quantitation of anionic substances in active
      pharmaceutical ingredients (API) during early development was developed using ion
      chromatography (IC). The method was developed to allow rapid characterization of
      APIs in support of early clinical studies The method parameters were chosen to
      allow quantitation of monovalent, divalent, and trivalent inorganic ions as well
      as monvalent and divalent carboxylic acids. These parameters were also chosen to
      ensure appropriate performance for regulated analyses using less than 10mg of API
      per replicate. The method was applied to and validated for a range of anionic
      analytes in APIs of varying hydrophobicity to demonstrate applicability to
      various analyses encountered during early development of pharmaceuticals.

PMID- 15013138
TI  - Analysis of competitive binding of ligands to human serum albumin using NMR
      relaxation measurements.
AB  - The competitive binding of two ligands, ibuprofen (IBP) and salicylic acid (SAL),
      to human serum albumin (HSA) was studied by using nuclear magnetic resonance
      (NMR) relaxation measurements. When the concentration of one ligand was increased
      in the solution containing IBP, SAL and HSA, the fractions of free IBP and SAL
      were increased because of the competitive binding. The 1H relaxation rates (R1)
      of both ligands were subsequently decreased. If a ligand is in fast exchanging
      between the free and bound forms, the observed 1H relaxation rate is a weighted
      average of that for the free ligand and the protein-ligand complex. The
      concentrations of the free and bound ligands can be quantitatively derived from
      the relaxation rates. The results presented in this work revealed that IBP and
      SAL shared certain low-affinity binding sites on the HSA molecule, in addition to
      the same high-affinity binding site of AIII.

PMID- 15013140
TI  - Development and validation of a reversed-phase liquid chromatographic method for
      analysis of degradation products of estradiol in Vagifem tablets.
AB  - A stability-indicating liquid chromatographic method for the determination of
      degradation products and impurities in Vagifem, estradiol vaginal tablets has
      been developed and validated. Vagifem is a low dose preparation containing only
      25microg 17beta-estradiol in a tablet matrix of 80mg (a drug to excipient ratio
      of 1:3200). This paper presents the rationale for the optimization of the sample
      preparation in order to minimize placebo interference as well as validation data
      for linearity, accuracy, precision, ruggedness, specificity and limits of
      detection and quantification. Data shows that the method is suitable for routine
      analysis of minute amounts of estradiol impurities.

PMID- 15013141
TI  - Separation of purine and pyrimidine bases by capillary electrophoresis using beta
      cyclodextrin as an additive.
AB  - Capillary electrophoresis was applied to separate purine and pyrimidine bases in
      the basis of their partial ionization in the alkaline buffer. The effects of
      buffer pH, buffer and beta-cylclodextrin concentration were systematically
      investigated using a commercial capillary electrophoresis instrument with UV
      detector at 254nm. We found that the resolutions of bases (especially for adenine
      and thymine) were significantly improved in the presence of beta-cylclodextrin.
      The satisfactory separation of five bases such as cytosine, thymine, adenine,
      guanine and uracil were achieved by capillary electrophoresis using beta
      cylclodextrin as an additive. Under the optimal conditions, the linear range was
      from 2 to 200microg/ml for bases (R= 0,991-0,9977 ) and the detection limits were
      from 0.8 to 1.8microg/ml (S/N = 2). The detection limit of 0.05microg/ml ( S/N=2
      ) for uracil was obtained by stacking injection mode. The assay was used to
      determine the deamination of cytosine to uracil by heating in the presence of
      sodium hydroxide. Our primarily results show that capillary electrophoresis is a
      very useful tool for determination of purine and pyrimidine bases and study on
      nucleic acids.

PMID- 15013142
TI  - Chiral ligand-exchange chromatography as the screening method for proposed
      modifications in exametazime synthesis to enhance diastereoselectivity.
AB  - 99M Tc (V)-d,l-HM-PAO complex is well-known radiopharmaceutical for regional
      cerebral blood flow imaging. The proposed modifications in exametazime,
      hexamethylpropyleneamine oxime (HM-PAO) (4,8-diaza-3,6,6,9-tetramethylundecane
      2,10-dione bisoxime) synthesis, for reduction of intermediary reactant
      diiminebisoxime (DI) (4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dione
      bisoxime) concerned two reductants (NaBH(4) and KBH(4)), two solvents (ethanol
      and 2-propanol), and three mole ratios of reactant/reductants (1:1, 1:1.5, and
      1:2). The simultaneous analysis of diastereo-enantiomeric HM-PAO content, as well
      as the content of starting DI, in different reduction mixtures were performed
      using chiral ligand-exchange chromatography (CLEC). The separation of the samples
      of investigated reduction mixtures, obtained in the second step of HM-PAO
      synthesis, has been accomplished by using an achiral sorbent (RP-18) and a chiral
      mobile phase (CMP) containing copper(II) complex with N,N-dimethyl-l
      phenylalanine (l-DM-PhA) as initial complex for CLEC. With 12 different reduction
      conditions, the obtained ratios of diastereoisomers d,l-HM-PAO: meso-HM-PAO
      varied from 69.2:30.8 to 15.9:84.1, in comparison to the reduction in routine
      synthesis of HM-PAO which gives an equal mixture of diastereoisomers. The ternary
      mixed complexes formation recorded spectrophotometrically on addition of HM-PAO
      or DI to the mobile phase with binary complex Cu(l-DM-PhA)(2), due to the
      evidence of bathochromic shift of 46nm for lambda(max) with significant
      difference in absorptivity contributes to separation mechanism.

PMID- 15013143
TI  - Analysis of flavonoids from Cyclanthera pedata fruits by liquid
      chromatography/electrospray mass spectrometry.
AB  - A liquid chromatography/mass spectrometry (LC/MS) based method was developed for
      the characterization of fruits of Cyclanthera pedata Scrabs (Caigua), a Peruvian
      food and medicinal plant. This method is based on the separation of flavonoid
      glycosides present in the methanolic extracts from C. pedata fruits using high
      performance liquid chromatography (HPLC) followed by detection with electrospray
      ionization mass spectrometry (ESI/MS). Chromatographic separation of the analytes
      of interest was achieved on a Symmetry C-18 column with detection in positive ion
      mode. Calibration graphs were obtained by determining the area ratio between
      external standard of each major compound and the internal standard naringine. Due
      to the sensitivity and the repeatability of the assay, this method is suitable
      for industrial quality control of raw materials and final products.

PMID- 15013144
TI  - Chemometric determination of amiloride hydrochloride, atenolol,
      hydrochlorothiazide and timolol maleate in synthetic mixtures and pharmaceutical
      formulations.
AB  - Different chemometric methods such as classical least squares (CLS), principal
      components regression (PCR) and partial least squares with one dependent variable
      (PLS-1) applied on UV spectral data (0 D) and on their first derivatives (1 D)
      were evaluated for the simultaneous quantification of samples containing mixtures
      of amiloride hydrochloride, atenolol, hydrochlorothiazide and timolol maleate.
      Their performances were compared by means of ANOVA tests, which evidenced that 0
      D-PCR, 0D-PLS-1, 1D-PCR, 1D-PLS-1, were reproducible and gave statistically
      similar results, while 0 D-CLS and 1D-CLS displayed higher variances than the
      former and failed to comply with the Levene's variance homogeneity test at
      different stages of the method comparison and validation process. The four
      statistically equivalent procedures were successfully applied to the analysis of
      synthetic samples with two to four analytes and to commercial tablet preparations
      containing amiloride hydrochloride and hydrochlorothiazide alone or in
      association with atenolol or timolol maleate.

PMID- 15013145
TI  - Simultaneous separation and quantitation of four antiepileptic drugs--a study
      with potential for use in patient drug level monitoring.
AB  - The purpose of this study was to illustrate the applicability of high-performance
      liquid chromatography (HPLC) coupled with evaporative light scattering detector
      (ELSD) in simultaneously separating and quantitating four commonly used
      antiepileptic drugs (AEDs). A mixture of the four AEDs were separated using a C8
      column using volatile mobile phases and were detected using ELSD. Optimal
      instrumental conditions were obtained by assessing the effect of various critical
      experimental parameters such as evaporator tube temperature, carrier gas flow
      rate, photomultiplier gain on separation efficiency, accuracy, reproducibility
      and sensitivity of measurement on all four AEDs. A novel, rapid, accurate,
      sensitive, reproducible and robust HPLC-ELSD method for simultaneous separation
      and quantitation of four commonly used AEDs was developed. The physical basis of
      the results obtained as a consequence of varying several critical experimental
      parameters has been explained. This study illustrates the potential for use of
      HPLC-ELSD in drug level monitoring of patients undergoing mono- or polytherapy
      for epilepsy.

PMID- 15013146
TI  - Quantitative analysis of oxytetracycline and its impurities by LC-MS-MS.
AB  - A liquid chromatographic-tandem mass spectrometric method using an Xterra MS
      C(18) chromatographic column ( 100 mm x 2.1 mm i.d., 3.5microm) that allows
      complete separation of oxytetracycline (OTC) and the impurities: 4-epi
      oxytetracycline (EOTC), tetracycline (TC), 4-epi-tetracycline (ETC), 2-acetyl-2
      decarboxamido-oxytetracycline (ADOTC), alpha-apo-oxytetracycline (alpha-AOTC) and
      beta-apo-oxytetracycline (beta-AOTC) was developed. Gradient elution was used and
      calibration curves were obtained using the scan mode selected reaction monitoring
      (SRM). Acceptable correlations were obtained for OTC, TC, EOTC and ADOTC whereas
      the correlations of alpha-AOTC and beta-AOTC were less accurate resulting in
      higher limits of quantification (LOQ) and limits of detection (LOD) relative to
      the other compounds. The intraday and interday accuracy varied for all the
      compounds from 90 to 112% and the intraday and interday precision were lower than
      7.1%. The method was applied for analysis of commercial available ointments
      containing OTC resulting in an acceptable quantification of OTC and the
      impurities in the drug preparations. The advantage of this method compared to the
      other separation methods is an empty separation window right after the large peak
      corresponding to OTC in the chromatogram, which facilitates an accurate
      determination of ADOTC and the other impurities.

PMID- 15013147
TI  - Study of freeze-dried quercetin-cyclodextrin binary systems by DSC, FT-IR, X-ray
      diffraction and SEM analysis.
AB  - The inclusion behavior of 2-hydroxypropyl beta-cyclodextrin (HPbetaCD) and beta
      cyclodextrin (betaCD), in solution and solid-state was studied towards a poorly
      water-soluble bioflavonoid, quercetin (QURC), chemically 3,3',4',5',7
      pentahydroxy flavone. Drug-cyclodextrin solid systems were prepared by freeze
      drying. Phase solubility study was used to evaluate the complexation in solution,
      of two cyclodextrins, i.e., betaCD and HPbetaCD. The stoichiometry and stability
      constants of QURC-betaCD (1:1 and 402M(-1)) and QURC-HPbetaCD (1:1 and 532M(-1))
      complexes were calculated by phase solubility method. The formation of inclusion
      complexes with betaCD and HPbetaCD in the solid-state were confirmed by infrared
      spectroscopy, differential scanning calorimetry, X-ray diffractometry, and
      scanning electron microscopy (SEM).

PMID- 15013148
TI  - Analysis of purity in 19 drug product tablets containing clopidogrel: 18 copies
      versus the original brand.
AB  - In this study, 18 copies of PLAVIX tablets containing clopidogrel hydrogensulfate
      were compared to the innovator drug product for uniformity of mass, impurity
      profile, content, dissolution properties and stability. In order to be able to
      separate the R-enantiomer of clopidogrel, an enantiospecific liquid
      chromatographic method was used to determine the impurities and to perform the
      assay. The paddle method was used for dissolution testing. Most of the copies
      were not similar compared to the original drug product: their amount of
      impurities was higher, the content of clopidogrel lower, the dissolution profiles
      different and after 3 months under stress conditions in the original packaging,
      the results for the samples and the reference were significantly different in
      most of the cases.

PMID- 15013149
TI  - Commercial and laboratory extracts from artichoke leaves: estimation of caffeoyl
      esters and flavonoidic compounds content.
AB  - Artichoke leaf extracts are widely used alone or in association with other herbs
      for embittering alcoholic and soft drinks and to prepare herbal teas or herbal
      medicinal products. Despite this wide diffusion, the European Pharmacopoeia does
      not report an official method for the determination of the active principles of
      artichoke leaf extracts. This work reports a quali-quantitative determination by
      HPLC/DAD and HPLC/MS techniques of both cynnamic acids and flavonoids present in
      some artichoke leaf commercial extracts (Com) compared with two different
      laboratory extracts (Lab). Most of the commercial extracts showed a similar quali
      quantitative pattern with a single exception having five-six times higher value.
      The quantitative data from the Italian Pharmacopoeia(IP) official method does not
      evaluate the flavonoidic fraction and showed an overestimation of the caffeoyl
      esters with respect to the HPLC/DAD results. The proposed HPLC/DAD method was
      able to completely characterize and quantify this matrix and represents a
      contribution to better quality control of these herbal extracts.

PMID- 15013151
TI  - A simple 96-well liquid-liquid extraction with a mixture of acetonitrile and
      methyl t-butyl ether for the determination of a drug in human plasma by high
      performance liquid chromatography with tandem mass spectrometry.
AB  - A simple 96-well plate liquid-liquid extraction (LLE), liquid
      chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed and
      validated for the determination of a basic drug candidate in human plasma.
      Against the wisdom of conventional approaches, an aqueous/organic miscible
      solvent, acetonitrile, was used for liquid-liquid extraction along with methyl t
      butyl ether. The use of acetonitrile effectively eliminated the formation of the
      irregular emulsion between aqueous/organic interfaces and modulated the polarity
      of the extraction solvents to achieve the desired recovery. This approach, which
      solved the emulsion problem, permitted the method to be automated using standard
      96-well plate technology. A practical application was demonstrated through the
      use of this technique in the measurement of a novel drug in human plasma samples
      by LC/MS/MS. Chromatographic separation was achieved isocratically on a
      Phenomenox C18(2) Luna column (2 mm x 50 mm, 5 microm). The mobile phase
      contained 60% of 0.1% formic acid and 40% acetonitrile. Detection was by positive
      ion electrospray tandem mass spectrometry. The standard curve, which ranged from
      1.22 to 979ng/ml, was fitted to a 1/x2 weighted quadratic regression model. The
      validation results show that this method was very rugged and had excellent
      precision and accuracy. The actual sample analysis results further demonstrated
      that this extraction procedure is well suited for real life applications. It is
      expected that with some modifications, this approach can be applied for the
      extraction of similar compounds from various biological fluids.

PMID- 15013150
TI  - Brain and plasma exposure profiling in early drug discovery using cassette
      administration and fast liquid chromatography-tandem mass spectrometry.
AB  - A method using reverse phase liquid chromatography-tandem mass spectrometry and
      cassette administration was developed for in vivo brain and plasma exposure
      profiling to assist early CNS drug discovery programs. Three to four compounds
      were grouped in cassettes for dosing and analysis. Compounds in the cassettes
      were selected to minimize possible analytical interference from each other, as
      well as from their potential metabolites. In order to improve the confidence of
      cassette administration, an analogue of the study compounds, with well
      established brain penetration data, was included in each cassette as a
      "biological internal standard". Compounds were administered to rats by
      intraperitoneal injection and extracted from plasma or brain homogenate by simple
      protein precipitation. Fast chromatographic separation was achieved by using a
      short narrow-bore column at a flow rate of 1.0ml/min with a fast gradient. The
      brain penetration of the compounds was evaluated by comparing their C(max) and
      AUC values in brain and plasma. This approach rapidly provided early brain
      penetration and plasma exposure information, thus making more of this data
      available to teams. Comparing the brain exposures to the EC(50) values (i.e. in
      vitro potency) of series compounds in the same discovery program provided another
      dimension of information to select lead compounds for future in vivo assessment.
      The method described here has been used for providing early brain penetration
      information in several CNS exploratory and discovery programs.

PMID- 15013152
TI  - Determination of urinary 13C-caffeine metabolites by liquid chromatography-mass
      spectrometry: the use of metabolic ratios to assess CYP1A2 activity.
AB  - A method using liquid chromatography coupled with mass spectrometry with an
      atmospheric pressure electrospray source was developed for analysis of labelled
      caffeine and fourteen of its metabolites in urine. Caffeine metabolic ratios were
      determined after an oral bolus of labelled caffeine in 20 healthy subjects with
      different characteristic CYP1A2 activity, relative to smoking habit and oral
      contraceptive intake. The use of labelled caffeine for the calculation of
      metabolic ratios avoided taking into account the important background of
      endogenous caffeine metabolites, very difficult to eliminate even after a
      specific diet. The selectivity and high sensitivity of mass spectrometry
      detection allowed urine collections for only a 3h period. Comparison between
      characteristic groups showed that labelled caffeine metabolic ratios were
      sensitive markers of changes in CYP1A2 activity.

PMID- 15013153
TI  - Determination of an endothelin receptor antagonist in rat plasma by
      radioimmunoassay.
AB  - A quantitative method based on radioimmunoassay for the determination of an
      endothelin receptor antagonist (C(31)H(33)NO(7), I) has been developed and
      validated. The immunogen was prepared by coupling I to the bovine serum albumin
      via the N-hydroxysuccinimide ester of I from which the radioligand was also
      prepared by the reaction with [125I]-iodotyrosine. The method was specific and no
      immunoactive material other than the parent drug was detectable in mammalian
      plasma. This direct assay, using 50 microl of rat plasma is sensitive (0.4
      ng/ml), without matrix interference, and has sufficient sensitivity, specificity,
      accuracy and precision for the analysis of dosed rat plasma samples.

PMID- 15013154
TI  - N-nitrosylation potential of mono-N-desethylamiodarone at physiological pH.
AB  - Amiodarone (AMI) is frequently used for the treatment of supraventricular
      arrhythmias. The parent drug is rapidly dealkylated to mono-N-desethylamiodarone
      (MDEA) and the plasma concentrations of AMI and MDEA are comparable. MDEA is a
      secondary amine and may thus undergo formation to the corresponding N-nitrosamine
      in combination with coadministered nitrovasodilators. Previous studies have shown
      that nitrovasodilators release the vasoactive NO? which may nitrosylate thiol or
      secondary amine groups in aqueous solutions. Therefore, the nitrosylation
      potential of MDEA at physiological pH was investigated. N-Nitroso
      monodesethylamiodarone (NO-MDEA) was synthesized, characterized and used as a
      reference product for the detection of the corresponding N-nitrosamine. HPLC and
      NMR results have shown that the NO-MDEA product is an equilibrium of two
      configurational isomers (syn and anti). NO-release was generated by sodium
      nitroprusside (SNP) which was exposed to light. The formation to NO-MDEA was
      assayed by HPLC-UV. It has been found that MDEA is nitrosylated in the higher
      nanomolar range and that varying oxygenation of the reaction mixture did not
      significantly affect the reaction yields. The addition of thiols such as serum
      albumin (0.6mM), l-cysteine (2.5mM) or N-acetylcysteine (2.5mM) inhibited the NO
      MDEA formation indicating that they may prevent N-nitrosamine formation in vivo.
      However, as S-nitrosothiols may also release NO?, in long term exposure to
      elevated levels of nitric oxide the nitrosylation of secondary amines may be
      taken into account.

PMID- 15013155
TI  - Development and validation of a MEKC method for the direct determination of
      cefozopran in human serum.
AB  - A method for determining the concentration of cefozopran, a cephem anti-microbial
      agent which has a broad spectrum, in human serum using micellar electrokinetic
      capillary chromatography (MEKC) by serum direct injection is developed and the
      validation of the assays of this method is performed. A borate buffer (25mM; pH
      10.0) containing sodium dodecyl sulfate (SDS) (50mM) is used as a run buffer. The
      electrophoresis of serum samples is carried out at 25kV and the detection of
      cefozopran at 244nm as its absorption maximum at the cathodic side of the
      capillary. The migration time of cefozopran is 6.5min. Linearity (0-200mg/l) is
      good and limit of quantification is 0.5mg/l at a signal-to-noise ratio of 3.
      Coefficient of variation (CV) of intra-day precision and that of inter-day
      precision are 2.4-4.0% (7.3-92.0mg/l) and 2.9-7.7% (22.5-71.4mg/l), respectively,
      and the recovery rate is 92-109%. The detection results of 12 other cephem anti
      microbial agents under the analytical conditions of this method show that the
      migration time of cefmetazole is identical with that of cefozopran, making it
      impossible to separate these two anti-microbial agents. This method is
      characterized by the fact that simple and economic determination can be achieved
      by directly injecting the serum samples of micro-quantities into the capillary.

PMID- 15013157
TI  - Analysis of roscovitine using novel high performance liquid chromatography and UV
      detection method: pharmacokinetics of roscovitine in rat.
AB  - Roscovitine (2-(R)-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine,
      is a potent and selective inhibitor of cyclin-dependent kinases (CDKs). It
      inhibits cdc2, cdk2, cdk5 and erk 1 and 2 by competing for the ATP binding domain
      of the kinases. It inhibits cell proliferation; induces DNA fragmentation and
      causes cell cycle arrest in S phase. Its stability and toxicity are not fully
      known. A liquid chromatography method was developed to measure roscovitine in
      human and rat plasma. The lower limit of quantitation (LLOQ) was 100ng/ml; the
      intra- and inter-day precision was below 10% at all control levels. Likewise, the
      accuracy between and within days was lower than 6% at all levels. The drug was
      stable at room temperature. Twenty-four hours at room temperature has result in a
      decrease of only 9% of the drug. The recovery of roscovitine from plasma was 84%
      at 750ng/ml. The present method was used to study the pharmacokinetics of the
      drug in a rat model. The present investigation, to the authors' knowledge, is the
      first analytical method reported and the first pharmacokinetics investigation of
      roscovitine in rat. Roscovitine was administered as a bolus injection (25mg/kg
      body weight). The pharmacokinetic analysis showed that roscovitine is fitted to a
      two-compartment open-mode with a biphasic elimination half-life (6 and 26min,
      respectively). The distribution volume was determined to 3.5l/kg and the
      clearance (Cl) was 29.5ml/min.

PMID- 15013156
TI  - Sample preparation and determination of gabapentin in venous and capillary blood
      using liquid chromatography-tandem mass spectrometry.
AB  - An analytical method for the determination of gabapentin in serum obtained from
      venous blood samples has been developed using high-performance liquid
      chromatography (HPLC)-tandem mass spectrometry. In addition, a comparative study
      between capillary plasma samples and venous serum samples was carried out. This
      demonstrates the potential for the use of the described analytical system using
      very small amounts of blood. As internal standard (S)-(+)-alpha-amino-cyclohexane
      propionic acid hydrate was used. Gabapentin and the internal standard are
      structural isomers, but have different m/z values for the fragments after
      collision induced dissolution. Gabapentin has 172-->154 and 172-->136 transitions
      and amino-cyclohexane-propionic acid hydrate has a 172-->126 transition which can
      be detected in tandem MS. Analysis of gabapentin was carried out on a C8 HPLC
      column using an isocratic mobile phase consisting of ammonium acetate (pH 3.0;
      5mM)-methanol (96:4, v/v). The analytical method was validated for venous serum
      samples. Limit of detection was 1.6ng/ml and lower limit of quantification was
      7.5ng/ml. R.S.D. values and bias values were within the range of acceptance for
      all concentration levels. The method developed for venous serum samples is being
      used in a gabapentin monitoring study using population pharmacokinetic modeling.

PMID- 15013158
TI  - Electrochemical study of hydrochlorothiazide and its determination in urine and
      tablets.
AB  - A voltammetric study of hydrochlorothiazide (HCTZ) at glassy carbon electrode was
      carried out. The drug in Britton-Robinson buffer (pH 3.3) is oxidized at +1040mV,
      giving rise to a well-defined peak. Cyclic voltammetric study indicates that the
      oxidation process is irreversible and diffusion-controlled. A sensitive, simple
      and time-saving differential pulse anodic voltammetric procedure has been
      developed. The procedure has been applied for the drug determination in human
      urine with no prior extraction and in commercial tablets. The proposed method has
      been validated. The limit of detection for the standard solution was 5.0ngml(-1)
      and for the drug in urine was 14.0ngml(-1). The results obtained from the
      analysis of commercial tablets were compared statistically with those obtained
      from the USP 26 high-performance liquid chromatographic (HPLC) method.

PMID- 15013159
TI  - Capillary electrophoretic method for determination of protease inhibitor
      indinavir sulfate used in human immunodeficiency virus therapy.
AB  - A simple, fast and reliable capillary electrophoresis (CE) method for
      determination of indinavir sulfate, a potent protease inhibitor used in human
      immunodeficiency virus (HIV) therapy, in commercial and simulated capsule
      formulations is described. The analysis was performed in a 75microm i.d. uncoated
      fused-silica capillary with 27cm length (effective length of 19.4cm) using a
      20mmoll-1 phosphate buffer at pH 2.52. Samples were injected hydrodynamically by
      applying 0.5psi pressure during 2s. The applied voltage was 28kV. Direct UV
      detection at 214nm led to an adequate sensitivity without interference from
      sample excipients and known impurities. For quantitative purposes, diazepam was
      used as internal standard. Under optimized conditions, the migration times for
      indinavir sulfate and diazepam were 1.06 and 1.66min, respectively. Analytical
      curve of peak area ratios versus concentration in the range of 20.0
      100.0microg/ml gave a coefficient of correlation of 0.9992, establishing the
      method linearity. The limits of detection and quantitation were 4.61 and
      14.0microg/ml, respectively. The within-day precision expressed as relative
      standard deviation was <1.5% for 10 consecutive sample injections. An average
      recovery of 100.81+/-0.56% at three concentration levels was obtained. Based on
      the performance characteristics, the proposed methodology was found suitable for
      the determination of indinavir sulfate in capsule formulations, presenting
      additional advantages inherent to the CE technology, such as low consumption of
      reagents and column endurance.

PMID- 15013160
TI  - Results of a collaborative study of the EDNAP group regarding mitochondrial DNA
      heteroplasmy and segregation in hair shafts.
AB  - A collaborative exercise was carried out by the European DNA Profiling Group
      (EDNAP) in order to evaluate the distribution of mitochondrial DNA (mtDNA)
      heteroplasmy amongst the hairs of an individual who displays point heteroplasmy
      in blood and buccal cells. A second aim of the exercise was to study
      reproducibility of mtDNA sequencing of hairs between laboratories using differing
      chemistries, further to the first mtDNA reproducibility study carried out by the
      EDNAP group. Laboratories were asked to type 2 sections from each of 10 hairs,
      such that each hair was typed by at least two laboratories. Ten laboratories
      participated in the study, and a total of 55 hairs were typed. The results showed
      that the C/T point heteroplasmy observed in blood and buccal cells at position
      16234 segregated differentially between hairs, such that some hairs showed only
      C, others only T and the remainder, C/T heteroplasmy at varying ratios.
      Additionally, differential segregation of heteroplasmic variants was confirmed in
      independent extracts at positions 16093 and the poly(C) tract at 302-309, whilst
      a complete A-G transition was confirmed at position 16129 in one hair.
      Heteroplasmy was observed at position 16195 on both strands of a single extract
      from one hair segment, but was not observed in the extracts from any other
      segment of the same hair. Similarly, heteroplasmy at position 16304 was observed
      on both strands of a single extract from one hair. Additional variants at
      positions 73, 249 and the HVII poly(C) region were reported by one laboratory; as
      these were not confirmed in independent extracts, the possibility of
      contamination cannot be excluded. Additionally, the electrophoresis and detection
      equipment used by this laboratory was different to those of the other
      laboratories, and the discrepancies at position 249 and the HVII poly(C) region
      appear to be due to reading errors that may be associated with this technology.
      The results, and their implications for forensic mtDNA typing, are discussed in
      the light of the biology of hair formation.

PMID- 15013161
TI  - MOR1 receptor mRNA expression in human brains of drug-related fatalities-a real
      time PCR quantification.
AB  - The expression of the human micro-opiate receptor (MOR1) in post mortem human
      brain tissue was examined using real-time PCR technology. Tissue samples from 11
      fatalities due to opiate overdose and five normal subjects with different causes
      of death were analysed in order to elucidate whether chronic opiate abuse is
      followed by a regulation of MOR1 expression. In each case nine selected brain
      regions (thalamus, caudate nucleus, hypothalamus, ventral tegmentum, hippocampus,
      amygdala, frontal cortex, nucleus accumbens, putamen) were evaluated. The MOR1
      mRNA level was determined relative to the housekeeping gene beta2-microglobulin.
      While in most regions the MOR mRNA levels in the brain of addicts were not
      different from the control group-with varying levels between 0 and 15% of
      housekeeping gene level-in the brains of three drug-related fatalities an
      enormous increase was encountered in the thalamus where the MOR-mRNA level
      amounted for up to 10,000% of the measured housekeeping gene level. The results
      obtained by toxicological hair analysis in the group of drug-related fatalities
      indicate that the enormous thalamic MOR1-expression is primarily found in
      individuals who died from acute heroin overdose but did not show signs of a
      substantial chronic administration of the drug. Further studies have to be
      performed to evaluate if the observed MOR1-mRNA up-regulation in the thalamus in
      a subpopulation of acute lethal intoxications mirrors a state of functional
      hypersensitivity associated with the occurrence of death.

PMID- 15013162
TI  - Cocaine-associated abscesses with lethal sepsis after splenic infarction in an 17
      year-old woman.
AB  - Well known complications related to cocaine use are myocardial insufficiency,
      myocardial infarction, myocarditis, aortic dissection, neurologic damages,
      ischemic colitis, thrombotic phenomenons, renal infarction and acute liver
      failure. Cases of splenic infarctions related to cocaine use are extremely rare.
      A 17-year-old drug addict was found by her boy-friend liveless in her bed. She
      was well known using cocaine since years. Autopsy revealed multiple splenic
      infarctions with secondary mixed bacterial infection and abscesses. Petechial
      bleedings were found and microabscesses in the myocardium, the meninges and the
      kidneys. The absolutely rare bacterial infection of the cocaine-associated
      splenic infarction leads to sepsis with lethal course.

PMID- 15013163
TI  - The mechanism of injury of the abducens nerve in severe head trauma: a postmortem
      study.
AB  - The aim of this study is to investigate the mechanism of injury of abducens nerve
      at petroclival region in severe head trauma. Twenty specimens provided from 10
      autopsied cases due to severe head trauma were investigated macroscopically and
      histopathogically. The slices of the abducens nerve taken consecutively along its
      course at petroclival region were stained with Hematoxylline-Eosin and evaluated
      under light microscope. In addition, coexisting cervical injuries in these cases
      were assessed macroscopically. Edema and perineural hemorrhagia of abducens nerve
      were identified in all cases. Nerve injury was found more exaggerated at the
      sites of dural entry point and petrous apex than any other parts of the abducens
      nerve. Furthermore, microscopically, also remarkable perineural hemorrhage of the
      abducens nerve was observed at the site of its anastomoses with the sympathetic
      plexus on the lateral wall of the internal carotid artery (ICA). Abducens nerve
      is injured at the sites of dural entry point, petrous apex and lateral wall of
      the ICA, directly proportional with the severity of the trauma. This finding is
      also significant in verification of the severe head trauma.

PMID- 15013165
TI  - Chemical fingerprinting of gasoline. 2. Comparison of unevaporated and evaporated
      automotive gasoline samples.
AB  - Analysis of the C(0)- to C(2)-naphthalene compounds present in automotive
      gasoline using gas chromatography-mass spectrometry with selected ion monitoring
      (GC-MS (SIM)) and principal component analysis (PCA) was used to discriminate
      between different samples of gasoline. Phase one of this study explored the
      ability of this method to differentiate gasoline samples at different levels of
      evaporation. A total of 35 random samples of unevaporated gasoline, covering
      three different grades (regular unleaded, premium unleaded and lead replacement),
      were collected in Sydney, Australia and examined. The high-boiling C(0)- to C(2)
      naphthalene compounds present in the gasoline were used to chemically fingerprint
      each sample at different levels of evaporation. Samples of 25, 50, 75 and 90%
      evaporated gasoline (by weight) were generated from the 35 samples of
      unevaporated gasoline. Analysis of the data by PCA followed by linear
      discriminant analysis (LDA) showed that the 35 samples formed 18 unique groups,
      irrespective of the level of evaporation. Good discrimination between gasoline
      samples that were collected on the same day was obtained. Phase two of this study
      examined the change in gasoline samples over time. The C(0)- to C(2)-naphthalene
      composition in 96 samples of gasoline collected from three service stations over
      a 16-week period was examined using the method described. In most cases, it was
      found that the C(0)- to C(2)-naphthalene profile changed from week to week, and
      from station to station. In a comparison of all 96 samples together it was found
      that the majority could be differentiated from one another. The application of
      the method to forensic casework is discussed.

PMID- 15013164
TI  - Application of compact ultrasound imaging device to postmortem diagnosis.
AB  - In regions with low autopsy rates, forensic examiners often have to rely on
      external findings. Imaging techniques can assist the external examination and
      provide a more objective diagnosis. The SonoSite 180, a portable ultrasound
      device, was used for the examination of dead bodies. The influence of different
      degrees of decomposition was estimated. Even in cases with intestinal gas
      formation images of internal organs could be obtained with special techniques.
      Various pathological findings were detected by ultrasound and verified by autopsy
      (e.g. pericardial tamponade, cardiac hypertrophy, fatty liver, aortic aneurysm,
      metastatic liver, etc.). The experiences with the SonoSite 180 are promising. The
      device can be carried to the death scene or to the morgue and therefore serve as
      a valuable tool for medicolegal applications.

PMID- 15013166
TI  - Discriminating red spray paints by optical microscopy, Fourier transform infrared
      spectroscopy and X-ray fluorescence.
AB  - Red spray paints from different European suppliers were characterised to
      determine the discriminating power of a sequence of analysing techniques. A total
      of 51 red spray paints were analysed with the help of three techniques: (1)
      optical microscopy, (2) Fourier transform infrared spectrometry and (3) X-ray
      fluorescence. Infrared spectra were classified according to binder type, filler
      and pigment composition and a searchable spectral library was created. Due to the
      difference in the elemental composition of spray paints, a further discrimination
      was possible. The microscopic analysis was not taken into consideration for
      classification purposes. The structure of the substrate under a paint coating
      strongly affects the surface characteristics of this spray paint. Together with
      the spectral library, a database of information of spray paints was build.

PMID- 15013167
TI  - Chemical fingerprinting of gasoline. Part 3. Comparison of unevaporated
      automotive gasoline samples from Australia and New Zealand.
AB  - A gas chromatography-mass spectrometry with selected ion monitoring (GC-MS (SIM))
      method was used to discriminate samples of unevaporated gasoline collected from
      Auckland, New Zealand and Sydney, Australia. This method was applied to 28
      samples of unevaporated gasoline, covering three different grades (regular
      unleaded, premium unleaded and premium plus unleaded), that were collected from
      service stations in Auckland, New Zealand in summer (February) and winter
      (August). The 14 samples of summer gasoline collected in New Zealand could be
      divided into seven unique groups. The 14 samples of winter gasoline from New
      Zealand could be divided into 14 unique groups. The 14 samples collected in New
      Zealand during February 2002 were then compared to 24 samples of unevaporated
      gasoline collected from service stations in Sydney, Australia during the same
      month. Most of the samples could be differentiated based on their country of
      origin.

PMID- 15013168
TI  - Differential rigor development in red and white muscle revealed by simultaneous
      measurement of tension and stiffness.
AB  - Based on the molecular mechanism of rigor mortis, we have proposed that stiffness
      (elastic modulus evaluated with tension response against minute length
      perturbations) can be a suitable index of post-mortem rigidity in skeletal
      muscle. To trace the developmental process of rigor mortis, we measured stiffness
      and tension in both red and white rat skeletal muscle kept in liquid paraffin at
      37 and 25 degrees C. White muscle (in which type IIB fibres predominate)
      developed stiffness and tension significantly more slowly than red muscle, except
      for soleus red muscle at 25 degrees C, which showed disproportionately slow rigor
      development. In each of the examined muscles, stiffness and tension developed
      more slowly at 25 degrees C than at 37 degrees C. In each specimen, tension
      always reached its maximum level earlier than stiffness, and then decreased more
      rapidly and markedly than stiffness. These phenomena may account for the
      sequential progress of rigor mortis in human cadavers.

PMID- 15013169
TI  - Driving under the influence of khat--alkaloid concentrations and observations in
      forensic cases.
AB  - The use of the herbal stimulant khat (Catha edulis FORSK) is maintained by
      immigrants from countries where it is part of their cultural life (Arabian
      Peninsula and eastern Africa). In western countries the drug and its effects are
      largely unknown and no experience in evaluating impairment symptoms due to the
      khat-alkaloids, e.g. cathinone, cathine and norephedrine exists. Blood and urine
      samples from khat users involved in 19 cases of suspected driving under the
      influence of drugs were analysed and correlated with the results of medical
      examination and police officer reports. In 3 cases impaired driving and in 10
      cases marked impairment of psychophysical functions was observed such as effects
      on the nervous system (slow pupil reaction to light, dry mouth, increased heart
      rate), trembling, restlessness/nervousness, daze/apathy/dullness, impairment of
      attention, walking and standing on one leg. However, the alkaloid concentrations
      assayed in blood did not correlate with the impairment symptoms. Apart from an
      acute phase of indirect sympathomimetic action the development of habituation and
      withdrawal symptoms must also be considered in explaining the diversity of
      effects observed. From these results it can be concluded that chewing khat may
      severely impair driving ability, but may also be without noticeable effects.

PMID- 15013170
TI  - Exploratory study on classification and individualisation of earprints.
AB  - The FearID research project is aimed at the individualisation of earprints for
      the purpose of forensic research. The study presented here was carried out within
      the framework of this project. It intends to combine a review of what is known
      from literature on the classification and individualisation of earprints with
      results from a preliminary study of earprints. Possibilities for, and limitations
      to, the use of earprints in forensic investigation are addressed. Differences
      between eliminating a suspect, placing a suspect at a crime scene, and linking
      crimes by prints left at different scenes are considered.

PMID- 15013171
TI  - Death following acute poisoning by moclobemide.
AB  - A fatality due to ingestion of a reversible inhibitor of monoamine-oxidase A (MAO
      A) is reported. Moclobemide is generally considered as a safe drug far less toxic
      than tricyclic anti-depressants. However, severe intoxications may result from
      interactions with other drugs and food such as selective serotonin reuptake
      inhibitors (SSRIs), anti-Parkinsonians of the MAOI-type (e.g. selegiline) or
      tyramine from ripe cheese or other sources. In the present case, high levels of
      moclobemide were measured in peripheral blood exceeding toxic values reported so
      far in the scientific literature. The body fluid concentrations of moclobemide
      were of 498 mg/l in peripheral whole blood, 96.3 mg/l in urine while an amount of
      approximately 33 g could be recovered from gastric contents. The other
      xenobiotics were considered of little toxicological relevance. The victim (male,
      48-year-old) had a past history of depression and committed one suicide attempt 2
      years before death. Autopsy revealed no evidence of significant natural disease
      or injury. It was concluded that the manner of death was suicide and that the
      unique cause of death was massive ingestion of moclobemide.

PMID- 15013172
TI  - Analysis of 683 drug packages seized from "body stuffers".
AB  - The wrappings and contents of 683 drug containers (bubbles) seized from 154
      street dealers have been analysed since 2001, when the law enforcement policy in
      Hamburg, Germany, allowed the application of emetics to be used by so-called body
      stuffers for the recovery of swallowed drug packages. Of the bubbles recovered
      96% contained cocaine. Cases of intoxication have not yet been observed but a 20
      year-old man with a previously unknown toxic cardiomyopathy died 3 days after a
      sudden cardiac arrest which followed the forced application of ipecacuanha via
      correctly placed nasogastral tube.

PMID- 15013173
TI  - Y-chromosomal STR haplotypes in Berber and Arabic-speaking populations from
      Morocco.
AB  - Twelve Y-chromosomal short tandem repeats (STRs), DYS19, DYS385, DYS389I,
      DYS389II, DYS390, DYS391, DYS392, DYS393, DYS388, DYS426 and DYS439 were typed in
      Berber-speaking (n=49) and Arabic-speaking (n=60) population samples from
      Morocco.

PMID- 15013174
TI  - Y-chromosome STR haplotypes in a population sample of the Byelorussian minority
      living in the northeastern Poland.
AB  - Haplotype and allele frequencies for the eight Y-STRs were determined in a
      population sample of 156 unrelated Byelorussian males. The most common haplotype
      was shared by 3.85% of the sample, while 121 haplotypes were unique. The gene
      diversity was 0.98.

PMID- 15013175
TI  - Han nation population in Shangdong province of china data for nine STR loci.
AB  - Allele frequencies for nine STR loci (D3S1358, TH01, TPOX, CSF1PO, D16S539,
      D7S820, D2S1338, D8S1179, D18S535) were obtained from a sample of 100/86
      unrelated healthy individual born in Shangdong province of China. chi(2)-Test
      indicated that the distribution of genotypes agreed with Hardy-Weinberg
      equilibrium.

PMID- 15013176
TI  - Population data for 16 Y-chromosome STRs in four populations from Pyrenees
      (Spain).
AB  - Population frequencies for the eight Y-STR loci included in the "minimal
      haplotype" from Y-STR Haplotype Reference Database (YHRD) plus other eight Y-STRs
      (DYS434, DYS435, DYS436, DYS437, DYS438, DYS439, GATA H4 and GATA A10) were
      obtained for a sample of 133 males from four main geographical areas in the
      Pyrenees (Spain): Vall D'Aran (Lerida), Cerdanya (Gerona), Alt Urgell (Lerida)
      and Jacetania (Huesca). Haplotype diversities were estimated in the four
      populations.

PMID- 15013177
TI  - Allele frequencies data and statistic parameters for 16 STR loci-D19S433,
      D2S1338, CSF1PO, D16S539, D7S820, D21S11, D18S51, D13S317, D5S818, FGA, Penta E,
      TH01, vWA, D8S1179, TPOX, D3S1358-in the Rio de Janeiro population, Brazil.
AB  - Allele frequencies for 16 short tandem repeats (STR) loci were determined with a
      sample of 230-300 unrelated individuals from the population of Rio de Janeiro,
      Brazil. The loci are the most commonly used in forensic and paternity testing,
      being analysed by the Identifiler (Applied Biosystems) and PowerPlex 2.1
      (Promega) commercial kits. It was proved that Penta E and D18S51 are the most
      polymorphic loci.

PMID- 15013178
TI  - Allele frequencies of 10 STR loci in Koreans.
AB  - Allele frequencies for the 10 STR loci, D6S1043, D9S925, D7S821, D4S2368,
      D21S2055, GATA193A07, D12S391, D10S2326, D15S822 and D18S51 were obtained from a
      sample of 217-310 unrelated Koreans. In this study, 2 out of the 10 loci did not
      meet Hardy-Weinberg expectation. The combined probability of identity for 10 loci
      tested was 4.93 x 10(-14).

PMID- 15013180
TI  - Influence of aqueous extract from Neurada procumbens L. on blood pressure of
      rats.
AB  - Neurada procumbens is a desert plant in the Arabian Peninsula. It has been
      considered edible by Bedouin and has been used traditionally as a medicinal herb.
      During a screening test of Arabian plants, the aqueous extract of Neurada
      procumbens increased the blood pressure of anaesthetized normotensive rats when
      it was administered orally. Further studies proved it elevated the blood pressure
      of conscious SHR, and produced vasoconstriction on the aortic strips of rats in
      vitro, which was reduced partially by phentolamine. This study demonstrates that
      the aqueous extract of the plant has an effect of increasing blood pressure that
      might be mediated through alpha-adrenergic receptors. Though more investigations
      are needed to prove its effect in humans, the present study warns that Neurada
      procumbens might not be so safe as it has been considered, and people, especially
      those with cardiovascular diseases, should be careful when they use the plant.

PMID- 15013179
TI  - Protective role of extracts of neem seeds in diabetes caused by streptozotocin in
      rats.
AB  - Effect of petroleum ether extracts of kernel (NSK) and husk (NSH) of neem
      (Azadirachta indica A. Juss, Meliaceae) seeds on the prevention of oxidative
      stress caused by streptozotocin (STZ) was investigated. Diabetes mellitus was
      induced in adult male Wistar rats after administration of STZ (55 mg/kg b.wt.,
      i.p., tail vein). The effect of NSK (2 gm/kg, b.wt.) and NSH (0.9 gm/kg, b.wt.)
      orally for 28 days was investigated in diabetic rats. Insulin-treated diabetic
      rats (6 U/kg, i.p., 28 days.) served as positive control. Diabetic rats given
      normal saline served as diabetic control. Rats that neither received STZ nor
      drugs served as normal control. Serum creatine phosphokinase (CPK) increased in
      diabetic rats was significantly decreased on insulin, NSK, and NSH treatments.
      The decrease in activities of superoxide dismutase (SOD) and catalase (CAT) and
      increase in lipid peroxidation (LPO) of erythrocytes as observed in diabetes was
      regained after insulin, NSH, and NSK treatments. However, there was insignificant
      improvement in SOD, CAT, and LPO of kidney on NSK and NSH treatment. In spite of
      increased CAT and SOD activities in liver and heart, LPO was also increased in
      diabetic rats. Insulin, NSH, and NSK treatments significantly protected animals
      from cardiac damage but not hepatic. Results suggest that NSH and NSK prevent
      oxidative stress caused by STZ in heart and erythrocytes. However, no such
      preventive effect was observed on renal and hepatic toxicity.

PMID- 15013181
TI  - Effect of polyherbal formulation on experimental models of inflammatory bowel
      diseases.
AB  - A polyherbal ayurvedic formulation from an ancient authentic classical text of
      ayurveda was evaluated for its activity against inflammatory bowel disease (IBD).
      The polyherbal formulation contained four different drugs viz., Bilwa (Aegle
      marmeloes), Dhanyak (Coriandrum sativum), Musta (Cyperus rotundus) and Vala
      (Vetiveria zinzanioids). The formulation has been tried before in clinical
      practice and was found to be useful in certain number of cases of IBD (ulcerative
      colitis), so was tried in the same form i.e., decoction (aqueous extract) in
      experimental animals to revalidate the claims of the same. The formulation was
      tried on two different experimental animal models of inflammatory bowel disease,
      which are acetic acid-induced colitis in mice and indomethacin-induced
      enterocolitis in rats. Prednisolone was used as the standard drug for comparison.
      The formulation showed significant inhibitory activity against inflammatory bowel
      disease induced in these experimental animal models. The activity was comparable
      with the standard drug prednisolone. The results obtained established the
      efficacy of this polyherbal formulation against inflammatory bowel diseases.

PMID- 15013182
TI  - Antioxidant, antimicrobial, antiulcer and analgesic activities of nettle (Urtica
      dioica L.).
AB  - In this study, water extract of nettle (Urtica dioica L.) (WEN) was studied for
      antioxidant, antimicrobial, antiulcer and analgesic properties. The antioxidant
      properties of WEN were evaluated using different antioxidant tests, including
      reducing power, free radical scavenging, superoxide anion radical scavenging,
      hydrogen peroxide scavenging, and metal chelating activities. WEN had powerful
      antioxidant activity. The 50, 100 and 250 microg amounts of WEN showed 39, 66 and
      98% inhibition on peroxidation of linoleic acid emulsion, respectively, while 60
      microg/ml of alpha-tocopherol, exhibited only 30% inhibition. Moreover, WEN had
      effective reducing power, free radical scavenging, superoxide anion radical
      scavenging, hydrogen peroxide scavenging, and metal chelating activities at the
      same concentrations. Those various antioxidant activities were compared to
      standard antioxidants such as butylated hydroxyanisole (BHA), butylated
      hydroxytoluene (BHT), quercetin, and alpha-tocopherol. In addition, total
      phenolic compounds in the WEN were determined as pyrocatechol equivalent. WEN
      also showed antimicrobial activity against nine microorganisms, antiulcer
      activity against ethanol-induced ulcerogenesis and analgesic effect on acetic
      acid-induced stretching.

PMID- 15013183
TI  - Hypoglycemic effect of Acosmium panamense bark on streptozotocin diabetic rats.
AB  - The hypoglycemic effects of water and butanolic extracts prepared from the bark
      of Acosmium panamense (Fabaceae) were studied in diabetic rats (streptozotocin
      (STZ)-induced). Oral application of water extracts at doses of 20 and 200 mg/kg
      and of butanol extracts at doses of 20 and 100 mg/kg significantly lowered the
      plasma glucose levels in diabetic rats within 3 h. Glibenclamide was used as
      reference and showed similar hypoglycemic effect like the extracts. Three
      structurally new compounds were isolated from the plant and shown to be the main
      constituents in both extracts.

PMID- 15013184
TI  - Antitrypanosomal and antiplasmodial activity of medicinal plants from Cote
      d'Ivoire.
AB  - The antitrypanosomal activity of 101 crude ethanol extracts derived from 88
      medicinal plants from Cote d'Ivoire was determined in vitro using Trypanosoma
      brucei rhodesiense. Of those extracts 8 showed good activity (IC50 values < or =8
      microg/ml), 37 revealed a weak activity (IC50 values between 25 and 8.1
      microg/ml) and 56 did not show any activity at all (IC50 values >25 microg/ml).
      The extracts of Enantia polycarpa (Annonaceae) and Trichilia emetica (Meliaceae)
      were the most promising ones. Their IC50 values were 0.5 and 0.04 microg/ml,
      respectively, and the selectivity index 616 and 209, respectively. This is the
      first report of in vitro antitrypanosomal activity of these two plants. Their
      high activities render them candidates for the isolation of compounds which could
      develop into new lead structures for drug development programs against African
      trypanosomiasis. Seven of the tested extracts exhibited an antiplasmodial
      activity against K1 strain of Plasmodium falciparum with IC50 values below 4
      microg/ml. The highest activity was found for Enantia polycarpa stem bark with an
      IC50 value of 0.126 microg/ml.

PMID- 15013185
TI  - Evaluation of hepatoprotective effect of Amalkadi Ghrita against carbon
      tetrachloride-induced hepatic damage in rats.
AB  - Amalkadi Ghrita (AG), a polyherbal formulation, was evaluated for its
      hepatoprotective activity against carbon tetrachloride (CCl4)-induced hepatic
      damage in rats. The hepatoprotective activity of AG was evaluated by measuring
      levels of serum marker enzymes like serum glutamate oxaloacetate transaminase
      (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP),
      and acid phosphatase (ACP). The serum levels of total proteins and bilirubin were
      also estimated. The histological studies were also carried out to support the
      above parameters. Silymarin was used as standard drug. Administration of AG (100
      and 300 mg/kg, p.o.) markedly prevented CCl4-induced elevation of levels of serum
      GPT, GOT, ACP, ALP, and bilirubin. The decreased level of total proteins due to
      hepatic damage induced by CCl4 was found to be increased in AG-treated group. The
      results are comparable to that of silymarin. A comparative histopathological
      study of liver exhibited almost normal architecture, as compared to CCl4-treated
      group. Hepatoprotective effect of AG is probably due to combined action of all
      ingredients.

PMID- 15013186
TI  - Inhibitory effect of a polysaccharide from Tinospora cordifolia on experimental
      metastasis.
AB  - Administration of the polysaccharide fraction from Tinospora cordifolia was found
      to be very effective in reducing the metastatic potential of B16F-10 melanoma
      cells. There was a 72% inhibition in the metastases formation in the lungs of
      syngeneic C57BL/6 mice, when the drug was administered simultaneously with tumour
      challenge. Biochemical parameters such as lung collagen hydroxyproline,
      hexosamines and uronic acids that are markers of neoplastic development were
      reduced significantly (P<0.001) in the treated animals compared with the
      untreated control animals. The treatment could also reduce serum gamma
      glutamyltranspeptidase (gamma-GT) and sialic acid levels as compared to the
      control animals.

PMID- 15013187
TI  - Effects of Aloe preparation on the histamine-induced gastric secretion in rats.
AB  - The effects of Aloe preparation containing 80% Aloe gel on the gastric acid,
      pepsin and mucus secretion were evaluated in histamine-induced gastric fistula
      model in rats by comparison to the effects of placebo and fresh Aloe gel. Aloe
      preparation and placebo at a dose of 8 ml/kg inhibited gastric acid but
      stimulated pepsin secretory rates. On the other hand, fresh Aloe gel at a dose of
      6.4 ml/kg prolonged histamine stimulatory effects on the gastric acid secretion
      while it inhibited gastric pepsin secretion. Both Aloe preparation and placebo
      increased soluble mucus secretory rate in a dose-dependent manner whereas fresh
      Aloe gel had no effect. The Aloe preparation and placebo at a dose of 8 ml/kg
      increased the gastric visible mucus content while fresh Aloe gel slightly
      increased the visible mucus content. This study reveals that fresh Aloe gel
      prolonged the effects of histamine-stimulated acid secretion and inhibits pepsin
      secretion in histamine-treated rats. The Aloe preparation inhibited gastric acid,
      stimulated pepsin and mucus secretion. However, there were no difference in the
      secretory rates of Aloe preparation and placebo-treated rats at the same doses.
      This result indicates that the observed effects of Aloe preparation was mostly
      due to other compositions of the preparation rather than Aloe gel itself. Since
      the highest dose of Aloe gel preparation used in the present study was limited by
      the volume of the instilled solution in gastric fistula model, the effects of
      Aloe vera gel were not able to be observed in the present study might be due to
      the inadequate dose of the preparation.

PMID- 15013188
TI  - Hypolipidemic activity of seeds of Cassia tora Linn.
AB  - Ethanolic extract of seeds of Cassia tora L. and its fractions were investigated
      for hypolipidemic activity on triton induced hyperlipidemic profile. Ethanolic
      extract and its ether soluble and water soluble fraction decreased serum level of
      total cholesterol by 42.07, 40.77 and 71.25%, respectively. On the other hand
      ethanolic extract, ether soluble fraction and water soluble fraction increased
      the serum HDL-cholesterol level by 6.72, 17.20 and 19.18%, respectively.
      Ethanolic extract, ether fraction and water fraction decreased triglyceride level
      by 26.84, 35.74 and 38.46%, respectively. The reduction in LDL-cholesterol level
      by ethanolic extract, ether soluble fraction and water soluble fraction were
      69.25, 72.06 and 76.12%, respectively.

PMID- 15013189
TI  - Effect of Kuibitang on lipopolysaccharide-induced cytokine production in
      peripheral blood mononuclear cells of chronic fatigue syndrome patients.
AB  - Kuibitang (KBT) is clinically used to treat patients suffering from chronic
      fatigue syndrome (CFS) in South Korea. However, its effect has not been
      investigated experimentally. Recent reports have shown that CFS patients display
      an altered cytokine production. We examined the effect of KBT on
      lipopolysaccharide (LPS)-induced various cytokines production in peripheral blood
      mononuclear cells (PBMC) of CFS patients and healthy controls. KBT (1 mg/ml)
      significantly inhibited LPS-induced tumor necrosis factor-alpha, interleukin-10,
      and transforming growth factor-beta1 production in PBMC of CFS patients. However,
      LPS-induced interferon-gamma production was significantly increased by KBT (0.01
      mg/ml). These results provide evidence of a novel activity of the KBT that
      regulate cytokines production related with CFS.

PMID- 15013190
TI  - Cytotoxic oleanane triterpenoids from the rhizomes of Astilbe chinensis (Maxim.)
      Franch. et Savat.
AB  - Bioassay-guided fractionation of the rhizomes of Astilbe chinensis afforded four
      cytotoxic pentacyclic triterpenoids, 3beta-hydroxy-olean-12-en-27-oic acid (1),
      3beta,6beta-dihydroxy-olean-12-en-27-oic acid (2), 3beta-acetoxy-olean-12-en-27
      oic acid (3), and 3beta-hydroxy-urs-12-en-27-oic acid (4). The isolation and
      purification of these compounds was conducted with the application of column
      chromatography. Their structures were elucidated on the basis of chemical and
      spectral evidence. 2D NMR techniques including 1H-1H COSY, HMQC, HMBC spectra and
      HREIMS were extensively applied to establish the structures. Compounds 1-4 showed
      cytotoxic activities against HO-8910, Hela and HL60 in vitro; moreover, compound
      1 induced apoptotic cell death of the HO-8910 in a dose-dependent manner, ranging
      from 2.5 to 40.0 microg/ml. The presence of these active compounds may be
      responsible, at least in part, for the antineoplastic action of the traditional
      crude drug Rhizoma Astilbe chinensis.

PMID- 15013191
TI  - Protection against murine endotoxemia by treatment with Ruta chalepensis L., a
      plant with anti-inflammatory properties.
AB  - The anti-inflammatory effect of the extract of Ruta Chalepensis L. (Rutaceae) on
      the course of lethal endotoxemia in BALB/c mice was studied. When administered by
      gavage as 1 g/kg per day starting 14 or 7 days prior to injection of 0.75 mg
      endotoxin (LPS: lipopolysaccharide), the extract markedly reduced lethality
      (32.5% in both experiments versus approximately 85% of the control mice). A delay
      in lethality, but not cumulative lethality, was observed when prophylaxis was
      given 24 and 1 h prior to LPS challenge. The effect was associated with reduced
      LPS-induced blood levels of nitrite, an indicator of nitric oxide production. In
      contrast, the blood levels of tumour necrosis factor, interleukin 6 and
      interleukin 10 did not differ significantly from those of controls given LPS
      alone. These data show that Ruta Chalepensis L. possesses powerful
      immunopharmacological properties that make it capable of counteracting the lethal
      effects of high doses of LPS in vivo.

PMID- 15013192
TI  - Modulation of rat and human cytochromes P450 involved in PhIP and 4-ABP
      activation by an aqueous extract of Phyllanthus orbicularis.
AB  - Phyllanthus orbicularis HBK (Euphorbiaceae) is a medicinal plant, endemic to
      Cuba, whose aqueous extract has proven antimutagenic effects against hydrogen
      peroxide and some promutagenic aromatic amines (AAs), in addition to its
      antiviral properties. In this paper, antimutagenesis of this extract against two
      carcinogenic AAs, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 4
      aminobiphenyl (4-ABP) has been studied. Liver microsomal fractions from both
      induced rats and humans were used to metabolise both procarcinogenic compounds in
      the Salmonella assay. The plant extract was effective in reducing the mutagenesis
      of these AAs, activated by both kinds of fractions. The optimal antimutagenic
      effect was obtained when both AAs were metabolised by human enzymes, with an
      almost total reduction of 4-ABP mutagenesis and a decrease of about 75% of PhIP
      mutagenicity. Mutagenicity of both AAs, activated by induced rat fraction, was
      only decreased by about 50%. Inhibition by plant extract of alkoxyresorufin O
      dealkylation activities, dependent on CYP1A, of both fractions was determined. In
      accordance with the results obtained, the inhibition or modulation of CYP1A
      subfamily activities, and possibly of CYP1A2, is thought to be the main mechanism
      of antimutagenesis of the aqueous extract of Phyllanthus orbicularis against 4
      ABP and PhIP.

PMID- 15013193
TI  - Evaluation of ethnobotanically selected Benin medicinal plants for their in vitro
      antiplasmodial activity.
AB  - Twenty extracts from nine Benin medicinal plants, traditionally used to treat
      malaria, were screened for in vitro antiplasmodial activity towards Plasmodium
      falciparum K1 chloroquine resistant and 3D7 chloroquine sensitive strains. All
      plants showed antiplasmodial activity below 10 microg/ml. Nine extracts exhibited
      IC50 values below 5 microg/ml towards one or both of the two strains. The most
      active extract towards the sensitive 3D7 strain was the methanolic extract of
      Croton lobatus aerial part, with an IC50 value of 0.38 microg/ml. The best
      inhibition of the growth of Plasmodium falciparum resistant K1 strain was
      observed with the methylene chloride extract of Hybanthus enneaspermus and with
      the methanolic extract of Croton lobatus roots (IC50=2.57 and 2.80 microg/ml,
      respectively).

PMID- 15013195
TI  - Herbal mixtures in the traditional medicine of eastern Cuba.
AB  - Herbal mixtures in the traditional medicine of Eastern Cuba. Traditional herbal
      mixtures in Eastern Cuba are investigated through interviews with 130
      knowledgeable people and traditional healers of the provinces of Santiago de Cuba
      and Guantanamo. One hundred seventy plant species and other products are used in
      199 formulas, galones being the more complex. Cocos nucifera L. (Arecaceae),
      Bidens pilosa L. (Asteraceae), Cissus sicyoides L. (Vitaceae), Erythroxylum
      havanense Jacq. (Erythroxylaceae) and Stachytarpheta jamaicensis (L.) Vahl.
      (Verbenaceae) are the species most frequently cited. The ecological distribution
      of the taxa and cultural and anthropological aspects of mixtures are highlighted;
      particularly American and African influences that have shaped local knowledge
      about plant combinations are discussed.

PMID- 15013194
TI  - Antiinflammatory evaluation of alcoholic extract of galls of Quercus infectoria.
AB  - Galls of Quercus infectoria Olivier (Fagaceae) possess pleiotropic therapeutic
      activities, with particular efficacy against inflammatory diseases. The present
      study was undertaken to evaluate the effect of alcoholic extract of Q. infectoria
      galls on various in vivo and in vitro experimental models of inflammation. Oral
      administration of gall extract significantly inhibited carrageenan, histamine,
      serotonin and prostaglandin E2 (PGE2) induced paw oedemas, while topical
      application of gall extract inhibited phorbol-12-myristate-13-acetate (PMA)
      induced ear inflammation. The extract also inhibited various functions of
      macrophages and neutrophils relevant to the inflammatory response. In vitro
      exposure of rat peritoneal macrophages to gall extract ameliorated
      lipopolysaccharide (LPS) stimulated PGE2 and nitric oxide (NO) production and PMA
      stimulated superoxide (O2*-) production in a dose dependent manner. Gall extract
      also scavenged NO and O2*-. Probing into mechanism of NO inhibition in
      macrophages revealed gall extract to ameliorate the induction of inducible NO
      synthase (iNOS), respectively without any inhibitory effect on its catalytic
      activities even at higher concentrations. Gall extract also significantly
      inhibited formyl-Met-Leu-Phe (fMLP) stimulated degranulation in neutrophils.
      These results suggest that alcoholic extract of galls of Q. infectoria exerts in
      vivo antiinflammatory activity after oral or topical administration and also has
      the ability to prevent the production of some inflammatory mediators.

PMID- 15013196
TI  - Studies on the anti-inflammatory and analgesic properties of Tithonia
      diversifolia leaf extract.
AB  - A methanol extract of the dried leaves of Tithonia diversifolia was investigated
      for anti-inflammatory and analgesic activities. The extract (50-200 mg/kg, p.o.)
      produced dose-related inhibition of carrageenan-induced paw oedema and cotton
      pellet-induced granuloma in rats. At the same doses, analgesic effect was also
      observed with hot plate latency assays maintained at (55 degrees C) as well as on
      the early and late phases of formalin-induced paw licking in rats. The results of
      the present study further confirm the use of Tithonia diversifolia traditionally
      for the treatment of painful inflammatory conditions.

PMID- 15013197
TI  - Effect of Retama raetam on lipid metabolism in normal and recent-onset diabetic
      rats.
AB  - The purpose of this study was to examine the effect of single and repeated oral
      administration of the aqueous extract of Retama raetam (Forssk) Webb (RR) (20
      mg/kg) on lipid metabolism in normal and streptozotocin-induced diabetic rats. In
      normal rats, the aqueous extract of RR induced a significant decrease of the
      plasma triglycerides concentrations one week after repeated oral administration
      (P<0.05). This reduction was maintained two weeks after once daily repeated oral
      administration (P<0.05). A significant decrease of plasma cholesterol levels was
      also observed one week (P<0.05) and two weeks (0.05) after repeated oral
      administration. In diabetic rats, RR treatment caused a significant decrease of
      plasma triglycerides levels after a single (P<0.05) and repeated (P<0.001) oral
      administration. A significant decrease of cholesterol levels was observed four
      hours after a single oral administration of the RR aqueous extract (P<0.05). One
      week after repeated oral administration of RR aqueous extract, the plasma
      cholesterol levels were significantly decreased (P<0.05) and still dropped after
      two weeks (P<0.005). On the other hand, the repeated oral administration of RR
      aqueous extract caused a significant decrease of body weight one week after
      repeated oral treatment in diabetic rats (P<0.05). We conclude that the aqueous
      extract of RR exhibits lipid and body weight lowering activities in both normal
      and severe hyperglycemic rats after repeated oral administration of RR aqueous
      extract at a dose of 20 mg/kg.

PMID- 15013198
TI  - Effects of an aqueous extract of Triticum repens on lipid metabolism in normal
      and recent-onset diabetic rats.
AB  - The aim of this study was to demonstrate the effects of single and repeated oral
      administration of the aqueous rhizomes extract of Triticum repens (TR) (20 mg/kg)
      on lipid metabolism in normal and streptozotocin-induced diabetic rats. In normal
      rats, the aqueous extract of TR induced a significant decrease in the plasma
      triglycerides concentrations 4 days (P<0.05) and 1 week after repeated oral
      administration (P<0.05). This reduction was abolished 2 weeks after once daily
      repeated oral administration. A significant decrease of plasma cholesterol levels
      was observed only 1 week (P<0.05) after repeated oral administration. In diabetic
      rats, TR treatment caused a significant decrease in plasma triglycerides levels
      after a single (P<0.01) and repeated (P<0.001) oral administration. A strong
      decrease in cholesterol level was observed 6 h after a single oral administration
      of the aqueous extract TR (P<0.001). Four days after repeated oral administration
      of TR aqueous extract, the plasma cholesterol level was significantly decreased
      (P<0.05) and still dropped after 2 weeks (P<0.001). On other hand, the repeated
      oral administration of aqueous TR extract caused a significant decrease in body
      weight 2 weeks after repeated oral treatment in diabetic rats (P<0.05). We
      conclude that the aqueous extract of TR exhibits lipid and body weight lowering
      activities in severe hyperglycaemic rats after repeated oral administration of
      aqueous TR extract at a dose of 20 mg/kg.

PMID- 15013199
TI  - Immunomodulatory and antitumor activity of Piper longum Linn. and piperine.
AB  - Alcoholic extract of the fruits of the plant Piper longum and its component
      piperine was studied for their immunomodulatory and antitumor activity. Alcoholic
      extract of the fruits was 100% toxic at a concentration of 500 microg/ml to
      Dalton's lymphoma ascites (DLA) cells and 250 microg/ml to Ehrlich ascites
      carcinoma (EAC) cells. Piperine was found to be cytotoxic towards DLA and EAC
      cells at a concentration of 250 microg/ml. Alcoholic extract and piperine was
      also found to produce cytotoxicity towards L929 cells in culture at a
      concentration of 100 and 50 microg/ml, respectively. Administration of alcoholic
      extract of Piper longum (10 mg/dose/animal) as well as piperine (1.14
      mg/dose/animal) could inhibit the solid tumor development in mice induced with
      DLA cells and increase the life span of mice bearing Ehrlich ascites carcinoma
      tumor to 37.3 and 58.8%, respectively. Administration of Piper longum extract and
      piperine increased the total WBC count to 142.8 and 138.9%, respectively, in
      Balb/c mice. The number of plaque forming cells also enhanced significantly by
      the administration of the extract (100.3%) and piperine (71.4%) on 5th day after
      immunization. Bone marrow cellularity and alpha-esterase positive cells were also
      increased by the administration of Piper longum extract and piperine.

PMID- 15013200
TI  - Anti-venom potential of butanolic extract of Eclipta prostrata against Malayan
      pit viper venom.
AB  - The butanolic and purified butanolic extracts (PBEs) of Eclipta prostrata were
      evaluated for their anti-venom potential. Inhibition of lethal, hemorrhagic,
      proteolytic, and phospholipase A2 activities of Calloselasma rhodostoma (Malayan
      pit viper (MPV)) venom by these extracts were determined. Demethylwedelolactone
      was identified as their major constituent. The butanolic extract, at 2.5 mg per
      mouse, was able to completely neutralize the lethal activity of 2LD50 of MPV
      venom, but increasing the dose diminished the effect. The PBE, at 1.5-4.5 mg per
      mouse, was able to neutralize the lethality of the venom at around 50-58%. Both
      extracts partially inhibited the hemorrhagic activity but displayed very low anti
      phospholipase A2 activity and did not inhibit proteolytic activity of MPV venom.

PMID- 15013201
TI  - In vitro antimicrobial activity of certain medicinal plants from eastern Ghats,
      India, used for skin diseases.
AB  - The paper deals with ethnopharmacological and antimicrobial properties of certain
      medicinal plants used by adivasi tribes of the Eastern Ghats of Andhra Pradesh,
      India. Ethanolic extracts of 23 crude drug samples used for various skin diseases
      were assayed for antimicrobial activity against four bacterial and one fungal
      human pathogens.

PMID- 15013202
TI  - Toxicity of crude rhizome extract of Kaempferia galanga L. (Proh Hom).
AB  - The ethanolic rhizome extract of Kaempferia galanga L. (Zingiberaceae) was
      studied by conventional pharmacological methods including the Hippocratic
      screening test, and acute and subacute toxicities in rats. The hexane fraction
      was tested for dermal irritation in rabbits. The ethanolic extract, when tested
      by the Hippocratic screening test, demonstrated signs that indicated CNS
      depression such as a decrease in motor activity and respiratory rate, and a loss
      of screen grip and analgesia. In the acute toxicity test, oral administration of
      5 g/kg of Kaempferia galanga produced neither mortality nor significant
      differences in the body and organ weights between controls and treated animals.
      Moreover, both gross abnormalities and histopathological changes were not
      comparatively detectable between all controls and treated animals of both sexes.
      In subacute toxicity studies, no mortality was observed when varying doses of 25,
      50 or 100 mg/kg of ethanolic Kaempferia galanga extract were administered orally
      per day for a period of 28 days. There were no significant differences in the
      body and organ weights between controls and treated animals of both sexes.
      Hematological analysis showed no differences in any of the parameters examined
      (WBC count, platelet, hematocrit and hemoglobin estimation) in either the control
      or treated groups of both sexes. However, the differential leukocyte counts
      showed a slight but significant decrease of lymphocyte count in the 50 and 100
      mg/kg male rat groups. In the blood chemistry analysis, no significant change
      occurred in the blood chemistry parameters, including glucose, creatinine, blood
      urea nitrogen (BUN), aspartate transaminase (AST), alanine transaminase (ALT),
      alkaline phosphatase (Alk-P), total protein and albumin of both sexes.
      Pathologically, neither gross abnormalities nor histopathological changes were
      observed. No sign of irritation was observed during the dermal irritation test of
      the hexane fraction of Kaempferia galanga.

PMID- 15013203
TI  - Inhibition of sustained repetitive firing in cultured hippocampal neurons by an
      aqueous fraction isolated from Delphinium denudatum.
AB  - In this report we investigated the effects of the aqueous fraction (AF) isolated
      from Delphinium denudatum on sustained repetitive firing in cultured neonatal rat
      hippocampal pyramidal neurons. Blockade of SRF is one of the basic mechanisms of
      antiepileptic drugs (AED) at the cellular level. The effects of aqueous fraction
      (0.2-0.6 mg/ml) were compared with the prototype antiepileptic drug, phenytoin
      (PHT). Using the whole cell current-clamp technique, sustained repetitive firing
      was elicited in neurons by a depolarizing pulse of 500 ms duration, 0.3 Hz and
      0.1-0.6 nA current strength. Similar to phenytoin, aqueous fraction reduced the
      number of action potentials (AP) per pulse in a concentration-dependent manner
      until no action potentials were elicited for the remainder of the pulse. There
      was a corresponding use-dependent reduction in amplitude and Vmax (velocity of
      upstroke) of action potentials. The Vmax and amplitude of the first action
      potential was not affected by phenytoin, while aqueous fraction exhibited
      concentration-dependent reduction. At 0.6 mg/ml aqueous fraction reduced Vmax to
      58-63% and amplitude to 16-20% of the control values. The blockade of sustained
      repetitive firing by aqueous fraction was reversed with hyperpolarization of
      membrane potential (-65 to -75 mV) while depolarization of membrane potential (
      53 to -48 mV) potentiated the block. The results suggest that aqueous fraction
      blocks sustained repetitive firing in hippocampal neurons in a use-dependent and
      voltage-dependent manner similar to phenytoin. However, unlike phenytoin, which
      interacts preferably with the inactive state of the Na+ channel, the compounds
      present in aqueous fraction apparently also interact with the resting state of
      the Na+ channels as suggested by dose-dependent reduction of Vmax and amplitude
      of first AP. We conclude that aqueous fraction contains potent anticonvulsant
      compounds.

PMID- 15013204
TI  - Chronic toxicity study of Portulaca grandiflora Hook.
AB  - We investigated the toxic effects of Portulaca grandiflora aqueous extract given
      to male and female Wistar rats for 6 months. The rats were divided into five
      groups of each sex that were control groups, three experimental groups and
      recovery groups. The control groups received 5 ml of distilled water/kg per day.
      The experimental groups were orally given the water extract of Portulaca
      grandiflora at doses of 10, 100 and 1000 mg/kg per day. The recovery groups
      received 1000 mg/kg per day for 6 months and were continued husbandry without
      giving the extract for further 14 days. Changes in the body weights, actual and
      relative organ weights were not significantly demonstrated in all groups
      throughout the study. No significant alteration in hematological, biochemical and
      histopathological parameters was observed in all female groups given the extract.
      It was found that any significant changes in hematological and biochemical
      parameters in the male rats at the doses of 100 and 1000 mg/kg per day were not
      dose-related. In addition, no histopathological lesions were observed in the male
      animals. Our results suggested that the water extract of Portulaca grandiflora at
      the doses given in the study did not induce any detrimental effects in the rats.

PMID- 15013205
TI  - Hepatotoxic effect of (+)usnic acid from Usnea siamensis Wainio in rats, isolated
      rat hepatocytes and isolated rat liver mitochondria.
AB  - Hepatotoxic effect of (+)usnic acid, the active constituent of Usnea siamensis
      Wainio was studied in rats, isolated rat hepatocytes and isolated rat liver
      mitochondria. In rats, after treatment with high dose of (+)usnic acid (200 mg/kg
      per day, i.p.) for 5 days, there was no significant change in serum transaminase
      activity (serum AST, ALT) while the electron micrographs showed apparent
      morphological damage of mitochondria and endoplasmic reticulum. (+)Usnic acid at
      high dose (1 mM) as well as carbon tetrachloride (CCl4, the reference
      hepatotoxin) induced loss of cell membrane integrity in isolated rat hepatocytes
      by increasing the release of cellular transaminases (AST, ALT). Increase in lipid
      peroxidation, decrease in glutathione (GSH) content and increase in aniline
      hydroxylase activity (CYP 2E1) were also found. Combination of (+)usnic acid and
      CCl4 showed the additive results. (+)Usnic acid (0.15-6 microM) possessed
      uncoupling activity in isolated rat liver mitochondria. It stimulated respiration
      by mitochondria respiring with glutamate plus malate or succinate as substrates
      and activated ATPase activity. Increasing concentration of (+)usnic acid (>6
      microM) exhibited loss of respiratory control and ATP synthesis. In conclusion,
      hepatotoxic effect of high dose (+)usnic acid may involve its reactive
      metabolite(s), causing loss of integrity of membrane like structures, resulting
      in destruction of mitochondrial respiration and oxidative phosphorylation.

PMID- 15013206
TI  - Ethnobotanical studies on medicinal plants used by the red-headed yao people in
      Jinping, Yunnan Province, China.
AB  - Sixty-six medicinal plant species traditionally collected and used by the Red
      headed Yao people in Jinping county, Yunnan Province, SW China, were investigated
      and studied through the approaches of ethnobotany, anthropology and participatory
      rural appraisal (PRA). Among these plants, 27 species were recorded to have
      medicinal values for the first time recorded in literature, 23 species were found
      to have different medicinal functions from those recorded in the literature. Many
      medicinal herbs are simultaneously wild food plants. The local Yao people take
      medicinal baths on some special days very common to treat and prevent diseases.
      The Red-headed Yao medicinal herb doctors have conserved medicinal plants and
      their habitats over the years. Most of the folk healers are old women, who are
      concerned about passing on their secrets to the younger generation. They fear
      that the younger generations have not learned enough about the herbal traditions
      to keep the practice going. The authors suggest that plants used by the Red
      headed Yao people need to be further studied phytochemically and
      pharmacologically.

PMID- 15013207
TI  - Ligusticum wallichi-induced vasorelaxation mediated by mitogen-activated protein
      kinase in rat aortic smooth muscle.
AB  - Traditional herbal medicines have been widely used for the treatment of
      cardiovascular disorders in oriental countries. To determine the effects of
      Ch1LW, a chloroform extract of Ligusticum wallichi, on the vascular system, we
      studied changes in rat aortic smooth muscle in terms of magnitude of contraction
      and the activity of mitogen-activated protein kinases (MAPKs). Ch1LW inhibited
      the muscle contraction induced by norepinephrine (NE) in aortic strips. Ch1LW
      also abolished Ca2+-independent contraction evoked by 12-deoxyphorbol 13
      isobutyrate in Ca2+-free medium containing 1 mM EGTA. Furthermore, western
      blotting analysis using phosphorylated MAPK antibodies showed that NE increased
      the activity of both extracellular signal-regulated kinase 1/2 (ERK1/2) and p38
      MAPK, which were inhibited by PD98059 and SB203580, blockers of ERK1/2 and p38
      MAPK, respectively. Furthermore, treatment with Ch1LW significantly abolished NE
      mediated activation of ERK1/2, whereas the activity of p38 MAPK was not affected
      by the extract. These results suggest that Ch1LW induces vasorelaxation in rat
      aortic smooth muscle, which may be mediated by the inhibition of ERK1/2 pathway,
      but not p38 MAPK.

PMID- 15013208
TI  - Isolation and anticomplement activity of compounds from Dendropanax morbifera.
AB  - Dendropanax morbifera Leveille (Araliaceae) is used in Korea for a variety of
      disease, such as migraine headache and dysmenorrhea. A new polyacetylene (1) and
      six known compounds (2-7) were isolated from the leaves of this plant by
      conventional chromatographic techniques. The structure of the new polyacetylene
      (1) was determined as (9Z,16S)-16-hydroxy-9,17-octadecadiene-12,14-diynoic acid
      by spectroscopic means including 2D NMR, which comprised the determination of a
      chiral by modified Mosher's ester method. Compounds 1-7 were investigated in
      vitro for their anticomplement activity against the classical pathway of the
      complement system. Of these, compound 1 showed significant anticomplement
      activity with 50% inhibitory concentration (IC50) value of 56.98 microM, whereas
      compounds 2-7 were inactive.

PMID- 15013209
TI  - Anti-inflammatory activity of Sedum kamtschaticum.
AB  - Sedum kamtschaticum Fischer (Crassulaceae) has been used as a folk medicine in
      North-East Asia for treating inflammatory disorders. The present investigation
      was carried out to establish in vivo anti-inflammatory activity and
      cyclooxygenase-2 modulating activity of this plant material. The methanol extract
      of Sedum kamtschaticum significantly inhibited mouse croton oil-induced ear edema
      (24-47% inhibition at 50-400 mg/kg) and rat paw edema (24-30% inhibition at 400
      800 mg/kg) by oral administration. Prednisolone (10 mg/kg) showed 54 and 36%
      inhibition in the same animal models, respectively. Sedum kamtschaticum also
      showed significant inhibitory activity against mouse ear edema induced by
      multiple treatment of phorbol ester for 3 days. In addition, Sedum kamtschaticum
      exhibited potent analgesic activity against mouse acetic acid-induced writhing
      (IC50=125 mg/kg), while aspirin (200 mg/kg) showed 57% inhibition. Using
      lipopolysaccharide-treated RAW 264.7 cells, down-regulation of cyclooxygenase-2
      expression was found to be one of the cellular action mechanisms of anti
      inflammation by Sedum kamtschaticum.

PMID- 15013210
TI  - Protective effect of Moutan Cortex extract on acetaminophen-induced
      hepatotoxicity in mice.
AB  - Previously, we demonstrated that Moutan Cortex prevents acetaminophen (AAP)
      induced cytotoxicity in vitro. The present study examined the protective effect
      of Moutan Cortex on AAP induced hepatotoxicity and the possible mechanisms
      underlying this effect in mice. When Montan Cortex was administered to ICR mice,
      followed by hepatotoxic dose of AAP (400 mg/kg, i.p.), Moutan Cortex pre-exposure
      prevented liver injury as indicated by the decrease of serum alanine
      aminotransferase level. Moutan Cortex also protected AAP-induced hepatic
      glutathione depletion. Cytochrome P450 2E1-dependent aniline and p-nitrophenol
      hydroxylases activities in microsomal incubations were significantly inhibited by
      Moutan Cortex. Abrogation of toxicity was also mirrored in DNA fragmentation.
      These observations demonstrate that Moutan Cortex pre-exposure may attenuate AAP
      induced GSH depletion, cytochrome P450 2E1 activity, and hepatic DNA damage in
      vivo.

PMID- 15013213
TI  - Midkine and pleiotrophin in neural development and cancer.
AB  - The midkine (MK) family consists of only two members, namely heparin-binding
      growth factors MK and pleiotrophin (PTN). During embryogenesis, MK is highly
      expressed in the mid-gestational period, whereas PTN expression reaches the
      maximum level around birth. Both proteins are localized in the radial glial
      processes of the embryonic brain, along which neural stem cells migrate and
      differentiate. Zebrafish and Xenopus MK can induce neural tissues. In addition,
      deposits of MK and/or PTN are found in neurodegenerative diseases, such as
      Alzheimer's disease and multiple system atrophy. Both molecules are induced in
      reactive astrocytes by ischemic insults. In this context, it is interesting that
      LDL receptor-related protein is a receptor for MK and PTN, and this receptor has
      been implicated in the pathogenesis of Alzheimer's disease. MK and PTN share
      receptors, and show similar biological activities that include fibrinolytic, anti
      apoptotic, mitogenic, transforming, angiogenic, and chemotactic ones. These
      activities explain how these molecules are involved in carcinogenesis. MK is
      detected in human carcinoma specimens from pre-cancerous stages to advanced
      stages. Strong expression of PTN is also detected in several carcinomas,
      although, in general, MK is expressed more intensely and in a wide range of
      carcinomas than PTN. The blood MK level is frequently elevated in advanced human
      carcinomas, decreases after surgical removal of the tumors, and is correlated
      with prognostic factors. Thus, it is a good market for evaluating the progress of
      carcinomas. Furthermore, antisense oligonucleotides for MK and ribozymes for PTN
      show anti-tumor activity. Therefore, MK and PTN are candidate molecular targets
      for therapy for human carcinomas.

PMID- 15013214
TI  - Hedgehog--Gli signaling in brain tumors: stem cells and paradevelopmental
      programs in cancer.
AB  - The Hedgehog-Gli signaling pathway is involved in the regulation of the
      proliferation of precursors in different organs of the normal vertebrate embryo.
      These cells express Gli1 and may be the target of cancer-causing agents. Many
      tumor types derived from organs that contain Gli1+ precursors appear to
      consistently express Gli1, indicating their origin and/or the presence of an
      active pathway. Inappropriate pathway activation in a variety of precursor cells
      in model organisms leads to tumor formation while inhibition of the pathway in
      human tumor cells leads to a decrease in their proliferation. In the brain we
      have documented the expression of Gli1 in germinative zones, and a variety of
      brain tumors express GLI1, including medulloblastomas of the cerebellum and a
      number of gliomas of the cerebral cortex. The requirement for SHH-Gli signaling
      in the growth of the mouse brain, together with the ability of inappropriate
      pathway activation in the cerebellum to cause medulloblastomas, and the
      inhibition of the growth of a number of brain tumors with cyclopamine, a SHH
      signaling inhibitor, underscores the critical role of the SHH-GLI pathway in
      brain growth and tumor formation. Moreover, they highlight the components of this
      pathway as prime targets for drug development, with special emphasis on the GLI
      proteins. Such reagents would allow a rational therapeutic approach to highly
      intractable diseases.

PMID- 15013215
TI  - Achaete-scute homolog-1 and Notch in lung neuroendocrine development and cancer.
AB  - Achaete-scute homolog-1 (termed Mash1 in rodents, hASH1 in humans) is a basic
      helix-loop-helix transcription factor important in early development of neural
      and neuroendocrine (NE) progenitor cells in multiple tissues including the CNS,
      autonomic nervous system, adrenal medulla, thyroid, lung, and prostate, among
      others. This review discusses how progress in developmental neurobiology of Mash1
      has translated into novel insights in NE tumor biology, particularly for small
      cell lung cancer. Inhibition of this factor by the Notch pathway is essential in
      regulating NE commitment in airway epithelial precursor cells, and may play a
      comparable role in modulating phenotypes of lung cancer and other tumors.

PMID- 15013217
TI  - MYCN in neuronal tumours.
AB  - MYCN is a member of the MYC family of oncogenes that encode nuclear proteins
      serving as transcription factors. Activation of MYC family genes, usually by
      genetic damage with the consequence of enhanced expression of a wild-type
      protein, has been found to participate in human and animal cancers. While
      activation of the MYC oncogene does not show an association with a particular
      cancer type, genetic damage involving MYCN has high preference for tumours of
      neuroectodermal derivation. In the vast majority of cases, the activation
      mechanism involves the increase of the MYCN gene dosage, either by amplification
      resulting in up to several hundred gene copies or by more subtle mechanisms, like
      duplication or polyploidization. In neuroblastoma, amplified MYCN is a strong
      prognostic indicator of poor prognosis, particularly in localized tumors where
      patients with normal MYCN gene dosage fare quite well. Identification of
      amplified MYCN in neuroblastomas has marked the clinical debut of oncogenes, and
      MYCN status now is being used world wide as a standard marker for neuroblastoma
      stratification.

PMID- 15013216
TI  - The Notch signaling cascade in neuroblastoma: role of the basic helix-loop-helix
      proteins HASH-1 and HES-1.
AB  - Neuroblastoma is a childhood tumor originating from cells of the developing
      sympathetic nervous system. The disease exhibits a remarkable phenotypic
      diversity reflected in the outcome, ranging from spontaneous regression to fatal
      disease. Mammalian achaete-scute homologue 1 (MASH-1 or HASH-1 in humans), a
      basic helix-loop-helix transcription (bHLH) factor, is transiently expressed in
      migrating sympatho-adrenal precursor cells. This gene, which is essential for
      proper development of the sympathetic nervous system, is expressed in a majority
      of primary neuroblastomas and neuroblastoma cell lines indicating an embryonal
      origin of the tumor. One important negative regulator of MASH-1 expression is the
      bHLH factor hairy and Enhancer of split homolog-1 (HES-1), which in turn is under
      positive control of the Notch signaling cascade. When neuroblastoma cells are
      induced to differentiate, as indicated by neuronal morphology and upregulation of
      neuronal marker genes, the HASH-1 expression is rapidly downregulated with a
      concomitant, transient upregulation of HES-1. Furthermore, a constitutively
      active form of Notch-1 inhibits induced differentiation of neuroblastoma cells.
      In this review, the role of the Notch-signaling cascade in neuroblastoma, with
      focus on the bHLH factors HASH-1 and HES-1, will be discussed.

PMID- 15013218
TI  - Id proteins in neural cancer.
AB  - Id proteins are general inhibitors of differentiation and positive regulators of
      proliferation in the nervous system. The role of Id is especially evident in
      neural development, a period during which Id proteins prevent premature
      differentiation and terminal cell cycle arrest. These activities have been
      related to the recognized ability of Id proteins to antagonize basic helix loop
      helix transcription factors and proteins of the Retinoblastoma tumor suppressor
      family. In recent experiments, it was shown that Id proteins-normally low or
      absent in post-natal tissues-are abnormally expressed by tumor and endothelial
      cells of neoplasms derived from the central nervous system and peripheral nervous
      system. In these tumors, deregulated Id activity has been associated with
      relentless proliferation, loss of differentiation and neo-angiogenesis, all key
      features of neural tumor progression. Future work will be required to fully
      elucidate the molecular networks engaged by Id proteins to contribute to the
      essential hallmarks of neural cancer.

PMID- 15013219
TI  - RET and neuroendocrine tumors.
AB  - Glial cell line-derived neurotrophic factor (GDNF), a ligand of RET tyrosine
      kinase, and its family ligands promote the survival and differentiation of a
      variety of neurons. Gene ablation studies have revealed that the GDNF-RET
      receptor system is essential for the development of kidney and peripheral
      neurons, including sympathetic, parasympathetic and enteric neurons. RET can
      activate various signaling pathways such as RAS/extracellular signal-regulated
      kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/AKT, p38 mitogen-activated
      protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways. These signaling
      pathways are activated via binding of adaptor proteins to intracellular tyrosine
      residues of RET phosphorylated by its own kinase activity. The RET is profoundly
      involved in the development of several human neuroendocrine diseases. The
      constitutive activation of the RET by somatic rearrangement with other partner
      genes or germ-line mutations causes a considerable population of human papillary
      thyroid carcinomas or multiple endocrine neoplasia (MEN) type 2A and 2B,
      respectively, whereas the dysfunction of RET by germ-line missense and/or
      nonsense mutations causes Hirschsprung's disease. Biological properties of mutant
      RET protein determine the disease phenotype. For example, the MEN 2B mutation
      alters the substrate specificity of RET tyrosine kinase and RET carrying the MEN
      2B mutation hereby induces the different set of genes from that carrying the MEN
      2A mutation. In this review, we describe the current knowledge about the
      molecular mechanism of RET activation in human neuroendocrine tumors as well as
      the physiological roles and signal transduction of RET tyrosine kinase.

PMID- 15013220
TI  - Comprehensive genomics linking between neural development and cancer:
      neuroblastoma as a model.
AB  - Cancer cells are derived from their precursor cells, which normally develop to
      the matured cells to form individual organs. Neuroblastoma, one of the most
      common pediatric solid tumors, originates from possible cancer stem cells derived
      from the neural crest. During the development, neural crest cells segregate into
      several lineages such as sensory, enteric and sympathetic neurons. However, the
      genetic events to cause neuroblastoma occur only in the sympathetic precursor
      cells or cancer stem cells. Furthermore, spontaneous regression of a subset of
      neuroblastoma found in patients under one year of age mimics a developmentally
      programmed neuronal cell death that occurs in normal sympathetic neurons during
      the perinatal period. Thus, the genetic events to cause neuroblastoma may be
      programmed to occur in a lineage-specific as well as developmentally regulated
      manner. In this review, we discuss about the molecular link between neural
      development and the genesis of neuroblastoma based on our comprehensive genomics
      approach.

PMID- 15013222
TI  - Observability in dynamic evolutionary models.
AB  - In the paper observability problems are considered in basic dynamic evolutionary
      models for sexual and asexual populations. Observability means that from the
      (partial) knowledge of certain phenotypic characteristics the whole evolutionary
      process can be uniquely recovered. Sufficient conditions are given to guarantee
      observability for both sexual and asexual populations near an evolutionarily
      stable state.

PMID- 15013221
TI  - The relationship between synonymous codon usage and protein structure in
      Escherichia coli and Homo sapiens.
AB  - The role of silent position in the codon on the protein structure is an
      interesting and yet unclear problem. In this paper, 563 Homo sapiens genes and
      417 Escherichia coli genes coding for proteins with four different folding types
      have been analyzed using variance analysis, a multivariate analysis method newly
      used in codon usage analysis, to find the correlation between amino acid
      composition, synonymous codon, and protein structure in different organisms. It
      has been found that in E. coli, both amino acid compositions in differently
      folded proteins and synonymous codon usage in different gene classes coding for
      differently folded proteins are significantly different. It was also found that
      only amino acid composition is different in different protein classes in H.
      sapiens. There is no universal correlation between synonymous codon usage and
      protein structure in these two different organisms. Further analysis has shown
      that GC content on the second codon position can distinguish coding genes for
      different folded proteins in both organisms.

PMID- 15013223
TI  - The scaling rule for environmental organizing systems in a gravitational field.
AB  - A recent thermodynamics and information study examined the basis of a scaling
      rule for simple living organisms. The present paper examines a scaling rule for
      the relationship between the integrated scaled metabolic energy and the mass of a
      system for a wide range of masses, from animals to the 4He cores of main-sequence
      stars, considering the effect of gravitational energy. The expected specific
      scaled energy for animals and the 4He cores of main-sequence stars is 1600 times
      greater than the specific scaled energy for fundamental living organisms, such as
      unicellular organisms. This difference results from their organization in a
      gravitational field or the lack thereof.

PMID- 15013224
TI  - Molecular solutions for the subset-sum problem on DNA-based supercomputing.
AB  - In this paper our main purpose is to give molecular solutions for the subset-sum
      problem. In order to achieve this, we propose a DNA-based algorithm of an n-bit
      parallel adder and a DNA-based algorithm of an n-bit parallel comparator to
      formally verify our designed molecular solutions for the subset-sum problem.

PMID- 15013225
TI  - Zipf's law in phonograms and Weibull distribution in ideograms: comparison of
      English with Japanese.
AB  - Frequency distribution of word usage in a word sequence generated by capping is
      estimated in terms of the number of "hits" in retrieval of web-pages, to evaluate
      structure of semantics proper not to a particular text but to a language.
      Especially we compare distribution of English sequences with Japanese ones and
      obtain that, for English and Japanese phonogram, frequency of word usage against
      rank follows power-law function with exponent 1 and, for Japanese ideogram, it
      follows stretched exponential (Weibull distribution) function. We also discuss
      that such a difference can result from difference of phonogram based- (English)
      and ideogram-based language (Japanese).

PMID- 15013226
TI  - The circular topology of rhythm in asynchronous random Boolean networks.
AB  - The analysis of previously evolved rhythmic asynchronous random Boolean networks
      [Biosystems 59 (2001) 185] reveals common topological characteristics indicating
      that rhythm originates from a circular functional structure. The rhythm
      generating core of the network has the form of a closed ring which operates as a
      synchronisation substrate by supporting a travelling wave of state change; the
      size of the ring corresponds well with the period of oscillation. The remaining
      nodes in the network are either stationary or follow the activity of the ring
      without feeding back into it so as to form a coherent whole. Rings are typically
      formed early on in the evolutionary search process. Alternatively, long chains of
      nodes are favoured before they close upon themselves to stabilize. Analysis of
      asynchronous networks with de-correlated (non-rhythmic, non-stationary)
      attractors reveals no such common topological characteristics. These results have
      been obtained using statistical analysis and a specifically developed bottom-up
      pruning algorithm. This algorithm works from local interactions to global
      configuration by eliminating redundant links. The suitability of the algorithm
      has been confirmed by both numerical and single lesion analysis. The ring
      topology solution for the generation of rhythm implies that it will be harder to
      evolve rhythmic networks for big sizes and small periods and for bigger number of
      connections per node. These trends are confirmed empirically. Finally, the
      identified mechanisms are utilised to handcraft rhythmic networks of different
      periods showing that a low number of connections suffices for a large variety of
      rhythms. Random asynchronous update forces the evolved solutions to be highly
      robust maintaining their performance in the presence of intrinsic noise. The
      biological implications of such robust designs for molecular clocks are
      discussed.

PMID- 15013227
TI  - Regulation of hippocampal synaptic plasticity by cyclic AMP-dependent protein
      kinases.
AB  - Protein kinases critically regulate synaptic plasticity in the mammalian
      hippocampus. Cyclic-AMP dependent protein kinase (PKA) is a serine-threonine
      kinase that has been strongly implicated in the expression of specific forms of
      long-term potentiation (LTP), long-term depression (LTD), and hippocampal long
      term memory. We review the roles of PKA in activity-dependent forms of
      hippocampal synaptic plasticity by highlighting particular themes that have
      emerged in ongoing research. These include the participation of distinct isoforms
      of PKA in specific types of synaptic plasticity, modification of the PKA
      dependence of LTP by multiple factors such as distinct patterns of imposed
      activity, environmental enrichment, and genetic manipulation of signalling
      molecules, and presynaptic versus postsynaptic mechanisms for PKA-dependent LTP.
      We also discuss many of the substrates that have been implicated as targets for
      PKA's actions in hippocampal synaptic plasticity, including CREB, protein
      phosphatases, and glutamatergic receptors. Future prospects for shedding light on
      the roles of PKA are also described from the perspective of specific aspects of
      synaptic physiology and brain function that are ripe for investigation using
      incisive genetic, cell biological, and electrophysiological approaches.

PMID- 15013228
TI  - Information processing, dimensionality reduction and reinforcement learning in
      the basal ganglia.
AB  - Modeling of the basal ganglia has played a major role in our understanding of
      this elusive group of nuclei. Models of the basal ganglia have undergone
      evolutionary and revolutionary changes over the last 20 years, as new research in
      the fields of anatomy, physiology and biochemistry of these nuclei has yielded
      new information. Early models dealt with a single pathway through the nuclei and
      focused on the nature of the processing performed within it, convergence of
      information versus parallel processing of information. Later, the Albin-DeLong
      "box-and-arrow" model characterized the inter-nuclei interaction as multiple
      pathways while maintaining a simplistic scalar representation of the nuclei
      themselves. This model made a breakthrough by providing key insights into the
      behavior of these nuclei in hypo- and hyper-kinetic movement disorders. The next
      generation of models elaborated the intra-nuclei interactions and focused on the
      role of the basal ganglia in action selection and sequence generation which form
      the most current consensus regarding basal ganglia function in both normal and
      pathological conditions. However, new findings challenge these models and point
      to a different neural network approach to information processing in the basal
      ganglia. Here, we take an in-depth look at the reinforcement driven
      dimensionality reduction (RDDR) model which postulates that the basal ganglia
      compress cortical information according to a reinforcement signal using optimal
      extraction methods. The model provides new insights and experimental predictions
      on the computational capacity of the basal ganglia and their role in health and
      disease.

PMID- 15013230
TI  - Drug, enzyme and peptide delivery using erythrocytes as carriers.
AB  - Erythrocytes are potential biocompatible vectors for different bioactive
      substances, including drugs. These can be used successfully as biological
      carriers of drugs, enzymes and peptides. There are currently diverse methods that
      permit drug encapsulation in erythrocytes with an appropriate yield. The methods
      most commonly employed are based on a high-haematocrit dialysis procedure, mainly
      hypo-osmotic dialysis. Erythrocytes loaded with drugs and other substances allow
      for different release rates to be obtained. Encapsulation in erythrocytes
      significantly changes the pharmacokinetic properties of drugs in both animals and
      humans, enhancing liver and spleen uptake and targeting the reticulo-endothelial
      system (RES). Amongst other applications, erythrocytes have been used for drug
      targeting the RES with aminoglycoside antibiotics; the selective transport to
      certain organs and tissues of certain antineoplastic drugs, such as methotrexate,
      doxorubicine, etoposide, carboplatin, etc.; the encapsulation of angiotensin
      converting enzyme (ACE) inhibitors, systemic corticosteroids, the encapsulation
      of new prodrugs with increased duration of action, etc. Erythrocytes are also
      attractive systems in the sense of their potential ability to deliver proteins
      and therapeutic peptides. Thus, erythrocytes have been used for the transport of
      enzymes destined for the correction of metabolic alterations as l-asparaginase,
      alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (AlDH) among others.
      Erythrocytes have been used successfully as carriers of anti-HIV peptides, such
      as AZT, nucleoside analogues, antisense oligonucleotides, antineoplastic
      peptides, erythropoietin, interleukin 3, etc. Amongst other applications, mention
      may be made of paramagnetic erythrocytes, encapsulation of MRI contrast agents or
      the study of the metabolism of the red cell. Although erythrocytes have been
      applied with different uses in human medicine, their deployment is still very
      limited due to difficulties involving storage, its exposure to contamination and
      the absence of a validated industrial procedure for its preparation.

PMID- 15013229
TI  - Genetically engineered polymers: status and prospects for controlled release.
AB  - Genetic engineering methodology has enabled the synthesis of protein-based
      polymers with precisely controlled structures. Protein-based polymers have well
      defined molecular weights, monomer compositions, sequences and stereochemistries.
      The incorporation of tailor-made motifs at specified locations by recombinant
      techniques allows the formation of hydrogels, sensitivity to environmental
      stimuli, complexation with drugs and nucleic acids, biorecognition and
      biodegradation. Accordingly, a special interest has emerged for the use of
      protein-based polymers for controlled drug and gene delivery, tissue engineering
      and other biomedical applications. This article is a review of genetically
      engineered polymers, their physicochemical characteristics, synthetic strategies
      used to produce them and their biomedical applications with emphasis on
      controlled release.

PMID- 15013231
TI  - Evaluation of novel one-step dry-coated tablets as a platform for delayed-release
      tablets.
AB  - Using a novel one-step dry-coated tablets (OSDRC) manufacturing method, which we
      have recently invented, we evaluated the possibility of its application to
      delayed-release tablets. The manufacturing method for OSDRC is different from
      conventional methods in that dry-coated tablets can be made with only one
      process. One of the major advantages of OSDRC is that we can expect to produce
      tablets, which always contain the core exactly in the center of the whole tablet.
      This characteristic means that the thickness of outer layer is constantly
      uniform, which is difficult to achieve with the conventional dry-coated tablets.
      The effects of different outer layer thicknesses and various compression
      pressures were examined using HPMC to evaluate OSDRC applicability to delayed
      release tablets. We proved that the lag-time can be adjusted only by changing the
      thickness of the outer layer without any arrangement of its ingredients, which is
      quite different from the conventional approach. Further, the lag-time of each
      OSDRC prepared in the 100-200 MPa compression pressure range was almost the same,
      indicating the lag-time of OSDRC under these compression pressures does not vary.
      The release rate of the drug (acetaminophen) from the OSDRC with 0.5 and 1.0 mm
      outer layer thicknesses was almost constant independent of compression pressure.
      On the other hand, the release rate of the OSDRC with a 2.0 mm outer layer
      thickness was delayed compared to that of other thicknesses. That is, in the
      tablets with 2.0 mm outer layer thickness, the release rate declined since its
      outer layer thickness was sufficient to form a gel-layer. In conclusion, OSDRC
      could be a platform for delayed-release tablets, which do not utilize the
      conventional method used for dry-coated tablets.

PMID- 15013232
TI  - Drug release properties of a gel bead prepared with pectin and hydrolysate.
AB  - A calcium-induced pectin gel bead (PB) containing pectin hydrolysate was
      prepared, and the drug release profiles and degradation properties of the PB were
      investigated in aqueous media. The stiff PB swelled in physiological saline and
      its drug release rate decreased with exposure to increasing concentrations of
      CaCl2 during preparation. And erosion of the PB was not observed in physiological
      saline. However, the PB did disintegrate in phosphate buffer (pH 6.8) and the
      rate of disintegration depended on the calcium chloride concentration used to
      prepare the PB. In addition, the drug release rate of the PB in buffer solution
      decreased as the rate of gel erosion declined. Consequently, it appears that the
      PB gel matrix is an effective medium by which to control the release of drug
      within the gastrointestinal tract.

PMID- 15013233
TI  - New vesicular ampicillin-loaded delivery systems for topical application:
      characterization, in vitro permeation experiments and antimicrobial activity.
AB  - In this paper, the experimental conditions for preparing ampicillin-loaded
      surfactant vesicles (SVs) are described. Our studies are focused on the potential
      use of a vesicular polymeric dispersion as ampicillin delivery system for topical
      application. The main components of the formulation are uncharged and charged SVs
      loaded with ampicillin and dispersed in a gellan solution. The following issues
      are addressed: the drug encapsulation efficiency (e.e.), the kinetic of drug
      release from the delivery systems, the antimicrobial activity of vesicle
      entrapped ampicillin. The in vitro permeation experiments through a synthetic
      lipophilic barrier (Silastic) and through porcine skin are carried out to
      evaluate the potential use as a dermal formulation. The use of both a synthetic
      and a biological membrane allows to discriminate between the effects related to
      variations of thermodynamic parameters and those correlated to biological
      factors. The release rate of ampicillin is increased by encapsulation in neutral
      and negatively charged SVs and the permeation rate was slowed by dispersion of
      drug-loaded SVs in gellan solution. Finally, studies of antimicrobial activity on
      prepared systems evidenced that ampicillin encapsulated in SVs exhibit a higher
      activity than the free drug.

PMID- 15013234
TI  - Comparative study of morphine diffusion from sustained release polymeric
      suspensions.
AB  - In recent years, great efforts have been devoted to the design of drug delivery
      systems. Many polymeric excipients have been studied in order to make drug
      release fit the desired profiles. The aim of this work was to design a morphine
      oral suspension, as sustained release pharmaceutical formulations. To this end,
      two different ethylcellulose suspensions were prepared: one with the drug
      incorporated during synthesis (suspension A) so that the drug was inside the
      polymeric microparticles. In the second group of suspensions the drug was
      incorporated after synthesis (suspension B), thus resulting in the drug being
      adsorbed on the surface. The analytical technique used, spectrophotometry, showed
      that suspensions A were able to spontaneously encapsulate approximately 92% of
      the drug, whereas suspensions B adsorbed only 15% dose on the particle surface.
      Moreover, the diffusion results obtained with Franz-cells showed that suspensions
      A offered the possibility of easy control of the release rate of the active
      substance. This system transfers morphine hydrocloride during 24 h in accordance
      with a Weibull kinetic model. This dosage form presents the clinical advantage of
      less frequent dosing, with increased quality of life for patients. This report
      documents the suitability of our ethylcellulose polymeric suspension for
      encapsulated morphine with a controlled release rate.

PMID- 15013236
TI  - Prolonged circulation of menatetrenone by emulsions with hydrogenated castor oils
      in rats.
AB  - Previously, we reported that plasma half-lives of a drug incorporated in lipid
      emulsions prepared with soybean oil (SO), a long-chain triglyceride, and
      hydrogenated castor oils (HCOs) (SO/HCOs) were markedly longer, while those as
      SO/polyoxyethylene sorbitan esters (SO/PSs) were similar, compared to that as
      SO/egg yolk phosphatides (SO/EYP) [J. Pharm. Pharmacol. 54 (2002) 1357; J. Drug
      Target. 11 (2003) 37]. In the present study, lipid emulsions were prepared with
      Miglyol 812 (MO), a medium-chain triglyceride, and HCOs, and the kinetics of the
      incorporated drug, menatetrenone, were examined. The plasma half-lives and the
      liver uptake of menatetrenone as MO/polyoxyethylene-(10)-hydrogenated castor oils
      (MO/HCO10s) were similar to and larger than those as MO/EYP, respectively. On the
      other hand, the plasma half-lives and liver uptake of menatetrenone as
      MO/polyoxyethylene-(20)-hydrogenated castor oils (MO/HCO20s) or
      MO/polyoxyethylene-(60)-hydrogenated castor oils (MO/HCO60s) were markedly longer
      and lower than those as MO/EYP, respectively. The pretreatment of dextran sulfate
      500,000, a reticuloendothelial system suppressor, raised the plasma concentration
      and inhibited liver uptake of menatetrenone as MO/HCO10, but not for MO/HCO20.
      These findings suggest that the minimum number of oxyethylene units within HCOs
      for the prolonged plasma circulation of menatetrenone was 20 for MO/HCOs,
      similarly to SO/HCOs.

PMID- 15013237
TI  - Effects of different cellulose derivatives on drug release mechanism studied at a
      preformulation stage.
AB  - As a matter of fact, in vitro dissolution is well known to be the method of
      choice for the pharmaceutical industry to develop effective medicines. However,
      many experiments must be performed all along a new product life and they
      represent an overcharge of work for researchers. The purpose of this paper was to
      assess the relevance of new parameters obtained during preformulation stage by
      Nuclear Magnetic Resonance (NMR) experiments to better understand drug release
      mechanism. This study was carried out with three cellulose derivatives currently
      used as carrier matrices (Microcrystalline cellulose (MCC), Hydroxypropylmethyl
      cellulose (HPMC) and Ethyl cellulose (EC)). Granules and tablets were produced
      with these three excipients (60% w/w) and theophylline as drug model (40%). On
      the one hand, in vitro dissolution studies were performed with the rotating
      paddle method displaying the different release behaviour of these three matrices
      (immediate release for MCC, steady release for HPMC and sustained release for
      EC). On the other hand, the evolution of the T2m spin-spin relaxation time in NMR
      experiments during granules hydration was recorded. NMR findings shore up
      dissolution data, both depending on interactions between the matrix and water.
      NMR spectroscopy appears to be a valuable tool for obtaining, at an earlier stage
      of drug development, more information about drug release mechanism.

PMID- 15013235
TI  - Polymer-conjugated bovine pancreatic and seminal ribonucleases inhibit growth of
      human tumors in nude mice.
AB  - The hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) was used for
      RNase A or BS-RNase modification to prevent their degradation in bloodstream or
      fast elimination. Two PHPMA chains (classic and star-like) were synthesized and
      their conjugates with both enzymes were tested on the CD-1 nude mice bearing
      various human tumors. These RNase conjugates injected intravenously or
      intraperitoneally into the mice bearing melanoma, neuroblastoma or ovarian tumor
      caused significant reduction of transplanted tumors following ten daily doses of
      2.5 and/or 1 mg/kg, respectively, while free RNase A or BS-RNase injected in
      doses of 10 mg/kg exerted only negligible antitumor activity. Histological
      examination confirmed potent cytotoxic effect of RNase A conjugates in ovarian
      tumor. Despite the antitumor activity observed in vivo, the in vitro cytotoxic
      activity of RNase A conjugates was not pronounced and did not differ from that
      caused by the free RNase A. The in vitro experiments with 125I-labeled
      preparations demonstrated that polymer conjugates were internalized by tumor
      cells very poorly in contrast to the dose-dependent internalization of the wild
      enzyme preparation. Surprisingly, mice injected with EL-4 leukemic cells, which
      were preincubated for 4 h with BS-RNase conjugates, exerted significantly
      prolonged survival compared with the control non-treated mice. It may be supposed
      that both BS-RNase and RNase A conjugates with PHPMA act after administration in
      vivo by a mechanism different from that or those occurring under in vitro
      conditions because in vivo they exert an antitumor action, whereas in vitro, they
      are ineffective. The experiments proved that RNase A, when conjugated to PHPMA,
      produced identical aspermatogenic and antitumor effects as BS-RNase conjugated to
      this polymer and that this preparation may be regarded as a potential anticancer
      drug.

PMID- 15013238
TI  - Theoretical analysis of the release of slowly dissolving drugs from spherical
      matrix systems.
AB  - Drug release from spherical matrix systems has been investigated theoretically,
      with numerical as well as analytical methods. The model used combines the Noyes
      Whitney and diffusion equations, and thus takes the effects of a finite
      dissolution rate into account. The release profile has been determined
      numerically, by using well-established FORTRAN routines. An approximate
      analytical formula for the amount of released drug has been derived, which is
      valid during the early stages of the release process. This analytical short-time
      approximation was compared to the numerical result, and to drug release models
      existing in the literature. From this comparison it was concluded that the
      analytical approximation provided a good description of the major part of the
      release profile, irrespective of the dissolution rate. Existing literature
      models, based on instantaneous dissolution, provided a good description of the
      release only when drug dissolution proceeded very rapidly in comparison with the
      diffusion process. Consequently, the new analytical short-time approximation
      complements the formulas existing in the literature, since it provides a superior
      description of the release of slowly dissolving drugs.

PMID- 15013240
TI  - Hepatocyte targeting of 111In-labeled oligo-DNA with avidin or avidin-dendrimer
      complex.
AB  - To establish an effective nonviral gene transfer vector to hepatocytes, various
      oligo-carrier complexes were developed employing dendrimer (G4) and avidin-biotin
      systems (Av-bt), and their biodistribution were evaluated. In-111-labeled-oligo,
      without any carriers, showed low uptake in normal organs other than the kidney
      (21.48% ID/g at 15 min, 18.48% ID/g at 60 min). In contrast, 111In-oligo coupled
      with avidin through biotin (111In-oligo-bt-Av) showed very high accumulation in
      the liver (50.95% at 15 min, 47.88% at 60 min). 111In-oligo complexed with G4
      showed high uptake in the kidney and spleen, but its hepatic uptake was
      relatively low (13.12% at 15 min, 10.67% at 60 min). When both G4 and Av-bt
      systems were employed, 111In-oligo/G4-bt-Av showed extremely high uptake in the
      lung (182.33% at 15 min, 125.54% at 60 min), probably due to the formation of
      large molecular weight complex and aggregates which are trapped in the lung, and
      its hepatic uptake was lower than 111In-oligo-bt-Av. 111In-oligo-bt-Av, which
      exhibited the highest hepatic uptake in vivo, also showed high and rapid
      internalization into hepatocytes. The avidin-biotin system seems to have
      potential as a carrier of oligo-DNA to the liver.

PMID- 15013239
TI  - Stabilization of oligonucleotide-polyethylenimine complexes by freeze-drying:
      physicochemical and biological characterization.
AB  - In the present study the lyophilization of oligodeoxynucleotide-polyethylenimine
      (ODN-PEI) complexes was investigated regarding the maintenance of physicochemical
      properties and influence on biological activity. To achieve this, we used PEI of
      different molecular weights, in the range of 800-0.8 kDa, as complexing agents
      for unmodified ODN and ribozymes. The hydrodynamic diameter was measured by
      photon correlation spectroscopy (PCS) and the zeta potential was determined using
      laser Doppler anemometry (LDA) of ODN complexes with PEI derivatives of different
      molecular weights both before and after lyophilization. Atomic force microscopy
      (AFM) was used to visualize freshly prepared, stored and lyophilized complexes in
      solution. The biological activity of the ODN, as well as of plasmid DNA, in
      lyophilized PEI complexes was examined and compared to freshly prepared complexes
      using standard transfection assays. All PEI derivatives formed very small
      complexes with ODN displaying hydrodynamic diameters ranging from 15 to 30 nm.
      Marginal changes in size after lyophilization were observed for ODN-PEI
      complexes. In contrast, plasmid complexed with PEI was found to aggregate. In
      either cases minimal or no influence of the added amount of lyoprotectant was
      observed. The shape of the very small and highly condensed ODN complexes was not
      altered by lyophilization as seen in the AFM images. The transfection efficiency
      of lyophilized ribozyme-PEI complexes relative to freshly prepared complexes was
      approximately 100%, whereas a decrease was seen for lyophilized plasmid-PEI
      complexes. An additive of the lyoprotectants trehalose, mannitol or sucrose
      preserved biological activity. This study demonstrates the particular suitability
      of ODN-PEI complexes to be formulated as lyophilized systems with no loss in
      physical stability or biological activity.

PMID- 15013241
TI  - Obsessive-compulsive bipolar comorbidity: focus on children and adolescents.
AB  - BACKGROUND: Growing evidence documents the frequent co-morbidity between
      Obsessive Compulsive Disorder (OCD) and Bipolar Disorder (BP) in adults. The aim
      of the present study is to explore some clinical aspects of this interface in
      children and adolescents, as it appears in a setting of routine clinical
      practice. METHOD: The sample comprised 102 consecutively referred children and
      adolescents, both inpatients and outpatients, with BP, OCD or co-morbid BP-OCD
      during a 3-year period. The mean age was 14.2 (SD=3.2); 65 (63.7%) were males.
      Diagnoses and clinical features were collected by means of structured interview
      according to DSM-IV (DICA-R) and a rating scale for OCD (CY-BOCS). Clinical
      outcome was evaluated prospectively by means of clinical global impression (CGI)
      as part of routine clinical care, throughout the follow-up. RESULTS: Thirty-seven
      (36.3%) patients (21 males and 16 females) were diagnosed as BP, 35 (34.3%)
      patients (26 males and 9 females) were diagnosed as OCD and 30 (29.4%) patients
      (18 males and 12 females) were diagnosed as BP-OCD. BP II, was more frequent in
      the BP-OCD than in BP. When OCD was co-morbid with BP, age of onset was
      significantly earlier than in the 'pure' OCD patients. On the contrary, age of
      onset of BP was not affected by co-morbid OCD. According to CGI baseline scores,
      OCD patients were significantly less impaired than BP-OCD and BP patients, while
      the severity of the symptomatology was similar in the last two groups. Severity
      scores at the end of the follow-up were significantly higher in BP-OCD patients
      than in OCD patients. Patients with pure BP showed lower rates of panic disorder
      agoraphobia than BP-OCD patients and higher rates of ADHD-conduct disorder. Pure
      OCD patients showed lower rates of ADHD and higher rates of Generalized Anxiety
      Disorder. The number of obsessions did not differentiate the two groups, whereas
      pure OCD patients showed significantly more compulsions. 'Other' obsessions-e.g.,
      existential, philosophical, odd and/or superstitious-were significantly more
      frequent in BP-OCD than in pure OCD patients. Ordering compulsions were
      significantly more frequent in pure OCD patients. LIMITATIONS: Possible low
      reliability of children's and their parents' recall of past episodes of mental
      disorder. CONCLUSIONS: In a tertiary care center, co-morbidity between OCD and BP
      is a significant clinical problem affecting a large number of patients. The
      correct identification of OCD-bipolar co-morbidity has relevant clinical
      implications as far as other concomitant disorders, symptomatological features,
      course, complications, and treatment management and outcome are concerned.

PMID- 15013242
TI  - Mood swings in patients with anxiety disorders compared with normal controls.
AB  - BACKGROUND: About 70-80% of patients with anxiety syndromes suffer from
      depression. Mood variability including hypomania, cyclothymia and hyperthymia
      have been described in 40-50% of patients with depression. There is an emerging
      literature that such variability could also characterize anxiety disorders. The
      aim of this study was to visually document and quantify mood variability in
      patients with anxiety disorders. METHODS: Twenty patients with anxiety disorders
      and 22 normal control subjects completed two visual analogue scales (VAS) on
      depressed mood and high mood, twice per day for 14 days. The Beck Depression
      Inventory and the Altman Self-Rating Mood Scale were used for concurrent
      validity. RESULTS: On the VAS, patients showed higher levels of depressed and
      high moods, and greater mood variability than the controls. Variability of
      depressed and high moods was highly correlated. LIMITATIONS: This was a
      relatively small sample from a single center. Patients were selected by
      convenience and were under treatment. The control subjects were not interviewed.
      CONCLUSIONS: Subsyndromal mood variability in patients with anxiety disorders can
      be visually depicted and quantified. The mood variability of patients with
      anxiety disorders who also complain of mood swings is greater than the mood
      fluctuations described by normal subjects.

PMID- 15013243
TI  - Prevalence, correlates and recognition of depression in the oldest old: the
      Leiden 85-plus study.
AB  - BACKGROUND: Various studies support the notion that the clinical picture of
      depression in the oldest old differs from that in younger elderly. Moreover,
      withstanding the serious negative effects of depression on well being and
      functioning, the detection rate of depression in several medical settings is low.
      METHODS: Prevalence of depression, correlates and the rate of recognition by
      general practitioners were assessed in an 85-year-old community-based population.
      The GDS-S was applied in 500 participants with a MMSE >18, from a representative
      sample of 599 community based 85-year-old subjects. Demographic data, daily
      functioning, health correlates, use of medication and recognition of depression
      were recorded in home visits and from the general practitioner and pharmacists
      registers. RESULTS: The prevalence of depression, as measured with a GDS-S score
      of 5 points or more, was 15.4%, which is comparable to previous studies. No
      demographic factors were correlated with depression. Perceived health,
      loneliness, impaired mobility, cognitive decline and functional disability were
      major correlates of depression. From the participants who were seen by their
      general practitioner, 25% were recognised as depressed. Antidepressive
      pharmacotherapy was almost nonexistent. LIMITATIONS: Formal diagnosis of
      depression was not available. The data were collected cross-sectionally.
      CONCLUSIONS: Depression is highly prevalent in the oldest old and strongly
      associated with functional disability and cognitive impairment. It is important
      to enhance recognition of depression in community based oldest old as a first
      step to possible interventions.

PMID- 15013244
TI  - Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis.
AB  - BACKGROUND: Clonazepam and lorazepam are used in the treatment of acute mania but
      trial results are conflicting. METHODS: Studies were identified by searching
      MEDLINE and EMBASE for lorazepam or clonazepam in acute mania between 1966 and
      2000. Seven randomized controlled trials were found comparing clonazepam or
      lorazepam to placebo, haloperidol or lithium in acute mania. Data on 206 patients
      were analyzed. RESULTS: The heterogeneity of trial designs and the use of
      different comparators necessitated a Bayesian hierarchical meta-analysis with
      three models: (a) random trial effect and fixed treatment effects, (b) random
      trial and treatment effects, (c) random trial and treatment effects with trial
      variance unknown. With all models, clonazepam decreased psychopathology scores
      statistically significantly with the following standardized responses: model (a):
      1.26 (95% predictive interval (PI) 0.33 to 2.28), model (b): 1.21 (95% PI 0.08 to
      2.53), model (c): 1.41 (95% PI 0.12 to 2.67). Lorazepam did not yield
      statistically significant standardized responses for any of the three models:
      model (a): 0.79 (95% PI -0.29 to 1.89), model (b): 0.77 (95% PI -0.57 to 2.24)
      and model (c): 0.74 (-0.82 to 2.20). Haloperidol yielded statistically
      significant standardized responses in the three models but lithium effect was
      statistically significant only in model (a). Safety data were in line with the
      usual safety profile of benzodiazepines. LIMITATIONS: Trial designs were
      heterogenous and patient number was limited. CONCLUSIONS: This meta-analysis
      suggests that clonazepam is efficient and safe in the treatment of acute mania,
      but the results remain inconclusive for lorazepam.

PMID- 15013245
TI  - Suicide risk in patients hospitalised because of an affective disorder: a follow
      up study, 1973-1993.
AB  - The aim of this study was to identify risk factors for suicide related to the
      course of treatment. METHODS: All persons in Denmark hospitalised for the first
      time because of an affective disorder during the period 1973-1993 were included.
      RESULTS: In 53466 patients, suicide was the cause of death in 3141 (6%) cases.
      The risk of suicide was high both immediately after admission and immediately
      following discharge. Increased risk was also associated with short duration of
      affective disorder, a history of multiple admissions, male gender, and increasing
      age. LIMITATIONS: We were not able to distinguish with certainty between manic
      and depressive episodes in bipolar disorder. Prior suicide attempts could not be
      included in the analyses. Lack of operationalised diagnostic criteria.
      CONCLUSIONS: Patients hospitalised because of an affective disorder are a highly
      relevant target group for suicide prevention. There is a need for improvement of
      preventive measures during admission and at discharge. Likewise, there is a need
      for preventive measures which can minimize the risk of relapse in affective
      disorders.

PMID- 15013247
TI  - Blood-injury related phobic avoidance as predictor of nonresponse to
      pharmacotherapy in panic disorder with agoraphobia.
AB  - BACKGROUND: Several factors have been investigated as possible predictors of
      nonresponse to pharmacotherapy in Panic Disorder (PD) patients. In 1995 a study
      was published by Slaap et al. in this journal that found high Blood-Injury phobia
      scores on the Marks and Matthews Fear Questionnaire were predictive for a worse
      treatment-outcome for drug treatment in PD. METHODS: The present paper describes
      a replication study with 61 PD patients, by means of a retrospective chart
      analysis, who were assessed at baseline and after 12 weeks of SSRI-treatment.
      Nonresponse was defined as still having panic attacks. Response was defined as
      absence of panic attacks and/or a reduction of at least 50% on the FQ Agoraphobia
      subscale. RESULTS: Twenty (32%) patients were nonresponders. Nonresponders had a
      higher score on the FQ Blood-Injury subscale more often (55%) than responders
      (19.5%), significant at P=0.008. These results fully support the findings of
      Slaap et al. Implications of these findings are further discussed. LIMITATIONS:
      Limitations of this study are the retrospective design, and the absence of other
      psycho-physiological parameters of the specific blood-injury phobic complex.
      CONCLUSIONS: However, it is tentatively concluded that the presence of comorbid
      blood-injury related phobic symptoms negatively affects treatment for panic
      disorder and agoraphobia.

PMID- 15013246
TI  - Prevalence of seasonal affective disorder in primary care; a comparison of the
      seasonal health questionnaire and the seasonal pattern assessment questionnaire.
AB  - BACKGROUND: Prevalence rates of SAD suggested by previous studies have ranged
      from 1 to 12% depending on the diagnostic criteria used. The Seasonal Pattern
      Assessment Questionnaire (SPAQ), a widely used screening tool, has been shown to
      have low specificity for SAD. The Seasonal Health Questionnaire (SHQ) was
      designed to better reflect the clinical criteria for SAD and has been shown to
      have a higher specificity then the SPAQ in a psychiatric outpatient setting.
      OBJECTIVE: The current study was designed to assess the validity of the SHQ in
      general practice against systematic research interviews, to compare the
      sensitivity, specificity and positive predictive values of the SHQ and the SPAQ
      and to use these data to estimate the prevalence of SAD in primary care. METHODS:
      809 subjects in a consecutive series of patients attending Southampton general
      practices in winter 2000/01 completed the SHQ followed by the SPAQ; 56 were
      interviewed using the Structured Clinical Interview for DSM (SCID). RESULTS: The
      SHQ was more sensitive and specific than the SPAQ and had higher positive and
      negative predictive values in screening for SAD. The SPAQ indicated a prevalence
      of SAD of 10.7% (95% CI 8.6-13.1) while the SHQ provided a significantly lower
      estimate of 5.6% (95% CI 4.2-7.4).

PMID- 15013248
TI  - Assessing the effects of bupropion SR on mood dimensions of depression.
AB  - BACKGROUND: We assessed the therapeutic effects of bupropion SR and placebo on
      mood and anxiety symptoms derived from the tripartite model of mood. Based on
      evidence indicating linkages between dopaminergic activity and the emotional
      dimension of positive affect/anhedonia, we hypothesized that the dopaminergic
      effects of bupropion SR would yield particularly pronounced effects on symptoms
      of anhedonia, relative to anxiety. METHODS: Nineteen depressed outpatients were
      randomly assigned to treatment with either bupropion SR 300 mg/day or placebo
      during a 6-week initial treatment phase. This was followed by a second open-label
      phase in which patients previously treated with bupropion SR had their dose
      increased to 400 mg/day, and the placebo group was initiated on bupropion SR 300
      mg/day. RESULTS: Random regression analyses revealed that during the initial
      double-blind phase, bupropion SR elicited greater declines than placebo on all
      measures except those that assessed anxiety. By contrast, the weakest placebo
      effects were evident on anhedonia. Items assessing the low positive affect pole
      of the anhedonia dimension were more sensitive to earlier/lower dose bupropion SR
      treatment, whereas items assessing the high positive affect pole were more
      sensitive to later/higher dose bupropion SR treatment. LIMITATIONS: Replication
      and extension using a larger sample size are mandated. CONCLUSIONS: This study
      suggests that the catecholaminergic effects of bupropion SR tended to produce
      more robust effects on anhedonia/positive affect than placebo.

PMID- 15013249
TI  - Monocytic parameters in patients with dysthymia versus major depression.
AB  - BACKGROUND: The studies on monocytic function during depression are
      controversial. A better knowledge of affective disorders may improve the
      differential diagnosis of depression subtypes. Our goals are to examine if there
      are differences in monocytic function in patients with major depression and
      dysthymia. METHOD: Twenty-two depressed patients (12 dysthymia and 10 major
      depression) and 15 healthy controls participated in the study. We analyzed
      monocyte count, monocyte subsets (CD14+, CD16+, and HLA class-II+), respiratory
      burst activity, phagocytic index and the interleukin (IL)-1beta, IL-6 and tumor
      necrosis factor (TNFalpha) production. RESULTS: Depressed patients showed
      elevated IL-1beta (P<0.05) and IL-6 (P<0.01), elevated monocytic respiratory
      burst activity (P<0.01); and reduced surface molecule expression HLA class-II and
      phagocytosis (P<0.01) compared with controls. We found no differences in any
      monocytic parameters between dysthymia and major depression. LIMITATIONS: The
      small sample size and the short wash-out reduce the reliability of the results.
      CONCLUSIONS: Major depression and dysthymia show similar signs of both monocytic
      activation and suppression. These alterations may be due to the depressive
      syndrome and not to the characteristics of depression subtypes studied.

PMID- 15013250
TI  - Timing of depression recurrence in the first year after birth.
AB  - BACKGROUND: Women who have suffered from one episode of postpartum-onset major
      depression (PPMD) experience increased risk for recurrence in the year following
      another birth. METHODS: Non-depressed women (N=51) who had at least one past
      episode of PPMD were recruited during pregnancy. After birth, subjects were
      assessed prospectively each week for 20 weeks with the Hamilton Rating Scale for
      Depression and Research Diagnostic Criteria for recurrence of major depression.
      Evaluations were carried out at 24, 36, and 52 weeks to assess for episodes
      beyond 20 weeks postpartum. RESULTS: The data revealed a clustering of cases,
      with five of the 21 recurrences (24%) occurring in the first 2 weeks. Thirteen of
      the 21 recurrences (67%) and 19/21 recurrences (90%) occurred in the first 20 and
      28 weeks following birth, respectively. LIMITATIONS: Although it is unusual for
      studies of this type to be prospective, the sample size is relatively small.
      CONCLUSIONS: The 1-year recurrence rate was 21/51 or 41%, with a clustering of
      cases near delivery. All recurrences except two occurred by 28 weeks postpartum.

PMID- 15013251
TI  - Treatment of bipolar mania with right prefrontal rapid transcranial magnetic
      stimulation.
AB  - BACKGROUND: Transcranial magnetic stimulation (TMS) has been suggested for the
      treatment of a variety of CNS disorders including depression and mania. METHODS:
      Nine bipolar (I) in-patients diagnosed with mania were treated with right
      prefrontal rapid TMS in an open and prospective study. Eight of nine patients
      received TMS as add-on treatment to an insufficient or only partially effective
      drug therapy. RESULTS: During the 4 weeks of TMS treatment a sustained reduction
      of manic symptoms as measured by the Bech-Rafaelsen mania scale (BRMAS) was
      observed in all patients. LIMITATIONS: Due to the open and add-on design of the
      study, a clear causal relationship between TMS treatment and reduction of manic
      symptoms cannot be established. CONCLUSIONS: Our data suggest that right
      prefrontal rapid TMS is safe and efficacious in the add-on treatment of bipolar
      mania showing laterality opposed to the proposed effect of rapid TMS in
      depression.

PMID- 15013253
TI  - Calculating clinically significant change in postnatal depression studies using
      the Edinburgh Postnatal Depression Scale.
AB  - BACKGROUND: Statistical significance between test scores can sometimes be
      obtained even when the actual difference between the scores is very small.
      Because of this researchers have recommended that clinical significance also be
      calculated when reporting results of interventions. The calculation of clinical
      significance between scores on a particular test takes into account the
      reliability of the test, as well as normative data from clinical and non-clinical
      samples. Jacobson and Truax (1991) describe the calculation of the Reliable
      Change Index (RCI) as a method of calculating this clinical significance. RESULT:
      The RCI for the Edinburgh Postnatal Depression Scale (EPDS) is calculated to be
      four points. This is the size of difference between two scores which is needed
      for a clinician to be 95% confident that this change reflects a real change in
      the individual's mood, and is not likely to be due to measurement error. Using
      the accepted EPDS cut-off score of 12/13 for major depression (English-speaking
      women), examples are given of the clinical significance classification of
      individual's pre-post EPDS scores. A further example of reporting both
      statistical significance and clinical significance on the EPDS scores of 23 women
      is given, highlighting the improved information that is obtained when this
      clinical significance is calculated. CLINICAL IMPLICATIONS: Statistical
      significance allows the interpretation of whether women 'on average' improve more
      in one condition than another. Clinical significance allows the further
      interpretation of how many women show improvement in each condition. This
      improvement can be categorised into those who recover, those who improve but are
      still in the distressed range, those who show no reliable change in their EPDS
      score, and those who deteriorate. Calculating clinical significance, using the
      reliable change index and cut-off classification, therefore adds to our
      understanding of the impact of postnatal depression treatment studies.

PMID- 15013254
TI  - Interleukin-1beta and tumor necrosis factor-alpha in children with major
      depressive disorder or dysthymia.
AB  - BACKGROUND: Immune function is altered in adult depressed patients. The aim of
      our study was to see whether or not cytokine secretion is impaired at a very
      young phase of development of depressive disorders, possibly being
      pathogenetically involved in their course. METHODS: Basal plasma concentrations
      of interleukin-1beta (Il-1beta) and tumor necrosis factor-alpha (TNF-alpha) were
      measured radioimmunologically in 22 drug-free children-adolescents, 11 with
      recurrent major depressive disorders (MDD) and 11 with dysthymia (DYS), and in 11
      psychophysically healthy age-sex matched controls. Depression was monitored using
      the Poznanski Rating Scale and Anxiety with the Reynold Rating Scale. RESULTS: Il
      1beta levels were not significantly different in MDD from controls and
      significantly higher than normal in DYS subjects. TNF-alpha levels were not
      significantly different in MDD patients from controls and significantly lower
      than normal in DYS patients. Cytokine concentrations were correlated with anxious
      and depressive symptomatology in MDD but not in DYS patients. CONCLUSIONS: There
      is a cytokine pathology in depressive disorders of obscure etiopathogenetical
      significance.

PMID- 15013252
TI  - Late onset dysthymic disorder and major depression differ from early onset
      dysthymic disorder and major depression in elderly outpatients.
AB  - BACKGROUND: Age of onset may affect clinical features and prognosis in elderly
      patients with major depression (MDD), but there is a lack of such data in elderly
      patients with dysthymic disorder (DD) and systematic comparisons of late onset
      MDD and DD have not been conducted. METHODS: In a Late Life Depression Clinic,
      patients > or = 60 years old who met DSM-III-R or DSM-IV criteria for MDD or DD
      were studied. The 24-item Hamilton Rating Scale for Depression (HRSD) and SCID-P
      were completed, family history was obtained, and medical illnesses were assessed.
      RESULTS: In the total sample (n=370; 211 MDD and 159 DD), compared to early onset
      patients, late onset (onset > or =60 years) patients had a higher rate of
      cardiovascular disease (chi(2)=4.12, df=1, P<0.05), lower rate of anxiety
      disorder (chi(2)=4.19, df=1, P<0.05), and a lower rate of family history of
      affective disorder (chi(2)=9.37, df=1, P<0.002). Late onset DD patients were more
      likely to have cardiovascular disease than early onset DD patients (chi(2)=5.63,
      df=1, P<0.02), but the rate of cardiovascular disease did not differ between late
      and early onset MDD patients (chi(2)=0.35, df=1, P<0.6). Late onset MDD patients
      were less likely to have a family history of affective disorder than early onset
      MDD patients (chi(2)=10.71, df=1, P<0.001). Prevalence of anxiety disorders did
      not differ between the early and late onset MDD patients (chi(2)=0.07, df=1,
      P<0.79), but was more common in the early onset DD compared to the late onset DD
      patients (17.98% versus 4.29%, chi(2)=6.98, df=1, P<0.01). Late onset DD did not
      differ from late onset MDD in the rates of cardiovascular disease, anxiety
      disorders, and family history of affective disorder. Excluding patients with
      double depression (n=32) did not alter the cardiovascular or family history
      findings, but the difference in anxiety disorders between early and late onset DD
      patients was no longer significant. LIMITATIONS: Academic clinic sample results
      may not generalize to community populations. CONCLUSIONS: In the elderly, late
      onset DD is typically different from early onset DD. Cerebrovascular disease
      appears to play a role in the etiology of late onset DD. The similarities between
      late onset DD and late onset MDD suggest a single condition along a continuum.

PMID- 15013255
TI  - Associations of the severity of depressive disorders in women with psychogenic
      low weight.
AB  - BACKGROUND: Depressive disorders are common in patients with anorexia nervosa
      (AN). Although depression with AN has been considered to be mainly secondary to
      the features of AN, other characteristics of such patients may also be causal, as
      personality disorders (PDs) often occur with AN and there are indications that
      PDs are causal factors for some depressive disorders. This study examined
      associations of the severity of depressive disorders in patients with low weight
      and a history of full or partial AN, to determine which characteristics of
      patients with AN are candidates as causal factors for depression in this context.
      METHODS: 66 patients of a psychiatric 'low-weight' clinic completed self-report
      questionnaires. These patients presented with a mean body mass index (BMI) of
      17.0 (S.D. 1.4) and their mean lowest BMI after the age of 16 had been 15.2 (S.D.
      1.3). RESULTS: Beck Depression Inventory (BDI) ratings were significantly
      associated with a range of eating disorder features (including age at
      presentation but not BMI) and with characteristics of a range of DSM-III-R PDs.
      LIMITATIONS: BDI ratings do not reflect clinical heterogeneity of depressive
      disorders, while self-report data for PD psychopathology can be subject to
      confounding variables. CONCLUSIONS: The results suggest that, first, features of
      AN (but not the degree of weight loss), and, second, psychopathology related to
      some features of all three DSM-III-R PD clusters may have causal roles in
      relation to depressive disorders in patients with AN and its variants. The
      findings indicate the need to consider a range of features of PDs in the
      management of patients with depression and AN.

PMID- 15013258
TI  - Violence exposure in real-life, video games, television, movies, and the
      internet: is there desensitization?
AB  - It is believed that repeated exposure to real-life and to entertainment violence
      may alter cognitive, affective, and behavioral processes, possibly leading to
      desensitization. The goal of the present study was to determine if there are
      relationships between real-life and media violence exposure and desensitization
      as reflected in related characteristics. One hundred fifty fourth and fifth
      graders completed measures of real-life violence exposure, media violence
      exposure, empathy, and attitudes towards violence. Regression analyses indicated
      that only exposure to video game violence was associated with (lower) empathy.
      Both video game and movie violence exposure were associated with stronger
      proviolence attitudes. The active nature of playing video games, intense
      engagement, and the tendency to be translated into fantasy play may explain
      negative impact, though causality was not investigated in the present design. The
      samples' relatively low exposure to real-life violence may have limited the
      identification of relationships. Although difficult to quantify, desensitization
      to violence should be further studied using related characteristics as in the
      present study. Individual differences and causal relationships should also be
      examined.

PMID- 15013257
TI  - The effects of violent video game habits on adolescent hostility, aggressive
      behaviors, and school performance.
AB  - Video games have become one of the favorite activities of American children. A
      growing body of research is linking violent video game play to aggressive
      cognitions, attitudes, and behaviors. The first goal of this study was to
      document the video games habits of adolescents and the level of parental
      monitoring of adolescent video game use. The second goal was to examine
      associations among violent video game exposure, hostility, arguments with
      teachers, school grades, and physical fights. In addition, path analyses were
      conducted to test mediational pathways from video game habits to outcomes. Six
      hundred and seven 8th- and 9th-grade students from four schools participated.
      Adolescents who expose themselves to greater amounts of video game violence were
      more hostile, reported getting into arguments with teachers more frequently, were
      more likely to be involved in physical fights, and performed more poorly in
      school. Mediational pathways were found such that hostility mediated the
      relationship between violent video game exposure and outcomes. Results are
      interpreted within and support the framework of the General Aggression Model.

PMID- 15013259
TI  - Exposure to violent video games increases automatic aggressiveness.
AB  - The effects of exposure to violent video games on automatic associations with the
      self were investigated in a sample of 121 students. Playing the violent video
      game Doom led participants to associate themselves with aggressive traits and
      actions on the Implicit Association Test. In addition, self-reported prior
      exposure to violent video games predicted automatic aggressive self-concept,
      above and beyond self-reported aggression. Results suggest that playing violent
      video games can lead to the automatic learning of aggressive self-views.

PMID- 15013260
TI  - Playing violent electronic games, hostile attributional style, and aggression
      related norms in German adolescents.
AB  - The relationship was examined between exposure to and preference for violent
      electronic games and aggressive norms as well as hostile attributional style.
      Following a pilot study to sample widely used electronic games varying in violent
      content, 231 eighth-grade adolescents in Germany reported their use of and
      attraction to violent electronic games. They also completed measures of hostile
      attributional style and endorsement of aggressive norms. There were significant
      gender differences in usage and attraction to violent electronic games, with boys
      scoring higher than girls. Significant relationships were found between
      attraction to violent electronic games and the acceptance of norms condoning
      physical aggression. Violent electronic games were linked indirectly to hostile
      attributional style through aggressive norms. The findings are discussed with
      respect to North American research on the aggression-enhancing effect of violent
      electronic games.

PMID- 15013261
TI  - Linking obesity and activity level with children's television and video game use.
AB  - This study examined the links between childhood obesity, activity participation
      and television and video game use in a nationally representative sample of
      children (N = 2831) ages 1-12 using age-normed body mass index (BMI) ratings.
      Results indicated that while television use was not related to children's weight
      status, video game use was. Children with higher weight status played moderate
      amounts of electronic games, while children with lower weight status played
      either very little or a lot of electronic games. Interaction analyses revealed
      that this curvilinear relationship applied to children under age 8 and that
      girls, but not boys, with higher weight status played more video games. Children
      ages 9-12 with lower weight status used the computer (non-game) for moderate
      amounts of time, while those with higher weight status used the computer either
      very little or a lot. This was also true for the relationship between print use
      and weight status for children of all ages. Results also indicated that children
      with higher weight status spent more time in sedentary activities than those with
      lower weight status.

PMID- 15013262
TI  - Online computer gaming: a comparison of adolescent and adult gamers.
AB  - Despite the growing popularity of online game playing, there have been no surveys
      comparing adolescent and adult players. Therefore, an online questionnaire survey
      was used to examine various factors of online computer game players (n = 540) who
      played the most popular online game Everquest. The survey examined basic
      demographic information, playing frequency (i.e. amount of time spent playing the
      game a week), playing history (i.e. how long they had been playing the game, who
      they played the game with, whether they had ever gender swapped their game
      character, the favourite and least favourite aspects of playing the game, and
      what they sacrifice (if anything) to play the game. Results showed that
      adolescent gamers were significantly more likely to be male, significantly less
      likely to gender swap their characters, and significantly more likely to
      sacrifice their education or work. In relation to favourite aspects of game play,
      the biggest difference between the groups was that significantly more adolescents
      than adults claimed their favourite aspect of playing was violence. Results also
      showed that in general, the younger the player, the longer they spent each week
      playing.

PMID- 15013263
TI  - Benchmarking the cultivation approach to video game effects: a comparison of the
      correlates of TV viewing and game play.
AB  - This study found significant relationships between first- and second-order
      cultivation measures and TV viewing, but found a relationship with video game
      play for only two variables in a sample of 322 Flemish 3rd and 6th year secondary
      school children. This suggests that the absence of a relationship with video game
      play is not the result of the absence of cultivation effects in Flanders. On the
      other hand it shows that the relationship between TV viewing and cultivation
      measures is not an artifact of systematic over reporting. The study concludes
      that cultivation measures typical of the "television world" are not related to
      playing video games. To study video game cultivation measures must be sought
      which reflect the mainstream of (particular genres of) video games. The role of
      selectivity needs to be studied more closely. As gamers play an active role in
      the violence of the games the possibility that self-protecting strategies are
      employed in processing video game contents must be taken into consideration.
      Existing process theories explaining what happens in television cultivation may
      be challenged by research into the cultivation effects of video games.

PMID- 15013264
TI  - An update on the effects of playing violent video games.
AB  - This article presents a brief overview of existing research on the effects of
      exposure to violent video games. An updated meta-analysis reveals that exposure
      to violent video games is significantly linked to increases in aggressive
      behaviour, aggressive cognition, aggressive affect, and cardiovascular arousal,
      and to decreases in helping behaviour. Experimental studies reveal this linkage
      to be causal. Correlational studies reveal a linkage to serious, real-world types
      of aggression. Methodologically weaker studies yielded smaller effect sizes than
      methodologically stronger studies, suggesting that previous meta-analytic studies
      of violent video games underestimate the true magnitude of observed deleterious
      effects on behaviour, cognition, and affect.

PMID- 15013265
TI  - The plasmin system in airway remodeling.
AB  - Recent studies suggest that the plasmin system plays an active role in tissue
      remodeling. Plasmin degrades the extracellular matrix (ECM), either directly
      removing glycoproteins from ECM or by activating matrix metalloproteinases
      (MMPs). PAI-1 blocking MMPs may prevent ECM degradation, but inhibiting
      fibrinolysis leads to fibrin accumulation and fibrosis. Components of the plasmin
      system including tissue plasminogen activator (t-PA), urokinase plasminogen
      activator (u-PA), and plasminogen activator inhibitors PAI-1 and PAI-2 are
      synthesised by airway cells, and inflammatory mediators affect their expression.
      The plasmin system, in turn, actively influences the production of inflammatory
      mediators and growth factors, extending pathological structural changes in the
      airway. Modulation of the plasmin system might be a new pharmacological strategy
      that could inhibit the development of airway remodeling.

PMID- 15013266
TI  - The stratification of platelet reactivity and activation in patients with stable
      coronary artery disease on aspirin therapy.
AB  - Heightened platelet reactivity may affect the occurrence of ischemic events in
      patients with coronary artery disease on aspirin therapy. However, a definition
      to stratify platelet reactivity in this group of patients has not been previously
      reported. We studied platelet reactivity and activation by measuring platelet
      aggregation and the expression of p-selectin, total GP IIb/IIIa and active GP
      IIb/IIIa (n=96). Patients were divided into quartiles by each of the markers;
      correlations were made between the markers; and a definition of heightened
      platelet reactivity was proposed. Marked variability in activation and reactivity
      were observed despite aspirin therapy. BACKGROUND: Heightened platelet reactivity
      and activation may affect the occurrence of ischemic events in patients with
      coronary artery disease on aspirin therapy. However, a definition to stratify
      platelet reactivity has not been previously reported. METHODS AND RESULTS:
      Platelet aggregation (5 and 20 micromol/l ADP), total GP IIb/IIIa, active GP
      IIb/IIIa and the expression of maximally stimulated p-selectin were measured in
      patients about to undergo elective coronary stenting (n=96). All patients had
      received aspirin (325 mg). There was marked variability in platelet reactivity
      and activation as measured by all markers. The highest quartile was defined by
      77+/-1% and 98+/-1% aggregation by 5 and 20 micromol/l ADP, respectively; 65+/-2%
      p-selectin positivity; 508+/-15 MFI for total GP IIb/IIIa; and 23.0+/-1.8 MFI for
      active GP IIb/IIIa. CONCLUSIONS: There is a wide range in platelet reactivity and
      activation as measured by multiple markers in stable coronary disease patients on
      aspirin therapy. From these indices, we can define those patients at the extremes
      of reactivity and activation and thus, the greatest potential risk of thrombosis
      and bleeding. These indices will serve as a guide to future studies investigating
      the relationships of platelet reactivity, activation, drug-induced inhibition and
      clinical outcomes.

PMID- 15013267
TI  - The outpatient treatment of deep vein thrombosis delivers cost savings to
      patients and their families, compared to inpatient therapy.
AB  - BACKGROUND: The outpatient treatment of deep vein thrombosis (DVT) with low
      molecular-weight heparin (LMWH) has been shown to be cost-effective from the
      perspective of a third party payer. The aim of this study is to determine if some
      or all of these cost savings to third party payers are shifted to patients and
      their families. METHODS: A prospective cohort study with micro-costing of
      patient/family costs was conducted at the thrombosis units of The Ottawa
      Hospital. Costs were determined by administering a questionnaire at the end of
      the patients' heparin therapy. Over a period of 4 months, consecutive patients
      presenting at the thrombosis units were approached at the initiation of their
      heparin therapy; 44 patients consented to participate and completed
      questionnaires were obtained for 41. RESULTS: The mean patient/family costs
      associated with outpatient therapy were significantly less than those associated
      with inpatient therapy (219.42 dollars versus 402.93 dollars, p=0.003); a savings
      of 190.91 dollars per patient. Even when lost income to patients/families was
      ignored, mean patient/family costs remained significantly less for outpatient
      therapy (72.00 dollars versus 134.29 dollars, p=0.004); a savings of 62.30
      dollars per patient. Furthermore, patients preferred outpatient to inpatient
      therapy by almost 3:1 (30 versus 11, respectively). INTERPRETATION: The
      outpatient treatment of DVT does not result in any net shifting of costs to
      patients and their families, and further, brings about cost savings. Given the
      cost savings associated with and the preference of patients for outpatient care,
      this study further supports the shift of DVT therapy from the inpatient unit to
      the outpatient clinic.

PMID- 15013268
TI  - Effects of pretreatment with clopidogrel on platelet and coagulation activation
      in patients undergoing elective coronary stenting.
AB  - BACKGROUND: Current data suggest that pretreatment with clopidogrel (in addition
      to aspirin) prior to elective percutaneous coronary intervention (PCI) might be
      associated with a reduced incidence of subsequent adverse ischemic events. The
      aim of this placebo-controlled study was to find out whether an extended
      pretreatment period with clopidogrel before an elective PCI might confer a
      superior inhibition of the platelet activation and aggregation than clopidogrel
      given not until PCI. METHODS: Twenty patients with stable angina being already on
      aspirin were randomly assigned to receive the loading dose of 300 mg clopidogrel,
      either 24 h before or immediately after stent implantation. At several time
      points before and after PCI, the activation of both the platelet and the
      coagulation system was determined by measuring beta-thromboglobulin (beta-TG) and
      prothrombin fragment f1.2 (f1.2), respectively, in venous blood and in blood
      emerging from a microvascular injury (shed blood). RESULTS: Pretreatment with
      clopidogrel before PCI exhibited a slight reduction of beta-TG (from 178 to 139
      ng/ml, p=0.085) and of f1.2 (from 0.81 to 0.75 nmol/l, p=0.045) in venous blood.
      Heparin administration (at the beginning of PCI) resulted in a 65% inhibition of
      ss-TG (from 10,590 to 2833 ng/ml) and 90% inhibition of f1.2 formation (from 38.7
      to 4.2 nmol/l) in shed blood of patients with clopidogrel pretreatment. The
      extent of inhibition was, however, comparable to that observed in patients
      without clopidogrel pretreatment (beta-TG: from 8025 to 2812 ng/ml, 76%
      inhibition, p=0.47; f1.2: from 34.9 to 3.8 nmol/l, 86% inhibition, p=0.80). After
      PTT normalisation (6 h after PCI), levels of beta-TG and f1.2 both in venous
      blood and in shed blood did not differ between the two treatment regimens up to
      48 h after PCI. CONCLUSION: Pretreatment with clopidogrel did not result in a
      pronounced inhibition of the platelet and coagulation system activation in
      patients on aspirin undergoing elective coronary stent implantation.

PMID- 15013270
TI  - Higher homocysteine concentrations in women undergoing caesarean section under
      general anesthesia.
AB  - To determine whether homocysteine, a risk factor for possible endothelial cell
      dysfunction, procoagulant effects and premature vascular disease but with a
      potential nutritional role for fetal and neonatal metabolism and development, is
      elevated in women at time of elective caesarean section with nitrous oxide
      general anesthesia. Plasma homocysteine levels were measured in 50 consecutive
      women, 25 of whom undergoing vaginal delivery and 25 elective caesarean section
      under nitrous oxide general anesthesia, and in the cord plasma of the respective
      offspring. Mean (+/-standard deviation) plasma homocysteine levels in the women
      of the caesarean section group were significantly higher than in the women of the
      vaginal delivery group (9.77+/-2.3 vs. 6.60+/-2.6 micromol/l, respectively;
      p<0.02). Cord plasma homocysteine levels in the neonates of the caesarean section
      group were also significantly higher than in the group of neonates vaginally
      delivered (9.47+/-3.94 and 7.36+/-2.35 micromol/l; p<0.01). Maternal homocysteine
      levels significantly correlated with cord levels of caesarean and vaginally
      delivered neonates (r=0.57; p<0.01 and r=0.66; p<0.001, respectively).
      Homocysteine levels were elevated at time of delivery in women undergoing
      elective caesarean section in nitrous oxide general anesthesia, and cord levels
      of corresponding neonates were affected by mode of delivery. Future studies are
      necessary to identify factors involved in the hyperhomocysteinemia observed in
      pregnant women at time of delivery by elective caesarean section in general
      anesthesia.

PMID- 15013271
TI  - Blood levels of homocysteine, folate, vitamin B6 and B12 in women using oral
      contraceptives compared to non-users.
AB  - BACKGROUND AND OBJECTIVES: To compare the levels of total homocysteine (tHcy),
      folate, vitamin B6 and B12, in women not using oral contraceptives (OC) vs. those
      using OC. MATERIALS AND METHODS: 219 healthy women were enrolled in the study;
      159 of them had not been using OC for at least 12 months prior to their
      enrollment, while 60 were on regular OC treatment. RESULTS: The median levels of
      vitamin B6 and B12 were significantly lower in OC users than in non-users (24.2
      vs. 32.9 nmol/l, p=0.029; 278 vs. 429 ng/ml, p<0.001). There were no
      statistically significant differences in the levels of tHcy (fasting and post
      methionine loading) and folate. CONCLUSIONS: In our cross-sectional study, OC use
      was associated with low vitamin B6 and B12 levels. Since low vitamin B6 levels
      are independently associated with heightened risks for arterial and venous
      thromboembolism (TE), they could partly account for the increased TE risk of OC
      users.

PMID- 15013269
TI  - Comparative evaluation of D-dimer assays for exclusion of deep venous thrombosis
      in symptomatic outpatients.
AB  - Diagnostic work-up of patients sent to the hospital for diagnosing of deep venous
      thrombosis (DVT) often combines the determination of D-dimer and the application
      of a clinical probability score. To fulfill diagnostic as well as economic needs,
      D-dimer assays should exhibit a high negative predictive value (NPV) as well as
      reasonable specificity. In this study, we evaluated both a latex-enhanced
      immunoassay for use on routine coagulation analyzers and a radial partition
      immunoassay (RPIA) for use on a point-of-care analyzer. Samples included were
      from 344 outpatients with suspected deep venous thrombosis. Among them, 100 had
      deep venous thrombosis. Results obtained for both assays show a good efficiency
      for exclusion of deep venous thrombosis with well-acceptable specificity.

PMID- 15013272
TI  - MRA versus angiogram for the diagnosis of peripheral arterial disease, a case
      report.

PMID- 15013273
TI  - The E-selectin S128R polymorphism is not a risk factor for coronary artery
      disease in patients with diabetes mellitus type 2.
AB  - AIM/HYPOTHESIS: E-selectin is thought to play a key role in the early stages of
      vascular disease by facilitating the attachment of leukocytes to the endothelium.
      Recently, a polymorphism in the E-selectin gene (S128R) has been associated with
      higher E-selectin levels in patients with diabetes mellitus and with premature
      coronary artery disease. The impact of the S128R polymorphism on the development
      of diabetic coronary artery disease has not been investigated yet. PATIENTS AND
      METHODS: A total of 254 patients recruited from the Division of Cardiology,
      University of Vienna with diabetes mellitus type 2 was assessed for the E
      selectin S128R polymorphism by a novel mutagenic separated PCR, allowing fast and
      reliable genotyping without restriction enzyme digest. Ninety-five patients had a
      history of myocardial infarction, 90 were admitted with stable coronary artery
      disease whereas in 69 the presence of CAD could be excluded. RESULTS: Of all 254
      individuals tested, 197 (77.6%) exhibited wildtype E-selectin 128S genotype, 54
      (21.3%) were heterozygous S128R and 3 (1.1%) were homozygous for the 128R allele.
      In all groups the genotype frequencies did not differ significantly. No
      associations were found between E-selectin genotype and coronary artery disease
      or myocardial infarction. CONCLUSION/INTERPRETATION: In subjects suffering from
      diabetes mellitus type 2 the E-selectin S128R polymorphism is not associated with
      coronary artery disease nor with an increased risk for myocardial infarction.
      Thus, screening for this polymorphism is not indicated for risk assessment of CAD
      in patients with diabetes mellitus.

PMID- 15013274
TI  - Activated platelets stimulate tissue factor expression in smooth muscle cells.
AB  - Tissue factor (TF)-induced activation of the coagulation plays a key role in the
      pathophysiology of acute coronary syndromes. Because TF represents the initial
      trigger of the coagulation cascade, its expression in the arterial wall is
      tightly regulated. OBJECTIVE: To determine whether and which soluble mediators
      released during platelet activation may upregulate TF expression in smooth muscle
      cells (SMCs). METHODS AND RESULTS: Rabbit SMCs were challenged with collagen
      activated platelets and their effects on TF mRNA transcription and protein
      expression were evaluated at different time points (30 min, 1, 2, 4, 8, 12 and 24
      h) by RT-PCR, immunofluorescence and a two-stage colorimetric assay. A
      progressive increase in TF mRNA, peaking at 2 h, was evident in SMCs stimulated
      with activated platelets with respect to baseline. The increase in TF mRNA
      expression was associated with a parallel increase in TF protein, as demonstrated
      by immunofluorescence and by colorimetric assay. In a different set of
      experiments, selected platelet-derived soluble mediators were shown to induce TF
      mRNA expression. CONCLUSIONS: Activated platelets upregulate TF, via release of
      several soluble mediators, in a cell population widely expressed in the vessel
      wall and in atherosclerotic plaques, such as SMCs. This phenomenon might play an
      important role in sustaining thrombus formation in vivo.

PMID- 15013275
TI  - Matrix metalloproteinase-2 contributes to increased platelet reactivity in
      patients with metastatic prostate cancer: a preliminary study.

PMID- 15013276
TI  - Differential effects of the iodinated contrast agents Ioxaglate, Iohexol and
      Iodixanol on thrombus formation and fibrinolysis.
AB  - INTRODUCTION: Contrast media (CM) possess both pro-thrombotic and anticoagulant
      properties. Here we investigate the effect of three classes of CM; Iohexol,
      Iodixanol and Ioxaglate, on thrombus formation and fibrinolysis in vitro and
      evaluated the contribution of platelets to this process. MATERIALS AND METHODS:
      Non-anticoagulated blood was mixed with CM or saline (50% or 20% (v/v)) for 1 min
      then citrated. Thrombi were produced in vitro under flow in a Chandler loop.
      Thrombus structure was visualized by immunohistochemistry using FITC-fibrin/ogen
      antibodies, and propidium iodide to identify nucleated blood cells. To measure
      fibrino/thrombolysis release of FITC-labeled fibrinogen, added prior to thrombus
      formation, was measured over 24 h. Platelet degranulation was analyzed by whole
      blood flow-cytometry. RESULTS: No thrombi formed from blood incubated with
      Ioxaglate. Thrombi formed with Iohexol or Iodixanol weighed > OR = 10x more than
      saline controls (116+/-52 and 230+/-128 mg vs. 11+/-3 mg, respectively;
      p<0.0005), and were more resistant to thrombolysis as evidenced by the release of
      FITC over 24 h (19.1+/-8.9 and 31.9+/-17.2 U vs. 65.1+/-19.1 U, respectively;
      p<0.02). Thrombi formed with Iodixanol and Iohexol had larger, more diffuse
      platelet-rich head areas and tail regions composed of a more open
      fibrinogen/fibrin meshwork enclosing denser RBC rich areas compared to controls.
      Iodixanol and Ioxaglate did not increase platelet degranulation, but Iohexol
      caused a significant increase compared to the saline control (percentage of
      platelets expressing P-selectin 68.9+/-23.43% vs. 4.93+/-1.44%, respectively;
      p=0.001). CONCLUSION: Thus thrombi formed with Iodixanol or Iohexol will be
      larger and more resistant to thrombolysis, whereas Ioxaglate may reduce the risk
      of thrombus formation.

PMID- 15013277
TI  - A comparison of fibrin sealants in relation to their in vitro and in vivo
      properties.
AB  - INTRODUCTION: Fibrin sealants (FS) have been used for many years to facilitate
      hemostasis and to provide suture support and sealing/adhesion of tissues after
      surgery. While their composition is similar, different formulations, application
      devices, and varying concentrations of key components mean that the properties of
      clots formed by individual FS can be diverse. MATERIALS AND METHODS: We performed
      several studies, including animal models, to compare the properties of 12
      different commercially available FS/application device combinations using partial
      liver and kidney resection models to assess hemostatic efficacy and a novel pig
      skin model to measure adhesive clot strength. The quality of mixing was
      determined using colored spray images. RESULTS: Although the FS tested shared the
      principle of combining fibrinogen and thrombin, major differences were found
      between the individual preparations with regard to hemostatic efficacy. Two pre
      requisites for successful early hemostasis were identified--adequate clottable
      protein content and the ability of the application device to effectively mix the
      fibrinogen and thrombin components of the FS. Factor XIII activity was a key
      determinant in prevention of re-bleeding and premature clot lysis. Furthermore,
      FS lacking measurable factor XIII activity formed the weakest, softest clots.
      CONCLUSIONS: Clearly, all FS are not the same, and their different
      characteristics may potentially translate into different clinical outcomes. In
      our studies, while all FS tested performed well on individual parameters,
      Beriplast P (Aventis Behring) was the foremost FS in consistently providing early
      hemostasis, minimizing the risk of re-bleeding, and providing strong adhesive
      clots capable of resisting mechanical forces.

PMID- 15013278
TI  - Prolonged bleeding time induced by anticoagulant glycosaminoglycans in dogs is
      associated with the inhibition of thrombin-induced platelet aggregation.
AB  - INTRODUCTION: The clinical use of unfractionated heparin (UFH) is complicated by
      hemorrhage. This has led to a search for safer alternatives, one of which, the
      recently identified depolymerized holothurian glycosaminoglycan (DHG), causes
      less bleeding and exhibits a better antithrombotic-hemorrhagic ratio in rats and
      dogs than UFH and low-molecular-weight heparin (LMWH). In contrast to UFH and
      LMWH, which exert their anticoagulant effects by inhibiting thrombin in the
      presence of antithrombin III (AT), DHG exerts its anticoagulant effect by
      inhibiting the intrinsic factor Xase complex and thrombin in the presence of
      heparin cofactor II (HCII). MATERIALS AND METHODS: The hemorrhagic effect of DHG
      was compared with those of UFH and LMWH in healthy dogs, and the mechanism
      responsible for prolonging bleeding time was examined both in dogs and with human
      platelets. RESULTS: DHG prolonged template-bleeding time in dogs less than UFH
      and LMWH do. Although the maximum noneffective concentrations of each
      glycosaminoglycan (GAG) that prolong the bleeding time are almost the same as the
      concentrations that inhibit thrombin-induced platelet aggregation, they are not
      related to those that inhibit ADP-induced platelet aggregation. Results of
      experiments on gel-filtered platelets from humans indicate that the inhibition of
      thrombin-induced platelet aggregation caused by UFH and LMWH in the presence of
      AT is more prominent than that caused by DHG with HCII. CONCLUSIONS: These
      results suggest that the prolongation of bleeding time caused by GAGs are
      associated with the inhibition of thrombin-induced platelet aggregation, and DHG
      may cause less bleeding than UFH and LMWH because of its different thrombin
      inhibition mechanism in platelet-rich plasma (PRP).

PMID- 15013279
TI  - Antithrombotic effect of Glycyrrhizin, a plant-derived thrombin inhibitor.
AB  - Glycyrrhizin (GL), an anti-inflammatory compound isolated from licorice
      (Glycyrrhiza glabra), has been previously identified as a thrombin inhibitor
      (Francischetti et al., Biochem Biophys Res Commun 1997;235:259-63). Here we
      report the in vivo effects of GL upon two experimental models of induced
      thrombosis in rats. Intravenous administration of GL caused a dose-dependent
      reduction in thrombus size on a venous thrombosis model that combines stasis and
      hypercoagulability. It was observed that GL doses of 180 mg/kg body weight
      produced 93% decrease on thrombus weight. This effect showed a time-dependent
      pattern being significantly reduced when the thrombogenic stimulus was applied 60
      min after drug administration. GL was also able to prevent thrombosis using an
      arteriovenous shunt model. GL doses of 180 and 360 mg/kg decreased the thrombus
      weight by 35 and 90%, respectively. Accordingly, the APTT ex vivo was enhanced by
      1.5- and 4.3-fold at GL doses of 180 and 360 mg/kg, respectively. In addition, GL
      doses above 90 mg/kg caused significant hemorrhagic effect. In contrast with
      heparin, GL did not potentiate the inhibitory activity of antithrombin III or
      heparin cofactor II towards thrombin. Altogether, data indicate that GL is an
      effective thrombin inhibitor in vivo, which may account for its other known
      pharmacological properties.

PMID- 15013280
TI  - Augmentation of in-stent clot dissolution by low frequency ultrasound combined
      with aspirin and heparin. An ex-vivo canine shunt study.
AB  - INTRODUCTION: Ultrasound can accelerate clot dissolution in vitro and in vivo. We
      used an ex vivo canine shunt to investigate low frequency ultrasound effects on
      platelet-rich stent thrombosis. METHODS AND RESULTS: Nitinol stents were expanded
      to 2 mm in diameter in two perfusion chambers in a parallel shunt and exposed to
      flowing arterial blood at 2100 s(-1) to generate stent thrombi (n=224 perfusion
      runs). Dethrombotic effects were assessed during treatment with saline and
      combined treatment with aspirin and heparin. One stent was exposed to ultrasound
      (27 kHz, 1.4 W/cm2), while the other was not. Stent thrombi were weighed before
      and after treatment. There was no significant effect of ultrasound during saline
      infusion. Treatment with aspirin+heparin alone reduced thrombus weight by 37+/
      25% (18.9+/-6.1 to 11.8+/-7.7 mg, p<0.0001). Combined treatment with
      aspirin+heparin+ultrasound produced a 49+/-23% reduction in thrombus weight
      (19.0+/-6.3 to 9.6+/-7.8 mg, p<0.0001). The reduction in thrombus weight was
      significantly greater in aspirin+heparin+ultrasound compared with aspirin+heparin
      alone (p=0.04). CONCLUSIONS: Transcutaneous ultrasound significantly enhances
      dethrombotic effect of aspirin plus heparin on preformed stent thrombi. These
      findings suggest the potential of ultrasound as an adjunct to antithrombotic
      therapy to improve effectiveness without increasing the risk of bleeding
      complications during treatment of vascular thrombosis.

PMID- 15013281
TI  - Lonomia obliqua venom action on fibrinolytic system.
AB  - Accidental skin contact with the Lonomia caterpillar bristles causes a severe
      hemorrhagic syndrome. While fibrinolytic activation is considered to be the main
      cause of hemorrhage in Lonomia achelous envenomation, a consumptive coagulopathy
      was found to be a major component involved in the bleeding complications observed
      in patients envenomed by contact with Lonomia obliqua. Although we have
      previously observed that in L. obliqua envenomations, fibrinolysis activation
      appeared to be secondary to coagulation system activation, there are no reports
      regarding the ability of L. obliqua venom to activate directly fibrinolytic
      pathways. We examined the action of L. obliqua crude bristles extract (LOCBE) on
      several fibrinolytic system components. We demonstrated that LOCBE degraded the A
      alpha fibrinogen chain only at high concentrations and after long incubation
      times. Under these conditions, LOCBE also induced prolongation of the fibrinogen
      clotting time, but no clot lysis was observed before 24 h. LOCBE did not contain
      t-PA- or u-PA-like activities. Gel filtration and SDS-PAGE showed that LOCBE did
      not induce FXIII digestion. In addition, no FXIII activity inhibition was
      detected by dansylcadaverin method. FXIII levels remained unchanged when FXIII
      was measured in fibrinogen-depleted LOCBE-treated rat plasma, suggesting that the
      observed 50% FXIII reduction in rats was related to consumption. In conclusion,
      our results clearly demonstrated that LOCBE did not display either FXIII
      inhibition or degradation nor fibrinolytic activity. Furthermore, although
      proteolytic activity on Aalpha fibrinogen chain was observed, cross-linked fibrin
      was not affected by LOCBE.

PMID- 15013282
TI  - Antithrombin activity of lepirudin adsorbed to silicone (polydimethylsiloxane)
      tubing.

PMID- 15013283
TI  - Stability of low molecular weight heparins stored in plastic syringes.

PMID- 15013284
TI  - Transient ischaemic attack associated with the new contraceptive Yasmin.

PMID- 15013286
TI  - Changing ethics in renal transplantation: presentation of Iran model.
AB  - This article reviews renal transplant (RTx) activity in USA to show that the
      ethics of RTx are changing, with steadily increasing numbers of living unrelated
      donors (LURD). In developing countries the numbers of RTx are inadequate
      emphasizing the need for controlled LURD RTx programs. The condemnation of all
      forms of compensated LURD RTx results in many patient deaths and the associated
      suffering is unethical. The Iran model, adopted in 1988, permits compensated and
      controlled LURD RTx. It has eliminated the RTx waiting list in Iran. At the end
      of 2002, among the 14,288 RTxs performed, 78% were from LURDs. The recipients of
      >50% of the kidneys from LURDs have been from the poor socioeconomic class of
      Iran. It has been recommended that each society should provide legally binding
      life-long benefits for LURDs.

PMID- 15013287
TI  - Health care professionals' knowledge of procedural issues in transplantation: the
      need for continuing education programs.
AB  - Organ transplantation is a multidisciplinary field that requires a good knowledge
      of the processes and excellent cooperation throughout the entire hospital. The
      aim of this study was to determine the level of knowledge of health care
      professionals (HCPs) at our transplantation center concerning general definitions
      and procedural issues related to transplantation. A questionnaire including nine
      items-five questions on general definitions and four on procedural issues-was
      distributed to 100 randomly selected HCPs. Four participants were excluded
      because they completed the questionnaire incorrectly; thus, there were 96 total
      respondents. The mean number (+/-SD) of correct answers overall was 5.78 +/-
      1.36. Concerning general definitions, 11.5% of the respondents answered all of
      the questions correctly. However, the corresponding rate for the procedural
      questions was 3.1%. One percent of the respondents answered 1 or zero definition
      questions correctly, and 19.8% answered 1 or zero procedural questions correctly.
      The HCPs showed better knowledge of general issues related to transplantation
      than procedural issues. The results of this study suggest that the knowledge of
      HCPs in transplantation centers in Turkey is limited to the extent that their
      specialty is linked to transplantation. It is important that continuing medical
      education programs be instituted in organ procurement and transplantation centers
      in Turkey. These in-service training programs would enhance HCPs' understanding
      of and participation in procedures related to transplantation, and thus improve
      the total quality of the transplantation process.

PMID- 15013288
TI  - Frequency of spinal reflex movements in brain-dead patients.
AB  - Spontaneous and reflex movements may occur in brain-dead patients. These
      movements originate from spinal cord neurons and do not preclude a brain-death
      diagnosis. In this study, we sought to determine the frequency and
      characteristics of motor movements in patients who fulfilled diagnostic criteria
      for brain death. Patients admitted to our department between January 2000 and
      March 2003 and diagnosed as brain-dead were prospectively evaluated in terms of
      spinal reflexes. Clinical brain death was diagnosed according to our national
      law. We also prefer to document the diagnosis of brain death with an EEG and/or
      TCD. Spinal reflex movements were observed in 18 out of 134 (13.4%) brain-dead
      patients during the study period. Lazarus sign, the most dramatic and complex
      movement seen in brain-dead patients, was observed a few times in two patients
      during an apnea test, an oculocephalic test, after a painful stimulus, and after
      removal of a ventilator. The other reflex movements observed in our brain-dead
      patients were finger and toe jerks, extension at arms and shoulders, and flexion
      of arms and feet. The occurrence of spinal reflexes in brain-dead patients may
      certainly delay decision making, such as starting a transplantation procedure,
      because of difficulties in convincing the family or even a physician taking part
      in the diagnosis of brain death. An awareness of spinal reflexes may prevent
      delays in and misinterpretations of the brain-death diagnosis.

PMID- 15013290
TI  - The role of the transplant coordinator on tissue donation in Turkey.
AB  - While solid organs represent the dramatic and lifesaving aspect of donation after
      death, the transplantation of tissues from donors after death is a much larger
      scale activity that benefits enormous numbers of patients, usually in a life
      enhancing rather than a lifesaving manner. Some types of tissue transplantation,
      such as heart valve and cornea transplantation, have been established for many
      decades and are reasonably well understood by health professionals and the
      public. Many other types of tissue donation, such as bone, skin, tendons, etc,
      are much less well known but nonetheless result in beneficial treatment for large
      numbers of patients. Skin is used to prevent fluid loss and infection following a
      major burn; bone is used to improve the clinical success of a range of orthopedic
      operations, such as joint replacements, spinal fusions, and reconstructions
      following trauma or tumor. In the United States more than 20,000 donors provided
      cadaveric tissue in 1999, compared to 6,000 in 1994. We ask all families of brain
      dead donors for consent for tissue donation. Between January 1, 1999, and January
      3, 2003, we had 58 actual cadaveric donors, procuring three skins, 15 tendons,
      six bones, 13 heart valves, and 40 corneas. We performed three skin, 40 tendon,
      and three bone transplants as well as storing other tissues. One donor can give
      health to 50 different recipients. In general, the argument runs for a transplant
      coordinator "if you can do it, then you must." We can save lives and present a
      better quality of life with solid organ and tissue donation.

PMID- 15013289
TI  - Brain death and donor management in the intensive care unit: experiences over the
      last 3 years.
AB  - We sought to examine the frequency of brain death in the ICU, the donation rate,
      and the problems encountered during donor management between the years of January
      2000, the date we began treating patients with neurologic pathologies and
      traumatic brain injury, and March 2003. Between January 2000 and March 2003, 134
      patients diagnosed with brain death in our ICU were studied prospectively for the
      reason of brain death, the time between admission to ICU, and the diagnosis of
      brain death, the frequency of diabetes insipidus, the inotrope requirement,
      hypothermia, electrolyte imbalance, arrhythmia, and cardiac arrest. Among the
      approximately 2600 patients admitted to the general 24-bed ICU, 940 had cerebral
      injuries. In this group, the mortality rate was 33.5% (315 out of 940 patients)
      including brain-dead patients. Donor care was performed in 94 patients with
      organs suitable for transplantation out of 134 brain-dead patients. Fifty (53.2%)
      out of 94 patients became organ donors. The donor ratio was 12 per million
      population per year as a mean value of the study period, which was approximately
      10 times higher than the average ratio in Turkey. Although we observed many life
      threatening problems during donor management, none of these patients died or had
      acute organ dysfunction.

PMID- 15013292
TI  - Advances in pre- and posttransplant immunologic testing in kidney
      transplantation.
AB  - Pre- and posttransplant risk estimation in kidney transplantation is important
      for the selection of appropriate treatment strategies. Recently, using new
      immunologic tests, we made observations within the framework of the Collaborative
      Transplant Study that may influence clinical practice. Complement-dependent
      lymphocytotoxic panel reactivity as a measure of anti-HLA sensitization, although
      criticized for its low sensitivity, is a useful indicator of an increased risk of
      rejection. Using the more sensitive complement-independent ELISA methodology,
      which utilizes solubilized HLA molecules instead of lymphocytes, we found that
      recipients with preformed complement-dependent anti-HLA antibodies showed a
      decreased graft survival only if their antibodies were directed against both HLA
      class I and class II, whereas isolated reactivity only against HLA class I or
      class II was of no clinical consequence. Pretransplant serum-soluble CD30 (sCD30)
      was found to be an independent and highly predictive factor of immunologic risk.
      The effects of sCD30 and anti-HLA antibodies were additive. Importantly, even
      patients without anti-HLA antibodies showed a strong HLA matching effect if their
      pretransplant serum contained high levels of sCD30. Although the role of anti-HLA
      antibody formation after transplantation remains uncertain, ELISA-detected sCD30
      was shown to indicate impending graft rejection as early as on posttransplant
      days 3 to 5. Another very sensitive indicator of impending rejection is provided
      by posttransplant monitoring of the cytotoxic T-lymphocyte effector genes,
      perforin and granzyme B, in peripheral blood using real-time PCR.

PMID- 15013293
TI  - Angiotensin-converting enzyme genotype is a predictive factor in the peak panel
      reactive antibody response.
AB  - The presence of a high panel-reactive antibody (PRA) level represents an
      independent risk factor for early graft failure and chronic allograft
      dysfunction. It has also been reported that patients with the ACE-DD and AGT-AA
      genotypes display poorer chronic allograft function. We investigated the effects
      of gene polymorphisms of the renin angiotensin system (RAS) on anti-HLA antibody
      production among renal transplant candidates. Genotyping was performed on 133
      dialysis patients for the ACE (I/D) and AGT (M235T) as well as the type 1
      (A1166C) and type 2 (A1223G) angiotensin II receptor genes. Patients with a peak
      PRA >/= 30% were considered to be positive for anti-HLA antibody (40.6% of 133
      patients). Genetic polymorphisms of the RAS were not associated with anti-HLA
      antibody production at this PRA level. Another analysis comparing the 29 patients
      with a peak PRA >/=50% with the 104 patients with a peak PRA <50% showed that
      previous transplants, the presence of ACE-DD genotype, history of blood
      transfusions, and dialysis duration were all associated with the high levels of
      antibody production by univariant analysis. A multivariate analysis using a
      logistic regression model revealed previous transplants, the presence of ACE-DD
      genotype, and history of blood transfusions to be predictors of anti-HLA antibody
      production. The ACE-DD genotype is an important risk factor for higher PRA
      levels. This study suggests that genetic control of RAS activity correlates with
      production of anti-HLA antibodies, possibly explaining the relationship to
      chronic allograft outcome.

PMID- 15013291
TI  - The solution to organ shortage in Turkey: trained transplant coordinators.
AB  - The organ shortage is a social, psychological, ethical, moral, and probably legal
      and political problem of the 21st century. It must be solved as soon as possible
      to save lives; transplant coordinators are important cornerstones in this effort.
      The first transplant coordinator training course was organized in May, 2002,
      including 27 participants from different hospitals, but unfortunately only 13
      were able to work as transplant coordinators in their hospitals after the course.
      After the course, the number of cadaveric donors in Turkey increased 12%,
      compared to 2001. Currently, only 14 hospitals have transplant coordinators and
      12 of them are transplant centers. There is no transplant coordinator at 10
      transplant centers. Only two nontransplant centers have a transplant coordinator.
      Eightyeight percent of donors are procured from hospitals with a transplant
      coordinator. According to data from the Transplantation Society meeting held in
      Rome, August 2000, there should be 1675 donors in Turkey, but we had only 100 for
      2002 and 49 in 1999. Transplant coordinators are essential to organize donation,
      seeking to achieve the maximum for potential generating capacity (60 brain-dead
      pmp). So we need approximately 200 (3/pmp) trained transplant coordinators in
      Turkey but we presently have only 15% of this number.

PMID- 15013294
TI  - Clinical consequences of intermittent elevation of C-reactive protein levels in
      hemodialysis patients.
AB  - An elevated C-reactive protein (CRP) level has been associated with malnutrition,
      with erythropoietin resistance during hemodialysis (HD) therapy, and with a
      higher risk of chronic transplant rejection. Meanwhile, the clinical consequences
      of intermittent elevations of CRP levels observed among a large group of HD
      patients are unclear. We sought to compare the inflammatory and nutritional
      parameters as well as the erythropoietin requirements for HD patients with
      persistent or intermittent CRP elevations versus subjects with CRP levels in the
      normal range. The 6-month retrospective clinical and laboratory data of 100 HD
      patients (age 48.4 +/- 14.3 years, HD duration 69.3 +/- 49.0 months) were divided
      into three groups on the basis of at least six monthly values of CRP: for
      persistent (group 1) or intermittent high (at least one level of CRP >/=10 mg/L);
      (group 2) versus normal CRP levels (group 3). We compared the estimates of
      fibrinogen, ICAM-1, VCAM-1, albumin, prealbumin, normalized protein catabolic
      rate (nPCR), interdialytic weight gain (IDWG), and rhuuEpo/kg/Htc. Significant
      differences, were observed in fibrinogen, albumin, prealbumin, ICAM-1, nPCR,
      IDWG, and rHUuEpo/kg/wk values. Like group 1, group 2 patients seemed to show
      inflammation and malnutrition, namely decreased albumin levels, nPCR, and rHUEpo
      resistance, when compared with group 3. Finally, intermittent elevations of CRP
      must be considered to reflect a state of chronic inflammatory response associated
      with malnutrition and erythropoietin resistance similar to that observed among
      hemodialysis patients with persistently high CRP levels.

PMID- 15013295
TI  - Influence of inflammation on the relation between markers of iron deficiency in
      renal replacement therapy.
AB  - Iron deficiency is an important factor in the management of anemia in both
      dialysis and transplant patients. Serum ferritin and transferrin saturation (TS)
      may be influenced by the presence of inflammation. Recently, the soluble
      transferrin receptor (s-TfR) has been considered to be a marker of functional
      iron stores. In this study, parameters of the iron state were investigated in
      terms of agreement (assessed by kappa) with the diagnosis of iron deficiency and
      with inflammation. The study was performed in 38 hemodialysis, 31 continuous
      ambulatory peritoneal dialysis, and 21 anemic renal transplant patients. CRP and
      amyloid A protein (AAP) were studied as markers of inflammation. Iron deficiency
      was defined as ferritin <100 mg/L, TS <20%, or s-TfR >1.76 mg/mL. We observed
      that s-TfR levels were significantly related to both dialysis duration (r = 0.28
      in dialysis and r = 0.60 in transplant patients, both P <.05) and PTH levels (r =
      0.23 in dialysis and r = 0.55 in transplant patients, both P <.05). Among the
      transplant group, ferritin and TS, as well as TS and s-TfR were significantly
      related (r = 0.84 and r = -0.64, respectively), but not s-TfR and ferritin. Among
      the dialysis group, ferritin and TS, and also TS and s-TfR, were significantly
      related (r = 0.35 and r = -0.30, respectively), whereas s-TfR and ferritin were
      not. In the transplant group, the kappa value for agreement between ferritin and
      TS in the diagnosis of iron deficiency was 0.76 (P =.006), and 0.33 (P =.04),
      respectively. Among patients with CRP levels <0.3 mg/L or AAP levels <6.4 mg/L,
      the relation between parameters of iron state was more robust. The kappa value
      for agreement between ferritin and s-TfR was 0.49 (P =.006) in the dialysis group
      and 1 (P =.002) for that between ferritin and TS in the transplant group. Our
      results suggest that PTH levels may influence s-TfR levels. Discordance between
      ferritin, TS, and s-TfR as markers of iron deficiency might be explained by the
      effects of inflammation.

PMID- 15013296
TI  - Seroprevalence of antibodies to legionella pneumophila in hemodialysis patients.
AB  - Patients with chronic renal failure are at increased risk for infections because
      of impaired cellular immunity. This study was designed to determine the
      prevalence of antibodies to Legionella pneumophila serogroups 1 to 6 and to
      evaluate the possible risk factors for Legionnaires' disease in hemodialysis
      patients. Serum samples to be screened for antibodies against L pneumophila and
      risk factor data were collected from 252 hemodialysis patients. The overall
      prevalence of L pneumophila antibodies in hemodialysis patients was found to be
      5.16% There was no statistically significant difference between L pneumophila
      seropositivity and potential risk factors. Further studies are needed to
      determine possible risk factors for Legionnaires' disease in hemodialysis
      patients.

PMID- 15013297
TI  - Association of helicobacter pylori infection with nutritional status in
      hemodialysis patients.
AB  - The presence of Helicobacter pylori (HP) infection may adversely influence
      outcome in renal transplant candidates because of its strong association with
      gastrointestinal disorders. We examined the association between HP infection and
      nutritional parameters in symptom-free hemodialysis patients and assessed
      prospectively the nutritional changes in patients who received therapy for the
      disease. The 163 study patients, including 114 men and 69 women of mean age 41.5
      +/- 12.9 years on dialysis for 67.2 +/- 47.6 months, were selected from among the
      group who underwent routine endoscopic evaluation according to our renal
      transplant protocol. Patients with active peptic ulcer, acute gastritis, chronic
      inflammatory disease, malignancy, or diabetes mellitus were excluded. Endoscopy
      results revealed normal findings in 60 (group 1), gastritis in 86 (group 2), or
      gastritis with HP in 17 patients (group 3). Group 3 patients received a 2-week
      course of triple therapy (omeprazole, amoxicillin, clarithromycin). The patient
      groups were compared for nutritional metrics (albumin, phosphorus, interdialytic
      weight gain [IDWG], body mass index [BMI]), inflammatory indices (CRP,
      fibrinogen), and iPTH levels. Group 3 patients were observed to be malnourished
      when compared with groups 1 and 2, namely abnormal values of albumin (P <.0001),
      phosphorus (P <.009), IDWG (P <.03), and BMI (P <.02). Repeat endoscopy revealed
      a 94% rate of eradication of HP with increased levels of albumin and phosphorus
      in group 3. Although symptom-free hemodialysis patients with HP-associated
      gastritis displayed a state of malnutrition; its eradication improved the
      nutritional status. Therefore, the presence of HP infection should be sought and
      its eradication mandatory for this patient population.

PMID- 15013298
TI  - Investigation of possible clinical and laboratory predictors of liver fibrosis in
      hemodialysis patients infected with hepatitis C virus.
AB  - Hepatitis C virus (HCV) infection is common in patients with end-stage renal
      disease. The severity of liver damage, including fibrosis, in these cases varies
      widely. Although many investigators have searched for noninvasive alternatives to
      liver biopsy for evaluating the extent of liver fibrosis, no useful noninvasive
      predictors have been found. Currently, liver biopsy is essential to assess the
      degree of fibrosis. The aim of this retrospective study was to investigate a
      range of clinical and laboratory parameters in HCV-infected hemodialysis (HD)
      patients and identify possible predictors of fibrosis. Ninety-five consecutive HD
      patients with HCV infection underwent liver biopsy. Each specimen was evaluated
      for fibrosis stage. Correlations were sought between the degree of fibrosis and
      the age, HD duration, time since first possible HCV exposure, body mass index,
      HCV RNA titer, serum ferritin level, and serum alanine aminotransferase (ALT)
      level. The analysis revealed no significant correlations between fibrosis stage
      and the parameters investigated (mean age: r =.017, P =.89; mean HD duration: r
      =.066, P =.576; body mass index r =.231, P =.152; HCV RNA titer: r =.015, P
      =.091; serum ferritin: r =.134, P =.32; serum ALT r =.108, P =.927). Links with
      serum ALT were reevaluated with upper normal levels arbitrarily set at 30 IU/L
      and 20 IU/L, but these analyses also revealed no correlations between fibrosis
      stage and ALT level (P =.98 and P =.449, respectively). Therefore liver biopsy is
      still essential for accurate assessment of liver pathology in HD patients with
      HCV.

PMID- 15013299
TI  - Pregnancy during hemodialysis: perinatal outcome in our cases.
AB  - The perinatal outcome of patients undergoing chronic hemodialysis has been
      improved in recent years. In this report we review the treatment and outcome of
      seven pregnancies in women undergoing chronic hemodialysis before and during
      pregnancy between 2000 and 2002. The hemodialysis schedule was increased from 4
      hours twice weekly to 4 hours four to six times weekly. Hemodialysis was
      performed using a high-flux dialyzer with volume-controlled ultrafiltration. The
      patients were followed in close collaboration between the obstetrician and the
      nephrologist. Monitoring of fetal well-being was started after 24 weeks'
      gestation, using cardiotocography by a nonstress test twice weekly and by weekly
      Doppler flow measurements. All patients underwent uterine contraction monitoring
      immediately after the dialysis. The mean gestational age at delivery was 32 weeks
      (range, 26 to 36 weeks). The causes of preterm delivery were premature
      contractions, premature rupture of membranes, preeclampsia, and intrauterine
      growth restriction. The outcomes were two pregnancies complicated by
      polyhydramnios and six pregnancies, that resulted in live births, all of whom
      survived. There was one neonatal death. The mean newborn birthweight was 1400 g
      (range, 420 to 2640 g) and the 1- and 5-minute Apgar scores ranged from 2/8 and
      4/10, respectively one infant at 29-weeks gestation experienced respiratory
      distress syndrome but did well after 12 days. Cesarean section was performed in
      four pregnancies. The mothers were discharged on postoperative days 3 to 5. It is
      well known that the management of pregnant patients undergoing chronic
      hemodialysis is difficult. However, advances in dialysis, obstetrics, and
      neonatal care have improved the outcomes.

PMID- 15013300
TI  - Efficacy and safety of sildenafil citrate in hemodialysis patients.
AB  - Erectile dysfunction (ED) is more frequent among end-stage renal failure patients
      than the normal population. Sildenafil citrate has been successfully used for the
      symptomatic treatment of erectile dysfunction. The aim of this study was to
      determine the efficacy and safety of sildenafil citrate in the treatment of ED in
      patients on hemodialysis. Fifty-five hemodialysis patients above 18 years
      suffering from ED with steady sexual partners were included in the study. The
      first five and fifteenth questions of the International Index of Erectile
      Function were employed to evaluate ED in the patient group. A Single 50-mg
      sildenafil citrate tablet was prescribed for each patient. The patients were
      encouraged to take it on the day after hemodialysis and 1 hour before sexual
      intercourse. The erectile function of the patients after the treatment was re
      evaluated in the same manner by International Index of Erectile Function. The
      ages of the patients ranged between 30 and 73 years (mean 50.6 +/- 10.9). The
      overall response rate was 74.5% (38/51). Side effects were nausea (n = 2),
      palpitation (n = 2), flushing (n = 1), and angina (n = 1). Sildenafil citrate (50
      mg) was observed to be safe and effective for treatment of hemodialysis patients
      with careful evaluation and proper patient selection.

PMID- 15013301
TI  - Exotic arteriovenous fistulas for hemodialysis.
AB  - The rate of patients with exhausted upper extremity arteriovenous fistula (AVF)
      sites who have lost all chances for a conventional upper extremity AVF has been
      increasing in line with the general increase in the hemodialysis patient
      population. In this prospective study, we report the early and late follow-up
      results of "exotic" AVFs in which central veins are used for the outflow.
      Patients having no chance for an upper extremity AVF based on previous
      catheterization, surgical AVF history, detailed physical examination, and
      radiological assessment, were included in the study. Between June 1999 and
      January 2003, 27 central AVFs were created with a 6 mm synthetic vascular graft
      in 26 patients. The inflow artery was the proximal axillary artery in all except
      one. All but one operation was done by the same surgeon. The outflow vein was the
      internal jugular vein in 16 and infraclavicular axillary vein in 11 cases. One
      year primary and secondary graft patency rates were 33.33 +/- 10.49 and 57.06 +/-
      11.29, respectively. The early complications were facial edema and hemiparesis,
      both of which resolved spontaneously. The only late complication, pseudoaneursym,
      was treated by a graft interposition. In selected patients who have no suitable
      upper extremity vessels for an AVF, the central veins may be used with an
      acceptable success rate. Another advantage of this procedure is the avoidance of
      undesired femoral interventions; sometimes it may be the only opportunity and
      lifesaving for the patient.

PMID- 15013302
TI  - Femoral vein transposition versus femoral loop grafts for hemodialysis: a
      prospective evaluation.
AB  - In this first clinical trial femoral vein transposition (FVT) was prospectively
      compared with its "graft" counterpart. Patients requiring vascular access due to
      occluded central veins were divided into two groups: group I (n = 17) underwent
      femoral loop grafts and group II (n = 15), FVT. Complications were recorded
      prospectively and patency rates were compared by the Kaplan Meier method with
      statistical comparisons by Mann Whitney U and chi-square tests as appropriate.
      Between 1999 and 2003 30 patients underwent 32 operations. Mean follow-up was 8.9
      months in group I and 6.8 months in group II (P >.05). Three group I patients
      developed a steal, requiring closure of the fistula in one. Five group II
      patients developed a steal, requiring closure of the fistula in one. The
      incidence of steal was similar in both groups (P >.05). The infection rates were
      similar: 35.3% and 26.7% in group I versus group II (P >.05), respectively. Among
      the six infections in group I, four patients required excision of the graft due
      to infection, whereas only one arteriovenous fistula (AVF) was closed in group II
      for infection. The 1-year primary patency rate in group I was 37.5% versus 86.7%
      in group II (P <.05). In conclusion, Femoral AVF grafts have been condemned
      because of the unacceptable high rate of septic complications. FVT obviates the
      need for a graft and has fewer infectious problems and better patency rates.

PMID- 15013303
TI  - Renal transplantation experience following endoscopic treatment of vesicoureteral
      reflux.
AB  - The most efficacious treatment for end-stage renal disease is renal
      transplantation. Because high-grade vesicoureteral reflux forecasts potential
      future complications, the patients studied were subjected to bilateral
      nephroureterectomy before transplantation. The aim of this study was to
      investigate the posttransplantation results of a subureteral injection performed
      before transplantation to treat high-grade vesicoureteral reflux in end-stage
      renal disease patients. Renal transplantation was performed on 14 of 52 end-stage
      renal disease patients that had undergone prior subureteral injection.
      Subureteral injection had been performed in 24 refluxing renal units of these 14
      patients. Ten patients had bilateral and 4 patients unilateral reflux. The
      treatment criterion was reflux of at least grade III; however, when low-grade
      reflux was present in the contralateral renal unit, it was also treated during
      the same session. Success was determined as no (complete) or decrease to grade I
      (partial) reflux. The patient ages ranged between 13 and 46 years (mean 29.3
      years). The reflux resolved in 20 of 24 renal units (83%) and was reduced to
      grade I in 3 of the others (12%), namely resulting in a total response rate of
      95%. Except for 1 patient who was lost to follow-up, the other recipients were
      observed for 6 to 47 months (mean 23 months). Only 1 patient experienced
      symptomatic urinary tract infection or asymptomatic bacteriuria after renal
      transplantation. Acute rejection occurred in 5 and chronic rejection in 3
      patients. In conclusion, subureteral injection instead of nephroureterectomy
      seems to be an efficient and minimally invasive alternative for renal transplant
      recipients with high-grade vesicoureteral reflux.

PMID- 15013304
TI  - Sirolimus: a ten-year perspective.
AB  - Sirolimus, a macrocyclic lactone that displays a novel mechanism of
      immunosuppressive action, is a critical-dose drug requiring therapeutic drug
      monitoring for optimal outcomes. This immunosuppressive agent was studied in two
      multicenter, blinded clinical trials to reduce the incidence of acute rejection
      episodes when used in combination with cyclosporine and steroids versus
      azathioprine or placebo comparators. Cyclosporine withdrawal studies documented a
      long-term benefit of chronic sirolimus therapy on renal function, albeit with a
      modestly enhanced incidence of acute rejection episodes. I believe that minimal
      initial cyclosporine exposures de novo mitigate the need for eventual withdrawal
      for chronic nephropathy while preserving the immunosuppressive synergy during the
      maintenance phase. Recipients treated de novo with a sirolimus-cyclosporine
      combination tolerate steroid withdrawal at 1 month after living-donor or at 3 to
      6 months after cadaveric kidney transplantation with only a 5% risk of acute
      rejection episodes and 6% incidence of chronic reactions within 3 years. However,
      sirolimus exacerbates the hypertriglyceridemic and hypercholesterolemic
      proclivities of transplant recipients and exerts myelosuppressive effects. Due to
      its apparent lack of nephrotoxicity, sirolimus has been employed for induction
      therapy in a calcineurin antagonist-free regimen in combination with either
      basiliximab or rabbit antilymphocyte sera for weak or strong immune responders,
      respectively, followed by introduction of a calcineurin antagonist upon
      resolution of the ischemia-reperfusion injury.

PMID- 15013305
TI  - Two-day induction with thymoglobulin in kidney transplantation: risks and
      benefits.
AB  - INTRODUCTION: The aim of this study was to develop an induction protocol to
      reduce allograft rejection with fewer posttransplant infections and malignancies.
      METHODS: In this prospective randomized study, a T- and B-cell depletion
      protocol, consisting of IV thymoglobulin (ATG 5 mg/kg/d) plus methylprednisolone
      (500 mg/d) plus azathiopurine (2 mg/kg/d), was on days 0 and 1 after renal
      transplantation. CyA was introduced at day 3.39 among patients undergoing either
      primary living related (n = 16) or cadaveric (n = 23) transplants excluding
      recipients of full-HLA-matched sibling, or five- and six-HLA-matched cadaveric
      donor kidneys. The adequacy of immunosuppression was evaluated by flow cytometric
      analysis for total, CD3+ (T-cell), and CD19+ (B-cell) lymphocytes. RESULTS: The
      acute rejection rate was 6% and 37/39 patients are alive with functioning grafts
      at an average follow-up of 14.5 months. The overall patient and graft survival
      rate was 95%. Their mean creatinine value was 1.27 mg/dL. Six patients (16%)
      required hospitalization due to serious infections. The two deaths were
      attributed to septicemia and brain abcess caused by unusual agents, namely,
      Rhodococcus equi and Sporobolomyces. One patient presented with a cutaneous
      Kaposi sarcoma in the 11th month posttransplant. CONCLUSION: A Two-day induction
      protocol with thymoglobulin yields acceptable acute rejection rates among renal
      transplants. However, caution is necessary for adverse events, particularly
      atypical bacterial and fungal infections.

PMID- 15013306
TI  - The pharmacokinetics of equoral versus neoral in stable renal transplant
      patients: a multinational multicenter study.
AB  - We studied the pharmacokinetics (PKs) of the new generic cyclosporine
      formulation, Equoral capsules, after the switch from original formulation Neoral
      capsules in stable renal transplant patients. The study was carried out in
      accordance with the basic principles defined in the US 21 CFR Part 312.20 and the
      principles of the Declaration of Helsinki. The study included clinically stable
      first renal transplant patients maintained on cyclosporine with no rejection
      episode during the past 6 months. Hematology, biochemistry, and urine chemistry
      were determined on day 7, and day 21. The patients were all switched to Neoral
      (lot number 416MFD0601) on day 0 when the first sparse sampling PK was performed.
      On day 14 a 12-hour PK profile included predose, 30 minutes; 1 hour; 1 hour 30
      minutes; 2 hours; 3 hours; 4 hours; 5 hours; 6 hours; 8 hours; 10-hours and 12
      hour samples. Cyclosporine levels were determined using a CYA kit (Abbott TDx).
      On day 15 the patients were switched from Neoral capsules to Equoral capsules
      (lot 5T111014) at an equivalent dosage (mg/mg). The second sparse sampling PK was
      performed on day 21 and a 12-hour PK was performed on day 28. On the morning of
      day 29 patients were switched from Equoral capsules to Neoral capsules at an
      equivalent dosage (mg/mg). Additional concentrations were measured on days -7,
      18, and 35. Safety parameters were monitored at each visit. The pharmacokinetics
      of both formulations were equivalent. The mean AUC for Neoral and Equoral was
      2856 and 2892, respectively. The ratios of LSM and the 90% confidence intervals
      for the in-transformed parameters (AUC o-t, AUC inf, and Cmax) of Equoral and
      Neoral SGC were 98% and 95%, respectively, suggesting that Equoral and Neoral SGC
      are bioequivalent.

PMID- 15013307
TI  - The role of generics in transplantation: TM-MMF versus Cellcept in healthy
      volunteers.
AB  - Because several studies having revealed a relation between early graft rejection
      and long-term graft survival, potential benefits have been attributed to MMF. The
      cost of the drug is, however, prohibitive, which renders its long-term use in
      countries with limited income. We thus compared the pharmacokinetic profiles of a
      new MMF generic formulation (MM-Cept developed by Ivax CR) with those of Cellcept
      (Hoffman La Roche) in healthy volunteers. This open label, balanced randomized,
      two-treatment, two-period, two-sequence, single-dose, crossover, comparative oral
      bioavailability study was conducted in non-smoking adult male healthy volunteers
      between the ages of 18 and 45 years. The study was performed in accordance with
      the basic principles defined in the US 21 CFR Part 312.20 and the principles
      enunciated in the Declaration of Helsinki (World Medical Association Declaration
      of Helsinki). The subjects were given a single oral 1 g dose with a washout
      period of 10 days. Pharmacokinetic profiles included blood levels at 0, 0.25,
      0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 10, 12, 16, 20, 24, 30, 36, and
      48 hours following each dose. The formulations were MMCept 500 mg tablets and
      Cellcept 500 mg tablets. Subjects were fasted overnight and for 4 hours
      postdosing. Mycophenolic acid (MPA) concentrations were determined using HPLC.
      Physical examinations, hematology, urinalysis, and serum chemistry tests
      including liver enzymes were performed at screening and at the end of the study.
      Subjects were monitored for safety and adverse events throughout the study. Both
      products showed similar bioavailability. The LSM were within the limits for FDA
      approval (80 to 125), suggesting that the two products are equivalent and
      switchable.

PMID- 15013308
TI  - Evaluation of the new EMIT tacrolimus assay in kidney and liver transplant
      recipients.
AB  - Tacrolimus (FK506) is a potent macrolide immunosuppressant used for prevention of
      organ transplant rejection following transplantation. Monitoring of blood
      tacrolimus concentrations is essential to assess organ rejection and toxicity,
      because of the agent's narrow therapeutic range, wide inter- and intraindividual
      pharmacokinetic variability as well as drug interactions mediated by alteration
      in cytochrome P450. Several methods have been developed to monitor tacrolimus;
      immunoassays, bioassays, and HPLC/MS. The purpose of this study was to compare
      two analytical methods: the well-established MEIA II tacrolimus immunoassay using
      the IMx analyzer and the new EMIT 2000 tacrolimus immunoassay on the Cobas
      Integra 400 system. Tacrolimus results obtained using the two methods have been
      compared on 180 whole blood samples from kidney and liver transplant patients.
      The analytical sensitivities of both methods were defined as 1.2 ng/mL for EMIT
      and 1.5 ng/mL for MEIA II. The within-run CVs (n = 15) obtained with four-level
      controls were 9.08%, 9.41%, 5.23% and 4.4% for EMIT 2000. The comparison showed
      the following relationship between two methods: MEIA = 1.08.EMIT + 0.20 (r
      =.893). In conclusion, the EMIT 2000 tacrolimus immunoassay is a reliable
      alternative for the MEIA II method to monitor tacrolimus in organ transplant
      recipients. It provides a valid quantitative measurement of tacrolimus with
      comparable % CVs in quality-control as well as patient blood samples.
      Additionally, the EMIT 2000 method provides a rapid analysis of a large number of
      samples in one run with a low turnaround time and possibilities to reanalyze
      critical samples.

PMID- 15013309
TI  - Protocol core needle biopsy and histological chronic allograft damage index as
      surrogate endpoint for Long-Term graft survival.
AB  - Following encouraging results from several single-center studies showing that
      early histological manifestations of chronic rejection are seen in the graft
      before a decline in transplant function, we tested this concept in a multicenter
      study and investigated whether protocol needle biopsy may be used as a surrogate
      to late graft survival in multicenter renal transplantation trials. During two
      mycophenolate mofetil trials, 621 representative protocol biopsies were obtained
      at baseline, 1 year, and 3 years. The samples were coded and evaluated blindly by
      two pathologists and a Chronic Allograft Damage Index (CADI) score was
      constructed. At 1 year only 20% of patients had elevated (>1.5 mg/100 mL) serum
      creatinine, whereas 60% of the biopsies demonstrated an elevated (>2.0) CADI
      score. The mean CADI score at baseline, 1.3 +/- 1.1, increased to 3.3 +/- 1.8 at
      1 year and to 4.1 +/- 2.2 at 3 years. The patients at 1 year were divided into 3
      groups, those with CADI <2, between 2 and 3.9, and >4.0, the first two groups
      having normal (1.4 +/- 0.3 and 1.5 +/- 0.6 mg/dL) and the third group
      pathological (1.9 +/- 0.8 mg/dL) levels of serum creatinine. At 3 years there
      were no lost grafts in the "low" CADI group, six lost grafts (4.6%) in the
      "elevated" CADI group, and 17 lost grafts (16.7%) in the "high" CADI group (P
      <.001). One-year histological CADI score predicts graft survival even when the
      graft function is still normal. This observation makes it possible to use CADI as
      a surrogate endpoint in prevention trials and to identify the patients at risk
      for intervention trials.

PMID- 15013310
TI  - Tubular CD44 expression in renal allograft biopsies.
AB  - CD44 is a type I transmembrane glycoprotein serving as a cell adhesion receptor,
      whose main ligand is hyaluronic acid, but also may interact with collagen,
      laminin, fibronectin, and osteopontin. This marker is involved in cell migration,
      homing, activation, metastasis, and inflammation. Tubular CD44 expression has
      been shown to correlate with scarring in renal diseases, but there is little data
      on allograft biopsies. This deficiency is important since experimental studies
      have shown that blockade of the CD44-hyaluronic acid interaction may prolong
      allograft survival. In an attempt to clarify the role of tubular CD44 expression
      in renal allografts, CD44 expression was determined immunohistochemically in 37
      allograft and 10 implantation biopsies, as the percentage of tubules expressing
      this marker. For implantation biopsies the mean tubular CD44 expression was 6% +/
      14%; for allograft biopsies, 13% +/- 20% (P =.17, Mann-Whitney U). By the
      Spearman correlation test, CD44 expression did not correlate with Banff scores,
      but was moderately correlated with serum creatinine values at the time of biopsy
      (P =.017, r =.4). These findings suggest an important role of tubular CD44
      expression in renal allografts. It appears to be induced by more than one
      pathway, resulting in a pattern of expression that correlated with renal
      function. However larger series are required before recommending the routine use
      of this marker.

PMID- 15013311
TI  - Scintigraphic evaluation of paired renal allografts from the same cadaveric
      donor.
AB  - The aim of this study was to compare the outcome of paired grafts in renal
      recipients from the same cadaveric donor using quantitative Tc-99m DTPA
      scintigraphy. Fifty recipients from 25 cadaveric donors were followed for a
      median period of 3 years. Serial Tc-99m DTPA scintigraphy was performed starting
      on the third posttransplant day and images evaluated quantitatively. The
      quantitative parameters included Hilson's perfusion index, time to maximum
      activity, time to half of maximum activity, the ratio of the graft activity at 20
      to 3 minutes, and glomerular filtration rate. In the early postoperative period,
      20 of 25 paired kidneys showed similar performances. At the end of the first year
      22 of 25 pairs showed a similar evolution. At the end of the third year, the
      number was 21 of 25. We concluded that if cold ischemia time was prudent, there
      was no difference in graft outcome between the first and the second recipient of
      a renal transplant from the same cadaveric donor.

PMID- 15013312
TI  - Serum cystatin C as an index of renal function in kidney transplant patients.
AB  - Management of renal transplant patients requires periodic measurement of renal
      function, which is usually assessed by measuring the glomerular filtration rate
      (GFR). The most commonly used marker for GFR is serum creatinine, although muscle
      wasting and tubular secretion may lead to overestimation of the actual GFR. Serum
      concentrations of the low-molecular-weight proteins, cystatin C and beta(2)
      microglobulin (B(2)M), may afford useful markers to determine a reduced GFR. We
      investigated whether these molecules provide reliable indicators of renal
      function in 75 renal transplant patients. Cystatin C and B(2)M correlated
      significantly with creatinine (r =.648, P <.05 and r =.578, P <.05,
      respectively). Inverse serum creatinine was superior to inverse cystatin C and
      inverse B(2)M when renal function equations were used (r =.95, P <.05, according
      to MDRD; r =.87, P <.05, according to Cockroft-Gault). Receiver operating
      characteristic (ROC) analysis was performed to quantitate the accuracy of the
      different markers to detect reduced GFR using a cutoff value of 70 mL/min. No
      significant difference between the areas under the ROC curves comparing cystatin
      C and B(2)M was observed; however, serum creatinine demonstrated a significantly
      greater value than cystatin C (.981 vs.724, P =.001). We conclude that serum
      creatinine is a more efficacious marker than serum cystatin C to assess renal
      function.

PMID- 15013313
TI  - Graft and patient outcomes among recipients of renal grafts with multiple
      arteries.
AB  - Anastomosis of multiple renal arteries in living donor kidney transplantation is
      technically demanding. Previously this condition was considered a relative
      contraindication to use of the donor, due to an increased risk of vascular and
      urologic complications. We conducted this retrospective study to determine the
      prevalence of multiple renal arteries in kidney transplants and their relation to
      graft and patient survival acute tubular necrosis, as well as vascular and
      urologic complications for comparison with the outcomes of recipients of single
      artery grafts. Among the 1425 patients who underwent renal transplantation at our
      center, between November 1975 and March 2003 the present analysis concerned the
      most recent 1095 recipients. Seventy-nine (7.2%) cases required multiple-artery
      anastomoses (group I) and 1016 (92.8%) a single-artery anastomosis (group II).
      There were no significant differences between groups I and II with respect to
      creatinine clearance at 1 year, cold ischemia time at 1 year, or serum creatinine
      values at 1, 2 or 5 years (P <.05 for all). There were also no significant
      differences between the groups with respect to rate of posttransplantation
      hypertension (P =.67), acute tubular necrosis (P =.55), or number of acute
      rejection episodes (P =.34). The respective graft survival rates at 1 and 5 years
      posttransplantation were 95.1% and 73.2% in group I and 95.0% and 79% in group
      II. The corresponding patient survival rates were 95% and 88% for group I and
      97.1% and 83.1% for group II. These findings indicate that kidney grafts with
      multiple arteries may be used with excellent results.

PMID- 15013314
TI  - Do multiple renal arteries restrict laparoscopic donor nephrectomy?
AB  - Laparoscopic donor nephrectomy is a new technique. For anatomical and technical
      reasons, many transplant centers restrict laparoscopic donor nephrectomy to
      kidneys with a single artery. However, we believe that with increased experience,
      laparoscopic donor nephrectomy in cases of multiple renal arteries does not
      affect donor or recipient outcomes. Among 115 living related renal
      transplantations performed between January 1996 and December 2002, 31
      nephrectomies were performed via laparoscopy including eight with multiple
      arteries and 84 via an open approach, including nine with multiple arteries. The
      17 patients with multiple arteries at the two procedures were compared in terms
      of donor and recipient outcomes. All the patients received the same
      immunosuppressive regimen. The demographic data were similar in the two groups.
      Mean durations of the donor operations (223 vs 247 minutes), side of nephrectomy
      (left/right, 5/4 vs 7/1), mean warm ischemia times (230 vs 432 seconds), mean
      serum creatinine levels at the end of 1 year follow-up, were statistically
      similar for the open versus the laparoscopy groups. Urological (11.1% vs 25%) and
      vascular complication rates (22.2% vs 25%), acute rejection rates (11.1% vs
      12.5%) were also statistically similar for open versus laparoscopy groups,
      respectively. One-year patient and graft survival rates were 87.5% for both
      groups. Laparoscopic donor nephrectomy was as safe a procedure as open surgery
      even in the presence of multiple renal arteries in the hands of experienced
      transplants surgeons.

PMID- 15013315
TI  - Cigarette smoking in renal transplant recipients.
AB  - Cigarette smoking may adversely influence patient and graft survival. In Europe
      and the United States the prevalence of cigarette smoking in dialysis patients is
      35% to 40% and 25%, respectively. In Turkey, the estimated prevalence of
      cigarette smoking rate in the normal population is 26%. This study evaluated the
      rate of smoking in 63 cadaveric, and 158 living-related renal transplant
      recipients including (150 men, and 76 women of 38 +/- 12 years; range, 8 to 70)
      who were operated between 1986 and 2001. Demographic data were collected with a
      questionnaire delivered to patients during their routine outpatient visits.
      During this time period, 8 patients had died, 4 from hemophagocytic syndrome, 2
      from cardiovascular disease, 1 from Kaposi sarcoma and 1 from a cerebrovascular
      accident. Twenty-three patients have lost their grafts. While at the time of
      transplantation 97 (42%) were smoking cigarettes, only 29 (12%) continued smoke
      after transplantation. Male gender significantly correlated with cigarette
      smoking (P =.000). Twelve smokers were single but 85 out of 97 were married, a
      statistically significant difference (P =.010). In contrast there was no
      significant relationship between pretransplant smoking and educational status (P
      =.354); graft loss and smoking (P =.129); or mortality and smoking (P =.224).
      There was a significant relationship between pretransplant and posttransplant
      smoking (P =.000). There was no relationship between pre- and post-transplant
      smoking and development of diabetes mellitus or hypertension. Interestingly the
      posttransplant serum albumin level was lower among smokers than nonsmokers (4.44
      +/- 0.02 g/dL vs 4.30 +/- 0.02 g/dL; P =.019). There was a close relationship
      between transplantation duration and smoking.

PMID- 15013317
TI  - The psychosocial impact of renal transplantation on living related donors and
      recipients: preliminary report.
AB  - We investigated the psychosocial and demographic features of living related
      kidney donors and recipients during follow-up visits between August 2002 and
      March 2003 using two new questionnaires, one for donors and one for recipients.
      The surveys were distributed to 22 donors and 55 recipients, 18 (81.8%) donors
      and 49 (89.1%) recipients completed their questionnaires. Concerning level of
      satisfaction with quality of life after transplantation, 93.9% of the recipients
      and 72.2% of the donors were "highly satisfied". Almost all donors (94.4%) said
      that they would make the same decision again and would also strongly encourage
      others to donate. Issues related to donor dissatisfaction involved beliefs that
      preoperative information was inadequate and perceived negative effects of
      transplantation on personal health at the time the survey was conducted. Only
      6.1% of the recipients said they were dissatisfied with their quality of life
      after the operation. The main issues were psychiatric morbidity and beliefs that
      preoperative information was inadequate. Overall, the vast majority of donors and
      recipients reported that they had a positive transplantation experience. Only a
      small proportion of the subjects developed psychosocial morbidity or were
      dissatisfied with their quality of life. These results are preliminary, but it
      appears that better psychological preparation for the transplantation process and
      close psychiatric follow-up would reduce negative outcomes.

PMID- 15013316
TI  - Depression levels before and after renal transplantation.
AB  - Depression is a frequent problem among end-stage renal disease patients and is
      closely associated with their physical well-being. We sought to compare the
      depression levels and confounding parameters in renal patients. The 88 patients
      (62 men, 26 women) included: renal transplant recipients (n = 27); renal
      transplant waiting list patients (n = 30); and chronic allograft rejection
      patients on dialysis therapy (n = 31). Their mean age was 31.05 +/- 11.78 years.
      Age, gender, marital status, presence of chronic rejection, duration of
      functional graft, and hemodialysis were retrieved from patient records.
      Depression levels were evaluated by the Beck Depression Inventory. The depression
      stage of the renal transplant recipients was significantly lower than that of
      hemodialysis patients with chronic allograft rejection (P =.003). The presence of
      depression was not related to age or gender. Married patients showed a lower
      percentage of depression (P <.03). There was an inverse correlation between
      depression and functional graft duration among patients with transplant failure
      (r = -.370, P =.04). In conclusion, the return to hemodialysis, especially after
      a short duration of graft function, is associated with depression. The lower
      depression percentage among married patients may be due to the psychosocial
      support of the spouses. Therefore, single persons and transplant failure patients
      who return to dialysis therapy need greater social and psychologic support.
      Placing greater numbers of patients on transplant waiting lists decreases
      depression and may provide a higher quality of life with a better outcome during
      dialysis therapy.

PMID- 15013318
TI  - Quality of life and mood in renal transplantation recipients, donors, and
      controls: preliminary report.
AB  - Currently, living related donors are involved in approximately 85% of all kidney
      transplantations performed at our institution. Health-related quality of life
      (HRQL) is an important outcome factor in chronic disease. Quality of life may be
      diminished by prolonged illness or certain treatment modalities and by negative,
      disabling effects on mood. We investigated HRQL and mood in renal transplant
      recipients, donors, and controls using the Beck Depression Inventory, Beck
      Anxiety Inventory, and 36-item Short Form Health Survey. Recipient depression
      scores were significantly higher (indicating more serious depression) than those
      of donors (P <.05), but similar to those of the controls. There was no
      significant difference between the donor and the control subjects' depression
      scores. The anxiety scores of the recipients and donors were similar; and
      recipient anxiety scores were significantly higher than those of the control
      subjects (P <.05). The recipient scores indicated significantly poorer physical
      functioning (P <.001), significantly greater physical limitation on roles (P
      <.01), and lower levels of general health (P <.01) compared to controls. The
      recipient scores for vitality, pain, social functioning, and emotional
      limitations on roles were similar to those of the controls. Our results indicate
      that most recipients and donors experience anxiety after renal transplantation.
      This study confirms that recipients have favorable outcomes with respect to
      social functioning and emotional well-being. Overall, the results of this
      preliminary study are positive, encouraging us to continue to perform living
      donor kidney transplantation.

PMID- 15013319
TI  - Is there any effect of compliance on clinical parameters of renal transplant
      recipients?
AB  - Noncompliance with regard to diet, medications and routine physician visits is
      frequently observed among some patient groups. This results in late graft
      dysfunction and behavior loss. In the present study, we defined compliance as
      attendance at 80% or more outpatient visits. The study included 63 cadaveric and
      158 living-related renal transplant recipients namely, 150 men and 76 women of 8
      to 70 years of age (median 38 +/- 12) who were operated between 1986 and 2001.
      Demographic data, number of visits attended per month, cigarette smoking, and
      alcohol intake were probed with a questionnaire that was delivered to the
      patients, 8 of whom died; hemophagocytic syndrome (n = 4), cardiovascular disease
      (n = 2), Kaposi' sarcoma (n = 1), and cerebrovascular bleeding (n = 1). Twenty
      three patients had lost their graft. Compliance among men was lower than among
      women, a result that trended toward statistical significance (P =.087).
      Compliance was not related to marital status (P =.297), but tended to increase
      with educational background (P =.059). Graft loss (P =.546) and aging (P =.509)
      were not related to compliance. There was no relationship between compliance and
      mortality rate (P =.526). Interestingly, living-related kidney transplant
      recipients showed lower compliance than cadaveric kidney recipients, a result
      that was statistically significant (P =.04). Noncompliance was also related to
      cigarette smoking during the pre- and posttransplant periods (P =.008 and P =.03,
      respectively), as well as alcohol intake (P =.000). In conclusion, male gender
      and living-related donation are related to noncompliance, but (in contrast with
      literature) not young age, graft loss, or mortality. Compliance increases with
      educational status of the patients. Smoking and alcohol intake are closely
      related to noncompliance.

PMID- 15013321
TI  - Current status of renal transplantation in the Kingdom of Saudi Arabia.
AB  - The reported annual incidence of end-stage renal disease in Saudi Arabia is 100
      to 120 patients per million population. The first dialysis unit in Saudi Arabia
      was established in 1971; thereafter, rapid advances have been made in the field
      of renal replacement therapy. At the end of 2002, there were 144 centers offering
      dialysis to about 7390 patients. A National Kidney Foundation was established in
      1985 to implement the cadaveric organ transplant program and to coordinate the
      renal care facilities. This center was renamed Saudi Center for Organ
      Transplantation (SCOT) in 1993 to encompass transplantation of organs other than
      the kidney. An impetus was achieved in 1982 with the approval by Islamic scholars
      of the concept of brain-death and organ transplantation. From 1979, when the
      first renal transplant was performed, until the end of 2002, more than 3810 renal
      transplants have been performed in 13 transplant centers in Saudi Arabia, in
      addition to 260 liver, 95 heart, 280 heart valve, 510 cornea, 4 pancreas, 8 lung,
      and 1000 bone marrow transplants. The survival of patients and (grafts) in those
      who received living related renal transplants was 98.4(96.9), 96.7(96.7), and
      96.7(92.2) at 1, 3, and 5 years, respectively. Moreover, the survival of patients
      and grafts among those who received cadaveric donor organs was 96.2(96.2),
      93(92.1), and 93(87.2), at 1, 3, and 5 years, respectively. In conclusion, there
      has been increased renal transplantation in Saudi Arabia and there is even more
      room to increase the frequency of these transplants to decrease the expanding gap
      between supply and demand through increasing the efforts for organ donation from
      living and cadaveric donors.

PMID- 15013320
TI  - Pregnancy and renal transplantation.
AB  - Ovarian dysfunction, anovulatory vaginal bleeding, amenorrhea, high prolactin
      levels, and loss of libido are the causes of infertility in women with chronic
      renal failure. After renal transplantation, endocrine function generally improves
      after recovery of renal function. In this study we retrospectively evaluated the
      prepregnancy and postdelivery renal function, outcome of gestation, as well as
      maternal and fetal complications for eight pregnancies in eight renal transplant
      recipients between November 1975 and March 2003 of 1095 among 1425. Eight planned
      pregnancies occurred at a mean of 3.6 years posttransplant. Spontaneous abortion
      occured in the first trimester in one case. One intrauterine growth retardation
      was observed with a full-term pregnancy; one intrauterine growth retardation and
      preterm delivery; one preeclampsia with preterm delivery and urinary tract
      infection; and one preeclampsia with preterm delivery and oligohydramnios. The
      mean gestation period was 35.5 +/- 3.0 weeks (31.2 to 38.0). Pregnancy had no
      negative impact on renal function during a 2-year follow-up. No significant
      proteinuria or acute rejection episodes were observed. Among the seven
      deliveries, no congenital anomaly was documented and no postpartum problems for
      the child and the mother were observed. Our study suggests that successful
      pregnancy is possible in renal transplant recipients. In cases with good graft
      function and absence of severe proteinuria or hypertension, pregnancy does not
      affect graft function or patient survival; however, fetal problems are
      encountered such as intrauterine growth retardation, low birth weight, and
      preeclampsia.

PMID- 15013322
TI  - The renin-angiotensin system and endothelial nitric oxide synthase gene
      polymorphisms and cyclosporine toxicity in renal transplant patients.
AB  - Although cyclosporine has improved graft survival, the toxicity of the drug
      frequently causes problem for renal transplant patients. Cyclosporine displays
      deleterious effects due to direct toxicity to the nephrons and vasoconstriction
      of afferent arterioles, effects that may be due to increased angiotensin II and
      decreased nitric oxide activity. We sought to examine the relation between
      cyclosporine toxicity and the RAS (angiotensin-converting enzyme, angiotesinogen,
      angiotensin 1 and 2 receptors, and ecNOS) gene polymorphisms in 111 renal
      transplant patients. Retrospectively, we correlated the results of graft biopsies
      from these 111 patients, with the cumulative drug doses (mg), mean blood levels
      (mg/mL), mean daily doses (mg), and mean doses (mg/kg/d) of cyclosporine. Overall
      125 patients (38 women, 87 men) were enrolled in the study. Their mean age was
      34.47 +/- 11.04 years. Twenty patients displayed cyclosporine toxicity on graft
      biopsy; 91 showed no evidence of the disorder. We could not find any relation
      between cyclosporine toxicity and gene polymorphisms (P >.05), although the mean
      mg/kg/d dose was significantly high among cyclosporine toxicity group (P =.028,
      RR = 1.42). In recent studies angiotensin II and nitric oxide have been suggested
      to be related to cyclosporine toxicity; however, our results failed to reveal an
      association between cyclosporine toxicity and angiotensin II or nitric oxide
      related gene polymorphisms.

PMID- 15013323
TI  - Cyclosporine-A induced nephrotoxicity is associated with decreased renal bone
      morphogenetic protein-7 expression in rats.
AB  - The aim of our study was to investigate bone morphogenetic protein-7 (BMP-7)
      expression in a rat model of chronic cyclosporine (CsA) toxicity compare with
      healthy controls, as well as the influence of treatment with the angiotensin
      converting enzyme inhibitor (ACEI) quinapril. Twenty-four male Wistar rats were
      divided into groups of eight animals treated with CsA (15 mg/kg
      intraperitoneally) for 8 weeks (CsA group) without or with quinapril (10 mg/kg
      per day in the drinking water: CsA group + Q) for comparison with healthy
      controls (H group). The renal tissues were examined by light microscopy for CsA
      toxicity; specifically, tubulointerstitial damage and afferent arteriolopathy as
      well as BMP-7 expression were semiquantitatively scored by immunohistochemical
      staining. Mean CsA levels were 1982 ng/mL and 1968 ng/mL for the CsA and CsA + Q
      groups, respectively. At the end of the study period, the mean serum creatinine
      levels were 0.8 +/- 0.2 mg/dL, 1.6 +/- 0.8 mg/dL, and 1.4 +/- 0.8 mg/dL for the
      H, CsA, and CsA + Q groups, respectively. Interstitial fibrosis, tubular atrophy,
      and afferent arteriolar hyalinization were present in the CsA group and, to a
      lesser degree, in the CsA + Q group, compared with the H group. CsA-treated rats
      displayed significantly decreased BMP-7 expression compared with healthy controls
      (P <.0005). BMP-7 expression was higher among the CsA + Q group than the the
      group CsA group. In a rat model histologic changes characteristic of CsA-induced
      nephrotoxicity are associated with decreased expression of BMP-7, which seems to
      be at least partially restored by ACE inhibition.

PMID- 15013325
TI  - Is "zero-hour" biopsy of the transplanted kidney risky?
AB  - "Zero-hour" renal allograft biopsy provides valuable diagnostic information for
      comparison to subsequent kidney material. However, the invasive nature of the
      biopsy procedure tends to limit its widespread use in many centers. We undertook
      this retrospective study to examine the rate and clinical importance of
      complications in our series of patients routinely undergoing zero-hour biopsies
      performed between 1994 and 2001. Two hundred thirty-six zero-hour biopsies
      included only one sample performed with a 14G needle from lower posterior part of
      kidney by using a manual tru-cut technique. Doppler ultrasonography was performed
      after first 5 days. An average of 34 +/- 19 glomeruli were obtained in the
      biopsies. The biopsy specimens were adequate for diagnosis in 77% of the
      procedures. Ten (4%) patients experienced complications of intraparenchymal
      arteriovenous fistula (n = 4), which regressed spontaneously; perirenal hematoma
      (n = 4); intraparenchymal hematoma (n = 2); and a minimal perirenal collection (n
      = 41). We conclude that zero-hour biopsy is a safe diagnostic method. The rate of
      complications is low, as well as generally mild and self-limiting.

PMID- 15013324
TI  - Comparison of tacrolimus and cyclosporin in renal transplantation by the protocol
      biopsies.
AB  - Acute and chronic lesion scores on renal allograft protocol biopsies may predict
      long-term graft function. The aim of this study was to compare the effects of
      tacrolimus (Tac) and cyclosporine microemulsion (CsA) based immunosuppressive
      protocols using protocol biopsies from well-functioning renal allografts. 35
      consecutive renal transplant patients were randomized to Tac (n: 17) versus CsA
      (n: 18) treatment arms. Patient age and sex, donor type and age,
      histocompatibility, cold ischemia time and prior delayed graft function were
      similar between the two groups. Treatment protocol consisted of prednisolone,
      azathioprine and Tac or CsA. Biopsies performed on the third, sixth and twelfth
      months were blindly evaluated by the same pathologist. The incidences of acute
      rejection (AR) episodes among CsA vs Tac groups were 33% vs 29%, respectively
      (NS). The Creatinine level was lower in Tac than CsA, although it was not
      significant (Table). Subclinical AR and subclinical chronic allograft nephropathy
      were detected on protocol biopsies in 3 (2 CsA, 1 Tac) and 12 (7 CsA, 5 Tac)
      patients, respectively. Acute lesion score at the third month PBx was
      significantly lower in the Tac group (p < 0.05). Chronic lesion scores in all
      biopsies were lower in the Tac group, although not significantly. The protocol
      biopsy findings suggest that graft injury may be less pronounced among the Tac
      group.

PMID- 15013326
TI  - New aspects of posttransplant nephrotic syndrome: clinicopathologic correlations
      with outcomes.
AB  - Although posttransplant nephrotic syndrome is frequent, its structural basis and
      prognosis have not been clearly defined. The biopsy findings of 54 patients with
      this disorder posttransplant, among 375 total renal transplant recipients
      engrafted during a 10-year period, were correlated with clinical follow-up data.
      The mean patient age was 41.7 +/- 12.3 years, female/male ratio 22/32, and
      cadaveric/living-related donor ratio 37/17. The nephrotic syndrome developed 3 to
      91 months posttransplant. At the onset the mean values of serum creatinine was
      2.9 +/- 1.8 mg/dL and proteinuria 4.5 +/- 0.8 g/d. The index biopsy findings
      showed chronic allograft nephropathy (CAN) in 33; de novo glomerulonephritis (GN)
      in 6, recurrent GN in 9, and undetermined GN in 6 who had an unknown primary
      renal disease. Among 21 follow-up biopsies during a mean of 44.3 +/- 28 months
      the CAN progressed but the GN remained the same. The treatment included augmented
      steroids alone (n = 1) or in combination with cyclophosphamide (n = 2) and with
      plasmapheresis (n = 1); angiotensin-converting enzyme inhibitors (ACEI) or
      angiotensin receptor blockers (ARB) along (n = 5); calcium channel blockers (CCB)
      alone (n = 24); or the two types of drugs together (n = 22). Complete or partial
      remission was achieved in 8 and 5, respectively, but nephrotic syndrome recurred
      in 3 of these patients at 45.1 +/- 18 months later. Sustained remission was more
      likely in cases of GN (minimal change disease and IgA nephropathy) and ACEI-ARB
      treatment (P <.01). Graft failure, which occurred in 35 patients, correlated
      strongly with serum creatinine at onset, being significantly greater in patients
      with CAN (P <.005). Both remission of the nephrotic syndrome and graft survival
      were greater among patients with GN as compared to those with CAN.

PMID- 15013327
TI  - Tacrolimus conversion in kidney transplant recipients: analysis of 107 patients.
AB  - Early results of an alteration in immunosuppressive protocol of tacrolimus
      conversion at a mean follow-up of 16 (range 1 to 36) months are presented with a
      mean time after transplantation of 34 +/- 1.4 months (range 1 to 158 months).
      Chronic allograft nephropathy in 16 (17%) patients, nephrotoxicity related to
      cyclosporine in 27(23%) patients and steroids resistant acute rejection in 64
      (58%) represented the indications for tacrolimus conversion. Before starting
      tacrolimus there were 1 acute rejection episode in 37 patients, 2 in 17 patients,
      and 3 in 10 patients. After the drug conversion, 1 acute rejection occurred in 18
      and 2 acute rejection in 4 patients. Graft loss was seen in 16 (16%) patients
      after drug conversion. Tacrolimus was withdrawn due to diabetes mellitus (n = 9),
      epilepsy (n = 4), and severe Nocardia sepsis, lymphoma and Kaposi sarcoma (each
      in one patient). Decreases in serum creatinine and increases in blood glucose
      levels were significantly associated with the tacrolimus doses (P = 0.0004 and P
      = 0.0400, respectively). The increase in creatinine clearance values were closely
      related to higher tacrolimus levels. The target range with maximum efficacy and
      minimum toxicity seemed to be 10 to 15 ng/mL. Tacrolimus conversion can be
      successful in cases of rejection and nephrotoxicity, but dose-dependent blood
      glucose elevations require close observation in these patients.

PMID- 15013328
TI  - Seasonal variations of blood pressure in hemodialysis and renal transplant
      recipients.
AB  - Seasonal variations influence blood pressure (BP) in healthy persons. Its effects
      on BP in renal replacement therapy, especially after renal transplantation (RTX),
      have not been proven clearly. We studied 80 stable RTX and 82 hemodialysis (HD)
      patients for 4 years. Systolic and diastolic BP, body weight (BW), cholesterol
      (Chol), triglyceride (TG), fasting blood sugar (FBS), blood urea nitrogen (BUN),
      and creatinine (Cr) were measured monthly. Their relationship with environmental
      temperature and humidity changes were assessed by Pearson tests and Fourier
      analysis. Ambient temperature and humidity were between 2.5 degrees C to 25.4
      degrees C and 68% to 31% in the winters versus summers, respectively. The mean
      systolic BP in HD patients was 144 +/- 18 mm Hg and 140 +/- 15 mm Hg during the
      winter and summer, respectively (P =.004). For the RTX recipients, it was 133 +/-
      12 mm Hg in winter and 128 +/- 19 mm Hg in summer (P <.001). The decrement in
      diastolic BP in warmer seasons was even more significant than that in systolic BP
      in both HD and RTX groups. Also, BW in summer was significantly lower than winter
      among HD (61.1 +/- 10 kg vs 63.2 +/- 9 kg; P <.001) and RTX (64.4 +/- 8 kg vs
      65.6 +/- 8.4; P <.001) groups. Serum Chol, TG, and FBS did not change
      significantly during summer and winter in the both groups. Among RTX recipients,
      BUN level was greater in summer than winter seasons (24.2 +/- 15 vs 39.4 +/- 20
      mg/dL; P =.01), but serum Cr did not differ. The degree of humidity did not
      correlate with BP, BW, or the above biochemical markers. We conclude that BP and
      BW are decreased in warmer seasons in both HD and RTX patients. The changes are
      not accompanied by changes in biochemical markers except for BUN in RTX patients.

PMID- 15013329
TI  - The factors affecting blood pressure in pediatric renal transplant recipients.
AB  - To investigate the parameters affecting systemic blood pressure in pediatric
      renal transplant recipients, we retrospectively examined the data from 19
      adolescent renal transplant recipients including 6 girls overall, mean age of
      15,47 +/- 3.56 years. Serum creatinine (Scr), fractional extraction of sodium
      (FENa), whole blood trough cyclosporine(C0), plasma total cholesterol (TC) and
      triglyceride levels, and systolic and diastolic blood pressure (SBP and DBP) were
      monitored during a total of 677 visits. SBP and DBP, classified as <95p (groups
      1s and 1d) and >95p (groups 2s and 2d), were correlated with differences between
      groups 1 and 2. Group 2s Scr and FENa levels were higher than group 1s (P =.002
      and P =.048, respectively), whereas C0 and FENa levels were higher in Group 2d
      than Group 1d (P = 0.028 and P = 0.036, respectively). Among the entire group,
      SBP and DBP positively correlated with C0; Scr and SBP, with FENa. While there
      was a positive correlation between SBP and C0 in groups 1s and 2s (r = 0.188, P
      <.000; and r = 0.145, P =.040), DBP was only associated with C0 in group 1d (P
      =.03, r = 0.156). In contrast, DBP showed a positive correlation with Scr in
      group 2d (P =.023, r = 0.132), and SBP with Scr in Group 1s. C0 and Scr levels
      were correlated in Groups 1s, 1d and 2d. At high BP levels (>95p), SBP is mostly
      affected by C0; DBP, with Scr. However, in both groups these two parameters
      positively correlate with each other. Thus, in adolescent renal transplant
      recipients the cause of high blood pressure does not appear to be solely related
      to cyclosporine related to induced allograft dysfunction.

PMID- 15013331
TI  - Intima media thickness as a predictor of atherosclerosis in renal
      transplantation.
AB  - It has been reported that an increase in carotid artery intima-media thickness
      (IMT), a sign of early atherosclerosis, has a predictive value for future
      cardiovascular (CV) events. There are limited data about IMT measurements in
      renal transplant patients who display a high rate of CV mortality. In this study
      carotid artery IMT was measured by high resolution B-mode ultrasonography in 102
      randomly selected RT patients to assess the relationship between IMT and CV
      disease and risk factors. A positive correlation was found between IMT and age,
      triglyceride level, and hematocrit. IMT was significantly higher among patients
      who were diabetic (0.68 +/- 0.27 vs 0.50 +/- 0.2) or had CV disease (0.88 +/-
      0.28 vs 0.53 +/- 0.21). An increased IMT was associated with a longer duration of
      ESRD, higher lipid level, lower serum albumin, and presence of previous CMV
      disease. CV disease was more frequent among patients with increased IMT.
      Considering its relation to CV risk factors, it is concluded that the measurement
      of carotid artery IMT is an easy, reliable and non-invasive method to be used to
      assess atherosclerotic disease in renal transplant patients.

PMID- 15013330
TI  - Characteristics of coronary heart disease in renal transplant recipients.
AB  - The aim of this study was to identify the characteristics of coronary heart
      disease (CHD) in renal transplant recipients as well as to assess the impact of
      coronary angiography on allograft function. The 21 cases including 2 women and 19
      men who underwent coronary angiography were retrospectively studied for age at
      transplantation and at diagnosis of coronary disease; risk factors; angio
      findings; serum creatinine and blood urea nitrogen (BUN) values before and after
      angio; and revascularization procedures. The mean ages at transplantation and at
      diagnosis were 40 +/- 7 years and 44 +/- 7 years, respectively. Eighteen patients
      (86%) had hypertension, 16 (76%) exhibited hyperlipidemia, and 5 (24%) diabetes
      mellitus. Coronary angiography revealed three-vessel disease in 10 patients, two
      vessel disease in 3 patients, one-vessel disease in 4 patients, ectatic vessels
      in 2 patients, and normal coronary arteries in 2 patients. The mean serum
      creatinine and BUN levels after angio were not significantly different from the
      baseline values (pre creatinine and BUN 1.7 +/- 0.5 mg/dL and 33.8 +/- 8.6 mg/dL
      versus post 1.8 +/- 0.6 mg/dL and 32.8 +/- 10.0 mg/dL, respectively). Ten
      patients with three-vessel disease underwent coronary artery bypass surgery; 4
      patients, coronary angioplasty. The other patients received medical therapy. The
      study showed an increased likelihood of three-vessel disease among recipients
      compared with the general population and confirmed that coronary artery bypass
      surgery may be performed successfully in these patients. In conclusion coronary
      angiography is a safe diagnostic procedure with respect to allograft function.

PMID- 15013333
TI  - Angiotensin-converting enzyme gene polymorphism significantly affects renal
      posttransplantation erythrocytosis.
AB  - Posttransplantation erythrocytosis (PE) is a frequent problem in renal transplant
      patients. The pathogenesis and mechanisms of both the problem and therapy
      strategy are unknown. Since ACE and angiotensin 2 receptor inhibitors have been
      used to successfully manage PE, we speculated a relation between gene
      polymorphisms and this complication. Ninety-six ( 30 women, 66 men, age 34.4 +/-
      11.0 years) renal transplant patients evaluated retrospectively, for gene
      polymorphisms of ACE, angiotensinogen, angiotensin 1 and 2 receptors (ATR1 and
      ATR2), as well as endothelial nitric oxide synthase (ecNOS). They were divided
      into two groups; patients with versus without PE, which was defined as >15 g/dL
      hemoglobin levels during the first year after renal transplantation. PE was found
      to be significantly more prevalent among D/D than I/I gene polymorphism of ACE
      genes (P <.04). The distribution of D/D, I/D, and I/I polymorphisms were 39.1%,
      45.9%, and 7.6%, respectively. There was no difference between D/D and I/D
      polymorphisms. Comparing the I/D and I/I polymorphisms showed PE to be
      statistically more prevalent in the I/D polymorphism (P <.01). Logistic
      regression analysis revealed that D/D and I/D polymorphisms were significant risk
      factors for PE (P <.05, RR = 7.714 and P <.03, RR = 10.199, respectively). While
      previous studies revealed a relation between angiotensin II and PE, our study
      discovered the contribution of ACE gene polymorphism.

PMID- 15013332
TI  - Plasma homocysteine levels in renal transplant patients on tacrolimus therapy.
AB  - Increased plasma total homocysteine levels afford an independent risk factor to
      assess cardiovascular morbidity in patients with normal and impaired renal
      function, including stable transplant recipients. The purpose of this study was
      to evaluate plasma homocysteine levels and factors known to influence
      homocysteine metabolism (folate and Vitamin B(12)) in renal transplanted patients
      treated with tacrolimus. Plasma homocysteine, serum folate and serum vitamin
      B(12) concentrations were measured in 18 cadaveric renal transplant patients with
      stable function both before and 3 months after the renal transplantation. While
      the mean plasma homocysteine level in the renal transplant group was
      significantly higher than in the control group, no significant change was
      observed following renal transplantation under tacrolimus therapy (16.84 +/- 6.43
      micromol/L vs 16.02 +/- 6.54 micromol/L). The levels of folate before and after
      transplantation were considerably lower than the control group; a significant
      effect of tacrolimus has not been observed (7.32 +/- 4.68 ng/mL and 7.55 +/- 5.20
      ng/mL). Serum vitamin B(12) levels in the transplant group were significantly
      lower than the control group; a significant decline was seen 3 months after the
      renal transplantation (448.94 +/- 230.03 pg/mL vs 334.38 +/- 240.61 pg/mL).
      Consequently, although plasma homocysteine levels of renal transplant recipients
      are higher, a lowering effect of tacrolimus therapy was not observed on plasma
      homocysteine levels. The lower levels of folate and Vitamin B(12) in the
      transplant group compared to a control group supports therapy with folate and
      Vitamin B(12) to decrease homocysteine concentrations.

PMID- 15013334
TI  - Causes of anemia in renal transplant recipients.
AB  - Iron-deficiency anemia is one of the major problems encountered in renal
      transplant recipients. The aim of this retrospective study was to reevaluate the
      causes of anemia among 100 anemic kidney recipients. Patients with serum
      creatinine levels greater than 2 mg/dL were excluded from the study. Female
      patients were considered to be anemic if the hemoglobin was <12 g/dL for males,
      <13 g/dL. Complete blood count, serum creatinine, serum iron, iron-binding
      capacity, ferritin, transferrin saturation, erythrocyte folate, and serum vitamin
      B(12) levels were measured in all patients. Mean hemoglobin value was 10.2 +/-
      1.4 g/dL for female and 9.9 +/- 1.3 for male patients, mean corpuscular volume
      (MCV) 91.3 +/- 4.9 fL. We observed normocytic anemia in 60, macrocytic anemia in
      30, and microcytic anemia in 10 patients. A low level of serum folate was
      observed in 9 (15%) and of vitamin B(12) in 5 (8.8%) of 60 patients with
      normocytic anemia. Folate deficiency was found in 18 (60%) and vitamin B(12)
      deficiency in 12 (40%) of 30 patients with macrocytic anemia. All patients with
      microcytic anemia had iron deficiency. Splenomegaly was seen significantly more
      often in patients with macrocytic than normocytic anemia (P =.008). Folate and
      vitamin B(12) deficiency were the major causes of nutritional anemia; oral or
      parenteral supplementation with these vitamins is likely to cure the anemia in
      the majority of cases.

PMID- 15013335
TI  - Clinical course of a renal transplant recipient with malignant fibrous
      histiocytoma: a case report.
AB  - Organ transplant (Tx) recipients are susceptible to develop various malignancies,
      most of which are uncommon in the general population. We present a case of post
      Tx malignant fibrous histiocytoma with complete remission of tumor and excellent
      allograft function 3 years after cessation of cyclosporine.

PMID- 15013336
TI  - Immunosuppressive therapy and Kaposi's sarcoma after kidney transplantation.
AB  - Immunosuppressive therapy for organ transplant recipients is complicated by high
      rates of malignant diseases, one of which is Kaposi's sarcoma (KS). Between
      November 1975 and March 2003, 1425 patients underwent renal transplantation at
      our center, including the 1095 most recent procedures. Fifty-two malignancies
      were observed in 50 patients (4.7%), including 16 cases of KS. The 16 recipients
      comprised 6 men and 10 women of mean age 39 +/- 9 years (range 10 to 62 years).
      At the time of KS diagnosis, 14 recipients were receiving cyclosporine,
      azathioprine, and prednisolone, and the other 2 azathioprine and prednisolone.
      The mean time from transplantation to diagnosis was 24 +/- 15.2 months (range 8
      to 74 months). One recipient showed a lymphoma concomitant with KS. Seven
      patients had lesions limited to the skin, 5 had the skin and gastrointestinal
      tract disease, and 4 had disseminated disease. After KS was confirmed, the first
      line treatment was cyclosporine and azathioprine withdrawal with tapering of
      prednisolone. The tumors were managed by appropriate surgical and/or medical
      therapy. At the time of this presentation, 9 individuals are alive, 4 with normal
      renal function. Five patients lost their grafts due to chronic rejection. We
      found that the combination of immunosuppressive drug withdrawal and chemotherapy
      is effective in patients with limited disease, but the results are poor in cases
      of generalized disease.

PMID- 15013337
TI  - Angiotension converting enzyme inhibition and calcium channel blockage improves
      cyclosporine induced glucose intolerance in rats.
AB  - The aim of this study was to evaluate the effects of quinapril, valsartan, and
      amlodipin on glucose tolerance in cyclosporine (CsA)-toxic rats. Among 40 male
      Wistar rats 32 were administered cyclosporine (CsA) (15 mg/kg) intraperitoneally
      for 6 weeks. Quinapril (10 mg/kg per day) (group Q), valsartan (40 mg/kg per day)
      (group V), and amlodipine (10mg/kg per day) (group A) were administered to
      individual sets of eight CsA-treated animals via the drinking water with the
      remaining untreated hosts followed as a control group (group C) and 8 healthy
      controls (group H). A Glucose-tolerance test was performed by administering oral
      glucose (2 g/kg) followed by blood samples obtained from the tail vein at
      baseline as well as 30,60,90, and 120 minutes after the glucose load. Glucose
      area under the curve (AUC) was calculated according to the trapezoidal rule. CsA
      levels were determined using an immunofluorescence method. Kruskal Wallis ANOVA
      test was used for statistical analysis. Median CsA levels were 1968 ng/mL, 1982
      ng/mL, 1580 ng/mL, 1600 ng/mL; and glucose AUC, 232.4 +/- 130 mg/min per dL, 63.1
      +/- 25 mg/min per dL, 115.0 +/- 90 mg/min per dL, 47.4 +/- 34 mg/min per dL 53.4
      +/- 38 mg/min per dL for groups C,Q,V,A and H, respectively. Quinapril-treated
      and amilodipine-treated rats displayed a lower glucose AUC than group C (P <.01),
      which had higher glucose levels than healthy controls (P <.001). In summary, CsA
      treated rats show impaired glucose tolerance, which is improved by quinapril or
      amlodipine treatment. Angiotensin converting enzymes inhibitors and calcium
      channel blockers affect beta cell function rather than insulin sensitivity.

PMID- 15013338
TI  - Influence of tacrolimus plus mycophenolate mofetil regimens on acute rejection
      rate and diabetes mellitus development in renal transplant recipients.
AB  - In this study we investigated the influence of a tacrolimus (TAC) plus
      mycophenolate mofetil (MMF) immunosuppressive regimen on the acute rejection rate
      and side effect profile in renal transplant recipients. The study included 80
      living-related and 40 cadaveric donor renal transplant recipients (82 men, 38
      women) of mean age 35 +/- 10 years (range, 16 to 58) who were operated between
      August 1999 and September 2002. The mean HLA mismatches was 3 +/- 1 (range, 0 to
      5). All patients received prednisolone, MMF (2 g/d for the first 14 days
      posttransplant and then 1 g/d) plus TAC (0.2 mg/kg/d). They were followed for the
      development of rejection attacks and side effects. Diabetes mellitus developed in
      13 patients (9 men, 4 women; 10.8%). Initially, patients required insulin therapy
      but after 6 months, 5 recipients no longer needed insulin therapy and were
      switched to oral hypoglycermic agents and diet control. Hypertension was
      diagnosed in 58 patients (48.3%). Neither gender nor donor origin (P =.14; P
      =.79, respectively) produced a significant difference in diabetes mellitus
      development. Biopsy proven acute rejection episodes were observed in 16 out of
      120 patients (13.3%). Six out of 120 patients lost their grafts throughout the
      study period including one death because of suicide, one because of
      cytomegalovirus disease and hemophagocytic syndrome, one due to posttransplant
      lymphoproliferative disease and two to a cardiac arrhythmia. Only one patient
      lost his graft due to acute accelerated vascular rejection. Biopsy-proven chronic
      rejection appeared in one patient. In conclusion, although the incidence of
      insulin-dependent diabetes mellitus during posttransplant 6 months, seems high it
      decreased to 1.6% upon reduction of the TAC dosage. TAC plus MMF
      immunosuppression seems effective and safe in terms of acute rejection rates and
      side effect profiles.

PMID- 15013339
TI  - Effects of different calcineurin inhibitors on sex hormone levels in transplanted
      male patients.
AB  - Hormonal abnormalities in male patients with end-stage renal diseases are
      primarily organic and related to uremia as well as the other comorbid factors
      that frequently contribute to chronic renal failure and concomitant drug
      administration. The restoration of hormonal profiles after successful renal
      transplantation is still controversial. Immunosuppressive drugs may influence
      hormonal profiles. Our cross-sectional study of 37 male kidney transplant
      recipients investigated two groups according to their calcineurin inhibitor
      therapy, namely 21 cyclosporine versus 16 tacrolimus patients. The two groups
      were matched for age, graft function, mean duration of dialysis before
      transplantation, and duration of follow-up after transplantation. There was no
      statistical significant difference in baseline circulating levels of follicle
      stimulating hormone (FSH), luteinizing hormone (LH), testosterone (TTE), and
      prolactin (PRL) between the two groups. We found that calcineurin inhibitors have
      favorable effects on sexual hormone levels of male renal transplant patients and
      that there is no difference in baseline hormone levels between cyclosporine- and
      tacrolimus-treated male patients.

PMID- 15013340
TI  - Posttransplant complications encountered in renal transplantation in the Middle
      East.
AB  - This paper discusses the commonly seen complications encountered in Middle
      Eastern transplant recipients, including posttransplant Kaposi's sarcoma,
      tuberculosis, infective diarrhea, and pregnancy.

PMID- 15013342
TI  - Stone disease in kidney transplantation.
AB  - The aim of this study was to evaluate etiologic, diagnostic, and management
      aspects of stone disease in renal transplant recipients and donors. Calculi from
      five patients were analyzed. The immunosuppressive regimen included tacrolimus or
      cyclosporine, mycophenolate mofetil, and corticosteroids in all cases. The
      etiology of the stone disease was cadaveric donor-gifted in one patient and de
      novo stone formation after transplantation in two patients. Additionally, stone
      disease was found and treated in living related donors in two patients. The mean
      follow-up was 32.4 +/- 19.7 months. In the living related donors, stones were
      initially treated by ESWL. Pyelotomy at the back table during the transplantation
      was required in one of them. The patient with cadaver-gifted stone was also
      treated by ESWL. In patients with de novo stone formation after transplantation,
      the stones were related to urinary infections and foreign body double-j (JJ)
      stent. A small stone in one of these patients (de novo formation) passed
      spontaneously after removal of the foreign body. Endoscopical lithotripsy was
      performed in the other patient. Stones are more frequently transplanted with
      allografts than expected; therefore, preoperative imaging of the donor is
      important. ESWL is recommended for medium-sized calculi in transplant kidneys. JJ
      stent insertion before ESWL might be needed in stones larger than 10 mm.

PMID- 15013341
TI  - Problems in postoperative renal transplant recipients who present to the
      emergency unit: experience at one center.
AB  - When a renal recipient in Turkey develops a postoperative problem, consultation
      by the transplant team in the emergency unit is often the first step toward a
      solution. The main aim of this study was to identify the types of postoperative
      problems that cause renal transplantation patients to visit the emergency room.
      Gathering this information was believed to be an important step toward developing
      new management strategies for these problems, in line with the quality management
      systems used throughout our hospital network. We collated the physical signs in
      the 78 patients when they presented to the emergency room. The most common one
      was fever (26.9%) followed by nausea/vomiting, diarrhea, abdominal pain, dyspnea,
      skin lesions, headache, musculoskeletal trauma, hematuria/dysuria, epistaxis,
      psychological disorders, angina pectoris, hypertension, epilepsy, and rectal
      bleeding. Among the 78 patients, 45 (57.7%) were hospitalized and 33 (42.3%) were
      discharged with medical advice or drug treatment. Among the 45 hospitalized
      patients, 97.8% were initiated on medical treatment. Knowing the surgical and
      medical emergency issues prevalent in recipients enables the development of new
      procedures and algorithms, leading to more effective management and follow-up of
      renal transplant recipients.

PMID- 15013343
TI  - Colonoscopy is a useful diagnostic tool for transplant recipients with lower
      abdominal symptoms.
AB  - Transplant recipients are at higher risk for infection and malignancy due to
      therapies aimed at preventing rejection. Early detection and successful treatment
      of such complications is of pivotal importance for both patient and graft
      survival. In this study, we evaluated findings of 91 colonoscopies and colonic
      histopathologic findings in recipients who presented with lower gastrointestinal
      system complaints between January 1996 and January 2003. The study group included
      79 renal and liver transplant patients. The indications for colonoscopy were
      diarrhea (n = 58), abdominal pain (n = 5), hematochezia (n = 19), unexplained
      anemia (n = 5), thickening of a colonic segment detected on computerized
      tomography (n = 2), screening for lymphoma (n = 1), and Kaposi's sarcoma (n = 1).
      During the procedures, all suspicious lesions were biopsied and specimens of
      normal-appearing mucosa collected when deemed necessary in relation to the
      clinical complaints. The endoscopic findings were classified as follows: 0 =
      "normal," with clear visualization of the vascular network and normal-appearing
      mucosa; 1 = "erythema", with tissues showing erythema, edema, hyperemia, and loss
      of normal vascular network; 2 = "ulcerative," with tissues exhibiting ulceration
      and fragility; and 3 = "coincidental findings," such as polyp or angiodysplasia.
      Colonoscopic and/or histopathologic abnormalities were detected in 44.5% of the
      91 colonoscopy procedures. The results indicate that colonoscopy is a valuable
      diagnostic tool for evaluation of transplant recipients with lower
      gastrointestinal complaints. After an initial workup colonoscopy is important to
      establish an accurate diagnosis.

PMID- 15013344
TI  - Experiences in liver transplantation for hepatocellular carcinoma.
AB  - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide.
      Beside surgical resection, orthotopic liver transplantation (OLT) is not only
      effective but also the only potentially curable treatment in selected cases of
      small tumors. We report our experience in 11 male patients transplanted for HCC
      from August 1998 to July 2002. Selection criteria for OLT were unresectability of
      the hepatic tumor and severity of the underlying liver disease. The tumor
      diagnosis was confirmed by histology, imaging techniques, and tumor markers. All
      patients received an orthotopic liver allograft using a modified piggyback
      technique. Six of the 11 patients are alive; one died due to acute rejection and
      four died from recurrent disease. In all four patients with recurrent disease,
      vascular invasion was shown histologically, whereas only one patient without
      evidence of recurrence showed vascular invasion. To prevent recurrence after OLT
      the immunosuppressive regime was adjusted to the underlying disease by early
      cessation of prednisolone and reduction in the long-term exposure to
      immunosuppressive drugs. Patients were screened for recurrence by ultrasound and
      computed tomography. Recurrent HCC were treated symptomatically. OLT is an
      effective treatment for subgroups of patients with HCC. It might be possible to
      downstage the liver tumor by chemoembolization and/or radiofrequency ablation and
      allow the patients to wait for a suitable donor. After OLT the early withdrawal
      of prednisolone and the reduction of other immunosuppression is feasible. In
      conclusion, OLT can be a potentially curative therapy for HCC.

PMID- 15013346
TI  - A liver transplant center experience with liver dialysis in the management of
      patients with fulminant hepatic failure: a preliminary report.
AB  - Among extracorporeal liver support devices, liver dialysis is cleared by the U.S.
      Food and Drug Administration to be used for the management of fulminant hepatic
      failure (FHF). The outcomes of patients following liver dialysis need to be
      clearly evaluated. Among the 25 patients with FHF admitted to the Liver ICU
      between May 2000 and November 2002, 12 underwent liver dialysis, including 6 men
      and 6 women, of mean age 32 years. The causes of FHF were identified as
      acetaminophen (n = 10), herbal medications (n = 1) and autoimmune disease (n =
      1). At presentation, the mean total bilirubin was 9.35 mg/dL (range, 0 to 1.3),
      mean ALT 3015 U/L (range, 0 to 48), mean AST 3457 (range, 0 to 42), mean ammonia
      98 micromol/L (range, 10 to 60) and mean INR 1.88. A control group including 13
      patients (2 men and 11 women), of mean age 27.8 years mean total bilirubin 5.66,
      mean ALT 3494, mean AST 3528, mean ammonia 113 and mean INR 3, were not treated
      with liver dialysis, due to the lack of machine availability or physician's
      choice. The causes of FHF were acute hepatitis B (n = 1), acetaminophen (n = 10)
      or unknown (n = 2). There was no statistically significant difference in the
      baseline characteristics of the two groups (P >.05). Among the liver dialysis
      group, 1 patient died, 2 underwent OLTx, and 9 were discharged home. Among the
      control group; 4 patients died, 2 underwent OLTx, and 7 were discharged home.
      Preliminary results seem to support survival benefit among patients who underwent
      liver dialysis compared to non-liver dialysis; however, further randomized
      control trials are warranted to verify this observation.

PMID- 15013345
TI  - Liver transplantation in the presence of portal vein thrombosis: report from a
      single center.
AB  - Portal vein thrombosis (PVT) is a frequent finding in liver transplantation, the
      management of which depends mainly on its extent. In cases of mild to moderate
      PVT, a low dissection of the portal trunk, a jump graft, or direct implantation
      of graft portal vein into large venous collaterals or thrombectomy offer
      alternatives. For severe PVT anecdotal reports suggest that cavoportal
      hemitransposition, portal arterialization, or combined liver and intestine
      transplantation may be attempted, although the results to date are not
      satisfactory. When extensive perivenous and venous inflammatory changes reach the
      infrapancreatic region, liver transplantation probably should not be performed
      due to the high mortality rate.

PMID- 15013347
TI  - Acceleration of hepatobiliary dynamics in liver transplant donors.
AB  - This study compared hepatobiliary scintigraphy findings in livers before and
      after liver graft donation to examine whether there is a change in hepatobiliary
      dynamics. Nine donors underwent hepatobiliary scintigraphy with intravenous
      injection of Tc-99m mebrofenin 1 day before and during the first week after left
      liver lobectomy. Five donors also underwent additional scintigraphy more than 1
      year postsurgery. Images were acquired every second for the first minute, and
      then every minute for the next 40 minutes. Hepatic arterial perfusion index and
      portal perfusion index(PPI) were calculated from the images acquired during the
      first minute. For the function phase the computed parameters included: hepatic
      extraction efficiency, (HEE), time to appearance of activity in the intrahepatic
      biliary channels, and in the intestine, time to half maximal activity, and
      activity retained in the liver parenchyma at 40 minutes. Time to appearance of
      intrahepatic biliary channels and of intestinal activity was shorter among
      scintigraphies obtained within 1 week postsurgery compared to the preoperative
      values. Early after the operation HEE increased and PPI decreased significantly.
      Visual inspection of the scintigraphy scan obtained in all donors, within the
      first week postsurgery revealed hypertrophy of the right liver lobe. None of the
      patients showed progression of right lobe activity to the left side, even among
      scans obtained more than 1 year after donation. Reduced time to activity in the
      biliary channels and intestine and increased HEE suggest acceleration of
      hepatobiliary dynamics.

PMID- 15013348
TI  - Bilio-TIPSS fistula in a right lobe split liver transplant.

PMID- 15013350
TI  - Early postoperative complications of pediatric liver transplantation: experience
      at one center.
AB  - To evaluate the postoperative complications within the first month among 20
      pediatric liver transplant recipients between April 1990 and March 2003 we
      retrospectively studied their medical charts to gather demographic data; primary
      diagnosis; operative duration; perioperative transfusions; time to extubation;
      length of intensive care unit (ICU) stay; mortality; perioperative laboratory
      values; and postoperative complications including respiratory, infections, renal,
      neurological, cardiovascular, and gastrointestinal tract (GIT) complications. Ten
      male and ten female patients of mean age 8 +/- 4 years had a mean operative
      duration, time to extubation, and length of stay in the ICU of 12.1 +/- 2.3
      hours, 11.1 +/- 15.0 hours, and 7.2 +/- 5.5 days, respectively. The most frequent
      postoperative complication was respiratory (n = 14, 70%), followed by infections
      (n = 13, 65%), renal (n = 8, 40%), neurological (n = 7, 35%), cardiovascular (n =
      4, 20%), and GIT (n = 4, 20%) infections. The overall mortality rate was 25% (n =
      5). Compared with patients who survived, those who died displayed significantly
      lower perioperative platelet counts (P <.05), as well as a significantly higher
      incidence of postoperative neurological disorders (P =.031), and cardiovascular
      complications (P =.032).

PMID- 15013349
TI  - Technical implications of living donor liver transplantation: a single-center
      experience.
AB  - Liver transplantation for end-stage liver disease is the treatment of choice in
      current surgical practice. However, the shortage of cadaveric organs has limited
      this treatment option for many years. Living donor liver transplantation (LDLT)
      may be an option to overcome the organ shortage. In the present series we report
      a single-center experience with 39 LDLT performed from March 2000 to June 2003.
      The main indications for LDLT was hepatitis B cirrhosis (11 patients). The
      recipient hepatectomy was performed with caval preservation. The hepatic vein
      anastomosis was performed either to recipient hepatic vein or inferior vena cava.
      The portal vein anastomosis was performed either to the recipient's main or right
      portal branch. Biliary diversion was performed to the recipient biliary ducts if
      possible, otherwise to a jejunal loop in Roux-en-Y fashion. The survival rate at
      the end of one year was 71%. The leading cause of mortality was sepsis in five
      patients. Biliary complications developed in 20% of the recipients. All bile
      leaks were from the Roux-en-Y hepaticojejunostomy. Hepatic artery thrombosis was
      diagnosed in four patients by loss of hepatic blood flow on Doppler ultrasound.
      LDLT is a major surgical option for end-stage liver disease, particularly for
      countries with low rates of organ donation. However, there are technical
      challenges to be overcome such as small vessels from segmental grafts and
      multiple small bile ducts.

PMID- 15013352
TI  - Percutaneous dilational tracheotomy in solid-organ transplant recipients.
AB  - Pulmonary complications, such as pneumonia and respiratory failure, are important
      contributors to posttransplantation morbidity and mortality among solid-organ
      transplant recipients. Percutaneous dilational tracheotomy (PDT) is cost
      effective in critically ill patients who require prolonged mechanical
      ventilation; however, the literature lacks reports about the effectiveness of
      this procedure in organ transplant recipients. Between August 2001 and February
      2003, five recipients underwent PDT in our intensive care unit: two kidney, two
      liver, and one heart transplant recipient. The respective mean values for age,
      weight and APACHE II score were 41 +/- 7 yrs (range, 33-51 years), 63 +/- 14 kg
      (range, 40-80 kg), and 23 +/- 9 (range, 15-35). All PDTs were performed at the
      bedside by an experienced staff anesthesiologist under endoscopic guidance using
      the Griggs forceps dilational technique. The mean interval from transplantation
      to PDT was 58 +/- 56 months (range, 8 days to 132 months). In all cases, the
      indication for PDT was prolonged mechanical ventilation due to acute respiratory
      failure. The mean duration of endotracheal intubation before PDT was 4 +/- 3 days
      (range, 1-8 days). Transient hypoxemia (n = 1) and mild extratracheal bleeding (n
      = 1) were the only early complications. There were no late complications
      (including peristomal infection) or deaths associated with the procedures. Among
      the two patients who survived their stay in the intensive care unit, the
      functional and cosmetic outcomes of PDT were excellent. We recommend this
      technique for prolonged airway management in solid-organ transplant recipients.

PMID- 15013353
TI  - Prospects and strategies for clinical tolerance.
AB  - The morbidity and mortality associated with chronic immunosuppression provide a
      strong motivation for development of clinical tolerance. This paper discusses the
      definition(s) of clinical (operational) tolerance, the role of chimerism in
      experimental and clinical tolerance, and the special role of bone marrow in
      tolerance induction. The states of microchimerism and macrochimerism are defined
      and related to certain clinical observations in solid organ transplantation.
      Current clinical strategies already being tested in the clinic are briefly
      reviewed. Certain principles for induction of clinical (operational) tolerance
      are elaborated.

PMID- 15013351
TI  - Risk factors for postoperative respiratory complications in adult liver
      transplant recipients.
AB  - To determine the types and the incidence of as well as risk factors for early
      postoperative (<30 days) respiratory complications in adult liver transplant (LT)
      recipients, we reviewed The data of 44 consecutive adult LT recipients who
      received their grafts from January 1995 through December 2002. The data included
      demographic features; primary diagnosis; number of intraoperative transfusions;
      preoperative and postoperative laboratory values; intraoperative and
      postoperative characteristics; and early postoperative (<30 days) mortality.
      Pulmonary atelectasis, pleural effusion, pneumonia, respiratory failure, and
      pulmonary edema were the respiratory complications investigated. Twenty-six
      patients (59.1%) developed at least one respiratory complication during the early
      postoperative period. The most frequent complication was pleural effusion (n =
      18, 40.9%), followed by atelectasis (n = 13, 29.5%), pneumonia (n = 10, 22.7%),
      acute respiratory failure (n = 5, 11.4%), pulmonary edema (n = 3, 6.8%), and
      pneumothorax (n = 2, 4.5%). Compared to the patients who did not develop these
      problems, the affected cohort was significantly older (27 +/- 12 years vs 36 +/-
      14 years, respectively; P =.039) and required more intraoperative transfusions (P
      =.005). Among the overall mortality rate of 15.9%, patients who developed
      pneumonia showed a significantly higher mortality (40.0% vs 8.8%, respectively; P
      =.037). Pleural effusion, atelectasis, and pneumonia are the main respriatory
      complications that occur in adult LT recipients. Patient age and intraoperative
      transfusion requirements are important predictors of early postoperative
      complications. Pneumonia is associated with a poor prognosis in this patient
      group.

PMID- 15013354
TI  - Effectiveness of transient immunosuppression using cyclosporine for xenomyoblast
      transplantation for cardiac repair.
AB  - We studied the survival of human myoblast for cellular myocardial reconstruction
      in a porcine model of chronic myocardial ischemia with immune tolerance using
      transient immunosuppression. A porcine model of chronic cardiac ischemia was
      created in 10 pigs (DMEM medium-injected n = 4; myoblast transplanted n = 6) by
      clamping ameroid ring around left circumflex coronary artery. Three weeks later,
      3 x 10(8) human myoblasts carrying lac-z reporter gene were transplanted in
      multiple sites (0.25 mL each) into the left ventricular wall. Immunosuppression
      was achieved with 5 mg/kg cyclosporine for 6 weeks after cell transplantation.
      After animals were euthanized between 6 and 30 weeks after cell transplantation;
      the heart was removed for histological studies. Discontinuation of
      immunosuppression after 6 weeks of cell transplantation did not result in donor
      cell rejection. The lac-z-positive donor cells were detected in porcine host
      cardiac tissue for up to 30 weeks posttransplantation, expressing human skeletal
      myosin heavy chain. The results highlight the effectiveness of transient
      immunosuppression for myoblast transplantation for cardiac repair.

PMID- 15013356
TI  - Trends in research support and productivity in the changing environment of
      academic surgery.
AB  - BACKGROUND: We hypothesized that the changing environment of academic surgery has
      resulted in a decrease in surgical research funding and basic surgical research
      productivity of academic departments of surgery. MATERIALS AND METHODS: Trends in
      National Institutes of Health (NIH) grants to Departments of Medicine and Surgery
      were analyzed from 1992 to 1999. To assess trends in research productivity,
      selected basic science journals were screened from 1988 to 1999 for the number of
      basic research publications where authors cited affiliation with a Department of
      Medicine or Surgery. RESULTS: NIH funding to Schools of Medicine increased 5.9%
      per year from 1992 to 1999. Funding to Departments of Medicine increased 21.1%
      per year, whereas funding to Surgery increased 3.1% per year. As a percentage of
      total funding to medical schools, NIH funding to Departments of Surgery declined
      slightly and funding to Departments of Medicine increased 1% per year. The number
      of grants awarded to Schools of Medicine and Departments of Surgery and Medicine
      remained constant from 1992 to 1999. The number of publications in basic science
      journals trended up for both Departments of Surgery and Departments of Medicine.
      As a percentage of departmental totals, Departments of Surgery publications
      increased by 9.5% yearly and Departments of Medicine increased 1.5% per year.
      CONCLUSION: Support for basic surgical research has been static. Despite static
      grant support, basic research productivity has increased for Departments of
      Surgery. Basic surgical research remains an integral part of academic surgery
      department activity.

PMID- 15013355
TI  - Noninvasive, quantitative assessment of left ventricular function in ischemic
      cardiomyopathy.
AB  - BACKGROUND: Coronary artery disease characteristically impacts left ventricular
      (LV) function on a regional basis, although ultimately global function may be
      affected as well. Echocardiography is commonly clinically used for the assessment
      of regional function; however, it is only semiquantitative and in its current
      iteration is only two-dimensional in nature. Magnetic resonance imaging (MRI)
      with tissue tagging offers the possibility for noninvasive, three-dimensional
      (3D) assessment of transmural and segmental left ventricular strain and, thereby,
      function. Accordingly, we have explored methodologies to accurately and
      quantitatively characterize regional systolic function in three dimensions in
      patients with ischemic heart disease using MRI. MATERIALS AND METHODS: MRI
      radiofrequency tissue tagging was performed at rest and during dobutamine
      administration (10 mg/kg/min) on 10 normal volunteers (age: 26 +/- 6) and 8
      patients with severe ischemic cardiomyopathy (age: 60 +/- 5, EF 26 +/- 11%).
      Three-dimensional global and regional systolic strain calculations were made
      based on 3D myocardial point displacements and compared with conventional
      measures. RESULTS: Global left ventricular strains were significantly decreased
      in ischemic patients at rest (0.14 +/- 0.04 versus 0.25 +/- 0.02, P < 0.001) and
      with dobutamine (0.14 +/- 0.03 versus 0.29 +/- 0.03, P < 0.001). In the regional
      analysis (216 LV wall segments) this methodology accurately differentiated normal
      from abnormally contracting regions. CONCLUSIONS: Noninvasive dobutamine MRI
      tissue tagging with calculation of 3D regional strains has significant promise as
      a clinical tool which is capable of the identification, quantification, and
      display of regionally varying ventricular function.

PMID- 15013357
TI  - Improved microcirculation of a liver graft by controlled portal vein
      arterialization.
AB  - BACKGROUND: The clinical results of portal vein arterialization (PVA) in liver
      transplantation are controversial without a standardized portal flow regulation.
      The aim of these experiments was to perform a flow-regulated PVA in liver
      transplantation, to examine the microcirculation and early graft function after
      heterotopic auxiliary liver transplantation (HALT) with flow-regulated PVA, and
      to compare this technique with HALT with porto-portal anastomosis. Using the
      recently developed orthogonal polarization spectral (OPS) imaging, for the first
      time the microcirculation of liver grafts with PVA was visualized. MATERIALS AND
      METHODS: HALT was performed in Lewis rats. The portal vein was either completely
      arterialized via the right renal artery in a standardized splint-technique (Group
      I, n = 8) or anastomosed end-to-end to the recipient's portal vein (Group II, n =
      8). RESULTS: After reperfusion, the average blood flow in the portal vein was
      within the normal range in Group I (1.7 +/- 0.4 ml/min/g liver weight) and
      significantly higher than in Group II (1.2 +/- 0.2 ml/min/g liver weight). The
      functional sinusoidal density in Group I (335 +/- 48/microm) was significantly
      higher than in Group II (232 +/- 58/microm), whereas the diameter of the
      sinusoids and the postsinusoidal venules yielded no significant differences
      between both groups. The bile production was comparable (27 +/- 8 versus 29 +/-
      11 microl/h/g liver weight). CONCLUSIONS: In our experiments it was possible to
      achieve an adequate flow regulation in the arterialized portal vein with good
      results concerning microcirculation and early graft function. We recommend that
      further investigations on liver transplantation with PVA should be performed with
      portal flow regulation, before PVA is employed in clinical transplantation.

PMID- 15013358
TI  - Altered cyclooxygenase-2 expression and nitric oxide metabolism following major
      elective surgery.
AB  - BACKGROUND AND AIMS: Postoperative variation in immune function leads to
      increased susceptibility to infections. Cyclooxygenase-2 (COX-2)-generated
      Prostaglandin-E(2) (PGE(2)), which signals through the PGE(2) receptor (EP
      receptor), as well as nitric oxide metabolites (NOx), appear to be important in
      postoperative immune dysfunction. It is unclear, however, how these substrates
      and receptors change over time. This study was conducted to evaluate
      postoperative changes in inflammatory mediator production and monocyte COX-2 and
      EP receptor expression. MATERIALS AND METHODS: Nineteen patients had blood drawn
      preoperatively and up to 1 week postoperatively. Plasma NOx levels were measured.
      Peripheral blood mononuclear cell (PBMC) COX-2 and EP receptor mRNA expression
      were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). PBMC
      PGE(2), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and IL-10
      productions were evaluated by enzyme-linked immunosorbent assay (ELISA) kits.
      Statistical analyses were by ANOVA and Student's t tests. RESULTS:
      Postoperatively, PBMC mean PGE(2) and IL-6 productions were significantly
      increased at all time points. Mean TNF-alpha production was maximal on
      postoperative day 2, while mean IL-10 production was unchanged. Mean circulating
      NOx levels demonstrated a biphasic response decreasing early postoperatively and
      normalizing at postoperative day (POD) 7. PBMC COX-2 enzyme and EP receptor mRNA
      expression were unchanged. CONCLUSIONS: Altered PBMC PGE(2) production and plasma
      NOx levels support a role for altered macrophage activity, which may contribute
      to immune dysfunction in the postoperative period.

PMID- 15013359
TI  - Limitations of implantable, miniature ultrasonic transducers to measure wall
      movement in the canine jejunum.
AB  - BACKGROUND: We used implantable miniature ultrasonic transducers to measure
      longitudinal distance, circumference, and wall thickness dynamically in vivo in
      canine jejunum. We hoped to differentiate circular from longitudinal smooth
      muscle contractions and to correlate physical measurements of change in distance
      within the jejunal wall with intraluminal manometry. MATERIALS AND METHODS: In
      acute experiments at the time of celiotomy, longitudinal distances,
      circumferences, and wall thickness were measured directly and by ultrasonic
      transducers sewn to serosa and mucosa. Measurements were obtained with the
      intestine empty and after distention with air, water, or semisolid slurry. In
      chronic in vivo experiments in conscious dogs with indwelling ultrasonic
      transducers and intraluminal manometers, sonometric dimensions were correlated
      with manometric recordings. In acute experiments, sonometric measurements were
      similar to direct measurements. In chronic experiments in vivo, smallest
      ultrasonometric measurements of circumferences of the jejunum correlated in a
      phase-locked temporal manner with both highest intraluminal pressures and
      greatest wall thickness. RESULTS: Longitudinal distances increased during
      decreases in circumference. Distances orad to the site maximal intraluminal
      pressure peaked at 0.58 +/- 0.04 s ( x +/- SEM) before, and those aborad to this
      point 0.42 +/- 0.04 s after attaining minimum circumferences. CONCLUSIONS:
      Ultrasonic crystals can monitor geometric changes in the bowel wall with certain
      limitations, especially when obtained in vivo. Contraction of circular and
      longitudinal muscles, although phase-locked, do not appear to occur exactly
      synchronously in canine jejunum.

PMID- 15013360
TI  - Young male smokers have altered platelets and endothelium that precedes
      atherosclerosis.
AB  - BACKGROUND: Cigarette smoking results in abnormalities of platelets and
      endothelium with platelet dysfunction implicated in vascular complications.
      Healthy endothelium plays a pivotal role in regulating hemostasis via the
      inhibition of platelet activation and aggregation. Thus, we examined if platelet
      dysfunction correlated with serum vWF levels-a circulating marker of endothelial
      dysfunction. MATERIALS AND METHODS: We tested this hypothesis in young male
      smokers. The parameters of platelet function tested included: CD62/CD63;
      Glycoprotein (GP) IIb/IIIa; Platelet function analzyer (PFA) studies, platelet
      aggregometry, flow assessment of platelet microparticles, platelet-leukocyte
      interactions and receptor numbers. Endothelial dysfunction was assessed with
      serum von Willebrand Factor (vWF). RESULTS: There was a significant increase in
      platelet CD62 receptor expression and aggregation with an associated delay in
      time to aggregation using PFA. Endothelial dysfunction was represented by higher
      serum levels of von Willebrand Factor. All other platelet parameters tested were
      within the standardized reference range. CONCLUSIONS: These initial data suggests
      that anti-platelet therapy may have a role in reduction of platelet activation
      and aggregation in young smokers and possibly alter vascular endothelial
      abnormalities.

PMID- 15013361
TI  - Effect of burn injury on glucocorticoid receptor binding activity in rat muscle.
AB  - Burn injury is associated with increased muscle proteolysis and up-regulated gene
      expression in the proteolytic pathway. Glucocorticoids (GCs) are the most
      important mediator of burn injury induced muscle cachexia. However, the
      understanding of the mechanisms of GCs action in response to burn injury remains
      elusive. It is well known that GC acts by binding its own receptor. Therefore, in
      the present study, we examined the influence of burn injury on the hormone
      binding activity of the glucocorticoid receptor (GR) in skeletal muscle. Burn
      injury resulted in increased hormone binding activity in extensor digitorum
      longus (EDL) and soleus muscles. Scatchard plots revealed that the increased GR
      hormone binding activity reflected increased numbers of hormone binding sites,
      whereas receptor affinity for GCs was unchanged. Western blot analysis showed
      that dissociation of GR/heat shock protein 90 heterocomplex or increase in GR
      protein may account for the effect of burn injury. The GR antagonist RU 38486
      blocked the burn injury-induced increase in GR hormone binding activity,
      implicating a positive regulatory effect of GCs on GR binding activity under the
      present experimental conditions.

PMID- 15013362
TI  - Melatonin ameliorates renal ischemia/reperfusion injury.
AB  - BACKGROUND: We studied whether melatonin is able to reduce organ damage during
      renal ischemia/reperfusion via its effects on the oxidative response in early and
      late reperfusion. MATERIALS AND METHODS: Renal ischemia/reperfusion injury (I/R)
      was induced in two groups of rats by 75 min occlusion of the left renal artery
      and vein and right nephrectomy, followed by reperfusion. The formation of
      reactive oxygen species was evaluated in the early reperfusion phase (60 min) by
      lipid peroxidation products and glutathione assay. In the late reperfusion phase
      (24 h) tissue neutrophil infiltration, inducible nitric oxide synthase (iNOS)
      gene expression, and histopathology were evaluated. Groups received either
      systemic melatonin (MEL) or normal saline (NS). There were two nonischemic sham
      control groups, one with and another without melatonin (S+MEL and S). RESULTS:
      Creatinine was higher in the NS group at all times. A reduction in glutathione
      and increases in lipid peroxidation products and myeloperoxidase activity induced
      by I/R indicated renal injury involving reactive oxygen formation. Melatonin
      reversed this oxidant response and reduced the rise in creatinine and iNOS
      expression. Seven-day group survivals were 5/10 for NS, 8/10 for MEL, and 10/10
      for both Sham groups. CONCLUSIONS: Exogenous melatonin is able to preserve renal
      functional status following I/R-induced injury by increasing glutathione and
      reducing lipid peroxidation in the early reperfusion phase, without any apparent
      effect on neutrophil infiltration in the late reperfusion phase.

PMID- 15013363
TI  - Evaluation of liver function for hepatic resection for hepatocellular carcinoma
      in the liver with damaged parenchyma.
AB  - BACKGROUND: Liver functional parameters, including the Child-Pugh score and
      indocyanine green clearance (ICG), and volumetric parameters influencing
      postoperative liver function were evaluated with the aim of obtaining
      standardardized criteria for selecting patients for, and deciding the extent of,
      hepatectomy for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The study
      population consisted of 120 patients with HCC undergoing hepatic resection
      excluding those with more than 3000 ml of intraoperative bleeding. Patients were
      classified as grades A, B, or C on the basis of, respectively, a Child-Pugh score
      of 5 or 6, 7-9, or >or=10 and were assigned to group D (postoperative liver
      dysfunction) or group N (no complication). Postoperative complications included
      massive ascites, pleural effusion, or hyperbilirubinemia. For each grade, the
      standardized estimated liver remnant ratio (STELR) was determined as the ratio of
      the liver remnant volume (estimated by computerized tomography) to the
      standardized total liver volume (STLV), estimated from the body surface area
      using the equation: liver volume [cm(3)] = 706 x body surface area [m(2)] + 2.4.
      The ICG retention rate at 15 min after injection (ICGR15) was then plotted
      against the STELR for each grade and a demarcation line separating patients in
      groups N and D was determined statistically by discriminant analysis. RESULTS:
      For grade A patients, the equation of the demarcation line was ICGR15 = 27.5 x
      STELR + 1.9 (Wilks' Lambda: 0.667, P < 0.001), indicating that, for safe hepatic
      resection in patients with an ICGR15 of 10%, the STELR should be greater than
      0.29. In contrast, for grade B patients, the equation was ICGR15 = 72 x STELR -
      22.1 (0.589, P < 0.001), indicating that, in patients with a 10% ICGR15, the
      STELR should be greater than 0.44, a larger value than in grade A patients. The
      number of grade C patients was too small for analysis. CONCLUSIONS: By combining
      the Child-Pugh score, ICG clearance, and liver volumetric parameters, criteria
      for the selection of patients for hepatic resection for HCC were established.

PMID- 15013364
TI  - Glucocorticoid pretreatment induces cytokine overexpression and nuclear factor
      kappaB activation in macrophages.
AB  - BACKGROUND: Glucocorticoids are widely used in treating inflammatory diseases.
      The contribution of adrenal glucocorticoids to inflammatory regulation is
      unknown. Endogenous glucocorticoids, as distinct from synthetic analogues, not
      only suppress but also enhance immune functions. Elevated circulating cortisol
      levels are characteristic of injured patients. In a model of trauma, an early
      glucocorticoid surge occurs concomitantly with decreased cellular cytokine
      responses. Cytokine production elevated late after injury is associated with
      increased mortality. We hypothesized that this glucocorticoid surge mediates the
      later heightened macrophage responses. MATERIALS AND METHODS: The murine
      macrophage like cells RAW 264.7 were incubated with corticosterone (35 ng/mL), or
      vehicle control, for 1 h, after which the cells were washed and corticosterone
      free medium added. At 0, 3, 6, 12, and 24 h after removal of the corticosterone,
      the cells were stimulated with lipopolysaccharide (LPS) and interferon-gamma.
      Supernatant tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and nitrite
      levels were measured. In separate experiments the effect of pretreatment with
      corticosterone on TNF-alpha, IL-6, and nitrite mRNA expression as well as nuclear
      factor-kappaB and glucocorticoid receptor activity was determined. CD14 receptor
      expression was determined by flow cytometry. RESULTS: Glucocorticoid pretreatment
      caused significantly increased RAW 264.7 cell production of nitrite, IL-6 and TNF
      alpha. mRNA for these inflammatory mediators was induced 6 h after the
      corticosterone pretreatment, and was associated with activation of nuclear factor
      kappaB in the presence of activated glucocorticoid receptor. Cell surface
      expression of CD14 was likewise increased. CONCLUSIONS: The results of this study
      demonstrate a novel role for glucocorticoids and provide a mechanism for the late
      upregulation in macrophage function after injury.

PMID- 15013365
TI  - Pattern of ischemia reperfusion injury in a mouse orthotopic liver transplant
      model.
AB  - BACKGROUND: The molecular pathways of ischemic injury after liver transplantation
      are complex and difficult to dissect because of the presence of many variables.
      Transgenic and genetically deficient strains of mice provide ideal models for the
      study of the contribution of a single gene product in biological processes in
      vivo. Although well described in rats, prolonged preservation has not been
      studied in a mouse model of orthotopic liver transplantation (mOLT). The aim of
      this study was to establish a model of cold ischemia and reperfusion injury in
      mOLT and describe the pattern of the regenerative response to various lengths of
      cold storage. MATERIALS AND METHODS: mOLT was performed using a syngeneic
      combination. Grafts were preserved at 4 degrees C in University of Wisconsin
      (Viaspan) solution for increasing periods of cold preservation. After cold
      storage, the liver grafts were transplanted and recipient survival was monitored.
      Hepatocellular injury was determined by histology, and the regenerative response
      was quantitated by interleukin 6 upregulation and DNA replication. RESULTS: Long
      term survival was 100%, 100%, 88%, and 0% for cold preservation of 1, 4, 8, and
      16 h, respectively. Grafts with short preservation times (1 and 4 h) demonstrated
      limited injury and a weak regenerative response, with slight IL-6 early
      upregulation and minimal cell division. Eight hours of cold ischemia resulted in
      prominent injury and an intense regenerative response accompanied by significant
      IL-6 upregulation and DNA synthesis. Sixteen hours of storage resulted in all
      recipients succumbing to liver failure, with histology showing extensive hepatic
      necrosis. CONCLUSIONS: This study demonstrated the feasibility of using the mOLT
      model for the study of molecular mechanisms associated with recovery from cold
      ischemia and reperfusion injury. Increasing lengths of cold ischemia correlate
      with progressive tissue damage whereas recovery is associated with a regenerative
      response that correlates with the severity of injury.

PMID- 15013366
TI  - Immune responses of graft mesenteric lymph node in small bowel transplantation.
AB  - BACKGROUND: The high proportions of lymphoid tissues are thought to be one of the
      underlying factors inducing severe allograft rejection following small bowel
      transplantation. Mesenteric lymph nodes (MLN) contained in the intestinal graft
      are not only a source of donor-derived professional antigen-presenting cells, but
      also offer a field for immune interaction between donor and host cells. We
      investigated immune responses in graft MLNs with or without FK506 to develop a
      novel strategy to control small bowel allograft rejection. MATERIALS AND METHODS:
      Heterotopic small bowel transplantations were performed from Brown Norway donors
      to Lewis recipients. Changes in population of lymphocytes, expressions of
      costimulatory molecules, apoptosis, and cytokine profiles in graft MLNs were
      evaluated. RESULTS: The increase in apoptotic cells and cytokine responses
      relating to rejection in the graft MLNs developed prior to those in graft
      jejunum. While donor lymphocytes in graft MLNs were rapidly replaced to host
      derived lymphocytes independent of FK treatment, increase in CD8(+) T cells in
      host population was seen only in recipients without FK506 treatment. The
      expressions of B7 molecules on donor cells in graft MLNs were significantly lower
      in the recipients with FK treatment. CONCLUSIONS: Immune responses in graft MLNs
      have significant impact on the outcome of the small bowel allograft. Apoptosis of
      graft MLN cells was well correlated with and ahead of progression of acute
      rejection. Modulation of costimulatory molecules on donor-derived MLN cells in
      the allograft and specific suppression of host CD8(+) T cells are possible ways
      to control severe rejection after allogeneic small bowel transplantation.

PMID- 15013367
TI  - Characteristic alteration of monocytes with increased intracellular IL-10 and IL
      12 in patients with advanced-stage gastric cancer.
AB  - BACKGROUND: It was previously reported that monocytes/macrophages play an
      important role in mediating T cell dysfunction in tumor-bearing hosts, in which
      monocytes/macrophages were found to induce the loss of T cell functions
      concomitantly with induction of defects in T cell signaling molecules. These
      observations encouraged us to investigate monocytes status in cancer-bearing
      hosts. MATERIALS AND METHODS: We characterized peripheral blood monocytes in
      gastric cancer patients with advanced disease (n = 14), in those with early
      disease (n = 17), and in healthy individuals (n = 14), based on surface marker,
      oxygen-burst capacity, and intracellular cytokine status (IL-10 and IL-12).
      RESULTS: Intracellular IL-10 and IL-12 status on monocytes in advanced disease
      was significantly increased in comparison with those in early disease or healthy
      individuals, while there were no differences in the surface marker or oxygen
      burst capacity of monocytes. To clarify which mediators induced the
      characteristic differences of monocytes in cancer-bearing hosts, healthy donor
      derived monocytes were coincubated with the patient's plasma. The plasma from the
      patients with advanced disease could induce healthy monocytes to increased
      intracellular IL-10 and IL-12 status. The phenomenon was significantly inhibited
      with neutralizing mAbs specific for VEGF. Furthermore, the contents of VEGF in
      the patient's plasma correlated with their capacity to induce healthy monocytes
      to increased intracellular IL-10. In addition, the treatment of healthy monocytes
      with exogenous VEGF resulted in increased intracellular IL-10. CONCLUSIONS:
      Monocytes in gastric cancer patients with advanced disease showed different
      characteristics in comparison with those with early disease or healthy
      individuals, which might be potentially induced by circulating VEGF in the
      patients.

PMID- 15013368
TI  - Neuroblastoma survival and death: an in vitro model of hypoxia and metabolic
      stress.
AB  - Heterogeneous oxygen tension and access to metabolites in solid tumors may
      produce variability in response to adjuvant therapy. To better understand these
      microenvironmental features, we examined survival and proliferation of
      neuroblastoma (NB) cells in an in vitro model of hypoxia and metabolite
      deprivation. Human NB cells (SH-SY5Y) were subjected to a "self-generated"
      diffusion gradient of nutrient and oxygen deprivation in a modified in vitro
      "sandwich model." In this model, the extent of both hypoxia and metabolite
      deprivation were individually altered, and the effects of each were studied.
      Cellular proliferation was confirmed by proliferating cell nuclear antigen (PCNA)
      immunocytochemistry and morphology and hypoxia by vascular endothelial growth
      factor (VEGF) and pimonidazole immunocytochemistry. We examined apoptotic cell
      death using TUNEL analysis, assaying for plasma membrane transfer of
      phosphotidylserine and the presence of the anti-apoptotic protein Bcl-2 using
      immunocytochemistry. As predicted, cellular survival diminished with increasing
      duration and severity of hypoxia and metabolite deprivation; oxygen deprivation
      was determined to be the more important contributory factor to early survival and
      proliferation. PCNA immunocytochemistry confirmed decreasing fractions of
      proliferating cells as a function of distance from oxygen and metabolites. VEGF
      and Bcl-2 immunoreactivity increased with prolonged exposure and increased extent
      of oxygen/metabolite deprivation. TUNEL analysis and phosphotidylserine transfer
      demonstrated cellular death of hypoxic and metabolite-deprived NB cells in a
      manner consistent with a mitochondrial apoptotic pathway. This in vitro model
      demonstrates that increasing the severity of hypoxia and metabolite deprivation
      results in diminished proliferation and greater apoptotic death, observations
      analogous to that of clinical NB tumors.

PMID- 15013369
TI  - Hemodynamics in a compliant hydraulic in vitro model of straight versus tapered
      PTFE arteriovenous graft.
AB  - BACKGROUND: Hemodialysis patients require a vascular access to deliver sufficient
      blood flow to the artificial kidney. Of these vascular accesses, 30% are
      prosthetic (mainly polytetrafluorethylene [PTFE]) graft implants. These grafts
      are prone to the development of stenosis in the vein due to intimal hyperplasia,
      subsequently leading to thrombosis and graft failure. AIM: We investigated the
      hemodynamics in a straight and a tapered PTFE-graft and compare the
      hydrodynamical behavior of both grafts. MATERIALS AND METHODS: Two different
      vascular access geometry models were examined: a 6-mm diameter straight graft and
      a 4- to 7-mm tapered graft. The grafts were sutured to a compliant silicon model
      of an artery and vein in a loop configuration. Flow rate varied between 500 and
      1500 mL/min. Two conditions were tested: 1). control: mean pressure is 100 mm Hg
      at the arterial inlet; and 2). low resistance condition: pressure is 20 mm Hg at
      the venous outlet. Pulse pressure is 60 mm Hg at the arterial inlet for both
      conditions. Pressure and flow velocity are measured continuously, while flow rate
      is measured volumetrically. RESULTS: The pressure drop at the arterial
      anastomosis of the tapered graft is three times higher compared to the straight
      graft model. Intragraft pressure drops are similar in both graft types. Mean
      pressure and pulse pressure in the graft and vein are decreased in the low
      resistance condition. Also, the difference between maximum and minimum velocity
      is smaller in this. CONCLUSIONS: No significant differences are noted between the
      graft geometries: pressure drop over the graft is almost equal. The major
      difference is the higher pressure drop at the arterial anastomosis of the tapered
      graft.

PMID- 15013370
TI  - Computational fluid dynamic study of flow optimization in realistic models of the
      total cavopulmonary connections.
AB  - OBJECTIVES AND BACKGROUND: In the Fontan circulation, pulmonary and systemic
      vascular resistances are in series. The influence of various inferior vena cava
      to pulmonary artery connections in this unique circulatory arrangement was
      evaluated using computation fluid dynamics methods. METHODS: Realistic three
      dimensional models of total cavopulmonary connections were created from
      angiographic measurements to include the hepatic vein, superior vena cava, and
      branches of the pulmonary arteries. Steady-state finite volume analyses were
      performed using identical in vivo boundary conditions. Computational solutions
      calculated the percent hydraulic power dissipation and left-to-right pulmonary
      arterial flow distribution. RESULTS: Simulations of the lateral tunnel, intra
      atrial tube, extracardiac conduit with left and right pulmonary artery
      anastomosis demonstrated extracardiac conduit with left pulmonary artery
      anastomosis having the lowest energy loss. Varying the extracardiac conduit from
      10 to 30 mm resulted in the least energy dissipation at 20 mm. Serial dilation of
      the lateral tunnel pathway showed a small incremental worsening of energy loss.
      CONCLUSIONS: Maximizing energy conservation in a low-energy flow domain, such as
      the Fontan circulation, can be significant to its fluid dynamic performance.
      Although computational modeling cannot predict postoperative failure or
      functional outcome, this study confirms the importance of local geometry of the
      surgically created pathway in the total cavopulmonary connection.

PMID- 15013371
TI  - Reversibility of leukocyte dysfunction in rats with obstructive jaundice.
AB  - BACKGROUND: The role of leukocytes in obstructive jaundice is obscure and the
      effect of relieving cholestasis on leukocyte function is unclear. We postulated
      that cholestasis affects systemic polymorphonuclear leukocyte function by
      deranging phagocytosis and hydrogen peroxide release and the leukocyte
      dysfunction is reversible by internal and external biliary drainage. MATERIALS
      AND METHODS: Sixty male Sprague Dawley rats were randomly assigned to four
      groups: obstructive jaundice (OJ), sham operation (SH), OJ with internal drainage
      (ID), and OJ with external drainage (ED). The phagocytic functions of neutrophils
      and monocytes in whole blood were measured with flow cytometry using fluorescent
      microspheres. Intracellular hydrogen peroxide production by leukocytes was
      assessed with flow cytometry using dihydrorhodamine-123 as probes. RESULTS:
      Leukocyte count and percentage of monocytes in rats with OJ was significantly
      increased compared with SH rats (P < 0.001). These elevations could be reversed
      by both ID and ED method (P < 0.001). The phagocytic function of neutrophils and
      monocytes was significantly depressed in OJ rats compared with that in SH rats (P
      < 0.001). After relief of the OJ, the suppressed phagocytic function of
      neutrophils and monocytes was completely improved in ID rats (ID versus OJ, P <
      0.001), but only partially reversed in ED rats. The hydrogen peroxide production
      by monocytes and lymphocytes was significantly increased in OJ rats (P < 0.05).
      ID reversed the increased hydrogen peroxide generation (P < 0.05), but ED only
      partially did. CONCLUSIONS: In our rodent model of biliary obstruction, deranged
      phagocytosis, and hydrogen peroxide generation by leukocytes was found. Internal
      drainage is superior to external drainage for reversal of the distorted leukocyte
      function.

PMID- 15013372
TI  - Microfocal CT: a method for evaluating murine cranial sutures in situ.
AB  - INTRODUCTION: The murine model is a well-established surrogate for studying human
      cranial suture biology. In mice, all sutures with the exception of the posterior
      frontal (PF) suture remain patent throughout life. Histology is regarded as the
      gold standard for analyzing sutures. On this basis, PF suture fusion begins on
      day of life 25 and is complete by day 45. Cranial suture histology, however,
      requires sacrifice of the animal to obtain tissue for analysis. As a result,
      knowledge of the kinetics of cranial suture fusion is based on a patchwork
      analysis of many sutures from many different animals. The behavior of a single
      suture through time is unknown. Our goal is to develop a noninvasive means to
      repeatedly image mouse cranial sutures in vivo. As a first step, the present
      study was performed to evaluate microfocal computer tomography (micro-CT)
      technology for the use of capturing images of a mouse cranium in situ. METHODS:
      The micro-CT system consists of a microfocal X-ray source and a large format CCD
      camera optically coupled to a high-resolution X-ray image intensifier, digitally
      linked to a computer. The PF and sagittal sutures lie in continuity along the
      midline of the skull. Holes were drilled in the calvaria on both sides of the PF
      and sagittal sutures of a 45-day-old euthanized mouse. A micro-CT scan of this
      animal was performed and hundreds of cross-sectional images were generated for
      the cranium. These images were used to reconstruct three-dimensional volumetric
      images of the entire cranium. Comparisons were made between (1). the gross
      specimen and the three dimensional reconstructions; (2). two-dimensional coronal
      images obtained by micro-CT and those obtained by histology. RESULTS: Analysis of
      PF and sagittal sutures demonstrated the following: (1). The drilled holes were
      accurately rendered by micro-CT, when compared to both the gross specimen and the
      histology. (2). The sagittal suture was found to be patent by both micro-CT and
      histology. (3). The PF suture is fused by histology, but unexpectedly, the PF
      suture appears incompletely fused by micro-CT. By micro-CT, however, the anterior
      and endocranial regions appear more extensively fused than the remainder of the
      PF suture, a finding consistent with published histologic analysis. CONCLUSIONS:
      We successfully imaged 45-day-old mouse cranial sutures in situ using micro-CT
      technology. Precise correlation between histologic sections and radiologic images
      is difficult, but convincing similarities exist between the gross specimen and
      images from micro-CT and histology. PF suture fusion in a 45-day-old animal
      appears different by micro-CT than by histology. One possible explanation for
      this apparent discrepancy is that suture fusion in histology is determined based
      on the appearance of bone morphology and not tissue density, as the specimens are
      necessarily decalcified to section the bone. Micro-CT, on the other hand,
      distinguishes tissues on the basis of density. Newly forming bone may require
      bone matrix formation prior to complete calcification; PF suture in 45-day-old
      mice may be morphologically complete but incompletely ossified. Studies
      correlating histologic and micro-CT assessment of suture development are
      underway. Micro-CT appears to be a promising method for noninvasive imaging of
      mouse cranial suture.

PMID- 15013373
TI  - Effects of peritoneal injury and endotoxin on myoelectric activity and transit.
AB  - BACKGROUND: The combined effects of peritoneal injury and intraabdominal
      infection on gastrointestinal motility in postoperative ileus are poorly
      understood MATERIALS AND METHODS: Sprague Dawley rats underwent placement of
      three electrodes on the small intestine and a tube gastrostomy. Animals were
      divided into four groups: a control (n = 12), a peritoneal injury (PI, n = 12), a
      peritoneal injection of lipopolysaccharide (LPS, n = 12), and a LPS + PI group (n
      = 12). After myoelectric activity recording on postoperative day (POD) 1, half of
      the rats in each group underwent intestinal transit studies. The remainder of the
      rats underwent another myoelectric activity recording as well as intestinal
      transit study at 48 h after operation RESULTS: Although six to eight of rats in
      the control, PI, and LPS groups recovered migrating myoelectric complex (MMC) on
      POD 1, no rats in the LPS + PI group recovered MMC by POD 1. The transit distance
      on POD 1 in the PI (36 +/- 2.5 cm) and LPS + PI group (38 +/- 2.8 cm) was shorter
      than that in the control group (53 +/- 2.0 cm, P < 0.05) CONCLUSIONS: Full
      recovery of liquid intestinal transit precedes the return of MMC activity after
      abdominal surgery in the rats. Peritoneal injury causes decreased intestinal
      transit and when combined with intraabdominal injection of LPS may cause the
      delayed recovery of MMC activity.

PMID- 15013375
TI  - Achieving balance in academic surgery.

PMID- 15013374
TI  - Leptin is a growth factor in cancer.

PMID- 15013376
TI  - Recognition of vocal and facial cues to affect in language-impaired and normally
      developing preschoolers.
AB  - The current study was designed to investigate whether reported difficulties in
      language-impaired children's ability to identify vocal and facial cues to emotion
      could be explained at least partially by nonparalinguistic factors. Children with
      specific language impairment (SLI) and control participants received an affect
      discrimination task, which consisted of the following cue situations: (1) facial
      expression and unfiltered speech; (2) lowpass-filtered speech only; (3) facial
      expression only; and (4) facial expression and filtered speech. The results of
      the study indicated that impaired and nonimpaired group performance differed only
      for the items including facial expression and nonfiltered speech. Developmental
      and investigative implications of this finding are addressed. LEARNING OUTCOMES:
      As a result of this activity, the participant will be able to summarize the
      findings from existing research on affect comprehension in children with language
      impairments (LI). As a result of this activity, the participant will be able to
      discuss ways in which language impairment and difficulties in understanding
      emotion cues are associated and propose how these associations might influence
      social interactions.

PMID- 15013377
TI  - Speech and language in Wolf-Hirschhorn syndrome: a case-study.
AB  - Wolf-Hirschhorn syndrome (WHS), a condition resulting from a distal deletion of
      the short arm of chromosome 4, is usually associated with a severe phenotypic
      expression including multiple malformations, delayed psychomotor development, and
      profound learning disabilities. As far as communicative development is concerned,
      speech is usually absent and comprehension is limited to simple orders or to a
      specific context. There is some suggestion, however, that the developmental
      outcome in WHS depends on deletion size. This paper reports on an individual with
      WHS illustrating that a smaller deletion may result in a milder phenotype with
      respect to communicative abilities. This 10-year-old girl developed speech and
      language to a considerable degree. Although most children with this syndrome are
      severely limited in communicative abilities, the school-based speech-language
      pathologist working with a special education caseload may encounter WHS children
      with smaller deletions (and thus less severe phenotypes) who may profit from
      speech language pathology services. LEARNING OUTCOMES: The reader will learn
      about the genetics, incidence, and clinical characteristics of Wolf-Hirschhorn
      syndrome, and about the communicative abilities and genotype/phenotype
      correlations in children with this syndrome.

PMID- 15013378
TI  - Stuttering and the International Classification of Functioning, Disability, and
      Health: an update.
AB  - The World Health Organization (WHO) recently presented a multidimensional
      classification scheme for describing health status and the experience of
      disablement. This new framework, the International Classification of Functioning,
      Disability, and Health (ICF; WHO, 2001), is a revision of WHO's prior framework
      for describing the consequences of disorders, the International Classification of
      Impairments, Disabilities, and Handicaps (ICIDH; WHO, 1980). In previous papers,
      Yaruss had shown how the original ICIDH could be adapted to describe the
      consequences of stuttering at several levels that are relevant to the
      communication and life experiences of the person who stutters. The current
      manuscript presents an update of the Yaruss (1998) model that accounts for the
      new structure of the ICF. A comparison of the WHO's ICIDH and ICF frameworks is
      presented, followed by an analysis of how the ICF can be adapted to describe the
      speaker's experience of the stuttering disorder. Emphasis is placed on the fact
      that stuttering involves more than just observable behaviors. Specifically, the
      speaker's experience of stuttering can involve negative affective, behavioral,
      and cognitive reactions (both from the speaker and the environment), as well as
      significant limitations in the speaker's ability to participate in daily
      activities and a negative impact on the speaker's overall quality of life.
      LEARNING OUTCOMES: As a result of reading this manuscript, participants, willgain
      an understanding of the updates to the World Health Organization's original
      International Classification of Impairments, Disabilities, and Handicaps that are
      seen in the International Classification of Functioning, Disability, and Health
      understand how the ICF can be applied to the study of stuttering recognize that
      health conditions such as stuttering are affected by both internal and external
      factors, and can involve more than just observable behaviors that are seen on the
      surface.

PMID- 15013379
TI  - Use of cloze and contrast word procedures in repeated storybook reading:
      targeting multiple domains.
AB  - The purposes of this study were: (1) to implement an intervention approach for
      children with language and phonological impairments, targeting multiple
      linguistic domains within a unitary activity, and (2) to investigate whether any
      observed changes in selected outcome measures were associated with particular
      scaffolding procedures. The intervention approach employed a variety of
      scaffolding procedures (cloze procedures; cloze procedures with expansions;
      contrast words) within an interactive repeated storybook reading activity. It was
      delivered across 12 sessions to three kindergarten children with language and
      phonological impairments. Pre-treatment and post-treatment probes, together with
      treatment data, provided indices of the semantic and phonological complexity of
      the participants' utterances. Changes in complexity levels were observed in all
      participants. Associations between increases in outcome measures and use of
      particular scaffolding techniques were identified. LEARNING OUTCOMES: (1) The
      reader will learn a rationale for use of cloze procedures, cloze procedures with
      expansions, and contrast words during repeated storybook reading as an
      intervention for some children with both language and phonological disorders. (2)
      The reader will learn how to implement cloze procedures, cloze procedures with
      expansions, and contrast words during repeated storybook reading. (3) The reader
      will learn how various outcome measures (e.g., level of semantic complexity) may
      be used to track change in performance over time.

PMID- 15013380
TI  - Phonemic characteristics of apraxia of speech resulting from subcortical
      hemorrhage.
AB  - Reports describing subcortical apraxia of speech (AOS) have received little
      consideration in the development of recent speech processing models because the
      speech characteristics of patients with this diagnosis have not been described
      precisely. We describe a case of AOS with aphasia secondary to basal ganglia
      hemorrhage. Speech-language symptoms consistent with subcortical AOS and aphasia
      are reported as well as description of the patient's speech characteristics using
      broad phonemic transcription. Significantly more phoneme substitution errors were
      observed than other types of errors and these occurred significantly more often
      in the initial rather than the medial or final positions of words. No differences
      were observed in the number of errors produced for the various types of phonemes
      included in this analysis. These findings challenge the hypothesis that speech
      motor planning disorders are uniquely the result of cortical damage. They also
      argue against the notion that subcortical AOS is indistinguishable from the
      cortical syndrome. LEARNING OUTCOMES: The reader will learn (1) the phonemic
      characteristics of AOS due to subcortical brain damage, (2) the similarities and
      differences between AOS due to cortical versus subcortical lesions, and (3) the
      implications of these patterns for current models of speech motor processing.

PMID- 15013381
TI  - Current knowledge on biosynthesis, biological activity, and chemical modification
      of the exopolysaccharide, pullulan.
AB  - The article presents an overview of the latest advances in investigations of the
      biosynthesis, molecular properties, and associated biological activity of
      pullulan. The literature survey on the pullulan biosynthesis is intended to
      illustrate how the great variety of environmental conditions as well as
      variability in strain characteristics influences the metabolic pathways of the
      pullulan formation and effects structural composition of the biopolymer.
      Molecular properties of pullulan as alpha-(1-->4)- and alpha-(1-->6)-glucan are
      discussed in terms of similarities with amylose and dextran structures, and an
      emphasis is made on the inherent biological activity of pullulan molecules. The
      author also attempts to summarize the concepts, options, and strategies in
      chemical modification of the biopolymer and to delineate future prospects in
      designing new biologically active derivatives.

PMID- 15013382
TI  - Cyclosophoraose as a catalytic carbohydrate for methanolysis.
AB  - A novel catalytic methanolysis can be induced by a natural cyclooligosaccharide,
      a cyclosophoraose (cyclic-(1-->2)-beta-D-glucan, Cys), which is a member of a
      family of unbranched cyclooligosaccharides produced as intra- or
      extraoligosaccharides by soil microorganisms of the genus, Rhizobium. Cys
      catalyzed the methanolysis for 5(4H)-oxazolones and various phospholipids. Cys
      enhanced the methanolysis reaction about 9200-fold for a benzylidene oxazolone or
      250-fold for dipalmitoylphosphatidylcholine comparing with control. In this
      study, we describe that natural cyclosophoraoses isolated from the Rhizobium
      species function as catalytic carbohydrates for the methanolysis.

PMID- 15013383
TI  - Comparative evaluation of D-glucosyl thiouronium, glucosylthio heterocycles,
      Daonil, and insulin as inhibitors for hepatic glycosidases.
AB  - Comparison of the in vivo and in vitro effects of S-(2,3,4,6-tetra-O-acetyl-beta
      D-glucopyranosyl)thiuronium bromide (1), 2-(2,3,4,6-tetra-O-acetyl-beta-D
      glucopyranosylthio-1,3,4-thiadiazolin-5-thione (2), and 2-(2,3,4,6-tetra-O-acetyl
      beta-D-glucopyranosylthio)-1,3-benzoxazole (3), as well as the antidiabetics
      Daonil and insulin on glycosidase enzymes has been investigated. Compound 1
      inhibited both alpha- and beta-glucosidases, but the inhibition was more potent
      with the beta-enzyme. Compound 2 was found to be a weaker inhibitor of these
      enzymes, while compound 3 showed a slight apparent activation.

PMID- 15013384
TI  - Structure of the O-polysaccharide of Idiomarina zobellii KMM 231T containing two
      unusual amino sugars with the free amino group, 4-amino-4,6-dideoxy-D-glucose and
      2-amino-2-deoxy-L-guluronic acid.
AB  - Mild acid degradation of the lipopolysaccharide of the bacterium Idiomarina
      zobellii, type strain KMM 231T, with aq 2% HOAc at 100 degrees C, yielded an
      oligosaccharide, which represents one repeating unit of the O-polysaccharide. A
      polysaccharide was obtained by mild base degradation of the lipopolysaccharide.
      The following structure of the O-polysaccharide was elucidated by 1H and 13C NMR
      spectroscopy of the oligosaccharide and base-degraded lipopolysaccharide,
      including COSY, TOCSY, ROESY, 1H, 13C HSQC, HSQC-TOCSY and HMBC experiments: [-
      >3)-alpha-D-Quip4N-(1-->4)-alpha-D-GlcpA-(1-->6)-alpha-D-GlcpNAc-(1-->4)-alpha-L
      GulpNA-(1-->3)-beta-D-FucpNAc-(1-->] The O-polysaccharide is distinguished by the
      presence of two unusual amino sugars, 4-amino-4,6-dideoxy-D-glucose (D-Qui4N) and
      2-amino-2-deoxy-L-guluronic acid (L-GulNA), both having the free amino group. The
      unexpectedly high acid lability of the glycosidic linkage of 2-acetamido-2,6
      dideoxy-D-galactose (D-FucNAc) could be associated with the presence of a free
      amino group adjacent to the site of attachment of FucNAc to Qui4N.

PMID- 15013385
TI  - Characterization and detection of lysine-arginine cross-links derived from
      dehydroascorbic acid.
AB  - Covalently cross-linked proteins are among the major modifications caused by the
      advanced Maillard reaction. So far, the chemical nature of these aggregates is
      largely unknown. L-dehydroascorbic acid (DHA, 5), the oxidation product of L
      ascorbic acid (vitamin C), is known as a potent glycation agent. Identification
      is reported for the lysine-arginine cross-links N6-[2-[(4-amino-4
      carboxybutyl)amino]-5-(2-hydroxyethyl)-3,5-dihydro-4H-imidazol-4-ylidene]-L
      lysine (9), N6-[2-[(4-amino-4-carboxybutyl)amino]-5-(1,2-dihydroxyethyl)-3,5
      dihydro-4H-imidazol-4-ylidene]-L-lysine (11), and N6-[2-[(4-amino-4
      carboxybutyl)amino]-5-[(1S,2S)-1,2,3-trihydroxypropyl]-3,5-dihydro-4H-imidazol-4
      ylidene]-L-lysine (13). The formation pathways could be established starting from
      dehydroascorbic acid (5), the degradation products 1,3,4-trihydroxybutan-2-one
      (7, L-erythrulose), 3,4-dihydroxy-2-oxobutanal (10, L-threosone), and L-threo
      pentos-2-ulose (12, L-xylosone) were proven as precursors of the lysine-arginine
      cross-links 9, 11, and 13. Products 9 and 11 were synthesized starting from DHA
      5, compound N6-[2-[(4-amino-4-carboxybutyl)amino]-5-[(1S,2R)-1,2,3
      trihydroxypropyl]-3,5-dihydro-4H-imidazol-4-ylidene]-L-lysine (16) via the
      precursor D-erythro-pentos-2-ulose (15). The present study revealed that the
      modification of lysine and arginine side chains by DHA 5 is a complex process and
      could involve a number of reactive carbonyl species.

PMID- 15013386
TI  - Preparation of gemini-type amphiphiles bearing cyclitol head groups and their
      application as high-performance modifiers for lipases.
AB  - Five gemini-type amphiphiles bearing cyclitol head groups, which have abundance
      of axial hydroxy groups, are newly synthesized. The syntheses are based on a
      common mixed anhydride method utilizing N,N'
      [iminobis(trimethylene)]bisquinamide, prepared from iminobispropylamine and quino
      1,5-lactone, and dialkyl N-(3-carboxypropanoyl)-L-glutamates as polar and
      hydrophobic components, respectively. Candida rugosa lipase (CRL) and Pseudomonas
      cepacia lipase (PCL) are co-lyophilized with these synthesized gemini-type
      amphiphiles, and their transesterification activities in organic solvents are
      evaluated. The modified PCL and CRL prepared by using each amphiphile showed
      highly enhanced and moderately enhanced enzyme activity, respectively. These
      results are discussed in terms of the increased preferential exclusion of the
      hydrophilic heads of the amphiphile and of the topological view of the
      amphiphile.

PMID- 15013387
TI  - Structural studies of the capsular polysaccharide of a non-neoformans
      Cryptococcus species identified as C. laurentii, which was reclassified as
      Cryptococcus flavescens, from a patient with AIDS.
AB  - Cryptococcus flavescens, a strain originally identified as C. laurentii, was
      isolated from the cerebrospinal fluid of an AIDS patient, and the soluble
      capsular polysaccharide of the yeast was investigated. Glucuronoxylomannan (GXM)
      was obtained from C. flavescens under conditions similar to those used to obtain
      C. neoformans polysaccharide. However, the GXM differed from C. neoformans
      polysaccharide in the decreased O-acetyl group content. The structure of GXM was
      determined by methylation analysis, partial acid hydrolysis, NMR analyses, and
      controlled Smith degradation. These analyses indicated that GXM has the following
      structure: an alpha-(1-->3)-D-mannan backbone with side chains of beta-D
      glucuronic acid residues bound to the C-2 position of the mannose residue. The C
      6 position of the mannose is substituted with D-man-beta-(1-->4)-D-xyl-beta-(1-->
      disaccharide. Furthermore, the existence of side chains containing more than two
      xylose residues was suggested. This mannosylxylose side chain is a novel
      structure in polysaccharides of C. neoformans and other Cryptococcus species.

PMID- 15013388
TI  - A highly regular fraction of a fucoidan from the brown seaweed Fucus distichus L.
AB  - A fucoidan fraction consisting of L-fucose, sulfate, and acetate in a molar
      proportion of 1:1.21:0.08 was isolated from the brown seaweed Fucus distichus
      collected from the Barents Sea. The 13C NMR spectrum of the fraction was typical
      of regular polysaccharides containing disaccharide repeating units. According to
      1D and 2D 1H and 13C NMR spectra, the fucoidan molecules are built up of
      alternating 3-linked alpha-L-fucopyranose 2,4-disulfate and 4-linked alpha-L
      fucopyranose 2-sulfate residues: -->3)-alpha-L-Fucp-(2,4-di-SO3-)-(1-->4)-alpha-L
      Fucp-(2SO3-)-(1-->. The regular structure may be only slightly masked by random
      acetylation and undersulfation of several disaccharide repeating units.

PMID- 15013389
TI  - Synthesis and characterization of carboxymethylated cyclosophoraose, and its
      inclusion complexation behavior.
AB  - Carboxymethylated cyclosophoraoses (CM-Cys) were synthesized by chemical
      modification of a family of neutral cyclosophoraoses isolated from Rhizobium
      leguminosarum biovar trifolii. Structural analyses of the CM-Cys were carried out
      using NMR and FTIR spectroscopies, and the molecular weight distributions were
      confirmed with MALDI-TOF mass spectrometry. Based on structural characterization,
      native cyclosophoraoses were successfully substituted with carboxymethyl groups
      at the OH-4 and OH-6 of the glucose residues with degrees of substitution (DS)
      ranging from 0.012 to 0.290. CM-Cys was also used as a host for the inclusion
      complexation with hydrobenzoin (HB) and N-acetyltryptophan (N-AcTrp) as guest
      molecules. NMR spectroscopic analyses of the complexes showed that the CM-Cys
      induced chemical shifts of some protons of the guest molecules upon the
      complexation. Phase solubility studies of the guest molecules by CM-Cys were
      performed using HPLC, and the results were compared with those of native
      cyclosophoraoses. The solubility of HB and N-AcTrp was enhanced by the CM-Cys
      about 5.1- and 299-fold, respectively.

PMID- 15013390
TI  - Structural analysis of the lipooligosaccharide from the commensal Haemophilus
      somnus genome strain 129Pt.
AB  - The structure for the carbohydrate moiety of the lipooligosaccharide (LOS) from
      the commensal Haemophilus somnus strain 129Pt was elucidated. The structure of
      the core oligosaccharide and O-deacylated LOS was established by monosaccharide
      and methylation analyses, NMR spectroscopy and mass spectrometry. The following
      structure for the major fully extended carbohydrate glycoform of the LOS was
      determined on the basis of the combined data from these experiments.
      [Carbohydrate structure: see text]. In the structure Kdo is 3-deoxy-D-manno
      octulosonic acid, Hep is L-glycero-D-manno-heptose and PEtn is
      phosphoethanolamine. Minor amounts of glycoforms containing nonstoichiometric
      substituents glycine and phosphate at the distal heptose residue were also
      identified.

PMID- 15013391
TI  - B3LYP/6-311++G** study of alpha- and beta-D-glucopyranose and 1,5-anhydro-D
      glucitol: 4C1 and 1C4 chairs, (3,O)B and B(3,O) boats, and skew-boat
      conformations.
AB  - Geometry optimization, at the B3LYP/6-311++G** level of theory, was carried out
      on 4C1 and 1C4 chairs, (3,O)B and B(3,O) boats, and skew-boat conformations of
      alpha- and beta-D-glucopyranose. Similar calculations on 1,5-anhydro-D-glucitol
      allowed examination of the effect of removal of the 1-hydroxy group on the energy
      preference of the hydroxymethyl rotamers. Stable minimum energy boat conformers
      of glucose were found, as were stable skew boats, all having energies ranging
      from approximately 4-15 kcal/mol above the global energy 4C1 chair conformation.
      The 1C4 chair electronic energies were approximately 5-10 kcal/mol higher than
      the 4C1 chair, with the 1C4 alpha-anomers being lower in energy than the beta
      anomers. Zero-point energy, enthalpy, entropy, and relative Gibbs free energies
      are reported at the harmonic level of theory. The alpha-anomer 4C1 chair
      conformations were found to be approximately 1 kcal/mol lower in electronic
      energy than the beta-anomers. The hydroxymethyl gt conformation was of lowest
      electronic energy for both the alpha- and beta-anomers. The glucose alpha/beta
      anomer ratio calculated from the relative free energies is 63/37%. From a
      numerical Hessian calculation, the tg conformations were found to be
      approximately 0.4-0.7 kcal/mol higher in relative free energy than the gg or gt
      conformers. Transition-state barriers to rotation about the C-5-C-6 bond were
      calculated for each glucose anomer with resulting barriers to rotation of
      approximately 3.7-5.8 kcal/mol. No energy barrier was found for the path between
      the alpha-gt and alpha-gg B(3,O) boat forms and the equivalent 4C1 chair
      conformations. The alpha-tg conformation has an energy minimum in the 1S3 twist
      form. Other boat and skew-boat forms are described. The beta-anomer boats
      retained their starting conformations, with the exception of the beta-tg-(3,O)B
      boat that moved to a skew form upon optimization.

PMID- 15013392
TI  - B3LYP/6-311++G** study of monohydrates of alpha- and beta-D-glucopyranose:
      hydrogen bonding, stress energies, and effect of hydration on internal
      coordinates.
AB  - Twenty-six monohydrates of alpha- and beta-D-glucopyranose were studied using
      gradient methods at the B3LYP/6-311++G** level of theory. Geometry optimization
      was carried out with the water molecules at different configurations around the
      glucose molecule. A new nomenclature for hydrated carbohydrates was developed to
      describe the water configurations. Zero-point vibrational energy, enthalpy,
      entropy, and relative free energy were obtained using the harmonic approximation.
      Hydrogen-bond energies for the monohydrates range from approximately -5 to -12
      kcal/mol, and the average relative free energy is approximately 5 kcal/mol. The 1
      hydroxy position is the most energetically favored site for hydration, and the
      region between the two and three positions is the next-most favored site. A water
      molecule approaching alpha-D-glucose between the 1- and 2-hydroxy positions pulls
      the 2-hydroxyl hydrogen atom away from the 1-hydroxy oxygen atom, thus increasing
      the hydrogen-bond length and also increasing the alpha-D-glucose energy. The
      increase in energy that occurs with a similar interaction on the beta-anomer is
      much less effective since the hydrogen bond is much longer. Using the calculated
      free energies of all 26 configurations, the anomer population (alpha/beta)
      increases in the beta-anomer population relative to the in vacuo case by
      approximately 10% at the expense of the alpha-anomer, giving an (alpha/beta)
      ratio of approximately 50/50. This result arises from entropy contributions
      favoring the beta-anomer more than the alpha-anomer. From analysis of donor and
      acceptor hydrogen-bond lengths, excellent correlation is found between the DFT
      calculated distances and those taken from carbohydrate structures in the
      Cambridge Crystallographic Data Bank.

PMID- 15013393
TI  - Characterization of the crystalline structure of cellulose using static and
      dynamic FT-IR spectroscopy.
AB  - The cellulose structure is a factor of major importance for the strength
      properties of wood pulp fibers. The ability to characterize small differences in
      the crystalline structures of cellulose from fibers of different origins is thus
      highly important. In this work, dynamic FT-IR spectroscopy has been further
      explored as a method sensitive to cellulose structure variations. Using a model
      system of two different celluloses, the relation between spectral information and
      the relative cellulose Ialpha content was investigated. This relation was then
      used to determine the relative cellulose Ialpha content in different pulps. The
      estimated cellulose I allomorph compositions were found to be reasonable for both
      unbleached and bleached chemical pulps. In addition, it was found that the
      dynamic FT-IR spectroscopy technique had the potential to indicate possible
      correlation field splitting peaks of cellulose Ibeta.

PMID- 15013394
TI  - Inactivated enzymes as probes of the structure of arabinoxylans as observed by
      atomic force microscopy.
AB  - The complex structures of water-soluble wheat arabinoxylans have been mapped
      along individual molecules, and within populations, using the visualisation of
      the binding of inactivated enzymes by atomic force microscopy (AFM). It was
      demonstrated that site-directed mutagenesis (SDM) can be used to produce inactive
      enzymes as structural probes. For the SDM mutants AFM has been used to compare
      the binding of different xylanases to arabinoxylans. Xylanase mutant E386A,
      derived from the Xyn11A enzyme (Neocallimastrix patriciarium), was shown to bind
      randomly along arabinoxylan molecules. The xylanase binding was also monitored
      following Aspergillus niger arabinofuranosidase pre-treatment of samples. It was
      demonstrated that removal of arabinose side chains significantly altered the
      binding pattern of the inactivated enzyme. Xylanase mutant E246A, derived from
      the Xyn10A enzyme (Cellvibrio japonicus), was found to show deviations from
      random binding to the arabinoxylan chains. It is believed that this is due to the
      effect of a small residual catalytic activity of the enzyme that alters the
      binding pattern of the probe. Control procedures were developed and assessed to
      establish that the interactions between the modified xylanases and the
      arabinoxylans were specific interactions. The experimental data demonstrates the
      potential for using inactivated enzymes and AFM to probe the structural
      heterogeneity of individual polysaccharide molecules.

PMID- 15013395
TI  - Vacuum-ultraviolet circular dichroism study of saccharides by synchrotron
      radiation spectrophotometry.
AB  - Vacuum-ultraviolet circular dichroism (VUVCD) spectra of five monosaccharides (D
      glucose, D-mannose, D-galactose, D-xylose, and D-lyxose) and five disaccharides
      (maltose, isomaltose, cellobiose, gentiobiose, and lactose) were measured to 160
      nm using a synchrotron-radiation VUVCD spectrophotometer in aqueous solution
      under high vacuum at 25 degrees C. Most of the saccharides show a positive peak
      with some shoulders at around 170 nm, except for D-galactose and lactose, which
      show two distinct negative peaks at around 165 and 177 nm. These spectra are
      influenced by such structural factors as alpha and beta anomers at C-1, axial and
      equatorial hydroxyl groups at C-2 and C-4, trans (T) and gauche (G) conformations
      of the hydroxymethyl group at C-5, and the type of glycosidic linkage.
      Deconvolution of the VUVCD spectra of D-glucose, D-mannose, and D-galactose into
      six independent Gaussian components for alpha-GG, alpha-GT, alpha-TG, beta-GG,
      beta-GT, and beta-TG conformations suggests that the alpha anomer has red-shifted
      spectra relative to the beta anomer, and that GG and GT conformations have
      positive and negative circular dichroism signs, respectively, while the sign for
      TG conformation is anomer dependent. These speculations from the deconvolution
      analyses are also supported by the VUVCD spectra of disaccharides. These results
      give new insight into the equilibrium conformations of saccharides, demonstrating
      the usefulness of synchrotron-radiation VUVCD spectroscopy.

PMID- 15013396
TI  - Cu(II) complex formation with xylitol in alkaline solutions.
AB  - The formation of four Cu(II)-xylitol complexes was observed in aqueous alkaline
      solutions (11.0< or =pH< or =14.0, I=1.0, 20 degrees C) by means of direct
      current polarography and VIS spectrophotometry. Mononuclear hydroxy complexes,
      CuXyl(OH)- (log beta=17.7 +/- 0.5), CuXyl(OH)2(2-) (log beta=20.2 +/- 0.3) and
      CuXyl2(OH)2(4-) (log beta=22.4 +/- 0.3), are formed at high ligand-to-metal
      ratios (L:M> or =10), whereas dinuclear complex Cu2Xyl (log beta=29.2 +/- 0.3) is
      the predominant species at low ligand-to-metal ratio (L:M=0.5). Diffusion
      coefficients and molar absorptivities of the complex species were determined. pH
      variable 13C NMR suggested that pKa values of xylitol are rather similar and
      equal to 13.8 +/- 0.2, 13.9 +/- 0.1 and 13.9 +/- 0.2 for OH-groups adjacent to (C
      1,C-5), (C-3) and (C-2,C-4) carbon atoms, respectively.

PMID- 15013397
TI  - Tertiary structure of human alpha1-acid glycoprotein (orosomucoid).
      Straightforward fluorescence experiments revealing the presence of a binding
      pocket.
AB  - Binding of hemin to alpha1-acid glycoprotein has been investigated. Hemin binds
      to the hydrophobic pocket of hemoproteins. The fluorescent probe 2-(p-toluidino)
      6-naphthalenesulfonate (TNS) binds to a hydrophobic domain in alpha1-acid
      glycoprotein with a dissociation constant equal to 60 microM. Addition of hemin
      to an alpha1-acid glycoprotein-TNS complex induces the displacement of TNS from
      its binding site. At saturation (1 hemin for 1 protein) all the TNS has been
      displaced from its binding site. The dissociation constant of hemin-alpha1-acid
      glycoprotein was found equal to 2 microM. Thus, TNS and hemin bind to the same
      hydrophobic site: the pocket of alpha1-acid glycoprotein. Energy-transfer studies
      performed between the Trp residues of alpha1-acid glycoprotein and hemin
      indicated that efficiency (E) of Trp fluorescence quenching was equal to 80% and
      the Forster distance, R0 at which the efficiency of energy transfer is 50% was
      calculated to be 26 A, revealing a very high energy transfer.

PMID- 15013398
TI  - Blocking nonspecific adsorption of native food-borne microorganisms by
      immunomagnetic beads with iota-carrageenan.
AB  - We present herein the partitioning characteristics of anti-Salmonella and anti
      Escherichia coli O157 immunomagnetic beads (IMB) with respect to the nonspecific
      adsorption of several nontarget food-borne organisms with and without an
      assortment of well-known blocking agents, such as casein, which have been shown
      to be useful in other immunochemical applications. We found several common food
      borne organisms that strongly interacted with both types of IMB, especially with
      anti-Salmonella form (av DeltaG0=-20 +/- 4 kJ mol(-1)) even in the presence of
      casein [1% (w/v): DeltaG0=-18 +/- 3 kJ mol(-1); DeltaDeltaG0 approximately -2 kJ
      mol(-1)]. However, when one of the most problematic organisms (a native K12-like
      E. coli isolate; DeltaG0=-19 +/- 2 kJ mol(-1)) was tested for nonspecific binding
      in the presence of iota-carrageenan (0.03-0.05%), there was an average decline of
      ca. 90% in the equilibrium capture efficiency xi (DeltaG0=-11 +/- 4 kJ mol(-1);
      DeltaDeltaG0 approximately -8 kJ mol(-1)). Other anionic polysaccharides (0.1%
      kappa-carrageenan and polygalacturonic acid) had no significant effect (av
      DeltaG0=-19 +/- 1 kJ mol(-1); DeltaDeltaG0 approximately 0 kJ mol(-1)). Varying
      iota-carrageenan from 0% to 0.02% resulted in xi significantly diminishing from
      0.69 (e.g., 69% of the cells captured; DeltaG0=-19 +/- 3 kJ mol(-1)) to 0.05
      (DeltaG0=-11 +/- 2 kJ mol(-1); DeltaDeltaG0 approximately -9 kJ mol(-1)) at about
      0.03% iota-carrageenan where xi leveled off. An optimum blocking ability was
      achieved with 0.04% iota-carrageenan suspended in 100 mM phosphate buffer. We
      also demonstrated that the utilization of iota-carrageenan as a blocking agent
      causes no great loss in the IMBs capture efficiency with respect to the capture
      of its target organisms, various salmonellae.

PMID- 15013399
TI  - Structure of the neutral O-polysaccharide and biological activities of the
      lipopolysaccharide of Proteus mirabilis O20.
AB  - Mild acid degradation of the lipopolysaccharide (LPS) of Proteus mirabilis O20
      resulted in depolymerisation of the O-polysaccharide to give a repeating-unit
      pentasaccharide. A polysaccharide was obtained by O-deacylation of the LPS
      followed by nitrous acid deamination. The derived pentasaccharide and
      polysaccharide were studied by NMR spectroscopy, including 2D 1H,1H COSY, TOCSY,
      ROESY, 1H,13C HMQC and HMQC-TOSCY experiments, along with chemical methods, and
      the following structure of the repeating unit of the O-polysaccharide was
      established: [Carbohydrate structure: see text]. As opposite to most other P.
      mirabilis O-polysaccharides studied, that of P. mirabilis O20 is neutral. A week
      serological cross-reactivity was observed between anti-P. mirabilis O20 serum and
      LPS of a number of Proteus serogroups with known O-polysaccharide structure. The
      ability of LPS of P. mirabilis O20 to activate the serine protease cascade was
      tested in Limulus amoebocyte lysate and in human blood plasma and compared with
      that of P. mirabilis O14a,14c having an acidic O-polysaccharide. The LPS of P.
      mirabilis O20 was found to be less active in both assays than the LPS of P.
      mirabilis O14a,14c and, therefore, the structurally variable O-polysaccharide may
      influenced the biological activity of the conserved lipid A moiety of the LPS.

PMID- 15013400
TI  - FT-IR study of the Chara corallina cell wall under deformation.
AB  - Fourier-transform infrared (FT-IR) microspectroscopy was used to investigate both
      the chemical composition of, and the effects of an applied strain on, the
      structure of the Chara corallina cell wall. The inner layers of the cell wall are
      known to have a transverse cellulose orientation with a gradient through the
      thickness to longitudinal orientation in the older layers. In both the native
      state and following the removal of various biopolymers by a sequential extraction
      infrared dichroism was used to examine the orientation of different biopolymers
      in cell-wall samples subjected to longitudinal strain. In the Chara system,
      cellulose microfibrils were found to be aligned predominantly transverse to the
      long axis of the cell and became orientated increasingly transversely as
      longitudinal strain increased. Simultaneously, the pectic polysaccharide matrix
      underwent molecular orientation parallel to the direction of strain. Following
      extraction in CDTA, microfibrils were orientated transversely to the strain
      direction, and again the degree of transverse orientation increased with
      increasing strain. However, the pectic polysaccharides of the matrix were not
      detected in the dichroic difference spectra. After a full sequential extraction,
      the cellulose microfibrils, now with greatly reduced crystallinity, were detected
      in a longitudinal direction and they became orientated increasingly parallel to
      the direction of strain as it increased.

PMID- 15013401
TI  - Enzymatic degradation and electrospray tandem mass spectrometry as tools for
      determining the structure of cationic starches prepared by wet and dry methods.
AB  - Cationic starches from various semi-technical processes, two 'wet' (slurry and
      paste modification) and two 'dry' procedures (dry modification and extrusion),
      each type in a DS range from 0.03 to 0.1, were investigated by electrospray
      ionisation mass spectrometry (ESIMS) and tandem mass spectrometry (ESIMS2) after
      enzymatic degradation with alpha-amylase and subsequent glucoamylase digestion.
      For comparison, chemically derived cationic oligosaccharides were also analysed
      by ESIMS. The cationisation pattern in the glucosyl units was analysed by GLC
      after methanolysis, permethylation and Hofmann elimination. Results from ESIMS
      are discussed and interpreted with respect to enzyme susceptibility, monomer
      composition and physical properties of the different types of cationic starches.

PMID- 15013402
TI  - Characterization of the lipopolysaccharide O-antigen of Francisella novicida
      (U112).
AB  - Francisella novicida (U112), a close relative of the highly virulent bacterium F.
      tularensis, was shown to produce a lipopolysaccharide in which the antigenic O
      polysaccharide component was found by chemical, 1H and 13C NMR and MS analyses to
      be an unbranched neutral linear polymer of a repeating tetrasaccharide unit
      composed of 2-acetamido-2-deoxy-D-galacturonamide (D-GalNAcAN) and 2,4
      diacetamido-2,4,6-trideoxy-D-glucose (D-Qui2NAc4NAc, di-N-acetylbacillosamine)
      residues (3:1) and had the structure: -->4)-alpha-D-GalNAcAN-(1-->4)-alpha-D
      GalNAcAN-(1-->4)-alpha-D-GalNAcAN-(1-->3)-alpha-D-QuiNAc4NAc-(1-->. With
      polyclonal murine antibody, the F. novicida O-antigen did not show serological
      cross-reactivity with the O-antigen of F. tularensis despite the occurrence of a
      common -->4)-D-GalpNAcAN-(1-->4)-alpha-D-GalpNAcAN-(1--> disaccharide unit in
      their respective O-antigens. Thus, O-PS serology offers a practical way to
      distinguish between the two Francisella species.

PMID- 15013403
TI  - Differentiation of isomeric oligosaccharide structures by ESI tandem MS and GC
      MS.
AB  - A mixture of arabinoxylan oligosaccharides from wheat seedling was permethylated
      and analyzed by electrospray ion trap MS and GC-MS. The presence of isomeric
      structures differing in degree of branching and position of the branched residue
      along the xylose backbone was demonstrated for oligosaccharides with four and
      five monosaccharide residues. No isomeric structures were found for
      oligosaccharides with three monosaccharide residues. Linkage analysis by GC-MS
      reveals that xylose residues were substituted with single arabinoxyl residues at
      C-3.

PMID- 15013404
TI  - Studies for the transformation of carbocycles into carbohydrates: approach toward
      the synthesis of higher sugar derivatives.
AB  - A highly stereocontrolled synthesis of a beta-D-ribo-hept-6-ulopyranosuronamide
      derivative, a useful intermediate for the synthesis of other higher sugars, has
      been developed using naturally occurring (-)-quinic acid as a chiral starting
      material. The transformation of carbocycle to carbohydrate, a key step in this
      sequence, occurred in a one-pot reaction: an ozonolysis carried out under mild
      conditions.

PMID- 15013405
TI  - An effective synthesis of an arabinogalactan with a beta-(1-->6)-linked
      galactopyranose backbone and alpha-(1-->2) arabinofuranose side chains.
AB  - An octasaccharide, beta-D-Galp-(1-->6)-[alpha-L-Araf-(1-->2)]-beta-D-Galp-(1-->6)
      beta-D-Galp-(1-->6)-[alpha-L-Araf-(1-->5)-alpha-L-Araf-(1-->2)]-beta-D-Galp-(1-
      >6)-beta-D-Galp-1-->OMP was synthesized. 4-methoxyphenyl 2,3,4-tri-O-benzoyl-beta
      D-galactopyranoside (5), 2,6-di-O-acetyl-3,4-di-O-benzoyl-alpha-D
      galactopyranosyl trichloroacetimidate (9), and 4-methoxyphenyl 2-O-acetyl-3,4-di
      O-benzoyl-beta-D-galactopyranoside (11), 2,3,4,6-tetra-O-benzoyl-alpha-D
      galactopyranosyl trichloroacetimidate (12), and 2,3,5-tri-O-benzoyl-alpha-L
      arabinofuranosyl trichloroacetimidate (17) were used as the synthons. A concise
      route was used to gain the tetrasaccharide donor 19 by the use of 11, 12, 5, and
      17. Meanwhile, treatment of 5 with 9 yielded beta-(1-->6)-linked disaccharide 20,
      and subsequent selective 6-O-deacetylation produced the disaccharide acceptor 21.
      Reaction of 21 with 19 gave 22, and subsequent selective 2-O-deacetylation
      afforded the hexasaccharide acceptor 23. Condensation of 23 with alpha-L-(1-->5)
      linked arabinofuranose disaccharide 24, followed by deprotection, yielded the
      target octasaccharide.

PMID- 15013406
TI  - Synthesis of mannopyranose disaccharides as photoaffinity probes for
      mannosyltransferases in Mycobacterium tuberculosis.
AB  - Mannosyltransferases play a crucial role in mycobacterial cell-wall biosynthesis
      and are potential new drug targets for the treatment of tuberculosis. Herein, we
      describe the synthesis of alpha-(1-->2)- and alpha-(1-->6)-linked mannopyranosyl
      disaccharides possessing a 5-azidonaphthlene-1-sulfonamidoethyl group as
      photoaffinity probes for active-site labeling studies of mannosyltransferases in
      Mycobacterium tuberculosis.

PMID- 15013407
TI  - Enzymatic supported synthesis of lacto-N-neotetraose using dendrimeric
      polyethylene glycol.
AB  - The lacto-N-neotetraose tetrasaccharide was synthesized on a new dendrimeric
      support, based on polyethylene glycol. Starting from 1-thio-beta-D-lactose, the
      trisaccharide (2-acetamido-2-deoxy-beta-D-glucopyranosyl)-(1-->3)-O-beta-D
      galactopyranosyl-(1-->4)-1-thio-beta-D-glucopyranose was obtained using Neisseria
      meningitidis beta-(1-->3)-N-acetylglucosaminyltransferase according to a soluble
      synthesis approach, bound on the support and galactosylated using the milk beta
      (1-->4)-galactosyl transferase to give after cleavage the tetrasaccharide lacto-N
      neotetraose.

PMID- 15013408
TI  - The synthesis of a novel thio-linked disaccharide of chondroitin as a potential
      inhibitor of polysaccharide lyases.
AB  - A thio-linked disaccharide based on the structure of the glycosaminoglycan
      chondroitin was synthesized as a potential inhibitor of chondroitin AC lyase from
      Flavobacterium heparinum for structural analysis of the active site. Instead it
      was found to be a slow substrate, thereby demonstrating that lyases, in contrast
      to glycosidases, can cleave thioglycoside links between sugars.

PMID- 15013409
TI  - Pyridinium-carbaldehyde: active Maillard reaction product from the reaction of
      hexoses with lysine residues.
AB  - Besides the formation of the aminotriazine N6-[4-(3-amino-1,2,4-triazin-5-yl)-2,3
      dihydroxybutyl]-L-lysine, the reaction of [1-13C]D-glucose with lysine and
      aminoguanidine leads to the generation of 6-[2
      ([[amino(imino)methyl]hydrazono]methyl)pyridinium-1-yl]-L-norleucine (14-13C1).
      The dideoxyosone N6-(2,3-dihydroxy-5,6-dioxohexyl)-L-lysine was shown to be a
      precursor in the formation of 14-13C1, which proceeds via the reactive carbonyl
      intermediate 6-(2-formylpyridinium-1-yl)-L-norleucine (13-13C1). In order to
      study the reactivity of 13-13C1, the model compound 1-butyl-2-formylpyridinium
      (18) was prepared in a two-step procedure starting from 2-pyridinemethanol. The
      reaction of the pyridinium-carbaldehyde 18 with L-lysine yielded the Strecker
      analogous degradation product 2-(aminomethyl)-1-butylpyridinium and another
      compound, which was shown to be as 1-butyl-2-[(2-oxopiperidin-3
      ylidene)methyl]pyridinium. Reaction of 18 with the C-H acidic 4-hydroxy-5
      methylfuran-3(2H)-one leads to the formation of the condensation product 1-butyl
      2-[hydroxy-(4-hydroxy-5-methyl-3-oxofuran-2(3H)-ylidene)methyl]-pyridinium.

PMID- 15013410
TI  - A novel alpha-glucosidase inhibitor from pine bark.
AB  - Inhibitors of carbohydrate-hydrolysing enzymes play an important role for the
      treatment of diabetes. To our knowledge, a number of inhibitors such as, 1
      deoxynojirimycin, acarbose and voglibose have been identified as a result of
      screening of secondary metabolites up to now. In this note, we report the
      inhibitory effect on carbohydrate hydrolysis of ethanol extracts from more than
      1400 species of plants with the aim of identifying a potential antihyperglycemic
      drug. Pinus densiflora bark extracts showed the highest inhibition activity
      against several carbohydrate-hydrolysing enzymes.

PMID- 15013411
TI  - High efficiency of transferring a native sugar chain from a glycopeptide by a
      microbial endoglycosidase in organic solvents.
AB  - We examined the transglycosylation reaction by the recombinant endo-beta-N
      acetylglucosaminidase from Mucor hiemalis (Endo-M) expressed in Candida boidinii
      in media containing organic solvents. The recombinant Endo-M could
      transglycosylate a disialo biantennary complex-type oligosaccharide from hen egg
      yolk glycopeptide to p-nitrophenyl N-acetyl-beta-D-glucosaminide even in the
      presence of 30% acetone, dimethyl sulfoxide, or methanol. The yield of the
      transglycosylation product reached 21-34% of the total amount of acceptor, while
      the yield was only about 14% in aqueous solution.

PMID- 15013412
TI  - Structure of the O-polysaccharide from the lipopolysaccharide of Hafnia alvei
      strain PCM 1529.
AB  - The following structure of the pentasaccharide repeating unit of an acidic O
      polysaccharide of Hafnia alvei PCM 1529 was established by sugar and methylation
      analyses along with 1D and 2D 1H and 13C NMR spectroscopy: [Carbohydrate
      structure: see text].

PMID- 15013413
TI  - Practical de-O-acylation reactions promoted by molecular sieves.
AB  - Methanol dried extensively over molecular sieves, or methanol in combination with
      powdered molecular sieves, serves as a good acceptor for acyl transfer reactions.
      Several O-acetylated and O-benzoylated sugar derivatives were efficiently de-O
      acylated using this approach. In the case of per-O-acetylated N
      acetylglucosamine, selective anomeric deprotection could be effected in high
      yield.

PMID- 15013414
TI  - The O-polysaccharide of Pseudomonas syringae pv. mori NCPPB 1656 is a beta-(1-
      >2)-linked homopolymer of L-rhamnose.
AB  - The O-polysaccharide from the lipopolysaccharide of the phytopathogenic bacterium
      Pseudomonas syringae pv. mori NCPPB 1656 was studied by sugar analysis along with
      1H and 13C NMR spectroscopy and found to be a new beta-(1-->2)-linked homopolymer
      of L-rhamnose.

PMID- 15013415
TI  - The structure of the core region of the lipopolysaccharide from Shewanella algae
      BrY, containing 8-amino-3,8-dideoxy-D-manno-oct-2-ulosonic acid.
AB  - The structure of the carbohydrate backbone of the lipid A-core region of the LPS
      from Shewanella algae strain BrY was analysed. The LPS was N,O-deacylated to give
      three products, which were isolated and studied by chemical methods, NMR and mass
      spectrometry: [Carbohydrate structures: see text]. All monosaccharides except L
      rhamnose had the D-configuration. This LPS presents a second example (after S.
      oneidensis) of the structure with a novel linking unit between the core and lipid
      A moieties, 8-amino-3,8-dideoxy-D-manno-oct-2-ulosonic acid (8-amino-Kdo).

PMID- 15013416
TI  - One-step synthesis of beta-C-glycolipid derivatives from unprotected sugars.
AB  - Condensations of nonsymmetrical or symmetrical beta-diketones and unprotected
      sugars in aq NaHCO3 soln were explored. C-glucosyl and C-maltosyl derivatives
      bearing lipophilic residue of 8 or 11 carbon atoms were prepared efficiently
      using this one-step procedure. The amphiphilic properties of these compounds were
      demonstrated by measuring their CMC.

PMID- 15013417
TI  - Photoaffinity labeling identifies the substrate-binding site of mammalian
      squalene epoxidase.
AB  - Squalene epoxidase (SE) catalyzes the conversion of squalene to (3S)-2,3
      oxidosqualene. Photolabeling and site-directed mutagenesis were performed on
      recombinant rat SE (rrSE) in order to identify the location of the substrate
      binding site and the roles of key residues in catalysis. Truncated 50-kDa rrSE
      was purified and photoaffinity labeled by competitive SE inhibitor (Ki=18.4
      microM), [(3)H]TNSA-Dza. An 8-kDa CNBr/BNPS-skatole peptide was purified and the
      first 24 amino acids were sequenced by Edman degradation. The sequence
      PASFLPPSSVNKRGVLLLGDAYNL corresponded to residues 388-411 of the full-length rat
      SE. Three nucleophilic residues (Lys-399, Arg-400, and Asp-407) were labeled by
      [(3)H]TNSA-Dza. Triple mutants were prepared in which bulky groups were used to
      replace the labeled charged residues. Purified mutant enzymes showed lower
      enzymatic activity and reduced photoaffinity labeling by [(3)H]TNSA-Dza. This
      constitutes the first evidence as to the identity of the substrate-binding site
      of SE.

PMID- 15013418
TI  - The N-terminal domain of the replication initiator protein RepE is a dimerization
      domain forming a stable dimer.
AB  - The initiator protein RepE of the mini-F plasmid in Escherichia coli plays an
      essential role in DNA replication, which is regulated by the molecular chaperone
      dependent oligomeric state (monomer or dimer). Crosslinking, ultracentrifugation,
      and gel filtration analyses showed that the solely expressed N-terminal domain
      (residues 1-144 or 1-152) exists in the dimeric state as in the wild-type RepE
      protein. This result indicates that the N-terminal domain functions as a
      dimerization domain of RepE and might be important for the interaction with the
      molecular chaperones. The N-terminal domain dimer has been crystallized in order
      to obtain structural insight into the regulation of the monomer/dimer conversion
      of RepE.

PMID- 15013419
TI  - Small HDL form via apo A-I a complex with atrial natriuretic peptide.
AB  - The goal of this study was to test the ability of small high density lipoproteins
      (small HDL) to bind human alpha-atrial natriuretic peptide (alpha-hANP), an
      amyloidogenic peptide whose involvement in cardiac pathologies is gaining
      increasing clinical evidence. After incubation of HDL with labeled ANP, the
      peptide associated to lipoprotein was detectable only in small HDL containing
      preparations. HDL-associated alpha-[(125)I]hANP was subjected to chromatography,
      electrophoresis, and autoradiography. The autoradiograph showed two radioactive
      bands, whose molecular weight was consistent with the chromatographic pattern.
      Immunoblotting showed the presence of apo A-I in both autoradiographic bands. The
      proteins of the main band were electroeluted, incubated with labeled ANP, and
      subjected to two-dimensional electrophoresis followed by autoradiography. The
      mass spectrometry and molecular weight analyses of the radioactive spot
      demonstrated the presence of an apo A-I dimer. This finding provided a novel
      solid evidence that small HDL via apo A-I dimer are involved in the ANP
      sequestration and thus may play a role in preventing amyloid fibril formation.

PMID- 15013420
TI  - Angiotensin II inhibitory peptide found in the receptor sequence using peptide
      array.
AB  - Peptide array consisting of hundreds of peptides spatially addressed and
      synthesized on a cellulose membrane support was used to screen ligand-inhibitory
      peptides. As a model, angiotensin II (Ang II), a significant peptide related to
      the treatment of cardiovascular diseases, was chosen as the target ligand.
      Peptide arrays covering the Ang II receptor type 1 sequence were prepared, and
      peptide domains with high affinity to the Ang II fluorescein conjugate were
      investigated. The peptide (VVIVIY) within the first transmembrane region
      exhibited the highest affinity to Ang II. The synthesized soluble VVIVIY peptide
      had an 84% inhibitory effect on Ang II-induced aorta contraction. These results
      indicate that our screening strategy utilizing peptide array is an effective
      approach for the peptide drug development.

PMID- 15013421
TI  - Dextran sulfate provides a quantitative and quick microarray hybridization
      reaction.
AB  - Microarray technology is a powerful tool to speed up genomics study, yet many
      technical aspects need to be improved. The hybridization reaction of microarray
      experiments is carried out for 16h or overnight in order to obtain reasonably
      strong signals for analysis in the presence of high salt buffer, like SSC.
      However, the quantitative aspect of microarray hybridization has seldom been
      investigated. In this study, we showed that higher overall signals from
      hybridization were achieved in a buffer system containing dextran sulfate, which
      can accelerate the kinetics of reaction by increasing the local concentration of
      the reactants. The dextran sulfate containing hybridization solution increases
      the reaction 4-fold (median) for cDNA microarray and 29-fold for oligonucleotide
      microarray. More importantly, the solution also provides a quantitative
      hybridization reaction, where the hybridization signals are proportional to the
      abundance of transcript added. The enhancement in the kinetics of hybridization
      is due to both dextran sulfate and formamide present in the solution, but the
      effect is not due to the higher temperature used during the reaction. With a
      slightly longer reaction time the hybridization reaction with the solution allows
      the detection of hybridization signals from rare transcripts that is not possible
      with regular hybridization buffers. With appropriate washing, the enhancement of
      kinetics by the solution does not increase the background signals at all,
      allowing higher signal-to-noise ratios to be achieved.

PMID- 15013422
TI  - Improvement of DNA vaccine immunogenicity by a dual antigen expression system.
AB  - This study examined whether increased antigen expression resulted in enhanced
      antigen-specific immune responses in the context of DNA vaccines. To increase
      antigen expression, two copies of antigen expression cassettes were arranged in a
      plasmid pDX. BALB/c mice were intramuscularly immunized with various constructs
      that express influenza antigens and analysed for DNA-raised immunity. The plasmid
      pDX that expresses two copies of the antigen gene induced stronger antigen
      specific immune responses than the plasmid pGA which expresses single antigen
      gene. To explore the in vivo transgene expression by pDX and pGA, luciferase
      activity was measured in the muscles transduced with luciferase expression
      plasmids. The pDX expressing two copies of luciferase induced the highest
      luciferase activity, which corresponded to the results from vaccination. We
      concluded that increasing the number of antigen expression cassettes in a vaccine
      construct improved antigen expression in the transduced tissue, which induced
      stronger DNA-raised immune responses.

PMID- 15013424
TI  - X-ray-induced telomeric instability in Atm-deficient mouse cells.
AB  - The gene responsible for ataxia telangiectasia (AT) encodes ATM protein, which
      plays a major role in the network of a signal transduction initiated by double
      strand DNA breaks. To determine how radiation-induced genomic instability is
      modulated by the dysfunction of ATM protein, we examined radiation-induced
      delayed chromosomal instability in individual cell lines established from wild
      type Atm(+/+), heterozygote Atm(+/-), and knock-out Atm(-/-) mouse embryos. The
      results indicate that Atm(-/-) mouse cells are highly susceptible to the delayed
      induction of telomeric instability and end-to-end chromosome fusions by radiation
      in addition to the elevated spontaneous telomeric instability detected by
      telomere fluorescence in situ hybridization (FISH). The telomeric instability was
      characterized by abnormal telomere FISH signals, including loss of the signals
      and the extra-chromosomal signals that were associated and/or not associated with
      chromosome ends, suggesting that Atm deficiency makes telomeres vulnerable to
      breakage. Thus, the present study shows that Atm protein plays an essential role
      in maintaining telomere integrity and prevents chromosomes from end-to-end
      fusions, indicating that telomeres are a target for the induction of genomic
      instability by radiation.

PMID- 15013423
TI  - Role of diacylglycerol induced by hypoxia in the regulation of HIF-1alpha
      activity.
AB  - Hypoxia-inducible factor 1 (HIF-1) is a critical transcription factor for the
      adaptation to lowered oxygen environments. We have previously reported that
      hypoxia induced phosphatidic acid (PA) accumulation through diacylglycerol kinase
      (DGK) activity and provided evidence that this PA production regulated HIF-1
      expression. Here we report that hypoxia also produces a marked intracellular
      accumulation of diacylglycerol (DAG) in different cell types. The previously
      proposed inhibitor of phosphatidylcholine phospholipase C (PC-PLC)/sphingomyelin
      synthase (SMS) activities, D609, specifically abrogates both hypoxia-dependent
      DAG accumulation and hypoxia-induced HIF-1 expression. We show that DAG-dependent
      protein kinase C (PKC) isoforms do not play an essential role in the regulation
      of HIF-1 expression. D609 inhibits PA accumulation triggered by hypoxia,
      suggesting that DAG could act as substrate for its conversion into PA by DGK upon
      these conditions. Therefore, this work provides novel evidence for the existence
      of DAG/PA-dependent intracellular mechanisms involved in the regulation of HIF-1
      expression.

PMID- 15013425
TI  - No influence of tumor growth by intramuscular injection of hepatocyte growth
      factor plasmid DNA: safety evaluation of therapeutic angiogenesis gene therapy in
      mice.
AB  - Recently, a novel therapeutic treatment for ischemic diseases using angiogenic
      growth factors to augment collateral artery development has been proposed. As
      intramuscular injection of naked human hepatocyte growth factor (HGF) plasmid DNA
      induced therapeutic angiogenesis in several animal test subjects, we have started
      a clinical trial to treat peripheral arterial disease. However, one might assume
      that over-expression of angiogenic growth factors could enhance tumor growth. To
      resolve this issue, we examined the over-expression of HGF in tumor bearing mice.
      Tumors on their backs were prepared with an intradermal inoculation of A431,
      human epidermoid cancer cells expressing c-Met. These mice were intramuscularly
      injected with human HGF plasmid or control plasmid into the femoral muscle. Human
      HGF concentration was increased only in the femoral muscle, but not in blood.
      Although recombinant HGF stimulated the growth of A431 cells in vitro, temporally
      and locally HGF elevation in hindlimb had no effect on tumor growth in mice.

PMID- 15013426
TI  - The Vif protein of human immunodeficiency virus type 1 is posttranslationally
      modified by ubiquitin.
AB  - The viral infectivity factor (Vif), one of the six HIV-1 auxiliary genes, is
      absolutely necessary for productive infection in primary CD4-positive T
      lymphocytes and macrophages. Vif overcomes the antiviral function of the host
      factor APOBEC3G. To better understand this mechanism, it is of interest to
      characterize cellular proteins that interact with Vif and may regulate its
      function. Here, we show that Vif binds to hNedd4 and AIP4, two HECT E3 ubiquitin
      ligases. WW domains present in those HECT enzymes contribute to the binding of
      Vif. Moreover, the region of Vif, which includes amino acids 20-128 and interacts
      with the hNedd4 WW domains, does not contain proline-rich stretches. Lastly, we
      show that Vif undergoes post-translational modifications by addition of ubiquitin
      both in cells overexpressing Vif and in cells expressing HIV-1 provirus. Vif is
      mainly mono-ubiquitinated, a modification known to address the Gag precursor to
      the virus budding site.

PMID- 15013428
TI  - ADAM28 is activated by MMP-7 (matrilysin-1) and cleaves insulin-like growth
      factor binding protein-3.
AB  - ADAM28, a member of a disintegrin and metalloproteinase (ADAM) family, has two
      isoforms, membrane-type form (ADAM28m) and secreted form (ADAM28s). Although
      ADAM28 is expressed and synthesized in a precursor form (proADAM28) by
      lymphocytes and some cancer cells, its activation mechanism and substrates remain
      unclear. Here, we report that proADAM28s of 65kDa is processed with active matrix
      metalloproteinase-7 (MMP-7) to 42- and 40-kDa forms which corresponds to active
      ADAM28s without propeptide. Processed ADAM28s digested insulin-like growth factor
      binding protein-3 (IGFBP-3) in both free and complex forms with IGF-I or IGF-II,
      and the digestion was prevented with EDTA, 1,10-phenanthroline, KB-R7785, tissue
      inhibitor of metalloproteinases-3 (TIMP-3), and TIMP-4. These data provide the
      first evidence that proADAM28s is activated by MMP-7 and ADAM28 digests IGFBP-3.

PMID- 15013427
TI  - The ectodermal dysplasia receptor represses the Lef-1/beta-catenin-dependent
      transcription independent of NF-kappaB activation.
AB  - EDAR plays a key role in the process of ectodermal differentiation via activation
      of the NF-kappaB pathway. We present evidence that EDAR also represses Lef-1/beta
      catenin-dependent transcription and this ability is defective in EDAR mutants
      associated with anhidrotic ectodermal dysplasia. While IKK1/IKKalpha and
      IKK2/IKKbeta are required for EDAR-induced NF-kappaB activation, they are
      dispensable for its ability to repress Lef-1/beta-catenin-dependent
      transcription. In contrast, NIK is not involved in EDAR-induced NF-kappaB
      activation or Lef-1/beta-catenin transcriptional repression. As Lef-1/beta
      catenin pathway controls the expression of EDAR ligand, ectodysplasin-A (EDA),
      our results point to a negative feedback regulation of EDA-EDAR axis.

PMID- 15013429
TI  - Metastin and its variant forms suppress migration of pancreatic cancer cells.
AB  - Metastin, a post-translationally modified variant of KiSS1, was recently
      identified as an endogenous peptide agonist for a novel G-protein coupled
      receptor, hOT7T175 (AXOR12, GPR54). In this study, we analyzed the role of KiSS1
      and hOT7T175 in both pancreatic cancer tissues and pancreatic cancer cell lines.
      Furthermore, we synthesized novel short variant forms of metastin and tested the
      inhibitory effect of those variants on in vitro cell functions that are relevant
      to metastasis. Pancreatic cancer tissues showed significantly lower expression of
      KiSS1 mRNA than normal tissues (p=0.018), while cancer tissues showed
      significantly higher expression of hOT7T175 mRNA than normal pancreatic tissues
      (p=0.027). In human pancreatic cancer cell lines, KiSS1 mRNA was highly expressed
      in 2 out of 6 pancreatic cancer cell lines, while hOT7T175 mRNA was expressed in
      all cell lines at various degrees. PANC-1 cells showed the highest expression of
      hOT7T175. Exogenous metastin did not suppress cell proliferation but
      significantly reduced the in vitro migration of PANC-1 cells (p<0.01). Metastin
      induced activation of ERK1 in PANC-1 and AsPC-1 cells. Finally, we synthesized 3
      novel short variant forms of metastin, FM053a2TFA, FM059a2TFA, and FM052a4TFA.
      These metastin variants significantly suppressed the migration of PANC-1 cells
      and activated ERK1. These data suggest that the metastin receptor, hOT7T175, is
      one of the promising targets for suppression of metastasis, and that small
      metastin variants could be an anti-metastatic agent to pancreatic cancer.

PMID- 15013430
TI  - Homeodomain protein CDX2 regulates COX-2 expression in colorectal cancer.
AB  - CDX2 is an intestine-specific tumor suppressor gene encoding homeodomain
      containing transcription factor, which is involved in a variety of developmental,
      proliferating, and differentiating processes. Moreover, the expression of CDX2 is
      reduced in a subset of primary colorectal cancers. In contrast, cyclooxygenase-2
      (COX-2) is often up-regulated in human colorectal cancers. However, the molecular
      relationship between CDX2 down-regulation and COX-2 up-regulation is unknown.
      Here we show that CDX2 down-regulates COX-2 promoter activity by interacting with
      NF-kappaB. The ectopic expression of CDX2 was found to suppress PMA-induced COX-2
      promoter activity in a dose-dependent manner. In addition, the treatment of
      colorectal cancer cells with PMA resulted in significant reduction in the level
      of endogenous CDX2 and a significant increase in the level of endogenous COX-2,
      in a dose-dependent manner. Furthermore, CDX2 was found to co-immunoprecipitate
      with the p65 subunit of NF-kappaB and to inhibit p65-induced NF-kappaB minimal
      promoter activity in colon cancer cells. These results suggest that reduced CDX2
      expression may be involved in colorectal carcinogenesis by enhancing NF-kappaB
      mediated inflammatory genes such as COX-2.

PMID- 15013431
TI  - Inhibition of FGF signaling causes expansion of the endoderm in Xenopus.
AB  - Fibroblast growth factor (FGF) is established as an initiator of signaling events
      critical for neurogenesis and mesoderm formation during early Xenopus
      embryogenesis. However, less is known about the role FGF signaling plays in
      endoderm specification. Here, we show for the first time that endoderm-specific
      genes are induced when FGF signaling is blocked in animal cap explants. This
      block of FGF signaling is also responsible for a significant enhancement of
      endodermal gene expression in animal cap explants that are injected with a
      dominant-negative BMP-4 receptor (DNBR) RNA or treated with activin, however,
      neural and mesoderm gene expression is diminished. Consistent with these results,
      the injection of dominant-negative FGF receptor (DNFR) RNA expands endodermal
      cell fate boundaries while FGF treatment dramatically reduces endoderm in whole
      embryos. Taken together, these results indicate that inhibition of FGF signaling
      promotes endoderm formation, whereas the presence of active FGF signaling is
      necessary for neurogenesis/mesoderm formation.

PMID- 15013433
TI  - Role of the N-terminal region of the crenarchaeal sHsp, StHsp14.0, in thermal
      induced disassembly of the complex and molecular chaperone activity.
AB  - Small heat shock protein is a ubiquitous molecular chaperone, which consists of a
      non-conserved N-terminal region followed by a conserved alpha-crystallin domain.
      To understand the role of the N-terminal region, we constructed N-terminal
      truncation mutants of StHsp14.0, the sHsp from Sulfolobus tokodaii strain 7. All
      the mutants formed a stable oligomeric complex similar to that of the wild type.
      Electron microscopy and size exclusion chromatography-multiangle light scattering
      showed that the N-terminal region should locate in the center of the oligomeric
      particle. The mutants exhibited reduced chaperone activity for the protection of
      3-isopropylmalate dehydrogenase from thermal aggregation. This reduction
      correlates with lowered subunit exchange efficiency. The oligomeric structure was
      retained even after incubation at 90 degrees C. These results suggest that the N
      terminal region of StHsp14.0 functions in the thermally induced disassembly of
      the complex.

PMID- 15013432
TI  - NF-kappaB-dependent induction of osteoprotegerin by Porphyromonas gingivalis in
      endothelial cells.
AB  - Porphyromonas gingivalis is a major etiological pathogen of adult periodontitis
      characterized by alveolar bone resorption. Vascular endothelial cells supply many
      inflammatory cytokines into periodontal tissue. However, whether the cells
      contribute to bone metabolism in periodontitis remains unknown. In this study, we
      investigated the effect of P. gingivalis on osteoprotegerin (OPG) and receptor
      activator of NF-kappaB ligand (RANKL) production, both of which are key
      regulators of bone metabolism, in human microvascular endothelial cells (HMVECs).
      We showed that P. gingivalis upregulated expression of OPG but not RANKL mRNA in
      HMVEC. P. gingivalis induced NF-kappaB activation, and the induction of OPG in
      HMVEC by the pathogen was blocked by the inhibitors of NF-kappaB. In addition,
      incubation of OPG with P. gingivalis supernatant resulted in loss of the protein.
      These results indicate that P. gingivalis-stimulated HMVEC secrete OPG via a NF
      kappaB-dependent pathway, while the OPG is partly degraded by the bacteria. Thus,
      microvascular endothelial cells can act as a source of OPG and thereby may play
      an important role in regulating bone metabolism in periodontitis.

PMID- 15013434
TI  - Oscillatory reaction of chondroitin sulfate induced by gradual introduction of
      calcium ion.
AB  - Rhythm is an important dynamic behavior in biological systems. We have been
      studying oscillatory reactions of enzymes induced by gradual entry of substances
      through semipermeable membrane. Not only enzymes but also a few species of
      substance of living system have been elucidated to cause oscillatory reaction.
      Here we present the oscillatory reaction by chondroitin sulfate in a system of
      gradual entry of calcium ion. Introducing calcium ion through dialysis membrane
      into chondroitin sulfate solution induces an oscillation of free calcium ion
      concentration in chondroitin sulfate solution. Simultaneously, it is elucidated
      that oscillation of conformation occurs with permeation of calcium ion. In both
      measurements, oscillations with 25h period are obtained. The phases of
      oscillation, however, differ slightly from each other. From these results, it is
      suggested that autocatalysis exerts in the contraction of chondroitin sulfate
      conformation. These phenomena are very intriguing for elucidating oscillation in
      living system.

PMID- 15013435
TI  - Primary structure and inducibility by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
      of aryl hydrocarbon receptor repressor in a TCDD-sensitive and a TCDD-resistant
      rat strain.
AB  - The aryl hydrocarbon receptor repressor (AHRR) is a negative regulator of AH
      receptor (AHR), which mediates most of the toxic and biochemical effects of
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AHR has been shown to be the major
      reason for the exceptionally wide (ca. 1000-fold) sensitivity difference in acute
      toxicity of TCDD between two rat strains, sensitive Long-Evans (Turku/AB) (L-E)
      and resistant Han/Wistar (Kuopio) (H/W), but there is another, currently unknown
      contributing factor involved. In the present study, we examined AHRR structure
      and expression in these rat strains to find out whether AHRR could be this
      auxiliary factor. Molecular cloning of AHRR coding region showed that consistent
      with AHRR proteins in other species, the N-terminal end of rat AHRR is highly
      conserved, but PAS B and Q-rich domains are severely truncated or lacking.
      Identical structures were recorded in both strains. Next, the time-, dose-, and
      tissue-dependent expression of AHRR was determined using quantitative real-time
      RT-PCR. In liver, AHRR expression was very low in untreated rats, but it
      increased rapidly after TCDD exposure (100microg/kg). Testis exhibited the
      highest constitutive expression of AHRR, whereas kidney, spleen, and heart showed
      the highest induction of AHRR in response to TCDD treatment. Again, no marked
      differences were found between H/W and L-E rats, implying that AHRR is not the
      auxiliary contributing factor to the strain difference in TCDD sensitivity.
      However, simultaneous measurement of CYP1A1 mRNA reinforced the view that AHRR is
      an important determinant of tissue-specific responsiveness to TCDD.

PMID- 15013436
TI  - Selection of genetically modified cell population using hapten-specific
      antibody/receptor chimera.
AB  - Efficient selection of the genetically modified cell population is a critical
      step to obtain the cells with desired properties. In this study, we propose an
      antigen-mediated genetically modified cell amplification (AMEGA) system employing
      an antibody/receptor chimera that triggers a growth signal in response to a non
      toxic hapten dimer. An anti-fluorescein single-chain Fv fused to the
      extracellular D2 domain of erythropoietin receptor and
      transmembrane/intracellular domains of gp130 was expressed together with a model
      transgene, enhanced green fluorescent protein (EGFP) downstream of IRES sequence,
      by retroviral infection to IL-3-dependent Ba/F3 cells. Addition of fluorescein
      dimers connected by various oligo-DNA linkers induced selective growth of
      transfectants, thus leading to efficient expansion of EGFP-positive cell
      population. Also, digestion of the oligonucleotides by specific restriction
      endonuclease completely suppressed cell growth. Because these hapten dimers are
      not harmful for normal cells, the approach will be especially useful for
      reversible in vitro or in vivo expansion of genetically modified cell population
      employed for cell therapy and tissue engineering.

PMID- 15013437
TI  - Role of phospholipase D in the activation of protein kinase D by lysophosphatidic
      acid.
AB  - Protein kinase D was auto-phosphorylated at Ser916 and trans-phosphorylated at
      Ser744/Ser748 in Rat-2 fibroblasts treated with lysophosphatidic acid. Both
      phosphorylations were inhibited by 1-butanol, which blocks phosphatidic acid
      formation by phospholipase D. The phosphorylations were also reduced in Rat-2
      clones with decreased phospholipase D activity. Platelet-derived growth factor
      induced protein kinase D phosphorylation showed a similar requirement for
      phospholipase D, but that induced by 4beta-phorbol 12 myristate 13-acetate did
      not. Propranolol an inhibitor of diacylglycerol formation from phosphatidic acid
      blocked the phosphorylation of protein kinase D, whereas dioctanoylglycerol
      induced it. The temporal pattern of auto-phosphorylation of protein kinase D
      closely resembled that of phospholipase D activation and preceded the trans
      phosphorylation by protein kinase C. These results suggest that protein kinase D
      is activated by lysophosphatidic acid through sequential phosphorylation and that
      diacylglycerol produced by PLD via phosphatidic acid is required for the
      autophosphorylation that occurs prior to protein kinase C-mediated
      phosphorylation.

PMID- 15013439
TI  - A new method for analysis of AZT-triphosphate and nucleotide-triphosphates.
AB  - We have developed a new method based on matrix-assisted laser
      desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) for
      analysis of zidovudine-triphosphate and (deoxy)nucleotide-triphosphates, which
      ultimately can be used for nucleoside reverse transcriptase inhibitor (NRTI)
      treatment monitoring in HIV-1 infected children and adults. Four different
      matrices were compared for sensitivity and reproducibility of zidovudine
      triphosphate detection and anthranilic acid mixed with nicotinic acid (AA/NA) was
      selected as most suitable matrix. Solutions of zidovudine-triphosphate, ATP, and
      dGTP were detected up to 0.5fmol per sample. Furthermore, intracellular
      zidovudine-triphosphate, ATP, and dGTP were detected in peripheral blood
      mononuclear cells (PBMCs). Zidovudine-triphosphate, ATP, and dGTP yield identical
      mass spectra, however MALDI-TOF post-source decay analysis can be used for
      discrimination between these compounds. We conclude that this method based on
      MALDI-TOF MS can be used for analysis of intracellular zidovudine-triphosphate
      and (deoxy)nucleotide-triphosphates in PBMCs.

PMID- 15013438
TI  - Human cytomegalovirus UL18 alleviated human NK-mediated swine endothelial cell
      lysis.
AB  - Human cytomegalovirus UL18, a MHC class I homologue, is known to serve as a
      natural killer cell (NK) decoy and to ligate NK inhibitory receptors to prevent
      lysis of an infected target cell. To explore whether the cell surface expression
      of UL18 represents a potential immune suppressive approach to evade NK-mediated
      cytotoxicity in the prevention of xenograft rejection, we examined the effect of
      the UL18 expression in vitro upon human NK-mediated cytotoxicity against swine
      endothelial cells (SECs). UL18 expression on SECs by a retroviral vector (PLNCX2)
      significantly suppressed NK-mediated SEC lysis by approximately 25-100%. The
      protective effect of UL18 could be mediated through ILT-2 inhibitory receptor on
      NKs. Additionally, the interaction between UL18 and NKs resulted in the
      significant reduction of IFN-gamma production. This study demonstrates that UL18
      can serve as an effective tool for the evasion of NK-mediated cytotoxicity and
      for the inhibition of IFN-gamma production during xenograft rejection.

PMID- 15013440
TI  - p70s6 kinase is a functional target of insulin activated Akt cell-survival
      signaling.
AB  - Insulin administration attenuates cardiac ischemia-reperfusion apoptosis via
      activation of Akt-mediated cell-survival signaling. As p70s6 kinase is a cognate
      Akt-mediated phosphorylation target we evaluated whether p70s6 kinase activation
      is a functional requirement in insulin-mediated cell survival program during post
      ischemic reoxygenation. Human cardiac-derived girardi cells were subjected to 6h
      of simulated ischemia and 2h of reoxygenation+/-insulin treatment [0.3mU/ml].
      Concurrently, cells were pre-treated with anti-sense oligodeoxynucleotides (ODNs)
      corresponding to the initiation start-site of human p70s6 kinase mRNA. Sense ODN
      and scrambled ODN were used as controls. Cell viability was measured using
      lactate dehydrogenase (LDH) release and propidium iodide (PI) exclusion. Insulin
      at reoxygenation enhanced cell viability with attenuated LDH release (>or=50% ,
      p<0.001 vs. ischemic controls) and reduced PI uptake by >or=30% vs. ischemic
      controls. The protection afforded by insulin was abolished by anti-sense ODN
      targeting p70s6 kinase, but not by the sense or scrambled ODNs. In parallel,
      insulin administration at reoxygenation significantly increased p70s6 kinase
      levels and activity compared with controls. P70s6 kinase activity was abolished
      by pre-treatment with anti-sense ODNs. Collectively, these data demonstrate that
      p70s6 kinase activation is a functional target of Akt following insulin-activated
      cytoprotection during ischemia-reoxygenation-induced injury.

PMID- 15013441
TI  - Sequence analysis of twin ATP binding cassette proteins involved in translational
      control, antibiotic resistance, and ribonuclease L inhibition.
AB  - Genome sequencing has identified open reading frames which belong to the ATP
      binding cassette (ABC) transporter family, but which are unlikely to be involved
      in transport phenomena. These frequently contain a pair of nucleotide binding
      domains (NBD) with no associated transmembrane domains. The functions of many of
      these twin-NBD proteins remain unknown. In this manuscript, sequence analysis has
      been employed to analyse two families of twin-NBD proteins, ABCE and ABCF. The
      ABCE proteins, postulated to be inhibitors of RNase L, are identified by two
      potential Fe-S metal-binding domains in addition to two NBDs. Surprisingly, ABCE
      homologues are identified in numerous species which apparently lack an RNase L,
      questioning the proposed function of these proteins. The ABCF proteins can be sub
      divided into more than a dozen sub-classes. Intriguingly, sequence similarity is
      shown between eukaryotic ABCF proteins, which are involved in translation
      initiation and elongation, and prokaryotic ABCF proteins which are implicated in
      resistance to macrolide inhibitors of protein synthesis.

PMID- 15013442
TI  - Expression of three carnitine palmitoyltransferase-I isoforms in 10 regions of
      the rat brain during feeding, fasting, and diabetes.
AB  - Inhibition of carnitine palmitoyltransferase-I (CPT-I) activity in the brain has
      been shown to decrease food intake in rats. We examined the expression of mRNA
      encoding all three known CPT-I isoforms (alpha, beta, and gamma in 10 different
      major regions of the rat brain in normal, chow-fed rats, in fasting rats, and in
      insulin-dependent diabetic rats. Compared with the effects of fasting and
      diabetes on CPT-I mRNA in the liver and heart, there was either less effect or no
      effect depending on the particular brain region examined. These results suggest
      that the regulation of CPT-I mRNA levels is different in the brain than in other
      tissues. A surprising result of this study was the discovery of very high, unique
      expression of CPT-Ibeta (the muscle isoform) in the cerebellum.

PMID- 15013443
TI  - The role of Slr1443 in pilus biogenesis in Synechocystis sp. PCC 6803:
      involvement in post-translational modification of pilins.
AB  - We isolated a transposon-induced nonmotile mutant of the cyanobacterium
      Synechocystis sp. PCC 6803. The mutant was revealed to have a Tn5 insertion in
      the slr1443 gene that showed sequence similarity to a eukaryotic-type protein
      kinase. Thick pili were not observed on the mutant cell surface under the
      electron microscope. The slr1443 gene was not involved in transcription or
      translation of the pilA1 gene encoding pilin, the major component of thick pili.
      In the mutant, lower molecular mass pilin peptides were detected than in the wild
      type. The pilin variant was not truncated at the N- or C-terminus of mature
      PilA1. The reduced molecular mass may have resulted from insufficient post
      translational modification. The amounts of pilin variants were remarkably reduced
      in the periplasmic and surface fractions. The pilin variants were released into
      liquid media without being assembled into pili. Our finding suggests that Slr1443
      plays an important role in pilus biogenesis at the level of the post
      translational modification of pilin.

PMID- 15013444
TI  - Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in
      rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet.
AB  - Non-alcoholic steatohepatitis (NASH) may progress to liver cirrhosis, and NASH
      patients with liver cirrhosis have a risk of development of hepatocellular
      carcinoma. Peroxisome proliferator-activated receptor (PPAR) gamma ligand has
      recently been reported to have improved the condition of patients with NASH. The
      aim of this study was to investigate whether pioglitazone, a PPARgamma ligand,
      has any influence on the animal model of NASH as well as isolated hepatic
      stellate cells. In vivo, the effects of pioglitazone were examined using the
      choline-deficient L-amino acid-defined (CDAA)-diet liver fibrosis model. After
      two weeks, pioglitazone improved hepatic steatosis, prevented liver fibrosis, and
      reduced preneoplastic lesions in the liver after 10 weeks. Pioglitazone reduced
      the expression of TIMP-1 and TIMP-2 mRNA without changing MMP-13 mRNA expression
      compared to the liver fed a CDAA diet alone. In vitro, pioglitazone prevented the
      activation of hepatic stellate cells resulting in reducing the expression of type
      I procollagen, MMP-2, TIMP-1, and TIMP-2 mRNA with increased MMP-13 mRNA
      expression. These results indicate that pioglitazone may be one of the candidates
      for the benefit drugs for the liver disease of patients with NASH.

PMID- 15013445
TI  - Identification and molecular cloning of Tetrahymena 138-kDa protein, a
      transcription elongation factor homologue that interacts with microtubules in
      vitro.
AB  - Macronucleus of Tetrahymena divides amitotically, although in a microtubule
      dependent fashion. Besides the localization study and pharmacological study of
      macronuclear microtubules, mechanism of the macronuclear division is poorly
      understood. A biochemical search for microtubule-associated protein was attempted
      from the isolated macronucleus. Improvement on macronucleus isolation method and
      microtubule coprecipitation assay led to the cloning of p138, a new homologue of
      transcription elongation factor FACT (facilitates chromatin transcription) 140kDa
      subunit. DNase treatment test of macronuclear extract and the sequence of p138
      suggested that p138 is associated with chromosome in the macronucleus. The
      release tests of p138 from microtubules indicated that p138 is released from
      microtubules in the presence of ATP but not in the presence of AMP-PNP. Together,
      the results suggest a novel function of FACT homologue, that p138 interacts with
      both microtubules and chromosome.

PMID- 15013446
TI  - A novel mitochondrial C1-tetrahydrofolate synthetase is upregulated in human
      colon adenocarcinoma.
AB  - To seek the genes involved in the development of colorectal cancer, we analyzed
      the microarray gene expression profiles of human normal and cancerous colon
      tissues using the BioExpress database platform. Through the analysis we found one
      gene named DKFZp586G1517 that was upregulated in colon adenocarcinomas. The full
      length cDNA of the DKFZp586G1517 cloned by polymerase chain reaction (PCR)
      encodes a protein with 978 amino acids, which is homologous to the human
      cytosolic C(1)-tetrahydrofolate synthetase and contains a mitochondrial target
      signal at N-terminus. The gene product expressed in 293 cells was localized in
      mitochondria and processed at the predicted signal cleavage site, supporting the
      idea that DKFZp586G1517 is a novel mitochondrial C(1)-tetrahydrofolate synthetase
      (mtC(1)-THFS). The overexpression of mtC(1)-THFS in 293 cells stimulated the
      colony formation. These results suggest that mtC(1)-THFS may participate in the
      progression of colorectal cancer by conferring growth advantage and could be a
      new molecular target for cancer therapy.

PMID- 15013447
TI  - Suppression of Epstein-Barr virus-encoded latent membrane protein-1 by RNA
      interference inhibits the metastatic potential of nasopharyngeal carcinoma cells.
AB  - Nasopharyngeal carcinoma (NPC) is a highly metastatic tumor characterized by
      close association with EBV. Of the EBV-encoded products, latent membrane protein
      1 (LMP-1) is thought to be the only oncoprotein playing an essential role in cell
      transformation as well as tumor metastasis. In this study, we tested the effect
      of suppressing LMP-1 by RNA interference (RNAi) on the proliferative and
      metastatic potentials of an EBV-positive NPC cell line, C666. We showed that
      stably suppressing LMP-1 by short hairpin RNA (shRNA) plasmid significantly
      altered cell motility, substratum adhesion, and transmembrane invasion ability.
      However, it has little effect on the rate of cell growth and cell cycle control.
      These results demonstrated the effectiveness of RNAi in suppressing LMP-1,
      supporting an important role of LMP-1 in NPC metastasis, and suggested a
      potential application of RNAi-mediated therapeutic strategy for EBV-related NPC.

PMID- 15013448
TI  - A novel mutation of the human 7-dehydrocholesterol reductase gene reduces enzyme
      activity in patients with holoprosencephaly.
AB  - Defects in cholesterol biosynthesis genes are recognized as a leading cause for
      holoprosencephaly (HPE). Previous reports suggest that mutations of human 7
      dehydrocholesterol reductase (Dhcr7), which catalyzes the final step of
      cholesterol biosynthesis, may cause HPE [Clin. Genet. 53 (1998) 155]. To
      determine whether Dhcr7 mutations are involved in HPE pathogenesis, we analyzed
      the sequence of exon 9, which contains both a catalytic domain and a mutational
      hot spot. We examined 36 prematurely terminated fetuses with HPE at their
      gestation ages in the range from 21 to 33 weeks by single strand conformation
      polymorphism analysis and DNA sequencing. A novel missense mutation was
      identified: G344D. Dhcr7 enzyme assays using overexpressed recombinant mutant
      proteins revealed altered enzyme activity. Mutant G344D harbored less than 50% of
      enzyme activity compared with the control. Two previously reported mutations,
      R404C and G410S, abolished enzyme activity. These results suggest that mutation
      of the Dhcr7 gene is involved in HPE pathogenesis.

PMID- 15013449
TI  - Biogenic capsules made of proteins and lipids.
AB  - Multilayer biogenic capsules with a micrometer scale were fabricated by self
      assembly of proteins and lipids at the interface of emulsion droplets. The
      optical microscopy images demonstrate that spherical capsules at a fluid
      interface have uniform walls and the dried capsules possess a high mechanical
      strength. The hollow shells obtained provide a novel class of assembly with
      encapsulating drug molecules based on the layer-by-layer technique.

PMID- 15013450
TI  - Deletion of OSH3 gene confers resistance against ISP-1 in Saccharomyces
      cerevisiae.
AB  - Sphingolipids have been reported to regulate the growth and death of mammalian
      and yeast cells, but their precise mechanisms are unknown. In this paper, it was
      shown that the deletion of the oxysterol binding protein homologue 3 (OSH3) gene
      confers hyper resistance against ISP-1, an inhibitor of sphingolipid
      biosynthesis, in the yeast Saccharomyces cerevisiae. Furthermore, the
      overexpression of the ROK1 gene, which directly binds to Osh3p, conferred
      resistance against ISP-1, and the deletion of the KEM1 gene, which regulates
      microtubule functions, exhibited ISP-1 hypersensitivity. And yet, an ISP-1
      treatment caused an abnormal mitotic spindle formation, and the ISP-1-induced
      cell cycle arrest was rescued by the deletion of the OSH3 gene. Taken together,
      it is suggested that the expression levels of the OSH3 gene influence the ISP-1
      sensitivity of S. cerevisiae, and the sphingolipids are necessary for normal
      mitotic spindle formation in which the Osh3p may play a pivotal role.

PMID- 15013451
TI  - High-level expression of codon optimized foot-and-mouth disease virus complex
      epitopes and cholera toxin B subunit chimera in Hansenula polymorpha.
AB  - A codon optimized DNA sequence coding for foot-and-mouth disease virus (FMDV)
      capsid protein complex epitopes of VP1 amino acid residues 21-40, 135-160, and
      200-213 was genetically fused to the N-terminal end of a 6x His-tagged cholera
      toxin B subunit (CTB) gene with the similar synonymous codons preferred by the
      methylotropic yeast Hansenula polymorpha. The fusion gene was synthesized based
      on a polymerase chain reaction (PCR) and subsequently overexpressed in H.
      polymorpha. The chimeric protein was successfully secreted into the culture
      medium (up to 100mg/L) and retained the antigenicity associated with CTB and FMDV
      antibodies by Western blot analysis. The chimera after purification through
      Co(2+)-charged resin column bound specifically to GM1 ganglioside receptor and
      thus retained the biological activity of CTB. This study has important
      implications in the construction of CTB chimera for mucosal vaccines against
      FMDV.

PMID- 15013452
TI  - Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene
      expression: role of tyrosine nitration.
AB  - Oxidative stress is a characteristic of chronic inflammatory diseases. The
      reactive oxygen intermediate hydrogen peroxide (H(2)O(2)) is an important
      signaling molecule that modulates gene expression. We have demonstrated that
      H(2)O(2) significantly enhanced cytokine production in BEAS-2B cells, with a
      maximal effect at 4h. This did not result from enhanced NF-kappaB activation, but
      through decreased activity of histone deacetylase (HDAC)2. This results in
      increased inflammatory gene expression following acetylation of specific histone
      residues. Decreased HDAC2 activity was associated with tyrosine nitration status.
      Peroxynitrite and SIN-1, a peroxynitrite generator, were also able to reduce
      HDAC2 activity via tyrosine nitration. Our data suggest that oxidative stress
      contributes to worsening inflammation via reduction of HDAC2 activity through
      HDAC2 nitration. This novel mechanism of inflammation may be important in
      increasing the severity and chronicity of inflammatory diseases.

PMID- 15013454
TI  - Timely initiation of basal insulin.
AB  - Recognition of the basal and postprandial components of hyperglycemia, in tandem
      with the development of new insulins and other clinical research, has led to a
      reassessment of type 2 diabetes mellitus treatment. In the future, insulin will
      be used earlier, treatment will intensify as the disease progresses, and
      combination therapy will be routine. Hyperglycemia can be controlled initially
      with sulfonylureas and metformin, agents that mainly improve control of fasting
      and preprandial glucose. When glycemic control can no longer be achieved with
      these and other oral agents alone, insulin treatment can be started as a single
      injection of a long-acting insulin. This method of supplementing basal insulin is
      safe, simple, and less likely to cause weight gain than multiple daily injections
      with shorter-acting insulins. Continuing oral agents during basal insulin therapy
      can provide a smoother transition to insulin and reduce the risk of loss of
      glycemic control. Of currently available insulins, glargine has the activity
      profile best suited to basal insulin therapy, with no prominent activity peak and
      a long duration of action, allowing a single daily injection in most cases.
      Although the traditional approach has been to introduce insulin therapy only
      after very high glucose values have persisted, despite prolonged use of oral
      agents alone, a more desirable strategy would be to prevent patients from ever
      experiencing the loss of glycemic control associated with hemoglobin A(1c)
      (HbA(1c)) elevations >7%. This goal could be achieved by diagnosing type 2
      diabetes earlier in its course and by adding basal insulin to oral therapy much
      earlier. To maintain the recommended <7% HbA(1c) target level of control,
      treatments that target postprandial hyperglycemia will have to be added to basal
      insulin later on, as endogenous insulin continues to decline.

PMID- 15013455
TI  - Basal insulin supplementation in type 2 diabetes; refining the tactics.
AB  - The burden of type 2 diabetes mellitus will become even greater in coming decades
      as more young people present with the disease and patients live longer with the
      devastating complications of chronic hyperglycemia. Conventional and largely
      ineffectual treatment strategies consisting of lifestyle measures and long-term
      oral therapy are being challenged by studies showing that the early addition of
      insulin to oral agents can significantly improve glycemic control in patients
      with type 2 diabetes. Further, 2 recent randomized, controlled trials support the
      clinical utility of supplementing oral pharmacotherapy with once-daily insulin
      glargine to achieve and maintain target glycosylated hemoglobin levels < or =7%.
      This simple treat-to-target strategy may be readily adopted in general practice
      through a widely translatable algorithm moving from oral pharmacotherapy to early
      addition of basal insulin glargine if glycemic targets are not met. The once
      daily flexible dosing of insulin glargine and its smooth, flat profile,
      associated with fewer episodes of nocturnal hypoglycemia, make it among the
      safest and most practical tools to date for transforming the paradigm of type 2
      diabetes management.

PMID- 15013456
TI  - Treatment of patients with severe insulin deficiency; what we have learned over
      the past 2 years.
AB  - The initial injection in 1922 of a pancreatic extract, or insulin as it came to
      be known, into a patient with diabetes mellitus has since been followed by the
      successive introduction of longer-acting insulins, more highly purified insulins,
      and insulins that have been modified to more closely match insulin activity to
      patients' physiologic requirements. The recently introduced rapid-acting insulin
      analogues lispro and aspart and the long-acting analogue glargine are further
      refinements of insulin therapy. Current treatment strategies for severe insulin
      deficiency are based on the need to provide 2 components of insulin replacement:
      basal and postprandial. Rapid-acting insulin has been shown to provide superior
      postprandial glucose control compared with regular insulin. Truly effective
      control of basal insulin has been achieved by the introduction of the insulin
      pump in the 1980s and insulin glargine in 2001. Insulin glargine is the first
      insulin analogue to provide, in a majority of patients, a continuous level of
      insulin without a pronounced peak after a single daily injection, closely
      mimicking the normal pancreatic release of basal insulin in healthy individuals.
      Clinical experience is providing many insights into how basal and prandial
      components of insulin therapy can be best combined, although evidence from
      controlled trials will take some years to accumulate. Experience and observations
      since 2001 indicate that insulin therapy should be introduced earlier in patients
      with type 2 diabetes to control blood glucose levels. More importantly, the
      greatest benefit of insulin glargine has been to change positively the way
      physicians and patients think about insulin therapy. Newer insulin analogues,
      improved devices for home glucose monitoring, and pulmonary inhaled insulin are
      other innovations that promise improvement of hemoglobin A(1c) levels.

PMID- 15013462
TI  - Decompressive hemicraniectomy in a new cat model. Methodological description of
      the PET study protocol.
AB  - Positron emission tomography (PET) is increasingly used to quantify regional
      hemodynamic and metabolic changes in different animal models. Most of these
      (multitracer) studies provided important early data on already functionally
      altered brain tissue, indicating selective vulnerability by a large variability
      in the functional blood flow threshold of individual neurons. To fill the gap
      between experimental studies at early time points and rather late clinical
      studies at well-defined but singular time points, we repeatedly measured cerebral
      blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction
      rate and cerebral metabolic rate of glucose (CMRglc) in three cats before and up
      to 28 h after decompressive hemicraniectomy on normal brain tissue. Decompressive
      hemicraniectomy in the cat decreased CBF, and to a lesser extent CMRO2 and CMRglc
      2 h after surgical intervention in normal brain tissue that last for at least 1
      day. CBF significantly decreased (p < 0.01) and oxygen extraction fraction (OEF)
      (p < 0.05) significantly increased. CMRO2 and CMRglc decreased only in regions
      with most severe CBF reduction. These effects remained for at least a day
      irrespective of corrective sustaining cranioplasty. The method and data analysis
      is decreased and discussed in detail in the presented protocol. In conclusion,
      serial positron emission tomography studies are best suited to repeatedly and non
      invasively demonstrate circulatory and biochemical changes by surgical
      interventions in normal brain tissue for at least one day. The transition of
      normal brain tissue into misery-perfused or non-viable regions can be followed
      over time. Such state-of-the-art imaging modalities as sequential high-resolution
      positron emission tomography provide insight into the dynamic of regional
      pathophysiology and may thus further justify the development of rational
      therapeutic strategies for decompressive hemicraniectomy, especially for disease
      with focal disturbances in cerebral blood flow.

PMID- 15013463
TI  - Isolation and culture of motor neurons from the newborn mouse spinal cord.
AB  - A protocol for the isolation and culture of motor neurons from postnatal day 1
      mouse spinal cord is described. After 72 h in culture, phase contrast microscopy
      reveals healthy cells with motor neuronal morphology and extensive neuritic
      processes. These neurons express the 75-kDa low-affinity neurotrophin receptor
      (p75NTR) and choline acetyltransferase (ChAT), both proteins are specifically
      expressed by neonatal and embryonic motor neurons in vivo. This protocol can be
      adapted for various postnatal motor neuron assays.

PMID- 15013464
TI  - Middle cerebral artery occlusion during MR-imaging: investigation of the
      hyperacute phase of stroke using a new in-bore occlusion model in rats.
AB  - Magnetic resonance imaging (MRI) provides insights into the dynamics of focal
      cerebral ischemia. Usually, experimental stroke is induced outside the magnet
      bore, preventing investigators from acquiring pre-ischemic images for later pixel
      by-pixel comparisons and from studying the earliest changes in the hyperacute
      phase of ischemia. Herein, we introduce a new and easy to apply in-bore occlusion
      protocol based on the intraarterial embolization of ceramic macrospheres. PE-50
      tubing, filled with saline and six macrospheres (0.315-0.355 mm in diameter), was
      placed into the internal carotid artery (ICA) of anesthetized Sprague-Dawley
      rats. The animals were transferred into an MRI scanner (7.0 T) and baseline
      diffusion-weighted imaging (DWI) and T2-imaging was performed. Then the
      macrospheres were injected into the internal artery to occlude the MCA. Post
      ischemic DWI and T2-imaging was started immediately thereafter. The apparent
      diffusion coefficient (ADC) (a marker for cytotoxic brain edema) and T2
      relaxation time (a marker for vasogenic brain edema) were determined in the
      ischemic lesions and compared to the unaffected hemisphere. ADC significantly
      declined within the first 5-10 min after stroke onset. T2-relaxation time
      increased as early as at the first T2-imaging time-point (20-35 min after
      embolization). After 150 min of ischemia, the lesions covered 18.0 +/- 7.4% of
      the hemispheres. The model failed in one out of nine animals (11%). This model
      allows MR-imaging from the initial minutes after permanent middle cerebral artery
      (MCA) occlusion. It does not permit reperfusion. This technique might provide
      information about the pathophysiological processes in the hyperacute phase of
      stroke.

PMID- 15013465
TI  - EEG-dependent ERP recording: using TMS to increase the incidence of a selected
      pre-stimulus pattern.
AB  - EEG dependent event-related potential (ERP) recording (interactive ERP) is an
      extension to ERP paradigms whereby stimuli are initiated in response to a
      selected pattern of background EEG. This form of recording is critically
      dependent upon the incidence of the particular pattern of interest. We introduce
      here a process that modifies the EEG in a predictable manner so as to increase
      the incidence of a particular pattern. Transcranial magnetic stimulation (TMS)
      stimuli are applied in response to a selected pattern of pre-TMS activity, and
      the post-TMS response is characterized by the incidence of a defined pattern of
      EEG activity. Analysis of validation test results obtained with the TMS
      modification part of the process verifies an increased incidence of the response
      pattern after TMS stimuli, compared with placebo stimuli. The TMS modification
      procedure is then combined with interactive ERP recording in a two step process
      to affect the ERP response to sensory stimuli. The post-TMS pattern from the
      first step becomes the pre-stimulus pattern of the interactive ERP recording in
      the second step. The TMS modified interactive ERP (TMIERP) process is illustrated
      here using an auditory oddball paradigm. The amplitude of the P300 peak obtained
      using this process was significantly higher than that obtained using the standard
      auditory oddball paradigm.

PMID- 15013466
TI  - A model for implanting neuronal tissue into the cochlea.
AB  - Immature dorsal root ganglion (DRG) neurons have previously been shown to survive
      implantation to the cavity of extirpated adult native DRG, send axons via the
      dorsal root into the host spinal cord and make functional sypnatic connections.
      Regeneration or replacement of the auditory nerve would provide a major
      intervention in the clinical treatment of severe hearing impairment. In this
      study we have exploited the potential of fetal DRG neurons to survive
      allografting into the cochlea of adult guinea pigs. In some animals implantation
      of fetal DRGs was combined with infusion of neurotropic substances into the
      cochlea. Survival of the implanted DRG neurons was found in the majority of
      grafted animals. Treatment with neurotrophic factors significantly increased the
      number of surviving implanted DRG neurons. However, even in the absence of
      neurotrophic substances survival of DRG neurons was found in a majority of the
      animals, indicating the presence of endogenous growth promoting factors within
      the cochlea and/or an intrinsic capacity of fetal DRG neurons themselves to
      survive in this heterotropic location.

PMID- 15013469
TI  - Bite force measurement in awake rats.
AB  - This report describes the implementation of bite force measurement in awake rats
      and software instruments (Spike 2 script programs) that quantify and analyze the
      bite force data. One script program employs user-defined control of threshold
      bite force, which allows an easy adjustment of target force prior to training the
      rat. Furthermore, the interactive program allows on-line control of threshold
      bite force at anytime during the training session. Upon detection of the bite
      force crossing the threshold, it automatically triggers the external water
      delivery system for reinforcement. Another script program detects successful
      biting attempts, compiles times stamps and force level for each attempted bite,
      and calculates the total number of bites, success rate and mean bite force per
      training session. Using the new methodology, we trained five adult rats to
      produce the bite force of 1300 g. Our results demonstrated that all rats achieved
      the target force with a similar time course and exhibited little variability in
      success rate and mean bite force. The script programs provided instant review and
      analyses of the captured data. These techniques simplify assessment of bite force
      in behaving rats.

PMID- 15013467
TI  - Comparison of contrast, sensitivity and efficiency of signal amplified and
      nonamplified immunohistochemical reactions suitable for videomicroscopy-based
      quantification and neuroimaging.
AB  - In recent years, many different technical modifications of immunohistochemical
      methods have been developed. The selection of a suitable technique for
      quantitative purposes such as mapping studies can be quite difficult. Various
      features of a certain method must be considered such as the sensitivity, costs,
      duration and practicability with respect to serial sectioned specimens.
      Background and foreground difference or contrast and the influence of artifacts
      are major problems of quantitative immunohistochemistry. It is not known which of
      the different modifications of immunohistochemical signal amplifications and non
      amplifications gives optimal results in respect to image analytical-based
      quantification. However, for image analysis, it is important to analyze sections
      which offer a sufficient contrast between foreground and background. The
      sensitivity of a system is crucial when quantitative immunohistochemistry should
      be applied to scarce material with longer postmortem and storage times which
      occur often by processing human brains. In addition, the enzyme-substrate
      reactions have an obvious influence on this criterion; therefore, different
      substrates were also tested. The contrast may be as well effected by the quality
      and specificity of the primary antibody, the type of tissue and naturally by
      preparative (fixation, postmortem delay, storage) and individual factors (age,
      circadian effects, diseases, sex). Because all of these factors may yield to
      different results by combining them with different neuronal structures, we used
      three different antigen expressions for a specific analysis: fibrillary,
      granulary and perikaryal antigen distributions in brains from Wistar rats.
      Principally, the sensitivity of the modifications of immunohistochemical
      amplifications is revealed more strongly than without enhancement steps; however,
      the contrast between foreground and background structures does not necessary
      increase by applying a certain amplification technique. The lowest contrast (15%)
      was detected after applying the labelled streptavidin-biotin technique. All other
      methods offer comparable contrasts in between 30% and 40%. The catalyzed signal
      amplification reaction has been found to give optimal results (40% contrast) for
      image analysis. However, from the technical point of view and variability of
      protein expression, storage and postmortem delay, it was necessary to adapt the
      commercial CSA Kit from Dako (K1500). The modified technique, called C2 method,
      offers better results with respect to sensitivity, total costs, duration and
      contrast (60%) and variability of contrast.

PMID- 15013468
TI  - Volumetric evaluation of the ischemic lesion size with serial MRI in a transient
      MCAO model of the rat: comparison of DWI and T1WI.
AB  - Magnetic resonance imaging (MRI) is applied in many studies on experimental
      cerebral ischemia in rodents to monitor the temporal evolution of ischemic
      damage. We report a protocol to evaluate the infarct size after middle cerebral
      artery occlusion with reperfusion (MCAO/R) in male Wistar rats. Imaging was
      performed with a 2.35 T scanner and we focused on diffusion-weighted imaging
      (DWI), T2-weighted imaging (T2WI) and postcontrast T1-weighted imaging (T1WI). We
      show the detailed procedure of volumetry, the contrast-to-noise ratio (CNR) and
      the intraindividual variability of infarct and hemispheric volumes at different
      reperfusion times. The presented method is of low variability if image contrast
      between ischemic and nonischemic tissue is very high, which is the case not only
      for all sequences at 8 and 12 h of reperfusion but also for DWI after 3 and 5 h
      of reperfusion. Furthermore, we describe the so-called mismatch region of lesion
      sizes depicted on DWI and postcontrast T1WI that suffers from cytotoxic edema but
      lacks contrast enhancement.

PMID- 15013471
TI  - Hypothyroxinaemia and thyroid function after preterm birth.
AB  - The concentration of thyroid hormone in preterm infants is lower than that in
      term infants. This phenomenon is referred to as transient hypothyroxinaemia of
      prematurity. Low thyroid hormone levels after very preterm birth are associated
      with worse developmental outcome in childhood, but only one randomized controlled
      trial has been carried out in the surfactant era to find out whether thyroid
      hormone supplementation is beneficial for developmental outcome. More studies are
      required to find out whether thyroid hormone supplementation is beneficial, and
      if so, for which preterm group.

PMID- 15013472
TI  - Adrenocortical function and dysfunction in the fetus and neonate.
AB  - Under normal circumstances, the fetus is exposed to very low concentrations of
      cortisol until late in gestation. Perturbations of the intra-uterine environment
      resulting in fetal exposure to increased cortisol may have consequences not only
      in infancy, but also into adult life. In the postnatal period, developmental
      immaturity and/or the effects of critical illness on adrenal function may result
      in insufficient cortisol production to maintain homeostasis in the face of acute
      stress or illness, a situation that has been labelled 'relative adrenal
      insufficiency' in other acutely ill populations. The definition of inadequate
      adrenal function in the newborn and its possible relationship to adverse outcomes
      in both premature and term infants are only beginning to be characterized.

PMID- 15013473
TI  - Perinatal calcium metabolism: physiology and pathophysiology.
AB  - Disturbances in mineral homeostasis are common in the neonatal period, especially
      in premature infants and infants who are hospitalised in an intensive care unit.
      In many cases these disturbances are thought to be exaggerated responses to the
      normal physiological transition from the intrauterine environment to neonatal
      independence. By contrast, some disturbances in calcium homeostasis are the
      result of genetic defects, which in many instances can now be identified at the
      molecular level. In other cases hypocalcaemia or hypercalcaemia may result from
      pathological intrauterine conditions, birth trauma or stress, or fetal
      immaturity. Diagnosis and management of hypocalcaemia and hypercalcaemia in the
      neonate and infant requires specific knowledge of perinatal mineral physiology
      and the unique clinical and biochemical features of newborn mineral metabolism.
      In this chapter we will provide a brief overview of calcium metabolism with an
      emphasis on the neonatal transition, followed by discussion of the common causes
      of hypercalcaemia and hypocalcaemia.

PMID- 15013474
TI  - Selected principles of perinatal-neonatal glucose metabolism.
AB  - While the fetus is completely dependent on his/her mother for glucose and other
      nutrient transfer across the placenta, the adult is completely independent,
      especially one who is neither pregnant nor diabetic. The neonate is considered to
      be in a transition between the complete dependence of the fetus and the complete
      independence of the adult. The heterogeneity that is the hallmark of neonatal
      glucose metabolism is illustrated by the observation that maintenance of
      euglycaemia in the sick and/or low-birthweight neonate is especially difficult.
      This reinforces the concept that the neonate is vulnerable to carbohydrate
      disequilibrium. In this discussion, we shall first evaluate the definition of
      euglycaemia by considering the ranges for hypo- and hyperglycaemia. We shall also
      review the considerable literature that has been published on measurement of the
      rate of glucose production and the rate of glucose utilization in the neonate.
      This review highlights where further work is necessary to understand the
      developing maturation (i.e. control) of glucose homeostasis in the neonate.

PMID- 15013475
TI  - Neonatal hypoglycaemia: aetiologies.
AB  - Diagnosis of glucose status requires knowledge of the homeostatic mechanisms that
      maintain the blood glucose concentration between the narrow range of 2.5 and 7.5
      mmol/l during periods of eating or fasting. Hypoglycaemia occurring within the
      first few hours after eating is suggestive of hyperinsulinism. Most glucose is
      subsequently converted into glycogen in the liver, and hypoglycaemia occurring
      during this phase is suggestive of glycogenosis. During fasting, gluconeogenesis
      progressively replaces glycogen as the major source of blood glucose, and
      hypoglycaemia occurring during this period is suggestive of impaired
      gluconeogenesis or fatty acid disorders. Growth hormone, glucagon, cortisol and
      insulin-like growth factor 1 deficiencies may also play a role. Other causes of
      hypoglycaemia have also been identified recently, namely glucose transporter
      disorders, respiratory chain disorders and congenital disorders of glycosylation.

PMID- 15013476
TI  - Neonatal and very-early-onset diabetes mellitus.
AB  - Transient (TNDM) and permanent neonatal diabetes mellitus (PNDM) are rare
      conditions occurring in one in 400,000-500,000 live births. In TNDM, growth
      retarded infants develop diabetes in the first few weeks of life only to go into
      remission in a few months with later relapse as permanent type 2 diabetes, often
      around the time of adolescence. We believe that pancreatic dysfunction in this
      condition is maintained throughout life with relapse initiated at times of
      metabolic stress such as puberty or pregnancy. The mechanisms involved in this
      rare condition may inform on fetal pancreatic development, islet cell physiology
      and predisposition to type 2 diabetes. In PNDM, insulin secretory failure occurs
      in the early postnatal period. A number of conditions are associated with PNDM,
      some of which have been elucidated at the molecular level. Insulin therapy is
      difficult to manage in the neonatal period, and in experienced hands, the insulin
      pump may provide a valuable tool to administer insulin.

PMID- 15013477
TI  - Long-term metabolic consequences of being born small for gestational age.
AB  - This article reviews the evidence for fetal and early origins of type 2 diabetes,
      insulin resistance, dyslipidaemia and obesity. Particular emphasis is given to
      the role of adipose tissue in catch-up growth and long-term metabolic
      complications following restricted fetal growth. To date, several pathways have
      been proposed to explain the development of insulin resistance following
      restricted fetal growth, but no precise mechanisms have been demonstrated. It
      appears that early postnatal growth may also be a critical step.

PMID- 15013478
TI  - Screening for neonatal endocrinopathies: rationale, methods and results.
AB  - The measurement of thyrotropin or thyroxine from dried blood spots collected from
      neonates allows diagnosis before clinical manifestations develop, and prevents
      mental deficiency from congenital hypothyroidism. However, severely hypothyroid
      newborns remain at risk of cognitive problems that may be avoided if they are
      treated within two weeks of birth, hence the importance of a quick turnaround
      time of the screening programme. This also applies to screening for congenital
      adrenal hyperplasia due to 21-hydroxylase deficiency based on the measurement of
      17-hydroxy-progesterone from dried blood; this was primarily designed to prevent
      neonatal deaths from acute adrenal insufficiency. This goal can be achieved by a
      high degree of clinical awareness of the diagnosis, but this has only been
      reported in a few jurisdictions. Furthermore, biochemical screening allows
      earlier treatment. On the other hand, there are many false positives, mostly in
      premature infants, so screening for 21-hydroxylase deficiency has not been
      universally adopted.

PMID- 15013479
TI  - Evaluation of radioiodinated (R)-N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine
      as a ligand for brain norepinephrine transporter imaging.
AB  - (R)-N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine (MIPP) was evaluated as a
      radiopharmaceutical for investigating brain norepinephrine transporters (NET) by
      single photon emission computed tomography (SPECT). (R)-[(125)I]MIPP was
      synthesized with high radiochemical yield (60%) and high radiochemical purity (>
      98%). In biodistribution experiments, (R)-[(125)I]MIPP indicated that the brain
      uptake of (R)-[(125)I]MIPP was rapid and retained, and that the regional cerebral
      distribution was consistent with the density of NET. Moreover, the administration
      of desipramine decreased the accumulation of (R)-[(125)I]MIPP in the brain. HPLC
      analysis of brain radioactivity showed that more than 90% was intact (R)-MIPP.
      These results suggested that (R)-[(123)I]MIPP is a potential radiopharmaceutical
      for imaging brain NET.

PMID- 15013480
TI  - A bolus/infusion paradigm for the novel NMDA receptor SPET tracer [123I]CNS 1261.
AB  - We have previously performed quantitative kinetic modeling of [(123)I]CNS 1261, a
      new SPET ligand for the MK801 intrachannel site of the NMDA receptor. We now
      report a bolus-infusion protocol, which eliminates the need for arterial blood
      sampling. Dynamic SPET scanning and venous blood sampling were performed in 7
      healthy volunteers. Good agreement was obtained between kinetic and equilibrium
      analysis. SPET scanning with a bolus-infusion protocol is a valid method to
      estimate the total volume of distribution for [(123)I]CNS 1261 in clinical
      populations.

PMID- 15013481
TI  - Quantitative measurement of histamine H(1) receptors in human brains by PET and
      [11C]doxepin.
AB  - The aim of this study is to establish a method for quantitative measurement of
      histamine H(1) receptor (H1R) in human brain by PET and [(11)C]doxepin
      ([(11)C]DOX). The estimated parameters with a two-compartment model were stable
      for the initial values for parameter estimation but those with a three
      compartment model were not. This finding suggests that the H1R measured by the
      [(11)C]DOX and PET can be evaluated with a two-compartment model.

PMID- 15013482
TI  - Binding of tritiated and radioiodinated ZM241,385 to brain A2A adenosine
      receptors.
AB  - Autoradiography on rat brain using tritiated (1*), mono- (2*) and di
      radioiodinated (3*) derivatives of the A(2A) adenosine receptor antagonist
      ZM241,385 showed high receptor density in striatum. K(D)s of 1*, 2* and 3* were
      0.4, 2.2 and 15 nM and nonspecific binding was 5, 40 and 50% of total binding.
      Striatal uptake of 2* in mice was approximately 0.2% ID/g 60 min post-injection;
      blocking by 2 was insignificant. Poor penetration of the blood brain barrier and
      high nonspecific binding make 2* unsuitable for imaging striatal receptors.

PMID- 15013483
TI  - 18F-labeled RGD peptide: initial evaluation for imaging brain tumor angiogenesis.
AB  - Brain tumors are highly angiogenesis dependent. The cell adhesion receptor
      integrin alpha(v)beta(3) is overexpressed in glioma and activated endothelial
      cells and plays an important role in brain tumor growth, spread and angiogenesis.
      Suitably labeled alpha(v)beta(3)-integrin antagonists may therefore be useful for
      imaging brain tumor associated angiogenesis. Cyclic RGD peptide c(RGDyK) was
      labeled with (18)F via N-succinimidyl-4-[(18)F]fluorobenzoate through the side
      chain epsilon-amino group of the lysine residue. The radiotracer was evaluated in
      vivo for its tumor targeting efficacy and pharmacokinetics in subcutaneously
      implanted U87MG and orthotopically implanted U251T glioblastoma nude mouse models
      by means of microPET, quantitative autoradiography and direct tissue sampling.
      The N-4-[(18)F]fluorobenzoyl-RGD ([(18)F]FB-RGD) was produced in less than 2 h
      with 20-25% decay-corrected yields and specific activity of 230 GBq/micromol at
      end of synthesis. The tracer showed very rapid blood clearance and both
      hepatobiliary and renal excretion. Tumor-to-muscle uptake ratio at 30 min was
      approximately 5 in the subcutaneous U87MG tumor model. MicroPET imaging with the
      orthotopic U251T brain tumor model revealed very high tumor-to-brain ratio, with
      virtually no uptake in the normal brain. Successful blocking of tumor uptake of
      [(18)F]FB-RGD in the presence of excess amount of c(RGDyK) revealed receptor
      specific activity accumulation. Hence, N-4-[(18)F]fluorobenzoyl labeled cyclic
      RGD peptide [(18)F]FB-RGD is a potential tracer for imaging alpha(v)beta(3)
      integrin positive tumors in brain and other anatomic locations.

PMID- 15013484
TI  - Evaluation of O-[11C]methyl-L-tyrosine and O-[18F]fluoromethyl-L-tyrosine as
      tumor imaging tracers by PET.
AB  - We investigated the potential of O-[(11)C]methyl-L-tyrosine and O-[(18)
      F]fluoromethyl-L-tyrosine as positron-emitting tracers for tumor imaging. The two
      tracers had similar distribution patterns in rats bearing AH109A hepatoma, with
      pancreas and, on a lesser extent, AH109A showing the highest uptake. Uptake of
      both tracers in the AH109A and uptake ratios of AH109A-to-tissues (with the
      exception of AH109A-to-bone) gradually increased for 60 min. O-[(11)C]methyl-L
      tyrosine was metabolically stable, whereas a negligible low amount of metabolites
      was observed for O-[(18)F]fluoromethyl-L-tyrosine. Both tracers showed the
      potential for tumor imaging.

PMID- 15013485
TI  - Preparation and biodistribution of technetium-99m-labeled 1-(2-nitroimidazole-1
      yl)-propanhydroxyiminoamide (N2IPA) as a tumor hypoxia marker.
AB  - A new hydroxyiminoamide ligand, 1-(2-nitroimidazole-1-yl)-propanhydroxyiminoamide
      (N2IPA) was synthesized. The biodistribution of (99m)Tc-N2IPA in mice bearing
      S180 tumor demonstrated that the complex showed a selective accumulation in tumor
      and slow clearance from it. The tumor-to-tissue uptake ratios increased with
      time. At 4 hours after injection, the uptake ratios of tumor to muscle, blood,
      liver, heart, and lung reached 8.4, 1.5, 0.6, 2.9, and 2.3, respectively.
      Moreover, the tumor-to-liver uptake ratio steadily increased to 0.9 at 8 hours
      and 2.3 at 24 hours. The complex showed little uptake and quick clearance in
      blood, lung and other organs. Compared with other proposed hypoxia-imaging
      agents, this novel agent has advantages of higher tumor-to-muscle and tumor-to
      blood uptake ratios and easier synthesis.

PMID- 15013486
TI  - Radiobromination of monoclonal antibody using potassium [76Br] (4
      isothiocyanatobenzyl-ammonio)-bromo-decahydro-closo-dodecaborate (Bromo-DABI).
AB  - The use of charged linkers in attaching radiohalogens to tumor-seeking
      biomolecules may improve intracellular retention of the radioactive label after
      internalization and degradation of targeting proteins. Derivatives of polyhedral
      boron clusters, such as closo-dodecaborate (2-) anion, might be possible charged
      linkers. In this study, a bifunctional derivative of closo-dodecaborate, (4
      isothiocyanatobenzyl-ammonio)-undecahydro-closo-dodecaborate (DABI) was labeled
      with positron-emitting nuclide (76)Br (T 1/2 = 16.2 h) and coupled to anti
      HER2/neu humanized antibody Trastuzumab. The overall labeling yield at optimized
      conditions was 80.7 +/- 0.6%. The label was proven to be stable in vitro in
      physiological and a set of denaturing conditions. The labeled antibody retained
      its capacity to bind to HER-2/neu antigen expressing cells. The results of the
      study demonstrated feasibility for using derivatives of closo-dodecaborate in
      indirect labeling of antibodies for radioimmunoPET.

PMID- 15013487
TI  - Biological comparison of 149Pm-, 166Ho-, and 177Lu-DOTA-biotin pretargeted by
      CC49 scFv-streptavidin fusion protein in xenograft-bearing nude mice.
AB  - The radiolanthanides (149)Pm, (166)Ho, and (177)Lu possess a range of half-lives
      and alpha(-) beta(-) energies for targeted radiotherapy of cancer. (149)Pm-,
      (166)Ho-, and (177)Lu-DOTA-biotin were pretargeted to LS174T colorectal tumors in
      nude mice with CC49 scFvSA antibody-streptavidin fusion protein. Tumor uptakes of
      (149)Pm (22.9% ID/g), (166)Ho (30.2% ID/g), and (177)Lu (35.4% ID/g) peaked at 1
      4 h. Rapid blood disappearance was accompanied by urinary excretion of 59-66% ID
      within 1 h. Biodistributions of these agents show promise for pretargeted
      radioimmunotherapy of cancer.

PMID- 15013488
TI  - The availability of contrast media in the application of Holmium-166-DTPA for
      vascular brachytherapy.
AB  - Since coronary angioplasty using a liquid radiation source is performed with
      computed tomography(CT) angiography, use of a CT contrast agent is a good
      alternative to see if the balloon has close contact with the blood vessel wall
      for the delivery of a sufficient radiation dose to the stenotic artery. In order
      to examine the usefulness of the CT contrast agent as a diluent of a liquid
      radiation source, various physicochemical studies and in vivo stability studies
      using animals were implemented using (166)Ho-DTPA for vascular brachytherapy and
      a PTCA balloon catheter. For this study, three CT contrast agents, Hexabrix
      (320)(Rx), Iomeron (350)(Rx) and Visipaque (320)(Rx) were used. Results showed
      that (166)Ho radiolabeled component of Hexabrix (320)(Rx) and the (166)Ho-complex
      was proposed to be (166)Ho-EDTA. However, in the case of Iomeron (350)(Rx) and
      Visipaque (320)(Rx), no other (166)Ho-complex was formed except the desired
      (166)Ho-DTPA. In the case where (166)Ho-EDTA (>98% radiolabeling yield) was
      administrated to rabbits, only 10% of the administered dose was excreted through
      the urinary track 30 min after injection. However, in the animal experiment where
      Hexabrix (320)(Rx) was added to the (166)Ho-DTPA vial with the volume ratio of
      1:1, over 80% of the administrated dose accumulated into the bladder within 30
      min after injection. Therefore, Hexabrix (320)(Rx) is applicable when it is used
      as a diluent of a (166)Ho-based liquid radiation source and its volume is applied
      in a minimal manner to visualize the balloon catheter. In conclusion, the use of
      a CT contrast agent in the clinical application of a liquid radiation source has
      beneficiary effects such as visualization of both the position and shape of the
      balloon are possible and most importantly, whether or not there is a formation of
      a void volume of liquid inside the balloon as well as the detection of radiation
      leakage on a real-time basis, on site during the angioplasty.

PMID- 15013489
TI  - Analysis of accumulation of 99mTc-octreotide and 99mTc-EDDA/HYNIC-Tyr3-octreotide
      in the rat kidneys.
AB  - The aim of this study was to compare renal handling and distribution of (99m)Tc
      octreotide and (99m)Tc-EDDA/HYNIC-Tyr(3)-octreotide (HYNIC-TOC) in rats. In
      kidney perfusion experiments, the renal clearance value of (99m)Tc-octreotide was
      three times lower than that of (99m)Tc-EDDA/HYNIC-TOC. The predominant renal
      excretion of (99m)Tc-EDDA/HYNIC-TOC was associated with a high and long-term
      renal accumulation up to 48 hrs. Microautoradiographic results indicated that
      (99m)Tc-EDDA/HYNIC-TOC was retained mainly in the renal medulla within the cells
      of the collecting ducts and in the surrounding tissue. Lower positivity was found
      in the proximal and distal tubular cells. We conclude that the mechanism of renal
      accumulation of somatostatin analogues renal accumulation is complex and that
      proximal tubular reabsorption is probably not the main mechanism for uptake of
      (99m)Tc-EDDA/HYNIC-TOC in the kidneys. The presence of the somatostatin
      receptors, differences in the tonicity level within kidneys and other possible
      mechanisms could participate in their renal accumulation.

PMID- 15013490
TI  - Biological studies of radiolabeled glucose analogues iodinated in positions 3, 4
      or 6.
AB  - The aim of this study was to assess the biological behavior of new radiolabeled
      glucose analogues proposed as tracers of glucose uptake in vivo and iodinated in
      position 3, 4, or 6. Biological results obtained in vitro on adipocytes and
      erythrocytes and in vivo in mice were compared to those obtained with the gold
      standard tracer of glucose uptake, 2-deoxy-D-glucose. None of these molecules had
      the same biological behavior than 2-deoxy-D-glucose. Therefore, these compounds
      cannot be considered as tracers of glucose uptake.

PMID- 15013491
TI  - Evaluation of anesthesia effects on [18F]FDG uptake in mouse brain and heart
      using small animal PET.
AB  - This study evaluates effects of anesthesia on (18)F-FDG (FDG) uptake in mouse
      brain and heart to establish the basic conditions of small animal PET imaging.
      Prior to FDG injection, 12 mice were anesthetized with isoflurane gas; 11 mice
      were anesthetized with an intraperitoneal injection of a ketamine/xylazine
      mixture; and 11 mice were awake. In isoflurane and ketamine/xylazine conditions,
      FDG brain uptake (%ID/g) was significantly lower than in controls. Conversely, in
      the isoflurane condition, %ID/g in heart was significantly higher than in
      controls, whereas heart uptake in ketamine/xylazine mice was significantly lower.
      Results suggest that anesthesia impedes FDG uptake in mouse brain and affects FDG
      uptake in heart; however, the effects in the brain and heart differ depending on
      the type of anesthesia used.

PMID- 15013492
TI  - Synthesis and preliminary biological evaluation of new radioiodinated MMP
      inhibitors for imaging MMP activity in vivo.
AB  - Non-invasive measurement of matrix metalloproteinase (MMP) activity in vivo is a
      clinical challenge in many disease processes such as inflammation, tumor
      metastasis and atherosclerosis. Therefore, radioiodinated analogues of the non
      peptidyl broad-spectrum MMP inhibitor (MMPI) CGS 27023A 1a were synthesized for
      non-invasive detection of MMP activity in vivo using single photon emission
      computed tomography (SPECT). The compounds Br-CGS 27023A 1b and HO-CGS 27023A 1d
      were synthesized from the amino acid D-valine and used as precursors for
      radioiodinated derivatives of CGS 27023A and their non-radioactive references I
      CGS 27023A 1c and HO-I-CGS 27023A 1e. Radioiodination of the precursors with
      [(123)I]NaI or [(125)I]NaI produced the no-carrier-added MMP inhibitors [(123)I]I
      CGS 27023A 1f, [(125)I]I-CGS 27023A 1g, HO-[(123)I]I-CGS27023A 1h, and HO
      [(125)I]I-CGS 27023A 1i. In vitro studies showed that the non-radioactive
      analogues of the MMP inhibitors exhibited affinities against gelatinase A (MMP-2)
      and gelatinase B (MMP-9) in the nanomolar range, comparable to the parent
      compound CGS 27023A. In vivo biodistribution using HO-[(125)I]I-CGS 27023A 1i in
      CL57 Bl6 mice showed rapid blood and plasma clearance and low retention in normal
      tissues. The preliminary biological evaluation warrant further studies of these
      radioiodinated MMP inhibitors as potential new radiotracers for imaging MMP
      activity in vivo.

PMID- 15013493
TI  - [11C]choline uptake in regenerating liver after partial hepatectomy or CCl4
      administration.
AB  - To characterize [methyl-(11)C]choline ([(11)C]choline) as an oncologic PET
      radiopharmaceutical, [(11)C]choline uptake in regenerating livers after partial
      hepatectomy as a model of typical proliferating tissue and after CCl(4) insult as
      that of proliferating tissue with inflammation, was studied in rats.
      [(11)C]Choline, [(18)F]2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) and [2
      (14)C]thymidine ([(14)C]TdR) uptake was studied in regenerating rat liver after
      70% partial hepatectomy or CCl(4)-administration. [(11)C]Choline uptake in
      regenerating liver after partial hepatectomy was significantly increased with
      [(14)C]TdR uptake as a marker of DNA synthesis at 18 hours after surgery. On the
      other hand, the uptake was not accelerated by CCl(4)-administration, though it
      significantly increased [(14)C]TdR uptake. There were no differences of
      [(11)C]choline uptake acceleration following partial hepatectomy among the three
      parts of the regenerating liver. [(18)F]FDG uptake was accelerated in the
      regenerating liver on either partial hepatectomy or CCl(4)-administration. The
      magnitude of the increase in [(18)F]FDG uptake in the regenerating liver induced
      by partial hepatectomy was greater than that for [(11)C]choline. [(11)C]Choline
      uptake in the liver was accelerated by partial hepatectomy, but not by CCl(4)
      administration. This might be expected given that the differentiation between
      proliferating tissues such as tumor and inflammatory tissue was possible by
      [(11)C]choline-PET.

PMID- 15013494
TI  - 99mTc-HMPAO distribution at SPECT is associated with succinate-cytochrome c
      reductase (SCR) activity in subjects with psychiatric disorders.
AB  - The origin of altered (99m)Tc-HMPAO distribution at SPECT in psychiatric
      disorders is unknown. Correlations between brain (99m)Tc-HMPAO distribution and
      muscle succinate-cytochrome c reductase (SCR, complex II + III) were assessed in
      20 unmedicated psychiatric patients. Significant negative correlations were found
      between (99m)Tc-HMPAO distribution in associative sensory regions and SCR
      activity. Sensory cortices are normally enriched in complex II activity. The
      production of electrons and reactive oxygen species affecting the redox state is
      considered to be highest from complex III, but complex II may also contribute.
      The negative relationship between (99m)Tc-HMPAO uptake and SCR activity may be
      due to redox state alterations influencing fixation of the radiopharmaceutical.

PMID- 15013496
TI  - Biological evaluation of 2'-[18F]fluoroflumazenil ([18F]FFMZ), a potential GABA
      receptor ligand for PET.
AB  - [(11)C]Flumazenil, a highly selective benzodiazepine antagonist is the most
      extensively used GABA(A) ligand for PET so far. To overcome half life
      disadvantages of (11)C a [(18)F]-labeled flumazenil derivative, 2'
      [(18)F]fluoroflumazenil (FFMZ) was developed and biologically evaluated with
      respect to the GABA(A) receptor. Organ with the highest uptake was the pituitary
      gland. Brain uptake was high and followed the order
      cortex>thalamus>cerebellum>rest brain. Fluoroflumazenil displaced
      [(3)H]flumazenil binding from membrane GABA(A) receptors with an IC(50)value (3.5
      nM) comparable to that of Flumazenil (2.8 nM). The presented data confirm the
      potential of [(18)F]FFMZ for PET imaging of the GABA-ergic system.

PMID- 15013495
TI  - 125I-iomazenil - benzodiazepine receptor binding and serum corticosterone level
      during psychological stress in a rat model.
AB  - To test the hypothesis that benzodiazepine receptor density decreases in response
      to stress, we correlated (125)I-iomazenil ((125)I-IMZ) binding with serum
      corticosterone levels in a rat model. Wistar male rats were divided into four
      groups; control group (CON, 10 rats), no physical or psychological stress; and
      one-, three-, and five-day stress groups of 12 rats each (1-DAY, 3-DAY, and 5
      DAY, respectively), receiving psychological stress for the given number of days.
      Psychological stress were given to rats with a communication box. The
      standardized uptake value (SUV) of (125)I-iomazenil of the 3-DAY and 5-DAY showed
      that (125)I-iomazenil-benzodiazepine receptor binding was significantly reduced
      in the cortices, accumbens nuclei, amygdala and caudate putamen (p<0.05). Serum
      corticosterone level ratio appeared to be slightly elevated in 3-DAY and 5-DAY,
      although this elevation was not significant. These data suggest that (125)I-IMZ
      is a useful radioligand to reflect received stress and its binding in the
      cortices, accumbens nuclei, amygdala and caudate putamen is strongly affected by
      psychological stress.

PMID- 15013497
TI  - Semi-automated 86Y purification using a three-column system.
AB  - The separation of (86)Y from (86)Sr was optimized by a semi-automated
      purification system involving the passage of the target sample through three
      sequential columns. The target material was dissolved in 4 N HNO(3) and loaded
      onto a Sr-selective (Sr-Spec) column to retain the (86)Sr. The yttrium was eluted
      with 4 N HNO(3) onto the second Y-selective (RE-Spec) column with quantitative
      retention. The RE-Spec column was eluted with a stepwise decreasing concentration
      of HNO(3) to wash out potential metallic impurities to a waste container. The
      eluate was then pumped onto an Aminex A5 column with 0.1 N HCl and finally with 3
      N HCl to collect the radioyttrium in 0.6-0.8 mL with a >80% recovery. This method
      enabled us to decontaminate Sr by 250,000 times and label 30 micro g of DOTA
      Biotin with a >95% yield.

PMID- 15013498
TI  - Cognitive influences in postural control of patients with unilateral vestibular
      loss.
AB  - The aim of this study was to investigate the interference between postural
      control and cognitive processing in patients with surgically confirmed unilateral
      vestibular lesions. These patients were well-compensated for vestibular lesions
      with no symptoms of dizziness or definable postural deficit. We hypothesized that
      attentional processes would play a greater role in postural control of these
      patients compared to healthy age-matched controls suggesting that successful
      compensation for a vestibular impairment involves ongoing increased attentional
      resources, and is not an automatic process. To explore this hypothesis, we used a
      dual-task paradigm that combined postural challenges with concurrently performed
      cognitive tasks. The postural conditions were seated, standing on a fixed floor,
      standing on a sway-referenced floor, and standing on a translating floor.
      Cognitive tasks were simple, inhibitory, and forced choice reaction time (RT)
      tasks. Patients had slower RTs compared to the controls under all conditions,
      including the seated condition. This effect was particularly large for the choice
      and inhibitory tasks. Both groups had increased RTs as the postural task became
      more challenging. Postural sway increased similarly in the patients and controls
      when performing the RT tasks for all postural conditions. These results suggest
      that patients with vestibular lesions that are well-compensated require increased
      attention compared to healthy controls; however, this increased demand on
      attention extends beyond postural control. The site of action may be at the
      sensory integration level resolving multiple sensory signals for spatial
      orientation.

PMID- 15013499
TI  - Reproducibility of electromyography and ground reaction force during various
      running techniques.
AB  - This study examined the validity of the assumption of electromyographic (EMG) and
      vertical ground reaction force (GRF) parameter reproducibility during running at
      different velocities and stride frequencies. Each of 12 female long distance
      runners ran on a treadmill in combinations of three velocities (2.5, 3.0 and 3.5
      m/s) and three stride frequencies (preferred, +/-10% from preferred). Seven
      parameters from the GRF and five parameters from the EMG signals from five
      muscles of the lower extremity were evaluated (1000 Hz). The GRF was analysed by
      a pressure measuring insoles. A total number of three trials for each running
      condition were recorded. GRF parameters during all running conditions showed high
      intraclass correlation coefficients (ICC average 0.87). The ICC of the EMG
      parameters of gastrocnemius medialis and lateralis were high (r>0.69 in 73% of
      the data), while those for vastus lateralis (22%), hamstrings (42%) and tibialis
      anterior (51%) were clearly lower. The results revealed that GRF parameters were
      reproducible during all running techniques indicating that a single trial would
      provide reproducible GRF-data. The reproducibility of the EMG parameters was not
      influenced by the running technique but dependent on the parameter itself and on
      the muscle studied.

PMID- 15013500
TI  - Kinematic and kinetic validity of the inverted pendulum model in quiet standing.
AB  - Movements of the whole-body center of mass during quiet standing have been
      estimated from measurements of body segment movements. These whole-body center of
      mass movements have been compared with movements of the center of mass as
      predicted from a simple inverted-pendulum model of standing. However, the total
      body center of mass is a weighted average of the center of mass of all individual
      body segments. The question arises as to how well the total body center of mass
      represents the individual segments and lower limb joint angles. This study
      focuses on the validity of how well the individual segments and lower limb angles
      temporally and spatially synchronize with the total body center of mass. Eleven
      healthy university students volunteered to participate. Kinematic data were
      collected using a 3D optoelectronic camera system; kinetic data were collected
      using a 3D force plate. Participants stood quietly, with eyes open, for 120 s.
      Segment and whole body centers of mass were calculated from a 14 segment, 3D
      bilateral model. Segment and joint angles were calculated for the lower limbs,
      bilaterally, and the trunk. Segment center of mass root-mean-square displacements
      were strongly correlated with center of mass height relative to the ankle joint
      and were synchronized, or temporally locked, to the movement of the whole body
      center of mass. Sagittal plane ankle angular displacements were highly correlated
      to sagittal plane center of mass movement; stronger correlations between body
      center of mass and lower limb angular displacement were observed, the result of
      compensatory knee joint angular displacements. These data support and extend the
      use of an inverted pendulum model to represent quiet standing postural control.

PMID- 15013501
TI  - Anthropometric parameters in children: a comparison of values obtained from dual
      energy x-ray absorptiometry and cadaver-based estimates.
AB  - Anthropometric data used in gait analysis for children are often estimated from
      older adult cadavers. The extent to which these estimates accurately represent
      children or affect the calculation of net joint moments during gait analysis is
      unknown. The purpose of this study was: (1) to compare dual energy X-ray
      absorptiometry (DXA)-derived anthropometric parameters to cadaver-based estimates
      in children, and (2) to determine if DXA-derived anthropometric data alter the
      results of gait analyses in children. Using DXA, the mass, center of mass
      location, and moment of inertia of the foot, shank, and thigh were obtained from
      7 to 13 year-old children (n=50) and compared to cadaver-based estimates.
      Additionally, lower extremity net joint moments were calculated (inverse dynamics
      equations) for three children during gait using (a) DXA-derived, and (b) cadaver
      based estimates of anthropometric parameters. Statistically significant
      differences were identified for most DXA-derived and cadaver-based anthropometric
      values. However, based on gait analysis of three children, it is likely that the
      differences between DXA-derived and cadaver-based anthropometric estimates would
      have a negligible effect on the calculation of net joint moments during gait in 7
      13 year-old children.

PMID- 15013502
TI  - Dynamic stability during walking following unilateral total hip arthroplasty.
AB  - The purpose of this study was to examine dynamic stability, defined as the
      vertical projection of the center of mass (COM) to the base of support (BOS)
      mediolaterally during walking in 16 healthy and 16 unilateral total hip
      arthroplasty (THA) persons. There was a significant effect of side for double
      limb support (DLS) for the healthy group and between groups but not significant
      for single limb support. The dynamic stability pattern for the THA group was to
      hold the COM in the midline during a longer DLS phase demonstrating a different
      motor control strategy compared to healthy adults.

PMID- 15013503
TI  - The effect of a single treatment of the Protonics system on biceps femoris and
      gluteus medius activation during gait and the lateral step up exercise.
AB  - INTRODUCTION: Patellofemoral pain, a frequent complaint among women, is
      attributed in part to excessive femoral internal rotation, leading to
      patellofemoral malalignment. The Protonics resistive dynamic knee orthosis was
      designed to facilitate hamstring activation, leading to a less anteriorly tilted
      pelvis and less femoral internal rotation. This decrease in femoral internal
      rotation is thought to improve patellofemoral joint alignment, thereby reducing
      knee pain. In this position, the gluteus medius (GM) would be more effective
      against the force of gravity. Therefore, this study's purpose was to determine
      the effects of a single application of the Protonics orthosis on knee pain and
      biceps femoris (BF) and GM activation. METHODS: 21 females (23.4+/-3.1 years,
      1.66+/-0.05 m, 65.3+/-20.4 kg) with a history of chronic PFP participated in the
      study. Data were collected during level walking and a lateral-step up exercise in
      three conditions: pre-treatment (PRE), a placebo condition collected after the
      orthosis was set at zero resistance (PLAC), and post-treatment (POST). PLAC and
      POST were performed after the orthosis had been removed from the subject's leg.
      Percent of gait cycle activated, integrated EMG (IEMG), and level of pain (VAS
      scale) were measured in each condition. An ANOVA was used to determine
      significance between conditions (alpha=0.05). RESULTS: Use of the Protonics
      orthosis did not result in any change in the level of knee pain, IEMG or duration
      of activation for the BF or GM. SUMMARY: Our results do not support an increase
      in hamstring activation or decrease in GM activation following a single treatment
      with the Protonics orthosis.

PMID- 15013504
TI  - Optimising the visual feedback technique for improving upright stance maintenance
      by delaying its display: behavioural effects on healthy adults.
AB  - The visual feedback technique (VFB) is recognized by several studies as a
      valuable tool for re-establishing the balance functions. However, one former
      study has highlighted the fact that the increased control induced by this
      technique infer both favourable (the amplitudes of the horizontal motions of the
      centre of gravity (CoG(h)) are diminished) and unfavourable features (the
      vertical difference between the CoG(h) motions and centre of pressure (CoP)
      trajectories are enhanced). One means to decrease these CoP-CoG(v) motions is to
      delay their display on the screen of the monitor. To assess these behavioural
      effects, 16 healthy adults were evaluated with various delays from 0 to 1200 ms.
      CoP displacements, measured through a force platform, were decomposed into two
      elementary motions: CoG(h) and the difference CoP-CoG(v). A fractional Brownian
      motion modelling of these motions allowed to determine from which distance and
      for how long the corrective process takes over and to what extent the motion is
      controlled. Compared to the VFB real time condition, increasing the delay induces
      some effects mainly on the CoP-CoG(v) motions which are largely diminished, the
      most striking effect appearing for delays exceeding 600 ms. Despite the lower
      forces these reduced amplitudes infer to control body sways, the amplitudes of
      the CoG(h) motions tend to increase slightly. Considered as a whole, whilst
      retaining the beneficial aspects of VFB without delay and significantly
      suppressing the unfavourable features, the data suggests that the method of
      delaying the screen display optimises the VFB technique.

PMID- 15013505
TI  - Effects of subthalamic nucleus stimulation and L-dopa in trunk kinematics of
      patients with Parkinson's disease.
AB  - In the advanced phase of Parkinson's disease (PD), high frequency electrical
      stimulation (HFS) of the subthalamic nucleus (STN) can represent a good
      therapeutic option, whose effects on walking have been recently quantified by
      kinematic and dynamic gait analysis. The goal of the present study was to
      compare, in a group of PD patients, the effects of STN stimulation and of L-dopa
      on trunk kinematics during walking. The additive effect of these two treatments
      was investigated as well. Ten idiopathic PD patients implanted bilaterally with a
      STN stimulation system and ten age-matched controls were studied using a three
      dimensional motion analyser. Four conditions were considered: with (s+) and
      without (s-) STN stimulation and with (m+) and without (m-) L-dopa
      administration. The results showed that both stimulation alone and L-dopa alone
      significantly increased the stride length and the gait speed, with an additional
      effect if applied simultaneously. Cadence was more influenced by L-dopa. The
      range of lateral bending and torsion of the trunk, which were reduced in s-/m-,
      increased similarly in s-/m+ and in s+/m- conditions. The exaggerated forward
      inclination of the trunk reduced towards control values in all therapeutic
      conditions. There was a tendency for L-dopa to increase trunk movements in the
      frontal plane, similar to events seen in quiet stance. Due to the presence of
      additive and synergistic effects, we concluded that the mechanisms of action of
      the two treatments are likely to be different.

PMID- 15013506
TI  - Comparison between subthalamic nucleus and globus pallidus internus stimulation
      for postural performance in Parkinson's disease.
AB  - Nine subjects with Parkinson's disease, five subjects with electrodes implanted
      in the subthalamic nucleus (STN) and four with electrodes in the globus pallidus
      internus (GPi), were compared with a population of ten age-matched control
      subjects. The measures studied include a set of summary statistic scores, two
      stochastic parameters, the distribution of the center of pressure (CoP)
      displacement angles under each foot, and the distribution of bilateral patterns
      of CoP displacement angles. A Bayes classifier was designed to monitor the trend
      of postural performance in patients, with different treatments. Results suggested
      that the selected measures were sensitive to Parkinsonian postural sway
      abnormalities and highlight differences in response to treatments. Deep brain
      stimulation restored a more normal postural sway and levodopa increased sway
      abnormalities. Furthermore, the selected measures appear to detect different
      responses to levodopa between the STN and GPi groups: the negative side effects
      of levodopa on posture were less severe for STN than for GPi patients, perhaps
      due to the decreased need for levodopa intake in STN subjects. The measures
      proposed in this preliminary study may be useful adjuncts to evaluate balance and
      postural control strategies in patients with Parkinson's disease and may allow
      the comparison of DBS electrode sites, on stance posture.

PMID- 15013507
TI  - Effects of postural disturbances with fatigued triceps surae muscles or with 20%
      additional body weight.
AB  - One of the main issues for balance control is the ability to generate enough
      forces to execute motions and uphold stability. This study aimed to investigate
      whether induced fatigue of the triceps surae muscles and decreased muscle force
      due to temporary additional body weight affected the ability to withstand balance
      perturbations. Another aim was to examine whether postural control adaptation
      over time was able to compensate for the changes induced by fatigue and
      additional body weight. Eleven normal subjects were exposed to vibratory
      proprioceptive stimulation during three test conditions; a baseline test during
      normal condition; when the body weight was increased by 20%, by adding additional
      weight load; and when the triceps surae muscles were fatigued. The tests were
      performed both with eyes open and closed. The body movements were evaluated by
      analyzing the anteroposterior and lateral torques induced towards the supporting
      surface measured with a force platform. Postural control was substantially
      affected both by the additional body weight, and by muscle fatigue in the triceps
      surae muscles. The anteroposterior and lateral body sway were larger both with
      added weight and fatigued muscles compared with the baseline test during quiet
      stance. However, the body sway induced by the vibratory stimulation was
      significantly larger with additional body weight compared with when the triceps
      surae muscles were fatigued. The differences between the test conditions were
      mostly pronounced during tests with eyes closed and in the high frequency body
      sway (>0.1 Hz). Postural control adaptation was able to reduce but not fully
      compensate for the changes induced by fatigue and additional body weight. Several
      hypotheses could account for these observations. (1) Fatigued muscles are less
      sensitive to muscle vibration, (2) muscle fatigue alters the muscle contractile
      efficiency and thus alters the ability to produce high-frequency, short-latency
      responses to balance perturbations.

PMID- 15013508
TI  - Muscle force redistributes segmental power for body progression during walking.
AB  - The ankle plantar flexors were previously shown to support the body in single-leg
      stance to ensure its forward progression [J. Biomech. 34 (2001) 1387]. The uni-
      (SOL) and biarticular (GAS) plantar flexors accelerated the trunk and leg
      forward, respectively, with each opposing the effect of the other. Around mid
      stance their net effect on the trunk and the leg was negligible, consistent with
      the body acting as an inverted pendulum. In late stance, their net effect was to
      accelerate the leg and trunk forward, consistent with an active push-off. Because
      other muscles are active in the beginning and end of stance, we hypothesized that
      their active concentric and eccentric force generation also supports the body and
      redistributes segmental power to enable body forward progression. Muscle-actuated
      forward dynamical simulations that emulated observed walking kinematics and
      kinetics of young adult subjects were analyzed to quantify muscle contributions
      to the vertical and horizontal ground reaction force, and to the acceleration and
      mechanical power of the leg and trunk. The eccentric uniarticular knee extensors
      (vasti, VAS) and concentric uniarticular hip extensors (gluteus maximus, GMAX)
      were found to provide critical support to the body in the beginning of stance,
      before the plantar flexors became active. VAS also decelerated the forward motion
      of both the trunk and the leg. Afterwards when VAS shortens in mid-stance, it
      delivered the power produced to accelerate the trunk and also redistributed
      segmental power to the trunk by continuing to decelerate the leg. When present,
      rectus femoris (RF) activity in the beginning of stance had a minimal effect. But
      in late stance the lengthening RF accelerated the knee and hip into extension,
      which opposed swing initiation. Though RF was lengthening, it still accelerated
      the trunk forward by decelerating the leg and redistributing the leg segmental
      power to the trunk, as SOL does though it is shortening instead of lengthening.
      Force developed from highly stretched passive hip structures and active force
      produced by the uniarticular hip flexors assisted GAS in swing initiation.
      Hamstrings (HAM) decelerated the leg in late swing while lengthening and
      accelerated the leg in the beginning of stance while shortening. We conclude that
      the uniarticular knee and hip extensor muscles are critical to body support in
      the beginning of stance and redistribution of segmental power by muscles
      throughout the gait cycle is critical to forward progression of the trunk and
      legs.

PMID- 15013509
TI  - Comments on "Biomechanics and muscle coordination of human walking: Parts I and
      II".

PMID- 15013511
TI  - Ave atque Vale.

PMID- 15013512
TI  - Master curves for gas amplification in low vacuum and environmental scanning
      electron microscopy.
AB  - The concept of universal amplification profiles for gas cascade amplification of
      signals in low vacuum and environmental scanning electron microscopes is
      demonstrated both experimentally and theoretically using water vapor. For a given
      gas, cascade amplification gain profiles can be plotted onto a single master
      curve where the independent reduced parameter is the ratio of pressure to
      amplification field strength. When plotted in this fashion, both desired
      secondary electron and spurious background signal components fall onto respective
      master curves, with the amplitude being a function of anode bias only. These
      master curves can be described by simple Townsend Gas Capacitor equations using
      only two gas-specific parameters. As long as single scattering conditions apply,
      this approach allows for simplified, direct comparison of the gain
      characteristics of different gases and allows more intelligent selection of
      imaging conditions. The utility of treating signal amplification in this manner
      is demonstrated through a series of images collected under a variety of
      conditions, but with the ratio of pressure to amplification field strength kept
      constant. In practice, the range of operational parameter space in which this
      description can be applied to imaging is limited, as images typically have a
      mixture of secondary and backscattered contributions.

PMID- 15013513
TI  - Simulation of electron energy loss near-edge structure at the Al and N K edges
      and Al L(23) edge in cubic aluminium nitride.
AB  - Calculations of electron energy near edge structures (ELNES) are compared with
      experimental data obtained in a high-resolution transmission electron microscope.
      This study concerns small precipitates of aluminium nitride in low carbon steel.
      The ELNES technique allows to clearly establish that these precipitates
      crystallize in a cubic rather than in a hexagonal crystallographic cell. The
      influence on simulated spectra of different parameters are investigated: the size
      of the atomic shell and its relation with the electron inelastic mean free path.
      We also examine the influence of the core hole and the sensitivity to cell
      parameters. We particularly examine the Al L(23) near edge structure and features
      relating to the different transition channels (A(1g), E(g) and T(2g)). Results of
      a multiple scattering and band structure calculations using ICXANES and WIEN97
      codes, respectively, are compared in the region from 0 to 30 eV above the edge
      onsets. Both calculations are in a rather good agreement.

PMID- 15013514
TI  - A new design of specimen stage for in situ magnetising experiments in the
      transmission electron microscope.
AB  - A new stage for carrying out in situ magnetising experiments in the transmission
      electron microscope has been designed, constructed and tested. The principal
      advantages of the stage are that it delivers horizontal fields with negligible
      perturbation to the illumination and is suitable for operation in pulsed or
      continuous field mode. Details of its performance, including field calibration,
      are given. The paper concludes with a description of where the stage is likely to
      be of most use.

PMID- 15013515
TI  - Measuring the absolute position of EELS ionisation edges in a TEM.
AB  - Measurements of absolute positions of electron energy loss spectroscopy (EELS)
      core-loss edges in a transmission electron microscopy (TEM) are hampered by
      noticeable errors caused by instabilities of the primary energy of the incident
      electrons. These instabilities originate from a continuous drift and random
      ripple of the high tension and are unavoidable in the present generation of TEM
      and scanning TEM microscopes. However, more precise measurements are desired, for
      instance, to study the shift of the edge onset between atoms of different valency
      or chemical environment, the so-called chemical shift. A solution to this problem
      is presented by collecting a series of short low-loss acquisitions immediately
      followed by core-loss ones. To ensure a minimal time lapse between core-loss and
      low-loss acquisitions, all operations must be computer controlled. Accumulation
      of a number of acquisitions and their summation corrected for energy drift allows
      to cancel the energy instabilities and to relate the core-loss EELS spectra to
      the absolute energy scale. A practical algorithm is presented as well as the
      necessary calibrations for such a procedure. Also, examples of spectra collected
      using this principle and the resulting measured chemical shifts in several metal
      oxides are presented.

PMID- 15013517
TI  - Anticancer research: a few hints for discovery of new targets.

PMID- 15013518
TI  - Green fluorescent protein as a tool to study epidermal growth factor receptor
      function.
AB  - The subcellular distribution of the epidermal growth factor receptor and its
      interaction with second messenger proteins has been explored using tagging with
      green fluorescent protein and its derivatives. EGFR itself has been fused with
      GFP and its natural life cycle and its internalisation in response to ligand
      determined. Several second messenger proteins including Shc and PI3kinase have
      also been tagged with fluorescent proteins and their subcellular redistribution
      in response to ligand activation has been filmed. The physical interaction of the
      EGFR with second messengers has been studied by FRET and other proximity assays.
      These systems will not only reveal much about the behaviour of the system in live
      cells but may also be useful for observing the effects of signal transduction
      inhibitor drugs such as antibodies and small molecule tyrosine kinase inhibitors.
      Finally, they have the potential to be developed into screens for new compounds
      which affect the system.

PMID- 15013519
TI  - From Ras signalling to ChoK inhibitors: a further advance in anticancer drug
      design.
AB  - Cancer is a genetic disease, most prominent in developed countries, with still a
      high mortality rate. Cancer cells are continuously proliferating, and this
      uncontrolled growth is mediated by the activation of different signal
      transduction pathways that ultimately lead to the carcinogenic process.
      Consequently, a large effort has been devoted to design specific molecules that
      interfere with these signaling cascades involved in tumorigenesis. In the last
      decades, research has resulted in improvements in both detection and treatment of
      cancer. However, it is still necessary to develop novel antitumoral therapies
      that would allow an appropriate treatment for each cancer patient. These novel,
      tumor- and patient-specific therapies will have a dramatic impact in improving
      the overall survival rates. Ras is one of the most important oncogenes so far
      identified in human carcinogenesis. Understanding the regulation of Ras-dependent
      signalling under normal and oncogenic environments may provide clues for the
      design of efficient specific antitumor strategies. In this review we will
      illustrate how the family of Ras GTPases may be a valid model for the development
      of new cancer therapies.

PMID- 15013520
TI  - Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular
      chaperone.
AB  - The molecular chaperone Hsp90 is not only of major current interest in
      fundamental biological research but also recognised as an exciting new target for
      the treatment of cancer and other diseases. In addition to playing an important
      role in response to proteotoxic heat shock and others stresses, Hsp90 is also
      critical for maintaining normal cellular homeostasis. Hsp90 is responsible for
      ensuring the conformational stability, shape and function of a selected range of
      key proteins, including many kinases and transcription factors. Furthermore,
      recent studies show that Hsp90 plays a key role in development and evolution.
      Hsp90 is overexpressed in cancer cells and is thought to be involved in dealing
      with the cellular stress associated with malignancy, as well as being essential
      for a range of key oncogenic proteins, including ErbB2, Raf-1, Akt/PKB, mutant
      p53 and many others. A major attraction of Hsp90 inhibitors is their potential to
      inhibit a range of 'mission critical' cancer pathways, thereby blocking all of
      the 'hallmark traits' of malignancy and exhibiting broad-spectrum antitumour
      activity. The first-in-class Hsp90 inhibitor 17AAG has entered clinical trials
      with promising early results and a range of other agents is under investigation
      and preclinical development. This article reviews the current status and future
      prospects for the exploitation of Hsp90 as a new molecular target for cancer
      treatment.

PMID- 15013521
TI  - Perspectives on farnesyl transferase inhibitors in cancer therapy.
AB  - The discovery that the transforming activity of oncogenic Ras depends upon its
      post-translational farnesylation has led to the development of farnesyl
      transferase inhibitors (FTIs). FTIs inhibit the growth of ras-transformed cells
      in vitro and induce tumor regression in Ras-dependent tumors. Currently, FTIs are
      undergoing clinical trials in various solid or hematological malignancies. In
      this review, we will summarize our current knowledge on cellular effect and
      molecular mechanism of FTIs. We will then describe recent clinical trials and
      propose some clues for their interpretation. Based on pre-clinical findings, we
      will emphasize on the optimal use of FTIs in anti-cancer strategy and lastly, we
      will insist on the interest of combining FTIs with chemotherapy, radiotherapy or
      other targeted agents.

PMID- 15013522
TI  - Ceramide synthesis and metabolism as a target for cancer therapy.
AB  - Sphingolipids, which include ceramides and sphingosine, are essential structural
      components of cell membranes that also have messenger functions that regulate the
      proliferation, survival, and death of cells. Exogenous application of ceramide is
      cytotoxic, and exposure of cells to radiation or chemotherapy is associated with
      increased ceramide levels due to enhanced de novo synthesis, catabolism of
      sphingomyelin, or both. Ceramide can be metabolized to less toxic forms by
      glycosylation, acylation, or by catabolism to sphingosine, which is then
      phosphorylated to the anti-apoptotic sphingosine 1-phosphate. Glucosylceramide
      synthase overexpression has been shown to enhance resistance to doxorubicin,
      suggesting that inhibition of ceramide metabolism or catabolism might enhance
      cancer chemotherapy. Several anticancer agents, including the cytotoxic retinoid,
      fenretinide (4-HPR), have been shown to act, at least in part, by increasing
      tumor cell ceramide via de novo synthesis. Combinations of 4-HPR and modulators
      of ceramide action and/or metabolism demonstrated increased anti-tumor activity
      in pre-clinical models with minimal toxicity for non-malignant cells, and were
      effective in a p53-independent manner against tumor cell lines resistant to
      standard cytotoxic agents. Phase I trials of ceramide metabolism inhibitors in
      combination with 4-HPR and with other cytotoxic agents are in development. Thus,
      pharmacological manipulation of sphingolipid metabolism to enhance tumor cell
      ceramide is being realized and offers a novel approach to cancer chemotherapy.

PMID- 15013523
TI  - Rho GTPases: potential candidates for anticancer therapy.
AB  - Low molecular weight Rho GTPases are proteins that, in response to diverse
      stimuli, control key cellular processes such as cell proliferation, apoptosis,
      lipid metabolism, cytoarchitecture, adhesion, migration, cell polarity, and
      transcriptional regulation. The high incidence of overexpression of some members
      of the Rho family of GTPases in human tumors suggests that these proteins are
      important in the carcinogenic process, and therefore potential candidates for a
      therapeutic intervention. In recent years, the characterization of downstream
      effectors to Rho GTPases has increased our understanding of the general cellular
      effects that permit aberrant proliferation and motility of tumor cells. In
      addition, several transcription factors have been identified to play important
      roles at various levels of Rho-induced tumorigenesis. Accordingly, drugs that
      specifically alter Rho signaling display antineoplastic properties both at the
      level of tumor growth and tumor metastasis. In this review, a brief summary of
      the progress made in understanding the biological functions elicited by Rho
      GTPases that contribute to tumor biology will be made. In addition, a description
      of new drugs available targeted to specific elements of Rho signaling with
      antineoplastic or antimetastatic activity is included.

PMID- 15013524
TI  - The IKK/NF-kappaB activation pathway-a target for prevention and treatment of
      cancer.
AB  - The importance of the IkappaB kinase (IKK)/NF-kappaB signaling pathway in
      immunoregulatory functions is well accepted. However, the relevance of IKK and NF
      kappaB in tumor maintenance, tumor promotion and possibly even in tumor
      initiation is becoming more evident. Activation of the IKK/NF-kappaB signaling
      pathway leads to the induction of target genes that can interfere with apoptosis,
      cell cycle regulation, cell invasion and metastatic growth as well as radio- and
      chemotherapy. By possibly bridging inflammation and cancer NF-kappaB might also
      contribute to tumorigenesis. Several natural compounds and synthetic drugs that
      are able to inhibit the IKK/NF-kappaB activation pathway have been shown to
      either prevent cancer or to inhibit cell growth in animal models. However, these
      compounds do not selectively inhibit any of the NF-kappaB activation pathways.
      Furthermore, general inhibition of NF-kappaB might lead to immunodeficiency. The
      investigation of the different NF-kappaB signaling pathways in different cell
      types and their role in certain diseases is therefore needed to evaluate the most
      successful therapeutic strategies.

PMID- 15013525
TI  - [Editorial of the SOFCEP].

PMID- 15013526
TI  - [Donor site morbidity after free fibula flap. Report of 42 consecutive cases].
AB  - Donor site morbidity after free fibula flap was assessed in 42 patients, 37 of
      whom had undergone mandibular reconstruction and five proximal humerus. Lower
      limb reconstructions were excluded. The study comprised functional assessment
      with two international orthopaedic scales (Karlsson and Kitaoka); comparative
      lower limb clinical and X-ray assessment. Mean Karlsson score was 90.4/100 with
      52% of excellent, 36% of good, and 12% of medium results. Mean Kitaoka score was
      93.7/100 with 64% of excellent, and 36% of good results. Fifty-two percent of
      patients were pain free, 29% had pain on walking on uneven terrain, and 19%
      occasionally; 7% experienced instability. For 76%, physical activity was
      unrestricted. Clinical examination found no alteration in hindfoot axis, no joint
      laxity, mild and acceptable reduction in hallux plantar flexion power in 76%
      cases, and superficial fibular nerve hypoesthesia in 5% of cases. Methodology and
      results are detailed and compared to the literature. In conclusion, we found only
      slight morbidity and free fibula flap remains our first choice as bone flap.

PMID- 15013527
TI  - [Treatment of Buruli ulcer desease by excision and skin graft].
AB  - INTRODUCTION: Buruli ulcer is the most common mycobacteria disease after leprosy
      and tuberculosis. The purpose of our study is to make our contribution to the
      surgical treatment of Buruli ulcer and to asses our results. METHOD: One hundred
      eighteen patients presenting progressive Buruli ulcers were operated on. The
      surgical procedure included excisions for necrotic lesions and grafts for clean
      wounds. The results were estimated on the time of hospitalization and appearance
      of complications. RESULTS: Seventy-three patients (62%) were subjected to
      excision followed by thin skin grafts and 35 patients (30%) were subjected to
      grafts only. The number of excision times varies from 1 to 7 per patient and from
      1 to 4 for the skin grafts. All our patients heal within a period of 120 days
      with extremes going from 14 to 265 days. We deplored 26 complications (22%):
      eight new focus, seven infectious complications, six recurrences, five
      stiffnesses and ankyloses. CONCLUSION: The treatment of Buruli ulcer by excision
      and grafts is efficient but does not prevent recurrences and new focus from
      happening and for their prevention, it is necessary to discover pharmaceutical
      molecules that are efficient on Mycobacterium ulcerans.

PMID- 15013528
TI  - [Umbilical reconstruction in children. Prospective report of 77 cases].
AB  - Umbilical hernia is as frequent pathology in our country. The skin excess is a
      real problem for the surgeon because it is inesthetical. We report 77 cases of
      children with umbilical hernia who we operated between 1999 and 2000. Fifty-five
      of them have a umbilical plasty. For this, we used three surgical techniques:
      lateral left plasty, "horseshoe" plasty and umbilical graft. We classed our
      results into three groups: 40 good results, seven middle results and three bad
      results. Twenty-seven patients are lost. These three surgical techniques are a
      simple and safe solution to this problem of skin excess in the umbilical hernia.

PMID- 15013529
TI  - [Mammaplasty: the "love position"].
AB  - The authors describe a new position of the patient that enables the surgeon to
      perform a bilateral and synchronous mammaplasty, without switching sides. The
      patient is first raised in the sitting position, then the thigh and leg holders
      of the operating table are spread out to a 45-60 degrees angle. The surgeon
      stands in between the thighs, where he faces the chest and can operate on the
      breasts. The entire operation is performed by the surgeon, approaching both
      breasts simultaneously without the need for switching positions. The direct and
      central access, along with the continuing visual control of the shaping, turns
      the operation into a simple and faster one with better control of the cosmetic
      result.

PMID- 15013531
TI  - A severe complication of muscle transfer: clostridial myonecrosis.
AB  - We present a case of gas gangrene as a severe complication of muscle transfer for
      opponensplasty. After debridement, the extensive palmar wound was covered by a
      free gracilis muscle transfer. This complication of muscle transfer has to our
      knowledge never been reported previously.

PMID- 15013530
TI  - [The "vessel case flap". About one case in the lower limb].
AB  - The authors report an atypical case of lower limb repair in a 69-year-old
      patient, who presented a closed fracture of the tibia initially fastened with a
      plate. Skin necrosis developed after osteosynthesis, exposing the plate and the
      fracture bone. Because of the vascular state of the patient (smoking, arteritis,
      diabetes), any microsurgical procedure seemed likely to fail. The incisions
      previously performed contraindicated any form of pedicle flap in the leg area. An
      original solution was then proposed, involving the long extensor muscle of the
      great toe pedicled proximally on the anterior tibial artery. After six months of
      follow-up, healing and bone consolidation have been achieved. The interest of
      this exceptional technique is considered with respect to therapeutic choices for
      lower limb repair.

PMID- 15013533
TI  - [Fournier's gangrene: remarks on two clinical cases].
AB  - Fournier's gangrene is a genital and perineal necrotizing fascitiis with a rapid
      evolution. It's an affection caused by aerobic and anaerobic micro-organisms,
      eventually associated with a superinfection by micetes. It has characterised by a
      deep oedema associated with lancinating pain and itching in external genitalia,
      rapidly evolves to perineal tissues necrosis and purulence. At this stadium
      patient's general conditions are still serious and patient may be comatose. When
      toxaemia is over, demarcation of necrotic areas can be remarkable and granulation
      start growing. Fournier's gangrene seems to be related to an ischemic necrosis
      caused by obliterative endoarteritis and thrombosis of internal pudendal and deep
      and superficial external pudendal artery. The infection gateway may be
      subcutaneous tissue lesion associated to trauma or surgical procedures in
      immunodeficient organism. Diagnosis is mainly clinical but a superficial
      ecography could be useful to demonstrate thickening in subcutaneous tissue with
      normal testicles. Both of them were middle aged males, heavy smokers, affected by
      hypertension and COPD. In both cases there was polymicrobial Gram positive
      bacterial infection. Antibiotic systemic therapy and topic therapy were
      administered. The patient also received hyperbaric oxygen therapy. Thirteen days
      after the admittance, the infection was defeated and we could start the surgical
      cover. To cover the scrotal wound we have used split-thickness skin grafts taken
      from the right thigh. These grafts took at 100% and the patient was discharged
      seven days after surgical operations. Follow-up at six months and at one year
      showed any functional limitation and a good aesthetic result.

PMID- 15013534
TI  - [Cutaneous necrosis in a clinical case of one face lift after the use of
      Surgicel].
AB  - The use of Surgicel, a local haemostatic absorbable gauze, is usually spread in
      surgery. The author reports a clinical case of face lift where the use of
      Surgicel 2, a more concentrated Surgicel, left under a precarious vascularized
      cutaneous flap led to a skin slough. He concludes that the full-thickness
      cutaneous necrosis is bound both to the chemical action of the soluble component
      (uronic acid) of Surgicel and above all to the "screen-effect" with the
      nourishing basement. Consequently, the Surgicel should be removed once the
      haemostasis obtained.

PMID- 15013535
TI  - [Botulic toxin].

PMID- 15013536
TI  - [Prescription of drugs without approval to be commercialized].

PMID- 15013537
TI  - [Advertizing for medicals devices: which laws?].

PMID- 15013539
TI  - Treatment of mandibular retrusion by distraction osteogenesis: a new technique.
AB  - We treated the mandibular retrusion of a 20-year-old man by distraction
      osteogenesis. Our aim was to avoid any visible discontinuities in the soft tissue
      profile that may result from conventional "one-step" genioplasty. The result was
      excellent. In addition to a good aesthetic outcome, there was increased bone
      formation not only between the two surfaces of the osteotomy but also adjacent to
      the distraction zone, resulting in improved coverage of the roots of the lower
      incisors. Only a few patients have been treated so far, but the method seems to
      hold promise for the treatment of extreme retrognathism, as these patients often
      have insufficient buccal bone coverage.

PMID- 15013540
TI  - The accuracy of preoperative orthognathic predictions.
AB  - We assessed the accuracy of preoperative OPAL trade mark orthognathic predictions
      by retrospective analysis of 25 Class II patients who had had orthodontic
      treatment combined with mandibular advancement osteotomy. Preoperative and
      postoperative lateral cephalographs were digitised and surgical predictions
      generated using OPAL software. Each prediction was compared with the
      corresponding clinical changes. We also made a method error study by doing a
      random retracing of 25 cephalographs. Predictions of some of the principal OPAL
      values (SNA, ANB, LAFH%, OJ, OB) were reasonably accurate in terms of mean
      values. However, there were large individual variations for most variables and
      predictions of the vertical skeletal, incisor, and Wits measurements were
      imprecise. In particular, there was a bias towards under-prediction of the
      vertical skeletal changes when there was more backward mandibular rotation than
      anticipated. Immediate postoperative cephalographs were also affected by a 2.1mm
      mean downward displacement of the mandible as a result of the surgical wafer.

PMID- 15013541
TI  - Incidence of neurosensory disturbance after sagittal split osteotomy alone or
      combined with genioplasty.
AB  - We mailed questionnaires to all patients who had had sagittal split osteotomies
      alone (n= 84) or in combination with genioplasty (n = 37) between 1995 and 2000,
      to find out the incidence of postoperative sensory disturbances. The patients
      with sagittal split osteotomies alone reported sensory disturbance in 48/131
      (37%) operated sides. When combined with genioplasty patients experienced them in
      20/54 (37%) operated sides. The incidences were 36/101 (36%) for mandibular
      advancement and 12/30 (40%) for mandibular setback. Out of the patients with
      sagittal split osteotomies alone, 59/66 (89%) were satisfied with the result of
      the operation, and when combined with the genioplasty the corresponding figure
      was 23/27 (85%). We conclude that differences in the incidence of sensory
      disturbance after sagittal split osteotomy for mandibular advancement and setback
      were not significant. The combination with genioplasty did not increase the
      incidence of sensory disturbance. Sensory changes after the osteotomies do not
      serve to be the main determinant of the patients' satisfaction.

PMID- 15013542
TI  - Anti-TGFbeta1 antibody for modulation of expression of endogenous transforming
      growth factor beta 1 to prevent fibrosis after plastic surgery in rats.
AB  - The cytokine transforming growth factor beta 1 (TGFbeta1) substantially
      influences synthesis of extracellular matrix, fibrosis, and neoangiogenesis
      during wound healing in a dose dependent manner. We carried out experiments in
      rats to measure the degree of reduction of disorders of wound healing and
      fibrosis produced by inhibition of endogenous TGFbeta1 by polyclonal antibodies
      (poAB). A free myocutaneous gracilis flap was transplanted from the groin to the
      neck region in 30 Wistar rats (300-450 g body weight). In 15 animals
      intraoperatively and daily from days 3 to 7 postoperatively, 1 microg anti
      TGFbeta1 poAB in 500 microl of phosphate buffered saline (PBS) were injected into
      the neck region. Fifteen animals served as controls. On postoperative days 3, 4,
      5, 7, 14, and 28 the expression of endogenous TGFbeta1 in cytoplasm was analysed
      by immunohistochemistry (ABC-POX; AEC), in situ hybridisation of TGFbeta1-mRNA,
      and Sirus Red staining of collagen matrix; it was quantified using labelling
      indices. Neutralisation of the TGFbeta1 activity by specific poAB resulted in
      inhibition of the cytoplasmatic expression compared with untreated animals. In
      the transition area between grafted tissue and graft bed, a significant reduction
      of TGFbeta1 expression (mean (S.D.) 34.7 (6.5)) was found from day 5 in the group
      treated with anti-TGFbeta1 poAB compared with the control group (mean (S.D.) 48.1
      (6.6)) (P <0.03). Up to day 14 the endogenous expression of TGFbeta1 (mean (S.D.)
      30.0 (2.8)) was reduced after the application of TGFbeta1 poAB compared with the
      control group (mean (S.D.) 44.0 (12.3)). Sirus Red staining indicated a more
      complex packed structure and generally more prominent collagen types I-IV fibres
      in untreated animals than in animals that were given anti-TGFbeta1 poAB.
      Expression of TGFbeta-mRNA by in situ hybridisation was reduced in fibroblasts in
      animals that were given anti-TGFbeta1 poAB. The results indicate that anti
      TGFbeta1 might improve the healing of free flaps in the graft beds of patients
      who are prone to excessive fibrosis.

PMID- 15013543
TI  - The influence of pre- and intraoperative positioning of the condyle in the centre
      of the articular fossa on the position of the disc in orthognathic surgery. A
      magnetic resonance study.
AB  - OBJECTIVE: We investigated the changes in the temporomandibular joint (TMJ) after
      bilateral sagittal split osteotomy of the mandible for orthognathic surgery and
      the influence of positioning of the condylar process in the centre of the
      articular fossa before and during the operation for preventing changes in the TMJ
      postoperatively. STUDY DESIGN: A total of 28 patients with mandibular
      retrognathism had bilateral sagittal split osteotomies for mandibular
      advancement. In one group of 14 patients (28 TMJ), the condyles were placed in
      the centre of the articular fossa before and during the operation, and in the
      other group they were not. Differences on magnetic resonance imaging (MRI) were
      calculated and the results were evaluated. RESULTS: The main differences were
      found at maximal mouth opening. 15/28 TMJs (54%) that had not been positioned
      changed the position of the disc from physiological to anterior disc derangement
      with and without reduction postoperatively. In the 28 that had been positioned,
      changes were found in only 3 TMJs (11%) postoperatively. CONCLUSIONS: Fixing the
      condylar process in the centre of the articular fossa intraoperatively before
      bilateral sagittal split osteotomy is a factor in preventing postoperative
      structural changes in the temporomandibular joint.

PMID- 15013544
TI  - Comparison of stability of absorbable and titanium plate and screw fixation for
      sagittal split ramus osteotomy.
AB  - Six unembalmed adult sheep mandibles were stripped of all soft tissues and
      sectioned at the midline. Each side had a sagittal split ramus osteotomy (SSRO)
      and was advanced 5 mm. Six of the hemimandibles were fixed with four-hole
      extended titanium miniplates and titanium screws, and the other six were fixed
      with four-hole extended absorbable plates and absorbable screws. All specimens
      were mounted in a servohydraulic testing unit, and a range of forces (0-140 N)
      was applied. Displacement of each proximal segment was recorded at 10 N
      increments from 0 to 140 N. Values for the two groups were compared using the
      Mann-Whitney U-test, and significant differences in displacement were seen only
      at loads between 10 and 50 N. The results indicate that when absorbable
      miniplates are used intermaxillary fixation may be necessary to stabilise the
      bony fragments in the early postoperative period.

PMID- 15013546
TI  - Falls in elderly people that result in facial injuries.
AB  - Falls in elderly people are increasing. Injuries of the upper limb that result
      from a fall usually suggest that an outstretched hand was used to curb the fall.
      Conversely, maxillofacial injuries in elderly people may result from alterations
      in consciousness as a result of a pre-existing medical condition. We investigated
      the nature of falls in an elderly population and compared two cohorts of patients
      those presenting with maxillofacial injuries, and those with isolated upper limb
      injuries, and there were 25 patients in each cohort. Comprehensive personal data
      and medical history were recorded together with details of the fall. We found a
      significant correlation between the nature of the injury and recollection of the
      event (P <0.01). Patients who sustain facial injuries are less likely to recall
      the event. This may be the result of the injury itself, but an underlying medical
      condition may have been responsible for the fall and should be excluded.

PMID- 15013545
TI  - Historical Article: Hirudo medicinalis: ancient origins of, and trends in the use
      of medicinal leeches throughout history.
AB  - Blood letting and the therapeutic use of Hirudo medicinalis date back to ancient
      Egypt and the beginning of civilisation. Their popularity has varied over the
      years, reaching such a peak in Europe between 1825 and 1850 that supplies were
      exhausted. Towards the end of the century they fell out of favour and, during
      this period, the leech, once used by the physicians of emperors and influential
      academic surgeons, became associated with lay therapists and quackery. Leeches
      have enjoyed a renaissance in reconstructive microsurgery during the last 15
      years, having been used by maxillofacial [Br. J. Oral Maxillofac. Surg 41 (2003)
      44] and other reconstructive surgeons to aid salvage of compromised microvascular
      free tissue transfers [Laryngoscope 108 (1998) 1129; Br. J. Plast. Surg. 34
      (1984) 358], replanted digits [Int. J. Microsurg. 3 (1981) 265], ears [Ann.
      Plast. Surg. 43 (1999) 427], lips [Plast. Reconstr. Surg. 102 (1998) 358; J.
      Reconstr. Microsurg. 9 (1993) 327] and nasal tips [Br. J. Oral Maxillofac. Surg.
      36 (1998) 462]. Peer-reviewed evidence suggests that the survival of compromised,
      venous-congested tissues is improved by early application of a leech [J.
      Reconstr. Microsurg. 12 (1996) 165; Arch. Otolaryngol. Head Neck Surg. 114 (1988)
      1395; Br. J. Plast. Surg. 45 (1992) 235]. Leeches have also recently been used to
      treat a wide range of conditions, including periorbital haematomas [Br. J.
      Ophthalmol. 75 (1991) 755], severe macroglossia [Otolaryngol. Head Neck Surg. 125
      (2001) 649; J. Laryngol. Otol. 109 (1995) 442] and purpura fulminans [Ann. Plast.
      Surg. 35 (1995) 300]. The first medicinal leech farm, Biopharm, was set up in
      Swansea in 1981 by Dr Roy Sawyer, and now supplies leeches to hospitals all over
      the world. In this paper, we summarise the history of treatment with Hirudo
      medicinalis from its origin to the present day, and take a brief look at the
      possible future of the annelid.

PMID- 15013547
TI  - Long-term results of functional open surgery for the treatment of internal
      derangement of the temporomandibular joint.
AB  - We studied 20 consecutive patients with internal derangements of the
      temporomandibular joint (TMJ), a median of 51 months after open operation on the
      joint and a rehabilitation programme. The design was a retrospective clinical
      study. The maximal opening and lateral active movements and the presence of
      clicking and joint pain were recorded preoperatively, after complete
      rehabilitation, and at the time of follow-up. Patients completed visual analogue
      scales of pain before operation and at the time of follow-up. Operation and
      postoperative rehabilitation reduced the variability of the opening and lateral
      movements, significantly increased maximal opening, and reduced clicking and
      pain.

PMID- 15013548
TI  - Experience of incorporating a mental health service into patient care after
      operations for cancers of the head and neck.
AB  - The psychological needs of patients with cancer have been increasingly
      recognised. Those with cancers of the head and neck have previously been found to
      be at relatively high risk of developing mental health difficulties after
      diagnosis and treatment. To provide for their psychological needs a mental health
      liaison nurse was attached to the local maxillofacial surgery unit for a trial
      period of 18 months. Fifty-eight different patients out of a total possible 63
      were seen on a total of 102 occasions. The main difficulties encountered were
      issues of adjustment. Ten patients required brief intervention and treatment as
      inpatients, and only two required treatment as outpatients. Most interventions
      were psychological and facilitated the normal adjustment process. Given the
      appreciable degree of psychopathology, we advocate a stepped care approach to
      deal with patients' mental health needs. Initial assessment, information, and
      support would be provided by ward-based staff with appropriate training and
      supervision. Patients who were identified as having more complex needs would be
      seen by a mental health liaison specialist.

PMID- 15013549
TI  - Swelling on the head--a forgotten lesson: a case report of an intradiploic
      epidermal cyst with an iatrogenic complication.
AB  - Swellings on the head are common, but all require appropriate investigation and
      caution must be exercised during surgical intervention. We report a patient in
      whom an attempt at biopsy of a swelling in the scalp was made without any
      radiological imaging and led to an intracranial complication that caused a
      neurological deficit. The lesion was an intradiploic epidermal cyst. Though
      appropriate precautions are usually taken, lessons previously learnt are
      sometimes forgotten. We would therefore like to remind readers that swellings of
      the scalp that seem to be attached to the skull on clinical examination should be
      investigated by radiographs and preferably by computed tomography before surgical
      intervention because of the possibility of intracranial extension.

PMID- 15013550
TI  - K-Y jelly as an aide to cryotherapy in the management of odontogenic keratocysts.
AB  - We describe a technique of cryotherapy for the management of odontogenic
      keratocysts using K-Y jelly as an aide.

PMID- 15013551
TI  - Iatrogenic pneumomediastinum and facial emphysema after endodontic treatment.
AB  - Subcutaneous emphysema is well known, but diffusion of gas into the mediastinum
      is not so common, particularly if it is caused by treatment of a root canal
      without apparent osseous fenestration or mucoperiostal lesions. We report a case
      of iatrogenic pneumomediastinum and facial emphysema after endodontic treatment.
      The diagnosis was confirmed by computed tomography, and the patient recovered
      after treatment with intravenous antibiotics and analgesia.

PMID- 15013552
TI  - Survival of a free flap after arterial disconnection at six days.
AB  - We know of no definition of how long it takes for a free flap to develop its own
      independent blood supply from its recipient bed. In this case report, we describe
      survival of a free flap after loss of the arterial anastomosis at 6 days.

PMID- 15013553
TI  - Use of a new instrument for lateral release in arthroscopic surgery of the
      temporomandibular joint: a preliminary study.
AB  - We developed a new instrument, which we call a lateral releaser, to improve the
      safety of either a blind lateral release or lateral stretching within the TMJ We
      used it during arthroscopic surgery in patients with chronic painful hypomobility
      of the temporomandibular joint (TMJ). We operated on 24 TMJs in 17 patients (15
      women and 2 men). At operation, the mean increase in the interincisal distance
      was 22 mm (range 10-32). No instruments were broken. No serious surgical
      complications were reported during or after operation. Many of the patients
      currently have an interincisal distance exceeding 38 mm.

PMID- 15013554
TI  - Two-stage orthognathic treatment of severe class III malocclusion: report of a
      case.
AB  - We report a two-stage orthognathic operation for a 16-year-old boy with a
      repaired isolated cleft palate. He had a severe class III malocclusion with an
      overjet of 20.4 mm. In the first stage, we did an anterior subapical segmental
      osteotomy with symphyseal ostectomy to reposition the mandibular anterior segment
      posteriorly and to reduce the transverse width of the mandible. During the second
      stage, we did a maxillary advancement by Le Fort I osteotomy, mandibular set-back
      by sagittal split osteotomy, reduction genioplasty, and shortening of the tongue.
      This unique two-stage surgical and orthodontic treatment considerably improved
      his overall facial aesthetics and occlusion.

PMID- 15013555
TI  - Peripheral dentinogenic ghost cell tumour presenting as a gingival mass.
AB  - A 71-year-old man presented with a gingival mass at an extraction site. The
      lesion was initially thought to be a peripheral ameloblastoma on incisional
      biopsy. It was finally diagnosed as dentinogenic ghost cell tumour after excision
      with a margin of sound bone. There has been no recurrence after 2 years.

PMID- 15013556
TI  - Re: Whitaker et al., Effective management of airway in Pierre Robin Syndrome.

PMID- 15013557
TI  - Corrugated drains and compromise of a microvascular free flap.

PMID- 15013558
TI  - An alternative use for drain tubing in head and neck surgery.

PMID- 15013559
TI  - Re: Oral endotracheal intubation in the management of midfacial fractures.

PMID- 15013561
TI  - Brain abscess in which Porphyromonas gingivalis was detected in cerebrospinal
      fluid.
AB  - In this paper, we report one case of severe brain abscess in which Porphyromonas
      gingivalis was detected in the spinal fluid.

PMID- 15013562
TI  - Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c
      mice.
AB  - Amyloid deposits resembling plaques found in Alzheimer's disease (AD) brains were
      formed in the brains of non-transgenic BALB/c mice following intranasal infection
      with Chlamydia pneumoniae. The mice were infected at 3 months of age with C.
      pneumoniae isolated from an AD brain. Infection was confirmed by light and
      electron microscopy in olfactory tissues of the mice. C. pneumoniae was still
      evident in these tissues 3 months after the initial infection indicating that a
      persistent infection had been established. Amyloid beta (Abeta) 1-42
      immunoreactive deposits were identified in the brains of infected BALB/c mice up
      to 3 months post-infection with the density, size, and number of deposits
      increasing as the infection progressed. A subset of deposits exhibited thioflavin
      s labeling. Intracellular Abeta1-42 labeling was observed in neuronal cells.
      Experimental induction of amyloid deposition in brains of non-transgenic BALB/c
      mice following infection with C. pneumoniae may be a useful model for furthering
      our understanding of mechanisms, linked to infection, involved in the initiation
      of the pathogenesis of sporadic AD.

PMID- 15013563
TI  - Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1 beta
      production.
AB  - In Alzheimer's disease (AD), chronically activated glia contribute to neuronal
      dysfunction through production of neuroinflammatory molecules like interleukin
      (IL)-1beta. As a first step to address the signaling pathways important for pro
      inflammatory cytokine induction, and whether different activators use distinct
      pathways, we tested the involvement of mitogen-activated protein kinase (MAPK)
      pathways in microglial IL-1beta production. Microglial cultures stimulated with
      lipopolysaccharide, S100B, or beta-amyloid showed rapid activation of three
      different MAPKs (p38, ERK1/2, and JNK) and a later increase in IL-1beta levels,
      consistent with a possible mechanistic relationship between MAPK and IL-1beta. To
      more directly test this possibility, we stimulated microglia in the presence of
      selective MAPK inhibitors, and found that inhibition of each of the three MAPK
      pathways inhibited IL-1beta production in a concentration-dependent manner. In
      addition, the relative importance of each MAPK to IL-1beta production depended on
      the activating stimulus. These data demonstrate that MAPK pathways are important
      for microglial IL-1beta production, and suggest that different glial activators
      use distinct sets of signaling pathways to induce the same disease-relevant end
      point in microglia.

PMID- 15013564
TI  - Linear width of the medial temporal lobe can discriminate Alzheimer's disease
      from normal aging: the Sunnybrook dementia study.
AB  - To discriminate Alzheimer's disease (AD) from healthy controls, the thinnest
      medial temporal lobe (tMTL) width on 3D-MRI was measured according to a newly
      developed method at the inter-collicular sulcus (ICS) level with scans aligned to
      the long axis of the hippocampus in 22 mild, 27 moderate probable AD patients and
      41 healthy controls. For comparison, MTL width replicating the technique of Jobst
      et al. (jMTL) as well as hippocampal and parahippocampal volumes, were also
      measured. Using logistic regression taking into account age, sex, and education,
      tMTL width classified mild AD from controls with a sensitivity of 86%,
      specificity of 95% and accuracy of 92%. Similar values were obtained for moderate
      or total AD group versus controls. By comparison, jMTL width was only useful in
      distinguishing moderate AD from controls, and volumetric measures were equally
      sensitive in classifying mild and moderate AD in our sample. This quick,
      reliable, and standardized measurement of tMTL can be helpful in differentiating
      even mild AD from controls with reasonable accuracy.

PMID- 15013565
TI  - Structural changes in the midbrain with aging and Parkinson's disease: an MRI
      study.
AB  - We measured midbrain structures of 59 subjects with Parkinson's disease (PD) and
      140 age- and gender-matched normal subjects without neurological disorders by
      using T2-weighted MR imaging. There is a significant increase in the maximum
      distance of the substantia nigra (SND) and a significant decrease in the average
      distance from the substantia nigra to the red nucleus (SNRND) in patients with PD
      compared with normal subjects in the 70 years old or less group. These findings
      may reflect the pathologic increase of iron concentration and the neuronal loss
      in the region. However, it is difficult to find differences between normal
      subjects and patients with PD in the greater than 70 years old group in the
      midbrain structures. These findings based on a large-scale morphometric study
      provide essential information to evaluate conventional MR images of PD.

PMID- 15013566
TI  - Voxel-based morphometry of human brain with age and cerebrovascular risk factors.
AB  - The objectives of this study were to evaluate the correlations of the volumes of
      the gray matter and white matter with age, and the correlations of the tissue
      probabilities of the gray matter and white matter with age and several
      cerebrovascular risk factors. We obtained magnetic resonance (MR) images of the
      brain and clinical information from 769 normal Japanese subjects. We processed
      the MR images automatically by correcting for inter-individual differences in
      brain size and shape, and by segmenting the MR images into the gray matter and
      white matter. Volumetry of the brain revealed a significant negative correlation
      between the gray matter volume and age, which was not observed between white
      matter volume and age. Voxel-based morphometry showed that age, systolic blood
      pressure, and alcohol drinking correlated with the regional tissue probabilities
      of the gray matter and white matter.

PMID- 15013567
TI  - Evaluation of HFE (hemochromatosis) mutations as genetic modifiers in sporadic AD
      and MCI.
AB  - BACKGROUND: Pathological brain iron deposition has been implicated as a source of
      neurotoxic reactive oxygen species in Alzheimer disease (AD). Recent reports
      suggest that heterozygosity for the two common hfe mutations responsible for
      hereditary hemochromatosis (HH) may be a risk factor for AD, possibly by
      accelerating brain iron accumulation. METHODS: To test this hypothesis, we
      genotyped 213 sporadic AD, 106 MCI, and 63 normal elderly control (NEC)
      individuals for the H63D and C282Y hfe mutations by polymerase chain reaction
      (PCR)/restriction fragment length polymorphism (RFLP) analysis. We determined the
      relationship of these mutations to the demographic, clinical, and
      neuropsychological features of AD and MCI, and evaluated whether an interaction
      existed between hfe and apolipoprotein E (apoE) status in these patients.
      RESULTS: We observed no significant impact of H63D or C282Y heterozygosity on age
      at AD symptoms onset or diagnosis, age at onset of cognitive symptoms (AD and MCI
      combined), rates of MCI-to-AD conversion or specific neuropsychological deficits.
      No interactions between hfe zygosity and apoE status were discerned. Patients
      homozygous for H63D exhibited trends towards accelerated MCI-to-AD conversion
      rates and a subset of younger individuals (aged 55-75) exhibited earlier onset of
      cognitive symptoms relative to wild-type hfe and H63D heterozygotes. CONCLUSIONS:
      Contrary to earlier reports, the results of the present study do not implicate
      the common hfe mutations as genetic modifiers of sporadic AD and MCI. Trends
      towards accelerated cognitive dysfunction in H63D homozygotes warrant further
      study.

PMID- 15013568
TI  - Enhanced cutaneous vascular response in AD subjects under donepezil therapy.
AB  - OBJECTIVE: Abnormal cutaneous vasodilatory responses to the iontophoresis of
      vasodilators were previously observed in Alzheimer's disease (AD). We sought to
      replicate these observations and further identify peripheral vascular components
      of AD pathology. METHODS: Methacholine chloride (MCh), acetylcholine chloride
      (ACh), and sodium nitroprusside (SNP) were applied iontophoretically to forearm
      skin. Laser Doppler imaging of treated areas yielded total perfusion response
      values. RESULTS: Response to MCh was enhanced 78% ( P=0.003 ) in AD subjects
      under therapy with the acetylcholinesterase inhibitor (AChEI) donepezil ( N=9 ),
      relative to age- and sex-matched controls ( N=12 ). Significant increases in
      perfusion were also observed after application of ACh (68%, P=0.03 ) and SNP
      (46%, P=0.04 ). CONCLUSIONS: A previous study reported attenuated response to ACh
      in AD. Paradoxically, we observed a substantially enhanced response that is
      likely a consequence of donepezil therapy. The increased response to the
      endothelium-independent vasodilator SNP indicates improved general vasodilatory
      response, perhaps due to preservation of endogenous ACh by donepezil. Cerebral
      perfusion in response to functional activation may be improved in this way,
      suggesting a secondary therapeutic mode of donepezil.

PMID- 15013569
TI  - Decreased level of brain acetylcholine and memory disturbance in APPsw mice.
AB  - To clarify whether amyloid beta protein (Abeta) amyloidosis induces a disturbance
      of cholinergic system leading to long-term memory deficits, we continuously
      examined memory disturbance using the passive-avoidance task, and measured Abeta
      burden and concentrations of acetylcholine in the brain of APPsw transgenic mice.
      Repetitive retention trials of the passive-avoidance task showed that the long
      term memory impairment in APPsw mice appeared from approximately 7.75 months old
      and progressively advanced. Significant decreases in acetylcholine levels were
      found in the brains of 10-month-old mice. A few senile plaques appeared in the
      cerebral cortex and the hippocampus at 8 months old, and increased in size and
      number with aging. The concentrations of brain Abeta40/42(43) gradually increased
      from 8 months old and exponentially increased thereafter. Advance of long-term
      memory disturbance was closely correlated with Abeta40/42(43) burden. These
      findings suggested that Abeta accumulation induced long-term memory impairment
      and disturbance of the cholinergic system, and that the passive-avoidance task
      and measuring acetylcholine were useful methods for evaluating this mouse model
      as well as Abeta accumulation.

PMID- 15013570
TI  - Neuronal susceptibility to damage: comparison of the retinas of young, old and
      old/caloric restricted rats before and after transient ischemia.
AB  - Compared to young rats, old age increases susceptibility and caloric restriction
      decreases susceptibility for the loss of retinal ganglion cells and displaced
      amacrine cells following retinal ischemia/reperfusion. In retinas of old animals
      before ischemia, reactive gliosis, including activation of Muller cells,
      microglia and astrocytes, is increased compared to retinas from young and
      old/caloric restricted animals. Post-ischemia, the existing reactive gliosis in
      retinas of old animals is not neuroprotective and the reactive gliosis is even
      further increased in old animals compared to young or old/caloric restricted
      animals. In retinas from old/caloric restricted animals, inducible heat shock
      protein-70 and brain-derived neurotrophic factor increased more markedly after
      ischemia/reperfusion compared to retinas from young and old animals. Thus,
      compared to retinas in young animals, neurons of old animals may be more
      susceptible to cell death by secondary glial mechanisms after retinal
      ischemia/reperfusion. Caloric restriction in old animals is neuroprotective
      against damage in the retina following ischemia, perhaps by suppressing glial
      activity and by the neuroprotective effects of inducible heat shock protein-70
      and brain-derived neurotrophic factor.

PMID- 15013571
TI  - Regional responses in antioxidant system to exercise training and dietary vitamin
      E in aging rat brain.
AB  - We have evaluated the effect of exercise, Vitamin E and a combination of both on
      the antioxidant enzymes (AOEs)-superoxide dismutase (SOD), glutathione peroxidase
      (GSH-Px) and catalase (CAT) along with the products of lipid peroxidation (LP)
      malondialdehyde (MDA) and lipofuscin-like auto fluorescent substances (LF-like
      AFS) in discrete brain regions of rats of 4 (young adults), 8 (old adults), 12
      (middle-age) and 22 months (mos) old of age. Hippocampus (HC) showed greater
      increase in GSH-Px activity than cerebral cortex (CC) to exercise and Vitamin E
      and was irrespective of the age. A combination of both was effective in the CC of
      all age groups but not in the supplemented sedentary of 12- and 22-mo-olds. CAT
      activity increased significantly in the HC of supplemented and trained rats but
      not in the combination group of any age. SOD increased in both the regions of
      supplemented trainees. However, old were more benefited in terms of maximal
      elevation in the HC. Vitamin E reduced MDA content in both regions of adult. LF
      like AFS decreased significantly in supplemented sedentary and trainees of all
      ages. Our results demonstrate that an age-related deficit in AOEs in the CC and
      HC can be overcome through Vitamin E plus exercise, and further suggests the
      rationale for looking at these markers of oxidative stress in several age-related
      neuronal diseases.

PMID- 15013572
TI  - Aged F344 rats exhibit altered electrophysiological activity in locomotor
      unrelated but not locomotor-related striatal neurons.
AB  - Multi-wire electrode arrays were chronically implanted and striatal
      electrophysiological activity was recorded in young (4-9 months) versus aged (24
      29 months) Fischer 344 (F344) rats in order to determine whether locomotor
      related striatal neurons exhibit age-related changes in electrophysiological
      activity during freely-moving conditions. Individual neurons were classified as
      locomotor-related if they exhibited significant differences in their firing rates
      between periods of locomotion versus periods of non-movement. While the activity
      of locomotor-related striatal neurons did not differ between young and aged rats,
      neurons that were not related to locomotion exhibited significantly greater
      activity in the aged rats during both periods of non-movement and bouts of
      locomotion. These results suggest that in the aged striatum, increased activity
      of nonlocomotor-related neurons may contribute to hypokinesia through their
      influence on basal ganglia output nuclei. Such studies may aid in the
      understanding of movement disorders seen in aging and Parkinson's disease.

PMID- 15013574
TI  - Impulsivity in youth predicts early age-related cognitive deficits in rats.
AB  - Impulsivity is a feature of psychiatric disorders such as mania, addictive
      behaviors or attention deficit-hyperactivity disorder (ADHD), which has recently
      been related to complaints of forgetfulness in adults. We investigated whether
      impulsiveness exerts a long-term influence on cognitive function in rats in a
      longitudinal study. Impulsivity, assessed by the ability to complete a sequence
      of presses to obtain food (conditioning box), spatial working memory (8-arm
      radial maze) assessed with varying degree of attentional load and recognition
      memory (Y-maze) were tested at different ages. Marked individual differences in
      impulsivity were observed at youth and remained stable at middle-age despite a
      general decline in the trait. Working memory scores of impulsive and non
      impulsive rats did not differ in youth, whereas by middle-age the impulsive group
      had impaired working memory and was more sensitive to a higher attentional
      demand. Thus, impulsiveness in youth predicts cognitive performance in middle
      age. These findings may help refine the search for early biological substrates of
      successful aging and for preventive follow-up of subjects at risk of impaired
      cognitive aging.

PMID- 15013573
TI  - Effects of age on circadian rhythms are similar in wild-type and heterozygous
      Clock mutant mice.
AB  - The amplitudes of many circadian rhythms, at the behavioral, physiological,
      cellular, and biochemical levels, decrease with advanced age. Previous studies
      suggest that the amplitude of the central circadian pacemaker is decreased in old
      animals. Recently, it has been reported that expression of several circadian
      clock genes, including Clock, is lower in the master circadian pacemaker of old
      rodents. To test the hypothesis that decreased activity of a circadian clock gene
      renders animals more susceptible to the effects of aging, we analyzed the
      circadian rhythm of locomotor activity in young and old wild-type and
      heterozygous Clock mutant mice. We found that the effects of age and the Clock
      mutation were additive. These results indicate that age-related changes in
      circadian rhythmicity occur equally in wild-type and heterozygous Clock mutants,
      suggesting that the Clock mutation does not render mice more susceptible to the
      effects of age on the circadian pacemaker.

PMID- 15013576
TI  - Age-related changes in nitric oxide synthase and arginase in the rat prefrontal
      cortex.
AB  - Increasing evidence suggests that nitric oxide (NO), generated by nitric oxide
      synthase (NOS) from l-arginine, plays an important role in the ageing process.
      The present study, for the first time, investigates age-related changes in NOS
      and arginase, an enzyme that shares a common substrate with NOS, in the
      prefrontal cortex of rats assessed with and without prior behavioural testing. A
      significant increase in total NOS activity was found in the prefrontal cortex in
      aged (24-month-old) as compared with young (4-month-old) rats. Western blotting
      revealed that there were no significant differences between young and aged rats
      in neuronal NOS (nNOS) and endothelial NOS (eNOS) protein expression. Inducible
      isoform of NOS (iNOS), in terms of activity and protein expression, was not
      detected in either group. Total arginase activity and arginase I and II protein
      expression did not differ between the young and aged groups. The present findings
      support the contribution of NOS/NO to ageing but question the importance of iNOS
      in the normal ageing process.

PMID- 15013575
TI  - Pentyl-4-yn-valproic acid reverses age-associated memory impairment in the Wistar
      rat.
AB  - Pentyl-4-yn-valproic acid (VPA), a cognition-enhancing agent whose mode of action
      has been attributed to cell adhesion molecule-mediated neuritogenesis, has been
      shown to enhance hippocampus-dependent spatial learning. Here, we investigated
      its potential to reverse age-related memory impairment that relates mainly to
      declarative memory. Aged spatial learning deficits in the water maze paradigm
      were demonstrated by swim angle analysis, the angle between axes of start-to
      platform and start-to-animal position, and latency to reach a submerged platform.
      Chronic pentyl-4-yn-VPA administration mediated a significant improvement in both
      search strategy and latency to find the submerged platform in aged animals.
      Pentyl-4-yn-VPA also facilitated task recall in aged animals as evidenced by
      increased time in the target quadrant during a probe trial 3 days following the
      final training session. The action of pentyl-4-yn-VPA on platform latency, search
      strategy and task recall suggests that this agent may have great benefit in the
      treatment of age-dependent cognitive decline.

PMID- 15013577
TI  - Aging and prefrontal functions: dissociating orbitofrontal and dorsolateral
      abilities.
AB  - This study aimed to determine whether age differentially affects performance on
      tasks tapping orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex
      (DLPFC). We administered prefrontal measures to healthy younger ( n=23; age=
      28.4+/-5.9, education = 15.7+/-2.6, MMSE=29.5+/-0.6 ) and older participants (
      n=20; age=69.1+/-5.0, education =15.5+/-3.4, MMSE =28.9+/-1.5). Groups did not
      differ on education or mental status, P>0.05. Tasks thought to involve greater
      OFC processing included the Iowa Gambling Task and Delayed Match and Non-Match to
      Sample Tasks. Tasks requiring greater DLPFC processing included Petrides' Self
      Ordered Pointing, WAIS-R Digit Span Backward, Letter Fluency, and Months Backward
      from the Boston Revision of WMS-Mental Control. Composite z-scores were
      calculated for OFC and DLPFC tasks. A 2 x 2 ANOVA revealed a Group x Task
      interaction: F(1,41) =5.55, P=0.02, and a Group main effect: F(1,41)= 12.16,
      P=0.001. Follow-up analyses revealed younger adults outperformed older adults on
      OFC tasks only ( younger = 0.37+/-0.46, older= -0.43+/-0.70; t(41) =4.5, P<0.001
      ). Post-hoc analyses of individual tasks confirmed that despite age differences
      on Petrides' Self-Ordered Pointing, measures requiring relatively greater OFC
      involvement showed larger effect sizes for age differences. Thus, tasks
      emphasizing OFC functions appear more sensitive to age effects when directly
      compared to measures of DLPFC functioning. Reasons for this difference in
      magnitude may stem from differential aging of prefrontal cortex or differential
      recruitment of alternative brain regions for successful task completion.

PMID- 15013578
TI  - Postoperative radiotherapy in stage II or IIIA completely resected non-small cell
      lung cancer: a systematic review and practice guideline.
AB  - The Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence
      based Care conducted a systematic review of literature published between 1985 and
      July 2003 and developed an evidence-based clinical practice guideline on
      postoperative radiotherapy in patients with completely resected pathologic stage
      II or IIIA non-small cell lung cancer (NSCLC). Forty-four Ontario clinicians
      reviewed the draft guideline. Evidence included one meta-analysis of individual
      patient data (from nine randomized controlled trials) and three randomized
      controlled trials (two including data reported in the meta-analysis) that
      compared surgery with or without postoperative radiotherapy. The meta-analysis
      and one trial detected a significant detriment to survival with postoperative
      radiotherapy. Two trials detected no survival difference. The meta-analysis
      detected a significant advantage in local recurrence-free survival (time to local
      recurrence or death) with surgery alone, although two trials detected a
      significant advantage in rate of local recurrence with postoperative
      radiotherapy. Subset analyses from the meta-analysis and one trial suggested that
      postoperative radiotherapy was detrimental to survival mainly in stage II
      disease; no benefit or detriment was evident for stage III disease.
      RECOMMENDATIONS: Postoperative radiation therapy following complete resection of
      stage II non-small cell lung cancer is not recommended. No definitive
      recommendation can be made for stage IIIA disease.

PMID- 15013579
TI  - Effectiveness of smoking cessation self-help materials in a lung cancer screening
      population.
AB  - Randomized controlled trials of smoking interventions have not been well
      documented for lung cancer screening populations. In this study, we randomly
      assigned 171 current smokers who were undergoing low-dose fast spiral chest CT
      (SCTS) for lung cancer screening to receive either standard written self-help
      materials or a written list of Internet resources for smoking cessation. At the 1
      year follow-up, more of the subjects receiving Internet-based resources reported
      making a stop attempt (68% versus 48%, P=0.011). However, there were no
      statistically significant differences in 7-day point prevalence quit rates (5%
      versus 10%) or advancement in motivational readiness to stop smoking (27% versus
      30%), respectively, between the groups. Clearly, more investigation is warranted
      into how to tailor smoking interventions for cancer screening participants.

PMID- 15013580
TI  - K-ras and p16(INK4A)alterations in sputum of NSCLC patients and in heavy
      asymptomatic chronic smokers.
AB  - NSCLC rates among the most frequent and lethal neoplasm world-wide and a
      significant decrease in morbidity and mortality relies only upon effective early
      diagnostic strategies. We investigated K-ras mutations and p16(INK4A)
      hypermethylation in tumor tissue and sputum of 50 patients with NSCLC and
      correlated them with sputum cytology and with tumor staging, grading and
      location, to ascertain, in sputum, their potential diagnostic impact. The same
      genetic/epigenetic abnormalities and cytological features were also evaluated in
      sputum from 100 chronic heavy smokers. Genetic analysis identified molecular
      abnormalities in 64% tumors (14/50 K-ras mutations and 24/50 p16(INK4A)
      hypermethylation) and in 48% sputum (11/50 K-ras mutations and 16/50 p16(INK4A)
      hypermethylation). In tumors K-ras mutations and p16(INK4A) hypermethylation were
      mostly mutually exclusive, being found in the same patients in 3 cases only.
      Genetic abnormalities in sputum were detected only in molecular abnormal tumors.
      Molecular changes in sputum had rates of detection similar to cytology (42%) but
      the cyto-molecular combination increased the diagnostic yield up to 60%.
      Interestingly, the rate of detection of genetic changes in sputum of tumors at
      early stage (T1) was not significantly different from that of tumors at more
      advanced stage (T2-T4). In fact K-ras point mutations were frequently recognised
      in tumors at early stage while p16(INK4A) inactivation prevailed in tumors at
      advanced stage ( P=0.0063). As expected, diagnostic cytological findings were
      more frequently found in tumors at advanced stage (P=0.004). No correlation was
      found between tumor grading and location (central versus peripheral) and
      molecular changes. p16(INK4A) hypermethylation, but not K-ras mutations, was
      documented in sporadic cases of asymptomatic heavy smokers (4%) where it was
      uncoupled from cytological abnormalities. In conclusion the cyto-molecular
      diagnostic strategy adopted in this study was able to detect the majority of
      tumors but in order to be proposed as effective and early diagnostic tool, this
      molecular panel needs to be tested in prospective studies with adequate follow
      up.

PMID- 15013581
TI  - p53 and FHIT mutations and microsatellite alterations in malignancy-associated
      pleural effusion.
AB  - Cancer is a genetic disease and thus is influenced by oncogenes and tumor
      suppressor genes. To determine whether the genetic analysis of pleural fluid can
      be used to diagnose malignant effusion, we investigated p53 and FHIT mutations
      and microsatellite alterations (MA) in the pleural fluid of 40 patients with
      pleural effusion associated with malignancy (ME) and in the pleural fluid of 17
      patients with tuberculous pleurisy (TB) as a control group. p53 mutations were
      detected in five ME patients (13%) and in no TB patient, and FHIT mutations were
      detected in seven ME patients (18%) and two TB patients (12%). For four
      microsatellite markers, D3S1234, D3S1285, D9S171, and TP53, in ME patients, loss
      of heterozygosity (LOH) was seen in 10 (25%), 5 (13%), 10 (25%), and 6 patients
      (15%), respectively, and microsatellite instability (MI) in 6 (15%), 0 (0%), 1
      (3%), and 3 patients (8%), respectively. Using the same markers, in TB patients,
      LOH was seen in three (18%), one (6%), three (18%), and one (6%), respectively,
      and MI in one (6%), zero (0%), zero (0%), and zero (0%), respectively. Twenty
      five ME cases (63%) exhibited MA (LOH or MI) in at least one marker. Moreover, in
      four (80%) of five ME cases with negative cytology and no carcinoembryonic
      antigen increase in pleural fluid, MAs were identified. In ME, positive cytology
      was found in 42.5%, and positive MA, using four markers, in 63%. Although still
      limited in terms of sensitivity and specificity, this study shows that molecular
      diagnostic strategies could enhance the diagnostic yield in cases of malignant
      effusion.

PMID- 15013582
TI  - Small lung tumors with the size of 1cm or less in diameter: clinical,
      radiological, and histopathological characteristics.
AB  - BACKGROUND: The detection rate of small nodules in the peripheral lung area is
      increasing due to the widespread use of CT scanning. However, the radiological
      and pathological characteristics of very small tumors have not been fully
      investigated. METHODS: We evaluated 44 lung tumors with the size of 1cm or less
      in diameter resected from 38 patients (19 men and 19 women, with an average of 62
      years) from 1997 through 2001. The clinical records, the findings of high
      resolution CT (HRCT) and histopathological features of resected specimens were
      analyzed. Adenocarcinoma was histologically further subclassified into types A to
      F according to the Noguchi's classification. RESULTS: Lobectomy was performed in
      20 patients, wedge resection in 15 and segmentectomy in 3, respectively. Thirty
      two tumors were adenocarcinomas, 4 were squamous cell carcinomas, and eight were
      atypical adenomatous hyperplasia (AAH), respectively. All carcinoma cases were
      proved to be stage IA. In adenocarcinoma, type A was detected in 12 tumors, type
      B in 13, type C in 1, type D in 2, type E in 1, and type F in 3, respectively.
      Most of AAH and type A showed pure ground-glass attenuation on HRCT scan, whereas
      types B to F as well as squamous cell carcinoma frequently had malignant CT signs
      such as lobulation and convergence of peripheral vessels. Lymphatic or vascular
      invasion was observed in two adenocarcinomas (types D and F) and two squamous
      cell carcinomas, and HRCT scan of these four tumors showed soft-tissue
      attenuation occupying more than two-thirds of each nodule. All patients are
      currently alive without signs of recurrence after a mean follow-up period of 35.5
      months. CONCLUSION: Types A and B of adenocarcinoma were the most common
      histologic types among lung tumors with the size of 1cm or less in diameter.
      Limited lung resection appears to be an adequate for such small lung tumors in
      which soft-tissue attenuation consists of less than two-thirds of the nodule on
      HRCT.

PMID- 15013583
TI  - Towards a minimally invasive staging strategy in NSCLC: analysis of PET positive
      mediastinal lesions by EUS-FNA.
AB  - STUDY OBJECTIVE: To asses the value of endoscopic ultrasound guided fine needle
      aspiration (EUS-FNA) in the nodal staging of patients with (suspected) non-small
      cell lung cancer (NSCLC) and a (18)FDG positron emission tomography (PET) scan
      suspect for N2/N3 mediastinal lymph node (MLN) metastases. BACKGROUND: Due to the
      imperfect specificity of positron emission tomography, PET positive MLN should be
      biopsied in order to confirm or rule out metastasis. Currently, invasive surgical
      diagnostic techniques such as mediastinoscopy/-tomy are standard procedures to
      obtain MLN tissue. The minimally invasive technique of EUS-FNA has a high
      diagnostic accuracy (90-94%) for the analysis of MLN in patients with enlarged
      MLN on computed tomography of the chest (CT). DESIGN AND PATIENTS: Thirty-six
      patients with proven n=26 or suspected n=10 non-small cell lung cancer and a PET
      scan suspect for N2/N3 lymph node metastases underwent EUS-FNA. When EUS-FNA did
      not confirm metastasis and the PET lesion was within reach of mediastinoscopy, a
      mediastinoscopy was performed. EUS-FNA negative patients with PET lesions beyond
      the reach of mediastinoscopy or those with a negative mediastinoscopy were
      referred for surgical resection of the tumour and MLN sampling or dissection.
      RESULTS: EUS-FNA confirmed N2/N3 disease in 25 of the 36 patients (69%) and was
      highly suspicious in one. In the remaining 10 patients, one PET positive and one
      PET negative N2 metastasis was detected at thoracotomy. The PPV, NPV,
      sensitivity, specificity and accuracy of EUS-FNA in analysing PET positive MLN
      were 100%, 80%, 93%, 100% and 94%, respectively. No complications of EUS-FNA were
      recorded. CONCLUSIONS AND SIGNIFICANCE: EUS-FNA yields minimally invasive
      confirmation of MLN metastases in 69% of the patients with potential mediastinal
      involvement at FDG PET. The combination of PET and EUS-FNA might qualify as a
      minimally invasive staging strategy for NSCLC.

PMID- 15013584
TI  - Lung cancer patients showing pure ground-glass opacity on computed tomography are
      good candidates for wedge resection.
AB  - Small lung cancers frequently have been detected in mass screening by computed
      tomography (CT) in recent years. Suitability of limited resection for these small
      lung cancers remains controversial. One hundred patients who underwent sublobular
      limited resection (wedge resection or segmentectomy) for lung cancer in our
      hospital from 1981 to 2002 were analyzed retrospectively. From CT findings,
      tumors were classified into two groups; pure ground-glass opacity (PGGO) and non
      PGGO. Patients included 44 women and 56 men, and ages ranged from 40 to 92 years
      (mean, 71.0). Histologic types included 76 adenocarcinomas, 21 squamous cell
      carcinomas, and 3 large cell carcinomas. Clinical stages included 83 stage IA and
      17 stage IB. By high-resolution CT, 27 tumors (27%) showed PGGO; at postoperative
      histopathologic examination, all of these were localized bronchioloalveolar
      carcinomas. Diameter of tumors showing PGGO was 9.3+/-mm (mean +/- S.D.); that of
      non-PGGO tumors was 21.2+/-13.7 mm. Overall and lung cancer-specific 5-year
      survival rates in all patients were 58.0 and 64.8%, respectively. Overall 5-year
      survival rate with small adenocarcinomas (<or=20mm) was 93.7%, significantly
      better than 24.8% with larger adenocarcinomas ( P<0.0001 ). No intrathoracic
      recurrence or distant metastasis has been observed in PGGO tumors. For peripheral
      localized bronchioloalveolar carcinoma showing PGGO, wedge resection appears to
      be the best operation. Definitive study of more patients with longer follow-up is
      needed.

PMID- 15013585
TI  - Multimodal management of stages III-IVa malignant thymoma.
AB  - PURPOSE: The optimal therapy for locally advanced malignant thymoma is
      controversial. We review our experience with a multimodal approach in 63
      consecutive cases. PATIENTS AND METHODS: Forty-three patients had stage III and
      20 stage IVa disease. Surgery with radical intent was initially performed in 30
      cases, while 33 cases not amenable to radical surgery underwent neoadjuvant
      treatment (radiotherapy in 8 and chemotherapy in 25) before surgical
      reassessment. All patients, whether or not surgically resected, received
      radiation therapy. RESULTS: Radical resection (RR) was performed in 20 patients
      ab initio (all stage III) and in 12 patients after neoadjuvant treatment (eight
      stage III and four stage IVa). With the addition of patients radically operated
      with neoadjuvant treatment, the radical resection rate increased from 46 to 65%
      in stage III patients, and from 0 to 20% in those with stage IVa disease,
      respectively. Radical surgery was associated with longer progression free
      survival and overall survival according to both univariate analysis ( P< 0.001
      and P<0.01, respectively) and multivariate analysis after adjustment for age,
      gender, histology and disease stage ( P<0.001 and <0.02, respectively).
      Progression free survival (median 56.9 months) was slightly lower in patients
      undergoing radical surgery after neoadjuvant approaches than in those radically
      resected ab initio (median not achieved), but overall survival (median not
      achieved) was similar in both groups. Subtotal surgical resection promoted
      complete response to subsequent radiation therapy. This condition significantly
      correlated with a better outcome. CONCLUSIONS: Complete surgical resection is an
      independent prognostic parameter in locally advanced thymoma treated with a
      multimodal approach. Preoperative treatment to increase the complete resection
      rate could improve the overall survival of these patients.

PMID- 15013586
TI  - Results following treatment to doses of 92.4 or 102.9 Gy on a phase I dose
      escalation study for non-small cell lung cancer.
AB  - BACKGROUND AND PURPOSE: The University of Michigan lung dose escalation study has
      increased the dose of external beam radiation for non-small cell lung cancer
      based on the volume of normal lung irradiated. The results of patients treated to
      either 92.4 or 102.9 Gy are reported. MATERIALS AND METHODS: Seventeen patients
      have completed treatment to 92.4 or 102.9 Gy and have been followed for at least
      6 months. The treatment planning goal was to minimize the effective volume
      (V(eff)) of total lung irradiated as computed using the Kutcher-Burman DVH
      reduction scheme. Dose was escalated independently within each of five V(eff)
      bins. Toxicity, freedom from local progression (FFLP), overall survival (OS) and
      cause specific survival (CSS) are reported. RESULTS: Thirteen patients were Stage
      I, one was Stage II and three were Stage III. V(eff) ranged from 0.06 to 0.21.
      The median pretreatment FEV(1) was 1.24 L or 44% of predicted. Median follow-up
      for survivors was 37.9 months. No patient had significant pulmonary toxicity. One
      patient each had grades 2 and 3 esophagitis. Median percent change in FEV1 was 
      11%. Two- and three-year actuarial FFLP and OS rates for the entire group were 68
      and 58% and 51 and 26%, respectively. For Stage I patients, the 2 and 3 year
      FFLP, OS and CSS rates were 82 and 68%, 54 and 33%, 76 and 48% respectively.
      CONCLUSIONS: These results suggest that doses of radiation of 92.4 and 102.9 Gy
      can be delivered safely to limited lung volumes with minimal toxicity.

PMID- 15013587
TI  - Combined modality treatment for locally advanced non-small cell lung cancer:
      preoperative chemoradiation does not result in a poorer quality of life.
AB  - The German Lung Cancer Cooperative Group (GLCCG) is assessing the impact of
      chemoradiation in addition to chemotherapy in the neoadjuvant treatment of stage
      III NSCLC. After three cycles of cisplatin/etoposide patients receive either
      hyperfractionated radiotherapy (RT) with concurrent carboplatin/vindesine and
      then surgery (arm A) versus surgery and then conventional RT (arm B). Quality of
      life (QL) was assessed throughout therapy using the EORTC QLQ-C30 and EORTC QLQ
      LC 13. Of 126 eligible patients, 54 completed treatment. For patients in both
      treatment arms physical functioning decreased, whereas dyspnoea, fatigue and pain
      increased from beginning to the end of treatment. For self-assessed QL no
      statistically significant effect was found in or between the two treatment arms.
      The combined modality approach with preoperative radio/chemotherapy proves to be
      feasible in treating locally advanced NSCLC patients without decreasing their
      subjective QL.

PMID- 15013588
TI  - Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2
      overexpressing, untreated, advanced non-small cell lung cancer: report of a phase
      II trial and findings regarding optimal identification of patients with Her2
      overexpressing disease.
AB  - The purpose of this study was to evaluate the feasibility, efficacy, safety, and
      pharmacokinetics of trastuzumab plus cisplatin and gemcitabine in patients with
      Her2-overexpressing stages IIIB or IV non-small cell lung cancer (NSCLC) and to
      study the relationship between results from the two methods for determining
      levels of Her2 overexpression. Chemonaive patients were eligible if they had
      stages IIIB or IV NSCLC with either a Her2 score of at least 1+ by
      immunohistochemical (IHC) analysis or a serum Her2 shed antigen level of at least
      15 ng/ml by enzyme-linked immunosorbent assay (ELISA). Treatment consisted of
      cisplatin 75 mg/m(2) day one plus gemcitabine 1250 mg/m(2) days one and eight
      plus trastuzumab 4 mg/kg day one and 2 mg/kg weekly thereafter on a 21-day cycle
      for six cycles followed by weekly maintenance trastuzumab therapy. Of the 21
      patients enrolled, 8 (38%) patients had a partial response. The 1-year survival
      rate was 62% (13/21). Median time to progression was 36 weeks. Pharmacokinetic
      studies revealed no interaction between trastuzumab and gemcitabine plus
      cisplatin. In patients screened for this study, Her2 expression was zero in
      283/360 (79%); 1+ in 32/360 (9%); 2+ in 27/360 (8%); and 3+ in 18/360 patients
      (5%). Serum Her2 shed antigen was >15 ng/ml in 27/ 288 (9%) patients. Of patients
      who had both Her2 assays, 24% (4/17) with ELISA scores >15 ng/ml had IHC scores
      of 3+, compared with only 2% (3/145) of the patients <15 ng/ml and 4% (7/162) of
      all patients. The addition of trastuzumab to cisplatin and gemcitabine was well
      tolerated, but further study will be required to determine whether this
      combination is superior to chemotherapy alone. This may be demonstrated if only
      those patients with Her2, having a score of IHC 3+ were eligible. Since IHC 3+ is
      rare in NSCLC, performing IHC in only those patients with serum Her2 shed antigen
      >15 ng/ml would greatly increase the efficiency of IHC screening though at the
      cost of excluding nearly half the patients with Her2 scores of 3+ on IHC
      analysis. Thus, if sequential screening consisting of serum ELISA followed by IHC
      analysis is implemented, it may make a trastuzumab trial feasible but should
      ultimately be supplanted by another screening system if trastuzumab is shown to
      be beneficial to some patients with IHC Her2 scores of 3+.

PMID- 15013590
TI  - Weekly administration of irinotecan (CPT-11) plus cisplatin for refractory or
      relapsed small cell lung cancer.
AB  - PURPOSE: Weekly administrations of CPT-11 plus cisplatin together with an anti
      diarrheal program, the Oral Alkalization and Control of Defecation [Int J Cancer
      1999;83:491; Int J Cancer 2001;92:269; Cancer Res 2002;62:179], were evaluated in
      this phase II study for patients with refractory or relapsed small cell lung
      cancer. METHODS: Patients were treated by weekly administrations of 60 mg/m(2)
      CPT-11 plus 30 mg/m(2) cisplatin on Days 1, 8 and 15 over 4 weeks. Coinciding
      with the infusions and for 4 days thereafter, the anti-diarrheal program was
      practiced using orally administered sodium bicarbonate, magnesium oxide and basic
      water. RESULTS: Twenty-five patients who had prior treatments of etoposide and
      platinum containing regimens (16 refractory patients and nine relapsed patients)
      were entered. The mean dose-intensities of CPT-11 and cisplatin were 154.8 and
      77.4 mg/m(2) per course, respectively. Therefore, 86% of the planned dose was
      delivered. There were 20 partial responses and an overall response rate of 80%
      (95% confidence interval, 62-96%) was obtained. The median time to progression
      and the median survival after starting this regimen were 3.6 and 7.9 months,
      respectively. The major toxicity was myelosuppression. Grades 3 and 4 neutropenia
      occurred in 24 and 12% of patients, respectively. One patient with febrile
      neutropenia was experienced, and Grade 3 diarrhea was observed in 8%. But there
      was no treatment death. CONCLUSION: Weekly administrations of CPT-11 plus
      cisplatin together with Oral Alkalization and Control of Defecation provide a
      practical and well tolerated regimen that was active for refractory or relapsed
      small cell lung cancer.

PMID- 15013589
TI  - A phase I study of Topotecan, as a radiosensitizer, for thoracic malignancies.
AB  - PURPOSE: To determine the maximum-tolerated dose (MTD) of daily Topotecan with
      full-dose thoracic radiotherapy (XRT). METHODS AND MATERIALS: Patients with
      advanced thoracic malignancies requiring full dose radiation received daily I.V.
      Topotecan prior to each daily session of XRT to 60 Gy over 6 weeks. Dose levels
      (and subjects studied at each) have been 0.2 (N=7), 0.3 (N=5), 0.4 (N=7), and
      0.5mg/m(2) per day (N=5) in a best-of-five design. Tumor response was assessed at
      4-8 weeks after completion of therapy. RESULTS: From March 1995 to December 1999,
      a total of 24 patients were treated. The MTD of Topotecan was 0.4 mg/m(2) per
      day, based on dose limiting toxicities (DLTs) observed at 0.5 mg/m(2) per day,
      which were grade 4 hematological toxicities or diarrhea and grade 3 esophagitis.
      Tumor responses included: zero complete response (CR), nine partial responses
      (PR), five stable disease (SD), nine progressive disease (PD) and one not
      evaluated (NE). Additionally, local response was also assessed separately (within
      the XRT ports) and there were 10 PR, 12 SD, 1 PD, and 1 NE. CONCLUSION: the MTD
      of Topotecan with concomitant thoracic radiotherapy is 0.4 mg/m(2) per day. The
      DLTs observed were grade 4 diarrhea, grade 3 esophagitis and grade 4
      hematological toxicities. Based on the known radiosensitizing effect of
      Topotecan, this dose is recommended for phase II testing.

PMID- 15013591
TI  - Bronchial typical carcinoid tumors: histological study of intra- versus
      extraluminal growth pattern.

PMID- 15013592
TI  - Automatic arrhythmia detection based on time and time-frequency analysis of heart
      rate variability.
AB  - We have developed an automatic arrhythmia detection system, which is based on
      heart rate features only. Initially, the RR interval duration signal is extracted
      from ECG recordings and segmented into small intervals. The analysis is based on
      both time and time-frequency (t-f) features. Time domain measurements are
      extracted and several combinations between the obtained features are used for the
      training of a set of neural networks. Short time Fourier transform and several
      time-frequency distributions (TFD) are used in the t-f analysis. The features
      obtained are used for the training of a set of neural networks, one for each
      distribution. The proposed approach is tested using the MIT-BIH arrhythmia
      database and satisfactory results are obtained for both sensitivity and
      specificity (87.5 and 89.5%, respectively, for time domain analysis and 90 and
      93%, respectively, for t-f domain analysis).

PMID- 15013593
TI  - A novel mathematical method based on urea kinetic modeling for computing the
      dialysis dose.
AB  - A novel normalized single pool urea kinetic model (nspUKM) for the quantification
      of the urea removal, dialyzer urea clearance and urea generation rate during a
      dialysis session, is presented. Its major goal is the computation of an accurate
      estimate of the fractional dialyzer urea clearance (dKt/V), which is denoted
      nKt/V, in contrast to the equilibrated Kt/V (eKt/V). This work clarifies the
      significance of dKt/V as a complement to eKt/V in hemodialysis (HD) prescription
      and quantification. This new model emerges from a generalization of the standard
      single pool urea kinetic model (spUKM) of the US National Cooperative Dialysis
      Study (NCDS), identified as gspUKM. Due to their significance, the standard
      single pool Kt/V (spKt/V) and the eKt/V are also analyzed from gspUKM in this
      work, with the aim of achieving a better interpretation of the results. Indices
      nKt/V, eKt/V and spKt/V have been compared with the dKt/V computed from a
      published and validated two-pool urea kinetic model (2pUKM). We present the
      results obtained from a clinical study carried out on a group of 30 end stage
      renal disease (ESRD) patients. The limits of agreement (mean+/-2S.D. (standard
      deviation) of the difference) between nKt/V and 2pKt/V were -0.077+/-0.72%
      (percentage of the dKt/V mean), while between eKt/V and 2pKt/V were -13.75+/
      17.39% and between spKt/V and 2pKt/V were -1.61+/-6.54%. These scores prove that
      the nspUKM model is able to provide a very accurate estimate of 2pKt/V and thus
      dKt/V, even with high flux (HF) HD. The presented method joins the simplicity of
      single-pool models to the accuracy of double-pool models, when the target is the
      identification of the dialyzer urea clearance, urea removal and urea generation
      rate, although it does not provide a good prediction of the urea dynamics.
      Finally, we think that our analytical and experimental findings throw light on
      the behavior and applicability of the different Kt/V indices analyzed.

PMID- 15013594
TI  - Predicting capacities required in cardiology units for heart failure patients via
      simulation.
AB  - The management of a department of cardiology has to plan the capacity of both
      elective and non-elective patients. Heart failure (HF) patients are admitted to
      the hospital in a non-elective way. The precision with which the capacity needed
      for non-elective patients can be predicted determines the degree of flexibility
      in planning the admission of elective patients. In this study we want to
      determine how accurately we can predict the bed occupancy of HF patients using a
      simulation model. Data of the year 2000 were used to obtain the necessary
      probability distribution functions. Data from the year 2001 were used for
      determining the prediction accuracy. The results show that the arrival of new HF
      patients can be adequately predicted. However, the bed occupancy by new and
      especially current patients is predicted less accurately. Still in 70% (90%) of
      the days of a 5-day-prediction interval the error is at most one (two) bed(s).
      The results may improve if the cardiologist is asked to predict the length of
      stay of the current patients.

PMID- 15013595
TI  - Validation of two algorithms to evaluate the interface between bone and
      orthopaedic implants.
AB  - The level of fit and fill of the prosthetic stem in the femoral canal is an
      important parameter when planning a cementless total hip arthroplasty. However,
      the standard templates used in combination with radiographs are not always
      effective in the pre-operative evaluation of the level of fitting. For this
      reason, two algorithms were developed able to provide clinically relevant three
      dimensional indicators of the implant fit and fill in the host femur, based on
      the CT data of each specific patient as collected in vivo. In this study the
      computational methods were described and validated using digital phantom
      datasets. Then the algorithms were applied for in vivo datasets and the
      sensitivity of each indicator was evaluated. The validation showed that the two
      algorithms are accurate from a computational point of view. Moreover, the in vivo
      testing demonstrated that the developed methods provide reasonable quantitative
      indicators of the stem positioning in the femoral CT dataset.

PMID- 15013596
TI  - Responses of central auditory neurons modeled with finite impulse response (FIR)
      neural networks.
AB  - To simulate central auditory responses to complex sounds, a computational model
      was implemented. It consists of a multi-scale classification process, and an
      artificial neural network composed of two modules of finite impulse response
      (FIR) neural networks connected to a maximum network. Electrical activities of
      single auditory neurons were recorded at the rat midbrain in response to a
      repetitive pseudo-random frequency modulated (FM) sound. The multi-scale
      classification process divides the training dataset into either strong or weak
      response using a multiple-scale Gaussian filter that based on response
      probability. Two modules of FIR neural network are then independently trained to
      model the two types of responses. This caters for the possible differences in
      neuronal circuitry and transmission delay. Their outputs are connected to a
      maximum network to generate the final output. After training, we use a different
      set of FM responses collected from the same neuron to test the performance of the
      model. Two criteria are adopted for assessment. One measures the matching of the
      modeled output to the actual output on a point-to-point basis. Another measures
      the matching of bulk responses between the two. Results show that the proposed
      model predicts the responses of central auditory neurons satisfactorily.

PMID- 15013597
TI  - Computer programs to facilitate the estimation of time-dependent drug effects on
      ion channels.
AB  - The programs I-VOC and I-ROC have been designed to facilitate the analysis of
      drug effects on currents through ion channels in the cell membrane, measured by
      means of voltage-clamp. They are written in Igor Pro (WaveMetrics) and read
      exported files or raw data files generated by the Pulse (HEKA Electronic) or
      pClamp (Axon Instruments) programs. With I-VOC, the sweeps of current through
      voltage-operated ion channels can be quantified within six time ranges, and
      current run-down can be corrected for after the currents are fitted during the
      control period. Linear leak current can be subtracted even when the P/n method is
      not used. The results are plotted and tabulated. With I-ROC, an analogous
      program, receptor-operated currents can be quantified, the peak current or rate
      of desensitization can be fitted and run-down corrected for. Chart-like data can
      be converted to a sweep-like format. Several procedures are incorporated for
      rapid graphical data presentation. These programs accelerate and improve the
      estimation of drug effects on ion channels.

PMID- 15013599
TI  - [Comparison of two electrical stimulation protocols on quadriceps muscle after
      anterior cruciate ligament surgery. Feasability study].
AB  - OBJECTIVES: To evaluate the feasibility of a study comparing the effects of two
      protocols of electrical stimulation of the quadriceps femoris after anterior
      cruciate ligament surgery. MATERIAL: Seven sportsmen with a mean age of 26 yrs
      were randomly grouped in two: a 20 Hz stimulated group (4 patients) and a 80 Hz
      stimulated group (3 patients). After surgery all patients received electrical
      stimulation of the quadriceps femoris, five days a week, for 12 weeks, and had a
      standard program of voluntary contractions. The main outcome assessed before and
      three months after surgery were: quadriceps and hamstring peak torque at 90, 180
      and 240 degrees /second, maximal isometric quadriceps at 75 degrees of flexion
      and muscle and subcutaneous fat volumes of the thigh using MRI. RESULTS: After 12
      weeks of rehabilitation, the thigh muscle volume deficit of the operated limb was
      between 3 and 9% in the 20 Hz stimulated group and between 1 and 2% in the 80 Hz
      stimulated group. Quadriceps peak torque deficit was less than 30% except for two
      patients in the 20 Hz stimulated group. Maximal isometric quadriceps deficit of
      the operated limb was higher than 30% except for two patients in the 20 Hz
      stimulated group. CONCLUSION: The study showed that comparison of two protocols
      of electrical stimulation of the quadriceps femoris after anterior cruciate
      ligament surgery is possible if stimulation period is not more than four weeks.

PMID- 15013598
TI  - [Urodynamics and uterine fibroid. Is there a specific parameter?].
AB  - AIM OF STUDY: To search for a urodymamical parameter and/or a VBN parameter
      (deduced from a modelized analysis of uroflows) which could characterize the
      voiding dysfunctions due to a uterine fibroid. POPULATION AND METHODS: Thirty
      women (31-69 years) with a uterine fibroid (exclusion criteria: neurological
      disease, diabetes mellitus, previous pelvic surgery, grade > I prolapse)
      underwent one urodynamic session which included the successive tests: free
      uroflow, urethral profilometry, cystometry and, if possible, a second free
      uroflow. Twenty-eight patients complained from stress urinary incontinence.
      Modelized analysis of the flow curves was performed in order to determine the
      value of two VBN parameters: urethral parameter g and recruitment ratio rr (which
      quantify the ratio of firing motor neurons during detrusor contraction). RESULTS:
      The fibroid (known for 23 subjects) was detected during gynaecological
      examination in seven cases. No significant change of the value of one
      urodynamical parameter which could be linked to the uterine fibroid rather than
      the urinary disorder has been found. Some urethral constrictive obstruction
      exists for 18 patients (g = 0.40 +/- 0.15) but is not meaningful. In the whole
      population, an effective abdominal pressure is found in 78% of the analyzed
      micturitions. CONCLUSION: Some urinary disorders result from the presence of a
      uterine fibroid; they are significantly improved by simple hysterectomy. If
      urodynamics does not have any specificity, concomitant physical examination
      allows to detect fibroids with only urinary symptomatology.

PMID- 15013600
TI  - [Range of motion of the scoliotic spine in adults].
AB  - OBJECTIVE: To describe the movement of the trunk in adults with untreated
      adolescent idiopathic scoliosis (AIS) and to evaluate their relationship with the
      age of the patients, the location and angle of the curve, and the number of
      involved intervertebral segments. MATERIALS AND METHODS: Two hundred adult
      subjects with untreated AIS, without associated signs, were analyzed with
      rachimetry. The flexion, extension, bending, and rotation of the trunk were
      determined for each patient. The results were compared with a different sample:
      healthy subjects without spinal disease/other groups with more severe scoliosis
      (treated). RESULTS: In the absence of discopathy, regardless of the angle,
      location of the curve, or age of the patient, adults with untreated AIS
      demonstrated a 24% increase in truncal flexion, and a 30% decrease in hip
      flexion. The other movements studied with rachimetry were comparable to normal
      subjects. Lesions of the intervertebral segments increased in number and severity
      with age. These lesions progressively limited the mobility of the spine,
      initially in extension; and then in bending and flexion. CONCLUSIONS: The
      measurement of the mobility of the spine and the pelvis is part of the systematic
      examination of patients with adult scoliosis. This information can be used to
      improve the patients' health and spinal function; independent of their age and
      degree of spinal deformity.

PMID- 15013601
TI  - [Influence of speed variation and age on the intrasubject variability of ground
      reaction forces and spatiotemporal parameters of children's normal gait].
AB  - OBJECTIVE: To assess the effect of age and speed on the variability of ground
      reaction forces (GRF) and stride parameters of gait in normal children. MATERIAL
      AND METHOD: Forty-seven children aged 4-10 years were split into three age
      groups. Each child walked at three constant speeds on a treadmill. Thirty
      consecutive steps of each leg were recorded. For each child, the mean parameters
      of the 30 steps were calculated. The mean parameter of each child was taken to
      calculate the mean parameters of the group. The variability was evaluated by the
      coefficient of variation (CV). The influence of both age and speed on the
      variability was examined with a to-way analysis of variance. RESULTS: The cross
      effect of age and speed on the variability was not significant. The variability
      of the parameters decreased significantly with age between 4 and 8 years. The
      variability of vertical forces increased significantly with speed (between 2.7
      and 4.5 km/h), while the variability of antero-posterior forces, the stride and
      the stance decreased between 2.7 and 3.6 km/h. However, the variability of double
      stance was not influenced by walking speed between 2.7 and 4.5 km/h. Except the
      time of production of the vertical force of propulsion (Tz3), the variability of
      temporal vertical parameters decreased significantly with speed between 2.7 and
      4.5 km/h and the variability of temporal antero-posterior parameters decreased
      significantly between 2.7 and 3.6 km/h. DISCUSSION-CONCLUSION: The variability of
      the GRF and spatio-temporal parameters in children was influenced by age between
      4 and 8 years old and by speed between 2.7 and 3.6 km/h. Moreover, the effect of
      age on the GRF persists up to 8 years. The variabilities of the time of
      production of the antero-posterior force of propulsion (Ty2) and stance duration
      were lower than the variabilities of the others parameters. These two variables
      could be the most reliable parameters when assessing gait in children aged 4-10
      years, walking at speeds between 2.7 and 4.5 km/h.

PMID- 15013602
TI  - [Epidemiology of pes varus and/or equinus one year after a first cerebral
      hemisphere stroke: apropos of a cohort of 86 patients].
AB  - OBJECTIVE: To determine the frequency and the functional consequences of varus
      equinus in stabilized vascular hemiplegia. METHODS: Prospective cohort study of
      86 hemiplegic patients. All patients consecutively admitted for a first
      hemispheral stroke between July 2001 and January 2002 were included. The
      evaluation consisted in a clinical examination and a descriptive study of gait.
      The functional capacity of patients with and without varus equinus were compared
      using the Barthel index, the New Functional Ambulation Classification (NFAC), the
      confortable ten meters gait speed and gait perimeter. RESULTS: The incidence of
      varus equinus was 18%. There was no difference in gait speed (0.8 m/s), NFAC or
      Barthel index between patients with or without varus equinus. Patients with varus
      equinus had had more specialized, intensive and prolonged rehabilitation. The
      only prognostic factor that could be identified was the motor impairment and the
      existence of spasticity. DISCUSSION: The mechanism of varus equinus is thought to
      be mainly the over-activity of gastrocnemius and solaris compared to that of the
      tibialis anterior, associated to the weakness of fibular muscles. The role of
      tibialis posterior is thought to be less important. The frequency of varus
      equinus after a first hemispheral stroke was low and the consequences were
      limited. This could be in part explained by the access of these patients to
      early, specialized and prolonged rehabilitation care.

PMID- 15013603
TI  - [The equino-varus foot deformity in patients with hemiplegia].

PMID- 15013604
TI  - Management of bilateral choanal atresia in the neonate: an institutional review.
AB  - The endoscopic repair of bilateral choanal atresia using powered instrumentation
      has become a common procedure performed by many pediatric otolaryngologists. A 10
      year retrospective review of the management of bilateral choanal atresia in the
      neonate was undertaken at the Hospital for Sick Children, a tertiary care
      pediatric institution in Toronto. Although many techniques were used for repair
      including the endoscopic technique, a simple puncture, dilation and stenting
      technique was used most frequently. Fifty-two patients were identified who
      underwent this technique. The modifications and refinements of this technique and
      post-operative care will be detailed. The results were as follows. All patients
      were successfully extubated within 24h of the operation. The average duration of
      nasal stenting was 3 months. Three patients required re-stenting, one of which
      had nasal stenting for the first year of life. This patient was born prematurely,
      had trisomy-21 and was stented weighing a mere 600g. One patient had a small
      septal perforation and only two patients required transpalatal repair later in
      life for persistent nasal symptoms. There were no CNS complications and no
      incidence of significant nasal hemorrhage or infection. All patients received
      topical antibiotics and steroid drops during the stenting period. Mitomycin C was
      not used. Granulation tissue was not a significant problem. Despite the advances
      in endoscopic technology, the puncture, dilation and stenting technique is still
      the senior author's preferred method of repair for neonatal bilateral choanal
      atresia.

PMID- 15013605
TI  - The prevalence of vocal fold nodules in school age children.
AB  - OBJECTIVES: To explore the actual prevalence of vocal nodules among school age
      children. METHODS: A total of 617 children aged from 7 to 16 years were examined.
      Their voices were recorded and analyzed by using acoustic analysis techniques,
      and vocal folds were examined by using rigid telescopic laryngoscope. The
      findings were noted as normal, minimal lesion, immature and mature nodules.
      RESULTS: Laryngoscopic examination revealed that 430 (69.7%) of the children were
      normal. Of the remaining 187 children, 82 (13.3%) had minimal lesion, 88 (14.3%)
      immature nodule, 16 (2.6%) mature nodule and 1 (0.2%) vocal polyp. Comparisons of
      acoustic parameters revealed that there were no statistically significant
      differences between normal and minimal lesion groups, and between immature and
      mature nodule groups. Actual vocal nodule ratios which include both immature and
      mature nodule groups among whole school children were found to be 21.6% in males
      and 11.7% in females.

PMID- 15013606
TI  - Is cidofovir a useful adjunctive therapy for recurrent respiratory papillomatosis
      in children?
AB  - OBJECTIVE: To assess the usefulness of cidofovir in treating recurrent
      respiratory papillomatosis in children. Cidofovir is an acyclic nucleoside
      phosphonate that has been reported to be effective in the treatment of
      respiratory papillomatosis in several small series of patients. METHODS: A
      prospective study was conducted in 11 children (mean, 2.1 years; range, 0.5-3
      years at diagnosis) with recurrent respiratory papillomatosis who at the start of
      the study were requiring debridement of papillomas at least every 6 weeks. After
      microlaryngoscopy with powered microdebridement of papillomas patients received
      intralesional injection of cidofovir (5mg/ml). The severity of papillomatosis was
      rated at each visit using a standardized papilloma severity scoring system. The
      success of therapy was measured by the trend in the patient's papilloma severity
      scores before and after cidofovir therapy and by whether the frequency of
      operative interventions decreased in the period after treatment began. RESULTS:
      Three patients had impressive improvements in severity scores and a decrease in
      the frequency of required operative interventions after cidofovir, two patients
      had a partial response, and for six patients cidofovir was considered
      ineffective. CONCLUSIONS: Intralesional cidofovir did not decrease the severity
      or frequency of operative intervention for recurrent respiratory papillomas in
      the majority of children in this study. The drug did improve papillomatosis in
      the minority of patients without causing notable morbidity. A large multi
      institutional controlled study is needed to better assess the efficacy of this
      treatment.

PMID- 15013607
TI  - Effects of tonsillectomy and adenoidectomy on hemoglobin and iron metabolism.
AB  - OBJECTIVES: To investigate a possible effect of adenoidectomy, tonsillectomy, or
      both operations combined in children on hemoglobin concentration and iron
      metabolism. METHODS: Children eligible for surgery due to recurrent tonsillitis
      or upper airway obstruction had a venous blood sample drawn at the time of the
      operation and 6 months later. One hundred and three preoperative and 91 blood
      samples at follow-up from patients not given iron supplementation were available
      for analysis of hemoglobin concentration, serum-ferritin and protoporphyrin-IX in
      erythrocytes. RESULTS: A 1.4g/dl median increase in hemoglobin concentration
      during the observation period was associated with a significant reduction of
      protoporphyrin-IX, while serum-ferritin remained unchanged and low. A
      preoperative prevalence of anemia of 56.3% was reduced to 7.71%. All combinations
      of normal and pathological values of serum-ferritin and protoporphyrin-IX were
      found in anemic and non-anemic patients. CONCLUSIONS: A beneficial effect of
      tonsillectomy and adenoidectomy on hemoglobin and iron metabolism was
      demonstrated. Iron deficiency was common.

PMID- 15013608
TI  - Cochlear implantation in children under the age of two--what do the outcomes show
      us?
AB  - OBJECTIVES: Literature that discusses the benefits of cochlear implantation (CI)
      in children under the age of two is limited. Previous concerns about surgical
      risk have been raised and addressed; however, actual benefit in terms of outcomes
      needs to be clearly defined. This study evaluates outcomes of children implanted
      under the age of two and compares them to children implanted at a later age.
      METHODS: Data were reviewed from the MED-EL International Children's study
      database. Thirty-seven children enrolled in the study have received cochlear
      implants before the age of two. Outcomes were assessed using the LiP and MTP
      tests and the MAIS and MUSS questionnaires pre-operatively and then at initial
      fitting, 1, 3, 6 and 12 months after first fitting and then annually thereafter.
      RESULTS: Statistical analysis demonstrated that these children's scores improved
      significantly over time. Improvement was shown to occur at a quicker rate than
      for children implanted at an older age with the MTP and MUSS, but not with the
      LiP and the MAIS. Scores may be limited by sample size and the fact that children
      reached ceiling on some tests. CONCLUSIONS: Results suggest a distinct advantage
      early implantation may have for severe to profoundly hearing impaired children.
      This may be particularly the case for skills necessary for development of
      receptive and expressive language skills.

PMID- 15013609
TI  - Cotton-tip applicators as a leading cause of otitis externa.
AB  - OBJECTIVE: Otitis externa (OE), also known as "swimmer's ear", is an inflammation
      or infection of the external auditory canal. Many risk factors have been
      identified, mainly excessive moisture in the canal from swimming. STUDY
      DESIGN/METHODS: To study the leading risk factors of otitis externa. Eighty-seven
      children aged 3.5-12 years (mean 68+/-6.5 months) who were diagnosed with otitis
      externa from December 1999 to March 2001 were studied for age, sex, cerumen
      cleaning habits, signs and symptoms. Findings were compared to an age-matched
      control group of 90 children without otitis externa. RESULTS: Sixty-one children
      (70.1%) in the study group had their ears cleaned with a cotton-tip applicator (Q
      tip) during the 10 days preceding the diagnosis of otitis externa. In the control
      group, only 31 (34%) used applicators routinely during the 10 days prior to
      diagnosis (P<0.001). Other risk factors for otitis externa were swimming in a
      pool (34%), wax removal (5.8%) and ventilation tubes (1.1%). CONCLUSIONS: Use of
      a cotton-tip applicator to clean the ear seems to be the leading cause of otitis
      externa in children and should be avoided.

PMID- 15013610
TI  - Effect of middle ear effusion on distortion product otoacoustic emission.
AB  - OBJECTIVES: It is well documented that children, particularly between the ages of
      about 2 and 6 years, exhibit a high prevalence and incidence of otitis media.
      Distortion product otoacoustic emissions (DPOAEs) offer great potential for
      clinical testing of cochlear function in children. The aim of the present study
      was to determine the influence of middle ear effusion and physical properties of
      the effusion on the recording of DPOAE. METHODS: Nineteen children (38 ears)
      undergoing myringotomy and/or tympanostomy tube insertion for secretory otitis
      media were studied. Pre-operative and post-operative first day DPOAE signal to
      noise ratios were compared. The results were analyzed by paired samples test and
      ANOVA statistical methods. RESULTS: We were found significant differences between
      pre-operative and post-operative first day DPOAE signal to noise at 1, 1.5, 2 and
      4kHz. In addition, comparison of the pre-operative DPOAE signal to noise ratio
      and per-operative middle ear findings are shown significant differences between
      glue (thick mucous) and the other three groups (mucous, serous and no-effusion
      groups) at 2 and 4kHz, and between glue and no effusion group at 8kHz. Also post
      operative DPOAE signal to noise ratio in relation to per-operative middle ear
      findings were significantly different at 2, 4 and 8kHz. The most increase of
      emissions at the post-operative first day was seen in ears with glue effusion at
      1 and 2kHz. CONCLUSIONS: Otitis media with effusion can be monitored by DPOAE
      measurement pre-operatively and post-operatively. In the pre-operative
      evaluation, glue effusion may cause a reduction in the emissions at 2, 4 and 8kHz
      more than the other kind effusions.

PMID- 15013611
TI  - Improvement of bruxism after T & A surgery.
AB  - Bruxism or tooth grinding is an oral habit that frequently occurs during sleep.
      Some authors suggest it is associated to sleep apnea. OBJECTIVES: The main goal
      of this study is compare the incidence of bruxism before and after
      adenotonsillectomy (T & A surgery) in children with sleep-disordered breathing.
      METHODS: This is a prospective study in which we evaluated 69 consecutive
      children from the Otolaryngology Department of the University of Sao Paulo
      Medical School in pre- and post-surgical periods of adenotonsillectomy. Before
      and after surgery parents answered a questionnaire about sleep-disturbed
      breathing and bruxism. Children were submitted to E.N.T. examination and speech
      pathologist evaluation. The orthodontist inspected malocclusion. Before surgery
      all the 69 children presented sleep apnea and 45.6% presented bruxism.
      Malocclusion could be found in 60.71%. Three months after surgery none of the
      children presented breathing problems and only 11.8% presented bruxism. There was
      no difference in malocclusion. CONCLUSIONS: This study suggests that there is a
      positive correlation between sleep-disordered breathing and bruxism. There was an
      important improvement of bruxism after T & A surgery. Otolaryngologists must be
      aware that this pernicious sleep disorder is associated to airway obstruction and
      so, it must be considered when evaluating T & A hyperplasia.

PMID- 15013612
TI  - Effect of adenoidectomy in children with complex problems of rhinosinusitis and
      associated diseases.
AB  - OBJECTIVES: The effectiveness of adenoidectomy in the management of pediatric
      sinusitis is still a controversial issue. The size of the adenoid and associated
      diseases are the factors for consideration. The adenoid has been studied and is
      proved to be a probable source of infection for the paranasal sinus. The purpose
      of this study is to evaluate the efficacy of adenoidectomy in reducing the
      frequency of sinusitis in children. METHODS: A prospective study was done in
      pediatric patients with rhinosinusitis admitted for adenoidectomy from January
      2000 to January 2002. Pre-operative frequency of rhinosinusitis, underlying
      diseases and the diseases caused by the adenoid were recorded. The adenoid size
      was evaluated by lateral skull X-ray. The patients were followed after surgery
      and frequency of rhinosinusitis and associated diseases were compared with the
      pre-operative period. RESULTS: There were 37 patients with mean age of 6+/-2.8
      years. Mean duration for pre-operative review was 436.7 days and mean duration
      for post-operative follow up was 450.2 days. Almost all (92%) of the patients had
      obstructive sleep disorder and 88.2% had adenoid-nasopharyngeal ratio >0.7. There
      was a statistically significant reduction of episodes per year of rhinosinusitis
      and obstructive sleep disorder after surgery (P-value < 0.001 and 0.008,
      respectively). CONCLUSIONS: Adenoidectomy was proved to be effective in the
      management of pediatric rhinosinusitis in this series. Adenoidectomy should be
      most beneficial as a surgical option before endoscopic sinus surgery (ESS),
      especially in younger children with obstructive symptoms.

PMID- 15013613
TI  - A comparison of nebulized budesonide, and intramuscular, and oral dexamethasone
      for treatment of croup.
AB  - OBJECTIVES: Croup or acute laryngotracheobronchitis is the most common cause of
      the upper airway obstruction. Cool mist, nebulized racemic epinephrine and
      steroids are commonly used for therapy. Although steroid treatment can be applied
      orally, in nebulized form, or parenterally, no study has compared these three
      regimens yet. In this study, the efficacy of nebulized budesonide, and oral and
      intramuscular dexamethasone are compared for treatment of croup. STUDY DESIGN:
      Sixty children aged 6-36 months were randomly allocated into four groups. The
      first three study groups (15 children in each) took nebulized budesonide, oral
      dexamethasone and intramuscular dexamethasone, respectively, in addition to
      salbutamol and other supportive measures and these were compared with the placebo
      group. All patients were evaluated with "Westley Croup Score" on admission to
      pediatric emergency department (0h) and at 24, 48 and 72h. RESULTS: At the end of
      the study, the croup scores of all steroid treatment groups were significantly
      lower than the placebo group, but there was no statistical difference among them.
      CONCLUSIONS: Nebulized budesonide, oral and parenteral dexamethasone have the
      same effectiveness for treatment of croup and the choice depends on conditions of
      the patient and the physician.

PMID- 15013614
TI  - Audiological performance after cochlear implantation in children with inner ear
      malformations.
AB  - OBJECTIVES: To prove that cochlear implantation is a beneficial method of
      rehabilitation in deaf children with malformations of the inner ear. DESIGN: The
      evaluation of auditory responses to speech (EARS) test battery was performed on
      the children in this study after an average implant use of 3 years. RESULTS:
      Individual results of six children with inner ear anomalies receiving cochlear
      implants are presented in this study. Three of the patients showed an incomplete
      partition (Mondini dysplasia), one had a cochlear hypoplasia and two suffered
      from an intraoperative cerebrospinal fluid leak. The majority of the children in
      this study are successful implant users. Wherever possible, test scores are
      included and subjective case reports given. CONCLUSIONS: Results are similar to
      those in children with normal cochleas, therefore inner ear malformations found
      in as many as 20% of patients with congenital sensorineural hearing loss are no
      contraindication for cochlear implantation. Nevertheless, factors influencing the
      success of implantation are multiple, including a thorough preoperative
      radiological examination, a well-performed surgery and an individually tailored
      postoperative rehabilitation programme.

PMID- 15013615
TI  - Multiple airway abnormalities in a patient with Rothmund-Thomson syndrome.
AB  - Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder that is
      characterized by skin manifestations, juvenile cataracts, and extracutaneous
      manifestations. The presence of congenital airway abnormalities has not
      previously been documented in Rothmund-Thomson syndrome. We report the case of a
      child with Rothmund-Thomson syndrome suffering from multiple airway
      abnormalities. Our case highlights the importance of suspecting multiple airway
      abnormalities in any child with respiratory distress with other systemic
      anomalies. This necessitates meticulous anatomical and dynamic examination of the
      laryngotracheo-broncheal tree.

PMID- 15013616
TI  - Button batteries in the ear, nose and upper aerodigestive tract.
AB  - OBJECTIVES: With the miniaturization of electronic devices, the demand and usage
      of button batteries has risen. As a result, button batteries are more readily
      available for young children to handle and potentially mishandle. They are
      frequently inadvertently placed by children in their ears or noses. Occasionally
      they are swallowed and lodged along the upper aerodigestive tract. METHODS: We
      outline the pathophysiology of button battery-induced trauma and present key
      radiological features of button batteries that are important in preventing
      delayed diagnosis after pediatric ingestion. RESULTS: Button batteries of all
      sizes have a distinctive double contour on radiographs. CONCLUSIONS: Button
      battery ingestion requires prompt diagnosis and removal. A high index of
      suspicion along with radiographs help assist with the diagnosis. Potential tragic
      complications can be averted with expeditious removal.

PMID- 15013617
TI  - A paediatric case of a solitary fibrous tumour of the parotid gland.
AB  - Solitary fibrous tumours are rare and they were first described in the pleura of
      the lungs. However this rare tumour is being increasingly recognised in the oro
      facial region and other extra-pleural sites among adults. We present a paediatric
      case of a solitary fibrous tumour of the parotid gland in an 11-year-old girl who
      was also diagnosed as having type I neurofibromatosis.

PMID- 15013618
TI  - Endoscope assisted removal of cementoossifying fibroma in the paranasal sinuses
      in a five-year-old girl.
AB  - We report a five-year-old girl with a sinonasal cementoossifying fibroma with CT
      findings that reveal the invasion of all paranasal sinuses and the remodeling of
      facial bones. It was possibly a congenital lesion and caused a slowly progressive
      nasal obstruction and anosmia. Tumor removal with transnasal endoscopic approach
      was applied and total removal of the mass was accomplished. It was found out to
      be the cementoossifying fibroma of the paranasal sinuses when the results of the
      pathological examinations were obtained.

PMID- 15013619
TI  - Apert syndrome and hearing loss with ear anomalies: a case report and literature
      review.
AB  - Acrocephalosyndactyly Type I, or Apert syndrome is a congenital disorder
      characterized by craniosynostosis and syndactyly. When hearing loss occurs, it is
      usually bilateral and conductive, often attributable to congenital stapes
      fixation. In determining treatment, the risk of gusher with stapedectomy becomes
      an important consideration. We present an adult with Apert syndrome and hearing
      loss, with particular emphasis on a progressive conductive component in one ear.
      Surgical exploration failed to reveal any definite middle ear abnormality and no
      stapedectomy was performed. A theory on the pathogenesis of the conductive loss
      in our patient follows a brief review of the literature on gusher in patients
      with ear malformations.

PMID- 15013620
TI  - Proboscis lateralis: a report of two cases.
AB  - Proboscis Lateralis (PL) is one of the congenital anomalies of the nose which
      presents as obvious deformity. This is a report of two cases of the rare anomaly
      PL. One presented with right PL and the second presented with left PL. In this
      rare anomaly, the nasal cavity on one side is completely normal while on the
      affected side, the nasal cavity is replaced by a tube of skin and soft tissue
      attached to the inner canthus of the eye. This anomaly occurs sporadic as an
      isolated defect or in association with other anomalies. It is usually associated
      with failure of the paranasal sinuses and the nasolacrimal duct development.
      Embryologically, this anomaly is a result of imperfect fusion of the lateral
      nasal wall and maxillary processes (Int. J. Pediatr. Otorhinolaryngol. 23 (1992)
      275).

PMID- 15013621
TI  - Isolated sphenoid sinusitis presenting with unilateral VIth nerve palsy.
AB  - Isolated sphenoid sinusitis is a rare disorder. There are some difficulties in
      its diagnosis and the first presentation of this disorder might be with
      complications. These complications are essentially due to the anatomical location
      of the sinus and its proximity to the intra-cranial and orbital contents, to
      which infection may easily spread. In this paper, we report a case of isolated
      sphenoid sinusitis in a 12-year-old girl who was presented with unilateral VIth
      nerve palsy. She was initially treated with parenteral antibiotherapy, the
      abducens nerve palsy recovered but as sphenoiditis persisted she underwent an
      endoscopic sphenoidotomy. We discuss the clinical features, the diagnostic tools,
      and the treatment options for this entity.

PMID- 15013622
TI  - Giant hamartoma of the retro- and parapharyngeal region. Case report and review
      of literature.
AB  - Hamartoma designates a tumor-like, non-neoplastic malformation, or in-born error
      of tissue development, often with an abnormal mixture of tissue indigenous to the
      region. In the head and neck, epithelial and mesenchymal hamartomas are uncommon.
      We present the case of a 9-year-old boy with a huge hamartoma of 800ml (cm(3))
      volume of the right retro- and parapharyngeal region. It had fully occluded the
      nasopharynx, indented the base of the tongue and left a minimal airway passage
      transorally. Food uptake was severely hampered by the lesion. The patient
      underwent a combined transoral and external approach for complete resection of
      the tumor. This is the first reported case of a retro- and parapharyngeal
      hamartoma with metaplastic bone formation in the literature and further more, the
      largest hamartoma in head and neck ever reported in this age group.

PMID- 15013623
TI  - Immuno-characterization of the switch of peptide elongation factors eEF1A-1/EF
      1alpha and eEF1A-2/S1 in the central nervous system during mouse development.
AB  - During early postnatal development, a switch occurs between eEF1A-1/EF-1alpha and
      eEF1A-2/S1, homologous peptide elongation factors, in brain, heart, and skeletal
      muscle; eEF1A-2/S1 becomes the major form expressed in maturity. By
      immunofluorescent labeling, we detected both homologues in the developing brains
      of wild-type and wasted mutant mice, carrying a deletion in the eEF1A-2/S1 gene;
      we found that brain expression of eEF1A-2/S1 protein is restricted to mature,
      terminally differentiated neurons, and coincides with the disappearance of eEF1A
      1/EF-1alpha 20 days after birth. Furthermore, no elongation factor 1A is present
      in wasted mutant mice neurons following the developmental switch, indicating that
      the genetic regulation silencing eEF1A-1/EF-1alpha is still functional.

PMID- 15013624
TI  - Mu and delta opioid receptor immunoreactivity and mu receptor regulation in
      brainstem cells cultured from late fetal and early postnatal rats.
AB  - Cultured cells from the rat brainstem were used to study opioid receptor (OpR)
      expression during late fetal and early postnatal development. Mu and delta opioid
      receptor (MOR and DOR) expression was investigated from embryonic day 16 (E16) to
      6 days postnatal (P6). Postnatal neurons showed more intense MOR immunoreactivity
      (IR) than neurons cultured from fetal brainstem (P < 0.006). DOR IR showed a
      similar pattern, but the differences between fetal and neonatal animals were not
      statistically significant. Using confocal microscopy, MOR and DOR IR were shown
      to be present on both the cell membrane and within the cytoplasm, in a similar
      pattern to the IR seen in SH-SY5Y neuroblastoma cells that endogenously express
      both MOR and DOR. Double-labeling experiments demonstrated colocalization of MOR
      and DOR in the same brainstem neurons; however, not all MOR IR regions of a
      single neuron were also positively stained for DOR, and not all DOR IR regions
      were also positive for MOR. MOR was down-regulated after a 1- or 2-h treatment
      with 1 microM DAMGO, a potent mu opioid agonist, in both non-transfected and MOR
      transfected SH-SY5Y cells and in primary cell cultures. It was concluded that
      many brainstem neurons express functional MOR or DOR or coexpress both receptors,
      although intracellular distributions of the receptors are unique for each
      receptor type.

PMID- 15013625
TI  - Very mild stress of pregnant rats reduces volume and cell number in nucleus
      accumbens of adult offspring: some parallels to schizophrenia.
AB  - Pregnant rats subjected to very mild stress give birth to pups who, when examined
      as adults, exhibited behavioral and anatomical anomalies that resemble some
      aspects of schizophrenia. The nucleus accumbens (NAcc) is reduced in volume by
      20.7 +/- 3.4% (p = 0.003) in pups born to mothers who were stressed during
      pregnancy by injections of either saline or amphetamine in saline. The total
      number of cells is decreased in proportion to the reduction in volume, so the
      volume cell density of the NAcc is not changed with treatment. The affected
      volume is localized in the ventral rostral area of the NAcc. Both males and
      females are affected, but males are slightly more sensitive to the challenge to
      the mother. Rats born to mothers stressed in mid-pregnancy appear to provide
      useful parallels to the fetal developmental hypothesis of schizophrenia and to
      the brain abnormalities seen in this disease.

PMID- 15013626
TI  - Requirement for enzymatically active lipoprotein lipase in neuronal
      differentiation: a site-directed mutagenesis study.
AB  - Lipoprotein lipase (LPL) is well known for its role in the catabolism of plasma
      triglyceride (Tg)-rich lipoproteins, such as very low density lipoproteins (VLDL)
      and chylomicrons. The action of LPL on Tg-rich lipoproteins provides free fatty
      acids to skeletal muscle and adipose tissues, the main sites of LPL synthesis.
      Several studies have demonstrated that LPL is widely expressed in the parenchyma
      of brain tissues. We have recently shown that LPL expression is essential for
      promoting VLDL-stimulated differentiation of Neuro-2A cells. In the present
      study, we have generated stably transfected Neuro-2A cell lines expressing either
      wild-type LPL or various LPL mutants, including three enzymatically inactive
      variants (Asp156Asn, Gly188Glu and Pro207Leu), an enzymatically defective variant
      (Asn291Ser) and a variant known to express increased LPL activity (Ser447Ter). In
      Neuro-2A cells expressing enzymatically inactive LPL variants, VLDL-stimulated
      differentiation and neurite extension were not observed. However, in Neuro-2A
      cells expressing partially active or overactive LPL variants, VLDL added to the
      cultured medium was able to induce the phenotypic differentiation similar to that
      observed in Neuro-2A cells expressing wild-type LPL. In summary, these data show
      that the availability of fatty acids, resulting from the catabolism of VLDL by
      LPL, is required to promote the phenotypical differentiation of neuroblastoma
      cells. These findings may have significant relevance to lipoprotein metabolism in
      the brain as well as to the maturation and regeneration of nervous tissues in
      carriers of mutant LPL.

PMID- 15013627
TI  - Developmental regulation of 5-HT1A receptor mRNA in the fetal limbic system:
      response to antenatal glucocorticoid.
AB  - The developmental changes in 5-HT1A receptor mRNA expression associated with
      advancing gestational age were examined in the fetal guinea pig hippocampus and
      dentate gyrus (DG) by in situ hybridization. We found that 5-HT1A receptor mRNA
      was present in the hippocampal CA1 subfield and dentate gyrus (DG), and was
      significantly (P < 0.05) elevated in the DG during the period of rapid brain
      growth [gestational day (gd) 50; term = 70 days]. Glucocorticoids have been shown
      to alter 5-HT1A receptor mRNA expression in the adult, but nothing is known about
      their impact on the developing fetal brain. Expression of 5-HT1A receptor mRNA in
      the fetal hippocampus was measured following repeated maternal administration
      (gd40, 41, 50, 51, 60 and 61) of synthetic glucocorticoid (dexamethasone; 1 and
      10 mg/kg). Levels of 5-HT1A receptor mRNA were significantly (P < 0.005) elevated
      in CA1 and DG following repeated exposure to high-dose glucocorticoid (10 mg/kg)
      in male, but not in female fetuses. Because fetal exposure to glucocorticoids
      programs hypothalamo-pituitary-adrenal (HPA) function, and hippocampal serotonin
      is known to influence glucocorticoid receptor (GR) expression, the glucocorticoid
      mediated changes in 5-HT1A receptor mRNA may play a role in the programming of
      HPA function.

PMID- 15013628
TI  - Age-dependent emergence of a parieto-insular corticocortical signal flow in
      developing rats.
AB  - By using the procedure that we developed for inducing population oscillation, it
      was previously demonstrated that insular cortex stimulation can evoke insulo
      parietal field potential propagation and synchronized population oscillation in
      the parietal cortex in slices obtained from mature rats (27-35 days old). By
      using the same procedure, we have now studied the reciprocal parieto-insular
      projection. Parietal cortex stimulation elicited synchronized population
      oscillation in the parietal--but not insular--cortex in mature tissues. In the
      insular cortex, the initial wavelet of the oscillation generated by parietal
      cortex stimulation propagated, but the entire oscillation did not. A prior
      induction--but not simultaneous occurrence--of oscillation in the parietal cortex
      sufficed to have this initial wavelet propagate. In immature tissue (9-10 days
      old), both the parietal cortex oscillation and the parieto-insular propagation
      were induced only with low [Mg2+]o. This age dependence is exactly the same as we
      previously observed for the reciprocal insulo-parietal propagation. Given that
      the parietal cortex receives somatosensory inputs from the oral cavity and the
      insular cortex receives primarily chemosensory inputs from the same source, the
      age-dependent changes in the availability of bidirectional signal traffic between
      these cortices might contribute to the development of multimodal responsiveness
      of taste neurons.

PMID- 15013630
TI  - Expression of the chemokine receptor Cxcr4 mRNA during mouse brain development.
AB  - The expression of Cxcr4 mRNA that encodes the receptor for the chemokine Sdf1 was
      studied during mouse brain development using in situ hybridization, from E9.5 to
      maturity at P21. At embryonic stages, expression is prominent in ventricular
      zones of stem cell proliferation. This abates during the postnatal period in
      parallel to the depopulation of ventricular zones. In addition, the Cxcr4 gene is
      expressed in some differentiating neuronal populations at E12.5, E14.5 and E17.5,
      such as scattered cells in the reticular formation, cranial nerve nuclei,
      peripheral ganglia, cerebellar external granule cells, zona incerta, ventral
      lateral geniculate thalamic nuclei, olfactory glomerular layer, hippocampal
      primordium and telencephalic preplate. High levels of expression are detected in
      preplate derivatives in all sectors of the marginal zone (MZ) of the
      telencephalic vesicles, including Cajal-Retzius (CR) cells, other MZ cells and
      subplate neurons. Cxcr4 expression is progressively downregulated postnatally,
      but remains significantly associated in the adult with Bergman glia in the
      cerebellum, the subgranular layer of the dentate gyrus, and the olfactory
      glomerular layer. In contrast, expression of Sdf1 mRNA is confined to the
      meninges and, in embryos, to the telencephalic intermediate zone. This expression
      pattern suggests that Sdf1 and its receptor Cxcr4 may exert trophic influences on
      precursor cell proliferation and some neuronal targets that remain to be
      identified and studied further.

PMID- 15013629
TI  - Methylmercury inhibits TrkA signaling through the ERK1/2 cascade after NGF
      stimulation of PC12 cells.
AB  - Using PC12 cells as a model of neuronal differentiation, we have shown that acute
      exposure to methylmercury (CH3Hg) inhibits nerve growth factor (NGF)-induced
      activation of TrkA. In the present study, we examined the effects of CH3Hg on
      pathways activated by NGF. NGF-induced phosphorylation of ERK1/2 in PC12 cells
      was time-dependent. Concurrent exposure to CH3Hg and NGF for 2.5 min resulted in
      a concentration-dependent inhibition of ERK1/2 phosphorylation (EC50 = 0.018
      microM). However, NGF-stimulated ERK1/2 phosphorylation was not altered after 5
      min of exposure to CH3Hg. In vitro studies revealed that CH3Hg did not directly
      inhibit the ERK kinase MEK. As reported in other neuronal tissue, CH3Hg can
      inhibit PKC activity in vitro. Incubation of PC12 cell lysates with CH3Hg
      produced a concentration-dependent inhibition of PKC activity that was
      significant at 0.3-10 microM. Further studies using recombinant enzymes examined
      the effect of CH3Hg on PKC isoforms expressed in PC12 cells. CH3Hg inhibited
      PKCdelta, and zeta activity in a concentration-dependent manner at higher
      concentrations (3-10 microM), while a significant increase in PKCalpha activity
      was observed at lower concentrations (0.1 microM). However, CH3Hg had no affect
      on NGF-induced PKC activity in intact cells. These results show that CH3Hg
      inhibition of NGF-stimulated TrkA activation in PC12 cells decreases downstream
      signaling through the Raf/MEK/ERK cascade. In intact cells PKC does not appear to
      be a primary target for CH3Hg.

PMID- 15013631
TI  - The GABA(B) receptor subunits R1 and R2 interact differentially with the
      activation transcription factor ATF4 in mouse brain during the postnatal
      development.
AB  - Gamma-aminobutyric acid type B receptors (GABA(B)R) belong to the family of G
      protein-coupled receptors that mediate synaptic actions by modulation of
      different ion channels. Here, we demonstrate that the receptor subunits GABA(B)R1
      and GABA(B)R2 interact directly with the soluble activating transcription factor
      4 (ATF4) in different regions of the neonatal mouse brain. We found that about 5
      12% of expressed ATF4 protein is involved in the complex formation with GABA(B)
      receptors. Confocal fluorescence microscopy showed that GABA(B)R and ATF4 are co
      localized in several well-defined spots in neurons and in glial cells. Co
      immunoprecipitation analysis also reveals that the interaction efficiency between
      GABA(B) receptors and ATF4 in the mouse brain markedly changed during postnatal
      development, and such changes in interaction were dependent on the GABA(B)
      receptor subtype.

PMID- 15013632
TI  - Postnatal development of the noradrenergic system in the dorsal lateral
      geniculate nucleus of the rat.
AB  - The noradrenergic innervation of the developing dorsal lateral geniculate nucleus
      of the rat was examined with light and electron microscopic immunocytochemistry.
      At birth, few, relatively thick, noradrenergic fibers innervated the nucleus.
      Their density was steadily increased and they became thinner, tortuous, and
      varicose with the progression of age. Only a minority (11-15%) of labeled
      varicosities made synaptic contacts. Most of these synapses were symmetrical and
      on dendritic shafts. The present findings demonstrate the establishment of the
      anatomical relationships between noradrenergic afferents and neurons of the
      dorsal lateral geniculate nucleus during development and may help to understand
      the role of noradrenaline in the processing of visual information.

PMID- 15013633
TI  - The immunological paradox of pregnancy: a reappraisal.
AB  - The survival of the allogeneic conceptus has long been an immunological paradox.
      Medawar was the first to propose an evasive mechanism based on the concept of
      self/non-self recognition described in classical transplantation immunology.
      Since then, several newer models of self/non-self recognition have been proposed,
      such as the PAMP/PRR system, the Missing Self and the Danger Hypothesis. The
      present paper considers the fetal-maternal relationship in the context of all
      these models. The conclusion reached is that none of them is really appropriate
      because the interface between trophoblast cells of the fetal placenta and the
      leukocytes of the maternal decidua is unique. Pregnancy is not simply a case of
      acceptance or rejection like a transplant. The immunological mechanism must
      provide a balanced environment whereby the conceptus is nurtured by the mother
      and yet prevented from excessive invasion. Future identification of trophoblast
      ligands and their respective receptors on uterine Natural Killer cells and other
      leukocytes is likely to offer the best insight as to how this symbiotic state is
      achieved.

PMID- 15013635
TI  - Differential expression of the nm23 genes in the developing human trophoblast.
AB  - NDP kinases are the non-specific enzymes which catalyse the synthesis of the NTPs
      through a transfer reaction using ATP as phosphoryl donor. In addition to their
      enzymatic activity, they display other not yet explained functions related to
      cell growth, differentiation and apoptosis, embryonic development, tumour
      progression and metastasis. In this study, the expression patterns of the three
      highly related NDP kinases A, B and C isoforms were investigated in the
      developing human trophoblast. Both NDP kinase A and B were found to be primarily
      present in the villous and extravillous cytotrophoblasts, while NDP kinase C was
      found almost exclusively in the syncytiotrophoblast layer. This suggests that NDP
      kinase A and B could be a marker for the mononuclear stage of differentiation of
      villous trophoblasts, while NDP kinase C could be a marker of the
      syncytiotrophoblast layer.

PMID- 15013634
TI  - Transcriptional control of the human pregnancy-specific glycoprotein 5 gene is
      dependent on two GT-boxes recognized by the ubiquitous specificity protein 1
      (Sp1) transcription factor.
AB  - Pregnancy-specific glycoprotein 5 gene (PSG-5) belongs to the human pregnancy
      specific glycoprotein family, encoded by eleven highly similar and
      transcriptionally active genes. High levels of PSG biosynthesis are restricted to
      the placenta syncytiotrophoblast and are essential for the maintenance of normal
      gestation in mammalian species. We have investigated here the nature of the
      transcription factors that recognize the FP1 (-455/-433) and the CPE (-147/-140)
      regulatory sequences that significantly contribute to basal PSG-5 promoter
      activity. Both elements bear a similar GT-box motif; and DNA-protein complex
      formation, as well as promoter activity, is largely dependent on the integrity of
      these GT-box sequences. Gel shift, super gel shift and UV-crosslinking
      experiments clearly demonstrate that the ubiquitous specificity protein 1 (Sp1)
      is the major transcription factor involved in complex formation with both cis
      acting elements in normal term placenta tissue and in PSG-non-expressing COS-7
      cells. Furthermore, transfection experiments indicate that Sp1 activates PSG-5
      promoter constructs. In addition, we show that Sp1 is indeed co-expressed with
      PSG genes in the syncytiotrophoblast cells, stressing its potential role in the
      in vivo regulation of PSG expression.

PMID- 15013636
TI  - Differentiation of placental trophoblast giant cells requires downregulation of
      p53 and Rb.
AB  - Trophoblast giant cells in the rodent placenta form the outermost layer of the
      extraembryonic compartment, establish direct contact with maternal cells, and
      produce a number of pregnancy-specific cytokine hormones. Giant cells
      differentiate from proliferative trophoblasts as they exit the cell cycle and
      enter a genome-amplifying endocycle, a process we show involves decreased
      expression of the G1 checkpoint proteins p53 and Rb. Although p53 mRNA levels are
      unchanged in proliferative compared to differentiated trophoblasts, p53 protein
      levels are markedly reduced in giant cells. Forced expression of wild type p53 in
      trophoblasts inhibits differentiation, and expression of a dominant negative p53
      peptide stimulates differentiation. Consistent with the loss of p53 protein,
      differentiated trophoblasts become resistant to apoptosis-inducing agents.
      Decreased expression of Rb is also detected during differentiation, and
      overexpression of Rb in trophoblasts inhibits giant cell differentiation.
      Although an increase in E2F activity would be expected with the loss of Rb, what
      is observed is an overall decrease in E2F DNA-binding complexes, a shift to new
      complexes, and a decrease in E2F-dependent gene expression in differentiating
      trophoblasts. Overall, these results indicate that the combination of a decrease
      in p53 and Rb represents a functionally important part of the transition of
      trophoblasts from a proliferative cell cycle to an endocycle in the giant cell
      differentiation programme.

PMID- 15013637
TI  - GTT1/StarD7, a novel phosphatidylcholine transfer protein-like highly expressed
      in gestational trophoblastic tumour: cloning and characterization.
AB  - We report the cDNA cloning and characterization of GTT1/StarD7, a novel
      gestational trophoblastic tumour gene, initially identified by its up-regulated
      expression in the choriocarcinoma JEG-3 cell line with respect to their
      nonmalignant counterpart, complete hydatidiform mole and normal trophoblastic
      tissue. Using the differential display fragment as a probe we screened placenta
      and HeLa cDNA libraries and isolated a clone carrying a 3315 bp insert (accession
      number AF270647). This cDNA encodes a protein of 295 amino acid residues with a
      molecular weight of approximately 34.7 kDa and a pI of 5.79. Computer-mediated
      homology search revealed that the deduced amino acid sequence had similarity to
      phosphatidylcholine transfer protein (PCTP) with a conserved StAR-related lipid
      transfer (START) domain extending between the amino acids 66 to 250. The GTT1
      gene contains at least 9 exons spread nearly 30 kb on chromosome 2p12-2p11.2.
      Northern blot assays of total RNA derived from normal early placenta (NEP),
      complete hydatidiform mole (CHM) and JEG-3 cell line revealed a 3.5 kb mRNA
      expressed exclusively in the JEG-3 cell line. However, semiquantitative RT-PCR
      analysis performed with the same RNA samples demonstrated GTT1 expression
      throughout all of them with the highest level in JEG-3 cell line. Examination of
      GTT1 mRNA expression by semiquantitative RT-PCR assays in a series of tumour cell
      lines indicated wide-spread GTT1 expression with predominance in both
      choriocarcinoma JEG-3 and JAR cells, colorectal adenocarcinoma HT29 and
      hepatocellular carcinoma HepG2 cells. In conclusion, the highly GTT1 expression
      profile in JEG-3 and JAR cell lines and its lipid binding domain suggest that
      GTT1 may play an important role in the phospholipid-mediated signalling of
      trophoblastic tumour cellular events.

PMID- 15013638
TI  - Transferrin expression by placental trophoblastic cells.
AB  - Transferrin (TF), a 76-80 kDa glycoprotein, is responsible for the transport of
      iron to cells within both the fetal and maternal systems, but it does not cross
      the multiple cell layer barrier of the placenta. Recent findings that both rat
      and human placental cells produce TF indicated that placental TF may function in
      some manner to transport or regulate iron passage across this barrier. However,
      placental production of TF was brought into question because the cell
      preparations used to identify TF were obtained using dispersed tissue and may
      have contained non-placental contaminating elements. In this study, cultures of
      phenotypically distinct cell types containing only placental cells were used to
      firmly establish whether or not TF is expressed, and if so to begin to identify
      the cell(s) associated with its synthesis. Utilizing RT-PCR, in situ
      hybridization, and Western blot analysis, we identified TF mRNA and protein in
      three trophoblast cell types, HRP-1 (rat), Rcho-1 (rat), and BeWo (human) cells.
      Additionally, TF mRNA and protein were found in Giant cells, the differentiated
      form of Rcho-1 cells. When taken together, these results demonstrate clearly that
      TF is expressed by both differentiated and non-differentiated placental cells,
      and when viewed in light of previous findings, strengthen the possibility that
      placental TF may be central to the passage of iron from the mother to the fetus
      during development.

PMID- 15013640
TI  - Reducing agent and tunicamycin-responsive protein (RTP) mRNA expression in the
      placentae of normal and pre-eclamptic women.
AB  - Recently, the gene encoding a new stress-induced protein termed reducing agent
      and tunicamycin-responsive protein (RTP) was identified. The function of RTP is
      unknown, however, the strong upregulation of RTP during cellular differentiation,
      and exposure to stress conditions including hypoxia suggests a specific role for
      RTP in these processes. In pre-eclampsia, impaired spiral artery remodelling and
      reduced perfusion may reduce oxygen tension in the placenta and thereby alter
      trophoblast differentiation and function. We therefore hypothesized that the
      expression of RTP mRNA is altered in the placentae of women with pre-eclampsia.
      The aims of this study were to determine the regional distribution and cellular
      localization of RTP mRNA expression and compare mRNA abundance in different
      regions of normotensive control and pre-eclamptic placentae. In normal and pre
      eclamptic placentae, RTP mRNA was expressed in the syncytiotrophoblasts and in
      the intermediate trophoblasts of the basal plate. In early onset pre-eclampsia,
      RTP mRNA was more abundant in the chorionic villi regions. A further increase was
      localized to the syncytial knots and to the trophoblasts in the peri-infarct
      regions. The increased RTP expression may reflect lower oxygen tension and/or
      other stress stimuli in the placenta in pre-eclampsia.

PMID- 15013639
TI  - PTH/PTHrP receptor and mid-molecule PTHrP regulation of intrauterine PTHrP:
      PTH/PTHrP receptor antagonism increases SHR fetal weight.
AB  - Parathyroid hormone-related protein (PTHrP) has important roles in fetal growth
      and development through stimulation of placental calcium transport,
      vasodilatation of the uteroplacental vasculature and regulation of cellular
      growth and differentiation. The growth restricted spontaneously hypertensive rat
      (SHR) has reduced fetal plasma, placental and amniotic fluid PTHrP concentrations
      compared to its progenitor, the Wistar Kyoto (WKY) rat. The aim of this study was
      to determine whether intrauterine PTHrP infusions can restore PTHrP levels and
      promote SHR fetal growth. PTHrP(1-34), midmolecule PTHrP(67-94), the PTH/PTHrP
      receptor antagonist [Asn(10), Leu(11)]-PTHrP(7-34) or vehicle were infused via a
      mini-osmotic pump between 10 and 20 days of gestation into the uterine lumen of
      SHR and WKY rats. Uterine, placental, amniotic fluid and plasma (fetal and
      maternal) PTHrP were measured via N-terminal radioimmunoassay. PTH/PTHrP receptor
      antagonism and mid-molecule PTHrP(67-94) induced endogenous intrauterine PTHrP
      production with receptor antagonism eliciting a greater and more wide spread
      effect. The PTH/PTHrP receptor antagonist [Asn(10), Leu(11)]-PTHrP(7-34) acting
      through a receptor other than the PTH/PTHrP receptor increased SHR fetal and
      placental weights above vehicle (P<0.05) to that of the WKY and restored SHR
      amniotic fluid volume (P<0.05). This was associated with a highly significant up
      regulation of placental, uterine and plasma (fetal and maternal) PTHrP (P<0.05).
      Modest increases in placental and uterine PTHrP (P<0.05) following intrauterine
      infusions of PTHrP(1-34) and PTHrP(67-94) had no effect on WKY and SHR fetal
      weight. Effective growth promoting actions of increased endogenous PTHrP were
      observed following PTH/PTHrP receptor antagonism rather than exogenous PTHrP
      administration. A novel finding was that mid-molecule PTHrP also up regulates
      endogenous intrauterine N-terminal PTHrP production supporting the existence of a
      mid-molecule receptor. This study highlights that an increase in endogenous
      uterine, placental and fetal plasma PTHrP following PTH/PTHrP receptor antagonism
      was associated with increased SHR fetal growth presumably by improving placental
      growth and function.

PMID- 15013641
TI  - Characterization of glucose transporter 8 (GLUT8) in the ovine placenta of normal
      and growth restricted fetuses.
AB  - Facilitated glucose transporters (GLUTs) in the chorionic epithelium are primary
      conduits for glucose delivery to placental and fetal tissues. The objective of
      this study was to characterize GLUT8 in the ovine placenta and determine if
      differences in mRNA and protein concentrations occur in an ovine model of
      intrauterine growth restriction (IUGR). A GLUT8 partial mRNA was generated, which
      shares 95 per cent identity with bovine GLUT8 nucleotide sequence. Northern
      hybridization identified a 2.1 kilobase transcript. GLUT8 mRNA concentrations
      normalized to beta-actin mRNA concentrations increased during late gestation.
      Western immunoblots with an affinity-purified anti-mouse GLUT8 antiserum detected
      GLUT8 in late gestation ovine placenta plasma membranes. GLUT8 was
      immunolocalized to the chorionic epithelial layer and uterine epithelial cells
      from mid to late gestation. GLUT8 mRNA and protein concentrations at 135 days
      gestational age were decreased by 34.8 per cent and 21.8 per cent, respectively
      (P<0.05), in an ovine placental insufficiency model of IUGR. Identification of
      GLUT8 in the ovine placenta indicates a potential role for GLUT8 in mediating
      glucose uptake within the placenta and transport to the fetus. Further studies
      are necessary to confirm this hypothesis and whether the observed decreases in
      GLUT8 in the PI-IUGR model might contribute, at least in part, to the placental
      glucose transport deficit that occurs in this model.

PMID- 15013642
TI  - Altered placental oxidative stress status in gestational diabetes mellitus.
AB  - Oxidative stress has been clearly linked to type 2 diabetes mellitus, however,
      limited data are available on the involvement of oxidative stress in gestational
      diabetes mellitus (GDM), a disease of similar pathophysiology. The aim of this
      study was to investigate the status of placental oxidative stress in healthy
      pregnant women and women with GDM. The hypothesis to be tested was that tissue
      markers of oxidative stress are significantly increased in GDM compared to normal
      placental tissues. Markers of oxidative stress measured were the release of 8
      isoprostane (8-epi-prostaglandin F(2alpha)) from human term placental explants
      (n=11), the activity of the antioxidant enzymes superoxide dismutase and
      glutathione peroxidase (n=10), and protein carbonyl content (n=12). Placental
      release of 8-isoprostane was 2-fold greater from women with GDM (P<0.001)
      compared to healthy pregnant women. Superoxide dismutase activity and protein
      carbonyl content were elevated in placentae obtained from women with GDM (P<0.04
      and P<0.004 respectively), whilst there was no significant difference in the
      activity of glutathione peroxidase. These data demonstrate the presence of
      oxidative stress in the placenta from women with GDM, in addition to the
      induction of a key antioxidant, collectively indicating a state of existing
      oxidative stress in this condition.

PMID- 15013643
TI  - Gap junction formation and connexin distribution in pig trophoblast before
      implantation.
AB  - This study describes the gap junctions in extraembryonic cell layers of the
      preimplantation pig embryo (trophectoderm and endoderm constituting the
      trophoblast). Using specific antibodies against connexins 31, 32 and 43, we found
      these connexins in embryos by immunodetection using Western blot and
      immunofluorescence analysis. By immunofluorescence, the first foci of connexin 31
      were detected in the four-cell stage blastomeres, and the first diffuse gap
      junctions appeared at the eight-cell stage. Intercellular communication was
      observed with Lucifer yellow transfer to start also at the eight-cell stage
      around the onset of compaction. Typical gap junctions developed in the
      trophectoderm of blastocysts, as observed by transmission electron microscopy of
      thin sections and freeze-fracture replicas. Connexin proteins were differently
      expressed in time and space: connexin 31 was continuously present in
      trophectoderm, connexin 32 was essentially found in endoderm during elongation;
      connexin 43 was distributed in both trophectoderm and endoderm during
      blastulation and expansion. Connexin 43 was also found in two isoforms,
      phosphorylated or not, at day 14. Such developmentally regulated connexin
      expression may be essentially useful to control the exponential growth of
      trophoblast in preimplantation pig blastocysts.

PMID- 15013644
TI  - Analysis of the fetal placental vascular tree by X-ray micro-computed tomography.
AB  - The current understanding of the placental vascular tree largely derives from
      time-consuming morphometric analyses performed by conventional histology,
      electron microscopy of corrosion casts and three-dimensional reconstructions
      based on physical tissue sections. In the present study, we demonstrate for the
      first time that micro-computed tomography (micro-CT) emerges as a new, non
      destructive and fast tool for imaging and quantifying fetoplacental vasculature.
      Term placentae (n=5) were perfused with contrast agent consisting of barium
      sulfate, gelatine and thymol shortly after Caesarean-section-delivery. Samples (1
      cm(3)) from eight different regions of the placenta were subsequently scanned in
      a micro-CT. Using tomographic reconstruction algorithms, three dimensional images
      were obtained by micro-CT allowing total stereoscopic visualization and
      continuous quantitative analysis of the vascular structure of the investigated
      samples. These samples were compared regarding vascular surface (VS) and vascular
      density (vascular volume fraction, TCVF). Quantitative assessment showed an
      average vascular density of 16 per cent (SD+/-0.4) and a vascular surface of 475
      mm(2)(SD+/-8) per total tissue volume (including intervillous space) of 125
      mm(3). Micro-CT image-analysis showed no significant differences in the fetal
      vascularization among term placentae. Micro-CT imaging is feasible for imaging
      and analysis of the villous vascular tree, allows further morphologic studies and
      immunohistochemistry of the placental specimens and may emerge as an additional
      tool in the investigation of the physiology and pathophysiology of the placental
      vasculature.

PMID- 15013646
TI  - Spontaneous activity and electrical coupling in human detrusor smooth muscle:
      implications for detrusor overactivity?
AB  - Large uncontrollable detrusor contractions, decreased compliance that increases
      luminal pressures during filling, and detrusor underactivity are all examples of
      abnormal bladder function. Studies of the nervous control of lower urinary tract
      function and measurement of the cellular properties of the component tissues of
      the bladder wall have been performed to deepen our knowledge of these problems.
      The resultant data have suggested that lower urinary tract smooth muscle should
      not be regarded solely as a collection of independent cellular contractile units
      that are each activated by separate neural inputs, but also as a syncytium of
      cells. Although this syncytial arrangement may not be as well developed as in
      other tissues, it should impose a new layer of activity that will affect overall
      bladder function. Recent studies have addressed this issue through investigation
      of spontaneous contractile activity, the cellular basis of syncytial function,
      and their normal and abnormal functional consequences. The results suggest that
      individual detrusor cells possess membrane properties that may lead to
      spontaneous activity fluctuations, which can affect adjacent cells and, thus,
      produce multicellular aberrant responses. It remains unclear whether these
      responses manifest themselves as dysfunctional activity in the whole bladder
      defects because the extent of local multicellular abnormalities is not known at
      present. The data do imply that myogenic defects can contribute to abnormal
      bladder function and, thus, suggest several new targeted drug models that should
      be explored.

PMID- 15013647
TI  - Response of bladder smooth muscle cells to obstruction: signal transduction and
      the role of mechanosensors.
AB  - Bladder hypertrophy and detrusor overactivity are well-known bladder responses to
      outlet obstruction. Mechanical stretch stress is considered the trigger inducing
      these responses in the urodynamically overloaded bladder. Several studies using
      an in vitro model of mechanical stress demonstrate that repetitive stretch
      stimulation of bladder smooth muscle cells results in increased expression of a
      variety of growth factors and other specific proteins. In the bladder smooth
      muscle cell, stretch-activated ion channels (SACs) and protein kinase C (PKC)
      sarcolemmal proteins may function as sensors for external mechanical forces. In
      particular, SACs couple mechanical stress to activation of c-jun NH2-terminal
      kinase, which leads to a rapid induction of nuclear transcription factors. PKC
      also may involve an indirect or direct regulation of nuclear events. In addition,
      mechanical stress may induce the release of angiotensin II in an autocrine
      fashion. These factors in turn stimulate expression of specific gene-encoding
      proteins, such as heparin-binding epidermal growth factor-like growth factor,
      nerve growth factor, and an isomer of cyclooxygenase-2, all of which have the
      potential to contribute to structural and functional alterations in the bladder
      after obstruction.

PMID- 15013648
TI  - Management of detrusor dysfunction in the elderly: changes in acetylcholine and
      adenosine triphosphate release during aging.
AB  - Numerous studies have detailed age-related changes in the structure and function
      of the bladder that may contribute to the high prevalence of overactive bladder
      (OAB) in the elderly population, but the relation of these changes to OAB
      symptoms remains unclear. Physiologic and neurochemical studies have been
      conducted in human detrusor strips obtained from people of different ages,
      focusing on potential changes in cholinergic and purinergic neurotransmission, as
      well as the release and actions of acetylcholine (ACh) from nonneuronal bladder
      cells. Results from physiologic and microdialysis experiments indicate that
      purinergic transmission increases with age, whereas cholinergic transmission
      decreases. These effects are most likely because of decreased release of ACh and
      increased release of adenosine triphosphate (ATP) from postganglionic
      parasympathetic axons innervating the bladder. Immunohistochemical experiments
      showed that choline acetyltransferase in the human detrusor is contained not only
      in parasympathetic axons, but also in cells of the urothelium. The release of
      nonneuronal ACh increases with age and detrusor stretch. The age-related increase
      in purinergic transmission in the detrusor and other data indicating that
      responses to ATP are increased in detrusor overactivity suggest that purinergic
      receptor antagonists may provide a useful complement to muscarinic receptor
      antagonists in the treatment of older patients with OAB. Nonneuronal ACh release
      may play a key role in the storage phase of the micturition reflex, and this may
      explain, at least in part, the effectiveness of antimuscarinic agents for the
      treatment of OAB.

PMID- 15013649
TI  - Control of bladder function by peripheral nerves: avenues for novel drug targets.
AB  - The micturition reflex involves afferent nerve activation when the bladder is
      sufficiently full and subsequent controlled firing of parasympathetic efferent
      nerves to contract the detrusor muscle as part of the voiding mechanism.
      Alteration of the sensitivity of afferent activation or loss of control over
      transmitter release could lead to sensory- or motor-activated incontinence,
      respectively. The control mechanisms that regulate these 2 activities remain
      poorly understood. Current opinion is that the sensation of bladder fullness is
      relayed by afferent nerves in the mucosal layer, which are activated by the
      release of chemical mediators, such as adenosine triphosphate (ATP), from the
      urothelium when it is stretched as the bladder fills. This hypothesis supports
      the concept that other chemical signals that affect bladder sensation (eg,
      changes in urine composition and agents such as capsaicin) can modulate the
      sensitivity of the basic system. It has also been proposed that a layer of
      myofibroblasts immediately below the basal lamina of the urothelium acts as a
      variable gain regulator of the sensory process between ATP release and afferent
      excitation. These myofibroblasts are functionally connected to form an electrical
      syncytium, make close contact with nerves, and respond by generating electrical
      responses and transient increases in intracellular Ca2+ when exposed to ATP. On
      the efferent side, using a guinea pig detrusor model, possible modulators of
      transmitter release have been investigated, including adenosine (the breakdown
      product of the neurotransmitter ATP). Adenosine reduces the force of nerve
      mediated contractions by acting predominantly at presynaptic sites at the nerve
      muscle junction via a subtype of an adenosine receptor-the A1 receptor. An
      additional effect, possibly via A2 receptors, is also present on the detrusor
      muscle itself. These actions of adenosine are less evident in human detrusor
      muscle but remain a potential modulatory target. In summary, the cellular and
      molecular regulation of bladder fullness sensation and efferent transmitter
      release are becoming better understood and represent potential drug targets for
      the management of detrusor overactivity.

PMID- 15013651
TI  - Clinical and socioeconomic relevance of overactive bladder.

PMID- 15013650
TI  - New pharmacologic targets for the treatment of the overactive bladder: an update.
AB  - Although currently available antimuscarinic agents are the standard of care for
      overactive bladder (OAB), they are limited by certain side effects, particularly
      dry mouth and constipation. Research aimed at discovering new therapies for OAB
      has resulted in the identification of some promising drugs. Investigations of
      pharmacologic targets in the central nervous system (CNS) have yielded
      encouraging results with several agents, including tramadol and gabapentin.
      Further investigation may show that drugs acting at serotonergic and
      noradrenergic CNS sites are clinically useful as therapies for OAB. Some
      peripherally acting drugs, such as resiniferatoxin and botulinum toxin, have
      already been proved to be of clinical value. However, development of other agents
      that block afferent or efferent nerve impulses in the bladder through activity at
      vanilloid, purinergic, or opioid-like receptor sites may result in clinically
      useful drugs.

PMID- 15013652
TI  - Role of antimuscarinics in the treatment of nonneurogenic daytime urinary
      incontinence in children.
AB  - Idiopathic or "functional" urinary incontinence in children--incontinence with no
      known neurologic or anatomic cause--may take the form of urge incontinence, the
      most common type of incontinence, which is characterized by detrusor overactivity
      during the filling phase, or dysfunctional voiding. The latter may be classified
      as staccato voiding (periodic bursts of pelvic floor activity with prolonged
      voiding and, in some cases, residual urine), interrupted voiding (insufficient
      bladder emptying, infrequent voiding with several phases of micturition), or
      "lazy bladder" syndrome (infrequent voiding and large bladder capacity). The
      etiology of functional incontinence is unknown. Theories include genetic
      predisposition, recurrent urinary tract infections, immaturity or too-early
      toilet training, and sexual abuse. A severe form of urge incontinence,
      nonneurogenic neurogenic (Hinman) bladder, may be the end stage of dysfunctional
      voiding, but an occult neurologic component should also be considered. Diagnostic
      procedures recommended for children with urinary incontinence include careful
      history taking, a voiding diary, and physical examination to identify symptoms
      and to minimize the need for invasive procedures. Treatments include behavioral
      modification, biofeedback, antibiotics, anticholinergics, counseling, and
      neuromodulation. The antimuscarinics oxybutynin and tolterodine are, at present,
      the most commonly used drugs to treat incontinence. Common side effects with
      these agents (ie, reduced saliva production and worsening constipation) can be
      severe and can cause up to 10% of children using oxybutynin to discontinue
      treatment. Current evidence suggests that tolterodine may have a more favorable
      safety profile than oxybutynin. In addition, new antimuscarinics in the pipeline,
      eg, darifenacin and solifenacin, are expected to possess more favorable safety
      and tolerability profiles and may therefore help to alleviate these limitations.

PMID- 15013653
TI  - Mixed incontinence.
AB  - The epidemiology and treatment of mixed incontinence has received relatively
      little attention. However, mixed incontinence--defined as the combination of
      stress and urge incontinence--accounts for approximately 33% of all cases of
      incontinence in women. The condition often responds poorly to treatment, either
      pharmacologic or surgical. Potential pharmacologic approaches for mixed
      incontinence include antimuscarinic agents, estrogen replacement therapy (for
      postmenopausal women), and dopamine, serotonin, or norepinephrine reuptake
      inhibitors. In a large-scale, multinational, placebo-controlled, clinical trial,
      the antimuscarinic agent tolterodine significantly reduced incontinence episodes
      in women with mixed symptoms. The benefits of tolterodine continued to increase
      during the 8 weeks of the trial and extended to additional end points, including
      frequency, urgency, and urge incontinence. A limited number of studies have
      examined the use of estrogen for mixed incontinence and have produced conflicting
      results. Duloxetine oxalate, a combined serotonin/norepinephrine reuptake
      inhibitor, has shown great promise in animal studies, as well as in phase 2 and 3
      clinical trials. This agent is the first to demonstrate efficacy as a sole
      therapy for stress incontinence and has exhibited favorable effects on bladder
      capacity, suggesting possible benefits in mixed incontinence. Only 5 studies (2
      of which were conducted during the 1980s) have specifically examined the use of
      surgery for the treatment of mixed incontinence; the cure rates reported have
      varied. The current body of information supports use of an antimuscarinic agent
      as initial therapy for mixed incontinence, although long-term trials are needed
      to shed more light on the duration of benefit.

PMID- 15013654
TI  - Behavioral and drug therapy for urinary incontinence.
AB  - In a randomized, controlled trial comparing biofeedback-assisted behavioral
      therapy and drug therapy with oxybutynin, both types of therapy were superior to
      placebo in older, community-dwelling women with urge or mixed incontinence.
      Behavioral therapy significantly reduced incontinence compared with oxybutynin
      therapy (80.7% vs 68.5%, P = 0.04). Patients expressed high levels of
      satisfaction with behavioral therapy, and 97% were willing to continue this
      therapy indefinitely, compared with 55% receiving drug therapy. Results of recent
      studies suggest that behavioral therapy without biofeedback or pelvic floor
      electrical stimulation also results in significant clinical benefits, which
      should make behavioral therapy a more practical approach in the general practice
      setting. Statistical analysis showed no significant relationship between
      posttreatment urodynamic changes and clinical outcomes, and thus, the mechanisms
      by which behavioral and drug therapies work remain unidentified. In a small trial
      of combination therapy, patients who received both drug and behavioral therapy
      experienced significant clinical improvements compared with the effects of
      monotherapy with either treatment.

PMID- 15013655
TI  - Mechanisms involved in new therapies for overactive bladder.
AB  - During the last few years, vanilloid substances and botulinum-A toxin were
      extensively investigated as new therapies for overactive bladder. Intravesical
      administration of capsaicin or resiniferatoxin--2 members of the vanilloid family
      -has been shown to increase bladder capacity and decrease urge incontinence in
      patients with neurogenic, as well as nonneurogenic, forms of detrusor
      overactivity. In addition, vanilloids have been shown also to reduce bladder pain
      in patients with hypersensitive disorders. Vanilloids are exogenous ligands of
      vanilloid receptor type 1 (VR1), an ion channel present in the membrane of type C
      primary afferent nerve fibers. This receptor, which plays a key role in pain
      perception and control of the micturition reflex, may be upregulated by nerve
      growth factor (NGF), a neurotrophic molecule detected in high concentrations in
      overactive detrusor tissue. Vanilloids, by reducing uptake of NGF through sensory
      neurons, may counteract VR1 upregulation. Intravesical injections of botulinum-A
      toxin, a neurotoxin produced by Clostridium botulinum, were shown to increase
      bladder capacity and to decrease urge incontinence episodes in patients with
      neurogenic detrusor overactivity. Botulinum-A toxin impedes the release of
      acetylcholine from cholinergic nerve endings at the neuromuscular junction,
      leading to paralysis of the detrusor smooth muscle.

PMID- 15013656
TI  - Etiology and management of pelvic pain syndrome.

PMID- 15013657
TI  - Etiology and management of chronic pelvic pain syndrome in men.
AB  - Prostatitis results in >2 million physician office visits annually. Characterized
      by pelvic pain and voiding symptoms, chronic pelvic pain syndrome (CPPS) is
      poorly defined. The Chronic Prostatitis Collaborative Research Network (CPCRN)
      has put forward a uniform set of classifications for chronic prostatitis based on
      pain being the primary symptom. The CPCRN has also created a valid instrument for
      measuring symptoms: the Chronic Prostatitis Symptom Index. After nonbacterial
      prostatitis has been diagnosed, treatment of patients should be individualized.
      The condition may be caused by bladder, prostate, pelvic side wall, or seminal
      vesicle pathology. In addition to currently used treatments, several new
      therapies are being investigated after promising pilot studies. Despite the
      multiple approaches to management of CPPS, no hard and fast guidelines have been
      developed. This review provides an overview of assessment techniques and
      management options for men with CPPS.

PMID- 15013658
TI  - Treatment of interstitial cystitis.
AB  - Although the symptoms of interstitial cystitis (IC)--a debilitating, chronic
      disease characterized by urinary urgency and frequency, and bladder and pelvic
      pain on bladder filling--are easily confused with those of urinary tract
      infections, there is an absence of an underlying infection, and antibiotic
      therapy is of no therapeutic benefit. Severe cases of this disorder, which
      affects mainly women, can have a great negative impact on the quality of life of
      patients because of extreme urinary frequency. The diagnosis of IC is difficult
      and should be based on patient history, physical examination, and cystoscopy. A
      large number of pharmacologic treatments have been used to treat this condition
      with limited success, including pentosan polysulfate, heparin, antihistamines,
      tricyclic antidepressants, intravesical dimethyl sulfoxide, and bacille Calmette
      Guerin. Among the potentially effective new treatment modalities currently under
      investigation are suplatast tosilate, resiniferatoxin, botulinum toxin, and gene
      therapy to modulate the pain response. As knowledge of the pathogenesis of IC
      increases through intensified research, the ability to provide effective
      treatment to patients with this disease will improve.

PMID- 15013660
TI  - Assessing natural variation in genes affecting Drosophila lifespan.

PMID- 15013661
TI  - Vascular genetic factors and human longevity.
AB  - Complex inter-relationships between age-associated illnesses, such as vascular
      disease and Alzheimer's disease (AD), suggest that biological and genetic
      pathways may be worthy of examination in centenarian populations to provide
      insights into human longevity. This is also borne out by the involvement of
      lipoprotein metabolism and a number of vascular genetic risk factors. Repeated
      findings of a higher frequency of the apolipoprotein E (APOE) epsilon4 allele in
      middle-aged subjects compared with centenarians were reported. Furthermore, we
      have also shown how in different populations there is a significant trend in
      reduction of serum APOE levels from APOE epsilon2- to epsilon4-carrier as well as
      significant differences in serum APOE levels respect to age in epsilon4-carriers
      but only after adjustment for HDL cholesterol. In contrast, findings of increased
      prevalence of the angiotensin I converting enzyme 1 (ACE1) D allele in French
      centenarians have not been replicated, suggesting the possibility that regional
      differences may occur in ACE1(*)D frequency within Europe in centenarians, as has
      been recently reported for APOE epsilon2 and epsilon4 alleles. A number of
      studies have examined the potential role in longevity of other genes involved in
      vascular risk, haemostasis, and blood pressure regulation
      [methyltetrahydrofolatereductase (MTHFR), apolipoprotein A1 (APOA-I),
      apolipoprotein C3 (APOC-III), apolipoprotein A4 (APOA-IV), paraoxonase 1 (PON1),
      plasminogen activator inhibitor type I (PAI-1)], with contrasting results. While
      further studies are needed to confirm the possible role of APOE concentration as
      putative longevity factor, this paper provides an overview of genetic vascular
      factors potentially involved in human longevity.

PMID- 15013662
TI  - Quantitative trait loci affecting natural variation in Drosophila longevity.
AB  - Limited life span and senescence are universal phenomena, controlled by genetic
      and environmental factors whose interactions both limit life span and generate
      variation in life span between individuals, populations and species. To
      understand the genetic architecture of longevity it is necessary to know what
      loci affect variation in life span, what are the allelic effects at these loci
      and what molecular polymorphisms define quantitative trait locus (QTL) alleles.
      Here, we used quantitative complementation tests to determine whether genes that
      regulate longevity also contribute to naturally occurring variation in Drosophila
      life span. Inbred strains derived from a natural population were crossed to
      stocks containing null mutations (m) or deficiencies (Df) uncovering the
      candidate genes, maintained over a Balancer (Bal) chromosome. We measured the
      life span of the resulting F(1) genotypes, +(i)/m (Df) and +(i)/Bal, where +(i)
      denotes one of the i natural alleles. Failure of the QTL alleles to complement
      the candidate gene mutation is indicated by a significant cross (mutant versus
      wild-type allele of the candidate gene) by inbred line interaction term from
      analysis of variance of life span. Failure to complement indicates a genetic
      interaction between the candidate gene allele and the naturally occurring life
      span QTL, and implicates the candidate gene as potential cause of variation in
      longevity. Of the 16 candidate regions and genes tested, Df(2L)c17, Df(3L)Ly,
      Df(3L)AC1 and Df(3R)e-BS2 showed significant failure to complement wild-type
      alleles in both sexes, and an Alcohol dehydrogenase mutant failed to complement
      in females. Several genes that regulate life span (e.g., Superoxide dismutase,
      Catalase, and rosy) complemented the life span effects of wild-derived alleles,
      suggesting little natural variation affecting longevity at these loci, at least
      in this sample of alleles. Quantitative complementation tests are therefore
      useful for identifying QTL contributing to segregating genetic variation in life
      span in nature.

PMID- 15013663
TI  - Senescence-associated decline of lymphocyte migration in gut-associated lymphoid
      tissues of rat small intestine.
AB  - Scenescence-induced changes in gut-associated lymphoid tissues may contribute
      largely to the impaired immune responses during aging. Age-related changes in
      lymphocyte recirculations were investigated in Peyer's patches of rat small
      intestine. Cell dynamics of labeled T lymphocytes were observed under an
      intravital fluorescence microscope and compared between young and aged rats.
      Lymphocyte transport through intestinal lymph was decreased in aged rats. The
      lymphocyte rolling and adherence in postcapillary venules (PCV) of Peyer's
      patches was also significantly impaired in aged rats, with decreased expression
      of L-selectin on lymphocyte surfaces. Immunohistochemical analysis revealed a
      significant decrease in the CD8-positive cell population in Peyer's patches of
      the aged group, although mucosal addressin cell adhesion molecule-1 (MAdCAM-1)
      expression in postcapillary venules was unaltered. Lymphocyte adoptive-transfer
      studies indicated that although both the donor and recipient factors influence
      the adherence of T cells, the former may play a predominant role in the age
      related change. This study clearly demonstrated in situ that T cell migration
      into Peyer's patches is significantly decreased in the aged intestine, which may
      reflect the impaired immune responses in the aging process.

PMID- 15013664
TI  - Heat shock proteins can protect aged human and rodent cells from different
      stressful stimuli.
AB  - Heat shock proteins (hsps) are induced by stressful stimuli and have been shown
      to protect cells and organs from such stresses both in vitro and in vivo. Because
      of this, mildly stressful stimuli, sufficient to induce hsp over-expression can
      protect against a subsequent more severe stress. In cells from aged individuals,
      however, no hsp induction is observed upon exposure to stress and no protective
      effect of a mild stress is observed. Here, we show that bypassing the block to
      hsp induction by artificially over-expressing hsps, can produce a protective
      effect against a variety of damaging stimuli in cells from aged rats or aged
      humans, indicating that hsps can have a protective effect in aged cells, provided
      successful over-expression can be achieved. Hence, hsps over-expression could be
      of therapeutic benefit in aged individuals if procedures to over-express the hsps
      can be developed either by devising non-stressful procedures to induce endogenous
      hsp over-expression or by developing vectors able to efficiently deliver
      exogenous hsps.

PMID- 15013665
TI  - Age-related changes in cardiac adenosine receptor expression.
AB  - Adenosine is an important cardioprotective agent that works via several adenosine
      receptor (ADOR) subtypes to regulate cardiovascular activity. It is well
      established that functional responses to adenosine decline with age. What is
      unclear, though, is whether these changes occur at the receptor, second messenger
      or translational level. In this study we determined the effect of age on cardiac
      adenosine receptor expression using the housekeeping gene 18S rRNA versus the
      adenosine A(2B) receptor gene as internal controls. Absolute quantification
      showed that no age-related changes occurred in the expression of 18S rRNA or
      adenosine A(2B) receptor internal control genes. Subsequently, relative analysis
      of the adenosine receptor subtypes using 18S rRNA found a significant age-related
      reduction in the expression of the adenosine A(1) receptor (5.5-fold), with no
      changes in the expression of the adenosine A(2A), A(2B) and A(3) receptors. When
      using the expression of the adenosine A(2B) receptor as the internal control
      gene, a significant down regulation of both the adenosine A(1) (5.4-fold) and
      A(2A) (2.2-fold) receptors with no change in the expression of adenosine A(3)
      receptor was found. Therefore, the high level of expression of the 18S rRNA
      housekeeping gene was found to mask a significant change in expression of the
      adenosine A(2A) receptor with age. Ultimately, these findings show an age-related
      reduction in adenosine A(1) and A(2A) receptor expression in rat heart.

PMID- 15013667
TI  - Reserve carbohydrates maintain the viability of Saccharomyces cerevisiae cells
      during chronological aging.
AB  - Glycogen and trehalose are well known to participate in many important cell
      functions, e.g., protection from stress factors, regulation of cell growth and
      division, spore formation. Since the aging is a complex process involving many
      aspects of cell metabolism, it was interesting to study the role of glycogen and
      trehalose in maintenance of viability of aging cells. We have revealed that cell
      aging is accompanied by an abrupt fall of glycogen and trehalose contents between
      the second and third weeks of aging. Simultaneously, we observed a decrease in
      the activity of glycolytic enzymes, phosphofructokinase and hexokinase. At the
      same time, the viability of aging cells abruptly declined. Although we found
      neither glycogen nor trehalose in the cells after the third week of aging, they
      remained viable for some time, apparently due to development of some compensatory
      metabolic pathways. In spite of this fact, complete death of the cells occurred
      by the eighth week of experiment, which confirmed irreplaceability of reserve
      carbohydrates in yeast cell metabolism. Possible reasons of the inability of
      aging cells to accumulate glycogen and trehalose are discussed in the work.

PMID- 15013666
TI  - Psychoneurodendocrine correlates of lymphocyte subsets during healthy ageing.
AB  - Ageing has been associated with increased cortisol levels and absolute counts of
      T lymphocytes with memory phenotype. Although the mechanisms underlying these
      changes are still unknown, it has been speculated that this could be related to a
      dysfunction in FAS/CD95 expression in naive or memory cells. In this study, we
      investigated the role of psychoneuroendocrine variables in regulating CD95
      expression on lymphocyte subsets. Forty-six elderly subjects (65-91 years) and 33
      young adults (20-40 years) were recruited accordingly the SENIEUR protocol. The
      psychological status was measured by structured clinical interviews, salivary
      cortisol was assessed along the day (9, 12 and 22h) and peripheral blood
      lymphocytes were immunophenotyped. The elderly were more stressed, depressed and
      anxious than the young subjects. Cortisol levels were increased in the elderly,
      indicating an activation of the hypothalamic-pituitary-adrenal (HPA) axis. We
      observed reduced counts of CD45RA+CD95+ cells in the elderly compared to young
      adults. The elderly subjects also showed a reduced expression of CD3 and CD62L in
      contrast to increased CD95 expression in CD45RA+ cells. The emotional state was
      positively correlated with the lymphocyte markers. Our data suggest the healthy
      ageing is associated with psychoneuroendocrine alterations that may be implicated
      in the regulation of CD95 expression on peripheral T cells.

PMID- 15013669
TI  - Modeling the ozonation of herbicide 2,4-D through a kinetic approach.
AB  - A quantitative estimation of the ozonation of a herbicide 2,4-D solution through
      a kinetic approach was studied and modelled. The ozonation of 2,4-D was found to
      follow a pseudo-first-order kinetic and the degradation rates depended on the
      initial pH and on the ozone concentration. A model was proposed to quantitatively
      predict the pseudo-first-order rate constants of the decay of 2,4-D under
      different ozone concentrations and initial pH levels based on some useful and
      practical assumptions. The proposed model was able to successfully describe the
      reaction with insignificant errors; therefore another practical equation was
      proposed to size the contact tower for 2,4-D ozonation by ozone concentration
      (overdosed) and initial pH level.

PMID- 15013668
TI  - Enhancement of Fas-mediated apoptosis in ageing human keratinocytes.
AB  - Cellular senescence and apoptosis are two metabolically related and seemingly
      synergistic processes that are involved in tissue maintenance and homeostasis,
      anti-tumor protection, and age-related diseases. Despite this apparent co
      operativity, senescence can inhibit apoptosis in certain conditions. Here, we
      describe senescence-apoptosis relationships in human epidermal cells by comparing
      apoptosis-related effector concentrations in keratinocyte cultures and epidermal
      skin cells at various stages of ageing. Using western blots, flow cytometry,
      enzyme-linked immuno-sorbent assay (ELISA) and immunofluorescence, we determined
      the amounts of apoptotic effectors in aged cells compared to young ones, in
      parallel with beta-galactosidase activity at neutral pH (senescence-associated
      beta-galactosidase, SA beta-gal), found to be a good indicator of cellular
      ageing. We observed increased levels of several Fas-mediated apoptosis effectors
      (Fas, Fas ligand, FADD, FLICE), both in cell cultures at advanced passages and in
      skin cells of aged donors (above 45 years). Furthermore, we found that while the
      pro-apoptotic p53 increased, the anti-apoptotic Bcl-2 declined. In spite of this,
      the extent of spontaneous apoptosis did not change in senescent keratinocyte
      cultures. The cells, however, became notably more susceptible to apoptosis when
      kept in exhausted growth medium, or upon Fas receptor activation by anti-Fas
      antibody binding. Our results are consistent with recent findings in senescent
      fibroblasts, showing that the death-signaling pathway is enhanced at senescence.

PMID- 15013670
TI  - The dechlorination of cyclodiene pesticides by methanogenic granular sludge.
AB  - Cyclodiene pesticides: aldrin, isodrin, dieldrin and endrin were dechlorinated by
      methanogenic granular sludge in spiked batch tests. Initial pesticides
      concentration was 7 or 9 mgl(-1). Two monodechlorinated analogues were formed
      during the conversions of aldrin and isodrin. Dieldrin was transformed into two
      monodechlorinated products as well as into aldrin and two monodechlorinated
      derivatives of aldrin. In respect of endrin three monodechlorinated and three
      didechlorinated products were found. The dechlorination of endrin was the most
      rapid, and was almost complete within 28 days. The dechlorinations of aldrin,
      isodrin and dieldrin were much slower: over a period of 3 months only 59%, 70%
      and 88% was transformed, respectively. The amounts of released chloride
      corresponded 0.54 +/- 0.23, 1.05 +/- 0.25, 1.10 +/- 0.12 of theoretical value for
      suggested reactions, for aldrin, isodrin and dieldrin respectively. For endrin it
      was much higher. These transformations did not occur in control samples
      containing autoclaved granules or in control blank samples without sludge.
      However, in aldrin spiked blanks, a conversion into a six-chlorinated analogue
      was found.

PMID- 15013671
TI  - Dechlorination of PCE in the presence of Fe0 enhanced by a mixed culture
      containing two Dehalococcoides strains.
AB  - A mixed culture capable of supplying its energy requirements by the oxidation of
      zero-valent iron (Fe0) and concomitant reduction of chlorinated ethenes was
      established. The culture contained Dehalococcoides species as determined by
      polymerase chain reaction (PCR) with genus specific primers. The use of a newly
      designed ARDRA procedure and subsequent sequencing revealed the presence of two
      Dehalococcoides strains, one closely related to Dehalococcoides ethenogenes
      strain 195, a bacterium respiring with chlorinated ethenes, and one closely
      related to strain CBDB1 a chlorobenzene and dioxin dehalogenating anaerobe. The
      mixed culture was used to study dechlorination of tetrachloroethene (PCE) to
      ethene in the presence of Fe0. Whereas abiotic transformation of PCE by Fe0 led
      to incomplete dechlorination, the mixed culture mediated fast and complete
      dechlorination of PCE to ethene with Fe0 as electron donor. Compared to cultures
      with hydrogen added as electron donor, cultures with Fe0 as electron donor showed
      the same or higher rates of PCE dechlorination. Growth of the Dehalococcoides
      strains in the mixed culture is linked to the presence of Fe0 as electron donor
      and PCE as electron acceptor demonstrating that Dehalococcoides spp. play a
      pivotal role in the dechlorination of chlorinated ethenes in Fe0 systems.

PMID- 15013672
TI  - Adsorption of phenolics on activated carbon--impact of pore size and molecular
      oxygen.
AB  - The impact of pore size of activated carbon fibers (ACFs) on adsorption capacity
      and on the potential for oligomerization of phenolic compounds on the surface of
      ACFs in the presence of molecular oxygen has been investigated in this study.
      Compared with granular activated carbon (GAC), ACFs have unique pore size
      distributions, suitable to be used to elucidate the effect of pore structure on
      adsorption. Adsorption isotherm data were collected for o-cresol and 2
      ethylphenol on four ACFs (ACC-10, ACC-15, ACC-20, and ACC-25) with different
      micropore volumes and BET surface area and on one type of GAC bituminous base.
      These isotherms were collected under anoxic (absence of molecular oxygen) and
      oxic (presence of molecular oxygen) conditions. No significant impact of the
      presence of molecular oxygen on adsorption capacity was noted for ACC-10. ACC-10
      has an average pore width of 19.2 A and total pore volume of 0.43 cm3g(-1). On
      the other hand, for the remaining ACFs, which have larger average pore width and
      larger pore volume, significant increase in the adsorptive capacity had been
      observed when molecular oxygen was present. The GAC gave the greatest difference
      between anoxic and oxic conditions when compared to all the ACFs studied. Binary
      adsorption of o-cresol and 2-ethylphenol on ACFs with the least pore size (ACC
      10) also showed no significant differences between oxic and anoxic environment.
      The binary system under both anoxic and oxic conditions was well predicted by the
      ideal adsorbed solution theory (IAST).

PMID- 15013673
TI  - Catalytic combustion of methane over commercial catalysts in presence of ammonia
      and hydrogen sulphide.
AB  - The performance of different commercially available catalysts (supported Pd, Pt,
      Rh, bimetallic Pd-Pt, and Cr-Cu-Ti oxide catalyst) for the oxidation of methane,
      alone and in presence of ammonia and hydrogen sulphide is studied in this work.
      Catalysts performance was evaluated both in terms of activity and resistance to
      poisoning. The main conclusions are that supported Pd and Rh, present the highest
      activities for methane oxidation, both alone and in presence of ammonia, whereas
      they are severely poisoned in presence of H2S. Pt and Cr-Cu-Ti are less active
      but more sulphur resistant, but their activity is lower than the residual
      activity of sulphur-deactivated Pd and Rh catalysts. The Pd-Pt catalyst exhibits
      low activity and it is quickly deactivated in presence of hydrogen sulphide.

PMID- 15013674
TI  - Chemical composition associated with different particle size fractions in
      municipal, industrial, and agricultural wastewaters.
AB  - A more detailed characterization of particulate organic matter in wastewater
      streams is needed to improve solid-liquid separation and biological processes for
      wastewater treatment. The objective of this paper was to evaluate particle size
      distributions and the associated chemical composition for municipal, industrial,
      and agricultural waste streams. Most of the organic matter in these wastewaters
      was larger than a molecular weight of 10(3) amu and therefore would require
      extracellular hydrolysis before any bacterial metabolism. Particle size
      distributions were significantly different for the studied waste streams. In
      municipal wastewater, the organic matter was evenly distributed in all eight size
      fractions ranging from 10(3) amu up to 63 microm. The industrial and agricultural
      wastewaters, however, contained mainly soluble organic matter (<10(3) amu) and
      larger particles (>1.2 microm for the industrial and >10 microm for the
      agricultural waste) leaving a gap in the size range of large macromolecules and
      colloids. The relative protein and carbohydrate concentrations varied for the
      different size fractions compared to the measured chemical oxygen demand (COD) in
      the corresponding size fraction. Thus, the design of the solid-liquid separation
      at a treatment plant could be used to purposefully modify the overall chemical
      composition of the organic matter before further biological treatment. Particle
      size distributions will influence design and operation of biological nutrient
      removal processes such as denitrification or biological phosphorus removal that
      may be carbon limited if a large fraction of the organic matter is composed of
      large particles with slow hydrolysis rates. Measured particle size distributions
      for the different waste streams in this study (municipal, industrial,
      agricultural) were significantly different requiring specific approaches for
      treatment plant design.

PMID- 15013675
TI  - Abiotic reductive dechlorination of chlorinated ethylenes by soil.
AB  - Abiotic reductive dechlorination of chlorinated ethylenes by soil in anaerobic
      environments was characterized to improve knowledge of the behavior of
      chlorinated ethylenes in natural systems, including systems modified to promote
      attenuation of contaminants. Target organics in the soil suspension reached
      sorption equilibrium in 2 days and the sorption isotherm of target organics was
      properly described by the linear sorption model. A modified Langmuir-Hinshelwood
      model was developed to describe the kinetics of reductive dechlorination of
      target organics by soil. The rate constants for the reductive dechlorination of
      chlorinated ethylenes at the reactive surfaces of reduced soils were found in the
      range between 0.055 (+/- 8.9%) and 2.60 (+/- 3.2%) day(-1). The main
      transformation products in reduced soil suspensions were C2 hydrocarbons. No
      chlorinated intermediates were observed at concentrations above detection limits.
      Five cycles of reduction of the soil followed by oxidation of the soil with
      trichloroethylene (TCE) did not affect the removal of TCE. The removal was
      affected by the reductants used and increased in the order: Fe(II) < dithionite <
      Fe(II) + dithionite.

PMID- 15013676
TI  - A comparative study of the effects of chloride, sulfate and nitrate ions on the
      rates of decomposition of H2O2 and organic compounds by Fe(II)/H2O2 and
      Fe(III)/H2O2.
AB  - The effects of chloride, nitrate, perchlorate and sulfate ions on the rates of
      the decomposition of hydrogen peroxide and the oxidation of organic compounds by
      the Fenton's process have been investigated. Experiments were conducted in a
      batch reactor, in the dark at pH < or = 3.0 and at 25 degrees C. Data obtained
      from Fe(II)/H2O2 experiments with [Fe(II)]0/[H2O2]0 > or = 2 mol mol(-1), showed
      that the rates of reaction between Fe(II) and H2O2 followed the order SO4(2-) >
      ClO4(-) = NO3- = Cl-. For the Fe(III)/H2O2 process, identical rates were obtained
      in the presence of nitrate and perchlorate, whereas the presence of sulfate or
      chloride markedly decreased the rates of decomposition of H2O2 by Fe(III) and the
      rates of oxidation of atrazine ([atrazine]0 = 0.83 microM), 4-nitrophenol ([4
      NP]0 = 1 mM) and acetic acid ([acetic acid]0 = 2 mM). These inhibitory effects
      have been attributed to a decrease of the rate of generation of hydroxyl radicals
      resulting from the formation of Fe(III) complexes and the formation of less
      reactive (SO4(*-)) or much less reactive (Cl2(*-)) inorganic radicals.

PMID- 15013677
TI  - Treatment of trinitrotoluene by crude plant extracts.
AB  - Crude plant extract solutions (spinach and parrotfeather) were prepared and
      spiked with 2,4,6-trinitrotoluene (TNT) (20 mgl(-1)). 90-h TNT removal by these
      solutions was compared to controls. Spinach and parrotfeather extract solutions
      removed 99% and 50% of the initial TNT, respectively; TNT was not eliminated in
      the controls or in extract solutions where removal activity was deactivated by
      boiling. A first-order removal constant of 0.052 h(-1) was estimated for spinach
      extract solutions treating 20 mgl(-1) TNT concentrations, which compared
      favorably to intact plant removal. Concentration variation was described by
      Michaelis-Menton kinetics. Detectable TNT degradation products represented only a
      fraction of the total TNT transformed, and the transformation favored the
      formation of 4-aminodinitrotoluene. The results indicated that crude plant
      extracts transform TNT, without the presence of the live plant.

PMID- 15013678
TI  - Kinetics of quinoline degradation by O3/UV in aqueous phase.
AB  - The kinetics of quinoline degradation by O3/UV in aqueous phase was studied in
      this paper. It was found that the stoichiometric factor for the number of ozone
      molecule consumed by per quinoline molecule was 1. The second-order rate
      constants at 15 degrees C for the direct reaction of quinoline with ozone and
      that for the reaction of quinoline with *OH were determined to be 51.0 and 7.24 x
      10(9) M(-1)s(-1), respectively. In O3/UV reaction system, *OH was the more
      important oxidant to degrade quinoline than ozone. For a comparison, in O3
      reaction system, the relative importance of the two oxidants depended on the pH
      value greatly. To make the degradation of quinoline more practical, improvement
      of the concentration of *OH is more feasible.

PMID- 15013679
TI  - Polycyclic aromatic hydrocarbons in solid residues from waste incineration.
AB  - Polycyclic aromatic hydrocarbons (PAH) levels in solid residues from clinical
      waste incineration were measured using HPLC with fluorescence detection. PAH mass
      emission rates and emission rates as a function of waste burned are also
      reported. For bottom ash, PAH levels and physical properties were found to be
      quite consistent. Levels of high molecular mass PAHs were comparable to levels
      previously reported in the literature when adjusted for differences in sample
      preparation techniques. However, levels of low molecular mass PAHs were
      considerably elevated in this study. Possible reasons for this finding include
      the composition of the waste, combustion conditions and methods of sample
      preparation. In contrast, no PAHs were found in fly ash, an unexpected finding
      which is probably attributable to matrix effects resulting from a surfeit of lime
      in the fly ash. Factors effecting the partitioning of PAHs and their
      environmental fate are also discussed.

PMID- 15013680
TI  - Biofiltration of trimethylamine-containing waste gas by entrapped mixed microbial
      cells.
AB  - The study provides novel attempt to use an aerobic biofiltration system
      containing entrapped mixed microbial cells (EMMC) for removal of (CH3)3N-dominant
      waste gases. In the study, heterotrophic microflora-immobilized cellulose was
      packed into an EMMC reactor to degrade (CH3)3N. Effects of (CH3)3N inlet
      concentrations in continuous mode of operation at various flow rates are
      indicated. The result indicated that the (CH3)3N removal efficiency is higher
      than 90% at inlet loading below 27.2 mgNh(-1) and retention time 5.3 min. In
      addition, the maximal mass loading to reach approximately 99% efficiency was 95.5
      mgNh(-1) for trimethylamine treatment. This EMMC biofiltration system also showed
      higher tolerance to endure fluctuations in concentrations and flow rates and
      still maintained in stable performance for removal. Adaptability test in response
      to gradual shift up and down of inlet TMA loading indicated that lack of steady
      state multiplicity and hysteresis guarantees the microbial communities more
      precisely adapted to continuous treatment for maintaining stability.

PMID- 15013681
TI  - pH indications in aqueous organic photodecompositions with carbonyl and hydroxyl
      groups.
AB  - A pH variation pattern during organic compound (ethylene glycol, phenol, and
      glucose) decomposition under UV/H2O2 of different schemes was observed. This
      method was successfully applied to reflect the organic carbon oxidation progress,
      especially the rapid chemical oxygen demand (COD) decrease timing in the later
      mineralization stage. The results were demonstrated in a sequential feed-batch
      advanced oxidation reactor, showing that pH can be used as an alternative
      indicator to provide complete oxidation and cycle time information.

PMID- 15013682
TI  - Effects of ultraviolet light (315 nm), temperature and relative humidity on the
      degradation of polylactic acid plastic films.
AB  - The influence of temperature (30, 45 and 60 degrees C) and relative humidity (RH)
      (30%, 50% and 100%) on the degradation of poly(l-lactic acid) (PLA) films were
      studied. In addition, the effects of ultraviolet (UV) light (315 nm) on the
      degradation of PLA films were also analyzed. Various analytical techniques were
      applied to observe changes in the properties of PLA polymer films. FTIR
      spectroscopy was used as semi-quantitative method to get information about the
      chemistry of the degradative process. The degradation rate of PLA was enhanced by
      increasing temperature and RH, factors responsible for a faster reduction of the
      weight-average molecular weight (M(W)), of the glass transition temperature (Tg)
      and of the percentage of elongation at break. Moreover, UV treatment accelerated
      these phenomena.

PMID- 15013683
TI  - Control of bacterial growth in water using synthesized inorganic disinfectant.
AB  - Chlorine is a popular method for controlling bacterial growth in cooling towers.
      However, there are several drawbacks such as the difficulties in maintaining the
      disinfection efficacy particularly at high temperature and pH. In order to
      overcome these difficulties, an inorganic disinfectant based on silver and
      copper, which is called EEKO-BALL (commercial name), was recently developed. EEKO
      BALL is made from specific ceramics and coating materials. This study was
      performed to evaluate the efficacy of EEKO-BALL and compare it with that of
      silver (Ag+) and copper (Cu2+) ions. In addition, a field study was undertaken to
      investigate the control of bacterial growth in several cooling tower systems. The
      results showed that the contact time required for inactivating 99% of E. coli was
      15 min in the EEKO-BALL stock solution at 25 degrees C, pH 7.3, with 0.05 mgl(-1)
      Ag and 0.05 mgl(-1) Cu. EEKO-BALL was approximately four times more effective
      than silver and copper ions in inactivating E. coli at 25 degrees C, pH 7.3. The
      control of bacterial growth in the cooling towers was found to be effective,
      lasting more than two months after a one-time installation of the EEKO-BALL.
      Overall, this study suggests that EEKO-BALL can effectively work as an inorganic
      disinfectant for bacterial growth control.

PMID- 15013684
TI  - Sorption of hydrophobic organic compounds onto organoclays.
AB  - The behavior and fate of nonionic hydrophobic organic compounds (HOCs) in the
      environment are mainly controlled by their interactions with various components
      of soils and sediments. Due to their large surface area and abundance in many
      soils, smectites may greatly influence the fate and transport of the contaminants
      in the environment. In our experiments, HOC sorption by
      hexadecyltrimethylammonium (HDTMA)-modified smectite linearly increased with the
      amount of HDTMA added to the clay. However, tetramethylammonium (TMA)- and
      dodecyltrimethylammonium (DTMA)-modified smectites showed not only inferiority in
      their sorption of HOC compared with the HDTMA-smectite, but also a partially
      decreased HOC sorption at specific surfactant loading levels. This means that the
      sorption of organoclays for organic contaminants was significantly influenced by
      the amount and size of the surfactants added on the clay. In addition, it seems
      that the interlayer structure (e.g., pore size) formed at each surfactant loading
      level plays an important role to adsorb HOC in different amount.

PMID- 15013685
TI  - The androgen receptor: a potential target for therapy of prostate cancer.
AB  - The androgen receptor plays a pivotal role in the prostate. Its primary function
      is to provide responsive gene products for differentiation and growth, but under
      abnormal conditions it contributes to the development of prostate cancer. The
      goal of this review is to elucidate the molecular functions of the androgen
      receptor and its role in prostate cancer. Initially the function of the androgen
      receptor will be described. Next, the clinical diagnosis, epidemiological impact,
      and treatments of androgen-dependent and -independent prostate cancer will be
      discussed. Finally we will examine how the mechanism of androgen action has
      played a role in the translation of new therapies and how this may influence
      future treatment modalities of prostate cancer.

PMID- 15013686
TI  - Chirality effect of C-20 on metabolism of methyl 11beta,17alpha,20-trihydroxy-3
      oxo-1,4-pregnadien-21-oate derivatives.
AB  - Epimers at C-20 of methyl 11beta,17alpha,20-trihydroxy-3-oxo-1,4-pregnadien-21
      oates, their 9alpha-fluoro analogs, their carbonate derivatives, and their
      acetonide derivatives were subjected to metabolism study in rat plasma and rat
      liver homogenate. These steroids were synthesized based on the antedrug concept.
      In rat plasma, the carboxy ester bonds of 20beta-triols and their acetonides were
      hydrolyzed with half-lives (T(1/2)) of between 5.7 and 7.7 min, while their
      corresponding alpha-epimers had longer half-lives of more than 2.5 h. A more
      profound difference was observed between the alpha- and beta-epimers of the
      carbonates, with the latter showing a T(1/2) less than 1 min (0.3 and 0.43 min
      for P20beta- and PF20beta-carbonate, respectively), while that of the former
      about 3 h (165 min for P20alpha-carbonate and 191 min for PF20alpha-carbonate).
      In rat liver homogenate, the triol and acetonide derivatives showed greater
      stability than they did in rat plasma, with T(1/2) for the beta-group in the
      range of 54-108 min, and T(1/2) for the alpha-group over 7 h. A significant
      difference in hydrolysis of the carbonate derivatives was also observed in rat
      liver homogenate. The half-lives of P20beta- and PF20beta-carbonate were 0.67 and
      0.66 min, respectively, and the alpha-isomers showed the similar metabolic rate
      with other alpha-isomers. An esterase inhibitor effectively blocked the
      hydrolysis of the ester bond, indicating that this metabolism is an enzymatic
      reaction. Molecular modeling studies show that steric hindrance around the ester
      group of the alpha-epimers is much greater than that of their beta-counterparts,
      affording one explanation for the large difference in the metabolic hydrolysis
      rate; i.e. the carboxy ester bond of beta-isomer which is less hindered
      sterically than their counter alpha-isomers is hydrolyzed faster than that of
      alpha-isomers. In conclusion, this study confirms that chirality at C-20 had
      profound effects on metabolism and pharmacological profile of the steroid acid
      ester derivatives.

PMID- 15013687
TI  - Ophirasterol, a new C31 sterol from the marine sponge Topsentia ophiraphidites.
AB  - Analysis of the sterol fraction obtained from the Colombian Caribbean sponge
      Topsentia ophiraphidites revealed that this sponge is a rich source of C30 and
      C31 sterols. Among them, a new C31 sterol, named ophirasterol, was isolated, and
      its structure was established as (22E,24R)-24-(1-buten-2-yl)cholesta-5,22-dien
      3beta-ol (1) by spectral means and comparison with synthetic C-24 epimers with
      known configuration. Other isolated C30 and C31 sterols were the known 24-ethyl
      24-methyl-22-dehydrocholesterol (2), 24-isopropyl-22-dehydrocholesterol (3), 24
      isopropylcholesterol (4), 24-ethyl-24-methylcholesterol (5), 24-isopropenyl-25
      methyl-22-dehydrocholesterol (6) and 24-isopropenyl-25-methylcholesterol (7), and
      24-isopropenyl-22-dehydrocholesterol (8).

PMID- 15013688
TI  - Screening of free 17-alkyl-substituted anabolic steroids in human urine by liquid
      chromatography-electrospray ionization tandem mass spectrometry.
AB  - A qualitative liquid chromatography-electrospray ionization tandem mass
      spectrometry method was developed for screening of the abuse of 4
      chlorodehydromethyltestosterone, danazol, fluoxymesterone, formebolone,
      metandienone, oxandrolone, and stanozolol. The introduced method measures
      simultaneously nine different 17-alkyl-substituted anabolic androgenic steroids
      or their unconjugated metabolites in human urine, using methyltestosterone as an
      internal standard. Sample preparation involved one-step liquid extraction. Liquid
      chromatographic separation was achieved on a reversed-phase column with methanol
      water gradient containing 5 mmol/l ammonium acetate and 0.01% (v/v) acetic acid.
      Compounds were ionized in the positive mode and detected by multiple reaction
      monitoring. All steroids within the study could be selectively detected in urine
      with detection limits of 0.1-2.0 ng/ml. The method showed good linearity up to
      250 ng/ml with correlation coefficients higher than 0.9947. With simple and fast
      sample preparation, low limits of detection, and high selectivity and precision,
      the developed method provides advantages over the present testing methods and has
      the potential for routine qualitative screening method of unconjugated 17-alkyl
      substituted anabolic steroids in human urine.

PMID- 15013689
TI  - Steroidal saponins from fresh stem of Dracaena cochinchinensis.
AB  - A further phytochemical investigation on the fresh stem of Dracaena
      cochinchinensis yielded 18 steroidal saponins. Fourteen of which are new
      compounds, designated as 25(R,S)-dracaenosides E-H, M, O-Q, dracaenosides I-L, R,
      and 25(S)-dracaenoside N. Their structures were determined by detailed
      spectroscopic analysis, including extensive 1D and 2D NMR data, and the result of
      hydrolytic reaction.

PMID- 15013690
TI  - The increase in plasma C19Delta5 steroids in subcutaneous abdominal and jugular
      veins of dairy cattle during pregnancy is unrelated to estrogenic activity.
AB  - Plasma concentrations of dehydroepiandrosterone (DHEA), 5-androstene-3beta,17beta
      diol (AED), and 17beta-estradiol (E2) in dairy cows and heifers and AED binding
      to uterine cytosolic estrogen receptor (ER) were studied. Plasma samples were
      collected from the subcutaneous abdominal (SA) and jugular (J) veins of heifers
      and cows in the non-pregnant state and at 15-45, 90-120, 180-210, and 250-280
      days of pregnancy (N = 5-12). Plasma DHEA, AED, and E2 were determined by RIA.
      DHEA and AED significantly increased (P < 0.001) in heifers and cows throughout
      pregnancy. The stage of pregnancy significantly (P < 0.001) affected the three
      steroids in heifers and cows. Plasma DHEA increased throughout pregnancy in both
      heifers and cows, and in heifers it was significantly greater in SA than in J
      veins at 90-120 days (P < 0.01). Plasma AED was greater in heifers than in cows
      in J veins at 90-120 days (P < 0.01) and 180-210 days (P < 0.05), and in SA
      veins, at 15-45 days (P < 0.01) and 90-120 days (P < 0.05). In heifers,
      circulating AED showed concentration values significantly greater than those in
      non-pregnant animals from 90 to 120 days (P < 0.05) and was significantly greater
      in SA than in J veins at 90-120 days (P < 0.05). In cows, plasma AED was
      significantly greater than in non-pregnant animals at 250-280 days (P < 0.01). In
      heifers, plasma E2 was significantly greater in the SA than in the J veins from
      180-210 to 250-280 days (P < 0.01). In cows, differences between E2 plasma
      concentrations in J and SA veins were observed only at 250-280 days of pregnancy.
      At 250-280 days, in both animal types plasma E2 was significantly greater than in
      non-pregnant animals (P < 0.001). We suggest that AED originates primarily from
      the feto-placental unit, while mammary E2 synthesis near term can affect plasma
      concentrations. Binding data showed that AED is a weak competitor for cytosolic
      ER (IC50 range: 1.44 x 10(-5) to 3.71 x 10(-5) M). These results suggest that a
      direct estrogenic activity for AED is unlikely in dairy cattle, and the
      physiological role of AED needs to be elucidated.

PMID- 15013692
TI  - Antioxidant effects of dehydroepiandrosterone and 7alpha-hydroxy
      dehydroepiandrosterone in the rat colon, intestine and liver.
AB  - This study examined in healthy male Wistar rats the in vivo antioxidant effect of
      dehydroepiandrosterone (DHEA) and 7alpha-hydroxy-DHEA administered by
      intraperitoneal injections (50 mg/kg body weight) for 2 or 7 days. Markers of
      oxidative damage to lipids (thiobarbituric acid-reacting substances, TBARS) and
      to proteins (protein carbonyls) were assessed in colon, small intestine, and
      liver homogenates. DHEA and 7alpha-hydroxy-DHEA caused a decrease in body weight.
      DHEA treatment significantly increased liver, colon, and small intestine cell
      weights. After 7 days, DHEA exerted an antioxidant effect in all organs studied.
      In the colon, oxidative damage protection was accompanied by a goblet cell
      proliferation and increase in acidic mucus production. After 2 days, the
      antioxidant effect of 7alpha-hydroxy-DHEA was mainly observed in the liver.
      Nonprotein sulfhydryl groups (mostly glutathione levels) were altered by DHEA in
      the liver whereas they remained unchanged after 7alpha-hydroxy-DHEA treatment.
      The results indicate that in healthy animals, DHEA exerts a protective effect,
      particularly in the colon, by reducing the tissue susceptibility to oxidation of
      both lipids and proteins. This effect was not limited to a specific tissue,
      whereas the metabolite 7alpha-hydroxy-DHEA exerted its antioxidant effect towards
      the two markers of oxidative damage earlier than DHEA, and mainly in the liver.

PMID- 15013691
TI  - Esterification of vertebrate-type steroids in the Eastern oyster (Crassostrea
      virginica).
AB  - Characteristics of acyl-coenzyme A (acyl-CoA):steroid acyltransferase from the
      digestive gland of the oyster Crassostrea virginica were determined by using
      estradiol (E2) and dehydroepiandrosterone (DHEA) as substrates. The apparent Km
      and Vmax values for esterification of E2 with the six fatty acid acyl-CoAs tested
      (C20:4, C18:2, C18:1, C16:1, C18:0, and C16:0) were in the range of 9-17 microM
      E2 and 35-74 pmol/min/mg protein, respectively. Kinetic parameters for
      esterification of DHEA (Km: 45-120 microM; Vmax: 30-182 pmol/min/mg protein)
      showed a lower affinity of the enzyme for this steroid. Formation of endogenous
      fatty acid esters of steroids by microsomes of digestive gland and gonads
      incubated in the presence of ATP and CoA was assessed, and at least seven E2
      fatty acid esters and five DHEA fatty acid esters were observed. Some peaks
      eluted at the same retention times as palmitoleoyl-, linoleoyl-, oleoyl/palmitoyl
      , and stearoyl-E2; and palmitoleoyl-, oleoyl/palmitoyl-, and stearoyl-DHEA. The
      same endogenous esters, although in different proportions, were produced by
      gonadal microsomes. The kinetic parameters for both E2 (Km: 10 microM; Vmax: 38
      pmol/min/mg protein) and DHEA (Km: 61 microM; Vmax: 60 pmol/min/mg protein) were
      similar to those obtained in the digestive gland. Kinetic parameters obtained are
      similar to those observed in mammals; thus, fatty acid esterification of sex
      steroids appears to be a well-conserved conjugation pathway during evolution.

PMID- 15013693
TI  - The uses of carcinogen-DNA adduct measurement in establishing mechanisms of
      mutagenesis and in chemoprevention.
AB  - DNA adducts generated by carcinogenic chemicals reflects human exposure and DNA
      adducts are related to tumor formation. Most chemical carcinogens require
      activation to reactive intermediates that bind to nucleophilic centers in
      proteins and nucleic acids thereby forming covalent adducts. Also, many of the
      chemicals considered carcinogenic for humans form covalent DNA adducts.
      Therefore, such DNA damage is generally considered to be causative and linked to
      tumor formation. In this article we have summarized the work done for many years
      on the role of DNA adduct formation as an indicator of their carcinogenicity. We
      have also addressed the important role for measurement of DNA adducts in studies
      with potential chemopreventive agents for which it is central to have a marker
      that can be measured more rapidly than changes in cancer incidence.

PMID- 15013694
TI  - Analysis of mutations and bone marrow micronuclei in Big Blue rats fed
      leucomalachite green.
AB  - Leucomalachite green (LMG) is the major metabolite of malachite green (MG), a
      triphenylmethane dye that has been used widely as an antifungal agent in the fish
      industry. Concern over MG and LMG is due to the potential for consumer exposure,
      suggestive evidence of tumor promotion in rodent liver, and suspicion of
      carcinogenicity based on structure-activity relationships. In order to evaluate
      the risks associated with exposure to LMG, female Big Blue rats were fed up to
      543 ppm LMG; groups of these rats were killed after 4, 16, or 32 weeks of
      exposure and evaluated for genotoxicity. We previously reported that this
      treatment resulted in a dose-dependent induction of liver DNA adducts, and that
      the liver lacI mutant frequency (MF) was increased, but only in rats fed 543 ppm
      LMG for 16 weeks. In the present study, we report the results from lymphocyte
      Hprt mutant assays and bone marrow micronucleus assays performed on these same
      rats. In addition, we have determined the types of lacI mutations induced in the
      rats fed 543 ppm LMG for 16 weeks and the rats fed control diet. No significant
      increases in the frequency of micronuclei or Hprt mutants were observed for any
      of the doses or time points assayed. Molecular analysis of 80 liver lacI mutants
      from rats fed 543 ppm LMG for 16 weeks revealed that 21% (17/80) were clonal in
      origin and that most (55/63) of the independent mutations were base pair
      substitutions. The predominant type of mutation was G:C --> A:T transition
      (31/63) and the majority (68%) of these involved CpG sites. When corrected for
      clonality, the 16-week lacI mutation frequency (36 +/- 10) x 10(-6) in treated
      rats was not significantly different from the clonally corrected control
      frequency (17 +/- 9 x 10(-6); P = 0.06). Furthermore, the lacI mutational
      spectrum in treated rats was not significantly different from that found for
      control rats (P = 0.09). Taken together, these data indicate that the DNA adducts
      produced by LMG in female rats do not result in detectable levels of
      genotoxicity, and that the increase in lacI MF observed previously in the liver
      of treated rats may be due to the disproportionate expansion of spontaneous lacI
      mutations.

PMID- 15013695
TI  - A statistical treatment of biases affecting the estimation of mutation rates.
AB  - We consider the estimation of mutation rates, using family data obtained from
      disputed paternity cases. It is shown how to take appropriate account of a number
      of complicating features-in particular, hidden mutation, differential mutation,
      and uncertain paternity-which can necessitate large corrections to simple
      estimates.

PMID- 15013696
TI  - Analysis of CYP1A1 exon 7 polymorphisms by PCR-SSCP in a Brazilian population and
      description of two novel gene variations.
AB  - CYP1A1 polymorphisms have been associated with a higher risk to develop lung
      cancer, particularly in Japanese. The type and the frequency of the polymorphisms
      can vary according to the ethnicity. In the present study, we aimed to determine
      the frequency of CYP1A1(*)2B and (*)4, and to look for other possible
      polymorphisms that may happen in exon 7 in individuals from Rio de Janeiro, an
      ethnic mixed population from Brazil. We developed a PCR-SSCP method for screening
      the genomic polymorphic region from 2289 to 2645 bp. Seven different migration
      patterns were found among 405 individuals, 130 healthy blood donors and 275
      outpatients from Hospital Universitario Pedro Ernesto located in Rio de Janeiro.
      Five of the migration patterns corresponded to the genotypes: (*)1/(*)1 (the wild
      type); (*)1/(*)2B; (*)1/(*)4, (*)2B/(*)4 (heterozygous polymorphic) and
      (*)2B/(*)2B (homozygous polymorphic). Two other patterns corresponded to gene
      alterations not yet published: a C > T transition localized at the position 2461,
      and a C > T transition localized at position 2445. The genotype frequencies of
      the studied polymorphisms were: for CYP1A1(*)2B - 83.7% to (*)1/(*)1, 15.1% to
      (*)1/(*)2B and 1.2% to (*)2B/(*)2B; for CYP1A1(*)4 - 93.1% to (*)1/(*)1, 6.9% to
      (*)1/(*)4. The distribution of CYP1A1(*)2B and (*)4 genotypes combined were
      similar between white and non-white individuals. However, when the non-white
      individuals were stratified between blacks and mulattos, and then compared with
      white, black individuals showed a higher frequency of the wild type genotype (P =
      0.008) and a lower frequency of genotype (*)1/(*)4 (P = 0.026). Additionally,
      when black and mulatto individuals were compared, blacks had a higher frequency
      of the wild type genotype (P = 0.008) and a lower frequency of the(*)1/(*)2B
      genotype (P = 0.0008), showing a different ethnic distribution of CYP1A1
      polymorphisms.

PMID- 15013697
TI  - Directly fishing out subtle mutations in genomic DNA with histidine-tagged
      Thermus thermophilus MutS.
AB  - Tth MutS, a mismatch repair protein from Thermus thermophilus, was reported to
      effectively recognize all eight possible types of base pair mismatches and
      insertions or deletions up to three base pairs at a wide temperature range up to
      60 degrees C. Here a procedure for directly fishing out subtle unknown mutations
      in bacterial genome with Tth MutS was described. Wild type genomic DNA and mutant
      one were mixed, digested with restriction enzymes, denatured and re-annealed.
      Hetero-duplex DNA carrying mispaired bases were bound to Tth MutS and recovered
      through Ni-NTA His-Bind((R)) Resin. The recovered DNA was cloned into plasmids,
      producing a mini-library with inserts of the mutated regions. Further DNA
      sequencing and genetic complementation demonstrated that the method was extremely
      efficient in fishing out the mutations from total genomic DNA. Using this method,
      the mutations existed in a Psedomonas aeruginosa mutant strain were screened,
      indicating that A/G transitions at nt 181 and nt 314 in chloramphenicol
      acetyltransferase (catB7) gene conferred this strain with a high chloramphenicol
      dosage resistant. Compared with those reported previously, this protocol can
      screen the mixed mutations more easily.

PMID- 15013698
TI  - A novel mutation of the IRF6 gene in an Italian family with Van der Woude
      syndrome.
AB  - Van der Woude syndrome (VWS) is the most common type of syndromic orofacial
      cleft, being characterised by variable association of lower lip pits, cleft lip
      and cleft palate. VWS is transmitted in an autosomal dominant manner, with high
      penetrance and variable expressivity, and a gene for this disease has been mapped
      in 1q32-q41. Very recently, mutations of the interferon regulatory factor 6
      (IRF6) gene have been found in VWS patients, suggesting that this gene plays an
      important role in the orofacial development. We report a novel mutation of the
      IRF6 in an Italian family with six members affected by VWS with different
      expression. This mutation, the W217X, produces a stop codon within exon 6 of the
      IRF6 gene, with loss of the SMIR domain of the IRF6 protein.

PMID- 15013699
TI  - Polycyclic aromatic hydrocarbon-DNA adducts determined by semiquantitative
      immunohistochemistry in human esophageal biopsies taken in 1985.
AB  - Esophageal endoscopic biopsy samples were obtained in 1985 in Linxian, China, a
      region with very high esophageal cancer incidence rates, and where ingested food
      is known to contain substantial amounts of polycyclic aromatic hydrocarbons
      (PAHs). In this study, the automated cellular imaging system (ACIS) was used for
      localization and semi-quantitation of PAH-DNA adducts. Fresh tissue sections were
      cut from archived paraffin blocks and incubated with an antiserum elicited
      against DNA modified with 7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10
      tetrahydro-benzo[a]pyrene (BPDE). Nuclear PAH-DNA adduct staining was observed in
      four out of five human samples incubated with the anti-BPDE-DNA. By visual
      inspection, nuclei in the basal layer of the esophageal epithelium had higher
      levels of PAH-DNA adducts compared to those found in the adjacent superficial
      squamous layer. Nuclear PAH-DNA staining was absent in serial sections incubated
      with either normal rabbit serum or BPDE-DNA-antiserum previously absorbed with
      the immunogen BPDE-DNA. Semi-quantitative evaluation by ACIS revealed that per
      nucleus values for PAH-DNA adducts in the basal layer of the esophageal
      epithelium were 5- to 40-fold higher than those in the adjacent superficial
      squamous layer (P < 0.0001), using a random effects model). This pilot study
      demonstrates the presence of PAH-DNA adducts in archived paraffin-embedded
      endoscopic esophageal biopsy samples that are close to 20 years old, and suggests
      that an appropriate set of archived samples could be used to prospectively
      correlate PAH-DNA adduct formation with risk of esophageal cancer development.

PMID- 15013700
TI  - Analysis of mutations in the Tk gene of Tk(+/-) mice treated as neonates with 3'
      azido-3'-deoxythymidine (AZT).
AB  - Mother-to-child transmission of the human immunodeficiency virus (HIV) is reduced
      by perinatal treatment with the antiretroviral nucleoside analogue 3'-azido-3'
      deoxythymidine (AZT, zidovudine). AZT, however, is genotoxic and carcinogenic in
      mice when administered either transplacentally or neonatally, suggesting a
      possible cancer risk for children later in life. In a previous study we found
      that treating B6C3F1/Tk(+/-) mice on postnatal days 1 through 8 with
      intraperitoneal injections of 200 mg AZT per kg body weight per day significantly
      increased spleen lymphocyte mutant frequencies in the autosomal Tk gene. Allele
      specific PCR of Tk mutants from treated mice indicated that 61% had lost the
      Tk(+) allele (loss of heterozygosity; LOH), compared with 35% of Tk mutants from
      control mice, a difference that was significant. In the present study, Tk mutant
      lymphocyte clones were analyzed further using polymorphic microsatellite markers
      that flank the Tk gene along the length of mouse chromosome 11. The analysis
      indicated that allele-loss mutations in control mice were due to either total
      chromosome loss, mitotic recombination, or both. The pattern of marker loss in
      mutants from AZT-treated mice differed significantly from the control mice and
      was consistent with chromosome loss, mitotic recombination, interstitial
      deletion, gene conversion, and an unusual discontinuous LOH. The results indicate
      that AZT induced a unique pattern of mutations in the Tk gene of mice and that
      the major mechanisms of mutation by AZT involved deletion and recombination.

PMID- 15013701
TI  - Somatic mutations in the D-loop and decrease in the copy number of mitochondrial
      DNA in human hepatocellular carcinoma.
AB  - Somatic mutations in mitochondrial DNA (mtDNA) have been detected in many human
      cancers, including hepatocellular carcinoma (HCC). The D-loop region was found to
      be a "hot spot" for mutation in mtDNA of the tumors. However, effects of the D
      loop mutations on the copy number of mtDNA in tumor tissues are poorly
      understood. Using direct sequencing, we examined mutations in the D-loop region
      of mtDNA in 61 HCCs and the corresponding non-tumor liver tissues. The results
      revealed that 39.3% of the HCCs carried somatic mutation(s) in the D-loop of
      mtDNA, and most of these mutations were homoplasmic. Moreover, 37.0% (10/27) of
      these mutations were T-to-C and G-to-A transitions and 40.7% (11/27) of them were
      located in the polycytidine stretch between nucleotide position (np) 303 and 309
      of mtDNA. In addition, we found that mtDNA copy number of HCC was significantly
      decreased in 60.5% of the patients with hepatoma, especially in those with
      somatic mutation(s) in the D-loop of mtDNA (17/24). This decrease in mtDNA copy
      number was highly associated with the occurrence of point mutations near the
      replication origin of the heavy-strand of mtDNA. Interestingly, we found that
      42.9% (6/14) of the HCCs without mutation in the D-loop had a reduced copy number
      of mtDNA, indicating that other unidentified factors involved in mitochondrial
      biogenesis might be defective in the tumor. The results obtained in this study
      strongly suggest that somatic mutations in the D-loop together with the decrease
      in the copy number of mtDNA may be an important event during the early phase of
      liver carcinogenesis.

PMID- 15013702
TI  - Occupational epidemiological study of workers in an acrylonitrile using factory
      with particular attention to cancers and birth defects.
AB  - An occupational epidemiological study was organised among workers in an
      acrylonitrile using factory in Hungary. Of the 888 workers, 783 were included in
      the study and three groups were differentiated: Group A (N = 452) with direct and
      continuous exposure, Group B (N = 171) with direct but occasional exposure and
      Group C (N = 160) without direct exposure, as referent. There were two main
      objectives: to determine the occurrence of cancer in workers and congenital
      abnormalities in their liveborn infants. The study did not indicate a higher
      occurrence of cancer among workers: only one lung cancer patient was found,
      prostate cancer did not occur. Among congenital abnormalities, the group of
      specified multiple congenital abnormalities showed a higher rate than expected
      but characteristic defect-pattern was not found among seven multimalformed
      babies, though five had cardiovascular malformations. In conclusion, our study
      did not indicate the carcinogenic, mutagenic and teratogenic effect of
      acrylonitrile among workers using this chemical in the factory.

PMID- 15013703
TI  - Spectrum of chromosomal aberrations in peripheral lymphocytes of hospital workers
      occupationally exposed to low doses of ionizing radiation.
AB  - Chromosome aberrations frequency was estimated in peripheral lymphocytes from
      hospital workers occupationally exposed to low levels of ionizing radiation and
      controls. Chromosome aberrations yield was analyzed by considering the effects of
      dose equivalent of ionizing radiation over time, and of confounding factors, such
      as age, gender and smoking status. Frequencies of aberrant cells and chromosome
      breaks were higher in exposed workers than in controls (P = 0.007, and P = 0.001,
      respectively). Seven dicentric aberrations were detected in the exposed group and
      only three in controls, but the mean frequencies were not significantly
      different. The dose equivalent to whole body of ionizing radiation (Hwb) did
      appear to influence the spectrum of chromosomal aberrations when the exposed
      workers were subdivided by a cut off at 50 mSv. The frequencies of chromosome
      breaks in both subgroups of workers were significantly higher than in controls (<
      or =50 mSv, P = 0.041; >50 mSv, P = 0.018). On the other hand, the frequency of
      chromatid breaks observed in workers with Hwb >50 mSv was significantly higher
      than in controls (P = 0.015) or workers with Hwb < or =50 mSv (P = 0.046).
      Regarding the influence of confounding factors on genetic damage, smoking status
      and female gender seem to influence the increase in chromosome aberration
      frequencies in the study population. Overall, these results suggested that
      chromosome breaks might provide a good marker for assessing genetic damage in
      populations exposed to low levels of ionizing radiation.

PMID- 15013704
TI  - Correlation of sister chromatid exchange formation through homologous
      recombination with ribonucleotide reductase inhibition.
AB  - We conducted the recombination and sister chromatid exchange (SCE) assays with
      five chemicals (hydroxyurea (HU), resveratrol, 4-hydroxy-trans-stilbene, 3
      hydroxy-trans-stilbene, and mitomycin C) in Chinese hamster cell line SPD8/V79 to
      confirm directly that SCE is a result of homologous recombination (HR). SPD8 has
      a partial duplication in exon 7 of the endogenous hprt gene and can revert to
      wild type by homologous recombination. All chemicals were positive in both assays
      except for 3-hydroxy-trans-stilbene, which was negative in both. HU, resveratrol,
      and 4-hydroxy-trans-stilbene were scavengers of the tyrosyl free radical of the
      R2 subunit of mammalian ribonucleotide reductase. Tyrosyl free radical scavengers
      disturb normal DNA replication, causing replication fork arrest. Mitomycin C is a
      DNA cross-linking agent that also causes replication fork arrest. The present
      study suggests that replication fork arrest, which is similar to the early phases
      of HR, leads to a high frequency of recombination, resulting in SCEs. The
      findings show that SCE may be mediated by HR.

PMID- 15013705
TI  - The genotoxic effect of carcinogenic PAHs, their artificial and environmental
      mixtures (EOM) on human diploid lung fibroblasts.
AB  - The aim of this study was to investigate the genotoxic effect of single
      carcinogenic polycyclic aromatic hydrocarbons (c-PAHs), as well as their binary
      and artificial mixtures containing c-PAHs in the same relative proportions as
      real complex mixtures, and to investigate the genotoxic effect of environmental
      mixtures such as EOM (extractable organic matter adsorbed to respirable air
      particles). We used normal human diploid lung fibroblasts (HEL) in a confluent
      ("quiescent") state as being closer to in vivo conditions. We determined DNA
      adducts by (32)P -postlabelling and the expression of p53 and p21(WAF1) proteins
      by Western blotting. Our results showed that the DNA binding potencies of c-PAHs
      in quiescent HEL cells were as follows: DB[al]P>>B[a]P>>B[b]F approximately CHRY
      approximately B[k]F approximately B[a]A approximately DB[ah]A approximately
      I[cd]P > B[ghi]P. Both DB[al]P and B[a]P were chosen to assess the genotoxic
      effect of other c-PAHs when present in binary mixtures. In all cases, co
      treatment resulted in significantly lower DNA adduct levels as compared with
      adduct levels resulting from single compounds. The highest inhibitory effect was
      found in the presence of DB[ah]A followed by B[k]F. In both artificial and EOM
      mixtures a strong inhibitory effect of other compounds was observed. BPDE-adduct
      levels were up to five-fold lower in an artificial c-PAH mixture and up to 10
      fold lower in an EOM sample than expected from applying B[a]P alone at the same
      concentration. These results suggest a competition for the metabolic activation
      enzymes, their saturation and/or inactivation by PAH metabolites. We did not
      observe the decrease of DNA adducts and induced levels of both p53 and p21(WAF1)
      proteins during the post-treatment period up to 6 days following exposure. We
      suggest that parent c-PAHs accumulate inside cells and that they are further
      activated by newly synthesised enzymes during the post-treatment period.
      Therefore, unaltered c-PAHs may act as a reservoir inside the cells for the long
      term production of active metabolites. The total DNA adduct levels induced in HEL
      cells after exposure to EOM were generally low as compared with exposure to B[a]P
      alone under the same conditions. Human diploid lung fibroblasts possess low
      metabolic capacity than other human target cells. Therefore, it may be easier to
      competitively inhibit the metabolising enzymes in this cell system. We
      hypothesise that this finding might explain the generally low PAH-DNA adduct
      levels detected in human studies using surrogate cells such as blood WBC or
      lymphocytes that also possess low metabolic capacity.

PMID- 15013706
TI  - Enhanced stimulation of chromosomal translocations by radiomimetic DNA damaging
      agents and camptothecin in Saccharomyces cerevisiae rad9 checkpoint mutants.
AB  - Saccharomyces cerevisiae rad9 checkpoint mutants exhibit pleiotropic phenotypes,
      including higher frequencies of chromosome loss, radiation sensitivity, and
      decreased induction of DNA damage-inducible genes. We had previously shown that
      rad9 mutants exhibit higher frequencies of DNA damage-associated translocations
      but lower frequencies of DNA damage-associated sister chromatid exchange (SCE),
      compared to wild type. Herein, we have shown that differences between the
      frequencies of DNA damage-associated recombination in the rad9 mutant and wild
      type depend on the identity and the concentration of the DNA damaging agent.
      Translocation and SCE frequencies were measured in strains containing truncated
      his3 fragments, located either on chromosomes II and IV, or located in tandem on
      chromosome IV, respectively. DNA damage-associated frequencies of translocations
      after exposure to hydrogen peroxide (H(2)O(2)), bleomycin, phleomycin, cisplatin,
      and camptothecin are higher in the rad9 diploid than in wild type. However,
      translocation frequencies after exposure to 4-nitroquinoline 1-oxide (4-NQO) and
      N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are similar in rad9 and wild-type
      strains. We suggest that the deficiency in triggering G(2) arrest after exposure
      to specific DNA damaging agents results in the higher levels of DNA damage
      associated translocations in rad9 mutants.

PMID- 15013708
TI  - David Skinner at the University of Chicago (1972-1987).

PMID- 15013707
TI  - Differential expression of the MAD2, BUB1 and HSP27 genes in Barrett's oesophagus
      their association with aneuploidy and neoplastic progression.
AB  - Chromosomal instability (CIN) leading to aneuploidy is a ubiquitous and early
      event in the progression of Barrett's oesophagus, but its origins are unknown.
      Hence, the transcriptional levels of components of the mitotic spindle checkpoint
      (important in ensuring precise chromosome segregation) were examined in Barrett's
      lesions and correlated with the degree of aneuploidy present in the tissues. Gene
      expression levels of the MAD2 and BUB1 mitotic spindle checkpoint genes were
      assessed in 37 Barrett's patients (with histology ranging from metaplasia to
      adenocarcinoma) by real-time RT-PCR. In addition, the transcriptional levels of
      HSP27 were also examined as firstly, its expression is known to be down regulated
      in Barrett's metaplasia (BM) and thus was included as a positive control for the
      real-time RT-PCR assay. While, secondly, the expression pattern of this gene
      during Barrett's neoplastic progression was investigated, as this has not been
      previously assessed. Both over and under expression of the MAD2 and BUB1 mitotic
      spindle checkpoint genes were detected at all Barrett's histological stages with
      no apparent selective trend with neoplastic progression. In addition, no
      correlation with aneuploidy was established, indicating an alternative mechanism
      must underlie Barrett's associated chromosomal instability. HSP27 expression was
      reduced in metaplasia and then significantly increased with progression. Gender
      related differences were observed and HSP27 expression was higher in poorly
      differentiated adenocarcinomas than in well-differentiated forms. HSP27
      transcriptional patterns therefore present potential as a prognostic tool to
      predict the aggressiveness of oesophageal adenocarcinomas (OA).

PMID- 15013709
TI  - Ischemia, reperfusion, and the role of surgery in the treatment of cardiogenic
      shock secondary to acute myocardial infarction: an interpretative review.
AB  - Cardiogenic shock (CS) is the leading cause of death for patients hospitalized
      with acute myocardial infarction (AMI). Despite contemporary management of AMI,
      the incidence of shock due to left ventricular failure has not declined and its
      mortality continues to be in excess of 50%. Furthermore, the role and indications
      of the different means of acute revascularization remain unclear. Recent
      observational and randomized studies have shown improved survival in patients
      acutely revascularized by either percutaneous interventions or conventional
      surgery, particularly in patients younger than 75 years of age. Current
      guidelines recommend surgical revascularization in selected patients with
      multiple vessel disease who develop shock due to progressive ischemia of the
      remote myocardium up to 18 h from the onset of shock. However, patients with
      single-vessel disease who develop shock as a consequence of the initial
      infarction can only be helped if revascularization is achieved during the first 4
      to 6 h after the occlusion of the infarct related artery, preferable by
      percutaneous techniques. Not all ischemic myocytes become irreversibly injured at
      the same time. Due to variability in the distribution of collateral flow, there
      is great variability in the severity of ischemia. Myocytes can exhibit different
      metabolic responses including hibernation, ischemic preconditioning, stunning,
      reperfusion injury, and necrosis. Precise knowledge of these biochemical and
      metabolic changes that take place in the myocardium after arterial occlusion and
      following reperfusion is paramount to the understanding of the indications for
      acute revascularization, the implementation of the different management
      strategies to enhance myocardial preservation and recovery, and the role of
      circulatory support in these exceedingly sick patients.

PMID- 15013710
TI  - Current status of multimodality therapy for esophageal carcinoma.

PMID- 15013711
TI  - Gastroesophageal reflux disease: a historical review of surgical therapy.

PMID- 15013712
TI  - Surgical management of esophageal motility disorders.

PMID- 15013713
TI  - Barrett's esophagus: management of high-grade dysplasia and cancer.
AB  - Esophagectomy remains the treatment of choice for the appropriate patient with
      Barrett's adenocarcinoma invading beyond the mucosa, without evidence of distant
      metastasis or invasion of adjacent organs. On the other hand, therapeutic
      management of patients with Barrett's high-grade dysplasia (HGD) or mucosal
      adenocarcinoma should be individualized, taking into account the patient's
      preferences, willingness to return for frequent endoscopic biopsies, and medical
      fitness to undergo esophagectomy. Surgery has to be considered the best treatment
      for HGD or superficial carcinoma, unless contraindicated by severe comorbidities,
      because it has proven to be the only treatment that is successful in curing the
      condition and preventing recurrent HGD or the development of invasive cancer.
      Nonsurgical treatment by photodynamic therapy or endoscopic mucosal resection may
      be a less invasive and organ-sparing option for elderly, poor-risk patients but
      it is still to be considered an investigational therapy that should only be
      conducted under a clinical trial protocol. Finally, intensive endoscopic biopsy
      surveillance of patients with HGD is another investigational option that may
      allow prompt treatment of cancer if it develops. However, few data document the
      safety of this observational approach.

PMID- 15013714
TI  - A laparoscopy-assisted surgical approach to esophageal carcinoma.
AB  - BACKGROUND: Surgical resection is the treatment of choice for esophageal
      carcinoma. Over the past decade, laparoscopy has proven an accurate staging
      modality for detecting peritoneal carcinosis and small metastatic liver deposits
      unsuspected at preoperative investigation. This has led to a change in surgical
      strategy in up to 20% of patients. In addition, by means of laparoscopic
      techniques, it is possible to mobilize the stomach and perform a safe transhiatal
      mediastinal dissection at least up to the level of the inferior pulmonary veins.
      PATIENTS AND METHODS: Laparoscopy-assisted esophagectomy was attempted in 43
      patients over the past 3 years. The esophagectomy was performed via laparoscopy
      combined with right thoracotomy (group A) or with left cervicotomy and
      transmediastinal endodissection (group B). RESULTS: The overall conversion rate
      to laparotomy was 11.6%. No hospital deaths occurred. The morbidity rate was 20%
      in group A and 30.7% in group B. The mean hospital stay was 11 in group A and 10
      days in group B. Five patients died between 11 and 19 months after surgery with
      recurrent disease. No port-site metastases were recorded during follow-up.
      CONCLUSIONS: This approach has proven feasible and safe in the medium-term follow
      up. Further experience and a longer follow-up are needed to assess the impact of
      these procedures on long-term survival.

PMID- 15013715
TI  - Extended surgery for cancer of the esophagus and gastroesophageal junction.
AB  - The overall prognosis of patients with carcinoma of the esophagus and
      gastroesophageal junction (GEJ) remains poor mainly because of the advanced stage
      of the disease at the time of presentation. As a result, controversy persists
      over the appropriate extent of surgery. This article reviews the impact of
      aggressive surgery on staging, disease-free survival, and cure rate. Despite
      recent advances in staging including positron emission tomography (PET), the
      findings after aggressive surgery indicate that the overall accuracy,
      sensitivity, and specificity of clinical staging are still too low. These
      shortcomings in clinical staging therefore question the value of the indications,
      results, and interpretation of outcomes in multimodality treatment regimens.
      Extended surgery increases the R(0) resection rate, which seems to have an
      undeniable beneficial effect on the incidence of locoregional recurrence and
      which should be considered as a parameter of surgical quality, especially within
      the context of multimodality trials. As to the effect on cure rate, the only
      randomized trial with published results did not indicate a significant difference
      between extended and more limited resections for adenocarcinoma of the esophagus
      and GEJ, albeit that a subsequent subanalysis did show a significant survival
      benefit favoring more extended surgery in distal third adenocarcinomas. However,
      the bulk of current literature suggests that better survival is achieved by more
      aggressive surgery. For three-field lymphadenectomy the available data suggest a
      potential survival benefit. It appears that positive cervical lymph nodes in
      patients with middle or proximal third carcinoma should no longer be considered
      as M(1a/b) distant lymph node metastasis but rather as N(1) regional disease.

PMID- 15013717
TI  - Side-to-side isoperistaltic strictureplasty in the treatment of extensive Crohn's
      disease.
AB  - BACKGROUND: First performed in 1992, the side-to-side isoperistaltic
      strictureplasty (SSIS) is a bowel-sparing surgical option for Crohn's patients
      presenting with sequentially occurring stenoses over long intestinal segments
      (>15 cm). This investigation was designed to study the outcomes and patterns of
      recurrence after a SSIS. MATERIALS AND METHODS: Between 1992 and 2003, 30
      patients underwent SSIS at the University of Chicago. Their data were gathered
      prospectively in an Institutional Review Board-approved database. RESULTS: A
      total of 31 SSISs were constructed in 30 patients. As an indication of the
      severity of disease in these patients, 25 of 30 (83%) required a concomitant
      bowel resection, and 13 (43%) underwent at least one additional strictureplasty.
      The average length of diseased bowel used to construct the SSIS was 51 cm. The
      average length of residual small bowel after performance of SSIS was 275 cm, and
      the SSIS represented an average 19% of the remaining small bowel that would have
      otherwise been sacrificed with resection. Three patients experienced
      perioperative complications (10%) and one died (3%). Seven patients (23%)
      required reoperation to treat recurrence of symptoms within the first 5 years. In
      four of these patients, recurrence was found at or near the previous SSIS.
      CONCLUSIONS: A side-to-side isoperistaltic strictureplasty (SSIS) is a safe and
      effective surgical option for sequentially occurring Crohn's strictures over long
      intestinal segments.

PMID- 15013718
TI  - Laparoscopic colon resection for colon cancer.
AB  - INTRODUCTION: Laparoscopic colon resection for cancer is as yet an unproven
      operation. This review article summarizes current data on the topic. METHODS: A
      Medline review identified articles published since 1990 summarizing patients with
      potentially curable colon cancer who underwent a laparoscopic-assisted colon
      resection. Only articles that were randomized or had a control group with
      historical or matched open cases were used. RESULTS: Very few prospective
      randomized controls exist. Several clinical trials are under way with one
      completed. Data thus far support some patient benefits with a laparoscopic
      approach. No differences in morbidity, oncologic data, or survival appear to
      exist. CONCLUSIONS: The results of ongoing clinical trials are still needed to
      further evaluate the role of laparoscopic assisted colon resection in patients
      with potentially curable colon cancer.

PMID- 15013716
TI  - Portal blood flow, effective hepatic blood flow, and outcome after partial portal
      decompression.
AB  - What a great time to practice Surgery! Things we only dreamed about 20 years ago
      are finding their way into clinical care and greater advances are around the
      corner. As practicing surgeons, we have prospered by being raised on the
      shoulders of giants in Surgery that trained and inspired us. Dr. David B. Skinner
      was such a giant.

PMID- 15013719
TI  - Lung cancer staging.
AB  - The staging of lung cancer is a continuously progressing field, with advances in
      technology not only improving prognostic accuracy, but fundamentally changing pre
      operative investigation algorithms. Noninvasive staging is currently undergoing
      revolutionary developments with the advent of Positron Emission Tomography,
      whereas Video-Assisted Thoracic Surgery has already been established as an
      essential, minimally invasive diagnostic tool for invasive histological staging.
      Molecular staging may transform future lung cancer staging, promising extremely
      accurate substaging, and potentially prompting a revision of our anatomically
      based conceptualization of lung cancer spread. This review presents an appraisal
      of current lung cancer staging modalities, and presents an overview of recent
      developments in molecular staging.

PMID- 15013720
TI  - Genomic surgery for lung cancer.
AB  - An emerging body of literature indicates that reversible alterations in chromatin
      structure modulate gene expression during malignant transformation. Chromatin
      structure is regulated in part by DNA methylation and histone acetylation; these
      independent yet highly interrelated epigenetic processes are influenced by a
      variety of signal transduction pathways. The present review highlights recent
      advances regarding cancer epigenetics, focusing on the potential utilization of
      chromatin remodeling agents to induce apoptosis and enhance the immunogenicity of
      thoracic malignancies.

PMID- 15013721
TI  - COX-2: a target for prevention and treatment of esophageal cancer.

PMID- 15013722
TI  - Prevalence of bone marrow micrometastases in esophagogastric cancer patients with
      and without neoadjuvant chemoradiotherapy.
AB  - BACKGROUND: Bone marrow micrometastases are present in a high proportion of
      patients undergoing curative resection for esophagogastric cancer. The
      incorporation of preoperative systemic therapies into these patients' treatment
      is widely practiced. This study investigates the effect of neoadjuvant
      chemoradiotherapy (CRT) on the incidence of micrometastases and the viability of
      detected tumor cells. MATERIALS AND METHODS: Rib bone marrow was obtained from
      patients (n = 106) in three centers, who were selected for potentially curative
      resection. Patients received neoadjuvant CRT plus surgery (n = 55), or surgery
      alone (n = 51). To detect micrometastases, mononuclear cells were isolated from
      fresh marrow and immediately stained immunohistochemically with an anti
      cytokeratin-18 antibody using the APAAP technique. Tumor cell viability was
      assessed by immunohistochemical staining of marrow cell cultures for cytokeratin
      positive cells. RESULTS: Micrometastases were detected in fresh marrow in 42%
      (23/55) of patients who received neoadjuvant CRT plus surgery, and in 67% (34/51)
      of patients treated with surgery alone. Viable tumor cells were demonstrated in
      10 of 18 marrow cultures from CRT plus surgery cases. In this patient subset,
      combination of results of staining fresh and cultured marrow significantly
      increased micromet detection to 78%. CONCLUSIONS: A significant proportion of
      patients with esophagogastric cancer have disseminated viable tumor cells at time
      of surgery, irrespective of pre-operative treatment. The use of marrow culture in
      parallel with fresh marrow staining may increase the detection of
      micrometastases. The persistence of tumor cells resistant to systemic therapy may
      explain why these regimens fail in a majority of patients.

PMID- 15013723
TI  - Noninvasive staging of esophageal carcinoma.

PMID- 15013724
TI  - Update on lung volume reduction.

PMID- 15013725
TI  - Management of liver metastases: new horizons for biologically based therapy.

PMID- 15013726
TI  - Steroid immunosuppression in kidney transplantation: a passing era.

PMID- 15013727
TI  - The pathobiology of aortic aneurysms.

PMID- 15013729
TI  - A comparison of verbal and written language in Alzheimer's disease.
AB  - Few studies have examined characteristics of both verbal and written language of
      individuals with Alzheimer's disease (AD). This study used parallel measures
      (picture description, word fluency, spelling to dictation, and confrontational
      naming) to compare verbal and written language of individuals with mild AD,
      moderate AD, and normal controls (14 participants per group). Goals were to
      determine whether verbal/written differences would be exhibited within groups,
      and to identify measures sensitive to the effects of mild AD. Results showed that
      increasing AD severity led to decline in performance for most tasks, but only
      word fluency differentiated subjects with mild AD from normal controls.
      Confrontational naming was the only task to identify a difference in verbal and
      written performance for an AD group but not controls; moderate AD subjects
      performed worse in written naming. Similar verbal and written performance for the
      spelling to dictation task indicates impairment to central spelling processes in
      AD. LEARNING OUTCOMES: As a result of this activity, participants will be able
      to: (1) identify verbal and written language measures which are sensitive to the
      effects of mild AD; (2) describe similarities and differences in verbal and
      written language performance among mild AD subjects, moderate AD subjects, and
      controls; (3) describe how findings may inform clinical practice for individuals
      with mild AD.

PMID- 15013730
TI  - Concurrent task sequencing in single-phoneme phonologic treatment and
      generalization.
AB  - Phonologic treatments have traditionally been designed to teach a target speech
      sound starting with presumed easy teaching tasks and progressing to harder tasks.
      This investigation evaluated the effects on single-phoneme acquisition,
      generalization, and maintenance of Concurrent Treatment, which randomly
      intermixed presumed easy and hard teaching tasks were utilized. A multiple
      baseline-across-subjects design was used with 4- to 7-year-old participants with
      /s/ misarticulations. All four participants rapidly acquired /s/ and showed
      generalization to untaught exemplars ranging from syllables to connected speech.
      Two participants showed generalization to within-clinic conversations and across
      settings. Results suggested that an easy-to-hard task sequence may be unnecessary
      for successful treatment outcomes and that the concurrent sequence may be
      beneficial. Implications for treatment design and future research are discussed.
      LEARNING OUTCOMES: (1) As a result of this activity, the participant will be able
      to explain the difference between incremental and concurrent task sequence. (2)
      As a result of this activity, the participant will be able to explain the
      procedures of Concurrent Treatment. (3) As a result of this activity, the
      participant will be able to explain the results of the experimental investigation
      of Concurrent Treatment.

PMID- 15013728
TI  - Speech-language pathologists' training and confidence in serving Spanish-English
      bilingual children.
AB  - The purpose of the investigation was to determine the level of training and
      confidence of speech-language pathologists in serving Spanish-English bilingual
      children. Surveys were completed by 213 speech-language pathologists working in
      the public schools. Comparisons were made among responses from non-diverse rural,
      non-diverse urban, and diverse urban areas. Results revealed that approximately
      one-third of the sample did not receive training in multicultural/multilingual
      issues as undergraduates or graduate students. Approximately, one-fifth of the
      sample could not recall whether or not they had received training in this area.
      Eighteen to 25% of the respondents in the three groups received information
      through lectures in one or more courses. A larger percentage of speech-language
      pathologists from non-diverse urban areas received training on specific topics
      related to multicultural/multilingual topics and participated in a larger number
      of continuing education activities than speech-language pathologists from diverse
      urban and non-diverse rural areas. No differences were found among the three
      groups with regard to their confidence in serving bilingual children. Although
      speech-language pathologists had some confidence when assessing bilingual
      children whose primary language was English, and when working with bilingual
      parents and interpreters, respondents lacked confidence when assessing bilingual
      children whose primary language was Spanish and when working with parents who do
      not speak English. Implications for the profession are discussed. LEARNING
      OUTCOMES: (1) As a result of this activity, the participant will be able to
      discuss the training speech-language pathologists have received in the area of
      multilingual/multicultural children. (2) As a result of this activity, the
      participant will be able to discuss speech-language pathologists' level of
      confidence when serving bilingual, Hispanic children. (3) As a result of this
      activity, the participant will be able to articulate the implications of this
      study for current training programs and the profession.

PMID- 15013731
TI  - Family pedigrees of children with suspected childhood apraxia of speech.
AB  - Forty-two children (29 boys and 13 girls), ages 3-10 years, were referred from
      the caseloads of clinical speech-language pathologists for suspected childhood
      apraxia of speech (CAS). According to results from tests of speech and oral motor
      skills, 22 children met criteria for CAS, including a severely limited consonant
      and vowel repertoire, difficulty sequencing syllables, and inconsistent and
      unusual errors. Family pedigrees for these children were constructed through
      parent interviews and direct testing of nuclear family members. Familial
      aggregation for speech-sound and language disorders was demonstrated with 86%
      reporting at least one nuclear family member affected. Based on parent report, 13
      of the 22 children (59%) had at least one affected parent. However, CAS was
      evident in only two siblings of probands with CAS and two probands with other
      speech-sound disorders. Based on testing, overall affection rates of speech
      sound/language disorders were higher in families of children with CAS than in
      families of children with other speech-sound disorders. Mothers of children with
      CAS demonstrated a higher affection rate than mothers of children with other
      speech-sound disorders. A sex-related threshold model of transmission was also
      supported with brothers more often affected than sisters for male probands only.
      If our inclusionary criteria for CAS are valid, these findings support a general
      verbal trait deficit hypothesis. LEARNING OUTCOMES: (1) As a result of this
      activity, the participant will understand potential familial risk factors for
      CAS; (2) will differentiate aggregation for speech-sound and language disorders
      in families with CAS from families of children who have other speech-sound
      disorders; (3) will distinguish how familial aggregation differs in families of
      boys and girls with CAS; (4) will determine how children with CAS differ in
      severity from those with other speech-sound disorders.

PMID- 15013732
TI  - Training caregivers to facilitate communicative participation of preschool
      children with language impairment during storybook reading.
AB  - This study reports the effects of training six adult caregivers to use an
      interactive reading routine, termed Complete Reading Cycle (CRC), during
      storybook reading with their preschool children, aged 3;2 to 3;5, who exhibited
      language impairment. Caregivers were taught to be more responsive to their
      children's communicative attempts during reading and to more actively engage the
      children in reading the story. Measures of child change included communicative
      participation and lexical diversity of utterances during adult-child shared
      reading. Children significantly increased the frequency of communicative turns,
      total number of words, and number of different words produced during shared
      storybook reading as a result of caregiver training. Five of the six children had
      higher mean frequencies for story initiations during training. However, increases
      in initiations were not statistically significant, with considerable variability
      across children for this measure. LEARNING OUTCOMES: (1) As a result of this
      activity, the participant will be able to discuss positive communicative changes
      in children with language impairment during adult-child storybook reading. (2) As
      a result of this activity, the participant will be able to use the storybook
      reading procedures with parents of preschool children exhibiting language
      impairment.

PMID- 15013733
TI  - The murine model of infection with Leishmania major and its importance for the
      deciphering of mechanisms underlying differences in Th cell differentiation in
      mice from different genetic backgrounds.
AB  - Mice from the majority of inbred strains are resistant to infection by Leishmania
      major, an obligate intracellular protozoan parasite of macrophages in the
      mammalian host. In contrast, mice from BALB strains are unable to control
      infection and develop progressive disease. In this model of infection,
      genetically determined resistance and susceptibility have been clearly shown to
      result from the appearance of parasite-specific CD4+ T helper 1 or T helper 2
      cells, respectively. This murine model of infection is considered as one of the
      best experimental systems for the study of the mechanisms operating in vivo at
      the initiation of polarised T helper 1 and T helper 2 cell maturation. Among the
      several factors influencing Th cell development, cytokines themselves critically
      regulate this process. The results accumulated during the last years have
      clarified some aspects of the role played by cytokines in Th cell
      differentiation. They are providing critical information that may ultimately lead
      to the rational devise of means by which to tailor immune responses to the
      effector functions that are most efficient in preventing and/or controlling
      infections with pathogens.

PMID- 15013734
TI  - Small nucleolar RNAs that guide modification in trypanosomatids: repertoire,
      targets, genome organisation, and unique functions.
AB  - Small nucleolar RNAs constitute a family of newly discovered non-coding small
      RNAs, most of which function in guiding RNA modifications. Two prevalent types of
      modifications are 2'-O-methylation and pseudouridylation. The modification is
      directed by the formation of a canonical small nucleolar RNA-target duplex.
      Initially, RNA-guided modification was shown to take place on rRNA, but recent
      studies suggest that small nuclear RNA, mRNA, tRNA, and the trypanosome spliced
      leader RNA also undergo guided modifications. Trypanosomes contain more
      modifications and potentially more small nucleolar RNAs than yeast, and the
      increased number of modifications may help to preserve ribosome function under
      adverse environmental conditions during the cycling between the insect and
      mammalian host. The genome organisation in clusters carrying the two types of
      small nucleolar RNAs, C/D and H/ACA-like RNAs, resembles that in plants. However,
      the trypanosomatid H/ACA RNAs are similar to those found in Archaea and are
      composed of a single hairpin that may represent the primordial H/ACA RNA. In this
      review we summarise this new field of trypanosome small nucleolar RNAs,
      emphasising the open questions regarding the number of small nucleolar RNAs, the
      repertoire, genome organisation, and the unique function of guided modifications
      in these protozoan parasites.

PMID- 15013736
TI  - The relationships between the burden of adult parasites, host age and the
      microfilarial density in human onchocerciasis.
AB  - We investigate the relationship between the microfilarial density in the skin and
      the burden of adult female Onchocerca volvulus by analysing pre-control
      nodulectomy data which allow for a direct approach, independent of exposure. The
      data of 169 patients in Burkina Faso and 182 patients in Liberia represent
      savannah and forest onchocerciasis in West Africa, respectively. Whereas in
      Burkina Faso, a saturating relationship between microfilarial density and worm
      burden suggests the operation of density-dependent processes within human hosts,
      the Liberian data show a linear relationship implying no density dependence. The
      differences may derive from differences between both parasite strains, i.e. the
      savannah or the forest strain of O. volvulus. Consistently for both parasite
      strains and independent of the worm burden, the microfilarial density increases
      with host age emphasising the concept of the acquisition of immunological
      tolerance. In male hosts in Liberia, the microfilarial density increases stronger
      with the worm burden than in female hosts, whereas such sex-specific differences
      cannot be found in Burkina Faso. In the methodological part of this
      investigation, we suggest the beta-distribution to be most appropriate for
      describing variability in microfilarial densities and we present an approach to
      consider the uncertainty in the adult parasite burden which cannot be determined
      precisely in helminth infections. Implications of density dependence are
      discussed with respect to immunological processes in the human host and with
      respect to the success of control programs. The relationships described show that
      regulatory processes between the parasite and the human host are multi
      dimensional, operating within a high degree of biological variability.

PMID- 15013735
TI  - Purification and biochemical characterisation of a membrane-bound alpha
      glucosidase from the parasite Entamoeba histolytica.
AB  - An alpha-glucosidase was solubilised from a mixed membrane fraction of Entamoeba
      histolytica and purified to homogeneity by a two-step procedure consisting of ion
      exchange chromatography in a Mono Q column and affinity chromatography in
      concanavalin A-sepharose. Although the enzyme failed to bind the lectin, this
      step rendered a homogenous and more stable enzyme preparation that resolved into
      a single polypeptide of 55 kDa after SDS-PAGE. As measured with 4
      methylumbelliferyl-alpha-D-glucopyranoside (MUalphaGlc) as substrate, glycosidase
      activity was optimum at pH 6.5 with different buffers and at 45 degrees C.
      Although the enzyme preferentially hydrolysed nigerose (alpha1,3-linked), it also
      cleaved kojibiose (alpha1,2-linked), which was the second preferred substrate,
      and to a lesser extent maltose (alpha1,4), trehalose (alpha1,1) and isomaltose
      (alpha1,6). Activity on alpha1,3- and alpha1,2-linked disaccharides was strongly
      inhibited by the glycoprotein processing inhibitors 1-deoxynojirimycin and
      castanospermine but was unaffected by australine. Glucose and particularly 3
      deoxy-D-glucose and 6-deoxy-D-glucose were strong inhibitors of activity, whereas
      2-deoxy-D-glucose and other monosaccharides had no effect. Enzyme activity on
      MUalphaGlc was very sensitive to inhibition by diethylpyrocarbonate suggesting a
      critical role of histidine residues in enzyme catalysis. Other amino acid
      modifying reagents such as N-ethylmaleimide and N-(3-dimethylaminopropyl)
      N'ethylcarbodiimide showed a moderate effect or none at all, respectively.
      Results are discussed in terms of the possible involvement of this glycosidase in
      N-glycan processing.

PMID- 15013737
TI  - Genetic diversity assessed by amplified fragment length polymorphism analysis of
      the parasitic nematode Dictyocaulus viviparus the lungworm of cattle.
AB  - We have examined the population genetic structure in a collection of nine
      isolates of the parasitic lungworm Dictyocaulus viviparus. Eight of the isolates
      were sampled from cattle in geographically separated farms throughout south
      central Sweden, and one isolate was a laboratory strain that has been maintained
      in experimentally infected calves for almost four decades. A total of 72 worms
      were examined, with eight individual worms from the same individual host
      representing each isolate. The genetic variation as revealed by amplified
      fragment length polymorphism analysis using four selective primer combinations
      was high. Depending on the primer combination a total of 66-79 restriction
      fragments were amplified, with 26-44 peaks of similar complexity from each of the
      isolates. The heterozygosity within populations was relatively small, as were the
      population mutation and immigration rates, which seemed to be in neutral
      equilibrium. The genetic diversity was therefore reasonably well structured in
      the field; and the laboratory isolate was quite distinct from the field samples.
      There was no relationship between the patterns of genetic diversity and the
      geographical proximity of the farms. The estimates of heterozygosity were much
      larger and more consistent than those previously estimated for this nematode
      species using mitochondrial sequencing, and the genetic structuring was thus much
      less pronounced and the gene flow greater. We attribute these differences in
      estimation to the broader sampling of loci available using amplified fragment
      length polymorphism markers, which may therefore constitute a superior technique
      for the study of patterns of lungworm diversity. Furthermore, the data estimating
      gene flow for D. viviparus was less than previously reported for closely related
      species in North America. This might be related to different rates of movements
      of infected hosts. It seems likely that lungworm infections are rather persistent
      on different farms, and the sudden outbreaks of disease that can be observed with
      host movements are most likely to be related to the introduction of susceptible
      stock.

PMID- 15013738
TI  - Plasmodium berghei parasite transformed with green fluorescent protein for
      screening blood schizontocidal agents.
AB  - High priority has been given to new assays that facilitate and accelerate the
      development of novel antimalarial compounds. Unlike evaluation of drugs in vitro,
      in which new approaches have been used to expedite identification of parasites,
      the conventional in vivo murine assay requires determination of parasitemia by
      light microscopy, an incompatible technique to test large numbers of drugs. We
      have investigated the possibility of using an autonomously fluorescent Plasmodium
      berghei strain, stably transformed with the green fluorescent protein, to rapidly
      quantify parasite growth by flow cytometry. The major improvement of this method
      is that P. berghei line transformed with green fluorescent protein parasites can
      be quickly and specifically detected in a drop of parasite-infected blood without
      any manipulation of the sample. Our results showed a clear correlation between
      the numbers of fluorescent cells detected by flow cytometry and conventional
      parasitemia, including a correspondence in the peaks of parasitemia. The
      validation of P. berghei line transformed with green fluorescent protein for
      chemotherapy studies was performed by evaluating its response to conventional
      antimalarial drugs such as chloroquine, quinine and sodium artesunate. The
      results of drug-susceptibility assays as determined by flow cytometry were
      comparable with those obtained by microscopic examination of Giemsa-stained
      slides. This PbGFP parasite should prove to be a rapid, simple and sensitive tool
      for the examination of the large number of compounds and conditions involved in
      the initial stages of drug development.

PMID- 15013739
TI  - Molecular cloning and characterisation of two kinds of proteins in excretory
      secretory products of Trichinella pseudospiralis.
AB  - Two genes encoding Trichinella pseudospiralis excretory-secretory proteins
      related to the Trichinella spiralis glycoproteins were cloned and the excretory
      secretory proteins were characterised. A cloned gene, designated Tp38 (Ts43),
      contained a cDNA transcript of 1035 bp, and the predicted amino acid sequence of
      the Tp38 (Ts43) pro-protein had a similarity of about 84% to that of the T.
      spiralis 43 kDa glycoprotein. A cloned gene, designated Tp53 (Ts53), contained a
      cDNA transcript of 1239 bp, and the predicted amino acid sequence of the Tp53
      (Ts53) pro-protein had a similarity of about 68% to that of the T. spiralis 53
      kDa glycoprotein. Southern blots indicated that the Tp38 (Ts43) and Tp53 (Ts53)
      genes were encoded in a single copy within the T. pseudospiralis genome. Western
      blots showed that T. pseudospiralis-infected sera recognised the Tp53 (Ts53)
      recombinant protein, but did not recognise the Tp38 (Ts43) recombinant protein.
      The Tp38 (Ts43) and Tp53 (Ts53) proteins in the excretory-secretory product were
      3 and 9 kDa greater than the expected molecular mass, respectively, and had three
      isoforms with a similar molecular size. Reverse transcription polymerase chain
      reaction results showed that the production of the mRNA transcript for the Tp38
      (Ts43) or Tp53 (Ts53) gene was restricted predominantly to muscle larvae. Western
      blots confirmed that the gene products were predominantly expressed by muscle
      stage larvae. An immunolocalisation study showed the Tp38 (Ts43) and Tp53 (Ts53)
      proteins were present within the alpha-stichocyte and the beta-stichocyte of
      muscle larvae, respectively.

PMID- 15013740
TI  - The current status of the small subunit rRNA phylogeny of the coccidia
      (Sporozoa).
AB  - There is no current comprehensive assessment of the molecular phylogeny of the
      coccidia, as all recently published papers either deal with subsets of the taxa
      or sequence data, or provide non-robust analyses. Here, we present a
      comprehensive and consistent phylogenetic analysis of the available data for the
      small-subunit ribosomal RNA gene sequence, including a number of taxa not
      previously studied, based on a Bayesian tree-building analysis and the
      covariotide model of evolution. The assumptions of the analysis have been
      rigorously tested, and the benefits and limitations highlighted. Our results
      provide support for a number of prior conclusions, including the monophyly of the
      families Sarcocystidae (cyst-forming coccidia) and Eimeriidae (oocyst-forming
      coccidia), but with bird-host Isospora species in the Eimeriidae and mammal-host
      species in the Sarcocystidae. However, it is clear that a number of previously
      reported relationships are dependent on the evolutionary model chosen, such as
      the placements of Goussia janae, Lankesterella minimia and Caryospora bigenetica.
      Our results also confirm the monophyly of the subfamilies Toxoplasmatinae and
      Sarcocystinae, but only some of the previously reported groups within these
      subfamilies are supported by our analysis. Similarly, only some of the previously
      reported groups within the Eimeriidae are supported by our analysis, and the
      genus Eimeria is clearly paraphyletic. There are unambiguous patterns of host
      parasite relationship within the coccidia, as most of the well-supported groups
      have a consistent and restricted range of hosts, with the exception of the
      Toxoplasmatinae. Furthermore, the previously reported groups for which we found
      no support all have a diverse range of unrelated hosts, confirming that these are
      unlikely to be natural groups. The most interesting unaddressed questions may
      relate to Isospora, which has the fewest available sequences and host-parasite
      relationships apparently not as straightforward as elsewhere within the suborder.

PMID- 15013741
TI  - Initial steps of speciation by geographic isolation and host switch in salmonid
      pathogen Gyrodactylus salaris (Monogenea: Gyrodactylidae).
AB  - To test the hypothesis that host-switching can be an important step in the
      speciation of gyrodactylid monogenean flatworms, we inferred the phylogeny within
      a cluster of parasites morphologically close to Gyrodactylus salaris Malmberg
      1957, collected from Atlantic, Baltic and White Sea salmon (Salmo salar), farmed
      rainbow trout (Oncorhynchus mykiss), and grayling (Thymallus thymallus) from
      Northern Europe. The internal transcribed spacer region of the nuclear ribosomal
      gene was sequenced for taxonomic identification. Parasites on grayling from the
      White Sea Basin differed from the others by one nucleotide (0.08%), the remainder
      were identical to the sequence published earlier from Norway (G. salaris on
      salmon), England (Gyrodactylus thymalli on grayling), and the Czech Republic
      (unidentified salaris/thymalli on trout). For increased resolution, 813
      nucleotides of the mitochondrial COI gene of 88 parasites were sequenced and
      compared with 76 published sequences using phylogenetic analysis. For all tree
      building algorithms (NJ, MP), the parasites formed a star-like phylogeny of six
      definite sister clades, indicating nearly simultaneous radiation. Average K2P
      distances between clades were 1.8-2.6%, and internal mean distances 0.2-1.1%. The
      genetic distance to the nearest known relative, Gyrodactylus lavareti Malmberg,
      was 24%. A variable salmon-specific mitochondrial Clade I was observed both in
      the Baltic Basin and in pathogenic populations introduced to the Atlantic and
      White Sea coasts. An invariable Clade II was common in rainbow trout farms in
      Sweden, Denmark and Finland; the same haplotype was also infecting salmon in a
      landlocked population in Russian Karelia, and in Oslo fjord and Sognefjord in
      Norway. Four geographically vicariant sister clades were observed on graylings:
      Clade III in the Baltic Sea Basin; Clade IV in Karelian rivers draining to the
      White Sea; Clade V in Norwegian river draining to Swedish lake Vanern; and Clade
      VI in rivers draining to Oslo fjord. The pattern fitted perfectly with the
      postglacial history of grayling distribution. Widely sampled clades from salmon
      and Baltic grayling had basal haplotypes in populations, which were isolated
      early during the postglacial recolonisation. The divergence between the six
      clades was clear and linked with their hosts, but not wide enough to support a
      species status for them. Parasites from the Slovakian type population of G.
      thymalli were not available, so this result does not mean that G. salaris and G.
      thymalli are synonyms. It is suggested that the plesiomorphic host of the
      parasite cluster was grayling, and the switch to salmon occurred at least once
      when the continental ice isolated Baltic salmon in an eastern freshwater
      refugium, 130,000 years ago. At the same time, parasites on grayling were split
      geographically and isolated into several allopatric refugia. The divergence among
      the parasite clades allowed a tentative calibration of the evolutionary rate,
      leading to an estimate of the divergence of 13.7-20.3% per million years for COI
      coding mtDNA. The results supported the hypothesis that parallel to the
      allopatric mode, host switch and instant isolation by host specificity can be
      operated as a speciation mechanism.

PMID- 15013742
TI  - Sex- and stage-related sensitivity of Schistosoma mansoni to in vivo and in vitro
      praziquantel treatment.
AB  - The efficacy of praziquantel against a Puerto Rican strain of Schistosoma mansoni
      was assessed using both in vivo and in vitro approach. The drug effective dose
      (50%) in the infected mouse model was about 30 times higher when determined
      against 28-day-old infections than against 7-week-old parasites. Single-sex
      female infections were also largely refractory to treatment and single-sex male
      infections moderately refractory, in comparison with bisexual infections. The in
      vitro approach consisted of overnight exposure of parasite cultures to various
      drug concentrations, followed by several days of culture in drug-free medium. In
      vitro results confirmed in vivo data and allowed for the observation of
      schistosome morphological phenomena after praziquantel exposure. Early worm
      contraction was observed in all cases, even after exposure to sub-lethal
      concentrations of praziquantel or upon exposure of the largely refractory 28-day
      old schistosomes. In these instances, however, worms resumed movements and normal
      shape upon drug removal and were able to survive. The inference of these
      observations on the clinical use of praziquantel and on its mechanism of action
      is discussed.

PMID- 15013743
TI  - Interactions among host diet, nutritional status and gastrointestinal parasite
      infection in wild bovids.
AB  - In this study, I explored the interactions among host diet, nutritional status
      and gastrointestinal parasitism in wild bovids by examining temporal patterns of
      nematode faecal egg shedding in species with different diet types during a
      drought and non-drought year. Study species included three grass and roughage
      feeders (buffalo, hartebeest, waterbuck), four mixed or intermediate feeders
      (eland, Grant's gazelle, impala, Thomson's gazelle) and two concentrate selectors
      (dik-dik, klipspringer). Six out of the nine focal species had higher mean faecal
      egg counts in the drought year compared to the normal year, and over the course
      of the dry year, monthly faecal egg counts were correlated with drought intensity
      in four species with low-quality diets, but no such relationship was found for
      species with high-quality diets. Comparisons of dietary crude protein and faecal
      egg count in impala showed that during the dry season, individuals with high
      faecal egg counts (> or =1550 eggs/g of faeces) had significantly lower crude
      protein levels than individuals with low (0-500 eggs/g) or moderate (550-1500
      eggs/g) egg counts. These results suggest that under drought conditions, species
      unable to maintain adequate nutrition, mainly low-quality feeders, are less able
      to cope with gastrointestinal parasite infections. In particular, during dry
      periods, reduced protein intake seems to be associated with declining resilience
      and resistance to infection.

PMID- 15013744
TI  - The European Research Council: the 'Mayor Group' report and the Commission's
      views on basic research and its impact.

PMID- 15013745
TI  - A hypothesis to explain division site selection in Escherichia coli by combining
      nucleoid occlusion and Min.
AB  - The positioning of the site of cell division in Escherichia coli results, it is
      generally believed, from the operation of nucleoid occlusion in combination with
      the Min system. Nucleoid occlusion prevents division over the nucleoids and
      directs it by default to the mid-cell region between segregating nucleoids or to
      polar regions while the Min system prevents division in polar regions. Unresolved
      questions include how these systems interact to control the earliest known event
      in division, the assembly at the membrane of the tubulin-like protein, FtsZ, and,
      more importantly, what exactly constitutes a division site. Evidence exists that
      (1) the coupled transcription, translation and insertion of proteins into
      membrane (transertion), can structure the cytoplasmic membrane into phospholipid
      domains, (2) the MinD protein can convert vesicles into tubes and (3) a variety
      of membranous structures can be observed at mid-cell. These data support a model
      in which transertion from the segregating daughter chromosomes leads to the
      formation of a distinct proteolipid domain between them at mid-cell; the
      composition of this domain allows phospholipid tubes to extend like fingers into
      the cytoplasm; these tubes then become the substrate for the dynamic assembly and
      disassembly of FtsZ which converts them into the invaginating fold responsible
      for division; the Min system inhibits division at unwanted sites and times by
      removing these tubes especially at the cell poles.

PMID- 15013746
TI  - AtHMA3, a plant P1B-ATPase, functions as a Cd/Pb transporter in yeast.
AB  - The Arabidopsis thaliana AtHMA3 protein belongs to the P(1B)-adenosine
      triphosphatase (ATPase) transporter family, involved in heavy metal transport.
      Functional expression of AtHMA3 phenotypically complements the Cd/Pb
      hypersensitive yeast strain Deltaycf1, but not the Zn-hypersensitive mutant
      Deltazrc1. AtHMA3-complemented Deltaycf1 cells accumulate the same amount of
      cadmium as YCF1-complemented Deltaycf1 cells or wild-type cells, suggesting that
      AtHMA3 carries out an intracellular sequestration of Cd. A mutant of AtHMA3
      altered in the P-ATPase phosphorylation domain did not complement Deltaycf1,
      suggesting that metal transport rather than chelation is involved. The fusion
      protein AtHMA3::green fluorescent protein (GFP) is localized at the vacuole,
      consistent with a role in the influx of cadmium into the vacuolar compartment. In
      A. thaliana, the mRNA of AtHMA3 was detected mainly in roots, old rosette leaves
      and cauline leaves. The expression levels were not affected by cadmium or zinc
      treatments.

PMID- 15013747
TI  - SHN-1, a Shank homologue in C. elegans, affects defecation rhythm via the
      inositol-1,4,5-trisphosphate receptor.
AB  - Protein localization in the postsynaptic density (PSD) of neurons is mediated by
      scaffolding proteins such as PSD-95 and Shank, which ensure proper function of
      receptors at the membrane. The Shank family of scaffolding proteins contain PDZ
      (PSD-95, Dlg, and ZO-1) domains and have been implicated in the localizations of
      many receptor proteins including glutamate receptors in mammals. We have
      identified and characterized shn-1, the only homologue of Shank in Caenorhabditis
      elegans. The shn-1 gene shows approximately 40% identity over 1000 amino acids to
      rat Shanks. SHN-1 protein is localized in various tissues including neurons,
      pharynx and intestine. RNAi suppression of SHN-1 did not cause lethality or
      developmental abnormality. However, suppression of SHN-1 in the itr-1 (sa73)
      mutant, which has a defective inositol-1,4,5-trisphosphate (IP(3)) receptor,
      resulted in animals with altered defecation rhythm. Our data suggest a possible
      role of SHN-1 in affecting function of IP(3) receptors in C. elegans.

PMID- 15013748
TI  - MEK inhibition impairs influenza B virus propagation without emergence of
      resistant variants.
AB  - Influenza A and B viruses are still a major worldwide threat. We demonstrate that
      influenza B virus infection induces signaling via the Raf/MEK/ERK cascade, a
      process required for efficient virus production. Expression of dominant-negative
      Raf and ERK mutants or treatment with a MEK inhibitor (U0126) strongly impaired
      viral propagation, while selective activation of the pathway resulted in
      increased virus titers. MEK inhibition appears to interfere with a distinct viral
      nuclear export process. Most importantly, no resistant virus variants emerged in
      the presence of U0126 demonstrating that influenza viruses cannot easily adapt to
      the missing cellular function.

PMID- 15013749
TI  - Regulation of a COPII component by cytosolic O-glycosylation during mitosis.
AB  - Endoplasmic reticulum (ER)-to-Golgi transport is blocked in mammalian cells
      during mitosis; however, the mechanism underlying this blockade remains unknown.
      Since COPII proteins are involved in this transport pathway, we investigated at
      the biochemical level post-translational modifications of COPII components during
      the course of mitosis that could be linked to inhibition of ER-to-Golgi
      transport. By comparing biochemical properties of cytosolic COPII components
      during interphase and mitosis, we found that Sec24p isoforms underwent post
      translational modifications resulting in an increase in their apparent molecular
      weight. No such modification was observed for the other COPII components Sec23p,
      Sec13p, Sec31p or Sar1p. Analyzing in more details Sec24p isoforms in interphase
      and mitotic conditions, we found that the interphase form of Sec24p was O-N
      acetylglucosamine modified, a feature lost upon entering into mitosis. This
      mitotic deglycosylation was coupled to Sec24p phosphorylation, a feature likely
      responsible for the increase in apparent molecular weight of these molecules.
      These modifications correlated with an alteration in the membrane binding
      properties of Sec24p. These data suggest that when entering into mitosis, the
      COPII component Sec24p is simultaneously deglycosylated and phosphorylated, a
      process which may contribute to the observed mitotic ER-to-Golgi traffic block.

PMID- 15013750
TI  - Ca2+ binding sites in calmodulin and troponin C alter interhelical angle
      movements.
AB  - Molecular dynamics analyses were performed to examine conformational changes in
      the C-domain of calmodulin and the N-domain of troponin C induced by binding of
      Ca(2+) ions. Analyses of conformational changes in calmodulin and troponin C
      indicated that the shortening of the distance between Ca(2+) ions and Ca(2+)
      binding sites of helices caused widening of the distance between Ca(2+) binding
      sites of helices on opposite sides, while the hydrophobic side chains in the
      center of helices hardly moved due to their steric hindrance. This conformational
      change acts as the clothespin mechanism.

PMID- 15013751
TI  - Gene fusions with beta-lactamase show that subunit I of the cytochrome bd quinol
      oxidase from E. coli has nine transmembrane helices with the O2 reactive site
      near the periplasmic surface.
AB  - The cytochrome bd quinol oxidase is a component of the respiratory chain of many
      prokaryotes. The enzyme contains two subunits, CydA and CydB, which were
      initially predicted based on the sequence of the Escherichia coli oxidase to have
      seven and eight transmembrane spans, respectively. More recently, the topological
      model of CydA was revised to predict nine transmembrane helices, based on
      additional sequence information from other organisms. In the current work, the
      topology of the E. coli oxidase was experimentally examined using beta-lactamase
      gene fusions. The results confirm the revised topology, which places the oxygen
      reactive site near the periplasmic surface.

PMID- 15013752
TI  - Functional analysis of PU.1 domains in monocyte-specific gene regulation.
AB  - The Ets family transcription factor PU.1 is required for the development of
      various lymphoid and myeloid cell lineages, and regulates the expression of
      several genes in a cell type-specific manner. Recently we found that
      overproduction of PU.1 in mouse bone marrow-derived mast cell progenitors induced
      the expression of monocyte-specific genes. This prompted us to analyze the
      functions of each domain of PU.1 in monocyte-specific gene expression, using
      transfection of mast cell progenitors with a series of retrovirus vectors for
      overexpression of various truncation mutants. Both the acidic region and the Ets
      domain of PU.1 were required for expression of monocyte-specific genes, and for
      enhanced interleukin-6 production in response to lipopolysaccharide. The Gln-rich
      region was suggested to be involved in expression of both MHC class II and F4/80.
      On the other hand, when PU.1 protein lacking the PEST domain was produced in the
      progenitor cells, expression of monocyte-specific genes was substantially
      enhanced, suggesting that the PEST domain plays a negative role in monocyte
      specific gene expression.

PMID- 15013753
TI  - Rev-erbalpha upregulates NF-kappaB-responsive genes in vascular smooth muscle
      cells.
AB  - Rev-erbalpha and retinoic acid receptor-related orphan receptor-alpha (RORalpha)
      are orphan nuclear receptors but their effects on transcription are opposed.
      Here, we show that Rev-erbalpha was expressed predominantly in vascular smooth
      muscle cells (VSMCs) rather than endothelial cells. Overexpression of Rev
      erbalpha upregulated the expression of interleukin-6 and cyclooxygenase-2, and
      increased transactivation by NF-kappaB and translocation of p65 to the nucleus in
      A7r5 VSMCs. Furthermore, the expression of Rev-erbalpha was upregulated by
      RORalpha1 but that upregulation was attenuated by Rev-erbalpha itself in A7r5
      VSMCs. These results suggest a regulatory link between Rev-erbalpha and the NF
      kappaB pathway.

PMID- 15013754
TI  - Cg-Rel, the first Rel/NF-kappaB homolog characterized in a mollusk, the Pacific
      oyster Crassostrea gigas.
AB  - We report here the identification and functional characterization of Cg-Rel, a
      gene encoding the Crassostrea gigas homolog of Rel/NF-kappaB transcription
      factors found in insects and mammals. Sequence and phylogenetic analysis showed
      that Cg-Rel shares the structural organization of Rel/NF-kappaB transcription
      factors of class II. It includes a Rel homology domain as well as a C-terminal
      transactivation domain (TD). Overexpression of Cg-Rel in the Drosophila S2 cell
      line activated the expression of a NF-kappaB-dependent reporter gene, whereas
      transfection with a Cg-Rel construct containing a C-terminal deletion of the TD
      or using a reporter gene with mutated kappaB binding sites failed to activate
      expression. These results suggest that Cg-Rel is a functional member of the Rel
      family of transcription factors, making this the sixth structurally homologous
      component of the Rel/NF-kappaB pathway characterized in C. gigas. Based on
      homology to other invertebrates' Rel/NF-kappaB cascade, the function of the
      oyster pathway may serve to regulate genes involved in innate defense and/or
      development. These findings serve to highlight a potentially important regulatory
      pathway to the study of oyster immunology, hence allowing comparison of the
      immune system in vertebrates and invertebrates, an important key issue to
      understand its evolution.

PMID- 15013755
TI  - Uridine 5'-polyphosphates (p4U and p5U) and uridine(5')polyphospho(5')nucleosides
      (Up(n)Ns) can be synthesized by UTP:glucose-1-phosphate uridylyltransferase from
      Saccharomyces cerevisiae.
AB  - UTP:glucose-1-phosphate uridylyltransferase (EC 2.7.7.9) from Saccharomyces
      cerevisiae can transfer the uridylyl moiety from UDP-glucose onto
      tripolyphosphate (P(3)), tetrapolyphosphate (P(4)), nucleoside triphosphates
      (p(3)Ns) and nucleoside 5'-polyphosphates (p(4)Ns) forming uridine 5'
      tetraphosphate (p(4)U), uridine 5'-pentaphosphate (p(5)U) and dinucleotides, such
      as Ap(4)U, Cp(4)U, Gp(4)U, Up(4)U, Ap(5)U and Gp(5)U. Unlike UDP-glucose, UDP
      galactose was not a UMP donor and ADP was not a UMP acceptor. This is the first
      example of an enzyme that may be responsible for accumulation of dinucleoside
      tetraphosphates containing two pyrimidine nucleosides in vivo. Occurrence of such
      dinucleotides in S. cerevisiae and Escherichia coli has been previously reported
      (Coste et al., J. Biol. Chem. 262 (1987) 12096-12103).

PMID- 15013756
TI  - Short interfering RNA-mediated gene targeting in the zebrafish.
AB  - Short interfering RNAs (siRNAs) have proved to be a useful tool in studying gene
      function in plants, invertebrates and mammalian systems. Here we report the use
      of siRNAs for targeting the zebrafish dystrophin gene. This study demonstrates
      the efficacy of siRNA-based gene silencing in this vertebrate model species, and
      illustrates the potential of this approach for determining the roles of multiple
      protein products expressed by a single gene during the early stages of
      development. In addition this study illustrates the usefulness of zebrafish as a
      model for muscle disease, and highlights the potential of siRNA-based gene
      targeting for disease analysis in this model organism.

PMID- 15013757
TI  - L-Arginine inhibits xanthine oxidase-dependent endothelial dysfunction in
      hypercholesterolemia.
AB  - Xanthine oxidase (XO)-derived superoxide contributes to endothelial dysfunction
      in humans and animal models of hypercholesterolemia (HC). Since L-arginine
      supplementation prevents defects in NO signaling, we tested the hypothesis that L
      arginine blunts the inhibitory effect of XO on vascular function. Acetylcholine
      mediated relaxation was significantly impaired in ring segments of HC rabbits, a
      response that was associated with an increase in plasma XO activity. L-Arginine
      treatment of HC rabbits reduced plasma XO and improved endothelial function. L
      Arginine also modestly prolonged the lag time for oxidation in isolated
      lipoprotein samples. These results reveal that the principal action of L-arginine
      is to protect against the XO-dependent inactivation of NO in arteries of HC
      rabbits.

PMID- 15013759
TI  - TNF-alpha and IL-4 regulate expression of fractalkine (CX3CL1) as a membrane
      anchored proadhesive protein and soluble chemotactic peptide on human
      fibroblasts.
AB  - The CX(3)C chemokine, fractalkine (FKN, CX(3)CL1), has multiple functions and
      exists as two distinct forms, a membrane-anchored protein and a soluble
      chemotactic peptide that cleaves from the cell surface FKN. In this study, we
      first demonstrated the expression of FKN in tumor necrosis factor (TNF)-alpha-
      and interleukin (IL)-4-stimulated human fibroblasts. The induction of FKN was
      observed for both forms. We also demonstrated monocyte chemotactic activity in
      the culture supernatant from the fibroblasts stimulated with these cytokines.
      These results suggest that TNF-alpha- and IL-4-stimulated fibroblasts may play an
      important role in accumulation of monocytes at inflammatory sites.

PMID- 15013758
TI  - The interplay between classical and alternative isoprenoid biosynthesis controls
      gammadelta T cell bioactivity of Listeria monocytogenes.
AB  - Isoprenoids are synthesised either through the classical, mevalonate pathway, or
      the alternative, non-mevalonate, 2-C-methyl-D-erythritol 4-phosphate (MEP)
      pathway. The latter is found in many microbial pathogens and proceeds via (E)-4
      hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), a potent activator of human
      Vgamma9/Vdelta2 T cells. Listeria monocytogenes is the only pathogenic bacterium
      known to contain both pathways concurrently. Strategic gene knockouts demonstrate
      that either pathway is functional but dispensable for viability. Yet, disrupting
      the mevalonate pathway results in a complementary upregulation of the MEP
      pathway. Vgamma9/Vdelta2 T cell bioactivity is increased in DeltalytB mutants
      where HMB-PP accumulation is expected, and lost in DeltagcpE mutants which fail
      to produce HMB-PP.

PMID- 15013760
TI  - The orientations of core antenna chlorophylls in photosystem II are optimized to
      maximize the quantum yield of photosynthesis.
AB  - In photosystem II (PSII) the probability that energy absorbed by core antenna
      chlorophyll (Chl) is transferred to the reaction center (RC) is extremely high.
      Although close proximity between antenna Chl ensures a high transfer efficiency,
      relative pigment orientation can fractionally modify it. This level of refinement
      has often been assumed to be superfluous as so many subsequent processes limit
      the overall efficiency of photosynthesis. Nevertheless, did natural selection act
      on the most efficient step of energy conversion in PSII by optimizing the
      orientation of antenna Chl? Our Monte Carlo simulations sampled the orientation
      space of Chls in kinetic models for excitation energy transfer based on the X-ray
      structures of PSII from Thermosynechococcus vulcanus and Synechocystis elongatus.
      Our results revealed that the orientations of key antenna Chls are optimized to
      maximize photosynthesis while the orientations of the two peripheral RC Chls
      (Chl(Z)) are not.

PMID- 15013761
TI  - MEF up-regulates human beta-defensin 2 expression in epithelial cells.
AB  - Human beta-defensin 2 (HBD2), an antimicrobial peptide, is widely expressed in
      epithelial tissues and displays a potent killing activity in response to the
      invasiveness of a wide range of microorganisms and the stimulation of various
      molecules. Myeloid ELF-1-like factor (MEF) has been reported to be involved in
      innate immunity responses, such as activation of perforin and lysozyme
      transcription. The role of MEF in the transcription regulation of HBD2, however,
      is unknown. Here, we show that MEF not only activated HBD2 promoter activity, but
      also increased the endogenous HBD2 transcription level. Moreover, the activated
      HBD2 promoter activity was attenuated by the antisense MEF RNA input and the loss
      of the ETS binding site (EBS: GGAA core sequence) in the HBD2 promoter. The
      interaction between the EBS and MEF protein was further confirmed by
      electrophoretic mobility shift assay. Thus, our data indicate that MEF may play
      an important role in regulating HBD2 expression in epithelial cells.

PMID- 15013762
TI  - Cholera toxin induces expression of ion channels and carriers in rat small
      intestinal mucosa.
AB  - Cholera toxin causes cyclic adenosine monophosphate (cAMP)-induced electrolyte
      and water secretion in the small intestine. The toxin-induced change in gene
      expression in rat small intestine was evaluated with microarray technique and the
      results were confirmed by semiquantitative polymerase chain reaction (PCR). The
      transporter CNT2 for nucleosides was upregulated between 6 and 18 h after
      challenge, whereas the level of GLUT1 transporter for glucose became elevated at
      6 h. Both changes probably facilitate uptake of these nutrients in the gut. At 18
      h, the major chloride channel in the villus, ClC2, was upregulated. Aquaporin 8
      was downregulated at 6 h and two mucin-producing genes were upregulated 18 h
      after toxin challenge. The expression was back to normal after 72 h, which is the
      turnover time for intestinal epithelial cells.

PMID- 15013763
TI  - Analysis of an activated ABI5 allele using a new selection method for transgenic
      Arabidopsis seeds.
AB  - The Arabidopsis abscisic acid (ABA) insensitive (ABI)5 transcription factor
      participates in the ABA-dependent induction of late embryogenesis abundant (LEA)
      genes in the final stages of seed development. We tested whether the VP16
      transcriptional activation domain is sufficient to provide ABI5 with the ability
      to activate the AtEm LEA genes in vegetative tissues. We took advantage of a new
      transgenic seed selection assay based on green fluorescent protein (GFP)
      fluorescence and found that VP16-ABI5 triggered growth retardation and ABA
      independent induction of AtEm1 in seedlings. These results indicate that ABI5
      activation potential is a limiting step and might be a target for ABA signaling.

PMID- 15013765
TI  - Glucosylceramides in Colletotrichum gloeosporioides are involved in the
      differentiation of conidia into mycelial cells.
AB  - Glucosylceramides (GlcCer) were extracted from the plant pathogen Colletotrichum
      gloeosporioides and purified by several chromatographic steps. By using
      electrospray ionization mass spectrometry and nuclear magnetic resonance, GlcCer
      from C. gloeosporioides were identified as N-2'-hydroxyoctadecanoyl-1-beta-D
      glucopyranosyl-9-methyl-4,8-sphingadienine and N-2'-hydroxyoctadecenoyl-1-beta-D
      glucopyranosyl-9-methyl-4,8-sphingadienine. Monoclonal antibodies against these
      structures were produced and used as tools for the evaluation of the role of
      GlcCer in the morphological transition of C. gloeosporioides. In the presence of
      antibodies to GlcCer, the differentiation of conidia into mycelia was blocked.
      Since GlcCer is present in several plant pathogens, the inhibitory activity of
      external ligands recognizing these structures may be applicable in other models
      of fungal infections.

PMID- 15013764
TI  - Generation of Arabidopsis thaliana plants with complex N-glycans lacking beta1,2
      linked xylose and core alpha1,3-linked fucose.
AB  - The plant glycosyltransferases, beta1,2-xylosyltransferase (XylT) and core
      alpha1,3-fucosyltransferase (FucT), are responsible for the transfer of beta1,2
      linked xylose and core alpha1,3-linked fucose residues to glycoprotein N-glycans.
      These glycan epitopes are not present in humans and thus may cause immunological
      responses, which represent a limitation for the therapeutic use of recombinant
      mammalian glycoproteins produced in transgenic plants. Here we report the genetic
      modification of the N-glycosylation pathway in Arabidopsis thaliana plants.
      Knockout plants were generated with complete deficiency of XylT and FucT. These
      plants lack antigenic protein-bound N-glycans and instead synthesise
      predominantly structures with two terminal betaN-acetylglucosamine residues
      (GlcNAc(2)Man(3)GlcNAc(2)).

PMID- 15013766
TI  - The role of heat shock protein 70 in the thermoresistance of prostate cancer cell
      line spheroids.
AB  - Heat shock protein 70 (Hsp70), a protein induced in cells exposed to sublethal
      heat shock, is present in all living cells and has been highly conserved during
      evolution. The aim of the current study was to determine the role of heat shock
      proteins in the resistance of prostate carcinoma cell line spheroids to
      hyperthermia. In vitro, the expression of Hsp70 by the DU 145 cell line, when
      cultured as monolayer or multicellular spheroids, was studied using Western
      blotting and enzyme-linked immunosorbent assay methods. The level of Hsp70 in
      spheroid cultures for up to 26 days at 37 degrees C remained similar to monolayer
      cultures. However, in samples treated with hyperthermia at 43 degrees C for 120
      min, the spheroid cultures expressed a higher level of Hsp70 as compared to
      monolayer culture. Under similar conditions of heat treatment, the spheroids
      showed more heat resistance than monolayer cultures as judged by the number of
      colonies that they formed in suspension cultures. The results suggest that cells
      cultured in multicellular spheroids showed more heat resistance as compared to
      monolayer cultures by producing higher levels of Hsp70.

PMID- 15013767
TI  - Significance of C-terminal sequence elements for Petunia flavanone 3beta
      hydroxylase activity.
AB  - Flavanone 3beta-hydroxylase (FHT), a 2-oxoglutarate-dependent dioxygenase (2
      ODD), catalyzes the hydroxylation of (2S)-flavanones to (2R/3R)-dihydroflavonols
      in plants as a key step towards the biosynthesis of flavonols, anthocyanins and
      catechins. Crystallographic studies of 2-ODDs typically revealed a jelly roll in
      the enzyme core, and the C-terminus of the enzyme polypeptides was proposed to
      form a lid covering the active site cavity, thereby reducing the chances for
      oxidative or proteolytic damage and unfolding. Moreover, it has been proposed
      that in some cases the C-terminus is involved in substrate selectivity of 2-ODDs.
      In a systematic approach with highly active Petunia FHT, four C-terminally
      truncated enzyme forms were generated by deletion of five, 11, 24 or 29 amino
      acids. The recombinant FHTs preserved their substrate selectivity, but the
      specific activity decreased gradually with the extent of truncation. Then, an
      enzyme chimera was constructed by domain swapping replacing the C-terminal 52
      amino acids of Petunia FHT by the equivalent region of flavonol synthase (FLS)
      from Citrus unshiu, an enzyme showing ambiguous FLS and FHT activity. The
      chimeric dioxygenase still revealed exclusively FHT activity, albeit at a
      moderate level only. The data predict that the selectivity of FHT is not governed
      by the C-terminal sequence accounting for about 13% of the enzyme polypeptide.

PMID- 15013768
TI  - Essential role of the family-22 carbohydrate-binding modules for beta-1,3-1,4
      glucanase activity of Clostridium stercorarium Xyn10B.
AB  - Clostridium stercorarium Xyn10B is a modular enzyme comprising two family-22
      carbohydrate-binding modules (CBMs), a family-10 catalytic module of glycoside
      hydrolases, a family-9 CBM, and two S-layer homologous modules consecutively from
      the N-terminus. To investigate the role of the family-22 CBMs, truncated proteins
      were constructed: a recombinant catalytic module polypeptide (rCD), a CBM
      polypeptide composed of two family-22 CBMs (rCBM) and a polypeptide composed of
      the family-22 CBMs and the catalytic module (rCBM-CD). We found that rCBM-CD was
      highly active toward beta-1,3-1,4-glucan; however, rCD was negligibly active
      toward the same substrate. The V(max)/K(m) value of rCBM-CD for beta-1,3-1,4
      glucan was 7.8 times larger than that for oat-spelt xylan, indicating that rCBM
      CD should be specified as a beta-1,3-1,4-glucanase rather than a xylanase despite
      the fact that family-10 catalytic modules are well-known xylanase modules. These
      results indicate that the family-22 CBMs in rCBM-CD are essential for hydrolysis
      of beta-1,3-1,4-glucan.

PMID- 15013769
TI  - Regiospecificity and kinetic properties of a plant natural product O
      methyltransferase are determined by its N-terminal domain.
AB  - A recently discovered, S-adenosyl-L-methionine and bivalent cation-dependent O
      methyltransferase from the ice plant, Mesembryanthemum crystallinum, is involved
      in the methylation of various flavonoid and phenylpropanoid conjugates.
      Differences in regiospecificity as well as altered kinetic properties of the
      recombinant as compared to the native plant O-methyltransferase can be attributed
      to differences in the N-terminal part of the protein. Upon cleavage of the first
      11 amino acids, the recombinant protein displays essentially the same substrate
      specificity as observed earlier for the native plant enzyme. Product formation of
      the newly designed, truncated recombinant enzyme is consistent with light-induced
      accumulation of methylated flavonoid conjugates in the ice plant. Therefore,
      substrate affinity and regiospecificity of an O-methyltransferase in vivo and in
      vitro can be controlled by cleavage of an N-terminal domain.

PMID- 15013770
TI  - Novel biological function of sialic acid (N-acetylneuraminic acid) as a hydrogen
      peroxide scavenger.
AB  - We have found that N-acetylneuraminic acid (NANA) consumes toxic hydrogen
      peroxide (H(2)O(2)) under physiological conditions. Close investigation of this
      finding revealed that NANA was oxidized by an equimolar amount of H(2)O(2) to
      provide its decarboxylated product, 4-(acetylamino)-2,4-dideoxy-D-glycero-D
      galacto-octonic acid (ADOA). To date, there have been little data on this
      reaction, and its physiological significance has not been discussed. Examining
      the detoxification of H(2)O(2) in cultured cells with NANA, we were able to
      confirm that the cell death caused by H(2)O(2) was suppressed by NANA in a dose
      dependent manner. These results revealed a novel role for NANA as a reactive
      oxygen scavenger. It is known that terminal NANA residues are removed by
      neuraminidase and that free NANA molecules are recycled or degraded by enzymes.
      We propose that released monomeric NANA is the potent defense molecule against
      oxidative damage.

PMID- 15013771
TI  - A cysteine-rich protein in the Theromyzon (Annelida: Hirudinea) cocoon membrane.
AB  - The aquatic leech, Theromyzon rude, secretes a flexible, proteinaceous cocoon
      that is resistant to a broad range of denaturing conditions (e.g. heat,
      denaturing chemicals). We have partially solubilized the Theromyzon cocoon
      membrane in 10% acetic acid and identified two major protein fragments.
      Microsequencing of both Theromyzon cocoon protein (Tcp) fragments generated an
      identical stretch of the amino-terminal sequence that was used to clone the
      corresponding gene. The predicted linear amino acid sequence of the resulting
      cDNA contained an unusually high cysteine content (17.8%). Sequence analysis
      identified six internal repeats, each comprising 12 ordered Cys residues in a
      approximately 62 amino acid repeating unit. Sequence comparisons identified
      homology with undescribed, Cys-rich repeats across animal phyla (i.e. Arthropod,
      Nematoda).

PMID- 15013772
TI  - Met144Ala mutation of the copper-containing nitrite reductase from Alcaligenes
      xylosoxidans reverses the intramolecular electron transfer.
AB  - Pulse radiolysis has been employed to investigate the intramolecular electron
      transfer (ET) between the type 1 (T1) and type 2 (T2) copper sites in the
      Met144Ala Alcaligenes xylosoxidans nitrite reductase (AxCuNiR) mutant. This
      mutation increases the reduction potential of the T1 copper center. Kinetic
      results suggest that the change in driving force has a dramatic influence on the
      reactivity: The T2Cu(II) is initially reduced followed by ET to T1Cu(II). The
      activation parameters have been determined and are compared with those of the
      wild-type (WT) AxCuNiR. The reorganization energy of the T2 site in the latter
      enzyme was calculated to be 1.6+/-0.2 eV which is two-fold larger than that of
      the T1 copper center in the WT protein.

PMID- 15013773
TI  - Alpha-chimaerin exists in a functional complex with the Cdk5 kinase in brain.
AB  - Cyclin-dependent kinase 5 (Cdk5) in association with its neuronal activators p35
      and p39 shows a complex involvement in the control of neurocytoskeletal dynamics.
      Here we show that alpha-chimaerin, a GTPase-activating protein specific for Rac
      and Cdc42, is a p35-binding protein. The interaction domains of p35 and alpha
      chimaerin were delineated. In transfected HeLa cells, p35 and alpha-chimaerin
      displayed an overlapping distribution pattern and they could be co
      immunoprecipitated from the cell lysate. As alpha-chimaerin has a regulatory
      function in actin repolymerization, these results suggested that the regulation
      of neurocytoskeleton dynamics by Cdk5 is mediated at least in part via alpha
      chimaerin.

PMID- 15013774
TI  - The existence of a putative post-transcriptional regulatory element in 3'-UTR of
      Drosophila antibacterial peptide diptericin's mRNA.
AB  - Antibacterial peptides' genes are rapidly and transiently expressed on immune
      stimulation, which is the characteristic of immediate early genes. It implies
      post-transcriptional regulation is an important pathway in antibacterial
      peptides' gene expression. In a search of putative post-transcriptional
      regulatory elements, we found a segment of an AU-rich sequence in 3'-untranslated
      region (UTR) of drosophila diptericin mRNA. 3'-UTR of diptericin mRNA can be
      specifically bound with Elav and this binding can be competed with the typical AU
      rich element (ARE) of c-fos mRNA. These results suggest that the AU-rich sequence
      in the 3'-UTR of diptericin mRNA may be a cis-acting element and involved in post
      transcriptional regulation.

PMID- 15013775
TI  - Multi-class cancer subtype classification based on gene expression signatures
      with reliability analysis.
AB  - Differential diagnosis among a group of histologically similar cancers poses a
      challenging problem in clinical medicine. Constructing a classifier based on gene
      expression signatures comprising multiple discriminatory molecular markers
      derived from microarray data analysis is an emerging trend for cancer diagnosis.
      To identify the best genes for classification using a small number of samples
      relative to the genome size remains the bottleneck of this approach, despite its
      promise. We have devised a new method of gene selection with reliability
      analysis, and demonstrated that this method can identify a more compact set of
      genes than other methods for constructing a classifier with optimum predictive
      performance for both small round blue cell tumors and leukemia. High consensus
      between our result and the results produced by methods based on artificial neural
      networks and statistical techniques confers additional evidence of the validity
      of our method. This study suggests a way for implementing a reliable molecular
      cancer classifier based on gene expression signatures.

PMID- 15013776
TI  - Specific isomyosin proportions in hyperexcitable and physiologically denervated
      mouse muscle.
AB  - We show here, by high resolution sodium dodecyl sulfate gel electrophoresis, that
      the proportions of myosin heavy chain (MyHC) isoforms of mouse muscles are
      specifically shifted by hereditary neuromuscular diseases. In wild-type and
      dystrophic MDX anterior tibial muscle (TA) about 60% of the MyHC is IIB, 30% IIX,
      at most 10% IIA and <2% type I (slow). In myotonic fast muscles,
      hyperexcitability leads to a drastic reduction of MyHC IIB which is compensated
      by IIA. Slow muscles, like soleus and diaphragm, were only marginally changed by
      myotonia. The MyHC pattern of TA of spinal muscular atrophy (SMA) 'wobbler' mice
      is shifted to a faster phenotype, with nearly 90% IIB. In the SMA mutant 'muscle
      deficient', all four adult isomyosins are expressed in the TA. These findings may
      be relevant for the future diagnosis of neurological disorders both in mouse
      disease models and in human patients.

PMID- 15013777
TI  - Inhibition of p53 degradation by Mdm2 acetylation.
AB  - Mdm2 is a RING finger E3 ubiquitin ligase, which promotes ubiquitination and
      proteasomal degradation of the p53 tumor suppressor protein. Acetylation of p53
      regulates p53's transcriptional activity and inhibits Mdm2-mediated p53
      ubiquitination and degradation. We now report that Mdm2 is also a target for
      acetylation. Mdm2 is acetylated in vitro by CREB-binding protein (CBP) and to a
      lesser extent by p300, but not by p300/CPB-associated factor. Acetylation occurs
      primarily within the RING finger domain of Mdm2. In vivo acetylation of Mdm2 was
      detected easily with CBP but not p300. Efficient in vivo acetylation required the
      preservation of the RING finger. An Mdm2 mutant (K466/467Q) mimicking acetylation
      is impaired in its ability to promote p53 ubiquitination, as well as Mdm2
      autoubiquitination. Moreover, K466/467Q is defective in promoting p53 degradation
      in living cells. We thus suggest that acetyltransferases may modulate cellular
      p53 activity not only by modifying p53, but also by inactivating Mdm2.

PMID- 15013778
TI  - Effect of hyperosmotic shock on phosphoenolpyruvate carboxykinase gene expression
      and gluconeogenic activity in the crab muscle.
AB  - Chasmagnathus granulata phosphoenolpyruvate carboxykinase (PEPCK) cDNA from jaw
      muscle was cloned and sequenced, showing a specific domain to bind
      phosphoenolpyruvate in addition to the kinase-1 and kinase-2 motifs to bind
      guanosine triphosphate (GTP) and Mg(2+), respectively, specific for all PEPCKs.
      In the kinase-1 motifs the GK was changed to RK. The first 19 amino acids of the
      putative enzyme contain hydrophobic amino acids and hydroxylated residues
      specific to a mitochondrial type signal. The PEPCK is expressed in
      hepatopancreas, muscles, nervous system, heart, and gills. Hyperosmotic stress
      for 24 h increased the PEPCK mRNA level, gluconeogenic and PEPCK activities in
      muscle.

PMID- 15013780
TI  - Chemical modification of glucose oxidase: possible formation of molten globule
      like intermediate structure.
AB  - Chemical modification of lysine residues in glucose oxidase was carried out using
      citraconic anhydride. Modification brought about changes in the kinetic
      properties of the enzyme as evident by substantial lowering of V(max) and K(m).
      Enhancement of tryptophan fluorescence was observed with a dramatic change in its
      pH dependence due to modification. Near- and far-UV circular dichroism spectra of
      the native and modified forms suggested formation of molten globule-like
      structures, further supported by 8-anilino-1-naphthalenesulfonic acid
      fluorescence which indicated higher exposure of hydrophobic residues as a result
      of chemical modification.

PMID- 15013779
TI  - Overexpression of LaMDR2, a novel multidrug resistance ATP-binding cassette
      transporter, causes 5-fluorouracil resistance in Leishmania amazonensis.
AB  - The ATP-binding cassette (ABC) proteins play an important role in drug resistance
      and detoxification in various organisms. Here we isolated LaMDR2, a new member of
      the multidrug resistance (MDR) subfamily of ABC proteins in Leishmania
      amazonensis. LaMDR2 exhibited 47% amino acid identity to its most closely related
      protein, LaMDR1, which was previously isolated from the same species.
      Promastigotes that overexpressed LaMDR2 showed significant resistance to 5
      fluorouracil (5-FU), but not to LaMDR1 substrates. Expression of LaMDR2 in the
      transfectants was relatively higher in the log phase than the stationary phase,
      and a lower accumulation of [(3)H]5-FU was observed in the log-phase cells. These
      results suggest that LaMDR2 is involved in extrusion of xenobiotics, but
      functionally different from LaMDR1.

PMID- 15013781
TI  - Novel sites in the p65 subunit of NF-kappaB interact with TFIIB to facilitate NF
      kappaB induced transcription.
AB  - Nuclear factor kappaB (NF-kappaB) transcription factors regulate a large number
      of genes in response to inflammation, infection and stressful conditions. In this
      study, we investigated whether NF-kappaB p65 regulates the transcription of
      target genes by interacting with components of the basal transcription machinery.
      We examined the interaction of p65 with the basal transcription factor IIB
      (TFIIB). Glutathione S-transferase pull down assays showed that the Rel homology
      domain of p65 is important for binding to TFIIB. Molecular modelling, together
      with the generation of specific point mutants, revealed that residues 41 R and 42
      S in the Rel homology domain of p65 facilitate the interaction with TFIIB.
      Mutation of these residues showed a decrease in p65 induced transcription,
      suggesting that they are involved in a functional interaction with TFIIB.

PMID- 15013782
TI  - Candida albicans Cdc37 interacts with the Crk1 kinase and is required for Crk1
      production.
AB  - Crk1, a Cdc2-related protein kinase from the human pathogenic fungus Candida
      albicans, plays an important role in hyphal development and virulence. To address
      its regulatory mechanisms, we searched for Crk1 interacting proteins by two
      hybrid screening. A CDC37 ortholog (CaCDC37) was cloned from the screening with
      the Crk1 kinase domain as the bait. The CaCdc37 interacted preferentially with
      the kinase domain of Crk1 (Crk1N) as shown by two-hybrid and immunoprecipitation
      experiments. CaCDC37 could complement a cdc37 thermosensitive mutant (cdc37-34)
      of Saccharomyces cerevisiae. Importantly, Crk1 protein was hardly detectable in
      the cdc37-34 mutant at restrictive temperature. However, upon expression of
      CaCdc37 in the cdc37 mutant, Crk1 protein was detected even at restrictive
      temperature. Our data suggested that CaCdc37 was required for the production of
      Crk1 kinase. Like Cdc37 proteins of S. cerevisiae and higher eukaryotes, CaCdc37
      might function as a molecular chaperone that stabilized Crk1 and other protein
      kinases in C. albicans. In support of this, CaSTI1 was identified from a two
      hybrid screen with the full-length Crk1 as the bait. CaSti1 showed two-hybrid
      interactions with both Crk1 and the CaCdc37.

PMID- 15013783
TI  - Wuchereria bancrofti: cloning and characterization of heat shock protein 70 from
      the human lymphatic filarial parasite.
AB  - Heat shock protein 70 (HSP70) was identified as an immunodominant antigen by
      screening a Wuchereria bancrofti (Wb) microfilarial cDNA library with pooled Wb
      infected sera, with 28% of the immunopositive clones coding for Wb-HSP70. The
      deduced amino acid sequence showed greater than 97 and 85% identity with HSP70
      from filarial nematodes and humans, respectively. Recombinant HSP70 (74 kDa) and
      a recombinant protein from the C-terminal portion (43 kDa) also reacted with
      pooled Wb-infected sera, suggesting that the C-terminal region of HSP70 contains
      at least one antibody epitope. Brugia malayi L3 larvae showed increasing levels
      of HSP70 with increasing temperatures. Further, a polyclonal mouse anti-Wb-HSP70
      antibody had reactivity to the HSP70 of cattle filarial parasite Settaria
      digitata and to human HSP70 derived from a Hep-2 cell line. Immune reactivity to
      Wb-HSP70 was strong, with uninfected non-endemic normal sera showing
      significantly greater reactions than sera from filaria-infected individuals. Both
      immunodominant self-HSP70 and HSP70 from other microbial infections may be
      primary targets for developing autoantibodies naturally.

PMID- 15013784
TI  - Entamoeba histolytica: kinetic and molecular evidence of a previously
      unidentified pyruvate kinase.
AB  - We report the kinetic characterization of a previously unidentified pyruvate
      kinase (PK) activity in extracts from Entamoeba histolytica trophozoites. This
      activity was about 74% of the activity of pyruvate phosphate dikinase. EhPK
      differed from most PKs in that its pH optimum was 5.5-6.5 and was inhibited by
      high PEP concentrations (1-5mM); these are concentrations at which PK is usually
      assayed. The optimal temperature was above 40 degrees C with negligible activity
      below 20 degrees C. EhPK exhibited hyperbolic kinetics with respect to both PEP
      (K(m) = 0.018 mM) and ADP (K(m) = 1.05 mM). However, it exhibited a sigmoidal
      behavior with respect to PEP at sub-saturating ADP concentrations. EhPK did not
      require monovalent cations for activity. Fructose-1,6 bisphosphate was a potent
      non-essential activator; it increased the affinity for ADP without modification
      of the V(max) or the affinity for PEP. Phosphate, citrate, malate, and alpha
      ketoglutarate significantly inhibited EhPK activity. A putative EhPK gene
      fragment found in EhDNA was analyzed. The data indicate that E. histolytica
      trophozoites contain an active PK, which might contribute to the generation of
      glycolytic ATP for parasite survival.

PMID- 15013785
TI  - Plasmodium falciparum: distribution of msp2 genotypes among symptomatic and
      asymptomatic individuals from the Wosera region of Papua New Guinea.
AB  - The merozoite surface protein 2 (MSP2) is a leading asexual-stage malaria vaccine
      candidate that has already proven to have an effect in phase I/IIb vaccine
      trials, where it was tested in combination with other antigens. Alleles of msp2
      fall within two major allelic families, 3D7 and FC27. We analyzed the msp2
      genotype in 306 asymptomatic and 63 symptomatic infections from the Wosera region
      of Papua New Guinea. The multiplicity of infection and the distribution of msp2
      alleles was similar to that found in previous studies in the region, but there
      was no association found between FC27-type or 3D7-type forms of MSP2 and clinical
      malaria.

PMID- 15013786
TI  - Isonicotinic acid hydrazide: an anti-tuberculosis drug inhibits malarial
      transmission in the mosquito gut.
AB  - We studied the transmission-blocking effect of isonicotinic acid hydrazide (INH),
      a widely used anti-tuberculosis drug, against Plasmodium gallinaceum and
      Plasmodium berghei. INH-treatment of infected animals did not inhibit parasite
      development in the blood of the vertebrate host, but did inhibit exflagellation,
      ookinete formation, and oocyst development in the mosquito. Oocyst development
      was inhibited in a dose-dependent manner. The ED(50) in the P.
      gallinaceum/chicken/Aedes aegypti model and P. berghei/mouse/Anopheles stephensi
      model was 72 and 109 mg/kg, respectively. In marked contrast, in vitro
      exflagellation and ookinete development were not directly affected by
      physiological concentrations of INH. We suggest that INH exerts its inhibitory
      effects on the mosquito stages of the malaria parasite by an indirect, and at
      present undefined mechanism. Further elucidation of the mechanism how INH
      inhibits parasite development specifically on mosquito stages may allow us to
      identify new targets for malaria control strategy.

PMID- 15013787
TI  - Trypanosoma brucei: a first-generation CRE-loxP site-specific recombination
      system.
AB  - The bacteriophage CRE-loxP system of DNA recombination is widely used to
      manipulate segments of the genomes of mice and other eukaryotes for the purpose
      of studying the regulation and functions of their genes. Since this recombination
      system could have similar applications in analyzing the genomes of
      trypanosomatids, we assessed the action of CRE recombinase on its loxP DNA
      recognition sites in Trypanosoma brucei after inserting tetracycline-regulated
      CRE and two 34-bp loxP sites into the T. brucei genome. We found that when loxP
      sites flank in a direct orientation the transcription termination sequence (1.1
      kb) of the T. brucei GPEET/PAG3 locus, CRE recombinase deletes this termination
      sequence, permitting transcription and subsequent expression of a downstream
      reporter gene for the green fluorescent protein (GFP). Thus, the CRE-loxP system
      is highly efficient in T. brucei, but the experimental results also indicate that
      a better way than the existing tetracycline-regulated system is required to
      completely silence expression of CRE in the T. brucei genome when it is not
      needed before the full range of CRE-loxP applications currently used in mice can
      be exploited in African trypanosomes.

PMID- 15013788
TI  - Identification of a rare point mutation at C-terminus of merozoite surface
      antigen-1 gene of Plasmodium falciparum in eastern Indian isolates.
AB  - Merozoite surface antigen-1 (MSA-1) of Plasmodium falciparum is highly
      immunogenic in human. Several studies suggest that MSA-1 protein is an effective
      target for a protective immune response. Attempt has been made to find new point
      mutations by analyzing 244 bp [codon 1655(R) to 1735 (I)] relatively conserved C
      terminus region of MSA-1 gene in 125 isolates. This region contains two EGF like
      domains, which are involved in generating protective immune response in human.
      Point mutations in this region are very much important in view of vaccine
      development. Searching of mutational hot spots in MSA-1 protein by sequencing
      method in a representative number of isolates is quite critical and expensive.
      Therefore, in this study slot blot and PCR-SSCP method have been used to find out
      new mutations in the individual isolates showing alterations in the mobility of
      DNA fragment. Sequencing of the altered bands from the SSCP gel shows a rare non
      synonymous point mutation in 7 (5.6%) of the 125 isolates at amino acid position
      1704 of MSA-1 gene where isoleucine is replaced by valine.

PMID- 15013789
TI  - Plasmodium falciparum: selenium-induced cytotoxicity to P. falciparum.
AB  - The in vitro antimalarial activity of sodium selenite (NaSe) was investigated and
      the mechanism of its action was studied. NaSe had antimalarial activity against
      both the chloroquine-susceptible strain FCR-3 and chloroquine-resistant strain K
      1 of Plasmodium falciparum. The shrunken cytoplasm of the parasite was observed
      in a smear 12 h after treatment with NaSe. Co-treatment with copper sulfate
      (CuSO(4)) in culture did not affect the antimalarial activity of NaSe, but NaSe
      cytotoxicity against the mammalian cell line Alexander was decreased
      significantly. The intracellular reduced glutathione level of parasitized red
      blood cells was decreased significantly by treatment with NaSe, and the decrease
      was consistent with their mortality. Treatment with NaSe had a strong inhibitory
      effect on plasmodial development, and NaSe cytotoxicity to human cells was
      decreased by co-treatment with CuSO(4). These results suggest that co-treatment
      with NaSe and CuSO(4) may be useful as a new antimalarial therapy.

PMID- 15013790
TI  - Specific tyrosine phosphorylation in response to bile in Fasciola hepatica and
      Echinostoma friedi.
AB  - Protein tyrosine phosphorylation (PY) is a well-known signalling mechanism which
      is also involved in host-parasite interactions. Despite its transcendence, PY has
      been poorly studied in parasitic helminths. The aim of this study is to examine
      the effect of bile salts on the PY pattern in parasitic trematodes. Two distinct
      adult models were analysed: Echinostoma friedi, of intestinal habitat, and
      Fasciola hepatica, naturally inhabitant of host biliary channels. Our results
      show that bile salts induce specific and distinct protein PY in both trematode
      species, indicating that this signalling process seems to be also involved in
      host-trematode relationships.

PMID- 15013791
TI  - Schistosoma mansoni: sex-specific modulation of parasite growth by host immune
      signals.
AB  - Development of female schistosomes from infectious cercariae to mature egg
      producing adults requires both male schistosomes and an intact adaptive immune
      system. By examining single sex infections in immunodeficient mice, we provide
      evidence that female schistosome development is not directly influenced by the
      adaptive immune system, whereas male development is. Our data are consistent with
      a sequential model of schistosome development, where the adaptive immune system
      signals development of mature males, which subsequently stimulate development of
      mature females. The male schistosome therefore appears to play a central role
      both in transducing signals from the adaptive immune system and in facilitating
      female development.

PMID- 15013792
TI  - Trichinella spiralis: activity of the cerebral pyruvate recycling pathway of the
      host (mouse) in hypoglycemia induced by the infection.
AB  - The activity of the cerebral pyruvate recycling pathway and energy metabolism in
      mice infected with Trichinella spiralis were investigated using (13)C-NMR and in
      vivo (31)P-NMR spectroscopy, respectively. The (13)C-NMR analysis, using [1,2
      (13)C(2)] acetate as a substrate, of whole-brain extracts demonstrated that
      activity of the pathway increased when T. spiralis infection induced hypoglycemia
      in the host. The in vivo (31)P-NMR observation showed that the cerebral ATP in
      normal level sustained throughout this experiment. These findings indicate that
      the pyruvate recycling pathway plays a role in the energy supply to the host in
      hypoglycemia induced by T. spiralis infection.

PMID- 15013793
TI  - Activation of Cdc2 kinase during meiotic maturation of axolotl oocyte.
AB  - Activity of Cdc2, the universal inducer of mitosis, is regulated by
      phosphorylation and binding to cyclin B. Comparative studies using oocytes from
      several amphibian species have shown that different mechanisms allow Cdc2
      activation and entry into first meiotic division. In Xenopus, immature oocytes
      stockpile pre-M-phase promoting factor (MPF) composed of Cdc2-cyclin B complexes
      maintained inactive by Thr14 and Tyr15 phosphorylation of Cdc2. Activation of MPF
      relies on the conversion of pre-MPF into MPF by Cdc2 dephosphorylation, implying
      a positive feedback loop known as MPF auto-amplification. On the contrary, it has
      been proposed that pre-MPF is absent in immature oocyte and that MPF activation
      depends on cyclin synthesis in some fishes and other amphibians. We demonstrate
      here that MPF activation in the axolotl oocyte, an urodele amphibian, is achieved
      through mechanisms resembling partly those found in Xenopus oocyte. Pre-MPF is
      present in axolotl immature oocyte and is activated during meiotic maturation.
      However, monomeric Cdc2 is expressed in large excess over pre-MPF, and pre-MPF
      activation by Cdc2 dephosphorylation takes place progressively and not abruptly
      as in Xenopus oocyte. The intracellular compartmentalization as well as the low
      level of pre-MPF in axolotl oocyte could account for the differences in oocyte
      MPF activation in both species.

PMID- 15013794
TI  - The Drosophila Brahma (SWI/SNF) chromatin remodeling complex exhibits cell-type
      specific activation and repression functions.
AB  - The Brahma (Brm) complex of Drosophila melanogaster is a SWI/SNF-related
      chromatin remodeling complex required to correctly maintain proper states of gene
      expression through ATP-dependent effects on chromatin structure. The SWI/SNF
      complexes are comprised of 8-11 stable components, even though the SWI2/SNF2
      (BRM, BRG1, hBRM) ATPase subunit alone is partially sufficient to carry out
      chromatin remodeling in vitro. The remaining subunits are required for stable
      complex assembly and/or proper promoter targeting in vivo. Our data reveals that
      SNR1 (SNF5-Related-1), a highly conserved subunit of the Brm complex, is required
      to restrict complex activity during the development of wing vein and intervein
      cells, illustrating a functional requirement for SNR1 in modifying whole complex
      activation functions. Specifically, we found that snr1 and brm exhibited opposite
      mutant phenotypes in the wing and differential misregulation of genes required
      for vein and intervein cell development, including rhomboid, decapentaplegic,
      thick veins, and blistered, suggesting possible regulatory targets for the Brm
      complex in vivo. Our genetic results suggest a novel mechanism for SWI/SNF
      mediated gene repression that relies on the function of a 'core' subunit to block
      or shield BRM (SWI2/SNF2) activity in specific cells. The SNR1-mediated
      repression is dependent on cooperation with histone deacetylases (HDAC) and
      physical associations with NET, a localized vein repressor.

PMID- 15013795
TI  - Role of myocardial hypoxia in the remodeling of the embryonic avian cardiac
      outflow tract.
AB  - The embryonic cardiac outflow myocardium originates from a secondary heart
      forming field to connect the developing ventricles with the aortic sac. The
      outflow tract (OFT) subsequently undergoes complex remodeling in the transition
      of the embryo to a dual circulation. In avians, elimination of OFT cardiomyocytes
      by apoptosis (stages 25-32) precedes coronary vasculogenesis and is necessary for
      the shortening of the OFT and the posterior rotation of the aorta. We
      hypothesized that regional myocardial hypoxia triggers OFT remodeling. We used
      immunohistochemical detection of the nitroimidazole EF5, administered by
      intravascular infusion in ovo, as an indicator of relative tissue oxygen
      concentrations. EF5 binding was increased in the OFT myocardium relative to other
      myocardium during these stages (25-32) of OFT remodeling. The intensity of EF5
      binding paralleled the prevalence of apoptosis in the OFT myocardium, which are
      first detected at stage 25, maximal at stage 30, and diminished by stage 32.
      Evidence of coincident hypoxia-dependent responses included the expression of the
      vascular endothelial growth factor (VEGF) receptor 2 by the OFT myocardium, the
      predominant expression of VEGF122 (diffusible) isoform in the OFT, and the
      recruitment of QH1-positive pro-endothelial cells to the OFT and vasculogenesis.
      Exposure of embryos to hyperoxia (95% O(2)/5% CO(2)) during this developmental
      window reduced the prevalence of cardiomyocyte apoptosis and attenuated the
      shortening and rotation of the OFT, resulting in double-outlet right ventricle
      morphology, similar to that observed when apoptosis is directly inhibited. These
      results suggest that regional myocardial hypoxia triggers cardiomyocyte apoptosis
      and remodeling of the OFT in the transition to a dual circulation, and that VEGF
      autocrine/paracrine signaling may regulate these processes.

PMID- 15013796
TI  - Fas ligand gene transfer to the embryonic heart induces programmed cell death and
      outflow tract defects.
AB  - The remodeling of the embryonic avian cardiac outflow tract (OFT) involves the
      removal of cardiomyocytes by programmed cell death (PCD). In contrast, the
      prevalence of PCD is low in the atrial or ventricular myocytes during this period
      of development. To determine if this selective PCD is due to the unique ability
      of the OFT cardiomyocytes to execute PCD, we transduced the embryonic chicken
      heart in ovo with recombinant adenovirus expressing a death (FasL) ligand. This
      resulted in programmed cell death in atrial, ventricular, and OFT cardiomyocytes
      as evidenced by chromosomal fragmentation, accumulation of lysosomes, and Caspase
      enzymatic activity. Consistent with the widespread induction of PCD, transcripts
      for the Fas receptor were detected in all chambers of the heart throughout
      development. The precocious and widespread activation of PCD in the OFT
      myocardium resulted in a marked dimunition of the subpulmonic myocardial
      infundibulum, and transposition of the aorta side-by-side with the pulmonary
      artery and connecting to the right ventricle. Defects in other cardiac structures
      are also described. We conclude that the regulated removal of OFT cardiomyocytes
      by PCD is required for the great vessels to make their proper connections with
      the ventricles in the transition to a dual circulation. The malalignment of the
      great vessels described in this animal model are similar to those described in
      congenital human conotruncal heart defects, suggesting that PCD-dependent
      remodeling of the OFT myocardium could be a target of genetic mutations or
      teratogens that cause human conotruncal heart defects.

PMID- 15013797
TI  - bullwinkle is required for epithelial morphogenesis during Drosophila oogenesis.
AB  - Many organs, such as the liver, neural tube, and lung, form by the precise
      remodeling of flat epithelial sheets into tubes. Here we investigate epithelial
      tubulogenesis in Drosophila melanogaster by examining the development of the
      dorsal respiratory appendages of the eggshell. We employ a culture system that
      permits confocal analysis of stage 10-14 egg chambers. Time-lapse imaging of GFP
      Moesin-expressing egg chambers reveals three phases of morphogenesis: tube
      formation, anterior extension, and paddle maturation. The dorsal-appendage
      forming cells, previously thought to represent a single cell fate, consist of two
      subpopulations, those forming the tube roof and those forming the tube floor.
      These two cell types exhibit distinct morphological and molecular features. Roof
      forming cells constrict apically and express high levels of Broad protein. Floor
      cells lack Broad, express the rhomboid-lacZ marker, and form the floor by
      directed cell elongation. We examine the morphogenetic phenotype of the
      bullwinkle (bwk) mutant and identify defects in both roof and floor formation.
      Dorsal appendage formation is an excellent system in which cell biological,
      molecular, and genetic tools facilitate the study of epithelial morphogenesis.

PMID- 15013798
TI  - Fundamental properties of the spiralian developmental program are displayed by
      the basal nemertean Carinoma tremaphoros (Palaeonemertea, Nemertea).
AB  - The first description of the cleavage program of the palaeonemertean Carinoma
      tremaphoros (a member of a basal clade of the Nemertea) is illustrated by
      confocal microscopy and microinjection and compared to development of more
      derived nemerteans and other eutrochozoans (Annelida, Mollusca, Sipunculida and
      Echiurida). Lineage tracers were injected into individual blastomeres of C.
      tremaphoros at the 2-, 4-, 8- and 16-cell stage. Subsequent development was
      followed to the formation of simple (so-called planuliform) planktonic larvae to
      establish the ultimate fates of the blastomeres. Results of labeling experiments
      demonstrate that the development of C. tremaphoros bears closer similarity to
      other Eutrochozoa than development of a previously studied hoplonemertean
      (Nemertopsis bivittata) and a heteronemertean (Cerebratulus lacteus) in that the
      first cleavage plane bears an invariant relationship to the plane of bilateral
      symmetry of the larval body. Additionally, our cell-labeling experiments support
      the earlier suggestion that the transitory pre-oral belt of cells in the larvae
      of C. tremaphoros corresponds to the prototroch of other Eutrochozoa. A unique
      feature of development of C. tremaphoros includes the oblique orientation of the
      trochal lineages with respect to the anterior-posterior axis of the larva. The
      significance and application of cleavage characters such as presence of molluscan
      vs. annelid cross for phylogenetic analyses is reviewed. We argue that molluscan
      or annelid cross, neither of which are present in nemerteans, are merely two out
      of much greater variety of patterns created by the differences in the relative
      size and timing of formation of micromere quartets and none can be considered, by
      itself, as evidence of close phylogenetic relationship between phyla.

PMID- 15013799
TI  - Three modules of zebrafish Mind bomb work cooperatively to promote Delta
      ubiquitination and endocytosis.
AB  - Precise regulation of Notch signaling activity is critical for development of
      many different tissues. Here, we show that the zebrafish insertional mutation
      Hi904 attenuates Notch signaling, and is allelic to mind bomb. We show that Mind
      bomb protein displays E3 ubiquitin ligase activity in vitro and that it is
      associated with Delta and enhances its ubiquitination and internalization in
      transfected cells. Furthermore, by functional analysis of three conserved regions
      of Mind bomb, we show that the N-terminal half is required for Delta association,
      the ankyrin repeats are important for Delta internalization, and the ring fingers
      are required for Delta ubiquitination. Thus, the three functionally distinct
      modules of Mind bomb work cooperatively to regulate Notch signaling by
      associating with, ubiquitinating, and internalizing Delta.

PMID- 15013800
TI  - The mammalian twisted gastrulation gene functions in foregut and craniofacial
      development.
AB  - Extracellular modulators of cell-cell signaling control numerous aspects of
      organismal development. The Twisted gastrulation (Twsg1) gene product is a small,
      secreted cysteine-rich protein that has the unusual property of being able to
      either enhance or inhibit signaling by the bone morphogenetic protein (BMP)
      subfamily of TGF-beta type factors in a context-dependent manner. In this report,
      we characterize the early embryonic and skeletal phenotypes associated with loss
      of Twsg1 function in mice. All Twsg1 mutant mice, irrespective of genetic
      background, exhibit deletions of neural arches in the cervical vertebrae. In a
      C57BL/6 background, we also observe pronounced forebrain defects including
      rostral truncations, holoprosencephaly, cyclopia, as well as alterations in the
      first branchial arch (BA1) leading to lack of jaw (agnathia). Characterization of
      marker expression suggests that these defects are attributable to loss of
      signaling from forebrain-organizing centers including Fgf8 from the anterior
      neural ridge (ANR) and Shh from the prechordal plate (PrCP). In addition, we find
      defects in the foregut endoderm and a reduction in Hex expression, which may
      contribute to both the forebrain and BA1 defects.

PMID- 15013802
TI  - Loss of AP-2alpha impacts multiple aspects of ventral body wall development and
      closure.
AB  - Human birth defects involving the ventral body wall are common, yet little is
      known about the mechanism of body wall closure in mammals. The AP-2alpha
      transcription factor knock-out mouse provides an exceptional tool to understand
      this particular pathology, since it has one of the most severe ventral body wall
      closure defects, thoracoabdominoschisis. To gain insight into the complex
      morphological events responsible for body wall closure, we have studied this
      developmental process in AP-2alpha knock-out mice. Several tissues involved in
      normal ventral body wall closure are defective in the absence of AP-2alpha,
      including those associated with the primary body wall, the umbilical ring, and
      the mesoderm of the secondary body wall. These defects, coupled with the
      expression pattern of AP-2alpha, suggest that AP-2alpha is involved in multiple
      developmental mechanisms directing the morphogenesis of the ventral body wall,
      including cell migration, differentiation, and death. There is a failure of
      migration and fusion of the body folds at the umbilical ring, as well as in the
      formation and migration of the abdominal bands and ventral musculature.
      Furthermore, the mechanism of cell deposition at the umbilical ring is disturbed.
      Consequently, the mesodermal compartment of the body wall is underdeveloped. We
      also suggest that AP-2alpha is required for signaling from the surface ectoderm
      to the underlying mesoderm for proper development and closure of the ventral body
      wall. These findings provide a fundamental understanding of how AP-2alpha
      functions in the closure of the ventral body wall, as well as offer insight into
      related human birth defects.

PMID- 15013801
TI  - Roles for Hedgehog signaling in androgen production and prostate ductal
      morphogenesis.
AB  - Previous studies have demonstrated that the Hedgehog (Hh) signaling pathway plays
      a critical role in the development and patterning of many endodermally derived
      tissues. We have investigated the role of Sonic hedgehog (Shh) in formation of
      the prostate gland by examining the urogenital phenotype of Shh mutant fetuses.
      Consistent with earlier work reporting an essential role for Shh in prostate
      induction, we have found that Shh mutant fetuses display abnormal urogenital
      development and fail to form prostate buds. Unexpectedly, however, we have
      discovered that this prostate defect could be rescued by three different methods:
      renal grafting, explant culture in the presence of androgens, and administration
      of dihydrotestosterone (DHT) to pregnant mice, indicating that the prostate
      defect in Shh mutants is due to insufficient levels of androgens. Furthermore, we
      find that the inhibition of Hh pathway signaling by treatment with cyclopamine
      does not block prostate formation in explant culture, but instead produces
      morphological defects consistent with a role for Hh signaling in ductal
      patterning. Taken together, our studies indicate that the initial organogenesis
      of the prostate proceeds independently of Shh, but that Shh or other Hh ligands
      may play a role in subsequent events that pattern the prostate.

PMID- 15013803
TI  - Loss of connexin 26 in mammary epithelium during early but not during late
      pregnancy results in unscheduled apoptosis and impaired development.
AB  - Gap junctions are intercellular channels that are formed by the protein family of
      connexins (Cxs). In mammary tissue, Cx26 and Cx32 are present in the secretory
      epithelium and Cx43 is localized in the myoepithelium. The expression of Cx26 and
      Cx32 is induced during pregnancy and lactation, respectively, thus suggesting
      unique roles for them in the functional development of the gland. The requirement
      for these connexins was explored using several strains of genetically altered
      mice: mice with an inactivated Cx32 gene, mice in which the Cx43 gene had been
      replaced with the Cx32 gene (Cx43KI32 mice) and mice in which the Cx26 gene was
      specifically ablated in mammary epithelium at different stages of development
      using Cre-loxP-based recombination. Normal mammary development was obtained in
      Cx32-null mice and in Cx43KI32 mammary tissue. In contrast, loss of Cx26 in
      mammary epithelium before puberty resulted in abrogated lobulo-alveolar
      development and increased cell death during pregnancy, which was accompanied by
      impaired lactation. Loss of Cx26 in mammary epithelium during the later part of
      pregnancy did not adversely interfere with functional mammary development. These
      results demonstrate that the presence of Cx26 is critical during early stages but
      not during the end of pregnancy when the tissue has completed functional
      differentiation. Cx26 is considered a tumor suppressor gene and Cx26-null mammary
      tissue was evaluated after five pregnancies. No hyperproliferation or hyperplasia
      was observed, suggesting that Cx26 does not function as a tumor suppressor.

PMID- 15013806
TI  - Spatial and temporal regulation of the homeotic selector gene Antennapedia is
      required for the establishment of leg identity in Drosophila.
AB  - Antennapedia is one of the homeotic selector genes required for specification of
      segment identity in Drosophila. Dominant mutations that ectopically express
      Antennapedia cause transformation of antenna to leg. Loss-of-function mutations
      cause partial transformation of leg to antenna. Here we examine the role of
      Antennapedia in the establishment of leg identity in light of recent advances in
      our understanding of antennal development. In Antennapedia mutant clones in the
      leg disc, Homothorax and Distal-less are coexpressed and act via spineless to
      transform proximal femur to antenna. Antennapedia is negatively regulated during
      leg development by Distal-less, spineless, and dachshund and this reduced
      Antennapedia expression is needed for the proper development of distal leg
      elements. These findings suggest that the temporal and spatial regulation of the
      homeotic selector gene Antennapedia in the leg disc is necessary for normal leg
      development in Drosophila.

PMID- 15013805
TI  - A novel role of the hedgehog pathway in lens regeneration.
AB  - Lens regeneration in the adult newt is a classic example of replacing a lost
      organ by the process of transdifferentiation. After lens removal, the pigmented
      epithelial cells of the dorsal iris proliferate and dedifferentiate to form a
      lens vesicle, which subsequently differentiates to form a new lens. In searching
      for factors that control this remarkable process, we investigated the expression
      and role of hedgehog pathway members. These molecules are known to affect retina
      and pigment epithelium morphogenesis and have been recently shown to be involved
      in repair processes. Here we show that Shh, Ihh, ptc-1, and ptc-2 are expressed
      during lens regeneration. The expression of Shh and Ihh is quite unique since
      these genes have never been detected in lens. Interestingly, both Shh and Ihh are
      only expressed in the regenerating and developing lens, but not in the intact
      lens. Interfering with the hedgehog pathway results in considerable inhibition of
      the process of lens regeneration, including decreased cell proliferation as well
      as interference with lens fiber differentiation in the regenerating lens vesicle.
      Down-regulation of ptc-1 was also observed when inhibiting the pathway. These
      results provide the first evidence of a novel role for the hedgehog pathway in
      specific regulation of the regenerating lens.

PMID- 15013807
TI  - Zebrafish periostin is required for the adhesion of muscle fiber bundles to the
      myoseptum and for the differentiation of muscle fibers.
AB  - The myoseptum of fishes, composed of dense collagen, is a connective tissue layer
      that forms in the embryo, dividing somites from the trunk, and its structure and
      function are similar to those of the mammalian tendon. Both the myoseptum and
      tendon serve as the transmitter of muscular contractility to bones and adjoining
      muscles, and their structure is indispensable for movement of vertebrate animals.
      We cloned the zebrafish periostin gene and examined its expression and function
      in the myoseptum. The expression in embryos started in the rostral part of each
      segmented somite in the early segmentation stage; and consequently, metameric
      stripes were observed. At the end of segmentation, the expression region shifted
      to the transverse myoseptum and the myotome-epidermis boundary, and each myotome
      was surrounded by periostin. Using a polyclonal antibody, we found that the
      periostin protein was localized to the transverse myoseptum. Consistently,
      periostin morpholino antisense oligonucleotide led to defects in myoseptum
      formation, a delay in the differentiation of myofibers, and disorder of
      connection between myofibrils and myoseptum. We demonstrated here that periostin
      is the first molecule involved in myoseptum formation and propose that periostin
      secretion on the surface of the myoseptum is required for the adhesion of muscle
      fiber bundles to the myoseptum and the differentiation of muscle fibers.

PMID- 15013804
TI  - TrkB receptors are required for follicular growth and oocyte survival in the
      mammalian ovary.
AB  - Although it is well established that both follicular assembly and the initiation
      of follicle growth in the mammalian ovary occur independently of pituitary
      hormone support, the factors controlling these processes remain poorly
      understood. We now report that neurotrophins (NTs) signaling via TrkB receptors
      are required for the growth of newly formed follicles. Both neurotrophin-4/5 (NT
      4) and brain-derived neurotrophic factor (BDNF), the preferred TrkB ligands, are
      expressed in the infantile mouse ovary. Initially, they are present in oocytes,
      but this site of expression switches to granulosa cells after the newly assembled
      primordial follicles develop into growing primary follicles. Full-length kinase
      domain-containing TrkB receptors are expressed at low and seemingly unchanging
      levels in the oocytes and granulosa cells of both primordial and growing
      follicles. In contrast, a truncated TrkB isoform lacking the intracellular domain
      of the receptor is selectively expressed in oocytes, where it is targeted to the
      cell membrane as primary follicles initiate growth. Using gene-targeted mice
      lacking all TrkB isoforms, we show that the ovaries of these mice or those
      lacking both NT-4 and BDNF suffer a stage-selective deficiency in early
      follicular development that compromises the ability of follicles to grow beyond
      the primary stage. Proliferation of granulosa cells-required for this transition
      and expression of FSH receptors (FSHR), which reflects the degree of biochemical
      differentiation of growing follicles, are reduced in trkB-null mice. Ovaries from
      these animals grafted under the kidney capsule of wild-type mice fail to sustain
      follicular growth and show a striking loss of follicular organization, preceded
      by massive oocyte death. These results indicate that TrkB receptors are required
      for the early growth of ovarian follicles and that they exert this function by
      primarily supporting oocyte development as well as providing granulosa cells with
      a proliferative signal that requires oocyte-somatic cell bidirectional
      communication. The predominance of truncated TrkB receptors in oocytes and their
      developmental pattern of subcellular expression suggest that a significant number
      of NT-4/BDNF actions in the developing mammalian ovary are mediated by these
      receptors.

PMID- 15013808
TI  - T-box binding sites are required for activity of a cardiac GATA-4 enhancer.
AB  - GATA-4 is a key regulator of a poorly understood cardiac morphogenetic program.
      We used genomic regions of the GATA-4 gene to target GFP expression to the
      developing heart of living fish. In these fish, GFP-expressing cells in the
      lateral plate mesoderm form two tubes that migrate ventrally to fuse into a
      linear heart tube. In addition, we find that a 14.8-kb fragment upstream of the
      transcription initiation site targets expression to both chambers and the valves
      of the heart. Truncation of 7 kb of the distal sequences eliminates expression in
      the atrium and the atrioventricular valve while expression is retained in the
      ventricle and the bulboventricular valve. Within this 7-kb distal regulatory
      region, we delineated a 1300-bp region with a cluster of consensus binding sites
      for T-box transcription factors. Mutation of these sequences significantly
      reduces reporter gene expression in the heart. This provides the first evidence
      that T-box factors function by directly regulating GATA-4 expression. Thus, GATA
      4 regulatory elements control gene expression differentially along the rostro
      caudal axis, and T-box binding elements in the GATA-4 promoter contribute to
      heart-specific expression.

PMID- 15013809
TI  - Expression of Pax2 in the intermediate mesoderm is regulated by YY1.
AB  - The transcription factor Pax2 is essential for the development of the urogenital
      system. Pax2 expression can be detected by mouse embryonic day 8.5 (E8.5) in the
      region of intermediate mesoderm fated to become the nephric duct, pronephros, and
      mesonephros. Elements that direct Pax2 expression to nephrogenic precursor cells
      must be responding to positional information that controls nephrogenic fate. A
      4.1-kb Pax2 promoter/enhancer fragment directs expression of a lacZ reporter to
      the nephrogenic region and the midbrain-hindbrain junction in transgenic mice. As
      kidney development proceeds, transgene expression is limited to the nephric duct
      and its derivatives, but not the metanephric mesenchyme. The early expression
      driven by the 4.1 promoter does not require the Pax2 protein, demonstrating that
      it receives positional information in the absence of a developing pro- or
      mesonephros. We have identified two DNAseI hypersensitive regions within this
      promoter, one at the start site of transcription initiation and a second
      approximately 2-kb upstream. Deletion of the more distal site significantly
      attenuates lacZ expression in the nephrogenic region but not in the midbrain
      hindbrain region. DNA footprinting of this fragment revealed a highly conserved
      sequence between mouse and human Pax2 promoter sequences. Using fractionated
      nuclear extracts, we identified the transcription factor Yin Yang 1 (YY1) as the
      protein that binds to this conserved sequence. Deletion of the YY1 element
      significantly attenuated expression of a full-length 4.1 promoter. Moreover,
      inclusion of this YY1 binding element significantly enhanced expression of a
      minimal Pax2 promoter/enhancer transgene in E12 embryos. These data point to a
      novel role for YY1 in the establishment of high level tissue-specific expression
      within the intermediate mesoderm.

PMID- 15013811
TI  - Computational identification of microRNA targets.
AB  - Recent experiments have shown that the genomes of organisms such as worm, fly,
      human, and mouse encode hundreds of microRNA genes. Many of these microRNAs are
      thought to regulate the translational expression of other genes by binding to
      partially complementary sites in messenger RNAs. Phenotypic and expression
      analysis suggests an important role of microRNAs during development. Therefore,
      it is of fundamental importance to identify microRNA targets. However, no
      experimental or computational high-throughput method for target site
      identification in animals has been published yet. Our main result is a new
      computational method that is designed to identify microRNA target sites. This
      method recovers with high specificity known microRNA target sites that have
      previously been defined experimentally. Based on these results, we present a
      simple model for the mechanism of microRNA target site recognition. Our model
      incorporates both kinetic and thermodynamic components of target recognition.
      When we applied our method to a set of 74 Drosophila melanogaster microRNAs,
      searching 3'UTR sequences of a predefined set of fly mRNAs for target sites which
      were evolutionary conserved between D. melanogaster and Drosophila pseudoobscura,
      we found that many key developmental body patterning genes such as hairy and
      fushi-tarazu are likely to be translationally regulated by microRNAs.

PMID- 15013810
TI  - Regulatory elements controlling Ci-msxb tissue-specific expression during Ciona
      intestinalis embryonic development.
AB  - The msh/Msx family is a subclass of homeobox-containing genes suggested to
      perform a conserved function in the patterning of the early embryo. We had
      already isolated a member of this gene family (Ci-msxb) in Ciona intestinalis,
      which has a very complex expression pattern during embryogenesis. To identify the
      regulatory elements controlling its tissue-specific expression, we have
      characterized the gene structure and the regulatory upstream region. By
      electroporation experiments, we demonstrated that a 3.8-kb region located
      upstream of the gene contains all the regulatory elements able to reproduce its
      spatial expression pattern. Analyzing progressively truncated fragments of this
      region, three discrete and separate regions driving LacZ reporter gene expression
      in the ventral epidermis, primordial pharynx and neural territories have been
      identified. We further investigated the element(s) necessary for Ci-msxb
      activation in the nervous system during embryonic development by in vivo and in
      vitro experiments. Both electroporation and gel-shift assays of overlapping wild
      type and mutated oligonucleotides demonstrated that a unique sequence of 30 bp is
      involved in Ci-msxb neural activation from neurula to larva stage. This sequence
      contains consensus binding sites for various ubiquitous transcription factors
      such as TCF11 whose possible implication in formation of the regulatory complexes
      is discussed.

PMID- 15013812
TI  - Positive autoregulation of the Myocyte enhancer factor-2 myogenic control gene
      during somatic muscle development in Drosophila.
AB  - The myocyte enhancer factor-2 (MEF2) transcription factor plays a central role in
      the activation and maintenance of muscle gene expression in fruit flies and
      vertebrates. The mechanism of action and downstream target genes of MEF2 have
      been defined in considerable detail, but relatively little is known about the
      mechanisms that regulate MEF2 expression during muscle development. Here we
      demonstrate that MEF2 maintains its own expression in all differentiated muscle
      cell types during late embryonic and larval development in Drosophila by binding
      a conserved MEF2 site in a muscle-specific regulatory enhancer. Ectopic
      expression of Mef2 is sufficient to directly activate this enhancer in some, but
      not all, non-muscle cells. Furthermore, activation of the Mef2 enhancer normally
      in muscle cells and ectopically in non-muscle cells is dependent upon the
      integrity of the MEF2 binding site. These findings suggest an evolutionarily
      conserved mechanism whereby MEF2 can stabilize the muscle phenotype by sustaining
      its own expression through a myogenic autoregulatory loop.

PMID- 15013813
TI  - In vitro metabolism and inductive or inhibitive effect of DL111 on rat cytochrome
      P4501A enzyme.
AB  - In vitro metabolism and the inductive or inhibitive effect of DL111, a non
      hormonal early pregnancy-terminating agent, toward cytochrome P450 (CYP) enzymes
      in rat liver microsomes were studied. In vitro metabolism of DL111 was performed
      in different rat liver microsomes (pretreated with phenobarbital (PB),
      dexamethasone (Dex), beta-naphthoflavone (BNF), DL111, respectively) and the
      catalytic abilities of these microsomes for DL111 were compared with control
      group. DL111 was well metabolized in microsomes pretreated with beta
      naphthoflavone and itself. The K(m) and V(max) was 41.76 +/- 3.26 microM and
      15.34 +/- 1.03 nM min(-1) mg(-1) protein for beta-naphthoflavone group, 48.17 +/-
      6.06 microM and 17.54 +/- 1.79 nM min(-1)mg(-1) protein for DL111 group, 77.81 +/
      4.73 microM and 3.087 +/- 0.202 nM min(-1)mg(-1) protein for control group,
      respectively. The rats were pretreated intraperitoneally with the same daily dose
      of DL111 for different days. The DL111-pretreated microsomal enzymatic activities
      were evaluated by measuring the metabolic abilities for specific substrates of
      various enzymes. The results showed that DL111 had the same inductive function as
      beta-naphthoflavone (the specific inducer of CYP1A) toward rat liver microsomes.
      The inhibitive effect of DL111 on CYP1A was investigated by coincubating DL111
      with the specific substrates of CYP1A-ethoxyresorufin or phenacetin in the
      microsome induced by beta-naphthoflavone, and the inhibitive level was compared
      with fluvoxamine (Flu), the specific inhibitor of CYP1A. DL111 inhibited
      significantly the metabolism of phenacetin and ethoxyresorufin with the
      inhibition constant (K(i)) 6.836 +/- 0.10 and 1.222 +/- 0.230 microM,
      respectively and its inhibition potential on CYP1A was higher than fluvoxamine.

PMID- 15013815
TI  - Enzymology of a carbonyl reduction clearance pathway for the HIV integrase
      inhibitor, S-1360: role of human liver cytosolic aldo-keto reductases.
AB  - S-1360, a 1,3-diketone derivative, was the first HIV integrase inhibitor to enter
      human trials. Clinical data suggested involvement of non-cytochrome P450
      clearance pathways, including reduction and glucuronidation. Reduction of S-1360
      generates a key metabolite in humans, designated HP1, and constitutes a major
      clearance pathway. For characterization of subcellular location and cofactor
      dependence of HP1 formation, [(14)C]-S-1360 was incubated with commercially
      available pooled human liver fractions, including microsomes, cytosol, and
      mitochondria, followed by HPLC analysis with radiochemical detection. Incubations
      were performed in the presence and absence of the cofactors NADH or NADPH.
      Results showed that the enzyme system responsible for generation of HP1 in vitro
      is cytosolic and NADPH-dependent, implicating aldo-keto reductases (AKRs) and/or
      short-chain dehydrogenases/reductases (SDRs). A validated LC/MS/MS method was
      developed for investigating the reduction of S-1360 in detail. The reduction
      reaction exhibited sigmoidal kinetics with a K(m,app) of 2 microM and a Hill
      coefficient of 2. The ratio of V(max)/K(m) was approximately 1 ml/(min mg
      cytosolic protein). The S-1360 kinetic data were consistent with positive
      cooperativity and a single enzyme system. The relative contributions of AKRs and
      SDRs were examined through the use of chemical inhibitors. For these experiments,
      non-radiolabeled S-1360 was incubated with pooled human liver cytosol and NADPH
      in the presence of inhibitors, followed by quantitation of HP1 by LC/MS/MS.
      Quercetin and menadione produced approximately 30% inhibition at a concentration
      of 100 microM. Enzymes sensitive to these inhibitors include the carbonyl
      reductases (CRs), a subset of the SDR enzyme family predominantly located in the
      cytosol. Flufenamic acid and phenolphthalein were the most potent inhibitors,
      with > 67% inhibition at a concentration of 20 microM, implicating the AKR enzyme
      family. The cofactor dependence, subcellular location, and chemical inhibitor
      results implicated the aldo-keto reductase family of enzymes as the most likely
      pathway for generation of the major metabolite HP1 from S-1360.

PMID- 15013814
TI  - Polypeptide from Chlamys farreri protects HaCaT cells from UVB-induced apoptosis.
AB  - A natural polypeptide from marine Chlamys farreri (a kind of scallop) (PCF), has
      been recently been found to be an effective photoprotective agent against
      ultraviolet rays B (UVB)-induced mitochondria damage in normal human fibroblasts.
      To investigate whether PCF has the antiapoptotic effect on human keratinocytes,
      in the present study, we established an apoptotic model on HaCaT cell line by
      means of UVB radiance of 30 mJ/cm(2) and compared the effect of different PCF
      treatments on UVB-radiated cells. Flow cytometry analyses showed that PCF
      treatment before UVB-irradiation inhibited UVB-induced apoptosis, the loss of
      mitochondrial membrane potential (Deltapsim) and the increase of free Ca(2+)
      level in HaCaT cells. In parallel with these results, UVB-irradiation enhanced
      activities of caspases-3, 8, 9, while this enhancement was inhibited by PCF
      treatment prior to irradiation. PCF added after irradiation neither reduced UVB
      induced activities of the three caspases nor synergized the effect of pre-added
      PCF. Cellular ultrastructural features obtained from transmission electron
      microscopy further confirmed the antiapoptotic effect of PCF pre-treatment. It is
      concluded that the antiapoptotic effect of PCF is not therapeutic but
      prophylactic. Caspases-3, 8, 9, Deltapsim and calcium are involved in UVB-induced
      apoptosis, while prophylactic PCF inhibits apoptosis of UVB-irradiated HaCaT
      cells by blocking the caspases activities, the Deltapsim lost and the elevation
      of intracellular free Ca(2+) level.

PMID- 15013816
TI  - Characterisation of androstenone metabolism in pig liver microsomes.
AB  - Androstenone (5 alpha-androst-16-en-3-one) is a steroid pheromone produced in the
      testis. Excessive accumulation of androstenone together with skatole (3-methyl
      indole) in the adipose tissue of some male pigs leads to "boar taint". In
      isolated pig hepatocytes androstenone represses the expression of cytochrome
      P450IIE1 (CYP2E1), the enzyme principally responsible for skatole metabolism.
      Androstenone can be metabolised in liver microsomes but the pathway has not been
      established. We have investigated androstenone metabolism in liver microsomes
      from two breeds of pigs exhibiting low and high levels of androstenone in adipose
      tissue-Large White (LW) and Meishan (M), respectively. Androstenone was reduced
      in isolated liver microsomes mainly to beta-androstenol using NADH as a co
      factor. The rate of beta-androstenol formation in the presence of NADPH was very
      low. In microsomes from LW pigs the rate of beta-androstenol formation from
      androstenone was six times higher than in M pigs. 3beta-hydroxysteroid
      dehydrogenase (3beta-HSD) was investigated as a likely candidate for the enzyme
      catalysing androstenone reduction in pig liver. RT-PCR analysis showed that there
      was no sequence difference in the cDNA encoding 3beta-hydroxysteroid
      dehydrogenase from LW and M pigs. However, competitive RT-PCR analysis showed
      that the expression of 3beta-hydroxysteroid dehydrogenase mRNA was about 12 times
      higher in the case of LW compared to M pigs. It is concluded that the rate of
      androstenone metabolism in pig liver microsomes is determined by the level of
      expression of hepatic 3beta-hydroxysteroid dehydrogenase. The differential
      expression of this enzyme could be a factor affecting the rate of hepatic
      androstenone metabolism which in turn may influence the level of hepatic CYP2E1
      expression and hence the rate of hepatic skatole metabolism.

PMID- 15013817
TI  - Biochemical background of toxic interaction between tiamulin and monensin.
AB  - Tiamulin, a diterpene antibiotic, is used for treatment of pulmonary and
      gastrointestinal infections in swine and poultry. Combined administration of
      tiamulin and ionophores (e.g. monensin) to farm animals may lead to intoxication
      manifested in severe clinical symptoms. Tiamulin metabolite complex with
      cytochrome P450 has been suggested to be the basis of drug-interactions. However,
      the formation of metabolic intermediate complex is questionable. The effect of
      tiamulin-treatment on cytochrome P450 activities was investigated in rats.
      Ethylmorphine and aminopyrine N-demethylation activities as well as monensin
      metabolism (O-demethylation) increased in liver microsomes of tiamulin-treated
      (200 mg/kg) animals. CYP3A1 induction caused by tiamulin was confirmed by the
      results of Western blot analysis. To test metabolic intermediate complex
      formation as a result of tiamulin treatment, cytochrome P450 activities were also
      determined in the presence of potassium ferricyanide. The findings together with
      those of in vitro complex formation suggested that formation of metabolic
      intermediate complexes of tiamulin with cytochrome P450 could be excluded. On the
      other hand, the results of inhibition studies showed significant decrease of
      ethylmorphine or aminopyrine as well as monensin demethylation in the presence of
      tiamulin. Our results proved that tiamulin has dual effect on cytochromes P450.
      It is able to induce and directly inhibit CYP3A enzymes, which are predominantly
      responsible for monensin O-demethylation. The direct effect of tiamulin as an
      inhibitor might play a more important role in toxicity than its putative effect
      as a chemical inducer of CYP3A enzymes.

PMID- 15013818
TI  - NADPH dependent activation of microsomal glutathione transferase 1.
AB  - Microsomal glutathione transferase 1 (MGST1) can become activated up to 30-fold
      by several mechanisms in vitro (e.g. covalent modification by reactive
      electrophiles such as N-ethylmaleimide (NEM)). Activation has also been observed
      in vivo during oxidative stress. It has been noted that an NADPH generating
      system (g.s.) can activate MGST1 (up to 2-fold) in microsomal incubations, but
      the mechanism was unclear. We show here that NADPH g.s treatment impaired N
      ethylmaleimide activation, indicating a shared target (identified as cysteine-49
      in the latter case). Furthermore, NADPH activation was prevented by sulfhydryl
      compounds (glutathione and dithiothreitol). A well established candidate for
      activation would be oxidative stress, however we could exclude that oxidation
      mediated by cytochrome P450 2E1 (or flavine monooxygenase) was responsible for
      activation under a defined set of experimental conditions since superoxide or
      hydrogen peroxide alone did not activate the enzyme (in microsomes prepared by
      our routine procedure). Actually, the ability of MGST1 to become activated by
      hydrogen peroxide is critically dependent on the microsome preparation method
      (which influences hydrogen peroxide decomposition rate as shown here), explaining
      variable results in the literature. NADPH g.s. dependent activation of MGST1
      could instead be explained, at least partly, by a direct effect observed also
      with purified enzyme (up to 1.4-fold activation). This activation was inhibited
      by sulfhydryl compounds and thus displays the same characteristics as that of the
      microsomal system. Whereas NADPH, and also ATP, activated purified MGST1, several
      nucleotide analogues did not, demonstrating specificity. It is thus an intriguing
      possibility that MGST1 function could be modulated by ligands (as well as
      reactive oxygen species) during oxidative stress when sulfhydryls are depleted.

PMID- 15013819
TI  - Hepatocellular bioactivation and cytotoxicity of the synthetic endoperoxide
      antimalarial arteflene.
AB  - Arteflene is a synthetic endoperoxide antimalarial. Its peroxide bridge undergoes
      iron(II)-mediated reduction in vitro which yields a carbon-centered cyclohexyl
      radical and a mixture of cis- and trans-alpha,beta-unsaturated ketones (enones).
      The enones are biliary metabolites in rats and therefore surrogate markers of
      bioactivation. Arteflene is reported to be more cytotoxic to primary rat
      hepatocytes than some non-endoperoxide antimalarials. Hepatic metabolism of
      arteflene was investigated in recirculating isolated perfused rat livers, and the
      drug's metabolism and cytotoxicity were compared using hepatocytes from male
      rats. Both preparations metabolized [(14)C]arteflene to cis- and trans
      [(14)C]enone, 8-hydroxyarteflene glucuronide and an unassigned isomeric
      glucuronide. During a 2 h liver perfusion, the cis- and trans-enones recovered in
      bile represented 8.1 +/- 3.4 and 11.3 +/- 4.6% (mean +/- S.D., N=6),
      respectively, of the [(14)C]arteflene (52 microM) added to the perfusate. After a
      3 h incubation of [(14)C]arteflene (10 microM) with hepatocytes in suspension,
      the cis- and trans-enones comprised, respectively, 14.8 +/- 7.1 and 2.1 +/- 1.0%
      (N = 4) of the recovered radioactivity; the corresponding data for cultured
      hepatocytes being 18.6 +/- 6.9 and 3.3 +/- 2.2%. Arteflene was significantly (P <
      0.05) toxic to isolated hepatocytes with reference to extramitochondrial
      reductase activity (tetrazolium reduction) but not enzyme leakage when the cells
      were exposed to drug concentrations > or =50 microM for 24 h. Cellular
      glutathione was depleted under these conditions. Therefore arteflene was acutely
      cytotoxic, though only at relatively high concentrations, when it was metabolized
      via a pathway which generates carbon-centered radicals.

PMID- 15013820
TI  - Estrogenic activity of procymidone in rainbow trout (Oncorhynchus mykiss)
      hepatocytes: a possible mechanism of action.
AB  - It is known that procymidone modifies sexual differentiation in vivo and in
      vitro, and that it induces vitellogenin (Vtg) synthesis in primary cultured
      rainbow trout hepatocytes. The aim of this study was to evaluate the mechanism
      underlying this latter in vitro estrogenic action. The cells were treated for 24
      h with procymidone 150 microM (with 17beta-estradiol [E2] 20 microM as a positive
      control) combined with an estrogen receptor (ER) antagonist (tamoxifen 20 microM
      or ICI 182,780 1 microM) or, given the drug toxic action on the production of
      reactive oxygen species (ROS), a free radical scavenger (alpha-tocopherol 30
      microM). The results from ELISA experiments provided evidence that procymidone
      Vtg-induction is inhibited by ER antagonists and by alpha-tocopherol suggesting
      that both ER and ROS are involved in this effect. The ROS detection revealed that
      the treatment with alpha-tocopherol and tamoxifen completely prevented ROS
      induction by procymidone, that was not inhibited by ICI 182,780. In exploring the
      mechanism mediating these events and its timing, we found that procymidone
      induced mitogen-activated protein kinase (MAPK) at 30 and 60 min, and that this
      effect was blocked by co-treatment with alpha-tocopherol. In summary, the results
      of the study clearly support the idea that the estrogenic activity of procymidone
      in primary cultured trout hepatocytes is mediated by ROS production, and that
      this activity is similar to that of the ligand-independent ER activation
      involving MAPK.

PMID- 15013821
TI  - Dose responses for DNA adduct formation in tissues of rats and mice exposed by
      inhalation to low concentrations of 1,3-[2,3-[(14)C]-butadiene.
AB  - Male Sprague-Dawley rats and B6C3F1 mice were exposed to either a single 6h or a
      multiple (5) daily (6h) nose-only dose of 1,3-[2,3-(14)C]-butadiene at exposure
      concentrations of nominally 1, 5 or 20 ppm. The aim was to compare the results
      with those from a similar previous study at 200 ppm. DNA isolated from liver,
      lung and testis of exposed rats and mice was analysed for the presence of
      butadiene related adducts, especially the N7-guanine adducts. Total radioactivity
      present in the DNA from liver, lung and testis was quantified and indicated more
      covalent binding of radioactivity for mouse tissue DNA than rat tissue DNA.
      Following release of the depurinating DNA adducts by neutral thermal hydrolysis,
      the liberated depurinated DNA adducts were measured by reverse phase HPLC coupled
      with liquid scintillation counting. The guanine adduct G4, assigned as N7-(2,3,4
      trihydroxybutyl)- guanine, was the major adduct measured in liver, lung and
      testis DNA in both rats and mice. Higher levels of G4 were detected in all mouse
      tissues compared with rat tissue. The dose-response relationship for the
      formation of adduct G4 was approximately linear for all tissues studied for both
      rats and mice exposed in the 1-20 ppm range. The formation of G4 in liver tissue
      was about three times more effective for mouse than rat in this exposure range.
      Average levels of adduct G4 measured in liver DNA of rats and mice exposed to 5 x
      6 h 1, 5 and 20 ppm 1,3-[2,3-(14)C]-butadiene were, respectively, for rats: 0.79
      +/- 0.30, 2.90 +/- 1.19, 16.35 +/- 4.8 adducts/10(8) nucleotides and for mice:
      2.23 +/- 0.71, 12.24 +/- 2.15, 48.63 +/- 12.61 adducts/10(8) nucleotides. For
      lung DNA the corresponding values were for rats: 1.02 +/- 0.44, 3.12 +/- 1.06,
      17.02 +/- 4.07 adducts/10(8) nucleotides, and for mice: 3.28 +/- 0.32, 14.04 +/-
      1.55, 42.47 +/- 13.12 adducts/10(8) nucleotides. Limited comparative data showed
      that the levels of adduct G4 formed in liver and lung DNA of mice exposed to a
      single exposure to butadiene in the present 20 ppm study and earlier 200 ppm
      study were approximately directly proportional across dose, but this was not
      observed in the case of rats. From the available evidence it is most likely that
      adduct G4 was formed from a specific isomer of the diol-epoxide metabolite, 3,4
      epoxy-1,2-butanediol rather than the diepoxide, 1,2,3,4-diepoxybutane. Another
      adduct G3, possibly a diastereomer of N7-(2,3,4-trihydroxybutyl)-guanine or most
      likely the regioisomer N7-(1-hydroxymethyl-2,3-dihydroxypropyl)-guanine, was also
      detected in DNA of mouse tissues but was essentially absent in DNA from rat
      tissue. Qualitatively similar profiles of adducts were observed following
      exposures to butadiene in the present 20 ppm study and the previous 200 ppm
      study. Overall the DNA adduct levels measured in tissues of both rats and mice
      were very low. The differences in the profiles and quantity of adducts seen
      between mice and rats were considered insufficient to explain the large
      difference in carcinogenic potency of butadiene to mice compared with rats.

PMID- 15013822
TI  - Dose responses for the formation of hemoglobin adducts and urinary metabolites in
      rats and mice exposed by inhalation to low concentrations of 1,3-[2,3-(14)C]
      butadiene.
AB  - Blood and urine were obtained from male Sprague-Dawley rats and B6C3F1 mice
      exposed to either a single 6 h or multiple daily (5 x 6 h) nose-only doses of 1,3
      [2,3- (14)C]-butadiene at atmospheric concentrations of 1, 5 or 20 ppM. Globin
      was isolated from erythrocytes of exposed animals and analyzed for total
      radioactivity and also for N-(1,2,3-trihydroxybut-4-yl)-valine adducts. The
      modified Edman degradation procedure coupled with GC-MS was used for the adduct
      analysis. Linear relationships were observed between the exposures to 1,3-[2,3
      (14)C]-butadiene and the total radioactivity measured in globin and the level of
      trihydroxybutyl valine adducts in globin. A greater level of radioactivity (ca.
      1.3-fold) was found in rat globin compared with mouse globin. When analyzed for
      specific amino acid adducts, higher levels of trihydroxybutyl valine adducts were
      found in mouse globin compared with rat globin. Average levels of trihydroxybutyl
      valine adduct measured in globin from rats and mice exposed for 5 x 6 h at 1, 5
      and 20 ppM 1,3-[2,3-(14)C]-butadiene were, respectively, for rats: 80, 179, 512
      pM/g globin and for mice: 143, 351, 1100 pM/g globin. The profiles of urinary
      metabolites for rats and mice exposed at the different concentrations of
      butadiene were obtained by reverse phase HPLC analysis on urine collected 24 h
      after the start of exposure and were compared with results of a previous similar
      study carried out for 6 h at 200 ppM butadiene. Whilst there were qualitative and
      quantitative differences between the profiles for rats and mice, the major
      metabolites detected in both cases were those representing products of epoxide
      hydrolase mediated hydrolysis and glutathione (GSH) conjugation of the
      metabolically formed 1,2-epoxy-3-butene. These were 4-(N-acetyl-l-cysteine-S-yl)
      1,2-dihydroxy butane and (R)-2-(N-acetyl-l-cystein-S-yl)-1-hydroxybut-3-ene, 1-(N
      acetyl-l-cystein-S-yl)-2-(S)-hydroxybut-3-ene, 1-(N-acetyl-l-cystein-S-yl)-2-(R)
      hydroxybut-3-ene, (S)-2-(N-acetyl-l-cystein-S-yl)-1-hydroxybut-3-ene,
      respectively. The former pathway showed a greater predominance in the rat. The
      profiles of metabolites were similar at exposure concentration in the range 1-20
      ppM. There were however some subtle differences compared with results of exposure
      to the higher 200 ppM concentrations. Overall the results provide the basis for
      cross species comparison of low exposures in the range of occupational exposures,
      with the wealth of data available from high exposure studies.

PMID- 15013823
TI  - Role of amygdala oscillations in the consolidation of emotional memories.
AB  - Much evidence indicates that emotional arousal generally improves memory and that
      the amygdala is responsible for this effect. The available data suggest that
      stress hormones and neuromodulators released in emotionally arousing conditions
      alter the activity of basolateral amygdala (BLA) neurons in the hours after the
      learning episode. In turn, these changes would facilitate synaptic plasticity
      elsewhere in the brain; however, the biological mechanisms underlying the
      facilitation of memory consolidation by the BLA remain unknown. This article
      focuses on data suggesting that synchronized oscillatory BLA activity promotes
      synaptic plasticity by facilitating interactions between neocortical and temporal
      lobe areas involved in declarative memory.

PMID- 15013824
TI  - Glial reduction in amygdala in major depressive disorder is due to
      oligodendrocytes.
AB  - BACKGROUND: A previous study reported reductions in glial density and glia/neuron
      ratio in the amygdala of individuals with major depressive disorder (MDD),
      without a change in neuronal density. It is not known, however, whether this
      glial loss is due to astrocytes, oligodendrocytes, or microglia. METHODS: Tissue
      samples, equally from the right and left hemispheres, were obtained from subjects
      diagnosed with MDD (n = 8), bipolar disorder (BD) (n = 9), or no psychiatric
      disorders (n = 10). Sections were stained immunohistochemically for S-100beta
      (for astrocytes) and human leukocyte antigen (for microglia), and with the Nissl
      method. In Nissl-stained sections, oligodendrocytes have more compact, darker
      stained nuclei, whereas astrocytes and microglia have larger, lighter-stained
      nuclei, with more granular chromatin. Neurons are larger, with a nucleolus and
      stained cytoplasm. The density of glia was determined with stereologic methods.
      RESULTS: The density of total glia and oligodendrocytes in the amygdala was
      significantly lower in MDD than in control subjects, but not significantly lower
      in BD compared with control subjects. The decreases were largely accounted for by
      differences in the left hemisphere. There was no significant decrease in
      astrocyte or microglia density in MDD or BD subjects. CONCLUSIONS: The glial cell
      reduction previously found in the amygdala in MDD is primarily due to
      oligodendrocytes.

PMID- 15013825
TI  - Amygdala cyclic adenosine monophosphate response element binding protein
      phosphorylation in patients with mood disorders: effects of diagnosis, suicide,
      and drug treatment.
AB  - BACKGROUND: Signal transduction abnormalities have been identified in patients
      with bipolar (BD) and major depressive (MDD) disorders and are targets for
      lithium and antidepressant drugs. A key downstream target for signal transduction
      pathways is the transcription factor cyclic adenosine monophosphate (cAMP)
      response element binding protein (CREB). Therefore, we measured the levels of
      phosphorylated CREB (pCREB) in the amygdala, a region critical to emotional
      processing and important in the pathophysiology of both BD and MDD. METHODS:
      Human postmortem amygdala sections were generously provided by the Stanley
      Foundation Neuropathology Consortium. Samples consisted of subjects with MDD, BD,
      schizophrenia (SCZ), and nonpsychiatric-nonneurologic comparison subjects (n = 15
      per group). Levels of pCREB were measured by immunohistochemistry, relative to
      total cell number. RESULTS: There were no differences between diagnostic groups-
      control subjects and subjects with BD, MDD, or SCZ--but increased numbers of
      pCREB stained cells were found in several amygdalar nuclei in subjects who had
      died by suicide. In contrast, patients treated with lithium at the time of death
      had significantly lower pCREB levels in the same region. CONCLUSIONS: These
      results suggest that CREB activity may be an important factor in the neurobiology
      of suicide and the well-documented antisuicidal effect of lithium.

PMID- 15013826
TI  - Subcortical and ventral prefrontal cortical neural responses to facial
      expressions distinguish patients with bipolar disorder and major depression.
AB  - BACKGROUND: Bipolar disorder (BD) is characterised by abnormalities in mood and
      emotional processing, but the neural correlates of these, their relationship to
      depressive symptoms, and the similarities with deficits in major depressive
      disorder (MDD) remain unclear. We compared responses within subcortical and
      prefrontal cortical regions to emotionally salient material in patients with BP
      and MDD using functional magnetic resonance imaging. METHODS: We measured neural
      responses to mild and intense expressions of fear, happiness, and sadness in
      euthymic and depressed BD patients, healthy control subjects, and depressed MDD
      patients. RESULTS: Bipolar disorder patients demonstrated increased subcortical
      (ventral striatal, thalamic, hippocampal) and ventral prefrontal cortical
      responses particularly to mild and intense fear, mild happy, and mild sad
      expressions. Healthy control subjects demonstrated increased subcortical
      responses to intense happy and mild fear, and increased dorsal prefrontal
      cortical responses to intense sad expressions. Overall, MDD patients showed
      diminished neural responses to all emotional expressions except mild sadness.
      Depression severity correlated positively with hippocampal response to mild
      sadness in both patient groups. CONCLUSIONS: Compared with healthy controls and
      MDD patients, BD patients demonstrated increased subcortical and ventral
      prefrontal cortical responses to both positive and negative emotional
      expressions.

PMID- 15013827
TI  - Infection with herpes simplex virus type 1 is associated with cognitive deficits
      in bipolar disorder.
AB  - BACKGROUND: In a previous investigation, we found an association between reduced
      cognitive functioning and the prevalence of antibodies to herpes simplex virus
      type 1 in individuals with schizophrenia. The current study was undertaken to
      determine if this association also occurs in individuals with bipolar disorder.
      METHODS: Cognitive functioning and serologic evidence of infection with
      potentially neurotropic herpesviruses were measured in 117 individuals with
      bipolar disorder and in 100 individuals without a history of psychiatric
      disorder. Cognitive functioning was evaluated with the Repeatable Battery for the
      Assessment of Neuropsychological Status. For each patient, serologic evidence of
      infection was ascertained by the measurement of serum immunoglobulin G class
      antibodies with specificities for six potentially neurotropic human
      herpesviruses. The association between serologic evidence of herpesvirus
      infection and cognitive functioning was analyzed by univariate analyses, as well
      as multivariate analyses that included demographic and clinical factors
      associated with cognitive functioning. RESULTS: Serologic evidence of infection
      with herpes simplex virus type 1 was an independent predictor of decreased
      cognitive functioning in the individuals with bipolar disorder (F = 20.5, p
      <.0001). Discriminant function analysis indicated that most of the difference in
      cognitive functioning between individuals who were antibody positive and antibody
      negative for herpes simplex virus type 1 could be attributed to immediate verbal
      memory (F = 12.07, p <.001). There was no significant association between
      cognitive functioning and the other human herpesviruses. No association between
      antibodies to herpesviruses and cognitive functioning was found in the control
      individuals without a history of psychiatric disorder. CONCLUSIONS: Serologic
      evidence of herpes simplex virus type 1 infection is associated with cognitive
      impairment in individuals with bipolar disorder.

PMID- 15013828
TI  - Distinct portions of anterior cingulate cortex and medial prefrontal cortex are
      activated by reward processing in separable phases of decision-making cognition.
AB  - BACKGROUND: Choosing between actions associated with uncertain rewards and
      punishments is mediated by neural circuitry encompassing the orbitofrontal
      cortex, anterior cingulate cortex (ACC), and striatum; however, the precise
      conditions under which these different components are activated during decision
      making cognition remain uncertain. METHODS: Fourteen healthy volunteers completed
      an event-based functional magnetic resonance imaging protocol to investigate
      blood-oxygenation-level-dependent (BOLD) responses during independently modeled
      phases of choice cognition. In the "decision phase," participants decided which
      of two simultaneous visually presented gambles they wished to play for monetary
      reward. The gambles differed in their magnitude of gains, magnitude of losses,
      and the probabilities with which these outcomes were delivered. In the "outcome
      phase," the result of each choice was indicated on the visual display. RESULTS:
      In the decision phase, choices involving large gains were associated with
      increased BOLD responses in the pregenual ACC, paracingulate, and right posterior
      orbitolateral cortex compared with choices involving small gains. In the outcome
      phase, good outcomes were associated with increased BOLD responses in the
      posterior orbitomedial cortex, subcallosal ACC, and ventral striatum compared
      with negative outcomes. There was only limited overlap between reward-related
      activity in ACC and orbitofrontal cortex during the decision and outcome phases.
      CONCLUSIONS: Neural activity within the medial and lateral orbitofrontal cortex,
      pregenual ACC, and striatum mediate distinct representations of reward-related
      information that are deployed at different stages during a decision-making
      episode.

PMID- 15013829
TI  - Posttraumatic stress disorder and fMRI activation patterns of traumatic memory in
      patients with borderline personality disorder.
AB  - BACKGROUND: Early traumatization and additional posttraumatic stress disorder are
      frequent in patients with borderline personality disorder (BPD). The purpose of
      this study was to investigate neural correlates of traumatic memory in BPD with
      and without posttraumatic stress disorder (PTSD) using functional magnetic
      resonance imaging (fMRI). METHODS: We studied 12 traumatized female patients BPD,
      6 of them with and 6 without PTSD. According to an autobiographical interview key
      words (cues) were defined for traumatic and for negative but nontraumatic
      episodes. In a block-designed fMRI task patients recalled these episodes.
      Contrasts between trauma condition and nontrauma condition were analyzed.
      RESULTS: Analyses for all subjects revealed activation of orbitofrontal cortex
      areas in both hemispheres, anterior temporal lobes, and occipital areas. In the
      subgroup without PTSD, activation of orbitofrontal cortex on both sides and
      Broca's area predominated. In the subgroup with additional PTSD, we observed
      right more than left activation of anterior temporal lobes, mesiotemporal areas,
      amygdala, posterior cingulate gyrus, occipital areas, and cerebellum.
      CONCLUSIONS: Dependent on absence or presence of additional PTSD different neural
      networks seem to be involved in the traumatic memory of patients with BPD.

PMID- 15013830
TI  - Neural correlates of the classic color and emotional stroop in women with abuse
      related posttraumatic stress disorder.
AB  - BACKGROUND: The anterior cingulate and medial prefrontal cortex play an important
      role in the inhibition of responses, as measured by the Stroop task, as well as
      in emotional regulation. Dysfunction of the anterior cingulate/medial prefrontal
      cortex has been implicated in posttraumatic stress disorder (PTSD). The purpose
      of this study was to use the Stroop task as a probe of anterior cingulate
      function in PTSD. METHODS: Women with early childhood sexual abuse-related PTSD
      (n = 12) and women with abuse but without PTSD (n = 9) underwent positron
      emission tomographic measurement of cerebral blood flow during exposure to
      control, color Stroop, and emotional Stroop conditions. RESULTS: Women with abuse
      with PTSD (but not abused non-PTSD women) had a relative decrease in anterior
      cingulate blood flow during exposure to the emotional (but not color) classic
      Stroop task. During the color Stroop there were also relatively greater increases
      in blood flow in non-PTSD compared with PTSD women in right visual association
      cortex, cuneus, and right inferior parietal lobule. CONCLUSIONS: These findings
      add further evidence for dysfunction of a network of brain regions, including
      anterior cingulate and visual and parietal cortex, in abuse-related PTSD.

PMID- 15013831
TI  - Salivary cortisol and posttraumatic stress disorder in a low-income community
      sample of women.
AB  - BACKGROUND: Studies of male combat veterans with posttraumatic stress disorder
      have demonstrated a profile of low cortisol. Studies with women with
      posttraumatic stress disorder (PTSD) have focused on childhood sexual abuse and
      holocaust survivors, both of whom experienced trauma during development, which
      could be different than adult trauma exposure. METHODS: Using an epidemiologic
      sample of low-income women from an urban area in Michigan, we conducted
      structured psychiatric interviews and saliva cortisol collection on a subsample
      of women with exposure to trauma but never PTSD (n = 72), recent PTSD (n = 29),
      and past PTSD (n = 70). Saliva cortisol was collected at awakening, 30 minutes
      later, at bedtime, and during a clinic visit. RESULTS: Recent trauma exposure but
      not past trauma exposure led to an increase in saliva cortisol. Neither recent
      PTSD nor past PTSD resulted in any saliva cortisol changes compared with the
      trauma exposed, never PTSD group. Recent major depression (past 12 months)
      demonstrated a weak effect (p =.08) on bedtime saliva cortisol. CONCLUSIONS:
      While recent trauma exposure can increase saliva cortisol, neither recent nor
      past PTSD affected saliva cortisol in our community sample of women. Our data do
      not support saliva cortisol changes associated with PTSD.

PMID- 15013832
TI  - Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic
      stress disorder in patients after cardiac surgery: a randomized study.
AB  - BACKGROUND: Traumatic experiences associated with cardiac surgery (CS) can result
      in traumatic memories and posttraumatic stress disorder (PTSD). Because it is
      known that subjects who develop PTSD often show sustained reductions in
      circulating cortisol concentrations, we performed a prospective, randomized study
      to examine whether exogenously administered stress doses of hydrocortisone during
      the perioperative period of CS reduces the long-term incidence of chronic stress
      and PTSD symptoms. METHODS: Patients (n = 91) were prospectively randomized to
      receive either stress doses of hydrocortisone or standard treatment during the
      perioperative period of CS. Of 48 available patients at 6 months after CS, 26 had
      received stress doses of hydrocortisone and 22 standard treatment. Traumatic
      memories and PTSD symptoms were diagnosed with previously validated
      questionnaires. RESULTS: As compared with patients after standard therapy,
      patients from the hydrocortisone group had significantly lower chronic stress
      symptom scores (p <.05). There was no significant difference regarding the number
      or type of traumatic memories between the hydrocortisone and the standard
      treatment groups. CONCLUSIONS: Stress doses of hydrocortisone in patients
      undergoing CS are associated with a lower intensity of chronic stress and PTSD
      symptoms at 6 months after CS.

PMID- 15013833
TI  - Genomic regions controlling corticosterone levels in rats.
AB  - BACKGROUND: The identification of genetic factors controlling stress
      responsiveness should advance the understanding of susceptibility to psychiatric
      illness. METHODS: Rat strains, F344/NHsd and LEW/NHsd, which differ in measures
      of stress-responsiveness and behaviors modeling psychiatric disorders, were bred
      to generate F2 progeny that were used in a quantitative trait loci (QTL) analysis
      to identify genomic regions influencing late-afternoon corticosterone levels.
      RESULTS: Regions on chromosomes 4 and 10 previously identified as influencing
      autoimmune phenomena were the most significant QTL observed, reaching suggestive
      significance at the genome-wide level. Congenic animals targeting these regions
      with F344/NHsd deoxyribonucleic acid on a DA/Bkl genomic background demonstrated
      corticosterone levels approximating those of F344/NHsd rats and differing
      significantly from DA/Bkl rats. CONCLUSIONS: Specific genomic regions influence
      both corticosterone levels and stress-related disease susceptibility. These
      findings not only represent the first identification of QTL controlling
      corticosterone levels but also suggest a mechanism underlying genetic differences
      in stress-responsiveness.

PMID- 15013834
TI  - Genetic contributions to social impulsivity and aggressiveness in vervet monkeys.
AB  - BACKGROUND: Impulsivity contributes to multiple psychiatric disorders and
      sociobehavioral problems, and the more serious consequences of impulsivity are
      typically manifest in social situations. This study assessed the genetic
      contribution to impulsivity and aggressiveness in a social context using a
      nonhuman primate model. METHODS: Subjects were 352 adolescent and adult vervet
      monkeys from an extended multigenerational pedigree. Behavior was assessed in the
      Intruder Challenge Test, a standardized test that measures impulsivity and
      aggressiveness toward a stranger. Genetic and maternal contributions to variation
      in the Social Impulsivity Index and its two subscales, impulsive approach and
      aggression, were estimated using variance components analyses. RESULTS: The
      results found significant genetic contributions to social impulsivity (h2 =.35 +/
      .11) and to each of the subscales, with no significant influence of maternal
      environment. There was a high genetic correlation between the impulsive approach
      and aggression subscales (rho =.78 +/-.12). CONCLUSIONS: This is the first study
      to demonstrate heritability of social impulsivity in adolescents and adults for
      any nonhuman primate species. The high genetic correlation suggests the same
      genes may influence variation in both impulsive approach and aggression. These
      results provide a promising basis for identification of susceptibility loci for
      impulsivity and aggressiveness.

PMID- 15013835
TI  - Frontal lobe gray matter density decreases in bipolar I disorder.
AB  - BACKGROUND: This study was conducted to explore differences in gray and white
      matter density between bipolar and healthy comparison groups using voxel-based
      morphometry (VBM). METHODS: Brain magnetic resonance imaging was performed for 39
      subjects with bipolar I disorder and 43 comparison subjects. Images were
      registered into a proportional stereotaxic space and segmented into gray matter,
      white mater, and cerebrospinal fluid. Statistical parametric mapping was used to
      calculate differences in gray and white matter density between groups. RESULTS:
      Bipolar subjects had decreased gray matter density in left anterior cingulate
      gyrus (Brodmann's area [BA] 32, 7.3% decrease), an adjacent left medial frontal
      gyrus (BA 10, 6.9% decrease), right inferior frontal gyrus (BA 47, 9.2%
      decrease), and right precentral gyrus (BA 44, 6.2% decrease), relative to
      comparison subjects. CONCLUSIONS: The observation of a gray matter density
      decrease in the left anterior cingulate, which processes emotions, in bipolar
      subjects is consistent with prior reports that used region-of-interest analytic
      methods. Decreased gray matter density in the right inferior frontal gyrus, which
      processes nonverbal and intrinsic functions, supports nondominant hemisphere
      dysfunction as a component of bipolar disorder.

PMID- 15013836
TI  - Elevation of cell adhesion molecule immunoreactivity in the anterior cingulate
      cortex in bipolar disorder.
AB  - BACKGROUND: Neuroimaging reports of increases in signal hyperintensities in white
      and deep gray matter and other work indicate that there might be an inflammatory
      response in affective disorders. METHODS: The microvascular immunoreactivity of
      intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 was
      measured with image analysis in postmortem tissue from the anterior cingulate
      cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) from 15 unipolar and 15
      bipolar subjects and compared with each other and with 15 subjects with
      schizophrenia and 15 control subjects. RESULTS: Intercellular adhesion molecule-1
      immunoreactivity in gray and white matter of the ACC in bipolar subjects was
      increased compared with control subjects (gray: p =.001; white: p <.001) and
      schizophrenic subjects (gray: p =.016; white: p =.025) and modestly increased in
      white matter compared with unipolar subjects (p =.049). No such differences were
      found in the DLPFC. CONCLUSIONS: These findings are consistent with the presence
      of an inflammatory response in the ACC in bipolar disorder.

PMID- 15013837
TI  - Cavum septum pellucidum in monozygotic twins discordant for combat exposure:
      relationship to posttraumatic stress disorder.
AB  - BACKGROUND: Abnormally large cavum septum pellucidum has been reported in
      posttraumatic stress disorder; however, the origin of this association is
      uncertain. METHODS: We utilized magnetic resonance imaging to measure cavum
      septum pellucidum in pairs of identical twins discordant for combat exposure in
      Vietnam. RESULTS: Presence of abnormal cavum septum pellucidum was significantly
      correlated between exposed and unexposed twins, indicating that it is partially
      determined by heredity and/or shared environment. There was a greater proportion
      of cavum septum pellucidum in combat-exposed twins with posttraumatic stress
      disorder and their noncombat-exposed co-twins. CONCLUSIONS: The presence of
      abnormally large cavum septum pellucidum is a familial vulnerability factor for
      posttraumatic stress disorder.

PMID- 15013838
TI  - Regulation of glutathione S-transferase P1-1 gene expression by NF-kappaB in
      tumor necrosis factor alpha-treated K562 leukemia cells.
AB  - Glutathione S-transferases (GSTs) play an important role in the protection of
      cells against xenobiotics and lipid hydroperoxides generated by oxidative stress.
      In human, the GSTP1-1 expression is commonly increased in many tumors and
      involved in the development of antineoplastic drug resistance. Reactive oxygen
      species are released at inflammation sites and oxidative stress conditions
      enhance the expression of genes encoding antioxidant enzymes such as GSTs. Here
      we investigated the regulation of the GSTP1-1 gene expression in the K562 cell
      line by nuclear factor kappaB (NF-kappaB) and the pro-inflammatory cytokine tumor
      necrosis factor alpha (TNFalpha). By studying GSTP1-1 mRNA expression and NF
      kappaB/GSTP1-1 promoter interactions, we showed the implication of NF-kappaB in
      the GSTP1-1 gene expression and we described a new specific TNFalpha-inducible NF
      kappaB binding site upstream of the minimal promoter. Moreover, TNFalpha
      treatment as well as cotransfection of NF-kappaB signaling pathway intermediates
      induced an activation of the GSTP1-1 gene promoter in K562 cells. Site-directed
      mutagenesis of the NF-kappaB site strongly inhibited TNFalpha- and NF-kappaBp65
      induced promoter activation. Altogether, we showed that a sequence located at 
      323/-314 within the GSTP1-1 promoter bound NF-kappaB p50/65 and p65/p65 dimers
      and that this kappaB site was involved in the regulation of the gene by TNFalpha.

PMID- 15013840
TI  - Differentiation of human hepatoma cells during confluence as revealed by gene
      expression profiling.
AB  - Certain human hepatocarcinoma cells undergo differentiation when grown at
      confluence. In order to understand the basis for this differentiation, we
      investigated the phenotypic changes occurring during confluent growth of the
      human hepatoma B16A2 cell line. The global gene expression profile of B16A2 cells
      grown during confluence for 5 weeks was investigated using microarrays containing
      complementary sequences corresponding to approximately 10,000 genes, and compared
      with profiles of adult human liver and HepG2 cells. The major part of gene
      products detected were shared by all three systems and the hepatoma cell lines
      expressed surprisingly high levels of liver-enriched transcription factors.
      During confluence of B16A2 cells, the majority of transcriptional changes
      monitored were directed towards the phenotype of adult human liver in vivo,
      although the changes accounted for less than 10% of those necessary to acquire a
      native hepatic phenotype. Several markers of liver differentiation and
      regeneration were changed in similar manner as observed in developing liver and
      during liver regeneration. In conclusion, the data indicate that differentiation
      in vitro of the B16A2 cell line during confluence partially resembles that of
      hepatic differentiation and regeneration in vivo, implying a partial
      normalization of a low differentiated phenotype.

PMID- 15013839
TI  - Inhibition of osteoclast differentiation and bone resorption by a novel
      lysophosphatidylcholine derivative, SCOH.
AB  - Osteoclasts are multinucleated cells formed by multiple steps of cell
      differentiation from progenitor cells of hematopoietic origin. Intervention in
      osteoclast differentiation is considered as an effective therapeutic approach to
      the treatment for bone diseases involving osteoclasts. In this study, we found
      that the organic compound (S)-1-lyso-2-stearoylamino-2-deoxy-sn-glycero-3
      phosphatidylcholine (SCOH) inhibited osteoclast differentiation. The inhibitory
      effect of SCOH was observed in mouse bone marrow cell cultures supported either
      by coculturing with osteoblasts or by adding macrophage colony stimulating factor
      (M-CSF) and receptor activator of nuclear factor kappaB ligand (RANKL). M-CSF and
      RANKL activate the ERK, Akt, and NF-kappaB signal transduction pathways, and SCOH
      suppressed this activation. SCOH also inhibited the bone resorptive activity of
      differentiated osteoclasts. It attenuated bone resorption, actin ring formation,
      and survival of mature osteoclasts. Reduced activation of Akt and NF-kappaB and
      decreased induction of XIAP were observed in mature osteoclasts treated with
      SCOH. Thus, this novel phosphatidylcholine derivative may be useful for treating
      bone-resorption diseases.

PMID- 15013841
TI  - The biphasic effects of cyclopentenone prostaglandins, prostaglandin J(2) and 15
      deoxy-Delta(12,14)-prostaglandin J(2) on proliferation and apoptosis in rat
      basophilic leukemia (RBL-2H3) cells.
AB  - Mast cells produce chemical mediators, including histamine and arachidonate
      metabolites such as prostaglandin D(2) (PGD(2)) after antigen stimulation.
      Cyclopentenone prostaglandins of the J series, prostaglandin J(2) (PGJ(2)) and 15
      deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), are thought to be derivatives
      of PGD(2). In this study, the biphasic effects of the PGJ(2) and 15d-PGJ(2) on
      proliferation and apoptosis in rat basophilic leukemia cells (RBL-2H3), a tumor
      analog of mast cells, were examined. At low concentrations, 1 or 3 microM PGJ(2)
      and 15d-PGJ(2) induced cell proliferation, respectively. At high concentrations
      (10-30 microM) both the inhibition of viability and decrease in histamine content
      in RBL-2H3 cells were dose dependent. These effects were independent of the
      nuclear hormone receptor, peroxisome proliferator-activated receptor gamma
      (PPARgamma), since troglitazone, an agonist of PPARgamma did not cause any
      effects in RBL-2H3 cells. Cell death induced by PGJ(2) and 15d-PGJ(2) was the
      result of apoptotic processes, since RBL-2H3 cells treated with 30 microM of the
      prostaglandins had condensed nuclei, DNA fragmentation and increase in activities
      of caspase-3 and -9. Moreover, PGJ(2) or 15d-PGJ(2)-induced apoptotic effects
      were prevented by the caspase inhibitor, z-VAD-fmk. In conclusion, the PGJ(2) or
      15d-PGJ(2)-induced apoptosis in RBL-2H3 cells occurs mainly via mitochondrial
      pathways instead of by PPARgamma-dependent mechanisms.

PMID- 15013842
TI  - Uridine diphosphate sugar-selective conjugation of an aldose reductase inhibitor
      (AS-3201) by UDP-glucuronosyltransferase 2B subfamily in human liver microsomes.
AB  - N-Glucosidation is known as a major metabolic reaction for barbiturates in
      humans. However, the enzyme(s) involved in this N-glucosidation has not been
      clarified yet. Thus, to clarify the enzyme(s) involved in the N-glucosidation in
      human liver microsomes, we investigated the N-glucosyltransferase activity in
      recombinant UDP-glucuronosyltransferases (UGTs) using AS-3201, an aldose
      reductase inhibitor, as a substrate. AS-3201 was found to be biotransformed to
      both N-glucoside and N-glucuronide in human liver microsomes. The N
      glucosyltransferase activities were detectable with multiple UGT isoforms
      (UGT1A1, UGT1A3, UGT1A4, UGT2B4, UGT2B7, and UGT2B15). In contrast, the N
      glucuronyltransferase activities for the same substrate were seen with UGT1A
      (UGT1A1, UGT1A3, UGT1A4, and UGT1A9) but not UGT2B isoforms. We then determined
      the relative activity factor of each recombinant UGT and estimated the
      contribution of each UGT isoform to the N-glucosidation in human liver
      microsomes. The results showed that UGT2B isoforms mainly contribute to AS-3201 N
      glucosidation in human liver microsomes. In addition, the activity of AS-3201 N
      glucosyltransferase significantly correlated with that of amobarbital N
      glucosyltransferase in microsomes from sixteen human livers (r=0.964, P<0.01),
      indicating that UGT2B isoforms were also involved in the barbiturate N
      glucosidation in humans. The findings of this study clearly show that UGT2B
      specifically utilizes UDP-glucose but not UDP-glucuronic acid as a sugar donor
      for the conjugation of AS-3201 in human liver microsomes.

PMID- 15013843
TI  - Discovery of novel peptide/receptor interactions: identification of PHM-27 as a
      potent agonist of the human calcitonin receptor.
AB  - Many naturally occurring peptides exhibit a high degree of promiscuity across G
      protein coupled receptor subtypes. The degree to which this phenomenon occurs,
      and its physiological significance is not well characterized. In addition, many
      'orphan' peptides exist for which there are no known receptors. Therefore, to
      identify novel interactions between biologically active peptides and G-protein
      coupled receptors, a library of nearly 200 peptides was screened against the
      human calcitonin (hCTr), human Parathyroid Hormone (PTH1R), human Corticotropin
      Releasing Factor (CRF1), and the human Glucagon-like peptide (GLP1) receptors
      using a cell-based functional assay (Receptor Selection and Amplification
      Technology). Functional profiling revealed that the 'orphan peptide' PHM-27
      selectively activated the hCTr; no activity was observed at the PTH1, CRF1, or
      GLP1 receptors. PHM-27 was a potent agonist at the hCTr, with similar efficacy as
      human calcitonin, and a potency of 11 nM. These results were confirmed in cyclic
      AMP assays. Responses to calcitonin and PHM-27 could be suppressed by the
      antagonist salmon calcitonin (8-32). In competition binding studies, salmon
      calcitonin (8-32), calcitonin, and PHM-27 were each able to inhibit (125)I
      calcitonin from cell membranes containing transiently expressed hCTr. These
      results indicate that the orphan peptide PHM-27 is a potent agonist at the hCTr.

PMID- 15013844
TI  - Interference of the polyphenol epicatechin with the biological chemistry of
      nitric oxide- and peroxynitrite-mediated reactions.
AB  - The formation of reactive nitrogen species in mammalians has both beneficial and
      undesirable effects. Nitric oxide (NO) production in endothelial cells leads to
      vascular smooth muscle relaxation, but if reactive nitrogen species are generated
      in high amounts by cells under inflammatory conditions they are toxic. Flavonoids
      like (-)-epicatechin show an inverse association of their intake with diseases
      thought to be associated with overproduction of reactive nitrogen species. We
      found that the formation of cyclic GMP in cultured porcine aortic endothelial
      cells was not affected by up to 1 mM (-)-epicatechin. Half maximal inhibition of
      interferon-gamma/lipopolysaccharide induced nitrite accumulation in murine
      macrophages required about 0.5 mM of the flavonoid. In contrast, nitration of
      free tyrosine triggered by 0.1 and 1 mM authentic peroxynitrite was inhibited by
      (-)-epicatechin with IC(50) values of 6.6 and 28.0 microM, respectively. The
      presence of 15 mM sodium bicarbonate had no significant effect. Nitration of
      protein-bound tyrosine in phorbol 12-myristate 13-acetate treated HL-60 cells in
      the presence of nitrite was inhibited by (-)-epicatechin at a similar
      concentration range (IC(50)=10-100 microM). Myeloperoxidase activity of phorbol
      12-myristate 13-acetate stimulated HL-60 cells was inhibited by (-)-epicatechin
      with an IC(50) value of 77.4 microM. Epicatechin inhibited dihydrorhodamine
      oxidation by 50 microM authentic peroxynitrite and 1 mM 3-morpholino-sydnonimine
      with IC(50) values of 11.8 and 0.63 microM, respectively. Our data suggest that
      at up to 0.1 mM (-)-epicatechin preferentially inhibits NO-related nitration and
      oxidation reactions without affecting NO synthesis and cyclic GMP signaling.

PMID- 15013845
TI  - Inhibitory effect of beta-cryptoxanthin on osteoclast-like cell formation in
      mouse marrow cultures.
AB  - The carotenoid beta-cryptoxanthin has been shown to have an inhibitory effect on
      bone-resorping factor-stimulated bone resorption in rat bone tissues in vitro.
      The effect of beta-cryptoxanthin on osteoclast-like cell formation in mouse
      marrow culture in vitro was investigated. The bone marrow cells were cultured for
      7 days in alpha-minimal essential medium containing a bone-resorbing agent
      [parathyroid hormone (1-34) (PTH), prostaglandin E(2), 1,25-dihydroxyvitamin
      D(3), lipopolysaccharide, or tumor necrosis factor-alpha (TNFalpha)] with an
      effective concentration. Osteoclast-like cell formation was estimated by staining
      for tartrate-resistant acid phosphatase, a marker enzyme of osteoclasts. The
      presence of PTH (10(-7)M), prostaglandin E(2) (10(-5)M), 1,25-dihydroxyvitamin
      D(3) (10(-7)M), lipopolysaccharide (10 microg/mL), or TNFalpha (10 ng/mL) induced
      a remarkable increase in osteoclast-like multinucleated cells. These increases
      were significantly inhibited in the presence of beta-cryptoxanthin (10(-8) to 10(
      6)M). beta-Cryptoxanthin (10(-7) and 10(-6)M) significantly inhibited dibutyryl
      cyclic adenosine monophosphate (DcAMP) (10(-5)M) or phorbol 12-myristate 13
      acetate (PMA) (10(-5)M), an activator of protein kinase C, induced osteoclast
      like cell formation. Also, beta-cryptoxanthin (10(-7) and 10(-6)M) had a
      significant inhibitory effect on osteoclast-like formation induced by receptor
      activator of NF-kappaB ligand (RANKL) (10 and 20 ng/mL) in the presence of
      macrophage colony-stimulating factor (M-CSF) (10 and 20 ng/mL). The stimulatory
      effect of RANKL and M-CSF on osteoclast-like cell formation was significantly
      enhanced in the presence of PMA, while such an effect was not seen by DcAMP. beta
      Cryptoxanthin (10(-6)M) significantly inhibited osteoclast-like cell formation
      induced by RANKL and M-CSF in the presence of PMA or DcAMP. Moreover, the
      inhibitory effect of beta-cryptoxanthin on RANKL plus M-CSF-, PTH-, or TNFalpha
      induced osteoclast-like cell formation was not observed in the presence of
      cycloheximide (10(-7)M), an inhibitor of protein synthesis at translational
      process, or 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole (10(-6)M), an
      inhibitor of transcription. This study demonstrates that beta-cryptoxanthin has a
      potent inhibitory effect on osteoclast-like cell formation in mouse marrow
      culture. The inhibitory action of beta-cryptoxanthin may partly involve in a
      newly synthesized protein component which is related to RANKL stimulation in
      osteoclastogenesis.

PMID- 15013846
TI  - Stimulatory effect of naturally occurring flavonols quercetin and kaempferol on
      alkaline phosphatase activity in MG-63 human osteoblasts through ERK and estrogen
      receptor pathway.
AB  - Many plant-derived substances have estrogenic activities. Due to their ability to
      bind the estrogen receptor (ER), these compounds have the potential to counteract
      the deleterious effects of estrogen deficiency on bone. In this study, we
      investigated the in vitro effect of two widespread flavonols, quercetin and
      kaempferol, on alkaline phosphatase (ALP) activity in MG-63 cultured human
      osteoblasts. We found that both flavonols significantly increased ALP activity.
      This effect was markedly reduced by PD 98059, an inhibitor of the extracellular
      regulated kinase (ERK) pathway, and by ICI 182780, an antagonist of ERs. Western
      blot studies confirmed that ERK is rapidly activated in cells treated by both
      flavonols. Finally, ICI 182780 markedly inhibits the flavonol-induced ERK
      activation. The data presented in this study support the conclusion that, in MG
      63 osteoblasts (i) the increase in ALP activity by flavonols involves a rapid
      stimulation of ERK activation but also involves the ER, and that (ii) the
      activation of ERK by flavonols occurs most likely downstream of the ERs
      activation. Taken together, these results suggest that flavonols derivatives as
      quercetin and kaempferol can stimulate osteoblastic activity. Such compounds may
      represent new pharmacological tools for the treatment of osteoporosis.

PMID- 15013848
TI  - Novel Gemini analogs of 1alpha,25-dihydroxyvitamin D(3) with enhanced
      transcriptional activity.
AB  - The active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)),
      exerts its effects through regulation of target gene transcription. Configuration
      at C-20 of 1,25(OH)(2)D(3) is important in determining potency, as shown by the
      high potency of analogs with inverted configuration at C-20 (20-epi compounds).
      Gemini analogs of 1,25(OH)(2)D(3) contain two side chains, combining a C-20
      normal with a C20-epi side chain. We studied the potency of analogs combining
      double (Gemini) side chains with a 23-triple bond and a C-26,27-hexafluoro
      substitution in either the 20-epi (analog 20R) or 20-normal (analog 20S) side
      chain. These novel Gemini analogs were 8-50-fold more potent than 1,25(OH)(2)D(3)
      in inducing U937, HL-60G, and THP-1 differentiation and 5-50-fold more potent in
      inducing transcription from the osteocalcin vitamin D response element or the 25
      hydroxyvitamin D(3)-24-hydroxylase (24OHase) promoter. In vivo, following i.p.
      injection in vitamin D-deficient mice, the 20S analog induced significantly
      higher levels of calbindin-D(9K) mRNA in intestine, and 24OHase and calbindin
      D(28K) in kidney than 1,25(OH)(2)D(3) or analog 20R. Increased potency did not
      correlate with ligand-receptor binding affinity. In GST-pull down assays using in
      vitro translated VDR, Gemini analogs showed equivalent (or even attenuated)
      potency to 1,25(OH)(2)D(3) in recruiting cofactors DRIP205 and GRIP-1 to VDR.
      However, Gemini analogs were up to 15-fold more potent than 1,25(OH)(2)D(3) in
      recruiting the same cofactors to VDR in GST-pull down assays using equal amounts
      of VDR from nuclear extracts of VDR transfected and hormone treated (24 hr) COS-7
      cells. Deletion of C-19 in either 20S or 20R Gemini analogs resulted overall in
      slightly less potent analogs compared to Gemini itself. We conclude that enhanced
      potency of the novel Gemini analogs is at least partly due to increased metabolic
      stability of the analogs, resulting in more cofactor binding and elevated levels
      of transcription.

PMID- 15013847
TI  - Differential regulation of IL-4 expression and degranulation by anti-allergic
      olopatadine in rat basophilic leukemia (RBL-2H3) cells.
AB  - Olopatadine hydrochloride (olopatadine) is an anti-allergic drug that functions
      as a histamine H(1) antagonist and inhibits both mast cell degranulation and the
      release of arachidonic acid metabolites in various types of cells. In this study,
      we examined the ability of olopatadine to inhibit the expression of cytokine
      genes in vitro via high-affinity receptors for immunoglobulin E in mast cells,
      using a rat basophilic leukemia (RBL-2H3) cell line and an in vivo mouse model.
      Levels of gene expression in RBL-2H3 cells were determined by semi-quantitative
      RT-PCR, and serum interleukin-4 (IL-4) level in mice was quantified by ELISA.
      Olopatadine inhibited significantly the induction of IL-4 expression by mast
      cells both in vivo and in vitro. Olopatadine inhibited Ca(2+) influx through
      receptor-operated channels (ROC) without affecting Ca(2+) release from
      intracellular stores. Comparative analysis of olopatadine with other anti
      allergic drugs and the ROC blocker SKF-96365 demonstrated that the potency of
      inhibition of Ca(2+) influx correlated with the degree of suppression of
      degranulation and arachidonic acid release. Inhibition of Ca(2+) influx decreased
      phosphorylation of p38 mitogen-activated protein kinase and c-Jun NH(2)-terminal
      kinase, which participate in regulation of cytokine (e.g. IL-4) gene expression.
      However, the rank order of inhibition of Ca(2+) influx did not correspond to
      reduction of IL-4 expression, suggesting that an unknown mechanism(s) of action,
      in addition to inhibition of Ca(2+) influx, is involved in the expression of
      cytokines in mast cells.

PMID- 15013849
TI  - Andrographolide suppresses endothelial cell apoptosis via activation of
      phosphatidyl inositol-3-kinase/Akt pathway.
AB  - Andrographolide (Andro), an active component isolated from the Chinese official
      herbal Andrographis paniculata, which has been reported to prevent oxygen radical
      production and thus prevent inflammatory diseases. In this study, we investigated
      the molecular mechanisms and signaling pathways by which Andro protects human
      umbilical vein endothelial cells (HUVECs) from growth factor (GF) deprivation
      induced apoptosis. Results demonstrated that HUVECs undergo apoptosis after 18 hr
      of GF deprivation but that this cell death was suppressed by the addition of
      Andro in a concentration-dependent manner (1-100 microM). Andro suppresses the
      mitochondrial pathway of apoptosis by inhibiting release of cytochrome c into the
      cytoplasm and dissipation of mitochondrial potential (Deltapsi(m)), as a
      consequence, prevented caspase-3 and -9 activation. Treatment of endothelial
      cells with Andro-induced activation of the protein kinase Akt, an anti-apoptotic
      signal, and phosphorylation of BAD, a down-stream target of Akt. Suppression of
      Akt activity by wortmannin, by LY-294002 and by using a dominant negative Akt
      mutant abolished the anti-apoptotic effect of Andro. In contrast, the ERK1/2
      activities were not affected by Andro. The ERK1/2 inhibitor, PD98059 failed to
      antagonize the protective effect of Andro. In conclusion, Andro exerts its anti
      apoptotic potential via activation of the Akt-BAD pathway in HUVECs and thus may
      represent a candidate of therapeutic agent for atherosclerosis.

PMID- 15013850
TI  - Synergistic interaction of a chloroquine metabolite with chloroquine against drug
      resistant malaria parasites.
AB  - We have previously shown that structural modification of chlorpromazine to
      introduce a basic side chain converts this chloroquine (CQ) resistance-reversing
      agent into a compound that has activity against Plasmodium falciparum in vitro.
      In an effort to further dissect the structural features that determine quinoline
      antimalarial activity and drug resistance-reversing activity, we have studied a
      series of aminoquinolines that are structurally related to CQ. We have analysed
      their haematin-binding activities, their antimalarial activities and their
      abilities to synergise the effect of CQ against drug-resistant P. falciparum. We
      found that a number of the aminoquinolines were able to interact with haematin
      but showed no or very weak antiparasitic activity. Interestingly, 4-amino-7
      chloroquinoline, which is the CQ nucleus without the basic side chain, was able
      to act as a resistance-reversing agent. These studies point to structural
      features that may determine the resistance-modulating potential of weakly basic
      amphipaths. Interestingly, 4-amino-7-chloroquinoline is a metabolic breakdown
      product of CQ and may contribute to CQ activity against resistant parasites in
      vivo.

PMID- 15013851
TI  - Histidine residues in human phenol sulfotransferases.
AB  - Sulfotransferases are phase II drug-metabolizing enzymes that catalyze the
      sulfation of hydroxyl-containing compounds, leading to detoxification of
      xenobiotic toxicants. The universal sulfuryl donor is adenosine 3'-phosphate-5'
      phosphosulfate. Human simple phenol sulfotransferase (P-PST) is one of the major
      human sulfotransferases that catalyze the sulfation of most phenols. Human
      monoamine phenol sulfotransferase (M-PST) has high affinity for monoamines and
      also catalyzes the sulfation of simple phenols at high substrate concentrations.
      In this report, the amino acid modification method was used for studies of His
      residues in the active site of P-PST and M-PST. The His specific modification
      reagent diethylpyrocarbonate was used for the modification of His residues in P
      PST and M-PST. Diethylpyrocarbonate inactivation kinetic data suggest that there
      is one His residue in the active site that is critical for catalytic activity of
      both P-PST and M-PST. The modification has no effect on phenol or monoamine
      substrate binding for M-PST, but it does have an effect on adenosine 3'-phosphate
      5'-phosphosulfate binding with M-PST. The experimental results agree with amino
      acid sequence alignment, mutation, and the crystal structures of P-PST and M-PST
      and suggest that His108 is the only critical His residue in both P-PST and M-PST.
      The differing roles His108 plays in P-PST and M-PST may explain the substrate
      specificity of the two isoforms.

PMID- 15013852
TI  - Functional characterization of aryl hydrocarbon receptor (zfAHR2) localization
      and degradation in zebrafish (Danio rerio).
AB  - The basic-helix-loop-helix/PAS (bHLH/PAS) family of proteins is a group of
      transcription factors that regulate key pathways during normal development and in
      the response to stress. The aryl hydrocarbon receptor (AHR) is a member of this
      family. Recently, Danio rerio (zebrafish) has become an important model system in
      the study of the signal transduction pathway and complements the results seen in
      mammalian models. However, studies of the AHR protein have been limited by the
      lack of antibody reagents and thus, little is known concerning the localization
      and degradation of the zebrafish AHR (zfAHR). In this report, we describe the
      production and characterization of specific polyclonal antibodies to the zfAHR2
      protein and the analysis of AHR-mediated signal transduction in the zebrafish
      liver cell line (ZFL). The results show that the zfAHR2 is degraded via the 26S
      proteasome following exposure of cells to beta-naphthoflavone (BNF).
      Interestingly, the time course is slower and the magnitude of zfAHR2 degradation
      is not as great as seen for the mammalian AHR. Studies also show that the zfAHR2
      is rapidly degraded in a ligand-independent manner by exposure of cells to
      geldanamycin (GA) to levels consistent with mammalian AHR. Finally,
      immunohistochemical staining of the ZFL cells suggest that the unliganded AHR
      resides in both the cytoplasm and nucleus and undergoes active nucleocytoplasmic
      shuttling in the absence of ligand. These results suggest that there is
      conservation of function between fish and mammals with respect to ligand
      dependent and -independent degradation of the AHR and that the zfAHR2 is degraded
      via the 26S proteasome.

PMID- 15013853
TI  - Mechanism of cell cycle arrest by sulfoquinovosyl monoacylglycerol with a C18
      saturated fatty acid (C18-SQMG).
AB  - We have screened the inhibitors of mammalian DNA polymerases from natural
      products, and in the process found that either sulfoglycolipids or
      sulfoquinovosyl monoacylglycerol with a C18-saturated fatty acid (C18-SQMG),
      potently and selectively inhibited the activity of mammalian DNA polymerase (pol)
      and moderately the pol alpha. C18-SQMG was a cancer cell growth suppressor and a
      promissive anti-tumor agent. The purpose of this study was to elucidate the cell
      growth inhibition mechanism of C18-SQMG using HeLa cells. Analyses of the cell
      cycle and cyclin expression suggested that C18-SQMG arrested the cell cycle at
      intra-S phase, and the inhibition manner of DNA replication by C18-SQMG was
      similar to that by hydroxyurea. However, the DNA replication block by C18-SQMG
      did not induce degradation of Cdc25A protein, which was required for the
      replication block by hydroxyurea. C18-SQMG somewhat delayed mitosis because it
      induced phosphorylation of protein kinases, such as checkpoint kinases 1 and 2.
      These results suggest that C18-SQMG at first blocked DNA replication at the S
      phase by inhibiting replicative DNA polymerases, such as alpha, and then as the
      result of the inhibition, the other checkpoint signals associated with the pol
      might have responded.

PMID- 15013854
TI  - Monoglyceride lipase-like enzymatic activity is responsible for hydrolysis of 2
      arachidonoylglycerol in rat cerebellar membranes.
AB  - 2-Arachidonoylglycerol (2-AG) is an endogenous cannabinoid that binds to CB1 and
      CB2 cannabinoid receptors, inducing cannabimimetic effects. However, the
      cannabimimetic effects of 2-AG are weak in vivo due to its rapid enzymatic
      hydrolysis. The enzymatic hydrolysis of 2-AG has been proposed to mainly occur by
      monoglyceride lipase (monoacylglycerol lipase). Fatty acid amide hydrolase
      (FAAH), the enzyme responsible for the hydrolysis of N-arachidonoylethanolamide
      (AEA), is also able to hydrolyse 2-AG. In the present study, we investigated the
      hydrolysis of endocannabinoids in rat cerebellar membranes and observed that
      enzymatic activity towards 2-AG was 50-fold higher than that towards AEA.
      Furthermore, various inhibitors for 2-AG hydrolase activity were studied in rat
      cerebellar membranes. 2-AG hydrolysis was inhibited by methyl
      arachidonylfluorophosphonate, hexadecylsulphonyl fluoride and
      phenylmethylsulphonyl fluoride with ic(50) values of 2.2 nM, 241 nM and 155
      microM, respectively. Potent FAAH inhibitors, such as OL-53 and URB597, did not
      inhibit the hydrolysis of 2-AG, suggesting that 2-AG is inactivated in rat
      cerebellar membranes by an enzyme distinct of FAAH. The observation that the
      hydrolysis of 1(3)-AG and 2-AG occurred at equal rates supports the role of MGL
      in 2-AG inactivation. This enzyme assay provides a useful method for future
      inhibition studies of 2-AG degrading enzyme(s) in brain membrane preparation
      having considerably higher MGL-like activity when compared to FAAH activity.

PMID- 15013855
TI  - Hepatic expression of multiple acute phase proteins and down-regulation of
      nuclear receptors after acute endotoxin exposure.
AB  - Acute systemic lipopolysaccharide (endotoxin, LPS) exposure, which can lead to
      septic shock, enhances the hepatic expression of inflammatory and acute-phase
      proteins (APPs). To better understand how LPS aggravates damage, changes in
      hepatic gene expression after a single LPS dose was screened by using microarrays
      for 1176 rat genes. We detected more than 20 new potential LPS-induced APPs.
      Following acute LPS challenge, significant up-regulation of the steady-state mRNA
      levels of several important early transcription factors, such as c-jun and STAT3,
      and cytokine-associated genes, was observed. In contrast, RT-PCR analysis
      revealed marked down-regulation of the nuclear receptors RXRalpha, PXR, FXR, LXR,
      PPARalpha and CAR. Also genes encoding lipolytic, antioxidant as well as drug-
      and alcohol-metabolizing enzymes were down-regulated. These data suggest that
      acute LPS treatment induces important early transcription factors and co
      ordinately down-regulates nuclear receptors, and that this results in altered
      expression of a large number of downstream genes.

PMID- 15013856
TI  - Resveratrol, a polyphenol found in grapes, suppresses oxidative damage and
      stimulates apoptosis during early colonic inflammation in rats.
AB  - Oxidative stress, neutrophil infiltration, proinflammatory cytokines and
      eicosanoid generation are clearly involved in the pathogenesis of intestinal
      bowel disease. Resveratrol, a polyphenolic compound found in grapes and wine, has
      been shown to have anti-inflammatory, antioxidant, antitumour and
      immunomodulatory activities, however, its effects on experimental colitis remain
      unknown. We have investigated the effects of resveratrol on the colon injury
      caused by intracolonic instillation of trinitrobenzenesulphonic acid (TNBS) in
      rats. We determined the production of prostaglandin (PG)E(2) and PGD(2) in colon
      mucosa and the expression of cyclo-oxygenases (COX)-1 and -2
      immunohistochemically. The inflammatory response was assessed by histology and
      myeloperoxidase activity, as an index of neutrophil infiltration. Interleukin-1
      beta production, histological and histochemical analysis of the lesions were also
      carried out. Finally, since resveratrol has been found to modulate apoptosis we
      intended to elucidate its effects on colonic mucosa under early acute
      inflammatory conditions. Resveratrol (5-10mg/kg/day) significantly reduced the
      degree of colonic injury, the index of neutrophil infiltration and the levels of
      the cytokine. Resveratrol did not revert the increased PGE(2) levels but produced
      a significant fall in the PGD(2) concentration. Compared with inflamed colon, no
      changes in staining for COX-1 were observed in colon of resveratrol and TNBS
      treated rats. In contrast, COX-2 expression was decreased. Furthermore,
      resveratrol enhanced apoptosis compared with already high level induced by TNBS.
      In conclusion, resveratrol reduces the damage in experimentally induced colitis,
      alleviates the oxidative events and stimulates apoptosis.

PMID- 15013857
TI  - Inhibitory mechanisms of YC-1 and PMC in the induction of iNOS expression by
      lipoteichoic acid in RAW 264.7 macrophages.
AB  - In the present study, the signal pathways involved in NO formation and iNOS
      expression in RAW 264.7 macrophages stimulated by LTA were investigated. We also
      compared the relative inhibitory activities and mechanisms of PMC, a novel potent
      antioxidant of alpha-tocopherol derivatives, with those of YC-1, an sGC
      activator, on the induction of iNOS expression by LTA in cultured macrophages in
      vitro and LTA-induced hypotension in vivo. LTA induced concentration (0.1-50
      microg/mL)- and time (4-24 hr)-dependent increases in nitrite (an indicator of NO
      biosynthesis) in macrophages. Both PMC (50 microM) and YC-1 (10 microM) inhibited
      NO production, iNOS protein, mRNA expression, and IkappaBalpha degradation upon
      stimulation by LTA (20 microg/mL) in macrophages. On the other hand, PMC (50
      microM) almost completely suppressed JNK/SAPK activation, whereas YC-1 (10
      microM) only partially inhibited its activation in LTA-stimulated macrophages.
      Moreover, PMC (10 mg/kg, i.v.) and YC-1 (5 mg/kg, i.v.) significantly inhibited
      the fall in MAP stimulated by LTA (10 mg/kg, i.v.) in rats. In conclusion, we
      demonstrate that YC-1 shows more-potent activity than PMC at abrogating the
      expression of iNOS in macrophages in vitro and reversing delayed hypotension in
      rats with endotoxic shock stimulated by LTA. The inhibitory mechanisms of PMC may
      be due to its antioxidative properties, with a resulting influence on JNK/SAPK
      and NF-kappaB activations. YC-1 may be mediated by increasing cyclic GMP,
      followed by, at least partly, inhibition of JNK/SAPK and NF-kappaB activations,
      thereby leading to inhibition of iNOS expression.

PMID- 15013858
TI  - Acivicin-induced alterations in renal and hepatic glutathione concentrations and
      in gamma-glutamyltransferase activities.
AB  - gamma-Glutamyltransferase (gamma-GT) catalyzes the hydrolysis of glutathione,
      glutathione S-conjugates, and gamma-substituted l-glutamate derivatives. Acivicin
      is an irreversible inhibitor of gamma-GT that has been used to study the role of
      gamma-GT in glutathione homeostasis and glutathione-dependent bioactivation
      reactions. The present studies were undertaken because of reported conflicting
      effects of acivicin on the nephrotoxicity of some haloalkenes that undergo
      glutathione-dependent bioactivation. The objective of this study was to test the
      hypothesis that acivicin may alter renal glutathione concentrations; acivicin
      induced changes in renal glutathione concentrations may alter the susceptibility
      of the kidney to the nephrotoxic effects of haloalkenes. Hence, diurnal and
      acivicin-induced changes in renal and hepatic glutathione concentrations along
      with renal and hepatic gamma-GT activities were investigated. The previously
      observed diurnal variations in hepatic glutathione concentrations in fed rats
      were confirmed, but no diurnal variations were observed in renal glutathione
      concentrations or in renal or hepatic gamma-GT activities. Renal and hepatic
      glutathione concentrations and gamma-GT activities were measured in tissue
      homogenates from rats given 0, 0.1, or 0.2 mmol acivicin/kg (i.p.) and killed 0,
      2, 4, 8, 12, or 24 hr later. Renal glutathione concentrations were increased
      above control values in acivicin-treated rats, whereas acivicin had no effect on
      hepatic glutathione concentrations. Renal gamma-GT activities decreased within 2
      hr after giving acivicin and remained decreased for 24 hr. Acivicin had no effect
      on hepatic gamma-GT activities, except at 24 hr after treatment when values in
      acivicin-treated rats were elevated compared with controls. Although the present
      studies do not afford an explanation of the mechanism whereby acivicin increases
      the nephrotoxicity of some haloalkenes, they do indicate that acivicin is not a
      reliable probe to investigate the role of gamma-GT in haloalkene-induced
      nephrotoxicity.

PMID- 15013859
TI  - Endothelial cell density after deep anterior lamellar keratoplasty (Melles
      technique).
AB  - PURPOSE: To measure the recipient endothelial cell loss after the Melles
      technique for deep anterior lamellar keratoplasty. METHODS: In 21 eyes of 21
      patients, a deep anterior lamellar keratoplasty procedure was performed. Before
      surgery and at 6, 12, and 24 months after surgery, specular microscopy was
      performed to evaluate the endothelial cell density. For each postoperative time
      interval, the mean endothelial cell loss relative to the preoperative value was
      calculated. RESULTS: Mean postoperative endothelial cell loss averaged 283
      cells/mm(2) (+/- 293) at 6 months, 335 cells/mm(2) (+/- 309) at 12 months, and
      421 cells/mm(2) (+/- 316) at 24 months. Estimate relative endothelial cell
      density losses obtained by mixed model analysis of variance were 11.1%, 2.0%, and
      1.2%, respectively, each time compared with its previous measurement point.
      Second order comparisons showed that the loss within the first 6 months was
      significantly higher than after 6 months. CONCLUSION: In deep anterior lamellar
      keratoplasty, the recipient corneal endothelium showed a small initial drop in
      endothelial cell density followed by a physiologic rate of cell loss. Cell
      survival after lamellar keratoplasty may be expected to be better when compared
      with that following penetrating keratoplasty.

PMID- 15013860
TI  - Total plasma homocysteine and primary open-angle glaucoma.
AB  - PURPOSE: To evaluate total plasma homocysteine (tHcy) levels in patients
      diagnosed with primary open-angle glaucoma (POAG) and normal subjects. DESIGN:
      Case-control study. METHODS: This study involved 55 POAG patients, 16 patients
      with secondary open-angle glaucoma or angle-closure glaucoma (non-POAG group),
      and 39 control healthy subjects undergoing ocular surgery. All glaucoma patients
      had characteristic glaucomatous optic disk damage and visual field loss. Fasting
      tHcy concentrations of all study participants were determined using high
      performance liquid chromatography. Analysis of variance was used to compare
      homocysteine levels among the three diagnostic groups, and multivariate analysis
      was conducted to assess the associations between tHcy and diagnostic group, age,
      gender, smoking status, systemic hypertension, hyperlipidemia, and cardiovascular
      or cerebrovascular disease. RESULTS: Mean +/- standard deviation of tHcy levels
      in POAG individuals, non-POAG patients and control subjects was 14.90 +/- 6.45
      micromol/l, 14.30 +/- 4.35 micromol/l, and 14.81 +/- 4.56 micromol/l,
      respectively (P =.93; ANOVA). No statistically significant difference was found
      in the proportion of patients with abnormal tHcy levels among the three
      diagnostic groups. In multivariate analysis, only age and positive smoking status
      were significantly correlated with total plasma homocysteine levels. CONCLUSION:
      No significant difference was found in plasma homocysteine levels among POAG
      patients and normal control individuals.

PMID- 15013862
TI  - New onset of herpes simplex virus epithelial keratitis after penetrating
      keratoplasty.
AB  - PURPOSE: To report a series of patients with no previous history of herpes
      simplex virus (HSV) infection who had new onset of herpetic keratitis after
      penetrating keratoplasty (PK). DESIGN: Noncontrolled, retrospective case series.
      METHODS: We included in the study the patients who had new onset of herpetic
      keratitis after penetrating keratoplasty for corneal diseases unrelated to HSV
      infection who were seen at the Cornea Service at Wills Eye Hospital
      (Philadelphia, Pennsylvania) from January 1996 to December 2002. The diagnosis of
      HSV epithelial keratitis was based on clinical characteristics of either a
      classic herpetic dendrite, a geographic ulcer, or a nonhealing epithelial defect
      that responded only to antiviral therapy. RESULTS: Fourteen patients were
      included in the study. Eight of these (57%) had presented with a geographic ulcer
      whereas six patients (43%) had a classic dendrite. The most common primary
      corneal disease that led to PK was pseudophakic bullous keratopathy (36%),
      followed by keratoconus (29%), Fuchs dystrophy (21%), and corneal scar unrelated
      to HSV (14%). CONCLUSIONS: The ophthalmologist should be aware of the possibility
      of herpetic keratitis in eyes after PK, even in patients with no previous history
      of HSV infection.

PMID- 15013863
TI  - Sensitivity and specificity of the 76-suprathreshold visual field test to detect
      eyes with visual field defect by Humphrey threshold testing in a population-based
      setting: the Thessaloniki eye study.
AB  - PURPOSE: To evaluate the screening performance of the 76-Suprathreshold (76-STHR)
      visual field test to detect eyes with visual field defect (VFD) as measured by
      Humphrey threshold testing in a population-based setting. DESIGN: Cross-sectional
      study. METHODS: All 88 subjects who agreed to participate in the pilot phase of
      the Thessaloniki Eye Study were included. Participants underwent a 76-STHR visual
      field test followed by a 30-full threshold (30-2 FTHR) test (Humphrey field
      analyzer). One eye/subject was randomly selected and included in the analysis.
      Sensitivity and specificity rates of the 76-STHR to detect eyes with VFD by the
      30 to 2 FTHR test were calculated. RESULTS: When eyes with borderline results in
      the 30 to 2 FTHR test were classified as having a VFD, sensitivity rates of the
      76-STHR to detect eyes with VFD by the 30 to 2 FTHR were 85.2%, 77.8%, and 74.1%,
      whereas specificity rates were 70%, 78%, and 86%, depending on the cutoff used
      for the 76-STHR. CONCLUSIONS: The 76-STHR test showed high sensitivity and low
      false-negative results at the "at least one point missed" cutoff level criterion
      to detect eyes with visual field defect by Humphrey threshold testing in a
      population-based setting. This criterion should be used when screening in a
      population-based study setting. By contrast, the 76-STHR would not be the
      appropriate screening test in a primary care setting with limited resources.

PMID- 15013861
TI  - Optic radiation involvement in optic pathway gliomas in neurofibromatosis.
AB  - PURPOSE: Optic pathway gliomas (pilocytic astrocytomas) in neurofibromatosis type
      1 (NF-1) typically involve some combination of the optic nerves, chiasm, or optic
      tracts. Involvement of the optic radiations is rare. DESIGN: This paper describes
      seven patients with NF-1 with gliomas involving the pregeniculate optic pathway
      in addition to the optic radiations. METHODS: A retrospective database review was
      made of all patients with NF-1 and optic pathway gliomas seen by one of the
      authors (G.T.L.) at the Children's Hospital of Philadelphia from July 1993 to
      October 2001. Patients with involvement of pregeniculate optic pathway and the
      optic radiations were identified. From November 2001 to February 2003, patients
      were sought prospectively. Cases were also identified from the practice of
      another author (M.C.B.) at Arkansas Children's Hospital. RESULTS: Four patients
      from Children's Hospital of Philadelphia (three of 83 total NF-1/optic pathway
      gliomas from July 1993 to October 2001 and one prospectively) and three from
      Arkansas Children's Hospital were identified. Two had expanding mass lesions
      within the white matter of the temporal or parietal lobes, which were
      histopathologically demonstrated to be pilocytic astrocytomas. The other five had
      radiographic involvement of the optic radiations but did not undergo biopsy. In
      three of the cases the vision was 20/200 or worse in each eye. CONCLUSIONS: Optic
      pathway gliomas in NF-1 may rarely involve the optic radiations. Optic radiation
      involvement may signal a more aggressive optic pathway glioma in patients with
      neurofibromatosis-1.

PMID- 15013864
TI  - Comparability of two fundus photograph reading centers in grading cytomegalovirus
      retinitis progression.
AB  - PURPOSE: To compare grading of cytomegalovirus retinitis progression by two
      different fundus photograph reading centers (FPRCs). DESIGN: Patients with AIDS
      followed in an ophthalmology service were enrolled in a prospective epidemiologic
      study of the prevalence and incidence of resistant cytomegalovirus in vitro.
      METHODS: We compared masked replicate gradings by two different FPRCs of monthly
      fundus photographs for retinitis progression (onset of a separate new lesion or
      expansion of an existing lesion by > or =one-half disk diameter). RESULTS: For 77
      patients, Kaplan-Meier plots of progression over time were similar between FPRCs
      (median time to progression, 65 vs 69 days). Agreement between FPRCs was 51%
      (kappa [kappa] =.37, "fair") on exact visit of progression (28 patients) or on
      absence of progression through follow-up (11 patients) and 62% (kappa =.38) on
      progression visit +/- 1 month. Eight of 12 patients with progression graded as
      more than 1 month apart were only 2 months apart. Considering each monthly visit
      as a choice point, overall agreement on progression was 78% (kappa =.55,
      "moderate"). Baseline evaluation of retinitis showed 95% agreement on
      presence/absence and a concordance correlation coefficient of.75 for extent in
      combined zones 1 and 2. Rates of retinal loss over follow-up were estimated as
      2.8%/month vs 2.0%/month (P =.015). CONCLUSIONS: By adopting similar protocols
      and procedures, different FPRCs can achieve good agreement on presence and extent
      of cytomegalovirus retinitis. Further efforts to harmonize evaluation through
      ongoing comparison of gradings would likely improve agreement on retinitis
      progression.

PMID- 15013865
TI  - The relation of retinal microvascular characteristics to age-related eye disease:
      the Beaver Dam eye study.
AB  - PURPOSE: To examine the relationship between microvascular characteristics
      (central retinal artery equivalent [CRAE], central retinal vein equivalent
      [CRVE], arteriole-to-venule ratio [AVR], focal retinal arteriolar narrowing,
      arteriovenous [A/V] nicking, and retinopathy) associated with systemic
      hypertension and ocular disease (age-related maculopathy [ARM], three types of
      cataract, and open-angle glaucoma). DESIGN: Population-based cohort study.
      METHODS: Standardized grading of microvascular characteristics was performed at
      baseline on fundus photographs taken on 4,926 persons aged 43 to 86 years who
      participated in the Beaver Dam Eye study at the baseline examination. Age-related
      maculopathy, cataract, and glaucoma status were determined at baseline; ARM and
      cataract were again determined at 5-year and 10-year follow-up examinations using
      standard protocols. RESULTS: While controlling for age and sex, generalized
      retinal arteriolar narrowing (lowest quintile of CRAE) was associated with the 10
      year cumulative incidence of retinal pigment epithelial (RPE) depigmentation
      (risk ratio [RR] 1st vs 5th quintile, 1.93; 95% confidence interval [CI], 1.11,
      3.34) and, inversely, with incident nuclear cataract (RR, 0.71; 95% CI, 0.50,
      0.99). Arteriovenous nicking was associated with the incidence of early ARM (RR,
      2.39; 95% CI, 1.02, 5.57). Otherwise, there were no statistically significant
      associations of focal arteriolar narrowing or retinopathy with incident ARM or
      any type of age-related cataract and no relation of CRAE, focal arteriolar
      narrowing, A/V nicking, or retinopathy with the prevalence of glaucoma.
      CONCLUSION: These data show that retinal vascular characteristics associated with
      hypertension are related to the incidence of ARM and nuclear cataract but not to
      prevalent glaucoma. Relationships, however, were weak and inconsistent.

PMID- 15013866
TI  - Screening for sight-threatening diabetic retinopathy: comparison of fundus
      photography with automated color contrast threshold test.
AB  - PURPOSE: To compare tritan contrast threshold (TCT) with fundus photography in
      screening for sight-threatening diabetic retinopathy (STDR), before significant
      visual loss. DESIGN: Prospective, comparative study. METHODS: A total of 510
      consenting diabetic patients attending a hospital-based photographic screening
      clinic were recruited over a 2-year period. Exclusion criteria included visual
      acuity of worse than 6/9, previous photocoagulation, and a history of previous
      eye disease known to affect color vision. The automated TCT test was performed
      using a computerized cathode ray tube-based technique. Retinal photography was
      performed using a Polaroid mydriatic fundus camera with a 45 degrees field.
      Grading of diabetic retinopathy was carried out by an ophthalmologist using slit
      lamp biomicroscopy and a 78-diopters lens. Assessments of sensitivity,
      specificity, and predictive values for both fundus photography and the TCT test
      were made. RESULTS: Both the fundus photography and TCT test correlated
      significantly with the presence of STDR (P <.0001, chi(2) test). The TCT test
      yielded a sensitivity of 94% (95% confidence interval [CI], 73%- 100%) and a
      specificity of 95% (95% CI, 92%- 96%) for detection of STDR compared with a
      sensitivity of 88% (95% CI, 66%-97%) and a specificity of 95% (95% CI, 93%-97%)
      with fundus photography. Combined modality improved overall screening
      performance. CONCLUSION: The TCT assessment is an effective and clinically viable
      technique, in comparison with fundus photography, to screen for STDR among a
      diabetic population. Additionally, our results also showed that combining the TCT
      test with fundus photography greatly increases the performance of screening for
      STDR.

PMID- 15013867
TI  - Ciprofloxacin and levofloxacin resistance among methicillin-sensitive
      Staphylococcus aureus isolates from keratitis and conjunctivitis.
AB  - PURPOSE: The majority of Staphylococcus aureus isolated from ocular infections
      are methicillin sensitive (MSSA). Fluoroquinolone resistance among methicillin-
      resistant Staphylococcus aureus is well known but not among MSSA. In this study
      we investigate the emergence of fluoroquinolone (ciprofloxacin, levofloxacin)
      resistance among methicillin-sensitive Staphylococcus aureus isolates from
      keratitis and conjunctivitis. DESIGN: Cross-sectional study. METHODS: Minimal
      inhibitory concentration susceptibility profiles for 1230 S. aureus isolates from
      keratitis and conjunctivitis were analyzed. Historical and current rates of
      emerging fluoroquinolone resistance for methicillin-resistant (MRSA) and
      methicillin-sensitive isolates (MSSA) were evaluated. Sensitivity patterns for
      vancomycin and gentamicin were also documented. RESULTS: Ciprofloxacin resistance
      among corneal and conjunctival S. aureus isolates during the first 6 years after
      its introduction (baseline) (1990-1995) was 8% and ranged from 3% to 11%. The
      rate for the most recent 6 years (current) (1996-2001) was 20.7%. Baseline
      ciprofloxacin resistance for MSSA isolates was 2% vs 55.8% for MRSA. The current
      resistance rate for MSSA is 5% vs 83.7% for MRSA. The general resistance rate
      from January 2000 to December 2001 for levofloxacin was 25.5% vs 33.2% for
      ciprofloxacin (P =.13). The levofloxacin-resistance rate for MSSA was 4.7% vs
      11.9% for ciprofloxacin (P =.05). In MRSA isolates, a higher resistance rate was
      found for ciprofloxacin (95.7%) vs levofloxacin (82.1%) (P =.04). No resistance
      for vancomycin was documented for any of the S. aureus isolates. Gentamicin
      susceptibility for MSSA was 99% and MRSA was 86%. CONCLUSIONS: Ciprofloxacin and
      levofloxacin resistance among methicillin-sensitive S. aureus corneal and
      conjunctival isolates is increasing. This is of concern because it narrows
      treatment choices for the management of these common ocular infections.

PMID- 15013868
TI  - Factor XII deficiency: a thrombophilic risk factor for retinal vein occlusion.
AB  - PURPOSE: Factor XII deficiency is among the coagulation disorders that have been
      implicated in major thromboembolic events. However, little is known about an
      association of this coagulation disorder and retinal vessel occlusion. In the
      current study, we investigated the prevalence of factor XII deficiency in
      patients with retinal vein occlusion (RVO) with reference to age and
      cardiovascular risk factors. DESIGN: Cross-sectional study. METHODS: A cohort of
      150 consecutive patients with central or branch retinal vein occlusion and 135
      subjects matched for age and gender were prospectively screened for factor XII
      deficiency. Both cohorts were divided into two subgroups (<= 45 or >45 years),
      depending on the patients' age at the time of the RVO or a previous
      thromboembolic event. RESULTS: Overall, factor XII deficiency was found to be
      present in 14 (9.3%) of 150 patients and in 1 (0.7%) of 135 controls (P =.0009).
      Patient age <= 45 years at the time of the RVO or a previous thromboembolic event
      was associated with a high prevalence of factor XII deficiency (18%). By
      contrast, only 5 (5%) of 100 patients >45 years (P =.016) and none of the young
      controls (P =.0001) tested positive for factor XII deficiency. The prevalence
      among patients >45 years was similar to that found in age-matched controls (2%; P
      =.66). CONCLUSIONS: Our results indicate that factor XII deficiency is highly
      prevalent in RVO patients <= 45 years of age. By contrast, the prevalence of
      factor XII deficiency in RVO patients older than 45 years appears to be similar
      to that seen in healthy individuals.

PMID- 15013869
TI  - Novel mutations in the carbohydrate sulfotransferase gene (CHST6) in American
      patients with macular corneal dystrophy.
AB  - PURPOSE: To further characterize the mutations within the CHST6 gene responsible
      for causing macular corneal dystrophy in a cohort of affected patients from the
      United States. DESIGN: Experimental study. METHODS: Genomic DNA was extracted
      from buccal epithelium of 16 affected patients (14 families), 17 unaffected
      relatives, and 127 controls, followed by polymerase chain reaction amplification
      and direct sequencing of the CHST6 coding region. Subtyping of affected patients
      into type I and II macular corneal dystrophy was performed by measuring antigenic
      keratan sulfate (AgKS) serum levels. Haplotype analysis was performed in families
      that demonstrated common mutations. RESULTS: CHST6 coding region analysis in 10
      patients identified as having type I macular corneal dystrophy revealed 10
      sequence changes: eight missense mutations, four of which are novel (Met104Val,
      Tyr110Cys, Gln122Pro, and Leu276Pro) and four of which have been reported
      previously (Ser51Leu, Pro72Ser, Cys102Gly, and Leu200Arg); one novel homozygous
      nonsense mutation in two patients from a single family (c. 1683C>T, Gln331X); and
      one frameshift mutation in a heterozygous state in a single patient
      (c.1744_1751dupGTGCGCTG). Mutation analysis in the four patients identified as
      having type II macular corneal dystrophy (serum samples were not obtained from
      two affected patients) revealed three patients heterozygous for either the
      c.923G>C, c.969C>A, or c.1519T>C sequence changes. The fourth patient was
      compound heterozygous for c.969C>A and c.1291T>G. None of these changes was
      observed in 127 control individuals. Haplotype analysis using microsatellite
      markers flanking the CHST6 gene did not reveal a common founder for the Leu200Arg
      (1291T>G) missense mutation, present in five families, identifying this position
      as a mutation hot-spot. CONCLUSIONS: A variety of previously unreported mutations
      in the coding region of the CHST6 gene are associated with type I macular corneal
      dystrophy in a cohort of patients from the United States.

PMID- 15013870
TI  - Anisometropia in Singapore school children.
AB  - PURPOSE: To report the prevalence rates of anisometropia in a school population
      and determine the relative contribution of refractive power and axial length to
      the measured anisometropia. DESIGN: Population-based cross-sectional study.
      METHODS: Autorefraction, keratometry, and ultrasonography studies were made.
      SETTING: Three schools, located on the eastern, northern, and western part of
      Singapore. STUDY POPULATION: In all, 1,979 children aged 7 to 9 years were
      recruited for this study. The study sample included Chinese (n = 1,481), Malay (n
      = 324), and Asian Indian (n = 174) children; 720 subjects have myopia (spherical
      equivalent <= -0.5 diopters) in at least one eye. MAIN OUTCOME MEASURE:
      Anisometropia. RESULTS: The prevalence rates of anisometropia, in terms of
      spherical equivalent (SE) difference of at least 1.5 diopters and 2.0 diopters
      were 1.57% (95% confidence interval [CI]: 1.1, 2.2) and 1.01% (95% CI: 0.6, 1.6),
      respectively. The prevalence rate of anisometropia (at least 2.0 diopters) among
      the children with at least one myopic eye was 2.4% (95% CI: 1.4, 3.8), whereas in
      those without any myopic eyes, the prevalence rate was only 0.2% (95% CI: 0.06,
      0.8). The spherical equivalent difference between the right and left eyes was
      positively correlated with the difference in axial lengths (P <.001). The
      difference in corneal refractive power is not statistically different between the
      anisometropic and the nonanisometropic children. CONCLUSIONS: The anisometropia
      prevalence rate in a childhood population with a relatively high prevalence of
      myopia was reported. The origin of the anisometropia is axial, and these results
      suggest that the differential rate of elongation between the two eyes of
      nonmyopic subjects results in anisometropia.

PMID- 15013871
TI  - J. Donald M. Gass, MD: Festschrift editorial.

PMID- 15013872
TI  - Photodynamic therapy for age-related macular degeneration: a candid appraisal.

PMID- 15013873
TI  - The epidemiology of age-related macular degeneration.
AB  - PURPOSE: To review the epidemiology of age-related macular degeneration (AMD).
      DESIGN: Evidence from epidemiologic data regarding the natural history of AMD and
      its risk factors are presented. RESULTS: Large, soft drusen associated with
      pigmentary abnormalities increase the risk of progression to advanced AMD. Large
      soft drusen may fade over time. Advanced AMD is more likely to be present in
      whites than blacks, despite the similar prevalence of soft drusen in both groups.
      Neovascular AMD is more frequent than geographic atrophy in most population-based
      studies in whites in America, Australia, and the Netherlands than in similar
      population-based studies in Iceland and Norway. After age and family history,
      there are few consistent relationships of risk factors to AMD. Of these, the
      relationship of smoking, hypertension, and cataract surgery to advanced AMD have
      been most consistent. CONCLUSIONS: Long-term epidemiologic studies have provided
      information on the distribution and the natural history of AMD and its associated
      risk factors. It is not known what effect reduction of blood pressure and the
      cessation of smoking might have on the incidence and progression of AMD.

PMID- 15013874
TI  - Choroidal neovascularization.
AB  - PURPOSE: To review clinicopathologic findings of choroidal neovascularization
      (CNV) in a historical framework with emphasis on pathobiology and correlation
      with treatment. DESIGN: Selective literature review combined with authors'
      experience. RESULTS: Choroidal neovascularization represents a stereotypic,
      nonspecific response to a specific stimulus. Although CNV differs among patients,
      the general growth patterns are subretinal pigment epithelium (type 1),
      subretinal (type 2), or combined. Choroidal neovascularization occurs over time
      in dynamic stages of initiation, active and involutional. Treatments are now
      being designed based on modern understanding of CNV growth. CONCLUSIONS: Progress
      continues to be made concerning understanding the pathobiology and treatment of
      CNV.

PMID- 15013875
TI  - Pathogenesis of lesions in late age-related macular disease.
AB  - PURPOSE: To review the evidence that exists concerning the pathogenesis of
      lesions in late age-related macular disease (AMD). DESIGN: Review of the
      literature. METHODS: A review of both experimental evidence and clinical
      observations that address these problems. RESULTS: There is good evidence that
      choroidal neovascularization (CNV) is due to a change in the balance of growth
      factors derived from the retinal pigment epithelial basolateral plasma membrane
      domain (retinal pigment epithelium). Retinal angiomatous proliferation may also
      have a similar pathogenesis involving the apical domain. Detachment of the
      retinal pigment epithelium is likely to be a consequence of increased resistance
      of the Bruch membrane to water flow due to deposition of lipids. Geographic
      atrophy is preceded by accumulation of autofluorescent material in the retinal
      pigment epithelium and possible causal relationships between the two have been
      demonstrated. CONCLUSION: There is increasing understanding concerning the
      sequence of events that lead to those lesions causing loss of central vision in
      AMD. Therapeutic approaches that address the underlying mechanisms are more
      likely to succeed than current treatment options. Such an approach has already
      been initiated in the management of choroidal neovascularization.

PMID- 15013876
TI  - Ophthalmic fundus imaging: today and beyond.
AB  - PURPOSE: To review and update techniques of posterior segment ophthalmic fundus
      imaging. DESIGN: Literature review and collective experience of the authors.
      METHODS: This perspective includes sections on digital imaging, fundus
      autofluorescence, ultrasonography, angiography, and optical coherence tomography
      (OCT) -ophthalmoscopy written by leading clinicians and researchers in these
      areas. RESULTS: Digital angiography has become the new standard in the ophthalmic
      community based upon improved technology which has enhanced resolution,
      processing time, and ease of image duplication, manipulation, and transmission. A
      relatively new imaging technique, fundus autofluorescence, highlights lipofuscin
      deposits and improves our understanding of the metabolic status of the retinal
      pigment epithelium. Diagnostic ultrasonography continues to be a major adjunct to
      ocular evaluation where advances now allow for exceptional versatility and
      portability. High speed angiographic techniques provide detailed visualization of
      choroidal perfusion which improves our understanding of both normal and
      pathologic vascular phenomenon. Advances in high-resolution OCT currently under
      development promise an even more detailed fundus representation. The integration
      of the scanning laser ophthalmoscope and OCT has produced a dynamic new
      instrument, the OCT ophthalmoscope, which simultaneously images the fundus in
      numerous ways with point to point correlation. CONCLUSIONS: Ophthalmic imaging
      technology has revolutionized fundus examination. Currently available systems
      have contributed significantly to our understanding of the pathophysiology and
      treatment of various retinal diseases. Future advances promise near histologic
      resolution of retinal structures as well as real-time image manipulation and
      instantaneous transmission world-wide.

PMID- 15013877
TI  - Pathogenesis of macular holes and therapeutic implications.
AB  - PURPOSE: To review the literature and identify consistencies and inconsistencies
      in existing theories of pathogenesis and to consider some of their possible
      therapeutic implications. DESIGN: Presentation of clinical case material with a
      synthesis of ideas on macular holes. METHODS: The literature of macular hole
      surgery is reviewed pertinent to pathogenic theories. Clinical examples of
      evolving macular holes shown on ocular coherence tomography are presented to
      illustrate issues. RESULTS: The history of pathogenesis and macular holes is
      interesting in that, in many ways pathogenic theory has come full cycle.
      Initially, anteroposterior traction was thought to cause direct formation of a
      macular hole. Subsequently, degenerative and then tangential tractional
      etiologies were proposed. Current imaging studies have greatly advanced our
      understanding of anatomic features of full-thickness holes and early full
      thickness hole conditions. These are most consistent with a focal anteroposterior
      traction mechanism, but some inconsistences in clinical cases suggest a role for
      degeneration of the inner retinal layers. CONCLUSIONS: Degeneration of the inner
      retinal layers at the central fovea may predispose the eye to macular hole
      formation. What may otherwise be incidental tractional forces appear to initiate
      the hole. These tractional elements are oriented perpendicularly to the retinal
      surface, rather than tangentially. Further observations, especially with
      sequential observations from ocular coherence tomography, may yield further
      insights into the pathogenesis of macular holes as well as implications regarding
      the best repair techniques.

PMID- 15013878
TI  - The white dot syndromes.
AB  - PURPOSE: To review the distinctive and shared features of the white dot
      syndromes, highlighting the clinical findings, diagnostic test results, proposed
      etiologies, treatments, and prognosis. DESIGN: Review. METHODS: Review of the
      literature. RESULTS: Common white dot syndromes are reviewed, including acute
      posterior multifocal placoid pigment epitheliopathy, birdshot chorioretinopathy,
      diffuse unilateral subacute neuroretinitis, multiple evanescent white dot
      syndrome, multifocal choroiditis with panuveitis, serpiginous choroiditis, and
      acute zonal occult outer retinopathy. CONCLUSIONS: The white dot syndromes are a
      group of disorders characterized by multiple whitish-yellow inflammatory lesions
      located at the level of the outer retina, retinal pigment epithelium, and
      choroid. For clinicians and researchers alike, they present significant
      diagnostic and therapeutic challenges.

PMID- 15013879
TI  - Learning effect among perimetric novices with screening C-20-1 frequency doubling
      technology perimetry.
AB  - PURPOSE: To investigate whether perimetric novices without glaucoma demonstrate a
      learning effect using screening-mode frequency doubling technology perimetry.
      DESIGN: Prospective observational study. METHODS: The study included 101 healthy
      subjects who had never undergone automated perimetry and who were administered
      the C-20-1 version of the frequency doubling technology. Subjects who returned an
      abnormal or unreliable test were retested until a normal result was obtained.
      RESULTS: Ninety-seven subjects (96%) returned a normal examination after one
      test, and 99 (98%) did so after two tests. Two subjects had abnormal initial
      tests, and two others had unreliable tests. These four subjects required repeat
      (up to four) testings to return a normal test. CONCLUSIONS: A small percentage of
      perimetric novices will demonstrate a learning effect using C-20-1 perimetry, but
      this mode has high specificity appropriate for glaucoma screening.

PMID- 15013880
TI  - Evaluation of eyes with relative pupillary block by indentation ultrasound
      biomicroscopy gonioscopy.
AB  - PURPOSE: To investigate changes in anterior chamber angle configuration with
      indentation ultrasound biomicroscopy gonioscopy of relative pupillary block
      (RPB). DESIGN: Cross-sectional study. METHODS: This study included 26 eyes of 26
      patients with RPB. We determined angle opening distance 500 and angle recess area
      using indentation ultrasound biomicroscopy gonioscopy and compared a small-sized
      standard eye cup with a new eye cup with an area for inducing pressure. RESULTS:
      Indentation ultrasound biomicroscopy images documented concavity of the iris in
      eyes with RPB. Both the new and the small standard eye cups widened the anterior
      chamber angle significantly (P <.0001) without causing corneal damage. Angle
      changes were significantly greater for the new eye cup design. CONCLUSIONS:
      Indentation ultrasound biomicroscopy gonioscopy is a useful technique for
      observation and diagnosis of RPB. Using a small standard or the newly designed
      eye cup, the procedure can be performed easily and without causing corneal
      damage.

PMID- 15013881
TI  - Ocular vaccinia following exposure to a smallpox vaccinee.
AB  - PURPOSE: To describe the presentation and management of the first identified case
      of ocular vaccinia infection associated with the current smallpox vaccination
      program. DESIGN: Case report. METHODS: Vaccinia virus was isolated by cell
      culture of a conjunctival swab. Direct staining with fluorescein isothiocyanate
      labeled vaccinia antibody and polymerase chain reaction testing confirmed the
      diagnosis. RESULTS: In February 2003, a 26-year-old woman developed right
      preseptal cellulitis and blepharoconjunctivitis following contact with a
      vaccinated member of the military. The preseptal cellulitis resolved with
      antibacterial therapy, and the conjunctival infection was treated successfully
      with a 14-day course of topical trifluridine and a single dose of intravenous
      vaccinia immune globulin. CONCLUSIONS: To facilitate rapid diagnosis and
      appropriate treatment, clinicians must maintain a high index of suspicion for
      ocular smallpox vaccine-associated adverse reactions in vaccine recipients and
      their close contacts.

PMID- 15013882
TI  - Visualization of retinal pigment epithelial cells in vivo using digital high
      resolution confocal scanning laser ophthalmoscopy.
AB  - PURPOSE: To visualize retinal pigment epithelial cells in vivo by fundus
      autofluorescence imaging using a confocal scanning laser ophthalmoscope. DESIGN:
      Experimental study and observational case report. METHODS: Digital in vivo
      autofluorescence images were recorded with a confocal scanning laser
      ophthalmoscope (excitation, 488 nm; emission, >500 nm) and compared with confocal
      scanning laser ophthalmoscope and fluorescence microscopic recordings from human
      donor eyes. RESULTS: A uniform pattern of the polygonal retinal pigment
      epithelial cell layer was visualized in vivo outside of absorbing retinal vessels
      and macular pigment. Autofluorescence intensities of individual cells showed
      marked variation. The pattern corresponded to in vitro findings. Visualization is
      based on the topographic distribution of autofluorescent lipofuscin granules and
      melanin granules in apical retinal pigment epithelium cytoplasm. CONCLUSIONS:
      High-resolution autofluorescence imaging may be useful to determine morphologic
      and lipofuscin-dependent alterations in retinal diseases and may be applicable
      for monitoring effects of therapeutic interventions targeting the retinal pigment
      epithelium.

PMID- 15013883
TI  - Large submacular hemorrhages after verteporfin therapy.
AB  - PURPOSE: To report the occurrence of large submacular hemorrhages after
      photodynamic therapy with verteporfin in age-related macular degeneration
      patients with subfoveal choroidal neovascularization (CNV) composed of occult
      with no classic CNV in whom the hemorrhage precluded determining if additional
      therapy should be given within 3 months after initiation of treatment. DESIGN:
      Retrospective, noncomparative case series. METHODS: The records of all age
      related macular degeneration patients who received verteporfin therapy for
      subfoveal lesions composed of occult with no classic CNV between February and
      July 2001 at The Wilmer Eye Institute were reviewed. Subjects who reported either
      having undergone a procedure to remove intraocular blood before a month 3 follow
      up visit, or who had submacular hemorrhage at the month 3 visit that was severe
      enough to preclude determining if additional verteporfin therapy should be given
      were identified. RESULTS: Fifty-five eyes of 52 patients were reviewed. Five eyes
      (9% [95% confidence interval, 1.4%-16.6%]) developed submacular hemorrhage that
      precluded determining if additional verteporfin therapy should be given. Visual
      acuity 3 months after documentation of the hemorrhage decreased a median of 8.5
      lines compared with pretreatment acuity. CONCLUSIONS: Even in the absence of
      acute severe visual acuity decrease, submacular hemorrhage after verteporfin
      therapy can be associated with severe vision loss and preclude determining if
      additional therapy should be given.

PMID- 15013884
TI  - Intraocular availability of triamcinolone acetonide after intravitreal injection.
AB  - BACKGROUND: To evaluate the intraocular concentration of triamcinolone acetonide
      after intravitreal injection. METHODS: The prospective clinical interventional
      case series study included 17 patients who had received a 20 to 25-mg
      intravitreal injection of triamcinolone acetonide as treatment for exudative age
      related macular degeneration, diffuse diabetic macular edema, or retinal vein
      occlusions. During a secondary intraocular surgery taking place 4.1 weeks to 25.7
      months after the intravitreal injection, aqueous humor samples were obtained.
      None of the eyes were vitrectomized. RESULTS: In the aqueous humor samples,
      triamcinolone acetonide was in low, but measurable, concentrations detected up to
      1.5 years after the intravitreal injection. Concentrations found in samples
      obtained during the first 6 months, or 7 to 12 months, respectively, after the
      injection ranged between 3.0 microg/l and 436 microg/l, and between 0.0 microg/l
      and 11.2 microg/l, respectively. CONCLUSIONS: After injection of triamcinolone
      acetonide, triamcinolone can be present in measurable concentrations up to 1.5
      years after the application.

PMID- 15013885
TI  - Validation of test duration as a screening criterion for frequency doubling
      perimetry.
AB  - PURPOSE: To validate the test duration in frequency doubling perimetry as an
      independent criterion to screen for glaucomatous field defects. DESIGN:
      Prospective cross-sectional study METHODS: Group I included 85 eyes (85 patients)
      with established field defects on automated perimetry. Group II comprised 41
      normal eyes (41 subjects). Both groups underwent Swedish interactive testing
      algorithm standard tests as well as frequency doubling perimetry (C20-1). A
      cutoff level of 90 seconds was used to calculate test duration sensitivity and
      specificity. We also categorized patients into those who took <=90 seconds or
      less and those who took >90 seconds to complete the test and compared frequency
      doubling perimetry (any two abnormal points) with Swedish interactive testing
      algorithm in these groups. RESULTS: Duration of the test >90 seconds had 97.5%
      specificity with 62.3% sensitivity. Eleven subjects with glaucoma completed test
      in <91 seconds). CONCLUSION: Test duration alone has a limited value in screening
      for glaucoma.

PMID- 15013886
TI  - Hypotonus maculopathy: magnetic resonance appearance.
AB  - PURPOSE: To report the magnetic resonance appearance of hypotonus maculopathy.
      DESIGN: Observational case report. METHODS: A 48-year-old man with a long history
      of glaucoma and subsequent trabeculectomy in the right eye developed hypotonus
      maculopathy. Visual acuity continued to decrease in both eyes of a relatively
      young individual with severe primary open angle glaucoma. A magnetic resonance
      image was requested to look for a compressive optic neuropathy. RESULTS: Magnetic
      resonance imaging showed an abnormal plaquelike thickening of the macula and
      flattening of the posterior globe. CONCLUSION: To our knowledge, this is the
      first case report of the magnetic resonance appearance of hypotonus maculopathy.

PMID- 15013887
TI  - Severe retinopathy in a child with hypoplastic left heart syndrome.
AB  - PURPOSE: We present the first reported case of a condition similar to retinopathy
      of prematurity in a full-term patient with hypoplastic left heart syndrome.
      DESIGN: Interventional case report. METHODS: We describe the clinical
      presentation and surgical treatment of a male baby with severe retinopathy and
      retinal detachments. RESULTS: The clinical course of this baby was similar to
      retinopathy of prematurity. The patient had areas of avascular retina,
      significant retinal neovascularization, fibrous proliferation, and tractional
      detachment. One eye had a totally detached retina; the other had functional
      vision after the retina was reattached by several vitreoretinal surgeries,
      including the use of intraocular silicone oil. CONCLUSIONS: This cyanotic
      condition can cause a retinopathy with chronic retinal neovascularization and
      retinal detachments. Permanent surgical retinal reattachment is difficult in the
      presence of neovascular activity that leads to intravitreous cicatrization.

PMID- 15013888
TI  - Compound heterozygous mutations of M1S1 gene in gelatinous droplike corneal
      dystrophy.
AB  - PURPOSE: To report the genetic findings in a Chinese patient diagnosed with
      gelatinous droplike corneal dystrophy (GDLD). DESIGN: Case report and
      experimental study. METHODS: Molecular genetic analysis was performed on the DNA
      extracted from peripheral leukocytes from a Chinese patient with GDLD and his
      unaffected parents. Fifty healthy, unrelated, Chinese participants were used as
      control subjects. The M1S1 gene was amplified by polymerase chain reaction and
      directly sequenced. RESULTS: The patient was clinically diagnosed with GDLD.
      Direct sequencing of the M1S1 gene revealed heterozygous changes in both alleles,
      a novel Y184C mutation on one allele and a Q118X mutation on the other that was
      reported as a founder mutation in the Japanese population. The patient's
      unaffected parents showed only the heterozygous Q118X or Y184C mutation. The
      mutation was not detected in the 50 unaffected subjects. CONCLUSIONS: This is the
      first genetic analysis of a Chinese patient with GDLD. Because the compound
      heterozygote mutations Q118X and Y184C cosegregated with the phenotype, they are
      likely the cause of GDLD in this patient.

PMID- 15013889
TI  - Diagnosis by polymerase chain reaction of ocular posttransplant
      lymphoproliferative disorder after pediatric renal transplantation.
AB  - PURPOSE: To report diagnosis by polymerase chain reaction of intraocular
      posttransplant lymphoproliferative disorder in a pediatric renal transplant
      patient. DESIGN: Observational case report. METHODS: Retrospective review.
      RESULTS: An 11-year-old girl developed infectious mononucleosis 15 months after
      renal transplantation for focal segmental sclerosis. Papillitis and hypopyon
      uveitis developed 8 months later, followed by iris nodules. Diagnosis of
      intraocular posttransplant lymphoproliferative disorder was made by polymerase
      chain reaction of aqueous humor for Epstein-Barr virus and confirmed by
      histopathology of an iris biopsy specimen. Infiltrating iris lymphocytes in the
      biopsy specimen were positive for Epstein-Barr DNA. Polymerase chain reaction
      also revealed gene rearrangement of the variable region of the heavy
      immunoglobulin chain, consistent with a monoclonal B-lymphocyte population. Iris
      nodules resolved with reduction in immunosuppressive medication. CONCLUSION:
      Polymerase chain reaction for Epstein-Barr virus may be helpful in diagnosis of
      intraocular posttransplant lymphoproliferative disorder.

PMID- 15013890
TI  - Intravitreal triamcinolone in the treatment of serous retinal detachment in Vogt
      Koyanagi-Harada syndrome.
AB  - PURPOSE: To report the use of intravitreal injection of triamcinolone acetonide
      during the acute phase of Vogt-Koyanagi-Harada disease. DESIGN: Prospective
      interventional case series. METHODS: Three eyes from two patients at the acute
      phase of Vogt-Koyanagi-Harada disease with serous retinal detachments were
      treated with a 4-mg intravitreal injection of triamcinolone acetonide. The
      following variables were evaluated: visual acuity, intraocular pressure, and
      height of the serous retinal detachment using optical coherence tomography.
      RESULTS: The optical coherence tomography images showed a marked decrease in the
      retinal detachment in the first week after the injection with subsequent return
      to normal retinal thickness in all eyes. CONCLUSIONS: Intravitreal triamcinolone
      acetonide provides short-term improvement in visual acuity and serous retinal
      detachments associated with Vogt-Koyanagi-Harada disease. These findings should
      be followed by future studies to evaluate long-term effects.

PMID- 15013891
TI  - Hemorrhagic complication in an unsuspected macular choroidal melanoma.
AB  - PURPOSE: To report a rare presentation of a hemorrhagic complication in a patient
      with unsuspected macular choroidal melanoma. DESIGN: Interventional case report.
      METHODS: A 32-year-old Chinese woman presented with disturbance of her left
      central vision. A hemorrhagic mass at the macula was noticed that was evacuated
      by submacular surgery. RESULTS: The mass expanded rapidly into a mushroom
      configuration after surgery. Fine-needle aspiration confirmed the diagnosis of
      malignant choroidal melanoma, and enucleation followed. Histology demonstrated
      moderately large epithelioid tumor cells with prominent nucleoli. The sclera was
      intact, and the optic nerve was not involved. The patient has been followed for 5
      years without signs of local recurrence or metastasis. CONCLUSION: We should be
      alert for atypical presentations of choroidal melanoma. Unnecessary or
      inadvertent surgical intervention may induce tumor growth and subsequent local
      spread or metastasis.

PMID- 15013892
TI  - Bull's-eye maculopathy associated with quinacrine therapy for malaria.
AB  - PURPOSE: To report a side effect of quinacrine therapy for malaria. DESIGN: Case
      report. METHODS: Review of clinical chart and photographs. SETTING: Private
      retina practice. RESULTS: A patient developed a bilaterally symmetric bull's-eye
      maculopathy 45 years after taking quinacrine for 18 months as prophylaxis against
      malaria. Progression of the clinical picture was documented over 15 years of
      follow-up. The clinical picture was identical to that of chloroquine and
      hydroxychloroquine maculopathy. CONCLUSIONS: Low dosages of quinacrine used for
      malaria prophylaxis can be associated with a delayed, severe maculopathy
      indistinguishable from chloroquine maculopathy in certain patients.

PMID- 15013893
TI  - Listeria monocytogenes-induced endogenous endophthalmitis: bioultrasonic
      findings.
AB  - PURPOSE: To report bioultrasonic findings in Listeria monocytogenes-induced
      endophthalmitis (LMIE) that have not been described previously. DESIGN:
      Interventional case report. METHODS: To rule out intraocular tumor, ultrasound
      biomicroscopy was performed in a patient referred for a 2-day history of uveitis
      with elevated intraocular pressure, dark hypopyon, and pigment dispersion in the
      anterior chamber. RESULTS: Ultrasound biomicroscopy examination showed increased
      iris thickness with rarefaction of tissue and irregular echogenicity as well as
      iris pigment epithelial detachment. A small choroidal detachment was also
      detected. The anterior chamber and vitreous sample confirmed the LMIE diagnosis.
      CONCLUSIONS: The detection of both pigment epithelial detachment and changes in
      the iris tissue could explain why black hypopyon frequently develops in LMIE with
      significant pigment dispersion in some cases.

PMID- 15013894
TI  - A prospective, pilot study of treatment of amblyopia in children 10 to <18 years
      old.
AB  - PURPOSE: To determine whether amblyopia can be successfully treated in older
      children and adolescents. DESIGN: Prospective, single group treatment trial.
      METHODS: Sixty-six amblyopic patients aged 10 to <18 years with amblyopic eye
      acuity of 20/40 to 20/160 were treated with daily patching (> or =2 hours a day)
      combined with at least 1 hour of near activities. Visual acuity was measured
      before and after 2 months of prescribed treatment. RESULTS: Visual acuity
      improved 2 or more lines from baseline in 18 (27%) of the 66 patients (95%
      confidence interval, 17%-40%), and the improvement appeared similar in 10- to <14
      year-olds and 14- to <18-year-olds. CONCLUSIONS: Amblyopia treatment can improve
      visual acuity in older children and adolescents. A randomized controlled trial is
      needed to determine if there is an upper age limit for which amblyopia treatment
      is successful.

PMID- 15013896
TI  - Three cases of intraocular foreign bodies as a result of walking or running along
      roadways.
AB  - PURPOSE: To report three cases of intraocular foreign bodies resulting from
      walking or running along roadways. DESIGN: Case reports. METHODS: Three separate
      incidents of walking or running along roadways with "traumatic events" resulting
      in intraocular foreign bodies. RESULTS: Each patient had pars plana vitrectomy
      with removal of intraocular foreign bodies. Chemical analysis was performed to
      give information on the potential origins of each foreign body. CONCLUSION: We
      hypothesize these intraocular foreign bodies were projected from the road surface
      with sufficient energy to penetrate the globe. Intraocular foreign bodies may
      result from simply walking or running along roadways.

PMID- 15013895
TI  - Delayed-onset, bleb-associated endophthalmitis caused by Lecythophora mutabilis.
AB  - PURPOSE: To report delayed-onset, bleb-associated endophthalmitis caused by
      Lecythophora mutabilis. DESIGN: Interventional case report. METHODS: Description
      of an otherwise healthy woman who developed delayed-onset fungal endophthalmitis
      associated with a preexisting filtering bleb. RESULTS: A 57-year-old woman who
      underwent trabeculectomy with Mitomycin C in her left eye 8 years earlier
      presented with a 10-day history of pain and decreased vision in her left eye. She
      underwent anterior chamber and vitreous taps and injection of intraocular
      antibiotics. Cultures grew the mold Lecythophora mutabilis. The patient underwent
      treatment with intraocular and systemic antifungal agents, three pars plana
      vitrectomies, partial iridectomy, and cryopexy to the bleb and angle structures.
      Four months after her last treatment, her left eye shows no residual infection,
      and vision corrects to 20/80. CONCLUSION: Bleb-associated endophthalmitis caused
      by L. mutabilis is resistant to amphotericin B but responsive to intravitreal and
      systemic voriconazole together with pars plana vitrectomy, iridectomy, and
      cryopexy to the bleb and angle structures.

PMID- 15013897
TI  - Lattice corneal dystrophy type I without typical lattice lines: role of
      mutational analysis.
AB  - PURPOSE: To describe a Japanese patient with lattice corneal dystrophy type I
      (LCD I) who lacked the typical lattice lines. DESIGN: Interventional case report.
      METHODS: A complete ophthalmologic examination was performed on a 54-year-old
      woman, and the TGFBI gene was analyzed by direct genomic sequencing. RESULTS: The
      patient had diffuse opacification of the central corneal stroma but without
      lattice lines and corneal epithelial erosions bilaterally. Molecular genetic
      analysis identified a lattice corneal dystrophy I-associated heterozygous
      missense alteration (C417T) that changed arginine in codon 124 to cysteine
      (R124C) in the TGFBI gene. CONCLUSIONS: The cornea of the patient appeared to
      represent late-stage lattice corneal dystrophy I, which suggests the existence of
      interactions of modifier genes, environmental factors during corneal aging, or
      both. The molecular genetic analysis of TGFBI can offer rapid, accurate diagnosis
      of patients with atypical corneal appearance.

PMID- 15013898
TI  - Internal limiting membrane staining with various concentrations of indocyanine
      green dye.

PMID- 15013900
TI  - Comment on papers by Ashikari, Ozeki, Tomida, Sakurai, Tamai, Ogura: retention of
      dye after indocyanine-green assisted internal limiting membrane peeling, and by
      Ciardella, Schiff, Barile, Vidne, Sparrow, Langton, Chang: persistent indocyanine
      green fluorescence after vitrectomy for macular hole.

PMID- 15013902
TI  - Visual function in an 11 year old with Fraser cryptophthalmos syndrome.

PMID- 15013904
TI  - Re: mitomycin-induced punctal stenosis.

PMID- 15013906
TI  - Intravitreal triamcinolone acetonide in eyes with cystoid macular edema
      associated with central retinal vein occlusion.

PMID- 15013908
TI  - Clinicopathologic findings in choroidal melanomas after failed transpupillary
      thermotherapy.

PMID- 15013911
TI  - Intravitreal triamcinolone acetonide in eyes with cystoid macular edema
      associated with central retinal vein occlusion.

PMID- 15013912
TI  - Intraocular pressure, goldmann applanation tension, corneal thickness, and
      corneal curvature in Caucasians, Asians, Hispanics, and African Americans.

PMID- 15013914
TI  - Case-control study of endophthalmitis after cataract surgery comparing scleral
      tunnel and clear corneal wounds.

PMID- 15013917
TI  - Economic rewarding of smoking cessation-facilitating drugs--a comparison of over
      the-counter and prescribed nicotine replacement therapy.
AB  - Smoking cessation represents a very difficult task for the smoker, often
      requiring medical assistance. The introduction of smoking cessation drugs has
      been crucial to this process. Currently, there are two standardly used
      treatments: nicotine replacement therapy (NRT) and the antidepressant bupropion.
      Soon after their introduction, NRTs were sold over-the-counter (OTC), as oppose
      to on prescription, although in most countries, bupropion remains available only
      on prescription. Both prescribed and OTC NRTs have similar efficacy (i.e., their
      use approximately doubles the cessation rate among users and their use has shown
      a high level of economic rewarding). The most important advantage of OTC NRT is
      availability, as some patients may not be comfortable with the use of prescribed
      drugs. The introduction of OTC NRT has led to a substantial rise in their use,
      increasing the proportion of ex-smokers in the population. However, there are a
      lack of published, cost-benefit analysis data comparing prescription with OTC
      NRT. Considering the different economic, social and cultural conditions within
      particular countries, it is difficult to formulate a common optimal economic
      model for the distribution of NRT. Authentic studies and trials in this field in
      order to develop the appropriate policies in each particular country, are clearly
      required.

PMID- 15013918
TI  - Prevention of coronary heart disease with aspirin and clopidogrel: efficacy,
      safety, costs and cost-effectiveness.
AB  - Atherothrombotic coronary artery disease is the single most common cause of death
      worldwide and a growing public health problem. Platelets play a central role in
      the pathogenesis of atherothrombosis and are therefore commonly targeted by one
      or more antiplatelet drugs as part of primary and secondary atherothrombosis
      prevention strategies. Aspirin reduces the risk of serious vascular events
      (myocardial infarction, stroke or cardiovascular death) by approximately 20% in a
      broad range of high-risk patients and remains the first-line antiplatelet drug
      because of its relative safety, low cost and cost-effectiveness. Compared with
      aspirin alone, clopidogrel reduces the risk of serious vascular events by
      approximately 10% and the combination of aspirin and clopidogrel reduces the risk
      by approximately 20% in patients with non-ST-segment elevation acute coronary
      syndrome. Clopidogrel has a similar safety profile to aspirin but clopidogrel
      tablets are substantially more expensive. However, the incremental cost
      effectiveness ratio of clopidogrel compared with aspirin is favourable,
      particularly in high-risk patients and is intermediate compared with a range of
      other effective therapeutic strategies for the treatment of coronary heart
      disease. Clopidogrel should be considered as a replacement for aspirin in
      patients who are allergic to aspirin, cannot tolerate aspirin, have experienced a
      recurrent atherothrombotic vascular event whilst taking aspirin and are at very
      high absolute risk of a serious vascular event (e.g., > 20%/year). The
      combination of clopidogrel and aspirin should be considered in patients with non
      ST-segment elevation acute coronary syndrome or undergoing percutaneous coronary
      intervention.

PMID- 15013919
TI  - Cost of cancer clinical trials in elderly patients.
AB  - Of all cancers, > 50% currently occur in individuals >or= 65 years of age and
      this figure is expected to rise to 70% by 2030, due to a progressive expansion of
      the older population [1]. Clinical trials are needed in order to establish the
      benefits and risks of antineoplastic treatment in older individuals. It is
      reasonable to expect that the costs of these trials may be higher than in younger
      individuals, as older patients are more vulnerable to therapeutic complications
      and may need more supportive care, and the benefits of treatment may be less
      because of a reduced life-expectancy and competitive causes of death [2]. This
      article explores a cost-effective approach to clinical trials in older
      individuals, after reviewing the basic concepts of economic analysis and unique
      aspects of geriatric oncology that may affect the cost of treatment. In the
      process, the cost differences of cancer treatment in younger and older patients
      will be explored.

PMID- 15013920
TI  - The RTOG Outcomes Model: economic end points and measures.
AB  - Recognising the value added by economic evaluations of clinical trials and the
      interaction of clinical, humanistic and economic end points, the Radiation
      Therapy Oncology Group (RTOG) has developed an Outcomes Model that guides the
      comprehensive assessment of this triad of end points. This paper will focus on
      the economic component of the model. The Economic Impact Committee was founded in
      1994 to study the economic impact of clinical trials of cancer care. A steep
      learning curve ensued with considerable time initially spent understanding the
      methodology of economic analysis. Since then, economic analyses have been
      performed on RTOG clinical trials involving treatments for patients with non
      small cell lung cancer, locally-advanced head and neck cancer and prostate
      cancer. As the care of cancer patients evolves with time, so has the economic
      analyses performed by the Economic Impact Committee. This paper documents the
      evolution of the cost-effectiveness analyses of RTOG from performing average cost
      utility analysis to more technically sophisticated Monte Carlo simulation of
      Markov models, to incorporating prospective economic analyses as an initial end
      point. Briefly, results indicated that, accounting for quality-adjusted survival,
      concurrent chemotherapy and radiation for the treatment of non-small cell lung
      cancer, more aggressive radiation fractionation schedules for head and neck
      cancer and the addition of hormone therapy to radiation for prostate cancer are
      within the range of economically acceptable recommendations. The RTOG economic
      analyses have provided information that can further inform clinicians and policy
      makers of the value added of new or improved treatments.

PMID- 15013921
TI  - Cost-effectiveness of antenatal HIV-testing: reviewing its pharmaceutical and
      methodological aspects.
AB  - This paper reviews the pharmacoeconomic aspects of antenatal testing for HIV. HIV
      is a retrovirus which is transmitted among humans through sexual contact,
      infected blood or blood products (needle sharing or percutaneous accidents) and
      from mother to child (vertical transmission). Vertical transmission from the HIV
      infected mother can occur in utero during and after delivery, through
      breastfeeding. Effective interventions available to reduce the risk of vertical
      transmission include: pharmacotherapy prior, during and after delivery; voluntary
      caesarean section; and replacing breastfeeding by bottle-feeding [1,2]. The
      existence of these effective interventions underlies the need to detect yet
      undiagnosed HIV-infection in pregnancy through antenatal testing. Contemporary
      pharmacotherapy consists of a combination of three or more antiretroviral drugs,
      also referred to as highly-active antiretroviral therapy (HAART). For newly
      detected HIV-infected mothers, the Centers for Disease Control suggests the use
      of a zidovudine-comprising combination with one other nucleoside analogue reverse
      transcriptase inhibitor and a protease inhibitor (PI) [3]. As HIV in pregnancy
      may be asymptomatic, structured antenatal HIV-testing therefore seems to offer an
      attractive prevention strategy. Two broad types of approaches exist: selective or
      targeted testing versus universal testing. The availability of effective - but
      expensive - combination therapies since 1996 has greatly enhanced the importance
      of pharmacoeconomic assessments in the field of HIV-infection. Treatment of the
      mother will incur additional costs but will also make any programme more
      effective. Furthermore, avoiding children becoming infected with HIV will also
      incur monetary benefits, as children are also being treated with HAART. In
      summary, the background of antenatal HIV-testing has undergone major changes
      compared with the early 1990s. This review of the pharmacoeconomics of antenatal
      HIV-testing followed a systematic approach as it was performed according to
      prespecified criteria, allowing valid comparisons in methodologies and findings
      of those studies that have yet been conducted in this area.

PMID- 15013922
TI  - Treatment options in the management of Ascaris lumbricoides.
AB  - Infection with Ascaris lumbricoides constitutes one of the most common helmintic
      diseases in the world, especially in tropical and subtropical regions.
      Transmission of this disease involves environmental contamination with eggs, and
      therefore, is classified as a soil-transmitted disease. The public health
      importance of ascariasis is made evident by the high number of infected
      individuals suffering its consequences, which can become severe, depending on the
      worm burden. Since the introduction of benzimidazoles, chemotherapy has improved
      significantly, offering fast and direct effects at relatively low cost, as a
      result of the simple and safe application of these drugs. Unfortunately, the
      effects are not long-lasting or permanent. The intervention with chemotherapy
      alone constitutes a fast and efficient way to reduce the worm burden in a
      population of high prevalence, but does not avoid reinfection. Therefore, the
      option of integrated control programmes based on chemotherapy in combination with
      sanitation and health education, together with strong community involvement, must
      be considered in order to ensure the positive long-term effects of such
      programmes.

PMID- 15013923
TI  - Macrolide antibiotics: current and future uses.
AB  - After a long history of anti-infective therapeutic use, macrolide antibiotics
      have not yet given up all their secrets. Interest in their therapeutic potential
      in inflammatory diseases (possibly including non-infectious diseases) has
      generated abundant fundamental research and therapeutic trials worldwide. The
      main question regarding the future prospects of this class of drugs is whether
      some macrolides are beneficial in such settings because they modulate host
      inflammatory responses (and cellular targets) or rather because they eliminate a
      latent, unidentified pathogen which triggers chronic inflammation. However, no
      clearcut results have yet been obtained.

PMID- 15013924
TI  - Management of herpes zoster (shingles) and postherpetic neuralgia.
AB  - Herpes zoster (HZ) results from recrudescence of varicella zoster virus latent
      since primary infection (varicella). The overall incidence of HZ is approximately
      3/1000 of the population per year rising to 10/1000 per year by 80 years of age.
      Approximately 50% of individuals reaching 90 years of age will have had HZ. In
      approximately 6%, a second attack may occur (usually several decades after the
      first). Patients with HZ can transmit the virus to a non-immune individual
      causing varicella. HZ is not contracted from individuals with varicella or HZ.
      Reduced cell-mediated immunity to HZ occurs with ageing, explaining the increased
      incidence in the elderly and from other causes such as tumours, HIV and
      immunosuppressant drugs. Diagnosis is usually clinical from typical unilateral
      dermatomal pain and rash. Prodromal symptoms, pain, itching and malaise, are
      common. The most common complication of HZ is postherpetic neuralgia (PHN),
      defined as significant pain or dysaesthesia present >or= 3 months after HZ. PHN
      results from damage and secondary changes within components of the nervous system
      subserving pain. Some motor deficit is common; severe and long-lasting paresis
      may rarely accompany HZ. More than 5% of elderly patients have PHN at 1 year
      after acute HZ. Predictors of PHN are, greater age, acute pain and rash severity,
      prodromal pain, the presence of virus in peripheral blood as well as adverse
      psychosocial factors. Therapy for acute HZ is intended to reduce acute pain,
      hasten rash healing and reduce the risk of PHN and other complications. Antiviral
      drugs are close to achieving these aims but do not entirely remove risk of PHN.
      Oral steroids show no protective effect against PHN. Adequate analgesia during
      the acute phase may require strong opioid drugs. Nerve blocks and tricyclic
      antidepressants (TCAs) may reduce the risk of PHN although firm evidence is
      lacking. PHN requires thorough evaluation and development of a management
      strategy for each individual patient. Initial therapy is with TCAs (e.g.,
      nortriptyline) or the anticonvulsant gabapentin. Topical lidocaine patches
      frequently reduce allodynia. Strong opioids are sometimes required. Topical
      capsaicin cream is beneficial for a small proportion of patients but is poorly
      tolerated. NMDA antagonists have not proved beneficial with the exception of
      ketamine. Transcutaneous Electrical Nerve Stimulation (TENS) may be effective in
      some cases. HZ is a common condition. Severe complications such as stroke,
      encephalitis and myelitis are relatively rare whereas sight threatening
      complications of ophthalmic HZ are more common. PHN is common, distressing and
      often intractable. Good management improves outcome.

PMID- 15013925
TI  - Is acetaminophen, and its combination with pamabrom, an effective therapeutic
      option in primary dysmenorrhoea?
AB  - Primary dysmenorrhoea is the most frequent gynaecological condition, with a
      prevalence of 40 - 90% in women within the reproductive age. It is characterised
      by cyclic pelvic pain related to menstrual period, vomiting and headache. As
      prostaglandins and leukotrienes appear to be a major causative factor in this
      condition, NSAIDs are the first choice for treatment. Acetaminophen is an over
      the-counter analgesic/antipyretic agent widely used in primary dysmenorrhoea as
      monotherapy or in combination. It has a weak inhibitory action on peripheral
      prostaglandin synthesis. Acetaminophen displays good gastrointestinal tolerance
      without any effect on haemostasis. Its combination with pamabrom, a mild diuretic
      agent, (Women s Tylenol Menstrual Relief Caplets, Midol Teen) was approved by the
      FDA for use in this indication. Nevertheless, the available information
      concerning the efficacy of acetaminophen in primary dysmenorrhoea is limited and
      not conclusive with respect to other NSAIDs or even placebo. The clinical
      evidence regarding the association with pamabrom is even more scarce. Well
      designed, randomised, controlled trials are required to demonstrate the efficacy
      of the combination of acetaminophen plus pamabrom in the treatment of primary
      dysmenorrhoea.

PMID- 15013926
TI  - Anti-inflammatory pharmacotherapy during pregnancy.
AB  - NSAIDs or cyclooxygenase inhibitors (COX inhibitors), including aspirin, are
      widely used to treat pain, fever and the articular symptoms of chronic rheumatic
      diseases. Manifestations of connective tissue or autoimmune diseases are commonly
      treated with glucocorticosteroids. The effect and side effects of NSAIDs depend
      on the isoforms of cyclooxygenases that they preferentially or selectively
      inhibit. The use of COX inhibitors has recently been associated with infertility
      and miscarriage. The classical nonselective COX inhibitors, including aspirin, do
      not increase the risk of congenital malformations in humans but administered in
      the latter part of gestation, they can affect pregnancy and the fetus. The
      ability of nonselective and selective COX inhibitors to prolong gestation has
      been used by obstetricians to inhibit premature delivery. The vascular effects of
      prostaglandin inhibitors can cause constriction of the fetal ductus arteriosus
      and reduce renal blood flow. These complications have been described for most
      nonselective COX inhibitors but are increasingly reported also for the selective
      COX-2 inhibitors. Aspirin, which causes irreversible inhibition of
      cyclooxygenases, differs from other NSAIDs with regard to indication, effects and
      side effects. Prematurity, which is increased in pregnancies of women with
      connective tissue diseases, is an additional risk factor for adverse effects of
      antenatal exposure to NSAIDs. Therefore, treatment with COX inhibitors should be
      discontinued at week 32 of gestation. The ability of NSAIDs to compromise
      reproductive function by inhibition of ovulation and as causative agents for
      miscarriage is still under debate. Glucocorticosteroids given in early pregnancy
      are a risk factor for the development of oral clefts. Therefore, the daily dose
      should be kept to <or= 15 mg during the first trimester. High doses of
      glucocorticosteroids in the second and third trimester are reserved for flares of
      autoimmune diseases. Intrauterine fetal growth restriction and premature delivery
      are possible side effects of high doses.

PMID- 15013927
TI  - The use of TNF-alpha blocking agents in rheumatoid arthritis: an overview.
AB  - TNF-alpha has been found to play a pivotal role in the pathogenic mechanisms of
      rheumatoid arthritis (RA). The overexpression of TNF-alpha in RA synovium, the
      data from in vitro synovial cell cultures with the use of anti-TNF-alpha antibody
      and the results from TNF-alpha blockade in animal models of arthritis argued for
      the importance of this cytokine in RA. Drugs targeting TNF-alpha have been
      developed to neutralise the deleterious effects of this inflammatory cytokine.
      There are currently three drugs available in the treatment of RA patients with
      active disease, which was refractory to conventional treatments including
      methotrexate, infliximab (a chimeric mouse/human monoclonal antibody), etanercept
      (a fusion protein combining 2 p75 TNF receptors with a Fc fragment of human IgG
      (1)) and adalimumab (a fully human monoclonal antibody). These three drugs have
      proved to be effective and safe in appropriate and well conducted clinical trials
      and showed effectiveness in slowing and even arresting the progression of
      radiographic damage. With the long-term surveillance of these drugs serious
      adverse events were described, particularly intracellular organism infections
      such as tuberculosis. Other drugs targeting TNF-alpha are in development and
      include monoclonal antibody (CDP571), pegylated molecules (CDP870 and PEG-r-Hu
      sTNF-RI) or soluble p55 TNF receptor construct (lenercept). These new biological
      therapies blocking TNF-alpha undoubtedly constitute a considerable advance in the
      management of RA, but careful evaluation at the initiation of the treatment and
      long-term surveillance of the patients receiving such drugs remains necessary.

PMID- 15013928
TI  - Initial antiretroviral therapy in chronically-infected HIV-positive adults.
AB  - Currently, there are 20 individual antiretroviral drugs and two co-formulation
      products that are approved by the FDA for the treatment of HIV-infected
      individuals. It is widely accepted that the selection of an appropriate first
      line regimen is critical in assuring durable treatment response. This article
      reviews the factors that should be considered in the selection of an initial
      antiretroviral regimen and present the currently available evidence regarding the
      status of individual antiretroviral agents and treatment strategies relative to
      these factors.

PMID- 15013930
TI  - Topical alprostadil cream for the treatment of erectile dysfunction.
AB  - Erectile dysfunction (ED) has serious negative consequences on both sexual
      experience and emotional well being and affects a broad range of age groups. The
      prevalence of ED is associated with increasing age and has been reported to be as
      high as 70%. Although the disorder is common and underdiagnosed, its treatment
      can significantly improve patients' quality of life. Systemic treatment with oral
      phosphodiesterase type-5 (PDE-5) inhibitors is the current standard of care for
      patients with ED. Some patients, however, have absolute contraindications for PDE
      5 inhibitors. In addition, these agents can be associated with adverse effects.
      Furthermore, because PDE-5 inhibitors are not as effective in patients who have
      undergone radical prostatectomy or who have severe vascular disease, a
      substantial unmet medical need exists among patients who have ED as a result of
      these conditions. Consequently, PDE-5 inhibitor therapy is associated with a high
      rate of discontinuation, as are intracavernosal or transurethral therapies, which
      are inconvenient and invasive. Several studies, including four double-blind,
      placebo-controlled, Phase II trials, show that alprostadil topical cream is
      efficacious and well-tolerated in ED in patients with mild-to-severe symptoms, in
      those undergoing treatment for cardiovascular diseases and diabetes and in
      otherwise healthy ED patients. Thus, alprostadil topical cream is a potential
      first-choice alternative for ED in patients who do not respond or who cannot
      tolerate or do not accept PDE-5 inhibitor therapy.

PMID- 15013929
TI  - Arsenic trioxide for the treatment of myelodysplastic syndromes.
AB  - The impressive activity of arsenic trioxide in acute promyelocytic leukaemia
      (APL) has renewed the interest in this old compound. Arsenic trioxide targets the
      sulfhydryl groups present in many proteins involved in oncogenesis and has a
      broad spectrum of biological activities. This article will review the mechanisms
      of action of the drug and their relevance to the treatment of myelodysplastic
      syndrome (MDS), a disease for which no standard treatment currently exists. The
      early clinical experience has confirmed the activity of arsenic trioxide in MDS.
      The preliminary results of ongoing Phase II studies conducted in patients with
      MDS suggest that arsenic trioxide produces haematological improvement including
      durable transfusion independence in approximately 30% of patients. The current
      data are presented and discussed in this review.

PMID- 15013931
TI  - Sibutramine and the management of obesity.
AB  - Sibutramine is a selective serotonin and noradrenaline re-uptake inhibitor
      approved for the long-term management of obesity. Its primary mechanism of action
      is increased satiety, although some evidence also suggests increased energy
      expenditure could play a role in sibutramine-induced weight loss. It has
      established general efficacy in long-term trials, with clinically-approved doses
      of 10 and 15 mg. Sibutramine has also been studied in a number of unique
      populations, including obese controlled hypertensives, diabetics and ethnic
      minorities, further establishing its effectiveness. However, it does have a
      consistent effect of increasing blood pressure and pulse. Thus, blood pressure
      and heart rate should be monitored in patients using sibutramine and it may not
      be applicable in obese patients with significant cardiovascular disease.

PMID- 15013932
TI  - Pimecrolimus for the treatment of inflammatory skin disease.
AB  - Pimecrolimus (SDZ ASM 981, Elidel ) is an ascomycin macrolactam derivative and a
      cell-selective inhibitor of inflammatory cytokines specifically developed to
      treat inflammatory skin diseases. Pimecrolimus combines high anti-inflammatory
      activity in the skin with a low potential to impair systemic immune reactions.
      Multi-centre studies have proved the efficacy and safety of pimecrolimus cream in
      patients with atopic dermatitis (AD) and confirmed that it is suitable for short
      term treatment and long-term management of AD in adults, children and infants as
      young as 3 months. Topical application in humans is not associated with the
      atrophogenic side effects observed with corticosteroids. Pimecrolimus blood
      levels remained consistently low after repeated topical application and no
      clinically relevant drug-related systemic adverse events have been reported among
      the 8000 patients treated in clinical trials so far. Short-term, Phase I/II and
      Phase II trials of pimecrolimus administered orally in psoriasis and AD have
      shown that this drug is highly effective in a dose-dependent manner in patients
      with these diseases and has high safety profile. This finding is confirmed by
      pharmacogenomic blood analysis. Available data thus indicates that pimecrolimus,
      in both the cream and oral formulations, may represent a new option for the
      treatment of inflammatory skin diseases.

PMID- 15013933
TI  - Antihypertensive efficacy of olmesartan medoxomil alone and in combination with
      hydrochlorothiazide.
AB  - Angiotensin receptor blockers (ARBs) are highly effective antihypertensive agents
      with excellent safety profiles. ARBs have been shown to improve cardiovascular
      morbidity and mortality in hypertensive patients with heart failure or diabetic
      nephropathy. For this later class of patients, the American Diabetes Association
      recommends ARBs as the primary treatment option. The ARBs function by blocking
      the binding of angiotensin-II (A-II) to its receptor, thereby inhibiting the
      action of A-II. Unlike the angiotensin-converting enzyme (ACE) inhibitors, which
      block the production of A-II through the ACE pathway, the ARBs effectively
      inhibit A-II regardless of whether it is produced through ACE or some alternate
      enzyme pathway. This difference in action offers a distinct advantage of ARBs
      over ACE inhibitors. Olmesartan medoxomil, the latest addition to the ARB class,
      is a long-acting, safe and well-tolerated antihypertensive drug. The combination
      of olmesartan medoxomil with a low-dose diuretic, potentiates the blood pressure
      lowering effect of either agent alone and is highly effective in achieving the
      recommended blood pressure goals in the majority of patients treated.

PMID- 15013934
TI  - A review of rizatriptan, a quick and consistent 5-HT1B/1D agonist for the acute
      treatment of migraine.
AB  - Rizatriptan is a second-generation triptan marketed as 5 and 10 mg tablets and
      rapidly disintegrating wafer formulations. In > 5000 acute migraine patients
      enrolled in short-term trials and almost 1800 patients in long-term, open-label
      trials treating approximately 47000 attacks, rizatriptan was effective and well
      tolerated. Controlled head-to-head data and a meta-analysis of 53 randomised,
      placebo-controlled trials of oral triptans in > 24000 patients have shown that
      rizatriptan 10 mg offers efficacy advantages over oral sumatriptan 50 and 100 mg
      and other oral triptans, both in terms of speed of onset of action and
      consistency. These advantages may reflect its improved pharmacological profile
      over sumatriptan in terms of higher oral bioavailability and a shorter time to
      maximum concentration. The wafer formulation offers the convenience of being
      administered without water. As a result of its superior efficacy profile and
      generally good tolerability, rizatriptan can be considered as a first-line
      treatment for acute migraine.

PMID- 15013935
TI  - A review of montelukast in the treatment of asthma and allergic rhinitis.
AB  - Montelukast sodium (Singulair, Merck) is a selective and orally-active
      leukotriene-receptor antagonist (LTRA) that inhibits the cysteinyl leukotriene 1
      (CysLT1) receptor. Montelukast is an effective and well-tolerated preventative
      treatment for asthma and allergic rhinitis in adults and children. The upper and
      lower airway show similar inflammatory responses to allergen challenge.
      Leukotrienes are inflammatory mediators that are known as the slow-reacting
      substance of anaphylaxis produced by a number of cell types including mast cells,
      eosinophils, basophils, macrophages and monocytes. Synthesis of these mediators
      results from the cleavage of arachidonic acid in cell membranes and they exert
      their biological effects by binding and activating specific receptors. This
      occurs in a series of events that lead to contraction of the human airway smooth
      muscle, chemotaxis and increased vascular permeability. These effects have led to
      their important role in the diseases of asthma and allergic rhinitis. As these
      agents lead to the production of symptoms in patients that are asthmatic or
      allergic, the use of LTRAs, particularly montelukast, may seem appropriate.
      Clinical trials have shown that montelukast is effective and safe in the
      treatment of patients with asthma, allergic rhinitis or both diseases.

PMID- 15013936
TI  - Candesartan for the prevention and treatment of stroke - results of the SCOPE and
      ACCESS trials.
AB  - Stroke is a leading cause of death and disability. The SCOPE clinical trial
      assessed the effects of the angiotensin Type 1 (AT(1))-receptor antagonist,
      candesartan, on major cardiovascular events in elderly hypertensive patients. A
      first major cardiovascular event (cardiovascular death, non-fatal myocardial
      infarction or non-fatal stroke) occurred to a lesser extent in the candesartan
      group (242 of 2477) than the placebo group (268 of 2460) and this difference
      represented a reduction in stroke rather than cardiac events. The ACCESS trial
      was designed to assess the safety of a modest blood pressure reduction with the
      AT 1 -receptor antagonist, candesartan, in the early treatment of stroke. What
      ACCESS actually showed was that, in the absence of blood pressure lowering,
      candesartan treatment for 7 days, started within 24 h of motor deficit associated
      with stoke, reduced the cumulative 12-month mortality rate (7.2 and 2.9% for
      placebo and candesartan, respectively) and vascular events (18.7 and 9.8% for
      placebo and candesartan, respectively). In conclusion, candesartan is safe to use
      in the prevention and treatment of acute stroke, and may provide therapeutic
      benefits.

PMID- 15013937
TI  - A review of the Vaccine Adverse Event Reporting System database.
AB  - The Vaccine Adverse Event Reporting System (VAERS) is an epidemiological database
      that has been maintained by the FDA and Centers for Disease Control and
      Prevention (CDC) since 1990. Authors from the National Immunization Programme of
      the CDC have previously described an epidemiological technique to make
      qualitative and quantitative measurement in the VAERS database. Application of
      this technique by ourselves (with further refinements and additions) have
      resulted in numerous publications showing the VAERS database has good positive
      predictive value in evaluating vaccine safety concerns that are compatible with
      observations by many other authors who have analysed different databases. In
      conclusion, VAERS studies will be particularly critical in the evaluation of the
      safety of many new or radically changed vaccines expected to be introduced in the
      relative near future.

PMID- 15013939
TI  - Potential new strategies to prevent the development of diabetic retinopathy.
AB  - Recent studies have demonstrated that diabetic retinopathy has several
      characteristics of a chronic inflammatory disease, such as increased nitric oxide
      production, intracellular adhesion molecule-1 upregulation, leukostasis and
      increased vascular permeability. In addition, diabetes leads to the activation of
      caspase-1, the enzyme responsible for the production of the pro-inflammatory
      cytokines IL-1beta and IL-18 in the retinae of diabetic animals and diabetic
      patients. Minocycline, a second-generation tetracycline derivative, was able to
      prevent the activation of capase-1 in the retinae of diabetic mice. Therefore,
      this review is focused on discussing the role of caspase-1 as a mediator of
      chronic inflammation and/or apoptosis inducer in the development of diabetic
      retinopathy and the suitability of caspase-1 as a new potential therapeutic
      target.

PMID- 15013938
TI  - Gut peptides in the treatment of diabetes mellitus.
AB  - It has been known for at least one century that agents secreted from the
      intestine during meal absorption regulates glucose assimilation. Extensive
      research during the past three decades has identified two gut hormones, glucagon
      like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, also
      known as gastric inhibitory polypeptide) that are important in postprandial
      glucose metabolism. Both peptides are incretins; they are secreted during
      carbohydrate absorption and increase insulin secretion. Since they are potent
      insulin secretagogues, GIP and GLP-1 have received considerable attention as
      potential diabetes therapeutics. However, only GLP-1 exerts insulinotropic
      properties when administered to patients with Type 2 diabetes. Both GLP-1 and GIP
      are rapidly inactivated in the circulation by the enzyme dipeptidyl peptidase IV
      (DPP-IV). The application of GLP-1 into clinical practice has been delayed due to
      the need to develop compounds that overcome this rapid inactivation. Two
      approaches have been taken to utilise the insulinotropic and glucose-lowering
      actions of GLP-1 as an antidiabetic agent: the development of DPP-IV-resistant
      analogues and the inhibition of DPP-IV. This review focuses on the physiology of
      GLP-1 and GIP and the advances that have been made thus far in developing
      treatments based on these physiological incretins for Type 2 diabetes.

PMID- 15013940
TI  - Recent advances in protein tyrosine phosphatase 1B inhibitors.
AB  - Type 2 diabetes and obesity are characterised by insulin and leptin resistance.
      Studies suggest that these may be due to defects in the insulin and leptin
      signalling pathways. Over the last decade, a considerable body of evidence has
      been amassed indicating that protein tyrosine phosphatase 1B (PTP1B) is involved
      in the downregulation of insulin and leptin signalling. Consequently, compounds
      that inhibit PTP1B have potential as therapeutics for treating Type 2 diabetes
      and obesity. This review covers recent advances in PTP1B inhibitors with an
      emphasis on recent attempts to create potent, selective and cell-permeable small
      molecule inhibitors.

PMID- 15013941
TI  - Peroxisome proliferator-activated receptor-gamma: therapeutic target for diseases
      beyond diabetes: quo vadis?
AB  - The discovery that the insulin-sensitising thiazolidinediones (TZDs), specific
      peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, have
      antiproliferative, anti-inflammatory and immunomodulatory effects has led to the
      evaluation of their potential use in the treatment of diabetic complications and
      inflammatory, proliferative diseases in non-insulin-resistant, euglycaemic
      individuals. Apart from improving insulin resistance, plasma lipids and systemic
      inflammatory markers, ameliorating atherosclerosis and preventing coronary artery
      restenosis in diabetic subjects, currently approved TZDs have been shown to
      improve psoriasis and ulcerative colitis in euglycaemic human subjects. These
      data imply that the activation of PPAR-gamma may improve cardiovascular risk
      factors and cardiovascular outcomes in both insulin-resistant diabetic and non
      diabetic individuals. Through their immunomodulatory and anti-inflammatory
      actions, TZDs and other PPAR-gamma agonists may prove to be effective in treating
      diseases unrelated to insulin resistance, such as autoimmune (e.g., multiple
      sclerosis), atopic (e.g., asthma, atopic dermatitis) and other inflammatory
      diseases (e.g., psoriasis, ulcerative colitis). Newer and safer selective PPAR
      gamma agonists are presently under development. Furthermore, of considerable
      interest is the recent discovery that a unique subset of currently prescribed
      antihypertensive angiotensin II Type 1 receptor antagonists has selective PPAR
      gamma-modulating activity. These discoveries pave the way for the development of
      drugs for treating chronic multigenic cardiovascular and metabolic diseases, for
      which therapy is presently insufficient or non-existent. The potential utility of
      the currently available TZDs rosiglitazone and pioglitazone and PPAR-gamma
      modulating angiotensin II Type 1 receptor antagonists in treating cardiovascular,
      metabolic and inflammatory diseases in insulin resistant and euglycaemic states
      is of immense clinical potential and should be investigated.

PMID- 15013942
TI  - Calcium agonists in hyperparathyroidism.
AB  - Primary hyperparathyroidism (PHPT), in addition to cancer, represents an
      important cause of hypercalcaemia in the general population. Furthermore,
      hypercalcaemia, in the course of uraemic HPT, represents the late stage of
      chronic renal failure refractory to therapy. Neck surgery is still the only
      curative approach for these forms of HPT and medical treatment rarely exhibits an
      effective control on HPT and HPT-dependent hypercalcaemia. Moreover, some HPT
      patients may not undergo neck surgery due to the presence of other concomitant
      disorders. Therefore, more effective therapeutic approaches are needed than the
      commonly used 'palliative' treatments. The identification of a specific membrane
      receptor able to bind extracellular calcium on cells of the parathyroid and other
      tissues has allowed the development of new molecules acting through this receptor
      to reduce both parathyroid hormone secretion and the rate of parathyroid cell
      proliferation. Consequently, they may substantially contribute to the regulation
      of bloodstream calcium levels in HPT patients. Preliminary results obtained in
      clinical trials are encouraging, demonstrating a good efficacy and safety of such
      drugs. However, more in vitro and in vivo, as well as long-term clinical studies,
      will be necessary before they can be commonly used as therapeutical molecules in
      the clinical practice.

PMID- 15013943
TI  - The therapeutic potential of angiotensin II receptor blockers in the treatment of
      heart failure.
AB  - In clinical heart failure (HF) the renin-angiotensin-aldosterone system is an
      important component of neurohormonal activation. Angiotensin-converting enzyme
      inhibitors have been shown to be of great clinical benefit in reducing the
      production of angiotensin II. However, they do not fully suppress angiotensin II
      production in HF because there are other pathways through which angiotensin II
      can be produced. Theoretically, angiotensin II receptor blockers (ARBs) have
      great potential because of their ability to directly block angiotensin II
      produced through any pathway. A large body of literature has accumulated
      examining the effects of ARBs in HF. The earlier, smaller studies examined
      outcomes such as symptoms, neurohormonal concentrations and cardiac function.
      More recent, larger studies have examined the effects of ARBs on mortality and
      morbidity. This paper reviews the data defining the role of ARBs in the treatment
      of HF patients, focusing more on the large randomised clinical outcome trials.

PMID- 15013944
TI  - New therapies for chronic obstructive pulmonary disease.
AB  - Chronic obstructive pulmonary disease (COPD) is the most common lung disease,
      carrying a significant mortality and morbidity. None of the therapeutic
      interventions currently available alter the progression of the disease. As our
      understanding of the basic mechanisms of alveolar destruction and airflow
      limitation improves, new targets are identified that may eventually result in
      treatment options which will affect the progression of this disease. In this
      review, we discuss some of the novel therapeutic options recently developed that
      may have an impact on the management of COPD. Future directions in research and
      development of pharmacological agents based on improved understanding of COPD are
      also discussed.

PMID- 15013945
TI  - Camptothecins in clinical development.
AB  - Following the realisation that DNA topoisomerase I is a useful therapeutic target
      to be exploited for the design of potential inhibitors, topoisomerase I
      inhibitors now represent an established class of effective agents. In spite of
      intense efforts in the field, only camptothecins have a clinical relevance.
      Several options in chemical manipulation of natural camptothecin have been
      explored to overcome the major drawbacks of the drug, which include water
      insolubility, lactone instability, reversibility of the drug-target interaction
      and drug resistance. Several analogues are currently in clinical development,
      including water soluble camptothecins, lipophilic camptothecins and polymer-bound
      camptothecins. The therapeutic advantages of novel camptothecins over the two
      analogues (topotecan and irinotecan) approved for clinical use remain to be
      defined. This article is an overview of the relevant features of the analogues
      that are undergoing clinical development.

PMID- 15013946
TI  - Can food intake be reduced with peptide YY3-36?
AB  - Obesity shortens life expectancy. The peripheral administration of peptide YY3-36
      (PYY3-36) inhibits food intake in mice and rats. The effects of PYY3-36 on food
      intake have been assessed in obese and lean subjects in a double-blind, placebo
      controlled, cross-over study. In fasting obese and lean subjects, infusion of
      PYY3-36 reduced the caloric intake in 24 h by 17 and 24%, respectively. Long-term
      studies to determine whether PYY3-36 reduces food intake in freely fed humans are
      now required.

PMID- 15013947
TI  - HEP DART 2003: Frontiers in drug development for viral hepatitis.
AB  - The biannual HEP DART conference in Hawaii provided an intimate setting for
      members of the viral hepatitis community to exchange ideas and information. The
      leaders in clinical research and drug development gathered with scientists to
      discuss the recent advances in a field dedicated to understanding and treating
      hepatitis. The topics ranged from the basic science of pathogenesis and
      therapeutic models, to the next generation of hepatitis B and hepatitis C virus
      inhibitors, to the important therapeutic information gleaned from the latest
      clinical trials. The therapeutic considerations for special populations, such as
      those co-infected with HIV, those with decompensated liver diseases or difficult
      to-treat genotypes, as well as those patients who have failed treatment, emerged
      as critical clinical topics under discussion.

PMID- 15013948
TI  - Incidence of breast cancer in Norway and Sweden during introduction of nationwide
      screening: prospective cohort study.
AB  - OBJECTIVE: To determine whether any increase in the incidence of breast cancer in
      women detected by mammography is compensated for by a drop in the incidence after
      age 69, years when women are no longer invited for screening. DESIGN: Population
      based cohort study of incidence of breast cancer during the introduction of
      nationwide screening programmes. SETTING: Norway and Sweden. PARTICIPANTS: All
      women aged above 30 years (1.4 and 2.9 million, respectively, in 2000). MAIN
      OUTCOME MEASURES: Changes in age specific incidence rates of invasive breast
      cancer associated with the introduction of the screening programmes. RESULTS: As
      a result of screening the recorded incidence of breast cancer in women aged 50-69
      years increased by 54% in Norway and 45% in Sweden. There was no corresponding
      decline in incidence after the age of 69 years. CONCLUSIONS: Without screening
      one third of all invasive breast cancers in the age group 50-69 years would not
      have been detected in the patients' lifetime. This level of overdiagnosis is
      larger than previously reported.

PMID- 15013949
TI  - Overexpression or ablation of JNK in skeletal muscle has no effect on glycogen
      synthase activity.
AB  - c-Jun NH(2)-terminal kinase (JNK) is highly expressed in skeletal muscle and is
      robustly activated in response to muscle contraction. Little is known about the
      biological functions of JNK signaling in terminally differentiated muscle cells,
      although this protein has been proposed to regulate insulin-stimulated glycogen
      synthase activity in mouse skeletal muscle. To determine whether JNK signaling
      regulates contraction-stimulated glycogen synthase activation, we applied an
      electroporation technique to induce JNK overexpression (O/E) in mouse skeletal
      muscle. Ten days after electroporation, in situ muscle contraction increased JNK
      activity 2.6-fold in control muscles and 15-fold in the JNK O/E muscles. Despite
      the enormous activation of JNK activity in JNK O/E muscles, contraction resulted
      in similar increases in glycogen synthase activity in control and JNK O/E
      muscles. Consistent with these findings, basal and contraction-induced glycogen
      synthase activity was normal in muscles of both JNK1- and JNK2-deficient mice.
      JNK overexpression in muscle resulted in significant alterations in the basal
      phosphorylation state of several signaling proteins, such as extracellular signal
      regulated kinase 1/2, p90 S6 kinase, glycogen synthase kinase 3, protein kinase
      B/Akt, and p70 S6 kinase, in the absence of changes in the expression of these
      proteins. These data suggest that JNK signaling regulates the phosphorylation
      state of several kinases in skeletal muscle. JNK activation is unlikely to be the
      major mechanism by which contractile activity increases glycogen synthase
      activity in skeletal muscle.

PMID- 15013950
TI  - Expression of the 56-kDa B2 subunit isoform of the vacuolar H(+)-ATPase in proton
      secreting cells of the kidney and epididymis.
AB  - B1 and B2 are two highly homologous isoforms of the vacuolar H(+)-ATPase (V
      ATPase) 56-kDa B subunit. We investigated whether the B2 subunit is expressed
      alongside B1 in proton-secreting cells of the rodent kidney collecting duct
      (intercalated cells, IC) and epididymis (clear cells) by using antibodies against
      distinct COOH-terminal peptides from the two B isoforms. B2 was detected not only
      in the kidney proximal tubule, thick ascending limb, distal convoluted tubule,
      and connecting segment but also in A- and B-type IC of collecting ducts (CD) in
      both rat and mouse. B2 had a predominant cytoplasmic localization in most IC but
      was clearly located in a tighter apical band together with the V-ATPase 31-kDa E
      subunit in some A-IC, especially in the medulla. Apical membrane staining was
      confirmed by immunogold electron microscopy. B2 was very weakly expressed on the
      basolateral membranes of B-IC in control kidney CD, but some connecting segment B
      IC had more distinct basolateral staining. In response to chronic carbonic
      anhydrase inhibition by acetazolamide, many A-IC showed a strong apical membrane
      localization of B2, where it colocalized with E and B1. In rat and mouse
      epididymis, B2 isoform expression was detected in clear cells, where it was
      concentrated in subapical vesicles. Unlike B1, B2 did not colocalize with the E
      subunit in the apical microvilli. These findings indicate that in addition to its
      role in the acidification of intracellular organelles, the B2 isoform could also
      contribute to transepithelial proton secretion and the maintenance of acid-base
      homeostasis.

PMID- 15013951
TI  - Obscurin regulates the organization of myosin into A bands.
AB  - Obscurin is a giant sarcomeric protein composed of adhesion modules and signaling
      domains. It surrounds myofibrils at the level of the Z disk and the M line. To
      study the role of obscurin during myofibrillogenesis, we used adenovirus-mediated
      gene delivery to overexpress part of its COOH terminus in primary cultures of
      postnatal day 1 (P1) skeletal myotubes. Examination of the subcellular
      distribution of a number of sarcomeric proteins revealed that the organization of
      myosin into A bands was dramatically reduced. Myosin assembled into A bands
      normally in mock- or control-infected P1 myotubes. Overexpression of the COOH
      terminus of obscurin did not affect the organization of other sarcomeric markers,
      including actin, alpha-actinin, titin, and myomesin. Assembly of myomesin into
      nascent M lines in treated myotubes suggests that these structures can form
      independently of A bands. Immunoblot analysis indicated that there was a small (
      approximately 20%) but consistent decrease in the amount of myosin expressed in
      cells infected with the COOH terminus of obscurin. Coimmunoprecipitation
      experiments in which we used adult skeletal muscle homogenates demonstrated that
      obscurin exists in a complex with myosin. Thus our findings suggest that the COOH
      terminal region of obscurin interacts with sarcomeric myosin and may play a
      critical role in its ability to assemble into A bands in striated muscle.

PMID- 15013952
TI  - Rapid desensitization of G protein-gated inwardly rectifying K(+) currents is
      determined by G protein cycle.
AB  - Activation of G protein-gated inwardly rectifying K(+) (GIRK) channels, found in
      the brain, heart, and endocrine tissue, leads to membrane hyperpolarization that
      generates neuronal inhibitory postsynaptic potentials, slows the heart rate, and
      inhibits hormone release. During stimulation of G(i/o)-coupled receptors and
      subsequent channel activation, it has been observed that the current
      desensitizes. In this study we examined mechanisms underlying fast
      desensitization of cloned heteromeric neuronal Kir3.1+3.2A and atrial Kir3.1+3.4
      channels and also homomeric Kir3.0 currents in response to stimulation of several
      G(i/o) G protein-coupled receptors (GPCRs) expressed in HEK-293 cells (adenosine
      A(1), adrenergic alpha(2A), dopamine D(2S), M(4) muscarinic, and GABA(B1b/2)
      receptors). We found that all agonist-induced currents displayed a similar degree
      of desensitization except the adenosine A(1) receptor, which exhibits an
      additional desensitizing component. Using the nonhydrolyzable GTP analog
      guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS), we found that this is due to a
      receptor-dependent, G protein-independent process. Using Ca(2+) imaging we showed
      that desensitization is unlikely to be accounted for solely by phospholipase C
      activation and phosphatidylinositol 4,5-bisphosphate (PIP(2)) hydrolysis. We
      examined the contribution of the G protein cycle and found the following. First,
      agonist concentration is strongly correlated with degree of desensitization.
      Second, competitive inhibition of GDP/GTP exchange by using nonhydrolyzable
      guanosine 5'-O-(2-thiodiphosphate) (GDPbetaS) has two effects, a slowing of
      channel activation and an attenuation of the fast desensitization phenomenon.
      Finally, using specific Galpha subunits we showed that ternary complexes with
      fast activation rates display more prominent desensitization than those with
      slower activation kinetics. Together our data suggest that fast desensitization
      of GIRK currents is accounted for by the fundamental properties of the G protein
      cycle.

PMID- 15013953
TI  - Increased tolerance to oxygen and glucose deprivation in astrocytes from
      Na(+)/H(+) exchanger isoform 1 null mice.
AB  - The ubiquitously expressed Na(+)/H(+) exchanger isoform 1 (NHE1) functions as a
      major intracellular pH (pH(i)) regulatory mechanism in many cell types, and in
      some tissues its activity may contribute to ischemic injury. In the present
      study, cortical astrocyte cultures from wild-type (NHE1(+/+)) and NHE1-deficient
      (NHE1(-/-)) mice were used to investigate the role of NHE1 in pH(i) recovery and
      ischemic injury in astrocytes. In the absence of HCO(3)(-), the mean resting
      pH(i) levels were 6.86 +/- 0.03 in NHE1(+/+) astrocytes and 6.53 +/- 0.04 in
      NHE1(-/-) astrocytes. Removal of extracellular Na(+) or blocking of NHE1 activity
      by the potent NHE1 inhibitor HOE-642 significantly reduced the resting level of
      pH(i) in NHE1(+/+) astrocytes. NHE1(+/+) astrocytes exhibited a rapid pH(i)
      recovery (0.33 +/- 0.08 pH unit/min) after NH(4)Cl prepulse acid load. The pH(i)
      recovery in NHE1(+/+) astrocytes was reversibly inhibited by HOE-642 or removal
      of extracellular Na(+). In NHE1(-/-) astrocytes, the pH(i) recovery after
      acidification was impaired and not affected by either Na(+)-free conditions or
      HOE-642. Furthermore, 2 h of oxygen and glucose deprivation (OGD) led to an
      approximately 80% increase in pH(i) recovery rate in NHE1(+/+) astrocytes. OGD
      induced a 5-fold rise in intracellular [Na(+)] and 26% swelling in NHE1(+/+)
      astrocytes. HOE-642 or genetic ablation of NHE1 significantly reduced the Na(+)
      rise and swelling after OGD. These results suggest that NHE1 is the major pH(i)
      regulatory mechanism in cortical astrocytes and that ablation of NHE1 in
      astrocytes attenuates ischemia-induced disruption of ionic regulation and
      swelling.

PMID- 15013954
TI  - Cortico-striatal contributions to feedback-based learning: converging data from
      neuroimaging and neuropsychology.
AB  - The striatum has been widely implicated in cognition, but a precise understanding
      of its role remains elusive. Here we present converging evidence for the role of
      the striatum in feedback-based learning. In a prior functional imaging study,
      healthy controls showed striatal activity during a feedback-based learning task,
      which was decreased when the same task was learned without feedback. In the
      present study, we show that individuals with striatal dysfunction due to
      Parkinson's disease are impaired on the feedback-based task, but not on a non
      feedback version of the same task. Parkinson's patients and controls also used
      different learning strategies depending on feedback structure. This study
      provides direct behavioural evidence from humans that cortico-striatal systems
      are necessary for feedback-based learning on a cognitive task. These findings
      also link between learning impairments in Parkinson's disease and the
      physiological and computational evidence for the role of midbrain dopaminergic
      systems in feedback processing.

PMID- 15013955
TI  - CSF quinolinic acid levels are determined by local HIV infection: cross-sectional
      analysis and modelling of dynamics following antiretroviral therapy.
AB  - Quinolinic acid (QUIN) is a product of tryptophan metabolism that can act as an
      endogenous brain excitotoxin when released by activated macrophages. Previous
      studies have shown correlations between increased CSF QUIN levels and the
      presence of the AIDS dementia complex (ADC), a neurodegenerative condition
      complicating late-stage human immunodeficiency virus type 1 (HIV) infection in
      some patients. CSF QUIN is putatively one of the important molecular mediators of
      the brain injury in this clinical setting and, more generally, serves as a marker
      of local macrophage activation. This study was undertaken to examine the
      relationship of CSF QUIN concentrations to local HIV infection and to define the
      effects of antiretroviral drug treatment on CSF QUIN using two complementary
      approaches. The first was an exploratory cross-sectional analysis of a clinically
      heterogeneous sample of 62 HIV-infected subjects, examining correlations of CSF
      QUIN levels with CSF and plasma HIV RNA levels and other salient parameters of
      infection. The second involved longitudinal observations of a subset of 20 of
      these subjects who initiated new antiretroviral therapy regimens. In addition to
      descriptive analysis, we used kinetic modelling of QUIN decay in relation to that
      of HIV RNA to assess further the relationship between CSF QUIN and infection in
      the dynamic setting of treatment. The cross-sectional studies showed strong
      correlations of CSF QUIN with both CSF HIV RNA and blood QUIN levels, as well as
      with elevations in CSF white blood cells, CSF total protein and CSF:blood albumin
      ratio. In this group of subjects with a low incidence of active, untreated ADC,
      CSF QUIN did not correlate with ADC stage or measures of quantitative
      neurological performance. Antiviral treatment reduced the CSF QUIN levels in all
      the longitudinally followed, treated subjects. Kinetic modelling of CSF QUIN
      decay indicated that CSF QUIN levels were driven primarily by CSF HIV infection
      with a lesser contribution from blood QUIN levels. In three subjects with new
      onset, untreated ADC, CSF QUIN decay paralleled both CSF HIV decrement and
      improvement in neurological performance. These studies show that CSF QUIN
      concentrations relate primarily to active CSF HIV infection and to a lesser
      extent to plasma QUIN. CSF QUIN serves as a marker of local infection with a wide
      dynamic range. The time course of therapy-induced changes links CSF QUIN to local
      infection and supports the action of antiviral therapy in ameliorating
      immunopathological brain injury and ADC.

PMID- 15013957
TI  - Editorial II: Preoperative hypertension: remain wary? "Yes"--cancel surgery?
      "No".

PMID- 15013956
TI  - Editorial I: Spinal anaesthesia for Caesarean delivery: keep the pressure up and
      don't spare the vasoconstrictors.

PMID- 15013958
TI  - Editorial III: Tissue oxygen tension (PTO2) in anaesthesia and perioperative
      medicine.

PMID- 15013959
TI  - Supplementary oxygen for elective Caesarean section under spinal anaesthesia:
      useful in prolonged uterine incision-to-delivery interval?
AB  - BACKGROUND: The benefit of administering supplementary oxygen during elective
      Caesarean section under regional anaesthesia is controversial. It has been
      hypothesized that its use would improve fetal oxygenation in the event of a
      prolonged uterine incision-to-delivery (U-D) interval. Our aim was to test this
      hypothesis in a prospective, randomized, double-blinded, controlled study.
      METHODS: We allocated randomly 204 women having elective Caesarean section under
      spinal anaesthesia to breathe 21, 40 or 60% oxygen. We recorded the U-D interval,
      umbilical arterial (UA) and venous (UV) blood gases and oxygen content and Apgar
      scores. Subgroup analysis was performed according to whether the U-D interval was
      prolonged (>180 s) or not. RESULTS: The U-D interval was <180 s in 159 patients
      and >180 s in 45 patients. There were no differences in UV or UA blood gases,
      oxygen content or Apgar scores between cases with and without a prolonged U-D
      interval. In cases without a prolonged U-D interval, administering 60% oxygen
      increased UV PO(2) (mean 4.3 (SD 1.1) vs 3.7 (1.0) kPa, P=0.003) and oxygen
      content (14.4 (3.3) vs 12.9 (2.7) ml dl(-1), P=0.007) compared with air. In cases
      with a prolonged U-D interval, administering 60% oxygen increased UV PO(2) (4.6
      (0.6) vs 3.9 (0.8) kPa, P=0.019) compared with air but there was no difference in
      UV oxygen content. There was no increase in the UV PO(2) or oxygen content when
      40% oxygen was administered compared with air. CONCLUSIONS: Supplementary oxygen
      did not increase fetal oxygenation in cases where the U-D interval was prolonged.
      Our data do not support the routine administration of supplementary oxygen during
      elective Caesarean section for this purpose.

PMID- 15013961
TI  - Should perioperative management target oxygen delivery?

PMID- 15013960
TI  - Hypertension, hypertensive heart disease and perioperative cardiac risk.
AB  - The evidence for an association between hypertensive disease, elevated admission
      arterial pressure, and perioperative cardiac outcome is reviewed. A systematic
      review and meta-analysis of 30 observational studies demonstrated an odds ratio
      for the association between hypertensive disease and perioperative cardiac
      outcomes of 1.35 (1.17-1.56). This association is statistically but not
      clinically significant. There is little evidence for an association between
      admission arterial pressures of less than 180 mm Hg systolic or 110 mm Hg
      diastolic and perioperative complications. The position is less clear in patients
      with admission arterial pressures above this level. Such patients are more prone
      to perioperative ischaemia, arrhythmias, and cardiovascular lability, but there
      is no clear evidence that deferring anaesthesia and surgery in such patients
      reduces perioperative risk. We recommend that anaesthesia and surgery should not
      be cancelled on the grounds of elevated preoperative arterial pressure. The
      intraoperative arterial pressure should be maintained within 20% of the best
      estimate of preoperative arterial pressure, especially in patients with markedly
      elevated preoperative pressures. As a result, attention should be paid to the
      presence of target organ damage, such as coronary artery disease, and this should
      be taken into account in preoperative risk evaluation. The anaesthetist should be
      aware of the potential errors in arterial pressure measurements and the impact of
      white coat hypertension on them. A number of measurements of arterial pressure,
      obtained by competent staff (ideally nursing staff), may be required to obtain an
      estimate of the "true" preoperative arterial pressure.

PMID- 15013962
TI  - Effect of adding dopexamine to intraoperative volume expansion in patients
      undergoing major elective abdominal surgery.

PMID- 15013963
TI  - Intra-atrial ECG guidance for positioning central vein catheters.

PMID- 15013964
TI  - Intraoperative blood transfusions.

PMID- 15013966
TI  - Inadvertence refers to a lack of attention.

PMID- 15013965
TI  - Endobronchial intubation.

PMID- 15013967
TI  - Heads up display.

PMID- 15013968
TI  - Antibody response of healthy adults to recombinant thrombospondin-related
      adhesive protein of cryptosporidium 1 after experimental exposure to
      cryptosporidium oocysts.
AB  - Thrombospondin-related adhesive protein of Cryptosporidium 1 (TRAP-C1) belongs to
      a group of proteins that are also found in Toxoplasma gondii, Eimeria tenella,
      and Plasmodium species. TRAP-related proteins are needed for gliding motility,
      host-cell attachment, and invasion. The objective of this study was to
      characterize the antibody response to recombinant TRAP-C1 (rTRAP-C1) in healthy
      volunteers exposed to C. parvum and their association with clinical illness. A
      total of 31 healthy adult volunteers participated. Seven volunteers received the
      C. parvum TAMU isolate (inocula, 10 to 300 oocysts), and 24 volunteers received
      the C. parvum UCP isolate (500 to 10(5) oocysts). The total antibody
      (immunoglobulin M [IgM], IgG, and IgA) response to rTRAP C-1 was measured by
      enzyme-linked immunosorbent assays prior to and after exposure to Cryptosporidium
      parvum (days 0 to 45). Results of this study showed that individuals who were
      uninfected demonstrated higher reactivity at baseline compared to those who
      became infected. After challenge, increases in antibody reactivity were seen on
      days 30 and 45 compared to the results seen on days 0 to 5. The increases in
      antibody reactivity were statistically significant in subjects with diarrhea and
      with or without detectable oocysts compared to the results seen with those who
      were uninfected and asymptomatic. These findings suggest that increases in
      antibody reactivity to rTRAP-C1 occur after recent exposure to C. parvum.

PMID- 15013969
TI  - Depressed type 1 cytokine synthesis by superantigen-activated CD4+ T cells of
      women with human papillomavirus-related high-grade squamous intraepithelial
      lesions.
AB  - Carcinoma of the cervix is causally related to infection with the human
      papillomavirus (HPV), and T cells play a pivotal role in the immune response of
      the host to rid itself of HPV infection. Therefore, we assessed the T-cell
      function of women with HPV-related cervical neoplasia against a superantigen,
      Staphylococcus enterotoxin B (SEB). Each woman provided a cervical brush specimen
      for HPV DNA testing and Papanicolaou (Pap) smears for the staging of cervical
      lesions. They also provided a blood specimen for determination of the ability of
      CD4(+) T and CD8(+) T cells to synthesize Th1 (interleukin-2 [IL-2], gamma
      interferon [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]) and Th2 (IL
      10) cytokines in response to activation with SEB. Compared with control subjects
      with self-attested negative Pap smears, women with high-grade squamous
      intraepithelial lesions (HSIL) had significantly lower percentages of activated
      CD4(+) T cells that produced IL-2 (P = 0.045), IFN-gamma (P = 0.040), and TNF
      alpha (P = 0.015) and a significantly lower percentage of activated CD8(+) T
      cells that produced IL-2 (P < 0.01). These data indicate that women with HPV
      related cervical HSIL show a decrease in Th1 cytokine production by activated
      CD4(+) T cells and suggested that compromised T-helper functions may negatively
      impact the function of cytotoxic CD8(+) T cells.

PMID- 15013970
TI  - Development of a nucleoprotein-based enzyme-linked immunosorbent assay using a
      synthetic peptide antigen for detection of avian metapneumovirus antibodies in
      Turkey sera.
AB  - Avian metapneumoviruses (aMPV) cause an upper respiratory tract disease with low
      mortality but high morbidity, primarily in commercial turkeys, that can be
      exacerbated by secondary infections. There are three types of aMPV, of which type
      C is found only in the United States. The aMPV nucleoprotein (N) amino acid
      sequences of serotypes A, B, and C were aligned for comparative analysis. On the
      basis of the predicted antigenicity of consensus sequences, five aMPV-specific N
      peptides were synthesized for development of a peptide antigen enzyme-linked
      immunosorbent assay (aMPV N peptide-based ELISA) to detect aMPV-specific
      antibodies among turkeys. Sera from naturally and experimentally infected turkeys
      were used to demonstrate the presence of antibodies reactive to the chemically
      synthesized aMPV N peptides. Subsequently, aMPV N peptide 1, which had the
      sequence 10-DLSYKHAILKESQYTIKRDV-29, with variations at only three amino acids
      among aMPV serotypes, was evaluated as a universal aMPV ELISA antigen. Data
      obtained with the peptide-based ELISA correlated positively with total aMPV viral
      antigen-based ELISAs, and the peptide ELISA provided higher optical density
      readings. The results indicated that aMPV N peptide 1 can be used as a universal
      ELISA antigen to detect antibodies for all aMPV serotypes.

PMID- 15013972
TI  - Comparison of benchtop microplate beta counters with the traditional gamma
      counting method for measurement of chromium-51 release in cytotoxic assays.
AB  - The most traditional method used to measure the lytic activity of cytotoxic T
      lymphocytes or natural killer (NK) cells is the chromium release assay (CRA). No
      study has been reported that systematically compares the traditional gamma
      counting method with various benchtop microplate scintillation formats to measure
      chromium release. Here we investigated the utilization of microplate beta
      counters in comparison with the traditional gamma counting method to quantitate
      antigen-specific cytolysis, lymphokine-activated killer (LAK) activity, and NK
      activity in the CRA. Supernatants from standard CRA (n = 7) were directly
      transferred to a 96-well microplate containing either a solid scintillant
      (Lumaplate) or a liquid scintillant (flexible beta plate). Samples were
      quantified by using two benchtop microplate beta counters, Wallac Microbeta
      Trilux (Lumalux and Trilux methods, respectively) and Packard TopCount
      instruments (TopCount method). These results were then compared with data from an
      identical assay run in parallel using the traditional gamma counting method
      (LKB). The lytic activity for influenza virus-stimulated effectors measured in
      the benchtop microplate beta counters using Lumalux and Trilux methods exhibited
      excellent correlations with the one measured in the traditional LKB (r = 0.967
      and 0.968, respectively). The TopCount method demonstrated a similar correlation
      (r = 0.966). Similar findings were observed for LAK and NK activity. The 96-well
      microplate format, specifically the dry-scintillant Lumaplates, offers several
      advantages over the traditional gamma counting format. Most notable are the
      reductions in sample volume needed and in the total sample preparation and
      counting time. Furthermore, this system reduces the amount of dry and mixed
      radioactive waste generated while using the same instrument for gamma- and beta
      emitting isotopes.

PMID- 15013971
TI  - Rectal nitric oxide gas and stool cytokine levels during the course of infectious
      gastroenteritis.
AB  - Nitric oxide (NO) is known to be an important inflammatory mediator with a
      potential role in gastrointestinal diseases. We prospectively studied the luminal
      NO levels in 51 patients with infectious gastroenteritis, 35 patients with
      nonenteric bacterial infections, and 11 healthy control subjects. The levels of
      proinflammatory cytokines were simultaneously measured in the stools of patients
      with gastroenteritis. Rectal gas was sampled with balloon catheters made of
      silicone and was analyzed for NO levels by chemiluminescence. The median rectal
      NO level was 2,450 ppb in the acute phase of gastroenteritis and gradually
      decreased to 225 ppb after 3 to 8 weeks, whereas the median NO values were 150
      ppb in patients with nonenteric bacterial infections and 100 ppb in healthy
      control subjects. Patients with Salmonella, Shigella, and Campylobacter
      infections generally had more severe symptoms and a higher median NO level
      (17,250 ppb) than patients with Clostridium difficile-associated diarrhea (median
      NO value, 275 ppb). Interleukin-1 beta levels were elevated in 82% of the
      patients at disease onset and decreased during the convalescent phase. In
      contrast, gamma interferon was detected in only 16% of the patients and was
      predominantly collected in stool samples collected during the subacute and
      convalescent stages. Our data point to the possibility of using this easy,
      minimally invasive method for luminal NO measurement as a diagnostic tool, among
      others, to evaluate the degree of intestinal inflammation in patients with
      infectious gastroenteritis.

PMID- 15013973
TI  - Role of C-terminal cysteine residues of Aspergillus fumigatus allergen Asp f 4 in
      immunoglobulin E binding.
AB  - Among the several allergens cloned and expressed from Aspergillus fumigatus, Asp
      f 4 is a major one associated with allergic bronchopulmonary aspergillosis
      (ABPA). The structure-function relationship of allergens is important in
      understanding the immunopathogenesis, diagnosis, and treatment of allergic
      diseases. These include the epitopes, conformational or linear, deletion of the N
      or C terminus or both N and C termini, and glycosylation or nonglycosylation, all
      of which affect immune responses. Similarly, the role of cysteine residues
      present in allergens may yield useful information regarding the conformational
      structure of allergens and the immunoglobulin E (IgE) epitope interaction. Such
      information may help in developing new strategies towards immunotherapy. In order
      to define the role of cysteine in the interaction of the antibody with Asp f 4,
      we have constructed mutants by selectively deleting cysteine residues from the C
      terminal region of the Asp f 4. Immunological evaluation of these engineered
      recombinant constructs was conducted by using sera from patients with ABPA,
      Aspergillus skin test-positive asthmatics, and healthy controls. The results
      demonstrate strong IgE binding with Asp f 4 and two truncated mutants, Asp f 4(1
      234) (amino acids [aa] 1 to 234) and Asp f 4(1-241) (aa 1 to 241), while another
      mutant, Asp f 4(1-196) (aa 1 to 196), showed reactivity with fewer patients. The
      result suggests that deletion of cysteines and the alteration of IgE epitopes at
      the C-terminal end resulted in conformational changes, which may have a potential
      role in the immunomodulation of the disease.

PMID- 15013974
TI  - Stimulation of interleukin-10 production by acidic beta-lactoglobulin-derived
      peptides hydrolyzed with Lactobacillus paracasei NCC2461 peptidases.
AB  - We have previously demonstrated that Lactobacillus paracasei NCC2461 may help to
      prevent cow's milk allergy in mice by inducing oral tolerance to beta
      lactoglobulin (BLG). To investigate the mechanisms involved in this beneficial
      effect, we examined the possibility that L. paracasei induces tolerance by
      hydrolyzing BLG-derived peptides and liberating peptides that stimulate
      interleukin-10 (IL-10) production. L. paracasei peptidases have been shown to
      hydrolyze tryptic-chymotryptic peptides from BLG, releasing numerous small
      peptides with immunomodulating properties. We have now shown that acidic tryptic
      chymotryptic peptides stimulate splenocyte proliferation and gamma interferon
      (IFN-gamma) production in vitro. Hydrolysis of these peptides with L. paracasei
      peptidases repressed the lymphocyte stimulation, up-regulated IL-10 production,
      and down-regulated IFN-gamma and IL-4 secretion. L. paracasei NCC2461 may
      therefore induce oral tolerance to BLG in vivo by degrading acidic peptides and
      releasing immunomodulatory peptides stimulating regulatory T cells, which
      function as major immunosuppressive agents by secreting IL-10.

PMID- 15013975
TI  - Development and evaluation of a tetraplex flow cytometric assay for quantitation
      of serum antibodies to Neisseria meningitidis serogroups A, C, Y, and W-135.
AB  - A rapid and simple method for the simultaneous quantitation of serum
      immunoglobulin G (IgG) antibodies specific for Neisseria meningitidis serogroups
      A, C, Y, and W-135 was developed and evaluated. Four bead sets were generated,
      each conjugated with one of the meningococcal capsular polysaccharides (A, C, Y,
      or W-135) and serologically assessed by the use of antimeningococcal
      international reference sera. Cross-reactivity studies demonstrated no inhibition
      between monoplex and multiplex assays, and the assay was linear over a 24-fold
      serum dilution range. Inhibition studies demonstrated that the assay is specific,
      with <25% heterologous inhibition occurring. The assay was also found to have low
      intra- and interassay variations and limits of detection < or =650 pg/ml. A
      comparison of the meningococcal bead assay with the standardized meningococcal
      enzyme-linked immunosorbent assay showed a good correlation between the IgG
      concentrations obtained by each assay. The tetraplex assay has the potential to
      be an important addition to the serologic evaluation of meningococcal capsular
      polysaccharide conjugate vaccines.

PMID- 15013976
TI  - Potential serological use of a recombinant protein that is a replica of a
      Mycobacterium tuberculosis protein found in the urine of infected mice.
AB  - The recent availability of numerous well-characterized Mycobacterium tuberculosis
      recombinant proteins has revived interest in the serological diagnosis of
      tuberculosis. Several promising results have been reported, particularly when
      more than one antigen is used in the test. However, thus far these antigens have
      not been used in routine diagnostic tests because they lack sufficient
      sensitivity. In addition, with the exception of one antigen, most recombinant M.
      tuberculosis proteins do not identify the majority of tuberculosis patients
      coinfected with human immunodeficiency virus (HIV). Here, we report a newer M.
      tuberculosis protein that is a promising candidate for increasing the sensitivity
      of the serological tests, in particular for patients coinfected with HIV. The
      protein was found in the urine of mice during the early stages of infection with
      M. tuberculosis (10 to 14 days), thus suggesting that the antigen is abundantly
      released during the in vivo growth of the mycobacterium. Reverse genetics was
      used to produce the recombinant protein, which we named U1 (for urine protein 1).
      Using a conventional enzyme-linked immunosorbent assay (ELISA), antibody to U1
      could be detected in 60% of patients with pulmonary tuberculosis with no signs of
      coinfection with HIV (n = 83). Conversely, anti-U1 antibody was detected in 87%
      of the sera from tuberculosis patients coinfected with HIV (n = 47). Out of 12
      HIV-infected nontuberculosis patients' sera, 9 did not react with U1 and three
      sera gave borderline ELISA signals (signal/cutoff of < or =1.75). These results
      suggest that the high efficiency of U1 in identifying tuberculosis patients
      coinfected with HIV may be related to abundant release of this protein during the
      initial phase of the HIV coinfection. The immediate availability of the antigen
      at a time point in which the patient's immune system is still competent would
      lead to a secondary immune response to U1 that persists for months in the
      patient's serum.

PMID- 15013977
TI  - Recombinant protein-based enzyme-linked immunosorbent assay and
      immunochromatographic tests for detection of immunoglobulin G antibodies to
      severe acute respiratory syndrome (SARS) coronavirus in SARS patients.
AB  - An enzyme-linked immunosorbent assay (ELISA) and a rapid immunochromatographic
      test for detection of immunoglobulin G (IgG) antibodies in severe acute
      respiratory syndrome (SARS) patients were developed by utilizing the well
      characterized recombinant proteins Gst-N and Gst-U274. The ELISA detected IgG
      antibodies to SARS-CoV in all 74 convalescent-phase samples from SARS patients
      while weakly cross-reacting to only 1 of the 210 control sera from healthy
      donors. This finding thus led to a kit sensitivity, specificity, and accuracy of
      100, 99.5, and 99.6%, respectively. The test thus provided a positive predictive
      value (PPV) of 98.7% and a negative predictive value (NPV) of 100%. In addition,
      the ELISA gave a positive delta of 5.4 and a negative delta of 3.6, indicating an
      excellent differentiation between positives and negatives. The same recombinant
      proteins were also applied to a newly developed platform for the development of a
      15-min rapid test. The resulting rapid test has an excellent agreement of 99.6%,
      with a kappa value of 1.00, with the ELISA. Again, this rapid test was able to
      detect 100% of the samples tested (n = 42) while maintaining a specificity of
      99.0% (n = 210). The PPV and NPV for the rapid test thus reached 95.3 and 100%,
      respectively.

PMID- 15013978
TI  - Specific HLA-DRB and -DQB alleles and haplotypes confer disease susceptibility or
      resistance in Bahraini type 1 diabetes patients.
AB  - Insofar as genetic susceptibility to type 1 diabetes is associated with HLA class
      II genes, with certain allelic combinations conferring disease susceptibility or
      resistance, this study assessed the distributions of HLA-DR and -DQ among 107
      unrelated patients with type 1 diabetes and 88 healthy controls from Bahrain, all
      of Arab origin. The HLA-DRB and -DQB genotypes were determined by PCR-sequence
      specific priming. The following alleles showed the strongest association with
      type 1 diabetes among patients versus controls according to their frequencies:
      DRB1*030101 (0.430 versus 0.097; P < 0.001), DRB1*040101 (0.243 versus 0.034; P <
      0.001), DQB1*0201 (0.467 versus 0.193; P < 0.001), and DQB1*0302 (0.229 versus
      0.091; P < 0.001). When the frequencies of alleles in controls were compared to
      those in patients, negative associations were seen for DRB1*100101 (0.085 versus
      0.014; P < 0.001), DRB1*110101 (0.210 versus 0.060; P < 0.001), DQB1*030101
      (0.170 versus 0.075; P = 0.006), and DQB1*050101 (0.335 versus 0.121; P < 0.001).
      In addition, the DRB1*030101-DQB1*0201 (70.1 versus 22.7%; P < 0.001) and
      DRB1*030101-DQB1*0302 (21.5 versus 0.0%; P < 0.001) genotypes were more prevalent
      among patients, thereby conferring disease susceptibility, whereas the
      DRB1*100101-DQB1*050101 (20.5 versus 2.8%; P < 0.001), DRB1*110101-DQB1*030101
      (28.4 versus 8.4%; P < 0.001), and DRB1*110101-DQB1*050101 (30.7 versus 0.9%; P <
      0.001) genotypes were more prevalent among controls, thus assigning a protective
      role. These results confirm the association of specific HLA-DR and -DQ alleles
      and haplotypes with type 1 diabetes and may underline several characteristics
      that distinguish Bahraini patients from other Caucasians patients.

PMID- 15013979
TI  - Practical evaluation of methods for detection and specificity of autoantibodies
      to extractable nuclear antigens.
AB  - Detection and specificity of autoantibodies against extractable nuclear antigens
      (ENA) play a critical role in the diagnosis and management of autoimmune disease.
      Historically, the detection of these antibodies has employed double
      immunodiffusion (DID). Autoantibody specificity was correlated with diagnoses by
      this technique. Enzyme immunoassays have been developed by multiple manufacturers
      to detect and identify the specificity ENA autoantibodies. To address the
      relationship of ENA detection by DID and enzyme immunoassay, the performances of
      five immunoassays were compared. These included two DID and three enzyme-linked
      immunoassays (ELISA) (both screening and individual antigen profile kits). The
      sample set included 83 ENA-positive, antinuclear-antibody (ANA)-positive
      specimens, 77 ENA-negative, ANA-positive specimens, and 20 ENA- and ANA-negative
      specimens. Sensitivity and specificity were calculated by two methods: first, by
      using the in-house DID result as the reference standard, and second, by using
      latent class analysis, which evaluates each kit result independently. Overall,
      the results showed that the ELISA methods were more sensitive for detection of
      ENA autoantibodies than DID techniques, but presence and/or specific type of ENA
      autoantibody did not always correlate with the patient's clinical presentation.
      Regardless of the testing strategy an individual laboratory uses, clear
      communication with the clinical staff regarding the significance of a positive
      result is imperative. The laboratory and the clinician must both be aware of the
      sensitivity and specificity of each testing method in use in the clinical
      laboratory.

PMID- 15013980
TI  - Innate immune responses of calves during transient infection with a noncytopathic
      strain of bovine viral diarrhea virus.
AB  - In this study, six immunocompetent calves were experimentally infected with a
      noncytopathic strain of bovine viral diarrhea virus (BVDV), and the effects of
      the viral infection on parameters of the innate immune response of the host were
      analyzed. Clinical and virological data were compared with the temporal
      activation of the alpha/beta interferon-regulated Mx gene in white blood cells
      (WBC) and skin as well as the upregulation of the acute-phase serum proteins
      haptoglobin (Hp) and serum amyloid A (SAA). The viral strain used did provoke
      transient health impairment, namely, fever and leukopenia that were associated
      with viremia, viral shedding with nasal secretions, and antiviral seroconversion.
      Complete recovery was observed within 3 weeks. Elevated levels of SAA and Hp were
      apparent from days 4 to 13 and 8 to 11, respectively. In WBC, the levels of Mx
      mRNA and Mx protein were elevated from days 2 to 15. In the context of this study
      with BVDV, the level of Mx protein expression in WBC provided the most telling
      diagnostic window to monitor the host's ongoing innate immune response.

PMID- 15013981
TI  - Combined use of enzyme-linked immunosorbent assay and flow cytometry to detect
      antibodies to Trypanosoma cruzi in domestic canines in Texas.
AB  - Canines may be sentinels and/or reservoirs for human Trypanosoma cruzi exposures.
      This study adapted a method originally designed for human diagnostics to detect
      serum immunoglobulin G to T. cruzi in canines. The method combined an enzyme
      linked immunosorbent assay (ELISA) for screening and flow cytometry detection of
      anti-live trypomastigote antibodies (ALTA) for confirmation. The assays were
      optimized by using known positive and negative control canine sera, and cutoff
      values were established. The ELISA and ALTA assay easily distinguished between
      reactive (positive controls) and nonreactive (negative controls) sera and were
      used to test sera collected in a cross-sectional seroprevalence survey of 356
      domestic canines from Harris County, Tex., and the surrounding area. Fifty-three
      (14.9%) of 356 asymptomatic canines in the survey were positive by ELISA, and 5
      (1.4%) were confirmed positive with the ALTA assay, with an additional 4 (1.1%)
      canines classified as "suspect positive." Thus, the overall prevalence of T.
      cruzi antibodies in this population was 2.6%. This is the first U.S. study to use
      the combination of ELISA and ALTA to detect serum antibodies to T. cruzi and the
      first report of the prevalence of T. cruzi infection in domestic canines in the
      Houston, Tex. (Harris County), region. Our results demonstrate that the
      combination of ELISA and ALTA has been successfully adapted for use in testing
      canines for serological evidence of T. cruzi infection. Seroprevalence survey
      results suggest that T. cruzi antibody-positive domestic canines in the
      peridomestic setting are present in the Houston, Tex., region and further suggest
      that T. cruzi is enzootic in the region.

PMID- 15013983
TI  - Heterophile antibody interference in a multiplexed fluorescent microsphere
      immunoassay for quantitation of cytokines in human serum.
AB  - While modern immunoassays provide sensitive and specific means for the
      quantitation of cytokines in biological fluids, heterophile antibodies are still
      a well-recognized cause of interference in the measurement of cytokines in these
      assays. We have developed a multiplexed fluorescent microsphere immunoassay for
      the simultaneous quantification of 10 cytokines in only 75 microl of serum.
      During the development of this multiplexed assay, the amount of assay
      interference due to heterophile antibodies was also determined, and methods for
      detecting heterophile interference and minimizing its effect were incorporated
      into the assay. Heterophile antibodies resulted in significantly elevated
      cytokine values compared to those of normal blood bank samples. These falsely
      elevated values, and thus the components of the assay the heterophile antibodies
      were binding to, were identified through the use of internal controls. This
      information was then used to design assay-specific blockers and absorbents that
      were shown to significantly reduce falsely elevated cytokine values while not
      affecting the standard and control values. The fluorescent multiplexed
      microsphere-based immunoassay can be used to quantitate multiple cytokines from a
      single sample and should be a useful tool in furthering our understanding of the
      role of cytokines in disease processes.

PMID- 15013982
TI  - Molecular cloning and characterization of tropomyosin, a major allergen of
      Chironomus kiiensis, a dominant species of nonbiting midges in Korea.
AB  - Chironomids are widely and abundantly distributed in the vicinity of standing
      waters. Larvae of Chironomus and some other genera are known to contain
      hemoglobins, which have been described as a major allergen, and the adults that
      have no hemoglobins also have been reported to contain allergens. In this study,
      we tried to establish the role of chironomid allergy and characterize the
      allergen of Chironomus kiiensis adults. Skin tests using C. kiiensis adult
      extracts were performed on patients with allergic symptoms. A cDNA library of C.
      kiiensis adults was screened with C. kiiensis immune mouse sera to identify
      allergens, and results were confirmed using skin test-positive human sera.
      Recombinant allergen was expressed in Escherichia coli and purified by affinity
      chromatography using nickel-nitrilotriacetic acid agarose to investigate its
      allergenic properties. Out of 275 allergic patients 14.2% showed a positive
      reaction to C. kiiensis adult crude extracts in the skin test. The tropomyosin
      was cloned by immunoscreening and expressed in Escherichia coli. C. kiiensis
      tropomyosin has a high homology at the amino acid level with tropomyosins which
      were previously known to be allergens in various arthropods (Periplaneta
      americana, 86.3%; Panulirus stimpson, 78.9%; Dermatophagoides pteronyssinus,
      76.5%). Specific immunoglobulin E antibodies reacting to recombinant tropomyosin
      were detected in 17 (81%) of 21 patients whose skin test results were positive.
      Cross-reactivity against house dust mites and other insects was noticed with
      mouse anti-recombinant tropomyosin immune serum. C. kiiensis adults were shown to
      be an important source of inhalant allergens in Korea. Molecular cloning of C.
      kiiensis tropomyosin was performed and IgE reactivity was demonstrated using skin
      test-positive human sera. Recombinant tropomyosin will be useful for further
      studies or clinical applications.

PMID- 15013984
TI  - D8/17 and CD19 expression on lymphocytes of patients with acute rheumatic fever
      and Tourette's disorder.
AB  - D8/17, an alloantigen found on B lymphocytes, has been reported to be elevated in
      patients susceptible to rheumatic fever and may be associated with autoimmune
      types of neuropsychiatric disorders. The pediatric-autoimmune-neuropsychiatric
      disorders-associated-with-streptococci model is a putative model of pathogenesis
      for a group of children whose symptoms of obsessive-compulsive disorder and
      Tourette's disorder (TD) are abrupt and may be triggered by an infection with
      group A streptococci. As a test of this model, we have examined D8/17 levels on
      the B cells of patients with TD and acute rheumatic fever (ARF) along with those
      on the B cells of normal controls by flow cytometry. We have utilized several
      different preparations of D8/17 antibody along with a variety of secondary
      antibodies but have been unable to show an association with an elevated
      percentage of D8/17-positive, CD19-positive B cells in either ARF or TD. We did
      find, however, that the percentages of CD19-positive B cells in ARF and TD
      patients were significantly elevated compared to those in normal controls. Group
      A streptococcal pharyngitis patients also had an elevated percentage of CD19 B
      cells, however. These studies failed to confirm the utility of determining the
      percentage of B cells expressing the D8/17 alloantigen in ARF patients or our
      sample of TD patients. In contrast, the percentage of CD19-positive B cells was
      significantly elevated in ARF and TD patients, as well as group A streptococcal
      pharyngitis patients, suggesting a role for inflammation and/or autoimmunity in
      the pathogenesis of these disorders.

PMID- 15013985
TI  - Effects of infection with transmissible gastroenteritis virus on concomitant
      immune responses to dietary and injected antigens.
AB  - Normal piglets weaned onto soy- or egg-based diets generated antibody responses
      to fed protein. Concurrent infection with transmissible gastroenteritis virus
      (TGEV) did not affect the responses to dietary antigens at weaning, nor did it
      affect the subsequent development of tolerance. However, TGEV infection did
      enhance the primary immunoglobulin M (IgM) and IgG1, but not IgG2, antibody
      responses to injected soy in comparison to those of uninfected animals.
      Paradoxically, TGEV-infected animals showed an enhanced primary IgG1 antibody
      response to injected soy at 4 weeks of age, but they subsequently showed a
      reduced secondary response after an intraperitoneal challenge at 9 weeks of age
      in comparison to uninfected animals. The results suggest that an enteric virus,
      either used as a vaccine vector or present as a subclinical infection, may not
      have significant effects on the development of dietary allergies but may have
      effects both on the primary response and on the subsequent recall response to
      systemic antigens to which the animal is exposed concurrently with virus
      antigens.

PMID- 15013986
TI  - Circulating beta (1-3) glucan and immunoglobulin G subclass antibodies to Candida
      albicans cell wall antigens in patients with systemic candidiasis.
AB  - Invasive candidiasis in patients who are immunocompromised or in intensive care
      units (ICUs) presents both diagnostic and therapeutic problems. We previously
      described antibodies that were directed against Candida albicans cell wall
      fragments (CW), periodate-treated CW (CW(IO4)), phosphopeptidomannan (PPM), and
      beta(1-3) glucan. In this study, circulating fungal antigens [mannan and beta(1
      3) glucan] and immunoglobulin G (IgG) subclass antibodies to these cell wall
      antigens (anti-CW) were analyzed in patients with systemic candidiasis. Sera were
      collected from 14 patients on two or three consecutive occasions, starting on the
      day when candidiasis was culture proven. The sera were analyzed by enzyme-linked
      immunosorbent assay. The control groups consisted of lactating mothers (n = 9)
      (group I) who had breast milk that was positive for C. albicans and also had
      acute inflammation of the nipples, and age-matched blood donors (n = 10) (group
      II). Within the first 3 weeks of Candida infection all of the patients were
      positive for beta(1-3) glucan by the Gluspecy test, but no patients were positive
      for mannan in the less-sensitive Pastorex Candida test. The controls were
      negative for both beta(1-3) glucan (<20 pg/ml) and mannan (<2.5 ng/ml). IgG1 anti
      CW and IgG2 anti-PPM antibodies were the most discriminatory antibodies. The
      ratio of IgG1 anti-CW to IgG2 anti-PPM was significantly lower in nonsurviving
      patients than in the other patients within the first week of candidiasis (P =
      0.019). The IgG2 levels of anti-CW(IO4) and antiglucan antibodies correlated
      strongly (r = 0.681; P < 0.0001), and the absence of these antibodies was
      associated with increased levels of beta(1-3) glucan. Increased levels of IgG1
      anti-CW or IgG2 anti-PPM antibodies (titer of > or = 3 logs) or of a combination
      of the two antibodies (log sum, > or = 5) showed 92% sensitivity, 100%
      specificity, and positive predictive values. In conclusion, beta(1-3) glucan and
      the two subclass antibodies appear to be early specific markers for the
      laboratory diagnosis of candidiasis. Furthermore, the kinetics of beta(1-3)
      glucan appearance in serum may assist in evaluating the therapeutic efficacy of
      antifungal treatments.

PMID- 15013987
TI  - Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in the
      adult populations of The Gambia, South Africa, and the United States.
AB  - One of the major limitations of the use of adenoviruses as gene therapy vectors
      is the existence of preformed immunity in various populations. Recent studies
      have linked failure of adenoviral gene therapy trials to the presence of
      antiadenoviral neutralizing antibodies (NAb). Understanding the distribution and
      specificity of such antibodies will assist in the design of successful
      recombinant adenoviral gene therapies and vaccines. To assess the prevalence of
      NAb to adenovirus serotypes 5 and 35 (Ad5 and Ad35), we analyzed serum samples
      from adult immunocompetent individuals living in The Gambia, South Africa, and
      the United States by using a neutralization assay. Serum samples were incubated
      with A549 lung carcinoma cells and adenoviruses encoding enhanced green or yellow
      fluorescent proteins; results were analyzed by fluorescence microscopy and flow
      cytometry. Using this technique, we found a high prevalence of NAb against Ad5 in
      Gambian, South African, and U.S. subjects at both low and high titers.
      Conversely, all subjects displayed a low prevalence of NAb to Ad35; when present,
      anti-Ad35 NAb were seen at low titers. Because of the ability of adenoviruses to
      elicit systemic and mucosal immune responses, Ad35 with its low NAb prevalence
      appears to be an attractive candidate vector for gene therapy applications.

PMID- 15013988
TI  - Sustained lipopolysaccharide-induced lung inflammation in mice is attenuated by
      functional deficiency of the Fas/Fas ligand system.
AB  - To determine whether the Fas/Fas ligand (FasL) (CD95/CD178) system contributes to
      the development of an inflammatory response in vivo, 2.5 microg of bacterial
      lipopolysaccharide (LPS; endotoxin) per g was administered intranasally to
      healthy mice (C57BL/6) and mutant mice deficient in either Fas (lpr mice) or FasL
      (gld mice). Sustained LPS-induced neutrophilic inflammation in the lungs was
      attenuated in both lpr and gld mice. These observations provide further evidence
      of a proinflammatory role for the Fas/FasL system in the lungs.

PMID- 15013989
TI  - Profiles of antibody responses against severe acute respiratory syndrome
      coronavirus recombinant proteins and their potential use as diagnostic markers.
AB  - A new coronavirus (severe acute respiratory syndrome coronavirus [SARS-CoV]) has
      been identified to be the etiological agent of severe acute respiratory syndrome.
      Given the highly contagious and acute nature of the disease, there is an urgent
      need for the development of diagnostic assays that can detect SARS-CoV infection.
      For determination of which of the viral proteins encoded by the SARS-CoV genome
      may be exploited as diagnostic antigens for serological assays, the viral
      proteins were expressed individually in mammalian and/or bacterial cells and
      tested for reactivity with sera from SARS-CoV-infected patients by Western blot
      analysis. A total of 81 sera, including 67 from convalescent patients and seven
      pairs from two time points of infection, were analyzed, and all showed
      immunoreactivity towards the nucleocapsid protein (N). Sera from some of the
      patients also showed immunoreactivity to U274 (59 of 81 [73%]), a protein that is
      unique to SARS-CoV. In addition, all of the convalescent-phase sera showed
      immunoreactivity to the spike (S) protein when analyzed by an immunofluorescence
      method utilizing mammalian cells stably expressing S. However, samples from the
      acute phase (2 to 9 days after the onset of illness) did not react with S,
      suggesting that antibodies to N may appear earlier than antibodies to S.
      Alternatively, this could be due to the difference in the sensitivities of the
      two methods. The immunoreactivities to these recombinant viral proteins are
      highly specific, as sera from 100 healthy donors did not react with any of them.
      These results suggest that recombinant N, S, and U274 proteins may be used as
      antigens for the development of serological assays for SARS-CoV.

PMID- 15013990
TI  - Preventive effects of Escherichia coli strain Nissle 1917 on acute and chronic
      intestinal inflammation in two different murine models of colitis.
AB  - Escherichia coli strain Nissle 1917 (EcN) is as effective in maintaining
      remission in ulcerative colitis as is treatment with mesalazine. This study aims
      to evaluate murine models of acute and chronic intestinal inflammation to study
      the antiinflammatory effect of EcN in vivo. Acute colitis was induced in mice
      with 2% dextran-sodium sulfate (DSS) in drinking water. EcN was administered from
      day -2 to day +7. Chronic colitis was induced by transfer of CD4(+) CD62L(+) T
      lymphocytes from BALB/c mice in SCID mice. EcN was administered three times/week
      from week 1 to week 8 after cell transfer. Mesenteric lymph node (MLN) cytokine
      secretion (of gamma interferon [IFN-gamma], interleukin 5 [IL-5], IL-6, and IL
      10) was measured by enzyme-linked immunosorbent assay. Histologic sections of the
      colon were analyzed by using a score system ranging from 0 to 4. Intestinal
      contents and homogenized MLN were cultured, and the number of E. coli-like
      colonies was determined. EcN was identified by repetitive extragenic palindromic
      (REP) PCR. EcN administration to DSS-treated mice reduced the secretion of
      proinflammatory cytokines (IFN-gamma, 32,477 +/- 6,377 versus 9,734 +/- 1,717 [P
      = 0.004]; IL-6, 231 +/- 35 versus 121 +/- 17 [P = 0.02]) but had no effect on the
      mucosal inflammation. In the chronic experimental colitis of the transfer model,
      EcN ameliorated the intestinal inflammation (histology score, 2.7 +/- 0.2 versus
      1.9 +/- 0.3 [P = 0.02]) and reduced the secretion of proinflammatory cytokines.
      Translocation of EcN and resident E. coli into MLN was observed in the chronic
      colitis model but not in healthy controls. Administration of EcN ameliorated
      acute and chronic experimental colitis by modifying proinflammatory cytokine
      secretion but had no influence on the acute DSS-induced colitis. In this model,
      preexisting colitis was necessary for translocation of EcN and resident E. coli
      into MLN.

PMID- 15013991
TI  - Establishment of an animal model using recombinant NOD.B10.D2 mice to study
      initial adhesion of oral streptococci.
AB  - An oral biofilm is a community of surface-attached microorganisms that coats the
      oral cavity, including the teeth, and provides a protective reservoir for oral
      microbial pathogens, which are the primary cause of persistent and chronic
      infectious diseases in patients with dry mouth or Sjogren's syndrome (SS). The
      purpose of this study was to establish an animal model for studying the initial
      adhesion of oral streptococci that cause biofilm formation in patients with dry
      mouth and SS in an attempt to decrease the influence of cariogenic organisms and
      their substrates. In nonobese diabetogenic (NOD) mice that spontaneously develop
      insulin-dependent diabetes mellitus (IDDM) and SS, we replaced major
      histocompatibility complex (MHC) class II (A(g7) E(g7)) and class I D(b) with MHC
      class II (A(d) E(d)) and class I D(d) from nondiabetic B10.D2 mice to produce an
      animal model that inhibited IDDM without affecting SS. The adhesion of oral
      streptococci, including Streptococcus mutans, onto tooth surfaces was then
      investigated and quantified in homologous recombinant N5 (NOD.B10.D2) and N9
      (NOD.B10.D2) mice. We found that a higher number of oral streptococci adhered to
      the tooth surfaces of N5 (NOD.B10.D2) and N9 (NOD.B10.D2) mice than to those of
      the control C57BL/6 and B10.D2 mice. On the basis of our observation, we
      concluded that these mouse models might be useful as animal models of dry mouth
      and SS for in vivo biological studies of oral biofilm formation on the tooth
      surfaces.

PMID- 15013992
TI  - Immunoglobulin M antibody responses to Mycobacterium ulcerans allow
      discrimination between cases of active Buruli ulcer disease and matched family
      controls in areas where the disease is endemic.
AB  - Buruli ulcer disease (BUD) is an emerging disease caused by Mycobacterium
      ulcerans. In the present study we have characterized the serological reactivities
      of sera from volunteer case patients with laboratory-confirmed BUD and controls
      living in three different regions of Ghana where the disease is endemic to
      determine if serology may be useful for disease confirmation. Our results showed
      highly reactive immunoglobulin G (IgG) responses among patients with laboratory
      confirmed disease, healthy control family members of the case patients, and sera
      from patients with tuberculosis from areas where BUD is not endemic. These
      responses were represented by reactivities to multiple protein bands found in the
      M. ulcerans culture filtrate (CF). In contrast, patient IgM antibody responses to
      the M. ulcerans CF (MUCF) proteins were more distinct than those of healthy
      family members living in the same village. A total of 84.8% (56 of 66) of the BUD
      patients exhibited strong IgM antibody responses against MUCF proteins (30, 43
      and 70 to 80 kDa), whereas only 4.5% (3 of 66) of the family controls exhibited
      such responses. The sensitivity of the total IgM response for the patients was
      84.8% (95% confidence interval [CI], 74.3 to 91.6%), and the specificity
      determined with sera from family controls was 95.5% (95% CI, 87.5 to 98.4%).
      These studies suggest that the IgM responses of patients with BUD will be helpful
      in the identification and production of the M. ulcerans recombinant antigens
      required for the development of a sensitive and specific serological assay for
      the confirmation of active BUD.

PMID- 15013993
TI  - High prevalence of antibodies to hepatitis A and E viruses and viremia of
      hepatitis B, C, and D viruses among apparently healthy populations in Mongolia.
AB  - The prevalence of infection with hepatitis A virus (HAV), HBV, HCV, HDV, and HEV
      was evaluated in 249 apparently healthy individuals, including 122 inhabitants in
      Ulaanbaatar, the capital city of Mongolia, and 127 age- and sex-matched members
      of nomadic tribes who lived around the capital city. Overall, hepatitis B surface
      antigen (HBsAg) was detected in 24 subjects (10%), of whom 22 (92%) had
      detectable HBV DNA. Surprisingly, HDV RNA was detectable in 20 (83%) of the 24
      HBsAg-positive subjects. HCV-associated antibodies were detected in 41 (16%) and
      HCV RNA was detected in 36 (14%) subjects, none of whom was coinfected with HBV,
      indicating that HBV/HCV carriers account for one-fourth of this population.
      Antibodies to HAV and HEV were detected in 249 (100%) and 28 (11%) subjects,
      respectively. Of 22 HBV DNA-positive subjects, genotype D was detected in 21
      subjects and genotype F was detected in 1 subject. All 20 HDV isolates recovered
      from HDV RNA-positive subjects segregated into genotype I, but these differed by
      2.1 to 11.4% from each other in the 522- to 526-nucleotide sequence. Of 36 HCV
      RNA-positive samples, 35 (97%) were genotype 1b and 1 was genotype 2a. Reflecting
      an extremely high prevalence of hepatitis virus infections, there were no
      appreciable differences in the prevalence of hepatitis virus markers between the
      two studied populations with distinct living place and lifestyle. A nationwide
      epidemiological survey of hepatitis viruses should be conducted in an effort to
      prevent de novo infection with hepatitis viruses in Mongolia.

PMID- 15013994
TI  - Comparison of ophthalmic sponges for measurements of immune markers from cervical
      secretions.
AB  - Measurements of cervical immunity are important for evaluating immune responses
      to infections of the cervix and to vaccines for preventing those infections.
      Three ophthalmic sponges, Weck-Cel, Ultracell, and Merocel, were loaded in vitro
      with interleukin-1 beta (IL-1 beta), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12,
      IL-15, IL-18, gamma interferon (IFN-gamma), granulocyte-macrophage colony
      stimulating factor (GM-CSF), immunoglobulin A (IgA), or IgG, and sponges were
      extracted and evaluated for total recovery by enzyme-linked immunosorbent assay
      (ELISA). There was excellent (>75%) recovery for all immune markers from all
      three devices except for IL-6, which was poorly recovered (<60%) for all sponge
      types, IFN-gamma, which was poorly recovered from both Weck-Cel and Ultracell
      sponges but was completely recovered from Merocel sponges, and IL-4, which was
      poorly recovered from Weck-Cel sponges but was completely recovered from
      Ultracell or Merocel sponges. We then compared the absolute recovery of selected
      markers (IL-10, IL-12, IgG, and IgA) from cervical secretion specimens collected
      from women using each type of sponge. There were no significant differences in
      the recoveries of IL-10, IL-12, and IgG from cervical specimens collected by any
      type of ophthalmic sponge, but there was reduced IgA recovery from Merocel
      sponges. However, the variability in these measurements attributable to sponge
      types (1 to 3%) was much less than was attributable to individuals (45 to 72%),
      suggesting that differences in sponge type contribute only in a minor way to
      these measurements. We infer from our data that the three collection devices are
      adequate for the measurements of IL-1 beta, IL-2, IL-5, IL-12, IL-15, IL-18, and
      IgG. Merocel may be a better ophthalmic sponge for the collection of cervical
      secretions and measurements of IL-4, IL-8, IL-10, GM-CSF, and IFN-gamma, but our
      data from clinical specimens, not in vitro-loaded sponges, suggested the
      possibility of reduced recovery of IgA. These findings require confirmation.

PMID- 15013995
TI  - Neutralization assay using a modified vaccinia virus Ankara vector expressing the
      green fluorescent protein is a high-throughput method to monitor the humoral
      immune response against vaccinia virus.
AB  - Vaccination against smallpox is again considered in order to face a possible
      bioterrorist threat, but the nature and the level of the immune response needed
      to protect a person from smallpox after vaccination are not totally understood.
      Therefore, simple, rapid, and accurate assays to evaluate the immune response to
      vaccinia virus need to be developed. Neutralization assays are usually considered
      good predictors of vaccine efficacy and more informative with regard to
      protection than binding assays. Currently, the presence of neutralizing
      antibodies to vaccinia virus is measured using a plaque reduction neutralization
      test, but this method is time-consuming and labor-intensive and has a subjective
      readout. Here, we describe an innovative neutralization assay based on a modified
      vaccinia virus Ankara (MVA) vector expressing the green fluorescent protein (MVA
      gfp). This MVA-gfp neutralization assay is rapid and sensitive and has a high
      throughput potential. Thus, it is suitable to monitor the immune response and
      eventually the efficacy of a large campaign of vaccination against smallpox and
      to study the vector-specific immune response in clinical trials that use
      genetically engineered vaccinia viruses. Most importantly, application of the
      highly attenuated MVA eliminates the safety concern in using the replication
      competent vaccinia virus in the standard clinical laboratory.

PMID- 15013996
TI  - Molecular expression of a cysteine proteinase of Clonorchis sinensis and its
      application to an enzyme-linked immunosorbent assay for immunodiagnosis of
      clonorchiasis.
AB  - We produced a recombinant cysteine proteinase of Clonorchis sinensis and tested
      its value as an antigen for serologic diagnosis of C. sinensis infections. The
      predicted amino acid sequence of the cysteine proteinase of C. sinensis was 58,
      48, and 40% identical to those of cathepsin L cysteine proteinases from
      Paragonimus westermani, Schistosoma japonicum, and Fasciola hepatica,
      respectively. Western blotting analysis showed that sera from patients infected
      with C. sinensis strongly reacted with the recombinant protein and that sera from
      patients infected with S. japonicum weakly reacted with the recombinant protein.
      Antibody against the recombinant protein stained proteins migrating at about 37
      and 28 kDa in C. sinensis adult worm crude extracts. Immunostaining revealed that
      the cysteine proteinase of C. sinensis was located in the intestinal epithelial
      cells of the adult parasite and in intrauterine eggs. The specificity and
      sensitivity of the recombinant antigen or C. sinensis adult worm crude extracts
      were assessed by an enzyme-linked immunosorbent assay (ELISA) using serum samples
      from humans infected with different parasites, including 50 patients with
      clonorchiasis, and negative controls. The sensitivities of the ELISA with the
      recombinant antigen and C. sinensis adult worm crude extracts were 96 and 88%,
      respectively. The specificities of the ELISA with the recombinant antigen and C.
      sinensis adult worm crude extracts were 96.2 and 100%, respectively. The results
      suggested that the recombinant cysteine proteinase-based ELISA could provide a
      highly sensitive and specific assay for diagnosis of clonorchiasis.

PMID- 15013997
TI  - Development of a Western blot assay for detection of antibodies against
      coronavirus causing severe acute respiratory syndrome.
AB  - To identify a major antigenic determinant for use in the development of a rapid
      serological diagnostic test for severe acute respiratory syndrome (SARS)
      coronavirus infection and to study the immune response during SARS coronavirus
      infection in humans, we cloned the full length and six truncated fragments of the
      nucleocapsid gene, expressed them, and purified them as glutathione S-transferase
      tagged recombinant proteins. The reactivities of the recombinant proteins to a
      panel of antibodies containing 33 SARS coronavirus-positive sera and 66 negative
      sera and to antibodies against other animal coronaviruses were screened. A
      truncated 195-amino-acid fragment from the C terminus of the nucleocapsid protein
      (N195) was identified that had a strong ability to detect antibodies against SARS
      coronavirus. No cross-reaction was found between the N195 protein and antibodies
      against chicken, pig, and canine coronaviruses. The N195 protein was used to
      develop a Western blot assay to detect antibodies against SARS coronavirus in 274
      clinically blinded samples. The specificity and sensitivity of this test were
      98.3 and 90.9%, respectively. The correlation between our Western blotting assay
      and an immunofluorescence assay (IFA) was also analyzed. The results of our
      Western blot assay and IFA for the detection of SARS coronavirus-positive sera
      were the same. Thus, the N195 protein was identified as a suitable protein to be
      used as an antigen in Western blot and other possible assays for the detection of
      SARS coronavirus infection.

PMID- 15013998
TI  - Prevalence of Bartonella clarridgeiae and Bartonella henselae in domestic cats
      from France and detection of the organisms in erythrocytes by immunofluorescence.
AB  - The prevalence of Bartonella infection in a pet cat population from France was
      found to be 8.1% (8 of 99 cats). The intraerythrocytic location of Bartonella
      clarridgeiae is shown for the first time, and we show that immunofluorescence
      detection of the organism in erythrocytes correlates with the number of bacteria
      in blood.

PMID- 15013999
TI  - Extracellular calcium and magnesium, but not iron, are needed for optimal growth
      of Blastomyces dermatitidis yeast form cells in vitro.
AB  - In the present study, we demonstrate that the yeast form of Blastomyces
      dermatitidis can proliferate for short periods of time in the absence of ferric
      iron but not in the absence of calcium or magnesium. The results of this study
      shed light on the resistance of B. dermatitidis to chelating agents, such as
      deferoxamine, and may explain how B. dermatitidis resists the iron-binding
      activity of serum transferrin.

PMID- 15014000
TI  - Performance characteristics of updated INNO-LiPA assays for molecular typing of
      human leukocyte antigen A (HLA-A), HLA-B, and HLA-DQB1 alleles.
AB  - We carried out a multicenter performance evaluation of three new DNA-based human
      leukocyte antigen (HLA) typing assays: INNO-LiPA HLA-A Update, INNO-LiPA HLA-B
      Update, and INNO-LiPA HLA-DQB1 Update. After optimization, the accuracy rates
      were all 100%, and the final observed resolutions were 99.4, 92.4, and 85.6%,
      respectively. These rapid and easy-to-perform assays yielded results fully
      concordant with other DNA-based tissue typing tests.

PMID- 15014002
TI  - Cyclooxygenase inhibition as a target for prevention of tobacco-related cancers.

PMID- 15014001
TI  - Comparison of hepatitis C viral loads in patients with or without coinfection
      with different genotypes.
AB  - Hepatitis C virus genotyping was assessed for 257 chronic hepatitis C patients
      with viral loads above 1,000 IU/ml. Twelve patients were coinfected with more
      than one genotype. Their median viral loads did not differ significantly from
      those observed for monoinfected patients, which in turn did not vary
      significantly among different genotypes.

PMID- 15014003
TI  - Predicting response to herceptin therapy.

PMID- 15014004
TI  - NSAIDs for the chemoprevention of oral cancer: promise or pessimism?: Commentary
      re J. L. Mulshine et al., randomized, double-blind, placebo-controlled, phase IIB
      trial of the cyclooxygenase inhibitor ketorolac as an oral rinse in oropharyngeal
      leukoplakia. Clin. Cancer Res., 10: 1565-1573, 2004.

PMID- 15014005
TI  - Randomized, double-blind, placebo-controlled phase IIb trial of the
      cyclooxygenase inhibitor ketorolac as an oral rinse in oropharyngeal leukoplakia.
AB  - PURPOSE: Nonselective cyclooxygenase (COX) inhibitors have been reported to
      decrease the frequency of upper aerodigestive cancers. Ketorolac tromethamine
      oral rinse has been shown to resolve another COX-dependent process, periodontal
      disease, without incurring gastrointestinal side effects. This trial evaluated if
      a topically delivered oral rinse containing ketorolac was as safe as and more
      effective than oral rinse alone in reducing the area of oral leukoplakia.
      EXPERIMENTAL DESIGN: 57 patients were randomized (2:1 ratio) in a double-blind,
      placebo-controlled study of ketorolac (10 ml of a 0.1% ketorolac rinse solution;
      n = 38) or placebo (10 ml of rinse solution; n = 19) given twice daily for 30 s
      over 90 days. Primary end point was evaluated visually obtaining bidimensional
      measurement of the size of leukoplakia lesion(s) at entry and at 90 days.
      Secondary end point was histological assessment of the leukoplakia as sampled by
      serial punch biopsy and independently reviewed by three pathologists. RESULTS:
      The patients included 67% males, 11% non-Caucasian, and 86% used tobacco with no
      significant differences between the two arms. Both rinses were well tolerated
      with good compliance, and there was no significant difference in adverse events
      (P = 0.27). Major response rate (complete response and partial response) was 30%
      for ketorolac and 32% for the placebo arm. There was no significant difference in
      change in histology between the two arms. CONCLUSION: Local delivery of a COX
      containing oral rinse was well tolerated but produced no significant reduction in
      the extent of leukoplakia compared with the placebo. However, the favorable
      response rate to placebo arm remains unexplained and additional investigation of
      the tissue penetration with ketorolac is warranted.

PMID- 15014006
TI  - Phase II randomized trial of autologous formalin-fixed tumor vaccine for
      postsurgical recurrence of hepatocellular carcinoma.
AB  - PURPOSE: We conducted a Phase II clinical trial with randomized patients to
      determine whether autologous formalin-fixed tumor vaccine (AFTV) protects against
      postsurgical recurrence of hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN:
      Forty-one patients with HCC who had undergone curative resection were randomly
      allocated to the vaccine treatment (n = 19) or no adjuvant control group (n =
      22). Three intradermal vaccinations were administered at 2-week intervals
      beginning 4-6 weeks after hepatic resection. A delayed-type hypersensitivity test
      was performed before and after vaccination. Primary and secondary end points are
      recurrence-free survival and overall survival, respectively. Observation
      continued until the majority of surviving patients had lived >12 months after the
      curative resection. RESULTS: In a median follow-up of 15 months, the risk of
      recurrence in vaccinated patients was reduced by 81% (95% confidence interval, 33
      95%; P = 0.003). Vaccination significantly prolonged the time to first recurrence
      (P = 0.003) and improved recurrence-free survival (P = 0.003) and overall
      survival rates (P = 0.01). AFTV played a significant role in preventing
      recurrence in patients with small tumors. Adverse effects were limited to grade 1
      or 2 skin toxicities such as erythema, dry desquamation, and pruritus.
      CONCLUSIONS: AFTV therapy is a safe, feasible, and effective treatment for
      preventing postoperational recurrence of HCC. Patients with low tumor burdens
      benefit from the treatment. This treatment should be advanced to a large-scale
      randomized trial.

PMID- 15014007
TI  - Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype
      ACA125: immunological response and survival (phase Ib/II).
AB  - PURPOSE: A Phase I/IIb multicenter study was conducted to evaluate the safety and
      immunogenicity of the anti-idiotypic antibody vaccine ACA125 that functionally
      imitates the tumor antigen CA125 in 119 patients with advanced ovarian carcinoma.
      A preliminary report on the initial 42 patients demonstrated safety and
      immunogenicity. EXPERIMENTAL DESIGN: Using the complete intention-to-treat
      population (n = 119) who received a mean of 9.7 ACA125 applications, survival was
      analyzed with respect to immunological responses. RESULTS: In 81 patients
      (68.1%), a specific anti-anti-idiotypic antibody (Ab3) response could be induced.
      Additionally, the development of CA125-specific antibodies (Ab1') and antibody
      dependent cell-mediated cytotoxicity of CA125-positive tumor cells was observed
      in 50.4% and 26.9% of patients, respectively. The median survival of all patients
      was 19.4 months (range, 0.5-56.1 months). Ab3-positive patients showed a
      significantly longer survival (median, 23.4 months; P < 0.0001) as compared with
      Ab3-negative patients (median, 4.9 months). A positive Ab3 response remained
      associated with longer survival when controlling for other prognostic factors
      including FIGO (International Federation of Gynecologists and Obstetricians)
      stage, response to and type of first-line chemotherapy, number of previous
      treatments, or concomitant antitumor therapy. With regard to safety, repeated
      vaccination was well tolerated. No serious adverse events related to the
      application of ACA125 occurred. CONCLUSIONS: Although the uncontrolled design of
      this study prevents definitive conclusions with respect to subgroups, the data
      support a relationship between Ab3 response and survival time. Thus, the need for
      further randomized, controlled clinical trials to establish efficacy of the
      vaccine ACA125 seems to be indicated.

PMID- 15014008
TI  - Osteopontin but not osteonectin messenger RNA expression is a prognostic marker
      in curatively resected non-small cell lung cancer.
AB  - PURPOSE: The purpose of this study was to better define the role of osteopontin
      (OPN) and osteonectin [also known as secreted protein acidic and rich in cysteine
      (SPARC)] in lung tumorigenesis by comparing the expressions of these genes in
      lung tumor tissue and matched normal tissue and by determining the prognostic
      significance of the gene expressions. EXPERIMENTAL DESIGN: Quantitative real-time
      reverse transcription-PCR was used to analyze OPN and SPARC mRNA expression in
      normal lung tissue and matching tumor samples from 82 patients with non-small
      cell lung cancer. Gene expression data for each patient were matched to survival
      data. RESULTS: The overall median mRNA expression level of OPN was about 20-fold
      higher in tumor tissues than in matching normal lung tissues (P < 0.001), whereas
      SPARC gene expression was not significantly different in both tissue types. Forty
      of 82 patients had high (>or=4.1) intratumoral OPN expression, and 15 of 82
      patients had high (>or15.5) SPARC expression. High OPN expression in the tumor
      tissue was associated with inferior survival (P = 0.014), whereas high SPARC
      expression showed a trend toward longer survival (P = 0.095). The impact of high
      OPN and low SPARC expression on patient survival was additive (P = 0.001).
      CONCLUSIONS: The large increase in OPN expression in tumors compared with normal
      tissue and its association with survival suggest a role for OPN in lung
      tumorigenesis.

PMID- 15014009
TI  - Missense mutations of MADH4: characterization of the mutational hot spot and
      functional consequences in human tumors.
AB  - PURPOSE AND EXPERIMENTAL DESIGN: The mutational spectrum of MADH4 (DPC4/SMAD4)
      opens valuable insights into the functions of this protein that confer its tumor
      suppressive nature in human tumors. We present the MADH4 genetic status
      determined on a new set of pancreatic, biliary, and duodenal cancers with
      comparison to the mutational data reported for various tumor types. RESULTS:
      Homozygous deletion, followed by inactivating nonsense or frameshift mutations,
      is the predominant form of MADH4 inactivation in pancreatic cancers. Among the
      naturally occurring MADH4 missense mutations, the MH2 domain is the most frequent
      target (77%) of missense mutations in human tumors. A mutational hot spot resides
      within the MH2 domain corresponding to codons 330 to 370, termed the mutation
      cluster region (MCR). A relationship was found between the locations of the
      missense mutations (the MH1 domain, the MH2-MCR, and the MH2 outside of the MCR)
      and the tumor types, suggesting environmental or selective influences in the
      development of MADH4 mutations. Immunohistochemical studies for Madh4 protein in
      nine archival cancers (six pancreatic cancers, two duodenal cancers, and one
      biliary cancer) with known missense mutations indicated that all mutations within
      the MH1 or MH2 domain COOH-terminal to the MCR (seven of nine cases) had negative
      or weak labeling, whereas two cancers with mutations within the MCR had strong
      positive nuclear labeling for Madh4 protein. CONCLUSIONS: These findings have
      important implications for in vitro functional studies, suggesting that the
      majority of missense mutations inactivate Madh4 by protein degradation in
      contrast to those that occur within the MCR.

PMID- 15014010
TI  - Quantitative detection of circulating tumor cells in cutaneous and ocular
      melanoma and quality assessment by real-time reverse transcriptase-polymerase
      chain reaction.
AB  - PURPOSE: Inconsistent reports on the detection of melanoma cells in peripheral
      blood by reverse transcriptase-PCR (RT-PCR) have resulted in uncertainty on the
      prognostic value of circulating melanoma cells. EXPERIMENTAL DESIGN: We developed
      real-time RT-PCR assays for quantitation of tyrosinase, MelanA/MART1, and gp100
      and for porphobilinogen deaminase housekeeping gene. Melanoma tissue (n = 18),
      peripheral blood samples from healthy donors (n = 21), and patients with
      cutaneous (n = 122) and uveal (n = 64) melanoma from our institution were
      analyzed. For quality control, an additional 251 samples from ongoing multicenter
      studies were compared with in-house samples. RESULTS: Tyrosinase was not detected
      in healthy donor blood samples. For the two other markers, cutoff values had to
      be defined to distinct patient samples from controls. Patients with stage IV
      uveal and cutaneous melanoma expressed all three markers more frequently and at
      higher levels in peripheral blood as compared with earlier stages. The variation
      of expression was 4 logs and correlated with tumor load and serum lactate
      dehydrogenase. In 2 of 3 uveal melanoma patients, detection of circulating tumor
      cells preceded the development of liver metastases. The diagnostic sensitivity
      was optimal in blood samples containing >0.1pg/ microl porphobilinogen deaminase
      (95.7% of in-house samples and 57.4% of multicenter samples). CONCLUSIONS: Real
      time RT-PCR is able to quantitatively define the quality of a sample and provides
      quantitative data for melanoma markers. Disparities in the results of previous
      studies may be attributable to undetected differences in sample quality. The
      prognostic relevance of this assay is currently under evaluation in several
      prospective randomized trials.

PMID- 15014011
TI  - Quantification of plasma beta-catenin mRNA in colorectal cancer and adenoma
      patients.
AB  - PURPOSE: Colorectal cancer is an important cause of cancer deaths. Here, we
      focused our investigation on the beta-catenin gene which is implicated in
      colorectal carcinogenesis and tested whether beta-catenin mRNA is detectable in
      the plasma of colorectal carcinoma and adenoma patients using quantitative
      reverse transcriptase-PCR. EXPERIMENTAL DESIGN: Plasma beta-catenin mRNA was
      measured from 58 colorectal carcinoma patients, 49 colorectal adenoma patients,
      and 43 apparently normal subjects using intron-spanning primers and Taqman
      probes. Five clinicopathological parameters were studied and correlated with
      plasma beta-catenin mRNA concentration. Additionally, 19 colorectal carcinoma
      patients after tumor removal were also recruited for plasma beta-catenin mRNA
      measurement to further demonstrate the clinical usefulness of this test. RESULTS:
      beta-catenin mRNA was detected with median concentrations of 8737 (range: 1480
      933100), 1218 (range: 541-2254) and 291 (range: 0-1366) copies/ml plasma in
      colorectal carcinoma, colorectal adenoma, and apparently normal subjects,
      respectively. Statistical analysis demonstrated that plasma beta-catenin mRNA
      concentration was correlated to tumor stage but not sex, age, lymph node status,
      and degree in differentiation. Moreover, plasma beta-catenin mRNA concentration
      decreased significantly after tumor removal in 16 of 19 (84%) colorectal
      carcinoma patients. CONCLUSIONS: We conclude that plasma beta-catenin mRNA may
      potentially serve as a marker for colorectal cancer.

PMID- 15014012
TI  - Monitoring of serum Her-2/neu predicts response and progression-free survival to
      trastuzumab-based treatment in patients with metastatic breast cancer.
AB  - PURPOSE: The present pilot study was performed to elucidate whether early changes
      in serum Her-2/neu extracellular domain (ECD) levels during trastuzumab-based
      treatment would predict the clinical course of disease in patients with
      metastatic breast cancer. EXPERIMENTAL DESIGN: Sera from 55 patients with Her
      2/neu-overexpressing metastatic breast cancer obtained immediately before each
      weekly administration of trastuzumab were analyzed by a serum Her-2/neu ELISA.
      RESULTS: Whereas response rates were significantly higher in patients with
      elevated (>or=15 ng/ml) ECD levels before initiation of treatment (35% versus 7%,
      P = 0.045), progression-free and overall survival did not differ significantly
      between patients with normal and elevated ECD levels. In patients responding to
      treatment, ECD levels decreased significantly as early as from day 8 of treatment
      onwards (all P for weekly measurements versus baseline <0.001). In contrast, no
      significant change in ECD levels was observed in patients with progressive
      disease. Multiple logistic regression analyses identified kinetics of ECD levels
      as the only factor that allowed for the accurate prediction of response
      likelihood as early as from day 8 of trastuzumab-based treatment onwards (P =
      0.020). In addition, determination of serial ECD levels allowed for the
      prediction of the risk for disease progression within the observed period as
      early as day 15 of treatment (P = 0.010). CONCLUSIONS: Serial monitoring of the
      ECD may represent a valuable tool for early prediction of the probability of
      response and progression-free survival to trastuzumab-based treatment and is thus
      likely to contribute to an optimization of treatment and resource allocation.

PMID- 15014014
TI  - Pretreatment with dexamethasone increases antitumor activity of carboplatin and
      gemcitabine in mice bearing human cancer xenografts: in vivo activity,
      pharmacokinetics, and clinical implications for cancer chemotherapy.
AB  - PURPOSE: The present study was undertaken to determine the effects of
      dexamethasone (DEX) pretreatment on antitumor activity and pharmacokinetics of
      the cancer chemotherapeutic agents carboplatin and gemcitabine. EXPERIMENTAL
      DESIGN: Antitumor activities of carboplatin and gemcitabine with or without DEX
      pretreatment were determined in six murine-human cancer xenograft models,
      including cancers of colon (LS174T), lung (A549 and H1299), and breast (MCF-7 and
      MDA-MB-468) and glioma (U87-MG). Effects of DEX on plasma and tissue
      pharmacokinetics of carboplatin and gemcitabine were also determined by using the
      LS174T, A549, and H1299 models. RESULTS: Although DEX alone showed minimal
      antitumor activity, DEX pretreatment significantly increased the efficacy of
      carboplatin, gemcitabine, or a combination of both drugs by 2-4-fold in all
      xenograft models tested. Without DEX treatment, the tumor exposure to
      carboplatin, measured by the area under the curve, was markedly lower than normal
      tissues. However, DEX pretreatment significantly increased tumor carboplatin
      levels, including 200% increase in area under the curve, 100% increase in maximum
      concentration, and 160% decrease in clearance. DEX pretreatment similarly
      increased gemcitabine uptake in tumors. CONCLUSIONS: To our knowledge, this is
      the first report that DEX significantly enhances the antitumor activity of
      carboplatin and gemcitabine and increases their accumulation in tumors. These
      results provide a basis for further evaluation of DEX as a chemosensitizer in
      patients.

PMID- 15014013
TI  - Serum protein profiles to identify head and neck cancer.
AB  - PURPOSE: New and more consistent biomarkers of head and neck squamous cell
      carcinoma (HNSCC) are needed to improve early detection of disease and to monitor
      successful patient management. The purpose of this study was to determine whether
      a new proteomic technology could correctly identify protein expression profiles
      for cancer in patient serum samples. EXPERIMENTAL DESIGN: Surface-enhanced laser
      desorption/ionization-time of flight-mass spectrometry ProteinChip system was
      used to screen for differentially expressed proteins in serum from 99 patients
      with HNSCC and 102 normal controls. Protein peak clustering and classification
      analyses of the surface-enhanced laser desorption/ionization spectral data were
      performed using the Biomarker Wizard and Biomarker Patterns software (version
      3.0), respectively (Ciphergen Biosystems, Fremont, CA). RESULTS: Several
      proteins, with masses ranging from 2778 to 20800 Da, were differentially
      expressed between HNSCC and the healthy controls. The serum protein expression
      profiles were used to develop and train a classification and regression tree
      algorithm, which reliably achieved a sensitivity of 83.3% and a specificity of
      100% in discriminating HNSCC from normal controls. CONCLUSIONS: We propose that
      this technique has potential for the development of a screening test for the
      detection of HNSCC.

PMID- 15014015
TI  - A randomized phase I and pharmacological trial of sequences of 1,3-bis(2
      chloroethyl)-1-nitrosourea and temozolomide in patients with advanced solid
      neoplasms.
AB  - PURPOSE: O(6)-alkylguanine-DNA alkyltransferase (AGAT) is modulated by
      methylating agents, which, in turn, abrogates nitrosourea resistance in
      preclinical studies. The feasibility of administering various sequences of 1,3
      bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TEM) in patients with
      advanced solid neoplasms was evaluated in this Phase I and pharmacological study
      to assess this premise in the clinical setting. The study also sought to
      determine the maximum tolerated dose (MTD) levels of BCNU and TEM as a function
      of Seq, to characterize the pharmacokinetic (PK) behavior of TEM administered
      both before and after BCNU, assess AGAT fluctuations in peripheral blood
      mononuclear cells (PBMCs), and seek preliminary evidence of anticancer activity.
      EXPERIMENTAL DESIGN: Sixty-three patients were randomized to receive treatment
      with oral TEM daily on days 1-5 and BCNU administered i.v., either on day 1
      before TEM [Sequence (Seq) B-->T] or day 5 after TEM (Seq T-->B). Treatment was
      repeated every 6 weeks. Blood sampling for PK studies was performed on both days
      1 and 5 of course one. PBMCs were sampled to evaluate major sequence-dependent
      effects on AGAT levels. RESULTS: Neutropenia and thrombocytopenia were the
      principal dose-limiting toxicities of the BCNU/TEM regimen. These effects were
      more prominent in patients receiving Seq T-->B, resulting in a much lower MTD of
      80/100 mg/m(2)/day compared with 150/110 mg/m(2)/day for Seq B-->T. Notable
      antitumor activity was observed in patients with glioblastoma multiforme,
      sarcoma, and ovarian carcinoma. No sequence-dependent PK effects were noted to
      account for sequence-dependent toxicological effects. At the MTD level, AGAT
      activity in PBMCs decreased 3-fold, on average, and AGAT fluctuations did not
      appear to be sequence-dependent. CONCLUSIONS: The principal toxicities of the
      BCNU/TEM regimen were neutropenia and thrombocytopenia, which were consistent and
      predictable, albeit sequence-dependent. Seq T-->B was substantially more
      myelosuppressive, resulting in disparate MTDs and dose levels recommended for
      subsequent disease-directed evaluations (150/110 and 80/100 mg/m(2)/day for Seq B
      ->T and T-->B, respectively). Sequence-dependent differences in TEM PK do not
      account for this clinically relevant magnitude of sequence-dependent toxicity.
      The characteristics of the myelosuppressive effects of BCNU/TEM, the paucity of
      severe nonhematological toxicities, and antitumor activity at tolerable doses
      warrant disease-directed evaluations on this schedule.

PMID- 15014016
TI  - A phase I and pharmacokinetic study of irinotecan given as a 7-day continuous
      infusion in metastatic colorectal cancer patients pretreated with 5-fluorouracil
      or raltitrexed.
AB  - PURPOSE: The purpose is to determine the plasma pharmacokinetics, the maximum
      tolerable dose and to preliminary evaluate the antitumor activity of irinotecan
      administered as a 7-day continuous infusion every 21 days in metastatic
      colorectal cancer patients pretreated with 5-fluorouracil or raltitrexed.
      EXPERIMENTAL DESIGN: A total of 13 patients entered the study. Three received
      irinotecan at 20 mg/m(2)/day (dose level I), 6 at 25 mg/m(2)/day (dose level II),
      and 4 at 22.5 mg/m(2)/day (dose level III). In 8 patients, plasma levels of
      irinotecan and its metabolites SN-38 and SN-38 glucuronide (SN-38glu) were
      measured by high-performance liquid chromatography and main pharmacokinetic
      parameters, including steady-state concentration, area under the time
      concentration curve, and clearance, were calculated and normalized to the dose
      level of 22.5 mg/m(2)/day. RESULTS: Dose-limiting toxicity was grade 3-4
      diarrhea, which occurred in 4 of 6 patients at dose level II and in 2 of 4
      patients at dose level III. Therefore, we defined 22.5 mg/m(2)/day the maximum
      tolerable dose and 20.0 mg/m(2)/day the recommended dose for Phase II studies.
      Hematological toxicity was rare. The pharmacokinetic data provided evidence that
      continuous infusion increased the metabolism of irinotecan to SN-38 with respect
      to standard 30/90-min administration. Indeed, the steady-state concentration of
      irinotecan, SN-38, and SN-38glu were 42.7 +/- 25.2, 14.9 +/- 1.9, and 31.7 +/-
      3.5 nmol/liter, respectively, and the area under the time-concentration curves of
      irinotecan, SN-38, and SN-38glu were 6.94 +/- 0.41, 1.92 +/- 0.30, and 4.23 +/-
      0.52 hx micro mol/liter, respectively. Twelve patients were evaluable for
      activity, and we observed 3 (25%) partial responses, 2 (17%) minor responses, and
      4 (33%) disease stabilizations. CONCLUSIONS: The administration of irinotecan as
      a 7-day continuous infusion every 21 days is feasible with diarrhea being the
      dose-limiting toxicity; recommended dose for Phase II studies is 20.0
      mg/m(2)/day. The comparison of the present data with those obtained after a
      standard 30-90 min. i.v. infusion of irinotecan demonstrates that continuous
      infusion improves the transformation of irinotecan to SN-38 and also results in
      increased glucuronidation of the active metabolite. Antitumor activity in
      pretreated metastatic colorectal cancer patients is encouraging.

PMID- 15014017
TI  - Combination phase I trial of a novel oral fluorouracil derivative S-1 with low
      dose cisplatin for unresectable and recurrent gastric cancer (JFMC27-9902).
AB  - PURPOSE: The Japanese Foundation for Multidisciplinary Treatment of Cancer
      conducted a Phase I study of a novel oral fluorouracil derivative, S-1, combined
      with a low dose of cisplatin in unresectable and recurrent gastric cancer.
      EXPERIMENTAL DESIGN: S-1 was administered orally at 80-120 mg/body/day, depending
      on body surface area. One course consisted of consecutive administration for 28
      days followed by a rest of 14 days. Low-dose cisplatin was given i.v. on days 1
      5, 8-12, 15-19, and 22-26 of each course. The dose escalation of cisplatin began
      with an initial dose of 1 mg/m(2)/day as level 1 and was stepped up to 2, 3, 4,
      and 6 mg/m(2)/day as level 2, 3, 4, and 5, respectively. The regimen was repeated
      for at least two courses. RESULTS: A total of 24 patients was entered in the
      study. There was no treatment-related death. At level 5, consisting of 5
      evaluable patients, dose-limiting toxicity was experienced as grade 3 appetite
      loss in 2 patients and grade 4 neutropenia in 1 patient. The maximum-tolerated
      dose of cisplatin was estimated to be 6 mg/m(2)/day. We decided on a recommended
      dose of cisplatin of 4 mg/m(2)/day because the dosage was one level under the
      maximum-tolerated dose. All 3 patients at level 4 showed partial response,
      suggesting promising clinical efficacy with this dosage. The serum concentration
      of cisplatin at level 4 was 918 +/- 92 ng/ml on day 26 of the first course.
      CONCLUSIONS: S-1 with low-dose cisplatin may become an effective regimen with
      acceptable toxicity for gastric cancer.

PMID- 15014018
TI  - A pooled analysis of eastern cooperative oncology group and intergroup trials of
      adjuvant high-dose interferon for melanoma.
AB  - PURPOSE: Nearly 2000 patients with stage IIB and III melanoma have participated
      in four multicenter, randomized trials, conducted by the Eastern Cooperative
      Oncology Group and the Intergroup, investigating adjuvant high-dose IFN-alpha 2b
      therapy. The objectives of this study were to update the analyses of each
      individual trial and to analyze prognostic factors and treatment effects based on
      pooled data. EXPERIMENTAL DESIGN: Survival and disease status were updated to
      April 2001. Analysis of prognostic factors using optimized statistical models was
      based on data from patients in E1684, E1690, E1694, and E2696. Analysis of
      treatment effects versus observation (Obs) was based on data from 713 patients
      randomized to high-dose IFN-alpha 2b (HDI) or Obs in Trials E1684 and E1690.
      RESULTS: Updated analysis of E1684, E1690, and E1694 confirmed their original
      conclusions, now at median follow-up intervals of 2.1-12.6 years. Based on two
      sided univariate log-rank analysis of pooled data from E1684 and E1690 (median
      follow-up, 7.2 years), relapse-free survival (RFS)-but not overall survival (OS)
      was significantly prolonged (two-sided log-rank P value = 0.006) for patients
      treated with HDI versus Obs. Among all patients, prognostic factors that
      significantly negatively impacted RFS and OS included ulceration, recurrent
      disease at entry, enrollment in E1684, and age > 49 years. Multivariate
      statistical models adjusting for these factors confirmed the statistically
      significant RFS benefit of HDI versus Obs but did not demonstrate a significant
      OS benefit in the pooled populations. CONCLUSIONS: In patients with high-risk
      resected melanoma, HDI is effective adjuvant therapy with strong evidence for
      improved RFS and evidence for moderate improvement in OS based on two prospective
      randomized studies but not the pooled analysis. Analyses of predictors of relapse
      and response are now needed to improve the therapeutic value of this modality.

PMID- 15014019
TI  - Prognostic significance of cyclooxygenase-2 in oropharyngeal squamous cell
      carcinoma.
AB  - PURPOSE: To determine the relative prognostic significance of cyclooxygenase
      (COX)-2 expression in patients with oropharyngeal squamous cell carcinoma (SCC).
      EXPERIMENTAL DESIGN: This retrospective cohort study included 82 patients with
      SCC referred to the Department of Therapeutic Radiology at Yale-New Haven
      Hospital (Connecticut) between 1980 and 1999 who were treated with primary
      external beam radiotherapy or gross total surgical resection and postoperative
      radiotherapy. A microarray of archival tumor tissue was constructed and stained
      with monoclonal antibodies directed against COX-2 and scored for intensity by a
      pathologist blinded to the clinical outcomes of the patients. COX-2
      immunoreactivity and clinicopathological data were analyzed with respect to
      survival endpoints using bivariate and multivariate techniques. RESULTS:
      Frequency of COX-2 overexpression was 45%. In multivariate analysis, COX-2
      positivity predicted poor 3-year survival (P = 0.02; odds ratio = 0.41; 95%
      confidence interval, 0.20-0.84). Increasing age was significantly associated with
      increased 3-year survival (P = 0.03; odds ratio = 1.04; 95% confidence interval,
      1.004-1.09). Positive COX-2 status trended toward predicting decreased 3-year
      disease-free survival. CONCLUSIONS: COX-2 was the most important predictor of
      poor survival in this patient cohort. In patients with oropharyngeal SCC treated
      with external-beam radiation therapy, overexpression of COX-2 may affect clinical
      outcome, and COX-2 may therefore prove valuable both as a prognostic factor and
      as a therapeutic target.

PMID- 15014020
TI  - Detection and grading of soft tissue sarcomas of the extremities with (18)F-3'
      fluoro-3'-deoxy-L-thymidine.
AB  - PURPOSE: The aim of the study was to investigate the feasibility of (18)F-3'
      fluoro-3'-deoxy-L-thymidine positron emission tomography (FLT-PET) for the
      detection and grading of soft tissue sarcoma (STS). EXPERIMENTAL DESIGN: Nineteen
      patients with 20 STSs of the extremities were scanned, using attenuation
      corrected whole-body FLT-PET. Standardized uptake values (SUVs) and
      tumor:nontumor ratios (TNTs) were compared with histopathological parameters
      using French and Japanese grading systems. RESULTS: Mean SUV, maximal SUV, and
      TNT could differentiate between low-grade (grade 1; n = 6) STS and high-grade
      (grade 2 and 3; n = 14) STS according to the French grading system (P = 0.001).
      Mean SUV, max SUV, and TNT correlated with mitotic score, MIB-1 score, the French
      and Japanese grading system (* = 0.550-0.747). CONCLUSIONS: FLT-PET is able to
      visualize STS and differentiate between low-grade and high-grade STS. The uptake
      of FLT correlates with the proliferation of STS.

PMID- 15014021
TI  - Breast cancer resistance protein impacts clinical outcome in platinum-based
      chemotherapy for advanced non-small cell lung cancer.
AB  - PURPOSE: The purpose of this study was to investigate the relationship between
      the level of expression of ATP-binding cassette (ABC) transporter proteins, and
      response to chemotherapy and prognosis in advanced non-small cell lung cancer
      (NSCLC). EXPERIMENTAL DESIGN: Expression of ABC transporter proteins, including P
      glycoprotein, multidrug resistance protein (MRP) 1, MRP2, MRP3, and breast cancer
      resistance protein (BCRP), was examined immunohistochemically in 72 formalin
      fixed tumor samples from untreated stage IIIB or IV NSCLC patients. All of the
      patients received platinum-based chemotherapy. Response to chemotherapy,
      progression-free survival (PFS), and overall survival were compared in relation
      to expression of each of the ABC transporter proteins and clinicopathological
      factors. RESULTS: Expression of P-glycoprotein, MRP1, and MRP3 was not
      significantly associated with response to chemotherapy or survival. MRP2
      expression was associated with overall survival (P = 0.002) but not with response
      to chemotherapy and PFS. By contrast, the response rate to chemotherapy of
      patients with BCRP-negative tumors was 44%, as opposed to 24% in patients with
      BCRP-positive tumors. Response rate was lower in BCRP-positive tumors, although
      this difference was not statistically significant (P = 0.08). BCRP-positive
      patients had also shorter PFS (P = 0.0003) and overall survival (P = 0.004) than
      BCRP-negative patients. Multivariate analysis confirmed BCRP status as an
      independent variable related to PFS (P = 0.001). CONCLUSIONS: Positive
      immunostaining for BCRP appears to be a predictor of survival in patients with
      advanced NSCLC. These findings indicate that BCRP may serve as a molecular target
      for reducing drug resistance to chemotherapy in advanced NSCLC patients.

PMID- 15014022
TI  - Epstein-barr virus-positive gastric carcinoma has a distinct protein expression
      profile in comparison with epstein-barr virus-negative carcinoma.
AB  - PURPOSE: EBV has been detected in 2-16% of gastric carcinomas. However, there is
      little information available about the gene expression profile of EBV-positive
      gastric carcinomas. EXPERIMENTAL DESIGN: EBV infection was examined using EBV
      encoded small RNAs (EBERs) in situ hybridization, and 63 (5.6%) of 1127
      consecutive gastric carcinomas were found to be EBV-positive. The expressions of
      27 tumor-associated proteins were evaluated immunohistochemically in 63 EBV
      positive gastric carcinomas and 287 EBV-negative carcinomas using the tissue
      array method. In addition, the genotype of EBV was investigated by PCR
      amplification of LMP1 (latent membrane protein 1), Epstein-Barr nuclear antigen 2
      (EBNA2), and EBNA3B genes. RESULTS: EBV-positive gastric carcinomas are
      characterized by the presence of lymphoid stroma, proximal location, and
      predominance in males. In comparison with EBV-negative carcinomas, EBV-positive
      carcinomas showed frequent loss of expression of p16, smad4, FHIT, and KAI-1
      (kangai 1; P < 0.05), but retained the expression of APC (adenomatous polyposis
      coli), DCC (deleted in colorectal cancer), and some DNA repair proteins (P <
      0.05). There was negative association between EBV infection and the expression of
      MUC1, MUC2, MUC5AC, p53, CEA, C-erbB2, and smad7. Using hierarchical cluster
      analysis, we divided EBV-positive gastric carcinomas into two clusters. Those
      patients with cluster 1 (42 cases) carcinomas had a better prognosis than those
      with cluster 2 (12 cases; P = 0.0002) or those with EBV-negative carcinomas (280
      cases; P = 0.0251). Fifty-one (92.7%) of 55 EBV-positive carcinomas demonstrated
      the 30-bp deletion in LMP1 gene, and 53 (96.4%) of 55 cases were type 1 for EBNA2
      and EBNA3B genes. CONCLUSION: EBV-positive gastric carcinomas have a distinct
      protein expression profile as well as distinct clinicopathological features, as
      compared with EBV-negative carcinomas. The subclassification of EBV-positive
      carcinomas, by hierarchical cluster analysis, is significantly associated with
      patient survival.

PMID- 15014023
TI  - Association between HER-2/neu and vascular endothelial growth factor expression
      predicts clinical outcome in primary breast cancer patients.
AB  - PURPOSE: Activation or overexpression of HER-2/neu is associated with up
      regulation of vascular endothelial growth factor (VEGF) in human breast cancer
      cells in vitro. Preclinical experiments indicate that increased expression of
      VEGF may in part mediate the biologically aggressive phenotype of HER-2/neu
      overexpressing human breast cancer. It was the purpose of this study to: (a).
      evaluate the association between HER-2/neu and VEGF expression in a large
      clinical cohort of primary breast cancer patients; (b). compare the prognostic
      significance of VEGF isoforms; and (c). analyze the combined effects of HER-2/neu
      and VEGF on clinical outcome. EXPERIMENTAL DESIGN: HER-2/neu and VEGF were
      measured by ELISA in primary breast tumor tissue lysates from 611 unselected
      patients with a median clinical follow-up of 50 months. At least six VEGF
      isoforms consisting of 121, 145, 165, 183, 189, or 206 amino acids are generated
      as a result of alternative splicing. The VEGF(121-206) ELISA uses antibodies that
      bind to VEGF(121) and, therefore, detects all of the VEGF isoforms with 121 and
      more amino acids. The VEGF(165-206) ELISA uses antibodies that bind to VEGF(165)
      and, therefore, detects all of the VEGF isoforms with 165 and more amino acids.
      VEGF(121-206) and VEGF(165-206) were analyzed both as continuous and categorical
      variables, using detectable expression as a cutoff for positivity. Cell lines
      with defined HER-2/neu expression levels were used to establish a cutoff point
      for HER-2/neu overexpression in breast tumor samples. RESULTS: Our findings
      indicate a significant positive association between HER-2/neu and VEGF
      expression. VEGF(121-206) and VEGF(165-206) expression was detectable in 88
      (77.2%) and 100 (87.7%), respectively, of the 114 patients with HER-2/neu
      overexpressing tumors, in contrast to 271 (54.5%) and 353 (71.0%), respectively,
      of the 497 patients with nonoverexpressing tumors (chi(2) test: P < 0.001 for
      both VEGF(121-206) and VEGF(165-206)). VEGF(121-206) and VEGF(165-206)
      demonstrate a comparable prognostic significance for survival in unselected
      primary breast cancer patients (univariate analysis: VEGF(121-206), P = 0.0068;
      VEGF(165-206), P = 0.0046; multivariate analysis: VEGF(121-206), P = 0.1475;
      VEGF(165-206), P = 0.1483). When the analyses were performed separately for node
      negative and node-positive patients, VEGF(121-206) and VEGF(165-206) were of
      prognostic significance for survival only in node-positive patients (univariate
      analysis: VEGF(121-206), P = 0.0003; VEGF(165-206), P = 0.0038; multivariate
      analysis: VEGF(121-206), P = 0.0103; VEGF(165-206), P = 0.0150). A biological
      concentration-effect relationship between VEGF expression and survival (VEGF(121
      206), P = 0.0280; VEGF(165-206,) P = 0.0097) suggests that VEGF levels, as
      determined by ELISA, could be of importance as a predictive marker for
      therapeutic strategies that target VEGF. Combining HER-2/neu and VEGF(121
      206)/VEGF(165-206) results in additional prognostic information for survival
      (VEGF(121-206), P = 0.0133; VEGF(165-206), P = 0.0092). CONCLUSION: The positive
      association between HER-2/neu and VEGF expression implicates VEGF in the
      aggressive phenotype exhibited by HER-2/neu overexpression, and supports the use
      of combination therapies directed against both HER-2/neu and VEGF for treatment
      of breast cancers that overexpress HER-2/neu.

PMID- 15014024
TI  - Alterations of p16 and prognosis in biliary tract cancers from a population-based
      study in China.
AB  - PURPOSE: Biliary tract cancer is an uncommon malignancy with a poor survival
      rate. We evaluated p16 gene alteration as a prognostic marker for this disease.
      EXPERIMENTAL DESIGN: We studied p16 gene alterations by sequencing, methylation,
      and loss of heterozygosity of chromosome 9p in 118 biliary tract carcinomas,
      including 68 gallbladder cancers, 33 extrahepatic bile duct cancers, and 17
      ampullary cancers. Survival was evaluated in 57 patients with gallbladder
      carcinomas, 27 with bile duct carcinomas, and 16 with ampullary carcinomas with
      and without somatic p16 alterations detected by two different methods. RESULTS:
      p16 gene alterations including silent mutations were present in 61.8% gallbladder
      cancers, 54.5% bile duct cancers, and 70.6% ampullary cancers. p16 gene nonsilent
      mutations, p16 methylation, and loss of chromosome 9p21-22 that targets p14, p15,
      and p16 genes were present in 13 of 53 (24.5%), 8 of 54 (14.8%), and 32 of 44
      (72.7%) gallbladder tumors; 5 of 25 (20.0%), 5 of 31 (16.1%), and 12 of 21
      (57.1%) bile duct tumors; and 3 of 13 (23.1%), 6 of 15 (40.0%), and 8 of 16
      (50.0%) ampullary tumors, respectively. The mean survival of patients with
      gallbladder cancers without p16 alterations was 21.5 +/- 14.8 months compared
      with 12.1 +/- 11.4 months for patients with p16 alterations (P = 0.02).
      CONCLUSIONS: Alteration of p16 gene alone or in combination with alterations of
      other tumor suppressor genes on chromosome 9p is a prognostic indicator in
      gallbladder carcinoma, with more favorable survival rates associated with
      carcinomas lacking p16 gene alterations.

PMID- 15014025
TI  - Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients
      with nonnasopharyngeal head and neck carcinomas.
AB  - PURPOSE: We investigated the detectability of EBV DNA in the plasma of patients
      with non-nasopharyngeal head and neck carcinomas (NNHNC). Previous studies have
      shown that EBV is present in the tumor tissue of some NNHNC. EXPERIMENTAL DESIGN:
      We recruited 101 patients with NNHNC and 48 healthy controls. Blood samples were
      taken from controls and patients before treatment. Tumor tissue samples were
      tested for the presence of EBV in the first 69 patients by in situ hybridization
      for small EBV-encoded RNA (EBER). Plasma EBV DNA was measured by real-time
      quantitative PCR in patients and controls. RESULTS: Squamous cell carcinoma (SCC)
      was the commonest histology (78 patients) followed by lymphoepithelial carcinoma
      (8 patients). EBER was detected in tumor cells in 7 of 69 patients tested. All of
      the EBER-positive tumors were lymphoepithelial carcinoma. Two controls (2 of 48;
      4.2%) had detectable plasma EBV DNA. Plasma EBV DNA was detected in all of the
      patients with EBER-positive tumors, and in 23 of 94 (24.5%) patients with tumors
      of EBER-negative or unknown status. The proportion of plasma EBV DNA-positive
      cases in either group was significantly higher than that in the control group (P
      < 0.0027). Plasma EBV DNA concentrations in patients with EBER-positive tumors
      (median, 3827 copies/ml) were significantly higher than those in the controls
      (median, 0 copy/ml; P = 0.0001). Of patients with SCC, 21 (26.9%) had detectable
      plasma EBV DNA (median concentration, 34 copies/ml). Plasma EBV DNA
      concentrations in the whole group of patients with SCC (median, 0 copy/ml;
      interquartile range, 0-4 copies/ml) were also significantly higher than those in
      the controls (P = 0.001). CONCLUSIONS: Our data indicate that plasma EBV DNA
      reflects tumoral EBER status, and it may be of use as a tumor marker for EBER
      positive NNHNC. The biological and clinical significance of low levels of
      circulating EBV DNA in the minority of patients with EBER-negative tumors remain
      to be elucidated.

PMID- 15014026
TI  - Hypermethylation of the retinoic acid receptor-beta(2) gene in head and neck
      carcinogenesis.
AB  - PURPOSE: Retinoic acid receptor-beta(2) (RAR-beta(2)) expression is suppressed in
      oral premalignant lesions and head and neck squamous cell carcinomas (HNSCCs).
      This study was conducted to determine whether RAR-beta(2) gene expression in such
      lesions can be silenced by promoter methylation. EXPERIMENTAL DESIGN: RAR-beta(2)
      methylation was analyzed in DNA samples from 22 pairs of primary HNSCC and
      adjacent normal epithelium, 124 samples of oral leukoplakia, and 18 HNSCC cell
      lines using methylation-specific PCR. RAR-beta(2) promoter was methylated in 67,
      56, and 53% of HNSCC tumors, HNSCC cell lines, and microdissected oral
      leukoplakia specimens, respectively. RAR-beta(2) hypermethylation was confirmed
      by sodium bisulfite-PCR combined with restriction enzyme digestion analysis and
      by random cloning and sequencing of bisulfite-treated DNA isolates. RESULTS:
      Significantly higher RAR-beta(2) hypermethylation levels were found in tumor
      tissue compared with adjacent normal tissue (P = 0.002). RAR-beta(2) methylation
      in the cell lines was correlated with loss of RAR-beta(2) expression (P = 0.013)
      and inversely related to the presence of mutated p53 (P = 0.025). The
      demethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR) restored RAR-beta(2)
      inducibility by all-trans-retinoic acid (ATRA) in some of the cell lines, which
      posses a methylated RAR-beta(2) promoter. In some cell lines, this effect was
      associated with increased growth inhibition after combined treatment with 5-aza
      CdR and ATRA. CONCLUSIONS: RAR-beta(2) silencing by methylation is an early event
      in head and neck carcinogenesis; 5-Aza-CdR can restore RAR-beta(2) inducibility
      by ATRA in most cell lines, and the combination of 5-aza-CdR and ATRA is more
      effective in growth inhibition than single agents.

PMID- 15014027
TI  - Prognostic significance of p27(kip-1) expression in colorectal adenocarcinomas is
      associated with tumor stage.
AB  - PURPOSE: Although the decreased expression of p27(kip-1), a cyclin-dependent
      kinase inhibitor, has been correlated with advanced tumor stage and short
      survival of patients with colorectal adenocarcinomas (CRCs), its prognostic value
      based on the tumor site, tumor stage, and patient ethnicity was not assessed.
      Therefore, in this study, we investigated whether the prognostic value of p27(kip
      1) expression varies with the tumor site, tumor stage and patient ethnicity.
      EXPERIMENTAL DESIGN: We evaluated 206 (85 African Americans and 121 Caucasians)
      archival tissue specimens of first primary CRCs for immunohistochemical
      expression of p27(kip-1), and its prognostic significance was analyzed using
      univariate Kaplan-Meier and multivariate Cox regression survival methods.
      RESULTS: Although, similar proportion of CRCs with decreased p27(kip-1)
      expression was observed in all stages (range, 26-36%), the decreased p27(kip-1)
      expression has been shown as a marker of poor prognosis only for patients with
      stage III tumors both in univariate (log-rank test, P = 0.014) and multivariate
      (hazard ratio = 3.2, 95% confidence interval = 1.3-7.7; P = 0.01) survival
      analyses. The decreased expression of p27(kip-1) was associated with a high
      histologic grade (P = 0.016) in stage II CRCs, and with distal tumors (P =
      0.001), tumor invasion (P = 0.044), and with local recurrence (P = 0.008) in
      stage III CRCs. CONCLUSIONS: No prognostic significance was found for p27(kip-1)
      expression in stages I, II, or IV CRCs, and its prognostic value was not
      associated with either ethnicity or tumor location. These studies suggest that
      decreased expression of p27(kip-1) is an indicator of poor prognosis and aids in
      identifying a subset of patients with aggressive forms of stage III CRCs.

PMID- 15014029
TI  - Allelic loss of a common microsatellite marker MYCL1: a useful prognostic factor
      of poor outcomes in colorectal cancer.
AB  - PURPOSE: Allelic loss involving chromosome arms 5q, 8p, 17p, and 18q is commonly
      detected in colorectal cancer (CRC). The short arm of chromosome 1 is also
      frequently affected in a whole range of cancer types, including CRC. Our aim in
      the present study was to determine whether allelic losses on 1p were likely to be
      of much value in predicting the prognosis of CRC cases. EXPERIMENTAL DESIGN:
      Genomic DNA was prepared from tumor and corresponding normal tissue specimens
      from 90 patients who had undergone curative resection for CRC. Loss of
      heterozygosity (LOH) on chromosome arms 1p, 2p, 5q, 7q, 8p, 17p, 17q, and 18q was
      examined using 14 microsatellite markers, and possible correlations between LOH
      and clinicopathological factors (including tumor recurrence and patient survival)
      were investigated. LOH at the MYCL1 microsatellite marker at 1p34 was detected in
      12 of 74 (16.2%) patients who were informative for this marker. RESULTS: After
      controlling for tumor stage and gender and excluding findings for patients with
      remote metastasis, we found that patients who were positive for LOH at MYCL1 were
      31 times more likely to experience recurrence than those who were negative for
      LOH at this locus (95% confidence intervals, 2.27- infinity; P = 0.04). There
      were indications of a similar tendency for LOH at the 14-3-3-sigma-TG
      microsatellite marker at 1p35, but we could find no evidence of a significant
      association between LOH at this site and tumor recurrence or patient survival. We
      were also unable to detect significant association between LOH at the various
      sites on 2p, 5q, 7q, 8p, 17p, 17q, and 18q and either tumor recurrence or patient
      survival. CONCLUSIONS: CRC patients whose tumors exhibited LOH at MYCL1 at
      chromosome 1p34 were likely to have a poor prognosis, suggesting that this marker
      may have clinical relevance.

PMID- 15014028
TI  - Incidence of BRAF oncogene mutation and clinical relevance for primary cutaneous
      melanomas.
AB  - PURPOSE: The purpose of the study was to clarify the incidence of B-raf oncogene
      (BRAF) mutations in primary cutaneous melanomas, their relation to tumor
      progression, and effect on disease outcome. Somatic mutations of BRAF kinase, a
      component of the Ras-mitogen-activated protein/extracellular signal-regulated
      kinase kinase-mitogen-activated protein kinase pathway, are frequently reported
      (>65%) in nevi and malignant melanomas. EXPERIMENTAL DESIGN: We assessed BRAF
      mutation frequency in exons 11 and 15 in primary (n = 59) and metastatic (n = 68)
      melanomas. Direct sequencing of PCR products was performed on DNA isolated and
      purified from microdissected tumors. RESULTS: Eighteen mutations (31%) at exon 15
      were detected in primary melanoma with a significantly (P = 0.001) higher
      frequency in patients < 60 years old. Incidence of BRAF mutation did not
      correlate with Breslow thickness. Presence of BRAF mutation of primary tumors did
      not effect overall disease-free survival. BRAF mutation frequency in metastatic
      lesions was 57% and significantly (P = 0.0024) higher than primary melanomas.
      CONCLUSIONS: The study suggests that BRAF mutation may be acquired during
      development of metastasis but is not a significant factor for primary tumor
      development and disease outcome.

PMID- 15014030
TI  - [(11)C]methionine positron emission tomography and survival in patients with bone
      and soft tissue sarcomas treated by carbon ion radiotherapy.
AB  - PURPOSE: The development of the novel carbon ion radiotherapy (CIRT) in the
      treatment of refractory cancers has resulted in the need for a way to accurately
      evaluate patient prognosis. We evaluated whether L-[methyl-(11)C]-methionine
      (MET) uptake and its change after CIRT were the early survival predictors in
      patients with unresectable bone and soft tissue sarcomas. EXPERIMENTAL DESIGN:
      MET positron emission tomography was prospectively performed in 62 patients with
      unresectable bone and soft tissue sarcomas before and within 1 month after CIRT.
      Tumor MET uptake was measured with the semiquantitative tumor:nontumor ratio (T/N
      ratio). The MET uptake in the tumor and relevant clinical parameters were entered
      into univariate and multivariate survival analysis. RESULTS: The overall median
      survival time was 20 months. Patients with a baseline T/N ratio of <or=6 had a
      significant better survival than patients with a baseline T/N ratio >6 (2-year
      survival rate: 69.4% versus 32.3%; P = 0.01). Patients with a post-CIRT ratio of
      <or=4.4 had a better survival than that with a post-CIRT ratio >4.4 (2-year
      survival rate: 63.7% versus 41.3%; P = 0.01). A significant higher survival rate
      was observed in patients with post-therapeutic MET uptake change of >30% than
      patients in lower change group (2-year survival rate: 74.6% versus 41.6%; P =
      0.049). The multivariate analysis showed that both baseline and post-CIRT T/N
      ratio were statistically significant independent predictors of patient survival.
      Tumors with larger T/N ratio had a significantly poorer prognosis. CONCLUSIONS:
      MET uptake as measured by either baseline or post-CIRT T/N ratio was an
      independent predictor of survival in patients with bone and soft tissue sarcomas
      treated by carbon ion radiotherapy, whereas post-therapeutic MET uptake change
      might have potential value for the same purpose.

PMID- 15014031
TI  - Expression of N-acetylglucosaminyltransferase v is associated with prognosis and
      histology in non-small cell lung cancers.
AB  - PURPOSE: N-Acetylglucosaminyltransferase V (GnT-V), a key enzyme in the formation
      of branching of asparagine-linked oligosaccharides, is strongly linked to tumor
      invasion and metastasis of colon and breast cancers. However, GnT-V is expressed
      in many tissues, including normal lung. GnT-V expression has not been examined
      previously in human lung cancers. The objective of this study is to examine GnT-V
      expression in non-small cell lung cancers (NSCLCs) and to determine its
      relationship to biological and clinicopathological characteristics and prognosis.
      EXPERIMENTAL DESIGN: GnT-V expression was studied by immunohistochemistry in 217
      surgically resected NSCLCs and analyzed statistically in relation to various
      characteristics. RESULTS: High GnT-V expression was found in 113 (52.1%) NSCLCs,
      and low GnT-V expression was found in 104 (47.9%) NSCLCs. Multivariate logistic
      regression analysis revealed a significant association between low GnT-V
      expression and squamous cell carcinomas, as compared with nonsquamous cell
      carcinomas (P = 0.02). Among biological characteristics of tumors, Ki-67 labeling
      index was higher in tumors with low GnT-V expression than in those with high GnT
      V expression, although this difference was not statistically significant (P =
      0.09). Patients with tumors having low GnT-V expression had significantly shorter
      survival time than patients with tumors having high GnT-V expression in 103
      patients with pStage I NSCLCs (5-year survival rates, 49% and 86%, respectively;
      P = 0.0009), as well as in 59 patients with pStage I non-squamous cell carcinomas
      (5-year survival rates, 54% and 89%, respectively; P = 0.007). Low GnT-V
      expression was a significant unfavorable prognostic factor in pStage I NSCLCs
      (hazard ratio, 2.86; P = 0.002) and in pStage I nonsquamous cell carcinomas
      (hazard ratio, 3.02; P = 0.02). Furthermore, beta1-6 branching of asparagine
      linked oligosaccharides, which are products of GnT-V, were increased highly or
      moderately in 8 of 10 tumors with high GnT-V expression, as judged by
      leukoagglutinating phytohemagglutinin staining. CONCLUSIONS: GnT-V expression is
      associated with histology in NSCLCs. Low GnT-V expression is associated with
      shorter survival and poor prognosis in pStage I overall NSCLCs and non-squamous
      cell carcinomas.

PMID- 15014032
TI  - Molecular pathology shows p16 methylation in nonadenomatous pituitaries from
      patients with Cushing's disease.
AB  - PURPOSE: The majority of cases of Cushing's disease are due to the presence of a
      corticotroph microadenoma. Less frequently no adenoma is found and histology
      shows either corticotroph hyperplasia, or apparently normal pituitary. In this
      study we have used molecular pathology to determine whether the tissue labeled
      histologically as "normal" is indeed abnormal. EXPERIMENTAL DESIGN: Tissue from
      31 corticotroph adenomas and 16 nonadenomatous pituitaries were subject to
      methylation-sensitive PCR to determine the methylation status of the p16 gene CpG
      island. The proportion of methylated versus unmethylated CpG island was
      determined using combined bisulphite restriction analysis. Methylation status was
      correlated with immunohistochemical detection of p16. RESULTS: Seventeen of 31
      adenomas (54.8%), 4 of 6 cases of corticotroph hyperplasia, and 7 of 10
      apparently normal pituitaries showed p16 methylation. Ten of 14 (71%; P = 0.01)
      adenomas and 2 of 3 cases of corticotroph hyperplasia, which were methylated,
      failed to express p16 protein. However, only 2 of 7 apparently normal pituitaries
      that were methylated failed to express p16 protein. Quantitative analysis of
      methylation using combined bisulphite restriction analysis showed only
      unmethylated CpG islands in postmortem normal pituitaries; however, in adenomas
      80-90% of the cells within a specimen were methylated. The reverse was true for
      corticotroph hyperplasia and apparently normal pituitaries where only 10-20% of
      the cells were methylated. Thus, the decreased proportion of cells that were
      methylated, particularly in those cases of apparently normal pituitary, is the
      most likely explanation for the lack of association between this change and loss
      of cognate protein in these cases. CONCLUSIONS: To our knowledge this is the
      first report that describes an intrinsic molecular change, namely methylation of
      the p16 gene CpG island, common to all three histological patterns associated
      with Cushing's disease. Thus, the use of molecular pathology reveals
      abnormalities undetected by routine pathological investigation. In cases of
      "apparently" normal pituitaries it is not possible to determine whether the
      change is associated with adenoma cells "scattered" throughout the gland, albeit
      few in number, or with the ancestor-clonal origin of these tumor cells.

PMID- 15014033
TI  - Predictive value of biological markers for hepatocellular carcinoma patients
      treated with orthotopic liver transplantation.
AB  - PURPOSE: To help stratify candidates with hepatocellular carcinoma (HCC) for
      orthotopic liver transplantation (OLT), biomarkers are needed that are capable of
      predicting recurrence of disease (ROD). We investigated the prognostic role in
      this setting of immunohistochemical markers reported previously to predict poor
      prognosis in HCC patients treated with resection. EXPERIMENTAL DESIGN: Eighty
      three patients with HCC who underwent OLT between 1987 and 2001 with a minimum
      clinical follow up of 12 months were included in this retrospective study. We
      analyzed immunohistochemical expression of the adhesion molecules E-cadherin and
      beta-catenin (membrane/nuclear localization), MIB-1 proliferative index and the
      cyclin-dependent kinase inhibitor p27, alongside the main clinical-pathological
      variables. RESULTS: At univariate analysis, vascular thrombosis, high MIB-1
      index, lower membrane expression of E-cadherin and beta-catenin, and nuclear beta
      catenin localization were associated with ROD. At multivariate analysis, only MIB
      1 index, low equal E-cadherin (with respect to non-neoplastic surrounding
      tissue), and nuclear beta-catenin appeared as independent predictors of ROD. The
      logistic regression analysis model indicated that detection of any one parameter
      was associated with at least 88% estimated risk of ROD (up to 99% for all three).
      CONCLUSIONS: We propose these three molecular parameters as an additional tool
      for rational selection of OLT candidates among HCC patients (stratification
      according to the risk of ROD might help provide a similar life expectancy for
      cirrhotic candidates with and without HCC).

PMID- 15014034
TI  - Elevated serum insulin-like growth factor binding protein-2 as a prognostic
      marker in patients with ovarian cancer.
AB  - PURPOSE: The purpose of this research was to examine the diagnostic and
      prognostic significance of elevated serum insulin-like growth factor binding
      protein (IGFBP)-2 levels in women with ovarian cancer from diagnosis through
      treatment to relapse or remission. EXPERIMENTAL DESIGN: Serum collected pre- and
      postoperatively in women newly diagnosed with ovarian cancer, during adjuvant
      chemotherapy cycles, at 6 months follow-up and at relapse was analyzed for IGFBP
      2. Control serum was from women undergoing pelvic or abdominal surgery for benign
      ovarian disease or nonovarian pathology. RESULTS: IGFBP-2 at diagnosis was
      significantly elevated (P < 0.0001) in women with ovarian cancer (887 +/- 62
      ng/ml) compared with benign controls (337 +/- 25 ng/ml), and women undergoing
      nonovarian surgery (439 +/- 49 ng/ml) and correlated positively with tumor stage
      and cellular differentiation but not with CA125. Unexpectedly, IGFBP-2 levels
      increased additionally 1-week postoperatively in ovarian cancer patients (1581 +/
      90 ng/ml; P = 0.0027) as well as controls (977 +/- 95 ng/ml; P < 0.0001) and was
      higher in women who had suboptimal debulking compared with optimal debulking of
      their tumor. IGFBP-2 levels returned to normal in women without evidence of
      progressive disease, but remained significantly elevated in women who later
      relapsed. Patients with IGFBP-2 levels in the highest tertile at diagnosis had a
      significantly shorter progression-free interval and overall survival. CONCLUSION:
      In ovarian cancer IGFBP-2 is elevated at diagnosis, and corresponds to stage and
      histology with patients in the highest tertile of IGFBP-2 more likely to relapse
      and have a poorer outlook. Identification of these patients at diagnosis may
      allow more individualized, aggressive adjuvant treatment and follow-up, and IGFBP
      2 may therefore be an important additional prognostic marker in this disease.

PMID- 15014035
TI  - The stable nitroxide tempol facilitates salivary gland protection during head and
      neck irradiation in a mouse model.
AB  - PURPOSE: Radiotherapy is commonly used to treat a majority of patients with head
      and neck cancers. The long-term radiation-induced reduction of saliva output
      significantly contributes to the posttreatment morbidity experienced by these
      patients. The purpose of this study was to test the ability of the stable-free
      radical Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), an established
      radioprotector, to prevent radiation-induced salivary hypofunction in mice.
      EXPERIMENTAL DESIGN: The heads of C3H mice were exposed to a range of single
      radiation doses with or without an i.p. injection of 275 mg/kg Tempol 10 min
      before treatment. Salivary gland output was assessed 8 weeks postirradiation.
      RESULTS: Radiation caused a dose-dependent reduction in salivary flow in this
      model. Tempol treatment alone significantly reduced radiation-induced salivary
      hypofunction. The combination of Tempol with mouth/nose shielding showed
      essentially complete radiation protection at 15 Gy and approximately 75%
      protection at 17.5 Gy. CONCLUSIONS: This study demonstrates for the first time
      that significant radioprotection of the salivary glands is possible with Tempol
      in C3H mice.

PMID- 15014036
TI  - Abrogation of p21 expression by flavopiridol enhances depsipeptide-mediated
      apoptosis in malignant pleural mesothelioma cells.
AB  - PURPOSE: Recent insights regarding the pathogenesis of malignant pleural
      mesothelioma (MPM) provide new opportunities for targeted molecular therapies for
      this highly lethal disease. The present study was undertaken to examine the
      effects of the histone deacetylase inhibitor, Depsipeptide (DP) FK228, in
      conjunction with the cyclin-dependent kinase inhibitor, Flavopiridol (FLA), in
      cultured MPM cells. EXPERIMENTAL DESIGN: Proliferation and apoptosis in drug
      treated, virally transduced, or control cells were assessed by 3-(4,5
      dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Apo-bromodeoxyuridine
      techniques. Western blot and ELISA techniques were used to examine signal
      transduction and cell cycle-related protein levels in MPM cells exposed to DP
      and/or FLA in the presence or absence of calphostin, phorbol-12,13-dibutyrate,
      5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole, or adenoviral p21
      transduction. RESULTS: DP (1-50 ng/ml x 6 h) or FLA (100-200 nM x 72 h) alone,
      mediated low-level, dose-dependent growth inhibition in MPM cells. In contrast,
      sequential DP/FLA treatment mediated marked growth inhibition and apoptosis in
      these cell lines. The cytotoxic effects of DP/FLA were considerably less
      pronounced in cultured normal cells. The proapoptotic effects of DP/FLA treatment
      coincided with inhibition of DP-mediated induction of p21 by FLA. Overexpression
      of p21 by adenoviral gene transfer techniques rendered MPM cells refractory to
      the cytotoxic effects of this treatment regimen. In p21 reporter assays, promoter
      activation by DP was antagonized by FLA. The magnitude of inhibition of DP
      mediated p21 induction by FLA exceeded that observed with the pTEFb antagonist
      5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole. Calphostin C abrogated p21
      induction mediated by DP and enhanced DP-mediated apoptosis in a manner
      comparable with FLA in MPM cells; in contrast, phorbol-12,13-dibutyrate blocked
      FLA-mediated inhibition of p21 induction by DP and markedly protected these cells
      from the apoptotic effects of sequential DP/FLA. CONCLUSIONS: FLA abrogates DP
      mediated induction of p21 expression, in part, via inhibition of protein kinase C
      signaling and markedly potentiates the cytotoxic effects of DP in MPM cells.

PMID- 15014037
TI  - VX-710 (biricodar) increases drug retention and enhances chemosensitivity in
      resistant cells overexpressing P-glycoprotein, multidrug resistance protein, and
      breast cancer resistance protein.
AB  - PURPOSE: The pipecolinate derivative VX-710 (biricodar; Incel) is a clinically
      applicable modulator of P-glycoprotein (Pgp) and multidrug resistance protein
      (MRP-1); we studied its activity against the third multidrug resistance (MDR)
      associated drug efflux protein, breast cancer resistance protein (BCRP).
      EXPERIMENTAL DESIGN: VX-710 modulation of uptake, retention, and cytotoxicity of
      mitoxantrone, daunorubicin, doxorubicin, topotecan, and SN38 was studied in cell
      lines overexpressing Pgp, MRP-1 and wild-type (BCRP(R482)) and mutant
      (BCRP(R482T)) BCRP. RESULTS: In 8226/Dox6 cells (Pgp), VX-710 increased
      mitoxantrone and daunorubicin uptake by 55 and 100%, respectively, increased
      their retention by 100 and 60%, respectively, and increased their cytotoxicity
      3.1- and 6.9-fold, respectively. In HL60/Adr cells (MRP-1), VX-710 increased
      mitoxantrone and daunorubicin uptake by 43 and 130%, increased their retention by
      90 and 60%, and increased their cytotoxicity 2.4- and 3.3-fold. In 8226/MR20
      cells (BCRP(R482)), VX-710 increased mitoxantrone uptake and retention by 60 and
      40%, respectively, and increased cytotoxicity 2.4-fold. VX-710 increased
      daunorubicin uptake and retention by only 10% in 8226/MR20 cells, consistent with
      the fact that daunorubicin is not a substrate for BCRP(R482), but, nevertheless,
      it increased daunorubicin cytotoxicity 3.6-fold, and this increase was not
      associated with intracellular drug redistribution. VX-710 had little effect on
      uptake, retention, or cytotoxicity of mitoxantrone, daunorubicin, doxorubicin,
      topotecan, or SN38 in MCF7 AdVP3000 cells (BCRP(R482T)). CONCLUSIONS: VX-710
      modulates Pgp, MRP-1, and BCRP(R482), and has potential as a clinical broad
      spectrum MDR modulator in malignancies such as the acute leukemias in which these
      proteins are expressed.

PMID- 15014038
TI  - Inhibition of orthotopic human bladder tumor growth by lentiviral gene transfer
      of endostatin.
AB  - PURPOSE: Inhibitors of endothelial cell proliferation, such as endostatin, result
      in suppression of tumor-associated angiogenesis and can achieve growth-inhibitory
      effects depending on the type of tumor treated. The purpose of this study was to
      investigate whether local overexpression of endostatin could serve to diminish
      tumor growth of bladder cancer in vivo. EXPERIMENTAL DESIGN: We examined the
      capability of lentiviral-mediated gene transfer in vitro and therapeutic effects
      of lentivirus-based vectors expressing endostatin on tumor growth using an
      orthotopic human bladder tumor model. RESULTS: We found that self-inactivating
      lentivirus vectors containing green fluorescent protein, alone or in combination
      with endostatin, were capable of efficient and stable gene transfer to a variety
      of human bladder tumor cell lines. The production and secretion of endostatin
      from lentivirus-transduced KU-7 human bladder cancer cells was confirmed by
      Western blot and competitive enzyme immunoassay. Intravesical instillation of
      untransduced, green fluorescent protein control lentivirus-transduced, and
      endostatin-transduced KU-7 cells was performed in murine models to establish
      orthotopic tumors. Sustained long-term expression of endostatin was achieved in
      lentivirus-transduced orthotopic bladder tumors, and it was associated with
      decreased vascularization and inhibition of tumor growth. Lentivirus vector
      mediated overexpression of endostatin did not affect the intrinsic production of
      basic fibroblast growth factor and vascular endothelial growth factor.
      CONCLUSIONS: These findings suggest that lentivirus-mediated gene transfer might
      represent an effective strategy for expression of angioinhibitory peptides to
      achieve inhibition of human bladder cancer proliferation and tumor progression.

PMID- 15014039
TI  - Blockage of 2-deoxy-D-ribose-induced angiogenesis with rapamycin counteracts a
      thymidine phosphorylase-based escape mechanism available for colon cancer under 5
      fluorouracil therapy.
AB  - PURPOSE: Colorectal neoplasms remain a leading cause of cancer-related deaths. A
      recognized weakness of conventional 5-fluorouracil (5-FU) therapy relates to
      expression of the intracellular enzyme, thymidine phosphorylase (TP). Although TP
      promotes 5-FU cytotoxicity, TP-derived 2-deoxy-D-ribose (dRib)
      counterproductively stimulates tumor angiogenesis. Here, the newly discovered
      antiangiogenic drug rapamycin was combined with 5-FU to counteract the potential
      escape mechanism of dRib-induced angiogenesis. EXPERIMENTAL DESIGN: Orthotopic
      tumor growth was assessed in rapamycin and 5-FU-treated BALB/c mice with TP
      expressing CT-26 colon adenocarcinoma cells. To examine liver metastasis, green
      fluorescent protein-transfected CT-26 cells were visualized by fluorescence
      microscopy after intraportal injection. Cell counting and Ki67 staining were used
      to determine in vitro and in vivo cell expansion, respectively. In vitro
      angiogenic effects of dRib were assessed with endothelial cell migration and
      aortic ring assays. Western blotting detected dRib effects on p70/S6 kinase
      activation. RESULTS: Rapamycin treatment of mice bearing orthotopic tumors
      inhibited tumor growth more than did 5-FU, and mice treated with both drugs
      typically developed no tumors. In the liver metastasis assay, combination therapy
      blocked metastatic expansion of solitary tumor cells. Interestingly, complex drug
      activities were suggested by tumor-cell proliferation being more sensitive to 5
      FU than to rapamycin in vitro, but more sensitive to rapamycin in vivo. With
      regard to angiogenesis, dRib-induced endothelial cell migration and aortic ring
      formation were completely abrogated by rapamycin, correlating with blockage of
      dRib-induced p70/S6 kinase activation in endothelial cells. CONCLUSIONS:
      Inhibition of dRib-induced angiogenesis with rapamycin counteracts a potential TP
      based escape mechanism for colorectal cancer under 5-FU therapy, introducing a
      novel, clinically feasible, combination treatment option for this common
      neoplasm.

PMID- 15014040
TI  - Interleukin 1beta enhances invasive ability of gastric carcinoma through nuclear
      factor-kappaB activation.
AB  - PURPOSE: We examined the role of interleukin (IL)-1beta in activation of nuclear
      factor kappaB (NF-kappaB) and the biological function of activated NF-kappaB in
      gastric carcinoma cells. EXPERIMENTAL DESIGN: Human gastric carcinoma cell line
      GCTM-1 was used to examine NF-kappaB activation by immunostaining and
      electrophoretic mobility shift assay. Matrix metalloproteinase (MMP)-9
      expression, which plays an important role in tumor invasion, was assessed by
      semiquantitative reverse transcription-PCR, Western blotting, and immunostaining.
      The invasive ability of GCTM-1 cells was measured by Matrigel invasion assay. In
      vivo expression of IL-1beta and MMP-9 and activation of NF-kappaB in 10
      surgically resected gastric carcinoma specimens were examined
      immunohistochemically. RESULTS: IL-1beta enhanced NF-kappaB activation, MMP-9
      expression, and the invasive ability of GCTM-1. A NF-kappaB inhibitor,
      pyrrolidine dithiocarbamate, suppressed both MMP-9 expression and invasiveness of
      IL-1beta-treated GCTM-1 cells. IL-1beta did not increase the invasive ability of
      GCTM-1 cells transfected with MMP-9 antisense oligonucleotide. Concomitant
      expression of IL-1beta and nuclear NF-kappaB was observed in 3 of 10 gastric
      carcinoma specimens. Cells producing IL-1beta were tumor-infiltrating macrophages
      in two specimens and gastric carcinoma cells in one specimen. CONCLUSIONS: One of
      the molecules that may play a role in NF-kappaB activation in some gastric
      carcinomas is IL-1beta. The present results suggest that IL-1beta increases the
      invasive ability of carcinoma cells through activation of NF-kappaB and the
      resulting MMP-9 expression.

PMID- 15014041
TI  - Osteoblast-derived factors induce androgen-independent proliferation and
      expression of prostate-specific antigen in human prostate cancer cells.
AB  - PURPOSE: Prostate cancer metastasizes to the skeleton to form osteoblastic
      lesions. Androgen ablation is the current treatment for metastatic prostate
      cancer. This therapy is palliative, and the disease will return in an androgen
      independent form that is preceded by a rising titer of prostate-specific antigen
      (PSA). Here, we investigated the possibility that human osteoblasts might secrete
      factors that contribute to the emergence of androgen-independent prostate cancer.
      EXPERIMENTAL DESIGN: Primary cultures of human osteoblasts were used as a source
      of conditioned medium (OCM). Proliferation, expression of androgen-regulated
      genes, and transactivation of the androgen receptor (AR) were monitored in LNCaP
      human prostate cancer cells in response to OCM using the 3-(4,5-dimethylthiazol-2
      yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Northern blot analysis, and
      reporter gene constructs. Levels of interleukin-6 (IL-6) present in OCM were
      measured, and its contribution to proliferation and expression of PSA were
      investigated by neutralization studies with anti IL-6 antibodies. RESULTS: OCM
      increased the proliferation and expression of PSA at both the protein and RNA
      levels in LNCaP cells. Synergistic increases in the activities of PSA (6.1 kb)-
      and pARR(3)-tk-luciferase reporters were measured in cells cotreated with both
      OCM and androgen. OCM targeted the NH(2)-terminal domain of the AR. The effect of
      OCM on transcriptional activity of the AR was inhibited by an antiandrogen.
      Neutralizing antibodies to IL-6 blocked proliferation and expression of PSA by
      OCM. CONCLUSION: Osteoblasts secrete factors, such as IL-6, that cause androgen
      independent induction of PSA gene expression and proliferation of prostate cancer
      cells by a mechanism that partially relies on the AR. Identifying such molecular
      mechanisms may lead to improved clinical management of metastatic prostate
      cancer.

PMID- 15014042
TI  - Specificity of microRNA target selection in translational repression.
AB  - MicroRNAs (miRNAs) are a class of noncoding RNAs found in organisms as
      evolutionarily distant as plants and mammals, yet most of the mRNAs they regulate
      are unknown. Here we show that the ability of an miRNA to translationally repress
      a target mRNA is largely dictated by the free energy of binding of the first
      eight nucleotides in the 5' region of the miRNA. However, G:U wobble base-pairing
      in this region interferes with activity beyond that predicted on the basis of
      thermodynamic stability. Furthermore, an mRNA can be simultaneously repressed by
      more than one miRNA species. The level of repression achieved is dependent on
      both the amount of mRNA and the amount of available miRNA complexes. Thus,
      predicted miRNA:mRNA interactions must be viewed in the context of other
      potential interactions and cellular conditions.

PMID- 15014043
TI  - Phosphorylation of RCC1 in mitosis is essential for producing a high RanGTP
      concentration on chromosomes and for spindle assembly in mammalian cells.
AB  - Spindle assembly is subject to the regulatory controls of both the cell-cycle
      machinery and the Ran-signaling pathway. An important question is how the two
      regulatory pathways communicate with each other to achieve coordinated regulation
      in mitosis. We show here that Cdc2 kinase phosphorylates the serines located in
      or near the nuclear localization signal (NLS) of human RCC1, the nucleotide
      exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate
      RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for
      spindle assembly and chromosome segregation. Moreover, phosphorylation of the NLS
      of RCC1 is required to prevent the binding of importin alpha and beta to RCC1,
      thereby allowing RCC1 to couple RanGTP production to chromosome binding. These
      findings reveal that the cell-cycle machinery directly regulates the Ran
      signaling pathway by placing a high RanGTP concentration on the mitotic
      chromosome in mammalian cells.

PMID- 15014044
TI  - Vestibular defects in head-tilt mice result from mutations in Nox3, encoding an
      NADPH oxidase.
AB  - The vestibular system of the inner ear is responsible for the perception of
      motion and gravity. Key elements of this organ are otoconia, tiny biomineral
      particles in the utricle and the saccule. In response to gravity or linear
      acceleration, otoconia deflect the stereocilia of the hair cells, thus
      transducing kinetic movements into sensorineural action potentials. Here, we
      present an allelic series of mutations at the otoconia-deficient head tilt (het)
      locus, affecting the gene for NADPH oxidase 3 (Nox3). This series of mutations
      identifies for the first time a protein with a clear enzymatic function as
      indispensable for otoconia morphogenesis.

PMID- 15014046
TI  - A systematic review of the history and physical examination to diagnose
      influenza.
AB  - BACKGROUND: Although influenza is a commonly encountered condition in primary
      care, and diagnosis is increasingly important given the availability of new
      treatments, there has been no systematic review of the evidence on clinical
      diagnosis. METHODS: This was a systematic review of the literature with meta
      analysis where appropriate. We included cohort studies and randomized trials that
      compared the history and physical examination with a reference laboratory test
      for the diagnosis of influenza A and/or B. The primary outcomes were the
      sensitivity, specificity, likelihood ratios, and area under the receiver
      operating characteristic (ROC) curve. RESULTS: Seven studies reported the
      sensitivity and specificity for a total of 59 variables. We combined studies of
      influenza A or B alone with those of influenza A and B. Rigors [likelihood ratio
      (LR) +7.2], the combination of fever and presenting within 3 days of the onset of
      illness (LR +4.0), and sweating (LR +3.0) were best at ruling-in influenza when
      present. When absent, the following decreased the likelihood of influenza: any
      systemic symptoms (LR -0.36), coughing (LR -0.38), not being able to cope with
      daily activities (LR -0.39), and being confined to bed (LR -0.50). Cough, nasal
      congestion, and fever (subjective or objective) had the highest calculable areas
      under the ROC curve. CONCLUSIONS: Individual signs and symptoms are of limited
      value for the diagnosis of influenza. Development of clinical decision rules that
      systematically combine symptoms may be a more useful strategy.

PMID- 15014045
TI  - Role of Unc51.1 and its binding partners in CNS axon outgrowth.
AB  - Previous studies showed that the serine/threonine kinase Unc51.1 is one of the
      earliest genes in neuronal differentiation and is required for granule cell axon
      formation. To examine the mechanism of Unc51.1 regulation of axon extension, we
      have identified two direct binding partners. The first, SynGAP, a negative
      regulator of Ras, is expressed within axons and growth cones of developing
      granule cells. Overexpression of SynGAP blocks neurite outgrowth by a mechanism
      that involves Ras-like GTPase cascade. The second binding partner is a PDZ domain
      containing scaffolding protein, Syntenin, that binds Rab5 GTPase, the activity of
      which is attenuated by SynGAP. Thus, our results demonstrate that the Unc51.1
      containing protein complex governs axon formation via Ras-like GTPase signaling
      and through regulation of the Rab5-mediated endocytic pathways within developing
      axons.

PMID- 15014047
TI  - Direct-to-consumer advertising: public perceptions of its effects on health
      behaviors, health care, and the doctor-patient relationship.
AB  - PURPOSE: To determine public perceptions of the effect of direct-to-consumer
      advertising (DTCA) of prescription medications on health behaviors, health care
      utilization, the doctor-patient relationship, and the association between
      socioeconomic status and these effects. METHODS: Cross-sectional survey of
      randomly selected, nationally representative sample of the US public using
      computer-assisted telephone interviewing. MAIN OUTCOME MEASURES: numbers and
      proportions of respondents in the past 12 months who, as a result of DTCA,
      requested preventive care or scheduled a physician visit; were diagnosed with
      condition mentioned in advertisement; disclosed health concerns to a doctor; felt
      enhanced confidence or sense of control; perceived an effect on the doctor
      patient relationship; requested a test, medication change, or specialist
      referral; or manifested serious dissatisfaction after a visit to a doctor.
      RESULTS: As a result of DTCA, 14% of respondents disclosed health concerns to a
      physician, 6% requested preventive care, 5% felt more in control during a
      physician visit; 5% made requests for a test, medication change, or specialist
      referral, and 3% received the requested intervention. One percent of patients
      reported negative outcomes, including worsened treatment, serious dissatisfaction
      with the visit, or that the physician acted challenged. Effects of DTCA were
      greater for respondents with low socioeconomic status. CONCLUSIONS: DTCA has
      positive and negative effects on health behaviors, health service utilization,
      and the doctor-patient relationship that are greatest on people of low
      socioeconomic status. The benefits of DTCA in terms of encouraging hard-to-reach
      sections of the population to seek preventive care must be balanced against
      increased health care costs caused by clinically inappropriate requests generated
      by DTCA.

PMID- 15014049
TI  - Adults' knowledge and behaviors related to human papillomavirus infection.
AB  - BACKGROUND: Our objective was to assess adults' knowledge, risk behaviors, and
      preference for information about human papillomavirus (HPV). METHODS: A cross
      sectional study using a self-administered questionnaire given in 3 locations (a
      university health service and 2 community family practice offices); 289 people
      completed the questionnaire. The primary outcome measure was a knowledge score
      calculated from the responses on specific items in the questionnaire. This
      knowledge score was developed by other investigators and has acceptable
      psychometric properties. RESULTS: Knowledge about HPV was low, with an average
      knowledge score of 5.50 (possible scores ranged from 0 to 14) and a mode of 0.
      Knowledge scores were significantly higher in women (P =.001) and married adults
      (P =.001). Knowledge scores were inversely related to age (P =.004) and
      positively correlated with years of education (P =.001) and self-assessment of
      knowledge (P <.001). Knowledge scores were positively correlated with condom use
      (P =.05) but not significantly associated with other risk behaviors. The most
      frequently desired time to receive information about HPV was before becoming
      sexually active. CONCLUSIONS: Adults seen in a typical family physician's office
      have limited knowledge of HPV. One tool family physicians can use to identify
      those with the least amount of knowledge is to ask patients how informed they are
      about HPV. The preferred time to receive information about HPV was before a
      patient became sexually active. However, it remains unclear whether educational
      intervention or knowledge changes risky behaviors.

PMID- 15014048
TI  - Physician-elder interaction in community family practice.
AB  - OBJECTIVE: To determine whether outpatient visits by elders seeing community
      family physicians differ in length or content from visits by younger patients;
      socioemotional preferences predict visit content; and satisfaction correlates
      with visit content differentially across age. METHODS: In a multimethod cross
      sectional study of 84 community family practices in northeastern Ohio, 3453 adult
      patient visits with 138 community family physicians were observed; 2362 of these
      patients completed self-report questionnaires. Three age groups were compared: 18
      to 64, 65 to 74, and over 74 years. Length and content of the physician-patient
      encounter was determined using the Davis Observation Code (DOC); satisfaction was
      assessed using the MOS 9-item Visit Rating Scale. RESULTS: Controlling for reason
      for visit and demographics, visit length averaged 10.7 minutes for each group.
      Visit content differed significantly on 13 of 20 DOC codes between one of the
      older groups and the younger group; in 4 instances, content varied between the 2
      older groups. Although visit content varied as predicted by socioemotional
      theory, no consistent patterns of association between visit content and
      satisfaction emerged. DISCUSSION: Older patient visits differ from those of
      younger patients as might be predicted by socioemotional selectivity theory;
      however, there was little association of visit content with patient satisfaction.

PMID- 15014050
TI  - Clinical and laboratory profile of febrile respiratory infections in general
      practice.
AB  - BACKGROUND: Respiratory tract infection (RTI) is a common diagnosis in the
      primary care setting. The aim of the study was to characterize the clinical
      course and laboratory manifestations of febrile RTI in Israeli adults presenting
      to primary care clinics. METHODS: A prospective study over a 3-month winter
      period in 3 urban university primary care clinics of 122 consecutive adult
      patients seen by their family practitioners. All participants were interviewed
      and had chest radiographs, tests of oxygen saturation, and blood tests. RESULTS:
      Study group included 122 adults (mean age, 44.8 +/- 14.2 years; men, 38%). Fever
      lasted for a mean of 4.0 +/- 1.7 days, and the mean number of days off
      work/activities was 5.3 +/- 1.0. Pneumonia was clinically suspected in 33
      patients (27%), but documented in 7 (6%). Antibiotics were given to 94 patients
      (77%). The group of treated patients had a lower mean oxygen saturation (P <.05)
      and a higher erythrocyte sedimentation rate (P <.05). Blood tests were found to
      be abnormal, although not clinically significant, in some patients, and all
      resolved spontaneously. CONCLUSIONS: RTIs are usually of short duration with a
      benign course where laboratory blood tests have no clinical implication.
      Radiographs may distinguish the 6% of patients having pneumonia from the 27% with
      suspected cases.

PMID- 15014051
TI  - The role of physicians in assessing older drivers: barriers, opportunities, and
      strategies.
AB  - BACKGROUND: Evaluation of the older driver is a difficult task for primary care
      physicians. We investigated the physician-perceived barriers to assessing older
      drivers in primary care practice. METHODS: Twenty family physicians whose
      patients had completed a clinical questionnaire and neuropsychological tests
      participated in one of 2 focus groups. Physicians were asked about barriers to
      assessing older drivers in primary care and the usefulness of neuropsychological
      tests for assessing driving ability. RESULTS: A number of themes emerged related
      to barriers in the assessment of the older driver. Major themes included concerns
      about being liable for the results of driving related screening and about
      patients reacting unfavorably to a driving assessment including cognitive tests.
      Physicians uniformly agreed that a protocol to guide driving assessment would be
      useful. CONCLUSIONS: Physicians encounter a number of barriers to assessing older
      drivers but recognize the importance of driving within the context of geriatric
      functional assessment.

PMID- 15014052
TI  - Relationship between health care costs and very low literacy skills in a
      medically needy and indigent Medicaid population.
AB  - OBJECTIVES: Previous research established that low literacy is independently
      associated with poorer health. Our objective was to determine whether low
      literacy skill also is associated with higher health care charges. METHODS: We
      studied persons enrolled in Medicaid because of medical need/indigence by testing
      literacy skills in English or Spanish and measuring annual health care charges.
      Statistical analyses determined if, after adjusting for sociodemographic
      variables, literacy was associated with charges. RESULTS: Mean charges among
      subjects with very low literacy skills (< or =3rd-grade reading level) were
      10,688 dollars/year, but only 2,891 dollars for those with better literacy skills
      (> or =4th-grade reading level), statistically significant difference (P =.025).
      This difference persisted after adjustment for potentially confounding
      sociodemographic variables. CONCLUSIONS: Based on this small study, very limited
      reading skills seem to be independently associated with higher health care
      charges among medically needy and medically indigent Medicaid patients.

PMID- 15014053
TI  - Cough as the presenting symptom of pancreatic adenocarcinoma.

PMID- 15014054
TI  - Nontraumatic rhabdomyolysis with long-term alcohol intoxication.

PMID- 15014055
TI  - Strength of recommendation taxonomy (SORT): a patient-centered approach to
      grading evidence in the medical literature.
AB  - A large number of taxonomies are used to rate the quality of an individual study
      and the strength of a recommendation based on a body of evidence. We have
      developed a new grading scale that will be used by several family medicine and
      primary care journals (required or optional), with the goal of allowing readers
      to learn one taxonomy that will apply to many sources of evidence. Our scale is
      called the Strength of Recommendation Taxonomy. It addresses the quality,
      quantity, and consistency of evidence and allows authors to rate individual
      studies or bodies of evidence. The taxonomy is built around the information
      mastery framework, which emphasizes the use of patient-oriented outcomes that
      measure changes in morbidity or mortality. An A-level recommendation is based on
      consistent and good quality patient-oriented evidence; a B-level recommendation
      is based on inconsistent or limited quality patient-oriented evidence; and a C
      level recommendation is based on consensus, usual practice, opinion, disease
      oriented evidence, or case series for studies of diagnosis, treatment,
      prevention, or screening. Levels of evidence from 1 to 3 for individual studies
      also are defined. We hope that consistent use of this taxonomy will improve the
      ability of authors and readers to communicate about the translation of research
      into practice.

PMID- 15014056
TI  - Fatal pneumococcal sepsis from a tuboovarian abscess.

PMID- 15014057
TI  - Prinzmetal variant angina associated with multiple sclerosis.
AB  - We report the case of a young woman with an acute coronary syndrome in the
      setting of a multiple sclerosis exacerbation. A connection between the 2,
      possibly caused by spinal cord pathology, is suggested.

PMID- 15014058
TI  - Sometimes (what seems to be) a heart attack is (really) a pain in the neck.
AB  - A 31-year-old patient complained of severe crushing chest pain that radiated to
      his left arm and jaw. After admission to the hospital, tests revealed a normal
      electrocardiogram, normal treadmill, normal coronary arteriogram, and normal
      cardiac enzymes. However, the patient continued to have pain, which was relieved
      by sublingual and intravenous nitroglycerine. He was discharged from the hospital
      with a diagnosis of "musculoskeletal" chest pain, taking nonsteroidal anti
      inflammatory drugs, muscle relaxants, and narcotics. Two weeks later, the patient
      returned with worsening symptoms. Cardiac work-up was again negative. Thoracic
      and cervical spine radiographs were ordered for possible discogenic pain. After
      abnormalities were found on cervical radiographs, magnetic resonance imaging
      (MRI) was ordered, and the patient was referred to an orthopedic surgeon. Further
      work-up revealed a herniated disk at C6-C7, with radicular pain. Surgery on the
      suspect disk totally relieved the patient's pain.

PMID- 15014060
TI  - Stability of benzylpenicillin during continuous home intravenous therapy.
AB  - OBJECTIVES: The aim of this study was to investigate the temperature profile of
      home intravenous (iv) antibiotic reservoirs and the stability of 16 megaunits of
      benzylpenicillin sodium in 120 mL of sodium chloride 0.9% at constant and
      variable temperatures. METHODS: A Tinytag computerized thermometer recorded
      temperatures every minute in the home iv antibiotic reservoir pouches of nine
      patients over a 24 h period. Similar bags containing benzylpenicillin sodium (16
      megaunits) were maintained either at a constant 36 degrees C, 26 degrees C or 21
      22 degrees C or were worn in a pouch by five healthy volunteers for a 24 h
      period. Other bags were stored at 3-5 degrees C for 10 days. The bags were
      sampled at timed intervals and benzylpenicillin concentrations assayed by HPLC.
      RESULTS: Median temperatures recorded in the infusion bags worn by the nine
      patients were in the range 16.7-34.1 degrees C. For infusion bags maintained at
      36 degrees C, 26 degrees C and 21-22 degrees C, the concentrations of
      benzylpenicillin dropped below 90% of the initial concentration at a mean time of
      5 h 18 min, 12 h 54 min and 13 h 20 min, respectively, whereas for bags worn by
      the healthy volunteers the mean time for 10% loss of benzylpenicillin was 9 h 20
      min. In contrast, at 3-5 degrees C, concentrations of benzylpenicillin only
      dropped below 90% of the initial concentration at 8 days. CONCLUSIONS:
      Significant temperature-dependent degradation of benzylpenicillin occurs during
      continuous home iv antibiotic programme infusions, which could result in loss of
      efficacy.

PMID- 15014061
TI  - An extended PCR-RFLP assay for detection of parC, parE and gyrA mutations in
      fluoroquinolone-resistant Streptococcus pneumoniae.

PMID- 15014062
TI  - Analysis of AmpC beta-lactamase expression and sequence in biochemically atypical
      ceftazidime-resistant Enterobacteriaceae from paediatric patients.
AB  - OBJECTIVES: To analyse the variation of ampC beta-lactamase gene sequence and
      expression in biochemically atypical Enterobacteriaceae isolates, and to identify
      them definitively. METHODS: beta-Lactamase gene-containing recombinant plasmids
      transformed into Escherichia coli were selected using ampicillin. PCR analysis
      was used to locate specific ampC and 16S rRNA genes, and the amplicons were
      sequenced. Random amplified polymorphic DNA PCR was used to group isolates and
      API 20E biochemical profiling was used to identify them putatively. RESULTS: Of
      50 ceftazidime-resistant clinical Enterobacteriaceae isolates, 36 were identified
      (>95% confidence)-using API 20E test strips-as being organisms known to express
      inducible class C beta-lactamases (Citrobacter freundii, Enterobacter cloacae,
      Morganella morganii or Hafnia alvei). The rest were biochemically atypical. Of
      these, isolate I113, putatively identified as E. coli, possesses a chromosomally
      encoded ampC which differs by 15% from C. freundii OS60 ampC and by >30% from E.
      coli ampC. A related ampC gene was found in another seven of the atypical
      isolates. The use of various identification methods, including ampC sequence
      analysis, revealed that these I113-like ampC-positive isolates represent
      Citrobacter murliniae and Citrobacter youngae. CONCLUSIONS: We report sequences
      for two new Citrobacter spp. ampC genes, and provide evidence that ampC
      sequencing is a discriminatory method for identifying atypical Citrobacter spp.
      isolates.

PMID- 15014063
TI  - Documentation of antibiotic prescribing controls in UK NHS hospitals.
AB  - OBJECTIVES: To identify the types, prevalence and nature of antibiotic
      prescribing control documents within NHS hospitals in the UK. METHODS: A self
      completion postal questionnaire was sent to each Chief Pharmacist at 465 NHS
      hospitals in 2001/2002. This contained questions covering hospital demographics,
      and hospital antibiotic prescribing control documentation, including format,
      dissemination, approval and review processes. RESULTS: In total, 253 (54%)
      completed questionnaires were returned. Of these, 168 respondents' hospitals had
      an antibiotic formulary, 107 had a policy for antibiotic prescribing and 216 had
      guidelines on antibiotic use. All three types of antibiotic prescribing documents
      were used by 82 hospitals but 18 did not have any documents; 44% of formularies,
      45% of policies and 35% of guidelines were available electronically. The Drug and
      Therapeutics Committee was the most frequently cited body for document approval
      and approximately one-third of documents had been approved during the current
      year of the questionnaire. Only about one-half of responding hospitals had an
      annual review of documents. CONCLUSIONS: Despite publication of high-profile
      national guidance in response to growing concerns regarding antimicrobial
      resistance, there has been little increase in the use of antibiotic prescribing
      control documents in NHS hospitals over the past decade. It is clear that
      appropriate controls for antibiotic prescribing are not yet universally applied
      in the UK and recommendations for action have been proposed.

PMID- 15014064
TI  - Benefits and limitations of testing for resistance to HIV drugs.
AB  - Since drug resistance was first described in HIV in 1989, great progress has been
      made in our understanding of its genetic basis and molecular mechanisms. Despite
      these advances and the introduction of many new antiretroviral drugs, resistance
      remains prevalent. The types of drug resistance tests and their relative
      advantages and disadvantages are reviewed. How and when these tests should be
      used to inform HIV clinical practice and their place in anti-HIV drug development
      are considered.

PMID- 15014065
TI  - Nosocomial bloodstream infections due to viridans streptococci in haematological
      and non-haematological patients: species distribution and antimicrobial
      resistance.
AB  - OBJECTIVES: We studied the species distribution and antimicrobial susceptibility
      of viridans streptococci (VS) isolates causing nosocomial bloodstream infections
      (BSIs) in Finnish hospitals. PATIENTS AND METHODS: Patients with nosocomial BSIs
      due to VS were identified through a hospital-wide prospective laboratory-based
      surveillance in two university and two regional hospitals during September 1998
      August 2001. Isolates of VS were sent to the reference laboratory for species
      confirmation and antimicrobial susceptibility testing. RESULTS: A total of 2038
      nosocomial BSIs were identified; 108 (5%) of the BSIs were caused by VS. Of the
      VS BSIs, 66% were in patients with a haematological malignancy, 14% in patients
      with a solid tumour and 18% in patients who had undergone surgery preceding the
      infection. The most common species group identified was Streptococcus mitis
      (82%). High-level penicillin resistance (> or = 4 mg/L) and cefotaxime resistance
      (> or = 4mg/L) were present in 5% and 4% of isolates, respectively; both were
      detected only in haematological patients. However, in non-haematological
      patients, resistance to erythromycin (17%), and reduced susceptibility to
      levofloxacin (14%) and penicillin (19%) were common. CONCLUSIONS: The resistance
      problems in VS are not limited to haematological patients. These findings may
      have significant clinical implications in the choice of both empirical antibiotic
      and antimicrobial prophylaxis regimens.

PMID- 15014066
TI  - A TM2 residue in the beta1 subunit determines spontaneous opening of homomeric
      and heteromeric gamma-aminobutyric acid-gated ion channels.
AB  - Gamma-aminobutyric acid type A (GABAA) receptors are major inhibitory
      neurotransmitter-gated ion channels in the central nervous system. GABAA
      receptors consist of multiple subunits and exhibit distinct pharmacological and
      channel properties. Of all GABAA receptor subunits, the beta subunit is thought
      to be a key component for the functionality of the receptors. Certain types of
      GABAA receptors have been found to be constitutively active. However, the
      molecular basis for spontaneous opening of channels of these receptors is not
      totally understood. In this study, we showed that channels that contain the beta1
      but not beta3 subunits opened spontaneously when these subunits were expressed
      homomerically or co-expressed with other types of GABAA receptor subunits in
      Xenopus oocytes. Using subunit chimeras and site-directed mutagenesis, we
      localized a key amino acid residue, a serine at position 265, that is critical in
      conferring an open state of the beta1 subunit-containing GABAA receptors in the
      absence of agonist. Moreover, some point mutations of Ser-265 also produced
      constitutively active channels. The magnitude of spontaneous activity of these
      receptors was correlated with the molecular volume of the residue at 265 for both
      homomeric and heteromeric GABAA receptors, suggesting that the spontaneous
      activity of the beta1 subunit-containing GABAA receptors may be mediated through
      a similar molecular mechanism that is dependent on the molecular volume of the
      residue at 265.

PMID- 15014067
TI  - 240s loop interactions stabilize the T state of Escherichia coli aspartate
      transcarbamoylase.
AB  - Here the functional and structural importance of interactions involving the 240s
      loop of the catalytic chain for the stabilization of the T state of aspartate
      transcarbamoylase were tested by replacement of Lys-244 with Asn and Ala. For the
      K244A and K244N mutant enzymes, the aspartate concentration required to achieve
      half-maximal specific activity was reduced to 8.4 and 4.0 mm, respectively, as
      compared with 12.4 mM for the wild-type enzyme. Both mutant enzymes exhibited
      dramatic reductions in homotropic cooperativity and the ability of the
      heterotropic effectors to modulate activity. Small angle x-ray scattering studies
      showed that the unligated structure of the mutant enzymes, and the structure of
      the mutant enzymes ligated with N-phosphonacetyl-L-aspartate, were similar to
      that observed for the unligated and N-phosphonacetyl-L-aspartateligated wild-type
      enzyme. A saturating concentration of carbamoyl phosphate alone has little
      influence on the small angle x-ray scattering of the wild-type enzyme. However,
      carbamoyl phosphate was able to shift the structure of the two mutant enzymes
      dramatically toward R, establishing that the mutations had destabilized the T
      state of the enzyme. The x-ray crystal structure of K244N enzyme showed that
      numerous local T state stabilizing interactions involving 240s loop residues were
      lost. Furthermore, the structure established that the mutation induced additional
      alterations at the subunit interfaces, the active site, the relative position of
      the domains of the catalytic chains, and the allosteric domain of the regulatory
      chains. Most of these changes reflect motions toward the R state structure.
      However, the K244N mutation alone only changes local conformations of the enzyme
      to an R-like structure, without triggering the quaternary structural transition.
      These results suggest that loss of cooperativity and reduction in heterotropic
      effects is due to the dramatic destabilization of the T state of the enzyme by
      this mutation in the 240s loop of the catalytic chain.

PMID- 15014068
TI  - Crystallographic and biochemical investigations of kumamolisin-As, a serine
      carboxyl peptidase with collagenase activity.
AB  - Kumamolisin-As (previously called ScpA) is the first known example of a
      collagenase from the sedolisin family (MEROPS S53). This enzyme is active at low
      pH and in elevated temperatures. In this study that used x-ray crystallographic
      and biochemical methods, we investigated the structural basis of the preference
      of this enzyme for collagen and the importance of a glutamate residue in the
      unique catalytic triad (Ser(278)-Glu(78)-Asp(82)) for enzymatic activity. Crystal
      structures of the uninhibited enzyme and its complex with a covalently bound
      inhibitor, N-acetyl-isoleucyl-prolyl-phenylalaninal, showed the occurrence of a
      narrow S2 pocket and a groove that encompasses the active site and is rich in
      negative charges. Limited endoproteolysis studies of bovine type-I collagen as
      well as kinetic studies using peptide libraries randomized at P1 and P1', showed
      very strong preference for arginine at the P1 position, which correlated very
      well with the presence of a negatively charged residue in the S1 pocket of the
      enzyme. All of these features, together with those predicted through comparisons
      with fiddler crab collagenase, a serine peptidase, rationalize the enzyme's
      preference for collagen. A comparison of the Arrhenius plots of the activities of
      kumamolisin-As with either collagen or peptides as substrates suggests that
      collagen should be relaxed before proteolysis can occur. The E78H mutant, in
      which the catalytic triad was engineered to resemble that of subtilisin, showed
      only 0.01% activity of the wild-type enzyme, and its structure revealed that
      Ser(278), His(78), and Asp(82) do not interact with each other; thus, the
      canonical catalytic triad is disrupted.

PMID- 15014069
TI  - Euglena gracilis rhodoquinone:ubiquinone ratio and mitochondrial proteome differ
      under aerobic and anaerobic conditions.
AB  - Euglena gracilis cells grown under aerobic and anaerobic conditions were compared
      for their whole cell rhodoquinone and ubiquinone content and for major protein
      spots contained in isolated mitochondria as assayed by two-dimensional gel
      electrophoresis and mass spectrometry sequencing. Anaerobically grown cells had
      higher rhodoquinone levels than aerobically grown cells in agreement with earlier
      findings indicating the need for fumarate reductase activity in anaerobic wax
      ester fermentation in Euglena. Microsequencing revealed components of complex III
      and complex IV of the respiratory chain and the E1beta subunit of pyruvate
      dehydrogenase to be present in mitochondria of aerobically grown cells but
      lacking in mitochondria from anaerobically grown cells. No proteins were
      identified as specific to mitochondria from anaerobically grown cells. cDNAs for
      the E1alpha, E2, and E3 subunits of mitochondrial pyruvate dehydrogenase were
      cloned and shown to be differentially expressed under aerobic and anaerobic
      conditions. Their expression patterns differed from that of mitochondrial
      pyruvate:NADP(+) oxidoreductase, the N-terminal domain of which is
      pyruvate:ferredoxin oxidoreductase, an enzyme otherwise typical of
      hydrogenosomes, hydrogen-producing forms of mitochondria found among anaerobic
      protists. The Euglena mitochondrion is thus a long sought intermediate that
      unites biochemical properties of aerobic and anaerobic mitochondria and
      hydrogenosomes because it contains both pyruvate:ferredoxin oxidoreductase and
      rhodoquinone typical of hydrogenosomes and anaerobic mitochondria as well as
      pyruvate dehydrogenase and ubiquinone typical of aerobic mitochondria. Our data
      show that under aerobic conditions Euglena mitochondria are prepared for
      anaerobic function and furthermore suggest that the ancestor of mitochondria was
      a facultative anaerobe, segments of whose physiology have been preserved in the
      Euglena lineage.

PMID- 15014070
TI  - Degradation of Mcl-1 by granzyme B: implications for Bim-mediated mitochondrial
      apoptotic events.
AB  - Recent studies have suggested that in the absence of Bid, granzyme B (GrB) can
      utilize an unknown alternative pathway to mediate mitochondrial apoptotic events.
      The current study has elucidated just such a pathway for GrB-mediated
      mitochondrial apoptotic alterations. Two Bcl-2 family members have been
      identified as interactive players in this newly discovered mitochondrial response
      to GrB: the pro-survival protein Mcl-1L and the pro-apoptotic protein, Bim.
      Expression of Mcl-1L, which localizes mainly to the outer mitochondrial membrane,
      decreases significantly in cells subjected to CTL-free cytotoxicity mediated by a
      combination of GrB and replication-deficient adenovirus. The data suggest that
      Mcl-1L is a substrate for GrB and for caspase-3, but the two enzymes appear to
      target different cleavage sites. The cleavage pattern of endogenous Mcl-1L
      resembles that of in vitro translated Mcl-1L subjected to similar proteolytic
      activity. Co-immunoprecipitation experiments performed with endogenous as well as
      with in vitro translated proteins suggest that Mcl-1L is a high affinity binding
      partner of the three isoforms of Bim (extra-long, long, and short). Bim, a BH3
      only protein, is capable of mediating the release of mitochondrial cytochrome c,
      and this activity is inhibited by the presence of exogenous Mcl-1L. The findings
      presented herein imply that Mcl-1L degradation by either GrB or caspase-3
      interferes with Bim sequestration by Mcl-1L.

PMID- 15014071
TI  - The sphingolipid pathway regulates Pkc1 through the formation of diacylglycerol
      in Cryptococcus neoformans.
AB  - The sphingolipid biosynthetic pathway generates bioactive molecules crucial to
      the regulation of mammalian and fungal physiological and pathobiological
      processes. In previous studies (Luberto, C., Toffaletti, D. L., Wills, E. A.,
      Tucker, S. C., Casadevall, A., Perfect, J. R., Hannun, Y. A., and Del Poeta, M.
      (2001) Genes Dev. 15, 201-212), we demonstrated that an enzyme of the fungal
      sphingolipid pathway, Ipc1 (inositol-phosphorylceramide synthase-1), regulates
      melanin, a pigment required for the pathogenic fungus Cryptococcus neoformans to
      cause disease. In this study, we investigated the mechanism by which Ipc1
      regulates melanin production. Because Ipc1 also catalyzes the production of
      diacylglycerol (DAG), a physiological activator of the classical and novel
      isoforms of mammalian protein kinase C (PKC), and because it has been suggested
      that PKC is required for melanogenesis in mammalian cells, we investigated
      whether Ipc1 regulates melanin in C. neoformans through the production of DAG and
      the subsequent activation of Pkc1, the fungal homolog of mammalian PKC. The
      results show that modulation of Ipc1 regulates the levels of DAG in C. neoformans
      cells. Next, we demonstrated that C. neoformans Pkc1 is a DAG-activated
      serine/threonine kinase and that the C1 domain of Pkc1 is necessary for this
      activation. Finally, through both pharmacological and genetic approaches, we
      found that inhibition of Pkc1 abolishes melanin formation in C. neoformans. This
      study identifies a novel signaling pathway in which C. neoformans Ipc1 plays a
      key role in the activation of Pkc1 through the formation of DAG. Importantly,
      this pathway is essential for melanin production with implications for the
      pathogenicity of C. neoformans.

PMID- 15014072
TI  - Membrane-delimited regulation of novel background K+ channels by MgATP in murine
      immature B cells.
AB  - In WEHI-231, a representative immature B cell line, Ca(2+) entry is paradoxically
      augmented by treatment with 2-aminoethoxydiphenyl borate (2-APB), a blocker of
      inositol 1,4,5-trisphosphate receptor and of nonselective cation channels (Nam,
      J. H., Yun, S. S., Kim, T. J., Uhm, D.-Y., and Kim, S. J. (2003) FEBS Lett. 535,
      113-118). The initial goal of the present study was to elucidate the effects of 2
      APB on membrane currents, which revealed the presence of novel K(+) channels in
      WEHI-231 cells. Under whole-cell patch clamp conditions, 2-APB induced background
      K(+) current (I(K,bg)) and hyperpolarization in WEHI-231 cells. Lowering of
      intracellular MgATP also induced the I(K,bg). The I(K,bg) was blocked by
      micromolar concentrations of quinidine but not by tetraethylammonium. In a single
      channel study, two types of voltage-independent K(+) channels were found with
      large (346 picosiemens) and medium conductance (112 picosiemens), named BK(bg)
      and MK(bg), respectively. The excision of membrane patches (inside-out (i-o)
      patches) greatly increased the P(o) of BK(bg). In i-o patches, cytoplasmic MgATP
      (IC(50) = 0.18 mm) decreased the BK(bg) activity, although non-hydrolyzable
      adenosine 5'-(beta,gamma-imino)triphosphate had no effect. A pretreatment with
      Al(3+) or wortmannin (50 microm) blocked the inhibitory effects of MgATP. A
      direct application of phosphoinositide 4,5-bisphosphate (10 microm) inhibited the
      BK(bg) activity. Meanwhile, the activity of MK(bg) was unaffected by MgATP. In
      cell-attached conditions, the BK(bg) activity was largely increased by 2-APB. In
      i-o patches, however, the MgATP-induced inhibition of BK(bg) was weakly reversed
      by the addition of 2-APB. In summary, WEHI-231 cells express the unique
      background K(+) channels. The BK(bg)s are inhibited by membrane-delimited
      elevation of phosphoinositide 4,5-bisphosphate. The activation of BK(bg) would
      hyperpolarize the membrane, which augments the calcium influx in WEHI-231 cells.

PMID- 15014073
TI  - Hyperglycemia and inhibition of glycogen synthase in streptozotocin-treated mice:
      role of O-linked N-acetylglucosamine.
AB  - Glycogen synthase is post-translationally modified by both phosphate and O-linked
      N-acetylglucosamine (O-GlcNAc). In 3T3-L1 adipocytes exposed to high
      concentrations of glucose, O-GlcNAc contributes to insulin resistance of glycogen
      synthase. We sought to determine whether O-GlcNAc also regulates glycogen
      synthase in vivo. Glycogen synthase activity in fat pad extracts was inhibited in
      streptozotocin (STZ)-treated diabetic mice. The half-maximal activation
      concentration for glucose 6-phosphate (A(0.5)) was increased to 830 +/- 120
      microm compared with 240 +/- 20 microm in control mice (C, p < 0.01), while the
      basal glycogen synthase activity (%I-form) was decreased to 2.4 +/- 1.4% compared
      with 10.1 +/- 1.8% in controls (p < 0.01). Glycogen synthase activity remained
      inhibited after compensatory insulin treatment. After insulin treatment kinetic
      parameters of glycogen synthase were more closely correlated with blood glucose
      (A(0.5), r(2) = 0.70; %I-form, r(2) = 0.59) than insulin levels (A(0.5), r(2) =
      0.04; %I-form, r(2) = 0.09). Hyperglycemia also resulted in an increase in the
      level of O-GlcNAc on glycogen synthase (16.1 +/- 1.8 compared with 7.0 +/- 0.9
      arbitrary intensity units for controls, p < 0.01), even though the level of
      phosphorylation was identical in diabetic and control mice either with (STZ: 2.9
      +/- 1.0 and C: 3.2 +/- 0.8) or without (STZ: 12.2 +/- 2.8 and C: 13.8 +/- 3.0
      arbitrary intensity units) insulin treatment. In all mice the percent activation
      of glycogen synthase that could be achieved in vitro by recombinant protein
      phosphatase 1 (230 +/- 30%) was significantly greater in the presence of beta-d-N
      acetylglucosaminidase (410 +/- 60%, p < 0.01). This synergistic stimulation of
      glycogen synthase due to codigestion by protein phosphatase 1 and beta-d-N
      acetylglucosaminidase was more pronounced in STZ-diabetic mice (310 +/- 70%)
      compared with control mice (100 +/- 10%, p < 0.05). The findings demonstrate that
      O-GlcNAc has a role in the regulation of glycogen synthase both in normoglycemia
      and diabetes.

PMID- 15014074
TI  - Role of the trans-activation response element in dimerization of HIV-1 RNA.
AB  - The HIV-1 genome consists of two identical RNA strands that are linked together
      through non-covalent interactions. A major determinant for efficient dimerization
      of the two RNA strands is the interaction between palindromic sequences in the
      dimerization initiation site. Here we use an interplay of bioinformatics,
      biochemistry, and atomic force microscopy to describe another conserved
      palindrome in the trans-activation response element (TAR) that functions as a
      strong dimerization site when transiently exposed to the viral nucleocapsid
      protein. In conjunction with the DIS interaction, the TAR dimerization induces
      the formation of a 65-nm higher-order circular structure in the dimeric HIV-1
      RNA. Our results provide a molecular model for the role of TAR in packaging and
      reverse transcription of the viral genome. The unique structure of the TAR-TAR
      dimer renders it an intriguing therapeutic target for the treatment of HIV-1
      infection.

PMID- 15014075
TI  - Purifying selection masks the mutational flexibility of HIV-1 reverse
      transcriptase.
AB  - DNA and RNA polymerases share a core architecture composed of three structurally
      conserved motifs: A, B, and C. Although the amino acid sequences of these motifs
      are highly conserved between closely related organisms, variation across broader
      evolutionary distances suggests that only a few residues in each motif are
      indispensable for polymerase function. To test this, we constructed libraries of
      human immunodeficiency virus type-1 (HIV-1) containing random single amino acid
      replacements in motif B of reverse transcriptase (RT), and we used selection in
      culture to assess RT function. Despite the nearly absolute constancy of motif B
      in vivo, virus replicating in culture tolerated a range of conservative and
      nonconservative substitutions at 10 of the 11 amino acid positions examined.
      These included residues that are invariant across all retroviral subfamilies and
      highly conversed in diverse retroelements. Several mutants retained wild type
      infectivity, and serial passage experiments revealed replacements that were
      neutral or even beneficial to viral fitness. In addition, a number of the
      selected variants exhibited altered susceptibility to the nucleoside analog
      inhibitors AZT and 3TC. Taken together, these data indicate that HIV-1 tolerates
      a range of substitutions at conserved RT residues and that selection against
      slightly deleterious mutations (purifying selection) in vivo masks a large
      repertoire of viable phenotypic variants. This mutational flexibility likely
      contributes to HIV-1 evolution in response to changing selection pressures in
      infected individuals.

PMID- 15014076
TI  - Insights into the molecular determinants of substrate specificity in glycoside
      hydrolase family 5 revealed by the crystal structure and kinetics of Cellvibrio
      mixtus mannosidase 5A.
AB  - The enzymatic hydrolysis of the glycosidic bond is central to numerous biological
      processes. Glycoside hydrolases, which catalyze these reactions, are grouped into
      families based on primary sequence similarities. One of the largest glycoside
      hydrolase families is glycoside hydrolase family 5 (GH5), which contains
      primarily endo-acting enzymes that hydrolyze beta-mannans and beta-glucans. Here
      we report the cloning, characterization, and three-dimensional structure of the
      Cellvibrio mixtus GH5 beta-mannosidase (CmMan5A). This enzyme releases mannose
      from the nonreducing end of mannooligosaccharides and polysaccharides, an
      activity not previously observed in this enzyme family. CmMan5A contains a single
      glycone (-1) and two aglycone (+1 and +2) sugar-binding subsites. The -1 subsite
      displays absolute specificity for mannose, whereas the +1 subsite does not
      accommodate galactosyl side chains but will bind weakly to glucose. The +2
      subsite is able to bind to decorated mannose residues. CmMan5A displays similar
      activity against crystalline and amorphous mannans, a property rarely attributed
      to glycoside hydrolases. The 1.5 A crystal structure reveals that CmMan5A adopts
      a (beta/alpha)(8) barrel fold, and superimposition with GH5 endo-mannanases shows
      that dramatic differences in the length of three loops modify the active center
      accessibility and thus modulate the specificity from endo to exo. The most
      striking and significant difference is the extended loop between strand beta8 and
      helix alpha8 comprising residues 378-412. This insertion forms a "double" steric
      barrier, formed by two short beta-strands that function to "block" the substrate
      binding cleft at the edge of the -1 subsite forming the "exo" active center
      topology of CmMan5A.

PMID- 15014077
TI  - The fetoprotein transcription factor (FTF) gene is essential to embryogenesis and
      cholesterol homeostasis and is regulated by a DR4 element.
AB  - The fetoprotein transcription factor (FTF) gene was inactivated in the mouse,
      with a lacZ gene inserted inframe into exon 4. LacZ staining of FTF+/- embryos
      shows that the mFTF gene is activated at initial stages of zygotic transcription.
      FTF gene activity is ubiquitous at the morula and blastocyst stages and then
      follows expression patterns indicative of multiple FTF functions in fetal
      development. FTF-/- embryos die at E6.5-7.5, with features typical of visceral
      endoderm dysfunction. Adult FTF+/- mice are hypocholesterolemic, and express
      liver FTF at about 40% of the normal level. Overexpression of liver FTF in
      transgenic mice indicates in vivo that FTF is an activator of CYP7A1. However,
      CYP7A1 expression is increased in FTF+/- liver. Gene expression profiles indicate
      that higher CYP7A1 expression is caused by attenuated liver cell stress
      signaling. Diet experiments support a model where FTF is quenched both by
      activated c-Jun, and by SHP as a stronger feedback mechanism to repress CYP7A1. A
      DR4 element is conserved in the FTF gene promoter and activated by LXR-RXR and TR
      RXR, qualifying the FTF gene as a direct metabolic sensor. Liver FTF increases in
      rats treated with thyroid hormone or a high cholesterol diet. The FTF DR4 element
      tightens functional links between FTF and LXRalpha in cholesterol homeostasis and
      can explain transient surges of FTF gene activities during development and FTF
      levels lower than predicted in FTF+/- liver. The FTF-lacZ mouse establishes a
      central role for FTF in developmental, nutritive, and metabolic functions from
      early embryogenesis through adulthood.

PMID- 15014078
TI  - Direct stimulation of the lambdapaQ promoter by the transcription effector
      guanosine-3',5'-(bis)pyrophosphate in a defined in vitro system.
AB  - The bacterial response to nutritional deprivation, called the stringent response,
      results in the introduction of the specific nucleotide guanosine-3',5'-(bis)
      pyrophosphate (ppGpp). This nucleotide interacts with RNA polymerase and alters
      its action so that transcription from certain promoters is inhibited, whereas
      transcription from others seems to be activated. The exact mechanism of
      transcriptional stimulation by ppGpp in vivo remains unknown. A passive control
      model has been proposed according to which transcription inhibition during the
      stringent response at several very active promoters, like those for rRNA and tRNA
      genes, makes more free RNA polymerase (RNAP) molecules available for
      transcription at promoters with weak binding affinities for RNAP, thus leading to
      their passive activation. Among promoters whose transcription is activated by
      ppGpp in vivo is the histidine operon promoter (hisGp). However, in vitro it is
      only possible to demonstrate this effect in a coupled transcription-translation
      system. Here we demonstrate, using another in vivo ppGpp-stimulated promoter, the
      phage lambdapaQ promoter, that activation by ppGpp in a defined in vitro system
      is direct. A systematic study of ppGpp effects on the stimulation of paQ revealed
      that, as in the case of promoters inhibited by this nucleotide, ppGpp decreases
      the half-life of paQ open complexes. Our results also indicate that the
      equilibrium binding affinity of RNA polymerase to paQ seems not to be affected in
      the presence of ppGpp. Our data indicate that the mechanism underlying ppGpp
      stimulation of paQ is due to an increased rate of productive open complex
      formation.

PMID- 15014079
TI  - Evidence for involvement of HMGB1 protein in human DNA mismatch repair.
AB  - Defects in human DNA mismatch repair predispose to cancer, but many components of
      the pathway have not been identified. We report here the identification and
      characterization of a novel component required for mismatch repair in human
      cells. A 30-kDa protein was purified to homogeneity by virtue of its ability to
      complement a depleted HeLa extract in repair of mismatched heteroduplexes. The
      complementing activity was identified as HMGB1 (the high mobility group box 1
      protein), a non-histone chromatin protein that facilitates protein-protein
      interactions and recognizes DNA damage. Evidence is also presented that HMGB1
      physically interacts with MutSalpha and is required at a step prior to the
      excision of mispaired nucleotide in mismatch repair.

PMID- 15014081
TI  - Functional uncoupling of twin polymerases: mechanism of polymerase dissociation
      from a lagging-strand block.
AB  - Replication forks are constantly subjected to events that lead to fork stalling,
      stopping, or collapse. Using a synthetic rolling circle DNA substrate, we
      demonstrate that a block to the lagging-strand polymerase does not compromise
      helicase or leading-strand polymerase activity. In fact, lagging-strand synthesis
      also continues. Thus, the blocked lagging-strand enzyme quickly dissociates from
      the block site and resumes synthesis on new primed sites. Furthermore, studies in
      which the lagging polymerase is continuously blocked show that the leading
      polymerase continues unabated even as it remains attached to the lagging-strand
      enzyme. Hence, upon encounter of a block to the lagging stand, the polymerases
      functionally uncouple yet remain physically associated. Further study reveals
      that naked single-stranded DNA results in disruption of a stalled polymerase from
      its beta-DNA substrate. Thus, as the replisome advances, the single-stranded DNA
      loop that accumulates on the lagging-strand template releases the stalled lagging
      strand polymerase from beta after SSB protein is depleted. The lagging-strand
      polymerase is then free to continue Okazaki fragment production.

PMID- 15014080
TI  - 3-O-deacylation of lipid A by PagL, a PhoP/PhoQ-regulated deacylase of Salmonella
      typhimurium, modulates signaling through Toll-like receptor 4.
AB  - Toll-like receptor 4 (TLR4)-mediated responses, which are induced by the lipid A
      portion of lipopolysaccharide, are important for host defense against Salmonellae
      infection. A variety of different data indicate that the acylation state of lipid
      A can alter TLR4-mediated responses. The S. typhimurium virulence gene product
      PhoP/PhoQ signals the presence of host microenvironments to regulate the
      expression of a lipid A 3-O-deacylase, PagL, and a lipid A palmitoyltransferase,
      PagP. We now demonstrate that 3-O-deacylation and palmitoylation of lipid A
      decreases its ability to induce TLR4-mediated signaling. Deacylated lipid A,
      deacylated and palmitoylated lipid A, palmitoylated lipid A, and unmodified lipid
      A species were purified from Escherichia coli heterologously expressing PagL
      and/or PagP. The purified lipid A preparations showed spectra of a single lipid A
      species on mass spectrometry and gave a single band on thin layer chromatography.
      The activity of purified lipid A species was examined using human and mouse cell
      lines that express recombinant human TLR4. Compared with unmodified lipid A, the
      modified lipid A species are 30-100-fold less active in the ability to induce NF
      kappaB-dependent reporter activation. These results suggest that the lipid A
      modifications reduce TLR4-signaling as part of Salmonellae adaptation to host
      environments.

PMID- 15014082
TI  - Requirement for ATP by the DNA damage checkpoint clamp loader.
AB  - The DNA damage clamp loader replication factor C (RFC-Rad24) consists of the
      Rad24 protein and the four small Rfc2-5 subunits of RFC. This complex loads the
      heterotrimeric DNA damage clamp consisting of Rad17, Mec3, and Ddc1 (Rad17/3/1)
      onto partial duplex DNA in an ATP-dependent manner. Interactions between the
      clamp loader and the clamp have been proposed to mirror those of the replication
      clamp loader RFC and the sliding clamp proliferating cell nuclear antigen (PCNA).
      In that system, three ATP molecules bound to the Rfc2, Rfc3, and Rfc4 subunits
      are necessary and sufficient for efficient loading of PCNA, whereas ATP binding
      to Rfc1 is not required. In contrast, in this study, we show that mutant RFC
      Rad24 with a rad24-K115E mutation in the ATP-binding domain of Rad24 shows
      defects in the ATPase of the complex and is defective for interaction with
      Rad17/3/1 and for loading of the checkpoint clamp. A similar defect was measured
      with a mutant RFC-Rad24 clamp loader carrying a rfc4K55R ATP-binding mutation,
      whereas the rfc4K55E clamp loader showed partial loading activity, in agreement
      with genetic studies of these mutants. These studies show that ATP utilization by
      the checkpoint clamp/clamp loader system is effectively different from that by
      the structurally analogous replication system.

PMID- 15014083
TI  - Expression of the HXT1 low affinity glucose transporter requires the coordinated
      activities of the HOG and glucose signalling pathways.
AB  - Expression of the HXT1 gene, which encodes a low affinity glucose transporter in
      Saccharomyces cerevisiae, is regulated positively in response to glucose by the
      general glucose induction pathway, involving the Snf3/Rgt2 membrane glucose
      sensors, the SCF-Grr1 ubiquitination complex and the Rgt1 transcription factor.
      In this study we show that, in addition to the glucose signaling pathway,
      regulation of HXT1 expression also requires the HOG pathway. Deletion of
      components in the glucose signaling pathway or in the HOG pathway results in
      impaired HXT1 expression. Genetic analyses showed that, whereas the glucose
      signaling pathway regulates HXT1 through modulation of the Rgt1 transcription
      factor, the HOG pathway modulates HXT1 through regulation of the Sko1-Tup1-Ssn6
      complex. Coordinated regulation of the two signaling pathways is required for
      expression of HXT1 by glucose and in response to osmostress.

PMID- 15014084
TI  - Distinct effects of topoisomerase I and RNA polymerase I inhibitors suggest a
      dual mechanism of nucleolar/nucleoplasmic partitioning of topoisomerase I.
AB  - Topoisomerase I is mostly nucleolar, because it plays a preeminent role in
      ribosomal DNA (rDNA) transcription. It is cleared from nucleoli following
      exposure to drugs stabilizing covalent DNA intermediates of the enzyme (e.g.
      camptothecin) or inhibiting RNA polymerases (e.g. actinomycin D), an effect
      summarily attributed to blockade of rDNA transcription. Here we show that two
      distinct mechanisms are at work: (i). Both drugs induce inactivation and
      segregation of the rRNA transcription machinery. With actinomycin D this leads to
      a co-migration of RNA-polymerase I and topoisomerase I to the nucleolar
      perimeter. The process has a slow onset (>20 min), is independent of
      topoisomerase I activity, but requires the N-terminal domain of the enzyme to
      colocalize with RNA polymerase I. (ii). Camptothecin induces, in addition,
      immobilization of active topoisomerase I on genomic DNA resulting in rapid
      nucleolar clearance and spreading of the enzyme to the entire nucleoplasm. This
      effect is independent of the state of rRNA transcription, involves segregation of
      topoisomerase I from RNA polymerase I, has a rapid onset (<1 min), and requires
      catalytic activity but neither the N-terminal domain of topoisomerase I nor its
      major sumoylation site. Thus, nucleolar/nucleoplasmic partitioning of
      topoisomerase I is regulated by interactions with RNA polymerase I and DNA but
      not by sumoylation.

PMID- 15014085
TI  - Calpain system regulates muscle mass and glucose transporter GLUT4 turnover.
AB  - The experiments in this study were undertaken to determine whether inhibition of
      calpain activity in skeletal muscle is associated with alterations in muscle
      metabolism. Transgenic mice that overexpress human calpastatin, an endogenous
      calpain inhibitor, in skeletal muscle were produced. Compared with wild type
      controls, muscle calpastatin mice demonstrated normal glucose tolerance. Levels
      of the glucose transporter GLUT4 were increased more than 3-fold in the
      transgenic mice by Western blotting while mRNA levels for GLUT4 and myocyte
      enhancer factors, MEF 2A and MEF 2D, protein levels were decreased. We found that
      GLUT4 can be degraded by calpain-2, suggesting that diminished degradation is
      responsible for the increase in muscle GLUT4 in the calpastatin transgenic mice.
      Despite the increase in GLUT4, glucose transport into isolated muscles from
      transgenic mice was not increased in response to insulin. The expression of
      protein kinase B was decreased by approximately 60% in calpastatin transgenic
      muscle. This decrease could play a role in accounting for the insulin resistance
      relative to GLUT4 content of calpastatin transgenic muscle. The muscle weights of
      transgenic animals were substantially increased compared with controls. These
      results are consistent with the conclusion that calpain-mediated pathways play an
      important role in the regulation of GLUT4 degradation in muscle and in the
      regulation of muscle mass. Inhibition of calpain activity in muscle by
      overexpression of calpastatin is associated with an increase in GLUT4 protein
      without a proportional increase in insulin-stimulated glucose transport. These
      findings provide evidence for a physiological role for calpains in the regulation
      of muscle glucose metabolism and muscle mass.

PMID- 15014086
TI  - Casein Kinase II phosphorylation-induced conformational switch triggers
      degradation of the papillomavirus E2 protein.
AB  - The major phosphorylation sites of the bovine papillomavirus E2 transactivator
      protein are two serine residues, 298 and 301, that are located in a flexible
      hinge region between the DNA binding and transactivation domains. Phosphorylation
      of serine residue 301 promotes ubiquitination and rapid degradation of the E2
      protein by the proteasome pathway. To understand the mechanism through which
      phosphorylation regulates the intracellular levels of this unique papillomavirus
      regulatory protein, we have carried out an extensive mutational analysis of the
      region surrounding the phosphorylation sites of the E2 protein. Our results
      indicate that casein kinase II phosphorylates serine 301. However,
      phosphorylation of serine 301 is not a sufficient recognition motif for
      proteasomal degradation; other residues that directly surround the
      phosphorylation sites are crucial for E2 degradation. The phenotypes of E2
      proteins mutated in this region indicate that phosphorylation of serine 301
      induces a conformational change that leads to degradation of the E2 protein. In
      support of this model, circular dichroism studies of the conformational
      tendencies of peptides from this region indicate that phosphorylation at position
      301 decreases the local thermodynamic stability of this region. Thus, this region
      appears to have evolved to display a marginal local thermodynamic stability that
      can be regulated by phosphorylation, leading to targeted degradation of the E2
      protein.

PMID- 15014087
TI  - Methodological and theoretical implications of intraindividual variability in
      perceptual-motor performance.
AB  - As an individual differences variable, lability (within-person variability) has
      often been neglected even though it has been shown to predict key outcomes such
      as mortality. We examine intraindividual variability in perceptual-motor
      performance and relate it to chronological age in a sample of adults. The
      magnitude of between-session variability was found to average between 25% and 50%
      of the between-person variability and was equivalent in magnitude to the
      variation that was apparent across an age range of 12 to 27 years in cross
      sectional comparisons. Age is related to the magnitude of intraindividual
      variability, which in turn is negatively related to performance on other
      cognitive tasks. Various implications of the findings are discussed.

PMID- 15014088
TI  - Aging and memory control beliefs: performance in relation to goal setting and
      memory self-evaluation.
AB  - We examined memory control beliefs in relation to memory performance and beliefs
      in the context of goal setting. Control beliefs showed significant effects on
      performance and self-efficacy. Higher goals were set by high-control younger
      adults than by older adults and low-control younger adults. Individuals with a
      high sense of control performed higher and maintained performance over trials
      regardless of whether they set explicit goals. Those with low control (primarily
      older adults) performed lower, but they achieved increased performance when
      motivated by goals. These results emphasized that performance limitations
      associated with low control can be overcome with goals, even in older adults. As
      with previous studies, however, younger adults showed a more positive response to
      goals than older adults.

PMID- 15014089
TI  - Age-related differences in response preparation: the role of time uncertainty.
AB  - This study explored the ability of younger and older participants to use a
      variable preparatory interval (PI) to enhance reaction time (RT) performance. In
      Experiment 1, 30 seniors and 15 young adults completed simple and choice RT tasks
      with short and long variable PIs. RT decreased with increasing PI duration in
      both younger and older adults, but the PI effect was larger in elderly
      individuals. The results of Experiment 2 (20 seniors and 20 young adults) showed
      an equivalent preparatory effect in older and younger adults when the probability
      of the shortest PI was increased. These findings suggest that older adults do not
      prepare as well as younger adults for unlikely events and that time uncertainty
      affects age-related differences in response preparation.

PMID- 15014090
TI  - Predictors of depressive symptoms in persons with Alzheimer's disease.
AB  - In a 4-year longitudinal study, we evaluated factors related to the development
      of depressive symptoms in 410 persons with Alzheimer's disease. We measured
      depressive symptoms annually by using the 17-item Hamilton Rating Scale, which we
      completed by using structured interviews with family members. On the basis of
      informant ratings of premorbid personality, we associated neuroticism with a
      higher rate of depressive symptoms, particularly mood disturbances. We associated
      greater cognitive impairment with a small reduction in mood symptoms and a modest
      increase in somatic symptoms. Among demographic variables, somatic symptoms were
      more common in men and mood symptoms were inversely related to age. Depressive
      symptoms in Alzheimer's disease appear to follow a more predictable pattern of
      expression than previously described.

PMID- 15014091
TI  - Practice and drop-out effects during a 17-year longitudinal study of cognitive
      aging.
AB  - Interpretations of longitudinal studies of cognitive aging are misleading unless
      effects of practice and selective drop-out are considered. A random effects model
      taking practice and drop-out into account analyzed data from four successive
      presentations of each of two intelligence tests, two vocabulary tests, and two
      verbal memory tests during a 17-year longitudinal study of 5,899 community
      residents whose ages ranged from 49 to 92 years. On intelligence tests,
      substantial practice effects counteracted true declines observed over 3 to 5
      years of aging and remained significant even with intervals of 7 years between
      successive assessments. Adjustment for practice and drop-out revealed
      accelerating declines in fluid intelligence and cumulative learning, linear
      declines in verbal free recall, and no substantial change in vocabulary.
      Socioeconomic status and basal levels of general fluid ability did not affect
      rates of decline. After further adjustment for demographics, variability between
      individuals was seen to increase as the sample aged.

PMID- 15014092
TI  - Consumption and meanings of age.

PMID- 15014093
TI  - Consumer discourse in assisted living.
AB  - OBJECTIVES: The aim of this article is to discuss the cultural construction of
      the assisted living consumer. Based on theories of consumer studies, it focuses
      on organizational strategies employed by assisted living practitioners to promote
      consumer choice and independence while mediating potential risks. METHODS: Data
      include field notes, participation in manager-training programs, and interviews
      with residents and family members during a 22-month study of three Oregon
      facilities. RESULTS: Consumer discourse is evident in four primary sources,
      including the state rules, manager-training programs, organizational practices,
      and an institutional belief in specific consumer demands like independence and
      choice. DISCUSSION: Personal care is a complex consumer "good" further
      complicated by residents with cognitive impairments, family demands, payment
      sources, and the very novelty of the assisted living philosophy. We conclude with
      a discussion of benefits and pitfalls based on the use of consumer discourse that
      represents older persons as active consumers, rather than recipients, of long
      term care services.

PMID- 15014094
TI  - Do impaired older persons with health care needs occupy U.S. assisted living
      facilities? An analysis of six national studies.
AB  - OBJECTIVES: The assisted living facility (ALF) is the fastest-growing
      noninstitutional long-term care alternative for frail older persons in the United
      States. This analysis assesses the extent to which older persons with physical
      and cognitive disabilities and health care needs occupy ALFs in the United
      States. METHODS: Information on study design and six indicators of the occupancy
      patterns of older persons in ALFs were abstracted from six national studies. The
      collected data were based on reports by the administrators of ALFs. RESULTS: The
      six reviewed studies had several methodologic weaknesses, resulting in different
      statistical populations of ALFs, samples with very different numerical and
      attribute properties, and findings based on disparate indicators. The older
      residents in ALFs were less physically and cognitively impaired than those in
      nursing homes. ALF facilities were more likely to admit or retain frail older
      persons when they had relatively minor or less serious physical or cognitive
      impairment or health care needs. DISCUSSION: ALFs are currently serving older
      residents who require less nursing care and who are less functionally and
      cognitively impaired than those found in nursing homes. The more restrictive
      admitting and discharge criteria of a substantial share of ALFs guarantee their
      less frail occupant profile. This is, however, an extraordinarily diverse shelter
      and care alternative, and very frail older persons with serious chronic health
      problems can be found in ALFs. Average duration of stays may be as long as 3
      years. Researchers must conduct more carefully executed studies with replicable
      methodologies that produce unbiased and generalized findings.

PMID- 15014095
TI  - Family caregiver satisfaction with the nursing home after placement of a relative
      with dementia.
AB  - OBJECTIVE: This article examines family caregiver satisfaction after nursing home
      placement of a relative with Alzheimer disease or a related dementia. Determining
      what contributes to family caregiver satisfaction is a critical step toward
      implementing effective quality improvement strategies. METHODS: A stress process
      model is used to study caregiver satisfaction among 285 family caregivers in
      relation to primary objective stressors (stage of dementia, length of stay,
      length of time in caregiving role, visitation frequency, involvement in nursing
      home, and involvement in hands-on care), subjective stressors (expectations for
      care), caregiver characteristics (education, marital status, familial
      relationship, workforce participation, distance from nursing home, and age), and
      organizational resources (rural/urban location, profit/nonprofit ownership,
      special care unit [SCU] designation, and custodial unit designation). SAS PROC
      MIXED is used in a multilevel analysis. RESULTS: Higher satisfaction is
      associated with earlier stage of dementia, greater length of time involved in
      caregiving prior to institutionalization, higher visitation frequency, less
      involvement in hands-on care, greater expectations for care, and less workforce
      participation. DISCUSSION: Multilevel analysis showed that primary stressors are
      the strongest predictors of satisfaction. Only one caregiver characteristic (work
      participation) and one organizational resource (rural/urban location) predict
      satisfaction. SCU designation was unrelated to satisfaction, perhaps because SCUs
      have less to offer residents in more advanced as opposed to earlier stages of
      Alzheimer disease. If family satisfaction is to be achieved, family presence in a
      nursing home needs to give caregivers a sense of positive involvement and
      influence over the care of their relative.

PMID- 15014096
TI  - Neighborhood problems and health among older adults: received and donated social
      support and the sense of mastery as effect modifiers.
AB  - OBJECTIVES: This study examines the associations between perceived neighborhood
      problems and mental and physical health, exploring the extent to which received
      social support, donated social support, and the sense of mastery moderate those
      associations. METHODS: In 2001-2002, face-to-face interviews were conducted with
      a sample of 1,167 adults over age 65 in several counties in Maryland and the
      District of Columbia. RESULTS: For men, received support and perceived mastery
      buffer against the detrimental effects of neighborhood problems on anger. In
      contrast, donated support exacerbates the negative physical health effects of
      neighborhood problems. For women, donated support amplifies the effects of
      neighborhood problems on anger. However, with anger and depression, the buffering
      effects of received support become evident only after accounting for the
      interaction between neighborhood problems and donated support. DISCUSSION: The
      findings have implications for the stress process model, the theoretical
      perspectives on different forms of social support, and the "buffering" and "cost
      of caring" predictions for women and men.

PMID- 15014097
TI  - Unmet need for personal assistance services: estimating the shortfall in hours of
      help and adverse consequences.
AB  - OBJECTIVES: Perceived unmet need for personal assistance services (PAS) in
      activities of daily living (ADLs) and instrumental ADLs and its association with
      reduced hours of help received and with adverse consequences due to lack of help
      are examined for adults aged 18 and older using data from the 1994-1997 National
      Health Interview Survey on Disability. METHODS: A two-part multivariate
      regression model of the probability of PAS use and hours of help received was
      developed to control for need level, living arrangements, and other
      characteristics that may differ between persons with met and unmet needs and to
      determine the shortfall in hours associated with unmet need. RESULTS: Individuals
      with unmet need for personal assistance with two or more of the five basic ADLs
      have a shortfall of 16.6 hours of help per week compared with those whose needs
      are met. The relative shortfall is twice as great for persons who live alone as
      for those who live with others. People who live alone and have unmet needs fare
      worse than people with unmet needs who live with others, and both groups are more
      likely than those whose needs are met to experience adverse consequences,
      including discomfort, weight loss, dehydration, falls, burns, and dissatisfaction
      with the help received. DISCUSSION: Overall, just 6.6% of needed hours are unmet
      among the 3.3 million people needing help in two or more ADLs. We estimate the
      annual cost of eliminating unmet need among persons with incomes under 300% of
      the Supplemental Security Income level between 1.2 and 2.7 billion dollars for
      those living alone and from 2.2 to 7.1 billion dollars for those living with
      others.

PMID- 15014098
TI  - Common facets of religion, unique facets of religion, and life satisfaction among
      older African Americans.
AB  - OBJECTIVES: Common facets of religion are those aspects of religion that can be
      shared by people from any racial group. In contrast, unique facets of religion
      are available only to people in specific racial groups. The purpose of this study
      is to evaluate the interface among common facets of religion, unique facets of
      religion, and life satisfaction in a nationwide sample of older Black people.
      METHODS: Interviews were conducted with a nationally representative sample of
      older African Americans. Survey items were administered to assess common
      religious factors (e.g., the frequency of church attendance) and unique religious
      factors (i.e., the belief that religion sustains Black people in the face of
      racial adversity). Subjective well-being was measured with a life satisfaction
      index. RESULTS: The findings reveal that both the common and the unique aspects
      of religion contribute to life satisfaction among older African Americans.
      DISCUSSION: Most studies on race differences in religion focus solely on common
      religious factors that may enhance the subjective well-being of older Whites as
      well as older Blacks. The findings from this study are important because they
      call attention to the insight that can be obtained by also taking the unique
      facets of religion for older Black people into consideration.

PMID- 15014099
TI  - Health-related quality of life in middle-aged African Americans.
AB  - OBJECTIVES: In this article we explore the measurement properties of the Medical
      Outcomes Study 36-Item Short-Form Health Survey (SF-36) in 49- to 65-year-old
      African Americans, compare their health-related quality of life (HRQoL) with that
      of the nation, and evaluate the association of selected covariates with HRQoL.
      METHODS: A probability sample of 998 African Americans in St. Louis received
      comprehensive in-home assessments. We used an item analysis, exploratory and
      confirmatory factor analysis, and internal consistency reliability to evaluate
      the measurement properties of the eight SF-36 scales and their
      interrelationships. We used a multiple linear regression analysis to characterize
      the effects of the demographic, socioeconomic status, psychosocial attributes,
      and biomedical markers. RESULTS: Assessments averaged 2.5 hr. Each SF-36 scale
      was unidimensional, all items had robust factor loadings, and all but one scale
      achieved excellent (alpha > or = .80) internal consistency reliability levels.
      The overall factor structure of the SF-36 scales was generally consistent with
      national norms. Substantial variance was explained by the covariates, mostly
      attributable to socioeconomic status and the biomedical markers. CONCLUSIONS: The
      SF-36 is a reliable and valid measure of HRQoL for use with African Americans. In
      this sample, the HRQoL was below national averages. Future social epidemiologic
      studies should include grip strength, vision, and hearing assessments, which had
      substantial and consistent associations with the SF-36 scale scores.

PMID- 15014100
TI  - Subthreshold resonance explains the frequency-dependent integration of periodic
      as well as random stimuli in the entorhinal cortex.
AB  - Neurons integrate subthreshold inputs in a frequency-dependent manner. For
      sinusoidal stimuli, response amplitudes thus vary with stimulus frequency.
      Neurons in entorhinal cortex show two types of such resonance behavior: stellate
      cells in layer II exhibit a prominent peak in the resonance profile at stimulus
      frequencies of 5-16 Hz. Pyramidal cells in layer III show only a small impedance
      peak at low frequencies (1-5 Hz) or a maximum at 0 Hz followed by a monotonic
      decrease of the impedance. Whether the specific frequency selectivity for
      periodic stimuli also governs the integration of non-periodic stimuli has been
      questioned recently. Using frozen-noise stimuli with different distributions of
      power over frequencies, we provide experimental evidence that the integration of
      non-periodic subthreshold stimuli is determined by the same subthreshold
      frequency selectivity as that of periodic stimuli. Differences between the
      integration of noise stimuli in stellate and pyramidal cells can be fully
      explained by the resonance properties of each cell type. Response power thus
      reflects stimulus power in a frequency-selective way. Theoretical predictions
      based on linear system's theory as well as on conductance-based model neurons
      support this finding. We also show that the frequency selectivity in the
      subthreshold range extends to suprathreshold responses in terms of firing rate.
      Cells in entorhinal cortex are representative examples of cells with resonant or
      low-pass filter impedance profiles. It is therefore likely that neurons with
      similar frequency selectivity will process input signals according to the same
      simple principles.

PMID- 15014101
TI  - Local GABA receptor blockade reveals hindlimb responses in the SI forelimb-stump
      representation of neonatally amputated rats.
AB  - In adult rats that sustained forelimb amputation on the day of birth, there are
      numerous multi-unit recording sites in the forelimb-stump representation of
      primary somatosensory cortex (SI) that also respond to cutaneous stimulation of
      the hindlimb when cortical receptors for GABA are blocked. These normally
      suppressed hindlimb inputs originate in the SI hindlimb representation and
      synapse in the dysgranular cortex before exciting SI forelimb-stump neurons. In
      our previous studies, GABA (A + B) receptor blockade was achieved by topically
      applying a bicuculline methiodide/saclofen solution (BMI/SAC) to the cortical
      surface. This treatment blocks receptors throughout SI and does not allow
      determination of where along the above circuit the GABA-mediated suppression of
      hindlimb information occurs. In this study, focal injections of BMI/SAC were
      delivered to three distinct cortical regions that are involved in the hindlimb-to
      forelimb-stump pathway. Blocking GABA receptors in the SI hindlimb representation
      and in the dysgranular cortex was largely ineffective in revealing hindlimb
      inputs ( approximately 10% of hindlimb inputs were revealed in both cases). In
      contrast, when the blockade was targeted at forelimb-stump recording sites, >80%
      of hindlimb inputs were revealed. Thus GABAergic interneurons within the forelimb
      stump representation suppress the expression of reorganized hindlimb inputs to
      the region. A circuit model incorporating these and previous observations is
      presented and discussed.

PMID- 15014102
TI  - Modular functional organization of cat anterior auditory field.
AB  - Two tonotopic areas, the primary auditory cortex (AI) and the anterior auditory
      field (AAF), are the primary cortical fields in the cat auditory system. They
      receive largely independent, concurrent thalamocortical projections from the
      different thalamic divisions despite their hierarchical equivalency. The parallel
      streams of thalamic inputs to AAF and AI suggest that AAF neurons may differ from
      AI neurons in physiological properties. Although a modular functional
      organization in cat AI has been well documented, little is known about the
      internal organization of AAF beyond tonotopy. We studied how basic receptive
      field parameters (RFPs) are spatially organized in AAF with single- and multiunit
      recording techniques. A distorted tonotopicity with an underrepresentation in
      midfrequencies (1 and 5 kHz) and an overrepresentation in the high-frequency
      range was found. Spectral bandwidth (Q-values) and response threshold were
      significantly correlated with characteristic frequency (CF). To understand
      whether AAF has a modular organization of RFPs, CF dependencies were eliminated
      by a nonparametric, local regression model, and the residuals (difference between
      the model and observed values) were evaluated. In a given isofrequency domain,
      clusters of low or high residual RFP values were interleaved for threshold,
      spectral bandwidth, and latency, suggesting a modular organization. However, RFP
      modules in AAF were not expressed as robustly as in AI. A comparison of RFPs
      between AAF and AI shows that AAF neurons were more broadly tuned and had shorter
      latencies than AI neurons. These physiological field differences are consistent
      with anatomical evidence of largely independent, concurrent thalamocortical
      projections in AI and AAF, which strongly suggest field-specific processing.

PMID- 15014103
TI  - Human midbrain sensitivity to cognitive feedback and uncertainty during
      classification learning.
AB  - Mesencephalic dopaminergic system (MDS) neurons may participate in learning by
      providing a prediction error signal to their targets, which include ventral
      striatal, orbital, and medial frontal regions, as well as by showing sensitivity
      to the degree of uncertainty associated with individual stimuli. We investigated
      the mechanisms of probabilistic classification learning in humans using
      functional magnetic resonance imaging to examine the effects of feedback and
      uncertainty. The design was optimized for separating neural responses to
      stimulus, delay, and negative and positive feedback components. Compared with
      fixation, stimulus and feedback activated brain regions consistent with the MDS,
      whereas the delay period did not. Midbrain activity was significantly different
      for negative versus positive feedback (consistent with coding of the "prediction
      error") and was reliably correlated with the degree of uncertainty as well as
      with activity in MDS target regions. Purely cognitive feedback apparently engages
      the same regions as rewarding stimuli, consistent with a broader characterization
      of this network.

PMID- 15014104
TI  - Supplementary eye fields stimulation facilitates anticipatory pursuit.
AB  - Anticipatory movements are motor responses occurring before likely sensory events
      in contrast to reflexive actions. Anticipatory movements are necessary to
      compensate for delays present in sensory and motor systems. Smooth pursuit eye
      movements are often used as a paradigmatic example for the study of anticipation.
      However, the neural control of anticipatory pursuit is unknown. A previous study
      suggested that the supplementary eye fields (SEFs) could play a role in the
      guidance of smooth pursuit to predictable target motion. In this study, we
      favored anticipatory responses in monkeys by making the parameters of target
      motion highly predictable and electrically stimulated the SEF before and during
      this behavior. Stimulation sites were restricted to regions of the SEF where
      saccades could not be evoked at the same low currents. We found that electrical
      microstimulation in the SEF increased the velocity of anticipatory pursuit
      movements and decreased their latency. These effects will be referred to as
      anticipatory pursuit facilitation. The degree of facilitation was the largest if
      the stimulation train was delivered near the end of the fixation period, before
      the moment when anticipatory pursuit usually begins. No anticipatory smooth eye
      movements could be evoked during fixation without an expectation of target
      motion. These results suggest that the SEF pursuit area might be involved in the
      process of guiding anticipatory pursuit.

PMID- 15014105
TI  - Environmental enrichment improves response strength, threshold, selectivity, and
      latency of auditory cortex neurons.
AB  - Over the last 50 yr, environmental enrichment has been shown to generate more
      than a dozen changes in brain anatomy. The consequences of these physical changes
      on information processing have not been well studied. In this study, rats were
      housed in enriched or standard conditions either prior to or after reaching
      sexual maturity. Evoked potentials from awake rats and extracellular recordings
      from anesthetized rats were used to document responses of auditory cortex
      neurons. This report details several significant, new findings about the
      influence of housing conditions on the responses of rat auditory cortex neurons.
      First, enrichment dramatically increases the strength of auditory cortex
      responses. Tone-evoked potentials of enriched rats, for example, were more than
      twice the amplitude of rats raised in standard laboratory conditions. Second,
      cortical responses of both young and adult animals benefit from exposure to an
      enriched environment and are degraded by exposure to an impoverished environment.
      Third, housing condition resulted in rapid remodeling of cortical responses in <2
      wk. Fourth, recordings made under anesthesia indicate that enrichment increases
      the number of neurons activated by any sound. This finding shows that the evoked
      potential plasticity documented in awake rats was not due to differences in
      behavioral state. Finally, enrichment made primary auditory cortex (A1) neurons
      more sensitive to quiet sounds, more selective for tone frequency, and altered
      their response latencies. These experiments provide the first evidence of
      physiologic changes in auditory cortex processing resulting from generalized
      environmental enrichment.

PMID- 15014106
TI  - Motor outputs from the primate reticular formation to shoulder muscles as
      revealed by stimulus-triggered averaging.
AB  - The motor output of the medial pontomedullary reticular formation (mPMRF) was
      investigated using stimulus-triggered averaging (StimulusTA) of EMG responses
      from proximal arm and shoulder muscles in awake, behaving monkeys (M.
      fascicularis). Muscles studied on the side ipsilateral (i) to stimulation were
      biceps (iBic), triceps (iTri), anterior deltoid (iADlt), posterior deltoid
      (iPDlt), and latissimus dorsi (iLat). The upper and middle trapezius were studied
      on the ipsilateral and contralateral (c) side (iUTr, cUTr, iMTr, cMTr). Of 133
      sites tested, 97 (73%) produced a poststimulus effect (PStE) in one or more
      muscles; on average, 38% of the sampled muscles responded per effective site. For
      responses that were observed in the arm and shoulder, poststimulus facilitation
      (PStF) was prevalent for the flexors, iBic (8 responses, 100% PStF) and iADlt (13
      responses, 77% PStF), and poststimulus suppression (PStS) was prevalent for the
      extensors, iTri (22 responses, 96% PStS) and iLat (16 responses, 81% PStS). For
      trapezius muscles, PStS of upper trapezius (iUTr, 49 responses, 73% PStS) and
      PStF of middle trapezius (iMTr, 22 responses, 64% PStF) were prevalent
      ipsilaterally, and PStS of middle trapezius (cMTr, 6 responses, 67% PStS) and
      PStF of upper trapezius (cUTr, 46 responses, 83% PStS) were prevalent
      contralaterally. Onset latencies were significantly earlier for PStF (7.0 +/- 2.2
      ms) than for PStS (8.6 +/- 2.0 ms). At several sites, extremely strong PStF was
      evoked in iUTr, even though PStS was most common for this muscle. The anatomical
      antagonists iBic/iTri were affected reciprocally when both responded. The
      bilateral muscle pair iUTr/cUTr demonstrated various combinations of effects, but
      cUTr PStF with iUTr PStS was prevalent. Overall, the results are consistent with
      data from the cat and show that outputs from the mPMRF can facilitate or suppress
      activity in muscles involved in reaching; responses that would contribute to
      flexion of the ipsilateral arm were prevalent.

PMID- 15014107
TI  - Calcium influx through HCN channels does not contribute to cAMP-enhanced
      transmission.
AB  - Serotonin is a native neuromodulator of synaptic transmission at glutamatergic
      neuromuscular junctions of crayfish limb muscles. During times of stress,
      serotonin binds to presynaptic receptors, which activate adenylyl cyclase to
      elevate presynaptic levels of cAMP. cAMP binds to two presynaptic target
      proteins, hyperpolarization and cyclic nucleotide-activated (HCN) ion channels
      and an exchange protein activated by cAMP (Epac), and activation of these
      effectors results in enhancement of transmitter release to action potentials.
      cAMP elevation also results in a small preterminal rise in [Ca(2+)](i), which we
      show here to result from Ca(2+) influx through the presynaptic HCN channels
      opened by cAMP. Little or no Ca(2+) influx occurs through voltage-dependent
      Ca(2+) channels, despite the small presynaptic depolarization caused by current
      through the HCN channels. Loading terminals with BAPTA delays the rise in
      preterminal [Ca(2+)](i) without affecting the enhancement of transmission to cAMP
      elevation. This dissociation of the dynamics of the [Ca(2+)](i) rise and synaptic
      enhancement, plus the small magnitude and location of [Ca(2+)](i) elevation
      distant from release sites, seems to preclude any direct role for this
      [Ca(2+)](i) elevation in cAMP-dependent enhancement of transmission.

PMID- 15014108
TI  - Steady-state levels of monoamines in the rat lumbar spinal cord: spatial mapping
      and the effect of acute spinal cord injury.
AB  - Monoamines in the spinal cord are important in the regulation of locomotor
      rhythms, nociception, and motor reflexes. To gain further insight into the
      control of these functions, the steady-state extracellular distribution of
      monoamines was mapped in the anesthetized rat's lumbar spinal cord. The effect of
      acute spinal cord lesions at sites selected for high resting levels was
      determined over approximately 1 h to estimate contributions to resting levels
      from tonic descending activity and to delineate chemical changes that may
      influence the degree of pathology and recovery after spinal injury. Measurements
      employed fast cyclic voltammetry with carbon fiber microelectrodes to give high
      spatial resolution. Monoamine oxidation currents, sampled at equal vertical
      spacings within each segment, were displayed as contours over the boundaries
      delineated by histologically reconstructed electrode tracks. Monoamine oxidation
      currents were found in well defined foci, often confined within a single lamina.
      Larger currents were typically found in the dorsal or ventral horns and in the
      lateral aspect of the intermediate zone. Cooling of the low-thoracic spinal cord
      led to a decrease in the oxidation current (to 71-85% of control) in dorsal and
      ventral horns. Subsequent low-thoracic transection produced a transient increase
      in signal in some animals followed by a longer lasting decrease to levels similar
      to or below that with cooling (to 17-86% of control values). We conclude that
      descending fibers tonically release high amounts of monoamines in localized
      regions of the dorsal and ventral horn of the lumbar spinal cord at rest. Lower
      amounts of monoamines were detected in medial intermediate zone areas, where
      strong release may be needed for descending activation of locomotor rhythms.

PMID- 15014109
TI  - Neuronal integration of synaptic input in the fluctuation-driven regime.
AB  - During sensory stimulation, visual cortical neurons undergo massive synaptic
      bombardment. This increases their input conductance, and action potentials mainly
      result from membrane potential fluctuations. To understand the response
      properties of neurons operating in this regime, we studied a model neuron with
      synaptic inputs represented by transient membrane conductance changes. We show
      that with a simultaneous increase of excitation and inhibition, the firing rate
      first increases, reaches a maximum, and then decreases at higher input rates.
      Comodulation of excitation and inhibition, therefore, does not provide a
      straightforward way of controlling the neuronal firing rate, in contrast to
      coding mechanisms postulated previously. The synaptically induced conductance
      increase plays a key role in this effect: it decreases firing rate by shunting
      membrane potential fluctuations, and increases it by reducing the membrane time
      constant, allowing for faster membrane potential transients. These findings do
      not depend on details of the model and, hence, are relevant to cells of other
      cortical areas as well.

PMID- 15014110
TI  - Efficient isolation and gene expression profiling of small numbers of neural
      crest stem cells and developing Schwann cells.
AB  - Schwann cells develop from multipotent neural crest stem cells and are important
      for neuronal survival, maintenance of axonal integrity, and myelination. We used
      transgenic mice expressing green fluorescent protein in a tissue-specific manner
      to isolate viable, pure populations of neural crest stem cells and developing
      Schwann cells, which are not readily accessible by microdissection. Starting with
      the minute amounts of RNA obtained, a two-round amplification procedure was used
      to achieve reproducible DNA array hybridizations. We validated our screening
      procedure by comparisons with the literature and by in situ hybridization. Stage
      to-stage comparisons and hierarchical clustering for neural crest and five stages
      of Schwann cell development suggest a wealth of candidates for genes involved in
      stem cell regulation and in early Schwann cell development. The combination of
      methods applied in this study should be generally useful for isolating and
      profiling other stem cell and difficult to isolate cell populations.

PMID- 15014111
TI  - Abnormal hippocampal axon bundling in EphB receptor mutant mice.
AB  - Axons travel frequently in bundles to reach their target. After arriving at the
      target, axon terminals defasciculate, migrate to topographically defined
      positions, and form synapses with appropriate target neurons. Here we present
      evidence that the B-type receptors of the erythropoietin-producing hepatocellular
      (Eph) family and a ligand, ephrin-B3, influence hippocampal axon defasciculation.
      The EphB receptors are expressed in the hippocampus, and the ligand, ephrin-B3,
      is transcribed in the lateral septum, the major subcortical target of hippocampal
      neurons. Ephrin-B3 promotes adhesion of hippocampal neurons to the ligand
      expressing substrates in vitro, and the loss of the receptor EphB2 abrogates the
      effects of ephrin-B3. In mice deficient in EphB2 and EphB3, many hippocampal
      axons remain in bundles. This phenotype was also observed in mice that were
      specifically deleted for the cytoplasmic domain of EphB2. These observations
      indicate that the EphB receptors and their ligand regulate hippocampal axon
      defasciculation at the septal target, possibly through a receptor-mediated
      forward signaling mechanism.

PMID- 15014112
TI  - Prokineticin 2 modulates the excitability of subfornical organ neurons.
AB  - The recent discovery of prokineticin 2 (PK2) expression in the suprachiasmatic
      nucleus and its receptors in critical autonomic control centers of the brain,
      including the subfornical organ (SFO), suggests the intriguing possibility that
      PK2 regulates the excitability of SFO neurons and thus influences autonomic
      function. Using current-clamp techniques to record from dissociated SFO neurons,
      we examined the effects of PK2 on the excitability of these cells. PK2 (20 nm)
      induced depolarizations in 40% of SFO neurons (n = 45; mean, 7.5 +/- 1.7 mV), an
      effect that was reversible, PK2-specific, and concentration dependent. The
      depolarization was accompanied by an increase in action potential frequency from
      0.4 +/- 0.1 to 1.4 +/- 0.5 Hz in responding cells (n = 10). This excitatory
      effect appears to be, in part, attributable to a PK2-induced decrease in the
      delayed rectifier potassium current (I(K)). In 10 SFO neurons recorded using
      perforated patch voltage-clamp techniques, six demonstrated a reversible decrease
      in I(K) (mean decrease, 26.7 +/- 6.4%) in response to 20 nm PK2, whereas
      artificial CSF alone was without an effect on these currents. These data are the
      first to show excitatory effects of PK2 on neurons and, in addition, demonstrate
      that this peptide modulates voltage-activated K(+) channels. The activation of
      SFO neurons by PK2 illustrates a mechanism through which this peptide may exert
      circadian control of autonomic functions.

PMID- 15014113
TI  - Postsynaptic TrkB-mediated signaling modulates excitatory and inhibitory
      neurotransmitter receptor clustering at hippocampal synapses.
AB  - Tyrosine receptor kinase B (TrkB)-mediated signaling modulates synaptic structure
      and strength in hippocampal and other neurons, but the underlying mechanisms are
      poorly understood. Full-length and truncated TrkB are diffusely distributed
      throughout the dendrites and soma of rat hippocampal neurons grown in vitro.
      Manipulation of TrkB-mediated signaling resulted in dramatic changes in the
      number and synaptic localization of postsynaptic NMDA receptor (NMDAR) and
      GABA(A) receptor (GABA(A)R) clusters. BDNF treatment resulted in an increase in
      the number of NMDAR and GABA(A)R clusters and increased the proportion of
      clusters apposed to presynaptic terminals. Downregulation of TrkB signaling
      resulted in a decrease in receptor cluster number and synaptic localization.
      Examination of the time course of the effects of BDNF on receptor clusters showed
      that the increase in GABA(A)R clusters preceded the increase in NMDAR clusters by
      at least 12 hr. Moreover, the TrkB-mediated effects on NMDAR clusters were
      dependent on GABA(A)R activation. Although TTX, APV, and CNQX treatment had no
      effect, blockade of GABA(A)Rs with bicuculline abolished the BDNF-mediated
      increase in NMDAR cluster number and synaptic localization. In contrast,
      application of exogenous GABA prevented the decrease in NMDAR clusters induced by
      BDNF scavenging. Together, these results suggest that TrkB-mediated signaling
      modulates the clustering of postsynaptic GABA(A)Rs and that receptor activity is
      required for a subsequent upregulation of NMDAR clusters. Therefore, TrkB
      mediated effects on postsynaptic neurotransmitter clusters may be part of a
      mechanism that balances inhibitory and excitatory synaptic transmission in
      developing neural circuits.

PMID- 15014114
TI  - Altered synapse formation in the adult somatosensory cortex of brain-derived
      neurotrophic factor heterozygote mice.
AB  - Increased sensory stimulation in the adult whisker-to-barrel pathway induces the
      expression of BDNF as well as synapse formation in cortical layer IV. Here, we
      investigated whether BDNF plays a role in the alterations of connectivity between
      neurons by analyzing the ultrastructure of the BDNF heterozygote mouse,
      characterized by a reduced level of BDNF expression. Using serial section
      electron microscopy, we measured synapse density, spine morphology, and synaptic
      vesicle distribution to show that mice with a reduced level of BDNF have a barrel
      neuropil that is indistinguishable from wild-type controls. After 24 hr of
      whisker stimulation, however, there is no indication of synapse formation in the
      heterozygous mouse. Whereas the balance between excitatory and inhibitory
      synapses is modified in the controls, it remains constant in the heterozygotes.
      The distribution of synaptic vesicles in excitatory synapses is the same in
      heterozygous and wild-type mice and is not influenced by the stimulation
      paradigm. Spine volume, however, is unchanged by stimulation in the wild-type
      animals, but does increase significantly in the heterozygous animal. These
      results provide evidence that, in vivo, BDNF plays an important role in the
      structural rearrangement of adult cortical circuitry as a consequence of an
      increased sensory input.

PMID- 15014115
TI  - Alterations in glucose metabolism induce hypothermia leading to tau
      hyperphosphorylation through differential inhibition of kinase and phosphatase
      activities: implications for Alzheimer's disease.
AB  - Alzheimer's disease (AD) brains contain neurofibrillary tangles (NFTs) composed
      of abnormally hyperphosphorylated tau protein. Regional reductions in cerebral
      glucose metabolism correlating to NFT densities have been reported in AD brains.
      Assuming that reduced glucose metabolism might cause abnormal tau
      hyperphosphorylation, we induced in vivo alterations of glucose metabolism in
      mice by starvation or intraperitoneal injections of either insulin or
      deoxyglucose. We found that the treatments led to abnormal tau
      hyperphosphorylation with patterns resembling those in early AD brains and also
      resulted in hypothermia. Surprisingly, tau hyperphosphorylation could be traced
      down to a differential effect of low temperatures on kinase and phosphatase
      activities. These data indicate that abnormal tau hyperphosphorylation is
      associated with altered glucose metabolism through hypothermia. Our results imply
      that serine-threonine protein phosphatase 2A plays a major role in regulating tau
      phosphorylation in the adult brain and provide in vivo evidence for its crucial
      role in abnormal tau hyperphosphorylation in AD.

PMID- 15014116
TI  - Stress enables synaptic depression in CA1 synapses by acute and chronic morphine:
      possible mechanisms for corticosterone on opiate addiction.
AB  - The hippocampus, being sensitive to stress and glucocorticoids, plays significant
      roles in certain types of learning and memory. Therefore, the hippocampus is
      probably involved in the increasing drug use, drug seeking, and relapse caused by
      stress. We have studied the effect of stress with morphine on synaptic plasticity
      in the CA1 region of the hippocampus in vivo and on a delayed-escape paradigm of
      the Morris water maze. Our results reveal that acute stress enables long-term
      depression (LTD) induction by low-frequency stimulation (LFS) but acute morphine
      causes synaptic potentiation. Remarkably, exposure to an acute stressor reverses
      the effect of morphine from synaptic potentiation (approximately 20%) to synaptic
      depression (approximately 40%), precluding further LTD induction by LFS. The
      synaptic depression caused by stress with morphine is blocked either by the
      glucocorticoid receptor antagonist RU38486 or by the NMDA-receptor antagonist D
      APV. Chronic morphine attenuates the ability of acute morphine to cause synaptic
      potentiation, and stress to enable LTD induction, but not the ability of stress
      in tandem with morphine to cause synaptic depression. Furthermore, corticosterone
      with morphine during the initial phase of drug use promotes later delayed-escape
      behavior, as indicated by the morphine-reinforced longer latencies to escape,
      leading to persistent morphine-seeking after withdrawal. These results suggest
      that hippocampal synaptic plasticity may play a significant role in the effects
      of stress or glucocorticoids on opiate addiction.

PMID- 15014117
TI  - Induction of brain-derived neurotrophic factor in plaque-associated glial cells
      of aged APP23 transgenic mice.
AB  - Brain-derived neurotrophic factor (BDNF) is a versatile neurotrophic factor that
      has been implicated in cell survival, cell differentiation, axonal growth, and
      activity-dependent synaptic plasticity. Changes in BDNF expression have also been
      reported during the course of several neurological disorders, including
      Alzheimer's disease (AD). The role of BDNF in AD, however, has remained elusive.
      To learn more about this neurotrophic factor, we investigated BDNF expression in
      brain of amyloid precursor protein overexpressing mice (APP23 transgenic mice).
      In situ hybridization revealed BDNF mRNA signals associated with amyloid plaques.
      Laser microdissection in combination with quantitative RT-PCR demonstrated a
      sixfold increase of BDNF mRNA in the immediate plaque vicinity, a threefold
      increase in a tissue ring surrounding the plaque, and control levels in
      interplaque areas comparable with those measured in age-matched nontransgenic
      mice. Double immunofluorescence localized BDNF to microglial cells and astrocytes
      surrounding the plaque. Cortical BDNF protein levels were quantified by ELISA
      demonstrating a >10-fold increase compared with age-matched controls. This
      upregulation of BDNF protein significantly correlated with the beta-amyloid load
      in the transgenic animals. Taken together, our data demonstrate a plaque
      associated upregulation of BDNF in APP23 transgenic mice and implicate this
      neurotrophin in the regulation of inflammatory and axonal growth processes in the
      plaque vicinity.

PMID- 15014119
TI  - Oscillating Purkinje neuron activity causing involuntary eye movement in a mutant
      mouse deficient in the glutamate receptor delta2 subunit.
AB  - How failures in regulation of synaptic transmission in the mammalian CNS affect
      neuronal activity and disturb motor coordination is addressed. The mutant mouse
      deficient in the glutamate receptor delta2 subunit, specifically expressed in
      cerebellar Purkinje neurons, has defects in synaptic regulations such as synaptic
      plasticity, stabilization, and elimination of synaptic connections and shows
      failures in motor coordination and learning. In this study, the cause of motor
      discoordination of the delta2 mutant mouse was analyzed by comparing its motor
      control ability with those of the wild-type mouse and the lurcher mutant mouse,
      which loses all Purkinje neurons, the sole output neurons in the cerebellar
      cortex. Unexpectedly, the delta2 mutant mouse showed severer motor
      discoordination than the lurcher mouse without any cerebellar cortical outputs.
      The delta2 mutant mouse showed involuntary spontaneous eye movement with
      characteristic 10 Hz oscillation, which disappeared by ablation of the cerebellar
      flocculus, suggesting that the delta2 mutant cerebellar cortex outputs an
      abnormal signal. In vivo extracellular recordings of neuronal activity revealed
      that Purkinje neurons tended to fire clustered action potentials and complex
      spikes at approximately 10 Hz in the delta2 mutant mouse. A whole-cell patch
      clamp recording from Purkinje neurons in cerebellar slices indicated that the
      clustered action potentials could be induced by climbing fiber activation. Taken
      together, our results suggest that the delta2 subunit deficiency produces the
      oscillating activity in Purkinje neurons by enhancing climbing fiber inputs,
      causing surplus movement and affecting motor control worse than no signal at all.

PMID- 15014118
TI  - The role of the dorsal hippocampus in the acquisition and retrieval of context
      memory representations.
AB  - It is argued that the hippocampus contributes to contextual fear conditioning by
      supporting the acquisition of a conjunctive memory representation of context,
      which associates with shock. This function was examined by studying the context
      pre-exposure facilitation effect (CPFE). A rat that is shocked immediately after
      being placed into a context subsequently displays almost no fear of that context.
      However, if it is pre-exposed to the context the day before immediate shock, it
      displays significant freezing to that context. By using 5-aminomethyl-3
      hydroxysoxazole to temporarily inactivate the dorsal hippocampus (DH) at three
      different phases of the procedure, which produces the CPFE, we show that the
      hippocampus is necessary for the following: (1) acquisition of the context
      memory, (2) retrieval of this memory at the time of immediate shock, and (3)
      retrieval of the context-shock memory at the time of testing. In contrast,
      inactivating the DH before a standard contextual shock experience had no effect
      on contextual fear conditioning. These results support the view that two
      processes can support contextual fear conditioning: (1) conditioning to the
      conjunctive representation, which depends on the hippocampus, and (2)
      conditioning to the features that make up the context, which does not.

PMID- 15014120
TI  - Targeted microlesions reveal novel organization of the hamster suprachiasmatic
      nucleus.
AB  - The role of the suprachiasmatic nuclei (SCN) in generating circadian rhythms in
      physiology and behavior is well established. Recent evidence based on clock gene
      expression indicates that the rodent SCN are composed of at least two functional
      subdivisions. In Syrian hamsters (Mesocricetus auratus), cells in a subregion of
      the caudal SCN marked by calbindin-D(28K) (CalB) express light-induced, but not
      rhythmic, clock genes (Per1, Per2, and Per3). In the SCN region marked by
      vasopressinergic cells and fibers, clock gene expression is rhythmic.
      Importantly, lesions of the CalB subregion that spare a significant portion of
      the SCN abolish rhythms in locomotor behavior. One possibility is that the CalB
      subregion is required to maintain SCN function necessary to support all
      behavioral and physiological rhythms. Alternatively, this subregion may control
      circadian rhythms in locomotor behavior, whereas other circadian responses in
      physiology and behavior are sustained by different SCN compartments. The present
      study sought to distinguish between these possibilities by examining the role of
      the CalB subregion in a battery of rhythms within an individual animal. The
      results indicate that lesions of the CalB subregion of the SCN abolish circadian
      rhythms in behavior (locomotion, drinking, gnawing), physiology (body
      temperature, heart rate), and hormone secretion (melatonin, cortisol), even when
      other SCN compartments are spared. Together, these findings suggest a novel
      fundamental property of SCN organization, with a subset of cells being critical
      for the maintenance of SCN function manifest in circadian rhythms in physiology
      and behavior.

PMID- 15014121
TI  - Direct impact of T cells on neurons revealed by two-photon microscopy in living
      brain tissue.
AB  - Encephalitogenic T cells invade the brain during neuroinflammation such as
      multiple sclerosis (MS), inducing damage to myelin sheaths and oligodendrocytes.
      Only recently, neuronal structures were reported to be a crucial target in the
      disease. Here, two-photon microscopy using ion-sensitive dyes revealed that
      within the complex cellular network of living brain tissue, proteolipid protein
      (PLP)-specific T cells and T cells recognizing the nonmurine antigen ovalbumin
      (OVA) directly and independently of the major histocompatibility complex (MHC)
      contact neurons in which they induce calcium oscillations. T cell contact finally
      resulted in a lethal increase in neuronal calcium levels. This could be prevented
      by blocking both perforin and glutamate receptors. For the first time, our data
      provide direct insight into the activity of T cells in the living brain and their
      detrimental impact on neurons.

PMID- 15014122
TI  - The two regulatory subunits of aplysia cAMP-dependent protein kinase mediate
      distinct functions in producing synaptic plasticity.
AB  - Activation of the cAMP-dependent protein kinase (PKA) is critical for both short-
      and long-term facilitation in Aplysia sensory neurons. There are two types of the
      kinase, I and II, differing in their regulatory (R) subunits. We cloned Aplysia
      RII; RI was cloned previously. Type I PKA is mostly soluble in the cell body
      whereas type II is enriched at nerve endings where it is bound to two prominent A
      kinase-anchoring-proteins (AKAPs). Disruption of the binding of RII to AKAPs by
      Ht31, an inhibitory peptide derived from a human thyroid AKAP, prevents both the
      short- and the long-term facilitation produced by serotonin (5-HT). During long
      term facilitation, RII is transcriptionally upregulated; in contrast, the amount
      of RI subunits decreases, and previous studies have indicated that the decrease
      is through ubiquitin-proteosome-mediated proteolysis. Experiments with antisense
      oligonucleotides injected into the sensory neuron cell body show that the
      increase in RII protein is essential for the production of long-term
      facilitation. Using synaptosomes, we found that 5-HT treatment causes RII protein
      to increase at nerve endings. In addition, using reverse transcription-PCR, we
      found that RII mRNA is transported from the cell body to nerve terminals. Our
      results suggest that type I operates in the nucleus to maintain cAMP response
      element-binding protein-dependent gene expression, and type II PKA acts at
      sensory neuron synapses phosphorylating proteins to enhance release of
      neurotransmitter. Thus, the two types of the kinase have distinct but
      complementary functions in the production of facilitation at synapses of an
      identified neuron.

PMID- 15014123
TI  - Noradrenaline and dopamine efflux in the prefrontal cortex in relation to
      appetitive classical conditioning.
AB  - We trained rats to learn that an auditory stimulus predicted delivery of reward
      pellets in the Skinner box. After 2 d of training, we measured changes in efflux
      of noradrenaline (NA) and dopamine (DA) in the medial prefrontal cortex using
      microdialysis on the third day. Animals were subjected to a normal rewarded
      session and an extinction session, in which the auditory stimulus was presented
      alone. In the rewarded session, both NA and DA efflux were increased, but in
      extinction, only NA was activated. The data suggest that NA has a role in the
      reaction to reward-predicting stimuli, which complements that of DA.

PMID- 15014124
TI  - Linkage of the actin cytoskeleton to the postsynaptic density via direct
      interactions of Abp1 with the ProSAP/Shank family.
AB  - Synaptic contacts contain elaborate cytomatrices on both sides of the synaptic
      cleft, which are believed to organize and link the different synaptic functions
      in time and space and can respond to different inner and outer cues with massive
      structural reorganizations. At the PSD (postsynaptic density), activity-dependent
      reorganizations of the cortical actin cytoskeleton are hypothesized to play a
      role in synaptic plasticity. Here, we report on interactions of the F-actin
      binding protein Abp1 with members of the ProSAP/Shank family: multidomain
      scaffolding PSD proteins interconnecting glutamate receptors with other synaptic
      components. Affinity-purification experiments demonstrate that the interactions
      are mediated by the Abp1 (actin-binding protein 1) SH3 (Src homology 3) domain,
      which associates with a proline-rich motif that is conserved within the C
      terminal parts of ProSAP1(proline-rich synapse-associated protein 1)/Shank2 and
      ProSAP2/Shank3. The distribution of Abp1, ProSAP1, and ProSAP2 overlaps within
      the brain, and all three proteins are part of the PSD and are particularly
      enriched in cortex and hippocampus. Coimmunoprecipitation of endogenous Abp1 and
      ProSAP2 and colocalization studies of Abp1 and ProSAPs in hippocampal neurons
      indicate the in vivo relevance of the interactions. Intriguingly, in vivo
      recruitment assays demonstrate that Abp1 can bind to dynamic F-actin structures
      and ProSAPs simultaneously, suggesting that Abp1 might link different organizing
      elements in the PSD. Importantly, different paradigms of neuronal stimulation
      induce a redistribution of Abp1 to ProSAP-containing synapses. Our data suggest
      that ProSAPs may serve to localize Abp1 to dendritic spines, thus serving as
      attachment points for the dynamic postsynaptic cortical actin cytoskeleton. This
      creates a functional connection between synaptic stimulation and cytoskeletal
      rearrangements.

PMID- 15014125
TI  - Synaptic vesicles: test for a role in presynaptic calcium regulation.
AB  - Membrane-bound organelles such as mitochondria and the endoplasmic reticulum play
      an important role in neuronal Ca(2+) homeostasis. Synaptic vesicles (SVs), the
      organelles responsible for exocytosis of neurotransmitters, occupy more of the
      volume of presynaptic nerve terminals than any other organelle and, under some
      conditions, can accumulate Ca(2+). They are also closely associated with voltage
      gated Ca(2+) channels (VGCCs) that trigger transmitter release by admitting
      Ca(2+) into the nerve terminal in response to action potentials (APs). We tested
      the hypothesis that SVs can modulate Ca(2+) signals in the presynaptic terminal.
      This has been a difficult question to address because neither pharmacological nor
      genetic approaches to block Ca(2+) permeation of the SV membrane have been
      available. To investigate the possible role of SVs in Ca(2+) regulation, we used
      imaging techniques to compare Ca(2+) dynamics in motor nerve terminals before and
      after depletion of SVs. We used the temperature-sensitive Drosophila dynamin
      mutant shibire, in which SVs can be eliminated by stimulation. There was no
      difference in the amplitude or time course of Ca(2+) responses during high
      frequency trains of APs, or single APs, in individual presynaptic boutons before
      and after depletion of SVs. SVs have a limited role, if any, in the rapid
      sequestration of Ca(2+) within the neuronal cytosol or the synaptic microdomain.
      We also conclude that SVs are not important for regulation of synaptic VGCCs.

PMID- 15014126
TI  - Subunit composition and alternative splicing regulate membrane delivery of
      kainate receptors.
AB  - Kainate receptors (KARs) are heteromeric ionotropic glutamate receptors (GluRs)
      that play various roles in the regulation of synaptic transmission. The KAR
      subunits GluR5 and GluR6 exist under different splice variant isoforms in the C
      terminal domain (GluR5a, GluR5b, GluR5c, GluR6a, GluR6b). The differential role
      of KAR subunit splice variants is presently unknown. In transfected COS-7 cells
      and neurons from wild-type and GluR5 x GluR6 mice, we have found that the
      subcellular localization and membrane delivery differed between these splice
      variants. GluR6a was highly expressed at the plasma membrane. GluR6b, GluR5a, and
      GluR5b were detected at lower levels in the plasma membrane and mainly
      colocalized with calreticulin in the endoplasmic reticulum (ER). GluR5c was
      strongly retained in the ER by an RXR motif. GluR6a acted as a key subunit splice
      variant promoting surface expression of ER-retained subunit splice variants when
      assembled in heteromeric KARs. Surface expression of GluR6a was independent of
      its PDZ (postsynaptic density-95/discs large/zona occludens-1) binding motif and
      was promoted by a stretch of four basic amino acid residues at its C terminus.
      Overall, splice variants and subunit composition of KARs regulate receptor
      trafficking from the endoplasmic reticulum to the plasma membrane.

PMID- 15014127
TI  - Novel dominant rhodopsin mutation triggers two mechanisms of retinal degeneration
      and photoreceptor desensitization.
AB  - A variety of rod opsin mutations result in autosomal dominant retinitis
      pigmentosa and congenital night blindness in humans. One subset of these
      mutations encodes constitutively active forms of the rod opsin protein. Some of
      these dominant rod opsin mutant proteins, which desensitize transgenic Xenopus
      rods, provide an animal model for congenital night blindness. In a genetic screen
      to identify retinal degeneration mutants in Drosophila, we identified a dominant
      mutation in the ninaE gene (NinaE(pp100)) that encodes the rhodopsin that is
      expressed in photoreceptors R1-R6. Deep pseudopupil analysis and histology showed
      that the degeneration was attributable to a light-independent apoptosis. Whole
      cell recordings revealed that the NinaE(pp100) mutant photoreceptor cells were
      strongly desensitized, which partially masked their constitutive activity. This
      desensitization primarily resulted from both the persistent binding of arrestin
      (ARR2) to the NINAE(pp100) mutant opsin and the constitutive activity of the
      phototransduction cascade. Whereas mutations in several Drosophila genes other
      than ninaE were shown to induce photoreceptor cell apoptosis by stabilizing a
      rhodopsin-arrestin complex, NinaE(pp100) represented the first rhodopsin mutation
      that stabilized this protein complex. Additionally, the NinaE(pp100) mutation led
      to elevated levels of G(q)alpha in the cytosol, which mediated a novel retinal
      degeneration pathway. Eliminating both G(q)alpha and arrestin completely rescued
      the NinaE(pp100)-dependent photoreceptor cell death, which indicated that the
      degeneration is entirely dependent on both G(q)alpha and arrestin. Such a
      combination of multiple pathological pathways resulting from a single mutation
      may underlie several dominant retinal diseases in humans.

PMID- 15014128
TI  - Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau
      phosphorylation in brains of transgenic mice.
AB  - Apolipoprotein E (apoE) is found in amyloid plaques and neurofibrillary tangles
      (NFTs) in Alzheimer's disease (AD) brains, but its role in their pathogenesis is
      unclear. Previously, we found C-terminal-truncated fragments of apoE in AD brains
      and showed that such fragments can cause neurodegeneration and can induce NFT
      like inclusions in cultured neuronal cells and in transgenic mice. Here, we
      analyzed apoE fragmentation in brain tissue homogenates from transgenic mice
      expressing apoE3 or apoE4 in neurons [neuron-specific enolase (NSE)-apoE] or
      astrocytes [glial fibrillary acidic protein (GFAP)-apoE] by Western blotting. The
      C-terminal-truncated fragments of apoE accumulated, in an age-dependent manner,
      in the brains of NSE-apoE4 and, to a significantly lesser extent, NSE-apoE3 mice;
      however, no fragments were detected in GFAP-apoE3 or GFAP-apoE4 mice. In NSE-apoE
      mice, the pattern of apoE fragmentation resembled that seen in AD brains, and the
      fragmentation was specific for certain brain regions, occurring in the neocortex
      and hippocampus, which are vulnerable to AD-related neurodegeneration, but not in
      the less vulnerable cerebellum. Excitotoxic challenge with kainic acid
      significantly increased apoE fragmentation in NSE-apoE4 but not NSE-apoE3 mice.
      Phosphorylated tau (p-tau) also accumulated in an age-dependent manner in NSE
      apoE4 mice and, to a much lesser extent, in NSE-apoE3 mice but not in GFAP-apoE3
      or GFAP-apoE4 mice. Intraneuronal p-tau inclusions in the hippocampus were
      prominent in 21-month-old NSE-apoE4 mice but barely detectable in NSE-apoE3 mice.
      Thus, the accumulation of potentially pathogenic C-terminal-truncated fragments
      of apoE depends on both the isoform and the cellular source of apoE. Neuron
      specific proteolytic cleavage of apoE4 is associated with increased
      phosphorylation of tau and may play a key role in the development of AD-related
      neuronal deficits.

PMID- 15014129
TI  - Styrylbenzoxazole derivatives for in vivo imaging of amyloid plaques in the
      brain.
AB  - Progressive deposition of senile plaques (SPs) is one of the major
      neuropathological features of Alzheimer's disease (AD) that precedes cognitive
      decline. Noninvasive detection of SPs could, therefore, be a potential diagnostic
      test for early detection of AD patients. For imaging SPs in the living brain, we
      have developed a series of styrylbenzoxazole derivatives that achieve high
      binding affinity for amyloid-beta (Abeta) fibrils. One of these compounds, 6-(2
      Fluoroethoxy)-2-[2-(4-methylaminophenil) ethenyl]benzoxazole (BF-168),
      selectively binds SPs in AD brain sections and recognizes Abeta1-42-positive
      diffuse plaques as well as neuritic plaques in AD brain sections. Intravenous
      injection of BF-168 in PS1/APP and APP23 transgenic mice resulted in specific in
      vivo labeling to both compact and diffuse amyloid deposits in the brain. In
      addition, (18)F-radiolabeled BF-168 demonstrated abundant initial brain uptake
      (3.9% injected dose/gm at 2 min after injection) and fast clearance (t(1/2) =
      24.7 min) after intravenous administration in normal mice. Furthermore,
      autoradiograms of brain sections from APP23 transgenic mice at 180 min after
      intravenous injection of [(18)F]BF-168 showed selective labeling of brain amyloid
      deposits with little nonspecific binding. These findings strongly suggest that
      styrylbenzoxazole derivatives are promising candidate probes for positron
      emission tomography and single-photon emission computed tomography imaging for
      early detection of amyloid plaque formation.

PMID- 15014130
TI  - Loss-of-function analysis of EphA receptors in retinotectal mapping.
AB  - EphA tyrosine kinases are thought to act as topographically specific receptors in
      the well-characterized projection map from the retina to the tectum. Here, we
      describe a loss-of-function analysis of EphA receptors in retinotectal mapping.
      Expressing patches of a cytoplasmically truncated EphA3 receptor in chick retina
      caused temporal axons to have reduced responsiveness to posterior tectal
      repellent activity in vitro and to shift more posteriorly within the map in vivo.
      A gene disruption of mouse EphA5, replacing the intracellular domain with beta
      galactosidase, reduced in vitro responsiveness of temporal axons to posterior
      target membranes. It also caused map abnormalities in vivo, with temporal axons
      shifted posteriorly and nasal axons anteriorly, but with the entire target still
      filled by retinal axons. The anterior shift of nasal axons was not accompanied by
      increased responsiveness to tectal repellent activity, in contrast to the
      comparable anterior shift in ephrin-A knock-outs, helping to resolve a previous
      ambiguity in interpreting the ephrin gene knock-outs. The results show the
      functional requirement for endogenous EphA receptors in retinotectal mapping,
      show that the receptor intracellular domain is required for a forward signaling
      response to topographic cues, and provide new evidence for a role of axon
      competition in topographic mapping.

PMID- 15014131
TI  - The processing of visual shape in the cerebral cortex of human and nonhuman
      primates: a functional magnetic resonance imaging study.
AB  - We compared neural substrates of two-dimensional shape processing in human and
      nonhuman primates using functional magnetic resonance (MR) imaging in awake
      subjects. The comparison of MR activity evoked by viewing intact and scrambled
      images of objects revealed shape-sensitive regions in occipital, temporal, and
      parietal cortex of both humans and macaques. Intraparietal cortex in monkeys was
      relatively more two-dimensional shape sensitive than that of humans. In both
      species, there was an interaction between scrambling and type of stimuli
      (grayscale images and drawings), but the effect of stimulus type was much
      stronger in monkeys than in humans. Shape- and motion-sensitive regions
      overlapped to some degree. However, this overlap was much more marked in humans
      than in monkeys. The shape-sensitive regions can be used to constrain the warping
      of monkey to human cortex and suggest a large expansion of lateral parietal and
      superior temporal cortex in humans compared with monkeys.

PMID- 15014132
TI  - Role of calcium in neurotensin-evoked enhancement in firing in mesencephalic
      dopamine neurons.
AB  - Neurotensin (NT) increases neurotransmission within the mesolimbic dopamine
      system by enhancing the firing rate of dopaminergic (DAergic) neurons and by
      acting at the nerve terminal level. The signal transduction pathways involved in
      these effects have not been characterized, but NT receptors are coupled to the
      phospholipase C pathway and Ca(2+) mobilization. However, an enhancement of
      intracellular Ca(2+) concentration ([Ca(2+)](i)) evoked by NT in DAergic neurons
      has yet to be demonstrated. Furthermore, the hypothesis that the excitatory
      effects of NT in DAergic neurons are Ca(2+) dependent is currently untested. In
      whole-cell recording experiments, DAergic neurons in culture were identified by
      their selective ability to express a cell-specific green fluorescent protein
      reporter construct. These experiments confirmed that NT increases firing rate in
      cultured DAergic neurons. This effect was Ca(2+) dependent because it was blocked
      by intracellular dialysis with BAPTA. Using Ca(2+) imaging, we showed that NT
      caused a rapid increase in [Ca(2+)](i) in DAergic neurons. Most of the Ca(2+)
      originated from the extracellular medium. NT-induced excitation and Ca(2+) influx
      were blocked by SR48692, an antagonist of the type 1 NT receptor. Blocking IP(3)
      receptors using heparin prevented the excitatory effect of NT. Moreover, Zn(2+)
      and SKF96365 both blocked the excitatory effect of NT, suggesting that
      nonselective cationic conductances are involved. Finally, although NT can also
      induce a rise in [Ca(2+)](i) in astrocytes, we find that NT-evoked excitation of
      DAergic neurons can occur independently of astrocyte activation.

PMID- 15014134
TI  - The functional neuroanatomy of temporal discrimination.
AB  - Two identical stimuli, such as a pair of electrical shocks to the skin, are
      readily perceived as two separate events in time provided the interval between
      them is sufficiently long. However, as they are presented progressively closer
      together, there comes a point when the two separate stimuli are perceived as a
      single stimulus. Damage to posterior parietal cortex, peri-supplementary motor
      area (peri-SMA), and basal ganglia can disturb this form of temporal
      discrimination. Our aim was to establish, in healthy subjects, the brain areas
      that are involved in this process. During functional magnetic resonance imaging
      scanning, paired electrical pulses, separated by variable inter-stimulus
      intervals (5-110 msec), were delivered to different sites on one forearm (8-64 mm
      from the midline). Subjects were required to simply detect the stimulus (control
      task) or to identify a stimulus property. For temporal discrimination (TD),
      subjects reported whether they felt one or two stimuli. For spatial
      discrimination, they reported whether the stimuli were located on the right or
      left side of the forearm. Subjects reported their choice by pressing a button
      with the opposite hand. Our results showed that discrimination, as opposed to
      simply detection, activated several brain areas. Most were common to both
      discrimination tasks. These included regions of prefrontal cortex, right
      postcentral gyrus and inferior parietal lobule, basal ganglia, and cerebellum.
      However, activation of pre-SMA and anterior cingulate was found to be specific to
      the TD task. This suggests that these two frontal regions may play a role in the
      temporal processing of somatosensory events.

PMID- 15014133
TI  - NT-3 replacement with brain-derived neurotrophic factor redirects vestibular
      nerve fibers to the cochlea.
AB  - Survival of inner ear sensory neurons depends on two neurotrophins, BDNF and NT
      3, and their respective receptors, TrkB and TrkC. Because both receptors are
      present in the same neuron, it has been suggested that BDNF and NT-3 are
      functionally redundant in promoting neuronal survival. Knock-in of one ligand
      into the locus of the other one confirmed this hypothesis for the cochlea,
      leaving open the question of why two neurotrophins are required for proper
      innervation of the mammalian ear. Here, we show that the precise spatiotemporal
      pattern of expression of the two neurotrophins is essential for proper patterning
      of the inner ear innervation. Mice expressing BDNF under the control of the NT-3
      promoter develop exuberant projections of vestibular sensory neurons to the basal
      turn of the cochlea. This projection can be enhanced by combining the transgene
      with a null mutation of BDNF. However, vestibular fibers rerouted into the
      cochlea do not reach hair cells and remain outside the organ of Corti, suggesting
      a chemotactic role for neurotrophins on these fibers. Our data provide genetic
      evidence that neurotrophins in the ear exert both survival and axon guidance
      roles.

PMID- 15014135
TI  - Regulation of CXCR4 receptor dimerization by the chemokine SDF-1alpha and the HIV
      1 coat protein gp120: a fluorescence resonance energy transfer (FRET) study.
AB  - Both the chemokine SDF-1alpha and the human immunodeficiency virus-1 (HIV-1) coat
      protein gp120 can bind to CXCR4 chemokine receptors but with different signaling
      consequences. To understand the molecular basis for these differences, we tagged
      the rat CXCR4 receptor with enhanced cyan (ECFP) and yellow (EYFP) derivatives of
      the green fluorescent protein and investigated CXCR4 receptor dimerization in
      human embryonic kidney (HEK)-tsA201 cells using fluorescence resonance energy
      transfer (FRET). Elevated FRET was detected under basal conditions from EYFP
      CXCR4 and ECFP-CXCR4 receptor-transfected cells indicating a high level of CXCR4
      receptor dimerization. In comparison, EYFP-CXCR4 and ECFP-mu-opioid receptor
      cotransfected cells displayed a much lower FRET signal. The FRET signal resulting
      from EYFP-CXCR4- and ECFP-CXCR4-expressing cells could be attenuated by
      coexpressing nontagged CXCR4 receptors suggesting competition with fluorophore
      tagged receptors in the membrane. Nontagged mu-opioid, kappa-opioid, and
      muscarinic receptors also decreased the FRET between the tagged CXCR4 receptor
      pairs but to a lesser extent. Application of the CXCR4 receptor agonist SDF
      1alpha (50 nM) further increased the FRET signal from tagged CXCR4 receptors, an
      effect that was inhibited by the CXCR4 antagonist AMD3100. SDF-1alpha had no
      effect when EYFP-CXCR4 and ECFP-mu-opioid receptors were coexpressed. The effect
      of gp120IIIB on CXCR4 FRET was dependent on the coexpression of human CD4 (hCD4)
      when it increased the FRET signal, and this was decreased by AMD3100
      pretreatment. FRET analysis of tagged hCD4 constructs demonstrated that there was
      significant association of hCD4 and CXCR4, as well as hCD4 dimerization. These
      data suggest that CXCR4 dimerization is involved in SDF-1alpha- and gp120-induced
      signaling events.

PMID- 15014136
TI  - Endogenous regulator of G protein signaling proteins suppress Galphao-dependent,
      mu-opioid agonist-mediated adenylyl cyclase supersensitization.
AB  - Chronic mu-opioid agonist treatment leads to dependence with withdrawal on
      removal of agonist. At the cellular level withdrawal is accompanied by a
      supersensitization of adenylyl cyclase, an effect that requires inhibitory Galpha
      proteins. Inhibitory Galpha protein action is modulated by regulator of G protein
      signaling (RGS) proteins that act as GTPase activating proteins and reduce the
      lifetime of Galpha-GTP. In this article, we use C6 glioma cells expressing the
      rat mu-opioid receptor (C6mu) to examine the hypothesis that Galphao alone can
      mediate mu-opioid agonist induced adenylyl cyclase supersensitivity and that
      endogenous RGS proteins serve to limit the extent of this supersensitization.
      C6mu cells were stably transfected with pertussis toxin (PTX)-insensitive Galphao
      that was either sensitive or insensitive to endogenous RGS proteins. Cells were
      treated with PTX to uncouple endogenous Galpha proteins followed by exposure to
      the mu-opioid agonists [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin or morphine.
      Supersensitization was observed in cells expressing wild-type Galpha, but this
      was lost on PTX treatment. In cells expressing PTX-insensitive Galphao
      supersensitization was recovered, confirming that Galphao alone can support
      supersensitization. In cells expressing the RGS-insensitive mutant Galphao, there
      was a greater degree of supersensitization and the concentration of micro-agonist
      needed to achieve half-maximal supersensitization was reduced by 10-fold. The
      amount of supersensitization seen did not directly relate to the degree of acute
      inhibition of adenylyl cyclase. These results demonstrate a role for Galphao in
      adenylyl cyclase supersensitization after mu-agonist exposure and show that this
      action is modulated by endogenous RGS proteins.

PMID- 15014137
TI  - Fipronil is a potent open channel blocker of glutamate-activated chloride
      channels in cockroach neurons.
AB  - Fipronil, a phenylpyrazole insecticide, displays high insecticidal activity and
      reduced mammalian toxicity. To better elucidate the mechanism of its selective
      toxicity between insects and mammals and activity against dieldrin-resistant
      insects, we studied fipronil action on glutamate-gated chloride channels
      (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach
      thoracic ganglion neurons, using the whole-cell patch clamp technique. Glutamate
      evoked two types of chloride currents, a desensitizing current and a
      nondesensitizing current. Fipronil differentially inhibited these two types of
      currents with different potencies and with different rates of reversibility.
      Fipronil inhibited the desensitizing and nondesensitizing GluCls with IC50 values
      of 801 and 10 nM, respectively. Kinetic analysis revealed that fipronil blocks
      required channel opening. Recovery of the desensitizing current from fipronil
      block required channel opening, whereas recovery of nondesensitizing current from
      block was independent of channel opening. The high potency of fipronil against
      the nondesensitizing current was due to a slow unblocking rate constant. In
      addition, when the nondesensitizing GluCls were occupied by picrotoxinin, the
      receptors became less sensitive to fipronil block. It is concluded that GluCls
      are a critical target for fipronil, especially for the selective toxicity between
      mammals and insects, and that fipronil block of GluCls may play a role in the
      lack of the cross-resistance with dieldrin.

PMID- 15014138
TI  - Expected rates and modes of evolution of enhancer sequences.
AB  - The evolution of new functions takes place partially through changes in the way
      transcription is controlled. Transcriptional control is brought about by the
      interactions of transcription factors with short target motifs in the DNAs of
      promoters and enhancers. One way in which changes in gene expression can evolve
      is through the acquisition of new transcription factor targets in enhancer
      sequences. Since such target sites are simple, they can be produced rapidly from
      random DNA by mutation and selection. Here we consider a population of organisms
      that finds itself in an ecological situation where bringing a particular target
      gene under the control of a particular transcription factor would be favored by
      natural selection. What will be the time required for such a process, as a
      function of the selection for the new target, the mutation rate, and the
      population size? The starting sequences considered are either real enhancers from
      the Drosophila melanogaster genome, or randomized versions of these. We find that
      the time required to find binding sites is strongly dependent on the existence in
      the starting sequence of sites that differ from binding sites by single
      substitutions (presites). The process of converting presites to binding sites is
      driven by natural selection, and thus the time required typically reduces with
      the strength of selection. However, if there is a strongly distorted G:C ratio in
      the starting sequence, presites will typically be absent, and the finding of
      binding sites will be preceded by a long time period of neutral evolution,
      however strong is the selection favoring sites. The positions of presites largely
      determine where binding sites will evolve. One result of this is that any
      incremental selective benefits that result from the relative positioning of sites
      have a surprisingly small impact on the final binding-site positions.

PMID- 15014139
TI  - Structure and molecular phylogeny of sasA genes in cyanobacteria: insights into
      evolution of the prokaryotic circadian system.
AB  - Cyanobacteria are the simplest organisms known to have a circadian system. In
      addition to the three well-studied kai genes, kaiA, kaiB, and kaiC, an important
      element of this system is a two-component sensory transduction histidine kinase
      sasA. Using publicly available data of complete prokaryotic genomes, we performed
      structural and phylogenetic analyses of the sasA genes. Results show that this
      gene has a triple-domain structure, and the domains are under different selective
      constraints. The sasA gene originated in cyanobacteria probably through the
      fusion of the ancestral kaiB gene with a double-domain, two-component sensory
      transduction histidine kinase. The results of the phylogenetic analyses suggest
      that sasA emerged before the kaiA gene, about 3,000-2,500 MYA, and has evolved in
      parallel with the evolution of the kaiBC cluster. The observed concordant
      patterns of the sasA and kaiBC evolution suggest that these genes might compose
      an ancient KaiBC-SasA-based circadian system, without the kaiA gene, and that
      such a system still exists in some unicellular cyanobacteria.

PMID- 15014140
TI  - Spiking of contemporary human template DNA with ancient DNA extracts induces
      mutations under PCR and generates nonauthentic mitochondrial sequences.
AB  - Proof of authenticity is the greatest challenge in palaeogenetic research, and
      many safeguards have become standard routine in laboratories specialized on
      ancient DNA research. Here we describe an as-yet unknown source of artifacts that
      will require special attention in the future. We show that ancient DNA extracts
      on their own can have an inhibitory and mutagenic effect under PCR. We have
      spiked PCR reactions including known human test DNA with 14 selected ancient DNA
      extracts from human and nonhuman sources. We find that the ancient DNA extracts
      inhibit the amplification of large fragments to different degrees, suggesting
      that the usual control against contaminations, i.e., the absence of long
      amplifiable fragments, is not sufficient. But even more important, we find that
      the extracts induce mutations in a nonrandom fashion. We have amplified a 148-bp
      stretch of the mitochondrial HVRI from contemporary human template DNA in spiked
      PCR reactions. Subsequent analysis of 547 sequences from cloned amplicons
      revealed that the vast majority (76.97%) differed from the correct sequence by
      single nucleotide substitutions and/or indels. In total, 34 positions of a 103-bp
      alignment are affected, and most mutations occur repeatedly in independent PCR
      amplifications. Several of the induced mutations occur at positions that have
      previously been detected in studies of ancient hominid sequences, including the
      Neandertal sequences. Our data imply that PCR-induced mutations are likely to be
      an intrinsic and general problem of PCR amplifications of ancient templates.
      Therefore, ancient DNA sequences should be considered with caution, at least as
      long as the molecular basis for the extract-induced mutations is not understood.

PMID- 15014141
TI  - Long perfect dinucleotide repeats are typical of vertebrates, show motif
      preferences and size convergence.
AB  - Microsatellites are simple sequence repeats (SSRs) showing complex patterns of
      length, motif sizes, motif sequences, and repeat perfection. We studied the
      structure of the dinucleotide SSR population at the genome level by analyzing
      assembled DNA sequence across species. Three dinucleotide populations were
      distinguished when SSR genome frequency was analyzed as a function of repeat
      length and repeat perfection. A population of low-perfection SSRs was identified,
      which is constituted by short repeats and represents the vast majority of genomic
      dinucleotide SSRs across eukaryotic genomes. In turn, the highly perfect repeats
      are 30 to 50 times less frequent and, in addition to short repeats, also contain
      a long repeat population that is uniquely represented in vertebrate species.
      Distinctive features of this population include the modal peak in the frequency
      distribution of repeat length and the strong preferential usage of the repeat
      motifs AC and AG. These results raise the hypothesis that the ability of carrying
      a distinct population of long, highly perfect dinucleotide repeats in the genome
      is a late acquisition in chordate evolution. Our analysis also suggests that
      different dinucleotide repeat populations have different dynamics and are likely
      to be underlined by different molecular mechanisms of generation and maintenance
      in the genome. Thus, these observations imply that caution should be taken in
      extrapolating results from studies on SSR mutability and on SSR phylogenetic
      comparisons that do not take into account the stratification of dinucelotide
      populations in the eukaryotic genome.

PMID- 15014142
TI  - A large variation in the rates of synonymous substitution for RNA viruses and its
      relationship to a diversity of viral infection and transmission modes.
AB  - RNA viruses successfully adapt to various environments by repeatedly producing
      new mutants, often through generating a number of nucleotide substitutions. To
      estimate the degree of variation in mutation rates of RNA viruses and to
      understand the source of such variation, we studied the synonymous substitution
      rate because synonymous substitution is exempt from functional constraints at the
      protein level, and its rate reflects the mutation rate to a great extent. We
      estimated the synonymous substitution rates for a total of 49 different species
      of RNA viruses, and we found that the rates had tremendous variation by 5 orders
      of magnitude (from 1.3 x 10(-7) to 6.2 x 10(-2) /synonymous site/year). Comparing
      the synonymous substitution rates with the replication frequencies and
      replication error rates for the RNA viruses, we found that the main source of the
      rate variation was differences in the replication frequency because the rates of
      replication error were roughly constant over different RNA viruses. Moreover, we
      examined a relationship between viral life strategies and synonymous substitution
      rates to understand which viral life strategies affect replication frequencies.
      The results show that the variation of synonymous substitution rates has been
      influenced most by either the difference in the infection modes or the
      differences in the transmission modes. In conclusion, the variation of mutation
      rates for RNA viruses is caused by different replication frequencies, which are
      affected strongly by the infection and transmission modes.

PMID- 15014143
TI  - NUMTs in sequenced eukaryotic genomes.
AB  - Mitochondrial DNA sequences are frequently transferred to the nucleus giving rise
      to the so-called nuclear mitochondrial DNA (NUMT). Analysis of 13 eukaryotic
      species with sequenced mitochondrial and nuclear genomes reveals a large
      interspecific variation of NUMT number and size. Copy number ranges from none or
      few copies in Anopheles, Caenorhabditis, Plasmodium, Drosophila, and Fugu to more
      than 500 in human, rice, and Arabidopsis. The average size is between 62 (baker's
      yeast) and 647 bps (Neurospora), respectively. A correlation between the
      abundance of NUMTs and the size of the nuclear or the mitochondrial genomes, or
      of the nuclear gene density, is not evident. Other factors, such as the number
      and/or stability of mitochondria in the germline, or species-specific mechanisms
      controlling accumulation/loss of nuclear DNA, might be responsible for the
      interspecific diversity in NUMT accumulation.

PMID- 15014144
TI  - Rapid evolution by positive Darwinian selection in the extracellular domain of
      the abundant lymphocyte protein CD45 in primates.
AB  - CD45, encoded by PTPRC in humans, is the most abundantly expressed protein on the
      surface of many lymphocytes. We investigated whether the extracellular region of
      CD45 was under positive selection in Old World primates, and whether there was
      differential selection across this region, particularly on exons that were
      involved in alternative splicing and those that were not alternatively spliced.
      The results show extraordinarily strong and consistent positive Darwinian
      selection on the extracellular part of CD45 throughout the evolution of Old World
      monkeys, apes and humans. Positive selection is concentrated in exons 9 and 14,
      which code for the previously neglected linker and fibronectin III domains. These
      exons have a high rate of evolution at nonsynonymous sites that is roughly twice
      as high as that of the intronic rate in this gene. In contrast, alternatively
      spliced exons 4-6, which code for the variable domains, are under weaker positive
      selection and are evolving more slowly than the intronic rate. These data provide
      a striking example of positive selection in a well-known gene that should provide
      an impetus for further functional studies to elucidate its species-specific
      function.

PMID- 15014145
TI  - A Bayesian mixture model for across-site heterogeneities in the amino-acid
      replacement process.
AB  - Most current models of sequence evolution assume that all sites of a protein
      evolve under the same substitution process, characterized by a 20 x 20
      substitution matrix. Here, we propose to relax this assumption by developing a
      Bayesian mixture model that allows the amino-acid replacement pattern at
      different sites of a protein alignment to be described by distinct substitution
      processes. Our model, named CAT, assumes the existence of distinct processes (or
      classes) differing by their equilibrium frequencies over the 20 residues. Through
      the use of a Dirichlet process prior, the total number of classes and their
      respective amino-acid profiles, as well as the affiliations of each site to a
      given class, are all free variables of the model. In this way, the CAT model is
      able to adapt to the complexity actually present in the data, and it yields an
      estimate of the substitutional heterogeneity through the posterior mean number of
      classes. We show that a significant level of heterogeneity is present in the
      substitution patterns of proteins, and that the standard one-matrix model fails
      to account for this heterogeneity. By evaluating the Bayes factor, we demonstrate
      that the standard model is outperformed by CAT on all of the data sets which we
      analyzed. Altogether, these results suggest that the complexity of the pattern of
      substitution of real sequences is better captured by the CAT model, offering the
      possibility of studying its impact on phylogenetic reconstruction and its
      connections with structure-function determinants.

PMID- 15014146
TI  - The enigmatic planctomycetes may hold a key to the origins of methanogenesis and
      methylotrophy.
AB  - Methanogenesis and methane oxidation are the major biological processes affecting
      the global cycling of the powerful greenhouse gas methane. To carry out the two
      alternative bioconversions, Nature has cleverly recycled key reactions for the C1
      transfers between the oxidation levels of formaldehyde and formate, and these
      involve analogous enzyme systems and common specialized cofactors, methanopterin
      and methanofuran. Until recently, the distribution of these functions has been
      limited to methanogenic archaea and methylotrophic proteobacteria, and their
      evolutionary history remained obscure. Single interdomain lateral transfer of the
      respective genes has been suggested to play a role. Here we show that genes for
      C1 transfer reactions linked to methanopterin and methanofuran are also present
      in diverse representatives of the enigmatic bacterial clade, the Planctomycetes.
      Phylogenetic analysis places the planctomycete sequences as distantly from their
      archaeal counterparts as from their proteobacterial counterparts, suggesting
      novel scenarios for the evolution of the C1 transfer functions in both
      methanogens and methylotrophs. This finding suggests a possible role for
      Planctomycetes in the evolution of the methane cycle on Earth.

PMID- 15014147
TI  - Fugu genome analysis provides evidence for a whole-genome duplication early
      during the evolution of ray-finned fishes.
AB  - With about 24,000 extant species, teleosts are the largest group of vertebrates.
      They constitute more than 99% of the ray-finned fishes (Actinopterygii) that
      diverged from the lobe-finned fish lineage (Sarcopterygii) about 450 MYA.
      Although the role of genome duplication in the evolution of vertebrates is now
      established, its role in structuring the teleost genomes has been controversial.
      At least two hypotheses have been proposed: a whole-genome duplication in an
      ancient ray-finned fish and independent gene duplications in different lineages.
      These hypotheses are, however, based on small data sets and lack adequate
      statistical and phylogenetic support. In this study, we have made a systematic
      comparison of the draft genome sequences of Fugu and humans to identify
      paralogous chromosomal regions ("paralogons") in the Fugu that arose in the ray
      finned fish lineage ("fish-specific"). We identified duplicate genes in the Fugu
      by phylogenetic analyses of the Fugu, human, and invertebrate sequences. Our
      analyses provide evidence for 425 fish-specific duplicate genes in the Fugu and
      show that at least 6.6% of the genome is represented by fish-specific paralogons.
      We estimated the ages of Fugu duplicate genes and paralogons using the molecular
      clock. Remarkably, the ages of duplicate genes and paralogons are clustered, with
      a peak around 350 MYA. These data strongly suggest a whole-genome duplication
      event early during the evolution of ray-finned fishes, probably before the origin
      of teleosts.

PMID- 15014148
TI  - On counting tandem duplication trees.

PMID- 15014149
TI  - Retrotransposon-gene associations are widespread among D. melanogaster
      populations.
AB  - We have surveyed 18 natural populations of Drosophila melanogaster for the
      presence of 23 retrotransposon-gene-association alleles (i.e., the presence of an
      LTR retrotransposon sequence in or within 1,000 bp of a gene) recently identified
      in the sequenced D. melanogaster genome. The identified associations were
      detected only in the D. melanogaster populations. The majority (61%) of the
      identified retrotransposon-gene associations were present only in the sequenced
      strain in which they were first identified. Thirty percent of the associations
      were detected in at least one of the natural populations, and 9% of the
      associations were detected in all of the D. melanogaster populations surveyed.
      Sequence analysis of an association allele present in all populations indicates
      that selection is a significant factor in the spread and/or maintenance of at
      least some of retroelement-gene associations in D. melanogaster.

PMID- 15014150
TI  - Frequent false detection of positive selection by the likelihood method with
      branch-site models.
AB  - Positive Darwinian selection promotes fixations of advantageous mutations during
      gene evolution and is probably responsible for most adaptations. Detecting
      positive selection at the DNA sequence level is of substantial interest because
      such information provides significant insights into possible functional
      alterations during gene evolution as well as important nucleotide substitutions
      involved in adaptation. Efficient detection of positive selection, however, has
      been difficult because selection often operates on only a few sites in a short
      period of evolutionary time. A likelihood-based method with branch-site models
      was recently introduced to overcome such difficulties. Here I examine the
      accuracy of the method using computer simulation. I find that the method detects
      positive selection in 20%-70% of cases when the DNA sequences are generated by
      computer simulation under no positive selection. Although the frequency of such
      false detection varies depending on, among other things, the tree topology,
      branch length, and selection scheme, the branch-site likelihood method generally
      gives misleading results. Thus, detection of positive selection by this method
      alone is unreliable. This unreliability may have resulted from its over
      sensitivity to violations of assumptions made in the method, such as certain
      distributions of selective strength among sites and equal transition/transversion
      ratios for synonymous and nonsynonymous substitutions.

PMID- 15014152
TI  - Coenzyme A biosynthesis: reconstruction of the pathway in archaea and an
      evolutionary scenario based on comparative genomics.
AB  - Coenzyme A (CoA) holds a central position in cellular metabolism and therefore
      can be assumed to be an ancient molecule. Starting from the known E. coli and
      human enzymes required for the biosynthesis of CoA, phylogenetic profiles and
      chromosomal proximity methods enabled an almost complete reconstruction of
      archaeal CoA biosynthesis. This includes the identification of strong candidates
      for archaeal pantothenate synthetase and pantothenate kinase, which are unrelated
      to the corresponding bacterial or eukaryotic enzymes. According to this
      reconstruction, the topology of CoA synthesis from common precursors is
      essentially conserved across the three domains of life. The CoA pathway is
      conserved to varying degrees in eukaryotic pathogens like Giardia lamblia or
      Plasmodium falciparum, indicating that these pathogens have individual uptake
      mechanisms for different CoA precursors. Phylogenetic analysis and phyletic
      distribution of the CoA biosynthetic enzymes suggest that the enzymes required
      for the synthesis of phosphopantothenate were recruited independently in the
      bacterial and archaeal lineages by convergent evolution, and that eukaryotes
      inherited the genes for the synthesis of pantothenate (vitamin B5) from bacteria.
      Homologues to bacterial enzymes involved in pantothenate biosynthesis are present
      in a subset of archaeal genomes. The phylogenies of these enzymes indicate that
      they were acquired from bacterial thermophiles through horizontal gene transfer.
      Monophyly can be inferred for each of the enzymes catalyzing the four ultimate
      steps of CoA synthesis, the conversion of phosphopantothenate into CoA. The
      results support the notion that CoA was initially synthesized from a prebiotic
      precursor, most likely pantothenate or a related compound.

PMID- 15014151
TI  - A specific genetic background is required for acquisition and expression of
      virulence factors in Escherichia coli.
AB  - In bacteria, the evolution of pathogenicity seems to be the result of the
      constant arrival of virulence factors (VFs) into the bacterial genome. However,
      the integration, retention, and/or expression of these factors may be the result
      of the interaction between the new arriving genes and the bacterial genomic
      background. To test this hypothesis, a phylogenetic analysis was done on a
      collection of 98 Escherichia coli/Shigella strains representing the pathogenic
      and commensal diversity of the species. The distribution of 17 VFs associated to
      the different E. coli pathovars was superimposed on the phylogenetic tree. Three
      major types of VFs can be recognized: (1) VFs that arrive and are expressed in
      different genetic backgrounds (such as VFs associated with the pathovars of mild
      chronic diarrhea: enteroaggregative, enteropathogenic, and diffusely-adhering E.
      coli), (2) VFs that arrive in different genetic backgrounds but are
      preferentially found, associated with a specific pathology, in only one
      particular background (such as VFs associated with extraintestinal diseases), and
      (3) VFs that require a particular genetic background for the arrival and
      expression of their virulence potential (such as VFs associated with pathovars
      typical of severe acute diarrhea: enterohemorragic, enterotoxigenic, and
      enteroinvasive E. coli strains). The possibility of a single arrival of VFs by
      chance, followed by a vertical transmission, was ruled out by comparing the
      evolutionary histories of some of these VFs to the strain phylogeny. These
      evidences suggest that important changes in the genome of E. coli have occurred
      during the diversification of the species, allowing the virulence factors
      associated with severe acute diarrhea to arrive in the population. Thus, the E.
      coli genome seems to be formed by an "ancestral" and a "derived" background, each
      one responsible for the acquisition and expression of different virulence
      factors.

PMID- 15014153
TI  - The evolutionary gain of spliceosomal introns: sequence and phase preferences.
AB  - Theories regarding the evolution of spliceosomal introns differ in the extent to
      which the distribution of introns reflects either a formative role in the
      evolution of protein-coding genes or the adventitious gain of genetic elements.
      Here, systematic methods are used to assess the causes of the present-day
      distribution of introns in 10 families of eukaryotic protein-coding genes
      comprising 1,868 introns in 488 distinct alignment positions. The history of
      intron evolution inferred using a probabilistic model that allows ancestral
      inheritance of introns, gain of introns, and loss of introns reveals that the
      vast majority of introns in these eukaryotic gene families were not inherited
      from the most recent common ancestral genes, but were gained subsequently.
      Furthermore, among inferred events of intron gain that meet strict criteria of
      reliability, the distribution of sites of gain with respect to reading-frame
      phase shows a 5:3:2 ratio of phases 0, 1 and 2, respectively, and exhibits a
      nucleotide preference for MAG GT (positions -3 to +2 relative to the site of
      gain). The nucleotide preferences of intron gain may prove to be the ultimate
      cause for the phase bias. The phase bias of intron gain is sufficient to account
      quantitatively for the well-known 5:3:2 bias in phase frequencies among extant
      introns, a conclusion that holds even when taxonomic heterogeneity in phase
      patterns is considered. Thus, intron gain accounts for the vast majority of
      extant introns and for the bias toward phase 0 introns that previously was
      interpreted as evidence for ancient formative introns.

PMID- 15014154
TI  - Positive selection on multiple antique allelic lineages of transferrin in the
      polyploid Carassius auratus.
AB  - Transferrin polymorphism has been studied in the polyploid Carassius auratus by
      cloning and sequence analysis of cDNAs from its three subspecies C. auratus
      gibelio, C. auratus auratus, and C. auratus cuvieri. DNA polymorphism of
      extremely high extent was shown for the transferrin gene by the 248 segregation
      sites among coding region sequences of its alleles. The deduced amino acid
      sequences of the transferrin alleles showed variable theoretical physicochemical
      parameters, which might constitute molecular basis for their electrophoretic
      heterogeneity. Positive selection was inferred by the replacement/synonymous
      ratios larger than 1 in partial allelic lineages which was subsequently confirmed
      by likelihood simulation under neutral or selection models. Furthermore, the
      correspondent sites to these selected codons were collectively located at two
      planes in the crystallographic structure of rabbit transferrin, which suggested
      that the rapid evolution of C. auratus transferrin might correlate to its
      adaptation to variable environmental elements such as oxygen pressure. The
      minimal 26 recombination events were detected among coding sequences of C.
      auratus transferrin, with partial mosaic sequences and breakpoints identified by
      identity scanning and information site analyses. Phylogenetic analyses revealed
      multiple antique allelic lineages of transferrin, which was estimated to diverge
      fifteen to twenty MYA. All these features strongly suggested the role of
      balancing selection in long persistence of high transferrin polymorphism in C.
      auratus. Furthermore, owing to its particular evolutionary backgrounds, the
      silver crucian carp might possess a distinctive balancing selection mechanism.

PMID- 15014155
TI  - A phylogenomic study of endosymbiotic bacteria.
AB  - Endosymbiotic bacteria of aphids, Buchnera aphidicola, and tsetse flies,
      Wigglesworthia glossinidia, are descendents of free-living gamma-Proteobacteria.
      The acceleration of sequence evolution in the endosymbiont genomes is here
      estimated from a phylogenomic analysis of the gamma-Proteobacteria. The tree
      topologies associated with the most highly conserved genes suggest that the
      endosymbionts form a sister group with Escherichia coli, Salmonella sp., and
      Yersinia pestis. Our results indicate that deviant tree topologies result from
      high substitution rates and biased nucleotide patterns, rather than from lateral
      gene transfer, as previously suggested. A reinvestigation of the relative rate
      increase in the endosymbiont genomes reveals variability among genes that
      correlate with host-associated metabolic dependencies. The conclusion is that
      host-level selection has retarded both the loss of genes and the acceleration of
      sequence evolution in endocellular symbionts.

PMID- 15014156
TI  - Functional microsatellite polymorphism associated with divergent social structure
      in vole species.
AB  - Forebrain vasopressin/vasotocin systems regulate a diverse set of complex social
      behaviors in a species-specific manner. Among mammals, vasopressin gene sequences
      and peptide distributions in the brain are highly conserved across species. In
      contrast, vasopressin V1a receptors (V1aR) are conserved at the protein level,
      but not at the level of gene structure or neuroanatomical distribution of the
      receptor. Here, we examine the functional role of a microsatellite segment in the
      5' region of V1aR that differs significantly between monogamous and nonmonogamous
      vole species with divergent V1aR expression patterns. Using luciferase reporter
      assays, we demonstrate that this microsatellite plays a significant role in
      transcriptional regulation in a cell-type-specific manner. These results suggest
      that significant evolutionary changes in social behavior can occur through
      variation in regulatory regions of genes already involved in social behavior.

PMID- 15014157
TI  - First application of the SINE (short interspersed repetitive element) method to
      infer phylogenetic relationships in reptiles: an example from the turtle
      superfamily Testudinoidea.
AB  - Although turtles (order Testudines) constitute one of the major reptile groups,
      their phylogenetic relationships remain largely unresolved. Hence, we attempted
      to elucidate their phylogeny using the SINE (short interspersed repetitive
      element) method, in which the sharing of a SINE at orthologous loci is indicative
      of synapomorphy. First, a detailed characterization of the tortoise polIII/SINE
      was conducted using 10 species from eight families of hidden-necked turtles
      (suborder Cryptodira). Our analysis of 382 SINE sequences newly isolated in the
      present study revealed two subgroups, namely Cry I and Cry II, which were
      distinguishable according to diagnostic nucleotides in the 3' region.
      Furthermore, four (IA-ID) and five (IIA-IIE) different SINE types were identified
      within Cry I and Cry II subgroups, respectively, based on features of
      insertions/deletions located in the middle of the SINE sequences. The relative
      frequency of occurrence of the subgroups and the types of SINEs in this family
      were highly variable among different lineages of turtles, suggesting active
      differential retroposition in each lineage. Further application of the SINE
      method using the most retrotranspositionally active types, namely IB and IC,
      challenged the established phylogenetic relationships of Bataguridae and its
      related families. The data for 11 orthologous loci demonstrated a close
      relationship between Bataguridae and Testudinidae, as well as the presence of the
      three clades within Bataguridae. Although the SINE method has been used to infer
      the phylogenies of a number of vertebrate groups, it has never been applied to
      reptiles. The present study represents the first application of this method to a
      phylogenetic analysis of this class of vertebrates, and it provides detailed
      information on the SINE subgroups and types. This information may be applied to
      the phylogenetic resolution of relevant turtle lineages.

PMID- 15014158
TI  - Similar rates but different modes of sequence evolution in introns and at exonic
      silent sites in rodents: evidence for selectively driven codon usage.
AB  - In mammals divergence at fourfold degenerate sites in codons (K(4)) and intronic
      sequence (K(i)) are both used to estimate the mutation rate, under the
      supposition that both evolve neutrally. Does it matter which of these we use?
      Using either class of sequence can be defended because (1) K(4) is the same as
      K(i) (at least in rodents) and (2) there is no selectively driven codon usage
      (hence no systematic selection on third sites). Here we re-examine these findings
      using 560 introns (for 136 genes) in the mouse-rat comparison, aligned by eye and
      using a new maximum likelihood protocol. We find that the rate of evolution at
      fourfold sites and at intronic sites is similar in magnitude, but only after
      eliminating putatively constrained sites from introns (first introns and sites
      flanking intron-exon junctions). Any approximate congruence between the two rates
      is not, however, owing to an underlying similarity in the mode of sequence
      evolution. Some dinucleotides are hypermutable and differently abundant in exons
      and introns (e.g., CpGs). More importantly, after controlling for relative
      abundance, all dinucleotides starting with A or T are more prevalent in
      mismatches in exons than in introns, whereas C-starting dinucleotides (except CG)
      are more common in introns. Although C content at intronic sites is lower than at
      flanking fourfold sites, G content is similar, demonstrating that there exists a
      strong strand-specific preference for C nucleotides that is unique to exons.
      Transcription-coupled mutational processes and biased gene conversion cannot
      explain this, as they should affect introns and flanking exons equally.
      Therefore, by elimination, we propose this to be strong evidence for selectively
      driven codon usage in mammals.

PMID- 15014159
TI  - Estimating absolute rates of synonymous and nonsynonymous nucleotide substitution
      in order to characterize natural selection and date species divergences.
AB  - The rate of molecular evolution can vary among lineages. Sources of this
      variation have differential effects on synonymous and nonsynonymous substitution
      rates. Changes in effective population size or patterns of natural selection will
      mainly alter nonsynonymous substitution rates. Changes in generation length or
      mutation rates are likely to have an impact on both synonymous and nonsynonymous
      substitution rates. By comparing changes in synonymous and nonsynonymous rates,
      the relative contributions of the driving forces of evolution can be better
      characterized. Here, we introduce a procedure for estimating the chronological
      rates of synonymous and nonsynonymous substitutions on the branches of an
      evolutionary tree. Because the widely used ratio of nonsynonymous and synonymous
      rates is not designed to detect simultaneous increases or simultaneous decreases
      in synonymous and nonsynonymous rates, the estimation of these rates rather than
      their ratio can improve characterization of the evolutionary process. With our
      Bayesian approach, we analyze cytochrome oxidase subunit I evolution in primates
      and infer that nonsynonymous rates have a greater tendency to change over time
      than do synonymous rates. Our analysis of these data also suggests that rates
      have been positively correlated.

PMID- 15014162
TI  - Assembling an arsenal: origin and evolution of the snake venom proteome inferred
      from phylogenetic analysis of toxin sequences.
AB  - We analyzed the origin and evolution of snake venom toxin families represented in
      both viperid and elapid snakes by means of phylogenetic analysis of the amino
      acid sequences of the toxins and related nonvenom proteins. Out of eight toxin
      families analyzed, five provided clear evidence of recruitment into the snake
      venom proteome before the diversification of the advanced snakes (Kunitz-type
      protease inhibitors, CRISP toxins, galactose-binding lectins, M12B peptidases,
      nerve growth factor toxins), and one was equivocal (cystatin toxins). In two
      others (phospholipase A(2) and natriuretic toxins), the nonmonophyly of venom
      toxins demonstrates that presence of these proteins in elapids and viperids
      results from independent recruitment events. The ANP/BNP natriuretic toxins are
      likely to be basal, whereas the CNP/BPP toxins are Viperidae only. Similarly, the
      lectins were recruited twice. In contrast to the basal recruitment of the
      galactose-binding lectins, the C-type lectins were shown to be Viperidae only,
      with the alpha-chains and beta-chains resulting from an early duplication event.
      These results provide strong additional evidence that venom evolved once, at the
      base of the advanced snake radiation, rather than multiple times in different
      lineages, with these toxins also present in the venoms of the "colubrid" snake
      families. Moreover, they provide a first insight into the composition of the
      earliest ophidian venoms and point the way toward a research program that could
      elucidate the functional context of the evolution of the snake venom proteome.

PMID- 15014161
TI  - Complete sequences of the highly rearranged molluscan mitochondrial genomes of
      the Scaphopod Graptacme eborea and the bivalve Mytilus edulis.
AB  - We have determined the complete sequence of the mitochondrial genome of the
      scaphopod mollusk Graptacme eborea (14,492 nts) and completed the sequence of the
      mitochondrial genome of the bivalve mollusk Mytilus edulis (16,740 nts). (The
      name Graptacme eborea is a revision of the species formerly known as Dentalium
      eboreum.) G. eborea mtDNA contains the 37 genes that are typically found and has
      the genes divided about evenly between the two strands, but M. edulis contains an
      extra trnM and is missing atp8, and it has all genes on the same strand. Each has
      a highly rearranged gene order relative to each other and to all other studied
      mtDNAs. G. eborea mtDNA has almost no strand skew, but the coding strand of M.
      edulis mtDNA is very rich in G and T. This is reflected in differential codon
      usage patterns and even in amino acid compositions. G. eborea mtDNA has fewer
      noncoding nucleotides than any other mtDNA studied to date, with the largest
      noncoding region only 24 nt long. Phylogenetic analysis using 2,420 aligned amino
      acid positions of concatenated proteins weakly supports an association of the
      scaphopod with gastropods to the exclusion of Bivalvia, Cephalopoda, and
      Polyplacophora, but it is generally unable to convincingly resolve the
      relationships among major groups of the Lophotrochozoa, in contrast to the good
      resolution seen for several other major metazoan groups.

PMID- 15014163
TI  - The considerable genome size variation of Hordeum species (poaceae) is linked to
      phylogeny, life form, ecology, and speciation rates.
AB  - Genome size variation in plants is thought to be correlated with cytological,
      physiological, or ecological characters. However, conclusions drawn in several
      studies were often contradictory. To analyze nuclear genome size evolution in a
      phylogenetic framework, DNA contents of 134 accessions, representing all but one
      species of the barley genus Hordeum L., were measured by flow cytometry. The 2C
      DNA contents were in a range from 6.85 to 10.67 pg in diploids (2n = 14) and
      reached up to 29.85 pg in hexaploid species (2n = 42). The smallest genomes were
      found in taxa from the New World, which became secondarily annual, whereas the
      largest diploid genomes occur in Eurasian annuals. Genome sizes of polyploid taxa
      equaled mostly the added sizes of their proposed progenitors or were slightly (1%
      to 5%) smaller. The analysis of ancestral genome sizes on the base of the
      phylogeny of the genus revealed lineages with decreasing and with increasing
      genome sizes. Correlations of intraspecific genome size variation with the length
      of vegetation period were found in H. marinum populations from Western Europe but
      were not significant within two species from South America. On a higher
      taxonomical level (i.e., for species groups or the entire genus), environmental
      correlations were absent. This could mostly be attributed to the superimposition
      of life-form changes and phylogenetic constraints, which conceal ecogeographical
      correlations.

PMID- 15014164
TI  - Stabilizing selection on behavior and morphology masks positive selection on the
      signal in a salamander pheromone signaling complex.
AB  - Natural selection maintains the integration and coordination of sets of
      phenotypic characters that collectively perform a task. In functional complexes
      in which characters span molecular to behavioral levels of organization, we might
      then expect similar modes of selection to produce similar patterns in
      evolutionary divergence at each level. To test this expectation, we diagnosed
      selection at behavioral, morphological, and molecular levels for courtship
      pheromone signaling by plethodontid salamanders. At the levels of morphology and
      behavior tens of millions of years of stasis (stabilizing selection) occur on
      each side of a transition from vaccination to olfactory delivery modes. As a
      proxy for the molecular level, we used plethodontid receptivity factor (PRF), a
      protein that is an active component of the pheromone. We cloned PRF from 12
      Plethodon spp. spanning the delivery transition and obtained multiple alleles
      from each individual surveyed. Analyses of 61 alleles for PRF identified elevated
      nonsynonymous over synonymous substitution rates along lineages in a molecular
      phylogeny, and at 8% of sites in the protein, indicating that positive
      (directional) selection has acted on this vertebrate pheromone gene. Structural
      models showed PRF is in a family of cytokines characterized by a four-alpha-helix
      bundle. Positive selection in PRF was associated with receptor binding sites that
      are under purifying selection in other cytokines of that family. The evolutionary
      dynamics of the plethodontid pheromone delivery complex consists of stabilizing
      selection on morphological and behavioral aspects of signal delivery but positive
      selection on the signal mediated by receptors. Thus, different selection modes
      prevail at different levels in this reproductive functional complex. Evolutionary
      studies of integrated sets of characters therefore require separate analyses of
      selective action at each level.

PMID- 15014165
TI  - Molecular evolution and structure of alpha-actinin.
AB  - The N-terminal actin-binding domain of alpha-actinin is connected to the C
      terminal EF-hands by a rod domain. Because of its ability to form dimers, alpha
      actinin can cross-link actin filaments in muscle cells as well as in nonmuscle
      cells. In the prototypic alpha-actinins, the rod domain contains four triple
      helical bundles, or so-called spectrin repeats. We have found some atypical alpha
      actinins in early diverging organisms, such as protozoa and yeast, where the rod
      domain contains one and two spectrin repeats, respectively. This implies that the
      four repeats present in modern alpha-actinins arose after two consecutive
      intragenic duplications from an alpha-actinin with a single repeat. Further, the
      evolutionary gene tree of alpha-actinins shows that the appearance of four
      distinct alpha-actinin isoforms may have occurred after the vertebrate
      invertebrate split. The topology of the tree lends support to the hypothesis that
      two rounds (2R) of genome duplication occurred early in the vertebrate radiation.
      The phylogeny also considers these atypical isoforms as the most basal to alpha
      actinins of vertebrates and other eukaryotes. The analysis also positioned alpha
      actinin of the fungi Encephalitozoo cuniculi close to the protozoa, supporting
      the suggestion that microsporidia are early eukaryotes. Because alpha-actinin is
      considered the basal member of the spectrin family, our studies will improve the
      understanding of the origin and evolution of this superfamily.

PMID- 15014166
TI  - Nucleotide variability at the acetyl coenzyme A carboxylase gene and the
      signature of herbicide selection in the grass weed Alopecurus myosuroides
      (Huds.).
AB  - Acetyl coenzyme A carboxylase (ACCase) is the target of highly effective
      herbicides. We investigated the nucleotide variability of the ACCase gene in a
      sample of 18 black-grass (Alopecurus myosuroides [Huds.]) populations to search
      for the signature of herbicide selection. Sequencing 3,396 bp encompassing ACCase
      herbicide-binding domain in 86 individuals revealed 92 polymorphisms, which
      formed 72 haplotypes. The ratio of nonsynonymous versus synonymous substitutions
      was very low, in agreement with ACCase being a vital metabolic enzyme. Within
      black grass, most nonsynonymous substitutions were related to resistance to
      ACCase-inhibiting herbicides. Differentiation between populations was strong, in
      contrast to expectations for an allogamous, annual plant. Significant H tests
      revealed recent hitchhiking events within populations. These results were
      consistent with recent and local positive selection. We propose that, although
      they have only been used since at most 15 black-grass generations, ACCase
      inhibiting herbicides have exerted a positive selection targeting resistant
      haplotypes that has been strong enough to have a marked effect upon ACCase
      nucleotide diversity. A minimum-spanning network of nonrecombinant haplotypes
      revealed multiple, independent apparitions of resistance-associated mutations.
      This study provides the first evidence for the signature of ongoing, recent,
      pesticide selection upon variation at the gene encoding the targeted enzyme in
      natural plant populations.

PMID- 15014167
TI  - The complete mitochondrial genome sequence of the spider Habronattus oregonensis
      reveals rearranged and extremely truncated tRNAs.
AB  - We sequenced the entire mitochondrial genome of the jumping spider Habronattus
      oregonensis of the arachnid order Araneae (Arthropoda: Chelicerata). A number of
      unusual features distinguish this genome from other chelicerate and arthropod
      mitochondrial genomes. Most of the transfer RNA (tRNA) gene sequences are greatly
      reduced in size and cannot be folded into typical cloverleaf-shaped secondary
      structures. At least nine of the tRNA sequences lack the potential to form TPsiC
      arm stem pairings and instead are inferred to have TV-replacement loops.
      Furthermore, sequences that could encode the 3' aminoacyl acceptor stems in at
      least 10 tRNAs appear to be lacking, because fully paired acceptor stems are not
      possible and because the downstream sequences instead encode adjacent genes.
      Hence, these appear to be among the smallest known tRNA genes. We postulate that
      an RNA editing mechanism must exist to restore the 3' aminoacyl acceptor stems to
      allow the tRNAs to function. At least seven tRNAs are rearranged with respect to
      the chelicerate Limulus polyphemus, although the arrangement of the protein
      coding genes is identical. Most mitochondrial protein-coding genes of H.
      oregonensis have ATN as initiation codons, as commonly found in arthropod mtDNAs,
      but cytochrome oxidase subunits 2 and 3 genes apparently use TTG as an initiation
      codon. Finally, many of the gene sequences overlap one another and are truncated.
      This 14,381-bp genome, the first mitochondrial genome of a spider yet sequenced,
      is one of the smallest arthropod mitochondrial genomes known. We suggest that
      posttranscriptional RNA editing can likely maintain function of the tRNAs, while
      permitting the accumulation of mutations that would otherwise be deleterious.
      Such mechanisms may have allowed for the minimization of the spider mitochondrial
      genome.

PMID- 15014160
TI  - Non-African populations of Drosophila melanogaster have a unique origin.
AB  - Drosophila melanogaster is widely used as a model in DNA variation studies.
      Patterns of polymorphism have, however, been affected by the history of this
      species, which is thought to have recently spread out of Africa to the rest of
      the world. We analyzed DNA sequence variation in 11 populations, including four
      continental African and seven non-African samples (including Madagascar), at four
      independent X-linked loci. Variation patterns at all four loci followed neutral
      expectations in all African populations, but departed from it in all non-African
      ones due to a marked haplotype dimorphism at three out of four loci. We also
      found that all non-African populations show the same major haplotypes, though in
      various frequencies. A parsimonious explanation for these observations is that
      all non-African populations are derived from a single ancestral population having
      undergone a substantial reduction of polymorphism, probably through a bottleneck.
      Less likely alternatives involve either selection at all four loci simultaneously
      (including balancing selection at three of them), or admixture between two
      divergent populations. Small but significant structure was observed among African
      populations, and there were indications of differentiation across Eurasia for non
      African ones. Since population history may result in non-equilibrium variation
      patterns, our study confirms that the search for footprints of selection in the
      D. melanogaster genome must include a sufficient understanding of its history.

PMID- 15014168
TI  - The evolutionary history of quorum-sensing systems in bacteria.
AB  - Communication among bacterial cells through quorum-sensing (QS) systems is used
      to regulate ecologically and medically important traits, including virulence to
      hosts. QS is widespread in bacteria; it has been demonstrated experimentally in
      diverse phylogenetic groups, and homologs to the implicated genes have been
      discovered in a large proportion of sequenced bacterial genomes. The widespread
      distribution of the underlying gene families (LuxI/R and LuxS) raises the
      questions of how often QS genes have been transferred among bacterial lineages
      and the extent to which genes in the same QS system exchange partners or
      coevolve. Phylogenetic analyses of the relevant gene families show that the genes
      annotated as LuxI/R inducer and receptor elements comprise two families with
      virtually no homology between them and with one family restricted to the gamma
      Proteobacteria and the other more widely distributed. Within bacterial phyla,
      trees for the LuxS and the two LuxI/R families show broad agreement with the
      ribosomal RNA tree, suggesting that these systems have been continually present
      during the evolution of groups such as the Proteobacteria and the Firmicutes.
      However, lateral transfer can be inferred for some genes (e.g., from Firmicutes
      to some distantly related lineages for LuxS). In general, the inducer/receptor
      elements in the LuxI/R systems have evolved together with little exchange of
      partners, although loss or replacement of partners has occurred in several
      lineages of gamma-Proteobacteria, the group for which sampling is most intensive
      in current databases. For instance, in Pseudomonas aeruginosa, a transferred QS
      system has been incorporated into the pathway of a native one. Gene phylogenies
      for the main LuxI/R family in Pseudomonas species imply a complex history of
      lateral transfer, ancestral duplication, and gene loss within the genus.

PMID- 15014169
TI  - False-positive selection identified by ML-based methods: examples from the Sig1
      gene of the diatom Thalassiosira weissflogii and the tax gene of a human T-cell
      lymphotropic virus.
AB  - Sexually induced gene 1 (Sig1) in the centric diatom Thalassiosira weissflogii is
      considered to encode a gamete recognition protein. Sorhannus (2003) analyzed
      nucleotide sequences of Sig1 using parsimony analysis and the maximum-likelihood
      (ML)-based Bayesian method for inferring positive selection at single amino acid
      sites and reported that positively selected sites were detected by the latter
      method but not by the former. He then concluded that for this type of study, the
      ML-based method is more reliable than parsimony analysis. Here we show that his
      results apparently represent false-positive cases of the ML-based method and that
      there is no solid evidence that this gene contains positively selected sites. We
      further demonstrate that in the tax gene of human T-cell lymphotropic virus type
      I (HTLV-I), all codon sites, including invariable sites, can be inferred as
      positively selected sites by the ML-based method. These observations indicate
      that the ML-based method may produce many false-positive sites. One of the main
      reasons for the occurrence of false positives is that in the ML-based method,
      codon sites are grouped into several categories, with different
      nonsynonymous/synonymous rate ratios (omegas), on a purely statistical basis, and
      positive selection is inferred indirectly by examining whether the average omega
      for each category is greater than 1. In parsimony analysis, however, the
      evolutionary change of nucleotides at each codon site is examined. For this
      reason, parsimony-based methods rarely produce false positives and are safer than
      ML-based methods for detecting positive selection at individual codon sites,
      although a large number of sequences are necessary.

PMID- 15014170
TI  - The complete mitochondrial DNA sequence of the green alga Pseudendoclonium
      akinetum (Ulvophyceae) highlights distinctive evolutionary trends in the
      chlorophyta and suggests a sister-group relationship between the Ulvophyceae and
      Chlorophyceae.
AB  - The mitochondrial genome has undergone radical changes in both the Chlorophyta
      and Streptophyta, yet little is known about the dynamics of mtDNA evolution in
      either of these lineages. In the Chlorophyta, which comprises four of the five
      recognized classes of green algae (Prasinophyceae, Trebouxiophyceae, Ulvophyceae,
      and Chlorophyceae), the mitochondrial genome varies from 16 to 55 kb. This genome
      has retained a compact gene organization and a relatively complex gene repertoire
      ("ancestral" pattern) in the basal lineages represented by the Trebouxiophyceae
      and Prasinophyceae, whereas it has been reduced in size and gene complement and
      tends to evolve much more rapidly at the sequence level ("reduced-derived"
      pattern of evolution) in the Chlorophyceae and the lineage leading to the
      enigmatic chlorophyte Pedinomonas. To gain information about the evolutionary
      trends of mtDNA in the Ulvophyceae and also to gain insights into the
      phylogenetic relationships between ulvophytes and other chlorophytes, we have
      determined the mtDNA sequence of Pseudendoclonium akinetum. At 95,880 bp,
      Pseudendoclonium mtDNA is the largest green-algal mitochondrial genome sequenced
      to date and has the lowest gene density. These derived features are reminiscent
      of the "expanded" pattern exhibited by embryophyte mtDNAs, indicating that
      convergent evolution towards genome expansion has occurred independently in the
      Chlorophyta and Streptophyta. With 57 conserved genes, the gene repertoire of
      Pseudendoclonium mtDNA is slightly smaller than those of the prasinophyte
      Nephroselmis olivacea and the trebouxiophyte Prototheca wickerhamii. This
      ulvophyte mtDNA contains seven group I introns, four of which have homologs in
      green-algal mtDNAs displaying an "ancestral" or a "reduced-derived" pattern of
      evolution. Like its counterpart in the chlorophycean green alga Scenedesmus
      obliquus, it features numerous small, dispersed repeats in intergenic regions and
      introns. Its overall rate of sequence evolution appears to be accelerated to an
      intermediary level as compared with the rates observed in "ancestral" and
      "reduced-derived" mtDNAs. In agreement with the finding that Pseudendoclonium
      mtDNA exhibits features typical of both the "ancestral" and "reduced-derived"
      patterns of evolution, phylogenetic analyses of seven mtDNA-encoded proteins
      revealed a sister-group relationship between this ulvophyte and chlorophytes
      displaying "reduced-derived" mtDNAs.

PMID- 15014171
TI  - Human-specific amino acid changes found in 103 protein-coding genes.
AB  - We humans have many characteristics that are different from those of the great
      apes. These human-specific characters must have arisen through mutations
      accumulated in the genome of our direct ancestor after the divergence of the last
      common ancestor with chimpanzee. Gene trees of human and great apes are necessary
      for extracting these human-specific genetic changes. We conducted a systematic
      analysis of 103 protein-coding genes for human, chimpanzee, gorilla, and
      orangutan. Nucleotide sequences for 18 genes were newly determined for this
      study, and those for the remaining genes were retrieved from the
      DDBJ/EMBL/GenBank database. The total number of amino acid changes in the human
      lineage was 147 for 26,199 codons (0.56%). The total number of amino acid changes
      in the human genome was, thus, estimated to be about 80,000. We applied the
      acceleration index test and Fisher's synonymous/nonsynonymous exact test for each
      gene tree to detect any human-specific enhancement of amino acid changes compared
      with ape branches. Six and two genes were shown to have significantly higher
      nonsynonymous changes at the human lineage from the acceleration index and exact
      tests, respectively. We also compared the distribution of the differences of the
      nonsynonymous substitutions on the human lineage and those on the great ape
      lineage. Two genes were more conserved in the ape lineage, whereas one gene was
      more conserved in the human lineage. These results suggest that a small
      proportion of protein-coding genes started to evolve differently in the human
      lineage after it diverged from the ape lineage.

PMID- 15014172
TI  - Generic scan using AFLP markers as a means to assess the role of directional
      selection in the divergence of sympatric whitefish ecotypes.
AB  - Under the ecological theory of adaptive radiation, adaptation and reproductive
      isolation are thought to evolve as a result of divergent natural selection.
      Accordingly, elucidating the genetic basis of these processes is essential toward
      understanding the role of selection in shaping biological diversity. In this
      respect, the number of genes that evolved by selection remains contentious. To
      address this issue, the pattern of genetic differentiation obtained using 440
      AFLP loci was compared with that expected under neutrality in four sympatric
      pairs of lake whitefish ecotypes that evolved adaptive phenotypic differences
      associated with the exploitation of distinct ecological niches. On average, 14
      loci showed restricted gene flow relative to neutral expectation, suggesting a
      role of directional selection on their divergence. Among all loci that are most
      likely under directional selection, six exhibited parallel patterns of
      divergence, which provided further support for the role of selection in driving
      their divergence. Overall, these results indicate that only a small proportion of
      scored AFLP loci (between 1.4% and 3.2%) might be linked to genes implicated in
      the adaptive radiation of lake whitefish.

PMID- 15014173
TI  - Selection versus demography: a multilocus investigation of the domestication
      process in maize.
AB  - The domestication of maize (Zea mays ssp. mays) from its wild ancestor (Zea mays
      ssp. parviglumis) led to a loss of genetic diversity both through a population
      bottleneck and through directional selection at agronomically important genes. In
      order to discriminate between those effects and to investigate the nature of the
      domestication bottleneck, we analyzed nucleotide diversity data from 12
      chromosome 1 loci in parviglumis. We found an average loss of nucleotide
      diversity of 38% across genes, but this average was skewed downward by four
      putatively selected loci (tb1, d8, ts2, and zagl1). To better understand the
      domestication process, we used the coalescent with recombination to simulate
      bottlenecks under various lengths and population sizes. For each locus, we
      determine the likelihood of the observed data using three summary statistics: the
      number of segregating sites, an estimate of the population recombination
      parameter, and Tajima's D. Based on the eight neutrally evolving loci, a model
      with a bottleneck had a significantly higher likelihood than a model without one.
      The four putatively selected loci had significantly different likelihood optimums
      than the neutral loci, and this approach confirmed that ts2 and d8 were selected
      either during domestication or breeding. Overall, the best-fitting models had a
      bottleneck in which the population size and the bottleneck duration had a ratio
      of approximately 4- to approximately 5; for example, if the initial domestication
      event occurred over a 500-year period, the population size was roughly 2,000 to
      2,500 individuals. However, this range did vary with the summary statistic used
      to assess the fit of simulations to data. In this context, Tajima's D performed
      poorly as a goodness-of-fit statistic, probably because Z. mays ssp. parviglumis
      has a frequency spectrum that is significantly skewed toward low-frequency
      variants. Finally, we found that demography is unlikely to account for the
      previously observed positive correlation between nucleotide diversity and the
      population-recombination parameter in maize, leaving this observation difficult
      to interpret.

PMID- 15014174
TI  - Evolution of sarcomeric myosin heavy chain genes: evidence from fish.
AB  - Myosin heavy chain (MYH) is a major structural protein, integral to the function
      of sarcomeric muscles. We investigated both exon-intron organization and amino
      acid sequence of sarcomeric MYH genes to infer their evolutionary history in
      vertebrates. Our results were consistent with the hypothesis that a multigene
      family encoded MYH proteins in the ancestral chordate, one gene ancestral to
      human MYH16 and its homologues and another ancestral to all other vertebrate
      sarcomeric MYH genes. We identified teleost homologues of mammalian skeletal and
      cardiac MYH genes, indicating that the ancestors of those genes were present
      before the divergence of actinopterygians and sarcopterygians. Indeed, the
      ancestral skeletal genes probably duplicated at least once before the divergence
      of teleosts and tetrapods. Fish homologues of mammalian skeletal MYH are
      expressed in skeletal tissue and homologues of mammalian cardiac genes are
      expressed in the heart but, unlike mammals, there is overlap between these
      expression domains. Our analyses inferred two other ancestral vertebrate MYH
      genes, giving rise to human MYH14 and MYH15 and their homologues. Relative to the
      skeletal and cardiac genes, MYH14 and MYH15 homologues are characterized by
      evolution of intron position, differences in evolutionary rate between the
      functionally differentiated head and rod of the myosin protein, and possible
      evolution of function among vertebrate classes. Tandem duplication and gene
      conversion appear to have played major roles in the evolution of at least cardiac
      and skeletal MYH genes in fish. One outcome of this high level of concerted
      evolution is that different fish taxa have different suites of MYH genes, i.e.,
      true orthologs do not exist.

PMID- 15014175
TI  - Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature
      and kinetics in vivo.
AB  - There is mounting evidence that the established paradigm of nitric oxide (NO)
      biochemistry, from formation through NO synthases, over interaction with soluble
      guanylyl cyclase, to eventual disposal as nitrite/nitrate, represents only part
      of a richer chemistry through which NO elicits biological signaling. Additional
      pathways have been suggested that include interaction of NO-derived metabolites
      with thiols and metals to form S-nitrosothiols (RSNOs) and metal nitrosyls.
      Despite the overwhelming attention paid in this regard to RSNOs, little is known
      about the stability of these species, their significance outside the circulation,
      and whether other nitros(yl)ation products are of equal importance. We here show
      that N-nitrosation and heme-nitrosylation are indeed as ubiquitous as S
      nitrosation in vivo and that the products of these reactions are constitutively
      present throughout the organ system. Our study further reveals that all NO
      derived products are highly dynamic, have fairly short lifetimes, and are linked
      to tissue oxygenation and redox state. Experimental evidence further suggests
      that nitroso formation occurs substantially by means of oxidative nitrosylation
      rather than NO autoxidation, explaining why S-nitrosation can compete effectively
      with nitrosylation. Moreover, tissue nitrite can serve as a significant
      extravascular pool of NO during brief periods of hypoxia, and tissue
      nitrate/nitrite ratios can serve as indicators of the balance between local
      oxidative and nitrosative stress. These findings vastly expand our understanding
      of the fate of NO in vivo and provide a framework for further exploration of the
      significance of nitrosative events in redox sensing and signaling. The findings
      also raise the intriguing possibility that N-nitrosation is directly involved in
      the modulation of protein function.

PMID- 15014176
TI  - Inducible costimulator-dependent IL-10 production by regulatory T cells specific
      for self-antigen.
AB  - In this study, we investigated the relationship between the expression levels of
      self-antigen and the function of self-reactive T cells in the periphery. To this
      end, we used two rat insulin promoter-ovalbumin (RIP-OVA) transgenic mice (RIP
      OVA(high), RIP-OVA(low)) in which was produced only in pancreatic beta-islet
      cells. The OVA-producing transgenic mice were crossed to DO.11.10 (DO) mice
      expressing a T cell antigen receptor specific for OVA(323-339). The
      responsiveness of peripheral CD4(+) T cells in the double transgenic mice was
      examined. We demonstrated that hyporesponsive but highly IL-10-producing T cells
      were developed in DO x OVA(high) mice only, not in DO x OVA(low) mice. These IL
      10-producing T cells exhibited regulatory activity both in in vitro and in vivo
      experiments. Moreover, these IL-10-producing regulatory T (Tr) cells expressed
      high levels of inducible costimulator (ICOS) before in vitro stimulation.
      Blockade of ICOS-signaling inhibited the production of IL-10 and abrogated the
      inhibitory function of these Tr cells. Thus, these results suggested that the
      development of IL-10-producing Tr cells depends on the expression levels of self
      antigen in vivo and that ICOS signal plays a critical role in immune regulation
      by IL-10-producing Tr cells in self-tolerance.

PMID- 15014178
TI  - CGRP-receptor antagonists--a fresh approach to migraine therapy?

PMID- 15014177
TI  - Uric acid and diet--insights into the epidemic of cardiovascular disease.

PMID- 15014179
TI  - Surgery for severe obesity.

PMID- 15014180
TI  - Paul Ehrlich's magic bullets.

PMID- 15014181
TI  - A randomized trial of exemestane after two to three years of tamoxifen therapy in
      postmenopausal women with primary breast cancer.
AB  - BACKGROUND: Tamoxifen, taken for five years, is the standard adjuvant treatment
      for postmenopausal women with primary, estrogen-receptor-positive breast cancer.
      Despite this treatment, however, some patients have a relapse. METHODS: We
      conducted a double-blind, randomized trial to test whether, after two to three
      years of tamoxifen therapy, switching to exemestane was more effective than
      continuing tamoxifen therapy for the remainder of the five years of treatment.
      The primary end point was disease-free survival. RESULTS: Of the 4742 patients
      enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to
      continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first
      events (local or metastatic recurrence, contralateral breast cancer, or death)
      were reported--183 in the exemestane group and 266 in the tamoxifen group. The
      unadjusted hazard ratio in the exemestane group as compared with the tamoxifen
      group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log
      rank test), representing a 32 percent reduction in risk and corresponding to an
      absolute benefit in terms of disease-free survival of 4.7 percent (95 percent
      confidence interval, 2.6 to 6.8) at three years after randomization. Overall
      survival was not significantly different in the two groups, with 93 deaths
      occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic
      effects of exemestane were rare. Contralateral breast cancer occurred in 20
      patients in the tamoxifen group and 9 in the exemestane group (P=0.04).
      CONCLUSIONS: Exemestane therapy after two to three years of tamoxifen therapy
      significantly improved disease-free survival as compared with the standard five
      years of tamoxifen treatment.

PMID- 15014182
TI  - Purine-rich foods, dairy and protein intake, and the risk of gout in men.
AB  - BACKGROUND: Various purine-rich foods and high protein intake have long been
      thought to be risk factors for gout. Similarly, the possibility that the
      consumption of dairy products has a role in protecting against gout has been
      raised by metabolic studies. We prospectively investigated the association of
      these dietary factors with new cases of gout. METHODS: Over a 12-year period, we
      prospectively examined the relationship between purported dietary risk factors
      and new cases of gout among 47,150 men who had no history of gout at base line.
      We used a supplementary questionnaire to ascertain whether participants met the
      American College of Rheumatology survey criteria for gout. Diet was assessed
      every four years by means of a food-frequency questionnaire. RESULTS: During the
      12 years of the study, we documented 730 confirmed new cases of gout. The
      multivariate relative risk of gout among men in the highest quintile of meat
      intake, as compared with those in the lowest quintile, was 1.41 (95 percent
      confidence interval, 1.07 to 1.86; P for trend = 0.02), and the corresponding
      relative risk associated with seafood intake was 1.51 (95 percent confidence
      interval, 1.17 to 1.95; P for trend = 0.02). In contrast, the incidence of gout
      decreased with increasing intake of dairy products; the multivariate relative
      risk among men in the highest quintile, as compared with those in the lowest
      quintile, was 0.56 (95 percent confidence interval, 0.42 to 0.74; P for trend
      <0.001). The level of consumption of purine-rich vegetables and the total protein
      intake were not associated with an increased risk of gout. CONCLUSIONS: Higher
      levels of meat and seafood consumption are associated with an increased risk of
      gout, whereas a higher level of consumption of dairy products is associated with
      a decreased risk. Moderate intake of purine-rich vegetables or protein is not
      associated with an increased risk of gout.

PMID- 15014183
TI  - Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute
      treatment of migraine.
AB  - BACKGROUND: Calcitonin gene-related peptide (CGRP) may have a causative role in
      migraine. We therefore hypothesized that a CGRP-receptor antagonist might be
      effective in the treatment of migraine attacks. METHODS: In an international,
      multicenter, double-blind, randomized clinical trial of BIBN 4096 BS, a highly
      specific and potent nonpeptide CGRP-receptor antagonist, 126 patients with
      migraine received one of the following: placebo or 0.25, 0.5, 1, 2.5, 5, or 10 mg
      of BIBN 4096 BS intravenously over a period of 10 minutes. A group-sequential
      adaptive treatment-assignment design was used to minimize the number of patients
      exposed. RESULTS: The 2.5-mg dose was selected, with a response rate of 66
      percent, as compared with 27 percent for placebo (P=0.001). The BIBN 4096 BS
      group as a whole had a response rate of 60 percent. Significant superiority over
      placebo was also observed with respect to most secondary end points: the pain
      free rate at 2 hours; the rate of sustained response over a period of 24 hours;
      the rate of recurrence of headache; improvement in nausea, photophobia,
      phonophobia, and functional capacity; and the time to meaningful relief. An
      effect was apparent after 30 minutes and increased over the next few hours. The
      overall rate of adverse events was 25 percent after the 2.5-mg dose of the drug
      and 20 percent for the BIBN 4096 BS group as a whole, as compared with 12 percent
      for placebo. The most frequent side effect was paresthesia. There were no serious
      adverse events. CONCLUSIONS: The CGRP antagonist BIBN 4096 BS was effective in
      treating acute attacks of migraine.

PMID- 15014184
TI  - Clinical practice. Photosensitivity.

PMID- 15014185
TI  - Hepatitis B virus infection--natural history and clinical consequences.

PMID- 15014186
TI  - Images in clinical medicine. Oculo-orogenital syndrome--a deficiency of vitamins
      B2 and B6.

PMID- 15014187
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 8-2004. A 28-year-old man with abdominal pain, fever, and a mass
      in the region of the pancreas.

PMID- 15014188
TI  - New stars in the sky of treatment for early breast cancer.

PMID- 15014189
TI  - Data safety and monitoring boards.

PMID- 15014190
TI  - Virtual colonoscopy to screen for colorectal cancer.

PMID- 15014191
TI  - Lp(a) lipoprotein, vascular disease, and mortality in the elderly.

PMID- 15014192
TI  - Conditions associated with ST-segment elevation.

PMID- 15014193
TI  - Rx: Canadian drugs.

PMID- 15014194
TI  - Hypokalemia.

PMID- 15014195
TI  - Choices about meningococcal vaccination.

PMID- 15014196
TI  - Myopathy in children receiving high-dose inhaled fluticasone.

PMID- 15014197
TI  - Images in clinical medicine. Interdigital pilonidal sinus.

PMID- 15014198
TI  - Educational research fellowships.

PMID- 15014199
TI  - Safety of tacrolimus in patients with rheumatoid arthritis: long-term experience.
AB  - OBJECTIVE: To evaluate the long-term safety of tacrolimus 3 mg/day in patients
      with rheumatoid arthritis (RA). METHODS: Patients with active RA who had
      discontinued all DMARDs for at least 2 weeks and had at least five tender/painful
      joints and three swollen joints, and required DMARD treatment in the opinion of
      the investigator, were enrolled into this open-label long-term safety trial. In
      addition, patients who had completed at least 3 months of treatment with
      tacrolimus 2 mg/day, tacrolimus 3 mg/day or placebo in a Phase III double-blind
      efficacy trial were allowed to roll over into this study. This latter group of
      patients did not have to fulfil any joint count requirements prior to entry into
      the long-term safety study, provided that no more than 14 days had elapsed
      between the end of their participation in the double-blind study and screening
      for the long-term safety study. All patients enrolled received tacrolimus 3
      mg/day in addition to their current regimen of NSAIDs and corticosteroids.
      RESULTS: 896 patients received at least one dose of tacrolimus 3 mg. The median
      duration of treatment was 359 days. 145 patients (16.2%) withdrew from the study
      for adverse events possibly or probably related to tacrolimus, 33 patients (3.7%)
      withdrew from the study for adverse events unrelated to tacrolimus and 112
      (12.5%) withdrew for lack of efficacy. No adverse event with an incidence >0.7%
      appeared for the first time after the first 3 months of treatment with 3 mg
      tacrolimus. 529 patients (59%) experienced an adverse event that was possibly or
      probably related to tacrolimus; the most common were diarrhoea (14.6%), nausea
      (10.3%), tremor (9.0%), headache (8.7%), abdominal pain (7.9%), dyspepsia (7.6%),
      increased creatinine (6.8%) and hypertension (5.4%). Twenty-four patients (2.7%)
      experienced serious adverse events possibly or probably related to study drug;
      the most common were pneumonia (0.6%), hyperglycaemia (0.3%), gastroenteritis
      (0.2%), pancreatitis (0.2%) and diabetes mellitus (0.2%). The mean creatinine
      level increased from 67+/-19 micromol/l (0.76+/-0.22 mg/dl) at baseline to 75+/
      26 micromol/l (0.85+/-0.30 mg/dl) (P<0.0001) at end of treatment. 351 (40.3%) of
      the 872 patients for whom creatinine levels were available at both baseline and
      during treatment had > or =30% increase from baseline in serum creatinine during
      the study, either related or unrelated to tacrolimus, with 73 patients (8.4%)
      having creatinine levels exceeding the normal range. At end of treatment, 177
      patients (20.3%) had a > or =30% increase from baseline in creatinine. Serum
      creatinine remained within the normal range throughout the trial in approximately
      90% of patients. At the end of treatment, the ACR20, ACR50 and ACR70 response
      rates were 38.4%, 18.6% and 9.0% respectively. Over 26% of patients had at least
      a 70% improvement in both swollen and painful/tender joints. CONCLUSION: This
      study demonstrates that tacrolimus was safe and well-tolerated and provided
      clinical benefit over a period of at least 12 months.

PMID- 15014200
TI  - Traditional cardiovascular risk factors measured prior to the onset of
      inflammatory polyarthritis.
AB  - BACKGROUND: Cardiovascular mortality is increased in patients with seropositive
      inflammatory polyarthritis (IP). We tested the hypothesis that the increased risk
      of cardiovascular disease (CVD) can be explained by elevated traditional CVD risk
      factor levels in persons prior to development of IP. METHODS: In a population
      based, prospective nested case-control study, 25 600 people aged 45-75 yr
      participated in a health survey, including standard CVD risk factor assessment,
      between the years 1993 and 1997. There were 91 incident IP cases (one-third were
      seropositive at presentation) identified during follow-up to the end of July
      2001. Baseline CVD risk factors in the IP cases were compared with those in two
      age/gender-matched controls. RESULTS: Current smokers had an odds ratio of 2.0
      (95% CI 1.0-4.0) for IP. Other risk factors, including total and LDL cholesterol,
      systolic and diastolic blood pressure and obesity, did not differ significantly
      between cases and controls. Importantly, in combination, using a standard
      coronary disease risk score, these factors only had a modest association with
      future IP, and no association when analysis was restricted to the smaller number
      of cases who were seropositive. CONCLUSION: Of the traditional cardiovascular
      risk factors, only smoking increases CVD risk prior to the onset of IP. Therefore
      the increased CVD observed in these patients is likely to be a consequence of
      factors operating after the onset of the arthritis.

PMID- 15014201
TI  - Sticking it to tau.

PMID- 15014202
TI  - To age or not to age--what is the question?
AB  - Over the past 50 years, a generally accepted theory about the evolution of aging
      has been developed. One common conclusion that has been deduced from this theory
      is that aging is inevitable in organisms in which there is a difference between
      offspring and parents. A recent paper by Sozou and Seymour questions this
      prediction using a mathematical model, but it remains to be seen whether their
      new results stand up to more general analysis.

PMID- 15014203
TI  - Can the clock be turned back on ovarian aging?
AB  - A basic tenet of reproductive biology is that female mammals are born with a set
      number of germ cells (oocytes). A new study by Johnson et al. challenges these
      beliefs by demonstrating that the postnatal mouse ovary contains actively
      dividing germ cells. These findings have implications for prolonging the
      reproductive life span of women.

PMID- 15014204
TI  - Development of behavioral sensitization to the cocaine-like fungicide triadimefon
      is prevented by AMPA, NMDa, DA D1 but not DA D2 receptor antagonists.
AB  - Triadimefon (TDF) is a triazole fungicide that blocks the reuptake of dopamine
      (DA) and leads to increased locomotor activity levels in mice and rats, effects
      similar to those of indirect DA agonists such as cocaine. We recently found in
      mice that intermittent TDF administration led to robust locomotor sensitization,
      a phenomenon reflecting neuronal plasticity, following challenge with the same
      TDF dose after a 2-week withdrawal period. The current study sought to determine
      whether antagonists to DA D1-like receptors (SCH 23390; SCH), DA D2-like
      receptors (remoxipride; Rem), ionotropic glutamate n-methyl-d-aspartate (NMDA)
      receptors (CPP), or ionotropic glutamate alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionic acid (AMPA) receptors (NBQX) could prevent the development of
      TDF behavioral sensitization, therefore indicating their mechanistic involvement
      in TDF sensitization. Mice were treated with either vehicle, SCH (0.015 mg/kg),
      remoxipride (Rem, 0.3 mg/kg), CPP (2.5 mg/kg) or NBQX (10.0 mg/kg), followed 30
      min later by vehicle or 75 mg/kg TDF (TDF), twice a week for 7 weeks, with
      locomotor activity measured post-dosing once a week. After a 2-week withdrawal
      period, mice were challenged with 75 mg/kg TDF or vehicle, to test for the
      presence of behavioral sensitization. Pretreatment with SCH, CPP, or NBQX, but
      not Rem, blocked the development of behavioral sensitization to TDF specifically
      for vertical activity. Antagonists that blocked TDF vertical sensitization also
      attenuated the increase in extracellular DA turnover (homovanillic acid [HVA]/DA)
      normally associated with this behavioral response. Therefore, DA D1, NMDA and
      AMPA receptors appear to be necessary for the development of behavioral
      sensitization to TDF. As such, TDF may be considered an environmental risk factor
      for behavioral dysfunctions linked to glutamatergic and dopaminergic systems.

PMID- 15014205
TI  - Use and application of stem cells in toxicology.
AB  - In recent years, stem cells have been the subject of increasing scientific
      interest because of their utility in numerous biomedical applications. Stem cells
      are capable of renewing themselves; that is, they can be continuously cultured in
      an undifferentiated state, giving rise to more specialized cells of the human
      body such as heart, liver, bone marrow, blood vessel, pancreatic islet, and nerve
      cells. Therefore, stem cells are an important new tool for developing unique, in
      vitro model systems to test drugs and chemicals and a potential to predict or
      anticipate toxicity in humans. The following review provides an overview of the
      applications of stem cell technology in the area of toxicology. Specifically,
      this review addresses core technologies that are emerging in the field and how
      they could fulfill critical safety issues such as QT prolongation and
      hepatotoxicity, two leading causes of failures in preclinical development of new
      therapeutic drugs. We report how adult stem cells derived from various sources,
      such as human bone marrow and placenta, can potentially generate suitable models
      for cardiotoxicity, hepatotoxicity, genotoxicity/epigenetic and reproductive
      toxicology screens. Additionally, this review addresses the role and advantages
      of embryonic stem cells in the aforementioned models for toxicity and how genetic
      selection is employed to overcome major limitations to the implementation of stem
      cell-based in vitro models for toxicology.

PMID- 15014206
TI  - On the application of data on mode of action to carcinogenic risk assessment.

PMID- 15014207
TI  - Effects of lead exposure on the expression of phospholipid hydroperoxidase
      glutathione peroxidase mRNA in the rat brain.
AB  - Oxidative damage associated with lead in the brain has been proposed as a
      possible mechanism of lead toxicity. Of the many antioxidant enzymes,
      phospholipid hydroperoxidase glutathione peroxidase (PHGPx) is known to protect
      cells from lipid peroxide-mediated damage by catalyzing lipid peroxide reduction.
      In this study, the effects of lead on the activity and expression of PHGPx mRNA
      were investigated in the brains of rats exposed to lead for 8 weeks. Male Sprague
      Dawley rats (3 week old, n = 40) were randomly divided into four groups of 10 and
      treated with four different concentrations of lead in drinking water: a low dose
      (0.1% lead acetate), a medium dose (0.3% lead acetate), and a high dose (1.0%
      lead acetate), and a control group (0% lead acetate). We compared the four groups
      in terms of body and brain weight, lead concentrations in the brain and blood,
      and the activities of superoxide dismutase (SOD), gluthatione peroxidase (GPx),
      and PHGPx mRNA in the brain. Phospholipid hydroperoxidase glutathione peroxidase
      was found to have a dominant role in lead exposure. We also performed in situ
      hybridization of PHGPx mRNA in the brain to identity PHGPx mRNA active sites. We
      found that the level of PHGPx mRNA in brain increased in the medium- and low-dose
      groups, but decreased in the high-dose group versus the non-lead-treated control
      group. These results suggest that lead exposure increases the expression of PHGPx
      mRNA in the low- and medium-dose groups without inducing structural changes, and
      that the reduced expression of PHGPx mRNA in the high-dose group was associated
      with structural damage. An In situ hybridization study showed that PHGPx mRNA in
      the brain is expressed mainly in the white matter of the cerebral hemisphere and
      in the Purkinje cells of the cerebellar hemispheres; these sites are known to be
      the vulnerable to lead toxicity.

PMID- 15014208
TI  - Existence of a threshold for induction of aberrant crypt foci in the rat colon
      with low doses of 2-amino-1-methyl-6-phenolimidazo[4,5-b]pyridine.
AB  - Until recently it has been generally considered that genotoxic carcinogens have
      no threshold in exerting their potential for cancer induction. However, the
      nonthreshold theory can be challenged with regard to assessment of cancer risk to
      humans. In the present study we show that a food derived, genotoxic
      hepatocarcinogen, 2-amino-1-methyl-6-phenolimidazo[4,5-b]pyridine (PhIP), does
      not induce aberrant crypt foci (ACF) as preneoplastic lesions at low dose (below
      50 ppm) or 8-hydroxy-2'-deoxyguanosine (below 400 ppm) in the rat colon. Moreover
      PhIP-DNA adducts were not formed at the lowest dose (below 0.01 ppm). Thus, the
      dose required to initiate ACF is approximately 5000 times higher than that needed
      for adduct formation. The results imply a no-observed effect level (existence of
      a threshold) for colon carcinogenesis by a genotoxic carcinogen.

PMID- 15014209
TI  - Induction of CYP1A1 in primary rat hepatocytes by 3,3',4,4',5
      pentachlorobiphenyl: evidence for a switch circuit element.
AB  - In vivo induction of CYP1A1 in hepatocytes by aryl hydrocarbon receptor agonists
      is heterogeneous. Using immunohistochemistry, cells appear to be either induced
      or not induced as if the response of an individual cell is better represented as
      a switch. We have examined induction of CYP1A1 in vitro in primary rat
      hepatocytes to distinguish the responses of populations of cells and responses of
      individual cells. Cells were treated with various concentrations of the aryl
      hydrocarbon receptor agonist, 3,3',4,4',5-pentachlorobiphenyl. Concentration
      response and time-course responses were determined for the population of cells by
      Western blotting for CYP1A1 protein and by real-time RT-PCR for CYP1A1 mRNA.
      Individual cell responses were visualized by immunocytochemistry (ICC) for
      protein and by in situ hybridization (ISH) for mRNA. CYP1A1 mRNA was quantified
      by frequency distribution analysis of grains observed on the ISH slides.
      Population responses showed time- and concentration-related increases in
      induction. Single cell responses appeared as all-or-none in the field, with cells
      appearing to be induced and others appearing to be not induced. Even at the
      highest concentrations (2.5 x 10(-7) M), some hepatocytes remained unresponsive.
      Distribution frequencies of single cell induction were more consistent with a
      switch with variable levels of induction in cells depending on treatment
      concentration. Combined with the reports from in vivo studies, our results
      support a switch with rheostat behavior for individual hepatocytes. Mechanistic
      studies in liver cell lines that are confirmed to exhibit switch-like induction
      of single cells will be necessary to assess the molecular pathways of this
      circuit element.

PMID- 15014210
TI  - The impact of atrial prevention and termination therapies on atrial
      tachyarrhythmia burden in patients receiving a dual-chamber defibrillator for
      ventricular arrhythmias.
AB  - INTRODUCTION: This prospective, multicenter, randomized trial evaluated the
      effects of atrial prevention and termination therapies on atrial tachyarrhythmia
      (ATA) burden in patients with a standard indication for an implantable
      cardioverter defibrillator (ICD). METHODS: A Jewel AF or GEM III AT ICD was
      implanted in 451 patients. At 1-month post-implant, patients were randomized to
      atrial prevention and termination therapies ON ( n = 199) or OFF ( n = 206) and
      followed for 6 additional months. Automatic atrial shocks were enabled in only
      14% of the ON group. The follow-up time after randomization was 6.9 +/- 2.4
      months ON versus 6.8 +/- 2.3 months OFF. RESULTS: There were 126/405 (31.1%)
      patients who had AT/AF episodes during follow-up. Only four patients received a
      shock to treat ATA's during follow-up. The median ATA burden was 0 hours/month in
      both the ON and OFF groups ( P = 0.40). The mean ATA burden was 4.3 +/- 20.0
      hours/month ON versus 9.0 +/- 50.0 hours/month OFF ( P = 0.11). In a subgroup of
      192 patients with a history of ATA's, the median burden was 0 hours/month in the
      both groups ( P = 0.23). However, the mean burden in this subgroup was 7.6 +/-
      27.1 hours/month ON versus 19.2 +/- 73.7 hours/month OFF ( P = 0.056).
      CONCLUSIONS: In patients receiving an ICD for ventricular arrhythmias, no
      significant change in ATA burden was observed when atrial prevention and
      termination therapies were enabled. This may have been due to the low ATA burden
      in this population. In a subgroup of patients with history of ATA's, there was a
      trend towards a reduction in mean burden.

PMID- 15014211
TI  - In vitro and in vivo evaluation of the thermal patterns and lesions of catheter
      ablation with a microwave monopole antenna.
AB  - BACKGROUND: Radiofrequency (RF) catheter ablation is an effective treatment for
      supraventricular tachycardia. The effectiveness of the technique is at times
      limited by the small lesion size produced by RF energy delivery. Previous reports
      have indicated that microwave energy is capable of producing a larger volume of
      heated tissue than radiofrequency energy, raising the possibility that microwave
      energy may offer a potential alternative energy source to radiofrequency for the
      substrate ablation of certain arrhythmias such as ventricular tachycardia or
      atrial flutter. METHODS: The present study evaluated the thermal profiles of a
      monopole microwave antenna delivering energy at 2.45 GHz frequency in a phantom
      tissue-equivalent material with dielectric and thermal properties similar to
      myocardium. In addition, microwave catheter ablations were performed in vivo in
      the ventricles of goats prior to the examination of the lesions. RESULTS: The
      measured thermal profiles in the phantom revealed that the antenna is capable of
      producing heating to a temperature associated with myocardial necrosis to a
      controllable depth that can be more than 8 mm, while the endocardial temperature
      is maintained relatively low. The ablation volume is significantly reduced but is
      still effective when there is only a partial contact between the antenna and the
      tissue surface. In vivo studies on goat models confirmed that the monopole
      antenna can produce a deep transmural lesion in the left ventricle without
      causing coagulation or charring on the endocardial surface.

PMID- 15014212
TI  - Fast pathway-His bundle connections in the rabbit heart.
AB  - OBJECTIVES: The incidence and the physiologic roles for direct fast pathway-His
      bundle connections were examined in 102 rabbit hearts. METHODS: Extracellular
      bipolar and intracellular microelectrode recordings were made from the superfused
      rabbit AV junction. RESULTS: In 13 of 27 preparations demonstrating anterior
      extensions of the fast pathway, the retrograde HA ERP and 2:1 block cycle length
      were shortened (128 +/- 12 and 145 +/- 5 msec, respectively) versus the remaining
      89 preparations (178 +/- 15 and 185 +/- 10 msec, respectively, p < 0.01). The
      former values were similar to the ERP and 2:1 block cycle length of fast pathway
      transitional cells (128 +/- 23 and 141 +/- 4 msec, respectively), suggestive of a
      direct fast pathway-His bundle connection. A deflection recorded between the A
      and H potentials of the His bundle electrogram could be dissociated from both
      atrial and His bundle activation. Intracellular microelectrode recordings and
      light microscopy confirmed the deflection to be an accessory pathway consisting
      of an anterior extension of fast pathway transitional cells connecting the atrium
      and His bundle. Transection along the AV groove anterior to the compact AV node (
      N = 5) increased the retrograde ERP and Wenckebach block cycle length by severing
      the AH connection, or transection of the penetrating bundle ( N = 4) produced
      antegrade AH block without altering rapid retrograde conduction. CONCLUSIONS:
      Fast pathway-His bundle connections were present in 13 of 102 rabbit hearts,
      providing an anatomic and physiologic basis for rapid retrograde VA conduction
      and a possible retrograde pathway for sustained AV nodal reentrant tachycardia.

PMID- 15014213
TI  - Minimum energy single-shock internal atrial defibrillation in sheep.
AB  - Well-tolerated internal atrial defibrillation shocks must be below the pain
      threshold, which has been estimated to be less than 1 Joule. Defibrillation of
      the atria with low energy is made possible by delivering shocks at the low end of
      the defibrillation dose-response curve. We studied low-energy defibrillation in
      sheep to test the hypothesis that the energy that defibrillates the atria 10% of
      the time (ED10) is less than 1 Joule. The ED10 was estimated in seven sheep with
      rapid pacing induced chronic atrial fibrillation (AF). Low-energy defibrillation
      shocks were delivered from coronary sinus (CS) to superior vena cava (SVC) and
      the ED10 and ED50 (energy that defibrillates the atria 50% of the time) were then
      calculated using logistic regression. The mean ratio of ED10 to ED50 was 0.50,
      indicating that on average, the ED10 was equal to half of the ED50. ED10 shocks
      had energies ranging from 1.2 to 5.8 Joules. These results suggest that painless
      single-shock low-energy defibrillation may not be feasible.

PMID- 15014215
TI  - Arrhythmia detection by patient and auto-activation in implantable loop
      recorders.
AB  - AIMS: The Reveal Plus implantable loop recorder offers additional automatic
      detection of arrhythmias that may not be symptomatic. We evaluated the clinical
      utility of this function compared with standard patient activation. METHODS: Over
      an 18 month period, 50 consecutive patients (age 54 +/- 20 years; 24 male) with
      unexplained dizziness, palpitations and/or syncope had ILR activations which were
      downloaded for analysis. Patient and auto-activation were analysed with respect
      to arrhythmia detection and the impact on management of patients was examined.
      RESULTS: Patient symptoms were syncope in 72% and non-syncope (dizziness and/or
      palpitations) in 28%. There were 181 patient activation events with 16% showing
      symptomatic arrhythmia leading to a positive diagnosis in 8 patients. Of 682 auto
      activations, detection was appropriate in 17% and inappropriate in 83%
      (undersensing in 76% and oversensing in 24%). In 8 patients clinically relevant
      arrhythmia was detected by patient activation alone. In 4 of these patients,
      further arrhythmia was detected by auto-activation. No patient had important
      arrhythmia detected only by auto-activation. CONCLUSION: Automatic detection of
      asymptomatic arrhythmia did not appear to improve the diagnostic utility of the
      ILR in our series. The large number of stored inappropriate auto-activation
      events limits the ability of this function to detect clinically relevant
      arrhythmia. Symptom-rhythm correlation using the patient activation function
      remains clinically useful in patients with unexplained syncope or palpitation.

PMID- 15014214
TI  - Effect of physical exercise on platelet activity and the von-Willebrand-factor in
      patients with persistent lone atrial fibrillation.
AB  - BACKGROUND: The risk of stroke is of great clinical importance in patients with
      atrial fibrillation (AF). It is not known whether physical exercise influences
      plasma coagulation and platelet aggregability during AF. The purpose of this
      study was to assess the effect of physical exercise on platelet activity,
      thrombin generation, and levels of von-Willebrand-factor in patients with
      persistent AF. METHODS: Thirteen patients with lone AF (>or=1 year) were compared
      with 13 matched patients in sinus rhythm. Patients with AF were anticoagulated
      effectively with coumarin. All patients underwent bicycle ergometry using a
      respiratory gas exchange technique for 20 min at one-third of the age-adjusted
      maximal workload. Thereafter, workload was increased until maximal exercise
      capacity was reached. Platelet factor-4 (PF-4), beta-thromboglobulin (beta-TG;
      marker for platelet activation), von-Willebrand-factor (vWF; marker for
      endothelial dysfunction), prothrombin fragment F1 + 2 (F1 + 2; marker for
      thrombin generation) and fibrinogen levels were determined throughout the study
      in all patients. RESULTS: Gas exchange variables, hemodynamic parameters and
      norepinephrine levels were comparable in the groups during moderate (45 +/- 5 W)
      and heavy exercise (198 +/- 38 W). In contrast to moderate exercise, PF-4 and
      beta-TG levels increased to 212 +/- 56% ( p < 0.05) and to 145 +/- 24% ( p <
      0.05), respectively, in patients with AF during heavy exercise. In contrast,
      physical exercise had no significant effect on platelet activity in patients with
      sinus rhythm. Levels of vWF increased by delta24% ( p < 0.05) in all patients
      during maximal exercise, whereas F1 + 2 levels increased only in patients with
      sinus rhythm. CONCLUSIONS: Heavy physical activity increases platelet activity
      and vWF levels during AF, whereas moderate exercise has no procoagulatory effect.
      Coumarin therapy prevents exercise-induced thrombin generation only. Future
      studies are needed to prove the hypothesis that heavy physical exercise is a risk
      factor for thromboembolic events in patients with AF.

PMID- 15014216
TI  - Clinical usefulness of cryomapping for ablation of tachycardias involving
      perinodal tissue.
AB  - OBJECTIVES: Radiofrequency (RF) ablation near the AV node carries a significant
      risk of AV block. We report our initial experience of using cryomapping function
      to aid the safe cryoablation close to the compact atrioventricular (AV) node.
      METHODS: Five consecutive patients with para-Hisian accessory pathways (AP) ( n =
      2), or focal atrial tachycardia (AT) originating near the AV node ( n = 3)
      underwent cryoablation using a 7F 4 mm-tipped catheter. At each prospective
      ablation site, cryo-mapping (-30 degrees C) which causes transient electrical
      dysfunction was performed, and in the absence of AH interval prolongation, a full
      cryoablation (<or=-70 degrees C) was applied to the same site. RESULTS: The AT
      foci, left in 2 patients and right in 1, and the APs were located 1.9 +/- 3.0 mm
      and 4.5 +/- 8.1 mm from the catheter recording the His deflection in two
      orthogonal radiographic projections. A His signal (0.18 +/- 0.07 mV) was recorded
      at the site of successful cryoablation in both patients with AP and 1 with right
      AT. There was no change in AV nodal function during/after ablation. At each
      successful cryoablation site, interruption of target pathway/focus function was
      observed during cryo-mapping after 19.8 +/- 12.4 s. Full cryoablation at sites
      where cryo-mapping had not caused an effect did not then produce any further
      electrophysiologic effect. All pathways and foci were ablated successfully
      without complications, using 3.2 +/- 3.9 cryothermic applications alone in 4
      patients, and after a supplementary RF ablation in 1. All patients remained free
      of arrhythmia at 15 +/- 8 months follow-up. CONCLUSION: Cryomapping may help
      identify sites for safe and effective ablation of pathways and foci located near
      the AV node.

PMID- 15014217
TI  - Radiofrequency catheter ablation using non-contact mapping for inappropriate
      sinus tachycardia.
AB  - INTRODUCTION: In this report we describe our experience using non-contact mapping
      for radiofrequency ablation in patients with inappropriate sinus tachycardia.
      METHODS AND RESULTS: Two female patients with persistent complaints of
      palpitations and documented inappropriate sinus tachycardia with failed medical
      management underwent radiofrequency ablation using non-contact mapping. Non
      contact mapping provided a continuous determination of the site of earliest
      breakthrough, facilitating the delivery and the assessment of the results of each
      radiofrequency application. CONCLUSION: Non-contact mapping is an effective
      mapping modality in the interventional treatment of inappropriate sinus
      tachycardia.

PMID- 15014218
TI  - Use of a non-fluoroscopic catheter navigation system for pulmonary vein
      isolation.
AB  - INTRODUCTION: Pulmonary vein (PV) isolation is commonly performed by using
      separate mapping and ablating catheters. Steering the ablation catheter to the
      target electrodes on the mapping catheter can be difficult and time consuming
      under fluoroscopic guidance. We investigated the use of a non-fluoroscopic
      catheter navigation system to facilitate radiofrequency pulmonary vein isolation.
      METHODS: The LocaLisa non-fluoroscopic catheter navigation system was used during
      PV isolation in 21 patients. Eleven control patients underwent the procedure
      under fluoroscopic guidance alone. PV isolation was performed by mapping the
      veins with a 10 or 20 pole circular mapping catheter and ablating at targeted
      mapping bipoles with a separate ablation catheter. RESULTS: The electrodes of
      both catheters were visualized in 3 dimensional virtual space by LocaLisa. There
      were no clinical differences between the LocaLisa and control patients. During
      mapping, electrical artifacts were produced on specific mapping electrodes by
      contact with the ablation catheter. A blinded observer using LocaLisa correctly
      identified the mapping electrodes being contacted by the ablation catheter in 368
      of 398 (92%) of cases. Total fluoroscopic time was reduced in the LocaLisa group
      (72 +/- 29 minutes) compared to the control group (102 +/- 37 minutes, p = 0.02).
      There were no differences between the groups in total procedure times, number of
      lesions given, complications or long term procedural success (all p > 0.45).
      CONCLUSIONS: The LocaLisa catheter navigation system accurately identifies the
      position of an ablation catheter relative to the target electrodes on a circular
      mapping catheter. The system also significantly reduces total fluoroscopic time
      for PV isolation.

PMID- 15014219
TI  - Radiofrequency catheter ablation of a posteroseptal accessory pathway along the
      morphologic tricuspid valve in a patient with congenitally corrected
      transposition of the great arteries and complete atrioventricular block.
AB  - We report a patient with Congenitally Corrected Transposition of the Great
      Arteries, complete atrioventricular block and a posteroseptal accessory pathway
      across the morphologic tricuspid valve. Ablation of the accessory pathway was
      performed for her symptomatic palpitations.

PMID- 15014220
TI  - Random internal component failure of an implantable cardioverter defibrillator.
AB  - Internal component failure of the Implantable Cardioverter Defibrillators (ICD)
      is a rare complication, which can have a potentially catastrophic outcome. We
      describe a patient with random component failure, which occurred due to
      electrical overstress damage to the high voltage hybrid as a result of
      inappropriate arcing, as detected by the manufacturer. This in turn damaged other
      components in the device. This secondary damage caused the device to reset,
      emitting a constant tone. A high current state was created, thereby depleting the
      battery prematurely. The problem was promptly detected and rectified by ICD
      generator replacement.

PMID- 15014221
TI  - Andreas R Gruntzig (1939-1985).

PMID- 15014222
TI  - Acculturation and health beliefs of Mexican Americans regarding tuberculosis
      prevention.
AB  - Mexican Americans are at particular risk of contracting tuberculosis. Yet too
      little is known about perceptions influencing their health. This study
      investigated gender and acculturation differences in TB-specific Health Belief
      Model (HBM) constructs, and the applicability of the HBM's traditional
      configuration to Mexican Americans. Acculturation and gender substantially
      influenced the findings. Traditional Mexican Americans reported higher perceived
      susceptibility and seriousness, more barriers, and greater attention to cues
      regarding TB prevention than Highly Integrated Biculturals. Women reported
      greater benefits, attention to cues, and intent to engage in TB prevention
      behaviors than men. Highly Integrated Bicultural men reported less attention to
      cues and less intent to engage in health behaviors than other groups. The
      traditional HBM configuration did not fit this sample. Reconfiguration did,
      however, result in adequate fit. Overall, higher perceived susceptibility, action
      benefits, attention to media cues, and female gender predicted greater intent to
      engage in TB health behaviors.

PMID- 15014223
TI  - Cultural feasibility assessment of tuberculosis prevention among persons of
      Haitian origin in South Florida.
AB  - A cultural feasibility study was conducted among persons of Haitian origin in
      South Florida to identify factors which might influence utilization of screening
      and treatment services for latent tuberculosis infection in this population. Five
      focus group interviews conducted among men and women explored cultural beliefs
      and practices related to TB, barriers and incentives to screening, and approaches
      to increasing treatment adherence. Key findings include the influence of social
      stigma and fears related to confidentiality of medical status as disincentives to
      screening. Cultural sensitivity to being labeled as a high risk group for these
      infections also emerged as a critical variable. Community-based approaches to
      health education for this population are described. Study recommendations include
      the planning of programs based on a service delivery model that stresses respect
      and personal attention to clients, improved interpersonal skills of health center
      staff, and coordination of services between private doctors and public health
      agencies.

PMID- 15014224
TI  - Quality of life among Iranian refugees resettled in Sweden.
AB  - The relationships between quality of life, psychopathological manifestations and
      coping related variables (coping resources, social support, sense of coherence)
      were examined among individuals who have perceived several severe traumata. One
      hundred Iranian refugees resettled in Sweden have been investigated by the
      Symptom Checklist (SCL-90-R), the Beck Depression Inventory (BDI), the Coping
      Resources Inventory (CRI), and the Interview Schedule for Social Interaction
      (ISSI), the Sense of Coherence Scale (SOC), and the WHOQoL-100 questionnaire in a
      cross-sectional study. Individuals, traumatized by combat experiences as a
      soldier during the war, with low BDI scores showed on average the significantly
      highest overall quality of life, the best physical health, the highest scores
      according to the sense of coherence most pronounced for "Meaningfulness," and the
      best availability of social integration compared to participants who did not had
      these experiences in combats and those with the experience but scored high in the
      BDI. Quality of life, coping resources, and social support were found closely
      related to psychopathological manifestations. Motivational orientations (highly
      developed Meaningfulness-SOC) and various coping competencies probably enable
      some traumatized individuals to resist against several traumata and to live in a
      good quality of life without psychopathological disturbances.

PMID- 15014225
TI  - Preimmigration beliefs of life success, postimmigration experiences, and
      acculturative stress: South Asian immigrants in the United States.
AB  - This study retrospectively explored the links between preimmigration beliefs of
      life success and postimmigration experiences and their influence on acculturative
      stress among a group of parents who recently immigrated with their children from
      three non-English speaking countries-Bangladesh, India, and Pakistan-to the
      United States. The respondents, 75 sets of parents residing in New York City,
      participated in semistructured qualitative interviews. Discrepancies between the
      parents' anticipated life success in the United States and actual experiences
      after immigration were associated with the parents' expectations of their
      children fulfilling parents' own dreams of success. Two criteria specific to
      Asian culture that guided parental expectations were the responsibility of
      children in enhancing family pride and the role of education as a way to advance
      through the social class and the caste systems. Implications for understanding
      immigrant parents' sociocultural contexts, the potential negative impact of
      unrealistic expectations on children's development, and the significance of
      acculturative stress for parents as well as their children were discussed.

PMID- 15014226
TI  - Osteoporosis health beliefs and practices among Korean immigrants in Nova Scotia.
AB  - The purpose of this research was to investigate osteoporosis knowledge, as well
      as health beliefs and practices among Korean immigrants in Nova Scotia. Twenty
      six participants (18 women and eight men) completed the questionnaire. The mean
      age of participants was 48, and their average length of stay in Canada was 14
      years. The mean osteoporosis knowledge score was 50% for both men and women and
      perceived susceptibility to the disease was low, especially in men. Perceived
      seriousness and health motivation was high relative to perceived susceptibility.
      Only 62% indicated both that their diet met their nutritional and cultural needs,
      and changes in dietary and exercise habits since arrival in Canada were reported
      by 73 and 64%, respectively. This study helped identify existing osteoporosis
      awareness weaknesses in this population: a). Perceived susceptibility, especially
      for men; and b). knowledge related to prevention and treatment options, including
      diet and exercise.

PMID- 15014228
TI  - Characterization of threonine side chain dynamics in an antifreeze protein using
      natural abundance 13C NMR spectroscopy.
AB  - The dynamics of threonine side chains of the Tenebrio molitor antifreeze protein
      (TmAFP) were investigated using natural abundance (13)C NMR. In TmAFP, the array
      of threonine residues on one face of the protein is responsible for conferring
      its ability to bind crystalline ice and inhibit its growth. Heteronuclear
      longitudinal and transverse relaxation rates and the [(1)H]-(13)C NOE were
      determined in this study. The C alpha H relaxation measurements were compared to
      the previously measured (15)N backbone parameters and these are found to be in
      agreement. For the analysis of the threonine side chain motions, the model of
      restricted rotational diffusion about the chi(1) dihedral angle was employed
      [London and Avitabile (1978) J. Am. Chem. Soc., 100, 7159-7165]. We demonstrate
      that the motion experienced by the ice binding threonine side chains is highly
      restricted, with an approximate upper limit of less than +/-25 degrees.

PMID- 15014227
TI  - An expectation/maximization nuclear vector replacement algorithm for automated
      NMR resonance assignments.
AB  - We report an automated procedure for high-throughput NMR resonance assignment for
      a protein of known structure, or of an homologous structure. Our algorithm
      performs Nuclear Vector Replacement (NVR) by Expectation/Maximization (EM) to
      compute assignments. NVR correlates experimentally-measured NH residual dipolar
      couplings (RDCs) and chemical shifts to a given a priori whole-protein 3D
      structural model. The algorithm requires only uniform (15)N-labelling of the
      protein, and processes unassigned H(N)-(15)N HSQC spectra, H(N)-(15)N RDCs, and
      sparse H(N)-H(N) NOE's (d(NN)s). NVR runs in minutes and efficiently assigns the
      (H(N),(15)N) backbone resonances as well as the sparse d(NN)s from the 3D (15)N
      NOESY spectrum, in O (n(3)) time. The algorithm is demonstrated on NMR data from
      a 76-residue protein, human ubiquitin, matched to four structures, including one
      mutant (homolog), determined either by X-ray crystallography or by different NMR
      experiments (without RDCs). NVR achieves an average assignment accuracy of over
      99%. We further demonstrate the feasibility of our algorithm for different and
      larger proteins, using different combinations of real and simulated NMR data for
      hen lysozyme (129 residues) and streptococcal protein G (56 residues), matched to
      a variety of 3D structural models.

PMID- 15014230
TI  - Adiabatic TOBSY in rotating solids.
AB  - A MAS solid state NMR approach for achieving efficient scalar coupling mediated
      through-bond (13)C chemical shift correlations of the aliphatic carbons in
      uniformly labelled peptides/proteins is described. The method involves the
      application of a continuous train of adiabatic inversion pulses, as in the
      adiabatic TOCSY experiments carried out in solution state NMR studies. While
      rotor synchronised application of adiabatic inversion pulses leads to dipolar
      correlations, it is shown here via numerical simulations and experimental
      measurements that asynchronous application of adiabatic pulses can facilitate the
      mapping of through-bond connectivities. The method employs a suitable phasing
      scheme for generating the desired isotropic mixing Hamiltonian and requires
      moderate (13)C RF field strength only.

PMID- 15014229
TI  - Side chain dynamics monitored by 13C-13C cross-relaxation.
AB  - A method to measure (13)C-(13)C cross-relaxation rates in a fully (13)C labeled
      protein has been developed that can give information about the mobility of side
      chains in proteins. The method makes use of the (H)CCH-NOESY pulse sequence and
      includes a suppression scheme for zero-quantum (ZQ) coherences that allows the
      extraction of initial rates from NOE buildup curves. The method has been used to
      measure (13)C-(13)C cross-relaxation rates in the 269-residue serine-protease
      PB92. We focused on C(alpha)-C(beta) cross-relaxation rates, which could be
      extracted for 64% of all residues, discarding serine residues because of
      imperfect ZQ suppression, and methyl (13)C-(13)C cross-relaxation rates, which
      could be extracted for 47% of the methyl containing C-C pairs. The C(alpha)
      C(beta) cross-relaxation rates are on average larger in secondary structure
      elements as compared to loop regions, in agreement with the expected higher
      rigidity in these elements. The cross-relaxation rates for methyl containing C-C
      pairs show a general decrease of rates further into the side chain, indicating
      more flexibility with increasing separation from the main chain. In the case of
      leucine residues also long-range C(beta)-C(delta) cross-peaks are observed.
      Surprisingly, for most of the leucines a cross-peak with only one of the methyl
      C(delta) carbons is observed, which correlates well with the chi(2) torsion-angle
      and can be explained by a difference in mobility for the two methyl groups due to
      an anisotropic side chain motion.

PMID- 15014232
TI  - Carbonyl carbon transverse relaxation dispersion measurements and ms-micros
      timescale motion in a protein hydrogen bond network.
AB  - A constant-time, Carr-Purcell-Meiboom-Gill (CPMG) transverse relaxation, R(2),
      dispersion experiment for carbonyl carbons was designed and executed to detect
      micros-ms time-scale dynamics of protein backbone carbonyl sites. Because of the
      large (ca. 55 Hz) C(alpha)-C' J-coupling, the carbonyl signal intensity is
      strongly modulated as the spacing between CPMG pulses is varied, in uniformly
      (13)C enriched proteins, unless care is taken to minimize the perturbation of the
      C(alpha) magnetization by the CPMG pulses. CPMG pulse trains consisting of either
      a band-selective pulse, such as RE-BURP, or rectangular (with an excitation null
      in the C(alpha) region of the spectrum) pulses were employed in order to minimize
      C' signal modulation by C(alpha)-C' J-coupling. The performance of these types of
      CPMG refocusing pulses was assessed by computer simulation, and by comparing
      dispersion profiles measured for (1) uniformly [(13)C,(15)N, (2)H] ((2)H at non
      labile hydrogen sites) labeled, and (2) uniformly (15)N/selectively-(13)C'
      labeled samples of HIV-1 protease bound to a potent inhibitor, DMP323. In
      addition, because the uniformly (13)C/(15)N/(2)H labeled sample was well suited
      to measure (15)N and (1)H R(2) dispersion as well as (13)C' dispersion,
      conformational exchange in the inter subunit beta-sheet hydrogen-bond network of
      the inhibitor-bound protease was elucidated using relaxation dispersion data of
      all three types of nuclei.

PMID- 15014231
TI  - Binding ability of a HHP-tagged protein towards Ni2+ studied by paramagnetic NMR
      relaxation: the possibility of obtaining long-range structure information.
AB  - The binding ability of a protein with a metal binding tag towards Ni(2+) was
      investigated by longitudinal paramagnetic NMR relaxation, and the possibility of
      obtaining long-range structure information from the paramagnetic relaxation was
      explored. A protein with a well-defined solution structure (Escherichia coli
      thioredoxin) was used as the model system, and the peptide His-His-Pro (HHP)
      fused to the N-terminus of the protein was used as the metal binding tag. It was
      found that the tag forms a stable dimer complex with the paramagnetic Ni(2+) ion,
      where each metal ion binds two HHP-tagged protein molecules. However, it was also
      found that additional sites in the protein compete with the HHP-tag for the
      binding of the metal ion. These binding sites were identified as the side chain
      carboxylate groups of the aspartic and glutamic acid residues. Yet, the
      carboxylate groups bind the Ni(2+) ions considerably weaker than the HHP-tag, and
      only protons spatially close to the carboxylate sites are affected by the Ni(2+)
      ions bound to these groups. As for the protons that are unaffected by the
      carboxylate-bound Ni(2+) ions, it was found that the long-range distances derived
      from the paramagnetic relaxation enhancements are in good agreement with the
      solution structure of thioredoxin. Specifically, the obtained long-range
      paramagnetic distance constraints revealed that the dimer complex is asymmetric
      with different orientations of the two protein molecules relative to the Ni(2+)
      ion.

PMID- 15014233
TI  - Cyclic enterobacterial common antigen: potential contaminant of bacterially
      expressed protein preparations.
AB  - We have previously reported the identification of the cyclic enterobacterial
      common antigen (ECA(CYC)) polysaccharide in E. coli strains commonly used for
      heterologous protein expression (PJA Erbel et al., J. Bacteriol. 185 (2003):
      1995). Following this initial report, interactions among several NMR groups
      established that characteristic N -acetyl signals of ECA(CYC) have been observed
      in (15)N-(1)H HSQC spectra of samples of various bacterially-expressed proteins
      suggesting that this water-soluble carbohydrate is a common contaminant. We
      provide NMR spectroscopic tools to recognize ECA(CYC) in protein samples, as well
      as several methods to remove this contaminant. Early recognition of ECA-based NMR
      signals will prevent time-consuming analyses of this copurifying carbohydrate.

PMID- 15014234
TI  - NMR assignment of the hypothetical ENTH-VHS domain At3g16270 from Arabidopsis
      thaliana.

PMID- 15014235
TI  - NMR assignment of the hypothetical rhodanese domain At4g01050 from Arabidopsis
      thaliana.

PMID- 15014236
TI  - Backbone 1H, 15N and 13C resonance assignments of alpha-ADT and beta-ADT.

PMID- 15014237
TI  - 1H, 13C, 15N backbone and sidechain resonance assignments of apo-NosL, a novel
      copper(I) binding protein from the nitrous oxide reductase gene cluster of
      Achromobacter cycloclastes.

PMID- 15014238
TI  - NMR assignment of HI1723 from Haemophilus influenzae--a sequence homologue from
      the iron sulfur cluster assembly (IscA) family.

PMID- 15014239
TI  - Assignment of the 1H, 13C and 15N resonances of the catalytic domain of guanine
      nucleotide exchange factor BopE from Burkholderia pseudomallei.

PMID- 15014240
TI  - 1H, 15N and 13C resonance assignments of the C345C domain of the complement
      component C5.

PMID- 15014268
TI  - Micromachines in spine surgery.

PMID- 15014269
TI  - Teaching, learning, leadership survival in the new order.

PMID- 15014270
TI  - Economic evaluation of a behavioral-graded activity program compared to physical
      therapy for patients following lumbar disc surgery.
AB  - STUDY DESIGN: An economic evaluation was conducted alongside a randomized
      controlled trial. SUMMARY OF BACKGROUND DATA: Little is known about the
      effectiveness of cognitive-behavioral treatment options for patients following
      lumbar disc surgery. If the knowledge available was supported by an economic
      evaluation, the information could then be used to make recommendations for the
      implementation of cognitive-behavioral treatment in the routine of rehabilitation
      following lumbar disc surgery. OBJECTIVE: To examine the cost-effectiveness of a
      behavioral-graded activity program, which is an operant treatment, compared to
      usual care as delivered by a physical therapist for patients following first-time
      lumbar disc surgery. METHODS: For the economic evaluation, a societal viewpoint
      was applied. The primary outcome measures (measured at the 12-month follow-up)
      were global perceived effect and functional status. To evaluate the economic
      consequences of the treatments, direct health care and non-health care costs were
      considered, as well as indirect costs. RESULTS: The clinical outcomes showed no
      relevant differences between behavioral-graded activity (n = 52) and UC (n = 53).
      Treatment costs were almost identical in the two intervention groups. The
      difference in direct health care costs was, although not statistically
      significant, 264 EURO [95% CI: -3-525] higher in behavioral-graded activity than
      in usual care per patient-year. It was mainly the excess cost of visiting the
      physiotherapist in the behavioral-graded activity group that accounted for this
      difference. The difference in direct non-health care costs, although not
      statistically significant, was 388 EURO [95% CI: -217; 992] lower in the usual
      care group due to unpaid help by friends or family. Consequently, although again
      not statistically significant, the total direct costs in behavioral-graded
      activity are 639 EURO [95% CI: -91; 1368] higher than in usual care. For the
      indirect costs, there was a statistically significant difference, behavioral
      graded activity being more expensive. The sensitivity analysis showed that these
      results are fairly robust. CONCLUSIONS: This study concludes that there are no
      differences between the two treatment conditions on any of the clinical outcome
      measures but that behavioral-graded activity is associated with higher costs.
      Consequently, there is no reason for the implementation of behavioral-graded
      activity as the standard treatment for patients following lumbar disc surgery.

PMID- 15014271
TI  - The anterior dural (Hofmann) ligaments.
AB  - STUDY DESIGN: A dissection-based study of 18 embalmed cadavers (7 male, 11
      female), mean age 84 (+/-8.4) years. OBJECTIVE: To determine the morphology and
      morphometry of the anterior dural (Hofmann) ligaments. SUMMARY OF BACKGROUND
      DATA: The attachment of the posterior longitudinal ligament to the dura mater is
      poorly understood. Anterior dural ligaments connect the anterior dura to the deep
      layer of the posterior longitudinal ligament, but appear to be limited to the
      lumbar region and have been observed to have a craniocaudal orientation. Their
      function is reported to help in supporting and protecting the dural sac and
      spinal cord. METHODS: The spinal canal was opened exposing the dural sac, the
      spinal nerve roots incised, and spinal cord removed to mobilize the dural sac and
      gain access to Hofmann ligaments. The extent, orientation, length, and level of
      origin and insertion of the ligaments were documented. RESULTS: The orientation
      of the ligaments changed from caudocranial (dura to posterior longitudinal
      ligament) at upper thoracic levels to transverse at the level of T8-T9 to
      craniocaudal at lower thoracic and lumbar levels, often with multiple ligaments
      being present at a single level. Ligament length varied from 0.5 to 28.8 mm and
      was positively correlated with vertebral level and negatively correlated with
      orientation. CONCLUSIONS: Hofmann ligaments are present at most levels between C7
      and L5; although most ligaments were limited to a single vertebral segment, some
      were observed to cross several segments.

PMID- 15014272
TI  - Chronic low back pain-associated paraspinal muscle dysfunction is not the result
      of a constitutionally determined "adverse" fiber-type composition.
AB  - STUDY DESIGN: Investigative case control study. OBJECTIVES: To determine whether
      excessive paraspinal muscle fatigue in chronic low back pain results from a
      paucity of muscle type I fiber content. SUMMARY OF BACKGROUND DATA: Paraspinal
      muscle function is vital for spinal protection. Prospective studies suggest that
      excessive paraspinal muscle fatigability may increase risk of first-time low back
      pain. As contractile performance of the paraspinal muscles is governed by their
      constitutionally determined fiber composition, the question arises whether a
      constitutionally determined "adverse" composition could predispose to low back
      pain through impaired spinal protection. METHODS: Thirty-five male patients with
      chronic low back pain were compared with 32 male control patients of similar age
      and anthropometry. During Sorensen and 60% of maximum voluntary isometric
      contraction fatigue tests, median frequency declines in the paraspinal muscle
      surface electromyograph signal were monitored and correlated with muscle
      histomorphometry. RESULTS: Patients were weaker than controls during maximum
      voluntary isometric contractions (84.47 [28.44]vs. 98.74 [18.11] kg,
      respectively; P = 0.02) and more fatigable during their Sorensen tests (endurance
      time 105.29 [28.53]vs. 137.50 [40.38] sec, respectively; P < 0.01). There were no
      between-group differences in median frequency declines during the Sorensen (-0.37
      [0.16]vs. -0.36 [0.12]%.sec) or 60% maximum voluntary isometric contraction (
      0.42 [0.31]vs. -0.51 [0.29]%.sec) tests, for patients and controls, respectively.
      There were no between-group differences in the percent number of paraspinal
      muscle type I fibers (64 [11]vs. 64 [9]%) or the percent area occupied by type I
      fibers (67 [11]vs. 69 [9]%), for patients and controls, respectively. Type I and
      II muscle fiber narrow diameters were similar for both groups. CONCLUSION: In the
      patients with chronic low back pain tested, their associated paraspinal muscle
      dysfunction was not the result of a constitutionally determined "adverse" fiber
      type composition.

PMID- 15014273
TI  - Biomechanical comparison of anterolateral plate, lateral plate, and pedicle
      screws-rods for enhancing anterolateral lumbar interbody cage stabilization.
AB  - STUDY DESIGN: A repeated measures in vitro flexibility experiment was performed
      in calf spines. OBJECTIVES: To determine the biomechanical differences among
      three techniques for augmenting stability of an anterolateral lumbar threaded
      interbody cage. BACKGROUND: Stand-alone interbody cages are known to inadequately
      stabilize the spine. Surgeons often add supplementary instrumentation for a more
      stable construct. METHODS: Six L2-L5 calf spines (L3-L4 level instrumented) were
      tested: 1) intact; 2) with a single anterolateral interbody cage; 3) with cage
      plus anterolateral plating; 4) with cage plus lateral plating; and 5) with cage
      plus pedicle screw fixation. Specimens were loaded in each anatomic plane
      quasistatically (maximum 5.0 Nm). Angular motion was measured
      stereophotogrammetrically. RESULTS: The stand-alone interbody cage allowed
      significantly less range of motion than normal during all loading modes except
      axial rotation. Addition of pedicle screws-rods, anterolateral plate, or lateral
      plate significantly further reduced range of motion in all planes. Pedicle screws
      slightly outperformed the anterolateral plate during extension and lateral
      bending and slightly outperformed the lateral plate during flexion, extension,
      and left axial rotation (range of motion differences <0.65 degrees, P < 0.05).
      The anterolateral plate outperformed the lateral plate during flexion and
      extension, whereas the lateral plate outperformed the anterolateral plate during
      lateral bending (range of motion difference <0.57 degrees, P < 0.05). CONCLUSION:
      Anterolateral or lateral lumbar plating increases stability significantly
      compared to stand-alone interbody cage fixation. These findings support
      anterolateral or lateral plate fixation as a potential clinical alternative to
      pedicle screws-rods in this role and may obviate the need for combined anterior
      and posterior approaches when spinal instability exists.

PMID- 15014274
TI  - Neural space integrity of the lower cervical spine: effect of anterior lesions.
AB  - STUDY DESIGN: A repeated measures study design was used to evaluate
      intervertebral foramen and spinal canal neural space integrity subsequent to
      sequential surgical anterior lesions of the lower cervical spine in a human
      cadaver model. OBJECTIVE: To investigate the degree to which sequential ablation
      of anterior vertebral elements places the neural structures at risk of injury.
      SUMMARY OF BACKGROUND DATA: Classic instability management utilizing functional
      structural criteria has been widely examined associating specific lesions or
      pathologies to a degree of mechanical instability. Unfortunately, these studies
      have not assessed the neuroprotective role of the vertebral column. METHODS:
      Eight human cadaveric lower cervical spines were instrumented with transducers to
      measure geometrical changes in the intervertebral foramen and spinal canal.
      Sequential lesions were performed anteriorly on the anterior and middle column
      structures (C4-C5 disc and C5 vertebra), and their effects on neural space
      integrity and range of motion were measured under physiologic loading. RESULTS:
      Range of motion significantly increased with successively more destructive
      lesions, whereas the spinal canal exhibited few changes. Intervertebral foramen
      integrity was statistically reduced for corpectomy (66% intact),
      hemivertebrectomy (62% intact) and full vertebrectomy (57% intact) lesions when
      loaded in concomitant extension and ipsilateral bending (4 Nm). CONCLUSIONS:
      Lesions more extensive than a surgical discectomy have significant effects on the
      cervical neural foramens specifically when the spine is placed in extension,
      ipsilateral bending, and coupled ipsilateral bending and extension. Our study
      establishes a quantitative relationship between the risk of neural structure
      compression and anterior lesions of the spinal column under physiologic loading.

PMID- 15014275
TI  - Electromyographic and kinematic exploration of whiplash-type neck perturbations
      in left lateral collisions.
AB  - STUDY DESIGN: Seven healthy volunteers were subjected to left lateral impacts of
      4.8, 7.9, 11, and 13.7 m/s acceleration at two levels of expectation: expected
      and unexpected. OBJECTIVES: The purpose of this study was to determine the
      response of the cervical muscles to increasing low-velocity left lateral impacts,
      and to compare the quantitative effects of expected and unexpected impact.
      SUMMARY OF BACKGROUND DATA: The literature contains little information on the
      etiology of whiplash injuries. Animal and cadaver studies have yielded some
      insight into the phenomenon. However, in vivo studies of the cervical muscular
      response and head-neck kinematics to lateral impacts are rare. METHODS: Bilateral
      electromyograms of the sternocleidomastoids, trapezii, and splenii capitis were
      recorded bilaterally. Triaxial accelerometers recorded the acceleration of the
      chair, torso at the shoulder level, and head of the participant. RESULTS: At an
      acceleration of 13.7 m/s, the sternocleidomastoids and trapezii generated
      approximately <or=50% of their maximal voluntary contraction electromyogram in
      both the expected and unexpected impact conditions. Study participants exhibited
      lower levels of their maximal voluntary contraction electromyogram when the
      impact was expected. The splenius capitis behaved similar to these muscles in the
      expected condition, but when the impact was unexpected, the splenius capitis
      muscle contralateral to the impact (i.e., right splenius in a left lateral
      impact) generated 94% of its maximal voluntary contraction electromyogram.
      Electromyographic variables were significantly affected by the levels of
      acceleration and expectation (P < 0.001). The onset time and peak electromyogram
      time for the sternocleidomastoid, splenii capitis, and trapezii on the side
      contralateral to the side of impact progressively decreased with increasing
      levels of acceleration. The onset time and peak electromyogram time for the
      sternocleidomastoid, splenii, and trapezii on the same side of impact
      progressively increased with increasing levels of acceleration. The kinetic
      variables and the electromyographic variables regressed significantly on the
      acceleration (P < 0.01). In response to left lateral impacts, muscle responses
      were greater with higher levels of acceleration, greater with unexpected impact
      conditions, and greatest for the splenius capitis muscle contralateral to the
      side of impact. CONCLUSIONS: Because the muscular component of the head-neck
      complex plays a central role in the abatement of higher acceleration levels, it
      may be a primary site of injury in the whiplash phenomenon in lateral collisions.
      Expecting or being aware of imminent impact may play a role in reducing muscle
      responses in low-velocity impacts.

PMID- 15014277
TI  - Pediatric sacral fractures.
AB  - STUDY DESIGN: Retrospective review. OBJECTIVES: To examine the epidemiologic,
      anatomic, mechanistic, and outcome characteristics in pediatric patients with
      sacral fractures and to look for correlation with the adult literature regarding
      sacral fractures and previous classification systems. SUMMARY OF BACKGROUND DATA:
      A review of the current literature reveals no systematic attempts to apply the
      results of studies of sacral fractures in adults to those in the pediatric
      population. METHODS: We reviewed all 4876 cases of pediatric trauma at 1
      children's hospital over a 7-year period. Eight children had documented sacral
      fractures. Their charts were reviewed, and follow-up interviews were conducted.
      RESULTS: All patients suffered either motor vehicle accidents or falls from
      height. Three patients' injuries were confined to the pelvic rim including the
      sacrum. Mean follow-up was 38 months. Six patients had Denis Zone I injuries, 1
      patient had a Zone II injury (no neurologic deficits in either category), and 1
      patient had a Zone III injury with significant neurologic injury. Only this
      patient required surgical intervention. Long-term recovery was good in those
      without comorbid injuries. CONCLUSIONS: Pediatric sacral fractures are rare
      (0.16% of pediatric trauma). As is the case in adults, most fractures are not
      associated with neurologic injury. Diagnosing pediatric sacral fractures requires
      high clinical suspicion and thorough radiographic evaluation. Correlation of
      neurologic injury with certain fracture types may be possible, but will require
      larger studies to be confirmed.

PMID- 15014278
TI  - A longitudinal study of congruent sagittal spinal alignment in an adult cohort.
AB  - STUDY DESIGN: A 10+-year longitudinal study of 100 adult volunteers. OBJECTIVES:
      To identify congruent lumbar lordosis in association with other sagittal
      spinopelvic parameters. SUMMARY OF BACKGROUND DATA: The aging spine poses
      difficult problems in determining appropriate lumbar lordosis. The concept of
      congruent spinal alignment is preferred over that of normal spinal alignment, yet
      the definition of sagittal spinal congruity in elderly population has not been
      well documented. METHODS: A population-based recruitment of adult volunteers and
      follow-up of 10+ years was conducted. A total of 100 healthy volunteers with
      baseline age of 50+ years were subjected to standing entire spine radiographs.
      Radiologic parameters included lumbar lordosis, sacral inclination, sagittal
      spinal balance, and other sagittal alignments. RESULTS: Average age of the
      subjects was 62.0 years at baseline and 73.9 years at follow-up. Lumbar lordosis
      with <5 degrees change during observation was defined as stable lumbar lordosis
      (n = 34). Regression analyses of the baseline parameters revealed that sacral
      inclination was the sole predictor of stable lumbar lordosis (lumbar lordosis =
      0.8 * sacral inclination, r = 0.94, P < 0.0001). Baseline lumbopelvic congruity,
      determined as 0.7 <or= lumbar lordosis/sacral inclination <or= 0.9, was
      associated with minimum alterations in sagittal spinal alignment, whereas
      subjects with incongruent lumbopelvic relationships were predisposed to
      developing kyphosis and spinal imbalance. CONCLUSIONS: Our study substantiates
      previous results showing that the strongest determinant of lumbar lordosis is
      sacral alignment. Appropriate lumbar lordosis was estimated to be 80% of sacral
      inclination using standing radiographs, and the proposed lumbopelvic congruity
      could measure stability in sagittal spinal alignment. This study provides
      practical data for the assessment of sagittal spinal alignment in the aging
      spine.

PMID- 15014276
TI  - Two-year fusion rate equivalency between Grafton DBM gel and autograft in
      posterolateral spine fusion: a prospective controlled trial employing a side-by
      side comparison in the same patient.
AB  - STUDY DESIGN: Multicenter, prospective equivalency trial with each patient
      serving as his/her own control. OBJECTIVES: To compare the effectiveness of a
      Grafton DBM gel composite with iliac crest autograft in posterolateral spine
      fusion. SUMMARY OF BACKGROUND DATA: While autograft remains the preferred graft
      material to facilitate spine fusion, the supply is limited and harvesting
      produces undesirable clinical consequences. METHODS: A total of 120 patients
      underwent posterolateral spine fusion with pedicle screw fixation and bone
      grafting. Iliac crest autograft was implanted on one side of the spine and a
      Grafton DBM/autograft composite was implanted on the contralateral side in the
      same patient. An independent, blinded reviewer evaluated anteroposterior and
      lateral flexion-extension radiographs. The fusion mass lateral to the
      instrumentation on each side was judged fused or not, and the mineralization of
      the graft was rated absent, mild, moderate, or extensive. The degree of
      correspondence in outcomes between sides was estimated by computing the
      percentage agreement and kappa statistic. RESULTS: Nearly 70% of patients (81 of
      120) provided complete 24-month radiographic studies. The bone graft mass was
      fused in 42 cases (52%) on the Grafton DBMside and in 44 cases (54%) on the
      autograft side. The overall percentage agreement for fusion status between sides
      was approximately 75% (61 of 81), indicating moderately strong statistical
      correspondence (kappa = 0.51, P < 0.0001). Bone mineralization ratings also were
      similar between treated sides. Perfect agreement was realized in almost 60% of
      patients (48 of 81) with moderate statistical correspondence (weighted kappa =
      0.54, P < 0.0001). CONCLUSIONS: Grafton DBM can extend a smaller quantity of
      autograft than is normally required to achieve a solid spinal arthrodesis.
      Consequently, a reduced amount of harvested autograft may be required,
      potentially diminishing the risk and severity of donor site complications.

PMID- 15014279
TI  - Real-time continuous intraoperative electromyographic and somatosensory evoked
      potential recordings in spinal surgery: correlation of clinical and
      electrophysiologic findings in a prospective, consecutive series of 213 cases.
AB  - STUDY DESIGN: Retrospective analysis of a prospectively accrued series of 213
      consecutive patients who underwent intraoperative neurophysiologic monitoring
      with electromyography and somatosensory-evoked potentials during thoracolumbar
      spine surgery. OBJECTIVES: To study the incidence of significant intraoperative
      electrophysiologic changes and new postoperative neurologic deficits. SUMMARY OF
      BACKGROUND DATA: Continuous intraoperative electromyography and somatosensory
      evoked potentials are frequently used in spinal surgery to prevent neural injury.
      However, only limited data are available on the sensitivity, specificity, and
      predictive values of intraoperative electrophysiologic changes with regard to the
      occurrence of new postoperative neurologic deficits. METHODS: We examined data on
      patients who underwent intraoperative monitoring with continuous lower limb
      electromyography and somatosensory-evoked potentials. The analysis focused on the
      correlation of intraoperative electrophysiologic changes with the development of
      new neurologic deficits. RESULTS: A total of 213 patients underwent surgery on a
      total of 378 levels; 32.4% underwent an instrumented fusion. Significant
      electromyograph activation was observed in 77.5% of the patients and significant
      somatosensory-evoked potential changes in 6.6%. Fourteen patients (6.6%) had new
      postoperative neurologic symptoms. Of those, all had significant electromyograph
      activation, but only 4 had significant somatosensory-evoked potential changes.
      Intraoperative electromyograph activation had a sensitivity of 100% and a
      specificity of 23.7% for the detection of a new postoperative neurologic deficit.
      Somatosensory-evoked potentials had a sensitivity of 28.6% and specificity of
      94.7%. CONCLUSIONS: Intraoperative electromyographic activation has a high
      sensitivity for the detection of a newpostoperative neurologic deficit but a low
      specificity. In contrast, somatosensory-evoked potentials have low sensitivity
      but high specificity. Combined intraoperative neurophysiologic monitoring with
      electromyography and somatosensory-evoked potentials is helpful for predicting
      and possibly preventing neurologic injury during thoracolumbar spine surgery.

PMID- 15014281
TI  - Children at risk: risk factors for low back pain in the elementary school
      environment.
AB  - STUDY DESIGN: A prevalence survey of 101 randomly selected elementary schools in
      the Israel Central District. OBJECTIVES: To identify and describe risk factors
      for low back pain that exist in the elementary school environment. SUMMARY OF
      BACKGROUND DATA: Recent surveys report a high prevalence of low back pain in
      children and adolescents that increases with age, with a correlation between low
      back pain in adolescence and that experienced in adulthood. Environmental risk
      factors have been associated with the development of low back pain in children.
      Because of the significant amount of time children spend in their school
      environment, risk factors need to be identified in this environment. METHODS: A
      questionnaire, completed by school nurses, measured risk factors among 10,000
      children in elementary schools in Israel. These included backpack and student
      weight, the availability of storage facilities, the appropriateness of chair and
      desk height to student height, seating arrangements during frontal lessons, and
      physical activity at recess. RESULTS: Between 30% and 54% of students carried
      >15% of their body weight. Nearly 15% of the first graders and 20% of sixth
      graders had inappropriate chairs. In 74% of the classes, students sat with their
      side facing the teacher and in 35% students sat with their backs. In 6% of
      schools, no physical activity is offered at recess. CONCLUSIONS: Shortcomings
      were found in all areas investigated. There is an urgent need for health
      promotion programs to increase awareness and reduce risks in the school
      environment.

PMID- 15014280
TI  - Similarities and differences in the treatment of spine trauma between surgical
      specialties and location of practice.
AB  - STUDY DESIGN: Questionnaires administered to practicing orthopedic and
      neurosurgical spine surgeons from various regions of the United States and
      abroad. OBJECTIVES: To determine similarities and differences in the treatment of
      spinal trauma. SUMMARY OF BACKGROUND DATA: Spinal trauma is generally referred to
      subspecialists of orthopedic or neurosurgical training. Prior studies have
      suggested that there is significant variability in the management of such
      injuries. METHODS: Questionnaires based on eight clinical scenarios of commonly
      encountered cervical, thoracic, and lumbar injuries were administered to 35
      experienced spinal surgeons. Surgeons completed profile information and answered
      approximately one dozen questions for each case. Data were analyzed with SPSS
      software to determine the levels of agreement and characteristics of respondents
      that might account for a lack of agreement on particular aspects of management.
      RESULTS: Of the 35 surgeons completing the questionnaire, 63% were orthopedists,
      37% were neurosurgeons, and 80% had been in practice for more than 5 years.
      Considerable agreement was found in the majority of clinical decisions, including
      whether or not to operate and the timing of surgery. Of the differences noted,
      neurosurgeons were more likely to obtain a MRI, and orthopedists were more likely
      to use autograft as a sole graft material. Physicians from abroad were, in
      general, more likely to operate and to use an anterior approach during surgery
      than physicians from the northeastern United States. CONCLUSIONS: More
      commonalities were identified in the management of spinal trauma than previously
      reported. When found, variability in opinion was related to professional and
      regional differences.

PMID- 15014282
TI  - New percutaneously inserted spinal fixation system.
AB  - STUDY DESIGN: We describe a new percutaneous minimally invasive spinal fixation
      system based on pedicle screws and inflatable rods. The rods are inserted in a
      flexible state and harden following deployment. We test this system in terms of
      biocompatibility, ferromagnetism, magnetic resonance artifact production, bench
      top mechanical testing, ease of insertion within cadavers, potential thermal
      damage to paraspinous muscles in pigs, and long-term device tolerability in
      sheep. OBJECTIVES: To determine the safety and utility of this system before its
      use in human subjects. SUMMARY OF BACKGROUND DATA: Composite materials and epoxy
      compounds have been used safely in a variety of implanted medical devices for
      years with no signs of systemic toxicity or significant device failures. METHODS:
      Long-term biocompatibility test of system components was conducted according to
      International Standards Organization 10993 and Food and Drug Administration Blue
      Book Memorandum #G95-1 standards. Device components were assessed for magnetic
      deflection and torque and imaged in a 1.5 Tesla magnetic resonance unit. Full
      constructs of the system were tested for compression strength, torque, and
      fatigue per American Society for Testing and Materials F1717 standards. The
      system was deployed using C-arm fluoroscopic guidance in 11 cadavers and 2 live
      sheep. Further, the inflatable rods were tested for exothermic damage to
      paraspinous musculature in 2 pigs. RESULTS: All system components were found to
      be biocompatible, nonferromagnetic, and produce little magnetic resonance
      artifact. Compression and torque results for the new system were found to be
      comparable to standard metallic pedicle screw and rod fixation systems. However,
      the new system displayed a superior modulus of elasticity relative to standard
      surgical systems. The new system endured 5 million cycles of repetitive
      compressions without breakage or significant wear. All cadaver and sheep
      insertions were performed successfully. Sheep suffered no complications, and
      minimal blood loss occurred during device insertions. One of the animals killed
      at 6 months demonstrated no internal organ damage. The self-curing version of
      polymer used to inflate the flexible rods cured to approximately 53% of its final
      strength in 90 minutes with maximum external rod temperature of 40.5 C. and no
      adjacent thermal damage within porcine paraspinous musculature. CONCLUSIONS: The
      new spinal fixation system is biocompatible, uses a nontoxic polymer, is magnetic
      resonance compatible, displays favorable biomechanical characteristics, can be
      easily deployed percutaneously using simple fluoroscopic guidance, is well
      tolerated in living sheep, caused no muscular thermal damage, and could be used
      in humans within a reasonable operative time frame. The new system demonstrates
      the feasibility of percutaneously constructing composite structures in situ
      within the body.

PMID- 15014283
TI  - Prevalence, incidence, and recurrence of low back pain in scaffolders during a 3
      year follow-up study.
AB  - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To describe the natural
      history of low back pain by its prevalence, incidence, and recurrence during a 3
      year period and identify risk factors for cumulative incidence and recurrence of
      low back pain in scaffolders. SUMMARY OF BACKGROUND DATA: Although some studies
      have described prevalence, incidence, or recurrence of low back pain, few studies
      have assessed two or more of these outcome measures simultaneously. Furthermore,
      little is known about the association between individual, physical, psychosocial,
      and health-related risk factors and cumulative incidence and recurrence of low
      back pain in scaffolders. METHODS: Between 1998 and 2001, a cohort of 288
      scaffolders (response 85%) completed a questionnaire at baseline and at three
      yearly follow-ups during 3 years. RESULTS: At baseline 60% of the study
      population had had an episode of low back pain in the past 12 months of which 22%
      was of chronic nature. During follow-up, the yearly incidence of low back pain
      varied between 20% and 28%, while yearly recurrence rates were 64% to 77%. Only
      few workers consistently reported the presence (20%) or absence (26%) of low back
      pain each year. Weak significant associations were present for the following: age
      35 to 44 years, moderate general health, high strenuous arm movements, and body
      mass index with the cumulative incidence of low back pain. Significant
      associations were found between high manual handling of material and high job
      demand and low job control and the cumulative recurrence of low back pain, while
      moderate general health only showed a weak significant association with this
      outcome measure. CONCLUSIONS: Low back pain was a dynamic process with high rates
      for incidence, recurrence, and recovery. General health and work-related physical
      and psychosocial factors influenced both the incidence and recurrence of low back
      pain. The incidence and recurrence of low back pain depend strongly on the recall
      period of low back pain and the time-window of investigation.

PMID- 15014284
TI  - Hip strategy for balance control in quiet standing is reduced in people with low
      back pain.
AB  - STUDY DESIGN: Quiet stance on supporting bases with different lengths and with
      different visual inputs were tested in 24 study participants with chronic low
      back pain (LBP) and 24 matched control subjects. OBJECTIVES: To evaluate postural
      adjustment strategies and visual dependence associated with LBP. SUMMARY OF
      BACKGROUND DATA: Various studies have identified balance impairments in patients
      with chronic LBP, with many possible causes suggested. Recent evidence indicates
      that study participants with LBP have impaired trunk muscle control, which may
      compromise the control of trunk and hip movement during postural adjustments
      (e.g., hip strategy). As balance on a short base emphasizes the utilization of
      the hip strategy for balance control, we hypothesized that patients with LBP
      might have difficulties standing on short bases. METHODS: Subjects stood on
      either flat surface or short base with different visual inputs. A task was
      counted as successful if balance was maintained for 70 seconds during bilateral
      stance and 30 seconds during unilateral stance. The number of successful tasks,
      horizontal shear force, and center-of-pressure motion were evaluated. RESULTS:
      The hip strategy was reduced with increased visual dependence in study
      participants with LBP. The failure rate was more than 4 times that of the
      controls in the bilateral standing task on short base with eyes closed. Analysis
      of center-of-pressure motion also showed that they have inability to initiate and
      control a hip strategy. CONCLUSIONS: The inability to control a hip strategy
      indicates a deficit of postural control and is hypothesized to result from
      altered muscle control and proprioceptive impairment.

PMID- 15014285
TI  - Atlantoaxial rotatory subluxation with ankylosis in an 11-year-old girl: a case
      report.
AB  - STUDY DESIGN: Report of an 11-year-old girl with a left atlantoaxial rotatory
      subluxation and ankylosis found 20 months after she sustained a cervical injury.
      OBJECTIVE: To describe the radiographic characteristics of this rare deformity
      assessed with a combination of spiral CT scan with multiplanar three-dimensional
      reformations and functional CT scan. SUMMARY OF BACKGROUND DATA: Atlantoaxial
      rotatory subluxation is a well-known condition, but its association with lateral
      C1-C2 ankylosis has not been reported to our knowledge. METHODS: For a complete
      assessment of the dislocation, a combined morphologic volumetric and functional
      CT study was performed. RESULTS: Spiral CT showed an atlantoaxial rotatory
      subluxation with lateral C1-C2 ankylosis. CT study also demonstrated a lateral C1
      C2 subluxation and an ipsilateral occipitoatlantal subluxation. Cervical MRI
      showed no spinal cord compression despite the seriousness of the dislocation
      process. CONCLUSIONS: Whereas "classic" spiral study with multiplanar and three
      dimensional reformations allows precise assessment of relationships between the
      upper cervical vertebrae, as well as bony changes, a functional CT study is
      essential for cervical biomechanic assessment of rotational instabilities of the
      craniovertebral junction and upper cervical spine.

PMID- 15014286
TI  - Avascular necrosis of spine: a rare appearance.
AB  - STUDY DESIGN: Avascular necrosis (AVN) of two contiguous vertebrae along with the
      intervening disc is presented. OBJECTIVES: AVN of two contiguous vertebrae and
      the intervening disc is a rare entity and can be confused with infective and
      neoplastic processes. We present the role of magnetic resonance imaging (MRI) in
      the diagnosis of AVN. SUMMARY OF BACKGROUND DATA: AVN of vertebral bodies is a
      known entity; however, involvement of two contiguous vertebrae along with the
      intervening disc is atypical. The imaging features can be confused with an
      infective etiology, which involves the disc more commonly as compared to AVN.
      Neoplastic destruction of vertebrae also needs to be ruled out in appropriate
      clinical situations. METHODS: Frontal and lateral radiographs of the lumbar spine
      were performed followed by an MRI. Subsequently CT-guided fine needle aspiration
      cytology was performed. RESULTS: These radiographic features were correlated with
      the clinical and pathologic findings. The MRI findings of a wedge-shaped lesion
      with classic fluid intensity (hyperintense signal, like that of cerebrospinal
      fluid on T2-weighted images) are characteristic of AVN. Fine needle aspiration
      cytology confirmed the diagnosis and excluded an infective or a neoplastic
      process. CONCLUSIONS: The MRI findings described in this report are very
      characteristic of AVN of spine. Clinical and radiologic correlation could help in
      making the diagnosis and avoid unnecessary investigations.

PMID- 15014288
TI  - Bone remodeling in a sheep femur.

PMID- 15014287
TI  - Extended total sacrectomy and reconstruction for sacral tumor.
AB  - STUDY DESIGN: This case report includes the results of long-term follow-up after
      extended total sacrectomy in a 13-year-old boy with a sarcoma originating in the
      sacrum with an extraskeletal extension and infiltration into the left ilium.
      OBJECTIVE: To report and discuss a case of sacral tumor treated by extended
      sacrectomy. SUMMARY OF BACKGROUND DATA: Sacral tumors are often at an advanced
      stage with a large volume at diagnosis. Although total or extended sacrectomy is
      the only radical means to treat the massive sacral tumor, unavoidable
      complications in total sacrectomy are serious in the treatment selection.
      METHODS: Initial histologic findings indicated a synovial sarcoma. Additional
      genetic analysis redesignated the tumor as an unclassified sarcoma. Preoperative
      neoadjuvant chemotherapy and radiotherapy were completed. The response to the
      preoperative treatment appeared as a reduction in tumor size (approximately 50%)
      on radiographs. After extended sacrectomy, the L5 vertebral body was fixed
      between the ilia, and the pelvic ring was compressed by the Zielke system. The
      ISOLA instrumentation system connected the lumbar spine and both ilia. All sacral
      nerve roots and the L5 root on the left side were cut. RESULTS: At the 5-year
      follow-up examination, the patient was disease-free, could walk with crutches,
      and could climb stairs using the handrail and one crutch. CONCLUSIONS: The
      patient's excellent response to preoperative antitumor treatment was considered
      crucial to the long-term outcome. But the decision between a radical resection
      with reconstruction and a less extensive procedure with combined therapy remains
      controversial.

PMID- 15014289
TI  - Safety and efficacy of trivalent inactivated influenza vaccine in young children:
      a summary for the new era of routine vaccination.
AB  - Increasing use of influenza vaccine in children is expected as this important
      virus becomes more widely recognized as a major cause of morbidity in young
      children. Clinicians and third party payers must consider the implications of
      national vaccine use recommendations, with their current focus on young children,
      on their practices and on the community at large. Two influenza vaccines are
      available in the United States, an inactivated, trivalent intramuscular
      formulation (TIV) which is approved for use among children > or =6 months of age;
      and a live, attenuated intranasal trivalent preparation (LAIV) indicated for
      healthy persons 5 to 49 years of age. This review summarizes available data
      regarding the safety and efficacy of TIV, in comparison with LAIV, with
      particular attention to children <9 years of age, the population for whom two
      doses of vaccine are recommended for first time vaccination. It is apparent that
      relatively few data are available on the safety of TIV in young children, that
      important age-specific differences in TIV vaccine efficacy exist and that LAIV
      appears similar to TIV with regard to safety and efficacy in younger children,
      but no head-to-head comparison of these two licensed products is available.

PMID- 15014292
TI  - Vancomycin usage in central venous catheters in a neonatal intensive care unit.
AB  - BACKGROUND: We previously reported that vancomycin in hyperalimentation solution
      reduces catheter-related infections in the neonatal intensive care unit. Since
      June 1993 vancomycin (25 microg/ml) was routinely added to central venous
      catheter solutions, primarily hyperalimentation solution. Because the
      prophylactic use of vancomycin could lead to the emergence of resistant
      organisms, the decision to discontinue this practice was made in April of 1999.
      The use of vancomycin was reserved for documented infections with vancomycin
      susceptible organisms. OBJECTIVE: To compare catheter longevity, rate of
      laboratory-confirmed blood stream infections and total vancomycin exposure
      between two 18-month periods before and after the cessation of prophylactic
      vancomycin use. METHODS: Data were evaluated for every neonate in whom a
      percutaneous central venous catheter was placed. RESULTS: There were 394 neonates
      enrolled. No statistically significant difference was identified between the two
      periods regarding the mean catheter days or number of catheters per patient.
      There was a higher rate of Gram-negative laboratory-confirmed blood stream
      infections during Period I in patients with percutaneous central venous catheters
      in place. There were more isolates of coagulase-negative staphylococci in Period
      II, resulting in more frequent vancomycin therapy institution and thus an overall
      increase in the amount of vancomycin used in that period CONCLUSION:
      Discontinuing the use of prophylactic vancomycin resulted in exposure of fewer
      neonates to vancomycin but a higher total amount of vancomycin used. The impact
      of low dose widespread exposure to vancomycin vs. high dose limited exposure on
      the microbiologic flora in the neonatal intensive care unit should be further
      examined.

PMID- 15014293
TI  - Infant immune response to human rotavirus serotype G1 vaccine candidate
      reassortant WI79-9: different dose response patterns to virus surface proteins
      VP7 and VP4.
AB  - BACKGROUND: Rotavirus is the leading cause of morbidity from gastroenteritis in
      the developed world and the leading cause of mortality from viral gastroenteritis
      (estimated 600000 deaths) worldwide. G1 is the most prevalent human serotype.
      Reassortant rotavirus between simian rotavirus RRV or bovine rotavirus WC3 and
      human strain rotaviruses have been extensively tested as candidate vaccines.
      Rotavirus (RV) reassortant strain WI79-9 consists of a human (strain WI79) G1
      serotype VP7 surface protein on a bovine (strain WC3) background. It is a key
      component of a pentavalent (G1, G2, G3, G4 and P1) WC3 reassortant vaccine
      candidate, RotaTeq, now being tested in Phase III clinical trials. METHODS: We
      studied 84 infants between the ages of 2 and 8 months who received 3 oral doses
      of WI79-9. Serum neutralizing antibody was measured to the human (WI79 serotype
      P1 G1) and bovine (WC3 serotype P7 G6) parent RV after each dose. A significant
      response was defined as a > or =3-fold rise in antibody titer between the predose
      and postdose sera. RESULTS: In two separate cohorts of vaccinees given three
      doses of WI79-9 reassortant rotavirus, 68 to 75% of infants demonstrated a
      significant response to WC3 (VP4, P7) after Dose 1, fewer (24 to 39%) responses
      were detected after Dose 2 and rare (0 to 4%) additional responses occurred after
      Dose 3. The cumulative response rate to WC3 after three doses was 95% in both
      trials. In contrast 23 to 37% had a significant response to WI79 (VP7, G1) after
      Dose 1, and 57 to 61% had a significant response after Dose 2. Additional
      significant responses after Dose 3 led to a cumulative response of 70 to 84%.
      CONCLUSION: Two doses of G1 reassortant WI79 were necessary to induce significant
      antibody responses to human G1 (VP7) antigen in >50% of infants. Three doses were
      required to achieve significant antibody responses to VP7 in >70% of infants.

PMID- 15014294
TI  - Comparison of pulsed field gel electrophoresis patterns of Bordetella pertussis
      isolates from unvaccinated children with severe or mild pertussis.
AB  - BACKGROUND: The clinical spectrum of pertussis ranges from mild cough illnesses
      of short duration to typical illness with paroxysmal cough, whooping and
      posttussive vomiting. We performed comparative genotyping of Bordetella pertussis
      isolates from children in Germany with severe or mild pertussis. METHODS: Pulsed
      field gel electrophoresis (PFGE) of genomic DNA, digested with the restriction
      endonucleases Xba I and Spe I, was used to determine the profiles of strains
      isolated from 31 unvaccinated children with severe symptoms of pertussis (with
      hospitalization and/or complications) compared with isolates from 32 matched
      children with mild symptoms. RESULTS: No significant differences in PFGE patterns
      were found in B. pertussis strains isolated from children with severe vs. mild
      illness. CONCLUSIONS: Differences in virulence of circulating B. pertussis
      strains can be absent or might not correlate with specific PFGE patterns. Other
      methods should be evaluated to identify differences in virulence.

PMID- 15014295
TI  - Genetic diversity of Chlamydia trachomatis and the prevalence of trachoma.
AB  - BACKGROUND: Considerable variation in the outer membrane protein (ompA) of
      Chlamydia trachomatis has been uncovered by immunotyping and, more recently, by
      genotyping. This diversity may assist Chlamydia in evading the human immune
      system; organisms may have a competitive advantage if they infect a host who has
      previously been infected only by other strains. If so, a diverse set of strains
      may attain a higher prevalence in a community than a single strain. We determined
      the predominant strains of ocular C. trachomatis in trachoma-endemic villages of
      Nepal and tested the hypothesis that strain diversity is associated with the
      prevalence of infection. METHODS: Major outer membrane protein gene sequences of
      chlamydial isolates were determined from ligase chain reaction-positive eye swab
      samples collected from 10 villages. The diversity of genovars was determined for
      each village, using Simpson's index. RESULTS: Two genovar families (Ba and C) and
      nine genovars were detected, with a single genovar (C1) comprising more than one
      half of the samples. The prevalence of clinically active trachoma was
      significantly associated with the genetic diversity in a village, controlling for
      village size and number of samples taken in a village. CONCLUSION: Genetic
      diversity of C. trachomatis is associated with the prevalence of infection in a
      community, consistent with the hypothesis that diversity may be necessary to
      attain a high prevalence in a community.

PMID- 15014296
TI  - Use of a computerized database to study the effectiveness of an attenuated
      varicella vaccine.
AB  - BACKGROUND: The varicella vaccine Varilrix (GlaxoSmithKline) was introduced in
      Israel in June 2000 as an optional vaccination for children. METHODS: We used the
      database of a single health maintenance organization that serves 25% of the
      population in Israel to assess the effectiveness of the vaccine retrospectively.
      Incidence and complications of varicella were derived from the database from
      January 1, 1998 until December 31, 2002. RESULTS: Since licensure >30000
      individuals younger than 10 years in this health maintenance organization have
      been immunized with the vaccine. Annual incidence of disease per 1000 in the
      study population was 86.6 in 1998, 74.6 in 1999, 74.0 in 2000, 37.1 in 2001 and
      44.6 in 2002. This declining trend in incidence of disease was statistically
      significant. Complications of varicella occurred in approximately 1% of patients
      throughout the 5-year study period, but there was a parallel decline in the
      number of patients with complications corresponding to the decline in disease
      incidence. Vaccine effectiveness for prevention of clinical disease in this
      population was 92% (95% confidence interval, 91.0 to 92.7). There were varying
      rates of utilization within communities of varied socioeconomic class, so that in
      the higher socioeconomic class there was an increased utilization and a
      corresponding decrease of attack rate; whereas in communities where there were
      lower utilization rates, corresponding increased numbers of varicella cases were
      seen. CONCLUSION: This database enables long term follow-up of the effectiveness
      of this vaccine in a large population.

PMID- 15014297
TI  - Double blind comparison of ibuprofen and paracetamol for adjunctive treatment of
      uncomplicated typhoid fever.
AB  - BACKGROUND: Antipyretics reduce the prolonged, high fever characteristic of
      typhoid fever. The benefits of nonsteroidal drugs in this role have not been
      quantified. There have been concerns about the safety of antipyretics in typhoid.
      METHODS: In a double blind randomized study, 80 Vietnamese children with
      uncomplicated typhoid fever were randomized to receive identical syrup
      preparations of ibuprofen (10 mg/kg) or paracetamol (12 mg/kg) every 6 h until 36
      h after defervescence. Children with a nalidixic acid-susceptible (Na) isolate of
      Salmonella typhi were treated with ofloxacin (15 mg/kg/day) for 3 days and those
      with a nalidixic acid-resistant (Na) isolate were treated for 7 days. RESULTS: S.
      typhi was isolated from 36 of 40 children randomized to ibuprofen (11 isolates
      Na) and 37 of 40 randomized to paracetamol (13 isolates Na). The median (range)
      fever clearance time (hours) was shorter in the ibuprofen group than the
      paracetamol group (68, 4 to 260 vs. 104, 12 to 404; P = 0.055) as was the area
      under the temperature time curve above 37 degree C (74, 0 to 237 vs. 127, 0 to
      573; P = 0.013). The differences occurred predominantly in the children infected
      with a NaS. typhi whose infections responded more slowly to antibiotic treatment.
      There were no major side effects associated with the use of either drug. There
      were no differences between the two treatment arms in the concentrations of
      circulating interleukin-6 and tumor necrosis factor alpha during the course of
      treatment. CONCLUSION: The antipyretic effect of ibuprofen is superior to that of
      paracetamol in children with typhoid fever, particularly those with prolonged
      fever. Both antipyretics appeared to be safe.

PMID- 15014298
TI  - Risk factors for surgical site infections after pediatric cardiovascular surgery.
AB  - BACKGROUND: Although risk factors for surgical site infection (SSI) after
      cardiovascular (CV) surgery have been well-documented among adults, few studies
      have been conducted in children. We performed a case-control study to identify
      risk factors for hospitalized SSI in children undergoing CV surgery. METHODS:
      National Nosocomial Infections Surveillance System criteria were used
      prospectively to identify cases of hospitalized SSI in patients who underwent CV
      surgery. Seventy-nine patients who underwent CV surgery without hospitalized SSI
      were randomly selected as controls. Cases were compared with controls to
      determine preoperative, intraoperative and postoperative risk factors for
      hospitalized SSI. Multivariable logistic regression was performed. RESULTS: An
      SSI developed in 19 of the 826 patients who underwent CV surgery (2.3 cases per
      100 surgeries) during the study period. Infection was limited to soft tissue in
      12, whereas deeper infection occurred in 7. Causative agents included
      Staphylococcus aureus (11), coagulase-negative Staphylococcus (5) and Escherichia
      coli (2). One patient did not have a pathogen isolated. In a multivariable
      analysis, duration of surgery (odds ratio, 1.4; 95% confidence interval, 1.2 to
      1.8) and age <1 month (odds ratio, 14; 95% confidence interval, 3.3 to 58.4) were
      independently associated with SSI. CONCLUSIONS: Age <1 month and longer duration
      of surgery were independently associated with hospitalized SSI after CV surgery
      in children.

PMID- 15014299
TI  - Thyroid dysfunction in antiretroviral treated children.
AB  - BACKGROUND: A high rate of thyroid disorders has been described in HIV-infected
      adults treated with highly active antiretroviral therapy (HAART), but data on
      children are lacking. We aimed to assess thyroid function in pediatric patients.
      METHODS: Fifty-two HIV-infected children receiving HAART were assessed for signs
      of thyroid dysfunction and serum concentrations of thyrotropin (TSH), free
      thyroxin (FT4), free triiodothyronine (FT3), thyroglobulin (TG), reverse
      triiodothyronine (rT3), anti-TG and antimicrosomal (anti-TSM) antibodies.
      RESULTS: Eighteen (35%) children showed thyroid abnormalities: isolated low FT4
      value in 16; subclinical hypothyroidism in 1; and symptomatic hypothyroidism in
      1. Children with low FT4 values as compared with the 34 children without thyroid
      dysfunction were similar for stage of disease, number of patients with
      undetectable HIV-RNA, FT3, TSH, TG, rT3, anti-TSM and anti-TG values, whereas
      they had shorter duration of HAART exposure (P = 0.019) and lower CD4 cell
      percentage (P = 0.035). The thyrotropin-releasing hormone (TRH) test was normal
      in all children with low FT4 values. Among children with low FT4, FT4
      concentrations correlated positively with CD4 cell percentage (P < 0.05) and
      duration of HAART exposure (P < 0.05). The case with subclinical hypothyroidism
      had high basal TSH (7.3 microunits/ml), normal TSH response to TRH test and
      normal FT4, FT3, TG, rT3, anti-TG and anti-TSM antibodies. The case with
      symptomatic hypothyroidism had low FT4 (6.6 pg/ml) and high TSH (44
      microunits/ml), TG (55 ng/ml), anti-TG (666 IU/ml) and anti-TSM (123 IU/ml).
      CONCLUSION: Thyroid abnormalities occur frequently in HAART-treated children even
      in the absence of clinical symptoms. These data suggest a need of regular thyroid
      function monitoring.

PMID- 15014300
TI  - Concomitant administration of a bivalent Haemophilus influenzae type b-hepatitis
      B vaccine, measles-mumps-rubella vaccine and varicella vaccine: safety,
      tolerability and immunogenicity.
AB  - BACKGROUND: The study was done to verify that concomitant administration of a
      bivalent Haemophilus influenzae type b-hepatitis B vaccine (Comvax), measles
      mumps-rubella vaccine (M-M-RII) and varicella vaccine (Varivax) would be well
      tolerated and suitably immunogenic with respect to all vaccine antigens. METHODS:
      We randomized 822 healthy 12- to 15-month-old children (1:1) to receive
      concomitant injections of Comvax, M-M-RII and Varivax (concomitant group) or
      Comvax followed 6 weeks later by injections of M-M-RII and Varivax
      (nonconcomitant group). Blood samples taken before and 6 weeks after vaccination
      were tested for antibodies to all vaccine antigens. RESULTS: Vaccinations were
      generally well-tolerated. Children in the concomitant and nonconcomitant
      treatment groups were similar with respect to the safety endpoint of primary
      interest (16.1 and 19.5%, respectively, had a fever > or =103 degree F rectally
      at any time within 14 days after either of two clinic visits). Fifteen serious
      adverse events were reported (eight in the concomitant group and seven in the
      nonconcomitant group); all resolved. Elements of two serious adverse events
      (fever, fever and measles-like rash; both in concomitant group children) were
      considered possibly related to vaccination. One child was withdrawn from the
      study because of a nonserious adverse event subsequently judged to be unrelated
      to vaccination. Similar proportions of vaccinees in the concomitant and
      nonconcomitant groups developed satisfactory antibody responses to the H.
      influenzae polysaccharide, polyribosylribitol phosphate (97.8 to 98.7%),
      hepatitis B surface antigen (99.2 to 100%), measles virus (99.4 to 99.6%), mumps
      virus (98.4 to 99.2%), rubella virus (100%) and varicella virus (93.2 to 94.6%).
      CONCLUSION: Concomitant administration of Comvax, M-M-RII and VARIVAX at the 12-
      or 15-month clinic visit is one satisfactory way of delivering some of the
      multiple vaccines indicated during the second year of life.

PMID- 15014301
TI  - National study of infants hospitalized with pertussis in the acellular vaccine
      era.
AB  - BACKGROUND: In Australia in 1999 acellular pertussis vaccine (DTPa) replaced
      locally manufactured whole cell vaccine given at 2, 4 and 6 months of age with
      coverage of about 95% by 12 months of age. Few data are available on pertussis
      hospitalizations or sources of infection in countries exclusively using DTPa.
      METHODS: In 2001 national active monthly surveillance of infant hospitalizations
      for pertussis was conducted through the Australian Pediatric Surveillance Unit,
      which surveys all child health specialists monthly. A standard questionnaire was
      completed for notified cases. RESULTS: There were 140 infants reported (median
      age at diagnosis, 8 weeks). The rate of hospitalization in indigenous infants was
      significantly higher than in nonindigenous infants (P < 0.01). Of 97 (69%)
      infants who had not been vaccinated for pertussis, 63 (65%) were <8 weeks old
      (before the first scheduled dose of DTPa vaccine). Of 76 infants age > or =8
      weeks, only 28 (37%) were appropriately immunized for age. Of 68 coughing
      contacts whose ages were known, 46 (68%) were adults, usually one of the infant's
      parents. Of 32 child contacts 16 (50%) were siblings. Four infants <6 weeks old
      died. CONCLUSION: Despite universal vaccination with DTPa in Australia, pertussis
      remains an important cause of hospitalization, morbidity and death in infants,
      most of whom were too young to be vaccinated or had missed vaccinations. The most
      common source of infection was a parent. Strategies to improve pertussis control
      in countries with high DTPa coverage could include adult-formulated booster
      pertussis vaccines for adolescents and recent parents and/or accelerated
      pertussis vaccine schedules for infants.

PMID- 15014302
TI  - The puzzling picture of acute necrotizing encephalopathy after influenza A and B
      virus infection in young children.
AB  - Acute necrotizing encephalopathy is a complication of influenza A and B virus
      infection in young children, especially in Japan. The disease is characterized by
      high fever, convulsions and coma. A prominent feature of this central nervous
      system disease is bilateral thalamic necrosis, documented by magnetic resonance
      imaging. The pathogenesis of the virus-associated brain pathology has not yet
      been elucidated. There is considerable circumstantial evidence that influenza
      immunization may decrease the likelihood of children developing acute necrotizing
      encephalopathy.

PMID- 15014303
TI  - Management of acute hematogenous osteomyelitis in children.

PMID- 15014304
TI  - Treatment of hepatitis C in children.

PMID- 15014305
TI  - Influenza A virus-associated acute necrotizing encephalopathy in the United
      States.
AB  - During the past several years, influenza-associated acute necrotizing
      encephalopathy has been well-recognized in Asia but has not yet been reported in
      the United States. We describe a 28-month-old patient who displayed the classical
      clinical features of acute necrotizing encephalopathy in association with a
      documented influenza A infection. This disease is characterized by fever, a rapid
      alteration in consciousness and seizures, with radiologic involvement of the
      bilateral thalami and cerebellum.

PMID- 15014307
TI  - Concurrent serious bacterial infections in 912 infants and children hospitalized
      for treatment of respiratory syncytial virus lower respiratory tract infection.
AB  - The objective of this study was to report the frequency of concurrent serious
      bacterial infections in infants and young children hospitalized for treatment of
      respiratory syncytial virus (RSV) lower respiratory tract infection. Data were
      collected through a retrospective review of the medical records of all 912
      patients with a discharge diagnosis of RSV bronchiolitis or pneumonia between
      July 1, 2000 and June 30, 2002. Two (0.43%) of 470 patients tested had a positive
      blood culture; both patients were >90 days of age. None of 101 patients tested
      had a positive cerebrospinal fluid culture, and 28 of 234 (12.0%) patients tested
      had a positive urine culture. Routine sepsis and meningitis workups are not
      necessary in non-toxic-appearing infants and young children with RSV lower
      respiratory tract infection.

PMID- 15014306
TI  - Oral valganciclovir in children: single dose pharmacokinetics in a six-year-old
      girl.
AB  - We report a pharmacokinetic study in a 6-year-old girl with congenital human
      immunodeficiency virus type 1 and cytomegalovirus coinfection maintained on iv
      ganciclovir for 6 years. Increasing infection and thrombosis caused by her iv
      device necessitated alternative therapy. Single dose pharmacokinetics of
      ganciclovir 4.4 mg/kg iv and valganciclovir 13.2 and 26.3 mg/kg po were studied
      with high performance liquid chromatography/tandem mass spectrometry. The two
      oral dosages yielded areas under the concentration curve of 14.3 and 28.7 microg
      x h/ml, equivalent to 43% bioavailability of ganciclovir from valganciclovir,
      which exceeded the area under the concentration curve of 11.1 microg x h/ml
      yielded by ganciclovir 4.4 mg/kg iv. Oral valganciclovir achieved therapeutic and
      dosage-proportional plasma concentrations in the child we studied.

PMID- 15014308
TI  - Immunogenicity of the seven valent pneumococcal conjugate vaccine in patients
      with ataxia-telangiectasia.
AB  - Immune responses to a 7-valent pneumococcal conjugate vaccine were determined in
      10 patients with ataxia-telangiectasia who are at high risk for pneumococcal
      disease because of immunodeficiency. Pneumococcal antibody titers for 7 serotypes
      measured increased 2.0- to 7.5-fold after immunization.

PMID- 15014309
TI  - Amantadine penetration into cerebrospinal fluid of a child with influenza A
      encephalitis.
AB  - The use of amantadine has been advocated as treatment for influenza A
      encephalitis despite limited information regarding cerebrospinal fluid
      concentrations and the pathogenesis of encephalitis associated with influenza
      virus infections. We report a 2-year-old child with influenza A encephalitis
      treated with amantadine who achieved a potentially therapeutic concentration in
      cerebrospinal fluid. Despite this the child developed significant neurologic
      impairment.

PMID- 15014310
TI  - Vertical transmission of toxoplasmosis from a chronically infected
      immunocompetent woman.
AB  - We report the vertical transmission of congenital toxoplasmosis from a
      chronically infected immunocompetent woman to her child. On the background of
      published knowledge in this field, vertical transmission must have developed
      after maternal reinfection or reactivation of the preexisting disease.

PMID- 15014311
TI  - Fatal coxsackievirus A16 infection.
AB  - A 15-month-old boy presenting with hand, foot and mouth disease died of
      myocarditis and intractable shock caused by coxsackievirus A16 infection. It is
      apparent that coxsackievirus A16 infection is not always a benign infection.

PMID- 15014312
TI  - Gardnerella vaginalis-infected scalp hematoma associated with electronic fetal
      monitoring.
AB  - Infections in the neonate caused by the vaginal commensal Gardnerella vaginalis
      are rare and mostly consist of bacteremia. A 4130-g term neonate developed an
      infection of a scalp hematoma with G. vaginalis. The infection developed in
      association with electronic fetal monitoring. The only clinical sign was an
      increase in size of the hematoma.

PMID- 15014313
TI  - Mother-to-child transmission of cryptococcus neoformans.
AB  - Cryptococcal meningitis was diagnosed in a 92-day-old boy who was not HIV-1
      infected and who survived after treatment, although with hydrocephalus. The
      mother was HIV-1-infected, delivered prematurely, had peripartum cryptococcal
      meningitis and died 14 days postpartum. There was no other possible source for
      cryptococcal infection in this infant. This is believed to be a case of mother-to
      child transmission of cryptococcosis.

PMID- 15014314
TI  - Pericarditis after meningococcal infection: case report of a child with two
      distinct episodes.
AB  - Pericarditis is a recognized consequence of meningococcal disease. The incidence
      among all age groups is 3 to 19%. Repeated episodes of pericarditis after
      meningococcal disease have been reported previously in two adults but not in
      children. We describe the clinical and laboratory features of a child with two
      distinct episodes of pericarditis after Neisseria meningitidis serogroup C
      infection.

PMID- 15014315
TI  - Nontypable haemophilus influenzae meningitis in an eleven-year-old.

PMID- 15014316
TI  - Correlation between bacteriologic eradication and clinical cure in acute otitis
      media.

PMID- 15014318
TI  - Newborn with suppurative nasal discharge and respiratory distress.

PMID- 15014319
TI  - Procalcitonin and C-reactive protein in vaccination-associated adverse reactions.

PMID- 15014320
TI  - Risk of severe respiratory syncytial virus disease, identification of high risk
      infants and recommendations for prophylaxis with palivizumab.

PMID- 15014338
TI  - Predictors of lower extremity injuries at the community level of Australian
      football.
AB  - OBJECTIVE: To identify risk factors for general lower extremity injury at the
      community level of Australian football. DESIGN: Prospective cohort study.
      SETTING: Community-level Australian football. PARTICIPANTS: One hundred twenty
      six adult players from 4 community-level Australian football clubs. METHODS:
      During the 2000 preseason period, all participants underwent a baseline
      assessment involving a self-report questionnaire and a battery of musculoskeletal
      screening tests to collect information about potential risk factors for lower
      extremity injury. Over the course of the season, injury surveillance and exposure
      data collection were undertaken at each club. MAIN OUTCOME MEASURE: A lower
      extremity injury, resulting in missed participation and/or treatment from a
      health professional, as the first injury during the season. RESULTS: For 59
      players, a lower extremity injury was the first injury sustained during the
      season. Only ankle dorsiflexion range of movement, measured using the
      weightbearing lunge test, was significantly associated with sustaining a lower
      extremity injury through univariate analyses. Using survival analyses, and after
      adjusting for exposure, age, frequency of weight training participation, and the
      past injury status of players were identified as independent, but not
      significant, predictors of time to sustaining a lower extremity injury.
      CONCLUSIONS: Despite the large number of potential risk factors studied and the
      high incidence of lower extremity injuries in the cohort, a definitive individual
      injury risk profile for all lower extremity injuries was not identified,
      potentially due to the heterogeneity of the outcome of interest. Further research
      should focus on the identification of risk factors for the most common and costly
      individual injuries in Australian football.

PMID- 15014339
TI  - Wrist fractures from snowboarding: a prospective study for 3 seasons from 1998 to
      2001.
AB  - OBJECTIVES: To elucidate the epidemiology and the mechanisms of snowboarding
      wrist injuries, especially distal radial fractures. DESIGN: A prospective survey
      of snowboarders with distal radial fractures. PARTICIPANTS: From November 21,
      1998, to April 22, 2001, we analyzed and interviewed 5110 injured snowboarders,
      and a total of 740 snowboarders with distal radial fractures were studied. On the
      basis of the medical records and radiographs, the severity of distal radial
      fracture was analyzed according to the AO classification. RESULTS: Distal radial
      fractures occurred at a rate of 0.31 per 1000 snowboarder visits and were
      assessed in 740 snowboarders in this study. Most of the injured snowboarders were
      either of beginner (42.0%) or intermediate level (48.1%). The most common events
      leading to an injury in snowboarding were falling (59.6%) and jumping (36.1%).
      Comminuted and articular fractures classified as AO types A3, B, and C, which
      required surgical treatment, made up 63.2% of distal radial fractures in
      snowboarders. The most remarkable differences between the first-time or beginner
      group and the intermediate or expert group were that the former had a
      significantly higher proportions of extra-articular fractures classified as AO
      type A (P < 0.05), and the latter were significantly more likely to have
      compression or complex intra-articular fractures such as AO type C (P < 0.05).
      Furthermore, first-time or beginner snowboarders were more likely to be injured
      because of a simple fall than were the intermediates or experts (P < 0.05). Over
      60% of distal radial fractures classified as AO type C in the intermediate or
      expert group resulted from jumping. Furthermore, the side opposite to the
      snowboarder's preferred direction of stance was more often affected. A high
      incidence of injury during opposite-side edging, which is used more frequently in
      snowboarding, was found in novice female snowboarders. CONCLUSIONS: This study
      suggested several patterns in the nature of wrist injuries sustained while
      snowboarding, and these facts should be taken into consideration in the diagnosis
      of wrist injuries in snowboarders.

PMID- 15014340
TI  - Incidence study of head blows and concussions in competition taekwondo.
AB  - OBJECTIVE: To examine the incidence of head blows and concussions in competition
      taekwondo. DESIGN: Incidence cohort design. SETTING: Taekwondo tournament in
      2001, in South Korea. PARTICIPANTS: A total of 2328 competitors (female, 676;
      male, 1652; age, 11-19 years) from 424 schools participated in the tournament.
      All recipients of head blows were interviewed immediately after the match. All
      matches were recorded on videotape. MAIN OUTCOME MEASURES: Head blow and
      concussion rates were calculated. Also, factors associated with head blows and
      concussions were analyzed. RESULTS: The incidence of head blows and concussions
      was 226 and 50 per 1000 athlete exposures, respectively. Only 17% of competitors
      reported that they had had a concussion in the last 12 months. A multinomial
      logistic model showed that head blows and concussions were associated with young
      age and a lack of blocking skills. CONCLUSIONS: The incidence of head blows and
      concussions is high in competition taekwondo. Promoting blocking skills to
      prevent head blows could decrease concussions in taekwondo.

PMID- 15014341
TI  - Head injuries presenting to emergency departments in the United States from 1990
      to 1999 for ice hockey, soccer, and football.
AB  - STUDY OBJECTIVE: To examine the number and rates of head injuries occurring in
      the community as a whole for the team sports of ice hockey, soccer, and football
      by analyzing data from patients presenting to US emergency departments (EDs) from
      1990 to 1999. DESIGN: Retrospective analysis. MAIN OUTCOME MEASURES: Data
      compiled for the US Consumer Product Safety Commission using the National
      Electronic Injury Surveillance System were used to generate estimates for the
      total number of head injuries, concussions, internal head injuries, and skull
      fractures occurring on a national level from the years 1990 to 1999. These data
      were combined with yearly participation figures to generate rates of injuries
      presenting to the ED for each sport. RESULTS: There were an estimated 17,008 head
      injuries from ice hockey, 86,697 from soccer, and 204,802 from football that
      presented to US EDs from 1990 to 1999. The total number of concussions presenting
      to EDs in the United States over the same period was estimated to be 4820 from
      ice hockey, 21,715 from soccer, and 68,861 from football. While the rates of head
      injuries, concussions, and combined concussions/internal head injuries/skull
      fractures presenting to EDs per 10,000 players were not always statistically
      similar for all 3 sports in each year data were available, they were usually
      comparable. CONCLUSION: While the total numbers of head injuries, concussions,
      and combined concussions/skull fractures/internal head injuries presenting to EDs
      in the United States are different for ice hockey, soccer, and football for the
      years studied, the yearly rates for these injuries are comparable among all 3
      sports.

PMID- 15014342
TI  - Effect of neuromuscular training on proprioception, balance, muscle strength, and
      lower limb function in female team handball players.
AB  - OBJECTIVE: Introduction of a neuromuscular training program will increase muscle
      strength, balance, and proprioception in elite female handball players. DESIGN:
      Prospective intervention study. PARTICIPANTS: Thirty-five female team handball
      players from 2 teams in the elite division participated. Their mean age was 23
      (+/-2.5) years, and their mean weight was 69.2 (+/-7.3) kg. They had played
      handball for 14.9 (+/-3.2) years, 4.7 (+/-2.8) years at the top level. The total
      number of training hours per week was 10 to 11. INTERVENTION: Based on earlier
      studies and knowledge about common risk situations in team handball, an anterior
      cruciate ligament (ACL) injury prevention program with 3 different sets of
      exercises was developed, each set with a 5-step progression from simple to more
      challenging exercises. The teams were instructed to use the program a minimum of
      3 times a week during a training period of 5 to 7 weeks, and then once a week
      during the season. The duration of each training session was approximately 15
      minutes. MAIN OUTCOME MEASURES: Balance (KAT 2000), proprioception (threshold to
      detection of passive motion), muscle strength (Cybex 6000), and 3 functional knee
      tests. The players were tested pretraining (test 1) and 8 weeks (test 2) and 12
      months (test 3) after the training started. RESULTS: There was a significant
      improvement in dynamic balance between test 1 and test 2, with a balance index
      (BI) of 924 (+/-225) and 778 (+/-174), respectively (P = 0.01). The effect on
      dynamic balance was maintained 1 year after training (BI, 730 +/- 156). For
      static balance, no statistically significant changes were found. For the other
      variables measured, there were no statistical differences during the study
      period. CONCLUSION: The ACL injury prevention training program improved dynamic
      balance in an elite team handball players.

PMID- 15014343
TI  - Umbilical and bilateral inguinal hernias in a veteran powerlifter: is it a
      pressure-overload syndrome?
AB  - Umbilical, inguinal and hiatal hernias are all thought to occur from basically
      the same etiology, a malformation in the tissue leading to herniation. The
      mechanisms for these malformations range from congenital to degenerative. Earlier
      studies proposed that hiatal hernias result from age-related degenerative changes
      in the phrenoesophageal ligament leading to subsequent herniation. We found that
      hiatal hernias occur in young power athletes secondary to intra-abdominal
      pressure overload of the phrenoesophageal ligament. We present a case of
      umbilical and bilateral inguinal hernias occurring in a veteran powerlifter. The
      pathogenesis of multiple hernias and the physiological pressure systems involved
      in the development of multiple hernias in a power athlete are discussed.

PMID- 15014345
TI  - Acute exertional compartment syndrome of the leg: consequences of a delay in
      diagnosis: a report of 2 cases.

PMID- 15014346
TI  - Urachal cyst in a collegiate football player.

PMID- 15014348
TI  - Quadriceps strength as a predictor of knee osteoarthritis progression.

PMID- 15014347
TI  - Exercise and risk of hip fracture in postmenopausal women.

PMID- 15014349
TI  - Extracorporeal shock wave therapy for lateral epicondylitis.

PMID- 15014350
TI  - Combretastatin A4 phosphate.
AB  - Combretastatin A4 phosphate (CA4P) is a water-soluble prodrug of combretastatin
      A4 (CA4). The vascular targeting agent CA4 is a microtubule depolymerizing agent.
      The mechanism of action of the drug is thought to involve the binding of CA4 to
      tubulin leading to cytoskeletal and then morphological changes in endothelial
      cells. These changes increase vascular permeability and disrupt tumor blood flow.
      In experimental tumors, anti-vascular effects are seen within minutes of drug
      administration and rapidly lead to extensive ischemic necrosis in areas that are
      often resistant to conventional anti-cancer treatments. Following single-dose
      administration a viable tumor rim typically remains from which tumor regrowth
      occurs. When given in combination with therapies targeted at the proliferating
      viable rim, enhanced tumor responses are seen and in some cases cures. Results
      from the first clinical trials have shown that CA4P monotherapy is safe and
      reduces tumor blood flow. There has been some promising demonstration of
      efficacy. CA4P in combination with cisplatin is also safe. Functional imaging
      studies have been used to aid the selection of doses for phase II trials. Both
      dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and positron
      emission tomography can measure the anti-vascular effects of CA4P in humans. This
      review describes the background to the development of CA4P, its proposed
      mechanism of action, the results from the first clinical trials with CA4P and the
      role of imaging techniques in its clinical development.

PMID- 15014351
TI  - Emerging antibody-targeted therapy in leukemia and lymphoma: current concepts and
      clinical implications.
AB  - The success of immune-mediated therapies has encouraged studies on passive and
      active immunotherapy in leukemia and lymphoma. This review outlines the impact of
      increasing insights from basic immunology studies on the potentiation of
      effective immune responses and the identification of new antigens as targets for
      antibody (Ab)-targeted therapies. The principles of treatment in leukemia and
      lymphoma based on current knowledge on the classification of hematologic
      malignancies are reviewed, and discussed in the context of a rationale to
      implement new Ab-targeted immunotherapeutic approaches. An update is provided on
      the use of Ab-targeted therapies in clinical trials with emphasis on new emerging
      strategies to further expand the successful field of immunotherapy in leukemia
      and lymphoma.

PMID- 15014352
TI  - Treatment of advanced pancreatic cancer with opioid growth factor: phase I.
AB  - Opioid growth factor (OGF) is an endogenous pentapeptide that inhibits growth of
      human pancreatic cancer cells in culture, as well as xenografts in nude mice. To
      establish the maximum tolerated dose (MTD), and determine safety and toxicity of
      OGF, a phase I trial was performed in patients with advanced unresectable
      pancreatic cancer. Patients with unresectable pancreatic adenocarcinoma were
      treated with escalating doses of OGF for 30 min i.v. to determine the MTD. The
      s.c. route of administration also was evaluated. Once the MTD was established, a
      group of patients was treated chronically, and monitored for safety and toxicity.
      Hypotension was the dose-limiting toxicity, resulting in a MTD of 250 microg/kg
      i.v. Due to limited solubility of OGF in small volumes, a maximum dose of 50
      microg/kg twice daily was determined by the s.c. route of administration. No
      adverse events were reported for oxygen saturation, cardiac rhythm, laboratory
      values or neurological status in either the acute or chronic parts of the study
      with the i.v. or s.c. routes. During the chronic i.v. phase, two subjects had
      resolution of liver metastases and one showed regression of the pancreatic tumor.
      Mean survival from the time of diagnosis was 8.7 months (range 2-23 months) in
      the i.v. group and 9.5 months (range 1-18 months) in the s.c. group. We conclude
      that OGF can be safely administered to patients with advanced pancreatic cancer.
      Further studies are needed to determine the efficacy of OGF alone or in
      combination with present modes of therapy for the treatment of pancreatic cancer.

PMID- 15014353
TI  - Phase I dose-finding study of biweekly irinotecan in combination with fixed doses
      of 5-fluorouracil/leucovorin, gemcitabine and cisplatin (G-FLIP) in patients with
      advanced pancreatic cancer or other solid tumors.
AB  - This phase I trial was initiated based on encouraging clinical data with 5
      fluorouracil (5-FU)/leucovorin (LV), gemcitabine and cisplatin (G-FLIP) in the
      therapy of solid tumors. In this trial, G-FLIP has been modified to facilitate
      outpatient administration and to optimize sequence-dependent synergistic
      activity. Treatment consisted of biweekly (once every 14 days) cycles of
      sequential gemcitabine 500 mg/m, irinotecan per dose escalation schedule, bolus 5
      FU 400 mg/m and LV 300 mg on day 1 followed by a 24-h 5-FU infusion 1500 mg/m,
      followed by cisplatin 35 mg/m on day 2. The irinotecan starting dose was 80 mg/m
      and escalated by 20 mg/m in cohorts of three patients until the maximum tolerated
      dose (MTD) was defined. Twenty-three patients were enrolled (13 men/10 women)
      with the following cancers: 11 pancreatic, five gallbladder, three squamous cell
      carcinoma of the head and neck, one hepatocellular carcinoma, one melanoma, one
      gastric, and one breast cancer. Median patient age was 63 years (range 44-78) and
      median Karnofsky performance status (KPS) was 80. Patients received a median of 8
      cycles (range 1-16) over five irinotecan dose levels (80, 100, 120, 140 and 160
      mg/m). Dose-limiting toxicity consisting of grade 3 nausea/vomiting despite
      aggressive anti-emetic therapy occurred in one patient at dose level 1 and three
      patients at dose level 3. Grade 3-4 hematological toxicities per patient
      consisted of thrombocytopenia (3%), anemia (6%), thrombosis (23%), neutropenia
      (16%) and neutropenic fever (10%). Of 18 patients evaluable for response, one
      complete response (pancreatic) and eight partial responses (three gallbladder,
      two pancreatic, two head and neck, and one breast) were attained. Seven patients
      had disease stabilization (five pancreatic, one hepatocellular and one gastric)
      for a median of 16 weeks (range 10-22). Median time to disease progression among
      all 23 patients enrolled to the phase I portion of the trial was 20.5 weeks
      (range 4-37). We conclude that G-FLIP is a novel outpatient chemotherapy regimen
      with acceptable toxicity at the maximum tolerated irinotecan dose of 120 mg/m.
      The phase II trial of G-FLIP using an irinotecan dose of 120 mg/m for patients
      with metastatic pancreatic cancer is ongoing.

PMID- 15014354
TI  - Phase I trial of sequential raltitrexed followed by bolus 5-fluorouracil in
      patients with advanced colorectal cancer.
AB  - Our objective was to determine the maximum tolerated dose (MTD) of sequential
      raltitrexed (Tomudex) and 5-fluorouracil (5-FU) by bolus administration every 3
      weeks in patients with advanced colorectal cancer (aCRC) and appendiceal
      adenocarcinoma. This phase I dose-escalation study was carried out in three
      stages: (1) 5-FU fixed at 900 mg/m, raltitrexed escalated from 0.5 to 3.0 mg/m,
      (2) raltitrexed fixed at 3.0 mg/m, 5-FU escalated from 900 mg/m until dose
      limiting toxicity (DLT) and (3) 5-FU fixed at the dose level below DLT,
      raltitrexed escalated from 3.0 mg/m until MTD. Seventy-one patients with
      measurable disease were enrolled. No DLTs were observed during stage 1 of
      treatment. At a fixed dose of raltitrexed 3.0 mg/m, DLT developed when 5-FU was
      increased to 1350 mg/m (stage 2). When 5-FU was fixed at 1200 mg/m and
      raltitrexed was increased to 6.0 mg/m (stage 3), DLT was dose limiting. The
      recommended doses for further study are 5.5 mg/m ralitrexed and 1200 mg/m 5-FU.
      Of the 69 patients evaluated for efficacy, one had a complete response (8.0
      months) and five had partial responses (5.1-11.6 months). Thirty patients had
      stable disease for 5 or more cycles of therapy (mean time to progression: 3.6
      months). Median survival was 11.7 months. We conclude that raltitrexed can be
      combined with bolus 5-FU, at raltitrexed doses that are higher than the
      recommended single-agent dose of 3.0 mg/m, with manageable toxicity. This
      combination shows encouraging activity, and survival appears promising in the pre
      treated aCRC patient population. Further clinical trials are warranted.

PMID- 15014355
TI  - 19F-magnetic resonance spectroscopy in patients with liver metastases of
      colorectal cancer treated with 5-fluorouracil.
AB  - The purpose of this study was to examine the uptake and metabolism of 5
      fluorouracil (5-FU) in human liver metastases. Patients with liver metastases of
      colorectal cancer were treated with 5-FU (500/600 mg/m)+folinic acid with or
      without trimetrexate. The clinical application of F-magnetic resonance
      spectroscopy (MRS) of 5-FU in a random group of patients (n=17) was investigated.
      MR spectra of all patients showed 5-FU and catabolite resonances, and
      fluoronucleotides were also seen in seven patients. A correlation was found
      between maximum levels of 5-FU catabolites as measured by F-MRS and response in a
      group with larger metastases. However, such correlation was not observed in a
      group with smaller metastases, probably because of a significant contribution of
      normal liver tissue to the MR spectra.

PMID- 15014356
TI  - Induction of remission in a patient with metastatic breast cancer refractory to
      trastuzumab and chemotherapy following treatment with gefitinib ('Iressa',
      ZD1839).
AB  - Despite new therapies and several treatment options, metastatic breast cancer
      (MBC) remains incurable. One reason for the low median survival rate may be
      intense cross-talk between growth factor receptors such as the epidermal growth
      factor receptor (EGFR/HER1) and the HER2 growth factor receptor. This report
      describes the case history of a patient with MBC whose disease had progressed
      despite surgery, radiotherapy and four different chemotherapy regimens, including
      trastuzumab (a monoclonal antibody that specifically blocks HER2) combined with
      docetaxel. However, treatment with 500 mg/day gefitinib ('Iressa', ZD1839), an
      EGFR tyrosine kinase inhibitor, and trastuzumab (2 mg/kg/week) caused a rapid and
      sustained regression of breast cancer metastases in skin and lymph nodes. Thus,
      for patients with MBC whose tumors co-express EGFR and HER2, gefitinib in
      combination with trastuzumab may prevent receptor cross-talk, improving the
      outcome of MBC.

PMID- 15014357
TI  - Complications mimicking lupus flare-up in a uremic patient undergoing pegylated
      liposomal doxorubicin therapy for cervical cancer.
AB  - Patients with systemic lupus erythematosus (SLE) have an increased risk for
      malignancy and end-stage renal disease itself might further augment the risk.
      Treating uremic patients with cervical cancer by cisplatin-based chemotherapy
      combined with radiation is hampered by the reduced renal excretion of cisplatin.
      Doxorubicin, a potential radiosensitizer with an established effect on carcinomas
      that arise in the ovary, uterine cervix and endometrium, might be applied in
      these cases. We describe a 36-year-old woman, who had a 9-year history of SLE and
      was maintained on dialysis, and who developed severe drug reaction manifesting as
      fever, skin rash and exfoliative dermatitis with positive lupus band test after
      infusion of pegylated liposomal doxorubicin therapy for advanced cervical cancer.
      These skin manifestations improved after i.v. methylprednisolone pulse therapy.

PMID- 15014358
TI  - Combination with liposome-entrapped, ends-modified raf antisense oligonucleotide
      (LErafAON) improves the anti-tumor efficacies of cisplatin, epirubicin,
      mitoxantrone, docetaxel and gemcitabine.
AB  - Raf-1 protein serine/threonine kinase plays an important role in cell
      proliferation and cell survival. We have previously described a novel cationic
      liposome-entrapped formulation of raf antisense oligodeoxyribonucleotide
      (LErafAON) and its use as a radiosensitizer. The aim of this study was to examine
      the effect of combination of LErafAON and a chemotherapeutic agent on growth of
      human prostate (PC-3) and pancreatic tumor xenografts in athymic mice (Aspc-1 and
      Colo 357). In PC-3 tumor-bearing mice, administration of a combination of
      LErafAON (i.v., 25 mg/kg/dose, x10/16) and cisplatin (i.v., 11.0 mg/kg/dose, x3),
      epirubicin (EPI) (i.v., 9.0 mg/kg/dose, x3) or mitoxantrone (MTO) (i.v., 2.5
      mg/kg/dose, x3) led to enhanced tumor growth inhibition as compared with single
      agents (LErafAON+cisplatin versus cisplatin, p<0.0002, n=8; LErafAON+EPI versus
      EPI, p<0.0001, n=6; LErafAON+MTO versus MTO, p<0.05, n=5). In prostate or
      pancreatic tumor-bearing mice, combination of LErafAON (i.v., 25 mg/kg/dose,
      x10/13) with docetaxel (Taxotere) (i.v., 5, 7.5 or 10 mg/kg/dose, x2/4) led to
      tumor regression or enhanced growth inhibition as compared with single agents (PC
      3: LErafAON+Taxotere versus Taxotere, p<0.02, n=7; Aspc-1: LErafAON+Taxotere
      versus Taxotere, p<0.03, n=5; Colo 357: LErafAON+Taxotere versus Taxotere,
      p<0.04, n=7). Combination of LErafAON (i.v., 25 mg/kg/dose, x10/13) with
      gemcitabine (i.v., 75 mg/kg/dose, x4/6) also caused a significant tumor growth
      inhibition in the two pancreatic carcinoma models studied (Aspc-1:
      LErafAON+gemcitabine versus gemcitabine, p<0.0001, n=7; Colo 357:
      LErafAON+gemcitabine versus gemcitabine, p<0.002, n =5). LErafAON treatment
      (i.v., 25 mg/kg/dose, x10) caused inhibition of Raf-1 protein expression in these
      tumor tissues (around 25-60%, n=4-7). Interestingly, Taxotere treatment per se
      also led to decreased steady state level of Raf-1 protein in PC-3 and Aspc-1
      tumor tissues (i.v., 10 mg/kg/dose, x1 or 7.5 mg/kg/dose, x2; around 25-80%,
      n=2/6). Present studies demonstrate enhanced tumor growth inhibition or
      regression in response to a combination of a chemotherapeutic drug and LErafAON.
      These data provide a proof-of-principle for the clinical use of LErafAON in
      combination with chemotherapy for cancer treatment.

PMID- 15014359
TI  - Assessment of cyclooxygense-2 expression with 99mTc-labeled celebrex.
AB  - Cyclooxygenase-2 (COX-2) plays an important role in angiogenesis and cancer
      progression. Since many tumor cells exhibit COX-2 expression, functional imaging
      of COX-2 expression using celebrex (CBX, a COX-2 inhibitor) may provide not only
      a non-invasive, reproducible, quantifiable alternative to biopsies, but it also
      greatly complements pharmacokinetic studies by correlating clinical responses
      with biological effects. Moreover, molecular endpoints of anti-COX-2 therapy
      could also be assessed effectively. This study aimed at measuring uptake of Tc-EC
      CBX in COX-2 expression in tumor-bearing animal models. In vitro Western blot
      analysis and cellular uptake assays were used to examine the feasibility of using
      Tc-EC-CBX to measure COX-2 activity. Tissue distribution studies of Tc-EC-CBX
      were evaluated in tumor-bearing rodents at 0.5-4 h. Dosimetric absorption was
      then estimated. Planar scintigraphy was performed in mice, rats and rabbits
      bearing tumors. In vitro cellular uptake indicated that cells with higher COX-2
      expression (A549 and 13762) had higher uptake of Tc-EC-CBX than lower COX-2
      expression (H226). In vivo biodistribution of Tc-EC-CBX in tumor-bearing rodents
      showed increased tumor:tissue ratios as a function of time. In vitro and
      biodistribution studies demonstrated the possibility of using Tc-EC-CBX to assess
      COX-2 expression. Planar images confirmed that the tumors could be visualized
      with Tc-EC-CBX from 0.5 to 4 h in tumor-bearing animal models. We conclude that
      Tc-EC-CBX may be useful to assess tumor COX-2 expression. This may be useful in
      the future for selecting patients for treatment with anti-COX-2 agents.

PMID- 15014360
TI  - Dysregulation of protein kinase C activity in chemoresistant metastatic breast
      cancer cells.
AB  - This study was performed to evaluate the role of protein kinase C (PKC) activity
      in the development of chemoresistance in clinical breast cancer cells. To
      simulate the clinical situation, native tumor cells derived from 10 patients with
      advanced breast cancer were brought into short-term cultures, and treated with
      anthracyclines (doxorubicin, mitoxantrone), paclitaxel and combinations,
      respectively. After 3 days of incubation, we determined total PKC activity
      relative to each control incubated with blank medium. Furthermore, we determined
      the chemoresistance against these drugs from each cell population separately.
      Relative PKC activity ranged from 14 to 249%; 64% (37 of 58) of the breast cancer
      cell suspensions were considered chemoresistant. There was a non-significant
      trend to a higher relative PKC activity in resistant cells compared to non
      resistant cells (p=0.058), regardless of the antineoplastic agent investigated.
      The individual variability in both PKC activity and chemoresistance pattern
      revealed that dysregulated PKC activity mediates resistance to antineoplastics.
      In order to achieve clinical value, evaluation of more data concerning the PKC
      signal-transduction pathway is necessary. New protocols of cancer treatment will
      require this information in order to be successful.

PMID- 15014362
TI  - Induction of growth inhibition and G1 arrest in human cancer cell lines by
      relatively low-toxic diamantane derivatives.
AB  - We describe the discovery of a novel series of antitumor diamantane derivatives
      which induces G1 arrest in Colo 205 cells. Eight diamantane derivatives were
      screened for their activity in vitro against 60 human cancer cell lines in the
      National Cancer Institute (NCI)'s anticancer drug screen. The relationships
      between structure and in vitro antitumor activity are discussed. The structure
      activity relationship (SAR) study of diamantane derivatives clarified that the
      conformation of 1,6-bis(4-(4-aminophenoxy)-phenyl)diamantane (1,6-DPDONH2) was
      essential for significant antitumor activity. Very strong growth inhibition of
      1,6-DPDONH2 (NSC-706829) was observed against one colon cancer line (Colo 205),
      four melanoma lines (MALME-3M, M14, SK-MEL-5 and UACC-257) and two breast cancer
      lines (MDA-MB-435 and MDA-N) with GI50 <1.0 microM, i.e. below 0.01, 0.23, 0.48,
      0.5, 0.32, 0.26 and 0.28 microM, respectively. 1,6-DPDONH2 also exhibited
      particular selectivity against one colon cancer line (Colo 205), four melanoma
      lines (MALME-3M, M14, SK-MEL-5 and UACC-257) and two breast cancer lines (MAD-MB
      435 and MDA-N) with GI50 < or=0.5 microM. In the same cancer subpanel, the
      selectivity of 1,6-DPDONH2 between these seven most sensitive lines and the least
      sensitive line ranged from 40- to 100-fold. With the exception of melanoma lines,
      1,6-bis(4-(4-amino-3-hydroxyphenoxy)-phenyl)diamantane (1,6-DPD/OH/NH2) (NSC
      706831) possessed stronger activity than 1,6-DPDONH2 against almost all tested
      cancer lines. Very strong growth inhibition of 1,6-DPD/OH/NH2 was observed
      against one leukemia line (HL-60(TB)), one NSCLC line (HOP-92), one ovarian
      cancer line (OVCAR-8) and one breast cancer line (T-47D) with GI50 <1.0 microM,
      i.e. 0.50, 0.85, 0.62 and 0.75 microM, respectively.

PMID- 15014361
TI  - Antimelanoma activity of 1,3,4-thiadiazolium mesoionics: a structure-activity
      relationship study.
AB  - The effect of a series of 4-phenyl-5-(2'-Y, 4'-X or 4'-X-cinnamoyl)-1,3,4
      thiadiazolium-2-phenylamine chlorides was evaluated against B16-F10 murine
      melanoma cells in vitro and against tumors resulting from implanted B16-F10 cells
      in C57BL/6 mice. These compounds differ from each other only at the cinnamoyl
      ring substituent (MI-J, X=OH; MI-2,4diF, X=Y=F; MI-4F, X=F and MI-D, X=NO2). The
      results were compared with those obtained for MI-D, which has already been shown
      to be a potent and promising drug against melanoma. On exposure of B16-F10 cells
      to MI-D, MI-2,4diF and MI-4F, all of them at the same micromolar concentration
      (50 microM) decreased the cell viability to 8, 50 and 22%, respectively, while MI
      J did not show any significant effect under the same conditions. However, low
      doses such as 10 microM MI-D were sufficient to impair cell growth over 72 h, but
      for MI-2,4diF and MI-4F the effect on B16-F10 proliferation was only observed at
      a concentration of 25 microM. Furthermore, MI-4F had a slightly better effect
      than MI-2,4diF in vitro; its effect on tumor growth in vivo was not significant.
      MI-D inhibited tumor growth by 77%. The greater effectiveness of MI-D compared
      with MI-2,4diF, MI-4F and MI-J against B16-F10 melanoma cells is probably due to
      its stronger electron-withdrawing group (NO2), which increases the positive
      charge on the mesoionic ring and allows extensive conjugation of the side-chain
      with the exocyclic moiety. This seems to be important for degree of anti-tumor
      activity of these compounds.

PMID- 15014363
TI  - Sequence-dependent effect of a cyclooxygenase-2 inhibitor on topoisomerase I
      inhibitor and 5-fluorouracil-induced cytotoxicity of colon cancer cells.
AB  - Selective cyclooxygenase-2 (COX-2) inhibitors have been found to induce anti
      proliferative and apoptotic activity in many cancer cells. However, interaction
      between COX-2 inhibitors and other chemotherapeutic agents remains to be
      determined. We investigated the interactive effects of a selective COX-2
      inhibitor, etodolac, in combination with 5-fluorouracil (5-FU) or SN-38 (active
      metabolite of irinotecan) on colon cancer cell lines, HT29 and SW620, in
      simultaneous and sequential administration schedules. Isobologram analysis
      demonstrated that etodolac in combination with 5-FU or SN-38 according to a
      simultaneous schedule resulted in only an additive effect; however, synergism was
      achieved in a sequential schedule. Apoptosis induction in both cell lines was
      also significantly increased after sequential treatment with etodolac followed by
      either 5-FU or SN-38 compared to that after simultaneous treatment with etodolac
      and either 5-FU or SN-38. Our study suggests apoptosis-inducing synergism
      resulted from administration of etodolac and either 5-FU or SN-38 sequentially,
      but not simultaneously.

PMID- 15014364
TI  - EDTA enhances the antitumor efficacy of intratumoral cisplatin in s.c. grafted
      rat colon tumors.
AB  - We have investigated whether EDTA, a calcium chelator, could improve the
      accumulation of platinum in tumors and enhance the antitumor efficacy by
      increasing drug diffusion through the extracellular tumor matrix. Intratumoral
      injection of 0.3 mg/kg cisplatin combined with 10 mg/ml EDTA in 2 ml saline serum
      led to tumor cure in four of eight rats and produced major tumor regression in
      the other animals. In contrast, intratumoral injection of cisplatin alone or EDTA
      alone had no antitumoral effect. EDTA increased platinum accumulation both in
      vivo and ex vivo in the PROb tumors. EDTA alone was cytotoxic at a concentration
      of 10 mg/ml, but neither increased platinum accumulation nor cisplatin toxicity
      on cultured PROb colonic cancer cells. We conclude that EDTA could be a useful
      and well-tolerated adjuvant for enhancing intratumoral cisplatin chemotherapy.

PMID- 15014365
TI  - Predictive oncology--second conference of the International Society for
      Chemosensitivity Testing in Oncology.

PMID- 15014370
TI  - Laser scanning analysis of cold cataract in young and old bovine lenses.
AB  - PURPOSE: This research involves the use of a laser scanning instrument to
      evaluate the formation of cold cataracts in young and older bovine lenses.
      METHODS: Bovine lenses from 18 (n=14) week old calf eyes and approximately 10
      (n=7) year old animals were extracted in a sterile environment. The lenses were
      placed in a specialized glass chamber with temperature controlled circulating
      culture medium. The temperature cycle inside the chamber started at 37 degrees C,
      slowly cooled to 4 degrees C, and then warmed back up to 37 degrees C. A laser
      scanning system (ScanTox) was used to analyze the optical quality of bovine
      lenses during a cooling and warming cycle. RESULTS: The relative light
      transmittance was measured as a function of pixel excitation caused by refracted
      beams and compared to pre-treatment measures. Each lens from each age group
      showed a significant decrease in transmittance at 4 degrees C, which recovered
      when the lenses were warmed to 37 degrees C. Lenses from young eyes showed less
      loss of refracted beam intensity than lenses from older eyes (32% versus 34%),
      although the difference was not significant. CONCLUSIONS: The results of the
      present study indicate cold cataracts can be induced in both old and young bovine
      lenses, as shown by using a scanning laser instrument.

PMID- 15014371
TI  - Guest editorial: Quality as an enduring and encompassing concept.

PMID- 15014372
TI  - AAN organizational age and stage: reflections.

PMID- 15014374
TI  - Measuring and improving health care quality: nursing's contribution to the state
      of science.

PMID- 15014375
TI  - The role of theory in improving patient safety and quality health care.

PMID- 15014376
TI  - Strategies to advance health care quality.

PMID- 15014377
TI  - Measuring nursing care quality and using large data sets in nonacute care
      settings: state of the science.

PMID- 15014378
TI  - Using large data sets in long-term care to measure and improve quality.

PMID- 15014379
TI  - Quality and the nursing workforce: APNs, patient outcomes and health care costs.

PMID- 15014380
TI  - Nurse staffing and patient falls on acute care hospital units.

PMID- 15014381
TI  - Quality agenda: priorities for action recommendations of the American Academy of
      Nursing Conference on Health Care Quality.

PMID- 15014382
TI  - Translational research: disrupting the status quo.

PMID- 15014383
TI  - Nursing education and nursing practice: collaboration essential to current
      differentiated entry level competencies of Texas Nursing Programs.

PMID- 15014384
TI  - TigerPlace: a partnership with Americare and the Sinclair School of Nursing.

PMID- 15014388
TI  - Verification of pediatric endotracheal tube placement.

PMID- 15014392
TI  - Ultrasound for the air medical clinician.

PMID- 15014393
TI  - Long-distance transport of ventilated patients: advantages and limitations of air
      medical repatriation on commercial airlines.
AB  - INTRODUCTION: To illustrate the advantages and limitations of transporting
      ventilated intensive care unit patients over intercontinental distances on
      commercial airlines, this case series reports 8 ventilated patients repatriated
      by an air medical transport company. PATIENTS: Eight ventilated patients, 3
      suffering from internal and 5 from neurologic diseases. Distances ranged from
      1700 to 10280 nautical miles with transport times from 04:10 hours to 21:55
      hours. For 3 patients, a dedicated patient transport compartment (PTC) in the
      aircraft cabin was used. All patients were ventilator-dependent for a minimum of
      11 days before transport (48 days median, 113 days maximum). RESULTS: One patient
      went into cardiac arrest during the flight and died. None of the other patients
      experienced any emergency or invasive procedures, other than peripheral venous
      access necessary during the flight. In all patients, ventilation was adjusted
      with respect to the blood gas analysis at least once during the transport. No
      technical failures or drop-outs occurred during the flights. None of the flights
      had to be diverted for technical or medical reasons. CONCLUSION: Long distance
      international transport of ventilated intensive care unit patients is an
      extremely cost intensive and logistically challenging task. In a certain subgroup
      of relatively stable ventilated patients, transport on commercial airlines offers
      advantages in terms of cost effectiveness and reduced transport time and
      acceleration/deceleration trauma as a result of multiple fuel stops.

PMID- 15014396
TI  - A case study: Boerhaave's syndrome.

PMID- 15014397
TI  - The application of heliox in the management of croup by an air ambulance service.

PMID- 15014398
TI  - Bedside blood gas analysis in airborne rescue operations.
AB  - The alveolar partial oxygen pressure (Pao(2)) recorded from 20 ventilated
      patients was found to decrease by 16 mm Hg during airborne rescue helicopter
      transport at an average altitude of 1780 feet mean sea level. The initial
      departure altitude was 192 feet, and the flight ascended to 2200 feet above
      ground level. Hence, the Pao(2) drop in patients was exclusively attributable to
      cruising altitude (atmospheric pressure = -42 mm Hg). Pathophysiological
      alterations include drops in the oxygenation index (-50 mm Hg), arterial partial
      oxygen pressure (-34 mm Hg), and heart rate (+7 beats per minute) and are
      attributable to growing disproportions in ventilation and perfusion. The absolute
      Pao(2) level does depend largely on the Fio(2) value.

PMID- 15014399
TI  - Children, adolescents, and the media.

PMID- 15014401
TI  - Award-winning research from home and abroad.

PMID- 15014403
TI  - The ABO's 75th anniversary: a retrospective glance at progress in the last
      quarter century.

PMID- 15014402
TI  - The ABO discrepancy index: a measure of case complexity.
AB  - A criterion for determining the acceptability of a case presented for the
      American Board of Orthodontics (ABO) Phase III clinical examination is case
      difficulty. Case difficulty can often be subjective; however, it is related to
      case complexity, which can be quantifiable. Over the past 5 years, the ABO has
      developed and field-tested a discrepancy index, made up of various clinical
      entities that are measurable and have generally accepted norms. These entities
      summarize the clinical features of a patient's condition with a quantifiable,
      objective list of target disorders that represent the common elements of an
      orthodontic diagnosis: overjet, overbite, anterior open bite, lateral open bite,
      crowding, occlusion, lingual posterior crossbite, buccal posterior crossbite, ANB
      angle, IMPA, and SN-GoGn angle. The greater the number of these conditions in a
      patient, the greater the complexity and the greater the challenge to the
      orthodontist. The ABO is considering several options for applying the discrepancy
      index to the Phase III clinical examination.

PMID- 15014404
TI  - Soft-tissue management of labially positioned unerupted teeth. July 1977.

PMID- 15014405
TI  - Treatment effects of Frankel functional regulator III in children with class III
      malocclusions.
AB  - The purpose of this study was to evaluate the skeletal and dental effects
      produced by the Frankel functional regulator III appliance in growing children
      with Class III malocclusions. Thirty preadolescents (initial mean age, 8.0 +/-
      1.2 years; mean treatment duration, 1.3 +/- 0.6 years) treated with the Frankel
      functional regulator III appliance were compared with 20 matched untreated Class
      III controls (initial mean age 8.2 +/- 1.1 years; mean observation period, 1.5 +/
      0.6 years). The treatment effects were mainly from backward and downward
      rotation of the mandible and linguoversion of the mandibular incisors.

PMID- 15014406
TI  - Intermittent 8-hour activation in orthodontic molar movement.
AB  - The duration of force application is an important factor, together with the
      magnitude of force, in stimulating osteoclast recruitment in the periodontal
      ligament. The purpose of this study was to examine the effect of duration of
      intermittent versus continuous force application on the amount of molar movement
      in rats. Seventy-six molars of 38 rats were randomly assigned to continuous,
      intermittent, and sham-operation groups. A calibrated nickel-titanium coil spring
      exerting 40 g of initial force was suspended between the maxillary first molars
      and the incisors for 13 days. In the intermittent group, the coil spring was
      suspended for 8 hours per day. Tooth movement was measured on radiographs. There
      was no significant difference in the initial tooth displacement between the
      continuous-force and intermittent-force groups. Tooth movement at day 7 was
      significantly (P <.05) less in the intermittent group than in the continuous
      group. Actual mesial tooth movement and total tooth movement in the intermittent
      group were 65.9% and 73.7%, respectively, of those in the continuous group. Our
      results suggest that the amount of tooth movement in response to intermittent
      force is less than that in response to continuous force, but that the amount of
      tooth movement achieved by intermittent force exceeds the expected value
      predicted by the duration (33.3%) of force application.

PMID- 15014407
TI  - Comparison of some effects of acetylsalicylic acid and rofecoxib during
      orthodontic tooth movement.
AB  - The purpose of this study was to examine the effects of 2 different anti
      inflammatory drugs on gingival crevicular fluid (GCF) volume and on prostaglandin
      E(2) (PGE(2)) levels of the GCF during orthodontic tooth movement. A total of 36
      extraction patients, aged 17.6 +/- 2.5 years (mean +/- standard deviation), were
      divided into 3 groups. Acetylsalicylic acid (aspirin) and rofecoxib (Vioxx,
      Merck, Whitehouse Station, NJ) were used for pain control in the first and second
      groups; the third group was used as a control. Gingival crevicular fluid was
      sampled at the beginning of tooth movement and at 24, 48, and 168 hours. An
      automated enzyme immunoassay was used to measure PGE(2) in GCF. The intragroup
      differences were evaluated with the Wilcoxon test, and the differences between
      the groups were determined with the Mann-Whitney U test. Gingival crevicular
      fluid volumes of the groups did not change significantly during the experimental
      period. Depending on the variations of fibroblast activation, PGE(2) levels of
      all the groups increased at 24 and 48 hours and decreased at 168 hours. When the
      drugs were compared, it was found that the inhibition effect of aspirin on PGE(2)
      was more than that of rofecoxib. The results suggest that rofecoxib can be used
      during orthodontic treatment, but further study is recommended.

PMID- 15014409
TI  - Materials-induced variation in the torque expression of preadjusted appliances.
AB  - The purpose of this article is to comprehensively investigate the sources of
      variation in the expression of torque in preadjusted appliances. Variables
      related to properties of materials were systematically analyzed, including (1)
      the inability to fill the slot because of the size difference of archwires and
      bracket slot, (2) irregularities from the manufacturing process of brackets
      precluding proper engagement, (3) differences in the stiffness of wire alloys
      engaged to the bracket slot, (4) variations between actual and reported bracket
      torque values, and (5) ligation modes, all of which might account for increased
      third-order clearance or bracket-archwire "play." The effect of these variations
      on the expression of torque is discussed, and the net buccolingual inclinations
      are provided as a function of wire size and composition for common bracket slot
      archwire combinations. Most reports published on this issue indicate a loss of
      torque control as high as 100% of the prescribed value. Furthermore, the fallacy
      of transferring the ideal crown inclination to the torque prescribed in the
      bracket is illustrated, along with the underestimation of the prescribed torque
      relative to the proper tooth crown. The realistically required torque is analyzed
      to its constituent components, involving tooth inclination, compensation for the
      slot-wire play, and incomplete ligation with elastomeric ligatures. Based on the
      evidence available, it is proposed that a high-torque prescription should be
      selected to account for the lack of full expression of the prescribed torque that
      occurs clinically.

PMID- 15014408
TI  - Buccolingual inclinations of posterior teeth in subjects with different facial
      patterns.
AB  - This study compared the buccolingual inclination of the posterior teeth in
      subjects with a horizontal growth pattern (proportionally short lower anterior
      face height) with that of subjects with a vertical growth pattern (proportionally
      long lower anterior face height). Seventy subjects with permanent dentition were
      divided into 2 groups. Group I comprised 35 subjects (16 male, 19 female) with
      Class II Division 2 malocclusion with a horizontal growth pattern, and group II
      comprised 35 subjects (15 male, 20 female) with a vertical growth pattern.
      Buccolingual inclinations of the first molar and second premolar were indirectly
      assessed on photocopies of buccolingual sections of these teeth by measuring
      their occlusal surface (represented by an imaginary line connecting the lingual
      and buccal cusps) inclination. The groups were compared with t tests (P <.05).
      The maxillary posterior teeth of subjects with a vertical growth pattern had a
      significantly greater buccal inclination compared with those of subjects with a
      horizontal growth pattern. However, there were no statistically significant
      differences in the inclinations of the mandibular posterior teeth between the 2
      groups.

PMID- 15014410
TI  - Evaluation of the debonding characteristics of 2 ceramic brackets: an in vitro
      study.
AB  - The objectives of this study were to evaluate and compare the shear bond
      strengths and bond failure locations of 2 currently available orthodontic ceramic
      brackets. Forty polycrystalline ceramic brackets (Clarity, 3M Unitek, Monrovia,
      Calif) and 40 monocrystalline ceramic brackets (Inspire, Ormco, Orange, Calif)
      were bonded to 80 extracted premolars with the same bonding system. All bonded
      specimens were placed in distilled water for 42 hours at 37 degrees C followed by
      thermal cycling for 700 complete cycles. Forty ceramic brackets, 20 of each type,
      were tested on a universal testing machine to determine the shear force levels
      required to debond them. Forty ceramic brackets were removed with the debonding
      pliers recommended by the manufacturers. All teeth were examined under an optical
      microscope, and the adhesive remnant index was used to assess the bond failure
      locations. The mean shear bond strength of the Clarity brackets was 21.67 +/-
      5.19 MPa, and the mean shear bond strength of the Inspire brackets was 20.32 +/-
      8 MPa. The mean shear bond strengths of both brackets were higher than those
      considered clinically optimal. Most of the brackets (85% of Clarity and 75% of
      Inspire) tested on the machine failed at the bracket-adhesive interface. One
      premolar bonded with an Inspire bracket had enamel fracture upon debonding. Most
      of the brackets (90% of Clarity and 95% of Inspire) debonded with pliers failed
      at the bracket-adhesive interface. No enamel damage was evident in any specimen
      when the brackets were removed with the appropriate pliers. The results indicate
      that the safest way to remove ceramic brackets with respect to reducing the
      chance of enamel damage is to use the debonding technique specifically designed
      for each.

PMID- 15014411
TI  - Shear bond strength of orthodontic brackets bonded with light-emitting diode
      curing units at various polymerization times.
AB  - Light emitting diode (LED) light-curing units have recently been used to
      polymerize resin-based orthodontic adhesives, and preliminary studies indicate
      their use has been successful. The purpose of this study was to evaluate the
      relationship between the shear bond strength of orthodontic brackets bonded to
      enamel and the duration of photopolymerization with LEDs and conventional quartz
      tungsten-halogen light-curing units. Three LED light-curing units (GC e-light, GC
      America, Alsip, Ill; Elipar FreeLight, 3M ESPE Dental Products, St Paul, Minn;
      and UltraLume LED 2, Ultradent Products, South Jordan, Utah) and 1 halogen-based
      light-curing unit (Ortholux XT, 3M Unitek, Monrovia, Calif) were evaluated. Two
      hundred forty metal orthodontic brackets were bonded to extracted molars.
      Specimens were divided into 12 groups of 20 teeth each. Each group was cured with
      a different light-curing unit for 40, 20, or 10 seconds. The specimens were
      stored in water at 37 degrees C for 24 hours and then subjected to a shear force
      with a universal testing machine until bracket failure. Two-way ANOVA detected
      significantly weaker mean shear bond strength with the GC e-light at 10 and 40
      seconds (P<.001) and higher mean shear bond strength for the UltraLume LED 2 at
      40 seconds (P<.001). All experimental groups had laboratory mean shear bond
      strengths greater than 8 MPa, even with a 10-second cure.

PMID- 15014412
TI  - Plasma arc versus halogen light curing of orthodontic brackets: a 12-month
      clinical study of bond failures.
AB  - The purpose of this randomized clinical trial was to evaluate the clinical
      performance of brackets cured with 2 different light-curing units (conventional
      halogen light and plasma arc light); 83 patients treated with fixed appliances
      were included in the study. With the "split-mouth" design, each patient's mouth
      was divided into 4 quadrants. In 42 randomly selected patients, the maxillary
      left and mandibular right quadrants were cured with the halogen light, and the
      remaining quadrants were cured with the plasma arc light. In the other 41
      patients, the quadrants were inverted. A total of 1434 stainless steel brackets
      were examined: 717 were cured with a conventional halogen light for 20 seconds;
      the remaining 717 were cured with the plasma arc light for 5 seconds. The number,
      cause, and date of bracket failures were recorded for each light-curing unit over
      12 months. Statistical analysis was performed with the Fisher exact test, the
      Kaplan-Meier survival estimates, and the log-rank test. No statistically
      significant differences were found between the total bond failure rates of the
      brackets cured with the halogen light and those cured with the plasma arc light.
      Neither were significant differences found when the clinical performances of the
      maxillary versus mandibular arches or the anterior versus posterior segments were
      compared. These findings demonstrate that plasma arc lights are an advantageous
      alternative to conventional light curing, because they significantly reduce the
      curing time of orthodontic brackets without affecting the bond failure rate.

PMID- 15014413
TI  - Comparison of the shear bond strength of 2 self-etch primer/adhesive systems.
AB  - Conventional adhesive systems use 3 different agents-an enamel conditioner, a
      primer solution, and an adhesive resin for bonding orthodontic brackets to
      enamel. A unique characteristic of some new bonding systems in operative
      dentistry is that they combine the conditioning and priming agents into a single
      application. Combining conditioning and priming saves time and should be more
      cost-effective to the clinician and indirectly to the patient. The purpose of
      this study was to assess and compare the effects of mix and no-mix self-etch
      primers/bonding systems on the shear bond strengths of orthodontic brackets. The
      brackets were bonded to extracted human molars according to the following
      protocols. In group I, a self-etch acidic primer/adhesive system, Transbond Plus
      (3M Unitek, Monrovia, Calif), was applied on the enamel surface as suggested by
      the manufacturer; it has 2 components that must be mixed before use. The brackets
      were then bonded with Transbond XT and light-cured for 20 seconds. In group II, a
      no-mix self-etch bracket adhesive system, Ideal 1 (GAG International, Islandia,
      NY), was applied to the teeth as suggested by the manufacturer. The self-etch
      primer has 1 component that does not need to be mixed before use. The brackets
      were then bonded with the adhesive and light-cured for 20 seconds. The in vitro
      findings indicated that the shear bond strength comparisons (t = 0.681) of the 2
      adhesive systems were not significantly different (P =.501). The mean shear bond
      strength of the 2-component acid etch primer was 5.9 +/- 2.7 MPa, and the mean
      for the 1-component system was 6.6 +/- 3.2 MPa. The clinician should consider the
      bond strength and the ease of application of the various components of the
      bracket bonding systems available on the market.

PMID- 15014414
TI  - Effect of fluoride varnish on the in vitro bond strength of orthodontic brackets
      using a self-etching primer system.
AB  - To reduce the number of steps involved with bonding procedures, manufacturers
      have simplified adhesive systems by combining the hydrophilic primer and the
      adhesive, or by combining the etchant, the primer, and the adhesive into 1 bottle
      and application. The purpose of this study was to investigate the relationship
      between the shear bond strength of orthodontic brackets to enamel, with or
      without fluoride varnish, by using either conventional or self-etching primer
      systems. Forty-eight extracted teeth were divided into 4 groups of 12 teeth each:
      group 1, fluoride varnish, conventional adhesive; group 2, fluoride varnish, self
      etching primer system; group 3, no fluoride varnish, conventional adhesive; and
      group 4, no fluoride varnish, self-etching primer system. The bonding procedure
      followed the manufacturers' recommendations for the materials. Precoated adhesive
      orthodontic brackets were light-cured to the facial surfaces of the teeth and
      stored in whole human saliva at 37 degrees C for 24 hours. The specimens were
      subjected to a shear force in a testing machine until failure. The adhesive
      remnant index was used to score the teeth. Data were analyzed with a 2-way
      analysis of variance to test for differences in shear bond strength with respect
      to fluoride varnish and type of adhesive system used. The results showed no
      difference in bond strength among any of the experimental groups. Similarly, chi
      square analysis determined that adhesive remnant index scores were not
      statistically different. The application of fluoride varnish does not affect the
      bond strength of orthodontic brackets to enamel with conventional or self-etching
      primer systems.

PMID- 15014415
TI  - Effect of blood contamination on shear bond strength of brackets bonded with
      conventional and self-etching primers.
AB  - This study assessed the effect of blood contamination on the shear bond strength
      and bond failure site of 2 different orthodontic primers (Transbond XT and
      Transbond Plus Self-Etching Primer, both from 3M Unitek, Monrovia, Calif) used
      with adhesive-precoated brackets. Four different enamel surface conditions were
      tested: (1) dry, (2) blood contamination before priming, (3) blood contamination
      after priming, and (4) blood contamination before and after priming.
      Noncontaminated enamel surfaces had the highest bond strengths for both
      conventional and self-etching primers, which produced almost the same strength
      values. Under blood-contaminated conditions, both primers showed significantly
      reduced shear bond strengths. For the conventional primer, no significant
      differences were reported among the blood-contaminated groups, whereas when the
      self-etching primer was used, condition 4 reduced significantly the bond strength
      values. Significant differences in debond locations were found among the groups
      bonded with the 2 primers under the various enamel surface conditions.

PMID- 15014416
TI  - Tooth-width ratio discrepancies in a sample of Peruvian adolescents.
AB  - Previous studies have demonstrated different tooth-width ratio discrepancies in
      different populations. The objective of this study was to determine maxillary to
      mandibular tooth-size ratios in a Peruvian sample; 200 children were selected who
      had complete permanent dentition, without clinically visible dental caries or
      proximal restorations, and no previous or active orthodontic treatment. Their
      dental casts were measured to the nearest 0.1 mm with a sliding caliper and a
      Vernier scale. The Kolmogorov-Smirnov test, t test, and Pearson correlation test
      were used. No significant differences were found in anterior (P =.713) and total
      (P =.174) tooth-size sums according to sex. The anterior tooth-width ratios were
      77.78% +/- 2.44% for females and 78.39% +/- 2.81% for males (P =.103). The total
      ratios were 90.79% +/- 1.71% for females and 91.33% +/- 2.07% for males (P
      =.048). For this reason, the combined male and female anterior total ratio was
      calculated (78.09 +/- 2.64%). There were clinically significant tooth-size
      discrepancies in almost one third of the sample. The 2-standard deviation range
      from the Bolton standard did not predict clinically significant anterior and
      total tooth-width ratio discrepancies.

PMID- 15014417
TI  - Craniofacial structure of Anatolian Turkish adults with normal occlusions and
      well-balanced faces.
AB  - This study aimed to develop cephalometric standards for Anatolian Turkish men and
      women. Fifty young men (mean age [+/- standard deviation], 22.61 +/- 1.22) and 55
      young women (mean age, 22.14 +/- 1.44 years) were studied. All subjects were born
      to Turkish parents and grandparents and were 19 to 25 years old. All had Class I
      occlusions with minor or no crowding, normal growth and development, well-aligned
      maxillary and mandibular dental arches, all teeth present except third molars,
      good facial symmetry determined clinically and radiographically, no significant
      medical history, no history of trauma, no previous orthodontic or prosthodontic
      treatment, and no maxillofacial or plastic surgery. Twenty-five measurements (14
      linear and 11 angular) were analyzed on each radiograph. Arithmetic mean and
      standard deviation were calculated for each measurement. For statistical
      evaluation, independent-samples t tests were performed. Our established values
      were compared with the norms of other investigators who studied facial esthetics.
      Significant racial differences were found in skeletal measurements (anterior
      nasal spine [ANS] to menton), dental measurements (maxillary incisor to sella
      nasion plane, mandibular incisor to nasion-Point B line, and mandibular incisor
      to mandibular plane), and soft tissue measurements (H angle, upper lip to E
      plane, and upper lip to Steiner S line). Significant sex differences were found
      in the measurements condylion to A point, condylion to gnathion, ANS to menton,
      and nasion to ANS. It is appropriate to put these cephalometric norms into daily
      orthodontic practice when an Anatolian Turkish population is being treated.

PMID- 15014418
TI  - Association between normative and self-perceived orthodontic treatment need among
      Arab high school students.
AB  - The aim of this study was to investigate whether there was an association between
      normative and self-perceived orthodontic treatment need, and to evaluate the
      influence of sex and socioeconomic background on treatment need. A total of 139
      high school students, aged 14 to 18 years, from 2 districts in Kuwait were
      included. The study consisted of a questionnaire and a clinical examination.
      Normative need for treatment was assessed clinically by using the index of
      orthodontic treatment need (IOTN). Both the dental health component (DHC) and the
      aesthetic component (AC) of the IOTN correlated positively with self-perceived
      treatment need. In 53% of the subjects, there was agreement between self
      perceived treatment need and the DHC score. Between the AC component and self
      perceived need, the agreement was 77%. The odds of self-perceived treatment need
      were 10-fold for subjects having AC scores higher than 4, indicating moderate or
      definite need. Sex and socioeconomic factors did not significantly affect the
      normative treatment need. These results suggest that the AC component of the IOTN
      clearly reflects the self-perceived need for treatment.

PMID- 15014419
TI  - Orthosurgical treatment with lingual orthodontics of an infraoccluded maxillary
      first molar in an adult.
AB  - The biological mechanism that leads to a cessation in the normal passive eruption
      of a tooth is unclear, and there are differing views as to whether ankylosis is
      involved. When infraocclusion of a permanent molar occurs in the permanent
      dentition, its effects are seen (1) locally, with exaggerated tipping and
      relative under-eruption of the adjacent teeth; (2) regionally, with overeruption
      of the opposing tooth or teeth; and (3) farther afield, with deviation of the
      dental midline to the affected side. Treatment aimed at eliminating these adverse
      conditions is warranted, and this might involve the skills of both an
      orthodontist and an oral surgeon. When the condition occurs in an adult, the
      changes in facial appearance that will be caused by traditional fixed orthodontic
      appliances might undermine the patient's willingness to accept treatment. This
      report describes the successful orthosurgical treatment with lingual orthodontics
      of an infraoccluded maxillary first molar in an adult. The challenges, treatment
      alternatives, and technical refinements are emphasized.

PMID- 15014420
TI  - What is the Foveon chip?

PMID- 15014421
TI  - Litigation, legislation, and ethics: defending claims for lack of informed
      consent.

PMID- 15014423
TI  - Population genetic structure of and inbreeding in an insular cattle breed, the
      Jersey, and its implications for genetic resource management.
AB  - The Jersey is a ubiquitous and successful breed of cattle that originates from
      the UK Channel Island of Jersey. While the breed has been exported extensively,
      no imports have taken place to the island since 1789, leading to a concern
      regarding possible losses of genetic diversity and increased inbreeding. We have
      conducted the first large-scale genetic analysis of the Jersey cattle using only
      samples from the island. A total of 223 cattle from all parishes except one were
      genotyped for 12 microsatellite loci. The average number of alleles per locus and
      expected heterozygosity were found to be comparatively high (n(A)=4, H(e)=0.64)
      with respect to that observed in a number of continental breeds. Only breeds that
      have been upgraded and are therefore the result of admixture are clearly more
      variable than the Jersey. We also found a significant but limited amount of
      genetic differentiation between parishes (F(st)=0.013), or even between farms
      (F(st)=0.035) despite an apparent lack of movement. This is confirmed by the
      application of two recent statistical methods. A Bayesian partition analysis
      shows that the most probable value of K, the number of possible hidden
      partitions, is 1 (P approximately 0.98). K=2 has a much lower probability (P
      approximately 0.02) while other values are essentially zero. Similarly, we were
      able to show that there was no support for departure from panmixia other than due
      to population structure, and thus that there is sufficient background gene flow
      across the island to overcome local drift. Overall, it appears that the current
      level of genetic diversity and its distribution within the island means it is
      unnecessary to import unrelated genetic material to the island for management
      purposes.

PMID- 15014422
TI  - Reproductive isolation of a new hybrid species, Senecio eboracensis Abbott & Lowe
      (Asteraceae).
AB  - The nature and extent of reproductive isolation was examined between a new self
      compatible hybrid species Senecio eboracensis (2n=40) and its parents, self
      incompatible S. squalidus (2n=20) and self-compatible S. vulgaris (2n=40). The
      triploid F(1) of S. eboracensis x S. squalidus exhibited very low seed set
      (x=0.63%), and F(2) and F(3) progeny were able to recover nominal levels of
      fertility (x=23.9 and 9.7%), while F(1) and F(2) offspring of S. eboracensis x S.
      vulgaris showed reduced seed set (x=63.8 and 58.8%). In both cases, evidence from
      previous work indicates that reduced fertility is associated with meiotic
      chromosome mispairing, and is a likely consequence of recombining both parental
      genomes within this new taxon. No hybrid offspring between S. eboracensis and S.
      squalidus were found in the wild, and only one such hybrid was recorded among 769
      progeny produced by S. eboracensis surrounded by S. squalidus on an experimental
      plot. Natural crossing between S. eboracensis and S. vulgaris was recorded to be
      very low (between 0 and 1.46%) in the wild, but rose to 18.3% when individuals of
      S. eboracensis were surrounded by plants of S. vulgaris. It was concluded that
      strong breeding barriers exist between the new hybrid species and its two
      parents. Prezygotic isolation between S. eboracensis and S. vulgaris is likely to
      be largely due to both species reproducing by predominant self-fertilisation.
      However, differences recorded for germination, seedling survival, time of
      flowering and characters associated with pollinator attraction, plus significant
      clumping of juvenile and adult conspecifics in the wild, probably also contribute
      to reproductive isolation and ecological differentiation.

PMID- 15014424
TI  - DNA diversity in Hawaiian endemic plant Schiedea globosa.
AB  - This is the first report of a study devoted to the population genetics of
      speciation in the endemic Hawaiian plant genus Schiedea (Caryophyllaceae). Here,
      we report the estimates of DNA sequence diversity and divergence in a newly
      isolated nuclear gene from Maui and Oahu Schiedea globosa populations. Overall,
      the species-wide average heterozygosity per silent site is pi = 0.3%. The silent
      DNA diversity on the older island of Oahu (pi = 0.24%) is almost twice as high as
      on the younger Maui (pi = 0.14%). Consistent with this, the haplotype phylogeny
      suggests a more recent origin of the Maui populations. There is no significant
      isolation between the two Maui populations (F(st)=0.027), while isolation between
      the two islands is high (F(st)=0.57, P<0.0001). Pairwise mismatch distributions
      suggest population growth approximately 660 and 310 thousand generations ago for
      the Oahu and the Maui populations, respectively, which may be the minimal age for
      these populations. This is consistent with a fairly neutral frequency spectrum
      (Tajima's D is 0.34 and -0.94 for the Oahu and the Maui populations,
      respectively), suggesting that both populations are sufficiently old to have
      recovered from any initial founder effects. Relatively high nuclear DNA diversity
      in the S. globosa populations illustrates the usefulness of a DNA sequence-based
      approach to the population genetics of island plant populations.

PMID- 15014425
TI  - Mating patterns and genetic diversity in the wild daffodil Narcissus longispathus
      (Amaryllidaceae).
AB  - Despite the importance of Narcissus to ornamental horticulture, there have been
      no population genetic studies of wild species, many of which have narrow
      distributions. Here, we measure selfing rates and levels of genetic diversity at
      allozyme loci in six populations of Narcissus longispathus, a self-compatible
      daffodil endemic to a few mountain ranges in southeastern Spain. The populations
      were distributed among four distinct river valleys encompassing two main
      watersheds in the Sierra de Cazorla mountains. Selfing rates averaged 0.37 (range
      0.23-0.46), resulting in significant inbreeding coefficients for the progeny (f =
      0.324). In contrast, estimates of inbreeding in parental genotypes were not
      significantly different from zero (f = 0.001), indicating that few selfed
      offspring survive to maturity because of inbreeding depression. Species-wide
      estimates of genetic diversity for the six populations were P(s) = 0.38, H(es) =
      0.119 and A(s) = 1.27 with significant genetic differentiation among populations
      theta = 0.15. The observed patterns of genetic differentiation among populations
      are likely influenced by the mating system, and a combination of local
      topography, watershed affinities and gene flow.

PMID- 15014426
TI  - Genetic diversity and differentiation in Eryngium alpinum L. (Apiaceae):
      comparison of AFLP and microsatellite markers.
AB  - Genetic diversity and structure of 12 populations of Eryngium alpinum L. were
      investigated using 63 dominant amplified fragment length polymorphism (AFLP) and
      seven codominant microsatellite (48 alleles) markers. Within-population diversity
      estimates obtained with both markers were not correlated, but the microsatellite
      based fixation index Fis was correlated with both AFLP diversity indices (number
      of polymorphic bands and Nei's expected heterozygosity). Only AFLP diversity
      indices increased with the size of populations, although they did not
      significantly differ among them (Kruskall-Wallis test). The discrepancy between
      AFLPs and microsatellites may be explained by a better coverage of the genome
      with numerous AFLPs, the higher mutation rates of microsatellites or the absence
      of significant difference among within-population diversity estimates. Genetic
      differentiation was higher with AFLPs (theta=0.40) than with microsatellites
      (theta=0.23), probably due to the higher polymorphism of microsatellites. Thus,
      we considered global qualitative patterns rather than absolute estimates to
      compare the performance of both types of markers. On a large geographic scale,
      the Mantel test and multivariate analysis showed that genetic patterns were more
      congruent with the spatial arrangement of populations when inferred from
      microsatellites than from AFLPs, suggesting higher homoplasy of AFLP markers. On
      a small spatial scale, AFLPs managed to discriminate individuals from neighboring
      populations whereas microsatellites did not (multivariate analysis), and the
      percentage of individuals correctly assigned to their population of origin was
      higher with AFLPs than with microsatellites. However, dominant AFLPs cannot be
      used to study heterozygosity-related topics. Thus, distinct molecular markers
      should be used depending on the biological question and the geographical scale
      investigated.

PMID- 15014427
TI  - Evidence for ancient genetic subdivision among recently fragmented populations of
      the endangered shrub Grevillea caleyi (Proteaceae).
AB  - The genetic effects of population fragmentation cannot be interpreted without
      understanding the underlying pattern of genetic variation resulting from historic
      population processes. We used AFLP markers to determine genetic structure and
      distribution of genetic diversity among populations of an endangered Australian
      shrub Grevillea caleyi (Proteaceae). Populations that occurred historically on
      four ridges have new been fragmented to varying degrees, producing some large,
      relatively pristine populations and very small populations consisting of fewer
      than 10 adult plants. We found marked population genetic structure (65.9% of
      genetic variation was among populations) and a significant relationship between
      genetic and geographic distance (rm=0.564, P=0.004). However, only 14% of overall
      genetic differentiation was attributable to variation among ridges, compared with
      52% among populations within ridges. Moreover, genetic diversity within samples
      of plants did not vary with either population size or degree of isolation. Thus,
      the present genetic structure of populations is probably almost entirely the
      product of historical events. Fine-scale structuring within populations prior to
      fragmentation may have been caused by limited seed and pollen dispersal, despite
      a complex suite of (mostly avian) pollinators, and a mixed mating system that
      allows a large amount of selfing. The combined effects of adult longevity and a
      soil-stored seed bank may have buffered the recently fragmented populations
      against the effects of dramatic reductions in numbers of adult plants.

PMID- 15014428
TI  - On the TRAIL of an arthritis cure.

PMID- 15014429
TI  - HLA-DQ6 and ingestion of contaminated water: possible gene-environment
      interaction in an outbreak of Leptospirosis.
AB  - Leptospirosis is a zoonosis that can cause severe multisystem disease. While host
      gene-environment interactions likely modify infectious disease susceptibility,
      including for leptopsirosis, this has not been documented. In a 1998
      leptospirosis outbreak investigation among triathletes in a lake swim, swallowing
      lake-water was a disease risk-factor. We used genomic DNA from 85 anonymized
      blood-sample remainders from that investigation to examine the association of
      laboratory-confirmed leptospirosis with gene polymorphisms (TNF-alpha alleles and
      serologically defined genotypes for HLA-DRB1 and HLA-DQB1). HLA-DQ6-positive
      triathletes had increased risk of laboratory-confirmed leptospirosis (OR=2.8,
      P=0.04) compared to DQ6-negatives. DQ6-positive triathletes swallowing lake-water
      had greatest risk (OR 8.46, P< or =0.001). This first report of a genetic risk
      factor affecting susceptibility to leptospirosis is also the first documented
      gene-environment interaction (DQ6 and swallowed water) affecting infectious
      disease susceptibility. Based on these preliminary findings, we hypothesize a
      role for superantigens in leptospirosis and underscore the importance of outbreak
      investigations for understanding infectious disease gene-environment
      interactions.

PMID- 15014430
TI  - Linkage analysis of SLE susceptibility: confirmation of SLER1 at 5p15.3.
AB  - We detected a novel susceptibility gene, SLER1, for systemic lupus erythematosus
      (SLE) at 5p15.3.(1) This finding was based on a selected subgroup of SLE
      families, where two or more family members have had alleged rheumatoid arthritis
      (SLE-RA). The main objective of this study was to replicate the linkage at 5p15.3
      based on an independent data set of 88 SLE-RA families. Heterogeneity in the
      genetic model led us to use a nonparametric allele-sharing method. Since our a
      priori hypothesis of linkage at 5p15.3 was fixed, we genotyped six markers at the
      linked region. Our new results replicate the initial linkage at 5p15.3 (Zlr=2.58,
      P<0.005, LOD=1.45). Moreover, evidence of linkage was sustained when analysis was
      restricted to the subset of SLE families who had 3 or more individuals with
      alleged RA (Zlr=3.32, P=0.008, LOD=2.40) The results of our previous findings,
      together with these new results, confirm the SLER1 linkage at 5p15.3. Our results
      also demonstrate the utility of clinically defined subgroup analysis for
      detecting susceptibility loci for complex genetic diseases, such as SLE.

PMID- 15014431
TI  - Defining the contribution of the HLA region to cis DQ2-positive coeliac disease
      patients.
AB  - The major genetic susceptibility to coeliac disease is contributed by the human
      leukocyte antigen (HLA) region. The primary association is with the HLA-DQ2
      molecule, encoded by the DQA1*05 and DQB1*02 alleles, which is expressed by over
      90% of patients. The aim of our study was to perform an extensive scan of the
      entire HLA region to determine whether there is evidence for the presence of
      additional HLA susceptibility genes for coeliac disease in the Dutch population,
      acting independently of DQ2. In all, 16 microsatellite markers and the DQA1 and
      DQB1 genes were genotyped in simplex cis DQ2-positive coeliac disease families
      and cis DQ2-positive control families. Allele frequencies of markers on phase
      known DQ2-positive haplotypes transmitted to patients were compared to a combined
      group of DQ2-positive nontransmitted and control haplotypes, thereby controlling
      for the DQ2 contribution. No significant differences at any of the marker loci
      were detected, suggesting that DQ2 is the major HLA risk factor for coeliac
      disease. Individuals homozygous for DQ2 or heterozygous for DQA1*05
      DQB1*02/DQA1*0201-DQB1*02 were found to be at five-fold increased risk for
      development of coeliac disease (P<10(-8)). This risk seems to be conferred by the
      presence of a second DQB1*02 allele next to one DQA1*05-DQB1*02 haplotype,
      independently of the second DQA1 allele.

PMID- 15014432
TI  - Linkage analysis of susceptibility to leprosy type using an IBD regression
      method.
AB  - Leprosy is a chronic disease caused by infection with Mycobacterium leprae, which
      is manifested across a wide clinical spectrum. There is evidence that
      susceptibility both to leprosy per se and to the clinical type of leprosy is
      influenced by host genetic factors. This paper describes the application of an
      identity by descent regression search for genetic determinants of leprosy type
      among families from Karonga District, Northern Malawi. Suggestive evidence was
      found for linkage to leprosy type on chr 21q22 (P<0.001). The methodological
      implications of the approach and the findings are discussed.

PMID- 15014434
TI  - Myo1c is designed for the adaptation response in the inner ear.
AB  - The molecular motor, Myo1c, a member of the myosin family, is widely expressed in
      vertebrate tissues. Its presence at strategic places in the stereocilia of the
      hair cells in the inner ear and studies using transgenic mice expressing a mutant
      Myo1c that can be selectively inhibited implicate it as the mediator of slow
      adaptation of mechanoelectrical transduction, which is required for balance.
      Here, we have studied the structural, mechanical and biochemical properties of
      Myo1c to gain an insight into how this molecular motor works. Our results support
      a model in which Myo1c possesses a strain-sensing ADP-release mechanism, which
      allows it to adapt to mechanical load.

PMID- 15014433
TI  - Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1
      transgenic mice.
AB  - Cyclooxygenase-2 (COX-2), the rate-limiting enzyme for prostanoid biosynthesis,
      plays a key role in gastrointestinal carcinogenesis. Among various prostanoids,
      prostaglandin E2 (PGE2) appears to be most responsible for cancer development. To
      investigate the role of PGE2 in gastric tumorigenesis, we constructed transgenic
      mice simultaneously expressing COX-2 and microsomal prostaglandin E synthase
      (mPGES)-1 in the gastric epithelial cells. The transgenic mice developed
      metaplasia, hyperplasia and tumorous growths in the glandular stomach with heavy
      macrophage infiltrations. Although gastric bacterial counts in the transgenic
      mice were within the normal range, treatment with antibiotics significantly
      suppressed activation of the macrophages and tumorous hyperplasia. Importantly,
      the antibiotics treatment did not affect the macrophage accumulation. Notably,
      treatment of the transgenic mice with lipopolysaccharides induced proinflammatory
      cytokines through Toll-like receptor 4 in the gastric epithelial cells. These
      results indicate that an increased level of PGE2 enhances macrophage
      infiltration, and that they are activated through epithelial cells by the gastric
      flora, resulting in gastric metaplasia and tumorous growth. Furthermore,
      Helicobacter infection upregulated epithelial PGE2 production, suggesting that
      the COX-2/mPGES-1 pathway contributes to the Helicobacter-associated gastric
      tumorigenesis.

PMID- 15014435
TI  - Dynacortin contributes to cortical viscoelasticity and helps define the shape
      changes of cytokinesis.
AB  - During cytokinesis, global and equatorial pathways deform the cell cortex in a
      stereotypical manner, which leads to daughter cell separation. Equatorial forces
      are largely generated by myosin-II and the actin crosslinker, cortexillin-I. In
      contrast, global mechanics are determined by the cortical cytoskeleton, including
      the actin crosslinker, dynacortin. We used direct morphometric characterization
      and laser-tracking microrheology to quantify cortical mechanical properties of
      wild-type and cortexillin-I and dynacortin mutant Dictyostelium cells. Both
      cortexillin-I and dynacortin influence cytokinesis and interphase cortical
      viscoelasticity as predicted from genetics and biochemical data using purified
      dynacortin proteins. Our studies suggest that the regulation of cytokinesis
      ultimately requires modulation of proteins that control the cortical mechanical
      properties that establish the force-balance that specifies the shapes of
      cytokinesis. The combination of genetic, biochemical, and biophysical
      observations suggests that the cell's cortical mechanical properties control how
      the cortex is remodeled during cytokinesis.

PMID- 15014436
TI  - Structure of a thrombospondin C-terminal fragment reveals a novel calcium core in
      the type 3 repeats.
AB  - Thrombospondins (TSPs) are extracellular regulators of cell-matrix interactions
      and cell phenotype. The most highly conserved region of all TSPs are the calcium
      binding type 3 (T3) repeats and the C-terminal globular domain (CTD). The crystal
      structure of a cell-binding TSP-1 fragment, spanning three T3 repeats and the
      CTD, reveals a compact assembly. The T3 repeats lack secondary structure and are
      organised around a core of calcium ions; two DxDxDGxxDxxD motifs per repeat each
      encapsulate two calcium ions in a novel arrangement. The CTD forms a lectin-like
      beta-sandwich and contains four strictly conserved calcium-binding sites.
      Disruption of the hairpin structure of T3 repeats 6 and 7 decreases protein
      secretion and stability. The availability for cell attachment of an RGD motif in
      T3 repeat 7 is modulated by calcium loading. The central architectural role of
      calcium explains how it is critical for the functions of the TSP C-terminal
      region. Mutations in the T3 repeats of TSP-5/COMP, which cause two human skeletal
      disorders, are predicted to disrupt the tertiary structure of the T3-CTD
      assembly.

PMID- 15014437
TI  - An intramolecular interaction between the FHA domain and a coiled coil negatively
      regulates the kinesin motor KIF1A.
AB  - Motor proteins not actively involved in transporting cargoes should remain
      inactive at sites of cargo loading to save energy and remain available for
      loading. KIF1A/Unc104 is a monomeric kinesin known to dimerize into a processive
      motor at high protein concentrations. However, the molecular mechanisms
      underlying monomer stabilization and monomer-to-dimer transition are not well
      understood. Here, we report an intramolecular interaction in KIF1A between the
      forkhead-associated (FHA) domain and a coiled-coil domain (CC2) immediately
      following the FHA domain. Disrupting this interaction by point mutations in the
      FHA or CC2 domains leads to a dramatic accumulation of KIF1A in the periphery of
      living cultured neurons and an enhancement of the microtubule (MT) binding and
      self-multimerization of KIF1A. In addition, point mutations causing rigidity in
      the predicted flexible hinge disrupt the intramolecular FHA-CC2 interaction and
      increase MT binding and peripheral accumulation of KIF1A. These results suggest
      that the intramolecular FHA-CC2 interaction negatively regulates KIF1A activity
      by inhibiting MT binding and dimerization of KIF1A, and point to a novel role of
      the FHA domain in the regulation of kinesin motors.

PMID- 15014438
TI  - MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association
      and ARE-mRNA decay.
AB  - Stress granules (SGs) are dynamic cytoplasmic foci at which stalled translation
      initiation complexes accumulate in cells subjected to environmental stress. SG
      associated proteins such as TIA-1, TIAR and HuR bind to AU-rich element (ARE)
      containing mRNAs and control their translation and stability. Here we show that
      tristetraprolin (TTP), an ARE-binding protein that destabilizes ARE-mRNAs, is
      recruited to SGs that are assembled in response to FCCP-induced energy
      deprivation, but not arsenite-induced oxidative stress. Exclusion of TTP from
      arsenite-induced SGs is a consequence of MAPKAP kinase-2 (MK2)-induced
      phosphorylation at serines 52 and 178, which promotes the assembly of TTP:14-3-3
      complexes. 14-3-3 binding excludes TTP from SGs and inhibits TTP-dependent
      degradation of ARE-containing transcripts. In activated RAW 264.7 macrophages,
      endogenous TTP:14-3-3 complexes bind to ARE-RNA. Our data reveal the mechanism by
      which the p38-MAPK/MK2 kinase cascade inhibits TTP-mediated degradation of ARE
      containing transcripts and thereby contributes to lipopolysaccharide-induced
      TNFalpha expression.

PMID- 15014439
TI  - Structural inhibition of the colicin D tRNase by the tRNA-mimicking immunity
      protein.
AB  - Colicins are toxins secreted by Escherichia coli in order to kill their
      competitors. Colicin D is a 75 kDa protein that consists of a translocation
      domain, a receptor-binding domain and a cytotoxic domain, which specifically
      cleaves the anticodon loop of all four tRNA(Arg) isoacceptors, thereby
      inactivating protein synthesis and leading to cell death. Here we report the 2.0
      A resolution crystal structure of the complex between the toxic domain and its
      immunity protein ImmD. Neither component shows structural homology to known
      RNases or their inhibitors. In contrast to other characterized colicin nuclease
      Imm complexes, the colicin D active site pocket is completely blocked by ImmD,
      which, by bringing a negatively charged cluster in opposition to a positively
      charged cluster on the surface of colicin D, appears to mimic the tRNA substrate
      backbone. Site-directed mutations affecting either the catalytic domain or the
      ImmD protein have led to the identification of the residues vital for catalytic
      activity and for the tight colicin D/ImmD interaction that inhibits colicin D
      toxicity and tRNase catalytic activity.

PMID- 15014440
TI  - Mechanism controlling perpendicular alignment of the spindle to the axis of cell
      division in fission yeast.
AB  - In animal cells, the mitotic spindle is aligned perpendicular to the axis of cell
      division. This ensures that sister chromatids are separated to opposite sides of
      the cytokinetic actomyosin ring (CAR). We show that, in fission yeast, spindle
      rotation is dependent on the interaction of astral microtubules with the cortical
      actin cytoskeleton. Interaction initially occurs with a region surrounding the
      nucleus, which we term the astral microtubule interaction zone (AMIZ).
      Simultaneous contact of astral microtubules from both poles with the AMIZ directs
      spindle rotation and this requires both actin and two type V myosins, Myo51 and
      Myo52. Astral microtubules from one pole only then contact the CAR, which is
      located at the centre of the AMIZ. We demonstrate that the anillin homologue
      Mid1, which dictates correct placement of the CAR, is necessary to stabilise the
      mitotic spindle perpendicular to the axis of cell division. Finally, we show that
      the position of the mitotic spindle is monitored by a checkpoint that regulates
      the timing of sister chromatid separation.

PMID- 15014441
TI  - Importin alpha associates with membranes and participates in nuclear envelope
      assembly in vitro.
AB  - Importin alpha is well known as an adaptor that functions with Importin beta in
      the nuclear import of proteins containing specific nuclear localization signals
      (NLSs). We show here that either an excess or a lack of Importin alpha blocks
      nuclear envelope (NE) assembly in vitro, and our data suggest that soluble
      Importin alpha functions in NE assembly in conjunction with NLS-containing
      partner proteins. Surprisingly, a significant proportion of Importin alpha is
      found to fractionate with Xenopus egg membranes. We demonstrate that membrane
      association of Importin alpha is regulated by phosphorylation. Using mutant forms
      of Importin alpha that either do not bind membranes or are not released from them
      by phosphorylation, we provide evidence that membrane-associated Importin alpha
      is required for NE formation. Unlike other functions of Importin alpha, this
      membrane-associated activity does not require interaction with NLS proteins.

PMID- 15014442
TI  - Structure of the translocator domain of a bacterial autotransporter.
AB  - Autotransporters are virulence-related proteins of Gram-negative bacteria that
      are secreted via an outer-membrane-based C-terminal extension, the translocator
      domain. This domain supposedly is sufficient for the transport of the N-terminal
      passenger domain across the outer membrane. We present here the crystal structure
      of the in vitro-folded translocator domain of the autotransporter NalP from
      Neisseria meningitidis, which reveals a 12-stranded beta-barrel with a
      hydrophilic pore of 10 x 12.5 A that is filled by an N-terminal alpha-helix. The
      domain has pore activity in vivo and in vitro. Our data are consistent with the
      model of passenger-domain transport through the hydrophilic channel within the
      beta-barrel, and inconsistent with a model for transport through a central
      channel formed by an oligomer of translocator domains. However, the dimensions of
      the pore imply translocation of the secreted domain in an unfolded form. An
      alternative model, possibly covering the transport of folded domains, is that
      passenger-domain transport involves the Omp85 complex, the machinery required for
      membrane insertion of outer-membrane proteins, on which autotransporters are
      dependent.

PMID- 15014443
TI  - Methanoarchaeal sulfolactate dehydrogenase: prototype of a new family of NADH
      dependent enzymes.
AB  - The crystal structure of the sulfolactate dehydrogenase from the
      hyperthermophilic and methanogenic archaeon Methanocaldococcus jannaschii was
      solved at 2.5 A resolution (PDB id. 1RFM). The asymmetric unit contains a
      tetramer of tight dimers. This structure, complexed with NADH, does not contain a
      cofactor-binding domain with 'Rossmann-fold' topology. Instead, the tertiary and
      quaternary structures indicate a novel fold. The NADH is bound in an extended
      conformation in each active site, in a manner that explains the pro-S
      specificity. Cofactor binding involves residues belonging to both subunits within
      the tight dimers, which are therefore the smallest enzymatically active units.
      The protein was found to be a homodimer in solution by size-exclusion
      chromatography, analytical ultracentrifugation and small-angle neutron
      scattering. Various compounds were tested as putative substrates. The results
      indicate the existence of a substrate discrimination mechanism, which involves
      electrostatic interactions. Based on sequence homology and phylogenetic analyses,
      several other enzymes were classified as belonging to this novel family of
      homologous (S)-2-hydroxyacid dehydrogenases.

PMID- 15014444
TI  - Brca2 is involved in meiosis in Arabidopsis thaliana as suggested by its
      interaction with Dmc1.
AB  - Two BRCA2-like sequences are present in the Arabidopsis genome. Both genes are
      expressed in flower buds and encode nearly identical proteins, which contain four
      BRC motifs. In a yeast two-hybrid assay, the Arabidopsis Brca2 proteins interact
      with Rad51 and Dmc1. RNAi constructs aimed at silencing the BRCA2 genes at
      meiosis triggered a reproducible sterility phenotype, which was associated with
      dramatic meiosis alterations. We obtained the same phenotype upon introduction of
      RNAi constructs aimed at silencing the RAD51 gene at meiosis in dmc1 mutant
      plants. The meiotic figures we observed strongly suggest that homologous
      recombination is highly disturbed in these meiotic cells, leaving aberrant
      recombination events to repair the meiotic double-strand breaks. The 'brca2'
      meiotic phenotype was eliminated in spo11 mutant plants. Our experiments point to
      an essential role of Brca2 at meiosis in Arabidopsis. We also propose a role for
      Rad51 in the dmc1 context.

PMID- 15014445
TI  - Separation of silencing from perinuclear anchoring functions in yeast Ku80, Sir4
      and Esc1 proteins.
AB  - In budding yeast, the nuclear periphery forms a subcompartment in which telomeres
      cluster and SIR proteins concentrate. To identify the proteins that mediate
      chromatin anchorage to the nuclear envelope, candidates were fused to LexA and
      targeted to an internal GFP-tagged chromosomal locus. Their ability to shift the
      locus from a random to a peripheral subnuclear position was monitored in living
      cells. Using fusions that cannot silence, we identify YKu80 and a 312-aa domain
      of Sir4 (Sir4(PAD)) as minimal anchoring elements, each able to relocalize an
      internal chromosomal locus to the nuclear periphery. Sir4(PAD)-mediated tethering
      requires either the Ku complex or Esc1, an acidic protein that is localized to
      the inner face of the nuclear envelope even in the absence of Ku, Sir4 or Nup133.
      Finally, we demonstrate that Ku- and Esc1-dependent pathways mediate natural
      telomere anchoring in vivo. These data provide the first unambiguous
      identification of protein interactions that are both necessary and sufficient to
      localize chromatin to the nuclear envelope.

PMID- 15014446
TI  - Tandem bromodomains in the chromatin remodeler RSC recognize acetylated histone
      H3 Lys14.
AB  - The coordination of chromatin remodeling with chromatin modification is a central
      topic in gene regulation. The yeast chromatin remodeling complex RSC bears
      multiple bromodomains, motifs for acetyl-lysine and histone tail interaction.
      Here, we identify and characterize Rsc4 and show that it bears tandem essential
      bromodomains. Conditional rsc4 bromodomain mutations were isolated, and were
      lethal in combination with gcn5Delta, whereas combinations with esa1 grew well.
      Replacements involving Lys14 of histone H3 (the main target of Gcn5), but not
      other H3 or H4 lysine residues, also conferred severe growth defects to rsc4
      mutant strains. Importantly, wild-type Rsc4 bound an H3 tail peptide acetylated
      at Lys14, whereas a bromodomain mutant derivative did not. Loss of particular
      histone deacetylases suppressed rsc4 bromodomain mutations, suggesting that Rsc4
      promotes gene activation. Furthermore, rsc4 mutants displayed defects in the
      activation of genes involved in nicotinic acid biosynthesis, cell wall integrity,
      and other pathways. Taken together, Rsc4 bears essential tandem bromodomains that
      rely on H3 Lys14 acetylation to assist RSC complex for gene activation.

PMID- 15014447
TI  - Combinatorial gene control involving E2F and E Box family members.
AB  - Various studies point to the potential role of combinatorial action of
      transcription factors as a mechanism to achieve the complexity of eukaryotic gene
      control with a finite number of regulatory proteins. Our previous work has
      focused on interactions involving the E2F family of transcription factors as an
      example of combinatorial gene control, leading to the identification of TFE3 and
      YY1 as transcription partners for several E2F proteins. We now show that
      additional E2F target genes share a common promoter architecture and are also
      regulated by the combined action of TFE3 and E2F3. In contrast, the thymidine
      kinase (TK-1) promoter is also regulated by E2F3 but independent of TFE3. Other
      promoters exhibit distinct specificity in the interaction with E2F proteins that
      includes a role for E2F1 but not E2F3, examples where both E2F1 and E2F3 are seen
      to interact, and promoters that are regulated by TFE3 but independent of an E2F.
      We propose that these examples of combinatorial interactions involving E2F
      proteins provide a basis for the specificity of transcription control in the
      Rb/E2F pathway.

PMID- 15014448
TI  - Boca-dependent maturation of beta-propeller/EGF modules in low-density
      lipoprotein receptor proteins.
AB  - The extracellular portions of cell surface receptor proteins are often comprised
      of independently folding protein domains. As they are translated into the
      endoplasmic reticulum (ER), some of these domains require protein chaperones to
      assist in their folding. Members of the low-density lipoprotein receptor (LDLR)
      family require the chaperone called Boca in Drosophila or its ortholog, Mesoderm
      development, in the mouse. All LDLRs have at least one six-bladed beta-propeller
      domain, which is immediately followed by an epidermal growth factor (EGF) repeat.
      We show here that Boca is specifically required for the maturation of these beta
      propeller/EGF modules through the secretory pathway, but is not required for
      other LDLR domains. Protein interaction data suggest that as LDLRs are translated
      into the ER, Boca binds to the beta-propeller. Subsequently, once the EGF repeat
      is translated, the beta-propeller/EGF module achieves a more mature state that
      has lower affinity for Boca. We also show that Boca-dependent beta-propeller/EGF
      modules are found not only throughout the LDLR family but also in the precursor
      to the mammalian EGF ligand.

PMID- 15014449
TI  - Distinct roles for ATP binding and hydrolysis at individual subunits of an
      archaeal clamp loader.
AB  - Circular clamps are utilised by replicative polymerases to enhance processivity.
      The topological problem of loading a toroidal clamp onto DNA is overcome by ATP
      dependent clamp loader complexes. Different organisms use related protein
      machines to load clamps, but the mechanisms by which they utilise ATP are
      surprisingly different. Using mutant clamp loaders that are deficient in either
      ATP binding or hydrolysis in different subunits, we show how the different
      subunits of an archaeal clamp loader use ATP binding and hydrolysis in distinct
      ways at different steps in the loading process. Binding of nucleotide by the
      large subunit and three of the four small subunits is sufficient for clamp
      loading. However, ATP hydrolysis by the small subunits is required for release of
      PCNA to allow formation of the complex between PCNA and the polymerase, while
      hydrolysis by the large subunit is required for catalytic clamp loading.

PMID- 15014452
TI  - Time for a French revolution.

PMID- 15014450
TI  - Induction of flowering by seasonal changes in photoperiod.
AB  - In many plants, major developmental transitions such as the initiation of
      flowering are synchronized to the changing seasons. Day length provides one of
      the environmental cues used to achieve this. We describe the molecular mechanisms
      that measure day length and control flowering in Arabidopsis. Also, we compare
      these mechanisms with those that control flowering time in rice. This comparison
      suggests that components of the Arabidopsis regulatory network are conserved in
      other species, but that their regulation can be altered to generate different
      phenotypic responses.

PMID- 15014454
TI  - Transgenic planting approved despite scepticism of UK public.

PMID- 15014451
TI  - A novel E1A-E1B mutant adenovirus induces glioma regression in vivo.
AB  - Malignant gliomas are the most frequently occurring primary brain tumors and are
      resistant to conventional therapy. Conditionally replicating adenoviruses are a
      novel strategy in glioma treatment. Clinical trials using E1B mutant adenoviruses
      have been reported recently and E1A mutant replication-competent adenoviruses are
      in advanced preclinical testing. Here we constructed a novel replication
      selective adenovirus (CB1) incorporating a double deletion of a 24 bp Rb-binding
      region in the E1a gene, and a 903 bp deleted region in the E1b gene that
      abrogates the expression of a p53-binding E1B-55 kDa protein. CB1 exerted a
      potent anticancer effect in vitro in U-251 MG, U-373 MG, and D-54 MG human glioma
      cell lines, as assessed by qualitative and quantitative viability assays.
      Replication analyses demonstrated that CB1 replicates in vitro in human glioma
      cells. Importantly, CB1 acquired a highly attenuated replicative phenotype in
      both serum-starved and proliferating normal human astrocytes. In vivo experiments
      using intracranially implanted D-54 MG glioma xenografts in nude mice showed that
      a single dose of CB1 (1.5 x 10(8) PFU/tumor) significantly improved survival.
      Immunohistochemical analyses of expressed adenoviral proteins confirmed
      adenoviral replication within the tumors. The CB1 oncolytic adenovirus induces a
      potent antiglioma effect and could ultimately demonstrate clinical relevance and
      therapeutic utility.

PMID- 15014455
TI  - Californian county bans transgenic crops.

PMID- 15014456
TI  - Wave of protest strikes Europe's universities.

PMID- 15014457
TI  - French scientists prepare for mass resignation.

PMID- 15014458
TI  - Terror watchdog set up for 'dual use' biology.

PMID- 15014459
TI  - Nigerian states disrupt campaign to eradicate polio.

PMID- 15014460
TI  - Problems of the poor set to face cost-benefit treatment.

PMID- 15014461
TI  - Biotechnologists seek to bridge South Asian divide.

PMID- 15014462
TI  - Air force clips the wings of UK wind power.

PMID- 15014465
TI  - Greenland's climate: a rising tide.

PMID- 15014463
TI  - Scheme to track rare dolphins hits troubled waters.

PMID- 15014466
TI  - Ageing: growing old gracefully.

PMID- 15014467
TI  - Time to choose the right site for a fusion reactor.

PMID- 15014468
TI  - US science has never been more coherent.

PMID- 15014469
TI  - More to consider about European research body.

PMID- 15014470
TI  - High-tech cluster bombs.

PMID- 15014475
TI  - Hurricanes and butterflies.

PMID- 15014476
TI  - Human longevity: the grandmother effect.

PMID- 15014477
TI  - Quantum information: flight of the qubit.

PMID- 15014478
TI  - Global change: an Earth on fire.

PMID- 15014480
TI  - Astrophysics: the inconstant constant?

PMID- 15014481
TI  - Condensed-matter physics: supramolecular twelve-a-side.

PMID- 15014482
TI  - Stem cells: more like a man.

PMID- 15014483
TI  - Planetary science: secrets of the deep.

PMID- 15014485
TI  - Live birth after ovarian tissue transplant.
AB  - Radiation and high-dose chemotherapy may render women with cancer prematurely
      sterile, a side-effect that would be avoided if ovarian tissue that had been
      removed before treatment could be made to function afterwards. Live offspring
      have been produced from transplanted ovarian tissue in mice and sheep but not in
      monkeys or humans, although sex steroid hormones are still secreted. Here we
      describe the successful transplantation of fresh ovarian tissue to a different
      site in a monkey, which has led to the birth of a healthy female after oocyte
      production, fertilization and transfer to a surrogate mother. The ectopically
      grafted tissue functions without surgical connection to major blood vessels and
      sets the stage for the transplantation of cryopreserved ovarian tissue in humans.

PMID- 15014486
TI  - Tissue engineering: creation of long-lasting blood vessels.
AB  - The construction of stable blood vessels is a fundamental challenge for tissue
      engineering in regenerative medicine. Although certain genes can be introduced
      into vascular cells to enhance their survival and proliferation, these
      manipulations may be oncogenic. We show here that a network of long-lasting blood
      vessels can be formed in mice by co-implantation of vascular endothelial cells
      and mesenchymal precursor cells, by-passing the need for risky genetic
      manipulations. These networks are stable and functional for one year in vivo.

PMID- 15014487
TI  - Animal behaviour: inequity aversion in capuchins?
AB  - Brosnan and de Waal have shown that capuchin monkeys are more likely to reject a
      cucumber slice after seeing that another capuchin has received a more attractive
      grape. In interpreting this finding, the authors make a link to work in humans on
      'inequity aversion' and suggest that capuchins, like humans, may reject rewards
      because they are averse to unequal pay-offs. Here I argue that this
      interpretation suffers from three problems: the results contradict the
      predictions of the inequity-aversion model that Bosnan and de Waal cite;
      experimental results indicate that humans do not behave like capuchins in similar
      circumstances; and the available evidence does not suggest that inequity aversion
      is cross-culturally universal.

PMID- 15014490
TI  - Animal behaviour: fair refusal by capuchin monkeys.
AB  - Brosnan and de Waal report that capuchin monkeys show evidence of a sense of
      fairness or 'inequity aversion' because they rejected a less preferred reward
      when they saw a partner monkey receive a preferred reward for the same task.
      However, this does not show that monkeys are averse to inequity, only that they
      reject a lesser reward when better rewards are available. There are risks
      inherent in seeking anthropomorphic explanations for non-human behaviour.

PMID- 15014491
TI  - Has the Higgs boson been discovered?
AB  - The standard model of particle physics describes the strong and electroweak
      interactions of fermions (spin-1/2), gauge bosons (spin-1) and a final vital
      ingredient--the spin-0 Higgs boson, which gives masses to the other particles.
      But the Higgs boson has yet to be discovered, and its own mass is not specified
      by the theory. There is some evidence (although statistically not very
      significant) for its detection at a mass of about 115 GeV/c2, from electron
      positron interactions at LEP (the Large Electron Positron collider). Indirect
      methods can also be used to constrain the mass of the Higgs boson, because it
      affects other observable quantities (for example, the mass of the W boson and
      some measurable properties of the Z boson). An indirect determination of the
      Higgs boson mass from the most recent measurements of such quantities yields a
      value compatible with 115 GeV/c2, but with some important caveats arising from
      inconsistencies in the present data.

PMID- 15014492
TI  - Germline stem cells and follicular renewal in the postnatal mammalian ovary.
AB  - A basic doctrine of reproductive biology is that most mammalian females lose the
      capacity for germ-cell renewal during fetal life, such that a fixed reserve of
      germ cells (oocytes) enclosed within follicles is endowed at birth. Here we show
      that juvenile and adult mouse ovaries possess mitotically active germ cells that,
      based on rates of oocyte degeneration (atresia) and clearance, are needed to
      continuously replenish the follicle pool. Consistent with this, treatment of
      prepubertal female mice with the mitotic germ-cell toxicant busulphan eliminates
      the primordial follicle reserve by early adulthood without inducing atresia.
      Furthermore, we demonstrate cells expressing the meiotic entry marker
      synaptonemal complex protein 3 in juvenile and adult mouse ovaries. Wild-type
      ovaries grafted into transgenic female mice with ubiquitous expression of green
      fluorescent protein (GFP) become infiltrated with GFP-positive germ cells that
      form follicles. Collectively, these data establish the existence of proliferative
      germ cells that sustain oocyte and follicle production in the postnatal mammalian
      ovary.

PMID- 15014493
TI  - Convective-region geometry as the cause of Uranus' and Neptune's unusual magnetic
      fields.
AB  - The discovery of Uranus' and Neptune's non-dipolar, non-axisymmetric magnetic
      fields destroyed the picture--established by Earth, Jupiter and Saturn--that
      planetary magnetic fields are dominated by axial dipoles. Although various
      explanations for these unusual fields have been proposed, the cause of such field
      morphologies remains unexplained. Planetary magnetic fields are generated by
      complex fluid motions in electrically conducting regions of the planets (a
      process known as dynamo action), and so are intimately linked to the structure
      and evolution of planetary interiors. Determining why Uranus and Neptune have
      different field morphologies is not only critical for studying the interiors of
      these planets, but also essential for understanding the dynamics of magnetic
      field generation in all planets. Here we present three-dimensional numerical
      dynamo simulations that model the dynamo source region as a convecting thin shell
      surrounding a stably stratified fluid interior. We show that this convective
      region geometry produces magnetic fields similar in morphology to those of Uranus
      and Neptune. The fields are non-dipolar and non-axisymmetric, and result from a
      combination of the stable fluid's response to electromagnetic stress and the
      small length scales imposed by the thin shell.

PMID- 15014494
TI  - Observation of entanglement between a single trapped atom and a single photon.
AB  - An outstanding goal in quantum information science is the faithful mapping of
      quantum information between a stable quantum memory and a reliable quantum
      communication channel. This would allow, for example, quantum communication over
      remote distances, quantum teleportation of matter and distributed quantum
      computing over a 'quantum internet'. Because quantum states cannot in general be
      copied, quantum information can only be distributed in these and other
      applications by entangling the quantum memory with the communication channel.
      Here we report quantum entanglement between an ideal quantum memory--represented
      by a single trapped 111Cd+ ion--and an ideal quantum communication channel,
      provided by a single photon that is emitted spontaneously from the ion.
      Appropriate coincidence measurements between the quantum states of the photon
      polarization and the trapped ion memory are used to verify their entanglement
      directly. Our direct observation of entanglement between stationary and 'flying'
      qubits is accomplished without using cavity quantum electrodynamic techniques or
      prepared non-classical light sources. We envision that this source of
      entanglement may be used for a variety of quantum communication protocols and for
      seeding large-scale entangled states of trapped ion qubits for scalable quantum
      computing.

PMID- 15014496
TI  - Seismic reflection imaging of two megathrust shear zones in the northern Cascadia
      subduction zone.
AB  - At convergent continental margins, the relative motion between the subducting
      oceanic plate and the overriding continent is usually accommodated by movement
      along a single, thin interface known as a megathrust. Great thrust earthquakes
      occur on the shallow part of this interface where the two plates are locked
      together. Earthquakes of lower magnitude occur within the underlying oceanic
      plate, and have been linked to geochemical dehydration reactions caused by the
      plate's descent. Here I present deep seismic reflection data from the northern
      Cascadia subduction zone that show that the inter-plate boundary is up to 16 km
      thick and comprises two megathrust shear zones that bound a >5-km-thick,
      approximately 110-km-wide region of imbricated crustal rocks. Earthquakes within
      the subducting plate occur predominantly in two geographic bands where the dip of
      the plate is inferred to increase as it is forced around the edges of the
      imbricated inter-plate boundary zone. This implies that seismicity in the
      subducting slab is controlled primarily by deformation in the upper part of the
      plate. Slip on the shallower megathrust shear zone, which may occur by aseismic
      slow slip, will transport crustal rocks into the upper mantle above the
      subducting oceanic plate and may, in part, provide an explanation for the
      unusually low seismic wave speeds that are observed there.

PMID- 15014495
TI  - Links between salinity variation in the Caribbean and North Atlantic thermohaline
      circulation.
AB  - Variations in the strength of the North Atlantic Ocean thermohaline circulation
      have been linked to rapid climate changes during the last glacial cycle through
      oscillations in North Atlantic Deep Water formation and northward oceanic heat
      flux. The strength of the thermohaline circulation depends on the supply of warm,
      salty water to the North Atlantic, which, after losing heat to the atmosphere,
      produces the dense water masses that sink to great depths and circulate back
      south. Here we analyse two Caribbean Sea sediment cores, combining Mg/Ca
      palaeothermometry with measurements of oxygen isotopes in foraminiferal calcite
      in order to reconstruct tropical Atlantic surface salinity during the last
      glacial cycle. We find that Caribbean salinity oscillated between saltier
      conditions during the cold oxygen isotope stages 2, 4 and 6, and lower salinities
      during the warm stages 3 and 5, covarying with the strength of North Atlantic
      Deep Water formation. At the initiation of the Bolling/Allerod warm interval,
      Caribbean surface salinity decreased abruptly, suggesting that the advection of
      salty tropical waters into the North Atlantic amplified thermohaline circulation
      and contributed to high-latitude warming.

PMID- 15014497
TI  - Unified spatial scaling of species and their trophic interactions.
AB  - Two largely independent bodies of scaling theory address the quantitative
      relationships between habitat area, species diversity and trophic interactions.
      Spatial theory within macroecology addresses how species richness scales with
      area in landscapes, while typically ignoring interspecific interactions.
      Complexity theory within community ecology addresses how trophic links scale with
      species richness in food webs, while typically ignoring spatial considerations.
      Recent studies suggest unifying these theories by demonstrating how spatial
      patterns influence food-web structure and vice versa. Here, we follow this
      suggestion by developing and empirically testing a more unified scaling theory.
      On the basis of power-law species-area relationships, we develop link-area and
      non-power-law link-species models that accurately predict how trophic links scale
      with area and species richness of microcosms, lakes and streams from community to
      metacommunity levels. In contrast to previous models that assume that species
      richness alone determines the number of trophic links, these models include the
      species' spatial distribution, and hence extend the domain of complexity theory
      to metacommunity scales. This generality and predictive success shows how
      complexity theory and spatial theory can be unified into a much more general
      theory addressing new domains of ecology.

PMID- 15014498
TI  - Pervasive alteration of tree communities in undisturbed Amazonian forests.
AB  - Amazonian rainforests are some of the most species-rich tree communities on
      earth. Here we show that, over the past two decades, forests in a central
      Amazonian landscape have experienced highly nonrandom changes in dynamics and
      composition. Our analyses are based on a network of 18 permanent plots unaffected
      by any detectable disturbance. Within these plots, rates of tree mortality,
      recruitment and growth have increased over time. Of 115 relatively abundant tree
      genera, 27 changed significantly in population density or basal area--a value
      nearly 14 times greater than that expected by chance. An independent, eight-year
      study in nearby forests corroborates these shifts in composition. Contrary to
      recent predictions, we observed no increase in pioneer trees. However, genera of
      faster-growing trees, including many canopy and emergent species, are increasing
      in dominance or density, whereas genera of slower-growing trees, including many
      subcanopy species, are declining. Rising atmospheric CO2 concentrations may
      explain these changes, although the effects of this and other large-scale
      environmental alterations remain uncertain. These compositional changes could
      have important impacts on the carbon storage, dynamics and biota of Amazonian
      forests.

PMID- 15014499
TI  - Fitness benefits of prolonged post-reproductive lifespan in women.
AB  - Most animals reproduce until they die, but in humans, females can survive long
      after ceasing reproduction. In theory, a prolonged post-reproductive lifespan
      will evolve when females can gain greater fitness by increasing the success of
      their offspring than by continuing to breed themselves. Although reproductive
      success is known to decline in old age, it is unknown whether women gain fitness
      by prolonging lifespan post-reproduction. Using complete multi-generational
      demographic records, we show that women with a prolonged post-reproductive
      lifespan have more grandchildren, and hence greater fitness, in pre-modern
      populations of both Finns and Canadians. This fitness benefit arises because post
      reproductive mothers enhance the lifetime reproductive success of their offspring
      by allowing them to breed earlier, more frequently and more successfully.
      Finally, the fitness benefits of prolonged lifespan diminish as the reproductive
      output of offspring declines. This suggests that in female humans, selection for
      deferred ageing should wane when one's own offspring become post-reproductive
      and, correspondingly, we show that rates of female mortality accelerate as their
      offspring terminate reproduction.

PMID- 15014500
TI  - Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against
      monkeypox.
AB  - The potential use of smallpox as a biological weapon has led to the production
      and stockpiling of smallpox vaccine and the immunization of some healthcare
      workers. Another public health goal is the licensing of a safer vaccine that
      could benefit the millions of people advised not to take the current one because
      they or their contacts have increased susceptibility to severe vaccine side
      effects. As vaccines can no longer be tested for their ability to prevent
      smallpox, licensing will necessarily include comparative immunogenicity and
      protection studies in non-human primates. Here we compare the highly attenuated
      modified vaccinia virus Ankara (MVA) with the licensed Dryvax vaccine in a monkey
      model. After two doses of MVA or one dose of MVA followed by Dryvax, antibody
      binding and neutralizing titres and T-cell responses were equivalent or higher
      than those induced by Dryvax alone. After challenge with monkeypox virus,
      unimmunized animals developed more than 500 pustular skin lesions and became
      gravely ill or died, whereas vaccinated animals were healthy and asymptomatic,
      except for a small number of transient skin lesions in animals immunized only
      with MVA.

PMID- 15014501
TI  - Myocardin and ternary complex factors compete for SRF to control smooth muscle
      gene expression.
AB  - Smooth muscle cells switch between differentiated and proliferative phenotypes in
      response to extracellular cues, but the transcriptional mechanisms that confer
      such phenotypic plasticity remain unclear. Serum response factor (SRF) activates
      genes involved in smooth muscle differentiation and proliferation by recruiting
      muscle-restricted cofactors, such as the transcriptional coactivator myocardin,
      and ternary complex factors (TCFs) of the ETS-domain family, respectively. Here
      we show that growth signals repress smooth muscle genes by triggering the
      displacement of myocardin from SRF by Elk-1, a TCF that acts as a myogenic
      repressor. The opposing influences of myocardin and Elk-1 on smooth muscle gene
      expression are mediated by structurally related SRF-binding motifs that compete
      for a common docking site on SRF. A mutant smooth muscle promoter, retaining
      responsiveness to myocardin and SRF but defective in TCF binding, directs ectopic
      transcription in the embryonic heart, demonstrating a role for TCFs in
      suppression of smooth muscle gene expression in vivo. We conclude that growth and
      developmental signals modulate smooth muscle gene expression by regulating the
      association of SRF with antagonistic cofactors.

PMID- 15014502
TI  - Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin
      ligase.
AB  - Skp2 and its cofactor Cks1 are the substrate-targeting subunits of the SCF(Skp2
      Cks1) (Skp1/Cul1/F-box protein) ubiquitin ligase complex that regulates entry
      into S phase by inducing the degradation of the cyclin-dependent kinase
      inhibitors p21 and p27 (ref. 1). Skp2 is an oncoprotein that often shows
      increased expression in human cancers; however, the mechanism that regulates its
      cellular abundance is not well understood. Here we show that both Skp2 and Cks1
      proteins are unstable in G1 and that their degradation is mediated by the
      ubiquitin ligase APC/C(Cdh1) (anaphase-promoting complex/cyclosome and its
      activator Cdh1). Silencing of Cdh1 by RNA interference in G1 cells stabilizes
      Skp2 and Cks1, with a consequent increase in p21 and p27 proteolysis. Depletion
      of Cdh1 also increases the percentage of cells in S phase, whereas concomitant
      downregulation of Skp2 reverses this effect, showing that Skp2 is an essential
      target of APC/C(Cdh1). Expression of a stable Skp2 mutant that cannot bind
      APC/C(Cdh1) induces premature entry into S phase. Thus, the induction of Skp2 and
      Cks1 degradation in G1 represents a principal mechanism by which APC/C(Cdh1)
      prevents the unscheduled degradation of SCF(Skp2-Cks1) substrates and maintains
      the G1 state.

PMID- 15014503
TI  - Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase
      promoting complex.
AB  - Cell-cycle transitions are driven by waves of ubiquitin-dependent degradation of
      key cell-cycle regulators. SCF (Skp1/Cullin/F-box protein) complexes and anaphase
      promoting complexes (APC) represent two major classes of ubiquitin ligases whose
      activities are thought to regulate primarily the G1/S and metaphase/anaphase cell
      cycle transitions, respectively. The major target of the Skp1/Cul1/Skp2
      (SCF(SKP2)) complex is thought to be the Cdk inhibitor p27 during S phase,
      whereas the principal targets for the APC are thought to be involved in chromatid
      separation (securin) and exit from mitosis (cyclin B). Although the role of the
      APC in mitosis is relatively clear, there is mounting evidence that APCs
      containing Cdh1 (APC(CDH1)) also have a function in the G1 phase of the cell
      cycle. Here, we show that the F-box protein Skp2 is polyubiquitinated, and hence
      earmarked for destruction, by APC(CDH1). As a result, accumulation of SCF(SKP2)
      requires prior inactivation of APC(CDH1). These findings provide an insight into
      the orchestration of SCF and APC activities during cell-cycle progression, and
      into the involvement of the APC in G1.

PMID- 15014504
TI  - Insight into tubulin regulation from a complex with colchicine and a stathmin
      like domain.
AB  - Microtubules are cytoskeletal polymers of tubulin involved in many cellular
      functions. Their dynamic instability is controlled by numerous compounds and
      proteins, including colchicine and stathmin family proteins. The way in which
      microtubule instability is regulated at the molecular level has remained elusive,
      mainly because of the lack of appropriate structural data. Here, we present the
      structure, at 3.5 A resolution, of tubulin in complex with colchicine and with
      the stathmin-like domain (SLD) of RB3. It shows the interaction of RB3-SLD with
      two tubulin heterodimers in a curved complex capped by the SLD amino-terminal
      domain, which prevents the incorporation of the complexed tubulin into
      microtubules. A comparison with the structure of tubulin in protofilaments shows
      changes in the subunits of tubulin as it switches from its straight conformation
      to a curved one. These changes correlate with the loss of lateral contacts and
      provide a rationale for the rapid microtubule depolymerization characteristic of
      dynamic instability. Moreover, the tubulin-colchicine complex sheds light on the
      mechanism of colchicine's activity: we show that colchicine binds at a location
      where it prevents curved tubulin from adopting a straight structure, which
      inhibits assembly.

PMID- 15014506
TI  - Cultural reflections.

PMID- 15014507
TI  - Making an impact.

PMID- 15014508
TI  - The new Silk Road.

PMID- 15014509
TI  - An embryonic nation.

PMID- 15014510
TI  - A case for conservation.

PMID- 15014511
TI  - Agriculture of the future.

PMID- 15014512
TI  - Making big money from small technology.

PMID- 15014513
TI  - Follow your nose.

PMID- 15014515
TI  - Running interference on the genome.

PMID- 15014514
TI  - Drug target identification: a question of biology.

PMID- 15014516
TI  - Drug discovery in reverse.

PMID- 15014517
TI  - Getting up speed.

PMID- 15014519
TI  - The waiting game.

PMID- 15014520
TI  - Reinventing the silk road.

PMID- 15014521
TI  - Graduate journal: the lab environment.

PMID- 15014522
TI  - Bricks and mortar. Building Copenhagen's BioCentre.

PMID- 15014524
TI  - Supramolecular dendritic liquid quasicrystals.
AB  - A large number of synthetic and natural compounds self-organize into bulk phases
      exhibiting periodicities on the 10(-8)-10(-6) metre scale as a consequence of
      their molecular shape, degree of amphiphilic character and, often, the presence
      of additional non-covalent interactions. Such phases are found in lyotropic
      systems (for example, lipid-water, soap-water), in a range of block copolymers
      and in thermotropic (solvent-free) liquid crystals. The resulting periodicity can
      be one-dimensional (lamellar phases), two-dimensional (columnar phases) or three
      dimensional ('micellar' or 'bicontinuous' phases). All such two- and three
      dimensional structures identified to date obey the rules of crystallography and
      their symmetry can be described, respectively, by one of the 17 plane groups or
      230 space groups. The 'micellar' phases have crystallographic counterparts in
      transition-metal alloys, where just one metal atom is equivalent to a 10(3)-10(4)
      atom micelle. However, some metal alloys are known to defy the rules of
      crystallography and form so-called quasicrystals, which have rotational symmetry
      other than the allowed two-, three-, four- or six-fold symmetry. Here we show
      that such quasiperiodic structures can also exist in the scaled-up micellar
      phases, representing a new mode of organization in soft matter.

PMID- 15014525
TI  - Immunophenotypic normalization of aberrant mast cells accompanies histological
      remission in imatinib-treated patients with eosinophilia-associated mastocytosis.

PMID- 15014526
TI  - Activation of the HIF pathway in childhood ALL, prognostic implications of VEGF.
AB  - Hypoxia-inducible factor 1 (HIF-1) controls angiogenesis and glycolysis, two
      leading characteristics of solid tumor invasion, metastasis, and lethality.
      Increased angiogenesis is also found in the bone marrow (BM) of leukemias. Less
      is known in leukemia about the role of HIF-1 and vascular endothelial growth
      factor (VEGF), the most important proangiogenic target gene of HIF-1. We show by
      immunohistochemistry that the oxygen-regulated component of HIF-1 (HIF-1alpha) is
      overexpressed in clusters of leukemic cells in BM specimens of childhood acute
      lymphoblastic leukemia (ALL) and absent in biopsies of normal BM. Half the HIF
      1alpha-positive ALL biopsies exhibited VEGF coexpression. Among 96 children with
      relapsed ALL, diagnostic BM aspirates with high VEGF mRNA levels were associated
      with a significantly lower probability of event-free survival at 3 years (0.31+/
      0.08 vs 0.65+/-0.07, P=0.003). Those with poor molecular response to therapy
      (evaluated by MRD assessment) had 2.2-fold higher VEGF levels than those
      responding well to chemotherapy (P=0.005). In conclusion, the data demonstrate
      activation of the HIF pathway in the BM of ALL patients and indicate that the
      expression of HIF target genes, such as VEGF, play an important role in leukemia
      progression, therapy response, and outcome.

PMID- 15014527
TI  - IL-6 regulates CD44 cell surface expression on human myeloma cells.
AB  - Multiple myeloma (MM) is a progressive B-lineage neoplasia characterized by the
      accumulation of slow proliferative malignant plasma cells in the bone marrow
      compartment where the microenvironment seems to be favorable for their growth and
      survival. Heparan sulfate proteoglycans such as syndecan-1 and CD44 are thought
      to play a central role in the survival signals provided by these bone marrow
      survival niches, which require complex interactions between myeloma cells,
      extracellular matrix, stromal cells and soluble factors. In this report, we
      demonstrate that interleukin-6 (IL-6), the main survival and growth factor for
      myeloma cells, strongly increases CD44 gene expression. In addition, we show that
      IL-6 modulates CD44 RNA alternative splicing and induces the overexpression of
      all CD44 variant exons. Finally, we show that IL-6-induced CD44 cell surface
      molecules have a functional polarized membrane distribution. As IL-6 secretion
      induced from bone marrow stromal cells by myeloma cells is partly mediated
      through direct cell-to-cell interaction involving CD44 adhesion molecules, our
      findings suggest that a CD44/IL-6 amplification loop plays a crucial role in
      myeloma cell survival.

PMID- 15014528
TI  - Growth autonomy and lineage switching in BCR-ABL-transduced human cord blood
      cells depend on different functional domains of BCR-ABL.
AB  - The tyrosine kinase activity of p210BCR-ABL is essential to its leukemogenic
      potential, but the role of other functional domains in primary human
      hematopoietic cells has not been previously investigated. Here we show that
      infection of normal human CD34+ cord blood (CB) cells with a retroviral vector
      encoding p210BCR-ABL rapidly activates a factor-independent phenotype and
      autocrine interleukin-3/granulocyte colony-stimulating factor/erythropoietin
      production in the transduced cells. These changes are characteristic of primitive
      chronic myeloid leukemic (CML) cells and are important to the leukemogenicity of
      BCR-ABL-transduced murine hematopoietic stem cells. When BCR-ABL-transduced human
      CB cells were incubated with imatinib mesylate, an inhibitor of the p210BCR-ABL
      kinase, or when human CB cells were transduced with a BCR-ABL cDNA lacking the
      SH2 domain (p210DeltaSH2), factor independence was significantly reduced. In
      contrast, deletion of the SH2 domain had little impact on the p210BCR-ABL kinase
      dependent promotion of erythropoietic differentiation also seen immediately
      following the BCR-ABL transduction of primitive human CB cells, but not in
      naturally occurring CML. Thus, p210BCR-ABL has distinct biological effects in
      primary human hematopoietic cells, which variably mimic features of human CML,
      and activation of these changes can show different dependencies on the integrity
      of the SH1 and SH2 domains of p210BCR-ABL.

PMID- 15014529
TI  - Secondary imatinib resistance associated with an aberrant bcr-abl fusion gene.

PMID- 15014530
TI  - Improvement of gene expression analysis by RQ-PCR technology: addition of BSA.

PMID- 15014531
TI  - Dendritic cells become BCR-ABL negative in chronic myeloid leukaemia patients
      successfully treated with imatinib.

PMID- 15014532
TI  - Endogenous and recombinant erythropoietin levels decline in human amniotic fluid
      and fetal plasma in vitro at 37 degrees C.
AB  - OBJECTIVE: To determine the in vitro stability of endogenous and recombinant
      erythropoietin (EPO) incubated at 37 degrees C in amniotic fluid (AF) and fetal
      plasma. STUDY DESIGN: Endogenous and recombinant EPO in AF, fetal plasma and
      phosphate buffer were incubated in vitro for 21 days at 37 degrees C. Serial
      aliquots were analyzed for EPO and the rates of EPO decline were compared within
      and between groups. RESULTS: Endogenous and recombinant EPO declined
      significantly in plasma and AF at 37 degrees C. Endogenous EPO displayed a
      similar linear rate of decline in AF and plasma, with nearly 70% of the initial
      hormone concentration remaining at 21 days. Recombinant EPO incubated in buffer
      did not change. CONCLUSIONS: Using the rate of decline in endogenous EPO we
      observed, EPO levels measured in AF or plasma within 21 days of fetal demise can
      be extrapolated back to the level likely present at fetal death.

PMID- 15014533
TI  - End tidal carbon monoxide levels are lower in women with gestational hypertension
      and pre-eclampsia.
AB  - BACKGROUND: The possible role of heme oxygenase and its byproduct carbon monoxide
      (CO) in the regulation of blood pressure is under investigation. The aim of this
      study was to compare end tidal breath CO (ETCO) levels in women with gestational
      hypertension (GH) or pre-eclampsia to the levels in healthy pregnant and
      nonpregnant women. MATERIALS AND METHODS: We prospectively performed ETCO
      measurements corrected for ambient CO (ETCOc) in two medical centers (Stanford,
      CA and Cleveland, OH). A Natus CO-Stat End Tidal Breath Analyzer (Natus Medical
      Inc., San Carlos, CA) was used. The study group included a convenience sample of
      31 women with GH/pre-eclampsia (PE). Control groups included 46 nonpregnant
      healthy women, 44 first-trimester and 48 third-trimester pregnant healthy women.
      RESULTS: Mean+/-SD ETCOc measurements were significantly lower in the GH/PE group
      compared to first-trimester (p=0.004) and third-trimester (p=0.001) normotensive
      pregnant and nonpregnant women (p=0.002) (1.36+/-0.30 vs 1.76+/-0.47, 1.72+/-0.42
      and 1.78+/-0.54 ppm, respectively). The ETCOc values were < or =1.6 ppm in 89% of
      GH/PE women compared with, respectively, only 45, 54, and 46% of nonpregnant,
      first- and third-trimester normotensive pregnant women (p<0.05). ETCO
      measurements were not influenced by maternal age, parity, ethnicity, body mass
      index, gestational age or presence of household smokers. In the two centers, the
      controls had a similar mean ETCOc and the differences found remained significant
      when results for each center were analyzed separately. CONCLUSIONS: ETCOc levels
      were found to be significantly lower in women with GH/PE. Further investigation
      is required to determine if the lower CO levels reflect a deficient compensatory
      response to the increase in blood pressure or whether these are primary changes
      of significance to our understanding of the pathogenesis of GH/PE.

PMID- 15014534
TI  - Birthweight by gestational age and sex at a rural referral center.
AB  - OBJECTIVE: Determine the distribution of birthweights in singleton births by
      gestational age and gender at Marquette General Hospital, a rural referral center
      in Michigan's upper peninsula. STUDY DESIGN: Birth log data were examined for
      prenatal factors and obstetrical outcomes. The birthweight distribution was
      compared to published values, and a linear regression model of prenatal factors
      was developed. RESULTS: Our median birthweights were significantly greater than
      published values. Males were 128 g heavier than female infants after adjusting
      for gestational age. In a multivariable linear regression model, birthweight was
      significantly associated with gestational age, sex of the infant, maternal age,
      primigravida status of mother, and maternal diabetes (all p<0.01). Using
      published standards resulted in an overdiagnosis of large for gestational age and
      an underdiagnosis of small for gestational age. CONCLUSION: Local birthweight
      distributions can differ significantly from historical or national distributions.
      The development of birthweight distributions accommodating for prenatal factors
      is needed.

PMID- 15014535
TI  - Low yield of ancillary diagnostic studies in neonates infected with Candida.
AB  - BACKGROUND: Fungal infection can be a significant complication for the critically
      ill neonate. However, the usefulness of extensive radiologic and ophthalmologic
      investigations in this population has not been thoroughly elucidated. OBJECTIVE:
      To report the incidence of organ fungal involvement diagnosed by ancillary
      testing (echocardiogram, ophthalmologic examination, brain imaging, and renal
      ultrasound (RUS)) among neonatal intensive care unit (NICU) patients with Candida
      infection. METHODS: This was a single center review of all NICU patients with
      Candida-positive cultures of blood, urine, peritoneal fluid, endotracheal tube
      aspirate, or cerebrospinal fluid from January 1, 1997 to June 1 2002. Data
      regarding the number of positive cultures, species isolated, and presence of
      specific risk factors and clinical symptoms were recorded for each case, as well
      as occurrence, timing and results of ancillary testing. RESULTS: In all, 66
      patients had at least one positive culture for Candida. The majority (71%) were
      <1500 g at birth, and mean gestational age was 29.5+/-5.6 weeks. Echocardiograms
      were obtained in 54/66 (82%), and ophthalmology examinations were obtained in
      36/66 (55%); none of these was consistent with fungal involvement. Brain imaging
      was performed in 50/66 (76%), only one of which was positive, in a patient with
      16 positive blood cultures for Candida albicans. RUS were performed in 58/66
      (88%) of patients, with concerning findings for fungal involvement in seven of
      the studies. RUS findings alone did not appear to consistently influence the
      length of therapy. CONCLUSIONS: Ancillary evaluations to investigate for fungal
      dissemination were undertaken frequently, but were of overall low yield. Although
      ancillary testing may be of limited additional value in centers with a low
      threshold for suspecting fungal infections and an aggressive approach to therapy,
      potentially important findings, which could impact management, may occur.

PMID- 15014536
TI  - Heart rate variability as an indicator of outcome in congenital diaphragmatic
      hernia with and without ECMO support.
AB  - OBJECTIVE: To examine differences in the spectral power content in neonates
      diagnosed with congenital diaphragmatic hernia (CDH) who survive or succumb.
      STUDY DESIGN: A case-series study design evaluated four neonates diagnosed with
      CDH, two of which were supported by extracorporeal membrane oxygenation (ECMO).
      The electrocardiogram signal was digitized at 1000 Hz and the Lomb periodogram
      was computed for the series of interbeat intervals. RESULTS: Neonates with CDH
      who survived had log total power values greater than 2. Those with CDH who did
      not survive had log total power less than 2, but generally exceeded 3 while they
      were supported by ECMO. CONCLUSIONS: Neonates who consistently displayed
      increasing total spectral energies had a better outcome than those whose spectral
      energies were low. Subjects who succumbed expressed the lowest values, suggesting
      that a frequency-based evaluation of HRV may be a sensitive prognosticator of
      outcome that requires further investigation.

PMID- 15014537
TI  - Arterial hypertension increases left ventricular mass: role of tight blood
      pressure control.
AB  - In middle-age hypertensives from the Gubbio Population Study, we evaluated the
      relationship between blood pressure (BP) control over a long time and the
      prevalence of left ventricular hypertrophy (LVH). A population survey was
      performed in 1982-1985 and repeated in 1989-1992. During the second survey,
      subjects in the age range 40-60 years were invited to undergo an M-mode
      echocardiographic examination. A total of 487 subjects who participated in both
      surveys are included in the present analysis. Some of them (294) were
      normotensive (Group 1), 110 were hypertensive but had never taken
      antihypertensive drugs (Group 2), 47 hypertensives on drugs were in good BP
      control (Group 3) and 36 hypertensives on drugs had uncontrolled hypertension
      (Group 4). BP values at the 1989-1992 examination were, respectively, 122/77,
      145/86, 124/78 and 153/91 mmHg, while 7 years earlier were 122/77, 133/84, 136/85
      and 152/95 mmHg. Despite normal BP levels in Group 3, left ventricular mass index
      (LVMi, g/m(2.7)) was greater than in normotensives (42.4+/-10, 46.6+/-13, 47.0+/
      10, 51.9+/-15 g/m(2.7)). Accordingly, the prevalence of LVH (LVMi >51 g/m(2.7))
      was 18, 26.4, 36.7 and 50% in groups 1-4, respectively. The 193 hypertensives
      were, thereafter, divided according to BP control (ie <140/90 mmHg) on both
      surveys (1983-1985 and 1989-1992): 27 hypertensives with optimal BP levels on
      both visits also had a ventricular mass similar to normotensives and
      significantly lower than the other hypertensives (LVMi 44.6+/-11.6 vs 48.5+/
      13.2, P<0.001). In conclusion, these findings indicate that hypertensive patients
      with BP values at levels similar to those in normotensives for a long period do
      not increase their left ventricular mass in comparison to subjects with normal BP
      levels.

PMID- 15014538
TI  - Epidemiological, pathophysiological and clinical significance of systolic,
      diastolic and pulse pressure.
AB  - Long-term population surveys and studies of untreated hypertensive patients both
      strongly suggest that over the age of about 45, the height of the systolic blood
      pressure is a better predictor of cardiovascular outcome than the diastolic
      pressure. Research into echocardiographic left ventricular size, endothelial
      function and thromborheology also back up this supposition. In clinical practice,
      the treatment of isolated systolic hypertension has been shown to be very
      worthwhile. There remains some uncertainty as to the relative significance of
      diastolic blood pressure when it is frankly high, as in severe systo-diastolic
      hypertension. However some clinicians and epidemiologists have questioned whether
      diastolic pressure is still worth measuring, given the overwhelming importance of
      the height of the systolic blood pressure at predicting outcome.

PMID- 15014539
TI  - Association between vascular dysfunction and reduced myocardial flow reserve in
      patients with hypertension: a LIFE substudy.
AB  - Impaired myocardial flow reserve (MFR) has been demonstrated in hypertension, and
      has been associated with peripheral vascular changes. We investigated whether MFR
      was impaired and associated with structural and/or functional vascular changes in
      hypertensive patients without evidence of coronary artery disease (CAD). We
      measured left ventricular (LV) mass index by echocardiography and MFR by positron
      emission tomography in 33 unmedicated, hypertensive patients with
      electrocardiographic LV hypertrophy without CAD, and 15 age- and gender-matched
      normotensive subjects. We also measured 24-h ambulatory blood pressure, minimal
      forearm vascular resistance (MFVR) by plethysmography, media:lumen ratio in
      isolated, subcutaneous resistance arteries by myography, intima-media cross
      sectional area of the common carotid artery, and flow-mediated (FMD) and
      nitroglycerin-induced dilatation (NID) of the brachial artery by ultrasound.
      Compared to the controls, the patients had impaired MFR (2.4 (95% CI 1.95-2.8) vs
      3.4 (2.7-4.2), P<0.01) due to increased resting myocardial blood flow (MBF) (0.82
      (0.73-0.91) vs 0.65 (0.56-0.75) ml/g min), and decreased dipyridamole-stimulated
      MBF (1.80 (1.55-2.1) vs 2.3 (1.80-2.8) ml/g min, both P<0.05). The difference in
      resting MBF disappeared (80 (74-87) vs 86 (74-97) microl/kg mmHg, NS) when
      normalized for blood pressure and heart rate. MFR correlated negatively to median
      24-h systolic blood pressure (r=-0.50, P<0.01) as well as to LV mass index (r=
      0.45, P<0.05) and MFVR in men (r=-0.47, P<0.05), and positively to FMD (r=0.44,
      P<0.05) and NID (r=0.40, P<0.05). Hypertensive patients with electrocardiographic
      LV hypertrophy without CAD had impaired MFR associated with cardiovascular
      hypertrophy and vasodilatory dysfunction. This suggests that MFR is impaired by
      LV hypertrophy and structural/functional vascular damage in the coronary and
      noncoronary circulation.

PMID- 15014540
TI  - Is inappropriate left ventricular mass related to neurohormonal factors and/or
      arterial changes in hypertension? A LIFE substudy.
AB  - We investigated whether inappropriately high left ventricular (LV) mass, defined
      as observed LV mass exceeding the level of individual LV mass predicted from
      gender, height, and stroke work, may be associated with an imbalance between
      growth-promoting and growth-inhibitory factors and/or structural vascular
      changes. In 53 patients with hypertension and electrocardiographic LV
      hypertrophy, 24-h ambulatory blood pressure (BP); echocardiographic LV mass,
      stroke volume and stroke work; minimal forearm vascular resistance (MFVR); and
      intima-media cross-sectional area in common carotid arteries (IMA) were evaluated
      after 2 weeks of placebo treatment. Serum insulin, plasma epinephrine,
      norepinephrine, endothelin, angiotensin II, aldosterone, and brain natriuretic
      peptide (BNP) were also measured. High observed LV mass was related to high IMA
      (r=0.46, P<0.001), MFVR (in men: r=0.36, P<0.05), 24-h ambulatory systolic BP
      (r=0.30, P=0.06), and lower plasma angiotensin II (r=-0.33, P<0.05), but not to
      other circulating growth factors. Stroke work was similarly related to IMA
      (r=0.42, P<0.01), MFVR (in men: r=0.41, P<0.05), and plasma angiotensin II (r=
      0.32, P<0.05). Inappropriate LV mass, identified by the ratio between observed LV
      mass and the value predicted for gender, height, and stroke work, was not
      significantly related to any of the arterial or neurohormonal variables. In this
      small series of older hypertensive patients, inappropriate LV mass was not
      significantly related to arterial changes or to measured circulating growth
      factors, although weak relations cannot be excluded. Alternatively,
      inappropriately high LV mass might be related to unmeasured factors such as local
      myocardial alterations in growth factors and/or genetic predisposition to develop
      excessive LV hypertrophy.

PMID- 15014541
TI  - In-home formation and emissions of trihalomethanes: the role of residential
      dishwashers.
AB  - This study involved an assessment of chloroform formation due to the use of
      hypochlorite-containing detergents in dishwashers. The objective of this research
      was to quantify in-home formation of trihalomethanes, particularly as related to
      dishwasher usage. A series of 14 flask and 15 laboratory experiments were
      completed. Flask experiments involved the mixing of food with dishwasher
      detergent in water for a 12-min reaction period, and were intended to identify
      chemicals and relative levels of those chemicals that may form from dishwasher
      usage with different food groups. Liquid concentrations of chloroform ranged from
      1 to 41 mg/l. Laboratory experiments involved collection of liquid and gas
      samples over the course of an operating cycle with an actual residential
      dishwasher. Background concentrations of chloroform in the water supply were
      generally between 0 and 10 microg/l; liquid chloroform levels in the wash cycle
      were typically at least 50 microg/l. Chloroform concentrations were as high as 20
      microg/l in the dishwasher headspace. Using mass balance equations for a typical
      residential house and laboratory results from this research, predicted
      concentrations resulting from dishwasher usage were similar to typical background
      concentrations in residential dwellings.

PMID- 15014542
TI  - Assessment of urinary metals following exposure to a large vegetative fire, New
      Mexico, 2000.
AB  - INTRODUCTION: In May 2000, a vegetative fire burned 47,000 acres in northern New
      Mexico, including 7500 acres of land administered by the Los Alamos National
      Laboratory. We evaluated potential human exposures from the fire. METHODS: We
      surveyed two populations (firefighters and the general population) in four cities
      for urine heavy metal concentrations. Reference concentrations were based on the
      Third National Health and Nutrition Examination Survey (NHANES III). Multivariate
      linear regression assessed the association of urinary metal concentrations with
      smoke exposure. We also performed isotopic analysis of uranium and cesium on a
      subset of specimens. RESULTS: A total of 92 firefighters and 135 nonfirefighters
      participated. In both populations, urinary nickel, cesium, chromium, and uranium
      concentrations were greater than expected compared with NHANES III reference
      values. No values required immediate medical follow-up. Regression analysis
      demonstrated that for National Guard members, arsenic and cadmium levels were
      significantly related to smoke exposure, and for firefighters, cesium and arsenic
      levels were significantly related to exposure; however, only for cesium in
      National Guard members was this association in the positive direction. Isotopic
      analysis demonstrated that the cesium and uranium were naturally occurring.
      CONCLUSIONS: Some people had spot urine metal concentrations above nationally
      derived reference values, and values for some metals were associated with smoke
      exposure. These associations had little public health or clinical importance.
      Studies of exposures resulting from vegetative fires are difficult, and careful
      consideration should be given to the technical and communication processes at the
      outset of a fire exposure investigation. Recommendations for future
      investigations include testing as soon as possible during or after a fire, and
      early clinical consultation with a medical toxicologist.

PMID- 15014543
TI  - Perspiration increased human pesticide absorption following surface contact
      during an indoor scripted activity program.
AB  - Homeowners and professional applicators frequently use chemicals to control
      insect pests in urban environments. The identification and evaluation of
      determinants of human exposure are critical to conduct reliable and responsible
      human exposure assessments following indoor residential chemical applications.
      The effect of sweat on absorbed dose in humans was evaluated with human
      volunteers who participated in a structured activity program (SAP). Participants
      (n=20) performed a warm-up exercise to induce light sweating prior to an SAP on
      chlorpyrifos(cp)-treated nylon carpet. Absorbed daily dosages (ADDs) were
      calculated using urinary biomonitoring of trichloropyridinol. In two separate
      exposures, participation in the warm-up exercise prior to the exposure SAP
      resulted in an increased ADD of CP equivalents by approximately 50%. Measured
      ADDs averaged 2.8 (SAP 1) and 2.0 (SAP 2) microg CP equivalents/kg/day in
      volunteers who participated in the warm-up exercise. In participants who rested
      prior to the exposures, ADDs were significantly lower at 1.9 (SAP 1) and 1.3 (SAP
      2) microg CP equivalents/kg/day. Perspiration may also be a determinant of
      exposure in active children and field workers. Measured ADDs were less than
      estimates of ADD made from environmental measurements including CP deposition,
      the California roller, and clothing dosimeters worn by participants.

PMID- 15014544
TI  - Interpersonal and daily variability of personal exposures to nitrogen dioxide and
      sulfur dioxide.
AB  - Chronic exposure is often assessed using a single measurement per individual or
      group. However, daily levels of personal exposure can vary greatly. Chronic
      exposure classification by a single measurement could be significantly affected
      by the interpersonal and daily variations of exposures. The purpose of this study
      is to determine the effect of using a single personal exposure measurement on
      estimating long-term exposure. This study used measurements of consecutive 14
      daily personal exposures to nitrogen dioxide (NO(2)) and sulfur dioxide (SO(2))
      of 50 individuals in Yeochun, Korea. The daily personal exposures were measured
      by passive samplers. Personal exposure to NO(2) was associated with gas cooking,
      and personal exposure to SO(2) was associated with ambient air pollution. Mixed
      effects models indicated that daily variability was greater than interpersonal
      variability for both the pollutants. Effectiveness of using single-day personal
      measurements for long-term population mean exposure was supported by relatively
      consistent daily population averages, but multiple-day measurements might be
      warranted for characterizing individual exposures or high-end population
      exposures such as the 95th percentile. Although classification of high and low
      exposure groups by 1-day exposure and by 14-day exposure produced similar group
      totals, 20% of individual NO(2) exposures and 31% of individual SO(2) exposures
      were misclassified using 1-day exposures. Average values of 1-day exposure and 14
      day exposure were significantly different, but the difference decreased by an
      increase in the number of measurements for the short-term exposure. The findings
      were similar for both NO(2) and SO(2), although the two air pollutants have
      different sources and behaviors.

PMID- 15014545
TI  - Quantification of lifetime accumulated ELF-EMF exposure from household appliances
      in the context of a retrospective epidemiological case-control study.
AB  - In Europe household appliances are a major source of indoor 50 Hz magnetic field
      exposure. A number of epidemiological studies have reported associations between
      leukemia risk and personal use of household appliances. In the "Norddeutsche
      Leukamie und Lymphomstudie" (NLL), which was conducted in Northern Germany
      (Schleswig-Holstein and Lower Saxony) between 1997 and 2001, lifetime use of a
      preselected array of electric appliances (microwave ovens, hair-dryers, motorized
      electrical alarm clocks (i.e. that use a motor to move their hands or digits),
      electric blankets and pillows, heated waterbeds, computers with conventional
      screens, TVs, and electric sewing machines) was recorded in a standardized,
      personal, computerized interview. Exposure was assessed on three different levels
      of precision: ever use, cumulative appliance-years, and average time of daily
      use. Additional questions referred to exposure modifying factors, including
      distance from screen while watching TV, position of an alarm clock at the bed
      etc.). Exposure to ELF-EMF from household appliances was quantified as ever vs.
      never use, gross and net appliance-years of lifetime use and cumulative microT
      hours. Flux densities were based on measurements of appliances from the published
      literature. These were used as weighting factors to account for the different
      device-specific contributions to overall ELF-EMF exposure. Resulting
      distributions (as quartiles) for exposure scores revealed systematic differences
      for different levels of precision. Our analysis indicates that valid assessment
      of ELF-EMF exposure from household appliances should be based on the highest
      possible degree of precision and hence provides a considerable challenge in
      analytic epidemiology.

PMID- 15014546
TI  - Simulation of working population exposures to carbon monoxide using EXPOLIS-Milan
      microenvironment concentration and time-activity data.
AB  - Current air pollution levels have been shown to affect human health.
      Probabilistic modeling can be used to assess exposure distributions in selected
      target populations. Modeling can and should be used to compare exposures in
      alternative future scenarios to guide society development. Such models, however,
      must first be validated using existing data for a past situation. This study
      applied probabilistic modeling to carbon monoxide (CO) exposures using EXPOLIS
      Milan data. In the current work, the model performance was evaluated by comparing
      modeled exposure distributions to observed ones. Model performance was studied in
      detail in two dimensions; (i) for different averaging times (1, 8 and 24 h) and
      (ii) using different detail in defining the microenvironments in the model (two,
      five and 11 microenvironments). (iii) The number of exposure events leading to
      exceeding the 8-h guideline was estimated. Population time activity was modeled
      using a fractions-of-time approach assuming that some time is spent in each
      microenvironment used in the model. This approach is best suited for averaging
      times from 24 h upwards. In this study, we tested how this approach affects
      results when used for shorter averaging times, 1 and 8 h. Models for each
      averaging time were run with two, five and 11 microenvironments. The two
      microenvironment models underestimated the means and standard deviations (SDs)
      slightly for all averaging times. The five- and 11-microenvironment models
      matched the means quite well but underestimated SDs in several cases. For 1- and
      24-h averaging times the simulated SDs are slightly smaller than the
      corresponding observed values. The 8-h model matched the observed exposure levels
      best. The results show that for CO (i) the modeling approach can be applied for
      averaging times from 8 to 24 h and as a screening model even to an averaging time
      of 1 h; (ii) the number of microenvironments affects only weakly the results and
      in the studied cases only exposure levels below the 80th percentile; (iii) this
      kind of model can be used to estimate the number of high-exposure events related
      to adverse health effects. By extrapolation beyond the observed data, it was
      shown that Milanese office workers may experience adverse health effects caused
      by CO.

PMID- 15014547
TI  - Persistent organic pollutants in dusts that settled indoors in lower Manhattan
      after September 11, 2001.
AB  - The explosion and collapse of the World Trade Center (WTC) was a catastrophic
      event that produced an aerosol impacting many residents, workers, and commuters
      after September 11, 2001. In all, 12 bulk samples of the settled dust were
      collected at indoor locations surrounding the epicenter of the disaster,
      including one sample from a residence that had been cleansed and was once again
      occupied. Additionally, one sample was collected from just outside a fifth story
      window on the sill. These samples were analyzed for many components, including
      inorganic and organic constituents as well as morphology of the various
      particles. The results of the analyses for persistent organic pollutants on dusts
      that settled at indoor locations are described herein, including polycyclic
      aromatic hydrocarbons, polychlorinated biphenyls, and select organo-chlorine
      pesticides. The Sigma(86)-PCB concentrations, comprising less than one part per
      million by mass of the bulk in the two samples analyzed, indicated that PCBs were
      of limited significance in the dust that settled at indoor locations across lower
      Manhattan. Likewise, organo-chlorine pesticides, Hexachlorobenzene, Heptachlor,
      4,4'-DDE, 2,4'-DDT, 4,4'-DDT and Mirex were found at even lower concentrations in
      the bulk samples. Conversely, Sigma(37)-PAHs comprised up to 0.04% (<0.005
      0.036%) by mass of the bulk indoor dust in the 11 WTC impacted bulk indoor
      samples. Analysis of one sample of indoor dusts collected from a vacuum cleaner
      of a rehabilitated home shows markedly lower PAH concentrations (<0.0005 mass%),
      as well as differing relative contributions for individual compounds. In addition
      to similar concentrations, comparison of PAH concentration patterns (i.e.
      chemical fingerprints) shows that dusts that settled indoors are chemically
      similar to previously measured WTC dusts found at outdoor locations and that
      these PAH analyses may be used in identifying dusts of WTC origin at indoor
      locations, along with ascertaining further needs for cleaning.

PMID- 15014548
TI  - Temporal error in biomarker-based mean exposure estimates for individuals.
AB  - Biomarker measurements from single time points are often used to make inferences
      about longer periods of toxicant intake. However, toxicant exposures rarely, if
      ever, occur under steady-state conditions, and biomarkers are typically most
      sensitive to recent toxicant exposures. Moreover, toxicant exposures are
      typically episodic and vary in magnitude over time. While it is often believed
      that the error introduced by the steady-state assumption is minimal and can
      safely be ignored, no rationale is typically presented to support this belief.
      Moreover, no guidelines have been established for determining a de minimus error
      level or for estimating the degree of error potentially introduced by a
      fallacious steady-state assumption in biomarker interpretation. We present a
      statistical framework for evaluating the potential magnitude of the error
      introduced by the steady-state fallacy and demonstrate applications of the
      framework to blood mercury and hair mercury exposure biomarkers in human adults.
      The magnitude of error clearly depends on many factors, including the exposure
      frequency, exposure magnitude, exposure duration, and exposure inference
      duration. Graphical presentation of the error as a function of those factors
      provides insight into the interpretation of mercury exposure biomarkers. We
      describe a general approach for determining the mean and variance of temporal
      error, present explicit solutions for several special cases, and demonstrate an
      example using the framework to evaluate the error resulting from the use of a
      steady-state model to estimate time-varying exposure from mercury biomarkers.

PMID- 15014550
TI  - Adverse haematological outcome and environmental lead poisoning.
AB  - The South-eastern Area (SA) of the Municipality of La Spezia (Liguria Region,
      Italy) is characterised by a heavy environmental lead (Pb) contamination, chiefly
      due to the emissions of a Pb-processing plant in operation since 1930. In order
      to assess the risk of Pb poisoning of residents of SA, and to estimate the degree
      of association between the blood Pb level (BLL) and haematocrit % (HCT), intended
      as a biomarker of early haematological dysfunction, we reanalysed data of 785
      individuals collected in 1992 as a part of a larger national biological
      monitoring project. Multiple normal regression modelling was applied to estimate
      the role of residence on log-transformed BLL, and Median Ratio (MR) was used as
      an index of effect. The same statistical modelling was also applied to reveal the
      relationship between HCT and BLL. Allowing for several confounders (including
      occupational exposure to Pb), residents of SA showed a 14% increase (MR=1.14, 95%
      IC=1.06-1.23%) in the median BLL value compared to people living outside SA. The
      excess reached 27% (MR=1.27, 95% IC=1.14-1.41%) after 30 years of residence.
      Parallel results were also obtained in a subgroup composed only of pupils (<18
      years, non-smokers, non-drinkers). Finally, regression analysis highlighted a
      statistically significant parabolic trend in HCT in relation to BLL. The non
      linear dose-response relationship, which attests to an adverse effect on the
      erythrocytic function of BLLs at least over 17.00 microg/dl, is in agreement with
      the findings of other authors and consistent with the results of an excess
      occurrence of self-reported anaemia obtained from a previous comparative survey
      carried out on the same population.

PMID- 15014549
TI  - Ambient hydrogen sulfide, total reduced sulfur, and hospital visits for
      respiratory diseases in northeast Nebraska, 1998-2000.
AB  - This analysis examined associations between total reduced sulfur (TRS) and
      hydrogen sulfide (H(2)S) levels, and hospital visits for respiratory disease
      among residents of Dakota City and South Sioux City, Nebraska, from January 1998
      to May 2000. For reference, the association between TRS, H(2)S, and digestive
      diseases was also examined. Time-series analyses of daily hospital visits in the
      selected outcome categories and measures of TRS and H(2)S were performed using
      generalized additive models with a Poisson link. TRS and H(2)S levels were
      categorized as high if at least one of the daily 30-min rolling averages was > or
      =30 ppb and as low if every rolling average was <30 ppb. Loess smoothers allowed
      for flexible modeling of the time effect and the effect of temperature and
      relative humidity. The measure of association used was the mean percent change in
      the average number of hospital visits recorded following a day with a high
      exposure versus a day with a low exposure. For children less than 18 years of
      age, a positive association was found between asthma hospital visits and 1-day
      lagged TRS levels. For adults, a positive association was found between asthma
      hospital visits and H(2)S levels on the previous day. A positive association also
      was found between hospital visits for all respiratory diseases, and H(2)S and TRS
      levels on the previous day for children but not for adults. No association was
      found between contaminant levels and hospital visits for all digestive diseases.
      These findings suggest that TRS or H(2)S levels may be associated with
      exacerbations of asthma or other respiratory diseases among the residents of
      Dakota City and South Sioux City.

PMID- 15014552
TI  - Clinical and sonographic assessment of the side effects of intracavernous
      injection of vasoactive substances.
AB  - The objective of this study is to evaluate the side effects of intracavernous
      vasoactive agents on clinical and sonographic basis. Two groups of patients were
      included, group I included 168 ED patients trained on self-injection therapy
      using one of the three protocols. Protocol A: papaverine; protocol B: PGE1; and
      protocol C: trimix (papaverine, phentolamine and PGE1). Patients were followed up
      clinically, sonographically and by laboratory investigations for 6 months to
      evaluate the occurrence of side effects. Group II included 21 patients presenting
      to our department for the first time with a complication of intracavernous
      injection pharmacotherapy (ICI) initiated elsewhere. In all, 168 patients of
      group I completed the study. Patients on papaverine had the highest incidence of
      complications concerning prolonged erection, subcutaneous hematoma and penile
      fibrosis. Postinjection penile pain was observed more with groups B and C than
      group A. No systemic side effects were reported. Duplex ultrasound was beneficial
      in detecting mild clinically impalpable fibrosis. In total, 10 patients of group
      II presented with prolonged erection, seven with penile fibrosis, three with
      cavernositis and one with intracavernous needle breakage. We conclude that
      although ICI therapy is an effective second-line treatment option, patients on a
      self-injection program should be followed up both clinically and sonographically
      both at the initiation phase and on regular follow-up visits.

PMID- 15014551
TI  - Nocturnal penile tumescence and rigidity (NPTR) findings in spinal cord injured
      men with erectile dysfunction.
AB  - This prospective study aimed at determining whether nocturnal penile tumescence
      and rigidity (NPTR) findings correlate to the neurologic disorders in spinal cord
      injured (SCI) patients suffering from erectile dysfunction (ED). A total of 25
      acute SCI male patients with post-traumatic ED underwent neurological,
      electrophysiological and urodynamic examinations, respectively, as well as NPTR
      recordings. The mean value for rigidity (R), tumescence (T) and duration (D)
      during NTPR tests were 83.3%, 3.3 cm, 6.4 min in patients with a complete lesion
      above the sacral (S2-S4) spinal cord (n=10), 46.1%, 1.6 cm, 5.5 min in patients
      with a complete lesion involving the sacral metameres (n=5) and 89.8%, 3.8 cm, 29
      min in patients with an incomplete suprasacral lesion (n=7). The differences
      among these groups were statistically significant (P<0.05). Patients with lesions
      involving both sacral and thoracolumbar spinal cord showed no erections (n=3). We
      found four NTPR patterns: (1) normal R and T, short D; (2) weak R and T, short D;
      (3) normal R, T and D; and (4) no erections, which can be assigned to different
      levels and completeness of spinal cord lesions. Nocturnal erections of normal
      quality need preservation of thoracolumbar and sacral neuronal control as well as
      partially intact connections of the spinal erection centres with brain areas
      responsible for sexual arousal.

PMID- 15014553
TI  - Hypersexual sensations and behavior in a multiple sclerosis exacerbation: a case
      report.

PMID- 15014554
TI  - Beliefs about illness and quality of life among men with erectile dysfunction.
AB  - The objective of the study was to apply an illness representations framework to
      examine patients' beliefs about erectile dysfunction (ED) and the association
      between those beliefs and reported quality of life. A total of 41 patients
      attending two secondary care clinics at a teaching hospital completed
      questionnaires examining quality of life, sexual functioning, illness
      representations (cause, time-line, coherence, consequences, cure, control and
      emotion) and perceptions of masculinity. Masculinity, sexual function, emotions
      and beliefs about consequences were found to be significantly correlated with
      quality of life. Multiple regression analysis revealed a model that accounted for
      almost 35% of the variance in quality of life of ED patients. The strongest
      predictor of higher quality of life was better sexual functioning (beta = -0.342,
      P < 0.05) followed by more positive beliefs about the effects of ED on
      masculinity (beta = 0.323, P < 0.05). The results suggest that when assessing the
      quality of life of men with ED, patients' illness representations should be
      considered along with their level of sexual functioning and the effects of ED on
      masculinity. Patients may benefit from an intervention programme that includes an
      educational component, thereby providing patients with more information about
      treatment options and available support.

PMID- 15014555
TI  - Concerns of health providers and parents affect immunisation coverage.

PMID- 15014556
TI  - Answers about coeliac disease and still more questions.

PMID- 15014558
TI  - Attitudes to immunisation: a survey of health professionals in the Rotorua
      District.
AB  - AIM: To examine the personal attitudes and practice of health professionals
      regarding childhood vaccinations in order to provide guidance to local
      professional education strategies. METHODS: A questionnaire was circulated to
      those involved in the implementation of the childhood immunisation schedule in
      the Rotorua District. Responses were stratified: a) community vs hospital; b)
      nurses, midwives, doctors, others. RESULTS: 85% responded, of whom 94% supported
      vaccinations. 91% considered science the most important basis for
      recommendations; 91% considered current scientific support adequate. 11% thought
      immunisations held unacceptable dangers; 17% were unsure. 41% of nurses, 45% of
      midwives, and 21% of doctors were unsure whether the MMR vaccine was associated
      with autism or Crohn's disease. Professional training, reading and personal
      experience were identified most often as having an influence on opinions, while
      the media and Internet ranked least often. Amongst respondents who had children,
      96% reported vaccination (no significant difference between professional groups,
      but lower rates for children of hospital providers). CONCLUSIONS: Strong national
      support of vaccinations was demonstrated in this survey of professionals involved
      with vaccination in one district. Significant underlying uncertainties or
      concerns were identified regarding risks, the MMR vaccine, and ethical tensions
      between community protection and perceived individual risk. Continuing education
      and dialogue through professional training and medical literature are indicated
      to address these concerns.

PMID- 15014557
TI  - Why do parents choose not to immunise their children?
AB  - AIMS: To ascertain the reasons why some parents choose not to immunise their
      children and where these parents obtained their immunisation information.
      METHODS: Seventy general practitioners (GPs) in Christchurch who kept a record of
      children whose parents declined immunisation were asked to recruit these parents.
      Half of the GPs were able to invite the 76 parents of children declining
      immunisation to take part in this study. Twenty one (28%) of these parents agreed
      to completing a structured questionnaire. RESULTS: Parents in this sample were
      highly educated and had used information from a variety of sources in making
      their decision not to immunise. Almost half of the parents had not discussed
      immunisation with their lead maternity carer. They viewed information from the
      Ministry of Health as biased. They were concerned about vaccine safety and
      efficacy and the effects of immunisation on their child's immune system.
      CONCLUSIONS: Parents who choose not to immunise their children are distrustful of
      information provided by the Ministry of Health. General practitioners are the
      main source of immunisation information for these parents and they must be able
      to provide accurate, unbiased information regarding the risks and benefits of
      immunisation.

PMID- 15014559
TI  - Serological evidence of Toxoplasma gondii infection among pregnant women in
      Auckland.
AB  - AIM: Severe congenital infection is a consequence of primary Toxoplasma gondii
      infection in early pregnancy. Antenatal screening is problematic because IgM
      antibody to Toxoplasma persists for months to years and thus may falsely indicate
      a recent infection. Serological screening for T. gondii infection is not
      currently included in routine antenatal testing in New Zealand. The aim of this
      study was to determine the prevalence of IgG and IgM antibody to T. gondii in
      pregnant Auckland women. METHODS: Five hundred serum samples submitted for
      routine antenatal blood tests were tested anonymously for IgG and IgM antibodies
      to T. gondii. One hundred consecutive serum samples were tested from five age
      groups: <20, 21-25, 26-30, 31-35, >36 years. The number of positive IgM results
      that would have occurred if there were routine screening for toxoplasmosis was
      estimated for the year 2000 by multiplying the number of women giving birth in
      the respective age groups by the proportion with positive IgM results in these
      samples. RESULTS: One hundred and sixty three (33%) women had IgG antibody to T.
      gondii and 12 (2.4%) also had IgM antibody. For the year 2000, if there had been
      routine screening for toxoplasmosis, 296 of 14 530 (2.03%, 95% CI: 1.8-2.2%)
      pregnant Auckland women would have had a positive IgM result. CONCLUSIONS:
      Screening would detect IgM antibodies in up to 2.2% of pregnant women.
      Significant and invasive further investigations would be required to identify the
      subset of pregnancies with fetal infection. Serological tests that are specific
      for recent primary infection are needed before routine screening could be
      considered for New Zealand. In the meantime, advice on how to avoid infection is
      necessary given that two thirds of pregnant Auckland women are susceptible to T.
      gondii.

PMID- 15014560
TI  - Norovirus outbreaks in a hospital setting: the role of infection control.
AB  - AIMS: Noroviruses (NV) (until recently known as Norwalk-like viruses) are a
      common cause of outbreaks of viral gastroenteritis and can result in significant
      hospital disruption. We report our experience of two outbreaks that occurred in a
      geriatric rehabilitation hospital and the role of infection control in limiting
      their spread. METHODS: The outbreaks occurred in two separate rehabilitation
      wards for older people. A case definition was developed and a register kept to
      record patient and staff sickness. The NV was identified from faecal specimens by
      reverse transcriptase polymerase chain reaction. RESULTS: There were 41 cases in
      the first outbreak, with an attack rate of 57.1% for patients and 41% for staff.
      The outbreak lasted 14 days and closed the ward for 11 days. During this outbreak
      one patient died, with gastroenteritis the precipitating event of his final
      illness. There were 24 cases in the second outbreak, with an attack rate of 56.5%
      for patients and 18% for staff. The outbreak lasted 16 days with the ward closed
      for six days. The mean duration of staff sickness was 3.5 days in the second
      outbreak compared with only 1.2 days in the first outbreak. In both outbreaks
      infection was contained within a single ward. CONCLUSIONS: NV infections can
      significantly disrupt hospitals through their rapid spread to patients and staff
      as well as the associated high attack rate. Early recognition of an outbreak and
      prompt implementation of infection control measures, staffing restrictions and
      ward closure can limit the spread of infection.

PMID- 15014561
TI  - A thirty-year (1970-1999) study of coeliac disease in the Canterbury region of
      New Zealand.
AB  - AIM: To determine the demography of coeliac disease (CD) in the Canterbury region
      of New Zealand between 1970 and 1999. METHODS: The records of patients resident
      in the Canterbury region of New Zealand with CD proven by intestinal biopsy
      (Marsh Type 3 histology) between the years of 1970 and 1999 were reviewed.
      Overall incidence figures were calculated using population data abstracted from
      five-yearly census reports and, for childhood CD, from birth statistics. RESULTS:
      Over the 30-year study period, 416 people were diagnosed as having CD. The
      overall incidence of newly recognised CD over this period was 2.2/100 000/year,
      rising from 1.4/100 000/year in the first three years of the study period (1970
      to 1972) to 12.9/100 000/year in the last three years (1997 to 1999). The
      cumulative incidence of childhood CD (0 to 12 years) over the 30-year period was
      0.40/1000 births, rising from 0/1000 births in the first three years to 1.40/1000
      births in the last three years. The incidence of CD began to rise in adults in
      the mid 1980s and, in children, in the early 1990s. At the time of diagnosis, 11%
      were aged 0-9 years and 12% were aged 60 years and over. The overall female to
      male ratio was 2.1:1, was highest for those aged 30-39 (3.3:1), and was lowest
      for those aged 0-19 years (1.4:1) and for those aged 60 years and over (1.15:1).
      CONCLUSIONS: CD is common in the Canterbury region of New Zealand in all age
      groups. The incidence of recognised CD rose during the study period, beginning in
      the mid 1980s for adults followed in the early 1990s by children. CD is most
      frequently recognised in women during the reproductive years of life. Factors
      contributing to the observed increase may include a greater awareness of CD,
      specific serological tests and endoscopic small-bowel biopsies.

PMID- 15014562
TI  - Seeking the ideal anti-hypertensive agent: a practical review of the hypertension
      drug trials.
AB  - Numerous trials and meta-analyses have been conducted over the last five years to
      identify an ideal anti-hypertensive drug. These reports, and the JNC 7 and
      European hypertension guidelines, have generated some controversy and confusion.
      A review of the comparative anti-hypertensive drug trials shows that the
      differences between drugs are minor and not consistently demonstrated by
      different studies. However, much data have now accumulated on the safety and
      value of diuretics, beta blockers, calcium-channel blockers (CCBs), angiotensin
      converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) in
      reducing blood pressure and preventing clinical disease. The importance of tight
      blood pressure control in reducing adverse events has been clearly shown, and
      clinicians should concentrate on achieving target blood pressure levels, which
      often requires a combination of anti-hypertensive drugs. The choice of anti
      hypertensive drug should be guided by the presence of concomitant clinical
      disease, as evidence has accumulated on the special efficacy of certain drugs in
      reducing damage to particular organ systems. In the absence of any associated
      clinical disease, it is good to initiate anti-hypertensive therapy with
      diuretics, provided the metabolic parameters are regularly reviewed.

PMID- 15014563
TI  - Emergency department overcrowding--can we fix it?

PMID- 15014564
TI  - Simultaneous presentation of Type 1 diabetes and thyrotoxicosis as a medical
      emergency.

PMID- 15014565
TI  - Spontaneous fracture of the humeral shaft associated with snowball throwing.

PMID- 15014566
TI  - Buteyko: an effective complementary therapy.

PMID- 15014568
TI  - Primary amoebic meningoencephalitis presenting without fever.

PMID- 15014569
TI  - A new push to help smokers, or time for a Holiday?

PMID- 15014570
TI  - The Green Prescription and the launch of the NZ Register of Exercise
      Professionals.

PMID- 15014571
TI  - The Green Prescription: being active is easy and can be fun.

PMID- 15014572
TI  - A Descriptive Study of Psychiatric Consultations in a Community Primary Care
      Center.
AB  - BACKGROUND: This retrospective chart review study describes on-site psychiatric
      consultations at a large, urban community primary care center. The referral
      population, diagnostic reliability of primary care providers (PCPs) and social
      workers, appropriateness of PCP-initiated treatment, impact of treatment
      recommendations, and outcomes are examined. METHOD: Charts of all patients who
      received psychiatric consultations (N = 78) during an 8-month period (August 1996
      to April 1997) were reviewed. RESULTS: Prereferral diagnoses by PCPs matched the
      psychiatrist's diagnosis based on DSM-IV diagnostic criteria approximately half
      the time. PCPs initiated psychopharmacology in half the referrals (39/78) and
      used generally appropriate medications (30/39) based on diagnosis by a
      psychiatrist, but at subtherapeutic doses (21/39). PCPs tended to continue
      medications recommended by the psychiatrist. At 1 year, PCPs clearly documented
      improvement in nearly a third of the consults (24/78). CONCLUSION: Diagnostic
      disagreement of caregivers, inadequate PCP psychopharmacology practices, and
      patient nonadherence are 3 main problems that impede optimal care within the
      model of psychiatric consultation described in this study.

PMID- 15014574
TI  - Mental Health Screening in Primary Care: A Comparison of 3 Brief Measures of
      Psychological Distress.
AB  - BACKGROUND: The current study compared 3 brief mental health screening measures
      in a sample of older patients in a primary care outpatient setting. Previous
      mental health screening research has been conducted primarily with younger
      patients, often with only 1 screening measure, thereby limiting the
      generalizability of findings. In addition, measures have not yet been compared in
      terms of their ability to discriminate between cases and noncases of psychiatric
      disorder. METHOD: One hundred thirty-four male patients attending their
      appointments at a primary care clinic in a Department of Veterans Affairs Medical
      Center participated in this study. Participants completed the General Health
      Questionnaire-12 (GHQ-12), the Symptom Checklist-10 (SCL-10), and the Primary
      Care Evaluation of Mental Disorders screening questionnaire and interview.
      RESULTS: Receiver operating characteristic analysis yielded the optimum cutoff
      scores on each brief mental health screening measure and showed that all 3
      measures discriminated well between cases and noncases of psychiatric disorders.
      The 3 measures performed slightly better in terms of discriminating between cases
      and noncases of mood or anxiety disorders than between cases and noncases of any
      psychiatric disorder. There were no significant differences between the measures'
      abilities to accurately identify cases and noncases of disorder. CONCLUSION:
      Primary care physicians are encouraged to use brief mental health screening
      measures with their patients, since many report symptoms of psychological
      distress and disorder. It is recommended that the SCL-10 and GHQ-12 be used to
      detect mood or anxiety disorders in patients such as these because of the
      accuracy and brevity of these measures.

PMID- 15014573
TI  - A Perspective on the Primary Care of Patients With Behavior, Mood, and Thought
      Disturbances: Clinical Applications of Olanzapine.
AB  - Primary care practitioners are in an ideal position to initiate treatment for
      patients with behavior, mood, and thought disturbances. It is believed that early
      identification and treatment of these symptomatic features of primary or
      secondary central nervous system disorders may significantly reduce morbidity and
      benefit the patient, his/her family, and involved caregivers, including the
      primary care physician. A broad list of central nervous system-active medications
      are utilized by family physicians to treat patients who exhibit symptoms of
      agitation, altered mood, and disordered thought. Some medications have
      demonstrated superiority over placebo or active medicines in reported clinical
      trials. This article is a brief overview of the safety and efficacy from reported
      studies of the use of medications frequently used to treat symptoms related to
      behavior, mood, and thought disturbances, with a specific focus on the clinical
      applicability of olanzapine.

PMID- 15014576
TI  - "Is the Only Way to Heal With Cold Blue Steel?"

PMID- 15014577
TI  - Teaching the Tools: Prolonging the Benefit of Psychotherapy.

PMID- 15014575
TI  - Trauma and Posttraumatic Stress Disorder in Primary Care Patients.
AB  - BACKGROUND: This article examines the nature of psychological trauma and
      posttraumatic stress disorder (PTSD) in 504 patients recruited from primary care
      settings. METHOD: Patients were screened for anxiety in waiting rooms at 14
      general medical settings, and those with a sufficient number and severity of
      anxiety symptoms were administered a standardized diagnostic clinical interview.
      Those who met DSM-IV criteria for an anxiety disorder and who were willing to
      participate were included in this study. Of the 504 patients, 185 met DSM-IV
      criteria for PTSD. RESULTS: Results indicated that 418 (83%) of primary care
      patients in our sample reported at least 1 traumatic event in their lifetime. The
      most prevalent traumas experienced by the entire sample of participants were
      witnessing others being seriously injured or killed, serious accidents, and rape.
      Of those participants with PTSD, rape was the strongest predictor of a PTSD
      diagnosis. Analyses examining gender differences indicated that, for women, a
      history of other unwanted sexual contact or witnessing a sexual assault, being
      attacked with a weapon or with intent to kill, or witnessing someone being
      injured were found to be risk factors for a PTSD diagnosis. Examination of
      clinical characteristics indicated a high rate of comorbidity of psychiatric
      disorders among patients with PTSD, including high rates of alcohol/substance
      abuse, depression, and suicide attempts. CONCLUSION: These findings emphasize the
      continued need to assess patients presenting at general medical facilities about
      trauma history.

PMID- 15014578
TI  - Dosing of Selective Serotonin Reuptake Inhibitors.

PMID- 15014579
TI  - Dr. Marken Replies.

PMID- 15014580
TI  - Dissociative Spectrum Disorders in the Primary Care Setting.
AB  - Dissociative disorders have a lifetime prevalence of about 10%. Dissociative
      symptoms may occur in acute stress disorder, posttraumatic stress disorder,
      somatization disorder, substance abuse, trance and possession trance, Ganser's
      syndrome, and dissociative identity disorder, as well as in mood disorders,
      psychoses, and personality disorders. Dissociative symptoms and disorders are
      observed frequently among patients attending our rural South Carolina community
      mental health center. Given the prevalence of mental illness in primary care
      settings and the diagnostic difficulties encountered with dissociative disorders,
      such illness may be undiagnosed or misdiagnosed in primary care settings. We
      developed an intervention model that may be applicable to primary care settings
      or helpful to primary care physicians. Key points of the intervention are
      identification of dissociative symptoms, patient and family education, review of
      the origin of the symptoms as a method of coping with trauma, and supportive
      reinforcement of cognitive and relaxation skills during follow-up visits. Symptom
      recognition, Education of the family, Learning new skills, and Follow-up may be
      remembered by the mnemonic device SELF. We present several cases to illustrate
      dissociative symptoms and our intervention. Physicians and other professionals
      using the 4 steps and behavioral approaches will be able to better recognize and
      triage patients with dissociative symptoms. Behaviors previously thought to be
      secondary to psychosis or personality disorders may be seen in a new frame of
      reference, strengthening the therapeutic alliance while reducing distress and
      acting-out behaviors.

PMID- 15014581
TI  - Munchausen Syndrome by Proxy: A Clinical Vignette.
AB  - Munchausen syndrome by proxy is the act of one person fabricating or inducing an
      illness in another to meet his or her own emotional needs through the treatment
      process. The diagnosis is poorly understood and controversial. We report here the
      case of a 6-year-old boy who presented with possible pneumonia, nausea, vomiting,
      and diarrhea and whose mother was suspected of Munchausen syndrome by proxy.

PMID- 15014582
TI  - Divalproex Sodium Versus Valproic Acid in Hospital Treatment of Psychotic
      Disorders.
AB  - BACKGROUND: Approximately 50% of pharmacy prescriptions in the United States are
      filled with generic drugs, which have improved substantially in quality owing to
      increased governmental regulations. The remaining medicoeconomic question regards
      whether or not brand-name medications are worth the price. This study evaluates
      these questions for the brand-name mood stabilizer divalproex sodium and its
      generic counterpart, valproic acid. METHOD: We conducted a retrospective chart
      review of all patients who had been taking divalproex and had been switched to
      valproic acid at 2 local mental health facilities in 1997. Data collected from
      the inpatient- and day-treatment charts for these 28 patients included dose,
      duration, side effects, and efficacy (determined using retrospective chart review
      and the Clinical Global Impressions scale [CGI]) of divalproex sodium compared
      with valproic acid treatment. RESULTS: t Tests for dependent samples revealed
      that valproic acid was administered at higher doses than divalproex sodium, but
      these treatments did not differ in efficacy on the basis of CGI scores. Fisher
      exact test analyses revealed a trend toward more nausea with valproic acid; also,
      the combination of nausea, abdominal discomfort, and diarrhea occurred more often
      in valproic acid-treated patients. There were no differences in the
      discontinuation of either medicine because of side effects, or in the use of
      medications to treat gastrointestinal side effects. Efficacy was similar for
      valproic acid and divalproex sodium. There was no single, significant side effect
      increase for valproic acid; however, when grouped together, gastrointestinal side
      effects were statistically significantly increased in valproic acid-treated
      patients. This appears clinically insignificant because of the lack of difference
      in drug discontinuation rate or gastrointestinal medication use. CONCLUSION:
      Given these results and that valproic acid is much less expensive than divalproex
      sodium, valproic acid appears to be a satisfactory substitution for divalproex
      sodium in the treatment of frequently hospitalized psychotic patients.

PMID- 15014583
TI  - Psychiatric and Somatic Markers of Anxiety: Identification and Pharmacologic
      Treatment.
AB  - Anxiety disorders are widely prevalent but insufficiently recognized and
      inadequately treated in primary care practice. The annual costs of morbidity and
      mortality of these disorders approach $50 billion, substantially more than costs
      for schizophrenia or all affective disorders combined. Somatization of anxiety
      contributes to the challenges of making an accurate diagnosis and to the indirect
      costs associated with delaying appropriate treatment. Pharmacologic interventions
      give clinicians the necessary tools to treat anxiety safely and effectively.
      Former therapeutic choices were limited to benzodiazepines, buspirone, and older
      antidepressants, but newer anxiolytic agents have become available. The selective
      serotonin reuptake inhibitors and agents with dual reuptake inhibition, such as
      venlafaxine XR, are optimizing therapy and yielding less risk for serious adverse
      events, greater safety in long-term therapy, and opportunity for improved patient
      compliance. These newer antidepressants provide substantial efficacy in patients
      with comorbid anxiety and depression, commonly seen in the primary care setting.

PMID- 15014584
TI  - Real-World Outcomes of Once-Daily Risperidone Dosing.
AB  - BACKGROUND: Recent reports have shown that risperidone, which has established
      antipsychotic efficacy, is effective and safe in a once-daily dosing regimen.
      METHOD: The efficacy and safety of once-daily risperidone were assessed in a
      retrospective study of 27 patients with a variety of psychiatric disorders who
      were attending a community day treatment program. Their DSM-IV diagnoses included
      schizophrenia, schizoaffective disorder, bipolar disorder, major depression with
      psychosis, and posttraumatic stress disorder. They had received once-daily
      risperidone for a mean of more than 18 months. RESULTS: Disorders of most
      patients were controlled with once-daily dosages of 1 to 6 mg/day of risperidone.
      The nighttime once-daily risperidone dosage was well tolerated by patients. In
      addition, there was no increase in antipsychotic-related side effects, and
      compliance was enhanced. CONCLUSION: Risperidone was well tolerated, and no
      patient needed antiparkinsonian medications even at high dosages of risperidone
      once daily.

PMID- 15014585
TI  - Irritable Bowel em leader or Simply Irritable?

PMID- 15014587
TI  - Dr. Wolff Replies.

PMID- 15014586
TI  - Gabapentin in the Treatment of Aggression Associated With Conduct Disorder.

PMID- 15014588
TI  - Possible Manic Phase Precipitated by Antidepressant Treatment.

PMID- 15014589
TI  - Citalopram and Hair Loss.

PMID- 15014590
TI  - National Patterns of Medication Treatment for Depression, 1987 to 2001.
AB  - BACKGROUND: We investigated trends in antidepressant use, as well as broader
      changes in depression treatment, following the availability of selective
      serotonin reuptake inhibitors (SSRIs). METHOD: Using data from the National
      Disease and Therapeutic Index, a nationally representative survey of U.S. office
      based physicians conducted by IMS HEALTH, we analyzed trends in antidepressant
      prescribing patterns from 1987 through the third quarter of 2001. Annual sample
      sizes of physician visits by patients reported to have depression ranged from
      3901 visits in 1987 to 6639 in 1998. Outcomes examined included the frequency of
      depression visits, the likelihood of antidepressant therapy, and the use of
      specific medications. RESULTS: The estimated national number of physician visits
      by patients with depression increased from 14.4 million visits in 1987 to 24.5
      million in 2001 (annualized). The rate of antidepressant medication treatment in
      these patients also increased from 70% in 1987 to 89% in 2001. In 1987, tricyclic
      antidepressants were prescribed to 47% of patients with depression. The most
      common individual antidepressants were amitriptyline (14%), trazodone (12%),
      doxepin (8%), and desipramine (6%). In 1989, a year after its introduction,
      fluoxetine was prescribed to 21% of patients with depression. The introduction of
      other SSRIs led aggregate SSRI use to grow to 38% in 1992, 60% in 1996, and 69%
      in 2000. In 2001, sertraline (18%), paroxetine (16%), fluoxetine (14%),
      citalopram (13%), and bupropion (9%) were the leading antidepressants, while
      tricyclics were used in only 2% of patients. The use of benzodiazepines in
      depression declined from 21% of patients in 1987 to 8% in 2001. CONCLUSION: The
      increasing therapeutic dominance of SSRIs may have contributed to other changes
      in depression treatment, including declining benzodiazepine use, increased
      aggregate antidepressant treatment rates, and increased reporting of depression.

PMID- 15014591
TI  - Treatment of Comorbid Tuberculosis and Depression.
AB  - Tuberculosis (TB) remains a leading infectious cause of mortality worldwide.
      While the overall prevalence of TB in the United States has declined in the
      general population, certain groups remain at high risk, including the homeless,
      those who are HIV seropositive, individuals with a history of alcohol or drug
      abuse, and immigrants from a country in which TB is endemic. Many recipients of
      psychiatric services possess 1 or more of these risk factors, and consequently TB
      may be overrepresented in this population. Conversely, psychiatric illness may
      develop subsequent to TB infection. Mood disorders seem to be particularly common
      in TB patients compared with those with other medical diagnoses. It is important
      that primary care physicians understand the high prevalence of mental illness in
      TB patients so that proper treatment provisions can be implemented. Likewise, it
      is important for psychiatrists to understand the clinical manifestations of TB so
      that when a patient presents with symptoms of TB proper precautions can be taken
      and appropriate referrals can be made. This article integrates information
      concerning mental illness in TB patients with diagnostic and treatment guidelines
      for TB. Brief suggestions are offered for the treatment of TB patients with
      comorbid mental illness.

PMID- 15014593
TI  - Social Security Claims of Psychiatric Disability: Elements of Case Adjudication
      and the Role of Primary Care Physicians.
AB  - When first introduced into law, social security was designed to safeguard
      economic security for U.S. citizens who were retired or disabled. Primary care
      physicians are often contacted by the Social Security Administration (SSA) to
      provide clinical information about the impairments affecting their patients who
      have applied for disability. The disability determination process is often
      elusive to physicians. This article is written to describe the process involved
      in adjudicating disability claims according to SSA standards. Because psychiatric
      disturbances constitute the largest reason for applications for disability, this
      article addresses the sorts of information required of clinicians that would
      expedite disability adjudication of claims involving psychiatric disorders.
      Practical suggestions are offered for clinicians to employ when preparing medical
      reports. The potential impact of the disability claim on the doctor-patient
      relationship is also discussed.

PMID- 15014594
TI  - "A Ginkgo Cocktail, Anyone?"

PMID- 15014595
TI  - Retirement.

PMID- 15014592
TI  - The Comorbidity of Major Depression and Anxiety Disorders: Recognition and
      Management in Primary Care.
AB  - BACKGROUND: Depressive and anxiety disorders commonly occur together in patients
      presenting in the primary care setting. Although recognition of individual
      depressive and anxiety disorders has increased substantially in the past decade,
      recognition of comorbidity still lags. The current report reviews the
      epidemiology, clinical implications, and management of comorbidity in the primary
      care setting. METHOD: Literature was reviewed by 2 methods: (1) a MEDLINE search
      (1980-2001) using the key words depression, depressivedisorders, and
      anxietydisorders; comorbidity was also searched with individual anxiety
      diagnoses; and (2) direct search of psychiatry, primary care, and internal
      medicine journals over the past 5 years. RESULTS: Between 10% and 20% of adults
      in any given 12-month period will visit their primary care physician during an
      anxiety or depressive disorder episode (although typically for a nonpsychiatric
      complaint); more than 50% of these patients suffer from a comorbid second
      depressive or anxiety disorder. The presence of depressive/anxiety comorbidity
      substantially increases medical utilization and is associated with greater
      chronicity, slower recovery, increased rates of recurrence, and greater
      psychosocial disability. Typically, long-term treatment is indicated, although
      far less research is available to guide treatment decisions. Selective serotonin
      reuptake inhibitor antidepressants are the preferred treatment based on efficacy,
      safety, and tolerability criteria. Knowledge of their differential clinical and
      pharmacokinetic profiles can assist in optimizing treatment. CONCLUSION:
      Increased recognition of the high prevalence and negative psychosocial impact of
      depression and anxiety disorder comorbidity will lead to more effective
      treatment. While it is hoped that early and effective intervention will yield
      long-term benefits, research is needed to confirm this.

PMID- 15014596
TI  - Treatment of Methamphetamine Cravings With Bupropion: A Case Report.

PMID- 15014597
TI  - Involvement of Family Members in Treatment of Depressed Individuals.

PMID- 15014598
TI  - The Hypothalamic-Pituitary-Adrenal Axis in Major Depressive Disorder: A Brief
      Primer for Primary Care Physicians.
AB  - BACKGROUND: One of the most enduring and replicated findings in biological
      psychiatry is activation of the hypothalamic-pituitary-adrenal (HPA) axis in a
      subset of patients with major depressive disorder. This review will discuss some
      of these findings and their pertinence to the assessment and treatment of
      depressed patients. METHOD: MEDLINE, PsychINFO, and Current Contents databases
      were searched for pertinent articles on the HPA axis in patients with depression.
      In addition, hand searches were conducted of references from these sources and
      abstracts from meetings and books on this topic. Articles that would provide an
      overview of major or interesting studies in the field were selected for
      inclusion. RESULTS: The data support that HPA axis activation is common in
      depressed patients. Frequently reported findings include elevated cortisol and
      corticotropin-releasing hormone (CRH), nonsuppression on the dexamethasone
      suppression test, a blunted adrenocorticotropic hormone (ACTH) response to CRH,
      and hippocampal volume reduction. Evidence of HPA axis activation appears to have
      prognostic value and is associated with increased risk of depression relapse and
      even suicide. CONCLUSION: Future research in this area will focus on a better
      understanding of the etiology and long-term consequences of HPA axis activation
      in depressed patients. In addition, medications that act on the HPA axis are
      currently in development and may be part of the psychiatrist's and primary care
      physician's pharmacopoeia in the near future.

PMID- 15014599
TI  - Treating Psychotic Symptoms in Elderly Patients.
AB  - Research has shown that elderly patients are especially at risk for the
      development of psychotic symptoms. A combination of factors contributes to the
      increased risk for psychosis in this patient population. Various DSM-IV
      diagnostic categories including delirium, schizophrenia, delusional disorder,
      mood disorders, dementia, substance abuse, and medical-neurologic conditions can
      be associated with psychotic symptoms. In general, medications are prescribed for
      specific target symptoms, started at low doses, and titrated gradually. Although
      buspirone, trazodone, valproic acid, and carbamazepine have been used with some
      success, antipsychotic medications have been the primary treatment of psychosis
      in the elderly. Because the atypical antipsychotics offer effective management of
      psychotic symptoms combined with low liability of extrapyramidal symptoms, these
      agents may be the current treatment of choice for psychotic symptoms in the
      elderly when used cautiously.

PMID- 15014600
TI  - Characteristics Of Patients Assigned Multiple Nonthreatening Medical Diagnoses.
AB  - BACKGROUND: Medical diagnoses can be separated on the basis of whether or not
      they are associated with significant 1-year mortality risk, i.e., "threatening"
      versus "nonthreatening," by employing the Charlson Comorbidity Index (CCI). The
      author examined the psychosocial characteristics and medical utilization patterns
      of patients assigned multiple nonthreatening medical diagnoses. METHOD: The study
      population included 125 general medical outpatients seen in psychiatric
      consultation. The author employed blinded reviews of medical charts,
      psychological measures, and billing records to assess patients' psychosocial
      characteristics and medical utilization. RESULTS: The number of nonthreatening
      diagnoses correlated significantly with age (r = 0.35, p </=.001), diagnosis of
      somatoform disorder (r = 0.29, p </=.001), somatosensory amplification (r = 0.36,
      p </=.001), number of ambulatory medical visits (r = 0.24, p </=.01), and
      emergency room visits (r = 0.18, p </=.05), but did not correlate with CCI scores
      or medical hospitalization. By contrast, the number of threatening diagnoses, as
      measured by the CCI, did not correlate with a diagnosis of somatoform disorder or
      somatic amplification, but did correlate with age and all measures of medical
      utilization, including hospitalization (r = 0.19, p </=.05). CONCLUSION: Patients
      with multiple nonthreatening medical diagnoses have different psychosocial
      characteristics and medical utilization patterns than patients with multiple
      threatening diagnoses. The association between the number of nonthreatening
      medical diagnoses assigned to a given patient and measures of somatization
      suggests that psychosocial factors contribute to diagnostic assignment in
      patients with multiple nonthreatening medical diagnoses.

PMID- 15014601
TI  - Steps Following Attainment of Remission: Discontinuation of Antidepressant
      Therapy.
AB  - Depressive disorders require long-term treatment with antidepressants,
      psychotherapy, or both. The goal of antidepressant therapy is complete remission
      of symptoms and return to normal daily functioning. Studies have shown that
      achieving remission and continuing antidepressant therapy long after the acute
      symptoms remit can protect against the relapse or recurrence of the psychiatric
      episode. Many patients, however, inadvertently or intentionally skip doses of
      their antidepressant, and even discontinue it, if their symptoms improve or if
      they experience side effects. Antidepressant discontinuation may increase the
      risk of relapse or precipitate certain distressing symptoms such as
      gastrointestinal complaints, dizziness, flu-like symptoms, equilibrium
      disturbances, and sleep disorders. Documented with all classes of
      antidepressants, these reactions may emerge within a couple of days, or even
      hours, after the abrupt discontinuation of an antidepressant with a short half
      life. These distressing responses may be mistaken for a relapse or recurrence. It
      is important to recognize the potential for these sequelae and educate patients
      about the need to take all antidepressants at the doses prescribed, warning them
      of the symptoms that may occur if they skip doses or stop their medication too
      quickly. Antidepressants should be tapered slowly over a period of days, weeks,
      or even months, depending on the dose, duration of treatment, and pharmacologic
      properties of the agent, as well as the patient's individual response. This
      article reviews the risks and reactions associated with discontinuation of
      antidepressants. It offers guidelines for distinguishing relapse and recurrence
      from discontinuation responses as well as for prevention and management of the
      antidepressant discontinuation syndrome.

PMID- 15014602
TI  - Little Fishies.

PMID- 15014603
TI  - Comorbid Major Depression and Social Phobia.

PMID- 15014604
TI  - Assessing Sexual Function of Patients Before Initiating SSRI Therapy.

PMID- 15014605
TI  - Dr. Berigan Replies.

PMID- 15014606
TI  - Oxcarbazepine in Bipolar Disorder.

PMID- 15014609
TI  - Medications for the Treatment of Sleep Disorders: An Overview.
AB  - Sleep disorders can be divided into those producing insomnia, those causing
      daytime sleepiness, and those disrupting sleep. Transient insomnia is extremely
      common, afflicting up to 80% of the population. Chronic insomnia affects 15% of
      the population. Benzodiazepines are frequently used to treat insomnia; however,
      there may be a withdrawal syndrome with rapid eye movement (REM) rebound. Two
      newer benzodiazepine-like agents, zolpidem and zaleplon, have fewer side effects,
      yet good efficacy. Other agents for insomnia include sedating antidepressants and
      over-the-counter sleep products (sedating antihistamines). Nonpharmacologic
      behavioral methods may also have therapeutic benefit. An understanding of the
      electrophysiologic and neurochemical correlates of the stages of sleep is useful
      in defining and understanding sleep disorders. Excessive daytime sleepiness is
      often associated with obstructive sleep apnea or depression. Medications,
      including amphetamines, may be used to induce daytime alertness. Parasomnias
      include disorders of arousal and of REM sleep. Chronic medical illnesses can
      become symptomatic during specific sleep stages. Many medications affect sleep
      stages and can thus cause sleep disorders or exacerbate the effect of chronic
      illnesses on sleep. Conversely, medications may be used therapeutically for
      specific sleep disorders. For example, restless legs syndrome and periodic limb
      movement disorder may be treated with dopamine agonists. An understanding of the
      disorders of sleep and the effects of medications is required for the appropriate
      use of medications affecting sleep.

PMID- 15014608
TI  - A Review of the Diagnosis, Pharmacologic Treatment, and Economic Aspects of
      Anxiety Disorders.
AB  - As many as 1 in 4 Americans will experience an anxiety disorder at some point in
      their lives, and many will also suffer the depression, substance abuse,
      distressing physical signs, and socioeconomic problems that often accompany these
      disorders when left untreated. Anxiety disorders can be detected using simple
      screening tools in the physician's office. Early and effective treatment with
      appropriate medication can significantly reduce the psychic and physical symptoms
      of anxiety, lowering the overall costs of the disorder to the health care system
      and society. Many drugs offer safe and effective relief of anxiety symptoms with
      few side effects or drug-drug interactions, and some offer symptomatic relief
      within 1 to 2 weeks.

PMID- 15014607
TI  - Recognition and Management of Behavioral Disturbances in Dementia.
AB  - Behavioral disturbances are seen in most patients with dementia at some point in
      their course. They cause immense patient suffering and are responsible for
      caregiver stress, institutionalization, and hospitalization. Identification of
      predisposing and precipitating factors is very important. The approach to the
      management of behavioral disturbances in dementia patients should be structured
      and thorough. Ensuring the safety of the patient and others should be paramount.
      Addressing the causes of behavioral disturbances such as comorbid medical
      illnesses, polypharmacy, pain, personal need, environmental factors, etc. is
      critical to a successful outcome. Many behavioral disturbances such as wandering
      and hoarding are not amenable to pharmacotherapy. Nonpharmacologic interventions
      are the mainstay of managing behavioral disturbances. Success of pharmacologic
      interventions will depend on accurate identification of specific syndromes, e.g.,
      depression-anxiety and psychosis and severity of symptoms. Response to
      pharmacologic interventions is usually modest and may be associated with
      significant symptom resolution. Many behavioral disturbances can be prevented by
      avoiding inappropriate medications and educating patient, family, caregivers, and
      health care providers. Hospitalization can be avoided and institutionalization
      delayed by early recognition and treatment of behavioral disturbances. Leadership
      from physicians to implement preventive measures is recommended. Research to
      clarify the biological underpinnings of behavioral disturbances and to address
      cost-effectiveness of currently identified interventions is needed.

PMID- 15014611
TI  - Give It to Me Here, Doc.

PMID- 15014610
TI  - Sexual Abuse of the Mentally Retarded Patient: Medical and Legal Analysis for the
      Primary Care Physician.
AB  - The primary care physician has a vital role in documenting and preventing sexual
      abuse among the mentally retarded populations in our community. Since the current
      national trend is to integrate citizens with mental retardation into the
      community away from institutionalized care, it is essential that all physicians
      have a basic understanding of the unique medical and legal ramifications of their
      clinical diagnoses. As the legal arena is currently revising laws concerning
      rights of sexual consent among the mentally retarded, it is essential that
      determinations of mental competency follow national standards in order to
      delineate clearly any instance of sexual abuse. Clinical documentation of sexual
      abuse and sexually transmitted disease is an important part of a routine
      examination since many such individuals are indeed sexually active. Legal codes
      adjudicating sexual abuse cases of the mentally retarded often offer scant
      protection and vague terminology. Thus, medical documentation and physician
      competency rulings form a solid foundation for future work toward legal recourse
      for the abused.

PMID- 15014612
TI  - A Marriage Between Pharmacotherapy and Psychotherapy.

PMID- 15014613
TI  - Dysphagia and Chronic Mental Illness: Looking Beyond Hysteria and Broadening the
      Psychiatric Differential Diagnosis.

PMID- 15014614
TI  - Mirtazapine-Associated Withdrawal Symptoms: A Case Report.

PMID- 15014615
TI  - A Proposed Algorithm for Improved Recognition and Treatment of the
      Depression/Anxiety Spectrum in Primary Care.
AB  - The International Consensus Group on Depression and Anxiety has held 7 meetings
      over the last 3 years that focused on depression and specific anxiety disorders.
      During the course of the meeting series, a number of common themes have
      developed. At the last meeting of the Consensus Group, we reviewed these areas of
      commonality across the spectrum of depression and anxiety disorders. With the aim
      of improving the recognition and management of depression and anxiety in the
      primary care setting, we developed an algorithm that is presented in this
      article. We attempted to balance currently available scientific knowledge about
      the treatment of these disorders and to reformat it to provide an acceptable
      algorithm that meets the practical aspects of recognizing and treating these
      disorders in primary care.

PMID- 15014616
TI  - The Importance of Residual Effects When Choosing a Hypnotic: The Unique Profile
      of Zaleplon.
AB  - BACKGROUND: Insomnia is a prevalent medical disorder that has significant effects
      on occupational performance, health, and quality of life. Insomnia places an
      enormous burden on society through increased visits to physicians, loss of
      productivity in the workplace, and an increased rate of accidents. An estimated
      sum of $100 million is spent each year on direct treatment of unresolved
      insomnia. Physicians need to initiate early effective treatment to prevent
      development of chronic insomnia and its associated morbidity. Institution of good
      sleep hygiene practices may be useful in some patients but may not be adequate
      for resolution of all sleep problems. Behavioral treatments, while effective and
      durable, are time consuming and not widely utilized in clinical practice.
      Pharmacotherapy includes benzodiazepine hypnotics, but concerns regarding adverse
      effects (e.g., residual sedation) prompted the search for safer options. DATA
      SOURCES: Published and presented studies containing clinical data on zaleplon, a
      new nonbenzodiazepine sleep medication, were identified via MEDLINE, Current
      Contents (ISI database), bibliographic reviews, and consultation with sleep
      specialists. RESULTS: Zaleplon effectively shortens sleep onset time and improves
      the quality of sleep in patients with insomnia. Whether administered at bedtime
      or later at night, zaleplon is devoid of residual sedative effects that impair
      next-day functioning. Follow-up studies evaluating the long-term efficacy and
      safety of zaleplon showed that decreased time to sleep onset was maintained
      during therapy lasting up to 52 weeks, without a withdrawal syndrome after
      discontinuation. CONCLUSION: Insomnia is recurrent and unpredictable in nature.
      Despite the long-term morbidity of this sleep disorder, research evidence and
      practice guidelines have not explored long-term use of hypnotics. Many patients
      could benefit from long-term drug therapy with a sleep medication that is devoid
      of residual effects and can be taken at bedtime or later as symptoms occur,
      rather than nightly in anticipation of a sleep problem.

PMID- 15014617
TI  - Atypical Antipsychotics and Glucose Dysregulation: A Series of 4 Cases.
AB  - There have been reports in the psychiatric literature of the association of
      glucose dysregulation and diabetes mellitus with the use of atypical and typical
      (conventional) antipsychotics. We present a series of 4 additional cases in which
      psychotic disorders (DSM-IV) were treated with atypical antipsychotics, and
      patients subsequently developed glucose dysregulation or diabetes mellitus. The
      implications of these findings are discussed.

PMID- 15014620
TI  - Fear in the Presence of Others.

PMID- 15014619
TI  - Home Improvement for Beginners.

PMID- 15014618
TI  - The Diagnosis and Management of Attention-Deficit/Hyperactivity Disorder in
      Pediatric Patients.
AB  - Attention-deficit/hyperactivity disorder (ADHD), characterized by developmentally
      inappropriate inattentiveness, impulsivity, and hyperactivity, is the most common
      and thoroughly researched neuropsychiatric disorder affecting children and
      adolescents. The diagnosis of ADHD requires a comprehensive clinical assessment
      including a detailed patient history, clinical interview and observation, and a
      thorough physical examination. A variety of other disorders can masquerade as
      ADHD or coexist with the disorder. The clinician must recognize environmental
      influences that may affect the severity of symptoms exhibited in the child or
      adolescent with ADHD. Clinically, treatment with a stimulant can be expected to
      result in an immediate, often dramatic, improvement in the core symptoms of ADHD.
      Studies published over the past 20 years indicate that the symptoms of ADHD,
      which were originally thought to diminish as a child matured, may persist into
      adolescence and adulthood. This article is a review of the most recent
      recommendations and clinical data regarding the diagnosis and management of ADHD
      in children and adolescents to assist with appropriate and prudent clinical
      decision making.

PMID- 15014621
TI  - Psychiatric Uses of Newer Anticonvulsants.

PMID- 15014622
TI  - Social Anxiety Disorder: More Than Just a Little Shyness.
AB  - Social anxiety is defined as a "marked and persistent fear of social or
      performance situations" and includes such symptoms as sweating, palpitations,
      shaking, and respiratory distress. Social anxiety is fairly common, occurring in
      as much as 13% of the population, and can be extremely disabling. It can be
      either specific (confined to 1 or 2 performance situations) or generalized, and
      can be diagnosed with a scale-based questionnaire. Social anxiety may coexist
      with other disorders, such as depression and dysthymia. The differential
      diagnosis for social anxiety includes panic disorder, agoraphobia, atypical
      depression, and body dysmorphic disorder. Treatment for social anxiety can be
      quite effective and consists of psychotherapy, pharmacotherapy (including such
      medications as beta-blockers, anxiolytics, antidepressants, and anticonvulsants),
      or a combination. This article details the prevalence, onset, disease impact, and
      etiology of social anxiety. Specific treatments, including both psychotherapy and
      pharmacotherapy, are presented in detail, along with other treatment
      considerations, such as comorbidity.

PMID- 15014623
TI  - Improved Health-Related Quality of Life and Reduced Productivity Loss After
      Treatment With Bupropion Sustained Release: A Study in Patients With Major
      Depression.
AB  - BACKGROUND: This open-label portion of a 2-phase study assessed the effects of
      the antidepressant bupropion sustained release (SR) on health-related quality of
      life (QOL) and workplace productivity in patients with major depression. METHOD:
      Patients (N = 816) with DSM-IV major depression were treated with bupropion SR,
      300 mg/day, for 8 weeks. The Clinical Global Impressions scale for Improvement of
      Illness (CGI-I) was completed at weekly clinic visits. At baseline and week 8,
      QOL and productivity were assessed. QOL was assessed using the Quality of Life in
      Depression Scale (QLDS). RESULTS: QOL and productivity were significantly
      improved from baseline after 8 weeks of treatment with bupropion SR. Mean QLDS
      scores were 18.98 and 10.36 at baseline and week 8, respectively (mean change =
      8.62; p <.001). At week 8 compared with baseline, patients working at a paid job
      reported missing 1.58 fewer hours of work because of depression during the past 7
      days, being 14.6% more effective on the job, working at reduced effectiveness
      less often, and incurring 6.37 fewer hours of overall lost productivity (p <.001
      each variable). Improvements in QOL and productivity were significantly (p <.001)
      greater in bupropion SR responders (i.e., those with CGI-I scores of "very much
      improved" or "much improved" during the last 3 weeks of open-label therapy) than
      in nonresponders. CONCLUSION: Effective treatment of major depression with
      bupropion SR for 8 weeks is associated with improvements in QOL and reductions in
      lost workplace productivity. Patients who responded clinically to bupropion SR
      showed significantly greater improvements in these variables than those who did
      not respond.

PMID- 15014624
TI  - Mood and Cognitive Changes During Systemic Corticosteroid Therapy.
AB  - BACKGROUND: Physicians in the United States write approximately 10 million new
      prescriptions for oral corticosteroids each year. Common side effects of
      corticosteroids include weight gain, osteoporosis, and diabetes mellitus. This
      article reviews the available literature on psychiatric and cognitive changes
      during corticosteroid therapy. METHOD: A search of the MEDLINE and psycINFO
      databases was conducted to find clinically relevant articles on psychiatric and
      cognitive side effects with corticosteroids using search terms including
      corticosteroid, prednisone, mania, depression, psychosis, mood, memory, and
      cognition. RESULTS: Symptoms of hypomania, mania, depression, and psychosis occur
      during corticosteroid therapy as do cognitive changes, particularly deficits in
      verbal or declarative memory. Psychiatric symptoms appear to be dose-dependent
      and generally occur during the first few weeks of therapy. Patients who must
      remain on corticosteroids may benefit from pharmacotherapeutic approaches, such
      as lithium and the new antipsychotic medications. CONCLUSION: Mood and cognitive
      changes with corticosteroids appear to be common but generally mild and
      reversible side effects. More studies are needed to determine effective treatment
      for steroid-induced psychiatric disorders.

PMID- 15014626
TI  - "Pour Me a Gin and Tonic, Honey; It's After 5 in Paris."

PMID- 15014625
TI  - SSRI Antidepressant Medications: Adverse Effects and Tolerability.
AB  - Side effects of antidepressants can be predicted by receptor selectivity and site
      of action. Although the selective serotonin reuptake inhibitors (SSRIs) have
      better overall safety and tolerability than older antidepressants, broad-based
      experience with SSRIs has shown the frequency and type of side effects to be
      increased relative to clinical trial data. The author explores the reasons for
      the different profiles and discusses adverse effects, especially sexual
      dysfunction, weight gain, and sleep disturbance, the most troubling adverse
      events seen during long-term SSRI therapy. The informed management of these side
      effects by primary care practitioners supports successful treatment of
      depression.

PMID- 15014627
TI  - Psychotherapy Clarified the Diagnosis and Treated the Problem.

PMID- 15014628
TI  - Augmentation With Modafinil to Achieve Remission in Depression: A Case Report.

PMID- 15014630
TI  - Selecting a Selective Serotonin Reuptake Inhibitor: Clinically Important
      Distinguishing Features.
AB  - Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat
      depression. Although these drugs presumably have the same mechanism of action,
      they vary in several clinically important ways, including how long they remain in
      the body and the extent to which they interfere with the metabolism of other
      medications. This article reviews the pharmacologic differences among SSRIs and
      how these differences may affect various aspects of treatment, such as dosing,
      administration, and discontinuation. Understanding the distinct properties of
      SSRIs may help primary care physicians to design the most appropriate therapeutic
      plan for individual patients.

PMID- 15014631
TI  - National Patterns of Depression Treatment in Primary Care.
AB  - BACKGROUND: While past studies suggest that primary care physicians underdiagnose
      and undertreat depression, little is known about recent national patterns of
      depression treatment. METHOD: Using the 1995 and 1996 National Ambulatory Medical
      Care Surveys, we analyzed 1322 primary care office visits by patients reported to
      have depression. Rates of psychotherapy/mental health counseling, antidepressant
      use, and benzodiazepine use were assessed. Independent predictors of depression
      therapy were examined using multiple logistic regression. Where instructive, we
      compared the practices of primary care physicians with those of psychiatrists
      (2418 depression visits). RESULTS: Primary care physicians reported depression in
      7.8% of their office visits. For these depression visits, antidepressants (42%)
      were the most common form of treatment, followed by psychotherapy/mental health
      counseling (28%) and benzodiazepines (21%). Among specific antidepressants,
      selective serotonin reuptake inhibitors were most often prescribed by primary
      care physicians (26% of depression visits). Rates of antidepressant and
      benzodiazepine use varied significantly by primary care specialty. In addition,
      geographic region and health insurance status influenced the likelihood of
      receiving benzodiazepines. In their depression visits, psychiatrists reported
      psychotherapy/mental health counseling (88%) most frequently, followed by
      antidepressants (64%) and benzodiazepines (25%). CONCLUSION: The predominant use
      of selective serotonin reuptake inhibitors suggests that primary care physicians
      have begun to adopt new therapeutic strategies for depression. The modest rate of
      antidepressant therapy for a clinical population specifically identified by
      primary care physicians as having depression may indicate undertreatment of
      depression in primary care settings. Furthermore, high rates of benzodiazepine
      use are inconsistent with treatment guidelines, and variations in treatment
      patterns suggest that nonclinical factors influence depression management.

PMID- 15014629
TI  - Atypical Antipsychotic Use in the Treatment of Psychosis in Primary Care.
AB  - Atypical antipsychotics are a class of novel agents increasingly employed for the
      treatment of psychotic disorders. The pharmacodynamic properties of the atypicals
      appear to impact a broader spectrum of psychotic symptoms than had been
      appreciated with older generation antipsychotics. In addition, the atypical
      agents appear to have a reduced risk of neurologic side effects compared with
      conventional antipsychotic use. Both of these features enhance the appeal of the
      atypical antipsychotics and may be associated with enhanced patient compliance.
      The atypical antipsychotics appear to be effective for schizophrenia as well as
      other psychotic disorders, including schizoaffective disorder and mood disorders
      with psychotic features. Consequently, atypical antipsychotics are now considered
      to be the first-line treatment for schizophrenia, with the exception of
      clozapine, which is considered a second-line agent because of risks associated
      with its use. This review will discuss the literature on atypical antipsychotic
      efficacy in psychotic disorders. Issues related to antipsychotic use, dosing,
      adverse effects, and drug interactions are also discussed.

PMID- 15014633
TI  - Toiling in the Herb Garden or Sitting in the Field of Dreams.

PMID- 15014634
TI  - Panic Disorder Presenting in Primary Care.

PMID- 15014632
TI  - An Update on Mood and Anxiety Disorders During Pregnancy and the Postpartum
      Period.
AB  - Because women in the childbearing years are vulnerable to mood and anxiety
      disorders, physicians in all patient care specialties need to be familiar with
      the prevalence and course of these disorders, particularly during pregnancy and
      the postpartum period. Systematic prospective data are limited on the onset of
      mood and anxiety disorders during pregnancy and the postpartum period as well as
      on the risk of relapse during these time periods in women with prior histories of
      the disorders. The literature on mood and anxiety disorders during pregnancy is
      frequently complicated by the use of various methodologies, procedures, and study
      populations, and inconsistencies in the postpartum time frame (up to 6 months
      after delivery) make the literature on epidemiology of postpartum disorders
      difficult to interpret. This article is an update of available information about
      the prevalence and course of mood and anxiety disorders in women during pregnancy
      and the postpartum period.

PMID- 15014635
TI  - Acetylcholinesterase Inhibitors: Treatment of Dementia-Related Behavioral
      Disturbances.

PMID- 15014636
TI  - Depression in Asthma: Prevalence and Clinical Implications.
AB  - BACKGROUND: Asthma and depression are both common illnesses. Data suggest that
      the prevalence of asthma and asthma-related morbidity and mortality has increased
      in the past 2 decades. Asthma has long been considered an illness in which mood
      and emotions contribute to symptom exacerbation. Therefore, we reviewed the
      recent literature on depression in persons with asthma. DATA SOURCES: The MEDLINE
      (1966-1999) and PSYCHINFO (1967-1999) databases were used to find English
      language articles on asthma and depression. Search terms included asthma,
      depression, dysthymia, and mood. DATA SYNTHESIS: This literature suggests
      depressive symptoms are more common in asthma patients than in the general
      population and perhaps even more common than in some other general medical
      conditions. Depression may be associated with asthma morbidity and mortality.
      Limited data suggest the older tricyclic antidepressants may improve both
      depression and asthma symptoms. However, no studies have examined the use of
      second-generation antidepressants in asthma patients. CONCLUSION: Depressive
      symptoms are common in asthma patients. However, the prevalence of depressive
      disorders in this population is not well determined. Future studies should focus
      on determining the prevalence of major depressive disorder in this population and
      the effect of antidepressants on mood and asthma symptoms.

PMID- 15014637
TI  - Methylphenidate Abuse and Psychiatric Side Effects.
AB  - Methylphenidate is a central nervous system stimulant drug that has become the
      primary drug of choice in treating attention-deficit/hyperactivity disorder in
      children. Side effects are usually mild and are generally well tolerated by
      patients. Along with increases in prescribing frequency, the potential for abuse
      has increased. Intranasal abuse produces effects rapidly that are similar to the
      effects of cocaine in both onset and type. The clinical picture of stimulant
      abuse produces a wide array of psychiatric symptoms. There is little in the
      literature to differentiate methylphenidate from other stimulants when they are
      abused. The need for education of all involved with the use of methylphenidate is
      discussed to help prevent an increasing pattern of methylphenidate abuse.

PMID- 15014638
TI  - Impact of Antipsychotics on Geriatric Patients: Efficacy, Dosing, and Compliance.
AB  - People today are living longer. Old age is the number one risk factor for
      dementia, which is often associated with behavioral disturbances and psychosis as
      well as cognitive and memory impairment. Elderly persons with dementia
      particularly those who are agitated or aggressive-are often placed in nursing
      homes and consequently treated with antipsychotic medications. Most of the
      studies of antipsychotic efficacy and safety have been conducted in young
      schizophrenic patients, but there are differences in dosing schedules, efficacy,
      and compliance when these drugs are used in elderly patients with dementia and
      psychosis. A review of both nonpharmacologic and pharmacologic treatment is
      herewith presented for the treatment of elderly dementia patients, especially
      those living in long-term care facilities.

PMID- 15014640
TI  - Hits and Near Misses.

PMID- 15014641
TI  - When Brief Therapy Worked and Medication Did Not.

PMID- 15014639
TI  - Depression: Diagnosis and Management for the Primary Care Physician.
AB  - BACKGROUND: Much has been learned in recent years about the diagnosis and
      treatment of depression, a serious, commonly overlooked psychiatric illness often
      seen initially by the primary care physician. The objective of this article is to
      review the diagnosis and treatment of depression in primary care practice.
      METHOD: Relevant articles on depression were identified by a comprehensive
      MEDLINE search and classified into the following categories: diagnosis and
      screening, nonpharmacologic therapy, pharmacologic therapy, newer antidepressant
      agents, and maximizing antidepressant therapy. The importance to primary care
      practice was considered in determining the significance of each article reviewed.
      RESULTS: Because no laboratory tests exist for depression and no biological
      markers can be measured routinely, the diagnosis of depression must be made with
      a number of reliable depression scales and questionnaires that can be completed
      quickly in the primary care setting. The considerable overlap between depressive
      and anxiety disorders further complicates an accurate diagnosis. Remission (i.e.,
      absence of symptoms) is the ultimate goal of therapy for patients who have
      depressive symptoms. CONCLUSION: Many patients can be treated safely and
      effectively for depression in the primary care setting with pharmacologic
      therapy, which, if completely successful, can lead to full remission of the
      disorder.

PMID- 15014642
TI  - A Ginkgo biloba-Associated Paranoid Reaction.

PMID- 15014643
TI  - Anticholinergic Side Effects in Perspective.

PMID- 15014644
TI  - Hypochondriacal Concerns: Management Through Understanding.
AB  - The medically unexplained complaint is often a symptom of hypochondriacal
      concerns. Patients with hypochondriasis may be managed with either naive realism
      or consideration of morbid categorization or via dimensional assessment of
      illness beliefs and behaviors. Naive realism will foster focus somatization and
      promote regression as well as lead to needless tests and treatments. Attention to
      categorical entities such a major depression or anxiety disorders will alert the
      clinician to comorbid psychiatric disorders that respond to traditional
      psychiatric treatments. Finally, by assessing the domains of illness behaviors
      such as disease conviction, beliefs in organic versus psychological causes, and
      denial, the clinician can document and then confront abnormal cognitive schema
      that revolve around somatic concerns that are a proxy for psychosocial
      difficulties.

PMID- 15014645
TI  - The Comparative Peripheral Anticholinergic-Like Adverse Event Profiles of
      Olanzapine and Risperidone.
AB  - OBJECTIVE: To test the hypothesis that reported in vitro muscarinic receptor
      affinity differences between olanzapine and risperidone would be reflected in
      peripheral solicited anticholinergic adverse event frequencies. METHOD: Data from
      a double-blind, randomized trial of olanzapine versus risperidone in 339 patients
      (age range, 18-65 years) with DSM-IV schizophrenia spectrum acute psychosis were
      retrospectively analyzed. Subgroups based on the median of the mean daily drug
      dose were constructed (olanzapine </= 17 mg; olanzapine > 17 mg; risperidone </=
      6 mg; risperidone > 6 mg). Mean daily dose of adjunctive anticholinergic
      medication was compared using ANOVA, and frequencies of treatment-emergent
      solicited adverse events defined by the Association de Methodologie et de
      Documentation en Psychiatrie (AMDP-5) were analyzed using categorical methods.
      RESULTS: Mean daily anticholinergic dose was significantly higher overall for the
      risperidone group (0.68 +/- 1.27 mg) than for the olanzapine group (0.27 +/- 0.76
      mg) (p =.002). When only patients who did not receive anticholinergic adjunct
      therapy were considered, no significant differences in the frequency of specific
      anticholinergic adverse events occurred in olanzapine-treated patients as
      compared with risperidone-treated patients (p >/=.245). There was also no
      significant difference between olanzapine and risperidone in the frequency of any
      anticholinergic adverse event (p =.458). CONCLUSION: At clinically effective
      doses, olanzapine and risperidone did not differ significantly in frequency of
      peripheral anticholinergic events. These results support the view that, for
      olanzapine and risperidone, in vitro anticholinergic receptor binding (K(i)
      values) may not predict in vivo peripheral events.

PMID- 15014646
TI  - Depression Across the Reproductive Life Cycle: Correlations Between Events.
AB  - BACKGROUND: This study examines whether women who become depressed at one
      reproductive cycle event, e.g., postpartum, are likely to become depressed at
      other such events. METHOD: Seventy-two women in treatment for major depression
      were asked to complete a questionnaire assessing mood at 4 different reproductive
      cycle events, i.e., while premenstrual, taking oral contraceptives, postpartum,
      or perimenopausal. All diagnoses were made using DSM-III-R criteria. Rank-order
      correlations (r) were determined between mood ratings for different reproductive
      cycle event pairs. RESULTS: Significant correlations were found between
      premenstrual and perimenopausal mood ratings (r = 0.41) and between postpartum
      and perimenopausal mood ratings (r = 0.64). Development of severe depression
      during the latter 2 events was strongly correlated (r = 0.87). Women who
      developed severe depression during at least 2 reproductive cycle events were more
      likely to have bipolar disorder, a family psychiatric history, and a younger age
      at onset. CONCLUSION: These findings suggest that there may be a unique subgroup
      of women who are vulnerable to depression at reproductive cycle events.

PMID- 15014647
TI  - Twelve-Step Programs as an Adjunct to Psychotherapy and Psychopharmacology.
AB  - With increasing constraints on time for traditional psychotherapy and patient
      counseling, it behooves us to find other methods of giving the patient tools to
      cope with his or her illness. In addition to psychotropic medications that have
      never before been available (selective serotonin reuptake inhibitors and related
      compounds) and crisis intervention, we have a plethora of 12-step programs that
      can give the individual ongoing support. Our goal is to restore the patient to
      full psychosocial function, avoiding self-medication, drug and alcohol abuse, and
      the cycle of hopelessness, despair, death, and suicide. We are concerned with the
      patient's lifelong maintenance and state of balance, finding a spiritual center
      from which to grow as an individual, and ultimately, to help others with similar
      problems. Twelve-step programs serve as a viable means of achieving these goals.
      Along with medication, support, encouragement, and therapy when available,
      patients can be guided to achieve new levels of meaning and fulfillment in their
      lives.

PMID- 15014648
TI  - Rivastigmine for Alzheimer's Disease: Improvement Versus Reduced Worsening.
AB  - BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in
      later life. It is manifested by gradual and progressive decline in cognitive
      function and ability to perform activities of daily living (ADL) and the
      development of behavioral disturbances. Progressive reduction in functional
      ability reduces independence and quality of life and adversely affects caregivers
      and society. Therefore, benefit from any AD therapy may be obtained not only from
      improved function but also from stabilization or reduced worsening of function.
      METHOD: This retrospective study of pooled data from 3 randomized, placebo
      controlled trials (N = 2126) compared the incidence of different levels of
      worsening between 2 rivastigmine treatment groups and a placebo group at week 26
      for cognition, using the Alzheimer's Disease Assessment Scale-Cognitive subscale
      (ADAS-Cog); global functioning, using the Clinicians' Interview-Based Impression
      of Change-Plus (CIBIC-Plus); and ADL, using the Progressive Deterioration Scale
      (PDS). Categories of worsening analyzed for each scale were as follows: ADAS-Cog:
      any decline, >/= 4-point decline, >/= 7-point decline; CIBIC-Plus:
      stabilized/worsened (rating = 4, 5, 6, or 7), any worsening (rating = 5, 6, or
      7); PDS: any worsening, >/= 10% worsening. RESULTS: Patients treated with
      rivastigmine, 6-12 mg/day, showed significantly less decline in cognition, global
      functioning, and ADL for all categories of worsening examined compared with
      patients who received placebo. The reduction in decline compared with placebo was
      greater in the group receiving 6-12 mg/day of rivastigmine compared with the
      treatment group receiving 1-4 mg/day of rivastigmine. CONCLUSION: Rivastigmine
      reduces the amount of worsening observed in cognition, global functioning, and
      ADL in a 6-month trial period.

PMID- 15014650
TI  - Comorbid Generalized Anxiety Disorder, Phobia, and Panic Disorder.

PMID- 15014649
TI  - All in the Family.

PMID- 15014651
TI  - The Use of Alosetron to Treat SSRI-Induced Gastrointestinal Symptoms.

PMID- 15014653
TI  - Novel Antipsychotics in the Treatment of Behavioral Disturbances and Psychoses
      Associated With Neurodegenerative Disorders.
AB  - Behavioral disturbances and psychosis are common features of neurodegenerative
      disorders and may be drug induced, intrinsic to the underlying pathology, or
      both. These disturbances, including psychotic and mood symptoms, apathy,
      aggression and other behavioral symptoms, and superimposed delirium, cause a
      great amount of disability to the patient and stress on the caregiver.
      Conventional neuroleptics have been shown to be effective in the treatment of
      these symptoms, but unacceptable side effects may occur. However, the novel
      antipsychotics, with their lower risk of inducing extrapyramidal symptoms, have
      shown promise in the treatment of behavioral disturbances and psychosis
      associated with neurodegenerative disorders.

PMID- 15014655
TI  - Topiramate in Bipolar and Schizoaffective Disorders: Weight Loss and Efficacy.
AB  - BACKGROUND: Although useful in bipolar disorder, mood stabilizers, such as
      lithium, divalproex sodium, and carbamazepine, can cause significant weight gain.
      METHOD: We conducted a retrospective chart review of 5 patients with DSM-IV
      bipolar disorder or schizoaffective disorder who were treated with topiramate as
      adjunctive therapy or monotherapy. RESULTS: All 5 patients had a good response to
      treatment at a mean topiramate dose of 195 mg/day (range, 100-375 mg/day). All
      patients lost a substantial amount of weight on topiramate treatment. The average
      weight loss was 22 lb (10 kg; range, 8-56 lb [4-25 kg]). None of the patients
      discontinued topiramate because of side effects. CONCLUSION: Topiramate may
      represent a valuable alternative to existing mood stabilizers, either as an
      adjunct or as monotherapy in patients with bipolar disorder or schizoaffective
      disorder.

PMID- 15014652
TI  - Anxiety and Depression: Optimizing Treatments.
AB  - Properly diagnosing and treating patients with anxiety, depression, or both is a
      challenging aspect of practicing medicine in the primary care setting. Patients
      often present with somatic complaints rather than classic psychiatric symptoms.
      In addition, there is significant overlap between anxiety and depression in this
      patient population. Comorbid anxiety and depression is often more resistant to
      pharmacologic treatment, and patients with coexisting disorders have a poorer
      medical prognosis than do patients with either disorder alone. Fortunately, many
      new therapies are available to assist the clinician in managing these patients.
      The newer antidepressants, in particular, are playing an increasingly important
      role in the treatment of both anxiety disorders alone and comorbid anxiety and
      depression. These new choices enable our goal of treatment to encompass not only
      improvement but also sustained complete remission. Of the newer agents, the
      selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake
      inhibitors have been studied quite extensively in these patient populations. The
      specific profiles of individual agents may assist the clinician in
      individualizing treatment. Characteristics such as robust efficacy, speed of
      onset of activity, the potential for drug-drug interactions, dose response, and
      tolerability are important considerations in optimizing treatment.

PMID- 15014654
TI  - The Effect of Brochures and Audiotape on Efficacy and Tolerability of Venlafaxine
      in Depressed Outpatients: A Single-Blind Parallel Study in General Practice.
AB  - OBJECTIVE: The possible positive effects of brochures and an audiotape containing
      information on efficacy and tolerance on side effects, dropout rate, and clinical
      outcome of treatment with venlafaxine were studied in 1048 depressed outpatients
      (as clinically judged by the general practitioner; 740 women and 308 men), aged
      18 to 85 years. METHOD: The study was of a single-blind, parallel-group design.
      All 4 groups were verbally informed: one group received only verbal information,
      a second group additionally received brochures, a third group additionally
      received information on audiotape, and a fourth group additionally received
      brochures and information on audiotape. There were 5 study visits, the first at
      baseline (week 0), followed by a visit at weeks 1, 2, 4, and 6. At each study
      visit, the Clinical Global Impressions scale, Zung Depression Scale, Quality of
      Life Scale, and State-Trait Anxiety Inventory were completed. The Patient's and
      Investigator's Subjective Ratings of Tolerance and Efficacy were completed at the
      final study visit. RESULTS: The brochures and audiotape reduced the dropout rate
      due to lack of efficacy (p =.01 and p =.04, respectively). In addition, the
      percentage of patients reporting side effects was lower in the group that
      received brochures than in the group that received only verbal information (p
      =.05). Additional information had no effect on efficacy measures. CONCLUSION:
      Supplying patients with education in the form of brochures and/or audiotape
      containing information on efficacy and tolerance of the drug reduces the dropout
      rate due to lack of efficacy. For the reduction of side effects, brochures in
      particular seem suitable. Information on audiotape or written information seems
      to lengthen the period that patients wait for the possible beneficial action of
      the medication. To reduce the dropout rate, it may be recommended that patients
      receive, in addition to brochures, spoken information on audiotape or compact
      disc.

PMID- 15014656
TI  - A Little Bit of Perspective.

PMID- 15014657
TI  - A Case of Alcohol Abuse.

PMID- 15014658
TI  - Gabapentin in the Treatment of Posttraumatic Stress Disorder.

PMID- 15014659
TI  - Rethinking Medical Education About Mood Disorders.

PMID- 15014660
TI  - The Healing Journey.
AB  - The following are excerpts of a speech made during the combined graduation
      ceremony of the 3 Memphis area Family Medicine residency programs on June 30,
      1997. At that time, the author was preparing to leave his faculty position at the
      University of Tennessee and accept one at the University of Connecticut. During
      the convocation, he shared his ideas and personal experiences in an address
      entitled "The Healing Journey."

PMID- 15014661
TI  - Treatment of Delirium With Quetiapine.
AB  - INTRODUCTION: Delirium, an organic psychiatric syndrome, occurs in 10% of
      hospitalized patients and is characterized by fluctuating consciousness and
      impaired cognition, perception, and behavior. METHOD: Charts of 11 consecutive
      patients with delirium were retrospectively reviewed. These patients were given
      quetiapine fumarate, a novel antipsychotic, as first-line treatment for their
      symptoms. The charts of a control group of 11 patients treated with haloperidol,
      the standard treatment for delirium, during the same time period were also
      evaluated. The Delirium Rating Scale (DRS) was used to evaluate the efficacy of
      each treatment. RESULTS: Ten of 11 patients in both groups had > 50% improvement
      in DRS scores. There was no difference in onset of symptom resolution, duration
      of treatment, and overall clinical improvement. Quetiapine was better tolerated
      in these medically ill patients. CONCLUSION: Quetiapine appears to be an
      efficacious and well-tolerated treatment for delirium. Further prospective
      studies are warranted.

PMID- 15014662
TI  - Prescribing Brief Psychotherapy.
AB  - Brief psychotherapy has demonstrated its effectiveness in treating emotional
      disorders and helping with problems that typically present to primary care
      physicians. Because practitioners receive little instruction about this treatment
      option and often have erroneous preconceived ideas about it, psychotherapy
      remains underprescribed. Effective brief therapy enables the patient to problem
      solve, facilitates the relationship with the provider, and ultimately clarifies
      the patient's situation. Referral of appropriate patients for psychotherapy will
      enhance the effectiveness of the doctor in primary care.

PMID- 15014663
TI  - Refractory Depressed and Anxious States in Hyperthymic Women: A Case Series
      Generated by a Speaking Engagement.
AB  - The author discusses 4 referrals that were the direct result of a case
      description from his own practice that he presented during a lecture on the
      treatment of mixed anxious and depressive illness in primary care. The cases
      depict energetic, productive women who suffer fatigue and episodic depressions.
      These cases suggest that hyperthymic temperaments complicated by depressive
      episodes represent a form of mood disorder presentation that is highly
      recognizable and responsive to pharmacologic intervention. Such premorbid
      temperamental hypomanic tendencies may represent a soft form of bipolar illness
      that requires somatic strategies in line with those of classic manic depressive
      illness. The cases underscore the challenge of treating mood disorders and the
      need for treatment research to reach primary care practitioners, who see the
      majority of depressed and anxious patients.

PMID- 15014665
TI  - The "Family" in Family Physician.

PMID- 15014664
TI  - Interventions for Weight Gain in Adults Treated With Novel Antipsychotics.
AB  - BACKGROUND: Weight gain is a significant side effect associated with typical and
      atypical antipsychotic agents. It has the potential to add to the increased
      morbidity and mortality associated with schizophrenia and schizoaffective
      disorder. Because the newer antipsychotic medications have proved to be superior
      to traditional agents in controlling the positive and negative symptoms of
      schizophrenia, it is additionally critical to address the relationship of these
      newer agents to weight gain. METHOD: Prior to the availability of novel
      antipsychotic medication, we looked at a group of 17 residents, of whom 71% had
      significant weight gain on treatment with traditional antipsychotic medications
      between 1991 and 1994. This prompted our interest in weight gain, especially
      after the introduction of novel antipsychotic medications, and our decision to
      look closely at their diets and help them make changes that would minimize their
      weight gain. We monitored the effect of a comprehensive primary intervention
      strategy on controlling obesity in a retrospective study of 32 patients with DSM
      IV schizophrenia or schizoaffective disorders. All patients were residents in an
      adult care facility for formerly homeless persons with serious mental illness.
      Intervention consisted of complete medical and psychiatric care; switch to a
      patient-optimal atypical drug; low-calorie, monitored diet; nutritional
      education; and supportive care. RESULTS: There was no significant change in mean
      body weight at 12 and 18 months after initiation of intervention. Weight gain was
      observed in only 30% of study patients after the intervention as opposed to 71%
      at the start of the study. In general, as the negative symptoms of schizophrenia
      improved, patients were found to become more receptive to education and to become
      proactive in their health care. The lack of weight gain was consistently seen
      with all 3 agents tested-clozapine, olanzapine, and risperidone. CONCLUSION: A
      patient's diet appears to be a better predictor of weight gain than the choice of
      novel antipsychotic medication. Clinicians might prescribe nutritional and
      lifestyle changes alongside medication with weight gain potential.

PMID- 15014666
TI  - Thyroid Augmentation of Mirtazapine: A Case Report.

PMID- 15014667
TI  - Effect of Citalopram on Blood Desipramine Levels.

PMID- 15014668
TI  - Effect of Bupropion SR on the Quality of Life of Elderly Depressed Patients With
      Comorbid Medical Disorders.
AB  - BACKGROUND: There is a need for additional studies of the quality of life (QOL)
      of elderly depressed subjects with medical comorbidity. METHOD: We conducted an 8
      week, open trial of bupropion sustained release (SR) in 18 elderly (60-81 years)
      subjects with DSM-IV major depressive disorder and one or more serious medical
      illnesses (e.g., congestive heart failure, type 1 diabetes mellitus, irritable
      bowel syndrome) with a week-12 follow-up interview. The intent-to-treat method
      with the last observation carried forward was used to analyze depression and QOL
      measures. Dosing was initiated at 100 mg once daily and increased at weekly
      intervals to a maximum of 150 mg twice daily as clinically indicated. RESULTS:
      Bupropion SR treatment was associated with reductions in Clinical Global
      Impressions-Severity of Illness scale (p <.0001) score and in the 17-item
      Hamilton Rating Scale for Depression (HAM-D) total score (p <.0001). QOL as
      measured by the Medical Outcomes Study Short Form-36 (SF-36) also tended to
      improve with treatment. The SF-36 "mental health" (p <.01) and "social
      functioning" (p <.0006) domains improved significantly by week 4. "Vitality" (p
      <.03) improved significantly by week 12. On the HAM-D, statistically significant
      improvement was noted on "depressed mood" (p <.0001), "feelings of guilt" (p
      <.01), "work and activities" (p <.001), "hypochondriasis" (p <.02), and
      "insomnia" (p <.01) at week 8. The mean dose of bupropion SR at endpoint was 222
      mg/day, and the drug was relatively well tolerated. Two subjects dropped out
      owing to adverse events and 2 owing to other reasons. No drug-drug interactions
      occurred. CONCLUSION: These data suggest that bupropion SR is well tolerated and
      may improve depression, insomnia, somatic symptoms, work functioning, and certain
      quality-of-life measures in elderly depressed subjects with medical disorders. A
      randomized, placebo-controlled study is warranted to confirm these promising
      findings.

PMID- 15014670
TI  - Sildenafil in the Treatment of SSRI-Induced Sexual Dysfunction: A Pilot Study.
AB  - BACKGROUND: Sexual dysfunction is a well-documented side effect of selective
      serotonin reuptake inhibitors (SSRIs). Commonly reported side effects include
      erectile impotence, anorgasmia, ejaculatory delay, pain, loss of sensation, and
      decreased pleasure. Early reports of the reversal of sexual dysfunction after
      using sildenafil in male and female patients receiving various types and dosages
      of SSRIs are promising and prompted this study. Our aim was to evaluate the
      effects of oral sildenafil on reported secondary sexual dysfunction in patients
      concurrently treated with SSRIs. METHOD: Fourteen male patients who developed
      sexual dysfunction while receiving SSRIs were screened using the Arizona Sexual
      Experience (ASEX) scale. An electrocardiogram was obtained at the beginning and
      at the end of the study. Each patient was prescribed sildenafil tablets to be
      taken twice a week, 25-100 mg, prior to sexual activity and told to record the
      findings in a running diary which he was to keep during his treatment period. The
      patients were seen weekly and evaluated by clinical interview and ASEX scale.
      Patients were treated for a total of 8 weeks. RESULTS: All but 1 of the 14
      patients experienced an improvement of sexual dysfunction, with 9 patients at the
      first dose of 25 mg and 4 at higher doses (3 at 50 mg and 1 at 75 mg). One
      patient required 100 mg to obtain minimal response. DISCUSSION: Sildenafil was
      shown to be helpful in the treatment of SSRI-induced sexual dysfunction. Three
      patients continued to experience ongoing positive effects after discontinuation
      of sildenafil; the other 10 patients relapsed.

PMID- 15014669
TI  - Collaboration Between Mental Health Services and Primary Care: The Bologna
      Project.
AB  - OVERVIEW: Management of anxiety and depressive disorders within the community
      necessitates collaboration between mental health services and primary care. While
      cooperative projects do exist in many countries, Italy's National Health System
      does not have a program designed to address this issue. In Bologna, a cooperative
      project arose as a spontaneous undertaking between mental health professionals
      and primary care physicians. A model of collaboration was designed specifically
      for the Italian National Health System, consisting of a network of primary care
      liaison services (PCLSs) instituted within the community mental health services.
      PCLSs are managed by a staff of specially trained mental health care
      professionals and are designed to facilitate communication between physicians,
      and they provide continual and multifaceted support consisting of diagnostic
      assessment and focused clinical intervention. PCLSs also provide formal
      consultation-liaison meetings and a telephone consultation service designed to
      promote communication and enrich diagnostic assessment and treatment. DISCUSSION:
      PCLSs are innovative, not only because they represent one of the first
      collaborative efforts in Italy to date, but also because of their innovative
      design, which is specific for the Italian National Health System. Overall, the
      project yielded a good result. Primary care physicians utilized the service
      extensively, and together with psychiatric personnel were satisfied with the
      outcome. These results, when compared with the traditional separation between the
      2 services, are encouraging. Our model could be adapted for most communities in
      Italy, but must be preceded by shared recognition of local need.

PMID- 15014671
TI  - Treatment-Refractory Depression in the Elderly: An Audit of Primary Care
      Referrals to Psychiatric Services in Swindon, U.K.
AB  - BACKGROUND: Our objective was to audit primary care referrals for depression to
      assess prereferral quality of antidepressant treatment. METHOD: We performed a
      retrospective audit of referrals from primary care to the Department of Old Age
      Psychiatry in Swindon, Wiltshire, U.K., for a new episode of depression,
      excluding life-threatening cases, between January 1, 1997, and December 31, 1998.
      To determine if treatment before referral met criteria for an adequate trial, for
      audit purposes we defined an adequate trial as 8 weeks at maximal dose as
      specified by the British National Formulary. RESULTS: A computer search
      identified 58 referrals: 33 cases were excluded-3 notes were unavailable for
      audit, 7 were wrongly coded, 8 were life-threatening, and 15 were non-primary
      care referrals. Of the 25 evaluable patients, 2 had had an adequate duration of
      treatment and 6 were taking maximal doses of antidepressants, but none was taking
      a dose for an adequate duration. CONCLUSION: Patients referred to secondary care
      for depression are often undertreated prior to referral, which may explain why
      the patients in this retrospective audit had failed to respond. Primary care
      physicians should be encouraged to use medication in elderly patients that
      requires little or no dose titration at high doses and for at least 8 weeks
      before considering the patient to be treatment refractory.

PMID- 15014672
TI  - Travel Itineraries, Jackhammers, and Acorns.

PMID- 15014673
TI  - Possible Sexual Dysfunction Associated With Bupropion for Smoking Cessation: A
      Case Report.

PMID- 15014675
TI  - A Trilogy Case Review Highlighting the Clinical and Pharmacologic Applications of
      Mirtazapine in Reducing Polypharmacy for Anxiety, Agitation, Insomnia,
      Depression, and Sexual Dysfunction.
AB  - BACKGROUND: Mirtazapine, a noradrenergic and specific serotonergic antidepressant
      (NaSSA), is characterized by a unique receptor-specific pharmacologic profile and
      tolerable side-effect profile in comparison to other antidepressants. It has been
      reported to have a low incidence of agitation, anxiety, and insomnia, which may
      be due to blockade of 5-HT(2) and 5-HT(3) receptors. This unique multireceptor
      mediated clinical pharmacologic profile may reduce the need for polypharmacy in
      selected patients. CASE REPORTS: Three cases are presented. In case 1,
      mirtazapine was able to rapidly treat anxiety and agitation in a 90-year-old
      woman. This was confirmed with 3 consecutive challenges with mirtazapine. In case
      2, both a mood disorder and insomnia were successfully treated with rapid
      resolution in a patient by using mirtazapine. In case 3, the patient experienced
      sexual dysfunction while receiving sertraline and developed insomnia with the
      addition of bupropion. The addition of mirtazapine and the discontinuation of
      sertraline and bupropion resolved the sexual dysfunction and insomnia.
      Polypharmacy interventions were decreased in these patients through receptor
      specific events from mirtazapine. CONCLUSION: The new antidepressant mirtazapine
      appears to be an effective strategy for treating anxiety, agitation, and insomnia
      and for diminishing SSRI-related sexual dysfunction without compromising the
      patient's therapeutic response to the medication while decreasing the need for
      additional pharmacotherapies. More than 70% of patients with major depression
      will have anxiety symptoms. The 5-HT(2) receptor seems to play a major role in
      the regulation of anxiety. The anxiolytic properties of mirtazapine may be due to
      its antagonism of 5-HT(2) receptors and can appear as early as the first week of
      treatment.

PMID- 15014676
TI  - When All Else Is Done: The Challenge of Improving Antemortem Care.
AB  - Recent findings from the Study to Understand Prognoses and Preferences for
      Outcomes and Risks of Treatments (SUPPORT) reveal that Americans are receiving
      antemortem care that is highly technical and interventional, but poorly
      consistent with patients' wishes. A growing body of research in palliative
      medicine describes a manner of care that restores the possibility of a "good
      death" to the vast majority of patients. By familiarizing themselves with the
      medical, psychological, legal, and existential aspects of antemortem care,
      primary care physicians can offer excellent palliative care, changing the
      landscape of postmodern medicine for the benefit of all patients-including
      ourselves.

PMID- 15014674
TI  - Competency and the Capacity to Make Treatment Decisions: A Primer for Primary
      Care Physicians.
AB  - Common law dictates that individuals possess autonomy and self-determination,
      which encompass the right to accept or refuse medical treatment. Management of
      medical treatment can be complicated in situations when the ability of the
      patient to make reasonable decisions is called into question. Our legal system
      endorses the principle that all persons are competent to make reasoned decisions
      unless demonstrated to be otherwise. This review will discuss the standards upon
      which capacity and competency assessments are made. Practical suggestions are
      offered for clinicians to employ in patient interviews conducted to assess
      capacity. Issues related to advance directives, surrogate decision making,
      guardianship, and implied consent are also discussed. The role psychiatric
      consultants take in capacity assessment can assist the primary care physician
      confronting the complexities encountered when attempting to treat the
      incapacitated or incompetent patient.

PMID- 15014677
TI  - From the Bench to the Trench: A Comparison of Sertraline Treatment of Major
      Depression in Clinical and Research Patient Samples.
AB  - BACKGROUND: New medications that enter the marketplace have been tested almost
      exclusively in controlled clinical trials conducted in specialty research
      settings. There is some concern that these carefully selected patient samples may
      not provide information generalizable to the "real world" clinical population.
      The purpose of this investigation was to compare results from a large, open-label
      study of sertraline in the treatment of major depression in the clinical practice
      setting with pooled results from 2 multicenter, double-blind, placebo-controlled
      studies conducted in specialty research settings. METHOD: Clinical practice
      patients (N = 1482), aged 21 to 65 years, from 228 psychiatric clinical practice
      sites across the United States participated in the open-label treatment study
      (Clinical Practice sample). Patients who met DSM-III-R criteria for moderate-to
      severe unipolar major depression (i.e., had pretreatment Hamilton Rating Scale
      for Depression [HAM-D] scores >/= 18) were treated for 8 weeks with sertraline in
      a flexible dosing fashion (50-200 mg daily). Outcomes on the HAM-D and Clinical
      Global Impressions-Improvement scale (CGI-I) were compared with the pooled
      results from 2 previously published placebo-controlled, multicenter treatment
      studies of sertraline in outpatients with major depression (N = 280). The overall
      response to sertraline in the Clinical Practice sample was compared with the
      outcome from the research study patient sample (Clinical Research sample).
      Additionally, comparison of outcomes of patients with common depressive subtypes
      (double depression, anxious depression, and melancholic ["endogenous"]
      depression) were examined. RESULTS: The percentage of sertraline-treated patients
      rated as responders on the CGI-I was significantly higher in the Clinical
      Practice sample compared with the Clinical Research sample (87% vs. 73%; p
      <.001). Sertraline was also much better tolerated in the Clinical Practice sample
      than in the Clinical Research sample as evidenced by significantly lower overall
      reports of adverse events (9.4% vs. 13.2%; p <.05) and lower patient dropout
      rates (17.5% vs. 34.3%; p <.01). Among clinical practice patients, sertraline was
      found to be equally effective in treating endogenous/melancholic and anxious
      subtypes and only mildly less effective in achieving a response in patients with
      double depression (chronic low-grade depression with a superimposed major
      depression). A regression analysis identified older age and double depression as
      being predictors of a slower time to response. More than 70% of patients who
      reported nonresponse to previous treatment with fluoxetine or a tricyclic
      antidepressant responded to sertraline. CONCLUSION: The effectiveness and
      tolerability of sertraline treatment was found to be significantly better in the
      Clinical Practice sample, suggesting that the results from controlled studies in
      research settings may represent an underestimate of the benefits of a drug. More
      effectiveness research is needed to confirm and extend these findings.

PMID- 15014678
TI  - "I hear voices em leader sometimes it's just Mom"

PMID- 15014679
TI  - Dr. Berigan Replies.

PMID- 15014680
TI  - Discontinuation of Therapy With Bupropion SR.

PMID- 15014682
TI  - A Case Series of Women With Postpartum-Onset Obsessive-Compulsive Disorder.
AB  - BACKGROUND: There is emerging evidence that postpartum women are at risk for the
      development or worsening of obsessive-compulsive disorder. The purpose of this
      study was to provide data regarding the demographics, phenomenology, associated
      psychiatric comorbidity, family history, and response to open treatment with
      fluvoxamine in subjects with postpartum-onset obsessive-compulsive disorder.
      METHOD: Seven consecutive subjects were recruited from an outpatient obstetrical
      practice and by advertisement. Subjects completed the Structured Clinical
      Interview for DSM-IV, the Yale-Brown Obsessive Compulsive Scale, and a
      semistructured interview for family history, demographic data, and clinical
      features. Three of the 7 subjects participated in a 12-week, open-label trial of
      fluvoxamine treatment of postpartum-onset DSM-IV obsessive-compulsive disorder.
      RESULTS: The women described a mean age at onset of 28 years, and 4 subjects had
      a chronic course. Six subjects reported onset after the birth of their first
      child, and the mean time to onset was 3.7 weeks postpartum. All subjects
      experienced both obsessions and compulsions and reported aggressive obsessions
      that involved their children. None of the subjects acted on their obsessions to
      harm the children, but 5 reported dysfunctional mother-child behavior. All 7
      subjects met criteria for at least 1 comorbid psychiatric disorder, with a mood
      disorder the most common. Family histories were notable for high rates of mood
      disorders and psychoactive substance use disorders in first-degree relatives. Two
      of the 3 subjects who entered the open-label trial of fluvoxamine experienced a
      positive response, defined as a 30% or greater decrease in the total score of the
      Yale-Brown Obsessive Compulsive Scale. CONCLUSION: Obsessive-compulsive disorder
      may present in the postpartum period and become chronic. Symptoms of the disorder
      may adversely affect the mother-child relationship, and it is important to assess
      for obsessions and compulsions in postpartum women who present with anxiety
      and/or depression. Fluvoxamine may be effective in reducing the symptoms of
      postpartum-onset obsessive-compulsive disorder. Controlled studies are needed to
      confirm these findings.

PMID- 15014681
TI  - Psychophysiologic Therapy for Chronic Headache in Primary Care.
AB  - BACKGROUND: Headaches account for a high percentage of office visits to primary
      care physicians, with migraine and tension-type headaches the most common. This
      article provides a summary of psychophysiologic therapies for migraine and
      tension-type headache and considers psychosocial factors relevant to headache.
      Psychophysiologic therapy of headache consists primarily of relaxation and
      biofeedback. METHOD: Representative controlled studies, meta-analysis, and
      reviews are utilized to assess the efficacy of biofeedback and relaxation for
      migraine and tension-type headache. RESULTS: Psychophysiologic therapy comprising
      biofeedback and relaxation can be provided in standard or limited therapist
      contact formulas to patients as sole therapy or concurrently with medical
      therapy. Effectiveness has been demonstrated for thermal biofeedback-and
      electromyograph biofeedback-assisted relaxation with minimal or no side effects.
      A typical treatment protocol is offered to exemplify the integration of
      psychophysiologic therapy into primary care practice. CONCLUSION:
      Psychophysiologic therapy represents an important adjunctive treatment for
      chronic benign headache that can be incorporated into primary care.

PMID- 15014683
TI  - Cocaine and Psychiatric Symptoms.
AB  - BACKGROUND: Cocaine is an addictive drug that produces numerous psychiatric
      symptoms, syndromes, and disorders. The symptoms include agitation, paranoia,
      hallucinations, delusions, violence, as well as suicidal and homicidal thinking.
      They can be primary to the drug's effect or secondary to exacerbation of comorbid
      psychiatric disorders. DATA SOURCES: A computerized literature search was
      conducted using MEDLINE to identify reports of psychiatric symptoms secondary to
      cocaine use. Additional reports were found via bibliographies of various
      published reports. DATA SYNTHESIS: The use of cocaine in the "crack" form is
      often associated with more frequent and intense symptoms. Paranoia occurs in 68%
      to 84% of patients using cocaine. Cocaine-related violent behaviors occur in as
      many as 55% of patients with cocaine-induced psychiatric symptoms. Homicide has
      also been associated with cocaine use in as many as 31% of homicide victims. In
      suicide, cocaine has been found to be present in as high as 18% to 22% of cases.
      Many patients with cocaine dependence have also been found to have a comorbid
      psychiatric disorder. CONCLUSION: Cocaine can produce a spectrum of psychiatric
      symptoms with which primary care practitioners need to be familiar. Comorbid
      psychiatric disorders are frequent in patients with cocaine use disorders and can
      worsen with cocaine use. Nonaddictive medication may be necessary to treat
      comorbid conditions such as anxiety and depressive disorders. Primary care
      practitioners need to be familiar with the treatment programs for patients with
      cocaine use disorders so appropriate referral can easily take place and follow-up
      care can be understood and maintained.

PMID- 15014685
TI  - Hidden Agendas and Inexorable Forces.

PMID- 15014684
TI  - Zaleplon, A Novel Nonbenzodiazepine Hypnotic, Effectively Treats Insomnia in
      Elderly Patients Without Causing Rebound Effects.
AB  - BACKGROUND: Insomnia is a very common symptom, particularly in the elderly. Thus,
      all hypnotic medications should be carefully evaluated in the elderly population.
      Zaleplon, a new nonbenzodiazepine hypnotic with a short elimination half-life
      (approximately 1 hour), was evaluated in the current study. METHOD: This
      multicenter, randomized, placebo-controlled outpatient study evaluated the
      efficacy and safety of zaleplon, 5 and 10 mg, in elderly patients with insomnia
      (as defined by DSM-IV); zolpidem, 5 mg, was the active comparator. Sleep was
      assessed in 549 elderly patients (>/= 65 years old) by using morning
      questionnaires completed after each of 7 baseline nights during which placebo was
      given, 14 nights of double-blind treatment, and 7 nights of placebo after
      discontinuation of active treatment. RESULTS: Zaleplon, 10 mg, and zolpidem, 5
      mg, significantly reduced sleep latency during both weeks of the study. Zaleplon,
      5 mg, reduced sleep latency only during week 2. Sleep duration was increased with
      zolpidem, 5 mg, during weeks 1 and 2 and with zaleplon, 10 mg, during week 1. No
      clinically significant rebound insomnia was observed after discontinuation of
      treatment with zaleplon, whereas evidence of rebound effects was seen with
      zolpidem. There was no significant difference between either zaleplon dose and
      placebo in the frequency of any central nervous system adverse events.
      CONCLUSION: Zaleplon is effective in reducing latency to sleep without evidence
      of undesired effects in elderly patients with insomnia.

PMID- 15014686
TI  - America Is Too Violent: What Can We Do About It?

PMID- 15014687
TI  - Running Amok: A Modern Perspective on a Culture-Bound Syndrome.
AB  - Running amok is considered a rare culture-bound syndrome by current psychiatric
      classification systems, but there is evidence that it occurs frequently in modern
      industrialized societies. The historical origins of running amok as a psychiatric
      condition are reviewed in this article, and its relevance to modern day episodes
      of violent behavior is discussed. Psychotic illnesses, personality disorders, and
      mood disorders are all possible causes of amok, and the identification and
      treatment of patients who are at risk for manifesting violent behavior are
      discussed.

PMID- 15014688
TI  - Valproate in Bipolar Disorder: Case Examples From a Family Practice.
AB  - Valproate, an antiepileptic drug, is useful in the management of various
      nonepileptic disorders. It is an effective and generally well-tolerated
      medication for the treatment of bipolar disorder and has been approved by the
      Food and Drug Administration for use in manic states. Studies also suggest that
      it is effective in other bipolar spectrum illnesses. This report describes 2
      clinical cases of DSM-IV bipolar disorder where valproate provided robust,
      sustained relief of mood symptoms. In the first case, valproate was chosen for
      initial therapy in a bipolar patient suffering from a mixture of hypomanic and
      depressive symptoms. In the second case, valproate replaced lithium in the
      management of a patient with an incomplete response to lithium plus an
      antidepressant. This report addresses relevant clinical issues and includes a
      brief review of the clinical pharmacology of valproate.

PMID- 15014690
TI  - Somatization in Family Practice: Comparing 5 Methods of Classification.
AB  - BACKGROUND: It has been suggested that patients with somatoform disorders are
      high utilizers of medical care, yet interpretation of studies has been difficult
      because of variant methods of diagnosis. The goal of this study was to compare 5
      different methods of classification on the same group of subjects and to examine
      prevalence rates of somatoform disorders and medical utilization. METHOD:
      Subjects completed a demographic questionnaire in the physician's office and the
      somatization section of the Diagnostic Interview Schedule (DIS) by telephone.
      Subsequently, their medical charts were examined. Using the 5 methods of
      diagnosis, somatizers were compared with nonsomatizers for level of utilization
      of medical services. The setting was a medical school-based family practice
      residency training center. Participants were 119 patients waiting to see their
      family doctors. The main outcome measures were prevalence of somatization
      symptoms and chart information (utilization, number of health problems). RESULTS:
      One subject met the Diagnostic and Statistical Manual (DSM-IV)-based DIS criteria
      for somatization disorder. With the Bucholz modification for scoring the DIS, 10
      subjects were diagnosed with somatization disorder. With the abridged Escobar
      criteria of 6 symptoms, 7 subjects met diagnostic criteria, while 28 met the
      criteria for multisomatoform disorder of 3 symptoms, as suggested by Kroenke. The
      diagnosis of undifferentiated somatoform disorder, requiring only 1 unexplained
      symptom, was obtained by 94 of the subjects. CONCLUSION: Findings from this study
      revealed widely divergent prevalence rates of somatoform disorders, depending on
      methods of diagnosis used. Correlation with rates of medical utilization is
      suggested as an external criterion for validating diagnostic methods.

PMID- 15014691
TI  - Be Sure to Take Your Vitamins Daily.

PMID- 15014689
TI  - Anticonvulsant Use in the Treatment of Bipolar Disorder: A Primer for Primary
      Care Physicians.
AB  - Primary care physicians may be directly or indirectly involved in the management
      of the bipolar patient. Bipolar affective illness is a chronic, recurrent
      disorder. Patients, their families and support systems, and the general public
      can face profound and enduring consequences if the illness is untreated or poorly
      treated. Consequently, increasing attention has been directed at developing
      treatment strategies to control symptoms associated with bipolar disorder. While
      lithium has been the mainstay of treatment for many years, recent investigations
      have demonstrated the utility of a number of anticonvulsant medications in
      bipolar disorder. This review will discuss the literature on anticonvulsant
      efficacy in bipolar disorder in light of the treatment guidelines set forth by
      the Bipolar Treatment Expert Consensus Panel and the American Psychiatric
      Association. To orient the clinician, issues related to anticonvulsant use,
      dosing, adverse effects, and drug interactions are also discussed.

PMID- 15014692
TI  - Primary Care in Perspective.

PMID- 15014693
TI  - The BATHE Method: Incorporating Counseling and Psychotherapy Into the Everyday
      Management of Patients.
AB  - Physicians today are required to do more than ever before; skills that were
      unnecessary in the past are now "givens." In order for physicians to keep
      patients well, help them manage chronic problems, and encourage them to adhere to
      medication regimens, a positive doctor/patient relationship is vital.
      Establishing patient rapport, obtaining patient trust, and allowing patients to
      tell their stories show respect and allow a healing partnership. Patients often
      expect help with emotional as well as physical problems, so it is important to
      obtain as much information from patients as possible. The BATHE technique is a
      psychotherapeutic procedure and serves as a rough screening test for anxiety,
      depression, and situational stress disorders. The BATHE technique consists of 4
      specific questions about the patient's background, affect, troubles, and handling
      of the current situation, followed by an empathic response; the procedure takes
      approximately 1 minute and must be practiced. Physicians may use the BATHE
      technique to connect meaningfully with patients, screen for mental health
      problems, and empower patients to handle many aspects of their life in a more
      constructive way.

PMID- 15014695
TI  - Bipolar II Disorder in a Primary Care Setting: Clinical Vignette.
AB  - Bipolar II disorders may be common in primary care settings, but most cases
      remain undiagnosed because hypomania is often difficult to recognize. Eliciting a
      history of recurrent periods of expanded mood interspersed with periods of major
      depression is important, since antidepressant monotherapy is often unproductive
      or even counterproductive. Once the diagnosis is made, appropriate medications to
      alleviate hypomanic episodes and depression should be initiated. These
      medications include mood stabilizers such as lithium and valproate, alone or in
      combination with antidepressants. Close monitoring of medication levels and
      patient response is essential in the ongoing treatment of this disorder.
      Psychotherapy is often an integral part of treatment.

PMID- 15014697
TI  - A Look at Neuropsychiatric Issues in Everyday Practice.

PMID- 15014696
TI  - Bupropion-Associated Withdrawal Symptoms: A Case Report.
AB  - Withdrawal symptoms associated with the cessation of therapy have been widely
      described for most antidepressants. The authors report irritable mood, anxiety,
      sleeplessness, headache, and generalized aches and pains associated with the
      abrupt discontinuation of bupropion treatment in a 32-year-old man being treated
      for nicotine dependence. The authors recommend a slow taper for antidepressant
      discontinuation, along with vigilance for withdrawal symptoms and educating
      patients to the benefits of compliance.

PMID- 15014698
TI  - Welcome! Why This Journal?

PMID- 15014694
TI  - Psychogenic Respiratory Distress: A Case of Paradoxical Vocal Cord Dysfunction
      and Literature Review.
AB  - BACKGROUND: Pulmonary disease such as asthma is a psychosomatic disorder
      vulnerable to exacerbations precipitated by psychological factors. A case is
      described in which a patient thought to have treatment-refractory asthma was
      discovered to have a conversion reaction, specifically paradoxical vocal cord
      dysfunction (PVCD), characterized by abnormal vocal cord adduction during
      inspiration. DATA SOURCES: Reports of PVCD were located using a MEDLINE search
      and review of bibliographies. MEDLINE (English language only) was searched from
      1966 through December 1998 using the terms functional asthma, functional upper
      airway obstruction, laryngeal diseases, Munchausen's stridor, paradoxical vocal
      cord dysfunction, psychogenic stridor, respiratory stridor, vocal cord
      dysfunction, and vocal cord paralysis. A total of 170 cases of PVCD were
      reviewed. STUDY FINDINGS: PVCD appears to be significantly more common among
      females. PVCD spans all age groups, including pediatric, adolescent, and adult
      patients. PVCD was most often misdiagnosed as asthma or upper airway disease.
      Because patients present with atypical and/or refractory symptoms, several
      diagnostic tests are employed to evaluate patients with PVCD; laryngoscopy is the
      most common. Direct visualization of abnormal vocal cord movement is the most
      definitive means of establishing the diagnosis of PVCD. A number of psychiatric
      disturbances are related to PVCD, including conversion and anxiety disorders.
      PVCD is associated with severe psychosocial stress and difficulties with
      modulation of intense emotional states. CONCLUSIONS: Psychogenic respiratory
      distress produced by PVCD can be easily misdiagnosed as severe or refractory
      asthma or other pulmonary disease states. Recognition of PVCD is important to
      avoid unnecessary medications and invasive treatments. Primary care physicians
      can detect cases of PVCD by attending to clinical symptoms, implementing
      appropriate laboratory investigations, and examining the psychological covariates
      of the disorder. Psychotherapy and speech therapy are effective in treating most
      cases of PVCD.

PMID- 15014699
TI  - The Angry Dying Patient.
AB  - Over 25 years ago, Kubler-Ross identified anger as a predictable part of the
      dying process. When the dying patient becomes angry in the clinical setting, all
      types of communication become strained. Physicians can help the angry dying
      patient through this difficult time by using 10 rules of engagement. When
      physicians engage and empathize with these patients, they improve the patient's
      response to pain and they reduce patient suffering. When physicians educate
      patients on their normal responses to dying and enlist them in the process of
      family reconciliation, they can impact the end-of-life experience in a positive
      way.

PMID- 15014700
TI  - A Review of Postpartum Depression.
AB  - Postpartum depression (PPD) is an irritable, severely depressed mood that occurs
      within 4 weeks of giving birth and possibly as late as 30 weeks postpartum.
      Manifestations include crying spells, insomnia, depressed mood, fatigue, anxiety,
      and poor concentration. Patients may experience mild, moderate, or severe
      symptoms. Many psychosocial stressors may have an impact on the development of
      PPD. Recent studies conclude that the majority of factors are largely social in
      nature. The greatest risk is in women with a history of depression or other
      affective illness and in those who have experienced depression during past
      pregnancies. Women with significant risk factors should be followed closely in
      the postpartum period. The severity of symptoms and degree of impairment guide
      the approach to treatment. Treatment should begin with psychotherapy and advance
      to pharmacotherapy if needed; however, many patients benefit from concomitant
      treatment with both psychotherapy and medication. Common forms of psychotherapy
      include interpersonal therapy and short-term cognitive-behavioral therapy.
      Postpartum depression demands the same pharmacologic treatment as major
      depression does, with similar doses as those given to patients with nonpuerperal
      depression. It is essential to use an adequate dose of antidepressants in a
      duration sufficient to ensure complete recovery. Mothers should continue
      medication for 6 to 12 months postpartum to ensure a complete recovery.
      Inadequate treatment of depression puts women at risk for the sequelae of
      untreated affective illness, and the depression may become chronic, recurrent,
      and/or refractory. Family physicians are key players in the detection and
      treatment of PPD owing to the nature of the disease and the tendency for new
      mothers to negate their feelings as something other than a treatable psychiatric
      illness.

PMID- 15014701
TI  - The Psychiatric Family Nurse Practitioner: A Collaborator in Family Practice.
AB  - The potential of the psychiatric family nurse practitioner (Psych.F.N.P.) to
      contribute to family practice through physical care and mental health care exists
      in the here and now. This role is a synthesis of 2 advanced practice roles, the
      psychiatric clinical nurse specialist (Psych.C.N.S.) and family nurse
      practitioner (F.N.P.), both of which continue to have great utility
      independently. This synthesis is a practical application of concepts that have
      evolved to meet the changing patterns of health care delivery. At this time, dual
      certification as a Psych.C.N.S. and F.N.P. best reflects the broad practice
      expertise of the psychiatric family nurse practitioner. The experienced
      psychiatric family nurse practitioner provides direct care for both physical and
      psychological needs of patients in a family practice setting.

PMID- 15014702
TI  - Teaching Family Physicians About Mood Disorders: A Procedure Suite for Behavioral
      Medicine.
AB  - BACKGROUND AND OBJECTIVES: One of the skills required of family physicians is the
      ability to recognize and treat individuals suffering from mood disorders. This
      study represents an interdisciplinary residency training approach that (1) is
      unique in family practice residencies; (2) trains faculty, residents, and
      students in mood disorder recognition and treatment; (3) has been evaluated by
      the Residency Review Committee and found compatible with psychiatry training
      guidelines; and (4) is adaptable to varied settings. METHOD: Existing psychiatric
      education at an urban family practice residency program was evaluated. A new
      curriculum was developed to emphasize clinical interactions that would allow
      residents to model the behavior of family physicians who demonstrate interest and
      expertise in psychiatry. The centerpiece of this curriculum is a family-physician
      led, multidisciplinary, in-house consultation service known as a mood disorders
      clinic (MDC). Educational effectiveness was evaluated by comparing resident
      identification rates of mood disorders before and after training. Educational
      utility was evaluated by implementation in a variety of settings. RESULTS: Fifty
      one residents rotated through 1 or more of 3 practice sites during a 60-month
      period. Psychiatric diagnoses for the 187 patients who remained in treatment for
      complete clinical assessment included all major mood and anxiety disorders
      outlined in the DSM-IV. A wide variety of associated psychosocial problems were
      also identified. A significant difference (p <.05) was seen between the number of
      continuity patients diagnosed with psychiatric conditions by resident physicians
      before and after the training experience. CONCLUSION: Implementation of this
      intensive training experience resulted in subjective as well as objective
      enhancement of resident education by providing an intensive, focused educational
      experience in primary care psychiatry. This concept is adaptable to a variety of
      practice sites and educational levels. The MDC could become the hub of an
      integrated delivery system for mental health services in an ambulatory primary
      care setting.

PMID- 15014703
TI  - A Look at Neuropsychiatric Issues in Everyday Practice.

PMID- 15014704
TI  - Depressive Symptoms in Inner-City Children With Asthma.
AB  - BACKGROUND: Asthma is a sometimes severe respiratory illness with an increased
      prevalence, especially in low-income, minority, and inner-city populations, over
      the past 2 decades. Prior reports have suggested a link between depression and
      asthma deaths. However, no studies have examined the relationship between
      objective measures of asthma severity and clinician-rated depressive symptom
      severity. METHOD: In this pilot study, 46 children receiving treatment at an
      inner-city asthma clinic were assessed with the Children's Depression Rating
      Scale, Revised (CDRS-R). The current percentage of forced expiratory volume in 1
      second (FEV(1)%) predicted and the inhaled steroid dose were recorded, as were
      oral steroid use, emergency room visits, and hospitalizations in the preceding
      year. RESULTS: Depressive symptoms were common in this sample, with 30% (N = 14)
      of the participants having CDRS-R scores consistent with likely, very likely, or
      almost certain major depressive disorder. When mean CDRS-R scores were compared
      between the sample divided by these asthma severity measures, only
      hospitalizations in the past year was associated with higher depressive symptom
      scores (p =.03). CONCLUSION: These findings suggest that in the patient sample
      studied, depressive symptoms appear to be common. However, depressive symptom
      severity is related only to hospitalization, not other measures of asthma
      severity. Larger studies are needed to confirm these findings and determine if
      other variables such as family history of depression or subjective assessment of
      asthma severity explain the high prevalence of depressive symptoms in these
      patients.

PMID- 15014705
TI  - On the Edge of Life, I: Assessment of, Reaction to, and Management of the
      Terminally Ill Recorded in an Intensive Care Unit Journal.
AB  - BACKGROUND: In a general hospital, few clinical settings match the intensity of
      the intensive care unit (ICU) experience. Clinical rotations in ICUs elicit and
      emphasize the struggles house officers face on a daily basis throughout their
      training. METHOD: These struggles were recorded by hundreds of residents in a
      journal maintained in the Massachusetts General Hospital's Medical ICU for the
      past 20 years. We systematically reviewed these unsolicited entries to define and
      to illustrate how house officers respond to caring for terminally ill patients.
      The 3 overarching topics that surfaced repeatedly were assessment of terminally
      ill patients, reaction to their prognosis, and management of their disease or
      their eventual demise. RESULTS: House officers record affective reactions and
      cognitive assessments to cope with the stress and dysfunction associated with the
      care of the critically ill and to facilitate their management of these patients.
      Journal entries by residents reveal a deep concern for the welfare of their
      patients, conflict about the technological advances and limitations of the
      system, and reflection on how involved physicians should become with their
      patients. CONCLUSION: House officer journal entries reflect a combination of
      newly gained medical knowledge and coping strategies in managing terminally ill
      patients. House officers also demonstrate a deep concern for the welfare of their
      patients. Insight from years of reflection from past house officers can help
      prepare trainees and residency programs for the breadth and intensity of the ICU
      experience and for work in clinical practice settings that follow completion of
      training.

PMID- 15014707
TI  - The Feasibility of Using the Spanish PHQ-9 to Screen for Depression in Primary
      Care in Honduras.
AB  - BACKGROUND: The Patient Health Questionnaire depression module (PHQ-9) is a brief
      (10 items) screening and monitoring measure designed for use in primary care
      settings that operationalizes most of the DSM-IV and ICD-9 diagnostic criteria
      for major depression. In the United States, the PHQ-9 has become the recommended
      depression measure in primary care settings. However, there are no published
      reports of its use in developing countries and no reports of the feasibility of
      using the Spanish version of the PHQ-9 to screen for depression. METHOD: During a
      medical brigade in October 2001, we tested the feasibility of using the Spanish
      PHQ-9 to screen for major depression in primary care clinics. A team of U.S. and
      Honduran physicians and medical students assessed 199 mothers of children under
      10 years of age as part of a depression prevalence study in 5 rural sites.
      RESULTS: The PHQ-9 proved easy to administer to this population of poor, rural,
      young, and mostly illiterate Honduran women who had never participated in
      research before. Rater training required about 30 minutes of instruction for this
      group of physicians and medical students, plus occasional questions on the first
      day of use. Duration of administration of the PHQ-9 by interview ranged from 3 to
      15 minutes. No items required major modification for cultural differences. The
      PHQ-9 identified a rate of 15% for major depression in this sample, and the PHQ-9
      results showed a sensitivity of 77% and a specificity of 100% compared with the
      Structured Clinical Interview for DSM-IV mood disorders module. CONCLUSION: Like
      the English PHQ-9, the Spanish PHQ-9 is an efficient and reliable screening
      measure for major depression in primary care. It is useful as a research measure
      for estimating the prevalence of major depression and as an aid to the primary
      care clinician in rural Honduras.

PMID- 15014706
TI  - On the Edge of Life, II: House Officer Struggles Recorded in an Intensive Care
      Unit Journal.
AB  - BACKGROUND: In a general hospital, few clinical settings match the intensity of
      the intensive care unit (ICU) experience. Clinical rotations in ICUs elicit and
      emphasize the struggles house officers face on a daily basis throughout their
      training. METHOD: These struggles were recorded by hundreds of residents in a
      journal maintained in one Medical ICU for the past 20 years. We systematically
      reviewed these unsolicited entries to develop categories that define and
      illustrate common stressors. RESULTS: Stressors for house officers include
      isolation, insecurity, care for the terminally ill, sleep deprivation, and long
      work weeks. CONCLUSION: By placing the struggles of house staff in context,
      trainees and their residency training programs can be prepared for the intensity
      of the experience and for work in clinical practice settings that follows
      completion of training.

PMID- 15014709
TI  - Rethinking the Treatment of Psychotic Disorders.

PMID- 15014708
TI  - Feeling Good and Losing Weight: The Chicken or the Egg?

PMID- 15014710
TI  - Uses of Newer Anticonvulsants: An Update.

PMID- 15014711
TI  - Escitalopram: A New SSRI for the Treatment of Depression in Primary Care.
AB  - Escitalopram is the S-enantiomer of the racemic compound citalopram, a selective
      serotonin reuptake inhibitor (SSRI) widely used for the treatment of depression.
      This review describes the current body of pharmacologic and clinical evidence
      supporting the use of escitalopram for the treatment of depression and anxiety.
      Preclinical studies have confirmed that it is primarily this molecule that
      provides the inhibition of serotonin reuptake responsible for the antidepressant
      effect of citalopram, with minimal-to-nonexistent affinity for other receptor
      sites. Clinical trials of escitalopram in depressed patients indicate that
      escitalopram, 10 mg/day, is as effective as 40 mg/day of its parent compound,
      citalopram, with an excellent safety and tolerability profile. Because of its
      increased selectivity, escitalopram represents a refinement in SSRI therapy for
      symptoms of depression and anxiety. This article also explores the implications
      of a more selective SSRI on the management of depressed patients in the primary
      care clinical practice.

PMID- 15014712
TI  - Celebrity Patients, VIPs, and Potentates.
AB  - BACKGROUND: During the second half of the 20th century, the literature on the
      doctor-patient relationship mainly dealt with the management of "difficult"
      (personality-disordered) patients. Similar problems, however, surround other
      types of "special" patients. METHOD: An overview and analysis of the literature
      were conducted. As a result, such patients can be subcategorized by their main
      presentations; each requires a specific management strategy. RESULTS: Three types
      of "special" patients stir up irrational feelings in their caregivers. Sick
      celebrities threaten to focus public scrutiny on the private world of medical
      caregivers. VIPs generate awe in caregivers, with loss of the objectivity
      essential to the practice of scientific medicine. Potentates unearth narcissism
      in the caregiver-patient relationship, which triggers a struggle between power
      and shame. Pride, privacy, and the staff's need to be in control are all
      threatened by introduction of the special patient into medicine's closed culture.
      CONCLUSION: The privacy that is owed to sick celebrities should be extended to
      protect overexposed staff. The awe and loss of medical objectivity that VIPs
      generate are counteracted by team leadership dedicated to avoiding any deviation
      from standard clinical procedure. Moreover, the collective ill will surrounding
      potentates can be neutralized by reassuring them that they are "special"-and by
      caregivers mending their own vulnerable self-esteem.

PMID- 15014714
TI  - Using Atypical Antipsychotics in Primary Care.

PMID- 15014715
TI  - Cocktails and Kitchen Sinks.

PMID- 15014716
TI  - Cognitive Therapy Lite.

PMID- 15014713
TI  - Evaluating the Impact of an Educational Program on Practice Patterns of Canadian
      Family Physicians Interested in Depression Treatment.
AB  - BACKGROUND: Depression is frequently unrecognized and undertreated. Therefore,
      there is a need to increase the knowledge and skills of primary care physicians
      regarding the diagnosis and treatment of depression. The aim of this study was to
      provide, and evaluate the impact of, a brief educational program with a number of
      practice tools and resources in order to improve family physicians' knowledge,
      diagnosis, and treatment of depression. METHODS: Two educational programs
      (general and enhanced) were delivered to family physicians interested in
      depression treatment. The enhanced program focused on more practical clinical
      issues such as use of diagnostic and symptom assessment tools, recommended dosing
      of citalopram, how to initiate and discontinue treatment, and relapse prevention.
      Physicians' knowledge of depression was assessed pretraining and posttraining.
      Chart audits were conducted for 6 months. Primary endpoints were recognition of
      depression and pharmacologic management (initial dose, maximum dose, length of
      treatment, adverse events, and concomitant psychotropic drugs). Secondary
      endpoints were patient satisfaction with treatment, compliance, withdrawal from
      the study, treatment outcome, use of adjunctive psychotherapy, and number of
      office visits. RESULTS: There was a global increase in physicians' knowledge of
      depression in the short term. Physicians in the enhanced group were more likely
      to use a symptom-based diagnostic checklist, record the diagnosis of depression,
      and prescribe the recommended initial dose of citalopram, and they referred less
      frequently for adjunctive psychotherapy. No difference between educational
      intervention groups was found in patient satisfaction, compliance, and treatment
      outcome. CONCLUSIONS: A well-designed brief, simple, and low-cost educational
      program can increase family physicians' knowledge of depression, improve their
      diagnostic skills, and optimize their treatment of depression.

PMID- 15014717
TI  - Modafinil Treatment of Excessive Daytime Sedation and Fatigue Associated With
      Topiramate.

PMID- 15014718
TI  - Physician Education.

PMID- 15014719
TI  - Successful Pain Management for the Recovering Addicted Patient.
AB  - Successful pain management in the recovering addict provides primary care
      physicians with unique challenges. Pain control can be achieved in these
      individuals if physicians follow basic guidelines such as those put forward by
      the Joint Commission on Accreditation of Healthcare Organizations in their
      standards for pain management as well as by the World Health Organization in
      their stepladder approach to pain treatment. Legal concerns with using pain
      medications in addicted patients can be dealt with by clear documentation of
      indication for the medication, dose, dosing interval, and amount provided. Terms
      physicians need to be familiar with include physical dependence, tolerance,
      substance abuse, and active versus recovering addiction. Treatment is unique for
      3 different types of pain: acute, chronic, and end of life. Acute pain is treated
      in a similar fashion for all patients regardless of addiction history. However,
      follow-up is important to prevent relapse. The goal of chronic pain treatment in
      addicted patients is the same as individuals without addictive disorders-to
      maximize functional level while providing pain relief. However, to minimize abuse
      potential, it is important to have 1 physician provide all pain medication
      prescriptions as well as reduce the opioid dose to a minimum effective dose, be
      aware of tolerance potential, wean periodically to reassess pain control, and use
      nonpsychotropic pain medications when possible. Patients who are at the end of
      their life need to receive aggressive management of pain regardless of addiction
      history. This management includes developing a therapeutic relationship with
      patients and their families so that pain medications can be used without abuse
      concerns. By following these strategies, physicians can successfully provide
      adequate pain control for individuals with histories of addiction.

PMID- 15014720
TI  - Assessment of Patients Who Attempt Suicide.
AB  - Suicidal behavior is influenced in varying degrees by biological, personal, and
      social factors. Identifying 4 common reasons for suicidal acts (psychosis, major
      depression, philosophical reasons, and poor impulse control) can be very helpful
      in evaluating suicidal patients quickly and making decisions about how patients
      should be treated. Educating the general public and primary care physicians about
      these reasons while addressing biological, personal, and social factors that
      contribute to them can improve understanding of suicidal behavior and patient
      involvement in and adherence to the treatment process.

PMID- 15014721
TI  - Comorbid Psychiatric Disorders and Predictors of Pain Management Program Success
      in Patients With Chronic Pain.
AB  - BACKGROUND: This prospective investigation assessed success rates of a pain
      management program for patients with and without DSM-III-R Axis I and II
      psychiatric disorders. METHOD: Subjects included 40 consecutive patients with
      chronic pain who were referred to a physical therapy-oriented, "standard" pain
      management program. Serial ratings of pain levels were measured via a visual
      analogue scale (VAS) at baseline, weekly throughout a 12-week program, and during
      a follow-up interval 1 month after completion of the program. Weekly reports of
      hours of gainful employment were recorded. VAS scores and number of hours worked
      per week were combined into a measure of pain improvement. This dependent
      variable was used to compare groups of patients across psychiatric disorders
      diagnosed via the Diagnostic Interview Schedule (DIS). Percentages of patients in
      each diagnostic group who met minimal criteria for improvement were computed and
      compared. A chi-square analysis was conducted on success rates between patients
      with and without any Axis I disorder, any Axis II disorder, and any substance
      abuse/dependence disorder. RESULTS: Overall, 70% of patients (N = 28) were found
      to have a DIS psychiatric disorder. There were differences in improvement between
      patients with and without Axis I disorders and between those with and without
      Axis II disorders. The presence of a diagnosis was associated with significantly
      lower improvement rates (p <.05). CONCLUSION: Patients with chronic pain enrolled
      in this clinic had a high prevalence of comorbid psychiatric disorders, and these
      comorbid patients were less likely to improve with standard chronic pain
      treatment. In a population of patients seeking treatment for chronic pain, these
      results suggest a need for detection and diagnosis of psychiatric disorders and
      further research on the efficacy of psychiatric treatment interventions in
      chronic pain management.

PMID- 15014723
TI  - Don't Cry Wolf With Me.

PMID- 15014722
TI  - Mood Disorders in Family Practice: Beyond Unipolarity to Bipolarity.
AB  - Primary care physicians increasingly have treated depressive disorders over the
      last decade. Unrecognized bipolar disorder, sometimes misdiagnosed as unipolar
      depression, may lead to treatment resistance or nonresponse. We describe
      differences between unipolar and bipolar disorders, focusing on recognition,
      diagnosis, and treatment of bipolar spectrum disorders such as bipolar I, bipolar
      II, antidepressant-induced mania, and cyclothymia. Broadening the understanding
      of these different disorders and their presentation in primary care settings can
      enable earlier and more targeted treatment. Though 3 mood stabilizers are U.S.
      Food and Drug Administration-approved for treatment of acute mania, no
      medications are currently approved for treating bipolar depression.

PMID- 15014724
TI  - Mastering Panic Anxiety.

PMID- 15014725
TI  - A Case Report of Methylphenidate-Induced Dyskinesia.

PMID- 15014727
TI  - The Mood Disorder Questionnaire in Primary Care: (Not) Ready for Prime Time?

PMID- 15014726
TI  - A Case Report of a Manic Episode Triggered by S-Adenosylmethionine (SAMe).

PMID- 15014728
TI  - The Mood Disorder Questionnaire: A Simple, Patient-Rated Screening Instrument for
      Bipolar Disorder.
AB  - Bipolar disorder is frequently encountered in primary care settings, often in the
      form of poor response to treatment for depression. Although lifetime prevalence
      of bipolar I disorder is 1%, the prevalence of bipolar spectrum disorders (e.g.,
      bipolar I, bipolar II, and cyclothymia) is much higher, especially among patients
      with depression. The consequences of misdiagnosis can be devastating. One way to
      improve recognition of bipolar spectrum disorders is to screen for them. The Mood
      Disorder Questionnaire is a brief, self-report screening instrument that can be
      used to identify patients most likely to have bipolar disorder. Once identified,
      and subsequently appropriately diagnosed, the lives of those with bipolar
      disorder may be considerably improved.

PMID- 15014730
TI  - Court Appointed Volunteers for Abused and Neglected Children.
AB  - A court appointed special advocate (CASA) volunteer is a trained citizen who is
      appointed by a judge to represent the best interests of an abused and neglected
      child in court. An independent voice, the volunteer gathers information and
      reports to the court. The CASA volunteer works in close cooperation with other
      professionals, physicians, lawyers, social workers, and teachers to find the most
      suitable permanent placement for a victimized child, whether it be a foster home,
      parental home, or adoptive home. Another function for CASA volunteers is to be
      supportive to the child during a time of uncertainty in his or her life and to
      help the youngster adjust to new and changing situations; the CASA volunteer may
      be the only consistent adult presence during this difficult period of transition.

PMID- 15014729
TI  - Paroxetine in Patients With Irritable Bowel Syndrome: A Pilot Open-Label Study.
AB  - BACKGROUND: Irritable bowel syndrome (IBS) is a common disorder and is the
      largest diagnostic cohort seen by gastroenterologists. There is a bidirectional
      comorbidity of IBS and psychiatric illness. Ours is the first study to examine
      the effect of any selective serotonin reuptake inhibitor in subjects with IBS.
      METHOD: Twenty subjects with Rome I criteria-diagnosed IBS were treated with 20
      to 40 mg of paroxetine for 12 weeks. We utilized a computer-administered patient
      daily questionnaire taken by patients over the telephone using an interactive
      voice response system. RESULTS: Sixty-five percent of patients (13/20) reported a
      reduction in abdominal pain, and 55% (11/20) reported a reduction in pain
      frequency (total or mean number of days per week in which the patient had the
      symptom decreased by >/= 50%). Constipation and diarrhea were reduced in 69% and
      57% of patients (9/13 and 8/14), respectively. Similarly, a clinically
      significant reduction in the symptoms of feeling of incomplete emptying (53%
      [9/17]) and bloating/abdominal distension (55% [11/20]) was apparent at study
      conclusion compared with baseline. On the Clinical Global Impressions scale at
      week 12, 47% (8/17) of the patients were much or very much improved. CONCLUSION:
      In our pilot open-label study, paroxetine was very effective in alleviating the
      abdominal pain and associated symptoms of IBS. These results warrant further
      examination in a placebo-controlled study.

PMID- 15014732
TI  - The Post-Call Blues.

PMID- 15014731
TI  - Stereoisomers in Psychiatry: The Case of Escitalopram.
AB  - Many medications in common clinical use consist of "mirror image" isomers that
      differ only in the direction in which they rotate plane-polarized light. These
      stereoisomers exist as mixtures of "right" and "left" handed molecules that are
      the product of chemical syntheses. However, the biochemical milieu of the human
      body is a highly stereospecific environment where the fit of medication and
      receptor may depend on the shape of the molecule in 3-dimensional space. Recent
      advances in chemistry have allowed the more ready preparation of single isomers
      of various drugs that were previously available only as racemic mixtures. For
      those compounds in which the isomers differ in stereospecificity, this separation
      into single isomers can result in significant changes in potency, tolerability,
      and efficacy. This article reviews some basic information about stereochemistry
      and describes the development of a new single isomer antidepressant,
      escitalopram, which is one of the components of the widely used selective
      serotonin uptake inhibitor citalopram.

PMID- 15014733
TI  - Overcoming Obstacles: Therapeutic Success Despite External Barriers.

PMID- 15014734
TI  - The Many Uses of Bupropion and Bupropion Sustained Release (SR) in Adults.

PMID- 15014735
TI  - Clinical Dimensions of Fatigue.
AB  - Because the symptom of fatigue is often vague, clinical evaluation requires the
      consideration of distinct features such as timing, precipitants, presence of
      libido, sleep quality, exercise capacity, and sedation. Fatigue has dimensions of
      affect and tolerability. In chronic illness, it is helpful to consider mood,
      physical conditioning, course of predictable treatment consequences, postural
      hypotension, and the well-being of caretakers. The differential diagnosis of
      acute and chronic fatigue is considered. Chronic fatigue of unknown etiology is
      placed in historical context, and an approach to the complexities of providing
      continuing evaluation and care is discussed.

PMID- 15014737
TI  - When Patients Are Normal People: Strategies for Managing Dual Relationships.
AB  - A significant number of generalist physicians, particularly those in rural areas,
      often find themselves participating in the care of patients for whom the
      therapeutic relationship overlaps with another relationship (e.g., social or
      professional). Although psychiatrists and psychologists are typically advised to
      avoid such "dual relationships," no such prohibition exists for generalists.
      Little, if any, guidance exists to aid in the management of such dual
      relationships for the generalist who provides treatment for psychiatric
      conditions for his or her patients. The author, a generalist with experience in
      the treatment of mood disorders, describes potential challenges faced by the
      generalist who chooses to provide care for "dual relationship" patients and
      outlines strategies for successfully meeting these challenges.

PMID- 15014736
TI  - Depression With Atypical Features: Diagnostic Validity, Prevalence, and
      Treatment.
AB  - Depression with atypical features is a treatable and relatively common disorder
      among depressed outpatients. A growing body of evidence suggests this is a
      biologically distinct subtype of depression. This assertion is supported by
      genetic epidemiologic studies and by a preferential response of the subtype to
      monoamine oxidase inhibitors compared with tricyclic antidepressants. The
      Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)
      includes atypical features as a parenthetical modifier for depressive illness.
      According to DSM-IV diagnostic criteria ("atypical features" specifier), the
      disorder is primarily characterized by 2 or more of the following symptoms as
      predominant features in patients with major depression or dysthymic disorder:
      overeating, oversleeping, "leaden paralysis," and interpersonal rejection
      sensitivity. Patients also show mood reactivity in response to actual or
      potential positive events. Despite aspects of the disorder resembling a
      maladaptive, persistent mode of behavior, patients diagnosed with depression with
      atypical features demonstrate a good response to antidepressant treatment.

PMID- 15014739
TI  - Hypervigilant? Who, Me?

PMID- 15014738
TI  - Possible Link Between Attention-Deficit/Hyperactivity Disorder and Reproductive
      Complications.
AB  - BACKGROUND: Initially conceptualized as a disorder of childhood, attention
      deficit/hyperactivity disorder (ADHD) is now emerging as a chronic disorder that
      may present in adolescence and persist into adulthood. Failure to recognize this
      common disorder in childhood may lead to disabling comorbid symptoms and a poor
      long-term prognosis in adulthood. Young adults with undiagnosed ADHD experience
      significant psychiatric comorbidity, including high rates of drug dependency and
      lower levels of global functioning. The public health consequences of poor
      impulse control (e.g., delinquency, criminal activity, drug use, risky sexual
      behaviors, high-risk pregnancies) are emerging, and a link between ADHD and
      poverty seems highly probable. CASE REPORT: I explore the sexual behaviors, and
      their consequences, of a young adolescent female. Her reproductive complications
      led me to consider undiagnosed ADHD. CONCLUSION: The long-term prognosis when
      ADHD is unrecognized and untreated in the adolescent is discouraging: maternal
      and perinatal morbidity may be anticipated and are biologically plausible. The
      actual assessment of risk in the setting of pregnancy and unrecognized ADHD
      remains largely unknown, and the benefits of timely diagnosis and appropriate
      treatment of ADHD during pregnancy have yet to be addressed. The following case
      presentation suggests an association between undiagnosed ADHD and reproductive
      complications.

PMID- 15014740
TI  - Psychotherapy of a Patient With Terminal Cancer.

PMID- 15014741
TI  - Olanzapine for the Treatment of Bipolar Disorder.

PMID- 15014742
TI  - Dr. Masand Replies.

PMID- 15014743
TI  - Developing Family Relationship Competencies.

PMID- 15014744
TI  - Rebuilding Family Relationship Competencies as a Primary Health Intervention.
AB  - The authors present Relationship Competence Training (RCT), which is an organized
      conceptual framework developed by them for assessing a family's ability to
      mobilize their relational support in times of distress. RTC is a process of
      studying family relationship patterns and how these patterns influence family
      health. The RTC model is described as a method of promoting mental health as a
      part of everyday family health, which is suitable for health care providers
      working in a wide variety of environments who have in common the desire to offer
      continuity and value in promoting the health of the families under their care.
      RCT provides an empathic way of dealing with the "compassion fatigue" that health
      care providers often experience when managing complex family health issues in
      constantly changing and quality-strained primary health care environments.

PMID- 15014746
TI  - Practical Principles for the Management of Alzheimer's Disease.
AB  - Alzheimer's disease is a complex disorder that is particularly challenging to
      treat and manage. Early recognition of Alzheimer's disease is the first step
      toward providing patients with optimal therapy and the best opportunity for
      treatment response. Subsequently, physicians will need to address issues that
      emerge as the disease inevitably progresses. As the number of elderly patients
      with Alzheimer's disease increases, it becomes increasingly important for the
      primary care physician-usually the first line of patient contact-to diagnose
      Alzheimer's disease early, and initiate and manage appropriate long-term
      cholinesterase inhibitor therapy, which has been shown to provide significant
      benefits to Alzheimer's disease patients. In this article, discussions of
      individual patients illustrate commonly encountered situations in the primary
      care setting.

PMID- 15014748
TI  - Yes, We Have No Bananas.

PMID- 15014749
TI  - Being Left.

PMID- 15014745
TI  - Panic Disorder and Chest Pain: Mechanisms, Morbidity, and Management.
AB  - Approximately one quarter of patients who present to physicians for treatment of
      chest pain have panic disorder. Panic disorder frequently goes unrecognized and
      untreated among patients with chest pain, leading to frequent return visits and
      substantial morbidity. Panic attacks may lead to chest pain through a variety of
      mechanisms, both cardiac and noncardiac in nature, and multiple processes may
      cause chest pain in the same patient. Panic disorder is associated with elevated
      rates of cardiovascular diseases, including hypertension, cardiomyopathy, and,
      possibly, sudden cardiac death. Furthermore, patients with panic disorder and
      chest pain have high rates of functional disability and medical service
      utilization. Fortunately, panic disorder is treatable; selective serotonin
      reuptake inhibitors, benzodiazepines, and cognitive-behavioral psychotherapy all
      effectively reduce symptoms. Preliminary studies have also found that treatment
      of patients who have panic disorder and chest pain with benzodiazepines results
      in reduction of chest pain as well as relief of anxiety.

PMID- 15014750
TI  - A Case Report of Drug-Induced Dermatitis With Weekly Fluoxetine.

PMID- 15014747
TI  - Comparison of Risperidone and Olanzapine in Bipolar and Schizoaffective
      Disorders.
AB  - OBJECTIVE: To compare risperidone and olanzapine for efficacy, tolerability, need
      for concomitant mood stabilizers, and cost of treatment in bipolar and
      schizoaffective disorders. METHOD: We conducted a retrospective chart review of
      36 consecutive outpatients with DSM-IV bipolar or schizoaffective disorder seen
      in 3 settings who received risperidone or olanzapine for at least 1 month between
      May and August 1997. RESULTS: The mean +/- SD doses were 3.7 +/- 3.5 mg/day of
      risperidone and 12.0 +/- 5.4 mg/day of olanzapine. Between-treatment differences
      in patient characteristics, psychiatric history, Clinical Global Impressions
      scale ratings, and duration of treatment were not significant. Similar
      proportions of patients in the 2 groups reported side effects, including
      extrapyramidal symptoms, akathisia, tardive dyskinesia, and precipitation of
      mania by the respective drug. Patients in the olanzapine group received a
      significantly higher dose of concomitant lithium than those receiving risperidone
      (mean daily lithium doses: risperidone group, 750 +/- 150 mg; olanzapine group,
      1211 +/- 186 mg; p =.006). The total daily acquisition cost per patient was
      $11.84 for olanzapine versus $5.81 for risperidone. CONCLUSION: Olanzapine and
      risperidone were equally efficacious and safe in the treatment of patients with
      bipolar or schizoaffective disorder, but treatment costs and dose of concomitant
      lithium were lower in risperidone-treated patients.

PMID- 15014751
TI  - Bupropion-Associated Withdrawal Symptoms Revisited: A Case Report.

PMID- 15014752
TI  - [Treatment selection of hemangioma and/or vascular deformities in oral and
      maxillofacial region].

PMID- 15014753
TI  - [The application of submental island flap in head and neck surgery].
AB  - OBJECTIVE: This article discusses the anatomy, surgical procedure,indication,
      advantages and disadvantages of the submental island flap in reconstruction of
      the defects after head and neck tumor surgery, based on our clinical experience.
      METHODS: The submental island flap was transferred with the submental
      vessels(A/V) as pedicle. In harvesting the flap, the flap was raised commencing
      from the contralateral side, dissecting all tissues off the mylohyoid muscles.
      Submandibular triangle dissection was taken until the facial artery and the
      facial vein. Then the submandibular gland and submandibular nodes were removed
      and submental vessels were left. This produces a large skin paddle which can be
      tunnelled to its recipient site. RESULTS: From Aug. 1998 to Oct. 1999, 16
      submental island flaps were performed in our department. 15 flaps survived well
      and 1 flap failed, with a success rate of 15/16 (93.8%). CONCLUSION: The
      submental island flap is appropriate for primary reconstruction of the defect
      after various head and neck tumor surgery. It has a long and reliable pedicle,
      rapid and simple to raise and free from vessel anastomosis. It leaves a well
      hidden donor site. However, it can't be applied to these cases whose donor site
      had been radiated before surgery and whose submental and submandibular triangles
      lymph nodes were positive.

PMID- 15014754
TI  - [Assessment of application of computerized local anesthetic delivery system in
      periodontal ligament injection].
AB  - OBJECTIVE: To assess the pain intensity and anesthetic effect in peridontal
      ligament injection using the computerized local anesthetic delivery system made
      by Milestone company in USA. METHODS: 40 cases were selected,and comparing the
      periodontal ligament injection through using the computerized local anesthetic
      delivery with traditional manul local anesthesia. RESULTS: By using the
      computerized local anesthetic delivery system the pain in peridontal ligament
      injection was significantly less than traditional methods. There was no
      difference in anesthetic effect when teeth were extracted. CONCLUSION: The
      peridontal ligament injection usually as an adjunctive anesthesia method could
      attain good anesthetic effect and would have a wide application by using the
      computerized local anesthetic delivery system.

PMID- 15014755
TI  - [Embolization in arteriovenous malformations of maxillofacial region with PVA].
AB  - OBJECTIVE: To evaluate the embolization of arteriovenous malformations of the
      maxillofacial region with PVA. METHODS: 8 cases (male:3, female:5) of
      arteriovenous malformations of the maxillofacial region comprised this study
      group. The embolic material used was PVA (Polyvinyl Alcohol Foam) particles (250
      500 microm) injected using 4.0 to 3.0 French-size catheters, catheterized
      selectively in the feeding pedicles of the AVM under the guidance of DSA machine
      (PHILIPS V3000). RESULTS: Five patients were embolized an a single session, and
      three patients needed two sessions. Immediate angiographical results showed total
      disappearance of the AVMs in all patients. Swelling, pulsation, and bruit were
      disappeared after embolization. Pericoronal oozing of blood and acute arterial
      bleeding was controllable. Local pain, swelling,and low-grade fever usually
      lasted from 3 to 7 days after embolization. CONCLUSION: The embolization of
      arteriovenous malformations of the maxillofacial region with PVA is effective and
      safe, and the longer follow-up is expected.

PMID- 15014757
TI  - [Correlation between the changes of soft and hard tissue after advanced Lefort I
      osteotomy in patients with cleft lip and palate].
AB  - OBJECTIVE: The purpose is to evaluate the correlation between the changes of soft
      and hard tissue after advanced Lefort I osteotomy in patients with complete
      unilateral cleft lip and palate. METHODS: Lateral cephalometric films were taken
      from before and after operation. The same landmarks in two films were compared
      horizontally and vertically. The correlation ratio between changes of soft and
      hard tissue were analysed statistically. RESULTS: After operation, the length of
      upper lip of the patients with CLP increased. The ratio between the movement of
      upper incisor and upper lip was 0.77 horizontally and 0.67 vertically,
      respectively. CONCLUSION: The slope between hard and soft tissue was treated as
      ratio. It is more significant than the horizontal difference between soft and
      hard tissue, since correlative factor was contained in the slope.

PMID- 15014756
TI  - [A survey of the changes of serum inorganic salts and alkaline phosphatase after
      jaw fractures].
AB  - OBJECTIVE: To study the changes of serum salts and alkaline phosphatase in
      patients with jaw fractures and its roles. METHODS: The serum salts and alkaline
      phosphatase were determined in 40 cases of jaw fracture and 14 health persons.
      RESULTS: The results showed that there was no significant difference in Na(+),
      K(+), Cl(-), Ca(2+) contents between jaw fracture group and normal group
      (P>0.05), but P(3-) Mg(2+), ALP levels were higher in jaw fracture group than
      that in normal group (P<0.05). Furthermore the Ca(2+), P(3-), Mg(2+), ALP were
      higher in multiple or communition fracture of jaw than in single or double line
      fracture (P<0.05) except Ca content. The level of Ca(2+) was higher in single jaw
      fracture than in jaw damage with whole body injury (P>0.05) but the levels of P(3
      ),Mg(2+), ALP were no difference (P>0.05). As the same all the Ca(2+), P(3-),
      Mg(2+), ALP levels were higher in early stage of fracture than in 4 weeks after
      fracture (P<0.05). CONCLUSION: The contents of Ca(2+) P(3-), Mg(2+) ALP were
      increased after the axilla mandible were fractured and it has an important
      regulation role in the activity of osteoblast and osteoclast in healing of
      fractured jaw.

PMID- 15014758
TI  - [Application of modified shuttle like incision in benign skin tumour in the
      maxillofacial region].
AB  - OBJECTIVE: To design a modified shuttle-like incision for benign skin tumours in
      the maxillofacial region. METHODS: Some merits of the modified shuttle like
      incision was verified through experiment upon Cadavers and accurate mathematical
      calculation. Then it was used in the resection of 24 patients with benign skin
      tumour in the maxillofacial region. RESULTS: If the radius of the tumours were
      separately 0.5 cm, 1.0 cm and 1.5 cm, the modified shuttle-like incision can save
      the skin area by 17.22%,15.42% and 16.98%; no(or little) tension was found in
      sewing. The sutural lines were levelly concealed in the kraissl's lines and
      no"cat ear"was found after sewing. After 1-7 years of following up, all of the
      scars of the 24 cases were appraised as good. CONCLUSION: The modified shuttle
      like incision was better than the traditional one. It can be performed widely in
      the clinical operation on benign skin tumours in the maxillofacial region.

PMID- 15014759
TI  - [Analysis of the proportion of salivary gland tumors in 528 elder patients].
AB  - OBJECTIVE: To analyse the clinical characteristic, evolution and prognosis of
      undifferentiated carcinoma with lymphoid stroma(malignant lymphoepithelial The
      purpose of this study was to investigate the present proportional ratio of
      salivary gland tumors in elder patients, to provide references for early
      diagnosis and treatment clinically. METHODS: The medical data of 528 elder
      patients with salivary gland tumors treated in our department in 1990s were
      reviewed and analyzed. RESULTS: The number of salivary gland tumors in elder
      patients had increased in recent years. These tumors were frequently found in
      patients of 60-74 years. The ratio of benign to malignant was 1.7:1. In benign
      tumors, the proportion of adenolymphoma approached pleomorphic adenoma. While in
      malignant tumors, adenoid cystic carcinoma accounted the most. These tumors were
      most commonly found in the parotid gland, followed by the palate. The prevalence
      of female had an increase trend. CONCLUSION: The proportion of salivary gland
      tumor in elder patients in 1990s was different from that in 1980s. This change
      should attract enough attention form the surgeons.

PMID- 15014760
TI  - [Detection of high risk human papillomavirus DNA in oral squamous cell
      carcinoma].
AB  - OBJECTIVE: To ascertain the prevalence of human papillomavirus(HPV) DNA in oral
      squamous cell carcinomas(OSCCs) and normal oral mucosa and to correlate the
      virologic data with other factors obtained from patients' records. METHODS: 113
      paraffin embedded tissue blocks including 73 OSCCs and 40 normal oral mucosa were
      studied by polymerase chain reaction (PCR) for HPV type 16 and 18 DNA. Medical
      records of patients were reviewed to obtained the following factors: age, sex,
      tobacco and alcohol usage, site of tumor, histologic grade and clinical stage.
      RESULTS: 74%(54/73) of OSCCs and 55%(22/40) of normal oral mucosa were HPV 16/18
      DNA positive. The presence of HPV DNA showed significant difference between OSCCs
      and normal oral mucosa (P=0.040). Statistical analysis indicated that age
      (60</=years) and sex (male) were associated with the presence of HPV16/18 DNA in
      the tumor. There were no significant association between HPV presence and other
      factors, include tobacco and alcohol usage, site of tumor, histologic grade and
      clinical stage. CONCLUSION: High risk HPV genotypes have a significant
      association with oral squamous cell carcinoma. It is a co-factor in oral
      carcinogenesis, particularly in male patients and patients under the sixth
      decade. HPV infection in the oral mucosa is common. HPV is not the single
      etiological factor responsible for human oral neoplasia.

PMID- 15014761
TI  - [Treatment experience of 3 cases with fatal hemorrhage in oral and maxillofacial
      region].

PMID- 15014762
TI  - [Study of sintering temperature of HN-97 porcelain stain].
AB  - OBJECTIVE: To determine the sintering temperature range and the best temperature
      of coloration of HN-97 porcelain stain,and matched porcelain powders. METHODS:
      (1) The authors used prepared experiments of sintering temperatures and different
      sintering temperatures with different porcelain powders. RESULTS: The results
      showed sintering temperature range of the stain was 820-955 degrees centigrade;
      (2)The stain can be matched with many porcelain powders (e.g.Vita,Densply. Shofu
      and Shanghai); (3)Surface of stain was smooth, colour was stable,integrate was
      good. CONCLUSION: The stain can be used once coloration and glaze for restoration
      of porcelain, autoglazing temperature of which is between 820-955 degrees
      centigrade and the operation is easy.

PMID- 15014763
TI  - [Experimental study of Ti-75(AlMoZrTi alloy) dental implants in dog mandible].
AB  - OBJECTIVE: The purpose of this study was to investigate the biocompatibility of
      Ti-75(AlMoZrTi Alloy) dental implants. METHODS: Four 6.5 to 16 kg dogs were
      used,after mandibular cuspids and premolar extraction, 16 implants were placed
      and left for six or twelve months. All of the dental implants were made of Ti-75
      (AlMoZrTi Alloy) and they were manufactured in two types-nonsubmerged and
      submerged threaded implants. RESULTS: The survival rate of the implants was 100%
      (submerged implants) and 91.7% (nonsubmerged implants). Histologically,all
      survival implants showed some degree of intimate bone to implant contact, but one
      of the nonsubmerged implants showed periimplantitis. No implants were observed to
      be mobile. The periotest values of the dental implants were near the periotest
      values of the nature teeth. CONCLUSION: This study demonstrated Ti-75 is a
      biocompatible material and periotest is worthy of detection of osseointegration.

PMID- 15014765
TI  - [A clinical study on iodoform and oxide eugenol paste as root canal filling paste
      in 116 teeth].

PMID- 15014764
TI  - [Mast cell in the gingival cancer: histochemical and electron microscopical
      study].
AB  - OBJECTIVE: To observe the relation between mast cells and gingival cancer.
      METHODS: The gingival cancer tissue of 24 cases and normal gingival tissue of 7
      cases were studied with histochemical and electron microscopical methods.
      RESULTS: The results showed that the number of mast cells around the periphery of
      gingival cancer tissue increased significantly. The histochemical properties of
      these mast cells differed from the normal gingival tissue. The former did not
      contain heparin which was present normally. Under electron microscope, according
      to the characteristic ultrastructure, the mast cells around the gingival cancer
      were TC mast cells. Some of them showed the appearance of degranulation, and
      contacted intimately with cancer cells, lymphocytes and macrophages. CONCLUSION:
      These results suggested that together with lymphocytes, macrophages, the mast
      cell contributed to the defense reaction to the cancer tissue.

PMID- 15014766
TI  - [The bacteria detection and drug sensitivity test from infected root canals].
AB  - OBJECTIVE: To provide bacteriological basis for curing infected root canals with
      sensitive drugs. METHODS: We have made bacterial cultivation for 56 cases with
      infected root canals and drug sensitive test with agar dilution. RESULTS: The
      rates of bacteria detection and positive rates from infected root canals were
      high. Anaerobia and aerobia were sensitive to different kinds of antibiotics.
      CONCLUSION: Bacteria have close relation to infected root canals. Sensitive drugs
      should be selected in clinical treatment.

PMID- 15014767
TI  - [Condyle process hypertrophy combined with beak malformation: report of one
      case].

PMID- 15014768
TI  - [A study of fluoride and dexamethasone affecting the proliferation in
      osteoblast].
AB  - OBJECTIVE: Investigate the effects of low dose of fluoride and dexamethasone on
      the proliferation of MC3T3-E1 osteoblast cell line in vitro, which was for
      determining the possible effects of fluoride and dexamthasone affecting the
      development and differentiation of osteoblast. METHODS: Observe the growing shape
      of MC3T3-E1 osteoblast cultured in vitro, and investigate the effects of low dose
      of fluoride and dexamethasone on the proliferation of osteoblast by cell count.
      RESULTS: MC3T3-E1 osteoblast grew stably. The cells in D group increased
      obviously in the early stage of the cell culture, however the cells in F group
      had no tendency of increasing during the whole culture. CONCLUSION: In vitro low
      doses of dexamethasone may promote the proloferation of osteoblast
      precursors,however,low dose of fluoride has no effect on promoting proliferation
      of MC3T3-E1 osteoblast.

PMID- 15014769
TI  - [Concentration of arsenic trioxide in animal tongue tissue by transartery
      catheterization].
AB  - OBJECTIVE: To compare the differences of As(2)O(3) concentration in rabbit tongue
      tissue between arterial infusion and intravenous injection. METHODS: 4 clean
      rabbits were divided into the artery group and the vein group at random. The
      rabbits in both groups received arsenic trioxide of the same concentration and
      same volume. The tongue tissue from tip to the base of the rabbit were resected
      at 30,60,120,240 minutes after medication. The concentration in tissue of
      As(2)O(3) was determined with Gas Chromatography. RESULTS: The concentration of
      As(2)O(3) in artery group is significantly higher than that in vein group
      (P<0.01). The average concentration was 7.9 micromol/L in artery group and 1.4
      micromol/L in vein group. CONCLUSION: The concentration of As(2)O(3) infused by
      transartery catheterization was greatly enhanced in local tissue, it reached the
      concentration that can effectively inhibit the cell proliferation of oral tongue
      squamous cell carcinoma.

PMID- 15014770
TI  - [Epidemiologic survey of dental fluorosis and caries in school students in Wensu
      county in Xinjiang].
AB  - OBJECTIVE: To assess the relationship between the dental fluorosis and caries,and
      their prevalence features in school students in Wensu country in Xinjiang.
      METHODS: The study groups consisted of 1527 Weuer and Han students at the age of
      6 to 16. Dental fluorosis and caries disease were assessed strictly by Dean's
      Classification Standard and WHO "Oral Health Surveys Basic Methods" (the 3rd ed).
      The concentration of fluorine in water and urine was measured by using selective
      electrode. RESULTS: The prevalence and index of dental fluorosis in Weuer and Han
      students were 73.70%, 64.67%, 1.647, 1.303,respectively. The prevalence of dental
      caries and DMFT were 61.19%, 42.66%, 1.648, 1.023 respectively. The corresponding
      values were 51.94%, 52.99%, 1.305, 1.449 for students of fluorosis group and non
      fluorosis group, respectively. The fluorine degree of water was 2-5mg/L,the
      average value of fluorine in urine was 3.64 mg/L in Han students, and 5.28 mg/L
      in Weuer students. CONCLUSION: The prevalence of dental caries didn't decrease,
      even though the grevalence of fluorosis was high in Weuer country. The prevalence
      of fluorosis dental caries in Weuer students were significantly higher than those
      in Han students. It showed no significant different between the group of
      fluorosis and the group of non-fluorosis in the prevalence of dental caries,
      perhaps due to the high fluorine intake, poor oral hygiene, and unqualified
      medical service.

PMID- 15014771
TI  - [3D geometric simulation of mandible with dental arch from CT data].
AB  - OBJECTIVE: A 3D geometric simulation of mandible with dental arch from CT has
      been obtained in this study. METHODS: This process uses automatic system assisted
      with interactive action to get 2D contour data from CT images,then 3D wireframe
      model and solid model were obtained by using CAD/CAM software Pro-E(USA) and
      DELCAM(UK). RESULTS: 3D solid model of mandible with dental arch were presented
      which can be fully edited. CONCLUSION: This model can be applied to further
      educational and clinical researches such as RP,biomechanics simulation in
      prosthetic dentistry.The processes of simulation has wide applications in
      clinical practice of dentistry and dental education.

PMID- 15014772
TI  - [3D solid model of mandible with dental arch via LOM method].
AB  - OBJECTIVE: Based on 3D reconstruction data from CT scanning, a solid model of
      mandible with dental arch is obtained via a rapid prototype machine using LOM
      method. METHODS: 3D reconstruction data is transferred to STL file using software
      of Delcam(UK),which will be fed to Magics RP software for detection and
      rebuilding. Reproduction of the papery model of mandible with dental arch is then
      performed with highly geometric similarity. RESULTS: The RP model of mandible
      with dental arch is obtained. CONCLUSION: Accuracy of the reproduction model
      meets the demands of students in prosthetic dentistry,which gives the possibility
      of computer aided design of prosthetic dentistry based on 3D solid model.

PMID- 15014773
TI  - [The experience on correcting the impacted maxillary anterior teeth with fixed
      orthodontic technique].

PMID- 15014774
TI  - [The personality patients with congenital cleft lip and palate after early
      repair].

PMID- 15014775
TI  - [Management of cervical lymph node metastasis in parotid carcinoma].

PMID- 15014776
TI  - [Five-year clinical observation of composite resin inlays filling the posterior
      teeth].

PMID- 15014779
TI  - [Electric ion operation for correction of lingual frenum of infant: experience in
      90 cases].

PMID- 15014777
TI  - [Perioperative management of patients with oral neoplasms and concomitant
      diabetes mellitus].

PMID- 15014778
TI  - [Mcnamara analysis of angle II-I malocclusion before and after orthodontics].

PMID- 15014781
TI  - [Advances in research of striped diseases of oral mucosa].

PMID- 15014780
TI  - [Treatment of temporomandibular joint disturbance syndrome by GAALAS laser:
      clinical observation].

PMID- 15014782
TI  - [Clinical application of 3D reconstruction in maxillofacial fractures].
AB  - OBJECTIVE: To study the value of 3D reconstructive technique in midfacial
      fractures,especially its significance in preoperative diagnosis and operation
      planning of complicated,multiple fractures in midface. METHODS: To preoperatively
      scan and reconstruct 47 fracture patients with spiral CT. RESULTS: 38 cases
      received operation which confirmed the preoperative diagnosis of 3D CT. The
      conservationed treatment was applied to other 9 patients. CONCLUSION: The 3D
      reconstruction can reveal the complicated fractures in midface as approximate
      model, and benefit the selection of the most suitable plan before operation.

PMID- 15014784
TI  - [CT manifestation of pterygopalatine fossa in adult skull].
AB  - OBJECTIVE: The aim of this study was to measure certain diameters of the
      pterygopalatine fossa (PPF) and to discuss the anatomic appearance of PPF on CT
      images. METHODS: 20 dry skulls were scanned by CT on axial and coronal plane with
      2 mm slice thickness. RESULTS: On CT imaging, the shape of superior 1/4 part of
      PPF is mainly shown as biconcavity. The maximal posteroanterial (PA)diameter was
      (6.6+/-2.2)mm. The maximal medialateral diameter (ML)was (13.7+/-3.7)mm. The
      shape of the middle 1/4 part of PPF was biconvexity with the PA and ML of (6.6+/
      2.1)mm and (12.1+/-2.7)mm. The shape of the inferior 1/2 part of PPF just liked a
      tube with the diameter of (3.8+/-1.7)mm. The foramen rotudum lied (5.2+/-2.3)mm
      under the inferior orbital fissure. The pterygoid canal lied (7.4+/-2.5)mm medial
      and (6.2.+/-4.2)mm inferior to the foramen rotudum. CONCLUSION: PPF has various
      shapes on axial and coronal CT images. Based on the distances and the
      relationship between the foramen and fissures, the normal and abnormal status of
      PPF can be evaluated.

PMID- 15014783
TI  - [Cephalometric analysis on patients with TMJ ankylosis in different ages].
AB  - OBJECTIVE: To determine the cephalometric characteristics of the patients with
      TMJ ankylosis in deferent ages and to find the relationship between the period
      with TMJ and the cephalometric characteristics. METHODS: By cephalometric
      analysis of 46 male patients with TMJ ankylosis and several normal people in
      deferent ages, we detected the relationship among the ages of the patients, the
      period with TMJ ankylosis and the cephalometric characteristics by means of SPSS
      for Win 95/98. RESULTS: The cephalometric characteristics of the patients showed
      their maxilla and mandible retruded in posterior and superior direction, the
      hyoid bone displaced posteriorly and inferiorly. The middle and inferior
      pharygeal space decreased, the TSA/OPA increased significantly. There was an
      obvious positive correlation between the period with TMJ and hyoid bone
      position(r=0.46, p=0.009; Y=1.58+0.56X), and remarkable positive correlation
      between the period with TMJ and TSA/OPA(r=0.5, p=0.00 Y=72.76+0.64X). CONCLUSION:
      In patients with TMJ ankylosis, the mandible and maxilla retruded posteriorly and
      superiorly,the hyoid bone displaced posteriorly and inferiorly, the middle and
      inferior pharygeal space decreased, the TSA/OPA increased remarkably. The longer
      the period with TMJ ankylosis, the more serious the deformities of the patients
      in craniomaxillofacial region.

PMID- 15014785
TI  - [Preliminary study on diagnosis of tumor like Sjogren's syndrome].
AB  - OBJECTIVE: To explore the clinical features and diagnosis of tumor like Sjogren's
      Syndrome. METHODS: 22 cases with tumor-like Sjogren's Syndrome of parotid gland,
      50 cases with pleomorphic adenoma of parotid gland and 25 cases with
      adenolymphoma of parotid gland were studied retrospectively. RESULTS: Statistical
      analysis showed that tumor like Sjogren's Syndrome is predominantly in middle
      aged women (40-59y) with a woman to man ratio of 6.33:1. Patients commonly
      present with salivary gland swelling repeatedly,varying in size,response
      effectively with antibiotics, accompanying dry mouth,dry eyes and aching joints.
      The mass probably displays medium texture and smooth appearance. The discriminant
      functions with tumor like Sjogren's Syndrome, pleomorphic adenoma and
      adenolymphoma were also established. CONCLUSION: The discriminate functions
      provide a simple and practical method to diagnose tumor-like Sjogren's Syndrome.

PMID- 15014786
TI  - [Study of bracket placement with the preadjusted appliance for extraction cases].
AB  - OBJECTIVE: To determine the bracket placement with the preadjusted appliance for
      extraction cases. METHODS: Sixty finishing occlusions were chosen as Andrews
      stated at debonding. The placement of the incisor teeth bracket was in the middle
      of the clinical crown, and retention arch wire was straight wire without step
      bends. The measurement from the incisal or occlusal edges to the bracket center
      was the height of the placement of the bracket. In order to produce bracket
      placement chart, the values of measurements +0.5 mm and +1.0 mm were added for
      larger teeth, and -0.5 mm and -1.0 mm for smaller teeth. RESULTS: The placement
      in the second bicuspid and first molar was different between extraction cases and
      nonextraction cases. CONCLUSION: The bracket placement chart improves the
      accuracy of bracket placement with the preadjusted appliance for extraction
      cases.

PMID- 15014787
TI  - [Clinical evaluation of the paste of erythromycin ethylsuccinate-metronidazole CP
      for root canal sterilization].
AB  - OBJECTIVE: The infected root canal was sterilized by anti-bacteria compound paste
      and the efficacy was compared with FC. METHODS: According to the mixed infection
      in infected root canal of anaerobic bacteria and obligate anaerobe, the paste
      made of erythromycin ethylsuccinate, metronidazole and CP was selected to seal
      and sterilize the root canal. RESULTS: The clinical observation of 180 patients
      with entirely developed root apex of acute and chronic apical periodontitis shown
      that there was no significant difference comparing erythromycin ethylsuccinate
      metronidazole-CP with FC in root canal sterilization, therefore, the irritability
      and poisonousness of the paste can be reduced by using erythromycin
      ethylsuccinate metronidazole CP instead of FC. CONCLUSION: The root canal
      sterilization drug of erythromycin ethylsuccinate metronidazole-CP was a safe and
      effective method to promote the restoration of root apex diseases.

PMID- 15014788
TI  - [Binding ability of fluoride-resistant strains of S. mutans and S. sobrinus in
      vitro].
AB  - OBJECTIVE: To investigate the binding ability of S.mutans and S.sobrinus after
      their fluoride-resistant mutation. METHODS: The binding amount and binding
      percentage of S.mutans, S.sobrinus and their F-resistant strains to saliva-coated
      hydroxyapatite(SHA)were measured and compared by(3)H-labeled binding assay.
      RESULTS: The binding percentages of F-resistant and their parent strains had few
      difference(P>0.05) whereas the binding percentage of S.sobrinus was significantly
      lower than S.mutans (P<0.01). CONCLUSION: The data showed that the binding
      ability to SHA between F-resistant and F-sensitive S.mutans had no significant
      difference which indicated that the emerge of F-resistant strains could not
      reduce the cariogenicity of S.mutans and S.sobrinus.

PMID- 15014789
TI  - [Separation and identification of polyclonal antibodies against type II fimbriae
      of actinomyces viscosus 5951].
AB  - OBJECTIVE: This study was aimed to prepare the polyclonal antibodies against type
      II fimbriae of actinomyces viscosus 5951. METHODS: Purified type II fimbriae of
      actinomyces viscosus 5951 were obtained by physical and chemical ways. Then
      antibodies against type II fimbriae were prepared through immunity of poly ways
      and tested by double immunodiffusion. RESULTS: The molecular quality of type II
      fimbriae was 34ku.Concentration of antibodies against type II fimbriae reached
      1:64 after immunity of poly ways. CONCLUSION: The molecular quality of type II
      fimbriae was 34ku.The titre of the antibodies was 1:64, and had mild cross
      reaction with type I fimbriae.

PMID- 15014790
TI  - [Experimental studies on the diel rhythm changes of blood cAMP in growthing rats
      after mandibular retraction].
AB  - OBJECTIVE: To document the effect of orthopedic therapy on the metabolism of
      rats. METHODS: Exerting backwards force on rats mandible and measuring
      concentration of rats' blood cAMP in three groups with radio-immunity. Drawing
      the time-concentration curve and making cosine analysis. RESULTS: In natural
      state, there was a diel rhythm change of concentration of cAMP in rats'
      blood(P<0.05); After being imposed orthopedic forces to inhibit mandibular
      growth, the normal diel rhythm of cAMP in blood still existed(P<0.05). The
      results of parameter-comparison among groups were more complicated. CONCLUSION:
      Further research is needed to clarify the mechanism whether local orthopedic
      forces influence the body metabolism.

PMID- 15014791
TI  - [An analysis of metablic organic acid of anaerobes by gas chromatography].
AB  - OBJECTIVE: The purpose of this study was to test the reliability of measurement
      of metablic organic acid of anaerobic bacteria by gas chromatography for the
      identification of anaerobes. METHODS: The metablic organic acid of 60 strains of
      6 species of oral residential anaerobes were tested by gas chromatography
      qualitatively and quantitatively. RESULTS: It was found that the types and
      quantities of metablic organic acid of all anaerobes but two strains of
      lactobacillus were coincident with the standard of identification of
      anaerobes,and the total coincidence was 97.67%. CONCLUSION: The anaerobes could
      be identified accurately and quickly by gas chromatography.

PMID- 15014792
TI  - [Experimental study on using mGTR and silicone gel tube connection to repair
      facial nerve defect in rabbits].
AB  - OBJECTIVE: To observe and compare the effects of using mGTR or Silicone tube to
      repair the defect of facial nerve. METHODS: mGTR and Silicone tube methods were
      performed on three groups of rabbits. Then physical and histological examination
      was carried out to get the results of these two repair methods. RESULTS: Both the
      two methods can induce regeneration of facial nerve. The mGTR was more effective
      and faster in repairing the nerve defect. Three months after operation, the
      distance of NCV between the two sides of facial nerve in mGTR group was 2.33+/
      1.2 m/s, 10.21+/-1.5 m/s in Silicone tube group, and 2.16+/-1.6 m/s in
      autogeneous nerve transplantation group. CONCLUSION: The mGTR is more effective
      than Silicone tube method in repair facial nerve. mGTR has some other advantages,
      it is likely to be a new method of nerve repair on clinical domain.

PMID- 15014793
TI  - [The TEM investigations of lymphatic vessels in the acute inflamed dental pulps].
AB  - OBJECTIVE: The purpose of this study was to investigate the possible
      ultrastructural modifications of the lymphatic capillaries in the acute inflamed
      dental pulps. METHODS: The ultrastructural features of the lymphatic vessels
      endothelial wall in the human normal and acute inflamed dental pulps were
      investigated by TEM using conventional methods. RESULTS: The lymphatic
      capillaries in normal dental pulp were characterized by a thin wall with an
      irregular profile. The endothelial cells were joined one another by specialized
      junctional complexes, such as end-to-end contacts, overlapping and more complex
      interdigitation. Opening junctions were never present in these vessels. The
      cytoplasm of the endothelial cells was rich in micropinocytotic vesicles. In the
      acute inflamed pulpal tissue, the lymphatic vessels were dilated and the
      intercellular adjoining structure were less intricate, end-to-end contacts and
      overlaping were most frequent ones. Opening junctions were frequently detectable.
      In particular, the micropinocytotic vesicles were almost absent. CONCLUSION: In
      the acute inflamed pulpal tissue, the modification occurs in the diameter of
      lymphatic capillaries, intercellular adjoining structures and the amounts of
      micropinocytotic vesicles, so we thought that a network of lymphatic vessels
      drained the dental pulp.

PMID- 15014794
TI  - [Apoptosis of Tca8113 cells induced by cisplatin and their cell cycle
      specificity].
AB  - OBJECTIVE: Evaluating the effect of apoptosis induced by cisplatin in human oral
      squamous cell carcinoma cells and their cycle specificity. METHODS: Hu man tongue
      squamous cell carcinoma cell line Tca8113 was used in vitro as a study object.
      Morphological features of apoptotic cell induced by cisplatin were observed by
      using of microscope, fluorescence microscope and transmission electronic
      microscope (TEM). The apoptotic rates were analyzed by DNA fluorescence staining
      assay and TEM observation. The cell cycle specificity was measured by using flow
      cytometry. RESULTS: The cell proliferation of Tca8113 cells was inhibited by
      cisplatin and their proliferation index decreased. Cells treated with cisplatin
      became smaller, rounded and then disattached. Red nuclear fragmentation with
      condensed chromatin was observed under fluorescence staining assay. Condensation
      and crack of nucleus and apoptotic bodies appeared in apoptotic Tca8113 cells
      observed under TEM. Cell cycle of Tca8113 cells was apparently arrested at S by
      cisplatin. CONCLUSION: Apoptosis was induced by cisplatin in Tca8113 cells, and
      it may be an important mechanism of SCC killed by cisplatin.

PMID- 15014795
TI  - [Preliminary clinical study on krypton laser photodynamic therapy for PWS].
AB  - OBJECTIVES: In order to explore an ideal PWS treatment, which could destroy the
      capillary of lesion without any damage to skin. Based on principle of improving
      elective therapeutic efficacy of photodynamic therapy, new Krypton laser PDT was
      introduced to this preliminary clinical trial. MATERIALS AND METHODS: The
      absorptive spectrum was measured on photosensitizer PsD-007. The therapeutic
      laser dosage and result and side effect were surveyed. Twenty cases of PWS were
      randomly selected by means of self-control. 413 nm wavelength laser PDT was
      carried on those patients. Lesion responses were investigated at different phases
      after treatment. More attention was paid to the result and side effect. Biopsy
      was taken from one case. RESULTS: PsD-007 has the soret peak at 408 nm. There was
      purplish reaction within a week, which disappeared spontaneously within two
      months. Lesion blanch with neither weeping soakage nor scar formation. All cases
      got dramatically blanch of lesions. Histological finding revealed red blood cells
      leaking through broken vessels, while dermal remained normal. CONCLUSION: 413 nm
      Krypton laser PDT had target elective effect, which had satisfactory result. It
      suggested good potential plication.

PMID- 15014796
TI  - [Derma spectrometer measurement for port wine stain].
AB  - OBJECTIVE: Twenty cases of PWS were measured by means of Derma Spectrometer with
      the goal of estimating PWS condition. MATERIALS AND METHODS: Twenty patients of
      PWS were chosen randomly in this study. Derma Spectrometer was used to detect
      lesion and control sides pre- and post- laser treatment. RESULTS: The mean normal
      skin's M-Index was (36.18+/-6.45)%, E-Index was (1.39+/-4.85)%. Lesion's M-Index
      and E-Index were (44.85+/- 6.61)%, (13.05+/-6.30)%. Lesion's M-Index and E-Index
      after one treatment were (41.00+/-5.30)% and (9.04+/-4.98)%. Significant
      difference existed between normal and lesion's M-Index. Also there were
      difference among normal skin, lesion and lesion treated. CONCLUSION: There is
      difference between normal and lesion M-Index. But none for lesion and lesion
      treated. Different E-Index were among normal skin, lesion and treated lesion. The
      E-Index was decreased at treated lesion. It suggested blanch of PWS after laser
      treatment. Derma spectrometer has the role of evaluation of PWS.

PMID- 15014797
TI  - [Comparative research on mixed and 488 nm argon laser PDT for port wine stain].
AB  - OBJECTIVE: In order to search a safer argon laser photodynamic method, this study
      used 488 nm wavelength and common mixed spectrum argon laser PDT for treating
      Port Wine Stain. The therapeutic effects and side effect were compared. METHODS:
      Fifty two cases of PWS were divided into two groups randomly. Argon laser PDT by
      two ways of laser irradiation were used. RESULTS: Our data revealed 19.23% cure
      rate in 488 nm laser PDT group, while that of mixed wavelength laser group was
      11.54%. There was no significant difference in the two groups. Also the effective
      rate of 488 nm laser group was 92.31% and that of mixed group was 88.46%. But the
      difference was not significant statistically. Side effect occurred often in mixed
      spectrum laser group. That was 57.69% for mixed group, 38.46% for 488 nm group.
      CONCLUSION: Argon laser PDT at 488 nm had the similar therapeutic result
      contrasted to mixed spectrum laser group, but it was safe.

PMID- 15014798
TI  - [Investigation of deciduous teeth caries in children under 14-year-old].
AB  - OBJECTIVE: To investigate the caries prevalence of children under 14-year-old in
      three districts (Nanshi,Luwan,Xuhui) of Shanghai. To provide the first-hand data
      for prevention of children caries. METHODS: The standard of second whole national
      investigation regime of oral epidemic disease was used. RESULTS: When the
      children grow up,the caries incidence and dft increased. In 7-year-old group the
      values were 83.33% and 3.78,respectively. After that the values decreased for the
      alternation of deciduous teeth and permanent teeth. The caries incidence was
      almost the same in boys and girls. The caries incidence in lower jaw was higher
      than that in upper jaw. The caries incidence was highest in lower jaw D and E.
      The lowest caries incidence was found in lower jaw A and B. The incidence and dft
      decreased compared with before. At the same time, the filling rate of deciduous
      teeth also decreased. CONCLUSION: The oral hygiene knowledge for children is
      disseminated. It is important for children to find a solution to improve the
      filling rate of deciduous caries.

PMID- 15014799
TI  - [The application of directional force in Tweed-Merrifield philosophy to the
      treatment of class II division I malocclusion].

PMID- 15014800
TI  - [Preservative treatment of the residual root and crown of the molars].

PMID- 15014801
TI  - [Clinical evaluation of 99mTc and ultrasonic B in diagnosis of parotid gland
      tumor].

PMID- 15014802
TI  - [The factors affecting the adaptability of colour in metal ceramic crowns].

PMID- 15014804
TI  - [An orthodontic approach for the treatment of periodontically involved teeth].

PMID- 15014803
TI  - [The effect of CO2 laser combined with chloroquini phosphate in the treatment of
      oral lichen planus: report of 80 cases].

PMID- 15014805
TI  - [The expression of oncoprotein p53 and C-erbB-2 in squamous cell carcinomas of
      oral mucosa and the epithelium adjacent to the tumors].

PMID- 15014806
TI  - [Experience of treatment of teeth with abnormal pulp chambers].

PMID- 15014808
TI  - The role of tissue engineering in maxillofacial reconstruction: past, present and
      the future.

PMID- 15014807
TI  - [Autologous tissue engineered skin for full thickness skin replacement].
AB  - OBJECTIVE: To evaluate the feasibility of regenerating or repairing damaged skin
      utilizing tissue engineering techniques. MATERIALS AND METHODS: Yorkshire pigs
      were used in the study. A critical size defect of six, full thickness, 4 cm in
      diameter round wounds, which were marked on the paravertebral region of the
      animal were excised. The skin defects were randomly divided into three groups.
      Group I as control group received no cells or polymer. Group II as a second
      control group received pluronic hydrogel with no cells. Group III as the
      experimental group received a mixture of cells (keratinocytes and fibroblasts)
      and pluronic hydrogel. All specimens were harvested at 4 and 6 weeks in vivo, and
      underwent gross, histological, and transmission electron microscope evaluation.
      RESULTS: Histologically, the skin in the experimental group was similar to normal
      skin with stratified epidermis overlying a moderately thick collageneous dermis.
      The interface of the tissue was apparently demarcated by epidermal ridges and
      dermal papillae. The control groups showed no skin formation except for
      granulation with infiltrating inflammatory cells in the wound. Transmission
      electron microscopy showed that the basal lamina of the experimental group was
      well developed and attached to the extracellular matrix. CONCLUSION: This finding
      demonstrates the successful use of tissue engineered skin with Pluronic F-127 as
      a cell carrier.

PMID- 15014809
TI  - [Experimental study of abnormal cell proliferation and differentiation in rat
      tongue carcinogenesis induced by 4NQO].
AB  - OBJECTIVE: To clarify the phenotypic characteristics of abnormal cell
      proliferation and differentiation in oral carcinogenesis. METHODS: The
      expressions of gp230, a marker of epithelium cell differentiation, and
      proliferating cell nuclear antigen (PCNA) in rat tongue carcinogenesis induced by
      4-nitroquinoline-1-oxide (4NQO) were detected by LSAB immunohistochemical
      staining. RESULTS: With the progress of oral carcinogenesis abnormal
      proliferation and differentiation patterns were indicated by reduced expression
      of gp230 and increased expression of PCNA. CONCLUSION: Oral carcinogenesis is the
      result of mucosa epithelium cell aberrant proliferation and differentiation.

PMID- 15014810
TI  - [In vitro study of Streptococcus mutans in the plaque on the surface of amalgam
      fillings on the conversion of inorganic mercury to organic mercury].
AB  - OBJECTIVE: To study the Streptococcus mutans in the plaque on the surface of
      amalgam fillings on the conversion of inorganic mercury to organic mercury.
      METHODS: Plaque was sampled from the amalgam restorations after amalgam filling
      regularly, serving the unfilled tooth as control. Streptococcus mutans was
      identified and inoculated to 10 ml TSB. After incubated 24 hours, mercury in
      water was added to the concentration of 100 ng/ml, incubated 24 hours again, the
      concentration of inorganic and organic mercury was determined. RESULTS: It was
      found that the difference of organic mercury and organic mercury between the
      baseline and the times after amalgam filling in test group and control was
      significant, while the difference between the times after amalgam filling was not
      significant, and the difference between the test group and the control was not
      significant, either. CONCLUSION: Streptococcus mutans can convert inorganic
      mercury to organic mercury in some way, and the mercury of amalgam plays some
      role in it.

PMID- 15014811
TI  - [Experimental study of mandibular reconstruction with Sr-HAP].
AB  - OBJECTIVE: Different ration of Sr-HAP was implanted in animals to study the
      bioreactions in order to prepare for the clinical applications in future.
      METHODS: 24 rabbits were divided into 3 groups for study.Bone defect of 6 x 12 x
      4 mm was made at the mandibular angle of rabbits and Sr-HAP of different
      proportion (10%,5%,0%) was applied to repair the defect. One group of animals
      were killed at 1 month, 3 months, 6 months to evaluate the biologic capacity with
      anatomy, tetracycline fluorescent marker and ration histology. RESULTS: Sr-HAP
      almost hadn't been rejected by hosts, and early after operation the new bone in
      the Sr-HAP was found with great quantities as the degradation of Sr-HAP much more
      than that in the pure HA, and the difference of bone quantity can be shown in
      statistics. New bone in 5% Sr-HAP looked more mature than those in 10% Sr-HAP
      with no statistic difference in quantity. Strong and bright fluorescent rings can
      be seen around Sr-HAP from the 3 months to 6 months. CONCLUSION: (1) Sr-HAP has a
      better biocompatibility, biodegradation than pure HA and an excellent
      osteoinductivity. (2) The ration of strontium isn't the key influencing the new
      bone quantity,total new bone quantity maybe associated with the degree of
      biodegradation. (3) The existence of Sr-HAP improves the total new bone quantity
      and prolongs the period of new bone increasing.

PMID- 15014812
TI  - [The use of two-route Cisplatin chemotherapy in the treatment of oral squamous
      cell carcinoma].
AB  - OBJECTIVE: To study the feasibility and efficacy of two-route cisplatin
      chemotherapy for locally advanced squamous cell carcinoma of oral cavity.
      METHODS: 23 cases with clinical advanced biopsy-proven oral squamous cell
      carcinoma received intraarterial chemotherapy with cisplatin (DDP), Pingyangmycin
      (PYM) and 5-fluorouracilum (5-Fu), at the same time intravenous infusion with
      natrii thiosulfas (STS) for rescue. DDP at 40-60 mg/d, PYM at 16 mg/d and 5-Fu at
      500 mg/d were applied for 5-7 consecutive days. RESULTS: 7 cases (33.3%) obtained
      a complete response (CR), 11(52.4%) had partial response (PR) with an objective
      response rate (RR) of 85.7%. No severe toxicity was observed, whereas the most
      frequent grade I and II drug related toxicities were nausea and vomiting. No
      nephrotoxicity,hepatotoxicity and severe bone marrow suppression were noted.
      CONCLUSION: Two-route cisplatin chemotherapy is, in our experience,a
      new,effective and safe therapeutic method for oral squamous cell carcinoma.

PMID- 15014813
TI  - [Open operation of the vertical condylar fracture].
AB  - OBJECTIVE: This article is mentioned to study the incidence, diagnosis,
      management of the vertical condylar fractures. METHODS: 11 patients, 14 cases of
      the vertical condylar fractures, were treated in our department between June 1997
      and August 1998. All the patients were diagnosed through history, physical
      examination, radiographs, computed tomography scan and three-dimensional
      reconstruction of a computed tomography scan, treated with various surgical
      approaches. RESULTS: All the patients had got satisfactory postoperative result
      in the aspects of occlusion, degree of opening, joint noise, pain in the area of
      temporomandibular joint, deviation in mandibular motion and healing of the
      incision. CONCLUSION: Enough attention should be paid to the vertical condylar
      fractures. The key to a successful open operation is the correct diagnosis, the
      accurate reduction and the stable fixation.

PMID- 15014814
TI  - [Early cracked teeth: clinical analysis of 70 cases].
AB  - OBJECTIVE: To determine the clinical features and x-ray findings in early cracked
      teeth,in order to provide theoretical basis. METHODS: 86 cracked teeth in 70
      cases were reviewed. Analysis of x-ray and articulation paper examination was
      combined. The teeth were repaired with composite resins. RESULTS: The study
      showed that the incidence of cracked first maxillary molar was highest in
      patients aged form 40 to 50 years. X-ray demonstrated characteristic changes of
      the diseased periodontal tissues in 57% teeth. Contour deformities were found in
      19% affected roots. The efficacy rate 1 year after treatment was 90.9%.
      CONCLUSION: The features of periodontal supporting tissues illustrating on x-ray
      films are considered to be useful to aid the diagnosis and treatment of early
      cracked teeth.

PMID- 15014815
TI  - [Classification of the orbital margin fractures].
AB  - OBJECTIVE: To study the classification of the orbital margin fractures. METHODS:
      There are 65 cases of the orbital margin fractures classified by Reduction
      Orbital-Classification from January 1995 to December 1999 in Macau Conde de Sao
      Juanuario Hospital. RESULTS: The 65 cases are classified into six type: I Stable
      orbital fracture, II Orbital floor (blow-out) fracture, III Orbital-zygomatic
      fracture, IV Orbital-naso-maxillary fracture, V Comminuted fracture of the
      inferior orbital rim, VI Complex orbital fractures. CONCLUSION: The Reduction
      Orbital-Classification are a complete, precise, practical, simple way for the
      orbital fractures; It not only presents the exist of the orbital margin fractures
      but also means the Classification for convenience of the treatment and treatment
      guiding the classification.

PMID- 15014816
TI  - [The management of 126 cases of posterior cracked crown of tooth and its
      effective observation].
AB  - OBJECTIVE: To detect the treatment and effect of posterior cracked tooth.
      METHODS: 162 posterior cracked teeth of 158 cases, including enamel fissure and
      dentin fissure, all there cases undergone the synthetical treatment and follow up
      in different period, the longest observation period was 2.5 years. RESULTS: The
      healing and improved rate of 162 cracked teeth 90.74%. Among cases of failure, we
      have founded 6 cases of acute pulpitis (3.7%), 3 cases of alveodental abscess
      (1.85%), 2 cases of chronic apical periodontitis (1.24%), 4 cases of tooth
      fracture (2.4%). CONCLUSION: Cracked tooth was caused by multiple factors. Early
      diagnosis, synthetical treatment, and follow up in different period are 3 main
      factors in treatment.

PMID- 15014817
TI  - A tissue engineering approach to site specific reconstruction of skeletal
      structures of the maxillofacial region: part II.

PMID- 15014818
TI  - [The experimental study of tissue engineered mandible condyle in the shape of
      human].
AB  - OBJECTIVE: This study evaluates the feasibility of creating a tissue engineered
      adult human mandible condyle composite of bone and cartilage. METHODS: A polymer
      template formed in the shape of the human mandible condyle using a scaffold
      composed of polyglycolic acid (PGA) and polylactic acid (PLA) was seeded with
      osteoblasts isolated from a bovine periosteum suspended in calcium alginate.
      Chondrocytes isolated from the same calf suspended in 30% pluronic were then
      "painted" onto the articular surface of the scaffold and implanted into
      subcutaneous pockets on the dorsa of athymic mice. Animals were divided into
      three groups: Group I (n=6) received PGA/PLA scaffold saturated with hydrogels
      not containing cells. Group II (n=6) received scaffolds seeded with both cell
      types suspended in saline rather than hydrogels. Group III (n=6) received
      scaffolds seeded with both cell types suspended in hydrogel composites.
      Constructs were harvested after 12 weeks, and evaluated grossly and
      microscopically using histologic stains. RESULTS: In group I, constructs formed a
      small mass without evidence of new bone or cartilage. In group II, constructs
      were small and irregular in shape. Microscopically they contained scattered
      islands of bone and cartilage. All specimens in group III retained their original
      condylar shapes and were quite firm in consistency. Microscopic evaluation
      revealed trabecular bone interfacing with hyaline cartilage on its articulating
      surface. CONCLUSION: These findings demonstrate that the composites of bone and
      cartilage can be engineered to serve as mandibular condylar substitutes. The
      interdigitation of bone and cartilage at their interface is similar to the normal
      interface of these composite tissues seen in articulating joints.

PMID- 15014819
TI  - [Study on midazolam used for awake blind intubation of maxillofacial surgery].
AB  - OBJECTIVE: To provide clinical data for midazolam to be used as an assistant drug
      for awake tracheal intubation. METHODS: 40 cases for maxillofacial surgery were
      selected and divided into 2 groups randomly with each group 20 cases. All cases
      received awake intubation using blind tracheal intubation instrument 5 minutes
      before intubation, patients in group 1 were administered fentanyl 4 microg/kg and
      midazolam 0.04 mg/kg by vein,patients in group 2 were only injected fentanyl 4
      microg/kg. The changes of sedation score (Ramsay score), bispectral analysis of
      electroencephalogram (BIS), heart rate (HR), mean artery pressure (MAP),
      respiration rate (RR), blood oxygen saturation of pulse (SpO(2)) and the incident
      rate of amnesia in the two groups at T1 (before administering drug), T2 (just
      before starting intubation), T3 (when oesophagus tracheal introducer was just
      located properly), T4 (when light cable was just inserted into tracheal) and T5
      (when tracheal tube was just inserted into tracheal) were observed. RESULTS: (1)
      To be compared with T1, Ramsay score increased and BIS decreased obviously
      (P<0.05) in group 1 after T2. (2) To be compared with T1, MAP and HR rose
      significantly (P<0.05) in group 2 after T3. (3) After T3, RR was obviously lower
      than T1 (P<0.05) in the two groups,but there was no change in SpO(2). The
      incident rate of amnesia for intubation procedure was 65% in group 1, and it was
      remarkly greater than that in group 2 (P<0.05). CONCLUSION: Midazolam can produce
      a good effect of sedation and anterograde amnesia, it is a proper assistant drug
      for awake intubation.

PMID- 15014820
TI  - [Evaluation of bispectral analysis of electroencephalogram in monitoring
      postanesthesia recovery of cleft palate surgery].
AB  - OBJECTIVE: To study the value of bispectral analysis of electroencephalogram in
      monitoring postanesthesia recovery of cleft palate surgery. METHODS: To select 30
      cases who were administered general anesthesia for cleft palate surgery, to
      monitor their postanesthesia recovery using bispectral analysis of
      electroencephalogram,and to observe the change of BIS in the different stage of
      recovery. RESULT: BIS increased gradually (P<0.05) following the patient
      cumulation percentage also rose progressively in the different stage of recovery,
      the graph of patient cumulation percentage BIS shifted to right. There was a
      significant linear correlation (r=0.84, P<0.05) between BIS and recovery score.
      CONCLUSION: The study suggests that it is simple and reliable for BIS in
      monitoring postanesthesia recovery of cleft palate surgery.

PMID- 15014821
TI  - [Epidemiology of dental caries and periodontal diseases in middle school students
      in Suzhou City].
AB  - OBJECTIVE: To assess the prevalence of dental caries and periodontal diseases in
      middle school students at the ages of 11 to 13 and 15 to 17. METHODS: Dental
      caries and periodontal diseases were assessed strictly by "national survey table
      of dental caries and periodontal diseases for school students". RESULTS: The
      study group consisted of 20 581 students. The percentage of dental caries, DMFT
      and DMFS in students 11 to 13 years of age were 23.6%,0.40 and 0.54,
      respectively. The corresponding results were 29.76%, 0.64 and 0.87 for students
      15 to 17 years of age, respectively. The percentage of gingivitis and dental
      calculus in students 11 to 13 years were 75.33% and 35.86%, respectively. The
      corresponding values in students 15 to 17 years of age were 73.1% and 44.91%,
      respectively. Female students have significantly few gingivitis and dental
      calculus than male students in both groups. CONCLUSION: Compared with the
      students at the same ages in other cities, students in Suzhou city have low
      percentage of dental caries and periodontal diseases.

PMID- 15014822
TI  - [Histologic study on impeding leukoplakia carcinogenesis of golden hamster cheek
      pouch about Erigeron breviscapus (Vant) Hand-Mazz].
AB  - OBJECTIVE: To observe the effect of Erigeron breviscapus (Vant) Hand Mazz (HEr)
      in impeding oral leukoplakia carcinogenesis, and to seek effective Chinese herb
      medicine that can impede precarcinoma of oral mucosas. METHODS: 132 golden
      hamsters were randomly divided into model group (60 animals), HEr group (60
      animals), and control group 12 animals. Salley's leukoplakia carcinogenesis model
      of golden hamster cheek pouch was used in this study. HEr was injected into the
      stomach to impede evolution of carcinogenesis. Pathological specimens were
      observed via naked eye and light microscope between model group and HEr group.
      Results were compared. RESULTS: Observation via naked-eye showed that leukoplakia
      rate of HEr group (18.2%) was lower than that of model group (27.3%). Observation
      via light microscope showed that carcinogenesis rate descended one fold and
      displasia rate descended 0.4 fold in HEr group. CONCLUSION: HEr has exact effect
      in impeding leukoplakia carcinogenesis.

PMID- 15014823
TI  - [Observation on alpha-SMA during Erigeron Breviscapus (Vant) Hand-Mazz obstructs
      the evolution of carcinogenesis of golden hamster cheek pouch].
AB  - OBJECTIVE: To observe dynamically that Erigeron Breviscapus (Vant) Hand-Mazz
      (HEr) affects the expression of alpha-smooth muscle actin (alpha-SMA). To discuss
      the probable mechanism of obstructing leukoplakia carcinogenesis of this
      medicine. METHODS: 120 golden hamsters were randomly divided into model group
      (48), HEr group (48) and control group (6). HEr was applied to obstruct the
      evolution of carcinogenesis of golden hamster cheek pouch. Immunohistochemistry
      was used to detect the expression level of alpha-SMA with cheek pouch specimen
      that besmears DMBA in 4-9 weeks. Results were compared with model group. RESULTS:
      Vessel density dyed with alpha-SMA continuously of HEr group was 65.76
      significantly higher than that of model group 42.12 (P<0.001). High
      classification cases in HEr group were much more than model group when cases were
      divided into five groups as follow: 100%, 50%, 20%, 10%, 3% (P<0.01). CONCLUSION:
      HEr can raise the expression level of alpha-SMA exactly during the evolution of
      leukoplakia carcinogenesis of golden hamster, which shows that this medicine
      obstructs carcinogenesis by keeping the normal physiological function of vascular
      myoepithelial cell and integrity of vascular basement membrane.

PMID- 15014824
TI  - [Study of resisting leukoplakia canceration and angiogenesis of Herba
      Erigerontis].
AB  - OBJECTIVE: To evaluate the effect of resisting canceration of Herba Erigerontis
      HEr and that of angiogenesis; seek the mechanism of angiogenesis. METHODS: 150
      golden hamsters were randomly divided into model group (66 animals), HEr group
      (66) and control group (18). Carcinomatous conversions of golden hamster cheek
      pouches induced by Sally way and interrupted by Herba Erigerontis. Ink perfusion,
      analysis of images, resin cast form of micro vessel, alpha-SMA detection and
      histopathological examination were applied to observe their changing patterns.
      RESULTS: The rate of leukoplakia canceration of Herba Erigerontis group was 50%
      lower than that of model group. The rate of normal cells was about four times
      more than that of model. alpha-SMA of Herba Erigerontis 65.76 was higher than
      that of model (P<0.001). There was no significant difference between angeion
      vessel area and density (P>0.05). Nevertheless, the resin cast form of micro
      vessel showed that its configuration and spacious arrangement was similar to
      control group. CONCLUSION: Herba Erigerontis has the function of preventing
      leukoplakia canceration absolutely. Maybe its mechanism is to upregulate the
      expression of alpha-SMA. It has no obvious effect of angio-hyperplasia and
      expansion in the course of leukoplakia canceration. However, it has the
      protecting function to angio-configuration and spacious arrangement and the
      integrity of angeion vessed wall. Probably its mechanism is promoting blood
      circulation by removing blood stasis and benign angiogenesis so as to resist
      canceration.

PMID- 15014825
TI  - [Preliminary clinical application of DNL for treatment of oral squamous cell
      carcinoma modified with TNF-alpha gene].

PMID- 15014826
TI  - [Treatment of dentin hypersensitivity with versatile therapeutic
      apparatus:analysis of 144 cases].

PMID- 15014827
TI  - [Use of the oblique third mandibular molar as the abutment for fixed bridges].

PMID- 15014828
TI  - [Clinical observation of thymosin and anti-inflammation for treatment of juvenile
      recurrent parotitis].

PMID- 15014829
TI  - [Removal of a broken needle in the left pterygoid fossa: report of one case].

PMID- 15014830
TI  - [Treatment of dry socket with tinidazole: clinical report of 38 cases].

PMID- 15014831
TI  - [Gorlin-Goltz syndrome with ophthal mosteresis: case report].

PMID- 15014832
TI  - [The clinical pathological observation of hemangioma treated by pingyangmycin].

PMID- 15014833
TI  - [Application of Begg's technique in correction of malocclusion with
      periodontitis].

PMID- 15014834
TI  - [A preliminary study on fimbriae subunits and molecular weight of actinomyces
      viscosus 5951]
AB  - OBJECTIVE:To preliminarily analyse the subunits and molecular weight of fimbriae
      of actinomyces viscosus 5951.METHODS:To do the immunoblotting test of the only II
      fimbriae type of mutant strain of T14V.RESULTS:It showed that there was only one
      31ku band,which indicated that the fimbriae of actinomyces viscosus 5951 was
      composed of the same subunits of 31ku molecular weight. CONCLUSION:According to
      the previous reports and results of present study,the molecular weight of
      fimbriae of actinomyces viscosus 5951 was speculated to be 124ku and the fimbriae
      was composed of 4 same subunits.

PMID- 15014835
TI  - [The Inhibitory Study of TNP  470 Combined CDDP on the Tumor Growth and Lung
      Metastasis of Adenoid Cystic Carcinoma ACC  M in Nude Mice]
AB  - OBJECTIVE:To study the effect of TNP-470 combined CDDP on the tumor growth and
      lung metastasis of cell strain ACC-M in vivo. METHODS:High  potential lung
      metastatic adenoid cystic carcinoma cell strains (ACC-M) 5x10(5) were injected
      simultaneously to 18 nude mice subcutaneously and enously. The animals were
      randomly divided into 3 groups. In group 1, TNP-470 was administered
      subcutaneously at the dose of 30mg/kg every other day for 2 weeks from the
      beginning of 3(rd) week to the end of 4(th) week. In group 2, 5mg/kg CDDP were
      injected into peritoneal cavity at the beginning of 3(rd) week and 4(th) week and
      TNP-470 in the same manner as group 1 additionally. In group 3, the same volume
      of 0.97% NaCl was injected in the manner of group 1. The mice were sacrificed by
      dislocating the neck at the end of 4 weeks. The tumor size and weights were
      recorded. The vascular density was measured by rabbit-anti-human factor VIII
      antibody stain. The results were analyzed by Student t and X(2) test.
      RESULTS:Group  1 and group  2 had fewer tumor weight and lung metastasis than the
      3(rd) group. There was significant difference in the tumor weight and lung
      metastasis between group  1 and group  2. But the vascular density had no
      difference among three groups. CONCLUSION:TNP-470 combined CDDP has stronger
      inhibition on both the tumor growth and lung metastasis of human adenoid cystic
      carcinoma ACC-M than used alone.

PMID- 15014836
TI  - [Three  dimensional Finite Element Analysis of the Effects of Posts and Cores
      with Different Angles]
AB  - OBJECTIVE:The test is an analogue of the conditions that cast post and core can
      be made with different angles to get the core incline lingually or facially in
      clinic, so that the arrangement of the anterior teeth may be
      improved.METHODS:Analyse the stress distribution and concentration in the dentin
      of posts and cores with different angles by Ansys three  dimensional finite
      element stress analysis method.RESULTS:The stress in root was positively related
      to the angles between the load and the axis of the tooth, the stress distributoin
      in dentin was related to the direction of the core but not related to the angles.
      The closer the distance from the load to cemento  enamel junction,the greater the
      effect of the load on the stress in dentin.CONCLUSION:When the cast post and core
      with angle was used to rectify the facially malpositional maxillary anterior
      teeth, the core should not be inclined lingually excessively. It is important to
      assure the thickness of the facial and lingual canal wall during tooth preparing
      and to adjust the occlusion so that the root fracture can be avoided.

PMID- 15014837
TI  - [Application of Continuous Wave Nd:YAG Laser Irradiation in the Management of
      Cavernous Hemangioma of Deep Oral-Maxillofacial Regions]
AB  - OBJECTIVE:Based on our previous clinical report of Nd:YAG laser irradiation as
      the means for deeling with cavernous hemangioma in deep oral-maxillofacial
      regions, this article detailed futher clinical application of this laser, trying
      to set up a non-surgical method for treatment of ang ioma. The relationship of
      laser dosage and therapeutic effect and possible surrounding tissue thermal
      damages were investigated.METHODS:Clinical study was carried out on 31 cases of
      deep hemangiomas involving different areas. Nd:YAG laser irradiation was
      delivered after surgical elevation of the flaps. All cases surveyed a follow  up
      of 1.5 to 3 years.RESULTS:Posttherapeutic clinical and imaging examinations were
      taken to compare the findings before and after treatment. There are 29 cases with
      complete regression (93.55%), 2 cases with partial regression (6.45%). No
      complication occurred.CONCLUSION:Nd:YAG laser irradiation after flap elevation
      has been confirmed to be a valuable means to treat deep hemangiomas. It has the
      advantages of target tissue selection and normal tissue preservation, simplified
      manipulation and less bleeding, fewer complications and hihger successful rate.

PMID- 15014838
TI  - [Clinical observation of semiconductor laster for treatment of hypersensitivity
      of the dentine]
AB  - OBJECTIVE: Observation of clinical results and SEM features in treatment of
      hypersensitive dentine by semiconductor laser.METHODS:Semiconductor laser was
      compared with conventional NaF method for the treatment of 100 teeth with typical
      hypersensitive dentine which were divided into two groups.RESULTS:The efficiency
      of the laser group was 96%,while that of NaF group was 76%.The laser irradiation
      could decrease hypersensitive dentive. There was marked difference between two
      groups.It was testified by SEM that the dentinal tubule was sealed by
      semiconductor laser irradiation.CONCLUSION:The safe,effective and easy methods
      was provided for treating the hypersentitive dentive by use of semiconductor
      laser.

PMID- 15014839
TI  - [The transfusion and blood transfusion in pediatric patients with palatoplasty]
AB  - OBJECTIVE: To study whether the pediatric patients with palatoplasty needs blood
      transfusion and the rational combination of transfusion during operation,in order
      to provide a basis for the management of clinical anesthesia and postoperative
      recovery in children.METHODS:20 subjects without blood transfusion were
      selected,the combination of transfusion during the operation was 5% glucose
      solution,sodium lactate ringers solution,gelofusine.The intraoperative and
      postoperative circulation, hemoglobulin, hematocrit were compared with the
      preoperative data.RESULTS:Both the intraoperative and the postoperative
      circulation of all subjects were steady, having no significant difference from
      the data base(P>0.05), the values of hemoglobulin and hematocrit descended,but
      were in the normal limit(P>0.05).CONCLUSION: During palatoplasty in pediatric
      patients, if transfusion was apporpriate, steady circulation can be substained
      without boold transfusion,which saved the blood, and avoided the side effects of
      blood transfusion.

PMID- 15014840
TI  - [Clinical analysis on 238 cases of longitudinal fracture of posterior teeth]
AB  - OBJECTIVE:To investigate the characteristics and clinical features of the
      longitudinal fractures of posterior teeth and evaluate the therapeutic
      methods.METHODS:The records of 238 cases with the longitudinal fractures of
      posterior teeth were analyzed retrospectively. The clinical features were sum med
      up. Eextractions of teeth were performed in 108 patients, and the conservative
      therapies in 130.RESULTS:The incidence of longitudinal fractures of posterior
      teeth was highest in the 30-59 years. The rate between male and female was 4:3.
      The longitudinal fractures of posterior teeth most occurred in the first molar of
      the maxilla with endodontic treatment. The follow  up peroid was more than 2
      years in 83 cases. The success rate was 75/83. CONCLUSION:The longitudinal
      fractures of posterior teeth can be cured by early fixation, and prevented by
      avoiding dysfunctional bite, treating subclinical fracture, and using proper
      methods of treatment of endodontics.

PMID- 15014841
TI  - [Pseudoaneurysm of the left internal carotid artery:case report]

PMID- 15014842
TI  - [Staining of complete denture: a preliminary clinical study]
AB  - OBJECTIVE:To study the relation between staining of complete denture and drinking
      tea, coffee and smoking, and to evaluate the result of denture  cleaning agent on
      removing stain of complete denture.METHODS:A survey of 176 patients with complete
      dentures were carried out, which included the history of drinking tea, coffee and
      smoking, the use of denture-cleaning agent and the times of daily use.
      Statistical analysis was performed to determine the relationship between staining
      of denture and the above factors. RESULTS:The results showed (1)The longer the
      complete denture was weared, the more serious the staining. (2)Drinking tea and
      smoking were the main causes for denture staining. (3)Daily use of cleaning agent
      can effictively remove stain of denture. CONCLUSION:Change of life habit(drinking
      less tea and stop of smoking) and daily use of cleaning agent can reduce denture
      staining.

PMID- 15014843
TI  - [A study on dental and cranioficial structure of normal shanghai adults occlusion
      I the craniofacial structure analysis with posterioanterior cephalometric
      roentgenography]
AB  - OBJECTIVE: To evaluate the characteristics of normal transverse craniofacial
      structure in Shanghai area and to establish the database of normal Shanghai
      adults occlusion for posterioanterior cephalometric
      roentgenography.METHODS:Posterioanterior-cephalometric of the 92 adults subjects
      with normalocclusion were measured and analysed by Jiffy orthodontic evaluation
      5.0 software package.RESULTS:The database of normal Shanghai adults occlusion for
      posterioanterior cephalometric roentgenography was established. Transverse
      measurements were intercorrelated, no statistically significant gender
      differences were demonstrated in craniofacial width, while the molar overjet of
      male was larger than that of female.CONCLUSION:The normal transverse cranioficial
      structure in Shanghai area has its own characteristics. The established database
      would provide a foundation for the diagnosis and treatment of malocclusion.

PMID- 15014844
TI  - [Mucoepidermoid carcinoma of the parotid gland:clinical analysis of 12 cases]

PMID- 15014845
TI  - [A Study On Dental and Craniofacial Structure Of Normal Shanghai Adults Occlusio
      II The Dental  Facial Symmetry Analysis with Posterioanterior Cephalometric
      Roentgenography]
AB  - OBJECTIVE:To evaluate the dental  facial symmetry in normal Shanghai adults
      occlusion with posterioanterior cephalometric roentgenography.
      METHODS:Posterioanterior films of the 92 adults subjects with normal occlusion
      were measured. Five facial midlines commonly used in posterioanterior
      cephalometric were analyzed according to the middle structure index and side
      middle structure index. The midline deviations were measured. RESULTS:The middle
      line through ANS and perpendicular to zygomaticofrontal line has less mean of
      middle structure index and side middle structure index. There are midline
      deviations in population with normal occlusion.CONCLUSION:The facial midline
      mentioned above was suitable for posterioanterior cephalometrics, but the
      reliability is not absolute. Normal occlusion also has midline deviations. The
      asymmetry of face was larger than that of dental occlusion.

PMID- 15014846
TI  - [A Study On Dental and Craniofacial Structure of Normal Shanghai Adults Occlusion
      III The Analysis of Dental Capacity and Craniofacial Structure]
AB  - OBJECTIVE:To examine the relationships between dental capacity and cranioficial
      structures.METHODS:Models, posterioanterior and lateral cephalometric films of 90
      adults with normal occlusion in Shanghai area were measured and
      analyzed.RESULTS:The canine width of lower arch extended an important influence
      on the upper and lower arch. The dental capacity was highly correlated not only
      with the width and depth of cranioficial structure  but with the height as well.
      The database of Coben analysis for normal Shanghai adults occlusion was
      established.CONCLUSION:The growth between dental and cranioficial structure was
      harmonized in three dimensions.

PMID- 15014847
TI  - [Myoepithelial carcinoma of buccal minor salivary gland:report of one case]

PMID- 15014848
TI  - [A tissue engineering approach to site-specific reconstruction of skeletal
      structures of the maxillofacial region:part I]
AB  - This article will present an image-based approach to design and manufacture of
      scaffolds for the tissue engineering of bone and cartilage constructs. Our vision
      of tissue-engineered bone and/or cartilage constructs utilizes 3-D designed and
      manufactured biodegradable scaffolds that are site  specific for the area of
      maxillofacial reconstruction. The fabricated site-specific scaffold can be
      constructed such that it will impart biologic cues to implanted cells placed
      within its interstices. These biologic cues should influence scaffold  implanted
      mesenchymal stem cells (MSC) or bone marrow stromal cells (BMSC) to form the
      necessary tissue for site  specific facial reconstruction. This new approach to
      tissue engineering of the maxillofacial region would be advantageous because of
      its site-specific anatomical configuration as well as its potential ability to
      adapt to the functional forces placed on it during function. The reconstruction
      of the condylar-ramus area of the temporomandibular joint (TMJ) will be used as
      an illustration of this approach.

PMID- 15014849
TI  - [Actinomycosis of right submandibular gland:case report]

PMID- 15014850
TI  - [Anatomical and histologic study of the cervical vessels in goats]
AB  - OBJECTIVE:To investigate the normal anatomic relations and histologic features of
      the cervical arteries and veins of goat, with the aim of providing a basis for
      resection and reconstruction of the common carotid artery.MATERIALS AND METHODS:
      Surgical dissection was performed on 15 healthy adult goats under general
      anaesthesia. The external diameters of the common carotid artery (CCA) and
      external jugular vein(EJV) were measured at their midpoints. 1 cm of the CCA and
      EJV was subject to light microscopic examination. Direct carotid angiography was
      performed on 2 selected goats to observe the course and branches of the carotid
      artery and normal blood flow mapping of the CCA was recorded using Laser Doppler
      Flowmeter. RESULTS:The average external diameter of the EJV was 5.4 mm for the
      left side and 5.3 mm for the right side. The average external diameter of the CCA
      was 3.8 mm for the left side and 3.6 mm for the right side. Histologic
      examinations found that the media of the carotid artery had 10-15 layers of
      smooth muscles. The EJV had valvulae, its wall was thin, only 1-2 layers of
      smooth muscle were contained in its medium. CONCLUSION:The CCA and EJV of the
      goat had a longer course in the neck, and a larger diameter (3-5 mm). Their
      histologic structures were similar to that of the human being, which makes it
      advantageous to be more often used as an animal model in experimental surgery.

PMID- 15014851
TI  - [Techniques in experimental surgery-general anesthesia of the goat]
AB  - To find an appropriate anesthesia for the goat in experimental surgery.METHODS:15
      goats were operated on with intravenous anestheia using ketamine hydrochloride
      gamma-OH-pentobarbital as anesthetic agents.They were grouped according to the
      weight.The physiologic index,drug dosage,operating time and awaking time were
      compared.RESULTS:There's no significant difference among the groups(P>0.05). All
      goats were anesthesised well,with advantage of long operating time(2.5-3.5h)and
      short awaking time(2-10min).CONCLUSION:The method reduces the drug dosage of
      intravenous anesthesia using pentobarbital as an anestheic,with minimal
      respiratory and cirulatory depression.gamma-OH can prolong the duration of
      general anesthesia and reduce ketamine's maintenance dosage.Endotracheal
      intubation rssured safety of operation.The method is simple,safe with
      satisfactory anesthetic effects.

PMID- 15014852
TI  - [Detection of HSV-1 Antibody in outpatients of dentistry]

PMID- 15014853
TI  - [Clinical study of pressured injection in the superior temporomandibular joint
      compartment for the treatment of internal derangements]

PMID- 15014854
TI  - [Treatment of oral leukoplakia with chinese herbs(No.1) and transferrin factor]

PMID- 15014855
TI  - [Surgical treatment of long-established dislocation of temporomandibular joint]

PMID- 15014856
TI  - [Zingg's classification and treatment for zygomatic fractures]

PMID- 15014857
TI  - [A study on the activity of GSH-PX in saliva of the patients with preiodontal
      diseases]

PMID- 15014858
TI  - [Clinical analysis of 462 cases with maxillofacial space infections]

PMID- 15014859
TI  - [The application of microwave coagulating instrument in otolaryngology and
      stomatology (report of 157 cases)]

PMID- 15014860
TI  - [The use of marginal adhesive surface in caries filling with light-curing resins]

PMID- 15014861
TI  - [Comparison between laser and traditional gingivectomy]

PMID- 15014862
TI  - [Filling of jaw defects after enucleation of cysts with hrdroxyapatite particles:
      report of 31 cases]

PMID- 15014863
TI  - [Cryosurgery for recurrent cancer of the oral cavity:experience in 5 cases]

PMID- 15014865
TI  - Cerebral arterial gas embolism: should we hyperventilate these patients?

PMID- 15014864
TI  - A randomised controlled study of the efficacy of hypromellose and Lacri-Lube
      combination versus polyethylene/Cling wrap to prevent corneal epithelial
      breakdown in the semiconscious intensive care patient.
AB  - OBJECTIVE: To compare the efficacy of two forms of eye care (hypromellose and
      Lacri-Lube combination vs polyethylene/Cling wrap covers) for intensive care
      patients. DESIGN: Randomised-controlled trial. SETTING: University affiliated,
      tertiary referral hospital. PATIENTS AND PARTICIPANTS: One hundred ten patients
      with a reduced or absent blink reflex were followed through until they regained
      consciousness, were discharged from the facility during study enrolment, died or
      developed a positive corneal ulcer or eye infection. INTERVENTIONS: All patients
      received standard eye cleansing every 2 h. In addition to this, group one ( n=60)
      received a treatment combining hypromellose drops and Lacri-Lube (HL) to each eye
      every 2 h. Group two ( n=50) had polyethylene covers only placed over the eye to
      create a moisture chamber. MEASUREMENTS AND RESULTS: Corneal ulceration was
      determined using corneal fluorescein stains and mobile slit lamp evaluation,
      performed daily. No patients had corneal ulceration in the polyethylene cover
      group, but 4 patients had corneal ulceration in the HL group. CONCLUSIONS:
      Polyethylene covers are as effective as HL in reducing the incidence of corneal
      damage in intensive care patients.

PMID- 15014866
TI  - [Bilateral localized osteolysis after cemented total hip replacement].
AB  - The incidence of focal progressive osteolysis after THR is about 8% and 56%. Most
      often osteolysis is correlated with macrophage-induced osteoclastic bone
      resorption as a sequel of inflammatory reaction to wear particles. Recently these
      findings were published in respect to allergic reactions to implants, their
      alloying constituents, or bone cement. We report about a patient who developed
      bilateral localized osteolysis just below the cement mantle 5 years after
      cemented THR with a Muller straight stem. In the middle of the osteolysis small
      fragments of bone cement could be detected. Epicutaneous testing showed no
      reaction against cobalt, chromium, or nickel. Further epicutaneous testing in
      respect to ingredients of the bone cement were refused by the patient.
      Histological examination revealed a histiocytic reaction to wear particles and
      surrounding giant cells. To our knowledge, this is the first case of bilateral
      localized osteolysis after cemented total hip replacement. Taking all results of
      the current case into account, it is still unclear if a lymphocytic allergic
      contact reaction did contribute to the sequel of this case. Reports of
      immunologically induced incompatibility to components of bone cement, the
      development of extended testing procedures, and further scientific research
      should contribute to optimizing the care of patients.

PMID- 15014867
TI  - [Total hip arthroplasty in Austria. Results of a nationwide survey based on a
      questionnaire].
AB  - Besides the number of annual total hip arthroplasty (THA) surgeries (11,978
      primary THA, 148 implantations per 10(5) inhabitants), little is known about the
      state of total hip replacement in Austria. We collected information about
      different aspects of THA treatment regimens. A questionnaire was developed and
      sent to all chairmen of orthopedic and traumatology departments posing 22
      questions regarding type of THA, surgical technique, number of surgeries, data
      collection, physical therapy and mobilization, length of hospital stay, and
      recommendations on sport activities as well as activities of daily life. In
      Austria cementless THA predominates (according to the questionnaire survey 85%).
      Postoperative mobilization with cementless implants is prescribed as full weight
      bearing in 52%, partial weight bearing in 42%, and no weight bearing in 6%. The
      length of hospital stay with cementless insertion is 14.2 days and with cemented
      implantation 14.9 days; the use of crutches is recommended for 6.0 and 5.4 weeks,
      respectively. Hip scores for documentation are used before surgery in 65% of
      orthopedic departments and 13% of traumatology departments and in the
      postoperative follow-up in 62% and 13%, respectively. In-patient rehabilitation
      is prescribed by 74% of orthopedic and 26% of traumatology departments. Austria
      ranks among the top nations in Europe regarding the number of total hip
      arthroplasty implantations. Documentation is insufficient and needs to be
      improved. In some aspects of managing patients with total hip arthroplasties
      there are remarkable differences between orthopedic and traumatology departments.

PMID- 15014873
TI  - Geographic distribution of chloroplast variation in Italian populations of beech
      (Fagus sylvatica L.).
AB  - The distribution of chloroplast DNA (cpDNA) variation in Italian beech ( Fagus
      sylvatica L.) populations was studied using PCR-RFLP and microsatellite markers.
      In total, 67 populations were analysed, and 14 haplotypes were identified by
      combining the two marker types. A remarkable subdivision of cpDNA diversity in
      Italian beech was found, as indicated by a high level of genetic differentiation
      ( G(st)=0.855). The highest level of total haplotype diversity ( h(t)=0.822) was
      estimated for southern Italian populations. The highest number of haplotypes was
      found in the central-southern region of the peninsula. The nested clade analysis
      provided evidence for past fragmentation events that may have been occurred
      during the Quaternary glaciations and had a major role in defining the genetic
      structure of the central-southern Italian beech populations. Only one haplotype
      apparently spread towards the north of Italy along the Apennine chain and reached
      the Italian slope of the western part of the Alps (Maritime Alps, Liguria). All
      haplotypes found along the Apennines remained trapped in the Italian peninsula.
      Southern and central Italy represent hotspots of haplotype diversity for Italian
      beech.

PMID- 15014874
TI  - Localization of a novel recessive powdery mildew resistance gene from common
      wheat line RD30 in the terminal region of chromosome 7AL.
AB  - Segregation analysis of resistance to powdery mildew in a F(2) progeny from the
      cross Chinese Spring (CS) x TA2682c revealed the inheritance of a dominant and a
      recessive powdery mildew resistance gene. Selfing of susceptible F(2) individuals
      allowed the establishment of a mapping population segregating exclusively for the
      recessive resistance gene. The extracted resistant derivative showing full
      resistance to each of 11 wheat powdery mildew isolates was designated RD30.
      Amplified fragment length polymorphism (AFLP) analysis of bulked segregants from
      F(3)s showing the homozygous susceptible and resistant phenotypes revealed an
      AFLP marker that was associated with the recessive resistance gene in repulsion
      phase. Following the assignment of this AFLP marker to wheat chromosome 7A by
      means of CS nullitetrasomics, an inspection of simple sequence repeat (SSR) loci
      evenly spaced along chromosome 7A showed that the recessive resistance gene maps
      to the distal region of chromosome 7AL. On the basis of its close linkage to the
      Pm1 locus, as inferred from connecting partial genetic maps of 7AL of populations
      CS x TA2682c and CS x Virest ( Pm1e), and its unique disease response pattern,
      the recessive resistance gene in RD30 was considered to be novel and tentatively
      designated mlRD30.

PMID- 15014875
TI  - QTL analysis of resistance to Fusarium head blight in Swiss winter wheat
      (Triticum aestivum L.).
AB  - Fusarium head blight (FHB) of wheat is a widespread and destructive disease which
      occurs in humid and semi-humid areas. FHB epidemics can cause serious yield and
      quality losses under favorable climatic conditions, but the major concern is the
      contamination of grains with mycotoxins. Resistance to FHB is quantitatively
      inherited and greatly influenced by the environment. Its evaluation is costly and
      time-consuming. The genetic basis of FHB resistance has mainly been studied in
      spring wheat. The objective of this study was to map quantitative trait loci
      (QTLs) for resistance to FHB in a population of 240 recombinant inbred lines
      (RILs) derived from a cross between the two Swiss winter wheat cultivars Arina
      (resistant) and Forno (susceptible). The RILs were genotyped with microsatellite
      and RFLP markers. The resulting genetic map comprises 380 loci and spans 3,086
      cM. The 240 RILs were evaluated for resistance to FHB in six field trials over 3
      years. Composite interval mapping (CIM) analyses carried out on FHB AUDPC (i.e.
      mean values across six environments) revealed eight QTLs which altogether
      explained 47% of the phenotypic variance. The three main QTLs were mapped on the
      long arms of chromosomes 6D ( R(2)=22%), 5B ( R(2)=14%) and 4A ( R(2)=10%). The
      QTL detected on 5B originated from the susceptible parent Forno. Other QTLs with
      smaller effects on FHB resistance were detected on chromosomes 2AL, 3AL, 3BL, 3DS
      and 5AL.

PMID- 15014876
TI  - QTL mapping for European corn borer resistance ( Ostrinia nubilalis Hb.),
      agronomic and forage quality traits of testcross progenies in early-maturing
      European maize ( Zea mays L.) germplasm.
AB  - In hybrid breeding the performance of lines in hybrid combinations is more
      important than their performance per se. Little information is available on the
      correlation between individual line and testcross (TC) performances for the
      resistance to European corn borer (ECB, Ostrinia nubilalis Hb.) in maize ( Zea
      mays L.). Marker assisted selection (MAS) will be successful only if quantitative
      trait loci (QTL) found in F(2) derived lines for ECB resistance are still
      expressed in hybrid combinations. The objectives of our study were: (1) to
      identify and characterize QTL for ECB resistance as well as agronomic and forage
      quality traits in a population of testcrossed F(2:3) families; (2) to evaluate
      the consistency of QTL for per se and TC performances; and (3) to determine the
      association between per se and TC performances of F(2:3) lines for these traits.
      Two hundred and four F(2:3) lines were derived from the cross between maize lines
      D06 (resistant) and D408 (susceptible). These lines were crossed to D171 and the
      TC progenies were evaluated for ECB resistance and agronomic performance in two
      locations in 2000 and 2001. Using these TC progenies, six QTL for stalk damage
      rating (SDR) were found. These QTL explained 27.4% of the genotypic variance in a
      simultaneous fit. Three QTL for SDR were detected consistently for per se and TC
      performance. Phenotypic and genotypic correlations were low for per se and TC
      performance for SDR. Correlations between SDR and quality traits were not
      significant. Based on these results, we conclude that MAS will not be an
      efficient method for improving SDR. However, new molecular tools might provide
      the opportunity to use QTL data as a first step to identify genes involved in ECB
      resistance. Efficient MAS procedures might then be based on markers designed to
      trace and to combine specific genes and their alleles in elite maize breeding
      germplasm.

PMID- 15014877
TI  - Genome and species relationships in genus Avena based on RAPD and AFLP molecular
      markers.
AB  - Species and genome relationships among 11 diploid (A and C genomes), five
      tetraploid (AB and AC genomes) and two hexaploid (ACD genome) Avena taxa were
      investigated using amplified fragment length polymorphisms (AFLPs) and random
      amplified polymorphic DNA (RAPD) markers. The two primer pairs used for the AFLP
      reactions produced a total of 354 polymorphic bands, while 187 reproducible bands
      were generated using ten RAPD primers. Genetic similarities amongst the entries
      were estimated using the Jaccard and Dice algorithms, and cluster analyses were
      performed using UPGMA and neighbor joining methods. Principle coordinate analysis
      was also applied. The highest cophenetic correlation coefficient was obtained for
      the Jaccard algorithm and UPGMA clustering method ( r=0.99 for AFLP and r=0.94
      for RAPD). No major clustering differences were present between phenograms
      produced with AFLPs and RAPDs. Furthermore, data produced with AFLPs and RAPDs
      were highly correlated ( r=0.92), indicating the reliability of our results. All
      A genome diploid taxa are clustered together according to their karyotype. The AB
      genome tetraploids were found to form a subcluster within the A(s )genome
      diploids (AFLPs), indicating their near-autoploid origin. The AC genome
      tetraploids are clustered to the ACD genome hexaploids. Finally, the C genome
      diploids form an outer branch, indicating the major genomic divergence between
      the A and C genomes in Avena.

PMID- 15014878
TI  - Interspecific relationships of the genus Cicer L. (Fabaceae) based on trnT-F
      sequences.
AB  - The trnT-F region in chloroplasts was sequenced to elucidate interspecific
      phylogenetic relationships in the genus Cicer. Twenty-five species representing
      four sections and two outgroups were analyzed. A phylogenetic analysis revealed
      three major clades in the genus Cicer. Inferred phylogenetic relationships
      support multiple origins of annual species in the genus Cicer. Low variation
      within the most perennial species in the sequence regions suggests they may have
      originated during a period of rapid diversification after the genus arose. High
      levels of sequence divergence, biogeographical patterns and morphological traits
      between African and Eurasian groups of species suggest that Cicer may have
      independently diverged on each continent. Phylogenetic analysis of sequence data
      did not support the monophyly of the currently recognized sections and indicated
      the need for a revision of the infrageneric classification.

PMID- 15014879
TI  - Mapping of transposable element Dissociation inserts in Brassica oleracea
      following plant regeneration from streptomycin selection of callus.
AB  - To investigate the potential of heterologous transposons as a gene-tagging system
      in broccoli (Brassica oleracea var. italica), we have introduced a Dissociation (
      Ds)-based two-element transposon system. Ds has been cloned into a 35S-SPT
      excision-marker system, with transposition being driven by an independent 35S
      transposase gene construct. In three successive selfed generations of plants,
      there was no evidence of germinal-excision events. In a previous study, we
      overcame this apparent inability to produce B. oleracea plants with germinal
      excisions by performing a novel tissue-culture technique to select for fully
      green shoots from seed with somatic excision events. The results showed a very
      high efficiency of regeneration of fully green plants (up to 65%), and molecular
      analysis showed that the plants contained the equivalent of a germinal-excision
      event. In this study, we followed the previous work by using inverse and nested
      PCR to generate probes of flanking genomic DNA adjacent to independently
      reinserted Ds elements, and these were hybridised to DNA from a double-haploid
      mapping population of B. oleracea. Seventeen Ds insertions and the original Ds T
      DNA site have been localised, and these are spread over six (out of nine) linkage
      groups. Distribution of inserts show that 15 were found on a different linkage
      group to the original 'launch' site, and of these 11 were found to be clustered
      on two separate groups. Previous studies in other plant species have found that
      germinal excision of Ds predominantly moves to sites linked close to the donor
      site. However, this study shows a potential to produce plants with Ds insertion
      scattered over many unlinked sites.

PMID- 15014880
TI  - Phenotypic and molecular evaluation of a recurrent selection program for a
      polygenic resistance to Phytophthora capsici in pepper.
AB  - 'Criollo de Morelos 334' (CM334) is one of the most promising sources of
      resistance to Phytophthora capsici in pepper. This Mexican accession is distantly
      related to bell pepper and its resistance displays a complex inheritance. The
      QTLs involved in resistance to P. capsici were previously mapped. In order to
      transfer the resistance factors from CM334 into a bell pepper genetic background,
      a modified, recurrent breeding scheme was initiated. The breeding population was
      divided into three sub-populations which were screened by distinct phenotypic
      tests of increasing severity. The plants from the first sub-population were
      screened with low-severity tests and backcrossed to the susceptible bell pepper;
      the plants from the second and third sub-populations were screened by more severe
      resistance tests and crossed with the plants from the first and second sub
      populations, respectively. In this study, the phenotypic data for the three sub
      populations during five screening/intermating cycles were analysed. In parallel,
      the changes in allelic frequencies at molecular markers linked to the resistance
      QTLs were reported. The resistance phenotype and allelic frequencies strongly
      depended on the sub-population and screening severity. Regarding allelic
      frequency changes across the selection cycles, a loss of resistant QTL alleles
      was observed in the first sub-population, particularly for the low-effect QTLs,
      whereas a better conservation of the resistant QTL alleles was observed in the
      two other sub-populations. The same trend was observed in the phenotypic data
      with an increasing resistance level from the first to the third sub-populations.
      The changes in the allelic frequencies of loci not linked to resistance QTLs and
      for horticultural traits across the breeding process indicated that the recovery
      of the recipient parent genome was not significantly affected by the selection
      for resistance.

PMID- 15014881
TI  - The development of SSR markers by a new method in plants and their application to
      gene flow studies in azuki bean [Vigna angularis (Willd.) Ohwi & Ohashi].
AB  - To gain a better understanding of wild and weedy azuki population structures in
      relation to the cultigens we have developed simple sequence repeat (SSR) markers
      based on a new methodology for plant material. In the azuki bean genome, the
      number of (AG)(n) and (AC)(n) motif loci per haploid genome has been estimated to
      be 3,500 and 2,100, respectively, indicating that (AG)(n) motifs are a rich
      source of markers. We constructed a (AG)(n)-SSR-enriched library in azuki bean in
      order to obtain a comprehensive range of SSR markers efficiently. The method
      applied in this study resulted in a 116-fold enrichment over the non-enriched
      genomic library, with a high percentage (98%) of successful single-locus
      amplification by the primer pairs designed. Consequently, this method can be
      applied to construct SSR-enriched libraries suitable for large-scale sequencing.
      We obtained 255 unique sequences from an (AG)(n)-enriched library for azuki bean.
      Fifty primer pairs were designed and screened against five populations of wild
      azuki bean. Among these five populations, one population from Bato town, Tochigi
      prefecture, Japan, showed greater polymorphism using these primers than the
      others and was therefore chosen for the in-depth study. The genotypes of 20
      individuals were investigated using eight of the SSR primers developed. The
      genetic relationships among individuals revealed a complex spatial pattern of
      population structure. Although azuki bean is considered to be a predominantly
      self-pollinating species, 3 of the 20 individuals tested in the population showed
      heterozygous genotypes, indicating outcrossing. Allele size and DNA sequence in
      each of the 20 individuals were compared with those of landraces and released
      cultivars of azuki bean. Plants in part of the population had many alleles of the
      same size and with the same sequence as those in cultivated azuki bean,
      suggesting that gene flow from the cultigen to wild plants has occurred in this
      population. Unintentional transgene escape from azuki could therefore occur when
      transgenic azuki is grown in areas where its wild and weedy relatives occur. The
      approach used here could be applied to biosafety monitoring of transgenic azuki
      bean.

PMID- 15014882
TI  - [Penile- and urethral anomalies].
AB  - Penile and urethral anomalies are common congenital disorders with some rare
      variations. For example, the floppy penis is dealt with in only a few
      publications with a small numbers of cases. Other anomalies have not been
      published at all, i.e., the ectopic penis. Some anomalies become apparent
      immediately at birth, others remain undiscovered until adolescence. To date there
      is no established classification system dealing with urethral and penile
      anomalies. Also, no established guidelines exist for diagnosing and treating
      these anomalies. Surgical corrections of penile and urethral anomalies should
      follow standardized procedures on the one hand, but must respect the individual
      anatomical situation on the other. Since genital anomalies are frequently part of
      a syndrome, interdisciplinary approaches are advisable. The following article
      presents a classification of penile and urethral anomalies. Since posterior
      urethral valves usually affect the bladder and upper urinary tract, this disorder
      is not included in this review.

PMID- 15014884
TI  - [Restless legs syndrome in childhood].
AB  - The diagnostic criteria of restless legs syndrome were defined in 1995 by the
      International Restless Legs Syndrome Study Group (IRLSSG). In light of the latest
      scientific evidence and increasing clinical experience, the diagnostic criteria
      were revised in a consensus workshop. Participants of the workshop considered the
      development of new diagnostic criteria especially important for the following
      subgroups: (1) for children and (2) for the cognitively impaired elderly. The
      common characteristic of both groups lies in their difficulty in expressing
      subjective symptoms adequately. This considerably impedes the diagnosis of
      restless legs syndrome. In 2002, a proposal for diagnostic criteria of restless
      legs syndrome in childhood was formulated by members of the study groups
      "Movement Disorders and Sleep" and "Paediatrics" of the German Sleep Society. The
      proposal was partially incorporated into the diagnostic criteria for restless
      legs syndrome in childhood suggested by the IRLSSG. The current criteria are
      recommendations to enhance further research and must be validated by clinical
      studies. The following article gives an overview of published studies on restless
      legs syndrome in childhood, reviews the proposals for diagnostic criteria, and
      summarizes the peculiarities to be considered in diagnosing restless legs
      syndrome in children.

PMID- 15014885
TI  - [Intraoperative quality control of the placement of bone tunnels for the anterior
      cruciate ligament].
AB  - The reconstruction of a ruptured anterior cruciate ligament (ACL) is a frequently
      performed operation, however technically demanding with a revision rate of
      approximately 10%. The correct placement of bone tunnels in femur and tibia is
      the most important variable to achieve a successful outcome. A distinct knowledge
      of the anatomic insertion sites is crucial. The ideal location for the femoral
      bone tunnel is achieved when a 1-2 mm posterior wall is left to the over-the-top
      position and when the entry to the bone tunnel is at 10 o'clock (right knees) or
      14 o'clock (left knees) in the frontal plane. The femoral bone tunnel can be
      drilled through the tibial bone tunnel (transtibial technique) or through an
      anteromedial arthroscopic portal. According to recent studies the use of an
      anteromedial portal helps to reduce the risk of misplacement of the bone tunnel.
      The center of the tibial bone tunnel should be located on an imaginary line
      between medial border of the anterior horn of the lateral meniscus and the medial
      tibial spine. The position of the tibial guide wire has to be far enough
      posterior to avoid impingement of the graft with the roof of the intercondylar
      notch. Measures for quality control include the intraoperative use of an image
      intensifier (fluoroscopy), instrumented laxity measurements and a postoperative
      radiograph in 2 planes. The use of computer assisted surgery cannot routinely be
      recommended at present.

PMID- 15014887
TI  - Sperm membrane protein (hSMP-1) and RanBPM complex in the microtubule-organizing
      centre.
AB  - hSMP-1 is a human sperm membrane protein expressed during development. It is a
      testis-specific component produced during male germ cell differentiation.
      Proteins that interact with hSMP-1 were identified by the application of the
      yeast two-hybrid system. One of the components, RanBPM, was found to be
      associated with hSMP-1 under both in vitro and in vivo conditions. In the human
      testis, RanBPM is produced in spermatogonia and primary spermatocytes, suggesting
      expression during the early stages of spermatogenesis; whereas in the rat testis,
      it is located in round and elongated spermatids, similar to hSMP-1, suggesting
      expression of both components during spermiogenesis. Images obtained by
      immunofluorescence and confocal scanning microscopy of CHO-K1 cells co
      transfected with pEGFP-C1-hSMP-1 and pDsRed1-Nl-RanBPM revealed that RanBPM and
      hSMP-1 are distributed in discrete loci throughout the cytoplasm. When
      superimposed, the stained spots appeared as congruent yellow areas, indicative of
      co-localization and probable complex formation of these two components. This
      interaction between hSMP-1 and RanBPM may be involved in the process of male germ
      cell differentiation. In CHO-Kl cells transfected with pEGFP-Cl-hSMP-1, the
      exogenously expressed hSMP-1 was found to co-localize with alpha-tubulin.
      Depolymerization of microtubules can be induced in CHO-Kl cells by cold
      treatment. In cells transfected with the pEGFP-Cl vector, the dispersed tubulins
      promptly reassembled upon warming. However, in cells transfected with pEGFP-Cl
      hSMP-1, reassembly of the dispersed tubulins was blocked even upon rewarming of
      the cells. These findings suggest that hSMP-1 interacts with tubulins and thereby
      may modulate microtubule assembly and/or activity.

PMID- 15014888
TI  - [A 52-year old female patient with recurrent shock of unclear origin,
      hemoconcentration and hypoalbuminemia].
AB  - Systemic capillary leak syndrome is a rare life threatening condition of unknown
      etiology. It was firstly described by Clarkson et al in 1960. It is characterised
      by recurrent attacks of severe hypovolemic shock, hemoconcentration and
      hypalbuminemia, caused by a sudden reversible increase in capillary permeability
      and shift of fluid and macromolecules to the extravascular compartment. A
      monoclonal paraprotein is always detectable in the serum of patients, without
      evidence of multiple myeloma. We describe the course of a patient, who died at a
      severe attack despite of prophylactic treatment after 25 months of illness.
      Application of cytostatics should be considered if prophylactic treatment fails
      even if there is no evidence of progression to multiple myeloma.

PMID- 15014889
TI  - [Effects of a Mediterranean diet on mortality].

PMID- 15014886
TI  - Prion protein conversion in vitro.
AB  - The infectious agents of prion diseases are composed primarily of an infectious
      protein designated PrPSc. In cells infected with prions, a host glycoprotein
      termed PrPC undergoes induced conformational change to PrPSc, but the molecular
      mechanism underlying this structural transition occurs remains unknown. The prion
      seeded conversion of PrPC to protease-resistant PrPSc-like molecules (PrPres) has
      been studied both in crude and purified in vitro systems in order to investigate
      the mechanism of protein conformational change in prion disease. Conversion of
      purified PrPC into PrPres is specific with respect to species-dependent and
      polymorphic differences in PrP sequence as well as biophysical variations between
      prion strains, recapitulating the specificity of prion propagation in vitro. The
      protein misfolding cyclic amplification (PMCA) technique, which utilizes crude
      brain homogenates, produces much higher yields of PrPres than conversion of
      purified PrP molecules, suggesting that additional cellular factors may stimulate
      PrPres formation. In a modified version of the PMCA technique, PrPres from
      diluted prion-infected brain homogenate can be amplified > ten-fold when mixed
      with normal brain homogenate without sonication or the anionic detergent sodium
      dodecyl sulfate (SDS). Under these conditions, PrPres amplification in vitro
      depends upon both time and temperature, has a neutral pH optimum, and does not
      require divalent cations. In vitro PrPres amplification is inhibited by both
      reversible and irreversible thiol blockers, indicating that the conformational
      change from PrPC to PrPres requires a thiol-containing factor. Stoichiometric
      transformation of PrPC to PrPres in vitro also requires specific RNA molecules,
      suggesting that host-encoded catalytic RNA molecules may play a role in the
      pathogenesis of prion disease. Heparan sulfate stimulates conversion of purified
      PrPC into PrPres in vitro, and heparan sulfate proteoglycan molecules are
      required for efficient PrPres formation in prion-infected cells. Future studies
      using in vitro PrPres conversion and amplification assays promise to provide new
      mechanistic insights about the PrP conversion process, and to generate clinically
      useful tools.

PMID- 15014890
TI  - [Dysfunction of a kidney allograft with life-threatening results].
AB  - Post-transplant lymphoproliferative disease (PTLD) is a serious complication
      after organ transplantation. We describe the case of a 45-year old patient who
      developed an EBV associated B-cell lymphoma in a cadaveric renal allograft. This
      case underscores the importance of considering PTLD as possible differential
      diagnosis for allograft dysfunction. Careful diagnostic evaluation should be
      undertaken in patients who present with risk factors for development of PTLD such
      as high doses of immunosuppression for rejection therapy, suspicious EBV
      serologies or negative EBV serologies before transplantation. PTLD can be of
      donor or recipient origin. Independent of its origin PTLD needs an immediate
      therapy which depends on the histology of the lymphoma and on the clinical
      conditions of the patient. Therapeutic options are reduction of the
      immunosuppression, chemotherapy or radiation, administration of lymphocyte
      specific antibodies or removal of the kidney allograft.

PMID- 15014891
TI  - [Navigation-controlled cochleostomy. Is an improvement in the quality of results
      for cochlear implant surgery possible?].
AB  - BACKGROUND: The correct positioning of the electrode, which is the limiting
      factor for the functional integrity of cochlear implants, is decisively
      influenced by the cochleostomy. Localisation and form of the drilling canal have
      been solely defined by the surgeon during the operation and an enlargement of the
      drilling canal is often necessary. Thanks to the improved resolution of new slice
      imaging techniques, computed tomography allows an exactly defined optimal point
      for cochleostomy. MATERIAL AND METHODS: In a cadaver study, we examined whether
      the target defined with computed tomography can be reached in a reproducible way
      with the help of navigated computer assisted surgery. We chose titanium screw
      markers as the gold standard for referencing. RESULTS: There was a real deviation
      of 1.6 mm in the target field. Thus, in a cochleostomy with a diameter of 0.5 mm
      the goal was not reached in a reproducible way. With this deviation a target of
      2.56 mm(2) is defined. CONCLUSIONS: A target assessed by navigation is better
      than one reached without navigation in view of reproducibility and accuracy. With
      further technical progress navigated cochleostomy will be possible.

PMID- 15014892
TI  - [Swelling of the medial canthus].

PMID- 15014893
TI  - [The management of postintubation stenoses in children].
AB  - Extubation difficulties after long-term endotracheal intubation in neonates and
      infants require immediate re-intubation with a somewhat thinner endotracheal
      tube, continuation of long-term intubation for another 7-14 days with antibiotic
      and antiphlogistic therapy including antireflux treatment as well as a subtile
      endoscopic examination. A tracheostomy is not indicated before several attempts
      of extubation have failed. An anterior cricoid split should be indicated with
      great care and in premature neonates only. In manifest cicatrical stenoses,
      subtile endoscopic diagnostics are an essential prerequisite for the choice of
      surgical method and time of surgery. In rather mild stenoses (grade II),
      laryngotracheal reconstruction (LTR) with anterior wall cartilage grafting is
      presently regarded as method of choice. For subglottic stenoses of higher degrees
      (grade III and IV), partial cricotracheal resection (PCTR) is felt to be the most
      successful procedure. For all scarred stenoses involving the glottic level, LTR
      with posterior and anterior wall cartilage grafting appears to be the only
      suitable treatment. LTR with anterior wall grafting only as well as the PCTR can
      be performed as a single stage procedure with postoperative long-term intubation
      on an intensive care unit for one or more days. LTR with posterior and anterior
      wall grafting requires long-term stenting for several weeks or months depending
      upon the individual condition. For long-term stenting, our so-called double-tube
      technique using a modified Montgomery T silicon tube together with a perforated
      tracheal cannula has proved to be the safest and least irksome technique.

PMID- 15014894
TI  - [Fever, bilateral conjunctivitis, cervical lymphadenopathy, lacquered lips and
      rash].

PMID- 15014895
TI  - [Consideration of anatomy in plexus block].

PMID- 15014896
TI  - [Livid discoloration of the hand as complication during plexus anaesthesia].
AB  - During axillary brachial plexus block for hand surgery, the axillary artery was
      accidentally punctured. After skin disinfection of the operation site a livid
      discoloration of the hand appeared. The initial intention of stopping surgery and
      performing an angiography for clarification of the suspicion of a vessel lesion
      was dismissed after recording the pulse at the wrist and all fingertips employing
      a pulsoximeter. Further investigation showed that the livid discoloration of the
      hand was a product of the interaction of the octenidin solution used for pre
      operative hand disinfection with the polyvidone-iodine solution used for surgical
      skin disinfection. This case report shows that interactions of topically
      administered pharmaceuticals have to be taken into consideration. Lack of
      knowledge might lead to unnecessary and unjustified diagnostic procedures which
      imply additional costs and dangers for the patient.

PMID- 15014897
TI  - The effects of degree of hepatic or renal impairment on the pharmacokinetics of
      exemestane in postmenopausal women.
AB  - PURPOSE: Two studies were conducted to compare the pharmacokinetics and
      tolerability of exemestane in postmenopausal subjects with various degrees of
      impairment of hepatic or renal function with those in healthy postmenopausal
      subjects. METHODS: All subjects were postmenopausal females. In study 1, nine
      subjects had normal hepatic function (Child-Pugh grade A), and nine had
      moderately (grade B) and eight severely (grade C) impaired hepatic function. In
      study 2, six subjects had normal renal function, and six moderately (creatinine
      clearance, CrCL, 30-60 ml/min per 1.73 m(2)) and seven severely (CrCL <29 ml/min
      per 1.73 m(2)) impaired renal function. Each subject took a single oral dose of
      25 mg exemestane. Samples of plasma (to 168 h after dosing) and urine (to 72 h in
      study 1, or 96 h in study 2) were taken for pharmacokinetic analysis. Safety and
      tolerability were assessed by monitoring vital signs, laboratory safety tests,
      ECG and adverse events. RESULTS: Exposure to exemestane was increased two- to
      threefold in patients with hepatic impairment. Thus, the geometric mean AUC(0-
      infinity ) values were 41.71 (90% CI 32.2 to 54.0), 99.02 (76.5 to 128.2) and
      118.59 ng.h/ml (90.2 to 156.0) in healthy subjects, and in patients with moderate
      and severe hepatic impairment, respectively ( P<0.01). C(max) also increased
      twofold. Compared with healthy subjects, patients with hepatic impairment had
      lower apparent oral clearance and apparent volume of distribution of exemestane.
      Renal impairment was also associated with two- to threefold increases in AUC(0-
      infinity ): 34.64 (90% CI 23.9 to 50.2), 94.10 (64.9 to 136.4) and 65.52 ng.h/ml
      (46.5 to 92.4) in healthy subjects, and in patients with moderate and severe
      hepatic impairment, respectively ( P<0.05). C(max) did not change significantly.
      Apparent oral clearance was directly correlated with CrCL ( r(2)=0.43).
      Exemestane was tolerated well, with no safety concerns. CONCLUSIONS: Oral
      clearance of exemestane was reduced in the presence of significant hepatic or
      renal disease. However, in view of the relatively large safety margin and the
      mild nature of the side effects of exemestane, the therapeutic implications of
      these changes in pharmacokinetics are considered minor and of no clinical
      significance.

PMID- 15014898
TI  - In vitro and in vivo effects of acetyldinaline on murine megakaryocytopoiesis.
AB  - PURPOSE: Acetyldinaline (CI-994) has shown preclinical efficacy in vitro and in
      vivo against solid tumor and leukemia cell lines. Since myelosuppression was the
      dose-limiting toxicity for acetyldinaline in preclinical and clinical studies,
      experiments were conducted to examine the in vitro and in vivo effects of
      acetyldinaline on murine megakaryocytic (CFU-meg) progenitor cells. METHODS: Bone
      marrow and spleen cells from untreated mice were continuously exposed in vitro to
      acetyldinaline or dinaline in clonal assays. For the in vivo study, BDF(1) mice
      were dosed orally with 50 mg/kg acetyldinaline every day for 14 days. RESULTS:
      Both acetyldinaline and dinaline induced an in vitro dose-dependent decrease in
      CFU-meg colonies derived from either the spleen or bone marrow. Splenic CFU-meg
      were more sensitive in vitro to acetyldinaline and dinaline than their marrow
      counterparts. In the in vivo experiments, platelet counts decreased throughout
      the 14-day dosing period and had returned to normal by day 18. Marrow and spleen
      CFU-meg declined after the first dose but had recovered by days 4 and 7,
      respectively. Elevated splenic CFU-meg counts were observed through day 20, 6
      days after dosing ended. Recovery of platelet counts in treated mice was
      associated with increases in both marrow and splenic CFU-meg. CONCLUSIONS: There
      was differential in vitro toxicity of acetyldinaline to murine CFU-meg derived
      from the bone marrow versus spleen. The in vitro assay predicted the more severe
      effect of acetyldinaline on splenic progenitors than on their marrow counterparts
      that was observed in the in vivo phase. In addition, megakaryocytopoiesis in the
      marrow showed evidence of recovery from drug toxicity in the face of continuing
      daily acetyldinaline treatments.

PMID- 15014899
TI  - Aneurysmatic dilatation of ascending aorta in a patient with beta-thalassemia and
      a pseudoxanthoma elasticum-like syndrome.
AB  - The development of a diffuse elastic tissue defect resembling pseudoxanthoma
      elasticum (PXE) is a recently established and frequently encountered clinical
      entity in beta-thalassemia. The clinical spectrum of this disorder is not yet
      completely understood as it is continuously being enriched with novel
      complications that are often serious. We present here a thalassemia intermedia
      patient with typical PXE manifestations and a fusiform aneurysmatic dilatation of
      the ascending thoracic aorta, a previously unknown complication in these
      patients. An aortic aneurysm has itself a notable morbidity, while it may also
      impair the particularly susceptible cardiac function of beta-thalassemia
      patients, hence affecting the overall prognosis of the main disease.

PMID- 15014900
TI  - Acute myeloid/NK precursor cell leukemia with trisomy 4 and a novel point
      mutation in the extracellular domain of the G-CSF receptor in a patient with
      chronic idiopathic neutropenia.
AB  - Chronic idiopathic neutropenia (CIN) has been well recognized as a granulocytic
      disorder not associated with increased risk to malignant transformation. Four
      cases, however, of acute myeloid leukemia have been recently reported in patients
      with CIN. In the current paper, we report on a CIN patient who developed acute
      myeloid/natural killer (NK) precursor cell leukemia 11 years after diagnosis and
      4 months after initiation of treatment with recombinant human granulocyte colony
      stimulating factor (rhG-CSF). Leukemic cells had trisomy 4 as the sole
      cytogenetic abnormality and, also, a novel point mutation in the extracellular
      domain of the G-CSF receptor (G-CSFR) leading to truncated protein with a loss of
      36 amino acids. There was no evidence that this receptor transmitted signals even
      in the presence of high doses of rhG-CSF in the cultures. We consider that CIN
      may be a preleukemic condition, at least in a subset of patients, and that rhG
      CSF administration is unlikely to be involved in the leukemic transformation in
      this patient, although such a possibility could not be completely ruled out.

PMID- 15014901
TI  - A novel triple-modality reporter gene for whole-body fluorescent, bioluminescent,
      and nuclear noninvasive imaging.
AB  - Two genetic reporter systems were developed for multimodality reporter gene
      imaging of different molecular-genetic processes using fluorescence,
      bioluminescence (BLI), and nuclear imaging techniques. The eGFP cDNA was fused at
      the N-terminus with HSV1-tk cDNA bearing a nuclear export signal from MAPKK (NES
      HSV1-tk) or with truncation at the N-terminus of the first 45 amino acids
      (Delta45HSV1-tk) and with firefly luciferase at the C-terminus. A single fusion
      protein with three functional subunits is formed following transcription and
      translation from a single open reading frame. The NES-TGL (NES-TGL) or
      Delta45HSV1-tk/GFP/luciferase (Delta45-TGL) triple-fusion gene cDNAs were cloned
      into a MoMLV-based retrovirus, which was used for transduction of U87 human
      glioma cells. The integrity, fluorescence, bioluminescence, and enzymatic
      activity of the TGL reporter proteins were assessed in vitro. The predicted
      molecular weight of the fusion proteins (~130 kDa) was confirmed by western blot.
      The U87-NES-TGL and U87-Delta45-TGL cells had cytoplasmic green fluorescence. The
      in vitro BLI was 7- and 13-fold higher in U87-NES-TGL and U87-Delta45-TGL cells
      compared to nontransduced control cells. The Ki of (14)C-FIAU was 0.49+/-0.02,
      0.51+/-0.03, and 0.003+/-0.001 ml/min/g in U87-NES-TGL, U87-Delta45-TGL, and wild
      type U87 cells, respectively. Multimodality in vivo imaging studies were
      performed in nu/ nu mice bearing multiple s.c. xenografts established from U87
      NES-TGL, U87-Delta45-TGL, and wild-type U87 cells. BLI was performed after
      administration of d-luciferin (150 mg/kg i.v.). Gamma camera or PET imaging was
      conducted at 2 h after i.v. administration of [(131)I]FIAU (7.4 MBq/animal) or
      [(124)I]FIAU (7.4 MBq/animal), respectively. Whole-body fluorescence imaging was
      performed in parallel with the BLI and radiotracer imaging studies. In vivo BLI
      and gamma camera imaging showed specific localization of luminescence and
      radioactivity to the TGL transduced xenografts with background levels of activity
      in the wild-type xenografts. Tissue sampling yielded values of 0.47%+/-0.08%,
      0.86%+/-0.06%, and 0.03%+/-0.01%dose/g [(131)I]FIAU in U87-NES-TGL, U87-Delta45
      TGL, and U87 xenografts, respectively. The TGL triple-fusion reporter gene
      preserves the functional activity of its subunits and is very effective for
      multimodality imaging. It provides for the seamless transition from fluorescence
      microscopy and FACS to whole-body bioluminescence imaging, to nuclear (PET, SPET,
      gamma camera) imaging, and back to in situ fluorescence image analysis.

PMID- 15014902
TI  - A new model for separation between brain dopamine and serotonin transporters in
      123I-beta-CIT SPECT measurements: normal values and sex and age dependence.
AB  - 123I-beta-CIT is a radioactive ligand for single-photon emission computed
      tomography (SPECT) imaging of the pre-synaptic (transporter) re-uptake sites for
      dopamine (DAT) and serotonin (5HTT), and it is widely used to visualize monoamine
      turnover. Since 123I-beta-CIT uptake occurs at 5HTT and DAT sites in conjunction
      with the presence of freely soluble 123I-beta-CIT in brain tissue, adequate
      separation of these three components is necessary. However, only partial
      separation is possible with current methods. Two main strategies have previously
      been used for 123I-beta-CIT component separation, based on the following
      considerations: (1) the faster uptake rate for 5HTT compared with DAT enables
      temporal separation by performing 5HTT imaging at 1-2 h and DAT imaging at 20-24
      h; (2) blocking the 5HTT re-uptake with citalopram renders 123I-beta-CIT imaging
      DAT (non-5HTT) specific. In a new analytical model, we combined these two
      approaches with methods to isolate the passively dissolved 123I-beta-CIT in brain
      tissue from the monoamine transporter uptake, and to correct the 5HTT and DAT
      values for concomitant uptake. The new analytical model was used to study brain
      5HTT and DAT in 23 normal subjects, with the aim of clarifying the effect of age
      and sex. A significant correlation between 5HTT and DAT values was found only in
      the thalamus, indicating successful component separation. Negative correlations
      between age and DAT were found for basal ganglia, thalami, brain stem and
      temporal lobes, but not for the frontal, parietal or occipital regions. No
      correlation with age was found for 5HTT. We found no sex difference for 5HTT or
      DAT.

PMID- 15014903
TI  - Comparison of 11C-choline PET and FDG PET for the differential diagnosis of
      malignant tumors.
AB  - We prospectively assessed and compared the usefulness of 11C-choline positron
      emission tomography (PET) with that of [18F]-2-fluoro-2-deoxy-D-glucose (FDG) PET
      for the differentiation between benign and malignant tumors. A total of 126
      patients with 130 lesions were studied (25 brain tumors, 51 head and neck tumors,
      15 bone tumors, 16 lung tumors, and 23 soft tissue tumors). 11C-choline PET and
      FDG PET were performed from 5 and 40 min, respectively, after injection of 275
      370 MBq tracer. PET data were evaluated using the standardized uptake value (SUV)
      and were analyzed in accordance with the pathologic data. The 11C-choline uptake
      in malignancies was 3.9+/-2.3 (n=81), which was significantly higher than that in
      benign lesions (n=49) (2.6+/-1.7, P<0.005). The FDG uptake in malignancies was
      5.9+/-3.8 (n=81) and was also significantly higher than that in benign lesions
      (2.8+/-2.0, P<0.0001). The 11C-choline uptake in the lesions correlated with FDG
      uptake (r=0.65, P<0.003). According to an ROC analysis, the areas under the ROC
      curves (AUCs) for 11C-choline PET were more than 0.8 in bone, head and neck,
      lung, and soft tissue tumors, while the AUC was 0.79 in brain tumors. The AUCs
      for FDG PET were similarly more than 0.8 in bone, head and neck, lung, and soft
      tissue tumors, but had a lower value of 0.585 in brain tumors. In brain, head and
      neck, bone, and soft tissue tumors, 11C-choline showed higher contrast than FDG.
      In conclusion, it is feasible to use 11C-choline PET for differentiation between
      malignant and benign tumours, especially of the brain, head and neck, bone, and
      soft tissue. However, attention needs to be drawn to the high uptake of 11C
      choline in some benign tumors and tumour-like lesions, as this will be of
      significance in clinical practice.

PMID- 15014905
TI  - "Characterization of basal hepatic bile...".

PMID- 15014904
TI  - Relationship of 99mTc-HYNIC annexin V uptake to microvessel density, FasL and MMP
      9 expression, and the number of tumour-infiltrating lymphocytes in head and neck
      carcinoma.
AB  - This study reports on the relationship between quantitative (99m)Tc-HYNIC
      radiolabelled annexin V tumour uptake measurements, Fas ligand (FasL) expression,
      matrix metalloproteinase-9 (MMP-9) expression, microvessel density (MVD) and the
      number of tumour-infiltrating lymphocytes in squamous cell carcinoma of the head
      and neck (SCCHN) patients. Twenty-eight patients (24 men and 4 women; mean age 59
      years, range 43-83 years) suffering from a primary ( n, number of patients=22) or
      locally recurrent ( n=6) SCCHN were studied. All patients underwent a spiral CT
      scan, allowing estimation of lesion size in three dimensions, and (99m)Tc-HYNIC
      annexin V scintigraphy within 1 week of each other. Biopsies or resection of the
      suspected primary tumour or local recurrence for histopathological analysis were
      performed on all patients within a period of 10 days following (99m)Tc-HYNIC
      annexin V scintigraphy. The percentage uptake of the injected dose of (99m)Tc
      HYNIC annexin V in visible tumour lesions on scintigrams divided by the tumour
      volume, derived from CT, was related to MVD and to histological score (HSCORE)
      values for MMP-9 and FasL expression as well as to the number of tumour
      infiltrating lymphocytes (CD45 staining). Median percentage absolute tumour
      uptake of the injected dose/cm(3) tumour volume derived from tomographic images
      was 0.0001% (SD 0.0001%) at 5-6 h p.i. (range: 0.000007-0.0003%). Mean HSCORE for
      MMP-9 tumour staining was 2.1 (SD 0.84). Mean HSCORE for FasL tumour staining was
      2.49 (SD 0.92). At the sites of tumour containing the highest number of vessels,
      the mean MVD was 20 vessels/field at the hot spot (range 1-73). The median number
      of tumour-infiltrating lymphocytes was 500 (range 100-5,000). The percentage
      absolute tumour uptake of the injected dose/cm(3) tumour volume derived from
      tomographic images correlated linearly with FasL HSCORES( r=0.47, P=0.02). No
      correlation was found between the percentage absolute tumour uptake of the
      injected dose/cm(3) tumour volume derived from tomographic images and MMP-9
      HSCORES, MVD or the number of tumour-infiltrating lymphocytes. MVD correlated
      significantly with MMP-9 HSCORES ( r=0.44, P=0.03).

PMID- 15014907
TI  - Helical kink and channel behaviour: a comparative study with the peptaibols
      alamethicin, trichotoxin and antiamoebin.
AB  - Kinks or bends introduced in peptides and proteins by "helical distorter"
      residues such as proline, other imino acids and glycine, especially when these
      are in close proximity in the sequence, are increasingly recognized as playing an
      essential role in the gating of channel-forming peptides as well as of
      physiological ion channels. Peptaibols are useful simple models for the much more
      complex biological ion channels, especially voltage-gated ones. In this short
      review, we compare the monomeric structures of three selected peptaibols
      (alamethicin, trichotoxin and antiamoebin) that widely differ with regards their
      near-central kink angles and dipolar moment orientations. These structural
      features are then shown to be correlated to the different patterns of channel
      activity, both at the macroscopic and single-channel levels of investigation.

PMID- 15014908
TI  - The influence of zinc on the modulatory effect of sphingosylphosphorylcholine on
      Kv1.3 channels in human T lymphocytes.
AB  - In the present study, the whole-cell patch-clamp technique was applied to
      investigate the influence of co-application of zinc ions and
      sphingosylphosphorylcholine (SPC) on the SPC-induced shift of the activation
      midpoint and slowing of activation kinetics of Kv1.3 channels in human T
      lymphocytes. The results obtained provided evidence that the effects exerted by
      SPC and Zn were not additive. The shift was significantly diminished in a
      concentration-dependent manner upon co-application of 10 microM SPC and Zn in the
      concentration range 10-300 microM. However, the shift was not abolished in the
      presence of 100 and 300 microM of Zn co-applied with SPC. It was shown that the
      extent of the shift upon SPC and Zn co-application was similar to the shift
      observed for Zn applied without SPC. The slowing of the activation kinetics was
      also diminished upon SPC and Zn co-application; however, no clear dependence on
      concentration was observed. Moreover, the slowing was not abolished in the
      presence of 100 and 300 microM of Zn. It was shown that the slowing of the
      activation kinetics upon Zn and SPC co-application was primarily due to the
      effect exerted by SPC. The steepness of the voltage dependence of steady-state
      activation of the channels was not changed upon SPC and Zn co-application.
      Possible mechanisms underlying the observed phenomena and their possible
      physiological significance are discussed.

PMID- 15014909
TI  - A single residue exchange between two HLA-B27 alleles triggers increased peptide
      flexibility.
AB  - For more than 30 years, human leukocyte antigen B27 (HLA-B27) has been known to
      be closely related to the autoimmune disease ankylosing spondylitis, yet little
      is known about the molecular mechanisms of pathogenesis. Crystal structures of
      two closely related, but differently disease-associated, subtypes (B*2705 and
      B*2709) also did not resolve this situation as they revealed the bound
      nonapeptide in essentially identical conformations. As the peptide is part of
      putative binding epitopes for the T cell receptor, we performed molecular
      dynamics simulations to gain deeper insight into the dynamic behaviour of HLA-B27
      molecules. We find increased flexibility of the peptide in the binding groove of
      subtype B*2709 due to weaker interactions in the F pocket. Possible implications
      of this flexibility for T cell recognition and signalling are discussed.

PMID- 15014911
TI  - Modulation of DMT1 activity by redox compounds.
AB  - Iron(II) exacerbates the effects of oxidative stress via the Fenton reaction. A
      number of human diseases are associated with iron accumulation including ischemia
      reperfusion injury, inflammation and certain neurodegenerative diseases. The
      functional properties and localization in plasma membrane of cells and endosomes
      suggest an important role for the divalent metal transporter DMT1 (also known as
      DCT1 and Nramp2) in iron transport and cellular iron homeostasis. Although iron
      metabolism is strictly controlled and the activity of DMT1 is central in
      controlling iron homeostasis, no regulatory mechanisms for DMT1 have been so far
      identified. Our studies show that the activity of DMT1 is modulated by compounds
      that affect its redox status. We also show that both iron and zinc are
      transported by DMT1 when expressed in Xenopus laevis oocytes. Radiotracer uptake
      and electrophysiological measurements revealed that H(2)O(2) and Hg(2+)
      treatments result in substantial inhibition of DMT1. These findings may have a
      profound relevance from a physiological and pathophysiological standpoint.

PMID- 15014910
TI  - Molecular mechanisms of electrogenic sodium bicarbonate cotransport: structural
      and equilibrium thermodynamic considerations.
AB  - The electrogenic Na(+)-HCO(3)(-) cotransporters play an essential role in
      regulating intracellular pH and extracellular acid-base homeostasis. Of the known
      members of the bicarbonate transporter superfamily (BTS), NBC1 and NBC4 proteins
      have been shown to be electrogenic. The electrogenic nature of these transporters
      results from the unequal coupling of anionic and cationic fluxes during each
      transport cycle. This unique property distinguishes NBC1 and NBC4 proteins from
      other sodium bicarbonate cotransporters and members of the bicarbonate
      transporter superfamily that are known to be electroneutral. Structure-function
      studies have played an essential role in revealing the basis for the modulation
      of the coupling ratio of NBC1 proteins. In addition, the recent transmembrane
      topographic analysis of pNBC1 has shed light on the potential structural
      determinants that are responsible for ion permeation through the cotransporter.
      The experimentally difficult problem of determining the nature of anionic species
      being transported by these proteins (HCO(3)(-) versus CO(3)(2-)) is analyzed
      using a theoretical equilibrium thermodynamics approach. Finally, our current
      understanding of the molecular mechanisms responsible for the regulation of ion
      coupling and flux through electrogenic sodium bicarbonate cotransporters is
      reviewed in detail.

PMID- 15014912
TI  - Ca(2+) calmodulin kinase and calcineurin mediate IGF-1-induced skeletal muscle
      dihydropyridine receptor alpha(1S) transcription.
AB  - The skeletal muscle L-type Ca(2+) channel or dihydropyridine(DHP)-sensitive
      receptor is a key molecule involved in membrane voltage-sensing, sarcoplasmic
      reticulum Ca(2+) release, and muscle contraction. Previous work from our
      laboratory has shown that the insulin-like growth factor-1 (IGF-1) increases
      skeletal muscle L-type Ca(2+) channel or dihydropyridine-sensitive receptor
      DHPRalpha(1S) transcriptional activity by acting on the cyclic AMP response
      element binding protein (CREB) element of the promoter region; however, the
      cellular signaling mediating this process is not known. In this study, we
      investigated the signaling pathway whereby IGF-1 enhances the expression of
      DHPRalpha(1S) in C2C12 myotubes, using a molecular, pharmacological and
      electrophysiological approach. We found that inhibition of the Ca(2+)/Calmodulin
      (CaM)-dependent protein kinase or calcineurin, influenced IGF-1-induced increase
      in DHPRalpha(1S) expression, as detected by recording the luminescence of the
      DHPRalpha(1S) promoter-luciferase fusion construct and by immunoblot analysis of
      the DHPR alpha1 subunit. IGF-1 significantly increased CaM kinase and calcineurin
      activity and the cellular levels of phosphorylated CREB in a time-dependent
      manner. The role of CaM kinase and calcineurin in DHPRalpha(1S) expression was
      confirmed by functional recording of the effects of the inhibition of the kinase
      and phosphatase on IGF-1-mediated enhancement of charge movement. These results
      support the conclusion that IGF-1 controls CREB phosphorylation by activating a
      phosphorylation and dephosphorylation cascade, which ultimately modulates the
      DHPRalpha(1S) gene transcription.

PMID- 15014913
TI  - The new permeability pathways induced by the malaria parasite in the membrane of
      the infected erythrocyte: comparison of results using different experimental
      techniques.
AB  - The membrane of erythrocytes infected with malaria parasites is highly permeable
      to a large variety of solutes, including anions, carbohydrates, amino acids,
      nucleosides, organic and inorganic cations and small peptides. The altered
      permeability is presumed to be due to the activation of endogenous dormant
      channels, the new permeability pathways. The latter have been studied by
      different techniques-isosmotic lysis and tracer fluxes-and recently by patch
      clamping. Here we analyze all available published data and we show that there is
      generally a good agreement between the two first methods. From the fluxes we
      calculate the number of channels per cell using reasonable assumptions as to the
      radius of the channel, and assuming that penetration through the channel is by
      diffusion through a water-filled space. The number of channels so calculated is
      <10 for most solutes, but approximately 400 for anions and the nucleosides
      thymidine and adenosine. This latter number is not far from that calculated from
      patch-clamp experiments. However, the anion flux measured directly by tracer is
      an order of magnitude larger than expected from conductance measurements. We
      conclude that the new permeability pathways consist of two types of channels; one
      is present in small number, and is charge- and size-selective. The other type is
      about 100-fold more abundant and is anion-selective, but does not admit non
      electrolytes other than perhaps nucleosides.

PMID- 15014914
TI  - Functional characterization of Na(+)/H(+) exchangers in primary cultures of
      prairie dog gallbladder.
AB  - Gallbladder Na(+) absorption is linked to gallstone formation in prairie dogs. We
      previously reported Na(+)/H(+) exchanger (NHE1-3) expression in native
      gallbladder tissues. Here we report the functional characterization of NHE1, NHE2
      and NHE3 in primary cultures of prairie dog gallbladder epithelial cells (GBECs).
      Immunohistochemical studies showed that GBECs grown to confluency are homogeneous
      epithelial cells of gastrointestinal origin. Electron microscopic analysis of
      GBECs demonstrated that the cells form polarized monolayers characterized by
      tight junctions and apical microvilli. GBECs grown on Snapwells exhibited
      polarity and developed transepithelial short-circuit current, I(sc), (11.6 +/-
      0.5 microA. cm(-2)), potential differences, V(t) (2.1 +/- 0.2 mV), and
      resistance, R(t) (169 +/- 12 omega. cm(2)). NHE activity in GBECs assessed by
      measuring dimethylamiloride-inhibitable (22)Na(+) uptake under a H(+) gradient
      was the same whether grown on permeable Snapwells or plastic wells. The basal
      rate of (22)Na(+) uptake was 21.4 +/- 1.3 nmol x mg prot(-1) x min(-1), of which
      9.5 +/- 0.7 (approximately 45%) was mediated through apically-restricted NHE.
      Selective inhibition with HOE-694 revealed that NHE1, NHE2 and NHE3 accounted for
      approximately 6%, approximately 66% and approximately 28% of GBECs' total NHE
      activity, respectively. GBECs exhibited saturable NHE kinetics ( V(max) 9.2 +/-
      0.3 nmol x mg prot(-1) x min(-1); K(m) 11.4 +/- 1.4 m M Na(+)). Expression of
      NHE1, NHE2 and NHE3 mRNAs was confirmed by RT-PCR analysis. These results
      demonstrate that the primary cultures of GBECs exhibit Na(+) transport
      characteristics similar to native gallbladder tissues, suggesting that these
      cells can be used as a tool for studying the mechanisms of gallbladder ion
      transport both under physiologic conditions and during gallstone formation.

PMID- 15014916
TI  - Architecture of the Alzheimer's A beta P ion channel pore.
AB  - We have proposed that the cytotoxic action of Alzheimer's amyloid beta protein
      might be initiated by the interaction with the neuronal cell membrane, and
      subsequent formation of toxic ion channels. Consequently, A beta P toxicity can
      be explained on the basis of harmful ion fluxes across A beta P channels. The
      conformation of A beta P in membranes is not known. However, several models
      suggests that a transmembrane annular polymeric structure is responsible for the
      ion channel properties of the membrane-bound A beta P. To identify that portion
      of the A beta P molecule making up the conducting pore we have hypothesized that
      the region of the A beta P sequence in the vicinity of the hypothetical pore
      might interact with complementary regions in the adjacent A beta P subunits. We
      have further hypothesized that an interaction by a peptide segment would block A
      beta P conductance. To test this hypothesis we synthesized peptides that
      encompass the histidine dyad (H-H) previously hypothesized to line the pore. We
      report here that peptides designed to most closely match the proposed pore are,
      in fact, the most effective at blocking ion currents through the membrane
      incorporated A beta P channel. As previously shown for Zn(2+) blockade, peptide
      blockade is also asymmetric. The results also provide additional evidence for the
      asymmetric insertion of the A beta P molecules into lipid membranes, and give
      support to the concept that rings of histidines line the entry to one side of the
      A beta P pore.

PMID- 15014917
TI  - Distributions-per-level: a means of testing level detectors and models of patch
      clamp data.
AB  - Level or jump detectors generate the reconstructed time series from a noisy
      record of patch-clamp current. The reconstructed time series is used to create
      dwell-time histograms for the kinetic analysis of the Markov model of the
      investigated ion channel. It is shown here that some additional lines in the
      software of such a detector can provide a powerful new means of patch-clamp
      analysis. For each current level that can be recognized by the detector, an array
      is declared. The new software assigns every data point of the original time
      series to the array that belongs to the actual state of the detector. From the
      data sets in these arrays distributions-per-level are generated. Simulated and
      experimental time series analyzed by Hinkley detectors are used to demonstrate
      the benefits of these distributions-per-level. First, they can serve as a test of
      the reliability of jump and level detectors. Second, they can reveal beta
      distributions as resulting from fast gating that would usually be hidden in the
      overall amplitude histogram. Probably the most valuable feature is that the
      malfunctions of the Hinkley detectors turn out to depend on the Markov model of
      the ion channel. Thus, the errors revealed by the distributions-per-level can be
      used to distinguish between different putative Markov models of the measured time
      series.

PMID- 15014915
TI  - What are aquaporins for?
AB  - The prime function of aquaporins (AQPs) is generally believed to be that of
      increasing water flow rates across membranes by raising their osmotic or
      hydraulic permeability. In addition, this applies to other small solutes of
      physiological importance. Notable applications of this 'simple permeability
      hypothesis' (SPH) have been epithelial fluid transport in animals, water
      exchanges associated with transpiration, growth and stress in plants, and
      osmoregulation in microbes. We first analyze the need for such increased
      permeabilities and conclude that in a range of situations at the cellular,
      subcellular and tissue levels the SPH cannot satisfactorily account for the
      presence of AQPs. The analysis includes an examination of the effects of the
      genetic elimination or reduction of AQPs (knockouts, antisense transgenics and
      null mutants). These either have no effect, or a partial effect that is difficult
      to explain, and we argue that they do not support the hypothesis beyond showing
      that AQPs are involved in the process under examination. We assume that since
      AQPs are ubiquitous, they must have an important function and suggest that this
      is the detection of osmotic and turgor pressure gradients. A mechanistic model is
      proposed--in terms of monomer structure and changes in the tetrameric
      configuration of AQPs in the membrane--for how AQPs might function as sensors.
      Sensors then signal within the cell to control diverse processes, probably as
      part of feedback loops. Finally, we examine how AQPs as sensors may serve animal,
      plant and microbial cells and show that this sensor hypothesis can provide an
      explanation of many basic processes in which AQPs are already implicated.
      Aquaporins are molecules in search of a function; osmotic and turgor sensors are
      functions in search of a molecule.

PMID- 15014918
TI  - Muscarinic agonists activate Ca2+ store-operated and -independent ionic currents
      in insulin-secreting HIT-T15 cells and mouse pancreatic beta-cells.
AB  - The neurotransmitter acetylcholine, a muscarinic receptor agonist, augments
      glucose-induced insulin secretion from pancreatic beta-cells by depolarizing the
      membrane to enhance voltage-gated Ca(2+) influx. To clarify the electrical events
      involved in this process, we measured ionic currents from a clonal beta-cell line
      (HIT-T15) and mouse pancreatic beta-cells. In whole-cell recordings, the
      muscarinic agonist carbachol (CCh) dose-dependently and reversibly activated a
      voltage-independent, nonselective current (whole-cell conductance 24 pS/pF,
      reversal potential of approximately -15 mV). The current, which we refer to as
      I(musc), was blocked by atropine, a muscarinic receptor antagonist, and SKF
      96365, a nonspecific ion channel blocker. The magnitude of the current decreased
      by 52% when extracellular Na(+) was removed, but was not affected by changes in
      extracellular Ca(2+), confirming that I(musc) is a nonselective current. To
      determine if I(musc) activates following release of Ca(2+) from an intracellular
      store, we blocked intracellular IP(3) receptors with heparin. Carbachol still
      activated a current in the presence of heparin, demonstrating the presence of a
      Ca(2+) store-independent, muscarinic agonist-activated ionic current in HIT
      cells. However, the store-independent current was smaller and had a more positive
      reversal potential (approximately 0 mV) than the current activated by CCh under
      control conditions. This result indicates that heparin had blocked a component of
      I(musc), which likely activates following release of stored Ca(2+). Depleting
      IP(3)-sensitive calcium stores with thapsigargin also activated a non-selective,
      SKF 96365-blockable current in HIT cells. The properties of this putative store
      operated current were similar to the component of I(musc) that was blocked by
      heparin, being voltage-independent and reversing near -30 mV. We conclude that
      I(musc) consists of store-operated and store-independent components, both of
      which may contribute to the depolarizing action of muscarinic agonists on
      pancreatic beta-cells.

PMID- 15014920
TI  - The geographic relationship between the use of antimicrobial drugs and the
      pattern of resistance for Streptococcus pneumoniae in Italy.
AB  - OBJECTIVES: A temporal relationship between the increasing use of antibiotics and
      the increasing levels of antibiotic resistance has been established for
      Streptococcus pneumoniae. There are also data that support the presence of a
      geographic correlation between the level of resistance and the pattern of use
      among different countries and even within the same country. The aim of this study
      was to evaluate the potential geographic correlation between the use of beta
      lactams and erythromycin in different Italian regions and the resistance of these
      antibiotics to invasive strains of S. pneumoniae during the period 1999-2000.
      METHODS: Ecological study. RESULTS: In Italy the mean level of resistance for
      penicillin and erythromycin was 11.4% and 28.9%, respectively. The highest level
      of resistance for both antibiotics was observed in central and southern regions
      (i.e. Campania, Lazio and the combined regions of Calabria, Puglia and Sicilia).
      These regions were also those with the highest consumption of antibiotics. A
      strong correlation was found between the prevalence of resistance to erythromycin
      and the regional use of macrolides (r=0.93, P=0.001) and beta-lactams (r=0.84,
      P=0.002). With regard to penicillin resistance, the greatest correlation was
      observed for oral penicillin (r=0.85, P=0.002). CONCLUSION: Our study provides
      further evidence of the association between regional level of antibiotic use and
      prevalence of antibiotic resistance.

PMID- 15014919
TI  - Kinetic characterization of apical D-fructose transport in chicken jejunum.
AB  - In mammals, D-fructose transport takes place across the brush-border membrane of
      the small intestine through GLUT5, a member of the facilitative glucose
      transporter family. In the present paper, we describe and characterize for the
      first time the apical transport of D-fructose in chicken intestine. Brush-border
      membrane vesicles (BBMV) were obtained from jejunum of 5- to 6-wk-old chickens. D
      Fructose uptake by BBMV from chicken jejunum comprises a saturable component and
      a simple diffusion process. The maximal rate of transport ( V(max)) for D
      fructose was 2.49 nmol.(mg prot)(-1).s(-1), the Michaelis constant ( K(m)) was 29
      mM, and the diffusion constant ( K(d)) was 25 nl.(mg prot)(-1).s(-1). The apical
      transport of D-fructose was Na(+)-independent, phlorizin-, phloretin-, and
      cytochalasin B-insensitive, and did not show cis-inhibition by D-glucose or D
      galactose. These properties, together with the detection of specific GLUT5 mRNA,
      indicate the presence of a low-affinity high-capacity GLUT5-type carrier in the
      chicken jejunum, responsible for the entry of D-fructose across the brush-border
      membrane of enterocytes.

PMID- 15014921
TI  - Drug use and increased HbA1c levels in non-diabetic very elderly persons: the
      Kungsholmen project.
AB  - OBJECTIVE: To examine the association between the use of drugs with potential
      hyperglycemic effects and increased HbA1c levels in a very elderly population.
      METHODS: This was a cross-sectional study of older subjects age 81 years and over
      from the second follow-up (1994-1996) of the Kungsholmen project, a population
      based study of elderly in an urban area of Stockholm, Sweden. The study
      population consisted of 578 subjects, with a mean age of 86.7 years, without
      known diabetes mellitus. Glucose levels were assessed using HbA1c. Information on
      drug use was based on personal interviews. Diagnoses of diabetes mellitus,
      hypertension, and congestive heart failure were obtained from personal or
      relative interviews, assessment by the examining physician, and from the
      computerized inpatient register. Measures of other factors that may influence
      glucose homeostasis included body mass index, s-K(+), s-Ca(2+), thyroid
      stimulating hormone, and sedimentation rate. RESULTS: High HbA1c levels (>5.3%)
      indicating hyperglycemia were seen in 11% of the women and 12% of the men. Use of
      loop diuretics was significantly associated with high levels of HbA1c in both
      women and men, even after adjusting for hypertension and congestive heart
      failure. Eighteen percent of users of loop diuretics had high levels compared
      with 8% among non-users. CONCLUSION: Our results indicate that loop diuretics may
      have hyperglycemic effects in the very elderly. This finding can be of clinical
      importance as loop diuretics are among the most commonly taken drugs in this
      population.

PMID- 15014923
TI  - Converging patterns of inputs from oral structures in the postcentral
      somatosensory cortex of conscious macaque monkeys.
AB  - Single neuronal activities were recorded in the oral region of the postcentral
      gyrus in conscious Japanese monkeys. Among 5,756 neurons isolated, receptive
      fields (RFs) and submodalities were identified in 1,502 neurons in area 3b, 970
      in area 1, and 1,461 in area 2. The relative incidence of neurons that had
      bilateral RFs increased gradually upon moving caudally from area 3b to area 2
      (bilateral integration). A total of 276 neurons had bimaxillary RFs covering both
      the maxillary and mandibular divisions of the trigeminal nerve, such as the upper
      and lower lips, upper and lower teeth, palate and tongue, or combinations
      thereof. There was also a tendency for the relative incidence of neurons with
      bimaxillary RFs to increase across the postcentral gyrus but with an abrupt
      change in area 2 (bimaxillary integration). A total of 382 neurons had composite
      RFs covering more than one of five oral structures: lip, cheek mucosa,
      teeth/gingiva, tongue, and palate. The relative incidence of neurons with
      composite RFs was significantly higher in area 2 than in areas 3b and 1
      (interstructural integration). These results indicate that the convergence of
      inputs from oral structures proceeds in a hierarchical manner across the
      postcentral gyrus, but chiefly in area 2 for the bimaxillary and interstructural
      integrations. The relative incidence of neurons with composite RFs was higher
      among neurons associated with the teeth/gingiva or palate than among neurons
      associated with the tongue or lip in all three areas. We interpret this to mean
      that anatomical or functional differences between oral structures might be
      reflected in the converging patterns in the oral representation.

PMID- 15014922
TI  - The scaling of motor noise with muscle strength and motor unit number in humans.
AB  - Understanding the origin of noise, or variability, in the motor system is an
      important step towards understanding how accurate movements are performed.
      Variability of joint torque during voluntary activation is affected by many
      factors such as the precision of the descending motor commands, the number of
      muscles that cross the joint, their size and the number of motor units in each.
      To investigate the relationship between the peripheral factors and motor noise,
      the maximum voluntary torque produced at a joint and the coefficient of variation
      of joint torque were recorded from six adult human subjects for four muscle/joint
      groups in the arm. It was found that the coefficient of variation of torque
      decreases systematically as the maximum voluntary torque increases. This
      decreasing coefficient of variation means that a given torque or force can be
      more accurately generated by a stronger muscle than a weaker muscle. Simulations
      demonstrated that muscles with different strengths and different numbers of motor
      units could account for the experimental data. In the simulations, the magnitude
      of the coefficient of variation of muscle force depended primarily on the number
      of motor units innervating the muscle, which relates positively to muscle
      strength. This result can be generalised to the situation where more than one
      muscle is available to perform a task, and a muscle activation pattern must be
      selected. The optimal muscle activation pattern required to generate a target
      torque using a group of muscles, while minimizing the consequences of signal
      dependent noise, is derived.

PMID- 15014924
TI  - How dependent are grip force and arm actions during holding an object?
AB  - In everyday life, when manipulating objects, arm actions and precision grip force
      are tightly coupled by the central nervous system. To investigate the extent of
      this neural coupling, 11 subjects were asked to perform tasks that encourage
      either the coupling (Task 1) or the dissociation (Task 2 and 3) of grip force and
      arm actions. During Task 1, subjects held a grasping device, with an extra load
      suspended underneath by a string. Then, using the other hand, subjects were asked
      to lift or release the suspended load, while maintaining unaffected the posture
      of the grasping arm. During Task 2, while holding the device, subjects received
      similar instructions, but this time the extra load was suspended underneath the
      forearm. During Task 3, subjects were explicitly asked to modulate their grip
      force without moving the arm. In Task 1, grip force changed in parallel with, or
      slightly ahead of, changes in load, which is consistent with the view of a
      feedforward mechanism making grip force largely subordinate to ongoing arm
      actions. In Task 2, even though subjects had no obvious reasons to modulate their
      force (i.e. the load of the device was constant) they did so, with a number of
      features that resemble performance in Task 1. In Task 3, as expected, voluntary
      modulations in grip force had no effect on arm actions. It is concluded that the
      neural coupling between arm actions and grip force (1) can possibly lead to
      clumsy reactions, (2) depends on the focal action, and (3) is only
      unidirectional.

PMID- 15014925
TI  - Short-term adaptation of the cervico-ocular reflex.
AB  - The cervico-ocular reflex (COR) works in conjunction with the vestibulo-ocular
      reflex (VOR) and the optokinetic reflex (OKR) in order to prevent visual slip
      over the retina during head movement. The COR induces eye movements in response
      to proprioceptive signals from the neck. We investigated whether the COR gain can
      be adapted by inducing a mismatch between vision and neck proprioception, in
      analogy to VOR adaptation. Thirteen healthy subjects were rotated in the dark in
      a trunk-to-head manner (the head fixed in space while the body passively rotated
      sinusoidally with a peak velocity of 1.25 degrees /s). Eye movements were
      recorded with infrared video-oculography under various adaptive conditions.
      Analysis showed a small but significant reduction in COR gain in the suppression
      conditions. This means that the cervico-ocular reflex can be modified after only
      10 min of concurrent visual and cervical stimulation.

PMID- 15014927
TI  - Effects of ciprofloxacin on joint cartilage in immature dogs immediately after
      dosing and after a 5-month treatment-free period.
AB  - A study in young beagle dogs was performed in which the animals were treated for
      2 weeks with ciprofloxacin at oral doses of 0, 10, 30 or 90 mg/kg per day.
      Immediately after treatment half of the number of animals were killed and all
      weight-bearing joints were subject to a thorough gross and histopathological
      investigation, including special staining of the cartilage matrix, and
      immunohistochemistry as well as electron microscopy. The remaining animals were
      maintained for an additional 5-months treatment-free period before being killed.
      Again, all weight-bearing joints were subject to a thorough gross and
      histopathological investigation. After 14 days of treatment with ciprofloxacin,
      oral doses of 30 and 90 mg/kg induced the characteristic arthropathy (blisters,
      erosions) in juvenile beagle dogs. As expected the lesions persisted while the
      animals were growing. In contrast, and to our knowledge demonstrated for the
      first time, an oral dose of 10 mg/kg ciprofloxacin did not induce joint lesions
      after short-term treatment in juvenile beagle dogs and was also not associated
      with arthrotoxicity when the dogs became older.

PMID- 15014926
TI  - Intraseptal injection of the 5-HT1A/5-HT7 agonist 8-OH-DPAT and working memory in
      rats.
AB  - RATIONALE: In rats, 5-HT(1A) receptors are present in the septal region, e.g. on
      cholinergic neurons of the medial septum, where they might be a substrate for
      cognitively relevant interactions between cholinergic and serotonergic systems.
      OBJECTIVE: The present experiment assessed the effects of the stimulation of
      septal 5-HT(1A) receptors on spatial working memory. METHODS: Stimulation of
      septal 5-HT(1A) receptors was carried out by infusions targetting the medial
      septum of the 5-HT(1A)/5-HT(7) receptor agonist 8-hydroxy-2-(di-n-propyl-amino)
      tetralin (8-OH-DPAT; 0.5 or 4 microg). Spatial memory was assessed in a water
      maze using a protocol placing emphasis on spatial working memory. The location of
      the hidden platform was changed every day and performance was assessed on two
      consecutive trials each day. RESULTS: In comparison to vehicle injections, the
      intraseptal infusion of 4 microg 8-OH-DPAT impaired performance significantly:
      rats treated with 8-OH-DPAT exhibited increased distances to reach the hidden
      platform on both trials 1 and 2. Rats infused with 0.5 microg showed similar
      changes that failed to be significant. Such effects were not observed when the
      platform was visible. CONCLUSIONS: These results extend those of a previous
      experiment which showed that intraseptal injections of 8-OH-DPAT impaired spatial
      reference memory. Based on the characteristics of the observed deficits, it is
      suggested that the 8-OH-DPAT-induced impairment, rather than being only the
      result of a true alteration of working memory, might reflect a more global
      cognitive deficiency in which alteration of general memory capacities may be
      biased by disrupted search strategies/exploration and/or dysfunctions of
      attention.

PMID- 15014928
TI  - Detection of acrolein-lysine adducts in plasma low-density lipoprotein and in
      aorta of cyclophosphamide-administered rats.
AB  - Cyclophosphamide (CY) is an alkylating agent used for the treatment of various
      types of cancer and is also used as a potent immunosuppressant. Acrolein, a
      metabolite of CY is cytotoxic and has the ability to covalently bind with
      proteins in vitro to form acrolein-protein adducts. These protein adducts are
      considered to be putative markers of oxidative stress and cause damage to protein
      in aging, atherosclerosis and diabetes. We have, for the first time, detected
      acrolein-lysine adducts in plasma low-density lipoprotein (LDL) and in the aorta
      of CY-treated animals by agarose gel electrophoresis, immunoblot and
      immunohistochemical methods. The extent of lipid peroxidation caused by the
      metabolite acrolein in plasma LDL was also measured quantitatively by using high
      performance liquid chromatography. These results confirm the role of acrolein
      lysine adducts in the development of atherosclerosis or atherogenesis.

PMID- 15014929
TI  - Purification and characterization of an H2O-forming NADH oxidase from Clostridium
      aminovalericum: existence of an oxygen-detoxifying enzyme in an obligate
      anaerobic bacteria.
AB  - Clostridium aminovalericum, an obligate anaerobe, is unable to form colonies on
      PYD agar plates in the presence of 1% O(2). When grown anaerobically in PYD
      liquid medium, the strain can continue normal growth after the shift from anoxic
      (sparged with O(2)-free N(2) carrier-gas) to microoxic (sparged with 3% O(2)/97%
      N(2) mixed carrier-gas) growth conditions in the mid exponential phase
      (OD(660)=1.0). When the strain grew under 3% O(2)/97% N(2), the medium remains
      anoxic. Thirty minutes after beginning aeration with 3% O(2), the activity of
      NADH oxidase in cell-free extracts increased more than five-fold from the level
      before aeration. We purified NADH oxidase to determine the characteristics of
      this enzyme in an obligate anaerobe. The purified NADH oxidase dominated the NADH
      oxidase activity detected in cell-free extracts. The enzyme is a homotetramer
      composed of a subunit with a molecular mass of 45 kDa. The enzyme shows a
      spectrum typical of a flavoprotein, and flavin adenine dinucleotide (FAD) was
      identified as a cofactor. The final product of NADH oxidation was H(2)O, and the
      estimated K(m) for oxygen was 61.9 microM. These data demonstrate that an O(2)
      response enzyme that is capable of detoxifying oxygen to water exists in C.
      aminovalericum.

PMID- 15014930
TI  - Bacillus amyloliquefaciens strains isolated from moisture-damaged buildings
      produced surfactin and a substance toxic to mammalian cells.
AB  - Fungicidic Bacillus amyloliquefaciens strains isolated from the indoor
      environment of moisture-damaged buildings contained heat-stable, methanol-soluble
      substances that inhibited motility of boar spermatozoa within 15 min of exposure
      and killed feline lung cells in high dilution in 1 day. Boar sperm cells lost
      motility, cellular ATP, and NADH upon contact to the bacterial extract (0.2
      microg dry wt/ml). Two bioactive substances were purified from biomass of the
      fungicidal isolates. One partially characterized substance, 1,197 Da, was
      moderately hydrophobic and contained leucine, proline, serine, aspartic acid,
      glutamic acid and tyrosine, in addition to chromophore(s) absorbing at 365 nm. In
      boar sperm and human neural cells (Paju), the compound depolarized the
      transmembrane potentials of mitochondria (Delta Psi(m)) and the plasma membrane
      (Delta Psi(p)) after a 20-min exposure and formed cation-selective channels in
      lipid membranes, with a selectivity K(+):Na(+):Ca(2+) of 26:15:3.5. The other
      substance was identified as a plasma-membrane-damaging lipopeptide surfactin.
      Plate-grown biomass of indoor Bacillus amyloliquefaciens contained ca. 7% of dry
      weight of the two substances, 1,197 Da and surfactin, in a ratio of 1:6 (w:w).
      The in vitro observed simultaneous collapse of both cytosolic and mitochondrial
      ATP in the affected mammalian cell, induced by the 1,197-Da cation channel,
      suggests potential health risks for occupants of buildings contaminated with such
      toxins.

PMID- 15014931
TI  - Functional limitations and poor physical performance as independent risk factors
      for self-reported fractures in older persons.
AB  - OBJECTIVE: This study examined whether three aspects of functioning (i.e.,
      functional limitations, physical performance, and physical activity) were
      associated with fractures in older men and women. DESIGN: A 3-year prospective
      cohort study. PARTICIPANTS AND SETTING: A total of 715 men and 762 women, aged 65
      years and older, of the population-based Longitudinal Aging Study Amsterdam.
      MEASUREMENTS: During an interview at home, three aspects of functioning were
      assessed: functional limitations (what people say they can do), physical
      performance, i.e., three performance tests and handgrip strength (what people are
      able to do), and physical activity (what people actually do). Afterward, a follow
      up on fractures was conducted for 3 years. RESULTS: 77 patients (5.2%) suffered a
      fracture during 3-year follow-up. Most patients suffered a hip fracture (1.6%) or
      a wrist fracture (1.4%). The fracture rate per 1,000 person-years was 20.1.
      During 3-year follow-up, a fracture was reported by 12%, 10%, 12%, and 6% of the
      respondents with functional limitations, low performance test score, poor
      handgrip strength, and low physical activity, respectively. Using Cox
      proportional hazard analysis, functional limitations (RR = 3.5; 95% CI, 2.1 to
      6.0), low performance test score (RR = 1.9; 95% CI, 1.1 to 3.3), low handgrip
      strength (RR = 2.5; 95% CI, 1.5 to 4.1), and low physical activity (RR = 1.9; 95%
      CI, 1.1 to 3.5) were significantly associated with fractures after adjustment for
      age and sex. Functional limitations (RR = 3.2; 95% CI, 1.8 to 5.5), low
      performance test score (RR = 1.8; 95% CI, 1.0 to 3.3) and low handgrip strength
      (RR = 2.0; 95% CI, 1.1 to 3.6) remained significantly associated with fractures
      after additional adjustment for body composition, chronic diseases, psychosocial
      factors, life style factors, and the other levels of functioning. No significant
      interaction terms were found. CONCLUSIONS: Functional limitations and poor
      physical performance were independent risk factors for fractures.

PMID- 15014932
TI  - Accuracy of cystoscopy in the diagnosis of ureteral injury in benign gynecologic
      surgery.

PMID- 15014933
TI  - Pelvic floor muscle training is effective in treatment of female stress urinary
      incontinence, but how does it work?
AB  - To date several randomized controlled trials (RCT) have shown that pelvic floor
      muscle (PFM) training is effective in the treatment of female stress (SUI) and
      mixed urinary incontinence and, therefore, it is recommended as a first-line
      therapy. While the effectiveness of treatment is established, there are different
      theoretical rationales for why PFM training is effective. The aims of this
      article are to discuss the theories behind why PFM training is effective in
      treating SUI and to discuss each theory in the framework of new knowledge of
      functional anatomy and examples of results from RCTs. There are three proposed
      theories to explain the effectiveness of PFM training for SUI: 1) women learn to
      consciously pre-contract the PFMs before and during increases in abdominal
      pressure (such as coughing, physical activity) to prevent leakage; 2) strength
      training builds up long-lasting muscle volume and thus provides structural
      support; and 3) abdominal muscle training indirectly strengthens the PFM. The
      first can be placed in a behavioral construct, while the two latter both have the
      aim of changing neuromuscular function and morphology, thus making the PFM
      contraction automatic. To date there are RCTs and basic anatomy studies to
      support the first two concepts only.

PMID- 15014934
TI  - Lack of the complete circular rhabdosphincter and a distinct circular smooth
      muscle layer around the proximal urethra in elderly Japanese women: an anatomical
      study.
AB  - Histological observations of semiserial sections obtained from the cadavers of 30
      elderly Japanese women (aged 61-93 years) found that the urethral rhabdosphincter
      (URS) usually occurred as a ventrally localized structure instead of exhibiting
      the normal completely circular configuration. The superoinferior length,
      thickness and muscle fiber density of the URS area showed significant
      interindividual variation. A thick fascicle, extending posterolaterally from the
      URS and radiating to the lateral vaginal wall and other perineal tissues, was
      usually observed. A circular smooth muscle layer, which immediately surrounded
      the longitudinal smooth muscle layer, was consistently present in the proximal
      urethral but not in the bladder neck. These findings suggest that voluntary
      sphincteric action is weak or incomplete in elderly Japanese women. We therefore
      hypothesize that upward retraction of the midurethra by the URS, compression of
      the distal urethra by its posterolateral extensions, and tonus provided by the
      outer circular smooth muscle layer all contribute to maintaining continence in
      these women.

PMID- 15014935
TI  - The split labium minus flap graft technique.
AB  - The split labium minus flap graft technique was used to restore tissue volume and
      therefore elasticity into the bladder neck area of vagina in eight patients.
      Three full-thickness vaginal incisions were made, a longitudinal incision
      extending from external urethral meatus to 3-4 cm beyond the bladder neck, and
      two transverse incisions, one just below the external urethral meatus and the
      other at the level of the bladder neck. The vagina, urethra and bladder neck were
      mobilized widely and the suburethral flaps rotated downwards, leaving a bare area
      below the urethra. A transverse incision was made across the base of one labium
      minus (LM) and the incision carried up on each side to the ridge of the LM. The
      inner wall was dissected clear of the outer wall, creating a flap. This was then
      rotated into the bare area formed by dislocation of the suburethral vagina. The
      flap was attached to the pubococcygeus muscles laterally, to the external meatus
      superiorly and to the vaginal skin inferiorly. All the cut surfaces of the vagina
      and LM were joined with 00 Dexon sutures. Postoperative pain was minimal. All
      patients were discharged within 48 h, and there was excellent anatomical
      restoration at 6 weeks' follow-up. The technique works well in patients with
      adequately large labia minora, and has potential uses for patients who have
      deficient vaginal tissue in the hammock or bladder neck areas of the vagina.

PMID- 15014936
TI  - Promoting urinary continence in postpartum women: 12-month follow-up data from a
      randomised controlled trial.
AB  - A physiotherapist-delivered continence promotion program was recently implemented
      with postpartum women in Australia. A previous randomised controlled trial
      demonstrated that the program was effective in promoting pelvic floor exercises
      and continence at 3 months postpartum. The present study compares pelvic floor
      exercise frequency and continence status for women in the intervention and 'usual
      care' control groups at 12 months postpartum. While there was no significant
      difference in continence status, women in the intervention group were more likely
      than those in the control group to be practising pelvic floor exercises at
      adequate frequencies. In turn, continued adherence to pelvic floor exercises at
      12 months was predictive of continence at that time. Potential strategies for
      enhancing women's adherence to pelvic floor exercise regimes during and beyond
      the postpartum year are discussed.

PMID- 15014937
TI  - Synergistic non-surgical management of pelvic floor dysfunction: second report.
AB  - The normal pelvic floor functions as a balanced synergistic system composed of
      muscle, connective tissue (CT), and nerve components, with CT being the most
      vulnerable. The aim was to address a wide range of pelvic floor dysfunctions by
      strengthening all possible components of the system with minimal time loss,
      weaving every element of treatment seamlessly into a daily routine. The study
      group consisted of patients from a tertiary referral pelvic floor clinic who,
      after testing, opted for nonsurgical treatment of their problem. There were no
      exclusion criteria. The patients had presented with symptoms which included
      stress, urge, frequency, nocturia, abnormal emptying and pelvic pain, and the
      fate of these was tracked prospectively. The regime comprised four visits in 3
      months. An anatomical classification guided diagnosis of anatomical defects in
      the anterior, middle and posterior compartments of the vagina. HRT was
      administered to all patients, electrotherapy 20 min per day for 4 weeks,
      squeezing 3 x 12 per day, reverse pushdowns 3 x 12 per day and squatting or
      equivalent up to 20 min per day. Of 147 patients (mean age 52.5 years), 53%
      completed the programme. Median QOL improvement reported was 66%, mean cough
      stress test urine loss reduced from 2.2 g (range 0-20.3 g) to 0.2 g (range 0-1.4
      g), p =<0.005, and 24-h pad loss from a mean of 3.7 g (range 0-21.8 g) to a mean
      of 0.76 g (range 0-9.3 m), p =<0.005. Frequency, nocturia and pelvic pain were
      significantly improved ( p=<0.005). Residual urine reduced from mean 202 ml to
      mean 71 ml ( p=<0.005). This method extends indications for nonsurgical therapy
      beyond stress incontinence, and the results appear to encourage this approach.
      Confirmation by other investigators is required.

PMID- 15014938
TI  - Comparison of the ICIQ-SF and 24-hour pad test with other measures for evaluating
      the severity of urodynamic stress incontinence.
AB  - This study compared the International Consultation on Incontinence Questionnaire
      Short Form (ICIQ-SF) and the 24-h pad test with other measures that assess
      severity of urinary loss in women with urodynamic stress incontinence (USI).
      Ninety-five women with primary or recurrent (secondary) USI were recruited.
      Assessment of the severity of urinary loss was made using the ICIQ-SF, a 24-h pad
      test, continence questionnaire, Stamey grade, and 3-day frequency volume diary.
      The relationship between these measures of incontinence severity was analysed.
      The mean age was 54 years (SD+/-12) and median parity 2 (IQR 1-3). In the primary
      USI group there was a strong correlation between the ICIQ-SF and the 24-h pad
      test (r=0.458, P =0.000). Both the ICIQ-SF (Kendall's' tau b=0.331, p =0.003) and
      24-h pad test (Kendall's tau b=0.399, p =0.002) also correlated with the mean
      frequency of urinary loss on diary but not with the Stamey grade. No subjective
      or objective tests correlated with each other in women with secondary USI. These
      results demonstrate a good correlation between the 24-h pad test diary loss, and
      ICIQ-SF in women with primary USI. Because it also includes a measure of quality
      of life impact in a short user-friendly format, we suggest that the ICIQ-SF
      should have widespread applicability as an outcome measure in patients with
      stress incontinence.

PMID- 15014939
TI  - Can quality of life be improved by pelvic floor muscle training in women with
      urinary incontinence after ischemic stroke? A randomised, controlled and blinded
      study.
AB  - The purpose of this study was to evaluate the effect of pelvic floor muscle
      training in women with urinary incontinence after ischemic stroke measured by
      quality of life (QoL) parameters. Three hundred thirty-nine medical records of
      stroke patients were searched. Twenty-six subjects were randomised to a Treatment
      Group or a Control Group in a single blinded, randomised study design. The
      intervention included 12 weeks of standardised pelvic floor muscle training. The
      outcome was measured by the Short Form 36 (SF-36) Health Survey Questionnaire and
      The Incontinence Impact Questionnaire (IIQ). Twenty-four subjects completed the
      study. The SF-36 and IIQ did not show significant difference between the two
      groups. Despite the high prevalence of stroke with urinary incontinence, it is
      difficult to include these patients in such studies. The samples were too small
      to detect any significant differences. Development of specific instruments for
      QoL in stroke patients with urinary incontinence can be recommended.

PMID- 15014940
TI  - Air-charged and microtransducer urodynamic catheters in the evaluation of
      urethral function.
AB  - This study aimed to compare measurements of urethral pressure profile and
      Valsalva leak point pressure (VLPP) obtained with air-charged and microtransducer
      catheters. Forty-five women with urogynecologic dysfunction underwent
      multichannel urodynamic evaluation including maximum urethral closure pressure
      (MUCP), functional urethral length (FUL), and VLPP with air-charged balloon
      catheters as well as microtransducer catheters. Lin's concordance coefficient was
      used to examine the agreement of MUCP, VLPP, and FUL measurements with the two
      catheters. The MUCPs measured with the two catheters had a high concordance
      coefficient of 0.69 (95% CI 0.50, 0.82). The VLPP measurements obtained with the
      catheters also agreed well, with a concordance coefficient of 0.71 (95% CI 0.43,
      0.87). The measurements of mean FUL had a low concordance of 0.35 (95% CI 0.085,
      0.57). Overall, air-charged and microtransducer catheters yield similar
      information when evaluating VLPP and MUCP. There were differences in FUL and
      these were likely due to different catheter diameters.

PMID- 15014941
TI  - TVT and Sparc suburethral slings: a case-control series.
AB  - Two midurethral slings, TVT and Sparc, are the subject of this case-control
      series aimed at assessing sling placement, voiding function, bladder symptoms and
      patient satisfaction. Thirty-seven Sparc and 69 TVT patients were matched for
      age, body weight, pre-existing urge incontinence, preoperative voiding,
      concomitant surgery and length of follow-up (mean 0.6, range 0.1-1.5 years).
      There were no significant differences for subjective cure/improvement,
      satisfaction or symptoms of incontinence. The clinical stress test was positive
      in 8/37 Sparc vs 4/69 TVT patients ( p=0.019). The TVT had a more negative effect
      ( p=0.001) on postoperative voiding. The Sparc was situated more cranially at
      rest and further from the symphysis pubis, and was more mobile ( p<0.001) on
      Valsalva. There are significant differences in medium-term outcomes after TVT and
      Sparc, affecting tape placement, mobility, effect on voiding function and
      objective stress continence. Patient satisfaction and subjective cure rates seem
      similar.

PMID- 15014942
TI  - A modified vaginal wall patch sling technique as a first-line surgical approach
      for genuine stress incontinence with urethral hypermobility: long-term follow up.
AB  - We describe our long-term outcome for patients with genuine stress incontinence
      (GSI) and urethral hypermobility using a modified vaginal wall patch sling
      technique. Fifty-three patients were studied. Preoperatively, all patients had a
      positive standing stress test and urethral hypermobility on Q-tip testing. On
      urodynamics, all patients had absence of detrusor contractions on subtracted
      cystometry. The mean age of the patients was 45+10.2 years. Forty-four patients
      demonstrated complete symptomatic and urodynamic improvement. Five patients had a
      noticeable failure observed within the first 12 months of follow up and four
      patients developed later recurrence despite initial success. The overall success
      rate after 5 years of follow up was 83% (n=44/53). The modified vaginal wall
      patch sling technique appears to have a good long-term success rate with low
      operative morbidity and minimal postoperative voiding dysfunction. The patch
      sling can be used as a first-line surgical approach for GSI with urethral
      hypermobility and be combined with other vaginal surgery.

PMID- 15014943
TI  - Needle tip control and its effect in reducing intraoperative complications during
      tension-free vaginal tape placement.
AB  - Tactile needle tip control was used to aid perforation during standard tension
      free vaginal tape (TVT) placement to treat urinary incontinence. The success and
      complications of this novel method were compared retrospectively with the
      reported results of the standard technique. One hundred nine patients had TVT
      placement between 1998 and 2001, with follow-up continuing into 2002.
      Preoperatively, the severity of urinary incontinence was assessed objectively.
      Postoperatively, TVT effectiveness was assessed subjectively by standardized
      questionnaire, completed by 78 of the 109 patients (72%). Objective 2-year rates
      for continence or improvement and most complication rates were similar to
      previously reported results. Needle tip control was helpful in lowering the
      occurrence of bladder perforation. Longer postoperative recovery times associated
      with postoperative dysuria or obstruction did not decrease patient satisfaction
      if the patient experienced a marked improvement in leakage.

PMID- 15014944
TI  - Fournier's gangrene after tension-free vaginal tape (TVT) procedure.

PMID- 15014945
TI  - Gene transfer to the tendon-bone insertion site.
AB  - This study investigated whether gene transfer to the tendon-bone insertion site
      is possible during early tendon-transplant healing using viral vectors. In
      addition, we evaluated the optimal gene delivery technique for an in vivo
      adenoviral gene transfer to a tendon-bone insertion site in a bone tunnel. Twenty
      six rabbits underwent a bilateral transfer of the flexor digitorum longus tendon
      into a bone canal in the calcaneus. The animals were divided into two groups. The
      first group (n=18) received a direct injection of an adenoviral vector carrying
      the luciferase marker gene into the tendon on the left side, while on the right
      side the adenoviral vector was first injected into the bone trough and the tendon
      was later inserted into the trough. The analysis of this experiment showed that
      over a 4-week period a higher luciferase activity was achieved using the bone
      trough immersion technique. In the second group (n=8) we therefore used the
      qualitative marker virus (Ad/-LacZ) with the bone trough immersion technique in
      order to show the site of gene expression. The histological analysis of this
      experiment demonstrated the presence of beta-galactosidase positive cells within
      the tendon-bone interface over a 4-week period. Therefore we showed in the first
      part of this study that the bone canal provides a more efficient target for
      direct adenoviral gene delivery than the tendon. In the second part of the study
      we demonstrated the feasibility of the bone trough immersion technique since
      sustained gene expression within the tendon-bone interface was obtained for up to
      4 weeks. This study has shown the feasibility of gene delivery to the tendon-bone
      interface and provides the basis for the application adenoviral delivery of
      growth factor genes to the tendon-bone insertion site.

PMID- 15014946
TI  - Dimethylation of histone H3 lysine 9 is a critical mark for DNA methylation and
      gene silencing in Arabidopsis thaliana.
AB  - The Arabidopsis KRYPTONITE gene encodes a member of the Su(var)3-9 family of
      histone methyltransferases. Mutations of kryptonite cause a reduction of
      methylated histone H3 lysine 9, a loss of DNA methylation, and reduced gene
      silencing. Lysine residues of histones can be either monomethylated, dimethylated
      or trimethylated and recent evidence suggests that different methylation states
      are found in different chromatin domains. Here we show that bulk Arabidopsis
      histones contain high levels of monomethylated and dimethylated, but not
      trimethylated histone H3 lysine 9. Using both immunostaining of nuclei and
      chromatin immunoprecipitation assays, we show that monomethyl and dimethyl
      histone H3 lysine 9 are concentrated in heterochromatin. In kryptonite mutants,
      dimethyl histone H3 lysine 9 is nearly completely lost, but monomethyl histone H3
      lysine 9 levels are only slightly reduced. Recombinant KRYPTONITE can add one or
      two, but not three, methyl groups to the lysine 9 position of histone H3.
      Further, we identify a KRYPTONITE-related protein, SUVH6, which displays histone
      H3 lysine 9 methylation activity with a spectrum similar to that of KRYPTONITE.
      Our results suggest that multiple Su(var)3-9 family members are active in
      Arabidopsis and that dimethylation of histone H3 lysine 9 is the critical mark
      for gene silencing and DNA methylation.

PMID- 15014947
TI  - Reasons for non-standard treatment in elderly patients with advanced head and
      neck cancer.
AB  - Elderly patients with head and neck cancer are less likely to receive standard
      treatment. This study assessed the influence that age, tumour characteristics,
      comorbidity, social support, depressive symptoms and quality of life have on
      treatment choice. One hundred and five patients between 45 and 60 years of age
      and 78 patients of > or =70 years of age with carcinoma of the oral cavity (stage
      > or =II), oro- and hypopharynx (stage > or =II) or larynx (stage > or =III)
      completed a questionnaire on quality of life (EORTC QLQ-C30 and H&N35),
      depressive symptoms (CES-D) and social support (RSS12-I). In the 45-60 age group,
      89% received standard treatment, compared with 62% of the > or =70 age group. A
      multivariate logistic regression analysis showed that the following factors
      predicted non-standard treatment: marital status (widowed), advanced tumour
      stage, comorbidity, less pain, considering the length of life less important than
      its quality and old age. This study showed that age itself independently
      influences treatment choice. However, it should be emphasised that the choice of
      a treatment should be based on a medical assessment and the patient's
      preferences, not on chronological age.

PMID- 15014948
TI  - A case of Cronkhite-Canada syndrome with vestibular disturbances.
AB  - A 66-year-old Japanese man with Cronkhite-Canada syndrome (CCS) presented with
      complaints of long-lasting dysequilibrium. On neuro-otological examination, he
      showed gaze-evoked nystagmus at the rightward and leftward gaze, and saccadic
      pursuit. On the caloric test, he showed no response in either side, and on the
      head-impulse test he showed bilateral loss of vestibule-ocular reflexes around
      the yaw axis, while he had bilateral normal responses on the vestibular-evoked
      myogenic potential testing. Neuro-otological findings suggested that he had
      lesions in the peripheral vestibular system as well as the central nervous
      system. Neurological disorders such as sensory neuropathy have been reported in
      patients with CCS. This patient's balance problems could be due to CCS itself.

PMID- 15014949
TI  - Relation between body mass and postmenopausal symptoms in surgically castrated
      women.
AB  - INTRODUCTION: Post-menopause androgens are the essential precursors for estrogen
      synthesis through their conversion in peripheral tissues. The main postmenopausal
      estrogen is estrone, which is also peripherally converted into estradiol.
      Concentrations of these two estrogens are directly proportional in circulation.
      We wanted to establish whether there is a direct correlation between body mass
      and postmenopausal symptoms in surgically castrated women. MATERIALS AND METHODS:
      We analyzed 30 patients with artificially induced menopause, 3-12 months after
      the operation (hysterectomy and bilateral adnexectomy). Prior to being put on
      hormone substitution therapy the following was obtained from the patients: Body
      Mass Index--BMI (kg/m(2)), measurement of estradiol (E(2)) by RIA method, and 12
      subjective symptoms analyzed according to intensity and frequency. The
      relationship between BMI, E(2) level and subjective symptoms were assessed.
      RESULTS: By analyzing the correlation coefficient it was shown that there was
      statistically significant causal-consequential connection between the E(2) level
      and BMI (R(2)=0.1647, p<0.05). There is no strong correlation between BMI and
      symptoms (R(2)=0.004, p<0.05). However, E(2) level correlated with subjective
      symptoms (R(2)=0.2123, p<0.05). CONCLUSIONS: Estrogen production in postmenopause
      is dependent on the substrate availability, and thus with adiposity. Therefore,
      we were surprised by the lack of correlation between BMI and symptoms. This
      suggests that estrogen metabolism and biological effects are not primarily
      affected by BMI, and that expression of postmenopausal symptoms does not depend
      only on estrogen level.

PMID- 15014950
TI  - Adenomyosis in a patient with mosaic Turner's syndrome.
AB  - BACKGROUND: Few case reports describing endometriosis in patients with gonadal
      dysgenesis have been published, but none has reported the presence of adenomyosis
      in a patient with Turner's syndrome. CASE: A 31-year-old woman with mosaic
      Turner's Syndrome (45,X/46,XX/47,XXX) was referred to us because of severe iron
      deficiency anaemia due to hypermenorrhea and persistent lower abdominal pain for
      more than six months. She presented normal secondary sex development, normal
      breast, normal pubic and axillary hair. The external genitalia were also normal.
      Laboratory examination showed normal gonadotropin, 17beta-estradiol, plasma
      androgens and cortisol levels. At transabdominal ultrasound a myoma (15 x 8.5 x 8
      cm) arising from the posterior uterine wall was suspected. The mass was removed
      during laparotomy. Histologic examination confirmed the presence of the myoma and
      revealed the presence of focal adenomyosis. CONCLUSION: Adenomyosis and
      leiomyomata are separate entities but they share a common pathology in that they
      develop primarily in women of reproductive age and their growth is oestrogen
      dependent. To our knowledge, this is the first case report in the literature of
      adenomyosis in a woman who had the Turner's syndrome.

PMID- 15014951
TI  - Serum levels of zinc and copper in hydatidiform mole.
AB  - OBJECTIVE: The aim of this study was to identify any association between serum
      levels of trace elements zinc and copper and development of hydatidiform mole.
      STUDY DESIGN: Blood samples of 35 patients with complete hydatidiform mole and 34
      pregnant women controls were evaluated for serum levels of zinc and copper.
      Student's t-test was used for comparison of mean values of serum zinc and copper
      and for demographic variables. p< or =0.05 was considered statistically
      significant. RESULTS: Levels of zinc in serum were found to be significantly
      higher in hydatidiform mole patients than controls (86.3 vs. 68.7 microg/l,
      p=0.027). Serum copper levels were significantly lower in hydatidiform mole
      patients than controls (123.8 vs. 147.8 microg/l, p=0.039; Table 2). CONCLUSION:
      This is the first study in the English scientific literature reporting higher
      serum levels of zinc and lower serum levels of copper associated with complete
      hydatidiform mole.

PMID- 15014952
TI  - Relative importance of IL-4 and IL-13 in lesional skin of atopic dermatitis.
AB  - BACKGROUND: Although both interleukin-4 (IL-4) and IL-13 induce immunoglobulin E
      (IgE) production in vitro, the relative contribution of the two cytokines in
      various skin lesions of atopic dermatitis remains unclear. OBJECTIVE: We examined
      the relative importance of IL-4 and IL-13 in lesional skin of atopic dermatitis
      for IgE production. METHODS: The study group comprised 28 atopic dermatitis
      patients with serum IgE levels more than 2000 IU/ml. The expression levels of IL
      4 mRNA and IL-13 mRNA versus that of glyceraldehyde-3-phosphate dehydrogenase
      (GAPDH) were determined using a semiquantitative reverse transcription-polymerase
      chain reaction (RT-PCR) method in samples of normal-appearing skin from seven
      patients, very mild lesions from eight patients, subacute lesions from ten
      patients and lichenified lesions from ten patients with atopic dermatitis, and in
      samples of normal skin from six healthy control subjects. RESULTS: IL-4 mRNA
      expression was identified in only two of the eight very mild lesions, one of the
      ten subacute lesions, and none of the ten lichenified lesions, whereas IL-13 mRNA
      expression was identified in 27 of the 28 skin lesions of atopic dermatitis. The
      IL-13 mRNA/GAPDH mRNA ratios (x100) in the subacute lesions (94.4+/-20.6) and
      lichenified lesions (71.4+/-40.4) were significantly greater than in the skin of
      healthy controls (13.1+/-17.7; P<0.01, P<0.05, respectively). CONCLUSIONS:
      Upregulation of IL-13 mRNA in subacute and chronic lesions of atopic dermatitis
      along with scant expression of IL-4 mRNA suggest that IL-13 is a crucial cytokine
      in lesional skin.

PMID- 15014954
TI  - Simple curettage without bone grafting for enchondromas of the foot.
AB  - BACKGROUND: Simple curettage without bone grafting for enchondromas of the hand
      and its good clinical results have been reported. Yet, there have been no reports
      regarding simple curettage without bone grafting for enchondromas of the foot.
      The purpose of this study is to elucidate the clinical results of this method for
      enchondromas of the foot. METHODS: We studied eight patients (ten bones) with
      enchondromas of the foot treated with simple curettage without bone grafting.
      After making an oval or round fenestration, the enchondroma was curetted. The
      cortical window of the fenestration was excised in five bones, whereas it was
      replaced at the fenestration site in the other five bones. RESULTS: The affected
      toe was immobilized with a tape in two patients. All patients began to walk on
      the day of surgery or the next day without crutches. Sclerotic changes on the
      plain radiographs were seen 6.4 weeks (range: 4-10 weeks) postoperatively. The
      patients returned to their normal daily activity including occupation and sport
      in 8.6 weeks (range: 0-12 weeks) postoperatively. The radiographic appearance was
      almost normalized in 8.4 months on average (range: 3-14 months). Function was
      classified as excellent in all bones according to a modified Tordai
      classification. CONCLUSION: We conclude that simple curettage without bone
      grafting can be one of the standard surgical treatments for enchondromas of the
      foot.

PMID- 15014953
TI  - Activation of phospholipase C-gamma1 in human keratinocytes by hyperosmolar shock
      without enzyme phosphorylation.
AB  - Human keratinocytes are exposed to strong physical changes, and have the
      potentiality to react to external stimuli by switching on adaptation mechanisms.
      In hyperosmotically shocked keratinocytes a rapid and strong increase in calcium
      has been observed. We showed that this increase could not be prevented by growing
      the cells in medium devoid of calcium and in the presence of EGTA, indicating
      that the intracellular calcium increase was due to delivery from internal stores.
      Further, we observed an increased synthesis of dyacylglycerol and inositol
      trisphosphates after shock, suggesting that phospholipase C mediates both events.
      Our experiments demonstrated that osmotic shock in human keratinocytes leads to
      activation of phospholipase C-gamma1, as measured using an in vitro assay system.
      This activation is independent of protein tyrosine phosphorylation and
      corresponded to a relocation of the enzyme to perinuclear membranes as shown by
      immunofluorescence.

PMID- 15014955
TI  - Glial reactions and the clearance of amyloid beta protein in the brains of
      patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type.
AB  - Although the amyloid beta protein (Abeta) E693Q mutation enhances Abeta
      fibrillization in vitro and cerebral amyloid angiopathy (CAA) in vivo, brain
      parenchymal Abeta deposition and tau pathology in hereditary cerebral hemorrhage
      with amyloidosis-Dutch type (HCHWA-D) are limited. To evaluate whether clearance
      of Abeta by glial cells may play a role in this regard, this immunohistochemical
      study of frontal cortex of 14 HCHWA-D autopsy brains was performed using double
      staining with glial markers and end-specific antibodies to Abetax-42 (Abeta42)
      and Abetax-40 (Abeta40). Tau pathology was also assessed. Numerous microglia
      and/or astrocytes carrying cytoplasmic Abeta42(+)40(-) granules were scattered
      among non-fibrillar (Congo red-negative) Abeta deposits, i.e., clouds, fine
      diffuse plaques, and Abeta42(+)40(-) dense diffuse plaques. On the other hand,
      activated microglia and reactive astrocytes associated with fibrillar (Congo red
      positive) Abeta deposition, i.e., Abeta42(+)40(+) dense diffuse plaques and CAA
      invading the parenchyma, were virtually devoid of Abeta granules. Tau pathology
      was scant and most frequently associated with CAA. These results suggest that
      relatively non-fibrillar parenchymal Abeta deposits may be liable to glial
      clearance. Abeta sequestration by glial cells may be a factor limiting the levels
      of neurotoxic soluble Abeta oligomers in HCHWA-D brain.

PMID- 15014956
TI  - Autologous-allotopic ileum mucosa transplantation for small bowel elongation. A
      morphological study.
AB  - INTRODUCTION: Since a standard therapy for short bowel syndrome does not yet
      exist, every search for new surgical methods would be worthwhile. In previous
      studies we could show that autologous-allotopic ileum mucosa transplantation is
      feasible. After a modification of our technique a vascularized colon muscle coat
      lined completely with transplanted ileum mucosa could be engendered. METHOD: In
      12 young beagles autologous ileum mucosa was transplanted in a demucosed
      vascularized transverse colon segment. The colon coat-ileum mucosa complex was
      anastomosed with the small bowel immediately after transplantation, 4 weeks later
      the animals were sacrificed and histology specimens were harvested from the colon
      coat-ileum mucosa complex, normal ileum and normal colon. After fixation in 2.5%
      glutaraldehyde the samples were frozen (-40 degrees C) and 14 micro m sections
      were stained with hemalaun and eosin. The lumen diameter, the mucosa, submucosa
      and colon muscle coat thickness, as well as the mucosal crypt depth were
      evaluated. RESULTS: The diameter of the colon coat-ileum mucosa-complex was
      smaller than the diameter of normal ileum and colon with no significant stenosis.
      There were no marked differences in thickness of mucosa and depth of the mucosal
      crypts compared to the controls, but the transplanted mucosa showed a slightly
      higher rate of shortened villi. The submucosal layer was thicker following
      transplantation and showed good neovascularization. The circular muscle layer of
      the transplanted colon coat was up to 178% thicker and the thickness of the
      transplanted longitudinal muscle layer differed between 58% and 143% in
      comparison to normal colon. CONCLUSIONS: Only a few histologic differences
      between transplanted and normal ileum mucosa could be observed after autologous
      allotopic ileum mucosa transplantation. Therefore a nearly normal function of the
      colon coat-ileum mucosa complex has to be expected. Long term experiments of the
      histologic changes as well as further functional studies are on-going in order to
      finally apply autologous-allotopic ileum mucosa transplantation clinically.

PMID- 15014957
TI  - Histologic changes in neuronal innervation of the ileum mucosa after autologic
      allotopic ileum mucosa transplantation.
AB  - INTRODUCTION: After successful experimental autologic-allotopic ileum mucosa
      transplantation, we investigated the remodeling of the transplanted submucous and
      mucous plexus, which is essential for the motility of the created colon coat
      ileum mucosa complex. METHOD: In 8 beagles we transplanted ileum mucosa in a
      demucosed vascularized transverse colon segment, which was reanastomosed with the
      small bowel immediately after transplantation. Four weeks later the animals were
      sacrificed and histology specimens taken from the anastomosis site of the colon
      coat-ileum mucosa complex, allowed comparison between transplanted and normal
      mucosa in the same section. After fixation in 4% formaldehyde and PBS the samples
      were embedded in paraffin and 7 micro m sections were prepared. The distribution
      of nerve fibers and submucous ganglia were examined in dewaxed sections, using
      antisera against protein gene product (PGP9.5), a general neuronal marker.
      RESULTS: The submucosal ganglia were prominent in all samples but they were
      smaller and the submucous nerve cells within the ganglia were less numerous
      compared to the controls. The innervation of the transplanted ileum mucosa was
      reduced as the number of nerve fibers in the mucosal villi was decreased. Besides
      these neuromorphologic changes the transplanted mucosa showed a slightly higher
      rate of shortened villi compared to normal ileum mucosa. CONCLUSIONS: After ileum
      mucosa transplantation the submucosal ganglia are smaller and less numerous.
      Furthermore there is a considerable loss of nerve fibers in the mucosal layer.
      Additionally a loss of microvilli in the transplanted ileum mucosa was found.
      Whether these findings represent a state of remodeling or a slow atrophy of the
      enteric nervous system in the transplanted areas is currently under
      investigation.

PMID- 15014958
TI  - Umbilicoplasty for large protruding umbilicus accompanying umbilical hernia: a
      simple and effective technique.
AB  - A large umbilical protrusion with redundant skin accompanying an umbilical hernia
      sometimes needs umbilicoplasty. Although several different techniques for making
      umbilical depression have been used, the results of the plastic surgery are
      sometimes unsatisfactory due to postoperative flattening or disappearance of the
      umbilical depression. To make a permanent umbilical depression that is
      cosmetically acceptable, we have modified the techniques. Umbilicoplasty was
      performed in 14 children whose ages ranged from 6 months-6 years and 3 months
      (median, 1 year and 10 months) and who had umbilical hernia with a large
      umbilical protrusion. After the fascial defect was closed, the diameter of the
      umbilicus was reduced to half that before surgery by removing fan-shaped skin
      flaps and approximating skin edges, and then inverting the umbilicus and fixing
      it caudally to the fascia and skin. There were no postoperative complications,
      and no flattening or disappearance of umbilical depression was observed during
      the follow-up of 10-19 months. The authors' technique of umbilicoplasty for a
      large protruding umbilicus accompanying umbilical hernia is a simple method that
      produces acceptable cosmetic results.

PMID- 15014959
TI  - Cauda equina compression syndrome in a child due to lumbar disc herniation.
AB  - INTRODUCTION: Cauda equina syndrome with sphincter dysfunction is an uncommon and
      feared complication of lumbar disc herniation. CASE REPORT: Lumbar disc disease
      in the pediatric age has been reported infrequently, but to the best of our
      knowledge, this is the first pediatric case of acute lumber disc herniation
      presenting with caudal compression.

PMID- 15014960
TI  - Urinary incontinence in a patient with Duchenne muscular dystrophy and cord in
      the normal position with fatty filum terminale.
AB  - INTRODUCTION: To our knowledge, muscular dystrophy and specifically, Duchenne
      muscular dystrophy, has not previously been associated with gross intrathecal
      abnormalities. CASE REPORT: We report a pediatric patient with Duchenne muscular
      dystrophy that was diagnosed a long time ago and recent onset urinary
      incontinence. MRI revealed a conus medullaris in a normal position with a fatty
      infiltrated filum terminale. Operative intervention was performed entailing
      sectioning of the filum terminale. This resulted in resolution of the child's
      urinary incontinence. CONCLUSION: Although seemingly rare and perhaps associated
      by serendipity, new, unusual neurological deficits in a patient with muscular
      dystrophy, especially of an upper motor neuron nature, should warrant MRI to rule
      out pathology of the spinal cord such as tethering.

PMID- 15014962
TI  - [Hereditary retinochoroidal dystrophies. Part 2: differential diagnosis].
AB  - A generally accepted classification for inherited retinochoroidal dystrophies
      does not exist. The names given to certain disorders are either based on
      ophthalmoscopic findings, or on histologic, electrophysiologic and genetic
      findings. Future research on the molecular genetic background will result in
      better definition of clinical entities. The purpose of this project is to outline
      a practical approach to inherited retinochoroidal dystrophies. For this reason,
      disorders with similar clinical symptoms are grouped together. Generalized
      retinochoroidal dystrophies affecting all retinal areas can be distinguished from
      regional dystrophies. Generalized dystrophies can be subdivided into those with
      peripheral onset, usually associated with initial rod function loss (night
      blindness, peripheral field loss: e.g. retinitis pigmentosa, choroideremia) and
      those with central onset associated with cone function loss (visual acuity loss,
      central scotoma, color vision deficits: e.g. cone or cone-rod dystrophies).
      Regionally limited dystrophies include the multitude of macular dystrophies and
      the autosomal dominant vitreoretinochoroidopathy, which remains limited to the
      periphery. It is important for a differential diagnosis to exclude involvement of
      other organ systems in syndromic disorders. Stationary inherited retinal
      dysfunction (e.g. monochromatism, congenital stationary night blindness) and
      other inherited or acquired diseases have to be excluded as well. Guidelines for
      differential diagnosis are presented.

PMID- 15014963
TI  - [Unclear connective tissue tumor].

PMID- 15014961
TI  - [Digital planimetry for long-term follow-up of glaucomatous optic disk injuries
      in patients with normal pressure glaucoma].
AB  - BACKGROUND: Aim of the study was to evaluate the validity of quantitative
      planimetry of the optic disc with a new digital method and to assess the
      correlation of the measurements with morphological changes in eyes with low
      tension glaucoma. MATERIAL AND METHODS: The study included 40 eyes from 40
      patients (age 61+/-12 years) with low tension glaucoma with a mean follow-up of
      4.9+/-2.1 (range 3-9) years. All patients underwent annually complete
      ophthalmological examination including 15 degrees color optic disc photographs
      and automated white-white visual fields. RESULTS: Out of 40 eyes morphological
      examination showed signs of progression in 18 eyes and in 22 eyes no
      morphological changes of the optic disc were detected The digital planimetrically
      measured optic disc area did not vary between the first and the last photos. The
      mean differences between measured values for optic disc area between two
      examinations were 0.027+/-0.071 mm(2) and the reliability coefficient (Cronbachs
      alpha) was 0.99. Neuroretinal rim area decreased statistically highly
      significantly in eyes with morphological progression, and in eyes without
      morphological changes decreased only slightly. CONCLUSIONS: The variation of
      measurements of the optic disc area can be minimized by consideration and
      adjustment of the individual image magnification of the photos using digital
      planimetry. This method allows the quantitative assessment even of slight changes
      of the neuroretinal rim area and is a useful examination for follow-up of
      glaucoma patients.

PMID- 15014964
TI  - [Adjustment of eyelid level in levator surgery for ptosis. Surgical aspects].
AB  - The main aim in ptosis surgery is to achieve a sufficient and symmetric
      adjustment of the lids. Successful adjustment is possible when consideration is
      given to preoperative factors and intraoperative findings. Any necessary
      postoperative readjustment using adjustable sutures or revision surgery in the
      1st week can optimize results in some cases. This article reviews the relevant
      surgical aspects of adjustment. We made a comparative analysis of diagnostic and
      surgical factors that influence the adjustment of the lid level.

PMID- 15014965
TI  - [Alternatives to lid reconstruction. Systematic presentation].
AB  - Eyelid reconstruction cannot be planned only by following current concepts. A
      systematic analysis of the defect considering the concentric zones, function,
      esthetics, and surgical trauma can help to select the appropriate technique among
      the possible alternatives.

PMID- 15014966
TI  - Sequence organization and matrix attachment regions of the human serine protease
      inhibitor gene cluster at 14q32.1.
AB  - The human serine protease inhibitor (serpin) gene cluster at 14q32.1 is a useful
      model system for studying the regulation of gene activity and chromatin
      structure. We demonstrated previously that the six known serpin genes in this
      region were organized into two subclusters of three genes each that occupied
      approximately 370 kb of DNA. To more fully understand the genomic organization of
      this region, we annotated a 1-Mb sequence contig from data from the Genoscope
      sequencing consortium (http://www.genoscope.cns.fr/ ). We report that 11
      different serpin genes reside within the 14q32.1 cluster, including two novel
      alpha1-antiproteinase-like gene sequences, a kallistatin-like sequence, and two
      recently identified serpins that had not been mapped previously to 14q32.1. The
      genomic regions proximal and distal to the serpin cluster contain a variety of
      unrelated gene sequences of diverse function. To gain insight into the chromatin
      organization of the region, sequences with putative nuclear matrix-binding
      potential were identified by using the MAR-Wiz algorithm, and these MAR-Wiz
      candidate sequences were tested for nuclear matrix-binding activity in vitro.
      Several differences between the MAR-Wiz predictions and the results of
      biochemical tests were observed. The genomic organization of the serpin gene
      cluster is discussed.

PMID- 15014967
TI  - Comparative genomics of the keratin-associated protein (KAP) gene clusters in
      human, chimpanzee, and baboon.
AB  - We have previously identified a cluster of 16 genes that encode hair-specific
      proteins, called keratin-associated proteins (KAPs), located on human Chromosome
      (Chr) 21q22.3. Here, we have identified similar KAP gene clusters in two
      primates, chimpanzee and baboon. DNA sequence comparison revealed the common
      cluster structure consisting of 16 KAP genes for these three primates, but a
      significant difference was found in the baboon. Baboon possesses a new KAP gene
      not found in human and chimpanzee, whereas one KAP gene ( KRTAP18.12) that exists
      in human and chimpanzee was lost in baboon, making no change in the total number
      of KAP genes. Interestingly, the sequence for coding regions are highly variable
      among species owing to insertions and deletions, resulting in variation of gene
      size. On the contrary, the sequences for the 5' upstream region are highly
      conserved among species. These findings suggest that the ancestral KAP gene
      cluster was composed of 17 genes before the divergence of Old World monkeys
      (baboon) to the anthropoid (human and chimpanzee).

PMID- 15014968
TI  - Genetic control of novel food preference in mice.
AB  - In food preference studies, mammals are often categorized as being either
      neophilic or neophobic, i.e., preferring or disliking a novel-tasting food. To
      date, the genetic factors influencing novel food preference have not been
      elucidated. To understand this phenomenon, we investigated the genetics of food
      preference in eight inbred strains of mice. We gave them plain-, cinnamon-, or
      cocoa-flavored powdered food on day 0 for 45 min and then a choice of cinnamon-
      or cocoa-flavored food 14 days later. We determined their preference for novel
      versus already-experienced flavored food and found that some inbred strains chose
      the food that they had been given previously, while others chose a different
      food. In particular, the DBA/2 strain chose more cinnamon-flavored food after it
      was pre-exposed to cinnamon, while the B6 strain chose less cinnamon-flavored
      food after this initial exposure. The BXD recombinant inbred (RI) strain set was
      then used to map quantitative trait loci (QTLs) that influence this novel food
      preference. One of these QTLs was found to map to the distal end of Chromosome
      (Chr) 8.

PMID- 15014969
TI  - Analysis of imprinting in mice with uniparental duplication of proximal
      chromosomes 7 and 15 by use of a custom oligonucleotide microarray.
AB  - We have developed an imprinting assay combining the use of mice carrying maternal
      or paternal duplication of chromosomal regions of interest with custom
      oligonucleotide microarrays. As a model system, we analyzed RNA from CNS tissue
      of neonatal mice carrying the reciprocal translocation T(7;15)9H and uniparental
      duplication of proximal Chr 7 and 15. The duplicated region includes the locus on
      proximal Chr 7 corresponding to the human Prader-Willi/Angelman Syndrome. The
      microarray contained 322 oligonucleotides, including probes to detect major genes
      involved in neural excitability and synaptic transmission, as well as known
      imprinted genes mapping to proximal Chr 7: Ndn, Snrpn, Mkrn3, Magel2, Peg3, and
      Ube3a. Imprinting of these genes in neonatal cortex and cerebellum was first
      confirmed by quantitative RT-PCR. Their inclusion on the microarray thus provided
      positive controls for evaluating the effect of background on the sensitivity of
      the assay, and for establishing the minimum level of expression required to
      detect imprinting. Our analysis extended previous work by revealing bi-allelic
      expression in CNS tissue of those queried genes mapping to proximal Chr 7 or 15,
      including the Gabrb3 gene, for which there have been conflicting reports.
      Microarray analysis also revealed no effect of the maternal or paternal disomy on
      expression levels of the unlinked genes detected, including those potentially
      implicated in the Prader-Willi or Angelman Syndrome. In addition, quantitative RT
      PCR revealed a gene dosage effect in both cerebellum and cortex for all of the
      known imprinted genes assayed, except for Ube3a in cerebellum.

PMID- 15014970
TI  - The neurological mutant quaking(viable) is Parkin deficient.
AB  - The mouse mutant quaking(viable) ( qk(v)) has been studied for almost four
      decades as a model for dysmyelination of the central nervous system (CNS). The
      genetic lesion associated with the qk(v) phenotype is a large deletion of
      approximately 1 Megabase on mouse Chromosome (Chr) 17. This deficiency alters the
      expression of transcripts from the qkI locus in oligodendrocytes, resulting in
      improper myelination of the CNS in animals homozygous for the deletion. To
      determine whether other genes within the deletion contribute to the
      quaking(viable) phenotype, we physically mapped and sequenced the deleted
      interval. We determined that the mouse Parkin gene, as well as the Parkin co
      regulated gene ( Pacrg), lies within the qk(v) deletion. We determined that qk(v)
      mutants completely lack the expression of the Parkin gene product. Loss-of
      function mutations in the human PARKIN gene cause autosomal juvenile Parkinson's
      disease (AR-JP). Our studies show that the deletion of Parkin in qk(v) brains
      does not result in the loss of dopaminergic neurons typical of AR-JP patients.
      Also, alpha-synuclein, a target of Parkin-dependent ubiquitination, does not
      accumulate in qk(v) mutant brains. Despite the lack of AR-JP-like neuropathology
      in qk(v) mice, this mutant may constitute a readily available model for the study
      of the cellular function of Parkin. This is the first report of a gene distinct
      from qkI affected by the qk(v) deletion. The discovery of the multigenic nature
      of this classical mouse mutation calls for the re-evaluation of its phenotypic
      characterization.

PMID- 15014971
TI  - Molecular cloning and functional analysis of porcine SULT1A1 gene and its
      variant: a single mutation SULT1A1 causes a significant decrease in sulfation
      activity.
AB  - The characterization of the SULT1A1 gene and its variants should have an
      important impact on the efforts to develop genetic markers to select for low
      skatole in pigs. Raising intact male pigs would have a significant economic
      impact on the pork industry; however, the presence of skatole (a major cause of
      boar taint) in meat from male pigs would be highly objectionable to consumers. It
      has been shown that the phase II metabolism of skatole metabolites by phenol
      sulfotransferase is related to the clearance of skatole in the liver. The aim of
      this study was to isolate and characterize the SULT1A1 gene from pig liver,
      examine its expression, identify genetic polymorphisms, and study how a genetic
      variation in this enzyme translates into interindividual variation in skatole
      levels. We show here that a substitution of A-->G at base 546 of SULT1A1 causes a
      significant decrease in its sulfation activity and thus may be at least partially
      responsible for a higher level of skatole in pigs. Our findings provide an
      important basis toward the goal of making it possible to predict the sulfation
      status in pigs and the development of genetic markers for low skatole.

PMID- 15014972
TI  - Beta-2-microglobulin haplotypes in U.S. beef cattle and association with failure
      of passive transfer in newborn calves.
AB  - Failure of passive transfer (FPT) is a condition in which neonates do not acquire
      protective serum levels of maternal antibodies. A principal component of antibody
      transport is the neonatal receptor for the Fc portion of immunoglobulin, a
      heterodimer of a MHC-1 alpha-chain homolog ( FCGRT) and beta-2-microglobulin (
      B2M). Previously, two FCGRT haplotypes were associated with differences in
      immunoglobulin G (IgG) passive transfer in cattle (Laegreid et al. (2002) Mamm
      Genome 13, 704-710). The present study had two objectives: first, to characterize
      the B2M haplotype structure in a diverse group of U.S. beef cattle, and second,
      to evaluate those haplotypes for association with either high or low serum IgG
      levels in newborn calves. Twelve single nucleotide polymorphisms (SNPs), assorted
      into eight haplotypes, were identified by sequencing regions of B2M exons II and
      IV in a multi-breed panel of 96 beef cattle. Calves homozygous for one of the
      eight haplotypes ( B2M 2,2) were at increased risk of FPT (odds ratio = 10.60,
      CI(95%) 2.07-54.24, p = 0.005). These results indicate that this haplotype is in
      linkage disequilibrium with genetic risk factors affecting passive transfer of
      IgG in beef calves, an important determinant of neonatal calf morbidity and
      mortality.

PMID- 15014974
TI  - A pragmatic approach to metal artifact reduction in CT: merging of metal artifact
      reduced images.
AB  - The purpose of this study was to improve metal artifact reduction (MAR) in X-ray
      computed tomography (CT) by the combination of two artifact reduction methods.
      The presented method constitutes an image-based weighted superposition of images
      processed with two known methods for MAR: linear interpolation of reprojected
      metal traces (LI) and multi-dimensional adaptive filtering of the raw data (MAF).
      Two weighting concepts were realized that take into account mean distances of
      image points from metal objects or additional directional components. Artifact
      reduction on patient data from the jaw and the hip region shows that although the
      application of only one of the MAR algorithms can already improve image quality,
      these methods have specific drawbacks. While MAF does not correct corrupted CT
      values, LI often introduces secondary artifacts. The corrective impact of the
      merging algorithm is almost always superior to the application of only one of the
      methods. The results obtained with directional weighting are equal to or in many
      cases better than those of the distance weighting scheme. Merging combines the
      advantages of two fundamentally different approaches to artifact reduction and
      can improve the quality of images that are affected by metal artifacts.

PMID- 15014973
TI  - MR assessment of fetal lung development using lung volumes and signal
      intensities.
AB  - The purpose of this study was to evaluate the monitoring and diagnostic potential
      of MRI in fetal lung development and disease using lung volume and signal
      intensity changes through gestation. Thirty-five healthy fetuses (22-42 weeks)
      were examined on a 1.5- T MR system using sagittal T2w single-shot fast spin-echo
      imaging (TR indefinite, TE 90 ms, slice thickness/gap 3-5/0 mm, FOV 26-40 cm, NEX
      0.5). Fetal body and lung were segmented manually and volumes calculated. Signal
      intensities (SI) of fetal lung and three reference values were measured on the
      section best displaying the lung. Regions of interests were defined by including
      the maximal organ area possible. The following SI ratios were generated:
      lung/liver, lung/amniotic fluid, lung/muscle, liver/fluid and liver/muscle.
      Volumes and ratios were correlated with gestational age. Data from seven fetuses
      with pulmonary pathology were compared with these normative values. Absolute lung
      volume varied from 12.3 to 143.5 cm(3) in correlation with gestational age (
      P<0.001); lung volume relative to total body volume ranged from 1.6 to 5.0%,
      decreasing with gestational age ( P=0.001). All SI ratios measured were unrelated
      to gestational age. Diagnoses in the seven abnormal fetuses were hydrothorax (
      n=2), congenital cystic adenomatoid malformation ( n=2), diaphragmatic hernia (
      n=2) and pulmonary sequestration ( n=1); their absolute and relative lung volumes
      were below normal ( P<0.001). The SI ratios did not differ significantly from
      those in the normal population. Normative MR fetal lung volumes may have
      important clinical applications in confirming and quantifying intrauterine
      pulmonary hypoplasia and in complementing ultrasound in the planning of fetal and
      post-natal surgery. No clinical relevance was found for fetal lung SI values.

PMID- 15014975
TI  - Magnetic resonance imaging findings of osteoid osteoma of the proximal femur.
AB  - Osteoid osteoma (OO) is a benign bone tumor whose main radiological finding is
      nidus. OO of the proximal femur can also result in non-specific findings such as
      hip joint effusion, perinidal bone marrow edema and soft tissue mass. Since the
      nidus may be difficult to identify with MR, these non-specific findings can lead
      to erroneous diagnosis. Therefore, MR imaging technique should be optimized in
      order to identify nidus. Since MR imaging has assumed increasing importance in
      the evaluation of disorders of the hip, radiologists must be aware of the
      spectrum of findings of OO of the proximal femur. The aim of this pictorial
      review is to show the MR imaging findings of intra-articular and extra-articular
      OO of the proximal femur.

PMID- 15014976
TI  - CT-guided radiofrequency ablation of osteoid osteoma: long-term results.
AB  - The aim of the study was to assess the safety and efficacy of CT-guided
      percutaneous radiofrequency (RF) ablation of osteoid osteoma (OO). From 1997 to
      2001, RF ablation was performed on 38 patients with OO, diagnosed clinically and
      by radiography, scintigraphy, contrast-enhanced MRI, and CT. Treatment was
      performed via percutaneous (n=29) or surgical (n=9) access, under CT guidance in
      all cases, with an 18-gauge straight electrode. Patients were discharged within
      24 h and followed up clinically (at 1 week and every 6-12 months) and with MRI
      (at 6 months) and scintigraphy (after 1 year). The technical success rate was
      100%. Complications occurred in two patients, consisting in local skin burns. The
      follow-up range was 12-66 months (mean +/- SD, 35.5+/-7.5 months). Prompt pain
      relief and return to normal activities were observed in 30 of 38 patients.
      Persistent pain occurred in eight patients; two patients refused further RF
      ablation and were treated surgically; RF ablation was repeated in six cases
      achieving successful results in five. One patient reported residual pain and is
      being evaluated for surgical excision. Primary and secondary clinical success
      rates were 78.9 (30/38 patients) and 97% (35/36 patients), respectively. CT
      guided RF ablation of OO is safe and effective. Persistent lesions can be
      effectively re-treated. Several imaging modalities are needed for the diagnosis
      of OO and for the follow-up after treatment, particularly in patients with
      persistent symptoms.

PMID- 15014977
TI  - Impact of a mutation in the mitochondrial LSU rRNA gene from Chlamydomonas
      reinhardtii on the activity and the assembly of respiratory-chain complexes.
AB  - Two substitutions A1090G and A1098C (together called the m mutation) located in
      the conserved GTPase domain of the mitochondrial LSU rRNA gene were recently
      shown to weakly compensate for the phenotypical effect of a -1T frameshift
      mutation in the mitochondrial cox1 gene of C. reinhardtii. In order to analyze
      the impact of the m mutation on the mitochondrial translational machinery, a
      strain carrying the m mutation but wild-type for the cox1 gene was isolated. We
      found that the growth and the respiratory rate of the m mutant were affected and
      that the activities of complexes I, III, and IV, all containing mitochondria
      encoded subunits, were lowered. In contrast the activities of complex II and of
      the alternative oxidase, both encoded exclusively by the nuclear genome, were not
      modified. The steady-state levels of complex I enzyme and of several components
      of the respiratory complexes I, III, and IV were also reduced in the mutant. We
      moreover showed that m did not suppress other frameshift or UGA stop mutations
      which affect mitochondrial genes.

PMID- 15014978
TI  - Extended haplotype analysis in the HLA complex reveals an increased frequency of
      the HFE-C282Y mutation in individuals with multiple sclerosis.
AB  - In order to resolve a multiple sclerosis (MS) susceptibility locus that we had
      identified in earlier work at the telomeric end of the HLA complex, we genotyped
      another 34 microsatellite markers (47 in total) across the class I/extended class
      I region in 166 Tasmanian MS case and 104 control families (D6S299-D6S265).
      Extended MS susceptibility haplotypes, up to 9 Mb in length, were observed in 11%
      of MS cases and 4% of controls. Direct comparison of the telomerically extended
      portion of the MS susceptibility haplotype in HFE-Cys282Tyr (C282Y)-homozygous
      haemochromatosis patients identified a common ancestry for this genomic segment,
      which translated into an increased frequency of the C282Y allele in 489 MS cases
      from Tasmania and Victoria (10.2%) compared with controls (6.7%). Six C282Y
      homozygotes (1.2%), a three-fold increased rate over the general population, and
      88 heterozygotes (18%) were identified. One C282Y-homozygous female was
      identified who had MS and was being treated for symptoms of iron overload.
      Interestingly, for 71 Victorian MS cases not of north western European (NWE)
      ancestry, a DR15-independent reduction in the frequency of the C282Y allele was
      observed, supporting the theory of a NWE origin for the C282Y-variant of the DR15
      ancestral haplotype (C282Y-HLA-A*0301-B*0702-DRB1*1501-DQB1*0602). The results of
      linkage disequilibrium (LD) and log linear modelling analyses suggest that C282Y
      is increased in MS cases of NWE ancestry because it is in LD with the ancestral
      DR15 susceptibility haplotype (7.1) and that it does not play an independent role
      in predisposition to MS. However, our findings provide the impetus for further
      investigations into the role of iron metabolism in the severity of MS.

PMID- 15014979
TI  - Fine mapping a gene for pediatric gastroesophageal reflux on human chromosome
      13q14.
AB  - We previously mapped a gene for severe pediatric gastroesophageal reflux disease
      ( GERD1) to a 9-cM interval on chromosome 13q14. In this report, we present the
      results of DNA sequencing and allelic association analyses that were done in an
      attempt to clone the GERD1 gene. Using a candidate transcript approach, we
      screened affected individuals for mutations in all transcribed regions of all
      genes, putative genes, and ESTs identified within the 6.2-Mb GERD1 locus based on
      alignments with the GenBank cDNA databases. From a total of 50 identifiable genes
      and 99 EST clusters in the GERD1 locus, we identified 163 polymorphisms (143 SNPs
      and 20 INDELs) in 21 genes and 37 ESTs. The patterns of inheritance and/or the
      high population frequencies of all polymorphic alleles identified in this study
      argued against causative relationships between any of the alleles and the GERD
      phenotype. Using a subset of 51 SNPs distributed throughout the GERD1 locus, we
      performed case-control and family (TDT) allelic association analyses on two sets
      of samples. The case-control study was performed with 73 GERD cases and 93
      controls, and the family study was performed using 22 small families. SNP 160
      (position 38,925,329 Mb, UCSChg15 map) gave a significant P value prior to
      multiple test correction in both the case control and family studies, while
      SNP168 (at 40,442,903 Mb) showed significant association after multiple test
      correction in the case-control sample, but was uninformative in the family
      sample. The results suggest that the GERD1 gene might be located near SNP160 or
      SNP168.

PMID- 15014980
TI  - SNURF-SNRPN and UBE3A transcript levels in patients with Angelman syndrome.
AB  - The imprinted domain on human chromosome 15 consists of two oppositely imprinted
      gene clusters, which are under the control of an imprinting center (IC). The
      paternally expressed SNURF-SNRPN gene hosts several snoRNA genes and overlaps the
      UBE3A gene, which is encoded on the opposite strand, expressed - at least in
      brain cells - from the maternal chromosome only, and affected in patients with
      Angelman syndrome (AS). In contrast to SNURF-SNRPN, imprinted expression of UBE3A
      is not regulated by a 5' differentially methylated region. Here we report that
      splice forms of the SNURF-SNRPN transcript overlapping UBE3A in an antisense
      orientation are present in brain but barely detectable in blood. In contrast,
      splice forms that do not overlap with UBE3A are of similar abundance in brain and
      blood. The tissue distribution of the splice forms parallels that of the snoRNAs
      encoded in the respective parts of the SNURF-SNRPN transcript. Using a
      quantitative PCR assay, we have found that the ratio of SNURF-SNRPN/UBE3A
      transcript levels is increased in blood cells of AS patients with an imprinting
      defect, but not in AS patients with a UBE3A mutation or an unknown defect. Our
      findings are compatible with the assumption that imprinted UBE3A expression is
      regulated through the SNURF-SNRPN sense- UBE3A antisense transcript.

PMID- 15014981
TI  - Sequencing of the Triticum monococcum hardness locus reveals good
      microcolinearity with rice.
AB  - The Hardness ( Ha) locus on chromosome 5D is the main determinant of grain
      texture in hexaploid wheat. The related genes Puroindoline-a and -b ( Pina-D1,
      Pinb-D1) and Grain Softness Protein ( Gsp-D1) are tightly linked at this locus.
      Mutations in the Pina-D1 and Pinb-D1 genes are associated with increased grain
      hardness. We report here the complete sequence of a 101-kb BAC clone from
      Triticum monococcum (A(m ) genome) which includes these three genes, and its
      comparison with the orthologous region in rice. The genes Gsp-A(m) 1, Pina-A(m) 1
      and Pinb-A(m) 1 are separated by 37 kb and 32 kb, respectively, and are organized
      in the same transcriptional orientation. Four additional genes, including a pair
      of duplicated genes, were identified upstream of Gsp-A(m) 1 within a high-density
      gene island. These additional genes were found in the same order and orientation,
      and the same relative distances apart as similar genes previously annotated on
      rice chromosome 12. An interesting discovery was a small unannotated putative
      rice gene that was similar to the Gsp-A(m) 1 gene of T. monococcum (65%
      similarity at the protein level), and that was disposed in the same orientation,
      and located in the same position relative to the other orthologous genes. The
      high gene density observed in this BAC (1 gene per 14 kb) was expected for a
      distal chromosome region, but the level of microcolinearity with rice was higher
      than that reported in similar distal regions of other wheat chromosomes. Most of
      the BAC sequence (40%) was represented by repetitive elements, mainly
      concentrated in regions adjacent to the genes Pina-A(m) 1 and Pinb-A(m) 1.
      Rearrangements among these repetitive elements might provide an explanation for
      the frequent deletions observed at this locus in the genomes of the polyploid
      wheat species.

PMID- 15014982
TI  - Horizontal gene transfer promoted evolution of the ability to propagate under
      anaerobic conditions in yeasts.
AB  - The ability to propagate under anaerobic conditions is an essential and unique
      trait of brewer's or baker's yeast ( Saccharomyces cervisiae). To understand the
      evolution of facultative anaerobiosis we studied the dependence of de novo
      pyrimidine biosynthesis, more precisely the fourth enzymic activity catalysed by
      dihydroorotate dehydrogenase (DHODase), on the enzymes of the respiratory chain
      in several yeast species. While the majority of yeasts possess a mitochondrial
      DHODase, Saccharomyces cerevisiae has a cytoplasmatic enzyme, whose activity is
      independent of the presence of oxygen. From the phylogenetic point of view, this
      enzyme is closely related to a bacterial DHODase from Lactococcus lactis. Here we
      show that S. kluyveri, which separated from the S. cerevisiae lineage more than
      100 million years ago, represents an evolutionary intermediate, having both
      cytoplasmic and mitochondrial DHODases. We show that these two S. kluyveri
      enzymes, and their coding genes, differ in their dependence on the presence of
      oxygen. Only the cytoplasmic DHODase promotes growth in the absence of oxygen.
      Apparently a Saccharomyces yeast progenitor which had a eukaryotic-like
      mitochondrial DHODase acquired a bacterial gene for DHODase, which subsequently
      allowed cell growth gradually to become independent of oxygen.

PMID- 15014985
TI  - Glutamic acid decarboxylase immunoreactive large neuron types in the granular
      layer of the human cerebellar cortex.
AB  - 'Non-traditional' large neurons of the granular layer of the cerebellar cortex
      include all its large neuronal types, except the Golgi neuron, which is instead
      one of the five 'classic' types of corticocerebellar neurons. The morphological,
      chemical and functional characteristics of the 'non-traditional' large neurons
      have not been entirely ascertained. The aim of this study was to ascertain
      whether morphological evidence can be provided of GABA synthesis within the 'non
      traditional' large neurons of the human cerebellar cortex by means of
      immunocytochemistry for glutamic acid decarboxylase (GAD). Fragments of
      postmortem cerebellar cortex of various lobules from the hemispheres and vermis
      were studied. Immunoreactions revealed large neurons distributed throughout the
      granular layer in all lobules examined. They were discriminated by analyzing the
      morphological features of their bodies and processes and were identified as Golgi
      neurons and as some 'non-traditional' types, such as the candelabrum, Lugaro and
      synarmotic neurons. In addition, immunoreactive large neurons, with their bodies
      and processes closely adjacent to microvessels, were observed throughout the
      layer: these perivascular neurons could represent a new type of 'non-traditional'
      neuron of the cerebellar cortex. This study supplies the first indication that in
      the human cerebellar cortex some types of 'non-traditional' large neurons are GAD
      immunoreactive, in addition to those neurons already known to be GABAergic (i.e.,
      stellate, basket, Purkinje and Golgi neurons). These morphological data further
      point out possible functional roles for GABA as a neurotransmitter/neuromodulator
      in intrinsic, associative and projective circuits of the cerebellar cortex.

PMID- 15014983
TI  - Genome-wide identification of NBS genes in japonica rice reveals significant
      expansion of divergent non-TIR NBS-LRR genes.
AB  - A complete set of candidate disease resistance ( R) genes encoding nucleotide
      binding sites (NBSs) was identified in the genome sequence of japonica rice (
      Oryza sativaL. var. Nipponbare). These putative R genes were characterized with
      respect to structural diversity, phylogenetic relationships and chromosomal
      distribution, and compared with those in Arabidopsis thaliana. We found 535 NBS
      coding sequences, including 480 non-TIR (Toll/IL-1 receptor) NBS-LRR (Leucine
      Rich Repeat) genes. TIR NBS-LRR genes, which are common in A. thaliana, have not
      been identified in the rice genome. The number of non-TIR NBS-LRR genes in rice
      is 8.7 times higher than that in A. thaliana, and they account for about 1% of
      all of predicted ORFs in the rice genome. Some 76% of the NBS genes were located
      in 44 gene clusters or in 57 tandem arrays, and 16 apparent gene duplications
      were detected in these regions. Phylogenetic analyses based both NBS and N
      terminal regions classified the genes into about 200 groups, but no deep clades
      were detected, in contrast to the two distinct clusters found in A. thaliana. The
      structural and genetic diversity that exists among NBS-LRR proteins in rice is
      remarkable, and suggests that diversifying selection has played an important role
      in the evolution of R genes in this agronomically important species.
      (Supplemental material is available online at http://gattaca.nju.edu.cn.)

PMID- 15014984
TI  - Carcinogenic potential of tobacco tar-resistant Staphylococcus aureus in buccal
      cavity.
AB  - PURPOSE: The effects of cigarette smoking on the association between inflammation
      and cancer were studied, since some bacteria induce the production of tumor
      necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine and endogenous
      tumor promoter, in cells. METHODS: Bacteria from a gargled solution from the
      buccal cavity of 20 individuals were cultured in the presence of 4 mg/ml
      cigarette-smoke condensates. Although cigarette-smoke condensates inhibited
      growth of Staphylococcus aureus strongly and that of Staphylococcus warneri
      weakly, tobacco tar-resistant S. aureus and S. warneri were obtained. RESULTS:
      One tobacco tar-resistant S. aureus strain (Sa-TA10) induced expression of the
      TNF-alpha gene in both Bhas 42 cells (v-Ha-ras transfected BALB/3T3 cells) and
      human lung cancer cell line H226B, while one tobacco tar-resistant S. warneri (Sw
      TA75) did not induce it significantly. Moreover, Sa-TA10 induced formation of
      transformed foci and soft-agar colony in Bhas 42 cells in cooperation with the v
      Ha-ras gene. The results suggested that Sa-TA10 has carcinogenic potential,
      whereas Sw-TA75 does not. CONCLUSION: These data suggest that tobacco tar
      resistant S. aureus, with carcinogenic potential, is present in the buccal cavity
      of some individuals, and that cigarette smoking simultaneously inhibits growth of
      most of the bacteria and selects carcinogenic bacteria.

PMID- 15014988
TI  - Salivary duct carcinoma with neuroendocrine features.

PMID- 15014986
TI  - Microcystic tubulopapillary carcinoma of the pancreas: a new tumor entity?
AB  - An unusual pancreatic tumor with microcystic and tubulopapillary features was
      observed in a 53-year-old woman. The tumor presented as a large, focally cystic
      mass in the head of the pancreas, which compressed the surrounding structures.
      The histological and immunohistochemical analysis revealed a neoplasm that could
      not be assigned to any of the known pancreatic tumor types. At the molecular
      level, the tumor showed inactivation of the DPC4/SMAD4 gene, deletion of exon 1
      of the p16(INK4A) gene and a point mutation at codon 34 (GGA>AGA) of beta
      catenin. Transcriptional profiling analyses and subsequent correspondence cluster
      analysis demonstrated that the transcriptional profile of the tumor differed
      distinctly from that of ductal adenocarcinomas, pancreatic cystic tumors and
      normal pancreatic tissues. These data suggest that the neoplasm most likely
      represents a new pancreatic tumor entity, which we would like to refer to as
      microcystic tubulopapillary tumor.

PMID- 15014987
TI  - Osteoclastogenesis in human breast carcinoma.

PMID- 15014989
TI  - Synovial sarcoma of the heart.

PMID- 15014990
TI  - Malignant solitary fibrous tumor of the meninges.
AB  - Increasing numbers of solitary fibrous tumors (SFTs) in the meninges have been
      reported since this entity was first recognized. While most cases previously
      reported were considered to be benign, the malignant potential of extrathoracic
      SFTs has not been excluded. The authors report a rare case of a meningeal SFT
      with malignant behavior occurring in a Japanese female patient, initially
      resected when she was 44 years old and recurring in the same place four times
      during a 26-year follow-up period. A metastatic tumor to the right lung arose 25
      years after the resection of the first meningeal tumor and focal invasion into
      the cerebellum was also observed with her last (5th) meningeal tumor.
      Immunohistochemical analysis showed all tumors to be diffusely positive for CD34
      and negative for EMA, with a so-called "patternless" histological pattern,
      featuring thin collagen fibers between tumor cells. A focal "staghorn" vascular
      pattern was also observed. Ki67 (MIB-1) labeling indices and mitosis rates were
      3.1+/-1.2% and less than 1/10 high power fields (HPF) in the first meningeal
      tumor and 16.1+/-6.4% and 6/10HPF in the last (5th) one, respectively. Thus, the
      present case suggests that meningeal SFTs possess malignant potential so that
      careful long-term follow up is required.

PMID- 15014992
TI  - Structure and developmental expression of hatching enzyme genes of the Japanese
      eel Anguilla japonica: an aspect of the evolution of fish hatching enzyme gene.
AB  - We isolated seven cDNA clones from embryos of the Japanese eel Anguilla japonica.
      Each deduced amino acid sequence consisted of a signal peptide, a propeptide and
      a mature enzyme portion belonging to the astacin protease family. A phylogenetic
      analysis showed that the eel enzymes resembled the high choriolytic enzyme (HCE)
      of medaka Oryzias latipes, and the hatching enzymes of the zebra fish Danio rerio
      and masu salmon Oncorhynchus masou. Hatching enzymes of these teleosts belonged
      to the group of the medaka HCE, and not the medaka low choriolytic enzyme (LCE),
      another hatching enzyme of medaka. Southern blot analysis showed that the genes
      of the eel hatching enzymes were multicopy genes like the medaka HCE genes.
      However, one of the eel hatching enzyme genes comprised eight exons and seven
      introns, and the exon-intron organization was similar to the medaka LCE gene,
      which is a single-copy gene. The molecular evolution of the fish hatching enzyme
      genes is discussed. In addition, whole-mount in situ hybridization and
      immunocytochemistry showed that the eel hatching enzyme was first expressed in
      the pillow anterior to the forebrain of early neurula, and finally in the cell
      mass on the yolk sac of later stage embryos. The early differentiation profile of
      eel hatching gland cells was similar to that of medaka, masu salmon and
      zebrafish, whereas the final location of the gland cells was different among
      fishes.

PMID- 15014991
TI  - Expression patterns of leg genes in the mouthparts of the spider Cupiennius salei
      (Chelicerata: Arachnida).
AB  - The leg genes extradenticle, homothorax, dachshund, and Distal-less define three
      antagonistic developmental domains in the legs, but not in the antenna, of
      Drosophila. Here we report the expression patterns of these leg genes in the
      prosomal appendages of the spider Cupiennius salei. The prosoma of the spider
      bears six pairs of appendages: a pair of cheliceres, a pair of pedipalps, and
      four pairs of walking legs. Three types of appendages thus can be distinguished
      in the spider. We show here that in the pedipalp, the leg-like second prosomal
      appendage, the patterns are very similar to those in the legs themselves,
      indicating the presence of three antagonistic developmental domains in both
      appendage types. In contrast, in the chelicera, the fang-like first prosomal
      appendage, the patterns are different and there is no evidence for antagonistic
      domains. Together with data from Drosophila this suggests that leg-shaped
      morphology of arthropod appendages requires an underlying set of antagonistic
      developmental domains, whereas other morphologies (e.g. antenna, chelicera) may
      result from the loss of such antagonistic domains.

PMID- 15014993
TI  - Expression and localisation analysis of the wheat sucrose transporter TaSUT1 in
      vegetative tissues.
AB  - Previously we reported the isolation of three sucrose transporter genes, TaSUT1A,
      1B and 1D, all expressed at high levels in the developing grains of hexaploid
      wheat ( Triticum aestivum L.), but also in a variety of other tissues. In order
      to further characterise the expression of the TaSUT1 genes in wheat plants, we
      have analysed TaSUT1 expression in their vegetative tissues using semi
      quantitative reverse transcription-polymerase chain reaction, in situ
      hybridisation and immunolocalisation. The three TaSUT1 genes, which encode 98%
      identical SUT proteins, all appeared to be expressed at the same level in leaf
      blades, leaf sheaths and internodes, as well as developing grains, of hexaploid
      wheat. In mature leaf blades, TaSUT1 protein localised to the plasma membrane of
      phloem sieve elements in all classes of veins. In contrast, TaSUT1 mRNA was found
      to be localised to phloem companion cells. A similar localisation pattern for
      TaSUT1 protein was observed in veins of leaf sheaths and internodes. These
      results suggest that the wheat SUT1 has a transport function in enucleate sieve
      elements, in both veins responsible for loading photoassimilates, and in veins
      for axial transport. Furthermore, transport of the fluorescent dye
      carboxyfluorescein was used to investigate symplasmic connectivity between sieve
      element-companion cell complexes and non-phloem cells. Observations in source
      leaves indicated that sieve element-companion cell complexes of minor veins were
      symplasmically restricted, suggesting a role of TaSUT1 in apoplasmic phloem
      loading. In contrast, the dye was able to move symplasmically out of the phloem
      in internodes. In these circumstances TaSUT1 may also have a role in retrieving
      sucrose leaked to the phloem apoplasm.

PMID- 15014994
TI  - Relationship between copper- and zinc-induced oxidative stress and proline
      accumulation in Scenedesmus sp.
AB  - A 4-h exposure of Scenedesmus sp. to Cu or Zn enhanced intracellular levels of
      both test metals and proline. The level of intracellular proline increased
      markedly up to 10 microM Cu, but higher concentrations were inhibitory. However,
      intracellular proline consistently increased with increasing concentration of Zn
      in the medium. Cu and Zn induced oxidative stress in the test alga by increasing
      lipid peroxidation and membrane permeability, and by reducing SH content.
      Pretreatment of the test alga with 1 mM proline for 30 min completely alleviated
      Cu-induced lipid peroxidation, minimized K+ efflux and also reduced depletion of
      the SH pool. But proline pretreatment could only slightly reduce Zn-induced
      oxidative stress. Interestingly, proline pretreatment increased the level of Cu
      (25-54%) and Zn (19-49%) inside the cells. It did not affect the activities of
      superoxide dismutase, ascorbate peroxidase or catalase, but improved glutathione
      reductase activity under Cu and Zn stress. A comparison of the effects of proline
      pretreatment on lipid peroxidation by Cu, Zn, methyl viologen and ultraviolet-B
      radiation suggests that proline protects cells from metal-induced oxidative
      stress by scavenging reactive oxygen species rather than by chelating metal ions.
      Pretreatment of cells with a known antioxidant (ascorbate) and a hydroxyl radical
      scavenger (sodium benzoate) considerably reduced metal-induced lipid peroxidation
      and proline accumulation. However, sodium benzoate had a very mild effect on Zn
      induced lipid peroxidation and proline accumulation. The present study
      demonstrates that proline possibly acts by detoxifying reactive oxygen species,
      mainly hydroxyl radicals, rather than by improving the antioxidant defense system
      under metal stress.

PMID- 15014995
TI  - A lyophilized aqueous extract of Maytenus ilicifolia leaves inhibits histamine
      mediated acid secretion in isolated frog gastric mucosa.
AB  - Lyophilized aqueous extract of Maytenus ilicifolia leaves (LAEMIL) is commonly
      used in Brazilian folk medicine in the treatment of dyspepsia as well as gastric
      ulcers. We have investigated the effect and the possible mechanism of action of
      the LAEMIL on acid secretion in isolated frog gastric mucosa incubated in an
      Ussing chamber. It was observed that LAEMIL (7-28 mg%) as well as cimetidine (125
      4,000 microM), a well-known histamine H2 receptor antagonist, decreased basal
      acid secretion in a concentration-dependent manner. Similarly to cimetidine (190
      microM), LAEMIL (21 mg%) also inhibited gastric acid secretion induced by
      increasing concentrations of histamine (50-800 microM). The EC50 values for
      histamine alone and histamine in the presence of LAEMIL or cimetidine were 94.6
      microM (71.1-125.9 microM), 244.9 microM (209.4-286.4 microM) and 142.2 microM
      (23.6-855.0 microM), respectively. LAEMIL, histamine and cimetidine were
      effective on acid secretion only when added to the serosal surface of the mucosa.
      Furthermore, simultaneous addition of LAEMIL and cimetidine at concentrations,
      per se, ineffective, caused a 16% reduction in the basal acid secretion [from 8.3
      +/- 0.3 to 6.9 +/- 0.2 microEq g(-1) (15 min)(-1), n=4]. Although effects such as
      inhibition of histamine biosynthesis and/or histamine release can not be ruled
      out, our data suggest that LAEMIL, like cimetidine, reduces acid secretion in the
      isolated frog gastric mucosa by antagonising histamine H2 receptors.

PMID- 15014996
TI  - Molecular and physiological evidence suggests the existence of a system II-like
      pathway of ethylene production in non-climacteric Citrus fruit.
AB  - Mature citrus fruits, which are classified as non-climacteric, evolve very low
      amounts of ethylene during ripening but respond to exogenous ethylene by ripening
      related pigment changes and accelerated respiration. In the present study we show
      that young citrus fruitlets attached to the tree produce high levels of ethylene,
      which decrease dramatically towards maturation. Upon harvest, fruitlets exhibited
      a climacteric-like rise in ethylene production, preceded by induction of the
      genes for 1-aminocyclopropane-1-carboxylate (ACC) synthase 1 (CsACS1), ACC
      oxidase 1 (CsACO1) and the ethylene receptor CsERS1. This induction was advanced
      and augmented by exogenous ethylene or propylene, indicating an autocatalytic
      system II-like ethylene biosynthesis. In mature, detached fruit, very low rates
      of ethylene production were associated with constitutive expression of the ACC
      synthase 2 (CsACS2) and ethylene receptor CsETR1 genes (system I). CsACS1 gene
      expression was undetectable at this stage, even following ethylene or propylene
      treatment, and CsERS1 gene expression remained constant, indicating that no
      autocatalytic response had occurred. The transition from system II-like behavior
      of young fruitlets to system I behavior appears to be under developmental
      control.

PMID- 15014997
TI  - Fusicoccin activates pathogen-responsive gene expression independently of common
      resistance signalling pathways, but increases disease symptoms in Pseudomonas
      syringae-infected tomato plants.
AB  - Fusicoccin (FC), an activator of the plant plasma membrane H+-ATPase, induces
      several components of plant pathogen resistance responses, including defence
      hormone biosynthesis and pathogenesis-related (PR) gene expression. The mechanism
      by which these responses occur, and the effect they have on plant-pathogen
      interactions is unknown. Here, we show that PR gene expression in response to FC
      in tomato (Lycopersicon esculentum Mill.) plants does not strictly require the
      common defence hormones, salicylic acid, jasmonic acid and ethylene. We also show
      that FC-induced PR gene expression requires neither Ca2+ nor reactive oxygen
      species, typical early pathogen-resistance response signals. The possibility that
      PR gene expression is related to FC-induced dehydration stress is also
      discounted. Finally, we show that the defence responses elicited by FC in tomato
      are not sufficient to confer resistance to the bacterial pathogen Pseudomonas
      syringae. Rather, FC increases the rate and severity of disease symptom formation
      in an ethylene-dependent manner.

PMID- 15014998
TI  - Increased fatty acid production in potato by engineering of acetyl-CoA
      carboxylase.
AB  - In contrast to oil seeds, potato (Solanum tuberosum L.) is characterized by a
      high amount of starch stored in the tubers. To assess the capacity for oil
      synthesis in potato tubers, the changes in lipid content and flux into lipid
      synthesis were explored in transgenic potatoes altered in carbohydrate or lipid
      metabolism. A strong decrease in the amount of starch observed in antisense lines
      for ADP-glucose pyrophosphorylase or plastidic phosphoglucomutase had no effect
      on storage-lipid content. Similarly, potato lines over-expressing the Arabidopsis
      thaliana (L.) Heynh. plastidic ATP/ADP transporter that contained an increased
      amount of starch were not altered in oil content, indicating that the plastidic
      ATP level is not limiting fatty acid synthesis in potato tubers. However, over
      expression of the acetyl-CoA carboxylase from Arabidopsis in the amyloplasts of
      potato tubers led to an increase in fatty acid synthesis and a more than 5-fold
      increase in the amount of triacylglycerol. Taken together, these data demonstrate
      that potato tubers have the capacity for storage-lipid synthesis and that malonyl
      CoA, the substrate for elongation during fatty acid synthesis, represents one of
      the limiting factors for oil accumulation.

PMID- 15014999
TI  - Effects of prolonged voluntary wheel-running on muscle structure and function in
      rat skeletal muscle.
AB  - We examined the effects of prolonged voluntary wheel-running on skeletal muscle
      functional and/or structural characteristics in rats. Male Sprague-Dawley rats (5
      weeks old) were divided into five groups: (1) 15W-SC, sedentary controls housed
      in normal plastic cages until age 15 weeks; (2) 15W-VE, housed in a voluntary
      exercise (running-wheel) device equipped with housing space until age 15 weeks;
      (3) 35W-SC, housed in normal plastic cages until age 35 weeks; (4) 35W-VE, housed
      in the voluntary-exercise device until age 35 weeks, and (5) 35W-MVE, housed in
      normal plastic cages until age 15 weeks, then in the voluntary-exercise device
      from age 16 weeks to 35 weeks ("middle age"). At the end of each rat's
      experimental period, the plantaris muscle was dissected from each hindlimb for
      analysis of the muscle's functional and/or structural characteristics. Total
      running distance was similar in 15W-VE and 35W-VE, both being significantly
      greater than in 35-MVE. The percentage of type IIb myosin heavy chain isoform was
      significantly lower in each VE group than in the corresponding SC group. This
      shift from type IIb was significantly greater for 35W-VE than for the other VE
      groups, which were similar to each other. The cross-sectional area of type IIx
      fibers was significantly greater in 35W-VE than in 35W-SC, but this was not true
      for 15W-VE versus 15W-SC or for 35W-MVE versus 35W-SC. No significant difference
      in citrate synthase activity was detected between any VE group and the
      corresponding SC group. These results suggest that a prolongation of voluntary
      wheel-running leads to some advantageous enhancements of functional and/or
      structural characteristics in rat plantaris.

PMID- 15015000
TI  - Lowering of skin temperature decreases isokinetic maximal force production
      independent of core temperature.
AB  - Based on studies using maximal isometric contractions, it is suggested that
      fatigue may be elicited due to hyperthermia-induced impairments in central
      neuromuscular activation. We investigated the effects of passive hyperthermia on
      isokinetic maximal force production. Twenty young healthy males [peak oxygen
      uptake 52.9 (6.8) ml x kg(-1) min(-1), body fat 11 (5)%] were passively warmed in
      a hot (42 degrees C) water bath to rectal temperature ( T(re)) of 39.5 degrees C
      and then cooled back to 38.0 degrees C. At 0.5 degrees C intervals, they
      performed two maximal voluntary knee extensions each at 60, 120, and 240 s(-1).
      Peak torques at 37.5 degrees C were 168 (34), 145 (29), and 112 (17) N m for 60,
      120, and 240 s(-1) contraction speeds, respectively, and 166 (38), 150 (31), and
      119 (17) N m at T(re) of 39.5 degrees C. No significant differences in peak
      torque at any of the three contraction speeds were observed over the range 37.5
      39.5 degrees C. Skin cooling, even with a warm core of 39.5 degrees C,
      immediately decreased peak torque [159 (42), 133 (34), 107 (22) N m at 60, 120,
      and 240 s(-1), respectively). We conclude that lowered skin temperature can
      impair isokinetic force production independent of core temperature.

PMID- 15015001
TI  - Passive hyperthermia reduces voluntary activation and isometric force production.
AB  - It has been suggested that a critically high body core temperature may impair
      central neuromuscular activation and cause fatigue. We investigated the effects
      of passive hyperthermia on maximal isometric force production (MVC) and voluntary
      activation (VA) to determine the relative roles of skin (T(sk)) and body core
      temperature ( T(c)) on these factors. Twenty-two males [VO(2max)=64.2 (8.9) ml x
      kg(-1) min(-1), body fat=8.2 (3.9)%] were seated in a knee-extension myograph,
      then passively heated from 37.4 to 39.4 degrees C rectal temperature (T(re)) and
      then cooled back to 37.4(o)C using a liquid conditioning garment. Voluntary
      strength and VA (interpolated twitch) were examined during an isometric 10-s MVC
      at 0.5 degrees C intervals during both heating and cooling. Passive heating to a
      T(c) of 39.4(o)C reduced VA by 11 (11)% and MVC by 13 (18)% (P<0.05), but rapid
      skin cooling, with a concomitant reduction in cardiovascular strain [percentage
      heart rate reserve decreased from 64 (11)% to 29 (11)%] and psychophysical strain
      did not restore either of these measures to baseline. Only when cooling lowered
      T(c) back to normal did VA and MVC return to baseline (P<0.05). We conclude that
      an elevated T(c) reduces VA during isometric MVC, and neither T(sk) nor
      cardiovascular or psychophysical strain modulates this response. Results are
      given as mean (SD) unless otherwise stated.

PMID- 15015002
TI  - A unified formula for calculating body surface area of humans and animals.
AB  - We previously derived a formula for calculating human body surface area (BSA)
      from V (body volume) and L (reference body length): BSA=(9 pi VL)(0.5). In this
      paper, we analyse first the effects of body density variation on BSA during
      growth and the scaling relation of BSA to body mass. Then we utilise the derived
      formula to calculate BSA of animals and compare the obtained data with the direct
      measurements on the same animals, including rat, chicken, dog, and cattle, from
      the literature. It is shown that two problems remain to be solved for applying
      the derived formula to all mammals and other animals: one is to find out the L
      for each species of animal by means of direct measurements, and the other is to
      obtain the variation of body density during growth.

PMID- 15015003
TI  - Role of EMG evaluation in muscle hyperactivity syndromes.
AB  - Muscle hyperactivity can be a clinical feature on its own or, more commonly, an
      observation on electromyography (EMG) examinations. Whatever manifestation it
      takes, muscle hyperactivity always means enhanced excitability of muscle, axons
      or neurons. Clinical findings may be variable, ranging from fasciculations to
      muscle cramps. Even though clinical examination may lead in most instances to
      suggest the diagnosis of the underlying disease, EMG studies are necessary to
      identify the type of abnormal discharges and suggest the site of their suspected
      origin. Although in clinical studies, the action potential showing abnormal
      muscle hyperactivity is practically always recorded from muscle fibers, the site
      in which the impulse has arisen will determine its shape and firing patterns. In
      this review, we describe the EMG characteristics observed in syndromes featuring
      muscle hyperactivity and the pathophysiology underlying the abnormal firing of
      muscle fibers.

PMID- 15015004
TI  - The role of oxidative stress in the pathogenesis of multiple sclerosis: the need
      for effective antioxidant therapy.
AB  - Accumulating data indicate that oxidative stress (OS) plays a major role in the
      pathogenesis of multiple sclerosis (MS). Reactive oxygen species (ROS), leading
      to OS, generated in excess primarily by macrophages, have been implicated as
      mediators of demyelination and axonal damage in both MS and experimental
      autoimmune encephalomyelitis (EAE), its animal model. ROS cause damage to
      cardinal cellular components such as lipids, proteins and nucleic acids (e. g.,
      RNA, DNA), resulting in cell death by necrosis or apoptosis. In addition,
      weakened cellular antioxidant defense systems in the central nervous system (CNS)
      in MS, and its vulnerability to ROS effects may increase damage. Thus, treatment
      with antioxidants might theoretically prevent propagation of tissue damage and
      improve both survival and neurological outcome. Indeed, several experimental
      studies have been performed to see whether dietary intake of several antioxidants
      prevents or reduces the progression of EAE. Although a few antioxidants showed
      some efficacy in these studies, little information is available on the effect of
      treatments with such compounds in patients with MS. Well-designed clinical
      studies using antioxidant intake, as well as investigations based on larger
      cohorts studied over a longer periods of time, are needed in order to assess
      whether antioxidant intake together with other conventional treatments, might be
      beneficial in treating MS.

PMID- 15015005
TI  - Progressive idiopathic axonal neuropathy--a comparative clinical and
      histopathological study with vasculitic neuropathy.
AB  - Patients with a progressive disabling idiopathic axonal neuropathy could have a
      potentially treatable immune mediated neuropathy. To evaluate whether progressive
      idiopathic axonal neuropathy could be a pathologically difficult to prove
      vasculitic neuropathy pathologically difficult to prove or if it could be a
      separate clinical entity (i. e. with the axon as the primary immunological
      target), we performed a comparative clinical and histopathological study in 10
      patients with progressive idiopathic axonal neuropathy, 10 patients with
      vasculitic neuropathy, and 12 patients with chronic idiopathic axonal
      polyneuropathy (CIAP). The clinical features and disease course in patients with
      progressive idiopathic axonal neuropathy and patients with vasculitic neuropathy
      were similar. Six patients with progressive idiopathic axonal neuropathy had been
      treated with prednisone and/or intravenous immunoglobulin. Disability decreased
      in all these six patients, but also in two of the four non-treated patients. Upon
      reviewing the sural nerve biopsy specimens, vasculitis was found in one patient
      with progressive idiopathic axonal neuropathy. Vasculitis-associated signs of
      ischemic injury or inflammation (most notably: large variation in fascicular
      axonal degeneration, perivascular inflammation, inflammation of the blood vessel
      wall without lumen obstruction) were found in four patients with progressive
      idiopathic axonal neuropathy, in all patients with vasculitic neuropathy, but
      were absent in patients with CIAP. The findings show that there is a small chance
      of finding sural nerve vasculitis upon scrutinising biopsy examination in
      progressive idiopathic axonal neuropathy. The presence of vasculitis-associated
      signs in progressive idiopathic axonal neuropathy suggests that some of these
      patients could have vasculitic neuropathy, even if vasculitic lesions cannot be
      demonstrated. However, if inflammatory changes cannot be demonstrated this does
      not preclude an immune-mediated origin.

PMID- 15015006
TI  - Effect of interferon beta-1a on serum matrix metalloproteinase-9 (MMP-9) and
      tissue inhibitor of matrix metalloproteinase (TIMP-1) in relapsing remitting
      multiple sclerosis patients. One year follow-up results.
AB  - There is emerging evidence that matrix metalloproteinases (MMPs) might be
      involved in blood brain barrier (BBB) breakdown in multiple sclerosis. A group of
      natural tissue inhibitors of metalloproteinases (TIMPS) regulates proteolytic
      activity to prevent tissue damage. TIMP-1 and MMP-9 are known to be secreted as
      heterodimers and TIMP-1 preferentially functions to inhibit MMP-9 activity. In
      this present study, the effects of IFNbeta-1a on serum MMP-9 and TIMP-1 were
      evaluated longitudinally during a one-year period. The MMP-9 levels showed no
      significant changes while TIMP-1 levels gradually and significantly increased
      during 3rd and 6th months of therapy compared with pretreatment levels.

PMID- 15015007
TI  - Water content and myelin water fraction in multiple sclerosis. A T2 relaxation
      study.
AB  - BACKGROUND: Measurements of the T2 decay curve provide estimates of total water
      content and myelin water fraction in white matter in-vivo, which may help in
      understanding the pathological progression of multiple sclerosis (MS). METHODS:
      Thirty-three MS patients (24 relapsing remitting, 8 secondary progressive, 1
      primary progressive) and 18 controls underwent MR examinations. T2 relaxation
      data were acquired using a 32-echo measurement. All controls and 18 of the 33 MS
      patients were scanned in the transverse plane through the genu and splenium of
      the corpus callosum. Five white matter and 6 grey matter structures were outlined
      in each of these subjects. The remaining 15 MS patients were scanned in other
      transverse planes. A total of 189 lesions were outlined in the MS patients. Water
      content and myelin water fraction were calculated for all regions of interest and
      all lesions. RESULTS: The normal appearing white matter (NAWM) water content was,
      on average, 2.2% greater than that from controls, with significant differences
      occurring in the posterior internal capsules, genu and splenium of the corpus
      callosum, minor forceps and major forceps (p<0.0006). On average, MS lesions had
      6.3% higher water content than contralateral NAWM (p<0.0001). Myelin water
      fraction was 16% lower in NAWM than for controls, with significant differences in
      the major and minor forceps, internal capsules, and splenium (p<0.05). The myelin
      water fraction of MS lesions averaged 52 % that of NAWM. CONCLUSIONS: NAWM in MS
      has a higher water content and lower myelin water fraction than control white
      matter. The cause of the myelin water fraction decrease in NAWM could potentially
      be due to either diffuse edema, inflammation, demyelination or any combination of
      these features. We present a simple model which suggests that myelin loss is the
      dominant feature of NAWM pathology.

PMID- 15015008
TI  - Incidence rates and determinants in meralgia paresthetica in general practice.
AB  - OBJECTIVE: To determine incidence rates for meralgia paresthetica (MP) in the
      primary care setting and establish determinants for MP in a case-control study in
      general practices. METHODS: Using a cohort (in total 173,375 patient years) of
      registered persons in primary care from a computerized registration network for
      general practitioners (GPs) in the Rotterdam area from 1990 to 1998, persons with
      the diagnosis MP were included. In a nested case-control study we studied the
      relationship between comorbidity (e. g. carpal tunnel syndrome, pregnancy,
      osteoarthritis of the hip, overweight, symptoms of the pubic bone, thrombosis of
      the leg, diabetes mellitus and the use of corticosteroids) and the occurrence of
      MP. RESULTS: The incidence rate of MP is 4.3 per 10,000 person years. MP is more
      often present in patients suffering from carpal tunnel syndrome OR 7.7 (95 % CI
      1.9-31.1) and is related to pregnancy OR 12.0 (95 % CI 1.2-118.0). CONCLUSIONS:
      This is the first report on incidence rates of MP and on suspected determinants
      studied in a case-control setting in general practice. Carpal tunnel syndrome and
      pregnancy are significantly related to MP. Calculating the Population
      Attributable Risk in this study leaves 79% of all MP unexplained. Our results
      suggest that MP is caused by a combined susceptibility for entrapment and a
      trigger causing entrapment. More research on determinants is needed. Because MP
      occurs in every GP practice at least once a year more studies are needed on
      prognosis and treatment.

PMID- 15015010
TI  - The clinical impact of interferon beta antibodies in relapsing-remitting MS.
AB  - We analysed the kinetics and clinical impact of binding antibodies (BAbs) and
      neutralizing antibodies (NAbs) to three interferon beta (IFNbeta) products in
      patients with relapsing-remitting MS (RRMS). Patients with RRMS received IFNbeta
      1b 8 MIU subcutaneously (SC) every other day, intramuscular (IM) IFNbeta-1a 30
      mcg once weekly, or SC IFNbeta-1a 22 mcg three times weekly for up to 4 years.
      The changes of BAbs and IFNbeta were measured using enzyme-linked immunosorbent
      assay (ELISA), and positive BAb samples were then analysed for neutralizing
      activity using an antiviral cytopathic effect assay. Patients were considered
      BAb+ if they had a positive sample with an optical density (OD)>mean + 3SD of the
      OD of the control sample; high BAb titers were defined as >1:500. Patients were
      considered NAb+ if they had titers > or =20 LU/mL, with high NAb titers defined
      as >1:100. The impact of BAbs and NAbs on relapses and Expanded Disability Status
      Scale (EDSS) score also was evaluated. Thirty patients were enrolled in each
      treatment group. Over the course of the study, 83% of patients developed BAbs to
      IFNbeta-1b, 13% to IM IFNbeta-1a, and 47 % to SC IFNbeta-1a. Forty percent of
      patients developed NAbs to IFNbeta-1b, 6.7% to IM IFNbeta-1a, and 26.7% to SC
      IFNbeta-1a. Of 22 NAb+ patients, 10 patients (45.5%) demonstrated high titers of
      both NAbs and BAbs (20% IFNbeta-1b, 3.3% IM IFNbeta-1a, 10% SC IFNbeta-1a). The
      relapse rate significantly increased after the appearance of high NAb titers
      (p=0.03); however, an even higher significance level (p<0.001) was observed in
      patients with high titers of both NAbs and BAbs. In 10 patients with high titers
      of both NAbs and BAbs, an increase in mean EDSS score from 2.2 +/- 0.8 at
      baseline to 3.6 +/- 1.2 at year 2 (p<0.01) was observed. NAb-negative patients
      showed no significant change in EDSS score at year 2. These findings demonstrate
      that high titers of both BAbs and NAbs reduce the clinical efficacy of IFNbeta in
      patients with RRMS, which is important for the long-term efficacy of these drugs.

PMID- 15015009
TI  - Differential diagnosis of 201 possible Creutzfeldt-Jakob disease patients.
AB  - Our objective was to describe the clinical signs of 'possible' Creutzfeldt-Jakob
      disease (CJD) and to investigate whether current diagnostic criteria can
      accurately differentiate between different forms of dementia. We studied clinical
      data of 'definite' CJD, Alzheimer's disease (AD), dementia with Lewy bodies
      (DLB), and vascular dementia (VD) patients. Two subgroups were used: the first
      consisted of patients with clinical signs compatible with 'possible' CJD but in
      whom another final diagnosis was made and a second group with a typical evolution
      of the respective dementia. More focal neurological deficits were observed in AD,
      DLB or VD patients initially classified as 'possible' CJD than in typical
      patients. A typical electroencephalogram showing periodic sharp wave complexes
      was observed in 26 (50%) CJD and 6% of other dementia patients. The 14-3-3
      protein was detected in all CJD and 8% of other dementia patients. In patients
      with rapidly progressive dementia and focal neurological signs, CJD should be
      considered. When faced with the triad: dementia, myoclonus, and initial memory
      problems AD should be considered if the disease duration is longer than 1 year.
      The diagnosis of DLB is suggested, if Parkinsonism or fluctuations are present,
      whereas a focal onset and compatible brain imaging can indicate VD. Findings
      suggestive of CJD on EEG, brain imaging, and CSF do not exclude other dementias
      but make them very unlikely. These observations cannot only assist in the
      differential diagnosis of CJD but also with the identification of AD, DLB or VD
      patients with atypical clinical history.

PMID- 15015011
TI  - Psychosocial effects and evaluation of the health-related quality of life in
      patients suffering from well-controlled epilepsy.
AB  - PURPOSE: To record the impact of epilepsy on the psychological health and HRQOL
      of patients suffering from mild epilepsy in a rural area of southeastern Greece.
      PATIENTS AND METHODS: We studied fifty outpatients suffering from well-controlled
      uncomplicated epilepsy who experienced from none up to four seizures per year and
      had the ability to sustain a regular job. We tried to record the psychosocial
      effects resulting from epilepsy and to evaluate their HRQOL, comparing them to 50
      healthy controls with similar demographic characteristics. To patients and
      controls were given the Short-Form Health Survey (SF-36) and a questionnaire
      based on the Hamilton and Mandr's depression scales. RESULTS: According to the
      two depression and anxiety scales used, a mild degree of anxiety and depression
      was diagnosed but with unimportant statistical difference (p=ns) between patients
      and healthy controls. Self-perceived HRQOL of patients appeared to be
      affected,with vitality (p<0.002), physical (p<0.001) and social functioning
      (p<0.003) as the most impaired subscales of the SF-36. The deterioration in their
      HRQOL was mainly related to the post-diagnosis alteration of their socioeconomic
      status. As assessed by the multiple regression analyses, none of the disease
      history and medication-related variables were found to have any influence on the
      results of the SF-36 subtests. CONCLUSION: Despite the fact that we studied a
      relatively small sample of patients with mild epilepsy, our results showed that
      their HRQOL was obviously affected, while their psychological health remained
      nearly unaffected.

PMID- 15015012
TI  - Weight loss, nutritional status and physical activity in patients with
      Alzheimer's disease. A controlled study.
AB  - The etiology of weight loss in Alzheimer's disease (AD) patients is still
      uncertain. This study was designed to investigate the possible factors that might
      contribute to weight change of AD patients. From July 1999 to June 2001, we
      recruited 51 AD patients and 27 non-demented controls. Demographic data,
      neuropsychological tests, Geriatric Depression Scale-Short Form, eating behavior
      questionnaire, dietary and physical activity diaries, anthropometric and
      laboratory measures of nutritional status were assessed. More than half of our AD
      patients developed body weight loss, and overall, the AD patients were
      significantly thinner than the non-demented subjects. Anthropometric and
      laboratory measures suggested a poorer nutritional status in the AD patients. The
      AD patients had fewer daily physical activities. More AD patients had the problem
      of poor appetite. However, daily calorie intake was not significantly different
      between the two groups. The AD patients, especially those who presented with body
      weight loss, even consumed more calories per body weight kilogram (kg) per day.
      In the food composition analysis, AD patients took more carbohydrate than
      controls. Multivariate regression analysis showed the existence of AD and poor
      appetite were the main risk factors of weight loss. We suggest that the
      pathophysiological process in AD gives rise to the changes of appetite and
      metabolic state in AD patients, and that these changes contribute to the weight
      loss.

PMID- 15015014
TI  - Effects of subthalamic nucleus stimulation on parkinsonian dysarthria and speech
      intelligibility.
AB  - Subthalamic stimulation is known to improve tremor, akinesia and rigidity in
      Parkinson's disease. However, other signs such as hypophonia and swallowing
      disorders can be relatively resistant to this technique. The effect on dysarthria
      remains unclear. The aim of this study was to investigate the effects of
      implantation of electrode and stimulation of the subthalamic nucleus (STN) on
      parkinsonian dysarthria. Seven patients were prospectively included. Electrodes
      (Medtronic) were implanted in both STN. The electrode contacts and stimulation
      parameters were adjusted to provide best relief of symptoms with fewest side
      effects. Assessment used global scales (Unified Parkinson Disease Rating Scale,
      UPDRS II and III), dyskinesia scale, exhaustive dysarthria assessment (bucco
      facial movements, voice, articulation, intelligibility) and the 'dysarthria' item
      from the UPDRS III. Evaluations were performed in six conditions: before and
      three months after surgery (pre-op, post-op) stimulation turned off or on (off
      stim, onstim), and without or with a suprathreshold levodopa dose (offdrug, on
      drug). Performance level on the UPDRS III significantly improved following
      electrode implantation and stimulation. For dysarthria, modest beneficial effects
      were observed on several motor parameters, especially lip movements. Voice mildly
      improved, especially for the modulation in loudness and pitch. Articulation was
      not affected. Furthermore, intelligibility was slightly reduced in the on
      stimulation condition, especially when patients received levodopa. At an
      individual level, negative effects on intelligibility were observed in two
      patients, and this was associated with a discrete increase in facial and trunk
      dyskinesias, but not with the electrode position or stimulation parameters. In
      conclusion, surgery had weak effects on dysarthria. Intelligibility can be
      worsened, especially in the on-drug condition. Thus, adaptation of the
      stimulation parameters can be difficult.

PMID- 15015013
TI  - Risk of cancer in patients with Guillain-Barre syndrome (GBS). A population-based
      study.
AB  - The possible relationship between Guillain-Barre syndrome (GBS) and cancer is
      still controversial and the existence of a paraneoplastic GBS remains
      unconfirmed. To better define whether there is a relationship between GBS and
      malignancy, we compared the observed and the expected number of patients with
      tumours in a population-based cohort of subjects with GBS. Clinical differences
      between GBS patients with or without malignancies were analysed. Data were
      obtained from the Piemonte and Valle d'Aosta Register for GBS (PARGBS) (years
      1990-1998). GBS was diagnosed according to NINCDS criteria. The number of
      expected cases of malignancy in the PARGBS population was calculated using the
      incidence rate of all types of cancer (ICD codes 140-208) in Piemonte [1985
      1987], and in the most important town of this region, that is Turin (years 1993
      1997). In the nine-year period, 435 incident patients with GBS were found. Nine
      of them developed cancer in the six months preceding or following GBS; in seven
      of them, the diagnosis of cancer and GBS was concomitant. The expected number of
      malignant tumours was 3.7 (using the incidence in Piemonte) and 3.8 (using the
      incidence in Turin); therefore, the odds ratios were 2.43 (95 % CI, 1.11-4.62)
      and 2.37 (95% CI, 1.09-4.50), respectively (p<0.01). Although the cases with
      malignancies were clinically similar to the other cases of GBS observed through
      the Register, the mortality in GBS patients with cancer was higher and was the
      final cause of death in two patients affected by severe cancer. These results
      suggest a possible correlation between some cases of GBS and cancer. However, GBS
      in cancer patients does not meet all the criteria for paraneoplastic diseases.

PMID- 15015015
TI  - Conversion from dopamine agonists to pramipexole. An open-label trial in 227
      patients with advanced Parkinson's disease.
AB  - BACKGROUND: Pramipexole is a nonergoline dopamine agonist with D2 and
      preferential D3 dopamine receptor activity. This selective activity may result in
      clinically different effects. Small clinical trials indicate that overnight
      switching from one agonist to another can be performed safely. Objective To
      determine safety and efficacy of overnight switching from dopamine agonists to
      pramipexole in patients with advanced Parkinson's disease (PD). OBJECTIVE: To
      determine safety and efficacy of overnight switching from dopamine agonists to
      pramipexole in patients with advanced Parkinson's disease (PD). METHODS: Patients
      with advanced PD and motor complications not optimally controlled by levodopa and
      a stable dose of bromocriptine, pergolide or ropinirole were converted to
      pramipexole overnight. Clinical assessments were performed just prior to
      conversion and after 2, 6 and 12 weeks of treatment, when an optimal dose of
      pramipexole was achieved. RESULTS: Two hundred and seventeen patients were
      included in the trial. One hundred and twenty five were converted from pergolide
      to pramipexole, 58 from bromocriptine and 34 from ropinirole. After 12 weeks, the
      average dose of pramipexole was 2.8, 2.9 and 3.4 mg/d in patients converted from
      bromocriptine, pergolide, and ropinirole, respectively. UPDRS II, III and IV
      scores were reduced by 26-30% in all patients (p<0.0001). Mean levodopa dose was
      slightly reduced in all groups (p: NS). No serious or unexpected side effects
      were reported. The dose equivalences calculated from this trial were:
      bromocriptine:pramipexole 6.9:1, pergolide:pramipexole 0.9:1,
      ropinirole:pramipexole 1.5:1. CONCLUSION: Switching from bromocriptine, pergolide
      or ropinirole to pramipexole in an overnight schedule is safe. The observed
      clinical improvement may be related to a placebo effect, to the use of low doses
      of dopamine agonists or to a direct effect of pramipexole.

PMID- 15015016
TI  - Prevalence of Parkinson's disease and other types of Parkinsonism. A door-to-door
      survey in Bidasoa, Spain.
AB  - OBJECTIVES: To assess the prevalence of Parkinson's disease and parkinsonism in
      two Spanish populations (Irun and Hondarribia, Bidasoa Region) and to compare the
      results with those of similar surveys. METHODS: The survey included 2000
      participants aged 65 years or older in a door-to-door, three-phase design. In the
      screening phase we used the SNES (Sicilian Neuro-Epidemiologic Study) screening
      questionnaire, which has 100% sensitivity. In phases 2 and 3 we carried out a 3
      year follow-up of all cases diagnosed with parkinsonism in phase 2. Progressively
      stricter diagnostic criteria were chosen in order to minimize the impact of false
      positives on the final results. RESULTS: The prevalence of Parkinson's disease
      (PD) was 1.5 % (95% confidence interval, 0.9 to 2.3) and the prevalence of other
      types of parkinsonism (OP) was 1.1 % (95% confidence interval 0.6 to 1.9). The
      overall prevalence by age group was 0.4 % (65-74 years), 4.7% (75-84 years), and
      2.9% (> or =85 years) for Parkinson's disease and 0.7%, 2%, and 3.9 % for
      parkinsonism, respectively. The other parkinsonism prevalence was 1.3 % in men
      and 1.6 % in women. CONCLUSIONS: These prevalence rates are similar than those
      found in studies made in other European countries. The prevalence of both
      Parkinson's disease and other types of parkinsonism increased with age, with no
      significant differences between men and women.

PMID- 15015017
TI  - Autonomous stump movements responsive to gabapentin.

PMID- 15015019
TI  - Diffusion tensor MRI post mortem demonstrated cerebral white matter pathology.

PMID- 15015018
TI  - Internal carotid artery dissection after mandibular third molar extraction.

PMID- 15015020
TI  - Two severe cases of tick-borne encephalitis despite complete active vaccination-
      the significance of neutralizing antibodies.

PMID- 15015021
TI  - The permeability of the blood-CSF barrier in hydrocephalus, polyradiculitis, and
      meningitis.

PMID- 15015023
TI  - New formulation of BOTOX. Complete antibody-induced therapy failure in hemifacial
      spasm.

PMID- 15015022
TI  - Neither collagen 8A1 nor 8A2 mutations play a major role in cervical artery
      dissection. A mutation analysis and linkage study.

PMID- 15015024
TI  - The future challenges in Parkinson's disease.

PMID- 15015025
TI  - Erno Jendrassik (1858-1921).

PMID- 15015032
TI  - African histoplasmosis infection with peritoneal involvement.

PMID- 15015030
TI  - Pharmacokinetic and pharmacodynamic issues in the treatment of bacterial
      infectious diseases.
AB  - This review outlines some of the many factors a clinician must consider when
      selecting an antimicrobial dosing regimen for the treatment of infection.
      Integration of the principles of antimicrobial pharmacology and the
      pharmacokinetic parameters of an individual patient provides the most
      comprehensive assessment of the interactions between pathogen, host, and
      antibiotic. For each class of agent, appreciation of the different approaches to
      maximize microbial killing will allow for optimal clinical efficacy and reduction
      in risk of development of resistance while avoiding excessive exposure and
      minimizing risk of toxicity. Disease states with special considerations for
      antimicrobial use are reviewed, as are situations in which pathophysiologic
      changes may alter the pharmacokinetic handling of antimicrobial agents.

PMID- 15015035
TI  - Matching vocalizations to vocalizing faces in a chimpanzee (Pan troglodytes).
AB  - Auditory-visual processing of species-specific vocalizations was investigated in
      a female chimpanzee named Pan. The basic task was auditory-visual matching-to
      sample, where Pan was required to choose the vocalizer from two test movies in
      response to a chimpanzee's vocalization. In experiment 1, movies of vocalizing
      and silent faces were paired as the test movies. The results revealed that Pan
      recognized the status of other chimpanzees whether they vocalized or not. In
      experiment 2, two different types of vocalizing faces of an identical individual
      were prepared as the test movies. Pan recognized the correspondence between
      vocalization types and faces. These results suggested that chimpanzees possess
      crossmodal representations of their vocalizations, as do humans. Together with
      the ability of vocal individual recognition, this ability might reflect
      chimpanzees' profound understanding of the status of other individuals.

PMID- 15015036
TI  - Screening for point mutations in the LDL receptor gene in Bulgarian patients with
      severe hypercholesterolemia.
AB  - Familial hypercholesterolemia (FH) is a common, autosomal dominant disorder of
      lipid metabolism, caused by defects in the receptor-mediated uptake of LDL (low
      density lipoproteins) due to mutations in the LDL receptor gene ( LDLR).
      Mutations underlying FH in Bulgaria are largely unknown. The aim of the present
      study was to provide information about the spectrum of point mutations in LDLR in
      a sample of 45 Bulgarian patients with severe hypercholesterolemia. Exons 3, 4,
      6, 8, 9, and 14, previously shown to be mutational hot spots in LDLR, were
      screened using PCR-single-strand conformation polymorphism (SSCP). Samples with
      abnormal SSCP patterns were sequenced. Three different, hitherto undescribed
      point mutations (367T>A, 377T>A, 917C>A) and two previously described mutations
      (858C>A and 1301C>T) in eight unrelated patients were identified; four of the
      detected point mutations being missense mutations and one, a nonsense mutation.
      One of the newly described point mutations (917C>A) is a base substitution at a
      nucleotide position, at which two other different base substitutions have already
      been reported. Thus, all three possible base substitutions at this nucleotide
      position have been detected, making it a hot spot for point mutations causing FH.
      This is the first such mutational hot spot described in exon 6 of LDLR.

PMID- 15015031
TI  - Antifungal agents: in vitro susceptibility testing, pharmacodynamics, and
      prospects for combination therapy.
AB  - As invasive fungal infections in immunocompromised patients become increasingly
      important, the field of antifungal chemotherapy continues to evolve rapidly. New
      agents have entered the clinical arena, providing physicians with a variety of
      choices for treatment of most infections. Standardized methods for testing the in
      vitro susceptibility of fungi have become available, and concentration-effect
      relationships are increasingly explored. Finally, the availability of an entirely
      new class of antifungal agents is opening new opportunities for combination
      therapy of infections that are notoriously difficult to treat and carry a dismal
      prognosis. However, the ongoing progress in these key areas has also made
      antifungal chemotherapy considerably more complex and susceptible to
      misconceptions. Continuing efforts in the laboratory and well designed
      collaborative clinical trials are needed more than ever to turn opportunities
      into lasting benefit for patients at risk for or suffering from life-threatening
      invasive mycoses.

PMID- 15015033
TI  - False-positive results and contamination in nucleic acid amplification assays:
      suggestions for a prevent and destroy strategy.
AB  - Contamination of samples with DNA is still a major problem in microbiology
      laboratories, despite the wide acceptance of PCR and other amplification
      techniques for the detection of frequently low amounts of target DNA. This review
      focuses on the implications of contamination in the diagnosis and research of
      infectious diseases, possible sources of contaminants, strategies for prevention
      and destruction, and quality control. Contamination of samples in diagnostic PCR
      can have far-reaching consequences for patients, as illustrated by several
      examples in this review. Furthermore, it appears that the (sometimes very
      unexpected) sources of contaminants are diverse (including water, reagents,
      disposables, sample carry over, and amplicon), and contaminants can also be
      introduced by unrelated activities in neighboring laboratories. Therefore, lack
      of communication between researchers using the same laboratory space can be
      considered a risk factor. Only a very limited number of multicenter quality
      control studies have been published so far, but these showed false-positive rates
      of 9-57%. The overall conclusion is that although nucleic acid amplification
      assays are basically useful both in research and in the clinic, their accuracy
      depends on awareness of risk factors and the proper use of procedures for the
      prevention of nucleic acid contamination. The discussion of prevention and
      destruction strategies included in this review may serve as a guide to help
      improve laboratory practices and reduce the number of false-positive
      amplification results.

PMID- 15015037
TI  - The obturator hernia: difficult to diagnose, easy to repair.
AB  - BACKGROUND: The aim of this paper is to present a simple method for obturator
      hernia repair in two cases with strangulated obturator hernia. METHODS: The
      authors report on two cases of mechanical bowel obstruction due to incarcerated
      obturator hernia in elderly, thin women. Both patients presented with clinical
      and radiological signs of small bowel obstruction. Neither of them had the
      Howship-Romberg or Hannington-Kiff sign. RESULTS: At laparotomy, incarcerated
      small bowel in a right-sided obturator hernia was observed in both patients. The
      small bowel was not necrotic, and no bowel resection was performed. The hernial
      defect was closed in two layers with interrupted and purse-string nonabsorbable
      sutures. CONCLUSIONS: Obturator hernia is rare and difficult to diagnose. Often
      the diagnosis is reached only at laparotomy for small bowel obstruction. The
      double-layer repair with interrupted and purse-string nonabsorbable sutures could
      be useful, especially in emergency laparotomies for incarcerated obturator
      hernia.

PMID- 15015038
TI  - Mortality following laparoscopic ventral hernia repair: lessons from 90
      consecutive cases and bibliographical analysis.
AB  - The popularity of laparoscopic repair of ventral hernias is increasing due to the
      apparent advantages of the procedure, but this approach is still a controversial
      technique. The aim of our study was to evaluate the mortality rate of
      laparoscopic ventral hernia repair and analyse the literature. The authors
      performed a prospective study in 90 patients with ventral hernia who were treated
      by laparoscopic repair. Clinical parameters and intra- and postoperative
      complications were evaluated. A case of mortality was reported due to a
      nonrecognised bowel injury. The mean follow-up (100%) was 42 months (range: 1-5
      years). A bibliographical analysis was carried out (MEDLINE). Four bowel injuries
      were presented (4.4%): three recognised, which required conversion (two treated
      with minilaparotomy and completed afterwards by laparoscopy, and one by
      laparotomy); and one nonrecognised, which was re-operated on but evolved to
      sepsis and multiorgan failure and resulted in death in 48 h (1.1%). Four further
      mortality rates have been documented in the literature (0.6%, 1.1%, 3.1%, and
      3.4% of their series). Bowel injury and mortality show a statistically
      significant tendency to decrease with the number of operations ( P<0.05). In
      conclusion, in our study the risk of mortality with laparoscopic ventral hernia
      repair has been higher than 1%, which must be made known. It is a risk that
      depends on the surgeon's experience but which does not seem to be predictable.

PMID- 15015039
TI  - Bendavid's editorial and the role of defective collagen metabolism in anatomical
      variations.

PMID- 15015040
TI  - Autocatalytic activation of acetyl-CoA synthase.
AB  - Acetyl-CoA synthase (ACS identical with ACS/CODH identical with CODH/ACS) from
      Moorella thermoacetica catalyzes the synthesis of acetyl-CoA from CO, CoA, and a
      methyl group of a corrinoid-iron-sulfur protein (CoFeSP). A time lag prior to the
      onset of acetyl-CoA production, varying from 4 to 20 min, was observed in assay
      solutions lacking the low-potential electron-transfer agent methyl viologen (MV).
      No lag was observed when MV was included in the assay. The length of the lag
      depended on the concentrations of CO and ACS, with shorter lags found for higher
      [ACS] and sub-saturating [CO]. Lag length also depended on CoFeSP. Rate profiles
      of acetyl-CoA synthesis, including the lag phase, were numerically simulated
      assuming an autocatalytic mechanism. A similar reaction profile was monitored by
      UV-vis spectrophotometry, allowing the redox status of the CoFeSP to be evaluated
      during this process. At early stages in the lag phase, Co(2+)FeSP reduced to
      Co(+)FeSP, and this was rapidly methylated to afford CH(3)-Co(3+)FeSP. During
      steady-state synthesis of acetyl-CoA, CoFeSP was predominately in the CH(3)
      Co(3+)FeSP state. As the synthesis rate declined and eventually ceased, the
      Co(+)FeSP state predominated. Three activation reductive reactions may be
      involved, including reduction of the A- and C-clusters within ACS and the
      reduction of the cobamide of CoFeSP. The B-, C-, and D-clusters in the beta
      subunit appear to be electronically isolated from the A-cluster in the connected
      alpha subunit, consistent with the ~70 A distance separating these clusters,
      suggesting the need for an in vivo reductant that activates ACS and/or CoFeSP.

PMID- 15015041
TI  - Structural study of copper(I)-bleomycin.
AB  - Previous NMR studies on Cu(I)-bleomycin have suggested that this adduct has a
      geometry distinct from Fe(II)BLM. The coordination chemistry of this bleomycin
      derivative has been investigated through the extension of the NMR data reported
      previously, and the use of molecular dynamics calculations. The data collected
      from the NMR experiments support the coordination to the metal center of the
      primary and secondary amines in beta-aminoalanine and the pyrimidine ring. The
      detection in the NMR spectra of the signal derived from the amide hydrogen in
      beta-hydroxyhistidine indicates that this amide is protonated in Cu(I)-bleomycin,
      precluding participation of the pyrimidinyl carboxamide nitrogen in the
      coordination of Cu(I), as previously reported. Three-dimensional solution
      structures compatible with the NMR data have been assayed for Cu(I)-bleomycin for
      the first time by way of molecular dynamics calculations, and two models showing
      four and five coordination have been found to be those that better fit the
      experimental data. In both models the primary amine in beta-aminoalanine is
      coordinated such that it is located on the same side, with respect to the
      coordination cage, as the peptide linker fragment. This result seems important
      for the favored models to be compatible with either their possible oxidation to
      become one of the reported structures for Cu(II)BLM, or their transformation into
      Fe(II) adducts able to cause DNA damage.

PMID- 15015042
TI  - On education, training, communication and writing.

PMID- 15015043
TI  - Angio-architecture of spinal cord arteriovenous shunts at presentation. Clinical
      correlations in adults and children. The Bicetre experience on 155 consecutive
      patients seen between 1981-1999.
AB  - OBJECTIVE: To analyse possible relationships between the symptoms and signs
      created by intradural spinal cord arteriovenous shunts (SCAVSs) and their angio
      architecture. METHODS: The clinical and radiological files of 155 patients, both
      adults and children, seen between 1981 and 1999 with a SCAVS were retrospectively
      reviewed. SCAVSs were divided into nidus type (small superficial or large
      intramedullary), and fistulas (micro (mAVFs)- or macrofistulas (MAVFs)). The
      angio-architectural points studied were arterial stenosis, proximal arterial
      aneurysm, distal arterial aneurysm, arteriovenous fistulas, pial venous drainage
      and/or reflux, venous ectasias, venous stenosis, venous thrombosis, false
      aneurysms. Correlations between architecture, location, age groups and symptoms
      and signs were made. FINDINGS: A male predominance was noted in both adults and
      children. Most of the lesions were located at the thoracic level, but hemorrhage
      occurred as the presenting event predominantly in cervical localizations. 30
      patients (20 AVMs; 4 mAVFs, 6 MAVFs) were children. 5 of the 6 MAVFs found in
      children were associated with Hereditary Hemorrhagic Telengiectasia (HHT1).
      Twenty one children (70%) had bled. Spontaneous total or subtotal recovery was
      the rule in 15 of those who had bled (72%) but early recurrent hemorrhages
      occurred in 2. Among 125 adults 56 presented with hemorrhage (45%). The
      proportions of those who recovered spontaneously (71%) or rebled (3,6%) in the
      same year after the initial episode were very similar to children. All other
      adults presented with acute or progressive non-hemorrhagic episodes. There was no
      significant difference in the angio-architecture between hemorrhagic and non
      hemorrhagic SCAVS, except for that occurrence of pseudo-aneurysms. Hemorrhage in
      SCAVSs may not be exclusively due to haemodynamic factors. Venous congestion was
      responsible for progressive symptoms. Acute deficits unrelated to bleeds were due
      to intralesional thrombosis or hemodynamic changes. INTERPRETATION: The short
      term prognosis of hemorrhagic SCAVSs is good, and there is no need for emergency
      treatment. MRI delineates the cord and makes the diagnosis of the lesion but
      angiography remains the gold standard for analysis of the vasculature. The angio
      architecture reflects the ageing of the lesion but there is not a precise
      correlation between angio-architecture and clinical symptoms, except for
      pseudoaneurysms which relate to the hemorrhagic portion of the lesion.

PMID- 15015044
TI  - Concepts of combined endovascular and surgical treatment for dural arteriovenous
      fistulae: concepts derived from experience in treating three unusual lesions.
AB  - BACKGROUND: We describe a treatment protocol for patients who have a dural
      arteriovenous fistulae (dAVF) not curable solely by an endovascular approach.
      MATERIAL AND METHODS: Three patients suffering from neurological impairment due
      to a complex dAVM (intracranial haemorrhage 2, intracranial hypertension 1) were
      treated by a combination of arterial embolization treatment and subsequent
      surgery. RESULTS: Marked reduction of flow was achieved by embolization of the
      main arterial feeders of the fistulae. Surgery eliminated the residual dAVFs
      completely and without permanent morbidity. CONCLUSION: It is necessary to
      eliminate a dural fistula completely, especially in a patient whose fistula had
      drainage or reflux into cortical veins, which have a high risk of intracranial
      haemorrhage and venous hypertension. We present an approach to treatment using
      transarterial embolization and early surgery which may offer a safe and effective
      way to achieve complete elimination of the lesion, avoiding increased risk to
      important venous drainage.

PMID- 15015045
TI  - Revascularization procedures in internal carotid artery pseudo-occlusion.
AB  - BACKGROUND: Surgical treatment of patients with suspected internal carotid artery
      (ICA) pseudo-occlusion and reduced cerebrovascular reactivity (CVR) is still
      uncertain regarding the diagnostic procedures, the risks and the optimal timing
      as well as performance of revascularization. METHOD: From 1983-2001, 781 patients
      with symptomatic ICA stenosis were treated surgically. In 53 patients, a final
      diagnosis of extracranial ICA pseudo-occlusion was established by repeating
      Digital Subtraction Angiography (DSA). Angiographical findings were anterograde
      "string-like" filling of ICA beyond the carotid bifurcation or retrograde filling
      of the proximal, so called "occluded" extracranial ICA, extending up to the skull
      base. The CVR was reduced. All patients underwent direct surgery of extracranial
      carotid artery. Diagnostic parameters, peri-operative risks and postoperative
      course of these patients were evaluated. FINDINGS: In 40 patients (75.5%) a
      successful revascularization of ICA was possible. ICA pseudo-occlusion was in all
      cases of atheromatous origin, moreover in 8 patients combined with a floating
      thrombus, distal to the stenosis. Thrombectomy was done by means of Fogarty
      catheter. In 13 patients (24.5%), a surgical re-opening of the ICA lumen was not
      possible. Five of these patients showed in DSA an anterograde "string sign",
      eight presented retrograde filling of ICA reaching the skull base. Peri-operative
      mortality was 1.9%, peri-operative morbidity was 7.5%. After a 4 years (mean)
      follow-up, 95% of the reopened ICA remained patent. CONCLUSION: In patients with
      explicit carotid artery occlusion signs, careful selective DSA should be
      compulsory with a late series to detect ICA pseudo-occlusion. There is a chance
      for extracranial reopening ICA, even with compromised CVR, if anterograde "string
      like" or retrograde filling of proximal so called "occluded" ICA as far as the
      skull base is angiographically identified.

PMID- 15015046
TI  - Angiographic follow-up after surgical treatment of intracranial aneurysms.
AB  - This study was undertaken to evaluate the long-term angiographic outcome of
      surgically treated aneurysms. In addition, the incidence of recurrent aneurysms,
      the fate of residual aneurysms and the de novo formation of aneurysms were
      evaluated. Moreover, morphological conditions such as dilatation, stenosis or
      irregularity in temporarily clipped vascular segments were analyzed.166 aneurysms
      were operated on in 136 patients and these 166 aneurysms subsequently underwent
      late follow-up angiography. Late angiographic follow-up review was obtained at a
      mean of 46.6+/-11.5 months postsurgery (range 36-85 months). Out of the 7
      aneurysms with known residua, 5 residual aneurysms were determined as unchanged,
      1 residual aneurysm as spontaneous thrombosis and 1 residual aneurysm as
      enlarged. No recurrent aneurysm was found, however two de novo aneurysms were
      found. During the surgery of 85 aneurysms, 137 vascular segments clipped
      temporarily were evaluated in terms of morphological changes in postoperative and
      long-term angiograms. No morphological changes were determined in any vascular
      segments. These anatomical long-term results confirm the long-term efficacy of
      aneurysm clipping, when perfect. Small residual aneurysms can be followed with
      periodically performed angiography.

PMID- 15015047
TI  - Routine clinical adoption of magnetic resonance imaging was associated with
      better outcome after surgery in elderly patients with a malignant astrocytic
      tumour: a retrospective review.
AB  - BACKGROUND: There is controversy about extensive surgical treatment for a
      malignant astrocytic tumour in more elderly patients who may have poorer outcomes
      and higher complication rates. This retrospective study investigated outcome in
      elderly patients with malignant astrocytic tumour before and after the adoption
      of routine clinical use of magnetic resonance (MR) imaging. METHODS: During 1982
      through 1999, 88 patients with malignant astrocytic tumour aged 60 years or over
      were treated in our institute. Thirty-seven patients had an anaplastic
      astrocytoma and 51 had a glioblastoma. Thirty-seven patients treated from 1982 to
      1988 did not have pre-operative evaluation by MR imaging (Group A), 26 patients
      treated from 1989 to 1995 had preoperative MR imaging evaluation (Group B), and
      25 patients treated after 1996 underwent preoperative MR imaging with functional
      brain mapping and intra-operative navigation system monitoring (Group C).
      FINDINGS: The median survival time was 8.8 months in Group A, 12.7 months in
      Group B, and 17.6 months in Group C. Patients with glioblastoma in Group B (11.7
      months, n = 15) and Group C (16.0 months, n = 19) had significantly longer median
      survival time than in Group A (6 months, n = 17) (P = 0.0054 between Groups A and
      B, P = 0.0024 between Groups A and C). Better preoperative performance status,
      more thorough surgical resection, and better performance status after the initial
      treatment was obtained after the introduction of MR imaging, and patients with
      the optimal indicators showed significantly longer survival time compared with
      the patients without these factors. INTERPRETATION: Pre-operative MR imaging may
      contribute to longer survival time by providing an earlier diagnosis in patients
      with better performance status, by allowing more thorough surgical resection, and
      resulting in better performance status after the treatment.

PMID- 15015048
TI  - Time course of CT evolution in traumatic subarachnoid haemorrhage: a study of 141
      patients.
AB  - BACKGROUND: Evidence of tSAH on an admission CT scan seems to be an early
      predictor of evolving posttraumatic lesions. Detection of these changes requires
      serial CT scanners. The goal of our study was to determine the optimal timing of
      follow-up CT scans in head injured patients with traumatic subarachnoid
      haemorrhage (tSAH). METHOD: We reviewed the initial and follow-up CT scans in 141
      patients with closed head injuries and evidence of tSAH on the initial CT scan.
      We used the Marshall classification to determine diffuse and focal injuries. The
      "worst CT scan", defined as the CT examination in which midline shift, cistern
      compression and/or intracranial focal lesions were greater, was also determined.
      Any worsening of the admission CT findings, occurring when the "worst CT
      examination" did not correspond to the initial CT study, was considered as a "CT
      evolution". Any "CT evolution" associated with a variation from a lower to a
      higher score in the Marshall classification score was indicated as a "significant
      CT evolution". FINDINGS: The median time between injury and the first CT scan was
      1.3 (IQR 1.5) hours. A CT evolution was found in 83/141 (58.9%) patients in whom
      the median time between the initial and worst CT scans was 27.7 hours (IQR 69.2
      hours). The worst CT studies were seen more often at 12-24 hours and at 24-48
      hours after the admission CT scan than in later studies. A similar temporal
      profile was observed when the timing of the "worst CT scan" was evaluated in
      38/83 (45.8%) subjects with a "significant CT evolution". INTERPRETATION: Our
      findings show that an early admission CT scan did not represent the full extent
      of the posttraumatic damage in more than half of our patients. They also suggest
      that to identify these changes in head injured patients with tSAH, CT scans
      should be repeated at 12-24 and possibly also at 24-48 hours from the admission
      CT examination to allow early detection and evacuation of evolving intracranial
      lesions.

PMID- 15015049
TI  - Intra-operative mapping of the subcortical visual pathways using direct
      electrical stimulations.
AB  - Despite the risk of postoperative visual field defect following surgery within
      the temporo-parieto-occipital region, visual mapping has rarely been described,
      in particular at the subcortical level. In this report, we successfully performed
      a subcortical mapping of the visual pathways using intra-operative electrical
      stimulations (IES), during surgery under local anesthesia for a low-grade glioma
      invading the whole temporal lobe and the temporo-occipital junction. The optic
      radiations then constituted the posterior and deep functional boundary of the
      resection, avoiding the occurrence of a post-operative hemianopsia, in spite of
      an asymptomatic quadrantanopsia. This preliminary experience illustrates the
      possibility to use intra-operative direct electrical stimulation during surgery
      of lesions involving the posterior afferent visual system, in order to identify
      and then preserve the visual pathways, as previously reported for sensorimotor
      and language subcortical fibers.

PMID- 15015050
TI  - Image fusion of MR images and real-time ultrasonography: evaluation of fusion
      accuracy combining two commercial instruments, a neuronavigation system and a
      ultrasound system.
AB  - OBJECTIVE: The aim of our study was to evaluate MRI/Ultrasonography fusion
      accuracy depending on three ultrasonographic parameters. METHOD: An
      ultrasonography and MRI compatible model was created, consisting of a plastic
      box, which contained 3 objects. MRI scans were performed with 128 sagittal
      slices. The objects were segmented and 3D reconstructions were created. A special
      ultrasound adapter with 3 reflective markers was fixed to the ultrasound probe.
      Thus, the probe could be tracked by the navigation system (Vector Vision(2),
      BrainLab, Heimstetten, Germany) and the segmented shape of the 3D-objects
      obtained from the MR images were overlaid onto the ultrasound display (Elegra,
      Siemens, Erlangen, Germany). The dependency of fusion accuracy on different depth
      of ultrasound display, different distances between probe and objects and
      different angles between the axis of the ultrasound probe and the centre of the
      spheres was evaluated. 435 single measurements were performed. FINDINGS: Overall
      fusion accuracy was 1.08 mm+/-0.61 mm (mean +/- standard deviation) for spheres
      and 1.6 mm+/-1.1 mm for arrow heads. If the ultrasound probe was directed more
      tangentially to the surface of the spheres the fusion became increasingly
      inaccurate (P<0.05). Fusion accuracy decreased the more distant the US probe was
      held to the object (P<0.05). Different depth of ultrasound display had no
      significant effect on fusion accuracy. CONCLUSIONS: Highly accurate fusion of MR
      images and real-time ultrasonography could be achieved. However, careful
      interpretation of the fused data is necessary, when different angles and
      distances of the US probe to the object are concerned.

PMID- 15015051
TI  - The value of expanded polytetrafluoroethylene in preventing early re-ossification
      after craniosynostosis surgery: an experimental animal study in the rat.
AB  - BACKGROUND: Early re-ossification at the suturectomy site after craniosynostosis
      surgery remains an important problem. Many surgical methods have been used to
      address this, including placement of various types of absorbable and non
      absorbable material between the bone edges at the site. This experimental study
      investigated the value of expanded polytetrafluoroethylene (ePTFE) membrane as a
      barrier to calvarial reclosure after craniosynostosis surgery in rats. METHOD:
      Thirty-five 2-week-old Sprague-Dawley rats were divided into two groups. In Group
      A (n = 17), ePTFE membranes were placed in the defect formed by a left coronal
      suturectomy. The Group B rats (n = 18) underwent left coronal suturectomy only.
      Animals were sacrificed at 1, 2 and 4 months postoperatively. In each case, the
      skull was removed and the operative site was examined for fibrosis, new bone
      formation, bone bridging, neovascularization and inflammatory response. FINDINGS:
      The two groups were similar with respect to neovascularization and new bone
      formation. By the end of the fourth postoperative month, 50% of the Group B
      specimens showed fibrosis and 50% showed bridging between the bone edges at the
      suturectomy site. In contrast, at the same stage in Group A, only 16.6% of the
      specimens exhibited a small amount of fibrosis, and none showed bone bridging
      between the edges. INTERPRETATION: Expanded PTFE is one of the most inert
      materials used in surgery. The study showed that inserting ePTFE membrane as a
      barrier between the bone edges at the suturectomy site prevents early re
      ossification after craniosynostosis surgery in rats.

PMID- 15015053
TI  - Stereotactic radiosurgery for nodular dissemination of anaplastic ependymoma.
AB  - Dissemination of primary intracranial ependymoma occurs in 10% of all cases and
      is difficult to treat, so this may be one of the major reasons for the poor
      prognosis. Two patients with nodular dissemination of anaplastic ependymoma were
      treated with repeated stereotactic radiosurgery using the gamma knife (GK),
      resulting in tumour control over 21 months. GK radiosurgery is a safe and
      effective treatment option for providing good local control in patients with
      nodular dissemination of ependymoma.

PMID- 15015052
TI  - Haemorrhagic tracheal necrosis as a lethal complication of an aneurysm model in
      rabbits via endoluminal incubation with elastase.
AB  - BACKGROUND: We describe a lethal complication of an aneurysm model in rabbits for
      saccular aneurysmal creation via endoluminal incubation with elastase. METHOD: In
      24 anaesthetized female New Zealand White rabbits, the right common carotid
      artery (CCA) was ligated distally to the arteriotomy. A 4F sheath was then placed
      retrograde into the CCA, and its origin was occluded endoluminally using a 2F
      Fogarty balloon. Elastase was incubated above the balloon in the separated vessel
      lumen for the duration of 20 minutes. Two weeks later, digital subtraction
      angiography was performed for aneurysm control. Two animals were then sacrificed
      and the aneurysm studied on histology. All animals that died within the
      experiment were examined post-mortem. FINDINGS: Following this protocol, an
      aneurysm with a mean size of 7.6 x 3.2 mm could be created in 11 out of 24
      animals. 9 out of 13 animals with lethal outcome died from haemorrhagic necrosis
      of the trachea with subsequent pulmonary complications. DSA releaved an arterial
      branch originating from the proximal CCA in a near 90 degree-angle aiming at the
      trachea. INTERPRETATION: The endoluminal incubation with elastase is suitable for
      aneurysm creation of reproducible size that are suited to test new endovascular
      devices such as stents and new coils. One should always be aware of an arterial
      branch of the CCA supplying the trachea. In case of elastase instillation into
      this branch, lethal haemorrhagic necrosis of the trachea occurs. Bearing this
      complication in mind, we have experienced a minimal loss of animals in subsequent
      studies.

PMID- 15015054
TI  - Spinal angiolipoma: case report and review of the literature.
AB  - Spinal angiolipomas are rare lesions usually found in the epidural space of the
      thoracic spine. This report presents a case of and reviews the literature on this
      rare entity. The etiology, clinical presentation, imaging, and treatment are
      discussed. In 92 reported cases of spinal angiolipoma 56 occurred in women (61%),
      and 36 in men (39%). Mean age of occurrence is 42.9 years (range 10 days-85
      years) with most patients presenting with slowly progressive symptoms of spinal
      cord compression. Most cases occur in the extradural compartment, and are of the
      non-invasive subtype. This rare clinical entity must be considered in the
      differential diagnosis of spinal epidural lesions. In most cases complete removal
      is possible, however, prognosis is good even for infiltrating lesions. Thus, one
      must not risk neurological damage to attain complete resection.

PMID- 15015056
TI  - Phrenic paresis and respiratory insufficiency associated with cervical
      spondylotic myelopathy.
AB  - Cervical spondylotic myelopathy is a common disease caused by chronic segmental
      compression of the spinal cord. Despite the fact that the columns of the nuclei
      of the phrenic nerve are located between the 3rd and 5th cervical nerve segments,
      phrenic nerve paresis is not usually clinically significant. We present one case
      of cervical spondylotic myelopathy with bilateral phrenic paresis in whom
      magnetic resonance imaging and surgical findings confirmed intrinsic cord disease
      as being the cause of this syndrome. This case report suggests that one
      pathophysiology of clinical phrenic nerve paresis may be segmental damage to the
      anterior horns caused by cervical spondylosis.

PMID- 15015055
TI  - Paraparesis due to pressure erosion of the thoracic spine by an aortic aneurysm:
      remission of symptoms following resection of the aneurysm and vertebral
      reconstruction.
AB  - BACKGROUND: There are only a few descriptions in the literature of thoraco
      abdominal aortic aneurysms responsible for erosion of the vertebral column and
      compression of the spinal cord. This case is therefore presented to provide an
      opportunity to discuss the pathomechanic aspects and to demonstrate the
      feasibility of total surgical repair by an interdisciplinary approach. METHODS: A
      thoraco-abdominal aortic aneurysm caused extensive erosion of vertebral bodies T5
      8, leading to invasion of the spinal canal and compression of the cord. The
      clinical signs were paraparesis and chronic thoracolumbar pain. In a combined
      operation the aneurysm was replaced by a Dacron prosthesis. Corpectomy of T5-8
      was carried out and a titanium mesh cage filled with autogenous bone tissue was
      inserted. The vertebral column was stabilized using dorsal and lateral
      instrumentation. FINDINGS: Clinical and imaging follow-up after three years
      showed remission of the patient's severe paraparesis and chronic pain and long
      term technical success of the vertebral and aortic reconstruction.
      INTERPRETATION: Complete thoraco-abdominal aortic replacement and spinal column
      repair can be successfully accomplished with good clinical and neurological long
      term results.

PMID- 15015057
TI  - Writing and publishing case reports: the road to success.
AB  - Case reports, by virtue of their simplicity, are ideal for the novice writer. The
      temptation is to write up anything that is remotely interesting in the hope that
      you get your name in print. One soon discovers that this is a self-defeating
      exercise when rejections of a mediocre manuscript come a plenty. Choosing an
      appropriate case is the difficult first step and getting started remains a
      challenge for the uninitiated. This article outlines our systematic approach for
      busy junior doctors to write high-quality and meaningful case reports with
      relative ease.

PMID- 15015060
TI  - Seasonal dynamics of arbuscular mycorrhizal fungi in differing wetland habitats.
AB  - The dynamics and role of arbuscular mycorrhizal fungi (AMF) have been well
      described in terrestrial ecosystems; however, little is known about how the
      dynamics of AMF are related to the ecology of wetland ecosystems. The seasonal
      dynamics of arbuscular mycorrhizal (AM) colonization within different wetland
      habitats were examined in this study to determine the factors that influence AM
      associations and to further assess the ecological role of AMF in wetlands. Fen
      and marsh habitats of four wetlands in west central Ohio were sampled monthly
      from March to September. AMF were found at all four sites for each month sampled
      and were present in all of the dominant plant species. A significant effect of
      month (P<0.001) on AM colonization did occur and was attributable to maximum
      colonization levels in the spring and minimum levels in late summer. This trend
      existed in all four wetlands in both fen and marsh habitats,regardless of
      variation in water levels, percent soil moisture, or available phosphorus levels.
      Because abiotic factors had minimal influence on AM colonization variation and
      the level of AM colonization paralleled plant growth patterns, we conclude that
      the AM seasonal dynamic was in response to plant phenology. Our data suggest that
      AM associations in temperate fen and marsh habitats are prevalent in the spring
      during new root and vegetative growth, even for plants experiencing flooded
      conditions. Evidence of an overriding AM seasonal trend indicates that future
      studies should include a seasonal component to better assess the role and
      distribution ofAMF in wetland ecosystems.

PMID- 15015061
TI  - Genetic analysis of phenotypic variation for ectomycorrhiza formation in an
      interspecific F1 poplar full-sib family.
AB  - A plant's capability to develop ectomycorrhizal symbiosis is under the control of
      both genetic and environmental factors. In order to determine the roles played by
      these different factors, we have performed a quantitative genetic analysis of the
      ability of poplar trees to form ectomycorrhizas. Quantitative genetics were
      applied to an interspecific family of poplar for which the two parental genetic
      maps had already been described, and for which data analyses concerning fungal
      aggressors were obtained. Quantitative trait loci (QTL) related to ectomycorrhiza
      formation were identified and located in the genetic maps of the two parents. One
      QTL was located at a linkage group of the genetic map of Populus trichocarpa
      showing a high concentration of several QTL involved in the pathogenic
      interaction with the fungus Melampsora larici-populina, the causal agent of leaf
      rust.

PMID- 15015062
TI  - The ratio of urinary cystatin C to urinary creatinine for detecting decreased
      GFR.
AB  - Glomerular filtration rate (GFR) and urine and serum concentrations of cystatin C
      and creatinine were measured in 40 boys and 42 girls. The fractional excretion of
      cystatin C (FE Cyst C) increased in proportion to the decrease in GFR. Since
      serum creatinine concentration (S-Creatinine) in the numerator of the fractional
      excretion equation and serum cystatin C concentration (S-Cystatin C) in the
      denominator have similar numerical values, they cancel out. The result is an
      equation in which the FE Cyst C is equal to the ratio of urinary cystatin C to
      urinary creatinine (u[cystatin-C/Cr]). The ratio of u[cystatin C/Cr] was compared
      with GFR. Using a receiving operating characteristic (ROC) plot, the data showed
      that a ratio of u[cystatin C/Cr]*100 that is > or =0.100 has a sensitivity of
      90.0% for identification of children with GFR < or =60 ml/min per 1.73 m(2). The
      false-positive rate is 16.1%. The u[cystatin C/Cr] ratio is a reliable screening
      tool for detecting decreased GFR that does not require a serum sample.

PMID- 15015063
TI  - Evaluation and treatment of pediatric idiopathic urolithiasis-revisited.
AB  - The objective of the study was to update the evaluation and treatment of
      idiopathic urolithiasis in children in Western society. A secondary goal was to
      evaluate patients' compliance with high fluid intake. Over 2 years we
      prospectively studied children referred to us for idiopathic urolithiasis
      confirmed radiographically, excluding those with secondary disorders. A metabolic
      urinalysis, which included calcium, citrate, uric acid, oxalate, cystine, and
      creatinine, was ordered in all patients. Hypercalciuric patients were first
      treated with a low-sodium (Na)/high-potassium (K) diet and if hypercalciuria
      persisted, thiazides or potassium citrate was added. Follow-up ultrasound scans
      were scheduled every 10-12 months. Urine specific gravity (SG) measured during
      clinic visits was used to assess compliance with high fluid intake. A survey was
      sent to pediatric urologists and nephrologists to establish a recommended maximal
      SG value. Thirty healthy school-aged children served as controls. There were 45
      children (24 males, 21 females) aged 10.4+/-2.0 years (median 11.0) studied.
      Stones were retrieved and analyzed in 28 showing calcium composition in all.
      Urine chemistry analysis was incomplete in 3, and in the others showed
      hypercalciuria in 33 (78.6%), hypocitraturia in 1 (2.4%), and normal values in 8
      (19.0%). Treatment of 33 hypercalciuric patients consisted of diet alone in 13,
      potassium citrate in 17, thiazides in 2, and potassium citrate and thiazide in 1.
      All 33 achieved normocalciuria, apart from 2 who remained mildly hypercalciuric
      on diet alone. The 12 normocalciuric children were treated by diet modification
      alone. Follow-up ultrasonography showed no new stones in 36 of 39 patients. In 3,
      new stone formation was associated with recurrence of hypercalciuria after the
      potassium citrate dose was lowered or discontinued. Upon their first clinic
      visit, the urine SG of stone formers (1.021+/-0.007) was significantly higher
      than the maximum SG recommended by 18 physicians of 1.010+/-0.003 ( P<0.001), and
      not different from the SG in the control group (1.018+/-0.007). Urine SG at
      follow-up visits was unchanged in stone formers. We therefore propose a step-wise
      approach in evaluating children with idiopathic urolithiasis in Western society,
      in which first only urine calcium is studied. Only if urine calcium is normal,
      should other chemistries be studied. In many hypercalciuric children, low-Na/high
      K diet alone is effective, while in most others the addition of potassium citrate
      is well tolerated, normalizes calciuria, and protects against new stone
      formation. Children rarely comply with the recommendation of high fluid intake.

PMID- 15015064
TI  - Pseudotumor cerebri following cyclosporine A treatment in a boy with
      tubulointerstitial nephritis associated with uveitis.
AB  - An 11-year-old boy with recurrent nephritis due to tubulointerstitial nephritis
      associated with uveitis (TINU syndrome) was treated with cyclosporin A (CSA) to
      induce sustained remission. CSA was introduced as a steroid-sparing drug because
      of extreme obesity (body mass index 32 kg/m(2)). Although the boy did not
      complain of any clinical symptoms, eye inspection after 7 months revealed
      bilateral disk edema with retinal bleeding and the patient developed
      cerebrospinal hypertension. Pseudotumor cerebri was diagnosed by measuring the
      intracranial pressure (31 cm H(2)O) and normal computer tomography and brain
      magnetic resonance imaging. Cessation of CSA therapy and treatment with
      mycophenolate mofetil led to resolution within 12 weeks.

PMID- 15015065
TI  - Development of IgA nephritis following cat scratch disease in a 13-year-old boy.
AB  - We describe a 13-year-old boy who presented with hematuria and intermittent low
      grade proteinuria at the time when he was diagnosed with cat scratch disease. Two
      months before presentation, he had a negative urinalysis during a routine
      physical evaluation. He continued to have microscopic hematuria for the next 6
      months, when he developed gross hematuria and recurrence of low-grade
      proteinuria. The renal biopsy showed evidence of mild/moderate IgA nephropathy.
      We speculate that the immunological changes associated with cat scratch disease
      in this patient may have triggered the development of IgA nephropathy. A history
      or serological evidence of infection with Bartonella henselae may need to be
      sought in patients presenting with IgA nephritis.

PMID- 15015066
TI  - Frangible seal on dialysis bag.

PMID- 15015067
TI  - Variable expression of vasculitis in siblings with familial Mediterranean fever.
AB  - Familial Mediterranean fever (FMF) is an autosomal recessive disorder
      characterized by recurrent and self-limited attacks of serosal inflammation with
      abdominal pain, chest pain, and arthritis usually accompanied by fever. Different
      vasculitides such as polyarteritis nodosa (PAN) and Henoch-Schonlein syndrome
      (HSS) may be associated with FMF. We report two sisters of a Turkish family with
      FMF who developed distinct vasculitides. The younger sister developed severe PAN
      with perirenal hematoma at the age of 13 years, the older sister presented with
      severe HSS and acute renal failure at the age of 19 years. Neither sister
      developed amyloidosis until the age of 30 years. This observation suggests that
      early events in the pathogenesis of PAN and HSS are generally quite similar.

PMID- 15015069
TI  - The clinical significance of vascular calcification in young patients with end
      stage renal disease.
AB  - Mortality statistics of young adults with childhood-onset end-stage renal disease
      (ESRD) show that cardiovascular disease (CVD) is responsible for most deaths on
      dialysis and after transplantation. This is most likely explained by the presence
      of a multitude of traditional and non-traditional risk factors in uremia,
      promoting the combination of classical atherosclerosis, uremic vasculopathy, and
      uremic cardiomyopathy. Vascular (arterial) calcifications occur with a high
      prevalence in young adults and their presence correlates with non-traditional
      risk factors, markers of inflammation, intake of calcium-containing phosphate
      binders, and the calcium-phosphorus product in serum. This might be explained by
      a high positive calcium and phosphorus balance in ESRD patients, which may be
      comparatively higher in the young. In addition, treatment with active vitamin D
      preparations may enhance the positive calcium and phosphorus balance and have a
      direct calcifying effect on the arterial wall. The biological process of vascular
      calcification resembles osteogenesis. These data indicate that vascular
      calcifications are related to non-traditional risk factors, inflammatory
      mechanisms, and disturbances in calcium and phosphorus metabolism in uremia. They
      provide strong evidence for a change in the current management of renal
      osteodystrophy in children and adolescents with ESRD.

PMID- 15015068
TI  - The enigma of hyperparathyroidism in hypophosphatemic rickets.
AB  - Familial hypophosphatemic rickets (XLH) is caused by inactivating mutations of
      the cell surface metalloproteinase PHEX. It is characterized by low-normal serum
      levels of 1,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], normocalcemia, and
      hypophosphatemia. Hyperparathyroidism is regularly seen in patients treated with
      phosphate supplements, although circulating serum phosphate levels do not reach
      the normal range. The mechanism is unknown. Decreased serum concentrations of
      ionized calcium following phosphate supplements might contribute to the
      development of hyperparathyroidism. Secondary and even tertiary
      hyperparathyroidism can, however, be observed in patients who have never received
      phosphate treatment. This points to an abnormal regulation of production and/or
      degradation of parathyroid hormone (PTH). Recently, the expression of the PHEX
      gene in hypertrophied parathyroid glands of a patient with XLH has been reported.
      It is unclear whether the mutant PHEX gene can induce hyperparathyroidism by
      abnormal regulation of peptidases.

PMID- 15015070
TI  - Pulse cyclophosphamide therapy in steroid-dependent nephrotic syndrome.
AB  - Intravenous cyclophosphamide (IVCP) has been shown to be effective in lupus
      nephritis. This is a randomized controlled trial to compare the effectiveness of
      IVCP with oral cyclophosphamide (OCP) in patients with steroid-dependent (SD)
      idiopathic nephrotic syndrome (INS). Forty-seven consecutive children who were SD
      were randomized to receive either OCP (2 mg/kg per dayx12 weeks) or IVCP (500
      mg/m(2) per month IVx6 months) after achieving a steroid-induced remission. The
      response was evaluated in terms of remission, change in steroid response status,
      duration of remission (i.e., proteinuria-free days), side effects, and
      compliance. Of the 47, IVCP was given to 26 children and OCP to 21 children. The
      demographic data, histopathology, biochemical profile, and duration of follow-up
      in the two groups were similar. On Kaplan-Meier survival analysis, the median
      proteinura-free time was 360+/-88 days compared with 96+/-88 days in the OCP
      group (values median+/-SE, log rank P=0.05). The actuarial cumulative sustained
      remission in our study was 73% in IVCP compared with 38.1% in OCP at 6 months
      after therapy, but was almost identical (18.6% in IVCP vs. 19%in OCP) after 2
      years. Thus in our study the overall improvement in steroid response category
      from SD to sustained remission, infrequent relapser, and frequent relapser (88%
      in IVCP vs. 57% in OCP) was significantly better in the IVCP group, although the
      number of children with persistent remission tended to be similar at 2 years.
      Furthermore, the response was observed with a 40% lower cumulative dose than OCP.
      Hence, we conclude that IVCP is a safe and effective therapeutic modality in
      children with INS who are SD.

PMID- 15015071
TI  - NPHS2 mutation associated with recurrence of proteinuria after transplantation.
AB  - Mutations in the NPHS2 gene encoding podocin are associated with steroid
      resistant nephrotic syndrome (SRNS) in childhood. Patients usually present with
      focal segmental glomerulosclerosis (FSGS). It is unclear to what extent SRNS due
      to NPHS2 mutations predisposes to recurrence of proteinuria/FSGS after renal
      transplantation (RTx). A 4-year-old girl with infantile SRNS was started on
      peritoneal dialysis because of end-stage renal disease due to FSGS. Mutational
      screening of the patient and her parents revealed a novel single nucleotide
      deletion in exon 8 of the NHPS2 gene (948delT), for which the patient was
      homozygous and her parents confirmed heterozygous asymptomatic carriers. At the
      age of 4.5 years the patient received a renal graft from her mother. On day 7
      after RTx, the patient developed progressive proteinuria (urine
      protein/creatinine ratio 2.4 g/g), which responded within 1 week to prednisone
      pulse therapy, an increased cyclosporin A dosage, and ramipril therapy. The
      patient has maintained stable graft function and no further recurrence of
      proteinuria has been observed. In conclusion, patients with SRNS due to NPHS2
      mutations are not protected from recurrence of proteinuria after RTx. The quick
      response to increased immunosuppression in our patient suggests an immune
      mediated pathomechanism for recurrence of proteinuria.

PMID- 15015073
TI  - Morphology and viability analysis of Streptomyces clavuligerus in industrial
      cultivation systems.
AB  - The effects of varying inoculum age and production scale upon the morphology and
      viability of Streptomyces clavuligerus were studied by analyzing visible and
      fluorescent light images acquired throughout pilot-plant and pre-industrial scale
      fermentations. Changes in production scale reveal that in 5 m(3) fermentors, the
      maximum hyphal area obtained is double the value obtained in 0.5 m(3) fermentors.
      It is probably due to the higher shear stresses acting upon hyphae in the 0.5
      m(3) fermentor caused by higher tip speeds observed in these. The morphological
      quantification based on elongation and branching rates allowed fermentations to
      be pattern classified into distinct physiological time zones namely elongation,
      branching, fragmentation, etc. The general pattern observed for fermentations
      inoculated with late exponential phase inocula was similar to the pattern of
      fermentations run with stationary phase inocula except that both the elongation
      and branching periods started earlier in the former case. Using the available
      staining technique and image acquisition system, the viability seemed to be
      generally high and constant throughout the time course of all the studied
      fermentations.

PMID- 15015072
TI  - Genitourinary anomaly in congenital varicella syndrome: case report and review.
AB  - We describe a 1-year-old boy with congenital varicella syndrome who had
      vesicoureteral reflux (VUR) and neurogenic bladder. His mother had varicella
      during the 3rd month of pregnancy. At birth the patient presented with right
      microphthalmia, right microcornea, and persistent hyperplastic primary vitreous
      of the right eye. He had chronic constipation from 3 months of age. He had
      urinary tract infection at 1 year of age. Urological investigation revealed left
      grade V VUR and neurogenic bladder. His varicella zoster virus IgG titer measured
      by ELISA was 39.4 antibody index (normal <0.1). He had repeated episodes of
      urinary tract infection despite antibiotic prophylaxis and clean intermittent
      catheterization, and underwent a uretero-vesiconeostomy at 2 years of age.
      Maternal infection during early pregnancy and the serological evidence of
      varicella zoster IgG antibodies without a history of varicella after birth led to
      the diagnosis of congenital varicella syndrome. Urogenital anomalies have
      previously been described in 14 cases of congenital varicella syndrome. Most of
      these patients had neurogenic bladder, the pathophysiology of which could be
      explained by the known neurotropic nature of the virus.

PMID- 15015074
TI  - Glucose oxidase catalysed oxidation of glucose in a dialysis membrane
      electrochemical reactor (D-MER).
AB  - The purpose of this work was to evaluate the effectiveness of a new Membrane
      Electrochemical Reactor (MER) for the production of gluconic acid by glucose
      oxidase (GOD) catalysed glucose oxidation. The GOD was confined against the
      electrode surface with a dialysis membrane. The role of the electrochemical step
      was to eliminate by oxidation the hydrogen peroxide that appeared as a by-product
      of the reaction and strongly inhibited and/or inactivated GOD. The dialysis MER
      gave a transformation ratio of 30% with an initial glucose concentration of
      around 300 mM. This result is significantly better than the maximum of 10%
      obtained when hydrogen peroxide was eliminated by addition of a large excess of
      catalase in solution, as is generally done. The D-MER also revealed unexpected
      properties of the enzyme kinetics, such as an oscillatory behaviour, which were
      discussed.

PMID- 15015075
TI  - Upward cascading effects of nutrients: shifts in a benthic microalgal community
      and a negative herbivore response.
AB  - We evaluated the effects of nutrient addition on interactions between the benthic
      microalgal community and a dominant herbivorous gastropod, Cerithidea californica
      (California horn snail), on tidal flats in Mugu Lagoon, southern California, USA.
      We crossed snail and nutrient (N and P) addition treatments in enclosures on two
      tidal flats varying from 71 to 92% sand content in a temporally replicated
      experiment (summer 2000, fall 2000, spring 2001). Diatom biomass increased
      slightly (approximately 30%) in response to nutrient treatments but was not
      affected by snails. Blooms of cyanobacteria (up to 200%) and purple sulfur
      bacteria (up to 400%) occurred in response to nutrient enrichment, particularly
      in the sandier site, but only cyanobacterial biomass decreased in response to
      snail grazing. Snail mortality was 2-5 times higher in response to nutrient
      addition, especially in the sandier site, corresponding to a relative increase in
      cyanobacterial biomass. Nutrient-related snail mortality occurred only in the
      spring and summer, when the snails were most actively feeding on the microalgal
      community. Inactive snails in the fall showed no response to nutrient-induced
      cyanobacterial growths. This study demonstrated strongly negative upward
      cascading effects of nutrient enrichment through the food chain. The strength of
      this upward cascade was closely linked to sediment type and microalgal community
      composition.

PMID- 15015076
TI  - The contribution of small individuals to density-body size relationships:
      examination of energetic equivalence in reef fishes.
AB  - A key relationship in ecology is that between density and body size, with the
      emphasis placed on energetic rules constraining the abundance of larger organisms
      below that of smaller organisms. Most studies have focused upon the density-body
      size relationship at the species level. However, energy is gathered at an
      individual level. We therefore examined this relationship in a coral reef fish
      assemblage, focusing on individuals. Using a comprehensive data set, with over
      14,000 observations we found that the relationship between local density and
      adult body size differs from the linear relationship predicted by the 'energetic
      equivalence rule'. However, excluding the smallest size classes, the relationship
      between body size and individual abundance for intermediate to larger fish did
      not depart from the predicted -0.75. Unlike plants and intermediate to large reef
      fishes, the smallest fishes appear to have constraints that may reflect different
      patterns of resource acquisition.

PMID- 15015077
TI  - Apoptosis shifts to necrosis via intermediate types of cell death by a mechanism
      depending on c-myc and bcl-2 expression.
AB  - Hypoxic and chemical hypoxia (antimycin A) commits cultured rat fibroblasts (Rat
      1) towards apoptosis, necrosis or an intermediate form of cell death
      (aponecrosis) depending on the degree of hypoxia. Aponecrosis also occurs in
      vivo. Here, we demonstrate that c-myc and bcl-2, two proto-oncogenes known to
      lower or to enhance, respectively, the apoptotic threshold, also affect the type
      of cell death: apoptosis shifts to aponecrosis and aponecrosis to necrosis,
      depending on c-myc or bcl-2 expression and the antimycin A concentration (100-400
      microM). In cells with basal gene expression, apoptosis shifts to
      aponecrosis/necrosis at 300 microM antimycin A (middle hypoxia). Overexpression
      of c-myc markedly increases cumulative cell death in response to antimycin A and
      lowers the antimycin A concentration required to shift apoptosis to
      aponecrosis/necrosis from 300 microM to 100 microM (low hypoxia). Overexpression
      of bcl-2 elicits the opposite effect, decreasing cumulative cell death in
      response to antimycin A and raising the drug concentration required to shift
      apoptosis to aponecrosis/necrosis to 400 microM (high hypoxia). The passage from
      one to the other form of cell death involves various aponecrotic features with
      observed intermediate aspects between apoptosis and necrosis, a progressive
      increase in necrotic features being correlated with an increase in antimycin A
      concentration. The mechanism underlying the various effects of c-myc and bcl-2 on
      cell-death type has been related to the ability of these genes to counteract, to
      various extents, the ATP decrease occurring in response to different degrees of
      chemical hypoxia.

PMID- 15015079
TI  - Endogenous indole-3-acetic acid and ethylene evolution in tilted Metasequoia
      glyptostroboides stems in relation to compression-wood formation.
AB  - Eight-year-old Metasequoia glyptostroboides seedlings were tilted at a 45 degrees
      angle to induce compression-wood formation on the lower side of the stems. After
      2 weeks of treatment, half of the seedlings were sampled and the remaining half
      were tilted to the opposite orientation to exchange the upper and lower sides and
      were kept for 2 more weeks until sampled. Cambium-emitted ethylene was analyzed
      by gas chromatography with flame-ionization detection. Endogenous indole-3-acetic
      acid (IAA) was measured by gas chromatography-mass spectrometry. Tracheid
      production and compression-wood formation were determined by light microscopy.
      Anatomical studies showed that tracheid production was promoted and compression
      wood tracheids always developed on the gravitationally lower side of tilted stems
      in both the original tilting and the subsequent reverse-tilting periods. These
      were accompanied by an increase in IAA content in and an accelerated ethylene
      evolution rate from the cambial region of the same side.

PMID- 15015082
TI  - End-chain segment ordering in lamellar sublayers of a diblock copolymer.
AB  - The segmental ordering within a lamellar polystyrene-polydimethylsiloxane diblock
      (PS-PDMS) was examined by NMR. A non-uniform stretching of the PDMS chains was
      evidenced. Although chain segments displaying isotropic reorientational motions
      are present along the chains, relaxation measurements on the free PDMS
      extremities demonstrate that these latter are oriented and submitted to a non
      zero constraint. This specific result allows to precise some features of the
      order distribution within the lamellae.

PMID- 15015081
TI  - Taxonomic and phytogeographic implications from ITS phylogeny in Berberis
      (Berberidaceae).
AB  - A phylogeny based on the internal transcribed spacer (ITS) sequences from 79 taxa
      representing much of the diversity of Berberis L. (four major groups and 22
      sections) was constructed for the first time. The phylogeny was basically
      congruent with the previous classification schemes at higher taxonomic levels,
      such as groups and subgroups. A notable exception is the non-monophyly of the
      group Occidentales of compound-leaved Berberis (previously separated as Mahonia).
      At lower levels, however, most of previous sections and subsections were not
      evident especially in simple-leaved Berberis. Possible relationship between
      section Horridae (group Occidentales) and the simple-leaved Berberis clade
      implies paraphyly of the compound-leaved Berberis. A well-known South America-Old
      World (mainly Asia) disjunctive distribution pattern of the simple-leaved
      Berberis is explained by a vicariance event occurring in the Cretaceous period.
      The ITS phylogeny also suggests that a possible connection between the Asian and
      South American groups through the North American species ( Berberis canadensis or
      B. fendleri) is highly unlikely.

PMID- 15015080
TI  - Xanthine dehydrogenase and aldehyde oxidase impact plant hormone homeostasis and
      affect fruit size in 'Hass' avocado.
AB  - The contribution of xanthine dehydrogenase (XDH, EC 1.1.1.204) to fruit size was
      investigated using the normal and small-fruit variants of Persea americana Mill.
      cv. 'Hass'. Inhibition of XDH by treatment of normal fruit, in the linear phase
      of growth (phase II), with allopurinol (Allo) arrested fruit growth. Adenine
      (Ade), a less effective inhibitor of this enzyme, also arrested fruit growth when
      applied in phase II and slowed fruit growth when applied in phase III. A time
      course study on the activity of XDH in mesocarp tissue from normal and small
      fruit showed that maximum activity occurred late in phase II and that the peak in
      activity was absent in mesocarp of the small fruit. Feeding Ade to growing fruit
      in phase III caused a transient decline in fruit growth (measured as change in
      fruit length). Thereafter, growth resumed although fruit size was irreversibly
      affected. Treatment of fruit with Ade and Ade-containing cytokinins altered
      activity of another molybdenum enzyme, aldehyde oxidase (EC 1.2.3.1). Cytokinin
      oxidase was induced by cytokinin and auxin. Purine catabolism via
      hypoxanthine/xanthine was operative in normal fruit and in mesocarp from the
      small-fruit variant and as expected, Allo treatment caused accumulation of
      xanthine and adenine. In the absence of an increase in XDH during growth of the
      small-fruit phenotype, low levels of Ade were interpreted as resulting from
      respiration-enhanced adenylate depletion. Stress and/or pathogen induction of the
      alternative oxidase pathway is proposed as a possible cause.

PMID- 15015083
TI  - Synergistic effects in mixed wormlike micelles of dimeric and single-chain
      cationic surfactants at high ionic strength.
AB  - The mixed micellization between the cationic gemini surfactant
      [C12H25(CH3)2N+(C2H4)N+(CH3)2C12H25*2Br-] and the cationic cetyltrimethylammonium
      bromide (CTAB) in 150 mM KBr solutions has been investigated. The variation of
      the cmc of the mixtures, measured by surface tension experiments, with
      composition revealed synergism in micelle formation. T-Jump and light scattering
      experiments performed in the vicinity of the crossover volume fraction showed the
      existence of two micellar populations, possibly linear and toroidal micelles.
      Rheological and dynamic light scattering experiments allowed to fully
      characterize the linear viscoelasticity of the mixtures. These measurements
      revealed synergistic gains in viscoelastic properties with a maximum of the
      stress-relaxation time around the equimolar composition. These effects are
      ascribed to a progressive intermicellar crosslinking resulting from a continuous
      increase of the end-cap energy with the 12-2-12 content in the mixture.

PMID- 15015085
TI  - Topological changes in a two-dimensional foam cluster.
AB  - Experiments on a small cluster of bubbles in a nominally two-dimensional foam
      show an instability in which a topological change forces one of the bubbles to be
      ejected to the outside of the cluster at a point where this is not predicted by a
      two-dimensional model of a foam. This is interpreted in terms of the energy of
      the initial and ejected states and of the finite liquid content of the
      experimental system. A description of the distribution of liquid in various
      experimental set-ups suggests that the exact response may depend critically upon
      the type of system used. This is demonstrated experimentally with reference to
      small clusters of bubbles undergoing a single topological change.

PMID- 15015084
TI  - Lateral and transverse diffusion in two-component bilayer membranes.
AB  - We study the lateral and transverse diffusion of amphiphiles in two-component
      bilayer membranes, using a coarse-grained model for amphiphilic molecules and
      combined Monte Carlo-Molecular Dynamics simulations. Membrane structural
      properties, such as the mean thickness, are also measured. The dependence of such
      properties on membrane composition, inter-molecular interactions, and amphiphile
      stiffness is determined. In particular, we show that addition of shorter
      amphiphiles drives the model membrane towards a more fluid state, with increased
      amphiphile lateral diffusion rates. These results can be understood in the
      framework of a simple free-volume model. Furthermore, we observe an increase in
      the trans-membrane diffusion when the interaction energy of amphiphiles with
      their neighboring molecules is decreased.

PMID- 15015086
TI  - Poling of liquid crystals in thin films.
AB  - We examine the effect of a strong DC electric field on the molecular
      orientational order and the nonlinear optical response of liquid crystals in thin
      films. We compare the results of second-harmonic generation measurements with the
      predictions of two models, one assuming that the dipoles carried by the molecules
      have no interactions (the isotropic model), and the other assuming that the
      dipoles evolve in a Maier-Saupe orienting field responsible for the liquid
      crystalline order (the Maier-Saupe model). In both cases, we take into account
      the effect of surfaces and confinement on the behavior of the molecules. We find
      that the molecular dipoles behave as predicted by the isotropic model, but that
      their reorientation is correlated in such a way that the apparent dipole moment
      of the reorienting units is one order of magnitude larger than the molecular
      dipole moment.

PMID- 15015088
TI  - 3d Monte Carlo simulation of site-bond continuum percolation of spheres.
AB  - We present off-lattice Monte Carlo simulations of site-bond percolation of semi
      penetrable spheres or, equivalently, of hard spheres with a finite bond range. We
      will show that the crucial parameter is the effective volume fraction (phie),
      i.e. the volume that is occupied or within the bond range of at least one
      particle. For the equivalent system of semi-penetrable spheres 1-phie is the
      porosity. The bond percolation threshold (pb) can be described in terms of phie
      by a simple analytical expression: log(phie)/log(phiec) + log(pb)/log(pbc)=1,
      with pbc=0.12 independent of the bond range and phiec a constant that decreases
      with increasing bond range.

PMID- 15015087
TI  - Elasticity and plasticity of two-dimensional amorphous solid layers of beta
      lactoglobulin.
AB  - We investigate the mechanical properties of a two-dimensional amorphous solid. It
      is formed spontaneously by the adsorption of a protein (the beta-lactoglobulin)
      at the surface of water. We measure its mechanical response in both elastic and
      plastic regimes by applying a point-like force (using a glass fiber). We compare
      our results with previous measurements of shear moduli using a floating torsion
      device.

PMID- 15015089
TI  - Flow phase diagrams for concentration-coupled shear banding.
AB  - After surveying the experimental evidence for concentration coupling in the shear
      banding of wormlike micellar surfactant systems, we present flow phase diagrams
      spanned by shear stress Sigma (or strain rate gamma) and concentration,
      calculated within the two-fluid, non-local Johnson-Segalman (d-JS-phi) model. We
      also give results for the macroscopic flow curves Sigma(gamma,phi) for a range of
      (average) concentrations phi. For any concentration that is high enough to give
      shear banding, the flow curve shows the usual non-analytic kink at the onset of
      banding, followed by a coexistence "plateau" that slopes upwards,
      dSigma/dgamma>0. As the concentration is reduced, the width of the coexistence
      regime diminishes and eventually terminates at a non-equilibrium critical point
      [Sigmac,phic,gammac]. We outline the way in which the flow phase diagram can be
      reconstructed from a family of such flow curves, Sigma(gamma,phi), measured for
      several different values of phi. This reconstruction could be used to check new
      measurements of concentration differences between the coexisting bands. Our d-JS
      phi model contains two different spatial gradient terms that describe the
      interface between the shear bands. The first is in the viscoelastic constitutive
      equation, with a characteristic (mesh) length l. The second is in the
      (generalised) Cahn-Hilliard equation, with the characteristic length xi for
      equilibrium concentration-fluctuations. We show that the phase diagrams (and so
      also the flow curves) depend on the ratio r congruent with l/xi, with loss of
      unique state selection at r=0. We also give results for the full shear-banded
      profiles, and study the divergence of the interfacial width (relative to l and
      xi) at the critical point.

PMID- 15015090
TI  - Self-healing slip pulses and the friction of gelatin gels.
AB  - We present an extensive experimental study and scaling analysis of friction of
      gelatin gels on glass. At low driving velocities, sliding occurs via propagation
      of periodic self-healing slip pulses whose velocity is limited by collective
      diffusion of the gel network. Healing can be attributed to a frictional
      instability occurring at the slip velocity V=Vc. For V>Vc, sliding is homogeneous
      and friction is ruled by the shear-thinning rheology of an interfacial layer of
      thickness of order the (nanometric) mesh size, containing a solution of polymer
      chain ends hanging from the network. In spite of its high degree of confinement,
      the rheology of this system does not differ qualitatively from known bulk ones.
      The observed ageing of the static friction threshold reveals the slow increase of
      adhesive bonding between chain ends and glass. Such structural ageing is
      compatible with the existence of a velocity-weakening regime at velocities
      smaller than Vc, hence with the existence of the healing instability.

PMID- 15015091
TI  - Instabilities in foam clusters related to the pressures in the bubbles.
AB  - We reinterpret an instability in a two-dimensional free foam cluster previously
      discussed by Weaire et al. (Eur. Phys. J. E 7, 123 (2002)) in terms of the excess
      pressure in the bubbles. We conclude that in a free foam cluster no bubble can
      have a pressure below that of the surrounding gas.

PMID- 15015092
TI  - Random inelasticity and velocity fluctuations in a driven granular gas.
AB  - We analyze the deviations from Maxwell-Boltzmann statistics found in recent
      experiments studying velocity distributions in two-dimensional granular gases
      driven into a non-equilibrium stationary state by a strong vertical vibration. We
      show that in its simplest version, the "stochastic thermostat" model of heated
      inelastic hard spheres, contrary to what has been hitherto stated, is
      incompatible with the experimental data, although predicting a reminiscent high
      velocity stretched-exponential behavior with an exponent 3/2. The experimental
      observations lead to refine a recently proposed random restitution coefficient
      model. Very good agreement is then found with experimental velocity distributions
      within this framework, which appears self-consistent and further provides
      relevant probes to investigate the universality of the velocity statistics.

PMID- 15015093
TI  - Transverse fluctuation analysis of single extended DNA molecules.
AB  - We observed fluctuations of elongated DNA molecules by fluorescence microscopy.
      The molecules are fixed at both ends and undulate. Mode analysis of the thermally
      excited undulations of the labeled DNA molecules gives access to the spectral
      density of the amplitude fluctuations. From these measurements we estimate the
      tension acting on the DNA molecules. We found the forces to be within the
      entropic elasticity range of a typical DNA molecule (measured on the single
      molecule level).

PMID- 15015094
TI  - Charge relaxation in polyampholytes of various statistics.
AB  - We discuss theoretically the relaxation of charge fluctuations in polyampholyte
      solutions. It has been shown previously by some of us (J. Wittmer et al.
      Europhys. Lett. 24, 263 (1993)) that the charge distribution along the
      polyampholyte backbone has a dramatic influence on the polarization energy and
      hence on the solubility. Here it is demonstrated that a similar effect exists for
      the charge relaxation. The charge relaxation mechanism qualitatively depends on
      the statistics: for alternating polyampholytes the relaxation is mainly due to
      local dipole inversion and is not primarily driven by electrostatic interactions,
      whereas for random polyampholytes it is driven by electrostatic interactions.
      Intermediate statistics (with short-ranged (exponential) correlations) appear as
      a combination of these two limiting cases: short-wavelength modes are insensitive
      to the loss of correlations along the backbone, whereas long-wavelength modes
      correspond to a random statistics with renormalized charges. The relaxation of
      the dielectric constant is also calculated.

PMID- 15015095
TI  - On the organization of self-assembled actin networks in giant vesicles.
AB  - We studied the formation of actin scaffolds in giant vesicles of
      dimyristoylphosphatidylcholine (DMPC). Polymerization of actin was induced at low
      ionic strength through ionophore-mediated influx of Mg2+ (2 mM). The spatial
      organization of the filamentous actin was visualized by confocal and
      epifluorescence microscopy as a function of the filaments length and membrane
      composition, by including various amounts of cholesterol or lipids with neutral
      and positively charged polyethyleneglycol headgroups (PEG lipopolymers). In
      vesicles of pure DMPC, the newly polymerized actin adsorbs to the membrane and
      forms a thin shell. In the presence of 2.5 mol% lipopolymers or of cholesterol at
      a molar fraction x=0.37, formation of a thin adsorbed film is impeded. A fuzzy
      cortex is predominantly formed in vesicles of diameter d smaller than the
      filament persistence length (d< or =15 microm) while for larger vesicles a
      homogeneous network formation is favoured in the bulk of the vesicle. The fuzzy
      cortex formation is interpreted as a consequence of the reduction of the bending
      energy if the actin filaments accumulate close to the vesicle wall.

PMID- 15015096
TI  - Structural characterization of a new lipid/DNA complex showing a selective
      transfection efficiency in ovarian cancer cells.
AB  - We investigated, for the first time, by using Energy Dispersive X-ray
      Diffraction, the structure of a new ternary cationic liposome formulated with
      dioleoyl trimethylammonium propane (DOTAP), 1,2-dioleoyl-3
      phosphatidylethanolamine (DOPE) and cholesterol (Chol) (DDC) which has been
      recently found to have a selective high gene transfer ability in ovarian cancer
      cells. Our structural results provide a further experimental support to the
      widely accepted statement that there is not a simple and direct correlation
      between structure and transfection efficiency and that the factors controlling
      cationic lipid/DNA (CL-DNA) complexes-mediated gene transfer depend not only on
      the formulations of the cationic liposomes and their thermodynamic phase, but
      also significantly on the cell properties.

PMID- 15015097
TI  - The influence of chain stretching on the phase behavior of multiblock copolymer
      and comb copolymer melts.
AB  - The subject of this paper is inspired by microphase-separated copolymer melts in
      which a small-scale structure is present inside one of the phases of a large
      scale structure. Such a situation can arise in a diblock copolymer melt, if one
      of the blocks of the diblock is in itself a multiblock copolymer or a comb
      copolymer. Due to the presence of the large-scale structure, the chains are
      stretched. The aim of this paper is to investigate the influence of this chain
      stretching on the formation of the small-scale structure. To gain insight we
      study infinite melts of infinitely long copolymer chains that are subjected to a
      stretching force. For melts of monodisperse multiblock copolymers we find that
      the stretching destabilizes the homogeneous phase. If the stretching is strong,
      the lamellar structure is the only stable structure. The periodicity increases
      with the degree of stretching. For melts of monodisperse comb copolymers the
      chain stretching has no influence on the stability of the homogeneous phase. If
      the stretching is strong, the lamellar structure and the hexagonal structure are
      the only stable structures. The periodicity is independent of the degree of
      stretching. For the multiblock copolymer we investigated the influence of block
      length polydispersity. For small polydispersity the period of the structure
      increases monotonically with the degree of stretching. For intermediate
      polydispersity, the period initially decreases before it starts to increase. For
      large polydispersity, the mean-field period at the spinodal is infinite, becoming
      finite once the stretching force exceeds some critical value. For very large
      polydispersity the mean-field period at the spinodal remains infinite for any
      value of the stretching force.

PMID- 15015098
TI  - Formation of adhesive contacts: spreading versus dewetting.
AB  - A soft bead (radius Rb) is pressed with a force F against a hydrophobic glass
      plate through a water drop ("wet" JKR set-up). We observe with a fast camera the
      growth of the contact zone bridging the rubber bead to the glass. Depending on
      the approach velocity V, two regimes are observed: i) at large V a liquid film is
      squeezed at the interface and dewets by nucleation and growth of a dry contact;
      ii) at low velocities, the bead remains nearly spherical. As it comes into
      contact, the rubber bead spreads on the glass with a characteristic time (in the
      range of one millisecond) tau approximately eta Rb2/F, where eta is the liquid
      viscosity. The laws of spreading are interpreted by a balance of global
      mechanical and viscous forces.

PMID- 15015100
TI  - Dynamical properties of the slithering-snake algorithm: a numerical test of the
      activated-reptation hypothesis.
AB  - Correlations in the motion of reptating polymers in a melt are investigated by
      means of Monte Carlo simulations of the three-dimensional slithering-snake
      version of the bond-fluctuation model. Surprisingly, the slithering-snake
      dynamics becomes inconsistent with classical reptation predictions at high chain
      overlap (created either by chain length N or by the volume fraction phi of
      occupied lattice sites), where the relaxation times increase much faster than
      expected. This is due to the anomalous curvilinear diffusion in a finite time
      window whose upper bound tau+(N) is set by the density of chain ends phi/N.
      Density fluctuations created by passing chain ends allow a reference polymer to
      break out of the local cage of immobile obstacles created by neighboring chains.
      The dynamics of dense solutions of "snakes" at t<<tau+ is identical to that of a
      benchmark system where all chains but one are frozen. We demonstrate that the
      subdiffusive dynamical regime is caused by the slow creeping of a chain out of
      its correlation hole. Our results are in good qualitative agreement with the
      activated-reptation scheme proposed recently by Semenov and Rubinstein (Eur.
      Phys. J. B, 1 (1998) 87). Additionally, we briefly comment on the relevance of
      local relaxation pathways within a slithering-snake scheme. Our preliminary
      results suggest that a judicious choice of the ratio of local to slithering-snake
      moves is crucial to equilibrate a melt of long chains efficiently.

PMID- 15015099
TI  - Polymers grafted to a fluid and flexible membrane: extreme sensitivity to the
      grafting density.
AB  - Equilibrium phase coexistence between two chemical species implies the equality
      of the chemical potentials and of the osmotic pressures. We study this problem on
      a deformable membrane when one type of the molecules serves as anchor for
      polymeric chains immersed in the surrounding medium (considered as a good
      solvent). We derive the general conditions for phase coexistence when both the
      curvature of the membrane and the density field of the anchor molecule are free
      to adjust themselves. We show that curvature favors phase segregation. Our model
      predicts that membranes decorated with polymeric chains exhibit new shape
      bifurcations without equivalent in fixed density systems.

PMID- 15015101
TI  - Friction and rotation modes in a packing of cylinders under shear stress.
AB  - We study the influence of collective processes such as rotations on the effective
      friction of sheared granular media made of two-dimensional array of cylinders. An
      original experimental device allows us to measure simultaneously grain rotations
      and the global friction force between the packing and the basal plane. It is
      shown that the correlation between these two quantities can be analyzed at two
      different time scales: 1. Averaging over the duration of a whole experiment, the
      mean sliding behavior of the first row on the base of the packing describes
      satisfactorily the global friction force. 2. At short-time, description of this
      correlation requires the knowledge of the propagation of rotation perpendicularly
      to the shear direction.

PMID- 15015102
TI  - Flow birefringence, stress optical rule and rheology of four micellar solutions
      with the same low shear viscosity.
AB  - The flow birefringence and the rheological properties of four viscoelastic
      solutions having nearly the same zero shear viscosity and subjected to shear
      flows are investigated in the linear and non-linear domains. The surfactant used
      for the samples is the cetyltrimethylammonium chloride in water at the
      concentration of 100 mmol/l with an organic salt, the sodium salicylate. The low
      shear viscosity curve versus the salt concentration is non-monotonic and has two
      maxima separated by a minimum forming four domains in which the salt
      concentration is chosen. For the two solutions belonging to the inner branch,
      i.e. between the two maxima, a simple Maxwellian behaviour is observed and shear
      banding occurs as confirmed by the flow birefringence pictures. Contrary to the
      results of P. Fisher (1996) where the unstable flow regime is restricted to the
      first decreasing part of the low shear viscosity curve of a cetylpyridinium
      chloride solution, we show that shear banding exits in a wider domain of the salt
      concentration.

PMID- 15015104
TI  - Effect of physical ageing in thin glassy polymer films.
AB  - We have studied the effect of physical ageing in thin supported glassy
      polystyrene films by using ellipsometry to detect overshooting in the expansivity
      temperature curve upon heating of aged samples. Films with thickness 10-200 nm
      have been aged at 70(degrees) C and 80(degrees) C (below the bulk glass
      transition temperature). We observe clear relaxation peaks in the expansivity
      temperature curve for films thicker than 18 nm but not for the 10 nm film. The
      intensity of the relaxation peak is inversely proportional to the film thickness,
      while the temperatures characteristic to the relaxation peak are almost
      independent of the film thickness. These observations are successfully
      interpreted by the idea that the surface layer of the order of 10 nm has liquid
      like thermal properties.

PMID- 15015105
TI  - Self-organization of N(*) inclusions in SmC(*) free-standing films.
AB  - The behaviour of freely suspended smectic-C* ( SmC(*)) films at the bulk SmC(*)
      cholesteric ( N(*)) phase transition has been investigated using polarized
      reflected-light microscopy. Our experimental observations show that above the
      bulk SmC(*)- N(*) phase transition the N(*) order appears in different ways
      according to the film thickness. In thin films, the conventional layer-by-layer
      thinning occurs. In films of intermediate thickness N(*) inclusions nucleate
      inside the SmC(*) film. The distortions of the in-plane orientational order of
      the SmC(*) host phase induce elastic interactions between the inclusions and lead
      to their self-organization in chain-like structures. Both the dynamic of the
      chaining and the parameters driving the equilibrium distance between the
      inclusions in the chain are investigated. In thick films, N(*) fingers grow
      inside the film. The influence of the experimental conditions on the various
      processes is analysed.

PMID- 15015103
TI  - Towards local rheology of emulsions under Couette flow using Dynamic Light
      Scattering.
AB  - We present local velocity measurements in emulsions under shear using heterodyne
      Dynamic Light Scattering. Two emulsions are studied: a dilute system of volume
      fraction phi = 20% and a concentrated system with phi = 75%. Velocity profiles in
      both systems clearly show the presence of wall slip. We investigate the evolution
      of slip velocities as a function of shear stress and discuss the validity of the
      corrections for wall slip classically used in rheology. Focussing on the bulk
      flow, we show that the dilute system is Newtonian and that the concentrated
      emulsion is shear-thinning. In the latter case, the curvature of the velocity
      profiles is compatible with a shear-thinning exponent of 0.4 consistent with
      global rheological data. However, even if individual profiles can be accounted
      for by a power law fluid (with or without a yield stress), we could not find a
      fixed set of parameters that would fit the whole range of applied shear rates.
      Our data, thus, raise the question of the definition of a global flow curve for
      such a concentrated system. These results show that local measurements are a
      crucial complement to standard rheological tools. They are discussed in the light
      of recent works on soft glassy materials.

PMID- 15015106
TI  - Survival and extinction in cyclic and neutral three-species systems.
AB  - We study the ABC model ( A + B mapsto 2 B, B + C mapsto 2 C, C + A mapsto 2 A),
      and its counterpart: the three-component neutral drift model ( A + B mapsto 2 A
      or 2 B, B + C mapsto 2 B or 2 C, C + A mapsto 2 C or 2 A.) In the former case,
      the mean-field approximation exhibits cyclic behaviour with an amplitude
      determined by the initial condition. When stochastic phenomena are taken into
      account the amplitude of oscillations will drift and eventually one and then two
      of the three species will become extinct. The second model remains stationary for
      all initial conditions in the mean-field approximation, and drifts when
      stochastic phenomena are considered. We analyzed the distribution of first
      extinction times of both models by simulations of the master equation, and from
      the point of view of the Fokker-Planck equation. Survival probability vs. time
      plots suggest an exponential decay. For the neutral model the extinction rate is
      inversely proportional to the system size, while the cyclic model exhibits
      anomalous behaviour for small system sizes. In the large system size limit the
      extinction times for both models will be the same. This result is compatible with
      the smallest eigenvalue obtained from the numerical solution of the Fokker-Planck
      equation. We also studied the behaviour of the probability distribution. The
      exponential decay is found to be robust against certain changes, such as the
      three reactions having different rates.

PMID- 15015107
TI  - Force-extension behavior of folding polymers.
AB  - The elastic response of flexible polymers made of elements which can be either
      folded or unfolded, having different lengths in these two states, is discussed.
      These situations are common for biopolymers as a result of folding interactions
      intrinsic to the monomers, or as a result of binding of other smaller molecules
      along the polymer length. Using simple flexible-chain models, we show that even
      when the energy epsilon associated with maintaining the folded state is
      comparable to k(B) T, the elastic response of such a chain can mimic usual
      polymer linear elasticity, but with a force scale enhanced above that expected
      from the flexibility of the chain backbone. We discuss recent experiments on
      single-stranded DNA, chromatin fiber and double-stranded DNA with proteins weakly
      absorbed along its length which show this effect. Effects of polymer
      semiflexiblity and torsional stiffness relevant to experiments on proteins
      binding to dsDNA are analyzed. We finally discuss the competition between
      electrostatic self-repulsion and folding interactions responsible for the complex
      elastic response of single-stranded DNA.

PMID- 15015108
TI  - An improved reflectometric method to measure the azimuthal anchoring energy of
      nematic liquid crystals.
AB  - Some years ago we developed an automatized reflectometric method to measure the
      surface azimuthal anchoring energy of nematic liquid crystals on an optically
      isotropic substrate. This method provides a high accuracy and sensitivity but
      requires the use of wedge glass plates and a sufficiently high anisotropy of the
      intensity reflectivity coefficients. This latter condition restricts greatly the
      number of possible substrates that can be investigated with this technique. Here
      we develop a new reflectometric method which offers comparable or better accuracy
      and sensitivity but does not require wedge plates and high anisotropy of the
      reflectivity coefficients. The method is fully automated and provides a direct
      measurement of the azimuthal director angle. The experimental procedure exploits
      the dependence of the reflectivity tensor on the surface director orientation.
      The measurement of the azimuthal angle does not require any knowledge of the
      optical parameters of the nematic material and of the optically isotropic
      substrate, and provides an absolute accuracy better than 0.2( degrees ) in the
      whole range 0-360( degrees ) and a sensitivity better than 0.1( degrees ). This
      reflectometric method can be also used with weakly anisotropic substrates as well
      as thin rubbed polymeric layers. In this latter case, the effective uncertainty
      in the measurement of the director azimuthal angle depends on the substrate
      anisotropy. A simple and direct experimental procedure to estimate this
      uncertainty is proposed.

PMID- 15015109
TI  - Controlled nucleation of point defects on a disclination line near a free surface
      during smectic-A-to-nematic directional melting.
AB  - A disclination line populated with point defects that break the translational
      symmetry forms near a free nematic (N) interface in a confined geometry. The
      disclination line is, however, absent in the smectic-A phase (SmA). We use this
      fact to control the formation of point defect distributions on a disclination
      line by directional melting of the SmA phase in a temperature gradient. A
      threshold velocity ( v(th)) exists below which a defect-free disclination line is
      formed. The frequency of nucleation of point defects increases steadily for v >
      v(th) and exhibits a remarkable regularity. We derive an empirical scaling for
      v(th) in terms of the experimental tuning parameters. We propose a simple model
      that allows to understand the formation of the point defects.

PMID- 15015110
TI  - A molecular theory of smectic C liquid crystals made of rod-like molecules.
AB  - Organic compounds exhibiting the smectic C phase are made of rod-like molecules
      that have dipolar groups with lateral components. We argue that the off-axis
      character of the lateral dipolar groups can account for tilt in layered smectics
      (SmC, SmC*, SmI etc.). We develop a mean-field theory of the smectic C phase
      based on a single-particle potential of the form UC is proportional to
      sin(2theta) cos phi, consistent with the biaxial nature of the phase, where theta
      and phi are the polar and azimuthal angles, respectively. The hard-rod
      interactions that favour the smectic A phase with zero tilt angle are also
      included. The theoretical phase diagrams compare favourably with experimental
      trends. Our theory also leads to the following results: i) a first-order smectic
      C to smectic A transition above some value of the McMillan parameter alpha,
      leading to a tricritical point on the smectic C to smectic A transition line and
      ii) a first-order smectic C to smectic C transition over a very small range of
      values of the model parameters. We have also extended the theory to include the
      next higher-order term in the tilting potential and to include the effect of
      different tilt angles for the molecular core and the chain in the SmC phase.

PMID- 15015111
TI  - Interactions and correlations of particulate inclusions in a columnar phase.
AB  - We calculate the elastic-field-mediated interaction between macroscopic particles
      in a columnar hexagonal phase. The interaction is found to be long-ranged and non
      central, with both attractive and repulsive parts. We show how the interaction
      modifies the particle correlations and the column fluctuations. We also calculate
      the interaction of particles with the topological defects of the columnar phase.
      The particle-defect interaction reduces the mobility of the defects.

PMID- 15015112
TI  - Slow regions percolate near glass transition.
AB  - A nanosecond scale in situ probe reveals that a bulk linear polymer undergoes a
      sharp phase transition as a function of the degree of conversion, as it nears the
      glass transition. The scaling behaviour is in the same universality class as
      percolation. The exponents gamma and beta are found to be 1.7 +/- 0.1 and 0.41 +/
      0.01 in agreement with the best percolation results in three dimensions.

PMID- 15015113
TI  - Dynamics of shape fluctuations of quasi-spherical vesicles revisited.
AB  - In this paper, the dynamics of spontaneous shape fluctuations of a single, giant
      quasi-spherical vesicle formed from a single lipid species is revisited
      theoretically. A coherent physical theory for the dynamics is developed based on
      a number of fundamental principles and considerations, and a systematic
      formulation of the theory is also established. From the systematic theoretical
      formulation, an analytical description of the dynamics of shape fluctuations of
      quasi-spherical vesicles is derived. In particular, in developing the theory we
      have made a new interpretation of some of the phenomenological constants in a
      canonical continuum description of fluid lipid-bilayer membranes and shown the
      consequences of this new interpretation in terms of the characteristics of the
      dynamics of vesicle shape fluctuations. Moreover, we have used the systematic
      formulation of our theory as a framework against which we have discussed the
      previously existing theories and their discrepancies. Finally, we have made a
      systematic prediction about the system-dependent characteristics of the
      relaxation dynamics of shape fluctuations of quasi-spherical vesicles with a view
      of experimental studies of the phenomenon and also discussed, based on our
      theory, a recently published experimental work on the topic.

PMID- 15015114
TI  - Mixing and sorting of bidisperse two-dimensional bubbles.
AB  - We have examined a number of candidates for the minimum-surface-energy
      arrangement of two-dimensional clusters composed of N bubbles of area 1 and N
      bubbles of area lambda (lambda< or =1). These include hexagonal bubbles sorted
      into two monodisperse honeycomb tilings, and various mixed periodic tilings with
      at most four bubbles per unit cell. We identify, as a function of lambda, the
      minimal configuration for N-->infinity. For finite N, the energy of the external
      (i.e., cluster-gas) boundary and that of the interface between honeycombs in
      "phase-separated" clusters have to be taken into account. We estimate these
      contributions and find the lowest total energy configuration for each pair (N,
      lambda). As lambda is varied, this alternates between a circular cluster of one
      of the mixed tilings, and "partial wetting" of the monodisperse honeycomb of
      bubble area 1 by the monodisperse honeycomb of bubble area lambda.

PMID- 15015115
TI  - Temperature effects on capillary instabilities in a thin nematic liquid
      crystalline fiber embedded in a viscous matrix.
AB  - Linear stability analysis of capillary instabilities in a thin nematic liquid
      crystalline cylindrical fiber embedded in an immiscible viscous matrix is
      performed by formulating and solving the governing nemato-capillary equations,
      that include the effect of temperature on the nematic ordering as well as the
      effect of the nematic orientation. A representative axial nematic orientation
      texture with the planar easy axis at the fiber surface is studied. The surface
      disturbance is expressed in normal modes, which include the azimuthal wave number
      m to take into account non-axisymmetric modes. Capillary instabilities in nematic
      fibers reflect the anisotropic nature of liquid crystals, such as the ordering
      and orientation contributions to the surface elasticity and surface normal and
      bending stresses. Surface gradients of normal and bending stresses provide
      additional anisotropic contributions to the capillary pressure that may
      renormalize the classical displacement and curvature forces that exist in any
      fluid fiber. The exact nature (stabilizing and destabilizing) and magnitude of
      the renormalization of the displacement and curvature forces depend on the
      nematic ordering and orientation, i.e. the anisotropic contribution to the
      surface energy, and accordingly capillary instabilities may be axisymmetric or
      non-axisymmetric. In addition, when the interface curvature effects are accounted
      for as contributions of the work of interfacial bending and torsion to the total
      energy of the system, the higher-order bending moment contribution to the surface
      stress tensor is critical in stabilizing the fiber instabilities. For the planar
      easy axis, the nematic ordering contribution to the surface energy, which
      renormalizes the effect of the fiber shape, plays a crucial role to determine the
      instability mechanisms. Moreover, the unstable modes, which are most likely
      observed, can be driven by the dependence of surface energy on the surface area.
      Low-ordering fibers display the classical axisymmetric mode, since the surface
      energy decreases by decreasing the surface area. Decreasing temperature gives
      rise to the encounter with a local maximum or to monotonic increase of the
      characteristic length of the axisymmetric mode. Meanwhile, in the presence of
      high surface ordering, non-axisymmetric finite wavelength instabilities emerge,
      with higher modes growing faster since the surface energy decreases by increasing
      the surface area. As temperature decreases, the pitches of the chiral
      microstructures become smaller. However, this non-axisymmetric instability
      mechanism can be regulated by taking account of the surface bending moment, which
      contains higher order variations in the interface curvatures. More and more non
      axisymmetric modes emerge as temperature decreases, but, at constant temperature,
      only a finite number of non-axisymmetric modes are unstable and a single fastest
      growing mode emerges with lower and higher unstable modes growing slower. For
      nematic fibers, the classical fiber-to-droplet transformation is one of several
      possible instability pathways, while others include chiral microstructures. The
      capillary instabilities' growth rate of a thin nematic fiber in a viscous matrix
      is suppressed by increasing either the fiber or matrix viscosity, but the
      estimated droplet sizes after fiber breakup in axisymmetric instabilities
      decrease with increasing the matrix viscosity.

PMID- 15015116
TI  - Heterogeneous dynamics at the glass transition in van der Waals liquids:
      determination of the characteristic scale.
AB  - Recent experiments have demonstrated that the dynamics in liquids close to the
      glass transition temperature is strongly heterogeneous. The characteristic size
      of these heterogeneities has been measured to be a few nanometers at Tg. We
      extend here a recent model for describing the heterogeneous nature of the
      dynamics which allows both to derive this length scale and the right orders of
      magnitude of the heterogeneities of the dynamics close to the glass transition.
      Our model allows then to interpret quantitatively small probes diffusion
      experiments.

PMID- 15015117
TI  - Swelling of cross-linked polyelectrolyte gels.
AB  - A model of a cross-linked polyelectrolyte gel has been examined using Monte Carlo
      simulations. The simple model contained a charged defect-free network represented
      by linked charged beads and explicit counterions. Pressure-density relations for
      the polyelectrolyte gel, a corresponding non-ionic polymer gel, and several
      partly or fully degraded gels have been determined. The polyelectrolyte gel
      displayed a very large swelling capacity, in agreement with experiments. The
      swelling mechanism and chain properties are discussed and foundations of current
      theories on gel swelling are examined.

PMID- 15015118
TI  - On the origin of the heterogeneous orientation dynamics of semiflexible polymers
      in solutions.
AB  - Collective rotational motion in nondilute isotropic solutions of semirigid chains
      is sensitively probed by depolarized light scattering over a broad time range.
      The bimodal shape and the peculiar dependence of the orientational relaxation
      function on the scattering angle might arise from the coupling between
      orientational and shear modes of molecular motion (P.G. de Gennes, Mol. Cryst.
      Liq. Cryst. 12, 193 (1971)). The dynamic heterogeneity, i.e. the separation of
      the time scales and the shape of the relaxation functions appears to be system
      specific.

PMID- 15015119
TI  - Long-time behavior of sand ripples induced by water shear flow.
AB  - The formation of sand ripples under water shear flow in a narrow annular channel
      and the approach of the ripple pattern towards a steady state were studied
      experimentally. Four results are obtained: i) The mean amplitude, the average
      drift velocity and the mean sediment transport rate of the evolving bed shape are
      strongly related. A quantitative characterization of this relation is given. ii)
      The ripple pattern reaches a stationary state with a finite ripple amplitude and
      wavelength. The time needed to reach the state depends on the shear stress and
      may be several days. iii) The onset of ripple formation is determined by the bed
      shear stress, but it seems neither to depend on the grain diameter nor on the
      depth of the water layer. iv) The ripple amplitude, drift velocity and sediment
      transport in this stationary state depend on the grain size. This dependency is
      neither captured by the particle Reynolds number nor by the Shields parameter: an
      empirical scaling law is presented instead.

PMID- 15015120
TI  - Elastic interaction of point defects on biological membranes.
AB  - The interaction between inclusions mediated by biological membranes undulations
      is analyzed. The interaction law is interpreted in terms of symmetries associated
      with inclusions. We show, in particular, that for a C3 and C3v symmetries the
      interaction law falls as 1/r3. We show that for completely isotropic inclusions,
      the dominant interaction vanishes to all orders, and the first contribution stems
      from the induced interaction which behaves as 1/r4. The same law holds for any
      other symmetry which is higher than C4. We introduce a straightforward method to
      compute these interactions. We point out important differences with results in
      the literature and explain the discrepancies.

PMID- 15015121
TI  - The effect of shear flow on the Helfrich interaction in lyotropic lamellar
      systems.
AB  - We study the effect of shear flow on the entropic Helfrich interaction in
      lyotropic surfactant smectic fluids. Arguing that flow induces an effective
      anisotropic surface tension in bilayers due to a combination of intermonolayer
      friction, bilayer collisions and convection, we calculate the reduction in
      fluctuations and hence the renormalised change in effective compression modulus
      and steady-state layer spacing. We demonstrate that non-permeable or slowly
      permeating membranes can be susceptible to an undulatory instability of the
      Helfrich-Hurault type, and speculate that such an instability could be one source
      of a transition to multilamellar vesicles.

PMID- 15015122
TI  - Incorporating DNA in a lamellar phase: a Flory model.
AB  - Following an experimental work demonstrating that DNA pieces can be incorporated
      in large quantity in a neutral lamellar phase, we propose a theoretical model
      showing that finite-size rod-like particles can be incorporated in a lyotropic
      smectic-A phase with an interlamellar spacing smaller than the rod length. This
      model based on a Flory-type description on a lattice allowed us to calculate a
      ternary (rods/water/surfactant) phase diagram. We demonstrate that a particle
      enriched lamellar phase and a particle-depleted lamellar phase can coexist. In
      the latter case the rods exhibit a long-range (nematic-like) orientational order.
      The predictions are in qualitative agreement with the experiments.

PMID- 15015123
TI  - Impurity in a Maxwellian unforced granular fluid.
AB  - We investigate velocity statistics of an impurity immersed in a uniform granular
      fluid. We consider the cooling phase, and obtain scaling solutions of the
      inelastic Maxwell model analytically. First, we analyze identical fluid-fluid and
      fluid-impurity collision rates. We show that light impurities have similar
      velocity statistics as the fluid background, although their temperature is
      generally different. Asymptotically, the temperature ratio increases with the
      impurity mass, and it diverges at some critical mass. Impurities heavier than
      this critical mass essentially scatter off a static fluid background. We then
      analyze an improved inelastic Maxwell model with collision rates that are
      proportional to the average fluid-fluid and fluid-impurity relative velocities.
      Here, the temperature ratio remains finite, and the system is always in the light
      impurity phase. Nevertheless, ratios of sufficiently high-order moments <vn
      impurity>/<vn fluid> may diverge, a consequence of the multiscaling asymptotic
      behavior.

PMID- 15015124
TI  - Foam drainage on a sloping weir.
AB  - Foam drainage is considered in a froth flotation tank with a sloping weir. The
      drainage is shown to be gravity dominated in most of the foam, except for thin
      boundary layers at the base of the froth, and along the sloping weir. The
      mathematical reason for the boundary layers is that capillary suction is a much
      weaker effect than gravity, but cannot be ignored altogether, because it
      represents a singular perturbation. The relative weakness of capillary suction
      with respect to gravity is represented by a key dimensionless parameter, denoted
      K, which satisfies K<<1. The volumetric flow at any point along the weir boundary
      layer is the accumulation of all liquid that has rained onto the weir above the
      point in question: typically, this flow is linear in distance measured downward
      from the weir lip. All liquid raining onto the weir is ultimately returned to the
      pulp phase as a high-speed jet. The jet velocity scales with the (2/3) power of
      distance from the weir lip, and is O(K(-2/3)) times larger than the typical
      velocity in the gravity-dominated flow in the bulk of the flotation tank. The
      liquid volume fraction in the jet is likewise O(K(-2/3)) larger than that in the
      bulk. Across the jet, the foam exhibits a known profile of liquid fraction vs.
      distance from the weir: this is known as the equilibrium profile. The foam
      requires a distance equivalent to O(K(4/3)) weir lengths to dry out significantly
      from the wetness value on the weir, but a larger O(K) distance to fall back to a
      wetness comparable with that in the bulk of the froth.

PMID- 15015125
TI  - Polymer depletion interaction between parallel walls--a Monte Carlo study.
AB  - An off-lattice bead-spring model of self-assembling equilibrium ("living")
      polymers is used to study the polymer-induced interaction between parallel walls
      immersed in polydisperse solutions of different concentration by means of Monte
      Carlo simulation. The two walls form an open slit in contact with an external
      reservoir so that the confined system may exchange monomers with the surrounding
      phase and adapt its polydispersity in order to relax the confinement constraint.
      We find that the properties of the polymers in the constrained system as well as
      the net force deltaF acting on the walls depend essentially on the polymer
      concentration in the reservoir which leads to qualitative differences in their
      behavior with changing inter-planar distance H: In a dilute polymer solution at
      concentration phi below the semi-dilute threshold phi* the force between the
      walls is attractive and decreases steadily with growing wall separation H, so
      that deltaF approximately 0 at H/ Rg> or =3 if H is measured in gyration radii Rg
      of the unperturbed polymers. The total monomer concentration within the slit is
      smaller than the concentration in the reservoir and decreases monotonically with
      H/Rg-->0. The ratio Nin/Nout of mean chain length Nin in the slit to that in the
      reservoir, Nout, decreases from unity at H-->infinity, goes through a minimum at
      H/Rg approximately 1, and then rises again to Nin/Nout>1 for wall separations
      H/Rg<1. In contrast, in a dense solution of equilibrium polymers at phi>phi* one
      detects no indirect wall-wall interaction, deltaF approximately 0, for H larger
      than the monomer size. Thus, earlier speculations about the existence of possible
      depletion interaction between parallel walls even in a dense polymer system
      cannot be confirmed. Inside the slit the monomer density is found to be always
      larger than in the reservoir while Nin/Nout<1 and decreases steadily as H/Rg-->0.
      The depletion force between parallel plates has been determined also in a
      monodisperse solution of conventional polymers. Qualitatively the force behavior
      does not differ from that of living polymers.

PMID- 15015126
TI  - Networks of helix-forming polymers.
AB  - Biological molecules can form hydrogen bonds between nearby residues, leading to
      helical secondary structures. The associated reduction of configurational entropy
      leads to a temperature dependence of this effect: the helix-coil transition.
      Since the formation of helices implies a dramatic shortening of the polymer
      dimensions, an externally imposed end-to-end distance R affects the equilibrium
      helical fraction of the polymer and the resulting force-extension curves show
      anomalous plateau regimes. In this article, we investigate the behaviour of a
      crosslinked network of such helicogenic molecules, particularly focusing on the
      coupling of the (average) helical content present in a network to the externally
      imposed strain. We show that both elongation and compression can lead to an
      increase in helical domains under appropriate conditions.

PMID- 15015127
TI  - An integrated approach for comparative mapping in rice and barley with special
      reference to the Rph16 resistance locus.
AB  - The accumulated sequence information of the almost completed rice genome and the
      transcriptome of other cereals provide an excellent starting point for
      comparative genome analysis. We performed targeted synteny-based marker
      saturation for the Rph16 leaf rust resistance locus in barley by extensively
      exploiting these newly available resources. Out of a collection of over 320,000
      public barley ESTs 309 non-redundant candidate syntenic clones have been
      identified for this region in a two-step in silico selection procedure. For
      mapping, 54 barley cDNA-clones were selected due to the even distribution of
      their homologs on a putatively collinear 3-Mb rice BAC contig. Out of these, 97%
      (30) of the polymorphic markers could be genetically assigned in collinearity to
      the target region in barley and a set of 11 markers was integrated into an rph16
      high-resolution map. Although, the collinear target region of rice does not
      contain an obvious candidate gene for rph16 the results demonstrate the potential
      of the presented procedure to efficiently utilize EST resources for synteny-based
      marker saturation. The systematic genome-wide exploitation of the increasing
      sequence data resources will strongly improve our current view of genome
      conservation and likely facilitate a synteny-based isolation of genes conserved
      across cereal species.

PMID- 15015129
TI  - Identification of 51 novel exons of the Usher syndrome type 2A (USH2A) gene that
      encode multiple conserved functional domains and that are mutated in patients
      with Usher syndrome type II.
AB  - The USH2A gene is mutated in patients with Usher syndrome type IIa, which is the
      most common subtype of Usher syndrome and is characterized by hearing loss and
      retinitis pigmentosa. Since mutation analysis by DNA sequencing of exons 1-21
      revealed only ~63% of the expected USH2A mutations, we searched for so-far
      uncharacterized exons of the gene. We identified 51 novel exons at the 3' end of
      the gene, and we obtained indications for alternative splicing. The putative
      protein encoded by the longest open reading frame harbors, in addition to the
      known functional domains, two laminin G and 28 fibronectin type III repeats, as
      well as a transmembrane region followed by an intracellular domain with a PDZ
      binding domain at its C-terminal end. Semiquantitative expression profile
      analysis suggested a low level of expression for both the long and the short
      isoform(s) and partial overlap in spatial and temporal expression patterns.
      Mutation analysis in 12 unrelated patients with Usher syndrome, each with one
      mutation in exons 1-21, revealed three different truncating mutations in four
      patients and two missense mutations in one patient. The presence of pathogenic
      mutations in the novel exons indicates that at least one of the putative long
      isoforms of the USH2A protein plays a role in both hearing and vision.

PMID- 15015130
TI  - Haplotype diversity across 100 candidate genes for inflammation, lipid
      metabolism, and blood pressure regulation in two populations.
AB  - Recent studies have suggested that a significant fraction of the human genome is
      contained in blocks of strong linkage disequilibrium, ranging from ~5 to >100 kb
      in length, and that within these blocks a few common haplotypes may account for
      >90% of the observed haplotypes. Furthermore, previous studies have suggested
      that common haplotypes in candidate genes are generally shared across populations
      and represent the majority of chromosomes in each population. The conclusions
      drawn from these preliminary studies, however, are based on an incomplete
      knowledge of the variation in the regions examined. To bridge this gap in
      knowledge, we have completely resequenced 100 candidate genes in a population of
      African descent and one of European descent. Although these genes have been well
      studied because of their medical importance, we demonstrate that a large amount
      of sequence variation has not yet been described. We also report that the average
      number of inferred haplotypes per gene, when complete data is used, is higher
      than in previous reports and that the number and proportion of all haplotypes
      represented by common haplotypes per gene is variable. Furthermore, we
      demonstrate that haplotypes shared between the two populations constitute only a
      fraction of the total number of haplotypes observed and that these shared
      haplotypes represent fewer of the African-descent chromosomes than was expected
      from previous studies. Finally, we show that restricting variation discovery to
      coding regions does not adequately describe all common haplotypes or the true
      haplotype block structure observed when all common variation is used to infer
      haplotypes. These data, derived from complete knowledge of genetic variation in
      these genes, suggest that the haplotype architecture of candidate genes across
      the human genome is more complex than previously suggested, with important
      implications for candidate gene and genomewide association studies.

PMID- 15015131
TI  - Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in
      patients affected by autosomal dominant hearing impairment (DFNA4).
AB  - Myosins have been implicated in various motile processes, including organelle
      translocation, ion-channel gating, and cytoskeleton reorganization. Different
      members of the myosin superfamily are responsible for syndromic and nonsyndromic
      hearing impairment in both humans and mice. MYH14 encodes one of the heavy chains
      of the class II nonmuscle myosins, and it is localized within the autosomal
      dominant hearing impairment (DFNA4) critical region. After demonstrating that
      MYH14 is highly expressed in mouse cochlea, we performed a mutational screening
      in a large series of 300 hearing-impaired patients from Italy, Spain, and Belgium
      and in a German kindred linked to DFNA4. This study allowed us to identify a
      nonsense and two missense mutations in large pedigrees, linked to DFNA4, as well
      as a de novo allele in a sporadic case. Absence of these mutations in healthy
      individuals was tested in 200 control individuals. These findings clearly
      demonstrate the role of MYH14 in causing autosomal dominant hearing loss and
      further confirm the crucial role of the myosin superfamily in auditive functions.

PMID- 15015133
TI  - Tissue-engineered human asthmatic bronchial equivalents.
AB  - The isolation of human bronchial epithelial (HBEC) and fibroblastic cells (HBFC)
      from biopsies of asthmatic and non-asthmatic volunteers provided unique cellular
      materials to be used for the production of bioengineered bronchial equivalents
      (BE) in vitro. The HBEC are grown on a mesenchymal layer seeded with HBFC and the
      BE can be maintained for at least 15 days in culture. Under the BE culture
      conditions established previously, HBEC undergo differentiation into ciliated and
      goblet cells, within a pseudostratified organization comparable to human bronchi.
      We published previously the results from histologic and functional analyses of
      such BE produced exclusively using non-asthmatic HBEC and HBFC. We report here
      the comparative analyses of BE produced with non-asthmatic and asthmatic living
      HBEC and HBFC (naBE and aBE, respectively). Our data indicated that all asthmatic
      HBEC populations grown on a mesenchymal layer, containing non-asthmatic HBFC,
      slowly reached a confluent state but then detached from the matrix upon culture
      time. These BE appear to be very good models to study the mechanisms involved in
      asthma in vitro.

PMID- 15015132
TI  - The Etruscans: a population-genetic study.
AB  - The origins of the Etruscans, a non-Indo-European population of preclassical
      Italy, are unclear. There is broad agreement that their culture developed
      locally, but the Etruscans' evolutionary and migrational relationships are
      largely unknown. In this study, we determined mitochondrial DNA sequences in
      multiple clones derived from bone samples of 80 Etruscans who lived between the
      7th and the 3rd centuries b.c. In the first phase of the study, we eliminated all
      specimens for which any of nine tests for validation of ancient DNA data raised
      the suspicion that either degradation or contamination by modern DNA might have
      occurred. On the basis of data from the remaining 30 individuals, the Etruscans
      appeared as genetically variable as modern populations. No significant
      heterogeneity emerged among archaeological sites or time periods, suggesting that
      different Etruscan communities shared not only a culture but also a mitochondrial
      gene pool. Genetic distances and sequence comparisons show closer evolutionary
      relationships with the eastern Mediterranean shores for the Etruscans than for
      modern Italian populations. All mitochondrial lineages observed among the
      Etruscans appear typically European or West Asian, but only a few haplotypes were
      found to have an exact match in a modern mitochondrial database, raising new
      questions about the Etruscans' fate after their assimilation into the Roman
      state.

PMID- 15015134
TI  - Effects of an intracellular Ca(2+) chelator on insulin resistance and
      hypertension in high-fat-fed rats and spontaneously hypertensive rats.
AB  - We explored the possibility that a sustained elevation of intracellular Ca(2+)
      concentration ([Ca(2+)](i)) may be a cellular abnormality common to both insulin
      resistance and hypertension. In high-fat diet (HFD) fed rats, the steady-state
      glucose infusion rate (GIR) during the euglycemic hyperinsulinemic clamp was
      reduced by 40% (P <.05) and mean arterial pressure (MAP) was elevated by 20 mm Hg
      (P <.01) in comparison to the normal chow-fed rats. Intravenous injection of 5,5'
      dimethyl derivative of bis(o-aminophenoxy)ethane-N,N,N',N' tetraacetic
      acetoxymethyl ester (dimethyl-BAPTA/AM), an effective intracellular Ca(2+)
      chelator, 90 minutes before the clamp not only restored about 50% of the reduced
      GIR, but also normalized MAP in the HFD rats. The chelator injection also
      significantly increased GIR by 25% (P <.01) and reduced MAP about 30 mm Hg (P
      <.01) in the spontaneously hypertensive rats (SHR). In addition, we have recently
      shown in the HFD rats that an injection of dimethyl-BAPTA/AM normalizes elevated
      [Ca(2+)](i) in adipocytes. These results together demonstrate that lowering
      [Ca(2+)](i) simultaneously ameliorates both insulin resistance and hypertension
      and provide presumptive evidence that sustained high levels of [Ca(2+)](i) may
      play a common pathophysiologic role in these 2 diseases.

PMID- 15015135
TI  - Abnormal regulation of serum lipid fatty acid profiles in short gut rats fed
      parenteral nutrition with lipid.
AB  - Despite absence of essential fatty acid deficiency (EFAD), increases in
      arachidonic acid to linoleic acid ratios occur in serum phospholipid of patients
      treated with chronic total parenteral nutrition (TPN). The parenteral lipid
      component of TPN contains abundant linoleate; thus low phospholipid linoleate may
      reflect increased conversion to arachidonate. Arachidonic acid excess has been
      associated with a proinflammatory milieu through increased eicosanoid production
      and might contribute to the increases in inflammatory markers seen in home TPN
      patients. We investigated fatty acid metabolism in a rodent model of
      malabsorption. We hypothesized that short gut rats would metabolize parenteral
      lipid differently from intact rats. We performed laparotomy and 80% small bowel
      resection (or sham surgery) in rats. Sixteen sham and 16 short gut rats were
      randomly assigned to TPN with lipid or fat-free TPN. After 5 days, weight loss
      was similar in all groups. Analysis of serum phospholipids demonstrated that
      20:3omega9 (eicosatrienoic acid) was relatively increased in fat-free TPN groups,
      irrespective of surgery type, as were distal very long chain omega3 class fatty
      acids, as anticipated. Uniquely, both nutrition (TPN/lipid v fat-free TPN) and
      surgery type (sham v short gut) were significant in determining arachidonic acid
      levels. Relatively elevated arachidonate occurred in both groups of fat-free
      rats, suggesting increased Delta6 and/or Delta5 desaturase activity, as expected.
      In contrast, giving TPN/lipid lowered arachidonate (suggesting appropriately
      downregulated desaturases) in sham animals, but not in short gut animals. Ratios
      of arachidonic and di-homo-gamma-linolenic to linoleic acids further suggested
      increased turnover of precursor omega6 to arachidonic acid in short gut rats
      given lipid compared with the other groups. These preliminary data show that
      intravenous (IV) lipid gave rise to serum lipid fatty acid profiles that differed
      in short gut and sham rats. The short gut rat may have a heightened hepatic
      desaturase activity, inappropriate for the quantity of linoleic acid provided
      parenterally. Therefore, the short gut rat is an appropriate model to study
      further arachidonic acid excess in home TPN patients.

PMID- 15015136
TI  - Treating hypothyroidism improves endothelial function.
AB  - Hypothyroidism patients have increased cardiovascular risk, although the
      mechanism is not defined. Endothelial dysfunction may initiate atherosclerosis,
      is present in patients with hypothyroidism, and therefore may link hypothyroidism
      and vascular disease. We are unaware of studies examining the effect of thyroid
      replacement therapy on endothelial function in hypothyroid patients. The present
      study examined the effect of treatment of hypothyroidism on brachial artery
      reactivity. Consequently, we measured endothelium-dependent (EDV) and endothelium
      independent (EIV) vasodilation using brachial artery ultrasonography in 8
      hypothyroid patients (5 men, mean age 48.9 +/- 5.5 years; mean thyrotropin [TSH]
      49.0 +/- 37.0 mIU/L) before and after thyroxine treatment. Thyroxine treatment
      reduced average TSH to 2.9 +/- 0.5 mIU/L and improved EDV (8.0% +/- 4.4% v 3.4%
      +/- 2.5%, P <.05), whereas EIV was unchanged (20.3% +/- 6.1% v 19.2% +/- 9.4%, P
      = not significant [NS]). Thyroxine treatment did not alter serum lipids. Thyroid
      replacement therapy improves endothelium-dependent vascular reactivity in
      patients with hypothyroidism irrespective of lipid changes.

PMID- 15015137
TI  - Plasma adiponectin concentrations do not increase in association with moderate
      weight loss in insulin-resistant, obese women.
AB  - Plasma adiponectin concentrations were measured before and after moderate weight
      loss in 20 obese women, divided at baseline into insulin-resistant (IR) and
      insulin-sensitive (IS) subgroups on the basis of their steady-state plasma
      glucose (SSPG) concentration at the end of a 180-minute infusion of octreotide,
      glucose, and insulin. The groups were similar in age and body weight and lost
      comparable amounts of weight (8 to 9 kg) during the weight loss period. Fasting
      plasma insulin and SSPG concentrations were significantly higher (P <.001) and
      adiponectin concentrations somewhat lower (P =.10) in the IR group (P <.001) at
      baseline. Both SSPG and plasma insulin concentrations decreased in IR subjects (P
      <.001), but did not change in IS individuals. Adiponectin concentrations did not
      change with weight loss in either group. Thus, neither weight loss, per se, nor
      enhanced insulin sensitivity resulted in a change in plasma adiponectin
      concentrations.

PMID- 15015138
TI  - Influence of resistance exercise training on glucose control in women with type 2
      diabetes.
AB  - The objective of the study was to evaluate the effects of acute and chronic
      resistance training on glucose and insulin responses to a glucose load in women
      with type 2 diabetes. Subjects consisted of type 2 diabetic women (n = 7) and age
      matched controls (n = 8) with normal glucose tolerance. All subjects participated
      in 3 oral glucose tolerance tests: pretraining, 12 to 24 hours after the first
      exercise session (acute) and 60 to 72 hours after the final training session
      (chronic). Exercise training consisted of a whole body resistance exercise
      program using weight-lifting machines 3 days per week for 6 weeks. Resistance
      training was effective in increasing strength of all muscle groups in all
      subjects. Integrated glucose concentration expressed as area under the curve
      (AUC) was 3,355.0 +/- 324.6 mmol/L. min pretraining, improved significantly (P
      <.01) after the acute bout of exercise (2,868 +/- 324.0 mmol/L. min), but was not
      improved with chronic training (3,206.0 +/- 337.0 mmol/L. min) in diabetic
      subjects. A similar pattern of significance was observed with peak glucose
      concentration (pre: 20.2 +/-1.4 mmol/L; acute: 17.2 +/- 1.7 mmol/L; chronic: 19.9
      +/- 1.7 mmol/L). There were no significant changes in insulin concentrations
      after any exercise bout in the diabetic subjects. There were no changes in
      glucose or insulin levels in control subjects. An acute bout of resistance
      exercise was effective in improving integrated glucose concentration, including
      reducing peak glucose concentrations in women with type 2 diabetes, but not age
      matched controls. There were no significant changes in insulin concentrations for
      either group. Resistance exercise offers an alternative to aerobic exercise for
      improving glucose control in diabetic patients. To realize optimal glucose
      control benefits, individuals must follow a regular schedule that includes daily
      exercise.

PMID- 15015139
TI  - Lisofylline, a novel anti-inflammatory agent, enhances glucose-stimulated insulin
      secretion in vivo and in vitro: studies in prediabetic and normal rats.
AB  - Previous studies from this laboratory have shown that the novel anti-inflammatory
      agent, lisofylline (LSF), improves oral glucose tolerance in streptozotocin (STZ)
      diabetic rats. Subsequent studies suggested that the improved glucose tolerance
      could be the result of enhanced beta-cell functioning. The possibility that LSF
      enhancement of insulin release in these animals is the result of direct effects
      of this agent on a residual population of functionally normal beta cells was
      further evaluated in these studies. In vivo studies: 6- to 8-week-old male rats
      were administered STZ (35 mg/kg body weight) intravenously. After 10 days, LSF
      administration (25 mg/kg body weight, twice daily) was initiated in the treated
      group (n = 11) for comparison with the vehicle-injected controls (n = 10). Body
      weight, food intake, and serum glucose and insulin levels were monitored weekly.
      Glucose and insulin responses to an oral glucose bolus were measured at 4 to 5
      weeks as an index of LSF effects on impaired glucose tolerance. Glucose areas
      under curve (AUC) during the 2-hour tolerance tests in the LSF-treated rats (n =
      11) were 23,390 +/- 253 versus 29,390 +/- 1,006 mg/dL x min (P <.0001) in the
      vehicle-injected rats (n = 10). Improved glucose tolerance was associated with
      increases in blood insulin levels in the LSF-treated rats, AUC (+LSF) = 6,564 +/-
      66 versus 5,127 +/- 633 microU/mL x min in the vehicle-injected STZ-rats (not
      significant [NS]). These observations suggested that the improved glucose
      tolerance is the result of direct effects of LSF on glucose-induced release of
      insulin. IN VITRO STUDIES: the validity of this hypothesis was subsequently
      tested using isolated perfused pancreas preparations from normal rats. In this
      series of experiments, 12-week-old animals were used, and pancreases were
      perfused in situ using single-pass technique. Three levels of LSF were directly
      infused into individual pancreas preparations and included 20 (n = 5), 40 (n =
      4), and 60 (n = 4) micromol/L. First (minutes 3 to 10) and second (minutes 13 to
      35) phase glucose-stimulated (300 mg/dL) insulin response areas (AUC) for the 2
      phases measured in the LSF-infused pancreases were compared with AUC in vehicle
      infused pancreases (n = 4). At LSF concentrations of 20 and 40 micromol/L, total
      insulin released during the first phase of glucose stimulation was more than
      twice that of the controls (3,919 +/- 739 and 3,643 +/- 630 microU, respectively
      v 1,481 +/- 269 microU, P <.03). A total of 60 micromol/L LSF did not
      significantly enhance first phase glucose-induced insulin secretion. Second phase
      comparisons of total insulin released in the LSF-infused versus the controls
      showed differences of comparable magnitude (about 2-fold) with statistical
      significance (P <.03) observed at all 3 levels of LSF. These findings demonstrate
      that LSF enhances glucose-stimulated insulin release in vitro. Enhanced beta-cell
      functioning by LSF likely represents an important factor underlying improved
      glucose tolerance in vivo. In addition, the in vitro observations in normal rat
      pancreas indicate that the LSF effect is not limited to beta-cell dysfunction per
      se. These results support the conclusion that agents, such as LSF, may have
      therapeutic benefits in type 2 diabetes.

PMID- 15015140
TI  - Correlation of plasma oxidized low-density lipoprotein levels to vascular
      complications and human serum paraoxonase in patients with type 2 diabetes.
AB  - The oxidative modification of low-density lipoprotein (LDL) plays a central role
      in the initiation and acceleration of atherosclerosis. Human serum paraoxonase
      (PON1) is associated with high-density lipoprotein (HDL) and has been shown to
      reduce the susceptibility of LDL to lipid peroxidation. We investigated whether
      circulating oxidized LDL (Ox-LDL) levels were associated with diabetic vascular
      complications, and whether the enzymatic activity and gene polymorphisms of PON1
      influenced Ox-LDL concentrations in vivo. There was no difference in the plasma
      Ox-LDL concentrations between diabetic patients with and without macrovascular
      diseases. However, Ox-LDL concentrations corrected by LDL-cholesterol (OxLDL/LDL
      C) or apolipoprotein B (apoB) concentrations (Ox-LDL/apoB), which probably
      reflect the proportion of oxidatively modified LDL to total LDL particles, were
      significantly higher in patients with macrovascular diseases than in those
      without. In addition, patients with peripheral neuropathy had a significantly
      higher Ox-LDL/apoB ratio than patients without this complication. The genotype TT
      of -108C/T polymorphism in the promoter region of the PON1 gene, which is
      associated with decreased PON1 expression, showed a significantly higher Ox
      LDL/apoB ratio than genotypes TC or CC (TT: 0.60 +/- 0.15, CT + CC: 0.55 +/-
      0.11, P =.02). Stepwise multiple regression analysis for Ox-LDL concentration
      revealed that the -108C/T polymorphism, subsequently to apoB concentration, was
      identified as a significant contributor. In summary, the Ox-LDL/apoB ratio was
      associated with macrovascular disease and peripheral neuropathy in Japanese
      patients with type 2 diabetes. Increased Ox-LDL/apoB may result, at least partly,
      from reduced serum antioxidant capacity in the diabetic state, including the
      attenuation of PON1 action. Increased Ox-LDL/apoB could be a significant marker
      for susceptibility to vascular complications in diabetic patients.

PMID- 15015141
TI  - Genetic variation in fatty acid-binding protein-4 and peroxisome proliferator
      activated receptor gamma interactively influence insulin sensitivity and body
      composition in males.
AB  - Obesity and type 2 diabetes are closely related, multifactorial metabolic
      conditions characterized by alterations in energy metabolism and glucose
      homeostasis, respectively. Peroxisome proliferator-activated receptor gamma
      (PPARgamma) is a ligand-dependent transcription factor that regulates genes
      involved in lipid and glucose homeostasis, including the adipocyte-specific fatty
      acid-binding protein (FABP4). In turn, FABP4 binds fatty acids and transports
      them to the nucleus where the FABP4/fatty acid complex activates PPARgamma in a
      positive feedback loop. In this study, we tested the hypothesis that the
      polymorphisms, FABP4-376 and PPARgamma Pro12Ala, interactively influence insulin
      sensitivity and body composition in nondiabetic, Hispanic and non-Hispanic white
      males (n = 314) participating in the San Luis Valley Diabetes Study (SLVDS).
      Although the individual sites were not statistically significantly associated
      with any of the outcomes, we found statistically significant interaction terms in
      2-way analysis of covariance (ANCOVA) models for homeostasis model assessment of
      insulin resistance (HOMA-IR) (P =.014) and lean mass (P =.019). While the
      PPARgamma Pro12Ala site was the only statistically significant predictor of fat
      mass in the 2-way model (P =.012), the FABP4 and PPARgamma main effect terms
      individually became stronger when considered in one model compared with the
      analysis of each polymorphism separately. These findings provide evidence that
      FABP4 and PPARgamma work together to influence a biologic pathway affecting
      insulin sensitivity and body composition, illustrating the importance of
      investigating the joint effect of genes in determining susceptibility for complex
      disease.

PMID- 15015142
TI  - Associations between the fatty acid content of triglyceride, visceral adipose
      tissue accumulation, and components of the insulin resistance syndrome.
AB  - Many factors are involved in the development of the insulin resistance syndrome,
      such as visceral obesity and the type of dietary fat. The main purpose of this
      study was to investigate the relationships between fatty acid content of
      triglyceride (TG), visceral adipose tissue (AT) accumulation, and metabolic
      components of the insulin resistance syndrome in a group of 97 Caucasian men with
      a mean age of 45.1 +/- 7.2 years (29 to 63 years). To reach these objectives,
      Spearman correlations, group comparisons, and stepwise multiple regression
      analyses were performed. The proportion of palmitic acid (16:0) in the TG
      fraction was positively associated with plasma fasting insulin (r =.25, P =.03),
      diastolic (r =.45, P <.001), and systolic (r =.29, P =.003) blood pressure. On
      the other hand, the proportion of alpha-linolenic acid (18:3n-3) was associated
      negatively with apolipoprotein (apo) B (r = -.29, P =.005) and positively with
      low-density lipoprotein (LDL) diameter (r =.29, P =.007), while the proportion of
      gamma-linolenic acid (18:3n-6) was associated negatively with plasma TG (r = 
      .33, P =.003), diastolic (r = -.29, P =.01), and systolic (r = -.35, P =.002)
      blood pressure and plasma fasting insulin (r = -.37, P =.0005) and positively
      with high-density lipoprotein (HDL)(2)-cholesterol (r =.27, P =.01) and LDL
      diameter (r =.25, P =.02). Stepwise multiple regression analyses were conducted
      to determine the contribution of visceral AT, body fat mass, and the fatty acid
      content of TG to the variance of metabolic variables studied. It was found that
      visceral AT contributed significantly to the variance in plasma TG (R(2) = 20.7%,
      P <.0001), apo B (R(2) = 9.0%, P =.007), HDL(2)-cholesterol (R(2) = 17.9%, P
      <.0001), LDL diameter (R(2) = 4.9%, P =.02), and area under the glucose curve
      (AUC-glucose) (R(2) = 8.2%, P =.006). On the other hand, body fat mass
      contributed significantly to the variance in fasting insulin (R(2) = 19.7%, P
      <.0001) and diastolic (R(2) = 6.8%, P =.007) and systolic (R(2) = 10.5%, P =.01)
      blood pressure. At least one fatty acid made a significant contribution to the
      variance of each metabolic variable studied. In fact, the proportion of 18:3n-6
      contributed significantly to the variance in both TG (R(2) = 8.9%, P = 0.007) and
      HDL(2)-cholesterol (R(2) = 6.0%, P =.01). Moreover, 18:3n-3 contributed to the
      variance of apo B (R(2) = 7.0%, P =.02), while 18:3n-6 made the largest
      contribution to the variance of LDL diameter (R(2) = 7.6%, P =.02). Finally, 16:0
      significantly contributed to the variance of AUC-glucose (R(2) = 11.4%, P
      =.0003), diastolic (R(2) = 25.2%, P <.0001), and systolic (R(2) = 6.8%, P =.002)
      blood pressure. In summary, results of this study suggest that the fatty acid
      content of TG is associated with many metabolic variables of the insulin
      resistance syndrome independently of body fat mass or visceral AT accumulation.

PMID- 15015143
TI  - Acute effect of drinking red and white wines on circulating levels of
      inflammation-sensitive molecules in men with coronary artery disease.
AB  - There is evidence that moderate consumption of red wine with its high content of
      polyphenolic antioxidants may be more protective than white wine against
      development of coronary artery disease (CAD). The aim of this study was to
      compare the acute effects of ingestion of red wine and white wine on markers of
      inflammation in men with CAD. Thirteen men with angiographically-proven CAD were
      studied in a cross-over trial. The men consumed 4 mL/kg (2 to 3 glasses) red wine
      and white wine in random order during a light meal and with at least a week
      between interventions. Later, the men also consumed an isoenergetic nonalcoholic
      beverage (control) in the same study protocol. Venous blood was taken at
      baseline, 1 hour, and 6 hours after the drinks. Plasma interleukin-6 (IL-6),
      vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1
      (ICAM-1), blood alcohol, plasma lipids, and plasma polyphenols were measured.
      Mean +/- SD blood alcohol was 6.5 +/- 2.2 mmol/L and 6.9 +/- 1.1 mmol/L at 1 hour
      and returned to baseline at 6 hours after intake of red wine and white wine,
      respectively. Plasma IL-6 concentration increased significantly (P =.01) during 6
      hours after ingestion of red wine (56%) and white wine (63%). The increase in
      plasma IL-6 concentration after ingestion of wine was significantly higher (P
      =.045) compared with the corresponding increase (11%) following intake of the
      nonalcoholic beverage. Plasma IL-6 levels at 6 hours (r =.631, P =.02) were
      correlated significantly with plasma alcohol levels at 1 hour after ingestion of
      red wine. These data suggest that moderate wine intake may acutely increase
      plasma levels of IL-6 in men with CAD. It is possible that this increase in
      plasma IL-6 is a response to alcohol-induced oxidative stress in the liver.

PMID- 15015144
TI  - Are major risk factors for myocardial infarction the major predictors of degree
      of coronary artery disease in men?
AB  - Although numerous cross-sectional studies have reported associations of
      hypertension, hypercholesterolemia, diabetes, smoking, and/or obesity with the
      presence of coronary artery disease (CAD), correlations of these risk factors for
      myocardial infarction (MI) with the degree or progression of CAD have been less
      consistent. Nevertheless, these risk factors are generally assumed to be major
      determinants not only of MI, but of the degree of CAD as well. The present study
      is an attempt to evaluate the relationship of major risk factors for MI to degree
      of CAD. From 182 men who underwent diagnostic coronary arteriography, the 154
      with CAD were selected for study. These 154 patients were divided into 2 groups,
      those with hypertension, hypercholesterolemia, diabetes, smoking, and/or obesity
      (n = 121) and those with none of these risk factors (n = 33). The mean degree of
      CAD in the group with risk factors for MI (44.4%) and in the group without
      (50.6%) was not significantly different (P =.15); nor was the increase in CAD
      with age augmented by the presence of these risk factors. On multiple regression
      analysis, none of these risk factors was associated with degree of CAD. Three
      other variables that were considered in this study, age, high-density lipoprotein
      cholesterol (HDL-C), and free testosterone (FT), did show an independent
      association with degree of CAD. These findings, together with the findings of
      previous studies from other laboratories, raise the possibility that in men
      selected for coronary arteriography, age, HDL-C, and FT may be stronger
      predictors of degree of CAD than are blood pressure, cholesterol, diabetes,
      smoking, and body mass index (BMI).

PMID- 15015145
TI  - Differential effects of glucose and alcohol on reactive oxygen species generation
      and intranuclear nuclear factor-kappaB in mononuclear cells.
AB  - It has previously been shown that oral intake of 300 calories of glucose (75 g),
      lipid, or protein increases reactive oxygen species (ROS) generation by
      polymorphonuclear cells (PMNL) and mononuclear cells (MNCs). We investigated the
      effects of 75 g glucose on proinflammatory transcription factor, nuclear factor
      kappaB (NFkappaB), in mononuclear cells. To further investigate whether the
      effects of macronutrient-induced oxidative stress are due to consumption of
      calories or are nutrient specific, we investigated the effects of acute oral
      challenge of equicaloric amounts of alcohol (300 calories) on ROS generation and
      NF-kappaB activation in MNCs and PMNL and compared them with those of glucose and
      water (control). Sixteen normal healthy adult volunteers were given either vodka
      (10 subjects), glucose solution (10 subjects), or 300 mL water (7 subjects).
      Vodka and glucose drinks were equivalent to 300 calories. We measured ROS
      generation and intranuclear NF-kappaB activation by PMNL cells and MNCs at 1
      hour, 2 hours, and 3 hours following ingestion. ROS generation by both MNC and
      PMNL increased significantly (P <.05 for MNC and P <.01 for PMNL) following
      intake of glucose solution, but did not change significantly following alcohol or
      water. NF-kappaB binding activity in MNC nuclear extracts also increased (P
      <.001) following ingestion of glucose solution, but did not change after the
      administration of alcohol or water. We conclude that (1) 75 g oral glucose
      increases NF-kappaB binding activity in MNCs. (2) While 75 g glucose (300
      calories) induces an increase in ROS generation and intranuclear NF-kappaB,
      equicaloric amounts of alcohol did not produce these effects.

PMID- 15015146
TI  - Synergistic effects of C-peptide and insulin on coronary flow in early diabetic
      rats.
AB  - The aims of the present study are (1) to examine whether coronary flow is
      increased and (2) to examine the role of C-peptide in relation to nitric oxide
      (NO) production and coronary flow in a rat heart (Wistar) during the early stages
      of type 1 diabetes. Coronary flow increased by 36.4% +/-10.6% (P <.05) during the
      early stages of streptozotocin-induced diabetes of isolated perfused rat hearts,
      but NO production increased without significance. C-peptide alone did not change
      coronary flow, but increased NO production in diabetes. In the presence of
      insulin, C-peptide reversed both flow and NO production to the control level of
      normal rats (P <.05). In conclusion, during the early stages of type 1 diabetes,
      coronary flow was increased, and C-peptide in the presence of insulin
      synergistically normalized the excessive flow and NO production induced by C
      peptide to the control level of normal rats.

PMID- 15015147
TI  - Proteasome production in human muscle during nutritional inhibition of
      myofibrillar protein degradation.
AB  - Protein undernutrition inhibits adenosine triphosphate (ATP)-dependent muscle
      protein degradation-a hallmark of the proteasome system. Here we report decreased
      myofibrillar protein degradation during dietary protein restriction without a
      concomitant decrease in proteasome gene expression, proteasome protein abundance,
      or proteasome in vivo fractional synthesis rate. Healthy human subjects consuming
      the average minimum adult protein requirement (0.71 g x kg(-1) fat-free mass x d(
      1)) exhibited substantially lower (68%) excretion of 3-methylhistidine, an
      indicator of myofibrillar protein breakdown, when compared with subjects
      consuming an ample, American-style protein intake (1.67 g x kg(-1) fat-free mass
      x d(-1)). However, they displayed no difference in the expression of mRNA for
      proteasome subunits C2 or C3, in the content of C2 protein, or in the rate of
      incorporation of stable isotopically labeled l-[1-(13)C]-leucine into proteasome
      proteins. The results demonstrate that nutritional inhibition of myofibrillar
      protein degradation does not involve suppression in vivo of proteasome production
      in man. This suggests that other elements of the ubiquitin-proteasome system,
      such as ubiquitination pathways, are more important than proteasome abundance in
      the nutritional regulation of skeletal muscle mass.

PMID- 15015148
TI  - Effects of oral contraceptives on glucoregulatory responses to exercise.
AB  - Some of the effects of oral contraceptives (OCs) to alter glucoregulation may be
      ameliorated by exercise. To test this premise, the effects of acute aerobic
      exercise on postprandial glucose, insulin, and C-peptide responses (area under
      the curve [AUC]) were measured in 8 users of low-dose estrogen and progestin OCs
      (OC(+)) and 10 women not using OCs (OC(-)). They completed 2 randomly ordered
      intervention trials: (1) aerobic exercise on 3 consecutive days with a 2.5-hour,
      75-g oral glucose tolerance test (OGTT) on day 4, and (2) no exercise for 3 days
      prior to the OGTT (control trial). The exercise was 50 minutes of treadmill
      walking at 70% (.-)VO(2max). The groups were similar in age (27 +/- 3 years),
      waist-to-hip ratio (0.74 +/- 0.01), and cardiorespiratory fitness (32.5 +/- 1.6
      mL x kg body mass(-1) x min(-1)). Fasting plasma glucose, C-peptide, and insulin
      levels were similar (P >.05) between groups in the control trial. In both trials,
      glucose(AUC) was significantly greater (13%, P <.05) in OC(+). Exercise resulted
      in a significant (P <.05) decrease in fasting plasma glucose and insulin,
      insulin(AUC), glucose(AUC) x insulin(AUC), and C-peptide(AUC) in both groups,
      suggesting enhanced insulin action and/or reduced pancreatic insulin secretion.
      Hepatic insulin extraction ([C-peptide(AUC) - insulin(AUC)())]/C-peptide(AUC))
      was increased following exercise only in OC(+). Thus, insulin action was enhanced
      in response to exercise in young sedentary women independent of OC use. The
      mechanisms for the acute exercise effect on insulin action may be different in OC
      users compared with normally menstruating women.

PMID- 15015149
TI  - Effect of antidiabetic medications on microalbuminuria in patients with type 2
      diabetes.
AB  - The progression of diabetes and hypertension complications is associated with
      microalbuminuria. Intensive glycemic control prevents or retards microalbuminuria
      in patients with type 2 diabetes, but little is known about the respective
      benefits of different antidiabetic drugs. We studied the effect of gliclazide and
      pioglitazone on microalbuminuria in patients with type 2 diabetes. We excluded
      patients with very poor glycemic control (glycated hemoglobin [HbA(1c)] >10%),
      impaired liver function, nondiabetic renal diseases, and those whose urine
      contained red blood cells, hemoglobin, or casts. Each patient received the
      designated drug for 12 weeks and their body weight, blood pressure (BP), fasting
      plasma glucose (FPG), HbA(1c), lipids (triglycerides [TG], total, and high
      density lipoprotein-cholesterol [HDL-C]), 1,5 anhidroglucitol (1,5-AG),
      immunoreactive insulin (IRI), and urinary albumin to creatinine ratio (UACR) were
      measured every month. The effects of the drugs were analyzed using 2-way repeated
      measures analysis of variance (ANOVA). The 2 groups of patients were well matched
      for age, duration of diabetes, retinal status, blood pressure, body mass index
      (BMI), IRI, FPG, HBA(1c), 1,5-AG, lipids, and UACR, as well as the use of
      antihypertensive drugs. After treatment, no significant differences were seen in
      drug efficacy between the 2 groups. Gliclazide and pioglitazone significantly
      reduced FPG (F = 26.0, P <.0001), HBA(1c) (F = 48.1, P <.0001), and total
      cholesterol (TC) levels (F = 3.5, P <.05). Decrements in these metabolic
      parameters were comparable between the groups. 1,5-AG increased in both groups (F
      = 27.5, P <.0001), and the increment was comparable in both groups. Gliclazide
      and pioglitazone significantly reduced UACR (F = 15.7, P <.0001) with a
      comparable decrement in both groups. No other variables changed significantly
      throughout the 12-week treatment. These results suggest that 12 weeks of
      treatment with gliclazide or pioglitazone are equally effective in reducing
      microalbuminuria with similar improvements in blood glucose and cholesterol
      levels, independent of their mechanisms of actions.

PMID- 15015150
TI  - Pathogenesis of polycystic ovary syndrome: what is the role of obesity?
AB  - Both obesity and the polycystic ovary syndrome (PCOS) are commonly seen in women
      of reproductive age. Fifty percent of all patients with PCOS are obese, and the
      presence of obesity affects the clinical manifestations of PCOS. The underlying
      pathogenetic mechanisms appear to involve insulin resistance and
      hyperinsulinemia, the magnitude of which is greater in obese than in non-obese
      women with PCOS. Specific effects of obesity on the manifestations of PCOS,
      underlying mechanisms of the interactions between obesity and PCOS, and
      therapeutic implications of these interactions are discussed in this article.

PMID- 15015152
TI  - Insulin resistance and GLUT-4 glucose transporter in adipocytes from hypertensive
      rats.
AB  - To investigate the mechanisms that cause insulin resistance in hypertension,
      experiments were performed to study the effect of insulin on glucose transport,
      GLUT-4 translocation from intracellular to plasma membranes and GLUT-4
      phosphorylation in isolated adipocytes from normotensive Wistar (W) and
      spontaneously hypertensive rats (SHR). Glucose transport was measured in
      adipocytes incubated with 3-O-d[Methyl-(3)H] glucose with and without insulin
      (0.1 to 5 nmol/L). GLUT-4 protein was determined by Western blot immunoanalysis
      with GLUT-4 antibody. Phosphorylation of GLUT-4 was measured by
      immunoprecipitation with GLUT-4 antibody followed by immunoanalysis with
      phosphoserine or phosphothreonine antibodies. Compared with adipocytes from W,
      insulin-stimulated glucose transport was lower in the SHR (P <.05). GLUT-4
      protein expression was similar in adipocytes from W and SHR. Insulin increased
      GLUT-4 translocation from intracellular to plasma membranes in both groups. This
      effect was lower in the SHR (P <.05). The effect of insulin on GLUT-4 serine
      phosphorylation showed no changes in plasma membranes from W and decreased in the
      SHR (P <.05). In intracellular membranes, insulin increased specific GLUT-4
      serine phosphorylation in both groups (P <.05), but the increase was lower in the
      SHR (P <.05). The results suggest that a deficient GLUT-4 translocation to plasma
      membranes in response to insulin shown in adipocytes from SHR, which was
      accompanied by a decrease in GLUT-4 phosphorylation at serine site, could be one
      of the causes of insulin resistance in hypertension.

PMID- 15015151
TI  - Effect of diet and exercise intervention on inflammatory and adhesion molecules
      in postmenopausal women on hormone replacement therapy and at risk for coronary
      artery disease.
AB  - Inflammation and the recruitment of monocytes into the artery wall are thought to
      be important aspects in the initiation and progression of atherosclerosis. The
      present study was designed to examine the effects of a rigorous diet and exercise
      intervention on plasma lipids and inflammatory and circulating adhesion
      molecules. Twenty postmenopausal women at risk for coronary artery disease (CAD)
      were placed on a high-fiber, low-fat diet, where food was provided ad libitum and
      daily aerobic exercise, primarily walking, was performed. In each subject, pre-
      and post-intervention fasting blood was drawn for serum lipid, insulin, glucose,
      C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6) and both
      soluble (s) intracellular and vascular adhesion molecule (sICAM-1 and sVCAM-1)
      were measured. After 2 weeks, significant reductions in body mass index (BMI) (P
      <.001), glucose (P <.05), insulin (P <.01), all serum lipids, and total
      cholesterol (total-C):high-density lipoprotein-cholesterol (HDL-C) (P <.01).
      Reductions in homeostasis model assessment for insulin resistance (HOMA-IR) (P
      <.01), CRP (P <.01), SAA (P <.01) and sICAM-1 (P <.05) were noted, as well as an
      increase in the quantitative insulin sensitivity check index (P <.05). Reductions
      were also noted in 5 women not using hormone replacement therapy (HRT). No
      significant reductions were found in IL-6 or sVCAM-1 in response to the
      intervention. Overall, this intervention resulted in improved metabolic and lipid
      profiles, reduced inflammatory, and cell adhesion molecules in postmenopausal
      women in the absence of caloric restriction. The rapid improvements may reduce
      the risk of acute myocardial infarction (MI), and if sustained, these changes may
      mitigate the risk for atherosclerosis progression and its clinical consequences.

PMID- 15015153
TI  - The hyperinsulinemic amino acid clamp increases whole-body protein synthesis in
      young subjects.
AB  - We propose that hyperinsulinemia stimulates protein synthesis when postabsorptive
      plasma amino acid (AA) concentrations are maintained. During a euglycemic
      hyperinsulinemic clamp, many AA, notably the branched-chain amino acids (BCAA),
      decline markedly. Therefore, we tested whether individual plasma AA could be
      maintained within the range of postabsorptive concentrations to assess the
      effects of insulin, infused at 40 mU/m(2) x min on whole-body protein and glucose
      metabolism, using [1-(13)C]-leucine and [3-(3)H]-glucose methodology. Validation
      studies of background [(13)C] enrichment and breath (13)CO(2) recovery factors
      were performed in a subset of 6 subjects. In 10 healthy, young men, infusion
      rates of an AA solution were based on fluorometric determinations of total BCAA
      every 5 minutes. All 21 plasma AA remained in the target range; 15, including the
      BCAA, alanine, and glycine were within 13% of baseline, and only 6 (Thr, His,
      Arg, Asn, Cit, Tyr) varied more (18% to 42%). Notably, both leucine flux and
      nonoxidative leucine R(d) (protein synthesis) increased with insulin (2.36 +/-
      0.06 to 2.81 +/- 0.10 and 1.79 +/- 0.05 to 2.18 +/- 0.10 micromol/kg fat-free
      mass (FFM) x min, respectively; P <.0005) while leucine oxidation only tended to
      increase (P =.05) and endogenous leucine R(a) (protein breakdown) decreased by
      18% (2.36 +/- 0.06 to 1.94 +/- 0.09 micromol/kg FFM x min; P <.0005), resulting
      in a marked elevation of net protein synthesis (-0.57 +/- 0.02 to 0.24 +/- 0.02
      micromol/kg FFM x min; P <.0000001). Thus, in vivo protein anabolism was induced
      when maintaining postabsorptive plasma amino acid concentrations during
      hyperinsulinemia through a suppression of whole-body protein breakdown, no
      significant change in oxidation and an elevation of synthesis compared with
      postabsorptive conditions.

PMID- 15015154
TI  - Resistance training enhances insulin-mediated glucose disposal with minimal
      effect on the tumor necrosis factor-alpha system in older hypertensives.
AB  - The purpose of the present study was to determine if the improvement in insulin
      sensitivity after resistance training (RT) is associated with a decline in plasma
      levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF-alpha receptor 1
      (sTNF R1), and soluble TNF receptor 2 (sTNF R2). Eleven older hypertensives (5
      men/6 women, 67 +/- 2 years) participated in a 4-month RT program. Following RT
      there was a significant increase in upper body (P =.029) and lower body strength
      (P =.001), assessed by the bench press 1-repetition maximum (1RM) and leg press
      1RM, respectively. The RT program produced a significant increase in lean body
      mass (LBM) (P =.029), a trend for a decline in percent body fat (P =.083), and no
      change in total body mass (P =.958). Insulin-mediated glucose disposal, assessed
      by the hyperinsulinemic euglycemic clamp procedure, significantly increased
      following RT (P =.026). Despite the increase in insulin action, plasma levels of
      TNF-alpha, sTNF R1, and sTNF R2 were not significantly altered by RT (TNF-alpha:
      P =.118, sTNF R1: P =.184, sTNF R2: P =.168). In conclusion, a 4-month RT program
      significantly increased insulin-mediated glucose disposal and LBM without a
      significant reduction in plasma levels of TNF-alpha, sTNF R1, and sTNF R2 in
      older hypertensive subjects.

PMID- 15015155
TI  - Vision, preeminence, and leadership in dental implant surgery: a specialty's
      progress.

PMID- 15015156
TI  - Status of the internal orbit after reduction of zygomaticomaxillary complex
      fractures.
AB  - PURPOSE: We sought to determine the status of the internal orbit before and after
      reduction of zygomaticomaxillary complex (ZMC) fractures when treated without
      internal orbital reconstruction. PATIENTS AND METHODS: We conducted a
      retrospective study of preoperative and postoperative computed tomography (CT)
      scans in 65 patients with unilateral ZMC fractures who were treated by reduction
      of the ZMC complex without internal orbital reconstruction. The size and location
      of the internal orbital defects, orbital soft tissue displacement, and orbital
      volume were assessed in the preoperative and postoperative CT scans. RESULTS:
      Reduction in the ZMC fractures was considered ideal in 58 of the 65 patients.
      Only minor malpositions occurred in the remaining 7 patients. The size of the
      internal orbital defects increased slightly with ZMC reduction but the internal
      orbital fractures were realigned, and few had increases in orbital volume or soft
      tissue sagging into the sinuses. Examination of follow-up CT scans in several
      patients taken weeks to months later showed that the residual defects became
      smaller and that none of these patients had an increase in orbital volume or soft
      tissue sagging. CONCLUSION: The preoperative CT scan can be used to assess the
      amount of internal orbital disruption for purposes of developing a treatment plan
      in patients with ZMC fractures. When there is minimal or no soft tissue
      herniation and minimal disruption of the internal orbit, ZMC reduction is
      adequate treatment.

PMID- 15015157
TI  - Comparison of cytokine level in synovial fluid between successful and
      unsuccessful cases in arthrocentesis of the temporomandibular joint.
AB  - PURPOSE: The aim of this study was to compare proinflammatory cytokine levels
      between successful cases and unsuccessful cases of arthrocentesis in patients
      with internal derangement of the temporomandibular joint (TMJ). PATIENTS AND
      METHODS: This study involved 73 joints judged as successful and 30 judged as
      unsuccessful of 103 joints in 100 patients diagnosed with internal derangement of
      the TMJ and who underwent arthrocentesis. The diluted synovial fluid before
      undergoing arthrocentesis was aspirated from the superior joint space. The
      concentrations of interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6, and
      IL-8 were measured using an enzyme-linked immunosorbent assay. The differences in
      the detection rate and concentration of each cytokine between successful cases
      and unsuccessful cases were analyzed statistically. RESULTS: There was a
      statistically significant difference between successful cases (72.2%) and
      unsuccessful cases (95.5%) in the detection ratio of IL-6 (P <.05). There was a
      statistically significant difference between successful cases (0.017 pg/100
      microg protein) and unsuccessful cases (0.046 pg/100 microg protein) in the
      concentration of IL-1beta (P <.05). CONCLUSION: It has been shown that the
      presence of IL-1beta and IL-6 in synovial fluid may be indicators of possible
      unsuccessful treatment following arthrocentesis for internal derangement of the
      TMJ.

PMID- 15015159
TI  - Impacted tooth in mandibular fracture line: treatment with closed reduction.
AB  - PURPOSE: Most mandibular fractures occur because of blunt trauma. In some cases,
      the mandible can be weakened by the presence of an unerupted or impacted tooth.
      The fate of this tooth in the fracture line and its effects on bone healing
      remain an important outcome event. MATERIALS AND METHODS: In this study, we
      analyzed the records of 117 patients with a total of 121 fractures having an
      unerupted tooth remaining in the fracture line who were treated and followed by
      the Dental Faculty of Ankara University between 1986 and 1996. All were open
      fractures, and none of the patients had a history of an acute inflammatory
      episode related to the unerupted tooth before the injury. Intermaxillary fixation
      was used in all cases. RESULTS: Three of the patients subsequently required open
      reduction with internal fixation. The unerupted tooth was not extracted in any
      patient. The fixation was maintained for an average of 45 days and followed up
      for 3 months. No complications were encountered. CONCLUSION: According to these
      results, we suggest that asymptomatic impacted teeth in the fracture line of
      uncomplicated mandible fractures do not cause delayed healing when treated with
      closed reduction.

PMID- 15015160
TI  - Effect of distraction osteogenesis on the severely hypoplastic mandible and
      inferior alveolar nerve function.
AB  - PURPOSE: The purpose of this study was to examine the effect of distraction
      osteogenesis surgery on the inferior alveolar nerve (IAN) and on the stability of
      the occlusion in patients undergoing mandibular osteotomy and advancement for
      correction of severe retrognathia. MATERIALS AND METHODS: Five patients (4 women
      and 1 man) underwent vertical posterior body osteotomy or bilateral sagittal
      split ramus osteotomy with the application of a distraction device for
      advancement of the mandible of 10 to 14 mm. After a period of latency, each
      mandible was advanced 1 mm per day until the patient achieved a Class I
      occlusion. Distraction devices were removed after a suitable period of
      consolidation (4 to 11 months). IAN sensory function was evaluated by 2-point
      discrimination, response to painful stimulus, and moving brush stroke
      identification. Testing of the IAN was performed on all patients at 7 different
      time intervals: preoperative (T0), postsurgery and predistraction (T1), within 7
      days after the end of distraction (T2), 3 months after T2 (T3), 6 months after T2
      (T4), 9 months after T2 (T5), and 1 year after T2 (T6). The same surgeon
      performed all IAN testing. RESULTS: There were no instances of malunion or
      fibrous union. At the 1-year follow-up, all 5 patients showed no relapse of their
      advancement as assessed by their maintenance of a Class I occlusion. Radiographic
      analysis was not done to discern skeletal versus dental stability. All 10 IANs
      were intact after the initial surgery. As time progressed, all 10 nerves showed
      improvement of function as measured by 2-point discrimination, response to
      painful stimulus, and moving brush stroke identification. At 1 year postsurgery,
      all 10 nerves showed function consistent with or very near presurgery levels.
      CONCLUSION: Stable mandibular advancements of 10 mm and greater can be
      successfully accomplished by distraction osteogenesis without producing
      significant damage to the IAN.

PMID- 15015161
TI  - Consonant intelligibility and tongue motility in patients with partial
      glossectomy.
AB  - PURPOSE: The primary determinants for good speech outcome after glossectomy are
      not well established. This study evaluated the effect of tongue motility, type of
      reconstruction, and affected muscles on speech intelligibility. METHODS: Fourteen
      German glossectomy patients participated in an intelligibility test, which
      targeted lingual consonants. Tongue motility was rated on nine 3-point scales.
      Surgical mapping documented type of reconstruction and affected muscles. RESULTS:
      Mean consonant intelligibility was 71.25% and mean tongue motility was 34%. There
      was a moderate correlation between tongue motility and consonant intelligibility
      (r = 0.619). Patients with platysma flap reconstructions (n = 6) had a tendency
      for more correctly identified consonants. Patients with an intact genioglossus (n
      = 4) had significantly better tongue motility scores. CONCLUSIONS: The findings
      support the hypothesis that good tongue motility is a precursor of good
      postglossectomy speech. Although flap reconstructions led to better consonant
      intelligibility in this study, this should be interpreted with caution due to the
      small sample size.

PMID- 15015162
TI  - Stability after distraction osteogenesis to lengthen the mandible: results in 50
      patients.
AB  - PURPOSE: The purpose of this study was to investigate mandibular stability after
      lengthening the mandible by means of distraction. MATERIALS AND METHODS: Fifty
      patients (mean age, 14.7 years; range, 11.2 to 37.3 years) with Angle Class II
      mandibular hypoplasia were treated by bilateral distraction osteogenesis to
      lengthen the mandible. Patients were divided into a high-angle group, with a high
      mandibular angle (sella/nasion-mandibular plane [SN-MP] >38 degrees), and a
      normal-to-low mandibular angle group (SN-MP <or=38 degrees). Clinical
      measurements and standardized cephalometric radiographs were taken just before
      operation; postdistraction at time of removal of the distraction devices, and 6
      months and 1 year postoperatively. Analysis was performed by means of angle
      measurements: sella/nasion-maxilla point A (SNA), sella/nasion-mandibular point B
      (SNB), and SN-MP. RESULTS: Eight of 14 high-angle patients showed a degree of
      relapse (57%), and only 3 of 36 patients showed relapse in the low/normal-angle
      group (8.3%). CONCLUSION: It can be concluded that high-angle patients are still
      at risk of relapsing and that distraction osteogenesis cannot prevent relapse in
      cases with a high mandibular plane angle. For low-angle patients, however,
      distraction is a safe and predictable procedure.

PMID- 15015163
TI  - The effects of Le Fort I osteotomies on velopharyngeal and speech functions in
      cleft patients.
AB  - PURPOSE: Orthognathic surgery alters or even worsens symptoms of velopharyngeal
      insufficiency in cleft patients. The goal of this study was to evaluate how
      advancing the maxilla would affect the speech and articulation disorders of these
      patients. PATIENTS AND METHODS: This was a retrospective study in which we
      compiled and evaluated the speech scores of 54 cleft lip and palate patients who
      underwent maxillary advancement between 1981 and 2001. Although 34 individuals
      underwent an isolated Le Fort I advancement, 20 patients had a combined Le Fort I
      advancement/mandibular setback operation. The following variables were recorded
      from both preoperative and postoperative speech evaluations: presence of a
      pharyngeal flap at the time of surgery, oronasal fistulas, nasality, 7 different
      articulation errors, velopharyngeal function assessment, and overall speech
      score. Preoperative and postoperative changes in the data were analyzed using the
      McNemar test and paired t test. RESULTS: A decrease in competent velopharyngeal
      function mechanisms was noted postoperatively (42% to 18%), increased borderline
      incompetence (9% to 22%), and complete velopharyngeal insufficiency (13% to 20%).
      Speech scores deteriorated significantly (P <.05), whereas articulation defects
      insignificantly (P =.146) improved after surgery (84% to 73%), with those related
      to the anterior dentition (P =.064) showing the greatest change (64% to 47%). The
      frequency of hyponasality decreased after surgery. The number of cases of mild to
      moderate hypernasality increased. CONCLUSION: This study confirms previous
      findings that patients with clefts of the lip and palate or palate alone are
      predisposed to velopharyngeal function alteration after maxillary advancement,
      particularly with borderline function preoperatively. However, the results show
      that surgical correction of skeletal relationships and occlusion may translate
      into improvements in certain aspects of speech disorders.

PMID- 15015164
TI  - Comparing the effects of V-Y advancement versus simple closure on upper lip
      aesthetics after Le Fort I advancement.
AB  - PURPOSE: The aim of this study was to compare upper lip movement and its
      dimensional changes after maxillary advancement via Le Fort I osteotomy, using V
      Y advancement versus simple continuous closure. The study investigates
      dimensional changes in the superior and inferior portions of the upper lip, as
      well as changes in lip length, resulting from the procedure. PATIENTS AND
      METHODS: The study group consisted of 35 patients who had undergone 1-piece Le
      Fort I osteotomy for maxillary advancement of 3 to 6 mm with less than 3 mm of
      vertical changes. Fixation was performed by rigid monocortical plating. Closure
      of soft tissue was achieved using V-Y advancement in 17 patients and simple
      continuous suturing in 18 patients. Lateral cephalometric radiographs were taken
      and measured preoperatively and then 6 months after surgery. RESULTS: The
      magnitude of upper lip movement was 88.89% of the maxillary advancement in the
      simple continuous suturing group and 90.77% in the V-Y advancement group. The
      superior portion of the upper lip thickened by 2.08 mm and 2.35 mm in the 2
      groups, respectively. The inferior portion of the upper lip thickened by -1.94 mm
      and -1.14 mm, respectively. The upper lip shortened by 0.79 mm in the simple
      continuous suturing group and lengthened by 1.10 mm in the V-Y advancement group.
      CONCLUSIONS: Upper lip movement and dimensional changes differ when simple
      continuous suturing and V-Y advancement closure are used.

PMID- 15015166
TI  - Computer-aided navigation in dental implantology: 7 years of clinical experience.
AB  - PURPOSE: This long-term study gives a review over 7 years of research,
      development, and routine clinical application of computer-aided navigation
      technology in dental implantology. Benefits and disadvantages of up-to-date
      technologies are discussed. MATERIALS AND METHODS: In the course of the current
      advancement, various hardware and software configurations are used. In the
      initial phase, universally applicable navigation software is adapted for
      implantology. Since 2001, a special software module for dental implantology is
      available. Preoperative planning is performed on the basis of prosthetic aspects
      and requirements. In clinical routine use, patient and drill positions are
      intraoperatively registered by means of optoelectronic tracking systems; during
      preclinical tests, electromagnetic trackers are also used. RESULTS: In 7 years
      (1995 to 2002), 55 patients with 327 dental implants were successfully positioned
      with computer-aided navigation technology. The mean number of implants per
      patient was 6 (minimum, 1; maximum, 11). No complications were observed; the
      preoperative planning could be exactly realized. The average expenditure of time
      for the preparation of a surgical intervention with navigation decreased from 2
      to 3 days in the initial phase to one-half day in clinical routine use with
      software that is optimized for dental implantology. CONCLUSIONS: The use of
      computer-aided navigation technology can contribute to considerable quality
      improvement. Preoperative planning is exactly realized and intraoperative safety
      is increased, because damage to nerves or neighboring teeth can be avoided.

PMID- 15015165
TI  - Surgical management of advanced degenerative arthritis of temporomandibular joint
      with metal fossa-eminence hemijoint replacement prosthesis: an 8-year
      retrospective pilot study.
AB  - PURPOSE: The purpose of this study was 2-fold: to evaluate the surgical outcome
      and surgical morbidity of the temporomandibular joint (TMJ) metal fossa-eminence
      hemijoint prosthesis replacement, implanted in patients with degenerative
      arthritis, and to establish whether future, more rigorous clinical trial
      assessment of the hemijoint replacement is warranted. MATERIALS AND METHODS:
      Eighty-four patients (79 females and 5 males) involving 108 joints (60
      unilateral, 24 bilateral) were operated on, and 112 joint metal fossa-eminence
      prostheses were placed. Information was gathered from patient response
      questionnaires and clinicoradiographic medical chart review. Change in pain
      intensity (preoperative versus current) was measured by 2 methods: 1) pain
      experience (1 to 6) and 2) pain intensity (visual analog scale, 1 to 10). Chewing
      ability, jaw opening, and joint noise were evaluated (visual analog scales, 1 to
      10). Surgical morbidity and implant survival were documented. RESULTS: The
      average period from initial TMJ symptoms to metal fossa-eminence implant surgery
      was 12.3 years. The average number of previous TMJ surgeries was 1.9. Pain was
      reduced 56% and 61.2% by 2 methods. Chewing ability, jaw opening, and joint noise
      were improved by 53.4%, 50.2%, and 64%, respectively. Nine of 112 implants were
      explanted during the study period. Patient satisfaction for the clinical outcome
      was 8.3 on a scale of 0 to 10. CONCLUSION: The surgical placement of the Co-Cr-Mo
      metal fossa-eminence prosthesis (partial joint replacement) provides significant
      focal preauricular pain relief and reduces TMJ dysfunction secondary to advanced
      degenerative arthritis. The results of this case series supports further
      investigation of this form of surgical management in a rigorously controlled
      prospective fashion.

PMID- 15015167
TI  - Staged protocol for resection, skeletal reconstruction, and oral rehabilitation
      of children with jaw tumors.
AB  - PURPOSE: The purpose of this study was to evaluate a staged protocol for
      resection of jaw tumors and reconstruction including implants in pediatric
      patients. PATIENTS AND METHODS: Nine children were evaluated retrospectively.
      Data included age at resection, tumor type, use of adjuvant therapy, type of bone
      graft, and number of implants. Occurrence of postoperative infection, tumor
      margins, recurrence, plate fractures, number of bone grafts, implants restored,
      and failures were recorded. RESULTS: Ages ranged from 3.5 to 16 years with 2
      maxillary and 7 mandibular tumors. Diagnoses included giant cell lesion (n = 3),
      osteosarcoma (n = 2), myofibroma (n = 1), ossifying fibroma (n = 1), desmoplastic
      fibroma (n = 1), and ameloblastoma (n = 1). No patients experienced postoperative
      infection, wound dehiscence, or jaw instability after en bloc resection. One
      patient had recurrence of a giant cell lesion. To date (mean, 56 months; range,
      24 to 93 months), there have been no additional recurrences. There was 1 plate
      fracture. Eight patients underwent iliac bone grafts (stage 2), and in 1 patient,
      the mandible regenerated. There were no graft infections or wound dehiscences.
      Three patients required additional bone grafting for implant placement. Twenty
      three implants were placed in 7 patients without complications, and 21 implants
      have gone to second stage. One implant failed to osseointegrate. Six patients
      have had prostheses placed and loaded for a mean of 26 months (range, 5 to 64
      months). One patient is scheduled for prosthetic restoration and 2 for implant
      placement. CONCLUSION: Pediatric maxillofacial tumors can be successfully treated
      by resection, rigid fixation, and delayed reconstruction with minimal morbidity
      and a high success rate.

PMID- 15015168
TI  - Maxillary sinus reconstruction with calvarium bone grafts and endosseous
      implants.
AB  - PURPOSE: The objectives of this study were 1) to evaluate the survival rate for
      implants placed in maxillary sinuses augmented with autogenous calvarium bone
      graft and 2) to evaluate the feasibility, complications, and morbidity of this
      technique as well as patient satisfaction. PATIENTS AND METHODS: Seventy-nine
      maxillary sinuses in 58 patients were reconstructed with calvarium grafts between
      1992 and 2002 with more than 1 year of prosthetic loading. Two hundred twenty
      three implants were placed 3 to 11 months after grafting. Bone levels were
      measured preoperatively after grafting and 1 year after prosthetic loading.
      RESULTS: Successful healing was observed in 77 sinuses (97.4%), and 2 patients
      (2.6%) showed dehiscence and graft loss. All implants integrated; 211 (94.6%)
      were used for fixed restorations and 12 implants (5.4%) were used in 2 patients
      for overdentures (6 implants each). The fixed prosthesis survival rate was 100%
      after 1 year of loading and remained successful in all cases during the follow
      up. At the second stage of surgery, crestal bone loss was measured with a
      caliper. No crestal bone loss was observed in 210 implants (94%). However, in 13
      implants (6%), a crestal bone loss between 1.5 and 2.5 mm was observed, but no
      further bone loss occurred during the follow-up, as shown on panoramic
      radiography. Panoramic radiograph measurements showed a total bone height
      (alveolar bone plus grafted bone) of more than 15 mm in all sinuses and of more
      than 20 mm in 25 sinuses (32.4%) with a mean of 18 mm. Bone levels were
      maintained during the follow-up. CONCLUSIONS: 1) Calvarium provides graft
      material of excellent quality and quantity. 2) Satisfactory results can be
      obtained with implants placed after sinus augmentation with calvarium bone graft
      as shown in this study with no implant failure. Bone levels, implants, and bridge
      survival were maintained during the follow-up.

PMID- 15015169
TI  - Material analysis of AO plate fracture cases.
AB  - PURPOSE: The clinical observation of fracture cases and material evaluation of
      fractured titanium plates were performed to investigate the causes of fracture.
      PATIENTS AND METHODS: Fracture of titanium plates occurred in 4 patients of the
      110 mandibular reconstructions. We clinically and experimentally evaluated plate
      fracture cases among cases in which primary reconstruction using titanium plates
      was performed after the mandibular resection. RESULTS: Titanium plate fracture
      was frequently observed in L-type defect cases in which angle-type plates were
      used, and fracture mainly occurred in the anterior region of the mandibular
      angle. Material analysis suggested that the occurrence of fracture can be
      prevented by eliminating constricted parts on the internal side of the plates.
      CONCLUSIONS: The causes of fracture were thought to be the use of plates under
      the conditions of comparatively frequent repeated application of stress or
      fatigue fracture caused by stress concentration, depending on the form of the
      plate.

PMID- 15015170
TI  - Influence of aging on tooth eruption: experimental canine mandibular allograft.
AB  - PURPOSE: Aging is clinically related to tooth eruption; however, there are no
      known studies that have elucidated the relationship. We examined whether tooth
      eruption would occur normally in a mature subject. MATERIALS AND METHODS: Using
      vascularized composite tissue mandibular transplantation, we extracted portions
      of immature mandibles including the tooth germs from young beagle dogs and placed
      them into unrelated immature and mature beagle dogs. We then examined eruption of
      the lower first molar in the grafted mandibular bone and compared the results
      clinically, radiographically, and histologically. RESULTS: Normal tooth eruption
      was observed in the transplanted mandibles in the young dogs. In the mature dogs,
      eruption from the gingiva was delayed, whereas that from alveolar bone occurred
      normally in the transplanted mandibles. Further, the whole crown was covered with
      a cap of gingival tissue in the mature dogs, although this cap was not gingival
      overgrowth. CONCLUSIONS: Tooth eruption is influenced by some unknown factors
      related to aging. Apparently, apoptosis did not occur in the connective tissues
      between the reduced enamel epithelia and oral epithelia that overlay the teeth in
      the mature subjects.

PMID- 15015171
TI  - Treatment of transverse (width) discrepancies in patients who require isolated
      mandibular surgery: the case for maxillary expansion.

PMID- 15015172
TI  - Mandibular narrowing: advantage in transverse problems.

PMID- 15015173
TI  - Submandibular salivary stones: current management modalities.

PMID- 15015174
TI  - Epignathus teratoma with bifid tongue and median glossal salivary mass: report of
      a case.

PMID- 15015175
TI  - Infantile cervical lipoblastoma: a case report and review of the literature.

PMID- 15015176
TI  - The submental island flap for palatal reconstruction: a novel technique.

PMID- 15015177
TI  - Expanding scope, maintaining standards of care.

PMID- 15015178
TI  - Infantile lateral nasal myxoma: is it odontogenic?

PMID- 15015179
TI  - Bisphosphonates and bone necrosis.

PMID- 15015180
TI  - The developing European Board Vascular Examination.

PMID- 15015181
TI  - Validity of an exam assessment in surgical skill: EBSQ-VASC pilot study.

PMID- 15015182
TI  - The European Society for Vascular Surgery and journal origins and early days.

PMID- 15015183
TI  - Saphenous vein versus PTFE for above-knee femoropopliteal bypass. A review of the
      literature.
AB  - The autogenous saphenous vein is considered the best bypass graft material for
      arterial bypasses below the inguinal ligament. However, a synthetic graft or
      prosthesis is considered an acceptable alternative, especially when the distal
      anastomosis is situated above the knee. Some studies even suggest that patency
      rates for vein and synthetic grafts are comparable, whereas others indicate that
      a vein graft is superior to a prosthetic graft, even above the knee. To test the
      hypothesis that both vein grafts and synthetic prostheses are equally beneficial
      in the above-knee position, we performed a systematic review of available studies
      comparing the patency of saphenous vein and polytetrafluoroethylene (PTFE) as
      bypass material. English and German medical literature from 1966 to 2002 was
      searched using Medline, and 25 articles meeting our inclusion and exclusion
      criteria were selected. The patency of venous bypasses was superior to that of
      PTFE bypasses at all time intervals studied. After 2 years, the primary patency
      rate of venous bypasses was 81% as compared to 67% for PTFE bypasses, and after 5
      years it was 69 and 49%, respectively. After 5 years, the secondary patency of
      PTFE bypasses reached 60%. When only randomized trials were considered, venous
      bypasses were again superior to PTFE bypasses at all intervals studied. After 2
      years, the primary patency rate of venous and PTFE bypasses was 80 and 69%,
      respectively, and after 5 years it was 74 and 39%, respectively. Since both
      randomized and retrospective studies comparing venous with PTFE bypasses showed
      that vein grafts were 'better' than PTFE prostheses, the null hypothesis that
      there is no difference between the two types of graft material was rejected
      (p=0.008). We conclude from this systematic review that if a saphenous vein is
      available, a venous bypass should be chosen at all times, even if patients have
      an anticipated short life expectancy (<2 years). If the saphenous vein is absent
      or not suitable for bypass grafting, PTFE is a good alternative as bypass
      material.

PMID- 15015184
TI  - Small aortic aneurysms: is evidence evident?

PMID- 15015185
TI  - Endograft treatment in ruptured abdominal aortic aneurysms using the Talent AUI
      stentgraft system. Design of a feasibility study.
AB  - OBJECTIVES: To study the outcome of patients with ruptured AAA treated by EVAR
      using the Talent AUI stentgraft system. DESIGN: A multicenter prospective
      consecutive patient cohort of 100 patients. MATERIALS: Consecutive patients with
      ruptured AAA will be screened for treatment by EVAR. All patients screened,
      including those excluded from EVAR, will be clustered and called the study group.
      The study group will be compared with a historical group of patients with
      ruptured AAA derived from literature. The New ERA study started February 2003.
      OUTCOME: Main outcome events are applicability rate and operative mortality rate
      of the study group. CONCLUSION: The study rationale and design are reported here.

PMID- 15015186
TI  - The UK Endovascular Aneurysm Repair (EVAR) trials: design, methodology and
      progress.
AB  - OBJECTIVES: The endovascular aneurysm repair (EVAR) trials aim to assess the
      efficacy of EVAR in the treatment of AAA in terms of mortality, quality of life,
      durability and cost-effectiveness. DESIGN: Male and female patients aged at least
      60 years with an AAA diameter measuring at least 5.5 cm on a computed tomography
      (CT) scan are assessed for anatomical suitability for EVAR. Suitable patients are
      offered entry either into EVAR Trial 1 if they are considered fit for
      conventional open repair or EVAR Trial 2 if they are considered unfit. EVAR 1
      randomly allocates patients to EVAR or open repair and EVAR 2 randomly allocates
      patients to EVAR with best medical treatment or best medical treatment alone.
      Target recruitment for EVAR Trials 1 and 2 is 900 and 280 patients, respectively.
      PROGRESS: Recruitment began in September 1999 and there are currently 40 UK
      centres participating in the trials. Monthly targets are being exceeded in EVAR
      Trial 1 with 1037 patients randomised by October 2003. EVAR Trial 2 is also
      meeting monthly targets with a total of 319 patients randomised. When recruitment
      closes in December 2003 patients will need to be followed for at least 1 year
      from their operation. Publication of full results for both trials is expected in
      mid 2005.

PMID- 15015187
TI  - Expansion rates of asymptomatic popliteal artery aneurysms.
AB  - OBJECTIVES: In the absence of symptoms the decision to operate on popliteal
      artery aneurysms (PA) is often made on PA diameter. Little information exists on
      growth rate and therefore optimum scanning intervals. The aim of this paper is to
      define growth rate of PA managed conservatively. METHODS: A prospective study of
      patients with asymptomatic PA was carried out. Patients were invited for
      ultrasound scanning at 6-12 months intervals. Diameter changes between
      consecutive pairs of scans were measured. A decision to operate was made in fit
      patients if PA became symptomatic and/or had a diameter above 3 cm. RESULTS:
      Twenty-one men (24 aneurysms) with a median age of 69 years (46-86) underwent 78
      scans. Sixteen PA were on the right and eight on the left. Eighteen patients had
      bilateral aneurysms, 15 of which were complicated on one side at presentation and
      were dealt with surgically on that side. The median size at first scan was 19 mm
      (14-36). The median time interval to the first follow-up scan was 9 months and
      subsequent scans were 12 months. The mean rate of expansion at aneurysm sizes
      below 20 mm diameter was 1.5 mm/year. PA grew by 3.0 mm/year at sizes 20-30 mm
      and by 3.7 mm/year at sizes >30 mm. Among the risk factors analysed, hypertension
      appeared to increase the risk of aneurysm growth. CONCLUSION: The expansion rate
      of PA increases with increasing size of the PA. This rate of growth in relation
      to size at previous scan and threshold diameter for intervention should be borne
      in mind when planning surveillance intervals.

PMID- 15015188
TI  - The changing face of femoral artery false aneurysms.
AB  - OBJECTIVES: To review the aetiology and method of treatment of all femoral artery
      false aneurysms from a single centre during the last 9 years. DESIGN:
      Retrospective case-note study. METHODS: All patients with a diagnosis of false
      aneurysm were identified from the hospital data-base between January 1995 and
      September 2003. A manual search of the case-notes was performed, and data
      collected on the location, cause and method of repair of the false aneurysm. For
      all patients with a diagnosis of femoral artery false aneurysm, the patients'
      medical and drug history and admission time attributable to the false aneurysm
      were recorded. RESULTS: One hundred and seven patients were identified. Seventy
      nine had false aneurysms of the femoral artery. The majority (40.5%) were caused
      by coronary angiography, the second commonest cause being breakdown of previous
      graft anastomosis (29.1%). Over time, the method of treatment became increasingly
      radiological (most commonly ultrasound-guided thrombin injection), resulting in a
      significantly reduced hospital admission time (P=0.018). CONCLUSIONS: The
      incidence of femoral artery false aneurysms appears to be increasing. This is
      largely a result of an increase in the number of cardiac interventional and
      diagnostic procedures performed. The introduction of ultrasound-guided thrombin
      injection has reduced the inpatient stay of patients with femoral false
      aneurysms.

PMID- 15015189
TI  - From Hippocrates to Palmaz-Schatz, the history of carotid surgery.
AB  - The extracranial carotid artery is the most common site for peripheral vascular
      procedures. Although the association of carotid disease and neurologic
      dysfunction was understood by the ancient Greeks, over 1700 years would pass
      before the relevant anatomy was described. In the 16th and 17th centuries,
      attempts at treatment of carotid injury and aneurysm by ligation were met with
      extremely high rates of stroke and death. It is not until the mid 20th century,
      with the introduction of carotid angiography and improved vascular surgical
      techniques, that the era of reconstructive carotid surgery begins. We present a
      synopsis of the history of carotid surgery from ancient times to present day.

PMID- 15015190
TI  - Local haemodynamic changes during carotid endarterectomy--the influence on
      cerebral oxygenation.
AB  - OBJECTIVES: To characterize carotid bifurcation haemodynamics and cerebral
      oxygenation during clamping and at reperfusion after carotid endarterectomy
      (CEA). MATERIALS AND METHODS: Sixty-two patients with a symptomatic high-grade
      stenosis of the internal carotid artery (ICA), who underwent CEA under general
      anaesthesia, were studied prospectively. Measurements of stump-pressure, volume
      flow (transit time flowmetry) and changes in cerebral oxygenation (near-infrared
      spectroscopy (NIRS)) were performed. Selective shunting was based on stump
      pressure only. RESULTS: Stump pressure correlated with both ICA flow before
      clamping (r=0.45; p=0.03) and changes in cerebral oxygenation (rSO2) during
      clamping (r=0.61; p=0.002), the latter was reversed by shunt placement. ICA flow
      before clamping also correlated with changes in rSO2 during clamping (r=0.41;
      p=0.01). CONCLUSION: Measurements with transit time flowmetry and cerebral
      oximetry are technically easy and help to determine the need for selective
      shunting during CEA. High ICA flow before clamping in combination with a low
      stump pressure usually indicates the need for a shunt. Volume flow measurements
      may also be useful in the quality assessment of the CEA.

PMID- 15015191
TI  - Thrombectomy for acute internal carotid thrombosis: five thrombectomy devices
      compared.
AB  - OBJECTIVE: To test the safety and efficiency of commercially available
      thrombectomy catheters in clearing simulated internal carotid artery (ICA)
      thrombosis. DESIGN: Comparative in vitro study. MATERIALS AND METHODS: A model of
      the ICA was filled with human thrombus, the 'circle of Willis' back pressure was
      set at either 10 or 30 cm of water. Five thrombectomy devices (Hydrolyser, Clot
      Buster, Acolysis System, AngioJet and Fogarty embolectomy catheter) were compared
      for (i) efficiency at removing thrombus, (ii) pressure changes at the tip of each
      device, and (iii) distal embolisation by flow cytometry. RESULTS: Thrombus
      clearance was greatest with the AngioJet (median 95%, range 92-97%) and least
      with the Acolysis System (median 34%, range 12-50%). The Clot Buster and
      Hydrolyser were safest as they produced only negative tip pressures, the AngioJet
      and Balloon catheter produced positive and negative pressures risking distal
      embolisation. The Acolysis system produced no pressure change during use. Distal
      embolisation (of particles between 5 and 40 microm diameter) was greatest with
      the Fogarty balloon catheter at 10 cm water (P<0.05) and least with the
      Hydrolyser and Clot Buster. CONCLUSION: Balloon embolectomy for ICA thrombosis
      risks further embolic cerebral damage. The Hydrolyser and the Clot Buster show
      the greatest promise for ICA thrombectomy.

PMID- 15015193
TI  - Laser Doppler skin perfusion pressure in the assessment of Raynaud's phenomenon.
AB  - OBJECTIVES: In the assessment of Raynaud's phenomenon, objective evaluation of
      digital microcirculatory flow is important, and so we investigated whether the
      measurement of laser Doppler skin perfusion pressure could be of use. MATERIALS
      AND METHODS: Ten fingers of five patients with secondary Raynaud's phenomenon due
      to systemic sclerosis, 22 fingers of 11 patients with primary Raynaud's
      phenomenon and 10 fingers of five control patients were examined. Skin perfusion
      pressure was measured on the third finger of both hands at rest, and then again 3
      min after local cold exposure. RESULTS: Laser Doppler skin perfusion pressure at
      rest in patients with secondary Raynaud's phenomenon was significantly lower than
      that in patients with primary Raynaud's phenomenon and the control patients
      (p<0.05). Skin perfusion pressure decreased significantly in both patient groups
      upon local cold exposure (p=0.005). There were significant differences in
      perfusion pressure after cold exposure among both groups (p<0.05). CONCLUSIONS:
      The low skin perfusion pressure at rest in patients with secondary Raynaud's
      phenomenon suggested the presence of obstructive arterial lesions. The marked
      pressure decrease in all Raynaud's patients after local cold exposure might be
      due to vasospasm of the microvasculature in the digits. These results indicate
      that the measurement of laser Doppler skin perfusion pressure is valuable in the
      diagnosis of Raynaud's phenomenon.

PMID- 15015192
TI  - Elevation in plasma MMP-9 following carotid endarterectomy is associated with
      particulate cerebral embolisation.
AB  - OBJECTIVES: To study plasma MMP-9 levels before and after carotid endarterectomy
      (CEA). DESIGN: Observational study. METHODS: Pre-operative (morning of surgery)
      and post-operative (48 h) plasma samples were obtained from 75 consecutive
      patients undergoing CEA. MMP-9 concentrations were quantified using ELISA.
      Transcranial Doppler monitoring was performed on each patient to detect
      particulate embolisation during the dissection phase of the CEA, until the
      application of carotid clamps. RESULTS: The median post-operative plasma MMP-9
      level of emboli-positive patients was significantly higher than their median pre
      operative value (14.9 ng/ml vs. 8.8 ng/ml; p=0.038). However, no significant
      difference was seen in the plasma MMP-9 level of emboli-negative patients (7.7
      ng/ml vs. 7.1 ng/ml; p=0.364). A greater rise was seen in the median plasma MMP-9
      levels of those patients suffering >2 emboli (from 3.4 to 19.3 ng/ml; p=0.041)
      than those patients suffering 1 or 2 emboli (from 10.1 to 12.8 ng/ml; p=0.340).
      CONCLUSIONS: Plasma MMP-9 only rises after CEA in patients with evidence of
      embolisation. This increase is more pronounced in those with high numbers of
      emboli. These data suggest that the increase in MMP-9 is due to cerebral damage
      caused by embolisation.

PMID- 15015194
TI  - Patency and limb salvage after distal prosthetic bypass associated with vein cuff
      and arteriovenous fistula.
AB  - OBJECTIVE: To assess the usefulness of vein cuff with or without arteriovenous
      fistula interposition as adjuvant techniques for improving patency and limb
      salvage in patients undergoing femorodistal bypass surgery using prosthetic
      grafts. METHOD: We undertook a retrospective study of 65 consecutive patients
      treated over a 5-year period with 67 prosthetic femorodistal bypasses with vein
      cuff, in whom an arteriovenous fistula was constructed at the distal anastomosis
      in 35. Patients were followed for a median time period of 23 months. RESULTS:
      Primary patency rates were 68, 53 and 44% at 1, 2 and 3 years, respectively. The
      corresponding figures for secondary patency, limb survival and patients' survival
      were 73, 64 and 58% for 1 year, 78, 76 and 73% for 2 years and 72, 66 and 63% for
      3 years. None of the criteria analyzed influenced patency or limb salvage on
      prosthetic bypasses using adjuvant techniques. No statistical differences were
      found between patency and limb salvage rates in patients for whom the vein cuff
      was constructed with or without an arteriovenous fistula. But patients who
      managed with a supplementary arteriovenous fistula had significantly fewer distal
      residual arteries in the limb (p=0.001). CONCLUSION: Although results in patients
      treated with adjunctive techniques differed little from those in patients treated
      with direct prosthetic bypasses procedures, those who eventually had an
      adjunctive procedure had inferior runoff. This indicates that an arteriovenous
      fistula might be a valuable supplement in patients with poor runoff who have
      distal revascularisation using a prosthetic graft.

PMID- 15015195
TI  - Long-term behaviour of cryopreserved arterial grafts versus prosthetic
      micrografts.
AB  - INTRODUCTION: When a patient has no suitable vessels for use as grafts in bypass
      or reconstruction procedures, two of the options available are the use of a
      cryopreserved vessel or an expanded polytetrafluoroethylene (ePTFE) prosthesis.
      This study was designed to compare the long-term behaviour of these vascular
      substitutes. MATERIAL AND METHODS: We established three study groups by grafting
      the following vessel substitutes to the iliac artery in Spraque-Dawley rats:
      arterial autografts (GI, n=12), cryopreserved syngenic arterial grafts
      (cryoisografts) (GII, n=12), and ePTFE micrografts (GIII, n=12). The animals were
      sacrificed 180 days after surgery, at which time the graft specimens were
      morphologically evaluated by light and electron microscopy, immunolabelling
      (ED1/alpha-actin) and morphometric analysis of the neointima. RESULTS: At the
      time of sacrifice, graft patency was 100% for the autografts and cryoisografts,
      while 10% of the ePTFE micrografts showed fully-occlusive thrombosis. Intimal
      hyperplasia was observed in grafts in GI and GII; the neointima being thinner in
      the cryoisografts (54.36 +/- 2.26 microm) than the autografts (161.30 +/- 3.91
      microm). The endothelium formed over the prosthetic micrografts was unstable,
      with areas of subendothelial thickening (9.37 +/- 3.18 microm). Cell loss and
      medial layer degeneration were observed in both GI and GII specimens, while the
      GIII grafts were colonised by cells on their luminal surface. CONCLUSIONS: All
      three grafts show good long-term tolerance when used in an arterial setting.
      Following long-term implant, autografts and cryoisografts show similar
      alterations that give rise to the complete loss of the muscle component of the
      tunica media along with the formation of a stable neointima. This new layer takes
      on the role of the tunica media.

PMID- 15015196
TI  - Hydroxy-methylglutaryl-coenzyme A reductase inhibition improves endothelial
      dysfunction in type-1 diabetes.
AB  - OBJECTIVE: We hypothesize that treatment with Pravastatin, a HMG CoA reductase
      inhibitor would improve flow-mediated dilation (FMD), a nitric oxide dependent
      phenomenon and the earliest detectable marker of endothelial dysfunction, in
      asymptomatic patients with type-1 diabetes. MATERIALS AND METHODS: FMD of the
      brachial artery in response to reactive hyperaemia was measured using high
      resolution ultrasonography. Young male patients with type-1 diabetes (n=9) were
      compared with age matched non-diabetic controls (n=8). RESULTS: The FMD response
      in the control group was a median increase in diameter of 7.9 (range 3.8-12.6)%.
      In the diabetic group the FMD response was impaired when compared with controls
      with a median increase only of 4.4 (range 3.7-5.8)% (p<0.01). Following
      Pravastatin, 40 mg per day for one month in the diabetic group, there was a
      significant diameter change in response to reactive hyperaemia with a median of
      8.4 (range 6.9-12.6)% (p<0.01). CONCLUSIONS: These data confirm the presence of
      endothelial dysfunction in young patients with type-1 diabetes. We have shown
      that 1-month of Pravastatin treatment normalizes FMD. This suggests that HMG CoA
      reductase inhibitors may have a role in the management of diabetes mellitus, even
      in the presence of normal serum cholesterol levels.

PMID- 15015197
TI  - Extended lower limb venous ultrasound for the diagnosis of proximal and distal
      vein thrombosis in asymptomatic patients after total hip replacement.
AB  - OBJECTIVE: To assess the performance of extended lower limb venous ultrasound
      (US) for the diagnosis of asymptomatic deep vein thrombosis (DVT) and to estimate
      a 3-month DVT incidence on repeated US after total hip replacement. DESIGN:
      Diagnostic performance study and prospective cohort study. MATERIALS AND METHODS:
      US was compared to phlebography in 70 consecutive patients and interobserver
      agreement was assessed in the last 48 patients at day 8. US was repeated in these
      48 patients at day 13 and day 90. RESULTS: Phlebography demonstrated a DVT in
      18/70 (26%) patients, with five proximal and 13 distal and US in 23/70 (33%)
      patients, with eight proximal and 15 distal. Sensitivity and specificity of US
      with 95% CI were 94% (73-100) and 89% (76-96), respectively. Sensitivity in
      isolated distal vein thrombosis was 92% (67-99). The Kappa coefficient for
      agreement between observers was 0.84 (0.66-1.00). Follow-up showed a DVT in 15/48
      (31%) patients on day 8, in 20/48 patients (42%) on day 13. DVT recurred in two
      patients during follow-up. CONCLUSIONS: The incidence of asymptomatic DVT is
      still significant despite prophylaxis but most DVTs remain distal and occur in
      the first 2 weeks. Extended US could replace phlebography for systematic
      screening in clinical trials using surrogate endpoints in view of its high
      accuracy and reliability.

PMID- 15015198
TI  - Emergency repair of type IV thoracoabdominal aneurysm with the use of a singular
      shunt to maintain visceral perfusion.

PMID- 15015199
TI  - Penile ulcer: an unusual presentation of cholesterol emboli.

PMID- 15015201
TI  - Re: e-EVAR in ruptured abdominal aortic aneurysms.

PMID- 15015203
TI  - Protein-loaded bioresorbable fibers and expandable stents: Mechanical properties
      and protein release.
AB  - There is an increasing interest in bioresorbable polymeric stents for coronary,
      urethral and tracheal applications. These stents can support body conduits during
      their healing process and release biologically active agents from an internal
      reservoir to the surrounding tissue. A removal operation is not needed.
      Bioresorbable poly(L-lactic acid) fibers were prepared through melt spinning
      accompanied by a postpreparation drawing process. Novel expandable bioresorbable
      stents were developed from these fibers. Bioresorbable microspheres containing
      albumin were prepared and attached to the stents, to serve as a protein reservoir
      coating. The controlled release of albumin from the microsphere-loaded stent was
      studied. The fibers combine high strength and modulus, together with good
      ductility and flexibility. An increase in draw ratio increases the tensile
      strength and modulus and decreases the ultimate strain. The stents demonstrated
      excellent initial radial compression strength and good in vitro degradation
      resistivity, which makes them applicable for supporting blood vessels for at
      least 20 weeks. Microspheres bound to these stents enable effective protein
      loading, without reducing the stent's mechanical properties. The protein release
      from the microsphere-loaded stent occurs by diffusion, is determined mainly by
      the initial molecular weight of the bioresorbable polymer and its erosion rate,
      and is strongly affected by the microsphere structure.

PMID- 15015204
TI  - Sublethal concentrations of Au (III), Pd (II), and Ni(II) differentially alter
      inflammatory cytokine secretion from activated monocytes.
AB  - Many transition metals have been viewed collectively as nonspecific biological
      toxins in cells, which has limited investigation into their possible therapeutic
      effects. In the current study, the effects of Au(III), Ni(II), and Pd(II) on the
      differential secretion of cytokines from monocytes has been investigated. This is
      critical to understanding any therapeutic potential of these metals, their
      allergenicity, or the clinical effects of current metal therapies such as
      chrysotherapy. Lethal concentrations (defined as > 50% suppression of
      mitochondrial succinate dehydrogenase (SDH) activity) of metals were determined
      by dose-response curves with the use of 72 h exposures to human THP-1 monocytes.
      Then, secretion of TNFalpha, IL1beta, and IL6 were measured after the monocytes
      were exposed to sublethal concentrations of metals, with or without stimulation
      by lipopolysaccharide. The concentrations of Au(III), Pd(II), and Ni(II) required
      to suppress SDH activity by 50% were found to be 255, 270, and 90 microM,
      respectively. No sublethal concentration of any metal alone caused secretion of
      the cytokines. However, LPS-induced cytokine secretion was significantly and
      differentially altered by sublethal concentrations of each metal. Differential
      responses were highly dependent on metal concentration and involved both
      suppression and potentiation of the LPS activation. In the case of Ni(II),
      potentiation of TNFalpha, IL1beta, and IL6 ranged from 200% for TNFalpha to over
      1200% for IL6. Metals such as Au(III), Pd(II), and Ni(II) differentially alter
      cytokine expression from monocytes. These results imply that metals have more
      specific effects on cell signaling than previously assumed. These results also
      are important in explaining multiple clinical effects often seen with
      chrysotherapy, identifying potential new avenues for metal therapy, and
      understanding the inflammatory effects of metals such as nickel.

PMID- 15015205
TI  - Development of a recombinant human collagen-type III based hemostat.
AB  - Animal-tissue-derived collagen, containing mostly type I collagen with a minor
      amount of type III collagen, has been widely used in the production of hemostats
      for many decades, although it has been known for a long time that type III
      collagen is more likely to induce platelet aggregation in vitro. Because it is
      hard to purify type III from animal tissue, it has not been possible to correlate
      this finding with in vivo data. In this report, it is demonstrated that
      recombinant human collagen III fibrils are more capable of inducing platelet
      aggregation in vitro than those comprised of bovine collagen I, in agreement with
      previously published data on tissue-derived type III collagen. When formed into
      three-dimensional matrices, the use of type III collagen results in formulations
      with better mechanical integrity, larger surface area, and higher hemostatic
      activity in a rabbit spleen injury model as compared with commercially available
      hemostats formed from bovine type I collagen.

PMID- 15015206
TI  - The effect of six years of water storage on resin composite bonding to human
      dentin.
AB  - The aim of this in vitro study was to evaluate dentin bond strength and marginal
      adaptation of direct resin composite fillings after different storage times.
      Three hundred sixty cavities were prepared in discs of freshly extracted human
      third molars and filled with resin composites. Multistep self-etching adhesives
      (Syntac Classic, A.R.T. Bond, both with and without total etching), three-step
      etch-and-rinse adhesives (Scotchbond Multi-Purpose Plus, EBS), and two-step etch
      and-rinse adhesives (Prime and Bond 2.0, Syntac Single-Component) were used for
      bonding. After 1, 90, and 2190 days of water storage and 24 h thermocycling (1150
      cycles), push-out testing was performed. From the 6-year group, replicas were
      made after 1 day, 90 days, and 1, 2, 3, 4, 5, and 6 years, and examined regarding
      marginal adaptation under an SEM (x 200 magnification). In all groups under
      investigation, push-out bond strengths remained stable after 90 days; however,
      the strengths significantly decreased after 6 years of water storage. The two
      step systems exhibited lower bond strengths than three-step systems after 6
      years. Marginal analysis revealed a significant loss regarding the percentage of
      perfect margins having been stable after 2 years for the three-step etch-and
      rinse systems. Overall, the older three-step systems proved to be more effective
      than the simplified adhesives Syntac Single-Component and Prime and Bond 2.0 with
      regard to bond strength and marginal adaptation.

PMID- 15015207
TI  - Sol-gel preparation and in vitro test of fluorapatite/hydroxyapatite films.
AB  - Fluorapatite/hydroxyapatite (FA/HA) films have been demonstrated to be a good
      alternative to pure hydroxyapatite (HA) ones in medical applications because of
      their bioactivity and relatively low solubility. In this study, Ca(NO(3))(2),
      P(2)O(5), and HPF(6) were used to prepare FA/HA films on Ti6Al4V substrate with
      the use of a sol-gel method. The F contents in the films could be tailored by
      adjusting the amount of HPF(6) added. The in vitro evaluation of the films was
      carried out in both SBF9# solution and TRIS buffer solution. The films with
      appropriate F contents showed a better ability to induce calcium phosphate
      deposition on their surfaces than either pure HA film and FA/HA films with even
      higher F content, as well as smaller dissolution amounts than HA film in TRIS
      buffer solution. Hence, the FA/HA films obtained in this work integrate both good
      bioactivity and stability, and could be a better choice for bioactive film on
      titanium alloys to produce high-quality implants.

PMID- 15015208
TI  - Analysis of cellular morphology, adhesion, and proliferation on uncoated and
      differently coated PVC tubes used in extracorporeal circulation (ECC).
AB  - The biggest challenge to improve extracorporeal circulation (ECC) circuits lays
      on avoiding platelet adhesion to their surfaces, because this contributes to
      thrombus formation, resulting in the activation of blood coagulation. One
      approach to minimize this effect is to improve the biocompatibility of ECC
      circuits by modifying their surfaces. This can be achieved by coating them with
      heparin or phospholipids. The present study investigated the adhesion and
      morphology characteristics of fibroblastic and blood cells cultured on uncoated
      poly (vinyl) chloride PVC tubes as well as on heparin, phosphatidylcholine
      (DMPC), and phosphatidylethanolamine (DMPE) -coated tubing. The results showed
      the importance of uniform coating regardless of the substance used, because the
      coatings cover the grooves on PVC surfaces, which favor cell adhesion. The
      comparison among the three different coatings showed the best biocompatibility
      results for the PVC tubes coated with heparin, followed by the coating with DMPE
      and with DMPC. For all coated tubes, cells did not spread on the PVC surfaces
      and, consequently, did not adhere to their surfaces, increasing the overall
      biocompatibility of PVC tubes. However, possible DMPE's alkylation, caused by
      sterilization, resulted in increased material hydrophobicity, which explains the
      decrease in fibroblastic adhesion. Furthermore, sterilization of DMPC-PVC
      improves its hydrophilic character, also decreasing adhesion. Based on these
      results, coating PVC with the phospholipids DMPC and DMPE seems to be a promising
      technique to improve the biocompatibility of PVC tubes, and is worthy of further
      investigation.

PMID- 15015209
TI  - Etched implants: a comparative surface analysis of four implant systems.
AB  - Surface texturing by acid etching has recently become popular among dental
      implant manufacturers. The aim of this study was to compare the surface
      topography of four implant systems and to check the reproducibility of the
      industrial process of each implant system. Three implants per system have been
      selected from three distinct batches. They were observed under a scanning
      electron microscope (SEM), and roughness was determined with a contact
      profilometer by measuring five height-descriptive parameters (Ra, Rq, Rz(ISO),
      Rt, and Rsk, a texture parameter Sm, and a hybrid parameter RDeltaq. The analysis
      showed that each implant system displayed a distinct surface topography that
      could not be mistaken. When sandblasting was performed prior to etching, surface
      topography was a combination of macro- and microroughness. The roughness and the
      amount of remaining sand varied among the batches, showing that the industrial
      process is not fully developed. Deviation from the released technical information
      was found for two out of four implant manufacturers. Based on the available
      biological and clinical data on textured surfaces, it is suggested that it is
      bone interlocking at the interface that maintains the biological properties of
      textured surfaces, rather than a strong implant fixation per se.

PMID- 15015210
TI  - Effects of various sterilization methods on the setting and mechanical properties
      of apatite cement.
AB  - Sterilization capability is a necessary requirement for any material that is to
      be used in a medical application. Therefore, it is necessary for apatite cement
      (AC) to be sterilized. Because there is little information on the sterilization
      methods of AC, the aims of this investigation were to evaluate the effects of
      various sterilization methods, including steam, dry heat, ethylene oxide (EtO)
      gas, and gamma irradiation sterilizations, on the setting and mechanical
      properties of AC. In the case of steam sterilization, because AC powder
      aggregated before setting-time measurements, the setting time could not be
      measured. When the powder was sterilized by dry heat or EtO gas, the setting time
      was prolonged significantly and the wet diametral tensile strength (DTS) value
      decreased significantly. Therefore, sterilizations with steam, dry heat, or EtO
      gas were suggested to be inappropriate methods for AC. Accordingly, the following
      experiments focused on gamma sterilization. The setting time of AC was retarded
      with an increase in gamma irradiation dose. The wet DTS value decreased with the
      increase in gamma irradiation dose. There was no compositional change due to the
      gamma irradiation. The following tests were carried out in order to examine the
      effect of the gamma irradiation on the setting reaction of AC in detail.
      Tetracalcium phosphate [TTCP: Ca(4)(PO(4))(2)O] and dicalcium phosphate anhydrous
      (DCPA: CaHPO(4)) were separately irradiated, and the cements were produced with
      the use of irradiated powder and nonirradiated powder. Although the wet DTS value
      of AC produced from irradiated TTCP and nonirradiated DCPA decreased with
      increasing gamma irradiation dose, there was no significant difference. In
      contrast, the wet DTS value of AC produced from irradiated DCPA and nonirradiated
      TTCP significantly decreased with the increase in gamma irradiation dose. In
      conclusion, although the detailed mechanism of the delayed setting time and
      decreased DTS value was not clarified by the present study, it was found that
      gamma irradiation affected DCPA more than TTCP.

PMID- 15015211
TI  - Development of medical guide wire of Cu-Al-Mn-base superelastic alloy with
      functionally graded characteristics.
AB  - A new type of medical guide wire with functionally graded hardness from the tip
      to the end was developed with the use of Cu-Al-Mn-based alloys. The
      superelasticity (SE) of the Cu-Al-Mn-based alloys in the tip is drastically
      improved by controlling the grain size, whereas the end of the wire is hardened
      using bainitic transformation by aging at around 200-400 degrees C. Therefore,
      the tip of the guide wire shows a superelasticity and its end has high stiffness.
      This guide wire with functionally graded characteristics shows excellent
      pushability and torquability, superior to that of the Ni-Ti guide wire.

PMID- 15015212
TI  - Apatite formation on the surface of wollastonite/tricalcium phosphate composite
      immersed in simulated body fluid.
AB  - Wollastonite/tricalcium phosphate composites were prepared and immersed in SBF
      for various periods to investigate the apatite-formation mechanism on their
      surfaces. Surface morphologies and composition before and after immersion were
      analyzed by SEM and EDS technologies. The concentration changes of calcium,
      silicon, and phosphorus in SBF due to the immersion of the samples were measured
      with inductively coupled plasma atomic emission spectroscopy, and the
      corresponding pH values in SBF were recorded. XRD and IR were used to examine the
      changes in crystalline phases and functional groups. It was found that, after
      immersion for 1 day, the samples were covered by pom-pom-like apatite granules,
      resulting from the dissolution of wollastonite and the simultaneous
      transformation of TCP. This quickly led to the subsequent precipitation of
      another apatite layer, which covered the earlier-formed surface completely. These
      results indicate that the wollastonite/tricalcium phosphate composite is a
      potential biomaterial candidate because of its high bioactivity and in situ
      porous structure.

PMID- 15015213
TI  - The physicochemical properties of the solidification of calcium phosphate cement.
AB  - In this article, the physicochemical properties of the solidification of calcium
      phosphate cement (CPC) were investigated, and the components of the solidified
      body and the characteristics involved in the application were measured. The
      setting process of CPC was moderate and slightly exothermic, the heat liberation
      rate was slow, and the temperature increased little. At the initial stage of the
      hydration, the compressive strength rose linearly with time, and reached the
      maximum value after 4 hours. The volume was slightly shrunken by 1% during the
      setting process, and the total heavy metal content was below 2 ppm. The porosity
      of the solidified body was about 30%, which was mainly the gel pore with size
      below 0.1 microm. The final product of hydration was low crystalline
      hydroxyapatite (HAP). Its real density was 2.859 g/cm(3), which was lower than
      the theoretical value. This may be due to the existence of lattice defects, which
      will lead to a slight rise in solubility when leached in physiological saline.

PMID- 15015214
TI  - Surface treatment of injectable strontium-containing bioactive bone cement for
      vertebroplasty.
AB  - A novel injectable bioactive bone-bonding cement (SrHAC) composed of strontium
      containing hydroxyapatite (Sr-HA) as the inorganic filler and bisphenol A
      diglycidylether dimethacrylate (Bis-GMA) as the organic matrix for vertebroplasty
      was developed previously. In this study, the Sr-HA powders were surface treated
      with methyl methacrylate (MMA) to improve the interface integration of the two
      phases. After surface treatment, the compression strength and Young's modulus,
      which were tested after immersion in distilled water at 37 degrees C for 24 h
      according to ISO 5833, were increased by 68.65 % (p <.001) and 31.02% (p <.001),
      respectively. The bending strength and bending stiffness of the bioactive bone
      cement were significantly improved by 54.44% (p <.001) and 83.90% (p <.001). In
      addition, the handling property of the cement was also enhanced. In vitro
      biomechanical testing showed that the stiffness of the fractured spine recovered
      to 82.5% (p <.01) of the intact condition after cementation with surface-treated
      SrHAC. The failure load of the spine cemented with original and MMA-treated SrHAC
      improved by 14.25% (p <.05) and 46.91% (p <.05) in comparison with the fractured
      spines. Results from this study revealed that the MMA-treated SrHAC has a better
      mechanical effect for orthopedic applications.

PMID- 15015215
TI  - Hydrolytic degradation and cracks in resin-modified glass-ionomer cements.
AB  - Water-absorption affects the basic properties of resin-modified glass-ionomer
      cements (RMGICs). Fick's law is usually invoked to explain the absorption
      process. The purpose of this study is to show that the absorption in accordance
      with the Fickian model cannot be extended to the whole of the specimen, and that
      microcrack formation is the main degradation mechanism for specimens cured in a
      closed environment. For this purpose, flat disk-shaped paste specimens 1.5 mm
      thick (aspect ratio 4), irradiated in closed conditions between two glass slides
      and stored in water for approximately 20 months, were analyzed periodically
      gravimetrically and under confocal fluorescence microscopy, with absorbed eosin
      used as the fluorescent probe. At pH 7.0, the specimen surface (10-20 micrometers
      in depth) absorbed water rapidly, swelled, and disintegrated in 20-40 days. Long
      term storage produced isolated cracks and grains, no progress in the swelling,
      and a slow weight decrease. A lower pH (pH 3.5) produced a significant increase
      of the number of microcracks. The decrease in the irradiation time (30 s or less)
      enhanced the erosion process, producing very broad cracks. It was concluded that
      the prevalent mechanism of long-term hydrolytic degradation was based on the slow
      formation of cracks, whereas only in the early stage of storage did absorption
      occur quickly in accordance with the Fickian diffusion.

PMID- 15015216
TI  - Transmittance of a bioceramic dental restorative material based on calcium
      aluminate.
AB  - This article investigates the transmittance of a new ceramic filling material as
      a function of time, thickness, wavelength, and addition of pigments. In the
      hardened state the ceramic material is composed of hydrates, calcium aluminate,
      and glass fillers. The radiopacity of the investigated material is also measured.
      The results of the transmittance are compared to a commercial glass ionomer
      cement (Fuji II) and resin composite (Tetric Ceram). The transmittance increased
      with time from low values after 1 h to values close to the glass ionomer cements
      after 1 week. The resin composite had almost twice the transmittance as the
      calcium aluminate material and the glass ionomer cement. The amount of light
      passing through the material was dependent on both the sample thickness and the
      wavelength. Samples of 0.5-mm thickness transmitted almost twice as much as 1-mm
      thick samples. Regarding the wavelength, blue light was scattered very
      effectively (low transmittance), whereas red light was not (high transmittance).
      Addition of pigments lowered the transmittance. The radiopacity was slightly
      higher than that of enamel.

PMID- 15015217
TI  - Effects of neutral sodium hydrogen phosphate on the setting property and
      hemostatic ability of hydroxyapatite putty as a local hemostatic agent for bone.
AB  - Hydroxyapatite (HAP) putty has been reported to have good hemostatic ability and
      excellent biocompatibility. Although the setting reaction of HAP putty and
      resulting transformation to HAP is the reason for this excellent
      biocompatibility, it also limits the handling period. In this study, the
      relationship between the setting reaction of HAP putty and its hemostatic ability
      was investigated, where neutral sodium hydrogen phosphate concentration and post
      preparation time were used as indexes. A higher concentration of neutral sodium
      hydrogen phosphate was found to result in decreased hemostatic ability. The
      hemostatic ability of HAP putty decreased with time after its preparation; thus
      it was important to use HAP putty within 10 min after its preparation. The
      adhesive strength of HAP putty to bone increased with time. Therefore reliable
      hemostasis can be expected with HAP putty. Although the limited handling time is
      a drawback, HAP putty is thought to have a good potential as a hemostatic agent
      it is highly reliable, and has a high hemostatic ability with excellent
      biocompatibility.

PMID- 15015218
TI  - Wear-particle-induced osteoclast osteolysis: the role of particulates and
      mechanical strain.
AB  - Periprosthetic osteolysis involves osteoclast activation by wear particulates and
      their exposure to mechanical perturbation through exposure to shear forces
      generated by periprosthetic fluid as well as interface micromotion. This study
      aimed to determine the interactions between wear particulates, mechanical
      stimulation, and osteoclasts. In static cultures, wear particulates increased
      osteoclast differentiation. Addition of neutralizing antibodies to RANKL
      (receptor activator of nuclear factor kappa ligand) inhibited the particle
      induced increase in osteoclast numbers. Cyclic 5000 microstrains were applied
      with the use of a custom-built device to marrow-derived cultures to assess the
      effect on osteoclast differentiation. Mechanical strain application alone
      decreased osteoclast differentiation, which was further decreased by the addition
      of particles despite increases in the soluble RANKL to osteoprotegerin (OPG)
      ratio. Mechanical strain alone induced mature osteoclast apoptosis in a dose
      dependent manner. In contrast, in the mature osteoclast model, the addition of
      nonmetal particulates protected the osteoclasts from becoming apoptopic. Titanium
      (Ti) and cobalt chromium (CoCr) particles, however, induced osteoclast apoptosis,
      whereas polyethylene (PE) and polymethylmethacrylate (PMMA) did not. Wear
      particulates and mechanical stimulation interact via an eicosanoid-dependent
      pathway to alter osteoclast function and survival. The addition of mechanical
      perturbation to a particle-laden system thus appears to enhance the potential for
      osteolytic activity by enhancing osteoclast survival.

PMID- 15015219
TI  - Drug misuse in pregnancy.

PMID- 15015221
TI  - [Cardiac amyloidosis. Comment on the case report by Brychta et al: Restrictive
      cardiomyopathy as a manifestation of primary amyloidosis].

PMID- 15015220
TI  - Elevated temperature and nursing home mortality during 2003 European heat wave.

PMID- 15015222
TI  - [Are we prepared for the expected increase in cardioverter-defibrillator
      implantation?].

PMID- 15015223
TI  - [Chronic myeloid leukemia and imatinib mesylate therapy].

PMID- 15015224
TI  - [Prognosis as a logical medical consideration].

PMID- 15015225
TI  - [Chronic venous insufficiency--outpatient study of risk factors].
AB  - The aim of the clinical study was to monitor and analyse possible causes of
      chronic venous insufficiency (CVI) in a randomised sample of patients with
      diagnosed CVI. There were 100 patients in the investigated sample, 82 women of an
      average age of 40.4 years and 18 men of an average age of 42.7 years. Monitoring
      of risk factors of development and advancement of CVI in our sample of patients
      showed following results: 1. frequent overweight and obesity (BMI > 25 kg/m2) in
      women (47.6%) and men (83%) with relatively frequent cases when a patient put on
      weight more than 5 kg within the last 5 years before development of CVI signs
      (24.4% of women and 22% of men); 2. a predominance of multiparas (68.3%) over
      women who have not given a birth or gave birth to 1 child (31.7%), we have found
      a big percentage of multiparas among both women younger than 40 (40%) and
      especially older women (> or = 40 years) where the percentage was 75.4%); 3. a
      positive family history in the majority of our patients with CVI (71%), in 88.7%
      in a first grade relative; 4. the major part of people in the sample were
      standing when working (59%), the number of people with sedentary work was high
      too (32%); 5. smoking admitted only minor part of the CVI patients (27%); 6.
      significant history of hormonal treatment in the female patients (37.8%),
      especially among women younger than 40 (48%); 7. other risk factors (accidents
      and surgeries of lower extremities, recurrent thrombophlebitis) appeared either
      in a very small percentage of the patients (lower limbs surgeries) or in
      significantly smaller percentage compared to risks in points 1 to 4 (accidents of
      lower extremities 20%), recurrent thrombophlebitis 22%).

PMID- 15015226
TI  - [Imatinib mesylate (Glivec) in treatment of chronic phase chronic myeloid
      leukemia].
AB  - The new knowledge in molecular biology and pathophysiology of chronic myeloid
      leukemia enabled the development of imatinib mesylate (Glivec, formerly STI571).
      Imatinib potently inhibits several protein tyrosine kinases, including BCR-ABL, c
      Kit, and PDGF receptor. Imatinib blocks the phosphorylation of downstream target
      proteins and interrupts the malignant transformation leading to the development
      of CML. Phase I and II studies demonstrated that imatinib is highly effective and
      well tolerated in all phase of CML. We got our experience with imatinib on more
      than two-year monitoring 34 patients within the Expanded Access Study CST1571
      0113. Imatinib 400 mg/d was administered orally to 10 women and 24 men in median
      age of 53 years (22-70) who were hematologically (n = 9) or cytogenetically (n =
      13) resistant, cytogenetically refractory (n = 3) or intolerant (n = 9) to
      interferon alpha. The median follow-up time was 97.5 weeks (23-115), the median
      time from CML diagnosis to the start of the study was 32.3 months (6-140.5).
      Complete hematologic response was achieved in 33 of 34 (97%) pts, total major
      cytogenetic response (complete plus major) in 21 of 33 (63%) pts. Cytogenetic
      relapse was observed in 2 of 33 pts (6%), cytogenetic progression in 4 (12%) pts.
      Non-hematologic toxicity was mild (grade 1 or 2) and no patient was excluded from
      the study due to it. Hematological toxicity grade 3 limited dose of imatinib in
      26% of patients and probably caused lower rate of cytogenetic responses in heavy
      pretreated patients. Both quantitative RT-PCR methods (competitive RT-PCR and
      real-time RT-PCR Light-Cycler) were found useful to monitor patients with CML on
      imatinib therapy. Our results confirmed high efficacy and safety of imatinib in
      late-chronic phase CML patients failing prior interferon therapy. The lower
      incidence of hematological toxicity and higher rate of cytogenetic responses in
      patients treated with imatinib in early-chronic phase CML justify according to
      our opinion the recommendation to administer imatinib early after the diagnosis
      of CML in patients who are not indicated for allogeneic transplantation.

PMID- 15015227
TI  - [Successful treatment of chronic hepatitis C in hemophiliacs based on historical
      development of therapeutic protocols].
AB  - Chronic infection with hepatitis C virus is very frequent among hemophilic
      patients in all developed counties, including the Czech Republic. Because of a
      possibility of developing serious terminal stages of infection, liver cirrhosis
      and hepatocellular carcinoma, the tendency in treatment of patients with chronic
      hepatitis C is to start it as soon as possible and thus reduce the probability of
      developing these advanced stages of disease which are difficult to treat.
      Treatment of hemophilic patients with chronic hepatitis C started in the
      Department of Infectious Diseases, University Hospital Brno Bohunice, in 1996.
      Used treatment schemes have reflected historical evolution of treatments used to
      treat chronic hepatitis C. Initially, alpha-interferon (IFN) was administered in
      monotheraphy (6 patients), later, since 1999, a combination of alpha-IFN and
      ribavirin was administered (13 patients), and since 2001 a combination of
      pegylated interferon (PEG-IFN) and ribavirin (3 patients) was administered. In
      all the patients the individual treatments took 12 month. Sustained
      negativization of HCV RNA in serum has not been achieved in any patient treated
      only with alpha-IFN. In patients who were administered the combination of alpha
      IFN and ribavirin this effect appeared in 4 from 7 cases without history of
      treatment with alpha-IFN (57%), one from 2 relapses and one from 3 non
      responders. The combination PEG-IFN and ribavirin was effective in the only one
      patient who relapsed after alpha-IFN and ribavirin and in one from the two non
      responders to this combination. The tolerance and safety of treatment was good in
      haemophilia patients and could be fully compared to those in other patients with
      chronic hepatitis C.

PMID- 15015228
TI  - [Thrombin activatable fibrinolysis inhibitor (TAFI) and its importance in the
      regulation of fibrinolysis].
AB  - Thrombin activatable fibrinolysis inhibitor (TAFI) also named procarboxypeptidase
      U (CPU), procarboxypeptidase R (CPR) and plasma procarboxypeptidase B (CPB)
      provides an important link between fibrinolysis and coagulation cascade.
      Activated TAFI (TAFIa) reduces a generation of plasmin because it cleaves off the
      carboxy-terminal lysine residues from partially degraded fibrin and thereby
      abrogates the fibrin cofactor function in the tPA-mediated catalysis of
      plasminogen to plasmin. TAFI is activated by thrombin-thrombomodulin complex.
      TAFI transformation to the activated TAFI (TAFIa) induced by thrombin supports
      the important role of coagulation cascade in regulation of fibrinolysis. This can
      be proved by a fact that the patients with a factor XI (FXI) deficiency are prone
      to bleeding from tissues with a high local fibrinolytic activity (urinary tract,
      nose, oral cavity, tonsils) that can be explained by a decreased thrombin
      mediated TAFI activation. On the other hand the prothrombotic mutation of factor
      V (FV Leiden) associated with a resistance to activated protein C (APC
      resistance) possess both mechanisms-an increased thrombin generation in
      coagulation cascade and a down regulation of fibrinolysis by a way of the
      thrombin-induced TAFI activation. For the future an inhibition of TAFI (e.g. by
      FXI inhibitors) offers the therapeutic possibilities to improve the decreased
      fibrinolysis and increase the efficiency of fibrinolytic therapy in thrombotic
      disorders. In bleeding disorders (hemophilia A, B) the drugs with a higher
      efficiency of TAFI for down regulation of an increased fibrinolysis could be
      used.

PMID- 15015229
TI  - [Importance of immunophenotyping in the diagnosis of B-cell lymphoproliferative
      diseases ].
AB  - The immunophenotyping of the lymphoproliferative diseases is considered to be an
      integral part of the diagnostic process pointing to the correct classification of
      the individual diseases and to the choice of the most suitable type of therapy.
      This article describes the immunophenotype of particular types of B
      lymphoproliferative disorders included in the World Health Organization
      classification (WHO) and the prognostic importance of some markers. The panel of
      specific monoclonal antibodies directed to B-cell lineage used in our department
      is displayed.

PMID- 15015230
TI  - [Care of patients with implanted cardioverters-defibrillators: what every
      physician should know].
AB  - Implantable cardioverter defibrillators have become an integral part of treatment
      of patients with malignant chamber arrhythmias over last 10 years both in
      secondary and primary prevention of sudden deaths. Based on monitoring of a group
      of 182 patients and based on information in literature, authors present a survey
      of the most frequent situations, rules and complications related to therapy with
      implantable defibrillators. In the end they try to answer summary of the most
      frequent questions of internal medicine physicians and GPs concerning patients
      with this implanted device.

PMID- 15015231
TI  - [Prognosis and prognostic factors in oncology and oncologic surgery ].
AB  - At present time, we can see increasing interest in prognosis and prognostic
      factors. This review refers to the problems of prognostics in oncology and
      oncosurgery. Authors emphasize importance of prognosis and its integrating role
      in issues of treatment tactics and strategy selection. This article presents main
      classification of prognostic factors, e.g. the subject-based one, which consists
      of three groups-tumor-related, host-related and environment related factors.
      Factors that belong to the first group are anatomic extent of disease that is
      classified according to the TNM classification, tumor histopathologic factors and
      a great number of molecular and genetic factors. The question of clinical
      relevance of those factors is discussed. Host-related prognostic factors include
      inherent demographic characteristics, performance status, comorbid conditions and
      others. Environment-related prognostic factors involve physician, the health care
      system and society as a whole. This group of prognostic factors is less studied,
      despite the fact that namely these factors can have fundamental importance in
      questions of disease outcome.

PMID- 15015232
TI  - [Restrictive cardiomyopathy as a manifestation of primary amyloidosis].
AB  - Primary amyloidosis is a rare disease, cardiac involvement occurs in up to 40% of
      patients. Diffuse amyloid deposits cause an impairment of myocardial systolic and
      diastolic function. In this paper we are presenting a case of a 54-year-old
      woman. The woman was admitted because of progressive fatigue, dyspnoea, chest
      pain, later she experienced hypotension, dyspepsia, and enterorrhagia. ECG showed
      decrease in QRS amplitude. We have found an echocardiographic evidence of wall
      hypertrophy. Right cardiac catheterization showed a restrictive situation.
      Immunobinding of serum and urine revealed monoclonal kappa light chains. The
      diagnosis was determined by rectal biopsy. Unfortunately, amyloid deposits caused
      progressive heart failure, hemorrhage, and death just before the diagnosis of
      primary amyloidosis could be determined on the basis of results of the
      immunofixations of serum and urine proteins (detection of the monoclonal light
      chains kappa) and from biopsy specimens taken from rectum (amyloid deposits).

PMID- 15015233
TI  - [Disagreement between findings of 99mTc-MIBI and 99mTc-pertechnetate scintigraphy
      scans in patients with primary hyperparathyroidism].
AB  - Sixty-two-year-old man was admitted to hospital for increased serum level of
      calcium (3.85 mmol/l) and incipient renal failure (urea 7.2 mmol/l, kreatinin 117
      mumol/l). The reason of hypercalcaemia was intensive explored. Serum level of
      intact PTH was 383.6 pg/ml. We performed two-dimensional early and delayed (2
      hours) scintigram after intravenous administration of 750 MBq 99mTc-sestamibi,
      i.e. double-phase technique. There was detected focus (diameter 20 mm) of
      increased sestamibi uptake with slow wash-out in distal part right thyroid lobe.
      Planar scintigraphy obtained after intravenous administration of 185 MBq 99mTc
      pertechnetate detected focus of increased 99mTc-pertechnetate uptake in the same
      point too. Patient underwent right thyroid lobectomy. There was colloid nodular
      goiter. Under right thyroid lobe was detected spherical particle. This particle
      was ablated (diameter 20 mm, weight 4 gram). It was parathyroid adenoma. One
      month after ablation of parathyroid adenoma serum level of PTH was 23.1 pg/ml and
      serum level of calcium was 2.52 mmol/l. There was overlap of scintigraphy image
      of parathyroid adenoma under distal part of right thyroid lobe on 99mTc-sestamibi
      two-dimensional scintigram and scintigraphy image of hyperplastic node with
      increased activity in distal part of right thyroid lobe on 99mTc-pertechnetate
      two-dimensional scintigram.

PMID- 15015234
TI  - Making the numbers work for you: establishing effective compensation.
AB  - It's the time of year that every employer looks to with trepidation--employee
      evaluation, which will determine individual workers' salaries for the coming
      year. Besides personal performance, employers must also take into account a
      number of other factors to ensure they are fairly compensating their employees in
      a manner that will enable them to retain the best and the brightest. What are
      their competitors paying? What is the rate of compensation inflation over the
      years? What "extra perks" make employees more likely to stay on? Knowing these
      factors can help employers tremendously in maintaining a satisfied and loyal
      workforce. Each year, the Hospital and Healthcare Compensation Service (HCS)
      gives home care and hospice providers easy access to this crucial information.

PMID- 15015235
TI  - Home care financial reflections & projections. Where are we headed?

PMID- 15015236
TI  - NAHC's chair offers a year in review.

PMID- 15015237
TI  - Profit margins projected to continue downward spiral.

PMID- 15015238
TI  - The state of hospice in America. Looking back, looking forward.

PMID- 15015239
TI  - The silent crisis: women and the need for long-term care insurance. The financial
      toll of caregiving--Part III.

PMID- 15015240
TI  - New legislation spells broad changes for Medicare home health benefit.

PMID- 15015241
TI  - New Medicare legislation expands hospice benefit.

PMID- 15015242
TI  - Home care aide training requirements revisited.

PMID- 15015243
TI  - [The teenager who finds it difficult to wake up in the morning: aberrant
      behavior, misperception or an underlying sleep disorder?].
AB  - Three teenagers, two girls aged 14 years and one boy aged 10 years, had had
      difficulty with getting to sleep in the evening and waking up in the morning from
      a very early age. These difficulties led to underperformance at school and/or
      tension in the household. The anamneses and a sleep study led to the following
      conclusions: 'delayed sleep phase syndrome', 'sleep state misperception' and
      'aberrant interaction between the child and its parents'. Treatment with
      phototherapy and regulation of the bedtimes, information and regulation of the
      bedtimes, and pedagogic advice, respectively, was successful within a few months.
      Teenagers often complain about problems with sleeping, in particular about late
      onset of sleep and difficulties with awakening. These problems are self-limiting
      in most cases, but can have a disastrous influence on social life and education.

PMID- 15015244
TI  - [Marked similarity between the Dutch Institute for Health Care Improvement
      guideline 'Aspecific low back pain complaints' and the Dutch College of General
      Practitioners guideline 'Low back pain'].
AB  - The Dutch Institute for Healthcare Improvement's (CBO) guideline on the diagnosis
      and treatment of aspecific, acute and chronic, low back complaints corresponds in
      general to the Dutch College of General Practitioners' guideline with regard to
      the following topics: time-contingent treatment, restricted use of X-ray
      examination, and the options for non-medical treatment. A noteworthy exception in
      the CBO-guideline is the suggestion of manipulation of the spine as a possible
      treatment although there is no mention of proof of effectiveness.

PMID- 15015245
TI  - [The Dutch Health Council report on haemopoietic stem cells].
AB  - The Dutch Health Council advised the government on the use of haemopoietic stem
      cells in clinical medicine in September 2003. Most stem cell transplantations
      (SCTs) are performed in closely co-operating centres for haematological intensive
      care, and these centres are required to have a license from the government. The
      introduction of non-myeloablative SCT, exploiting the immunological effects of
      donor T cells, extends the variety of diseases for which SCT is a useful
      treatment option, as well as extending the age limits. The capacity of the
      centres appears to be sufficient, but their finances are not. This, together with
      strict adherence to accepted indications, is probably one of the main reasons why
      the number of SCTs performed in the Netherlands is rather low as compared to
      other European countries. The Council stresses that the harvesting and handling
      of umbilical cord stem cells is a public rather than a private matter, with the
      purpose of creating a bank for these preparations from which patients may benefit
      if the need so dictates. The Council pleads for support to advance the basic
      research on stem cells and the immunological aspects of stem cell
      transplantation.

PMID- 15015246
TI  - [Job-sharing in postgraduate medical training: not automatically a nice duet].
AB  - Part-time work is an increasingly common phenomenon amongst medical
      professionals. Therefore many postgraduate training programmes for resident
      physicians also offer the opportunity of part-time work, which is usually in the
      form of an 80% full-time equivalent post. A new initiative has created the
      possibility of job-sharing, in which each of the participants fulfills 50% of one
      training position. Although the experience of the participants is mainly
      positive, it is unclear how this development will impact the quality of patient
      care and how it will affect the fulfillment of the training objectives. A more
      systematic evaluation of job-sharing in postgraduate medical training programmes
      is required to clarify these points.

PMID- 15015247
TI  - [The Dutch Institute for Health Care Improvement (CBO) guideline for the
      diagnosis and treatment of aspecific acute and chronic low back complaints].
AB  - Under the auspices of the Dutch Institute for Healthcare Improvement (CBO), a
      guideline has been developed for the diagnosis and treatment of aspecific low
      back pain, based on the recent scientific literature. So-called 'red flags' are
      used to identify physical disorders. To obtain insight into psychosocial factors,
      'yellow flags' are used. Acute low-back pain (0-12 weeks) is treated in a time
      contingent manner. Staying active is better than bed rest. If chronicity
      threatens, exercise therapy can be advised. As part of an activating management,
      manipulation can be used. For pain relief, paracetamol is the drug of choice. The
      treatment of chronic low-back pain is aimed at the optimisation of the patients'
      functionality. Staying active is preferred here as well. Varied exercise therapy
      is advised. Back training may be considered. Manipulation can be used as part of
      an activating management. Paracetamol is preferred for pain relief. There is a
      limited role for percutaneous lumbar facet denervation. Behaviour therapy can be
      employed and there is a place for multidisciplinary programmes if other methods
      of treatment have proved insufficiently effective.

PMID- 15015248
TI  - [Teledermatological consultation].
AB  - Teledermatological consultation can be effected in two ways. One is 'store-and
      forward' which involves storing photographic digital images and sending them to a
      consultant dermatologist who then replies by e-mail, and the other is by
      videoconferencing using a real time interactive audiovisual link. In daily
      general practice the first method is the easiest to implement. In 76-90% of
      cases, a diagnosis or differential diagnosis made in this way corresponds with
      the diagnosis made at the more usual face-to-face examination. The advantage of
      teledermatological consultation is that diagnosis and therapy take place faster
      than after regular referral and it is better than no referral at all. The
      referring physician should deliver data on the patient's history and physical
      examination in a standardized format. The same is true for the encoded personal
      data, the working diagnosis, and referral request. One overview and 2 detailed
      photos from two angles are normally taken. The overview shows the extent and
      localization of the skin abnormality. The patient has to consent to a
      teledermatological consultation. The responsibility for the treatment lies with
      the doctor who sees the patient face-to-face. The data that is transmitted must
      be encrypted or coded in such a way that it cannot be traced back to one
      particular person.

PMID- 15015249
TI  - [Diagnostic image (176). A man with a black thumb. Necrosis of the thumb as a
      symptom of rheumatoid vasculitis].
AB  - A 72-year-old man presented with necrosis of the thumb as a symptom of rheumatoid
      vasculitis.

PMID- 15015250
TI  - [Cystadenomas with ovarian stroma in liver and pancreas: indications of embryonic
      migration of the gonadal epithelium].
AB  - OBJECTIVE: To provide an embryological explanation for the presence of ovarian
      stroma in cystadenomas of the liver and pancreas. DESIGN: Investigation of
      patients and embryos. METHOD: From 1997 to 2001 in the Academic Medical Centre,
      Amsterdam, the Netherlands, nine women were treated for a cystadenoma with
      ovarian stroma, six of which were situated in the liver and three in the tail of
      pancreas. In one patient with a cystadenoma in the liver, malignant changes had
      taken place. In embryos at 5-8 weeks development, the regional differences in the
      morphology of the epithelium of the peritoneal cavity and the position of the
      gonads in relation to the embryonic liver, pancreas and spleen were examined.
      RESULTS: In the foetal period before the gonads begin to descend, they are
      situated directly dorsal to the liver, tail of pancreas and spleen, but are
      separated from these by the peritoneal cavity. The cells that cover the
      urogenital folds distinguish themselves from those elsewhere in the peritoneal
      cavity as they are bulging in shape as opposed to flattened. This activated
      morphology suggests that on physical contact with a neighbouring organ the cells
      covering the gonads may become detached and lodge in that organ. CONCLUSION: It
      is likely that cystadenomas of the liver and pancreas have their origin in the
      cells that cover the embryonic gonads. The anomalous morphology of these covering
      cells in fact suggests that they are relatively easily mobilized. They are
      probably comparable with inoculation metastasis in the coelomic cavity. Taking
      the chance of malignant transformation of a cystadenoma into account, the
      treatment of choice is radical resection of the abnormality.

PMID- 15015251
TI  - [Bronchocentric granulomatosis and mycoplasmal pneumonia].
AB  - A 61-year-old man presented with dyspnoea, chest pain, high fever and rigour.
      Chest X-ray revealed a combination of alveolar consolidations and abnormal
      nodular and interstitial markings. His clinical condition deteriorated despite
      treatment with antibiotics prescribed on a working diagnosis of pneumonia with an
      atypical pathogen. Finally, an open-lung biopsy specimen showed the
      characteristic picture of bronchocentric granulomatosis. Serological testing
      supported a primary infection with Mycoplasma pneumoniae. The patient responded
      well to treatment with prednisolone and erythromycin and five months after
      discharge, no radiological abnormalities were found. The combination of
      bronchocentric granulomatosis and mycoplasmal pneumonia has never been described
      in the literature and a causal relation can only be suggested. This case-report
      illustrates the importance of invasive diagnostic procedures if a patient with a
      clinical pneumonia fails to respond to adequate treatment.

PMID- 15015252
TI  - [Part-time medical specialist training; experiences with job-sharing for trainee
      internists].
AB  - Due to various factors such as social changes, an increasing number of couples
      with two incomes, and a growing proportion of female doctors, there has been a
      growing demand for part-time work in recent years. This is also true for resident
      physicians. Objections such as a discontinuity in care and the decline in the
      quality of education frequently prevent resident physicians from working part
      time. Over the past two years, the University Medical Centre Nijmegen, the
      Netherlands, has experimented with job-sharing on clinical wards for resident
      physicians in internal medicine. This approach works well in practice, as long as
      a number of conditions, including the proper transfer of medical information and
      good communication, are satisfied. Job-sharing is one means of satisfying the
      growing demand for part-time work among resident physicians and specialists.

PMID- 15015253
TI  - [Increased serum activity of creatine kinase: usually not a sign of disease].

PMID- 15015254
TI  - [Severe chronic obstructive pulmonary disease in young women who smoke].

PMID- 15015255
TI  - [Leopold Meyler (1903-1973): a pioneer in the field of side affects of drugs].

PMID- 15015256
TI  - [Establishment of the national macro-management system on Chinese medicinal
      resource--base of the modernization for Chinese medicine].
AB  - OBJECTIVE: To establish a national management system on the utilization and
      protection, reserves and wastes of Chinese medicinal resources, and provide a
      scientific basis for the national administering authorities for the macro
      management. METHOD: Many modern high technologies of community ecology,
      statistics, 3S technologies (remote sensing RS, geographic information system
      GIS, global positioning system GPS) and computer information system were based
      upon, and a national monitoring and protection system for the Chinese medicinal
      resources was set up. RESULT AND CONCLUSION: The national Chinese medicinal macro
      management system will integrate modern high technologies with administrative
      supervision, so as to protect Chinese medicinal resources and economy towards a
      sustainable utilization and development, and finally make our country and people
      more prosperous and powerful.

PMID- 15015257
TI  - [Cataplasma of traditional Chinese medicine].
AB  - The TCM (traditional Chinese medicine) transdermal plaster (also known as
      "cataplasma") are flexible adhesive patches used for treatment of pain, resulted
      from arthritis, sprain and bruise, tendovaginitis, lumbar spine protrude,
      neuralgia, hyperosteogeny ache, abdominal discomfort and metastatic cancer, etc.
      Since the 1980's, investigators in China have used this modern patch delivery
      system for herbal drugs and obtained satisfactory results especially from the
      treatment of various types of pain associated with bone diseases, abdominal
      discomfort, and tumors, etc. The production of TCM cataplasma was successfully
      scaled up in early 90's and the commercial product line for an antirheumatic
      agent was first established in Shanghai by Leiyunshang Group. Thus far, a number
      of products in the form of TCM cataplasma became commercially available in the
      market, and clinical investigations with these products indicated that topically
      applicable herbal preparations, especially in the form of cataplasma, are
      preferred formulations with respect to the treatment comfort of the patient.
      Compared to the traditional preparations which utilize rubber and rosin as
      adhesives, cataplasma is advantageous in that the lipophilic and hydrophilic
      ingredients of the herbal extracts are solubilized and then "gellified" with the
      organic polymers, and that the drug matrix containing up to 40%-70% of water
      serves as a "drug reservoir" that will sustain the quick and continuous release
      of herbal ingredients over several days across the skin. While there are
      conventional remedies for palliation of pain and discomfort associated with bone
      diseases or cancers, administration of oral medicinal herbs combined with topical
      agents such as TCM cataplasma may significantly alleviate the symptoms and
      improve their quality of life. This article provides a review on three aspects,
      which include the process development, characteristics and developmental status
      of TCM cataplasma, and future development of such a technology.

PMID- 15015258
TI  - [Study on the origin of Rana temporaria for quality Oviduetus Ranae].
AB  - OBJECTIVE: To determine the origin of Rana temporaria for quality Oviduetus Ranae
      in the light of historical documents and modern researches on the classification
      of Rana temporaria chensinensis. METHOD: Works of Chinese meteria medica of all
      ages, related historical documents and reports from home and abroad on researches
      of R. temporaria chensinensis were consulted, sorted out, analyzed and
      summarized. RESULT: The original Shange recorded in the works of Chinese meteria
      medica is R. temporaria chensinensis, which is the independent species, not one
      of species of European forest frogs. R. temporaria chensinensis is divided into 4
      subspecies: R. temporaria chensinensis, Lanzhou, Kangding, and Changbaishan. The
      origin of R. temporaria is Changbaishan subspecies of R. temporaria chensinensis.
      CONCLUSION: Changbaishan subspecies of R. temporaria chensinensis is determined
      as the origin for quality Oviduetus Ranae.

PMID- 15015259
TI  - [Preservation of germplasm of Rehmannia glutinosa in vitro].
AB  - OBJECTIVE: To establish a method for the germplasm preservation of R. glutinosa.
      METHOD: Plantlets of different cultivars obtained by tip culture were inoculated
      into test tubes with MS medium supplemented with 0.2 mg.L-1 BA and 0.02 mg.L-1
      NAA, and preserved at 4-6 degrees C in dark. At the same time, different media
      (A. distilled water + 10 g.L-1 agar; B. 1/2 MS + 5 g.L-1 agar; C. MS + 10 g.L-1
      agar; D. 1/2 MS + 0.5 BA + 0.02 NAA + 10 g.L-1 agar; E. MS + 0.5 BA + 0.02 NAA +
      10 g.L-1 agar) were set to conserve plantlets of "85-5" on the same condition.
      RESULT: 4 months later, the death rate of "Xinggeda" was 73%, "Tucheng" 60%, "85
      5" 33%, and "Beijing 1" 9%. All of the plantlets of "85-5" in different media
      kept alive. 10 months later, most of the preserved plantlets browned and wilted
      except those on medium A. CONCLUSION: The low temperature endurance of R.
      glutinosa is cultivar-dependent. Medium A can preserve "85-5" for more than 10
      months in vitro.

PMID- 15015260
TI  - [Studies on organ phytomorphology of leaves from Rehmannia glutinosa].
AB  - OBJECTIVE: To set up the fittest medium and optimum condition for leaves from
      Rehmannia glutinosa to form regenerated plantlets directly and to induce
      microtubers. METHOD: Leaves of different phases obtained from the virus-free
      plantlets were incubated in some kinds of media on the back side. RESULT AND
      CONCLUSION: The fittest medium for the formation of regenerated plantlet was MS +
      6-BA 2.0 mg.L-1 and the fittest medium for the induction of microtuber was MS + 6
      BA 1.0 mg.L-1 + NAA 0.5 mg.L-1. The optimum incubation temperaue was 25 degrees C
      and the light length was (2,000-3,000 lx) 12 h.d-1.

PMID- 15015261
TI  - [Presearch on preventing the medicinal plant diseases with Trichoderma harzianum
      preparation].
AB  - OBJECTIVE: To control the medicinal plant diseases with the preparation of
      Trichoderma harzianum. METHOD: Antagonistic action of the preparation to the
      pathogens of the medicinal plants in vitro, and controling effects of the
      preparation on these diseases in greenhouse and in the field were tested. RESULT:
      The test in vitro showed that Trichoderma harzianum, used as a biocontrol factor,
      had stronger antagonistic action to Fusarium equiseti, Sclerotinia sp. and
      Rhizoctonia solani which were the medicinal plant pathogens of Astragalus
      membranaceus, Glehnia littoralis and Panax quinquefolium respectively. Biological
      controling effects on sclerotium root rot of Glehnia littoralis were 83.6% and
      72.5% respectively in greenhouse and in the field with the preparation of
      Trichoderma harzianum. And controling effects on root rot of Astragalus
      membranaceus and seedling damping-off of Panax quinquefolium were 80% and 60%
      respectively in the field. The dosage of the preparation used in the field was 10
      g.m-2. CONCLUSION: The preparation of Trichoderma harzianum can be used as a
      substitute for such chemicals as Carbendazim. Using the preparation to control
      medicinal plant diseases provides a technical safeguard for the good agricultural
      practice of medicinal plants.

PMID- 15015262
TI  - [Study on selective breeding of medicinal Chrysanthemum morifolium].
AB  - OBJECTIVE: To investigate botanical characters and yield of four cultivars of
      Chrysanthemum morifolium for further study on their genetic diversity and
      selective breeding. METHOD: The characters were observed and yield was
      investigated by field randomized block and analysis of variance. RESULT AND
      CONCLUSION: The botanical characters are difference among four cultivars; the
      amount of single flower head is the main factor influencing on the output of
      Chrysanthemum morifolium (r = 0.925); the yield of "Hongxinju" and "Xiaobaiju"
      are remarkably higher than that of "Dabaiju" and "Changbanju".

PMID- 15015263
TI  - [Study on extraction process of zhanjin ruji].
AB  - OBJECTIVE: To select the optimum extraction process of Zhanjin Ruji. METHOD: To
      observe influence of extraction time upon the extraction rate of volatile oil,
      the orthogonal test was adopted to observe the extraction process by alcohol from
      the extraction rate and content of the total saponins in Radix Notoginseng.
      RESULT: The three kinds of herbs including Radix Angelicae Sinensis, Resina
      Olibani and Myrrha were extracted with water for 3 hours, 95% of volatile oil can
      be distilled. The three kinds of herbs including Radix Notoginseng, Herba
      Lycopodii and Radix Gentianae Macrophyllac were extracted by alcohol. Four
      factors such as alcohol concentration(A), extraction times(B), extraction
      time(C), and solvent amount(D), had not significant effect on the content of
      total saponins in Radix Notoginseng in herbal extraction, but factor A and B had
      significant effect on the extraction rate. The optimum extraction process was as
      follows extracted with 5 times the amount of the solvent volum 60% alcohol for 3
      times and with each time for 1 hour. Three times experiments showed that the
      extraction rate was 26.5% and the content of the total saponins in Radix
      Notoginseng was 17.28% mg.g-1. CONCLUSION: The above experimental results can
      provide experimental basis for deciding the extraction process of Zhanjin Ruji.

PMID- 15015264
TI  - [Determination of schisandrin in shengmaiyin by HPLC].
AB  - OBJECTIVE: To determine the concentration of schisandrin in Shengmaiyin with
      HPLC. METHOD: The sample was extracted with ethyl acetate through supersonic
      wave. The solution was filtrated and evaporated. The residue was resolved with
      methanol and determined by HPLC using PHENOMENEX C18 (4.6 mm x 250 mm, 5 microns)
      chromatographic column, methanol-acetonitrile-water (15:15:10) as mobile phase.
      The wavelength for detection was 254 nm. RESULT: The peak of schizandrin appears
      on about 7.10 minutes. The standard curves of schizandrin were linear in the
      concentration range of 0.2-2.0 micrograms, r = 0.9996. The average recovery of
      schizandrin were 100.5% (RSD 2.84%). CONCLUSION: This method was found to be
      sensitive, quick and accurate for the measurement of schizandrin concentrations
      in Shengmaiyin.

PMID- 15015265
TI  - [Flavonoids from rhizome of Alpinia tonkinensis].
AB  - OBJECTIVE: To find out the bioactive principles of Alpinia tonkinensis, by
      investigating its chemical constituents. METHOD: It was extracted with MeOH,
      distributed by different solvents, and isolated via column chromatography on
      silica gel. RESULT: Six compounds were elucidated through spectral analysis,
      which were as follows: 4',7-dimethylkaempferol(I), 5-hydroxy-3',4',7
      trimethoxyflavanone(II), kumatakenin(III), 4',5,7-trimethoxyflavonol(IV),
      ombuine(V), and kaempferol(VI). CONCLUSION: Six flavonoids were isolated from
      this plant for the first time, and so were four compounds from genus Alpinia.

PMID- 15015266
TI  - [Isolation and elucidation of chemical constituents with antiviral action from
      yinqiaosan on influenza virus].
AB  - OBJECTIVE: To study the chemical constituents with antiviral action from
      Yinqiaosan on influenza virus. METHOD: Constituents were isolated by different
      kinds of column chromatography and their structures were elucidated with chemical
      and spectral methods. RESULT: Eleven chemical constituents were isolated and
      elucidated as arctiin, phillyrin, forsythiaside, liquiritigenin, liquiritin,
      genistein, formononetin, daidzein, glycitrin, 3,3',4-tri-omethlellagic acid and
      chlorogenic acid. CONCLUSION: Genistein, daidzein, glycitrin and 3,3',4-tri
      omethlellagic acid were isolated from Yinqiaosan for the first time.

PMID- 15015267
TI  - [Determination of puerarin, daidzin and daidzein in root of Pueraria lobata of
      different origin by HPLC].
AB  - OBJECTIVE: To develop an HPLC method to determine Puerarin, Daidzin and Daidzein
      in Pueraria lobata. METHOD: The separation was performed in a SYMMETRY C18 column
      with a mobile phase of methanol-1% HAC solution (gradient elution), the The
      detection wavelength being 250 nm. RESULT: The average recovery was respectively
      101.7%, 100.7% and 101.7% (n = 3), RSD 0.43%, 0.82% and 1.50% (n = 3) for
      Puerarin, Daidzin and Daidzein. CONCLUSION: This method is suitable for the
      determination of Puerarin, Daidzin and Daidzein in Pueraria lobata and its
      preparation.

PMID- 15015268
TI  - [Study on the anti-apopotosis induced by hypoxia/hypoglycemia and reoxygenation
      of panax notoginseng saponins in cultured rat hippocampal neurons].
AB  - OBJECTIVE: To study the inhibitory effects of Panax Notoginseng Saponins(PNS) on
      apoptosis induced by hypoxia/hypoglycemia and reoxygenation in cultured rat
      hippocampal neurons. METHOD: Apoptosis were measured by flow cytometry,
      intracellular free calcium concentration([Ca2+]i) was measured with confocal
      laser scanning microscopy, morphological changes and neuronal necrosis were
      observed with fluorescence microscope, and meanwhile the leakage of lactic
      dehydrogenase(LDH) was measured. RESULT: Hypoxia/hypoglycemia cultures for 5
      hours and reoxygenation induced neuronal apoptosis and necrosis, and
      significantly increased neuronal [Ca2+]i and the leakage of LDH. The effects were
      increased with the extending time of reoxygenation. PNS has could significantly
      decrease the percentage of neuronal apoptosis and necrosis, and reduce neuronal
      [Ca2+]i and the leakage of LDH. CONCLUSION: PNS has inhibitory effect on neuronal
      apoptosis. This effect might be related to its effect of decreasing intracellular
      free calcium concentration.

PMID- 15015270
TI  - [Effects of musk glucoprotein on chemotaxis of polymorphonuclear leukocytes in
      vivo and in vitro].
AB  - OBJECTIVE: To investigate the effects of Musk glucoprotein on chemotaxis of
      Polymorphonuclear leukocytes(PMN). METHOD: The chemotaxis of PMN in abdominal
      cavity in rat induced by carboxymethyl cellulose(CMC) was used as an in vivo
      animal model and in in vitro it was evaluated by Boyden chamber. The
      concentration of cytosolic free Ca2+ was quantitated with the fluorescent Ca2+
      indicator Fura-2. RESULT: The water extract of Musk at dose of 5, 20, 80 mg.kg-1
      (s.c.) significantly inhibited the chemotaxis of PMN in rat; Musk-1 at
      concentration of 1-100 micrograms.mL-1 can significantly inhibit the chemotaxis
      of rabbit PMN in vitro; Musk-1 at concentration of 1-100 micrograms.mL-1 can
      significantly inhibit the increase of cytosolic Ca2+ concentration in PMN of rat.
      CONCLUSION: Part of mechanisms underlying antiinflammatory action of Musk is to
      inhibit the chemotaxis of PMN.

PMID- 15015269
TI  - [The effects of banxia houpu decoction on a chronic mild stress model of
      depression].
AB  - OBJECTIVE: To study the effect of Banxia Houpu Decoction on a chronic mild stress
      model of depression and investigate the antidepressive mechanism. METHOD: With
      consumption of a 1% sucrose solution as an index, and by subjecting rats to a
      variety of mild stressors for a prolonged period of time, a chronic mild stress
      model was developed. The levels of the blood lipid were measured by blood lipid
      kits, the natural kill (NK) cell activity in the spleen was measured with the
      method of the enzyme lactate dehydrogenase (LDH) released, the superoxide
      dismutase (SOD) activity in red blood cell was assayed by the Autoxidation of
      Pyrogallol method, the NO synthase (NOS) activity in serum and tissue was
      measured by NOS kits, and the content of malondialdehyde(MDA) was measured by MDA
      kits. RESULT: Banxia Houpu Decoction significantly increased the consumption of
      sucrose solution, increased the level of the high density lipoprotein (HDL-C),
      decreased the level of the Triglyceride(TG) in serum, enhanced the activity of
      the NK in spleen, decreased the activity of the SOD in red blood and the activity
      of the NOS in serum and tissue, and reduced the content of MDA in tissue by
      effect on lipid Peroxidation in CNS model of depression. CONCLUSION: Banxia Houpu
      Decoction has antidepressant effect in different ways.

PMID- 15015271
TI  - [Effects of puerarin on fatty superoxide in aged mice induced by D-galactose].
AB  - OBJECTIVE: To study the effect of puerarin on fatty superoxide of aged mice
      induced by D-galactose. METHOD: The aged mice were induced by s.c. 0.12 g.kg-1 D
      galactose for 6 weeks. Meanwhile, they were treated with three doses of puerarin
      once a day for 6 weeks. Then the spontaneous behavior was tested in the aged mice
      using open field at the next day after the last treatment. And the activity of
      SOD, the contents of MDA and lipofuscin in brain, liver, and serum were measured
      with Ultravioletray spectrometer and Fluorospectrophometer analysis system.
      RESULT: Compared with the D-galactose control group, puerarin of 50 mg.kg-1 and
      100 mg.kg-1 puerarin significantly increased the spontaneous behavior, remarkably
      promoted the activity of SOD of brain, liver, and serum in the aged mice, and
      significantly decreased the contents of MDA and lipofuscin. CONCLUSION: Puerarin
      can improve the activity of antioxidase of the modelling aged-mice induced by D
      galactose.

PMID- 15015272
TI  - [Effect of TCTS on experimental endometriosis of rats].
AB  - OBJECTIVE: To study the effect of TCTS on endometriosis rats. METHOD: On the
      model of surgical induced rat endometriosis, weight and pathological changes of
      endometrial transplant and serum hormones were observed. RESULT: Weight of
      endometrial transplants was reduced by TCTS 11.2 g.kg-1 and 22.5 g.kg-1 and
      transplants of TCTS treated rat showed poorly developed epithelium, thinner
      stroma, fewer stromal cells and glands. At the same time elevated serum E2, FSH
      and LH were reduced by TCTS. CONCLUSION: TCTS can inhibit the growth of
      endometrial transplants, which is related with serum hormone, especially E2.

PMID- 15015273
TI  - [Clinical study of effect of tianzhi granule on senile vascular demetia].
AB  - OBJECTIVE: To investigate the clinical effect of Tianzhi Granule (TZK) on senile
      vascular dementia (VaD), which is classified as sthenia of liver-yang. METHOD:
      Two hundred VaD patients were treated with TZK (0.5 g/bag), which was taken one
      bag each, three times a day. The treatment course was one month and they were
      treated for rwo courses. RESULT: TZK could remarkably increase gnosia and
      activity, with no striking difference from that of positive control group (P >
      0.05). Simultaneously, TZK could significantly improve the clinical syndrome of
      traditional Chinese medicine and viability. It could also drastically reduce the
      whole blood and plasma viscosity and improve erythrodegeneration and abnormality
      of aggregation index in the abnormal blood viscosity patients. CONCLUSION: TMC
      has certain effects on senile VaD.

PMID- 15015274
TI  - [Clinical study on treatment of 405 cases of irregular menstruation by tiaojing
      zhixue granules].
AB  - OBJECTIVE: To provide scientific and objective basis for Tiaojing zhixue granules
      treating irregular menstruation of clinical effect. METHOD: Choose 405 cases
      suffering from irregular menstruation and make a systematic study 304 patients
      were treated with Tiaojing Zhixue granules, 101 patients received Fuxuening
      treatment. RESULT: After treatment, the obvious effective rate of Tiaojing Zhixue
      granules was 78.3% and the total effective rate 97.4%, granule cure rate of
      Fuxuening was 38.6% and the total effective rate 87.1%. Comparison showed
      significant difference (P < 0.001). Safety spithetical observation did not
      discover harmful effects and toxicity and side effects antagonize common symptoms
      26 entries of clinical studying, the 7 entry are: weary and tired, short breaths,
      sore loins, weak knees, insomnia and eccessive dreaming, rapid and thready pulse,
      colliquative, distending pain in the lower abdomen and hypochondria. Among them,
      the comparison showed significant difference about treatments(P < 0.01-0.001).
      CONCLUSION: Tiaojing Zhixue granules treatment irregular menstruation are
      scientific and effective.

PMID- 15015275
TI  - [Advances in studies on chemical constituents of Senecio].
AB  - The large cosmopolitan genus Senecio, a perennial medicinal herb of the family
      compositae, has been utilized as a anthmicrobial agent. A variety of
      pyrrolizidine alkaloids and furanoeremophilanes are widespread in the genus
      Senecio, which are responsible for the hepatotoxic and carchnogenic effects. Some
      of them have been screened for anti-tumour activity, but their liver toxicity
      renders their use in chemotherapy. This article reviews the recent advances in
      chemical constituents, identification methods and pharmacological activities of
      it.

PMID- 15015276
TI  - [Advances of polymeric materials applied in TCM preparation and separation].
AB  - In this paper, the advance of polymeric materials applied in the development of
      traditional Chinese medicine (TCM) and natural products was reviewed. Especially
      the research progresses in use of the polymeric membranes, polymeric flocculating
      agents, polymeric sorbents and polymeric drug delivery system (DDS) in the
      separation and preparation of herb and TCM were discussed in details. In
      addition, the future develorment of polymeric materials in TCM preparation was
      also discussed.

PMID- 15015277
TI  - [Advances in the study of Allium macrostemon Bunge].
AB  - OBJECTIVE: To review the progress in the study of chemical ingrediens,
      pharmacological effects and clinical application of Allium macrostemon Bunge.
      METHOD: Documents of experimental and clinical study on A. macrostemon in recent
      10 years were consulted and summarized. RESULT: A. macrostemon had many active
      ingredients, pharmacology effects and wild clinical application. CONCLUSION: The
      results provide a rational foundation for the further development and utilization
      of A. macrostemon.

PMID- 15015278
TI  - Antidiabetic drugs of plant origin used in China: compositions, pharmacology, and
      hypoglycemic mechanisms.
AB  - The paper reviewed compositions and pharmacological effects of eight antidiabetic
      herbal drugs that have been approved by health regulatory agency for commercial
      use in China. Investigators attributed the hypoglycemic effect of these products
      to their ability to restore the functions of pancreatic tissues and cause an
      increase in insulin output, to inhibit the intestinal absorption of glucose, or
      to the facilitation of metabolites in insulin-dependent processes. Treatment with
      herbal drugs has an effect on protecting beta cells and smoothing out
      fluctuations in glucose levels. The use of these naturally derived agents in
      conjunction with conventional drug treatments such as an chemical agent or
      insulin permits the use of lower doses of the drug and/or decreased frequency of
      administration which decreases the side effects most commonly observed.

PMID- 15015279
TI  - [Analysis on the geologic background and physicochemical properties of cultivated
      soil of Flos Lonicerae in the geo-authentic and non-authentic producing areas].
AB  - OBJECTIVE: To study the relationship between the Geo-authentic and Geologic
      Background System (GBS) and physicochemical properties of cultivated soil in the
      Flos Lonicerae. METHOD: The analysis on the physicochemical properties of
      cultivated soil, the geologic background system in 5 producing areas of Flos
      Lonicerae was compared. RESULT: The distribution of genuine Flos Lonicerae was
      restricted by GBS, which was mainly restricted in the temperate continental
      monsoon semi-arid climate zone between north latitude 34-36 degrees and east
      longitude 113-118 degrees. CONCLUSION: The most suitable soil for the genuine
      Flos Lonicerae is the neutral or weak alkali sandy loamy soil with higher ion
      exchanging capacity, and the soils from those producing areas are determined by
      soil-forming parent materials.

PMID- 15015280
TI  - [Study on plant tissue culture of Cornus officinalis].
AB  - OBJECTIVE: To set up the optimums of tissue culture for Cornus officinalis.
      METHOD: A section of stems of the fine varieties of Cornus officinalis were
      strictly sterilized, cultivated and geminated in medium with addition of
      different kinds of hormone. RESULT AND CONCLUSION: The WPM medium with 6-BA 2.0
      mg.L-1 + ZT 0.1 mg.L-1 + NAA 0.1 mg.L-1 was the optimum medium for the
      multiplication of adventitious buds. The WPM medium with 6-BA 1.0 mg.L-1 + ZT 0.1
      mg.L-1 + GA3 0.5 mg.L-1 + NAA 0.1 mg.L-1 was the optimum medium for cultivation
      in strength. The plantlet could root well in 1/2 MS medium with IBA 1.0 mg.L-1 +
      6-BA 0.1 mg.L-1.

PMID- 15015282
TI  - [Study on gallnuts development and its tannin amount].
AB  - OBJECTIVE: To find out the suitable time for collecting gallnuts. When Kaburgaia
      rhusicola parasailed on leaflets of Rhus potainii, the parts of the leaflets
      developed into gallnuts. METHOD: The regulation of development and tannin amount
      during whole growing stage were studied. RESULT: K. rhusicola lived in gallnuts
      for about 80 days. The gallnuts developed quickly during earlier stage and slowly
      during later stage. Gallnuts maturated from 12th, July to 30th, July, which had
      no relations with the size and the time for forming, but had relations with
      development at earlier stage. It developed quickly with earlier maturation and
      developed slowly with later maturation. Its tannin amount kept stable during the
      whole growing stage. CONCLUSION: The best harvesting days are those shortly after
      7th, July.

PMID- 15015281
TI  - [Study on the soil fertility changes in planting base to develop the special
      fertilizer for cultivation of Chrysanthemum morifolium].
AB  - OBJECTIVE: To study the changes of soil fertility in Sheyang county where
      Chrysanthemum morifolium has been cultivated for more than 30 years and to
      develop the special fertilizer for cultivation of C. morifolium. METHOD: The pH
      values, organic matter and the contents of total and available N, P, K and Zn in
      the soil layer of 0 to 40 cm, as well as the total N, P, K and Zn contents in the
      flowers, roots, stems and leaves of the plants, were analysed. The balanced
      fertilization plan for cultivation of C. morifolium was put forward. In addition,
      the formula of special fertilizer for cultivation of C. morifolium was determined
      according to flower yield and utilization rate of N, P, and K. RESULTS AND
      CONCLUSION: The soil had high pH values and high soil salt contents, with
      unbalanced application of N, P, and K fertilizers and a shortage of available Zn
      after cultivation of C. morifolium. The contents of soil organic carbon, N and P
      declined with increasing cultivation time of C. morifolium, which resulted from
      the improper rotations and fertilization. The balance fertilization practice and
      the special fertilizer utilization are effective ways to improve soil fertility
      for C. morifolium.

PMID- 15015284
TI  - [Study on process of removing impurity from water-extraction of gutianquan
      capsule].
AB  - OBJECTIVE: To study the result of removing impurity from water-extraction of
      Gutianquan-capsule with macro-reticular absorbing resin, chitosans clarification,
      water-extraction and alcohol-precipitation methods. METHOD: Coefficient of
      Unguent of macro-reticular absorbing resin, chitosans clarification method, water
      extraction and alcohol-precipitation methods were compared, and qualitative assay
      of Ginsenoside Rg1, Re, and snide measurement of Ginsenoside Rg1, Ferulic acid,
      and stability experiment were made. RESULT: Coefficient of Unguent of water
      extraction and alcohol-precipitation method was 17.2%, Coefficient of Unguent of
      chitosans clarification method was 12.8%, and macro-reticular absorbing resin
      method was 3.1%. They could clarify liquor of water-extraction. CONCLUSION:
      Chitosans clarification method is suitable for process of Gutianquan-capsule.

PMID- 15015283
TI  - [Effects of processing on contents of saccharides in huangqi].
AB  - OBJECTIVE: To explore the effect of processing on the contents of saccharides in
      Huangqi. METHOD: The contents of reducing saccharides, water-soluble saccharides
      and poly saccharides in Huangqi and its processed products were determined with
      phenol-H2SO4 method. RESULT: The contents of poly saccharides in the alcohol
      broiled product were the highest of all the products. The others were all higher
      than those in the crude drug. CONCLUSION: Different processing methods result in
      different effects on the above saccharides, which administers to the
      interpretation of the theory of Huangqi processing.

PMID- 15015285
TI  - [Determination of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside in yangan
      oral liquid by HPLC].
AB  - OBJECTIVE: To establish the determination method of 2,3,5,4'-tetrahydroxystilbene
      2-O-beta-D-glucoside in Yangan Oral Liquid. METHOD: 2,3,5,4'-tetrahydroxystilbene
      2-O-beta-D-glucoside was determined by HPLC on C18 column, in acetonitrile-water
      (14:86) solution as a mobile phase, detection wavelength as 320 nm. RESULT: This
      method showed a good linear relationship. The average recovery was 99.05% and RSD
      was 1.31%. CONCLUSION: The method was simple with styong specificity and good
      repriducibility and can be used for quality control for Yangan Oral Liquid.

PMID- 15015286
TI  - [Studies on new trierpenoid constituents from the Rhizoma of Cimicifuga foetida].
AB  - OBJECTIVE: To find new active constituents from Rhizome of Cimicifuga foetida.
      METHOD: Various column chromatographic techniques were employed for isolation and
      purification. The structures were elucidated on the basis of spectral and
      chemical evidences. RESULT: Four triterpenoid compounds were isolated and
      identified as 7,8-didehydro-27-deoxyactein(1), 24-O-acetylshengmanol-3-O-beta-D
      xyl (23R, 24R)[2], cimigenol(3), cimigenol-3-O-beta-D-xyl(4). CONCLUSION:
      Compound 1 is a new compound, 2-4 were obtained from this medicinal material for
      the first time. The antiosteoporosis activity screening in vitro(by the method of
      SRB) indicates that Compounds 1, 2 and 4 can promote the proliferation for rat
      Osteoblastoma cell line (UMR106) at the concentration of 10(-9) kg.L-1.

PMID- 15015287
TI  - [Studies on chemical constituents from the stems of Schisandra sphaerandra].
AB  - OBJECTIVE: To investigate the chemical constituents from the stems of Schisandra
      sphaerandra. METHOD: Compounds were isolated from ethanolic extract of the titled
      herb by silica gel column chromatography, and their structures were elucidated by
      physical and chemical evidences and spectroscopic analysis. RESULT: 12 compounds
      were obtained and identified as wuweizisu C (1), ganwuweizic acid (2), nigranoic
      acid (3), catechin (4), 2 alpha,24-dihytroxyursolic acid. (5), 3 beta-O
      acetylursolic acid (6), ursolic acid (7), slyceryl 26-hydroxyhexacosanoate (8),
      slyceryl hexacosanoate (9), fat acids (10), beta-sitosterol (11), daucosterol
      (12), respectirely. CONCLUSION: Three pentacyclic triterpene carboxylic acid (5
      7) were isolated from Schisandreae for the first time.

PMID- 15015288
TI  - [Studies on chemical constituents from the bark of Morus macroura].
AB  - OBJECTIVE: To study the chemical constituents from the bark of Morus macroura.
      METHOD: The compounds were isolated with silica gel column chromatography and
      their structures were elucidated on the basis of chemical evidences and spectral
      analysis (IR, EI-MS, 1H-NMR, 13C-NMR). RESULT: Five compounds were identified as
      alpha-amyrin acetate (1), gult-5-en-3 beta-yl acetate (2), 3 beta-hydroxylup-20
      (29)-en-28-oic acid (3), 3 beta-hydroxylup-12-en-28-oic acid (4), butyrospermol
      acetate (5).

PMID- 15015289
TI  - [Chemical pattern recognition in the Rhizoma of Atractylodes macrocephala].
AB  - OBJECTIVE: To establish chemical pattern recognition method for the
      identification and evaluation of Atractylodes macrocephala. METHOD: The chemical
      constituents in methanol extract of 32 samples of A. macrocephala were determined
      by HPLC. The fingerprints were obtained and were handled by hierarchical
      clustering analysis and stepwise discriminant analysis. RESULT AND CONCLUSION:
      According to the result of classification, all samples collected were devided
      into three Grades--the superior, the ordinary and the fake. Chemical pattern
      recognition method was established. It may be of practical value for the quality
      control of A. macrocephala.

PMID- 15015290
TI  - [Identification of volatile components in rat urine after oral administration of
      "wu-hu-tang"].
AB  - OBJECTIVE: To identify the volatile components in rat urine after oral
      administration of "Wu-Hu-Tang" (WHT). METHOD: GC-MS technique was applied to
      analyzing urine samples. RESULT: Eighteen components were detected in the WHT
      treated rat urine other than the corresponding control. Among them, 14 components
      were identified, and 7 were also found in the extract of WHT. CONCLUSION: The
      above detected components might be derived from WHT, and some of them are
      effective components of WHT.

PMID- 15015291
TI  - [Effects of Angelica sinensis polysaccharides on hepatic drug metabolism enzymes
      activities in mice].
AB  - OBJECTIVE: To study the effects of Angelica sinensis Polysaccharides (ASP) on the
      hepatic drug metabolism enzymes activities in normal mice and those prednisolone
      (PSL)-induced liver injury. METHOD: The activities of phase II enzymes (GSH
      related enzymes) and cytochrome P450 enzymes were measured by biochemical method.
      RESULT: ASP increased the activities of glutathione S-transferase in liver
      microsomes and mitochondria. The cytochrome P450 content, NADPH-cytochrome c
      reductase, aminopyrine N-demethylase, and aniline hydroxylase activities in liver
      microsomes were also increased. PSL significantly increased serum ALT levels, and
      decreased the liver mitochondrial glutathione content. At the same time, other
      enzymes activities were all increased. When mice were treated with ASP 2.0 g.kg
      1, the PSL-induced changes on cytochrome P450 enzymes, glutathione S-transferase,
      and GSH content were restored. CONCLUSION: ASP can modulate the activities of
      drug metabolism enzymes.

PMID- 15015292
TI  - [Effect of SS8, the active part of Spatholobus suberectus Dunn, on proliferation
      of hematopoietic progenitor cells in mice with bone marrow depression].
AB  - OBJECTIVE: To investigate the effect of SS8, a monomer extracted from Spatholobus
      suberectus Dunn used for invigorating the circulation of blood, on proliferation
      of hematopoietic progenitor cells in mice with bone marrow depression. METHOD:
      The method of semi-solid culture with methylcellulose of CFU-GM, CFU-E, BFU-E,
      CFU-Meg was adopted in bone marrow depressed mice which were treated with SS8 for
      a long time. RESULT: The experimental data demonstrated that the numbers of CFU
      GM, CFU-E, BFU-E, CFU-Meg in bone marrow depressed mice were raised distinctly
      under the control of SS8 as compared with those of contrast group. The effect of
      SS8 became stronger as time went on and the dosage rose. CONCLUSION: SS8 can
      distinctly stimulate the proliferation of hematopoietec progenitor cells in mice
      with bone marrow depression in a time-and-dosagedependent manner.

PMID- 15015293
TI  - [Effect of Astragalus membranaceus on baroreflex sensitivity in spontaneously
      hypertensive rats].
AB  - OBJECTIVE: To observe the chronicity decompression effect of Astragalus
      Membranaceus(AM) and evaluate the effect on baroreflex sensitivity (BRS). METHOD:
      Nineteen spontaneously hypertensive rats(SHR) were randomly divided into four
      groups. The AM groups were intraperitoneally administered with AM parenteral
      solution 0.9 mL, 1.2 mL and 1.8 mL respectively and the control group was not
      given AM for eight weeks. Then the change of blood pressure was observed
      successivly. After eight weeks, BRS were also determined. At last, the difference
      of blood pressure and BRS among the groups were compared. RESULT: Blood pressure
      in the control group became higher and higher frome the third week to the eighth
      week, but the other SHR admistered with AM showed no changein blood pressure
      level. We also found that the BRS in AM group was higher than that in the control
      group(P < 0.01). CONCLUSION: AM can promote the BRS in SHR.

PMID- 15015294
TI  - [Effect of the compound of traditional Chinese drugs on gene expression of renal
      endothelin and its receptor of experimental diabetic nephropathy].
AB  - OBJECTIVE: To study the effect of the Compound of traditional Chinese drugs and
      Benazepril on gene expression of renal endothelin and its receptor of
      experimental diabetic nephropathy(DN). To discove the mechanism of the compound
      of traditional Chinese drugs in treating DN. METHOD: Streptozotocin DN model was
      built and influenced with the compound of traditional Chinese drugs and
      Benazepril. The changes of Upro, Glu, HbA1C and (PT-PCR) mRNA expression levels
      of ET-1, ETA-R of the renal cortex were tested, and thus the histopathological
      character of the kidney was analysed. RESULT: The compound of traditional Chinese
      drugs and Benazepril have significant difference from normal saline in the
      improvement of Upro, Glu, HbA1C. The compound of traditional Chinese drugs have
      significant difference from Benazepril in the improvement of Glu, HbA1C. The mRNA
      expression level of ET-1, ETA-R of the renal cortex of DN model was raised. After
      influenced by the compound of traditional Chinese drugs and Benazepril, the over
      expression level de-creased (still higher than normal control ones). The compound
      of traditional Chinese drugs were more effective than Benazepril to inhibit the
      proliferation of the stalk region and the third cells. CONCLUSION: ET takes part
      in the process of diabetic glo-Merulosclerosis. Both the compound of traditional
      Chinese drugs and Benazepril can influence the expression quantity from the level
      of gene transcription of ET and its receptor. The compound of traditional Chinese
      drugs can not only reduce urinary albumin of DN, but also improve blood glucose,
      glycosylated hemoglubin. And it can inhibit nonenzymatic glucosylation of protein
      as well as the proliferation of the stalk region and the third cells.

PMID- 15015295
TI  - [The effects of Erigeron breviscapus preparation on the imaging and neuronal
      metabolites at the early time points after reperfusion following the ischemic
      cerebral injury in rats].
AB  - OBJECTIVE: To investigate the effects of Erigeron breviscapus preparation on the
      imaging and neuronal metabolites after reperfusion in the ischemic cerebral
      injury in rats. METHOD: Twenty-three male Sprague Dawley rats with an average
      body weight of (165 +/- 15) g (mean +/- S) were used, and were randomly divided
      into two groups: group A rats (n = 11) underwent an operation of ischemic brain
      injury, group B rats (n = 12) underwent the same operation and received the
      treatment of Erigeron breviscapus preparation (1.5 mg.kg-1 weight, i.p.). The
      right middle cerebral artery occlusion (MCAO) of rats in both groups was induced
      by 5/0 nylon suture for 2 hours. The reperfusion was conducted for four hours and
      six hours respectively following MCAO. T2 weighted-imaging (T2WI) and 1H-magnetic
      resonance spectroscopy (1H-MRS) were performed, to study the changes of the
      imaging and the neuronal metabolites N-acetyl aspartate (NAA),
      creatine/phosphocreatine (Cr/PCr), choline (Cho) and lactose (Lac) in cerebrum
      following cerebral ischemia. RESULT: The hyperintense signals in the right
      cerebrum in group B decreased compared with those in group A, the T2 values
      decreased, the level of NAA increased, the ratio of Cr/NAA and Cho/NAA decreased,
      and no lactose was observed. The brain surface vessels of rats in group B were in
      the state of dilation. CONCLUSION: Erigeron breviscapus preparation is beneficial
      to the reestablishment of the blood circulation in the ischemic brain, and to the
      improvement of the neuronal metabolism and survival.

PMID- 15015296
TI  - [Progress on research of rapid propagation system of Pinellia ternata].
AB  - OBJECTIVE: To improve the rapid propagation system of Pinellia ternata. METHOD:
      Documentaries at home and abroad were consulted. RESULT: The tissue culture's
      conditions and research results of P. ternata were summarized. CONCLUSION:
      Advanced research on the structure of calli and litter tubercle should be made.
      Traditional rapid propagation system may be improved from the following aspects:
      the best cooperation of hormones, the most active ex-plant, one time culture and
      suitable transplant.

PMID- 15015297
TI  - [Advance of chemical constituents and bioactivity of Saururuaceae plants].
AB  - Essential oil, flavonoids, alkaloids and lignas were isolated from Saururuaceae
      plants. They possesses antibacteral, antiviruses, antiinflammatory. Inhibitory of
      plaleted aggregation activites and exhibit significant neuroleptic activity.

PMID- 15015298
TI  - [The current status of the determination of the bacterial endotoxin in
      traditional Chinese medicine].
AB  - OBJECTIVE: To review the current status of the determination of the bacterial
      endotoxin in traditional chinese medicine injections with the limulus lysate
      test, and to evaluate the feasibility of this test for the determination of the
      bacterial endotoxin in these injections. METHOD: The data related to the topic
      was collected, analyzed and summarized. RESULT: The limulus lysate test was not
      available for most of traditional chinese medicine injections due to the
      interference. And the same injection may uield different test results because of
      different factories, batch numbers, different techniques and preparational
      conditions. CONCLUSION: There is still a long way to go to apply the limulus
      lysate test to the determination of the bacterial endotoxin in traditional
      chinese medicine injections.

PMID- 15015299
TI  - [Study on licorice resources and their sustainable utilization in center and
      western area of China].
AB  - OBJECTIVE: To investigate the latest wild and cultivated licorice resource
      status; bring forward the licorice resource protection and sustainable
      utilization countermeasures in the center and western area of China. METHOD: With
      study both in interview survey and field survey. RESULT: All samples investigated
      were the species of Glycyrrhiza uralensis. Human actions is concerned with the
      community status, reserves per unit and quality. Excessive exploitation made the
      licorice quality lower and reserves decrease. CONCLUSION: Enforcing the wild
      licorice resource protection and improving licorice cultivated technique are
      brought forward to act as the sustaining countermeasures.

PMID- 15015300
TI  - [Analyses on the trace elements of soils in geo-authentic and non-authentic
      production areas of Flos lonicearae].
AB  - OBJECTIVE: To analyse the trace elements presented in the same germplasm of Flos
      Lonicerae with the soil in different producing areas of crude drugs and to
      investigate, the relationship between the trace elements and the characteristics
      of the geo-authentic Flos Lonicerae in the soil and crude drugs. METHOD: The
      analyses on the trace elements of soil and crude drugs were made by ICP-AES.
      RESULT: The contents of Sr, K, Na, Mg and Ca were higher in the geo-authentic
      areas, and the contents of Ca, Sr and Fe were higher, but the Cr and Pb were
      lower in the geo-authentic Flos Lonicerae. The geo-authentic crude drugs had a
      strong tendency to accumulate P and Cu. CONCLUSION: There are no direct
      relationship between the concentrations of trace elements in Flos Lonicerae and
      those in their corresponding soil. There are good relationship between the
      absorption and accumulation of Ca and Cr, Co, Na and Fe; Zn and Co, Cr, Mn; Na
      and Co; Mg and Mn.

PMID- 15015301
TI  - [Studies on callus induced from leaves and plantlets regeneration of the
      traditional Chinese medicine Chrysanthemum morifolium].
AB  - OBJECTIVE: To set up the optimums for the leaf tissue culture of Chrysanthemum
      morifolium cultivated in Anhui Province. METHOD: Leaves were cut and cultured
      onto the same kind of media on different sides and defferent kinds of media on
      the same side, and induced to form the whole plantlet. RESULT AND CONCLUSION: All
      the media used could induce callus, while the results of callus redifferentiation
      were very distinct. The media with NAA 0.1 mg.L-1 + 6-BA 0.1-1.0 mg.L-1 were much
      better than others when callus were induced. The MS medium with 6-BA 2.0 mg.L-1
      and NAA 0.5 mg.L-1 was the preferable medium for the bud sprouting. The
      regenerated plantlets produced variation of leaf shape.

PMID- 15015302
TI  - [The study of characteristics of absorption and separation of different glycoside
      on macropore resins].
AB  - OBJECTIVE: To study the absorption and separation of different glycoside on
      different macropore resins. METHOD: Take baikal skullcap root, cape jasmine fruit
      and white peony root as samples and study the different characterstics of
      absorption and separation of these samples on macropore resins such as D101 and
      so on. RESULT: The static absorption effect of the the three aglycones on six
      different macropore resins is baicalin > lactiflorin > gardoside. Their elution
      are 75% CH3OH, 25% CH3OH, and 45% CH3OH. Their elution rates are 60%, 93%, and
      93%. CONCLUSION: Similar molecules may not have similar absorption abilities on
      same macropore resins, but the effect of absorption has something to do with the
      structures of the molecules, the more double-bonds the molecules have, the
      greater the absorption force the resins have.

PMID- 15015304
TI  - [Studies on stability of chlorogenic acid in extract of Flos lonicerae].
AB  - OBJECTIVE: To investigate the stability of chlorogenic acid in extract of flos
      lonicerae in different conditions. METHOD: The stability of chlorogenic acid in
      extract of flos lonicerae in phosptat buffe with different pH values, methanol,
      ethanol and different base solutions(Ca(OH)2 and NaOH) was investigated by the
      classical isothermal method. RESULT: The experiments showed the chlorogenic acid
      in extract of flos lonicerae was more stable in acidic water than in basic water.
      It was stable in these organic solutions and base solution[Ca(OH)2]. CONCLUSION:
      In different conditions, the stability of chlorogenic acid in extract of flos
      lonicerae was different. It provided a reference to the extraction and analysis
      of chlorogenic acid and production of chlorogenic acid preparation.

PMID- 15015303
TI  - [Studies on variation of danshensu content in accelerated stability tests].
AB  - OBJECTIVE: To study the variation Laws of content of danshensu accelerated in
      control and in danshen injection in order to provide reference for stability
      investigation of danshensu. METHOD: The tests was carried out by classic
      isothermal method and the content of danshensu was determined by HPLC. RESULT:
      The contents of danshensu in accelerated tests increase in control and decrease
      in danshen injection respectively. CONCLUSION: The component of phenic acidity
      would be hydrolyzed to become danshensu in the accelerated tests. Much attention
      should be paid to the unusual increase when studies of danshen preparations are
      carried out.

PMID- 15015305
TI  - [Study on recovery of ethyl acetate after extracting tripterygium wifordii
      extractum with ethyl acetate].
AB  - OBJECTIVE: To increase the recovery rate of ethyl acetate after extracting
      tripterygium wifordii extractum and to decrease product cost. METHOD: After
      extracting tripterygium wifordii extractum with ethyl acetate, 3 times saturated
      salt water was added in it so as to recovery ethyl acetate distilled under normal
      atmospheric pressure. Ethyl acetate containing salt water was purified through
      Na2SO4 column. RESULT: Ethyl acetate purified could be used repeatedly and the
      recovery rate was up to 85%. CONCLUSION: This method is completely adapted for
      mass production.

PMID- 15015306
TI  - [Studies on the new triterpenoid saponin of the aerial part of Cimicifuga
      foetida].
AB  - OBJECTIVE: To find new active constituents from the aerial part of Cimicifuga
      foetida. METHOD: Various column chromatographic techniques were used for the
      isolation and purification of the principles. The structures were elucidated on
      the basis of spectral data and chemical evidences. RESULT: Four 9,19-cycloartane
      triterpenoid saponins were obtained and identified as Cimifoetiside III (25
      anhydrocimigenol-3-O-beta-D-galactopyranoside, 1), 25-O-acetyl-cimigenol
      xylopyranoside (2), 25-O-acetyl-cimigenol galactopyranoside (3), 7 beta
      hydrocimigenol xylopyranoside (4). CONCLUSION: Compound 1 is new and compound 4
      was isolated from this plant for the first time.

PMID- 15015307
TI  - [Study on chemical constituents in rhizome of Smilax perfoliate].
AB  - OBJECTIVE: To investigate the components of Smilax perfoliate. METHOD: The
      chemical components were isolated by solvent extraction and column
      chromatography. The chemical structures were identified on the base of physical
      and spectral data. RESULT: Nine compounds were isolated and identified as
      palmitic acid(I), beta-sitosterol(II), delta 7-5 alpha-cholesten-3-beta-ol(III),
      naringenin(IV), succinic acid(V), apigenin(VI), resveratrol(VII),
      daucosterol(VIII) and juncusyl ester B(IX). CONCLUSION: Compound(I), (III), (IV),
      (VI) and (IX) were obtained from the genus Smilax for the first time.

PMID- 15015308
TI  - [Studies on the constituents from the herb of Vernonia patula].
AB  - OBJECTIVE: To isolate and elucidate the chemical constituents of the whole plant
      of Vernonia patula, and to provide samples for biological activity screening.
      METHOD: The chromatography on silica gel was used and the structures were
      determined by IR, NMR and MS spectra analysis and physicochemical property
      comparion. RESULT: Four triterpenoids were isolated and identified as bauerenyl
      acetate(I), friedelin(II), epifriedelanol(III), 20(30)-taraxastene-3 beta, 21
      alpha-diol(IV). CONCLUSION: Compounds I and IV were isolated from genus Vernonia
      for the first time and compounds II and III were isolated from the whole plant of
      V. patula for the first time. The four compounds show no inhibitory effect on the
      growing of PC-12 cells.

PMID- 15015310
TI  - [Study on selective isolation of volatile oil in the seed of Fructus foeniculi].
AB  - OBJECTIVE: To study the selective isolation of a single chemical component from
      volatile oil of Fructus foeniculi by inclucion method. METHOD: The host molecule
      was selected and a single chemical component isolated from volatile oil by the
      host-guest recognition. RESULT: X-ray single crystal analysis showed that 1,1,6,6
      tetraphenylhexa-2, 4-diyne-1, 6-diol could successfully include 4-[1-propenyl]
      benzaldehyde from volatile oil of Fructus foeniculi. CONCLUSION: The host-guest
      inclusion technology can be used to isolate a single component selectively from
      mixture.

PMID- 15015309
TI  - [Studies on chemical constituents in the peels of Citrus changshan-huyou (I)].
AB  - OBJECTIVE: To reveal the pharmacological activities of the components for their
      further utilization and development by studying the chemical constituents of
      Citrus changshan-huyou. METHOD: The structures were determined by repeated silica
      gel chromatographic separation and spectral analysis. RESULT: Five compounds were
      obtained, and identified as 3-oxo friedelin (I), limonin (II), beta-sitosterol
      (III), 8-(2',3'-dihydroxy-4'-methylbutane)-7-methoxycoumarin (IV), sucrose (V).
      CONCLUSION: The five compounds were obtained from this plant for the first time.

PMID- 15015311
TI  - [Comparative study on antibacterial effects of huangqin-tang and its metabolites
      produced by intestinal flora].
AB  - OBJECTIVE: To compare the antibacterial effects of Huangqin-Tang with its
      metabolites produced by intestinal flora. METHOD: The antibacterial tests in
      vitro and in vivo were performed by agar dilution method and lethal protection of
      animal respectively. RESULT: Huangqin-Tang and its metabolites had antibacterial
      action on bacteria in vitro, however the antibacterial activity of metabolites of
      Huangqin-Tang on Salmomella, Dysentery bacillus and Proteus in vitro was stronger
      than Huangqin-Tang. The metabolites of Huangqin-Tang had protective effect on the
      animals infected by Staphylococcus aureus and Escherichia coli respectively from
      death, but Huangqin-Tang had no lethal protection action. CONCLUSION: The
      antibacterial effects of metabolites of Huangqin-Tang in vitro and in vivo are
      stronger than that of Huangqin-Tang, which shows that intestinal flora play a
      very important role in antibacterial effects of Huangqin-Tang.

PMID- 15015313
TI  - [The effect of niaoduqing tablet on the diuresis in normal rats and the
      hemorheology in blood-stasis rats].
AB  - OBJECTIVE: To observe the effect of the Niaoduqing Tablet(NDT) on the diuresis in
      normal rats and the hemorheology in rats of blood stasis and compare it with the
      Niaoduqing Granule(NDG), so as to provide some laboratory data for the clinic
      application and innovation of the dosage forms. METHOD: Diuretic effect of the
      NDT on experimental rats burthened with 1% Sodium deoxycholate was observed by
      using the metabolize cage examination. The changes of whole blood and plasma
      viscosity in the blood-stasis rat-model were measured with Viscometer-R80. Plasma
      was separated and fibrinogen measured by using the turbidimetric method. RESULT:
      Every dose of NDT had the diuretic effect on experiment rats, but only the big
      and middle dose increasing the urine quantity in 6 hours had the significance.
      Each dose could reduce the viscosity of whole blood and the fibrinogen in the
      blood-stasis rat model, and had the superiority to NDG. CONCLUSIONS: NDT has the
      diuretic effect and can ameliorate the hemorheology in the blood-stasis rat
      model, which may delay the course of the chronic renal failure (CRF).

PMID- 15015312
TI  - [Effects of tanguticum maxim polysaccharide on ulcerative colitis induced by TNBS
      in rats].
AB  - OBJECTIVE: To evaluate the effects of Tanguticum Maxim polysaccharide (TMP-1) on
      TNBS-induced colitis in rats. METHOD: Rats with TNBS/ethanol-induced colitis were
      used and treated with TMP-1 and dexamethasone (DX). Seventy-two rats, including
      animals with TNBS-induced colitis, were treated with saline, TMP-1 (100, 200, 400
      mg.kg-1) and DX. White blood cells were counted on the fifth day and the rats
      were killed by ether on the sixth day. SOD activity in serum, MPO and SOD
      activity of colonic tissue were measured. RESULT: The remarkable effects of TMP-1
      at dosage of 200, 400 mg.kg-1 on TNBS-induced colitis were observed. The
      ulcerative area was diminished and weight of colon was reduced. White blood cell
      population was reduced, SOD activity in serum and SOD activity of colon tissue
      were remarkably increased, and, MPO activity of colonic tissue was reduced.
      CONCLUSION: TMP-1 has significant effects on TNBS-induced colitis in rats with
      lower side effects, which suggests the effective component of rhubarb on colitis
      perhaps is TMP. The mechanism of the actions of TMP may relate to its
      antiflammation, antioxidation and immunoloregulation.

PMID- 15015314
TI  - [Laboratory study of the yi-fu-ning soft gelatin capsules in treating climacteric
      syndrome].
AB  - OBJECTIVE: To study the therapeutic mechanism of YFN on climacteric syndrome by
      investigating the effect of Yi-Fu-Ning soft gelatin capsules (YFN), which can
      nourish the kidney and activate blood, on serum sex hormone levels and
      hypothalamic monoamine transmitters contents in ovariectomized rats. METHOD:
      Fifty female mature Sprague-Dawley rats were randomly divided into 5 groups:sham
      operation;ovariectomy(OVX);OVX with diethylstilbestrol tablets(DT);OVX with
      YFN(high dose and low dose). After drugs had been given for 4 weeks, hypothalamic
      monoamine transmitters (NE, DA, 5-HT, 5-HIAA) contents were detected by
      fluorospectrophotometric method and serum sex hormone by radioimmunoassay.
      Adrenal gland index, uterus index and thymus index were also determined. RESULT:
      YFN could obviously improve serum E2 and increase adrenal gland and uterus index
      in OVX rats (P < 0.01 or P < 0.05). It could reduce hypothalamic 5-HT and 5-HIAA,
      which were increased in OVX rats(P < 0.01); It could also increase reduced NE and
      DA in OVX rats and reduce the ratio of 5-HT to NE and 5-HT to DA(P < 0.01).
      CONCLUSION: YFN can regulate procreate endocrine in various ways and ameliorate
      the function of hypothalamic monoamine neurotransmitter in OVX rats. So it can
      stabilize inner condition of body and relieve symptoms of climacteric syndrome.

PMID- 15015315
TI  - [Experimental research of songzhi pills on inducement of interferon in mice and
      rats].
AB  - OBJECTIVE: To develop a new drug of treating the hepatitis C virus by studing the
      mechanisms of songzhi pills. METHOD: The four-wee old mice and two-month old rats
      were chosen to induce interferon. RESULT: The contents of interferon among the
      groups treated with songzhi pills were significantly higher than those of the
      normal group and the model group (P < 0.01), CONCLUSIONS: Songzhi pills may have
      the function of inducing interferon.

PMID- 15015317
TI  - [The influence of the different components of nourishing kidney herbs on
      osteoporosis rats].
AB  - OBJECTIVE: To observe the influent of the different components of nourishing
      kidney herbs on the main items of bone metabolism in osteoporosis rats induced
      with Dexamethasona(DXM). METHOD: Models of three-month old SD female rats with
      osteoporosis here made by being fed with low calcium diet (containing calcium
      0.2%) and distilled water, and injected with DXM 0.1 mg/100 g weight
      intramuscularly, twice a week. Then the osteoporosis rats were treated with
      different components of nourishing kidney herbs, and the change of calcium,
      phosphate, alkaline phosphatase(ALP), calcitonin(CT), PTH, CT/PTH, estrogen(E2),
      testosterone(T), T/E2 and bone section and bone quantitative morphology in these
      osteoporosis rats were observed. RESULT: The total components of nourishing
      kidney herbs could improve the general condition of osteoporosis rats, decrease
      PTH, increase CT, estrogen, testosterone, CT/PTH and T/E2. The total components
      of nourishing kidney herbs could improve osteoporotic state, promote bone
      formation, and inhibite bone resorption. But no effect of the A, B, C, D
      components of nourishing kidney herbs on the main items of bone metabolism in
      osteoporosis rats induced with DXM was found. CONCLUSION: It is possible that the
      purification and separation of these herbs weaken or destroy the integrative
      effect of nourishing kidney herbs or destroy effective components of nourishing
      kidney herbs during the process of purification and separation.

PMID- 15015316
TI  - [The influence on hemodynamics of myocardial ischemic dogs and blood pressure of
      animals with shenfu injection].
AB  - OBJECTIVE: To investigate the influence of Shenfu injection on the hemodynamic
      indexes of myocardial ischemic dogs and blood pressure of dogs and rats. METHOD:
      Myocardial ischemic model was made and hypotension in the dogs was induced with
      ligating left front descending limb coronary artery method, and secondary
      hypertension by narrowing nephridium artery of rats, Shenfu injection was
      administered with 5, 10 mL.kg-1 to the above dogs and rats separately to
      investigate the influence of it on the hemodynamic indexes of myocardial ischemic
      dogs and blood pressure of rats. RESULT AND CONCLUSION: Shenfu injection enhanced
      the capacity of myocardial work markedly; it augmented the myocardium
      contractility and cardiac output without raising the oxygen consume, and at the
      same time it returned normal the blood pressure in myocardial ischemic; but it
      had no effects on the normal blood pressure and secondary hypertension of rats.

PMID- 15015318
TI  - [Studies on effects of xuedan on the experimental gastric ulcer].
AB  - OBJECTIVE: To study the protective effects of Xuedan on the experimental gastric
      ulcer and the effects of anti-inflammatory, analgesic and bacteriostasis. METHOD:
      The anti-gastric ulcer effects of Xuedan was investigated with gastric ulcer
      models induced by being immersed in cold water, having pylorus ligature and HAC
      injected into serous membrane in rats. The influence of gastric juice secrete in
      normal rats, the anti-inflammation action resulted from auricle swelling in mice,
      the analgesic action by mice body torsion method and the bacteriostotic effect in
      vitro were observed. RESULT: Xuedan could reduce the ulcer area and decrease
      ulcer index, and gastric juice secrete. The hydrochloric acid in gastric juice
      and the activity of pepsin were reduced in rats. It could inhibit and disinfect
      Helicobacter pylori, lessen auricle swelling and the number of body torsion in
      mice. CONCLUSION: Xuedan obvious preventive and treating effects on experimental
      gastric ulcer.

PMID- 15015319
TI  - [Some research clues on Chinese herbal medicine for SARS prevention and
      treatment].
AB  - OBJECTIVE: To provide some research clues from Chinese herbal medicine for SARS
      prevention and treatment. METHOD: According to the experience and information, to
      select several perspective candidates from anti-SARS effective TCM prescriptions
      and drugs. RESULT: A list of Chinese herbal medicine and more than 14 botanical
      taxa could be served for further anti-SARS investigation. CONCLUSION: This
      investigation indicated that Chinese herbal medicine will be an important source
      for ant-SARS new drug searching.

PMID- 15015320
TI  - Screening of traditional Chinese remedies for SARS treatment.
AB  - The SARS epidemic is breaking out worldwide. To select suitable herbal drugs for
      clinical uses is important and urgent amongst the controversial treatment
      proposals. Nine pharmacological experimental models were used to evaluate the
      comprehensive efficacy of traditional Chinese remedies by cross validation in
      different institutes. Eight drugs were optimized for controlling different
      symptoms of SARS.

PMID- 15015321
TI  - [The progress of research on ginlcgobiobal flavone].
AB  - OBJECTIVE: The research on flavonoid in the recent years is extensive, such as
      Soybeans flavone, Baicalensis flavone, Epimedium flavone. Experiments show the
      effects of flavonoid is closely related to human health. There are a lot of
      reports about Ginkcobiobal flavone. In order to make further progress research on
      ginlcgobiobal flavone, we sum up the articles and reports on ginlcgobiobal
      flavone in the recent years. METHOD: To searche the articles about ginlcgobiobal
      flavone studies in the past five years. RESULT: Ginlcgobiobal flavone is not only
      a vasodilator, but also has the effects of anti-inflammation, analgesia, lowering
      blood lipids, preventing senile and inhibiting tumor, treating leukaemia,
      regulating gene and biotransformation. CONCLUSION: Ginlcgobiobal flavone has the
      potential value for drug research and development.

PMID- 15015322
TI  - [Identification of six species of Cassia seeds by capillary electrophoresis].
AB  - OBJECTIVE: To identify Cassia seeds of six species by capillary electrophoresis.
      METHOD: The water-soluble extracts of Cassia seeds of six species were analyzed
      by capillary electrophoresis. The running buffer was 0.1 mol.L-1 borate, 0.1
      mol.L-1 SDS, pH 8.5. The separation voltage was 25 kV. RESULT: Four common peaks
      could be found in the electropherograms of six species Cassia seeds, and the
      characteristic peaks could also be observed. CONCLUSION: Fingerprints of the six
      species of Cassia seeds show significant differences, which can be used for their
      identification.

PMID- 15015323
TI  - [Identification and evaluation of TCM shayuanzi].
AB  - OBJECTIVE: To understand the varieties of Shayuanzi on sale and establish the
      method for evaluating its quality. METHOD: 22 samples collected from all over the
      country were identified by TLC and the contents of total flavone in them were
      determined with UV. RESULT: All samples could be classified into three varieties,
      and they could be identified by TLC. The contents of total flavone in them were
      0.3%-1.0%. CONCLUSION: Shayuanzi on sale mainly includes Astragalus complanatus,
      and there are A. adsuragen and A. sinicus as well. TLC is a better method for the
      identification of shayuanzi. The total flavone in A. complanatus is 0.33%-0.82%.

PMID- 15015324
TI  - [Salt-tolerance evaluation of seedlings of medicinal Chrysanthemum morifolium
      cultivar].
AB  - OBJECTIVE: To evaluate salt tolerance of seedlings of 4 medicinal C. morifolium
      cultivars to be transplanted, and to expand the planting area. METHOD: Seedlings
      were cultivated in hoagland nutrient solution containing various concentrations
      of NaCl for 30 days. The height, dry weight and chlorophyll content were
      investigated. Identification index mainly in relative growth rate, the evaluation
      of NaCl effects on the growth, K+, Na+ and Cl- distribution in seedlings were
      surveyed. RESULT AND CONCLUSION: The salt tolerance was difference among four
      cultivars of C. morifolium. The salt tolerance of "Dabaiju" and "Changbanju" was
      weak, while "Hongxinju" and "Xiaobaiju" was strong. "Hongxinju" and "Xiaobaiju"
      may be planted in salinte soil area.

PMID- 15015325
TI  - [Study on the pollination characteristic of Cistanche deserticola].
AB  - OBJECTIVE: To study the Pollination Characteristic of C. deserticola. METHOD:
      Four pollination methods were used, cross pollination coming different plant,
      cross pollination in one plant, wind pollination and no-pollination. RESULT:
      Cross pollinations coming different plant are fructiferous. The average
      fructication rate of cross pollination coming different plant is 94.1%; the
      average fructication rate of cross pollination in one plant is 52.2%; The seed
      qulitity of cross pollination coming different plant is better than the cross
      pollination in one plant. CONCLUSION: Cross pollinations coming different plant
      have a high quantity and quality of seeds of C. deserticola.

PMID- 15015326
TI  - [Studies on preparation technology of Flos Magnoliae essential oil-beta
      cyclodextrin inclusion complex].
AB  - OBJECTIVE: To find the best condition of the preparation technology of Flos
      Magnoliae essential oil-beta-cyclodextrin inclusion complex. METHOD: L9(3(4))
      table was used to examine the effects of 4 factors, and the inclusion rate of
      each test was determined of orthogonal test. RESULT: The best condition
      was:oil:beta-cyclodextrin:water = 1:8:60 (mL:g:mL), stirring for 1 hour at 80
      degrees C. CONCLUSION: The complex prepared on the condition aforementioned is
      stable and stirring has a highest inclusion rate.

PMID- 15015327
TI  - [Studies on pharmacokinetics of loganin and morroniside in Cornus officinalis
      injection in mice].
AB  - OBJECTIVE: To establish a revered-phase HPLC method for the study of
      pharmacokinetics of loganin and morroniside in Cornus officinalis injectionin
      mice after a single oral and intravenous administrations. METHOD: The Diamonsil
      C18 column (4.6 mm x 250 mm, 5 microns) was used as the analytical column and the
      mobile phase consisted of acetonitrile-methanol-0.2% formic acid (12:8:80) with
      the flow rate at 1.0 mL.min-1. The UV detection was set at 237 nm. RESULT: The
      calibration curves of loganin and morroniside were linear in the range from 0.38
      to 68.25 mg.L-1(r = 0.9999), and from 0.66 to 117.22 mg.L-1(r = 0.9999),
      respectively. The lowest determination concentrations of loganin and morroniside
      were 0.10 and 0.16 mg.L-1, respectively. The recoveries and relative standard
      deviations of loganin were 99.6% (2.0%), 102.0% (1.0%), 87.9% (7.2%), and those
      of morroniside were 99.2% (2.5%), 104.1% (1.2%), 92.7% (4.2%), respectively. The
      relative standard deviations of within-day and between-day precision for the
      method were all less than 6.8%. After a single intravenous administration of
      Cornus officinalis injection to mice, the mean plasma concentration-time courses
      were found to fit a two-compartment open model, the main pharmacokinetic
      parameters of loganin were as follows: T1/2(alpha), T1/2(beta), K21, K12, K10,
      V(c), AUC, CL were 3.2 min, 25.1 min, 5.997 h-1, 4.981 h-1, 3.564 h-1, 0.551 L.kg
      1, 13.59 mg.L-1.h, 1.965 L.kg-1.h-1, respectively and those of morroniside were
      3.6 min, 21.5 min, 5.926 h-1, 3.833 h-1, 3.797 h-1, 0.647 L.kg-1, 27.15 mg.L-1.h,
      2.457 L.kg-1.h-1, respectively. CONCLUSION: It is the first time to establish the
      revered-phase HPLC method to determine concentrations of loganin and morroniside
      in plasma and to obtain their pharmacokinetic parameters and characteristics.

PMID- 15015328
TI  - [Qualitative and quantitative studies on qianliebeixi capsules].
AB  - OBJECTIVE: To establish a method of quality control on qianliebeixi capsules.
      METHOD: To clarify semen vaccarine by TLC, to determinate the contents of quertin
      and kaempferol in prepations, by HPLC. Chromatographic conditions: C18 column
      with METH-0.2%H3PO4(47:53) as mobile phase; the temperature of column was 40
      degrees C, and quercetin was detected at 370 nm with flowing rate 1 ml/min.
      RESULT: The spots of semen vaccarine were clear in TLC, no interference in
      negative contrast. The average recovery rate of quertin was 98.9% and the RSD was
      2.2%; the average recovery rate in kaempferol was 100.4% and the RSD was 1.7%.
      CONCLUSION: The resolution of spots were perfect in TLC, the spots were easy to
      distinguish, The method is simple, rapid as well as reproducible and can control
      the quality of qianliebeixi capsules effectively.

PMID- 15015329
TI  - [The contents of paeoniflorin in different combination jingzhixuefuzhuyu].
AB  - OBJECTIVE: To investigate the contents of paeoniflorin in different combination
      Jingzhixuefuzhuyu. METHOD: Using RP-HPLC to determine the contents of
      paeoniflorin in different combination Jingzhixuefuzhuyu extracts, an ODS column
      was used with a mobile phase of MeOH-H2O-HAC(25:75:0.15) and DAD detector at the
      wavelength of 230 nm. RESULT AND CONCLUSION: Different combinations of
      Jingzhixuefu zhuyu had great influence to the contents of paeoniflorin.

PMID- 15015330
TI  - [Study on the chemical constituents of the roots of commercial ginseng].
AB  - OBJECTIVE: To isolate and elucidate the constituents from the roots of Commercial
      Ginseng. METHOD: Column chromatography and HPLC were used to isolate chemical
      constituents. Physico-chemical characters and spectr-oscopic analysis were
      employed for structural identification. RESULT: Sixteen compounds were identified
      as: notoginsenoside-R2(1), ginsenoside-Rg2(2), 20 (R)-Rg2 (3), ginsenoside-Rg1
      (4), -Rf(5), -Re(6), -Rd(7), -Rc(8), -Rb1(9), -Rb2(10), -Rb3(11), -Ra3(12), 
      Ra2(13), -Ra1 (14), notoginsenoside-R4(15) and ginsenoside -Ro(16). CONCLUSION:
      Compound 1 was obtained from the plant for the first time.

PMID- 15015331
TI  - [Studies on chemical constituents from the root of Polygonatum kingianum].
AB  - OBJECTIVE: To investigate the anti-HIV constituents from the root of Polygonatum
      kingianum. METHOD: The compounds were isolated by column chromatography on silica
      gel, Sephadex LH-20, MCI-gel CHP-20P and their structures were determined on the
      basis of their spectroscopic evidence including IR, MS and NMR data. RESULT: 13
      compounds were isolated, of which nine compounds were identified as
      liquiritigenin, isoliquiritigenin, 4', 7-dihydroxy-3'-methoxyisoflavone, (6aR,
      11aR)-10-hydroxy-3, 9-dimethoxypterocarpan, 5-hydroxymethyl-2
      furancarboxaldehyde, salicylic acid, n-butyl-beta-D-fructopyranoside, n-butyl
      beta-D-fructofuranoside, n-butyl-alpha-D-fructofuranoside. CONCLUSION: Compounds
      1-6 were obtained from this plant for the first time.

PMID- 15015332
TI  - [Chemical constituents from the leaves of Dalbergia hainanensis].
AB  - OBJECTIVE: To study the chemical constituents from the leaves of Dalbergia
      hainanensis. METHOD: Compounds were isolated by chromatographic techniques on
      silica gel and polyamide column. Their structures were elucidated by chemical and
      spectroscopic methods. RESULTS: Thirteen compounds were identified as 8-C
      glucosylprunetin (1), 8-C-glucosylgenistein (2), 2-hydroxy-5-methoxy biochanin A
      (3), formononetin (4), 3,5-dimethoxy-4-hydroxybenzaldehyde (5), 1-O-beta-D
      glucopyranosyl-(2S, 3S, 4R, 8Z)-2-[(2R)-2-hydroxyl docosylamino]-8-octadecene-1,
      3, 4-triol (6), friedelin (7), taxaxerol (8), 3(-hydroxy-glutin-5-ene (9),
      ursolic acid (10), beta-sitosterol (11), daucosterol (12), lupeol (13).
      CONCLUSION: All the compounds were isolated from the plant for the first time.

PMID- 15015333
TI  - [Studies on flavonoids of Anaphalis sinica].
AB  - OBJECTIVE: To investigate the chemical constituents of Anaphalis sinica. METHOD:
      Various chromatographic techniques were employed for the isolation and
      purification of the constituents. The structures were elucidated by chemical and
      spectral analysis. RESULT: Six flavonoid compounds were isolated and identified
      as kaempferol, tiliroside, quercetin, quercetin -3-O-beta-D-glucosides,
      scutellarin, 5,7-dihydroxy-8-methoxyflavone and one pyrone were isolated and
      identified as helipyrone. CONCLUSION: All of these compounds was isolated from
      the plant for the first time.

PMID- 15015334
TI  - [Analysis of fatty acids in the seeds of Sterculia lychnophora by GC-MS].
AB  - OBJECTIVE: To analyze and identify fatty acids in the seeds of Sterculia
      lychnophora. METHOD: The compositions was isolated and determined by GC-MS
      technique, and area normalization method was used to make quantitative analyze of
      the content of compositions. RESULTS: 21 Fatty acids and 5 other compositions
      were isolated and determined. CONCLUSION: The major fatty acids are 9,12(Z,Z)
      octadecadienoic acid(37.96%), hexadecanoic acid(24.77%), 9-(Z)-octadecenoic
      acid(19.77%) and octadecanoic acid(5.01%).

PMID- 15015335
TI  - [Establishment of drug screening model based on transcriptional regulation of
      estrogen responsive element].
AB  - OBJECTIVE: AIM To establish a drug screening model based on transcriptional
      regulation of estrogen responsive element (ERE) and use it to screen compounds
      for discovering new ligands of estrogen receptor (ER) subtypes. METHOD: A
      recombinant reporter vector pERE-TAL-SEAP was constructed by inserting a
      synthetic sequence composed of five tandem copies of EREs upstream of promoter of
      the reporter vector pTAL-SEAP. The pERE-TAL-SEAP and the internal control plasmid
      pCMV were transiently co-transfected into Hela cells expressing ER subtype or ER
      subtype, and the effects of pure ER agonists 17estradiol, phytoestrogen genistein
      and pure ER antagonist ICI182, 780 on reporter gene SEAP expression were
      observed. RESULT: In the Hela cells expressing ER alpha or ER beta subtype, the
      expression of SEAP gene were induced in a dose dependent manner by 17-estrodiol
      with a maximal effect at approximately 10 nmol.L-1 and with EC50 of (80.58 +/-
      8.51) pmol.L-1 and (103.90 +/- 5.29) pmol.L-1, respectively, so done by
      phytoestrogen genistein with a maximal effect at 1 mumol.L-1 and with EC50 of
      (10.86 +/- 0.75) nmol.L-1 and (39.38 +/- 2.26) nmol.L-1, respectively. The
      maximal level induced by estrodiol and genistein were about 7-14 fold higher than
      that of vehicle. The pure antiestrogen ICI182, 780 at concentration of 1 mumol.L
      1 completely blocked the inductions of 17-estrodiol and genistein. CONCLUSION:
      The cellular drug screening model can be established by transfecting reporter
      vector pERE-TAL-SEAP in Hela cell lines expressing ER alpha or ER beta. The cell
      lines can be used to screen compounds with estrogenicity by testing SEAP activity
      in the culture media of cells growing in microtitier wells. The system should
      provide an efficient model for screening and analyzing the activity of large
      numbers of ligands of ER.

PMID- 15015336
TI  - [Effect and mechanism of bishudiwan(BSDW) against allergy].
AB  - OBJECTIVE: To investigate the effect and mechanism of BSDW on the model of
      allergic rhinitis and the model of guinea pigs by histamine shocking in guinea
      pigs. METHOD: Using the model of allergic rhinitis in guinea pigs caused by 10%
      TDI, we observed the effect of BSDW on physiological and pathological symptoms of
      allergic rhinitis in guinea pigs, the effect of the levels of serum IgE and serum
      and nasal histamine. Using the model of guinea pigs by histamine shocking, we
      observed the effect of BSDW on physiological symptoms in guinea pigs. RESULT:
      BSDW significantly relieved the pathological symptoms of allergic rhinitis in
      guinea pigs, alleviated the hyperplasia of columnar epithelium, decreased the
      number of monocyte and eosinocyte compared with the model group. It also reduced
      the levels of serum IgE, and decreased the release of serum and nasal histamine.
      BSDW significantly prolonged the occurent time of gasping, eclampsia and death
      caused by shock, reduced the times of gasping in the model of guinea pigs by
      histamine shocking. CONCLUSION: BSDW has significant effect against allergy. The
      mechanism relates to its effects of decreasing the levels of serum IgE and
      inhibiting the release of serum and nasal histamine.

PMID- 15015337
TI  - [Experimental studies on antianimia effect of shengxuesu].
AB  - OBJECTIVE: Using animal anemia models to observe the antianemia effect of
      Shengxuesu, and to afford an experimental basis for preventing and treating
      anemia. METHOD: Rat model of iron deficiency induced by denutrition and mouse
      model of nemorrhagic anemia by blood lefting were established. Indices of
      hemoglobin(HB), red blood cell count(RBC), hematocrit(HCT), mean corpuscular
      hemoglobin count(MCHC), serum iron(SI), serum ferritin (SF) and total iron
      binding capacity(TIBC) were monitored. RESULT: A dosage of Shengxuesu 0.5-2 g.kg
      1 was given to the rat model of hypoferric anemia by gavage for 15 days, and to
      the mouse model of hemorrhagic anemia by gavage for 7 days. The result shows that
      HB, RBC, HCT, MCHC in blood and iron, ferroprotein in serum were elevated
      significantly; but total bounding iron in serum was decreased. Meanwhile, diet
      amount, diet consumption and general activity of the model rats were increased.

PMID- 15015338
TI  - [The protection of seed oil of Hippophae rharmnoides on ischemic cerebral
      infarction in rats].
AB  - OBJECTIVE: To study the protection of seed oil of Hippophae rhamnoides on
      ischemic cerebral infarction in rats and the mechanism of the action. METHOD:
      Focal cerebral ischemia model was made by middle cerebral artery occlusion(MCAO)
      in rats. Behavior obstacles of rats were observed. Cerebral infarction volume was
      determined by Megnetic Resonance Imaging(MRI). RESULT: Seed oil of Hippophae
      rhamnides 0.7 and 0.35 g.kg-1 could markedly reduce infarction volume after
      occlusion of middle cerebral artery in rats and also could ameliorate the
      behavior obstacles of rats. CONCLUSION: These results suggested that seed oil of
      Hippophae rhamnoides had distinct protection to ischemic cerebral infarction in
      rats.

PMID- 15015339
TI  - [Effects of realgar on tissue factor expression of NB4 and MR2 cells].
AB  - OBJECTIVE: To investigate the effects of Realgar on procoagulant activity (PCA),
      tissue factor expression and tissue factor mRNA transcription in acute
      promyelocytic leukemia (APL) cell lines NB4 and MR2 cells. METHOD: NB4 and MR2
      cells were treated with 300 micrograms.L-1 Realgar PCA of the treated cells was
      detected using one-stage clotting assay. TF antigen was detected by ELISA and
      TFmRNA by semi-quantitive RT-PCR. RESULT: The PCA and TF antigen level in NB4 and
      MR2 cells were significantly higher than that in HL-60 and K562 cells. Realgar
      could down-regulate the membrane PCA, TF antigen and TF mRNA transcription of NB4
      and MR2 cells in a time-dependent manner. CONCLUSION: Down-regulating TF
      expression and PCA of NB4 and MR2 cells by Realgar may be one of the mechanism of
      its improvement effect on DIC-related hemorrhage of APL patients.

PMID- 15015340
TI  - [Studies on therapeutic effects of zhenzhu qishi wan on stroke and hypertension
      of SHRsp].
AB  - OBJECTIVE: To study the effect of Zhenzhu Qishi Wan on blood pressure(BP), body
      weight(BW), stroke and survival rate of stroke-prone spontaneously hypertension
      rats(SHRsp). METHOD: 8-week-old SHRsp was randomly divided into three groups:
      control group, Zhenzhu Qishi Wan prevention group and therapy group (n = 10).
      SHRsp of prevention group were treated with Zhenzhu Qishi Wan by ig 150 mg.kg-1
      per day for 6 weeks, and therapy group were given the same treatment two weeks
      later. Behavior and stroke were observed everyday; BW were weighted every week;
      BP were estimated every 2 weeks. Time of the first cerebral seizure of SHRsp was
      recorded. RESULT: Zhenzhu Qishi Wan had obvious preventive and therapeutic effect
      on genetic hypertension. The BP of prevention and therapy groups were
      significantly lower than that of control group (P < 0.05 [symbol: see text] P <
      0.01). The drug ameliorated general behavior of SHRsp, BW of prevention group
      increased faster than that of control group(P < 0.05 or P < 0.01), and BW of
      therapy group were also heavier than that of control group at the age of 14
      weeks(P < 0.05). When the experiment ended, 60% SHRsp of control group showed
      stroke and 20% of them were dead, while only 20% SHRsp in each of Zhenzhu Qishi
      Wan-treated groups showed stroke and none of them died. CONCLUSION: Zhenzhu Qishi
      Wan had significant hypotensive effect, and some protective effect on the stroke
      caused by hypertension.

PMID- 15015341
TI  - [Effects of extracts of root of kudzu vine on mammary gland and uterus
      development in rats].
AB  - OBJECTIVE: To study the effects of extracts of root of kudzu vine on mammary
      gland and uterus development in rats. METHOD: 40 Wistar rats weighting 65-85 g
      were randomly divided into 4 groups: control group, estrogen group, extracts of
      root of kudzu vine group of high dose, extracts of root of kudzu vine group of
      low dose. (10 rats in each group). After having been treated for 7 days, the rats
      were killed; mammary glands and uterus were removed and weighed. Serum was
      isolated and kept at 4 degrees C for determination of hormones. RESULT: 1.
      Administration of the root of kudzu vine significantly increased the weigh of
      mammary gland and uterus in rats. 2. Administration of the root of kudzu vine
      increased serum FSH, LH, E2 and decreased PRL. CONCLUSION: Extracts of root of
      kudzu vine could enhance the weight of mammary gland and uterus growth in rats,
      which may provide experimental evidence for the development of new drug used for
      promoting mammary gland and uterus.

PMID- 15015342
TI  - [Determination of danshensu in rat serum after oral administer compound Salvia
      recipe].
AB  - OBJECTIVE: To investigate the absorption of the water soluble components of
      Salvia miltiorrhiza and establish methods to determine Danshensu in rat serum
      after ig compound Salvia recipe. METHOD: Used liquid-liquid extraction to deal
      with the serum, then determined the sample by high-performance liquid
      chromatography. The conditions for HPLC were as the following: the mobile phase,
      CH3OH-CH3CN-0.5% CH3COOH (2.5:3.5:94) with a flow rate of 1.0 mL.min-1; detection
      wavelength, 281 nm; internal standard, 4-hydroxy-benzoic acid. RESULT: Danshensu
      and an unknown compound whose reserved time was little shorter than
      protocatechuic aldehyde were found in the rat serum after ig compound Salvia
      recipe, while protocatechuic aldehyde weren't found in the serum. CONCLUSION:
      Danshensu can be absorbed into blood after ig compound Salvia recipe.

PMID- 15015343
TI  - [Applied studies of biological control techniques on healthful Chinese crude
      drugs].
AB  - Medicinal plants always suffer from diseases and pests in their cultivation and
      growing, and the yield and quality are reduced. At present, chemical pesticide is
      mainly used to control the diseases and pests. The long-term use and over-use of
      pesticide result in pesticide residue, pests resistance to pesticide, water and
      soil pollution and other environmental contamination. It is necrssary to provide
      the integrated pests management, including new technology of biological control
      for developing green drug. This project makes research on the following aspects:
      1. Applied studies on bethyloid wasp (Scleroderma guani) control for stem borer;
      2. To develop Trichoderma spp. and use it to control the diseases of medicinal
      plants; 3. Applying Agro-antibiotics 120 to control phytophthora root rot of
      ginseng; 4. Researches on application of entomopathogenic nematodes against ten
      spotted lema (Lema decempuntata) et al.

PMID- 15015344
TI  - [Advances in the research on targeted preparations of traditional Chinese
      medicine and natural drugs].
AB  - OBJECTIVE: Targeting dosage form is a kind of targeting drug delivery system
      which can be used to lock drugs aroud the target organs, tissues, cells and
      obtain more effective treatment for dose concentration, thus reducing the side
      effects of such drugs while increasing their effeciveness. Targeting dosage form
      is the fourth-generation drug dosage form and it is ideal system for
      administration because it release the theraping drugs in the targeting-site.
      Particular emphasis was placed on liposome due to it was used as a drug carrier.
      Meanwhile, the highlights of research were on magnetic and enzyme targeting
      preparations. In addition, oral colon targeting drug delivery system, drugs were
      carried to ileocecum and release to get local and whole effect, is also an
      important part of targeting dosage form. The study on traditional chinese
      medicine (TCM) targeting dosage form is still at beginning stage in China. At
      present, most of study on TCM and natural products targeting drugs were focus on
      simple effective component and merely on TCM effective positions in relative with
      the difficult for determing their quality standard and procedure of preparing. It
      is the kernel item for TCM modernization and the key for TCM internationalization
      to develop new dosage form and new technology of TCM. There is a need in
      collaboration with multiple discipline. It will be a important research subject
      to develop TCM targeting preparation in the near future. TCM targeting dosage
      form can be classified into liposome, nanoparticles, multiple emulsion etc
      according to the difference of carrier and oral, rectal, colonic, nasal, dermal,
      ocular system on a basis of administration and so on. This paper made a summary
      on TCM and natural products targeting dosage form according to different
      targeting positions and introduce the procedure of preparing compared with the
      effect in vivo and manifest that TCM and natural products targeting dosage form
      will have good exploit prospect.

PMID- 15015345
TI  - [Anti-oxygenation effect of procyanidins in plant medicine].
AB  - This article summarized the chemical construction and plant resources,
      biochemical and pharmacologicaly activity and the anti-oxygenation effect of
      procyanidins.

PMID- 15015346
TI  - [Ribosomal DNA ITS sequences analysis of the Chinese crude drug fructus
      schisandrae sphenantherae and fruts of Schisandra viridis].
AB  - OBJECTIVE: To find the patterns of the rDNA ITS sequence variation of Schisandra
      sphenanthera and S. viridis, and to establish the molecular biological method for
      the identification of Fructus Schisandrae Sphenantherae and the fruits of S.
      viridis. METHOD: PCR products were sequenced directly and the sequences were
      analyzed with PAUP 4.0b10. NJ systematic tree was obtained with neighbor-joining
      method. RESULT: The Complete ITS sequence of S. sphenanthera was 691-692 bp, of
      which there were 282 bp of ITS1 and 246-247 bp of ITS2. The complete sequence of
      S. viridis was 694-695 bp, consisting of 285-286 bp of ITS1 and 246-247 bp of
      ITS2. There were three informative sites in ITS1 regions for the two species. In
      the NJ tree with Kadsura anamosma and K. coccinea as outgroups, five different
      populations of S. viridis were the monophyletic group with the bootstrap value of
      68%. These populations included one from Tianmushan, Zhejiang province, three
      populations from Jigongshan, Henan Province and the other two populations of S.
      viridis cited the sequences from GeneBank (registration numbers are AF263438 and
      AF163703 respectively). CONCLUSION: The rDNA internal transcribed spacer is a
      good marker to distinguish the Fructus Schisandrae Sphenantherae from the fruits
      of S. viridis.

PMID- 15015347
TI  - [Comparative study on pesticide and heavy metal residuals of four cultivars of
      Chrysanthemum morifolium].
AB  - OBJECTIVE: To study organochlorine pesticide and heavy metal residuals of
      Chrysanthemum morifolium. METHOD: The contents of organochlorine pesticide
      residuals was determined by chromatography, Cu, Pb, Cd was determined by AAS, and
      As, Hg was determined by AFS. RESULT AND CONCLUSION: The contents of
      organochlorine pesticide and heavy metals residuals are up to "Green Trade
      Standards of Importing & Exporting Medicinal plants & Preprations" (MOFTEC,
      2001), but the contents are different among four cultivars clearly.

PMID- 15015348
TI  - [Biological effect of seed-coating in Carthamus tinctorins].
AB  - OBJECTIVE: To study the Biological effect of seed-coating in Carthamus
      tinctorins. METHOD: Two kinds of seedcoating chemicals SCF1 and SCF2 were used in
      this experiment, the seed YM-99 and 27981-99 were coated by three kinds of ratio
      of seedcoating chemicals to seed. It was investigated that the germination energy
      and germination percentage in the room and the emergence rate, seedling stage
      growing, pest in the field. RESULT: Seedoating can improve the emergence rate and
      seedling stage growing, it also can effectively control aphid, rust and virosis
      during the growing period in C. tinctorins. CONCLUSION: Seedcoating has
      significant biological effect in C. tinctorins.

PMID- 15015349
TI  - [Analysis on yield and quality of different Houttuynia cordata].
AB  - OBJECTIVE: To study the yield of different Houttuynia cordata and the changing
      regularity of their main officinal components in different periods, and provide a
      basis for harvesting in good time and breeding new varieties. METHOD: The main
      officinal composition and wet weight of overground parts per acreage of different
      accessions were determined periodically. The plot yields were tested when
      harvested and analyzed by analysis of variance. RESULT: The difference of the
      yields of different accessions was significant. The varying tendency of the
      content of main officinal component methyl nonyl ketone and its total content per
      acreage of different accessions were different. CONCLUSION: The integrate
      characters of Qionglai and Wangyu wild accessions are relatively better, worthy
      to be widely applied in production.

PMID- 15015350
TI  - [Study on in vitro dissolution rate of geniposide in huangqin qingfei dispersible
      tablet].
AB  - OBJECTIVE: To study in vitro dissolution rate of geniposide in Huangqin Qingfei
      dispersible tablet. METHOD: A reversed-phase HPLC method was developed for
      determination of geniposide. In vitro dissolution rates were compared between
      Huangqin Qingfei dispersible tablet and conventional tablet in the dissolution
      medium of pH 1.0, 2.85, 4.5, 6.8, and 8.0 accordingly. Zero-class model, single
      index model, logarithm normal school model, and Weibull distributing model were
      used to simulate the dissolution curve. RESULT: The dissolution rate of two
      tablets is not affected by pH so much, and they can dissolve within 5 to 10
      minutes. Weibull distributing model is the best simulation for in vitro
      dissolution. Comparing with conventional tablet, dispersible tablet dissolve
      quickly and completely. CONCLUSION: The in vitro dissolution rate of geniposide
      in Huangqin Qingfei dispersible tablet conforms to Weibull distributing model.
      The dispersible tablet is able to release rapidly.

PMID- 15015351
TI  - [Studies on the quality standard of xingnao tinctures].
AB  - OBJECTIVE: To establish the method for quality control of Xingnao tinctures.
      METHOD: The Mentholum, Flos Caryophylli and Borneoum Syntheticum in this medicine
      were identified by TLC method. The content of Mentholum was determined by GC.
      Conditions of GC were: With Naphthalene as an internal standard, packed glass
      column, Shimadzu 7G 2.1 mm x 3.2 m, carrier gas N2, flow rate 50 mL.min-1, column
      temperature. 145 degrees C, ingector and detector temperature. 180 degrees C,
      injection way of splitless and injection volume 3 microL. RESULT: The spots on
      TLC plates were clear, with no interference in the blank reference. The precision
      and repeatability of GC were are good respectively. The average recovery was
      98.4%, RSD = 0.94%. CONCLUSION: This method was fast, simple, accurate and
      suitable for quality control of Xingnao tinctures.

PMID- 15015352
TI  - [Studies on chemical constituents in herb of Lamium maculatum L. var Kansuense].
AB  - OBJECTIVE: To study the chemical constituents from Lamium maculatum L. var
      Kansuense. METHOD: The chemical constituents were isolated and repeatedly
      purified by silica gel column chromatography and the structures were elucidated
      by the NMR spectra and physico-chemical properties. RESULT: Ten compounds were
      obtained and they were identified as D-mannitol, beta-sitosterol, stigmasterol,
      rutin, 3'-methylquercetin-3-O-rutinoside, n-butyl-beta-D-fructopyranoside,
      daucosterol, acteoside, 20-hydroxyecdysone, allantoin. CONCLUSION: All the
      compounds were obtained from L. maculatum L. var Kansuense for the first time.

PMID- 15015353
TI  - [Studies on the chemical constituents from the water-soluble part of Euphrasia
      regelii].
AB  - OBJECTIVE: To study the chemical constituents from the water-soluble part of
      Euphrasia regelii. METHOD: The compounds were isolated by macroporous resin and
      column chromatography, and identified by IR, NMR data. RESULT: Two special
      compounds were isolated and identified. CONCLUSION: Two compounds were isolated
      from this plant for the first time.

PMID- 15015355
TI  - [Determination of shionone in Radix Asteris by HPLC].
AB  - OBJECTIVE: To determine the content of shionone in Radix Aster from several
      different locations and markets. METHOD: The HPLC analysis was used to determine
      shionone directly, using Polaris C18 column and acetonitrile as the mobile phase
      with a flow rate of 1.0 mL.min-1, and the UV detection wavelength was 200 nm.
      RESULT AND CONCLUSION: The content of shionone was from 0.06% to 0.18%, depending
      on different locations and markets.

PMID- 15015354
TI  - [Determination of glycosides in traditional Chinese medicine liu-wei di-huang by
      RP-HPLC].
AB  - OBJECTIVE: To establish a RP-HPLC method for determination of glycosides in
      Traditional Chinese Medicine Liu-wei Di-huang. METHOD: The samples were analyzed
      on an ODS column at 30 degrees C, with mobile phase of methanol/water (33:67) at
      flow rate 1.0 mL.min and detection at wavelength of 236 nm. RESULT: Three major
      components reached base-line separation and were identified to be mononiside,
      loganin, paeoniflorin. Respectively for the three components, linear correlations
      were found between peak areas and concentrations in the ranges of 7.4-60, 7.7-62
      mg.L-1 and 8.5-68 mg.L-1, and the recoveries were 98.8%, 98.3%, 99.6%.
      CONCLUSION: The established method is proved to be suitable for simultaneous
      quantification of three major glycosidic components in Liuwei Dihuang decoction
      and can be used for evaluation of the quality of Liuwei Dihuang preparations.

PMID- 15015356
TI  - [Study on the constituents of volatile oil from Ocimum basilicum].
AB  - OBJECTIVE: To study the constituents of volatile oil from Ocimum basilicum.
      METHOD: GC-MS technique was used. RESULT: Forty-five compounds was elucidated
      through consulting literature and searching database by computer. CONCLUSION: The
      main constituent in volatile oil from O. basilicum are 1, 7-dimethyl-1, 6
      octadien-3-ol, which accounts for 29.87%.

PMID- 15015357
TI  - [Experimental study on effect of the water extract of dogwood fruits on the liver
      and testis in rats model of kidney-yang deficiency].
AB  - OBJECTIVE: To explore the effect of Dogwood fruits on tonifying kidney-yang.
      METHOD: The effect of the water extract of Dogwood fruits on rats model of kidney
      yang deficiency with the hydrocortisone was observed. RESULT: The water extract
      of Dogwood fruits could make normal the liver weight, and mitigate hepatocyte
      pathologic changes, increase the heptocellular levels of RNA and hepatin, and
      decrease the malondialdehyde (MDA) in rats model of kidney-yang deficiency. It
      could also make the viscera quotiety return to normal way and increase the levels
      of RNA in the interstitial cells of testicle in rats model of kidney-yang
      deficiency. CONCLUSION: Water extract of Dogwood fruits can protect and improve
      the functions of the liver and testicle in rats model of kidney-yang deficiency.

PMID- 15015358
TI  - [Effects of yishenjiangyafang on blood pressure and protecting renal function in
      RPH rats].
AB  - OBJECTIVE: To study the effects and mechanism of Yishenjiangyafang, a
      prescription of Chinese traditional herbs used for renal hypertension, on blood
      pressure and protecting renal function of RPH rats. METHOD: The 5/6 kidney of rat
      was resected to set up the RPH rat model. Blood pressure, Cr(creatinine),
      Ccr(creatinine clearance) and BUN(urea nitrogen) were measured dynamically. After
      eight weeks treatment, plasma content of PAR A II TXB2, 6-keto-PGF1 were
      measured. At same time, The change of renal pathology was observed. RESULT:
      Yishenjiangyafang could reduce blood pressure Cr, but had no effect on BUN of RPH
      rat. The indexes of PAR, A II of each different dosage group of Yishenjiangyafang
      were decreased. At the same time, it reduced plasma content of TXB2, and
      increased 6-keto-PGF1 alpha. Glomerulosclerosis and atrophy of renal tubule in
      Yishenjiangyafang group RPH rats were better than those of the contrast group and
      the Capten group. CONCLUSION: Yishenjiangyafang can reduce blood pressure of RPH
      rats and has protective effects on its kidney. Yishenjiangyafang can perform its
      effects of reducing blood pressure and protecting kidney by influencing the RAS
      of RPH rats.

PMID- 15015359
TI  - [Effects of one Chinese herbs on improving cognitive function and memory of
      Alzheimer's disease mouse models].
AB  - OBJECTIVE: To investigate Chinese herbs with the effect on significantly
      improving the cognitive function and retention of patients with Alzheimer's
      disease. METHOD: AD mouse models were established by injecting poly-beta-AP25-35
      into the cerebral ventricle of mice. The curative effects of traditional Chinese
      herbs Dangguishaoyaosan, Chaihujialonggumulitang and two herbs (CHP I and CHP II)
      developed by the authors on improving the memory and cognitive function of AD
      mouse models were studied by the detection of behavioral and histochemical tests,
      with piracetam serving as control. RESULT: CHP II has profound curative effects
      on improving the memory and cognitive function of AD-like animal model.
      CONCLUSION: The present study indicates that it has a satisfactory prospect to
      seek new drugs from Chinese herbs to treat AD.

PMID- 15015360
TI  - [Effects of yixintong on regulating cellular calcium channels].
AB  - OBJECTIVE: To explore the protecting mechanism of Yixintong for heart ischemia
      reperfusion injury at cellular and subcellular levels, by observing the effects
      of Yixintong on three kinds of calcium channels. METHOD: The effects of Yixintong
      on Ca2+ influx on leak calcium channel, receptor-operationg calcium channel (ROC)
      and pulse-dependent calcium channel (PDC) were observed respectively, by using
      rat aortic smooth muscle cell and radioactive 45Ca technique. RESULT: Yixintong
      has no effects on leak calcium channel, but can inhibit the Ca2+ influx in ROC
      and PDC significantly. CONCLUSION: Yixintong can inhibit the Ca2+ influx in slow
      channel in a dose-dependent manner.

PMID- 15015361
TI  - [Protective effect of curcumin on experimental liver injury in mice].
AB  - OBJECTIVE: To Study the protective effect of curcumin on three models of
      experimental liver injury in mice. METHOD: The experimental models of live injury
      were induced by carbon tetrachloride (CCl4), D-galactosamine (D-Gal N), and
      Bacillus Calmette-Guerin (BCG) Plus lipolysaccharides (LPS), respectively, in
      mice. The serum ALT, AST, NO and liver MDA were measured to evaluate the
      protective effect of curcumin on experimental injury in mice. RESULT: Curcumin
      (50 mg.kg-1, 100 mg.kg-1, 150 mg.kg-1), like biophenyldicarboxylate, were shown
      to significantly inhibit the increase of serum ALT, AST, NO and liver
      molondialdehyde (MDA) content induced by CCl4, D-Gal N, BCG + LPS. CONCLUSION:
      Curcumin showed protective effect against liver injury induced by CCl4, D-Gal N,
      BCG plus LPS.

PMID- 15015362
TI  - [Experimental studies on the apoptosis of HL-60 cells induced by Brucea javanica
      oil emulsion].
AB  - OBJECTIVE: To investigate the inducing effect of Brucea javanica on the apoptpsis
      of HL-60 cells. METHOD: HL-60 cells were treated with Brucea javanica 1:100,
      1:40, 1:20 (v/v) respectively for 6 h and DNA agarose gel electrophoresis, flow
      cytometry, fluorescence microscope, electron microscope were used to observe the
      apoptosis inducing effect of Brucea javanica. RESULT: DNA ladder was seen in the
      1:40 group. The apoptosis cell percentages of 1:40 and 1:20 group were 86.8% and
      97% respectively. Cells of 1:40 group showed obvious apoptosis character under
      fluorescence microscope. Cells were induced apoptosis in 1:20 and 1:40 Brucea
      javanica under electron microscope. CONCLUSION: 1:20 and 1:40 Brucea Javanica
      showed obvious apoptosis inducing effect of HL-60.

PMID- 15015363
TI  - [The inhibitive effect of tea polyphenols on oxidized low density lipoprotein
      intake in cultured rat mesangial cells].
AB  - OBJECTIVE: To study the inhibitive effect of tea polyphenols (TP) on oxidized low
      density lipoprotein (OX-LDL) intake in cultured rat mesangial cells. METHOD: Rat
      mesangial cells incubated in 80 mg.L-1 OX-LDL were treated with TP at different
      concentrations. Total cholesterol (TC) content of the mesangial cells and
      proportion of mesangial cells containing lipid droplets were measured, and
      ultrastructure observation was performed. RESULT: Foam cells were observed in
      mesangial cells stimulated by OX-LDL, and both the TC content and the proportion
      of lipid-droplet-containing cell were higher in these cells than in mesangial
      cells cultured in lipid free conditions. There were concentration-dependent
      decreases both in TC content and lipid-droplet-containing cell proportions when
      treated with TP from 40 ng.L-1 to 40 mg.L-1. The number of lipid droplets was
      also decreased in TP treated mesangial cells. CONCLUSION: TP has an inhibitive
      effect on OX-LDL intake in cultured rat mesangial cells, which is in a
      concentration-dependent manner from 40 ng.L-1 to 40 mg.L-1.

PMID- 15015364
TI  - [Effects of the extract from bergamot and boxthorn on the delay of skin aging and
      hair growth in mice].
AB  - OBJECTIVE: To study the effects of the extract from bergamot and boxthorn on the
      skin and the hair growth in mice. METHOD: The skin on the back of mice was shaved
      topically and smeared with bergamot and boxthorn extract for 42 days. Then the
      activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA)
      and collagen in the mice were measured. The growth of hair was also observed.
      RESULT: Compared with control group, the extract from bergamot and boxthorn
      obviously increased the activity of superoxide dismutase (P < 0.05) and the
      content of collagen (P < 0.001), and decreased the content of malondialdehyde (P
      < 0.05) in the skin of mice. It also significantly promoted the growth of hair (P
      < 0.001). CONCLUSION: The extract from bergamot and boxthorn plays an active role
      in skin and the promotion of hair growth.

PMID- 15015366
TI  - [Study of Chinese herbs and its compound prescription guided by traditional
      Chinese medical theory].
AB  - It is the key problem of TCM study in the new times to strengthen the research
      and application of Chinese herbs and its compound prescription directed by TCM
      theory by combining medicine and drugs, accelerating the creation and
      construction of modern the new system. In the study of compound, animal mode
      should be set up by the combination of modern experimental method according to
      TCM clinical requirements. A breakthrough in compound prescription needs to be
      found out from observation of pharmacodynamics and analysis of clinical therapy.
      Methodology and clarification of effective materials should be paid enough
      attention to in study the pharmacokinetics of the compounds. Since the
      therapeutic effects of compound prescriptions are different, or even opposite to
      itself under different Syndromes, it is so important to pay attention to Syndrome
      Differention. Multiple ways of TCM study have given active exploration on the
      developing of TCM academic level from different aspects. The aim of constructing
      a system of developing TCM and Syndrome-corresponding compound prescription is to
      build up a normalized standard of new and highly effective theory in treating
      disease clinically, designing methodology, Syndrome-corresponding prescription
      and monitor the compound prescription used. In this way, a new TCM clinical
      standard could be set up in Chinese medicine and its compound prescription in
      clinical experiments to raise the medical level continuously.

PMID- 15015365
TI  - [Effect of xue hanjing oral fluid on mice immunological function].
AB  - OBJECTIVE: To observe effect of Xue Hanjing oral fluid on mice immunological
      function. METHOD: The weight of thymus gland and spleen and the function of
      abdominal cavity macrophage were measured. Production of the hemolysin antibody,
      the immunoglobulin of blood serum and complement and the proliferation of T
      lymphocytes were observed respectively by means of microblood, immune
      turbidimetry and MTT staining. RESULT: Xue Hanjing oral fluid could enhance index
      of the thymus gland and spleen and the phago-percent of abdominal cavity
      macrophage, increase the immunoglobulin of blood serum(IgG and IgM), and
      accelerate production of the hemolysin antibody and the proliferation of T
      lymphocytes. CONCLUSIONS: Xue Hanjing oral can reinforce immunological function
      in mice.

PMID- 15015367
TI  - [The importance and approaches of physicochemical properties analysis of active
      compounds of traditional Chinese herbs in development of new medicine].
AB  - Biological activity and physicochemical properties are two key factors to screen
      active compounds of traditional Chinese herbs during early discovery phases. As a
      great number of the compounds are got in the world, a new strategy is developed
      to research the physicochemical properties of the compositions of herbs, so that
      the election of active compounds from the compositions has become more effective
      and more economical than before. The new strategy and associated technology have
      emerged and it was used extensively. The physicochemical properties of the
      compounds of traditional Chinese medicine(TCM) relate to pharmaceutical and ADME
      (Absorption, distribution, metabolism and elimination), and development, clinical
      effect and safety are evaluated with the properties. Therefore, the
      physicochemical properties are important in the development of TCM.

PMID- 15015368
TI  - [Advance in the pharmacological research on matrine].
AB  - OBJECTIVE: The progress in the research on matrine was involved to provide
      references for the exploitation and utilization of the matrine. METHOD:
      Pharmacological functions and mechanism were reviewed according to related
      experimental studies. RESULT: Matrine has various pharmacological activities.
      CONCLUSION: Matrine has extensive applied prospect and will be developed further.

PMID- 15015369
TI  - [Preparation and characterization of Radix Salvia reference material for heavy
      metals under GAP control].
AB  - OBJECTIVE: To prepare and characterize the heavy metal reference material of
      radix salvia planted in Zhongjiang, Sichuan province under the good agricultural
      procedure (GAP). METHOD: After being prepared, the reference material was
      digested with 65% HNO3 and H2O2 by microwave-assisted oven systems, and the heavy
      metals in Radix salvia reference material were accurately determined by
      inductively coupled plasma mass spectrometry (ICP-MS). RESULT: The measuring
      method was validated by running certificated reference materials, including bush
      twigs and leaves (GBW07602) and tea twigs and leaves (GBW07605) under the same
      conditions. The recoveries of the elements mostly ranged from 90% to 110%, and
      the RSD was within 5%. The measurement of radix salvia reference material was
      carried out by different laboratories with ICP-MS and by several time intervals
      in one year for the stability. The results showed that the concentration of the
      heavy metals provided were accurate and the reference material was stable.
      CONCLUSION: The reference material is suitable to be the criterions of heavy
      metals for radix salvia in the qualities controlling, and is also suitable to be
      the criterion of poisonous heavy metals of other herbs in the administration of
      GAP.

PMID- 15015370
TI  - [Application of hierarchical cluster with high-performance liquid chromatography
      in the classification of genus Clinopodium chinensis].
AB  - OBJECTIVE: To realize the relationships of the plants of genus C. chinensis in
      our country and confirm the feasible quality of the application of Hierarchical
      cluster in the classification of genus C. chinensis. METHOD: The chemical
      information of 20 samples of 10 kinds of plants was obtained with high
      performance liquid chromatographic method and classification based on their
      chemical information was made through Hierarchical cluster. Flavonoids and
      saponins were the main components of the C. chinensis plants. We did the high
      performance liquid chromatography from the flavonoids and saponins side
      respectively. RESULT: Expected results were achieved in the Hierarchical clusters
      of the chromatographic data of the plants of genus C. chinensis which supplied
      the foundation for studying crude drugs categorys and those close of C.
      chinensis. CONCLUSION: The cluster and identification results show the method is
      acceptable, simple, rapid, inexpensive and repeatable.

PMID- 15015371
TI  - [Study on the fingerprints of the alkaloids in Sophora flavescens].
AB  - OBJECTIVE: To establish a method for HPLC fingerprint determination of the
      alkaloids in S. flavescens. METHOD: RP-HPLC, linear gradient elution, LC/MS, etc.
      were used to determine the fingerprint and identify the main peaks in the HPLC
      fingerprint. RESULT: A satisfactory method for HPLC fingerprint determination of
      the alkaloids in S. flavescens. was established, and 5 peaks in the HPLC
      fingerprint were identified. CONCLUSION: The perfect fingerprint can be obtained
      and the method can be used for quality control of S. flavescens.

PMID- 15015372
TI  - [Identification on genuine and pseudo shayuanzi collected from different place by
      HPLC fingerprint].
AB  - OBJECTIVE: To establish the identification method for genuine and pseudo
      Shayuanzi by HPLC fingerprint. METHOD: The flavone, a kind of active composition
      in genuine (Astragalus complanatus) and analysed species was analysed by RP-HPLC.
      RESULT: The fingerprints of genuine Shayuanzi collected from different places
      showed the similar characteristics, but they were different from those of pseudo
      species A. adsuragen and A. sinicus. CONCLUSION: The HPLC fingerprint can be an
      identifing method for Shayuanzi.

PMID- 15015373
TI  - [Studies on chemical constituents in roots of Polygala tenuifolia].
AB  - OBJECTIVE: To study the chemical constituents from the roots of Polygala
      tenuifolia. METHOD: Column chromatographic techniques were employed for isolation
      and purification of chemical constituents of the plant and the structures were
      elucidated by spectroscopic analysis. RESULT: Five chemical constituents were
      isolated and elucidated as 4-C-beta-glucopyranosyl-1,3,6-trihydroxy-7
      methoxyxanthone (1), 4-C-[beta-D-apiofuranosyl-(1-->6)-beta-D-glucopyranosyl]
      1,3,6- trihydroxy-7-methoxyxanthone (2), presenegenin (3), presenegenin-3-O-beta
      D-glycopyranoside (4) and daucosterol (5), respectively. CONCLUSION: Compounds
      1,3,4 and 5 were isolated from this plant for the first time. Compound 1 is a new
      natural product.

PMID- 15015374
TI  - [Studies on saponin constituents in roots of Panax quinquefolium].
AB  - OBJECTIVE: To examine the saponins constituents in roots of Panax quinquefolium
      cultivated in China. METHOD: The methanol extract from roots of P. quinquefolium
      cultivated in Jiling province of China was extracted by chloroform and n-butanol
      successively. Ten pure saponins were isolated from the n-butanol extract by
      silica gel and RP-8 reversed-phase column chromatography. Their structures were
      identified by means of spectral methods and compared with known compounds.
      RESULT: Ten saponins were isolated from P. quinquefolium. They were identified as
      ginsenoside Rg1(2), Re(5), Rd(7), Rc(8), Rb1(9), Rb2(10), 24(R)-ginsenoside
      Rg3(3), 24(R)-pseudoginsenoside RT5(1), F11(4) and notoginsenoside K(6),
      respectively. CONCLUSION: This work has elucidated the saponins constituents of
      P. quinquefolium cultivated in Jilin province of China and has shown that
      compound 1 was isolated from this plant for the first time.

PMID- 15015375
TI  - [Studies on chemical constituents in leafs of Ilex kudingcha].
AB  - OBJECTIVE: To study chemical constituents of Ilex kudingcha. METHOD: The
      constituents were isolated by chromatographic method and the structures were
      identified on the basis of spectral analysis. RESULT: Seven compounds, lupeol(I);
      3 beta-hydroxyl-lup-20(29)-ene-24-methyl ester(II); lup-20(29)-ene-3 beta-, 24
      diol(III); beta-sitosterol(IV); ursolic acid(V); daucosterol (VI); mannitol were
      obtained(VII). CONCLUSION: I, III, VI and VII compounds were obtained from genus
      Ilex for the first time.

PMID- 15015376
TI  - [Distinctive compound in Rhizome of Pinellia ternata].
AB  - OBJECTIVE: To look for and determine the distinctive compound in Pinellia
      ternata. METHOD: With TLC, HPLC, the distinctive compound was found and obtained
      by using the method of HPLC preparation. Its structure was elucidated by spectral
      analysis and physico-chemical properties. RESULT: The compound was identified as
      inosine. CONCLUSION: Inosine is the distinctive compound in Rhizome of P.
      ternata, and it was isolated from Banxia for the first time.

PMID- 15015377
TI  - [RP-HPLC determination of mangiferin in the leafs of Folium mangiferae sampled in
      different months and regions].
AB  - OBJECTIVE: To develop a new method for determination of Mangiferin in the leafs
      of Folium mangiferae. By this new method, Mangiferin in F. mangiferae sampled in
      different months and in different regions was determinated. METHOD: A RP-HPLC
      method was set up, using Shim pack CLC-ODS column, methanol-0.05 mol.L-1
      H3PO4(65:134, pH 3.5) as mobile phase, with 258 nm of detection wave, at room
      temperature, 1 mL.min-1. F. mangiferae sampled in Nanning, Qinzhou and Tianyang,
      Guangxi province and sampled respectively in January to December were
      determinated. RESULT: The average recovery of the RP-HPLC was 99.2%, RSD = 1.05%
      (n = 5). The content of Mangiferin in F. mangiferae was statistically different
      due to different sample-regions or sample-time. CONCLUSION: This RP-HPLC method
      is simple, specific and exact. The contents of Mangiferin in the leafs of F.
      mangiferae sample in Nanning and Tinayang were statistically similar, but higher
      than that in Qinzhou. The contents of Mangiferin in the leafs of F. mangiferae
      sampled in July to October were higher than that in the other months. The content
      in September was the highest, the content in February was the lowest.

PMID- 15015378
TI  - [A comparison of the protective activity of liver injury induced by D-galact
      osamine between huangqin-tang and their metabolites by human intestinal
      bacteria].
AB  - OBJECTIVE: To compare the protective activity of liver injury induced by D
      galactosamine (GalN) between Huangqin-Tang and their metabolites by human
      intestinal bacteria(HIB). METHOD: The liver injuries in conventional and pseudo
      germfree mice were induced by GalN. After oral administration of Huangqin-Tang
      and their metabolites mixtures by HIB, the serum transaminase (ALT and AST)
      activities were detected. RESULT: In conventional mice, large and medium doses
      (20 and 10 g.kg-1) of Huangqin-Tang decoction significantly reduced the increase
      of serum ALT activity after 18 h GalN treatment. In pseudo-germfree mice,
      metabolites significantly reduced the ALT levels. However, Huangqing-Tang didn't
      affect the ALT levels in this kind of mice. To all of the animals, AST levels
      remained the same after oral Huangqin-tang or their metabolites. CONCLUSION: The
      metabolism by intestinal bacteria plays a role in pharmacological effects of
      constituents of Chinese herbal medicine. The metabolites of the constituents by
      intestinal bacteria were the real active components in vivo.

PMID- 15015379
TI  - [Effects of Valeriana officinalis var. latifolia on expression of transforming
      growth factor beta 1 in hypercholesterolemic rats].
AB  - OBJECTIVE: To evaluate the effect of Valeriana officinalis var latifolia(VOL) on
      expression of transforming growth factor beta 1 (TGF-beta 1) in
      hypercholesterolemic rats and study its possible mechanisms. METHOD: Dietary
      induced hypercholesterolemia was induced in male Wistar rats by given 4%
      cholesterol and 1% cholic acid diet for 16 weeks. Changes of serum lipid, urinary
      albumin, renal function and Mesangial matrix index were assessed. Moreover,
      immunohistochemical stain for TGF-beta 1 and type IV collagen were performed.
      RESULT: VOL could reduce the serum levels of total cholesterol, low density
      lipoprotein, urinary albumin and serum creatinine. Light microscopy and
      immunohistochemical stain revealed that in the same time of lowing serum lipid,
      Mesangial matrix index was significantly reduced, accompanied by decreased
      expression of TGF-beta 1 and type IV collagen. CONCLUSION: VOL has the protective
      effect on lipid-induced nephropathy, and the inhibition of TGF-beta 1 expression
      might be the mechanism of VOL on renal protection.

PMID- 15015380
TI  - [Analysis of anthraquinones in serum and urine after oral administration of semen
      Cassiae].
AB  - OBJECTIVE: To analysie the anthraquinones absorbed into serum by different
      animals (or human beings) after oral administration of Semen Cassiae. METHOD:
      Anthraquinones in serum and urine of rats and urine of healthy men after taking
      Semen Cassiae orally were detected with HPLC. RESULT: Only some of the
      anthraquinones were absorbed into serum. There were differences in absorption and
      metabolism of anthraquinones between rats and men and some new anthraquinones
      were produced in the process. CONCLUSION: Anthraquinones absorbed into serum by
      the experimental animals or men should become target for researching into active
      compounds of anthraquinones in Semen Cassiae.

PMID- 15015381
TI  - [The relationship between the protection of ginsenoside for spinal cell and
      nitric oxide].
AB  - OBJECTIVE: To study the relationship between the protection of Ginsenoside(GS)
      for spinal cells and nitric oxide (NO). METHOD: Spinal cells were cultured in
      vitro, the model of peripheral nerve was established by scarifying the cells, and
      NO was measured by Griess method. RESULT: NO in injury group was high than that
      in noninjury group and NO in group cultured by GS was less than that in group
      cultured by common medium. CONCLUSION: NO increases when peripheral nerve is
      injuried, and the protective effect of GS on spinal cells may be through
      inhibiting NO release.

PMID- 15015382
TI  - [Effect of daidzein on antiarrhythmia].
AB  - OBJECTIVE: To study the effect of Daidzein on Antiarrhythmia. METHOD: The
      conventional antiarrhythmia methods were used. RESULT: Daidzein was remarkedly
      effective in preventing ventricular fibrillation induced by chloroform in mice
      and arrhythmia induced by aconitine in rats. The arrhythmia induced by adrenalin
      in rabbits was antagonized by Daidzein and it could obviously inhibit the action
      potential amplitude of isolated sciatic nerves in toads. And it could also
      prevent ventricular fibrillation induced by calcium chloride in rats, and
      obviously reduce the death rate of rats. Its anti-arrhythmic effect was dose
      dependent. CONCLUSION: Daidzein has obvious protective effect on drug-induced
      arrhythmia, which may be related to its inhibition of Na+ or Ca2+ influx and its
      blocking beta-adrenergic receptor.

PMID- 15015383
TI  - [Study of cerebral protective effects of naosaitong in animals].
AB  - OBJECTIVE: To investigate the influence of Naosaitong (NST) on the cerebral blood
      flow (CBF), the infarct areas and blood rheology in animals. METHOD: NST's
      cerebral protective effects were investigated by using middle cerebral artery
      occlusion (MCAO), bilateral common carotid artery ligation, and carrogeenin
      induced thrombus model rats, being administrated with medicine for seven days.
      RESULTS: Three dosage groups of NST increased CBF in anesthetized rabbits,
      reduced the infarct areas in MCAO rats, decreased the physical sign indexes, and
      water quantities. They increased the activities of Glutathione peroxidase (GPX)
      and Catalase (CAT), decreased the contractions of Lipid peroxidase (LPO) and
      Lactate (LD) in the cerebral ischemia-reperfusion rats; shortened the length of
      thrombus and improved the blood rheology in the carrogeenin-induced thrombus
      model rats, and prolonged hypoxia-resisting time in mice. CONCLUSION: NST can
      evidently increase CBF in rabbits, improve the cerebral edema brain tissues'
      injure and nervous physical sign indexes in the cerebral ischemia-reperfusion
      rats, reduce the infarct areas in MCAO rats, postpone thrombosis course and have
      antioxidation effects, which show that NST can obviously protect the brain
      tissues in the experimental cerebral infarct model rats.

PMID- 15015384
TI  - [Effect of shu di-huang on the transmitter and receptor of amino acid in brain
      and learning and memory of dementia model].
AB  - OBJECTIVE: To observe the mechanism of SHU-Dihuang on the function of learning
      and memory. METHOD: On the dementia model mouse caused by AlCl3 and the rats
      model damaged thalamic arcuate nucleus with MSG, we observed the function of
      learning and memory by step down task and Morris water maze task, mensurated the
      content of glutamic acid and gamma-aminobutyric acid by TLC, and observed the
      expression of NMDAR1 and GABAR in hippocampi by immunohistochemical means.
      RESULT: Shu Di Huang could decrease the times of mistakes and prolong the
      incubation period in step down task, and shorten the incubation period of seeking
      the platform in Morris water maze task. Shu Di Huang could adjust the content of
      Glu and GABA in brain, and increase the expression of hippocampal NMDAR1 and
      GABAR as well. CONCLUSION: Shu Di Huang can improve the function of learning and
      memory of dementia animal model, and its mechanism may be related to the
      adjustment of the content of Glu and GABA in brain, and increase of the
      expression of hippocampal NMDAR1 and GABAR.

PMID- 15015385
TI  - [Effect of qianlie huichun capsular on Fas expression and cell apoptosis of
      prostate gland tissue in rat].
AB  - OBJECTIVE: To investigate the effect of Qianlie Huichun capsular on Fas
      expression and cell apoptosis of prostate gland tissue in the model rat. METHOD:
      Hypertrophy of prostate model rat was established by injecting testosterone to
      gelding male rats. After being treated with Qianlie Huichun ig 30 days, the rats
      were killed and prostate glands were resected for examination. The Fas expression
      was examined by immunobistochemical SABC. The cell apoptosis and the peak of cell
      apoptosis in the prostate gland of the rats were examined by flow cytometry.
      Compared with model group, the weight of prostage gland tissue in groups treated
      with Qianlie Huichun capsular was light (P < 0.01). RESULT: Compared with model
      group, the Fas expression in all treatment groups increase(P < 0.05, P < 0.01).
      Compared with normal and model groups, cell apoptosis in all treatment groups
      increase at different level(P < 0.01). CONCLUSION: The Qianlie Huchun capsular
      increases the Fas expression and cell apoptosis of model rats, and shows a
      definite treatment effect on the hypertrophy of prostate by promoting the
      apoptosis of prostate cell.

PMID- 15015386
TI  - [The effects of silymarin on hepatic microsomal and mitochondrial membrane
      fluidity in mice].
AB  - OBJECTIVE: To observe the effects of silymarin on hepatic microsomal and
      mitochondrial membrane fluidity in mice. METHOD: Liver microsomal and
      mitochondrial membranes were labled by ANS and DPH. Membrane fluorensent
      intensity (F), fluorensent polarization(P) and microviscosily(eta) of liver
      microsome and mitochondria were determined. RESULT: Sil increased the external
      membrane fluidities of liver microsome and mitochondria, and decreased the
      internal membrane fluidities of liver microsome and mitochondria. Pretreatment
      with CCl4, the external membrane fluidity of liver microsome and mitochondria
      were increased, and the internal membrane fluidities of liver microsome and
      mitochondria were decreased. After given sil 140,280 mg.kg-1, the increased
      external membrane fluidities of liver microsome and mitochondria were lowered,
      and the decreased internal membrane fluidities of liver microsome and
      mitochondria were enhanced in a dose-dependent manner. CONCLUSION: The protective
      effects of sil on liver injury may be related to the recovery of the membrane
      fluidities of liver microsome and mitochondria.

PMID- 15015388
TI  - [Comparative study on angiogenesis effect of Astragalus membranaceus and Angelica
      sinensis in chick embryo choriollantoic membrane].
AB  - OBJECTIVE: To explore the angiogenesis effect of Astragalus membranaceus and
      Angelica sinensis with different ratio in chick embryo chorioallantoic membrane
      (CAM). METHOD: Chicken CAM model was adopted. The rat blood serum containing
      different ratio of Astragalus membranaceus and Angelica sinensis was put daily
      into 3-day chick embryo. CAMs and CAM angiogenesis were observed at 72 h after
      incubation. RESULT: Better effects were obtained in the formation of capillary
      and the count of blood vessel in groups treated by Astragalus memhranaceus and
      Angelica sinensis in the ratio of five to one, compared with the NS control group
      and the other ratio groups of Astragalus memhranaceus and Angelica sinensis.
      CONCLUSION: Astragalus memhranaceus and Angelica sinensis in 5:1 ratio have
      certain promotive effect on the formation of capillary. The Danggui Buxue
      Decoction has the best ratio.

PMID- 15015389
TI  - Welcome to the virtual hospital library.

PMID- 15015387
TI  - [Antioxidation activity and protective effection of ginger oil on DNA damage in
      vitro].
AB  - OBJECTIVE: To study the antioxidation activity and protective effect of ginger
      oil on DNA damage. METHOD: Chemical light assay was used to detect the oxygen
      radicals scavenging capacity of ginger oil. The erythrocyte oxidation damage was
      induced by H2O2. The effect of ginger oil on oxidative erythrocyte was observed
      by the colorimetric analysis assay, and the content of malondialdehyde (MDA) in
      rabit hepatocyte was measured. The anaylsis of DNA damage was made with single
      cell gel electrophoresis(SCGE) technique. RESULT: Ginger oil might decrease light
      value compared with control group and inhibited erythrocyte oxidation damage.
      Compared with that in control group, the degress of DNA damage reduced
      significantly in the protected groups. Ginger oil might decrease the content of
      MDA remarkably and inhitibition rate was 48.16%. CONCLUSION: Ginger oil has
      dominantive protective effect on DNA damage induced by H2O2. Ginger oil might act
      as a scavenger of oxygen radical and might be used as an antioxidant.

PMID- 15015390
TI  - Chronic obstructive pulmonary disease: resource list for healthcare professionals
      & consumers.

PMID- 15015391
TI  - Never pay retail again. HHS' Thompson says hospitals' discounts to uninsured are
      legal, as advocates celebrate and hospitals ponder pricing strategies.
AB  - Consumer advocates praised HHS' assertion that hospitals can legally give
      discounts to the uninsured, but hospitals expressed more cautious optimism. The
      declaration fell short of a legal safe harbor, which the AHA requested, and Dara
      Corrigan, left, HHS' acting principal deputy inspector general, says hospitals
      will have to be careful. Still, the decision may prompt more hospitals to change
      billing practices.

PMID- 15015393
TI  - Harmonic divergence. Cedars-Sinai joins others in holding off on CPOE.

PMID- 15015392
TI  - Indigent-care spending low.

PMID- 15015394
TI  - Foreign certification. AHA seeks delay on regs for immigrant nurses.

PMID- 15015395
TI  - Someday we'll all be on the same page. The long journey toward common health data
      record-keeping is well under way.

PMID- 15015396
TI  - Capital crunch eats away at IT. Annual survey shows lack of funding among
      obstacles slowing adoption of computerized physician order entry, other projects.

PMID- 15015397
TI  - Boosting IT immunity. Expanding computer networks and widespread use of the
      Internet leave healthcare systems highly vulnerable to viral attacks.

PMID- 15015398
TI  - Connect the docs. Study shows IT issues could create common ground for physicians
      and hospitals.

PMID- 15015399
TI  - It's about time. The government is focusing on healthcare IT--and AMDIS couldn't
      be happier.

PMID- 15015400
TI  - On the defensive. A physician's confidence can shatter in the wake of a lawsuit.

PMID- 15015401
TI  - The numbers speak for him. Richard Cartabuke, M.D., named first AAASC/MP Medical
      Director of the year.

PMID- 15015403
TI  - Perspectives. Policymakers seek elusive cures for health disparities.

PMID- 15015402
TI  - The list. Number of physicians by specialty; median physician compensation.

PMID- 15015404
TI  - Kerry & Agent Orange.

PMID- 15015406
TI  - Policing a rural plague.

PMID- 15015405
TI  - Protecting the welfare state.

PMID- 15015407
TI  - The war on strokes.

PMID- 15015408
TI  - How a brain heals.

PMID- 15015409
TI  - Automate--without an EMR.

PMID- 15015410
TI  - Voice recognition moves up a notch.

PMID- 15015411
TI  - White coat. Red face. Doctors' most embarrassing moments.

PMID- 15015412
TI  - My malpractice carrier broke my heart.

PMID- 15015413
TI  - Should you give references?

PMID- 15015414
TI  - When did this patient die?

PMID- 15015415
TI  - Our search for marketing magic.

PMID- 15015416
TI  - How to neutralize the sympathy factor.

PMID- 15015417
TI  - Make your payment policy clear.

PMID- 15015419
TI  - My stand against DTC ads.

PMID- 15015418
TI  - If you consult for a medical spa.

PMID- 15015420
TI  - The new landscape: a fresh look at long-term incentives for corporate America.
AB  - Today's environment presents us with a torrent of issues surrounding the design
      and management of long-term and equity-related incentives, both for top
      executives and employees at large. This article reviews, at a conceptual level,
      the most important characteristics, advantages and disadvantages of the various
      principal long-term incentive types as they appear from key perspectives. The
      authors conclude with predictions about the future of long-term and equity
      related incentives.

PMID- 15015421
TI  - The "perfect storm" in compensation: convergence of events leads to a greater
      need to review compensation strategies.
AB  - The recent unprecedented convergence of significant strategic events in the
      compensation arena has created the need for ongoing and extensive compensation
      planning. This article reviews the events leading to this point, describes the
      implications of the results from a recent Aon study with WorldatWork, and
      suggests what employers can do to successfully navigate the "perfect storm" in
      compensation.

PMID- 15015422
TI  - Value rules: senior management incentives in the post-option era.
AB  - Big changes are in the news and on boardroom agendas. This is a good time for
      many companies to step back and think fundamentally about how senior management
      incentives are structured and how these programs should be redesigned for better
      business results. This article describes the main problems with current incentive
      structures. It then shows how "value rules" can help employers make better use of
      incentive plans and create a real stake in business units' long-term results, so
      that the overall structure of executive incentives consistently encourages value
      creation for shareholders.

PMID- 15015423
TI  - Executive pay trends and golden parachute tax: a collision on the horizon.
AB  - Ironically, many corporations will likely discover that tying equity-based
      executive compensation more closely to performance will cost millions of dollars
      when there is a merger or acquisition. The reason: Internal Revenue Code Section
      280G, which is designed to discourage "excess" parachute payments, often assesses
      a significantly higher toll on performance-based compensation than on time-vested
      equity payments. There is no magic remedy, but advance planning can often help
      mitigate the impact. This article describes the dilemma and suggests several
      approaches to the challenge.

PMID- 15015424
TI  - Sales compensation governance: the last frontier of corporate reform.
AB  - The area of sales compensation has remained relatively untouched by recent
      pressures for compensation reform. This article highlights some of the ways that
      sales organizations stumble in managing their compensation programs, and why it
      takes more than a simple tactical fix to address these problems effectively. The
      authors describe a more structured governance framework that not only identifies
      and resolves key sales compensation issues, but ultimately safeguards the
      effectiveness and financial integrity of the sales organization itself.

PMID- 15015425
TI  - The HIPAA privacy rule and HR/benefits outsourcing: does the business associate
      label belong on your recordkeeper?
AB  - Employers that sponsor group health plans and serve as the plan administrator of
      those plans are required by the HIPAA Privacy Rule to execute business associate
      contracts with vendors that provide services on behalf of the plans. The business
      associate contracts must contain many specific provisions regarding the
      protection, use and disclosure of health information. This article looks at the
      implications of imposing business associate contract obligations on an integrated
      HR and benefits-outsourcing recordkeeper and cautions employers against an overly
      broad application of the requirements.

PMID- 15015426
TI  - Public sector health benefits--same-sex domestic partners. Irizarry v. Board of
      Education of the city of Chicago, 251 F.3d 604 (7th Cir. 2001).

PMID- 15015427
TI  - Trinkaus: an informal look.

PMID- 15015428
TI  - The new drug war.

PMID- 15015430
TI  - Your next survey will be customized; get ready for JCAHO's priority focus.

PMID- 15015429
TI  - Biology's bad boy is back.

PMID- 15015431
TI  - Measures help surveyors compare hospitals.

PMID- 15015432
TI  - Help pharmacists meet new medication standards.

PMID- 15015433
TI  - Patient Satisfaction Planner. Centralized schedulers are boon to efficiency.

PMID- 15015434
TI  - Patient Satisfaction Planner. Nurses play strong role in patient satisfaction.

PMID- 15015435
TI  - Killer practitioners: what can you do to stop them?

PMID- 15015436
TI  - Are your care continuum linkages strong or weak?

PMID- 15015437
TI  - [Multicenter prospective study on relationship of TCM syndrome type and renal
      pathology in 286 patients with IgA nephropathy].
AB  - OBJECTIVE: To study the distribution pattern of TCM Syndrome type and its
      relationship with renal pathology in patients with IgA nephropathy. METHODS:
      Apopting multicenter coordinated method, patients' TCM Syndrome type was
      differentiated according to their clinical manifestations, data concerning
      laboratory examination and renal pathology were collected to establish a database
      for analyzing the relationship between TCM Syndrome type and renal pathology in
      286 patients. RESULTS: Patients of Pi-Fei Qi-deficiency type (type 1) and both Qi
      Yin deficiency type (type 2) showed rather milder pathological changes, by Lee
      classification, most of them belonged to grade I-III (72.3%, 70.2%); patients of
      Gan-Shen Yin deficiency type (type 3) had severe pathological change and majority
      of them belonged to grade III-IV (84.6%); and the most severe pathological change
      was shown in patients of Pi-Shen Yang-deficiency type (type 4), and the Lee's
      grade IV-V was dominant (88.0%) in them. Syndrome type of patients was
      significantly correlated with their Lee's grade (r = 0.26, P < 0.01). Percentage
      of glomerular sclerosis in patients of type 4 was higher than that in patients of
      the other three types. Semi-quantitative scoring upon pathological changes showed
      that the total, glomerular, tubulo-interstitial and vascular scores were
      significantly higher in patients of type 4 than in those of the other three
      types; those scores were higher in patients of type 3 than in type 1; the total,
      glomerular and vascular scores were higher in patients of type 3 than in type 2;
      and scores in patients of type 1 and type 2 showed insignificant difference.
      CONCLUSION: Multicentric prospective study proves that the TCM Syndrome typeof
      patients with IgA nephropathy is significantly correlated with the grade and
      severity of their renal pathological changes, thus, the TCM Syndrome typing shows
      definite referential importance to conclude the severity of renal pathological
      change in patients with IgA nephropathy.

PMID- 15015439
TI  - [Effect of jiawei yupingfeng powder on T-lymphocyte subsets in patients with
      senile chronic bronchitis in acute onset stage].
AB  - OBJECTIVE: To explore the effect of Jiawei Yupingfeng Powder (JYP) on T
      lymphocyte subsets in patients with senile chronic bronchitis in acute onset
      stage (SCB-AOS). METHODS: Patients were divided, according to the randomized
      controlled principle, into two groups, the 44 patients in the treated group and
      the 40 in the control group. The conventional western medicinal therapy was given
      to both groups, but to the treated group, JYP was administered additionally. The
      therapeutic course to them was 14 days. Changes of CD3, CD4, CD8 and the ratio of
      them were observed. RESULTS: Increase of CD3, CD4 and CD4/CD8 (P < 0.05) and
      decrease of CD8 (P < 0.01) were significantly shown in the treated group after
      treatment, but no change in the control group. Besides, comparison of the total
      effective rate in the two groups also showed significant difference (P < 0.05).
      CONCLUSION: Cellular immune function disturbance exists in patients with SCB-AOS,
      JYP could enhance the efficacy by way of modulating cellular immune function.

PMID- 15015440
TI  - [Clinical study on treatment of severe acute respiratory syndrome by integrative
      Chinese and Western medicine].
AB  - OBJECTIVE: To evaluate the effect of integrative Chinese and western medicine
      (ICWM) in treating severe a cute respiratory syndrome (SARS). METHODS: Sixty SARS
      patients were diagnosed and observed according to the universal standard, and
      divided into the ICWM group (n = 31, treated with ICWM) and the control group (n
      = 29, treated by conventional western medicine alone). RESULTS: ICWM showed
      better effect than that of western medicine alone in improving clinical symptoms,
      promoting the absorption of inflammation in lung, increased oxygen saturation (P
      < 0.01) and decreased the dosage of corticoid used (P < 0.05). CONCLUSION: The
      effect of ICWM is better than that of simple western medicine in treating SARS.

PMID- 15015438
TI  - [Effect of combination of bushen jianpi recipe and erythropoietin on serum tumor
      necrosis factor alpha in patients with anemia].
AB  - OBJECTIVE: To study the effect of treatment of renal anemia by combination of
      Bushen Jianpi Recipe (BJR, a Chinese experience recipe for supplementing Shen and
      supporting Pi) and low dosage erythropoietin (EPO), and the influence of
      treatment on change of serum tumor necrosis factor alpha (TNF-alpha) so as to
      explore the possible mechanism of integrative Chinese and western medicine (ICWM)
      in treating renal anemia. METHODS: Patients with renal anemia were randomly
      divided into two groups, the ICWM group and the control group, symptomatic and
      supporting treatment such as dialysis, supplementing of ferrous, foliac acid and
      vitamin B12, was given to both groups. Additionally, to the ICWM group, 50 IU/kg
      of EPO subcutaneous injection for twice every week, and oral intake of BJR, one
      dose per day taken in two parts, were given, and to the control group, EPO alone,
      50 IU/kg by subcutaneous injecting, 3 times per week, was given. The therapeutic
      course for two groups was 3 months. Blood levels of hemoglobin (Hb), hematocrit
      (Hct), TNF-alpha were measured before treatment and the therapeutic effect was
      observed. RESULTS: After treatment, the levels of Hb and Hct increased
      significantly in both groups (P < 0.01), comparison between the two groups in Hb
      and Hct after being treated for 3 months showed significant difference (P <
      0.05). The serum level of TNF-alpha was markedly higher than normal range in both
      groups before treatment, it significantly lowered after treatment in the ICWM
      group (P < 0.05), but unchanged in the control group. CONCLUSION: Combination of
      BJR and EPO could significantly inhibit the production of TNF-alpha, this may be
      an important factor for ICWM in effectively improving sensitivity to EPO.

PMID- 15015441
TI  - [Clinical observation on treatment of female delayed acne vulgaris with qingre
      cuochuang tablet].
AB  - OBJECTIVE: To observe the clinical therapeutic effect of Qingre Cuochuang tablet
      (QCT) in treating female delayed acne vulgaris (FDAV, with patients age more than
      25 years old), to evaluate objectively the sexual hormone in patients and to
      assess the effect of QCT on sexual hormone. METHODS: Sixty FDAV patients were
      randomly divided into the treated group (n = 40) and the control group (n = 20),
      they were treated with QCT and western medicine (including antisterone,
      tetracycline and metronidazole) respectively. Besides, 10 healthy female subjects
      aged > or = 25 years were selected as normal control. Serum levels of
      testosterone (T) and estradiol (E2) in all patients and healthy subjects as well
      as the clinical therapeutic effect of the treatments were observed and compared.
      RESULTS: The total effective rate in the treated group and the control group was
      92.5% and 90.0% respectively, comparison between them showed insignificant
      difference. Serum level of T in the patients before treatment were higher than
      that in healthy subjects (P < 0.01), and showed no difference between the treated
      group and the control group. After treatment, it lowered significantly in the
      treated group (P < 0.01), but unchanged in the control group, E2 level showed no
      significant change in both groups before and after treatment. CONCLUSION: QCT has
      definite clinical effect in treating FDAV, it could lower the serum level of T
      and with few adverse reaction.

PMID- 15015443
TI  - [Modulatory effect of Astragalus membranaceus on Th1/Th2 cytokine in patients
      with herpes simplex keratitis].
AB  - OBJECTIVE: To explore the influence of Astragalus membranaceus (AM) on serum
      cytokines, Th1, including interleukin-2 (IL-2) and gamma-interferon (gamma-IFN),
      and Th2, including interleukin-4 (IL-4) and interleukin-10 (IL-10), in patients
      with herpes simplex keratitis (HSK). METHODS: One hundred and six HSK patients
      were randomly divided into the AM treated group and the ribavirin treated group.
      Levels of serum IL-2, IL-4, IL-10 and gamma-IFN of all the patients and 62
      healthy person, selected from donors for control group, were determined by
      sandwich enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: Levels of
      serum IL-4 and IL-10 in HSK patients were significantly higher and those of IL-2
      and gamma-IFN were significantly lower than those in the healthy control (all P <
      0.01). These parameters were significantly improved in the patients of the AM
      group after treatment, but with no change in patients of the ribavirin group.
      CONCLUSION: AM can modulate the imbalance state of Th1/Th2 in HSK patients,
      improve their immune function disturbance, that shows important significance in
      treating HSK.

PMID- 15015442
TI  - [Effect of kebimin decoction in treating allergic rhinitis and on blood levels of
      nitric oxide and superoxide dismutase].
AB  - OBJECTIVE: To observe the therapeutic effect of Kebimin decoction (KD) on
      allergic rhinitis (AR) and its effect on blood levels of nitric oxide (NO) and
      superoxide dismutase (SOD) activity. METHODS: Eighty-two AR patients were
      randomly divided into two groups, the treated group and the control group, 41 in
      each group. To the treated group, KD was given one dose per day for 10 days as
      one therapeutic course and 1-3 courses were given successively. The control group
      was treated with Xinfang Rhinitis capsule for 30 days. Blood levels were
      determined and compared before and after treatment. RESULTS: The total effective
      rate in the treated group was 93%, which was better than that in the control
      group (51%), the difference was significant (chi 2 = 17.704, P < 0.01). Serum
      level of NO was higher and that of SOD activity was lower in the AR patients than
      that in healthy persons (P < 0.01), KD could significantly lower the former and
      increase the latter (P < 0.01). CONCLUSION: The therapeutic effect of KD in
      treating AR was significant, its mechanism might be related with the lowering of
      NO and increasing of SOD activity in serum, as well as the scavenging of oxygen
      free radical.

PMID- 15015444
TI  - [Observation on treatment of post-remission acute myeloid leukemia patients by
      lingxiong piaoling powder and longchan cigu decoction].
AB  - OBJECTIVE: To explore the effect of the treatment for long-term disease-free
      survival (DFS) of post-remission patients with acute myeloid leukemia (AML).
      METHODS: Twenty-nine AML patients with completely remission (CR) and 17 with
      partial remission (PR) were treated with Chinese medicine, Longchan Cigu
      Decoction 1 dose per day and Lingxiong Piaoling Powder 7 doses per month, and
      combined with DA or HA regimen of chemotherapy one course per year. Patients
      peripheral blood picture, bone marrow smear, biopsy and human leukocyte antigen
      DR (HLA-DR) cells were examined before and after treatment, and their disease
      free survival (DFS) was followed up. RESULTS: After treated with above mentioned
      treatment for 2 months, percentage of patients with normal peripheral blood count
      increased, including patients with WBC > or = 4.0 x 10(9)/L raised from 46% to
      70%, with Hb > or = 120 g/L from 17% to 46% and with PLT > or = 100 x 10(9)/L
      from 63% to 85%; nucleated cell volume in bone marrow increased from 35.83 +/-
      28.42% to 60.46 +/- 17.73% (P < 0.01); HLA-DR cell was also increased
      significantly from 10.55 +/- 4.95% to 14.84 +/- 4.94%, (P < 0.01); while the
      residual leukemia cells were not increased in one year, from 5.90 +/- 5.09%
      before and 5.82 +/- 2.42% after treatment (P > 0.05). The maximal DFS in patients
      was 123 months. The 3-year survival rate was 64.15 +/- 1.96% and 5-year survival
      rate was 51.19 +/- 16.25%. CONCLUSION: The integrative Chinese and western
      medicine treating program used in this study is beneficial for the long-term
      treatment of AML patients after complete remission.

PMID- 15015445
TI  - [Effect of panaxadiol saponin and panaxtrol saponin on proliferation of human
      bone marrow hemopoietic progenitor cells].
AB  - OBJECTIVE: To observe the effect of panaxadiol saponin (PDS) and panaxtrol
      saponin (PTS) on proliferation of human bone marrow hemopoietic progenitor cells
      (HPC). METHODS: PDS and PTS were separated and purified from ginsenosides, and
      the effects on HPC were studied using in vitro hemopoietic progenitor cell colony
      forming technique, by observing the proliferation of human burst forming unit
      erythroid progenitor (BFU-E), colony-forming unit-erythroid (CFU-E), colony
      forming unit-granulocyte/macrophage (CFU-GM) and colony-forming unit-pluripotent
      hemopoietic progenitor (CFU-Mix) in mice after PDS and PTS stimulation. RESULTS:
      Different concentration of PDS (2.5-200 micrograms/ml) could stimulate the
      proliferation of HPC obviously, showing increase of CFU-E, BFU-E, CFU-GM and CFU
      Mix by 54.9 +/- 6.3%, 48.8 +/- 5.1%, 27.6 +/- 4.2% and 48.9 +/- 3.9%
      respectively, which was higher than that of the control group. While stimulated
      by PTS of the same concentration, the CFU-E and BFU-E was lower than that of
      control significantly (P < 0.05); when the terminal concentration of PTS was 200
      micrograms/ml, CFU-E and BFU-E was zero respectively. In the CFU-GM culture, PTS
      in concentration of 12.5 micrograms/ml could cause the proliferation increased by
      29.7 +/- 2.2% (P < 0.05), but in concentration of 100 micrograms/ml and 200
      micrograms/ml, it showed inhibitory effect on CFU-GM, the inhibition rate being
      48.6 +/- 3.9% and 100% respectively. CONCLUSION: PDS is the effective component
      of ginsenosides in stimulating proliferation of human bone marrow HPC. PTS is an
      component with inhibitory action on proliferation of CFU-E and BFU-E and its
      effect on CFU-GM was depending on its concentration.

PMID- 15015446
TI  - [Experimental study on treatment of pulmonary fibrosis by Chinese drugs and
      integrative Chinese and Western medicine].
AB  - OBJECTIVE: To compare the effects of treatment of pulmonary fibrosis (PF) by the
      Chinese herbal medicines, Radix Salviae miltiorrhizae (C1), Radix Astragalus
      membranaceus (C2) and Caulis Tripterygium wilfordii (C3); western drugs,
      hydrocortisone (W1) and azathioprine (W2), and combined W2 with C3. METHODS:
      Eighty SD rats were divided into 8 groups. Except the 10 rats in the normal
      control group, the other 70 rats were made into animal model of PF by bleomycin
      administration, and treated with various medicines, except the 10 rats in the
      model control group. The treatment started from the 15th day of modeling, the
      model animals were perfused with C1, C2, C3, W1, W2 and W2 + C3 respectively for
      14 days. Rats were sacrificed by the end of experiment, their lung tissue was
      taken for pathological section to conduct the pathological examination under
      light microscope and computerized image quantitative analysis to evaluate the
      effects of the treatments objectively. RESULTS: The therapeutic effect of C1 was
      the best, that of W1 the second and C2 the third. W2 showed some effect, but PF
      worsened after the combined therapy of W2 and C3 was applied. CONCLUSION: Radix
      Salviae miltiorrhizae shows definite therapeutic effect in treating PF.

PMID- 15015447
TI  - [Effect of buyang huanwu decoction drug serum on expression of p53 and p21 genes
      in cultured rat's cerebral cortical neuron after hypoxia in vitro].
AB  - OBJECTIVE: To explore the effect of Buyang Huanwu decoction (BHD) drug serum on
      rat's in vitro cultured cerebral cortical neuron apoptosis induced by hypoxia,
      and on the expression of p53 and p21 genes in hypoxia process. METHODS: The model
      of hypoxia neuron apoptosis was established adopting Daniel method and treated
      with BHD drug serum. The neuron apoptosis rate was determined by flow cytometry
      with propidium iodide staining, the p53 and p21 gene expression was tested by
      immunohistochemical method with flow cytometry. RESULTS: BHD could significantly
      inhibit the neuron apoptosis induced by hypoxia and down-regulate the expressions
      of p53 and p21 genes. CONCLUSION: BHD shows inhibition on neuron hypoxia
      apoptosis and down-regulating of the p53 and p21 gene expression is one of its
      mechanisms.

PMID- 15015448
TI  - [Effect of yiqi huoxue huayu recipe on vascular collagen turnover and relevant
      gene expression].
AB  - OBJECTIVE: To explore the effect of Yiqi Huoxue recipe (YHR), a Chinese herbal
      medicine for supplementing Qi, activating blood circulation to remove stasis, on
      vascular extracellular matrix (ECM) remodeling and its molecular mechanism.
      METHODS: Vascular smooth muscle cell (VSMC) proliferation activity and collagen
      turnover rate were detected by 3H-TdR test and hydroxyproline amount determined
      by 3H-Pro incorporation. Expression activity of MMP-2 and osteopontin genes was
      detected by Northern blotting and MMP-2 zymography analysis. RESULTS: YHR could
      markedly inhibit VSMC collagen synthesis stimulated by blasic fibroblast growth
      factor (bFGF) and lower the collagen turnover rate induced by vascular de
      endothelialization. The expression level of MMP-2 and osteopontin genes was down
      regulated by YHR in cultured VSMC and vascular wall with endothelial injury, and
      VSMC proliferation was inhibited by the serum obtained from YHR treated rats.
      Removing protein from the drug serum made no change on the effect of YHR to VSMC.
      CONCLUSION: YHR could inhibit and/or retard ECM remodeling through regulating the
      expression of MMP-2 and osteopontin genes and lowering the collagen turnover
      rate.

PMID- 15015449
TI  - [Experimental study on differentiation of human hepatocarcinoma cells induced by
      zhengganfang drug serum in vitro].
AB  - OBJECTIVE: To study the effect of Zhengganfang (ZGF) drug serum in inducing
      differentiation of Bel-7402 human hepatocarcinoma cell (HHC) and its influence of
      the telomerase activity. METHODS: Rats were fed with ZGF decoction to prepare the
      drug-serum of ZGF, and the drug-serum was used for Bel-7402 HHC culture. Serum of
      normal rat, was taken as negative control and retinoic acid (RA) as the positive
      control. Cell proliferation was detected by MTT colorimetric assay,
      nucleocytoplasm ratio by image assay, alpha-fetoprotein (AFP) by RIA, alkaline
      phosphatase (ALP) activity and gamma-glutamyl transpeptidase (gamma-GT) by
      dynamic colorimetric assay and telomerase activity of Bel-7402 cell by PCR-ELISA.
      RESULTS: Drug-serum of ZGF could inhibit the proliferation of Bel-7402 cell,
      markedly reduce the nucleocytoplasm ratio and the secretion of AFP, decrease
      gamma-GT activity, increase ALP activity and suppress the telomerase activity of
      Bel-7402 cell. CONCLUSION: ZGF can induce the differentiation of Bel-7402 HHC,
      the main mechanism maybe through the suppression of telomerase activity.

PMID- 15015450
TI  - [Effect of yirong oral liquid on the reperfusion injury in rats with cerebral
      infarction undergoing thrombolysis].
AB  - OBJECTIVE: To observe the effect of Yirong Oral Liquid (YROL) on reperfusion
      injury in rats with cerebral infarction undergoing thrombolysis. METHODS:
      Clinical reperfusion under thrombolysis was simulated by applying thrombolysis on
      reversible local cerebral ischemic rat model. In the rat model, effect of YROL on
      parameters concerning anti-oxidation capability, cerebral edema and
      ultrastructure of brain were observed. RESULTS: YROL could alleviate the cerebral
      edema after reperfusion, markedly increase the activity of superoxide dismutase
      in blood plasma, decrease the content of malonyldialdehyde, inhibit the post
      reperfusion lipid peroxidation, and significantly reduce the ischemia/reperfusion
      injury of nerve cells in brain of rat. CONCLUSION: YROL has definite protecting
      effect on brain.

PMID- 15015451
TI  - [Study on the mechanism of naofucong granule in improving memory of cerebral
      ischemic mice].
AB  - OBJECTIVE: To explore the effect of Naofucong Granule (NFCG), a self-manufactured
      Chinese herbal preparation, on memory and cerebral cholinergic system in cerebral
      ischemic mice. METHODS: Mice model of learning/memory impairment was established
      by bilateral ligation of internal carotid arteries. The memory ability of mice
      was assessed by measuring latent period in the Morris Water Maze. RESULTS: Seven
      days after modeling, the latent period and swimming course of mice (82.3 +/- 32.0
      seconds and 986.7 +/- 414.5 cm) were longer than those of control (sham-operated
      mice, 35.3 +/- 37.9 seconds and 410.4 +/- 507.0 cm, P < 0.01). Administration of
      NFCG could ameliorate these changes to 30.6 +/- 31.3 seconds and 378.1 +/- 386.3
      cm (P < 0.01) and normalized. In the model animals, the choline acetylase
      activity in brain cortex and hippocampus was 35.64 +/- 4.96 and 45.08 +/- 4.96
      respectively, which was significantly lower than that in the control (40.52 +/-
      4.74 and 53.96 +/- 8.53); so was the activity of cholinergic receptor M in
      cerebral cortex (44.41 +/- 10.67 vs 57.56 +/- 6.98) and the activity of
      cholinergic receptor N in cerebral cortex and hippocampus (232.41 +/- 21.99 and
      303.72 +/- 72 +/- 28.78 vs 276.66 +/- 32.46 and 385.56 +/- 46.88), P < 0.05 or P
      < 0.01. Administration of NFCG also could reverse them and elevate to normal
      level. CONCLUSION: NFCG has protective function on intellectual deficits in
      cerebral ischemic mice, which may be related to its action in enhancing function
      of cholinergic system.

PMID- 15015452
TI  - [Analysis of the therapeutic effect of integrated Chinese and Western medicine in
      treating acute biliogenic pancreatitis after papillary myotomy].

PMID- 15015453
TI  - [Evaluation on effect of gennianshu in treating 85 patients with climacteric
      syndrome using modified Kupperman scoring].

PMID- 15015454
TI  - [Effect of xingding injection on platelet coagulation and fibrinolysis activity
      in patients with advanced stage chronic pulmonary heart disease].

PMID- 15015455
TI  - [Effect of compound xiancao capsule on serum transforming growth factor beta 1
      level in patients with primary chronic glomerulonephritis].

PMID- 15015456
TI  - [To actively display the superiority of integrated Chinese and Western medicine
      in treating infectious febrile diseases].

PMID- 15015457
TI  - [Study on the plant estrogen in Chinese herbal medicine].

PMID- 15015458
TI  - [Statistical analysis of the fund supported articles issued in Chinese journal of
      integrated, traditional and Western medicine].

PMID- 15015459
TI  - [Progress of the study on effective integredients from Chinese herbal medicine in
      anti-tumor metastasis].

PMID- 15015460
TI  - [Progress of the study on immunological mechanism of endometriosis and its
      Chinese herbal medical treatment].

PMID- 15015461
TI  - [Minute of the 2003 National Conference on the Dermatology of Integrative Chinese
      and Western Medicine].

PMID- 15015462
TI  - [Summary of academic conference on mainland-Taiwan integrative Western and
      Chinese medicine].

PMID- 15015463
TI  - All's fair in competition? FTC relies on insurer complaints over price increases
      to buttress first challenge of hospital merger after the fact.
AB  - The Federal Trade Commission's antitrust complaint against a prominent suburban
      Chicago healthcare system marks a shift in enforcement policy. Basing its
      complaint on real market data from payers, the FTC is challenging a merger that
      has already been consummated--the first such case ever. If the agency prevails,
      Evanston Northwestern Healthcare may be forced to sell Highland Park (III.)
      Hospital.

PMID- 15015464
TI  - Looking for a slowdown. CMS says spending growth slowed, but not all see it.

PMID- 15015465
TI  - Damage control. Thompson: positive slant on racial report a mistake.

PMID- 15015466
TI  - Round 3. Doc privileges fight heating up; lawsuit in Ark.

PMID- 15015467
TI  - 20/20 hindsight. Divestiture would snuff Tenet's long-term strategy.

PMID- 15015469
TI  - Planning ahead. Survey: few not-for-profits have succession plans.

PMID- 15015468
TI  - Cashing in. Former CMS head Scully joins boards of three healthcare companies.

PMID- 15015470
TI  - Ulterior motive? FTC searching for evidence with look back at merger.

PMID- 15015471
TI  - The silent treatment. Premier reneges on promise to disclose compensation.

PMID- 15015472
TI  - Tax-free but of little account. Without changes, health savings plans unlikely to
      achieve lofty goals.

PMID- 15015473
TI  - Whose turn for tax returns? Millions of dollars are at stake in a federal tax
      case. At question: whether some medical residents are 'students' or just
      'employees'.

PMID- 15015474
TI  - By the numbers. Largest healthcare law firms. Ranked by total membership in the
      American Health Lawyers Association.

PMID- 15015475
TI  - The clone is out of the bottle.

PMID- 15015476
TI  - Gravisensing: ionic responses, cytoskeleton and amyloplast behavior.
AB  - In Zea mays L., changes in orientation of stems are perceived by the pulvinal
      tissue, which responds to the stimulus by differential growth resulting in upward
      bending of the stem. Gravity is perceived in the bundle sheath cells, which
      contain amyloplasts that sediment to the new cell base when a change in the
      gravity vector occurs. The mechanism by which the mechanical signal is transduced
      into a physiological response is so far unknown for any gravity perceiving
      tissue. It is hypothesized that this involves interactions of amyloplasts with
      the plasma membrane and/or ER via cytoskeletal elements. To gain further insights
      into this process we monitored amyloplast movements in response to
      gravistimulation. In a pharmacological approach we investigated how the dynamics
      of plastid sedimentation are affected by actin and microtubule (MT) disrupting
      drugs. Dark grown caulonemal filaments of the moss Physcomitrella patens respond
      to gravity vector changes with a reorientation of tip growth away from the
      gravity vector. MT distributions in tip cells were monitored over time and MTs
      were seen to accumulate preferentially on the lower flank of the tip 30 min after
      a 90 degree turn. Using a self-referencing Ca2+ selective ion probe, we found
      that growing caulonemal filaments exhibit a Ca2+ influx at the apical dome,
      similar to that reported previously for other tip growing cells. However, in
      gravistimulated Physcomitrella filaments the region of Ca2+ influx is not
      confined to the apex, but extends about 60 micrometers along the upper side of
      the filament. Our results indicate an asymmetry in the Ca2+ flux pattern between
      the upper and side of the filament suggesting differential activation of Ca2+
      permeable channels at the plasma membrane.

PMID- 15015478
TI  - [Proceedings and abstracts of the 2nd Meeting of the Polish Society of Pediatric
      Oncology and Hematology. 29-30 May 2003, Krakow].

PMID- 15015477
TI  - A tubulopapillary adenoma of the gallbladder in a child of 3 years.
AB  - Adenoma is the most frequent type of gall-bladder (GB) neoplasm; however, GB
      neoplasms are unusual and unsuspected diagnoses in childhood. The average patient
      age is 50 +/- 16.3 years. We present a case of tubulopapillary adenoma of the
      gallbladder in a 3-year-old girl. She was admitted to the hospital with a 6-month
      history of abdominal pain and nausea and vomiting. Ultrasonography (USG) revealed
      an echogenic soft tissue lesion in the lumen of the GB. She underwent
      cholecystectomy. A tubulopapillary adenoma and adenomatous hyperplasia of the GB
      were diagnosed histologically. According to the literature, this is the youngest
      patient found to have gallbladder adenoma.

PMID- 15015479
TI  - [Abstracts of the 2nd Polish Conference on Sleep Apnea. Legnica, November 14-16,
      2002].

PMID- 15015480
TI  - Relcalitrant leg ulcers.

PMID- 15015482
TI  - Discrimination based on HIV/AIDS and other health conditions: "disability" as
      defined under federal and state law.

PMID- 15015483
TI  - Genetic discrimination: why Bragdon does not ensure protection.

PMID- 15015481
TI  - Is there a pink slip in my gene? Genetic discrimination in the workplace.

PMID- 15015484
TI  - The definition of disability: perspective of the disability community.

PMID- 15015485
TI  - Adverse impact of predisposition testing on major life activities: lessons from
      BRCA1/2 testing.

PMID- 15015486
TI  - Bragdon v. Abbott: extending the Americans with Disability Act to asymptomatic
      individuals.

PMID- 15015487
TI  - Bragdon v. Abbott, asymptomatic genetic conditions, and antidiscrimination law: a
      conservative perspective.

PMID- 15015489
TI  - [Prospects of biological study of carcinoma in China from the clinical trials of
      gene therapy with p53].

PMID- 15015490
TI  - Special issue in honor of Frank B. Livingstone: papers presented at the 2002
      Annual Meeting of the American Association of Physical Anthropologists. Buffalo,
      New York, USA. April 10-13, 2002.

PMID- 15015488
TI  - Leisure time physical activity and change in body mass index: an 11-year follow
      up study of 9357 normal weight health women 20-49 years old.
AB  - OBJECTIVE: To study the association between self-reported leisure time physical
      activity at baseline (1984-1986) and change in body mass index (BMI) during an 11
      year follow-up period (1995-1997). The study population was 9357 healthy women,
      aged 20-49 years, who had a normal body weight (BMI 18.5-24.9 kg/m2) at baseline.
      METHODS: A general population-based health survey was performed both in 1984-1986
      (HUNT 1) and 1995-1997 (HUNT 2). Leisure time physical activity at HUNT 1 was
      categorized into high, moderate, and low levels based on self-reported intensity,
      duration, and frequency. Women who at baseline reported diabetes, stroke, angina,
      myocardial infarction, or long-term illnesses impairing their activities of
      living were excluded. RESULTS: Physical activity was a significant predictor of
      BMI at HUNT 2 adjusted for BMI,age, and education at HUNT 1. Low level of leisure
      time physical activity compared with high level at baseline was significantly
      associated with a higher BMI 11 years later. Those with high level of activity
      gained 0.18 kg/m2 (95% CI 0.05, 0.32) less than those with low level of physical
      activity over 11 years. CONCLUSIONS: This study has demonstrated that leisure
      time physical activity has a moderate effect on BMI. However, not even a high
      level of leisure time physical activity was sufficient to prevent weight gain and
      BMI increase in all subgroups of the study population.

PMID- 15015491
TI  - [Current status, limitations and prospects in clinical trials of cancer gene
      therapy].

PMID- 15015492
TI  - [Surgical treatment of pancreatic carcinoma: more efforts are needed].

PMID- 15015493
TI  - Frank B. Livingstone: introduction and bibliography.

PMID- 15015494
TI  - Simian virus 40 infection in humans and association with human diseases: results
      and hypotheses.
AB  - Simian virus 40 (SV40) is a monkey virus that was introduced in the human
      population by contaminated poliovaccines, produced in SV40-infected monkey cells,
      between 1955 and 1963. Epidemiological evidence now suggests that SV40 may be
      contagiously transmitted in humans by horizontal infection, independent of the
      earlier administration of SV40-contaminated poliovaccines. This evidence includes
      detection of SV40 DNA sequences in human tissues and of SV40 antibodies in human
      sera, as well as rescue of infectious SV40 from a human tumor. Detection of SV40
      DNA sequences in blood and sperm and of SV40 virions in sewage points to the
      hematic, sexual, and orofecal routes as means of virus transmission in humans.
      The site of latent infection in humans is not known, but the presence of SV40 in
      urine suggests the kidney as a possible site of latency, as it occurs in the
      natural monkey host. SV40 in humans is associated with inflammatory kidney
      diseases and with specific tumor types: mesothelioma, lymphoma, brain, and bone.
      These human tumors correspond to the neoplasms that are induced by SV40
      experimental inoculation in rodents and by generation of transgenic mice with the
      SV40 early region gene directed by its own early promoter-enhancer. The
      mechanisms of SV40 tumorigenesis in humans are related to the properties of the
      two viral oncoproteins, the large T antigen (Tag) and the small t antigen (tag).
      Tag acts mainly by blocking the functions of p53 and RB tumor suppressor
      proteins, as well as by inducing chromosomal aberrations in the host cell. These
      chromosome alterations may hit genes important in oncogenesis and generate
      genetic instability in tumor cells. The clastogenic activity of Tag, which fixes
      the chromosome damage in the infected cells, may explain the low viral load in
      SV40-positive human tumors and the observation that Tag is expressed only in a
      fraction of tumor cells. "Hit and run" seems the most plausible mechanism to
      support this situation. The small tag, like large Tag, displays several
      functions, but its principal role in transformation is to bind the protein
      phosphatase PP2A. This leads to constitutive activation of the Wnt pathway,
      resulting in continuous cell proliferation. The possibility that SV40 is
      implicated as a cofactor in the etiology of some human tumors has stimulated the
      preparation of a vaccine against the large Tag. Such a vaccine may represent in
      the future a useful immunoprophylactic and immunotherapeutic intervention against
      human tumors associated with SV40.

PMID- 15015495
TI  - Liver Transplantation and Hepatitis C. Proceedings of a consensus development
      symposium.

PMID- 15015496
TI  - Viral DNA polymerase scanning and the gymnastics of Sendai virus RNA synthesis.
AB  - mRNA synthesis from nonsegmented negative-strand RNA virus (NNV) genomes is
      unique in tht the genome RNA is embedded in an N protein assembly (the
      nucleocapsid) and the viral RNA polymerase does not dissociate from the template
      after release of each mRNA, but rather scans the genome RNA for the next gene
      start site. A revised model for NNV RNA synthesis is presented, in which RNA
      polymerase scanning plays a prominent role. Polymerase scanning of the template
      is known to occur as the viral transcriptase negotiates gene junctions without
      falling off the template.

PMID- 15015497
TI  - Where now for primate research?

PMID- 15015498
TI  - Codon optimization of the HIV-1 vpu and vif genes stabilizes their mRNA and
      allows for highly efficient Rev-independent expression.
AB  - Two HIV-1 accessory proteins, Vpu and Vif, are notoriously difficult to express
      autonomously in the absence of the viral Tat and Rev proteins. We examined
      whether the codon bias observed in the vpu and vif genes relative to highly
      expressed human genes contributes to the Rev dependence and low expression level
      outside the context of the viral genome. The entire vpu gene as well as the 5'
      half of the vif gene were codon optimized and the resulting open reading frames
      (ORFs) (vphu and hvif, respectively) were cloned in autonomous expression vectors
      under the transcriptional control of the CMV promoter. Codon optimization
      efficiently removed the expression block observed in the native genes and allowed
      high levels of Rev- and Tat-independent expression of Vpu and Vif. Most of the
      higher protein levels detected are accounted for by enhanced steady-state levels
      of the mRNA encoding the optimized species. Nuclear run-on experiments show for
      the first time that codon optimization has no effect on the rate of
      transcriptional initiation or elongation of the vphu mRNA. Instead, optimization
      of the vpu gene was found to stabilize the vphu mRNA in the nucleus and enhance
      its export to the cytoplasm. This was achieved by allowing the optimized mRNA to
      use a new CRM I-independent nuclear export pathway. This work provides a better
      understanding of the molecular mechanisms underlying the process of codon
      optimization and introduces novel tools to study the biological functions of the
      Vpu and Vif proteins independently of other viral proteins.

PMID- 15015499
TI  - The relevance of complement to virus biology.

PMID- 15015500
TI  - Interactions of staff and residents with pharmaceutical industry: a survey of
      psychiatric training program policies.
AB  - OBJECTIVES: In response to perceived controversies regarding interactions between
      physicians and the pharmaceutical industry, we undertook a study to look at the
      relationship between Canadian psychiatry training programs and the pharmaceutical
      industry. METHODS: The authors distributed a survey to the residency program
      directors and chief residents of the 16 psychiatry training programs in Canada.
      RESULTS: Of respondents, 75 per cent were either unaware of or noted an absence
      of policies or guidelines regarding interactions with the pharmaceutical industry
      in their training programs; 70 per cent viewed staff psychiatrists and residents
      to be at least 50 per cent familiar with the Canadian Medical Association's
      policy summary; and 74 per cent were unaware of any structural teaching regarding
      potential conflicts of interest between psychiatry and the pharmaceutical
      industry. A significant number of respondents perceived occasional excessive
      influence by the pharmaceutical industry on residents' training. CONCLUSIONS:
      Despite concerns about potential conflicts of interest, there are a few
      guidelines in most psychiatry training programs in Canada regarding the
      relationship between physicians and the pharmaceutical industry.

PMID- 15015501
TI  - Ethics in qualitative health research.
AB  - BACKGROUND: Since the release of the Tri-Council Policy Statement (TCPS), there
      has been a growing interest in research ethics concommitant with an increase in
      the use of qualitative design for health research. Qualitative studies present
      unique ethical problems that may be poorly understood by researchers and research
      ethics boards (REBs). OBJECTIVE: To describe the ethical problems in qualitative
      research, and to make recommendations that will help researchers develop ethical
      qualitative proposals, and help REBs review these proposals. METHOD: Review of
      literature and philosophical analysis. RESULTS AND CONCLUSION: Qualitative
      studies raise unique issues with respect to methods, protection from harm,
      informed consent, privacy, and confidentiality, all of which are central to the
      principles of the TCPS. The problems are partly inherent, as the design tends to
      emerge as the study proceeds, and the research question may change. Researchers
      and REBs must become more aware, through education and critical reflection, of
      the types of problems that might arise in these studies, and of the approaches
      that might be taken to minimize risk to participants.

PMID- 15015502
TI  - Considerations for research ethics boards in evaluating qualitative studies:
      lessons from an ethnographic study with adolescent females.
AB  - Research ethics boards (REBs) have traditionally been required to evaluate
      quantitative research proposals. They are, however, increasingly facing the need
      to evaluate the ethical implications of proposals involving qualitative research.
      This article discusses one form of qualitative research, ethnography, in light of
      possible ethical concerns. It suggests ways in which ethical issues may be
      addressed, and provides examples drawn from an ethnographic study of adolescent
      girls' health concerns in their dating relationships. Recommendations for REBs
      are included.

PMID- 15015503
TI  - Learning from the experience of others: ethical issues surrounding the use of
      clinical data for teaching and other professional activities.
AB  - Effective education in medicine and other health sciences commonly relies on the
      use of clinical cases. This enables learners to advance their understanding of
      complex clinical problems. It also allows experienced clinicians to impart their
      knowledge of unusual problems or innovative approaches. Can the use without
      consent of private patient information be justified? This article reviews the
      practitioner's obligations toward confidentiality, and examines the ethical
      issues involved with the non-clinical use of information about patients.
      Strategies for ensuring sound ethical standards are recommended.

PMID- 15015504
TI  - Medical-ethics teaching in Canadian physical medicine and rehabilitation
      residency training programs.
AB  - BACKGROUND: Medical-ethics education is a required component of all Royal College
      residency training programs in Canada. There have been no studies to determine
      how and to what extent this teaching is done in physical medicine and
      rehabilitation training programs. OBJECTIVE: To assess the state of medical
      ethics teaching in Canadian physical medicine and rehabilitation residency
      training programs. METHODS: A six-question survey was faxed to the program
      directors of the 10 physiatry residency training programs in Canada. We asked
      whether medical-ethics teaching is being done, who is doing the teaching, which
      pedagogic methods is used, how many hours are dedicated to the topic, which
      topics are taught, and what evaluation method is used. RESULTS: The response rate
      was 90 per cent. The study confirmed that medical-ethics teaching is done in all
      Canadian physiatry training programs. However, the person doing the teaching, the
      number of hours allocated to ethics education, the pedagogic method used, and the
      topics being taught vary from program to program. CONCLUSION: Although medical
      ethics teaching is done in all programs, there is a need for more standardization
      in the curriculum and in evaluation. The curriculum should focus on ethical
      issues that are most likely to be encountered in daily physiatric practice. Small
      group, case-based teaching should be used for maximum effectiveness. Whenever
      possible, teaching should be done by a physiatrist.

PMID- 15015505
TI  - [OR-manager: surgeon or anesthesiologist? An interdisciplinary study].

PMID- 15015506
TI  - A crime against humanity.

PMID- 15015507
TI  - Medical image. Suspicious pulmonary nodules.

PMID- 15015508
TI  - Listen to the patients.

PMID- 15015509
TI  - The protest of a troubled bioethicist.

PMID- 15015510
TI  - 'The Death of Ivan Ilyich' and the resuscitation of Christian medical ethics.

PMID- 15015511
TI  - Is the Code of Ethics of the American Medical Association ethical?

PMID- 15015512
TI  - A clinical ethics perspective on assisted reproductive technology.

PMID- 15015513
TI  - A conflict of interest in reproductive medicine.

PMID- 15015514
TI  - Is the human embryo our neighbour?

PMID- 15015515
TI  - Paradise lost: the devolution of medical practice.

PMID- 15015516
TI  - Redefining the active/passive euthanasia debate: introducing new categories to
      aid proper moral contemplation.

PMID- 15015517
TI  - Ethical issues in cochlear implantation of children.

PMID- 15015518
TI  - The impact of the pill on implantation factors--new research findings.

PMID- 15015519
TI  - The abortifacient effect of the birth control pill and the principle of 'double
      effect'.

PMID- 15015520
TI  - Quality of life--three competing views.
AB  - The aim of the present paper is to describe three different attempts, which have
      been made by philosophers, to define what quality of life is; and to spell out
      some of the difficulties that faces each definition. One, Perfectionism, focuses
      on the capacities that human beings possess: capacities for friendship, knowledge
      and creative activity, for instance. It says that the good life consists in the
      development and use of these capacities. Another account, the Preference Theory,
      urges that satisfying one's preferences, or desires, is what improves one's
      quality of life. And a third account, Hedonism, sees life-quality as consisting
      in the enjoyment of pleasure and the avoidance of pain. The paper describes and
      evaluates objections to each of these views, thereby displaying their weaknesses
      and strengths. Since no view comes out as the right one there is a choice to be
      made. At the end of the paper it is being discussed how well each of the views
      cohere with different methodologies used in quality of life research. Also it is
      suggested that consideration about what the research is to be used for are
      relevant.

PMID- 15015521
TI  - Quality of life--evaluation or description?
AB  - 'Quality of life' is part of many different discourses and has been used in a
      variety of meanings ranging from purely descriptive (as in some medical contexts)
      to distinctly evaluative meanings (as in some social science and political
      contexts). The paper argues that there are good normative reasons to make the
      concept of descriptive as possible at least in its medical applications and,
      furthermore, to reconstruct it in a thoroughgoing subjectivist way, making the
      reflexive self-evaluation of the subject himself or herself the ultimate
      standard. Attention is drawn to the fact that only few of the measures of quality
      of life applied in present-day medicine correspond to these requirements.

PMID- 15015522
TI  - Principles and problems in the assessment of quality of life in health care.
AB  - A remarkable surge in efforts to assess the quality of life of patients has
      occurred in recent years in medical research. Philosophical discussions of these
      developments have focused, on the one hand, on epistemological reservations about
      the plausibility of measuring quality of life and, on the other hand, on moral
      and ethical qualms about the meaning of life conveyed in such assessments. Whilst
      providing an important note of caution, such critiques fail to recognise two
      basic principles of quality of life in medical research. Firstly, it is intended
      to provide understanding about groups and categories of patients rather than
      individuals. Secondly the purpose of such research is to produce generalisations
      about the relative costs and benefits of specific health care interventions
      rather than absolute judgements regarding the quality of life of patients per se.
      Selecting a good quality of life measure for a clinical trial requires balancing
      criteria such as validity with practical feasibility. Such measures will play an
      increasingly central role in providing research evidence to improve health care.

PMID- 15015523
TI  - Inequalities in health and intergenerational equity.
AB  - In the popular folklore three-score-years-and-ten is treated as a fair innings
      for people, and thereby serves as an informal reference point for judgements
      about distributive justice within a community. But length of life alone is an
      insufficient basis for such judgements--a person's health-related quality-of-life
      also needs to be taken into account. If one of the objectives of public policy is
      to reduce inequalities in lifetime health, it will be demonstrated that this is
      very likely to require systematic discrimination against the older members of a
      community. The notion of community solidarity will also be tested, because a
      decision will need to be made as to whether the same fair innings applies to all
      members of the community, or whether some are entitled to more than others. The
      strength of the fair innings principle is that it brings these issues to the fore
      in a systematic way which should aid their resolution in a practical context.

PMID- 15015524
TI  - Intention and responsibility in double effect cases.
AB  - I argue that the moral distinction in double effect cases rests on a difference
      not in intention as traditionally stated in the Doctrine of Double Effect (DDE),
      but in desire. The traditional DDE has difficulty ensuring that an agent intends
      the bad effect just in those cases where what he does is morally objectionable. I
      show firstly that the mental state of a rational agent who is certain that a side
      effect will occur satisfies Bratman's criteria for intending that effect. I then
      clarify the nature of the moral distinction in double effect cases and how it can
      be used to evaluate the moral blameworthiness of agents rather than the moral
      status of the acts. The agent's blameworthiness is reduced not by his lack of
      intention but by his desire not to bring about the side-effect, and the
      'counterfactual test' can be used to determine whether he desires the effect in
      acting. In my version, the DDE has its rationale in virtue ethics; it is not
      liable to abuse as the traditional version is; and it makes more plausible
      distinctions when applied to standard examples.

PMID- 15015527
TI  - Normal-incidence efficiencies of multilayer-coated laminar gratings for the
      extreme-ultraviolet imaging spectrometer on the solar-B mission.
AB  - The normal-incidence efficiencies of two laminar gratings and the reflectances of
      two parabolic mirrors with matching multilayer coatings were measured by
      monochromatic synchrotron radiation and were compared with modeling calculations.
      These optics were developed for the Extreme-Ultraviolet Imaging Spectrometer to
      be launched on the Japanese Solar-B mission. Each optic has two sectors coated
      with Mo/Si multilayers that reflect the 17-21-nm and 25-29-nm wave bands at
      normal incidence. The measured peak grating efficiencies are in the 8%-12% range
      and are in good agreement with efficiency calculations that account for the
      effects of groove profile and the microroughness as determined by atomic force
      microscopy.

PMID- 15015526
TI  - Desires in palliative medicine. Five models of the physician-patient interaction
      on palliative treatments related to Hellenistic therapies of desires.
AB  - In this paper, we explore the desires that play a role at the palliative stage
      and relate them to various approaches to patient autonomy. What attitude can
      physicians and other caregivers take to the desires of patients at the palliative
      stage? We examine this question by introducing five physicians who are consulted
      by Jackie, an imaginary patient with metastic lung carcinoma. By combining the
      models of the physician-patient relationship developed by Emanuel and Emanuel
      (1992) and the Hellenistic approaches to desires analyzed by Nussbaum (1994),
      five different ways of dealing with desires in the context of palliative care are
      sketched. The story of Jackie shows that desires are to a certain extent
      responsive to reasoning. In the palliative process, that can be a reason to
      devote attention to the desires of patients and caregivers and to determine which
      desires need to be fulfilled, which are less important, and how they are linked
      to emotions the patient has.

PMID- 15015525
TI  - Solidarity in perinatal medicine.
AB  - In this paper it is argued that questions in perinatal medicine concerning
      treatment or non-treatment of severely handicapped children, after or before
      birth, cannot be answered solely by referring to the general aims and objectives
      of medical treatment and its specific deontology. Justifications of decisions
      about treatment and non-treatment need to be placed in a broader context of
      discussions about social justice and the social significance of medical practice
      as a whole.

PMID- 15015528
TI  - Step-height measurement by means of a dual-frequency interferometric confocal
      microscope.
AB  - A novel instrument, the dual-frequency interferometric confocal microscope
      (DICM), which facilitates the measurement of step features, is investigated. It
      combines the advantages of the high resolution (subnanometer) of heterodyne
      interferometry and the relatively large measurement range (approximately 5
      microm) of confocal microscopy. The axial response curves of the confocal
      microscopy system are compared in experiments in which microscopic objects with
      various numerical apertures and magnifications are used. The results prove that
      the variation in light intensity is enough to permit discrimination of different
      orders of interference fringes. The DICM has been successfully utilized to
      measure the step height of a standard mask, and the experimental results agree
      well with those measured by scanning probe microscopes. The results also show
      that the system has good repeatability, with a maximum deviation of 5 nm.

PMID- 15015529
TI  - Detection and measurement of waviness on thin metallic wires.
AB  - We propose a model for determining the far-field diffraction pattern of wires
      with waviness. Analytical solutions are obtained by means of the stationary phase
      method, which allows us to determine dimensional parameters such as wire diameter
      and waviness factor. Experimental results are presented, which are in accordance
      with our theoretical description.

PMID- 15015530
TI  - Nondestructive measurement of an optical fiber refractive-index profile by a
      transmitted-light differential interference contact microscope.
AB  - A novel transmitted-light differential interference contrast (DIC) system is used
      for nondestructive measurement of the refractive-index profile (RIP) of an
      optical fiber. By means of this system the phase of a measured light beam can be
      modulated with an analyzer, and the phase distribution of a fiber is obtained by
      calculation of the various interference patterns. The measurement theory and
      structure and some typical applications of this system are demonstrated. The
      results of measuring RIPs in graded-index fiber are presented. Both the
      experimental results and theoretical analysis show that the system takes the
      advantage of high index resolution and of sufficient measurement accuracy for
      measuring the refractive index of the optical fiber. The system has strong
      ability to overcome environmental disturbance because of its common-path design.
      Moreover, one can use the system to measure the RIP along the fiber axis and
      acquire an image of the three-dimensional RIP of the fiber.

PMID- 15015531
TI  - Image formation in low-coherence and confocal interference microscopes.
AB  - Image formation in the coherence probe microscope (CPM) and in optical coherence
      tomography (OCT) are compared. These systems differ in that CPM is a conventional
      interference microscope, but OCT is a confocal interference microscope. A major
      disadvantage of CPM for imaging through thick object structures is that there is
      no optical sectioning for the background image, which can saturate the detector.
      The behavior of the interference term in the presence of aberrations also
      exhibits some differences: Aberrations can be compensated in CPM, but not in OCT.

PMID- 15015532
TI  - Effects of phase change on reflection in phase-measuring interference microscopy.
AB  - We show by analytical and numerical calculations that the phase change on
      reflection that occurs in interference microscopy is almost independent of the
      numerical aperture of the objective. The shift of the microscope interferogram
      response due to the phase change on reflection, however, increases with the
      numerical aperture. Measurements of the interferogram shift are made with a
      Linnik interference microscope equipped with various numerical-aperture
      objectives and are reported and compared with theory.

PMID- 15015533
TI  - Transmission of visible light through oxidized copper films: feasibility of using
      a spectral projected gradient method.
AB  - Transmittance measurements at normal incidence were carried out over the visible
      spectral range for metallic thin films deposited by electron beam evaporation on
      thick glass substrates. The presence of an inhomogeneous thin layer of Cu2O
      covering the deposited Cu films is required for a satisfactory model of the
      measurements taken from various samples with increasing thickness. A spectral
      projected gradient method is used to invert the transmission spectra from which
      the wavelength dependence of the effective dielectric function of the oxidized
      coating layer is obtained. Then an effective medium model is used to estimate the
      volume fraction of internal voids randomly distributed through the surface layer.

PMID- 15015535
TI  - Performance evaluation of iterative tomography algorithms for incomplete
      projection data.
AB  - Projection data obtained through optical techniques for tomographic measurements,
      such as interferometry for refractive-index-based measurements, are often
      incomplete. This is due to limitations in the optical system, data storage, and
      alignment and vignette issues. Algebraic iterative reconstruction techniques are
      usually favored for such incomplete projections. A number of iterative
      algorithms, based on additive and multiplicative corrections, are used with a
      known simulated phantom and noise source to assess the reconstruction performance
      of incomplete data sets. In addition, we present reconstructions using
      experimental data obtained from a coherent gradient sensing interferometer for a
      steady temperature field in a fluid medium. We tested the algorithms using the
      simulated data set for incompleteness conditions similar to those found in the
      experimental data, and the best-performing algorithm is identified.

PMID- 15015534
TI  - Linear dichroism of the cornea.
AB  - The dichroic properties of in vitro sheep corneas were studied with a
      spectrophotometer in transmission mode for several angles of incidence of light
      beams. Several models of corneal anisotropy have been presented in the
      literature. The results presented here allow us to believe that the cornea
      behaves as a dichroic biaxial crystal. Furthermore, this dichroism is weak when
      the angle of incidence on the corneal surface stays small. The mathematical model
      that describes these optical properties of the cornea uses Mueller matrices.

PMID- 15015536
TI  - Volume holographic imaging in transmission geometry.
AB  - We address the performance of transmission geometry volume holograms as depth
      selective imaging elements. We consider two simple implementations using
      holograms recorded with spherical and plane beams. We derive the point-spread
      function (PSF) of these systems using volume diffraction theory and use the PSF
      to estimate depth resolution. Furthermore, we show that appropriately designed
      objective optics can significantly improve the depth resolution or the working
      distance of plane-wave reference holographic imaging systems. These results are
      confirmed experimentally and demonstrated for objects with millimeter axial
      features, imaged from the 5- to 50-cm range.

PMID- 15015537
TI  - Hiding an image with a light-scattering medium and use of a contrast
      discrimination method for readout.
AB  - Hiding image data with a material such as a light-scattering medium is useful as
      an initial stage of data protection, because the hidden image can be detected
      only by observation with a specific technique. A light-scattering medium is used
      to hide the image data, and a low-temporal-coherence interferometer performs the
      readout processing. A new readout method for detecting pixel values of the image
      is proposed to overcome spatial variation of the light intensity and distortion
      of the interference fringes. The introduction of spatial coding further improves
      the performance by overcoming spatial variations of the light-scattering medium
      and variations in the reflectance of given pixels.

PMID- 15015538
TI  - Beam steering experiment with two cascaded ferroelectric liquid-crystal spatial
      light modulators.
AB  - The design, construction, and evaluation of a laser beam steerer that uses two
      binary ferroelectric liquid-crystal (FLC) spatial light modulators (SLMs)
      operated in conjunction are presented. The system is characterized by having few
      components and is in principle lossless. Experimentally, a throughput of
      approximately 20% was achieved. The simple system design was achieved because of
      the high tilt angle FLC material used in the SLMs, which were specifically
      designed and manufactured for this study. By coherently imaging the first SLM
      onto the second SLM, pixel by pixel, we obtained an effective four-level phase
      structure with a phase step of 90 degrees. An appropriate alignment procedure is
      presented. The beam steering performance of the system is reported and analyzed.

PMID- 15015539
TI  - Birefringent omnidirectional reflector.
AB  - Anisotropic optical coatings offer unique polarizing properties, unmatched by
      conventional isotropic devices. Here we demonstrate the fabrication of a
      birefringent omnidirectional reflector, a type of photonic crystal, which
      exhibits complete reflection of radiation at 1.1 microm for all incidence angles
      and polarizations. The thin-film device was deposited from electron-beam
      evaporated silicon, with refractive-index variation arising from atomic-scale
      porosity created with glancing-angle deposition. Birefringence was found to
      enhance the performance of the device compared with its isotropic counterpart by
      enlarging the photonic bandgap region of omnidirectional reflection.

PMID- 15015540
TI  - Scheme for feed-forward polarization mode dispersion compensation.
AB  - We propose a feed-forward polarization mode dispersion (PMD) compensator with
      three segments that is capable of compensating for the first- and second-order
      PMD in a transmission fiber. All control parameters are analytically obtained by
      the PMD concatenated rules. The influence of all possible perturbations on the
      compensation is investigated with Monte Carlo simulations. The main advantage of
      our PMD compensation module over the models reported so far is that it shows
      excellent robustness to all possible perturbations.

PMID- 15015541
TI  - Distributed brillouin scattering sensor for discrimination of wall-thinning
      defects in steel pipe under internal pressure.
AB  - A distributed Brillouin scattering sensor has been employed to identify several
      inner wall cutouts in an end-capped steel pipe by measuring the axial and hoop
      strain distributions along the outer surface of the pipe. The locations of
      structural indentations that constitute 50-60% of the inner pipe wall are found
      and distinguished by use of their corresponding strain-pressure data. These
      results are quantified in terms of the fiber orientation, defect size and depth,
      and behavior relative to those of unperturbed pipe sections.

PMID- 15015542
TI  - Scattering optics of snow.
AB  - Permanent snow and ice cover great portions of the Arctic and the Antarctic. It
      appears in winter months in northern parts of America, Asia, and Europe.
      Therefore snow is an important component of the hydrological cycle. Also, it is a
      main regulator of the seasonal variation of the planetary albedo. This seasonal
      change in albedo is determined largely by the snow cover. However, the presence
      of pollutants and the microstructure of snow (e.g., the size and shape of grains,
      which depend also on temperature and on the age of the snow) are also of
      importance in the variation of the snow's spectral albedo. The snow's spectral
      albedo and its bidirectional reflectance are studied theoretically. The albedo
      also determines the spectral absorptance of snow, which is of importance, e.g.,
      in studies of the heating regime in snow. We investigate the influence of the
      nonspherical shape of grains and of close-packed effects on snow's reflectance in
      the visible and the near-infrared regions of the electromagnetic spectrum. The
      rate of the spectral transition from highly reflective snow in the visible to
      almost totally absorbing black snow in the infrared is governed largely by the
      snow's grain sizes and by the load of pollutants. Therefore both the
      characteristics of snow and its concentration of impurities can be monitored on a
      global scale by use of spectrometers and radiometers placed on orbiting
      satellites.

PMID- 15015543
TI  - Truth [editorial].

PMID- 15015544
TI  - Proliferation of biological weapons: challenges and responses.
AB  - The threat posed by the proliferation of biological weapons (BW) confronts all
      strata of our society, from the individual, the nation, or the region to the
      truly international. The history of state-run offensive BW programmes and the
      attacks in the United States with powdered anthrax demonstrate that existing
      measures fall short of addressing this threat. This article examines the current
      regime and the concerns that confront it in order to suggest possible responses
      across the social strata that may mitigate future proliferation of BW.

PMID- 15015545
TI  - William Penn and the peace of Europe.
AB  - The Quaker William Penn proposed a European Union to ensure peace in the
      continent in 1693. Penn was unusual among Quakers in being of the landed upper
      classes. When converted, he became a leader of the Quakers and other Dissenters.
      He had the two related ideals of peace and religious toleration, and dreamed of
      realizing both ideals in the New World. A practical idealist, he took advantage
      of four factors: friends at Court made through his social position; King Charles
      II's gratitude for services rendered by his father, Admiral Sir William Penn; the
      King's desire to conciliate the City merchants, who were ready to invest in
      Penn's scheme; and above all the King's concern to get North America settled by
      British colonists. Penn received a charter to found Pennsylvania in 1681. In
      England he worked hard, especially in collaboration with James II, for toleration
      for the cruelly persecuted Quakers and other Dissenters. In Pennsylvania he was
      able to establish complete toleration and his fair and friendly treatment gave
      the colony 70 years of peaceful co-existence with the Indians. In his essay on
      the peace of Europe, he virtually invented collective security and with amazing
      foresight planned in detail something very like the present European Union.

PMID- 15015546
TI  - A framework for the assessment of non-lethal weapons.
AB  - In many government, police and military circles, attention is being given to so
      called 'non-lethal' weapons as means of reducing many of the negative effects
      directly or indirectly associated with the use of force. Despite the purported
      ability of the adoption of such weaponry to lessen grounds for contention and
      concern, past experience suggests the need for scepticism regarding the purported
      benefits. Rather than relying on poorly substantiated claims, comprehensive
      procedures are needed to ensure the appropriateness of force options. This
      article outlines some of the institutional structures required for 'carefully
      evaluating' and 'carefully controlling' non-lethal weapons, with a discussion of
      the perennial tensions associated with ensuring the relative 'acceptability' of
      the use of force.

PMID- 15015547
TI  - International law and law enforcement firearms.
AB  - Several international agreements set constraints on the legitimate use of
      firearms as representing lethal force. Their meaning in terms of weapons
      technology must take into account their operational frame of reference, and
      legitimate warfare can be regarded as a law enforcement operation with similar
      principles on the use of force. Changes in weapons technology, such as new types
      of ammunition, transforming firearms into weapons with less-lethal and even
      humanitarian options, require new interpretations of the legislation. A division
      into lethal and non-lethal weapons is an oversimplification and the separation of
      international humanitarian law into military and law enforcement provisions can
      be questioned from the technical aspect. The type of technology acceptable for
      law enforcement use of firearms should be defined. An assessment for weapon
      injury should not be based on lethality, but rather on the potential for tissue
      damage and its reversibility.

PMID- 15015548
TI  - The Maralinga Rehabilitation Project: final report.
AB  - Maralinga, South Australia was an important site in the United Kingdom nuclear
      weapons test programme. Seven bombs were exploded and a series of 'safety' tests
      carried out; the latter in particular disseminated appreciable amounts of uranium
      and plutonium over a wide area. A programme to clean up the test site over
      several years was instituted, with in-situ vitrification as a principal measure.
      The final report on the programme has now been published. However, both the
      programme and the Report are seriously flawed; this article provides criticisms
      of both.

PMID- 15015549
TI  - Conference round-up 2003: historians and war.
AB  - Although the days when historians could be content to describe war largely in
      terms of battles 'won' or 'lost' (and medical historians to repeat the maxim that
      'war is good for medicine') have long gone, the topic remains a favourite for
      authors and researchers. The 2003 conference season brought a rich crop of
      events, selectively reviewed here, with war either as the overall theme or as the
      subject of panel sessions and individual papers, approaching it from an
      impressive variety of different angles and analysing it in thoughtful and thought
      provoking ways.

PMID- 15015550
TI  - Vasculogenesis and angiogenesis.
AB  - Two distinct mechanisms, vasculogenesis and angiogenesis implement the formation
      of the vascular network in the embryo. Vasculogenesis gives rise to the heart and
      the first primitive vascular plexus inside the embryo and in its surrounding
      membranes, as the yolk sac circulation. Angiogenesis is responsible for the
      remodeling and expansion of this network. While vasculogenesis refers to in situ
      differentiation and growth of blood vessels from mesodermal derived
      hemangioblasts, angiogenesis comprises two different mechanisms: endothelial
      sprouting and intussusceptive microvascular growth (IMG). The sprouting process
      is based on endothelial cell migration, proliferation and tube formation. IMG
      divides existing vessel lumens by formation and insertion of tissue folds and
      columns of interstitial tissue into the vessel lumen. The latter are termed
      interstitial or intervascular tissue structures (ITSs) and tissue pillars or
      posts. Intussusception also includes the establishment of new vessels by in situ
      loop formation in the wall of large veins. The molecular regulation of these
      distinct mechanisms is discussed in respect to the most important positive
      regulators, VEGF and its receptors flk-1 (KDR) and flt-1, the Angiopoietin/tie
      system and the ephrin-B/EpH-B system. The cellular mechanisms and the molecular
      regulation of angiogenesis in the pathological state are summarized and the
      differences of physiological and pathological angiogenesis elaborated.

PMID- 15015551
TI  - Morphogenesis of embryonic CNS vessels.
AB  - This chapter focuses on the morphology of blood vessel formation in and around
      the early central nervous system (CNS, i.e., brain and spinal cord) of avian
      embryos. We discuss cell lineages, proliferation and interactions of endothelial
      cells, pericytes and smooth muscle cells, and macrophages. Due to space
      limitations, we can not review the molecular control of CNS angiogenesis, but
      refer the reader to other chapters in this book and to recent publications on the
      assembly of the vasculature (1,2).

PMID- 15015552
TI  - Mathematical modelling of tumour-induced angiogenesis: network growth and
      structure.
AB  - Angiogenesis, the formation of blood vessels from a pre-existing vasculature, is
      a process whereby capillary sprouts are formed in response to externally supplied
      chemical stimuli. The sprouts then grow and develop, driven initially by
      endothelial cell migration, and organise themselves into a branched, connected
      network. Subsequent cell proliferation near the sprout-tips permits further
      extension of the capillaries and ultimately completes the process. Angiogenesis
      occurs during embryogenesis, wound healing, arthritis and during the growth of
      solid tumours. In this chapter we first of all present a review of a variety of
      mathematical models which have been used to describe the formation of capillary
      networks and then focus on a specific recent model which uses novel mathematical
      modelling techniques to generate both 2 and 3 dimensional vascular structures.
      The modelling focusses on key events of angiogenesis such as the migratory
      response of endothelial cells to exogenous cytokines (tumour angiogenic factors,
      TAF) secreted by a solid tumour; endothelial cell proliferation; endothelial cell
      interactions with extracellular matrix macromolecules such as fibronectin; matrix
      degradation; capillary sprout branching and anastomosis. Numerical simulations of
      the model, using parameter values based on experimental data, are presented and
      the theoretical structures generated by the model are compared with the
      morphology of actual capillary networks observed in in vivo experiments. A final
      section discusses the use of the mathematical model as a possible angiogenesis
      assay and implications for chemotherapy regimes.

PMID- 15015553
TI  - Histologic measures of angiogenesis in human primary brain tumors.
AB  - Quantitative determination of the degree of vascularity has been shown to be
      independently prognostically significant in many human tumor types. In
      particular, tumor vascularity has known importance in astrocytomas, in which
      endothelial proliferation is a criterion for anaplasia in many grading schemes.
      This chapter summarizes the known associations of quantitated microvessel
      parameters obtained from histologic sections of human brain tumors with clinical
      outcome, or other pathobiologic factors that have been examined. Among the
      conclusions are 1) brain tumors have the unique feature of complex "glomeruloid"
      vessels, as well as heterogeneity of microvascular distribution and caliber; 2)
      lower-grade astrocytomas incorporate pre-existing vessels, while glioblastomas
      develop new vessels; 3) quantitation may have additional independent prognostic
      value over and above routine histologic grade in low-grade astrocytomas with low
      tumor cell proliferative indices. These findings have implications for the
      appropriateness of antiangiogenic therapies

PMID- 15015554
TI  - Angiogenesis in transgenic models of multistep angiogenesis.
AB  - The histopathology and the epidemiology of human cancers, as well as studies of
      animal models of tumorigenesis, have led to a widely accepted notion that
      multiple genetic and epigenetic changes have to accumulate for progression to
      malignancy. Formation of new blood vessels (tumor angiogenesis) has been
      recognized, in addition to proliferative capabilities and ability to down
      modulate cell death (apoptosis), as essential for the progressive growth and
      expansion of solid tumors. Mice overexpressing activated forms of oncogenes or
      carrying targeted mutations in tumor suppressor genes have proven extremely
      useful for linking the function of these genes with specific tumor features such
      as continuous proliferation, escape from apoptosis, invasion and neo
      angiogenesis. The interbreeding of these mice allows for studying the extent of
      cooperativity between different genetic lesions in disease progression, leading
      to a greater understanding of multi-stage nature of tumorigenesis.

PMID- 15015555
TI  - Models for angiogenesis in gliomas.
AB  - During the last decades a lot of attention has been focussed on mechanisms of
      glioma vascularization, particularly in terms of investigating vascular growth
      factors and receptors. Recently, these efforts resulted in various approaches for
      antiangiogenic treatment strategies using in vitro cell culture systems as well
      as experimental orthotopic and non-orthotopic brain tumors. These basic science
      and preclinical trials need an assortment of models, which should allow
      investigating a variety of questions. Several objectives concerning basic
      endothelial cell (EC) characteristics can adequately be studied in vitro using EC
      monolayer assays. Three-dimensional spheroid techniques respect the more complex
      cell-cell and cell-environment interplay within a 3-dimensional culture. Recent
      advances in molecular genetic techniques offer a wide access to the genome of EC.
      Using these micro array or chip methods differences between micro- and
      macromolecular EC as well as variations within the gene pool of different organ
      specific EC can be assessed. To optimize the imitation of the crucial interaction
      of human gliomas with host endothelial cells, immunological cells and
      extracellular matrix, animal models are mandatory. An essential rule is to
      utilize an orthotopic model, since tumor-host-interaction is organ specific. To
      avoid alloimmunogenic responses, it is desirable to use weak or non-immunogenic
      glioma grafts, which is best accomplished in a syngeneic model. However, since
      rat gliomas poorly resemble human glioma growth patterns, human glioma
      xenografting into immunocompromized animals should be considered. In vivo
      monitoring techniques like videoscopy via a cranial window or magnetic resonance
      imaging (MRI) allow for functional studies and improve the validity of the model
      employed. Finally, it is essentially to recognize the limitations of each model
      considered and to select that model which seems to be most appropriate for the
      objectives to be investigated.

PMID- 15015557
TI  - Protocol for MRI monitoring of orthotopic glioma growth in the rat brain.

PMID- 15015556
TI  - Protocol for isolation of HCEC.

PMID- 15015558
TI  - Methods to study angiogenesis in vitro.

PMID- 15015559
TI  - The rabbit corneal pocket assay for the study of angiogenesis.

PMID- 15015560
TI  - Role of nitric oxide in tumor angiogenesis.
AB  - Nitric oxide (NO) is an important signalling molecule that acts in many tissues
      to regulate different physiological and pathological processes. We have
      contributed to demonstrate that NO stimulates angiogenesis and mediates the
      effect of different angiogenic molecules. In human tumors NOS expression and
      activity correlate with tumor growth and aggressiveness, through angiogenesis
      stimulation and regulation of angiogenic factor expression. Drugs affecting the
      NOS pathway appear promising antitumor strategies by reducing edema, inhibiting
      angiogenesis and facilitating the delivery of chemotherapeutical agents.

PMID- 15015562
TI  - Role of VEGF in developmental angiogenesis and in tumor angiogenesis in the
      brain.

PMID- 15015561
TI  - Angiogenesis-related growth factors in brain tumors.
AB  - Numerous growth factors have been implicated in glioma angiogenesis. This chapter
      focuses on the role of scatter factor/hepatocyte growth factor, fibroblast growth
      factor, platelet-derived growth factor and transforming growth factor beta. We
      review the expression pattern of these factors in gliomas, their functional
      contribution to tumor angiogenesis - also in relation to vascular endothelial
      growth factor, and the effects resulting from their inhibition or overexpression
      in gliomas in vivo.

PMID- 15015563
TI  - Hypoxia and hypoxia inducible factors (HIF) as important regulators of tumor
      physiology.
AB  - Regions of low oxygen tension are common findings in malignant tumors and are
      associated with increased frequency of tumor invasion and metastasis. Indeed, the
      ability to initiate homeostatic responses and adapt to hypoxia, e.g. by induction
      of angiogenesis, represents an important and crucial aspect in solid tumor
      growth. A significant advance in our understanding of the hypoxia response stems
      from the discovery of the hypoxia inducible factors (HIF) which act as key
      regulators of hypoxia-induced gene expression. Both, low levels of oxygen,
      apparently via reduced activity of a recently identified class of 2-oxoglutarate
      dependent oxygenases, and various tumor specific genetic alterations
      synergistically act to induce the HIF system. A widespread HIF activation can be
      observed in a variety of malignant tumors including brain tumors. The HIF system
      induces adaptive responses including angiogenesis, glycolysis, and pH regulation
      which confer increased resistance towards the hostile tumor microenvironment.
      Apart from protumorigenic the wide-ranging HIF pathway is known to harbor
      antitumorigenic components, which may, however, be disabled by tumor specific
      genetic alterations. Thus, mounting evidence has identified HIF as a crucial
      regulator of tumor growth and progression constituting an intriguing and novel
      target for therapeutic intervention.

PMID- 15015564
TI  - Vascular microenvironment in gliomas.
AB  - Structural and functional abnormalities of the vascular microenvironment
      determine pathophysiological characteristics of gliomas, such as loss of blood
      brain barrier function, tumor cell invasiveness, or permselectivity for large
      molecules. Moreover, the effectiveness of various therapeutic strategies
      critically depends upon the successful transvascular delivery of molecules. In
      order to shed more light on the vascular microenvironment in gliomas, a variety
      of experimental and clinical techniques have been applied to study the glioma
      microvasculature, including histology, vascular corrosion casts,
      microangiography, autoradiography, tracer washout techniques, magnetic resonance
      imaging, as well as intravital fluorescence microscopy. This review summarizes
      the characteristic features of vascular morphology, angio-architecture, tumor
      perfusion, microvascular permeability, and microvessel-related immunological
      competence in gliomas. An improved understanding of the vascular microenvironment
      in gliomas will help in the future to optimize glioma imaging and to improve
      delivery of vectors for gene therapy or encapsulated drug carriers for
      pharmacotherapy in patients.

PMID- 15015565
TI  - Angiogenesis and invasion in gliomas.
AB  - Angiogenesis and tumor cell invasion are pathophysiological processes playing a
      pivotal role in glioma development and growth since the earliest phase.
      Angiogenesis and tumor invasion both can be considered as an invasive process in
      which cells are activated, and move away from their initial location, by modyfing
      the adhesiveness with the extracellular matrix, expressing new adhesion
      molecules, and degrading the extracellular matrix components by the active
      secretion of proteases. This process requires a complex cross-talking between
      endothelial and tumor cells, extracellular matrix components, and cellular
      elements of the host microenviroment. Both processes are under the tight
      regulation of a balance between stimulating and inhibiting factors. The existence
      of common mechanisms of regulation and the presence of naturally occurring
      factors that inihibit angiogenesis and invasion, makes the inhibition of both
      processes possible. Tumor cells may develop adapting mechanims that can allow the
      tumor to partially escape to the treatment, particularly when only one mechanism
      or one process is inhibited. The ideal treatment should simultaneously affect
      both angiogenesis and invasion, by the isolation or development of novel
      therapeutics capable of influencing both processes. As their efficacy seems also
      be dependent on the mode of delivery, additional studies are also needed to
      improve these modalities, in order to ultimately improve the extent and the
      duration of the therapeutic response. The most widely used in vitro and in vivo
      models to study angiogenesis and invasion are also discussed.

PMID- 15015566
TI  - Metastasis and angiogenesis.
AB  - Angiogenesis and the development of metastases are intrinsically connected.
      Experimental data suggest that establishment and growth of metastases are
      influenced by soluble factors secreted from the originating solid tumor. Among
      these factors are so-called endogenous inhibitors of angiogenesis which keep
      metastasis in a non-proliferating quiescent state. For a number of tumors it has
      been shown that this dormant state is mediated through inhibition of
      angiogenesis. This dormant state is characterized by normal proliferation,
      increased apoptosis, and insufficient neovascularization. Removal of inhibiting
      antiangiogenic factors leads to growth of dormant metastases. Several endogenous
      inhibitors have been identified so far and some of them have already been
      successfully applied in experimental therapeutic trials. This might be of special
      interest for the treatment of cerebral metastases which are the most common type
      of malignant brain tumors. Similar to the spread of metastases, it is known that
      single glioma cells can be found in distant parts of the brain. While local
      recurrence is a common phenomenon in glioma, formation of clinical apparent
      distant metastasis occurs rarely. Several lines of evidence suggest that growth
      inhibition of remote glioma cells may be mediated by an endogenous inhibitory
      mechanism.

PMID- 15015567
TI  - Inhibition of angiogenesis as a therapeutic strategy against brain tumors.
AB  - Multidisciplinary treatment strategies for patients with malignant brain tumors
      have resulted in only small gains in terms of prognosis in spite of the use of
      aggressive therapy. There is a growing realization that a paradigm shift is
      needed in the conceptual approaches to glioma therapy. Such approaches will rely
      on identification and modification of key cellular targets that define the
      biological behavior of these tumors. Among the targets for such treatment
      approaches, tumor angiogenesis has captured the attention of not only the medical
      field but also of the lay public because of its conceptual departure from
      traditional methods of cancer therapy. Angiogenesis and vascular proliferation
      are particularly important in the growth and progression of malignant gliomas and
      are used as indicators of the degree of malignancy. Recent studies have helped us
      gain a better understanding of the molecular mediators of this process. It is now
      evident that after the initial formation of malignancy the continued growth of a
      glioma is critically dependent on its angiogenic potential. Hence, several
      approaches to control angiogenesis are being developed and tested. Preliminary
      results from clinical studies have shown that angiogenesis inhibition is a valid
      approach as a therapeutic strategy against gliomas but it is also becoming
      evident that inhibition of individual modulators of this process may not yield
      the expected impact on prognosis. To fully realize the potential of
      antiangiogenic therapy, a deeper understanding of the interplay between the tumor
      vasculature and its environment is needed. Angiogenesis inhibitors have made the
      transition from preclinical studies to the clinical arena; it remains for ongoing
      human trials of such agents to fully explore the feasibility and efficacy of
      these agents in order to exploit the potential of this approach.

PMID- 15015568
TI  - Anti-angiogenic chemotherapy in central nervous system tumors.
AB  - Primary central nervous system tumors are infrequent lesions observed in both
      pediatric and adult patients that account for a disproportionate amount of cancer
      related morbidity and mortality. A significant number of advances in
      neurosurgical and radiation therapy techniques have occurred over the last few
      decades and yet only small improvements in long-term outcome have resulted. The
      major reason for this is the ability of these advances to minimize surgical or
      radiation morbidity on surrounding normal tissue rather than eradicating the
      microscopic infiltrating disease that remains after up-front standard therapy. As
      such, a great deal of effort has gone into adjuvant chemotherapy that might
      complement the standard surgical and radiation approaches. This paper will review
      the literature on anti-angiogenic therapies in central nervous system (CNS) tumor
      models and clinical disease, with a focus on anti-angiogenic chemotherapy (also
      referred to as metronomic or low-dose chemotherapy) and the utilization of this
      approach in conjunction with standard radiation and surgery. A number of
      excellent reviews covering related aspects of this topic are also available (1
      13).

PMID- 15015569
TI  - Effects of tumor suppressor gene (p53) on brain tumor angiogenesis and expression
      of angiogenic modulators.
AB  - BACKGROUND: p53 retarded tumor growth by several known mechanisms, including
      suppression of cell proliferation and inhibition of tumor angiogenesis. Vascular
      endothelial growth factors (VEGF) and angiopoietins (Ang-1, Ang-2) are major
      angiogeneic modulators. The current study examined the effect of p53 on the
      expression of these factors in conjunction with tumor growth and vascular
      formation. MATERIALS AND METHODS: Growth characteristics of rat glioma cells (RT
      2) infected with retrovirus (MSCV) encoding a full-length human wild-type p53
      gene were examined by clonogenic assay. Expression of the transgene in vitro was
      verified by RT-PCR and immunoprecipitation. Tumor morphology, vascular
      architecture and the expression of VEGF, Ang-1, Ang-2 and Tie-2 were examined by
      immunohistochemistry and semi-quantitative RT-PCR. RESULTS: p53-infected cells
      showed retardation in growth and colony formation. In vivo, expression of the
      transgene resulted in prolonged survival and reduction of tumor volume (62%) and
      reduced the expression of VEGF (57.8%) and Tie-2 (15.4%) but not Ang-1 and Ang-2.
      The tumor exhibited increased necrosis (38%), hemorrhage and abnormal vascular
      architecture. CONCLUSION: p53 causes tumor regression by suppressing tumor
      proliferation and indirectly induces involution of tumor vessels by fostering
      unopposed activity of Ang-2 in an environment of diminishing VEGF.

PMID- 15015570
TI  - Activated Akt expression has significant correlation with EGFR and TGF-alpha
      expressions in stage I NSCLC.
AB  - BACKGROUND: In vitro studies have indicated that epidermal growth factor receptor
      (EGFR) may intensify signaling output by the receptor's overexpression,
      heterodimerization with HER-2, or autocrine expression of ligands. The purpose of
      the present study was to evaluate the correlation between EGFR and its related
      proteins and to explore the prognostic value of the proteins. MATERIALS AND
      METHODS: Immunohistochemical staining of transforming growth factor alpha (TGF
      alpha), EGFR, HER-2, and phosphorylated (p-)Akt was performed in specimens
      surgically excised from 91 consecutive patients with p-stage I non-small cell
      lung cancer (NSCLC). Expression or coexpression of TGF-alpha and the receptors
      were related to expression of p-Akt. The prognostic impact of these peptides was
      also tested. RESULTS: TGF-alpha, EGFR and HER-2 overexpressions were detected in
      32%, 79% and 13% of tumors, respectively. Coexpressions of TGF-alpha & EGFR and
      EGFR & HER-2 were observed in 29% and 11% of tumors, respectively. P-Akt
      expression was found in 73% of tumors. Significant correlations between EGFR TGF
      alpha or coexpression of TGF-alpha & EGFR and p-Akt expression were found
      (p=0.006, 0.008 and 0.010, respectively). No proteins examined had an impact on
      relapse-free survival. CONCLUSION: The Akt pathway is frequently involved in
      NSCLC and overexpression of EGFR and autocrine expression of TGF-alpha may
      increase the potency of Akt activation.

PMID- 15015571
TI  - CGH analysis shows genetic similarities and differences in atypical fibroxanthoma
      and undifferentiated high grade pleomorphic sarcoma.
AB  - BACKGROUND: Atypical fibroxanthoma (AFX) and undifferentiated high grade
      pleomorphic sarcoma (UpS) are histologically very similar, if not identical.
      However, they differ significantly in clinical outcome. MATERIALS AND METHODS: We
      used comparative genomic hybridization (CGH) to screen 24 AFX and 12 UpS for
      genomic alterations. RESULTS: DNA copy number changes were observed in 20/24 AFX
      and in all UpS. The most frequent alterations occurring with comparable frequency
      in both tumors were deletions on chromosomes 9p and 13q. We also detected
      statistically significant differences of genetic alterations between the two
      tumors concerning deletions on 1q, 3p, 5q, 11p, 11q, gains on 7q, 12q and high
      level gains on 5p and 11q. CONCLUSION: Despite their very similar histology, AFX
      and UpS show clear differences in their genetic alterations. This might
      contribute to the different biological behavior of the two tumors. On the other
      hand the similarities in genetic alterations on chromosomes 9p and 13q might
      suggest a common pathogenetic pathway.

PMID- 15015572
TI  - Paclitaxel-induced apoptosis may occur without a prior G2/M-phase arrest.
AB  - BACKGROUND: Paclitaxel, a naturally occurring antineoplastic agent, can cause
      both mitotic arrest and apoptotic cell death, but the relationship between these
      two events is not entirely clear. The focus of this study was to determine
      whether apoptosis induced by paclitaxel may occur independent of mitotic arrest
      and to examine the underlying molecular mechanisms of paclitaxel-induced
      apoptosis. MATERIALS AND METHODS: Two paclitaxel-sensitive tumor cell lines,
      human breast cancer BCap37 and human epidermoid carcinoma KB cells, were pulsed
      exposed to various concentrations of paclitaxel. Multiple methods were used to
      analyze the possible correlation between paclitaxel-induced apoptosis and
      paclitaxel-induced mitotic arrest. A series of assays were also performed in
      which we utilized parthenolide, a specific inhibitor of NF-kappaB, to analyze the
      possible role that the NF-kappaB/IkappaB signaling pathway has in mediating
      paclitaxel-induced apoptosis. RESULTS: Both tumor cell lines treated with pulsed
      paclitaxel exposures exhibited a significant number of cells undergoing
      apoptosis, however many fewer cells were arrested at the G2/M-phase of the cell
      cycle when compared to the continuous paclitaxel exposures. Short exposures to
      paclitaxel also induced the phosphorylation and degradation of IkappaB-alpha,
      which in turn caused the activation of NF-kappaB in both cell lines. Parthenolide
      was found to inhibit paclitaxel-induced activation of the NF-kappaB/IkappaB
      signal pathway as well as apoptotic cell death. CONCLUSION: These findings
      suggest that paclitaxel-induced apoptosis might occur independent of a prior G2/M
      phase arrest and be mediated or regulated by the NF-kappaB/IkappaB signal
      pathway.

PMID- 15015573
TI  - Immune cell infiltration of intrinsic and metastatic intracranial tumours.
AB  - BACKGROUND: Immune escape is one prerequisite for the formation of neoplasms that
      is reflected by the pattern of immune cell infiltration. Abundant monocytic
      infiltration without apparent phagocytic activity is well known in human gliomas,
      while other types of human intracranial tumours have not yet been investigated.
      MATERIALS AND METHODS: We analysed LCA-positive lymphocytes and CD68-positive
      macrophages/microglia by immunohistochemistry in 67 intracranial neoplasms: 18
      glioblastomas (GBM), 14 primitive neuroectodermal tumours and medulloblastomas
      (PNET), metastases of 9 adenocarcinomas and of 8 malignant melanomas, and 18
      benign meningiomas. RESULTS: Levels of monocytic infiltration in GBM and
      adenocarcinomas were higher than in PNET and meningiomas. Lymphocytes were rare
      in all tested tumours. No differences were found between all malignant neoplasms
      and benign meningiomas and between primary intracranial and metastatic tumours.
      CONCLUSION: Malignancy or primary intracranial origin seem not to be major
      determinants of immune cell infiltration. Different patterns of cytokine
      production may explain the differences in single tumour entities.

PMID- 15015574
TI  - In-silico analysis of kallikrein gene expression in pancreatic and colon cancers.
AB  - Human kallikreins are a cluster of 15 serine protease genes located in the
      chromosomal band 19q13.4, a non-randomly rearranged region in many solid tumors,
      including pancreatic cancer. We utilized the SAGE and EST databases of the Cancer
      Genome Anatomy Project to perform in-silico analysis of kallikrein gene
      expression in normal and cancerous pancreatic and colon tissues and cell lines
      using virtual Northern blotting (VNB), digital differential display (DDD) and X
      profiler. At least two kallikreins, KLK6 and KLK10, are significantly up
      regulated in pancreatic cancer. We probed 2 normal and 6 pancreatic cancer SAGE
      libraries with gene-specific tags for each of these kallikreins. KLK6 was found
      to be expressed in 5/6 cancer libraries and showed the most marked (5-fold)
      increase in average expression levels in cancer vs. normal. These data were
      verified by screening the EST databases, where all mRNA clones isolated were from
      cancerous libraries, with no clones detected in normal pancreatic tissues or cell
      lines. X-profiler comparison of two pools of normal and cancerous pancreatic
      libraries further verified the significant increase of KLK6 expression levels in
      pancreatic cancer. DDD data showed a 13-fold increase in KLK10 expression in
      pancreatic cancer. Three kallikrein genes, KLK6, 8 and 10 are overexpressed in
      colon cancer compared to normal colon, while one kallikrein, KLK1, is down
      regulated. While no expression of KLK6 was detected in normal colon, KLK6
      specific tags were detectable in 2 cancer libraries. Similar results were
      obtained by EST screening; no KLK6 clones were detected in any of the 28 normal
      libraries examined, while 10 KLK6 EST clones were found in colon adenocarcinoma.
      KLK10 was not detectable in normal colon. Gene-specific tags were, however,
      detectable with high density in colon cancer and 7 EST clones were found to be
      expressed in colon Adenocarcinoma.

PMID- 15015575
TI  - Spontaneous apoptosis in the intra-ductal component's stroma of breast invasive
      carcinoma.
AB  - Spontaneous apoptosis by in situ detection of DNA fragmentation (DNAf) was
      investigated in breast invasive ductal carcinoma (IDC) frozen samples removed
      from 61 untreated patients. The incidence of DNAf was low in carcinoma cells and
      was mainly detected in the stroma. In the stroma at a distance from carcinoma
      cells, DNAf was inversely related to estradiol plasma level variations (p=0.01),
      indicating that it probably remained under physiological hormonal regulation. In
      the stroma adjacent to carcinoma cells, DNAf was correlated to tumor progression
      parameters such as the presence of a comedo intra ductal carcinoma (DCIS)
      component (p=0.001) and axillary lymph node metastasis (p=0.002), suggesting that
      this stromal compartment more probably represented a tumoral component closely
      associated to epithelial tumor cells. Therefore, the detection of DNAf in the
      adjacent stroma of breast carcinoma could help to predict progression in non
      invasive tumors and also in invasive tumors in those patients without lymph node
      invasion.

PMID- 15015576
TI  - Activity of irofulven against human pancreatic carcinoma cell lines in vitro and
      in vivo.
AB  - BACKGROUND: Irofulven (MGI 114), a novel antitumor agent synthesized from the
      natural product illudin S, has a unique mechanism of action involving
      macromolecule adduct formation, S-phase arrest and induction of apoptosis.
      MATERIALS AND METHODS: This study utilized MiaPaCa pancreatic xenografts to
      demonstrate irofulven antitumor activity using either a daily or intermittent
      dosing schedule. Additionally, irofulven and gemcitabine were tested in vitro and
      in vivo to assess the anticancer activity of the combination. RESULTS: Both
      dosing regimens of irofulven demonstrated curative activity against the MiaPaCa
      xenografts. Similar activity of irofulven on the intermittent schedule was
      observed at lower total doses compared to the daily dosing schedule. Furthermore,
      enhanced antitumor activity was observed when irofulven and gemcitabine were
      combined compared to single agent activity. CONCLUSION: These results support
      further clinical characterization of intermittent irofulven dosing schedules and
      suggest that irofulven combined with gemcitabine may have activity in patients
      with pancreatic tumors.

PMID- 15015577
TI  - BZLF1 controlled by family repeat domain induces lytic cytotoxicity in Epstein
      Barr virus-positive tumor cells.
AB  - BACKGROUND: BZLF1, an EBV (Epstein-Barr virus) immediate early gene, is required
      for EBV lytic replication that causes the death of host cells. EBNA1, the product
      of EBV latent gene, binds to the family repeats (FR) of the origin of replication
      (Orip) regulating EBV replication. MATERIALS AND METHODS: A vector pFR-Z (BZLF1
      controlled by FR domain of EBV) was constructed and transfected into EBV-positive
      5-8F and-negative HNE3 nasopharyngeal carcinoma cells and BZLF1-induced
      cytotoxicity was tested. RESULTS: EBNA1 expression was detected in 5-8F but not
      HNE3 cells and, in agreement, pFR controlled luciferase expression was activated
      in 5-8F cells but inhibited in HNE3 cells. Gardella gel assay demonstrated that
      pFR-Z effectively induced EBV lytic replication in 5-8F but not HNE3 cells. The
      lytic cytotoxicity was confirmed by a diminished cell survival and the induction
      of lytic proteins EA-D and gp125. The cytotoxicity was also strikingly enhanced
      by addition of GCV (gancyclovir) that kill cells with lytic form EBV. CONCLUSION:
      pFR-Z is a specific gene therapy vehicle for EBV-positive carcinomas.

PMID- 15015578
TI  - Activation of expression of p15, p73 and E-cadherin in leukemic cells by
      different concentrations of 5-aza-2'-deoxycytidine (Decitabine).
AB  - BACKGROUND: Inactivation of genes that suppress neoplasia by aberrant DNA
      methylation is a key event that occurs during the development of leukemia. The
      inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (5AZA), which can re
      activate these genes, is under clinical investigation for therapy of leukemia.
      The objective of this study was to determine the concentrations of 5AZA that will
      re-activate target silent genes in human leukemic cell lines. MATERIALS AND
      METHODS: RT-PCR was used to evaluate the effect of concentrations of 1 to 100
      ng/ml of 5AZA on the re-activation of p15 and p73 in KG1a myeloid leukemic cells
      and E-cadherin in HL-60 myeloid leukemic cells. The effect of 5AZA on inhibition
      of growth, DNA synthesis and colony formation in these cell lines was also
      investigated. RESULTS: The extent of activation of the target genes was dependent
      on the concentration of 5AZA. For p15, pronounced activation was observed at 10
      ng/ml or greater. For p73 and E-cadherin significant activation was observed at
      100 ng/ml of 5AZA. Maximal inhibition of growth, DNA synthesis and colony
      formation occurred at 100 ng/ml. CONCLUSION: The in vitro antineoplastic and gene
      re-activation activity of 5AZA is dependent on the concentration of this analog.
      These data may be helpful in the design of the optimal dose-schedule of 5AZA for
      the clinical therapy of leukemia.

PMID- 15015579
TI  - Expression of interleukin-21 and -23 in human esophageal tumors produced
      antitumor effects in nude mice.
AB  - Interleukin (IL)-21 induces proliferation of activated T and natural killer (NK)
      cells and enhances the lytic function of NK cells. IL-23, a heterodimer composed
      of p19 and p40 molecule, can also enhance T cell proliferation and interferon
      gamma production from activated T cells; however, its effects on NK cells are
      currently unknown. We therefore examined whether human tumors expressing IL-21 or
      IL-23 could produce antitumor effects in inoculated nude mice. Esophageal tumor
      T.Tn cells were retrovirally transduced with the IL-21 gene (T.Tn/IL-21) or the
      p19-linked p40 genes (T.Tn/IL-23). The proliferation in vitro and the class I
      expression of the major histocompatibility complexes of these transduced cells
      were not different from those of parent cells. T.Tn/IL-21 and T.Tn/IL-23 cells
      developed small tumors in nude mice, but the tumors regressed spontaneously
      thereafter in contrast to parent tumors. Expressed IL-21 or IL-23 in human
      esophageal tumors can produce antitumor effects in a T cell-defective condition.

PMID- 15015580
TI  - PCR and flow cytometric analysis of paclitaxel-inhibited arylamine N
      acetyltransferase activity and gene expression in human osteogenic sarcoma cells
      (U-2 OS).
AB  - Human epidemiological studies suggest an association between N-acetyltransferase
      (NAT) activity and the incidence of bladder and colorectal cancers. In this
      study, paclitaxel was selected to examine the inhibition of arylamine NAT
      activity, gene expression and 2-aminofluorene-DNA adduct formation in a human
      osteogenic sarcoma cell line (U-2 OS). The activity of NAT was determined by high
      performance liquid chromatography (HPLC) assay for the amounts of acetylated 2
      aminofluorene (AF) and p-aminobenzoic acid (PABA) and nonacetylated AF and PABA.
      Human osteogenic sarcoma cell cytosols and intact cells were used to examine the
      NAT activity, gene expression and AF-DNA adduct formation. The results
      demonstrated that NAT activity percent of NAT in examined cells, gene expression
      (NAT1 mRNA) and AF-DNA adduct formation in human osteogenic sarcoma cells were
      inhibited and decreased by paclitaxel in a dose-dependent manner. The results
      also demonstrated that paclitaxel decreased the apparent values of Km and Vmax
      from intact human osteogenic sarcoma cells (U-2 OS). Thus, paclitaxel is an
      uncompetitive inhibitor of the NAT enzyme.

PMID- 15015582
TI  - Thorium and actinium polyphosphonate compounds as bone-seeking alpha particle
      emitting agents.
AB  - The present study explores the use of alpha-particle-emitting, bone-seeking
      agents as candidates for targeted radiotherapy. Actinium and thorium 1,4,7,10
      tetraazacyclododecane N,N',N'',N''' 1,4,7,10-tetra(methylene) phosphonic acid
      (DOTMP) and thorium-diethylene triamine N,N',N'' penta(methylene) phosphonic acid
      (DTMP) were prepared and their biodistribution evaluated in conventional Balb/C
      mice at four hours after injection. All three bone-seeking agents showed a high
      uptake in bone and a low uptake in soft tissues. Among the soft tissue organs,
      only kidney had a relatively high uptake. The femur/kidney ratios for 227Th-DTMP,
      228-Ac-DOTMP and 227Th-DOTMP were 14.2, 7.6 and 6.0, respectively. A higher liver
      uptake of 228Ac-DOTMP was seen than for 227Th-DTMP and 227Th-DOTMP. This suggests
      that some demetallation of the 228Ac-DOTMP complex had occurred. The results
      indicate that 225Ac-DOTMP, 227Th-DOTMP and 227Th-DTMP have promising properties
      as potential therapeutic bone-seeking agents.

PMID- 15015581
TI  - The inhibitory effects of gossypol on human prostate cancer cells-PC3 are
      associated with transforming growth factor beta1 (TGFbeta1) signal transduction
      pathway.
AB  - BACKGROUND: Racemic gossypol [(+/-)-GP], a naturally occurring polyphenolic
      yellow pigment present in cottonseed products, inhibits in vitro proliferation of
      Dunning prostate cancer cells (MAT-LyLu), human prostate cancer cells derived
      from a bone marrow metastasis (PC3), MCF-7 and primary cultured human prostate
      cells. (+/-)-GP also has the ability to inhibit the metastasis of lung and lymph
      nodes of the androgen-independent rodent prostate cancer cell line, MAT-LyLu,
      after implantation into Copenhagen rats. MATERIALS AND METHODS: The effects of
      (+/-)-GP on the proliferation of human prostate cancer PC3 cells were determined
      by thymidine incorporation assay and doubling-time (DT) determination. The
      mechanisms of action of (+/-)-GP on the proliferation of PC3 cells were
      determined by RT-PCR analysis, ELISA assay and Western blot analysis. RESULTS:
      The results show that (+/-)-GP caused reductions in DNA synthesis and prolonged
      the DTs in PC3 cells. RT-PCR and ELISA results show that (+/-)-GP elevate the
      mRNA expression and protein secretion of transforming growth factor beta1
      (TGFbeta1) in PC3 cells. Consistent with these findings, (+/-)-GP has been shown
      to decrease the cyclin D1 mRNA expression and protein expression in PC3 cells.
      Furthermore, the growth inhibition of PC3 cells by conditioned media collected
      from the (+/-)-GP-treated-PC3 cells was completely reversed by addition of 25
      microg/ml of mouse monoclonal anti-TGFbeta1, -beta2, -beta3 antibody, suggesting
      the involvement of TGFbeta1 in (+/-)-GP-induced growth inhibition of PC3 cells.
      CONCLUSION: These results indicate that the inhibitory effects of (+/-)-GP on the
      proliferation of human prostate cancer PC3 cells are associated with induction of
      TGFbeta1, which in turn influences the expression of the cell cycle-regulatory
      protein, cyclin D1, in prostate cancer cells.

PMID- 15015583
TI  - Transitional increase in growth fraction estimated by Ki-67 index after
      irradiation to human tumor in xenograft.
AB  - The cell kinetics of human tumor cells (HSG) in vivo were estimated by Ki-67
      index to analyze the biological behavior of quiescent cells after irradiation.
      The increment of Ki-67 index was dose-dependent up to 15 Gy irradiation. The Ki
      67 index of tumor cells increased gradually from 35+/-5.0% before irradiation to
      56+/-5.0% at day 5 after single irradiation of 15 Gy. Flow-cytometric study
      showed that the G1 population was decreased and the G2M population was elevated
      at day 5 after the irradiation. In fractionated irradiation, the time-course in
      the change of the Ki-67 index was similar to that of single irradiation. It was
      likely that tumor cells were recruited into the cell cycle from quiescent phase
      after irradiation. We consider the Ki-67 index to be a reliable indicator of
      growth fraction and useful to estimate the cell kinetics of irradiated tumors in
      vivo. The growth fraction estimated by Ki-67 index during radiotherapy is
      expected to be useful in predicting tumor response to radiation therapy.

PMID- 15015584
TI  - Numerical aberrations of chromosome 17 and the p53 locus in small hepatocellular
      carcinomas.
AB  - To investigate numerical aberrations of chromosome 17 and the p53 locus in early
      stages of hepatocellular carcinoma (HCC), 12 fresh-frozen specimens of small HCCs
      (less than 30 mm in size) were examined by dual-color fluorescence in situ
      hybridization. We used a chromosome 17 alpha-satellite DNA probe and a p53 locus
      specific DNA probe. We also performed immunohistochemical analysis for p53
      protein in the same cases. Gain of chromosome 17 was the most frequently observed
      anomaly, present in 58% of cases, and deletion of the p53 locus was observed in
      50% of cases. The combination of chromosome 17 gain and p53 locus deletion was
      observed in 33.3% of cases. However, overexpression of p53 protein was not
      observed in any specimens. Our results suggest that gain of chromosome 17 and
      deletion of the p53 locus could represent early genetic events, prior to
      overexpression of p53 protein due to mutation, in early stage HCC.

PMID- 15015585
TI  - Repair of short oligodeoxyribonucleotides containing a stable adduct and an
      apurinic site by extracts of MCF-10A1 cells.
AB  - BACKGROUND: DNA with two sites of damage in close proximity might not be repaired
      as efficiently as DNA with a single damage site. MATERIALS AND METHODS: To study
      this hypothesis, we utilized short oligodeoxyribonucleotides with a stable adduct
      7 or 16 nucleotides (nt) downstream from an apurinic (AP) site. Repair by
      extracts of human breast epithelial MCF-10A1 cells was assayed by quantifying the
      incorporation of [alpha-32P]dTTP. RESULTS: The level of repair of an
      oligodeoxyribonucleotide with an AP site 7 nt from a stable adduct was comparable
      to that of the oligodeoxyribonucleotide with only an AP site. A decrease in
      overall repair of oligodeoxyribonucleotides containing an AP site and a stable
      adduct was observed if these lesions were 16 nt apart compared to the presence of
      only an AP site. CONCLUSION: The ability of human breast MCF-10A1 cells to repair
      DNA adducts and AP sites is affected by other near-by lesions.

PMID- 15015586
TI  - A P-glycoprotein- and MRP1-independent doxorubicin-resistant variant of the MCF-7
      breast cancer cell line with defects in caspase-6, -7, -8, -9 and -10 activation
      pathways.
AB  - BACKGROUND: Several mechanisms are known to cause resistance to chemotherapy in
      cancer cells, but the mechanisms of drug resistance due to a lack of apoptosis
      are not well elucidated. MATERIALS AND METHODS: To understand the mechanisms of
      resistance to apoptosis induced by doxorubicin (DOX), we developed a DOX
      resistant variant of MCF-7 referred to as MCF-7/Adr-20, measured growth
      inhibition by methylene blue cell survival assay, quantitated apoptosis by
      annexin V binding assay and detected activation of caspases-6, -7, -8, -9 and -10
      in these cells. RESULTS: The resistant cells expressed 20-fold resistance to
      apoptosis induced by DOX compared to MCF-7 cells. MCF-7/Adr-20 cells did not
      express MDR1 mRNA or its product P-glycoprotein and they did not overexpress MRP
      1. Treating MCF-7 cells with 0.01, 0.1 and 1 microM DOX for 72 h induced 8, 14
      and 28% apoptosis, respectively. However, only 1 microM DOX was able to trigger
      about 8% apoptosis in MCF- 7/Adr-20 cells. Moreover, apoptosis triggered by 0.01
      and 0.1 microM DOX in MCF-7 cells was mainly caspase-dependent, but at 1 microM
      about 70% of apoptosis was caspase-dependent. Western blot analysis revealed that
      caspase-7 was activated at 0.1 and 1 microM DOX treatment and caspases-6, -8, -9
      and 10 were only activated at 1 microM DOX treatment in MCF-7 cells, but none of
      the caspases checked were activated in MCF-7/Adr-20 cells. Moreover, DOX at 0.01
      and 0.1 microM induced p53 and p21(WAF-1/CIP-1) to the same extent in both MCF-7
      and MCF-7/Adr-20 cells. Therefore, while DOX triggers growth arrest and induces
      p53 and p21(WAF-1/CIP-1) in these cells, defects in activation of the initiator
      and executioner caspases play a major role in resistance to apoptosis triggered
      by DOX.

PMID- 15015587
TI  - Modulation of the constitutive activated STAT3 transcription factor in pancreatic
      cancer prevention: effects of indole-3-carbinol (I3C) and genistein.
AB  - BACKGROUND: The signal transducer and activator of transcription 3 (STAT3) is a
      latent transcription factor required in proliferation and differentiation. STAT3
      is activated constitutively in a number of cancers. MATERIALS AND METHODS: This
      study was conducted to assess the possible involvement of STAT3 activation in
      pancreatic cancer and the potential for this pathway as a target in
      chemopreventive strategy. RESULTS: STAT3 was shown for the first time to be
      constitutively activated in human pancreatic carcinoma specimens but not in
      normal pancreatic tissues. Constitutively activated STAT3 was also found in
      pancreatic tumor cell lines (Panc-1 and MIA PaCa-2) which could be modulated by
      indole-3-carbinol (13C) and genistein. At concentrations higher than 10 microM,
      STAT3 constitutive activation is inhibited by both agents. Induction of apoptosis
      by 13C was also demonstrated. CONCLUSION: Given its critical role in
      tumorigenesis, our results suggest that STAT3 activation provides an important
      and appropriate target for chemoprevention in pancreatic cancer treatment.

PMID- 15015588
TI  - Beta-galactosidase and alpha-mannosidase inhibit formation of multicellular
      nodules in breast cancer cell cultures.
AB  - In response to an estrogen, confluent monolayers of MCF-7 cell cultures develop
      multi-cellular nodules, termed foci. Post-confluent development of foci occurs
      with physiologic levels of 17beta-estradiol and are inhibited by various anti
      estrogens acting through either the estrogen or aryl hydrocarbon receptors. In
      the present paper we report that disruption of the terminal sugars on membrane
      receptors results in inhibition of foci. Treatment with 0.013-0.05 units/ml of
      beta-galactosidase completely inhibited the development of foci while leaving the
      monolayer of cells intact. Trials with alpha-mannosidase resulted in a similar
      but less potent inhibition of foci. Lectin-fluorescent conjugates, RCA (Ricinus
      communis agglutinin), and ConA (Canavalia ensiformis agglutinin) were used to
      identify membrane surface carbohydrates on MCF-7 cells. Binding of the RCA
      fluorescent conjugate was inhibited by co-treatment with galactose or lactose.
      Binding of ConA-fluorescent conjugate was significantly inhibited by mannose and
      n-acetyl-glucosamine. This is the first report of inhibition of foci development
      in MCF-7 cell cultures by disruption of surface carbohydrates on membrane
      receptors.

PMID- 15015589
TI  - Drug-induced caspase-3 activation in a Ewing tumor cell line and primary Ewing
      tumor cells.
AB  - Ewing sarcoma is a rare malignancy occurring in childhood and adolescence which
      has a prognosis of about 50% long-term event-free survival, depending on risk
      factors such as tumor volume, initial metastases at the time of diagnosis and
      tumor response to presurgical chemotherapy. In order to tailor therapy to the
      individual patient, new prognostic factors need to be identified. In this study,
      we showed that etoposide and actinomycin D kill Ewing tumor cells (RD-ES cell
      line) mainly via a caspase-dependent mechanism. Both drugs induced a significant
      caspase-3 activation, which can be detected with a new caspase-3 assay. Dose
      response analyses showed that induction of cell death and caspase-3 activation is
      mediated by similar concentration ranges of both drugs. In addition to the cell
      line, caspase-3 activation was also shown during drug-mediated stimulation of
      freshly isolated cells from tumor biopsies. In conclusion, actinomycin D and
      etoposide stimulated caspase-3 activation in a Ewing tumor cell line and in
      freshly isolated tumor cells, causing drug-induced cell death. Thus,
      determination of caspase-3 activation might be a suitable method for drug
      sensitivity testing in patients with Ewing tumors before initiating treatment.
      This assay could therefore help individualize therapy in future tumor patients.

PMID- 15015590
TI  - Genomic imbalance and onco-protein expression of ovarian endometrioid
      adenocarcinoma arisen in an endometriotic cyst.
AB  - BACKGROUND: Malignant transformation in endometriosis is a rare but well known
      complication. However, detailed mechanisms of malignant transition and
      tumourigenesis in endometriosis remain unknown. We here describe the case of an
      endometrioid carcinoma arisen in endometriotic ovarian cyst fulfilling Sampson's
      criteria for malignant transformation of endometriosis. We compared genetic
      alterations and oncoprotein expression in the endometriotic ovarian cyst and the
      associated endometrioid adenocarcinoma. MATERIALS AND METHODS: Genomic
      instability was evaluated by comparative genomic hybridization (CGH). Onco
      protein expression was analysed by immunohistochemistry with antibodies against
      bcl-2, c-MYC, cyclin D1, p53, HER-2 and KIT protein. RESULTS: CGH revealed a gain
      of 8q, including the locus of the oncogene c-MYC at 8q24. Immunohistochemistry
      disclosed a differing protein expression profile between the epithelia of the pre
      existing cyst and adenocarcinoma. Apart from HER-2, all onco-proteins were more
      strongly expressed in epithelial cells of the adenocarcinoma than of the
      endometriotic cyst. CONCLUSION: The solitary genomic imbalance of chromosome 8
      possibly reflects the importance for initiation and/or progression of
      endometrioid carcinoma. Overexpression of onco-proteins then may occur
      subsequently in the malignant transformation of ovarian endometriosis. However,
      the exact mechanisms of malignant transition in ovarian endometriosis remain to
      be elucidated in future studies with a higher number of cases.

PMID- 15015591
TI  - Numerical aberrations of chromosome 8 in gastric cancer detected by fluorescence
      in situ hybridization.
AB  - BACKGROUND: Limited data are available on the genetic events underlying gastric
      cancer. Studying a few cases by conventional cytogenetic techniques, we
      previously reported that chromosome 8 might be frequently involved. The aim of
      our study was to evaluate the numerical aberrations of chromosome 8 in gastric
      cancer using fluorescence in situ hybridization (FISH). MATERIALS AND METHODS:
      FISH, with an a-satellite DNA probe specific for chromosome 8, was applied to 37
      primary gastric tumors directly processed for cytogenetic study. RESULTS:
      Numerical aberrations of chromosome 8 were observed in 23 out of 37 tumors
      (62.16%). Trisomy was detected in 16 cases (43.24%), tetrasomy in 4 cases
      (10.81%) and monosomy in 3 cases (8.10%). No correlation was found between
      polysomy 8 and the histopathologic characteristics of the tumors. CONCLUSION: An
      increase in the number of chromosome 8 may frequently occur in gastric cancer.
      Advanced and more aggressive gastric tumors did not harbor polysomy 8. Further
      studies at molecular and clinical level must be carried out to identify the gene
      alterations reflected by polysomy 8 and possibly to facilitate the detection of
      specific tumors subtypes.

PMID- 15015592
TI  - Synthesis and evaluation of a hematoporphyrin derivative in a folate receptor
      targeted solid-lipid nanoparticle formulation.
AB  - PURPOSE: This study was aimed at the synthesis, formulation and in vitro
      evaluation of folate receptor (FR)-targeted solid-lipid nanoparticles (SLNs) as a
      carrier for a lipophilic derivative of the photosensitizer hematoporphyrin (Hp),
      in FR-overexpressing tumor cells. MATERIALS AND METHODS: FR-targeted
      hematoporphyrin-stearylamine (HpSa) SLN composed of Triolein:Egg
      phosphatidylcholine (EPC):Tween-80 (T-80) (64:25:10), with 0.5 mole % of folate
      polyethyleneglycol-cholesterol (FPC) or polyethyleneglycol
      distearoylphosphatidylethanolamine (PEG-DSPE), were prepared by ethanol injection
      method. Stability of the SLN was monitored by changes in particle size at 4
      degrees C and drug retention at various time points. Cellular uptake and IC50
      values of the FR-targeted formulations were determined in vitro in the FR (+) KB
      cells. RESULTS: Stable targeted SLNs were prepared by ethanol injection
      encapsulating greater than 95 percent of 5 mole % of HpSa, having a mean diameter
      < 200 nm. In vitro cytotoxicity assay on the FR-targeted SLN gave IC50 of 1.57
      microM in KB cells and non-targeted SLNs gave an IC50 of 5.17 microM. FR
      selectivity was confirmed by fluorescence microscopy. CONCLUSION: FR-targeted
      SLNs incorporating the lipophilic drug HpSa were capable of specific receptor
      binding in cultured KB cells, which warrants further investigation.

PMID- 15015593
TI  - HIF transcription factor expression and induction of hypoxic response genes in a
      retroperitoneal angiosarcoma.
AB  - Angiosarcoma is a rare and highly aggressive tumor of endothelial origin. The
      molecular mechanisms driving angiosarcoma growth have not been fully elucidated,
      although autocrine stimulation by vascular endothelial growth factor (VEGF)
      secretion may play a role in the pathogenesis of this tumor. We identified a
      patient with a very rare form of angiosarcoma arising from the retroperitoneum.
      Immunohistochemical analysis demonstrated widespread up-regulation of the hypoxic
      response pathway as a mechanism of enhanced VEGF expression. Disordered
      regulation of the hypoxic response pathway can result in the expression of
      factors such as VEGF and erythropoietin, which may promote autocrine tumor growth
      in angiosarcoma.

PMID- 15015594
TI  - IFN-gamma responses in peptide-treated melanoma patients measured by an ELISPOT
      assay using allogeneic dendritic cells.
AB  - BACKGROUND: Several melanoma-specific peptides are currently used in clinical
      trials. However, the monitoring of the T cell response remains non-standardised
      and is often limited by shortage of cells. MATERIALS AND METHODS: We established
      an IFN-gamma ELISPOT assay to detect the CD8+ T cell response in HLA-A2-positive
      melanoma patients using pre-frozen, peptide-loaded HLA-A2-positive but otherwise
      allogeneic, monocyte-derived dendritic cells (DC) as antigen-presenting cells. We
      tested HLA-A2-positive stage III or IV melanoma patients before and after peptide
      immunotherapy. RESULTS: The number of EBV and influenza-specific IFN-gamma-spots
      were comparable irrespective of the use of autologous or allogeneic HLA-A2
      immature DCs when using purified CD8+ cells as responder cells, but a high
      allogeneic background was seen when using PBMC. We observed modifications of the
      in vitro response to the melanoma peptides in three out of four responding
      patients, while virus responses remained constant; however, similar results were
      seen in the group with progressive disease. CONCLUSION: This demonstrates the
      possibility of monitoring an immune response by using allogeneic DCs, reducing
      the consumption of patient cells. The in vitro IFN-gamma responses increased in
      response to the peptide therapy, however this could not be correlated to clinical
      outcome.

PMID- 15015596
TI  - Computational simulation of chronic persistent virus infection: factors
      determining differences in clinical outcome of HHV-6, HIV-1 and HTLV-1 infections
      including aplastic, hyperplastic and neoplastic responses.
AB  - A computational model was recently designed to simulate cellular changes in the T
      cell immune system. The model was validated by simulating cell changes in viral
      infections which target the same CD4+ T cell, yet cause either hyperplastic,
      aplastic or neoplastic responses. Respective case material for comparison was
      available from human infections with human herpesvirus-6 (HHV-6), human
      immunodeficiency virus (HIV-1) or human T cell leukemia virus (HTLV-1). Starting
      with cell values for a healthy human individual, factorial changes that influence
      the individual course of the various infections were determined by an algorithm
      search procedure. Such factorial differences determining a clinical course with
      aplasia, hyperplasia or neoplasia are outlined and further discussed in this
      paper.

PMID- 15015595
TI  - Abilities of 3,4-diarylfuran-2-one analogs of combretastatin A-4 to inhibit both
      proliferation of tumor cell lines and growth of relevant tumors in nude mice.
AB  - BACKGROUND: Combretastatin A-4 (CA-4) and its analogs are potent inhibitors of
      tubulin polymerization and display strong inhibitory activity on both solid tumor
      and tumor cell growth. Since natural CA-4 is difficult to synthesize and also
      isomerizes to an inactive form quite readily, a recently reported new 3,4
      diarylfuran-2-one-based series of CA-4 analogs was investigated, in the hope of
      bypassing some of these difficulties. These analogs appear to offer a valuable
      tool for CA-4 research because of their extremely facile synthesis from readily
      available starting materials. MATERIALS AND METHODS: The CA-4 analogs were
      evaluated by MTT assay, cell cycle analysis, tubulin polymerization and tumor
      inhibiting experiments. RESULTS: Various benzene ring substitutions on the furan
      2-one skeleton (analogs to the two aromatic rings on the CA-4 styrene skeleton)
      quickly demonstrated that the structure-activity relationships are quite similar
      to previously synthesized CA-4 analogs. The most interesting analog appears to be
      an anilino compound (NV-5-9) which was also quite soluble. Analog NV-5-9 was
      remarkably potent in all tested tumor cell lines and could strongly inhibit
      tubulin polymerization at doses as low as 1 mM. Further experiments with tumor
      bearing mice indicated that NV-5-9 and other potent analogs (NV-4-82 and NV-4-86)
      were effective in treating human prostate PC-3 and SCLC NCI-H69 tumors at well
      below an oral MTD dose of around 200 mg/kg body weight. This suggests some
      bioavailability by this route. CONCLUSION: These data strongly support that NV-5
      9 is extremely potent, readily synthesizable and apparently suitable for in vivo
      studies employing transplanted tumors.

PMID- 15015597
TI  - The matrix metalloproteinase-21 gene 572C/T polymorphism and the risk of breast
      cancer.
AB  - BACKGROUND: Matrix metalloproteinases (MMPs) contribute in multiple ways to all
      stages of tumor development, and a number of DNA polymorphisms in the MMP genes
      are associated with an increased risk of cancer. We previously identified the MMP
      21 gene 572C/T polymorphism leading to Ala191Val substitution within the enzyme's
      catalytic domain. We performed a case-control study to test association between
      this polymorphism and the risk of breast cancer. PATIENTS AND METHODS: 572C/T
      polymorphism was analyzed by RFLP method in 396 unrelated Russian females: 76
      breast cancer patients and 320 disease-free blood donors. RESULTS: The
      frequencies of C/C, T/C and T/T genotypes in patients (69.7%, 25.0% and 5.3%) did
      not differ significantly from those in controls (61.9%, 34.7% and 3.4%); the
      polymorphism was not associated with the increased tumor size and the presence of
      metastases. CONCLUSION: The MMP-21 gene 572C/T polymorphism has no significant
      effect on the development and progression of breast cancer.

PMID- 15015598
TI  - Potential antitumor agents. 34.(1) Synthesis and antitumor activity of
      guanylhydrazones from imidazo[2,1-b]thiazoles and from diimidazo[1,2-a: 1,2-c]
      pyrimidine.
AB  - We report the synthesis of new guanylhydrazones from imidazo[2,1-b]thiazoles and
      of a bis-guanylhydrazone from diimidazo[1,2-a:1,2-c]pyrimidine. The compounds
      were tested as potential antitumor agents at the National Cancer Institute. Two
      derivatives are now under review by BEC: one of these was also subjected to a
      test for positive inotropic activity in view of a possible coanthracyclinic
      activity. Tyrosine kinase receptors may be involved as molecular targets in the
      mechanism of action of the guanylhydrazones described.

PMID- 15015599
TI  - Simultaneous targeting of VEGF message and VEGF receptor signaling as a
      therapeutic anticancer approach.
AB  - BACKGROUND: Vascular endothelial growth factor (VEGF) is one of the most
      important factors involved in tumor angiogenesis. MATERIALS AND METHODS:
      Antisense phosphorothiolate oligodeoxynucleotides (PS-ODNs) were used to reduce
      VEGF production while the small molecule PD0203359-0002 (PD203359) was used to
      inhibit VEGF/bFGF receptor tyrosine kinase activity. RESULTS: PD203359 exposure
      was found to profoundly impair the growth of human endothelial cells (HMVEC-L) at
      doses 20-fold less than those affecting human renal cell carcinoma (Caki-1) cell
      growth. In vivo, treatment with PD203359 inhibited tumor cell-induced
      angiogenesis and resulted in a significant tumor growth delay. Treatment with
      VEGF antisense PS-ODNs also significantly increased the time for tumors to grow
      to five times the starting size. Most importantly, when the PD203359 and VEGF
      antisense treatments were combined, a greater antitumor response than could be
      achieved with either therapy alone was observed. CONCLUSION: Simultaneously
      targeting VEGF production and VEGF receptor signaling enhances the anticancer
      efficacy of either therapy alone.

PMID- 15015600
TI  - Apoptosis induced by oxaliplatin in human colon cancer HCT15 cell line.
AB  - BACKGROUND: Oxaliplatin (L-OHP), active in a wide range of human and animal
      tumours, also CDDP-resistant, possesses unique molecular characteristics of
      action. However, the mechanisms by which the damage induced by L-OHP triggers a
      death signal are not yet fully defined. MATERIALS AND METHODS: After L-OHP
      treatment of the HCT15 human colon cancer cell line, apoptosis was evaluated by
      DNA laddering detection and by flow cytometry; the effect on specific caspase-3, 
      8 and -9 inhibitors, mitochondrial membrane permeability transition, cytochrome C
      release and expression of CD95 and CD95L were also assessed. RESULTS: HCT15 cells
      underwent apoptosis when treated with all used drug concentrations (7-25 microM).
      Treatment of cells with L-OHP resulted in the activation of caspase-8, -9 and -3,
      in a mitochondrial membrane depolarisation, and in an increase of CD95 receptor
      and CD95 ligand levels. CONCLUSION: The results correlated well with the ability
      of L-OHP to induce apoptosis and give further insights into the mechanisms
      underlying the L-OHP-induced apoptosis of tumor cells.

PMID- 15015601
TI  - Effects of the Medicago scutellata trypsin inhibitor (MsTI) on cisplatin-induced
      cytotoxicity in human breast and cervical cancer cells.
AB  - BACKGROUND: Snail medic (Medicago scutellata L.) seeds exhibit a significantly
      higher content of a trypsin inhibitor than other Medicago species. This inhibitor
      belongs to the Bowman-Birk family of serine protease inhibitors (BBI) and
      exhibits a good sequence homology with the BBI from soybean, while presenting
      some differences. It has been suggested that BBIs have antitumoral and radio
      protective activity. MATERIALS AND METHODS: In order to assess whether the
      inhibitor from Medicago scutellata (MsTI) seeds show similar properties to those
      of BBI from soybean with respect to potentiation of cisplatin-induced
      cytotoxicity, we evaluated the effects of MsTI on cisplatin-induced cell killing
      in MCF7 human breast carcinoma cells and HeLa human cervical carcinoma cells.
      RESULTS: The 24-hour treatment of MsTI in the cell culture medium decreased the
      clonogenic survival of MCF7 and HeLa cells in a dose-dependent manner and
      enhanced cisplatin-induced cytotoxicity. The presence of MsTI during the entire
      incubation period reduced the D37 of cisplatin by 40% in both the cell lines.
      CONCLUSION: MsTI could be an useful agent for the potentiation of cisplatin
      mediated cancer treatment.

PMID- 15015602
TI  - YY1 transcription factor is not responsible for the negative regulation of
      hamster Muc1 transcription.
AB  - Muc1 is the cell surface glycoprotein abundantly expressed in cancer cells and
      has been shown to be involved in tumor metastasis and promotion. Recently, we
      identified a 37 bp segment on the hamster Muc1 promoter with the ability to
      suppress Muc1 transcription. This 37 bp putative negative regulatory element
      (NRE) binds to a transcriptional regulator Yin Yang 1 (YY1). In the present
      study, we examined whether binding of YY1 is responsible for the negative
      regulatory effect by the 37 bp segment using a hamster pancreatic cancer cell
      line, HP-1 cells, transfected with various expression plasmid constructs. Our
      results showed that: (1) overexpression of YY1 up-regulated the transcriptional
      activity of the full-length hamster Muc1 promoter in a dose-dependent manner; (2)
      the mutation of the YY1 binding site did not affect either the basal
      transcriptional activity or the increased transcriptional activity by YY1; and
      (3) even the deletion of the 37 bp NRE segment could not abrogate the increased
      transcriptional activity by YY1. We conclude that the NRE acts in a YY1
      independent manner and that YY1 instead enhances Muc1 transcriptional activity.
      Further study of the precise mechanism by which YY1 augments Muc1 gene expression
      should be worthwhile.

PMID- 15015603
TI  - Increased plasma levels of serine proteinase inhibitors in lung cancer patients.
AB  - BACKGROUND: Tumor growth and invasiveness occur through infiltration of tumor
      cells into the host cells and by angiogenesis, which is modulated by proteinases
      and antiproteinases released from tumor cells that carry out tissue remodelling.
      A number of studies have revealed variations in the plasma levels of serine
      proteases and their inhibitors among tumor types. PATIENTS AND METHODS: By
      immunological methods we analysed the levels of serine protease inhibitors AAT,
      ACT and SLPI in newly diagnosed lung cancer patients (n=14) compared to non
      smoker and smoker, age- and gender-matched control groups (n=16), and also in an
      expanded group of lung cancer patients with local tumors (n=14) and with
      metastasis (n=18). RESULTS: Our data show that plasma levels of AAT, ACT and SLPI
      were elevated in lung cancer patients by 1.43-fold, p<0.01, 2.57-fold, p<0.01 and
      1.6-fold, p<0.001, respectively when compared to controls. In addition, we found
      that levels of AAT and ACT were higher by 1.47-fold, p<0.001 and 2.27-fold,
      p<0.001, respectively in lung cancer cases with metastasis compared to localized
      tumor. CONCLUSION: These inhibitor levels may provide measures of cancer
      progression in individual patients and possibly offer useful information for an
      understanding of the mechanisms of metastasis.

PMID- 15015605
TI  - Polo-like kinase 1 (PLK1) expression is associated with cell proliferative
      activity and cdc2 expression in malignant lymphoma of the thyroid.
AB  - BACKGROUND: Polo-like kinase 1 (PLK1) is one of the serine threonine kinases that
      plays a role in cellular proliferation by activating the CDC25C-CDK1 (cdc2) loop.
      We recently demonstrated that cdc2 expression is associated with the biological
      aggressiveness of malignant lymphoma of the thyroid. In this study, we
      investigated PLK1 expression in thyroid lymphoma in order to elucidate its
      physiological significance in this disease. MATERIALS AND METHODS: We
      immunohistochemically investigated PLK1 expression in 46 cases of thyroid
      lymphoma and 10 cases of chronic thyroiditis. RESULTS: Normal follicular cells
      did not express PLK1, whereas follicular cells in those in chronic thyroiditis
      and malignant lymphoma demonstrated a high level of PLK1 expression. In
      lymphocytes in chronic thyroiditis with strong lymphocyte infiltration, PLK1 was
      weakly expressed. In malignant lymphoma, PLK1 expression was observed in all
      cases, but PLK1 was more strongly expressed in cases with high cell proliferative
      activity and with cdc2 expression. CONCLUSION: These results suggest that PLK1
      regulates the cell cycle progression of thyroid lymphoma cells in the G2-M-phase.

PMID- 15015604
TI  - Orbital rhabdomyosarcoma: relationship between DNA ploidy, p53, bcl-2, MDR-1 and
      Ki67 (MIB1) expression and clinical behavior.
AB  - BACKGROUND: As for rhabdomyosarcoma (RMS) of other anatomic regions, the
      evaluation of traditional clinicopathological parameters does not allow the
      unequivocal outcome prediction of the single cases of orbital RMS. We
      investigated the role of DNA ploidy and immunohistochemical expression of p53,
      bcl-2, MDR-1 and Ki67 (MIB1) in the prognostic evaluation of orbital
      rhabdomyosarcomas. MATERIALS AND METHODS: The study population consisted of 11
      selected cases. Serial sections of each tumor, stained with Feulgen's technique,
      were analyzed for the DNA content, using the QUANTIMET 500c Leica analyzer,
      QWINVO200A software. The results were compared with the immunohistochemical
      expression of p53 (wild plus mutated, W&M and mutated), bcl2, MDR-1 and Ki67
      (MIB1), and with follow-up data. RESULTS: The statistical analysis of results
      showed that the cases of tetraploid and/or multiploid RMS, overexpressing p53
      (W&M and mutated) and MDR-1, were characterized by an overall worse prognosis. On
      the contrary, the tumors with a favourable clinical course showed hyperexpression
      of MIB1 and absence of mutated p53 expression. Significantly higher MIB1
      expression was found in the relapse-free group of tumors, with respect to the RMS
      with relapse (both in primary tumors and relative relapses, p<0.05). This finding
      could justify the higher sensibility to pharmacological therapy of RMS of the
      first group. The group of RMS with a worse prognosis (primary tumors and
      relapses) showed instead p53 overexpression (W&M and mutated), MDR-1 expression
      and multiploidy, with high 5cEE values and tetraploid peaks. No significant
      difference was found concerning the expression of bcl-2 among the two groups of
      RMS (p>0.05). CONCLUSION: The evaluation of DNA ploidy, p53, MIB1 and MDR-1
      expression could be used for subtyping of orbital RMS into two prognostically
      different subcategories, respectively RMS responder to the therapy, with
      favourable clinical outcome, and RMS with a worse prognosis, requiring more
      aggressive therapeutic protocols.

PMID- 15015606
TI  - Palliative management of malignant rectosigmoidal obstruction. Colostomy vs.
      endoscopic stenting. A randomized prospective trial.
AB  - BACKGROUND: Colostomy was the palliative treatment of choice in patients with
      malignant unresectable rectosigmoid obstruction. Palliative endoscopic treatment
      of malignant rectosigmoid obstruction by endoluminal self-expanding metallic
      stents is nowadays a well-established procedure. PATIENTS AND METHODS: Twenty-two
      patients, referred for treatment with diagnosis of malignant obstruction of the
      rectosigmoid region presenting an advanced unresectable stage, were enrolled.
      Patients were randomly assigned into two treatment groups (endoscopic stenting vs
      colostomy) according to random-number tables. The length of procedure, morbidity
      and mortality rate, canalization of the gastrointestinal tract, restoration of
      oral intake and hospital stay were assessed. RESULTS: Endoscopic group: The
      median length of procedure was 36 minutes. No death was observed. None of the
      patients reported complications. All patients resumed bowel function within 24
      hours. The restoration of oral intake was achieved one day after stent placement.
      The median hospital stay was 2.6 days. Colostomy group: The median length of the
      operation was 75.4 minutes. No mortality was reported. In 1 patient (9.1%) stoma
      prolapse was observed 3 days after the operation. Canalization of the
      gastrointestinal tract was restored when colostomy was opened (on postoperative
      day 3). All patients were able to resume oral feedings on postoperative day 3.
      The median hospital stay was 8.1 days. CONCLUSION: There were no statistically
      significant differences between the 2 groups concerning morbidity and mortality.
      Endoscopic stenting was significantly more effective concerning operative time,
      restoration of bowel function and oral intake and median hospitalization. Our
      results would suggest that endoscopically placed metal stents offer an effective
      alternative to surgical palliation in patients suffering from unresectable
      malignant rectosigmoid obstruction.

PMID- 15015607
TI  - Palliative management of malignant antro-pyloric strictures. Gastroenterostomy
      vs. endoscopic stenting. A randomized prospective trial.
AB  - BACKGROUND: Gastroenterostomy was the palliative treatment of choice in patients
      with malignant unresectable gastric outlet obstruction. Palliative endoscopic
      treatment of malignant gastric outlet obstruction with endoluminal self-expanding
      metallic stents is nowadays a well-established procedure. PATIENTS AND METHODS:
      Eighteen patients referred for treatment with diagnosis of malignant strictures
      of the antro-pyloric tract presenting at an advanced unresectable stage. The
      patients were randomly assigned into two treatment groups (endoscopic vs.
      surgery) according to random-number tables. The length of procedure, morbidity
      and mortality rate, restoration of oral intake and gastric emptying at 8, 15 days
      and 3 months from treatment and hospital stay were assessed. RESULTS: Endoscopic
      group: The median length of procedure was 40 minutes. No death and one minor
      complication (11.1%) was reported. Mean time for oral intake was 2.1 days.
      Gastric emptying was satisfactory in 88.9% after 8 days and in 100% of patients
      after 15 days and 3 months. The median hospital stay was 3.1 days. Surgery group:
      The median length of the operation was 93 minutes. No mortality was reported. One
      patient (11.1%) developed anastomotic bleeding which required relaparotomy. Mean
      time for oral intake was 6.3 days. Gastric emptying was satisfactory in 66.7% of
      patients after 8 days, in 88.9% after 15 days and in 100% after 3 months. The
      median hospital stay was 10 days. CONCLUSION: There were no statistically
      significant differences between the 2 groups even with respect to morbidity,
      mortality, delayed gastric emptying and clinical outcomes at 3-month follow-up.
      Endoscopic stenting was significantly more effective with respect to operative
      time, restoration of oral intake and median hospitalization. Our results would
      suggest that endoscopically placed metal stents offer an effective alternative to
      surgical palliation in patients with unresectable malignant strictures.

PMID- 15015608
TI  - Immunohistochemical dihydropyrimidine dehydrogenase expression is a good
      prognostic indicator for patients with Dukes' C colorectal cancer.
AB  - BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is an enzyme that catabolizes 5
      fluorouracil (5-FU), which is widely used for chemotherapy in patients with
      advanced colorectal cancer (CRC). However, the clinical importance of tumor
      dihydropyrimidine dehydrogenase (DPD) expression in patients with CRC treated
      with 5-FU remains unclear. MATERIALS AND METHODS: We investigated DPD activities
      in normal mucosa (N) and tumors (T) by enzyme-linked immunosorbent assay (ELISA)
      in 64 surgically resected patients with Dukes' C CRC who were treated orally with
      postoperative adjuvant FU-based chemotherapy. We also immunohistochemically
      investigated DPD expression in these specimens. The clinicopathological
      importance of DPD activity and expression was evaluated in the patients. RESULTS:
      Positive DPD expression was detected in 28 tumors (43.8%) and tumor DPD activity
      significantly correlated with tumor DPD immunoreactivity (p=0.0121). Further,
      tumor DPD activity and immunoreactivity also correlated with lymph node
      metastatic status (p=0.0409). The disease-free survival rate of patients with
      positive-tumor DPD expression was significantly worse than that of patients with
      negative-tumor DPD expression (39.3% vs. 72.2%, p=0.0127). However, DPD activity
      in tumors or normal mucosa did not correlate with patient prognosis. Tumor DPD
      expression appeared to be an important poor prognostic factor in patients with
      Dukes' C CRC by multivariate analysis (p=0.013). CONCLUSION: Immunohistochemical
      DPD expression in tumors is a useful prognostic parameter in patients with Dukes'
      C CRC treated with postoperative adjuvant FU-based chemotherapy.

PMID- 15015609
TI  - Loss of BRCA2 correlates with reduced long-term survival of sporadic breast
      cancer patients.
AB  - BACKGROUND: The present study was undertaken to analyze the prognostic value of
      loss of heterozygosity (LOH) at 13q12-13, 17q21 and 17p13, harboring BRCA2, BRCA1
      and p53 to predict the clinical course of sporadic breast cancer patients.
      MATERIALS AND METHODS: LOH analysis was performed by PCR amplification of genomic
      DNA using nine microsatellite markers. Fifty-three sporadic breast cancer
      patients were followed clinically for a median of 55 months. Disease-free and
      overall survival was documented as the endpoint for statistical evaluation.
      RESULTS: Patients presenting with LOH in their tumor samples at at least one of
      the loci examined were found to have a reduced overall survival time compared to
      those retaining heterozygosity (61% versus 48%). Focusing on the three target
      regions, patients with LOH at the BRCA2 locus died earlier compared to patients
      retaining heterozygosity (69% versus 50%) and, in addition, BRCA2 LOH-positive
      patients showed a shorter metastasis-free interval (30 versus 37 months). In a
      multivariate analysis, LOH at the 13q12-13 locus was found to be a significant
      predictor for reduced long-term survival (risk ratio 2.33, 95% C.I., 1.0-5.3;
      p<0.05) and earlier metastases manifestation (risk ratio 2.32, 95% C.I., 1.0-5.3,
      p<0.05). CONCLUSION: Allelic loss at the BRCA2 locus may be of use as a negative
      predictor for metastases-free and overall survival.

PMID- 15015610
TI  - Multidrug resistance proteins in primary and metastatic soft-tissue sarcomas:
      down-regulation of P-glycoprotein during metastatic progression.
AB  - BACKGROUND: Chemotherapy sensitivity of soft-tissue sarcomas (STS) is limited,
      which may be due to multidrug resistance (MDR). MDR is associated with expression
      of P-glycoprotein (P-gp), Multidrug Resistance-associated Protein 1 (MRP1) and
      Lung Resistance-related Protein (LRP). It is unknown whether in STS metastasis is
      more resistant than the primary counterpart. MATERIALS AND METHODS: In 35
      chemonaive STS and their metastases (86% chemonaive), MDR proteins were
      immunohistochemically assessed. Eleven metastases presented synchronously, 24
      metachronously. Expression was scored positive (>5% positive tumour cells) or
      negative. RESULTS: P-gp was positive in 31/34 primaries (91%), versus 22/32
      metastases (69%) (p=0.005). This difference was significant for metachronous
      metastases (p=0.008). MRP1 was positive in 18/32 primaries (56%) and 22/33
      metastases (67%). MRP1 was more expressed in synchronous metastases than
      primaries (p=0.047), but for the overall group this significance disappeared. LRP
      expression did not differ: 27/34 primaries (80%), versus 28/34 metastases (82%).
      CONCLUSION: P-gp, MRP1, LRP expression in the primary tumours was high.
      Metastatic progression did not coincide with MDR-protein up-regulation.

PMID- 15015611
TI  - Clinical and immunohistochemical analysis of patients with unknown primary
      tumour. A search for prognostic factors in UPT.
AB  - BACKGROUND: The unknown primary tumour (UPT) is an intriguing clinical finding in
      approximately 5% of all newly diagnosed patients with cancer. To evaluate a
      correlation between the specific immunohistochemical alterations in UPT cells and
      the unique clinical features of UPT patients, to define the natural history of
      UPT and to verify prognostic factors, we undertook a detailed clinical and
      immunohistochemical analysis of patients with the diagnosis of adenocarcinoma of
      UPT. RESULTS: Patients with UPT present with a short history and have a poor
      prognosis. Univariate analysis was performed with clinical, biological and
      immunohistochemical variables. Patients with a higher age (>60 years), a poor
      performance score (2-3), liver metastases or more than two organ sites involved,
      or patients with elevated LDH-levels, were found to have worse prognosis. We
      confirm that the prognostic model published by Culine is a valuable model for the
      prediction of prognosis in patients with UPT. Immunohistochemical detection of
      proliferation (MIB-1), p53, vascular endothelial growth factor-A, CD34, CD44v6
      and Her2neu indicated that these factors were of no prognostic value. CONCLUSION:
      In conclusion, patients with UPT have a very poor median prognosis of 12 weeks.
      Prognostically favourable factors are young age, good performance status, no
      liver metastases and normal LDH level. We found no relationship with
      immunohistochemical factors.

PMID- 15015612
TI  - Impact of complementary mistletoe extract treatment on quality of life in breast,
      ovarian and non-small cell lung cancer patients. A prospective randomized
      controlled clinical trial.
AB  - Standardized aqueous mistletoe extracts have been applied to cancer patients for
      several decades as complementary medicine. A multicentric, randomized, open,
      prospective clinical trial was conducted in three oncological centers in the
      People's Republic of China in Bejing, Shenyang and Tianjin. Following the
      guidelines of "Good Clinical Practice" (GCP) this study was performed to get
      information on efficacy safety and side-effects of the standardized mistletoe
      extract (sME). Two hundred and thirty-three patients with breast (n=68), ovarian
      (n=71) and non-small cell lung cancer (NSCLC; n=94) were enrolled into this
      study. Two hundred and twenty-four patients fulfilled the requirements for final
      analysis (n=115 treated with sME HELIXOR A; n=109 comprising the control group
      being treated with the approved immunomodulating phytopharmacon Lentinan). All
      patients were provided with standard tumor-destructive treatment schedules and
      complementarily treated with sME or Lentinan during chemotherapy according to
      treatment protocol. Biometrically, the patients of the control and sME treatment
      group were comparable regarding distribution, clinical classification (WHO) and
      treatment protocols. Analysis was performed according to the "Intention to treat
      principle". Quality of life (QoL) was significantly (p<0.05) improved for
      patients who were complementarily treated with sME, as determined by the
      questionnaires FLIC (Functional Living Index-Cancer), TCM (Traditional Chinese
      Medicine Index) and the KPI (Karnofsky Performance Index) in comparison to the
      control group. Additionally, the occurrence of adverse events (AEs) was less
      frequent in the sME than in the control group (total number of AEs 52 versus 90
      and number of serious AEs 5 versus 10 in study and control group, most of them
      due to chemotherapy). Only one serious AE was allocated to complementary
      treatment in each group (1 angioedema in sME group). All other side-effects of
      the sME (7 harmless local inflammatory reactions at subcutaneous injection site,
      4 cases with fever) were self-limiting and did not demand therapeutic
      intervention. This study showed that complementary treatment with sME can
      beneficially reduce the side-effects of chemotherapy in cancer patients and thus
      improve quality of life.

PMID- 15015613
TI  - Catestatin--a novel neuropeptide in carcinoid tumors of the appendix.
AB  - BACKGROUND: The aim of the study was to investigate the immunohistochemical
      distribution of the novel neuropeptide catestatin in carcinoid tumors.
      Catestatin, a novel 21 amino acid neuropeptide derived from chromogranin A, was
      determined immunohistochemically in 30 carcinoid tumors of the appendix and
      various carcinoid tumors of other localities. MATERIALS AND METHODS: Paraffin
      embedded tissues from 30 carcinoid tumors of the appendix and 16 other carcinoid
      tumors (5 bronchus-, 5 stomach-, 2 small bowel-, 4 large bowel carcinoid tumors)
      were incubated with antibodies specific for catestatin, chromogranin A and
      chromogranin B. Immunohistochemical staining of catestatin was compared to
      staining with chromogranin A and B. Western blot analysis was performed in one
      patient with ileal carcinoid. RESULTS: Thirty patients (20 women, 10 men) with
      carcinoid tumors of the appendix and 16 patients with other localized carcinoid
      tumors were investigated. Twenty-six of the appendiceal tumors were localized in
      the apex of the appendix and 4 tumors in the midportion; none of the tumors was
      localized at the base of the appendix. Median tumor diameter was 10.7 mm (range 4
      18 mm). Immunoreactivity to catesatatin was positive in 28 patients (negative in
      2, 0-10% in 11 patients, 11-50% in 14 patients, 51-100% in 3 patients). In 16
      patients with carcinoid tumors in various other localizations, catestatin was
      also expressed. Western blot analysis of ileal carcinoid showed abundant
      catestatin reactivity with accelerated processing of chromogranin A in the tumor
      tissue. CONCLUSION: Catestatin derived from chromogranin A, which is the most
      widely distributed marker of neuroendocrine tumors, is expressed in high
      frequency in carcinoid tumors of the appendix (93.3%).

PMID- 15015614
TI  - Complete response of severe symptomatic bone marrow metastases from heavily
      pretreated breast cancer with a 3-weekly trastuzumab schedule. A clinical case.
AB  - Overexpression of HER-2/neu in breast cancer has been associated with more
      aggressive disease and poor overall survival. Trastuzumab, a recombinant
      humanized monoclonal antibody with high affinity for the HER-2 protein, inhibits
      the growth of breast cancer cells overexpressing HER-2. Trastuzumab showed, as
      second-line treatment, 15% of objective response in metastatic breast cancer.
      Bone marrow metastases are detectable in 23% of the patients with advanced breast
      cancer at first relapse and this rate increases in patients with metastatic
      disease. We report a case of a complete response of bone marrow metastases from
      breast cancer using a 3-weekly trastuzumab schedule, in a heavily pretreated
      patient with severe symptomatic pancytopenia.

PMID- 15015615
TI  - Differential expressions of BRCA1 and BRCA2 in infantile gynecomastia.
AB  - BRCA1 and BRCA2 breast cancer susceptibility genes are responsible for most of
      the hereditary breast cancers. No or very few sporadic breast tumors have been
      shown to harbor mutations in the coding sequence of BRCA1 or BRCA2. In contrast
      to normal breast epithelial cells, BRCA1 mRNA levels in tumors appeared to be
      down-regulated by methylation, while BRCA2 showed significant overexpression in
      sporadic breast cancers. We report herein an infantile gynecomastia in a two-year
      old boy, studied by immunohistochemistry of anti-BRCA1 and anti-BRCA2 antibodies.
      We demonstrated that BRCA1 proteins, like BRCA2, are widely expressed in the
      nuclei of epithelial cells surrounding the lumen of the ducts in infantile
      gynecomastia. The intensive nuclear staining of both proteins in the mammary
      tissues means that BRCA1 and BRCA2 proteins are largely expressed in infantile
      gynecomastia.

PMID- 15015616
TI  - The impact of stromal cell contamination on chemosensitivity testing of head and
      neck carcinoma.
AB  - BACKGROUND: Reliable chemosensitivity testing of head and neck squamous cell
      carcinoma (HNSCC) still faces methodical limitations. Since stromal cell
      contamination has been found to preclude reliable radiosensitivity testing of
      HNSCC as well as chemosensitivity testing of lung tumors, the present study
      investigates the impact of stromal cell contamination on chemosensitivity testing
      of HNSCC. PATIENTS AND METHODS: Seventeen biopsies from HNSCC were analyzed. The
      specimens were investigated using an ex vivo colony formation assay which allows
      for the quantitative and separate determination of the overall, as well as the
      epithelial, and stromal response to carboplatin, 5-fluorouracil and docetaxel.
      RESULTS: The overall chemoresponse was dominated by stromal cell multidrug
      resistance. However, by selective evaluation of the epithelial chemoresponse,
      individual chemosensitivity patterns could be identified. CONCLUSION: Multidrug
      resistant stromal cells preclude the reliable assessment of the chemoresponse of
      HNSCC specimens. Carefiul correction for stromal cell effects is a prerequisite
      for the generation of therapeutically useful information.

PMID- 15015617
TI  - Immunohistochemical detection of HER-2/neu, c-kit (CD117) and vascular
      endothelial growth factor (VEGF) overexpression in soft tissue sarcomas.
AB  - PURPOSE: The aim of this study was to determine the incidence of HER-2/neu, VEGF
      and CD117 overexpression in soft tissue sarcomas (STS) and to study the effect of
      this overexpression, if present, on survival in patients with specific
      histological subtypes of STS. MATERIALS AND METHODS: We conducted a retrospective
      observational study on patients diagnosed with STS during the period of 1986
      2001. HER-2/neu overexpression was measured in these patients by
      immunohistochemistry (IHC) using the Hercep test developed by DAKO. VEGF
      expression was detected by the avidin-biotin-complex method using Santa Cruz
      biotechnology (SC 7629). Immunohistochemical staining for c-kit was performed
      using a 1:250 dilution of the rabbit polyclonal antibody A4502 (IMPATH, CA) with
      the EnVision detection system. RESULTS: Two hundred and seventy three patients
      were diagnosed as having STS between 1986 and 2001, however of these patients,
      only 90 (51 females and 49 males) had enough sample available for testing.
      Patients who overexpressed VEGF had a significantly shorter survival (23 vs. 52
      months; p=0.01). There was no effect of overexpression of either CD117 or HER
      2/neu on survival. Studying the individual histological subtypes we found that,
      in malignant fibrous histiocytoma, overexpression of either VEGF or CD117
      increased survival (41.3 vs. 19.5 months, p=0.01; and 84.5 vs. 17 months, p=0.006
      respectively). In leiomyosarcoma, VEGF overexpression significantly decreased
      survival (7.5 vs. 76 months, p=0.03), while CD117 overexpression significantly
      increased survival (70.9 vs. 46.3 months, p=0.03). CONCLUSION: VEGF
      overexpression is associated with an adverse outcome in STS. Whether this is true
      of any particular histological subtype is unclear and needs further
      investigation. Also, site-specific agents targeting these three bio-markers
      (alone or with conventional therapy) may have a therapeutic role and need to be
      elaborated in future clinical trials.

PMID- 15015618
TI  - Pulmonary radiofrequency ablation--an international study survey.
AB  - BACKGROUND: The lung is the most common site for primary cancer worldwide as well
      as being a common site of metastases for various malignancies. Percutaneous
      radiofrequency ablation (RFA) is rapidly evolving as a new minimally invasive
      tool for the treatment of pulmonary tumors. PATIENTS AND METHODS: A questionnaire
      was sent by e-mail to 14 centres around the world, which we knew or thought were
      performing percutaneous pulmonary RFA, to retrospectively survey their experience
      in this field including the number of ablations done to date, indications,
      method, peri- and postprocedural complications. RESULTS: Seven centers reported
      493 percutaneous procedures in lung tumors. Two deaths have been reported.
      Complications were subdivided into major and minor complications. Pneumothorax
      occurred in up to 30% of interventions with less than 10% requiring intercostal
      drainage. Pleural effusion requiring aspiration occurred in less than 10% of
      cases. CONCLUSION: With almost 500 procedures done to date, percutaneous
      pulmonary RFA appears to be a safe, minimally invasive tool for local pulmonary
      tumor control with negligible mortality, little morbidity, short hospital stay
      and gain in quality of life.

PMID- 15015619
TI  - Paclitaxel and carboplatin concurrent with radiotherapy for primary cervical
      cancer.
AB  - BACKGROUND: Concurrent radiochemotherapy is currently considered the new standard
      treatment in locally advanced cervical cancer. PATIENTS AND METHODS: Eight women
      with cervical cancer stage IB2-IVA were treated with standard radiation therapy
      in combination with standard carboplatin (AUC=2, once weekly, x 6) and escalating
      doses of paclitaxel (60 mg/m2, once weekly, x 4, then x 5 and x 6). RESULTS: At
      the lowest dose level, four weekly paclitaxel cycles in six patients, three
      developed grade III diarrhoea and one severe radiation enteritis several weeks
      after radiotherapy. Two patients did not achieve complete remission and underwent
      additive salvage hysterectomy. All patients remained free of local recurrence,
      but one patient had distant metastases after 13 months. The median disease-free
      survival was 25 months with a median follow-up of 26 months. CONCLUSION: Standard
      pelvic radiotherapy in combination with weekly carboplatin and paclitaxel is
      poorly tolerated due to dose-limiting diarrhoea.

PMID- 15015620
TI  - Radiotherapy in the treatment of stage III-IV hypopharyngeal carcinoma.
AB  - BACKGROUND: The aim of this study was to evaluate the role of radiation therapy
      alone, employing standard fractionation, in stage III-IV hypopharyngeal
      carcinoma. MATERIALS AND METHODS: Fourteen (38.9%) stage III and 22 (61.1%) stage
      IV patients with hypopharyngeal carcinoma were submitted, with curative intent,
      to exclusive radiotherapy to the primary tumor and regional draining lymph nodes,
      level II, III, IV, V and VI. Total dose ranged from 68 to 72 Gy. RESULTS: The 5
      year overall survival (OS) and disease-specific survival (DSS) rates were 15.6%
      and 28.1%, respectively. Five-year OS in stage III and IV patients was,
      respectively, 33% and 5% (p=0.028) and DSS was, respectively, 50% and 16%
      (p=0.029). Five-year OS and DSS rate in N0 versus N+ patients were respectively
      37.5% and 75% versus 8.3% and 12.5% (p=0.07 and p=0.05). CONCLUSION: Overall
      survival at 5 years for III-IV hypopharyngeal tumor treated with radiotherapy
      alone is poor. It is possible that the addition of the best radiation
      fractionation to the best concurrent chemotherapy may improve the results, with
      acceptable toxicity.

PMID- 15015621
TI  - Phase II study of weekly oxaliplatin and high-dose infusional 5-fluorouracil plus
      leucovorin in pretreated patients with metastatic colorectal cancer.
AB  - BACKGROUND: Chemotherapy with oxaliplatin, fluorouracil (5-FU) and leucovorin
      (LV) has proven efficacy in patients with advanced colorectal carcinoma (CRC),
      although the optimal dosage and administration schedule are still unclear. This
      phase II trial investigated the tolerability and activity of weekly oxaliplatin,
      high-dose infusional 5-FU and LV in pretreated patients with metastatic CRC.
      MATERIALS AND METHODS: Patients received weekly courses of i.v. oxaliplatin 50
      mg/m2 (1-h infusion), LV 100 mg/m2 (1-h infusion) and 5-FU 2100 mg/m2 (24-h
      infusion) until disease progression or unacceptable toxicity. NCI-CTC criteria
      were used for assessment of side-effects (at each cycle) and WHO criteria for
      assessment of tumour response (every 8 cycles). For descriptive purposes, time to
      progression, overall survival and duration of objective response were also
      calculated. RESULTS: Forty-four patients were enrolled and received a total of
      606 cycles (median 13/patient, range 4-33), and 70% of courses (421/606) were
      delivered at 100% of the planned dose. The most frequent side-effects were
      gastrointestinal and neurological and incidence rates were: diarrhoea 66% (grade
      III: 29%), nausea/vomiting 54%, neurotoxicity 34% (grade III: 2%), fatigue 27%,
      mucositis 22%, leucopenia 14%. No grade IV toxicity was observed. Objective
      response rates were: partial response 23% (10 patients), stable disease 59% (26)
      and progressive disease 11% (5). Median time to progression was 7 months, overall
      survival 13 months and the duration of partial response and stable disease were 9
      and 6 months, respectively. CONCLUSION: The study demonstrated that this regimen
      has a favourable tolerability profile and is an active combination in the
      pretreated metastatic CRC patient, deserving further evaluation in phase III
      trials.

PMID- 15015622
TI  - Molecular and clinicopathological analysis of ovarian carcinomas with and without
      microsatellite instability.
AB  - BACKGROUND: Microsatellite instability (MSI) occurs in sporadic ovarian
      carcinomas. This study tests the hypothesis that ovarian carcinomas arising
      through the mutator pathway have distinctive clinical and molecular features that
      affect clinical outcome. MATERIALS AND METHODS: The MSI status was evaluated in
      66 ovarian carcinomas and 11 epithelial ovarian tumors of low malignant
      potential. For the analysis with the microsatellite markers, a fluorescence-based
      PCR method was employed and the prognostic significance of the MSI status was
      assessed. DNA copy number changes in tumors with and without MSI were analyzed by
      comparative genomic hybridization. RESULTS: High-frequency MSI (MSI-H) was found
      in 30% of the carcinomas, whereas low-frequency MSI (MSI-L) occurred in 32%. In
      LMP tumors, only MSI-L was detected (18%). There was a trend for tumors with MSI
      H and MSI-L to have a poor prognosis, but this relationship did not reach
      significance (p=0.09 and p=0.07, respectively). MSI-H in carcinomas was
      significantly associated with poor differentiation (p=0.03) and higher clinical
      stage (p=0.03). No correlation was found between different histological types of
      ovarian carcinoma and the microsatellite status. In a multivariate analysis, MSI
      at the dinucleotide repeat D5S346 was found to be of independent prognostic
      significance (p<0.008) for disease-specific survival. There was no association
      between the total number of genetic aberrations per tumor and the MSI status.
      CONCLUSION: Microsatellite instability is a relatively common event in ovarian
      carcinoma. The data indicate that instability of a single microsatellite marker
      on chromosome 5 (D5S346) might be indicative of disease progression when detected
      in early clinical stages.

PMID- 15015623
TI  - Assessment of microvessel density in core needle biopsy specimen in breast
      cancer.
AB  - AIM: Estimation of microvessel density (MVD) in primary breast cancer in core
      needle biopsies (CNB) may predict response to systemic therapy. The aim of the
      present study was to explore the accuracy of assessment of MVD in CNB related to
      MVD in excised tumours. MATERIAL AND METHODS: MVD was estimated in core biopsies
      and subsequently excised tumours in 54 consecutive patients with breast cancer
      without pre-operative treatment. RESULTS: The correlation between MVD in CNB and
      excised tumours was non-significant. However, in tumours larger than 20 mm
      (r=0.56, p=0.005) and in lobular carcinomas (r=0.55, p=0.014) a significant
      correlation was observed. CONCLUSION: The overall accuracy between estimation of
      MVD on CNB and excised breast tumours was non-significant. The usefulness of MVD
      in CNB as a marker of response to systemic therapy should be further validated
      before it can be used in clinical practice.

PMID- 15015624
TI  - Yearly alterations in prognostic factors in gastric cancer during the post
      operative period.
AB  - BACKGROUND: Prognostic factors in gastric cancer may alter with time after
      surgery. Ascertaining prognostic factors appropriate for each post-operative year
      should contribute to the establishment of better therapeutic strategies and
      ultimately to the improvement of their long-term results. PATIENTS AND METHODS:
      In the present study, in order to elucidate whether prognostic factors would
      alter annually, cause of death, recurrence patterns and prognostic factors of
      gastric cancer by uni- and multivariate analysis were evaluated retrospectively
      in 833 consecutive patients who underwent potentially curative gastrectomy.
      RESULTS: During the first 2 years, the prognostic factors were age, T3-4, pN3,
      tumor diameter and number of metastatic lymph nodes. During the 3rd and 4th
      years, they were age, pN2 and number of metastatic lymph nodes; for the fourth
      year, age and number of metastatic lymph nodes; for the fifth year, age alone.
      Peritoneal recurrence was predominant throughout the post-operative period, but
      its incidence decreased gradually with time. The incidence of hematogenous
      recurrence increased while that of lymphatic recurrence did not change with time.
      CONCLUSION: As prognostic factors change over time, appropriate alterations to
      therapeutic strategy should be established for each successive period.
      Particularly, effective therapeutic strategy for peritoneal metastasis should be
      established in patients with a high number of metastatic lymph nodes during the
      first five years. Moreover, the treatment of concomitant disease and the
      evaluation of other malignant disease should be continued after the 5th year.

PMID- 15015625
TI  - Palliative second-line treatment with weekly high-dose 5-fluorouracil as 24-hour
      infusion and folinic acid (AIO) plus oxaliplatin after pre-treatment with the AIO
      regimen in colorectal cancer (CRC).
AB  - BACKGROUND AND AIMS: The aim of this work was to evaluate the efficacy and safety
      of second-line treatment with weekly high-dose 5-Fluorouracil (5-FU) as a 24-hour
      infusion (24-h inf.) and folinic acid (FA) (AIO-regimen) plus Oxaliplatin (L-OHP)
      after pre-treatment with the AIO regimen, focusing in particular on the efficacy
      of palliative first- and second-line treatment in colorectal carcinoma (CRC).
      PATIENTS AND METHODS: Patients with non-resectable distant CRC metastases were
      enrolled in a prospective phase II study for palliative second-line treatment
      after previous palliative first-line treatment in accordance with the AIO
      regimen. On an outpatient basis, the patients received a treatment regimen
      comprising biweekly 85 mg/m2 L-OHP in the form of a 2-hour intravenous (i.v.)
      infusion and 500 mg/m2 FA as a 1 to 2-hour i.v. infusion, followed by 2,600 mg/m2
      5-FU administered as a 24-h inf. i.v. once weekly. A single treatment cycle
      comprised 6 weekly infusions followed by 2 weeks of rest. RESULTS: During second
      line treatment, a total of 26 patients received 340 chemotherapy applications. As
      the main symptom of toxicity, diarrhoea (NCI-CTC toxicity grade 3+4) presented in
      5 patients (19%; 95% CI: 4-34), followed by nausea (CTC grade 3) in one patient
      (4%; 95% CI: 0-11). Twenty-three patients were evaluable for treatment response.
      The remission data can be summarised as follows: Complete remission (CR): n=1
      (4%; 95% CI: 0-13); partial remission (PR): n=3 (13%; 95% CI: 0-27); stable
      disease (SD): n=11 (48%; 95% CI: 27-68) and progressive disease (PD): n=8 (35%;
      95% CI: 15-54). The median progression-free survival (PFS) rate (n=26) was 3.3
      months (range 0-11.5), the median survival time counted from the start of second
      line treatment (n=26) 11.6 months (range 2.1-33.0) and the median survival time
      counted from the start of first-line treatment (n=26) 19.9 months (range 7.7
      49.8). CONCLUSION: Palliative second-line treatment according to the AIO regimen
      plus L-OHP is feasible in an outpatient setting and well tolerated by the
      patients. Tumour control (CR + PR + SD) was achieved in 65% of the patients, the
      median survival time being 11.6 months. The AIO regimen followed by the 'AIO
      regimen plus L-OHP' therapy sequence led to a promising median survival time of
      19.9 months (range 7.7-49.8).

PMID- 15015626
TI  - Long-term effect of gefitinib (ZD1839) on squamous cell carcinoma of the lung.
AB  - This case report describes the effects of long-term treatment with the epidermal
      growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) gefitinib ('Iressa',
      ZD1839) on a patient with squamous cell carcinoma of the lung. Gefitinib is an
      orally active agent that blocks signal transduction pathways implicated in the
      proliferation and survival of cancer cells and host-dependent processes that
      promote tumor growth. A 62-year-old Japanese man with a history of heavy smoking
      was diagnosed with squamous cell carcinoma of the lung, clinical stage IIIB
      (T4N3M0), in August 2000. He received two cycles of cisplatin-based chemotherapy
      and subsequently underwent left upper lobectomy followed by thoracic
      radiotherapy. After these treatments, he underwent partial lobectomy and
      pneumonectomy because of disease recurrence. In June 2002, he started treatment
      with gefitinib 250 mg/day orally because of mediastinal lymph node recurrence and
      an elevated serum cytokeratin 19 fragment (CYFRA) level. As a result, the
      mediastinal lymph node markedly regressed and the serum CYFRA level became
      normalized. Although he experienced recurrence three times during the 18 months
      prior to treatment with gefitinib, recurrence has not been experienced in the 13
      months since the start of gefitinib treatment, while tolerability has been
      acceptable.

PMID- 15015627
TI  - Cloning of chicken anemia virus vp3 gene and apoptosis inductive effect of vp3
      gene in vitro.
AB  - Using PCR technique, the vp3 gene of chicken anemia virus (CAV) was cloned into
      the eukaryotic expression vector pcDNA3 to construct a recombinant pcDNA-vp3.
      Restriction enzyme digestion and sequencing analysis revealed that CAV vp3 gene
      was correctly inserted into the blank vector pcDNA3. After LipofectAMINE-mediated
      transfection in vitro with pcDNA-vp3 and pcDNA3 respectively, the total mRNA was
      extracted from liver carcinoma cell lines HepG2 and diploid cell line L-02, and
      RT-PCR was performed afterward. The results of RT-PCR suggested that vp3 gene was
      expressed in these two cell lines. At the same time, using in situ apoptotic
      detection assay, TUNEL kits, the apoptotic cells were found in pcDNA-vp3
      transfected HepG2, but not in mock transfected cell lines. VP3 could induce cell
      death by apoptosis in cancer cell lines, but not in diploid cell lines. All the
      results indicated that CAV vp3 gene, a potential therapeutic agents, has the
      potential of being used for cancer treatment.

PMID- 15015628
TI  - Observation on in situ hybridization and immunocytochemistry of matrix
      metalloproteinases in rat pancreas.
AB  - In situ hybridization and immunocytochemical techniques were employed to examine
      the expression of matrix metalloproteinases-1 (MMP-1) and to identify the pattern
      of its distribution in rat pancreas. The results indicated that the signal of MMP
      1 mRNA and MMP-1 positive immunoreaction were detected in some fiberoblasts
      around interlobular ducts and exocrine cell in margin acinus of some lobules, but
      the signal of MMP-1 mRNA and MMP-1 positive immunoreaction could not be detected
      in most of other acinus and islets of pancreas. It is concluded that the
      expression of MMP-1 in above cells of rat might play an important role in acinar
      proliferation and differentiation of rat pancreatic tissues.

PMID- 15015629
TI  - In vitro biological activity of anti-C II TA hammerhead ribozyme--a novel
      approach for autoimmune diseases.
AB  - This study investigated the feasibility of using an hammerhead ribozyme against C
      II TA, a major regulator of MHC II antigens, to repress the expression of MHC II
      molecules on Hela cells. A hammerhead ribozyme (Rz464) specific to 463-465 GUC
      triplet of C II TA and its target gene were transcribed, then mixed up and
      incubated in vitro. The cleavage products were analyzed by PAGE and silver
      staining. Rz464 was then inserted into the pIRES2-EGFP vector (pRz464). Stable
      transfectants of Hela with pRz464 were tested for class II MHC induction by
      recombinant human interferon-gamma (IFN-gamma). mRNA of C II TA was measured by
      RT-PCR. Our results showed that Rz464 could exclusively cleave C II TA RNA. When
      induced with IFN-gamma, the expression of HLA-DR, -DP, -DQ on pRz464+ Hela was
      induced, and the mRNA content of C II TA decreased too. It is concluded that
      Rz464 could inhibit C II TA and thus the family of genes was regulated by C II
      TA:MHC II molecules. These results provided insight into the future application
      of Rz464 as a new nucleic acid drug against auto-immune diseases.

PMID- 15015630
TI  - A comparative study on the effect of BCG-PSN and thymopeptides on T-lymphocyte
      subsets of normal and immunosuppressed mice.
AB  - To compare the effects of polysaccharide nucleic acid fraction of bacillus
      calmette guerin (BCG-PSN) and thymopeptides on T-lymphocytes of normal and
      immunosuppressed mice, CD4+ and CD8+ T-lymphocyte subsets of single nucleic cell
      in thymus, spleen and peripheral blood were detected successively by flow
      cytometry after application of BCG-PSN and thymopeptides. Meanwhile, CD4+/CD8+
      ratio was also calculated. The results showed that both BCG-PSN and thymopeptides
      could decrease the proportion of CD4+ CD8+ T-lymphocyte subsets in the thymus, at
      the same time increase CD4+ T-lymphocyte, CD8+ T-lymphocyte proportion in the
      three tissues. The fluctuation in amplitude was greater in thymopeptides group
      than that in BCG-PSN group. It is concluded that acting location of thymopeptides
      is in thymus, its stimulating action is stronger than that of BCG-PSN, while BCG
      PSN not only accelerates the differentiation in thymus, but also has some direct
      stimulation to peripheral CD4+ T-lymphocytes, and can maintain CD4+/CD8+ ratio
      within normal range. So, BCG-PSN is safer.

PMID- 15015631
TI  - Selective depletion of the allo-antigen specific T cells by Fas/FasL pathway by
      cytokine IFN-gamma and IL-2.
AB  - To investigate the value of apoptosis of the allo-antigen specific T cells
      induced by Fas/FasL pathway in preventing graft-versus-host disease (GVHD), the
      CD34+ cells transfected with FasL or not, used as stimulus cells, were mixed with
      allo-antigen specific T lymphocytes in presence or absence of IFN-gamma and IL-2.
      After 5 days, apoptosis of T cells was detected by TdT nick end mediated dUTP
      labeling (TUNEL) and flow cytometry (FCM). The affects of these two cytokines on
      CD34+ cells in the graft were also compared. The ratio of apoptosis of T cells
      was 12.1+/-1.5% when CD34+ cells transfected with FasL was used as stimulus
      cells, much higher than that of CD34+ cells non-transfected (3.2+/-1.1%, P<0.01).
      And in presence of IFN-gamma or IL-2, the ratio reached 20.1+/-2.3%, 17.6+/-1.3%
      respectively (P<0.01). However, IFN-gamma up-regulated Fas expression of CD34+
      cells and increased the sensibility of CD34+ cells to soluble FasL (sFasL); IL-2
      showed no such effect. It is possible to induce apoptosis of the allo-antigen
      specific T cells of grafts activated by allo-antigen by exogenous Fas ligand
      expressed on recipient cells and this might provide a new approach for preventing
      GVHD and IL-2 may be more suitable for clinical application.

PMID- 15015632
TI  - The effects of Ligustrazine on the expression of bFGF and bFGFR in bone marrow in
      radiation injured mice.
AB  - To study the expression of the bFGF and its receptor in the mouse bone marrow by
      treatment with acute radioactive injury and Ligustrazine, 56 mice were divided
      into 3 groups: normal group, radiation-injured group and Ligustrazine group.
      After irradiation by 6.0 Gy 60Co gamma-ray, each mouse was orally given 0.1 ml
      Ligustrazine twice a day for 13 days in Ligustrazine group, and each mouse in
      radiation injured group was orally given equal amount of saline. On the 3rd, 7th,
      14th day after irradiation, bone marrow mono-nuclear cells (BMMNC) were counted,
      and the expression levels of bPGF and bFGFR in bone marrow were evaluated by
      immunohistochemistry and flow cytometry analysis respectively. On the 3rd, 7th,
      14th day after irradiation, expression of bFGF in bone marrow were significantly
      lower than in normal group (P<0.05 or P<0.01). Expressions of bFGF and bFGFR were
      much higher in Ligustrazine treated group than that in the control group (P<0.05
      or P<0.01). Ligustrazine potentiate the expression of bFGF and bFGFR in bone
      marrow MNC to recover the bone marrow hematopoiesis inductive microenvironment,
      which is one of the mechanisms by which Ligustrazine rebuild the bone marrow
      hematopoiesis after acute radioactive injury.

PMID- 15015634
TI  - The role of endogenous carbon monoxide in the hypoxic vascular remodeling of rat
      model of hypoxic pulmonary hypertension.
AB  - We investigated the expression of heme oxygenase-1 (HO-1) gene and production of
      endogenous carbon monoxide (CO) in the rat lung tissue at different time points
      of chronic hypoxic pulmonary hypertension and the effect of hemin on the
      expression of HO-1 gene and pulmonary hypertension. A rat model of hypoxic
      pulmonary hypertension was recreated by exposure to intermittent normobaric
      hypoxic environment (10% O2). Reverse transcriptase polymerase chain reaction (RT
      PCR) was performed to determine the level of HO-1 mRNA in the rat lung tissue and
      double wave length spectrophotometry was used to evaluate the quantity of COHb in
      arterial blood. Cardiac catheterization was employed to measure the right
      ventricular systolic pressure (RVSP) and HE staining was performed in dissected
      lung tissue to observe the pathological changes of the intra-acinar pulmonary
      arteries (IAPA). It was found that (1) There was a low level of HO-1 mRNA in
      normal rat lung tissue, but the level of HO-1 mRNA increased by 2-4 times in the
      lung tissue of hypoxic rats (P<0.01). The quantity of COHb was 2-3 times those of
      control group (P<0.01 or P<0.05). These were accompanied by the increased of RVSP
      and the thickened IAPA; (2) Hemin could keep the HO-1 mRNA and COHb in the
      hypoxic rat lung tissue at a high level, and partially suppressed the increase of
      rat RVSP, thereby ameliorating the pathological changes of IAPA. In conclusion,
      the upregulation of the expression of HO-1 gene and production of CO in the rat
      lung of hypoxic pulmonary hypertension plays a role of inhibition in the
      development of hypoxic pulmonary hypertension. Hemin has a therapeutic effect on
      hypoxic pulmonary hypertension.

PMID- 15015633
TI  - The effect of costimulatory factors in the pathogenesis of chronic idiopathic
      thrombocytopenic purpura.
AB  - To investigate the effect of costimulatory factors in the pathogenesis of chronic
      idiopathic thrombocytopenic purpura (CITP), we examined the expression of CD80 on
      platelets and megakaryocytes in patients with CITP and the controls by FACS. By
      using CD80 monoclonal antibody (McAb) to inhibit interaction among cells which is
      mediated by costimulatory factors, we observed the effect of CD80 McAb on the
      growth and maturation of megakaryocytic progenitors of patients with CITP in
      vitro. The results showed the expression of CD80 on platelets and megakaryocytes
      in CITP group was significantly higher than that in controls (P<0.01). There was
      a significantly positive correlation between the expression of CD80 on platelets
      and serum PAIgG in CITP (r=0.86, P<0.05). The mean of various clone numbers (CFU
      MK, BFU-MK and mCFU-MK) in CITP were all lower than those in controls (P<0.05).
      In megakaryocytes co-cultured with CD80 McAb, there was an increasing tendency of
      the number of CFU-MK and big CFU-MK (the number of megakaryocyte with GP IIIa
      positive was more than 20) and mediate CFU-MK (the number of megakaryocyte with
      GP IIIa positive was 11-20). When the concentration of CD80 McAb was 10 microg/L,
      there was a significant difference in the number of megakaryocytic colony
      formation (CFU-MK, BFU-MK and mCFU-MK) between the group with CD80 McAb and that
      without it (P<0.05). These showed the abnormality of costimulatory factors had
      important effect in the pathogenesis of CITP.

PMID- 15015635
TI  - Expression of P53, P21 in human lung adenocarcinoma A549 cell strains under
      hypoxia conditions and the effect of TSA on their expression.
AB  - This paper was designed to investigate the expression of p53, p21 of A549 cell
      strains under hypoxic condition and the effect of trichostatin A (TSA), the
      inhibitor of histone deacetylasel (HDAC1) on their expression. The authors
      designed 1 normoxia group (control group) and 6 hypoxia groups (experimental
      group): hypoxia 6 h group (A), TSA+hypoxia 6 h (B), hypoxia 12 h group (C),
      hypoxia 24 h group (D), TSA+hypoxia 24 h (E), hypoxia 48 h group (F). The
      expression of HDAC1 in A549 cells was examined by using Western blot and the
      expression of p53, p21 in A549 cells and the effect of TSA on them were
      determined by using immunohistochemistry and reverse transcription-polymerase
      chain reaction (RT-PCR). The A value expressed by HDAC1 in A549 cell strains was
      138+/-11 in the control group, 78+/-4, 86+/-5, 124+/-3, 120+/-9 in experimental
      groups A, C, D, F, respectively. The A value of the expression of the protein and
      mRNA of p53 in A549 cell strains were 0.12+/-0.02, 0.62+/-0.02 in the control
      group, 0.10+/-0.03, 0.32 +/-0.03; 0.11+/-0.01, 0.33+/-0.02; 0.13+/-0.03, 0.58+/
      0.01; 0.12+/-0.02, 0.56+/-0.02 in experimental group A, B, D, E, respectively.
      The A value of the expression of the protein and mRNA of p21 in A549 cell strains
      were 0.17+/-0.03, 0.62+/-0.03 in the control group, 0.16+/-0.02, 0.50+/-0.02;
      0.14+/-0.02, 0.36+/-0.02; 0.15+/-0.03, 0.49+/-0.03; 0.13+/-0.02, 0.33+/-0.02 in
      experimental groups A, B, D, E, respectively. These results indicate that the
      expression of HDAC1 is regulated by hypoxia and the effect of TSA is closely
      related to the expression of P21 under hypoxia condition.

PMID- 15015636
TI  - Expression of angiopoietin-2 gene in non-small cell lung cancer.
AB  - To study the expression of Angiopoietin 2 (Ang-2) gene and its relationship with
      clinical pathological characteristics of non-small cell lung cancer (NSCLC),
      expression of the Ang-2 mRNA was evaluated by employing reverse transcription
      polymerase chain reaction (RT-PCR) in cancerous tissues and paired adjacent
      noncancerous tissues from 52 patients. The expression of Ang-2 gene was detected
      in a significantly greater proportion of cancerous tissues (80.8%) than paired
      adjacent noncancerous tissues (53.8%, P<0.01). No significant relationship was
      found between Ang-2 gene expression and patients' age, sex, histology of tumors,
      differentiation and TNM stages (P>0.05). It is concluded that the up-regulation
      of Ang-2 gene may play a role in the pathway of NSCLC carcinogenesis and Ang-2
      may be used as a potential therapeutic agent for lung cancer.

PMID- 15015637
TI  - Prophylactic anti-inflammation inhibits cigarette smoke-induced emphysema in
      guinea pigs.
AB  - In this study, the effect of prophylactic anti-inflammation on the development of
      smoke-induced emphysema was investigated. Young male guinea-pigs aged 1.5-2
      months (weighing 198.3+/-26.9 g) were randomly divided into 4 groups: group A
      (cigarette smoke exposure only), group B (cigarette smoke exposure plus
      pentoxifylline-rich (PTX, 10 mg/d) forage feeding), group C (cigarette smoke
      exposure plus intermittent cortical steroid injection (Triamcinolone acetonide, 3
      mg, i.m., every three weeks) and control group (group D: animals with sham smoke
      exposure, raised under the same conditions). Animals in group A, B and C were
      exposed to smoke of cigarettes for 1 to 1.5 h twice a day, 5 days a week. All
      animals were killed at the 16th week and followed by morphometrical analysis of
      the midsagittal sectioned lung slices. Smoke exposure of 16 weeks resulted in
      visible emphysematous development in Group A but not in Group B and C. It was
      evidenced by the indicator of air-space size, mean linear intercept (Lm): 120.6+/
      16.0 microm in Group A; 89.8+/-9.2 microm in Group B and 102.4+/-17.7 microm in
      Group C. The average Lm in either group B or group C was shorter than that in
      Group A (ANOVA and Newman-Keuls test, F=8.80, P=0.0002) but comparable to that
      (94.8+/-13.2 microm) in group D (P>0.05). It is concluded that long-term
      prophylactic anti-inflammation inhibits pulmonary emphysema induced by cigarette
      smoking in the guinea pigs.

PMID- 15015638
TI  - Construction of antisense RNA expression plasmid for u-PAR and its transfection
      to highly invasive PC-3M cell subclones.
AB  - To evaluate the specific inhibition of antisense u-PAR on the u-PAR expressions
      in highly invasive cell subclones and to determine its blocking function in the
      invasion by those cells, a cDNA fragment of u-PAR obtained by RT-PCR was inserted
      into a plasmid vector named pcDNA3 in antisense orientation. Then the antisense u
      PAR recombinant was transfected into highly invasive cell subclones. The u-PAR
      expression in neo-resistant cells was examined by RT-PCR and immunohistochemical
      assay. Compared to the control cells, the content of mRNA and protein of u-PAR in
      transfected cells decreased sharply, and the rate of inhibition was 53% and 73%,
      respectively, indicating that an antisense u-PAR might have played a specific
      inhibitory role in its expression in the cells, which may provide a good cell
      model for making further investigation of the inhibitory effects of the antisense
      u-PAR on invasion in highly invasive cell subclones of human prostate carcinoma.

PMID- 15015639
TI  - Immunohistochemical studies of the expression of matrix metalloproteinase-2 and
      metalloproteinase-9 in human prostate cancer.
AB  - To study the expression of matrix metalloproteinase-2 and -9 in human prostate
      cancer, matrix metalloproteinase-2 and -9 were immunohistochemically detected in
      tissues of prostate cancer and benign prostatic hyperplasia (BPH). Our results
      showed that matrix metalloproteinase-2 and -9 levels in prostate cancer were much
      higher than those in tissues of BPH, with the cancer invasion being positively
      correlated with the expression of the metalloproteinases. It is concluded that
      matrix metalloproteinase-2 and -9 are better molecular markers, which are of help
      in the diagnosis and prediction of prognosis of prostate cancer.

PMID- 15015640
TI  - Suramin inhibits the in vitro expression of encephalitis B virus proteins NS3 and
      E.
AB  - In this study, the mechanism by which Suramin inhibits the replication of
      epidemic encephalitis B virus was explored to provide a theoretical basis for its
      further application in clinical practice. After viral infection of HepG2 and IMR
      32 cells, different concentrations of Suramin were added to the culture media,
      and then the cultural supernatants and infected cells were collected 48 h later.
      For the evaluation of the curative effect, cytopathic effect (CPE), virus titers,
      the expression of viral protein and viral RNA were determined by Western blot, RT
      PCR and in vitro RNA synthesis, respectively. At the concentration of 50
      microg/ml of Suramin, HepG2 and IMR-32 infected with epidemic encephalitis B
      virus decreased by 51.8% and 0.03% respectively, as compared with controls. It
      was suggested that expression of encephalitis B virus proteins NS3 and E was
      notably reduced by Suramin. This is especially true of E protein. At RNA level,
      however, no difference in RNA virus was found between Suramin-treated virus and
      non-treated cells. Our results suggest that Suramin can inhibit viral replication
      by blocking the production of viral proteins.

PMID- 15015641
TI  - Dynamic expression of bFGF and TGFbeta2 in glomus cell grafts of carotid body in
      rat model of Parkinson disease.
AB  - To investigate the changes in the expression of basic fibroblast growth factor
      (bFGF) and transforming growth factor beta 2 (TGFbeta2) in glomus cell grafts of
      carotid body in the rat model of 6-hydroxydopamine-induced Parkinson disease,
      immunohistochemical staining of bFGF and TGFbeta2 in the sections of striate body
      was done on the 2nd, 4th and 12th week after transplantation. The results showed
      that on the 2nd week after transplantation, bFGF and TGFbeta2 were not detectable
      in the glumous cell grafts. On the 4th week after graft, bFGF and TGFbeta2
      immunoreactivity was increased within the grafts and at the graft-host interface
      but was restricted only to astrocytes. In the striatum surrounding the graft,
      bFGF was expressed persistently, while TGFbeta2 showed transient expression. It
      was suggested that the transient expression of TGFbeta2 was likely due more to
      the trauma imposed by the graft procedure than to an intrinsic. The deficiency in
      astrocytic bFGF early after graft may be responsible for the poor survival of
      grafted glomus cells of carotid body.

PMID- 15015642
TI  - The inhibition of apoptosis of hepatoma cells induced by HBx is mediated by up
      regulation of survivin expression.
AB  - To investigate the effect of HBx on expression of survivin in hepatoma cells and
      mechanisms of inhibition of apoptosis on hepatoma cells induced by HBx, the
      expression plasmid pHA-HBx encoding full length of HBx was transfected into HepG2
      cells and the transformed cells were identified by RT-PCR. The expression of
      survivin both in HepG2 cells and HBx-transfected cells was examined with RT-PCR.
      The nude mice model of hepatoma was established by injecting HepG2 cells and HBx
      transfected cells into the flank of nude mice subcutaneously. The expression
      level of survivin both in HepG2 formed tumors and HBx-transfected cell-formed
      tumors in nude mice was examined with Western-blot. The TUNEL assay was used to
      detect the apoptotic cells of tumor tissues in nude mice after intraabdominal
      chemotherapy with adriamycin. The results indicated that the amplification of
      survivin in HBx-transfected HepG2 cells was up-regulated when compared with that
      in non-transfected cells. Western-blot showed that the tumor cells expressing HBx
      in nude mice had a positive band of survivin expression and the tumor cells
      without HBx expression had no positive band. The result of TUNEL assay showed
      that there were less apoptotic cells in tumor tissues expressing HBx than that in
      control group cells. It was concluded that HBx could up-regulate the expression
      of survivin in hepatic carcinoma cells, which can inhibit apoptosis of hepatic
      carcinoma cells induced by adriamycin.

PMID- 15015643
TI  - An antisense plasmid targeting survivin expression induces apoptosis and
      sensitizes hepatocarcinoma cells to chemotherapy.
AB  - To explore the change of sensitivity to chemotherapy of antisense RNA targeting
      survivin on hepatocarcinoma carcinoma cells in vitro. Survivin mRNA structure
      region was amplified by RT-PCR and inserted inversely into eukaryotic expression
      vector pcDNA3. The antisense expression plasmid pcDNA3/survivin was transfected
      into HepG2 with lipofectAMINE 2000 (LF2000), with low concentration of 5
      fluorouracil (5-Fu) added. Survivin protein was detected by Western-blot, the
      growth activity was measured by MTT, and apoptosis was detected by Flow Cytometry
      12 h, 24 h, 48 h after transfection. The activity of caspase-3 was found by
      quantitative assay 48 h after transfection. The construction of antisense RNA
      vector pcDNA3/survivin was verified by restricted endonuclease digestion and
      nucleotide sequencing. Compared with normal group, 5-Fu and antisense survivin
      group, the cells growth inhibition, apoptosis index, and caspase-3 activity were
      increased in antisense survivin transfected + 5-Fu group. The threshold of
      apoptosis was decreased after survivin was silenced, and the sensitivity to
      chemotherapy was increased. These findings suggest the existence of a potential
      new target for gene therapy.

PMID- 15015644
TI  - Gene cloning of murine alpha-fetoprotein gene and construction of its eukaryotic
      expression vector and expression in CHO cells.
AB  - To clone the murine alpha-fetoprotein (AFP) gene, construct the eukaryotic
      expression vector of AFP and express in CHO cells, total RNA were extracted from
      Hepa 1-6 cells, and then the murine alpha-fetoprotein gene was amplified by RT
      PCR and cloned into the eukaryotic expression vector pcDNA3.1. The recombinant of
      vector was identified by restriction enzyme analysis and sequencing. After
      transient transfection of CHO cells with the vector, Western blotting was used to
      detect the expression of AFP. It is concluded that the 1.8 kb murine alpha
      fetoprotein gene was successfully cloned and its eukaryotic expression vector was
      successfully constructed.

PMID- 15015645
TI  - Effects of cyclin D1 antisense oligodeoxyneucleotides on the growth and
      expression of G1 phase regulators in gastric carcinoma cells.
AB  - To investigate the effects of Cyclin D1 antisense oligodeoxyneucleotides (ASODN)
      on the growth, cell cycle progression and expression of G1 phase regulators in
      human gastric carcinoma cell lines SGC7901 and HS746T, phosphorothioate-modified
      Cyclin D1 ASODN were encapsulated by LipofectAMINE2000 and transfected into
      gastric carcinoma cells. Dose-dependent inhibitory effects were induced by Cyclin
      D1 ASODN in two gastric carcinoma cell lines. Treatment of gastric carcinoma
      cells with 0.2 micromol/L Cyclin D1 ASODN for 24 h could significantly inhibit
      their growth in vitro and in vivo, reduce expression of Cyclin D1 mRNA to 26.3%
      (SGC7901) and 17.3% (HS746T) respectively. The percentage of cells in G0/G1 phase
      was increased as revealed by flow cytometry. Immunohistochemical staining showed
      that the expression of p21 was increased and the expression of Cyclin D1 and pRb
      was decreased in the two cell lines; the expression of p27 was increased in
      HS746T, but unchanged in SGC7901. Cyclin D1 ASODN could inhibit the growth and
      the expression of Cyclin D1 mRNA in gastric carcinoma cells, influence the cell
      cycle and expression of its regulators.

PMID- 15015646
TI  - Diagnosis and management of severe acute pancreatitis complicated with abdominal
      compartment syndrome.
AB  - Presented in this paper is our experience in the diagnosis and management of
      abdominal compartment syndrome during severe acute pancreatitis. On the basis of
      the history of severe acute pancreatitis, after effective fluid resuscitation, if
      patients developed renal, pulmonary and cardiac insufficiency after abdominal
      expansion and abdominal wall tension, ACS should be considered. Cystometry could
      be performed to confirm the diagnosis. Emergency decompressive celiotomy and
      temporary abdominal closure with a 3 liter sterile plastic bag must be performed.
      It is also critical to prevent reperfusion syndrome. In 23 cases of ACS, 18 cases
      received emergency decompressive celiotomy and 5 cases did not. In the former, 3
      patients died (16.7%) while in the later, 4 (80%) died. Total mortality rate was
      33.3% (7/21). In 7 death cases, 4 patients developed acute obstructive
      suppurative cholangitis (AOSC). All the patients who received emergency
      decompressive celiotomy 5 h after confirmation of ACS survived. The definitive
      abdominal closure took place mostly 3 to 5 days after emergency decompressive
      celiotomy, with longest time being 8 days. 6 cases of ACS at infection stage were
      all attributed to infected necrosis in abdominal cavity and retroperitoneum. ACS
      could occur in SIRS stage and infection stage during SAP, and has different
      pathophysiological basis. Early diagnosis, emergency decompressive celiotomy and
      temporary abdominal closure with a 3L sterile plastic bag are the keys to the
      management of the condition.

PMID- 15015647
TI  - Protective effect of heparin-coated circuits on the platelets during
      cardiopulmonary bypass.
AB  - To observe the protective effect of heparin-coated circuits (HCC) on the platelet
      function during cardiopulmonary bypass (CPB), 23 patients with heart valve
      replacement were studied. The system heparin dose was 3 mg/kg in the control
      group (n = 15) and heparin-coated circuits in the HCC group (n = 8). Platelet
      count, alpha-granule membrane protein-140 (GMP-140) concentrations were
      determined before CPB, at 60 min of CPB, 30 and 60 min after protamine
      administration, first 12 h after CPB, respectively. At end of CPB the arterial
      filters in the circuits were observed by electron microscopy. The amount of first
      12-h postoperative blood loss was measured. There was significant reduction in
      platelet loss during and after CPB in the HCC group in contrast to the control
      group during CPB (P<0.05). During the first 12 h, postoperative blood loss was
      reduced in the HCC group as compared with that in the control group (218+/-61 ml,
      vs. 332+/-118 ml, P<0.05). Electron microscopy showed that in the HCC group the
      filter meshes and their fringes were clear and fragments of floccules were
      occasionally seen, without adherent cells or only few adherent cells on their
      surfaces, whereas several cellular and fibrous components were found to adhere to
      the surfaces of the filter meshes in the control group. This study indicates that
      heparin-coated circuits might reduce the platelet loss and activation during CPB
      and improve hemocompatibility of cardiopulmonary bypass equipment.

PMID- 15015648
TI  - Cardioprotective effects of melatonin on recovery of rat donor hearts after 12
      hour preservation.
AB  - The cardioprotective effects of melatonin on recovery of rat donor hearts after
      12 h of preservation were investigated. Wistar rats weighing 200 to 250 g (n=24)
      were randomly divided into 3 groups. In the non-storage group (n=8), donor hearts
      were not stored. In the melatonin group (n=8), donor hearts were stored in 4
      degrees C St. Thomas solution with melatonin (0.1 mmol/L). In the control group
      (n=8), donor hearts were stored in 4 degrees C St. Thomas solution only. The
      coronary flow (CF), cardiac function, coronary vasodilatory response, creatine
      kinase (CK) and high energy phosphate levels were measured after the hearts had
      been preserved for 12 h. Transmission electron microscopy was used to examine the
      microstructural changes after 12 h of preservation. The recovery of cardiac
      function and coronary vasodilatory response were significantly improved in the
      melatonin group (P<0.01). CK release decreased greatly in the melatonin group
      (P<0.01). High energy phosphate levels were significantly better preserved in the
      melatonin group (P<0.01). Histological findings were much better in the melatonin
      group than in the control group. These results suggest that melatonin has
      cardioprotective effects on the recovery of rat donor hearts after 12 h of
      preservation.

PMID- 15015649
TI  - The characteristics of acute rejection after limb allotransplantation in rats--an
      experimental study.
AB  - To study the characteristics of acute rejection after limb allotransplantation,
      29 male Sprague-Dawley rats were randomly divided into 2 groups, with 15 rats in
      control group and 14 rats in experimental group. Each rat in control group
      underwent limb replantation. Each rat in experimental group received limb
      transplantation from Wistar rat. No immunosuppressive drugs were used after
      operation. The circulation of the transplanted limb, time and signs of rejection,
      histopathological changes in the tissues of the limb graft when rejected and
      survival time of limb grafts were evaluated. In the control group, no signs of
      rejection were observed, the circulation of each replanted limb was normal, it
      could survive for a longer time. The experimental group showed clinical signs of
      rejection (sub dermal edema and erythema) after a mean time of 3.36+/-1.15 days,
      and the mean survival time of the allografts was only 7+/-0.78 days.
      Histopathological examination showed most violent rejection reaction in skin. It
      is concluded that with Wistar-to-SD limb transplantation without use of
      immunosuppression, rejection of the grafts would occur after a mean time of
      3.36+/-1.15 days; the earliest signs of rejection were edema and erythema of the
      skin, skin being the most representative component of limb graft rejection.

PMID- 15015650
TI  - The effect of zinc on the apoptosis of cultured human retinal pigment epithelial
      cells.
AB  - To clarify the effects of zinc on the proliferation and apoptosis of cultured
      human retinal pigment epithelia (RPE) and the expression of caspase-3 in RPE
      cells. The effect of Zinc on the proliferation of RPE were examined with MTT
      method. TUNEL method was used to detect the apoptosis of RPE cells. Caspase-3 was
      detected by immunohistochemistry. A concentration of zinc higher than 0.001
      microM could inhibit the proliferation of RPE. And the relationship between
      concentration of zinc higher than 10 microM and growth prohibition rate of RPE
      cells was dose-dependent. All concentrations of zinc including 0.001 microM
      enhanced the expression of caspase-3 of RPE. But only the concentration of zinc
      higher than 0.01 microM could induce apoptosis of RPE. It is concluded that zinc
      could enhance the expression of caspase-3 of RPE cells and induce apoptosis of
      RPE cells. Caution should be taken when using zinc supplements for the treatment
      of ARMD patients without deficiency of zinc.

PMID- 15015651
TI  - Fenestrated basilar artery associated with multiple aneurysms.

PMID- 15015652
TI  - Prediction of trend between water environment pollution of D Lake and death rate
      of malignancy in population.
AB  - Grey system analysis method was used to study the correlation between water
      pollution in D Lake area and death rate of malignancy with death rate of
      malignancy as effect sequence and a variety of water pollution index as factor
      sequence. On the basis of grey correlation analysis, grey system predication
      model was established for death rate of malignancy in population in D Lake area
      including GM(1, N) model for death rate of malignancy [MR(t+1) = (9.9987E1 +
      5.0001E2 + 10.8994E3 + 1.1114E4 + 165.1029) x e(-0.0070t) - 9.9987E1 - 5.0001E2 -
      10.8994E3 - 1.1114E4] and GM(1, 1) model for related factors [E1(t+1) = 52.1214 -
      46.9468e(-0.0058t), E2(t+1) = 4.6114 - 4.5664e(0.0015t), E3(t+1) = 1.1389 -
      1.1212e(0.0065t), E4(t+1) = 554.5867 - 549.8006e(0.0016t)], and the trend of
      death rate of malignancy from 2000 to 2010 was predicted.

PMID- 15015653
TI  - A bibliometric analysis of research on the behavior therapy in China and its
      trend.
AB  - To get formed of the status of research and application of the domestic behavior
      therapy and its development trend, the time distribution and the subject
      distribution were bibliometrically analyzed of the literature on behavior therapy
      from 1981 to 2000 in the CBMdisc. Our results showed that the number of
      literature of behavior therapy has been increasing in exponential manner over the
      past 20 years; the behavior modification, the biofeedback and the cognitive
      therapy are extensively used in China. In clinical practice, the behavior
      modification and the biofeedback have been applied in all departments of medical
      institutions, especially for treating the cardiovascular and the neurological
      conditions. The cognitive therapy has been employed mainly for the treatment of
      mental disorders (or dysphrenia), the aversive therapy mainly for material
      withdrawal, and the systematic desensitization for phobia. There was no report
      found on the clinical use of meditation. It is concluded that the study and
      application in behavior therapy in China is currently developing very fast.

PMID- 15015654
TI  - Stochastic kinetics of intracellular calcium oscillations.
AB  - A stochastic model of intracellular calcium oscillations is put forward by taking
      into account the random opening-closing of Ca2+ channels in endoplasmic reticulum
      (ER) membrane. The numerical results of the stochastic model show simple and
      complex calcium oscillations, which accord with the experiment results.

PMID- 15015655
TI  - Neuro-oncology in a nutshell.

PMID- 15015656
TI  - Molecular genetic study of a metastatic oligodendroglioma.
AB  - Extracranial spread of neuroectodermal tumors is an unusual event, most
      frequently expected from glioblastomas and medulloblastomas. Single cases of
      metastatic oligodendrogliomas have been described, but no genetic data are
      reported. Oligodendrogliomas are characterized by distinct genetic alterations,
      i.e. loss of heterozygosity (LOH) of 1p and 19q; therefore, molecular genetic
      analysis of metastatic cases is of considerable interest. It may be instrumental
      in defining the distant tumor as metastatic oligodendroglioma and give clues to
      the genetic events associated with the highly malignant transformation. We
      present the case of a patient with multiple bone metastases from a cerebral
      oligodendroglioma. Oligodendroglioma grade II was the diagnosis both at original
      and second operation, performed 7 and 1 years before the extracranial
      dissemination. The extraneural spread presented before the local intracranial
      recurrence. The patient received procarbazine, lomustine, vincristine
      chemotherapy and radiotherapy after the second surgery. The computed tomography
      guided biopsy of the bone lesions revealed tumor cells positive for GFAP, S-100
      and Leu-7 and negative for cytokeratin, LCA and EMA. The genetic analysis of DNA
      from the original tumor, the bone metastasis and the autoptic brain tumor showed
      LOH of 1p; heterozygous deletion of CDKN2A/p 16 was detected as additional
      alteration in the metastasis and in the intracranial tumor at autopsy. TP53, MDM2
      and CDKN2A/p14ARF genes were unchanged. Repeated brain surgery and extended
      survival may have acted as promoter of extraneural dissemination. Loss of CDKN2A
      most probably played an important role in the malignant progression: its
      involvement in metastatic potential remains to be clarified. Our data confirm
      that malignant transformation of oliogodendrogliomas may be undetected by
      histology and underscore the importance of genetic analysis. Coincidentally with
      intensive anticancer therapy, chemotherapy included, employed in patients with
      oligodendroglioma and the ensuing long survival, the frequency of metastatic
      oliogodendrogliomas may increase.

PMID- 15015657
TI  - Constitutive activation of the neuregulin-1/erbB signaling pathway promotes the
      proliferation of a human peripheral neuroepithelioma cell line.
AB  - Neuregulin-1 (NRG-1) proteins, acting through their erbB receptors, promote the
      differentiation, survival and/or proliferation of many cell types in the
      developing nervous system, including neural crest cells and neural crest-derived
      Schwann cells. We have recently found that the proliferation of a neoplastic
      Schwann cell line is dependent on constitutive activation of the NRG-1/erbB
      signaling pathway and that overexpression of NRG-1 in myelinating Schwann cells
      induces the formation of malignant peripheral nerve sheath tumors. These
      observations suggested that NRG-1 might similarly promote mitogenesis in a
      variety of neural neoplasms including peripheral neuroepitheliomas, aggressive
      neural crest-derived neoplasms that arise in nerves and soft tissues. To test
      this hypothesis, we examined the expression of NRG-1 and its erbB receptors in SK
      N-MC neuroepithelioma cells. SK-N-MC cells expressed multiple NRG-1 proteins and
      mRNAs encoding several alpha and beta isoforms from the sensory and motor neuron
      derived factor NRG-1 subfamily as well as the NRG-1 receptor subunits erbB2,
      erbB3, and erbB4. The erbB receptors expressed by SK-N-MC cells were
      constitutively tyrosine phosphorylated and inhibiting these kinases with the erbB
      specific inhibitor PD158780 reduced SK-N-MC DNA synthesis in a dose-dependent
      manner. We conclude that constitutive activation of the NRG-1/erbB signaling
      pathway promotes the proliferation of SK-N-MC neuroepithelioma cells in vitro and
      hypothesize that NRG-1/erbB autocrine, paracrine or juxtacrine signaling may
      contribute to the development and/or progression of neuroepitheliomas in vivo.

PMID- 15015659
TI  - Images in neuro-oncology.

PMID- 15015658
TI  - Inhibition of human glioma cell growth by a PHS-2 inhibitor, NS398, and a
      prostaglandin E receptor subtype EP1-selective antagonist, SC51089.
AB  - Prostaglandin H synthase (PHS) is a key enzyme in the synthesis of prostaglandins
      (PGs). Recently, enhanced expression of PHS-2 in brain tumors and the correlation
      between the PHS-2 level and the histopathological grade of glioma has been
      reported. Furthermore, in vitro inhibition of glioma cell growth by a specific
      PHS-2 inhibitor, NS398, has been demonstrated. It has also been shown that
      prostaglandin E2 (PGE2) contributes to colon carcinogenesis by binding to the
      prostaglandin E receptor subtype EP1. We therefore evaluated the effects of NS398
      and two EP1 antagonists, SC51089 and AH6809, on glioma cell lines. To evaluate
      mechanisms of NS398's action, two glioma cell lines, a PHS-2-positive cell line
      (KMG4) and a PHS-2-deficient cell line (A 172), were used. NS398 inhibited both
      the anchorage-dependent and -independent growth of glioma cell lines regardless
      of PHS-2 expression, suggesting that some PHS-2-independent mechanisms underlie
      the antineoplastic effect of NS398. However, the antineoplastic effect was
      attenuated by the addition of PGE2, which is one of the main products of PHS,
      suggesting the predominant mechanism is PHS-dependent. The EP1 antagonists,
      SC51089 and AH6809, inhibited the growth of glioma cell lines in vitro.
      Furthermore, NS398 or SC51089 slowed tumor growth in vivo, which was assessed
      using KMG4 tumor xenografts on SCID mice. PHS-2 inhibitors and EP1 antagonists
      might be useful in the prevention and/or treatment of glioma.

PMID- 15015661
TI  - Radiation-induced tumor after stereotactic radiosurgery and whole brain
      radiotherapy: case report and literature review.
AB  - Radiation-induced neoplasms are extremely rare after stereotactic radiosurgery.
      To date, only 3 cases meet Cahan's criteria in the world literature. We present a
      fourth case of a radiation-induced neoplasm arising after radiosurgery. The
      patient is a 43-year-old woman who presented with a right cerebellar anaplastic
      astrocytoma 64 months after radiosurgery for metastatic melanoma. Initially, 3
      brain metastases involving the inferior right temporal (2 tumors) and right
      frontal regions were treated. Following radiosurgery, the patient underwent whole
      brain radiotherapy (37.5 Gy). Twenty-two months later, a second radiosurgical
      procedure was performed for a recurrent right temporal lobe metastasis. The area
      of cerebellum where the glioma developed received a maximum dose of 7.7 and 1.5
      Gy during the 2 procedures, respectively. Support that radiosurgery contributed
      to the development of this glioma are the tumor's location and the rarity of
      adult cerebellar astrocytomas. The risk of radiation-induced tumors after
      radiosurgery is unknown. To better define the incidence of radiation-induced
      neoplasms after radiosurgery, all potential cases should be presented and
      discussed in an open, candid fashion.

PMID- 15015660
TI  - Stabilization of a progressive hemangioblastoma under treatment with thalidomide.
AB  - After the second recurrence of spinal seeding in hemangioblastoma not associated
      to von-Hippel-Lindau disease, we treated an adult female patient with thalidomide
      200 mg orally/day at night for longer than 1 year. The patient reported
      subjective relief of symptoms after 1 month. Magnetic resonance imaging (MRI)
      controls 1,6 and 11 months after begin of thalidomide treatment did not show
      further tumor progression. She remained wheelchair-bound, but mobility of her
      arms continuously improved. There was no thalidomide associated side-effect in
      this patient until her death from pneumonia due to legionnaire's disease.
      Antiangiogenic treatment with interferon (IFN) alpha-2a and IFN alpha-2b and with
      SU 5416 has been reported to be effective and well tolerated in several patients
      with previously progressive angioblastomas and hemangioblastomas. This case adds
      further evidence of the efficacy of an antiangiogenic treatment concept in a
      progressive hemangioblastoma.

PMID- 15015662
TI  - Primary leptomeningeal sarcomatosis; a pathology proven case with challenging MRI
      and clinical findings.
AB  - A 20-year-old male patient admitted with intractable seizures and progressive
      dementia is presented. Magnetic resonance imaging (MRI) examinations revealed
      diffuse leptomeningeal thickening, enhancement especially in the basal cisterns
      and multiple cystic formations in the brain stem, temporal lobes and basal
      ganglia. The pathologic examination from the right temporal lobe was consistent
      with leptomeningeal sarcoma. Marked regression of the symptoms and MRI lesions
      were detected following radiotherapy.

PMID- 15015663
TI  - Brain metastases in patients with ovarian carcinoma: prognostic factors and
      outcome.
AB  - Between January 1975 and April 2001, 8,225 patients with ovarian cancer were seen
      at The University of Texas M.D. Anderson Cancer Center. Brain metastases
      developed in 72 of these patients (0.9%). The medical records of these patients
      were reviewed to assess the incidence of these metastases and their correlates of
      survival, as well as to describe the various treatment modalities used against
      them and their respective outcomes. The mean age of patients at the time of brain
      metastasis diagnosis was 53.7 years. The median interval between the diagnosis of
      the primary cancer and brain metastasis was 1.84 years. Neurological deficit,
      headache, and seizure were the most common symptoms. The brain was the only site
      of metastasis in 43% of patients. Multiple metastases were seen in 65% of them,
      although this may be a slight underestimate, as brain metastases in 17% of
      patients were evaluated prior to the magnetic resonance imaging era. The median
      survival time after the diagnosis of brain metastases was 6.27 months (95% CI,
      4.48-8.06 months). The combination of surgical resection and whole-brain
      radiation therapy (WBRT) resulted in a longer survival time (median, 23.07
      months) than did WBRT alone (median, 5.33 months) or surgery alone (median, 6.90
      months) (p < 0.01 in both instances, multivariate Cox proportional hazards model
      analysis). The prognosis for patients with brain metastases from ovarian cancer
      appears to be poor. The existence of systemic dissemination at the time of brain
      metastasis was associated with a worse survival trend. The only significant
      predictor of survival in our series was the treatment modality. In particular,
      the resection of brain metastasis from ovarian cancer followed by WBRT appeared
      to be superior to resection alone or WBRT alone.

PMID- 15015665
TI  - Delayed radiation toxicity after focal or whole brain radiotherapy for low-grade
      glioma.
AB  - To evaluate the influence of radiation volume and other risk factors for the
      development of delayed radiation toxicity in patients treated for low-grade
      glioma, a retrospective analysis of 41 adult patients treated with focal or whole
      brain radiotherapy (WBRT) was performed. For all patients CT and MRI scans were
      revised to quantify brain atrophy and white matter lesions. Medical data were
      reviewed concerning baseline and tumor characteristics, treatment, survival,
      signs and symptoms of clinical encephalopathy and cardiovascular risk factors. In
      patients treated with WBRT an increased risk was found for brain atrophy (RR
      3.1), white matter lesions (RR 3.8) and clinical encephalopathy (RR 4.2). An
      increased risk of atrophy (RR 2.2) and white matter lesions (RR 2.9) was also
      found in patients aged over 40 years. Furthermore, brain atrophy and white matter
      lesions were more severe in patients treated with WBRT and in older patients. In
      conclusion, both the incidence and the severity of abnormalities is greater in
      patients treated with WBRT and in older patients.

PMID- 15015664
TI  - Single brain metastases of carcinoid tumors.
AB  - Carcinoid tumors are one among the most uncommon source of metastatic lesion to
      the brain. Four cases of single brain metastases from carcinoid tumors operated
      upon and verified by both histology and immunohistochemical staining are
      reported. The site of the primary carcinoid tumor was the lung in two cases,
      ileum in one and the left colon in another. The location of the brain metastasis
      was supratentorial in two cases and cerebellar in two. A high vascular tumor with
      large blood channels was found at surgery. Immunohistochemical studies showed in
      all four cases positive staining for synaptophysin, neuron-specific enolase,
      chromogranine and cytocheratine and negative staining for S-100 and HMB-45. The
      postoperative survival time ranged from 5 to 18 months. The epidemiological,
      surgical and pathological features of brain metastases from carcinoid tumors are
      also discussed from the analysis of 44 well-documented cases reported in the
      literature.

PMID- 15015666
TI  - Ganglioneurocytoma of the third ventricle.
AB  - We present a very rare case of an intracranial ganglioneurocytoma. This 57-year
      old female patient noticed some concentration difficulties for about 5 months.
      Visual acuity was 80% on both sides. CT and MRI of her head demonstrated a 3 x
      2.5 x 2.8 cm3 lesion within the third ventricle with inhomogenous enhancement of
      contrast medium. After a right pterional approach the tumor could be removed
      completely. Postoperatively there was a paresis of the oculomotor nerve on the
      right side and psychological changes. Histological examination revealed neuronal
      differentiation with neurocytes and small ganglionic cells and the tumor was
      graded as a ganglioneurocytoma (WHO grade II). Follow-up examination 6 months
      after the operation showed improvement of her third nerve paresis and of her
      neuropsychological deficits. MRI showed no recurrence.

PMID- 15015667
TI  - Toxic epidermal necrolysis in patients receiving anticonvulsants and cranial
      irradiation: a risk to consider.
AB  - Toxic epidermal necrolysis (TEN) is an infrequent disease but with a high
      mortality rate. It is a mucocutaneous reaction resulting from hypersensitivity to
      a variety of agents including most anticonvulsants. Many patients with primary or
      metastatic intracranial tumours receive anticonvulsants for seizure prophylaxis
      despite their efficacy not having been clearly demonstrated. Moreover, several
      cases have been reported in the literature in which serious adverse drug
      reactions such as TEN and Stevens-Johnson syndrome (SJS) have occurred following
      anticonvulsants exposure. In some of these cases the effect of radiation therapy
      and the tapering of steroid dose on the pathogenesis of these reactions have been
      highlighted. We report, here, a case of TEN that appeared in a patient receiving
      phenytoin, and shortly after the end of cranial and thoracic irradiation therapy
      for brain metastases of non-small cell lung cancer. Clinical considerations about
      diagnosis of SJS and TEN are presented. The use of prophylactic anticonvulsants
      is also discussed as well as a review of the literature.

PMID- 15015668
TI  - Pattern of recurrence following local chemotherapy with biodegradable carmustine
      (BCNU) implants in patients with glioblastoma.
AB  - OBJECTIVE: Recently a randomized placebo-controlled phase III trial of
      biodegradable polymers containing carmustine has demonstrated a significant
      survival benefit for patients treated with local chemotherapy. A local
      chemotherapy applied directly to the resection cavity may act directly on
      residual tumor cells in adjacent brain possibly leading to a local control of the
      tumor and increased survival. METHODS: We have analyzed the pattern of recurrence
      using serial MRI studies of 24 patients treated with GLIADEL Wafers or placebo
      wafers following resection of glioblastomas. RESULTS: Of 24 patients 11 received
      carmustine wafers and 13 placebo. The age distribution and Karnowsky performance
      scores of the two populations were not different. However, the median survival
      (14.7 versus 9.5 months; P = 0.007) and the time to neurological deterioration
      (12.9 +/- 4.85 vs. 9.4 +/- 2.73 months; P = 0.035) was significantly longer in
      the treatment group versus the placebo treated control. Preoperative and follow
      up MRI studies were evaluated in a blinded fashion. Out of 24 patients that
      entered the analysis 11 showed clearance of all contrast enhancement following
      resection of glioblastomas. Seventeen tumors progressed locally and 7 showed
      different patterns of distant failure. Within the carmustine treated group 8
      patients showed a local treatment failure with recurrent tumors immediately
      adjacent to the resection cavity or progression form a residual tumor. Three
      patients showed a multifocal distant and local pattern of failure after complete
      or subtotal removal. In no case the local chemotherapy resulted in a distant
      recurrence only. However, the time to radiographic progression was 165.1 +/-
      80.75 days for the GLIADEL Wafer group and 101.9 +/- 43.06 days for the placebo
      group (P = 0.023). CONCLUSION: In this subgroup analysis of a phase III trial
      population both the clinical progression and radiological progression were
      significantly delayed in patients treated with local chemotherapy, resulting in
      an increased survival time. Local chemotherapy with carmustine containing wafer
      implants did not result in an altered pattern of recurrence and did not promote
      multifocal patterns of recurrence.

PMID- 15015669
TI  - Unusual metastatic features in a patient with concomitant malignant orbital
      melanoma and prostate carcinoma.
AB  - A 73-year-old man with a history of malignant orbital melanoma and prostate
      carcinoma was admitted for progressive visual disturbance. Brain magnetic
      resonance imaging showed a suprasellar enhancing nodular lesion with major
      impingement on the anterior optical ways and sellar invasion. The extensive
      imaging work-up could not demonstrate with certainty its origin. Surprisingly,
      the transphenoidal biopsy of this patient revealed a prostate cancer metastasis
      outlining the importance of a histopathological diagnosis of cerebral metastases
      in patients with multiple malignancies when there is a doubt about the nature of
      the lesion.

PMID- 15015670
TI  - A prospective blinded study of the predictive value of an extreme drug resistance
      assay in patients receiving CPT-11 for recurrent glioma.
AB  - This adjunct to a prospective phase II blinded study of 48 patients with
      recurrent malignant glioma evaluated the predictive reliability of an extreme
      drug resistance (EDR) to identify clinical resistance to irinotecan (CPT-11),
      using fresh tumor biopsies obtained from recurrent patients immediately prior to
      their first dose of CPT-11 therapy. In vitro tumor response to SN38 (bioactive
      species of CPT-11 used in the EDR assay) determined prior to treatment was
      correlated with objective response, time to tumor progression (TTP) and survival
      following the administration of CPT-11. SN38 activity was tested in 19 of 29
      tumors, with 15 of 18 assay results evaluable for correlation with clinical
      outcomes. In vitro drug resistance was classified as either extreme, intermediate
      (IDR), or low (LDR). TTP and survival were estimated by the Kaplan-Meier method,
      and compared using the Mantel-Haenszel log-rank and Fisher's exact test
      statistics. In vitro tumor response was bifurcated into either EDR (n = 4) or
      IDR/LDR (n = 11) categories for comparison with outcomes. Results correlated
      significantly with both TTP and survival. Median TTP for IDR/LDR cases was 3
      months versus 6 weeks for EDR cases (log-rank test; p = 0.0288, hazards ratio =
      3.06). A 13-week median survival for EDR cases was significantly shorter compared
      to 38 weeks for IDR/LDR cases (p = 0.029). Further, 100-day survival favored the
      IDR/LDR cases (Fisher's exact test; p = 0.008). At last follow-up, two of three
      survivors were patients who had tumors IDR/LDR to SN38. These prospective data
      support the notion that patients should avoid agents to which their tumor
      demonstrates EDR.

PMID- 15015671
TI  - Central neurocytoma: a review.
AB  - Central neurocytomas are rare intraventricular neoplasms of the central nervous
      system, compromising 0.25-0.5% of brain tumors. The diagnosis and management of
      these tumors remains controversial since most clinical series are small.
      Typically, patients with central neurocytomas have a favorable prognosis, but in
      some cases the clinical course is more aggressive. Although histological features
      of anaplasia do not predict biologic behavior, proliferation markers including
      MIB-1 might be more useful in predicting relapse. The most important therapeutic
      modality is surgery, and a safe maximal resection confers the best long-term
      outcome. In cases of a subtotal resection,'standard external beam radiation can
      be added or radiation can be delayed until tumor progression occurs. Smaller
      residual tumor volumes or recurrences can be treated with more conformal
      radiation or focused radiosurgery. Re-operation for recurrence should be
      considered if the procedure can be safely performed. Chemotherapy may be useful
      for recurrent central neurocytomas that cannot be resected and have been
      radiated, although long-term responses have not been reported for chemotherapy.
      Overall, this paper reviews the findings of the larger studies and highlights
      some of the important case reports that contribute to the current management of
      central neurocytomas.

PMID- 15015672
TI  - The Society for Research in Child Development at 70: progress and promise.
AB  - The major conceptual and empirical advances in the field of child development and
      in the Society for Research for Child Development (SRCD) as a professional
      organization over the last 70 years are examined. First, despite reasons for some
      skepticism, it is argued that both the field and organization have achieved
      significant progress. Second, several issues that need more attention in the
      future are noted. These include the need for a culturally diverse approach to
      child development, an interdisciplinary approach to the field, and increased
      attention to interdomain links. Finally, the value of a multisite, multi
      investigator collaborative model as a complement to an individual-investigator
      paradigm for developmental science is emphasized.

PMID- 15015673
TI  - The relations of effortful control and impulsivity to children's resiliency and
      adjustment.
AB  - The unique relations of effortful control and impulsivity to resiliency and
      adjustment were examined when children were 4.5 to 8 years old, and 2 years
      later. Parents and teachers reported on all constructs and children's attentional
      persistence was observed. In concurrent structural equation models, effortful
      control and impulsivity uniquely and directly predicted resiliency and
      externalizing problems and indirectly predicted internalizing problems (through
      resiliency). Teacher-reported anger moderated the relations of effortful control
      and impulsivity to externalizing problems. In the longitudinal model, all
      relations held at T2 except for the path from impulsivity to externalizing
      problems. Evidence of bidirectional effects also was obtained. The results
      indicate that effortful control and impulsivity are distinct constructs with some
      unique prediction of resiliency and adjustment.

PMID- 15015674
TI  - Child care in poor communities: early learning effects of type, quality, and
      stability.
AB  - Young children in poor communities are spending more hours in nonparental care
      because of policy reforms and expansion of early childhood programs. Studies show
      positive effects of high-quality center-based care on children's cognitive
      growth. Yet, little is known about the effects of center care typically available
      in poor communities or the effects of home-based care. Using a sample of children
      who were between 12 and 42 months when their mothers entered welfare-to-work
      programs, this paper finds positive cognitive effects for children in center
      care. Children also display stronger cognitive growth when caregivers are more
      sensitive and responsive, and stronger social development when providers have
      education beyond high school. Children in family child care homes show more
      behavioral problems but no cognitive differences.

PMID- 15015675
TI  - The construction of experience: a longitudinal study of representation and
      behavior.
AB  - Continuity in relationship representation and developmental links between
      relationship representation and behavior from infancy to late adolescence were
      examined using longitudinal data from a risk sample (N = 185). Significant
      correlations were found among diverse representational assessments (e.g.,
      interview, drawing, projective narrative) and between representational and
      concurrent observational measures of relationship functioning. Structural
      equation models were analyzed to investigate the relations among caregiving
      experience in infancy; relationship representation and experience in early
      childhood, middle childhood, and early adolescence; and socioemotional
      functioning in adolescence. A model representing interactive contributions of
      representational and behavioral experience represented the data significantly
      better than a model representing noninteractive contributions. Findings support
      an organizational developmental view that socioemotional adaptation arises from
      the progressive construction of mutually informing expectations and experience.

PMID- 15015676
TI  - Sleepless in Chicago: tracking the effects of adolescent sleep loss during the
      middle school years.
AB  - The influence of the sleep patterns of 2,259 students, aged 11 to 14 years, on
      trajectories of depressive symptoms, self-esteem, and grades was longitudinally
      examined using latent growth cross-domain models. Consistent with previous
      research, sleep decreased over time. Students who obtained less sleep in sixth
      grade exhibited lower initial self-esteem and grades and higher initial levels of
      depressive symptoms. Similarly, students who obtained less sleep over time
      reported heightened levels of depressive symptoms and decreased self-esteem. Sex
      of the student played a strong role as a predictor of hours of sleep, self
      esteem, and grades. This study underscores the role of sleep in predicting
      adolescents' psychosocial outcomes and highlights the importance of using
      idiographic methodologies in the study of developmental processes.

PMID- 15015678
TI  - Adult attachment, parent emotion, and observed parenting behavior: mediator and
      moderator models.
AB  - In a middle-class sample of mothers of 2-year-olds, adult attachment
      classifications measured in the Adult Attachment Interview (AAI) were related to
      maternal self-reported emotional well-being and observed parenting behavior, and
      the potential mediating and moderating roles of maternal emotion were tested.
      Mothers classified as dismissing on the AAI reported significantly lower levels
      of positive affectivity. Mothers classified as preoccupied reported significantly
      higher levels of negative affectivity and anxiety. Preoccupied mothers were
      observed to be significantly higher on angry/intrusive parenting, but this
      association was not mediated by attachment-related differences in maternal
      emotion. Maternal emotional well-being did, however, moderate the associations
      between adult attachment and parenting behavior: Dismissing attachment was
      significantly associated with lower warmth/responsiveness only among mothers with
      higher levels of depressive symptoms.

PMID- 15015677
TI  - Moderate level alcohol during pregnancy, prenatal stress, or both and limbic
      hypothalamic-pituitary-adrenocortical axis response to stress in rhesus monkeys.
AB  - This study examined the relationship between moderate-level prenatal alcohol
      exposure, prenatal stress, and postnatal response to a challenging event in 6
      month-old rhesus monkeys. Forty-one rhesus monkey (Macaca mulatta) infants were
      exposed prenatally to moderate level alcohol, maternal stress, or both. Offspring
      plasma cortisol and adrenocorticotrophic hormone (ACTH) were determined from
      blood samples before maternal separation and after separation. Behavioral
      observations were made repeatedly across separation. Moderate-level prenatal
      alcohol exposure was associated with significantly higher plasma ACTH response to
      maternal separation. Offspring exposed to prenatal alcohol, prenatal stress, and
      prenatal alcohol and stress showed reduced behavioral adaptation to stress
      compared with controls. Baseline, 2-hr, and 26-hr plasma ACTH levels were
      intercorrelated and predicted behavior during separation.

PMID- 15015679
TI  - Salient and emerging developmental tasks in the transition to adulthood.
AB  - Drawing on data from a normative sample of 205 children tracked into adulthood,
      this study examined the predictive links from 3 salient (friendship, academic,
      conduct) and 2 emerging (work, romantic) developmental tasks during the
      transition years around age 20 to adult adaptation 10 years later. Results (a)
      confirm the utility of salient developmental tasks for predicting adult success,
      (b) suggest that emerging domains have limited long-term predictive significance,
      and (c) more generally support a view that developmental tasks follow a course
      through life of waxing and waning salience and organization that has implications
      for future adaptation.

PMID- 15015680
TI  - Parental perceived control over caregiving and its relationship to parent-infant
      interaction.
AB  - In this sample of 66 dual-earner mothers and fathers and their 1-year-old
      infants, associations among parental ratings of infant difficulty, parental
      perceived control over caregiving outcomes, and parental sensitive and directive
      behavior were examined during a triadic free-play session in the home. Perceived
      infant difficulty was related to maternal directiveness for mothers with low
      perceived control. Fathers with low perceived control exhibited more
      directiveness, regardless of their ratings of infant difficulty. For both mothers
      and fathers, there was a negative association between sensitivity and
      directiveness but no association between sensitive behavior and parental
      perceived control. Although parents scored similarly overall on various other
      measures, mothers with low perceived control demonstrated more categorical
      thinking about children's development than other mothers.

PMID- 15015681
TI  - From censure to reinforcement: developmental changes in the association between
      aggression and social status.
AB  - Developmental changes were examined in the associations among physical and
      relational aggression, and sociometric and perceived popularity based on peer
      nominations. Participating in the longitudinal study were 905 children (440
      girls, 465 boys) from ages 10 to 14. Associations between the forms of status and
      between the forms of aggression decreased over time. Relational aggression
      increasingly predicted high social prominence but low social preference; physical
      aggression was increasingly less disliked but decreasingly predictive of
      prominence. The effect of relational aggression on perceived popularity was
      strong for girls. Perceived popularity preceded physical and relational
      aggression for both genders. Implications for the attainment of high status,
      processes of peer influence on antisocial behavior, and gender differences in the
      meaning of status are discussed.

PMID- 15015682
TI  - Japanese mothers' views of young children's areas of personal discretion.
AB  - Sixty-four Japanese mothers of 3- to 6-year-olds were interviewed concerning
      their conceptions of children's areas of personal control. Mothers granted
      children choices regarding recreational activities, clothes, and friends to
      foster autonomy and competence, but they set limits around daily routines,
      recreational activities, and interpersonal confrontation based on moral,
      conventional, and prudential concerns. Mothers believed in reaffirming children's
      personal boundaries when children failed to follow through with their initial
      decisions. Mothers experienced conflict with children around daily routines and
      recreational activities and used various resolution strategies. Mothers perceived
      child resistance as egocentric whereas fewer considered it as establishing
      personal boundaries. Some age and gender differences were observed. Results
      supported the heterogeneity of social judgments and practices of individuals
      within cultures.

PMID- 15015683
TI  - Attitudes toward family obligation among adolescents in contemporary urban and
      rural China.
AB  - A sense of obligation to support, assist, and respect the family was examined
      among approximately 700 urban and rural 10th- (M = 16.6 years) and 12th- (M =
      18.9 years) grade students in the People's Republic of China. Urban male
      adolescents reported a weaker sense of family obligation than did rural male
      adolescents and both urban and rural female adolescents. Only children did not
      differ from those with siblings in terms of their attitudes toward family support
      and respect. A sense of family obligation was generally associated with more
      positive family relationships and a higher level of academic motivation among
      Chinese adolescents. Discussion focuses on how the shift to a market economy may
      influence adolescents' identification with the family in contemporary China.

PMID- 15015684
TI  - Evening activities as a potential confound in research on the adrenocortical
      system in children.
AB  - The relation among children's evening activities, behavioral characteristics, and
      activity of the hypothalamic-pituitary-adrenocortical axis was assessed in
      normally developing children ages 7 to 10 years. Salivary cortisol at bedtime was
      compared on evenings when children had structured activities outside of the home
      with unstructured evenings at home in relation to parental reports of children's
      behavioral characteristics. Participating in evening activities, particularly
      sport activities, was associated with small increases in bedtime cortisol levels
      in boys but not in girls. Differences in cortisol on activity versus no-activity
      nights were negatively related to children's social isolation. These results show
      that in studies with children, nights on which participants engage in sport
      activities should be avoided when collecting ambulatory measures of salivary
      cortisol concentrations.

PMID- 15015685
TI  - Linked lives: stability and change in maternal circumstances and trajectories of
      antisocial behavior in children.
AB  - Drawing on the notion of linked lives, this study examined the effects of
      stability and change in maternal circumstance on developmental trajectories of
      antisocial behavior in children 4 to 7 years of age. Using data from a national
      sample of young mothers and growth curve analysis, the study demonstrated that
      early maternal circumstances influences early antisocial behavior, whereas
      stability and change in these circumstances both exacerbate and ameliorate
      behavior problems. Of particular note, meaningful escape from poverty attenuates
      antisocial behavior whereas persistence in poverty or long-term movement into
      poverty intensifies such problems. These findings highlight the importance of
      structural context for parenting practices and the need to consider child
      development in light of dynamic and changing life-course fortunes of parents.

PMID- 15015687
TI  - The role of children's lay theories about the malleability of human attributes in
      beliefs about and volunteering for disadvantaged groups.
AB  - Two studies with 9- to 12-year-old children supported the hypothesis that lay
      theories about the malleability of human traits impact judgments of and behavior
      toward groups in need of volunteer help. The more children endorsed an
      incremental view (attributes can change), the more they reported liking, desiring
      social contact with, and perceiving similarity between themselves and a
      disadvantaged outgroup (homeless, UNICEF-funded children). Moreover, children
      endorsing more of a malleable view reported greater past volunteering, active
      participation in collecting money for a UNICEF event, and intentions to volunteer
      again. These findings held when controlling for the effects of participants'
      gender, self-esteem, and perceived social pressure to help others. How a
      malleable view and intergroup volunteerism may be mutually sustaining is
      discussed.

PMID- 15015686
TI  - Mothers' parenting cognitions in cultures of origin, acculturating cultures, and
      cultures of destination.
AB  - Japanese and South American immigrant mothers' parenting cognitions (attributions
      and self-perceptions) were compared with mothers from their country of origin
      (Japan and Argentina, respectively) and European American mothers in the United
      States. Participants were 231 mothers of 20-month-old children. Generally, South
      American immigrant mothers' parenting cognitions more closely resembled those of
      mothers in the United States, whereas Japanese immigrant mothers' cognitions
      tended to be similar to those of Japanese mothers or intermediate between
      Japanese and U.S. mothers. This study provides insight into the nature of
      parenting cognitions generally and those of immigrant mothers specifically and
      therefore the parenting climate in which immigrant children are reared.

PMID- 15015688
TI  - Psychophysiological and behavioral evidence for varying forms and functions of
      nonsocial behavior in preschoolers.
AB  - Four-year-old children showing low levels of social behavior in a laboratory play
      session with unfamiliar peers were classified as reticent (unoccupied or
      onlooking behaviors) or solitary-passive (solitary constructive or exploratory
      play). Compared with a group of more social children, the children in both low
      social groups were rated high on maternal reports of shyness and displayed a
      pattern of right frontal EEG asymmetry. However, only the reticent group was
      elevated on measures indicative of a fearful temperament, both concurrently and
      retrospectively. A subset of children in the solitary-passive group showed
      increasing levels of reticent behavior over the course of the visit, suggesting
      that for some children solitary-passive behaviors provide a means for coping with
      feelings of unease.

PMID- 15015689
TI  - Holism, contextual variability, and the study of friendships in adolescent
      development.
AB  - This study treated a key relationship in the developmental ecology of
      adolescence, friendships, as multidimensional and context specific. First, it
      examined 4 characteristics of friends (academic achievement, alcohol use,
      emotional distress, and extracurricular participation) as independent factors and
      as components in holistic friendship group profiles. Longitudinal analyses of
      9,224 adolescents (ages 12-20) revealed that multiple characteristics of friends
      predicted adolescent behavioral problems, as did membership in the best adjusted
      group profile. Second, the study examined whether the associations between
      friendship factors and adolescent behavior varied as a function of the larger
      peer network and school context, finding that network centrality, school academic
      press, and intergenerational bonding in schools conditioned the role of friends'
      characteristics and group profiles in positive and negative ways.

PMID- 15015690
TI  - Are child developmental outcomes related to before- and after-school care
      arrangements? Results from the NICHD study of early child care.
AB  - Data from the National Institute of Child Health and Human Development (NICHD)
      Study of Early Child Care, a prospective, longitudinal study involving 933
      children, were used to examine relations between cumulative participation in 5
      types of out-of-school care (before- and after-school programs, extracurricular
      activities, sitters, fathers, and nonadult care) and child developmental outcomes
      in the latter part of first grade (approximately age 7 years). Children who
      consistently participated in extracurricular activities during kindergarten and
      first grade obtained higher standardized test scores than children who did not
      consistently participate in these activities, controlling for child and family
      factors and children's prior functioning. Participation in other types of out-of
      school care was not associated with child functioning in first grade when
      background factors were controlled.

PMID- 15015691
TI  - Child care and low-income children's development: direct and moderated effects.
AB  - A large literature has documented the influence of child care on young children's
      development, but few studies have examined low-income children in community care
      arrangements. Using data from Welfare, Children, and Families: A Three-City Study
      (N = 204), this study examined the influence of child care quality and the extent
      of care on low-income children's (ages 2-4 years) cognitive and socioemotional
      development over time. Higher levels of child care quality were modestly
      associated with improvements in children's socioemotional development, and
      extensive hours in child care were linked to increases in children's quantitative
      skills and decreases in behavior problems. Analyses suggest that child care
      quality may be particularly salient for subgroups of children from low-income
      families.

PMID- 15015693
TI  - Biodiversity conservation and resource tenure regimes: a case study from
      northeast Cambodia.
AB  - The management of tropical protected areas is a contentious issue in resource
      management and often leads to an unproductive polarization of viewpoints
      supporting either "protectionist" or "sustainable development" paradigms. This
      paper argues for a context-driven approach whereby effective management requires
      inputs from both paradigms in different situations. A key element of context is
      understanding long-practiced resource tenures and their ability to meet future
      conservation and livelihood goals. Different types of tenure arrangements are
      often required for different resources. This approach is illustrated by analysis
      of Virachey National Park in NE Cambodia. This park encompasses part of the
      ancestral territory of ethnic Brao people, who rely upon swidden agriculture,
      fish, terrestrial wildlife, and various nontimber forest products (NTFPs) for
      their livelihoods. These people have developed a mix of resource tenure regimes
      to promote sustainable use and to maximize local benefits. In the face of
      contemporary pressures, some of these traditional approaches are effective, while
      others are not. The paper suggests avenues for building on long-established
      management practices of the Brao to achieve park management goals while enhancing
      the welfare of the Brao people. A mix of private ownership, common property
      management, and central government involvement may be required to maximize
      benefits to local people and ensure long-term protection of biodiversity.

PMID- 15015692
TI  - Wetland mitigation compliance in the western upper peninsula of Michigan.
AB  - The Army Corps of Engineers (ACE) is generally responsible for the implementation
      of federal Clean Water Act wetland regulations. It therefore plays an important
      role in the protection of wetlands within the United States. Unfortunately, past
      evaluators of ACE's implementation of these regulations found low rates of
      regulatory compliance. However, the fact that two states have taken
      responsibility for the implementation of these regulations within their
      boundaries provided the opportunity to assess whether one of these states might
      be doing a better job of enforcement. This paper reports on compliance with some
      of these regulations within one Michigan region. We evaluated permittee
      compliance with paperwork filing requirements related to wetland mitigation
      projects. Sixty-seven percent of county road commission permittees were out of
      compliance with at least one filing requirement. Forty percent of private and non
      county government permittees were out of compliance. Our results therefore
      suggest that serious problems exist with Michigan's implementation of wetland
      regulations. They do not suggest that compliance in this state is significantly
      better than in states under ACE administration. We believe that increased agency
      monitoring and enforcement would improve compliance.

PMID- 15015694
TI  - Sustainable land use requires attention to ecological signals.
AB  - This case study details the difficulties of landscape management, highlighting
      the challenges inherent in managing natural resources when multiple agencies are
      involved, when the land users have no incentive for conservation, and when
      government agencies have too few resources for effective management. Pumping of
      groundwater from the aquifer of La Costa de Hermosillo in the state of Sonora,
      Mexico, began in 1945 and developed so quickly that by the late 1950s salinity
      intrusion from the Gulf of California was occurring in the wells. In the 1970s,
      the irrigatable land in La Costa peaked at 132,516 ha and the extracted volume of
      water from the aquifer peaked at around 1.14 billion cubic meters annually. By
      the 1980s, 105 wells of the total of 498 were contaminated with seawater and,
      therefore, identified for closure. At present La Costa de Hermosillo still
      represents 15% of the total harvested land, 16% of the total annual production,
      and 23% of the gross agricultural production of the state of Sonora. However,
      there are approximately 80,000 ha of abandoned fields due to salt water
      intension, lack of water and/or lack of credit available to individual farmers.
      This unstable situation resulted from the interplay of water management policies
      and practices, and farm-land policies and practices. While government agencies
      have been able to enforce better water use for agricultural production, there
      remains a significant area that requires restoration from its degraded state. For
      this piece of the ecosystem management puzzle, government agencies have thus far
      been unable to affect a solution.

PMID- 15015695
TI  - Changing role of non-timber forest products (NTFP) in rural household economy:
      the case of Sinharaja World Heritage site in Sri Lanka.
AB  - This paper examines the modified patterns of utilizing non-timber forest products
      (NTFP) and associated behavioral changes around tropical forest areas in the
      context of conservation-related objectives and other commercially driven
      objectives. Our study introduces a conceptual framework based on the household
      production theory and tests empirically the hypotheses drawn at Sinharaja World
      Heritage in Sri Lanka. The results show that conditions introduced by forest
      conservation programs and the spread of small-scale commercial tea cultivation
      are transforming the economy around Sinharaja. The process is an economically
      rational one where resident communities decide upon their actions based on the
      opportunity cost of time involved with NTFP in the absence of observable prices.
      Although the process, overall, has led to a decline in the role of NTFP in the
      household economy, its impact over different NTFP are not uniform, leaving
      sustained demand for certain NTFP. This situation calls for a multifaceted
      approach in forest management programs to address the various household needs
      fulfilled by NTFP-based activities.

PMID- 15015696
TI  - Landscape trends in Mid-Atlantic and Southeastern United States ecoregions.
AB  - Landscape pattern and composition metrics are potential indicators for broad
      scale monitoring of change and for relating change to human and ecological
      processes. We used a probability sample of 20-km x 20-km sampling blocks to
      characterize landscape composition and pattern in five US ecoregions: the Middle
      Atlantic Coastal Plain, Southeastern Plains, Northern Piedmont, Piedmont, and
      Blue Ridge Mountains. Land use/and cover (LULC) data for five dates between 1972
      and 2000 were obtained for each sample block. Analyses focused on quantifying
      trends in selected landscape pattern metrics by ecoregion and comparing trends in
      land cover proportions and pattern metrics among ecoregions. Repeated measures
      analysis of the landscape pattern documented a statistically significant trend in
      all five ecoregions towards a more fine-grained landscape from the early 1970s
      through 2000. The ecologically important forest cover class also became more fine
      grained with time (i.e., more numerous and smaller forest patches). Trends in
      LULC, forest edge, and forest percent like adjacencies differed among ecoregions.
      These results suggest that ecoregions provide a geographically coherent way to
      regionalize the story of national land use and land cover change in the United
      States. This study provides new information on LULC change in the southeast
      United States. Previous studies of the region from the 1930s to the 1980s showed
      a decrease in landscape fragmentation and an increase in percent forest, while
      this study showed an increase in forest fragmentation and a loss of forest cover.

PMID- 15015697
TI  - Multicriteria decision aid in supporting decisions related to groundwater
      protection.
AB  - In the recent decades, there have been frequent conflicts between groundwater
      resources and environmentally hazardous activities. An example is the
      construction of the new highway through the important glaciofluvial esker aquifer
      Nybroasen, which passes the protection zone of the water supply for the Kalmar
      municipality, in the southeastern part of Sweden. The decision to build the new
      road through this important aquifer has been strongly questioned by the
      municipality and the public because the value of the water resources in Nybroasen
      was not taken into consideration during the first phase of the decision-making
      process. Multicriteria decision aid (MCDA) is applied as a tool to structure and
      analyze the four road alternatives proposed in the environmental impact
      assessment for the above conflict. The alternatives, including the existing road,
      are in conflict with water resources, agriculture, natural, and cultural values.
      The impacts on the water resources have been predicted by a two-dimensional
      physically based time-variant flow and solute groundwater model, which has been
      calibrated and evaluated. The MCDA illustrates how it can be used to identify (1)
      actors and their concerns, (2) ranking of alternative road scenarios according to
      actors' preferences, and (3) coalition groups of actors, i.e., groups that have
      similar views with regard to the road alternatives. The analysis shows that the
      two best compromise solutions obtained in the MCDA were unacceptable by the
      strongest coalition group, showing that either the family of criteria was not
      well chosen or new alternatives should have been developed.

PMID- 15015698
TI  - Effectiveness of constructed overland flow areas in decreasing diffuse pollution
      from forest drainages.
AB  - Forestry is the largest scale human impact affecting catchments in Finland and a
      prominent source of diffuse pollution in many water courses. Among the forestry
      activities, draining of wetlands had the most pronounced impacts on sediment,
      nutrient, and metal loading in the past. At present, renovation of old ditches
      and fertilization of peatlands constitute the major risk of forestry-induced
      diffuse pollution. Contemporary forestry aims at decreasing this risk with
      various riparian buffer strip designs. Among such designs, creation of overland
      flow areas by plugging the outlet ditches is increasingly used. Our objectives
      were to evaluate the potential of constructed overland flow areas to function as
      riparian buffers and estimate the quality and quantity of diffuse pollution from
      old versus recent forest drainages. We studied retention and release of
      pollutants from 20 constructed, 2- to 10-m-wide overland flow areas receiving
      drainage water from forested peatlands. Drainage waters were sampled above and
      below the plugged ditches three times per year from 1998 to 1999. Chemical oxygen
      demand and nutrient and metal loads and concentrations varied strongly between
      seasons, years, and drainage areas. Areas subjected to recent ditch renovations
      and fertilizations had clearly elevated seasonal loads and concentrations of
      total phosphorus (TP), PO4, Fe, and Al in comparison to old treatment areas.
      Especially TP loads were high above the national average values measured for
      forestry-induced diffuse pollution. In general, water quality above and below the
      buffer strips did not differ significantly. Our results indicate that plugged
      outlet ditches and associated narrow overland flow areas do not function as
      proper buffers in peatland areas. We suggest that wider buffers with extensive
      overland flow areas are needed in order to control diffuse pollution from
      forested and drained peatlands.

PMID- 15015699
TI  - Modeling habitat suitability for complex species distributions by environmental
      distance geometric mean.
AB  - This paper presents a new habitat suitability modeling method whose main
      properties are as follows: (1) It is based on the density of observation points
      in the environmental space, which enables it to fit complex distributions (e.g.
      nongaussian, bimodal, asymmetrical, etc.). (2) This density is modeled by
      computing the geometric mean to all observation points, which we show to be a
      good trade-off between goodness of fit and prediction power. (3) It does not need
      any absence information, which is generally difficult to collect and of dubious
      reliability. (4) The environmental space is represented either by an expert
      selection of standardized variables or the axes of a factor analysis [in this
      paper we used the Ecological Niche Factor Analysis (ENFA)]. We first explain the
      details of the geometric mean algorithm and then we apply it to the bearded
      vulture (Gypaetus barbatus) habitat in the Swiss Alps. The results are compared
      to those obtained by the "median algorithm" and tested by jack-knife cross
      validation. We also discuss other related algorithms (BIOCLIM, HABITAT, and
      DOMAIN). All these analyses were implemented into and performed with the ecology
      oriented GIS software BIOMAPPER 2.0.The results show the geometric mean to
      perform better than the median algorithm, as it produces a tighter fit to the
      bimodal distribution of the bearded vulture in the environmental space. However,
      the "median algorithm" being quicker, it could be preferred when modeling more
      usual distribution.

PMID- 15015700
TI  - Fuzzy modeling of interactions among environmental stressors in the ecosystem of
      Lake Koronia, Greece.
AB  - The development of a model for assessing the impact and interactions of stressors
      in the ecosystem of Lake Koronia, based on fuzzy inference, is presented in this
      paper. The proposed fuzzy inference model assesses the synergistic interactions
      among several significant stressors on fish production. These stressors include
      industrial pollution, pesticide and nutrient usage due to agricultural
      activities, and water level decrease due to irrigation works. Apart from the
      experts' knowledge, expressed in a set of fuzzy rules, a number of parameters
      such as pH, conductivity, biochemical and chemical oxygen demand, and nitrate
      concentration were used as stressor indicators. The proposed model is capable of
      simulating the effect of a large variety of environmental conditions, and it can
      be used as a dynamic tool for ecosystem risk assessment since it produces both
      qualitative and quantitative results, allowing for comparisons of predictions
      with on-going observational research and ecosystem monitoring. Its operation was
      successfully verified for a number of different conditions, ranging from low
      stressor impact to high stressor impact (where, in fact, the fish production was
      diminished). Moreover, the proposed fuzzy inference model can be used as a tool
      for the investigation of the behavior of the aquatic ecosystem under a large
      number of hypothetical environmental risk scenarios.

PMID- 15015701
TI  - Changes in physical and biological soil quality indicators in a tropical crop
      system (Havana, Cuba) in response to different agroecological management
      practices.
AB  - The objective of our study was to assess the response of physical (aggregate
      stability and bulk density) and biological (enzyme activities and microbial
      biomass) soil quality indicators to the adoption of agroecological management
      practices, such as the planting of forage species (forage area) and the rotation
      of local crops (polycrop area), carried out in a representative tropical pasture
      on an integrated livestock-crop farm. The pasture system was used as control
      (pasture area). In all three areas, the values of water-soluble C were higher in
      the rainy season compared to the dry season. Pasture and forage areas had the
      highest percentage of stable aggregates in the rainy season, while polycrops
      developed soils with less stable aggregates. Soil bulk density was lower in the
      pasture and forage areas than in the polycrop area. In the pasture area, the
      microbial biomass C values, dehydrogenase, urease, protease-BAA, acid
      phosphatase, and beta-glucosidase activities were higher than in the forage and
      polycrop areas, particularly in the dry season. The highest increase in the
      microbial biomass C in the rainy season, with respect to the dry season, was
      recorded in the pasture area (about 1.2-fold). In conclusion, the planting of
      forage species can be considered an effective practice for carrying out
      sustainable, integrated livestock-crop systems, due to its general maintenance of
      soil quality, while the adoption of polycrop rotations appears to be less
      favorable because it decreases soil quality.

PMID- 15015702
TI  - Spatial modeling of harvest constraints on wood supply versus wildlife habitat
      objectives.
AB  - We studied the effects of spatial and temporal timber harvesting constraints on
      competing objectives of sustaining wildlife habitat supply and meeting timber
      harvest objectives in a boreal mixedwood forest. A hierarchical modeling approach
      was taken, where strategic and tactical level models were used to project
      blocking and scheduling of harvest blocks. Harvest block size and proximity,
      together with short- and long-term temporal constraints, were adjusted in a
      factorial manner to allow creation of response-surface models. A new measure of
      the habitat mosaic was defined to describe the emergent pattern of habitat across
      the landscape. These models, together with multiple linear regression, were used
      to provide insight on convergence or divergence between spatial objectives. For
      example, green-up delay (defined as time required before a harvest block adjacent
      to a previously logged block can be scheduled for harvest) had an adverse effect
      on the amount of annual harvest area that could be allocated and blocked
      spatially, and habitat supply responded in an opposite direction to that of wood
      supply, where caribou, moose wintering, and marten habitat supply increased when
      harvest blocks were further apart, maximum block size smaller, and both a green
      up delay and mesoscale stratification were applied. Although there was no
      "solution space" free of conflicts, the analysis suggests that application of the
      mesoscale stratification, together with a diversity of harvest block sizes and a
      between-harvest block proximity of 250 m, will perform relatively well with
      respect to wood supply objectives, and at the same time create a less fragmented
      landscape that better reflects natural forest patterns.

PMID- 15015703
TI  - Neoadjuvant chemotherapy for primary breast cancer: lessons learned and
      opportunities to optimize therapy.

PMID- 15015704
TI  - Importance of correlative science in advancing hormonal therapy and a new
      clinical paradigm for neoadjuvant therapy.
AB  - Improvement in endocrine therapy for estrogen receptor (ER)-positive breast
      cancer will require prevention or modulation of resistance, based on
      identification and targeting of the responsible molecular mechanisms. Our
      approach to this problem has been to focus on neoadjuvant endocrine treatment
      because that permits comparative evaluation of pretreatment tumor biopsies and
      surgical tumor specimens. We have begun utilizing this clinical paradigm by
      exploring semiquantitative changes in the expression of molecular markers within
      tumors treated with either tamoxifen or the aromatase inhibitor letrozole in a
      randomized trial. This investigation is beginning to elucidate the influence of
      growth factor pathways that interact with the ER, especially HER1 (epidermal
      growth factor receptor [EGFR]) and HER2. The results indicate that the distinct
      mechanisms by which tamoxifen and letrozole inhibit ER signaling may produce
      quite marked differences in clinical and biomarker outcomes in the subset of
      tumors that coexpress HER1 and/or HER2 with ER, favoring estrogen-deprivation
      therapy. Ongoing investigations are examining gene expression profile changes
      associated with neoadjuvant endocrine therapy, as well as inhibitors of growth
      factor signaling that may modulate tamoxifen resistance.

PMID- 15015705
TI  - Role of endocrine therapy in the neoadjuvant surgical setting.
AB  - Most neoadjuvant (preoperative) therapy of breast cancer has involved the use of
      chemotherapy, but primary endocrine therapy has also been shown to be effective
      in postmenopausal women with estrogen receptor-positive tumors. Neoadjuvant
      therapy can reduce tumor volume, permitting surgery for otherwise inoperable
      tumors or allowing breast-conserving surgery rather than mastectomy for operable
      tumors. The preoperative treatment setting also allows for assessment and
      comparison of responses to different agents, which may then be used in the
      adjuvant therapy setting following surgery. Since tumor biopsies can be obtained
      before, during, and after preoperative therapy, the relationship between
      biomarkers and response or resistance to surgery can be investigated. In the
      Edinburgh Breast Unit, neoadjuvant endocrine therapy with aromatase inhibitors
      has been more successful than with tamoxifen. Recurrence rates following
      preoperative endocrine therapy and breast-conserving surgery have been acceptably
      low, provided that radiation therapy was also administered postoperatively. Both
      the probability of response to neoadjuvant letrozole or tamoxifen and the degree
      of tumor shrinkage increased as estrogen receptor expression increased,
      consistent with the results of other studies. Attempts to identify biomarkers of
      response to neoadjuvant endocrine therapy are under way, with early indications
      that reduced cell proliferation 14 days after initiation of treatment correlates
      with responses to tamoxifen.

PMID- 15015706
TI  - The role of clinical trials in changing therapy for ductal carcinoma in situ.
AB  - Some aspects of the diagnosis of ductal carcinoma in situ (DCIS) are well
      established, but consideration of other variables may be critical to optimize
      treatment. Mastectomy was once standard surgery, to reduce the probability of
      invasive breast carcinoma recurrence (to < 1%). However, the ability to control
      DCIS to a comparable extent but without resorting to mastectomy has been a major
      goal. There are indications from clinical studies that excision plus radiation
      therapy is as effective as mastectomy in reducing recurrence in patients with low
      risk DCIS. Furthermore, following surgery and irradiation with long-term
      endocrine therapy appears to further reduce the risk of local DCIS progression.
      Variables that should be considered in making a treatment decision are extent of
      disease within the breast, nuclear grade of the lesion, age of the patient, and
      margin of surgical excision. Several randomized trials are currently evaluating
      the clinical value of these variables in optimizing treatment for patients with
      low-risk DCIS. Future improvements in treatment may depend on more sophisticated
      cellular and molecular markers of disease extent and prognosis at diagnosis.

PMID- 15015707
TI  - Applying the neoadjuvant paradigm to ductal carcinoma in situ.
AB  - Local treatment options for ductal carcinoma in situ (DCIS) are virtually
      identical to those for early invasive breast cancer, despite the fact that the
      survival from this condition is much higher. Our ability to more appropriately
      tailor therapy for DCIS is hampered by a lack of understanding of the natural
      history of DCIS, our limited ability to predict the rate of progression to
      invasive cancer and the response to therapy, and the absence of tools to follow
      patients who have not had invasive treatments. Neoadjuvant therapy, which has
      been proven to be both safe and effective in tailoring treatments for invasive
      cancer, could be ideally suited to DCIS. However, neoadjuvant therapy requires
      that doctors and patients delay surgical treatment that has known benefits. In
      order to successfully introduce this approach into clinical practice, risk
      assessment and decision support tools will be needed to help physicians and
      patients feel comfortable that they are not being exposed to unnecessary or
      excessive risk. In addition, we need better imaging to track extent and
      progression of disease. Among the possible benefits of the neoadjuvant approach,
      we may discover that many lesions are responsive and some even reversible,
      leaving us with treatments that might be tailored to biology and with important
      clues for breast cancer prevention in high-risk women.

PMID- 15015708
TI  - Neoadjuvant hormonal therapy for ductal carcinoma in situ: trial design and
      preliminary results.
AB  - For some women, the treatment for ductal carcinoma in situ (DCIS) may be even
      more aggressive than treatments undertaken for early-stage invasive disease.
      Expectant management is not a tenable alternative, given that in a significant
      percentage of patients, DCIS eventually progresses to invasive cancer.
      Nevertheless, if this progression could be halted or reversed with primary
      medical therapy alone, a significant portion of the 50,000 women diagnosed with
      DCIS in the United States annually could potentially avoid the morbidity of
      surgery and radiation for this disease. The most promising therapeutic candidates
      in this regard are those treatments targeting hormone receptors on breast cancer
      cells. We have initiated a clinical trial of neoadjuvant hormonal therapy for
      women with hormone receptor-positive DCIS. We discuss the clinical rationale and
      study design for this trial and present our preliminary results.

PMID- 15015709
TI  - Population pharmacokinetics of imipenem in burn patients.
AB  - The interindividual variability of imipenem pharmacokinetic parameters in burn
      patients suggest that these parameters have to be estimated with a large number
      of patients. The aim of this study is (i) to estimate these parameters with a
      population pharmacokinetic approach, and (ii) to test the influence of factors on
      pharmacokinetics parameters. Data are provided by therapeutic drug monitoring (n
      = 47,118 samples) and analysed by a nonlinear mixed effect modelling method.
      Among the tested covariates (age, gender, body weight, height, size of burn and
      creatinine plasma level) creatinine plasma level affects imipenem pharmacokinetic
      parameters substantially. The best fit is obtained with a two-compartment model
      integrating a linear-inverse relationship between imipenem clearance and
      creatinine plasma level. The estimates of imipenem clearance (16.37 +/- 0.204
      L/h) and of the distribution volume of the central compartment (0.376 +/- 0.039
      L/kg) are higher in the population of burn patients than the estimates in healthy
      subjects. This result is connected with high values of glomerule filtration rate
      and confirms the interest of therapeutic drug monitoring of imipenem in burn
      patients and particularly for patients with extreme values of creatinine
      clearance.

PMID- 15015710
TI  - Short- and long-term effects of treatment of chronic hepatitis B and delta virus
      by IFN.
AB  - Chronic hepatitis B virus (HBV) infection is a common infectious disease in the
      world. Two percent of the patients with chronic HBV infection will develop
      cirrhosis each year, and will die prematurely from cirrhosis or hepatocellular
      carcinoma. So far interferon alfa and lamivudine are the only effective drugs.
      Interferon alfa can be used at the dosage of 9-10 million units thrice a week for
      4-6 months either intramuscularly or subcutaneously for standard treatment.
      Interferon provides sustained response in 1/3 of the patients when HBe Ag is (+).
      Response rate to interferon therapy in HBe Ag(-) patients was similar to that
      reported in HBe Ag(+) ones. However the responses were not sustained in many
      patients, serum HBV-DNA reappear in most after stopping the treatment. Extension
      of therapy to 1 year may be needed in patients who are unresponsive to therapy
      and having HBV-DNA levels <10 pg/ml and ALT >100 IU. Establishment of
      unresponsiveness in early phases of the therapy is important and careful follow
      up of serum HBe Ag may be helpful. Interferon alfa treatment of chronic HDV
      infection may result in temporary normalization of ALT values. Disappearance of
      HBV-DNA and HBs Ag from the serum upon completion of therapy dictates sustained
      response in chronic HDV infection. The long term effect of interferon with
      respect to virological and histopathological responses is poor in HDV infection
      and longer periods of therapy in higher doses may be beneficial.

PMID- 15015711
TI  - Clinical pharmacology of anti-Alzheimer drugs.
AB  - Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by
      a progressive loss of cognitive and functional abilities, associated with various
      degrees of behavioural disturbances, with a devastating impact on public health
      and on the whole society. Slowing of cognitive impairment, duration of disease,
      self-sufficiency and behavioural disturbances represent the best outcomes of the
      pharmacologic therapy. Cholinesterase inhibitors (ChE-I) have been shown to be
      effective in the treatment of the cognitive, behavioural, and functional deficits
      of AD. In addition to ChE-I, a number of studies have been carried out to
      investigate the possible use of other compounds and pharmacologic strategies;
      more compounds, postsynaptic muscarinic and nicotinic receptor agonists, are
      under investigation. The standard suggested care for pharmacologic management of
      the cognitive and functional disabilities of AD at present consists of treatment
      with ChE-I. Practice recommendations and treatment guidelines are derived from
      clinical trials.

PMID- 15015713
TI  - The contractile response of the mesenteric resistance arteries to prostaglandin
      F2alpha; effects of simultaneous hyperlipemia-diabetes.
AB  - The effect of hyperlipemia associated with diabetes on the contractility of
      resistance arteries to prostaglandin F2alpha (PGF2alpha) was investigated
      employing 4 weeks simultaneously hyperlipemic-diabetic (HD), hyperlipemic (H),
      diabetic (D) and normal hamsters (controls, C). The isometric force produced by
      explanted arteries in the presence of 10(-8) to 10(-5) M PGF2alpha was recorded
      by the myograph technique. The results showed that compared with controls, the
      contractile response to 10(-5) M PGF2alpha was approx. 2 fold increased in HD
      group, and approx. 1.75 and 1.62-fold enhanced in H and D groups, respectively.
      Activation of protein kinase C with 10(-6) M phorbol 12-myristate 13-acetate
      increased the contractility to PGF2alpha in all groups and particularly in HD
      hamsters (approx. 10.16-fold). Inhibition of cyclooxygenase by indomethacin
      increased approx. 1.81-fold the arterial contractility to PGF2alpha in C group,
      whereas in H, D and HD hamsters had no effect. Blockage of Ca(2+)-activated K(+)
      channels with 10(-3) M tetraethylammonium augmented the contraction to PGF2alpha
      approx. 6.43-fold in C group, and at significantly lower levels in H, D and HD
      groups, i.e. approx. 3.84, 3.72 and 3.33-fold, respectively. The results validate
      two conclusions: (i) simultaneous insult of hyperlipemia-hyperglycemia is
      associated with the highest contractility of the resistance arteries to
      PGF2alpha; the highest circulating glucose and cholesterol levels, and the
      enhancement in the protein kinase C pathway underlay the augmented contractility;
      (ii) no matter the pathology induced (hyperlipemia, diabetes or both
      simultaneously) a common dysfunctional response to PGF2alpha was installed; this
      consists in a reduced effect of cyclooxygenase inhibition, and a altered activity
      of Ca(2+) dependent K(+) channels.

PMID- 15015714
TI  - Clarithromycin reduces Isus and Ito currents in human atrial myocytes with minor
      repercussions on action potential duration.
AB  - The macrolide antibacterial agent clarithromycin has been shown to cause QT
      interval prolongation on the electrocardiogram. In rabbit heart preparations
      clarithromycin (concentration dependently) lengthened the action potential
      duration and blocked the delayed rectifier current. The aim of the present study
      was to investigate the clarithromycin effects: (i) on the Ca2+ L-type and the
      main K+ repolarizing currents on human atrial myocytes, using whole-cell patch
      clamp recordings and (ii) on action potentials recorded from human atrial and
      ventricular myocardium using conventional microelectrodes. It has been found that
      (i) 10-30 microM clarithromycin reduced the sustained current Isus significantly
      and that a 100 microM concentration was needed to cause a significant reduction
      in the transient outward current Ito, whereas clarithomycin did not affect the
      calcium current and (ii) clarithromycin (10-100 microM) prolonged the action
      potential duration in atrial preparations but did not alter the different
      parameters of the ventricular action potential. It is concluded that
      clarithromycin exerts direct cardiac electrophysiological effects that may
      contribute to pro-arrythmic potential.

PMID- 15015712
TI  - Vasorelaxant effects of grape polyphenols in rat isolated aorta. Possible
      involvement of a purinergic pathway.
AB  - The purpose of this study was to investigate the mechanism of the vascular
      relaxation produced by polyphenolic substances from red wine, with a particular
      focus on the possible involvement of purinoceptors. With this aim, relaxing
      responses induced by procyanidin from grape seeds (GSP), anthocyanins, catechin
      and epicatechin were assessed in rat isolated aortic rings left intact (+E) or
      endothelium-denuded (-E). In preparations precontracted with noradrenaline,
      incubation with NG-nitro-L-arginine methyl ester (100 microM, 30 min) fully
      inhibited the GSP-induced relaxations. Concentration-effect curves to these
      substances (from 10(-7) to 10(-1) g/L) were determined in depolarized (60 mM KCl)
      preparations in control condition, after incubation with reactive blue 2 (an
      antagonist of P2Y purinoceptors, 30 microM), with apyrase (an enzyme which
      hydrolyses ATP and ADP, 0.8 U/mL) or with alpha,beta-methylene ATP (an inhibitor
      of ecto ATPases, 10 microM). In (+E) rings, relaxations (expressed as percentage
      of initial contraction) were 41 +/- 2 and 37 +/- 3 for GSP and anthocyanins,
      respectively. Only modest relaxations (ca. 10%) were observed in (-E) rings, as
      it was the case for catechin and epicatechin in (+/- E) rings. Reactive blue 2 or
      apyrase inhibited the GSP- and anthocyanin-induced relaxations in (+E) rings,
      while alpha,beta-methylene ATP shifted to the left the relaxation curves obtained
      with GSP. These data confirm that modest relaxations observed with catechin and
      epicatechin are not endothelium-dependent but that GSP and anthocyanins induce a
      relaxing effect, which is related to the integrity of the endothelium and the
      synthesis and release of nitric oxide (NO). Furthermore, the inhibition by
      apyrase and the increase by ecto-ATPase inhibition of the GSP- and anthocyanin
      induced relaxation suggest that these substances could act via an initial release
      of nucleotides, which in turn could activate P2Y1 and/or P2Y2 purinoceptors of
      endothelial cells, trigger the synthesis and release of NO and then lead to
      relaxation.

PMID- 15015715
TI  - Protective effect of exogenous administration of alpha-tocopherol in middle
      cerebral artery occlusion model of cerebral ischemia in rats.
AB  - Oxidative stress due to increased free radical generation and depletion of
      endogenous antioxidants have been implicated in ischemia-reperfusion-induced
      neuronal injury. The present study was carried out to study the effect of acute
      administration of alpha-tocopherol in the middle cerebral artery (MCA) occlusion
      model of stroke in rats. Rats were anesthetized using chloral hydrate (400 mg/kg
      i.p.) and subjected to 2 h of transient MCA occlusion. alpha-Tocopherol was
      administered at the dose of 125 and 250 mg/kg orally 1 h prior to the occlusion
      of MCA. Motor performance test (grip test, foot fault test, rotarod performance
      test, spontaneous locomotor activity), markers of oxidative stress and 2,3,5
      triphenyl tetrazolium chloride staining were carried out 24 h after MCA
      occlusion. A vehicle-treated group was run parallel. It was observed that alpha
      tocopherol at the dose of 125 mg/kg neither improved neurologic deficit, nor
      decreased the raised level of oxidative stress markers in comparison with the MCA
      occluded rats. However, higher dose of alpha-tocopherol (250 mg/kg p.o.) afforded
      significant protection as evident by increase in motor performance tests and a
      decrease in the volume of infarction. The raised levels of malondialdehyde after
      MCA occlusion were also significantly attenuated. The results demonstrate that
      exogenous administration of alpha-tocopherol is able to reduce the neuronal
      damage caused during ischemia-reperfusion, which can be attributed to its
      antioxidant activity.

PMID- 15015716
TI  - Direct demonstration of nitric oxide formation in organs of rabbits treated by
      transdermal glyceryl trinitrate using an in vivo spin trapping technique.
AB  - Glyceryl trinitrate (GTN) is commonly delivered by a patch for the treatment of
      angina pectoris. The idea is now generally accepted that GTN requires a
      biotransformation process that activates the drug, in particular through nitric
      oxide (NO) generation. However, the pharmacokinetics of NO delivery from GTN
      still remains obscure. The objective of this study was to assess GTN-derived NO
      formation in vascular tissues and organs in rabbit given GTN patches. NO levels
      were evaluated in rabbits after 3 h of treatment with a 10 mg GTN patch (GTN
      group; n = 7) or a placebo patch (CTL; n = 7). Nitrosylhaemoglobin (HbNO) was
      evaluated by electron spin resonance (ESR) spectroscopy in red cell suspension.
      In vivo spin trapping technique using FeMGD as a spin trap, associated with ESR
      was used to quantify NO in tissues. The NO-spin trap complex, which is a
      relatively stable product, has been measured in several tissues. The ESR spectrum
      corresponding to HbNO was not found in red cell of GTN or CTL rabbits. The
      spectrum corresponding to the NO-spin trap complex was observed in all analysed
      tissues of CTL rabbits. The signal was significantly increased in liver, renal
      medulla, heart left ventricle and spleen of GTN-treated rabbits, and to a lesser
      extent in right ventricle and lung. No difference was shown between NO-spin trap
      levels measured in aorta or inferior vena cava from GTN or CTL rabbits. These
      data suggest that GTN patch treatment induced NO release, and that tissue
      specific differences in transdermal GTN-derived NO exist. The GTN-NO pathway
      appears to be largely involved in organs such as the liver, kidney and heart.

PMID- 15015718
TI  - Prescribing antibiotics in odontology and stomatology. Recommendations by the
      French Health Products Safety Agency.
AB  - In order to limit the onset of adverse effects and the increasing emergence of
      bacterial resistance, the prescription of antibiotics must be reserved strictly
      for situations where their efficacy has been demonstrated. The French Health
      Products Safety Agency (Afssaps) has updated recommendations concerning the use
      of antibiotic treatment in odontology and stomatology. The general strategy for
      the prescription of antibiotics proposed by the present recommendations relies on
      a professional consensus. The full-length, discussed and referenced text is
      available at the web site of Afssaps (http://www.afssaps.sante.fr) in the
      'Documentation et publications' rubric'.

PMID- 15015717
TI  - Study of the mechanism of Flavobacterium sp. for hydrolyzing organophosphate
      pesticides.
AB  - The biotransformation by Flavobacterium sp. of the following organophosphate
      pesticides was experimentally and theoretically studied: phorate,
      tetrachlorvinphos, methyl-parathion, terbufos, trichloronate, ethoprophos,
      phosphamidon, fenitrothion, dimethoate and DEF. The Flavobacterium sp. ATCC 27551
      strain bearing the organophosphate-degradation gene was used. Bacteria were
      incubated in the presence of each pesticide for a duration of 7 days. Parent
      pesticides were identified and quantified by means of a gas-chromatography mass
      spectrum system. Activity was considered as the amount (micromol) of each
      pesticide degraded by Flavobacterium sp. Also, structural parameters obtained by
      means of the CAChe program package for biomolecules, the reactivity index of
      phosphorus, of oxygen at the P = O function and of sulfur at the P = S function,
      and lipophilicity (log Poct) (ALOGPS v. 2.0) were obtained for each pesticide.
      Pesticides were hydrolyzed at the bond between phosphorous and the heteroatom,
      producing phosphoric acid and three metabolites. Enzymatic activity was
      significantly explained by the following multiple linear relationship: Enzymatic
      activity = 162.2 - 9.5(dihedral angle energy) - 25.0(Total energy) -
      0.51(Molecular weight). Finally, a mechanism of Flavobacterium sp. to hydrolyze
      pesticides was proposed.

PMID- 15015719
TI  - Multimodal image fusion in ultrasound-based neuronavigation: improving overview
      and interpretation by integrating preoperative MRI with intraoperative 3D
      ultrasound.
AB  - OBJECTIVE: We have investigated alternative ways to integrate intraoperative 3D
      ultrasound images and preoperative MR images in the same 3D scene for visualizing
      brain shift and improving overview and interpretation in ultrasound-based
      neuronavigation. MATERIALS AND METHODS: A Multi-Modal Volume Visualizer (MMVV)
      was developed that can read data exported from the SonoWand neuronavigation
      system and reconstruct the spatial relationship between the volumes available at
      any given time during an operation, thus enabling the exploration of new ways to
      fuse pre- and intraoperative data for planning, guidance and therapy control. In
      addition, the mismatch between MRI volumes registered to the patient and
      intraoperative ultrasound acquired from the dura was qualified. RESULTS: The
      results show that image fusion of intraoperative ultrasound images in combination
      with preoperative MRI will make perception of available information easier by
      providing updated (real-time) image information and an extended overview of the
      operating field during surgery. This approach will assess the degree of
      anatomical changes during surgery and give the surgeon an understanding of how
      identical structures are imaged using the different imaging modalities. The
      present study showed that in 50% of the cases there were indications of brain
      shift even before the surgical procedure had started. CONCLUSIONS: We believe
      that image fusion between intraoperative 3D ultrasound and preoperative MRI might
      improve the quality of the surgical procedure and hence also improve the patient
      outcome.

PMID- 15015720
TI  - Soft tissue scanning for patient registration in image-guided surgery.
AB  - Prior to an image-guided surgical intervention, a correlation between the
      patient's data set and the surgical site is required. This study introduces a
      markerless registration method for cranio-maxillofacial surgery that is based on
      a high-resolution laser scan of the patient's skin surface. The Surgical Segment
      Navigator SSN++ rejects contaminated surface measurements in a way similar to the
      bluescreen technique. Acquisition of the spatial position and the corresponding
      surface color of each laser-scanned point facilitates this bluescreen method,
      removing points with a defined surface color, e.g., blue or green points. The
      accuracy of the laser-scan-based registration was measured via additional
      intraoral titanium-markers. These markers served only to check the accuracy of
      the markerless registration process. In twelve patients, the stability and
      accuracy of the data set alignment was evaluated for high-(300,000 surface
      points), medium-, and low-resolution (down to 3,750 surface points) laser
      scanning. The accuracy of the registration technique was best for high-resolution
      laser scanning (mean deviation 1.1 mm; maximum deviation 1.8 mm). Low-resolution
      laser scans revealed inaccuracies up to 6 mm.

PMID- 15015721
TI  - Real-time three-dimensional ultrasound for guiding surgical tasks.
AB  - OBJECTIVE: As a stand-alone imaging modality, two-dimensional (2D) ultrasound
      (US) can only guide basic interventional tasks due to the limited spatial
      orientation information contained in these images. High-resolution real-time
      three-dimensional (3D) US can potentially overcome this limitation, thereby
      expanding the applications for US-guided procedures to include intracardiac
      surgery and fetal surgery, while potentially improving results of solid organ
      interventions such as image-guided breast, liver or prostate procedures. The
      following study examines the benefits of real-time 3D US for performing both
      basic and complex image-guided surgical tasks. MATERIALS AND METHODS: Seven
      surgical trainees performed three tasks in an acoustic testing tank simulating an
      image-guided surgical environment using 2D US, biplanar 2D US, and 3D US for
      guidance. Surgeon-controlled US imaging was also tested. The evaluation tasks
      were (1) bead-in-hole navigation; (2) bead-to-bead navigation; and (3) clip
      fixation. Performance measures included completion time, tool tip trajectory, and
      error rates, with endoscope-guided performance serving as a gold-standard
      reference measure for each subject. RESULTS: Compared to 2D US guidance,
      completion times decreased significantly with 3D US for both bead-in-hole
      navigation (50%, p = 0.046) and bead-to-bead navigation (77%, p = 0.009).
      Furthermore, tool-tip tracking for bead-to-bead navigation demonstrated improved
      navigational accuracy using 3D US versus 2D US (46%, p = 0.040). Biplanar 2D
      imaging and surgeon-controlled 2D US did not significantly improve performance as
      compared to conventional 2D US. In real-time 3D mode, surgeon-controlled imaging
      and changes in 3D image presentation made by adjusting the perspective of the 3D
      image did not diminish performance. For clip fixation, completion times proved
      excessive with 2D US guidance (> 240 s). However, with real-time 3D US imaging,
      completion times and error rates were comparable to endoscope-guided performance.
      CONCLUSIONS: Real-time 3D US can guide basic surgical tasks more efficiently and
      accurately than 2D US imaging. Real-time 3D US can also guide more complex
      surgical tasks which may prove useful for procedures where optical imaging is
      suboptimal, as in fetal surgery or intracardiac interventions.

PMID- 15015722
TI  - Computer simulation of prostate cryoablation--fast and accurate approximation of
      the exact solution.
AB  - OBJECTIVE: Cryosurgery is a minimally invasive cancer treatment that uses liquid
      nitrogen or supercooled argon to freeze and destroy tumors. To achieve complete
      ablation of the prostate, we have developed a computer program that can determine
      treatment effects by calculating iceball formation. This is based on a three
      dimensional (3D) model of the patient's prostate constructed from ultrasound
      images. The program predicts the best set of cryoablation parameters and
      cryoprobe spatial positions, then displays these parameters in graphical or
      numerical form. The objective of this work was to improve our prostate
      cryoablation modeling software by making its partial differential equation (PDE)
      solver more accurate and faster. MATERIALS AND METHODS: CryoSim, our software
      package, accepts a set of acquired and processed 3D ultrasound images of the
      prostate, then models heat diffusion using numerical approximations of the heat
      equation. RESULTS: We describe the latest version of the CryoSim software, which
      models cryoablation therapy. Solving the problems of low spatial resolution (now
      down to a fraction of a millimeter, as compared to 5 mm in the old version) and
      modeling cryosurgery in a short time (down to few minutes versus hours) provides
      a platform for proper planning of cryosurgery and a tool for the training of
      surgeons. CONCLUSION: Changes in the PDE solver algorithm produce more accurate
      results, leading to an improved visualization of the iceball, with a precision of
      a few mm and a significant decrease in computation time.

PMID- 15015723
TI  - Model of surgical procedures for multimodal image-guided neurosurgery.
AB  - OBJECTIVE: Improvement of the planning stage of image-guided surgery requires a
      better anticipation of the surgical procedure and its anatomical and functional
      environment. This anticipation should be provided by acquisition of multimodal
      medical images of the patient and by a better understanding of surgical
      procedures. In this paper, we propose improvements to the planning and
      performance of multimodal image-guided neurosurgery through the use of
      information models related to neurosurgical procedures. MATERIALS AND METHODS: A
      new generic model of surgical procedures is introduced in the context of
      multimodal image-guided craniotomies. The basic principle of the model is to
      break down the surgical procedure into a sequence of steps defining the surgical
      script. In the model, a step is defined by an action. The model assigns to each
      surgical step a list of image entities extracted from multimodal preoperative
      images (i.e., anatomical and/or functional images) which are relevant to the
      performance of that particular step. A semantic validation of the model was
      performed by instantiating the model entities for 29 surgical procedures.
      RESULTS: The resulting generic model is described by a UML class diagram and a
      textual description. The validation showed the relevance of the model, confirming
      the main underlying assumptions. It also provided some leads to improve the
      model. CONCLUSION: While further validation is needed, the initial benefits of
      this approach can already be outlined. It should add real value to the different
      levels of image-guided surgery, from preprocessing to planning, as well as during
      surgery. Models of surgical procedures can manage image data according to the
      surgical script, which should lead to better anticipation of surgery through the
      development of simulation tools. Furthermore, the models may improve the
      performance of surgery using microscope-based neuronavigation systems by making
      it possible to adapt both visualization and interaction features of multimodal
      preoperative images according to the model.

PMID- 15015724
TI  - EI-2346, a novel interleukin-1beta converting enzyme inhibitor produced by
      Streptomyces sp. E-2346. I. Taxonomy of producing strain, fermentation,
      isolation, physico-chemical properties, and biological properties.
AB  - EI-2346, a novel interleukin-1beta converting enzyme (ICE) inhibitor, was
      isolated from the culture broths of Streptomyces sp. E-2346. EI-2346 selectively
      inhibited the human recombinant ICE activity with an IC50 value of 3.9 microM,
      without inhibiting elastase and cathepsin B. EI-2346 also inhibited mature
      interleukin-1beta secretion from THP-1 cells induced by LPS with an IC50 value of
      5.2 microM.

PMID- 15015725
TI  - Melanocins A, B and C, new melanin synthesis inhibitors produced by Eupenicillium
      shearii. I. Taxonomy, fermentation, isolation and biological properties.
AB  - New melanin synthesis inhibitors, melanocins A, B and C, were isolated from the
      fermentation broth and mycelium extract of Eupenicillium shearii F80695.
      Melanocin A, an isocyanide compound, inhibited mushroom tyrosinase and melanin
      biosynthesis of B16 melanoma cells with IC50 value of 9.0 nM and MIC value of 0.9
      microM, respectively. Melanocin A also inhibited growth of Streptomyces
      bikiniensis. While, the structurally very related but non-isocyanide compounds
      melanocins B and C did not show inhibitory activity in these assays. Melanocins
      A, B and C showed potent antioxidant activity with scavenging activity of DPPH
      radical and superoxide anion radical.

PMID- 15015726
TI  - Melanocins A, B and C, new melanin synthesis inhibitors produced by Eupenicillium
      shearii. II. Physico-chemical properties and structure elucidation.
AB  - New melanin synthesis inhibitors, melanocins A, B and C, were isolated from the
      fermentation broth and extract of mycelium of Eupenicillium shearii F80695. The
      structures of melanocins were established by spectroscopic methods. They are
      formamide compounds. In particular, melanocin A has an isocyanide group.

PMID- 15015728
TI  - Kigamicins, novel antitumor antibiotics. II. Structure determination.
AB  - Kigamicin A (1), B (2), C (3), D (4) and E (5) are novel antitumor antibiotics.
      Their structures were determined by spectroscopic analyses including various NMR
      measurements. Kigamicins have a unique aglycone of fused octacyclic ring system
      containing seven of six-membered rings and one oxazolidine. The aglycone links a
      sugar chain composed of one to four deoxysugars. These sugars were found to be
      amicetose and oleandrose.

PMID- 15015727
TI  - Kigamicins, novel antitumor antibiotics. I. Taxonomy, isolation, physico-chemical
      properties and biological activities.
AB  - Novel antibiotics named kigamicin A, B, C, D, and E were discovered from the
      culture broth of Amycolatopsis sp. ML630-mF1 by their selective killing activity
      against PANC-1 cells only under a nutrient starved condition. Under a condition
      of nutrient starvation, kigamicins A, B, C, and D inhibited PANC-1 cell survival
      at 100 times lower concentration than in normal culture. Kigamicins showed
      antimicrobial activity against Gram-positive bacteria including methicillin
      resistant Staphylococcus aureus (MRSA). Kigamicin D inhibited the growth of
      various mouse tumor cell lines at IC50 of about 1 microg/ml.

PMID- 15015729
TI  - Isolation, structure and HIV-1 integrase inhibitory activity of exophillic acid,
      a novel fungal metabolite from Exophiala pisciphila.
AB  - HIV-1 integrase is one of the three enzymes that are critical for replication and
      spread of HIV and its inhibition is one of the most promising new drug targets
      for anti-retroviral therapy with potential advantage over existing therapies.
      This paper describes the isolation and structure elucidation of exophillic acid,
      a novel dimeric 2,4-dihydroxy alkyl benzoic acid, derived from Exophiala
      pisciphila, a fungus isolated from a soil sample collected in Georgia, USA.
      Exophillic acid (1) and aquastatin A (2), a related compound, inhibited the
      strand transfer reaction of HIV-1 integrase with IC50 values of 68 and 50 microM,
      respectively.

PMID- 15015730
TI  - Arborcandins A, B, C, D, E and F, novel 1,3-beta-glucan synthase inhibitors:
      physico-chemical properties and structure elucidation.
AB  - Arborcandins A, B, C, D, E and F, which possess potent 1,3-beta-glucan synthase
      inhibitory activity, were isolated from the cultured broth of a filamentous
      fungus, strain SANK 17397. The structures of arborcandins A, B, C, D, E and F
      were elucidated by a combination of NMR and mass spectrometry, and established to
      be novel cyclic peptides containing uncommon amino acid residues.

PMID- 15015731
TI  - Novel alpha-pyrones produced by a marine Pseudomonas sp. F92S91: taxonomy and
      biological activities.
AB  - Inhibitors of the enzymes involved in fatty acid biosynthesis (FAB) have been
      reported as antibacterial agents. These include thiolactomycin, cerulenin,
      triclosan, diazoborine, naphthyridinones, aminopyridines and pyridoindoles. Our
      search for new FAB inhibitors, using a lacZ reporter cell-based screen, led to
      several confirmed hits. Culture F92S91, later identified as a Pseudomonas sp.
      based on 16S profiling, was found to produce two alpha-pyrones (I and II) and
      three high molecular weight peptides. The pyrones were unstable under acidic
      conditions, and they were rearranged into a furanone derivative (III). Of these
      compounds, pyrone I was the most active with MICs (microg/ml) against B. subtilis
      (1 to approximately 2), MRSA (2 to approximately 4), M. catarrhalis (4) and VRE
      (2 to approximately 64). Effects on macromolecular synthesis and membrane
      functions were tested in B. subtilis. Pyrone I nonspecifically inhibited
      incorporation of radiolabeled precursors into DNA, RNA and protein within 5
      minutes of drug exposure, similar to that of triclosan. Both compounds also
      inhibited the cellular uptake of these precursors. Cerulenin did not have an
      effect until 30 minutes of drug treatment. Pyrone I and triclosan were membrane
      active (BacLight test); however, pyrone I (at < or = 128 microg/ml concentration)
      was not hemolytic to human RBCs in contrast to triclosan, which was hemolytic at
      16 microg/ml. These data suggest that pyrone-I, unlike triclosan, selectively
      affects bacterial membrane function.

PMID- 15015732
TI  - Isolation and characterization of inhibitors of the essential histidine kinase,
      YycG in Bacillus subtilis and Staphylococcus aureus.
AB  - The set of sensor kinase YycG and response regulator YycF is the only essential
      two-component system (TCS) in Bacillus subtilis and Staphylococcus aureus. We
      have developed a screening method for antibacterial agents that inhibit YycG, the
      essential histidine kinase (HK). To increase screening sensitivity, a temperature
      sensitive yycF mutant (CNM2000) of B. subtilis with super-sensitivity to HK
      inhibitors was constructed, which was used for the screening of acetone extracts
      from 4000 microbes. A total of 11 samples showed higher sensitivity to CNM2000
      than to wild-type parent 168, and seven of those were characterized to be potent
      inhibitors against autophosphorylation of YycG. One sample compound was purified
      and identified as aranorosinol B, a known antibacterial agent against Gram
      positive bacteria including B. subtilis and S. aureus. Aranorosinol B inhibited
      YycG from both B. subtilis and S. aureus with a half-maximum inhibitory
      concentration (IC50) of 223 and 211 microM, respectively.

PMID- 15015733
TI  - Pradimicin-resistance of yeast is caused by a point mutation of the histidine
      containing phosphotransfer protein Ypd1.
AB  - Pradimicin is an antifungal antibiotic which induces apoptosis like cell death in
      the yeast Saccharomyces cerevisiae. Pradimicin-resistant mutants were isolated
      from the S. cerevisiae and the mutation points were analyzed. A point mutation of
      YPD1 that led to a substitution of the 74th glycine (Gly74) to cysteine (Cys) was
      identified in a mutant strain NH1. In S. cerevisiae, Ypd1 transfers a phosphoryl
      group from the sensor kinase Slnl to the response regulator Sskl which regulates
      a downstream MAP kinase in response to hyperosmotic stress. Gly74 is located in a
      three-residue reverse turn domain that connects two alpha-helices, one of which
      contains a histidine residue which is phosphorylated. In the reverse turn,
      glycine (relative position +10 to the active-site histidine) is highly conserved
      in Ypd1 and other histidine-containing phosphotransfer proteins. It was therefore
      suggested that the substitution of Gly74 to Cys altered the Ypd1 structure, which
      resulted in the resistance to pradimicin.

PMID- 15015734
TI  - Lactonamycin Z, an antibiotic and antitumor compound produced by Streptomyces
      sanglieri strain AK 623.

PMID- 15015735
TI  - The synthesis and antibacterial activity of tetracyclic macrolides.

PMID- 15015736
TI  - The World Oral Health Report 2003: continuous improvement of oral health in the
      21st century--the approach of the WHO Global Oral Health Programme.
AB  - Chronic diseases and injuries are the leading health problems in all but a few
      parts of the world. The rapidly changing disease patterns throughout the world
      are closely linked to changing lifestyles, which include diets rich in sugars,
      widespread use of tobacco, and increased consumption of alcohol. In addition to
      socio-environmental determinants, oral disease is highly related to these
      lifestyle factors, which are risks to most chronic diseases as well as protective
      factors such as appropriate exposure to fluoride and good oral hygiene. Oral
      diseases qualify as major public health problems owing to their high prevalence
      and incidence in all regions of the world, and as for all diseases, the greatest
      burden of oral diseases is on disadvantaged and socially marginalized
      populations. The severe impact in terms of pain and suffering, impairment of
      function and effect on quality of life must also be considered. Traditional
      treatment of oral diseases is extremely costly in several industrialized
      countries, and not feasible in most low-income and middle-income countries. The
      WHO Global Strategy for Prevention and Control of Noncommunicable Diseases, added
      to the common risk factor approach is a new strategy for managing prevention and
      control of oral diseases. The WHO Oral Health Programme has also strengthened its
      work for improved oral health globally through links with other technical
      programmes within the Department for Noncommunicable Disease Prevention and
      Health Promotion. The current oral health situation and development trends at
      global level are described and WHO strategies and approaches for better oral
      health in the 21st century are outlined.

PMID- 15015737
TI  - X-chromosome inactivation: a multi-disciplinary approach.

PMID- 15015738
TI  - The Lyon and the LINE hypothesis.
AB  - X-chromosome inactivation (XCI) was first suggested as an explanation for the
      variegated phenotypes in mice heterozygous for X-linked colour genes or for X
      autosome translocations involving autosomal coat colour genes. The effects seen
      in X-autosome translocations led to the suggestion of an X-inactivation centre
      (Xic) from which the inactivation was initiated, and this suggestion has led to
      major advances in understanding. Another feature of X-autosome translocations is
      incomplete inactivation of the attached autosomal segment, implying that the X
      chromosome is enriched in features favouring inactivation. Interspersed repeat
      elements, and in particular long interspersed elements (LINEs), have been
      suggested as the relevant enriching features. Recent evidence concerning this
      hypothesis is discussed.

PMID- 15015739
TI  - Imprinted X-chromosome inactivation: enlightenment from embryos in vivo.
AB  - There are two forms of X chromosome inactivation (XCI) in the laboratory mouse,
      random XCI in the fetus and imprinted paternal XCI limited to the extraembryonic
      tissues supporting the fetal life in utero. Imprinted XCI has been studied
      extensively because it takes place first in embryogenesis and it may hold clues
      to the mechanism of control of XCI in general and to the evolution of random'
      XCI. Classical microscopic and biochemical studies of embryos in vivo provide a
      basis for interpreting the multifaceted information yielded by various inventive
      approaches and for planning further experiments.

PMID- 15015740
TI  - Controlling X-inactivation in mammals: what does the centre hold?
AB  - Controlling gene expression is one of the most fundamental task of living
      organisms, from prokaryotes to higher eukaryotes, in order to develop, grow, and
      reproduce in an ever changing environment. In many cases, the expression status
      of a given gene is controlled independently of that of its neighbours through
      localised cis DNA elements responsible for the recruitment of specific factors
      and enzymatic activities. However, in a growing number of cases, genomic regions
      including several genes have been shown to be regulated in a coordinated manner.
      X-chromosome inactivation, the dosage compensation mechanism encountered in
      mammals, is one of the most Striking example of such coordinated gene regulation.
      This process, which occurs at the chromosome-wide level, affecting many hundreds
      of genes, is under the control of a unique, cis acting region, termed the X
      inactivation centre, whose complexity is just beginning to be unravelled.

PMID- 15015741
TI  - Beyond sense: the role of antisense RNA in controlling Xist expression.
AB  - The Xist RNA is a critical component of X inactivation, and Tsix is a non-coding
      antisense RNA to the Xist gene. We review the data from mouse that demonstrates
      that Tsix serves to regulate Xist expression. TSIX antisense transcripts have
      also been detected in humans, but without a manipulatable system to study the
      inactivation process in humans it remains unknown whether these antisense
      transcripts are functional in regulating human XIST. After a review of the
      differences between the human and mouse antisense, we discuss how the question of
      whether or not the human TSIX is functional impacts models of Tsix function.

PMID- 15015742
TI  - Micromanipulating dosage compensation: understanding X-chromosome inactivation
      through nuclear transplantation.
AB  - Nuclear transfer (NT) studies have provided insight into the functional
      importance of epigenetic alteration of the X chromosomes during X-inactivation.
      Uniparental embryos created by NT have been informative as to the time and
      location at which the imprint controlling extraembryonic X-inactivation is
      established. Experiments with female somatic cells, have demonstrated that the
      inactive X chromosome (Xi) is reactivated after NT, leading to random X
      inactivation in the embryonic lineages of cloned embryos. However, in the
      extraembryonic lineages of clones, epigenetic information from the donor cell
      nucleus persists, leading to preferential inactivation of the donor cell's
      inactive X in the placenta of cloned animals. These results suggest epigenetic
      information established during embryonic X-inactivation is functionally
      equivalent to the gametic imprint.

PMID- 15015743
TI  - Barring gene expression after XIST: maintaining facultative heterochromatin on
      the inactive X.
AB  - X chromosome inactivation refers to the developmentally regulated process of
      silencing gene expression from all but one X chromosome per cell in female
      mammals in order to equalize the levels of X chromosome derived gene expression
      between the sexes. While much attention has focused on the genetic and epigenetic
      events early in development that initiate the inactivation process, it is also
      important to understand the events that ensure maintenance of the inactive state
      through subsequent cell divisions. Gene silencing at the inactive X chromosome is
      irreversible in somatic cells and is achieved through the formation of
      facultative heterochromatin (visible as the Barr body) that is remarkably stable
      and faithfully preserved. Here we review the many features of inactive X
      chromatin in terminally differentiated cells and address the highly redundant
      mechanisms of maintaining the inactive X chromatin.

PMID- 15015744
TI  - The cell biology of a novel chromosomal RNA: chromosome painting by XIST/Xist RNA
      initiates a remodeling cascade.
AB  - X chromosome inactivation begins when a novel chromosomal RNA (cRNA) from the
      imprinted mouse Xist or human XIST locus coats or "paints" one X chromosome in
      cis and initiates a cascade of chromosome remodeling events. Molecular
      cytological studies have proven invaluable for understanding the distinctive
      cellular behavior of this singular RNA involved in chromosome structure and
      regulation. While the detailed mechanism of XIST/Xist (X-inactivation Specific
      Transcript) RNA function remains largely unknown, recent advances provide new
      insights into the complex cellular factors which impact the RNA's localization to
      the chromosome, as well as the early events of chromosome remodeling that follow
      painting by Xist RNA. Because chromatin changes can be directly visualized on a
      silenced chromosome, X chromosome inactivation provides an advantageous model to
      investigate genome-wide heterochromatin formation and maintenance, with wide
      ranging implications for normal cells and disease.

PMID- 15015745
TI  - [Mite allergy in the domestic horse: experience of an equine veterinarian
      specializing in the field of allergy].
AB  - When medical history and clinical examination for a recurrent or chronic cough
      reveal the presence of perennial allergy, the practitioner would be advised to
      look for mites present in the horse's environment. He can propose this service to
      his clients.

PMID- 15015746
TI  - [Recurrent or chronic urticaria in thoroughbred race-horses: clinical
      observations].
AB  - Recurrent or chronic urticaria seems to be a food allergy in thoroughbred race
      horses during the training season. In resistant cases, allergologic techniques
      will be required to determine aetiology. Intradermal skin tests with fresh
      allergenic food may cause syndromic reaction as urticaria and akin to enteritis
      in some horses. In most cases, an elimination of the allergen responsible brings
      a rapid and long-lasting result. Study about 22 cases.

PMID- 15015747
TI  - [Idiopathic anaphylaxis].
AB  - Idiopathic anaphylaxis (IA) has been described as a clinical entity by North
      America authors. The symptoms are brisk and relapsing episodes of angioedema,
      urticaria, bronchospasm, digestive symptoms, cardio-vascular collapse. Adults,
      females more than males, are mainly concerned. The seriousness is linked to
      laryngeal angioedema or to hypotension. Nevertheless lethality is rare. The first
      step of the procedure is aimed at the detection of several rare pathologies
      mimicking IA: the paroxystic capillary leak syndrome induced by a monoclonal
      gammapathy or by a release of cytokines, a carcinoid syndrome, cutaneous or
      visceral mastocytosis, hereditary or acquired deficiency of C1 esterase
      inhibitor, relapsing benign flushes and factitious anaphylaxis. These diseases
      being excluded, the diagnosis of anaphylaxis is established, and the diagnostic
      process searches for exceptional causes: food allergy elicited by unusual
      trophallergens, exercise-induced anaphylaxis, allergy to parasitic antigens, to
      inhalants, or hormonal allergy. The negativity of thorough investigations
      establishes the plausibility of IA. Several unconfirmed pathogenic hypotheses
      have been put forward: abnormal easiness to non specific release of mediators
      from mast cells and/or basophils, anti-IgE antibodies as a specific kind of auto
      immunity, angiotensin II deficiency. Treatment of emergency relies on self
      administration of epinephrine. A daily therapeutic regimen using corticosteroids
      and anti-H1 drugs is currently prescribed and can be efficient, but no randomized
      studies have asserted the validity of this management. The lack of immunological
      studies, contrasting with numerous clinical reports, questions whether IA is
      really an entity or solely anaphylaxis in search of unknown eliciting allergenic
      agents.

PMID- 15015748
TI  - [From atopic dermatitis to asthma: the development of atopy. Environmental risk
      factors].

PMID- 15015749
TI  - [Allergic conjunctivitis: diagnosis and treatment].
AB  - Allergic conjunctivitis are the most frequent presentation of ocular allergy.
      They concern two specialists, ophthalmologists and allergists, who must establish
      a close collaboration, to succeed in an etiological diagnosis and consequent
      efficacious treatment. On one hand the history of allergy must be deep and on the
      other a simple pollen etiology giving simple functional signs: skin tests (pricks
      or epicutaneous) after a flawless questioning, at need completed by the
      measurement of specific and total IgE titres in the tears and even sometimes by a
      conjunctival provocation test, minimal other ophthalmological examination,
      researching anomalies in the tear level and signs of cellular suffering (Break-up
      time: time of rupture of the tear film). The differential diagnosis falls into
      the field of the ophthalmologist: traumatic or infectious conjunctivitis
      (herpes), vernal kerato-conjunctivitis for acute conjunctivitis; dry eye, viral
      conjunctivitis, anomalies of convergence for the most frequent signs of chronic
      conjunctivitis. The treatments are symptomatic to relieve the patient, eye
      lotions without preservatives for long term treatment and etiological that
      include allergen avoidance, without forgetting specific desensitisation (mites,
      pollens) that may need a rigorous indication.

PMID- 15015750
TI  - An agent-based model of sleeping sickness: simulation trials of a forest focus in
      southern Cameroon.
AB  - An agent-based model (AMB) used to simulate the spread of Human African
      Trypanosomiasis is presented together with the results of simulations of a focus
      of the disease. This model is a completely spatialized approach taking into
      account a series of often overlooked parameters such as human behaviour (activity
      related movements), the density and mobility of the disease vectors--tsetse flies
      (Glossina spp.)--and the influence of other tsetse feeding hosts (livestock and
      wild animal populations). The agents that represent humans and tsetse flies move
      in a spatially structured environment managed by specialized location agents.
      Existing compartmental mathematical models governed by differential equations
      fail to incorporate the spatial dimension of the disease transmission.
      Furthermore, on a small scale, transmission is unrealistically represented by
      entities less than one. This ABM was tested with data from one village of the
      Bipindi sleeping sickness focus (southern Cameroon) and with obtained realistic
      simulations of stable transmission involving an animal reservoir. In varying
      different spatial configurations, we observe that the stability of spread is
      linked to the spatial complexity (number of heterogeneous locations). The
      prevalence is very sensitive to the human densities and to the number of tsetse
      flies initially infected in a given location. A relatively low and durable
      prevalence is obtained with shortening the phase I. In addition, we discuss some
      upgrading possibilities, in particular the linkage to a Geographical Information
      System (GIS). The agent-based approach offers new ways to understanding the
      spread of the disease and a tool to evaluate risk and test control strategies.

PMID- 15015751
TI  - [Effect of dehydration on nitric oxide, corticotropic and vasopressinergic axis
      in rat].
AB  - Effect of dehydration on nitric oxide, corticotropic and vasopressinergic axis in
      rat. The purpose of our work is to study, in the male 'Wistar' rat, the effects
      of a chronic dehydration, by deprivation of water for three days out of four,
      during four repeated cycles, on the evolution of certain blood variables, on the
      activities of both corticotropic and vasopressinergic axis and on the synthesis
      of nitric oxide. The chronic dehydration causes a considerable reduction of the
      body weight, an activation of the vasopressinergic axis and an increase in the
      circulating rates of the nitrates/nitrites, which represent the final metabolites
      of the reaction of oxidation of nitric oxide. The pituitary-adrenal axis is not
      statistically affected by the chronic dehydration. This seems to be in favour of
      a possible adaptation of corticotropic axis to chronic water deprivation. The
      activation of synthesis of nitric oxide shows its implication in the regulation
      of the water balance and its buffer effect on vasoconstriction and hypertension
      induced by water stress.

PMID- 15015752
TI  - Electron microprobe analysis into interactions of a resin-modified glass-ionomer
      cement and a modified composite with human dentin in vitro.
AB  - When materials used in restorative dentistry, such as a glass-ionomer cement or a
      compomer, were applied to dentin, ion exchanges occur between the material and
      the dentin. This work is based on an assessment in vitro of the ion exchanges
      occurring over time between (i) a glass-ionomer cement and dentin and (ii) a
      compomer and dentin. An electron microprobe analysis, technique not previously
      used for such a study, permitted qualitative and quantitative analysis of the
      interface and of the peripheral dentin. Analysis of the distribution of the
      elements in the interface and nearby showed continuous, progressive exchanges
      between the glass-ionomer cement and the dentin and absence of diffusion between
      the compomer and the dentin.

PMID- 15015754
TI  - Habitat selection and density of couas in Madagascar: implication for their
      conservation.
AB  - The forests in Madagascar are threatened by logging and burning. Because of their
      importance for biodiversity conservation, monitoring their animal populations is
      also important. We worked at two stations in the western dry forest where we
      studied three species of terrestrial couas in several forest plots, which
      differed in their degradation state. Some were burnt; others were logged. By
      measuring vegetation characteristics and bird densities, it was possible to
      indicate which characteristics were important for these birds and which
      conservation measures would be necessary to apply for this forest.

PMID- 15015753
TI  - Multiple co-inertia analysis: a tool for assessing synchrony in the temporal
      variability of aquatic communities.
AB  - Multitable techniques are rarely used for investigating patterns in ecological
      data surveys despite their ability to deal with the spatial and/or temporal
      stability of assemblages. Based on a covariance optimisation criterion, Multiple
      Co-inertia analysis (MCOA) enables the simultaneous ordination of several tables.
      Such analysis allows the representation of the stable vs. unstable part of the
      assemblage structure in comparison to a reference derived from each table. We
      used MCOA on multiple time series of invertebrate sampling to show that synchrony
      in the temporal variability of communities can establish between geographically
      distant locations despite the spatial and temporal plasticity of the faunistic
      responses to long-term changes in environmental conditions.

PMID- 15015755
TI  - [Intertidal macrozoobenthos evolution of the "Baie des Veys' between 1985 and
      2000].
AB  - Intertidal macrozoobenthos evolution of the 'Baie des Veys' between 1985 and
      2000. The distribution of intertidal macrozoobenthos in the 'Baie des Veys'
      (French coast of the eastern English Channel) has been studied in 2000. Results
      were compared with those of 1985, which are included in a long-term monitoring
      program established since 1973. The populations remained distributed along an
      estuarine-marine gradient, with a particularity on the eastern side, which is
      isolated from the rest of the bay by a river channel. The western and central
      tidal flats became more subjected by marine influence, which led to a
      homogenisation of the benthic communities. Oyster farming locally caused a fast
      decrease of the typical eastern community, which was characterized by Scoloplos
      armiger and Urothoe poseidonis.

PMID- 15015756
TI  - A subterranean generalist predator: diet of the soil-dwelling caecilian
      Gegeneophis ramaswamii (Amphibia; Gymnophiona; Caeciliidae) in southern India.
AB  - Biologists have paid relatively little attention to subterranean predators,
      especially their ecology. Although diets of some subterranean lower vertebrates
      suggest specialisation, there remains a lack of quantitative data. The diet of
      the caecilian amphibian Gegeneophis ramaswamii was investigated through analyses
      of gut contents of 67 specimens collected in randomised surveys at three
      localities in Kerala, southern India, in early and mid-monsoon. Although termites
      were the most frequently ingested items in the mid-monsoon, the specialist
      predator hypothesis was rejected because of differences in diet found in early
      monsoon samples, when earthworms contributed the greatest mass. That guts of some
      G. ramaswamii contained many individuals of only a single dietary taxon was
      interpreted as feeding on patchily distributed prey rather than specialisation.
      No ontogenetic differences in diet were apparent, but more sampling is required
      to investigate this further. Subadults largely feed on fewer items of the same
      prey as adults, though there is an indication that subadult diet is less diverse.
      The data do not support differences between male and female diet. High densities
      of G. ramaswamii, and perhaps of other terrestrial caecilians and subterranean
      lower vertebrates feeding on soil-ecosystem engineers (termites, earthworms and
      ants), might substantially impact soil ecology.

PMID- 15015757
TI  - Humicolous microcharmid scorpions: a new genus and species from Madagascar.
AB  - A new genus and species of humicolous microcharmid scorpion are described on the
      basis of a single specimen collected in the Ankarana Reserve, Madagascar. New
      considerations regarding the taxonomy and morphology of micro-buthoid Malagasy
      scorpions are proposed, based mainly on the study of the peg-shaped sensillae of
      the pectines by scanning electron microscopy.

PMID- 15015758
TI  - Web-building management in an orb-weaving spider, Zygiella x-notata: influence of
      prey and conspecifics.
AB  - According to optimal foraging theory, spiders should adapt their web building to
      environmental variations. Until now, there was no data on the influence of
      simultaneous information coming from different environmental factors on web
      building behaviour. Under laboratory conditions, we studied the behaviour of
      Zygiella x-notata in the presence of prey, conspecifics, or both simultaneously.
      There was a stimulating effect of prey, but web building was not affected by the
      presence of conspecifics. When spiders and prey were present simultaneously, the
      effect was similar to that of prey alone; it seemed that there was no interactive
      influence of both factors. We discussed about the use of environmental
      information by spiders in foraging behaviour.

PMID- 15015759
TI  - Determination of safety levels of horseradish peroxidase-iodide system to human
      gingival keratinocytes and fibroblasts in vitro.
AB  - The peroxidase-iodide (I-) system is a potential antimicrobial agent, and its
      bacteriocidal activity against various periodontal bacteria has been shown in
      many studies. The aim of this study was to investigate the possible cytotoxic
      effects of a non-physiological horseradish peroxidase (HRP)-I- system on human
      gingival keratinocytes and fibroblasts. Immortalized human skin keratinocyte cell
      line was used as a reference. Three indicators were studied: membrane
      permeability (trypan blue staining), cell growth (crystal violet staining) and
      metabolic activity (alamarBlue stain). The cells were cultured in microtitration
      plates, and the most commonly used exposure time to the HRP system was 1 h. The
      effects of HRP system on cell growth and metabolic activity were observed at
      lower I- and H2O2 concentrations than its effects on membrane permeability.
      Gingival fibroblasts were more prone to detachment than keratinocyte cell lines,
      but no differences in changes of growth or metabolic activities were observed
      between gingival fibroblasts and gingival keratinocytes. The highest
      concentrations of the HRP-I- system components which did not have any significant
      detrimental effects on the metabolic activity and cell growth of gingival
      keratinocytes and fibroblasts were: 50 microg/ml HRP, 500 micromol/L I- and 500
      micromol/L H2O2. Although this system has been shown to be antibacterial against
      oral bacteria, no recommendations about the usage of the HRP-I- system in oral
      cavity can be made yet due to the in vitro nature of this study. Our results form
      the basis for future safety studies investigating the chronic toxicity of this
      system to oral epithelium.

PMID- 15015760
TI  - Adaptation of subcellular glutathione detoxification system to stress conditions
      in choline-deficient diet induced rat fatty liver.
AB  - The response of fatty liver to stress conditions (t-butyl hydroperoxide [t-BH] or
      36 h of fasting) was investigated by assessing intracellular glutathione (GSH)
      compartmentation and redox status, GSH peroxidase (GSH-Px) and reductase (GSSG
      Rx) activities, lipid peroxidation (TBARs) and serum ALT levels in rats on a
      choline-deficient diet. Baseline cytosolic GSH was similar between fatty and
      normal livers, while the mitochondrial GSH content was significantly lower in
      fatty livers. With the except of cytosolic GSH-Px activity, steatosis was
      associated with significantly higher GSH-related enzymes activities. Liver TBARs
      and serum ALT levels were also higher. Administration of t-BH significantly
      decreased the concentration of cytosolic GSH, increased GSSG levels in all the
      compartments, and increased TBARs levels in cytosol and mitochondria and serum
      ALT; all these alterations were more marked in rats with fatty liver. Fasting
      decreased the concentration of GSH in all the compartments both in normal and
      fatty livers, increased GSSG, TBARs and ALT levels, and decreased by 50% the
      activities of GSH-related enzymes. Administration of diethylmaleimide (DEM)
      resulted in cytosolic and microsomal GSH pool depletion. Administration of t-BH
      to DEM-treated rats further affected cytosolic GSH and enhanced ALT levels,
      whereas the application of fasting to GSH depleted rats mainly altered the
      mitochondrial GSH system, especially in fatty livers. This study shows that fatty
      livers have a weak compensation of hepatic GSH regulation, which fails under
      stress conditions, thus increasing the fatty liver's susceptibility to oxidative
      damage. Differences emerge among subcellular compartments which point to
      differential adaptation of these organelles to fatty degeneration.

PMID- 15015761
TI  - Prophylactic action of melatonin against cyclophosphamide-induced oxidative
      stress in mice.
AB  - The present study investigated the prophylactic influence of melatonin against
      cyclophosphamide-induced oxidative stress in mouse tissues. Lipid peroxidation,
      reduced glutathione (GSH), glutathione disulphide (GSSG), glutathione peroxidase
      (GSH-Px) and serum phosphatase levels were analyzed in brain, spleen liver,
      lungs, kidney and testes. Fifteen days oral administration with melatonin (0.1
      mg/kg bw per day) before treatment checked the augmentation of the level of lipid
      peroxidation, blood GSSG and acid phosphatase caused by an acute treatment with a
      radiomimetic drug, cyclophosphamide (75 mg/kg bw). Cyclophosphamide-induced
      depletion in the level of GSH, GSH-Px and alkaline phosphatase was made up
      statistically significant by chronic melatonin administration given orally. The
      results indicate the antioxidative properties of melatonin resulting into its
      prophylactic property against the cyclophosphamide-induced biochemical
      alterations. The finding support the idea that melatonin is a potent free-radical
      scavenger and antioxidant.

PMID- 15015762
TI  - Caspase-6 mediated cleavage of guanylate cyclase alpha 1 during deoxycholate
      induced apoptosis: protective role of the nitric oxide signaling module.
AB  - Hydrophobic bile acids such as deoxycholate are known tumor promoters in the
      gastrointestinal tract. We have previously shown that deoxycholate induces
      apoptosis in colon epithelial cells and that these cells can be made resistant to
      deoxycholate-induced apoptosis. We now show that the nitric oxide synthase/nitric
      oxide/guanylate cyclase/cyclic guanosine monophosphate/cGMP-activated protein
      kinase (NOS/NO/GC/cGMP/PKG) signaling module contributes, in part, to the
      observed resistance of the cultured DOC-resistant colon epithelial cells (HCT
      116R) using pharmacological inhibitors/antagonists (NS2028, Rp-8pCPT-cGMP,
      KT5823) of members of this signaling module. A novel finding from this study is
      the caspase-6 mediated cleavage of guanylate cyclase alpha 1 during deoxycholate
      induced apoptosis of deoxycholate-sensitive HCT-116SA cells and the absence of
      guanylate cyclase alpha 1 cleavage in deoxycholate-treated HCT-116R resistant
      cells using Western blot analyses. This cleavage was specific to caspases as
      lysosomal, proteasomal, serine protease, cathepsin and calpain inhibitors failed
      to prevent the cleavage, whereas a general caspase inhibitor and a specific
      caspase-6 inhibitor did prevent guanylate cyclase alpha 1 cleavage.

PMID- 15015763
TI  - Alpha-difluoromethylornithine, ornithine decarboxylase inhibitor, antagonizes
      H2O2-induced cytotoxicity in HL-60 leukemia cells: regulation of iron-dependent
      lysosomal damage.
AB  - Recent studies indicate that reactive oxygen species, such as H2O2, can be
      generated by anti-cancer drugs, can damage cells, and then induce apoptotic cell
      death. In this study, we reported whether polyamines were capable of affecting
      apoptotic cell death triggered by H2O2 in leukemia cells or not. Alpha
      difluoromethylornithine treatment (DFMO, 3 mmol/L, 48 h), which depletes
      intracellular putrescine by inhibiting ornithine decarboxylase, reduced H2O2
      induced cell death in the HL-60 leukemia cells. Cytotoxicity caused by H2O2 in
      putrescine-depleted cells was 50% lower than that in the control cells, as
      determined by propidium iodide, the annexin V and DNA fragmentation assays.
      Following putrescine (1 mmol/L) supplement, cell death induction caused by H2O2
      was restored to a similar level as the DFMO-untreated control cells. It seems
      that this partly resulted from the intralysosomal iron-dependent oxidation of the
      cells because DFMO did not significantly affect the increment of enzymes related
      to oxidative-stress resistance. Putrescine depletion by DFMO treatment reduced
      the cellular iron uptake of the cells by about 70%. In parallel to the reduction
      of iron uptake, lysosomal damage (assayed by acridine orange relocalization or
      uptake test) in the DFMO-treated cells was far less than that in the control
      cells. Moreover, putrescine supplement also restored the iron uptake to the
      control cell levels. Pre-incubation with desferrioxamine (DFO), which chelates
      iron and forms a non-reactive Fe-DFO complex that is localized in the lysosomal
      compartment, inhibited H2O2-induced cell death. This work suggests that
      polyamines may play a critical role in apoptotic cell death triggered by H2O2 via
      the regulation of the iron-dependent instability of the lysosome.

PMID- 15015764
TI  - Identification of HLA a*0201 glioblastoma multiforme cell lines for immunotherapy
      by PCR-SSP and DNA sequencing.
AB  - Most tumor specific antigens characterized to date are restricted by HLA a*0201,
      which is the major HLA subtype in many ethnic groups. Cancer cells that express
      tumor antigens in association with the HLA a*0201 subtype have been shown to be
      responsive to various immunotherapies. We therefore sought to identify glioma
      cell lines that also express this HLA subtype and determine whether they had the
      molecular properties needed for tumor-peptide presentation. The HLA a*0201 allele
      was identified with PCR using sequence-specific primers followed by DNA
      sequencing. With this method, we screened 15 glioma cell lines to determine if
      they were of the HLA a*0201 genotype. Glioma cell lines that express the HLA
      a*0201 subtype were further studied for the expression of MHC class I and beta-2
      microglobulin (beta2m) molecules by flow cytometry, and peptide presentation
      molecules TAP-1, TAP-2, and tapasin by RT-PCR. We identified six out of fifteen
      cell lines that were of the HLA a*0201 subtype. These cell lines are U87, T98,
      U373, U138, CRL2365 and UMN-4. All these six cell lines exhibited high levels of
      MHC class I and beta2m molecules. In addition, these cell lines all expressed
      molecules required for peptide presentation as shown by the presence of peptide
      presentation-related molecules TAP-1, TAP-2 and tapasin. The identification of
      glioma cell lines that express the HLA a*0201 subtype along with the necessary
      molecules for peptide-presentation will enable their use in developing new
      immunotherapeutic approaches for treating brain tumors. The method used to
      identify HLA a*0201 glioma cells is rapid and inexpensive, and suitable for
      screening tumor cells.

PMID- 15015765
TI  - Transforming growth factor-beta effects on meningioma cell proliferation and
      signal transduction pathways.
AB  - The role of transforming growth factor-beta (TGF-beta) in regulation of
      meningioma growth and intracellular events transducing its signals are not
      established. In this study, we evaluated the effects of TGF-beta1 on basal
      meningioma cell proliferation in 10 primary human meningioma cell cultures and
      whether TGF-beta's signals are transduced by the Smad 2/3, MAPK/Erk kinase-1 (MEK
      1)-mitogen-activated protein kinase (MAPK), Akt-p70(S6K) or p38-JUNK pathways in
      5. We also tested whether neutralizing antibodies to TGF-beta alter CSF
      stimulation of meningioma cell proliferation. On average, TGF-beta reduced
      meningioma cell [3H]-thymidine incorporation to 58% of controls at 24% and to 61%
      of controls at 36 h. TGF-beta inhibition of meningioma cell proliferation was
      associated with a suggestion increased phosphorylation of Smad 2/3 in 2 cases and
      high basal phosphorylation in 3 but no change in activation of the MEK-1-MAPK,
      Akt-p70(S6K) or p38-JUNK pathways. As shown previously, CSF stimulated meningioma
      cell proliferation in the 3 cultures tested. Neutralizing antibody against TGF
      beta augmented this stimulation in 2 of 3 cultures. These findings suggest that
      TGF-beta exerts a largely inhibitory effect on basal meningioma proliferation,
      perhaps in part through Smad 2/3.

PMID- 15015766
TI  - Pleomorphic xanthoastrocytoma: a developmental glioneuronal tumor with prominent
      glioproliferative changes.
AB  - Pleomorphic xanthoastrocytoma (PXA) is a rare primary brain tumor, which usually
      involves the superficial cortex in children and young adults. Although PXA is
      considered an astrocytic tumor, recent studies suggest the presence of neuronal
      differentiation and an origin from multipotential precursor cells. To clarify the
      clinicopathological characteristics, which have not been well established due to
      the rarity of this tumor, eight cases of histologically proven PXA were
      retrospectively analyzed, paying special attention to immunohistochemical
      findings and associated cortical dysplasia. Three males and five females of
      median age 17 years (range, 11-24 years) were enrolled in the study. All patients
      presented with epilepsy. Tumor sites included the temporal (n = 5), frontal (n =
      2), and temporoparietal (n = 1) lobes. 18F-FDG PET (positron emission tomography)
      showed hypometabolism of PXA. Immunohistochemical study was performed in six
      cases using various antibodies for glial and neuronal markers. Gross total
      resection of the PXA was achieved in all cases. The follow-up period ranged from
      7 to 14 years except for two recent cases. All patients are doing well with
      neither radiological nor clinical evidence of recurrence. The surgical treatment
      rendered all patients seizure free. The three temporal lobe PXAs were associated
      with cortical dysplasia. In one tumor, clusters of dysmorphic ganglion cells were
      found. All examined PXAs demonstrated immunoreactivity for both neuronal and
      glial markers in the various tumor cells. The immunohistochemical studies
      undertaken as a part of this study support the proposed astrocytic and neuronal
      differentiation of PXA, and indicate that PXA is probably a developmental
      neuroglial tumor with prominent glioproliferative changes associated with focal
      cortical dysplasia. Cortical dysplasia may be a cause of persistent epilepsy even
      after complete surgical excision of PXA.

PMID- 15015767
TI  - Matrix metalloproteinase-2 and matrix metalloproteinase-9 expressions correlate
      with the recurrence of intracranial meningiomas.
AB  - BACKGROUND: We studied whether or not the expressions of MMP-2 and MMP-9 were
      correlated with the proliferative potential or recurrence of intracranial
      meningiomas. METHODS: The expressions of MMP-2 and MMP-9 of 56 meningioma tissues
      were examined and scored by immunohistochemistry (IHC). Expressions of the mRNA
      of each MMP were also examined by reverse transcriptase polymerase chain reaction
      (RT-PCR) assay in 15 cases. The relationships between IHC score and each of age,
      sex, tumor location, histology, MIB-1 labeling index (LI), and recurrence or
      regrowth rate were studied. RESULTS: Nine of 56 cases showed recurrence or
      regrowth. IHC revealed that MMP-2 was highly expressed in 13 of 56 cases, whereas
      MMP-9 was highly expressed in 22 of 56 cases. Among the 15 cases analyzed by RT
      PCR assay, MMP-2 and MMP-9 were expressed in 9 and 13 cases, respectively. Based
      on the Kaplan-Meier curve, the high expressions of MMPs were related to
      recurrence/regrowth (MMP-2: p < 0.001; MMP-9: p < 0.05). No significant
      relationship was observed between the expressions of MMPs and either age, sex,
      tumor location, or MIB-1 LI. CONCLUSIONS: Our study indicated that MMP-2 and MMP
      9 expressions are prognostic factors predicting the recurrence of meningioma,
      independent of proliferative potential.

PMID- 15015769
TI  - Increased hMSH2 protein expression in glioblastoma multiforme.
AB  - hMSH2 and hMLH1 are the most commonly studied mismatch repair proteins and their
      absence is associated with microsatellite instability (MSI) especially in
      hereditary non-polyposis colorectal cancer, and also in some sporadic tumors.
      However, there are some tumors, namely, urothelial neoplasms and salivary gland
      tumors, where overexpression of the proteins has been reported, though the
      implications of these findings are not very clear. There is no report on the
      expression of these proteins in different grades of human astrocytic tumors. We
      have studied the expression pattern of hMSH2 and hMLHI in high (Grade IV,
      glioblastoma multiforme (GBM)) and low (Grade II, astrocytoma (AS)) grade primary
      human gliomas by immunohistochemistry. We observed that there was a significantly
      higher expression of hMSH2 protein in 28 GBM (mean 703.07 +/- 236.28) as compared
      with 27 AS (mean 307.03 +/- 204.71), p = 1.47 x 10(-8) by a two-tailed t-test of
      unpaired samples. However, for hMLH1 no such difference was observed, mean counts
      being 543.29 +/- 320.35 for 27 GBM and 505.92 +/- 342.37 for 26 AS, p = 0.67. A
      small proportion of tumors was observed to be immunonegative for either of the
      proteins in both high- and low-grade tumors. While MSI has been shown previously
      to be infrequent in human astrocytic tumors, the implications of the
      overexpression of hMSH2 in GBM are not clear.

PMID- 15015768
TI  - Effects of combined granulocyte-macrophage colony-stimulating factor (GM-CSF),
      interleukin-2, and interleukin-12 based immunotherapy against intracranial glioma
      in the rat.
AB  - Cytokines play a major role in the regulation of the immune system. Granulocyte
      macrophage colony-stimulating factor (GM-CSF) has been shown to be useful for
      immunotherapy against glioma because it can stimulate dendritic cells to present
      tumor antigen. Interleukin-2 (IL-2) is involved in T-cell expansion, and
      interleukin-12 (IL-12) drives the T-helper cell type I response. Previous studies
      have shown that each of these cytokines alone can induce the regression of tumor
      cells. In the present study we postulated that peripheral infusion of GM-CSF
      along with either IL-2 or IL-12 and irradiated tumor cells can lead to increased
      survival from 9L brain tumors. 9L gliosarcoma cells (10(6)) were implanted in the
      brains of syngeneic Fischer 344 rats. Osmotic minipumps were utilized for
      subcutaneous, continuous delivery of GM-CSF, either alone or with IL-2 or IL-12.
      Irradiated 9L cells were injected subcutaneously at various time points during
      treatment. Delayed-type hypersensitivity (DTH) and immunohistological analysis
      were used to further characterize the anti-tumor response. Treatment with GM-CSF
      and irradiated tumor cells led to an increase in survival rate in rats with
      intracranial 9L tumors when compared to untreated animals. The addition of IL-2
      or IL-12 to the GM-CSF/tumor cell therapy further increased the survival rate up
      to 90%. The anti-tumor response was associated with vigorous DTH against 9L cells
      and increased infiltration of CD4+ and CD8+ lymphocytes into the tumor. These
      results suggest that the combined infusion of GM-CSF and other cytokines may be
      effective adjuvants in treating brain tumors.

PMID- 15015770
TI  - Diagnostic impact of ornithine decarboxylase in meningiomas.
AB  - The objective of this study was to investigate whether activity and protein
      expression of ornithine decarboxylase (ODC) the metabolism-rate limiting enzyme
      of the polyamine biosynthesis, which is involved in the regulation of cellular
      growth and differentiation, reflects the distinct histopathologic characteristics
      indicative of atypia and anaplasia in meningiomas as well as their impact in
      recurrences. The authors previously evaluated its value as a critical factor of
      tumor development in various brain tumors. Among 152 meningiomas, World Health
      Organisations (WHO) grade I meningiomas (n = 121) exhibited a low ODC activity,
      while meningiomas WHO grade II (n = 22) and WHO grade III (n = 9), respectively,
      showed a significantly increased ODC activity. Recurrent WHO grade I meningiomas
      exhibited the same low enzyme activity and immunohistochemical staining index for
      ODC positive tumor cells as their primary tumors, whereas raising ODC activity
      and protein expression in recurrent meningiomas paralleled malignant
      transformation. These results indicate that ODC reflects aggressive growth and
      malignization in meningiomas. Especially in recurrent meningiomas, the
      determination of its activity and protein expression by immunohistochemistry may
      provide a useful diagnostic tool to recognize malignant progression.

PMID- 15015771
TI  - Multidrug resistance-associated protein MRP1 expression in human gliomas:
      chemosensitization to vincristine and etoposide by indomethacin in human glioma
      cell lines overexpressing MRP1.
AB  - The 190 kDa multidrug resistance protein MRP1 is likely to be involved in the
      multidrug resistance phenotype of human gliomas. MRP1 expression was evaluated in
      surgical tumor samples from 17 patients with gliomas. In addition, the impact of
      the MRP's inhibitor, indomethacin, on the chemosensitivity to etoposide (VP16)
      and vincristine (VCR) of two glioblastoma cell lines expressing MRP1 (GL15 and
      8MG) was investigated. When evaluated in tumor samples, MRP1 expression was
      observed in all of them with more than 90% of stained tumor cells in 14/15 high
      grade gliomas. MRP1 was also strongly expressed at the membrane of the vascular
      endothelial cells in the same 14 tumor samples, suggesting that the permeability
      to anticancer drugs could be also limited across brain tumor vessels. At
      concentrations comprised between 5 and 50 microM, indomethacin significantly
      increased the cytotoxic effect of etoposide in both cell lines but it was more
      efficient in increasing the cytotoxicity of VCR on GL15 cells, as compared with
      8MG cells. These results suggest that the association of indomethacin to VCR or
      etoposide could be of interest in the clinical management of gliomas.

PMID- 15015772
TI  - Induction of apoptosis in resistant glioma cells by synthetic caspase-activation.
AB  - The detailed mechanisms behind the resistance of malignant gliomas to therapy are
      not known. Inherent resistance to apoptosis is, however, one plausible
      explanation. In the present study we tried to delineate the molecular defects and
      to induce apoptosis by inducible caspases in three apparently apoptosis resistant
      glioma cell lines. U-105 MG, U-251 MG, and SF-767 were resistant to Fas-induced
      apoptosis as shown by the lack of Fas-induced cell death, morphological changes,
      annexin-V reactivity, Parp cleavage, caspase-3 cleavage, and caspase-3
      activation. The glioma cells showed no consistent down-regulation of the pro
      apoptotic proteins Fas, Fadd, caspase-3, caspase-8, caspase-9, Apaf-1, Bid, Bad,
      or Bax, and no consistent up-regulation of the anti-apoptotic proteins Bcl-x or
      Bcl-2. In U-105 MG, Fas was, however, not detected at the cell surface indicating
      intracellular retention. To assess if the apoptotic blocks could be by-passed, we
      introduced the so-called artificial death switches, i.e., inducible caspases and
      Fadd, into the glioma cells. Synthetic activation of inducible caspase-3, but not
      of caspase-8, resulted in apoptosis in the three glioma cell lines and inducible
      Fadd induced apoptosis in SF-767. The results were consistent with a block in the
      apoptotic signaling pathways of glioma cells between caspase-8 and caspase-3
      activation, and that inducible Fadd could induce caspase-8 independent apoptosis
      in some cells. Apparently resistant glioma cells could thus be induced to undergo
      apoptosis by activation of appropriate death switches. This might have
      implications for the design of future therapeutic strategies.

PMID- 15015773
TI  - Metastatic lung disease to the central nervous system: in vitro response to
      chemotherapeutic agents.
AB  - BACKGROUND: Metastatic lung disease to the central nervous system (CNS) comprises
      a significant percentage of cranial metastases. For those cases where
      chemotherapy may be of palliative or therapeutic benefit, in vitro chemoresponse
      testing may identify the agent(s) most likely to be effective clinically.
      METHODS: Tumor-derived cell cultures were established from 14 surgically excised
      lung lesions metastatic to the CNS. In vitro chemoresponse testing was performed
      with a variety of anticancer agents on the tumor cells that grew out of the
      cultured tissue specimens. Drug concentrations and exposure times were adjusted
      to bracket approximate average peak plasma levels that are observed typically in
      vivo. For each tumor-derived cell culture, a complete dose-response curve was
      established for each chemotherapeutic agent tested. RESULTS: Approximately 80% of
      the 14 tumor cell cultures had a definitive response to one or more
      chemotherapeutic agents in vitro, with approximately one-third of these cultures
      displaying a response to at least three of the drugs tested. There was
      considerable heterogeneity in the response of individual tumor cell cultures to
      the chemotherapeutic drugs. The agents that showed the highest cytotoxic response
      rate against the individual tumor cell cultures included lomustine, carboplatin,
      cisplatin and etoposide. CONCLUSIONS: The tumor cells isolated from individuals
      with lung lesions metastatic to the brain demonstrated differential
      chemoresponses to the agents tested. No single agent was effective against every
      tumor cell culture. These data suggest that in vitro chemoresponse testing of
      cultured tumor cells may be useful to identify biologically effective
      chemotherapeutic agents for individual patients, thereby addressing at least one
      factor in this complex therapeutic challenge.

PMID- 15015774
TI  - Drug-induced apoptosis by a matrix metalloproteinase inhibitor, SI-27 on human
      malignant glioma cell lines; in vitro study.
AB  - Matrix metalloproteinase (MMP) plays important roles in cell invasion and tumor
      angiogenesis. SI-27, an anti-MMP agent, has already been shown to possess both in
      vitro anti-invasive and anti-angiogenic properties against malignant gliomas in
      non-cytotoxic dose concentrations. However, to the best of our knowledge, the
      molecular mechanism mediating the cytotoxic action by this agent and the
      molecular mechanism in the cytotoxic action against malignant glioma cell have
      not yet been clarified. Therefore, we assessed the effect in the cytotoxic dose
      concentrations to investigate whether this cytotoxic action is related to
      apoptosis in this study. The effect on human glioma cell lines (U87MG, U251MG,
      and U373MG) was examined by transmission electron microscope, agarose gel
      electrophoresis with the DNA fragmentation, flow cytometry with FITC-conjugated
      Annexin V, and detection of caspase activity. Drug-induced apoptosis was observed
      in the cytotoxic dose. The result indicated that the cytotoxity of SI-27 might be
      related to the drug-induced apoptosis mediated by caspase.

PMID- 15015776
TI  - Inverse correlation between genetic aberrations and malignancy grade in ependymal
      tumors: a paradox?
AB  - OBJECTIVE: The goal of our study was to investigate the inverse correlation
      between number of genetic aberrations and malignancy grade in ependymal tumors at
      the ploidy level. METHODS: we examined seven myxopapillary ependymomas (mpEs)
      (WHO grade I), 28 spinal and cerebral ependymomas (Es) (WHO grade II), and 18
      cerebral anaplastic ependymomas (aEs) (WHO grade III) using image DNA cytometry.
      The ploidy status was correlated with clinicopathological characteristics and
      with the results obtained by comparative genomic hybridization (CGH) analysis
      that we performed in about half of these tumors. RESULTS: mpEs were exclusively
      located in the spinal cord and aEs in the cerebrum only, whereas Es were located
      in both the spinal cord and brain. We found aneuploidy or tetraploidy to be
      common in the group of mpEs (6 out of 7) and much less frequent in Es (6 out of
      28) and aEs (4 out of 18). Three-year postoperative survival was 100% for mpEs,
      100% for spinal Es, 92% for cerebral Es, and 33% for aEs. Our CGH results in a
      selection of these tumors revealed the highest number of genetic aberrations in
      the mpEs (average 16; n = 2), a lower number in Es (average 12; n = 11) and the
      lowest number in aEs (average 5; n = 6). Interestingly, in the group of Es and
      aEs, a high number of genetic aberrations as detected by CGH was not correlated
      with aneuploidy or tetraploidy. Three patients, all with mpEs had local seeding.
      CONCLUSION: These results underline that mpEs are distinctly different from Es
      and aEs at the genetic level and that extensive genomic alterations and
      aneuploidy in ependymal tumors are not in itself an indicator of malignant
      behavior.

PMID- 15015775
TI  - Neurotrophin effects on neuroblastoma cells: correlation with trk and p75NTR
      expression and influence of Trk receptor bodies.
AB  - Neurotrophins are key signalling molecules in the development of the nervous
      system. They elicit diverse cellular responses such as proliferation,
      differentiation, survival and apoptosis. Neurotrophins (NTs) bind to two
      different classes of cell surface receptors, Trk receptor tyrosine kinases and
      p75NTR, both of which are expressed by neuroblastoma cells. Neurotrophin
      signalling via Trks was shown to promote both survival and differentiation of
      neuroblastoma cells in vitro. The expression of certain Trk receptors is
      considered to be a prognostic indicator. The p75NTR receptor is the founding
      member of the Fas/TNF-R family, which is best known for its function in the
      induction of apoptosis. Its function in neuroblastomas is thus far poorly
      understood. We analysed neurotrophin receptor (NTR) expression of neuroblastoma
      cells by surface biotinylation assays and applied recombinant nerve growth factor
      (NGF), brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 to
      these cell lines assessing their survival and proliferation in long-term assays
      lasting 6 days. NGF increased proliferation of Neuro 2a cells, which express
      p75NTR but no TrkA receptors on their surface. On the other hand, SK-N-BE cell
      proliferation was decreased after NGF treatment, even though these cells also
      express p75NTR but no TrkA receptors on their surface. Interestingly,
      neurotrophin-scavenger proteins (TrkB-Fc and TrkC-Fc) as well as chemical
      blockers of Trk receptor signalling (K252a, Wortmannin, PD98059) slowed down the
      proliferation of both cell lines in medium containing serum. Taken together, our
      results indicate that p75NTR activation has diverse effects on neuroblastomas,
      depending on the specific neuroblastoma clone. In addition, our studies point
      towards TrkB-Fc or TrkC-Fc receptor bodies as useful tools to influence the
      survival of neuroblastoma cells.

PMID- 15015777
TI  - Apoptosis induction with 5-fluorocytosine/cytosine deaminase gene therapy for
      human malignant glioma cells mediated by adenovirus.
AB  - Previously, we evaluated the therapeutic efficacy of the adenovirus-mediated
      transduction of the cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) for
      malignant gliomas. However, the molecular pathways that mediate the 5-FC/CD gene
      therapy-induced cell death remains to be elucidated. In this study, we examined
      the induction of apoptosis and the role of caspases in 5-FC/CD gene therapy using
      human malignant glioma cells [Gli36delta5 (mutated p53) and U87MG (wild p53)].
      The treatment with 5-FC/CD gene-therapy-induced apoptosis both in Gli36delta5
      cells and in U87MG cells according to flow cytometric analysis. Immunoblot
      analysis revealed that caspases 3 and 9 were processed in response to 5-FC/CD in
      a concentration- and time-dependent manner, but caspase 8 was not. Each caspase 3
      and 9 inhibitor significantly reduced apoptosis triggered by 5-FC/CD, but the
      caspase 8 inhibitor did not affect apoptosis induction. 5-FC/CD significantly
      promoted the release of cytochorme c from mitochondria in a concentration
      dependent manner. These results indicate that 5-FC/CD gene therapy induces
      apoptosis in human malignant glioma cells and that the apoptotic cell death is
      mediated by the activation of mitochondrial caspase cascades involving caspases 3
      and 9. This is the first report concerning the apoptotic mechanism of 5-FC/CD
      gene therapy, and these findings could be used to increase the efficacy of
      suicide gene therapy systems for the treatment of malignant glioma.

PMID- 15015778
TI  - Autocrine pathways of the vascular endothelial growth factor (VEGF) in
      glioblastoma multiforme: clinical relevance of radiation-induced increase of VEGF
      levels.
AB  - In tumour-induced angiogenesis of gliomas, vascular endothelial growth factor
      (VEGF) and its receptors fms-like tyrosine kinase (Flt-1) and kinase-insert
      domain-containing receptor (KDR) play a major role and are promising targets for
      tumour therapy. Nevertheless, preliminary results of such therapies could not
      prove clinical efficacy and thus make a profound knowledge of VEGF regulation
      essential. Based on earlier results, which demonstrated an inhibitory influence
      of VEGF on Flt-1-expressing glioblastoma cells, in the present study we focused
      on the extent of VEGF and VEGF receptor coexpression and possible therapeutical
      consequences. Protein expression of VEGF, Flt-1 and KDR was analysed by
      immunohistochemistry in native tumour tissues of 63 glioblastomas. VEGF could be
      detected in all glioblastomas. Additionally and independently to the expected Flt
      1 and KDR expression in tumour endothelia, we found a coexpression of VEGF with
      Flt-1 in tumour cells of 46 and with KDR in 45 glioblastomas. After exposure of
      glioblastoma cells to X-ray radiation we observed a strong dose-dependent
      increase of VEGF secretion in two glioblastoma cell cultures by up to 46% and
      96%, respectively that originated from an increased VEGF mRNA expression. In
      contrast, under the same conditions secretion of HGF/SF was only slightly
      elevated and bFGF despite being strongly increased remained at very low overall
      amounts compared to VEGF. Based on previous data on an autocrine function of VEGF
      in Flt-1-expressing glioblastoma cells we hypothesise that the X-ray radiation
      induced upregulation of VEGF might result in a downregulation of tumour cell
      proliferation and thus lead to a reduced sensitivity to radiation therapy.
      Therefore our results support the idea that a combination of anti-VEGF and
      radiation therapy might prove a promising new option in fighting against one of
      the most fatal tumour types.

PMID- 15015780
TI  - MIP-1alpha antagonizes the effect of a GM-CSF-enhanced subcutaneous vaccine in a
      mouse glioma model.
AB  - Subcutaneous vaccination using granulocyte-macrophage colony-stimulating factor
      (GM-CSF)-transduced glioma cells substantially prolongs survival in the mouse
      GL261 glioma model. To potentiate the efficacy of GM-CSF-based vaccination,
      syngeneic C57BL/6 mice bearing pre-implanted intracerebral GL261 gliomas were
      vaccinated twice subcutaneously with various combinations of glioma cells
      retrovirally engineered to release GM-CSF, interleukin (IL)-4 or macrophage
      inflammatory protein (MIP)-1alpha. More than 80% of the animals vaccinated with
      GM-CSF-secreting or GM-CSF- and IL-4-secreting cells were long-term survivors (>
      120 days). Their survival was significantly prolonged compared with animals
      vaccinated with wild-type cells, which died after a median survival time of 30
      days. The combination of IL-4 with GM-CSF did not provide a survival advantage
      over GM-CSF alone, regardless of whether the animals carried a small or large
      intracranial tumor load. Further, when the animals were vaccinated with a mixture
      of GM-CSF-, IL-4- and MIP-1alpha-secreting cells, the median survival was 37
      days, and only 22% of the animals in this group were long-term survivors, similar
      to the vaccination effect of non-modified glioma cells. Thus, unexpectedly, the
      co-expression of MIP-1alpha, which was meant to attract T cells for stimulation
      by GM-CSF- and IL-4-stimulated dendritic cells, nullified the induction of an
      immune response against the GL261 glioma by a GM-CSF- and IL-4-expressing
      subcutaneous vaccine.

PMID- 15015779
TI  - CD44 expression and tumour cell density correlate with response to
      tamoxifen/carboplatin chemotherapy in glioblastomas.
AB  - In order to identify response predictors for a post-operative glioblastoma
      therapy consisting of tamoxifen, carboplatin and radiotherapy, expression of 12
      antigens was evaluated in 36 newly diagnosed tumours and 13 recurrences. Results
      were correlated with the clinical course of the disease. Antigen expression was
      assessed immunohistochemically for CD44s, TGF-beta2, TGF-alpha, progesterone
      receptor, estrogen receptor, EGFR, urokinase, urokinase inhibitor 1, CD87, p53
      protein and Ki-67. Vessel density was determined by labelling of endothelia with
      von Willebrand factor. Response to chemotherapy correlated positively with cell
      density (p < 0.05) and negatively with CD44 over-expression (p < 0.02). Further,
      a positive correlation between age and CD44 expression (p < 0.05) and a negative
      correlation between age and p53 accumulation (p < 0.01) was found. In tumour
      recurrences expression of CD44 was significantly higher in local recurrences than
      in distant multifocal recurrences (p < 0.02), suggesting that CD44 may
      predominantly be associated with cell adhesion in glioblastomas.

PMID- 15015781
TI  - Expression of somatostatin receptor mRNA in human meningiomas and their
      implication in in vitro antiproliferative activity.
AB  - Somatostatin receptors (SSTRs) have been detected in many normal and malignant
      tissues. This wide expression has been used for diagnostic, prognostic and
      therapeutic purposes. Five SSTR subtypes (SSTR 1-5) have been identified whose
      activation is responsible for the signal transduction through many different
      intracellular pathways. In the present study the expression of SSTR mRNA was
      determined by reverse-transcriptase (RT)-PCR in 42 meningiomas. About 88% of the
      tumors analyzed (37/42) were positive for at least one of the five SSTR subtypes
      displaying a variable pattern of expression of the different SSTR subtypes. SSTRI
      and SSTR2 were the most frequently mRNA detected (69% and 79% of the sample
      analyzed, respectively). The other subtypes were found in the 43%, 33% and 33% of
      cases for SSTR3, SSTR4 and SSTR5, respectively. In 22, out of 42 patients (52%)
      three or more SSTRs were detected. The expression of the different SSTR subtypes
      did not correlate with the expression of bcl-2 (apoptosis-associated protein) and
      MIB-1 (a proliferation marker), assessed by immunohistochemistry in a series of
      34 tumor samples, while a correlation between the expression of SSTR3 and p53 was
      observed (p = 0.08). To evaluate a possible role of SSTR in the control of human
      meningioma cell proliferation, seven primary cell cultures obtained from fresh
      meningioma surgical tissues, were analyzed for their proliferative behavior by
      MTT assay and for their response to SST by [3H]-thymidine incorporation. In four
      out of six tumors (in one case no SSTR were detected) the treatment with SST
      caused a significant inhibition of DNA synthesis induced by the tumor-promoter
      phorbol myristate acetate. The evidence of the expression of SSTRs, mainly of
      SSTR2, in this series of specimens we analyzed altogether with in vitro
      antiproliferative effects of SST may open interesting perspectives for the
      diagnosis and the therapy of meningiomas.

PMID- 15015782
TI  - Leptomeningeal carcinomatosis in gastric cancer.
AB  - We analyzed 19 cases of cytologically confirmed leptomeningeal carcinomatosis
      (LMC) treated at our institution over the past 11 years. LMC was the initial
      manifestation of gastric cancer in 2 patients. With the exception of 1 patient,
      the primary gastric cancer was Borrmann type III or IV, and 88% had poorly
      differentiated or signet-ring cell histology. The gastric cancer was progressive
      or a recurrent disease in most of the patients. The distribution of extraneural
      metastasis suggested that Batson's venous plexus might be the predominant route
      to the subarachnoid space. Eighty percent of the patients had multiple neuraxis
      syndrome, and the combination of brain plus cranial nerve syndrome was the most
      common manifestation. Computed tomography (CT) findings were abnormal in a minor
      proportion of the patients, while magnetic resonance imaging (MRI) revealed
      abnormality in 67% of the patients, which could help the diagnosis. LMC
      complicating gastric cancer was ultimately fatal. Median survival was very short,
      4 weeks. By univariate analysis, good performance status, intrathecal
      chemotherapy, and low CSF LDH concentration favored survival. Multivariate
      analysis revealed that the administration of CSF chemotherapy was the independent
      prognostic factor for survival.

PMID- 15015783
TI  - Solitary brain metastases from uterus carcinoma: report of three cases.
AB  - Solitary brain metastases from uterine carcinoma are uncommon. Intracranial
      metastases from uterus usually occur in widely disseminated disease. We report
      three cases of solitary brain metastasis from uterine cancer. In one of these
      patients metastasis was detected prior to diagnosis of primitive cancer. In a
      review of the literature only seven cases of solitary brain metastasis preceding
      the diagnosis of uterine cancer have been documented.

PMID- 15015784
TI  - Second-line chemotherapy with the association of liposomal daunorubicin,
      carboplatin and etoposide in children with recurrent malignant brain tumors.
AB  - Progressive or recurrent high-grade gliomas are characterized by a very poor
      prognosis, and the relevance of second-line chemotherapy is still unassessed.
      Although it has been reported that liposomal anthracyclines and carboplatin show
      some activity in these patients, their association has never been investigated.
      We have treated six children with recurrent high-grade glioma after surgery,
      radiotherapy and chemotherapy, and one child with progressive teratoid/rhabdoid
      tumor with the combination of liposomal daunorubicin and carboplatin plus
      etoposide. Five out of seven children showed a major response and the 29 month
      progression-free survival was 38%. The above regimen was feasible and children
      showed only little and transient hematological toxicity. In our opinion, these
      results justify further investigation of the above combination chemotherapy for
      recurrent or progressive malignant brain tumors in children.

PMID- 15015785
TI  - The efficacy of stereotactic radiosurgery in the management of intracranial
      ependymoma.
AB  - OBJECTIVE: A retrospective analysis was performed to determine the outcome of
      patients with intracranial ependymoma treated with stereotactic radiosurgery
      (SRS). METHODS: Nine ependymoma patients have been treated with SRS (four with
      linear accelerator and five with Gamma Knife) since 1990. Two patients had WHO
      grade III tumors, and the remaining seven had WHO grade II tumors. Eight of nine
      patients received external beam radiation therapy at some point prior to
      radiosurgery to a total median dose of 54 Gy. The radiosurgery dose ranged from
      14 to 20 Gy. RESULTS: The median follow-up was 28 months. The median age of
      patients at diagnosis was 35 years. Four patients developed progressive disease
      following radiosurgery, and two patients have died of progressive disease. The 3
      year relapse-free survival was 55.6%. The 3-year overall survival was 71.1%.
      Patients treated with radiosurgery as a component of initial treatment (generally
      as a boost following external beam) had an improved relapse-free survival (100%)
      compared to those treated with radiosurgery to salvage an external beam local
      failure (20%). CONCLUSION: SRS is an effective treatment for intracranial
      ependymoma. Further clinical trials are warranted incorporating radiosurgery as a
      component of initial management in selected ependymoma patients.

PMID- 15015787
TI  - Long term survival in a patient with recurrent malignant glioma treated with
      intratumoral infusion of an IL4-targeted toxin (NBI-3001).
AB  - Intratumoral infusion of a recombinant targeted toxin (NBI-3001) consisting of
      the receptor binding domain of human interleukin 4 (IL-4) and Pseudomonas
      aeruginosa exotoxin A is an investigational treatment for malignant brain tumors.
      This 27-year-old male patient presented with a recurrent malignant glioma WHO
      grade IV after surgery and adjuvant radiation and chemotherapy. The recurrence
      was treated with intratumoral infusion of NBI-3001 at a dose of 9 microg/ml in 66
      ml of infusate. Treatment resulted in long-term survival for 3 years after toxin
      infusion with a durable tumor response. There were some permanent neurological
      side effects resulting from toxin infusion. The patient eventually died after a
      late local recurrence of the known brain tumor. Such clinical evolution of a
      malignant glioma after a single round of immunotoxin infusion is rather unusual.
      The late local recurrence may suggest that repeated courses rather than a single
      infusion of intratumoral toxin are possibly needed for successful long-term tumor
      control.

PMID- 15015786
TI  - Malignant intracerebellar schwannoma.
AB  - The authors report an exceptional case of malignant cerebellar schwannoma in a 29
      year-old woman, explored by computed tomography and angiography; a solid and
      vascular vermian tumor was removed at operation. The histological diagnosis of
      malignant schwannoma with epithelioid areas was confirmed by immunohistological
      staining (positive S-100 protein, Leu 7 and vimentin, negative glial fibrillary
      acid protein, cytokeratin, desmin and HMB45). The patient died 8 months after
      surgery for tumor recurrence. The literature review has shown 44 cases of
      schwannomas occurring in the cerebral hemispheres, 9 within the brain stem and 14
      in the cerebellum. All but one reported cerebellar schwannomas were benign, with
      prevalence of young patients and vermian localization. The present case is the
      second reported malignant intracerebellar schwannoma.

PMID- 15015788
TI  - Phase II trial of cisplatin plus temozolomide, in recurrent and progressive
      malignant glioma patients.
AB  - We report a phase II trial of cisplatinum and temozolomide (TMZ) combination in
      recurrent malignant glioma patients. The DNA repair protein O(6)-alkylguanine-DNA
      alkyltransferase (AGAT) is important in glioblastoma resistance to alkylating
      antitumor agents. In vitro, cisplatin (CDDP) decreases MGMT activity in a time-
      and dose-dependent manner. Thirty-three recurrent malignant glioma patients (20
      GBM-13 AA) were treated at recurrence or progression with a CDDP and TMZ
      association. On days 1 and 2, iv CDDP (40 mg/sqm) was administered. TMZ (at the
      dose of 200 mg/sqm) was administered as a single oral daily-dose on days 2-6
      (starting 24 h after the first CDDP dose), the cycle was repeated every 4 weeks.
      All patients had been previously treated with surgery followed by radiotherapy
      and CDDP + BCNU chemotherapy. The primary endpoint of the study was progression
      free survival at 6 months (PFS-6). Secondary endpoints included radiological
      response and toxicities. Thirty-three patients received a total of 113 courses
      (median 3 range 1-11). Complete responses were not observed, partial responses
      were 18.8% with an additional 39.9% of stable disease. For the whole group of
      patients the PFS at 6 and 12 months was 52% and 15% with a median TTP of 33
      weeks. PFS-6 for GBM and Anaplastic astrocytoma (AA) were 35% and 69%,
      respectively. PFS-12 for GBM and AA were 13.8% and 17.3%, respectively. Median
      TTP was 21.3 and 39.5 weeks, respectively. The principal toxic effects of the
      regimen were: neutropenia (5 WHO grade IV), thrombocytopenia (4 WHO grade IV),
      nausea and vomiting.

PMID- 15015790
TI  - Long-term cognitive and MRI findings in a patient with paraneoplastic limbic
      encephalitis.
AB  - This case study describes the long-term course of behavioral alterations and MRI
      findings in a patient with a combined limbic and cerebellar paraneoplastic
      syndrome, which was associated with a squamous lung carcinoma. Clinical
      equivalents were cerebellar ataxia, as well as severe anterograde memory loss,
      frontal executive dysfunction and behavioral alterations. MRI revealed
      inflammatory changes followed by progressive atrophy affecting the cerebellum and
      both temporal lobes. Tumor surgery yielded only a partial and transient recovery
      of neurological symptoms, and paraneoplastic atrophy continued to progress
      despite radical excision of the carcinoma. This case of paraneoplastic
      encephalitis suggests that the related atrophy may present as a chronic,
      progressive, multifocal encephalopathy and that the associated cognitive
      impairments may include several cognitive domains.

PMID- 15015789
TI  - Intractable vomiting as an early clinical symptom of cerebrospinal fluid seeding
      to the fourth ventricle in patients with high-grade astrocytoma.
AB  - OBJECT: Cerebrospinal fluid (CSF) seeing of high-grade astrocytoma is common, but
      the early clinical symptoms are not well characterized. Here, we report five
      patients with disseminated high-grade astrocytoma in the fourth ventricle region
      who presented with intractable vomiting prior to the detection of the metastatic
      deposits with enhancement. PATIENTS AND METHODS: From 1994 to 2000, 133 patients
      of high-grade astrocytoma were treated in our institute and were followed up
      until December 2002. Follow-up magnetic resonance (MR) imaging was performed in
      all patients every 2-3 months. The CSF seeding was defined as leptomeningeal
      enhancement. Signs and symptoms of CSF seeding were checked at the monthly
      outpatient examination. RESULTS: Among them, 5 patients aged from 27 to 58 years
      (mean 43.8 years) with one anaplastic astrocytoma and four glioblastomas showed
      intractable vomiting without signs of high intracranial pressure as evaluated by
      MR imaging or ocular fundus examination prior to the detection of the fourth
      ventricle dissemination. Fourth ventricle dissemination appeared 1-3 months after
      vomiting in five patients. One patient with glioblastoma received gamma knife
      radiotherapy for a fourth ventricle lesion appearing as a high intensity area on
      T2-weighted imaging before the appearance of the enhanced nodule, and this lesion
      was cured. Four patients died of progression of the fourth ventricle lesion.
      CONCLUSION: Intractable vomiting may be an early clinical symptom of CSF seeding
      to the fourth ventricle in patients with high-grade astrocytoma. Early detection
      and immediate radiotherapy for this lesion are recommended to control fourth
      ventricle dissemination.

PMID- 15015791
TI  - Prognostic factors and therapeutic problems of primary intracranial
      choriocarcinoma/germ-cell tumors with high levels of HCG.
AB  - OBJECTIVE: Primary intracranial choriocarcinoma (PICCC)/germ-cell tumors (GCTs)
      with high levels of human chorionic gonadotropin (HCG) (PICCC/GCTs with HL-HCG)
      are rare and malignant. The goal of this study was to report our 3 cases of
      PICCC/GCTs with HL-HCG and to review the literature to elucidate the clinical
      problems and prognostic factors and to discuss the therapeutic modalities of this
      rare tumor. METHODS: Survival was analyzed in 66 previously reported PICCC/GCTs
      with HL-HCG including our 3 cases, of which the clinical results have been
      described in the literature since 1975. In the 66 cases (mean age: 12.1 years;
      male/female: 45/21), 35 were verified histologically as pure choriocarcinoma, 23
      were as mixed GCTs with choriocarcinoma element, and 8 were not verified as
      including choriocarcinoma element histologically but with very high HCG levels.
      Significance of the differences among survival curves concerning each parameter
      (age, sex, tumor location, serum HCG/beta-HCG level, precocious puberty, extent
      of surgery, radiotherapy, chemotherapy, mixture of other non-germinomatous GCT
      elements and extraneural metastasis) was tested using univariate and multivariate
      analyses. RESULTS: The median survival time and the 1- and 2-year survival rates
      were 22 months, 61.2% and 49.8%, respectively. In univariate analysis, male,
      subtotal removal or more, radiotherapy and chemotherapy were revealed to be
      significantly good prognostic factors. However, suprasellar region and tumor
      hemorrhage were poor prognostic factors. Multivariate analysis showed that extent
      of surgery, radiotherapy and chemotherapy were independent prognostic factors.
      CONCLUSIONS: Although, we should mind the limitations of this study design
      because of case selection bias, different treatment protocols and incomplete
      follow-up of patients, this study led the following results and suggestive
      conclusions. Tumor hemorrhage and progressive extraneural and cerebrospinal fluid
      metastasis were characteristic clinical problems of PICCC/GCTs with HL-HCG. In
      the cases with extremely elevated levels of HCG, biopsy for histological
      diagnosis may be no longer needed. Initial biopsy and radiotherapy may lead to
      tumor hemorrhage. To prevent tumor hemorrhage, gross tumor removal followed by
      radiotherapy and chemotherapy should be aimed for. A few courses of chemotherapy
      before surgery may prevent metastasis. Stereotactic radiotherapy and high dose
      chemotherapy may be promising options for treatment.

PMID- 15015793
TI  - Complete response of a recurrent, multicentric malignant glioma in a patient
      treated with phenylbutyrate.

PMID- 15015794
TI  - Varicose veins--an old dog and some new tricks.
AB  - There are many new methods to treat varicose veins being tried and tested around
      the world, many using patented techniques. They would appear to demonstrate many
      of the features a military surgeon might deem beneficial for treating a service
      population, a rapid return to duties amongst them. There are some significant
      drawbacks. All of these modalities need to offer long-term evidence of efficacy
      to demonstrate advantage over current standard. The endovenous therapies utilise
      expensive equipment that limit their introduction and provide a potential for
      novel complications as well as novel therapy. Modified sclerotherapy as described
      here has many advantages; it is incredibly cheap, minimally invasive and easily
      repeatable--in fact planned re-intervention is used in some protocols. Until long
      term results are available, it would seem premature to recommend any of these new
      treatments for use in service personnel with primary varicose veins. Military
      vascular surgeons will await these results with interest, as the service
      population would have much to gain from a modality that reliably treats the veins
      and ensures a swift return to service.

PMID- 15015792
TI  - Linear accelerator-based radiosurgery in the management of skull base
      meningiomas.
AB  - From May 1994 to December 1999, 43 patients with meningiomas in the base of the
      skull underwent linear accelerator (LINAC)-based stereotactic radiosurgery (SRS)
      at Chung Gung Memorial Hospital. SRS was performed as a primary treatment in 14
      patients, and after resection in 29 patients. The mean tumor volume was 5.68 cc,
      and the mean target surface dose was 16 Gy, delivered with an average of three
      isocenters. The median follow-up was 74.5 months. The 7-year local control rate
      and 7-year overall survival rate were 89.7% and 80.2%, respectively. The 7-year
      local control was 100% and 84.4% in SRS alone group and surgical excision with
      SRS group (p = 0.21), respectively. A stationary tumor following SRS was seen in
      23 (53.5%) patients, partial shrinkage was seen in 16 (37.2%) patients, and
      complete disappearance in one patient was seen (2.3%). Furthermore, disease
      progression was noted in three (7%) patients, one of whom died of disease. The
      median time to tumor response was 15.4 months (range 5.8-52.8 months). Cases
      remained stable or had improved neurological statuses without any deterioration
      in 37.9% and 78.7% of the groups treated with surgery and SRS and SRS alone,
      retrospectively. In summary, LINAC-based SRS is an effective and safe modality of
      treating unresectable or partially resected meningiomas in the base of the skull.
      For tumors with diameters of 3 cm or less, particularly in patients without or
      with minimal clinical neurological symptom, SRS alone can provide a good local
      control without causing cranial neuropathy.

PMID- 15015795
TI  - Consensus statement on the early management of crush injury and prevention of
      crush syndrome.
AB  - Crush Syndrome remains rare in European practice. It is however common in areas
      of civil disorder and where the normal structures of society have given way to
      civil war or natural disaster. Western Doctors are becoming increasingly involved
      in such situations and there is no reason to believe that instances due to more
      conventional causes, such as collapse in the elderly or road traffic accidents
      will cease. For all these reasons it is important that clinicians who deal
      infrequently with crush syndrome have access to appropriate guidelines. This
      consensus report seeks to provide such advice.

PMID- 15015796
TI  - Degenerative disease in lumbar spine of military parachuting instructors.
AB  - Parachuting, be it static line or skydiving, places enormous stresses on the
      human spine. It is, therefore, important to determine the prevalence and severity
      of degenerative changes in the lumbar spine of subjects who practice this sport
      activity. Seventy four parachuting instructors, mean age 33 years and with an
      average of 410 static line and skydiving jumps, were included in the study. Past
      radiographs were examined and compared to current anterolateral and lateral views
      of the lumbar spine, in order to determine the prevalence of degenerative changes
      and document possible progression. Doubtful radiographic changes in the lumbar
      spine were identified in 47.4 percent of the parachuting instructors, mild
      degeneration in 9.6 percent, moderate degenerative disease in 10.9 percent and
      severe radiographic changes in 5.5 percent. Schmorll nodes were found in 8.1
      percent of the subjects. Traction spurs--osteophytes were identified in 6.8
      percent. The degenerative changes correlated with age and the number of jumps.
      Spondylolysis of L5-S1 and L3-L4 segments were observed in 12.2 and 1.4 percent
      respectively. Progressive spondylolisthesis was found in 2 subjects. No
      correlation was found between the severity of radiographic changes and either the
      prevalence and the severity of low back pain. The present findings provide a
      rational for considering repeated sheer stress as an etiology of degenerative
      changes in the spinal cord, and as a possible contributing factor to the
      pathogenesis of spondylolysis. Further study has to be done comparing parachuting
      instructors to a non-parachuting group, or equivalent physically active
      individuals, in order to assess the effect of sport-background on the development
      of degenerative changes.

PMID- 15015797
TI  - The trends of vasectomy reversal in the forces.
AB  - A reversal of a vasectomy is required in about 3% of men who undergo vasectomy.
      We set out to examine the relationships between the age at which vasectomy was
      performed and the interval before subsequent reversal within the context of the
      armed forces. Thirty seven patients were identified from hospital records, as
      having undergone a reversal of vasectomy in the preceding two years, and thirty
      one sets of notes were available for inspection. Ages at vasectomy and at
      reversal were recorded and, where stated in the notes, if there had been a change
      in partner prior to the reversal request. Twelve (39%) men were under the age of
      thirty years at the time of their vasectomy, with a mean time to reversal of 4.4
      years. Nineteen (61%) were over the age of thirty years at time of the vasectomy
      and their mean time to reversal was 7.2 years. Where recorded, the reason for
      requesting a reversal was a change in partner in 90% of men. Men who had their
      vasectomies before reaching the age of thirty were more likely to undergo
      reversal in a significantly shorter period of time when compared to those over
      thirty years. The disseminated criteria for vasectomy should be adhered to and
      appropriate preoperative counselling by surgeons may be useful.

PMID- 15015798
TI  - Medical confidentiality and human immunodeficiency virus (HIV) infection: a
      hypothetical case.
AB  - This paper describes a hypothetical case of a HIV positive pilot. It explores
      legal and ethical aspects of medical confidentiality and discusses who, inside
      and outside military and medical circles, can be told of his condition in the
      light of the particular circumstances. Disclosure without the patient's consent
      is a serious step that should not be undertaken without advice from Service
      medico-legal departments and medical protection organisations.

PMID- 15015799
TI  - A lesson not yet learned.
AB  - OBJECTIVES: Accounts of numerous military campaigns throughout history have shown
      that casualties from medical illness usually greatly outnumber combat injuries.
      We aimed to see whether this remained the case in a modern campaign where
      predominantly surgical facilities were deployed. METHODS: We examined 1511
      hospital records of inpatients in the Oman theatre during the last three months
      of Exercise Saif Sareea II and the initial period of Operation Veritas. RESULTS:
      Of the 1399 records included, 1033 (74%) required care from a physician, whereas
      366 (26%) were treated by surgeons. However, of patients returning to duty in
      theatre (total 985), 884 (90%) had been treated by physicians and 101 had been
      treated by surgeons. Notably, only 23 (2%) of these had undergone a surgical
      procedure. CONCLUSIONS: Experience in Oman suggests that the lessons of history
      in respect of casualties in times of conflict are both unlearned and being
      repeated. The role of the medical specialities in military secondary care should
      be recognised and deployed facilities should not be defined by surgical
      capability alone.

PMID- 15015800
TI  - Impact of deployment of personnel with chronic conditions to forward areas.
AB  - AIM: To identify reasons for inappropriate deployment of soldiers with chronic
      conditions to an operational environment. SETTING: Two British Army field
      hospitals in Kuwait, 08 February to 17 March 2003, during the period of troop
      concentration prior to war-fighting (Operation Telic). POPULATION: All British
      military personnel on land during the concentration phase, rising to an estimated
      28,000 troops. METHODS: Real-time electronic record maintained of all cases
      presenting to 22 and 33 Field Hospitals judged to be inappropriately deployed.
      RESULTS: 50 sequential cases were analysed. 34% were downgraded prior to
      deployment. Of those who were P2 FE, 85% were judged to have required protection
      from deployment by down-grading. 20% of all cases had a history of chronic
      asthma, and of the asthmatics 60% (6/10) were not downgraded. 18% of all cases
      were deployed while waiting for secondary care investigation or review that
      should have ensured protection from deployment. No patient had an existing "FT"
      (forward temperate) or "LT" (lines of communication temperate) grading: but in
      four cases it was predictable that the patient's underlying condition would be
      adversely affected by deployment to a desert environment. In 5 cases it was
      identified that the inappropriate deployment could be attributed to clinical
      management within the civilian sector, with a consequent failure to institute the
      necessary downgrading process. CONCLUSIONS: Review of the medical grading process
      is needed to protect those soldiers who are awaiting outpatient opinion or
      definitive diagnosis from investigation, and to provide an employability grading
      that matches a soldier's fitness for operational role.

PMID- 15015801
TI  - The experience of the intensive care unit in a British Army field hospital during
      the 2003 Gulf conflict.
AB  - Over the last few years the Surgeon General's Department has overseen a major
      update in equipment scales for medical units in the field; anaesthesia and
      intensive care. This is to meet the aspiration of the Defence Chiefs, that
      injured servicemen on active service should receive the same standard of care as
      available in the United Kingdom. This paper discusses the experiences of the
      Intensive Care Unit operating within a Field Hospital both during the initial war
      fighting phase and subsequent peace keeping phase of the 2003 Gulf conflict (OP
      TELIC). Observations are made on patient activity, treatment strategy, and
      equipment adequacy.

PMID- 15015802
TI  - The Thomas splint--a necessary tool in the management of battlefield injuries.
AB  - The Thomas splint was developed for the stabilisation of femoral fractures at the
      end of the nineteenth century, and since the First World War has been extensively
      used by the British Army. It has been shown to improve the outcome after
      ballistic fractures of the femur, but recently there have been moves to abandon
      this device in favour of more modern splints such as the Sager splint. This is
      predominately due to the ease of use and smaller size of newer devices, which
      makes them more suitable for the pre-hospital environment. However, we present
      our experience of managing both ballistic and closed femoral injuries using
      Thomas splints during the recent Gulf Conflict. It is our belief that the Thomas
      splint is an essential tool in the management of military femoral injuries at
      role three facilities and must be retained.

PMID- 15015804
TI  - Battlefield advanced training life support. Chapter 14. Analgesia.
AB  - Resuscitation using the BATLS method comes first. Effective analgesia is an
      essential part of casualty management. Methods used depend on your training, the
      number of casualties, the resources available and the injuries to be managed.
      Start simple, for example, splint limbs and cool burns. Effective analgesia may
      need a combination of techniques and drugs. If unsure, get help.

PMID- 15015803
TI  - Poland's syndrome and military personnel.
AB  - We describe three cases of undiagnosed Poland's syndrome in Army personnel and
      discuss their fitness according to the PULHHEEMS system. This syndrome has
      variable clinical features that include unilateral chest wall and upper limb
      abnormalities. The syndrome is not hereditary and is of unknown origin. If the
      syndrome was diagnosed prior to enlistment the potential recruit would normally
      be graded P8, and unfit to enlist. However, these individuals had managed to pass
      routine medical examination as well as successfully complete basic training. The
      suitability of continuation in the army of personnel with Poland's syndrome is
      discussed.

PMID- 15015805
TI  - Acute coronary syndrome.
AB  - Acute coronary syndromes encompass a heterogenous group of patients with
      different clinical presentations, who have differences in both the extent and
      severity of underlying coronary atherosclerosis and who have different degrees of
      risk of progression to myocardial infarction. For each patient, the pre-hospital
      practitioner should make individual treatment decisions based on the history and
      examination, the ECG findings, the facilities and diagnostic equipment available
      and the transfer time to the nearest appropriate hospital. Patients with acute
      ischaemic chest pain should have oxygen, aspirin, nitrates and opioid analgesia.
      A 12 lead ECG should be performed within 5 minutes of initial assessment. If the
      ECG reveals ST-segment elevation or presumed new LBBB, this signifies acute
      myocardial infarction and in most cases immediate reperfusion therapy should be
      considered. The evidence of benefit in terms of mortality and morbidity following
      prompt anti-platelet and fibrinolytic therapy in such cases is unequivable. Pre
      hospital fibrinolysis is now well established and should be undertaken in
      patients with acute infarction on clinical and ECG grounds if the transfer to
      hospital is likely to exceed 30 minutes and it is less than 12 hours since the
      onset of pain. Patients with no ECG evidence of infarction may still be at
      considerable risk and should still be conveyed to the nearest appropriate medical
      facility. Whilst en-route, they should receive aspirin, nitrates, low molecular
      weight heparin (LMWH) and beta blockers provided there are no contra-indications.

PMID- 15015806
TI  - Self assessment exercises in toxicology.

PMID- 15015807
TI  - What's new in...general surgery.

PMID- 15015808
TI  - Preparing for the MRCSEd (A&E).

PMID- 15015809
TI  - Dr Hunter Holmes McGuire, Chief Medical Officer to General Stonewall Jackson.

PMID- 15015810
TI  - Shrapnel: the man, the missile and the myth.

PMID- 15015811
TI  - Organisation for the relief of concentration camps.
AB  - OBJECTIVE: To review the essential principles involved in rescue missions for
      natural and man-made disasters. METHOD: A description of the relief of a
      concentration camp in 1945 as an example of the logistics required in any major
      disaster or rescue. RESULTS: The arrival of trained Army rescue teams on the
      first day and dealing systematically with priorities in salvage, treatment and
      nursing saved many lives, even of desperately ill patients. CONCLUSIONS: A
      centralised administration and organisation of supplies is the first priority.
      Suitable intravenous and very light nutrients, and the prevention and combating
      of infections are more urgent than the provision of shelter and clothing.

PMID- 15015812
TI  - Froelich, fertility and a French emperor. Commentary on 'Napoleon's sex life' by
      Maj Gen F M Richardson.
AB  - This article, some forty-odd years old now sheds an interesting light on one of
      the great men of history; whether he was homosexual or not I think matters
      little, as he will be remembered for his Empire building and battles far more
      than his penis and prowess. The fact that a medical condition can tentatively be
      put forward as a mitigating circumstance against his less laudable behaviours, is
      of interest more for the value of the medical detective work that was involved,
      than the expunging of the blemishes from his legend. As a testament to the
      breadth of interest portrayed by the Journal all those years ago I feel it is a
      splendid reminder that articles other than randomised controlled trials or
      evidence based guidelines still make for enjoyable, if not directly practical,
      relevant reading.

PMID- 15015813
TI  - Napoleon's sex life. 1961-2 [classical article].

PMID- 15015814
TI  - Dealing with the disturbed soldier.

PMID- 15015815
TI  - The first Royal Air Force aeromedical evacuation?

PMID- 15015816
TI  - The evolution of casualty evacuation in the 20th Century (Part 5)--Into the
      future.
AB  - This is the final part of a series of papers that review the evolution of the
      military casualty evacuation system in the 20th Century. This paper draws
      together the themes that have been presented in the previous papers to describe
      the mandatory functions of such a system. The forward surgical hospital is the
      key treatment node if wounded soldiers are to have the maximum chance of
      survival. Suggestions are made for the minimum size, organisation and clinical
      capability of such a military medical unit. However, the majority of military
      casualties are likely to be less seriously injured or non-trauma cases. The
      casualty evacuation system must also have sufficient capacity to accommodate
      these patients.

PMID- 15015817
TI  - No pain, no gain--Part I. A brief history of British Army psychiatry origins,
      experiences, and understandings.

PMID- 15015818
TI  - Acute and late clinical outcomes of coronary balloon angioplasty with or without
      stenting in diabetes--the fact in the "real world".
AB  - BACKGROUND: Diabetes mellitus (DM) is one of the major risk factors of coronary
      artery disease (CAD). Both short- and long-term prognoses of plain old balloon
      angioplasty (POBA) are poorer in CAD patients with DM than in those without.
      Recent evidence indicates that coronary stenting significantly improves clinical
      results of POBA in CAD patients. However, the benefit of coronary stenting
      remains controversial in DM patients. The purpose of this study was to evaluate
      the acute and late clinical outcomes of coronary stenting as compared with POBA
      in diabetic patients with CAD in the real setting of our daily practice. METHODS:
      Between June 1997 and September 1998, more than 400 consecutive CAD patients
      receiving POBA with or without coronary stenting were evaluated. The patients
      were those who had definite clinical diagnosis of DM and received coronary
      intervention for the first time on their de novo, native lesion(s). Patients were
      divided into 2 groups according to POBA alone or balloon dilatation followed by
      coronary stenting. The immediate angiographic results and clinical outcomes,
      including major adverse cardiovascular events (MACE) as well as recurrent angina
      within 24 hours after the procedure (acute) and more than 6 months (late) after
      the procedure were evaluated in the both groups of patients. RESULTS: A total of
      124 DM patients, aged 68 +/- 8 years with 85% male and 60% multivessel disease,
      were studied. There was no difference in baseline demographic data between those
      patients receiving POBA alone (POBA, n = 79) and in combination with coronary
      stenting (stent, n = 45). The minimal luminal diameter of the target lesion
      immediately after balloon dilatation was smaller in the stent group than in POBA
      group (1.36 +/- 0.67 vs. 1.96 +/- 1.31 mm, p < 0.001). However, the final luminal
      gain was much larger (1.60 +/- 0.64 vs. 0.80 +/- 0.88 mm, p < 0.001) and the
      acute event-free survival rate was higher (97.7% vs. 82.9%, p = 0.019) in stent
      group than in POBA group. While the percutaneous revascularization rate tended to
      be less in patients with stent than with POBA (31.8% vs. 49.3%, p = 0.08), the
      total late MACE rate was similar between both groups (50% vs. 64.7%, p = NS).
      However, the late event-free survival rates were significantly higher in stenting
      patients than in those with POBA (34.9% vs. 16.4%, p = 0.037). CONCLUSIONS:
      Diabetic patients with significant CAD were clinically found to be old and
      largely with multivessel disease for coronary intervention. The immediate
      angiographic results were better if treated with stenting than with POBA alone.
      Though the rate of late MACE was similarly high in both groups, coronary stenting
      rendered a better acute event-free survival rate and especially late event-free
      survival rate, suggesting its benefit for percutaneous coronary revascularization
      in diabetic patients.

PMID- 15015819
TI  - Atrial demand pacemakers in sick sinus syndrome: an efficient and reliable
      approach in selected patients.
AB  - BACKGROUND: Atrial demand pacemakers offer the advantages of lower cost and less
      cumbersome implantation in selected sick sinus syndrome patients with acceptable
      atrioventricular (AV) conduction. However, concerns about their long-term
      performance and AV conduction degeneration still worry certain implantation
      physicians. There were still limited long-term follow-up data of atrial demand
      pacemakers, especially in oriental people. Thus, we reviewed our long-term follow
      up results. METHODS: From January 1996 to December 1998, all symptomatic sick
      sinus syndrome patients with atrial demand pacemaker (AAI, AAIR) treatment were
      retrospectively studied. They were all regularly followed up at our pacemaker
      clinic. The patients' clinical presentations, coronary angiography,
      electrophysiology results and their initial implantation parameters were
      collected. All outpatient follow-up histories, electrocardiogram (EKG) rhythm
      strips, and chronic threshold test data were also retrieved. RESULTS: There were
      51 patients enrolled in this study, with a mean age of 68 +/- 7 years. The
      average follow-up duration was 44 +/- 17 months. The baseline His bundle
      ventricular (HV) interval was 40 +/- 6 ms and AV 1:1 conduction cycle lengths
      were up to 388 +/- 65 ms. Two patients (2/51, 3.9%) had acute lead dislodgement
      within three days and needed reimplantation. During the long-term follow-up, all
      patients maintained good pacing function. Five patients (5/51, 9.8%) had
      occasions of sensing failure, as detected by 12-lead surface EKG or Holter
      monitor, which all resolved after reprogramming of the sensing threshold. Only 1
      patient ( 1/51, 1.9%) developed Wenckebach AV block in the daytime as shown by
      EKG and was later upgraded to a DDDR pacemaker uneventfully. No patient became
      victim of chronic atrial fibrillation during the long-term follow-up.
      CONCLUSIONS: Our follow-up study again suggests that atrial demand pacemakers
      have good initial implantation and long-term results. The chance of developing AV
      conduction degeneration during follow-up is quite low (1.9%, average annual
      incidence 0.5%). AAI and AAIR pacemakers are a reliable and physiological
      approach to selected sick sinus syndrome patients and should be the pacemaker of
      choice in suitable cases.

PMID- 15015820
TI  - Study on the effect of food on the absorption of theophylline.
AB  - BACKGROUND: The pharmacokinetics of theophylline under fasting and normal meal
      have been widely studied, but that of Euphyllin Retard in Chinese subjects has
      not been reported. Since various food-induced absorption changes occur with
      sustained-release theophylline, it is of interest to study the food effect
      (especially Chinese food) on this drug product. METHODS: A total of 10 non
      smoking healthy male volunteers were involved in the study with a 2-period
      crossover comparison. They were randomly divided into 2 groups. In the first
      phase study, group A took a single dose of 350 mg Euphyllin Retard (theophylline
      ethylenediamine formulation, containing 255 anhydrous theophylline) under fasting
      condition. Group B took the same dose with breakfast. Blood samples were
      collected before and during the 36 hours following administration of the drug.
      For the second-phase study after 2 weeks, the group A acted as fasting group and
      group B as non-fasting group. The difference in the absorption of theophylline
      with fasting versus non-fasting administration was assessed using pharmacokinetic
      parameters derived from a serum theophylline concentration (STC) vs time curve.
      RESULTS: The means of maximum drug concentration (Cmax), unextrapolated area
      under the concentration vs time curve (AUC) from time 0 to 24 hours (AUCun),
      extrapolated AUC from time 0 to infinity (AUCex), and terminal elimination rate
      constant (Kel) were higher in the non-fasting group. The fasting group showed a
      more delayed time to maximum concentration (Tmax). The mean of half-life (T50%)
      was slightly higher in fasting group. In comparing each of the variables, no
      statistically significant differences were demonstrated between the 2 modes of
      administration except Cmax. CONCLUSION: Food increases the rate but not the
      extent of the absorption of Euphyllin Retard, and one should be aware of the
      possibility of unwanted side effects caused by high peak concentration. There
      were wide variations in serum drug levels among individuals, so serum
      theophylline level monitoring is necessary for an optimal effect. This study was
      performed in a limited number of normal healthy subjects and the same result is
      yet to be in asthmatic patients and a larger population of normal subjects.

PMID- 15015821
TI  - Surgical techniques for emergent repair of post-infarction ventricular septal
      defect: compare endocardial patch and infarct exclusion method with traditional
      method.
AB  - BACKGROUND: The traditional surgical repair of post-infarction ventricular septal
      defect (VSD) includes excision of necrotic myocardium and approximation of the
      remaining of healthy ventricular wall and septal portion. The exclusion method
      emphasizes no excision of infarcted myocardium, preservation of the left
      ventricular geometry and exclusion of infarction area. We discuss our experiences
      in 13 patients and compared the results obtained from 2 different surgical
      methods. METHODS: From July 1996 to December 2001, 13 patients with post
      infarction VSD received emergent repair. Seven patients were repaired in the
      traditional way and the other 6 with infarct exclusion method. There were 9 men
      and 4 women, ranging in age from 57 to 79. In the traditional group, all 7
      patients were classified as NYHA IV and supported by intra-aortic balloon counter
      pulsation (IABP) and 4 patients were for synchronous coronary bypass grafting.
      Patients using exclusion method were the 1 classified as NYHA III and 5 as IV
      with cardiogenic shock and supported by IABP. Coronary bypass grafting was
      performed concomitantly in 2 patients. RESULTS: Five patients died within 30 days
      after the surgery. Four patients (mortality rate = 57.1%) had reconstruction in
      traditional way and 1 (mortality rate = 16.6%) in exclusion way. The complication
      rate was higher in the traditional group (= 100%, n = 7, p = 0.005). In the
      traditional group, 1 patient received heart transplantation due to persistent
      severe pump failure and recovered well. Two received tracheostomy due to
      respiratory failure and 1 died 2 months later. In the group of exclusion method,
      1 patient suffered recurrent VSD 2 days after the first surgery and died due to
      ventricular arrhythmia. CONCLUSIONS: The surgical mortality caused by acute post
      infarction VSD has decreased with endocardial patch and infarction exclusion
      method. Rapid diagnosis, appropriate preoperative management and delicate
      surgical repair improve the overall results and help to attain long-term
      survival.

PMID- 15015822
TI  - Angiographic embolization for emergent and prophylactic management of obstetric
      hemorrhage: a four-year experience.
AB  - BACKGROUND: To retrospectively evaluate the efficacy and safety of emergent and
      prophylactic arterial embolization for obstetric hemorrhage within the past 4
      years. METHODS: We retrospectively collected 21 obstetric patients with treatment
      of selective arterial embolization between 1999 and 2002. Two groups of patients
      were identified. The first group consisted of 15 patients who experienced
      postpartum hemorrhage and underwent emergent embolization. The second group was
      made up of 6 patients who underwent prophylactic embolization with risk factors
      of severe obstetric bleeding. They had abnormal placentation antepartum diagnosed
      and accepted termination of pregnancy followed by hysterectomy. RESULTS: In the
      first group, 12 of 15 cases had a favorable outcome treated by single
      embolization session. One patient expired 4 days after embolization due to severe
      disseminated intravascular coagulopathy and multiple organ failure. One retained
      placenta with recurrent bleeding was controlled by repeated selective arterial
      embolization. One uterine subinvolution with persistent mild bleeding and genital
      tract infection was improved by conservative treatment. Further surgical
      procedure was not necessary for all cases. One woman delivered her next baby 13
      months after embolization. In the second group, all women had abnormal
      placentation with histopathological confirmation, including 1 accreta, 3 increta,
      and 2 percreta. No immediate complication was noted after embolization. The
      estimated blood loss during operation ranged from 300 to 3000 mL (mean, 1770 mL).
      CONCLUSIONS: Our study indicates that selective arterial embolization should be
      the early management for intractable postpartum hemorrhage after conservative
      treatment fails and before more invasive surgical intervention is considered. Our
      experience also confirms the effectiveness and safety of prophylactic selective
      arterial embolization for anticipated high morbidity or mortality of obstetric
      surgery.

PMID- 15015823
TI  - Antiandrogen-associated hepatotoxicity in the management of advanced prostate
      cancer.
AB  - BACKGROUND: Antiandrogens available for patients with advanced prostate cancer
      are reported to cause hepatotoxicity. The aim of this study is to investigate the
      antiandrogen-associated hepatotoxicity in patients with advanced prostate cancer.
      METHODS: By retrospective charts review, 229 patients (47-89 years old) with
      advanced prostate cancer treated by total androgen blockade (TAB) with bilateral
      orchiectomy or LHRH (luteinizing hormone-releasing hormone) analogues plus
      antiandrogen, or antiandrogen-radiotherapy were enrolled in this study. There
      were 124 patients taking flutamide 750 mg daily and 105 patients taking
      cyproterone acetate (CPA) 150 mg daily. Hepatotoxicity defined by the
      International Consensus Meeting in 1990 and Food and Drug Administration, USA was
      used to evaluate the hepatotoxicity (including serious hepatotoxicity). RESULTS:
      There was a higher occurrence of hepatotoxicity in patients taking flutamide
      (15.3%) than taking CPA (9.5%) (p = 0.034). The occurrence of serious
      hepatotoxicity of flutamide and CPA was 4.8% (6/124) and 3.8% (4/105),
      respectively. The mean latency period of hepatotoxicity for CPA was 4.8 +/- 2.0
      months for flutamide and 5.8 +/- 1.9 months for CPA, respectively. The 2 groups
      made no significant difference of liver enzyme (mean maximal alanine
      aminotransaminase (ALT) and aspartate aminotransaminase (AST) = 284.2 +/-
      99.3/300.6 +/- 58.5 U/L versus 341.8 +/- 67.1/301.6 +/- 80.5 U/L). All of the 19
      patients (100%) and 9 of 10 patients (90%) with flutamide and CPA-induced
      hepatotoxicity got self-resolution after discontinuation of the antiandrogens.
      The average time of self-resolution is 4.5 +/- 3.1 months and 6.3 +/- 4.7 months
      for flutamide and CPA, respectively. Five patients of flutamide-induced and 2
      patients of CPA-induced hepatotoxicity got resolution after changing to other
      antiandrogen. CONCLUSIONS: Flutamide and CPA appear to cause hepatotoxic effects
      in some patients. Discontinuation of the antiandrogens seems to be the resolution
      of hepatotoxicity. A change to other antiandrogen may be the alternative strategy
      to the antiandrogen-induced hepatotoxicity. The results of this study suggest
      that all patients received flutamide and CPA should be monitored carefully for
      signs and symptoms referable to hepatic injury to prevent the development of
      serious hepatic dysfunction.

PMID- 15015824
TI  - Risk factors of mortality after surgical treatment of intestinal obstruction in
      patients having prior laparotomy for non-malignancy.
AB  - BACKGROUND: Intestinal obstruction has remained one of the most common surgical
      emergencies, and its clinical spectrum has shifted in past decades. The factors
      contributing to its surgical mortality were studied in these selected patients
      with a view to finding pointers which help surgeons to identify patients with
      high surgical risk of mortality. METHODS: Those adult patients who had prior
      laparotomy for non-malignancy and were operated on for intestinal obstruction
      were included and studied retrospectively. Thirteen possible risk factors,
      including co-existing medical illness, tachycardia, preoperative shock, age,
      bowel ischemia, operative complication, leukocytosis, durations from symptom
      onset to hospitalization, from hospitalization to operation, and from symptom
      onset to operation, prior laparotomy number, time interval from last laparotomy
      to this operation, and operation method, were analyzed using univariate analysis
      and, then, multivariate analysis to find out the independent risk factors for
      surgical death. RESULTS: Adhesion-related etiologies were the most common. Still,
      one-tenth of cases were not adhesion-related. Obstruction in the small bowel
      (172/176) was more frequent than in the large bowel (4/176). The surgical
      mortality rate was 6.8% (12/176). The independent risk factors of mortality after
      surgical treatment were co-existing medical illness, bowel ischemia, preoperative
      shock, and operative complication. Old age seemed to be a risk factor on
      univariate anlaysis, but not on multivariate analysis. Duration from symptom
      onset to hospitalization, from hospitalization to operation, or from symptom
      onset to operation was not significantly related to surgical mortality.
      CONCLUSIONS: High risk patients could be identified by 4 independent factors:
      coexisting medical illness, bowel ischemia, preoperative shock, and operative
      complication. Old age itself was not an independent risk factor.

PMID- 15015825
TI  - Chronic glue sniffing with transient central hypothyroidism and
      hypergonadotropism.
AB  - Neuropsychiatric, gastrointestinal and muscular disorders associated with glue
      sniffing have been widely reported, but endocrinologic abnormalities of glue
      exposure are rarely mentioned in the literature. We report a 26-year old male
      patient, a chronic glue sniffer, who presented with weakness of both lower limbs.
      On physical examination, he had reduced muscle strength of his 4 limbs,
      especially in his lower limbs. Laboratory examination revealed hypokalemia with
      hyperchloremic metabolic acidosis. His thyroid function showed low TSH, T4, T3,
      free T4 and reverse T3 level. Other pituitary functions were normal apart from
      high FSH and LH level. TSH response to TRH stimulation was normal, but there was
      impaired T3 response to TRH. MRI of pituitary showed no significant changes. He
      continued glue sniffing after discharge. He repeatedly came to our hospital for
      recurrent hypokalemic paralysis. His serum T4 and free T4 level were low when he
      had certain amount of glue sniffing and it returned to normal after he stopped
      sniffing or sniffed less amount of glue. His serum T3 concentrations were normal
      most of the times thereafter. His FSH and LH level were persistently elevated,
      even after he did not sniff glue for 2 weeks. Low free T4, TSH and reverse T3
      level associated with glue sniffing in our patient were compatible with central
      hypothyroidism. Toluene, a neurotoxic organic solvent, is present in glues. Being
      highly lipophilic, it can easily enter and is retained within the lipid-rich
      nervous system after being inhaled. Like other organic solvents, toluene has been
      shown to affect dopaminergic and adrenergic turnover within various parts of the
      brain. The effects on these neurotransmitters could lead to abnormal secretion of
      pituitary hormones resulting in transient central hypothyroidism and abnormal
      gonadotropin levels. Long-term harmful effect of central hypothyroidism and
      chronic influence of abnormal gonadotropins to reproduction function needs
      further observation.

PMID- 15015827
TI  - Retrograde intramedullary Huckstep nailing for supracondylar fracture of femur
      after total knee arthroplasty.
AB  - Supracondylar fracture of femur after total knee arthroplasty (TKA) presents a
      challenge for orthopedic surgeons. It is controversial to treat such a fracture
      by using closed method or open method. Nonunion, malunion, knee rigidity and
      other complications in prolonged immobilization were noted in the closed method.
      Implant migration, infection, nonunion and malunion were also reported in open
      reduction treatment because of the difficulty to achieve rigid fixation. In this
      periprosthetic fracture, retrograde intramedullary Huckstep nailing provides a
      better chance to get rigid fixation compared with other fixation device,
      especially in osteopenic bone. We reported 2 cases with supracondylar fracture of
      femur after total knee arthroplasty that have been successfully treated with
      retrograde intramedullary nailing.

PMID- 15015826
TI  - Extraparotid Warthin's tumor presented as a neck mass.
AB  - Warthin's tumor is one of the benign tumors of major salivary glands. It was
      mostly found in parotid glands of male patients in their sixties. Warthin's tumor
      with extraparotid location is rare. We here report a 65-year-old male patient
      with a movable mass about 25 x 20 x 15 mm over his leftjugular-digastric area.
      The fibroscopic examination found no malignancy over the head and neck region.
      Computed tomographic scan showed a soft tissue mass about 18 mm in diameter in
      the left upper neck. The mass was not in connection with the parotid gland or the
      submandibular gland and was excised completely through a transverse neck
      incision. Histopathologic examination revealed Warthin's tumor. We present an
      original report of a case of Warthin's tumor with its unusual extraparotid
      location.

PMID- 15015828
TI  - Expression of Y7 cross-reactive idiotope on human IgM molecules.
AB  - In this paper we report data regarding the IgM Y7 cross-reactive idiotope (CRIo)
      obtained by analysis of: 1) its V-gene subgroup dependance, 2) the frequency of
      its expression on human monoclonal IgMs and IgM molecules from normal and
      pathological sera. Furthermore, comparison of epitopic repertoire and nature of
      binding of human monoclonal IgMs expressing Y7 CRIo was performed to confirm the
      natural antibody properties of these molecules. IgM isolated from sera of patient
      DJ (IgM DJ) which expresses the Y7 idiotope has been classified to VH3/VL2
      subgroup. From ten IgMs tested only IgM from patient RD (IgM RD) has been shown
      to express Y7 idiotope. Y7+ human IgMs bound to ssDNA, lactic acid bacteria,
      mouse laminin, porcine thyroglobulin and mouse IgG. Higher percentage of the
      expression of Y7 CRIo was detected in the sera of patients suffering from
      autoimmune diseases such as lupus, rheumatoid arthritis and psoriasis vulgaris as
      well as in patients suffering from chronic infections of the lower urinary tract.
      Antigen binding repertoire and properties of Y7+ monoclonal IgM, frequency of Y7
      expression on monoclonal IgMs and its concentration in normal and pathological
      sera indicate the important biological role of this CRIo within the immune
      system.

PMID- 15015829
TI  - Immunization with Trichinella spiralis Korean isolate larval excretory-secretory
      antigen induces protection and lymphocyte subset changes in rats.
AB  - Protection and immune responses were studied in rats immunized with Trichinella
      spiralis muscle stage larval excretory-secretory antigen (ES Ag) without
      adjuvant. Protection was assessed by the degree of adult worm burden and the
      yield of muscle (diaphragmatic) larvae after challenge infection with live
      larvae. Lymphocyte subsets were identified by flow cytometry in the spleen and
      peripheral blood. Cytokine production and specific IgG, IgG1 and IgG2a antibody
      responses were measured. Immunization with ES Ag produced highly significant
      protection against adult stages (98.4%) and muscle larvae (82.9%). Th2 type
      cytokines (IL-10, IL-4) were predominant. Anti-muscle stage larval ES Ag antibody
      was significantly elevated in the order IgG2a > IgG1 > IgG on the 2nd day after
      final immunization and on the 7th day after challenge infection. Expression of
      CD4+ and the CD4+/CD8+ ratio from spleen and blood were significantly increased
      compared to the control. These results demonstrate that immunization with T.
      spiralis antigen can elicit robust immune response, resulting in complete
      protection against infective larvae, and this protection can be achieved without
      the use of any adjuvant.

PMID- 15015831
TI  - The complement-fixing activity of immune complexes containing IgG antibodies of
      different functional affinities: effects on superoxide production by rabbit
      neutrophils.
AB  - When neutrophil phagocytes are stimulated by IgG containing immune complexes (IgG
      IC), with or without the participation of the complement system, they show a
      sharp increase in oxygen uptake and begin to release large quantities of
      superoxide anions (O2-) and hydrogen peroxide (H2O2) into the surrounding medium.
      The aim of the present investigation was to provide insights into the production
      and release of O2- by rabbit neutrophils activated with immune complexes (IC)
      containing IgG antibodies of different functional affinity, opsonized and not
      opsonized by complement system components. For this purpose, two populations of
      polyclonal anti-ovalbumin (OVA) IgG antibodies with different functional
      affinity, 5 x 10(8) M(-1) and 2 x 10(7) M(-1), were prepared. The production of
      O2- was measured spectrophotometrically by a method using the superoxide
      dismutase-inhibited reduction of ferricytochrome C to the ferrous form. The
      activation of complement by different IgG-IC was determined by estimating the
      total residual haemolytic activity of the alternative and classical pathways in
      sera treated with different concentrations of anti-OVA IgG/ OVA immune complexes
      formed at equivalence. The results showed that: 1) antibody functional affinity
      influenced O2- production and the complement-fixing activity induced by the IC.
      In general, the higher functional affinity antibodies were more efficient in
      stimulating the respiratory burst of neutrophils and in activating complement by
      the classical and alternative pathways than the lower functional affinity
      antibodies at all IC concentrations tested; 2) complement components incorporated
      into the immune complex lattice caused an increase in the stimulatory activity of
      both IgG antibodies to produce O2- (approximately equal to 15% for the IC of IgG
      with Ka = 5 x 10(8) M(-1) and approximately equal to 7% for the IC of IgG with Ka
      = 2 x 10(7) M(-1)). This effect was dependent on antibody affinity and
      concentration; 3) there was a direct relationship between the overall level of
      complement activation, antibody affinity and superoxide production by
      neutrophils. Thus, we conclude that antibody affinity influences immune complex
      lattice formation, modulating its three-dimensional structure and the disposition
      of Fc fragments interfering with the antibody's biological properties. These
      results can help understand the precise role of antibody functional affinity in
      antigen-antibody complex diseases and define the immunochemical characteristics
      of pathogenic complexes.

PMID- 15015830
TI  - The role of RANTES in a murine model of food allergy.
AB  - Food allergy is an important and common health issue, and there is a need to
      identify and characterize the sensitizing mechanisms. One of the common causes of
      food allergy is ovalbumin (OVA), a dietary antigen from eggs. We hypothesized
      that OVA-induced food allergy in the gut involves the activation of the chemokine
      regulated on activation, normal T cell expressed and secreted (RANTES), which
      then recruits eosinophils to lesioned tissue. The purpose of this study was to
      clarify whether RANTES expression correlates with eosinophil infiltration in the
      gut of OVA-sensitized BALB/c mice in response to oral OVA challenge. BALB/c mice
      were immunized with OVA 1 microg and sensitized after 2 weeks by intragastric
      administration of OVA. Sensitization to the oral OVA challenge was analyzed by
      examining eosinophil infiltration into the gut tissue (immunohistochemistry),
      mucosal eosinophil cationic protein (ECP) concentration, and RANTES mRNA
      expression (reverse-transcriptase polymerase chain reaction and Southern
      blotting) at 3, 6, 12, and 24 h after the challenge. There was marked edema of
      the intestinal villi, and eosinophil infiltration to the lamina propria peaked at
      6 h in OVA-sensitized mice. RANTES mRNA expression peaked at 3 h and 6 h and
      declined thereafter. The expression of RANTES mRNA in the allergic mice was much
      higher than in the nonallergic, normal, or unsensitized control mice. Tissue
      eosinophilia and intestinal ECP levels were significantly correlated with the
      RANTES mRNA level. We conclude that RANTES may play a central role in the
      pathogenesis of food-mediated gastrointestinal allergy.

PMID- 15015832
TI  - Relationships between IgG, IgM, IgE and resistance to reinfection during the
      early phase of infection with Clonorchis sinensis in rats.
AB  - An enzyme linked immunosorbent assay (ELISA) was used to study the correlation
      between the levels of IgG, IgM and IgE immunoglobulin isotypes and resistance to
      reinfection in rats during the first month of infection with Clonorchis sinensis.
      Rats were infected with Clonorchis sinensis (primary infection), and then treated
      with praziquantel on the 1st, 3rd, 7th, 14th and 28th day post infection (p.i.).
      To measure resistance, rats were re-infected with C. sinensis (secondary
      infection), 2 weeks after the treatment and worms were recovered 4 weeks later.
      During the primary infection, significantly increased levels of IgG isotype were
      observed on days 14 and 28 p.i. (P < 0.001) and IgM levels were significantly
      increased on 3rd and 28th day (P < 0.001). During the secondary infection,
      significantly increased levels of IgG isotype were found from 3rd to 28th day and
      IgE isotype on 7th and 14th day (P < 0.01) while significant levels of IgM were
      found on the 3rd and 28th day (P < 0.05). Furthermore, significant differences of
      worm numbers between infected and control group was found on the 14th and 28th
      day (P < 0.001). An inverse correlation betwee the IgG levels and the resistance
      to re-infection was also observed (r = -0.948, P = 0.004), indicating that the
      resistance to reinfection is highly associated with the levels of IgG during the
      early phase of infection, and then with the IgM and IgE.

PMID- 15015833
TI  - Serum levels of soluble TNFalpha receptors (sTNFR1 and sTNFR2) during
      corticosteroid treatment in patients with Graves' ophthalmopathy.
AB  - TNFalpha was shown to play an important role in the autoimmune inflammatory
      process of Graves' ophthalmopathy (GO). In our previous study we found no
      significant changes in serum TNFalpha levels in GO patients. The aim of the
      present study was to estimate an influence of corticosteroids on serum levels of
      TNFalpha receptors (sTNFR1 and sTNFR2) in GO patients and to assess their
      potential as a guideline of immunosuppressive therapy. We detected serum sTNFRI
      and sTNFR2 in three groups of subjects: 18 patients with clinical symptoms of
      ophthalmopathy [Clinical Activity Score (CAS) > or = 4, anamnesis of GO > or = 1
      yr], 16 patients with Graves' disease without ophthalmopathy (Gd) and 14 healthy
      volunteers. Corticosteroid therapy consisted of intravenous infusions of
      methylprednisolone (MP) and subsequent treatment with oral prednisone (P). The
      serum samples were collected 24 hours before MP, 24 hours after MP, 14 days of
      treatment with prednisone and after the end of the corticosteroid therapy. The
      levels of serum sTNFR1 and sTNFR2 were determined by ELISA. Serum levels of
      sTNFR1 were significantly higher in GO individuals as compared to the control
      group (p < 0.01). We have found a significant decrease in sTNFR1 concentration in
      corticosteroid-respondent patients (satisfactory clinical effect, decrease of CAS
      > or = 1) as compared to the pretreatment values after MP treatment (p < 0.05)
      and after 14 days of prednisone (p < 0.01). There were significant differences in
      sTNFR2 level after MP treatment (p < 0.02) and after corticosteroid
      administration (p < 0.05) between responders and non-responders. Baseline values
      of sTNFRI in GO individuals were positively correlated with CAS (r = 0.6, p <
      0.02). CONCLUSIONS: TNFalpha acting through its receptors plays an important role
      in the pathogenesis of Graves' ophthalmopathy. Moreover, the beneficial influence
      of corticosteroids on the course of GO may be explained, at least in part, by an
      inhibition of sTNFR1 and sTNFR2. Measurement of soluble TNFalpha receptors might
      potentially serve as an indicator in prognostic estimation of corticosteroids'
      efficacy.

PMID- 15015835
TI  - X-linked agammaglobulinemia: a survey of 33 Iranian patients.
AB  - In order to determine the clinical and laboratory features of X-linked
      agammaglobulinemia, the records of 33 male patients with XLA were reviewed during
      22 years (1980-2002) in the Iranian referral center of primary immunodeficiency
      disorders. The patients' ages ranged from 20 to 360 months (median 113 months).
      The median age at the onset of the disease was 8 months and the median age of
      diagnosis was 48 months, with a median diagnosis delay of 33 months. Almost all
      of the patients presented common infectious diseases, which were: pneumonia,
      otitis, diarrhea, sinusitis, and arthritis. During the course of illness,
      infections in the respiratory tract, gastrointestinal tract, central nervous
      system, and musculoskeletal system were seen in 93.9%, 75.8%, 33.3%, and 21.2% of
      XLA patients, respectively. The most common complications of these patients were
      chronic infections in 75.8% of them, including: chronic otitis media, chronic
      sinusitis, chronic diarrhea, and bronchiectasis.

PMID- 15015834
TI  - The role of cow milk allergy in increasing the severity of atopic dermatitis.
AB  - Previous studies have shown that up to 33% of children with atopic dermatitis
      have experienced food hypersensitivity and among different kinds of food
      allergens Cow Milk (CM) has almost always been one of the most common food
      allergens in children. The aim of this study is to evaluate the cow milk allergy
      (CMA) as an increasing factor of severity of atopic dermatitis. One hundred and
      nineteen children (between 1.5 months and 12 years of age) with atopic dermatitis
      in the sense of Hanifin and Rajka's criteria entered this study and the severity
      of atopic dermatitis was identified via the SCORAD index. In order to make the
      diagnosis of cow milk allergy, a careful history, and a familial history of
      allergy was taken and the results of skin prick test (SPT) with CM and 4 other
      food allergen extracts, Radioallergosorbent test (RAST) with CM allergens and a
      food challenge test with cow milk (fresh or dried) were used. Also a total serum
      IgE determination and an eosinophil count (with a stool exam) were accomplished.
      The clinical manifestations of atopic dermatitis in patients was started from
      their first day of life up to 10 years of age. The family history in 83% of the
      patients was positive. Positive skin prick test and RAST with CM allergens were
      positive in 37.9% and 29.3% of cases respectively and the response to challenge
      test with cow milk was positive in 35 out of 40 patients and in total 44.5% had
      CMA according to a positive history of cow milk allergy and a positive outcome of
      the IgE tests (SPT and/or RAST) or a positive challenge test with CM allergens.
      The results showed that the most common food allergens in patients with atopic
      dermatitis are certainly cow milk allergens (44.5%) whereas other food allergens
      are tomato (29.41%), egg (28.57%), nuts (9.24%) and wheat (3.36%) according to
      the skin prick test. The mean total serum IgE was 307.11 +/- 6.56 IU/ml (range =
      6-5000) in children with CMA and 81.04 +/- 5.97 IU/ml (range = 1-5000) in
      children without CMA while the mean eosinophil count was 569.52 +/- 3.02 count/ml
      (range = 67-8500) and 314.22 +/- 2.94 count/ml (range = 5-5000) respectively. The
      mean severity of atopic dermatitis according to the SCORAD index was 60.76 in
      children with CMA and 44.29 in children without CMA. The severity of atopic
      dermatitis in patients with CMA was significantly higher than patients without
      CMA (p < 0.0001). Also the mean total serum IgE and mean eosionophil counts in
      children with CMA were significantly higher than in children without CMA (P <
      0.01 and p < 0.0001, respectively). It shows the important role of CM allergen
      proteins in the induction and in increasing the severity of AD in children.

PMID- 15015837
TI  - [The changing face of tropical dermatology].

PMID- 15015836
TI  - Increased expression of phospholipase D in the heart with experimental autoimmune
      myocarditis in Lewis rats.
AB  - The expression of phospholipase D (PLD) in the hearts of rats with experimental
      autoimmune myocarditis (EAM) was studied to elucidate the functional role of PLD
      in the pathogenesis of EAM. Western blot analysis showed that the level of the
      PLD1 isoform was significantly increased in the hearts of rats with EAM on days
      14, 17 and 21 postimmunization (pi) (P < 0.01; control vs EAM at 14 pi, 17 pi and
      21 pi). The phenotypes of cells exhibiting increased PLD1 expression were
      primarily inflammatory cells, including ED1 positive macrophages, in the
      inflammatory EAM lesions. Some cardiomyocytes also showed increased PLD1
      immunoreaction in and around EAM lesions. Some PLD1-positive cells were also
      positive for proliferating cell nuclear antigen in some cardiomyocytes or
      terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling in
      some macrophages, suggesting that PLD1 positive cells have a capacity for
      proliferation or apoptosis depending on cell types in the target organ. Thus, it
      is postulated that increased expression of PLD1 in EAM may support an early
      inflammatory response in proliferating inflammatory cells, and its expression in
      cardiomyocytes may help them to survive by activation of survival factors in
      hearts with EAM.

PMID- 15015838
TI  - [Public health and dermatology in developing countries].
AB  - Recently some common skin diseases (SD) (i.e. pyoderma, scabies, and superficial
      mycosis) received special interest in terms of public health assessing their
      significance in developing countries (DC). The importance of this problem has
      been established through several kinds of studies: studies from specialized
      dermatology centres, where the main reasons for consulting were common infectious
      skin diseases; prevalence studies in the general population pointing out very
      high prevalence rates for common infectious SD; and studies conducted in non
      specialized health centres, where those SD represented about 10% of the total
      number of consultations. Classical complications of common infectious SD, such as
      post-streptococcic nephritis, appear rather unusual. However, the costs related
      to SD have been established as significant; this is partly due to the low
      efficiency of the health agents when trying to manage SD, and to their usual lack
      of training. So far, SD have been considered as having a very low priority level,
      due to their low lethality rate, and therefore have been ignored by health
      authorities. However, it seems unwise to ignore a health problem for which such a
      demand of the populations is expressed. Health policies aiming at the improvement
      of this situation have to be aware of the economic and health system context in
      DC, and should take into account every step of the health system. The following
      actions have been proposed: definition of SD priorities; training of non
      specialized health agents to a basic management of SD priorities; promotion of
      use and availability of low-cost "essential dermatologic drugs"; education of the
      populations regarding measures to prevent certain SD. The feasibility and the
      impact of such a "public health dermatology" program remain to be evaluated.

PMID- 15015839
TI  - [Current guidelines for leprosy treatment].
AB  - During the last 20 years, the global leprosy situation has strikingly changed
      with a decrease of cases from 12 millions estimated cases in 1982 to 600,000
      registered cases in the year 2000. However, during the past 15 years, about
      700,000 new cases are still detected annually. The systematic use of multidrug
      therapy (MDT), as recommended by a WHO Study Group in 1982, has proven its
      efficacy as assessed by the low reported relapse rate (less than 1% per year).
      The initial PCT schedule has been modified several times, but this PCT remains
      the recommended chemotherapy for the great majority of patients. New potent
      antibacillary drugs (ofloxacin, minocycline, clarithromycine) have been
      discovered; however, their current use is limited and should remain limited until
      under way trials could confirm their efficacy. With the use of PCT, the frequency
      of immunologically mediated reactional states have changed. The occurrence of
      reversal reaction, (type 1 reaction) has significantly increased while that of
      erythema nodosum leprosum (ENL, type 2) appeared less common. Because of the high
      risk of neurological permanent damage, reversal reaction needs to be diagnosed
      and treated as soon as possible. Here in, the current antibacillary and
      antireactionnal treatments are being reviewed.

PMID- 15015840
TI  - [Clinical forms of the cutaneous tuberculosis].
AB  - Since Laennec's description of the "prosector's wart" in 1826, science has made
      great strides forward. The cutaneous forms of the infection with Mycobacterium
      tuberculosis are various. The most common clinical forms of cutaneous
      tuberculosis are lupus vulgaris and scrofuloderma. The clinical forms of
      cutaneous tuberculosis are usually classified according to the patient's immune
      status, and the way through which the skin has been infected. Nonetheless, as in
      leprosy, a classification based on the importance of the bacterial inoculum in
      situ is possible. Subsequently the diagnosis should be considered as easy in the
      multibacillary forms and much more difficult in the paucibacillary forms. In the
      former, the diagnosis should rely on bacteriological data. In the latter, the
      diagnosis will rely on the association of epidemiological, clinical and
      histological data whereas genomic amplification with PCR may be of potential
      interest.

PMID- 15015841
TI  - [Mycobacterium ulcerans infection: epidemiological, clinical and therapeutical
      aspects].
AB  - Mycobacterium ulcerans causing Buruli ulcer is an environmental mycobacteria
      responsible for an infectious necrotizing panniculitis. The epidemiology of this
      disabling disease is strongly linked to the aquatic ecosystem. Occuring mainly in
      children, it is an emergent public health threat in many humid rural tropical
      areas. Human contamination probably follows a direct percutaneous route from
      humid environment, but some insects may play a role in transmission. The clinical
      features develop in three phases: pre-ulcer, ulcer with unstick margins, healing
      leading to functional sequelae. Treatment relies on antibiotics in order to
      sterilize the infectious focus, together with the surgical repair of lost skin
      and joint deformities, as well as early physiotherapy. Despite uncertainties of
      in vivo efficacy of antibiotics, it seems logical to administer chemotherapy with
      both Rifampicin and Aminoglycosid or Fluroquinolon and Aminoglycosid. Surgical
      treatment depends on the size of the ulcer, as well as available techniques and
      skills on the field. Wide excision and graft are often recommended, however
      limited excision followed by small islet grafts may be successful.

PMID- 15015842
TI  - [Principles for the control of sexually transmitted infections in tropical
      areas].
AB  - Owing to their frequency and their own complications, sexually transmitted
      infections (STI) constitute a very classical health problem, especially in
      developing areas. The interest for those diseases has been on the rise since the
      beginning of the AIDS pandemic. Conventional sexually transmitted diseases (such
      as syphilis, chancroid, infections due to Neisseria gonorrhoeae and to Chlamydia
      trachomatis) are potent cofactors of HIV transmission. It has been established
      that the treatment of patients with STI was able to lower the HIV incidence at
      the community level. Today the fight against STI relies mainly on preventive
      measures (promotion of lower risk sexual behaviours, blood transfusion safety),
      and on medical management of patients with STI. In order to treat rapidly cheaply
      and efficiently a great number of patients, standardised syndromic approaches,
      using generic drugs, have been elaborated for the most common STI. Other
      important complementary measures are based on the treatment of sexual partners
      and on the promotion of condom use. In addition to prevention of their specific
      complications, the fight against STI has become a major component of health
      policies against AIDS in developing countries.

PMID- 15015843
TI  - [Management of mycetoma in West-Africa].
AB  - Mycetoma is still endemic in the northern areas of West-Africa. This infection is
      more common in males, rural inhabitants, between 20 and 40 years of age. Mycetoma
      is generally easy to identify on clinical presentation, it is a chronic
      subcutaneous inflammatory tumor with discharging sinuses. The commonest affected
      site is the foot (70%), leg, knee, thigh, hand and arm are the most frequent
      extrapodal localizations. Diagnosis must be confirmed by the presence of grains
      at direct and histological examinations. It is indispensable to distinguish
      actinomycetoma (caused by aerobic bacteria) and eumycetoma (caused by fungi) as
      their treatments are different. The main etiological agents in West-Africa:
      Streptomyces somaliensis, Actinomadura pelletieri, Actinomadura madurae
      (actinomycetes), Madurella mycetomatis and Leptosphaeria sp (fungi) can be
      identified in most cases by histological examination of the grain. In the West
      Sahelian belt actinomycetoma is more frequent than eumycetoma except in
      Mauritania. When a mycetoma is diagnosed it is fundamental to determine as
      precisely as possible the extent of the lesion. Bone involvement is the major
      complication and must be systematically investigated by radiology. Mycetoma has
      characteristic ultrasonographic features, ultrasonographic technique appears to
      be very useful in medical centers where no mycological tests can be done.
      Ultrasonography is also an accurate technique to delimit the extent of the
      process. Computed tomography is also sensitive to assess the extent of mycetoma
      in soft tissues and can detect early bone involvement but is more onerous than
      ultrasonography. Ketoconazole or itraconazole in combination with surgery is
      recommended for eumycetoma patients. Actinomycetoma responds to antibacterial
      agents, different therapeutic schemes can be proposed and depend on the
      etiological agent.

PMID- 15015844
TI  - [Cutaneous leishmaniasis in France: towards the end of injectable therapy?].
AB  - Today no drug likely to be efficient on the majority of human-infecting species,
      well tolerated, and easy to administer is available for the treatment of human
      cutaneous leishmaniasis. But recent progress has been made. Efficient against
      visceral leishmaniasis, orally administered miltefosine may supplant pentavalent
      antimonials for the treatment of cutaneous leishmaniasis acquired in the New
      World. Right now, the reference treatment is still parenteral pentavalent
      antimonials 20 mg Sbv/kg/d for a duration that may probably be reduced from 20 to
      10 days. The benefit/risk ratio of pentamidine still compares well with that of
      pentavalent antimonials for the treatment of lesions due to species belonging to
      the L. panamensis/L. guyanensis/L. shawi group. Pentamidine, which is easier to
      handle than antimonials, remains the reference treatment for cases from areas
      where these species predominate. Oral fluconazole is an improvement, readily
      available for cases from L. major foci. If its efficacy is confirmed in other
      foci and against other species, mechanisms will have to be implemented to make
      this therapeutic improvement affordable to poor patients in endemic countries.
      The development of an efficient and well tolerated topical treatment is still
      warranted. A new formulation of aminosidine is currently under evaluation. One
      can hope that the treatment of cutaneous leishmaniasis will soon become simpler,
      both for patients and doctors. For the benefits of this simplification to be
      rapidly affordable to all patients, the pharmaceutical and clinical research
      outlay must be maintained.

PMID- 15015845
TI  - [Cosmetic use of skin depigmentation products in Africa].
AB  - The use of skin lightening products represents a real social phenomenon in many
      Sub-Saharan African countries. A few studies have been published on this
      subjects. An important proportion of the adult female population, estimated
      between 25 and 67% uses regularly and daily these creams. Today the products used
      are mainly dermocorticosteroids and hydroquinone. Their use over a long period of
      time is responsible for many cutaneous side effects mainly acne, pigmentary
      disorders, stretch marks and cutaneous infections. Systemic side effects have
      recently been reported, mainly related to the use of corticosteroids. The
      necessary control of the products by the local health authorities remains
      difficult.

PMID- 15015847
TI  - [Gigantic keloids after chicken-pox. A case report].
AB  - Keloids are tumors which appear after a lesion or spontaneously. They are
      frequent on black skin. We report a gigantic keloid case appeared after chicken
      pox on a 29 year-old black girl who had viral infection when she was 6 years old.
      The tumors increased after chirurgical treatment and became very unaesthetic.
      This observation specific by its clinical presentation relates the treatment
      difficulties of these tumors in our area.

PMID- 15015846
TI  - [Characteristics of genetically pigmented skins].
AB  - The analysis shows that apart from the relative hyperpigmentation of the "black"
      skin (genetically determined and variable according to ethnic group, age, sex and
      solar exposure), which determines the secondary dyschromic reactions to the
      majority of the dermatosis, and, except the differences of frequency of diseases
      related especially to geographical or epidemiologic determinisms, there is no
      true specificity although some entities are little or not described on "white"
      skin (dermatosis papulosa nigra, acral punctuated hyperkeratosis, progressive
      macular hypomelanosis of the trunk, acne keloidalis, pseudofolliculitis barbae,
      ainhum...).

PMID- 15015848
TI  - [Diagnosis of Mycobacterium ulcerans infection by PCR: report of 3 cases observed
      in French Guiana].
AB  - Mycobacterium ulcerans infection is the third most important mycobacterial
      infection in the world. It has been described in many different countries
      including French Guiana. The diagnosis of M. ulcerans infection by culture is
      often difficult because culture is hard to perform in endemic areas and their
      sensitivity is not reliable. As a result the diagnosis of this infection is often
      delayed. However, molecular methods are now available to diagnose rapidly
      infections by M. ulcerans and distinguish it from other mycobacteria. We report
      three cases of skin infection due to M. ulcerans observed in French Guiana.
      Diagnosis was initially made by polymerase chain reaction and was confirmed later
      by culture (in two patients) and inoculation to mice (in one patient). A faster
      diagnosis of M. ulcerans infection should lead to a better prognosis of this
      infection.

PMID- 15015849
TI  - [Recurrence after surgical treatment of Buruli ulcer in Cote d'Ivoire].
AB  - Current treatment of Buruli ulcer is mainly surgical. However, surgical
      management is difficult due to occurrence of more and more recurrent cases after
      treatment. This cross section study has been carried out from records of 346
      Buruli ulcer patients who have received surgical treatment in three health
      centers in Cote d'Ivoire. Its purposes consisted in assessing the recurrence
      rate, in describing its aspects and in identifying its causes. Results showed
      that recurrent cases during Buruli ulcer were relatively frequent after surgery
      with a rate of 17.1%. They occurred early during hospitalization in an average of
      5 months after surgery. They appeared mostly in ulceration form and were located
      on the previous lesion site. After statistical analysis, the following risk
      factors are associated with Buruli ulcer recurrent cases: patient under 30 years
      old, previous contact with a watercourse, duration of the disease exceeding 75
      days before hospitalization, secondary infection before or after surgery
      disability, treatment by excision and skin graft, ongoing healing of operated
      wound. Recurrent cases after surgical treatment should not be neglected during
      Mycobacterium ulcerans infection. Surgeon must consider their prevention during
      patients treatment.

PMID- 15015850
TI  - [Local administration of ivermectin for the treatment of Cochliomyia
      hominivorax's myiasis].
AB  - Myiasis with Cochliomyia homonivorax induce sensitive and nauseating cutaneous
      ulcerations. The usual treatment is limited to the mechanical extraction of the
      larvae. The authors have made a report on the treatment of C. hominivorax by
      local application of ivermectin. The use of this molecule paralyses and then
      kills the larvae. This allows rapid alleviation of pain and makes the extraction
      of the larvae easier.

PMID- 15015851
TI  - [Effectiveness of 20% salicylated vaseline in the treatment of profuse tungiasis.
      Report of 8 cases in French Guiana].
AB  - The treatment of tungiasis involves the mechanic extraction of the gravid females
      of Tunga penetrans. We have observed on 8 patients profuse tungiasis diagnosed in
      the centre hospitalier de Cayenne. We have carried out different types of
      treatment, including the occlusive application of 20% of salicylated vaseline
      during 12 or 24 hours. This procedure causes the death of the parasites and
      facilitates their extraction.

PMID- 15015852
TI  - [Skin complications of stonefish envenomation in 6 travellers returning from the
      Indo-Pacific maritime region].
AB  - Stonefish (Synanceja verrucosa) sting has been known for a long time to be a
      medical hazard. It is a common cause of severe marine envenomation. Immediate
      complications (collapsus, pulmonary oedema) have been described extensively. Late
      complications (oedema, tissue necrosis) have not been studied in details although
      they are common and a cause of invalidity and pain. We have observed six
      travellers with complications of stonefish sting over a 10 year-period in our
      department. All the patients were coming back from the Indo-Pacific maritime
      region. They presented with cutaneous abcess (in one) or necrotic complications
      (foot ulcers in two, cellulitis in three) associated with painfull oedema in two
      and lymphangitis in three. Surgery has been performed in four patients, two of
      them undergoing many operations. Two had long term sequelae. Such complications
      could be avoided. Appropriate initial treatment (i.e., neutralization of the
      venom by hot water, disinfection, antivenom and antibioprophylaxis) seems to be
      able to reduce late complications. Antivenom is indicated in severe systemic
      manifestations which are life threatening and in case of crucial pains.
      Prevention is the most important part of therapy and relies on appropriate
      information of the travellers.

PMID- 15015853
TI  - [Paracelsianism, astrology and medical ethics in the polemical writings of
      Tommaso Bovio (1521-1609)].
AB  - Tommaso Bovio was a representative of North Italian non-academic medicine in the
      early modern period. His "dialogues", published in the second half of the 16th
      century, were written in the Italian vernacular and enjoyed a certain popularity
      also in Germany. Although Bovio used to exaggerate for rhetorical effect, his
      portrayal of patients, illness and treatments provides interesting insights into
      everyday urban life in his time. Sympathising with Paracelsus, Bovio propagated
      an image of empirics as humanitarians and fought for the recognition of his own
      practical knowledge and skills. Bovio was a most original figure in the medicine
      of the period of counter reformation. His writings exemplify the lively debate
      between the learned medical tradition and unorthodox reform.

PMID- 15015855
TI  - [Protagonists, conflicts, and interests: Wilhelm Griesinger's trials in the
      reforming of the psychiatric ward of the Berlin Charite, 1865-1868].
AB  - In June 1865, two months after his appointment as head of the Psychiatric Ward of
      the Berlin Charite hospital, Wilhelm Griesinger (1817-1868) made reform proposals
      for introducing the method of non-restraint treatment. After tough negotiations,
      the hospital's administrator, Karl Heinrich Esse, approved only some of
      Griesinger's proposals. Further conflicts with other relevant agents, such as the
      ward's inspector and the nursing staff, illustrate the complex "making" of non
      restraint psychiatry.

PMID- 15015854
TI  - [The Tabulae anatomicae (1794-1803) of Justus Christian Loder: anatomical
      illustration between science, art and commerce].
AB  - With the publication of his Tabulae anatomicae in 1803, the Jena anatomist Justus
      Christian Loder (1753-1832) fulfilled the desideratum of a complete collection of
      anatomical illustrations of the entire human body. His "Tables" were one of the
      largest and most ambitious anatomical atlases in the German-speaking countries
      around 1800. The work reflects Loder's scientific concepts, the quality of his
      artists and the economic conditions of his publisher. Intended for a wide use in
      academic instruction, Loder's Tabulae popularised a style of illustration that
      focused on anatomical facts as basic statements and avoided artistic additions or
      culturally normative symbolism. Loder opposed theoretical transcendence and
      standardisation in the representation of human anatomy.

PMID- 15015856
TI  - ["Eternal physicianship" or "new medical ethics" 1939-1945? Hippocrates and
      historians in the service of war].
AB  - What changes, if any, came with the so-called "new medical ethics" that was
      propagated during the Nazi period and the war of 1939-1945? This article analyses
      the context of the publication series "Ewiges Arzttum" ("eternal physicianship"),
      which was edited during World War II. The first volume--"Hippocrates"--included
      an introduction by the "Reichsfuhrer-SS", Heinrich Himmler, and was edited by the
      "Reichsarzt-SS", Ernst Grawitz. B. J. Gottlieb, the medical historian who
      arranged the excerpts from Hippocratic texts, later headed an SS-Institute for
      the History of Medicine in Graz. Gottlieb was a pupil of Paul Diepgen, the head
      of the large Department for the History of Medicine and Natural Sciences at the
      University of Berlin. What were the goals of historians under National Socialism
      when they constructed continuities between the ethics of ancient times and the
      Nazi ethos? How did the moral points of view change under political pressure and
      in the circumstances of war? The series "Ewiges Arzttum", its context, and the
      correspondence between the persons involved are striking examples of the
      instrumentalisation of history for other purposes, even for "total war".

PMID- 15015857
TI  - Tobacco consumption in India: a new look using data from the National Sample
      Survey.
AB  - This paper examines the various issues surrounding tobacco use in India, using
      National Sample Survey and other data. The study demonstrates that 150 million
      Indians used tobacco in 1998 and that during the 1990's, the prevalence increased
      for both rural and urban areas, as well as in both sexes and in all age groups.
      Such large numbers have staggering implications for the country's economy, health
      outcomes and resources, and the magnitude of tobacco control challenges. Bidis
      hand-rolled cigarettes remain the most commonly used form of tobacco. However,
      major differences in rates and types of tobacco used were seen among various sex,
      age, economic and social class groups, suggesting that public health efforts to
      reduce consumption will require focused initiatives to target various populations
      and products.

PMID- 15015858
TI  - Tobacco consumption in India.

PMID- 15015859
TI  - Preventing illegal tobacco and alcohol sales to minors through electronic age
      verification devices: a field effectiveness study.
AB  - Efforts to prohibit the sales of tobacco and alcohol products to minors are
      widespread. Electronic Age Verification (EAV) devices are one possible means to
      improve compliance with sales to minors laws. The purpose of this study was to
      evaluate the implementation and effectiveness of EAV devices in terms of the
      frequency and accuracy of age verification, as well as to examine the impact of
      EAV's on the retailer environment. Two study locations were selected:
      Tallahassee, Florida and Iowa City, Iowa. Retail stores were invited to
      participate in the study, producing a self-selected experimental group. Stores
      that did not elect to test the EAV's comprised the comparison group. The data
      sources included: 1) mystery shopper inspections: two pre- and five post-EAV
      installation mystery shopper inspections of tobacco and alcohol retailers; 2)
      retail clerk and manager interviews; and 3) customer interviews. The study found
      that installing EAV devices with minimal training and encouragement did not
      increase age verification and underage sales refusal. Surveyed clerks reported
      positive experiences using the electronic ID readers and customers reported
      almost no discomfort about being asked to swipe their IDs. Observations from this
      study support the need for a more comprehensive system for responsible retailing.

PMID- 15015860
TI  - A gadget can't fix what's wrong with the tobacco distribution system.

PMID- 15015861
TI  - The World Health Organization's Framework Convention on Tobacco Control:
      implications for global epidemics of food-related deaths and disease.
AB  - This paper reviews the major elements of the WHO Framework Convention on Tobacco
      Control and considers those that can be applied to diet and nutrition. Tobacco
      and food policy have important differences: the two commodities have distinctly
      different health impacts, and food companies may be more responsive to public
      concerns than the tobacco industry. Nevertheless, both food and tobacco policy
      address public health issues surrounding legal products. Both require
      comprehensive and multi-sector approaches at global and national levels. The
      degree of flexibility possible in interacting and partnering with the private
      sector and food and related industries and the related implications for
      regulations and laws are reasons for a more nuanced approach to diet and physical
      activity policy.

PMID- 15015862
TI  - Lessons from tobacco control for the obesity control movement.

PMID- 15015863
TI  - The future role of health centers in improving national health.
AB  - International health rankings for the US are heavily influenced by striking
      racial and socioeconomic health status disparities. Current discussions of health
      determinants frequently relegate or entirely dismiss health care contributions
      despite increasing evidence of the importance of access to primary care. Health
      centers deliver community-based primary care to a considerable and growing
      proportion of the nation's most vulnerable and have produced significant health
      improvements, especially for women and children. Policies that disproportionately
      benefit those in greatest need are likely to produce the largest gains in
      national health. Continued expansion of the health center network to ensure
      primary care for those who remain underserved is both an effective and
      politically acceptable strategy to improve national health.

PMID- 15015864
TI  - Community health centers and the underserved: eliminating disparities or
      increasing despair.

PMID- 15015865
TI  - The association of doctor-patient race concordance with health services
      utilization.
AB  - We examined a national sample of African-American, white, Hispanic, and Asian
      American respondents to test the hypothesis that when patients are race
      concordant with their physicians, they are more likely to utilize health
      services. The analysis used the 1994 Commonwealth Fund Minority Health Survey to
      construct a series of multivariate models. Using three dimensions of health
      services utilization, we found support for the hypothesis. Compared to patients
      whose regular doctors are of a different race, patients who are of the same
      racial or ethnic group as their physicians were more likely to use needed health
      services (OR=.62; 95% CI .46, .81); were less likely to postpone or delay seeking
      care (OR=.78; 95% CI .65, .94); and reported a higher volume of use of health
      services (OR=2.68; 95% CI 2.07, 3.45). Analysis within race-specific sub-samples
      found this pattern to be most consistent among white and African-Americans and
      less prevalent among Hispanic and Asian-Americans. Adjusting the models for
      health status and a variety of other known predictors of health care utilization
      did not substantially affect the relationship between doctor-patient race
      concordance and health services use.

PMID- 15015866
TI  - Are we ready to act on racial concordance?

PMID- 15015867
TI  - The waiting list elite.

PMID- 15015868
TI  - Grassroots advocacy for gun violence prevention: a status report on mobilizing a
      movement.
AB  - The recent experience of gun violence prevention advocates with building an
      active, engaged grassroots holds important lessons for the future of gun violence
      prevention. However, formal research methods are rarely used to examine the role
      of grassroots advocacy efforts within public health. In order to assess the state
      of the grassroots gun violence prevention movement, learn from their experiences,
      and understand the challenges they face, the author conducted qualitative, semi
      structured interviews with eighteen leaders in the gun violence prevention
      community. The author then assessed the findings from the analysis of interview
      data within a social health movement framework, and developed recommendations for
      addressing the identified challenges. Results from this study provide insight
      into the state of U.S. grassroots gun violence prevention efforts prior to 2001.
      Grassroots advocacy efforts represent an important, influential component of
      injury prevention and public health. Understanding the perspective of the
      grassroots, their contribution to the field, and the challenges to such efforts
      is critical to ensuring a connection among the research, practice, policy and
      education efforts aimed at reducing injuries and violence.

PMID- 15015869
TI  - The Million Mom March: engaging the public on gun policy.

PMID- 15015870
TI  - The epidemiology of U.S. firearm injuries.

PMID- 15015871
TI  - Urban premature mortality in the U.S. between 1980 and 1990: changing roles of
      income inequality and social spending.
AB  - Measuring the effects of policy and social inequality is complicated because
      inequalities and policies may have delayed or accumulative effects on health. The
      objective of this study is to build on the body of work on population mortality
      and income inequality by investigating the association between income inequality
      and mortality at the city level at two points in time (1980 and 1990) as well as
      to determine whether indicators of 1980 social policies of cities are associated
      with 1990 mortality rates due to delayed or accumulative effects. We found that
      1980 income inequality and police spending is associated with increased premature
      mortality for 1990. In conclusion, there appear to be long-term consequences of
      city levels of income inequality on population health, although this relationship
      is incompletely understood. While a lack of information on how inequality
      operates on health should not preclude us from making policy decisions aimed at
      creating greater social equality, for example, through improvements in education,
      we would benefit from longitudinal research on specific macroeconomic and
      environmental factors, inequality, and health. Establishing such causal
      relationships is critical in creating social policies that optimally promote
      health and well-being.

PMID- 15015872
TI  - "Where does the damp come from?" Investigations into the indoor environment and
      respiratory health in Boston public housing.
AB  - The self-reported prevalence of asthma increased by 75% from 1980 to 1994, a
      trend found to be significant and evident in every region of the country. The
      increase has been most marked in children 0-14 years of age, and there is
      evidence that, as with lead poisoning, inner-city and urban populations are most
      at risk. Attention has turned to the role of indoor environment risk factors,
      especially in homes and schools. Such factors include moisture and mold growth,
      pest infestation, dust mites, the building envelope, heating systems, inadequate
      ventilation, NO2, and environmental tobacco smoke. The Healthy Public Housing
      Initiative (HPHI) is a Boston-based community-centered research and intervention
      project designed to engage Boston Housing Authority residents in a collaborative
      process to improve respiratory health, quality of life, building conditions, and
      building maintenance in public housing. This article summarizes the significant
      research findings from four pilot studies in housing developments that lay the
      foundation for the larger HPHI asthma-related environmental intervention study.
      The research design for the pilot projects is informed by principles of community
      collaborative research. The strengths of this model of research to our work are
      also discussed.

PMID- 15015873
TI  - Empirical science meets moral panic: an analysis of the politics of needle
      exchange.
AB  - The paper presents an analysis of the policy advocacy strategies used by both
      proponents and opponents of needle exchange programs in the US, drawing on the
      analytic framework developed by Stone. Based on a case study of the politics of
      needle exchange in Massachusetts, we argue that proponents of needle exchange
      have relied almost exclusively on empirical scientific arguments to build their
      case, while opponents have generally resorted to normative ethical arguments.
      Since the frames of argument are unrelated, the two sides talk past one another,
      bypassing progress towards resolution or consensus. By failing to address the
      ethical concerns raised by opponents, public health advocates of needle exchange
      are losing the larger public debate. The paper concludes with specific
      recommendations for how public health advocates should respond to the normative
      dimensions of this public policy issue.

PMID- 15015874
TI  - Abstinence-only education: how we got here and where we're going.
AB  - This paper examines the history of abstinence education in the United States and
      the empirical evidence of its effectiveness in preventing teenage pregnancy. It
      concludes that abstinence education has not yet been proven effective, and
      therefore recommends that federal policy and funding should be directed towards
      teen pregnancy prevention programs that have demonstrated success.

PMID- 15015875
TI  - Clinical experience with MultiHance in CNS imaging.
AB  - The use of Gd-BOPTA as a contrast agent for morphological and functional MR
      imaging allows improved detection and delineation of CNS lesions compared with
      conventional gadolinium agents. This not only leads to more confident diagnoses
      being made, but also results in a substantially improved differential diagnostic
      process. The higher relaxivity of Gd-BOPTA helps to optimize functional MR
      imaging studies, for example, perfusion MR imaging and dynamic MR angiographic
      protocols.

PMID- 15015876
TI  - Contrast-enhanced cardiac MR imaging.

PMID- 15015877
TI  - Gadobenate dimeglumine (MultiHance) for magnetic resonance angiography: review of
      the literature.
AB  - Although limited in number, reports describing the use of Gd-BOPTA for 3D CE-MRA
      reveal that this agent is safe, well tolerated and effective for CE-MRA at doses
      up to 0.3 mmol/kg bodyweight. The use of Gd-BOPTA leads to additional
      diagnostically relevant information comparable to that attainable with
      conventional DSA and superior to that on non-enhanced MRA in most arterial
      territories. In studies in which Gd-BOPTA is compared at equal dose with other
      gadolinium-based MR contrast agents, Gd-BOPTA has consistently shown
      significantly better quantitative and qualitative performance. Thus, Gd-BOPTA can
      be considered to have a very favorable risk/benefit ratio for MRA. In summary, it
      is likely the documented superiority of Gd-BOPTA for MR angiography will lead to
      its broad usage for this indication wherever the agent becomes available.

PMID- 15015879
TI  - High-concentration contrast media in MDCT angiography: principles and rationale.

PMID- 15015878
TI  - MR imaging of the breast: indications, established technique, and new directions.

PMID- 15015880
TI  - Contrast-enhanced MDCT of the thorax.

PMID- 15015881
TI  - Advances in cardiac imaging.

PMID- 15015882
TI  - MDCT of the abdominal aorta: basics, technical improvements, and clinical
      applications.

PMID- 15015884
TI  - What is the current situation in liver imaging?

PMID- 15015883
TI  - Advances in vascular and cardiac MDCT imaging: peripheral arteries.

PMID- 15015885
TI  - Characterization of focal liver lesions with contrast-enhanced ultrasound.

PMID- 15015886
TI  - Imaging of liver metastases with contrast-specific low-MI real-time ultrasound
      and SonoVue.

PMID- 15015887
TI  - Guidance and control of percutaneous treatments with contrast-enhanced
      ultrasound.

PMID- 15015888
TI  - Contrast-enhanced ultrasound: beyond the liver.

PMID- 15015890
TI  - Thalidomide with or without dexamethasone for refractory or relapsing multiple
      myeloma.
AB  - Both thalidomide and intermittent high-dose dexamethasone are agents with
      established activity against multiple myeloma. We summarized our experience with
      thalidomide alone, and then in combination with dexamethasone, for groups of
      patients with myeloma resistant or relapsing despite standard treatments.
      Criteria of response were based on greater than 50% reduction of serum myeloma
      protein and/or greater than 75% reduction of Bence Jones protein for patients
      treated with thalidomide alone and greater than 75% reduction of serum myeloma
      protein and/or greater than 90% reduction of Bence Jones protein for those who
      received thalidomide with dexamethasone. Among patients with resistant or
      relapsing disease treated with a combination of thalidomide and dexamethasone,
      47% of patients achieved remission with significant prolongation of survival for
      responsive patients. Among patients in stable partial remission after intensive
      therapy who received the same program, myeloma protein was reduced further by
      greater than 90% in 52% of patients who had not received prior
      thalidomide/dexamethasone. Side effects were frequent, mild and reversible, and
      often preventable. Our program of thalidomide/dexamethasone was a safe and
      effective combination for patients with resistant or relapsing disease, or as
      consolidation of partial remission after intensive therapy.

PMID- 15015891
TI  - Thalidomide in relapsed/refractory multiple myeloma: pivotal trials conducted
      outside the United States.
AB  - Recently completed phase II trials and retrospective analyses conducted outside
      the United States, primarily in Europe and Australia, have confirmed results of
      landmark US trials that established the efficacy of thalidomide in multiple
      myeloma. These trials evaluated thalidomide alone or in combination in patients
      with heavily pretreated relapsed/ refractory multiple myeloma. Single-agent
      thalidomide induced objective responses in approximately one third of patients
      and prolonged survival by approximately 1 year. These trials also indicated a
      possible dose-response relationship of thalidomide and identified several poor
      prognostic factors, including advanced age, high lactose dehydrogenase level, low
      platelet count, and low hemoglobin level. The combination of thalidomide with
      dexamethasone increased overall response by approximately 20% and reduced the
      time to response compared with thalidomide alone. In addition, lower doses of
      thalidomide used in the combination may increase patient tolerability. Finally,
      thalidomide in combination with chemotherapy yields response rates of
      approximately 60%, with median survival times of approximately 18 months.
      Randomized trials are needed to confirm these results and further explore the
      role of thalidomide in these treatment settings.

PMID- 15015893
TI  - The role of immunomodulatory drugs in multiple myeloma.
AB  - Thalidomide has shown promise in the treatment of newly diagnosed multiple
      myeloma and relapsed/refractory disease, but side effects such as somnolence,
      constipation, and neuropathy limit its use. CC-5013, an immunomodulatory drug
      (IMiD), is more potent than thalidomide. CC-5013 has various immunomodulatory
      effects, including growth arrest or apoptosis of drug-resistant myeloma cell
      lines and inhibition of binding of myeloma cells to bone marrow stromal cells.
      Clinically, 17 of 24 patients (71%) with relapsed/refractory disease experienced
      a reduction of paraprotein of > or = 25% following treatment with CC-5013,
      including 11 who had a history of treatment with thalidomide. Another two
      experienced stable disease. Median time to best response was 2 months (range, 1
      to 11) and median duration was 6 months (range, 2 to 18). Grade 3
      thrombocytopenia was seen in 20% of patients; grade 3 neutropenia was seen in
      60%; and grade 4 neutropenia was seen in 16%. CC-5013 use was not associated with
      somnolence, constipation, or neuropathy. This article reviews thalidomide in
      multiple myeloma, the effects of thalidomide analogues IMiDs, and the preclinical
      and clinical data on CC-5013 in relapsed/refractory multiple myeloma.

PMID- 15015892
TI  - Thalidomide in newly diagnosed multiple myeloma and overview of experience in
      smoldering/indolent disease.
AB  - Based on the activity of single-agent thalidomide demonstrated in relapsed or
      refractory multiple myeloma, investigators have evaluated the role of this agent
      in the treatment of earlier stage disease. Two key phase II trials of thalidomide
      plus dexamethasone in patients with previously untreated symptomatic multiple
      myeloma have yielded overall response rates of 64% to 73%. Comparable response
      rates, reduced toxicity, and increased patient convenience with oral
      administration suggest it may offer an alternative to standard infusional
      chemotherapies, such as vincristine/doxorubicin/dexamethasone (VAD), before stem
      cell mobilization and high-dose chemotherapy in patients with active disease;
      further study is warranted. Two key phase II trials of single-agent thalidomide
      in patients with smoldering/indolent (asymptomatic) disease have yielded overall
      response rates of approximately 35%, and further study of thalidomide in this
      setting is also indicated. The primary toxicities of thalidomide-based therapy
      are neuropathy, sedation/fatigue, constipation, and rash. Studies of thalidomide
      in combination with dexamethasone suggest toxicities of both agents may be
      increased due to the synergy of these agents. Phase III trials of thalidomide in
      newly diagnosed symptomatic multiple myeloma or smoldering/indolent disease are
      ongoing.

PMID- 15015894
TI  - Thalidomide and CC-5013 in multiple myeloma: the University of Arkansas
      experience.
AB  - Based on the activity of single-agent thalidomide in relapsed/refractory multiple
      myeloma in a landmark phase II study of 169 patients conducted at the University
      of Arkansas for Medical Sciences (UAMS), UAMS initiated several trials of
      thalidomide and the more potent thalidomide analog CC-5013. In an ongoing trial
      evaluating thalidomide plus the proteasome inhibitor bortezomib and dexamethasone
      in patients with relapsed/refractory disease following stem cell transplantation,
      approximately 50% of patients have experienced a paraprotein reduction of 50% or
      greater. In patients without cytogenetic abnormalities, the estimated 12-month
      event-free and overall survival rates are 69% and 100%, respectively. In a second
      ongoing trial building on the UAMS Total Therapy I regimen, newly diagnosed
      patients are randomized to thalidomide or no thalidomide pretransplantation
      followed by consolidation therapy with dexamethasone and multiagent chemotherapy
      post-transplantation (Total Therapy II). Although the Total Therapy II regimen
      appears to be superior to the original Total Therapy I regimen, assessment of the
      effect of thalidomide on Total Therapy II is pending accrual completion. Lastly,
      based on the increased potency and reduced toxicity profile of CC-5013 compared
      with thalidomide, a study of CC-5013 in patients with relapsed/refractory disease
      following transplantation was initiated. Patients are randomized to CC-5013 25 mg
      daily for 20 days versus CC-5013 50 mg every other day for 10 days. Preliminary
      results indicate the superiority of the 25-mg arm, with 40% of patients
      randomized to that arm experiencing a paraprotein reduction of 50% or greater.
      These preliminary results corroborate the role for thalidomide and CC-5013 in
      relapsed/refractory and newly diagnosed multiple myeloma based on the UAMS phase
      II study as well as several other studies of these agents outside of UAMS.

PMID- 15015895
TI  - Hohenheimer Consensus Talk. Oxidative and premature skin ageing.
AB  - To elucidate the scientific state of the art with respect to the role of
      nutrition in skin ageing, nine experts from different disciplines discussed the
      role of micronutrients on 'oxidative and premature skin ageing'. In this 25th
      Hohenheim Consensus Meeting, 13 questions were discussed and, based on published
      valid data, answered by mutual agreement. The consensus answers achieved during
      the meeting are justified by a scientific background text. The importance of in
      vitro and in vivo models regarding oxidative and premature skin ageing was
      critically evaluated. There was a special focus on prevention and intervention of
      skin ageing with nutrition. Finally, the paper summarizes the scientific
      background from different areas related to oxidative and premature skin ageing.

PMID- 15015896
TI  - Partnering occupational therapy and community development.

PMID- 15015897
TI  - Functional assessment of injured workers: a profile of assessor practices.
AB  - BACKGROUND: Considerable controversy and limited information surrounds the use of
      performance-based functional assessments for determining an injured worker's
      ability to function at work. PURPOSE: Amidst a variety of protocols, philosophies
      and tools, the key aspects of different assessment approaches are described and
      compared across a range of assessment provider organizations. METHOD: Qualitative
      and quantitative strategies were used to generate an in-depth understanding of
      the different assessment practices among 23 Southern Ontario assessment
      providers. RESULTS: Assessment approaches share common elements and variations
      that can be described along the continua of five dimensions: nature of assessor
      evaluee interactions, fixed or flexible protocol delivery, efforts to
      contextualize, perceptions and use of evidence, and provider organizational
      environment. These approach dimensions are offered as a focus for appraising
      practices. PRACTICE IMPLICATIONS: Assessors need to reflect upon to what extent
      they are using a whole person, client-centred approach directed by clinical
      reasoning amidst a market driven industry.

PMID- 15015898
TI  - The time of our lives: the experience of temporality in occupation.
AB  - BACKGROUND: This paper synthesizes research and theory on aspects of activities
      producing variations in perceived temporality and subjective experience.
      SYNTHESIS: A proposed continuum of variations of six temporal experience are
      described: 1) protracted duration--elapsed time feels greater than actual elapsed
      clock time; 2) synchronicity--match of clock and perceived time; 3) compression-
      perceived time feels shorter than clock time; 4) flow--a sense of timelessness;
      5) interstitial--perceived stoppage of clock time; and 6) temporal rupture-
      disruption of synchronicity of clock time. Five contextually situated steps that
      generate each of these temporal variations explain how these variations unfold in
      the experience of occupation. This synthesis is the basis for the Dynamic
      Occupation in Time (DOiT) Model which also incorporates the key occupational
      therapy concepts of human agency, personal engagement, context, and culture.
      PRACTICE IMPLICATIONS: Investigating how occupations produce various
      temporalities and experiences will allow occupational scientists to investigate
      the underlying complexities of occupation-based practice. Also, by understanding
      more about the dynamic nature of occupations and appreciating the fluid quality
      of persons within their occupational context, occupational therapists can improve
      their design of occupation-based interventions.

PMID- 15015899
TI  - Hemiplegic shoulder pain: implications for occupational therapy treatment.
AB  - BACKGROUND: Hemiplegic shoulder pain is common after stroke causing hemiplegia.
      It adversely affects the recovery of arm function and independence in activities
      of daily living. Subluxation, abnormal tone and limited range of motion or
      capsular constrictions have been reported as potential causes. Other factors such
      as rotator cuff tears, brachial plexus injury, shoulder-hand syndrome and other
      pre-existing pathological conditions may also be associated with hemiplegic
      shoulder pain. The etiology remains unclear, but hemiplegic shoulder pain may
      result from a combination of the above factors. SCOPE: This literature review
      examines the possible causes of hemiplegic shoulder pain and discusses the
      implications for occupational therapy treatment. Occupational therapy
      interventions include proper positioning, facilitation of movement through
      purposeful therapeutic activities, increasing passive range of motion,
      implementation of external supports and treatment of shoulder-hand syndrome.
      PRACTICE IMPLICATIONS: Understanding the processes involved will assist with
      effective assessment, treatment and prevention of hemiplegic shoulder pain. This
      will facilitate clients' participation in rehabilitation programs and move them
      towards attainment of optimal function.

PMID- 15015900
TI  - Strategy application test: discriminate validity studies.
AB  - PURPOSE: Having a method of testing strategy application abilities provides
      important information for occupational performance. The goal of the present study
      was to investigate the discriminate validity of a strategy application test. This
      test measures the ability to apply and maintain a working strategy for efficient
      execution of tasks. The advantages of this test are that it is standardized,
      short, simple to administer, and applicable to various clinical populations.
      METHOD: Five different groups of participants were studied: senior healthy
      people, children affected by attention-deficit hyperactivity disorder, people
      with multiple sclerosis or with depression and schizophrenia. All of these
      individuals had some frontal lobe involvement, thus suggesting possible executive
      dysfunction. RESULTS: As hypothesized, the results demonstrated strategy
      application skill impairment in all the clinical groups, as well as a gradual
      decline in strategy application abilities with advanced aging. PRACTICE
      IMPLICATIONS: These results exhibit the discriminate validity of the strategy
      application test and add to the accumulating evidence of executive dysfunction in
      these populations.

PMID- 15015901
TI  - Should antiepileptic drugs be withdrawn in seizure-free patients?
AB  - Discontinuation of antiepileptic drug (AED) treatment is a valuable option in
      patients with epilepsy who have been seizure free for 2 years or longer. However,
      the decision to withdraw AEDs must be based on a balanced view of the overall
      risk of seizure relapse, the factors most likely to affect that risk, and the
      medical, emotional and social implications of treatment continuation versus
      treatment withdrawal. In a critical review of 28 studies accounting for 4571
      patients (2758 children, 1020 adults and a combined group of 793), most with at
      least 2 years of seizure remission, the proportion of patients with relapses
      during or after AED withdrawal ranged from 12 to 66%. Using life-table analysis,
      the cumulative probability of remaining seizure-free in children was 66-96% at 1
      year and 61-91% at 2 years after withdrawal of AEDs. The corresponding values in
      adults were 39-74% and 35-57%, respectively. The relapse rate was highest in the
      first 12 months (especially in the first 6 months) after withdrawal and tended to
      decrease thereafter. Based on a previously published meta-analysis of data
      published up to 1992, the pooled relapse risk was 25% (95% CI 21, 30%) at 1 year
      and 29% (95% CI 24, 34%) at 2 years after AED withdrawal. The factors associated
      with a higher-than-average risk of seizure relapse included adolescent-onset
      epilepsy, partial seizures, the presence of an underlying neurological condition,
      and abnormal EEG findings at the time of AED withdrawal in children. Factors
      associated with a lower-than-average risk were childhood-onset epilepsy,
      idiopathic generalised epilepsy and - for children - a normal EEG. Selected
      epilepsy syndromes (e.g. benign epilepsy with centrotemporal spikes and juvenile
      myoclonic epilepsy) may be associated with significantly different outcomes after
      AED withdrawal. All these factors and their combinations may contribute to the
      development of guidelines for practising physicians to help them in making the
      best decision related to treatment discontinuation. The decision plan should also
      take into account social factors (driving license, job and leisure activities) as
      well as emotional and personal factors, and must be tailored to and discussed
      with the individual patient and his/her family.

PMID- 15015902
TI  - Antipsychotic-induced rabbit syndrome: epidemiology, management and
      pathophysiology.
AB  - Rabbit syndrome is an antipsychotic-induced rhythmic motion of the mouth/lips,
      resembling the chewing movements of a rabbit. The movement consists of a vertical
      only motion, at about 5Hz, with no involvement of the tongue. Usually, the
      involuntary movements associated with rabbit syndrome appear after a long period
      (in most cases months or years) of antipsychotic treatment; however, a few
      patients with the syndrome have had treatment histories with no antipsychotic
      involvement. The reported prevalence of rabbit syndrome ranges from 2.3 to 4.4%
      of patients treated with typical antipsychotics. There have been isolated reports
      of rabbit syndrome in patients treated with the atypical agents risperidone and
      clozapine. Patients with rabbit syndrome are most often misdiagnosed as having
      oral tardive dyskinesia. In such cases the key for correct diagnosis is the
      involvement of tardive tongue movements, which does not occur in rabbit syndrome.
      The treatment of rabbit syndrome is empirical, reflecting poor understanding of
      its neuropathology. The first step is to reduce the amount of antipsychotic
      treatment as much as possible. However, since, in most cases, full withdrawal of
      antipsychotic treatment is impossible, the syndrome cannot be completely
      abolished without additional measures. The next stage of treatment involves
      specific drugs that aim to control the syndrome. Anticholinergic drugs are the
      best known treatment. Rabbit syndrome does not respond to treatment with levodopa
      or dopamine agonists. The most striking aspect of this syndrome is its
      specificity. Rabbit syndrome affects only the buccal region, and within this area
      it involves a highly stereotyped involuntary movement. This immediately focuses
      attention on the basal ganglia, in particular the substantia nigra pars
      reticulata, which is also implicated in oral dyskinesia. Continuing
      neurophysiological and pharmacological research of the basal ganglia holds the
      key to better understanding and treatment of this syndrome in the coming years.

PMID- 15015904
TI  - Pharmacokinetic considerations in the treatment of attention-deficit
      hyperactivity disorder with methylphenidate.
AB  - Methylphenidate is commonly used for the treatment of attention-deficit
      hyperactivity disorder (ADHD). Its efficacy in improving the core symptoms of
      ADHD, as well as some of the aggressive and oppositional behaviours, is well
      documented, based on a large volume of research. Methylphenidate has a wide
      margin of safety and relatively mild adverse effects, most commonly appetite
      suppression and insomnia. Methylphenidate is a rapidly absorbed medication that,
      in its d-isomer form, readily penetrates the CNS, particularly the striatum. It
      appears to function by blocking the reuptake of dopamine. Both the plasma
      concentrations and behavioural effects of methylphenidate demonstrate a time to
      maximum of between 1 and 3 hours, with the maximum behavioural effects occurring
      when the plasma concentrations are increasing. Because of the rapid onset of
      action, the effects of methylphenidate can be dramatic but usually last only
      about 4 hours with the immediate-release formulation. The behavioural responses
      of individuals are also highly variable, so that it is necessary to start
      treatment at a low dosage and increase up to a maximally effective dosage
      (usually starting at 10-15 mg/day with increases of 10-15mg at weekly intervals
      to a maximum dosage of 60 mg/day, irrespective of formulation). Because of the
      variability in behavioural responses, assessment of plasma concentrations is not
      clinically useful nor does weight help in deciding an appropriate dosage. The
      difficulties in administering methylphenidate multiple times a day, particularly
      during the school day, have been alleviated in the past few years by the
      development of extended-release preparations with varying behavioural effects
      lasting 8-12 hours. The 8-hour preparations (Metadate) CD and Ritalin) LA)
      utilise a microbead technology, while the 12-hour preparation (Concerta) utilises
      an osmotic pump system. All extended-release formulations effectively control the
      symptoms of ADHD. While pharmacokinetic differences appear to exist between some
      of these new formulations, there are currently no clinical data available to
      demonstrate clinical efficacy differences between them.

PMID- 15015906
TI  - Searching PubMed/MEDLINE, Ingenta, and the Music Therapy World Journal Index for
      articles published in the Journal of Music Therapy.
AB  - The purpose of this study was to carry out a comparison between references to
      articles published in the Journal of Music Therapy before December 2002
      identified through searching PubMed/MEDLINE, the Ingenta database and those
      actually published in the journal. To carry out this comparison we have created a
      new database, called the Music Therapy World Journal Index, which includes
      complete indexes of selected music therapy journals. All articles published in
      the Journal of Music Therapy since its commencement in 1964 are referenced in
      this database. We found a large number of articles that are not identified by
      searching PubMed/MEDLINE. There is an under-representation of both the amount of
      articles published in this journal and in the range of areas for clinical
      application and research in music therapy. The Ingenta database is comprehensive
      but limited in its coverage of the early years. To carry out a comprehensive
      research of the literature, it is necessary to consult an expert database, such
      as the Music Therapy World Journal Index, that guarantees an unequivocal level of
      completeness.

PMID- 15015903
TI  - Secondary prevention of stroke: a practical guide to drug treatment.
AB  - Stroke is a disease of the elderly and, as a result of the expected demographic
      changes in many industrialised countries, its incidence is likely to increase in
      the future. A first-ever stroke significantly increases the likelihood of further
      events; thus, secondary prevention is of major importance. Only a minority of
      recurrent strokes can be prevented by surgical or other invasive methods, meaning
      that most secondary preventive measures involve drug treatment, which has become
      increasingly sophisticated in recent years. Ischaemic stroke constitutes the vast
      majority of all strokes; effective secondary prevention depends on a variety of
      factors, of which the correct classification in terms of subtypes and
      aetiological mechanisms is a pivotal prerequisite, as is the assessment of the
      patient's cardiovascular risk profile. In addition to the evaluation of
      pathomechanisms, stratification of subtypes of brain infarction is mainly based
      on morphology seen with brain imaging techniques, which provides additional
      evidence for the presumed cause of the stroke. Inhibitors of platelet function
      and anticoagulants are the two major groups of antithrombotic drugs used for the
      secondary prevention of stroke. Antiplatelet agents are still indicated in the
      majority of patients after ischaemic stroke, especially if an arterial origin is
      presumed. In addition to aspirin (acetylsalicylic acid), the position of which as
      the first-line antiplatelet drug is increasingly being questioned, other
      compounds with antiplatelet activity have been developed and have proven
      effective in secondary stroke prevention, including ticlopidine, clopidogrel and
      dipyridamole. Anticoagulants are principally indicated after cardioembolic
      ischaemic stroke; however, their inherent bleeding risks render their use in many
      cases rather difficult, in particular for elderly patients. Patient compliance
      with the recommended treatment is of major importance, given the somewhat limited
      efficacy of antithrombotic agents in stroke prevention. Since 'real world'
      experience does not match the circumstances under which clinical trials are
      conducted, this article will also deal with problems not covered by specific
      studies, such as risk stratification for anticoagulant treatment and how to
      proceed in cases of unknown stroke aetiology. The management of major
      cardiovascular risk factors is the other mainstay of secondary stroke prevention.
      Recent evidence indicates that antihypertensive treatment may be as effective as
      antithrombotic drugs for secondary prevention of stroke. This still needs to be
      proven for the treatment of other cardiovascular risk factors, such as diabetes
      mellitus and hypercholesterolemia. Nevertheless, the results of recent studies
      investigating the effect of HMG-CoA reductase inhibitors ('statins') on
      cardiovascular events strongly suggest a stroke-preventive effect.

PMID- 15015907
TI  - A survey of music therapy methods and their role in the treatment of early
      elementary school children with ADHD.
AB  - Attention-Deficit Hyperactivity Disorder (ADHD) has recently been receiving more
      frequent attention in professional circles and in the press, and some sources
      would assert that its occurrence in the general population is consistently
      growing. Because music therapists often work with preschool and school-age
      children, it is likely that they will increasingly be treating children with a
      diagnosis of ADHD. However, there is little in the music therapy literature about
      music therapy treatment for ADHD. The purpose of this survey was to ascertain
      what music therapy methods are being used for children with an ADHD diagnosis,
      how effective this treatment is perceived to be, and the role that music therapy
      treatment plays in relation to other forms of treatment. Results of the survey
      indicated that music therapists often utilize a number of music therapy methods
      in the treatment of children with ADHD. They often address multiple types of
      goals, and treatment outcome is generally perceived to be favorable. Referrals
      for music therapy services are received from a number of different sources,
      although parents and teachers were indicated to be the most frequent referral
      sources. Most children with ADHD receiving music therapy services also receive
      other forms of treatment, with an overwhelming majority receiving medication. The
      implications of these results are discussed, and areas for continuing research
      into the use of music therapy with ADHD are identified.

PMID- 15015905
TI  - Dopamine partial agonists: a new class of antipsychotic.
AB  - This review examines the development of dopamine partial agonists as a new class
      of antipsychotic agents. Partial agonists have a lower intrinsic activity at
      receptors than full agonists, allowing them to act either as a functional agonist
      or a functional antagonist, depending on the surrounding levels of naturally
      occurring neurotransmitter (full agonist). In the absence of a full agonist,
      partial agonists show functional agonist activity, binding to the receptor to
      produce a response. In the presence of a full agonist, partial agonists show
      functional antagonist activity, as receptor binding reduces the response from
      that seen with the full agonist. A partial agonist at dopamine D(2) receptors
      therefore offers an attractive option for the treatment of schizophrenia. It
      should act as a functional antagonist in the mesolimbic dopamine pathway, where
      excessive dopamine activity is thought to cause positive symptoms, but show
      functional agonist activity in the mesocortical pathway, where reduced dopamine
      activity is thought to be associated with negative symptoms and cognitive
      impairment. In addition, it should avoid the complete blockade of the
      nigrostriatal or tuberoinfundibular pathways, associated with extrapyramidal
      symptoms (EPS) and elevated prolactin levels, respectively. Clinical trials with
      aripiprazole - a new antipsychotic, which shows partial agonist activity at D(2)
      receptors and serotonin 5-HT(1A) receptors, and antagonist activity 5-HT(2A)
      receptors - have demonstrated the value of this treatment approach. Aripiprazole
      produced significant improvements in positive and negative symptoms in short- and
      long-term studies of patients with schizophrenia or schizoaffective disorder.
      Improvements occurred rapidly after the start of treatment, and were sustained
      throughout studies lasting up to 52 weeks. Significantly more patients responded
      to aripiprazole treatment than to haloperidol in the 52-week study, and
      aripiprazole-treated patients showed significantly greater improvements in
      negative and depressive symptoms than those receiving haloperidol. Aripiprazole
      treatment was well tolerated in both short- and long-term studies, showing a low
      liability for EPS and hyperprolactinemia, a lack of QTc prolongation, and minimal
      weight gain or sedation. In conclusion, the findings from clinical studies of
      aripiprazole show that dopamine partial agonists offer a novel, effective and
      well-tolerated treatment approach for patients with schizophrenia.

PMID- 15015908
TI  - Music therapy to promote prosocial behaviors in aggressive adolescent boys--a
      pilot study.
AB  - This pilot study was undertaken to investigate whether music therapy is effective
      in promoting prosocial behaviors in aggressive adolescent boys who have social,
      emotional, and learning difficulties. Fifteen subjects (aged 11-15 years),
      enrolled at a special residential school in New Zealand, were randomly assigned
      to music therapy treatment groups (n = 6, n = 5), and a waitlist control group (n
      = 4). Examination of demographic data identified differences between groups for
      diagnosis (p =.044), with Group 1 all having Attention Deficit Hyperactivity
      Disorder (ADHD), and for age (p =.027), with Group 2 having a mean age 1.38 years
      older. Measures included parent and teacher versions of the Developmental
      Behaviour Checklist (DBC-P & DBC-T) (Einfeld & Tonge, 1994; Einfeld, Tonge, &
      Parmenter, 1998). While no definite treatment effects could be detected, results
      suggest that a music therapy program promoting autonomy and creativity may help
      adolescents to interact more appropriately with others in a residential villa
      setting, but might also lead to a temporary mild increase in disruptive behavior
      in the classroom. A more highly structured program and smaller group numbers may
      be advantageous for boys who have ADHD.

PMID- 15015909
TI  - Music interventions and group participation skills of preschoolers with visual
      impairments: raising questions about music, arousal, and attention.
AB  - The purposes of this pilot study were two-fold: First, to document and compare
      attentive behavior during music and play-based group instructional sessions and
      second, to document and compare 4 group participation behaviors during music and
      play-based sessions. The 4 group participation behaviors included facing a
      central speaker, following onestep directions, manipulating objects according to
      their function, and remaining seated. Six of the 12 children enrolled completed
      the study, with all participants enrolled in an early intervention program due to
      visual impairments. Study participants were between the ages of 4 and 6 years
      inclusively. Children participated in 4, 30-minute instructional sessions. Two
      instructional sessions were music-based and two were play-based with the 4
      sessions equally distributed across a 2-week period. An ABBA design was used to
      control for possible order effects. Each session was videotaped to facilitate
      collection of behavioral data. Statistical analysis of these data revealed that
      attentive behavior was significantly higher during music based-sessions (t(5) =
      5.81; p =.002). Mean scores for the remaining group participation behaviors were
      higher in the music condition, but these differences were not statistically
      significant. Discussion regarding differential outcomes among participants, as
      well as an exploration of theories related to music, arousal, and attention are
      discussed in an effort to guide future research.

PMID- 15015910
TI  - Can dementia be prevented? Brain aging in a population-based context.
AB  - As a consequence of global aging of the human population, the occurrence of
      cognitive impairment and dementia is rapidly becoming a significant burden for
      medical care and public health systems. By the year 2020, the WHO predicts there
      will be nearly 29 million demented people in both developed and developing
      countries. Primary and secondary prevention of dementia through individual and
      population-level interventions could reduce this imminent risk. Vascular risk
      factors such as type 2 diabetes, hypertension, dietary fat intake, high
      cholesterol, and obesity have emerged as important influences on the risk of both
      vascular and Alzheimer's dementia. Understanding the reasons for differences
      between populations in genetic vulnerability and environmental exposures may help
      to identify modifiable risk factors that may lead to effective prevention of
      vascular and Alzheimer's dementia.

PMID- 15015911
TI  - Public health surveillance of low-frequency populations.
AB  - Public health agencies often require data that address the needs of special
      populations, such as minority groups. Sources of surveillance data often contain
      insufficient numbers of subjects to fully inform health agencies. In this review,
      we address the problems of and potential approaches for situations with
      insufficient surveillance data. We use the examples of race and ethnic minority
      groups throughout our discussion. However, many of the broad issues are
      applicable to other special groups with low frequency or who are especially hard
      to reach. Our recommendations are based, in part, on a symposium held in Missouri
      with the collaboration of state health agency, community, and academic research
      participants. We review problems in using existing data and collecting new data,
      especially from nonprobability samples. We also describe fieldwork issues for
      reaching and collecting information from special populations. Decisions among
      methods and solutions may require seeking additional resources for surveillance.

PMID- 15015912
TI  - Statistical and substantive inferences in public health: issues in the
      application of multilevel models.
AB  - Multilevel statistical models have become increasingly popular among public
      health researchers over the past decade. Yet the enthusiasm with which these
      models are being adopted may obscure rather than solve some problems of
      statistical and substantive inference. We discuss the three most common
      applications of multilevel models in public health: (a) cluster-randomized
      trials, (b) observational studies of the multilevel etiology of health and
      disease, and (c) assessments of health care provider performance. In each area of
      investigation, we describe how multilevel models are being applied, comment on
      the validity of the statistical and substantive inferences being drawn, and
      suggest ways in which the strengths of multilevel models might be more fully
      exploited. We conclude with a call for more careful thinking about multilevel
      causal inference.

PMID- 15015913
TI  - Trends in the health of the elderly.
AB  - Health among the older population as measured by most dimensions has improved
      during the last two decades. Mortality has continued to decline, and disability
      and functioning loss are less common now than in the past. However, the
      prevalence of most diseases has increased in the older population as people
      survive longer with disease, and the reduction in incidence does not counter the
      effect of increased survival. On the other hand, having a disease appears to be
      less disabling than in the past.

PMID- 15015914
TI  - What do we do with missing data? Some options for analysis of incomplete data.
AB  - Missing data are a pervasive problem in many public health investigations. The
      standard approach is to restrict the analysis to subjects with complete data on
      the variables involved in the analysis. Estimates from such analysis can be
      biased, especially if the subjects who are included in the analysis are
      systematically different from those who were excluded in terms of one or more key
      variables. Severity of bias in the estimates is illustrated through a simulation
      study in a logistic regression setting. This article reviews three approaches for
      analyzing incomplete data. The first approach involves weighting subjects who are
      included in the analysis to compensate for those who were excluded because of
      missing values. The second approach is based on multiple imputation where missing
      values are replaced by two or more plausible values. The final approach is based
      on constructing the likelihood based on the incomplete observed data. The same
      logistic regression example is used to illustrate the basic concepts and
      methodology. Some software packages for analyzing incomplete data are described.

PMID- 15015915
TI  - Emission trading and public health.
AB  - Emission trading policies are increasingly important in environmental protection,
      especially in controlling air pollution in the United States. Their popularity
      results in part from the limitations and frustrations of centralized command and
      control regulation. Well-designed emission trading programs can achieve the same
      or better environmental and health outcomes as command and control regulations
      but provide regulated industries with greater flexibility. This lowers costs and
      improves the process of negotiating environmental policy. We present key concepts
      and important applications of emission trading, focusing on health impacts. These
      programs generally are well-designed, speeding emission abatement; improving
      health outcomes; and reducing compliance costs. Flaws have stopped a few poorly
      designed emission trading programs. A key issue in evaluating emission trading is
      our inability to know what the environmental outcome would have been under
      another approach.

PMID- 15015916
TI  - Genetic testing in the workplace: ethical, legal, and social implications.
AB  - With the completion of the Human Genome Project, it is likely that genetic
      testing for susceptibility to a wide range of diseases will increase in society.
      One venue for such increased testing is likely to be the workplace as employers
      attempt to protect workers from unhealthy gene-environment interactions, improve
      productivity, and control escalating health care costs. Past and recent examples
      of genetic testing in the workplace raise serious concerns that such testing
      could pose a significant threat to workers' privacy, autonomy, and dignity. Thus,
      defining the ethically, legally, and socially appropriate and inappropriate uses
      of genetic testing in the workplace presents a major challenge for occupational
      health professionals in the years ahead.

PMID- 15015917
TI  - Health effects of chronic pesticide exposure: cancer and neurotoxicity.
AB  - Pesticides are widely used in agricultural and other settings, resulting in
      continuing human exposure. Epidemiologic studies indicate that, despite premarket
      animal testing, current exposures are associated with risks to human health. In
      this review, we describe the routes of pesticide exposures occurring today, and
      summarize and evaluate the epidemiologic studies of pesticide-related
      carcinogenicity and neurotoxicity in adults. Better understanding of the patterns
      of exposure, the underlying variability within the human population, and the
      links between the animal toxicology data and human health effects will improve
      the evaluation of the risks to human health posed by pesticides. Improving
      epidemiology studies and integrating this information with toxicology data will
      allow the human health risks of pesticide exposure to be more accurately judged
      by public health policy makers.

PMID- 15015918
TI  - Implications of the precautionary principle for primary prevention and research.
AB  - The precautionary principle (PP) is an extension of the public health presage
      that prevention is better than cure. The PP has recently achieved new relevance
      in regard to serious but uncertain threats to human health and the environment
      and has now entered national and international legislation. However, frameworks
      for its unambiguous application in practice are yet to be designed. They will
      depend on legal and cultural circumstances and are likely to involve pluralities
      of perspectives and stakeholder participation. The rules for causal reasoning and
      dose dependence need to be addressed and may be conveniently expressed in
      accordance with probability theory. Although the PP will allow action before
      convincing evidence is secured, it is not science averse. However, it provides an
      occasion to review environmental health research strategies, methodologies, and
      research-reporting traditions. From this perspective, current research is
      afflicted by important biases and insufficient focus on major environmental
      health problems.

PMID- 15015919
TI  - Issues of agricultural safety and health.
AB  - Agricultural work is the most prevalent type of employment in the world. In the
      United States only a few are engaged in creating food and fiber for many.
      Agriculture includes farming, ranching, fishing, and forestry, and together they
      carry significant risk for the development of injury or illness. There are
      numerous special-population issues related to agriculture. Farmers are old and
      growing older, many workers are children, and migrant and seasonal help, often
      foreign born, make up a large percentage of the workforce. It has been only
      relatively recently that concerns of agricultural safety and health have become a
      major research focus in the United States.

PMID- 15015921
TI  - Developing and using the Guide to Community Preventive Services: lessons learned
      about evidence-based public health.
AB  - The Guide to Community Preventive Services (Community Guide) is being developed
      under the leadership of the independent, nonfederal Task Force on Community
      Preventive Services. The Task Force makes recommendations for the use of public
      health programs and policies based on scientific evidence about what practices
      have worked to improve health. The Community Guide thoroughly searches scientific
      literature for topic-relevant studies, evaluates their quality according to
      established criteria, and makes recommendations based on the overall strength of
      the body of evidence and the size and variability of reported effects. In
      addition, the Community Guide identifies promising interventions that have not
      been adequately researched, thus helping to inform the public health research
      agenda. The continuously updated and expanded body of recommendations and
      research agenda formulated by this rigorous process have been published on the
      Internet and in various publications since 1999 and constitute a highly valued
      and objective evidence-based resource for guiding current and future public
      health activities. More remains to be learned, however, on how best to
      disseminate Community Guide findings to key target audiences and encourage their
      use to inform practice, policy, and additional research.

PMID- 15015920
TI  - Time-series studies of particulate matter.
AB  - Studies of air pollution and human health have evolved from descriptive studies
      of the early phenomena of large increases in adverse health effects following
      extreme air pollution episodes to time-series analyses based on the use of
      sophisticated regression models. In fact, advanced statistical methods are
      necessary to address the challenges inherent in the detection of a relatively
      small pollution risk in the presence of potential confounders. This paper reviews
      the history, methods, and findings of the time-series studies estimating health
      risks associated with short-term exposure to particulate matter (PM), though much
      of the discussion is applicable to epidemiological studies of air pollution in
      general. We review the critical role of epidemiological studies in setting
      regulatory standards and the history of PM epidemiology and time-series analysis.
      We also summarize recent time-series results and conclude with a discussion of
      current and future directions of time-series analysis of particulates, including
      research on mortality displacement and the resolution of results from cohort and
      time-series studies.

PMID- 15015922
TI  - Modeling infection transmission.
AB  - Understanding what determines patterns of infection spread in populations is
      important for controlling infection transmission. The science that advances this
      understanding uses mathematical and computer models that vary from deterministic
      models of continuous populations to models of dynamically evolving contact
      networks between individuals. These provide insight, serve as scientific
      theories, help design studies, and help analyze data. The key to their use lies
      in assessing the robustness of inferences made using them to violation of their
      simplifying assumptions. This involves changing model forms from deterministic to
      stochastic and from compartmental to network, as well as adding realistic detail
      and changing parameter values. Currently inferences about infection transmission
      are often made using stratified rate or risk comparisons, logistic regression
      models, or proportionate hazards models that assume an absence of transmission.
      Robustness assessment will show many of these inferences to be wrong. A community
      of epidemiologist modelers is needed for effective robustness assessment.

PMID- 15015923
TI  - The current state of public health in China.
AB  - In the past 50 years, China has made great achievements in controlling infectious
      diseases and improving the public's health and hygiene. However, in the twenty
      first century, owing to the negative effects brought on by aging of the
      population and the burdens of diseases, urbanization, industrialization, and
      globalization, Chinese public health officials are encountering greater
      difficulties than ever. Old operating models of public health cannot meet present
      requirements. The main problems are poor capacity to respond to public health
      emergencies, severe inequality of health care services, and lagging development
      of public health information systems. Public health in China can gradually meet
      the requirements of social development and the increasing public demand for
      health care services only when the public health is directed by informatization,
      globalization, technification, and humanization.

PMID- 15015924
TI  - The public health workforce.
AB  - The development of a fully-competent public health workforce as a key component
      of the nation's public health infrastructure has become the focus of increasing
      attention. The subject is included in one, and is the major topic of a second,
      report from the Institute of Medicine published late in 2002. Workforce issues
      have stimulated the convening of the majority of public health-related
      associations in a range of collaborations on the subjects of defining,
      enumerating, credentialing, educating, and studying the workforce. The authors
      review the major questions confronting the field and introduce key components of
      current thinking about approaches to improvement.

PMID- 15015925
TI  - Assuring the health of immigrants: what the leading health indicators tell us.
AB  - Over the past 20 years, the United States has experienced one of the largest
      waves of immigration in its history. Understanding the health status and needs of
      immigrants is important because of their growing numbers and their contribution
      to the health of the nation, but it is challenging because of gaps in national
      databases, the heterogeneity of immigrant populations, and uncertainty about how
      migration affects health. Healthy People 2010 outlines the nation's public health
      objectives for the current decade. It includes ten leading health indicators
      (LHIs) chosen because of their importance as public health issues, their ability
      to motivate action, and the availability of data to measure their progress. In
      this paper, we discuss the health of immigrants from the perspective of these
      LHIs, as they provide a framework for anticipating some of the future health
      needs of immigrants and help define priority areas for research and action.

PMID- 15015926
TI  - Harm reduction approaches to reducing tobacco-related mortality.
AB  - Tobacco harm reduction approaches are gaining increased attention. Much of this
      attention is due to a growing concern that significant populations of smokers
      either do not want to quit or believe they are unable to quit smoking, and to a
      concern over tobacco-industry attempts to produce tobacco products that claim to
      result in less toxin exposure. Decreasing tobacco toxin exposure as a method for
      reducing mortality and morbidity may be a reasonable tobacco control strategy.
      However, the impact of this strategy must be explored both on individual and
      population levels. A significant amount of independent research is needed to
      inform policy decisions. Regulatory authority over potential reduced exposure
      products is also essential.

PMID- 15015927
TI  - Housing and public health.
AB  - This review considers the broad area of housing and public health, one of the
      traditional and core areas of public health research and intervention. The review
      takes into account the range of factors, acting at different levels, directly and
      indirectly, through which housing affects health. In public health terms, housing
      affects health in a myriad of relatively minor ways, in total forming one of the
      key social determinants of health. The paper closes by considering how the
      improvement of housing and neighborhoods has been a core activity of public
      health and a central component in tackling poverty. Investment in housing can be
      more than an investment in bricks and mortar: It can also form a foundation for
      the future health and well-being of the population. Addressing poor-quality
      housing and detrimental neighborhoods, in the broadest sense, is thus a task that
      should be grasped with vigor and determination by all those involved in public
      health.

PMID- 15015928
TI  - Lessons learned from public health mass media campaigns: marketing health in a
      crowded media world.
AB  - Every year, new public health mass media campaigns are launched attempting to
      change health behavior and improve health outcomes. These campaigns enter a
      crowded media environment filled with messages from competing sources. Public
      health practitioners have to capture not only the attention of the public amid
      such competition, but also motivate them to change health behaviors that are
      often entrenched or to initiate habits that may be new or difficult. In what ways
      are public health mass media campaigns now attempting to succeed in a world
      crowded with media messages from a myriad of sources? What are the conditions
      that are necessary for a media campaign to successfully alter health behaviors
      and alter outcomes in the long term? To what extent can the successes and
      failures of previous campaigns be useful in teaching important lessons to those
      planning campaigns in the future? In this chapter we attempt to answer these
      questions, drawing from recent literature on public health mass media campaigns.

PMID- 15015929
TI  - The role of culture in health communication.
AB  - This paper examines the role of culture as a factor in enhancing the
      effectiveness of health communication. We describe culture and how it may be
      applied in audience segmentation and introduce a model of health communication
      planning--McGuire's communication/persuasion model--as a framework for
      considering the ways in which culture may influence health communication
      effectiveness. For three components of the model (source, message, and channel
      factors), the paper reviews how each affects communication and persuasion, and
      how each may be affected by culture. We conclude with recommendations for future
      research on culture and health communication.

PMID- 15015930
TI  - Economic implications of increased longevity in the United States.
AB  - The elderly population in America is growing in size owing to declining death
      rates, increasing life expectancy, and the aging of the baby boomers. Although
      the prevalence of chronic illness and disability increases with age, successful
      aging in the elderly population is widespread, and the elderly are generally
      healthy. Indeed, the prevalence of disability among the elderly is declining, and
      expenditures for their care are increasingly concentrated at the end of life
      rather than during extra years of relatively healthy life. Nevertheless, health
      care costs will undoubtedly increase during the next 30 years as a result of the
      baby boomers entering late life. The economic and social impact of future growing
      health care expenditures for the elderly will be significant. Important policy
      issues will include the continued viability of the Medicare and Social Security
      programs, future needs for long-term care, improvement of the health status of
      the elderly, technological advances, the need for a geriatric work force, and
      development of viable strategies to pay for escalating medical care costs.

PMID- 15015931
TI  - International differences in drug prices.
AB  - This paper addresses how and why drug prices differ across countries. Studies of
      international variation in drug prices reach varied conclusions owing to
      methodological and data disparities. Price differences do exist across countries,
      with the United States footing the highest bill, but the differences are not
      nearly as large as they appear at first glance. The higher prices in the United
      States are concentrated among a subset of brand-name drugs and among those
      without insurance covering drugs. Some U.S. health plans obtain price concessions
      from manufacturers similar to those obtained by national governments. Price
      concessions occur whenever purchasers are willing to let price be a consideration
      in decisions about access and utilization. In low-income countries the vast
      majority are unwilling to pay for effective drugs simply because they are unable
      to pay. Low-income nations need more price discrimination--and vastly lower
      prices--if they are ever to afford the world's most effective medicines.

PMID- 15015932
TI  - Physician gender and patient-centered communication: a critical review of
      empirical research.
AB  - Physician gender has stimulated a good deal of interest as a possible source of
      variation in the interpersonal aspects of medical practice, with speculation that
      female physicians are more patient-centered in their communication with patients.
      Our objective is to synthesize the results of two meta-analytic reviews the
      effects of physician gender on communication in medical visits within a
      communication framework that reflects patient-centeredness and the functions of
      the medical visit. We performed online database searches of English-language
      abstracts for the years 1967 to 2001 (MEDLINE, AIDSLINE, PsycINFO, and
      BIOETHICS), and a hand search was conducted of reprint files and the reference
      sections of review articles and other publications. Studies using a communication
      data source such as audiotape, videotape, or direct observation were identified
      through bibliographic and computerized searches. Medical visits with female
      physicians were, on average, two minutes (10%) longer than those of male
      physicians. During this time, female physicians engaged in significantly more
      communication that can be considered patient-centered. They engaged in more
      active partnership behaviors, positive talk, psychosocial counseling,
      psychosocial question asking, and emotionally focused talk. Moreover, the
      patients of female physicians spoke more overall, disclosed more biomedical and
      psychosocial information, and made more positive statements to their physicians
      than did the patients of male physicians. Obstetrics and gynecology may present a
      pattern different from that of primary care: Male physicians demonstrated higher
      levels of emotionally focused talk than their female colleagues. Female primary
      care physicians and their patients engaged in more communication that can be
      considered patient-centered and had longer visits than did their male colleagues.
      Limited studies exist outside of primary care, and gender-related practice
      patterns might differ in some subspecialties from those evident in primary care.

PMID- 15015933
TI  - The direct care worker: the third rail of home care policy.
AB  - Home health aides, home care workers, and personal care attendants form the core
      of the paid home care system, providing assistance with activities of daily
      living and the personal interaction that is essential to quality of life and
      quality of care for their clients. High turnover and long vacancy periods are
      costly for providers, consumers, their families, and workers themselves. In 2002,
      37 states identified worker recruitment and retention as major priority issues.
      Demographic and economic trends do not augur well for the future availability of
      quality home care workers. Policymakers in the areas of health, long-term care,
      labor, welfare, and immigration must partner with providers, worker
      organizations, and researchers to identify and implement the most successful
      interventions for developing and sustaining this workforce at both policy and
      practice levels. The future of home care will depend, in large part, on this
      "third rail" of long-term care policy.

PMID- 15015934
TI  - The chitinase 3-like protein human cartilage glycoprotein 39 inhibits cellular
      responses to the inflammatory cytokines interleukin-1 and tumour necrosis factor
      alpha.
AB  - Expression of the chitinase 3-like protein HC-gp39 (human cartilage glycoprotein
      39) is associated with conditions of increased matrix turnover and tissue
      remodelling. High levels of this protein have been found in sera and synovial
      fluids of patients with inflammatory and degenerative arthritis. In order to
      assess the role of HC-gp39 in matrix degradation induced by inflammatory
      cytokines, we have examined its effect on the responses of connective tissue
      cells to TNF-alpha (tumour necrosis factor-alpha) and IL-1 (interleukin-1) with
      respect to activation of signalling pathways and production of MMPs (matrix
      metalloproteases) and chemokines. Stimulation of human skin fibroblasts or
      articular chondrocytes with IL-1 or TNF-alpha in the presence of HC-gp39 resulted
      in a marked reduction of both p38 mitogen-activated protein kinase and stress
      activated protein kinase/Jun N-terminal kinase phosphorylation, whereas nuclear
      translocation of nuclear factor kappaB proceeded unimpeded. HC-gp39 suppressed
      the cytokine-induced secretion of MMP1, MMP3 and MMP13, as well as secretion of
      the chemokine IL-8. The suppressive effects of HC-gp39 were dependent on
      phosphoinositide 3-kinase activity, and treatment of cells with HC-gp39 resulted
      in AKT-mediated serine/threonine phosphorylation of apoptosis signal-regulating
      kinase 1. This process could therefore be responsible for the down-regulation of
      cytokine signalling by HC-gp39. These results suggest a physiological role for HC
      gp39 in limiting the catabolic effects of inflammatory cytokines.

PMID- 15015935
TI  - RNA interference-mediated silencing of synaptotagmin IX, but not synaptotagmin I,
      inhibits dense-core vesicle exocytosis in PC12 cells.
AB  - Although PC12 cells express three synaptotagmin isoforms (Syts I, IV and IX), all
      of which have been proposed to regulate dense-core vesicle exocytosis, it remains
      unknown which of the Sytisoforms acts as the major Ca2+ sensor for dense-core
      vesicle exocytosis. In the present study, it has been shown by immunoaffinity
      purification and immunocytochemistry that Syts I and IX, but not Syt IV, are
      present on the same secretory vesicles in PC12 cells. Silencing of Syt IX with
      specific small interfering RNA significantly reduced high KCl-dependent
      neuropeptide Y secretion from PC12 cells, whereas silencing of Syt I with
      specific small interfering RNA had no significant effect. The results indicate
      that Syts I and IX are not functionally equivalent and that Syt IX, and not Syt
      I, is indispensable for the regulation of Ca2+-dependent dense-core vesicle
      exocytosis in PC12 cells.

PMID- 15015936
TI  - Thimerosal stimulates Ca2+ flux through inositol 1,4,5-trisphosphate receptor
      type 1, but not type 3, via modulation of an isoform-specific Ca2+-dependent
      intramolecular interaction.
AB  - Thiol-reactive agents such as thimerosal have been shown to modulate the Ca2+
      flux properties of IP3 (inositol 1,4,5-trisphosphate) receptor (IP3R) via an as
      yet unidentified mechanism [Parys, Missiaen, De Smedt, Droogmans and Casteels
      (1993) Pflugers Arch. 424, 516-522; Kaplin, Ferris, Voglmaier and Snyder (1994)
      J. Biol. Chem. 269, 28972-28978; Missiaen, Taylor and Berridge (1992) J. Physiol.
      (Cambridge, U.K.) 455, 623-640; Missiaen, Parys, Sienaert, Maes, Kunzelmann,
      Takahashi, Tanzawa and De Smedt (1998) J. Biol. Chem. 273, 8983-8986]. In the
      present study, we show that thimerosal potentiated IICR (IP3-induced Ca2+
      release) and IP3-binding activity of IP3R1, expressed in triple IP3R-knockout R23
      11 cells derived from DT40 chicken B lymphoma cells, but not of IP3R3 or [D1-225]
      IP3R1, which lacks the N-terminal suppressor domain. Using a 45Ca2+-flux
      technique in permeabilized A7r5 smooth-muscle cells, we have shown that Ca2+
      shifted the stimulatory effect of thimerosal on IICR to lower concentrations of
      thimerosal and thereby increased the extent of Ca2+ release. This suggests that
      Ca2+ and thimerosal synergetically regulate IP3R1. Glutathione S-transferase pull
      down experiments elucidated an interaction between amino acids 1-225 (suppressor
      domain) and amino acids 226-604 (IP3-binding core) of IP3R1, and this interaction
      was strengthened by both Ca2+ and thimerosal. In contrast, calmodulin and sCaBP-1
      (short Ca2+-binding protein-1), both having binding sites in the 1-225 region,
      weakened the interaction. This interaction was not found for IP3R3, in agreement
      with the lack of functional stimulation of this isoform by thimerosal. The
      interaction between the IP3-binding and transmembrane domains (amino acids 1-604
      and 2170-2749 respectively) was not affected by thimerosal and Ca2+, but it was
      significantly inhibited by IP3 and adenophostin A. Our results demonstrate that
      thimerosal and Ca2+ induce isoform-specific conformational changes in the N
      terminal part of IP3R1, leading to the formation of a highly IP3-sensitive Ca2+
      release channel.

PMID- 15015937
TI  - Epigenetic modifications affect Dnmt3L expression.
AB  - Imprinted genes are expressed from a single allele due to differential
      methylation of maternal or paternal alleles during gametogenesis. Dnmt3L (DNA
      cytosine-5-methyltransferase 3 like), a member of de novo methyltransferase Dnmt3
      protein family, is a regulator of maternal imprinting. In the present study, we
      have characterized the promoter region of the mouse Dnmt3L gene. Transient
      transfection assays performed with 5'-deletion promoter constructs indicated a
      minimal promoter area within 440 bp upstream from the translational start site.
      Longer promoter constructs showed decreased activity, suggesting the presence of
      repressor elements within the upstream sequences. According to electrophoretic
      mobility-shift assays and mutation analysis, the minimal promoter region
      contained four functional binding sites for the Sp1 (specificity protein 1)
      family of transcription factors, Sp1 and Sp3. In vitro methylation of Dnmt3L
      promoter constructs decreased the transcriptional activity significantly,
      demonstrating down-regulation by cytosine methylation. This was supported by the
      results from bisulphite sequencing and real-time quantitative reverse
      transcriptase-PCR analysis of different mouse cell lines and tissues. In testis
      and embryonic stem cells showing strong Dnmt3L expression, all CpG sites studied
      were fully unmethylated, whereas non-expressive cell lines and tissues with
      lesser Dnmt3L expression showed complete or diverse CpG methylation levels.
      Treatment of Dnmt3L non-expressive cell lines with deacetylase inhibitor
      trichostatin A and methyltransferase inhibitor 5-aza-2'-deoxycytidine induced the
      expression of Dnmt3L mRNA. Furthermore, we show that the repressional effect of
      longer promoter fragments was also relieved by these inhibitors, altogether
      indicating an epigenetic control for Dnmt3L gene regulation.

PMID- 15015939
TI  - Theoretical model of the three-dimensional structure of a sugar-binding protein
      from Pyrococcus horikoshii: structural analysis and sugar-binding simulations.
AB  - The three-dimensional structure of a sugar-binding protein from the thermophilic
      archaea Pyrococcus horikoshii has been predicted by a homology modelling
      procedure and investigated for its stability and its ability to bind different
      sugars. The model was created by using as templates the three-dimensional
      structures of a maltodextrin-binding protein from Pyrococcus furiosus, a
      trehalose-maltose-binding protein from Thermococcus litoralis and a maltodextrin
      binding protein from Escherichia coli. According to the suggestions from the CASP
      (Critical Assessment of Structure Prediction) meetings, the homology modelling
      strategy was applied by assessing an accurate multiple sequence alignment, based
      on the high structural conservation in the family of ATP-binding cassette
      transporters to which all these proteins belong. The model has been deposited in
      the Protein Data Bank with the code 1R25. According to the origin of the protein,
      several characteristics in the organization of the secondary-structure elements
      and in the distribution of polar and non-polar amino acids are very similar to
      those of thermophilic proteins, compared with proteins from mesophilic organisms,
      and are analysed in detail. Finally, a simulation of the binding of several
      sugars in the binding site of this protein is presented, and interactions with
      amino acids are highlighted in detail.

PMID- 15015940
TI  - Overall volumetric oxygen transfer coefficient in an aerated bench-top stirred
      fermenter in aqueous dispersions of sodium alginate.
AB  - The dynamic gassing-out method was used to assess the effect of stirrer speed,
      air flow rate and alginate concentration on the overall volumetric oxygen mass
      transfer coefficient (K(L)a) in a bench-top stirred fermenter equipped with two
      Rushton-type turbines. As the alginate concentration in the medium was increased
      from 0 to 2% (w/v), the liquid film time constant (tau(F)) increased from approx.
      30 to 300% of the electrode time constant (tau(E)), clearly showing that the
      liquid-probe diffusion film affected the oxygen-electrode response. By accounting
      for delayed probe response, liquid film time constant and gas residence time, the
      corrected values of K(L)a were empirically correlated with the above independent
      variables as converted into gassed power input and aeration number per unit
      liquid volume and the effective liquid/water shear viscosity ratio. Despite an
      average error of 19%, such a correlation might be useful to adjust the oxygen
      transfer in bench-top stirred reactors during viscous aerobic fermentations.

PMID- 15015938
TI  - Expression pattern of the deoxyribonuclease 1 gene: lessons from the Dnase1
      knockout mouse.
AB  - The tissue distribution of deoxyribonuclease 1 (DNASE1, DNase I), a Ca2+ and
      Mg2+/Mn2+-dependent secretory endonuclease, has previously been investigated.
      However, most of these studies did not account for the existence of different
      members of the DNASE1 gene family, did not differentiate between endogenous
      DNASE1 protein synthesis and its extracellular occurrence or were not performed
      with methods allowing both a sensitive and a specific detection. Now we re
      examined the DNASE1 gene expression pattern by taking advantage of the Dnase1
      knockout mouse model. Direct comparison of samples derived from wild-type
      (Dnase1+/+) and knockout (Dnase1-/-) mice allowed an unambiguous detection of
      Dnase1 gene expression at the mRNA and protein level. For the detection of Dnase1
      activity, we developed a highly sensitive nuclease zymogram method. We observed
      high Dnase1 gene expression in the parotid and submandibular gland as well as in
      the kidney and duodenum, intermediate expression in the ileum, mesenterial lymph
      nodes, liver, ventral prostate, epididymis, ovary and stomach, and low expression
      in the sublingual, preputial, coagulation and pituitary gland. We report for the
      first time the lachrymal and thyroid glands, the urinary bladder and the eye to
      be Dnase1-expressing organs as well. Since Dnase1 knockout mice with the
      129xC57Bl/6 mixed genetic background have indicated the protection against an
      anti-DNA autoimmune response as a new physiological function of Dnase1, knowledge
      of the physiological sites of its synthesis might prove helpful to find new
      therapeutic strategies.

PMID- 15015941
TI  - Surface characteristics of implants influence their bone integration after
      simultaneous placement of implant and GBR membrane.
AB  - The purpose of this study was to evaluate the influence of titanium surface
      characteristics on bone integration of implants, and to describe the pattern of
      peri-implant tissue healing after simultaneous implant placement and guided bone
      regeneration. In four healthy mongrel dogs mandibular premolars were extracted.
      Two weeks following full mouth prophylaxis and 4 months after extractions,
      simultaneous membrane and implant surgeries were performed. Efforts were made to
      produce bony defects with dimensions of 7 x 7 x 7 mm. Into these, 24 standard ITI
      implants (diameter = 4.1 mm; length = 8 mm) with either a titanium plasma-sprayed
      (TPS) or a machined surface (MS) were placed. Although implants were inserted 4
      mm into cancellous bone, difficulties in achieving optimal primary stability were
      encountered. All dogs were maintained on a soft diet. Chlorhexidine rinses were
      performed three times a week. Full mouth prophylaxis was performed every 2 weeks.
      In the case of membrane exposure, the membranes were removed prematurely (4-6 or
      14-15 weeks after surgery). Two dogs were sacrificed at 16 weeks and two at 24
      weeks after surgery. Nondecalcified histologic sections were processed and
      histometric analyses were carried out. When membranes were removed after 4-6
      weeks, a vertical bone growth (VB) of 45-61% of the original defect was noted.
      After membrane removal at 14-15 weeks, similar VB was observed. However, if
      membranes were left in situ for 24 weeks, VB was between 79% and 96%. In this
      group of sites, the VB was 66% at 16 weeks and 86% at 24 weeks. Osseointegration
      in the regenerated bone area ranged from 12% to 32% for the TPS and from 0.0% to
      3.6% for the MS implants at 16 and 24 weeks combined. Osseointegration in the
      pristine host bone area ranged from 16% to 35% for the TPS and from 0.0% to 11%
      for the MS sites at 16 and 24 weeks. In conclusion, the fraction of implant-bone
      integration was much higher in the pristine bone compared to that in the
      regenerated bone. TPS surfaces positively influenced the fraction of
      osseointegration in comparison to MS surfaces for both regenerated and pristine
      bone. Furthermore, early membrane removal negatively affected the fraction of
      bone defect fill.

PMID- 15015942
TI  - Simultaneous or staged installation with guided bone augmentation of transmucosal
      titanium implants. A 3-year prospective cohort study.
AB  - A prospective cohort study of 45 nonsmoking consecutively admitted patients was
      studied for the treatment outcomes following jaw bone augmentation in conjunction
      with installment of oral implants. Twenty-eight patients were treated for both
      bone augmentation and implant treatment simultaneously, while 17 patients were
      treated with a staged approach with the bone augmentation being performed 6-8
      months prior to implant installation. Three months following this, prosthetic
      reconstructions were incorporated. One year thereafter, baseline data and 3 years
      after reconstruction, follow-up data were obtained. Moderately low mean scores
      for the bleeding on probing percentage were found at baseline (24%) and after 3
      years of function (17%), while the corresponding values at the implant sites were
      40.6% and 52.4%, respectively. However, the modified gingival index (mGI) = 2 was
      found in only 4.8%, and 6.9% at the baseline and 3-year examinations. Peri
      implant Probing depth (PPD) and level of attachment mean values did not vary
      between baseline and follow-up examinations. Only a small proportion of 1.8%
      yielded PPD = 6.0 mm after 3 years of function. Radiographic bone level
      measurements showed that 18.2% of the implants lost 0.5 mm during the observation
      period. Seventy percent of the sites were considered completely stable. It was
      concluded that predictable treatment outcomes resulted for oral implant
      installation combined with or staged after jawbone augmentation. Only 6.5% of the
      sites had lost 1.5% crestal bone with the staged approach while 14% of the sites
      had lost 1.5 mm, when the implants were placed simultaneously. This suggests that
      the staged approach may have a lower risk for greater amounts of crestal bone
      loss as the simultaneous approach. In general, crestal bone loss encountered in
      the present study corresponded very well with that reported following placement
      of the same implant system into nonaugmented bone.

PMID- 15015943
TI  - Tissue response to titanium implantation in the rat maxilla, with special
      reference to the effects of surface conditions on bone formation.
AB  - Tissue responses to titanium implantation with two different surface conditions
      in our established implantation model in rat maxillae were investigated by light
      and transmission electron microscopy and by histochemistry for tartrate-resistant
      acid phosphatase (TRAPase) activity. Here we used two types of implants with
      different surface qualities: titanium implants sandblasted with Al2O3 (SA-group)
      and implants coated with hydroxyapatite (HA-group). In both groups, bone
      formation had begun by 5 days postimplantation when the inflammatory reaction had
      almost disappeared in the prepared bone cavity. In the SA-group, however, the
      bone formation process in the bone cavity was almost identical to that shown in
      our previous report using smooth surfaced implants (Futami et al. 2000): new bone
      formation, which occurred from the pre-existing bone toward the implant, was
      preceded by active bone resorption in the lateral area with a narrow gap, but not
      so in the base area with a wide gap. In the HA-group, direct bone formation from
      the implant toward the pre-existing bone was recognizable in both lateral and
      base areas. Many TRAPase-reactive cells were found near the implant surface. On
      the pre-existing bone, new bone formation occurred with bone resorption by
      typical osteoclasts. Osseointegration around the implants was achieved by
      postoperative day 28 in both SA- and HA-groups except for the lateral area, where
      the implant had been installed close to the cavity margin. These findings
      indicate that ossification around the titanium implants progresses in different
      patterns, probably dependent on surface properties and quality.

PMID- 15015944
TI  - Early loading of endosseous implants in the augmented maxilla: a 1-year
      prospective study.
AB  - In 10 patients, 68 endosseous implants were inserted in the augmented edentulous
      maxilla using a one-stage implant placement technique. Three months before
      implant insertion, the width and height of the alveolar crest were augmented with
      autologous bone grafts from the iliac crest. In all cases, the resulting bone
      volume was sufficient for implant insertion. According to an early loading
      protocol, the implant-supported overdenture was fabricated 2 months after
      insertion of the implants. Evaluation was performed according to a standardised
      protocol immediately and 1 year after fabrication of the prosthetic construction.
      The protocol included assessment of both clinical (bleeding score, pocket depth,
      implant mobility) and radiographic (marginal bone level on standardised
      radiographs) parameters. Three implants in two patients in the upper jaw were
      lost (survival rate: 95.6%). The peri-implant tissues had a healthy appearance
      and bone loss was minimal. Overall, the patients were very satisfied with the
      prosthetic construction. From this preliminary study, it is concluded that in
      selected cases, early loading of implants may develop into a predictable
      treatment modality after augmentation of the maxilla.

PMID- 15015945
TI  - Osseotite vs. machined surface in poor bone quality. A study in dogs.
AB  - Implant sites with low bone content have exhibited lower implant survival rates
      than dense bone areas. Alterations of the implant surface seem to influence the
      bone-to-implant contact rate and may have an impact on implant failure rates in
      such sites. It was the objective of this animal study to histomorphometrically
      compare two different implant surfaces in so-called poor bone quality sites. All
      premolars on one side of the mandible were extracted in five fox hounds. After a
      healing time of 8 months, four screw-type implants (two with a machined surface
      (ICE group) and two with a double acid-etched (Osseotite) surface (OSS group))
      were inserted into the mandible. Upon insertion, the implant apex was located in
      the 'hollow' part of the dog mandible, where the bone content is low. After 4
      months healing, histomorphometric evaluations were performed. All implants
      osseointegrated clinically and histologically. Periapical density measurements
      revealed similar bone contents in both groups (ICE 49.9+/-16.7%, OSS 52.2+/-8.4%;
      P>0.05). Despite these similar amounts of bone content in the apical area around
      the implant, the Osseotite implant surface had a significantly higher bone-to
      implant contact rate than the machined surface (OSS 62.9+/-12.4%, ICE 39.5+/
      13.0%; P<0.01). It is concluded from this animal experiment that, in poor bone
      quality sites, an implant with an Osseotite surface can achieve a significantly
      higher bone-to-implant contact compared to a machined surface.

PMID- 15015946
TI  - Gelatinase B is associated with peri-implant bone loss.
AB  - The aim of this study was to clear whether gelatinase B is associated with peri
      implant bone loss (PBL). Peri-implant sulcus fluid was collected from 46 implant
      sites in 12 patients. These sites were also characterized using modified Gingival
      Index (mGI). Activated and total gelatinase B levels, measured using a modified
      urokinase assay, showed correlation with PBL (n = 46, Spearman's rank correlation
      test). Activated and total gelatinase B values were significantly higher in PBL >
      3 mm group (n = 6) compared to PBL < 1 mm (n = 29) and 1 < PBL < 3 mm (n = 11)
      groups (rank sum test). Activated gelatinase B level in mGI > 0.5 group (n = 24)
      was clearly higher compared to mGI = 0 (n = 13) and < or = 0.5 (n = 9) groups
      (Rank sum test). We conclude that gelatinase B is associated with PBL. Activation
      of gelatinase B together with elevated mGI eventually reflect active phases of
      peri-implantitis and may prove to be diagnostically useful.

PMID- 15015947
TI  - Comparison of the diagnostic potential of direct digital and conventional
      intraoral radiography in the evaluation of peri-implant conditions.
AB  - The aims of this study were to examine whether viewers agreed on details seen in
      direct (real time) digital and conventional film radiographs of implants, and
      whether there were differences in agreement between the systems. Intra-oral
      radiographs of implants were exposed both as direct digital and conventional film
      radiographs. Fifty pairs of radiographs with similar projection and exposure were
      selected, showing 59 implants. Ten viewers assessed the radiographs separately
      and noted eight different details. The viewers showed very high agreement in
      their assessments of radiographs of each technique separately, and there were no
      statistically significant differences. However, there was a tendency to stronger
      agreement in the direct digital radiographs in four assessed points out of eight.
      The patients' experience of having radiographs exposed with the two methods was
      also studied by questionnaire. The patients' opinions on the two techniques did
      not differ statistically. This study shows that digital radiography has at least
      equal diagnostic yield compared to film radiography.

PMID- 15015948
TI  - Retention and postinsertion maintenance of bar-clip, ball and magnet attachments
      in mandibular implant overdenture treatment: an in vivo comparison after 3 months
      of function.
AB  - It could be hypothesised that attachments, which provide more retention against
      vertical and horizontal dislodgement, will be associated with more favourable
      parameters of oral function. This in vivo study is designed to provide data
      regarding initial retention force, loss of retention force after 3 months of
      function and postinsertion maintenance and complications associated with the use
      of magnet, bar-clip and ball attachments in mandibular overdenture treatment.
      Eighteen edentulous subjects received two permucosal implants in the inter
      foramina region of the mandible, a new denture and three successive
      suprastructure modalities (magnet-, bar-clip and ball attachments). The retention
      force of the attachments at baseline and after 3 months was measured in a
      standardised way. The amount and type of postinsertion maintenance that was
      related to the attachment were evaluated. No differences in retention force at
      baseline and after 3 months of loading were observed for all three attachment
      types. The mean retention forces of magnet attachments, bar-clip attachments and
      ball attachments were 8.1, 31.3 and 29.7 N respectively. Functional maintenance
      complications related to the attachments were predominantly observed in 11/36
      magnet attachments. Functional problems in the ball attachment group were
      relatively rare, easily manageable and seen in 4/36 attachments. The bar-clip
      attachments exhibited no maintenance problems at all.

PMID- 15015949
TI  - Effect of the additional installation of implants in the posterior region on the
      prognosis of treatment in the edentulous mandibular jaw.
AB  - The aim of this study was to elucidate the effect of the additional installation
      of implants in the posterior region on the prognosis of treatment in the
      edentulous mandibular jaw. Fifteen patients who had received implants (Branemark
      system, Nobel Biocare, Goteborg, Sweden) in the edentulous mandible and completed
      a 1-year follow-up after the fitting of implant-anchored fixed prostheses were
      selected. In seven patients (Group A), four or five implants were installed
      between the mental foramina, and in eight patients (Group P), one or two
      implants, one on each side, were installed in the posterior regions in addition
      to the implants between the foramina. All implants of both groups achieved
      osseointegration. In Group A, there was no implant loss after loading. Six
      implants were lost in five patients of Group P within 1 year after loading. All
      of them were located in the posterior region. To elucidate whether or not the
      failure rate of the implants in the posterior region of Group P after loading was
      especially high, the failures were also compared with 89 implants, which were
      installed in the posterior region of the mandibles to support implant-anchored
      fixed partial prosthesis, during the same period (Group C). The cumulative
      survival rate of the implants of Group P was 60%, while that of the implants of
      Group C was 100% (P<0.001). When the survival rates of posterior implants with
      the same length of the two groups were compared, there were significant
      differences for the 7- and 10-mm-length implants only. These data demonstrate
      that the posterior implants in Group P are at greater risk. Deformation of the
      mandible due to jaw movement was thought to be the most likely cause of the
      implant loss. Therefore, when such modified treatment is chosen, it should be
      performed with meticulous attention.

PMID- 15015950
TI  - Effect of bioresorbable fibres (Polyfibre) and a bioresorbable foam (Polyfoam) on
      new bone formation. A short term experimental study on the rabbit skull.
AB  - The aim of the study was to evaluate two bioresorbable polylactic acid (PLA)
      filler materials in a guided bone regeneration (GBR) model system. The first was
      Polyfibre, a fibrous PLA filler material. Polyfoam, the second material tested,
      consisted of a spongy PLA filler material. In each group there were eight
      rabbits. In test rabbits a flap was raised uncovering the calvaria. A
      hemispherical PLA dome was filled with Polyfibre or Polyfoam material and
      periphereal blood and anchored onto the calvaria. Eight rabbits with the same
      domes, filled with blood alone, served as controls. The rabbits were sacrificed
      at 1 or 2 months. Histomorphometric measurements of regenerated total tissue
      volume, bone height and bone volume were carried out in undecalcified sections
      under a light microscope. At 1 month the totally filled volume attained 87%
      (range 82-91) in the fibre group, including 25% (23-27) fibres, 87% (85-95) in
      the foam group, including 15% (15-16) foam, and 55% (16-100) in the controls. The
      volume of mineralized bone was 12% (7-15) in the fibre group, 15% (12-18) in the
      foam group and 6% (1-11) in control domes. Bone height attained 48% (27-79) in
      the fibre group, 37% (31-58) in the foam group and 45% (14-67) in the control
      group. At 2 months, tissue volume attained 86% (85-87) including 26% (22-29)
      fibres, bone volume attained 13% (7-21) and bone height attained 56% (42-78) in
      the Polyfibre group. In the Polyfoam group, they were 83% (55-99) including 18%
      (15-19) foam, 13% (7-24) and 49% (29-74). In control domes, tissue volume was 82%
      (35-100), bone volume 20% (9-27) and bone height 86% (60-100). The Polyfibre and
      Polyfoam material was excellently integrated. No adverse reactions were found in
      the surrounding tissues. Direct bone apposition was observed onto the material.
      In conclusion, Polyfibre and Polyfoam material had a positive effect on initial
      bone and tissue formation but was a hindrance to increasing tissue volume, bone
      volume or bone height at 2 months compared to control specimens. The Polyfibre
      and Polyfoam material provoked no adverse reactions in the surrounding tissues
      and allowed for extensive angiogenesis.

PMID- 15015951
TI  - The fluorohydroxyapatite (FHA) FRIOS Algipore is a suitable biomaterial for the
      reconstruction of severely atrophic human maxillae.
AB  - Grafting of the maxillary sinus is an established treatment modality to provide
      sufficient bone for the fixation of dental implants. We stated the hypothesis
      that the porous fluorohydroxyapatitic (FHA) biomaterial FRIOS Algipore could be
      used as a suitable biomaterial for sinus grafting in severely atrophic maxillae.
      To investigate the accuracy of our hypothesis, 69 trephine specimens from 26
      patients who received maxillary sinus grafting with FRIOS Algipore were retrieved
      during the installation of dental implants. The specimens were processed
      undecalcified and subjected to histomorphological and histomorphometrical
      examination. After a mean healing time of 7 months, 23.0% (+/-8.3) new bone had
      formed around the implanted particles. Bone formation was also evident within the
      pores of the particles. Statistical analysis indicated that bone formation
      originated from the sinus floor. Particles provided scaffolding for the promotion
      of newly formed bone towards apical sinus portions. Mineral dissolution from the
      walls of the pores was observed prior to and during bone apposition. Thereafter,
      portions of the particles were resorbed during bone remodeling and replaced by
      newly formed bone. The present investigation shows that the biomaterial FRIOS
      Algipore is a suitable biomaterial for sinus grafting of severely atrophic
      maxillae.

PMID- 15015952
TI  - Healing of transplanted composite bone grafts-implants: a pilot animal study.
AB  - This experimental pilot study was undertaken to evaluate healing of titanium
      implants transplanted with the surrounding bone into recipient osseous sites in
      the rabbit mandible. One short implant was inserted in the horizontal portion of
      the mandible in each of 10 New Zealand rabbits. Subsequently, and during the same
      session, the implant with 1.5-2.0 mm of bone circumferentially was removed using
      a trephine bur and immediately transplanted in a through-and-through hole
      prepared in the contralateral aspect of the mandible. Three months following the
      transplantation, the animals were sacrificed and the mandibles processed for
      histological evaluation. The healing pattern was assessed in relation to (1) bone
      bridging at the interface between the bone core and the surrounding recipient
      osseous tissue, (2) differences in bone density between the transplanted bone
      cylinder and the bone at the margins of the recipient site, and (3) bone-to
      implant contact (BIC) at the interface. The transplanted graft-implant cores were
      integrated within the recipient sites in five out of the 10 specimens while the
      remaining five bone-implant cores showed fibrous encapsulation. Various patterns
      of resorption were observed within the peri-implant transplanted hard tissues.
      Percentage BIC ranged between 1% and 72% in the fibrous-encapsulated specimens
      and between 20% and 62% in the integrated transplants. Within the limits of this
      pilot study, the results suggest that immediate transplantation of endosseous
      implants with their surrounding bone into congruous recipient osseous sites
      cannot predictably yield graft-implant incorporation and osseointegration of the
      implants. This alternative surgical modality of immediately transplanting a
      composite bone graft-implant from highly cortical intraoral or extraoral sites to
      enhance bone quality and/or volume in implant recipient sites such as the
      maxillary sinus and tuberosity areas needs to be further investigated.

PMID- 15015953
TI  - Fate of monocortical bone blocks grafted in the human maxilla: a histological and
      histomorphometric study.
AB  - Local bone defects in the anterior maxilla are commonly grafted with monocortical
      blocks of autologous bone in order to restore the defect site prior to the
      placement of dental implants. Increasing evidence suggests that osteocytes are
      involved in the control of bone remodelling and thus may be important for
      optimalisation of bone structure around implants, and thus for implant
      osseointegration. However, it is not well known whether osteocytes will survive
      when bone blocks are grafted into defects. We grafted 19 patients with
      monocortical bone blocks derived from the symphysis, to the defect site in the
      maxillary alveolar process. The bone grafts were left to heal for times varying
      from 2.5 to 7 months. During implant installation, bone biopsies were removed
      using a trephine burr, and processed for hard tissue histology. Bone histology
      and histomorphometry were then carried out in order to gain insight into the
      density, viability and remodelling of the graft. Clinically, all the bone grafts
      were successful, with no implant failures, and little resorption was seen.
      Histologically, bone volume expressed as percentage of tissue volume at the
      implant site varied from 27% to 57% with an overall average of 41%. Bone fields
      with empty osteocyte lacunae were observed and measured. The amount of this so
      called nonvital bone (NVB) varied between 1% and 34% of the total tissue volume.
      The amount of NVB decreased significantly with the time of healing. The data
      suggest that the majority of the osteocytes of the monocortical bone do not
      survive grafting. The results indicate that the NVB is progressively remodelled
      into new vital bone 7 months after grafting.

PMID- 15015955
TI  - Efficacy of bovine bone mineral for alveolar augmentation: a human histologic
      study.
AB  - The purpose of this study was to evaluate the osteoconductivity of bovine bone
      mineral in humans. Fifteen patients referred to a private specialist surgical
      practice were treated consecutively for the repair of alveolar defects, and/or
      ridge maintenance at the site of extraction sockets, prior to implantation. Bio
      Oss xenograft (Geistlich Pharma, Wolhusen, Switzerland) was utilized as the
      principal grafting material. Bone cores were trephined out at the time of implant
      placement and processed and examined to evaluate the tissue response under the
      light microscope. A total of 22 trephines were processed for histomorphometric
      evaluation to calculate the mean percentage of bone, residual graft and
      connective tissue by area. In addition, the mean percentage bone-to-graft contact
      was also calculated. The mean percentage area of new bone formation was 26.9%,
      and the percentage of residual graft and connective tissue as 25.6% and 47.4%
      respectively. The mean percentage contact length between bone and residual graft
      was 34%. One implant placed into a site, which was histologically identified as
      having little new bone and, unusually, an inflammatory infiltrate, failed with
      mobility at abutment connection. All other implants were restored into function,
      with a survival rate at baseline of 97%.

PMID- 15015954
TI  - Effects of sinus lifting on voice quality. A prospective study and risk
      assessment.
AB  - A variety of potential complications associated with sinus lift surgery have been
      reported in the literature. However, potential alterations of voice quality
      following sinus elevation have so far not been mentioned or evaluated
      scientifically. For the majority of patients, slight changes of the voice pattern
      are of no importance. However, for voice professionals, whose voices have become
      part of their distinctive profession or trademark, minimal changes may have
      dramatic consequences. This specific group of patients, such as speakers, actors
      and singers, depend on the particular quality and timbre of their voice for their
      livelihood. Consequently, the purpose of this study was to assess the effects of
      sinus lifting on voice quality in the above patient group. In a collaborative
      interdisciplinary effort, the Departments of Oral Surgery and
      Otorhinolaryngology, Section of Phoniatrics and Logopedics, thoroughly evaluated
      a series of voice parameters of four patients undergoing sinus lifting pre- and
      postoperatively. The parameters analyzed included pitch, dynamic range, sound
      pressure level, percent jitter, percent shimmer and noise-to-harmonics ratio with
      special emphasis on formant analysis. No changes were detected in any of the
      commonly evaluated parameters. These were rated subjectively by patients and
      their friends or relatives and objectively with instrumental tools under isolated
      phoniatric lab conditions. In conclusion, sinus lift surgery appears to be a
      safe, predictable evidence-based method for regenerating the highly atrophic
      posterior maxilla, which does not jeopardize the individual characteristic voice
      pattern of high-profile patients critically dependent on their voices for their
      livelihood.

PMID- 15015956
TI  - Effects of an Er:YAG laser and the Vector ultrasonic system on the
      biocompatibility of titanium implants in cultures of human osteoblast-like cells.
AB  - The aim of the present study was to investigate the effects of an Er:YAG laser
      (ERL) and the Vector ultrasonic system (VS) on the biocompatibility of titanium
      implants in cultures of human osteoblast-like cells (SAOS-2). One hundred and
      sixty-eight titanium discs with four different surfaces (sand-blasted and acid
      etched, titanium plasma-sprayed, machine-polished, and hydroxyapatite-coated)
      were used to evaluate cell attachment. The samples were equally and randomly
      assigned to the following groups: (1) an ERL at an energy level of 100 mJ/pulse
      and 10 Hz using a special application tip, (2) the VS using carbon fibre tips, or
      (3) untreated control (C). The discs were placed in culture plates, covered with
      a solution of SAOS-2 cells, and incubated for 7 days. The specimens were then
      washed with phosphate buffer to remove cells not attached to the surface, and the
      adherent cells were stained with hematoxilin-eosin. Cells were counted using a
      reflected light microscope and the cell density per mm2 was calculated.
      Additionally, cell morphology and surface alterations of the titanium discs after
      treatment were investigated using scanning electron microscopy (SEM). All
      titanium discs treated with ERL demonstrated nearly the same cell density per mm2
      as the untreated C surfaces. There was a significant decrease in the number of
      cells that attached to the implant surfaces treated with VS. The SEM examination
      showed no visible differences between lased and C titanium surfaces. All surfaces
      treated with VS showed conspicuous surface damage and debris of the used carbon
      fibres. The results of the present study indicate that (i) ERL does not damage
      titanium surfaces and subsequently does not influence the attachment rate of SAOS
      2 cells, and (ii) VS, used with this type of carbon fibre tip, does not seem to
      be suitable for the instrumentation of titanium surfaces.

PMID- 15015958
TI  - Denaturation of demineralized bone matrix significantly reduces bone formation by
      guided tissue regeneration.
AB  - AIM: To examine in a discriminating capsule model whether denaturation of
      demineralized bone matrix (DBM) by heating may influence bone formation.
      MATERIALS AND METHODS: DBM was produced from the long bones of rats. Half the
      portion of DBM was denatured by heating in distilled water for 20 min at
      temperatures between 70 degrees C and 90 degrees C. Prior to the study, the
      destruction of the osteoinductive properties of the DBM was confirmed in three
      rats following intramuscular implantation. Thirty, 4-month-old, male albino rats
      of the Wistar strain were used in the study. Following surgical exposure of the
      mandibular ramus, a hemispherical Teflon capsule (internal diameter = 5.0 mm) was
      placed, with its open part facing the lateral aspect of the ramus. On one side
      (test side), the capsule was loosely packed with denatured DBM, while on the
      contralateral side, serving as control, the capsule was loosely packed with the
      same amount of non-denatured DBM. After healing periods of 30, 60, and 120 days,
      groups of 10 animals were killed and 40-70 microm thick undecalcified sections of
      the capsules were produced. Three sections from each specimen, representing the
      mid-portion of the capsule, were subjected to histological analysis and computer
      assisted planimetric measurements. RESULTS: Increasing amounts of newly formed
      bone were observed in both test and control capsules during the experimental
      period. At 4 months, the new bone formed in the control capsules occupied 46.7%
      of the cross-sectional area of the capsules, while it was only 19.1% in the test
      capsules (P<0.05). CONCLUSION: Denaturation of DBM by heating significantly
      reduces bone formation by guided tissue regeneration.

PMID- 15015957
TI  - Long-term functional loading of dental implants in rhBMP-2 induced bone. A
      histologic study in the canine ridge augmentation model.
AB  - Osseointegration [direct bone-implant contact (BIC)] is a primary goal following
      installation of endosseous dental implants. Such bone contact provides stability
      for the dental implant over time. The objective of this study was to evaluate
      bone formation and BIC at long-term, functionally loaded, endosseous dental
      implants placed into bone induced by recombinant human bone morphogenetic protein
      2 (rhBMP-2) in an absorbable collagen sponge (ACS) carrier. Mandibular, saddle
      type, alveolar ridge defects (approximately 15 x 10 x 10 mm), two per jaw
      quadrant, were surgically induced in each of six young adult American fox hounds.
      The defects were immediately implanted with rhBMP-2/ACS. Two defects per animal
      additionally received a nonresorbable expanded polytetrafluoroethylene (ePTFE)
      membrane or a bioresorbable polyglycolide fiber membrane. Healing was allowed to
      progress for 3 months, when the ePTFE membrane was removed, and machined,
      threaded, titanium dental implants were installed into the rhBMP-2/ACS induced
      bone and into the adjacent resident bone. At 4 months of osseointegration, the
      implants were exposed to receive abutments and prosthetic treatment (two- or
      three-unit bridges). Some implants were removed for histologic analysis. The
      remainder of implants were exposed to functional loading for 12 months at which
      time the animals were killed for histometric analysis. One animal died
      prematurely due to kidney failure unrelated to the experimental protocol and was
      not included in the analysis. The 12-month block sections from a second animal
      were lost in the histological processing. Four sites receiving rhBMP-2/ACS and
      ePTFE or resorbable membranes experienced wound failure and membrane exposure,
      and subsequently exhibited limited bone formation. Defects without wound failure
      filled to contour with the adjacent alveolar bone. The newly formed bone
      exhibited features of the resident bone with a re-established cortex; however, it
      commonly included radiolucent areas that resolved over time. Dental implants
      block biopsied at 4 months exhibited limited, if any, crestal resorption, whereas
      those exposed to functional loading for 12 months exhibited some crestal
      resorption. Implants biopsied at 4 months exhibited a mean (+/- SD) BIC of 40.6
      +/- 8.2% in rhBMP-2/ACS induced bone vs. 52.7 +/- 11.4% in resident bone. Dental
      implants exposed to 12 months of functional loading exhibited a mean BIC of 51.7
      +/- 7.1% in rhBMP-2/ACS induced bone vs. 74.7 +/- 7.0% in resident bone. There
      were no significant differences between dental implants placed into rhBMP-2/ACS
      induced bone and resident bone for any parameter at any observation interval. In
      conclusion, rhBMP-2/ACS-induced bone allows installation, osseointegration, and
      long-term functional loading of machined, threaded, titanium dental implants in
      dogs.

PMID- 15015959
TI  - Evaluation of a cell-permeable barrier for guided tissue regeneration combined
      with demineralized bone matrix.
AB  - AIM: To evaluate whether bone formation by guided tissue regeneration (GTR) and
      demineralized bone matrix (DBM) can be enhanced by the use of a cell-permeable
      Teflon barrier allowing the penetration of undifferentiated mesenchymal cells
      from the surrounding soft tissues. MATERIAL AND METHODS: DBM was produced from
      the long bones of rats, and its bone-inductive properties were tested in three
      rats prior to the study by intramuscular implantation. Thirty, 4-month-old, male
      albino rats of the Wistar strain were used. Following surgical exposure of the
      mandibular ramus, a cell-permeable Teflon capsule, loosely packed with DBM, was
      placed with its opening facing the lateral surface of the ramus (test side). At
      the contralateral side, serving as control, a non-perforated (cell-occlusive)
      Teflon capsule, loosely packed with the same amount of DBM, was placed. After
      healing periods of 30, 60, and 120 days, groups of 10 animals were killed, and 40
      70 microm thick undecalcified sections of the capsules were produced. RESULTS:
      Computer-assisted planimetric measurements on the histological sections disclosed
      similar amounts of newly formed bone in both test and control capsules. After 4
      months, the new bone in the control capsules occupied 45.0% of the cross
      sectional area of the capsule, while it was 50.5% in the test capsules. This
      difference was not statistically significant (P<0.05). CONCLUSION: Similar
      amounts of bone formed in cell-permeable and cell-occlusive capsules grafted with
      DBM, suggesting that invasion of undifferentiated mesenchymal cells from the
      surrounding soft tissues into the barrier-protected area is unnecessary for bone
      formation with GTR.

PMID- 15015960
TI  - Vascular endothelial growth factor and interleukin 6 expression by Hodgkin/Reed
      Sternberg cells.

PMID- 15015961
TI  - Chediak-Higashi syndrome.

PMID- 15015962
TI  - New insights into haematopoietic stem cell transplantation for patients with
      haemoglobinopathies.

PMID- 15015963
TI  - Plasminogen activator inhibitor 1 (PAI-1): in vitro activities and clinical
      relevance.

PMID- 15015964
TI  - Treatment advances in multiple myeloma.

PMID- 15015966
TI  - Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1alpha
      and MIP-1beta correlates with lytic bone lesions in patients with multiple
      myeloma.
AB  - Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta have been identified
      as candidates for multiple myeloma (MM)-derived bone-resorbing factors. To
      validate the clinical relevance of these observations, we investigated
      correlations between the ability of MM cells to secrete these chemokines and the
      extent of MM bone lesions as well as levels of biochemical bone markers in
      patients with MM. Patients with multiple bone lesions exhibited higher MIP-1alpha
      and MIP-1beta secretion from MM cells along with elevated urinary
      deoxypyridinoline (Dpd), without significant elevation of serum bone-specific
      alkaline phosphatase (BALP) or osteocalcin compared with those with minimal bone
      lesions. MIP-1alpha and MIP-1beta levels correlated positively with urinary Dpd
      and serum BALP but not with serum osteocalcin. These results provide further
      evidence for a causal role of MIP-1alpha and MIP-1beta in the development of
      lytic bone lesions, and suggest that MM cells suppress osteoblastic bone
      formation to cause an imbalance of bone turnover and development of destructive
      bone lesions.

PMID- 15015965
TI  - Overexpression of the Ikaros 6 isoform is restricted to t(4;11) acute
      lymphoblastic leukaemia in children and infants and has a role in B-cell
      survival.
AB  - The Ikaros transcription factor has been shown to play an important role in the
      differentiation of both myeloid and lymphoid lineages. Mice heterozygous for a
      dominant negative (DN) ikaros isoform develop T-cell leukaemia and lymphoma with
      100% penetrance. Overexpression of DN Ikaros isoforms has been reported in some
      forms of leukaemia, such as childhood acute myelomonocytic and monocytic
      leukaemias, adult B-cell acute lymphoblastic leukaemias (B ALL) and in childhood
      and adult pre-B ALL. In this study, the expression of Ikaros isoforms in 49
      infant and childhood leukaemia patients was analysed by reverse transcription
      polymerase chain reaction and Western blot analysis. We found overexpression of
      the DN Ikaros 6 (Ik6) isoform in a subset of leukaemia patients harbouring
      t(4;11) translocations. To further study the consequences of Ik6 overexpression
      in B ALL, we inducibly expressed Ik6 in BaF3 cells and found that Ik6
      overexpression delayed cell death after interleukin-3 withdrawal, suggesting that
      overexpression of Ik6 found in t(4;11) B cells could contribute to
      leukaemogenesis by preventing the apoptosis of cells in an environment with
      reduced survival factors.

PMID- 15015967
TI  - Elevated levels of transferrin receptor 2 mRNA, not transferrin receptor 1 mRNA,
      are associated with increased survival in acute myeloid leukaemia.
AB  - Transferrin receptor 1 (TfR1) is a type II membrane protein that mediates
      cellular iron uptake. Transferrin receptor 2(TfR2), another receptor for
      transferrin (Tf), has recently been cloned. We examined expression levels of
      TfR1, TfR2-alpha (membrane form) and TfR2-beta (non-membrane form) transcripts in
      cells from 67 patients with de novo acute myeloid leukaemia (AML) using reverse
      transcription-polymerase chain reaction (RT-PCR), and correlated the results with
      a variety of clinical features and disease outcomes of these patients.
      Significant correlations were noted between the levels of both TfR1 and TfR2
      alpha (r = 0.771, P < 0.001) and TfR1 and TfR2-beta (r = 0.534, P < 0.001).
      Unexpectedly, initial white blood cell (WBC) counts were inversely correlated
      with levels of expression of either TfR1(r = -0.357, P = 0.003), TfR2-alpha (r = 
      0.486, P < 0.0001), or TfR2-beta (r = -0.435, P = 0.0003). Only TfR2 expression
      was significantly associated with either serum iron (r = -0.270, P = 0.045) or
      serum ferritin (r = -0.364, P = 0.008). Multivariate analyses using Cox's
      proportional hazard model showed that elevated TfR2-alpha, but not TfR1 or TfR2
      beta mRNA levels significantly contributed to a better prognosis for AML
      patients. Furthermore, a group with high expression levels of both TfR2-alpha and
      TfR2-beta survived significantly longer than a group without high expression of
      both of them (P < 0.01 by log-rank). The present study suggests that (i) TfRs
      independent iron uptake might have an important role in in vivo proliferation of
      AML cells; (ii) expression of TfR2 (especially the alpha form) is a novel
      prognostic factor for patients with AML.

PMID- 15015968
TI  - Computer-based drug management in a bone marrow transplant unit: a suitable tool
      for multiple prescriptions even in critical conditions.
AB  - Drug prescription or administration errors are the most common causes of adverse
      events for hospital patients. Computer-based systems can be effective in reducing
      these errors. The aim of this study was to assess whether computer-based systems
      are easily exploitable even in critical conditions. The oral and handwritten
      system for drug management was completely replaced by a computer-based system in
      our bone marrow transplant unit, chosen because: (i) the intensive treatments
      could test the efficiency of the system; (ii) the very frequent occurrence of
      complications and emergencies could test the flexibility of the system; and (iii)
      the pre-existing system could be used as comparison. From May to November 2002,
      41 patients were repeatedly admitted to undergo high-dose chemotherapy,
      autologous/allogeneic stem cell transplantation or because of severe
      complications. In 27 consecutive admissions, 2264 drug prescriptions (average, 29
      drugs/patient admission) and 36 786 drug administrations (39.8/patient/d) were
      carried out. Despite the large number of procedures, the computerized system
      effectively replaced the oral and handwritten transmission of information among
      medical staff, pharmacists and nurses, and lowered the error risks. In addition,
      it contributed to medical updating through warnings on potential problems in case
      of multiple drug prescriptions, and gave the pharmacy a valuable tool to monitor
      drug use.

PMID- 15015969
TI  - Transplantation of highly purified CD34+ progenitor cells from alternative donors
      in children with refractory severe aplastic anaemia.
AB  - Without transplantation from a human leucocyte antigen-identical family donor,
      refractory severe aplastic anaemia (SAA) has an unfavourable prognosis.
      Conventional transplantation from a matched unrelated donor carries a high rate
      of mortality. We transplanted large numbers of highly purified CD34+ cells from
      matched unrelated (n = 4), mismatched unrelated (n = 4) and mismatched related (n
      = 1) donors into nine children with refractory SAA. The grafts consisted of
      granulocyte colony-stimulating factor-mobilized peripheral positively selected
      CD34+ cells. A median of 15.1 x 106/kg CD34+ stem cells and 11 x 103/kg CD3+ T
      lymphocytes were infused. No additional pharmacological graft versus host disease
      (GVHD) prophylaxis was given. At a median follow-up of 47 (range 37-72) months,
      eight patients (89%) were in complete remission with >90% donor chimaerism and no
      evidence of GVHD. One patient died on day +238 as a consequence of GVHD. The use
      of highly purified mobilized CD34+ stem cells warrants further clinical
      exploration in children with refractory SAA.

PMID- 15015970
TI  - The t(4;14) is associated with poor prognosis in myeloma patients undergoing
      autologous stem cell transplant.
AB  - The frequency and prognostic relevance of translocations t(11;14) and t(4;14),
      the most common translocations involving the immunoglobulin heavy chain (IgH)
      gene in multiple myeloma (MM), were investigated in 128 patients treated with
      intensive chemotherapy and autologous stem cell transplant. Myeloma cells were
      identified by cytoplasmic light chain immunofluorescence combined with
      fluorescence in situ hybridization (cIg-FISH) for detection of translocations
      t(11;14) and t(4;14). Overall, t(11;14) was detected in 16 of 125 (12.8%) and
      t(4;14) in 15 of 120 (12.5%) patients. Progression-free and overall survivals
      were similar for patients with or without t(11;14). However, patients with
      t(4;14) had significantly shorter progression-free (median 9.9 months vs. 25.8
      months; P = 0.0003) and overall survivals (median 18.3 months vs. 48.1 months; P
      < 0.0001) than patients without t(4;14). The t(4;14) was associated with IgA and
      t(11;14) with light chain MM. There was no association between the t(11;14) or
      t(4;14) and other biological parameters including age, gender, haemoglobin, beta
      2 microglobulin, C-reactive protein, calcium, creatinine, albumin, or the
      percentage of bone marrow plasma cells. Multivariate analysis identified t(4;14)
      as the only adverse prognostic factor for both progression-free survival and
      overall survival. Our results indicate that the t(4;14) detected by cIg-FISH is
      associated with a poor prognosis in MM patients receiving intensive chemotherapy
      and autotransplant.

PMID- 15015971
TI  - Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting
      laboratory parameters of haemostasis in critically ill patients.
AB  - This study assessed the effect on coagulation tests of fresh frozen plasma (FFP),
      given according to guidelines compared with higher doses in critically ill
      patients. Group 1 (10 patients) received 12.2 ml/kg and group 2 (12 patients)
      33.5 ml/kg FFP. Prothrombin time, activated partial thromboplastin time and
      factors I-XII were measured before and after FFP infusion. Factor levels of 30
      IU/dl (1 g/l for fibrinogen) were considered haemostatic. A retrospective review
      showed 10 of 22 (five in group 1 and five in group 2) patients had not required
      FFP. Of those that needed FFP, one of five in group 1 and seven of seven in group
      2 had coagulation factor levels above the target post-FFP. Increments for group 1
      versus 2 were: fibrinogen 0.4 vs. 1.0 g/l, FII 16 vs. 41*, FV 10 vs. 28*, FVII 11
      vs. 38*, FVIII 10 vs. 17, FIX 8 vs. 28*, FX 15 vs. 37*, FXI 9 vs. 23 and FXII 30
      vs. 44 IU/dl* (*P < 0.01). In vivo recovery of coagulation factors was the same
      for both groups and the observed increments correlated with the dose of FFP. In
      conclusion, coagulation screens were poor predictors of coagulation factor levels
      and current guidelines on the use of FFP result in predictably small increments
      in coagulation factors in critically ill patients and should be reviewed.

PMID- 15015972
TI  - Thrombotic disease in systemic lupus erythematosus is associated with a
      maintained systemic platelet activation.
AB  - Patients with systemic lupus erythematosus (SLE) have an increased risk of
      thrombosis. Platelet-induced extracellular phosphorylation of plasma proteins
      suggests that this is due to persistent activation of the platelets. We examined
      30 SLE patients (15 with thrombotic disease), 18 non-SLE patients with deep vein
      thrombosis (DVT) and 50 healthy controls by analysing beta-thromboglobulin,
      activated factor XI-antithrombin complexes and fibrinogen-bound phosphate. All
      parameters were elevated in SLE patients, particularly those with thrombosis, but
      normal in DVT cases and healthy controls. We conclude that thrombotic disease in
      SLE patients is associated with a persistent systemic platelet activation that
      may lower the threshold for induction of thrombosis.

PMID- 15015973
TI  - In vivo and in vitro effects of different anaesthetics on platelet function.
AB  - Different effects of thiopental, propofol and sevoflurane on platelets have been
      reported. Patients undergoing thyroid surgery were anaesthetized with thiopental
      fentanyl-sevoflurane (n = 11) or propofol-fentanyl-sevoflurane (n = 9). Platelet
      aggregation and thromboxane A2 generation were studied at baseline, and at the
      end of anaesthesia induction and surgery. Dose-response experiments were also
      performed in vitro with single agents. Thiopental-fentanyl-sevoflurane
      significantly reduced collagen-induced aggregation by the end of induction, while
      ADP-induced aggregation and thromboxane generation were unaffected. Propofol
      fentanyl-sevoflurane had no effect on platelets. Thiopental dose-dependently
      inhibited platelets in vitro, while fentanyl or propofol did not. In conclusion,
      thiopental reduces platelet function both ex vivo and in vitro and propofol might
      be considered haemostatically safer.

PMID- 15015974
TI  - Outcomes of an automated procedure for the selection of effective platelets for
      patients refractory to random donors based on cross-matching locally available
      platelet products.
AB  - In 1999, we implemented an automated platelet cross-matching (XM) programme to
      select compatible platelets from the local inventory for patients refractory to
      random donor platelets. In this study, we evaluated platelet count increments in
      40 consecutive refractory patients (8.3% of 480 consecutive platelet recipients)
      given 569 cross-match-negative platelets between April 1999 and December 2001. XM
      was performed automatically with a commercially available immunoadherence assay.
      Pre-, 1- and 24-h post-transfusion platelet counts (mean +/- SD) for the 569 XM
      negative platelet transfusions containing 302 +/- 71 x 109 platelets were 7.7 +/-
      5.5, 32.0 +/- 21.0 and 16.8 +/- 15.5 x 109/l respectively. Increments were
      significantly higher (P < 0.05, t-test) than those observed in the same patients
      given 303 random platelet pools (dose = 318 +/- 52 x 109 platelets) during the
      month before refractoriness was detected, when pre-, 1- and 24-h post-transfusion
      counts were 7.0 +/- 8.6, 15.9 +/- 16.1 and 9.6 +/- 12.8 x 109/l respectively. The
      cost of the platelet XM disposable kit per transfusion to produce 1-h post
      transfusion platelet count increments >10 x 109/l was euro 447. This programme
      enabled the rapid selection of effective platelets for refractory patients, from
      the local inventory.

PMID- 15015975
TI  - Incidence of idiopathic thrombocytopenic purpura among adults.

PMID- 15015977
TI  - Treatment of beta-thalassaemia-associated osteoporosis with zoledronic acid.

PMID- 15015979
TI  - Adult T-biphenotypic acute leukaemia: clinical and biological features and
      outcomes.

PMID- 15015980
TI  - Use of recombinant factor VIIa in inherited platelet disorders.

PMID- 15015981
TI  - Thalidomide in patients with multiple myeloma and renal failure.

PMID- 15015982
TI  - Is once-weekly epoetin beta 'highly effective' in treating anaemia in patients
      with lymphoproliferative malignancy?

PMID- 15015984
TI  - Epoetin once weekly in anaemic patients with cancer.

PMID- 15015986
TI  - The next 25 years of perinatal epidemiology.

PMID- 15015987
TI  - Effects of maternal characteristics on cesarean delivery rates among U.S.
      Department of Defense healthcare beneficiaries, 1996-2002.
AB  - BACKGROUND: National rates of cesarean birth continue a three decade-long
      escalation, despite widespread recognition that a reduction in the use of the
      procedure is a continuing appropriate public health goal, as evidenced by the
      Healthy People 2010 reduction targets. Nonclinical factors associated with
      cesarean delivery include maternal age, race, socioeconomic status, and insurance
      coverage. This study compared cesarean delivery rates and trends for the U.S.
      Department of Defense healthcare beneficiary population from 1996 to 2002 with
      those observed nationally, and assessed the association of these nonclinical
      factors with cesarean rate variation in the U.S. Department of Defense healthcare
      beneficiary population. METHODS: Hospital discharge and claims records for babies
      born in the military and civilian hospitals that comprise the Department of
      Defense healthcare network were used to calculate total and primary cesarean
      delivery rates and vaginal birth after cesarean (VBAC) rates from 1996 to 2002.
      Annual cesarean rates for subgroups defined by maternal age, race, and
      socioeconomic status were calculated to examine rate variations and rate trends
      within the study population. Pooled data from 1999 to 2002 were used to compare
      rates across socioeconomic status, stratified by age and race. Statistical
      significance of the differences calculated for subgroups was assessed using chi
      square. RESULTS: Total and primary cesarean delivery rates among the U.S.
      Department of Defense population were lower than those reported nationally for
      every year examined. Cesarean delivery and VBAC rate trends in the national and
      Department of Defense populations were similar. Within the Department of Defense
      population, total cesarean delivery increased with increasing maternal age and
      was more highly associated with racial minorities relative to white women. The
      higher socioeconomic subgroup (defined as active duty, retired, and warrant
      officers and their families in this study) was generally associated with reduced
      cesarean delivery rates. CONCLUSIONS: Cesarean deliveries are performed less
      frequently for the U.S. Department of Defense healthcare beneficiary population
      relative to the national population. Associations between socioeconomic factors
      and cesarean rates reported for the national population were not apparent in the
      study population. The consistent pattern of rate variation across racial
      subgroups in the Department of Defense population suggests that factors beyond
      those examined in this study are needed to explain the elevated cesarean rates
      for racial minorities.

PMID- 15015989
TI  - A negative birth experience: prevalence and risk factors in a national sample.
AB  - BACKGROUND: A woman's dissatisfaction with the experience of labor and birth may
      affect her emotional well-being and willingness to have another baby. The aim of
      this study was to investigate the prevalence and risk factors of a negative birth
      experience in a national sample. METHODS: A longitudinal cohort study of 2541
      women recruited from all antenatal clinics in Sweden during 3 weeks spread over 1
      year was conducted. Data were collected by three questionnaires, which measured
      women's global experience of labor and birth 1 year after the birth, and obtained
      information on possible risk factors during pregnancy and 2 months after the
      birth. RESULTS: Seven percent of the women had a negative birth experience. The
      following risk factors were found: (1) factors related to unexpected medical
      problems, such as emergency operative delivery, induction, augmentation of labor,
      and infant transfer to neonatal care; (2) factors related to the woman's social
      life, such as unwanted pregnancy and lack of support from partner; (3) factors
      related to the woman's feelings during labor, such as pain and lack of control;
      and (4) factors that may be easier to influence by the caregivers, such as
      insufficient time allocated to the woman's own questions at antenatal checkups,
      lack of support during labor, and administration of obstetric analgesia.
      CONCLUSIONS: Many risk factors were related to unexpected medical problems and
      participants' social background. Of the established methods to improve women's
      birth experience, childbirth education and obstetric analgesia seemed to be less
      effective, whereas support in labor and listening to the woman's own issues may
      be underestimated.

PMID- 15015988
TI  - Rising trends in cesarean section rates in Egypt.
AB  - BACKGROUND: Cesarean section rates have been increasing worldwide, but little
      research exists on trends of cesarean section delivery for any country in the
      Arab world. The purpose of this study was to document recent levels and trends of
      cesarean section rates in Egypt, and to estimate trends in cesarean section by
      type of hospital from three population-based national surveys. METHODS: This
      descriptive study used merged data files from three nationally representative
      samples of ever-married women aged 15 to 49 years. RESULTS: A significant rise in
      cesarean deliveries occurred for all births, from a low of 4.6 percent in 1992 to
      10.3 percent in 2000. However, hospital-based cesarean deliveries were much
      higher in 1987-1988 (13.9%), increasing to 22.0 percent in 1999-2000. Although
      the cesarean section rate was slightly higher in private hospitals, the rate also
      increased consistently in public hospitals. CONCLUSIONS: The high and
      unprecedented increase in cesarean section rates reported in this study may be
      partly due to cesarean sections that are not medically indicated, and suggest
      that physician practice patterns, financial incentives or other profitability
      factors, and patient preferences should be explored.

PMID- 15015990
TI  - Does a pregnant woman's intended place of birth influence her attitudes toward
      and occurrence of obstetric interventions?
AB  - BACKGROUND: A home confinement with midwifery care is still an integral part of
      Dutch maternity care. It has been argued that the existence of home birth itself
      influences the course of the birth process positively, which is why obstetric
      interventions are low in comparison with neighboring countries. This study
      examined the impact of women's intended place of birth (home or hospital) and the
      course of pregnancy and labor when attended by midwives. METHODS: This is a
      prospective study of 625 low-risk pregnant women, gestation 20 to 24 weeks,
      enrolled in 25 independently working midwifery practices. The course of labor was
      measured by the frequency of interventions by midwives and obstetricians.
      RESULTS: A more non-technological approach to childbirth was observed within the
      women opting for a home birth compared with the women opting for a hospital
      birth. Data showed a relationship between interventions and planned birth site:
      sweeping membranes and amniotomy by midwives were more likely to be conducted in
      women opting for a home birth. Multiparas opting for hospital birth were more
      likely to experience consultations and referrals. Within the group of multiparas
      referred for obstetrician care, women intending to have a home birth experienced
      fewer interventions (e.g., induction, augmentation, pharmacologic pain relief,
      assisted delivery, cesarean section) compared with those who had opted for a
      hospital birth. CONCLUSIONS: A large proportion of women desire a home birth. The
      impact of that choice demonstrated a smoother course of the birth process,
      compared with women who desired to deliver in the hospital, as measured by fewer
      obstetric interventions. We suggest that psychological factors (expectation and
      perceptions) influence both a woman's decision of birthplace and the actual birth
      process.

PMID- 15015991
TI  - Considering a simple strategy for detection of women at risk of psychological
      distress after childbirth.
AB  - BACKGROUND: Postpartum depression is a common, severe, yet often undetected
      condition. Between 10 and 15 percent of new mothers suffer from depressive
      disorders in the first year after childbirth. The objective of this study was to
      investigate whether asking women questions about their daily life constituted a
      useful strategy to detect women at risk of developing psychological distress
      after childbirth. METHODS: A prospective study of 330 first- and second-time
      mothers was conducted. Structured interviews with women were performed at the
      maternity unit 1 to 2 days after childbirth, and postal questionnaires were sent
      to participants 5 months later. An interviewer wrote down her perception of the
      mood of participants, in the form of three short statements, immediately after
      the interview. This perception was compared with the score of the woman on the
      General Health Questionnaire scale, which was included in the 5 months'
      questionnaire. RESULTS: The interviewer's perception of women's mood was
      significantly associated with the score on the General Health Questionnaire scale
      5 months later. Multivariate analysis showed that the interviewer's perception of
      anxiety was a better predictor of postpartum psychological distress at 5 months
      than women's answers to questions about their mood before pregnancy and 1 to 2
      days after delivery. CONCLUSIONS: Asking the new mother questions about her
      private and occupational life can be considered as one of many possible ways to
      improve the identification of women at risk of developing postpartum depression.

PMID- 15015992
TI  - What makes a good family-centered partnership between women and their
      practitioners? A qualitative study.
AB  - BACKGROUND: Family-centered maternity care is an approach based on mutually
      beneficial partnerships between health care providers and families. It offers new
      ways of thinking about the relationship among childbearing women, their families,
      and health caregivers. This study was designed to identify health care practices
      that promoted or limited a family-centered philosophy. METHODS: A qualitative
      design, using reflexive interviews and focus groups, investigated the
      perspectives of 34, primarily African American women who used maternity services
      at a large urban hospital; some women traveled from rural areas for delivery.
      Inductive data analysis was conducted on the transcribed audiotapes of the
      interviews and groups. RESULTS: Barriers to family-centered maternity care were
      categorized as issues in coordination of services among health caregivers,
      patient-health caregiver relationships and systems, and access to services.
      Facilitators of family-centered maternity care were identified as perceived
      response to high-risk patients, health-related support outside the hospital, and
      special resources. Narratives, or personal stories told by the women, were used
      to illustrate barriers and facilitators. CONCLUSIONS: Education about family
      centered maternity care is vitally important for health caregivers. In clinical
      situations, each childbearing woman and her family should be treated as if they
      are extraordinary. In this way, practitioners can alter routines that cause the
      woman and her family to lose individualized care.

PMID- 15015993
TI  - Childbirth preferences after cesarean birth: a review of the evidence.
AB  - BACKGROUND: Conflicting evidence on maternal and fetal safety of vaginal and
      cesarean childbirth after a previous cesarean makes patients and practitioners
      uncertain about pursuing a trial of labor or an elective repeat cesarean
      delivery. This review systematically evaluated and summarized the evidence
      related to women's preference for delivery. METHODS: The Cochrane Database of
      Systematic Reviews and Registry of Controlled Trials and the MEDLINE, HealthSTAR,
      PsycINFO, and CINAHL databases were searched from 1980 to August 2002. We
      reviewed controlled trials, case-control studies, and observational studies that
      contained original patient data on preference for women with a previous cesarean
      delivery and that were of "good" or "fair" quality. RESULTS: Women with a
      previous vaginal delivery were more likely to select trial of labor than women
      who did not have one. The most commonly cited reason for selecting trial of labor
      was ease of recovery and desire to return quickly to caring for other children
      (reported in 6 of 7 studies). Safety for the mother and/or infant was cited as an
      important reason for delivery choice in 4 of 11 studies. Important ethnic
      differences were reported. Nonwhite women were more likely to identify their
      provider as an important influence (39% vs 19%), and perceived labor as something
      to be avoided if another option resulted in a healthy baby compared with white
      women, who perceived labor as a challenge and an experience not to be missed.
      CONCLUSIONS: A woman's choice for delivery was often based on family obligations,
      such as the need for a shorter recovery so that she could care for her infant and
      children at home, rather than the safety of herself or her infant. It remains
      unclear if education on vaginal birth after cesarean increases the proportion of
      women who choose trial of labor. Future studies should evaluate the impact of
      education and timing of education on patient preference.

PMID- 15015994
TI  - Recommendations from Listening to Mothers: the first national U.S. survey of
      women's childbearing experiences.
AB  - Listening to Mothers is the first national United States survey that explored
      women's attitudes, feelings, and knowledge about their maternity care and
      childbearing experiences. The report also systematically documented at the
      national level the frequency of many aspects of childbearing from prepregnancy
      care through postpartum physical and mental health outcomes. The results have
      increased understanding about many dimensions of childbearing in the United
      States and identified opportunities for improving the maternity experience in the
      country. The survey was a project of the Maternity Center Association in New York
      City, which also developed recommendations published in response to survey
      results.

PMID- 15015995
TI  - Promoting oral health to reduce adverse pregnancy outcomes.

PMID- 15015996
TI  - Sheila Kitzinger's letter from Europe: what's happening to midwives in Europe?

PMID- 15015999
TI  - Postpartum length of stay and breastfeeding duration.

PMID- 15016001
TI  - The push against vaginal birth.

PMID- 15016002
TI  - Windows in space and time.

PMID- 15016004
TI  - Multiple sclerosis trait: the premorbid stage of multiple sclerosis. A
      hypothesis.
AB  - The unexpectedly low rate of concordance in monozygotic (MZ) twins with multiple
      sclerosis (MS) suggests that they share a systemic condition called the multiple
      sclerosis trait. This trait constitutes the premorbid stage of the disease and is
      quite distinct from asymptomatic MS. It results from the action of an antigenic
      challenge to the immune system of a genetically susceptible person but is short
      of producing lesions of the central nervous system parenchyma; in fact, the
      disease may never develop in people with the trait. An environmental triggering
      event is required to transform the trait into the disease. The discordance of
      clinical involvement and magnetic resonance images in MZ twins reflects
      differences in the effect of environmental influences.

PMID- 15016005
TI  - Predictors of seizure outcome after temporal lobectomy for intractable epilepsy.
AB  - OBJECTIVES: To assess predictors of outcome of temporal lobectomy for intractable
      epilepsy. MATERIAL AND METHODS: In 63 adult patients operated with anterior
      temporal lobectomy during 198892, we used logistic regression analysis to assess
      predictors of being seizure-free (Engel's class I) 2 years after surgery. As
      potential predictors, we included the following variables: gender, age at
      operation, age at onset of seizures, epilepsy duration, etiology, generalized vs
      not generalized seizures, seizure frequency, intelligence quotient, ictal
      electroencephalography, magnetic resonance imaging (MRI), single-photon emission
      computed tomography (SPECT), side of resection, and extent of the resection.
      RESULTS: About 44% of the surgery patients were seizure-free (Engel's class I) 2
      years after surgery. In multivariate analysis (n = 55), MRI pathology defined as
      atrophy in the temporal lobe, angioma, tumor or mesial temporal sclerosis (odds
      ratio, OR 7.4, 95%CI: 1.7-32.9) and extent of the hippocampal resection (increase
      of 1 cm) (OR 2.2, 95%CI: 1.1-4.6) predicted being seizure-free. CONCLUSION: Focal
      pathology in preoperative MRI and the extent of the hippocampal resection were
      the only significant predictors of being seizure-free after 2 years.

PMID- 15016006
TI  - Epilepsy and traditional medicine in Bobo-Dioulasso (Burkina Faso).
AB  - OBJECTIVES: To contribute to a better knowledge of how epilepsy is perceived by
      traditional healers in Burkina Faso; what means they use to treat it, and how
      they think about modern treatment. MATERIAL AND METHODS: Individual interviews
      with 65 traditional healers chosen at random from members of the Reelwende
      Association. RESULTS: All traditional practitioners were of male gender. Most of
      them were above 50 years of age, and 75% had more than 10 years' experience.
      Epilepsy was considered to be contagious by 44% of the traditional practitioners,
      and hereditary according to 40% of them. Roughly, 15% of the healers think that
      the problem is localized in the head of a person and 7.8% think that they have
      worms in their head. Thirty-one per cent of them diagnose epilepsy if there is a
      combination of 'convulsions, sudden fall, dribbling and amnesia'. Another 15%
      require a combination of 'convulsions, amnesia and dribbling', the remaining 54%
      make the diagnosis based on one symptom or various combinations of two symptoms
      of 'grand mal' (generalized tonic clonic) seizures and most claim they have a
      treatment for it. For a quarter of them, therapeutic-means include concoctions of
      herbs or roots, baths and infusions. During the fit, 31% of the traditional
      practitioners think that nothing should be performed. According to 75% of them,
      traditional and modern treatments are complementary. CONCLUSION: Notwithstanding
      important differences in culture and religions (Muslim, Christian and Original),
      there is great similarity between the knowledge and beliefs about epilepsy
      reported from other parts of Africa and those presented by our study-group,
      suggesting an ancient origin of the concepts. Further study is needed to find out
      how other facets of epilepsy (e.g. complex partial seizures, absences) are
      perceived and how these are being treated. Ways need to be found to raise
      awareness about epilepsy without interfering with religious and cultural beliefs.

PMID- 15016007
TI  - Clinical features and associated psychopathology in a Tourette syndrome cohort.
AB  - OBJECTIVE: This study explored in detail the association between tic
      symptomatology, related clinical variables, and psychopathology in 91 consecutive
      adult TS subjects from a UK clinic. METHODS: Consecutive patients from a
      specialized Tourette clinic who met the DSM-III criteria for TS were evaluated
      using standardized rating scales for Tourette syndrome and other psychopathology.
      RESULTS: The male female ratio in our cohort was 1.8:1. Significantly more males
      had an earlier age at onset of TS and history of birth complications. Obsessive
      compulsive behaviors in the patient was positively correlated with presence of
      attention deficit hyperactivity disorder and self-injurious behaviors. With
      regard to adult psychopathology, principal components factor analysis yielded two
      factors, 'obsessionality' and 'anxiety/depression', which accounted for 72% of
      the variance. CONCLUSION: Our results support the high occurrence of anxiety,
      depression and obsessionality in adult TS subjects.

PMID- 15016008
TI  - Nitric oxide synthase expression and enzymatic activity in multiple sclerosis.
AB  - We used post-mortem magnetic resonance imaging (MRI) guidance to obtain paired
      biopsies from the brains of four patients with clinical definite multiple
      sclerosis (MS). Samples were analyzed for the immunoreactivity (IR) of the three
      nitric oxide (NO) synthase isoforms [inducible, neuronal and endothelial nitric
      oxide synthase (NOS)], and enzymatic NO synthase activity. MRI guided biopsies
      documented more active plaques than macroscopic examination, and histological
      examination revealed further lesions. Inducible NOS (iNOS) was the dominant IR
      isoform, while reactive astrocytes were the dominant iNOS expressing cells in
      active lesions. NOS IR expressing cells were widely distributed in plaques, in
      white and gray matter that appeared normal macroscopically, and on MR.
      Endothelial NOS (eNOS) was highly expressed in intraparenchymal vascular
      endothelial cells of MS patients. A control group matched for age and sex showed
      no such changes. Our data support the hypothesis that NO is a pathogenic factor
      in MS, and that NOS IR is strongly expressed in brain regions appearing normal by
      MRI.

PMID- 15016009
TI  - A role of late Epstein-Barr virus infection in multiple sclerosis.
AB  - OBJECTIVE: To assess Epstein-Barr virus (EBV) seroconversion in a high multiple
      sclerosis (MS) prevalence area and to evaluate the recall of diagnosed infectious
      mononucleosis in MS patients. METHODS: The study was based on information or
      blood samples, or both, from schoolchildren, young MS patients and matched
      controls. EBV serology was performed on 1154 blood samples. RESULTS: We
      demonstrate that more than one third of the population in a high MS prevalence
      area is seronegative to EBV at puberty. This is in contrast to the virtually
      complete seroconversion to EBV early in life in individuals from areas with a low
      prevalence of MS. Furthermore, we demonstrate that recall of diagnosed infectious
      mononucleosis (IM), but not recall of common childhood diseases, is significantly
      more frequent among MS patients than healthy controls. All MS patients, including
      patients without prior immunosuppressive treatment, were EBV seropositive.
      CONCLUSION: During or after puberty, EBV is transmitted to a major proportion of
      the population in an MS high-prevalence area. Together with our previous
      documentation of an association between late infection with EBV and an increased
      risk of developing MS, these data support a role of EBV infection in MS.

PMID- 15016010
TI  - R-R interval variation in Parkinson's disease and multiple system atrophy.
AB  - OBJECTIVE: To investigate whether the cardiac R-R interval variation (RRIV) is of
      value in differentiating patients with Parkinson's disease (PD) from multiple
      system atrophy (MSA). BACKGROUND: RRIV assessment is a simple procedure,
      reflecting mainly vagal efferent activity. Reduced RRIV was reported in MSA.
      METHODS: RRIV at rest and after 120 s of deep breathing was assessed blindly to
      clinical diagnosis in 22 PD and 20 MSA patients. The results were compared with
      data from 23 age-matched healthy subjects. RESULTS: RRIV at rest was 7.1 +/- 2.7%
      in PD and 9.7 +/- 7.2% in MSA, increasing after deep breathing to 11.2 +/- 6.3
      and 12.3 +/- 6.6% correspondingly. The frequency of the RRIV abnormalities in the
      PD group (4/22, 18.2%) and MSA (6/20, 30%) were higher than among controls (P <
      0.004). CONCLUSIONS: RRIV, either at rest or after deep breathing, may be
      abnormal both in PD and MSA, but does not distinguish between these disorders.

PMID- 15016011
TI  - Ictal SPECT in clinical perisylvian syndrome.
AB  - In the congenital bilateral perisylvian syndrome, pseudobulbar symptoms,
      cognitive deficits and cortical malformations in the perisylvian region are
      typical features. We report two initially magnetic resonance imaging (MRI)
      negative patients from our epilepsy surgery program that shared the same seizure
      and ictal SPECT characteristics suggesting seizure onset localized in the
      perisylvian region. In one patient, reevaluation revealed perisylvian cortical
      malformation on MRI while in the other patient MRI was normal. In these patients,
      subtraction ictal SPECT coregistered with MRI (SISCOM) proved useful together
      with clinical data in diagnosing the patients with mild forms of perisylvian
      syndrome.

PMID- 15016012
TI  - An electrophysiological severity scale in tarsal tunnel syndrome.
AB  - OBJECTIVE: To propose a neurophysiological classification of tarsal tunnel
      syndrome. MATERIAL AND METHODS: We retrospectively reviewed the medical records
      of two electromyography laboratories. Case inclusion criteria were based on
      clinical parameters. Motor conduction velocity, distal motor latency (DML),
      sensory conduction velocity (SCV) and sensory action potential (SAP) from big toe
      (T1) and from fifth toe (T5) to medial malleolus were measured in the medial and
      plantar nerves. When SCVs of T1 and T5 were normal, we considered the difference
      in T1 SCV between affected and unaffected side and in T1 SCV of the affected side
      with sural nerve distal SCV. Feet with TTS were classified in six
      electrophysiological classes: 0, normal SCV and DML; 1, normal absolute SCV with
      abnormal comparative tests; 2, slowing of T1 and T5 SCV and normal DML; 3,
      slowing of SCV and DML; 4, absence of T1 and T5 SAPs and abnormal DML; 5, absence
      of sensory and motor response. RESULTS: A total of 111 feet belonging to 96
      patients (27 men, 69 women; mean age 49.6 years) were diagnosed with TTS. T1 and
      T5 SCV were abnormal in 82 and 73% of cases, respectively, and comparative tests
      were abnormal in a further 7% of cases. DML was abnormal in 82 feet (73.9%).
      Eight feet (7%) were without neurographic abnormalities. The distribution of feet
      in neurophysiological classes was: stage 0, 7%; stage 1, 9%; stage 2, 10%; stage
      3, 39%; stage 4, 32%; stage 5, 3%. Higher clinical scores coincided with higher
      neurographic classes. CONCLUSION: The progression of neurographic abnormalities
      in TTS reflects the relation between SCV and DML, and between neurographic values
      and clinical severity. The scale assigns severity classes in a reliable and non
      arbitrary way. This classification can easily be used by electrophysiological
      laboratories with their own electrophysiological techniques and normal values.

PMID- 15016013
TI  - rTMS reduces focal brain hyperperfusion in two patients with EPC.
AB  - OBJECTIVE: This study was performed to evaluate the acute effect of a single
      repetitive transcranial magnetic stimulation (rTMS) session in a focal
      hyperperfusion epileptogenic region to induce a transitory decrease of
      epileptiform activity. CASE REPORT: Two epilepsia partialis continua (EPC)
      diagnosed patients, received one session with 15 trains of rTMS (20 Hz; 2 s
      train, inter-train of 58 s). Before rTMS session, a brain ictal single photon
      emission computed tomography (SPECT) was performed to localize the focal frontal
      hyperperfusion region to establish the stimulation site. Immediately after the
      rTMS session another ictal SPECT was performed. Both patients showed a decrease
      of perfusion in the stimulated regions. For patient 1 epileptic seizures became
      intermittent until they stopped in the following 24 h. Patient 2 showed only a
      minimal improvement with a frequency decrease of epileptic spikes. CONCLUSIONS:
      Our findings suggest that a single rTMS session reduces focal epileptogenic
      activity and could be an alternative approach for epileptic-resistant patients,
      but efficacy should be confirmed in a larger series.

PMID- 15016014
TI  - Hyperammonemic encephalopathy induced by a combination of valproate and
      pivmecillinam.
AB  - We describe the clinical and neurophysiological findings in a case of
      hyperammonemic encephalopathy. A 72-year-old woman taking valproate (VPA), as
      monotherapy for her partial epilepsy developed urinary tract infection. She was
      treated with pivmecillinam 600 mg daily. The following days she deteriorated and
      became stuporous. At admission her serum ammonia level was increased (113 mmol/l)
      but the liver function appeared normal. EEG showed bilateral triphasic waves and
      continuous high-amplitude delta-theta wave. The patient recovered rapidly after
      discontinuation of VPA and i.v. treatment with cefuroxime for her urinary tract
      infection. VPA-induced hyperammonemic encephalopathy in adults is a rare
      phenomenon, especially when VPA is used as monotherapy. It has been suggested
      that the VPA-induced hyperammonemic encephalopathy is due to reduced serum
      carnitine concentration. Pivmecillinam, a widely used antibiotic for treatment of
      urinary tract infections, is also known to decrease the serum carnitine
      concentration. Our case shows that caution is required when treatment with VPA is
      combined with pivmecillinam due to the risk of developing hyperammonemic
      encephalopathy.

PMID- 15016017
TI  - Quadrant root planing versus same-day full-mouth root planing.
AB  - OBJECTIVES: The aim of this study was to determine whether same-day full-mouth
      scaling and root planing (FM-SRP) and quadrant scaling and root planing (Q-SRP)
      resulted in variations in the systemic humoral immune response dynamics (antibody
      titres and avidity) during active treatment and 3 and 6 months post-therapy.
      MATERIALS AND METHODS: Forty patients with chronic periodontitis were recruited
      into this study. Subjects were randomised into two groups and received either
      scaling and root planing quadrant by quadrant at 2-weekly intervals (Q-SRP group)
      or same-day full-mouth scaling and root planing (FM-SRP group). Clinical
      measurements and serum samples were obtained at baseline and approximately 6
      weeks after the last clinical intervention (R1) and 6 months after the initiation
      of therapy (R2). Furthermore, serum samples were obtained from each patient
      undergoing therapy (Q-SRP and FM-SRP) at 3 bi-weekly instances so as to determine
      the short-term effects of each session of scaling and root planing on the
      dynamics of the humoral immune response. Serum antibody titre was assayed by
      enzyme-linked immunosorbent assay (ELISA) and antibody avidity was measured by
      thiocyanate dissociation against five putative periodontal pathogens:
      Porphyromonas gingivalis; Actinobacillus actinomycetemcomitans; Prevotella
      intermedia; Treponema denticola and Bacteroides forsythus. RESULTS: Both
      therapies resulted in similar antibody titre reductions against the majority of
      the organisms tested and although there was a distinct trend for antibody avidity
      to increase following therapy, this was not found to be statistically
      significant, reflecting marked inter-individual variation. In addition, no
      evidence emerged from this study to support increased antibody titres following
      the active phases of both treatment approaches due to an inoculation effect.
      Nevertheless, significant short-term increases in antibody avidity to most test
      bacteria were noted for both treatment strategies. CONCLUSION: Both therapies
      were associated with a reduction in antibody titres and an increase in the
      binding ability or avidity of antibodies, but there was a marked inter-subject
      variability and statistical significance was reached for only some of the test
      bacteria. No significant differences in the humoral antibody dynamics were found
      between the two treatment approaches.

PMID- 15016018
TI  - Comparative effectiveness of hand and ultrasonic instrumentations in root surface
      planing in vitro.
AB  - BACKGROUND/AIMS: A variety of techniques are employed for planing and scaling of
      the superficial root surfaces, of which hand and ultrasonic instrumentations have
      been preferentially used in routine periodontics clinics. This study was
      undertaken to compare the effectiveness of ultrasonic scalers and hand curettes
      in facilitating fibroblast attachment to the scaled root surfaces. MATERIALS AND
      METHODS: Sixteen patients with periodontally involved teeth and nine subjects
      without periodontal diseases (control subjects) were selected. Two single-rooted
      teeth were extracted from each subject. Mesial and distal surfaces of teeth were
      selected in treated and untreated groups, respectively. The mesial surface of
      each tooth was randomly chosen to be treated either by hand curettes or
      ultrasonic instrumentation. The degree of cell attachment on the root surfaces of
      treated and untreated groups from control subjects and patients was then
      determined by the use of a gingival fibroblast line established and employed at
      early passages. The attachment and proliferation of gingival fibroblasts on the
      root surfaces were evaluated using neutral red assay and scanning electron
      microscopy (SEM). RESULTS: Fibroblast survival and proliferation on the surfaces
      of untreated periodontally involved roots were found to be significantly lower
      compared with control untreated surfaces (p<0.0001) or treated surfaces from
      patients (p<0.0001). No significant difference, however, was observed between
      root surfaces treated either by hand curettes or ultrasonic scalers. CONCLUSION:
      These results indicate the beneficial effectiveness of both techniques in root
      treatment and planing.

PMID- 15016019
TI  - Debridement and local application of tetracycline-loaded fibres in the management
      of persistent periodontitis: results after 12 months.
AB  - BACKGROUNDS/AIMS: The aim of our study was to evaluate the clinical, radiological
      and microbiological response to the local delivery of tetracycline (TE) of sites
      with persistent periodontal lesions. MATERIALS AND METHODS: The study was
      conducted in a split-mouth design. Nineteen patients with at least four bilateral
      pockets 4-5 mm and bleeding on probing (BOP) were treated with scaling and root
      planing (SRP) plus TE fibres (test sites) or with SRP alone (control sites).
      Clinical and radiological measurements were taken at baseline, 6 months and 12
      months post-operatively. Subgingival plaque samples were collected at baseline,
      at fibres removal, 6 and 12 months following treatment and analysed by polymerase
      chain reaction. RESULTS: Both treatments yielded a statistically significant
      (p<0.05) reduction of probing depth (2.05 and 1.21 mm), gain of clinical
      attachment level (1.71 and 0.53 mm) and reduction of BOP scores (23.68% and
      57.89%) for TE and SRP groups, respectively, when comparing 12-month data with
      baseline. The differences between two groups were significant. The prevalence of
      Treponema denticola and Bacteroides forsythus decreased after therapy in both
      groups but only in the test sites Actinobacillus actinomycetemcomitans and
      Prevotella intermedia were not yield detected. The pathogens could be eliminated
      from five periodontal pockets by SRP alone, while 21 TE sites were not
      recolonized at 12 months. CONCLUSIONS: SRP plus TE fibres gave the greatest
      advantage in the treatment of periodontal persistent lesions at least 12 months
      following treatment.

PMID- 15016020
TI  - Accuracy of probing attachment levels using a CEJ probe versus traditional
      probes.
AB  - BACKGROUND: Current interest in the assessment of probing attachment level
      measurements has been stimulated by recent introduction of novel periodontal
      probes as well as by the reclassification of periodontal diseases. Clinical
      attachment level (CAL) is currently the "gold standard" for diagnosing and
      monitoring periodontal diseases. AIM: To evaluate the performance of the newly
      introduced cementoenamel junction (CEJ) Probe in detecting CAL using the CEJ as a
      fixed reference point, and to compare the CEJ Probe with the Florida Disk Probe
      and a standard Manual Probe (North Carolina Probe). MATERIALS AND METHODS: Three
      examiners probed 12 periodontal patients to determine intra- and inter
      consistency of both the probes and the examiners, over a 4-week time interval.
      Subjects ranged in age from 22 to 74 years. The experimental design was
      structured to balance the intra- and inter-examiner consistency at the same site
      during the two visits. RESULTS: Using the PROC MIXED of SAS, a strong interaction
      (p<0.001) between the examiner and probes was found. The consistency of probing
      (repeatability of measurements) depended upon the type of periodontal probe used
      as well as the skill (experience) of the examiner. Overall, the CEJ Probe
      displayed a more consistent performance. The CEJ Probe demonstrated greater intra
      examiner consistency than the Disk Probe for two examiners (p<0.01). The CEJ
      Probe also showed increased inter-examiner consistency (p<0.01). CONCLUSIONS: The
      CEJ Probe has the potential to offer the dental team an efficient, accurate
      mechanism to chart and monitor attachment level measurements over time.
      Additional studies, using large numbers of examiners, are needed to assess more
      clearly the performance of each individual probe.

PMID- 15016021
TI  - Effect of a combination of amine/stannous fluoride dentifrice and mouthrinse in
      periodontal maintenance patients.
AB  - AIM: The purpose of the present study was to evaluate the beneficial effect of
      using a dentifrice and mouthrinse containing amine fluoride (AmF) and stannous
      fluoride (SnF(2)) in a group of periodontal maintenance patients. Efficacy
      parameters were plaque, gingival inflammation, pocket depth and attachment loss.
      An additional parameter was development of stain. MATERIAL AND METHODS: In total,
      80 patients who had been treated for moderate-to-severe periodontitis agreed to
      participate in this study. Subjects received supportive periodontal therapy at
      regular intervals of 3-4 months for at least a period of 1 year. The patients
      were randomly divided into two groups: (1). the test group used an AmF/SnF(2)
      dentifrice and mouthrinse and (2). the control group used a sodium fluoride (NaF)
      containing dentifrice and mouthrinse. Clinical assessments were performed at
      baseline, 3, 6, 12, 18 and 24 months. RESULTS: The mean plaque index score after
      3 months in the test group (0.24) was significantly lower than that in control
      group (0.34) (p<or=0.05), a difference that was maintained throughout the
      remainder of the study. In terms of bleeding on probing, at no point in time were
      significant differences between test and control group found. No significant
      differences were noted between the two groups, nor were there any significant
      changes in comparison with baseline values with respect to pocket depth and
      attachment level. At baseline, the mean percentage of sites with no staining was
      98% for both the test and control groups. At all further assessments, the
      staining in both groups was elevated as compared with baseline. Smoking did not
      affect the outcome of the study. CONCLUSION: The combined use of an AmF/SnF(2)
      dentifrice and mouthrinse did not affect the parameters of inflammation (bleeding
      upon marginal probing and probing pocket depth), but it has shown to be more
      effective in terms of plaque reduction when compared with the use of an NaF
      dentifrice and mouthrinse in a group of periodontal patients placed under regular
      maintenance care.

PMID- 15016022
TI  - Hertwig's epithelial root sheath, enamel matrix proteins, and initiation of
      cementogenesis in porcine teeth.
AB  - OBJECTIVES: The aim of this study was to analyze the association between
      Hertwig's epithelial root sheath (HERS) cells, enamel matrix proteins (EMPs), and
      cementogenesis. MATERIAL AND METHODS: Porcine teeth were examined at the
      beginning of root formation by light and transmission electron microscopy.
      Colloidal gold immunocytochemistry was used to analyze the protein expression of
      amelogenin and ameloblastin. RESULTS: Before and during disintegration of HERS,
      its cells displayed the cytologic features of protein synthesis and secretion.
      While some cells assumed an ameloblast-like phenotype, others extended their
      territory away from the root surface. A collagenous matrix filled the widening
      intercellular spaces, and tonofilaments and desmosomes were still present in
      cells featuring the morphologic characteristics of cementoblasts. Labeling for
      amelogenin was observed but ameloblastin was not immunodetected. Labeling was
      associated with organic matrix deposits that were sporadically and randomly
      distributed both along the root surface and away from it among the dissipated
      epithelial cells. CONCLUSIONS: These findings suggest that HERS' cells
      occasionally assume a lingering ameloblastic activity at the beginning of root
      formation in the pig. While the results do not support the hypothesis of a causal
      relationship between EMPs and cementogenesis, they lend support to the concept of
      an epithelial origin of cementoblasts.

PMID- 15016023
TI  - Comparative clinical responses related to the use of various periodontal
      instrumentation.
AB  - AIM: The aim of this study was to evaluate in vivo the effectiveness of scaling
      and root planing of a power-driven mechanism compared with hand instruments and
      ultrasonic insert alone with a split-mouth design after 3 and 6 months. METHODS:
      Healing events after initial periodontal therapy were investigated in 20 patients
      with moderate-to-severe adult periodontitis. Plaque index (PlI), bleeding on
      probing (PBI), probing pocket depth (PPD), probing attachment level (PAL) and
      number of moderate and deep pockets (NMP, NDP) were recorded at baseline and 3
      and 6 months after treatment. Oral hygiene instruction was provided for each
      patient. Randomly assigned quadrants per patient were scaled and root planed with
      hand instrumentation (curettes, hoes and files), with reciprocating power-driven
      instruments, with ultrasonic scaler alone and with the combined use of ultrasonic
      scaler and power-driven inserts. The Friedman test was applied to test the
      significance of difference between the various methods of root instrumentation.
      Repeated measures of analysis of variance (manova) were used to analyse the time
      effect on the different treatments. RESULTS: At the 6-month evaluation, all
      groups in the scaling and root planing treatment presented with an improvement in
      the measured clinical parameters, as compared with baseline. No statistical
      differences (p>0.05) were observed in the assessed periodontal indices among the
      study sites between the four groups for either treatment. CONCLUSIONS: Under our
      experimental conditions, this clinical study demonstrates that mechanized root
      planing with power-driven instruments, as effective as the usual procedures (hand
      and sonic instruments), represents a satisfactory and alternative means of
      nonsurgical root therapy.

PMID- 15016024
TI  - Clinical and microbiological effects of different restorative materials on the
      periodontal tissues adjacent to subgingival class V restorations.
AB  - OBJECTIVES: The relationship between subgingival dental restorations and
      periodontal health has been thoroughly investigated for many years. However,
      longitudinal data on the subgingival microflora features after the placement of
      well-finished subgingival restorations are still lacking. Therefore, this study
      compares the short-term clinical and microbiological features occurring in the
      gingiva after the completion of different subgingival restorations. MATERIAL AND
      METHODS: Sixteen systemically healthy subjects, 10 males and six females (ages:
      31.7-45.8 years; mean age 39.3+/-5.1 years), who were non-smokers and were
      positive for the presence of three cervical abrasion/erosion defects to be
      restored in three different adjacent teeth were enrolled in this study. The
      cervical abrasion/erosion defects were each restored by using one of three
      different materials: amalgam, glass ionomer cement, or composite resin.
      Immediately before class V cavity preparations and restorations (baseline),
      clinical monitoring and subgingival plaque sampling were performed in the mid
      buccal aspect of each experimental restored tooth and in one adjacent sound, non
      treated, control tooth. These procedures were repeated every 4 months over the
      following 1 year. RESULTS: Throughout the study, the clinical parameters recorded
      did not change significantly in any of the experimental groups, and no
      differences were detected among them at each clinical session. Over this time, no
      significant changes in the composition of the subgingival microflora were
      observed in amalgam, glass ionomer cement, and control groups. Conversely, in the
      composite resin group, there was a significant increase in the total bacterial
      counts, and a significant (p<0.05) decrease in Gram-positive, aerobic bacteria,
      which was associated with a significant (p<0.05) increase in the Gram-negative,
      anaerobic microbiota. CONCLUSIONS: Over a 1-year observation period, amalgam,
      glass ionomer cement, and composite resin subgingival restorations do not
      significantly affect the clinical parameters recorded. However, composite resin
      restorations may have some negative effects on the quantity and quality of
      subgingival plaque.

PMID- 15016025
TI  - Patient-based assessments of clinical periodontal conditions in relation to
      alveolar bone loss.
AB  - BACKGROUND: Limited subject-based information exists on the relationship between
      clinical and radiographic periodontal data. AIMS: To use subject-based data to
      assess the extent of concurrence between clinical and radiographic information,
      and to study what clinical information best predicts alveolar bone loss (ABL).
      MATERIAL AND METHODS: Subject-based data on smoking habits, bleeding on probing,
      plaque scores, pocket probing depth (PD), and evidence of alveolar BL were
      obtained, and functional periodontal pentagon risk diagrams (PPRDs) were studied
      from 168 consecutive subjects attending a medical clinic. RESULTS: The mean age
      of the subjects was 62.7 years (SD+/-9.0). The average number of teeth was 21.3
      (SD+/-8.0) with on average 5.6 molars remaining (SD+/- 3.9). In this subject
      cohort, 33.1% had never smoked, 44.2% had quit smoking, and 22.7% were currently
      smokers. Mean plaque and bleeding scores were high or 60.2% (SD+/-24.0) and 53.1%
      (SD+/-23.6), respectively. PDs >or=6.0 mm were found in 55.9% of the subjects.
      Binary logistic regression analysis demonstrated that tooth loss and proportional
      plaque scores were the predominant factors included in the equations associated
      with ABL. Wald coefficients varied between 3.99 and 9.15, and with p-values
      between 0.05 and 0.01. When included, the PPRD score became the exclusive factor
      at several cut-off levels (Wald's coefficients between 19.8 and 15.6, p<0.001).
      Consequently, the best receiver operator curve was identified for the PPRD at the
      >40% cut-off ABL level (area under the curve: 0.81; 95% CI: 0.74-0.89; p<0.001).
      CONCLUSIONS: The number of teeth lost and the proportion of plaque scores
      provided significant predictive factors for ABL. The functional PPRD demonstrated
      an exclusive and highly predictable association with ABL. Subject-based
      proportional data for PDs >4.0 mm provided poor substitute measures for the
      extent of ABL.

PMID- 15016026
TI  - Plaque development in relation to the periodontal condition and bacterial load of
      the saliva.
AB  - AIM: To investigate the influence of the oral bacterial load on plaque
      development in various groups of periodontitis patients and in healthy subjects.
      MATERIAL AND METHODS: This study included subjects with a healthy periodontium, a
      healthy reduced periodontium after treatment, an inflamed reduced periodontium
      after treatment and untreated periodontitis. At the start of the study, subjects
      were instructed to rinse with 10 ml reduced transport fluid (RTF) for 10 s in
      order to evaluate the oral bacterial load. The microbiological evaluation
      included anaerobe culture and phase-contrast microscopy. Next, the amount of
      plaque and the clinical condition were evaluated. Thereafter, all supragingival
      plaque was removed and patients were instructed to refrain from all oral hygiene
      procedures for 19 h. Subsequently, the rinsing procedure and the evaluation of
      the amount of plaque were repeated. RESULTS: The amount of plaque that developed
      in 19 h was significantly higher in the untreated periodontitis group as compared
      with the two healthy groups. In case of an inflamed reduced periodontium, sites
      with deep pockets developed more plaque in 19 h than sites with shallow pockets.
      The number of bacteria present in the rinsing samples of the two inflamed groups
      was considerably higher than of the two periodontally healthy groups. A
      significant correlation was found between the bleeding index at intake and the
      plaque index at 19 h. No correlations were found between gingival recession and
      the bacterial counts at intake, and the plaque index at 19 h. CONCLUSION: The
      present findings support the concept that the periodontal condition is the
      dominating factor in relation to the rate of plaque formation. The number of
      bacteria present in the oral cavity as ascertained by means of a rinsing sample
      does not seem to play a role.

PMID- 15016027
TI  - Influence of a SLS-containing dentifrice on the anti-plaque efficacy of a
      chlorhexidine mouthrinse.
AB  - BACKGROUND: Chlorhexidine (CHX) and sodium lauryl sulphate (SLS), the most widely
      used detergent in dentifrice, may counteract. Consequently, studies about this
      interaction suggested that care is required when combining both these compounds,
      even when they are introduced separately into the oral cavity. The purpose of the
      present study was to investigate the effect of toothbrushing with a SLS
      containing dentifrice in one jaw, on the plaque inhibition of a CHX mouthrinse in
      the opposite jaw during a 4-day study period. METHODS: The study was an examiner
      blind, randomised two-cell, crossover design. It used a 4-day plaque accumulation
      model to compare two different oral hygiene regimens with a washout period of 17
      days. Sixteen healthy volunteers were enrolled in the study and received a
      thorough dental prophylaxis at the beginning of each 4-day test period. One jaw
      (upper or lower) was randomly assigned as the "study" jaw. The opposite jaw was
      assigned as the "dentifrice" jaw and served only to introduce the effect of
      brushing with a dentifrice in the study model. Two oral hygiene regimens were
      evaluated. During one randomly assigned test period, the "dentifrice" jaw was
      treated by toothbrushing with a 1.5% SLS-containing dentifrice and rinsed
      together with the "study" jaw with 0.2% CHX, thus forming regimen 1. As a control
      during the other test period, both the "dentifrice" jaw and "study" jaw were only
      rinsed with 0.2% CHX, forming regimen 2. No other oral hygiene methods were
      allowed. After 4 days of undisturbed plaque accumulation, the amount of plaque
      was evaluated (Silness & Loe 1964). The "study" jaw was used to study the effect
      of the two regimens on the level of plaque accumulation at the end of the 4-day
      period. RESULTS: The overall plaque index was 0.36 for regimen 1 and 0.34 for
      regimen 2. There was no significant difference in plaque accumulation between the
      two regimens. CONCLUSIONS: Within the limitations of the present study design, it
      can be concluded that ordinary brushing with a 1.5% SLS-containing dentifrice
      (Colgate Bi-Fluor), followed by rinsing with water does not appear to reduce the
      level of plaque inhibition offered by a post-brushing CHX rinse.

PMID- 15016028
TI  - Local biochemical markers of bone turnover: relationship to subsequent density of
      healing alveolar bone defects.
AB  - OBJECTIVES: This pilot study was designed to test whether biochemical markers of
      bone turnover in washes of periosteal or trabecular alveolar bone surfaces could
      be correlated with increases in bone density of an adjacent healing implant
      socket. METHODS: Ten subjects had a canula inserted into the alveolar crest and
      sterile phosphate-buffered saline was washed over the periosteal and trabecular
      surfaces and collected. Surgical flaps were reflected, 5 mm diameter bone cores
      were removed from the bone wash site, and standardized radiographs were taken.
      The sites were allowed to heal for 12 weeks, and radiographs were repeated. Bone
      washes of the healing sites were also collected after 2 and 12 weeks. Washes were
      analysed for bone turnover markers osteocalcin (OC; radioimmunoassay) and C
      terminal telopeptide of Type 1 collagen (ICTP; enzyme-linked immunosorbent assay
      (ELISA)), and blood component albumin (ALB; ELISA). Changes in bone density
      during healing were determined by radiographic absorptiometry. RESULTS: OC/ALB
      and ICTP/ALB ratios were higher for trabecular than periosteal washes at baseline
      (p<or=0.01). Trabecular OC/ALB and ICTP/ALB were inversely correlated with
      increasing bone density of the healing bone core socket (r=-0.72, p=0.03;
      Pearson's correlation coefficient). CONCLUSIONS: Biochemical markers of bone
      turnover in bone washes of specific alveolar bone sites may prove helpful in
      predicting how the bone density will increase around healing dental implants.

PMID- 15016029
TI  - Does cavitation occur around powered toothbrushes?
AB  - AIMS/OBJECTIVES: The aim of this investigation was to determine if cavitational
      activity occurred around powered toothbrushes using a chemical dosimeter system
      based on terephthalic acid (TA). MATERIAL AND METHODS: Five powered toothbrushes
      were used in this investigation: Braun Plaque Remover D8, Braun Oral-B 3D,
      Philips Jordan Sensiflex HX2520, Sonicare PS-1 and Sonicare Elite HX 7351/02.
      Each brush head was inserted into a conical flask containing 50 cm3 of aqueous TA
      solution. Brushes were operated for 10 and 20 min and a cuvette of the solution
      was placed in a fluorescence spectrometer (Perkin Elmer 3000). The fluorescence
      emitted at wavelength 425 nm, which is proportional to *OH radical concentration,
      was monitored. RESULTS: Any cavitational activity that may have been produced by
      the powered toothbrushes was below the limit of detection of the system (<10(-8)
      M) for the timescales investigated. CONCLUSIONS: This work has demonstrated that
      cavitational activity does not occur around powered toothbrushes. Operating the
      toothbrushes for periods up to 20 min resulted in no cavitational activity being
      detected.

PMID- 15016030
TI  - Reconstruction of the maxillary midline papilla following a combined orthodontic
      periodontic treatment in adult periodontal patients.
AB  - OBJECTIVE: The aim of the present study was to evaluate the role of a combined
      orthodontic-periodontic treatment in determining the reconstruction of midline
      papilla lost following periodontitis. MATERIAL AND METHODS: Twenty-eight
      patients, with infrabony defect and extrusion of one maxillary central incisor,
      were treated. At baseline, all patients presented opening of the interdental
      diastema and loss of the papilla. At 7-10 days after open-flap surgery, the
      intrusive movement started. For each patient, probing pocket depth (PPD),
      clinical attachment level (CAL) and papilla presence index (PI) were assessed at
      baseline, end of treatment and after 1 year. PI was also evaluated independently
      in patients with narrow or wide periodontal biotype (NPB-WPB). RESULTS: All
      parameters showed statistical improvement between the initial and final
      measurements, and showed no changes at follow-up time. The mean residual PPD was
      2.50 mm, with a decrease of 4.29 mm, while the mean CAL gain was 5.93 mm. Twenty
      three out of 28 patients improved the PI score at the end of therapy. No
      statistical difference was recorded in PI values between groups NPB and WPB.
      CONCLUSION: The presented clinical protocol resulted in the improvement of all
      parameters examined. At the end of orthodontic treatment, a predictable
      reconstruction of the interdental papilla was reported, both in patients with
      thin or wide gingiva.

PMID- 15016031
TI  - Impact of mouthrinses on morning bad breath in healthy subjects.
AB  - BACKGROUND: During sleep, a proliferation of oral bacteria is responsible for the
      release of offending gases in morning breath even in healthy people. Thus, the
      aim of this study was to evaluate the bad breath-inhibiting effect of four
      commercially available mouthrinses (0.03% triclosan, 0.12% chlorhexidine
      gluconate, 0.05% cetylpyridinium chloride and essential oils) on morning breath
      when compared with a positive and a negative control. METHOD: A six-step double
      blind, crossover, randomised study was conducted in 12 dental students with
      healthy periodontium, who refrained from mechanical plaque control during a 4-day
      period. The subjects were instructed to rinse twice daily with the assigned
      product during each period. Fifteen-day washout intervals were used. Before
      professional plaque and tongue coating removal (baseline), the morning breath was
      scored through volatile sulphur compounds (VSCs) level measured by a sulphide
      monitor. After 4 days, VSCs and plaque index (PI) were recorded. RESULTS: Even in
      the absence of mechanical plaque control, there was a decrease in VSC level with
      the use of all mouthrinses, with the exception of an increase with the use of the
      negative control. The VSC formation was inhibited in descending order, by
      positive control (0.2% chlorhexidine), 0.12% chlorhexidine, triclosan and
      essential oils and cetylpyridinium chloride. Plaque formation was inhibited by
      chlorhexidine mouthrinses and essential oils. CONCLUSIONS: These findings suggest
      that mouthrinses can reduce morning bad breath, and that such a reduction is not
      attributable only to the reduction of supragingival plaque formation.

PMID- 15016032
TI  - Effect of oxybenzone on PGE2-production in vitro and on plaque and gingivitis in
      vivo.
AB  - OBJECTIVES: To study the effect of oxybenzone on prostaglandin E2 (PGE2)
      production in cell culture and to evaluate the effect of an oxybenzone-containing
      dentifrice on plaque and gingivitis in a 6-week clinical trial. MATERIAL AND
      METHODS: Human embryo palatal mesenchyme (HEPM) cells were used for testing the
      inhibition of IL-1beta-stimulated PGE2-production in vitro by different
      concentrations of oxybenzone. For the in vivo study, a total of 66 individuals
      with a Quigley & Hein plaque index of at least 1.5 and an Ainamo & Bay gingival
      index of at least 0.2 were included in a double-blind clinical trial with two
      cells and a parallel design. Two compositions of fluoride dentifrice were used,
      one with the addition of 0.5% oxybenzone, and one without. Plaque and gingival
      index were obtained at three time points: (1) at baseline, (2) after 3 weeks, and
      (3) after 6 weeks. RESULTS: A dose-dependent inhibition of PGE2-production was
      found in the HEPM cell culture following oxybenzone exposure. In the clinical
      trial, a 25% reduction of gingival index was observed in the oxybenzone group
      (p<0.001) after 6 weeks as compared with 2% for the placebo group. CONCLUSIONS:
      These findings indicate that PGE2-production is reduced by oxybenzone in vitro
      and that the use of oxybenzone in a dentifrice reduces gingivitis in vivo.

PMID- 15016033
TI  - A clinical study to assess the ability of a powered toothbrush to remove
      chlorhexidine/tea dental stain.
AB  - AIM: A single-center, single-blind, two-way crossover study was performed to
      compare the effects of an electric powered toothbrush with a conventional manual
      toothbrush at removing chlorhexidine/tea tooth staining. METHODS: This study used
      24 subjects. During the week before the study, the subjects received a
      prophylaxis to remove all staining, plaque and calculus deposits. On the Monday
      of the following week, subjects returned to the clinic to receive a further
      prophylaxis. Under direct supervision, they then rinsed with a 0.2% chlorhexidine
      mouthrinse, immediately followed by a rinse with a warm black tea solution. This
      cycle was repeated hourly eight times throughout the day and on the following
      days until the Friday. Throughout this period, volunteers omitted all other forms
      of oral hygiene except rinsing with the chlorhexidine mouthwash. On the Friday,
      the level of stain was assessed both prior to and immediately after brushing with
      the allocated brush with toothpaste for 1 min. This was done in an adjoining room
      (out of sight of the clinical scorer). Subjects were then instructed to use the
      toothbrush at home according to their normal oral hygiene practices. On the
      following Friday, subjects returned to the clinic when the stain present was re
      assessed. Each subject received a thorough prophylaxis to remove all plaque
      calculus and staining before starting the second period of the study and again on
      completion of the study. RESULTS: The study showed relatively little difference
      between the ability of the two brushes to remove stain at a single test brushing.
      However, there was some evidence that the powered brush was more effective than
      the manual brush in minimising stain level during the home use period, overall
      and in particular for gingival crescent sites. CONCLUSIONS: This study has
      suggested that the powered brush may become more effective at reducing dental
      stain, the longer the brush is used under normal home conditions.

PMID- 15016034
TI  - Effects of smoking on clinical parameters and the gingival crevicular fluid
      levels of IL-6 and TNF-alpha in patients with chronic periodontitis.
AB  - OBJECTIVE: Smoking is an important environmental risk factor for the initiation
      and progression of periodontal diseases. The aim of this study was to evaluate
      the effects of smoking on clinical parameters and the gingival crevicular fluid
      (GCF) contents of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor
      necrosis factor-alpha (TNF-alpha) levels in patients with chronic periodontitis.
      MATERIAL AND METHODS: The study base consisted of 41 patients including 22
      volunteer current smokers with an age range of 32-59 (44.41+/-7.88) years and 19
      volunteer non-smokers with an age range of 36-59 (46.94+/-6.07) years. The first
      month after non-surgical periodontal therapy was accepted as the baseline of the
      study. The clinical parameters including plaque index (PI), gingival index (GI),
      bleeding on probing (BOP), probing depth (PD), clinical attachment loss (CAL)
      were recorded and GCF samples were collected for analysis of GCF contents of IL-6
      and TNF-alpha levels. At the 3rd and 6th months, all of these procedures were
      repeated. RESULTS: In smokers, only CAL was significantly higher at the 3rd month
      compared with non-smokers (p<0.05). GI and BOP were higher in non-smokers than
      smokers in both periods (p<0.05). PI showed increases from the initial to the 6th
      month in smokers (p<0.05). Although the differences between two groups with
      regard to IL-6 and TNF-alpha were not significant (p>0.05), the total amount of
      TNF-alpha in GCF decreased from the initial to the 6th month in smokers (p<0.05).
      There were no significant correlations between the mean total amount of IL-6 and
      TNF-alpha in GCF and clinical parameters in both evaluation periods in smokers
      (p>0.05). CONCLUSION: The present study demonstrated that cigarette smoking
      increases the amount of dental plaque over time in smokers and does not influence
      GCF contents of IL-6 and TNF-alpha.

PMID- 15016035
TI  - Radiographic parameters as prognostic indicators for healing of class II
      furcation defects.
AB  - OBJECTIVE: To evaluate radiographic measurements for use as prognostic indicators
      for healing of class II furcation defects following regenerative therapy.
      MATERIAL AND METHODS: In 17 patients (eight females), 33 class II furcation
      defects (mandibular buccal (n=10) and lingual (n=12), and maxillary buccal
      (n=11)) were treated using the barrier membrane technique. Twenty-six furcations
      were treated using a bioabsorbable membrane, while a nonresorbable membrane was
      used to treat the remaining seven furcation defects. Clinical parameters and
      standardized radiographs were obtained before as well as 6 and 24 months after
      therapy. All radiographs were digitized and evaluated by an examiner blinded to
      the clinical data. The following distances were measured: cemento-enamel junction
      line (CEJ-line) to alveolar crest (AC) at the furcation site (AC-CEJ line), CEJ
      line to the furcation fornix (Fx-CEJ line), width of the furcation at the level
      of the AC (FW) as well as the distance from Fx to a straight line between the AC
      mesial and distal of the tooth (Fx-AC line). RESULTS: Statistically significant
      (p<0.001) horizontal attachment gains could be observed 6 and 24 months after
      therapy (6 months: 1.49+/-0.85 mm; 24 months: 1.14+/-0.91 mm). However, a small
      but statistically significant (p=0.031) attachment loss of 0.35 mm was observed
      between the 6 and 24 months examination. Multilevel regression analyses
      identified baseline probing depth (p=0.0017) and 3 of the radiographic distances
      as prognostic factors: Fx-CEJ line (p=0.014), FW (p=0.0535), Fx-AC line
      (p=0.0827). CONCLUSION: The analysis of presurgical radiographs may yield
      information on the success of the regenerative therapy of buccal and lingual
      class II furcation defects. A long root trunk, a wide furcation entrance and an
      Fx coronal to the AC have negative influences on the success of therapy. Further,
      a deep probing depth at the furcation site at baseline increases the likelihood
      for more favourable horizontal attachment gain in furcations.

PMID- 15016036
TI  - Validity and reliability of partial examination to assess severe periodontitis.
AB  - OBJECTIVES: To compare the extent and severity index (ESI) with a gold standard
      represented by actual readings of loss of attachment on six sites around all
      teeth present (excluding third molars). METHODS: Five standardized dentists
      (kappa=0.6) examined 712 subjects > or =20 years of age at a dental school (1993
      1995). Sensitivity, specificity, positive and negative predictive values, and
      true and apparent prevalence were established. RESULTS: True severe periodontitis
      prevalence was 95.8%. ESI underestimated the severity (0.1 mm), extent (4%), and
      prevalence (16%) of periodontitis. The severity, as established by ESI, coincided
      23.4% with the gold standard. ESI failed to identify 16.7% of subjects with
      severe periodontal disease, but specificity and positive predictive value were
      very high. CONCLUSIONS: The underestimation of severe periodontitis through ESI
      may lead to inadequate recommendations for further treatment. Accurately
      identifying subjects with severe periodontitis requires a full-mouth examination.
      Because the ESI relies on measurements taken on only 28 periodontal sites to
      estimate the periodontitis status of the entire mouth, the validity and
      reliability of ESI may be modified by the prevalence of severe periodontal
      disease and the distribution of disease according to age and operational
      definitions.

PMID- 15016037
TI  - Incidence of periodontal attachment loss over 5 years among older South
      Australians.
AB  - OBJECTIVES: This study described the 5-year incidence of periodontal attachment
      loss (ALOSS) among older Australians. MATERIAL AND METHOD: Clinical examination
      data were obtained at baseline and 5 years from participants in a cohort study of
      South Australians aged 60+. Periodontal measurements (gingival recession, GR;
      probing depth, PD) were made for each tooth at 3 sites. An incident case of ALOSS
      was identified as an individual having 2+ sites with 3+ mm ALOSS. RESULTS: Some
      342 (42.7%) of the 801 individuals examined at baseline were re-examined after 5
      years, contributing longitudinal data from a total of 15,522 sites (6102 in the
      maxilla and 9420 in the mandible). Most sites showed no change in either GR or
      PD. Using a threshold of 3+ mm for change, ALOSS occurred at 2.3% of mesiobuccal
      sites, 2.5% of buccal sites, and 3.4% of distolingual sites. Distolingual sites
      on molars showed the highest progression rates. The major component of ALOSS was
      increased GR. Overall, only 10.1% of the observed ALOSS was contributed by
      increases in PD. Nearly two-thirds of the sites that experienced ALOSS had <3 mm
      of ALOSS at baseline. The weighted 5-year incidence estimate for ALOSS was 43.2%
      (N=145), and was higher among diabetics or those who had lost 1+ teeth since
      baseline. Smoking was not a significant predictor. CONCLUSION: The rates and
      patterns of ALOSS among older South Australians are largely similar to those
      recently reported for North Carolinians. Most ALOSS in older people manifests as
      increases in GR, rather than PD. Diabetics should be targeted for intensive
      primary and secondary prevention of periodontal disease.

PMID- 15016038
TI  - Prevalence of gingival overgrowth in transplant patients immunosuppressed with
      tacrolimus.
AB  - AIMS: The study aims to determine the prevalence and severity of gingival
      overgrowth in a group of adult organ transplant recipients immunosuppressed with
      tacrolimus in comparison with ciclosporin, and to examine various risk factors
      for the development of gingival overgrowth. METHODS: Forty patients taking
      tacrolimus were compared with 197 ciclosporin patients. Demographic,
      pharmacological and periodontal data were recorded for all patients. Comparison
      between the groups was made using independent sample t-tests, chi2 statistic or
      Mann-Whitney test. The effects of risk variables on overgrowth severity were
      examined using forward and backward stepwise regression analysis. RESULTS: Those
      taking tacrolimus had a significantly lower mean gingival overgrowth score
      (14.1%) compared with ciclosporin (22.4%). Fifteen percent of the tacrolimus
      group had clinically significant gingival overgrowth compared with 30% in the
      ciclosporin group (p=0.053). CONCLUSIONS: The prevalence and severity of gingival
      overgrowth is less in adult transplant patients taking tacrolimus compared with
      ciclosporin. Concomitant use of calcium channel blockers and previous medication
      with ciclosporin are significant risk factors for the presence and severity of
      gingival overgrowth. Patients who have alteration of their immunosuppressant from
      ciclosporin to tacrolimus may persist in demonstrating gingival overgrowth
      attributable to their ongoing therapy with calcium channel blockers.

PMID- 15016039
TI  - Quadrant root planing versus same-day full-mouth root planing. I. Clinical
      findings.
AB  - OBJECTIVES: The aim of this study was to test the hypothesis that same-day full
      mouth scaling and root planing (FM-SRP) resulted in greater clinical improvement
      compared to quadrant scaling and root planing (Q-SRP) in chronic periodontitis
      patients over a period of 6 months. MATERIAL AND METHODS: Forty patients were
      recruited into this study. Subjects were randomised into two groups. The FM-SRP
      group received full-mouth scaling and root planing completed within the same day,
      while the Q-SRP group received quadrant root planing at 2-weekly intervals over
      four consecutive sessions. Whole-mouth clinical measurements were recorded with a
      manual periodontal probe at baseline (BAS) and at reassessment 1 (R1)
      (approximately 6 weeks after the completion of therapy), and at reassessment 2
      (R2) (6 months after the initiation of therapy). Selected site analyses were
      performed on the deepest site in each quadrant before and after therapy (R1 and
      R2) and clinical indices were recorded with an electronic pressure sensitive
      probe. In addition, during the active phase of treatment clinical data were
      collected at 2-weekly intervals from the remaining untreated quadrants in the Q
      SRP group only. RESULTS: Both therapies resulted in significant improvements in
      all clinical indices both at R1 and R2. A continuous clinical improvement was
      seen for both treatment groups during the experimental period, which reached peak
      levels at 6 months (DeltaPD=1.8 mm, DeltaCAL=1.1 mm, p<0.001; PD: pocket depth;
      CAL: clinical attachment level). The selected-site analysis revealed no
      significant differences in any clinical index between the two treatment groups at
      R2 (DeltaPD=2.8 mm, DeltaRAL=1.1 mm; RAL: relative attachment level). At the
      selected sites, the analysis of the deep pockets (>7 mm) showed a significantly
      greater gain in RAL for the FM-SRP group compared to the Q-SRP group at R2
      (p<0.05). The results of this analysis however, should be interpreted with care
      due to the small number of deep pockets. Data from the Q-SRP group provided an
      insight into how treated and untreated quadrants responded during the initiation
      of plaque control measures. There were significant reductions in PD, suppuration
      (SUP), modified gingival index (MGI) and plaque index (PI) in the remaining
      untreated quadrants in the Q-SRP group during the initial phase of treatment
      (p<0.05), while minimum changes in RALs and bleeding on probing (BOP) occurred.
      Nevertheless, the improvement in PD was clearly inferior to that seen after
      scaling and root planing. CONCLUSION: Following both therapeutic modalities,
      there were marked clinical improvements at both R1 and R2 (6 months) from
      baseline. The current study, in contrast to previous findings, failed to show
      that FM-SRP is a more efficacious periodontal treatment modality compared to Q
      SRP. However, both modalities are efficacious and the clinician should select the
      treatment modality based on practical considerations related to patient
      preference and clinical workload.

PMID- 15016040
TI  - Quadrant root planing versus same-day full-mouth root planing. II.
      Microbiological findings.
AB  - OBJECTIVES: The aim of this study was to test the hypothesis that over a period
      of 6 months, same-day full-mouth scaling and root planing (FM-SRP) resulted in
      greater reductions in the detection frequency of five putative periodontal
      pathogens compared with quadrant scaling and root planing (Q-SRP) in chronic
      periodontitis patients. MATERIALS AND METHODS: Forty patients were recruited into
      this study. Subjects were randomised into two groups. The FM-SRP group received
      full-mouth scaling and root planing completed within the same day, while the Q
      SRP group received quadrant root planing at 2-weekly intervals over four
      consecutive sessions. Selected-site analyses were performed on the deepest site
      in each quadrant before and after therapy, at approximately 3 and 6 months from
      baseline (R1 and R2) and clinical indices were recorded with an electronic
      pressure-sensitive probe. In addition, subgingival plaque samples were collected
      from these sites at baseline (BAS), at reassessment 1 (R1), approximately 6 weeks
      after the completion of therapy and at reassessment 2 (R2), 6 months from
      baseline. Polymerase chain reaction (PCR) was used to determine the presence of
      Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Prevotella
      intermedia, Treponema denticola and Bacteroides forsythus in plaque. RESULTS:
      Both therapies resulted in significant improvements in all clinical indices both
      at R1 and R2. A marked reduction in the presence of all candidate periodontal
      pathogens was noted after both treatment modalities, reaching statistical
      significance for the majority of the test organisms. These improvements were
      maintained over a period of 6 months. When the two treatment groups were
      compared, a significantly higher percentage of Q-SRP patients was positive for P.
      intermedia at R1 compared with FM-SRP patients (p<0.05). In addition, a greater
      reduction in the patient prevalence for T. denticola was found for the FM-SRP
      group than the Q-SRP group at R1 and R2 from baseline (p<0.005), but the
      significance of this is questionable given the skewed detection frequency of this
      organism at baseline between the two treatments (p<0.01). CONCLUSION: This study
      failed to confirm that same-day FM-SRP resulted in greater microbiological
      improvements compared with Q-SRP at 2-weekly intervals over a 6-month period, as
      determined by PCR.

PMID- 15016042
TI  - Patient-prosthesis mismatch after small-size stentless aortic valve replacement.
AB  - OBJECTIVE: The aim of this study was to determine the occurrence of patient
      prosthesis mismatch (P-PM) after aortic valve replacement (AVR) with a small-size
      Cryolife O'Brien (CLOB) bioprosthesis and to evaluate its clinical and
      hemodynamic implications. METHODS: Sixty-two patients (mean age 70.9 +/- 5.2
      years, 77.8% females), receiving a labeled 21-23 mm CLOB between 1993 and 2000,
      were retrospectively studied. Effective orifice area (EOA) was calculated by the
      continuity equation and then indexed to the patient's body surface area (BSA) to
      obtain the indexed EOA (EOAI). Based on previous observations a mismatch was
      defined as EOAI <or= 0.85 cm2/m2. RESULTS: Twelve patients (20%) at discharge,
      two (3.3%) at 6 months and none at late controls had an EOAI <or= 0.85 cm2/m2. At
      ANOVA determinants of mismatch were female sex (p < 0.001), age (p = 0.01), and
      patient's annulus index (PAI, p < 0.001). Patients with mismatch had higher mean
      gradients (MG, p = 0.01, and p < 0.001 at discharge and 6 months, respectively)
      and EOAI correlated with MG at discharge (r2= 0.72, p < 0.001) and 6-month (r2=
      0.40, p = 0.001) studies. At 1 year no difference in MG was detected between
      patients with or without mismatch (p = ns) and EOAI did not correlate with MG
      (r2= 0.01, p = ns). Midwall fractional shortening did not differ in patients with
      or without mismatch (p = ns). Patients with an EOAI >or= 0.8 cm/m2 showed an
      earlier concentric remodeling up to 1 year; no difference was demonstrated at
      later studies between groups. Survival and clinical status results were not
      affected by an EOAI <or= 0.85 cm2/m2. CONCLUSIONS: After AVR with CLOB mismatch
      occurred early postoperatively in a small number of patients without clinical
      repercussions. EOAI, significantly increasing over time, was adequate to BSA in
      all patients at late controls.

PMID- 15016043
TI  - Is patient outcome adversely affected by early versus late prosthesis-patient
      mismatch?

PMID- 15016044
TI  - Ruptured congenital sinus of valsalva aneurysms.
AB  - BACKGROUND AND AIM OF THE STUDY: Rupture of the sinus of Valsalva is rare, and
      there is a higher incidence of such rupture in Oriental countries than elsewhere.
      The objective of this study is to present the pathologic features and the
      clinical outcome after surgery in such patients. METHODS: Between 1980 and 2001,
      a total of 17 patients (15 males and 2 females) with ruptured aneurysm of sinus
      of Valsalva underwent surgical intervention at the Tri-Service General Hospital,
      Taiwan. Their age ranged from 22 to 59 years with a mean of 33.5 years. These
      surgical operations made up 0.51% of the total cardiac operations (3305)
      performed during this period. The medical records were retrospectively reviewed.
      RESULTS: The origin of the ruptured aneurysm of the sinus of Valsalva was the
      right coronary sinus in 12 patients, the noncoronary sinus in 4, and the left
      coronary sinus in one patient. The aneurysms ruptured into the right ventricle in
      12 patients, into the right atrium in 3 patients, and into the left ventricle in
      2 patients. Associated cardiac anomalies were aortic regurgitation in eight
      patients, ventricular septal defect in seven, and coronary artery fistula in one
      patient. There was no early postoperative death and one patient underwent a
      second operation after aneurysm of the sinus of Valsalva (ASV) relapse.
      CONCLUSIONS: The operation for a ruptured aneurysm of sinus of Valsalva carries a
      low operative risk and results in excellent long-term survival after surgical
      treatment.

PMID- 15016046
TI  - Off-pump versus on-pump reoperative CABG via a left thoracotomy for circumflex
      coronary artery revascularization.
AB  - OBJECTIVE: Reoperative CABG via a left thoracotomy (RCLT) has become a useful
      approach for revascularization of the circumflex coronary territory for patients
      who are at high risk for conventional approach. This study compares the results
      of RCLT using cardiopulmonary bypass (CPB) with those of a beating heart
      technique (OPCAB). METHODS: Thirty-two patients who underwent RCLT over the past
      10 years were included. Fourteen patients undergoing on-pump RCLT (CPB) were
      compared to 18 patients undergoing off-pump RCLT (OPCAB). Baseline
      characteristics of the study groups were similar. Follow-up was 100% complete. A
      single graft was performed in all patients except one who had two grafts.
      RESULTS: There were no deaths or perioperative myocardial infarctions in either
      group. The incidence of atrial fibrillation (CPB: 29% vs. OPCAB: 11%) and the
      percentage of patients requiring ventilator support longer than 24 hours (21% vs.
      6%) was not significantly different between the groups. However, allogeneic blood
      product utilization (0.9 +/- 1.2 vs. 0.3 +/- 0.7 units, p = 0.04), ICU stay (65
      +/- 79 vs. 28 +/- 16 hours, p = 0.04) and total hospital length of stay (8 +/- 4
      vs. 5 +/- 1 days, p = 0.001) were significantly lower in the OPCAB group. Average
      follow-up for the entire cohort was 33 +/- 9.8 months (range 2-102 months). Three
      year survival was 74 +/- 9% with 9 deaths (28%) during the follow-up, but only 3
      (9%) were cardiac related. Reinterventions were indicated in 6 patients (19%)
      (PTCA; 5, CABG: 1). Follow-up was longer for the CPB group (51 +/- 33 vs. 19.5 +/
      14 months, p = 0.001). Three-year survival (CPB 69 +/- 13%, OPCAB: 82 +/- 12%, p
      = 0.47) and reintervention rates (CPB: 3 [21%], OPCAB: 3 [17%], p = 0.33) were
      similar between the groups. CONCLUSIONS: RCLT is an effective and safe approach
      for circumflex artery revascularization with excellent short- and mid-term
      results using either technique. The OPCAB technique is associated with reduced
      blood product utilization and shorter ICU and hospital length of stay and,
      therefore, is more cost-effective.

PMID- 15016045
TI  - Anomalous origin of the right pulmonary artery from the ascending aorta.
AB  - OBJECTIVES: The aim was to review our experience with the surgical repair of the
      anomalous origin of the right pulmonary artery (AORPA) from the aorta. MATERIALS
      AND METHOD: Between January 1991 and March 2001, five patients with AORPA
      underwent surgical correction. One patient presented isolated AOPA from the
      aorta. Implantation of the anomalous PA to the main PA trunk was performed by
      (1). direct anatomosis employing an autologous pericardial patch in two patients;
      (2). using an aortic flap in two patients with AORPA; and (3). using an aortic
      and pulmonary flaps in another patient. The mean follow-up time was 27 months.
      RESULTS: One patient died due to progressive heart failure unresponsive to
      inotropic support. Early postoperative pulmonary hypertension crisis was
      identified in patient 4, that was managed by intravenous prostacyclin. The same
      patient necessitated mechanical ventilation for 11 days. The mean residual
      gradient for all survivors was 9.5 +/- 4 mmHg. The postoperative Tc-99 m
      scintigraphy demonstrated 72 +/- 4.5(%) lung perfusion. At follow-up the survival
      was 100%. None of the followed patients required reoperation. CONCLUSION: The
      AORPA from the aorta is a rare but important entity, necessitating a scrupulous
      preoperative and intraoperative evaluation. The techniques employing autologous
      tissues for enlarging and lengthening the AORPA seem to be associated with better
      results in terms of postoperative restenosis.

PMID- 15016047
TI  - Skeletal muscle ventricles with a single-limb conduit: the importance of
      hemodynamic design.
AB  - BACKGROUND: Skeletal muscle ventricles (SMVs) connected to the descending
      thoracic aorta have the potential for providing long-term diastolic augmentation.
      A successful existing design employs a bifurcated conduit, but aortic
      constriction between the limbs of the conduit is required to ensure obligatory
      flow-through. Here we evaluate an alternative approach in which connection to the
      aorta is made by a single-limb conduit. METHODS: In two groups of dogs SMVs were
      constructed from the left latissimus dorsi muscle and connected to the
      circulation via a single-limb conduit of length 110-120 mm (Group 1, n = 5) or 70
      mm (Group 2, n = 5). The animals were followed over 10 weeks. RESULTS: Although
      all animals showed significant augmentation of diastolic aortic pressure at the
      outset, substantial thrombus developed in the SMVs of both groups. The results
      were analyzed by reference to design criteria for a single-limb conduit SMV,
      developed from empirical, in-vitro flow studies and formulated mathematically.
      CONCLUSION: The SMVs constructed in this experiment appeared to meet the criteria
      for adequate mixing of blood within the ventricle. They did not, however, achieve
      adequate exchange of blood with the circulation. Thrombosis was therefore
      attributable to excessive residence time of blood in the SMV and conduit. Both
      the experimental study and the mathematical analysis point to the need for SMVs
      of this configuration to be constructed closer to the aorta. Preliminary results
      are reported for such an experiment in the pig, in which the SMV was thrombus
      free when terminated electively after 1 week.

PMID- 15016048
TI  - Should we give prophylactic renal-dose dopamine after coronary artery bypass
      surgery?
AB  - OBJECTIVE: A prospective double-blind randomized study undertaken to assess the
      effect of postoperative prophylactic "renal-dose" dopamine on post-coronary
      artery bypass grafting surgery's clinical outcome. METHODS: Eighty-five
      consecutive patients undergoing CABG operation were randomized to receive either
      3-5 microg/kg/min dopamine (group D, n = 41) or saline as placebo (group P, n =
      45) for 48 postoperative hours. Clinical outcome parameters were collected for
      four postoperative days. RESULTS: Preoperative and operative parameters were
      similar in both groups. Four patients from group P and none from group D reached
      an end-point of the study (oliguria, renal dysfunction) and received dopamine.
      Two patients from group P and none from group D needed an additional inotropic
      support. Mean arterial pressure values were similar during the first 24 hours
      after operation, but left atrial pressure values tended to be higher in group P
      (10 +/- 4 vs 7 +/- 3 mmH2O, p = 0.18). The mean pH was higher in group D at 8
      hours after operation (7.38 +/- 0.2 vs 7.36 +/- 0.3, p = NS), due to higher
      bicarbonate levels (23 +/- 2 mmol/l vs 21 +/- 2, p = 0.49). The incidence of lung
      congestion in chest X-rays and CT scans was significantly higher in group P (50%
      vs 29%, p = 0.073 at 48 hours postoperatively). Room air blood O2 saturation and
      maximal expiratory volume tended to be higher in group D (at 72 hours after
      operation- 92 +/- 4 vs 90%+/- 5, p = 0.29 and 646 +/- 276 vs 485 ml +/- 206, p =
      0.16, respectively). There was no statistical difference in urine output but the
      amount of furosemide given to patients in group P was significantly higher
      (during the first 8 hours 2.5 +/- 0.5 vs. 0.3 mg +/- 1.6, p = 0.07). Plasma
      creatinine levels were significantly lower in group D (at 24 hours 0.93 +/- 0.02
      vs 1.05 mg/dL +/- 0.02, p = 0.02). Mobilization after surgery was faster in group
      D. CONCLUSIONS: Prophylactic dopamine administration after coronary artery bypass
      grafting surgery improves patient hemodynamic and renal status, reduces the need
      for additional medical support (inotropes and furosemide) and thus, provides
      stable postoperative course.

PMID- 15016050
TI  - Total mediastinal traverse with isolated internal mammary artery transection.
AB  - Transmediastinal gunshot wounds are infrequent but life-threatening injuries. The
      course of the projectile and the bullet track often is unpredictable. Prompt and
      specific diagnostic and therapeutic interventions are necessary to quickly
      identify and repair potentially life-threatening injuries to the heart, great
      vessels, and the aerodigestive tract. Multiple diagnostic algorithms exist for
      work-up of these injuries, and the therapeutic interventions are diverse and
      challenging. We describe a patient with total mediastinal traverse, who presented
      with right-sided hemopneumothorax. The work-up revealed surprisingly an isolated
      left internal mammary artery transection with a significant hemorrhage that
      mandated surgical intervention in left chest.

PMID- 15016049
TI  - Cardiac tamponade rapidly evolving toward constrictive pericarditis and shock as
      a first manifestation of noncardiac cancer.
AB  - A 44-year-old man presented with symptoms and signs of cardiac tamponade.
      Cytologic examination of the pericardial fluid was negative for malignancy and no
      manifestations of primary tumor were detected. Two weeks after pericardiocentesis
      the patient developed constrictive pericarditis. An emergency exploratory
      thoracotomy revealed a thick, fibrotic pericardium firmly adherent to the
      underlying myocardium. Histologic examination of the pericardium showed the
      presence of an adenocarcinoma, suspected to be a metastatic dissemination from a
      primary pulmonary source. The lymphatic spread of the tumor to the heart may
      explain the early development of pericardial effusion without malignant cells and
      the later development of pericardial and epicardial thickening. Cardiac tamponade
      of unknown origin should prompt a search for metastatic carcinoma, including in
      presence of a negative cytology.

PMID- 15016051
TI  - Spindle cell sarcoma of the pericardium: a case report.
AB  - Malignancy of the pericardium is a very rare entity. We describe here a case of a
      38-year-old male admitted because of chest pain and shortness of breath.
      Following magnetic resonance imaging and CT-guided biopsy of the mediastinal
      mass, spindle cell sarcoma of the pericardium was diagnosed. The tumor was deemed
      unresectable due to invasion of vital mediastinal structures. The patient then
      underwent neoadjuvant chemotherapy with three cycles of ifosfamide, doxorubicin,
      and mesran. This resulted in a noticeable reduction in tumor size confirmed by
      follow-up magnetic resonance imaging and repeat transesophogeal echo. Both
      studies showed marked reduction in tumor bulk with no obvious invasion of the
      left atrium or pulmonary veins. The pericardial mass was resected utilizing
      cardiopulmonary bypass through a left thoracotomy in order to remove the tumor
      from the superior pulmonary veins and pulmonary hilum. The patient was discharged
      on postoperative day 6. Spindle cell sarcoma of the pericardium is a very rare
      tumor and other pericardial sarcomas may be best treated by combined neoadjuvant
      therapy followed by aggressive surgical resection when necessary, possibly
      utilizing cardiopulmonary bypass.

PMID- 15016052
TI  - Saphenous vein graft to the left radial artery: an uncommon anastomosis during
      coronary artery bypass surgery.

PMID- 15016053
TI  - Congenital bicuspid aortic valve disease with an aneurysm of the ascending aorta
      in adults: vertical reduction aortoplasty with distal external synthetic
      wrapping.
AB  - In three adult patients with diseased congenital bicuspid aortic valves and
      aneurysms of the ascending aorta, we performed aortic valve replacements, and
      combined a proximal and middle vertical reduction aortoplasty with a distal
      external synthetic wrapping. During a mean follow-up of 23.3 months there is no
      evidence of compression of the innominate artery by the distal external synthetic
      wrap, and no redilatation of the ascending aorta.

PMID- 15016054
TI  - Sandwich technique via right ventricle incision to repair postinfarction
      ventricular septal defect.
AB  - We describe two cases where postinfarction ventricular septal defect (VSD) was
      treated with a new technique. Application of direct ultrasonography to the right
      ventricular (RV) wall enables the surgeon to visualize the region and perform
      appropriate incision into the right ventricle and trabecula resection. The VSD is
      sealed with gelatin-resorcin-formal (GRF) glue between two patches, one placed on
      the left ventricular side and the other on the right ventricular side. RV
      incision provides easy bleeding control and the "sandwich technique" using two
      patches and GRF sealing provides geometric preservation of the left ventricular
      shape and prevents residual shunt.

PMID- 15016055
TI  - Repeat median sternotomy after prior ante-aortic crossover right internal
      thoracic artery grafting.
AB  - BACKGROUND: In situ bilateral internal thoracic artery (ITA), with ante-aortic
      crossover right ITA (RITA) is gaining popularity. However, the retrosternal
      position of the crossover RITA has raised concerns with regard to its compromise
      during subsequent resternotomy. METHODS: Ten patients underwent repeat median
      sternotomy after prior ante-aortic crossover RITA grafting. Specific RITA routing
      and fixation had been performed in the initial operation. Preoperative imaging,
      including computed tomography (CT) angiography, was performed to confirm RITA
      position in relation to the sternum and assess feasibility. RESULTS: Resternotomy
      was performed 4-48 months after the initial operation (median, 22 months). Nine
      crossover RITA grafts were functioning at the time of resternotomy. CT
      angiography was performed in four patients in whom the premarked RITA could not
      be localized on the plain chest radiograph. The feasibility of conducting a
      nonmodified resternotomy was determined based on preoperative imaging. All RITA
      grafts resumed their original position and none was injured during reentry. There
      was no early mortality, perioperative stroke, or reexploration for bleeding. One
      patient sustained myocardial infarction, however, not in a RITA-related
      distribution. CT angiography was predictive in confirming a free retrosternal
      space. CONCLUSIONS: Resternotomy after prior ante-aortic crossover RITA grafting
      can be performed at acceptable risk. Confirmation of a free retrosternal space by
      preoperative imaging may contribute to the safety of the procedure. Maneuvers
      performed during the first operation are useful in preventing RITA adherence to
      the sternum.

PMID- 15016056
TI  - Aortic root abscess with aortico-mitral discontinuity after a ross operation in a
      child: reconstruction with an oversized homograft.
AB  - A case of early neo-aortic root abscess following a Ross operation in a 3(1/2)
      year-old child is described. The infection destroyed neo-aortic wall with two of
      the semilunar leaflets detached, and the abscess cavity extended across the
      intervalvular fibrous body into the left atrium and onto the native mitral valve
      creating partial "aortico-mitral discontinuity." Reconstruction was successful
      with an oversized cryopreserved homograft.

PMID- 15016057
TI  - Coronary-coronary bypass with composite radial artery graft.
AB  - Coronary-coronary bypass by using composite radial artery graft is performed
      between the proximal right coronary artery (RCA) and distal RCA branches. The
      radial artery (RA) is harvested, then the distal portion of RA is transected. A
      10-mm long arteriotomy is performed on the main RA graft. The transected distal
      portion of RA is anastomosed on the main RA graft with 8-0 polyprolene suture
      material. Longitudinal arteriotomy is done on the proximal part of RCA followed
      by proximal anastomosis of the composite graft. Patency of the proximal part of
      the RCA is controlled by antegrade cardioplegia infusion. The distal limb of the
      composite graft is anastomosed on to the posteriolateral branch and then the
      second limb is anastomosed on to posterior the descending branch of the RCA.

PMID- 15016059
TI  - Chronic effects of transmyocardial laser revascularization in the nonischemic
      myocardium: a word of caution.
AB  - BACKGROUND: Transmyocardial laser revascularization (TMLR) has been shown to
      induce angiogenesis and improve regional myocardial blood flow. However, the
      biological response to laser of different energy doses in nonischemic myocardium
      has not been well studied. We study the time course of histological appearance
      following high- and low-energy TMLR in a rodent model of normal myocardium.
      METHODS: The animals were randomized to two groups (high-energy (1.4 J/pulse)
      TMLR group and low-energy (0.6 J/ pulse) TMLR group). TMLR was applied to the
      anterolateral wall of the left ventricle. Then the animals were sacrificed (one
      every 2 or 3 days up to 6 weeks, then one every week) to give a series of hearts
      from 1 week to 12 weeks following TMLR. RESULTS: No patent laser channels were
      identified. All laser channel remnants were composed of granulation tissue,
      fibrosis, and various amounts of vascular structures. Changes in vascular density
      demonstrated a similar pattern in both groups over time. The initial increase in
      vascular density within the laser channel remnants and the surrounding areas was
      more marked in group I than in group II. Gradual decline of vascular density
      occurred during a later follow-up. More fibrosis and less vasculature were
      demonstrated 12 weeks after laser therapy in group I. CONCLUSION: Angiogenic
      response to the Holmium:YAG laser in the nonischemic myocardium is nonspecific
      and unsustainable. TMLR might chronically impair the myocardium function by
      enhancing regional scar formation. Therefore, we should clearly identify the
      ischemic area for laser therapy. Reduction of laser energy might prevent this
      potential complication.

PMID- 15016060
TI  - Multiparameter fiber optic sensor for the assessment of intramyocardial
      perfusion.
AB  - OBJECTIVES: The objective of this study was to characterize a multiparameter
      fiber optic sensor for detection of changes in intramyocardial perfusion and to
      demonstrate a method of determining critical values for pH, PCO2, and PO2 to
      indicate onset of anaerobic metabolism. METHODS: Six swine underwent a 20-minute
      occlusion of the left anterior descending coronary artery (LAD). Myocardial pH,
      PCO2, and PO2 were measured continuously in the LAD and left circumflex coronary
      artery (CFX) territories. Critical values for each parameter were calculated from
      these data. RESULTS: During occlusion LAD myocardial pH declined from 7.36 +/-
      0.04 to 6.85 +/- 0.04; PCO2 rose from 57.0 +/- 2.9 to 154.0 +/- 18.0 torr, PO2
      fell from 78 +/- 20 to 6 +/- 5 torr. No myocardial pH or PCO2 changes were
      observed in the CFX region, however, CFX PO2 was affected in some animals during
      LAD occlusion and release. Methods for determining the ischemic threshold from
      these sensor data are presented. CONCLUSIONS: Multiparameter fiber optic sensors
      reliably respond to coronary occlusion and thus have the potential to help guide
      myocardial protection strategies for both on- and off-pump cardiac surgery.

PMID- 15016061
TI  - Repair of complete atrioventricular septal defect with tetralogy of fallot: our
      experience and literature review.
AB  - OBJECTIVES: The aim of this report is to describe the rationale of our surgical
      approach, to explore the best management for complete atrioventricular septal
      defect associated with the tetralogy of Fallot (CAVSD-TOF), and to present our
      outcome in relation to the previously reported series. MATERIALS AND METHODS:
      Between January 1990 and January 2002, 17 consecutive children with CAVSD-TOF
      underwent complete correction. Nine patients (53%) underwent previous palliation.
      Mean age at repair was 2.9 +/- 1.9 years. Mean gradient across the right
      ventricular outflow tract was 63 +/- 16 mmHg. All children underwent closure of
      septal defect with a one-patch technique, employing autologous pericardial patch.
      Maximal tissue was preserved for LAVV reconstruction by making these incisions
      along the RV aspect of the ventricular septal crest. LAVV annuloplasty was
      performed in 10 (59%) patients. Six patients (35%) required a transannular patch.
      RESULTS: Three (17.6%) hospital deaths occurred in this series. Causes of death
      included progressive heart failure in two patients and multiple organ failure in
      the other patient. Two patients required mediastinal exploration due to
      significant bleeding. Dysrhythmias were identified in 4 of 11 patients undergoing
      a right ventriculotomy versus none of the patients undergoing a transatrial
      transpulmonary approach (p = ns). The mean intensive care unit stay was 3.2 +/-
      2.4 days. Two patients required late reoperation due to severe LAVV regurgitation
      at 8.5 and 21 months, respectively, after the intracardiac complete repair. The
      mean follow-up time was 36 +/- 34 months. All patients survived and are in NYHA
      functional class I or II. The LAVV regurgitation grade at follow-up was
      significantly lower than soon after operation, 1.1 +/- 0.4 versus 1.7 +/- 0.5 (p
      = 0.002). At follow-up, the mean gradient across the right ventricular outflow
      tract was 17 +/- 6 mmHg, significantly lower than preoperatively (p < 0.001).
      CONCLUSIONS: Complete repair in patients with CAVSD-TOF seems to offer acceptable
      early and mid-term outcome in terms of mortality, morbidity, and reoperation
      rate. Palliation prior to complete repair may be reserved in specific cases
      presenting small pulmonary arteries or severely cyanotic neonates. The RVOT
      should be managed in the same fashion as for isolated TOF; however, a transatrial
      transpulmonary approach is our approach of choice.

PMID- 15016064
TI  - Bridging the idiographic-nomothetic divide in ratings of self and others on the
      Big Five.
AB  - Recent discussions of the idiographic-nomothetic debate were initially reviewed
      in this paper. Three important issues stemming from this debate were then
      expounded within the context of Personal Construct Theory and evaluated in an
      empirical study. Participants were required to rate themselves and people they
      knew on 25 marker items for the Big Five personality traits and on 12 of their
      own unique personal constructs. The ratings were analyzed using a number of novel
      statistical methods, including a simple type of confirmatory factor analysis and
      an informative graphing procedure. Results indicated that at least half of the
      statistical information derived from the idiographic, personal construct ratings
      was unique when compared to ratings on the nomothetic Big Five items. The
      implications of these methods and results for person-centered and trait
      conceptualizations of personality were discussed.

PMID- 15016062
TI  - Pericardial suspension to prevent encroachment of emphysematous lungs in cardiac
      surgery.

PMID- 15016065
TI  - Personality factors in older women's perceived susceptibility to diseases of
      aging.
AB  - Personality correlates of older women's perceived susceptibility to breast
      cancer, heart disease, and osteoporosis were examined in a community sample of
      312 women aged 40-86. A latent factor of general perceived susceptibility to
      disease was shown to underlie disease-specific perceptions of susceptibility.
      Affect-related personality traits (neuroticism, extraversion, optimism, worry,
      and self-deceptive enhancement) and internal and chance health locus of control
      predicted general perceived susceptibility. Perceived disease characteristics
      (e.g., perceived controllability, severity) and the use of cognitive heuristics
      (i.e., perceived similarity to those who contract each disease) also displayed
      marked consistency across the three distinct diseases. Finally, our results
      suggested that general beliefs about the characteristics of health threats and
      the use of cognitive heuristics may mediate the link between personality traits
      and perceived risk.

PMID- 15016066
TI  - High self-control predicts good adjustment, less pathology, better grades, and
      interpersonal success.
AB  - What good is self-control? We incorporated a new measure of individual
      differences in self-control into two large investigations of a broad spectrum of
      behaviors. The new scale showed good internal consistency and retest reliability.
      Higher scores on self-control correlated with a higher grade point average,
      better adjustment (fewer reports of psychopathology, higher self-esteem), less
      binge eating and alcohol abuse, better relationships and interpersonal skills,
      secure attachment, and more optimal emotional responses. Tests for curvilinearity
      failed to indicate any drawbacks of so-called overcontrol, and the positive
      effects remained after controlling for social desirability. Low self-control is
      thus a significant risk factor for a broad range of personal and interpersonal
      problems.

PMID- 15016067
TI  - A longitudinal study of the relationships between conscientiousness and the
      social-environmental factors and substance-use behaviors that influence health.
AB  - The present study tested the relationships among conscientiousness-related
      traits, social-environmental factors that affect health, and substance-use
      behaviors across a 30-year period from age 21 to age 52 in the Mills Longitudinal
      study of women (N=99). Results showed that the trait of social responsibility (a
      facet of conscientiousness) assessed at age 21 predicted family, work, and
      substance use outcomes at midlife (age 43 and age 52). In turn, marital quality,
      duration of marriage, divorce, participating in paid work, status level of work,
      and marijuana consumption were associated with changes in social responsibility.
      The implications for personality, health, and personality development are
      discussed.

PMID- 15016068
TI  - The effect of daily stress, personality, and age on daily negative affect.
AB  - The current study examined whether stress reactivity becomes stronger or weaker
      with age. Daily stress and daily negative affect were modeled using 1,012
      subjects from the National Study of Daily Events (NSDE), an 8-day daily diary
      study. Age ranged from 25 to 74. Data were modeled using within-person HLM
      techniques. Daily stress and neuroticism interacted in their effect on daily
      negative affect. There was a stronger association between daily stress and
      negative affect for persons high in neuroticism as compared to those low on the
      trait. In addition, daily stress and age interacted in their effect on daily
      negative affect. There was a stronger association between daily stress and
      negative affect for older as compared to younger adults. Results suggest
      heightened reactivity to stressors in older adulthood, perhaps due to kindling
      effects. Changes in the aging brain may explain this effect. Our investigations
      illuminate the complexities that characterize the set of associations among
      negative affect, stress, personality, and age, and point to potential aging or
      cohort effects.

PMID- 15016069
TI  - The effect of health value and ethnicity on the relationship between hardiness
      and health behaviors.
AB  - Associations among hardiness, health value, and health protective behaviors were
      examined as a function of ethnicity among 80 African American and 100 European
      American college students. The role of health value as moderator versus mediator
      in the hardiness-health behavior link was explored. Racial differences in
      correlations among hardiness, control, and commitment were found, with stronger
      relations for African American than European Americans. Moderate positive
      relations between hardiness, control, commitment, and health value for African
      American, as contrasted with weak relations between commitment and health value
      for European Americans, were also shown. A partial mediational effect for health
      value with personal distress and moderator effects for health value with personal
      distress and health habits were found for African American only. Race predicted
      hardiness variables, tobacco and alcohol use, personal distress, and health
      habits beyond what was accounted for by occupation and income. The ramifications
      of these data with regard to future studies on hardiness, health value, and
      health behaviors for African American are discussed.

PMID- 15016070
TI  - Extraordinary moral commitment: young adults involved in social organizations.
AB  - The personality of exemplary young adults was studied in an effort to paint a
      portrait of moral excellence that expanded upon the traditional emphasis on moral
      reasoning maturity. These young adults were nominated based on their
      extraordinary moral commitment towards various social organizations. The sample
      included 40 moral exemplars and 40 matched comparison individuals who responded
      to a battery of questionnaires and participated in a semistructured interview. It
      was found that moral exemplars, in contrast to comparison individuals, were more
      agreeable, more advanced in their faith and moral reasoning development, further
      along in forming an adult identity, and more willing to enter into close
      relationships. These findings are discussed in the context of describing moral
      excellence from a multifaceted, personality perspective.

PMID- 15016071
TI  - Dynamic changes in glypican-1 expression in dorsal root ganglion neurons after
      peripheral and central axonal injury.
AB  - Glypican-1, a glycosyl phosphatidyl inositol (GPI)-anchored heparan sulphate
      proteoglycan expressed in the developing and mature cells of the central nervous
      system, acts as a coreceptor for diverse ligands, including slit axonal guidance
      proteins, fibroblast growth factors and laminin. We have examined its expression
      in primary sensory dorsal root ganglion (DRG) neurons and spinal cord after
      axonal injury. In noninjured rats, glypican-1 mRNA and protein are constitutively
      expressed at low levels in lumbar DRGs. Sciatic nerve transection results in a
      two-fold increase in mRNA and protein expression. High glypican-1 expression
      persists until the injured axons reinnervate their peripheral targets, as in the
      case of a crushed nerve. Injury to the central axons of DRG neurons by either a
      dorsal column injury or a dorsal root transection also up-regulates glypican-1, a
      feature that differs from most DRG axonal injury-induced genes, whose regulation
      changes only after peripheral and not central axonal injury. After axonal injury,
      the cellular localization of glypican-1 changes from a nuclear pattern restricted
      to neurons in noninjured DRGs, to the cytoplasm and membrane of injured neurons,
      as well as neighbouring non-neuronal cells. Sciatic nerve transection also leads
      to an accumulation of glypican-1 in the proximal nerve segment of injured axons.
      Glypican-1 is coexpressed with robo 2 and its up-regulation after axonal injury
      may contribute to an altered sensitivity to axonal growth or guidance cues.

PMID- 15016072
TI  - Generation of embryonic stem cells and transgenic mice expressing green
      fluorescence protein in midbrain dopaminergic neurons.
AB  - We have generated embryonic stem (ES) cells and transgenic mice with green
      fluorescent protein (GFP) inserted into the Pitx3 locus via homologous
      recombination. In the central nervous system, Pitx3-directed GFP was visualized
      in dopaminergic (DA) neurons in the substantia nigra and ventral tegmental area.
      Live primary DA neurons can be isolated by fluorescence-activated cell sorting
      from these transgenic mouse embryos. In culture, Pitx3-GFP is coexpressed in a
      proportion of ES-derived DA neurons. Furthermore, ES cell-derived Pitx3-GFP
      expressing DA neurons responded to neurotrophic factors and were sensitive to DA
      specific neurotoxin N-4-methyl-1, 2, 3, 6-tetrahydropyridine. We anticipate that
      the Pitx3-GFP ES cells could be used as a powerful model system for functional
      identification of molecules governing mDA neuron differentiation and for
      preclinical research including pharmaceutical drug screening and transplantation.
      The Pitx3 knock-in mice, on the other hand, could be used for purifying primary
      neurons for molecular studies associated with the midbrain-specific DA phenotype
      at a level not previously feasible. These mice would also provide a useful tool
      to study DA fate determination from embryo- or adult-derived neural stem cells.

PMID- 15016074
TI  - Ultrastructural study of depolarization-induced translocation of NRF-2
      transcription factor in cultured rat visual cortical neurons.
AB  - Nuclear respiratory factor (NRF)-2 or GA-binding protein is a potential
      transcriptional, bigenomic coordinator of mitochondrial and nuclear-encoded
      subunits of cytochrome oxidase genes. It is composed of an alpha subunit that
      binds DNA and a beta subunit that has the transactivating domain. Previously, we
      found that the level of NRF-2 paralleled that of cytochrome oxidase under normal
      and functionally altered states. The goal of our present study was to increase
      the resolution to the ultrastructural level and to quantify changes before and
      after depolarizing stimulation. We used a pre-embedding immunogold-silver method
      for the two subunits of NRF-2 in cultured rat visual cortical neurons. NRF-2alpha
      and beta were normally located in both the nucleus and the cytoplasm. In the
      nucleus, both subunits were associated primarily with euchromatin rather than
      heterochromatin, consistent with active involvement in transcription. In the
      cytoplasm, they were associated mainly with free ribosomes and occasionally with
      the Golgi apparatus and the outer membrane of the nuclear envelope. Labelling was
      not found in the mitochondria, confirming the specificity of the antibodies.
      Neuronal depolarization by KCl for 5 h induced a six- to seven-fold increase in
      the nuclear-to-cytoplasmic ratio of both subunits (P < 0.001) without increases
      in total labelling densities. These results strongly indicate that both NRF
      2alpha and NRF-2beta respond to increased neuronal activity by translocating from
      the cytoplasm to the nucleus, where they engage in transcriptional activation of
      target genes. Our results also indicate that the cytoplasmic to nuclear movement
      of transcription factors is a dynamic process induced by neuronal activity.

PMID- 15016075
TI  - Hippocampal neurons in organotypic slice culture are highly resistant to damage
      by endogenous and exogenous nitric oxide.
AB  - Nitric oxide (NO) has been proposed to mediate neurodegeneration arising from
      NMDA receptor activity, but the issue remains controversial. The hypothesis was
      re-examined using organotypic slice cultures of rat hippocampus, with steps being
      taken to avoid known artefacts. The NO-cGMP signalling pathway was well preserved
      in such cultures. Brief exposure to NMDA resulted in a concentration-dependent
      delayed neuronal death that could be nullified by administration of the NMDA
      antagonist MK801 (10 microm) given postexposure. Two inhibitors of NO synthesis
      failed to protect the slices, despite fully blocking NMDA-induced cGMP
      accumulation. By comparing NMDA-induced cGMP accumulation with that produced by
      an NO donor, toxic NMDA concentrations were estimated to produce only
      physiological NO concentrations (2 nm). In studies of the vulnerability of the
      slices to exogenous NO, it was found that continuous exposure to up to 4.5 microm
      NO failed to affect ATP levels (measured after 6 h) or cause damage during 24 h,
      whereas treatment with the respiratory inhibitors myxothiazol or cyanide caused
      ATP depletion and complete cell death within 24 h. An NO concentration of 10
      microm was required for ATP depletion and cell death, presumably through
      respiratory inhibition. It is concluded that sustained activity of neuronal NO
      synthase in intact hippocampal tissue can generate only low nanomolar NO
      concentrations, which are unlikely to be toxic. At the same time, the tissue is
      remarkably resistant to exogenous NO at up to 1000-fold higher concentrations.
      Together, the results seriously question the proposed role of NO in NMDA receptor
      mediated excitotoxicity.

PMID- 15016073
TI  - Temporally induced Nurr1 can induce a non-neuronal dopaminergic cell type in
      embryonic stem cell differentiation.
AB  - The nuclear transcription factor Nurr1 is involved in the development and
      maintenance of the midbrain dopaminergic (DA) neuronal phenotype. We analysed the
      cellular and biological effects of Nurr1 during embryonic stem (ES) cell
      differentiation using the ROSA26-engineered Tet-inducible ES cell line J1-rtTA
      that does not express transgenes in mature neurons. Induction of Nurr1 at nestin
      positive precursor and later stages of ES cell differentiation produced a non
      neuronal DA cell type including functional DA transporters. In these cells, we
      found a clear correlation between Nurr1 and TH gene expression and specific
      midbrain DA cellular markers such as AADC, AHD2 and calbindin. Nurr1 did not
      alter gene expression of non-DA neuronal phenotypes and did not influence other
      midbrain developmental transcription factors, such as Otx1, Otx2, En-1, GBX2,
      Pitx3 and lmx1b. In addition, Nurr1 expression was required for maintenance of
      the DA phenotype and mediated up-regulation of the tyrosine kinase Ret and
      associated trophic factor GDNF-family receptors alpha 1, 2, and 4. This
      demonstrates that Nurr1 is sufficient to induce and maintain a midbrain-like DA
      biochemical and functional cellular phenotype independent of neurogenesis.

PMID- 15016076
TI  - Functional and morphological alterations in compound transgenic mice
      overexpressing Cu/Zn superoxide dismutase and amyloid precursor protein
      [correction].
AB  - Down's syndrome (DS), the phenotypic manifestation of trisomy 21, involves
      overexpression of chromosome 21-encoded genes. The gene for amyloid precursor
      protein (APP), known to be involved in AD pathology, resides on chromosome 21
      along with the gene for Cu/Zn superoxide dismutase (SOD1), a key enzyme in the
      metabolism of oxygen free radicals. We investigated the consequences of a
      combined increase in APP and SOD1, in a double-transgenic (tg)-APP-SOD1 mouse.
      These mice expressed severe impairment in learning, working and long-term memory.
      Expression of long-term potentiation in hippocampal slices was impaired in both
      tg-SOD and tg-APP-SOD mice, but not in tg-APP mice, indicating that increased APP
      by itself did not affect in vitro synaptic plasticity. In tg-APP-SOD mice,
      membrane-bound high molecular weight APP species accumulated while APP cleavage
      products did not increase and levels of secreted APP were unchanged. Severe
      morphological damage, including lipofuscin accumulation and mitochondria
      abnormalities, were found in aged tg-APP-SOD but not in the other mice. Thus, a
      combined elevation of the two chromosome 21 genes in tg-APP-SOD mice induced age
      dependent alterations in morphological and behavioural functions.

PMID- 15016077
TI  - Low-dose gamma-irradiation promotes survival of injured neurons in the central
      nervous system via homeostasis-driven proliferation of T cells.
AB  - Protective autoimmunity was only recently recognized as a mechanism for
      attenuating the progression of neurodegeneration. Using a rat model of optic
      nerve crush or contusive spinal cord injury, and a mouse model of
      neurodegenerative conditions caused by injection of a toxic dose of intraocular
      glutamate, we show that a single low dose of whole-body or lymphoid-organ gamma
      irradiation significantly improved the spontaneous recovery. Animals with severe
      immune deficiency or deprived of mature T cells were unable to benefit from this
      treatment, suggesting that the irradiation-induced neuroprotection is immune
      mediated. This suggestion received further support from the findings that
      irradiation was accompanied by an increased incidence of activated T cells in the
      lymphoid organs and peripheral blood and an increase in mRNA encoding for the pro
      inflammatory cytokines interleukin-12 and interferon-gamma, and that after
      irradiation, passive transfer of a subpopulation of suppressive T cells
      (naturally occurring regulatory CD4(+)CD25(+) T cells) wiped out the irradiation
      induced protection. These results suggest that homeostasis-driven proliferation
      of T cells, induced by a single low-dose irradiation, leads to boosting of T cell
      mediated neuroprotection and can be utilized clinically to fight off
      neurodegeneration and the threat of other diseases in which defense against toxic
      self-compounds is needed.

PMID- 15016078
TI  - Cloning and expression of short interspersed elements B1 and B2 in ischemic
      brain.
AB  - Global ischemia causes an extensive cell death 3 days after the ischemia in the
      CA1 region of the hippocampus, which is preceded by induction of a spectrum of
      genes with both neuroprotective and detrimental properties. This delayed cell
      death has been suggested to be mainly caused by programmed cell death. Here we
      applied differential display to characterize transcripts induced by global
      ischemia after 1 day in Mongolian gerbils, when the cells in the CA1 region are
      still viable, but initiating the cell death pathway. One of the cloned
      transcripts turned out to be a repeat sequence termed SINE B2. We also cloned the
      other member of the SINE family, SINE B1, and found it also to be slightly
      induced by ischemia in the CA1 region. The SINE repeat regions are not translated
      and their role in ischemia may be related the neurons' attempt to cope with
      decreased translational levels and/or genomic reorganization. Together with the
      previous data demonstrating the inducibility of the SINE transcripts using in
      vitro stress models, the present study shows that SINE transcripts are stress
      inducible factors in the central nervous system.

PMID- 15016079
TI  - Regulation of MAPK/ERK phosphorylation via ionotropic glutamate receptors in
      cultured rat striatal neurons.
AB  - Extracellular signals may regulate mitogen-activated protein kinase (MAPK)
      cascades through a receptor-mediated mechanism. As a signaling superhighway to
      the nucleus, active Ras-MAPK cascades phosphorylate transcription factors and
      facilitate gene expression. In cultured rat striatal neurons, the present work
      systemically examined the linkage between glutamate receptors and the
      extracellular signal-regulated kinase 1/2 (ERK1/2) subclass of MAPK. We found
      that glutamate induced a rapid and transient phosphorylation of ERK1/2. Similar
      responses of ERK1/2 phosphorylation were also induced by the ligands selective
      for each of three subtypes of ionotropic receptors (NMDA, AMPA and kainate),
      although not by the subgroup-selective agonists for three subgroups of
      metabotropic glutamate receptors after 8-9 days in culture. The ERK1/2
      phosphorylation induced by all ionotropic receptor agents was dose-, time- and
      Ca(2+) influx-dependent and occurred in neurons, but not glia. The NMDA-, AMPA-
      and kainate-induced ERK1/2 phosphorylation was blocked only by the antagonists
      selective for respective subtypes. The ERK1/2 phosphorylation induced by these
      agents was also sensitive to the MAPK kinase 1 (MEK1) inhibitor PD98059 and the
      MEK1/2 inhibitor U0126. In a further attempt to evaluate the role of active
      ERK1/2 in activating a downstream transcription factor cAMP response element
      binding protein (CREB), NMDA, AMPA, and kainate were found to increase CREB
      phosphorylation. The NMDA- and AMPA/kainate-induced CREB phosphorylation was
      completely and partially blocked by U0126, respectively. These results revealed a
      positive linkage between ionotropic glutamate receptors and MEK-sensitive ERK1/2
      phosphorylation in striatal neurons. The active ERK1/2 cascade activates the
      downstream transcription factor CREB to participate in the regulation of gene
      expression.

PMID- 15016080
TI  - Optical survey of neural circuit formation in the embryonic chick vagal pathway.
AB  - The multiple-site optical recording technique with a voltage-sensitive dye,
      NK2761, was used to survey functional organization of neural circuits related to
      the vagus nerve in the embryonic chick brainstem. When we stimulated the vagus
      nerve, in addition to the responses in the vagal sensory nucleus (nucleus of the
      tractus solitarius (NTS)) and motor nucleus (dorsal motor nucleus of the vagus
      nerve (DMNV)) on the stimulated side, another response area was discriminated at
      the level of the pons/rostral medulla on the contralateral side. Characteristics
      of the contralateral optical signals suggested that they correspond to the neural
      activity in the second/higher-ordered nucleus of the vagal pathway, possibly the
      parabrachial nucleus, which receives inputs from the NTS. Blockade of non-N
      methyl-d-aspartate (NMDA) receptors abolished the responses on the contralateral
      side, together with the postsynaptic firing in the NTS, suggesting the
      significance of non-NMDA receptor function in sensory information transfer via
      the NTS. The responses on the contralateral side were first detected from the 7
      day-old embryonic stage, when the glutamatergic excitatory postsynaptic
      potentials were first expressed in the NTS. The results suggest that the synaptic
      pathway from the NTS to the contralateral nucleus is already generated when the
      primary vagal afferents make functional synapses on NTS neurons.

PMID- 15016081
TI  - Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes
      axon growth across adult rat spinal cord injuries.
AB  - The formation of misaligned scar tissue by a variety of cell types expressing
      multiple axon growth inhibitory proteoglycans presents a physical and molecular
      barrier to axon regeneration after adult spinal cord injuries. Decorin is a
      small, leucine-rich proteoglycan that has previously been shown to reduce
      astrogliosis and basal lamina formation in acute cerebral cortex stab injuries.
      We have therefore tested whether mini pump infusion of hr-decorin into acute stab
      injuries of the adult rat spinal cord can not only inhibit formation of an
      astroglial limitans but also deposition of the axon growth inhibitory
      proteoglycans neurocan, NG2, phosphacan and brevican. Combined
      immunohistochemical and quantitative Western blot analysis revealed major
      reductions in levels of core protein expression (>80% for 130-kDa neurocan,
      145/80-kDa brevican, 300-kDa phosphacan) and immunoreactivity for all four
      chondroitin sulfate proteoglycans (CSPGs) within decorin-treated injuries
      compared with untreated controls. Astrogliosis within lesion margins and the
      accumulation of OX42+ macrophages/microglia within lesion centres were also
      significantly reduced. These decorin-induced changes in scar formation combined
      to promote the striking ability of axons from microtransplanted adult sensory
      neurons to enter, grow within and exit decorin-infused spinal cord injuries, in
      sharp contrast to the complete failure of axons to cross untreated, CSPG-rich
      lesions. Decorin pretreatment of meningial fibroblasts in vitro also resulted in
      a three-fold increase in neurite outgrowth from co-cultured adult sensory neurons
      and suppression of NG2 immunoreactivity. The ability of decorin to promote axon
      growth across acute spinal cord injuries via a coordinated suppression of
      inflammation, CSPG expression and astroglial scar formation make decorin
      treatment a promising component of future spinal cord regeneration strategies.

PMID- 15016083
TI  - Effects of variability in anatomical reconstruction techniques on models of
      synaptic integration by dendrites: a comparison of three Internet archives.
AB  - The first step in building a realistic computational neuron model is to produce a
      passive electrical skeleton on to which active conductances can be grafted. For
      this, anatomically accurate morphological reconstructions of the desired cell
      type are required. In this study compartmental models were used to compare from a
      functional perspective three on-line archives of rat hippocampal CA1 pyramidal
      cell morphologies. The topological organization of cells was found to be similar
      for all archives, but several morphometric differences were observed. The three
      dimensional size of the cells, the diameter and tortuosity of dendrites, and the
      electrotonic length of the main apical dendrite and of the branches in stratum
      lacunosum moleculare were dissimilar. The experimentally measured kinetics of
      somatically recorded inhibitory postsynaptic currents evoked in the stratum
      lacunosum moleculare (data from the literature) could be reproduced only using
      the archives that contained cells with an electrotonically short main apical
      dendrite. In the amplitude attenuation of the simulated postsynaptic currents and
      the voltage escape from the command potential under voltage clamp conditions, a
      two- to three-fold difference was observed among archives. Upon activation of a
      single model synapse on distal branches, cells with low dendritic diameter showed
      a voltage escape larger than 15 mV. The diameter of the dendrites influenced
      greatly the results, emphasizing the importance of methods that allow an accurate
      measurement of this parameter. Our results indicate that there are functionally
      significant differences in the morphometric data available in different archives
      even if the cell type, brain region and species are the same.

PMID- 15016082
TI  - Convergence of excitatory and inhibitory inputs onto CCK-containing basket cells
      in the CA1 area of the rat hippocampus.
AB  - The number and distribution of excitatory and inhibitory inputs affect the
      integrative properties of neurons. These parameters have been studied recently
      for several hippocampal neuron populations. Besides parvalbumin- (PV) containing
      cells that include basket and axo-axonic cells, cholecystokinin (CCK)-containing
      interneurons also form a basket cell population with several properties distinct
      from PV cells. Here, at the light microscopic level, we reconstructed the entire
      dendritic tree of CCK-immunoreactive (IR) basket cells to describe their
      geometry, the total length and laminar distribution of their dendrites. This was
      followed by an electron microscopic analysis of serial ultrathin sections
      immunostained against gamma-aminobutyric acid, to estimate the density of
      excitatory and inhibitory synapses on their somata, axon initial segments and
      different subclasses of dendrites. The dendritic tree of CCK-IR basket cells has
      an average length of 6300 microm and penetrates all layers. At the electron
      microscopic level, CCK basket cells receive dendritic inputs with a density of 80
      230 per 100 microm. The ratio of inhibitory inputs is relatively high (35%) and
      increases towards the soma (83%). The total numbers of excitatory and inhibitory
      synapses converging onto CCK-IR cells are approximately 8200. Comparison of the
      two, neurochemically distinct basket cells reveals that CCK-containing basket
      cells receive much less synaptic input than PV cells; however, the relative
      weight of inhibition is higher on CCK cells. Additional differences in their
      anatomical and physiological properties predict that CCK basket cells are under a
      more diverse, elaborate control than PV basket cells, and thus the function of
      the two populations must be different.

PMID- 15016084
TI  - Thalamic innervation of striatal and subthalamic neurons projecting to the rat
      entopeduncular nucleus.
AB  - The present study analyses the anatomical arrangement of the projections linking
      the Wistar rat parafascicular thalamic nucleus (PF) and basal ganglia structures,
      such as the striatum and the subthalamic nucleus (STN), by using neuroanatomical
      tract-tracing techniques. Both the thalamostriatal and the striato-entopeduncular
      projections were topographically organized, and several areas of overlap between
      identified circuits were noticed, sustaining the existence of up to three
      separated channels within the Nauta-Mehler loop. Thalamic afferents arising from
      dorsolateral PF territories are in register with striatofugal neurons located in
      dorsolateral striatal areas, which in turn project to dorsolateral regions of the
      entopeduncular nucleus (ENT). Medial ENT regions are innervated by striatal
      neurons located within medial striatal territories, these neurons being the
      target for thalamic afferents coming from medial PF areas. Finally, afferents
      from neurons located in ventrolateral PF areas approached striatal neurons in
      ventral and lateral striatal territories, which in turn project towards ventral
      and lateral ENT regions. Efferent STN neurons projecting to ENT were found to be
      the apparent postsynaptic target for thalamo-subthalamic axons. The thalamo
      subthalamic projection was also topographically organized. Medial, central and
      lateral STN territories are innervated by thalamic neurons located within medial,
      ventrolateral and dorsolateral PF areas, respectively. Thus, each individual PF
      subregion projects in a segregated fashion to specific parts of the striato
      entopeduncular and subthalamo-entopeduncular systems. These circuits enabled the
      caudal intralaminar nuclei to modulate basal ganglia output.

PMID- 15016085
TI  - Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to
      tuberomammillary neurons.
AB  - High activity of the histaminergic neurons in the tuberomammillary (TM) nucleus
      increases wakefulness, and their firing rate is highest during waking and lowest
      during rapid eye movement sleep. The TM neurons receive a prominent innervation
      from sleep-active gamma-aminobutyric acidergic (GABAergic) neurons in the
      ventrolateral preoptic nucleus, which inhibits them during sleep. They also
      receive an excitatory input from the orexin- and dynorphin-containing neurons in
      the lateral hypothalamus, which are critically involved in sleep regulation and
      whose dysfunction causes narcolepsy. We have used intracellular recordings and
      immunohistochemistry to study if orexin neurons exert control over the GABAergic
      inputs to TM neurons in rat hypothalamic slices. Dynorphin suppressed GABAergic
      inputs and thus disinhibits the TM neurons, acting in concert with orexin to
      increase the excitability of these neurons. In contrast, both orexin-A and orexin
      B markedly increased the frequency of GABAergic potentials, while co-application
      of orexin and dynorphin produced responses similar to dynorphin alone. Thus,
      orexins excite TM neurons directly and by disinhibition, gated by dynorphin.
      These data might explain some of the neuropathology of narcolepsy.

PMID- 15016086
TI  - Roles of glutamate transporters in shaping excitatory synaptic currents in
      cerebellar Purkinje cells.
AB  - Several subtypes of glutamate transporters are abundantly expressed near the
      excitatory synapses on cerebellar Purkinje cells. We investigated the roles of
      the glutamate transporters in shaping the excitatory postsynaptic currents
      (EPSCs) and regulating the levels of extracellular glutamate in the mouse
      cerebellum using a potent blocker of glutamate transporters, dl-threo-beta
      benzyloxyaspartate (dl-TBOA). This drug markedly prolonged AMPA receptor-mediated
      EPSCs in Purkinje cells evoked by stimulating both parallel fibres and climbing
      fibres. The decay phase of the prolonged EPSCs was fitted by double exponentials,
      of which the slower component was preferentially inhibited by a low-affinity
      competitive antagonist of AMPA receptors, gamma-d-glutamyl-glycine, indicating
      that the slow component induced by dl-TBOA was the AMPA receptor-mediated current
      activated by lower concentrations of glutamate than those contributing to the
      peak of the EPSC. This result suggests that dl-TBOA prolongs the stay of
      synaptically released glutamate in the synaptic cleft and also induces glutamate
      spillover to extrasynaptic targets as well as neighbouring synapses. Furthermore,
      high concentrations of dl-TBOA in the presence of cyclothiazide generated a
      continuous inward current in Purkinje cells, of which the amplitude reached the
      peak level of the climbing-fibre EPSC. This continuous inward current was
      abolished by the blocker of AMPA receptors, indicating that the strong inhibition
      of glutamate uptake causes the rapid accumulation of glutamate in the
      extracellular space. These results highlight the importance of glutamate
      transporters in maintaining the proper glutamatergic transmission in Purkinje
      cell synapses.

PMID- 15016087
TI  - Calcium-dependent subthreshold oscillations determine bursting activity induced
      by N-methyl-D-aspartate in rat subthalamic neurons in vitro.
AB  - We used whole-cell patch recordings in current clamp to investigate the ionic
      dependence of burst firing induced by N-methyl-d-aspartate (NMDA) in neurons of
      the subthalamic nucleus (STN) in slices of rat brain. NMDA (20 microm) converted
      single-spike firing to burst firing in 87% of STN neurons tested. NMDA-induced
      bursting was blocked by AP5 (50 microm), and was not mimicked by the non-NMDA
      receptor agonist AMPA (0.6 microm). Tetrodotoxin (1 microm) converted bursts to
      oscillations of membrane potential, which were most robust when oscillations
      ranged between -50 and -70 mV. The NMDA bursts were blocked by an elevated
      extracellular concentration of Mg(2+), but superfusate containing no added Mg(2+)
      either reduced or increased burst firing, depending upon the amount of
      intracellular current injection. Block of K(+) conductances by apamin and
      tetraethylammonium prolonged burst duration, but iberiotoxin had no effect. NMDA
      induced burst firing and membrane oscillations were completely blocked by
      superfusate containing no added Ca(2+), and they were significantly reduced when
      patch pipettes contained BAPTA. Selective antagonists for T-type (mibefradil, 10
      microm), L-type (nifedipine, 3 microm), and N-type (omega-conotoxin GVIA, 1 micro
      m) Ca(2+) channels had no effect on NMDA burst firing. Superfusate containing a
      low concentration of Na(+) (20 mm) completely abolished NMDA-induced burst
      firing. Flufenamic acid (10 microm), which blocks current mediated by Ca(2+)
      activated nonselective cation channels (I(CAN)), reversibly abolished NMDA
      depended bursting. These results are consistent with the hypothesis that NMDA
      induced burst firing in STN neurons requires activation of either an I(CAN) or a
      Na(+)-Ca(2+) exchanger.

PMID- 15016089
TI  - Pharmacological profile of nociceptin/orphanin FQ receptors regulating 5
      hydroxytryptamine release in the mouse neocortex.
AB  - A synaptosomal preparation was employed to pharmacologically characterize the
      role of presynaptic nociceptin/orphanin FQ (N/OFQ) receptors (NOP receptors) in
      the regulation of 5-hydroxytryptamine release in the Swiss mouse neocortex. In
      the present study, the NOP receptor ligands N/OFQ, Ac-RYYRWK-NH(2) and
      [Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)-NH(2) inhibited the K(+)-induced [(3)H]-5
      HT overflow with similar maximal effects ( approximately -35%) but different
      potencies (pEC(50) of 8.56, 8.35 and 7.23, respectively). The novel agonist
      [Arg(14),Lys(15)]N/OFQ also inhibited [(3)H]-5-HT overflow, but the concentration
      response curve was biphasic and the efficacy higher ( approximately -45%).
      Receptor selectivity of NOP receptor agonists was demonstrated by showing that
      synaptosomes from NOP receptor knockout mice were unresponsive to N/OFQ,
      [Arg(14),Lys(15)]N/OFQ and [Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)-NH(2) but
      maintained full responsiveness to endomorphin-1. Moreover, the inhibitory effect
      of N/OFQ was prevented by peptide ([Nphe(1)]N/OFQ(1-13)-NH(2) and UFP-101) and
      nonpeptide (J-113397 and JTC-801) NOP receptor selective antagonists.
      Desensitization occurred under perfusion with high (3 and 10 microm) N/OFQ
      concentrations. This phenomenon was prevented by the protein kinase C inhibitor,
      bisindolylmaleimide. Moreover, N/OFQ-induced desensitization did not affect mu
      opioid receptor responsiveness. Finally, it was observed in a similar preparation
      of rat cerebrocortical synaptosomes, although it was induced by higher N/OFQ
      concentrations than that used in the mouse. Together, these findings indicate
      that presynaptic NOP receptors inhibit 5-hydroxytryptamine release in the mouse
      neocortex. Based on present and previous studies, we conclude that NOP receptors
      in the mouse are subtly different from the homologous receptor population in the
      rat, strengthening the view that there exist species differences in the
      pharmacology of central NOP receptors.

PMID- 15016088
TI  - The actions of monoamines and distribution of noradrenergic and serotoninergic
      contacts on different subpopulations of commissural interneurons in the cat
      spinal cord.
AB  - Modulatory actions of monoamines were investigated on spinal commissural
      interneurons which coordinate left-right hindlimb muscle activity through direct
      projections to the contralateral motor nuclei. Commissural interneurons located
      in Rexed lamina VIII, with identified projections to the contralateral
      gastrocnemius-soleus motor nuclei, were investigated in deeply anaesthetized
      cats. Most interneurons had dominant input from either the reticular formation or
      from group II muscle afferents; a small proportion of neurons had input from
      both. Actions of ionophoretically applied serotonin and noradrenaline were
      examined on extracellularly recorded spikes evoked monosynaptically by group II
      muscle afferents or reticulospinal tract fibres. Activation by reticulospinal
      fibres was facilitated by both serotonin and noradrenaline. Activation by group
      II afferents was also facilitated by serotonin but was strongly depressed by
      noradrenaline. To investigate the possible morphological substrates of this
      differential modulation, seven representative commissural interneurons were
      labelled intracellularly with tetramethylrhodamine-dextran and neurobiotin.
      Contacts from noradrenergic and serotoninergic fibres were revealed by
      immunohistochemistry and analysed with confocal microscopy. There were no major
      differences in the numbers and distributions of contacts among the interneurons
      studied. The findings suggest that differences in modulatory actions of
      monoamines, and subsequent changes in the recruitment of subpopulations of
      commissural interneurons in various behavioural situations, depend on intrinsic
      interneuron properties rather than on the patterns of innervation by
      monoaminergic fibres. The different actions of noradrenaline on different
      populations of interneurons might permit reconfiguration of the actions of the
      commissural neurons according to behavioural context.

PMID- 15016090
TI  - Neuromodulation of the locomotor network by dopamine in the isolated spinal cord
      of newborn rat.
AB  - We have analysed the action of the neuromodulatory catecholamine, dopamine (DA),
      on the lumbar locomotor network using an isolated in vitro newborn rat spinal
      cord preparation. We have also attempted to determine the respective contribution
      of the D1- and D2-like receptors on the dopamine-mediated effects. Bath
      application of DA-induced slow locomotor-like rhythmic activity (cycle-period 20
      30 s) in ventral motor roots. Bursts were alternating between segmental right and
      left side and between ipsilateral flexor and extensor units. This rhythm was
      blocked by D1 (SCH-23390) and D2 (raclopride, sulpiride) receptor antagonists,
      but was unaffected by the dopamine-beta-hydroxylase blocker, fusaric acid,
      thereby ruling out indirect noradrenaline-mediated effects. The D1 agonist, SKF
      81297 induced prolonged slow rhythmic bursting, while the selective D2 agonists,
      quinpirole and quinelorane, had no effect. DA and the D1 agonist, SKF-81297 also
      increased the period and burst amplitude of N-methyl-d-l-aspartate-induced
      locomotor activity. The effects of dopamine and SKF-81297 on the N-methyl-d-l
      aspartate-induced rhythm were long-lasting; persisting for 1 hour after washout.
      The DA action was blocked by MDL-12 330 A, an inhibitor of adenylate cyclase,
      suggesting the involvement of cAMP. Together these results indicate that dopamine
      can exert neuromodulatory actions on mammalian motor networks via short-lasting
      permissive influences and a newly reported, long-lasting modulation of motor
      network activity.

PMID- 15016091
TI  - Expression of hyperpolarization-activated and cyclic nucleotide-gated cation
      channel subunit 2 in axon terminals of peptidergic nociceptive primary sensory
      neurons in the superficial spinal dorsal horn of rats.
AB  - Hyperpolarization-activated cyclic nucleotide-gated cation channel proteins (HCN1
      4), which are potentially able to modulate membrane excitability, are abundantly
      expressed by neurons in spinal dorsal root ganglia (DRG). In the present
      experiment, we investigated whether HCN2 protein is confined exclusively to the
      perikarya of DRG neurons or is transported from the somata to the central axons
      of DRG neurons that terminate in the spinal dorsal horn. Using
      immunohistochemical methods, we have demonstrated that laminae I-IIo of the
      superficial spinal dorsal horn of the adult rat spinal cord show a strong
      punctate immunoreactivity for HCN2. Dorsal rhizotomy resulted in a complete loss
      of immunostaining in the dorsal horn, suggesting that HCN2 is confined to axon
      terminals of primary afferents. In double labelling immunohistochemical studies,
      we have also shown that HCN2 widely co-localizes with calcitonin gene-related
      peptide, but is almost completely segregated from isolectin-B4 binding,
      indicating that HCN2 is primarily expressed in peptidergic nociceptive primary
      afferents. The expression of HCN2 in central terminals of peptidergic primary
      afferents was also verified with electron microscopy. Utilizing the pre-embedding
      nanogold method, we found that HCN2 is largely confined to axon terminals with
      dense-core vesicles. Within these terminals, some of the silver grains marking
      the accurate location of HCN2 molecules were associated with the cell membrane,
      and others were scattered in the axoplasm. Within the cell membrane, HCN2 was
      found almost exclusively in extrasynaptic locations. The results suggest that
      HCN2 may contribute to the modulation of membrane excitability of nociceptive
      primary afferent terminals in the spinal dorsal horn.

PMID- 15016092
TI  - Background potassium channel block and TRPV1 activation contribute to proton
      depolarization of sensory neurons from humans with neuropathic pain.
AB  - Protons cause a sustained depolarization of human dorsal root ganglion (DRG)
      neurons [Baumann et al. (1996) Pain, 65, 31-38]. In the present study we sought
      to determine which ion channels are expressed in human DRG neurons that could
      mediate the sustained responses observed in the patch-clamp recordings. RT-PCR of
      material from the DRG tissue revealed the presence of mRNAs for a nonselective
      cation channel that is activated by protons (TRPV1) and background potassium
      channels that are blocked by protons (TASK-1, TASK-3 and Kir2.3). Highly acidic
      solution (pH 5.4) applied to cultured DRG neurons evoked prolonged currents that
      were associated with a net increase in membrane conductance. Consistent with the
      involvement of TRPV1, these proton-evoked currents were blocked by capsazepine
      and were only found in neurons that responded to capsaicin with an increase in
      membrane conductance. Less acidic extracellular solution (pH 6.0) evoked such
      currents only rarely, but was able to strongly enhance the currents evoked by
      capsaicin. Capsazepine (1 microm) blocked the currents evoked by capsaicin at pH
      7.35, as well as the potentiated responses to capsaicin at pH 6.0. In neurons
      that were not excited by capsaicin, moderate extracellular acidification (pH 6.0)
      caused a sustained decrease in resting membrane conductance. The decrease in
      membrane conductance by protons was associated with inhibition of background
      potassium channels. This excitatory effect of protons was not blocked by
      capsazepine. We conclude that in most neurons the sustained depolarization in
      response to moderately acidic solutions is the result of blocked background
      potassium channels. In a subset of neurons, TRPV1 also contributes.

PMID- 15016094
TI  - High-frequency synaptic input contributes to seizure initiation in the low-[Mg2+]
      model of epilepsy.
AB  - High-frequency field potential activity between 50 and 400 Hz occurs throughout
      seizure-like events recorded from the CA3 region of juvenile rat hippocampal
      slices under low-[Mg(2+)] condition. Another (400-800 Hz) component occurred
      mainly during preictal paroxysmal spiking and the onsets of seizure-like events
      (97%) and less frequently during tonic and clonic phases (38% and 70%,
      respectively). Short epochs of oscillations in this range were associated with
      fast negative field potential deflections at the start of field potential
      transients. Voltage-clamp recordings from putative CA3 pyramidal cells showed the
      occurrence of synaptic inputs in the same frequency range at the onset of seizure
      like events and the beginning of preictal or clonic paroxysmal spikes, while the
      frequency of action potentials never reached that range. The amplitude of fast
      negative field potential deflection, the rise time of membrane potential or
      voltage-clamp current changes and the mean phase coherence were consistent with
      an increase of synchronization towards the onset of a seizure-like event. Their
      parallel changes indicate the involvement of both synaptic and nonsynaptic
      mechanisms in the synchronization of neuronal activity and the development of
      seizure-like events in the low-[Mg(2+)] model of epilepsy.

PMID- 15016093
TI  - Short-term plasticity visualized with flavoprotein autofluorescence in the
      somatosensory cortex of anaesthetized rats.
AB  - In the present study, short-term plasticity of somatosensory neural responses was
      investigated using flavoprotein autofluorescence imaging in rats anaesthetized
      with urethane (1.5 g/kg, i.p.) Somatosensory neural activity was elicited by
      vibratory skin stimulation (50 Hz for 1 s) applied on the surface of the left
      plantar hindpaw. Changes in green autofluorescence (lambda = 500-550 nm) in blue
      light (lambda = 450-490 nm) were elicited in the right somatosensory cortex. The
      normalised maximal fluorescence responses (deltaF/F) was 2.0 +/- 0.1% (n = 40).
      After tetanic cortical stimulation (TS), applied at a depth of 1.5-2.0 mm from
      the cortical surface, the responses elicited by peripheral stimulation were
      significantly potentiated in both peak amplitude and size of the responsive area
      (both P < 0.02; Wilcoxon signed rank test). This potentiation was clearly
      observed in the recording session started 5 min after the cessation of TS, and
      returned to the control level within 30 min. However, depression of the responses
      was observed after TS applied at a depth of 0.5 mm. TS-induced changes in
      supragranular field potentials in cortical slices showed a similar dependence on
      the depth of the stimulated sites. When TS was applied on the ipsilateral
      somatosensory cortex, marked potentiation of the ipsilateral responses and slight
      potentiation of the contralateral responses to peripheral stimulation were
      observed after TS, suggesting the involvement of commissural fibers in the
      changes in the somatosensory brain maps. The present study clearly demonstrates
      that functional brain imaging using flavoprotein autofluorescence is a useful
      technique for investigating neural plasticity in vivo.

PMID- 15016095
TI  - Behavioural parameters in aged rats are related to LTP and gene expression of
      ChAT and NMDA-NR2 subunits in the striatum.
AB  - Striatal parameters were assessed for their relevance to age-related behavioural
      decline. Forty aged rats (28-30 months) were tested in the water maze and open
      field. Of these, seven superior and seven inferior learners were compared with
      each other in terms of levels of in vitro short- and long-term potentiation (STP
      and LTP), and gene expression of choline acetyltransferase (ChAT) as well as of
      the NMDA-NR2A-C subunits assessed by quantitative RT-PCR. Results revealed that
      the superior as compared with the inferior learners had higher levels of ChAT
      mRNA in the striatum. For the superior group, ChAT mRNA was correlated with
      escape on to the cued platform in the water maze, whereas level of LTP was
      predictive of place learning in the water maze and rearing activity in the open
      field. For the inferior group, expression of NR2A and NR2B was positively
      correlated with place learning and probe trial performance in the water maze. The
      results show that individual differences in various behaviours of aged rats were
      accounted for by variability in striatal parameters, i.e. LTP, ChAT and NMDA-NR2
      subunit mRNA. Notably, the correlations found were heterogeneous amid the groups,
      e.g. variability in place learning was explained by variability in levels of LTP
      in the superior learners, but in levels of NR2A-B mRNA in the inferior group.

PMID- 15016096
TI  - Learning and memory performance in mice lacking the GAL-R1 subtype of galanin
      receptor.
AB  - The neuropeptide galanin induces performance deficits in a wide range of
      cognitive tasks in rodents. Three G-protein-coupled galanin receptor subtypes,
      designated GAL-R1, GAL-R2 and GAL-R3, have been cloned. The present study
      examined the role of GAL-R1 in cognition by testing mice with a null mutation in
      Galr1 on several different types of learning and memory tasks. Assessments of
      general health, neurological reflexes, sensory abilities and motor functions were
      conducted as control measures. Mutant mice were unimpaired in social transmission
      of food preference and the Morris water maze. In tests of fear conditioning,
      mutant mice were unimpaired in a delay version of cued fear conditioning.
      However, mice homozygous for the null mutation were impaired in a trace version
      of cued fear conditioning. Mutant mice were unimpaired in contextual fear
      conditioning, whether training was by the delay or trace protocol. General
      health, neurological reflexes, sensory abilities and motor functions did not
      differ across genotypes, indicating that the trace fear conditioning deficit was
      not an artifact of procedural disabilities. The findings of normal performance on
      several cognitive tasks and a selective deficit in trace cued fear conditioning
      in homozygous GAL-R1 mutant mice are discussed in terms of hypothesized roles of
      the GAL-R1 subtype. The generally normal phenotype of GAL-R1 null mutants
      supports the use of this line for identification of the receptor subtypes that
      mediate the cognitive deficits produced by exogenous galanin.

PMID- 15016097
TI  - Monkey brain areas underlying remote-controlled operation.
AB  - We can control distant tools effectively by manipulating other objects as
      controllers in various remote-operated ways, even when the two mechanics are
      altered. To master the remote operation, we may rely on internal representation
      to organize individual moves of the controller and tool into a set of sequences
      by mapping the motor space among hand, controller and tool as a continuum. The
      present study confirmed that monkeys could also organize a sequence by mapping
      such a motor space or reorganize by remapping even after alteration. In addition,
      to investigate the neural substrates underlying such mapping/remapping, we
      measured the regional cerebral blood flow of two monkeys during joystick
      controlled operation with alterable function of mechanics using positron emission
      tomography with. The monkeys were scanned during three different tasks produced
      by altering the directional gains of the x or y axis of the joystick - the two
      mechanics are congruent (standard task) and not congruent (reversed in the X or Y
      axis, X reverse or Y reverse task, respectively). Compared with random movement
      of the joystick as the control task, increased activities were detected in the
      prefrontal cortex, higher-ordered motor cortex, posterior parietal cortex and
      cerebellum during the standard task. Common brain areas during performance of the
      X reverse and Y reverse task were identified as showing almost the same pattern
      as during the standard task. These shared areas may not simply be associated with
      organization of individual motor imagery, but also with context-dependent
      processing of reorganization based on current functions by means of internal
      representation.

PMID- 15016098
TI  - Four types of novelty-familiarity responses in associative recognition memory of
      humans.
AB  - Animal studies show that, like inferior temporal neurons, dorsolateral prefrontal
      and parietal neurons often respond more strongly to individual novel than to
      individual familiar stimuli. It is currently unclear whether the novelty
      preference of prefrontal and parietal neurons extends to associative memory. We
      used electromagnetic recordings (MEG/EEG) and functional magnetic resonance
      imaging in two groups of healthy young adults to identify neural populations
      outside the inferior temporal cortex that exhibit associative novelty (stronger
      responses for new than for old configurations of two familiar items), and to
      distinguish them from associative familiarity (stronger responses for old than
      for new configurations of two familiar items). Subjects were required to learn
      and were later tested for associations based on the spatial configurations of two
      stimuli (a face and a tool). At test, learned (old) and rearranged (new) spatial
      stimulus configurations had to be discriminated. This recognition memory test
      could only be solved through the associative relationship between individual
      items because all component items of the stimulus configurations were equally
      familiar. In both imaging modalities, right dorsolateral prefrontal cortex and
      right parietal cortex showed an associative novelty response, whereas the right
      superior temporal cortex showed an associative familiarity response. With EEG/MEG
      only, the right extrastriate cortex showed an early associative familiarity and a
      late associative novelty response, whereas the opposite pattern emerged in
      bilateral frontopolar cortex. Thus, through a multimodal approach, it was
      possible to identify four types of associative novelty/familiarity responses
      outside the inferior temporal cortex.

PMID- 15016099
TI  - The developmental dynamics of the brain is reflected by a regionally specific
      rise and fall of molecular complexity.
AB  - Tissue samples of inferior colliculus and cerebellar cortex were obtained from
      rat brains at various postnatal developmental stages. Samples were analysed by
      two-dimensional SDS gel electrophoresis. Spots of proteins and their variants
      were visualized with automated silver staining, the number of spots was
      determined with a computer-based image analysis system, and age groups were
      statistically compared. Judging from the waxing and waning of protein spot
      numbers, colliculus and cerebellum take distinctly different routes through
      postnatal development. Whereas molecular complexity in the colliculus was
      initially high, it decreased soon after the onset of hearing and settled on a
      significantly lower adult level. By contrast, the cerebellum initially showed low
      molecular complexity, rose sharply in complexity to reach highest values at late
      juvenile stages corresponding to peak scores of explorative behaviour, and fell
      off again to an adult level that remained, however, significantly higher than
      that of the colliculus. We conclude that the changing diversity of proteins may
      be used to identify landmarks in brain development.

PMID- 15016101
TI  - Asymmetric activation to the context-dependent right in the right inferior
      frontal region.
AB  - In human spatial recognition, right and left are not recognized symmetrically.
      Although there have been many studies on the hemispheric asymmetry of the human
      brain, asymmetries in high-level recognition (such as independence from input or
      output hemisphere) have not been studied extensively. We found that the human
      brain recognizes right and left asymmetrically in high-level recognition.
      Experiments were performed in which participants crossed their hands and were
      required to judge the side of a tactile stimulus on the index finger in two
      different contexts: 'which hand was touched' or 'on which side of the space the
      touched hand was located'. The right inferior frontal region was significantly
      more activated by the 'contextually defined right' stimulus (right-hand
      stimulation in the 'which hand' context and right-space stimulation in the 'which
      space' context) than by the 'contextually defined left' stimulus. However, no
      activation that was more activated by the 'contextually defined left' than by the
      'contextually defined right' was found. This asymmetric activation suggests that
      'right' is the more outstanding side for human spatial recognition.

PMID- 15016100
TI  - Daily body temperature rhythm and heat tolerance in TRPV1 knockout and capsaicin
      pretreated mice.
AB  - Daily body temperature (DBT) rhythm of mice lacking one of the transient receptor
      potential (TRP) family of proteins, the capsaicin receptor or TRPV1, was recorded
      by biotelemetry and found to have significantly higher amplitude than that of
      wild-type mice. Capsaicin-desensitized wild-mice exhibited an even higher DBT
      amplitude than did TRPV1 deficient mice. A standard heat load (radiant
      temperature of 36-37 degrees C) resulted in similar rises in body core
      temperature in wild-type mice and in TRPV1 deficient mice, while capsaicin
      desensitized wild-type mice exhibited a robust heat-intolerance. The lack of
      TRPV1 slightly modifies amplitude of daily body temperature rhythm but does not
      seem to influence physiological heat defence in mice. In vivo evidence for a TRP
      protein functioning in the physiological heat-defence range is still lacking.

PMID- 15016102
TI  - Cortical mechanisms of smooth pursuit eye movements with target blanking. An fMRI
      study.
AB  - Smooth pursuit eye movements are evoked by retinal image motion of visible moving
      objects and can also be driven by the internal representation of a target due to
      extraretinal mechanisms (e.g. efference copy). To delineate the corresponding
      neuronal correlates, functional magnetic resonance imaging at 1.5 T was applied
      during smooth pursuit at 10 degrees /s with continuous target presentation and
      target blanking for 1 s to 16 right-handed healthy males. Eye movements were
      assessed during scanning sessions by infra-red reflection oculography. Smooth
      pursuit performance was optimal when the target was visible but decreased to a
      residual velocity of about 30% of the velocity observed during continuous target
      presentation. Random effects analysis of the imaging data yielded an activation
      pattern for smooth pursuit in the absence of a visual target (in contrast to
      continuous target presentation) which included a number of cortical areas in
      which extraretinal information is available such as the frontal eye field, the
      superior parietal lobe, the anterior and the posterior intraparietal sulcus and
      the premotor cortex, and also the supplementary and the presupplementary eye
      field, the supramarginal gyrus, the dorsolateral prefrontal cortex, cerebellar
      areas and the basal ganglia. We suggest that cortical mechanisms such as
      prediction, visuo-spatial attention and transformation, multimodal visuomotor
      control and working memory are of special importance for maintaining smooth
      pursuit eye movements in the absence of a visible target.

PMID- 15016103
TI  - Human immuno-deficiency virus and infant feeding in complex humanitarian
      emergencies: priorities and policy considerations.
AB  - Issues surrounding mother-to-child transmission of HIV/AIDS pose considerable
      challenges in complex humanitarian emergencies. The risk of vertical transmission
      through breastfeeding is well recognised, but safe alternatives are limited by
      the social, economic and environmental conditions of emergency situations. In
      2000, the World Health Organisation published a technical report on behalf of the
      UNFPA/UNICEF/WHO/UNAIDS Inter-agency Task Team on Mother-to-child Transmission of
      HIV which outlined revised recommendations for infant feeding by HIV-positive
      women. This paper outlines reasons why these recommendations may be insufficient
      during the initial stages of complex humanitarian emergencies and proposes
      recommendations for establishing infant-feeding policy. Methods of mother-to
      child transmission of HIV are reviewed and recent research findings are
      discussed. Rationale for modifying the 2000 UNFPA/UNICEF/WHO/UNAIDS infant
      feeding recommendations in complex emergency situations is explored from the
      perspective of the infant, the mother and humanitarian field staff. Ethical
      limitations and future priorities are considered. The paper concludes with
      recommendations and a policy decision-making framework for consideration during
      the initial stages of humanitarian crises.

PMID- 15016104
TI  - From disaster to sustainable civil society: the Kobe experience.
AB  - Nine years after the Kobe earthquake in Japan, social issues are still prominent,
      and the rehabilitation process is still ongoing. The earthquake caused two major
      changes in Japanese society: an increase in voluntary and non-government
      activities, and the enhancement of cooperation between local government and the
      residents' association. People's participation in the decision-making process was
      a significant achievement. To sustain the efforts generated after the earthquake,
      the Kobe Action Plan was formulated and tested in different disaster scenarios.
      The current study suggests that civil societies in urban areas are sustainable
      if, first, the activities related to daily services are provided by the
      resident's associations; and second, these are linked to economic incentives.
      Leadership plays a crucial role in collective decision-making. Creation of the
      support system is essential for long-term sustainability of civil-society
      activities. These observations are exemplified in the case study in Nishi Suma,
      one of the worst-affected areas in the Kobe city.

PMID- 15016105
TI  - Human vulnerability, dislocation and resettlement: adaptation processes of river
      bank erosion-induced displacees in Bangladesh.
AB  - The purpose of this research was to identify and analyse patterns of economic and
      social adaptation among river-bank erosion-induced displacees in Bangladesh. It
      was hypothesised that the role of social demographic and socio-economic variables
      in determining the coping ability and recovery of the river-bank erosion-induced
      displacees is quite significant. The findings of the research reveal that
      displacees experience substantial socio-economic impoverishment and
      marginalisation as a consequence of involuntary migration. This in part is a
      socially constructed process, reflecting inequitable access to land and other
      resources. Vulnerability to disasters is further heightened by a number of
      identifiable social and demographic factors including gender, education and age,
      although extreme poverty and marginalisation create complexity to isolate the
      relative influence of these variables. The need to integrate hazard analysis and
      mitigation with the broader economic and social context is discussed. It is
      argued that the capacity of people to respond to environmental threats is a
      function of not only the physical forces which affect them, but also of
      underlying economic and social relationships which increase human vulnerability
      to risk. Hazard analysis and mitigation can be more effective when it takes into
      account such social and demographic and socio-economic dimensions of disasters.

PMID- 15016106
TI  - Housing reconstruction after two major earthquakes: the 1994 Northridge
      earthquake in the United States and the 1999 Chi-Chi earthquake in Taiwan.
AB  - The idea of pre-impact recovery planning has recently been promoted by
      researchers and practitioners, but very little research has been done to evaluate
      its effects on disaster recovery. This study compared two jurisdictions--the city
      of Los Angeles, California and Taichung county in Taiwan--in their recovery from
      earthquakes. Although the two cases also differ with respect to variables other
      than the presence of pre-impact recovery plans, the available data suggest that
      having a pre-impact recovery plan facilitates housing reconstruction and allows
      local officials to make more effective use of the window of opportunity after
      disaster to integrate hazard mitigation into the recovery process.

PMID- 15016107
TI  - Where to go? Strategic modelling of access to emergency shelters in Mozambique.
AB  - This paper, through spatial-analysis techniques, examines the accessibility of
      emergency shelters for vulnerable populations, and outlines the benefits of an
      extended and permanently established shelter network in central Mozambique. The
      raster-based modelling approach considers data on land cover, locations of
      accommodation centres in 2000, settlements and infrastructure. The shelter
      analysis is a two-step process determining access for vulnerable communities
      first, followed by a suitability analysis for additional emergency shelter sites.
      The results indicate the need for both retrofitting existing infrastructure
      (schools, health posts) to function as shelters during an emergency, and
      constructing new facilities - at best multi-purpose facilities that can serve as
      social infrastructure and shelter. Besides assessing the current situation in
      terms of availability and accessibility of emergency shelters, this paper
      provides an example of evaluating the effectiveness of humanitarian assistance
      without conventional mechanisms like food tonnage and number of beneficiaries.

PMID- 15016108
TI  - Diabetes UK Annual Professional Meeting, 17-19 March 2004, Birmingham, United
      Kingdom. Abstracts.

PMID- 15016111
TI  - Fluoride ingestion from toothpaste: background to European Union-funded
      multicentre project.
AB  - As in most other established market economies throughout the world the prevalence
      of dental caries has declined in most Member States of the European Union (EU).
      There is evidence that the increased use of fluoride toothpaste has been a major
      factor in this improvement. Recently there has been increasing debate on the
      alleged link between increased use of fluoride toothpaste, particularly by
      infants and young children, and increased levels of enamel fluorosis. Central to
      these discussions are two issues, namely measurement of the amount of fluoride
      ingested by infants and young children and measurement of enamel opacities
      including fluorosis. The aims of the project described in this special issue
      addressed these two measurement issues. Seven EU Partners participated.
      Standardized methods for recording the amount of fluoride ingested when using
      fluoride toothpaste were developed and used in the seven sites. Similarly a
      standardized photographic method for recording enamel opacities, including
      fluorosis, was developed.

PMID- 15016112
TI  - A review of fluorosis in the European Union: prevalence, risk factors and
      aesthetic issues.
AB  - Fluoride has played a key role in caries prevention for the past 50 years but
      excessive ingestion of fluoride during tooth development may lead to dental
      fluorosis. Throughout Europe many vehicles have been, and are currently, employed
      for optimal fluoride delivery including drinking water, toothpaste, fluoride
      supplements, salt and milk. Several indices, both descriptive and aetiological,
      have been developed and used for measuring fluorosis. This factor, combined with
      the lack of use of a standardized method for measurement of fluorosis, has made
      comparison between studies difficult and assessment of trends in fluorosis
      prevalence unreliable. Overall the evidence would appear to indicate, however,
      that diffuse enamel opacities are more prevalent in fluoridated than in
      nonfluoridated communities and that their prevalence at the very mild level may
      be increasing. In addition to fluoridated drinking water, risk factors for
      fluorosis include inadvertent ingestion of fluoride toothpaste and the
      inappropriate use of fluoride supplements. The risk is of aesthetic concern
      primarily during the period of enamel development of the permanent central
      incisors, although this largely appears to be a cosmetic rather than a public
      health issue. It is concluded that there is a need to co-ordinate studies
      measuring fluorosis throughout Europe and that development of a standardized
      photographic method would be useful. Furthermore, the aesthetic importance of
      fluorosis needs to be determined in more detail in each country in the light of
      each country's respective risk factors and dental health policies.

PMID- 15016113
TI  - A standardized photographic method for evaluating enamel opacities including
      fluorosis.
AB  - OBJECTIVES: The objective of this study was to demonstrate the reproducibility of
      a standardized photographic technique for recording fluorosis when used by a
      group of epidemiologists as part of a large multicentred European study. METHODS:
      Studies were first carried out to develop the equipment specification and
      photographic method. The author (JAC) was then trained and calibrated in this
      method. She was then responsible for the training and calibration of examiners
      from a further six European study sites. The method involved taking two
      transparencies of the permanent maxillary central incisors of 8-year-old
      children, the first after 8 s while the teeth were still wet and the second after
      105 s when the teeth had been allowed to dry out naturally. Data were collected
      at a central location during a training/calibration exercise and subsequently,
      during the conduct of a large study to measure fluorosis prevalence, at the seven
      sites. Intra- and interexaminer reproducibility of the photographic method were
      measured by grading the transparencies produced by all the examiners according to
      the DDE and TF indices. RESULTS: The time period in which the transparencies were
      taken was to within 4 s among the examiners. Transparencies scored according to
      the TF index gave a range of Kappa values of 0.45-0.66 for intraexaminer
      reliability and 0.32-0.55 for interexaminer reliability. When using the DDE index
      Kappa values ranged from 0.43 to 0.70 for intraexaminer reliability and from 0.34
      to 0.69 for interexaminer reliability. CONCLUSION: The photographic method was
      mostly robust and reproducible when used by epidemiologists from seven European
      study sites.

PMID- 15016115
TI  - Parental perception of fluorosis among 8-year-old children living in three
      communities in Iceland, Ireland and England.
AB  - OBJECTIVES: To assess the impact of enamel fluorosis in three of the communities
      examined in 'Project FLINT', it was decided to conduct a structured telephone
      interview with the parents of some of the children who took part in the study.
      METHODS: Three communities involved in this project were able to conduct this
      investigation: Reykjavik (Iceland), Cork (Ireland) and Knowsley (England). The
      aim was to interview the parents of children with a range of Thylstrup and
      Fejerskov (TF) index grades selected from each participating centre with respect
      to the appearance of their child's permanent maxillary central incisors.
      Interviewers were blinded as to the TF grade of the subject. RESULTS: Interviews
      were conducted with parents of 215 children: 69 with TF grade 0; 70 with TF grade
      1; 60 with TF grade 2 and 16 with TF grade 3 or greater. There was a trend
      towards more parents being unhappy with the appearance of their child's teeth
      with increasing TF grade. However, the main reasons given by parents for being
      unhappy with the appearance of their child's teeth was tooth alignment followed
      by the more yellow colour of permanent compared with primary teeth. Only with a
      TF grade of 3 was any appreciable concern expressed about fluorosis. CONCLUSION:
      It would appear that there is a public awareness of both developmental defects
      and enamel fluorosis although this is not always expressed as dissatisfaction.
      Further research is required into the clinical impact of both fluorosis and other
      developmental defects of enamel.

PMID- 15016114
TI  - A comparison of the prevalence of fluorosis in 8-year-old children from seven
      European study sites using a standardized methodology.
AB  - OBJECTIVES: The objectives of this study were to report on the prevalence of
      enamel opacities from seven European study sites using a standardized
      photographic method, and to investigate the importance of variables responsible
      for enamel fluorosis. METHODS: The sample comprised a randomly selected group of
      300 8-year-old children in each of the study areas. One examiner from each area
      was trained and calibrated in the use of a standardized photographic technique.
      Two transparencies were taken of each child's permanent maxillary central incisor
      teeth; one to represent the teeth 'wet' and one when the teeth had been allowed
      to dry out naturally for 105 s. The transparencies were viewed 'blind' by the
      author (JAC) and scored using the DDE and TF indices. Data relating to variables
      considered to be associated with enamel fluorosis were also collected. RESULTS:
      The prevalence of diffuse opacities ranged from 61% in fluoridated Cork (Ireland)
      to 28% in Athens (Greece). The percentage of subjects with a TF score of three or
      more ranged from 4% in Cork and nonfluoridated Haarlem (the Netherlands) to zero
      in Oulu (Finland) and Athens. Fluoridated water and the prolonged use of fluoride
      tablets were found to be significant contributory factors to fluorosis.
      CONCLUSIONS: The prevalence of fluorosis was found to be highest in fluoridated
      Cork. The prolonged use of fluoride supplements was also found to be a
      significant risk indicator associated with fluorosis.

PMID- 15016116
TI  - Development of a standardized method for comparing fluoride ingested from
      toothpaste by 1.5-3.5-year-old children in seven European countries. Part 1:
      Field work.
AB  - OBJECTIVES: To develop a standardized method for measuring the variables
      affecting fluoride ingestion from toothpaste in young children between the ages
      of 1.5 and 3.5 years, and to use the method at seven European sites. METHODS:
      Random samples of children were invited to take part in the study. Parents who
      gave consent were visited at home. The children brushed their teeth using the
      toothpaste brand and toothbrush type currently in use. Variables measured were:
      type of toothpaste used, fluoride concentration of toothpaste used, weight of
      toothpaste used, frequency of brushing and body weight of the child. RESULTS: It
      was not possible to follow the agreed protocol in all seven countries and in
      three countries appropriate alternative methods were employed. There was
      considerable variation between countries in the variables investigated. Use of
      children's toothpaste ranged from 69% in Ireland to 98% in Portugal. In the
      Netherlands up to 60% of the children were using toothpaste containing <400 ppm F
      and in Finland up to 27% of children were using toothpaste containing >1200 ppm
      F. Over half of the children used <0.25 g of toothpaste per brushing and the
      majority of children brushed once or twice per day. CONCLUSION: Although
      adherence to the agreed protocol was not possible at all study sites there was a
      clear picture of considerable variation in the oral hygiene practices of young
      children throughout Europe.

PMID- 15016117
TI  - Development of a standardized method for comparing fluoride ingested from
      toothpaste by 1.5-3.5-year-old children in seven European countries. Part 2:
      Ingestion results.
AB  - OBJECTIVES: To develop a standardized method for measuring the variables
      affecting fluoride ingestion from toothpaste in young children between the ages
      of 1.5 and 3.5 years, and to use the method at seven European sites. METHODS:
      Random samples of children were invited to take part in the study. Parents who
      gave consent were visited at home. The children brushed their teeth using the
      toothpaste brand and toothbrush type currently in use. The difference between the
      fluoride dispensed onto the toothbrush and the fluoride recovered after
      accounting for losses was deemed to be the fluoride ingested. Details of other
      oral health-care habits were collected by questionnaire. For each child, the
      fluoride concentration of the toothpaste used was measured in the laboratory,
      from which an estimate of total daily fluoride ingestion was made. RESULTS: There
      was considerable variation between countries in the types of toothpaste used and
      in the amounts of toothpaste applied and ingested. The amount of fluoride
      ingested ranged from 0.01 to 0.04 mg fluoride per kg of body weight per day.
      CONCLUSION: The amount of fluoride ingested that is likely to be a risk factor
      for the development of dental fluorosis during tooth formation is equivocal and
      was found to vary widely between European countries. There appears to be a need
      for clearer health messages regarding the use of fluoridated toothpaste by young
      children.

PMID- 15016118
TI  - Fluoride ingestion from toothpaste: fluoride recovered from the toothbrush, the
      expectorate and the after-brush rinses.
AB  - OBJECTIVES: The aim of this study was to determine the effects of rinsing and
      spitting on fluoride ingestion from toothpaste during normal oral-hygiene
      procedures of younger children, and hence to make recommendations on rinsing
      during toothbrushing. METHODS: The brushing habits of 166 Dutch and 185 Irish
      children between 1.5 and 3.5 years were observed during home visits. The weight
      of the toothpaste tube was determined before and after use. After brushing, the
      toothbrush and any associated expectorate and rinses, combined with any
      toothpaste spilled during the brushing procedures, were collected. The amounts of
      fluoride retained on the toothbrush and in the associated expectorate and rinses
      were measured. RESULTS: Over 90% of the Dutch children used a special toddlers'
      toothpaste with < or =500 ppm F. Eleven per cent of the younger (<2.5 years)
      Dutch children and 22% of the older children rinsed after brushing. Of the Irish
      children approximately 52% used a children's toothpaste containing around 500 ppm
      F. Of the younger Irish children 31% spat without rinsing, while another 31%
      rinsed during or after brushing. For the older Irish children, these percentages
      were 14 and 70%, respectively. On average, 22% of the fluoride dispensed on the
      toothbrush was retained on the brush after brushing irrespective of the rinsing
      and spitting behaviour of the children. The maximum ingestible amount of fluoride
      from toothpaste assuming no rinsing or spitting was calculated. CONCLUSIONS:
      Fluoride ingestion from toothpaste is significantly reduced by rinsing and/or
      spitting during toothbrushing. Recommendations that younger children use small
      amounts of toothpaste (< 0.5 g) and that children using toothpaste with > or =
      1000 ppm F rinse their mouths after brushing continue to be valid.

PMID- 15016119
TI  - Urinary fluoride excretion by preschool children in six European countries.
AB  - OBJECTIVE: To measure and compare 24-h urinary fluoride excretion in children
      aged 1.5-3.5 years from European study sites and to use these data to estimate
      the 24-h fluoride intake. METHOD: Twenty-four-hour urine samples were collected
      from 3-year-old children (n = 86) who were already participating in a European
      multicentre study. Samples were collected from Cork, Ireland (n = 19) where the
      water is fluoridated to a concentration between 0.8 and 1.0 ppm and from five
      sites with a water fluoride concentration <0.15 ppm: Knowsley, England (n = 18);
      Oulu, Finland (n = 18); Reykjavik, Iceland (n = 4); Haarlem, the Netherlands (n =
      6); Almada/Setubal, Portugal (n = 21). The volume of the samples was measured;
      they were analysed for fluoride concentration and the 24-h urinary fluoride
      excretion was calculated. From this an estimate of the daily fluoride intake was
      made. RESULTS: It was found that the mean fluoride excretion in response to the
      usual conditions of fluoride intake in the children in the nonfluoridated areas
      ranged from 0.16 mg (+/-0.08) in Oulu to 0.33 mg (+/-0.27) in Almada/Setubal with
      an overall mean of 0.23 mg (+/-0.19). The mean 24-h fluoride excretion in
      fluoridated Cork was 0.37 mg (+/-0.11). There was a significant difference
      between the fluoride excretion in the nonfluoridated areas and that in the
      fluoridated areas, and the data were broadly in agreement with WHO standards.
      CONCLUSIONS: The daily urinary fluoride excretion and estimated fluoride intake
      in these children appeared to be within acceptable limits.

PMID- 15016120
TI  - A European perspective on fluoride use in seven countries.
AB  - OBJECTIVES: The aim of this study was to collate data on national policies for
      the use of fluoride in the seven European countries participating in the FLINT
      project. METHODS: Policies on the use of fluoride were obtained for each of the
      study areas. Data collected included the presence of water fluoridation and
      regulations governing fluoride toothpaste and fluoride supplements. RESULTS: In
      Ireland 74% of the population had a fluoridated water supply but in all the other
      countries fluoride toothpaste was the principal form of delivering fluoride,
      usually recommended as a dose of a pea-sized amount. Fluoride supplement use
      varied considerably between countries. The Netherlands had the clearest
      regulations covering the use of fluoride supplements and definition of at-risk
      individuals. Most countries, even if they recognized particular caries-risk did
      not define the term clearly. In Iceland all children were regarded as being at
      high risk of developing caries. CONCLUSION: Considerable variation exists between
      European countries in their policies for fluoride use and no clear definitions of
      high-caries-risk individuals were found. The results show that there is even a
      lack of coherent thought and planning within the different countries, let alone
      between them.

PMID- 15016121
TI  - Fluoride ingestion from toothpaste: conclusions of European Union-funded
      multicentre project.
AB  - An important challenge encountered in this multicentred project was the need to
      take account of the different cultural and legal differences between the seven
      sites when agreeing the protocol. Examples such as access to registers of births
      and subject consent dictated that there were some differences in the methods used
      in the different sites. The data presented showed that it was possible to train
      and calibrate a number of examiners in a standardized photographic method for
      recording enamel fluorosis. This method has a number of important advantages for
      the objective monitoring of enamel fluorosis over time. There were considerable
      differences between the seven sites in the formulations of the toothpaste used
      and in the pattern of their use. The results indicate that it is possible to
      agree and adopt a standardized method for measuring fluoride ingestion from
      toothpaste. The aesthetic impact of enamel fluorosis seemed low in the
      populations included in this project, but further work is required on this issue.

PMID- 15016122
TI  - Basiliximab in association with tacrolimus and steroids in caucasian cadaveric
      renal transplanted patients: significant decrease in early acute rejection rate
      and hospitalization time.
AB  - Safety and tolerability of basiliximab in renal transplantation have been proven
      in different immunosuppressive regimens. Few informations are available about the
      association of basiliximab with tacrolimus and steroids. We present a
      retrospective analysis performed in Caucasian cadaveric renal transplant
      recipients, comparing a basiliximab, tacrolimus and steroids induction protocol
      (GrA: 51 patients) with a tacrolimus and steroids protocol (GrB: 46 patients). A
      significant decrease in acute rejection rate in the first 3 months (2.0% vs.
      17.4%; p < 0.01) was noted. Interestingly, the recipients in GrA were at major
      immunologic risk for the younger age of recipients, the greater number of
      mismatches and the higher rate of second transplants. The hospitalization times
      resulted reduced of 5.3 d in GrA vs. GrB (20.8 d vs. 26.1 d; p < 0.05). The
      adverse events patterns and profiles were similar in the two treatments groups.
      One patient in each group had a post-transplant lymphoprolipherative disorder. No
      significant difference was found in patient and graft survival. According to the
      results of this study, in a Caucasian adult population, basiliximab in
      association with tacrolimus and steroids is a safe and efficacious tool for acute
      rejection prevention and it is cost saving by reducing the hospitalization times.

PMID- 15016123
TI  - Serial monitoring of immunological parameters following human hand transplant.
AB  - BACKGROUND: Although early successes have been achieved in human hand transplant,
      the changes of immunological parameters in the recipients and their relations to
      clinical events were not yet known. METHODS: In two patients undergoing hand
      transplantation, we prospectively determined lymphocyte subsets using flow
      cytometry as well as the serum levels of interleukin (IL)-2, IL-10, tumor
      necrosis factor (TNF)-alpha, and interferon (IFN)-gamma using enzyme linked
      immunosorbent assays during the first 6 months after transplantation. RESULTS:
      The decreases in CD, CD, CD T cell, the activated T cell (CD/CD, CD/HLA-DR(+)) as
      well as IL-2, IFN-gamma and corresponding significant peak in IL-10 in human hand
      transplant during the first post-transplant week were observed. Then these
      parameters recovered to the pre-transplant level except for an even higher level
      of CD T cell. The low CD/CD ratio was been maintained constantly. After 7 wk, IL
      2, IFN-gamma, and IL-10 decreased to be maintained at a low or undetectable level
      except for slight increase in IL-10 at post-transplant month 5. There are no
      significant variation in TNF-alpha early after transplant. After 3 months, IL-10
      was not detected again. CONCLUSIONS: The immunosuppressive agents had
      significantly effects on the immunological status in human hand transplant
      recipients. These profiles of immunological parameters would be useful data for
      the future immunomonitoring in human hand transplant recipients.

PMID- 15016124
TI  - The variability of liver graft function and urinary 6beta-hydroxycortisol to
      cortisol ratio during liver regeneration in liver transplant recipients.
AB  - The urinary ratio of 6beta-hydroxycortisol to cortisol (6beta-OHF/F) is
      considered to be the simplest and most practical method for estimation of hepatic
      cytochrome P450 3A4 (CYP3A4) activity as a non-invasive marker of human in vivo
      CYP3A4 activity. However, the inter- and intra-individual variability of the
      urinary 6beta-OHF/F ratio during liver regeneration and the effect of variability
      on optimal dose of tacrolimus have not yet been clarified. The objective of this
      study was to clarify the change in the urinary 6beta-OHF/F ratio during liver
      regeneration and to determine the effect of the liver graft function on the
      optimal tacrolimus dose in liver transplant recipients. Two liver transplant
      recipients (one male and one female) and eight healthy volunteers (five males and
      three females) were enrolled in this study. Urine samples were collected from the
      recipients from 08.00 hours for 24 h on post-transplant period, 1-10 and 21-30
      days postoperatively. In the healthy volunteers, morning spot urine samples were
      collected at 08.00 hours. The mean urinary 6beta-OHF/F ratio in the immediate
      postoperative period was significantly low (p < 0.05). However, a marked
      difference in the regulation of CYP3A4 activity during liver regeneration was
      found in the two recipients. A significant correlation was found between the
      urinary 6beta-OHF/F ratio and the C/D ratio of tacrolimus (R = 0.658, p < 0.05).
      The urinary 6beta-OHF/F ratio is a useful probe for estimating the variability of
      CYP3A4 activity in liver transplant recipients in early postoperative phase.
      Future studies should evaluate the clinical usefulness of the urinary 6beta-OHF/F
      ratio as a predictor of tacrolimus pharmacokinetics in liver transplantation.

PMID- 15016126
TI  - Perioperative treatment with octreotide minimizes technical complications after
      enteric conversion of bladder-drained pancreas transplants.
AB  - We review our experience with enteric conversion of previously bladder-drained
      pancreas transplants (PTx) using a short perioperative course of octreotide
      (OCT). Between July 1994 and December 2001, 45 consecutive primary bladder
      drained PTx were performed. Immunosuppression consisted of a combination of
      tacrolimus, mycophenolate mofetil and steroids after induction with monoclonal or
      polyclonal antibodies. A total of 16 patients underwent enteric conversion at an
      average of 3 months after the initial transplant. Each patient received OCT
      perioperatively. We report no technical complications with the exception of one
      superficial wound infection and good early and late PTx survival rates.
      Perioperative treatment with octreotide is well tolerated and may reduce
      technical complications while performing enteric conversion of previously bladder
      drained PTx.

PMID- 15016125
TI  - Serum cholestasis markers as predictors of early outcome after liver
      transplantation.
AB  - BACKGROUND: Early cholestasis is not uncommon after liver transplantation and
      usually signifies graft dysfunction. The aim of this study was to determine if
      serum synthetic and cholestatic parameters measured at various time points after
      transplantation can predict early patient outcome, and graft function. METHODS:
      The charts of 92 patients who underwent 95 liver transplantations at Rabin
      Medical Center between 1991 and 2000 were reviewed. Findings on liver function
      tests and levels of serum bilirubin, alkaline phosphatase (ALP), and gamma
      glutamyl transpeptidase (GGT) on days 2, 10, 30, and 90 after transplantation
      were measured in order to predict early (6 months) patient outcome (mortality and
      sepsis) and initial poor functioning graft. Pearson correlation, chi(2) test, and
      Student's t-test were performed for univariate analysis, and logistic regression
      for multivariate analysis. RESULTS: Univariate analysis. Serum bilirubin >/=10
      mg/dL and international normalized ratio (INR) >1.6 on days 10, 30, and 90, and
      high serum ALP and low albumin levels on days 30 and 90 were risk factors for 6
      month mortality; serum bilirubin >/=10 mg/dL on days 10, 30, and 90, high serum
      ALP, high GGT, and low serum albumin, on days 30 and 90, and INR >/=1.6 on day 10
      were risk factors for sepsis; high serum alanine aminotransferase, INR >1.6, and
      bilirubin >/=10 mg/dL on days 2 and 10 were risk factors for poor graft function.
      The 6-month mortality rate was significantly higher in patients with serum
      bilirubin >/=10 mg/dL on day 10 than in patients with values of <10 mg/dL (29.4%
      vs. 4.0%, p = 0.004). Patients who had sepsis had high mean serum ALP levels on
      day 30 than patients who did not (364.5 +/- 229.9 U/L vs. 70.8 +/- 125.6 U/L, p =
      0.005). Multivariate analysis. Significant predictors of 6-month mortality were
      serum bilirubin >/=10 mg/dL [odds ratio (OR) 9.05, 95% confidence intervals (CI)
      1.6-49.6] and INR >1.6 (OR 9.11, CI 1.5-54.8) on day 10; significant predictors
      were high serum ALP level on day 30 (OR 1.005, 1.001-1.01) and high GGT level on
      day 90 (OR 1.005, CI 1.001-1.01). None of the variables were able to predict
      initial poor graft functioning. CONCLUSIONS: Several serum cholestasis markers
      may serve as predictors of early outcome of liver transplantation. The strongest
      correlation was found between serum bilirubin >/=10 mg/dL on day 10 and early
      death, sepsis, and poor graft function. Early intervention in patients found to
      be at high risk may ameliorate the high morbidity and mortality associated with
      early cholestasis.

PMID- 15016127
TI  - Platelet activation in heart transplant recipients.
AB  - An inappropriate and persistent immune activation has been suggested to
      contribute to long-term mortality and morbidity after heart transplantation.
      Several lines of evidence suggest that platelets do not only promote thrombus
      formation, but also act as inflammatory cells. In the present study, we
      investigated if long-time survivors of heart transplantation (mean time since
      transplantation 6.5 yr) were characterized by enhanced platelet activation as
      assessed by different experimental approaches. Our main findings when comparing
      heart transplant recipients (n = 52) and age- and sex-matched healthy controls (n
      = 38) were: (i) platelets from heart transplant recipients showed enhanced
      expression of both P-selectin and CD63 as assessed by flow cytometry; (ii)
      platelets from these patients also contained significantly increased levels of
      soluble CD40 ligand and tended to release higher levels of this cytokine upon
      SFLLRN stimulation as assessed by enzyme immunoassay; (iii) heart transplant
      recipients had increased levels of soluble P-selectin in platelet-free plasma;
      and (iv) the enhanced platelet activation after heart transplantation was most
      pronounced in those with concomitant hypertension. These findings suggest that
      long-term survivors of heart transplantation are characterized by enhanced
      activation of platelets, possibly contributing to the persistent immune
      activation and clinical complications in these patients.

PMID- 15016129
TI  - The incidence and significance of late acute cellular rejection (>1000 days)
      after liver transplantation.
AB  - Acute cellular rejection (ACR) after liver transplantation occurs in as much as
      70% of patients within the first year. There is very little known about ACR that
      occurs more than 1 yr after transplant, and it is generally believed that late
      occurring ACR may be more resistant to medical treatment and is associated with a
      higher rate of chronic ductopenic rejection and graft loss. A total of 532
      recipients with more than 1000 d follow-up and who did not have hepatitis C were
      identified. Forty-three (8.1%) had biopsy proven late ACR at a mean of 1545 +/-
      441 d post-transplant. Additionally, 38 of the 43 (88.4%) patients with late ACR
      had earlier episodes of ACR before 1000 d post-transplant vs. only 295 of the 488
      patients (60.5%) that did not have late ACR (p < 0.01). The incidence of primary
      sclerosing cholangitis (PSC) was 32.6% among patients with late ACR and 11.1%
      among patients without late ACR (p < 0.01). The overall patient survival for
      patients who had late ACR (n = 43) is 81.4% while for patients without late ACR
      (n = 488) it is 82.0% (p = ns). Patients remain at risk for ACR even after 1000 d
      post-transplant, particularly those with PSC.

PMID- 15016128
TI  - Relationship between endomyocardial biopsy score and cyclosporine 2-h post-dose
      levels (C) in heart transplant patients receiving anti-thymocyte globulin
      induction.
AB  - BACKGROUND: Cyclosporine (CsA) 2-h post-dose levels (C(2)) correlate better with
      the area-under-the-curve compared with trough levels. The purpose of this study
      was to determine the relationship between C(2) and endomyocardial biopsy (EMB)
      score in heart transplant patients receiving anti-thymocyte globulin (ATG)
      induction. METHODS: We reviewed 517 EMB performed during the first year in 39
      adult heart transplant patients receiving ATG-induction, corticosteroids,
      mycophenolate mofetil and CsA. C(2) obtained on the day of EMB was related to the
      International Society for Heart and Lung Transplantation classification (score
      </=2 or >/=3A). Furthermore, EMB were related to C(2) (ng/mL), sorted according
      to the lower recommended range in liver (0-3 months: 850; 4-6 months: 700; 7-12
      months: 500) or renal transplantation (0-1 month: 1500; 2-3 months: 1200; 4-6
      months: 1000; 7-12 months: 800). RESULTS: Overall, C(2) did not significantly
      differ in patients with EMB </=2 or >/=3A. However, during the first month, EMB
      </=2 was associated with a trend towards a higher mean C(2) compared with EMB
      >/=3A (750 ng/mL vs. 530 ng/mL). When C(2) were sorted according to the lower
      recommended range in liver or renal transplantation, no significant difference
      was observed when EMB was </=2 or >/=3A. CONCLUSIONS: In heart transplant
      patients receiving ATG-induction, C(2) did not significantly differ according to
      EMB </=2 or >/=3A. No significant relationship was found between EMB score and
      C(2) based on the lower recommended range in liver or renal transplantation.
      However, mean C(2) >750 ng/mL appears to be associated with a lower rejection
      score during the first month.

PMID- 15016130
TI  - Interstitial alterations in renal cortex in acute tubular necrosis (ATN) post
      renal transplantation and in patients with ATN not related to renal transplant.
AB  - BACKGROUND: Abnormalities of renal function with long-term implications can
      persist after acute tubular necrosis (ATN), probably because of permanent loss of
      nephrons. Residual areas of fibrosis are also observed in the renal cortex post
      ATN. In this study, we investigate the interstitial alterations post-ATN using
      histological and immunohistochemical methods. METHODS: We studied 11 patients
      with ATN of different etiologies and 19 patients with ATN post-renal
      transplantation. Eleven patients with ATN post-renal transplantation and one with
      ATN not related to renal transplantation were submitted to more than one biopsy
      because of delayed renal function recovery. The immunohistochemical studies were
      performed using alpha-smooth muscle-actin (alpha-SM-actin), endothelin, nuclear
      factor-kappaB (NF-kappaB), Jun-N-terminal kinase (p-JNK) and fibronectin
      antibodies. We also analyzed the urinary content of transforming growth factor
      beta (TGF-beta) during the acute phase of ATN. RESULTS: The immunohistochemical
      studies showed increased alpha-SM-actin, fibronectin, endothelin, p-JNK and NF
      kappaB staining in the tubulointerstitium area from the renal cortex of all
      patients when compared with controls (p < 0.001), and these increase persisted in
      the patients submitted to sequential biopsies. One of the patients with ATN
      without renal transplant and six patients with ATN post-renal transplant
      developed chronic renal failure. There was a significant increase of TGF-beta
      excretion in the urine of patients with acute renal failure (p < 0.01) compared
      with control. CONCLUSIONS: Our data show that the enhancement of renal TGF-beta
      production and the persistent increase of myofibroblasts, fibronectin,
      endothelin, p-JNK and NF-kappaB in renal cortex tubulointerstitium post-ATN may
      explain the impaired recovery of renal function observed in patients post-ATN
      frequently observed in patients with ATN post-renal transplant.

PMID- 15016131
TI  - Pegylated interferon alpha-2b plus ribavirin in the treatment of post-liver
      transplant recurrent hepatitis C.
AB  - BACKGROUND: Histological recurrence of the hepatitis C virus (HCV) occurs in the
      majority of persons transplanted for cirrhosis as a result of HCV. Herein we
      analyze our experience with the use of both conventional and pegylated (PEG)
      interferon (IFN) in combination with ribavirin (RBV) in liver transplant
      recipients with recurrent HCV. METHODS: Patients transplanted between 1992 and
      2001 with post-orthotopic liver transplantation (OLT) histological recurrence of
      HCV, and who were treated with at least 6 months of IFN or PEG-IFN in combination
      with RBV were included in this analysis. A retrospective chart review was
      performed. RESULTS: A total of 31 patients were included. Fifteen were treated
      with IFN/RBV and 16 with PEG-IFN/RBV. Of these 16, 11 had been begun on IFN/RBV
      and were changed to PEG-IFN/RBV because of persistent viremia. Three patients
      (20%) in the IFN/RBV group and six patients (37.5%) in the PEG-IFN/RBV group
      experienced a virologic response (VR) on therapy. Of the six patients
      experiencing VR in the PEG-IFN/RBV group, three (50%) were IFN/RBV non
      responders. There were two sustained VRs (SVR). The 65.6% of all patients
      experienced a biochemical response (BR) on therapy. Seven deaths were observed.
      Dose modifications of IFN or PEG-IFN (87.1%) and RBV (80.6%) and the requirement
      for hematopoietic growth factors were frequent. CONCLUSIONS: Treatment of
      recurrent HCV infection with combination of IFN or PEG-IFN and RBV produced an on
      therapy VR in 29% and BR in 65% of patients. Hematologic toxicity and dose
      modifications were frequent. Our experience with antiviral therapy for HCV post
      OLT remains disappointing but PEG-IFN + RBV appears to produce VR in a sizable
      portion of IFN + RBV non-responders.

PMID- 15016132
TI  - In vivo IL-10 and TGF-beta production by PBMC from long-term kidney transplant
      recipients with excellent graft function: a possible feedback mechanism
      participating in immunological stability.
AB  - BACKGROUND: Interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta)
      are Th2-derived multifunctional cytokines that exhibit potent immunoregulatory
      and anti-inflammatory properties which might prolong graft survival. The aim of
      this study was to explore whether spontaneous production of IL-10 and TGF-beta by
      blood mononuclear cells correlates with excellent long-term graft function.
      METHODS: A cross-sectional study was carried out in 32 kidney transplant
      recipients, without albuminuria, treated with azathioprine and prednisone.
      Spontaneous IL-10 and TGF-beta were measured by enzyme-linked immunosorbent assay
      in supernatants from 24 h cultured unstimulated peripheral blood mononuclear
      cells. Both cytokines were also determined in 10 healthy kidney donors. RESULTS:
      There was no correlation between IL-10 or TGF-beta with any variable tested,
      namely age, SCr, histocompatibility, and post-transplant follow-up. In vivo IL-10
      production displayed a statistical trend to be higher in transplant recipients
      than in controls (362.3 +/- 465, range 12.5-1929.3 pg/ml, and 189 +/- 170, range
      4.17-485.7 pg/ml, respectively; p = 0.08), whereas no difference was observed in
      TGF-beta among the same groups (134.7 +/- 79.2, range 68-421 pg/ml, and 121.4 +/-
      25.8, range 75-151 pg/ml, respectively). Interestingly, a statistically
      significant inverse correlation was observed between IL-10 and TGF-beta in kidney
      transplant recipients (p = 0.03). CONCLUSIONS: The higher IL-10 production
      observed in long-term kidney transplant recipients supports the notion that this
      cytokine contributes in decreasing allogenic immune responses and allows
      prolongation of allograft survival. The balance between TGF-beta and IL-10 may be
      of paramount importance in graft acceptance.

PMID- 15016133
TI  - Delay of CMV infection in high-risk CMV mismatch lung transplant recipients due
      to prophylaxis with oral ganciclovir.
AB  - Cytomegalovirus (CMV) is a common opportunistic infection in lung transplant
      recipients. Despite the use of early post-operative intravenous ganciclovir, most
      high-risk patients develop CMV infection. We conducted this retrospective study
      to determine the efficacy of extended CMV prophylaxis with oral ganciclovir in
      high-risk, donor-positive-recipient-negative, lung recipients. All patients
      initially received 3 months of intravenous ganciclovir and CMV hyperimmune
      globulin. Clinical outcomes in all CMV mismatch patients undergoing lung
      transplant surviving at least 3 months were included (n = 42). Since 1998, 14
      patients received no oral ganciclovir prophylaxis (group 1) and 28 patients
      received indefinite oral ganciclovir after completion of intravenous therapy
      (group 2). In those patients receiving oral ganciclovir, the prevalence of post
      transplant CMV infection was significantly reduced over the first 180 d post
      transplant (50% in group 1 vs. 4% in group 2; p < 0.001). Although some CMV
      events were observed with additional follow-up in group 2, there remained a
      significantly greater freedom from CMV infection by Kaplan-Meier analysis in
      group 2 as compared with group 1, with over 30 months follow-up time in each
      group (log-rank, p = 0.02). A moderate rate of drug discontinuation was observed
      in group 2, and no severe drug-related events occurred. In high-risk lung
      transplant recipients, CMV prophylaxis with intravenous ganciclovir, followed by
      indefinite oral ganciclovir, significantly delays and reduces post-transplant CMV
      infections. A larger prospective randomized study is needed to confirm the
      benefits of oral ganciclovir on CMV prevention.

PMID- 15016135
TI  - Factors associated with (un)willingness to be an organ donor: importance of
      public exposure and knowledge.
AB  - BACKGROUND: Transplantation is increasingly limited by the supply of donor
      organs. Identifying subgroups that do not support organ donation will allow
      targeted efforts to increase organ donation. METHODS: A total of 185 non-acutely
      ill outpatients visiting a community physician's office voluntarily completed a
      survey designed to capture views and general knowledge/misconceptions about
      cadaveric organ donation/transplantation. RESULTS: Of 185 patients, 86 were
      willing to donate, 42 were unwilling, and 57 were unsure. Willingness to donate
      was significantly associated with: having discussed the topic with family; having
      known a cadaveric organ donor; age 55 yr; having graduated high school;
      recognizing the organ shortage as the primary problem in transplantation; having
      received a post-high school degree; having seen public information within 30 d;
      and having a family member in health care (all p</=0.05). Not significant were:
      gender; race; religious affiliation or regular church attendance; knowing a
      transplant recipient or wait-listed patient; and having easy internet access.
      Those unwilling/unsure more often thought: organ allocation is based on
      race/income; organ donation is expensive for the donor family; designated donors
      may not receive full emergency room care; a brain-dead person can recover.
      CONCLUSIONS: Intense efforts to improve public awareness and knowledge about
      organ donation/transplantation are necessary to maximize donation and the overall
      success of transplantation.

PMID- 15016134
TI  - Aldosterone resistance in kidney transplantation is in part induced by a down
      regulation of mineralocorticoid receptor expression.
AB  - BACKGROUND: After renal transplantation immunosuppressive drugs-like cyclosporin
      A (CsA) and FK506 induce either hypoaldosteronism or pseudo-hypoaldosteronism
      presenting with hyperkalemia and metabolic acidosis. We investigated the
      relationship between renal allograft function under CsA therapy and plasma
      aldosterone concentration, potassium- and water homeostasis and mineralocorticoid
      receptor (MR) expression level in peripheral leukocytes. METHODS: We studied 21
      renal transplant patients under CsA therapy and 12 healthy controls. Transplant
      recipients were studied before and under fludrocortisone treatment. Using
      quantitative reverse-phase polymerase chain reaction (RT-PCR) specific for the
      MR, we analyzed the level of expression of MR in peripheral leukocytes. RESULTS:
      In acidotic transplant recipients (HCO(3) 18.5 +/- 1.2 mM) renal function was
      only slightly impaired with 2.0 +/- 0.2 mg creatinine/dL when compared with 1.8
      +/- 0.3 mg/dL (ns) in non-acidotic patients (HCO(3) 23.0 +/- 2.8 mM). Mean plasma
      aldosterone levels in renal transplant recipients did not differ from control
      levels (150 +/- 33 pg/mL vs. 148 +/- 33 pg/mL, ns). In contrast, the expression
      level of MR in peripheral leukocytes of renal transplant recipients treated with
      CsA was significantly decreased when compared with healthy controls without renal
      disease (120 +/- 78 vs. 423 +/- 73 RNA molecules/0.5 microg total RNA, p < 0.01).
      The level of expression of MR in renal transplant recipients did not differ
      between acidotic patients and non-acidotic patients (ns). The application of
      fludrocortisone reversed hyperkalemia and metabolic acidosis without significant
      effect on MR expression. CONCLUSIONS: The present data demonstrate that
      hyperkalemia and metabolic acidosis following CsA treatment in kidney
      transplantation might be associated with a down-regulation of MR expression on
      peripheral leukocytes. Electrolyte imbalance is reversible on application of
      fludrocortisone. This observation supports fludrocortisone treatment in
      transplant patients with severe electrolyte disturbances.

PMID- 15016137
TI  - Liver transplant for hepatocellular cancer: a treatment for the select few.
AB  - Hepatocellular cancer (HCC) is increasing in incidence and liver transplant (LT)
      is likely the best treatment for long-term survival and decreased recurrence in
      those with localized disease. Optimal treatment for HCC is limited by advanced
      stage at presentation and available donors. We retrospectively reviewed 232 cases
      of HCC from 1993 to 2002 referred to our medical center, which also has the only
      transplant program in the state. Demographic data, risk factors, stage, previous
      treatment, candidacy for LT, and outcome were noted. Stage distribution was as
      follows: stage I - nine patients, II - 115 patients, III - 31 patients, and IV -
      76 patients. Mean age was 61.1 yr and 62 patients were over the age of 70 yr.
      Thirty-five patients (15.1%) were offered LT evaluation. Nineteen patients (8.2%)
      eventually underwent LT, five are currently on a transplant waiting list, three
      were on a list but removed due to death or progression of disease, six were
      evaluated but not listed, and two refused evaluation. Five patients were
      transplanted because implementation of the Model of End-stage Liver Disease
      (MELD) system for organ allocation. Of 19 patients who underwent LT, 14 are still
      alive 3-52 months post-transplant, three developed recurrent HCC, and two died of
      lung cancer. Although LT may be the best treatment for HCC, a relatively small
      number of patients (15%) will qualify for this therapy. About half of those who
      qualify will actually undergo LT. This further emphasizes the need for other
      strategies such as vaccination, chemoprevention, and early detection to improve
      survival from HCC.

PMID- 15016138
TI  - Internal hernia of the small bowel after right-lobe live donor liver
      transplantation.
AB  - Internal hernia of small bowel is an uncommon but potentially fatal complication
      of liver transplantation. We report on four patients in whom internal hernia of
      small bowel occurred after right-lobe live donor liver transplantation (LDLT).
      Three patients had small bowel herniation with volvulus around the Roux-en-Y loop
      whereas the other patient had herniation through the mesenteric window of
      transverse mesocolon after hepaticojejunostomy for biliary reconstruction. Based
      on clinical and radiologic findings, early diagnosis was made in all cases. All
      patients survived following surgical reduction of the hernia and closure of the
      mesenteric defect without bowel resection. Transplant surgeons should be aware of
      this serious complication so that early diagnosis and appropriate operative
      intervention can be made. The complication can be avoided with duct-to-duct
      biliary reconstruction or meticulous closure of all mesenteric defects with non
      absorbable suture materials after hepaticojejunostomy in patients undergoing
      right-lobe LDLT.

PMID- 15016136
TI  - Cardiovascular disease in renal allograft recipients is associated with elevated
      sialic acid or markers of inflammation.
AB  - BACKGROUND: Cardiovascular disease (CVD) is more common in patients with renal
      failure, even after renal transplantation. We wished to examine the relationship
      between markers of inflammation and CVD in stable renal transplant patients.
      METHODS: Ninety stable renal transplant outpatients with no recent illnesses or
      rejection were invited for study. Blood was drawn for a variety of inflammatory
      markers including total plasma sialic acid (SA) levels. RESULTS: Patients with
      CVD were significantly older than patients without (54 +/- 12 vs. 42 +/- 14 yr, p
      < 0.01) and had significantly lower total cholesterol (4.5 +/- 1.6 vs. 5.1 +/-
      1.0 mmol/L, p < 0.01). Time from transplantation, present creatinine and blood
      pressure, smoking history were similar in both groups. Patients with CVD had
      significantly higher levels of SA (89.2 +/- 22.3 vs. 77.4 +/- 13.9 mg/dL, p =
      0.01); fibrinogen [4.6 (2.2-6.7) vs. 3.6(1.9-5.7) g/L; p = 0.05); and C-reactive
      protein (CRP) [2.2 (1.5-8.0) vs 1.5 (0.7-3.0) microg/dL] than those without CVD.
      A logistic multiple linear regression analysis of the data with CVD as the
      dependent variable, and all the other parameters as independent variables, showed
      significant associations (F = 16.9; p < 0.001) with diastolic blood pressure
      (beta = 5.6; p = 0.02) and CRP (beta = 4.4; p = 0.04). CONCLUSIONS: This study
      suggests that inflammation is associated with a higher prevalence of
      cardiovascular disease in patients with renal allografts. The measurement of
      sialic acid as a risk factor may be superior to that of CRP in this group as its
      concentration is independent of renal function.

PMID- 15016139
TI  - The unrecognized posterior gastric artery: a potential cause of surgical
      complications in pancreas transplantation.
AB  - BACKGROUND: Our report describes, for the first time, a pre-transplant vascular
      complication in a pancreas graft related to the posterior gastric artery - a
      major, but relatively unknown side branch of the splenic artery. The posterior
      gastric artery that was overlooked by a surgical procurement team during donor
      pancreatectomy led to distortion of the peripancreatic vascular anatomy and set
      the stage for a splenic artery injury. METHODS: We identified the transected,
      partially resected graft splenic artery during backtable preparation of the
      pancreas, and repaired it using standard vascular surgical techniques. RESULTS:
      The recipient's post-operative course was uncomplicated. At 9-yr post-transplant,
      the recipient is alive with good pancreas graft function. CONCLUSIONS: The
      relevance of the posterior gastric artery with regard to general surgical
      procedures was only recently recognized. Our case demonstrates that the posterior
      gastric artery is also important in transplant surgery. Awareness of this
      anatomical structure during organ procurement would help minimize pre-transplant
      vascular complications.

PMID- 15016143
TI  - Islet cell transplantation in pediatric diabetes.

PMID- 15016140
TI  - Immunization by blood-type antigen in human immunoglobulin products before ABO
      incompatible kidney transplantation.
AB  - A 29-year-old man wanted to receive an ABO-incompatible kidney transplant. His
      blood type was O, and the donor, his father, was A1. After endoscopic splenectomy
      performed before kidney transplantation, the recipient developed a high fever and
      leukocytosis, and he was treated with antibiotics and 5 g of human immunoglobulin
      products by intravenous infusion for 3 d. Soon after the infusions, his anti
      blood type A antibody titer (anti-A titer) rose, and several sessions of plasma
      exchange (PEX) and double-filtration plasmapheresis (DFPP) failed to lower it.
      Three courses of anti-CD20 monoclonal antibody were administered to suppress the
      antibody production more specifically, and the rituximab infusions and repeated
      PEX and DFPP session lowered the anti-A titer and enabled kidney transplantation.
      Mild humoral rejection was observed 16 d after transplantation, but the
      recipient's serum creatinine was 1.5 mg/dL when discharged from the hospital. The
      increased anti-A titer may have been due to immunization by blood-type A antigen,
      with the human immunoglobulin products given to the patient being the source of
      the antigen. Administration of human immunoglobulin products to recipients of ABO
      incompatible kidney transplants should be avoided, because it may cause an
      unexpected increase in anti-blood-type antibody titer.

PMID- 15016141
TI  - Hepatic venous outflow reconstruction in adult living donor liver transplants
      without portal hypertension.
AB  - Graft congestion is one of the causes of poor graft function in segmental liver
      transplantation. Three factors are implicated in segmental graft congestion:
      graft size, hepatic venous outflow and portal inflow. The graft size must be
      matched to the body weight, which is conventionally done by using graft to body
      weight ratio. Hepatic blood outflow must be optimized by hepatic vein
      reconstruction, which can be complicated. High portal blood flow has been shown
      to be detrimental to small-for-size grafts. These factors are strictly connected
      to each other. They can all contribute to graft congestion and poor function,
      while one factor can compensate for the others and decrease congestion. Ideally,
      all the accessory veins should be reconstructed, if possible, to maximize the
      outflow. In the absence of portal hypertension and with an adequate sized graft,
      complex venous reconstruction may not be necessary. We present a case report of
      an adult living donor liver transplant with the favorable conditions of normal
      portal pressure and a large sized graft, but complicated by the presence of
      several accessory hepatic veins. A simple hepatic vein anastomosis was sufficient
      for adequate outflow and prompt graft function.

PMID- 15016144
TI  - Characteristics of glycemic control in young children with type 1 diabetes.
AB  - BACKGROUND: The Diabetes Control and Complications Trial (DCCT) demonstrated that
      the rate-limiting step to the intensification of diabetes management in
      adolescents and adults was hypoglycemia. Young children were presumed to be at
      even greater risk for hypoglycemia with severe consequences, particularly if they
      had HbA1c levels < 8%. SUBJECTS: A retrospective chart review was performed on
      148 patients with type 1 diabetes on insulin injection therapy who were < 8 yr of
      age (mean age 5.7 +/- 1.5, mean diabetes duration 3.0 +/- 1.4 yr) followed
      quarterly from July 1999 to June 2001. METHODS: The subjects were divided into
      two groups based on their mean HbA1c values (< 8 vs. > or = 8%) averaged over the
      2-yr time period. The following variables were analyzed comparing the two groups:
      age, duration of diabetes, insulin dose, severe hypoglycemic episodes, episodes
      of diabetic ketoacidosis (DKA), percentage of glucose levels above, within, and
      below the target range, and number of diabetes home-management competencies
      obtained. RESULTS: Patients with HbA1c < 8% spent more time within target range
      (40.0 vs. 29.5%, p = 0.0001) and less time above their target range (36.9 vs.
      51.2%, p = 0.0003). There was no difference in the percentage of glucose levels
      below target (23.2 vs. 19.4%, p = NS), percentage of severe hypoglycemic episodes
      (3 vs. 7 episodes per 100 patient-yr, p = NS), or episodes of DKA (1 vs. 3
      episodes per 100 patient-yr, p = NS) between the two groups. SUBJECTS with lower
      HbA1c levels had acquired more home-management competencies (4.0 vs. 3.5, p =
      0.01). CONCLUSIONS: If families are competent in fundamental diabetes management,
      young children can achieve HbA1c levels < 8.0% without increasing the risk of
      hypoglycemia.

PMID- 15016145
TI  - Role of exposure to air pollutants in the development of type 1 diabetes before
      and after 5 yr of age.
AB  - OBJECTIVE: To assess the role of ambient air pollutants in type 1 diabetes in
      children. DESIGN AND METHODS: Prediagnosis exposure to five air pollutants was
      studied in two subgroups with onset of type 1 diabetes before and after 5 yr of
      age, and two matched subgroups of healthy children. Zip codes and dates of
      residence from birth to diagnosis were used to obtain geographic- and time
      specific air concentrations of SO(2), NO(2), ozone (O(3)), SO(4), and particulate
      matter < 10 micro m in diameter (PM(10)). Prediagnosis time-adjusted pollutant
      exposure levels were created by summing up zip code-specific pollution data and
      dividing by months of exposure from birth to diagnosis. Two-tailed t-test and
      logistic regression were used to evaluate relative effects and test data between
      cases and controls. RESULTS: Prediagnosis average O(3) exposure was significantly
      higher in children with type 1 diabetes than in healthy controls. Prediagnosis
      PM(10) exposure was significantly higher in children diagnosed before 5 yr of
      age, when compared with healthy controls. SO(2) exposure was significantly higher
      in children with later-onset diabetes compared with those with early-onset
      diabetes (EOD). NO(2), SO(2) and SO(4) exposure was significantly lower in
      children diagnosed after 5 yr of age, when compared with healthy controls. O(3),
      NO(2), SO(4) and PM(10) levels did not significantly differ between the two
      diabetic subgroups. CONCLUSION: Increased ozone exposure may be a contributory
      factor to the increased incidence of type 1 diabetes. PM(10) may be a specific
      contributory factor to the development of type 1 diabetes before 5 yr of age.

PMID- 15016146
TI  - Linear growth and height outcomes in children with early onset type 1 diabetes
      mellitus--a 10-yr longitudinal study.
AB  - OBJECTIVE: To assess the linear growth and height outcomes and the influence of
      metabolic control on the near-final height in children with early onset type 1
      diabetes mellitus (DM). STUDY DESIGN AND METHODS: Retrospective longitudinal
      evaluation of 99 children with prepubertal onset of type 1 DM before 8 yr of age,
      who were regularly assessed, clinically and metabolically, from 8 yr of age to
      17.99 yr of age. RESULTS: The mean prepubertal height Z scores at 8 yr of age
      were -0.17 (standard deviation, SD = 0.99) for boys and -0.29 (1.19) for girls,
      respectively. There was normal linear growth in girls with their mean near-final
      height Z score being -0.13 (1.07). This was not statistically different from the
      mean at 8 yr (p = 0.13). The mean near-final height Z score in boys was -0.39
      (0.98), which was 0.22 SD lower than their mean prepubertal height Z score (p =
      0.03). There was no significant correlation between metabolic control and linear
      growth in either males or females. CONCLUSIONS: Linear growth and near-final
      height in children with type 1 DM compares favorably with the general population.
      Although there was some evidence of suboptimal peripubertal growth in boys, the
      actual extent of this height reduction was minimal and was not correlated with
      their metabolic control.

PMID- 15016147
TI  - Dynamic changes in the trends in incidence of type 1 diabetes in children in
      Hungary (1978-98).
AB  - OBJECTIVE: To determine the recent trends in incidence, to analyze the age and
      geographic distribution, as well as the seasonal pattern of type 1 diabetes in
      Hungarian children aged 0-14 yr for the period from 1978 to 1998. METHODS:
      Primary ascertainment of cases was by retrospective (1978-88) and by prospective
      (1989-98) registration using hospital notifications. The level of ascertainment
      was estimated by the capture-recapture method. The temporal trend was estimated
      by fitting Poisson regression models to the yearly incidence data. Roger's test
      was used to investigate possible seasonal variation in time of diagnosis.
      Heterogeneity between geographic areas was assessed by Poisson regression.
      RESULTS: A total of 2616 patients (1214 in the first 11 yr, 1402 in the remaining
      10 yr) were identified; the male:female ratio was 0.93. The overall standardized
      incidence rate was 7.87 (95% CI = 7.57-8.18) per 100,000 person-yr, the lowest in
      the youngest (0-4 yr) and highest in the oldest (10-14 yr) age group. There was
      an increasing trend in incidence with a largest relative annual increase in the
      youngest age group. Seasonal and regional variations in incidence were also
      observed. CONCLUSION: Our 21-yr study shows dynamic changes in incidence of
      childhood type 1 diabetes in Hungary, probably reflecting changes in the
      environment.

PMID- 15016148
TI  - The incidence of type 1 diabetes mellitus in Greek-Cypriot children and
      adolescents in 1990-2000.
AB  - OBJECTIVES: To ascertain the exact incidence of type 1 diabetes mellitus (DM1) in
      Greek-Cypriots under the age of 15 yr, to analyze possible gender differences in
      the age of onset and to observe any seasonal variation in the manifestation of
      the disease. RESEARCH DESIGN AND METHODS: All cases of newly diagnosed DM1
      patients under the age of 15 yr from 1990 to 2000 were collected and relevant
      information was obtained. The data were statistically processed in relation to
      the population data provided by the Department of Statistics and Research of the
      Ministry of Finance. RESULTS: The mean annual incidence of DM1 in the Greek
      population of Cyprus under the age of 15 yr for the period 1990-2000 is
      11.32/100,000. There is a trend towards increasing incidence during this period.
      There is a gender influence on the age of onset: more males develop DM1 before
      the age of 6 yr and after 13 yr. Moreover, there is a gender difference in the
      group who manifest DM1 in the age range 5-9 yr, with females having a mean age of
      onset of 8.1 yr, compared with 7.3 yr for males. There is a statistically
      significant seasonal variation, but not among preschool subjects who manifest DM1
      before the age of 4 yr. CONCLUSIONS: DM1 is a common condition in Greek-Cypriots
      under the age of 15 yr. The gender difference in the age of onset probably
      reflects the peripubertal period of each gender. The seasonal variation cannot be
      solely attributed to weather and temperature changes. This survey covers a 10-yr
      period and deals with an adequate number of reported cases; therefore, it could
      contribute to the international effort to determine the exact pathogenesis of
      DM1.

PMID- 15016149
TI  - TRMA syndrome (thiamine-responsive megaloblastic anemia): a case report and
      review of the literature.
AB  - Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal
      recessive disorder with features that include megaloblastic anemia, mild
      thrombocytopenia and leukopenia, sensorineural deafness and diabetes mellitus. In
      this disease, the active thiamine uptake into cells is disturbed. Treatment with
      pharmacological doses of thiamine ameliorates the megaloblastic anemia and
      diabetes mellitus. Previous studies have demonstrated that the disease is caused
      by mutations in the SLC19A2 gene encoding a high-affinity thiamine transporter.
      We present a 5-yr-old-boy with TRMA and, because of its rarity, we review the
      literature.

PMID- 15016150
TI  - Islet/pancreas transplantation: challenges for pediatrics.
AB  - Beta cell replacement is a valid alternative to exogenous insulin injections to
      treat type 1 diabetic patients. The rate of success obtained after whole-pancreas
      transplantation, performed alone or in combination with kidney, and, as shown
      recently, by islet transplantation, justifies optimism and sets the stage for a
      larger clinical application of these approaches. Lifetime immunosuppression,
      however, required to protect the graft against recurrent autoimmune destruction
      and allorejection, raises serious doubts about the safety of its employment in
      children. While it is evident that children may be helped even more than adults
      by the possibility to correct diabetic metabolic disorders without exogenous
      insulin, and to lower in a more effective way the chance to develop secondary
      complications, the drawbacks of the currently used immunosuppressive drugs
      largely overcome the potential benefits. A great step forward for immediate
      applicability of transplantation to children involves the optimization of
      tolerogenic protocols and a better understanding of the concept of immune
      ignorance. Functional tolerance should be sufficient to entail the absence of
      immune reactivity against self- and graft antigens, while maintaining immune
      reactivity against other non-self, non-donor antigens. In addition, novel
      strategies aimed at utilizing surrogate beta cells obtained from non-islet cells,
      or by genetic manipulation of beta-cell precursors merit consideration as the use
      of xenogeneic donors. However, much work is still needed for their safe clinical
      implementation.

PMID- 15016151
TI  - Technology advances in glucose monitoring.

PMID- 15016152
TI  - Use of the GlucoWatch biographer in children and adolescents with diabetes.
AB  - OBJECTIVE: This study was done to evaluate the accuracy and safety of measuring
      glucose with the GlucoWatch biographer in children and adolescents with diabetes.
      METHODS: Accuracy was assessed by comparing biographer glucose measurements with
      hourly blood glucose measurements using the HemoCue (Aktiebolaget Leo,
      Helsingborg, Sweden) Photometer for up to 12 h of monitoring. Safety was
      evaluated by examining the biographer application sites immediately upon removal
      of the devices, and then at regular intervals. RESULTS: Sixty-six subjects each
      wore three biographers at sites including the forearm, upper arm, leg, and torso.
      For forearm biographers, the mean absolute relative difference between biographer
      readings and blood glucose was 21%. Ninety-five per cent of biographer readings
      fell into the A or B regions of the Clarke error grid, and 97.3% into the A or B
      regions of the consensus error grid. Data from biographers worn at the
      alternative sites were similar to data from the forearm biographers. Two strong
      reactions to the adhesive pad of the biographer AutoSensor were observed. Most
      skin reactions were mild. CONCLUSIONS: The GlucoWatch biographer is well
      tolerated by children and adolescents with diabetes. Performance is similar when
      the device is worn at different anatomical sites, and is similar to the
      performance on the forearm, previously reported in adults.

PMID- 15016153
TI  - Correlates of depressive symptoms in adolescents with type 1 diabetes.
AB  - PURPOSE: To determine correlates of depression in adolescents with type 1
      diabetes. METHODS: Data on 117 adolescents participating in a longitudinal study
      (72 F, 45 M; 95 W; age = 14.3 +/- 2.0 yr; duration = 6.3 +/- 3.7) were collected
      with the Children's Depression Inventory (CDI), Diabetes Family Behavior Scale
      (DFBS), Family Adaptability and Cohesion Scale (FACES), and chart review at study
      entry and 2-year follow-up. RESULTS: Fifteen per cent of adolescents in this
      sample demonstrated depressive symptoms (CDI > 13) at study entry and 10% at 2 yr
      follow-up. Adolescents aged 14.1-16 yr and those with diabetes > 10 yr
      demonstrated the highest rates. When demographic/clinical variables were
      controlled, the DFBS warmth-caring subscale (p = 0.001) and the FACES
      adaptability subscale (p = 0.005), but not DFBS guidance-control (p = 0.635),
      contributed significantly to the explained variance in depressive symptoms (R(2)
      = 0.27) at study entry. At 2 yr follow-up, study entry CDI scores were the only
      significant predictor of depressive symptoms (R(2) = 0.40). By 2 yr, adolescents
      with depressive symptoms had significantly higher HbA1c than those without (p =
      0.03). CONCLUSION: The prevalence of depressive symptoms in adolescents with type
      1 diabetes coupled with the potential impact of depressive symptoms on metabolic
      control suggest the need for early diagnosis and treatment. Greater attention to
      psychosocial outcomes of youth, family functioning, and the potential burden of
      diabetes over time to youth/families is indicated.

PMID- 15016154
TI  - Development of autoantibodies to islet antigens during childhood: implications
      for preclinical type 1 diabetes screening.
AB  - OBJECTIVE: Serum islet antibodies signify increased risk for type 1 diabetes
      (T1D). Knowledge of the relationship between age and seroconversion would guide
      screening for at-risk individuals. We aimed to determine the effectiveness of
      islet antibody screening in early childhood, in particular the proportion of
      negative children who subsequently seroconverted. METHODS: We identified 554
      children with a first-degree relative with T1D who had tested negative for islet
      cell antibodies (ICA) and insulin autoantibodies (IAA) when first screened at a
      mean age of 7.2 yr. Of 423 who were eligible, 350 consented to re-testing for ICA
      and IAA and antibodies to glutamic acid decarboxylase (GADAb) and tyrosine
      phosphatase-like insulinoma antigen IA-2 (IA2Ab) at a mean age of 11.1 yr. GADAb
      and IA2Ab were measured in 239 of the initial stored samples. RESULTS: Of the 350
      children who tested negative at first screening, 12 (3.4%) subsequently
      seroconverted, becoming positive for ICA (n = 4), IAA (n = 7), GADAb (n = 6) or
      IA2Ab (n = 2). Of 239 initially negative for ICA and IAA, 8/239 (3.3%) now tested
      positive for GADAb (n = 7) or IA2Ab (n = 1). Four of these children were positive
      for GADAb in both tests; the one child initially positive for IA2Ab only was
      positive for all four antibodies 4.6 yr later and developed diabetes. CONCLUSION:
      Screening for ICA and IAA failed to identify 2-3% of genetically at-risk children
      who subsequently developed islet antibodies. Testing for GADAb and IA2Ab would
      not have avoided this. Maximizing the sensitivity of detecting risk for T1D
      requires repeat screening for islet antibodies throughout childhood.

PMID- 15016155
TI  - Insulin autoantibodies are of less value compared with islet antibodies in the
      clinical diagnosis of autoimmune type 1 diabetes in children older than 3 yr of
      age.
AB  - BACKGROUND: Insulin autoantibodies (IAA), antibodies against endogenous insulin,
      may be detected in type 1 diabetic children before the start of insulin
      treatment. OBJECTIVE: To relate IAA to islet antibodies (i.e., islet cell
      antibodies [ICA], and antibodies against two ICA-related islet antigens, glutamic
      acid decarboxylase 65 [GADA] and protein tyrosine phosphatase IA-2 [IA-2 A]) at
      diagnosis, and to endogenous beta-cell function at follow-up after diagnosis in
      diabetic children. SUBJECTS: We investigated 74 children, aged 1-15 yr, at the
      diagnosis of diabetes and 1-10 yr later. Insulin treatment may induce antibody
      development against exogenous insulin. Patients with insulin treatment > or = 1
      wk (n = 5) were therefore excluded from the final analysis. METHODS: Radioligand
      binding assays based on human recombinant antigen were used to measure IAA, GADA,
      and IA-2 A. ICA were determined with indirect immunofluorescence. RESULTS: IAA
      were detected at a significantly lower frequency (43%; p < or = 0.001) than ICA
      (86%), GADA (72%), and IA-2 A (80%). In agreement, IAA measurements only
      marginally increased the frequency of positive autoimmune markers at diagnosis of
      diabetes (from 97 to 99% positive for at least one autoantibody). Preserved beta
      cell function (detectable fasting p-C-peptide levels) was found in only nine
      patients, who were older (13 +/- 3 vs. 7 +/- 6 yr, p = 0.002) and had fewer of
      the antibodies (IAA, GADA, IA-2 A, ICA) in high titer (> median) compared with 60
      patients with undetectable p-C-peptide levels. CONCLUSIONS: Insulin
      autoantibodies are of less clinical value compared with islet antibodies in the
      diagnosis of autoimmune type 1 diabetes in children.

PMID- 15016156
TI  - Single photon emission tomography (SPECT) study of regional cerebral blood flow
      in normoalbuminuric children and adolescents with type 1 diabetes.
AB  - Cerebral damage in diabetes can be related to chronic hyperglycemia and recurrent
      severe hypoglycemia as well as due to the associated vasculopathy. The pattern of
      regional cerebral blood flow using cerebral single photon emission tomography
      (SPECT) was evaluated in normoalbuminuric type 1 diabetic children and
      adolescents and its relation to the metabolic control and cognitive functions.
      Thirty-one type 1 diabetics aged 10-18 yr (mean 14.7 +/- 3.4) were included, 16
      males and 15 females, divided into four groups: group I (n = 8) with history of
      recurrent severe hypoglycemia (> or = 3); group II (n = 8) with history of severe
      diabetic ketoacidosis (> or = 3); group III (n = 7) with recurrent minor
      hypoglycemia (> or = 3/week); and group IV (n = 8) with controlled diabetes. The
      control group (V) comprised seven healthy children, aged 10-18 yr (mean 14.2 +/-
      3.1). SPECT was done using technetium-99m hexamethyl propylene amine oxime. There
      was significant brain hypoperfusion in diabetics compared with controls, mainly
      in the basal ganglia (p < 0.01) and frontal regions (p < 0.01), with less changes
      in parietal and temporal regions. These changes were not related to the age, sex,
      diabetes duration, mean blood glucose or HbA1C. Basal ganglia hypoperfusion was
      significant in groups I (p < 0.01) and II (p < 0.01) compared with controlled
      diabetics. There was no correlation between cerebral SPECT changes and cognitive
      scores in type 1 diabetics. CONCLUSION: Subclinical alterations in cerebral blood
      flow (hypoperfusion) are present in children and adolescents with type 1 diabetes
      mainly affecting the basal ganglia and frontal regions, usually not associated
      with measurable alterations of the cognitive functions

PMID- 15016157
TI  - Rodent models for the study of type 2 diabetes in children (juvenile diabesity).

PMID- 15016158
TI  - Freedom of choice--did children with diabetes from former East Germany profit
      from reunification?

PMID- 15016159
TI  - Changes in pediatric diabetes care throughout a 30-yr period at one institution
      for pediatric diabetology in Germany.
AB  - AIMS: The objective of the present study was to investigate putative changes in
      pediatric diabetes care at one institution between 1969 and 1998. METHODS: A
      structured questionnaire was used to analyze all medical records from the
      Hospital for Children and Adolescents of the University of Leipzig, Germany, from
      1969 to 1998, in order to review the number of cases of type 1 diabetes mellitus
      and the length of hospital stay of children with diabetes during the 30-yr
      period. RESULTS: Between 1969 and 1998, 441 children and adolescents (211 boys
      and 230 girls) with newly diagnosed diabetes mellitus type 1 were treated at the
      Hospital for Children and Adolescents in Leipzig. The number of patients newly
      diagnosed increased from 55 between 1969 and 1973 to 105 between 1994 and 1998 (p
      < 0.0003). The initial therapy and diabetes education were carried out in an in
      patient setting. The average duration of hospital stay was 36 d in the years 1969
      73, and 17 d in the years 1994-98 (p < 0.0002). This reduction of time spent in
      hospital was achieved by establishing structured training courses and exact
      planning of treatment in relation to the degree of illness at presentation.
      CONCLUSION: The number of patients with type 1 diabetes mellitus receiving care
      in this single institution between the years 1969 and 1998 has increased
      continuously. With the help of quality-assured structured training courses in a
      clinic for pediatric diabetes care, a dramatic reduction of the duration of
      hospital stay was achieved.

PMID- 15016160
TI  - Sweet dreams?--nocturnal hypoglycemia in children with type 1 diabetes.
AB  - Hypoglycemia is an inevitable consequence of the treatment of type 1 diabetes in
      childhood. Nocturnal hypoglycemia is often considered as merely the submerged
      part of this serious complication yet there are reasons to believe that
      hypoglycemia occurring during sleep may be different in physiological terms.
      Glucose homeostasis during fasting, delayed effects of exercise and alterations
      in sleep physiology, itself, may not only affect the risk of nocturnal
      hypoglycemia but may influence the ability to correct glucose concentration as it
      falls, leading to episodes of hypoglycemia which are both profound and prolonged.
      The etiology and potential repercussions are incompletely understood and the most
      appropriate defense remains unclear. A greater understanding of this enigmatic
      phenomenon is essential before appropriate methods for hypoglycemia avoidance can
      be developed.

PMID- 15016161
TI  - Trends in diabetic ketoacidosis in childhood and adolescence: a 15-yr experience.
AB  - The number of episodes of diabetic ketoacidosis (DKA) is a significant outcome
      measure for diabetes care. We ascertained patterns of admission due to DKA over
      15 yr to determine whether this indicator of diabetes care had improved in
      parallel with clinical practices. Between 1 January 1985 and 31 December 1999,
      630 admissions were reviewed. We subanalyzed these admissions according to
      whether the patient was newly diagnosed, had infrequent episodes of DKA (non
      relapsers) or had frequent (> or = 2/yr) episodes of DKA (relapsers). Overall
      there was a slight downward trend in the incidence of DKA admissions over the
      study period. There was a proportionate increase in the incidence of DKA amongst
      newly diagnosed patients, with a proportionate decrease in the incidence of DKA
      seen in relapsers. DKA occurring in non-relapsers remained relatively stable.
      Adverse clinical events during the admission were relatively uncommon and
      occurred in all three subgroups. There was no significant difference in HbA1C
      prior to admission between the relapser and non-relapser groups and there was
      similarity in the degree of acidosis between all three subgroups. The frequency
      of significant complications associated with DKA remained unchanged over the
      study period. Slower rehydration policies were not associated with decreases in
      either cerebral edema or death rates. DKA remains a significant complication of
      type 1 diabetes associated with a variety of significant adverse events. Our
      experience indicates that further efforts to reduce the occurrence of DKA must be
      focused upon earlier diagnosis and intervention in newly diagnosed patients.

PMID- 15016162
TI  - DNA extraction and HLA genotyping using mailed mouth brushes from children.
AB  - The need for blood samples in genetic epidemiologic studies often leads to low
      response rate among non-diseased individuals, and the collection of blood samples
      is costly and labor-intensive. We tested the feasibility of extracting DNA for
      human leukocyte antigen (HLA) typing from buccal cells collected with mailed,
      self-administered mouth brushes. A random sample of 1474 Norwegian children aged
      0-17 yr was contacted by mail and received information about the study and mouth
      brushes for buccal cell samples. Brushes were returned by mail, DNA was extracted
      and the HLA-DQA1 and -DQB1 allelic polymorphisms were determined using polymerase
      chain reaction (PCR) and sequence-specific oligonucleotide probes. Mouth swabs
      were returned from 1068 (72.5%). Of these, DNA was extracted and HLA typing
      successfully completed for 1056 individuals (98.9%). In conclusion, we have
      described an efficient and safe set of methods for application in genetic
      epidemiologic studies of type 1 diabetes and other HLA-related diseases. A large
      proportion of randomly selected children returned self-administered mouth swabs
      with DNA of sufficient quality and quantity for HLA genotyping.

PMID- 15016163
TI  - Personnel costs and perceived benefit of telephone care in the management of
      children with type 1 diabetes.
AB  - Intensive management of patients with type 1 diabetes improves control and
      reduces rates of long-term complications. Telephone care as an adjunct to office
      visits is important in the management of children with type 1 diabetes in
      pediatric endocrine practices in the USA. The goal of this project was to assess
      the personnel costs and patients' perceptions of telephone care in a moderately
      sized pediatric diabetes care center (301 patients with a diagnosis of type 1
      diabetes). There were two parts to this study. First, telephone logs were kept by
      three pediatric endocrine nurses (2.2 full-time equivalents [FTEs]) and three
      pediatric endocrinologists (2.0 FTEs) for two 1-wk blocks. Computerized databases
      were used to determine the number of clinic visits in 1998. Second, a survey
      assessing the frequency, perceived value and consequences of phone contact with
      the diabetes team was distributed to 40 families at clinic visits. Mean
      nurse/certified diabetes educator (CDE) time spent on the phone was 12.1 h/wk,
      with an additional 9.7 h/wk spent preparing and documenting. Physicians spent 6.4
      h/wk on the phone, and 6.1 h/wk preparing/supervising/documenting. For our 301
      patients with diabetes, the weekly personnel cost for telephone care at our
      institution was 1367 US dollars or 236 US dollars/patient/yr. Of the families
      surveyed, 80% reported that they had used the phone to obtain care for their
      child with diabetes and 55% had paged the doctor on call in the previous 6
      months. Seven patients reported that phone contact prevented a total of 13
      emergency department (ED) visits and 35 office visits. Using a cost estimate of
      550 US dollars per ED visit, and 103 US dollars per office visit, the cost of
      prevented visits was 232 US dollars/patient/yr in our center. These data indicate
      that telephone care is effective in reducing the cost of reimbursable care via
      the ED and office visits, as well as avoiding hospitalization. However, the cost
      of providing this telephone care is not reimbursable to providers.

PMID- 15016164
TI  - Evaluation of sensorimotor polyneuropathy in children and adolescents with type I
      diabetes: associations with microalbuminuria and retinopathy.
AB  - To investigate diabetic polyneuropathy, we measured peroneal motor conduction
      velocity, sural sensory nerve conduction velocity and vibratory sense threshold
      (biothesiometry) in 28 children and adolescents with insulin-dependent diabetes
      (type 1), and in 28 age- and sex-matched, normal controls. Age varied from 8 to
      19 yr (mean +/- SD = 13.04 +/- 2.61); age at the onset of diabetes from 9 months
      to 12 yr (4.53 +/- 2.42 yr); and the duration of diabetes from 5 to 16 yr (8.48
      +/- 2.98). Eight patients (28%) fulfilled the minimal criteria for the diagnosis
      of polyneuropathy. Four of these patients showed symptoms while three had
      clinical signs of neuropathy. Eight patients had abnormal, sural sensory nerve
      conduction velocities. The presence of polyneuropathy did not correlate with the
      duration of diabetes or degree of metabolic control of diabetes. The prevalence
      of microvascular complications (microalbuminuria and retinopathy) was 32%. The
      presence of microvascular complications did not correlate with metabolic control
      but did with the duration of diabetes. The relationship between polyneuropathy
      and microvascular complications was 34%.

PMID- 15016165
TI  - Neonatal diabetes mellitus.

PMID- 15016166
TI  - Treatment of hypertension and microalbuminuria in children and adolescents with
      type 1 diabetes mellitus.
AB  - Nephropathy is the main cause of morbidity and mortality in patients with type 1
      diabetes and, in adults, persistent microalbuminuria is the best marker of the
      consequent risk for its development. In the pediatric population, puberty
      represents the most important risk factor for the development of microangiopathic
      complications, although it is not necessarily associated with the progression to
      frank proteinuria. As many as 50% of subjects may revert to normoalbuminuria.
      Hypertension is a further risk factor and may accelerate the progression of micro
      and macrovascular complications. There is evidence that angiotensin-converting
      enzyme (ACE) inhibitors reduce renal damage by one or more mechanisms independent
      of their antihypertensive effects--hence they represent the drug of choice for
      the treatment of diabetic nephropathy. However, as angiotensin II receptor
      antagonists are more specific, they may become the obvious treatment choice in
      the near future. There is no consensus as to who should be treated and when
      treatment with renoprotective drugs should begin in the pediatric population, due
      to the lack of a clear definition of the natural history of microalbuminuria in
      this age group. In this review some models and controversial aspects of this
      issue are presented and discussed.

PMID- 15016167
TI  - Ethnic differences in pubertal metabolism--seeking the causes of type 2 diabetes
      in youth.

PMID- 15016168
TI  - Insulin resistance of puberty in African-American children: lack of a
      compensatory increase in insulin secretion.
AB  - Type 2 diabetes has been increasing in children, mostly affecting minority
      populations at around the age of puberty. Despite a multitude of studies
      demonstrating pubertal insulin resistance/hyperinsulinemia in white children,
      data are almost non-existent in African-American children. The aim of the present
      study was to investigate the impact of puberty on glucose metabolism, insulin
      sensitivity and secretion in African-American children. Twenty prepubertal and 16
      pubertal African-American subjects participated. All underwent a 3-h
      hyperinsulinemic (40 mU/m(2)/min) euglycemic clamp to determine insulin
      stimulated glucose disposal, and a 2-h hyperglycemic (12.5 mmol/L) clamp to
      assess first- and second-phase insulin secretion. Body composition was assessed
      by dual energy X-ray absorptiometry (DEXA) and visceral and subcutaneous
      abdominal adiposity with computed tomography (CT) scan at L4-L5. Total glucose
      disposal, glucose oxidation and non-oxidative glucose disposal were significantly
      lower in the pubertal group compared with the prepubertal one (53.8 +/- 3.9 vs.
      72.2 +/- 5.0 micromol/kg/min, p = 0.009; 23.3 +/- 1.1 vs. 31.6 +/- 1.7
      micromol/kg/min, p = 0.001; and 30.0 +/- 3.3 vs. 40.5 +/- 3.9 micromol/kg/min, p
      = 0.049, respectively). Insulin sensitivity was approximately 30% lower in the
      adolescents compared with the prepubertal children. However, first- and second
      phase insulin secretions were not different between the two groups (971.4 +/-
      180.6 vs. 1044.0 +/- 191.4 pmol/L and 999.6 +/- 159.6 vs. 955.8 +/- 142.2 pmol/L,
      respectively). In conclusion, despite approximately 30% lower insulin sensitivity
      in African-American adolescents compared with prepubertal children, insulin
      secretion is not higher. This is in contrast to published findings in white
      children in whom insulin secretion is higher during puberty. These racial
      differences in physiologic adaptation to puberty could play a role in the higher
      prevalence of type 2 diabetes in African-American children at the time of
      puberty.

PMID- 15016169
TI  - Insulin pump therapy in pediatrics: a therapeutic alternative to safely lower
      HbA1c levels across all age groups.
AB  - OBJECTIVE: To examine the efficacy and safety of using continuous subcutaneous
      insulin infusion (CSII) therapy in a large group of patients 18 months to 18 yr
      from a single pediatric diabetes program. RESEARCH DESIGN AND METHODS: All
      patients < or = 18 yr of age starting on CSII from 1 January 1997 to 31 March
      2000 at the Yale Children's Diabetes Program were included. Clinical data were
      collected prospectively before and during pump treatment. HbA1c was the primary
      efficacy outcome and rates of diabetes-related adverse events were the primary
      safety measures. RESULTS: One hundred and sixty-one children ranging in age from
      18 months to 18 yr received CSII for an average of 32 +/- 9 months when data
      collection was closed on 31 October 2001, including 26 preschoolers (< 7 yr), 76
      school-agers (7-11 yr) and 59 adolescents (12-18 yr). Mean HbA1c levels were 7.1%
      in the preschoolers, 7.8% in the school-agers and 8.1% in the adolescents prior
      to the start of CSII. There was a significant and consistent reduction in mean
      HbA1c levels after 12 months of CSII (to 6.5% in preschoolers, 7.3% in school
      agers and 7.4% in adolescents, p < 0.02 vs. prepump) that was maintained at the
      most recent visit. Improved diabetes control was achieved with CSII without
      increasing daily insulin doses and in association with a decrease in the
      frequency of severe hypoglycemic events (p < 0.05 vs. prepump, all three age
      groups combined). CONCLUSIONS: CSII is an effective alternative to injection
      therapy in a large pediatric diabetes clinic setting. Even very young patients
      can utilize CSII to safely lower HbA1c levels.

PMID- 15016170
TI  - Re-hospitalization after diagnosis of diabetes varies by gender and socioeconomic
      status in urban African-American and Latino young people.
AB  - PURPOSE: To examine risk factors for re-hospitalization after diagnosis of
      diabetes mellitus amongst urban minority children. METHODS: Families of insulin
      treated African-American and Latino patients aged < 18 yr at diagnosis (n = 216)
      were interviewed about sociodemographics and other characteristics, on average
      5.9 yr after diagnosis. RESULTS AND CONCLUSIONS: About 60% of respondents were re
      hospitalized at least once for diabetes-related reasons (n = 128). Half of those
      questioned had Medicaid or no health insurance at all; 23% fit criteria for a non
      autoimmune, type 2 diabetic phenotype. Those who avoided re-hospitalization were
      more likely to have been seen initially at a tertiary care facility, to have
      private health insurance, and to be males. They had, on average, 2 yr shorter
      duration of diabetes at the time of interview. Risk for re-hospitalization was
      not associated with age at diagnosis, ethnicity, diabetic phenotype, or source of
      care during the past year. In multivariate analysis, predictors of re
      hospitalization were gender [odds ratio (OR) 1.98 for females vs. males (95%
      confidence interval (CI) = 1.05-3.72)], duration of diabetes [OR = 1.46 per yr
      (95% CI = 1.36-1.57)], initial ascertainment at a community hospital [OR = 5.44
      vs. tertiary care facility (95% CI = 2.61-11.29)] and having Medicaid or no
      insurance [OR = 2.73 (95% CI = 1.42-5.24)], compared with those with another type
      of health insurance. There is a high risk of re-hospitalization after the initial
      diagnosis of diabetes among insulin-treated minority children, particularly the
      uninsured and those on Medicaid, in part related to duration of disease and where
      the initial treatment occurred.

PMID- 15016171
TI  - Incidence, prevalence, and mortality of insulin-dependent (type 1) diabetes
      mellitus in Lithuanian children during 1983-98.
AB  - AIMS/HYPOTHESIS: Our purpose is to analyze interrelations of the incidence,
      prevalence and mortality of childhood-onset insulin-dependent diabetes mellitus
      (type 1) in Lithuania. METHODS: Incidence and prevalence rates were based on the
      national type 1 diabetes register during 1983-98. The cohort study was performed
      to evaluate the standardized mortality ratios. RESULTS: The average incidence of
      type 1 diabetes during the 16-yr study period was 7.36 per 100,000/yr. For both
      males and females the highest incidence of type 1 diabetes was recorded in the 10
      14 yr age group. The regression-based linear trends of the increase in incidence
      in various age groups and the annual percentage change for both genders was 2.05
      (p = 0.0039) and the greatest regression slope is observed for both genders in
      the 10-14 yr age group. Regression-based linear trends in type 1 diabetes
      prevalence indicate an even growth in all age groups (3.47; p = 0.001), although
      the annual percentage change is most prominent in the 5-9 yr age group for girls
      (4.95%/yr) and in the 10-14 yr age group for boys (4.06%/yr). The standardized
      mortality ratio of all-cause mortality in people with diabetes is higher than in
      the common population 7.71 (p < 0.0001). The standard mortality ratio for all
      causes increases with longer diabetes duration. CONCLUSION/INTERPRETATION: The
      significant increasing trend of incidence and prevalence during 1983-98 is
      observed. The annual percentage change is similar. The young patients with type 1
      diabetes have a higher mortality risk.

PMID- 15016172
TI  - Ambulatory blood pressure monitoring (ABPM) in normotensive adolescents with type
      1 diabetes.
AB  - OBJECTIVE: To evaluate 24-h ambulatory blood pressure monitoring (ABPM) for early
      detection of hypertension in adolescents with type 1 diabetes mellitus (DM1).
      DESIGN: Patients underwent fundoscopy, albuminuria determinations, two repeated
      autonomic cardiovascular tests, heart rate (HR) variation during deep breathing
      and blood pressure (BP) variation during sustained handgrip. Twenty-four hour BP
      measurements were taken automatically by an oscillometric portable monitor.
      SETTING: A specialty pediatric diabetes clinic and subjects' homes. PARTICIPANTS:
      Eighteen children aged 10-17 yr with 2+ yr of DM1, without long-term
      complications, and 34 controls. RESULTS: Higher ambulatory HR during the day than
      at night did not differ between DM1 subjects and controls. Mean systolic (s) and
      diastolic (d) BP in patients during the daytime were not significantly different
      from the control values. During the night, both sBP and dBP mean values in
      patients differed from those of controls. Statistical analysis of day and night
      HR and BP measurements were not different in both groups. The percentage decrease
      during the night in sBP and dBP was significantly smaller in patients than in
      controls. There were no differences by gender or duration of diabetes > or < 5 yr
      or by HbA1 above and below 10%. No difference in nocturnal sBP or dBP decline was
      observed between patients with or without abnormal autonomic test results.
      CONCLUSION: ABPM is more reliable than casual BP measurement in detecting early
      BP alterations during the night, before the appearance of microalbuminuria, in
      young patients with DM1.

PMID- 15016173
TI  - Urinary excretion of n-acetyl-beta-D-glucosaminidase and retinol binding protein
      as alternative indicators of nephropathy in patients with type 1 diabetes
      mellitus.
AB  - Diabetic nephropathy (DN) is usually characterized by glomerular dysfunction,
      with microalbuminuria as an early indicator. Urinary excretion of smaller
      molecular weight proteins such as n-acetyl-beta-glucosaminidase (beta-NAG) and
      retinol binding protein (RBP) indicate proximal tubular dysfunction, and may
      identify diabetic patients at risk of developing diabetic nephropathy. In a trial
      to assess renal tubular function, urinary excretion of beta-NAG (by colorimetric
      assay) and RBP (by ELISA) were determined in 59 type 1 diabetic patients (mean
      age 15 +/- 3.2 yr). Of the 59 patients, 11 were microalbuminuric while 48 had
      normal urinary albumin excretion (UAE). Patients were compared with 40 matched
      healthy subjects. Diabetic patients with microalbuminuria (n = 11) had
      concomitant renal tubular disorder indicated by high urinary beta-NAG in all
      (100%) and RBP in 10 (90.9%) of them. Meanwhile, patients without
      microalbuminuria (n = 48) had both tubular markers excreted in urine in
      significantly higher amounts than controls (mean beta-NAG = 6.88 vs. 3.76 U/g Cr,
      p < 0.001; RBP = 386.6 vs. 151.8 microg/dL, p < 0.001). Among those patients, 29
      (61%) had raised urinary beta-NAG activity, and 39 (82%) had increased loss of
      RBP in urine. A significant correlation was found between urinary beta-NAG and
      RBP in normoalbuminuric patients (r = 0.66, p < 0.001), as well as between each
      of the two tubular markers and HbA1c (r = 0.83, p < 0.001). At 30 and 36 months
      of follow-up, two out of 48 (4.2%) diabetic patients developed persistent
      microalbuminuria. Both had elevated baseline HbA1C, and urinary beta-NAG. In
      conclusion, proximal tubular dysfunction may occur independent of glomerular
      alteration. Whether tubular markers precede the development of microalbuminuria
      needs further study.

PMID- 15016174
TI  - Incidence of enteropathy-associated T-cell lymphoma in celiac disease:
      implications for children and adolescents with type 1 diabetes.
AB  - The long-term consequences of screening for celiac disease in diabetic children
      are not known. Routine screening is not practiced in our pediatric diabetic
      population. This study of the incidence of the most severe and specific long-term
      complication of untreated celiac disease, i.e., enteropathy-associated T-cell
      lymphoma (EATCL) and its association with diabetes, is done in order to justify
      our strategy not to practice routine screening. In the first phase of this study,
      a questionnaire was sent to all Swiss pathologists. The second phase consisted of
      a search in the cancer registry of the canton of Zurich. The incidence of EATCL
      in the general population of a Swiss region and the theoretical risk for a
      diabetic patient to develop this type of lymphoma were calculated. Ten cases of
      EATCL were found. Five had a long history of malabsorption, three of them since
      childhood. The mean age of the patients was 61.9 yr. None suffered from diabetes
      mellitus. The incidence of EATCL was 0.07/100,000 inhabitants/year. The expected
      risk for EATCL in patients with type 1 diabetes is 12.4/100,000 diabetic patients
      over a period of 60 yr. The data suggest that the risk for EATCL is small in
      diabetic patients. Therefore, we restrict the investigation for celiac disease to
      patients with typical and atypical symptoms, but do not perform routine
      screening.

PMID- 15016178
TI  - One step back, two steps forward.

PMID- 15016175
TI  - Regulation of pancreatic cell differentiation and morphogenesis.
AB  - Organogenesis requires tissue interactions to initiate the cascade of inductive
      and repressive signals necessary for normal organ development. Tissue
      interactions initiate the pancreatic lineage within the primitive foregut
      endodermal epithelium and continue to direct the morphogenesis and
      differentiation of the endocrine, exocrine and ductal portions of the pancreas.
      An understanding of the mechanisms controlling pancreatic growth would enable the
      development of alternative therapies for diseases such as type 1 diabetes.

PMID- 15016179
TI  - Varying clinical presentations at onset of type 1 diabetes mellitus in children-
      epidemiological evidence for different subtypes of the disease?
AB  - OBJECTIVE: On the basis of 2121 case observations between 1987 and 1997, we
      describe the clinical and laboratory characteristics of diabetes mellitus type 1
      at its onset. Our objective is to analyze whether clinical presentation follows a
      uniform pattern or whether there is evidence for different subtypes. RESEARCH
      DESIGN AND METHODS: Thirty-one pediatric hospitals and one diabetes center in
      Baden-Wuerttemberg (BW), Germany, participated in this study. The hospital
      records of 2121 children below 15 yr of age were examined retrospectively.
      Statistical analysis was done after logarithmic transformation into a normal
      distribution. RESULTS: The average duration of symptoms was found to be 15.2 d
      (95% CI (Confidence Intervals) = 14.3-16.1) ranging between 2.0 and 180 d (95%
      central range). The most frequent symptoms were polyuria and polydipsia; 7.2%
      presented with altered level of consciousness. The mean blood glucose value was
      407.9 mg/dL (95% CI = 400.0-416.0), corresponding to 23.3 mmol/L (95% CI = 22.8
      23.8). The median pH value was 7.35 (95% CI = 7.34-7.36), and the median base
      excess was -5 mmol/L (95% CI =-5 to -4). The younger patients had a shorter
      duration of symptoms and suffered most frequently from ketoacidosis. CONCLUSIONS:
      Although the symptoms of diabetes at its onset follow a uniform pattern, the
      clinical presentation and duration of symptoms indicate that there may be various
      forms of type 1 diabetes.

PMID- 15016180
TI  - The changing presentation of children with newly diagnosed type 1 diabetes
      mellitus.
AB  - Although it is known that the incidence of type 1 diabetes mellitus (DM) in
      childhood is progressively increasing, it is less clear whether the presentation
      of newly diagnosed DM is changing. The aim of this study was to establish whether
      any biochemical or clinical presentation parameters have altered over time. A
      retrospective study was performed comparing newly diagnosed children with DM in
      two 24 month time intervals, 8 yrs apart (1988-89 and 1995-96). Fifty-seven
      children were diagnosed with type 1 DM in 1988-89 and 70 children in 1995-96. At
      presentation, children born in the later cohort had a higher pH (p < 0.001) and
      lower serum glucose (p < 0.05). Although the frequency of diabetic ketoacidosis
      (DKA) was higher in the 1988/89 cohort (63% vs. 42% in 1995/96) the absolute
      number of children with DKA in each time interval was similar (33 subjects in
      1988-89 vs. 30 subjects in 1995/96). Islet cell antibody (ICA) levels were very
      different between the two cohorts; higher antibody levels were found in the
      1988/89 group (p < 0.01). DKA was also associated with higher ICA titres (p <
      0.05). Hospital admission stay decreased from 6.5 DS to 3.4 DS over the 8-year
      period (p < 0.0001). At our institution, the presentation of children with type 1
      DM is changing with many more children diagnosed before developing DKA. We
      speculate that a new environmental factor(s) may be responsible for the absolute
      increase in patients presenting without DKA, while older etiologies (both genetic
      and environmental) are responsible for the steady, unchanging number of patients
      with a more severe presentation. Greater awareness of diabetes in children is not
      the factor contributing to earlier diagnosis before DKA develops.

PMID- 15016182
TI  - Screening for prediabetes in the general child population: maternal attitude to
      participation.
AB  - Screening to predict serious diseases in the general population has been regarded
      as unethical as it is supposed to make people anxious. Therefore we have
      evaluated whether mothers become anxious when their babies participate in a
      project to predict diabetes in the general child population. Out of 21 700
      newborn children, 16 300 (75%) entered the ABIS project (All Babies in South-east
      Sweden). The parents (usually the mothers) answered a questionnaire at the
      child's birth and then again after 1 yr. A total of 10 868 representative birth
      questionnaires had been analyzed. To the question, 'How do you feel when you know
      that your child is participating in this study?', only 2.5% of mothers of
      children with type 1 diabetes in the family answered 'more anxious/much more
      anxious', and even fewer (1.5%) of the mothers in the general population (p <
      0.01). A total of 52.5% of the general population answered 'calmer/more
      reassured' (29.3% 'calmer' and 23.2% 'much calmer'), while 43.3% felt unaffected.
      Those 1.5% of mothers who reported becoming more anxious were more likely to be
      in an unstable social situation (unemployed, p < 0.001; born abroad, p < 0.001;
      low education, p < 0.001). At the 1-yr follow-up, 4948 unselected questionnaires
      had been analyzed. Only 1.2% of the mothers felt 'more anxious', while the
      overwhelming majority felt either unaffected (58.7%) or calmer (38.6%). At this
      follow-up, most of those who had felt 'more anxious' at birth did not feel that
      way any longer, and none of those with diabetes in the family. We conclude that
      large-scale screening studies for the prediction of diabetes in the general
      population can be performed without causing increased anxiety. A few parents,
      most often found in the group with known social problems, might need extra
      information and support.

PMID- 15016183
TI  - Insulin in human milk and the prevention of type 1 diabetes.
AB  - Although controversial, exclusive breast milk feeding was shown to exert a
      protective effect in preventing type 1 diabetes. In contrast, an early
      introduction of cow's milk-based formula in young infants may enhance the risk of
      disease, especially in genetically susceptible children, presumably by an
      increase of intestinal permeability to macromolecules such as bovine serum
      albumin and beta-casein, which may arouse autoimmunity. We have shown that human
      milk contains insulin in substantial concentrations, while insulin is barely
      detectable (if at all) in infant formulas. Orally administered insulin was
      demonstrated to promote gut maturation and to reduce intestinal permeability to
      macromolecules. Furthermore, oral insulin may induce tolerance to insulin and
      protect against the development of type 1 diabetes. We herewith raise a
      hypothesis that human milk is protective against the development of type 1
      diabetes by virtue of the effects of its substantial content of insulin.

PMID- 15016181
TI  - The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes
      (JSGIT): initial aims and impact of the family history of type 1 diabetes
      mellitus in Japanese children.
AB  - The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes
      (JSGIT) was established in July 1994 with the chief aim to improve the quality of
      therapy for type 1 diabetes in children, an entity far less common in Japan than
      in Europe. We proposed four initial research topics: (i) to determine the current
      status of medical care and glycemic control in Japanese children with type 1
      diabetes mellitus; (ii) to standardize the measurement of hemoglobin A1c; (iii)
      to establish a registry of a large cohort of patients in order to enable
      prospective studies to improve the quality of therapy for children with type 1
      diabetes in Japan; and (iv) to enable participants of the JSGIT to hold a
      workshop twice annually. We registered a total of 736 patients from 45 hospitals
      throughout Japan. Intervention via insulin treatment was instituted after 2 yr
      for those patients whose hemoglobin A1c level was more than 8.1%. The proportion
      of patients receiving multiple insulin injections increased after intervention;
      however, average hemoglobin A1c in females remained significantly higher than in
      males. We identified two forms of diabetes in Japanese children: a rapidly
      progressive form and a more slowly progressive form. There was a significantly
      higher prevalence of a family history of diabetes in first-degree relatives in
      the slowly progressive form. These preliminary findings are the result of the
      first collaborative study of childhood diabetes in Japan.

PMID- 15016184
TI  - CD40/154 blockade and rejection of islet allografts in the streptozotocin and
      autoimmune diabetic rat.
AB  - Islet transplantation in children with autoimmune diabetes will require
      immunosuppression that has minimal toxicity and side-effects, and overcomes the
      barrier of autoimmunity. Since antibodies directed against the CD40/154 co
      stimulatory pathway may meet these criteria, we have tested the ability of
      hamster antirat CD154 (AH.F5, Biogen) to prevent rejection of renal subcapsular
      islet allografts in streptozotocin (STZ) or autoimmune (AUTO) diabetic diabetes
      resistant biobreeding (DRBB) rats. STZ diabetic rats that received anti-CD154 at
      15 mg/kg per dose but not 10 mg/kg per dose did not have evidence of rejection
      until about 80-120 d post-transplantation, by which time antibody concentrations
      had returned to undetectable levels. Rats retreated with anti-CD154 before
      recurrence of diabetes had a prolonged period of disease-free survival. Most of
      these rats had recurrence following a spleen cell challenge. In contrast, AUTO
      diabetic DRBB rats treated with anti-CD154 had recurrence of diabetes between 7
      and 12 d following transplantation of the Dark Agouti (DA) islets. In a separate
      set, AUTO diabetic rats that received a simultaneous islet isograft, islet
      allograft and thyroid allograft had focal accumulation of lymphocytes at the
      periphery of the isograft, while the islet and thyroid allografts had diffuse
      infiltration with lymphocytes and destruction of tissue with no residual staining
      for glucagon. Therefore, autoimmunity adds an additional barrier to islet
      allotransplantation that is not overcome with CD40/154 blockade in an animal
      model that closely parallels autoimmune diabetes in humans. The results indicate
      the importance of testing regimen of islet transplantation in animal models of
      autoimmune diabetes.

PMID- 15016185
TI  - Detection of serum collagen type IV in children with type 1 (insulin-dependent)
      diabetes mellitus--a longitudinal study.
AB  - The basement membrane is a major focus of scientific interest because of its role
      in a variety of diseases. In diabetes mellitus, a thickening of the capillary
      basement membrane results in microangiopathic lesions. To monitor the metabolism
      of the basement membrane protein collagen type IV (CIV) in diabetes mellitus,
      serum levels of CIV were measured using an enzyme-linked immunosorbent assay
      (ELISA) method in 28 children with type 1 diabetes mellitus over a period of 6
      years. These values were compared to serum CIV levels in 24 age and sex matched
      controls. In the first 3 years, serum CIV levels were normal. In the 4th year, 1
      patient and in years 5 and 6, 4 patients had increased CIV serum levels. At the
      end of the investigation, 3 children had developed retinopathy, 6
      microalbuminuria, and 2 both microalbuminuria and retinopathy. Only those
      patients with microalbuminuria had increased CIV serum levels. In conclusion, we
      suggest that CIV serum levels can be used as a marker for the development of
      diabetic microalbuminuria.

PMID- 15016186
TI  - Use of hypertonic saline in the treatment of cerebral edema in diabetic
      ketoacidosis (DKA).
AB  - Cerebral edema is the primary cause of morbidity and mortality in children and
      adolescents with diabetic ketoacidosis (DKA). We report a case of an adolescent
      female with life-threatening DKA-related cerebral edema who responded to a
      combination of mannitol and hypertonic saline. This is the first report of the
      use of hypertonic saline in the treatment of cerebral edema due to DKA.

PMID- 15016187
TI  - Pancreatic stem cells: a therapeutic agent that may offer the best approach for
      curing type 1 diabetes.
AB  - Type 1 (insulin-dependent) diabetes is one of the most costly chronic diseases of
      children and adolescents in North America and Europe. It occurs in genetically
      predisposed individuals when the immune system attacks and destroys specifically
      the insulin-producing beta cells of the pancreatic islets of Langerhans. Although
      routine insulin injections can provide diabetic patients their daily insulin
      requirements, non-compliance commonly results in blood glucose excursions that
      eventually lead to microvascular and macrovascular complications and early death.
      The only real 'cure' for type 1 diabetes is replacement of the beta-cell mass
      which, today, is either an ectopancreatic transplant or an islet of Langerhans
      implant. Two new developments may offer additional options: surrogate, non
      endocrine cells genetically modified to secrete insulin in response to high blood
      glucose levels; and stem cells that possess the capacity to differentiate to
      endocrine pancreas. In this short review, we discuss the efforts currently being
      made to regulate pancreatic stem cell growth in order to produce large numbers of
      functional islets that can be used as implants. Hopefully, autologous stem cell
      derived islet cell implants without lifelong immunosuppressive therapy may one
      day be realized.

PMID- 15016190
TI  - How should we manage celiac disease in childhood diabetes?

PMID- 15016191
TI  - HLA class II genetic association of type 1 diabetes mellitus in Czech children.
AB  - To examine human leukocyte antigen (HLA) class II association of type 1 diabetes
      mellitus (DM) in Czech children, we performed a case-control study of 261
      patients diagnosed before the age of 15 and 289 non-diabetic control children.
      Complete HLA-DQA1, DQB1 genotyping and DRB1*04 subtyping were carried out by
      polymerase chain reactions with sequence-specific primers. The effect of the
      DRB1*04 subtypes was studied in DRB1*04 alleles carried on DQB1*0302-DQA1*03
      haplotypes. The risk was statistically evaluated by testing 2 x 2 tables,
      considering corrected p-values < 0.05 significant. The DQB1*0302 (odds ratio, OR
      = 9.0), DQB1*0201 (OR = 3.4) and DQA1*03 (OR = 7.5) alleles were significantly
      associated with diabetes risk, while the DQB1*0602 (OR = 0.02), DQB1*0301 (OR =
      0.08), DQB1*0503 (OR = 0.13), DQB1*0603 (OR = 0.20), DQA1*01 (OR = 0.28) and
      DQA1*02 (OR = 0.26) alleles were significantly protective. Of the DQA1-DQB1
      genotypes, we point out the extremely high risk of OR = 116 conferred by HLA
      DQA1*05-DQB1*0201/DQA1*03-DQB1*0302. Among DRB1*04 subtypes, DRB1*0403 was
      significantly protective (OR = 0.05, CI 95% 0.01-0.45). Since none of the
      remaining DRB1*04 subtypes was associated with type 1 DM, our study may present
      another piece of evidence that the DRB1*0401 and DRB1*0404 alleles do not modify
      type 1 diabetes risk generally in European populations.

PMID- 15016192
TI  - Significant urban/rural differences in the incidence of type 1 (insulin
      dependent) diabetes mellitus among Bulgarian children (1982-1998).
AB  - The systematic registration of the incidence of childhood (0-14 yr) type 1
      (insulin-dependent) diabetes mellitus in Bulgaria dates back to 1973, with an
      invariably present difference in the incidence according to the area of
      residence. The present study has been undertaken to assess the trends in the
      incidence of type 1 diabetes among children in eastern Bulgaria (1982-1998) with
      respect to area of residence at onset. The data were collected prospectively,
      with an ascertainment of the primary source of 95.8%. The mean annual incidence
      is 6.99/100,000 (95% CI = 6.45-7.54), varying between 5.09 and 11.54/100,000. The
      mean annual incidence in towns is higher than in villages: 7.89 vs. 5.26/100,000,
      p < 0.0001. A linear trend of increase in the incidence with time is revealed
      applying Poisson regression analysis, with the area of residence as a strong
      predictor of the risk (p < 0.001). According to the model, the age-adjusted
      incidence rose by 4.1% annually. The stratified analysis by age group has found a
      significant linear trend in those aged 5-9 (p < 0.001) and 10-14 yr (p = 0.002)
      for both sexes. In conclusion, the markedly increasing incidence of type 1
      diabetes among children in this study is strongly dependent on area of residence
      at onset. We suggest that in conjunction with the pronounced seasonality at the
      onset of diabetes and its connection with population density, this phenomenon
      should be regarded as a reflection of environmental influence and further
      explored.

PMID- 15016193
TI  - Diabetic ketoacidosis with intracerebral complications.
AB  - PURPOSE: To describe 11 instances of severe diabetic ketoacidosis (DKA) with
      secondary intracerebral complications (ICCs), nine of whom were treated early and
      showed complete recovery. METHODS: Three hundred and eighty-one episodes of DKA
      were treated at Denver Children's Hospital (DCH) from January 1989 to December
      1999. Nine instances of DKA with ICC were prospectively identified during this
      time period. Two additional occurrences were identified via a medical records
      search (total incidence, 2.9%). The signs, symptoms and laboratory values which
      led to their diagnosis and treatment are identified. RESULTS: All nine children
      who received early treatment with i.v. mannitol showed complete recovery. An
      additional patient had central nervous system involvement upon arrival at our
      hospital and showed almost complete recovery. Another patient suffered a
      cardiorespiratory arrest before transfer to our hospital and died without being
      treated for cerebral edema. CONCLUSION: Prevention of ICCs by the earlier
      diagnosis of diabetes and by being aware of possible risk factors for cerebral
      edema is the eventual goal. Based on our experience, mannitol should be given
      promptly for the treatment of ICCs indicated by the clinical course even if
      cerebral edema is not documented by a computed tomography (CT) scan.

PMID- 15016195
TI  - IGF-I treatment of diabetes.

PMID- 15016194
TI  - Subtotal pancreatectomy for hypoglycemia due to congenital hyperinsulinism: long
      term follow-up of neurodevelopmental and pancreatic function.
AB  - OBJECTIVE: To evaluate neurodevelopmental status as well as endocrine and
      exocrine pancreatic function in children who have undergone subtotal
      pancreatectomy for hypoglycemia due to congenital hyperinsulinism. PATIENTS AND
      METHODS: Out of 15 identified patients, eight children (mean age 12.7 +/- 0.8 yr)
      participated in detailed psychometric testing and studies assessing glucose
      homeostasis, secretion of proinsulin, insulin, glucagon and C-peptide during a
      test meal. Additionally, a 24-h fast, glucagon challenge test, 72-h stool
      collection, and ultrasonography of the pancreatic remnant were performed.
      RESULTS: Five of the 15 initially identified children had seizure disorders,
      including two with mental retardation. Diabetes developed in two of 15 children.
      All eight children investigated in the present study had evidence for attentional
      control impairment and 50% had subnormal intellectual functioning. Two had
      symptomatic hypoglycemia during the 24-h fast, while one had an elevated fasting
      glucose concentration. Four children, including the latter patient, had
      proinsulin/insulin ratios resembling patients with type 2 diabetes. Exocrine
      pancreatic function was normal in all eight children. No correlation was found
      between pancreatic endocrine function and pancreatic remnant size, nor between
      multiple pre- and postoperative factors (i.e., age at diagnosis and surgery) and
      neurodevelopmental outcome. CONCLUSION: While severe mental retardation or
      diabetes occurred infrequently in our patient population compared with previous
      reports, all of the studied children had subtle anomalies in their cognitive
      performance tests and the majority had endocrine test results indicative of
      abnormal insulin secretion and stressed pancreatic beta cells. Although partial
      pancreatectomy remains the treatment of choice after medical therapy fails,
      improved therapeutic means are necessary to achieve better clinical outcome.

PMID- 15016196
TI  - Neurohumoral regulation of body weight gain.
AB  - The regulation of body weight is a complex process which relies on a balance
      between supply of nutrients and demand on these nutrients in the form of energy
      expenditure. Various central and peripheral mechanisms play a crucial role in
      maintaining this balance. While various neuropeptides in the central nervous
      system (CNS), particularly in the hypothalamus, maintain the necessary harmony
      between hyperphagia and anorexia, peripheral signals arising from the
      gastrointestinal tract (cholecystokinin-8 [CCK-8], amylin), pancreas (insulin)
      and adipose tissue (leptin) provide the necessary stimuli or a feedback
      inhibition for the synthesis and secretion of these hypothalamic neuropeptides.
      Various metabolites of the carbohydrate and fat metabolism are also involved in
      regulating the neuronal activity in the hypothalamus which ultimately leads to a
      release of key neuropeptides. In addition to the central mechanisms, peripheral
      mechanisms that regulate energy expenditure, particularly in the brown adipose
      tissue and skeletal muscle, are critical in maintaining the overall balance.
      Insight into these mechanisms sets the stage for developing novel strategies in
      the treatment of emerging childhood diseases such as obesity, anorexia nervosa,
      and bulimia. Further, delineation of these processes in the fetus and newborn
      sets the stage for investigating their role in molding the adult phenotype due to
      intrauterine adaptations.

PMID- 15016197
TI  - Continuous subcutaneous insulin infusion and continuous subcutaneous glucose
      monitoring in children with type 1 diabetes mellitus: boon or bane?

PMID- 15016198
TI  - Life with continuous subcutaneous insulin infusion (CSII) therapy: child and
      parental perspectives and predictors of metabolic control.
AB  - OBJECTIVE: The purpose of this study was twofold (i): to evaluate metabolic
      control in patients receiving CSII therapy in a routine pediatric diabetes clinic
      by describing reasons for initiating therapy and daily management issues,
      including needle fear; and (ii) to assess the change in parental involvement and
      anxiety once their child initiated CSII therapy. RESEARCH DESIGN AND METHODS: The
      study included 52 subjects (aged 7.6-23.6 yr) from a general pediatric diabetes
      clinic. Management issues were defined as diet, exercise, home blood glucose
      monitoring (HBGM) frequency, and self/staff assessment of needle fear.
      Characteristics were analyzed both according to a 0.5% change in HbA1c status
      (decreased vs. stable vs. increased) compared with pre-CSII therapy, and final
      HbA1c achieved (< or = 8.1 vs. > 8.1%). RESULTS: The primary recommendation
      source for CSII use was most often the physician/diabetes team (48.1%), followed
      by a combination of the former with a personal referral source (32.7%). The most
      common reason (71.2%) for CSII initiation was a combination of wanting to achieve
      better metabolic control, dislike of insulin injections, and/or increased
      flexibility in daily living. Over one-quarter (26.9%) of subjects were identified
      as being needle-fearful, and this characteristic was predictive of final
      metabolic control (3/25 subjects </= 8.1% vs. 11/27 subjects > 8.1%, p = 0.03).
      On CSII therapy, dietary carbohydrate consistency was highly variable, and most
      subjects (65.3%) exclusively used an insulin to carbohydrate ratio for insulin
      bolus dosage calculation. The most common adjustment strategy (63.5%) for
      exercise was a combination of decreasing the insulin basal rate, disconnecting
      the pump, and/or eating extra carbohydrates. For the total cohort, the frequency
      of HBGM significantly increased on CSII therapy (4.31-4.85 tests/day, p = 0.02).
      Females did not have a significant change in HBGM frequency, while the youngest
      subjects had the highest HBGM frequency. Parental involvement and anxiety
      primarily stayed the same or decreased, regardless of the child's age (< or = 18
      vs. > 18 yr) or metabolic control. CONCLUSIONS: Analyses of the various
      characteristics identified only needle fearfulness as being predictive of poor
      metabolic control. Interestingly, poor control with CSII therapy did not result
      in a significant increase in parental involvement and/or anxiety.

PMID- 15016199
TI  - Prediction of silent celiac disease at diagnosis of childhood type 1 diabetes by
      tissue transglutaminase autoantibodies and HLA.
AB  - AIMS: The aims were to estimate the diagnostic sensitivity and specificity of
      autoantibodies to tissue transglutaminase (IgA- and IgG-tTG), gliadin (AGA) and
      endomysium (EMA) in relation to human leukocyte antigen (HLA)-DQB1 alleles to
      identify silent celiac disease at diagnosis of type 1 diabetes. METHODS: IgA- and
      IgG-tTG were measured in radioligand binding assays in 165 type 1 diabetic
      patients. Data on HLA-DQB1 were available for 148 patients and on both AGA and
      EMA for 164 patients. For patients considered positive for AGA or EMA, or both,
      an intestinal biopsy was suggested. HLA-DQB1 typing was carried out by polymerase
      chain reaction and hybridization with allele specific probes. RESULTS: Three
      patients, left out from further study of antibodies, but not from HLA-DQB1
      analysis, had treated celiac disease at diagnosis. Out of the other 162 type 1
      diabetic patients tested, nine had IgA-tTG, six IgG-tTG, eight EMA, and 11 AGA.
      Biopsy was suggested for nine patients, of whom six showed villous atrophy, one
      did not and two refused to participate. Thus, silent celiac disease was probable
      in 8/162 and biopsy-verified in 6/162, where five patients were AGA-positive and
      six either EMA-, IgA-tTG- or IgG-tTG-positive. Of the 11 patients with celiac
      disease (three with treated and eight with silent celiac disease), 10 were HLA
      DQB1-typed, of whom 65% (13/20) had the DQB1*02 allele, compared with 36%
      (100/276; p = 0.011) of those without celiac disease. IgA-tTG levels were higher
      in patients having either *02 or *0302 (0.6; -1.3-112.4 RU) compared with those
      not having these alleles (0.4; -0.7-3.4 RU; p = 0.023). CONCLUSION: IgA-tTG are
      HLA-DQB1*02-associated autoantibodies with high sensitivity and specificity for
      silent celiac disease at diagnosis of type 1 diabetes.

PMID- 15016200
TI  - The GH-IGF-I axis and diabetes complications.

PMID- 15016201
TI  - Risk assessment, prediction and prevention of type 1 diabetes.
AB  - Circulating antibodies to pancreatic beta-cell antigens are markers of islet
      autoimmunity. In first-degree relatives of persons with type 1 diabetes, the
      levels and range of antigen specificities of these islet antibodies reflect the
      risk for clinical diabetes. However, in the general population, in which the
      disease prevalence is up to 30-fold lower, the predictive value of islet
      antibodies is correspondingly less. Islet antibody assays are primarily research
      tools to identify 'prediabetic' individuals for secondary prevention trials, but
      can also discriminate type 1 diabetes in several clinical situations. Loss of
      first-phase insulin response (FPIR) to intravenous glucose signifies imminent
      diabetes, but FPIR is normal in most islet-antibody-positive individuals. The
      contribution of a single FPIR measurement to risk assessment is therefore
      limited, but rate of fall of FPIR may be a useful predictor. Although beta cells
      are destroyed by autoreactive T cells, the assay of islet antigen-reactive T
      cells is not routine. Genetically, the major histocompatibility complex encoding
      human leukocyte antigen (HLA) alleles accounts for about 50% of familial
      clustering of type 1 diabetes. HLA typing is not diagnostic, but can be used to
      differentiate high- from low-risk individuals, e.g. at birth. While 'preclinical'
      diagnosis raises important medical and ethical questions, an optimized screening
      strategy provides a basis for counselling and follow-up. Recent knowledge of
      disease mechanisms and 'proof-of-principle' in the non-obese diabetic (NOD) mouse
      model justify expectations that type 1 diabetes is preventable, and even
      intervention that only delays onset of clinical diabetes is likely to be cost
      effective.

PMID- 15016203
TI  - An ounce of prevention...

PMID- 15016202
TI  - Retinopathy in juvenile diabetes: a 10-year (1990-2000) review.
AB  - Diabetic retinopathy (DR) is the most frequent complication of diabetes and a
      leading cause of impaired vision in the Western world. There is general agreement
      that early diagnosis and treatment of DR can slow its progression and help to
      prevent blindness. However, as a result of its asymptomatic nature and its
      etiopathogenesis, which is still unclear due to its multifactorial complexity, DR
      related blindness has a growing social impact in industrialized countries.
      Therefore, in order to gain a better understanding of this serious disease, the
      author performed an updated 10-year review of risk factors and management of DR
      in type 1 diabetes.

PMID- 15016204
TI  - Type 1 diabetes intervention trials.

PMID- 15016205
TI  - Is now the time for an intervention to prevent autoimmune type 1 diabetes?

PMID- 15016206
TI  - Prevention of type 1a diabetes mellitus*.
AB  - Type 1 diabetes begins with the progressive autoimmune mediated destruction of
      the insulin-producing beta cells. When sufficient beta cell function is lost, the
      endocrine phase, characterized by insulin deficiency and hyperglycemia,
      supervenes. While a genetic predisposition to diabetes is an important
      precondition, most believe an environmental factor or factors serve as the
      trigger for initiating this process. In this paper we review trials designed to
      prevent or delay the clinical onset of diabetes. In these studies, high-risk
      individuals are identified by their genetic predisposition to diabetes, and/or by
      the presence of immune markers indicating activation of the autoimmune process
      directed against islet cells. The Deutsche Nicotinamide Intervention Study
      (DENIS) randomized 55 high-risk subjects to either nicotinamide or placebo and
      found no significant benefit. The European Nicotinamide Diabetes Intervention
      Trial (ENDIT) completed enrollment in May 1998. ENDIT screened over 40 000
      relatives, randomizing 552 to either nicotinamide or placebo. Results are
      expected in May of 2003. Designed to test if avoidance of cow's milk in infancy
      will decrease the incidence of diabetes, the Trial to Reduce Type I Diabetes in
      the Genetically at Risk (TRIGR). High-risk infants are randomly assigned to
      different supplemental formulas in the first 6 months of life. Initial results
      suggest that removing cow's milk has a protective effect. The ongoing, NIH
      funded, multicenter Diabetes Prevention Trial-Type 1 (DPT-1) is testing two
      antigen-based (insulin) interventions in relatives at high risk for diabetes. Now
      in its sixth year, the DPT-1 study group has screened over 84,000 individuals. As
      of November 2000, 339 subjects have been randomized in the parenteral insulin
      study, completing the enrollment phase. Enrollment continues in the oral insulin
      study. Results of this trial are not yet available. Different epitopes of insulin
      and its analogs, monoclonal antibodies, and cytokine-based therapy, among others,
      have all been proposed as potential new interventional agents. While a great deal
      of effort will be required to test these approaches, the potential benefits of
      prevention justify these research efforts.

PMID- 15016207
TI  - The effects of co-therapy with recombinant human insulin-like growth factor I and
      insulin on serum leptin levels in adolescents with type 1 diabetes mellitus.
AB  - We previously demonstrated that in patients with type 1 diabetes mellitus (DM),
      co-therapy with subcutaneous (s.c.) recombinant human insulin-like growth factor
      I (rhIGF-I) and insulin improves glycemic control and reduces daily insulin
      requirements without inducing a significant change in body weight. However, it
      has been postulated that treatment with IGF-I may promote beneficial changes in
      body composition. Consequently, we assayed serum leptin, a peptide highly
      correlated with total fat mass, before and during chronic rhIGF-I administration.
      We studied 14 adolescents with type 1 DM (age range 12-19 yr). All patients were
      treated for 12 weeks with twice daily (BID) sc rhIGF-I in combination with
      standard BID split-mix insulin. At baseline, leptin concentrations were
      positively correlated with body mass index (BMI) (r(2) = 0.52, p = 0.004), as
      previously described for non-diabetic individuals. Leptin levels in diabetic
      females were higher than in diabetic males, and more than two times higher than
      in non-diabetic female controls. Baseline leptin levels did not correlate with
      patient age, duration of DM or hemoglobin A1c (HbA1c) measurements. The
      relationship between leptin concentrations and gender was maintained throughout
      treatment; however, average leptin levels did not change during 12 weeks of IGF-I
      + insulin co-therapy. These data suggest that despite treatment-induced
      improvements in HbA1c and serum IGF-I levels, serum leptin concentrations are
      unchanged by co-therapy with IGF-I + insulin. Moreover, these results suggest
      that improved metabolic control with IGF-I therapy is not obtained at the expense
      of increasing adiposity, a complication seen frequently with intensive insulin
      therapy.

PMID- 15016209
TI  - Influence of perinatal factors on the appearance of islet autoantibodies in
      offspring of parents with type 1 diabetes.

PMID- 15016208
TI  - Reproductive health beliefs and behaviors in teens with diabetes: application of
      the Expanded Health Belief Model.
AB  - OBJECTIVE: To identify significant correlates among constructs of the Expanded
      Health Belief Model (EHBM) with reproductive health behaviors [preventing an
      unplanned pregnancy and seeking preconception counseling (PC)] and metabolic
      control in teenaged women with type 1 diabetes. RESEARCH DESIGN AND METHODS:
      Eighty adolescent women with type 1 diabetes participated in a multisite,
      exploratory, case-control study. Subjects (only cases, and not controls, were
      used for the analyses of this paper) had a single, 1-h structured phone interview
      with a trained, same gender research assistant. Variables of interest were
      awareness, knowledge, health beliefs, attitudes, intention and behaviors
      regarding diabetes and reproductive health. RESULTS: Several major constructs of
      the EHBM were significantly correlated in the expected direction with
      reproductive health behaviors and metabolic control of adolescents with type 1
      diabetes. In particular, perceived susceptibility, barriers, threat, intention,
      and self-efficacy with birth control (BC) use, and motivational cue (initial
      awareness of PC) with seeking PC. CONCLUSIONS: Being told by a health care
      professional to seek out PC is a motivational cue that triggers action. The
      timing of this message would seem to play an important role in preventing an
      unplanned pregnancy. Therefore, interventions focusing on changing health beliefs
      and on increasing awareness may be effective in promoting positive reproductive
      health behaviors in adolescent females with diabetes.

PMID- 15016210
TI  - Clinical picture of childhood type 1 diabetes mellitus in the Eastern Province of
      Saudi Arabia.
AB  - AIM: Study of the clinical presentation and laboratory data of type 1 diabetes in
      the Eastern Province of Saudi Arabia. METHODS: The medical records of all
      affected children during the period 1986-1997 were reviewed for the analysis of
      clinical and laboratory data. RESULTS: Type 1 diabetes was diagnosed in 46
      children, 27 girls and 19 boys, with a mean age at diagnosis of 9.0 yr. The mean
      duration of symptoms prior to diagnosis was 12.5 d. Depressed consciousness
      occurred in 10.8% of the patients (none was comatose) and ketoacidosis in 77%.
      There was no episode of increased intracranial pressure during treatment, nor was
      there any death. There was a correlation between the central nervous system
      depression and the degree of hyperglycemia, and also with the severity of
      acidosis. CONCLUSIONS: Although more than three quarters of patients with type 1
      diabetes had ketoacidosis on presentation, none was comatose or developed
      clinical cerebral edema during treatment. The presentation of type 1 diabetes in
      children from Saudi Arabia seems to differ from reports from developed countries.

PMID- 15016212
TI  - Intra-uterine growth retardation and subsequent insulin secretion/action.

PMID- 15016213
TI  - No evidence for a major beta-cell dysfunction in young adults born with intra
      uterine growth retardation.
AB  - The association between low birth weight and the later development of type 2
      diabetes is well established. It has been hypothesized that in utero
      undernutrition may affect pancreatic beta-cell development, leading to an
      impaired beta-cell function in adulthood. We have previously demonstrated that
      intrauterine growth retardation (IUGR) is associated with insulin-resistance
      early in adulthood. The aim of this study was to test whether IUGR would affect
      beta-cell function in young adults. Twelve 25-yr-old insulin-resistant subjects
      with IUGR were matched for age gender and body mass index (BMI) to 13 controls.
      All of them had normal glucose tolerance. Mean fasting plasma glucose did not
      significantly differ between the group with IUGR and the control group (97 +/- 7
      vs. 98 +/- 4 mg/dL; p = 0.83). Blood glucose was maintained at 124.8 +/- 6.5 vs.
      126.2 +/- 7.5 mg/dL above the basal glycemia in the IUGR and control groups (p =
      0.64) throughout the hyperglycemic clamp. Serum insulin concentrations did not
      significantly differ between the group with IUGR and the control group either
      during the first (0-10 min) phase (311 +/- 252 vs. 248 +/- 184 pmol/L, p = 0.85)
      or during the second (80-100 min) phase (575 +/- 284 vs. 559 +/- 413 pmol/L, p =
      0.72). C-peptide concentrations were similar in both groups during the two phases
      (2.35 +/- 1.44 vs. 2.59 +/- 1.10 nmol/L, p = 0.39 and 4.86 +/- 1.36 vs. 4.96 +/-
      1.41 nmol/L, p = 0.91). In conclusion, our data do not argue in favor of an
      impairment of beta-cell function at 25 yr of age as a consequence of in utero
      undernutrition, but rather suggest that insulin resistance might be the primary
      defect responsible for the development of metabolic disorders associated with
      IUGR in adulthood.

PMID- 15016214
TI  - Impaired insulin-mediated glucose uptake in monocytes of short children with
      intrauterine growth retardation.
AB  - AIMS: To determine whether there was an impairment in insulin-mediated glucose
      uptake in monocytes from short children with intrauterine growth retardation
      (IUGR) when compared with control subjects. METHODS: Circulating monocytes were
      isolated by histopaque gradient separation followed by adherence. Monocytes were
      incubated with insulin at the following concentrations; 0, 0.1, 0.2, 0.6, 1, 2
      and 6 nm. 2-deoxyglucose (2-DG) uptake was measured after incubation with [(3)H]2
      DG and expressed as pmol/min/10(6) cells. Insulin-stimulated glucose uptake was
      determined in two ways: 6 nm insulin concentration minus baseline (6-0 nm) and
      the regression slope of glucose uptake over the range of log insulin
      concentrations (slope value). Insulin sensitivity was determined from a 90-min
      frequently sampled intravenous glucose tolerance test with the minimal model.
      RESULTS: Short children with IUGR (n = 16) had lower slope (4.6 +/- 1.1 vs. 9.5
      +/- 2.0, p = 0.002) and 6-0 nm (8 +/- 2 vs. 15 +/- 3 pmol/min/10(6) cells, p =
      0.048) glucose uptake values than normal children (n = 11). There was no
      difference in baseline glucose uptake between IUGR and normal children (36 +/- 5
      vs. 48 +/- 7 pmol/min/10(6) cells). In the five subjects with IUGR that were
      evaluated, the in vivo insulin sensitivity index and glucose effectiveness were
      found to be positively correlated with insulin-mediated glucose uptake in
      monocytes (r = 0.54) and baseline glucose uptake in monocytes, respectively (r =
      0.69). CONCLUSIONS: Short children with IUGR have impairment in insulin-mediated
      glucose uptake in monocytes when compared with normal children. Our hitherto
      limited data indicate that insulin-mediated glucose uptake in monocytes is
      correlated with in vivo assessment of insulin sensitivity in children with IUGR.

PMID- 15016215
TI  - Screening for preclinical type 1 diabetes in a discrete population with an
      apparent increased disease incidence.
AB  - Environmental agents are proposed to play a role in triggering or exacerbating
      pancreatic islet autoimmunity in people genetically predisposed to type 1
      diabetes. However, with few exceptions, these agents remain enigmatic. Clues to
      environmental agents may be found by investigating population/geographic clusters
      or 'hotspots' of high disease incidence. We were alerted to a small community
      where the incidence of type 1 diabetes appeared to be five-fold higher than
      expected. Because type 1 diabetes is now recognized to have a subclinical phase
      during which anti-islet antibodies can be detected, we aimed to identify and
      characterize a reservoir of children with subclinical disease in this community.
      Venous blood samples were collected from 1906/2347 (81%) local school children
      during one week. Islet cell antibodies (ICAs) were detected in 122 (6.4%)
      children, 18 (0.9%) being high titer (> or = 20 Juvenile Diabetes Foundation
      units (JDFu)). On retest, 15 months later, the majority of low titer ICAs were
      undetectable, whereas high-titer ICAs persisted. The latter were found in two
      distinct age-related, ethnically similar groups. The younger group, aged 6-9 yr,
      had antibodies to insulin (IAAs), glutamic acid decarboxylase (GAD) and tyrosine
      phosphatase IA2 in addition to ICA, human leukocyte antigen (HLA) genes
      associated with susceptibility to type 1 diabetes, and lower first-phase insulin
      responses (FPIRs) to intravenous glucose. The older group, aged 13-16 yr, the age
      cohort of the index clinical cases, had few antibodies other than ICA, non
      susceptibility HLA genes and normal FPIRs. During follow-up, three children, all
      from the younger group with multiple antibodies and FPIRs less than the first
      percentile, developed diabetes 4, 6 and 7 yr after screening. The finding of two
      age groups of subclinical disease suggests that if environmental agents triggered
      islet autoimmunity they did not act constantly on the community. Furthermore, the
      absence of multiple autoantibodies and/or HLA susceptibility genes in the older
      group, the source of index clinical cases, implies they are a residual subgroup
      with slow or absent progressive beta-cell destruction. This study illustrates
      that the natural history of type 1 diabetes may be elucidated by analyzing age
      related subclinical disease in the general population.

PMID- 15016216
TI  - Prevalence of coeliac disease and longitudinal follow-up of antigliadin antibody
      status in children and adolescents with type 1 diabetes mellitus.
AB  - Coeliac disease (CD) is more prevalent in individuals with type 1 diabetes
      mellitus (DM), and when untreated is associated with a number of medical
      complications, including poor glycaemic control. Identification of patients with
      CD has been facilitated in recent years by serological screening, including the
      use of antigliadin antibodies (AGAs) and endomysial antibodies (EMAs). The aim of
      this study was to assess the prevalence of CD in a clinic-based paediatric
      population with type 1 DM, and to study longitudinal changes in AGA status. Two
      hundred-and-eighty-one children and adolescents with type 1 DM aged 9.9 +/- 3.8
      yr were screened using AGAs of immunoglobulin A (IgA) and immunoglobulin G (IgG)
      classes (AGA-IgA and AGA-IgG). Thirty-five patients had both antibodies positive
      and underwent gastro-duodenoscopy and multiple biopsies. Fifteen of the 35
      patients had histological evidence of CD, and the overall clinic prevalence of CD
      was 5.7%. A number of patients did not exhibit florid symptoms, and recurrent
      unexplained hypoglycaemia was a significant finding. Patients who perceived
      themselves to be asymptomatic had more problems with compliance with a gluten
      free diet (GFD). Ninety-seven patients had follow-up AGAs performed after 2.5 +/-
      1.5 yr. One patient with initially normal AGAs developed positive antibodies and
      histological findings of CD. Antibody status has fluctuated in other patients. CD
      is common in patients with DM, and diagnosis is important to detect to minimize
      long-term morbidity related to both disorders. Initial normal screening does not
      exclude CD and repeat screening is indicated.

PMID- 15016217
TI  - Fructosamine levels demonstrate improved glycemic control for some children
      attending a diabetes summer camp.
AB  - Residential summer camps for youths with diabetes may have a positive effect on
      glycemic control. Hemoglobin A1c (HbA1c) is considered the best measure of
      control, but it reflects too long a period to evaluate a camp session. The
      fructosamine test reflects control over a period of 2-3 wk and may be ideal for
      this purpose. A portable device was used to examine the relationship between 2 wk
      of glycemic control and the change in fructosamine in order to determine whether
      control improved at camp. Thirty children, 8-12 yr old, were studied during a 2
      wk session of a diabetes summer camp. Pre-camp HbA1c levels were obtained from
      the childrens' physicians. Each camper measured his/her blood glucose four times
      daily. Insulin doses were readjusted frequently by camp physicians. Each child's
      fructosamine was measured at the beginning and end of camp. The baseline
      fructosamine correlated with HbA1c. The final fructosamine correlated with the 2
      wk mean glucose. The subgroup who started camp in below average glycemic control
      improved their fructosamine levels by the end of camp. Those who started camp in
      better control did not change. Without continuous glucose monitoring, it is
      impossible to accurately determine how well fructosamine reflects glucose levels.
      In this study, fructosamine correlated with the mean glucoses and with an HbA1c
      obtained prior to camp. Fructosamine appears to be a valid measure of glycemic
      control and being at camp was at least transiently beneficial to the children who
      needed it most.

PMID- 15016218
TI  - Do doctors cause or prevent cerebral edema in children with diabetic
      ketoacidosis?

PMID- 15016219
TI  - The role of the gut in beta-cell autoimmunity and type 1 diabetes: a hypothesis.
AB  - The origin of autoimmunity leading to the destruction of insulin-producing beta
      cells is not known. Several studies suggest that a link exists between the gut
      immune system and the islets infiltrating lymphocytes. Inflamed pancreatic islets
      express the same adhesion molecules involved with the homing of gut-associated
      lymphocytes. The manifestation of autoimmune diabetes in the animal models can be
      modified by dietary factors, which cause changes in the cytokine production by
      islet-infiltrating lymphocytes. Increased risk of type 1 diabetes has been
      associated with an early introduction of cows' milk formula in infancy,
      indicating that triggering of the gut immune system in early infancy may
      contribute to the later development of beta-cell autoimmunity. Enhanced immune
      reactivity to cow milk (CM) proteins in the patients with type 1 diabetes
      suggests aberrant regulation of the gut immune system in this disease. In the
      patients with newly diagnosed type 1 diabetes, anti-glutamate decarboxylase (GAD)
      reactivity was found in the subpopulation of lymphocytes expressing gut
      associated homing receptor alpha 4 beta 7. Based on these findings, the
      hypothesis that aberrant function of the gut immune system would lead to the
      development of beta-cell autoimmunity and type 1 diabetes has recently received a
      lot of attention. The possibility that regulation of the gut immune system is not
      normal in subjects at risk of autoimmune diabetes should be considered when
      treatments interfering with mucosal immunity for the prevention of type 1
      diabetes are planned.

PMID- 15016220
TI  - Atypical diabetes mellitus: time for a consensus?
AB  - A subgroup of diabetic patients presents with features typical of type 1
      diabetes, but over months to years has variable insulin requirements and develops
      features of type 2 diabetes. This subgroup is referred to as atypical diabetes
      mellitus (ADM). Over a span of 50 yr, reports on disease epidemiology, clinical
      characteristics, and metabolic/genetic features of the entity now referred to as
      ADM remain conflicted. This article reviews the available literature on ADM,
      proposes atypical diabetes mellitus syndrome (ADMS) as an encompassing
      nomenclature, and recommends expansive criteria for disease definition pending
      the release of a consensus recommendation by a panel of experts.

PMID- 15016221
TI  - The end of the beginning.

PMID- 15016222
TI  - Profound changes in the GH-IGF-I system in adolescent girls with IDDM: can IGFBP1
      be used to reflect overall glucose regulation?
AB  - Disturbances in the relations between insulin, growth hormone (GH) and insulin
      like growth factor I (IGF-I) may be a major cause behind deteriorated metabolic
      control in adolescent girls with type I diabetes. These patients have increased
      GH secretion and low IGF-I concentrations. The aim of this study was to identify
      possible endocrine mechanisms behind good and poor glycaemic control in such
      girls, focusing on the insulin-GH-IGF-I axis. Ten girls with well-controlled
      insulin-dependent diabetes mellitus (IDDM), hemoglobin A1c (HbA1c) 6.5+/-0.4%
      (normal range 3.9-5.2%) and nine healthy controls were investigated and compared
      with 11 girls with poor glucose regulation, HbA1c 10.9+/-0.4%, and their
      corresponding controls. Serum profiles of glucose, insulin, GH and IGF-binding
      protein 1 (IGFBP1) were analysed in addition to IGF-I and HbA1c. Two interesting
      observations were made. GH concentrations were equally elevated in the two
      diabetic groups regardless of metabolic control (mean 24 h GH - girls with poorly
      controlled diabetes 10.0+/-1.0 mU/L vs 9.8+/-1.7 - girls with well-controlled
      diabetes; p=ns). Likewise, the IGF-I concentrations were reduced to the same
      extent (233+/-19 vs 242+/-23 microg/L; p=0.75). Secondly, despite similar insulin
      concentrations (mean 24 h insulin - girls with poorly controlled diabetes 22.9+/
      2.6 and girls with well-controlled diabetes 27.3+/-2.9 mU/L, respectively;
      p=0.26), there was a marked difference in IGFBP1 concentrations between the two
      groups with IDDM (mean IGFBP1 - girls with poorly controlled diabetes 70.5+/-9.1
      microg/L vs girls with well-controlled diabetes 28.6+/-3.3; p<0.001). Despite
      equally elevated GH concentrations that may induce insulin resistance, the
      markedly lower concentrations of IGFBP1 in the well-controlled group indicate a
      higher hepatic insulin sensitivity in these girls compared with those with a poor
      control. Furthermore, in spite of similar total IGF-I concentrations, the lower
      IGFBP1 concentrations may result in higher IGF-I bioactivity in the well
      controlled group. This may be reflected in better growth of the well-controlled
      group whose height of 168.7+/-0.9 vs 163.6+/-1.2 cm was significantly different
      (p<0.004). IGFBP1 may be a marker of overall insulinization in adolescents with
      type 1 diabetes, independent of the absolute insulin dose used for therapy.

PMID- 15016223
TI  - Diabetic autoimmunity in infants and pre-schoolers with type 1 diabetes.
AB  - The incidence of type 1 diabetes is increasing most rapidly in children under 5
      yrs of age, a group where the disease appears to be more accelerated than
      traditional type 1 diabetes. Little is known about demographics, and markers of
      diabetes autoimmunity, in infants and pre-schoolers with type 1 diabetes. We
      report an analysis of 47 children diagnosed with type 1 diabetes prior to 5 yrs
      of age compared with a representative cohort (n=49) diagnosed after 5 yrs of age,
      and all were followed at Loma Linda University (LLU) Children's Hospital. Ethnic,
      familial, seasonal, and autoimmune marker characteristics are outlined. To
      determine the prevalence of diabetes autoimmune markers, ICA512, GAD65 and
      insulin autoantibodies (IAA) antibodies were measured. Children with early-onset
      diabetes had a significantly higher incidence of viral illness symptoms (p=0.005)
      and diabetic ketoacidosis (DKA; p=0.017) at the time of diagnosis. However,
      hemoglobin A1C (HbA1c) levels at diagnosis were significantly higher in the later
      onset group (p=0.001). A honeymoon period was reported in 14.8% of children
      diagnosed before 5 yrs of age compared with 42.1% in those diagnosed over 5 yrs
      of age (p=0.038). Islet-cell antibodies (ICAs) and glutamic acid decarboxylase
      (GAD) antibody titers were significantly different between early- and later-onset
      groups. ICA titers were positive in 35.29%, and GAD in 41.38% of the early-onset
      group versus 70.83 and 71.74% in children with later-onset disease, (p=0.001 and
      0.009, respectively). IAA titers, drawn after instituting insulin therapy, were
      not significantly different between the two groups. GAD and ICA512 antibody
      results suggest a relative lack of diabetes immune markers in infants and
      toddlers with new-onset diabetes. This finding, and the apparent shorter pre
      clinical phase reflected in the lower HbA1c values, may indicate age-related
      differences in type 1 diabetes autoimmunity or the existence of non-autoimmune
      diabetogenic mechanisms in younger children.

PMID- 15016224
TI  - Insulin lispro versus regular insulin in children with type 1 diabetes on twice
      daily insulin.
AB  - OBJECTIVE: The aim of this study was to compare the clinical efficacy and safety
      of insulin lispro with regular insulin in 5- to 10-yr-old prepubertal children on
      twice daily insulin. RESEARCH DESIGN AND METHODS: Thirty-five children (16 M, 19
      F) completed an open-label randomised crossover study, with each child receiving
      insulin lispro for 3 months and regular insulin for 3 months in addition to their
      intermediate-acting insulin. Families were instructed to give regular insulin 30
      min before meals and insulin lispro immediately before meals. Glycaemic control
      was monitored by eight-point blood glucose profiles and six weekly hemoglobin
      A1cs (HbA1cs) and the frequency and severity of hypoglycaemia was documented.
      RESULTS: The endpoint HbA1c after 3 months on insulin lispro (8.33%, SD+/-0.89)
      was not significantly different to that on regular insulin (8.14%, SD+/-0.77). No
      significant differences were found in blood glucose levels before or after meals,
      2-h postprandial glucose excursions or in blood glucose levels before bed between
      the treatments. However, blood glucose levels at 3 am were significantly lower on
      regular insulin than on insulin lispro (mean difference -2.35 mmol/L (95%CI: 
      3.98, -0.72, p=0.01). There was no significant difference in the frequency of
      hypoglycaemic episodes between the groups. CONCLUSIONS: The main advantage of
      insulin lispro in children on twice daily insulin was found to be its greater
      convenience, this being achieved without a deterioration in glycaemic control.
      The higher 3 am blood glucose levels in those on insulin lispro could translate
      to reduced nocturnal hypoglycaemia in some individuals.

PMID- 15016225
TI  - Thinner needles do not influence injection pain, insulin leakage or bleeding in
      children and adolescents with type 1 diabetes.
AB  - AIMS: To investigate pain, leakage and bleeding when injecting insulin with
      different diameters of needles. METHODS: Sixty children and adolescents aged 9-21
      yrs participated in study A and 40 aged 8-20 yrs in study B. Both were double
      blind and randomized. In study A, we evaluated the pain when injecting with three
      needles [Novo 27G/13 mm (N27), B-D MicroFine IV 28G/13 mm (B28), NovoFine 28G/12
      mm (N28)] and in study B, with three needles [NovoFine 28G/12 mm (N28), B-D
      MicroFine+ 29G/13 mm (B29), NovoFine 30G/8 mm (N30)] and one placebo injection
      (no needle mounted). Abdominal and thigh injections were given in a 45 degrees
      angle with a lifted two-finger skinfold on two different visits, scoring pain on
      a 10-cm visual analog scale (VAS), and in study B faces were added to the scale.
      RESULTS: The median VAS scores in study A were 1.2 cm (N27), 1.2 cm (B28) and 1.0
      cm (N28) for abdominal injections, and 1.2 cm (N27), 0.7 cm (B28) and 1.1 cm
      (N28) (n.s.) for thigh injections. The median VAS scores in study B were 2.5 cm
      (N28), 2.3 cm (B29) and 2.8 cm (N30) (n.s.) for abdominal injections, and 2.0 cm
      (N28), 1.5 cm (B29) and 1.9 cm (N30) (n.s.) for thigh injections. The overall
      median score of placebo injections was 0.1 cm (p=0.0001). Bleedings were less
      common with the B29 needle (35.5%) than with the N28 needle (48.1%) (p=0.028) but
      with no difference compared to the N30 needle (39.2%). Leakage of insulin was
      found in 14% of abdominal and 25% of thigh injections (p=0.0001) with no
      difference between the needles. VAS scores were higher in study B which may be
      explained by the facial VAS scale increasing the range of answers. CONCLUSIONS:
      We found no difference in injection pain, preference, bleeding or insulin leakage
      between the needles. Decreasing the needle diameter from 0.4 to 0.3 mm (27-30G)
      does not seem to decrease pain perception in this age group.

PMID- 15016226
TI  - Fetal growth, adrenocortical function and the risk for type 2 diabetes.

PMID- 15016227
TI  - Lipoatrophy syndromes: when 'too little fat' is a clinical problem.

PMID- 15016228
TI  - The expanding insulin family: structural, genomic, and functional considerations.

PMID- 15016229
TI  - Basic, clinical and translational research: an essential pediatric diabetes
      partnership.

PMID- 15016230
TI  - Changes in body composition after a 12-wk aerobic exercise program in obese boys.
AB  - Previous studies have shown that vigorous aerobic training programs for obese
      children result in minimal weight changes, and concluded that they may not be
      beneficial. Weight change alone may not detect important beneficial changes in
      body composition associated with vigorous training in these children. Fifteen
      obese boys (aged 9-12 yr, body mass index (BMI) 31.8+/-6.5, average percent body
      fat (%BF) 41+/-4.2) underwent a supervised aerobic and resistance training
      program (12 wk, 2 days/wk for 30 min/session), to investigate the effects on
      weight and body composition. After the 3-month training period, weight loss
      averaged only 1.5+/-1.0 kg (not significant), but total body fat decreased by
      4.1+/-1.8 kg (p<0.05) and fat-free mass (FFM) increased by 2.6+/-1.1 kg (p<0.05)
      based on hydrostatic weighing. As a result, %BF fell by 10% (p<0.01). There was a
      5.8+/-2.8 mL/kg/min (p<0.05) increase in peak volume of oxygen uptake (VO(2)),
      along with a 248+/-120 kcal/d (p<0.05) increase in resting energy expenditure
      (REE). Activity questionnaires showed a significant increase in high intensity
      recreational activities (6.5+/-1.5 vs 3.5+/-0.5 h physical activity/wk; p<0.01)
      in the home and a significant decrease in low intensity activities (7+/-2.0 vs
      12+/-3.5 h TV viewing/wk; p<0.01). CONCLUSIONS: Vigorous supervised aerobic
      training in obese boys has beneficial effects on body composition, fitness and
      leisure time activities that are not apparent by measurement of changes in body
      weight alone.

PMID- 15016231
TI  - Defective insulin receptors in Rabson-Mendenhall syndrome cause complete
      peripheral insulin resistance but minimal hepatic insulin response remains.
AB  - In Rabson-Mendenhall syndrome, severe insulin resistance is caused by defective
      insulin receptors. The patient studied lacks insulin receptor binding due to a
      truncation mutation of one allele and a point mutation of the other allele of the
      insulin receptor alpha-subunit. He developed pulmonary hypertension and cor
      pulmonale, and was considered for organ transplantation. A trial of prednisone
      1.2 mg/kg/d was initiated to determine if he could tolerate immunosuppressive
      therapy without deterioration of his pre-existing, difficult to control diabetes
      mellitus. Insulin responsiveness was measured prior to and after 4 d of
      glucocorticoid administration ('Before GC' and 'After GC') using the
      hyperinsulinemic glucose clamp and stable isotope tracer dilution techniques.
      After a 12-h fast and 24 h of intravenous insulin, a primed continuous infusion
      of 6,6-(2)H(2)-glucose was administered during a 2-h tracer equilibration period
      followed by a 2-h insulin-deficient period, and a 2-h hyperinsulinemic glucose
      clamp period during which insulin was infused at 7 u/kg/h. Blood glucose
      concentrations during the basal periods, while no insulin was infused, were 245+/
      7 and 138+/-8 mg/dL in the studies Before GC and After GC, respectively. During
      both hyperinsulinemic glucose clamp periods, the blood glucose was 171+/-1 and
      167+/-5 mg/dL, respectively. Hepatic glucose production (HGP) was higher during
      the basal period Before GC than during the same period After GC (7.86+/-0.23 vs.
      5.31+/-0.19 mg/kg/min). HGP rate was suppressed by insulin to 1.48+/-0.45
      mg/kg/min Before GC, but was not suppressed After GC (4.19+/-0.81 mg/kg/min). The
      hyperinsulinemic glucose clamp did not increase the glucose utilization rate nor
      the glucose clearance rate over basal in either Before GC or After GC, indicating
      complete peripheral insulin resistance. In summary, the liver showed some
      response to insulin in the absence of insulin receptors but the peripheral
      tissues had no response to insulin. Glucocorticoids worsened insulin resistance
      in the liver in this patient.

PMID- 15016232
TI  - Type 1 diabetic children have abnormal lipid profiles during pubertal years.
AB  - AIM/HYPOTHESIS: To study the prevalence of hypercholesterolemia,
      hypertriglyceridemia and the relationship between metabolic control, pubertal
      status and plasma lipoprotein levels in children with diabetes mellitus. SUBJECTS
      AND METHODS: A cross-sectional study was conducted on 126 subjects with type I
      diabetes followed at our institution. There were 57 boys and 69 girls (mean age:
      13.4+/-3.4 yr; mean duration of diabetes: 7.3+/-2.1 yr), on whom fasting
      lipoprotein levels and pubertal status were determined. Mean glycated hemoglobin
      (HbA1c) of the preceding year was used in the analysis. Cholesterol (CT) and
      triglyceride (TG) levels were transformed into standard deviations (SD) using age
      dependent normal values. RESULTS: 1) CT levels of DM children (mean level: +0.9+/
      1.2 SD) are higher for both sexes and at each age. Sixteen percent of the cases
      had CT level > or =2 SD. Within the range of the HbA1c observed (9.1+/-1.2%), CT
      levels are not correlated with the degree of metabolic control. In contrast to
      non-diabetic children, CT levels of the diabetic children did not vary throughout
      pubertal stages. CT levels correlated highly with apolipoprotein B (r=0.79;
      p<0.00001 and r(2)=82%, in univariate and multivariate analysis, respectively. 2)
      Plasma TG levels are comparable in the diabetic children (mean level: -0.11+/-0.9
      SD) and non-diabetic children. Only 5% of the diabetic children have a TG level >
      or =2 SD. The TG levels are significantly, but weakly, positively correlated with
      duration of diabetes and the degree of metabolic control (r(2)=12% and 16%,
      respectively, p<0.0001 for both). CONCLUSIONS: Plasma CT levels of type I
      diabetic children are increased in comparison to non-diabetic children and do not
      follow the usual decreasing pattern during puberty.

PMID- 15016234
TI  - Molecular and biochemical analysis of the MODY syndromes.
AB  - Maturity onset diabetes of the young (MODY) is characterized by youth-onset
      diabetes that is inherited in an autosomal dominant (monogenic) pattern. Classic
      MODY accounts for less than 5% of cases of childhood diabetes in Caucasians,
      presents prior to age 25 years, is nonketotic, and may not require insulin
      treatment. A variant form of MODY that lacks a clearly defined genetic basis
      occurs in African Americans [atypical diabetes mellitus (ADM)] clinically
      presents more acutely and is initially insulin requiring. To date, five molecular
      causes of classic MODY have been identified: hepatocyte nuclear factor-4 alpha
      (HNF-4 alpha; MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF
      1 alpha; MODY3), insulin promoter factor-1 (IPF-1, MODY4), and hepatocyte nuclear
      factor-1 beta (HNF-1 beta; MODY5). MODY is studied as a model of beta cell
      hypofunction and modest insulinopenia. Clinical recognition of ADM is important
      for patient management to avoid confusion with type 1 diabetes mellitus.

PMID- 15016233
TI  - Racial variation in factors related to obesity and insulin sensitivity in
      children and youth.

PMID- 15016236
TI  - Limitations of first-phase insulin response to evaluate insulin secretion in
      children.
AB  - The first-phase insulin response (FPIR) is a widely used method to evaluate beta
      cell function during the prediabetic phase of evolving type 1 diabetes mellitus
      (DM). The aim of the present study was to evaluate the influence of clinical and
      methodological variables on FPIR in normal children and adolescents. Children and
      adolescents who were first-degree relatives of those with type 1 DM and healthy
      young adults were studied. All subjects were islet cell antibody-negative. A FPIR
      test was performed on all subjects while fasting. Insulin samples were drawn at
      0, 1, 2, 3, 4, 5, 6, 8, and 10 min after 0.3 g/kg of dextrose. FPIR(1-10) was
      calculated as the area under the FPIR curve corrected for baseline. Eighty-five
      subjects aged 4-22 yr were studied, 43 of whom were pre-pubertal, 24 pubertal,
      and 18 post-pubertal. FPIR(1-10) values were lower in the pre-pubertal group when
      compared to either the pubertal and post-pubertal groups (415 [179-965, 2SD], 756
      [256-2 223] and 684 [235-1 180] mU/L, respectively; p<0.05). Obese subjects had a
      higher FPIR than non-obese subjects (856 vs. 520 mU/L; p<0.005). Despite
      correcting for the influence of puberty and obesity, there remained considerable
      unaccounted variability in FPIR(1-10) (R=0.46). Further variables found to
      influence FPIR(1-10) were: fasting insulin level (r(2)=0.49); weight for length
      index (r(2)=0.38); peak blood glucose level (r(2)=0.38, all p<0.001); and pre
      pubertal age (r(2)=0.20, p<0.05). CONCLUSION: FPIR exhibited wide inter-subject
      variability and was influenced by a number of clinical and methodological factors
      that make interpretation more difficult without more specifically defined
      standards.

PMID- 15016237
TI  - Glutamic acid decarboxylase and IA-2 autoantibodies in type 1 diabetes: comparing
      sample substrates for autoantibody determinations.
AB  - Large-scale programs designed to assess risk for type 1 diabetes through
      serologic assessment of autoantibodies to recombinant beta-cell autoantigens are
      hampered by several limitations, including the methods for sample collection and
      assay performance, as well as the volume required for autoantibody
      determinations. The present study was designed to develop a low sample-volume,
      primary screening method for autoantibody detection of high specificity and
      sensitivity, and to determine the feasibility of dried blood spots collected on
      filter paper in serving as vehicles for such determinations. Autoantibodies to
      glutamic acid decarboxylase (GAD) and ICA512bdc (IA-2), both individually and in
      combination, were determined in persons with type 1 diabetes, healthy controls,
      or individuals with other autoimmune disorders. Autoantibody results for serum,
      plasma, and dried blood spots were compared. GAD, IA-2, and combined GAD/IA-2
      autoantibodies were concordant in their measurement from minimal volumes of
      serum, plasma, and whole blood extracted from dried filter paper. The
      autoantibody levels from the dried blood spots were, however, lower than
      corresponding serum samples, and, as currently designed, failed to detect low
      titer autoantibodies. Despite this limitation, screening for diabetes risk can be
      performed using small volumes of whole blood, serum, or plasma collected onto
      filter paper. These methodological improvements should simplify matters, reduce
      costs, and increase the efficacy of screening programs for type 1 diabetes.
      Further development of better substrates/methods for blood-specimen collection
      seems necessary to exploit the full potential of this and other autoantibody
      measurement strategies for screening large populations.

PMID- 15016238
TI  - Type 1 diabetes in offspring of parents with type 1 diabetes: the tip of an
      autoimmune iceberg?
AB  - The objective of the present study was to examine the prevalence of self-reported
      autoimmune diseases among offspring of type 1 fathers, type 1 diabetic mothers,
      and non-diabetic parents. Type 1 diabetic probands (n=265; mean age=42 yr), who
      were ascertained from the Children's Hospital of Pittsburgh Registry for 1950
      1964, recently participated in the Familial Autoimmune and Diabetes Study. Non
      diabetic probands (n=96), identified from voter registration lists and matched by
      age, race, median income, and duration of residence in the Pittsburgh area, were
      also enrolled. Offspring of type 1 diabetic probands were more likely to have a
      reported autoimmune disease (5.8% vs. 2.4%; p=0.067) than offspring of non
      diabetic probands. Half the cases in the diabetic families were disorders other
      than type 1 diabetes, (e.g., rheumatoid arthritis, Crohn's disease, etc.).
      Stratification by parental gender revealed a marginally higher risk for type 1
      diabetes among offspring of type 1 diabetic fathers compared to mothers (4.9% vs.
      3.4%; p=0.38, respectively, through age 20 yr). However, the risk for other
      autoimmune disorders was statistically significantly increased among offspring of
      type 1 diabetic mothers (0% vs. 6.2%; p=0.02, respectively, through age 20 yr).
      These data suggest that offspring of type 1 diabetic parents may be at high risk
      of developing other autoimmune disorders during childhood, with pediatric
      diabetes representing the 'tip of an autoimmune iceberg'. The observed risk
      differences by parental gender, which have also been reported for other
      autoimmune disorders, warrant further investigation.

PMID- 15016240
TI  - Fetal and childhood nutrition in type 2 diabetes in children and adults.

PMID- 15016239
TI  - Recent advances in the treatment of childhood obesity.
AB  - The rapid increase in the prevalence of obesity in the last decade indicates a
      need for effective treatment programs. We conducted a short-term, repeated
      measures, clinical-outcome trial in three groups of children and adolescents in
      two different locations. Two cohorts (n=34) were enrolled in a 36-wk multi
      disciplinary weight-management program at the Children's Hospital of New Orleans.
      One cohort (n=16) was enrolled in a similar intervention at the General Clinical
      Research Center (GCRC) at the Medical Center of Louisiana for a 10-wk summer
      weight-loss program. Subjects were offered a protein-sparing modified fast (PSMF)
      diet (600-800 kcal/d; 2 g protein/kg body weight), followed by a balanced
      hypocaloric diet, and they participated in behavior-modification sessions and a
      moderate-intensity (45-55% volume of oxygen consumed at maximal effort
      [VO(2)max]), progressive exercise program. The following parameters were examined
      at baseline, 10 wk, and 36 wk (cohort 1 only): Weight, height, percentage of
      ideal body weight (%IBW), relative body fat (%fat), fat free body (FFB) mass,
      estimated VO(2)max mL/kg min(BW) [adjusted for body weight]), blood chemistries,
      lipid profiles (total cholesterol [TC], triglycerides [TG], low-density
      lipoprotein [LDL], high-density lipoprotein [HDL], and insulin-like growth factor
      1 [IGF-1]). All three groups experienced significant decreases in weight, %IBW
      and %fat at 10 wk. The weight loss was maintained at 26 wk in cohorts 1 and 2,
      and at 36 wk in cohort 1. There were no significant decreases in height velocity
      during the study. In addition, measures of estimated VO(2)max mL/kg/min(BW) and
      IGF-1 parameters were significantly greater at 10 wk compared to baseline.
      Measures of TC, TG, and LDL were significantly lower at 10 wk, with no
      significant changes noted in HDL. We conclude that a multi-disciplinary weight
      management program, including PSMF, behavior modification, and exercise, provides
      an effective method of treatment for obesity in children and adolescents. Long
      term, randomized, and controlled clinical trials are needed to confirm the
      results of this preliminary, short-term observation.

PMID- 15016241
TI  - Cystic fibrosis-related diabetes: an approach to diagnosis and management.
AB  - Diabetes is a common complication of cystic fibrosis (CF). Because of evidence
      that it is associated with increased morbidity and mortality, prompt diagnosis
      and aggressive management of CF-related diabetes (CFRD) is important. The Cystic
      Fibrosis Foundation held a consensus conference in 1998 to define the current
      standards for the diagnosis and care of this disease [Moran A, Hardin D, Rodman D
      et al. Diagnosis, screening, and management of CFRD: a consensus conference
      report. J Diabetes Res Clin Pract 1999: 45: 61-73]. This article reviews those
      recommendations, and presents the practical approach to the management of CFRD
      used at the University of Minnesota.

PMID- 15016242
TI  - Synthesis, secretion and biological actions of the glucagon-like peptides.
AB  - Glucagon-like peptides-1 and -2 (GLP-1 and GLP-2) are co-encoded along with
      glucagon in a single mammalian proglucagon gene that is expressed in islets and
      enteroendocrine L cells of the small and large intestine. Both peptides are
      liberated following cleavage by prohormone convertase 1/3 and secreted from the
      intestine following nutrient ingestion. A key determinant of GLP-1 and GLP-2
      bioactivity is the enzyme dipeptidyl peptidase-IV, which inactivates both
      peptides by cleavage at the position-2 alanine. GLP-1 regulates blood glucose via
      actions on gastric emptying and islet hormones, including the regulation of
      insulin, glucagon, and somatostatin secretion. GLP-1 action is essential for beta
      cell function, because the disruption of GLP-1 signaling results in reduced
      insulin secretion, decreased islet cyclic adenosine monophosphate, and abnormal
      intracellular calcium oscillations. GLP-1 also decreases appetite and induces
      satiety in human subjects, and inhibits food intake in rodents following
      intracerebroventricular administration. GLP-2 does not appear to directly
      regulate blood glucose, but contributes to nutrient assimilation via trophic
      effects on the intestinal mucosa. GLP-2 also decreases apoptosis in the crypts
      and villi, reduces intestinal epithelial permeability, and promotes intestinal
      glucose transport. The actions of GLP-1 and GLP-2 in experimental models of
      diabetes or intestinal injury, respectively, suggest that GLP-1 may be useful for
      the treatment of human diabetes, whereas GLP-2 may be of therapeutic benefit in
      patients with intestinal injury and compromised nutrient assimilation.

PMID- 15016245
TI  - Social determinants and their unequal distribution: clarifying policy
      understandings.
AB  - Public health policy in older industrialized societies is being reconfigured to
      improve population health and to address inequalities in the social distribution
      of health. The concept of social determinants is central to these policies, with
      tackling the social influences on health seen as a way to reduce health
      inequalities. But the social factors promoting and undermining the health of
      individuals and populations should not be confused with the social processes
      underlying their unequal distribution. This distinction is important because,
      despite better health and improvement in health determinants, social disparities
      persist. The article argues that more emphasis on social inequalities is required
      for a determinants-oriented approach to be able to inform policies to address
      health inequalities.

PMID- 15016247
TI  - Changes in elderly disability rates and the implications for health care
      utilization and cost.
AB  - Recent research indicates declining age-adjusted chronic disability among older
      Americans, which might moderate health care costs in the coming decades. This
      study examines the trend's underlying components using data from the 1984-1999
      National Long-Term Care Surveys to better understand the reasons for the declines
      and potential implications for acute and long-term care. The reductions occurred
      primarily for activities like financial management and shopping. Assistance with
      personal care activities associated with greater frailty fell less, and
      independence with assistive devices rose. Institutional residence was stable.
      More needs to be known about the extent to which these declines reflect
      environmental improvements allowing greater independence at any level of health,
      rather than improvements in health, before concluding that the declines will mean
      lower costs.

PMID- 15016246
TI  - Addressing the "risk environment" for injection drug users: the mysterious case
      of the missing cop.
AB  - Ecological models of the determinants of health and the consequent importance of
      structural interventions have been widely accepted, but using these models in
      research and practice has been challenging. Examining the role of criminal law
      enforcement in the "risk environment" of injection drug users (IDUs) provides an
      opportunity to apply structural thinking to the health problems associated with
      drug use. This article reviews international evidence that laws and law
      enforcement practices influence IDU risk. It argues that more research is needed
      at four levels--laws; management of law enforcement agencies; knowledge,
      attitudes, beliefs, and practices of frontline officers; and attitudes and
      experiences of IDUs--and that such research can be the basis of interventions
      within law enforcement to enhance IDU health.

PMID- 15016244
TI  - Is income inequality a determinant of population health? Part 1. A systematic
      review.
AB  - This article reviews 98 aggregate and multilevel studies examining the
      associations between income inequality and health. Overall, there seems to be
      little support for the idea that income inequality is a major, generalizable
      determinant of population health differences within or between rich countries.
      Income inequality may, however, directly influence some health outcomes, such as
      homicide in some contexts. The strongest evidence for direct health effects is
      among states in the United States, but even that is somewhat mixed. Despite
      little support for a direct effect of income inequality on health per se,
      reducing income inequality by raising the incomes of the most disadvantaged will
      improve their health, help reduce health inequalities, and generally improve
      population health.

PMID- 15016248
TI  - Genetic modification of preimplantation embryos: toward adequate human research
      policies.
AB  - Citing advances in transgenic animal research and setbacks in human trials of
      somatic cell genetic interventions, some scientists and others want to begin
      planning for research involving the genetic modification of human embryos.
      Because this form of genetic modification could affect later-born children and
      their offspring, the protection of human subjects should be a priority in
      decisions about whether to proceed with such research. Yet because of gaps in
      existing federal policies, embryo modification proposals might not receive
      adequate scientific and ethical scrutiny. This article describes current policy
      shortcomings and recommends policy actions designed to ensure that the
      investigational genetic modification of embryos meets accepted standards for
      research on human subjects.

PMID- 15016250
TI  - Modulation of clinical expression of plaque-induced gingivitis. I. Background
      review and rationale.
AB  - OBJECTIVES: The purpose of this article is to provide the necessary background
      and rationale for the accompanying studies, which are ultimately aimed at
      identifying genetic and environmental factors determining gingivitis
      susceptibility. MATERIALS AND METHODS: The literature on factors reported to
      modify the clinical expression of gingivitis, i.e., factors that determine
      individual variability in gingival inflammatory response to plaque, is presented.
      RESULTS: Clinical evidence suggests that the gingival inflammatory response to
      plaque accumulation may differ substantially among individuals. However, most of
      the available studies are of small scale and not purposely designed to address
      the issue. Systemic factors implicated in modulation of the clinical expression
      of gingivitis include metabolic, genetic, environmental and other factors. The
      significance of such factors in designing and conducting a large-scale
      experimental gingivitis trial and means to account for them are discussed.
      CONCLUSION: Although several factors have been implicated, genetic or
      environmental factors underlying differences in gingivitis expression are not
      fully elucidated. The accompanying studies aim to identify and characterize,
      among participants in a specifically designed large-scale experimental gingivitis
      trial, subjects that differ significantly in their gingival inflammatory response
      to plaque. This is the first step in an effort to determine genetic or
      environmental factors underlying such differences.

PMID- 15016251
TI  - Modulation of clinical expression of plaque-induced gingivitis. II.
      Identification of "high-responder" and "low-responder" subjects.
AB  - AIM: The aims of this study were to validate a randomized, split-mouth, localized
      experimental gingivitis model and to identify subjects with different gingivitis
      susceptibility. MATERIAL AND METHODS: In each of 96 healthy subjects, one
      maxillary quadrant was randomly assigned as "test" (experimental gingivitis) and
      the contralateral quadrant as "control". Plaque index (PlI), gingival index (GI),
      gingival crevicular fluid volume (GCF), and angulated bleeding score (AngBS) were
      recorded in both quadrants at days 0, 7, 14, and 21. Cumulative plaque exposure
      (CPE), i.e. PlI over time, was calculated. Day-21 GCF was standardized according
      to CPE, and residuals of GCF on CPE were calculated. Two subpopulations were then
      defined, based on upper and lower quartiles of GCF-residual distribution and
      were, respectively, identified as "high-responder" (HR; n=24) and "low-responder"
      (LR; n=24). RESULTS: At test quadrants, all parameters significantly increased
      throughout the trial, while in control quadrants, PlI, GI, and AngBS remained
      low. Significant differences were noted between test and control quadrants on
      days 7, 14, and 21 for all parameters. Significant increases in GI, AngBS, and
      GCF were observed in test quadrants over the course of the study in both HR and
      LR groups. Significant differences were noted between HR and LR groups for all
      gingivitis parameters on day 21 in test quadrants, without any significant
      differences in PlI or CPE between the groups. CONCLUSIONS: We identified two
      subpopulations characterized by significant differences in clinical parameters of
      plaque-induced gingival inflammation, despite similar amounts of plaque deposits
      and plaque accumulation rates.

PMID- 15016252
TI  - Modulation of clinical expression of plaque-induced gingivitis. III. Response of
      "high responders" and "low responders" to therapy.
AB  - AIM: The aim of the present study was to characterize the subject-based clinical
      behavior of the gingiva in response to a tooth-cleaning regimen in two
      subpopulations, "high-responder" (HR) and "low-responder" (LR) groups, presenting
      a different inflammatory response to plaque accumulation. MATERIAL AND METHODS:
      The study population comprised of 96 systemically and periodontally healthy
      subjects, 46 males and 50 females, non-smokers, enrolled in an experimental
      gingivitis trial. At completion of the experimental gingivitis period (day 21),
      all subjects were prescribed the same 21-day treatment regimen of amine/stannous
      fluoride (AmF/SnF(2))-containing toothpaste and mouthrinse. Plaque index (PlI),
      gingival index (GI), gingival crevicular fluid volume (GCF), and angulated
      bleeding score (AngBS) were recorded on three selected teeth. Treatment efficacy
      was evaluated in the overall population as well as in HR and LR groups,
      separately. RESULTS: A statistically significant decrease of PlI was observed
      after treatment (p<0.001), with PlI reversing to baseline levels. Changes in PlI
      revealed the same trend in both HR and LR groups, without differences between
      groups. Treatment also resulted in a significant decrease of all gingivitis
      parameters (p<0.001 for all comparisons). After treatment, GI, AngBS, and GCF
      were comparable with baseline condition. However, when the two groups were
      compared, day 42-GCF was significantly higher in the HR group than the LR group.
      CONCLUSIONS: A treatment regimen based on mechanical plaque control supplemented
      with AmF/SnF(2)-containing toothpaste and mouthrinse is effective in reducing
      plaque accumulation and re-establishing healthy gingival conditions after
      experimentally induced gingivitis, even in subjects with different inflammatory
      response to plaque accumulation.

PMID- 15016254
TI  - Smoking cessation increases gingival blood flow and gingival crevicular fluid.
AB  - OBJECTIVES: The purpose of the present study was to determine the effect of
      smoking cessation on gingival blood flow (GBF) and gingival crevicular fluid
      (GCF). MATERIAL AND METHODS: Sixteen male smokers (aged 22-39 (25.3+/-4.0)
      years), with no clinical signs of periodontal and systemic diseases, were
      recruited. The experiment was performed before (baseline) and at 1, 3 and 5 days,
      and at 1, 2, 4 and 8 weeks after smoking cessation. The status of smoking and
      smoking cessation was verified by exhaled carbon monoxide (CO) concentration, and
      by serum nicotine and cotinine concentrations. A laser Doppler flowmeter was used
      to record relative blood flow continuously, on three gingival sites of the left
      maxillary central incisor (mid-labial aspect of the gingival margin and bilateral
      interdental papillae). The GCF was collected at the mesio- and disto-labial
      aspects of the left maxillary central incisor and the volume was calculated by
      the Periotron 6000(R) system. The same measurements except for the GBF were
      performed on 11 non-smoking controls (four females and seven males), aged 23-27
      (24.4+/-1.2) years. RESULTS: Eleven of 16 smokers successfully completed smoking
      cessation for 8 weeks. At 1 day after smoking cessation, there was a
      significantly lower CO concentration than at baseline (p<0.01). Also, nicotine
      and cotinine concentrations markedly decreased at the second measurement. The GBF
      rate of smokers was significantly higher at 3 days after smoking cessation
      compared to the baseline (p<0.01). While the GCF volume was significantly
      increased at 5 days after smoking cessation compared to the baseline (p<0.01), it
      was significantly lower than that of non-smokers until 2 weeks after smoking
      cessation (p<0.01). CONCLUSION: The results show that the gingival
      microcirculation recovers to normal in the early stages of smoking cessation,
      which could activate the gingival tissues metabolism/remodeling, and contribute
      to periodontal health.

PMID- 15016253
TI  - Influence of tobacco smoking on periodontal bone height. Long-term observations
      and a hypothesis.
AB  - AIM: The aim of the investigation was to estimate the magnitude of the long-term
      influence of chronic smoking on the periodontal bone height. METHODS: The study
      population included 19 continuous smokers, 28 former smokers and 44 non-smokers
      in the age range 20-60 years at baseline. The participants were examined at two
      points in time with an interval of 10 years. The height of the periodontal bone
      was determined from bite-wing radiographs of the first and second premolars of
      the maxilla and the mandible and measured from the cemento-enamel junction (CEJ)
      to the periodontal bone crest (PBC) mesially and distally to the preselected
      teeth. RESULTS: The mean (SD) CEJ-PBC distance at baseline was 1.82 (1.01) mm for
      smokers, 1.65 (0.81) mm for former smokers, and 1.16 (0.59) mm for non-smokers
      (p=0.016). The mean (SD) 10-year bone height reduction was 0.74 (0.59) mm for
      smokers as against 0.26 (0.31) mm for former smokers and 0.27 (0.29) mm for non
      smokers. Controlling for age and baseline bone height level, the magnitude of the
      reduction was significantly dependent of smoking (p=0.000). The widening gap
      between smokers and non-smokers over time suggested that the bone height
      reduction of smokers took place at an accelerated rate. CONCLUSION: On the basis
      of the observations it is hypothesized that smoking induces an acceleration of
      the periodontal bone height reduction rate and that smoking cessation results in
      a return towards non-smoker rate.

PMID- 15016255
TI  - The effect of written information on pain experience during periodontal probing.
AB  - OBJECTIVES: To study the effect of providing written information prior to
      periodontal treatment on the pain experience during periodontal probing.
      MATERIALS AND METHODS: Patients were randomly assigned to the experimental or
      control condition and had to read the accompanying information. Information was
      manipulated to enhance perceptions of control. Anticipated pain (Numerical Rating
      Scale, NRS), dental anxiety (short version of the Dental Anxiety Inventory, S
      DAI), and the Dental Control List were filled out before treatment; the McGill
      Pain Questionnaire (MPQ) and experienced pain (NRS) were filled out after
      treatment. RESULTS: No significant differences were found in anticipated or
      experienced pain. However, the experimental condition evaluated treatment as less
      negative (MPQ-evaluative scale, F(1,55)=11.56, p<0.001), and scored lower on most
      measures. Subjects experiencing a discrepancy between desire for control and felt
      control showed the highest anticipatory distress (S-DAI, F(3,53)=6.32, p<0.001;
      anticipated pain, F(3,53)=3.28, p<0.03). CONCLUSION: Providing patients with
      written information prior to periodontal probing can alter the pain experience.
      Future research will be aimed at strengthening the impact of information.

PMID- 15016256
TI  - Clinical and microbiological effects of subgingival administration of two active
      gels on persistent pockets of chronic periodontitis patients.
AB  - OBJECTIVES: The present controlled, single-blind study was performed to assess
      and compare the clinical healing and the microbiological findings following
      repeated intrasulcular applications of 1% metronidazole or 1% chlorhexidine gels
      in persistent periodontal pockets previously treated by scaling and root planing
      (SRP). MATERIAL AND METHODS: Sixty-three systemically healthy subjects, 25 males
      and 38 females (mean age 48.4+/-7.2 years), diagnosed for chronic periodontitis
      were enrolled in this study. They underwent SRP and received oral hygiene
      instructions (OHI). Three months later, at baseline, a single persistent pocket
      with a probing depth (PD) of 5-9 mm was chosen as the experimental site in each
      patient; the subjects were stratified into three matched experimental groups on
      the basis of the treatment to be performed, which consisted of the subgingival
      administration of 1% metronidazole gel (MG, n=19), 1% chlorhexidine gel (CG,
      n=20) or placebo gel (PG, n=24). The treatments consisted of four repeated
      administrations of subgingival gels, each separated by 7 days, starting at the
      baseline. Clinical assessment was performed at the baseline and at the 180-day
      follow-up, after the end of treatment. For microbiological evaluations,
      subgingival plaque was sampled from the experimental sites at baseline, prior to
      the first subgingival gel administration, and at 7, 15, 30 and 90 days after the
      end of the treatment (days 28, 36, 51 and 111 from baseline). RESULTS: Plaque
      accumulation did not change significantly in all three groups. Bleeding on
      probing and clinical attachment levels reduced in the MGs and CGs only. PD was
      significantly reduced by the same amount in all experimental groups. In the MGs
      and CGs a remarkable reduction in the frequencies of detection of several
      periodontopathic micoorganisms was recorded after the treatment. The same was not
      seen for the PGs. CONCLUSIONS: Subgingival administration of MG or CG, both at
      1%, may have a role in the management of persistent pockets during chronic
      periodontitis.

PMID- 15016257
TI  - Comparison of the pharmacokinetic profiles of two locally administered
      doxycycline gels in crevicular fluid and saliva.
AB  - BACKGROUND: Controlled-release delivery systems enable the clinician to extend
      the half-life period of locally administered antibiotics in gingival crevicular
      fluid (GCF) significantly. The aim of this split-mouth study was to compare the
      pharmacokinetic profile of two different doxycycline gels (DOXY and ATRI) for
      topical subgingival application. Pharmacokinetics of both doxycycline gels were
      analyzed in GCF and saliva. METHODS: In 10 patients suffering from severe
      periodontitis, 10 pairs of contralateral defects (pocket depth > or =5
      mm/bleeding on probing or > or =6 mm) were randomly assigned either to the first
      application of DOXY or ATRI. Fourteen days after the topical application of the
      first antibiotic gel, the application of the second gel in the contralateral
      defect took place. Clinical examinations at baseline showed no significant
      differences between sites treated with DOXY and ATRI. Samples of GCF and saliva
      were drawn baseline, 2, 5 and 24 h after application, 2, 3, 4, 7, 9 and 11 days
      after application. Separation and quantitative measurement of both doxycycline
      gels was performed with HPLC- and UV-detection at lambda=260 nm. RESULTS: In
      saliva specimens, time-dependent changes of mean doxycycline concentration were
      almost identical for both doxycycline-gels and declined from a maximum 2 h after
      application (ATRI: 6653.90+/-3096.14 microg/ml; DOXY: 5386.60+/-1542.02 microg/ml
      [arithmetic mean+/-SEM]) to zero values 9 days after application. In crevicular
      fluid specimens, sites treated with ATRI exhibited a faster decrease of mean
      doxycycline concentration (1085.30, 264.00, 273.94, and 258.00 microg/ml measured
      2, 5, 24, and 48 h after application) than sites treated with DOXY (1388.38,
      1300.40, 803.73, and 235.10 microg/ml). The faster decrease of ATRI compared with
      DOXY could not be proved to be statistically significantly different.
      CONCLUSIONS: Both doxycycline gels showed pharmacokinetics of controlled-release
      delivery systems.

PMID- 15016258
TI  - Surface wear on cervical restorations and adjacent enamel and root cementum
      caused by simulated long-term maintenance therapy.
AB  - BACKGROUND: In an in vitro study, the surface wear on cervical restorations and
      adjacent enamel and root cementum caused by different tooth-cleaning methods in
      simulated long-term therapy was investigated. METHODS: Cervical restorations of
      amalgam (Oralloy), modified composite resin (Dyract), glass-ionomer cement
      (ChemFill Superior), and composite (Tetric) were instrumented by POL (polishing),
      CUR+POL (curette and polishing), US+POL (ultrasonic device with polishing) and
      the polishing agents Cleanic and Proxyt in a computer-controlled test bench.
      Treatment time corresponding to a real-time period of 5 or 10 years. Substance
      loss from instrumented surfaces was measured with a digital gauge. A three-way
      anova was used in the statistical evaluation. RESULTS: The results showed that
      POL led to slight substance loss, which was greater using Cleanic (27 microm)
      than Proxyt (5 microm). CUR+POL produced a significantly greater substance loss
      than did US+POL, with 186 microm versus 35 microm on glass-ionomer cement,
      respectively, and 123 microm versus 18 microm, respectively, on root cementum,
      followed by composite (111 microm versus 27 microm, respectively), polyacid
      modified composite resin/compomer (89 microm versus 36 microm), amalgam (75
      microm versus 19 microm), and enamel (32 microm versus 23 microm). CONCLUSIONS:
      As opposed to the use of US+POL or POL, substance loss on cervical restorations
      and especially root cementum must be expected to result from tooth-cleaning
      during long-term maintenance treatment using CUR+POL.

PMID- 15016259
TI  - Submerged or non-submerged healing of endosseous implants to be used in the
      rehabilitation of partially dentate patients.
AB  - OBJECTIVE: To evaluate bone-level alterations that occurred at implants of the
      Astra Tech(R) System that were placed in the load carrying, posterior parts of
      the dentition using either a submerged (two-stage) or a non-submerged (one-stage)
      installation protocol. MATERIAL AND METHODS: Eighty-four patients that required
      115 fixed partial dentures (FPDs or cases) entered the prospective study. All
      subjects were assigned one patient and > or =one case numbers. For the
      randomization of cases, a custom-made program based on balanced random permuted
      blocks was utilized. The cases were assigned to two treatment groups, namely one
      stage installation procedure, non-submerged technique (group A) and two-stage
      installation procedure, submerged technique (group B). Several subjects
      contributed with cases to both groups A and B. Periodontal, endodontal and open
      caries lesions were treated prior to implant installation. All patients received
      careful oral hygiene instruction and training in self-performed plaque control
      measures. The surgical technique used for fixture installation followed the
      outline described in the manual for the Astra Tech System. The FPDs were placed 3
      months (mandible) and 6 months (maxilla) following implant installation.
      Immediately following FPD placement, a baseline examination was performed that
      included assessment of plaque, soft-tissue inflammation and bone level.
      Clinicians who were otherwise not involved in the study performed the
      radiographic measurements. Clinical and radiographical examinations were repeated
      once a year after the baseline examination. DATA ANALYSIS: The primary outcome
      variable was the change in the bone level at the implants from the time of
      placement of the bridge (FPD) to the 1- and 2-year reexaminations. Fisher's
      permutation test was used to test if differences existed between groups A and B,
      and between patients (men/women, smokers/non-smokers, age), sites
      (maxilla/mandible) and implants (length, diameter). Pitman's test was used to
      study correlations between bone shape and quality data and different radiographic
      bone-level data. RESULTS: It was demonstrated that tissue healing following
      implant installation appeared to be independent of the surgical protocol, i.e.
      whether the marginal portions of the implants during surgery were fully or only
      partly submerged under the ridge mucosa. Thus, (i) in both treatment groups the
      number of implants that failed to osseointegrate (early failures) was small
      (<2%); (ii) at the end of the recommended periods of bone healing prior to
      loading, - in both groups, maxilla=6 months and mandible=3 months - the level of
      the marginal bone was close to the coronal rim of the fixture; group A: 1.54+/
      0.92 mm, group B: 1.31+/-0.77 mm. The current study also demonstrated that
      irrespective of surgical protocol (two-stage, one-stage), implants supporting the
      FPDs exhibited only small amount of radiographic bone loss during the first year
      of function (group A: 0.02+/-038 mm, group B: 0.17+/-0.64 mm). Moreover, during
      the second year of function, the amount of additional bone loss that occurred in
      the two treatment groups was close to zero. CONCLUSION: Periimplant bone-level
      change during function seemed to be unrelated to whether initial soft- and hard
      tissue healing following implant installation had occurred under submerged or non
      submerged conditions.

PMID- 15016260
TI  - Resolution of bone defects of varying dimension and configuration in the marginal
      portion of the peri-implant bone. An experimental study in the dog.
AB  - BACKGROUND: It was demonstrated that a marginal defect of about 1 mm between the
      bone wall and the metal surface after implant installation can heal with a high
      degree of bone fill and osseointegration. OBJECTIVE: The aim of the present
      animal experiment was to study bone healing at implant sites with hard tissue
      defects of varying dimensions and configuration. MATERIAL AND METHODS: Four
      Labrador dogs were used. All mandibular premolars and first molars were
      extracted. After 3 months of healing, five experimental sites, two control (C1,
      C2) and three test (T1, T2, T3) sites, were identified. In all five sites, custom
      made implants with a sand-blasted, large-grit, acid-etched (SLA) surface and with
      an outer dimension of 3.3x10 mm, were used. In site C1, traditional implant
      installation was performed. In site C2, the marginal 5 mm of the canal, prepared
      for the implant, was widened to 5.3 mm using a step-drill. Thus, following the
      installation of the implant, a circumferential gap occurred between the bone
      tissue and the metal rod that was 5 mm deep and between 1 and 1.25 mm wide. In
      test site T1, the canal was widened to establish a marginal gap of 2-2.25 mm. In
      test sites T2 and T3, the marginal 5 mm of the canal was first widened to 5.3 mm
      (T2) or 7.3 mm (T3). The buccal bone wall opposite the defect was subsequently
      removed. Following the placement of a cover screw in sites C2, T1, T2, and T3, a
      resorbable membrane was placed over the defect. All implants were submerged.
      After 4 months of healing, block biopsies of each implant site were dissected and
      processed for ground sectioning. RESULTS: The observations disclosed that four
      wall defects of different dimensions (1-2.25 mm wide) that occurred in the
      marginal portion of the recipient sites following implant installation were
      resolved during healing. Further, at sites where the buccal bone wall during
      defect preparation was intentionally removed, healing resulted in defect
      resolution at the mesial, distal, and lingual aspects. At the buccal aspects,
      healing was incomplete but the dimension of the defect was reduced by the limited
      amounts of new bone formation extending from the lateral and apical borders of
      the defect. CONCLUSION: Wide marginal defects may during healing be filled with
      bone. In such defects a high degree of osseointegration may occur to implants
      designed with an SLA surface.

PMID- 15016261
TI  - Reproducibility and accuracy of automated probe measurements of gingiva and bone
      levels on stone casts following guided bone regeneration treatment.
AB  - OBJECTIVES: For evidence-based evaluation of guided bone regeneration (GBR),
      accurate registration of changes in gingiva and bone levels is needed. A new
      method is introduced and evaluated. METHODS: In a clinical trial with 30
      patients, alginate impressions of the surgical area including the interproximal
      gingiva and alveolar bone at the adjacent teeth were made in duplicate prior to
      and during GBR surgery, fixture installation and abutment connection. Poured in
      hard stone, the casts were used for repeated measurements of the level of the
      free gingival margin and the alveolar bone with an automated probe (Florida disc
      probe(R)), using the incisal edge as a fixed reference point. The reproducibility
      and accuracy of these measurements were evaluated by means of the Intraclass
      Correlation Coefficients and Generalizability Theory. The effect of treatment was
      evaluated by multivariate analysis of variance. RESULTS: Generalizability Theory
      indicated a high accuracy of the gingiva- and bone-level measurements: the
      Intraclass Correlation Coefficients for gingiva and bone levels were 0.99 and
      0.98, respectively. The intra-cast reproducibility was 0.09+/-0.07 mm (mean+/-SD)
      and the inter-cast reproducibility was 0.10+/-0.09 and 0.20+/-0.07 mm for gingiva
      and bone levels, respectively. Clinical applicability is demonstrated by the fact
      that manova revealed on average a small but highly significant (p=0.001) effect
      of the staged surgical intervention on the gingiva and bone levels at the
      adjacent teeth. CONCLUSION: It is concluded that the presented method makes it
      possible to evaluate reproducibly and accurately changes in gingiva and bone
      levels for GBR studies.

PMID- 15016263
TI  - Elementary school teachers' strategies to handle externalizing classroom
      behavior: a study of relations between perceived control, teacher orientation and
      strategy preferences.
AB  - Strategies for dealing with problematic student behavior are an important part of
      the teacher role. Relations between teachers' perceptions of control over
      children's classroom behavior, teacher orientation and teachers' strategy
      preferences when confronted with externalizing child behaviors were investigated.
      Eighty-six primary school teachers, 91% of all first grade teachers in one
      municipality in Sweden, completed a questionnaire. Disciplinary strategy
      preferences were measured through vignettes describing externalizing child
      behaviors, with response alternatives modeled after the Parental Discipline
      Interview (Scarr, Pinkerton & Eisenberg, 1991). Perceived control was measured
      with a subscale applied to teachers from the Parental Locus of Control Scale
      (Campis, Lyman & Prentice-Dunn, 1986). Newly constructed measures of teacher
      orientation were used. The results indicated that perceived low control over
      one's classroom situation and a custodial teacher orientation were associated
      with preferences for authoritarian strategies (firm verbal reprimands, physical
      restraint) and perceived high control and a humanistic teacher orientation were
      associated with non-authoritarian strategies (e.g. reasoning with students).
      Teachers' strategy preferences and associations between perceived control,
      teacher orientation and strategy preferences were to some extent validated in
      relations to observed teacher behavior in a subsample of the classrooms.

PMID- 15016264
TI  - Dismissing-avoidant pattern of attachment and mimicry reactions at different
      levels of information processing.
AB  - Individuals with a dismissing-avoidant pattern of attachment are assumed to
      repress anxiety-related signals, a disposition hypothesized to interfere with
      facial mimicry and emotional contagion. Further, they are assumed to have one
      internal working model associated with anxiety, operating out of awareness at
      early, automatic stages of information processing, and another positive model
      operating at later, cognitively controlled stages of processing. The main aim of
      the present investigation was to compare facial mimicry in dismissing-avoidant
      and non-dismissing subjects at different levels of information processing.
      Pictures of happy and angry faces were exposed to 61 subjects at three different
      exposure times (17, 56, and 2,350 ms) in order to elicit facial muscle reactions,
      first at automatic levels and then at a more controlled levels. Corrugator
      activity ("frowning muscles") represented negative emotions and zygomaticus
      activity ("smiling muscles") positive emotions. The dismissing-avoidant subjects
      scored significantly lower on emotional empathy than the non-dismissing subjects.
      At the automatic level the dismissing-avoidant subjects showed "normal"
      corrugator responses (negative emotions) upon exposure to angry faces. At the
      cognitively controlled level of processing (2,350 ms) a significant interaction
      effect was shown between Faces x Muscles x Attachment pattern. The dismissing
      avoidant subjects showed no corrugator response and an increased zygomaticus
      response ("smiling reaction") to the angry face, whereas the non-dismissing
      subjects reacted with a significant mimicking reaction. The dismissing-avoidant
      subjects' tendency to "smiling" in response to the angry face at the controlled
      level (2,350 ms) may be interpreted as a repression of their earlier,
      automatically evoked (56 ms) negative emotional reaction.

PMID- 15016265
TI  - Relations between enabling skills and reading comprehension: a follow-up study of
      Latvian students from first to second grade.
AB  - In order to examine the relationships among various phonological skills and
      reading comprehension, Latvian children were followed from grade 1 to grade 2 and
      were tested with a battery of phonological, word reading, and reading
      comprehension tasks. A principal component analysis of the phonological tasks
      revealed three salient factors: a phonemic awareness factor, a rapid naming
      factor, and a short-term memory factor. In order to analyze the relationship
      between various phonological skills and reading comprehension, a structural
      modeling analysis was performed. Phonemic awareness and rapid naming explained
      approximately the same amount of unique variance in reading comprehension, but
      phonemic awareness had most predictive power indirectly via word decoding. Only
      rapid naming had a significant direct impact on reading comprehension.

PMID- 15016266
TI  - Effects of age and anxiety on episodic memory: selectivity and variability.
AB  - Selective age-related differences in source memory relative to item memory, and
      individual differences in memory performance in relation to anxiety were explored
      with high- and low-anxious subjects screened from normal young and elderly
      adults. They were read false facts about the locations of well-known and unknown
      sights in a male or female voice. Intentional and incidental learning
      instructions were administered for source memory. Selective age-related deficits
      in source memory were observed under both encoding conditions. Higher level of
      anxiety was related to lower memory performance only in the old group; this
      relation was stronger in source recall. The findings suggest that the presence of
      such selectivity is unrelated to the tradeoff between item encoding and source
      encoding. Anxiety affects the variability, and mediates the selectivity of age
      effects on episodic memory.

PMID- 15016267
TI  - Mental health, life stress and social support among young Norwegian adolescents
      with immigrant and host national background.
AB  - The first aim of the study was to investigate differences in level of mental
      health, life stress and social support among adolescents with immigrant and
      domestic background. A second aim was to identify culture group and gender
      specific sources of risk and protective factors and their relation to mental
      health. Questionnaire data were collected from 633 students, aged 13, in Oslo,
      Norway. Immigrant adolescents reported higher level of psychological distress and
      lower social support than host students. Of the four gender-culture groups,
      immigrant boys reported the highest level of problems, with a 28% prevalence of
      anxiety/depression. There were no significant differences in prevalence among the
      girls. Specific patterns of relationships between life stress, support, and
      mental health were found across gender and culture. The results were discussed
      within a framework of culture differences in values and gender role expectancies,
      underscoring the importance of studying each gender/culture group separately.

PMID- 15016269
TI  - The Strategy and Attribution Questionnaire: Psychometric properties of a
      Lithuanian translation in an adolescent sample.
AB  - The present study provides a preliminary validation of the Lithuanian version of
      the Strategy and Attribution Questionnaire (SAQ, Nurmi, et al., 1995), a self
      reported measure of social and cognitive behavioral strategies. An attempt to
      validate SAQ subscales was made by correlating them with the Youth Self-Report
      (Achenbach, 1991) and school grades. This was done with a sample of 14- to 17
      year-old adolescents (N= 734). The results showed that although internal
      consistency reliabilities were good, they were lower when compared with the
      original version of SAQ. The SAQ subscales were moderately associated with
      various validity criteria, such as anxiety/depression, withdrawal, social
      problems and somatic complaints and school grades. Results also showed moderate
      correlations between similar strategic components across achievement and
      affiliative situations. The results provide preliminary evidence for concurrent
      validity of the Lithuanian version of SAQ.

PMID- 15016268
TI  - Assessing Type A behavior in children: a longitudinal exploration of the overlap
      between Type A behavior and hyperactivity.
AB  - Child Type A behavior and its relation to hyperactivity were investigated
      developmentally using a longitudinal normal sample of 91 children (46 boys and 45
      girls) between the ages of 4 and 8-9. In light of the overlap found in several
      studies between Type A behavior, as measured by the Matthews Youth Test for
      Health (MYTH) questionnaire, and hyperactivity measured by questionnaires, an
      attempt was made to measure Type A behavior as distinct from hyperactivity using
      behavioral observations. The MYTH questionnaire and behavioral observations were
      used to assess Type A behavior and questionnaire-based measures and behavioral
      observations were used to assess hyperactivity. Predictions were made regarding
      individual stability in phenomena and in measures. The results indicated
      considerable stability in the respective Type A and hyperactivity measures over
      time, and further, that behavioral observations make it possible to measure
      Global Type A behavior and Type A Competitiveness as distinct from hyperactivity,
      although the status of Type A Impatience at early ages is not yet settled. The
      MYTH and the observed Type A behavior showed differential relations to external
      criteria, such as achievement measures and problem behavior. This has
      implications for future measurement and perhaps conceptualization of Type A
      behavior in children, and thereby also for studying the developmental aspects of
      Type A behavior.

PMID- 15016270
TI  - Norwegian versions of the Living with Asthma Questionnaire (LWAQ) and Asthma
      Bother Profile (ABP), validation and comparison of two asthma groups.
AB  - The Living with Asthma Questionnaire (LWAQ) and the Asthma Bother Profile (ABP)
      were translated into Norwegian using conventional back translation procedures,
      and completed by 30 asthma outpatients and 30 asthma patients admitted to
      inpatient rehabilitation. Reliability (Cronbach's alpha and retest-reliability)
      was shown to be good for both scales. Validity was established by showing
      significantly poorer health in the rehabilitation sample, and correlations with
      state and trait anxiety. The Norwegian translations are reliable and valid
      versions of the original questionnaires.

PMID- 15016271
TI  - Psychosocial correlates of parenting stress, lack of support and lack of
      confidence/security.
AB  - The purpose of the current study was to identify important correlates of
      parenting stress, frequently conceptualized as a mediator of suboptimal family
      function, and of social support and confidence/security, often regarded as
      buffers. Potential correlates of these concepts were assessed in questionnaires
      at delivery and at one year, in a sample of 16,000 families in Sweden. Predictors
      (1) of parenting stress were parental dissatisfaction and poor child sleeping
      patterns; (2) of lack of support included lack of confidence/security, parents
      born abroad, single motherhood, and maternal health problems; and (3) of lack of
      confidence/security were lack of support and serious life events. Mothers lacking
      social support or confidence/security exhibited significantly higher stress.
      Although parenting stress is a complex phenomenon certain risk factors can be
      emphasized, such as sleep problems which appear more important than child health
      problems. These risk factors can be used both in efforts to prevent stress and in
      studies of stress effects.

PMID- 15016272
TI  - Strategies of professional assistance after traumatic deaths: empowerment or
      disempowerment?
AB  - Referring to research and theory in the field, this discussion paper addresses
      the more overarching question of current strategies for professional assistance
      to populations bereaved by traumatic death. The issues and controversies that
      have long surrounded the "medicalization" of mental health arise anew with
      respect to the medicalization and professionalization of psychosocial help for
      people who have been traumatically bereaved. Who should provide what help and
      how? To what extent should the bereaved be expected to help themselves, receive
      help and support from friends and family, or even the wider community; and to
      what extent should the bereaved be able to access appropriate professional help
      when they are in crisis? Recent studies have indicated that bereaved parents want
      to receive help from mainstream crisis psychology, and this is not always
      available. Families experiencing traumatic bereavement are not able to access
      appropriate services along the same lines as those suffering similar levels of
      somatic complaints. It is argued that the main factors contributing to this
      situation are the lack of knowledge and inadequate organization of services; the
      fact that somatic issues take priority over psychosocial difficulties and
      dysfunction, and curative services over prophylactic intervention; and
      particularly the de-medicalization ideology. By not listening to the needs of
      user groups, the de-medicalization movement disempowers rather than empowers
      users - the very opposite of the desired effect.

PMID- 15016273
TI  - After images and pain tolerance: a descriptive study on their interrelationship.
AB  - After images are based on physiological processes, they can also be treated as
      subjective phenomena with a psychological meaning. This statement also applies to
      pain. The basic working hypothesis of this study concerned the relationship
      between the two phenomena. Forty-one respondents (23 females, 18 males, age range
      20-45 years) were given the Cold Pressor Test and the Serial After Image
      Technique. The data analysis was done by means of cross-tables and an exploratory
      optimal scaling program (OVERALS). Three pain tolerance groups (low, medium,
      high) could be differentiated fairly well on the basis of the after image
      characteristics of the respondents. Pain intolerant respondents more frequently
      had small and "immature" after images, whereas highly pain tolerant respondents
      had more large and "mature" after images. The implications of these results for a
      bio-psycho-social theoretical frame of reference for pain are discussed.

PMID- 15016274
TI  - Psychological reactions in Icelandic earthquake survivors.
AB  - The aim of this study was to explore the psychological consequences of two
      earthquakes in Iceland in two probability samples of subjects--residents in the
      exposed area and a control group from an unexposed area. The sample was composed
      of 52 adults exposed to the earthquakes and 29 adults in a control group. Three
      months after the earthquakes, both groups were approached with questions from a
      survey consisting of the Harvard Trauma Questionnaire (HTQ), the Trauma Symptom
      Checklist (TSC), the Coping Styles Questionnaire (CSQ), the World Assumption
      Scale (WAS), and the Crisis Support Scale (CSS). The results revealed that 24% in
      the exposed group had Posttraumatic Stress Disorder (PTSD), and none in the
      control group had PTSD. Earthquake-related anxiety, inability to express one's
      thoughts and feelings, and emotional coping predicted 81% of the HTQ variance for
      both groups. Previous life events, low self-worth, and luck attributions,
      together with numbing and the feeling of being let down, predicted 56% of the
      symptom variance for both groups. When degree of traumatization and emotional
      coping were added to the model, another 30% of the variance could be explained.

PMID- 15016275
TI  - Adolescents with Turkish background in Norway and Sweden: a comparative study of
      their psychological adaptation.
AB  - Using a questionnaire survey, this study compared psychological adaptation (self
      esteem, life satisfaction, and mental health problems) of Turkish adolescents in
      Norway and Sweden, and examined to what extent ethnic and majority identities,
      acculturation strategies, and perceived discrimination accounted for adaptation
      among Turkish adolescents. The samples consisted of 407 Turks (111 in Norway and
      296 in Sweden) with a mean age of 15.2 years and 433 host adolescents (207 in
      Norway, 226 in Sweden) with a mean age of 15.6 years. Turks in Norway reported
      poorer psychological adaptation than Turks in Sweden. Predictors of good
      adaptation were Turkish identity and integration, whereas poor adaptation was
      related to marginalization and perceived discrimination. The results indicated
      that the poorer adaptation of Turks in Norway compared to that of Turks in Sweden
      could be due to lower degree of Turkish identity and higher degree of perceived
      discrimination.

PMID- 15016276
TI  - Preference for current mood, anticipated emotional reaction, and experienced
      emotional reaction.
AB  - Two experiments investigated how preference for emotions is related to valence
      and activation of current mood, anticipated emotional reaction, and experienced
      emotional reaction. In Experiment 1, 40 undergraduates on one occasion rated
      valence and activation of and preference for their emotional reaction to an
      aircraft noise, then on a later occasion rated valence and activation of and
      preference for their recalled or anticipated emotional reaction to the same
      aircraft noise. On both occasions they also rated valence and activation of
      current mood. In Experiment 2, another 40 undergraduates rated valence and
      activation of current mood followed by ratings of preference for and valence and
      activation of anticipated emotional reaction to descriptions of familiar emotion
      eliciting situations. The results showed that preference is related to valence
      and activation of current mood, anticipated emotional reaction, or experienced
      emotional reaction. The valence of current mood was also found to influence
      preference for anticipated and experienced emotions.

PMID- 15016277
TI  - Note on the rationality of rule-based versus exemplar-based processing in human
      judgment.
AB  - This paper reports a study of the relationship between rule- versus exemplar
      based processing and criteria for rationality of judgment. Participants made
      probability judgments in a classification task devised by S. W. Allen and L. R.
      Brooks (1991). In the exemplar condition, the miscalibration was accounted for by
      stochastic components of the judgment with a format-dependence effect, implying
      simultaneous over- and underconfidence depending on the response scale. In the
      rule condition, there was an overconfidence bias not accounted for by the
      stochastic components of judgment. In both conditions the participants were
      additive on average and reasonably transitive, but the larger stochastic
      component in the exemplar condition produced somewhat larger absolute deviations.
      The results suggest that exemplar processes are unbiased but more perturbed by
      stochastic components, while rule-based processes may be more prone to bias.

PMID- 15016278
TI  - Personality traits in leadership behavior.
AB  - Correlational analyses of the personality traits measured by the Revised NEO
      Personality Inventory (NEO PI-R; Costa & McCrae, 1992) and three leadership
      styles, that is, Change, Production, and Employee (CPE) measured by Ekvall and
      Arvonen's (1991) CPE questionnaire, were performed. The sample was 106 Norwegian
      leaders. Three common factors comprising leadership styles and personality
      domains were interpreted as "looking for new possibilities,""hard working," and
      "dealing with people." Considering personality traits as behavior tendencies in
      unspecified situational contexts and leadership styles as behavioral tendencies
      in the leadership context, and due to the self-report nature of the data, it is
      argued that the factors show consistency in self-perceptions independent of
      context. The strongest predictors of the CPE total score were Conscientiousness
      and Extraversion; Openness and Agreeableness were specific predictors of Change
      and Employee, respectively.

PMID- 15016279
TI  - Modification of performance on the Span of Apprehension Task in a group of young
      people with early onset psychosis.
AB  - The aim of the study was to examine the effect of contingent monetary
      reinforcement and enhanced instructions on Span of Apprehension (SPAN)
      performance in a group of young people with early onset psychosis. Twenty-five
      participants (mean age 16.7) received a 3- and 12-letter version of the SPAN task
      six times: baseline, three x intervention, post-test, and 10-day follow-up. No
      significant effects of time were found in the 3-letter condition, indicating a
      ceiling effect for accuracy. In the 12-letter condition detection rates improved
      significantly reaching a maximum at the third intervention (p < 0.001).
      Performance showed a temporary decline at post-test, but performance returned to
      the maximum level at the 10-day follow-up. The study suggests that SPAN
      performance can be improved in young people with early onset psychosis using
      relatively simple interventions and that performance gains are relatively
      durable.

PMID- 15016280
TI  - Interpreting the uninterpretable: The effect of self-esteem on the interpretation
      of meaningless feedback.
AB  - People often seek out and retain positive information about themselves via self
      enhancement processes. Under other circumstances, they seek out and retain self
      confirmatory information via self-verification processes. Research on both of
      these self-evaluation processes has been based heavily on domains such as social
      skills, in which people have a large database of prior information that
      presumably influences the way in which incoming self-relevant information is
      interpreted. In the present research, participants were asked to evaluate
      themselves on a set of imaginary "pseudotraits" to investigate how self-esteem
      influences the self-evaluation process when prior information is unavailable.
      Participants who had been identified through pre-testing as either high or low in
      self-esteem received false feedback on five pseudotraits (e.g., "casortic"),
      after which they evaluated the favorability of this feedback. High self-esteem
      participants tended to view their feedback as favorable, whereas low self-esteem
      participants did not.

PMID- 15016281
TI  - Child-rearing in an indigenous Sami population in Norway: a cross-cultural
      comparison of parental attitudes and expectations.
AB  - Semi-structured interviews of 76 Sami mothers and 58 Sami fathers, and 86
      Norwegian mothers and 58 Norwegian fathers of four-year olds, revealed consistent
      cross-cultural differences in parenting. ANCOVA results showed that parental
      permissiveness was higher in the Sami group. Moreover, the effect of ethnicity
      was different for boys and girls (mothers' reports). Co-sleeping and self
      regulation of food and sleep were commonly practiced in the Sami, but not in the
      Norwegian families. Sami children were more socially independent than their
      Norwegian peers. Indirect or internal types of control were used more by Sami
      parents, and they were less tolerant of child aggression, in the form of temper
      tantrums and displays of jealousy. These patterns are similar to those found in
      other indigenous cultures in the circumpolar region. The results are discussed
      with reference to the Individualism-Collectivism dimension. The study challenges
      the Individualism-Collectivism construct for apparently confounding the
      individualism common in European liberalism with the individual autonomy commonly
      encountered among hunting-gathering peoples.

PMID- 15016282
TI  - The longitudinal and concurrent role of neuroticism for partner relationships.
AB  - Neurotic characteristics of spouses have often been associated with
      dissatisfaction with the partner relationship. This article addresses the
      question whether the link between dissatisfaction with the relationship and
      neuroticism appears during the partner relationship, or whether it is present
      before the person enters the relationship. Utilizing data from a Swedish
      longitudinal project, satisfaction with the partner relationship was linked with
      neuroticism both in adolescence and in adulthood. Adolescent neuroticism was
      measured at age 15 with the High School Personality Questionnaire (HSPQ), and
      adult neuroticism was measured at age 37 with the Eysenck Personality
      Questionnaire (EPQ-I). Results showed that a lower degree of satisfaction in
      partner relationships in mid-life was linked with higher concurrent neuroticism
      scores. Opposing most of the previous studies, this association appeared for both
      men and women. Higher neuroticism in adolescence was, however, not significantly
      associated with satisfaction in partner relationships in mid-life.

PMID- 15016283
TI  - Assessment of parental sensitivity towards pre-school children born with very low
      birth weight.
AB  - The article introduces the Parental Sensitivity Assessment Scale (PSAS) and
      examines the influence of the PSAS score and other factors on the general
      cognitive level in pre-school children born with very low birth weight (VLBW).
      McCarthy general cognitive index (GCI) was obtained for 102 VLBW and 92 normal
      birth weight (NBW) control children in Denmark in the mid-1980s. The mean ages of
      the two groups were 52.4 vs. 53.1 months. Parental sensitivity was assessed using
      PSAS. There was no significant difference in the mean PSAS score between the two
      birth weight groups (p > 0.3). Birth weight group (p < 0.001) and mother's
      schooling (p= 0.026) significantly correlated with GCI in the children. The PSAS
      score was highly significantly correlated to the variance of the GCI (p < 0.001),
      which was not explained by VLBW and mother's schooling. We found no interactional
      effect between parental sensitivity and birth weight group (p > 0.5) - the
      prematurely born children were not more affected by low parental sensitivity than
      were the control children.

PMID- 15016284
TI  - The mind's nose: Effects of odor and visual imagery on odor detection.
AB  - We examined odor imagery by looking for its effects on detection of weak odors.
      Seventy-two healthy subjects performed a forced-choice odor detection task in one
      of three conditions: after being told to imagine an odor (odor imagery), after
      being told to imagine an object (visual imagery), or without having received
      imagery instructions (no-imagery control). For the two imagery conditions, the
      presented and imagined stimuli were either the same (matched) or different
      (mismatched). There was a significant difference between detection in the matched
      and mismatched conditions for odor imagery, but not for visual imagery. We
      conclude that our paradigm does measure odor imagery and that the effect of
      imagery on detection is both content- and modality-specific. Further, the
      difference between conditions was due to lower detection with mismatched odor
      imagery than without imagery, indicating that interference underlies the effect.

PMID- 15016285
TI  - True photographs and false memories.
AB  - Some trauma-memory-oriented psychotherapists advise clients to review old family
      photo albums to cue suspected "repressed" memories of childhood sexual abuse. Old
      photos might cue long-forgotten memories, but when combined with other suggestive
      influences they might also contribute to false memories. We asked 45
      undergraduates to work at remembering three school-related childhood events (two
      true events provided by parents and one pseudoevent). By random assignment, 23
      subjects were also given their school classes' group photos from the years of the
      to-be-recalled events as memory cues. As predicted, the rate of false-memory
      reports was dramatically higher in the photo condition than in the no-photo
      condition. Indeed, the rate of false-memory reports in the photo condition was
      substantially higher than the rate in any previously published study.

PMID- 15016286
TI  - Transformations in the couplings among intellectual abilities and constituent
      cognitive processes across the life span.
AB  - Two-component theories of intellectual development over the life span postulate
      that fluid abilities develop earlier during child development and decline earlier
      during aging than crystallized abilities do, and that fluid abilities support or
      constrain the acquisition and expression of crystallized abilities. Thus,
      maturation and senescence compress the structure of intelligence by imposing age
      specific constraints upon its constituent processes. Hence, the couplings among
      different intellectual abilities and cognitive processes are expected to be
      strong in childhood and old age. Findings from a population-based study of 291
      individuals aged 6 to 89 years support these predictions. Furthermore, processing
      robustness, a frequently overlooked aspect of processing, predicted fluid
      intelligence beyond processing speed in old age but not in childhood, suggesting
      that the causes of more compressed functional organization of intelligence differ
      between maturation and senescence. Research on developmental changes in
      functional brain circuitry may profit from explicitly recognizing transformations
      in the organization of intellectual abilities and their underlying cognitive
      processes across the life span.

PMID- 15016288
TI  - Attention and the processing of emotional words and names: not so special after
      all.
AB  - Previous research has suggested that a person's own name or emotionally charged
      stimuli automatically "grab" attention, potentially challenging limited-capacity
      theories of perceptual processing. In this study, subjects were shown two digits
      surrounding a word and asked to make a speeded judgment about whether the parity
      of the two digits matched. When the subject's own name was presented on a few
      scattered trials, responses were markedly slowed (replicating a previous study).
      However, in a subsequent block of trials in which half the words were the
      subject's name, the slowing did not occur. The same slowing occurred (but even
      more fleetingly) when an emotionally charged word was presented between the
      digits. When the name was embedded among multiple distractor words, it ceased to
      slow reaction times. The results suggest that perceptual analysis of high
      priority stimuli is subject to the usual capacity limitations of other stimuli,
      but when enough capacity is available for a high-priority stimulus to be
      perceived, a transient surprise reaction may interrupt ongoing processing.

PMID- 15016287
TI  - Cherry pit primes Brad Pitt: Homophone priming effects on young and older adults'
      production of proper names.
AB  - This study investigated why proper names are difficult to retrieve, especially
      for older adults. On intermixed trials, young and older adults produced a word
      for a definition or a proper name for a picture of a famous person. Prior
      production of a homophone (e.g., pit) as the response on a definition trial
      increased correct naming and reduced tip-of-the-tongue experiences for a proper
      name (e.g., Pitt) on a picture-naming trial. Among participants with no awareness
      of the homophone manipulation, older but not young adults showed these homophone
      priming effects. With a procedure that reduced awareness effects (Experiment 2),
      prior production of a homophone improved correct naming only for older adults,
      but speeded naming latency for both age groups. We suggest that representations
      of proper names are susceptible to weak connections that cause deficits in the
      transmission of excitation, impairing retrieval especially in older adults. We
      conclude that homophone production strengthens phonological connections,
      increasing the transmission of excitation.

PMID- 15016289
TI  - Paying attention to meaning.
AB  - Several paradigms show that responses to one event compromise responses to a
      second event for around 500 ms. Such effects are generally attributed to
      attentional capacity limitations associated with processing information in the
      first event. In a task in which targets could be distinguished only by their
      meaning, we varied the semantic relationship between distractors and targets
      following at different lags. Semantic relatedness alone produced a classic
      attentional blink. We conclude by discussing how attention theory might best
      accommodate these new effects.

PMID- 15016290
TI  - Unifying representations and responses: perseverative biases arise from a single
      behavioral system.
AB  - A dominant account of perseverative errors in early development contends that
      such errors reflect a failure to inhibit a prepotent response. This study
      investigated whether perseveration might also arise from a failure to inhibit a
      prepotent representation. Children watched as a toy was hidden at an A location,
      waited during a delay, and then watched the experimenter find the toy. After six
      observation-only A trials, the toy was hidden at a B location, and children were
      allowed to search for the toy. Two- and 4-year-olds' responses on the B trials
      were significantly biased toward A even though they had never overtly responded
      to this location. Thus, perseverative biases in early development can arise as a
      result of prepotent representations, demonstrating that the prepotent-response
      account is incomplete. We discuss three alternative interpretations of these
      results, including the possibility that representational and response-based
      biases reflect the operation of a single, integrated behavioral system.

PMID- 15016291
TI  - Show your pride: evidence for a discrete emotion expression.
AB  - Three experiments provide converging evidence that pride has a distinct,
      recognizable expression. Experiment 1 showed that judges can agree in identifying
      a posed expression as showing pride and can reliably distinguish pride
      expressions from expressions of related emotions such as happiness. Experiment 2
      showed that judges can identify the pride expression when the task uses an open
      ended response format that does not cue them with the label "pride." Experiment 3
      showed that the pride expression includes a small smile, with head tilted
      slightly back, visibly expanded posture, and arms raised above the head or hands
      on hips. Overall, these findings challenge the assumption that all positive
      emotions share the same expression, and suggest that pride may be added to the
      pantheon of basic emotions generally viewed as evolved responses.

PMID- 15016292
TI  - Unconscious color priming occurs at stimulus- not percept-dependent levels of
      processing.
AB  - Although past studies have shown that visual information can be processed without
      awareness, the types and levels of this processing have yet to be determined. We
      used metacontrast masking to explore unconscious priming effects of white, blue,
      and green stimuli generated on a color video display. We found that a white prime
      tends to act more like a green than a blue one. Color confusions among unmasked
      and masked primes and calibrations of the display phosphors show that physical
      rather than perceptual properties of the stimuli best explain the white prime's
      effects. We conclude that unconscious color priming in normal observers occurs at
      early wavelength-dependent levels of processing prior to later color-percept
      dependent levels.

PMID- 15016293
TI  - Women's preferences for male behavioral displays change across the menstrual
      cycle.
AB  - Women prefer both the scent of symmetrical men and masculine male faces more
      during the fertile (late follicular and ovulatory) phases of their menstrual
      cycles than during their infertile (e.g., luteal) phases. Men's behavioral
      displays in social settings may convey signals that affect women's attraction to
      men even more strongly. This study examined shifts in women's preferences for
      these behavioral displays. A sample of 237 normally ovulating women viewed 36 or
      40 videotaped men who were competing for a potential lunch date and then rated
      each man's attractiveness as a short-term and a long-term mate. As predicted,
      women's preference for men who displayed social presence and direct intrasexual
      competitiveness increased on high-fertility days relative to low-fertility days,
      but only in a short-term, not a long-term, mating context. These findings add to
      the growing literature indicating that women's mate preferences systematically
      vary across the reproductive cycle.

PMID- 15016294
TI  - The role of motivation in the age-related positivity effect in autobiographical
      memory.
AB  - This study reveals that older adults have a positivity effect in long-term
      autobiographical memory and that a positivity bias can be induced in younger
      adults by a heightened motivation to regulate current emotional well-being. Three
      hundred nuns, ages 47 to 102 years, recalled personal information originally
      reported 14 years earlier. They did so under experimental conditions that
      repeatedly primed them to focus on their current emotional states or on their
      memory accuracy, or that provided no instructional focus (control condition).
      Both older control participants and participants who were focused on emotional
      states showed a tendency to remember the past more positively than they
      originally reported in 1987. In contrast, both younger control participants and
      participants who were focused on accuracy tended to remember the past more
      negatively than originally reported.

PMID- 15016295
TI  - Using census data to test the critical-period hypothesis for second-language
      acquisition.

PMID- 15016298
TI  - Autocrine and paracrine regulation of melanocytes in human skin and in pigmentary
      disorders.
AB  - Recently melanogenic paracrine or autocrine cytokine networks have been
      discovered in vitro between melanocytes and other types of skin cells. These
      include endothelin (ET)-1, granulocyte macrophage colony stimulating factor,
      membrane-type stem cell factor (SCF) and growth-related oncogene-alpha for
      interactions between keratinocytes and melanocytes, and hepatocyte growth factor
      and soluble type SCF for interactions between fibroblasts and melanocytes. These
      networks are also associated with corresponding receptors expressed on
      melanocytes, including ET B receptor and the SCF receptor, c-KIT. Consistent with
      in vitro findings on the melanogenic paracrine or autocrine cytokine networks, we
      have found that the up- or down-regulation of such networks is intrinsically
      involved in vivo in the stimulation of melanocyte functions in several epidermal
      hyper- or hypo-pigmentary disorders. These are ET-1/ET B receptor as well as
      membrane type SCF/c-KIT for ultraviolet B-melanosis, granulocyte macrophage
      colony stimulating factor for ultraviolet A-melanosis, ET-1/ET B receptor as well
      as membrane type SCF for lentigo senilis, growth related oncogene-alpha for
      Riehl's melanosis, sphingosylphosphorylcholine for hyperpigmentation in atopic
      dermatitis, ET-1 for seborrhoeic keratosis, soluble type SCF as well as
      hepatocyte growth factor for dermatofibroma and cafe-au-lait macules, and c-KIT
      for vitiligo vulgaris. These unveiled regulatory mechanisms involved in the
      abnormal up- or down-regulated levels of lesional melanocyte function provide new
      insights into therapeutic tools utilizing blockage of responsible cytokine
      networks.

PMID- 15016299
TI  - The melanosome as a model to study organelle motility in mammals.
AB  - Melanosomes are lysosome-related organelles within which melanin pigment is
      synthesized. The molecular motors that allow these organelles to move within
      melanocytes have been the subject of intense study in several organisms. In
      mammals, melanosomes travel bi-directionally along microtubule tracks. The
      anterograde movement, i.e., towards microtubule plus-ends at the periphery, is
      accomplished by proteins of the kinesin superfamily, whereas the retrograde
      movement, i.e., towards microtubule minus-ends at the cell center, is achieved by
      dynein and dynein-associated proteins. At the periphery, melanosomes interact
      with the actin cytoskeleton via a tripartite complex formed by the small GTPase
      Rab27a, melanophilin and myosin Va, an actin-based motor. This interaction is
      essential for the maintenance of a dispersed state of the melanosomes, as shown
      by the perinuclear clustering of organelles in mutants in any of the referred
      proteins. In the retinal pigment epithelium, a similar complex formed by Rab27a,
      a melanophilin homolog called MyRIP and myosin VIIa is probably responsible for
      the tethering of melanosomes to the actin cytoskeleton. The coordination of motor
      activities is still poorly characterized, although some models have emerged in
      recent years and are discussed here. Unraveling regulatory mechanisms responsible
      for melanosome motility in pigmented cells will provide general insights into
      organelles dynamics within eukaryotic cells.

PMID- 15016300
TI  - The spleen pigment cells in some amphibia.
AB  - It was demonstrated that the spleen pigment cells of Amphibia are macrophages:
      they show an ultrastructurally distinctive morphology, are able to phagocytose
      and react positively for non-specific esterases. These pigmented macrophages
      express mRNA for tyrosinase and also they show dopa oxidase activity; therefore
      they are able to synthesize melanins, as Kupffer cells do.

PMID- 15016301
TI  - Melanogenic response of the Kupffer cells of Rana esculenta L to melanocyte
      stimulating hormone.
AB  - We have previously shown that Kupffer cells (KCs) of Rana esculenta L. possess
      melanogenic ability. The melanogenic enzyme activities in these cells are
      different from those described in skin melanocytes, and very little is known
      about their regulation by extracellular signalling molecules. In order to study
      this regulation, we analysed the effects of NDP-MSH on the levels of expression
      of the tyrosinase gene and on dopa-oxidase activity, using primary cultures of
      KCs. Incubation of the cells with NDP-MSH increases tyrosinase gene
      transcription, within the first 24 h of stimulation. To gain insight into the
      signalling mechanism involved in the cell response to the hormone, KCs in culture
      were incubated with IBMX or forskolin. These agents mimic the effects of alpha
      MSH on melanocytes by increasing the intracellular level of cAMP. The
      experimental results showed that while the hormonal treatment always activated
      the KC tyrosinase system, treatment with IBMX or forskolin never did. Therefore,
      in KCs the tyrosinase-stimulating action of NDP-MSH was not mimicked by cAMP
      elevating agents. Assays of cAMP levels in cells stimulated with NDP-MSH
      demonstrated that the hormone does not produce significant increases in
      intracellular cAMP. On the contrary, forskolin produced significant increases in
      cAMP starting from 30 min of incubation. These results suggest that tyrosinase
      induction by melanocortins in KCs is not mediated by the cAMP pathway, and
      highlight the existence of substantial differences in the hormone signal
      transduction mechanisms between amphibian KCs and melanocytes or melanoma cells.

PMID- 15016302
TI  - Interference of some tryptophan metabolites in the formation of melanin in vitro.
AB  - Melanin (eumelanin) is commonly produced in mammals starting from tyrosine and/or
      3,4-dioxyphenylalanine (DOPA) under the action of tyrosinase. 3
      Hydroxyanthranilic acid and 3-hydroxykynurenine are intermediates occurring in
      the kynurenine pathway of tryptophan catabolism. In this paper, we show that
      these substances can interfere in melanin formation in vitro when tyrosine or
      DOPA is oxidized by molecular oxygen under catalysis by tyrosinase. In
      particular, when 3-hydroxyanthranilic acid is present, a brown and apparently
      water-soluble pigment is formed, whereas the typical eumelanin granules seem to
      become more and more rare as the concentration of 3-hydroxyanthranilic acid
      increases. Also in the presence of the latter, the rate of tyrosine and/or DOPA
      consumption decreases. A very complicated (13)C-NMR spectrum indicates the high
      complexity of the reaction. This involves both the true melanin precursor(s) and
      the tryptophan metabolite, even if with peculiar mechanism and kinetics. When 3
      hydroxykynurenine is substituted for 3-hydroxyanthranilic acid the reaction leads
      to reddish pigments whereas xanthommatins (the typical oxidation products of 3
      hydroxykynurenine) are absent. A possible relationship between some dischromic
      pathologies and tryptophan metabolic disorders is suggested.

PMID- 15016303
TI  - Dct::lacZ ES cells: a novel cellular model to study melanocyte determination and
      differentiation.
AB  - Embryonic stem (ES) cells differentiate into various cell lineages in vitro. A
      procedure was previously designed to promote the differentiation of ES cells
      towards the melanocyte lineage and to obtain large and reproducible amounts of
      melanocytes. To elucidate the main events that lead to the development of
      melanocytes in vitro, we used transgenic Dct::lacZ mouse blastocysts to establish
      ES cell lines expressing the lacZ reporter gene under the control of the Dct
      promoter. Dct, a melanoblast marker, is expressed just after melanoblast
      determination in vivo. We evaluated the importance of recruitment, proliferation
      and differentiation during melanocyte ontogeny after the in vitro differentiation
      of Dct::lacZ ES cells into melanocytes. We showed that bFGF and cholera toxin
      induce precocious melanoblast determination, associated with early melanocyte
      differentiation. Edn3 induced melanoblast proliferation and long-term melanoblast
      recruitment, but not precocious determination. The lack of basic Fibroblast
      Growth Factor (bFGF) and cholera toxin can be partially compensated by Edn3.
      Thus, Dct::lacZ ES cells can be used as a model to study determination,
      proliferation and differentiation in the melanocyte lineage in vitro.

PMID- 15016304
TI  - Effects of ultraviolet light on melanocyte differentiation: studies with mouse
      neural crest cells and neural crest-derived cell lines.
AB  - To evaluate the etiologic role of ultraviolet (UV) radiation in acquired dermal
      melanocytosis (ADM), we investigated the effects of UVA and UVB irradiation on
      the development and differentiation of melanocytes in primary cultures of mouse
      neural crest cells (NCC) by counting the numbers of cells positive for KIT (the
      receptor for stem cell factor) and for the L-3,4-dihydroxyphenylalanine (DOPA)
      oxidase reaction. No significant differences were found in the number of KIT- or
      DOPA-positive cells between the UV-irradiated cultures and the non-irradiated
      cultures. We then examined the effects of UV light on KIT-positive cell lines
      derived from mouse NCC cultures. Irradiation with UVA but not with UVB inhibited
      the tyrosinase activity in a tyrosinase-positive cell line (NCCmelan5).
      Tyrosinase activity in the cells was markedly enhanced by treatment with alpha
      melanocyte-stimulating hormone (alpha-MSH), but that stimulation was inhibited by
      UVA or by UVB irradiation. Irradiation with UVA or UVB did not induce tyrosinase
      activity in a tyrosinase-negative cell line (NCCmelb4). Levels of KIT expression
      in NCCmelan5 cells and in NCCmelb4 cells were significantly decreased after UV
      irradiation. Phosphorylation levels of extracellular signal-regulated kinase 1/2
      in cells stimulated with stem cell factor were also diminished after UV
      irradiation. These results suggest that UV irradiation does not stimulate but
      rather suppresses mouse NCC. Thus if UV irradiation is a causative factor for ADM
      lesions, it would not act directly on dermal melanocytes but may act in indirect
      manners, for instance, via the overproduction of melanogenic cytokines such as
      alpha-MSH and/or endothelin-1.

PMID- 15016305
TI  - The tyrosinase gene of the i(b) albino mutant of the medaka fish carries a
      transposable element insertion in the promoter region.
AB  - The i locus of the medaka fish contains the tyrosinase gene whose product is the
      key enzyme required for melanin biosynthesis. The i(b) allele at this locus, also
      denoted as i( 5), causes oculocutaneous albinism in homozygous carriers. Its
      albino phenotype is very weak, characterized mainly by small and varying sized
      melanophores in juveniles. Cloning and sequencing analyses of the tyrosinase gene
      for the i (b) allele revealed the presence of a 4.7-kb extra DNA fragment in the
      5' untranslated region, this being Tol2, a DNA-based transposable element of the
      hobo Activator Tam3 (hAT) family which had previously been identified as a cause
      of another mutant allele i(4). Its insertion point was 85 bp upstream of the main
      transcription initiation site and 50 bp downstream of the CATGTG motif that has
      been suggested to be essential for the promoter function of the tyrosinase gene.
      The transcription level of the tyrosinase gene was decreased in i(b)/i(b) fish,
      compared with wild-type fish. The insertion is thus a likely cause of the weak
      albino phenotype. The Tol2 element transposes in a cut-and-paste fashion, and its
      excision is mostly imprecise, leaving some nucleotides and/or removing excess
      nucleotides. The i (b) mutant strain can thus be expected to serve as a source
      from which various other mutations in the promoter region can be derived.

PMID- 15016306
TI  - Characterization of melanophore morphology by fractal dimension analysis.
AB  - Fractal or focal dimension (FD) analysis is a valuable tool to identify
      physiologic stimuli at the cellular and tissue levels that allows for
      quantification of cell perimeter complexity. The FD analysis was determined on
      fluorescence images of caffeine- or epinephrine-treated (or untreated control)
      killifish Fundulus heteroclitus (Linneaus) melanophores in culture. Cell
      perimeters were indicated by rhodamine-phalloidin labeling of cortical
      microfilaments using box-counting FD analysis. Caffeine-treated melanophores
      displayed dispersed melanosomes in cells with less serrated edges and reduced FD
      and complexity. Complexity in epinephrine-treated cells was significantly higher
      than the caffeine-treated cells or in the control. Cytoarchitectural variability
      of the cell perimeter is expected because cells change shape when cued with
      agents. Epinephrine-treated melanophores demonstrated aggregated melanosomes in
      cells with more serrated edges, significantly higher FD and thus complexity.
      Melanophores not treated with caffeine or epinephrine produced variable
      distributions of melanosomes and resulted in cells with variably serrated edges
      and intermediate FD with a larger SE of the regression and greater range of
      complexity. Dispersion of melanosomes occurs with rearrangements of the
      cytoskeleton to accommodate centrifugal distribution of melanosomes throughout
      the cell and to the periphery. The loading of melanosomes onto cortical
      microfilaments may provide a less complex cell contour, with the even
      distribution of the cytoskeleton and melanosomes. Aggregation of melanosomes
      occurs with rearrangements of the cytoskeleton to accommodate centripetal
      distribution of melanosomes. The aggregation of melanosomes may contribute to
      centripetal retraction of the cytoskeleton and plasma membrane. The FD analysis
      is, therefore, a convenient method to measure contrasting morphologic changes
      within stimulated cells.

PMID- 15016307
TI  - Comparative expression of NFkappaB proteins in melanocytes of normal skin vs.
      benign intradermal naevus and human metastatic melanoma biopsies.
AB  - Nuclear factor kappa B (NFkappaB) is an essential regulator of gene transcription
      for hundreds of genes, including many critically involved in apoptosis. NFkappaB
      complexes containing cRel generally activate pro-apoptotic genes, while those
      with RelA activate anti-apoptotic genes. We have previously shown that NFkappaB
      binding by RelA is constitutively elevated in human metastatic melanoma cultures
      relative to normal melanocytes. Here we extended our investigation to
      immunohistochemical analysis of human tissue biopsies. We found that RelA
      expression is significantly elevated in melanocytes of human naevi and melanomas
      relative to normal skin, but expression of its inhibitor IkappaB-alpha is
      significantly lower in metastatic melanomas than in intradermal naevi. Antibodies
      specific for the nuclear localization signal of RelA also showed significantly
      increased staining in metastatic melanoma biopsies. Notably, in melanomas and in
      naevi, we also found that RelA is phosphorylated at serine 529, and this
      activated form accumulates in the nuclei of melanomas. This suggests that
      increased expression and phosphorylation of RelA occurs at the stage of the
      benign naevus, but IkappaB-alpha is able to sequester RelA in the cytoplasm and
      regulate RelA transcriptional transactivation. We also found that antibodies
      against cRel show a progressive increase in staining from naevi to melanoma.
      However, staining for IkappaB-epsilon, which primarily inhibits the nuclear
      localization of cRel was also progressively increased, and cRel expression was
      predominantly cytoplasmic in melanomas. These results confirm that the altered
      expression of RelA found in metastatic melanoma cells in tissue culture is
      relevant to human tumors and offer new insights into the deregulation of NFkappaB
      signaling.

PMID- 15016308
TI  - Association of HLA class I antigens and HLA class II alleles with vitiligo in a
      Turkish population.
AB  - As is the case with many other autoimmune diseases, there is an association
      between vitiligo and HLA complex. HLA subtypes vary with racial/ethnic
      background. The purpose of this study was to determine which HLA class I antigens
      and HLA class II alleles are associated with Turkish vitiligo patients. Forty-one
      patients with vitiligo and 61 healthy control subjects were typed for HLA class
      II alleles. Thirty-three out of 41 patients with vitiligo and 100 healthy
      transplant donors were typed for HLA class I antigens. HLA DNA typing was
      performed by polymerase chain reaction/sequence specific primer method for class
      II. HLA typing for class I was performed by serological method. The frequency of
      HLA DRB1*03 was 0.6340 in patients compared to 0.2950 in controls (P = 0.0014).
      The frequency of HLA DRB1*04 was found to be 0.6830 in patients compared to
      0.2950 in controls (P = 0.00026). The allele HLA DRB1*07 was present in 0.390 of
      patients compared to 0.0820 of the controls (P = 0.0004). A preventive antigen
      for the manifestation of vitiligo has not been identified in this study. Our
      findings suggest that DRB1*03, DRB1*04 and DRB1*07 alleles are genetic markers
      for general susceptibility to vitiligo in a Turkish population.

PMID- 15016309
TI  - Population differences in the frequency of the agouti signaling protein g.8818a>G
      polymorphism.
AB  - The role of agouti signaling protein (ASIP) in human pigmentation pathways is not
      definitively understood although its murine homologue regulates, in part,
      pheomelanogenesis. We have reported an association of a polymorphism in the 3'
      untranslated region of ASIP (g.8818A>G) with dark hair and eye color among a
      group of European-Americans (Am J Hum Genet 2002 March;70:770). Among 147 healthy
      control subjects, the frequency of the G-allele was 0.12. We hypothesized that
      this polymorphism would occur at different frequencies among different population
      groups. Using PCR-RFLP, we genotyped 25 East Asian, 86 African-American, and 207
      West African individuals for the ASIP g.8818A>G polymorphism. The g.8818G-allele
      was present in the West African sample at a frequency of 0.80, in the African
      American sample at a frequency of 0.62, and in the East Asian sample at 0.28. The
      difference in allele frequency among population groups was statistically
      significant (P < 0.0001). Although the effect of the g.8818A>G polymorphism upon
      ASIP function is unknown, the large difference in allele frequency between our
      West African and European-American sample populations lends support to the notion
      that this gene may be important in human pigmentation.

PMID- 15016310
TI  - On the use of regulatory regions from pigmentary genes to drive the expression of
      transgenes in mice.

PMID- 15016311
TI  - The pigmented life of a redhead.
AB  - As a redhead I have had a personal interest in red hair, freckles and sunburns
      since childhood. An observation of a formaldehyde-induced fluorescence in human
      epidermal melanocytes initiated my scientific interest in these cells. Prota and
      Nicolaus demonstrated that oxidation products of cysteinyldopas are the main
      components of pheomelanin. Our identification of 5-S-cysteinyldopa as the source
      of formaldehyde-induced fluorescence of normal and pathological melanocytes
      started a series of investigations into this amino acid, enzymatic and non
      enzymatic oxidation of catecholic compounds and the metabolism of thiols. All
      melanocytes with functioning tyrosinase produce cysteinyldopas and the levels of
      5-S-cysteinyldopa in serum and urine are related to the size and pigment forming
      activity of the melanocyte population. The determination of 5-S-cysteinyldopa in
      serum or urine is a sensitive diagnostic method in the detection of melanoma
      metastasis. Some non-specific formation of cysteinyldopa is present in the body,
      as demonstrated by 5-S-cysteinyldopa in individuals with tyrosinase-negative
      albinism.

PMID- 15016317
TI  - Molecular footprints of human lung cancer progression.
AB  - Lung cancer is the leading cause of cancer-related death in the world. To
      understand the molecular processes and pathways of, and contributing factors to
      lung cancer progression, genetic alterations in various progression stages of
      lung cancer cells have been studied, since these alterations can be regarded as
      molecular footprints representing the individual processes of multistage lung
      carcinogenesis. The results indicate that defects in both the p53 and RB/p16
      pathways are essential for the malignant transformation of lung epithelial cells.
      Several other genes, such as K-ras, PTEN and MYO18B, are genetically altered less
      frequently than p53 and RB/p16 in lung cancer cells, suggesting that alterations
      in these genes are associated with further malignant progression or unique
      phenotypes in a subset of lung cancer cells. However, it is still unclear what
      genes control the metastatic potential of lung cancer cells. Further analyses of
      molecular footprints in lung cancer cells, in particular in the cells of
      metastatic sites, will give us valuable information to fully understand the
      process of lung cancer progression, and to find novel ways of controlling it.
      Molecular footprints at the sites of p53 mutations and p16 deletions further
      indicate that DNA repair activities for G:C to T:A transversion and non
      homologous end-joining of DNA double-strand breaks play important roles in the
      accumulation of genetic alterations in lung cancer cells. Thus, identification of
      environmental as well as genetic factors inducing or suppressing the occurrence
      of such alterations would be a clue to find novel ways of lung cancer prevention.

PMID- 15016318
TI  - Rapid induction of skin and mammary tumors in human c-Ha-ras proto-oncogene
      transgenic rats by treatment with 7,12-dimethylbenz[a]anthracene followed by 12-O
      tetradecanoylphorbol 13-acetate.
AB  - We have established a transgenic rat line carrying 3 copies of the human c-Ha-ras
      proto-oncogene with its own promoter region (Jcl/SD-TgN(HrasGen)128Ncc) (Hras128
      rat), expression being detectable in almost all organs. We have already
      demonstrated that the rat is highly sensitive to mammary, esophagus and bladder
      carcinogenesis. In the present study, male and female transgenic and wild-type
      littermates were topically treated with 2.5 mg of 7,12-dimethylbenz[a]anthracene
      (DMBA) dissolved in 1.0 ml of acetone on the back skin at 50 days after birth.
      Starting 1 week thereafter, they were again topically treated with 100 nmol of 12
      O-tetradecanoylphorbol 13-acetate (TPA) dissolved in 0.5 ml of acetone 3 times
      weekly for the following 31 weeks. In males treated with DMBA and/or TPA, skin
      tumors, including both squamous cell papillomas (SCP) and carcinomas (SCC), were
      preferentially induced at the DMBA-TPA painting sites: DMBA-TPA, 15/15 (100%);
      DMBA, 6/8 (75%); TPA, 1/6 (16.7%). They were also, unexpectedly, induced on
      remote scrotal skin: DMBA-TPA, 13/15 (86.7%); DMBA, 5/8 (62.5%); TPA, 0/6 (0%).
      Lesions were thus more frequent in the DMBA-TPA group than with DMBA or TPA
      alone. In females, adenomas and adenocarcinomas of the mammary glands were
      preferentially induced: DMBA-TPA, 12/14 (85.7%); DMBA, 6/8 (75%); TPA, 3/6 (50%),
      with only a few small skin papillomas at painting sites. Incidences and numbers
      of the mammary and skin tumors were much greater in Hras128 rats than in their
      wild-type counterparts. PCR-RFLP analysis of the transgene indicated that the
      percentage of the cell populations harboring a mutation in codons 12 and/or 61
      ranged from 2% to 60% in individual tumors; skin tumors showed more mutations in
      codon 61 in the DMBA-treated groups. In contrast, no mutations were detected in
      the endogenous rat c-Ha-ras gene. These results indicate that the Hras128 rat is
      highly susceptible to DMBA-TPA skin and mammary carcinogenesis, thus providing a
      unique painting model for skin as well as mammary gland carcinogenesis, that
      would be suitable for investigating the role of transgene mutations.

PMID- 15016316
TI  - Regulation of COX-2 protein expression by Akt in endometrial cancer cells is
      mediated through NF-kappaB/IkappaB pathway.
AB  - BACKGROUND: Cyclooxygenase-2 (COX-2) has been shown to be highly expressed in a
      broad series of primary endometrial tumors and its expression may be closely
      associated with parameters of tumor aggressiveness. In human endometrial cancer,
      tumor suppressor phosphatase tensin homologue (PTEN) is frequently mutated. In
      the presence of a mutated PTEN protein, Akt phosphorylation levels increase
      leading to the activation of this survival pathway. The nuclear transcription
      factor kappaB (NF-kappaB) is a well establish regulator of genes encoding
      cytokines, cytokine receptors, and cell adhesion molecules that drive immune and
      inflammatory responses. More recently, NF-kappaB activation has been connected
      with multiple aspects of oncogenesis, including the control of apoptosis, cell
      cycle, differentiation, and cell migration. It is known that Akt may act through
      NF-kappaB pathway and that COX-2 gene has been shown to be regulated at the
      promoter level by NF-kappaB. Recently, we showed that Akt regulates COX-2 gene
      and protein expressions in phospho-Akt expressing endometrial cancer cells. The
      present study was undertaken to determine the involvement of NF-kappaB pathway
      and IkappaB (an inhibitor of NF-kappaB) in the regulation of COX-2 expression and
      to determine more precisely the downstream targets of Akt involved in this
      process. RESULTS: Three different human endometrial cancer cell lines known to
      have wild type PTEN (HEC 1-A) or a mutated inactive PTEN protein (RL 95-2 and
      Ishikawa) were used for these studies. Expression IkappaB and Phospho-IkappaB
      were evaluated by Western analysis. The presence of IkappaB phosphorylation was
      found in all cell lines studied. There was no difference between cell lines in
      term of NF-kappaB abundance. Inhibition of PI 3-K with Wortmannin and LY294002
      blocked IkappaB phosphorylation, reduced NF-kappaB nuclear activity, reduced COX
      2 expression and induced apoptosis. Transfection studies with a dominant negative
      Akt vector blocked IkappaB phosphorylation and reduced COX-2 expression. On the
      opposite, constitutively active Akt transfections resulted in the induction of
      IkappaB phosphorylation and up-regulation of COX-2. CONCLUSION: These results
      demonstrate that Akt signals through NF-kappaB/IkappaB pathway to induce COX-2
      expression in mutated PTEN endometrial cancer cells.

PMID- 15016319
TI  - Unique characteristics of rectal carcinoma cell lines derived from invasive
      carcinomas in ulcerative colitis patients.
AB  - To identify the characteristics of ulcerative colitis (UC)-associated carcinomas,
      8 lesions, high-grade dysplasias and invasive carcinomas, were implanted into
      severely combined immunodeficient (SCID) mice and/or cultured in vitro.
      Intramucosal neoplasias consisting of high-grade dysplasia showed extremely slow
      proliferation after implantation (2/3 cases) and in vitro culture failed (4
      cases). However, invasive carcinomas demonstrated rapid growth both after SCID
      mouse implantation and in vitro (4/4 cases). From two cases of invasive
      carcinomas, 6 cell lines were established, and these are the first to be
      described in the literature. In addition to variation in immunohistochemically
      determined phenotypic expression regarding alpha-fetoprotein, chromogranin A and
      estrogen receptors, the established cell lines showed varying differentiation
      (moderately or poorly differentiated adenocarcinoma, adenosquamous carcinoma and
      poorly differentiated adenocarcinoma with multinuclear giant cells and bone
      formation). The results are in contrast with findings for sporadic colorectal
      carcinomas. Although the prevalence of DNA alterations is not frequent, loss of
      heterozygosity (17p and 18q) and deletion of exons 8 to 11 in DPC-4 were revealed
      in all of 6 cell lines, suggesting relatively high genetic instability. We found
      loss or translocation of many chromosomes (#3, 5, 6, 8, 10, 11, 13, 16, 17, 18
      and 19) other than chromosomes 1, 5, 8, 11, 13, 17 and 18, which are frequently
      involved in sporadic colorectal carcinoma cell lines. Thus, the established cell
      lines may be good models of tumorigenesis and progression in the chronic
      inflammation-carcinoma sequence.

PMID- 15016320
TI  - Expression profiling to predict postoperative prognosis for estrogen receptor
      negative breast cancers by analysis of 25,344 genes on a cDNA microarray.
AB  - Estrogen receptor (ER) status is an essential determinant of clinical and
      biological behavior of human breast cancers. While ER-positive breast cancers
      respond well to adjuvant hormone therapy, ER-negative tumors are generally
      resistant. To date, no attempts have succeeded in finding molecular markers for
      classifying ER-negative breast cancers with respect to postoperative prognosis.
      To identify a set of prognostic markers for this type of cancer, we used a cDNA
      microarray consisting of 25,344 human genes to investigate expression profiles of
      ten primary breast cancers from patients who had died of breast cancer within 5
      years after surgery (5y-D) and 10 from patients who had survived disease-free for
      more than 5 years (5y-S). Sets of genes characterizing each group were identified
      by Mann-Whitney and random-permutation tests. We documented 71 genes with higher
      expression in the 5y-D group than in the 5y-S group, and 15 with higher
      expression in the 5y-S group than in the 5y-D group. Semi-quantitative RT-PCR
      experiments were carried out to confirm the results of the microarray analysis.
      We established a scoring system for predicting postoperative prognosis of ER
      negative breast cancers on the basis of aberrant gene expression. The list of
      genes reported here provides valuable information with regard to progression of
      breast cancer and is a source of possible target molecules for development of
      novel drugs to treat patients with ER-negative breast cancers.

PMID- 15016321
TI  - Phenotypic differences of proliferating fibroblasts in the stroma of lung
      adenocarcinoma and normal bronchus tissue.
AB  - Fibroblasts in tumor tissue are thought to interact with tumor cells directly
      and/or indirectly and to have important roles in tumor invasion and metastasis.
      To characterize the phenotype of proliferating fibroblasts in pulmonary
      adenocarcinoma, we established short-term fibroblast cell lines from both normal
      bronchus and adenocarcinoma tissues obtained from the same patients and compared
      the gene expression profiles. Four sets of fibroblast cell lines (eight cell
      lines in total) were used in the analysis. Total RNA was extracted from each cell
      line and hybridized with 550 cancer-related RNAs blotted on a cDNA filter array.
      Five up-regulated genes and 12 down-regulated genes (total of 17 genes) were
      detected in the fibroblast cell lines from the tumor tissues compared with those
      from normal bronchus. Using real-time quantitative RT-PCR methods, the expression
      profile of each gene was examined; five genes, one up-regulated (MLH1) and four
      down-regulated (Cox1, FGFR4, p120, and Smad3), were confirmed. Furthermore, the
      protein expression levels of the five genes in the cancerous and normal tissues
      were examined immunohistochemically, and the up-regulation of MLH1 and the down
      regulation of Cox1 in cancerous tissue were confirmed in vivo. These results
      indicate that the proliferating fibroblasts in pulmonary adenocarcinomas are
      phenotypically different from fibroblasts in normal bronchus tissues.

PMID- 15016322
TI  - Influence of hospital procedure volume on ovarian cancer survival in Japan, a
      country with low incidence of ovarian cancer.
AB  - The survival of ovarian cancer patients has been reported to be superior at
      hospitals with a high volume of operations. A population-based study was carried
      out to assess whether this is true in Japan, where the incidence rate is
      relatively low as compared with other developed countries. The Osaka Cancer
      Registry's data were used to investigate associations between hospital procedure
      volume and survival of ovarian cancer patients. Hospitals were ranked according
      to the number of operations for ovarian cancer performed per year
      (high/medium/low/very low). Survival analysis was restricted to the reported 2450
      cases who lived in Osaka Prefecture (except for Osaka City) diagnosed in 1975
      1995, or those who resided in Osaka City in 1993-1995, since active follow-up
      data on vital status 5 years after the diagnosis were available. The relative 5
      year survival for all ovarian cancer cases was 38.8%, and the survival was higher
      with greater hospital volume (22.3% / 34.2% / 46.2% / 55.0%). After adjustment
      for age, histologic type and cancer stage by the Cox regression model, patients
      receiving care in very-low-volume hospitals were seen to have a 60% higher risk
      of death than patients receiving care in high-volume hospitals (P < 0.01).
      Although some limitations existed in this study, the results indicated that
      further centralization of operative treatment in high-volume hospitals might
      improve survival of ovarian cancer patients in Japan.

PMID- 15016323
TI  - A case-control study of diet and prostate cancer in Japan: possible protective
      effect of traditional Japanese diet.
AB  - The age-adjusted incidence of prostate cancer is low in Japan, and it has been
      suggested that the traditional Japanese diet, which includes many soy products,
      plays a preventive role against prostate cancer. We performed a case-control
      study on dietary factors and prostate cancer in order to assess the hypothesis
      that the traditional Japanese diet reduces the risk of prostate cancer. Four
      geographical areas (Ibaraki, Fukuoka, Nara, and Hokkaido) of Japan were selected
      for the survey. Average daily intake of food from 5 years before the diagnosis
      was measured by means of a semi-quantitative food frequency questionnaire. We
      studied 140 cases and 140 individually age ( +/- 5 years)-matched hospital
      controls for analysis. Estimates of age-adjusted odds ratios (ORs) and linear
      trends were calculated by conditional logistic regression models with adjustment
      for cigarette smoking and total energy intake as confounding factors. Consumption
      of fish, all soybean products, tofu (bean curds), and natto (fermented soybeans)
      was associated with decreased risk. ORs of the fourth vs. first quartile and 95%
      confidence intervals (95%CIs) were 0.45 (0.20-1.02) for fish, 0.53 (0.24-1.14)
      for all soybean products, 0.47 (0.20-1.08) for tofu, and 0.25 (0.05-1.24) for
      natto. Consumption of fish and natto showed significantly decreasing linear
      trends for risk (P < 0.05). Consumption of meat was significantly associated with
      increased risk (the OR of the second vs. first quartile was 2.19, 95%CI 1.00
      4.81). Consumption of milk, fruits, all vegetables, green-yellow vegetables, and
      tomatoes showed no association. Our results provide support to the hypothesis
      that the traditional Japanese diet, which is rich in soybean products and fish,
      might be protective against prostate cancer.

PMID- 15016324
TI  - A prospective study on the possible association between having children and colon
      cancer risk: findings from the JACC Study.
AB  - If having children is regarded as an exposure in life, its effect on a host could
      be considered as being due to female sex hormones associated with pregnancy in
      women and some lifestyle factors associated with large families in both men and
      women. To explore the roles of having children in the etiology of colon cancer,
      we examined 36,629 women and 24,877 men aged 40-79 years who completed a
      questionnaire on the number of children and other lifestyle factors from 1988 to
      1990 in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk.
      During 291,080 and 200,648 person-years of follow-up, we documented 198 female
      and 202 male incident colon cancers, respectively. After adjusting for some
      factors known or suspected to modify the risk of colon cancer, compared with the
      women with no children, the multivariate-adjusted relative risks of colon cancer
      were 0.74 (95% confidence interval [CI]: 0.30-1.84) for one child, 1.00 (95% CI:
      0.46-2.20) for two, 0.70 (95% CI: 0.31-1.55) for three, and 0.59 (95% CI: 0.26
      1.33) for four or more. The risk of colon cancer showed a significantly monotonic
      decrease with increasing number of children (P value for trend = 0.047). There
      was no association between the number of children and colon cancer risk among
      men. From these prospective data, having children may reduce risk of colon cancer
      among women, but not among men, suggesting that modifications of hormone profiles
      secondary to pregnancies may influence female colon cancer risk.

PMID- 15016325
TI  - Tumor-derived heat shock protein 70-pulsed dendritic cells elicit tumor-specific
      cytotoxic T lymphocytes (CTLs) and tumor immunity.
AB  - Vaccination with autologous tumor-derived heat shock proteins (Hsp), such as
      Hsp70, Hsp90 and gp96, has been demonstrated to elicit specific immune responses
      against the tumor from which the Hsps were isolated. The effect of Hsp
      immunization is wholly dependent on the presence of functional antigen-presenting
      cells (APCs) in the immunized host, and Hsp receptors on APCs have recently been
      identified. Here we show that bone marrow-derived dendritic cells (DCs) are able
      to internalize HSP-peptide complex and that peptides are re-presented by DCs via
      the major histocompatibility complex (MHC) class I presentation pathway. In
      addition, immunization with tumor-derived HSP-pulsed DCs induces strong cytotoxic
      T cell (CTL) responses against multiple antigenic peptides in a transporter
      associated antigen processing (TAP)-dependent manner. The results of the present
      study provide strong evidence of an efficient cross-priming activity of Hsp70,
      which could be exploited in the development of new and more effective
      immunotherapeutic strategies for cancer patients.

PMID- 15016326
TI  - Analysis of CD8 T-cell response by IFNgamma ELISPOT and H-2L(d)/pRL1a tetramer
      assays in pRL1a multiple antigen peptide-immunized and RL male 1-bearing BALB/c
      and (BALB/c x C57BL/6) F(1) mice.
AB  - We previously identified an H-2L(d)-binding peptide pRL1a (IPGLPLSL) on RL male 1
      that is predominantly recognized by cytotoxic T-lymphocytes (CTLs). MAP is a
      multibranched lysine core with antigenic peptides. Immunization of BALB/c mice
      with pRL1a MAP effectively induced pRL1a CTLs. Here, we demonstrate the presence
      of pRL1a-recognizing CD8(+) T-cells in pRL1a MAP-immunized and RL male 1-bearing
      BALB/c and (BALB/c x C57BL/6)F(1) mice by using IFNgamma ELISPOT and H
      2L(d)/pRL1a tetramer assays. A few IFNgamma ELISPOTs and no tetramer-positive
      cells were detected ex vivo in spleen cells from BALB/c mice immunized with pRL1a
      MAP. After a single in vitro stimulation with RL male 1, 432 and 741 IFNgamma
      ELISPOTs/10(5) cells were detected and tetramer-positive CD8(+) T-cells occurred
      at relative frequencies of 5.7% and 30.8% in splenic CD8(+) T-cells from mice
      that had been doubly and triply immunized, respectively, against pRL1a MAP.
      Tetramer-positive cells displayed two distinct cell populations, CD62L(low) and
      CD62L(high). Secondary in vitro stimulation expanded CD62L(high) cells more
      efficiently than CD62L(low) cells. Furthermore, a higher frequency of IFNgamma
      producing and tetramer-positive CD8(+) T-cells was detected ex vivo in RL male 1
      bearing semi-allogeneic (BALB/c x C57BL/6)F(1) than in BALB/c mice on day 14
      after tumor inoculation.

PMID- 15016327
TI  - Expression of RCAS1 in human gastric carcinoma: a potential mechanism of immune
      escape.
AB  - RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) inhibits the in
      vitro growth of receptor-expressing cells and induces apoptosis, which may
      contribute to the ability of tumor cells to evade host immune surveillance. In
      this study, we investigated RCAS1 expression in gastric cancer and precancerous
      lesions by immunohistochemical means. We then analyzed the relationship between
      RCAS1 expression and clinicopathological variables, and examined whether RCAS1
      expression is associated with infiltration of tumor-infiltrating lymphocytes
      (TILs) and apoptosis of TILs. Of 54 gastric cancers analyzed, RCAS1 expression
      was positive in 52 (96%) of them. The expression pattern of RCAS1 in gastric
      cancer cells could be classified as granular staining either enriched in the
      glandular side of the cytoplasm with polarity (P pattern) or scattered diffusely
      in the cytoplasm and on the cell membranes (D pattern). Nineteen of 39 intestinal
      type carcinomas (49%) showed the P pattern, and all of 13 diffuse type carcinomas
      (100%) showed the D pattern. In contrast, all RCAS1-positive specimens of gastric
      adenoma and metaplastic mucosa were of the P pattern. The D pattern of gastric
      cancers was more frequently recognized in carcinomas with large size (P < 0.01),
      in those with regional lymph node metastasis (P < 0.05) and in those that had
      invaded beyond the submucosa (P < 0.01), compared with the P pattern. On the same
      sections, significantly less TILs were identified in RCAS1-positive areas than
      RCAS1-negative areas. Furthermore, the rate of apoptosis of TILs was
      significantly higher in RCAS1-positive areas than in RCAS1-negative areas. The
      expression and distribution of RCAS1 may be involved in malignant transformation,
      tumor progression, histological type and tumor escape from host immune
      surveillance in gastric cancer.

PMID- 15016329
TI  - Dephosphorylation of Bcl-2 by protein phosphatase 2A results in apoptosis
      resistance.
AB  - The anti-apoptotic protein, Bcl-2 was phosphorylated at the Ser-87 residue in
      normal human blood cells, while it was not phosphorylated in tumor cells. We
      identified protein phosphatase 2A (PP2A) as a Bcl-2-associated phosphatase that
      is responsible for dephosphorylation of Bcl-2 in tumor cell lines. Treatment of
      the tumor cells with a PP2A inhibitor resulted in the appearance of Bcl-2
      phosphorylation at Ser-87. This observation suggests that Bcl-2 is constitutively
      phosphorylated, but is immediately dephosphorylated by PP2A in tumors.
      Phosphorylation of Bcl-2 protein at the Ser-87 residue resulted in a reduction in
      anti-apoptotic function in human tumor cell lines. Thus, not only the expression
      level, but also the dephosphorylation status may have important implications for
      the oncogenic activity of Bcl-2.

PMID- 15016328
TI  - Proteasome inhibitor PS-341 down-regulates prostate-specific antigen (PSA) and
      induces growth arrest and apoptosis of androgen-dependent human prostate cancer
      LNCaP cells.
AB  - Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple
      myeloma (MM) cells via inactivation of nuclear factor kappaB (NF-kappaB) in
      vitro. In addition, recent clinical studies of PS-341 have demonstrated some
      objective responses in individuals with relapsed, refractory MM. However, the
      activity of PS-341 against non-hematological malignancies remains to be fully
      elucidated. In this study, we found that PS-341 induced growth arrest and
      apoptosis of androgen-dependent human prostate cancer LNCaP cells in conjunction
      with markedly up-regulated levels of p21(waf1) and p53. In addition, we found
      that PS-341 down-regulated both 5alpha-dihydrotestosterone (DHT)- and interleukin
      6 (IL-6)-induced expression of prostate-specific antigen (PSA) as measured by
      western blot analysis. PS-341 down-regulated basal levels of the androgen
      receptor (AR) in the nucleus; however, it did not affect DHT-induced nuclear
      translocation of AR in these cells. Reporter assays using a series of promoters
      of the PSA gene showed that down-regulation of PSA by PS-341 was caused by
      inhibition of the transcriptional activity of the androgen receptor response
      element (ARE) in these cells. Taken together, the results indicate that PS-341
      induced growth arrest and apoptosis of LNCaP cells by blockade of the AR
      signaling pathway. The proteasome may be a molecular target for treatment of a
      variety of cancers including prostate cancer.

PMID- 15016330
TI  - Ninth Japanese-German Workshop on Molecular and Cellular Aspects of
      Carcinogenesis, Essen, Germany, 18-20 September, 2003.
AB  - The Japanese-German Workshops "Molecular and Cellular Aspects of Carcinogenesis,"
      held biennially since 1987, have been organized traditionally at the University
      of Essen Medical School and West German Cancer Center Essen in Germany. This 9th
      Workshop was held on September 18-20, 2003. It was generously supported by the
      Cancer Research Program of the Ministry of Education, Culture, Sports, Science
      and Technology and the International Cooperation Program for the 2nd Term
      Comprehensive 10-Year Strategy for Cancer Control of the Ministry of Health,
      Labour and Welfare on the Japanese side, and by the Deutsche
      Forschungsgemeinschaft (DFG) on the German side. Additional support from many
      other sponsors in Germany and Japan is gratefully acknowledged. The Workshop
      participants are listed at the end of this Report.

PMID- 15016331
TI  - 2004 Contraception Guidelines.

PMID- 15016332
TI  - Joint policy statement: Cervical cancer prevention in low-resource settings.

PMID- 15016333
TI  - Health sciences research and Aboriginal communities: pathway or pitfall?
AB  - OBJECTIVE: To provide health researchers and clinicians with background
      information and examples regarding Aboriginal health research challenges, in an
      effort to promote effective collaborative research with Aboriginal communities.
      METHODS: An interdisciplinary team of experienced Aboriginal-health researchers
      conducted a thematic analysis of their planning meetings regarding a community
      based Aboriginal health research training project and of the text generated by
      the meetings and supplemented the analysis with a literature review. RESULTS:
      Four research challenges are identified and addressed: (1) contrasting frameworks
      of Western science and indigenous knowledge systems; (2) the impact of historic
      colonialist processes upon the interface between health science research and
      Aboriginal communities; (3) culturally relevant frameworks and processes for
      knowledge generation and knowledge transfer; and (4) Aboriginal leadership,
      governance, and participation. CONCLUSION: Culturally appropriate and community
      controlled collaborative research can result in improved health outcomes in
      Aboriginal communities and contribute new insights and perspectives to the fields
      of public health and medicine in general.

PMID- 15016334
TI  - SOGC clinical practice guidelines: Canadian contraception consensus.
AB  - OBJECTIVE: To provide guidelines for health-care providers on the use of
      contraceptive methods to prevent pregnancy and sexually transmitted diseases.
      OUTCOMES: Overall efficacy of cited contraceptive methods, assessing reduction in
      pregnancy rate, risk of infection, safety, ease of use, and side effects; the
      effect of cited contraceptive methods on sexual health and general well-being;
      and the cost and availability of cited contraceptive methods in Canada. EVIDENCE:
      Medline and the Cochrane Database were searched for articles in English on
      subjects related to contraception, sexuality, and sexual health from January 1988
      to March 2003, in order to update the Report of the Consensus Committee on
      Contraception published in May-July 1998. Relevant Canadian Government
      publications and position papers from appropriate health and family planning
      organizations were also reviewed. VALUES: The quality of the evidence is rated
      using the criteria described in the Report of the Canadian Task Force on the
      Periodic Health Examination. Recommendations for practice are ranked according to
      the method described in this Report.

PMID- 15016339
TI  - New directions in classification and outcome assessment in ankylosing
      spondylitis.
AB  - In 2003, several manuscripts on the classification of patients as having
      ankylosing spondylitis and the further development of outcome assessment tools
      have been published. It is obvious that the use of radiographic sacroiliitis is a
      problematic part of the classification criteria because there is major
      interobserver variation and is one of the causes of a long delay between onset of
      symptoms and diagnosis. Especially in patients without human leukocyte antigen
      B27, the diagnostic delay is long. Existing outcome tools, such as the Bath
      Ankylosing Spondylitis Disease Activity Index, have been adapted and validated
      for use in other languages. New instruments to assess quality of life (Ankylosing
      Spondylitis Quality of Life Index; Patient Generated Index) and physical
      functioning (World Health Organization Disability Assessment Schedule II) have
      been developed and validated for the use in ankylosing spondylitis. In addition,
      a new and feasible tool to assess enthesitis has been constructed and validated.
      Because fatigue is an important symptom for patients with ankylosing spondylitis,
      a recommendation to use a specific fatigue instrument was created. The
      statistically derived Assessment in Ankylosing Spondylitis response criteria have
      been compared with expert opinion and are strict criteria. Responders as defined
      by the Assessment in Ankylosing Spondylitis response criteria also are considered
      by the experts as responders.

PMID- 15016335
TI  - Complement as a source of biomarkers in systemic lupus erythematosus: past,
      present, and future.

PMID- 15016340
TI  - Imaging in spondyloarthropathies.
AB  - Seronegative spondyloarthropathies comprise a group of inflammatory arthritides,
      which consists of ankylosing spondylitis, psoriatic arthritis, reactive arthritis
      (Reiter's syndrome), enteropathic arthritis, and undifferentiated
      spondyloarthropathy. All of them share common laboratory, clinical, and imaging
      findings, with characteristic involvement of the sacroiliac joints, spine, and,
      to various degrees, peripheral joints. For many years, conventional radiography
      was the mainstay for definitive diagnosis of sacroiliitis and for follow-up of
      the anatomic changes in the spine, peripheral joints, and entheses. Conventional
      radiographs remain the imaging investigation of choice; however, they are unable
      to detect early inflammatory changes of sacroiliitis, which are important for
      establishing a diagnosis without delay. Other imaging modalities, such as
      computed tomography, bone scintigraphy, magnetic resonance imaging, and
      ultrasonography have improved the capabilities of detecting early disease and
      became useful adjuncts to plain films. In addition, they also have enabled more
      accurate detection of pathology at various anatomic sites of the musculoskeletal
      system predominantly involved in spondyloarthropathies. This article will review
      and highlight the role of each of these modalities in the assessment of the axial
      and peripheral skeleton in seronegative spondyloarthropathies.

PMID- 15016341
TI  - Disease mechanisms in reactive arthritis.
AB  - Reactive arthritis (ReA) occurs after a preceding bacterial infection of the
      urogenital or gastroenteral tract. The bacteria triggering ReA persist in vivo
      and seem to be responsible for triggering an immune response. A cytokine
      imbalance with a relative lack of T-helper 1 cytokines may play an important role
      allowing these bacteria to survive. This seems to be relevant for manifestation
      and chronicity of the arthritis. For the chronic cases and cases evolving into
      ankylosing spondylitis, the interaction between bacteria and human leukocyte
      antigen B27 plays an additional crucial role. Among others, the arthritogenic
      peptide hypothesis is one way to explain this association. Human leukocyte
      antigen B27-restricted peptides from Yersinia and Chlamydia, which are
      stimulatory for CD8+ T cells derived from patients with ReA, have been
      identified. The exact role of such peptides for the pathogenesis of ReA and other
      spondyloarthritides still has to be defined.

PMID- 15016342
TI  - The genetic basis of spondyloarthritis.
AB  - Spondyloarthritis tends to cluster in families and, to a great extent, is
      associated with human leukocyte antigen (HLA) B27. In fact, the population
      frequency of spondyloarthritis in most groups is proportional to that of HLA-B27.
      But the frequency of HLA-B27 in the population-at-large far exceeds that of
      spondyloarthritis, suggesting other genetic factors also are operative. Other
      major histocompatibility complex genes have been implicated, especially HLA-DR,
      though linkage to HLA-B27 confounds the analysis of this in many studies. Genome
      wide scans have implicated regions on chromosomes 2q, 6p, 6q, 10q, 11q, 16q, 17q,
      and 19q in ankylosing spondylitis, on 4, 6p, and 17q in psoriasis, and on 7q and
      16q in inflammatory bowel disease. The search for non-major histocompatibility
      complex candidate genes has been complicated by inadequate power, because of the
      small effect they exert on overall disease susceptibility, although recent
      studies are revealing promising candidates that must be confirmed by other
      groups.

PMID- 15016343
TI  - Scleroderma renal crisis: new insights and developments.
AB  - Scleroderma renal crisis (SRC) was once a uniformly fatal complication of
      systemic sclerosis (SSc). With the introduction of angiotensin-converting enzyme
      inhibitors as treatment, outcomes have improved significantly, though 39% to 50%
      of SSc patients who develop SRC continue to have poor outcomes, including
      permanent dialysis and death. Early recognition and treatment with angiotensin
      converting enzyme inhibitors are important in the effective management of SRC,
      though given the continuing morbidity and mortality caused by SRC, they are
      clearly not sufficient. Newer therapies based on the pathophysiologic mechanisms
      underlying the development and perpetuation of SRC are needed. This article
      reviews the epidemiology, pathogenesis, risk factors, clinical features, and
      treatment of SRC, with an emphasis on recent insights and developments.

PMID- 15016344
TI  - The heart in systemic sclerosis.
AB  - The heart is one of the major organs involved in scleroderma. Cardiac involvement
      can be manifested by myocardial disease, conduction system abnormalities,
      arrhythmias, or pericardial disease. Additionally, scleroderma renal crisis and
      pulmonary hypertension lead to significant cardiac dysfunction secondary to
      damage in the kidney and lung. This report summarizes the recent advances to
      further understand the types and mechanism of abnormalities in the heart in
      scleroderma. New cardiac technology shows significant frequencies of asymptomatic
      cardiac abnormalities. Further long-term studies are necessary to determine the
      outcome and the best approach to treatment of such abnormalities. Diastolic
      dysfunction has been carefully evaluated in scleroderma in recent years and
      appears to be more common than once realized. There is controversy as to whether
      this is a significant finding independent to other cardiopulmonary problems. More
      extensive evaluation of the conduction and the arrhythmia ablative therapy has
      helped manage these life-threatening complications.

PMID- 15016345
TI  - The pathogenesis of fibrosis and renal disease in scleroderma: recent insights
      from glomerulosclerosis.
AB  - Acute and chronic renal diseases remain common complications of systemic
      sclerosis. Although treatment for acute scleroderma renal crisis may arrest the
      rapid progression of renal disease, many patients develop persistent renal
      dysfunction. Based on recent insights gained from progressive renal diseases of
      diverse etiologies, novel approaches to understanding the pathobiology of
      scleroderma renal disease may be applicable. Key factors involved in progression
      of renal disease include accumulation of extracellular matrix in the glomerular
      and tubulointerstitial compartments, epithelial to mesenchymal transformation,
      and vascular changes. The relevant factors mediating these events include the
      renin-angiotensin system, the profibrotic growth factors, transforming growth
      factor-beta and connective tissue growth factor, and reactive oxygen species.
      Much of the molecular details of the role of these factors have been revealed and
      promise to alter the practice of therapy of progressive renal disease.

PMID- 15016346
TI  - Vascular injury in systemic sclerosis: angiotensin-converting enzyme
      insertion/deletion polymorphism.
AB  - The microvascular involvement in systemic sclerosis (SSc) is characterized by
      endothelial damage and smooth muscle cell migration in the intima. The vascular
      pathologic modifications in SSc are strikingly similar to those of
      atherosclerosis. SSc also is characterized by an accelerated macrovascular
      disease. The gene encoding for angiotensin-converting enzyme (ACE) is a 21-kb, 26
      exon gene, localized on chromosome 17 (17q23). Polymorphic sites are an
      insertion/deletion (I/D) that consists of three genotypes: DD and II homozygotes,
      and ID heterozygote. ACE gene polymorphisms have been linked to vascular
      disorders (coronary artery disease, hypertension, cerebrovascular disease,
      hypertrophic cardiomyopathy, and diabetic or nondiabetic nephropathy). In
      particular, the possession of ACE D allele was associated with an increased risk
      of developing malignant vascular injury. ACE D allele frequency of the I/D
      polymorphism was associated with an increased risk of SSc, suggesting a genetic
      contribution to the disease. The discrepancy between the high prevalence of D
      allele and reduced ACE plasma levels in SSc demonstrate the lack of knowledge on
      the regulation and function of renin-angiotensin system in SSc.

PMID- 15016347
TI  - Antibodies in scleroderma: direct pathogenicity and phenotypic associations.
AB  - Scleroderma is an autoimmune disease involving endothelial cell damage and
      fibroblast overproduction of extracellular matrix. Several autoantibodies present
      in the sera of patients with scleroderma, including anti-endothelial cell,
      antifibroblast, anti-matrix metalloproteinase, and antifibrillin-1 antibodies,
      may directly contribute to disease pathogenesis. Scleroderma also is
      characterized by the presence of antinuclear and antinucleolar antibodies, which
      correlate with particular phenotypes. These include antitopoisomerase-I,
      anticentromere, antihistone, anti-polymyositis/scleroderma, anti-Th/To, anti-U3
      small nucleolar ribonucleoprotein particle, anti-U1-small nuclear
      ribonucleoprotein particle, anti-RNA polymerase, and anti-B23 antibodies. Other
      antibodies classically associated with other autoimmune diseases, such as
      antiphospholipid, antineutrophil cytoplasmic, and antimitochondrial antibodies,
      also have been described in patients with scleroderma. This review will summarize
      the various autoantibodies associated with scleroderma, their putative pathogenic
      roles, and their phenotypic correlations.

PMID- 15016349
TI  - Targeting the end; the structure of the Ku80 C-terminal domain.

PMID- 15016348
TI  - Antifibrotic therapy in scleroderma: extracellular or intracellular targeting of
      activated fibroblasts?
AB  - Therapeutic anticytokine approaches have revolutionized the treatment of chronic
      inflammatory diseases, and targeting of transforming growth factor-beta (TGF
      beta), a key factor in the pathogenesis of fibrosis, is undergoing evaluation for
      scleroderma. Several considerations dictate a cautious approach to anti-TGF-beta
      interventions. These include the possibility of multiple cytokines having
      overlapping roles in the pathogenesis of fibrosis and concerns that, in light of
      its numerous homeostatic functions, blocking TGF-beta may have serious adverse
      consequences. Furthermore, as autonomously activated cells, scleroderma
      fibroblasts may be unresponsive to blockade of TGF-beta signaling. This article
      reviews the experimental evidence underlying these concerns, and indicates
      rational approaches to addressing and overcoming them.

PMID- 15016350
TI  - Dissecting the structure of LcrV from Yersinia pestis, a truly unique virulence
      protein.

PMID- 15016351
TI  - Cofactors in fatty acid biosynthesis-active site organizers and drug targets.

PMID- 15016352
TI  - Coenzyme binding in F420-dependent secondary alcohol dehydrogenase, a member of
      the bacterial luciferase family.
AB  - F(420)-dependent secondary alcohol dehydrogenase (Adf) from methanogenic archaea
      is a member of the growing bacterial luciferase family which are all TIM barrel
      enzymes, most of which with an unusual nonprolyl cis peptide bond. We report here
      on the crystal structure of Adf from Methanoculleus thermophilicus at 1.8 A
      resolution in complex with a F(420)-acetone adduct. The knowledge of the F(420)
      binding mode in Adf provides the molecular basis for modeling F(420) and FMN into
      the other enzymes of the family. A nonprolyl cis peptide bond was identified as
      an essential part of a bulge that serves as backstop at the Re-face of F(420) to
      keep it in a bent conformation. The acetone moiety of the F(420)-acetone adduct
      is positioned at the Si-face of F(420) deeply buried inside the protein.
      Isopropanol can be reliably modeled and a hydrogen transfer mechanism postulated.
      His39 and Glu108 can be identified as key players for binding of the acetone or
      isopropanol oxygens and for catalysis.

PMID- 15016353
TI  - Crystal structure of the A domain from complement factor B reveals an integrin
      like open conformation.
AB  - Complement factor B is a 90 kDa protein consisting of three domains: a three
      module complement control protein, a von Willebrand factor A domain, and a C
      terminal serine protease (SP) domain that adopts a default inactive (zymogen)
      conformation. The interaction between factor B and pathogen-bound C3b is mediated
      by its A domain, triggering a conformational change in factor B that ultimately
      creates the "C3 convertase" of the alternative complement pathway. We report the
      crystal structure of the A domain from factor B and show that it contains an
      integrin-like MIDAS motif that adopts the "open" conformation typical of integrin
      ligand complexes, with an acidic residue (provided by a fortuitous crystal
      contact) completing the coordination of the metal ion. Modeling studies indicate
      that the factor B A domain can also adopt the closed conformation, supporting the
      hypothesis that an "integrin-like switch" is conserved in complement proteins and
      perhaps in 60 other A domains found within the human proteome.

PMID- 15016354
TI  - Anion binding to nucleic acids.
AB  - Nucleic acids are generally considered as efficient cation binders. Therefore,
      the likelihood that negatively charged ions might intrude their first hydration
      shell is rarely considered. Here, we show on the basis of (i) a survey of the
      Nucleic Acid Database, (ii) several structures extracted from the Cambridge
      Structural Database, and (iii) molecular dynamics simulations, that the
      nucleotide electropositive edges involving mainly amino, imino, and hydroxyl
      groups can cast specific anion binding sites. These binding sites constitute also
      good locations for the binding of the negatively charged groups of the Asp and
      Glu residues or the nucleic acid phosphate groups. Furthermore, it is observed in
      several instances that anions, like water molecules and cations, do mediate
      protein/nucleic acid interactions. Thus, anions as well as negatively charged
      groups are directly involved in specific recognition and folding phenomena
      involving polyanionic nucleic acids.

PMID- 15016355
TI  - De novo design and characterization of a helical hairpin eicosapeptide; emergence
      of an anion receptor in the linker region.
AB  - De novo design of supersecondary structures is expected to provide useful
      molecular frameworks for the incorporation of functional sites as in proteins. A
      21 residue long, dehydrophenylalanine-containing peptide has been de novo
      designed and its crystal structure determined. The apolar peptide folds into a
      helical hairpin supersecondary structure with two right-handed helices, connected
      by a tetraglycine linker. The helices of the hairpin interact with each other
      through a combination of C-H.O and N-H.O hydrogen bonds. The folding of the
      apolar peptide has been realized without the help of either metal ions or
      disulphide bonds. A remarkable feature of the peptide is the unanticipated
      occurrence of an anion binding motif in the linker region, strikingly similar in
      conformation and function to the "nest" motif seen in several proteins. The
      observation supports the view for the possible emergence of rudimentary functions
      over short sequence stretches in the early peptides under prebiotic conditions.

PMID- 15016356
TI  - Crystal structure of RumA, an iron-sulfur cluster containing E. coli ribosomal
      RNA 5-methyluridine methyltransferase.
AB  - RumA catalyzes transfer of a methyl group from S-adenosylmethionine (SAM)
      specifically to uridine 1939 of 23S ribosomal RNA in Escherichia coli to yield 5
      methyluridine. We determined the crystal structure of RumA at 1.95 A resolution.
      The protein is organized into three structural domains: The N-terminal domain
      contains sequence homology to the conserved TRAM motif and displays a five
      stranded beta barrel architecture characteristic of an
      oligosaccharide/oligonucleotide binding fold. The central domain contains a
      [Fe(4)S(4)] cluster coordinated by four conserved cysteine residues. The C
      terminal domain displays the typical SAM-dependent methyltransferase fold. The
      catalytic nucleophile Cys389 lies in a motif different from that in DNA 5
      methylcytosine methyltransferases. The electrostatic potential surface reveals a
      predominately positively charged area that covers the concave surface of the
      first two domains and suggests an RNA binding mode. The iron-sulfur cluster may
      be involved in the correct folding of the protein or may have a role in RNA
      binding.

PMID- 15016357
TI  - Structure and flexibility of individual immunoglobulin G molecules in solution.
AB  - In contrast to averaging methods of determining structure, such as X-ray
      diffraction, NMR, and single-particle tomography, cryo-electron tomography allows
      three-dimensional imaging of an individual object in solution. The method has
      previously been used to study cells and very large macromolecules. We have used
      cryo-electron tomography to analyze a monoclonal IgG, with a molecular weight of
      only 150 kDa. Tomograms reveal y-shaped IgG molecules with three protruding
      subunits. Docking X-ray structures enabled us to recognize the three subunits as
      two ellipsoidal Fab arms and a heart-shaped Fc stem. Each subunit has a similar
      structure in the tomograms and in the X-ray map. Notably, the positions of the
      Fab arms relative to the Fc stem differed greatly from one molecule to another.
      The large flexibility of IgG in solution is most likely of functional
      significance in antigen recognition. This distribution of individual structures
      provides a qualitative insight into the system dynamics.

PMID- 15016358
TI  - Cofactor-induced conformational rearrangements establish a catalytically
      competent active site and a proton relay conduit in FabG.
AB  - beta-Ketoacyl-acyl carrier protein reductase (FabG) is a key component in the
      type II fatty acid synthase system. The structures of Escherichia coli FabG and
      the FabG[Y151F] mutant in binary complexes with NADP(H) reveal that
      mechanistically important conformational changes accompany cofactor binding. The
      active site Ser-Tyr-Lys triad is repositioned into a catalytically competent
      constellation, and a hydrogen bonded network consisting of ribose hydroxyls, the
      Ser-Tyr-Lys triad, and four water molecules creates a proton wire to replenish
      the tyrosine proton donated during catalysis. Also, a disordered loop in FabG
      forms a substructure in the complex that shapes the entrance to the active site.
      A key observation is that the nicotinamide portion of the cofactor is disordered
      in the FabG[Y151F].NADP(H) complex, and Tyr151 appears to be necessary for high
      affinity cofactor binding. Biochemical data confirm that FabG[Y151F] is defective
      in NADPH binding. Finally, structural changes consistent with the observed
      negative cooperativity of FabG are described.

PMID- 15016359
TI  - Structural basis for allosteric regulation of the monomeric allosteric enzyme
      human glucokinase.
AB  - Glucokinase is a monomeric enzyme that displays a low affinity for glucose and a
      sigmoidal saturation curve for its substrate, two properties that are important
      for its playing the role of a glucose sensor in pancreas and liver. The molecular
      basis for these two properties is not well understood. Herein we report the
      crystal structures of glucokinase in its active and inactive forms, which
      demonstrate that global conformational change, including domain reorganization,
      is induced by glucose binding. This suggests that the positive cooperativity of
      monomeric glucokinase obeys the "mnemonical mechanism" rather than the well-known
      concerted model. These structures also revealed an allosteric site through which
      small molecules may modulate the kinetic properties of the enzyme. This finding
      provided the mechanistic basis for activation of glucokinase as a potential
      therapeutic approach for treating type 2 diabetes mellitus.

PMID- 15016360
TI  - Peptide sequence and amyloid formation; molecular simulations and experimental
      study of a human islet amyloid polypeptide fragment and its analogs.
AB  - We present a combined experimental and theoretical investigation of the
      tendencies to form amyloid fibrils by a hexapeptide derivative of the human islet
      amyloid polypeptide, the NFGAIL (22-27) fragment and its mutants. We performed a
      complete alanine scan of this fragment and studied the capability of the wild
      type and its mutant analogs to form ordered fibrils by ultrastructural and
      biophysical analyses. In parallel, we conducted a meticulous characterization of
      each sequence-complex at an atomistic level by performing nine independent
      molecular dynamics simulations for a total of 36 ns. These allowed us to
      rationalize the experimental observations and to establish the role of every
      residue in the fibrillogenesis. The main factor that determines the formation of
      regular fibrils is a coherent organization of the intersheet space. In
      particular, phenylalanine side chains cement the macromolecular assemblies due to
      their aromatic chemical character and restricted conformational flexibility when
      interacting with aliphatic residues.

PMID- 15016361
TI  - Noncatalytic assembly of ribonuclease III with double-stranded RNA.
AB  - Ribonuclease III (RNase III) represents a family of double-stranded RNA (dsRNA)
      endonucleases. The simplest bacterial enzyme contains an endonuclease domain
      (endoND) and a dsRNA binding domain (dsRBD). RNase III can affect RNA structure
      and gene expression in either of two ways: as a dsRNA-processing enzyme that
      cleaves dsRNA, or as a dsRNA binding protein that binds but does not cleave
      dsRNA. We previously determined the endoND structure of Aquifex aeolicus RNase
      III (Aa-RNase III) and modeled a catalytic complex of full-length Aa-RNase III
      with dsRNA. Here, we present the crystal structure of Aa-RNase III in complex
      with dsRNA, revealing a noncatalytic assembly. The major differences between the
      two functional forms of RNase III.dsRNA are the conformation of the protein and
      the orientation and location of dsRNA. The flexibility of a 7 residue linker
      between the endoND and dsRBD enables the transition between these two forms.

PMID- 15016362
TI  - Reaction trajectory of pyrophosphoryl transfer catalyzed by 6-hydroxymethyl-7,8
      dihydropterin pyrophosphokinase.
AB  - 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) catalyzes the Mg(2+)
      dependent pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin
      (HP). The reaction follows a bi-bi mechanism with ATP as the first substrate and
      AMP and HP pyrophosphate (HPPP) as the two products. HPPK is a key enzyme in the
      folate biosynthetic pathway and is essential for microorganisms but absent from
      mammals. For the HPPK-catalyzed pyrophosphoryl transfer, a reaction coordinate is
      constructed on the basis of the thermodynamic and transient kinetic data we
      reported previously, and the reaction trajectory is mapped out with five three
      dimensional structures of the enzyme at various liganded states. The five
      structures are apo-HPPK (ligand-free enzyme), HPPK.MgATP(analog) (binary complex
      of HPPK with its first substrate) and HPPK.MgATP(analog).HP (ternary complex of
      HPPK with both substrates), which we reported previously, and HPPK.AMP.HPPP
      (ternary complex of HPPK with both product molecules) and HPPK.HPPP (binary
      complex of HPPK with one product), which we present in this study.

PMID- 15016363
TI  - ADP-ribosyl cyclase; crystal structures reveal a covalent intermediate.
AB  - ADP-ribosyl cyclase catalyzes the elimination of nicotinamide from NAD and
      cyclization to cADPR, a known second messenger in cellular calcium signaling
      pathways. We have determined to 2.0 A resolution the structure of Aplysia cyclase
      with ribose-5-phosphate bound covalently at C3' and with the base exchange
      substrate (BES), pyridylcarbinol, bound to the active site. In addition, further
      refinement at 2.4 A resolution of the structure of nicotinamide-bound cyclase,
      which was previously reported, reveals that ribose-5-phosphate is also covalently
      bound in this structure, and a second nicotinamide site was identified. The
      structures of native and mutant Glu179Ala cyclase were also solved to 1.7 and 2.0
      A respectively. It is proposed that the second nicotinamide site serves to
      promote cyclization by clearing the active site of the nicotinamide byproduct.
      Moreover, a ribosylation mechanism can be proposed in which the cyclization
      reaction proceeds through a covalently bound intermediate.

PMID- 15016364
TI  - Crystal structure of the type III effector AvrB from Pseudomonas syringae.
AB  - AvrB is a Pseudomonas syringae type III effector protein that is translocated
      into host plant cells during attempted pathogenesis. Arabidopsis harboring the
      corresponding resistance protein RPM1 can detect AvrB and mount a rapid host
      defense response, thus avoiding active infection. In the plant cell, AvrB induces
      phosphorylation of RIN4, a key component in AvrB/RPM1 recognition. Although the
      AvrB/RPM1 system is among the best characterized of the numerous bacterial
      effector/plant resistance protein systems involved in plant disease resistance
      and pathogenesis, the details of the molecular recognition mechanism are still
      unclear. To gain further insights, the crystal structure of AvrB was determined.
      The 2.2 A structure exhibits a novel mixed alpha/beta bilobal fold. Aided by the
      structural information, we demonstrate that one lobe is the determinant of
      AvrB/RPM1 recognition specificity. This structural information and preliminary
      structure-function studies provide a framework for the future understanding of
      AvrB function on the molecular level.

PMID- 15016365
TI  - Solution structure of the C-terminal domain of Ku80 suggests important sites for
      protein-protein interactions.
AB  - The solution structure of Ku80 CTD from residue 566 to 732 has been solved in
      order to gain insights into the mechanisms of its interactions with other
      proteins. The structure reveals a topology similar to several common scaffolds
      for protein-protein interactions, in the absence of significant sequence
      similarity to these proteins. Conserved surface amino acid residues are clustered
      on two main surface areas, which are likely involved in mediating interactions
      between Ku80 and other proteins. The Ku70/Ku80 heterodimer has been shown to be
      involved in at least three processes, nonhomologous end joining, transcription,
      and telomere maintenance, and thus it needs to interact with different proteins
      involved in these different processes. The three-dimensional structure of the
      Ku80 C-terminal domain and the availability of NMR chemical shift assignments
      provide a basis for further investigation of the interactions between Ku80 and
      other proteins in these Ku-dependent cellular functions.

PMID- 15016367
TI  - Active-site dynamics in RNA polymerases.
AB  - New crystal structures of transcription complexes formed by bacteriophage T7 RNA
      polymerase reveal a nucleotide-addition cycle driven by active-site
      conformational changes similar to those observed in DNA polymerases, and suggest
      provocative hypotheses for the more complex multisubunit RNA polymerases of free
      living organisms.

PMID- 15016366
TI  - Modulation of agrin function by alternative splicing and Ca2+ binding.
AB  - The aggregation of acetylcholine receptors on postsynaptic membranes is a key
      step in neuromuscular junction development. This process depends on alternatively
      spliced forms of the proteoglycan agrin with "B-inserts" of 8, 11, or 19 residues
      in the protein's globular C-terminal domain, G3. Structures of the neural B8 and
      B11 forms of agrin-G3 were determined by X-ray crystallography. The structure of
      G3-B0, which lacks inserts, was determined by NMR. The agrin-G3 domain adopts a
      beta jellyroll fold. The B insert site is flanked by four loops on one edge of
      the beta sandwich. The loops form a surface that corresponds to a versatile
      interaction interface in the family of structurally related LNS proteins. NMR and
      X-ray data indicate that this interaction interface is flexible in agrin-G3 and
      that flexibility is reduced by Ca(2+) binding. The plasticity of the interaction
      interface could enable different splice forms of agrin to select between multiple
      binding partners.

PMID- 15016368
TI  - Can you adhere me now? Good.
AB  - The FLO genes of Saccharomyces cerevisiae encode a family of proteins important
      in determining diverse aspects of cell-surface function. In this issue of Cell,
      Halme et al. show that both genetic and epigenetic mechanisms control expression
      of the FLO genes, thereby generating significant cell-surface diversity within a
      population of yeast cells.

PMID- 15016369
TI  - Allostery and coupled sequence variation in nuclear hormone receptors.
AB  - The analysis of correlated sequence variation in evolutionarily related proteins
      is beginning to provide useful information regarding allosteric coupling between
      different functional sites. Such an analysis has been carried out for the nuclear
      hormone receptors, and the conclusions tested by making mutations that switch the
      allosteric response to ligands of RXR heterodimers.

PMID- 15016370
TI  - Pulling back to move forward.
AB  - Animal cells can change shape and move by using actin polymerization to drive
      plasma membrane protrusion. Giannone and coworkers (this issue of Cell) describe
      how cells periodically pull back on these protrusions in order to sense and
      respond to the rigidity of their environment.

PMID- 15016371
TI  - Bacterial mitotic machineries.
AB  - Here, we review recent progress that yields fundamental new insight into the
      molecular mechanisms behind plasmid and chromosome segregation in prokaryotic
      cells. In particular, we describe how prokaryotic actin homologs form mitotic
      machineries that segregate DNA before cell division. Thus, the ParM protein of
      plasmid R1 forms F actin-like filaments that separate and move plasmid DNA from
      mid-cell to the cell poles. Evidence from three different laboratories indicate
      that the morphogenetic MreB protein may be involved in segregation of the
      bacterial chromosome.

PMID- 15016372
TI  - M protein, a classical bacterial virulence determinant, forms complexes with
      fibrinogen that induce vascular leakage.
AB  - Increased vascular permeability is a key feature of inflammatory conditions. In
      severe infections, leakage of plasma from the vasculature induces a life
      threatening hypotension. Streptococcus pyogenes, a major human bacterial
      pathogen, causes a toxic shock syndrome (STSS) characterized by excessive plasma
      leakage and multi-organ failure. Here we find that M protein, released from the
      streptococcal surface, forms complexes with fibrinogen, which by binding to beta2
      integrins of neutrophils, activate these cells. As a result, neutrophils release
      heparin binding protein, an inflammatory mediator inducing vascular leakage. In
      mice, injection of M protein or subcutaneous infection with S. pyogenes causes
      severe pulmonary damage characterized by leakage of plasma and blood cells. These
      lesions were prevented by treatment with a beta2 integrin antagonist. In
      addition, M protein/fibrinogen complexes were identified in tissue biopsies from
      a patient with necrotizing fasciitis and STSS, further underlining the pathogenic
      significance of such complexes in severe streptococcal infections.

PMID- 15016373
TI  - Structural basis for substrate selection by t7 RNA polymerase.
AB  - The mechanism by which nucleotide polymerases select the correct substrate is of
      fundamental importance to the fidelity of DNA replication and transcription.
      During the nucleotide addition cycle, pol I DNA polymerases undergo the
      transition from a catalytically inactive "open" to an active "closed"
      conformation. All known determinants of substrate selection are associated with
      the "closed" state. To elucidate if this mechanism is conserved in homologous
      single subunit RNA polymerases (RNAPs), we have determined the structure of T7
      RNAP elongation complex with the incoming substrate analog. Surprisingly, the
      substrate specifically binds to RNAP in the "open" conformation, where it is base
      paired with the acceptor template base, while Tyr639 provides discrimination of
      ribose versus deoxyribose substrates. The structure therefore suggests a novel
      mechanism, in which the substrate selection occurs prior to the isomerization to
      the catalytically active conformation. Modeling of multisubunit RNAPs suggests
      that this mechanism might be universal for all RNAPs.

PMID- 15016374
TI  - The structural mechanism of translocation and helicase activity in T7 RNA
      polymerase.
AB  - RNA polymerase functions like a molecular motor that can convert chemical energy
      into the work of strand separation and translocation along the DNA during
      transcription. The structures of phage T7 RNA polymerase in an elongation phase
      substrate complex that includes the incoming nucleoside triphosphate and a
      pretranslocation product complex that includes the product pyrophosphate (PPi)
      are described here. These structures and the previously determined
      posttranslocation elongation complex demonstrate that two enzyme conformations
      exist during a cycle of single nucleotide addition. One orientation of a five
      helix subdomain is stabilized by the phosphates of either the incoming NTP or by
      the product PPi. A second orientation of this subdomain is stable in their
      absence and is associated with translocation of the heteroduplex product as well
      as strand separation of the downstream DNA. We propose that the dissociation of
      the product PPi after nucleotide addition produces the protein conformational
      change resulting in translocation and strand separation.

PMID- 15016375
TI  - Genetic and epigenetic regulation of the FLO gene family generates cell-surface
      variation in yeast.
AB  - The FLO gene family of Saccharomyces cerevisiae includes an expressed gene,
      FLO11, and a set of silent, telomere-adjacent FLO genes. This gene family encodes
      cell-wall glycoproteins that regulate cell-cell and cell-surface adhesion.
      Epigenetic silencing of FLO11 regulates a key developmental switch: when FLO11 is
      expressed, diploid cells form pseudohyphal filaments; when FLO11 is silent, the
      cells grow in yeast form. The epigenetic state of FLO11 is heritable for many
      generations and regulated by the histone deacetylase (HDAC) Hda1p. The silent
      FLO10 gene is activated by high-frequency loss-of-function mutations at either
      IRA1 or IRA2. FLO10 is regulated by the same transcription factors that control
      FLO11: Sfl1p and Flo8p, but is silenced by a distinct set of HDACs: Hst1p and
      Hst2p. These sources of epigenetic and genetic variation explain the observed
      heterogeneity of cell-surface protein expression within a population of cells
      derived from a single clone.

PMID- 15016376
TI  - Structural determinants of allosteric ligand activation in RXR heterodimers.
AB  - Allosteric communication underlies ligand-dependent transcriptional responses
      mediated by nuclear receptors. While studies have elucidated many of the
      components involved in this process, the energetic architecture within the
      receptor protein that mediates allostery remains unknown. Using a sequence-based
      method designed to detect coevolution of amino acids in a protein, termed the
      statistical coupling analysis (SCA), we identify a network of energetically
      coupled residues that link the functional surfaces of nuclear receptor ligand
      binding domains. Functional analysis of these predicted residues demonstrates
      their participation in an allosteric network that governs the ability of
      heterodimeric receptors to activate transcription in response to ligand binding
      by either partner. Interestingly, mutation of a single network residue can
      discriminate between receptor activation by endocrine, dietary, and synthetic
      agonists. These results reveal a structural network required for RXR heterodimer
      allosteric communication and suggest that the specificity of ligand response and
      permissivity coevolved to enable signal discrimination.

PMID- 15016377
TI  - Periodic lamellipodial contractions correlate with rearward actin waves.
AB  - Cellular lamellipodia bind to the matrix and probe its rigidity through forces
      generated by rearward F-actin transport. Cells respond to matrix rigidity by
      moving toward more rigid matrices using an unknown mechanism. In spreading and
      migrating cells we find local periodic contractions of lamellipodia that depend
      on matrix rigidity, fibronectin binding and myosin light chain kinase (MLCK).
      These contractions leave periodic rows of matrix bound beta3-integrin and
      paxillin while generating waves of rearward moving actin bound alpha-actinin and
      MLCK. The period between contractions corresponds to the time for F-actin to move
      across the lamellipodia. Shortening lamellipodial width by activating cofilin
      decreased this period proportionally. Increasing lamellipodial width by Rac
      signaling activation increased this period. We propose that an actin bound,
      contraction-activated signaling complex is transported locally from the tip to
      the base of the lamellipodium, activating the next contraction/extension cycle.

PMID- 15016378
TI  - APPL proteins link Rab5 to nuclear signal transduction via an endosomal
      compartment.
AB  - Signals generated in response to extracellular stimuli at the plasma membrane are
      transmitted through cytoplasmic transduction cascades to the nucleus. We report
      the identification of a pathway directly linking the small GTPase Rab5, a key
      regulator of endocytosis, to signal transduction and mitogenesis. This pathway
      operates via APPL1 and APPL2, two Rab5 effectors, which reside on a subpopulation
      of endosomes. In response to extracellular stimuli such as EGF and oxidative
      stress, APPL1 translocates from the membranes to the nucleus where it interacts
      with the nucleosome remodeling and histone deacetylase multiprotein complex
      NuRD/MeCP1, an established regulator of chromatin structure and gene expression.
      Both APPL1 and APPL2 are essential for cell proliferation and their function
      requires Rab5 binding. Our findings identify an endosomal compartment bearing
      Rab5 and APPL proteins as an intermediate in signaling between the plasma
      membrane and the nucleus.

PMID- 15016379
TI  - Complete polarization of single intestinal epithelial cells upon activation of
      LKB1 by STRAD.
AB  - The LKB1 gene encodes a serine/threonine kinase that is mutated in the Peutz
      Jeghers cancer syndrome. LKB1 is homologous to the Par-4 polarity genes in C.
      elegans and D. melanogaster. We have previously reported the identification and
      characterization of an LKB1-specific adaptor protein, STRAD, which activates LKB1
      and translocates it from nucleus to cytoplasm. We have now constructed intestinal
      epithelial cell lines in which inducible STRAD activates LKB1. Upon LKB1
      activation, single cells rapidly remodel their actin cytoskeleton to form an
      apical brush border. The junctional proteins ZO-1 and p120 redistribute in a
      dotted circle peripheral to the brush border, in the absence of cell-cell
      contacts. Apical and basolateral markers sort to their respective membrane
      domains. We conclude that LKB1 can induce complete polarity in intestinal
      epithelial cells. In contrast to current thinking on polarization of simple
      epithelia, these cells can fully polarize in the absence of junctional cell-cell
      contacts.

PMID- 15016381
TI  - A simple and effective algorithm for detection of arbitrary Hartmann-Shack
      patterns.
AB  - The Hartmann-Shack sensor is well known for its capability of detecting optical
      aberrations from telescopic images, normally caused by the atmospheric
      turbulence. Since the mid-1990s, this sensor has been adapted to work with
      ophthalmic instrumentation to measure aberrations of the human eye. In
      astronomical applications, the image processing is implemented using robust
      closed-loop hardware systems, allowing for very high frequencies (usually in the
      range of 30-500 Hz). In ophthalmic instruments, this hardware solution is not
      proper, for two reasons: first, prices of ophthalmic instrumentation have to be
      at more accessible prices and, second, there is no need for ultra-high frequency
      closed-loop systems; in fact, as we will see along the text, recent studies of
      the dynamics of the eye's aberrations show that closed-loop systems of very much
      lower frequencies (from 10 to 40 Hz) may well eliminate the undesired micro
      fluctuations in the eye's aberrations and allow for diffraction limited
      measurements. We have developed an effective algorithm for detection of HS
      patterns using an affordable commercial hardware configuration and easy to
      implement software. To our knowledge, this type of information has not been
      thoroughly disclosed elsewhere, probably due to proprietary reasons.

PMID- 15016380
TI  - Translational control by MAPK signaling in long-term synaptic plasticity and
      memory.
AB  - Enduring forms of synaptic plasticity and memory require new protein synthesis,
      but little is known about the underlying regulatory mechanisms. Here, we
      investigate the role of MAPK signaling in these processes. Conditional expression
      of a dominant-negative form of MEK1 in the postnatal murine forebrain inhibited
      ERK activation and caused selective deficits in hippocampal memory retention and
      the translation-dependent, transcription-independent phase of hippocampal L-LTP.
      In hippocampal neurons, ERK inhibition blocked neuronal activity-induced
      translation as well as phosphorylation of the translation factors eIF4E, 4EBP1,
      and ribosomal protein S6. Correspondingly, protein synthesis and translation
      factor phosphorylation induced in control hippocampal slices by L-LTP-generating
      tetanization were significantly reduced in mutant slices. Translation factor
      phosphorylation induced in the control hippocampus by memory formation was
      similarly diminished in the mutant hippocampus. These results suggest a crucial
      role for translational control by MAPK signaling in long-lasting forms of
      synaptic plasticity and memory.

PMID- 15016382
TI  - Model-free functional MRI analysis based on unsupervised clustering.
AB  - Conventional model-based or statistical analysis methods for functional MRI
      (fMRI) are easy to implement, and are effective in analyzing data with simple
      paradigms. However, they are not applicable in situations in which patterns of
      neural response are complicated and when fMRI response is unknown. In this paper
      the "neural gas" network is adapted and rigourosly studied for analyzing fMRI
      data. The algorithm supports spatial connectivity aiding in the identification of
      activation sites in functional brain imaging. A comparison of this new method
      with Kohonen's self-organizing map and with a fuzzy clustering scheme based on
      deterministic annealing is done in a systematic fMRI study showing comparative
      quantitative evaluations. The most important findings in this paper are: (1) both
      "neural gas" and the fuzzy clustering technique outperform Kohonen's map in terms
      of identifying signal components with high correlation to the fMRI stimulus, (2)
      the "neural gas" outperforms the two other methods with respect to the
      quantization error, and (3) Kohonen's map outperforms the two other methods in
      terms of computational expense. The applicability of the new algorithm is
      demonstrated on experimental data.

PMID- 15016383
TI  - Diagnostic fidelity of the Z-buffer segmentation algorithm: preliminary
      assessment based on intracranial aneurysm detection.
AB  - We have developed an algorithm known as the Z-buffer segmentation (ZBS) algorithm
      for segmenting vascular structures from 3D MRA images. Previously we evaluated
      the accuracy of the ZBS algorithm on a voxel level in terms of inclusion and
      exclusion of vascular and background voxels. In this paper we evaluate the
      diagnostic fidelity of the ZBS algorithm. By diagnostic fidelity we mean that the
      data preserves the structural information necessary for diagnostic evaluation.
      This evaluation is necessary to establish the potential usefulness of the
      segmentation for improved image display, or whether the segmented data could form
      the basis of a computerized analysis tool. We assessed diagnostic fidelity by
      measuring how well human observers could detect aneurysms in the segmented data
      sets. ZBS segmentation of 30 MRA cases containing 29 aneurysms was performed.
      Image display used densitometric reprojections with shaded surface highlighting
      that were generated from the segmented data. Three neuroradiologists
      independently reviewed the generated ZBS images for aneurysms. The observers had
      80% sensitivity (90% for aneurysms larger than 2mm) with 0.13 false positives per
      image. Good agreement with the gold standard for describing aneurysm size and
      orientation was shown. These preliminary results suggest that the segmentation
      has diagnostic fidelity with the original data and may be useful for improved
      visualization or automated analysis of the vasculature.

PMID- 15016384
TI  - Synergy between medical informatics and bioinformatics: facilitating genomic
      medicine for future health care.
AB  - In this paper, we review the results of BIOINFOMED, a study funded by the
      European Commission (EC) with the purpose to analyse the different issues and
      challenges in the area where Medical Informatics and Bioinformatics meet.
      Traditionally, Medical Informatics has been focused on the intersection between
      computer science and clinical medicine, whereas Bioinformatics have been
      predominantly centered on the intersection between computer science and
      biological research. Although researchers from both areas have occasionally
      collaborated, their training, objectives and interests have been quite different.
      The results of the Human Genome and related projects have attracted the interest
      of many professionals, and introduced new challenges that will transform
      biomedical research and health care. A characteristic of the 'post genomic' era
      will be to correlate essential genotypic information with expressed phenotypic
      information. In this context, Biomedical Informatics (BMI) has emerged to
      describe the technology that brings both disciplines (BI and MI) together to
      support genomic medicine. In recognition of the dynamic nature of BMI,
      institutions such as the EC have launched several initiatives in support of a
      research agenda, including the BIOINFOMED study.

PMID- 15016386
TI  - Cognitive and usability engineering methods for the evaluation of clinical
      information systems.
AB  - Increasingly healthcare policy and decision makers are demanding evidence to
      justify investments in health information systems. This demand requires an
      adequate evaluation of these systems. A wide variety of approaches and
      methodologies have been applied in assessing the impact of information systems in
      health care, ranging from controlled clinical trials to use of questionnaires and
      interviews with users. In this paper we describe methodological approaches which
      we have applied and refined for the past 10 years for the evaluation of health
      information systems. The approaches are strongly rooted in theories and methods
      from cognitive science and the emerging field of usability engineering. The focus
      is on assessing human computer interaction and in particular, the usability of
      computer systems in both laboratory and naturalistic settings. The methods
      described can be a part of the formative evaluation of systems during their
      iterative development, and can also complement more traditional assessment
      methods used in summative system evaluation of completed systems. The paper
      provides a review of the general area of systems evaluation with the motivation
      and rationale for methodological approaches underlying usability engineering and
      cognitive task analysis as applied to health information systems. This is
      followed by a detailed description of the methods we have applied in a variety of
      settings in conducting usability testing and usability inspection of systems such
      as computer-based patient records. Emerging trends in the evaluation of complex
      information systems are discussed.

PMID- 15016385
TI  - GeneWays: a system for extracting, analyzing, visualizing, and integrating
      molecular pathway data.
AB  - The immense growth in the volume of research literature and experimental data in
      the field of molecular biology calls for efficient automatic methods to capture
      and store information. In recent years, several groups have worked on specific
      problems in this area, such as automated selection of articles pertinent to
      molecular biology, or automated extraction of information using natural-language
      processing, information visualization, and generation of specialized knowledge
      bases for molecular biology. GeneWays is an integrated system that combines
      several such subtasks. It analyzes interactions between molecular substances,
      drawing on multiple sources of information to infer a consensus view of molecular
      networks. GeneWays is designed as an open platform, allowing researchers to
      query, review, and critique stored information.

PMID- 15016387
TI  - Medical ethics don't stop at the courtroom door.

PMID- 15016389
TI  - Mild hypothermia, blood loss and complications in elective spinal surgery.
AB  - BACKGROUND CONTEXT: Spinal surgery carries risks of incidental spinal cord and
      nerve root injury. Neuroprotection, to minimize the extent of such injuries, is
      desirable. However, no neuroprotective strategies have been conclusively
      validated in nonvascular spinal surgery. Mild hypothermia resulting from general
      anesthesia is a readily achievable potential neuroprotective strategy. Mild
      hypothermia, however, has been associated with wound infection, increased
      operative blood loss and other complications. No previous studies have
      specifically evaluated whether mild hypothermia is associated with an increased
      risk of these complications in elective spinal surgery. PURPOSE: We investigated
      the association between incidental mild hypothermia, perioperative complications
      and operative blood loss. STUDY DESIGN/SETTING: This is a retrospective study
      employing cohort analysis, rank analysis and single and multivariate linear
      regression. The setting was the Veterans Administration Medical Center, a
      teaching hospital of the University of Miami. PATIENT SAMPLE: Data on a total of
      70 adult veterans aged 23 to 81 years undergoing complex spinal procedures in
      which passive cooling was employed during surgical decompression. OUTCOME
      MEASURES: The variables measured were temperature, blood loss, mean arterial
      pressure (MAP) and duration of anesthesia. The outcome measured was the presence
      or absence of complications. METHODS: After 70 patients had been acquired,
      regression and rank analyses were performed to test for a link between mild
      hypothermia and blood loss. In addition, two cohorts, patients who experienced
      complications, and those who did not experience complications in the
      perioperative period, were compared for several variables including three
      measures of exposure to hypothermia. Surgical procedures included 60 cervical, 1
      occipitocervical, 1 cervicothoracic, 7 thoracic and 1 thoracolumbar procedure.
      Hypothermia followed induction of anesthesia; esophageal or bladder temperature
      was monitored. Cooling was passive; warming utilized a forced air blanket.
      Temperature data from anesthetic records was used to derive mean intraoperative
      temperature, nadir intraoperative temperature and the rates of cooling and
      rewarming. The time course of hypothermia, the overall fluctuation in core
      temperature and the quantity of subbaseline temperature were determined. Medical
      and surgical complications were included. Two patients with complications
      considered irrelevant to hypothermia were removed from further analysis. Patients
      with and without complications were compared as cohorts for differences in mean
      values of age, comorbid risk factors, intraoperative MAP, intraoperative blood
      loss, anesthetic duration and temperature-related measures. Relationships between
      blood loss, anesthesia duration and temperature parameters were assessed in rank
      and regression analyses. RESULTS: Patients with complications (n=12) had longer
      mean anesthetic durations (p=.0001) and larger mean surgical blood losses
      (p=.001) than patients without complications (n=56). Neither mean nor nadir
      intraoperative hypothermic temperatures were statistically associated with
      complications. However, large hypothermic integrals (p=.04) and the total
      quantity of recorded temperature fluctuation (p=.01) were both associated with
      complications. Comorbid risk factors, MAP and age were not statistically linked
      to complications. Finally, no relationship between any of the temperature
      measures and increased blood loss was found. CONCLUSION: Operative blood loss was
      not linked to any index of the patient's temperature. Longer anesthesia durations
      were linked to complications and increased blood loss. Regarding mild
      hypothermia, neither mean nor nadir hypothermic temperatures were linked to
      complications, but the estimated total quantity of subbaseline temperature was
      linked, as was total fluctuation in temperature. Lengthy exposure to mild
      hypothermia appeared to be associated with wound infections. The use of mild
      hypothermia as a potential neuroprotective strategy during spinal surgery appears
      to be reasonably safe, but to avoid complications, the duration of hypothermic
      exposure should be minimized.

PMID- 15016390
TI  - A treatment and outcomes analysis of patients with coccydynia.
AB  - BACKGROUND CONTEXT: Coccydynia is a painful condition of the terminal portion of
      the spine often resulting from direct trauma, childbirth or unknown etiology.
      This is a relatively rare condition with no universally accepted treatment
      protocol. PURPOSE: To more clearly determine the optimal treatment for patients
      with coccydynia and to assess the outcomes after conservative and surgical
      therapy. STUDY DESIGN: Retrospective review of outcomes of all patients
      presenting with symptoms of coccydynia during a 5-year period. PATIENT SAMPLE:
      Thirty-two patients presented to an orthopedic spine surgeon during a 5-year
      period with symptoms of coccydynia. OUTCOME MEASURES: Patients completed visual
      analog pain scales (VAS) and the Oswestry (OSW) functional capacity index.
      METHODS: Of the 32 patients in the study, 4 (13%) were treated with nonsteroidal
      anti-inflammatory drugs (NSAIDs) alone, 17 (53%) were treated with NSAIDs
      followed by local injections and 11 (34%) underwent coccygectomy after failure of
      NSAIDs and local injections. Patients completed VAS and OSW forms. Pain drawings
      were also completed. RESULTS: Patients undergoing surgery had significantly
      greater pretreatment VAS scores (8.3 vs 5.4, p=.002). Surgical patients also had
      greater OSW scores, but not significantly (36.6 vs 24.2, p=.223). Marked
      improvement was reported by 9 of 11 (82%) surgical patients. Three of 11 (27%)
      surgical patients developed wound infections and 1 (9%) wound dehiscence. All
      infections resolved following irrigation and debridement and a short course of
      oral antibiotics. CONCLUSIONS: Patients with coccydynia should be managed
      conservatively when possible. Treatment should include NSAIDs and local steroid
      injections. Patients will often require repeat injections over time. Surgery can
      offer reasonable results for patients failing conservative treatment, but they
      should be warned of the high rate of infection.

PMID- 15016391
TI  - Human lumbar facet joint capsule strains: I. During physiological motions.
AB  - BACKGROUND CONTEXT: The lumbar facet joint capsule is innervated with nociceptors
      and mechanoreceptors, and is thought to play a role in low back pain as well as
      to function proprioceptively. PURPOSE: In order to examine the facet capsule's
      potential proprioceptive role, relationships between intracapsular strain and
      relative spine position were examined. STUDY DESIGN/SETTING: Lumbar facet joint
      capsule strains were measured in human cadaveric specimens during displacement
      controlled motions. METHODS: Ligamentous lumbar spine specimens (n=7) were potted
      and actuated without inducing a moment at the point of application. Spines were
      tested during physiological motions of extension, flexion, left and right lateral
      bending. Intervertebral angulations (IVA) were measured using biaxial
      inclinometers mounted on adjacent vertebrae. Joint moments were determined from
      the applied load at T12 and the respective moment arms. Capsule plane strains
      were measured by optically tracking the displacements of infrared reflective
      markers glued to capsule surfaces. Statistical differences (p<.05) in moment, IVA
      and strain were assessed across facet joint levels using analysis of variance and
      comparison of linear regressions. RESULTS: The developed moments and IVAs
      increased monotonically with increasing displacements; the relationships were
      highly correlated for all four motion types. Although highly variable among
      specimens, principal strains also increased monotonically in magnitude with
      increasing displacements during extension and flexion, but were more complex
      during lateral bending. At a given joint level, the absolute magnitudes of
      principal strains and IVA were largest during the same motion type. CONCLUSIONS:
      Distinct patterns in principal strains and IVA were identified during
      physiological motions, lending biomechanical support to the theory that lumbar
      facet joint capsules could function proprioceptively.

PMID- 15016392
TI  - Human lumbar facet joint capsule strains: II. Alteration of strains subsequent to
      anterior interbody fixation.
AB  - BACKGROUND CONTEXT: In cases of low back pain associated with biomechanical
      lumbar instability, anterior interbody fixation can be used as a surgical
      treatment, but its affect on facet joint capsule strains is unknown. PURPOSE: To
      determine the effect of a single-level anterolateral interbody fixation, the
      changes in lumbar facet joint capsule strains at the level of and adjacent to the
      fixation were evaluated. STUDY DESIGN/SETTING: Human cadaveric lumbar spine
      specimens were tested under displacement control before and after the addition of
      a single anterior thoracolumbar plate (ATLP) on the L4-L5 motion body. METHODS:
      Ligamentous lumbar spine specimens (n=7) were potted and actuated before and
      after fixation of the L4-L5 motion segment with an ATLP in motions of extension,
      flexion, left and right bending. Joint moments were calculated from the applied
      load and respective moment arms. Intervertebral angulation was measured using
      biaxial inclinometers mounted onto adjacent vertebrae. Plane strains of the
      capsules were measured by optically tracking the displacements of small, infrared
      reflective markers glued to capsule surfaces. Statistical differences (p<.05) in
      moment, intervertebral angle and capsular strain were assessed using analysis of
      variance and comparison of linear regression lines. RESULTS: Fixation resulted in
      an increase in moment at the three vertebral levels for all motions. There was
      also an increase in intervertebral angle at L3-L4 and L5-S1, and a decrease in
      intervertebral angle at L4-L5 for all motions. Plane strains in the L3-L4 and L5
      S1 facet capsules increased as a result of the fixation. L4-L5 facet capsules
      experienced decreased and increased strains ipsilateral and contralateral,
      respectively, to the instrumentation. CONCLUSION: Restriction of a vertebral
      motion segment using a single ATLP increased adjacent capsular strains, which if
      suprathreshold for capsule nociceptors, could play a role in low back pain.

PMID- 15016393
TI  - Revised protocol for the kinematic assessment of impairment.
AB  - BACKGROUND CONTEXT: Marras et al. developed a functional motion performance tool
      that accurately identified impaired low back motion performance, with sensitivity
      of 90% and specificity of 94%. However, the protocol required testing of five
      controlled tasks and was relatively time consuming. PURPOSE: To determine whether
      a more time-efficient low back motion functional performance evaluation tool with
      acceptably high sensitivity and specificity could be developed. STUDY
      DESIGN/SETTING: Low back functional motion (kinematic) performance evaluations
      were completed on two groups, consisting of controls (no history of back pain)
      and low back pain patients. A second low back pain population was also evaluated
      prospectively to assess recovery. PATIENT SAMPLE: The study population consisted
      of 335 patients and 374 controls. Thirty acute low back pain patients were
      monitored prospectively. OUTCOME MEASURES: Kinematic low back functional
      performance measures. METHODS: Low back motion functional performance was
      measured using the lumbar motion monitor. A revised discriminant function model
      was developed using data from only one of the five original functional motion
      performance control tasks. Prospective study data were used to track differences
      in recovery time between the revised and original discriminant function models.
      RESULTS: The revised model using functional motion performance from the
      controlled sagittally symmetric task had a sensitivity of 90% and specificity of
      92%. When comparing the revised and original model results, the time to recovery
      was the same in 90% of cases. CONCLUSIONS: The revised (more time efficient)
      testing procedure yielded high sensitivity and specificity.

PMID- 15016394
TI  - Smoking status and psychosocioeconomic outcomes of functional restoration in
      patients with chronic spinal disability.
AB  - BACKGROUND CONTEXT: Studies have revealed smoking to have a negative impact on
      spinal surgery. It is assumed that this is the result of the negative impact of
      nicotine on revascularization of damaged tissue. However, there is a paucity of
      research on the role of smoking with regard to nonsurgical rehabilitation, but
      there exists a clear bias for believing that smoking is strongly associated with
      poor socioeconomic and psychosocial outcome. PURPOSE: This study was designed to
      examine the relationship between smoking and outcomes in a chronically disabled
      work-related spinal disorder (CDWRSD) cohort undergoing functional restoration.
      STUDY DESIGN: A prospective comparison cohort study investigating the effects of
      smoking status on functional restoration treatment outcomes. PATIENT SAMPLE: A
      cohort of 1,141 consecutive CDWRSD patients were divided into four groups: Group
      A, patients who did not smoke (n=710); Group B, patients who smoked less than one
      cigarette pack/day (n=157); Group C, patients who smoked 1.0 to 1.9 packs/day
      (n=218); Group D, patients who smoked 2.0 or more packs/day (n=56). OUTCOME
      MEASURES: Before the start of functional restoration, and upon its completion,
      patients received a standard psychosocial assessment battery and were assessed on
      a variety of physical factors. A structured clinical interview examining
      socioeconomic outcomes was conducted 1 year after the program. METHODS: Patients
      underwent an intensive functional restoration chronic pain management
      rehabilitation program consisting of quantitatively directed exercise progression
      and a multimodal disability management program for CDWRSD. The program consisted
      of four phases, the most significant of which involved a 3-week full-day
      intensive phase after preparatory preprogram phases and before a work transition
      phase. RESULTS: Analysis revealed that the percent of males increased as the
      smoking level increased (Group A=51.8% vs Group D=73.2%; p<.001). Also, as
      smoking increased, the level of education significantly decreased. In addition,
      as smoking level increased, the percent of patients completing the rehabilitation
      program decreased (from 86.3% to 75%; p=.03). No significant differences in 1
      year posttreatment socioeconomic outcomes of work status, health utilization,
      recurrent injury or case closure were related to smoking except work retention,
      which decreased with more smoking (85 to 71%, p<.05). Surprisingly, the physical
      cumulative score at posttreatment increased as smoking frequency increased
      (p<.01). This finding indicates that those who smoked more performed at a higher
      level on physical measures. Those who smoked more frequently before treatment
      also appeared more depressed (p<.001), but after treatment, these differences
      disappeared. Self-reported pain intensity differed only after treatment, and
      posttreatment disability ratings showed a significant linear trend. CONCLUSIONS:
      Contrary to popular belief, CDWRSD patients who smoke do not differ significantly
      in socioeconomic or psychosocial outcomes relative to those who do not. Although
      this study does indicate that those who smoke more evidence lower rehabilitation
      completion rates, those who completed the program had identical 1-year
      posttreatment outcomes of socioeconomic importance except in retraining work at
      year end as those who did not smoke. Smokers had slightly higher posttreatment
      self-reported pain and disability ratings mixed and limited. Overall, there is
      evidence for the widely held belief that smoking negatively affects tertiary
      rehabilitation.

PMID- 15016395
TI  - The influence of intense exercise-based physical therapy program on back pain
      anticipated before and induced by physical activities.
AB  - BACKGROUND CONTEXT: Pain anticipated before and induced by physical activities
      has been shown to influence the physical performance of patients with chronic
      back pain. Limited data exist as to the influence of treatment on this component
      of pain. PURPOSE: This study attempted to determine if pain anticipated before
      and induced by physical activities was altered during an exercise-oriented
      physical therapy program for chronic back pain. STUDY DESIGN/SETTING: Subjects
      were recruited from three physical therapy sites with similar spine
      rehabilitation programs that used intense exercise delivered in a group format.
      During the recruitment period, 70 subjects with chronic low back pain and
      disability agreed to participate and complied with recommended treatments. The
      primary outcome measures were anticipated and induced pain as assessed by visual
      analog scales (VAS) during six tests of back flexibility and strength. Additional
      outcome measures included the performance levels of these six tests (trunk
      flexion, extension, straight leg raising, back strength, lifting from floor to
      waist and waist to shoulder height), global back and leg VAS and Oswestry Low
      Back Pain Disability Questionnaire scores. METHODS: At evaluation for the spine
      rehabilitation programs, we recorded the anticipated and induced pain levels
      associated with the six tests of back function, the performance levels on each
      test and global pain and disability scores. Subjects then participated in the
      spine rehabilitation program that consisted of intense exercise delivered up to
      three times per week, for 2 hours over a period of 6 weeks. All outcome measures
      were reassessed at discharge. Pre- and posttreatment outcome scores were
      statistically compared using paired sample t tests and chi-squared test. Spearman
      correlation coefficients were used to compare anticipated and induced pain
      results with global back and leg pain VAS scores, Oswestry scores and physical
      performance levels for each physical test. RESULTS: Most measures of anticipated
      and induced pain improved between evaluation and discharge. Improvements were
      noted for global back pain (p<.001), leg pain (p=.001), disability (p<.001) and
      performance on each physical testing (p<.001) after treatment. Performances on
      all physical testing correlated with anticipated and induced pain for all tests
      at evaluation but only for measures of flexibility at discharge. Improvements in
      global pain and disability correlated with improvements in anticipated and
      induced pain with physical testing. CONCLUSION: Anticipated and induced pain with
      physical activities was lessened after physical therapy using exercise.
      Anticipated and induced pain with physical activities related to physical
      performance levels, global pain and disability ratings. These findings may help
      explain how exercise exerts a positive influence on chronic back pain and
      disability.

PMID- 15016396
TI  - Anterior cervical discectomy and fusion with implantable titanium cage: initial
      impressions, patient outcomes and comparison to fusion with allograft.
AB  - BACKGROUND CONTEXT: The use of metal cage prosthetic devices in anterior cervical
      discectomy with fusion (ACDF) has increased rapidly. One of these devices is the
      titanium Rabea cage (Signus, Alzenau, Germany) [correction]. There are no peer
      reviewed objective reports on the use of these cages in cervical discectomy.
      PURPOSE: The authors present preliminary outcomes data on the Rabea cage. This
      study is intended to provide adjunct data for surgeons who are using or are
      considering the use of these devices. STUDY DESIGN/SETTING: Patients in a private
      practice were studied prospectively as part of a long-term assessment of outcomes
      using several surgical procedures. Data were collated and analyzed by an
      independent researcher. PATIENT SAMPLE: Rabea cages were used in consecutive
      candidates (n=37) for ACDF. The results using Rabea cages were compared with two
      prospectively studied control groups, one historical (n=66) and one concurrent
      (n=28), both groups using ACDF with bone allograft and no instrumentation.
      OUTCOME MEASURES: Success at 6 months after surgery was determined using six
      major patient-reported outcome measures, including visual analog scales (VAS) for
      arm and neck pain, the Oswestry pain and disability scale, four-part (excellent
      through-poor) scales for measurement of return to activities of daily living or
      to work and satisfaction with the results of surgery. Perioperative
      complications, number of vertebral levels fused, and worker's compensation and
      smoking status were also compared among the study groups. Fusion and subsidence
      were evaluated for the Rabea cage group. METHODS: Criteria for inclusion
      consisted of consecutive patients who presented with unremitting radicular arm
      pain, with or without neck pain, and/or a neurological deficit that correlated
      with appropriate level and side neural compression on magnetic resonance imaging
      or computed tomography. Questionnaire follow-up was at 6 months after surgery
      with 100% compliance. RESULTS: A total of 50 cages were implanted in the 37
      patients. At 6-month follow-up, 78% of patients reported successful arm pain
      relief (VAS scores below 5). Patient satisfaction was successful in 78% of the
      cases. Other success rates included neck pain relief in 73% and Oswestry pain and
      disability scale in 70%. There was a median improvement in the Oswestry scores of
      28 points (61% change). Worker's compensation patients fared dramatically worse
      than did the noncompensation patients in all outcome measurements. Combining all
      three study groups resulted in significantly worse outcomes for multilevel than
      for single-level procedures and for smokers compared with nonsmokers, but low
      case numbers precluded conclusive analysis for the Rabea group alone. In the
      Rabea group there were two complications, neither cage related, whereas none were
      reported for the ACDF controls. Rabea group fusion rates were 84% at 3 months and
      95% at 6 months, but the clinical relevance of this radiological evidence when
      metal prostheses are used is questionable. The outcomes results were clinically
      and statistically indistinguishable from those of our control groups and were
      similar to published studies using other titanium cages. CONCLUSIONS: This is the
      first prospective, independently conducted report on Rabea cages. Results of the
      short-term (6 months) follow-up did not differ from outcomes results in our
      patients who have undergone ACDF with bone allograft. Although this is a
      preliminary assessment, the Rabea cage may represent an alternative to bone
      dowels and hip graft. As is the case for other allografts, artificial or bone,
      the main advantage is elimination of donor site complications, and the
      disadvantages include difficulty in radiographic assessment of fusion and
      potential for cage subsidence.

PMID- 15016398
TI  - Thoracic scoliosis fusion in adolescent and adult idiopathic scoliosis using
      posterior translational corrective techniques (Isola): is maximum correction of
      the thoracic curve detrimental to the unfused lumbar curve?
AB  - BACKGROUND CONTEXT: Postoperative coronal decompensation in selective thoracic
      fusion was reported with derotation maneuvers when using the Cotrel-Dubousset
      (CD) system. Isola instrumentation is a multiple anchor system that corrects
      spine deformity with segmental vertebral translation to a predetermined contoured
      longitudinal member. PURPOSE: To evaluate the efficacy of translational
      corrective techniques using Isola instrumentation in thoracic fusion for
      adolescent and adult idiopathic scoliosis patients. STUDY DESIGN/SETTING: This is
      a retrospective review of adolescent and adult patients with idiopathic scoliosis
      who underwent posterior thoracic fusion using translational corrective techniques
      with Isola instrumentation. PATIENT SAMPLE: Twenty-two patients (14 adolescents
      with idiopathic scoliosis, 8 adults with scoliosis) who underwent posterior
      thoracic fusion using translational corrective techniques were evaluated. OUTCOME
      MEASURES: The charts, radiographs and self-assessment questionnaire were
      reviewed. METHODS: Comparative analysis was done between patients who had Lenke
      Type A curves (Group 1) and Lenke Type B or C curves (Group 2) for both
      adolescent and adult scoliosis groups. RESULTS: The mean follow-up was 54 months
      (range, 33 to 80 months). The mean preoperative Cobb angle of thoracic and lumbar
      curves in all 22 patients was 48 degrees (range, 34 to 64 degrees) and 31 degrees
      (range, 20 to 46 degrees), respectively. Postoperative measurements were 16
      degrees (range, 0 to 28 degrees) for thoracic and 13 degrees (range, 2 to 25
      degrees) for lumbar (67% thoracic and 60% lumbar correction) in Group 1, and 19
      degrees (range, 1 to 33 degrees) for thoracic and 12 degrees (1 to 21 degrees)
      for lumbar at latest follow-up (61% thoracic and 61% lumbar correction) in Group
      2. There was no difference in the final correction of the lumbar curves between
      Groups 1 (64%) and 2 (58%), although the Cobb angle in Group 2 was larger.
      Radiographic coronal decompensation occurred in only one patient in Group 2, who
      remained asymptomatic and required no further treatment. Clinical outcome
      assessment showed 100% satisfaction (n=15), 92% relief of symptoms (n=13) and 92%
      improvement of activities in both groups. CONCLUSIONS: Fusion of the major
      thoracic curve using translational corrective technique (Isola) in patients with
      idiopathic scoliosis is an effective procedure that achieves high patient
      satisfaction while providing excellent correction of both the thoracic and lumbar
      curves. Unlike rotational corrective techniques (CD), clinical decompensation
      requiring further treatment did not occur in any patient treated with this
      method.

PMID- 15016399
TI  - Neurophysiological monitoring of spinal cord function during instrumented
      anterior cervical fusion.
AB  - BACKGROUND CONTEXT: Somatosensory evoked potentials (SSEPs) monitor global spinal
      cord function, and the interpretation of motor loss is based on inferred rather
      than direct measurements. Therefore, SSEPs may not be useful for identifying
      motor function deficits caused by anterior spinal column injury or nerve root
      injury during decompression or placement of instrumentation. For these reasons,
      adjunctive methods for monitoring may be especially useful during cervical spine
      surgery. PURPOSE: To evaluate the effectiveness of SSEP and transcranial
      electrical motor evoked potential (tceMEP) monitoring of spinal cord function
      during anterior fusion of the cervical spine. STUDY DESIGN/SETTING: Retrospective
      review. PATIENT SAMPLE: Consecutive instrumented, anterior cervical spine
      surgeries performed by the same surgeon at a single institution for 119 patients.
      OUTCOME MEASURES: Record of neurophysiological alerts during surgery and record
      of postoperative neurological deficits not present before surgery. METHODS:
      Spinal cord function was monitored intraoperatively with recordings of ulnar and
      posterior tibial nerve SSEPs and tceMEPs. RESULTS: Six neurophysiologic alerts
      occurred that prompted surgeon and/or anesthesiologist intervention. Three
      patients developed new motor weakness after surgery. One patient had temporary
      right-leg weakness that was predicted accurately by the disappearance of the
      right lower extremity tceMEPs. One patient had additional temporary postoperative
      compromise of the right C5-C6 spinal nerve roots that could not be detected
      intraoperatively because of absent baseline tceMEPs from the affected muscles.
      For one patient who developed quadriparesis postoperatively, tceMEP monitoring
      was precluded by the excessive use of neuromuscular blockade during the
      procedure. CONCLUSIONS: The results illustrate the potential utility of
      intraoperative SSEPs and the tceMEPs for detection of changes in spinal cord
      function related to patient positioning and hemodynamic effects during anterior
      cervical fusion.

PMID- 15016400
TI  - Modified transpedicular approach for the surgical treatment of severe
      thoracolumbar or lumbar burst fractures.
AB  - BACKGROUND CONTEXT: Conventional transpedicular decompression of the neural canal
      requires a considerable amount of lamina, facet joint and pedicle resection. The
      authors assumed that it would be possible to remove the retropulsed bone fragment
      by carving the pedicle with a high-speed drill without destroying the vertebral
      elements contributing to spinal stabilization. In this way, surgical treatment of
      unstable burst fractures can be performed less invasively. PURPOSE: The purpose
      of this study is to demonstrate both the possibility of neural canal
      decompression through a transpedicular approach without removing the posterior
      vertebral elements, which contribute to spinal stabilization, and the adequacy of
      posterior stabilization of severe vertebral deformities after burst fractures.
      STUDY DESIGN: Twenty-eight consecutive patients with complete or incomplete
      neurological deficits as a result of the thoracolumbar burst fractures were
      included in this study. All patients had severe spinal canal compromise (mean,
      59.53%+/-14.92) and loss of vertebral body height (mean, 45.14%+/-7.19). Each
      patient was investigated for neural canal compromise, degree of kyphosis at
      fracture level and fusion after operation by computed tomography and direct
      roentgenograms taken preoperatively, early postoperatively and late
      postoperatively. The neurological condition of the patients was recorded in the
      early and late postoperative period according to Benzel-Larson grading systems.
      The outcome of the study was evaluated with regard to the adequate neural canal
      decompression, fusion and reoperation percents and neurological improvement.
      METHODS: Modified transpedicular approach includes drilling the pedicle for
      removal of retropulsed bone fragment under surgical microscope without damaging
      the anatomic continuity of posterior column. Stabilization with pedicle screw
      fixation and posterior fusion with otogenous bone chips were done after this
      decompression procedure at all 28 patients included in this study. RESULTS:
      Twenty-three of 28 patients showed neurological improvement. The percent of
      ambulatory patients was 71.4% 6 months after the operation. The major
      complications included pseudarthrosis in five patients (17.8%), epidural hematoma
      in one (3.5%) and inadequate decompression in one (3.5%). These patients were
      reoperated on by means of an anterior approach. Of the five pseudarthrosis cases,
      two were the result of infection. CONCLUSION: Although anterior vertebrectomy and
      fusion is generally recommended for burst fractures causing canal compromise, in
      these patients adequate neural canal decompression can also be achieved by a
      modified transpedicular approach less invasively.

PMID- 15016402
TI  - Gunshot wounds to the spine.
AB  - BACKGROUND CONTEXT: The incidence of violent crimes has risen over the past
      decade. With it, gunshot injuries have become increasingly more common in the
      civilian population. Among the most devastating injuries are gunshot wounds to
      the spine. PURPOSE: The purpose of this article is to provide a thorough review
      of the pathomechanics, diagnosis and treatment of gunshot wounds to the spine.
      STUDY DESIGN/SETTING: Literature review article. CONCLUSIONS: Treatment of
      gunshot spine fractures differs from other mechanisms. Fractures are usually
      inherently stable and rarely require stabilization. In neurologically intact
      patients, there are few indications for surgery. Evidence of acute lead
      intoxication, an intracanal copper bullet or new onset neurologic deficit can
      justify operative decompression and/or bullet removal. Overzealous laminectomy
      can destabilize the spine and lead to late postoperative deformity. For complete
      and incomplete neural deficits at the cervical and thoracic levels, operative
      decompression is of little benefit and can lead to higher complication rates than
      nonsurgically managed patients. With gunshots to the T12 to L5 levels, better
      motor recovery has been reported after intracanal bullet removal versus
      nonoperative treatment. The use of steroids for gunshot paralysis has not
      improved the neurologic outcome and has resulted in a greater frequency of
      nonspinal complications. Although numerous recommendations exist, 7 to 14 days of
      broad-spectrum antibiosis has lead to the lowest rates of infection after
      transcolonic gunshots to the spine.

PMID- 15016401
TI  - Percutaneous vertebral augmentation.
AB  - BACKGROUND CONTEXT: With the aging of the population, painful osteoporotic
      compression fractures are becoming more common. PURPOSE: To review the
      physiologic implications of these injuries as well as treatment options and
      outcomes, especially with reference to newer, percutaneous "augmentation"
      procedures, that is, vertebroplasty and kyphoplasty. STUDY DESIGN/SETTING: A
      literature review. METHODS: No direct, randomized studies comparing
      vertebroplasty, kyphoplasty and standard, nonoperative care are available.
      RESULTS: The growing literature suggests a role for kyphoplasty and
      vertebroplasty in the management of patients with intractable pain or progressive
      vertebral collapse after vertebral compression fracture. Both procedures likely
      offer similar rates of pain relief. Kyphoplasty, although more expensive, may
      allow fracture reduction. The void created with the balloon tamp allows a more
      viscous cement to be applied, thereby decreasing the risk of extravasation.
      CONCLUSIONS: More study is required to understand the ideal role of these new
      techniques in the management of spinal osteoporosis and associated fractures.
      However, for carefully selected cases, current data suggest that the complication
      rates are low and pain relief can be profound.

PMID- 15016403
TI  - Difficulties inherent in the interpretation and performance of randomized
      controlled clinical trials.

PMID- 15016406
TI  - IL-1 and LPS but not IL-6 inhibit differentiation and downregulate PPAR gamma in
      brown adipocytes.
AB  - Brown adipose tissue (BAT) is well recognized as a heat-producing organ of
      rodents and generally all young mammals. There is good experimental evidence that
      its thermogenic activity plays a role also during development of fever and that
      this activation is mediated exclusively via an adrenergic pathway. However, we
      have shown that brown adipocytes highly express receptors for pyrogenic factors
      (IL-1, LPS) and that after their activation, brown adipocytes are capable of
      responding by production of IL-6 and IL-1alpha. In this study we examined the
      effect of chronic treatment of mouse brown adipocytes in primary culture with
      pyrogens (IL-1beta, IL-6 and LPS) on their ability to differentiate into mature
      adipocytes. We found that treatment with IL-1beta or LPS, but not with IL-6,
      inhibited the differentiation of brown adipocytes, which was accompanied by a 2.5
      10-fold decrease in PPARgamma mRNA. The anti-adipogenic effect of IL-1beta and
      LPS could thus be mediated via downregulation of PPARgamma levels, similar to the
      anti-adipogenic action of another pyrogenic cytokine--TNFalpha. We also found
      that pretreatment of brown adipocytes with IL-1beta or LPS led to a more
      pronounced (2-4-fold) induction of IL-6 transcripts upon whole 24h time course of
      adrenergic stimulation. These results support the view that BAT functions not
      only as an effector but also as a mediator of the febrile response; while the
      thermogenic activity is associated with terminally differentiated cells, earlier
      developmental states of brown adipocytes seem to be able to play a mediatory
      role.

PMID- 15016405
TI  - Interleukin-1 beta inhibits Na+-K+ ATPase activity and protein expression in
      cardiac myocytes.
AB  - Recent studies have shown that heart diseases are always accompanied with high
      levels of IL-1beta and a decrease in Na+-K+ ATPase concentrations. This work
      studies the involvement of the cytokine in the observed changes in the pump. Rats
      were injected intraperitoneally with 400 mg of IL-1beta and 4 h later, the heart
      was isolated and a crude homogenate of the right and left ventricles was prepared
      and tested for Na+-K+ ATPase activity and protein expression. IL-1beta inhibited
      by around 70% the activity of the ATPase in the left and right ventricles. This
      inhibition of the pump was ascribed to a decrease in its protein expression as
      demonstrated by western blot analysis. A dose and time response study conducted
      on isolated cardiac myocytes confirmed the inhibitory role of the cytokine on the
      ATPase and showed that IL-1beta exerts its maximal down-regulatory effect at 2 h
      and at a dose of 20 ng/ml. The cytokine caused also an up-regulation of the
      NaKCl2 cotransporter. Both MEK and p38MAPK were shown to be involved in the
      signaling pathway activated by the cytokine. It can be concluded that the
      decrease in the Na+-K+ ATPase concentration observed in heart diseases is a
      consequence of the accompanying high levels of IL-1beta, and may be responsible
      for the different symptoms that accompany cardiac ischemia.

PMID- 15016407
TI  - TNF-alpha promoter, Nod2 and toll-like receptor-4 polymorphisms and the in vivo
      and ex vivo response to endotoxin.
AB  - Humans exhibit substantial inter-individual differences in TNF-alpha production
      upon endotoxin stimulation. To determine to what extent the lipopolysaccharide
      induced TNF-alpha production capacity in vivo and ex vivo is determined by
      polymorphisms in toll-like receptor-4 (TLR4), the TNF-alpha promoter region and
      Nod2, we screened for two TLR4 polymorphisms, a Nod2 polymorphism and the TNF
      alpha promoter polymorphisms. We measured the perioperative endotoxemia and TNF
      alpha production and the TNF-alpha production capacity of each patient in a whole
      blood stimulation assay using blood drawn before anesthesia, using various LPS
      concentrations, in patients undergoing elective cardiac surgery. This operation
      represents a major surgical trauma associated with ischemia-reperfusion injury
      and triggers an endotoxemia and profound inflammatory response. In vivo TNF-alpha
      production was positively correlated with the level of endotoxemia after aortic
      declamping; thus TNF-alpha levels were higher in patients having endotoxemia
      compared to patients without endotoxemia. This correlation was observed in
      patients with any of the genotypes studied, and did not differ between the
      various genotypes. In vivo TNF-alpha levels correlated best with those ex vivo
      after stimulation with 1000 ng/mL LPS, and the estimated maximal TNF-alpha
      release capacity. Subjects with the wild-type TLR4 gene had similar levels of TNF
      alpha upon LPS stimulation ex vivo as compared with patients carrying Asp299Gly
      and/or the Thr399Ile TLR4 polymorphism. Our results indicate that polymorphisms
      in the TLR4 receptor, Nod2 and TNF-alpha promoter region are not strongly
      associated with in vivo and ex vivo TNF-alpha production capacity upon endotoxin
      stimulation. This suggests that in this model of natural LPS release, the
      variation between individuals in TNF-alpha release can only modestly be
      determined by genetic background (TNF-alpha promoter, Nod2 and TLR4) of the
      individual.

PMID- 15016408
TI  - Modification of cord blood IL-6 production with IgM enriched human immunoglobulin
      in term and preterm infants.
AB  - Pro-inflammatory cytokines contribute significantly to the morbidity of premature
      infants. IL-6 and IL-8 are involved in the pathogenesis of pulmonary and cerebral
      tissue injury. The effect of human immunoglobulin preparations on cytokine
      production in preterm infants has not been studied. We investigated the influence
      of immunoglobulin on LPS stimulated IL-6 and IL-8 production in cord blood of
      healthy preterm neonates. Ten non-infected preterm infants delivered by cesarean
      section and 5 healthy term neonates were included. In the preterm infants,
      significant IL-6 production was observed in the absence of immunoglobulin after 4
      h [median 113 (39-725) pg/ml], 8 h [375 (234-1795) pg/ml] and 12 h [360 (248
      2765) pg/ml] of LPS incubation. IL-6 concentrations were significantly lower
      after incubation with LPS+immunoglobulin after 4 h [median 38 (5-568) pg/ml;
      p=0.005], 8 h [178 (10-1830) pg/ml; p=0.001] and 12 h [182 (29-2530) pg/ml;
      p=0.002]. Cultures from term infants produced IL-6 levels approx. 4 times of
      those from premature infants unaffected by immunoglobulin. IL-8 production also
      correlated to gestational age and was not affected by immunoglobulin in both
      groups. Human immunoglobulin preparation may modify IL-6 production in cord blood
      cultures from premature infants.

PMID- 15016409
TI  - Middle ear epithelial mucin production in response to interleukin-6 exposure in
      vitro.
AB  - OBJECTIVES: To investigate the role of the inflammatory cytokine interleukin-6
      (IL-6) in the regulation of mucin secretion by middle ear epithelia. MATERIALS
      AND METHODS: Primary chinchilla middle ear epithelial cultures were established
      and exposed to IL-6 in a dose- and time-dependent manner. Mucin secretion was
      characterized by exclusion chromatography and liquid scintillation. RESULTS:
      Epithelial cultures exposed to increasing doses of IL-6 demonstrated greater
      amounts of mucin secretion (p=0.018). Additionally, cultures exposed to IL-6 at
      50 ng/ml showed significant increased secretion of mucin over control in time
      dependent experiments at 6-, 15- and 24-h time points (p=0.003). CONCLUSIONS: IL
      6 upregulates mucin secretion from cultured middle ear epithelial cells in a dose
      and time-dependent manner. Elucidating the effect of specific cytokines on the
      regulation of mucin secretion is vital to understanding the pathophysiology of
      otitis media and the development of novel therapeutic strategies.

PMID- 15016410
TI  - Molecular cloning and characterization of a novel rat CXC chemokine, rPBP, the
      homologue of human and mouse PBP.
AB  - We have previously cloned the mouse platelet basic protein (mPBP), a homologue of
      human PBP, from mouse thymic stromal cells. Using EST alignment and RT-PCR, the
      rat homologue of human and mouse PBP was cloned from lung and named as rPBP. The
      complete open reading frame and part of the 3'- and 5'-non-coding regions were
      obtained through rapid amplification of cDNA ends. The rPBP cDNA encodes a
      protein of 111 amino acids containing a signal peptide of 37 amino acids at the N
      terminus, with the mature protein of 74 amino acids. The rPBP is a new member of
      ELR+CXC chemokines. The mature protein of rPBP shares 69% and 45% homology with
      mouse and human PBP, respectively. In situ hybridization assay revealed rPBP to
      be predominantly localized in the pulmonary vascular endothelial cells. The
      eukaryotic expression vector pCDNA3-rPBP was constructed and transiently
      transfected into COS-7 cells. In the in vitro chemotaxis assay, the
      polymorphonuclear leukocytes (PMNs) were chemoattracted to the supernatants from
      transfected COS-7 cells in a dose-dependent manner. The implication of rPBP found
      in rat lung is that this chemokine may have the function to recruit PMNs to fight
      against pulmonary infection.

PMID- 15016412
TI  - Modelling the biochemical degradation of solid waste in landfills.
AB  - This paper describes the concept of a generic spatially distributed numerical
      model that has been developed to contain and link sub-models of landfill
      processes in order to simulate solid waste degradation and gas generation in
      landfills. The model includes the simulation of the transport of leachate and
      gases, and the consolidation of the solid waste. The structure of the model
      consists of linked discrete constant volume elements. The paper outlines the
      theoretical background that provides the framework to contain the numerical
      procedures that make up the model. Details are also given of the approach to the
      modelling of the chemistry and microbiology of solid waste degradation.

PMID- 15016413
TI  - Stochastic modelling of landfill processes incorporating waste heterogeneity and
      data uncertainty.
AB  - A landfill is a very complex heterogeneous environment and as such it presents
      many modelling challenges. Attempts to develop models that reproduce these
      complexities generally involve the use of large numbers of spatially dependent
      parameters that cannot be properly characterised in the face of data uncertainty.
      An alternative method is presented, which couples a simplified microbial
      degradation model with a stochastic hydrological and contaminant transport model.
      This provides a framework for incorporating the complex effects of spatial
      heterogeneity within the landfill in a simplified manner, along with other key
      variables. A methodology for handling data uncertainty is also integrated into
      the model structure. Illustrative examples of the model's output are presented to
      demonstrate effects of data uncertainty on leachate composition and gas volume
      prediction.

PMID- 15016414
TI  - Extended phase relations and load effects in MSW.
AB  - The moisture retention and compression characteristics of municipal solid waste
      under self-weight are likened to those of an unsaturated soil. By assuming that
      the solid organic fraction in waste retains a relatively immobile micropore
      moisture and that deformation at low confining stress occurs at the expense of a
      relatively large macropore system, an insight into the variation of density and
      moisture with depth can be gained. With data on the composition of the waste, the
      phase composition can be extended to distinguish between solid organic and solid
      inorganic fractions, resulting in a four phase material model. The model is
      developed using detailed moisture and waste composition data from the Lyndhurst
      Sanitary Landfill site in Victoria, Australia. Finally, comparison of the model
      with large scale compression test results provides an insight into the nature of
      waste compression and moisture content data at low confining stress.

PMID- 15016415
TI  - Modelling the compression behaviour of landfilled domestic waste.
AB  - This paper discusses the mechanisms involved in the compression of domestic
      waste, and how the resulting compression behaviour may be modelled. Reference is
      made to experimental data illustrating the effect of gas content and pore water
      pressure on bulk density and drainable porosity, and a theoretical model able to
      reproduce some but not all features of the data is presented.

PMID- 15016416
TI  - Modelling flow to leachate wells in landfills.
AB  - Vertical wells are frequently used as a means of controlling leachate levels in
      landfills. They are often the only available dewatering option for both old
      landfills without any basal leachate collection layer and for newer sites where
      the installed drainage infrastructure has failed. When the well is pumped, a
      seepage face develops at the entry into the well so that the drawdown in the
      surrounding waste will not be as great as might be expected. The numerical
      groundwater flow model MODFLOW-SURFACT, which contains the functionality to model
      seepage surfaces, has been used to investigate the transient dewatering of a
      landfill. The study concludes that the position of the seepage face and
      information about the characteristics of the induced seepage flow field are
      important and should not be neglected when designing wells in landfills.

PMID- 15016417
TI  - An environmentally sustainable decision model for urban solid waste management.
AB  - The aim of this work is to present the structure and the application of a
      decision support system (DSS) designed to help decision makers of a municipality
      in the development of incineration, disposal, treatment and recycling integrated
      programs. Specifically, within a MSW management system, several treatment plants
      and facilities can generally be found: separators, plants for production of
      refuse derived fuel (RDF), incinerators with energy recovery, plants for
      treatment of organic material, and sanitary landfills. The main goal of the DSS
      is to plan the MSW management, defining the refuse flows that have to be sent to
      recycling or to different treatment or disposal plants, and suggesting the
      optimal number, the kinds, and the localization of the plants that have to be
      active. The DSS is based on a decision model that requires the solution of a
      constrained non-linear optimization problem, where some decision variables are
      binary and other ones are continuous. The objective function takes into account
      all possible economic costs, whereas constraints arise from technical, normative,
      and environmental issues. Specifically, pollution and impacts, induced by the
      overall solid waste management system, are considered through the formalization
      of constraints on incineration emissions and on negative effects produced by
      disposal or other particular treatments.

PMID- 15016418
TI  - Waste management models and their application to sustainable waste management.
AB  - The purpose of this paper is to review the types of models that are currently
      being used in the area of municipal waste management and to highlight some major
      shortcomings of these models. Most of the municipal waste models identified in
      the literature are decision support models and for the purposes of this research,
      are divided into three categories-those based on cost benefit analysis, those
      based on life cycle assessment and those based on multicriteria decision making.
      Shortcomings of current waste management models include that they are concerned
      with refinements of the evaluation steps (e.g. stage four of AHP or the
      improvement of weight allocations in ELECTRE) rather than addressing the decision
      making process itself. In addition, while many models recognise that for a waste
      management model to be sustainable, it must consider environmental, economic and
      social aspects, no model examined considered all three aspects together in the
      application of the model.

PMID- 15016419
TI  - Cogeneration from thermal treatment of selected municipal solid wastes. A
      stoichiometric model building for the case study on Palermo.
AB  - This paper aims to calculate the energetic and environmental effects of an
      integrated solid waste management system in Palermo, Italy. In particular, the
      thermal treatment of Municipal Solid Waste (MSW) with energy recovery is
      assessed. The current characterization at the local scale is taken into account.
      Two different options of collection are taken into account: (1) unselected
      wastes; and (2) sorted collection, according to the current Italian regulation.
      Combustion process is analyzed and the following features are calculated: (1)
      stoichiometric content of air and air excess; and (2) temperature and enthalpy of
      flue gases. Energy recovery is performed in the hypothesis of Hirn cycle both
      with steam condensation to produce only power, and with bleeding cycle for the
      combined production of power and thermal energy. Total electric efficiency is
      assumed as representative index of the technological level of the assessed plant.
      Results show that the thermal treatment of selected MSW, associated with a
      cogenerative recovery of energy, represents a relevant sustainable strategy of
      waste valorization as an alternative to fossil fuels.

PMID- 15016420
TI  - Sympathetic nervous system mediates cold stress-induced suppression of natural
      killer cytotoxicity in rats.
AB  - The aim of the present study is to investigate the mechanisms of suppression of
      splenic natural killer (NK) cytotoxicity caused by cold stress, using 6
      hydroxydopamine (6-OHDA) as chemical sympathectomy. The NK activity was measured
      by (51)chromium release assay. Central sympathectomy with intracerebroventricular
      injection of 6-OHDA significantly reduced the elevation of the plasma
      corticosterone level, the expression of Fos in hypothalamic paraventricular
      nucleus and in locus coeruleus, as well as the suppression of NK activity induced
      by cold stress at 4 degrees C for 4 h. Peripheral sympathectomy with
      intraperitoneal (i.p.) injection of 6-OHDA and blockade of beta-adrenergic
      receptor with i.p. injection of propranolol also reversed the cold stress-induced
      suppression of NK cytotoxicity, but without significant effect on Fos expression
      in the brain. The results suggest that the activation of the hypothalamic
      pituitary-adrenal axis induced by cold stress might be mediated, at least
      partially, by the central noradrenergic system, and that the cold stress-induced
      suppression of NK cytotoxicity might be mediated by the activation of the
      peripheral sympathetic nerve.

PMID- 15016421
TI  - Poorer cognitive performance in humans with mild cognitive impairment carrying
      the T variant of the Glu/Asp NOS3 polymorphism.
AB  - Mild cognitive impairment (MCI) is a transitional state between normal aging and
      Alzheimer's disease (AD) and is a high-risk condition for dementia. The
      endothelial nitric oxide synthase (NOS3) gene encodes endothelial NOS, an enzyme
      that regulates the production of the vasodilatory nitric oxide associated with
      the cerebral small vessel pathology observed in early AD. We studied the
      distribution of genotype and allele frequencies of the NOS3 Glu/Asp polymorphism
      in a sample of 62 MCI subjects and 136 controls. Though no association between
      NOS3 gene variation and MCI status was observed, MCI cases carrying the Asp
      variant (T+) performed worse in the Mini-Mental State Examination, Wechsler
      Memory Scale (Revised) long-term visual memory and the phonetic verbal fluency
      tests. These results suggest that the T allele is a genetic risk factor for
      cognitive impairment in the elderly.

PMID- 15016422
TI  - Participation of transcription factors from the Rel/NF-kappa B family in the
      circadian system in hamsters.
AB  - We have studied the presence and activity of components of the nuclear factor
      kappaB (NF-kappaB) transcription factor in the hamster circadian system analyzing
      wheel-running activity, protein expression and DNA binding activity by
      electrophoresis mobility shift assays (EMSA). Non-rhythmic specific
      immunoreactive bands corresponding to a NF-kappaB subunit (p65) were found in
      hamster suprachiasmatic nuclei (SCN) homogenates. The active form of NF-kappaB
      evidenced by EMSA was clear and specific in SCN nuclear extracts. The
      administration of the NF-kappaB inhibitor pyrrolidine-dithiocharbamate (PDTC)
      blocked the light-induced phase advance at circadian time 18 (vehicle+light
      pulse: 2.08+/-0.46 h, PDTC+light: 0.36+/-0.35 h). These results demonstrate the
      presence and activity of Rel/NF-kappaB family proteins in the hamster SCN and
      suggest that these proteins may be related to the entrainment and regulation of
      circadian rhythms.

PMID- 15016423
TI  - Enhancement of dopamine-induced signaling responses in the forebrain of mice
      lacking dopamine D3 receptor.
AB  - It is well known that the dopamine D(3) receptor plays a critical role in several
      psychological disorders, such as drug dependence. The present study was designed
      to investigate the influence of lacking dopamine D(3) receptors in dopamine
      induced G-protein activation and Ca(2+) influx in the mouse forebrain. The
      deletion of dopamine D(3) receptor gene caused the enhancement of dopamine
      induced G-protein activation in the limbic forebrain of dopamine D(3) receptor
      knockout (D(3)KO) mice. Furthermore, the dopamine-induced Ca(2+) influx was
      enhanced in the coculture of neuron/glia cells obtained from the forebrain of
      D(3)KO mice. The present data provide direct evidence that a deletion of central
      dopamine D(3) receptor enhances the dopamine D(1)/D(2) receptor-mediated
      intracellular signaling.

PMID- 15016424
TI  - Circadian patterns of neurotransmitter related gene expression in motor regions
      of the rat brain.
AB  - Mammalian motor activity displays circadian patterns in normal behaviour and in
      many movement disorders, like levodopa responsive dystonia and Parkinson's
      disease. Here, we hypothesized that a circadian pattern of dopamine synthesis
      would trigger rhythms in the expression of genes in regions receiving
      dopaminergic innervation. Indeed tyrosine hydroxylase and cholecystokinin mRNA
      were upregulated in the substantia nigra and ventral tegmental area in the course
      of the day. However, in the caudate putamen, the mRNA levels, for dopamine D2 and
      adenosine 2A receptor, dynorphin, and substance P were lower during the day than
      during the night, whereas the expression of dopamine D1 receptor, enkephalin, and
      somatostatin was stable. In the frontal cortex, a clear midday peak of enkephalin
      expression was detected, while cholecystokinin and vasoactive intestinal peptide
      expression did not vary. Clear circadian gene expression patterns can therefore
      be demonstrated in brain regions involved in motor regulation, but they do not
      follow a simple dopaminergic drive and more complex regulatory patterns have to
      be assumed.

PMID- 15016425
TI  - Antihyperalgesic effect of the cannabinoid agonist WIN55,212-2 is mediated
      through an interaction with spinal metabotropic glutamate-5 receptors in rats.
AB  - In the current study, a possible interaction between spinal cord dorsal horn
      cannabinoid and mGlu5 receptors was evaluated in rats with a peripheral nerve
      injury. Following unilateral loose ligation of a sciatic nerve, rats developed
      decreased withdrawal thresholds to noxious pressure (mechanical hyperalgesia) of
      the ligated but not the unoperated contralateral hind paw. Systemic
      (subcutaneous) injection of synthetic cannabinoid agonist WIN55,212-2 increased
      withdrawal thresholds of both the ligated and the unoperated hind paw. Systemic
      injection of 2-methyl-6-(phenylethynyl)pyradine (MPEP), an antagonist selective
      for the mGlu5 receptor, did not alter the antinociceptive and antihyperalgesic
      effects of systemic WIN55,212-2. Intrathecal (i.t.) injection of WIN55,212-2
      increased thresholds of the ligated but not the unoperated hind paw. Intrathecal
      injection of MPEP reversed the antihyperalgesic effect of i.t. WIN55,212-2.
      Neither systemic nor i.t. injection of MPEP alone altered withdrawal thresholds.
      These data suggest that the antihyperalgesic effect of WIN55,212-2 is mediated
      through an interaction with spinal mGlu5 receptors.

PMID- 15016426
TI  - Mental calculation impairment in Alzheimer's disease: a functional magnetic
      resonance imaging study.
AB  - This functional MRI study investigates cerebral activations during mental
      arithmetic performance, in patients diagnosed with probable Alzheimer's disease
      (with mild to moderate severity) and age-matched healthy controls. The arithmetic
      task consisted in three-digit addition and subtraction problems. The task
      elicited bilateral parietal and prefrontal activations in the control group, in
      agreement with previous imaging studies of mental arithmetic. In the Alzheimer
      group, inferior parietal and lateral prefrontal activations were significantly
      reduced when compared to controls (corrected P < 0.05 ). This important reduction
      of activity was likely responsible for the patients' poor performance in the
      task. These results confirm the deficit in calculation abilities, which occurs
      early in Alzheimer's disease, and provide additional knowledge of the neural
      mechanisms underlying this impairment.

PMID- 15016427
TI  - Mental retardation and hypotonia seen in the knock out mouse for Canavan disease
      is not due to succinate semialdehyde dehydrogenase deficiency.
AB  - Canavan disease (CD) is an autosomal recessive disorder caused by aspartoacylase
      deficiency leading to accumulation of N-acetylaspartic acid and spongy
      degeneration of the brain. The mouse model for CD showed low levels of glutamate
      and gamma-aminobutyric acid (GABA) in the brain. Whether the low levels of
      glutamate and GABA observed in the CD mouse brain lead to abnormal production of
      glutamate-GABA associated enzymes and resulting succinate production is not
      obvious. While glutamate dehydrogenase and alpha-ketoglutarate dehydrogenase
      complex activities are lower in the cerebellum and brain stem of the CD mouse,
      alanine aminotransferase and succinate semialdehyde dehydrogenase (SSADH)
      activities and succinate level are similar to the levels observed in the wild
      type. Deficiency of SSADH has been suggested to be associated with mental
      retardation and hypotonia, similar to the clinical features of CD. The normal
      SSADH activity in the CD mouse brain suggests that mental retardation and
      hypotonia seen in the CD mouse is not due to SSADH activity and if documented
      also in patients with CD.

PMID- 15016428
TI  - 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) increases GABAA receptor-mediated
      spontaneous postsynaptic currents in the dentate granule cells of rat hippocampal
      slices.
AB  - 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) is widely used as an antagonist on
      non-NMDA glutamate receptors. However, several studies have shown that CNQX
      increases the spontaneous inhibitory postsynaptic current frequency at
      hippocampal pyramidal neurons and cerebellar granule cells. Dentate granule cells
      are known to be another distinctive type of principal neurons in hippocampus, and
      receive dense synaptic input from hilar interneurons. Thus, we examined the
      effects of CNQX on the dentate granule cells and hilar interneurons with whole
      cell recording. CNQX increased the frequency of GABAergic spontaneous
      postsynaptic currents (sPSCs) on the granule cells, and increased the resting
      potential and the action potential frequency of the hilar interneurons. These
      increases were not observed with other glutamate receptor antagonists. The
      increases in sPSC frequency may be caused by the depolarization and the action
      potentials of the interneurons.

PMID- 15016429
TI  - Riluzole restores motor activity in rats with post-traumatic peripheral
      neuropathy.
AB  - Riluzole is a presynaptic inhibitor of glutamate release with neuroprotective
      properties. In order to evaluate the effects of riluzole on motor activity in
      post-traumatic peripheral neuropathy (PTPN), the sciatic nerve of Wistar male
      rats was exposed monolaterally and subjected to crushing for one min by a
      surgical forceps. Animals received an intraperitoneal treatment with riluzole (2,
      4 or 8 mg/kg per day), diclofenac (5, 10 or 20 mg/kg) or with vehicle for 3 days.
      Motor activity and coordination was evaluated in a circular open field and in the
      rotorod test. The treatment with riluzole stimulated ambulation in PTPN rats and
      improved their motor performance and coordination. The effect of treatment with
      riluzole on locomotor activity was greater than that of treatment with diclofenac
      and was dose-dependent. Furthermore, in contrast to vehicle- and diclofenac
      treated rats, animals treated with riluzole showed a long-lasting improvement of
      locomotor activity as it was assessed 7 days after the end of treatment. These
      findings suggest that riluzole may improve motor performance in PTPN, and this
      does not depend on its antinociceptive activity. Its neuroprotective properties
      are possibly involved in this effect.

PMID- 15016430
TI  - Paraoxonase 1 gene polymorphisms and dementia in humans.
AB  - Several clinical and epidemiological studies suggest that Alzheimer's disease
      (AD) and vascular dementia share common risk factors. Oxidative stress is one of
      these well recognized factors. It can result from an excess of free-radical
      activity and impaired antioxidant defenses. Paraoxonase (PON1), a component of
      high density lipoproteins, has antioxidative potential and was previously
      associated with an increased risk of cardiovascular diseases. The impact of two
      polymorphisms in PON1 (Gln192Arg associated with enzyme activity and T-107C
      associated with enzyme concentration) was examined in a case-control study. The
      two polymorphisms were independent risk factors for nonAD dementia, particularly
      in APOE-4 noncarriers. An at-'risk haplotype' could be constructed including the
      Gln192 and the T-107 alleles, suggesting that subjects at risk have lower plasma
      paraoxonase levels and this enzyme is less active.

PMID- 15016431
TI  - Dipolar source modelling of brain potentials evoked by painful electrical
      stimulation of the human sigmoid colon.
AB  - The aim of the study was to compare the cerebral generators following painful
      stimulation of the sigmoid colon and the abdominal skin in 11 healthy subjects.
      The evoked potentials (EPs) were recorded from 31 surface electrodes following
      painful electrical stimuli of the sigmoid colon, and of the referred pain area on
      the abdomen. Current dipole models estimating the EPs amplitude and topography
      were calculated. For colon stimulation, the earliest cortical activities were
      described by dipoles in the bilateral insula and in the anterior cingulate
      cortex, while both secondary somatosensory areas were activated later. When the
      skin was stimulated, early bilateral dipoles in the primary and secondary
      somatosensory areas were estimated, followed by a dipole in the frontal region.
      This suggests that painful cutaneous and visceral stimuli are processed
      differently in the brain.

PMID- 15016432
TI  - The dual pattern of corticothalamic projection of the primary auditory cortex in
      macaque monkey.
AB  - The distribution and terminal morphology of the corticothalamic projection
      originating from the primary auditory cortex (A1) were established in a macaque
      monkey, using the anterograde (and retrograde) tracer biotinylated dextran amine.
      A dense corticothalamic projection from A1 was found in the ventral (vMGB) and
      dorsal (dMGB) divisions of the medial geniculate body and, to a lesser extent, in
      the medial division (mMGB), the posterior thalamic nucleus (PO) and the
      suprageniculate nucleus. Most terminal boutons were small (<1 microm), except
      some large boutons (2-6 microm) located in PO and vMGB. The data demonstrate that
      the corticothalamic projection from A1 in primate consists of two types of
      terminals (small and giant endings) in line with previous observations in rat and
      cat. Retrogradely labeled thalamocortical neurons formed clusters generally
      overlapping the corticothalamic terminal fields.

PMID- 15016433
TI  - Dopaminergic contributions to modulatory functions of a dual-transmitter
      interneuron in Aplysia.
AB  - The feeding central pattern generator of Aplysia produces motor programs that can
      differ in the degree to which they are ingestive or egestive. A number of pattern
      generating interneurons that play an important role in shaping motor programs
      have been identified. One of these interneurons, B65, is unusual in that it
      contains two classical neurotransmitters, dopamine and gamma-aminobutyric acid.
      Here, we study the role of one of these transmitters, dopamine, using a
      combination of pharmacological and electrophysiological means. We show that B65
      uses dopamine to elicit fast synaptic potentials in several follower neurons.
      Furthermore, we demonstrate that the dopamine antagonist sulpiride mimics the
      effect of bilateral B65 hyperpolarization on egestive motor programs. Thus our
      data suggest that dopaminergic transmission serves to increase the degree of
      egestiveness of motor programs, and decrease the duration of the protraction
      phase.

PMID- 15016434
TI  - Experimental autoimmune encephalomyelitis in mice with a targeted deletion of the
      inducible nitric oxide synthase gene: increased T-helper 1 response.
AB  - Mice with a targeted deletion of the cytokine-inducible nitric oxide synthase
      gene (iNOS(-/-)) show increased severity of experimental autoimmune
      encephalomyelitis (EAE). We studied the mechanisms of susceptibility to myelin
      basic protein-induced 'active' EAE in iNOS(-/-) mice. Spleen cells and lymph node
      cells from iNOS(-/-) mice with EAE showed a significantly enhanced ex vivo
      proliferation and production of T-helper 1 (Th1) cytokines (interferon-gamma by
      157 and 57% and tumor-necrosis-factor-alpha by 86 and 27%, respectively). We
      conclude that NO produced by iNOS plays a protective role in EAE probably by
      inhibiting the production of Th1 cytokines and T cell proliferation.

PMID- 15016435
TI  - Single-cell RT-PCR analysis of GIRK channels expressed in rat locus coeruleus and
      nucleus basalis neurons.
AB  - G protein-coupled inward rectifier potassium channels (GIRK, Kir3) play a crucial
      role in determining neuronal excitability. Currently, four mammalian GIRK members
      (GIRK1-4) have been genetically identified. We have been investigating
      physiological properties of GIRKs in cultured noradrenergic neurons from the
      locus coeruleus (LC) and cholinergic neurons from the nucleus basalis (NB). Yet,
      precise information is lacking about which types of GIRK channels are present in
      these neurons. We performed single-cell RT-PCR on these cultured neurons. In 13
      noradrenergic LC neurons, GIRK1, GIRK2, GIRK3, and GIRK4 mRNAs existed in 12, 13,
      nine, and six neurons, respectively. In six cholinergic NB neurons, GIRK1, GIRK2,
      GIRK3, and GIRK4 mRNAs existed in six, four, one, and three neurons,
      respectively. Therefore, GIRK1 and GIRK2 mRNAs are most frequently encountered in
      both LC and NB neurons.

PMID- 15016436
TI  - A study of bile acids as opioid receptor ligands in rat brain membranes.
AB  - There is evidence to suggest that the pruritus that results from liver disease is
      mediated, at least in part, by opioid receptor-ligand interactions; a central
      component has been proposed. Opiate drugs with agonist activity at opioid
      receptors induce naloxone-reversible pruritus. Bile acids accumulate in tissues
      in liver disease. We studied the ability of bile acids to displace specific
      opioid ligands from opioid receptors in rat and guinea pig brain membrane
      preparation in binding assays. None of the bile acids studied displaced
      significantly the opioid ligands from their receptors suggesting that bile acids
      in vitro are not opioid receptor ligands. The results of this study do not
      support a role of these bile acids as direct pruritogens by an opioid receptor
      mediated mechanism.

PMID- 15016438
TI  - Bioremediation of soils contaminated with explosives.
AB  - The large-scale industrial production and processing of munitions such as 2,4,6
      trinitrotoluene (TNT) over the past 100 years led to the disposal of wastes
      containing explosives and nitrated organic by-products into the environment. In
      the US, the Army alone has estimated that over 1.2 million tons of soil have been
      contaminated with explosives, and the impact of explosives contamination in other
      countries is of similar magnitude. In recent years, growing concern about the
      health and ecological threats posed by man-made chemicals have led to studies of
      the toxicology of explosives, which have identified toxic and mutagenic effects
      of the common military explosives and their transformation products (Bruns-Nagel
      et al., 1999a; Fuchs et al., 2001; Homma-Takeda et al., 2002; Honeycutt et al.,
      1996; Rosenblatt et al., 1991; Spanggord et al., 1982; Tan et al., 1992 and Won
      et al., 1976). Because the cleanup of areas contaminated by explosives is now
      mandated because of public health concerns, considerable effort has been invested
      in finding economical remediation technologies. Biological treatment processes
      are often considered, since these are usually the least expensive means of
      destroying organic pollution. This review examines the most important groups of
      chemicals that must be treated at sites contaminated by explosives processing,
      the chemical and biological transformations they undergo, and commercial
      processes developed to exploit these transformations for treatment of
      contaminated soil. We critically examine about 150 papers on the topic, including
      approximately 60 published within the past 5 years.

PMID- 15016437
TI  - A qualitative tool combining an interaction matrix and a GIS to map vulnerability
      to traffic induced air pollution.
AB  - Local authorities and transport planners need fast and straightforward tools to
      perform their preliminary air quality assessments. Such tools are required to
      provide an initial impression of the local air quality and to highlight areas
      requiring a more rigorous investigation. This paper presents a technique to
      develop such a tool, for performing an initial assessment of air quality due to
      traffic in an urban area. The technique combines an interaction matrix
      methodology as developed for rock engineering systems, with Geographical
      Information System (GIS) map overlaying. This interaction matrix methodology
      incorporates a total system approach, which identifies the main parameters and
      quantifies the interactions between them. Weighting values for these parameters
      are obtained either through parametric studies, using numerical modelling, or
      from engineering judgement. These weightings are applied to spatial datasets for
      a study area using a GIS. The GIS results are presented in the form of a
      vulnerability map, which highlights the areas susceptible to poor air quality.
      This visual interpretation of the results is ideal for local authorities, who
      have to report to a wide range of non-specialists in the field, for example,
      planners, councillors and the public. The vulnerability map compares favourably
      with pollutant concentration patterns, obtained from an advanced dispersion
      model.

PMID- 15016439
TI  - Assessment of AWT systems in the metro Atlanta area.
AB  - A study was conducted to evaluate the performance of six advanced wastewater
      treatment facilities using biological nutrient removal processes as the primary
      mechanism for removing carbon, nitrogen, and phosphorus from domestic wastewater.
      One year of operating data was obtained from monthly operating reports provided
      by the Georgia Environmental Protection Division (EPD) in Atlanta. Additional
      information about facility operations and the types of chemicals used was
      gathered through review of EPD files and interviews with plant personnel. Data
      evaluated were: influent and effluent five-day Biochemical Oxygen Demand
      (BOD(5)); influent and effluent total suspended solids (TSS); influent Total
      Kjeldahl Nitrogen and effluent Total Nitrogen; and influent and effluent Total
      Phosphorus (TP). Although varying from plant to plant, effluent requirements for
      BOD(5), TSS, ammonia, and TP were met. Chemicals utilized, design capacity, and
      monthly effluent concentrations are presented in this study.

PMID- 15016440
TI  - Selecting agri-environmental indicators to facilitate monitoring and assessment
      of EU agri-environmental measures effectiveness.
AB  - Since its introduction in the early 1960s, the EU Common Agricultural Policy
      (CAP) has demonstrated a capacity to adapt and change in the face of new
      challenges. The reformed CAP, under AGENDA 2000, encourages more environmentally
      friendly farming practices. In the context of their rural development plans,
      Member States are required to link policies on agriculture with protection of the
      environment and to ensure that farmers meet environmental standards.
      Additionally, Member States should maintain and restore the quality of both their
      aquatic and adjacent terrestrial ecosystems according to the Directive
      2000/60/EU, 'Establishing a framework for Community Action in the field of Water
      Policy'. Within this framework, agri-environmental indicators play an important
      role in planning and implementing CAP guidelines. However, selection and use of
      the proper indicators remains unresolved, considering that ecosystem processes
      are complex and interactions in most cases not obvious. This paper proposes a
      methodology for assessing the environmental state and impacts of current land use
      and management when implementing agri-environmental measures of CAP. The proposed
      methodology includes a modified Driving forces-Pressures-Impacts-Responses
      (DPSIR) framework, identification of Zones of Specific Functional Interest
      (ZSFI), and criteria for selecting agri-environmental indicators, which assess
      the functional performance of each zone and meet existing legislation. The
      Mygdonia Watershed (Greece) is an example where through use of both the
      appropriate Minimum Data Set of agri-environmental indicators at the identified
      zones and the proposed modified DPSIR, the functioning performance of each ZSFI
      can be assessed to evaluate the applied agri-environmental measures.

PMID- 15016441
TI  - Controlling Rhododendron ponticum in the British Isles: an economic analysis.
AB  - What resources should be committed to the control of invasive species? This study
      is based on a survey of nature conservation and forestry authorities, wildlife
      trusts and private landowners which investigated the extent of the ecological and
      economic impacts of the invasive non-native plant Rhododendron ponticum in the
      British Isles. There are data on 52,000 ha of land affected by R. ponticum, more
      than 30,000 ha of it in nature reserves. For nearly all nature reserves,
      displacement of native species and habitat changes were both reported. In 2001,
      respondents controlled 1275 ha of R. ponticum at a cost of pound 670,924. To test
      the optimality of this, we apply a model of social expenditure. The external
      costs of R. ponticum control are estimated from the probability that it will
      spread to contiguous sites and the damage done on invaded sites. These are then
      used to calculate the socially optimal level of expenditure on R. ponticum
      control, and the funding gap it identified by comparing the result with current
      levels of expenditure. The results suggest that a socially optimal level of
      control effort requires a significant increase in social funding for R. ponticum
      control, although the size of the increase varies between landholders.

PMID- 15016442
TI  - An approach for integrating economic impact analysis into the evaluation of
      potential marine protected area sites.
AB  - Marine protected areas (MPAs) are one tool that can be used in the comprehensive
      management of human activities in areas of the ocean. Although researchers have
      supported using MPAs as an ecosystem management tool, scientific research on MPAs
      in areas other than fisheries and fisheries management is limited. This paper
      presents a model for designing marine protected areas that protect important
      components of the ecosystem while minimizing economic impacts on local
      communities. This model combines conservation principles derived specifically for
      the marine environment with economic impact assessment. This integrated model
      allows for consideration of both fishery and non-fishery resources and activities
      such as shipping and recreational boating. An illustration of the model is
      presented that estimates the total economic impacts on Massachusetts' coastal
      counties of restricting fishing and shipping at certain sites in an area in the
      southern Gulf of Maine. The results suggest that the economic impacts on the
      region would differ according to the site in which shipping and fishing were
      restricted. Restricting activities in certain sites may have considerable impacts
      on local communities. The use of the model for evaluating and comparing potential
      MPA sites is illustrated through an evaluation of three different policy
      scenarios. The scenarios demonstrate how the model could be used to achieve
      different goals for managing resources in the region: protecting important
      components of the ecosystem, minimizing economic impacts on the local region, or
      a combination of the two.

PMID- 15016443
TI  - Estimating the opportunity costs of biodiversity protection in the Brigalow Belt,
      New South Wales.
AB  - The New South Wales Government recently introduced the Native Vegetation
      Conservation Act to protect the native grassland and woodland of the state. The
      Act protects biodiversity by preventing farmers from clearing such vegetation on
      their properties but, as a consequence, reduces farm incomes and land values. An
      economic model of the relationship between land value and percentage of farm in
      native vegetation is integrated with an ecological model of the relationship
      between species lost and percentage of the farms in native vegetation. The
      integrated framework is applied to estimate the opportunity costs of the Act for
      one important agricultural area of the state, the northern part of the Brigalow
      Belt South Bio-Region. If all the vegetation were protected, the reduction in
      land value would be at least 14.3%, which is an opportunity cost of at least
      148.5 dollars m for the area. Both the benefits and costs of biodiversity
      protection must be accounted for, so risk simulations are then combined with
      benefit-cost analysis to compare the benefits of biodiversity protection to these
      costs.

PMID- 15016444
TI  - Perception of drinking water in the Quebec City region (Canada): the influence of
      water quality and consumer location in the distribution system.
AB  - The purpose of every water utility is to provide consumers with drinking water
      that is aesthetically acceptable and presents no risk to public health. Several
      studies have been carried out to analyze people's perception and attitude about
      the drinking water coming from their water distribution systems. The goal of the
      present study is to investigate the influence of water quality and the geographic
      location of consumers within a distribution system on consumer perception of tap
      water. The study is based on the data obtained from two surveys carried out in
      municipalities of the Quebec City area (Canada). Three perception variables were
      used to study consumer perception: general satisfaction, taste satisfaction and
      risk perception. Data analysis based on logistic regression indicates that water
      quality variations and geographic location in the distribution system have a
      significant impact on the consumer perception. This impact appears to be strongly
      associated with residual chlorine levels. The study also confirms the importance
      of socio-economic characteristics of consumers on their perception of drinking
      water quality.

PMID- 15016445
TI  - Biochemical characterization of a novel hydantoin racemase from Agrobacterium
      tumefaciens C58.
AB  - A novel hydantoin racemase gene of Agrobacterium tumefaciens C58 (AthyuA2) has
      been cloned and expressed in Escherichia coli BL21. The recombinant protein was
      purified in a one-step procedure and showed an apparent molecular mass of 27000
      Da in SDS-gel electrophoresis. Size exclusion chromatography analysis determined
      a molecular mass of approximately 100000 Da, suggesting that the native enzyme is
      a tetramer. The optimum pH and temperature for hydantoin racemase activity were
      7.5 and 55 degrees C, respectively, with L-5-ethylhydantoin as substrate. Enzyme
      activity was strongly inhibited by Cu(2+) and Hg(2+). No effect on enzyme
      activity was detected with any other divalent cations, EDTA or DTT, suggesting
      that it is not a metalloenzyme. Kinetic studies showed the preference of the
      enzyme for hydantoins with short rather than long aliphatic side chains or
      hydantoins with aromatic rings.

PMID- 15016446
TI  - Expression patterns and phylogenetic analysis of two xylanase genes (htxyl1 and
      htxyl2) from Helminthosporium turcicum, the cause of northern leaf blight of
      maize.
AB  - A xylanase gene (htxyl2) was cloned from Helminthosporium turcicum, the cause of
      northern leaf blight of maize by screening the genomic library from the fungus
      using a approximately 500 bp PCR fragment of the gene as a probe. The gene is a
      second xylanase gene cloned from the fungus and it is different from the
      previously cloned xylanase gene (htxyl1). The two genes are grouped into separate
      clades in a phylogenetic tree based on DNA sequences. The patterns of htxyl1 and
      htxyl2 transcript accumulation were studied in vitro with different carbon and
      nitrogen sources and during infection of maize by the pathogen. In culture high
      htxyl1 transcript was detected in mycelium obtained from medium containing
      birchwood xylan and birchwood xylan plus xylose as sole carbon sources. On the
      other hand htxyl2 transcript was detected in a medium containing birchwood xylan
      plus xylose but not in the medium where only birchwood xylan was used as the sole
      carbon source. Addition of glucose to the basal inducing media had inhibitory
      effect to the expression of both genes. The htxyl1 transcript accumulation
      declined sharply with an increase in concentration of ammonium sulphate and
      glutamic acid, while increased htxyl2 transcript was observed with an increase in
      concentrations of the two nitrogen sources. Abundant htxyl2 transcript was
      detected at early and late stages of infection of maize by Helminthosporium
      turcicum. On the other hand no detectable htxyl1 transcript was found in northern
      blot under the test conditions. This study demonstrated that in H. turcicum
      xylanolytic system htxyl1 and htxyl2 are differentially expressed and might play
      important roles in the saprophytic and pathogenic phases of the fungus,
      respectively.

PMID- 15016447
TI  - Secondary structure of the 3' UTR of bicoid mRNA.
AB  - Formation of the Bicoid morphogen gradient in early Drosophila embryos requires
      the pre-localization of bicoid mRNA to the anterior pole of the egg. The program
      of bcd mRNA localization involves multiples steps and proceeds from oogenesis
      until early embryogenesis. This process requires cis-elements in the 3' UTR of
      bcd mRNA and successive and/or concomitant critical protein interactions.
      Furthermore, numerous RNA elements and binding proteins contribute to regulate
      bcd expression. In the present paper, we investigated the secondary structure of
      the full length 3' UTR of the bcd mRNA, using a variety of chemical and enzymatic
      structural probes. This RNA probing analysis allowed us to give a detailed
      description of the 3' UTR of the bcd mRNA and its organization into five well
      defined and independent domains (I-V). One prominent result that emerges from our
      data is the unexpected high degree of flexibility of the different domains
      relative to each others. This plasticity relies upon the open conformation of the
      central hinge region interconnecting domains II, III, and IV + V. Otherwise,
      dimerization of the 3' UTR, which participates to anchoring bcd mRNA at the
      anterior pole of the embryo, only results in discrete and local change in domain
      III. Domain I that contains sites for trans-acting factors exhibiting single
      stranded RNA binding specificity is mainly unstructured. By contrast, each core
      domains (II-V) is highly organized and folds into helices interrupted by bulges
      and interior loops and closed by very exposed apical loops. These elements mostly
      built specific determinants for trans-acting factors. Besides, these findings
      provide a valuable database for structure/function studies.

PMID- 15016448
TI  - Ontogenic and adult whole body distribution of aminopeptidase N in rat
      investigated by in vitro autoradiography.
AB  - Aminopeptidase N (APN), which is widely distributed in mammalian tissues, is able
      to cleave numerous regulatory peptides. The selective inhibitor of APN, [(125)I]
      RB129, has been used to study the distribution of this exopeptidase during rat
      prenatal development and adult life by in vitro whole-body autoradiography. In
      the central nervous system, APN shows a weak labeling compared to the major part
      of the non-nervous tissues in the embryo and in the adult. APN is progressively
      expressed in kidney, intestine, heart, lung, sensory organs, eye, and thymus. In
      organs such as the liver, the cartilages and the bones, altered levels of APN
      expression are observed during the development, or in the embryo compared to the
      adult, suggesting a role of APN during the liver haematopoiesis and bone growth.
      At this time, all the physiological functions of APN are still incompletely
      known, however its developmental pattern of expression strongly suggests a
      function of modulation of this enzyme during the development, next in
      physiological and/or pathological situations in adult. In this way, APN could
      represent a new therapeutic target in pathological processes, such as tumoral
      proliferation and/or angiogenesis associated with cancer development, where an
      increase in the level of this enzyme has been observed.

PMID- 15016449
TI  - Expression of galectin 4 in the rat small intestine during postnatal development.
AB  - We determined the expression of an endogenous lectin, galectin 4, in the rat
      small intestine during postnatal development. The mRNA levels of galectin 4 did
      not change significantly between birth and adulthood. In contrast, the protein
      was present at higher levels after than before weaning, and the potential ligands
      for galectin 4 were more highly represented in the enterocyte microvilli of
      weaned than of suckling rats. These results suggest possible differences either
      in galectin 4 mRNA stability, in its translation regulation or in the protein
      stability.

PMID- 15016450
TI  - Isotopic discrimination between D-[1-(13)C]fructose and D-[2-(13)C]fructose in
      rat liver cells.
AB  - When liver cells from either normal or hereditarily diabetic rats are exposed to
      (13)C-enriched D-fructose (10 mM) and unlabelled D-glucose (also 10 mM) in the
      presence of D(2)O, the output of (13)C-enriched D-glucose generated from D-[1
      (13)C]fructose is significantly lower than that from D-[2-(13)C]fructose. This
      coincides with a higher generation of (13)C-enriched L-lactate and L-alanine from
      D-[1-(13)C]fructose, as compared to D-[2-(13)C]fructose. In absolute terms, the
      mean paired difference in the output of (13)C-enriched D-glucose generated from D
      [1-(13)C]fructose versus D-[2-(13)C]fructose is not significantly different from
      the mean paired difference in the production of (13)C-enriched L-lactate and L
      alanine from the same precursors, with an overall mean value of 7.01 +/- 1.59
      micromol (n = 8; P < 0.005). It is proposed that these findings indicate isotopic
      discrimination at the phosphoglucoisomerase level between (12)C and (13)C for the
      carbon atom in position 1 (as compared to that in position 2) of D-fructose 6
      phosphate.

PMID- 15016451
TI  - Unfolding kinetics of dimeric creatine kinase measured by stopped-flow small
      angle X-ray scattering.
AB  - The unfolding kinetics of creatine kinase (CK) in various concentrations of urea
      or guanidine hydrochloride (GuHCl) was investigated by small angle X-ray
      scattering (SAXS) using synchrotron radiation, and compared with the results
      obtained by stopped-flow circular dichroism and stopped-flow fluorescence. Using
      the three methods, the unfolding kinetics of CK fits well to a single exponential
      function with similar apparent rate constants, and the amplitude of the
      monophasic kinetics covers the entire range of the equilibrium values. The
      results suggest that the unfolding time-course measured by integrated SAXS
      intensity corresponds to the intramolecular loss of globular structure. The
      refolding kinetics of 8 M urea-denatured CK was monitored in a stopped-flow
      apparatus by following the spectroscopic changes, and the final state of folding
      was investigated by SAXS. A substantial part of the ellipticity is recovered
      within a burst phase, indicating that the secondary structure forms at an early
      stage in refolding. The R(g) value of the final folded state was 33.6 A when the
      folding buffer contained 20% glycerol, which is characteristic of native-like
      compactness and globularity.

PMID- 15016452
TI  - Mutation of amino acid 475 of rat organic cation transporter 2 (rOCT2) impairs
      organic cation transport.
AB  - Protein sequence alignments revealed one amino acid position, where organic
      cation transporters (OCTs, aspartate (D) at position 475 of rOCT2) and organic
      anion transporters (OATs, arginine (R) at position 466 of rOAT1) are charged
      oppositely. To address the impact of this amino acid for protein function we
      cloned rat organic cation transporter 2 (rOCT2), the renal electrogenic cation
      transporter of the basolateral side of proximal tubule cells. Site-directed
      mutagenesis was used to generate rOCT2-D475R (rOCT2-mut). Heterologous expression
      of rOCT2 wild-type (rOCT2-wt) in A6 cells resulted in a significant uptake of the
      fluorescent organic cation 4-(4-dimethylaminostyryl)-N-methylpyridinium (ASP(+)).
      Accordingly, rOCT2-wt-transfected COS 7 cells showed an almost fourfold uptake of
      25 microM [(14)C]-TEA, whereas rOCT2-mut did not exhibit any uptake of [(14)C]
      TEA. These data indicate that rOCT2 transports both ASP(+) and TEA and that
      aspartate at position 475 of rOCT2 plays a critical role in transport function.

PMID- 15016453
TI  - Snake postsynaptic neurotoxins: gene structure, phylogeny and applications in
      research and therapy.
AB  - Snake venoms are complex mixtures of biologically active polypeptides that target
      a variety of vital physiological functions in mammals. alpha-Neurotoxins, toxins
      that cause paralysis by binding to the nicotinic receptors at the postsynaptic
      region of the neuromuscular junction have been widely studied in terms of their
      structure-function relationships as well as gene structure, organization and
      expression. In this review, we describe the structure of alpha-neurotoxin genes
      and discuss their evolutionary relationships. Almost all members of neurotoxins
      have been found to exhibit a common evolutionary origin. The importance of alpha
      neurotoxins in therapy and research has also been discussed to highlight their
      potential applications especially in the area of drug discovery.

PMID- 15016454
TI  - Purification and characterization of ascorbic acid 2-kinase from Flavobacterium
      devorans ATCC 10829.
AB  - Maximum activity for phosphorylating C(2)-OH of the ascorbic acid was observed at
      the time of 16 h incubation from the culture of Flavobacterium devorans ATCC
      10829. The enzyme was purified 1.178-fold, via ammonium sulfate fractionation,
      Fast Q anion exchange, and phenyl agarose chromatography. Gel chromatography and
      SDS-polyacrylamide electrophoresis experiments showed that the enzyme is a
      tetramer with subunit MW of 29 kDa. Among available second substrates,
      pyrophosphate showed the highest activity. Optimum temperature and pH were 45
      degrees C and 5.5, respectively. The enzyme was chemically modified only by
      diethylpyrocarbonate and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC),
      indicating that histidine and carboxylate are in the active site. pH studies
      showed that two histidines are involved in the binding of the substrates and a
      carboxylate in catalysis. Therefore, the chemical mechanism of the enzyme is
      likely that two histidines bind to pyrophosphate and carboxylate, respectively,
      and a carboxylate acts as a general base.

PMID- 15016455
TI  - Heavy metals--geochemical bogey men?
AB  - Heavy metals is a loose term usually used to indicate environmentally "bad"
      metals. It is poorly defined with a multitude of often contradictory definitions
      based on density, atomic weight, atomic number or other properties of the
      elements or their compounds. Alternative, scientifically rigorous definitions
      exist for subgroups of metals and should be used instead.

PMID- 15016456
TI  - Relationship between hydrocarbon measurements and toxicity to a chironomid, fish
      larva and daphnid for oils and oil spill chemical treatments in laboratory
      freshwater marsh microcosms.
AB  - This research investigated the extent to which various common hydrocarbon
      measures can be used to predict toxicity to freshwater aquatic organisms due to
      fouling by oil. Actual toxicity results, on laboratory freshwater marsh
      microcosms using two water-column species and a benthic species, were described
      earlier. The hydrocarbon measures used were TPH(g), TPH(FID), TPH(MS), TTAH (sum
      of 41 target aromatic hydrocarbons), principal components of 41 TAHs, and each
      individual TAH. In general, toxicity was more closely related to TPH(MS) levels
      than to TPH(FID) and (especially) TPH(g) levels. The strongest relationships were
      found for TTAH levels and for the principal components of the TAHs. Regressions
      of toxicity on many individual TAHs were also strong, with a single group of
      compounds explaining as much as 59% of the variation in survival. While the
      various regressions were highly significant statistically and at times able to
      accurately predict broad differences in toxicity, the high variation in survival
      at a specific hydrocarbon concentration indicates that these hydrocarbon measures
      can not substitute for actual toxicity determinations in accurately ranking the
      toxicity of samples from oiled freshwater marshes.

PMID- 15016457
TI  - Do laboratory salinity tolerances of freshwater animals correspond with their
      field salinity?
AB  - The degree to which laboratory derived measures of salinity tolerance reflect the
      field distributions of freshwater biota is uncertain. In this paper we compare
      laboratory-derived acute salinity tolerance (LC(50) values) of freshwater
      macroinvertebrates (range 5.5-76 mS/cm) and fish (range 2.7-82 mS/cm) from
      southeastern Australia with the salinity from which they have been collected in
      the field. Only 4% of the macroinvertebrates were collected at salinity levels
      substantially higher than their 72-h LC(50) obtained from directly transferring
      animals from low salinity water to the water they were tested (direct transfer
      LC(50)). This LC(50) value was correlated with the maximum salinity at which a
      species had been collected. For common macroinvertebrates, the maximum field
      salinity was approximated by the direct transfer 72-h LC(50). For adult
      freshwater fish, 21% of species were collected at salinities substantially
      greater than their acute direct transfer LC(50) and there was a weak relationship
      between these two variables. Although there was a weak correlation between the
      direct transfer LC(50) of early life stages of freshwater fish and the maximum
      field salinity, 58% of the field distribution were in higher than their LC(50)
      values. In contrast, LC(50) determined from experiments that acclimated adult
      fish to higher salinity (slow acclimation) provided a better indication of the
      field distribution: with only one fish species (7%) being in conflict with their
      maximum field salinity and a strong positive relationship between these
      variables. This study shows that laboratory measures of acute salinity tolerance
      can reflect the maximum salinity that macroinvertebrate and fish species inhabit
      and are consistent with some anecdotal observations from other studies.

PMID- 15016458
TI  - Earthworm biomass as additional information for risk assessment of heavy metal
      biomagnification: a case study for dredged sediment-derived soils and polluted
      floodplain soils.
AB  - The important role of earthworms in the biomagnification of heavy metals in
      terrestrial ecosystems is widely recognised. Differences in earthworm biomass
      between sites is mostly not accounted for in ecological risk assessment. These
      differences may be large depending on soil properties and pollution status. A
      survey of earthworm biomass and colonisation rate was carried out on dredged
      sediment-derived soils (DSDS). Results were compared with observations for the
      surrounding alluvial plains. Mainly grain size distribution and time since
      disposal determined earthworm biomass on DSDS, while soil pollution status of the
      DSDS was of lesser importance. Highest earthworm biomass was observed on sandy
      loam DSDS disposed at least 40 years ago.

PMID- 15016459
TI  - Biomarker responses of the earthworm Aporrectodea tuberculata to copper and zinc
      exposure: differences between populations with and without earlier metal
      exposure.
AB  - Biomarkers in the earthworm Aporrectodea tuberculata (Eisen) were measured to
      find out their possible induction under Cu and Zn exposure and differences in the
      responses between two populations with different exposure history. The biomarkers
      applied were concentration of metallothioneins (MT), and cytochrome P4501A
      (CYP1A) monooxygenase and glutathione-S-transferase (GST) activities. These were
      measured from earthworms sampled at three distances from a steel smelter in
      Finland and from the individuals from two populations, one with and another
      without earlier metal exposure, exposed to three combined Cu/Zn concentrations in
      the laboratory. In the field, MT concentration, and cytochrome CYP1A and GST
      activities decreased with increasing distance from the smelter. In the
      laboratory, biomarker responses varied in relation to the duration and level of
      exposure, and they were also dependent on the population. The endpoints appeared
      to be analytically reproducible and sensitive parameters in A. tuberculata, and
      thus, they can be used in ecotoxicological field monitoring and in experimental
      research in the laboratory.

PMID- 15016460
TI  - Using experimental and forest soils to investigate the uptake of polycyclic
      aromatic hydrocarbons (PAHs) along an urban-rural gradient.
AB  - Spatial and temporal variation in the atmospheric deposition of PAHs to soil was
      examined by deploying experimental soils for approximately 165 days and
      conducting a survey of forest soils at several sites along an urban-rural
      transect extending from downtown Toronto to approximately 80 km north of the
      city. PAH concentrations decreased with distance from the urban centre-by a
      factor of 2 and 60 for the experimental and forest soils respectively. The large
      gradient for the forest soils is generally consistent with air concentrations of
      PAHs measured using high volume and passive air samplers. The smaller gradient
      for the experimental soils was due to kinetic limitations of PAH accumulation and
      the relatively short deployment period of approximately 165 days. Mean effective
      deposition velocities (gas+particle) for the full range of PAHs for the
      experimental soils at the urban, suburban, and the rural sites were 2, 31 and 26
      cm s(-1), respectively. These were incorporated into a dynamic model that was
      used to assess the long-term uptake of PAHs in forest soils. Model results
      indicate that lower molecular weight PAHs may achieve equilibrium and become
      involved in soil-air exchange whereas higher molecular weight PAHs are
      accumulated for much longer time periods.

PMID- 15016461
TI  - Coral skeletal tin and copper concentrations at Pohnpei, Micronesia: possible
      index for marine pollution by toxic anti-biofouling paints.
AB  - We present 40 year-long skeletal chronologies of tin (Sn) and copper (Cu) from an
      annually-banded coral (Porites sp.) collected from Pohnpei Island, Micronesia
      (western equatorial Pacific). Both the elements are present in antifouling marine
      paints and are released inadvertently into ambient seawater. Especially, Sn has
      often been used in the form of tributyltin (TBT). Based on a stepwise
      pretreatment examination, Sn and Cu both inside and outside the aragonite lattice
      of the coral skeleton show a potential for providing marine pollution indicators.
      High values of extra-skeletal Cu/Ca and Sn/Ca atomic ratios were found between
      late 1960s and late 1980s during a period of active use of TBT-based antifouling
      paints worldwide. However, a significant decrease in both the ratios in the
      beginning of 1990s can be attributed to regulation of the use of TBT on cargo
      ships by countries such as the USA, Japan and Australia.

PMID- 15016462
TI  - Risk assessment of heavy metal pollution for detritivores in floodplain soils in
      the Biesbosch, The Netherlands, taking bioavailability into account.
AB  - Floodplains of the European rivers Rhine and Meuse are heavily polluted. We
      investigated the risk of heavy metal pollution (Cd, Cu, Pb, Zn) for detritivores
      living in a floodplain area, the Biesbosch, the Netherlands, affected by these
      rivers. Total soil, pore water and 0.01 M CaCl(2) extractable concentrations and
      concentrations in plant leaves, earthworms, isopods and millipedes were measured
      in two sites and compared with literature data to assess possible risks. Based on
      total metal concentrations in soil, serious effects on detritivores were
      expected. However, 0.01 M CaCl(2) extractable, pore water and plant leaf
      concentrations were similar to metal concentrations found in unpolluted areas.
      Concentrations of Cu and Cd in earthworms and Cu in millipedes were higher in the
      Biesbosch than in animals from reference areas. All other measured concentrations
      of heavy metals in earthworms, isopods and millipedes were similar to the ones
      found in reference areas. Despite high total soil concentrations, effects of Zn,
      Cu, Pb and Cd pollution on isopods are therefore not expected, while millipedes
      may only be affected by Cu. Since Cu and Cd levels in earthworms were increased
      compared to animals in unpolluted soils, this faunal group seems to be most at
      risk. Given the engineering role of earthworms in ecosystems, effects on the
      ecological functioning of floodplain soils therefore cannot be excluded.

PMID- 15016463
TI  - The intestinal parasite Pomphorhynchus laevis (Acanthocephala) from barbel as a
      bioindicator for metal pollution in the Danube River near Budapest, Hungary.
AB  - Concentrations of As, Al, Ag, Ba, Bi, Cd, Co, Cr, Cu, Fe, Ga, Mg, Mn, Ni, Pb, Sb,
      Sn, Sr, Tl, V and Zn were analyzed by inductively coupled mass spectrometry (ICP
      MS) in the intestinal helminth Pomphorhynchus laevis and its host Barbus barbus.
      The fish were caught in the Danube river downstream of the city of Budapest
      (Hungary). Ten out of twenty one elements analyzed were found at higher
      concentrations in the acanthocephalan than in different tissues (muscle,
      intestine, liver and kidney) of barbel. Considering the fish tissues, most of the
      elements were present at highest concentrations in liver, followed by kidney,
      intestine and muscle. Spearman correlation analyses indicate that there is
      competition for metals between the parasites and the host. The negative
      relationships between parasite number and metal levels in organs of the barbel
      support this hypothesis. The bioconcentration factors for Ag, As, Ba, Bi, Cu, Ga,
      Mn, Pb, Sr, Tl, and Zn showed that the parasites concentrated metals to a higher
      degree than the fish tissues. They accumulated the metals As, Cd, Cu, Fe, Ni, Pb,
      Sr and Zn even better than established bioindicators such as the mussel Dreissena
      polymorpha as revealed by data from the literature. The results presented here
      emphasize that acanthocephalans of fish are very useful as sentinels for metal
      pollution in aquatic ecosystems. Ratio of metal concentrations in the parasites
      and the host tissues provide additional information. Not including
      acanthocephalans in accumulation bioindication studies with fishes (as still
      customarily done) may lead to false results.

PMID- 15016464
TI  - Persistent organochlorine residues in human breast milk from Hanoi and Hochiminh
      City, Vietnam: contamination, accumulation kinetics and risk assessment for
      infants.
AB  - Despite the ban on persistent organochlorines (OCs) in most of the developed
      nations, their usage continued until recently in many Asian developing countries
      including Vietnam, for agricultural purposes and vector-borne disease eradication
      programs. In this study, we collected human breast milk samples from the two big
      cities in Vietnam: Hanoi (n=42) and Hochiminh (n=44) and determined the
      concentrations of persistent OCs such as PCBs, DDT and its metabolites (DDTs),
      hexachlorocyclohexanes (HCHs), hexachlorobenzene (HCB), chlordane compounds
      (CHLs) and tris-4-chlorophenyl-methane (TCPMe). The contamination pattern of OCs
      was in the order of DDTs > PCBs > HCHs > CHLs approximately HCB approximately
      TCPMe. Compilation of available data indicated that DDT residue levels in human
      breast milk from Vietnam were among the highest values reported for Asian
      developing countries as well as developed nations. This result suggests recent
      usage of DDTs in both north and south Vietnam. Interestingly, in both cities, the
      p,p'-DDT portion was higher in multiparas than those in primiparas. Considering
      the fact that the interval between the first and the second child of a mother in
      Vietnam is usually short, this result probably indicates continuous intake of
      DDTs in the population. Analysis of infant exposure to DDTs via breast milk
      suggested that the daily intake rates for number of individuals are close to or
      above the threshold for adverse effects which may raise concern on children
      health.

PMID- 15016465
TI  - Biokinetics of cadmium, selenium, and zinc in freshwater alga Scenedesmus
      obliquus under different phosphorus and nitrogen conditions and metal transfer to
      Daphnia magna.
AB  - The uptake of Cd, Se(IV) and Zn by the freshwater alga Scenedesmus obliquus and
      the subsequent transfer and release budget in Daphnia magna were investigated
      under different nutrient additions and cell incubation conditions. An increase in
      ambient phosphate concentrations from 0.5 micromol l(-1) to 50 micromol l(-1)
      significantly increased the intracellular accumulation of Cd (by 18x) and Zn (by
      5x), but decreased the accumulation of Se (by 126x) in the alga. The percentage
      of these metals distributing in the intracellular pool of algae also increased
      substantially with increasing ambient P concentrations. Nitrate addition from 5.0
      to 200 micromol l(-1) did not influence the uptake of any of the three metals,
      although a significant decrease in the intracellular Se distribution was
      observed. Radiolabeled algae under different nutrient manipulations (semi
      continuous culture, starvation, and P-pulse treatments) were used to measure
      trophic transfer assimilation efficiency (AE) in Daphnia. When the algal cells
      were grown in a semi-continuous culture, starved for N and P, or were treated
      with P-pulse, the AEs of Cd and Zn were generally independent of the nutritional
      conditions, but the Se AE was significantly affected by different P levels. The
      efflux rate constants, determined during 10 d depuration following 7 days of
      dietary uptake, decreased significantly for Cd and Zn, but were relatively
      constant for Se with increasing P concentration. N-addition caused no effect on
      the metal efflux rate constants. P- or N-additions did not influence the release
      budget (including molting, neonates, excretion and feces) for all three elements
      in Daphnia. Our study indicated that phosphate enrichment may substantially
      increase metal uptake in green alga S. obliquus. Responses of trophic transfer in
      Daphnia to nutrient enrichment were metal specific. P-enrichment can possibly
      lead to considerable decrease on Se transfer from algae to zooplankton.

PMID- 15016467
TI  - Influences of dissolved and colloidal organic carbon on the uptake of Ag, Cd, and
      Cr by the marine mussel Perna viridis.
AB  - The cross-flow ultrafiltration and radiotracer techniques were used to study the
      influences of natural dissolved organic carbon (DOC) and colloidal organic carbon
      (COC) on the bioavailability of Ag, Cd, and Cr to the green mussel Perna viridis.
      We examined the uptake of these metals by the mussels at different concentrations
      of DOC and COC from different origins (estuarine, coastal, and diatom
      decomposed). Using the DOC originating from the decomposed diatom (Thalassiosira
      pseudonana), we demonstrated that Cd and Cr uptake, quantified by the
      concentration factor (DCF), increased linearly with increasing DOC concentration.
      There was, however, no consistent influence of natural DOC concentration on the
      metal uptake when the DOC was obtained from different sources of seawater
      (coastal and estuarine). The influences of COC on metal bioavailability were
      metal-specific and dependent on the geochemical properties of colloids and
      colloid-metal complexation. Cd uptake rate was not influenced by the COC
      concentrations. Uptake of diatom-decomposed colloidal Cr was enhanced by 3.4x,
      whereas the uptake of diatom-decomposed colloidal Ag was decreased by 8.2x
      compared with the uptake of low molecular weight Cr and Ag (<1 kDa). The uptake
      of diatom-decomposed colloidal Cr and Ag was generally lower than the uptake of
      metals bound with the same type of colloids for 2 days. Further aging of the
      colloid-metal binding reduced metal bioavailability to the mussels. In the
      presence of different sizes of colloidal particles where there was no major
      binding of colloids with the metals, metal uptake by the mussels was not
      influenced by different COC concentrations. Overall, our study suggests that
      although metal dissociation from colloids may be an important step for the uptake
      of colloidal metals, other mechanisms such as pinocytosis and co-transport may
      also be involved in the uptake of these metals, especially in aquatic
      environments with high DOC and COC concentrations.

PMID- 15016466
TI  - Effects of storage method and duration on the toxicity of marine sediments to
      embryos of Crassostrea gigas oysters.
AB  - The objective of laboratory sediment bioassays is to estimate in situ toxicity.
      This goal is difficult to achieve, as one of the main limitations of sediment
      toxicity tests is disruption of sediment geochemistry during sampling, handling
      and preservation. The effects of storage on the estimation of marine sediment
      toxicity to Crassostrea gigas embryos and larvae were investigated. Three storage
      methods and four storage periods were compared with three different sediment
      types contaminated by heavy metals, polycyclic aromatic hydrocarbons (PAHs) and
      both contaminants. Freezing and freeze-drying considerably increased the toxicity
      of decanted sediments and their elutriates as compared to the toxicity obtained
      with fresh sediments. Concerning the elutriates, the toxicity found with frozen
      and freeze-dried sediments was correlated with DOC, ammonia and PAH contents.
      However, the toxicity of fresh sediments kept at 4 degrees C increased with
      increasing duration of storage and was also correlated with the amount of ammonia
      in the elutriates.

PMID- 15016468
TI  - Arsenic mobility in contaminated lake sediments.
AB  - An arsenic contaminated lake sediment near a landfill in Maine was used to
      characterize the geochemistry of arsenic and assess the influence of
      environmental conditions on its mobility. A kinetic model was developed to
      simulate the leaching ability of arsenic in lake sediments under different
      environmental conditions. The HM1D chemical transport model was used to model the
      column experiments and determine the rates of arsenic mobility from the sediment.
      Laboratory studies provided the information to construct a conceptual model to
      demonstrate the mobility of arsenic in the lake sediment. The leaching ability of
      arsenic in lake sediments greatly depends on the flow conditions of ground water
      and the geochemistry of the sediments. Large amounts of arsenic were tightly
      bound to the sediments. The amount of arsenic leaching out of the sediment to the
      water column was substantially decreased due to iron/arsenic co-precipitation at
      the water-sediment interface. Overall, it was found that arsenic greatly
      accumulated at the ground water/lake interface and it formed insoluble
      precipitates.

PMID- 15016469
TI  - Source apportionment of ambient non-methane hydrocarbons in Hong Kong:
      application of a principal component analysis/absolute principal component scores
      (PCA/APCS) receptor model.
AB  - Receptor-oriented source apportionment models are often used to identify sources
      of ambient air pollutants and to estimate source contributions to air pollutant
      concentrations. In this study, a PCA/APCS model was applied to the data on non
      methane hydrocarbons (NMHCs) measured from January to December 2001 at two
      sampling sites: Tsuen Wan (TW) and Central & Western (CW) Toxic Air Pollutants
      Monitoring Stations in Hong Kong. This multivariate method enables the
      identification of major air pollution sources along with the quantitative
      apportionment of each source to pollutant species. The PCA analysis identified
      four major pollution sources at TW site and five major sources at CW site. The
      extracted pollution sources included vehicular internal engine combustion with
      unburned fuel emissions, use of solvent particularly paints, liquefied petroleum
      gas (LPG) or natural gas leakage, and industrial, commercial and domestic sources
      such as solvents, decoration, fuel combustion, chemical factories and power
      plants. The results of APCS receptor model indicated that 39% and 48% of the
      total NMHCs mass concentrations measured at CW and TW were originated from
      vehicle emissions, respectively. 32% and 36.4% of the total NMHCs were emitted
      from the use of solvent and 11% and 19.4% were apportioned to the LPG or natural
      gas leakage, respectively. 5.2% and 9% of the total NMHCs mass concentrations
      were attributed to other industrial, commercial and domestic sources,
      respectively. It was also found that vehicle emissions and LPG or natural gas
      leakage were the main sources of C(3)-C(5) alkanes and C(3)-C(5) alkenes while
      aromatics were predominantly released from paints. Comparison of source
      contributions to ambient NMHCs at the two sites indicated that the contribution
      of LPG or natural gas at CW site was almost twice that at TW site. High
      correlation coefficients (R(2) > 0.8) between the measured and predicted values
      suggested that the PCA/APCS model was applicable for estimation of sources of
      NMHCs in ambient air.

PMID- 15016470
TI  - Use of autotrophic sulfur-oxidizers to remove nitrate from bank filtrate in a
      permeable reactive barrier system.
AB  - This study was conducted to evaluate the potential applicability of an in situ
      biological reactive barrier system to treat nitrate-contaminated bank filtrate.
      The reactive barrier consisted of sulfur granules as an electron donor and
      autotrophic sulfur-oxidizing bacteria as a biological component. Limestone was
      also used to provide alkalinity. The results showed that the autotrophic sulfur
      oxidizers were successfully colonized on the surfaces of the sulfur particles and
      removed nitrate from synthetic bank filtrate. The sulfur-oxidizing activity
      continuously increased with time and then was maintained or slightly decreased
      after five days of column operation. Maximum nitrate removal efficiency and
      sulfur oxidation rate were observed at near neutral pH. Over 90% of the initial
      nitrate dissolved in synthetic bank filtrate was removed in all columns tested
      with some nitrite accumulation. However, nitrite accumulation was observed mainly
      during the initial operation period, and the concentration markedly diminished
      with time. The nitrite concentration in effluent was less than 2 mg-N/l after 12
      days of column operation. When influent nitrate concentrations were 30, 40, and
      60 mg-N/l and sulfur content in column was 75%, half-order autotrophic
      denitrification reaction rate constants were 31.73 x 10(-3), 33.3 x 10(-3), and
      36.4 x 10(-3) mg(1/2)/l(1/2)min, respectively. Our data on the nitrate
      distribution profile along the column suggest that an appropriate wall thickness
      of a reactive barrier for autotrophic denitrification may be 30 cm when influent
      nitrate concentration is less than 60 mg-N/l.

PMID- 15016471
TI  - The role of glutamine transaminase K (GTK) in sulfur and alpha-keto acid
      metabolism in the brain, and in the possible bioactivation of neurotoxicants.
AB  - Glutamine transaminase K (GTK), which is a freely reversible glutamine
      (methionine) aromatic amino acid aminotransferase, is present in most mammalian
      tissues, including brain. Quantitatively, the most important amine donor in vivo
      is glutamine. The product of glutamine transamination (i.e., alpha
      ketoglutaramate; alphaKGM) is rapidly removed by cyclization and/or conversion to
      alpha-ketoglutarate. Transamination is therefore "pulled" in the direction of
      glutamine utilization. Major biological roles of GTK are to maintain low levels
      of phenylpyruvate and to close the methionine salvage pathway. GTK also catalyzes
      the transamination of cystathionine, lanthionine, and thialysine to the
      corresponding alpha-keto acids, which cyclize to ketimines. The cyclic ketimines
      and several metabolites derived therefrom are found in brain. It is not clear
      whether these compounds have a biological function or are metabolic dead-ends.
      However, high-affinity binding of lanthionine ketimine (LK) to brain membranes
      has been reported. Mammalian tissues possess several enzymes capable of
      catalyzing transamination of kynurenine in vitro. Two of these kynurenine
      aminotransferases (KATs), namely KAT I and KAT II, are present in brain and have
      been extensively studied. KAT I and KAT II are identical to GTK and alpha
      aminoadipate aminotransferase, respectively. GTK/KAT I is largely cytosolic in
      kidney, but mostly mitochondrial in brain. The same gene codes for both forms,
      but alternative splicing dictates whether a 32-amino acid mitochondrial-targeting
      sequence is present in the expressed protein. The activity of KAT I is altered by
      a missense mutation (E61G) in the spontaneously hypertensive rat. The symptoms
      may be due in part to alteration of kynurenine transamination. However, owing to
      strong competition from other amino acid substrates, the turnover of kynurenine
      to kynurenate by GTK/KAT I in nervous tissue must be slow unless kynurenine and
      GTK are sequestered in a compartment distinct from the major amino acid pools.
      The possibility is discussed that the spontaneous hypertension in rats carrying
      the GTK/KAT I mutation may be due in part to disruption of glutamine
      transamination. GTK is one of several pyridoxal 5'-phosphate (PLP)-containing
      enzymes that can catalyze non-physiological beta-elimination reactions with
      cysteine S-conjugates containing a good leaving group attached at the sulfur.
      These elimination reactions may contribute to the bioactivation of certain
      electrophiles, resulting in toxicity to kidney, liver, brain, and possibly other
      organs. On the other hand, the beta-lyase reaction catalyzed by GTK may be useful
      in the conversion of some cysteine S-conjugate prodrugs to active components in
      vivo. The roles of GTK in (a) brain nitrogen, sulfur, and aromatic amino
      acid/kynurenine metabolism, (b) brain alpha-keto acid metabolism, (c)
      bioactivation of certain electrophiles in brain, (d) prodrug targeting, and (e)
      maintenance of normal blood pressure deserve further study.

PMID- 15016472
TI  - Alterations of markers related to synaptic function in aging rat brain, in normal
      conditions or under conditions of long-term dietary manipulation.
AB  - Neurochemical alterations of markers related to synaptic function are potential
      candidates for age-related impairment of brain function and cognition. The
      process of aging, including brain aging, can be counteracted to some degree by
      maintaining animals in long-term conditions of caloric restriction, or
      supplementing their diet with antioxidant substances. We report here that the age
      related decline of the cholinergic and GABAergic systems, that takes place in
      some CNS regions of aged rats, is not affected by maintaining them under
      conditions of dietary restriction and, therefore, of reduced calorie intake, from
      the 12th to the 30th month of age. We also notice the same lack of effect by
      adding, during the same period, the aging rat diet with the potential antioxidant
      substance, N-acetylcysteine (NAC). The same dietary manipulations are also unable
      to counteract the derangement of the first step of the main biosynthetic pathway
      for polyamines, putative neuromodulators in the CNS, that occurs in the aged
      spinal cord. Some age-related alterations in the expression of different subunits
      of the NMDA-type glutamate receptors in some CNS regions of aged rats were
      instead, at least in some cases, counteracted by long-term dietary manipulation.

PMID- 15016473
TI  - Hyperbaric oxygen treatment: the influence on the hippocampal superoxide
      dismutase and Na+,K+-ATPase activities in global cerebral ischemia-exposed rats.
AB  - The influence of hyperbaric oxygen (HBO) treatment on the activities of
      superoxide dismutase (SOD) and Na(+),K(+)-ATPase was determined during different
      time periods of reperfusion in rats exposed to global cerebral ischemia. Ischemic
      animals were either sacrificed or exposed to the first HBO treatment 2, 24, 48 or
      168 h after ischemic insult (for SOD activities measurement) or immediately, 0.5,
      1, 2, 6, 24, 48, 72 or 168 h after ischemic procedure (for Na(+),K(+)-ATPase
      activities measurement). Hyperbaric oxygenation procedure was repeated for seven
      consecutive days. The results of presented experiments demonstrated the
      statistically significant increase in the hippocampal SOD activity 24 and 48 h
      after global cerebral ischemia followed by a decrease in the enzymatic activity
      168 h after ischemic insult. In the ischemic rats treated with HBO the level of
      hippocampal SOD activity was significantly higher after 168 h of reperfusion in
      comparison to the ischemic, non HBO-treated animals. In addition, it was found
      that global cerebral ischemia induced a statistically significant decrease of the
      hippocampal Na(+),K(+)-ATPase activity starting from 1 to 168 h of reperfusion.
      Maximal enzymatic inhibition was obtained 24 h after the ischemic damage. Decline
      in Na(+),K(+)-ATPase activity was prevented in the animals exposed to HBO
      treatment within the first 24 h of reperfusion. Our results suggest that global
      cerebral ischemia induces significant alterations in the hippocampal SOD and
      Na(+),K(+)-ATPase activities during different periods of reperfusion. Enhanced
      SOD activity and preserved Na(+),K(+)-ATPase activity within particular periods
      of reperfusion, could be indicators of a possible beneficial role of HBO
      treatment in severe brain ischemia.

PMID- 15016474
TI  - The putative pheromone androstadienone activates cortical fields in the human
      brain related to social cognition.
AB  - Using 15O-butanol positron emission tomography (PET), we measured regional
      cerebral blood flow changes in five healthy young women during exposure to
      androstadienone, a putative human pheromone, as well as pleasant (gamma-methyl
      ionone), unpleasant (methyl-thio-butanoate), and neutral (dipropylene glycol;
      vehicle compound) odours. Compared with the odorous substances, androstadienone
      activated a widely distributed neuronal network. Two large cortical fields
      exhibited consistent activation in each contrast: the anterior part of the
      inferior lateral prefrontal cortex (PFC) and the posterior part of the superior
      temporal cortex (STP). Intriguingly, these areas were deactivated by gamma-methyl
      ionone and methyl-thio-butanoate. These brain regions can be identified as
      cortical fields underlying other than olfactory functions, including various
      aspects of social cognition and attention.

PMID- 15016475
TI  - Ischemia-related change of ceruloplasmin immunoreactivity in neurons and
      astrocytes in the gerbil hippocampus and dentate gyrus.
AB  - In the present study, we investigated the temporal and spatial alterations of
      ceruloplasmin immunoreactivity in the gerbil hippocampus and dentate gyrus after
      5 min transient forebrain ischemia. In sham-operated animals, ceruloplasmin
      immunoreactivity in the hippocampal CA2/3 areas was higher than that of other
      areas. Ceruloplasmin immunoreactivity and its protein content significantly
      increased and were highest in the CA1 area 1 day after ischemia-reperfusion. At
      this time point, the immunoreactivity was shown in pyramidal cells of the CA1
      area. Four days after ischemia-reperfusion, ceruloplasmin immunoreactivity was
      shown in astrocytes in the hippocamapal CA1 area. These results suggest that
      reactive oxygen species (ROS) do not immediately damage neuronal cytosol, unlike
      DNA. An interval of time is required for the full expression of the cytoplasmic
      protein injury by ROS. This delayed neuronal injury 1 day after ischemic insult
      might provide a window of opportunity for therapeutic interventions using
      antioxidants.

PMID- 15016476
TI  - Reverse microdialysis of a dopamine D2 receptor antagonist alters extracellular
      adenosine levels in the rat nucleus accumbens.
AB  - Recent evidence suggests that modulation of dopaminergic transmission alters
      striatal levels of extracellular adenosine. The present study used reverse
      microdialysis of the selective dopamine D(2) receptor antagonist raclopride to
      investigate whether a blockade of dopamine D(2) receptors modifies extracellular
      adenosine concentrations in the nucleus accumbens. Results reveal that perfusion
      of raclopride produced an increase of dialysate adenosine which was significant
      with a high (10 mM) and intermediate (1 mM) drug concentration, but not with
      lower drug concentrations (10 and 100 microM). Thus, the present study
      demonstrates that a selective blockade of dopamine D(2) receptors in the nucleus
      accumbens produced a pronounced increase of extracellular adenosine. The cellular
      mechanisms underlying this effect are yet unknown. It is suggested that the
      increase of extracellular adenosine might be related to a homeostatic modulatory
      mechanism proposed to be a key function of adenosine in response to neuronal
      metabolic challenges.

PMID- 15016477
TI  - Diurnal, circadian and photic regulation of calcium/calmodulin-dependent kinase
      II and neuronal nitric oxide synthase in the hamster suprachiasmatic nuclei.
AB  - Mammalian circadian rhythms are entrained by light pulses that induce
      phosphorylation events in the suprachiasmatic nuclei (SCN). Ca(2+)-dependent
      enzymes are known to be involved in circadian phase shifting. In this paper, we
      show that calcium/calmodulin-dependent kinase II (CaMKII) is rhythmically
      phosphorylated in the SCN both under entrained and free-running (constant dark)
      conditions while neuronal nitric oxide synthase (nNOS) is rhythmically
      phosphorylated in the SCN only under entrained conditions. Both p-CaMKII and p
      NOS (specifically phosphorylated by CaMKII) levels peak during the day or
      subjective day. Light pulses administered during the subjective night, but not
      during the day, induced rapid phosphorylation of both enzymes. Moreover, we found
      an inhibitory effect of KN-62 and KN-93, both CaMKII inhibitors, on light-induced
      nNOS activity and nNOS phosphorylation respectively, suggesting a direct pathway
      between both enzymes which is at least partially responsible of photic circadian
      entrainment.

PMID- 15016478
TI  - Serotonin-mediated phosphorylation of extracellular regulated kinases in
      platelets of patients with panic disorder versus controls.
AB  - Phosphorylation of extracellular signal-regulated kinases (ERK 1/2) represents a
      converging intracellular signalling pathway which is involved in the modulation
      of gene transcription and may contribute to the feed-back regulation of
      neurotransmitter receptor functioning. The purpose of the current study was to
      investigate the serotonin-mediated phosphorylation of ERK 1/2 in platelets from
      patients (n = 17) with panic disorder, with respect to healthy volunteers (n =
      17). Patients presented a severe symptomatology as assessed by the self-report
      rating scales for panic-agoraphobic (PAS-SR) and mood (MOOD-SR) spectrum, and by
      Clinical Global Impression Severity Scale (CGI-S). In platelets from healthy
      volunteers, serotonin induced a rapid increase of ERK 1/2 phosphorylation with a
      transient monophasic kinetic. The dose-response curves showed this effect was
      concentration dependent with an average of the EC(50) value of 22.8 +/- 2.4
      microM. Platelet pre-incubation with 5HT(1A) and 5HT(2A) antagonists, pindobind
      and ritanserin, significantly inhibited serotonin-mediated kinase activation with
      an EC(50) of 3.2 +/- 0.2 and 1.99 +/- 0.08 nM, respectively, suggesting an
      involvement of these specific receptor subtypes in serotonin-mediated response.
      Furthermore, the 5HT(1A) and 5HT(2A) agonists, 8-hydroxy-N,N-dipropyl
      aminotetralin (8OH-DPAT) and 1-(2,5-dimethoxy)-4-iodophenyl-2-aminopropane (DOI),
      were able to modulate ERK 1/2 phosphorylation in a concentration-dependent manner
      with an EC(50) value of 3.1 +/- 0.2 and 76 +/- 4.5 nM, respectively. ERK 1/2
      phosphorylation was not observed after serotonin treatment of platelets from drug
      free panic disorder patients, suggesting an alteration in intracellular
      phosphorylative pathways. Since ERK 1/2 responsiveness to other stimulus, such as
      collagen and thrombin, was comparable in platelets from healthy volunteers and
      patients, our results suggested that a specific alteration of serotonergic system
      occurred in panic disorder. Further studies to investigate 5HT(1A) and 5HT(2A)
      receptor expression and threonine phosphorylation levels showed that,
      nevertheless no significant differences in the receptor expression levels were
      detected, an increase of both 5HT receptor phosphorylation, on threonine
      residues, occurred in platelet from panic patients with respect to controls,
      suggesting that a reduction of serotonin receptor functioning was involved in the
      loss of serotonin responsiveness in panic.

PMID- 15016479
TI  - Altered nitric oxide production in mouse brain after administration of 1-methyl-4
      phenyl-1,2,3,6-tetrahydro-pyridin or methamphetamine.
AB  - Several studies have demonstrated the involvement of reactive nitrogen and oxygen
      species (RNOS) in the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydro
      pyridin (MPTP) and methamphetamine (METH), so the contribution of altered nitric
      oxide synthase (NOS) enzyme function can be suspected. In this study, about 50%
      increase in nitric oxide (NO) production in the mouse striatum was found between
      4 and 12 h after a single MPTP injection, allowing an increased peroxynitrite
      (ONOO-) formation in the target brain region. However, METH injection induced a
      rapid decrease of NO formation both in mouse striatum and hippocampus, reaching
      its minimum level at 2 h, and restored to the control value after 6 h in the
      striatum and 12 h in the hippocampus. The uncoupled function of NOS with
      increased superoxide (O2*-) production after METH injection is suggested.

PMID- 15016480
TI  - The catastrophic failures of public health.

PMID- 15016481
TI  - Risk to the coronary arteries of intracoronary stem cell infusion and G-CSF
      cytokine therapy.

PMID- 15016482
TI  - The lessons of MMR.

PMID- 15016483
TI  - Retraction of an interpretation.

PMID- 15016484
TI  - Effects of intracoronary infusion of peripheral blood stem-cells mobilised with
      granulocyte-colony stimulating factor on left ventricular systolic function and
      restenosis after coronary stenting in myocardial infarction: the MAGIC cell
      randomised clinical trial.
AB  - BACKGROUND: Bone-marrow stem-cell transplantation has been shown to improve
      cardiac function in patients with myocardial infarction. We examined the
      feasibility and efficacy of granulocyte-colony stimulating factor (G-CSF) therapy
      and subsequent intracoronary infusion of collected peripheral blood stem-cells
      (PBSCs) in such patients. METHODS: We prospectively randomised 27 patients with
      myocardial infarction who underwent coronary stenting for the culprit lesion of
      infarction into three groups; cell infusion (n=10), G-CSF alone (n=10), and
      control group (n=7). Changes in left ventricular systolic function and perfusion
      were assessed after 6 months. By December, 2003, seven patients from the cell
      infusion group, three from the G-CSF group, and one from the control group had
      been assessed. FINDINGS: G-CSF injection and intracoronary infusion of the
      mobilised PBSC did not aggravate inflammation and ischaemia during the
      periprocedural period. Exercise capacity (mean treadmill exercise time: 450 s [SD
      178] at baseline vs 578 s [168] at 6 months' follow-up, p=0.004), myocardial
      perfusion (perfusion defect 11.6% [9.6] vs 5.3% [5.0], p=0.020) and systolic
      function (left ventricular ejection fraction 48.7% [8.3] vs 55.1% [7.4], p=0.005)
      improved significantly in patients who received cell infusion. However, we noted
      an unexpectedly high rate of in-stent restenosis at culprit lesion in patients
      who received G-CSF, and therefore we stopped enrollment. INTERPRETATION: G-CSF
      therapy with intracoronary infusion of PBSC showed improved cardiac function, and
      promoted angiogenesis in patients with myocardial infarction. However,
      aggravation of restenosis could be a serious problem. In future studies with G
      CSF based stem-cell therapy, patients should be carefully monitored for
      unexpected effects.

PMID- 15016485
TI  - Effects of cholesterol-lowering with simvastatin on stroke and other major
      vascular events in 20536 people with cerebrovascular disease or other high-risk
      conditions.
AB  - BACKGROUND: Lower blood cholesterol concentrations have consistently been found
      to be strongly associated with lower risks of coronary disease but not with lower
      risks of stroke. Despite this observation, previous randomised trials had
      indicated that cholesterol-lowering statin therapy reduces the risk of stroke,
      but large-scale prospective confirmation has been needed. METHODS: 3280 adults
      with cerebrovascular disease, and an additional 17256 with other occlusive
      arterial disease or diabetes, were randomly allocated 40 mg simvastatin daily or
      matching placebo. Subgroup analyses were prespecified of first "major vascular
      event" (ie, non-fatal myocardial infarction or coronary death, stroke of any
      type, or any revascularisation procedure) in prior disease subcategories.
      Subsidiary outcomes included any stroke, and stroke sub-type. Comparisons are of
      all simvastatin-allocated versus all placebo-allocated participants (ie,
      "intention-to-treat"), which yielded an average difference in LDL cholesterol of
      1.0 mmol/L (39 mg/dL) during the 5-year treatment period. FINDINGS: Overall,
      there was a highly significant 25% (95% CI 15-34) proportional reduction in the
      first event rate for stroke (444 [4.3%] simvastatin vs 585 [5.7%] placebo;
      p<0.0001), reflecting a definite 28% (19-37) reduction in presumed ischaemic
      strokes (p<0.0001) and no apparent difference in strokes attributed to
      haemorrhage (51 [0.5%] vs 53 [0.5%]; rate ratio 0.95 [0.65-1.40]; p=0.8). In
      addition, simvastatin reduced the numbers having transient cerebral ischaemic
      attacks alone (2.0% vs 2.4%; p=0.02) or requiring carotid endarterectomy or
      angioplasty (0.4% vs 0.8%; p=0.0003). The reduction in stroke was not significant
      during the first year, but was already significant (p=0.0004) by the end of the
      second year. Among patients with pre-existing cerebrovascular disease there was
      no apparent reduction in the stroke rate, but there was a highly significant 20%
      (8-29) reduction in the rate of any major vascular event (406 [24.7%] vs 488
      [29.8%]; p=0.001). The proportional reductions in stroke were about one-quarter
      in each of the other subcategories of participant studied, including: those with
      coronary disease or diabetes; those aged under or over 70 years at entry; and
      those presenting with different levels of blood pressure or lipids (even when the
      pretreatment LDL cholesterol was below 3.0 mmol/L [116 mg/dL]). INTERPRETATION:
      Much larger numbers of people in the present study suffered a stroke than in any
      previous cholesterol-lowering trial. The results demonstrate that statin therapy
      rapidly reduces the incidence not only of coronary events but also of ischaemic
      strokes, with no apparent effect on cerebral haemorrhage, even among individuals
      who do not have high cholesterol concentrations. Allocation to 40 mg simvastatin
      daily reduced the rate of ischaemic strokes by about one-quarter and so, after
      making allowance for non-compliance in the trial, actual use of this regimen
      would probably reduce the stroke rate by about a third. HPS also provides
      definitive evidence that statin therapy is beneficial for people with pre
      existing cerebrovascular disease, even if they do not already have manifest
      coronary disease.

PMID- 15016487
TI  - Association of outcome with early stroke treatment: pooled analysis of ATLANTIS,
      ECASS, and NINDS rt-PA stroke trials.
AB  - BACKGROUND: Quick administration of intravenous recombinant tissue plasminogen
      activator (rt-PA) after stroke improved outcomes in previous trials. We aimed to
      analyse combined data for individual patients to confirm the importance of rapid
      treatment. METHODS: We pooled common data elements from six randomised placebo
      controlled trials of intravenous rt-PA. Using multivariable logistic regression
      we assessed the relation of the interval from stroke onset to start of treatment
      (OTT) on favourable 3-month outcome and on the occurrence of clinically relevant
      parenchymal haemorrhage. FINDINGS: Treatment was started within 360 min of onset
      of stroke in 2775 patients randomly allocated to rt-PA or placebo. Median age was
      68 years, median baseline National Institute of Health Stroke Scale (NIHSS) 11,
      and median OTT 243 min. Odds of a favourable 3-month outcome increased as OTT
      decreased (p=0.005). Odds were 2.8 (95% CI 1.8-4.5) for 0-90 min, 1.6 (1.1-2.2)
      for 91-180 min, 1.4 (1.1-1.9) for 181-270 min, and 1.2 (0.9-1.5) for 271-360 min
      in favour of the rt-PA group. The hazard ratio for death adjusted for baseline
      NIHSS was not different from 1.0 for the 0-90, 91-180, and 181-270 min intervals;
      for 271-360 min it was 1.45 (1.02-2.07). Haemorrhage was seen in 82 (5.9%) rt-PA
      patients and 15 (1.1%) controls (p<0.0001). Haemorrhage was not associated with
      OTT but was with rt-PA treatment (p=0.0001) and age (p=0.0002). INTERPRETATION:
      The sooner that rt-PA is given to stroke patients, the greater the benefit,
      especially if started within 90 min. Our results suggest a potential benefit
      beyond 3 h, but this potential might come with some risks.

PMID- 15016488
TI  - Two prognostically significant subtypes of high-grade lung neuroendocrine tumours
      independent of small-cell and large-cell neuroendocrine carcinomas identified by
      gene expression profiles.
AB  - BACKGROUND: Classification of high-grade neuroendocrine tumours (HGNT) of the
      lung currently recognises large-cell neuroendocrine carcinoma (LCNEC) and small
      cell lung carcinoma (SCLC) as distinct groups. However, a similarity in histology
      for these two carcinomas and uncertain clinical course have led to suggestions
      that a single HGNT classification would be more appropriate. Gene expression
      profiling, which can reproduce histopathological classification, and often
      defines new subclasses with prognostic significance, can be used to resolve HGNT
      classification. METHODS: We used cDNA microarrays with 40?386 elements to analyse
      the gene expression profiles of 38 surgically resected samples of lung
      neuroendocrine tumours and 11 SCLC cell lines. Samples of large-cell carcinoma,
      adenocarcinoma, and normal lung were also included to give a total of 105 samples
      analysed. The data were subjected to filtering to yield informative genes before
      unsupervised hierarchical clustering that identified relatedness of tumour
      samples. FINDINGS: Distinct groups for carcinoids, large-cell carcinoma,
      adenocarcinoma, and normal lung were readily identified. However, we were unable
      to distinguish LCNEC from SCLC by gene expression profiling. Three independent
      rounds of unsupervised hierarchical clustering consistently divided SCLC samples
      into two main groups with LCNEC samples largely integrated with these groups.
      Furthermore, patients in one of the groups identified by clustering had a
      significantly better clinical outcome than the other (83% vs 12% survived for 5
      years; p=0.0094. None of the highly proliferative SCLC cell lines subsequently
      analysed clustered with this good-prognosis group. INTERPRETATION: Our findings
      show that HGNT of the lung can be classified into two groups independent of SCLC
      and LCNEC. To this end, we have identified many genes, some of which encode well
      characterised markers of cancer that distinguish the HGNT groups. These results
      have implications for the diagnosis, classification, and treatment of lung
      neuroendocrine tumours, and provide important insights into their underlying
      biology.

PMID- 15016489
TI  - c-ANCA as a serological pitfall.

PMID- 15016490
TI  - Intra-coronary arterial injection of mesenchymal stromal cells and
      microinfarction in dogs.
AB  - Mesenchymal stromal cells (MSCs) have the potential to treat many myocardial
      diseases. We investigated whether these multipotent stem cells derived from bone
      marrow could be administered safely into the coronary circulation of healthy
      dogs. We injected about 0.5 million cells per kg bodyweight of early passage
      autologous MSCs into the left circumflex coronary artery of anaesthetised dogs.
      During administration, we noted ST segment elevation and T wave changes
      characteristic of acute myocardial ischaemia. 7 days later, macroscopic and
      microscopic evidence of myocardial infarction was noted. Histological sections of
      myocardium showed several scattered regions of dense fibroplasia accompanied by
      macrophage infiltrates only in areas where the MSCs were observed. We also noted
      raised plasma concentrations of cardiac troponin I and collagen fibril deposition
      in the lesions. These findings show acute myocardial ischaemia and subacute
      myocardial microinfarction after intracoronary arterial injection of MSCs into
      dogs.

PMID- 15016491
TI  - Hypothyroidism.
AB  - Hypothyroidism is common, potentially serious, often clinically overlooked,
      readily diagnosed by laboratory testing, and eminently treatable. The condition
      is particularly prevalent in older women, in whom autoimmune thyroiditis is
      common. Other important causes include congenital thyroid disorders, previous
      thyroid surgery and irradiation, drugs such as lithium carbonate and amiodarone,
      and pituitary and hypothalamic disorders. Worldwide, dietary iodine deficiency
      remains an important cause. Hypothyroidism can present with nonspecific
      constitutional and neuropsychiatric complaints, or with hypercholesterolaemia,
      hyponatraemia, hyperprolactinaemia, or hyperhomocysteinaemia. Severe untreated
      hypothyroidism can lead to heart failure, psychosis, and coma. Although these
      manifestations are neither specific nor sensitive, the diagnosis is confirmed or
      excluded by measurements of serum thyrotropin and free thyroxine. Thyroxine
      replacement therapy is highly effective and safe, but suboptimal dosing is common
      in clinical practice. Patient noncompliance, drug interactions, and pregnancy can
      lead to inadequate treatment. Iatrogenic thyrotoxicosis can cause symptoms, and,
      even when mild, provoke atrial fibrillation and osteoporosis. We summarise
      present understanding of the history, epidemiology, pathophysiology, and clinical
      diagnosis and management of hypothyroidism.

PMID- 15016492
TI  - Endovascular treatment of cerebrovascular diseases and intracranial neoplasms.
AB  - Cerebrovascular diseases are an important cause of morbidity and mortality
      worldwide. Endovascular treatment has emerged as a minimally invasive approach to
      treat cerebrovascular diseases and possibly intracranial neoplasms. Practice
      patterns for selection of patients for endovascular treatment are continuously
      being modified on the basis of new information derived from clinical studies. In
      this review, I discuss the various endovascular treatments for diseases such as
      ischaemic stroke, carotid and intracranial stenosis, intracranial aneurysms,
      arteriovenous malformations, malignant gliomas, and meningiomas.

PMID- 15016493
TI  - Scale up: meeting targets in global tuberculosis control.
AB  - Despite great progress, global targets for tuberculosis case detection and cure
      might not be reached by 2005. In particular, there is a serious case-detection
      gap between estimated annual incident cases and those reported under the strategy
      for tuberculosis control branded as DOTS. Delays in reaching targets result in
      lack of effect on incidence of disease, which is of particular concern in regions
      where incidence is increasing-eg, sub-Saharan Africa and the former Soviet Union.
      Four key actions will speed up progress towards reaching global targets: 1)
      equipping national tuberculosis programmes to have a stewardship role in engaging
      all health providers in implementing the DOTS strategy; 2) establishing the
      feasibility of national certification systems of DOTS coverage; 3) promoting
      community action to contribute to patient care and to voice demand for the DOTS
      strategy; and 4) increasing support to sub-Saharan Africa for implementation of a
      strategy of expanded scope to counter HIV-1-fuelled tuberculosis.

PMID- 15016494
TI  - Facilitating learning groups in CME.

PMID- 15016496
TI  - Child abuse.

PMID- 15016497
TI  - Patient-free hospitals.

PMID- 15016500
TI  - Assessing the benefit and cost for a voluntary indoor air quality certification
      scheme in Hong Kong.
AB  - A voluntary indoor air quality certification scheme has been proposed in Hong
      Kong for assessing and evaluating the indoor air quality level in a variety of
      public places like offices, restaurants and pubs. The scheme intends to promote
      the public well being, however, its technical and financial practicality has led
      to serious discussions among the government officials, practitioners and premises
      owners. Accordingly, this study intends to develop a protocol for examining its
      financial viability by linking the appropriate dose-response and economic data
      with the results from indoor micro-environment models. The financial viability of
      the scheme is evaluated by examining the cost and benefit associated with
      compliance on the different prescribed indoor particulate (PM10) levels.
      According to our analysis, the indoor action level of 180 microg/m3 as 8-h mean
      (with the objective of protecting the health of general public) does not require
      office owners to improve beyond the base setting. Nevertheless, owners should
      consider altering the base settings in their air conditioning systems so as to
      secure more benefit on every dollar they spent. On the contrary, the 20 microg/m3
      level as 8-h mean (with the objective of providing comfort) is not considered to
      be financially viable for office owners as they will incur financial loss on
      compliance. Subsequent sensitivity analysis indicates that the total net benefit
      derived have a great dependency on the value-of-life estimates used. If
      conservative health estimates are adopted, the optimum level determined to be
      beneficial to both owners and the society will be 55 microg/m3, which can be
      obtained by operating the air conditioning system with a ventilation rate of 10
      l/s, primary filters of 80-85% efficiency and secondary filters efficiency of 60
      65% arrestance. This information should be extremely valuable for government
      officials and policy makers in assessing the financial viability of the voluntary
      indoor assessment scheme.

PMID- 15016501
TI  - Total blubber burden of organochlorine pollutants in phocid seals; methods and
      suggested standardization.
AB  - The purpose of the present paper was to investigate methods for calculating the
      total blubber burden of organochlorine pollutants (OCs) in phocid seals. Harp
      seals (Phoca groenlandica) were used as the model species. A sample of fat pre
      breeding adult females (N = 9) and a sample of thin moulting adult females (N =
      7) were collected. From each animal blubber samples from five different body
      sites (complete blubber columns and samples from different blubber layers), in
      addition to a sample from a homogenate derived from the entire blubber mass, were
      analyzed for selected OCs. Significant differences in the concentrations of major
      OC contaminants were found between inner and outer blubber layer. Within each
      seal group, no significant difference in OC concentrations was found between
      homogenates from whole blubber columns from the five different sites of the
      animals or when comparing these with the OC concentrations found in the blubber
      sample deriving from a homogenate of the entire blubber mass. When comparing the
      two seal groups, the mean OC concentrations were significantly higher in the thin
      seals. However, blubber burden of OCs measured directly and calculated indirectly
      were not significantly different, and did not vary between the two groups of
      seals. Since these seals are of the same age and sex group and from the same
      population, this is not an unexpected result. The present results suggest that
      comparison of blubber concentrations of OCs in phocid seals should be avoided,
      especially when comparing differences between geographical areas or for time
      trend analyses. For this type of study, we suggest that the blubber burden of OCs
      is applied as standard in the future. Furthermore, since blubber depth at a
      specific sampling site is required when using the estimator for calculation of
      the percent blubber content in phocid seals (the LMD-index), we suggest that this
      sampling site (central dorsally) is introduced as a standard when sampling
      blubber for OC analyses in phocid seals.

PMID- 15016502
TI  - Effects of low doses of short-term gamma irradiation on growth and development
      through two generations of Pisum sativum.
AB  - The effects of short-term gamma radiation on pea plants were investigated by
      exposing 5-day-old seedlings with doses ranging from 0 to 60 Gy, and studying
      plant growth and development over two generations after irradiation. Doses higher
      than 6 Gy significantly inhibited the G1 plant growth and productivity, and no
      seedling survived irradiation with 40 Gy and above. These effects were
      transmitted and were even more severe in the next generation, G2. Irradiated G1
      (> or =10 Gy) and G2 (> or = 0.4 Gy) plants were significantly smaller than
      controls. The mean number of pods produced per plant was reduced by at least 20%
      at all doses in both G1 and G2. In parallel, the mean numbers of ovules and
      normally developed seeds per pod were significantly reduced after 10 Gy in G1 and
      after 0.4 Gy in G2, leading to a significant drop in seed production. This effect
      was correlated with a linear decrease in male fertility linked to abnormal
      meiosis (tetrads with micronuclei) as a function of doses from 0 to 10 Gy, in G1
      and G2 plants. These long-term changes in plant development demonstrate a genomic
      instability induced by irradiation. However, there were neither quantitative nor
      qualitative changes in storage proteins in G1 seeds at any of the irradiation
      doses tested from 0 to 10 Gy.

PMID- 15016503
TI  - Effects of microelements on soil nematode assemblages seven years after
      contaminating an agricultural field.
AB  - Long-term effects of Cd, Cr, Cu, Se and Zn were studied 7 years after
      artificially contaminating plots of an agricultural field on a calcareous
      chernozem soil. Effects of three to four different contamination levels
      (originally 10, 30, 90 and 270 mg kg(-1)) were studied. Nematode density was
      significantly reduced by 90 and 270 mg kg(-1) Se as well as by 270 mg kg(-1) Cr,
      while 90 and 270 mg kg(-1) Se also reduced nematode generic richness. Maturity
      Index values (calculated for c-p 2-5 nematodes) consistently decreased with
      increasing Cr and Se concentration and to a lesser extent in Zn plots as well.
      Structure Index showed decreasing trends in increasing Cr, Se and (to a lesser
      extent) in Zn treatments, while in Cd it shows a moderate increase. Distribution
      of c-p groups was negatively affected by the increasing Cr and Se concentration,
      while in Zn plots, this decrease was not significant. Response of feeding groups
      to pollutions was similar to other parameters: Cr and Se caused significant
      changes toward the loss of variability. The proportion of the most sensitive
      omnivorous and predatory nematodes decreased clearly as a consequence of Cr and
      Se treatments. Zn pollution also resulted in a slight decrease in this group,
      while Cd caused an increase. Nematode diversity profiles showed a significant
      decrease in the plots of increased Cr and Se concentrations, while increased
      concentrations of Cu and Zn resulted in ambiguous effects. Besides providing
      evidence on the harmful effects of Cr and Se on a soil nematode assemblage, our
      results suggest that simultaneous analysis of Maturity Index, Structure Index and
      diversity profiles provide a promising tool in nematological indication of soil
      pollution.

PMID- 15016504
TI  - Using the Mallard to biomonitor heavy metal contamination of wetlands in north
      western Poland.
AB  - Contents of iron, zinc, copper, manganese, nickel, lead and cadmium were
      determined in the brain, pectoral muscle, kidney, liver and bones of the Mallard
      (Anas platyrhynchos), a cosmopolitan, herbivorous duck species. Both immature
      (im; in the first year of life) and older (adult, ad) ducks were studied. The
      birds originated from wetlands in two areas in north-western Poland, one located
      in the Slonsk waterfowl reserve (n = 32 im + 24 ad) and the other near the city
      of Szczecin (n = 21 im + 21 ad). There were numerous significant age-dependent
      differences in the metal contents of the organs of the Mallards obtained from
      near Szczecin (Sz) and/or Slonsk (S). Copper contents in the brain (Sz and S),
      muscles (Sz) and kidneys (Sz) as well as cadmium contents in the liver (Sz, S),
      kidneys (Sz, S) and muscles (S) were observed to increase with age. Between-area
      differences in metal contents of individual organs were recorded as well. The S
      Mallard showed higher contents of iron and copper (in muscles, liver and
      kidneys), zinc (in liver and kidneys) and cadmium (in muscles, liver and
      kidneys), while the Sz ducks revealed higher contents of manganese and lead (in
      brain and bones). The differences observed may be related to the habitat
      specificity: the Sl?onsk reserve is periodically flooded by the River Odra (Oder)
      waters that carry pollutants from a copper mining area 250 km away. On the other
      hand, the mid-field ponds near Szczecin are affected by pollutants, including
      those that are manganese-rich, generated by agriculture and traffic.

PMID- 15016505
TI  - Gaseous and particulate air pollution in the Lanzhou Valley, China.
AB  - Gaseous and particulate matter measurements were performed from January 1999 to
      December 2001 to assess seasonal and diurnal patterns of air pollutions in the
      Lanzhou Valley, China. The objectives are the determination of the temporal
      variability of total suspended particulate (TSP) matter and PM10 levels, and
      their relationship with the SO2 and NOx emissions and desert dust intrusions from
      the dust sources in the Hexi Corridor in Gansu Province. The results showed that
      concentrations of gaseous and particulate pollutants undergo seasonal variations
      characterized by a winter maximum levels for SO2 (0.094-0.208 mg/m3) and NO2
      (0.068-0.089 mg/m3) and a spring maximum levels for TSP (0.885-1.037 mg/m3).
      Linear regression analysis indicated that the diurnal mean TSP/PM10 ratio may
      approximate to 3.0, and that the annual NO2/NOx ratio was approximately 0.86,
      with its highest monthly average of 0.91 in June and its lowest monthly average
      of 0.788 in January. The origin of PM10 episodes was investigated by correlating
      the PM10 episodes in the Lanzhou Valley with the high wind speeds in Jinchang
      (dust sources) in the Hexi Corridor, and also, by comparing the PM10 levels with
      the SO2 and NOx concentrations. Most of the 'high PM10 episodes' (1-h mean
      maximum >1.0 mg/m3) were attributed to the desert dust intrusions from the Hexi
      Corridor. The influence of the industrial and domestic emissions in the PM10
      levels was evidenced during most of the periods with the PM10 levels less than
      1.0 mg/m3.

PMID- 15016506
TI  - Mesoscale variability of vertical profiles of environmental radionuclides (40K,
      226Ra, 210Pb and 137Cs) in temperate forest soils in Germany.
AB  - Vertical profiles of environmental radionuclides (40K, 226Ra, 210Pb and 137Cs)
      were investigated in several temperate forest soils in Germany to estimate
      heterogeneity of the soil horizon of interest. Absolute values of the activity
      concentrations of these nuclides varied to a large extent depending on the
      properties of individual forests as well as local geology. Several trends were
      generally observed independent of the location: (1) Activity concentrations of
      40K increased with increasing soil density reflecting that most potassium is
      contained in mineral components of the soil. The variations in the 40K activity
      with depth may relate to biological activities in subsoil, such as root uptake of
      the nutrients. (2) Profiles of 226Ra with depth could be an indicator for
      evaluating soil heterogeneity within a horizon of interest. They are also useful
      to estimate anthropogenic 210Pb (210Pbexc) derived from the atmosphere via dry
      fallout or wet deposition. In several forests, there appeared surface enrichment
      of 210Pb down to a depth of approximately 10 cm, in which the 210Pb would have
      come from the atmosphere by combustion of fossil fuels. (3) Depth profiles of
      137Cs were roughly divided into three types in which (a) the activity
      concentration decreased exponentially with soil depth, (b) small amounts of 137Cs
      existed only in the upper-most layer of the soil (0-5 cm) and (c) 137Cs
      disappeared at certain depths and appeared again at deeper portions of the soil.
      Consequences of bioturbation could be deduced from variability in vertical
      profiles of the environmental radionuclides. It is probable that a site showing
      an exponential decrease of the 137Cs activity with depth and also having a
      surface enrichment of 210Pb is not significantly influenced by bioturbation.

PMID- 15016507
TI  - Heavy metal contamination of water, soil and produce within riverine communities
      of the Rio Pilcomayo basin, Bolivia.
AB  - The Rio Pilcomayo heads on the Cerro Rico de Potosi precious metal-polymetallic
      tin deposits of Southern Bolivia. Mining of the Potosi deposits began in 1545 and
      has led to the severe contamination of the Pilcomayo's water and sediments for at
      least 200 km downstream of the mines. This investigation addresses the potential
      human health affects of metal and As contamination on four communities located
      along the upper Rio Pilcomayo by examining the potential significance of human
      exposure pathways associated with soils, crops and water (including river,
      irrigation and drinking water supplies). The most significantly contaminated
      agricultural soils occur upstream at Mondragon where Cd, Pb and Zn concentrations
      exceed recommended guideline values for agricultural use. Further downstream the
      degree of contamination decreases, and metal concentrations are below Dutch,
      German and Canadian guideline values. Metal and As concentrations in agricultural
      products from the four communities were generally below existing guidelines for
      heavy metal content in commercially-sold vegetables. Thus, the consumption of
      contaminated produce does not appear to represent a significant exposure pathway.
      A possible exception is Pb in carrots, lettuce and beetroots from Sotomayor and
      Tuero Chico; 37% and 55% of the samples, respectively, exceeded recommended
      guidelines. Most communities obtain drinking water from sources other than the
      Rio Pilcomayo. In general, dissolved concentrations of metals and As in drinking
      water from the four studied communities are below the WHO guideline values with
      the exception of Sb, which was high at Tasapampa. The inadvertent ingestion of
      contaminated water from irrigation canals and the Rio Pilcomayo represents a
      potential exposure pathway, but its significance is thought to be minimal. Given
      the degree of soil contamination in the area, perhaps the most significant
      exposure pathway is the ingestion of contaminated soil particles, particularly
      particles attached to, and consumed with vegetables. The risks associated with
      this pathway can be reduced by thoroughly washing or peeling the vegetables prior
      to consumption. Other exposure pathways that are currently under investigation
      include the consumption of contaminated meat from livestock and poultry, which
      drink polluted waters and the ingestion of contaminated wind-blown dust.

PMID- 15016508
TI  - Characterization and availability of cyanide in solid mine tailings from gold
      extraction plants.
AB  - The aim of this study was to investigate the availability and fate of cyanide in
      gold mill solid tailings. For this purpose, aged (6-9 years) and recently
      discharged (3 months) tailings were sampled at various depths from two gold
      mining sites in Quebec (Canada). A physicochemical characterization of the
      tailings along with a bacterial enumeration was performed and batch-leaching
      tests with water and caustic solution were conducted to assess the soluble
      cyanide fraction. Following the standard acid reflux/distillation method, the
      total cyanide concentration (CN(T)) in fresh tailings was higher (average of 19.5
      +/- 2.0 compared to 3.2 +/- 0.7 mg/kg) and the pH more alkaline (10.6 +/- 0.1
      compared to 7.6 +/- 0.2) compared to aged ones. In aged tailings, the enumeration
      of total heterotrophic (10(4)-10(6) cfu/g) and cyanide-resistant bacteria (10(2)
      10(5) cfu/g) showed a significant indigenous microflora, but no growth on agar
      plates was detected in fresh tailings, suggesting an evolution and a gradual
      acclimatization of bacterial populations with weathering. Elevated concentrations
      of CN(T), weak acid dissociable cyanide (CN(WAD)), cyanate (CNO-), and
      thiocyanate (SCN-) were measured in the supernatant solution of the fresh
      tailings samples collected in-situ, highlighting their reactivity, whereas these
      species were not detectable in aged tailings. Accordingly, when batch-leaching
      tests were performed with fresh samples, 68-72% of the total cyanide was released
      into aqueous solution with more than 20% being CN(WAD). Again, CN(T) and CN(WAD)
      were not detectable during leaching of aged tailings. In fresh tailings,
      approximately 50% of the cyanides were quantifiable with the standard acid
      reflux/distillation method (readily soluble cyanides, and weak to moderately
      strong complexes), whereas in aged tailings only 15 to 33% of the actual total
      cyanide content was measured by the standard method. These results stress the
      necessity of performing a preliminary alkaline extraction prior to total cyanide
      determination. In summary, this study revealed a difference in physicochemical
      properties, cyanide concentration and speciation, viable bacterial populations
      and cyanide leaching behavior between aged and fresh solid mine tailings. The
      findings indicate that the more reactive cyanide species initially associated
      with the solid tailings have naturally degraded within the mine tailings
      impoundment area, resulting primarily from volatilization (decrease in pH),
      leaching, and bacterial degradation.

PMID- 15016509
TI  - Response of three paleo-primary production proxy measures to development of an
      urban estuary.
AB  - In this study we present a novel comparison of three proxy indicators of
      paleoproductivity, pigments, biogenic silica (BSi), and cysts of autotrophic
      dinoflagellates measured in cored sediments from New Bedford Harbor,
      Massachusetts. In addition to detailed historical reports we use palynological
      signals of land clearance, changes in the ratio of centric and pennate diatoms,
      sedimentary organic carbon and stable carbon isotopes to constrain our
      interpretations. Our study spans the period from prior to European settlement to
      approximately 1977, during which watersheds were cleared, port development
      occurred and much of the coastal property became industrialized. The combined
      effects of nutrient loading from watershed clearance and urban sewage on the
      estuarine ecosystem shifted not only levels of primary production, but also the
      nature of the production. Our proxies show that when European colonists first
      arrived the estuarine production was benthic-dominated, but eventually became
      pelagic-dominated. Importance of water column production (by diatoms and
      dinoflagellates) rapidly increased as soil nitrogen was released following forest
      clearance. Stabilization in rates of forest clearance is reflected as a decline
      in production. However, population increases in the urbanizing watershed brought
      new sources of nutrients through direct sewage discharge, apparently again
      stimulating primary production. We assume that early 20th century changes in
      sewage discharge and introduction of heavy metals into Harbor waters caused a
      temporary reduction in primary production. The introduction of a new sewer
      outfall near the core site and changes in estuarine hydrography due to
      construction of a hurricane barrier across the mouth of the harbor are reflected
      by renewed water column production, but decreases in the population of diatoms
      and dinoflagellates. Fossil pigments suggest renewed water column production in
      the latest years recorded by our sediment core.

PMID- 15016510
TI  - Lead levels of edibles grown in contaminated residential soils: a field survey.
AB  - Plants grown in lead contaminated soils can accumulate lead from the adherence of
      dust and translocation into the plant tissue. In order to evaluate the potential
      health hazard due to the consumption of plants grown in residential gardens
      contaminated by lead, a survey of the lead concentrations in a typical array of
      edible vegetables, fruits and herbs was conducted. Samples of garden plants
      harvested from the field were washed with detergent or water alone to remove
      adhered soil. They were dried, separated into sections including root, shoot and
      edible fruit, and then analyzed for lead content using inductively coupled plasma
      atomic emission spectrometry (ICP-AES). Soil samples, taken in conjunction with
      the plant harvesting, were analyzed using flame atomic absorbance (FAA). A
      pattern of lead transference from soil through the root to the stem and leaves of
      garden crops was found. The majority of the lead was concentrated in the roots
      (root:soil ranging from 0.02 to 0.51), with some translocation into the shoots
      (shoot:soil as high as 0.10). This pattern is a concern particularly for crops in
      which the root, stems, stalks or leaves are edible. The lead concentration in
      fruiting vegetables was less than the detection limit of 10 ppm (microgram
      lead/gram dry plant matter). Some edible portions of the leafy vegetables and
      herbs, however, were found to have lead levels that, if consumed, could
      contribute to the total body burden of lead. Therefore, urban gardeners should
      test the lead levels in their soils and develop strategies to ensure safety.

PMID- 15016511
TI  - Arsenic oxidation and bioaccumulation by the acidophilic protozoan, Euglena
      mutabilis, in acid mine drainage (Carnoules, France).
AB  - In the acid stream (pH 2.5-4.7) originating from the Carnoules mine tailings, the
      acidophilic protozoan Euglena mutabilis grows with extremely high sulfate (1.9
      4.9 g/l), iron (0.7-1.7 g/l) and arsenic concentrations (0.08-0.26 g/l). Strong
      variations in flow rate and high sulfate concentrations (up to 4.9 g/l) have been
      registered in early winter and might be the reason for the reduction in cell
      number of the protozoan from October to December 2001. No relation was
      established between arsenic concentration and/or speciation and abundance of the
      protozoan in the stream. Arsenite, which is the most toxic form, predominates in
      water. The oxidation of arsenite to arsenate occurred within a few days in
      laboratory experiments when E. mutabilis was present in Reigous Creek water and
      synthetic As(III)-rich culture medium. Methylated compounds (MMA, DMA) were not
      identified in the culture media. The protozoan bioaccumulated As in the cell (336
      +/- 112 microg As/g dry wt.) as inorganic arsenite (105 +/- 52 microg As/g dry
      wt.) and arsenate (231 +/- 112 microg As/g dry wt.). Adsorption of As at the cell
      surface reached 57 mg/g dry wt. in the As(V) form for E. mutabilis grown in 250
      mg/l As(III) synthetic medium. Both intracellular accumulation and adsorption at
      the cell surface increased for increasing As(III) concentration in the medium but
      the concentration factor in the cell relative to soluble As decreased.

PMID- 15016512
TI  - Direct photolysis of estrogens in aqueous solutions.
AB  - Direct photolysis of two estrogens 17beta-estradiol (E2) and estrone (E1) in
      aqueous solutions radiated by UV-light and UV-Vis-light was studied
      preliminarily. The results suggest that the photolysis of E2 in aqueous solutions
      occurs under irradiation with UV disinfection lamp (lambda = 254 nm, 30 W), while
      E1 can also undergo photolysis under irradiation with a high-pressure mercury
      lamp (lambda > or = 365 nm, 125 W). The photolysis reactions of E2 and E1 at the
      concentration of 3.0-20 mgl(-1) in aqueous solutions were all in accordance with
      pseudo-first-order law. The photolysis rate of estrogens in aqueous solutions
      reached the lowest value at pH approximately 5.0, while the highest at pH 8.0
      over the range of 2.0-8.0. The higher the initial concentration of the two
      estrogens, the lower the rate of photolysis.

PMID- 15016513
TI  - Retention and removal of pathogenic bacteria in wastewater percolating through
      porous media: a review.
AB  - Properly designed biological filters or infiltration systems have the capacity to
      significantly reduce effluent concentrations of pathogenic microorganisms in
      wastewater. The retention and elimination of microbial cells in biological
      wastewater filter systems is influenced by several factors. In this review, these
      factors are discussed. Immobilization of microbial cells moving through a porous
      media is influenced by mechanisms such as physical straining as well as
      adsorption to porous media. The grain size of porous media and bacterial cell
      size are important factors affecting the straining of bacteria, as are the
      hydraulic loading rate or the extent of clogging layer development in the filter.
      Adsorption of cells to the porous media is influenced by the content of organic
      matter, degree of biofilm development, and electrostatic attraction due to ion
      strength of the solution or electrostatic charges of cell- and particle surfaces.
      The rate of inactivation of pathogenic microorganisms, in adsorbed or liquid
      phases, has been shown to be affected by abiotic and biotic factors such as
      moisture content, pH, temperature, organic matter, bacterial species, predation,
      and antagonistic symbiosis between microorganisms in the system.

PMID- 15016514
TI  - Interspecies electron transfer in methanogenic propionate degrading consortia.
AB  - Propionate is a key intermediate in the conversion of complex organic matter
      under methanogenic conditions. Oxidation of this compound requires obligate
      syntrophic consortia of acetogenic proton- and bicarbonate reducing bacteria and
      methanogenic archaea. Although H(2) acts as an electron-carrier in these
      consortia, evidence accumulates that formate plays an even more important role.
      To make energy yield from propionate oxidation energetically feasible for the
      bacteria and archaea involved, the concentrations of H(2) and formate have to be
      extremely low. On the other hand, the diffusion distance of these carriers has to
      be small to allow high propionate conversion rates. Accordingly, the high
      conversion rates observed in methanogenic bioreactors are due to the fact that
      the propionate-oxidizing bacteria and their methanogenic partners form micro
      colonies within the densely packed granules.

PMID- 15016515
TI  - Anaerobic sludge granulation.
AB  - This paper reviews different theories on anaerobic sludge granulation in UASB
      reactors that have been proposed during the past two decades. The initial stages
      of the formation of anaerobic granules follow the same principles as biofilm
      formation of bacteria on solid surfaces. There exist strong evidence that inert
      carriers play an important positive role in granulation. Most researchers
      conclude that Methanosaeta concilii is a key organism in granulation. Only the
      Cape Town Hypothesis presumes that an autotrophic hydrogenotrophic organism,
      i.e., Methanobacterium strain AZ, growing under conditions of high H(2)
      pressures, is the key organism in granulation. Many authors focus on the initial
      stage of granulation, and only a few contributions discuss the latter stages in
      granulation: granule maturation and multiplication. Granule enhancing factors in
      the latter stages predominantly rely on manipulation of the selection pressure,
      through which selectively heavier sludge particles are retained in the UASB
      reactor.

PMID- 15016516
TI  - The influence of substrate kinetics on the microbial community structure in
      granular anaerobic biomass.
AB  - The development of a strong, active granular sludge bed is necessary for optimal
      operation of upflow anaerobic sludge blanket reactors. The microbial and
      mechanical structure of the granules may have a strong influence on desirable
      properties such as growth rate, settling velocity and shear strength. Theories
      have been proposed for granule microbial structure based on the relative kinetics
      of substrate degradation, but contradict some observations from both modelling
      and microscopic studies. In this paper, the structures of four granule types were
      examined from full-scale UASB reactors, treating wastewater from a cannery, a
      slaughterhouse, and two breweries. Microbial structure was determined using
      fluorescence in situ hybridisation probing with 16S rRNA-directed oligonucleotide
      probes, and superficial structure and microbial density (volume occupied by cells
      and microbial debris) assessed using scanning electron microscopy (SEM), and
      transmission electron microscopy (TEM). The granules were also modelled using a
      distributed parameter biofilm model, with a previously published biochemical
      model structure, biofilm modelling approach, and model parameters. The model
      results reflected the trophic structures observed, indicating that the structures
      were possibly determined by kinetics. Of particular interest were results from
      simulations of the protein grown granules, which were predicted to have slow
      growth rates, low microbial density, and no trophic layers, the last two of which
      were reflected by microscopic observations. The primary cause of this structure,
      as assessed by modelling, was the particulate nature of the wastewater, and the
      slow rate of particulate hydrolysis, rather than the presence of proteins in the
      wastewater. Because solids hydrolysis was rate limiting, soluble substrate
      concentrations were very low (below Monod half saturation concentration), which
      caused low growth rates.

PMID- 15016517
TI  - Column experiments for microbiological treatment of acid mine drainage: low
      temperature, low-pH and matrix investigations.
AB  - The lifetime of traditional sulfate-reducing bacteria (SRB) bioreactors that
      utilize a source of reducing equivalents contained within the matrix (e.g.
      manure) is limited by the amount of readily available reducing equivalents within
      that matrix. In order to extend bioreactor lifetime indefinitely, the addition of
      known concentrations of alternative reducing equivalents (methanol and ethanol)
      to a depleted matrix was tested at low pH and low temperatures. Following
      acclimation, up to 100% efficiencies of reducing equivalents were directed toward
      sulfate reduction. Alcohol was added in stoichiometric concentrations to remove
      50% of the added sulfate (900 mg/L), producing sufficient sulfide to precipitate
      all of the iron from solution. An average of 42% of the sulfate was removed
      following acclimation, reflecting 84% efficiency. An average of 93% of the iron
      was removed (93 mg/L). Bacteria acclimated to ethanol more rapidly than methanol,
      although both alcohols were effective as carbon sources. Efficient treatment was
      observed at the lowest temperatures (6 degrees C) and lowest pHs (pH=2.5) tested.
      The use of ethanol-fed, highly permeable bioreactor matrices of wood chip,
      pulverized plastic and rock was also examined to determine which of these porous
      matrices could be implemented in a field bioreactor. Results indicated that >95%
      of the 100mg/L iron added was removed by all matrices. Sufficient reducing
      equivalents were added to remove 450 mg/L of sulfate, wood and rock matrices
      removed approximately 350 mg/L plastic removed approximately 225 mg/L. A study
      comparing rock size indicated that small rocks removed iron and sulfate more
      efficiently than medium- and large-size rocks. The results suggest that wood and
      rock in conjunction with ethanol are viable alternatives to traditional
      bioreactor matrices. These findings have direct application to semi-passive
      sustained operation of SRB bioreactors for treatment of acidic drainage at remote
      sites.

PMID- 15016518
TI  - Treatment of strongflow wool scouring effluent by biological emulsion
      destabilisation.
AB  - The stable oil-in-water emulsion contained in wool scouring effluent was
      destabilised by aerobic biological treatment as the basis of a potential new
      effluent treatment process. The de-emulsified wool wax, which is recalcitrant to
      biodegradation, can then be readily removed by centrifugation. In 12-day batch
      experiments, 97% of wool wax and 87% of COD were removed after gentle
      centrifuging at 200 x g, compared to only 6% and 8%, respectively, for sterile
      controls. Steady-state chemostat experiments under optimum conditions gave
      essentially complete removal of wool wax and 90% removal of COD at less than 40 h
      retention time, and demonstrated that the mechanism of pollutant removal was by
      bioflocculation rather than aerobic degradation. At 100 L pilot scale, 95% of
      wool wax and 82% of COD were consistently removed over a period of 116 days of
      continuous operation at 38 h retention time and 30 degrees C, producing a
      spadable sludge of 5.7 mL/g. Variable influent concentration or filamentous
      bacteria did not disrupt this process and foaming was readily controlled using a
      mechanical foam breaker. After a shutdown period of 15 days the process could be
      restarted easily, achieving normal performance within one retention time. The
      successful operation of the pilot reactor suggests this process could be
      developed to full scale and incorporated into an overall treatment package.

PMID- 15016519
TI  - Characterizing algogenic organic matter (AOM) and evaluating associated NF
      membrane fouling.
AB  - Occasional algal blooms, comprised of blue-green algae and/or green algae, cause
      significant challenges in drinking water treatment due to the release of
      algogenic organic matter (AOM) into water extracellularly and, upon cell lysis,
      intracellularly. AOM has been extracted from blue-green algae (cyanobacteria) by
      various means and analyzed by UV absorbance scanning, HPSEC-UV-fluorescence-DOC,
      UV absorbance ratio index (URI), FTIR, and fluorescence excitation emission
      matrix (EEM). AOM extracted in water as a solvent exhibited a high hydrophilic
      fraction (57.3%) with a low SUVA (1.0 L/m-mg). The molecular weight (MW)
      distribution showed a significant heterogeneity (high value of polydispersivity)
      and high protein content (as indicated by specific fluorescence). Significant
      amounts of proteinaceous components such as mycosporine-like amino acids (MAAs,
      UV-screening components) and phycobilins (light-harvesting pigment) were detected
      by UV/visible absorption. The presence of proteins was confirmed by FTIR (at 1661
      and 1552 cm(-1)), EEM spectra (EX:278-282 nm and EM:304-353 nm), and high URI
      values (3.1-6.0). A bench-scale cross-flow unit, employing a flat-sheet membrane
      specimen, was used to examine nanofiltration (NF) membrane fouling and removal of
      natural organic matter (NOM) derived from different blends of Suwannee River
      humic acid (SRHA) and AOM: SRHA 10 mgC/L, AOM 3mg C/L + SRHA 7 mgC/L, AOM 7 mgC/L
      + SRHA 3 mgC/L, and AOM 10 mgC/L. The study focused mainly on the effects of two
      different sources of organic matter on NF (NF 200) membrane fouling under
      otherwise similar conditions. Flux decline and organic matter rejection as a
      function of delivered DOC (cumulative mass of feed DOC per unit area) showed
      significantly different results depending on the organic matter composition of
      samples even though the test conditions were the same (organic matter
      concentration, pH, temperature, inorganic salt composition and concentration, and
      recovery). A higher flux decline was observed with increasing proportions of AOM.
      Organic matter rejections also decreased with higher AOM contributions to the
      samples, indicating that lower molecular weight (MW) AOM components were not well
      rejected by the NF 200 membrane having a 360 Da MWCO. However, SRHA that
      exhibited a relatively high MW (1000-5000 Da range) and high SUVA (7.4 L/m-mg)
      was preferentially rejected through electrostatic repulsion/size exclusion by the
      NF 200 membrane, having a high negative charge, low MWCO, and relatively low
      hydrophobicity. Even though the DOC concentration of feed water is a decisive
      factor for membrane fouling along with membrane properties and operating
      conditions, the characteristics of organic matter are more influential in fouling
      potential. Protein-like and polysaccharide-like substances were found as major
      foulants by FTIR.

PMID- 15016520
TI  - Mercury distribution, speciation and flux in the Sepetiba Bay tributaries, SE
      Brazil.
AB  - Dissolved gaseous Hg, reactive Hg, total dissolved Hg and particulate Hg
      concentrations were measured in samples of majors tributaries of the Sepetiba
      Bay, SE Brazil (Itimirim, Itingucu, Guarda, Guandu, Sao Francisco and Ita
      rivers), in dry and rainy seasons. The average Hg concentrations found varied
      from 0.02 to 0.18 ng L(-1) for dissolved gaseous Hg, from 0.1 to 18.1 ng L(-1)
      for reactive Hg, from 0.1 to 66.6 ng L(-1) for total dissolved Hg and from 0.3 to
      250 ng L(-1) for particulate Hg. During the rainy season, a decrease in the
      dissolved Hg concentrations and an increase in the particulate Hg concentrations
      was observed. Positive correlations were found between the reactive Hg and the
      total dissolved Hg concentrations (r = 0.99), between the particulate Hg and TSS
      concentrations (r = 0.82) and between total Hg and particulate Hg concentrations
      (r = 0.95). The instantaneous Hg fluxes varied among rivers from 0.02 to 412
      microgs(-1) for total dissolved Hg and from 0.03 to 12,572 microgs(-1) for
      particulate Hg. The log Kd varied from 3.76 to 6.43 and showed a significant
      increase in rainy season following an increase in particulate Hg and a decrease
      in dissolved Hg concentrations. These results suggest that erosion and runoff are
      the major pathways of Hg transport to rivers and eventually to Sepetiba Bay.

PMID- 15016521
TI  - Cosolvency effect in subsurface systems contaminated with petroleum hydrocarbons
      and ethanol.
AB  - In Brazil, most gas stations and terminals store tanks containing hydrated
      ethanol, gasohol and diesel. In case of spills, it is possible that a high
      aqueous ethanol concentration can facilitate the transfer of hydrocarbons into
      the aqueous phase, enhancing contaminant concentrations in groundwater, a process
      called cosolvency. This study investigates the cosolvency effect of ethanol on
      the aqueous solubility of mono- and polycyclic aromatic hydrocarbons, and
      presents a simple log-linear model to predict this effect under equilibrium
      conditions. Cosolvency experiments were carried out in batch reactors under
      equilibrium conditions for pure mono- and polycyclic aromatic hydrocarbons,
      gasohol and diesel. A linear relationship between cosolvency power and Kow was
      determined, which allows predictions of the increase of aromatic hydrocarbon
      solubility due to the presence of ethanol. Results indicate that cosolvency would
      be significant only for high aqueous ethanol concentrations (higher than 10%).
      Under these conditions, cosolvency may be critical only in cases of large gasohol
      spills or in simultaneous releases of neat ethanol and other fuels. In this way,
      the hydrophobic and toxic polycyclic aromatic hydrocarbons (PAHs), that are
      usually present in minor aqueous concentrations in fuel spills without ethanol,
      may be dissolved in larger amounts in groundwater.

PMID- 15016522
TI  - Survival of Mycobacterium avium in a model distribution system.
AB  - A pilot study was designed to examine the impact of nutrient levels, pipe
      materials, and disinfection on the survival of M. avium in model drinking water
      distribution system biofilms. Studies showed that the survival of the organism
      was dependant upon a complex interaction between pipe surface, nutrient levels,
      and disinfectants. The findings showed that when no disinfection was applied, M.
      avium could be recovered from biofilms at nutrient levels of 50microg/L
      assimilable organic carbon. M. avium concentrations were lower on copper pipe
      surfaces following disinfection with free chlorine as compared to monochloramine.
      However, due to the interference of corrosion products, chloramination of iron
      pipe surfaces controlled M. avium levels better than free chlorine. These data
      demonstrate the significance of pipe materials on the survival of M. avium
      complex in biofilms. Elimination of competitive heterotrophic bacteria on copper
      pipe surfaces by the application of disinfection resulted in a population of
      nearly 100% M. avium. Heat treatment of M. avium biofilms was affected by the
      pipe composition and organic content of the water. Effluent temperatures >53
      degrees C were required to control the occurrence of M. avium in the pipeline
      system. Although additional studies are required using improved detection
      methods, the results of this investigation suggest that reducing the
      biodegradable organic material in drinking water, control of corrosion,
      maintenance of an effective disinfectant residual, and management of hot water
      temperatures can help limit the occurrence of M. avium complex in drinking water
      biofilms.

PMID- 15016523
TI  - Characterization of natural organic matter fractions separated by ultrafiltration
      using flow field-flow fractionation.
AB  - Natural organic matter (NOM) from two sites in South Australia were separated by
      Amicon YM and YC ultrafiltration (UF) membranes into five nominal fractions
      (<0.5, 0.5-3, 3-10, 10-30 and >30 kDa). These nominal fractions were then
      characterized for size and molecular weight (MW) distributions using flow field
      flow fractionation. The results show that separation by UF did not produce
      fractions with the expected MW and size. Electrophoretic mobility measurements of
      the NOM fractions adsorbed to colloidal goethite showed no significant difference
      between the fractions. However solid-state (13)C NMR of the NOM fractions showed
      that the separation was influenced by molecular structure as well as molecular
      size. The results suggest that great caution needs to be exercised when
      interpreting molecular size and speciation results for humic substances obtained
      by membrane UF.

PMID- 15016524
TI  - Complexation of organic compounds in the presence of Al3+ during micellar
      flocculation.
AB  - Complexes of Al and model pollutants phenol, benzoic acid, 2,4-D (2,4
      dichlorophenoxyacetic acid) and 2,4-DB (2,4-dichlorophenoxybutiric acid) play a
      key role in the removal of organic pollutants by co-adsorption on micelles of
      anionic surfactants flocculated by means of Al(3+). This technique, known as
      adsorptive micellar flocculation (AMF), is related to removal of organic
      compounds by coagulation-precipitation with Al and Fe salts. Some of the
      stoichiometries found (6Al:1L and higher, with "L" the organic compound) indicate
      that complexes of a cationic nature form in the presence of high excesses of Al,
      possibly polyaluminium complexes related to the species [Al(13)O(4)(OH)(24)](7+).
      In the case of phenol it has been established by spectroscopic measures that in
      the range of [Al(2)(SO(4))(3)](tot) between 5 x 10(-5) and 3 x 10(-4)M and
      [phenol](tot) between 10(-3) and 6 x 10(-3)M complexes exist at pH as low as 2.4.
      The results show that AMF may be explained by the chemisorption of molecules of
      organic compounds able to incorporate into the polyaluminic complexes occurring
      within the Stern layer of flocculating micelles.

PMID- 15016525
TI  - Model-based design of horizontal subsurface flow constructed treatment wetlands:
      a review.
AB  - The increasing application of constructed wetlands for wastewater treatment
      coupled with increasingly strict water quality standards is an ever growing
      incentive for the development of better process design tools. This paper reviews
      design models for horizontal subsurface flow constructed treatment wetlands,
      ranging from simple rules of thumb and regression equations, to the well-known
      first-order k-C* models, Monod-type equations and more complex dynamic,
      compartmental models. Especially highlighted in this review are the model
      constraints and parameter uncertainty. A case study has been used to demonstrate
      the model output variability and to unravel whether or not more complex but also
      less manageable models offer a significant advantage to the designer.

PMID- 15016526
TI  - Chromium bioaccumulation: comparison of the capacity of two floating aquatic
      macrophytes.
AB  - The capacity of Salvinia herzogii and Pistia stratiotes to remove Cr (III) from
      water and their behaviour at different Cr (III) concentrations were studied in
      outdoor experiments. Cr distribution in aerial parts and roots with time and the
      possible mechanisms of Cr uptake were analyzed. Both macrophytes efficiently
      removed Cr from water at concentrations of 1, 2, 4 and 6 mgCrL(-1). S. herzogii
      was the best adapted species. At a greater initial concentration, greater
      bioaccumulation rates were observed. Root Cr uptake was a rapid process that was
      completed within the first 24h. Cr uptake through direct contact between the
      leaves and the solution is the main cause of the increase of Cr in the aerial
      parts, Cr being poorly translocated from the roots to the aerial parts. Both
      mechanisms were fast processes. The Cr uptake mechanism involves two components:
      a fast component and a slow one. The former occurs mainly due to the roots and
      leaves adsorption and is similar for both species. The slow component is
      different for each species probably because in P. stratiotes a Cr precipitation
      occurs induced by the roots.

PMID- 15016527
TI  - Reactivity of natural organic matter with aqueous chlorine and bromine.
AB  - While both aqueous bromine (HOBr/OBr(-)) and chlorine (HOCl/OCl(-)) react with
      natural organic matter (NOM) during water treatment, limited direct parallel
      comparison of bromine versus chlorine has been conducted. Experiments with model
      compounds and natural waters indicated more efficient substitution reactions with
      bromine than chlorine. Kinetic experiments with NOM isolates with and without pre
      ozonation were conducted to obtain second-order rate constants (k) with bromine
      and chlorine. Two-stage reaction kinetics (rapid initial and slower consumption
      stages) were observed. Bromine reacted about 10 times faster than chlorine with
      NOM isolates during both stages. The rapid initial stage reactions were too fast
      to quantify k values, but qualitative estimates ranged between 500 and 5000 M(
      1)s(-1). For the slower second stage k values for bromine were 15 to 167 M(-1)s(
      1) over the pH range of 5-11, and lower for chlorine (k = 0.7-5M(-1)s(-1)).
      Values of k correlated with initial SUVA values of NOM (UVA measured at 254 nm
      divided by DOC). Based upon UV/VIS and solid-state (13)C-NMR spectroscopy,
      chlorine addition to a NOM isolate resulted in significant oxidation of aromatic
      and ketone groups while bromine had significantly less change in spectra.
      Overall, the improved knowledge that bromine reacts faster and substitutes more
      efficiently than chlorine will be useful in developing strategies to control
      disinfection by-product formation during water treatment.

PMID- 15016528
TI  - Mechanisms of inactivation of hepatitis A virus in water by chlorine dioxide.
AB  - In this study, to elucidate the mechanisms of inactivation of hepatitis A virus
      (HAV) by chlorine dioxide, cell culture, enzyme-linked immunosorbent assay
      (ELISA), and long-overlapping RT-PCR were used to detect the infectivity,
      antigenicity, and entire genome of HAV before and after disinfection. The results
      revealed the complete inactivation of infectivity after a 10-min exposure to
      7.5mg of chlorine dioxide per liter; and the highest level of sensitivity in the
      5'non-translated regions (5'NTR) (the sequence from bp 1 to 671), inactivation of
      which took as much time as the inactivation of infectivity of HAV by chlorine
      dioxide; the complete destruction of antigenicity after a 10-min exposure to
      7.5mg of chlorine dioxide per liter. It is suggested that the inactivation
      mechanism of HAV by chlorine dioxide was due to the loss of the 5'NTR and/or
      destruction of the antigenicity, which is not similar to that of chlorine (Appl
      Environ Microbiol 68: 4951).

PMID- 15016529
TI  - Occurrence and fate modeling of MTBE and BTEX compounds in a Swiss Lake used as
      drinking water supply.
AB  - Emissions of fuel components from boating use on multiple-use lakes and
      reservoirs are of high concern with regard to the drinking water supply from such
      water bodies. We report results of a detailed study on the occurrence, sources
      and fate of aromatic hydrocarbons and methyl tert-butyl ether (MTBE) in a typical
      holomictic lake, Lake Zurich, that supplies drinking water for the largest Swiss
      city. Emphasis of the investigation was on the fuel oxygenate MTBE, which was
      found in concentrations up to 1.4 microg/L in the epilimnion and up to
      0.05microg/L in the hypolimnion of the lake. The concentration difference was due
      to the stratification of the lake during the boating season with very limited
      water exchange across the thermocline. MTBE and BTEX nearly completely
      volatilized before vertical lake mixing occurred in winter. Spatial and temporal
      variations of MTBE concentrations in the lake were observed and successfully
      predicted using two complementary box models (MASAS Light and Aquasim). The
      drinking water supply from holomictic lakes is not at risk for the scenarios
      studied if water is extracted from well below the thermocline. Since emissions of
      unburned gasoline into such water bodies are caused predominantly by boating
      activities, restrictions of highly emitting two-stroke engines could
      substantially reduce the MTBE and BTEX load of the epilimnion during the boating
      season.

PMID- 15016530
TI  - Overcoming oxygen limitations in membrane-attached biofilms--investigation of
      flux and diffusivity in an anoxic biofilm.
AB  - The possibility of overcoming oxygen limitations in membrane-attached biofilms
      has been investigated by using nitrate as an electron acceptor instead of oxygen
      in an extractive membrane bioreactor (EMB) degrading toluene. The effect of
      nitrate concentration on toluene flux, the effective diffusivity in the biofilm
      and the biofilm activity has been investigated. A counter-diffusion-reaction
      model is also presented, describing the pollutant flux versus biofilm thickness.
      The toluene flux decreased with increasing biofilm thickness under excess nitrate
      concentrations, similar to the experiment with low nitrate. Mathematical
      modelling indicated that this was either due to decreasing activity, and/or
      different diffusivities in the biofilm. The effective diffusivity was
      investigated by using an inert tracer molecule. It remained constant for biofilm
      thicknesses up to 1.8mm, with a value twice that in water. The biofilm activity
      was investigated by inactivating a mature biofilm using sodium azide. The toluene
      flux remained the same before and after the addition of sodium azide, suggesting
      that the activity in the biofilm is very low. We conclude that the decreasing
      toluene flux with increasing biofilm thickness is due to the diffusional
      resistance of the inactive biofilm.

PMID- 15016531
TI  - An evaluation procedure for flocculation of coal preparation plant tailings.
AB  - In solid-liquid separation of coal preparation plant tailings by flocculation, in
      addition to the type and amount of flocculants, the composition of waste
      materials including clay minerals must be determined in order to devise an
      effective and economic sedimentation system. In this study, the characterization
      of organic and inorganic impurities was made with the help of mineralogical data
      and instrumental analysis techniques. The effects of polymer type (medium and low
      anionic, cationic and nonionic), polymer dosage and suspension pH on flocculation
      mechanism of tailings particles (-0.18 mm) in the Tuncbilek Coal Preparation
      Plant tailings of Tuncbilek (Turkey) were investigated. Medium anionic polymer
      accelerated the settling rate of particles. An optimum settling rate (300 mm/min)
      was reached at a dosage rate of 34.19 g/ton-solids (2.0 mg/l), 51.28 g/ton-solids
      (3.0 mg/l), 102.56 g/ton-solids (6.0 mg/l) and 119.66 g/ton-solids (7.0mg/l) for
      medium anionic, low charged anionic, nonionic and cationic polymers,
      respectively. The lowest turbidity values at low polymer dosages were obtained by
      the cationic polymer at around 25.64 g/ton-solids (1.5 mg/l) polymer dosages;
      however, the low anionic and nonionic polymers produced lower turbidity values at
      higher dosages (>25.64 g/ton-solids). At optimum dosages of the polymer, the
      settling rate decreased at low and high pHs indicating that the natural pH (pH
      8.3) of the suspension is the most appropriate pH for the settling rate. On the
      other hand, the water clarity values at natural pHs were high for all of the
      polymers.

PMID- 15016533
TI  - Effect of phosphorus stripping on water chemistry and diatom ecology in an
      eastern lowland river.
AB  - The effect of nutrient removal at Ashford sewage treatment works on the benthic
      diatom ecology of the River Stour was studied. This paper describes assemblages
      above and below the works both before and after phosphorus stripping was
      installed. Taxa typical of eutrophic conditions dominated all samples, including
      those upstream of the works, suggesting that the river was already eutrophic
      before receiving the sewage effluent. Once nutrient removal was installed,
      phosphorus concentrations measured downstream of the works were similar to those
      measured upstream; however, there was little change in the diatom flora. Analysis
      of chemical data collected from the site suggest that the river may be nitrogen
      limited for part of the year, and that, even with phosphorus stripping installed,
      the river still exceeds the Environment Agency's proposed interim targets for
      phosphorus concentrations in a eutrophic river.

PMID- 15016532
TI  - Electro-oxidative abatement of low-salinity reverse osmosis membrane
      concentrates.
AB  - The present study encompasses the application of electrolysis as novel treatment
      technique for the abatement of low-salinity concentrates generated from the
      filtrative treatment of water and wastewater. Four different materials have been
      tested as anode for a number of brine samples in a one-compartment electrolytic
      cell in galvanostatic mode. It was found that PbO(2) and SnO(2) anodes initiated
      electrochemical precipitation through an increase of the pH. Boron-doped diamond
      (BDD) and RuO(2) anodes successfully oxidised the pollutants in the brine and a
      linear removal of total ammonia nitrogen (TAN) and chemical oxygen demand (COD)
      was observed during the first phase of oxidation. Oxidation was predominantly
      achieved through indirect hypochlorite bulk oxidation; the higher oxidation rate
      and extent for the BDD anode was attributed to the higher selectivity and
      activity of the latter. Overall performance of the BDD electrode was higher than
      for RuO(2): higher rates for TAN (17.9 vs. 13.5mg/Ah) and COD (74.5 vs.
      20.0mg/Ah) removal as well as higher overall current efficiencies (35.2% vs.
      14.5%). Extensive colour removal was observed for both anodes (>90% decrease in
      absorbency at 455 nm).

PMID- 15016534
TI  - Optimisation of clarifier-thickeners processing stable suspensions for turn
      up/turn-down.
AB  - Solid-liquid separation equipment operating on wastewater duties seldom functions
      at steady state and may be expected to perform over a wide range of feed loads.
      Satisfactory control of the solids residence time in these clarifiers and
      thickeners is critical to their successful operation. High solids residence times
      can lead to hydrolysis and rising sludge. This paper addresses the design of
      clarifiers and thickeners with minimum solids residence times. A one-dimensional
      force balance theory of sedimentation is used as the basis for the optimal
      design. Turn-up and turn-down are considered directly within the optimisation. A
      robust algorithm is presented for the repeated solution of the design equations
      and the constrained optimisation of the solids residence time. Three types
      controlling phenomena are identified and illustrated with design cases. The
      designs are found to be taller with smaller plan areas than their point optimised
      equivalents.

PMID- 15016535
TI  - Evaluation of the salt accumulation process during inundation in water resource
      of Contas river basin (Bahia-Brazil) applying principal component analysis.
AB  - The high salinization in some reservoirs of the Contas river basin (Bahia-Brazil)
      has been erroneously attributed only to concentration by evaporation. However,
      recent studies of this basin have shown that in period of intense rainfalls,
      occur an increase of the saline concentration in the flowing rivers of the
      reservoirs. The application of statistical methods (cluster and principal
      components analysis) have shown that this fact can be attributed to the discharge
      of saline waters from the small reservoirs of every drained area, provoked by
      inundation, is also an important factor in the salinization process. Thus the
      study of the geochemical variables: Na(+), K(+), Ca(2+), Mg(2+), Cl(-), SO(4)(2-)
      and CO(3)(2-), showed one group formed by Na(+) and Cl(-), attributed to the
      discharge of saline water provoked by inundation from a small reservoir, and a
      second group constituted by Ca(2+), Mg(2+), K(+) and SO(4)(2-), due to an
      increase provoked by the evaporation in the salinization process.

PMID- 15016536
TI  - Deploying a metal adsorbent in situ: a technique for indicating bioavailable
      Cd(II) in marine waters.
AB  - This paper reports a study into the deployment of a metal adsorbent in situ to
      estimate bioavailable Cd(II) in marine waters. Eight adsorbents were screened in
      the laboratory to test their ability to accumulate Cd(II) from deionised water
      and artificial seawater, and an oxidised activated carbon was selected for
      further investigation. The adsorption isotherm at Cd(II) concentrations 0.16-38
      microgl(-1) and at salinity 15 followed the Freundlich equation. The adsorbent
      was contained in nylon bags (pore size 35 microm) and dialysis tubes (membrane
      pore size 2 nm) to produce deployable devices and to investigate the effect of
      housing material on Cd(II) accumulation. The devices were tested in the
      laboratory and deployed at four field sites for up to 3 weeks. The adsorbent in
      the nylon bags reached equilibrium towards the end of this period and the
      measured contents were in good agreement with expected contents predicted from
      known seawater Cd(II) concentrations and the adsorption isotherm. The dialysis
      tubes accumulated significantly lower amounts of Cd(II) than the nylon bags,
      probably due to an initial lag as Cd(II) diffused into the dialysis bag and due
      to biofouling which reduced diffusion. The relationship between concentrations of
      Cd(II) accumulated by the mussels (indicating the bioavailable Cd(II) fraction)
      and the devices at different field sites could be described by the Freundlich
      model. The goodness of fit of this relationship was better for the dialysis tubes
      than the nylon bags. The adsorbent in the nylon bags may have collected small
      particles from seawater which affected the Cd(II) analysis. Both devices
      demonstrate potential as indicators of the relative bioavailable fraction of
      Cd(II) to Mytilus edulis in marine waters.

PMID- 15016538
TI  - Relationship between intensity, concentration, and temperature for drinking water
      odorants.
AB  - Odor analyses experiments indicated that, for the concentrations and temperatures
      tested, odor intensity was a function of both aqueous concentration and water
      temperature for water containing 1-butanol, free available chlorine, geosmin, n
      hexanal, 2-methylisoborneol, and trans-2, cis-6 nonadienal. At weak odorant
      concentrations (approximately 4 on the flavor profile rating scale) the perceived
      odor intensity of these six chemicals was greater when the temperature was 45
      degrees C than was 25 degrees C. Both of these temperatures are commonly
      encountered by consumers when they use tap water. Odor response to water
      containing isobutanal was affected by concentration but not water temperature.
      Experiments also revealed that reduction in aqueous concentration did not
      consistently reduce odor intensity; for some aqueous concentrations and chemicals
      an increase in odor intensity occurred at lower concentrations.

PMID- 15016537
TI  - Assessment of enhancement in biodegradation of dichlorodiethyl ether (DCDE) by
      pre-oxidation.
AB  - The objective of this study is to assess the enhancement in biodegradation of
      dichlorodiethyl ether (DCDE) by ozonation and Fenton treatment. Acclimated and
      non-acclimated sludge cultures were used to test the biodegradability of the
      preoxidized DCDE solutions by three different tests: Short-term and long-term
      respirometry through continuous monitoring of oxygen consumption, and the mid
      term test in which the amount of remaining organic matter was measured by TOC and
      COD tests. These tests were applied to solutions of DCDE preoxidized at the
      levels of 25%, 50%, 75%, and 100%. The results indicated that the
      biodegradability of oxidized DCDE solutions improved substantially compared to
      non-oxidized solutions. Fenton-treated DCDE exhibited toxicity to microorganisms
      under long-term exposure. Higher levels of preoxidation of DCDE led to
      mineralization of larger amounts of organic matter during subsequent
      biodegradation. There was no significant difference in the rate of biodegradation
      of oxidized products by either acclimated or non-acclimated bacteria.

PMID- 15016539
TI  - Mechanisms of microwave irradiation involved in the destruction of fecal
      coliforms from biosolids.
AB  - Microwaves have been found to be effective in destructing pathogens in sewage
      sludge (biosolids) (75th Annual Water Environment Federation Conference, Chicago,
      September 29-October 2, 2002; Third World Water Congress, International Water
      Association, Melbourne, Australia, April 7-12, 2002). Mechanisms and roles of
      microwaves on fecal coliform destruction were investigated using bacterial
      viability tests, electron transport system (ETS) and beta-galactosidase activity
      assays, gel electrophoresis, and genomic deoxyribonucleic acid (DNA) optical
      density (OD) measurements with fecal coliforms isolated from biosolids. Bacterial
      viability tests demonstrated cell membrane damage as microwave irradiation
      intensity and temperature increased. Above 60+/-3 degrees C, viable cells were
      rarely found when pure fecal coliforms were irradiated with microwaves. ETS and
      beta-galactosidase activity assays revealed increased activity for externally
      heated samples due to fecal coliform growth but decreased activity for microwave
      irradiated samples as temperature was increased from 20 degrees C to 57 degrees
      C, indicating other destruction mechanisms besides heating. Between 57 degrees C
      and 68 degrees C, microwave irradiation led to a more rapid decrease in activity
      than external heating by convection. Above 68 degrees C, bacterial activity
      almost ceased for both pretreatments. DNA bands in gel electrophoresis tests and
      OD of genomic DNA decreased more rapidly for microwave-irradiated samples than
      for externally heated samples, implying that microwaves disrupted DNA in fecal
      coliform cells at lower temperatures than external heating. Microwave irradiation
      of sludge appears to be a viable and economical method of destructing pathogens
      and generating environmentally safe sludge.

PMID- 15016540
TI  - Effect of O2 exposure on perchlorate reduction by Dechlorosoma sp. KJ.
AB  - Anaerobic bioreactors have been developed to remove perchlorate from water, but
      backwashing and operational interruptions can expose biofilms to oxygen. While it
      is well known that oxygen is a preferential electron acceptor to perchlorate for
      perchlorate-respiring bacteria, little is known about the effect of oxygen
      exposure or redox potentials on perchlorate reduction. Four different dissolved
      oxygen scavengers were tested for their ability to quickly restore anaerobic
      conditions and allow perchlorate reduction by a facultative, perchlorate
      respiring bacterium Dechlorosoma sp. KJ. Of the four different oxygen scavengers
      tested (Oxyrase trade mark, L-cysteine, Na2S and FeS), only Oxyrase trade mark
      was able to rapidly (<30 min) scavenge dissolved oxygen and allow cell growth.
      There was no cell growth after addition of Na2S and FeS, and l-cysteine produced
      a long lag in cell growth. To investigate the effect of dissolved oxygen on
      perchlorate reduction, anaerobically grown cultures Dechlorosoma sp. KJ, were
      exposed to dissolved oxygen for various periods ranging from 1 to 32 h.
      Perchlorate reduction and redox potential were then measured for cells returned
      to an anaerobic environment containing an oxygen scavenger. It was determined
      that cells exposed to dissolved oxygen for more than 12h were incapable of
      reducing perchlorate. Cells exposed to dissolved oxygen for less than 12h quickly
      reduced the redox potential to negative values (-127 mV to -337 mV) and were able
      to reduce perchlorate or chlorite. Our results suggest that aeration during
      backwashing of biofilm reactors, or exposure of perchlorate-degrading cell
      suspensions to dissolve oxygen for less than 12h, will not be detrimental to the
      ability of perchlorate-degrading bacteria to use perchlorate as an electron
      acceptor.

PMID- 15016541
TI  - Macroscale and microscale analyses of nitrification and denitrification in
      biofilms attached on membrane aerated biofilm reactors.
AB  - A membrane aerated biofilm reactor (MABR), in which O(2) was supplied from the
      bottom of the biofilm and NH(4)(+) and organic carbon were supplied from the
      biofilm surface, was operated at different organic carbon loading rates and intra
      membrane air pressures to investigate the occurrence of simultaneous chemical
      oxygen demand (COD) removal, nitrification and denitrification. The spatial
      distribution of nitrification and denitrification zones in the biofilms was
      measured with microelectrodes for O(2), NH(4)(+), NO(2)(-), NO(3)(-) and pH. When
      the MABR was operated at approximately 1.0 g-COD/m(2)/day of COD loading rate,
      simultaneous COD removal, nitrification and denitrification could be achieved.
      The COD loading rates and the intra-membrane air pressures applied in this study
      had no effect on the start-up and the maximum rates of NH(4)(+) oxidation in the
      MABRs. Microelectrode measurements showed that O(2) was supplied from the bottom
      of the MABR biofilm and penetrated the whole biofilm. Because the biofilm
      thickness increased during the operations, an anoxic layer developed in the upper
      parts of the mature biofilms while an oxic layer was restricted to the deeper
      parts of the biofilms. The development of the anoxic zones in the biofilms
      coincided with increase in the denitrification rates. Nitrification occurred in
      the zones from membrane surface to a point of ca. 60microm. Denitrification
      mainly occurred just above the nitrification zones. The COD loading rates and the
      intra-membrane air pressures applied in this study had no effect on location of
      the nitrification and denitrification zones.

PMID- 15016542
TI  - Light-absorption ratio variation approach to determination of nickel (II) in
      ng/ml level with 1, 5-di(2-hydroxy-5-sulfophenyl)-3-cyanoformazan.
AB  - The light-absorption ratio variation approach (LARVA) has been described and
      applied to the quantitative detection of ultramicro amounts of Ni by
      spectrophotometry, which raises notably the detection sensitivity. The
      complexation between 1, 5-di(2-hydroxy-5-sulfophenyl)-3-cyanoformazan (DSPCF) and
      Ni(II) at pH 9.11 was investigated and the binary complex was characterized by
      the spectral correction technique. Results have shown that deltaAr-1 (deltaAr-
      light-absorption ratio variation) is linear in the range of Ni(II) between 5 and
      200 ng/ml. The limit of detection (3sigma) of Ni(II) is only 1.3 ng/ml. The
      complexation is selective in the presence of fluoride, hexametaphosphate,
      ethylene diamine tetraacetate and thioglycollic acid. It has been applied to
      analysis of water quality with satisfactory results.

PMID- 15016543
TI  - Nuclear entry of poliovirus protease-polymerase precursor 3CD: implications for
      host cell transcription shut-off.
AB  - Host cell transcription mediated by all three RNA polymerases is rapidly
      inhibited after infection of mammalian cells with poliovirus (PV). Both genetic
      and biochemical studies have shown that the virus-encoded protease 3C cleaves the
      TATA-binding protein and other transcription factors at glutamine-glycine sites
      and is directly responsible for host cell transcription shut-off. PV replicates
      in the cytoplasm of infected cells. To shut-off host cell transcription, 3C or a
      precursor of 3C must enter the nucleus of infected cells. Although the 3C
      protease itself lacks a nuclear localization signal (NLS), amino acid sequence
      examination of 3D identified a potential single basic type NLS, KKKRD, spanning
      amino acids 125-129 within this polypeptide. Thus, a plausible scenario is that
      3C enters the nucleus in the form of its precursor, 3CD, which then generates 3C
      by auto-proteolysis ultimately leading to cleavage of transcription factors in
      the nucleus. Using transient transfection of enhanced green fluorescent protein
      (EGFP) fusion polypeptides, we demonstrate here that both 3CD and 3D are capable
      of entering the nucleus in PV-infected cells. However, both polypeptides remain
      in the cytoplasm in uninfected HeLa cells. Mutagenesis of the NLS sequence in 3D
      prevents nuclear entry of 3D and 3CD in PV-infected cells. We also demonstrate
      that 3CD can be detected in the nuclear fraction from PV-infected HeLa cells as
      early as 2 h postinfection. Significant amount of 3CD is found associated with
      the nuclear fraction by 3-4 h of infection. Taken together, these results suggest
      that both the 3D NLS and PV infection are required for the entry of 3CD into the
      nucleus and that this may constitute a means by which viral protease 3C is
      delivered into the nucleus leading to host cell transcription shut-off.

PMID- 15016544
TI  - Genome sequence and characterization of a virus (HaRNAV) related to picorna-like
      viruses that infects the marine toxic bloom-forming alga Heterosigma akashiwo.
AB  - Heterosigma akashiwo (Rhaphidophyceae) is a unicellular, flagellated, bloom
      forming, toxic alga of ecological and economic importance. Here, we report the
      results of sequencing and analyzing the genome of an 8.6-kb single-stranded RNA
      virus (HaRNAV-SOG263) that infects H. akashiwo. Our results show that HaRNAV is
      related to picorna-like viruses, but does not belong within any currently defined
      virus family. This is based on the genome organization and sequence comparisons
      of putative RNA-dependent RNA polymerase (RdRp), helicase, and capsid protein
      sequences. The genome sequence predicts a single open reading frame (orf)
      encoding a polyprotein that contains conserved picorna-like protein domains, with
      putative nonstructural protein domains present in the N-terminus and the
      structural proteins in the C-terminus of the polyprotein. We have analyzed and
      compared the virus structural proteins from infectious and noninfectious
      particles. In this way, we identified structural protein cleavage sites as well
      as protein processing events that are presumably important for maturation of
      virus particles. The combination of genome structure and sequence relationships
      to other viruses suggests that HaRNAV is the first member of a proposed new virus
      family (Marnaviridae), related to picorna-like viruses.

PMID- 15016546
TI  - The prophages of Lactobacillus johnsonii NCC 533: comparative genomics and
      transcription analysis.
AB  - Two non-inducible, but apparently complete prophages were identified in the
      genome of the sequenced Lactobacillus johnsonii strain NCC 533. The 38- and 40-kb
      long prophages Lj928 and Lj965 represent distinct lineages of Sfi11-like pac-site
      Siphoviridae unrelated at the DNA sequence level. The deduced structural proteins
      from Lj928 demonstrated aa sequence identity with Lactococcus lactis phage TP901
      1, while Lj965 shared sequence links with Streptococcus thermophilus phage O1205.
      With the exception of tRNA genes, inserted between DNA replication and DNA
      packaging genes, the transcription of the prophage was restricted to the genome
      segments near both attachment sites. Transcribed genes unrelated to phage
      functions were inserted between the phage repressor and integrase genes; one
      group of genes shared sequence relatedness with a mobile DNA element in
      Staphylococcus aureus. A short, but highly transcribed region was located between
      the phage lysin and right attachment site; it lacked a protein-encoding function
      in one prophage.

PMID- 15016545
TI  - Simian virus 40 infection disrupts p130-E2F and p107-E2F complexes but does not
      perturb pRb-E2F complexes.
AB  - In its native host species, the Rhesus Macaque, simian virus 40 (SV40) forms a
      persistent infection in the kidneys with no apparent harmful side effects. We
      show that SV40 infection of growth-arrested monkey kidney epithelial cells
      results in the specific disruption of certain Rb-E2F family complexes. Throughout
      the course of infection, p130-E2F and p107-E2F complexes are disrupted, but
      surprisingly pRb-E2F complexes remain intact. This suggests that the presence of
      some pRb-E2F complexes is not inhibitory to productive infection. Additionally,
      while a decrease of p130 steady state levels is observed during the later time
      points of infection, early during infection, p130 is readily detectable. This
      suggests SV40 infection overrides p130-mediated growth arrest through a
      mechanism(s) in addition to the well-documented T antigen-mediated degradation of
      p130. Finally, infection induces a dramatic relocalization of E2F4 from the
      nucleus to the cytoplasm. The implications of these observations to the life
      cycle of the virus are addressed.

PMID- 15016547
TI  - Comparison of SIVmac239(352-382) and SIVsmmPBj41(360-390) enterotoxic synthetic
      peptides.
AB  - To characterize the active domain of the simian immunodeficiency virus (SIV)
      surface unit (SU) enterotoxin, peptides corresponding to the V3 loop of SIVmac239
      (SIVmac) and SIVsmmPBj41 (SIVpbj) were synthesized and examined for enterotoxic
      activity, alpha-helical structure, and interaction(s) with model membranes.
      SIVmac and SIVpbj induced a dose-dependent diarrhea in 6-8-day-old mouse pups
      similar to full-length SU. The peptides mobilized [Ca(2+)](i) in HT-29 cells with
      distinct oscillations and elevated inositol triphosphate levels. Circular
      dichroism analyses showed the peptides were predominantly random coil in buffer,
      but increased in alpha-helical content when placed in a hydrophobic environment
      or with cholesterol-containing membrane vesicles that are rich in anionic
      phospholipids. None of the peptides underwent significant secondary structural
      changes in the presence of neutral vesicles indicating ionic interactions were
      important. These data show that the SIV SU enterotoxic domain localizes in part
      to the V3 loop region and interacts with anionic membrane domains on the host
      cell surface.

PMID- 15016548
TI  - PB2 amino acid at position 627 affects replicative efficiency, but not cell
      tropism, of Hong Kong H5N1 influenza A viruses in mice.
AB  - A single amino acid substitution, from glutamic acid to lysine at position 627 of
      the PB2 protein, converts a nonlethal H5N1 influenza A virus isolated from a
      human to a lethal virus in mice. In contrast to the nonlethal virus, which
      replicates only in respiratory organs, the lethal isolate replicates in a variety
      of organs, producing systemic infection. Despite a clear difference in virulence
      and organ tropism between the two viruses, it remains unknown whether the
      dissimilarity is a result of differences in cell tropism or the reduced
      replicative ability of the nonlethal virus in mouse cells in general. To
      determine how this single amino acid change affects virulence and organ tropism
      in mice, we investigated the growth kinetics of the two H5N1 viruses both in
      vitro and in vivo. The identity of the PB2 amino acid at position 627 did not
      appreciably affect viral replicative efficiency in chicken embryo fibroblasts and
      a quail cell line; however, viruses with lysine at this position instead of
      glutamic acid grew better in the different mouse cells tested. When the effect of
      this substitution was investigated in mice, all of the test viruses showed the
      same cell tropism, but infection by viruses containing lysine at position 627
      spread more rapidly than those viruses containing glutamic acid at this position.
      Further analysis showed a difference in local immune responses: neutrophil
      infiltration in lungs infected with viruses containing lysine at position 627
      persisted longer than that associated with viruses lacking a glutamic acid
      substitution. Our data indicate that the amino acid at position 627 of the PB2
      protein determines the efficiency of viral replication in mouse (not avian)
      cells, but not tropism among cells in different mouse organs. The presence of
      lysine leads to more aggressive viral replication, overwhelming the host's
      defense mechanisms and resulting in high mortality rates in mice.

PMID- 15016549
TI  - Enhanced resistance to herpes simplex virus type 1 infection in transgenic mice
      expressing a soluble form of herpesvirus entry mediator.
AB  - Herpesvirus entry mediator (HVEM) is a member of the tumor necrosis factor (TNF)
      receptor family used as a cellular receptor by virion glycoprotein D (gD) of
      herpes simplex virus (HSV). Both human and mouse forms of HVEM can mediate entry
      of HSV-1 but have no entry activity for pseudorabies virus (PRV). To assess the
      antiviral potential of HVEM in vivo, three transgenic mouse lines expressing a
      soluble form of HVEM (HVEMIg) consisting of an extracellular domain of murine
      HVEM and the Fc portion of human IgG1 were generated. All of the transgenic mouse
      lines showed marked resistance to HSV-1 infection when the mice were challenged
      intraperitoneally with HSV-1, but not to PRV infection. The present results
      demonstrate that HVEMIg is able to exert a significant antiviral effect against
      HSV-1 infection in vivo.

PMID- 15016550
TI  - Red clover necrotic mosaic virus replication proteins accumulate at the
      endoplasmic reticulum.
AB  - Red clover necrotic mosaic virus (RCNMV) encodes N-terminally overlapping
      proteins of 27 and 88 kDa (p27 and p88) known to be required for replication.
      Green fluorescent protein (GFP) fusions were used to visualize the location of
      p27 and p88 within Nicotiana benthamiana cells. GFP:p27 fusions localized to the
      endoplasmic reticulum (ER), co-localized with ER-targeted yellow fluorescent
      protein and caused membrane restructuring and proliferation. Cellular
      fractionation of virus-inoculated N. benthamiana leaves confirmed the association
      of p27 with ER membranes. GFP:p88 fusions also localized to the ER and co
      localized with GFP:p27. Both fusion proteins co-localize to the cortical and
      cytoplasmic ER and were associated with invaginations of the nuclear envelope.
      Independent accumulation in, and perturbation of, the ER suggests that p27 and
      p88 function together in the replication complex. This is the first report of a
      member of the Tombusviridae replicating in association with the ER.

PMID- 15016551
TI  - Bovine adenovirus type 3 containing heterologous protein in the C-terminus of
      minor capsid protein IX.
AB  - Earlier, we detected pIX of BAdV-3 as a 14-kDa protein in purified virions.
      Analysis of BAdV-3 pIX using different region antibodies revealed that the N
      terminus and central domain of the pIX contain immunogenic sites and are not
      exposed on the surface of BAdV-3 virion. This suggested that the C-terminus of
      BAdV-3 pIX (125 amino acid) may be exposed on the virion and may be used as a
      site for incorporation of heterologous peptides or proteins. We constructed
      recombinant BAV950 containing a small peptide (21 amino acid), including the RGD
      motif or recombinant BAV951 containing enhanced yellow-green fluorescent protein
      (EYFP) fused to the C-terminus of pIX. Western blot analysis demonstrated that
      the chimeric pIX-RGD was incorporated into virion capsids. Incorporation of the
      RGD motif into the pIX resulted in significant augmentation of BAdV-3 fiber knob
      independent infection of the integrin-positive cells, suggesting that RGD motifs
      are displayed on the surface of virion capsids and are accessible for binding to
      integrins. Analysis of BAV951 revealed that the chimeric pIX is incorporated into
      virion capsids and EYFP containing the C-terminus of pIX is exposed on the
      surface of the virion. Moreover, insertion of chimeric pIXs was maintained
      without change through successive rounds of viral replication. These results
      suggested that in contrast to major capsid proteins (hexon, penton, fiber), the
      minor capsid protein IX can be use for the incorporation of targeting ligands
      based on either small peptides or longer polypeptides.

PMID- 15016552
TI  - Simultaneous human papilloma virus type 16 E7 and cdk inhibitor p21 expression
      induces apoptosis and cathepsin B activation.
AB  - Human papillomavirus type 16 (HPV-16) is the major risk factor for development of
      cervical cancer. The major oncoprotein E7 enhances cell growth control. However,
      E7 has in some reports been shown to induce apoptosis suggesting that there is a
      delicate balance between cell proliferation and induction of cell death. We have
      used the osteosarcoma cell line U2OS cells provided with E7 and the cdk2
      inhibitor p21 (cip1/waf1) under inducible control, as a model system for the
      analysis of E7-mediated apoptosis. Our data shows that simultaneous expression of
      E7 and p21 proteins induces cell death, possibly because of conflicting growth
      control. Interestingly, E7/p21-induced cell death is associated with the
      activation of a newly identified mediator of apoptosis, namely cathepsin B.
      Activation of the cellular caspases is undetectable in cells undergoing E7/p21
      induced apoptosis. To our knowledge, this is the first time a role for cathepsin
      B is reported in HPV-induced apoptotic signalling.

PMID- 15016553
TI  - Tip, an Lck-interacting protein of Herpesvirus saimiri, causes Fas- and Lck
      dependent apoptosis of T lymphocytes.
AB  - Saimiriine herpesvirus-2 (Herpesvirus saimiri) transforms T lymphocytes,
      including human, to continuous growth in vitro. H. saimiri-induced transformation
      is becoming an important tool of T-cell biology, including studies of HIV
      replication. Two proteins of H. saimiri subgroup C, Tip and StpC, are essential
      for T-cell transformation. In spite of the important role of these proteins,
      their biological functions and the molecular mechanisms of their action remain
      insufficiently understood. To further elucidate the effects of Tip on T cells, we
      transduced T lymphocytes, using an efficient lentiviral gene transfer system, to
      express Tip in the absence of other H. saimiri proteins. Our results indicate
      that Tip specifically inhibits IL-2 production by human T lymphocytes.
      Furthermore, Tip promotes T-cell apoptosis, which appears to be the reason for
      the observed decrease in IL-2 production. Finally, the apoptotic effect of Tip in
      T cells is mediated by Fas and requires the presence of active Lck in the cell.

PMID- 15016554
TI  - A naturally derived gastric cancer cell line shows latency I Epstein-Barr virus
      infection closely resembling EBV-associated gastric cancer.
AB  - In a process seeking out a good model cell line for Epstein-Barr virus (EBV)
      associated gastric cancer, we found that one previously established gastric
      adenocarcinoma cell line is infected with type 1 EBV. This SNU-719 cell line from
      a Korean patient expressed cytokeratin without CD19 or CD21 expression. In SNU
      719, EBNA1 and LMP2A were expressed, while LMP1 and EBNA2 were not. None of the
      tested lytic EBV proteins were detected in this cell line unless stimulated with
      phorbol ester. EBV infection was also shown in the original carcinoma tissue of
      SNU-719 cell line. Our results support the possibility of a CD21-independent EBV
      infection of gastric epithelial cells in vivo. As the latent EBV gene expression
      pattern of SNU-719 closely resembles that of the EBV-associated gastric cancer,
      this naturally derived cell line may serve as a valuable model system to clarify
      the precise role of EBV in gastric carcinogenesis.

PMID- 15016555
TI  - Bimatoprost: establishing its role in glaucoma management.

PMID- 15016556
TI  - Update on the mechanism of action of bimatoprost: a review and discussion of new
      evidence.
AB  - Bimatoprost is a pharmacologically unique and highly efficacious anti-glaucoma
      agent. It appears to mimic the activity of the prostamides, which are
      biosynthesized from the natural endocannabinoid anandamide by the enzyme cyclo
      oxygenase 2 (COX-2). Bimatoprost has also been suggested to lower intraocular
      pressure by behaving as a prodrug or, alternatively, by stimulating FP receptors
      directly. These three distinctly different hypotheses for the mechanism of
      bimatoprost activity are discussed in the light of current evidence.

PMID- 15016557
TI  - Ocular hypotensive efficacy of bimatoprost 0.03% and travoprost 0.004% in
      patients with glaucoma or ocular hypertension.
AB  - PURPOSE: To evaluate the IOP-lowering efficacy of bimatoprost and travoprost for
      the treatment of glaucoma and ocular hypertension. METHODS: Randomized,
      investigator-masked, parallel-group clinical trial. After completing a washout
      from all glaucoma medications, patients (n=26) were randomized to bimatoprost or
      travoprost for 6 months. Visits were at baseline, week 1, and months 1, 3, and 6.
      IOP was measured at 9 am at each visit and also at 1 and 4 pm at baseline and
      months 3 and 6. RESULTS: At the baseline visit, there were no significant between
      group differences in IOP at 9 am, 1 pm, or 4 pm (P> or =.776). After 6 months of
      therapy, both medications provided significant mean reductions from baseline IOP
      at every time point (P< or =.007). Mean IOP reductions ranged from 7.4 mm Hg to
      8.8 mm Hg (34% to 36%) with bimatoprost and from 4.6 mm Hg to 7.2 mm Hg (19% to
      29%) with travoprost (P> or =.057) after 6 months of medication. At the final
      study visit, more patients achieved low target pressures with bimatoprost than
      with travoprost at each time point. Both study medications were well tolerated
      and ocular redness was the most commonly reported adverse event in both treatment
      groups. CONCLUSION: Although both bimatoprost and travoprost effectively lowered
      IOP in patients with glaucoma or ocular hypertension, bimatoprost provided larger
      mean IOP reductions than travoprost. More patients achieved low target pressures
      with bimatoprost than with travoprost. The between-group differences were not
      statistically significant due to the small sample size. These findings are being
      further evaluated in an ongoing multicenter clinical trial.

PMID- 15016558
TI  - A randomized, investigator-masked comparison of diurnal responder rates with
      bimatoprost and latanoprost in the lowering of intraocular pressure.
AB  - In glaucoma and ocular hypertension, clinically relevant intraocular pressure
      lowering due to a new medication is frequently defined as at least a 15% or 20%
      reduction from baseline intraocular pressure. This report compares the
      percentages of treated patients achieving such reductions in intraocular pressure
      after 6 months of treatment with bimatoprost or latanoprost. In the previously
      published study (Noecker et al: A six-month randomized clinical trial comparing
      the intraocular pressure-lowering efficacy of bimatoprost and latanoprost in
      patients with ocular hypertension or glaucoma. Am J Ophthalmol 135:55-63, 2003),
      patients with glaucoma or ocular hypertension were randomly assigned to once
      daily treatment with bimatoprost 0.03% (n=133) or latanoprost 0.005% (n=136),
      after washout of any previous glaucoma medications. The primary outcome measure
      of that study was mean change from baseline intraocular pressure. The secondary,
      post hoc analysis presented here compares the diurnal and long-term responder
      rates observed with bimatoprost and latanoprost patients. Diurnal responders were
      defined as patients who achieved at least a 15% or 20% reduction from baseline
      intraocular pressure at each of the three timepoints (8 am, 12 pm, and 4 pm) on a
      given visit. At week 1 and months 1, 3, and 6, in the bimatoprost group, 70.7
      81.2% of patients achieved at least a 15% reduction in IOP at each timepoint, and
      57.9-68.4% achieved at least a 20% reduction. Significantly fewer patients
      receiving latanoprost achieved a 15% or a 20% decrease in IOP at each timepoint:
      48.5-61.8% of patients achieved at least a 15% decrease and 36.0-47.1% achieved
      at least a 20% decrease. (P< or =.007). The data presented here suggest that
      patients using bimatoprost are more likely than patients using latanoprost to
      achieve intraocular pressure reductions of at least 15% or 20% from baseline
      throughout the day.

PMID- 15016559
TI  - 24-Hour IOP control with once-daily bimatoprost, timolol gel-forming solution, or
      latanoprost: a 1-month, randomized, comparative clinical trial.
AB  - PURPOSE: To compare the efficacy and safety of once-daily (QD) bimatoprost,
      latanoprost, and timolol gel-forming solution in providing 24-hour intraocular
      pressure (IOP) control. DESIGN: This was a randomized, multicenter, investigator
      masked, prospective, parallel-group, clinical trial. PARTICIPANTS: Patients with
      open-angle glaucoma or ocular hypertension. INTERVENTION: After washout of any
      previous ocular hypotensive medications, patients were randomly assigned to
      treatment with bimatoprost 0.03% ophthalmic solution QD (n=38) or latanoprost
      0.005% ophthalmic solution QD (n=38) between 7 and 9 pm, or timolol maleate 0.5%
      gel-forming ophthalmic solution QD (n=39) between 7 and 9 am for 1 month. MAIN
      OUTCOME MEASURES: The primary outcome measure, circadian IOP, was measured at
      eight time points over the course of 24 hours beginning at 8 am on day 28 and
      with the last measurement at 8 am on day 29. IOP was also measured at 8 am and 10
      am at baseline and at 8 am on day 14. Safety measures included adverse events,
      biomicroscopy, visual acuity, heart rate, and blood pressure. RESULTS: At 10 am
      (peak drug effect) on day 28, the mean IOP reduction from baseline was
      significantly greater with bimatoprost (9.3 mm Hg, 40.3%) than with timolol gel
      (7.1 mm Hg, 31.1%; P=.024, Wilcoxon rank sum test) or latanoprost (7.4 mm Hg,
      33.3%). In the overall analysis of IOP measured over the course of 24 hours, mean
      IOP was significantly lower with bimatoprost or latanoprost than with timolol gel
      (P<.001; analysis of repeated measures). The analysis of repeated measures also
      showed a significant difference between bimatoprost and latanoprost (P=.003). In
      the area-under-the-curve analysis, bimatoprost and latanoprost were superior to
      timolol gel (P< or =.018) but comparable to each other (P> or =.223). All
      treatment regimens were well tolerated, with few discontinuations due to adverse
      events. There were no significant effects on systemic safety parameters.
      CONCLUSION: Once-daily bimatoprost or latanoprost provided significantly better
      24-hour IOP control than timolol gel in patients with glaucoma or ocular
      hypertension. Some measurements suggested a trend for greater efficacy of
      bimatoprost over latanoprost. All three treatments were well tolerated.

PMID- 15016560
TI  - A cost-effectiveness comparison of bimatoprost versus latanoprost in patients
      with glaucoma or ocular hypertension.
AB  - To compare the cost-effectiveness of bimatoprost versus latanoprost for the
      treatment of glaucoma and ocular hypertension, a cost-effectiveness algorithm was
      developed to estimate the annual costs and cost per treatment success (cost
      effectiveness) for bimatoprost 0.03% QD compared with latanoprost 0.005% QD.
      Medication costs for the model were abstracted from published sources. Clinical
      assumptions for the model were based on the treatment success rates from one 3
      month controlled clinical trial comparing bimatoprost versus latanoprost (n =119
      and 113, respectively), and another 6-month controlled clinical trial comparing
      bimatoprost versus latanoprost (n=133 and 136, respectively). Treatment success
      was defined as the percentage of patients achieving various target intraocular
      pressures. A larger percentage of patients achieved low target IOPs on
      bimatoprost than on latanoprost. The cost per treatment success for patients who
      started treatment on bimatoprost monotherapy was less than for patients started
      on latanoprost, despite the fact that the estimated yearly costs were similar for
      these drugs. In this model bimatoprost was found to be more cost-effective than
      latanoprost, given the average wholesale price of these medications and the
      assumptions of the cost-effectiveness algorithm about clinical success at the 3-
      and 6-month decision points.

PMID- 15016561
TI  - Two-year double-masked comparison of bimatoprost with timolol in patients with
      glaucoma or ocular hypertension.
AB  - The object of this study was to compare the long term efficacy and safety of
      bimatoprost with timolol in patients with glaucoma or ocular hypertension. In a
      12-month extension of two identically designed 1-year, multicenter, randomized,
      double-masked clinical trials, patients were treated topically with bimatoprost
      0.03% QD (n=167), bimatoprost 0.03% BID (n=131), or timolol 0.5% BID (n=81). Main
      outcome measures were IOP at 8 am and 10 am and safety parameters. Bimatoprost QD
      provided significantly greater mean reduction from baseline IOP than did timolol
      at both measurements at each study visit (P< or =.001). At 10 am (peak timolol
      effect) at month 24, the mean reduction from baseline IOP was 7.8 mm Hg with
      bimatoprost QD and 4.6 mm Hg with timolol (P<.001). Patients treated with
      bimatoprost QD also sustained significantly lower mean IOP than timolol-treated
      patients at every follow-up visit throughout the 2-year study period (P< or
      =.006). At 10 am at month 24, a significantly greater proportion of bimatoprost
      QD than timolol patients achieved target pressures of < or =13-18 mm Hg (P< or
      =.010). Bimatoprost sustained an excellent safety profile during the second year
      of treatment. Most adverse events were mild, and there were no reports of
      increased iris pigmentation, uveitis, or CME. The incidence of hyperemia was
      significantly higher with bimatoprost QD (13.8%) than with timolol (2.5%)
      (P=.006). Mean reduction from baseline IOP with bimatoprost BID was not
      significantly different from that with timolol at month 24 at 10 am (P=.474). We
      conclude that bimatoprost QD provides superior IOP lowering to timolol, and is
      safe and well tolerated over 24 months of treatment.

PMID- 15016562
TI  - Chemosystematics of the hepaticae.
AB  - Most liverworts (Hepaticae) contain oil bodies which are composed of lipophilic
      terpenoids and aromatic compounds. The chemosystematics of 36 families of the
      Jungermannidae and seven families of the Marchantiidae of the Hepaticae are
      discussed using terpenoid and aromatic components.

PMID- 15016563
TI  - Purification and characterization of tyrosinase from gill tissue of Portabella
      mushrooms.
AB  - A group of tyrosinase isoforms with isoelectric points between 4.9 and 5.2 was
      isolated from gill tissue of Portabella mushrooms. Use of protease inhibitors was
      not able to increase the amount of latent forms significantly in crude extracts
      or to preserve latent tyrosinase activity during purification. The tyrosinase in
      gill tissue extracts showed latent activity above pH 5.5 and suppressed or
      displayed no latent activity below pH 5.5 when assayed in the presence of SDS.
      The purified isoforms showed monophenolase activity toward 4-hydroxyanisole but
      practically no activity toward tyrosine or tyramine. The purified isoforms showed
      greater activity toward catechol than either 4-methylcatechol, dopa, dopamine,
      chlorogenic acid, t-butylcatechol, or catechin. The Km for catechol was similar
      for the group of isolated isoforms (4.3 mM) compared to the isoforms in crude
      extracts (5.3 mM). Crude extracts showed several isoforms ranging from 50 to 230
      kDa after partially denaturing SDS PAGE, while the purified isoforms showed
      molecular weights of 70 kDa.

PMID- 15016564
TI  - Cytochrome P450-catalyzed brassinosteroid pathway activation through synthesis of
      castasterone and brassinolide in Phaseolus vulgaris.
AB  - The last reaction in the biosynthesis of brassinolide has been examined
      enzymatically. A microsomal enzyme preparation from cultured cells of Phaseolus
      vulgaris catalyzed a conversion from castasterone to brassinolide, indicating
      that castasterone 6-oxidase (brassinolide synthase) is membrane associated. This
      enzyme preparation also catalyzed the conversions of 6-deoxocastasterone and
      typhasterol to castasterone which have been reported to be catalyzed by
      cytochrome P450s, CYP85A1 of tomato and CYP92A6 of pea, respectively. The
      activities of these enzymes require molecular oxygen as well as NADPH as a
      cofactor. The enzyme activities were strongly inhibited by carbon monoxide, an
      inhibitor of cytochrome P450, and this inhibition was recovered by blue light
      irradiation in the presence of oxygen. Commercial cytochrome P450 inhibitors
      including cytochrome c, SKF 525A, 1-aminobenzotriazole and ketoconazole also
      inhibited the enzyme activities. The present work presents unanimous
      enzymological evidence that cytochrome P450s are responsible for the synthesis of
      brassinolide from castasterone as well as of castasterone from typhasterol and 6
      deoxocastasterone, which have been deemed activation steps of BRs.

PMID- 15016566
TI  - Investigation of the importance of the C-2 oxygen function in the transformation
      of stemodin analogues by Rhizopus oryzae ATCC 11145.
AB  - A new stemodinoside, stemodin-alpha-L-arabinofuranoside (5), was isolated from
      the plant Stemodia maritima. Incubation of stemodin (2) with Rhizopus oryzae ATCC
      11145 gave 2 alpha,7 beta,13(S)-trihydroxystemodane (17) and 2 alpha,3
      beta,13(S),16 alpha-tetrahydroxystemodane (18) whilst stemodinone (8) afforded 6
      alpha,13(S)-dihydroxystemodan-2-one (19). The bioconversion of 2 beta,13(S)
      dihydroxystemodane (10) by the fungus yielded 2 beta,7 beta,13(S)
      trihydroxystemodane (20) whereas stemod-12-en-2-one (9) provided 7 beta,17
      dihydroxystemod-12-en-2-one (21). The results provide useful information about
      the relationship between the functional groups of the substrates and their
      potential for bioconversion.

PMID- 15016565
TI  - Universally occurring phenylpropanoid and species-specific indolic metabolites in
      infected and uninfected Arabidopsis thaliana roots and leaves.
AB  - A total of eleven alkali-released, aromatic compounds were identified by HPLC, MS
      and NMR analyses in cell wall extracts from Arabidopsis thaliana roots. Nine of
      them together constituted the three complete series of 4-hydroxy-, 4-hydroxy-3
      methoxy, and 4-hydroxy-3,5-dimethoxy-substituted benzaldehydes, benzoic acids and
      cinnamic acids. The other two were indolic metabolites: indole-3-carboxylic acid
      and indole-3-carbaldehyde. Qualitatively similar, but quantitatively distinct
      profiles were obtained using cell-wall extracts from A. thaliana leaves. Several
      of these compounds, particularly indole-3-carboxylic acid, 4-hydroxybenzoic acid
      and all four aldehydes, increased considerably in concentration upon infection of
      roots with Pythium sylvaticum, as did at least some of them upon infection of
      leaves with Pseudomonas syringae pv tomato. Comparison of these results with
      analogous data on a variety of different plant species suggests a remarkable
      structural uniformity among the majority of constitutive as well as infection
      induced, aromatic cell wall-bound compounds throughout the entire plant kingdom
      in sharp contrast to the highly species-specific, chemically highly divers
      bouquets of soluble aromatic metabolites.

PMID- 15016567
TI  - Protective role of 20-hydroxyecdysone against lead stress in Chlorella vulgaris
      cultures.
AB  - Treatment of cultured C. vulgaris cells with 10(-6)-10(-4) M lead decreased their
      growth and chemical composition during the first 48 h of cultivation. However, at
      concentrations above 10(-4) M, lead is cytotoxic to Chlorella vulgaris cells,
      resulting in cellular fragmentation and lysis. In contrast, at concentrations
      below 10(-6) M lead had no influence on the growth and metabolism of C. vulgaris
      cells. 20-Hydroxyecdysone (20E) (10(-10)-10(-8) M) increased growth and chemical
      composition of C. vulgaris cells over a concentration range. Levels per cell of
      chlorophylls, protein, sugars are all increased by 20E treatment, when compared
      to non-treated control cells. However, the cultures treated with 20E and lead
      show a lower stimulation than the cultures treated with 20E alone. The effects of
      20E mixed with lead on the growth and the level of cellular lead, chlorophyll,
      sugar and protein in C. vulgaris are also reported. The decreased growth and
      composition of C. vulgaris cells treated with lead was restored by the 20E.
      Application of 20E to C. vulgaris cultures reduced the impact of lead stress on
      growth, prevented chlorophyll, sugar and protein loss and increased
      phytochelatins synthesis. Furthermore, 20E did not restore toxic effect of lead
      on C. vulgaris cells. The combined treatment with lead and 20E appeared to have a
      stimulatory effect on the above parameters during the 48 h of cultivation, as
      compared to the control. 20E reduced the toxicity of lead and the growth
      recovered to the level of cells treated with 20E alone. Concentration-dependent
      stimulation was observed with increasing concentration of 20E and decreasing
      concentration of lead.

PMID- 15016568
TI  - Fatty acid composition of individual polar lipid classes from marine macrophytes.
AB  - Major glycolipids [monogalactosyldiacylglycerol (MGDG),
      digalactosyldiacylglycerol (DGDG), sulfoquinovosyldiacylglycerol (SQDG)) and
      phospholipids (phosphatidylcholine (PC), phosphatidylethanolamine (PE) and
      phosphatidylglycerol (PG)] as well as betaine lipid 1,2-diacylglycero-O-4'-(N,N,N
      tri-methyl)-homoserine (DGTS) were isolated from Anfeltia tobuchiensis
      (Rhodophyta), Laminaria japonica, Sargassum pallidum (Phaeophyta), Ulva
      fenestrata (Chlorophyta) and Zostera marina (Embriophyta), harvested in the Sea
      of Japan. GC analysis of their fatty acid (FA) composition revealed that the n-6
      polyunsaturated FAs (PUFAs) shared the most part of the sum of n-6 and n-3 PUFAs
      in PC and PE compared with glycolipids and PG. In algae, it was related to the
      prevalence of 20:4n-6 over 20:5n-3 in non-photosynthetic lipids. Percentage of n
      6 PUFAs as well as the sum of n-3 and n-6 PUFAs decreased in the following
      sequence: PC-->PE-->PG. The saturation increased in the lines of MGDG-->DGDG-
      >SQDG and PC-->PE-->PG. PG was close to SQDG by the level of saturation.
      Distribution of C(18) and C(20) PUFAs in polar lipids depended on taxonomic
      position of macrophytes. Balance between C(18) and C(20) PUFAs was preferably
      shifted to the side of C(20) PUFAs in PC and PE that was observed in contrast to
      glycolipids and PG from L. japonica containing both series of FAs. The set of
      major FAs of polar lipid classes can essentially differ from each other and from
      total lipids of macrophytes. For example, MGDG was found to accumulate
      characteristic fatty acids 16:4n-3, 16:3n-3, 18:3n-6 and 18:4n-3, 20:3n-6 in U.
      fenestrata, Z. marina, L. japonica and S. pallidum, respectively.

PMID- 15016569
TI  - Phytotoxic cis-cinnamoyl glucosides from Spiraea thunbergii.
AB  - Spiraea thunbergii Sieb. was found to contain 1-O-cis-cinnamoyl-beta-D
      glucopyranose and 6-O-(4'-hydroxy-2'-methylene-butyroyl)-1-O-cis-cinnamoyl-beta-D
      glucopyranose as major plant growth inhibitory constituents along with related
      compounds of lower phytotoxicity including 6-O-(trans-cinnamoyl)-1-O-(4"-hydroxy
      3"-methyl-furan-2"-one)-beta-D-glucopyranose, 6-O-(4'-hydroxy-2'-methylene
      butyroyl)-1-O-trans-cinnamoyl-beta-D-glucopyranose, and 1-O-trans-cinnamoyl-beta
      D-glucopyranose. The former three compounds were cinnamoyl glucosides.

PMID- 15016570
TI  - Acetylated glucuronide triterpene bidesmosidic saponins from Symplocos glomerata.
AB  - Nine new bidesmosidic 3-O-glucuronide oleanane triterpenoid saponins were
      isolated from the stem bark of Symplocos glomerata King along with two known
      saponins, salsoloside C and copteroside E, and two major lignans, (-)-pinoresinol
      and (-)-pinoresinol-4'-O-beta-D-glucopyranoside. The structures of the new
      saponins were established using one- and two-dimensional NMR spectroscopy and
      mass spectrometry as, 3-O-[beta-D-xylopyranosyl(1-->4)-[2-O-acetyl]-beta-D
      glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, 3-O-[beta-D
      xylopyranosyl(1-->4)-[3-O-acetyl]-beta-D-glucuronopyranosyl]-28-O-[beta-D
      glucopyranosyl]-oleanolic acid, 3-O-[beta-D-xylopyranosyl (1-->4)-[2,3-O
      diacetyl]-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid,
      3-O-[alpha-L-arabinopyranosyl(1-->4)-beta-D-glucuronopyranosyl]-28-O-[beta-D
      glucopyranosyl]-oleanolic acid, 3-O-[alpha-L-arabinopyranosyl (1-->4)-[2-O
      acetyl]-beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, 3
      O-[[beta-D-xylopyranosyl (1-->2)]-[beta-D-xylopyranosyl (1-->4)]-[3-O-acetyl]
      beta-D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, 3-O
      [[beta-D-glucopyranosyl (1-->2)]-[beta-D-xylopyranosyl (1-->4)]-[3-O-acetyl]-beta
      D-glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, 3-O-[[beta-D
      glucopyranosyl (1-->2)]-[alpha-L-arabinofuranosyl (1-->4)]-[3-O-acetyl]-beta-D
      glucuronopyranosyl]-28-O-[beta-D-glucopyranosyl]-oleanolic acid, and 3beta-O
      [beta-D-xylopyranosyl(1-->4)-[2-O-acetyl]-beta-D-glucuronopyranosyl]-28-O-[beta-D
      glucopyranosyl]-morolic acid. The EtOH and EtOAc extracts of the stem bark showed
      no cytotoxic activity. At a concentration of 370 microg/ml, the saponin mixture
      showed haemolytic activity and caused 50% haemolysis of a 10% suspension of sheep
      erythrocytes.

PMID- 15016571
TI  - Aryltetralone lignans and 7,8-seco-lignans from Holostylis reniformis.
AB  - Aryltetralone lignans and two 7,8-seco-lignans were isolated from the acetone and
      hexane extracts of the roots of Holostylis reniformis, together with (-)
      galbacin. Their structures were determined by spectroscopic methods.

PMID- 15016573
TI  - The assessment of fatigue: a practical guide for clinicians and researchers.
AB  - OBJECTIVES: Fatigue is a common feature of physical and neurological disease as
      well as psychiatric disorders, often reported amongst patients' most severe and
      distressing symptoms. A large number of scales have been developed attempting to
      measure the nature, severity and impact of fatigue in a range of clinical
      populations. The aim of the present review is to guide the clinician and
      researcher in choosing a scale to suit their needs. METHODS: Database searches of
      Medline, PsycINFO and EMBASE were undertaken to find published scales. RESULTS:
      Details of 30 scales are reported. These vary greatly in how widely they have
      been used and how well they have been evaluated. The present review describes the
      scales and their properties and provides illustrations of their use in published
      studies. CONCLUSIONS: Recommendations are made for the selection of a scale and
      for the development and validation of new and existing scales.

PMID- 15016572
TI  - Chronic fatigue--chronically confusing but growing information.

PMID- 15016574
TI  - Factor analysis of symptoms among subjects with unexplained chronic fatigue: what
      can we learn about chronic fatigue syndrome?
AB  - OBJECTIVE: Chronic fatigue syndrome (CFS) case definitions agree that fatigue
      must be unexplained, debilitating and present for at least 6 months, but they
      differ over accompanying symptoms. Our objective was to compare the 1994 CFS case
      defining symptoms with those identified by factor analysis. METHODS: We surveyed
      the Wichita population and measured the occurrence of 21 symptoms in 1391
      chronically fatigued subjects who did not report fatigue-associated medical or
      psychiatric conditions. We used factor analyses to identify symptom dimensions of
      fatigue and cluster analysis to assign subjects to subgroups. RESULTS: Forty
      three subjects had CFS. We confirmed three factors: musculoskeletal, infection
      and cognition-mood-sleep, essentially defined by CFS symptoms. Although factor
      scores were higher among CFS subjects, CFS and non-CFS distributions overlapped
      substantially. Three clusters also showed overlap between CFS and non-CFS
      subjects. CONCLUSION: CFS symptomatology is a multidimensional phenomenon
      overlapping with other unexplained fatiguing syndromes and this must be
      considered in CFS research.

PMID- 15016575
TI  - Autonomic function and serum erythropoietin levels in chronic fatigue syndrome.
AB  - OBJECTIVE: Given previous findings, we wished to investigate whether there was
      evidence of autonomic dysfunction in patients with chronic fatigue syndrome, and
      whether this could be related to reduced erythropoietin levels and altered red
      blood cell indices. METHODS: We assessed autonomic function and analysed blood
      parameters (including erythropoietin) in 22 patients with chronic fatigue
      syndrome who were medication-free and without comorbid depression or anxiety.
      Results were compared to 23 iron-deficiency anaemia patients and 18 healthy
      individuals. RESULTS: Autonomic testing in patients with chronic fatigue syndrome
      yielded a significantly greater increase in heart rate together with a more
      pronounced systolic blood pressure fall on standing compared to healthy
      individuals. Heart rate beat-to-beat variation on deep breathing and responses to
      the Valsalva manoeuvre were normal. Two of 22 patients with chronic fatigue had
      mild normochromic normocytic anaemia with normal ferritin, vitamin B12 and folate
      levels. Serum erythropoietin levels were within reference range. CONCLUSION: Some
      autonomic dysfunction is present in chronic fatigue syndrome (CFS) patients; the
      explanation remains uncertain, but could relate to cardiovascular deconditioning.
      There were no major haematological, biochemical or immunological abnormalities in
      these patients.

PMID- 15016576
TI  - Psychological aspects of fibromyalgia: research vs. clinician impressions.
AB  - OBJECTIVE: This study was designed to compare the psychological features of
      patients with fibromyalgia, as described in the research literature, with
      physicians' clinical impressions. METHOD: Using a survey method, physicians
      (n=44) and physicians-in-training (n=54) were polled regarding their clinical
      impressions of 18 psychological features, culled from the research literature,
      which are attributed to fibromyalgia patients. RESULTS: Over 90% of respondents
      reported that fatigue, muscle tension, pain proneness, depression and anxiety
      were clinically associated with fibromyalgia patients "frequently" or "very
      frequently." The majority of respondents (52%) endorsed 10 of 18 items as
      occurring "frequently" or "very frequently." CONCLUSIONS: Physicians and
      physicians-in-training appear to observe in fibromyalgia patients over half of
      the psychological features identified in the research literature. For the
      remainder of items, we discuss possible explanations for the disparity.

PMID- 15016577
TI  - A randomised, controlled, triple-blind trial of the efficacy of homeopathic
      treatment for chronic fatigue syndrome.
AB  - OBJECTIVE: There is no management regime for chronic fatigue syndrome (CFS) that
      has been found to be universally beneficial and no treatment can be considered a
      "cure". Patients with CFS may use complementary and alternative medicine (CAM).
      Our aim was to evaluate homeopathic treatment in reducing subjective symptoms of
      CFS. METHOD: Using a triple-blind design (patient and homeopath blind to group
      assignment and data analyst blind to group until after initial analyses to reduce
      the possibility of bias due to data analyst), we randomly assigned patients to
      homeopathic medicine or identical placebo. One hundred and three patients meeting
      the Oxford criteria for CFS were recruited from two specialist hospital out
      patient departments. Patients had monthly consultations with a professional
      homeopath for 6 months. Main outcome measures were scores on the subscales of the
      Multidimensional Fatigue Inventory (MFI) and proportions of each group attaining
      clinically significant improvements on each subscale. Secondary outcome measures
      were the Fatigue Impact Scale (FIS) and the Functional Limitations Profile (FLP).
      Ninety-two patients completed treatment in the trial (47 homeopathic treatment,
      45 placebo). Eighty-six patients returned fully or partially completed
      posttreatment outcome measures (41 homeopathic treatment group who completed
      treatment, 2 homeopathic treatment group who did not complete treatment, 38
      placebo group who completed treatment, and 5 placebo group who did not complete
      treatment). RESULTS: Seventeen of 103 patients withdrew from treatment or were
      lost to follow-up. Patients in the homeopathic medicine group showed
      significantly more improvement on the MFI general fatigue subscale (one of the
      primary outcome measures) and the FLP physical subscale but not on other
      subscales. Although group differences were not statistically significant on four
      out of the five MFI subscales (the primary outcome measures), more people in the
      homeopathic medicine group showed clinically significant improvement. More people
      in the homeopathic medicine group showed clinical improvement on all primary
      outcomes (relative risk=2.75, P=.09). CONCLUSIONS: There is weak but equivocal
      evidence that the effects of homeopathic medicine are superior to placebo.
      Results also suggest that there may be nonspecific benefits from the homeopathic
      consultation. Further studies are needed to determine whether these differences
      hold in larger samples.

PMID- 15016578
TI  - Chronic fatigue syndrome and sexual dysfunction.
AB  - OBJECTIVE: The study was undertaken to determine if ambulant female patients with
      the chronic fatigue syndrome (CFS) report problems with their sexual functioning.
      METHODS: We studied 35 female CFS patients and 36 healthy female controls. The
      severity of CFS was measured with a fatigue questionnaire and the presence and
      severity of sexual dysfunction with a questionnaire about sexual functioning.
      RESULTS: The mean fatigue score was 24.8 in the CFS patients and 11.9 in the
      controls (P=.000). No increase in sexual dysfunction was found in the CFS group.
      The control group showed negative correlations between the score of the fatigue
      questionnaire and the frequency of "sexual fantasies," "(desire for) sexual
      contact" and "satisfaction with sex life." Such correlations were absent in the
      CFS group. CONCLUSION: The satisfaction with sex life was similar in patients and
      controls. The results suggest that patients and controls have a different
      perception of fatigue.

PMID- 15016579
TI  - Alcohol use in chronic fatigue syndrome.
AB  - OBJECTIVE: To examine the anecdotal observation that patients with chronic
      fatigue syndrome develop alcohol intolerance. METHODS: A consecutive case series
      of 114 patients fulfilling UK criteria for chronic fatigue syndrome referred to a
      specialist clinic. Self-reported alcohol use pre- and postdiagnosis, fatigue
      symptoms and comorbidity measures were collected. RESULTS: Two-thirds reduced
      alcohol intake. The most common reasons were increased tiredness after drinking
      (67%), increased nausea (33%), exacerbated hangovers (23%) and sleep disturbance
      (24%). One-third of the subjects also stopped drinking because "it seemed
      sensible." Some had been advised to avoid alcohol, but the majority (66%) did so
      on the basis of personal experience. CONCLUSION: Our data supports the anecdotal
      belief that chronic fatigue syndrome patients reduce or cease alcohol intake.
      This is associated with greater impairment in employment, leisure and social
      domains of function, and may hint at psycho-pathophysiological processes in
      common with other conditions that result in alcohol intolerance.

PMID- 15016580
TI  - Monozygotic twins discordant for chronic fatigue syndrome: objective measures of
      sleep.
AB  - PURPOSE: Chronic fatigue syndrome (CFS) is characterized by profound fatigue
      accompanied by disturbances of sleep, cognition, mood, and other symptoms. Our
      objective was to describe sleep architecture in CFS-discordant twin pairs.
      METHODS: We conducted a co-twin control study of 22 pairs of monozygotic twins
      where one twin met criteria for CFS and the co-twin was healthy. Twins underwent
      two nights of polysomnography. RESULTS: The percentage of Stage 3 and REM sleep
      was greater among the CFS twins than their healthy co-twins (P< or = .05 for
      both), but no other differences in sleep architecture including sleep latency,
      REM latency, and total sleep time were observed. Compared to their co-twins, CFS
      twins had higher values for the apnea-hypopnea index and apnea-hypopnea arousal
      index (P< or =.05 for both). CONCLUSION: These results do not provide strong
      evidence for a major role for abnormalities in sleep architecture in CFS.
      Respiration appears impaired in CFS, but these clinical abnormalities cannot
      alone account for the prominence of sleep complaints in this illness. The co-twin
      control methodology highlights the importance of selecting well-matched control
      subjects.

PMID- 15016581
TI  - The Italian version of the Fibrofatigue Scale, a reliable tool for the evaluation
      of fibromyalgia symptoms.
AB  - OBJECTIVE: To validate a translated Italian version of the Fibrofatigue Scale
      (FFS). METHODS: The Italian version of FFS was administered to 60 patients
      affected by fibromyalgia (FM) (57 patients were interviewed again 10 days later)
      together with the Italian version of the Fibromyalgia Impact Questionnaire (FIQ),
      the Stanford Health Assessment Questionnaire (HAQ) and the Medical Outcome Survey
      Short Form-36 (SF-36). All patients were asked about the severity of pain today
      (10-cm visual analogue scale) and the duration of symptoms. Test-retest
      reliability was assessed using Spearman correlations. Internal consistency was
      evaluated with Cronbach's alpha of reliability. Construct validity of the FFS was
      evaluated by correlations among the FFS, the FIQ and the subscales of the SF-36.
      RESULTS: Mean duration of symptoms was 7.6 years, and mean age of participants
      was 56.3 years. Test-retest reliability was between 0.70 and 0.95 for the single
      items as well as for the total FFS and other components. Internal consistency was
      0.90 for the overall FFS. Significant correlations were obtained between the FFS
      items and the SF-36. CONCLUSIONS: The Italian FFS is a reliable and valid
      instrument for detecting and measuring functional disability and symptoms
      severity in Italian patients with FM.

PMID- 15016582
TI  - Illness and disability in Danish Chronic Fatigue Syndrome patients at diagnosis
      and 5-year follow-up.
AB  - OBJECTIVE: Evaluation of the life impact of Chronic Fatigue Syndrome (CFS) over 5
      years. METHODS: Thirty-three adult patients meeting 1988 and 1994 CDC case
      criteria answered identical questionnaires at diagnosis and 5 years later, when a
      retrospective questionnaire was also completed. RESULTS: Work disability was very
      high and increased further, social isolation remained high, emotional adjustment
      improved. There were increased problems with reading and with allergies. Two
      measures of improvement were used: The relation between these measures was weak.
      Length of illness, extent of disability and emotional adjustment were poorly
      related to measures of improvement. Average illness scores were unchanged, but
      most individuals improved in some ways while worsening or remaining the same in
      others. Only one participant (3%) neared recovery, one other was substantially
      better but still severely disabled. CONCLUSION: CFS patients exhibit severe, long
      term functional impairment. Substantial improvement is uncommon, less than 6%.
      Allergies and aspects of cognition may worsen, emotional adjustment often
      improves.

PMID- 15016583
TI  - Sleep patterns in college students: gender and grade differences.
AB  - OBJECTIVE: Since gender effect is inconsistent and grade effect has not been
      addressed in previous studies, we investigated both effects on the daily sleep
      patterns in a group of young college students. METHODS: The sample consisted of
      237 students aged 18-24 years. Each subject completed a 7-day sleep log. RESULTS:
      Gender differences were found in several sleep variables and those were mostly
      not dependent on weekday/weekend difference. The female students went to bed and
      rose earlier and had longer sleep latency, more awakenings, and poorer sleep
      quality than the male. Gender differences were also shown in the relationship
      between sleep quality and other sleep variables. The correlation between sleep
      quality and rise time, time in bed, and sleep efficiency was stronger in men than
      in women. In contrast, grade differences were mostly dependent on weekday/weekend
      difference. The freshmen rose earlier and had shorter sleep time than did the
      other students on weekdays only. Sleep latency was the longest in seniors on
      weekdays only. CONCLUSION: This study showed that gender differences in sleep
      patterns and sleep difficulties were remarkable in the group of young college
      students. Alarmed by the high prevalence of sleep difficulties among general
      college students, it is recommended that the students should be informed of their
      sleep problems and the consequences.

PMID- 15016584
TI  - Self-reported sleep across the menstrual cycle in young, healthy women.
AB  - OBJECTIVE: To establish the association between subjective sleep and phase of the
      menstrual cycle in healthy, young, ovulating women. METHODS: Twenty-six women
      (mean age: 21 years) who did not suffer from any menstrual-associated disorders,
      and in whom we had detected ovulation, completed daily questionnaires about their
      sleep over 1 month. RESULTS: The women reported a lower sleep quality over the 3
      premenstrual days and 4 days during menstruation, compared to the mid-follicular
      and early/mid luteal phases. Total sleep time, sleep onset latency, number and
      duration of awakenings, and morning vigilance were not affected by the menstrual
      cycle. CONCLUSION: The normal, ovulatory cycle is associated with changes in the
      perception of sleep quality but not sleep continuity in healthy, young women. The
      temporal relationship of sleep complaints with menstrual phase should be
      considered in the evaluation of sleep disorders, particularly insomnia, in women.

PMID- 15016585
TI  - A preliminary investigation of the effectiveness of a sleep apnea education
      program.
AB  - OBJECTIVES: This study aimed to evaluate a standardised sleep apnea patient
      education program and develop a study design that may be used to evaluate other
      such education programs. METHOD: Thirty-four adults diagnosed with obstructive
      sleep apnea hypopnea syndrome (OSAHS) underwent a standard sleep apnea education
      program and completed measures of knowledge of and beliefs about sleep apnea
      before, after, and 3 months following education. Two outcome measures were used:
      the Apnea Knowledge Test (AKT) and the Apnea Beliefs Scale (ABS). RESULTS: AKT
      results showed significant knowledge gains posteducation, which were maintained
      at follow-up. Patients also reported more positive beliefs about their ability to
      change their behaviour and comply with continuous positive airway pressure (CPAP)
      treatment recommendations after education. DISCUSSION: Findings from this
      preliminary investigation suggest that the education program used in this study
      may improve patients' knowledge of CPAP and promote functional beliefs about
      OSAHS treatment. This program clearly warrants further research, and ultimately
      such programs may prove important in improving CPAP compliance.

PMID- 15016586
TI  - Objective assessment of personality disorder in chronic fatigue syndrome.
AB  - OBJECTIVES: This study aims to objectively assess the prevalence and nature of
      personality disorders in depressed and nondepressed chronic fatigue syndrome
      (CFS) patients and compare this to depressed and healthy control groups. METHODS:
      Sixty-one patients attending a tertiary referral clinic with chronic fatigue
      syndrome, 40 psychiatric inpatients with depressive disorder and 45 healthy
      medical students completed the Structured Clinical Interview for DSM-III-R
      Diagnoses (SCID-II) in addition to providing routine clinical and demographic
      information. RESULTS: Thirty-nine percent of the CFS group, 73% of the depressed
      group and 4% of the healthy group were diagnosed with personality disorders.
      Cluster C disorders were the most common in both the CFS and depressed group. The
      depressed CFS patients had more Cluster B personality disorders than nondepressed
      CFS patients. Overall for CFS patients there was no association between mood
      state and personality disorder. CONCLUSIONS: High levels of personality disorder
      are found on objective assessment of CFS patients attending a teaching hospital
      clinic. This cannot be accounted for by comorbid depression.

PMID- 15016587
TI  - Rains, J., Penzien, D. Sleep and chronic pain: challenges to the alpha-EEG sleep
      pattern as a pain specific sleep anomaly.

PMID- 15016588
TI  - The effects of carbon monoxide on respiratory chemoreflexes in humans.
AB  - As protection against low-oxygen and high-carbon-dioxide environments, the
      respiratory chemoreceptors reflexly increase breathing. Since CO is also
      frequently present in such environments, it is important to know whether CO
      affects the respiratory chemoreflexes responsiveness. Although the peripheral
      chemoreceptors fail to detect hypoxia produced by CO poisoning, whether CO
      affects the respiratory chemoreflex responsiveness to carbon dioxide is unknown.
      The responsiveness of 10 healthy male volunteers were assessed before and after
      inhalation of approximately 1200 ppm CO in air using two iso-oxic rebreathing
      tests; hypoxic, to emphasize the peripheral chemoreflex, and hyperoxic, to
      emphasize the central chemoreflex. Although mean (SEM) COHb values of 10.2 (0.2)%
      were achieved, no statistically significant effects of CO were observed. The
      average differences between pre- and post-CO values for ventilation response
      threshold and sensitivity were -0.5 (0.9) mmHg and 0.8 (0.3) L/min/mmHg,
      respectively, for hyperoxia, and 0.7 (1.1) mmHg and 1.2 (0.8) L/min/mmHg,
      respectively, for hypoxia. The 95% confidence intervals for the effect of CO were
      small. We conclude that environments with low levels of CO do not have a
      clinically significant effect acutely on either the central or the peripheral
      chemoreflex responsiveness to carbon dioxide.

PMID- 15016589
TI  - Ozone, area social conditions, and mortality in Mexico City.
AB  - We investigated whether the association of daily mortality and ambient ozone
      differs by age and area social conditions of the region of residence using a time
      series analysis. The study setting was metropolitan Mexico City, a high altitude
      city situated in a valley, with an estimated 20 million inhabitants, large
      socioeconomic gradients, and ozone levels frequently exceeding international
      standards. We stratified daily deaths by six census-derived socioeconomic
      indicators, based on characteristics of the county where decedents lived. We used
      Poisson regression to model the association between daily mortality and ozone
      levels (on the day of death and the previous day) in separate models, stratified
      by area socioeconomic level and age, and controlling for time trends and
      temperature. Ozone was positively associated with total mortality [0.65% increase
      per 10 ppb increment, 95% confidence interval (CI): 0.02%, 1.28%] and for
      mortality among those over age 65 [1.39% increase per 10 ppb increment, 95% CI:
      0.51%, 2.28%]. Associations between ozone and all-age mortality did not show any
      consistent patterns according to socioeconomic gradients. We conclude that
      elderly people are at higher risk for ozone-associated mortality. Though county
      level social indicators in Mexico City were not strong markers of vulnerability
      to ozone-associated acute mortality in this analysis, complex associations
      between individual and area-level factors may exist that would require additional
      data and further analyses to elucidate.

PMID- 15016590
TI  - Genotoxic differences by sex in nasal epithelium and blood leukocytes in subjects
      residing in a highly polluted area.
AB  - We describe differences by sex in genotoxic damage found in a population of
      medical students exposed to a highly oxidative atmosphere, compared with a
      control group, measured by the single-cell gel electrophoresis assay and
      histological changes in nasal epithelium smears. Cells were obtained from the
      nasal epithelium and blood leukocytes. Higher DNA damage in nasal cells and
      leukocytes was found in males compared to females and control subjects. The
      percentage of squamous metaplastic changes in the nasal epithelium was also
      higher in males compared with females and controls. The co-mutation of normal
      nasal epithelium by squamous cells might modify its protective function in the
      nose, increasing the risk of damage to the lower respiratory tract. Although, as
      medical students, males and females were exposed to the same environment and
      activity patterns, male genotoxicity damage was higher in control and exposed
      subjects. More research should be done in order to identify direct or indirect
      sexual hormone intervention.

PMID- 15016591
TI  - Difference in the relation between daily mortality and air pollution among
      elderly and all-ages populations in southwestern France.
AB  - Numerous time series studies around the world have reported an association
      between mortality and particulate air pollution. We investigated the distribution
      over time of effect of air pollution on short-term mortality among subjects aged
      65 years and older and of all ages in Bordeaux, France. Statistical analysis was
      based on generalized additive models using either loess or penalized spline
      smoothing. Our study found a significant positive association between air
      pollution and all nonaccidental mortality and specific mortality in both group of
      population (all ages and elderly) with a greater effect among the elderly,
      particularly for respiratory mortality. For this case, we observed a greater
      effect according to distributed lag models (0-5 days) among the elderly, with an
      estimated increase of 9.2% in the daily number of deaths for 10 microg/m(3) of
      daily black smoke [95% CI, 3.4-15.3]. These results contribute to the efforts
      made to understand how air pollution promotes adverse health effects and to
      identify susceptible subgroups.

PMID- 15016592
TI  - 2,3-Dimercaptopropanol, 2,3-dimercaptopropane-1-sulfonic acid, and meso-2,3
      dimercaptosuccinic acid inhibit delta-aminolevulinate dehydratase from human
      erythrocytes in vitro.
AB  - The effects of dithiol chelating agents meso-2,3-dimercaptosuccinic acid (DMSA),
      2,3-dimercaptopropane-1-sulfonic acid (DMPS), and 2,3-dimercaptopropanol (BAL) on
      delta-aminolevulinate dehydratase (delta-ALA-D) from human erythrocytes were
      evaluated. Furthermore, possible protective effects of zinc chloride (ZnCl(2)),
      dithiothreitol (DTT), and cysteine were studied. delta-ALA-D activity from human
      erythrocytes was inhibited by dithiol chelating agents in a concentration
      dependent manner. Cysteine, at all concentrations tested, did not protect the
      inhibitory effect of 1 and 4 mM DMPS and DMSA, but protected 1 mM BAL inhibition.
      Dithiotreitol was able to protect the inhibition caused by 1 mM BAL (28%), DMPS
      (56%), and DMSA (40%) in a concentration-dependent manner. Zinc chloride
      protected and restored 1 mM BAL inhibitory effect on delta-ALA-D. Zinc chloride
      at 500 microM and 1 mM, respectively, protected inhibitory effects of DMPS and
      DMSA (1 and 4 mM), but did not reverse its effects. The preincubation of dithiol
      chelating agents with enzyme demonstrated that DMSA was the most potent delta-ALA
      D inhibitor of human erythrocytes. These data are in agreement with delta-ALA-D
      activity from purified enzyme. ZnCl(2) (1 microM) added, in the reaction mixture,
      increased enzyme activity and DTT (100 microM) totally restored the enzyme
      activity for all chelating agents tested.

PMID- 15016593
TI  - Identification of cytochrome P450 isoforms involved in 1-hydroxylation of pyrene.
AB  - Urinary 1-hydroxypyrene (1-OHP) has been used as a biomarker for environmental
      polyaromatic hydrocarbon (PAH) exposure. However, it is known that there is an
      interindividual variability in metabolism of pyrene to 1-OHP depending on the
      activities of the metabolizing enzymes, especially cytochrome P450s (CYPs). In
      this study, we investigated the 1-hydroxylation of pyrene by 10 forms of cDNA
      expressed human P450s in order to identify the principal isoforms of P450s that
      are involved in the major metabolic pathway of pyrene. The pyrene 1-hydroxylation
      activity was found to be the highest in CYP1A1 at both 0.5 and 50microM of
      pyrene, followed by CYP1B1 and 1A2, whereas other enzymes, including CYP2A6, 2C8,
      2C9*1, 2C19, 2D6, 2E1, 3A4, and control microsomes, showed very low or
      undetectable rates of 1-hydroxylation. In conclusion, CYP1A1, 1B1, and 1A2 are
      major metabolizing enzymes in 1-hydroxylation of pyrene in vitro. This suggests
      that the individual difference of these enzymes must be included in
      epidemiological studies to evaluate PAH exposure using urinary 1-OHP.

PMID- 15016594
TI  - Induction of hypospadias in a murine model by maternal exposure to synthetic
      estrogens.
AB  - We tested the hypothesis that maternal exposure to synthetic estrogen can cause
      hypospadias in male offspring and defined the morphological changes in the
      disrupted urethral seam. Timed pregnant C57/6 mice were exposed to synthetic
      estrogens. The genital tubercles were examined for the presence of hypospadias
      using histology, three-dimensional computer reconstruction, and plastic cast
      injection molds of the urethra. Microscopic serial analysis confirmed the
      presence of hypospadias, which occurred in approximately 50% of the synthetic
      estrogen-treated male fetuses. No effect was seen in the female embryos. Plastic
      cast injection showed that affected males had a shorter total urethral length and
      loss of male anatomic features such as the prostatic utricle. Exposure to
      synthetic estrogens during pregnancy affects the normal development of the
      urethra in the mouse. We conclude that endocrine disrupters play an important
      role in genital tubercle anomalies.

PMID- 15016595
TI  - Protective role of aryl and alkyl diselenides on lipid peroxidation.
AB  - The concept that selenium-containing molecules may be better nucleophiles (and
      therefore antioxidants) than classical antioxidants has led to the design of
      synthetic organoselenium compounds. In the present study we appraised the
      antioxidant potential, thiol peroxidase activity, and rate of dithiotreitol and
      reduced glutathione oxidation of simple organodiselenide compounds in rats and
      mice. The present results demonstrate that alkyl and aryl diselenides are
      antioxidant compounds. We verified that the substitution on the aromatic moiety
      of diphenyl diselenide or the replacement of on aryl group by an alkyl substitute
      on diselenides changes their antioxidant and thiol peroxidase-like properties.
      The diaryl diselenides (PhSe)(2) and (p-ClPhSe)(2) presented higher thiol
      peroxidase activity and demonstrated better antioxidant potential than the other
      diselenides tested. In fact, the results revealed that alkyl diselenides, at low
      concentrations, were prooxidants and that aryl diselenides did not present this
      effect. Alkyl diselenides [(C(2)H(5)Se)(2) and (C(3)H(7)Se)(2)] demonstrated a
      higher potential for -SH group oxidation than aryl diselenides. In addition, this
      study demonstrated that diselenide protection against lipid peroxidation was
      different in mice and rats. The compounds tested acted more as antioxidants in
      the brains of mice than in the brains of rats.

PMID- 15016596
TI  - Childhood urine mercury excretion: dental amalgam and fish consumption as
      exposure factors.
AB  - The authors investigated the effect of amalgam fillings and fish consumption on
      urine mercury level (UHg), in children aged 4-8 years old inclusive. Using a
      sample of 60 children, we found that children with amalgam fillings had
      significantly higher UHg levels than children without amalgams (geometric
      mean=1.412microg Hg/g versus 0.436 microg Hg/g, respectively, P = 0.0001).
      Subjects with reported higher fish consumption also had significantly higher UHgs
      (P = 0.004). Univariate analyses provide evidence of an association between
      elevated UHg level and young age (P = 0.009), short height (P = 0.024), and low
      weight (P = 0.049) in children with amalgam chewing surfaces. We also found a
      negative correlation between urine mercury and age (-0.378), height (-0.418), and
      weight (-0.391). A multiple logistic regression model shows that the presence of
      amalgam fillings leads to increased odds of high UHg in children (OR=47.18), even
      after adjusting for high fish consumption (OR=8.66) and height (OR=11.36).

PMID- 15016597
TI  - Estimation of occupational and nonoccupational nitrogen dioxide exposure for
      Korean taxi drivers using a microenvironmental model.
AB  - Occupational and nonoccupational personal nitrogen dioxide (NO(2)) exposures were
      measured using passive samplers for 31 taxi drivers in Asan and Chunan, Korea.
      Exposures were also estimated using a microenvironmental time-weighted average
      model based on indoor, outdoor and inside the taxi area measurements. Mean NO(2)
      indoor and outdoor concentrations inside and outside the taxi drivers' houses
      were 24.7+/-10.7 and 23.3+/-8.3 ppb, respectively, with a mean indoor to outdoor
      NO(2) ratio of 1.1. Mean personal NO(2) exposure of taxi drivers was 30.3+/-9.7
      ppb. Personal NO(2) exposures for drivers were more strongly correlated with
      interior vehicle NO(2) levels (r = 0.89) rather than indoor residential NO(2)
      levels (r = 0.74) or outdoor NO(2) levels (r = 0.71). The main source of NO(2)
      exposure for taxi drivers was considered to be occupational driving.
      Interestingly, the NO(2) exposures for drivers' using LPG-fueled vehicles (26.3+/
      1.3 ppb) were significantly lower than those (38.1+/-1.3 ppb) using diesel-fueled
      vehicle (P <0.01). Since drivers spent most of their time inside their vehicle
      and indoors at home, a microenvironmental model was used to estimate the personal
      NO(2) exposure with indoor and outdoor NO(2) levels of the residence, and
      interior vehicle NO(2) levels (P <0.001). Some subpopulations, such as
      professional drivers, might be exposed to high NO(2) levels because they drive
      diesel-using vehicles outdoors in Korea.

PMID- 15016598
TI  - Lead in residential soil and dust in a mining and smelting district in northern
      Armenia: a pilot study.
AB  - This pilot study of sources of lead exposure in residential settings was
      conducted in a mining and smelting district in northern Armenia. Samples of
      exterior soil and dust and interior house dust were collected in and around
      apartment buildings in Alaverdi where the country's largest polymetallic smelter
      is located, and in nearby mining towns of Aghtala and Shamlugh. The NITON XL-723
      Multi-Element XRF analyzer was used for lead testing. Lead levels in samples from
      Alaverdi were higher than those in Shamlugh and Aghtala. In all three towns, the
      highest lead levels were found in loose exterior dust samples, and lead
      concentrations in yard soil were higher than those in garden soil. Many soil
      samples (34%) and the majority of loose dust samples (77%) in Alaverdi exceeded
      the US Environmental Protection Agency standard of 400 mg/kg for bare soil in
      children's play areas. In addition, 36% of floor dust samples from apartments in
      Alaverdi exceeded the US Environmental Protection Agency standard of 40
      microg/ft(2) for lead loading in residential floor dust. The Armenian Ministry of
      Health and other interested agencies are being informed about the findings of the
      study so that they can consider and develop educational and preventive programs
      including blood lead screening among sensitive populations.

PMID- 15016600
TI  - Human exposure to uranium in groundwater.
AB  - High concentrations of uranium (mean=620 microg/L) were detected in water samples
      collected from private wells in a residential community. Based on isotopic
      analyses, the source of the uranium contamination appeared to be from naturally
      occurring geological deposits. In homes where well water concentrations of
      uranium exceeded the drinking water standard, the residents were advised to use
      an alternate water source for potable purposes. Several months after the
      residents had stopped drinking the water, urine samples were collected and tested
      for uranium. Elevated concentrations of uranium (mean=0.40 microg/g creatinine)
      were detected in urine samples, and 85 percent of the urine uranium
      concentrations exceeded the 95th percentile concentration of a national reference
      population. Urine uranium concentrations were positively correlated with water
      uranium concentrations, but not with the participants' ages or how long they had
      been drinking the water. Six months later, a second urine sample was collected
      and tested for uranium. Urine uranium concentrations decreased in most (63
      percent) of the people. In those people with the highest initial urine uranium
      concentrations, the urine levels decreased an average of 78 percent. However,
      urine uranium concentrations remained elevated (mean=0.27 microg/g), and 87
      percent of the urine uranium concentrations exceeded the 95th percentile
      concentration of the reference population. The results of this investigation
      demonstrated that after long-term ingestion of uranium in drinking water,
      elevated concentrations of uranium in urine could be detected up to 10 months
      after exposure had stopped.

PMID- 15016599
TI  - Evaluation of exposure to carbon monoxide associated with passive smoking.
AB  - The current study measured breath carbon monoxide (CO) concentrations prior to
      and at prescribed time intervals after exposure to passive smoking under
      controlled conditions, along with the air CO concentration in the exposure room
      during the exposure periods. The postexposure breath CO levels were 1.4-2.7 times
      higher than the background breath CO levels after 30 min of exposure, yet only
      slightly higher after 10 min of exposure, thereby confirming that exposure to CO
      from passive smoking causes a significant body burden of CO. The air CO
      concentration gradually increased during the burning of a cigarette(s),
      regardless of the exposure duration, whereas it slightly decreased after burning.
      However, the pattern of breath CO decay was similar for the two different types
      of exposure (during and after a cigarette(s)) in each subject. The decrease in
      the postexposure alveolar CO concentrations was slow even in the early phase of
      the decay curves, indicating a monocompartment uptake and elimination model for
      the human body. The half-lives (78-277 min) estimated in the present study were
      comparable to those reported in previous studies associated with CO exposure from
      active smoking or other activities. The current study also evaluated the CO
      exposure of visitors and workers at three different types of recreation facility
      (bars, Internet cafes, and billiard halls) typically associated with passive
      smoking. The results confirmed that passive smoking is the major contributor to
      the CO exposure of nonsmoking visitors in a recreation environment. In addition,
      workplace exposure to CO from passive smoking was found to be the most important
      contributor to the daily CO exposure of nonsmoking recreation workers.

PMID- 15016601
TI  - Indoor air quality in ice skating rinks in Hong Kong.
AB  - Indoor air quality in ice skating rinks has become a public concern due to the
      use of propane- or gasoline-powered ice resurfacers and edgers. In this study,
      the indoor air quality in three ice rinks with different volumes and resurfacer
      power sources (propane and gasoline) was monitored during usual operating hours.
      The measurements included continuous recording of carbon monoxide (CO), carbon
      dioxide (CO(2)), total volatile organic compounds (TVOC), particulate matter with
      a diameter less than 2.5 microm (PM(2.5)), particulate matter with diameter less
      than 10 microm (PM(10)), nitric oxide (NO), nitrogen dioxide (NO(2)), nitrogen
      oxide (NO(x)), and sulfur dioxide (SO(2)). The average CO, CO(2), and TVOC
      concentrations ranged from 3190 to 6749 microg/m(3), 851 to 1329 ppm, and 550 to
      765 microg/m(3), respectively. The average NO and NO(2) concentrations ranged
      from 69 to 1006 microg/m(3) and 58 to 242 microg/m(3), respectively. The highest
      CO and TVOC levels were observed in the ice rink which a gasoline-fueled
      resurfacer was used. The highest NO and NO(2) levels were recorded in the ice
      rink with propane-fueled ice resurfacers. The air quality parameters of PM(2.5),
      PM(10), and SO(2) were fully acceptable in these ice rinks according to HKIAQO
      standards. Overall, ice resurfacers with combustion engines cause indoor air
      pollution in ice rinks in Hong Kong. This conclusion is similar to those of
      previous studies in Europe and North America.

PMID- 15016603
TI  - Drug pathways: moving beyond single gene pharmacogenetics.

PMID- 15016602
TI  - Metal levels in eggs of common terns (Sterna hirundo) in New Jersey: temporal
      trends from 1971 to 2002.
AB  - Managers and public policy makers require information on the status of and trends
      in contaminant levels in organisms to assess ecosystem health. Seabirds are
      excellent bioindicators because they are long-lived, feed at different trophic
      levels, and are at the top of the food chain, and many are abundant and widely
      distributed. They can reveal spatial or temporal trends in contaminant levels. In
      this paper, we examine temporal trends in the levels of cadmium, chromium, lead,
      manganese, mercury, and selenium in eggs from common terns (Sterna hirundo)
      nesting on several salt marsh islands in Barnegat Bay, New Jersey. We test the
      null hypothesis that there are no temporal differences in levels of cadmium,
      lead, and mercury from 1971 to 2002 and in chromium, manganese, and selenium from
      1992 to 2002. Arsenic was also analyzed in recent years. Levels were highest for
      manganese, followed by selenium, mercury, arsenic, lead, chromium, and cadmium.
      The eggs of Barnegat Bay common terns show a decline in levels of cadmium,
      chromium, and lead. Mercury declined from 1971 to 1982, increased dramatically in
      1999, and declined thereafter. Manganese, an essential element, showed a decline
      (except for 2001), and selenium declined initially, but then remained stable. The
      data indicate that common terns can serve as useful bioindicators of temporal
      trends in exposure and that some of the metals of concern in estuarine
      environments (lead, cadmium) have declined over the past 30 years, although
      mercury levels are higher than in the early 1980s. The spike in 1999 is
      unexplained.

PMID- 15016604
TI  - Inventors and their attorneys must beware of their actions before the US Patent &
      Trademark Office.

PMID- 15016606
TI  - The 6th international meeting on single nucleotide polymorphism and complex
      genome analysis. November 20-23, 2003, Chantilly, VA, USA.

PMID- 15016607
TI  - Variation in the human genome and risk to common disease. Keystone Symposium on
      'Human Genome Sequence Variation and the Inherited Basis of Common Diseases'.
      January 8-13, Breckenridge, Colorado, USA.

PMID- 15016608
TI  - Genomic approaches in dissecting complex biological pathways.
AB  - Advances in genomic research have provided many types of large-scale data that
      contain rich information on various biological pathways. Intensive efforts have
      been made to qualitatively or quantitatively model biological pathways using
      these genomic data. Some general network properties, such as the scale-free
      property and network motifs, have been discussed and various network models have
      been applied to reconstruct pathways. However, there is a lack of systematic
      integration of prior knowledge and different genomic data in these analyses. In
      this review, we discuss pathway reconstruction under the consideration of the
      complexity embedded in the biological system, and the global and local properties
      of biological pathways. We review major methodologies, including clustering
      methods, scale-free networks models, Bayesian networks models, Boolean networks
      models, systems of differential equations, and data integration methods. We focus
      on the difficulty of each methodology in modeling biological pathways, and
      emphasize that different models capture different aspects of biological pathways
      or genomic data. The 'noisy' large-scale genomic data require the mathematical
      models and computational methods to be both robust and identifiable. In addition,
      we believe that ideal models should have the capability of incorporating various
      data types and these models need to be assessed through rigorous comparisons with
      empirical data.

PMID- 15016609
TI  - Pharmacogenomics of proton pump inhibitors.
AB  - Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, rabeprazole,
      esomeprazole, and pantoprazole, are metabolized by cytochrome P450 isoenzyme 2C19
      (CYP2C19) in the liver. There are genetic differences that affect the activity of
      this enzyme. The genotypes of CYP2C19 are classified into three groups:
      homozygous extensive metabolizer (homEM), heterozygous extensive metabolizer
      (hetEM), and poor metabolizer (PM). The pharmacokinetics and pharmacodynamics of
      PPIs differ among the different CYP2C19 genotype groups. Plasma PPI and
      intragastric pH levels during PPI treatment are the lowest in the homEM group and
      the highest in the PM group. These CYP2C19 genotype-dependent differences in
      pharmacokinetics and pharmacodynamics of PPIs are reflected in the cure rates for
      gastroesophageal reflux disease and Helicobacter pylori infection with PPI-based
      therapies. The CYP2C19 genotyping test is a useful tool for deciding on the
      optimal treatment regimen using a PPI, including a dual (PPI plus antibiotic) or
      a triple (PPI plus two antibiotics) therapy.

PMID- 15016610
TI  - Association of genetic variations in HLA-B region with hypersensitivity to
      abacavir in some, but not all, populations.
AB  - Abacavir is an effective antiretroviral drug used to treat HIV-1 infection.
      Approximately 5% of patients treated with abacavir develop a hypersensitivity
      reaction that requires discontinuation of the drug. In an initial pharmacogenetic
      study conducted in a predominantly White male population, multiple markers in the
      human leukocyte antigen (HLA)-B chromosomal region were associated with
      hypersensitivity to abacavir. The HLA-B*5701 association has now been confirmed
      in White males in a subsequent, larger study (n=293, p=4.7 x 10(-18)) and is also
      observed in White females (n=56, p=6.8 x 10(-6)) and Hispanics (n=104, p=2.1 x
      10(-4)). HLA-B*5701 was not associated with hypersensitivity in Blacks (n=78,
      p=0.27). HLA-B*5701 alone lacks sufficient predictive value to identify patients
      at risk for hypersensitivity to abacavir across diverse patient populations.
      Efforts are ongoing to identify markers with sufficient sensitivity and
      specificity to be clinically useful. Even after a marker set is identified,
      appropriate clinical identification and management of hypersensitivity to
      abacavir must remain the cornerstone of clinical practice.

PMID- 15016611
TI  - Personalized psychiatry: a realistic goal.
AB  - It is becoming increasingly evident that the implementation of true personalized
      medicine will not come as rapidly and smoothly as initially hoped. In the
      aftermath of the drafting of the human genome in 2001, the popular and scientific
      media featured numerous commentaries heralding the approaching arrival of
      personalized medicine to the clinic, and describing its huge benefits for
      patients. Media coverage predicted a drastic transformation for the practice of
      medicine, second to the revolution brought about by the discovery of vaccines and
      antibiotics. From the perspective of another 3 years, during which substantial
      new insights were made into the enormous complexity of human genome variation, it
      seems that true personalized medicine may still be decades away for many aspects
      of medical treatment. Nonetheless, the prospects for implementation of at least
      certain elements of personalized medicine for one key discipline, psychiatry,
      might be relatively close and more realistic. With the correct focus, realization
      of some benefits of genetic patient profiling for psychiatric pharmacotherapy
      might be near, and in due course, lead the way for true personalized psychiatry.

PMID- 15016612
TI  - Angiotensin II type 1 receptor interaction is an important regulator for the
      development of pancreatic fibrosis in mice.
AB  - The renin-angiotensin system (RAS) plays important roles in various
      pathophysiological processes. However, the role of the RAS in pancreatic fibrosis
      has not been established. We investigated the role of angiotensin II (ANG II)-ANG
      II type 1 (AT(1)) receptor pathway in the development of pancreatic fibrosis with
      AT(1a) receptor-deficient [AT(1a)(-/-)] mice. To induce pancreatic fibrosis,
      AT(1a)(-/-) and wild-type (WT) mice were submitted to three episodes of acute
      pancreatitis induced by six intraperitoneal injections of 50 microg/kg body wt
      cerulein at hourly intervals, per week, for four consecutive weeks. Pancreatic
      fibrosis was assessed by histology and hydroxyproline content. Pancreatic
      stellate cell (PSC) activation and the localization of AT(1) receptors were
      assessed by Western blot analysis for alpha-smooth muscle actin and
      immunostaining. Transforming growth factor-beta(1) (TGF-beta(1)) mRNA expression
      in the pancreas was assessed by RT-PCR. Six intraperitoneal injections of
      cerulein induced acute pancreatitis in both AT(1a)(-/-) and WT mice. There were
      no significant differences between two groups with regard to serum amylase and
      histological changes. Pancreatic fibrosis induced by repeated episodes of acute
      pancreatitis was significantly attenuated in AT(1a)(-/-) mice compared with that
      in WT mice. This finding was accompanied by a reduction of activated PSCs. Dual
      immunofluorescence staining in WT mice revealed that activated PSCs express AT(1)
      receptors. The level of TGF-beta(1) mRNA was lower in AT(1a)(-/-) mice than in WT
      mice. Our results demonstrate that the ANG II-AT(1) receptor pathway is not
      essential for the local pancreatic injury in acute pancreatitis but plays an
      important role in the development of pancreatic fibrosis through PSC activation
      and proliferation.

PMID- 15016613
TI  - Neutrophils augment recovery of porcine ischemia-injured ileal mucosa by an IL
      1beta- and COX-2-dependent mechanism.
AB  - Polymorphonuclear neutrophils (PMNs) play a critical role in intestinal mucosal
      injury and repair. To study effects of PMNs on acutely injured mucosa, we applied
      PMNs isolated from circulation or peritoneal fluid from animals with chemically
      induced peritonitis to ischemia-injured porcine ileal mucosa. In preliminary
      experiments, PMNs enhanced recovery of transepithelial electrical resistance
      (TER), and this action was inhibited by pretreatment with the nonselective
      cyclooxygenase (COX) inhibitor indomethacin. Because COX-2 is upregulated by
      inflammatory mediators such as IL-1beta, which is released by PMNs, we postulated
      that PMNs enhance recovery of ischemia-injured mucosa by a pathway involving IL
      1beta and COX-2. Application of 5 x 10(6) PMNs to the serosal surface of ischemia
      injured mucosa significantly enhanced recovery of TER (P < 0.05), an effect that
      was inhibited by the selective COX-2 inhibitor NS-398 (5 microM) and by an IL
      1beta receptor antagonist (0.1 mg/ml). Addition of 10 ng/ml IL-1beta to the
      serosal surface of injured tissues caused a significant increase in TER (P <
      0.05) that was inhibited by pretreatment with NS-398. Western blot analysis of
      mucosal homogenates revealed dramatic upregulation of COX-2 in response to IL
      1beta or peritoneal PMNs, and the latter was inhibited by an IL-1beta receptor
      antagonist. Real-time PCR revealed that increased mRNA COX-2 expression preceded
      increased COX-2 protein expression in response to IL-1beta. We concluded that
      PMNs augment recovery of TER in ischemia-injured ileal mucosa via IL-1beta
      dependent upregulation of COX-2.

PMID- 15016614
TI  - Differential requirement of members of the MAPK family for CCL2 expression by
      hepatic stellate cells.
AB  - Hepatic stellate cells (HSC) coordinate the liver wound-healing response through
      secretion of several cytokines and chemokines, including CCL2 (formerly known as
      monocyte chemoattractant protein-1). In this study, we evaluated the role of
      different proteins of the MAPK family (ERK, p38(MAPK), and JNK) in the regulation
      of CCL2 expression by HSC, as an index of their proinflammatory activity. Several
      mediators activated all three MAPK, including TNF, IL-1, and PDGF. To assess the
      relative role of the different MAPKs, specific pharmacological inhibitors were
      used; namely, SB203580 (p38(MAPK)), SP600125 (JNK), and PD98059 (MEK/ERK). The
      efficacy and specificity of the different inhibitors in our cellular system were
      verified analyzing the enzymatic activity of the different MAPKs using in vitro
      kinase assays and/or testing the inhibition of phosphorylation of downstream
      substrates. SB203580 and SP600125 dose-dependently inhibited CCL2 secretion and
      gene expression induced by IL-1 or TNF. In contrast, inhibition of ERK did not
      affect the upregulation of CCL2 induced by the two cytokines. Finally, activin A
      was also found to stimulate CCL2 expression and to activate ERK, JNK, p38, and
      their downstream targets. Unlike in cells exposed to proinflammatory cytokines,
      all three MAPKs were required to induce CCL2 secretion in response to activin. We
      conclude that members of the MAPK family differentially regulate cytokine-induced
      chemokine expression in human HSC.

PMID- 15016615
TI  - In vitro activation of murine DRG neurons by CGRP-mediated mucosal mast cell
      degranulation.
AB  - Upregulation of CGRP-immunoreactive (IR) primary afferent nerve fibers
      accompanied by mastocytosis is characteristic for the Schistosoma mansoni
      infected murine ileum. These mucosal mast cells (MMC) and CGRP-IR fibers, which
      originate from dorsal root (DRG) and nodose ganglia, are found in close
      apposition. We examined interactions between primary cultured MMC and CGRP-IR DRG
      neurons in vitro by confocal recording of intracellular Ca(2+) concentration
      ([Ca(2+)](i)). The degranulatory EC(50) for the mast cell secretagogue compound
      48/80 (C48/80; 10 microg/ml) and the neuropeptides CGRP (2.10(-8) M) and
      substance P (SP; 3.10(-8) M) were determined by measurement of extracellular
      release of the granule chymase, mouse mast cell protease-1. Application of C48/80
      (10 microg/ml) and CGRP and SP (both 10(-7) M) to Fluo-4-loaded MMC induced a
      transient rise in [Ca(2+)](i) after a lag time, indicative of mast cell
      degranulation and/or secretion. The CGRP response could be completely blocked by
      pertussis toxin (2 microg/ml), indicating involvement of G(i) proteins.
      Application of MMC juice, obtained by C48/80 degranulation of MMC, to Fluo-4
      loaded DRG neurons induced in all neurons a rise in [Ca(2+)](i), indicative of
      activation. Degranulation of MMC by C48/80 in culture dishes containing Fluo-4
      loaded DRG neurons also caused activation of the DRG neurons. In conclusion,
      these results demonstrate a bidirectional cross-talk between cultured MMC and
      CGRP-IR DRG neurons in vitro. This indicates that such a communication may be the
      functional relevance for the close apposition between MMC and CGRP-IR nerve
      fibers in vivo.

PMID- 15016616
TI  - Different responsiveness of excitatory and inhibitory enteric motor neurons in
      the human esophagus to electrical field stimulation and to nicotine.
AB  - To compare electrical field stimulation (EFS) with nicotine in the stimulation of
      excitatory and inhibitory enteric motoneurons (EMN) in the human esophagus,
      circular lower esophageal sphincter (LES), and circular and longitudinal
      esophageal body (EB) strips from 20 humans were studied in organ baths. Responses
      to EFS or nicotine (100 microM) were compared in basal conditions, after N(G)
      nitro-l-arginine (l-NNA; 100 microM), and after l-NNA and apamin (1 microM). LES
      strips developed myogenic tone enhanced by TTX (5 microM) or l-NNA. EFS-LES
      relaxation was abolished by TTX, unaffected by hexamethonium (100 microM), and
      enhanced by atropine (3 microM). Nicotine-LES relaxation was higher than EFS
      relaxation, reduced by TTX or atropine, and blocked by hexamethonium. After l
      NNA, EFS elicited a strong cholinergic contraction in circular LES and EB, and
      nicotine elicited a small relaxation in LES and no contractile effect in EB.
      After l-NNA and apamin, EFS elicited a strong cholinergic contraction in LES and
      EB, and nicotine elicited a weak contraction amounting to 6.64 +/- 3.19 and 9.20
      +/- 5.51% of that induced by EFS. EFS elicited a contraction in longitudinal
      strips; after l-NNA and apamin, nicotine did not induce any response. Inhibitory
      EMN tonically inhibit myogenic LES tone and are efficiently stimulated both by
      EFS and nicotinic acetylcholine receptors (nAChRs) located in somatodendritic
      regions and nerve terminals, releasing nitric oxide and an apamin-sensitive
      neurotransmitter. In contrast, although esophageal excitatory EMN are efficiently
      stimulated by EFS, their stimulation through nAChRs is difficult and causes weak
      responses, suggesting the participation of nonnicotinic mechanisms in
      neurotransmission to excitatory EMN in human esophagus.

PMID- 15016617
TI  - Surfactant protein-d enhances phagocytosis and pulmonary clearance of respiratory
      syncytial virus.
AB  - Surfactant protein (SP)-D gene targeted (SP-D-/-) and wild-type mice were
      infected with respiratory syncytial virus (RSV) by intratracheal instillation.
      Decreased clearance of RSV was observed in SP-D-/- mice. Deficiency of SP-D was
      associated with increased inflammation and inflammatory cell recruitment in the
      lung after infection. In vitro, SP-D bound RSV-infected Vero cells. Binding was
      inhibited with ethylenediamine tetraacetic acid and maltose, suggesting that the
      carbohydrate recognition domain of SP-D recognizes RSV glycoproteins in a calcium
      dependent manner. SP-D bound specifically to the RSV proteins G and F.
      Phagocytosis of RSV by alveolar macrophages was reduced in the absence of SP-D in
      vivo, and SP-D enhanced phagocytosis of RSV by alveolar macrophages and
      neutrophils but not peritoneal macrophages in vitro. Oxygen radical production by
      alveolar macrophages from SP-D+/+ and SP-D-/- mice was decreased after RSV
      infection, and SP-D ameliorated the inhibitory effects of RSV on oxygen radical
      production by macrophages and neutrophils in vitro. Because the airway is the
      usual portal of entry for RSV and other respiratory pathogens, the local
      production of SP-D is likely to play a role in innate defense responses to
      inhaled viruses.

PMID- 15016618
TI  - Plasma membrane surface increases with tonic stretch of alveolar epithelial
      cells.
AB  - Cyclic stretch stimulates numerous responses in alveolar epithelial cells--some
      beneficial, some injurious--often through mechanosensitive membrane-associated
      proteins such as stretch-activated ion channels. Tonic stretch, in contrast,
      stimulates only some of these responses. In this study, we hypothesized that the
      plasma membranes of alveolar epithelial cells expand during tonic stretch, not
      only through cell surface unfolding, but also through recruitment of additional
      phospholipids. Such plasma membrane expansion would reduce membrane tension and
      decrease stimulation of mechanosensitive membrane proteins. Primary rat alveolar
      epithelial cells were isolated, cultured for 48 h, and stretched between 3 and
      40% change in basal membrane surface area. Gross changes in total cell surface
      area were obtained from stacks of thin fluorescent confocal micrographs; fine
      changes in plasma membrane area were measured via whole cell capacitance. A 1:1
      correspondence linked changes in basal and total cell surface area, implying that
      cell surface area change is dominated by stretch of the attached basal surface.
      We also found that plasma membrane increased proportionally with surface area
      within 5 min of tonic stretch, showing that, given time to occur, plasma membrane
      expansion via lipid recruitment preponderates the changes in cell surface shape
      and size demanded by stretching the cell. Similarly, in cells tonically stretched
      10 min to allow lipid insertion and then returned to an unstretched state,
      reabsorption of excess lipid occurred within 5 min. Finally, we found that lipid
      insertion induced by tonic stretch was unaffected by F-actin disassembly, ATP
      depletion, and calcium deprivation.

PMID- 15016619
TI  - Inhibiting polymerization: new therapeutic strategies for Z alpha1-antitrypsin
      related emphysema.
AB  - The Z variant of alpha1-antitrypsin (Z-AT) is present in 4% of Northern Europeans
      and is associated with liver cirrhosis and emphysema. Polymers accumulate within
      the hepatocyte and the subsequent plasma deficiency of AT renders the lungs
      susceptible to proteolysis and early onset emphysema. We have previously
      demonstrated that the Phe-Leu-Glu-Ala-Ile-Gly (6 mer) peptide specifically binds
      to Z-AT and inhibits polymerization. Here we present the first detailed
      biochemical study of the purified Z-AT-6 mer binary complex. Biochemical studies
      indicated that this complex was inactive as a proteinase inhibitor and the
      peptide annealed to beta-sheet A of Z-AT. Removal of the N-acetyl terminus of the
      6 mer peptide did not affect the peptide's ability to prevent polymer formation.
      However, the nonacetylated 6 mer-Z-AT complex dissociated at a rate 2.75 x faster
      than the acetylated 6 mer-Z-AT complex to yield an active inhibitor; Koff 5.5 +/-
      1.07 versus 2.0 +/- 0.25 10(6) s(-1), respectively. These biochemical data
      indicate a potential therapeutic approach whereby polymerization is prevented in
      the liver, with the gradual release of the peptide from the binary complex
      restoring proteinase inhibitory function within the tissues. Thus, it raises the
      novel prospect of ameliorating both the cirrhosis and the emphysema associated
      with Z-AT.

PMID- 15016620
TI  - p42/44 Mitogen-activated protein kinase regulated by p53 and nitric oxide in
      human pulmonary arterial smooth muscle cells.
AB  - Although nitric oxide (NO) is known to inhibit vascular smooth muscle cell
      proliferation, the subcellular molecular mechanisms involved with the inhibitory
      signal transduction pathways are uncertain. We investigated the effect of
      exogenous NO on cell proliferation and the expression of p53, p21, and
      phosphorylated p42/44 mitogen-activated protein kinase (MAPK) in human pulmonary
      arterial smooth muscle cells (HPASMC). Both S-nitroso-N-acetyl penicillamine and
      diethylenetriaminelNONOate dose-dependently suppressed [3H]-thymidine
      incorporation in cultured HPASMC, and induced the expression of p53 and p21
      protein. Further, the NO donors transiently increased the phosphorylation of
      p42/44 MAPK and then suppressed it. Although MAPK kinase inhibitors suppressed
      [3H]-thymidine incorporation by the cells, no significant change was observed in
      the expression of p53 and p21. The NO donors also suppressed the activation of
      p42/44 MAPK evoked by transient transfection of the wild-type p53 gene; however,
      they failed to suppress the activation of p42/44 MAPK in constitutive-active
      mutations of the Ras or Raf genes trasnsfected from HPASMC. These results
      indicate that exogenous NO is able to transiently activate p42/44 MAPK via the
      induction of p53, and then suppress it via inactivation of the Ras and Raf
      cascades.

PMID- 15016621
TI  - Perturbations in homocysteine-linked redox homeostasis in a murine model for
      hyperhomocysteinemia.
AB  - Elevated plasma levels of homocysteine are a risk factor for cardiovascular
      diseases, neural tube defects, and Alzheimer's disease. The transsulfuration
      pathway converts homocysteine to cysteine, and approximately 50% of the cysteine
      in glutathione is derived from homocysteine in human liver cells, which suggests
      the hypothesis that defects in the transsulfuration pathway perturb redox
      homeostasis. To test this hypothesis, we examined a murine model for
      hyperhomocysteinemia in which the gene encoding the first enzyme in the
      transsulfuration pathway, cystathionine beta-synthase (CBS), has been disrupted.
      Limited metabolite profiling and CBS expression studies in liver, kidney, and
      brain reveal tissue-specific differences in the response to Cbs disruption.
      Homozygous disruption of Cbs lowered cysteine concentration in all three organs.
      Glutathione concentration was diminished in liver and brain, thus affecting the
      redox buffering capacity in these organs, whereas the approximately twofold
      higher glutathione synthesis capacity in kidney helped preserve the glutathione
      pool size despite loss of the transsulfuration pathway in this organ. In
      contrast, disruption of a single Cbs allele elicited only minor redox
      perturbations. Furthermore, the Cbs+/- genotype did not confer a significant
      disadvantage compared with the Cbs+/+ genotype in hepatocytes challenged by
      oxidative stress from exposure to tertiary butylhydroperoxide. These studies
      provide evidence that homozygous disruption of Cbs perturbs redox homeostasis and
      reduces cysteine levels, raising the possibility that these changes may be
      important in the etiology of the clinical manifestations of CBS deficiency.

PMID- 15016622
TI  - Time course analysis of the mechanism by which silver inhibits active Na+ and Cl-
      uptake in gills of rainbow trout.
AB  - A time course analysis using (110m)Ag, (24)Na(+), and (36)Cl(-) examined gill
      silver accumulation and the mechanism by which waterborne silver (4.0 x 10(-8) M;
      4.3 microg/l) inhibits Na(+) and Cl(-) uptake in gills of freshwater rainbow
      trout. Analyses of gill and body fluxes allowed calculation of apical uptake and
      basolateral export rates for silver, Na(+), and Cl(-). To avoid changes in silver
      bioavailability, flow-through conditions were used to limit the buildup of
      organic matter in the exposure water. For both Na(+) and Cl(-) uptake, apical
      entry, rather than basolateral export, was the rate-limiting step; Na(+) and Cl(
      ) uptake declined simultaneously and equally initially, with both uptakes reduced
      by approximately 500 nmol.g(-1).h(-1) over the 1st h of silver exposure. There
      was a further progressive decline in Na(+) uptake until 24 h. Carbonic anhydrase
      activity was inhibited by 1 h, whereas Na(+)-K(+)-ATPase activity was not
      significantly inhibited until 24 h of exposure. These results indicate that
      carbonic anhydrase inhibition can explain the early decline in Na(+) and Cl(-)
      uptake, whereas the later decline is probably related to Na(+)-K(+)-ATPase
      blockade. Contrary to previous reports, gill silver accumulation increased
      steadily to a plateau. Despite the rapid inhibition of apical Na(+) and Cl(-)
      uptake, apical silver uptake (and basolateral export) increased until 10 h,
      before decreasing thereafter. Thus silver did not inhibit its own apical uptake
      in the short term. These results suggest that reduced silver bioavailability is
      the mechanism behind the pattern of peak and decline in gill silver accumulation
      previously reported for static exposures to silver.

PMID- 15016623
TI  - Increased heat loss affects hibernation in golden-mantled ground squirrels.
AB  - During hibernation at ambient temperatures (T(a)) above 0 degrees C, rodents
      typically maintain body temperature (T(b)) approximately 1 degrees C above T(a),
      reduce metabolic rate, and suspend or substantially reduce many physiological
      functions. We tested the extent to which the presence of an insulative pelage
      affects hibernation. T(b) was recorded telemetrically in golden-mantled ground
      squirrels (Spermophilus lateralis) housed at a T(a) of 5 degrees C; food intake
      and body mass were measured at regular intervals throughout the hibernation
      season and after the terminal arousal. Animals were subjected to complete removal
      of the dorsal fur or a control procedure after they had been in hibernation for 3
      4 wk. Shaved squirrels continued to hibernate with little or no change in minimum
      T(b), bout duration, duration of periodic normothermic bouts, and food intake
      during normothermia. Rates of rewarming from torpor were, however, significantly
      slower in shaved squirrels, and rates of body mass loss were significantly
      higher, indicating increased depletion of white adipose energy stores. An
      insulative pelage evidently conserves energy over the course of the hibernation
      season by decreasing body heat loss and reducing energy expenditure during
      periodic arousals from torpor and subsequent intervals of normothermia. This
      prolongs the hibernation season by several weeks, thereby eliminating the
      debilitating consequences associated with premature emergence from hibernation.

PMID- 15016624
TI  - Long-term hypoxia alters ovine fetal endocrine and physiological responses to
      hypotension.
AB  - Exposure to long-term hypoxia (LTH) results in altered cortisol responses in the
      ovine fetus. The present study was designed to test the hypothesis that LTH
      alters adrenal responsiveness to fetal hypotension. Pregnant ewes were maintained
      at high altitude (3,820 meters) from day 30 of gestation. Normoxic control and
      LTH fetuses were catheterized on day 132 of gestation. In the LTH group, maternal
      Po(2) was maintained comparable to that observed at altitude ( approximately 60
      mmHg) by nitrogen infusion through a tracheal catheter. On day 137, fetuses
      received a 5-h saline infusion followed by infusion of sodium nitroprusside to
      reduce fetal arterial pressure by 30-35% for 10 min. The study was repeated on
      day 139 of gestation with a continuous cortisol infusion (10 microg/min).
      Hypothalamic and pituitary tissues were collected from additional fetuses for
      assessment of glucocorticoid receptors. During the saline infusion in response to
      hypotension, plasma ACTH increased over preinfusion mean values in both groups (P
      < 0.05). Plasma cortisol concentrations increased in both groups concomitant with
      increased ACTH secretion. However, peak values in the LTH fetuses were
      significantly higher compared with controls (P < 0.05). During the cortisol
      infusion, the ACTH response was eliminated in both groups, with ACTH levels
      significantly lower in the LTH group (P < 0.05). Glucocorticoid receptor binding
      was not different between groups. These results demonstrate an enhanced cortisol
      response to hypotension in LTH fetuses that does not appear to be the result of
      an increase in negative feedback sensitivity of the hypothalamic-pituitary
      adrenal axis.

PMID- 15016625
TI  - Total heart volume variation throughout the cardiac cycle in humans.
AB  - Variations in total heart volume (atria plus ventricles) during a cardiac cycle
      affect efficiency of cardiac pumping. The goals of this study were to confirm the
      presence, extent, and contributors of total heart volume variation during the
      cardiac cycle in healthy volunteers with the use of MRI. Eight healthy volunteers
      were examined by MRI at rest. Changes in total cardiac volume throughout the
      cardiac cycle were calculated using the following methods: 1) planimetry derived
      from gradient-echo cine images and 2) flow-sensitive sequences to quantify flow
      in all vessels leading to and from the heart. The maximum total heart volume
      diminished during systole by 8.2 +/- 0.8% (SEM, range 4.8-10.6%) measured by
      method 1 and 8.8 +/- 1.0% (SEM, range 5.6-11.8%) by method 2 with good agreement
      between the methods [difference according to Bland-Altman analysis -0.6% +/- 1.0%
      (SD), intraclass correlation coefficient = 0.999]. This decrease in volume is
      predominantly explained by variation at the midcardiac level at the widest
      diameter of the heart with a left-sided predominance. In the short axis of the
      heart, the change of slice volume was proportional to the end-diastolic slice
      volume. The present study has confirmed the presence of total heart volume
      variation that predominantly occurs in the region of atrioventricular plane
      movement and on the left side. The total heart volume variation may relate to the
      efficiency of energy use by the heart to minimize displacement of surrounding
      tissue while accounting for the energy required to draw blood into the atria
      during ventricular systole.

PMID- 15016626
TI  - LPS-induced microvascular leukocytosis can be assessed by blue-field entoptic
      phenomenon.
AB  - Administration of low doses of Escherichia coli endotoxin [a lipopolysaccharide
      (LPS)] to humans enables the study of inflammatory mechanisms. The purpose of the
      present study was to investigate whether the blue-field entoptic technique may be
      used to quantify the increase in circulating leukocytes in the ocular
      microvasculature after LPS infusion. In addition, combined laser Doppler
      velocimetry and retinal vessel size measurement were used to study red blood cell
      movement. Twelve healthy male volunteers received 20 IU/kg iv LPS as a bolus
      infusion. Outcome parameters were measured at baseline and 4 h after LPS
      administration. In the first protocol (n = 6 subjects), ocular hemodynamic
      effects were assessed with the blue-field entoptic technique, the retinal vessel
      analyzer, and laser Doppler velocimetry. In the second protocol (n = 6 subjects),
      white blood cell (WBC) counts from peripheral blood samples and blue-field
      entoptic technique measurements were performed. LPS caused peripheral blood
      leukocytosis and increased WBC density in ocular microvessels (by 49%; P = 0.036)
      but did not change WBC velocity. In addition, retinal venous diameter was
      increased (by 9%; P = 0.008), but red blood cell velocity remained unchanged. The
      LPS-induced changes in retinal WBC density and leukocyte counts were
      significantly correlated (r = 0.87). The present study indicates that the blue
      field entoptic technique can be used to assess microvascular leukocyte
      recruitment in vivo. In addition, our data indicate retinal venous dilation in
      response to endotoxin.

PMID- 15016627
TI  - Reversible effects of isoproterenol-induced hypertrophy on in situ left
      ventricular function in rat hearts.
AB  - The aim of the present study was to evaluate specifically left ventricular (LV)
      function in rat hearts as they transition from the normal to hypertrophic state
      and back to normal. Either isoproterenol (1.2 and 2.4 mg.kg(-1).day(-1) for 3
      days; Iso group) or vehicle (saline 24 microl.day(-1) for 3 days; Sa group) was
      infused by subcutaneous implantation of an osmotic minipump. After verifying the
      development of cardiac hypertrophy, we recorded continuous LV pressure-volume (P
      V) loops of in situ ejecting hypertrophied rat hearts. The curved LV end-systolic
      P-V relation (ESPVR) and systolic P-V area (PVA) were obtained from a series of
      LV P-V loops in the Sa and Iso groups 1 h or 2 days after the removal of the
      osmotic minipump. PVA at midrange LV volume (PVA(mLVV)) was taken as a good index
      for LV work capability (13, 15, 20, 21). However, in rat hearts during
      remodeling, whether PVA(mLVV) is a good index for LV work capability has not been
      determined yet. In the present study, in contrast to unchanged end-systolic
      pressure at midrange LV volume, PVA(mLVV) was significantly decreased by
      isoproterenol treatment relative to saline; however, these measurements were the
      same 2 days after pump removal. Simultaneous treatment with a beta(1)-blocker,
      metoprolol (24 mg.kg(-1).day(-1)), blocked the formation of cardiac hypertrophy
      and thus PVA(mLVV) did not decrease. The reversible changes in PVA(mLVV) reflect
      precisely the changes in LV work capability in isoproterenol-induced
      hypertrophied rat hearts mediated by beta(1)-receptors. These results indicate
      that the present approach may be an appropriate strategy for evaluating the
      effects of antihypertrophic and antifibrotic modalities.

PMID- 15016628
TI  - Internal elastic lamina affects the distribution of macromolecules in the
      arterial wall: a computational study.
AB  - The internal elastic lamina (IEL), which separates the arterial intima from the
      media, affects macromolecular transport across the medial layer. In the present
      study, we have developed a two-dimensional numerical simulation model to resolve
      the influence of the IEL on convective-diffusive transport of macromolecules in
      the media. The model considers interstitial flow in the medial layer that has a
      complex entrance condition because of the presence of leaky fenestral pores in
      the IEL. The IEL was modeled as an impermeable barrier to both water and solute
      except for the fenestral pores that were assumed to be uniformly distributed over
      the IEL. The media were modeled as a heterogeneous medium composed of an array of
      smooth muscle cells (SMCs) embedded in a continuous porous medium representing
      the interstitial proteoglycan and collagen fiber matrix. Results for ATP and low
      density lipoprotein (LDL) demonstrate a range of interesting features of
      molecular transport and uptake in the media that are determined by considering
      the balance among convection, diffusion, and SMC surface reaction. The ATP
      concentration distribution depends strongly on the IEL pore structure because ATP
      fluid-phase transport is dominated by diffusion emanating from the fenestral
      pores. On the other hand, LDL fluid-phase transport is only weakly dependent on
      the IEL pore structure because convection spreads LDL laterally over very short
      distances in the media. In addition, we observe that transport of LDL to SMC
      surfaces is likely to be limited by the fluid phase (surface concentration less
      than bulk concentration), whereas ATP transport is limited by reaction on the SMC
      surface (surface concentration equals bulk concentration).

PMID- 15016629
TI  - Leukotriene B4 is an indirectly acting vasoconstrictor in guinea pig aorta via an
      inducible type of BLT receptor.
AB  - Leukotriene B(4) (LTB(4)) is a potent leukocyte chemoattractant recently
      implicated in the pathogenesis of atherosclerosis. The aim of this study was to
      assess the effects of LTB(4) on isolated aortic preparations. Rings of guinea pig
      aorta were challenged with LTB(4) for recording mechanical responses and
      measurements of mediator release, and LTB(4) receptor (BLT(1)) expression was
      assessed by RT-PCR. Single concentrations of LTB(4) induced concentration
      dependent contractions that were inhibited by treatment with antihistamines,
      indomethacin, or the thromboxane receptor antagonist BAYu3405 as well as by
      denudation of endothelium. In addition, LTB(4) increased the release of histamine
      and thromboxane in the bath. The contractions induced by LTB(4) were inhibited by
      either the unselective BLT receptor antagonist ONO-4057 or the selective BLT(1)
      receptor antagonist U-75302. Pretreatment with all-trans-retinoic acid enhanced
      the contractions and the release of histamine induced by LTB(4), without
      affecting either the contractions induced by histamine or the histamine release
      evoked by calcium ionophore A23187. Analysis by RT-PCR indicated the expression
      of a BLT(1) receptor in the guinea pig aorta and that BLT(1) receptor mRNA was
      upregulated after treatment with retinoic acid. These results suggest that LTB(4)
      contracts the guinea pig aorta via an indirect mechanism involving the release of
      histamine and thromboxane and that this BLT(1) receptor-mediated response can be
      upregulated by all-trans-retinoic acid.

PMID- 15016630
TI  - Cardiac sympathetic nerve stimulation does not attenuate dynamic vagal control of
      heart rate via alpha-adrenergic mechanism.
AB  - Complex sympathovagal interactions govern heart rate (HR). Activation of the
      postjunctional beta-adrenergic receptors on the sinus nodal cells augments the HR
      response to vagal stimulation, whereas exogenous activation of the presynaptic
      alpha-adrenergic receptors on the vagal nerve terminals attenuates vagal control
      of HR. Whether the alpha-adrenergic mechanism associated with cardiac
      postganglionic sympathetic nerve activation plays a significant role in
      modulation of the dynamic vagal control of HR remains unknown. The right vagal
      nerve was stimulated in seven anesthetized rabbits that had undergone sinoaortic
      denervation and vagotomy according to a binary white-noise signal (0-10 Hz) for
      10 min; subsequently, the transfer function from vagal stimulation to HR was
      estimated. The effects of beta-adrenergic blockade with propranolol (1 mg/kg
      i.v.) and the combined effects of beta-adrenergic blockade and tonic cardiac
      sympathetic nerve stimulation at 5 Hz were examined. The transfer function from
      vagal stimulation to HR approximated a first-order, low-pass filter with pure
      delay. beta-Adrenergic blockade decreased the dynamic gain from 6.0 +/- 0.4 to
      3.7 +/- 0.6 beats x min(-1) x Hz(-1) (P < 0.01) with no alteration of the corner
      frequency or pure delay. Under beta-adrenergic blockade conditions, tonic
      sympathetic stimulation did not further change the dynamic gain (3.8 +/- 0.5
      beats x min(-1) x Hz(-1)). In conclusion, cardiac postganglionic sympathetic
      nerve stimulation did not affect the dynamic HR response to vagal stimulation via
      the alpha-adrenergic mechanism.

PMID- 15016631
TI  - Asymmetric dimethylarginine upregulates LOX-1 in activated macrophages: role in
      foam cell formation.
AB  - Intimal infiltration by monocytes and accumulation of lipids represent a critical
      step in the formation of fatty streaks during atherogenesis. Because elevated
      plasma levels of asymmetric dimethylarginine (ADMA), a potent nitric oxide (NO)
      synthase (NOS) inhibitor, are prevalent in diverse cardiovascular diseases, the
      goal of this study was to examine the contribution of NO deficiency to macrophage
      lipid accumulation. Inhibition of NO synthesis in PMA-primed human monocytic
      leukemia HL-60 cells resulted in a twofold increase in expression of the receptor
      for oxidized LDL (OxLDL), termed the lectin-like OxLDL receptor (LOX-1). Blockade
      of inducible NOS in activated macrophages resulted in 1,1'-dioctadecyl-3,3,3',3'
      tetramethylindocarbocyanine perchlorate (DiI)-OxLDL accumulation and imparted
      macrophages with a foamy appearance as detected with oil-red O lipid staining.
      ADMA (15 microM) or N(G)-nitro-l-arginine methyl ester (l-NAME, 300 microM), both
      of which suppress inducible NOS activity, increased oil-red staining 1.9- and 2.8
      fold, respectively. Macrophages treated with ADMA or l-NAME showed a 2.4-fold
      increase in accumulation of DiI-OxLDL. To examine the role of LOX-1 in this
      process, we used small interfering RNA (siRNA) duplex-mediated LOX-1 gene
      silencing. LOX-1 expression was suppressed twofold by siRNA as shown by Western
      blot analysis. This suppression was associated with a two- to fourfold decrease
      in DiI-OxLDL uptake as identified by fluorescence microscopy and decreased oil
      red O staining by activated macrophages. In conclusion, accumulation of ADMA (a
      competitive inhibitor of NOS) in patients with chronic renal failure may be
      responsible for upregulation of LOX-1 receptor and increased OxLDL uptake, thus
      contributing to lipidosis and foam cell formation. The data illustrate an
      additional nonendothelial mode of antiatherogenic action of NO: prevention of LOX
      1 induction and lipid accumulation by macrophages.

PMID- 15016632
TI  - Angiotensin II receptor blockade corrects altered expression of gap junctions in
      vascular endothelial cells from hypertensive rats.
AB  - Blockade of the renin-angiotensin system improves the impaired endothelium
      dependent relaxations associated with hypertension and aging, partly through
      amelioration of endothelium-derived hyperpolarizing factor (EDHF)-mediated
      responses. Although the nature of EDHF is still controversial, recent studies
      have suggested the involvement of gap junctions in EDHF-mediated responses. Gap
      junctions consist of connexins (Cx), and we therefore tested whether the
      expression of Cx in vascular endothelial cells would be altered by hypertension
      and antihypertensive treatment. Spontaneously hypertensive rats (SHR) were
      treated with either the angiotensin II type 1 receptor antagonist candesartan or
      the combination of hydralazine and hydrochlorothiazide for 3 mo from 5 to 8 mo of
      age. Confocal laser scanning microscopy after immunofluorescent labeling with
      antibodies against Cx37, Cx40, and Cx43 revealed that the expression of Cx37 and
      Cx40 in endothelial cells of the mesenteric artery was significantly lower in SHR
      than in WKY. Treatment with candesartan, but not the combination of hydralazine
      and hydrochlorothiazide, significantly increased the expression of Cx37 and Cx40,
      although blood pressure decreased similarly. On the other hand, the expression of
      Cx43, though scarce and heterogeneous, was increased in SHR compared with WKY,
      and candesartan treatment lowered the expression of Cx43. These findings suggest
      that renin-angiotensin system blockade corrects the decreased expression of Cx37
      and Cx40 in arterial endothelial cells of hypertensive rats, partly independently
      of blood pressure, whereas the expression of Cx43 changed in the opposite
      direction. It remains to be clarified whether these changes in Cx37 and Cx40 are
      related to endothelial function, particularly that attributable to EDHF.

PMID- 15016633
TI  - Quantitative microcomputed tomography analysis of collateral vessel development
      after ischemic injury.
AB  - Transgenic mouse models are increasingly being used to investigate the functions
      of specific growth factors or matrix proteins to design therapeutic strategies
      for controlling blood vessel growth. However, the available methodologies for
      evaluating angiogenesis and arteriogenesis in these models are limited by animal
      size, user subjectivity, the power to visualize the three-dimensional vessel
      networks, or the capability to employ a vigorous quantitative analysis. In this
      study, we employed contrast-enhanced microcomputed tomography imaging to assess
      collateral development after induction of hindlimb ischemia in the mouse. The
      morphological parameters vessel volume, connectivity, number, thickness,
      thickness distribution, separation, and degree of anisotropy were evaluated in
      control and surgery limbs 0, 3, and 14 days postsurgery. Results indicate that
      the vascular volume of the surgically manipulated limb was reconstituted as early
      as 3 days after femoral artery excision through development of a series of highly
      connected, small caliber, closely spaced, and isotropically oriented collateral
      vessels. Parametric analyses were completed to assess the sensitivity of the
      calculated morphological parameters to variations in image binarization threshold
      and voxel size. Images taken at the 36-microm voxel size were found to be optimal
      for evaluating collateral vessel formation, whereas 8- to 16-microm voxel sizes
      were needed to resolve smaller vascular structures. This study demonstrates the
      utility of microcomputed tomography as a robust method for quantitative, three
      dimensional analysis of blood vessel networks. Whereas these initial efforts
      focused on the mouse hindlimb ischemia model, the developed techniques may be
      applied to a variety of model systems to investigate mechanisms of angiogenesis
      and arteriogenesis.

PMID- 15016634
TI  - Effect of aging on renal blood flow velocity during static exercise.
AB  - During exercise, activation of the sympathetic nervous system causes reflex renal
      vasoconstriction. The effects of aging on this reflex are poorly understood. This
      study evaluated the effects of age on renal vasoconstrictor responses to
      handgrip. Seven older (65 +/- 9 yr) and nine younger (25 +/- 2 yr) subjects were
      studied. Beat-by-beat analyses of changes in renal blood flow velocity (RBV;
      duplex ultrasound) were performed during two handgrip paradigms. Arterial blood
      pressure (BP) and heart rate were also measured, and an index of renal vascular
      resistance (RVR) was calculated (BP/RBV). In protocol 1, fatiguing handgrip [40%
      of maximal voluntary contraction (MVC)] caused a greater increase in RVR in the
      older subjects (old 90% +/- 15 increase, young 52% +/- 4 increase; P = 0.03).
      During posthandgrip circulatory arrest (isolates muscle metaboreflex), the
      increases in RVR were only approximately 1/2 of the increase seen at end grip. In
      protocol 2, 15-s bouts of handgrip at graded intensities led to increases in RVR
      in both subject groups. This effect was not seen until 50% MVC workload (P <
      0.05). RVR responses occurred early and were greater in older than in younger
      subjects at 50% MVC (32 +/- 6% vs. 16 +/- 5%; P = 0.02) and 70% MVC (39 +/- 11%
      vs. 24 +/- 8%; P = 0.02). Static exercise-induced renal vasoconstriction is
      enhanced with aging. Because the characteristics of this response suggest a
      predominant role for mechanoreceptor engagement, we hypothesize that
      mechanoreceptor responses are augmented with aging.

PMID- 15016635
TI  - Exercise-induced and nitroglycerin-induced myocardial preconditioning improves
      hemodynamics in patients with angina.
AB  - In humans, regional myocardial dysfunction during ischemia may be improved by
      ischemic and pharmacological preconditioning. We assessed the possibility that
      exercise- and nitroglycerin-induced myocardial preconditioning may improve global
      cardiac performance during subsequent efforts in patients with angina. Ten
      patients suffering from chronic stable angina and ten healthy volunteers were
      studied. Through impedance cardiography we assessed hemodynamics during a maximal
      exercise test, which was used as a baseline (Bas test) and considered as a
      preconditioning exercise. The Bas test was followed by a sequence of maximal
      efforts performed during the first (FWOP; 30 min after the Bas test) and second
      (SWOP; 48 h after the Bas test) windows of protection conferred by ischemic
      preconditioning. Hemodynamics was further evaluated during maximal exercise
      performed 48 h later with pharmacologically induced SWOP (PI-SWOP) obtained by
      transdermal administration of 10 mg of nitroglycerin. In the angina patients,
      FWOP, SWOP, and PI-SWOP delayed the time to ischemia and allowed them to achieve
      higher workloads compared with the Bas test. Furthermore, heart rate and cardiac
      output at peak exercise were enhanced during all the preconditioning phases with
      respect to the Bas test. However, only SWOP and PI-SWOP increased myocardial
      contractility and stroke volume. No changes in hemodynamics were detectable in
      the control subjects. This study demonstrates that in patients with stable
      angina, although hemodynamics during exercise can be positively improved during
      both FWOP and SWOP, differences exist between these two phases. Furthermore, the
      mimicking of exercise-induced SWOP by PI-SWOP with transdermal nitroglycerin may
      represent an important clinical aspect.

PMID- 15016636
TI  - In vivo and in vitro evidence for ACh-stimulated L-arginine uptake.
AB  - Whereas L-arginine is clearly recognized as the precursor for nitric oxide
      synthesis, and its entry into endothelial cells via system y(+) transport is
      established, few data exist regarding the acute regulation of this transport
      process. We specifically investigated the effect of ACh and isoprenaline (Iso) on
      L-arginine uptake in the human forearm and in cultured bovine aortic endothelial
      cells (BAEC). Sixteen healthy males were studied. During a steady-state intra
      arterial infusion of [(3)H]L-arginine (100 nCi/min), the effects of ACh (9.25 and
      37 microg/min), Iso (25-50 and 200 microg/min), and sodium nitroprusside (SNP) (1
      2 and 8 microg/min) on forearm plasma flow (FPF), L-[(3)H]arginine uptake, and L
      [(3)H]citrulline release were determined. In parallel experiments, the effects of
      ACh, Iso, and SNP on L-[(3)H]arginine uptake were studied in BAEC. L-Arginine
      uptake was inversely related to FPF (r = -0.50; P < 0.005). At a similar FPF (ACh
      56.82 +/- 9.25, Iso 58.49 +/- 5.56, SNP 57.92 +/- 4.96 ml/min; P = ns), intra
      arterial ACh significantly increased forearm uptake of L-[(3)H]arginine (54,655
      +/- 8,018 dpm/min), compared with that observed with either Iso (40,517.23 +/-
      6,841 dpm/min; P = 0.01) or SNP (36,816 +/- 4,650 dpm/min; P = 0.011). This was
      associated with increased ACh-induced L-[(3)H]citrulline release compared with
      Iso and SNP (P = 0.046). Similarly, in BAEC, ACh significantly increased L
      [(3)H]arginine uptake compared with control, Iso, or SNP (ACh 12.0 x 10(7) +/-
      1.83 x 10(7) vs. control 6.67 x 10(7) +/- 1.16 x 10(7) vs. Iso 7.35 x 10(7) +/-
      1.63 x 10(7) vs. SNP 6.01 x 10(7) +/- 1.11 x 10(7) fmol.min(-1).mg(-1) at 300
      micromol/l L-arginine; P = 0.043). Taken together, these data indicate that ACh
      stimulates L-arginine uptake in cultured endothelial cells and in human forearm
      circulation, indicating the potential for acute modulation of endothelial L
      arginine uptake.

PMID- 15016638
TI  - Effect of ATP-sensitive potassium channel inhibition on coronary metabolic
      vasodilation in humans.
AB  - OBJECTIVE: Experimental evidence indicates that ATP-sensitive potassium (K(ATP))
      channels regulate coronary blood flow (CBF). However, their contribution to human
      coronary metabolic vasodilation is unknown. METHODS AND RESULTS: Seventeen
      patients (12 male, age 58+/-10 years) were studied. Coronary hemodynamics were
      assessed before and after K(ATP) channel inhibition with subselective
      intracoronary glibenclamide infused at 40 microg/min in an angiographically
      smooth coronary artery after successful percutaneous coronary intervention to
      another vessel. Metabolic vasodilation was induced by 2 minutes of rapid right
      ventricular pacing. Coronary blood velocity was measured with a Doppler guidewire
      and CBF calculated. The time course of hyperemia was recorded for 2 minutes after
      pacing, and hyperemic volume was estimated from the area under the flow-versus
      time curve (AUC). Compared with vehicle infusion (0.9% saline), glibenclamide
      reduced resting CBF by 9% (P=0.04) and increased resting coronary vascular
      resistance (CVR) by 15% (P=0.03). Glibenclamide reduced pacing-induced peak CBF
      (50.8+/-6.8 versus 42.0+/-5.4 mL/min, P=0.001), peak CBF corrected for baseline
      flow (25.1+/-4.6 versus 17.6+/-3.1 mL/min, P=0.01), and increased minimum CVR
      (2.6+/-0.3 versus 3.1+/-0.3 mm Hg/mL per minute, P=0.002). Compared with vehicle,
      glibenclamide reduced total AUC at 2 minutes (3535+/-397 versus 3027+/-326 mL,
      P=0.001). CONCLUSIONS: Vascular K(ATP) channels appear to be involved in
      functional coronary hyperemia after metabolic stimulation.

PMID- 15016639
TI  - Regional body composition changes exhibit opposing effects on coronary heart
      disease risk factors.
AB  - OBJECTIVE: We investigated how regional body composition measured by dual-energy
      X-ray absorptiometry (DXA) is associated with risk factors for coronary heart
      disease (CHD) during weight reduction in obese women. METHODS AND RESULTS: Data
      were gathered from 128 overweight and obese women, aged 34 to 66 years, during a
      14-week intervention study with diet and exercise. Regional (arms, legs, and
      trunk) fat tissue (FT) and lean soft tissue (LST) were measured by DXA. The FT
      change in legs correlated negatively with changes in diastolic blood pressure,
      low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), and
      the number of CHD risk factors per subject (r=-0.17, P<0.05 to -0.26, P<0.01) in
      response to weight reduction, whereas truncal FT change had positive correlations
      with changes in triglycerides, LDL-C, FPG, and the number of CHD risk factors per
      subject (r=0.17, P<0.05 to 0.25, P<0.01). LST change in legs correlated
      negatively with changes in systolic blood pressure, FPG, and the number of risk
      factors (r=-0.20 to -0.21, P<0.05). CONCLUSIONS: Regional body composition
      information is important for evaluating improvement of CHD risk factors during
      weight-reduction treatment for obesity; differential FTs had opposing effects on
      CHD risk factors during weight reduction in obese women.

PMID- 15016640
TI  - Cell cycle-dependent regulation of smooth muscle cell activation.
AB  - OBJECTIVE: Although numerous diseases involving cellular proliferation are also
      associated with phenotypic changes, there has been little direct evidence that
      cell phenotype and the cell's response to external stimuli are modified during
      passage through different phases of the cell cycle. In this study, we demonstrate
      that an association exists between cell cycle progression and the expression of
      genes involved in cellular activation. METHODS AND RESULTS: Early cell cycle
      arrest of aortic smooth muscle cells was found to inhibit the tumor necrosis
      factor alpha (TNFalpha)-induced upregulation of vascular cell adhesion molecule-1
      and intercellular adhesion molecule-1, important markers of vascular cell
      activation in diseases such as atherosclerosis. A combination of
      immunocytochemistry and flow cytometry were used to document that TNFalpha
      induced adhesion molecule upregulation was inhibited during G1-phase and S-phase,
      but not in G0-phase or G2/M-phase cells. The inhibition of adhesion molecule
      expression occurred at the level of transcription, as demonstrated by changes in
      the patterns of mRNA and protein accumulation in cycling and arrested cells.
      CONCLUSIONS: Early cell cycle phases may represent states in which the responses
      to a variety of stimuli that influence cell fate can be modulated, and these
      observations may have novel implications for the prevention and/or therapy of
      vascular proliferative, neoplastic, and inflammatory diseases.

PMID- 15016641
TI  - Overexpression of uncoupling protein 2 in THP1 monocytes inhibits beta2 integrin
      mediated firm adhesion and transendothelial migration.
AB  - OBJECTIVE: Uncoupling protein 2 (UCP2) belongs to the mitochondrial anion carrier
      family and regulates production of reactive oxygen species in macrophages.
      Previous studies have shown that selective genetic disruption of UCP2 in bone
      marrow cells results in excess accumulation of monocytes/macrophages in the
      vascular wall of hypercholesterolemic low-density lipoprotein receptor-deficient
      (LDLR-/-) mice. Here we investigated whether UCP2 regulates expression of genes
      involved in monocyte recruitment. METHODS AND RESULTS: UCP2 overexpression in
      THP1 monocytes, which induced a 10-fold increase in mitochondrial UCP2 protein
      levels, reduced steady-state level of intracellular reactive oxygen species (ROS)
      and H2O2-induced ROS production. THP1 monocytes with UCP2 overexpression showed
      lower intracellular calcium levels and less H2O2-triggered intracellular calcium
      mobilization, and less protein and mRNA levels of beta2 integrins, most notably
      CD11b. UCP2 overexpression reduced beta2 integrin-mediated firm adhesion of
      monocytes to either tumor necrosis factor-alpha (TNF-alpha)-stimulated human
      aortic endothelial cell (HAEC) monolayers or to plates coated with intercellular
      adhesion molecule-1, not vascular cell adhesion molecule-1. UCP2 overexpression
      also inhibited cell spreading and actin polymerization in monocytes treated with
      TNF-alpha and monocyte chemoattractant protein-1 (MCP-1), and reduced MCP-1
      induced transmigration of monocytes through HAEC monolayers. CONCLUSIONS:
      Mitochondrial UCP2 in circulating monocytes may prevent excessive accumulation of
      monocytes/macrophages in the arterial wall, thereby reducing atherosclerotic
      plaque formation.

PMID- 15016643
TI  - Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the
      treatment of elderly patients with aggressive lymphomas: results of the NHL-B2
      trial of the DSHNHL.
AB  - Cyclophosphamide, doxorubicin, vincristine, and prednisone, given every 3 weeks
      (CHOP-21), is standard chemotherapy for aggressive lymphomas. To determine
      whether biweekly CHOP (CHOP-14) with or without etoposide is more effective than
      CHOP-21, 689 patients ages 61 to 75 years were randomized to 6 cycles of CHOP-21,
      CHOP-14, CHOEP-21 (CHOP plus etoposide 100 mg/m2 days 1-3), or CHOEP-14. Patients
      in the 2-weekly regimens received granulocyte colony-stimulating factor (G-CSF)
      starting from day 4. Patients received radiotherapy (36 Gy) to sites of initial
      bulky disease and extranodal disease. Complete remission rates were 60.1% (CHOP
      21), 70.0% (CHOEP-21), 76.1% (CHOP-14), and 71.6% (CHOEP-14). Five-year event
      free and overall survival rates were 32.5% and 40.6%, respectively, for CHOP-21
      and 43.8% and 53.3%, respectively, for CHOP-14. In a multivariate analysis, the
      relative risk reduction was 0.66 (P =.003) for event-free and 0.58 (P <.001) for
      overall survival after CHOP-14 compared with CHOP-21. Toxicity of CHOP-14 and
      CHOP-21 was similar, but CHOEP-21 and in particular CHOEP-14 were more toxic. Due
      to its favorable efficacy and toxicity profile, CHOP-14 should be considered the
      new standard chemotherapy regimen for patients ages 60 or older with aggressive
      lymphoma.

PMID- 15016644
TI  - Durable responses after ibritumomab tiuxetan radioimmunotherapy for CD20+ B-cell
      lymphoma: long-term follow-up of a phase 1/2 study.
AB  - We previously demonstrated that yttrium-90 (Y-90) ibritumomab tiuxetan (Zevalin)
      radioimmunotherapy (RIT) was safe and effective for relapsed or refractory
      CD20(+), B-cell, non-Hodgkin lymphoma (NHL). We now provide long-term follow-up
      data in responding patients based on International Workshop Response Criteria.
      Complete (CR), CR unconfirmed (CRu), and partial response (PR) rates were 29%,
      22%, and 22%, respectively (overall response rate 73%, 51% in CR/CRu). Mean time
      to progression (TTP) and duration of response (DR) in responders were 12.6 months
      and 11.7 months, respectively. At the maximum tolerated dose (0.4 mCi/kg [14.8
      MBq/kg]), TTP and DR in complete responders (CR/CRu) were 28.3 and 27.5 months,
      respectively. Nine patients (24% of responding patients) had a TTP of more than 3
      years. Long-term responders (> 5 years) have been identified. Ibritumomab
      tiuxetan produces durable responses in patients with indolent and diffuse large B
      cell lymphoma.

PMID- 15016645
TI  - Mitochondrial DNA sequence heterogeneity in circulating normal human CD34 cells
      and granulocytes.
AB  - We have reported marked mitochondrial DNA (mtDNA) sequence heterogeneity among
      individual CD34 clones from adult bone marrow (BM) and the age-dependent
      accumulation of mtDNA mutations in this mitotically active tissue. Here, we show
      direct evidence of clonal expansion of cells containing mtDNA mutations and that
      the mtDNA sequence may be easily determined by using peripheral blood (PB) as a
      CD34 cell source. Analysis of 594 circulating CD34 clones showed that 150 (25%)
      had mtDNA sequences different from the same donor's corresponding aggregate
      sequence. Examination of single granulocytes indicated that 103 (29%) from the
      same 6 individuals showed mtDNA heterogeneity, with sequences distinct from the
      corresponding aggregate tissue sequence and from the sequences of other single
      granulocytes. Circulating and BM CD34 cells showed virtually identical patterns
      of mtDNA heterogeneity, and the same changes were seen in progeny granulocytes as
      in their progenitors, indicating that blood sampling could be used in studies to
      determine whether mtDNA reflects an individual's cumulative or recent exposure to
      mutagens; as a marker of individual hematopoietic progenitors, stem cells, and
      their expansion; and for the detection of minimal residual disease in hematologic
      malignancies of CD34 cell origin.

PMID- 15016646
TI  - Identification of an HLA-A*0201-restricted CD8+ T-cell epitope SSp-1 of SARS-CoV
      spike protein.
AB  - A novel coronavirus, severe acute respiratory syndrome (SARS)-associated
      coronavirus (SARS-CoV), has been identified as the causal agent of SARS. Spike
      (S) protein is a major structural glycoprotein of the SARS virus and a potential
      target for SARS-specific cell-mediated immune responses. A panel of S protein
      derived peptides was tested for their binding affinity to HLA-A*0201 molecules.
      Peptides with high affinity for HLA-A*0201 were then assessed for their capacity
      to elicit specific immune responses mediated by cytotoxic T lymphocytes (CTLs)
      both in vivo, in HLA-A2.1/K(b) transgenic mice, and in vitro, from peripheral
      blood lymphocytes (PBLs) harvested from healthy HLA-A2.1(+) donors. SARS-CoV
      protein-derived peptide-1 (SSp-1 RLNEVAKNL), induced peptide-specific CTLs both
      in vivo (transgenic mice) and in vitro (human PBLs), which specifically released
      interferon-gamma (IFN-gamma) upon stimulation with SSp-1-pulsed autologous
      dendritic cells (DCs) or T2 cells. SSp-1-specific CTLs also lysed major
      histocompatibility complex (MHC)-matched tumor cell lines engineered to express S
      proteins. HLA-A*0201-SSp-1 tetramer staining revealed the presence of significant
      populations of SSp-1-specific CTLs in SSp-1-induced CD8(+) T cells. We propose
      that the newly identified epitope SSp-1 will help in the characterization of
      virus control mechanisms and immunopathology in SARS-CoV infection, and may be
      relevant to the development of immunotherapeutic approaches for SARS.

PMID- 15016647
TI  - Platelet deposition inhibits tissue factor activity: in vitro clots are
      impermeable to factor Xa.
AB  - Upon plaque rupture or vascular injury, tissue factor (TF) protein in the vessel
      wall becomes exposed to flowing blood, initiating a cascade of reactions
      resulting in the deposition of fibrin and platelets on the injured site.
      Paradoxically, the growing thrombus may act as a barrier, restricting the
      convective and diffusive exchange of substrates and coagulation products between
      the blood and reactive vessel wall, thus limiting the role TF plays in thrombus
      growth. In this study, various in vitro, platelet-fibrin clots were prepared on
      TF:VIIa-coated surfaces and the rate at which factor (F) X in the well-mixed clot
      supernatant permeates the clot and is converted to X(a) was monitored over
      several hours. The apparent diffusion coefficients of FX((a)) in fibrin and
      platelet-fibrin clots at 37 degrees C was 2.3 x 10(-7) and 5.3 x 10(-10)
      cm(2)/second, respectively, indicating that the mean time required for FX((a)),
      and likely FIX((a)), to diffuse 1 mm in a fibrin clot is 4 hours, and in the
      presence of platelets, 3.6 months. As complete human thrombotic occlusion has
      been observed within 10 minutes, an alternative source of procoagulant activity
      that can localize to the outer surface of growing thrombi, such as platelet
      factor XI or blood-borne TF, appears essential for rapid thrombus growth.

PMID- 15016648
TI  - Deletion of the major GATA1 enhancer HS 1 does not affect eosinophil GATA1
      expression and eosinophil differentiation.
AB  - Expression of the myeloid transcription factor GATA1 is required for early stages
      of eosinophil differentiation. Defining mechanisms regulating eosinophil GATA1
      expression will be important to understand development of this lineage. However,
      the cis-elements required for eosinophil GATA1 expression are not fully
      characterized. Previous work identified HS 1 as a major GATA1 enhancer, but its
      role in eosinophil GATA1 expression is unclear. Here, we show that mouse HS 1
      deletion leaves eosinophil GATA1 mRNA expression and eosinophil differentiation
      unaffected. Chromatin isolated from eosinophils and encompassing HS 1 is weakly
      enriched for acetylated histones H3/H4. HS 1 deletion does not alter eosinophil
      GATA1 locus histone acetylation. In eosinophils, GATA1 and CCAAT/enhancer binding
      protein epsilon (C/EBP epsilon) do not bind HS 1 but bind selectively a cis
      element in the first GATA1 intron. Thus, HS 1 is not required for eosinophil
      GATA1 expression. Instead, this study suggests a previously unsuspected role for
      the GATA1 intron element for this function.

PMID- 15016649
TI  - Comparative expressed sequence hybridization studies of hairy cell leukemia show
      uniform expression profile and imprint of spleen signature.
AB  - Comparative expressed sequence hybridization (CESH) to chromosomes is a recently
      introduced technique that identifies chromosomal regions corresponding to a
      differential gene expression. This technique is analogous to comparative genomic
      hybridization (CGH) that detects genomic imbalances. We applied CESH for the
      study of hairy cell leukemia (HCL), a disorder with a largely unknown expression
      profile. Twelve HCL cases with spleen involvement were investigated by CESH and
      CGH. While the latter analysis identified only a few nonrecurrent genomic
      imbalances, CESH showed a consistent expression profile in all HCL cases. In
      addition, pairing normal spleen with normal lymph node, a "spleen signature" was
      established by CESH. This signature most likely reflects the expression profile
      of spleen-specific components, such as the sinusoidal lining cells from the red
      pulp and the marginal zone B cells from the white pulp. Imprint of the spleen
      signature was found in the HCL expression profile, suggesting that HCL may
      originate from a particular B-cell subset present in these splenic components.
      Besides pairing HCL with normal lymph node and spleen, we identified an "HCL
      signature" comprising several chromosome regions with altered expression. The
      most significantly underexpressed regions include 3p24, 3p21, 3q13.3-q22, 4p16,
      11q23, 14q22-q24, 15q21-q22, 15q24-q25, and 17q22-q24; and 13q31 and Xq13.3-q21
      were the most significantly overexpressed. These regions possibly harbor genes
      related to the biology and the pathogenesis of HCL. Their identification warrants
      further molecular investigations.

PMID- 15016650
TI  - Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that
      regulates expression of inflammatory markers on activated endothelial cells.
AB  - We conducted a genome-wide analysis of genes that are regulated by vascular
      endothelial growth factor (VEGF) in endothelial cells and identified DSCR1 to be
      most significantly induced. Consistent with an antagonistic function on
      calcineurin (CnA) signaling, expression of DSCR1 in endothelial cells blocked
      dephosphorylation, nuclear translocation, and activity of nuclear factor of
      activated T cell (NFAT), a transcription factor involved in mediating CnA
      signaling. DSCR1 was not only induced by VEGF, but also by other compounds
      activating CnA signaling, suggesting a more general role for DSCR1 in activated
      endothelial cells. Transient expression of DSCR1 attenuated inflammatory marker
      genes such as tissue factor (TF), E-selectin, and Cox-2, identifying a previously
      unknown regulatory role for DSCR1 in activated endothelial cells. In contrast,
      knock-down of endogenous DSCR1 increased NFAT activity and stimulated expression
      of inflammatory genes on activated endothelial cells. Thus, the negative
      regulatory feedback loop between DSCR1 and CnA signaling in endothelial cells
      identified may represent a potential molecular mechanism underlying the
      frequently transient expression of inflammatory genes following activation of
      endothelial cells.

PMID- 15016651
TI  - Primary human CD34+ hematopoietic stem and progenitor cells express functionally
      active receptors of neuromediators.
AB  - Recently, overlapping molecular phenotypes of hematopoietic and neuropoietic
      cells were described in mice. Here, we examined primary human CD34(+)
      hematopoietic stem and progenitor cells applying specialized cDNA arrays, real
      time reverse-transcriptase-polymerase chain reaction (RT-PCR), and fluorescent
      activated cell sorter (FACS) analysis focusing on genes involved in neurobiologic
      functions. We found expression of vesicle fusion and motility genes, ligand- and
      voltage-gated ion channels, receptor kinases and phosphatases, and, most
      interestingly, mRNA as well as protein expression of G protein-coupled receptors
      of neuromediators (corticotropin-releasing hormone 1 [CRH 1] and CRH 2 receptors,
      orexin/hypocretin 1 and 2 receptors, GABAB receptor, adenosine A(2)B receptor,
      opioid kappa 1 and mu 1 receptors, and 5-HT 1F receptor). As shown by 2-color
      immunofluorescence, the protein expression of these receptors was higher in the
      more immature CD38(dim) than in the CD38(bright) subset within the CD34(+)
      population, and completely absent in fully differentiated blood cells, suggesting
      that those receptors play a role in developmentally early CD34(+) stem and
      progenitor cells. The intracellular concentration of cyclic adenosine
      monophosphate (cAMP) in CD34(+) cells was diminished significantly upon
      stimulation of either CRH or orexin receptors, indicating that those are
      functionally active and coupled to inhibitory G proteins in human hematopoietic
      cells. In conclusion, these findings suggest a molecular interrelation of
      neuronal and hematopoietic signaling mechanisms in humans.

PMID- 15016652
TI  - Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia.
AB  - Extracellular superoxide dismutase (SOD3) is the primary extracellular enzymatic
      scavenger of superoxide ((.)O(2)(-)). SOD3's expression is highest in the kidney,
      but its distribution and biologic functions there are unknown. To investigate the
      function of renal SOD3, we colocalized it with erythropoietin (EPO) to proximal
      tubules using in situ hybridization and immunohistochemistry. We then exposed
      wild-type (Wt) and SOD3 knock-out (KO) mice to hypoxia and found a late
      hematocrit response in the KO strain. EPO mRNA expression was attenuated in KO
      mice during the first 6 hours of hypoxia preceded at 2 hours by less accumulation
      of nuclear hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha) protein.
      Meanwhile KO mice exposed to hypoxia showed increases in renal mRNA for
      superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
      (NOX4) and early significant increases in glutathione disulfide
      (GSSG)/glutathione (GSH), a marker of oxidative stress, compared with Wt mice.
      Plasma nitrite/nitrate and renal 3-nitrotyrosine (3-NTyr), indicating
      peroxynitrite formation, increased later in hypoxia, and renal endothelial nitric
      oxide synthase protein induction was similar in both strains. These data show
      that hypoxic activation of HIF-1 alpha and its target gene EPO in mouse kidney is
      regulated closely by the oxidant/antioxidant equilibrium involving SOD3, thus
      identifying renal SOD3 as a regulatory element in the body's innate adaptation to
      hypoxia.

PMID- 15016653
TI  - CD28 disruption exacerbates inflammation in Tgf-beta1-/- mice: in vivo
      suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-beta1.
AB  - Tgf-beta1-/- mice develop a progressive, lethal, inflammatory syndrome, but
      mechanisms leading to the spontaneous activation of Tgf-beta1-/- T cells remain
      unclear. Here we show the disruption of CD28 gene expression accelerates disease
      in Tgf-beta1-/- mice, and we link this increase in severity to a reduction in the
      number of CD4+CD25+ regulatory T cells. CD4+CD25+ T cells develop normally in Tgf
      beta1-/- mice and display characteristic expression of cytotoxic T lymphocyte
      associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor
      receptor (GITR), alpha(E)beta7 integrin, and Foxp3. Adoptive transfer of Tgf
      beta1-/- splenocytes to Tgf-beta1+/+/Rag2-/- mice induced an autoimmune
      inflammatory disease with features similar to those of the Tgf-beta1-/-
      phenotype, and disease transfer was accelerated by the depletion of Tgf-beta1-/-
      CD4+CD25+ T cells from donor splenocytes. Cotransfer of Tgf- beta1-/- CD4+CD25+ T
      cells clearly attenuated disease in Rag2-/- recipients of CD25+-depleted Tgf
      beta1-/- spleen and lymph node cells, but suppression was incomplete when
      compared with Tgf-beta1+/+ CD4+CD25+ T cells. These data demonstrate that
      CD4+CD25+ regulatory T cells develop in complete absence of endogenous
      transforming growth factor-beta1 (TGF-beta1) expression and that autocrine TGF
      beta1 expression is not essential for these cells to suppress inflammation in
      vivo.

PMID- 15016655
TI  - Identification of one exon deletion of intestinal alkaline sphingomyelinase in
      colon cancer HT-29 cells and a differentiation-related expression of the wild
      type enzyme in Caco-2 cells.
AB  - Sphingomyelin (SM) metabolism in the gut has been implicated in colonic
      tumorigenesis. Intestinal alkaline sphingomyelinase (alk-SMase) hydrolyses SM in
      the intestinal content and at the brush border. The enzyme activity is decreased
      in the tissues of human colorectal tumours. This study examines whether site or
      chain-mutation of alk-SMase occurs in colon cancer HT-29 cells and Caco-2 cells.
      Total RNA was isolated and the cDNA of alk-SMase was amplified by RT-PCR. The
      size of the cDNA from HT-29 cells was smaller than that of the wild-type cDNA.
      DNA sequencing identified a deletion of exon 4 in alk-SMase cDNA in HT-29 cells.
      No mutation in genomic alk-SMase DNA from exon 3 to 5 was identified. The exon 4
      deletion was caused by a shift of RNA splice site in chromosome 17q25. In Caco-2
      cells, no mutation of alk-SMase cDNA was identified. Transient expression in COS
      7 cells showed that the enzyme from the cDNA in HT-29 cells had little alk-SMase
      activity whereas that in Caco-2 cells was as active as the wild-type alk-SMase.
      The deleted region included residue His353, which is predicted to form a
      substrate-binding site of alk-SMase. H353A substitution resulted in a protein
      with no alk-SMase activity. In monolayer cultured Caco-2 cells and HT-29 cells
      the alk-SMase activities were low. However, to culture the cells under polarizing
      conditions increased alk-SMase activity and reduced SM level in Caco-2 cells. The
      alk-SMase activity varied in parallel with alkaline phosphatase activity. In
      conclusion, we identified an inactive deletion in alk-SMase in HT-29 cells, and a
      differentiation-related expression of the enzyme in Caco-2 cells. The results
      provide a molecular mechanism related to previous findings of reduced alk-SMase
      activity in human colon cancers.

PMID- 15016654
TI  - Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like
      receptor ligand incompatibility against melanoma and renal cell carcinoma cells.
AB  - Cellular inactivation through killer immunoglobulin-like receptors (KIRs) may
      allow neoplastic cells to evade host natural killer (NK) cell-mediated immunity.
      Recently, alloreactive NK cells were shown to mediate antileukemic effects
      against acute myelogenous leukemia (AML) after mismatched transplantation, when
      KIR ligand incompatibility existed in the direction of graft-versus-host disease
      (GVHD). Therefore, we investigated whether solid tumor cells would have similar
      enhanced susceptibility to allogeneic KIR-incompatible NK cells compared with
      their KIR-matched autologous or allogeneic counterparts. NK populations enriched
      and cloned from the blood of cancer patients or healthy donors homozygous for HLA
      C alleles in group 1 (C-G1) or group 2 (C-G2) were tested in vitro for
      cytotoxicity against Epstein-Barr virus-transformed lymphoblastic cell lines (EBV
      LCLs), renal cell carcinoma (RCC), and melanoma (MEL) cells with or without a
      matching KIR-inhibitory HLA-C ligand. Allogeneic NK cells were more cytotoxic to
      tumor targets mismatched for KIR ligands than their KIR ligand-matched
      counterparts. Bulk NK populations (CD3(-)/CD2(+)/CD56(+)) expanded 10(4)-fold
      from patients homozygous for C-G1 or C-G2 had enhanced cytotoxicity against KIR
      ligand-mismatched tumor cells but only minimal cytotoxicity against KIR ligand
      matched targets. Further, NK cell lines from C-G1 or C-G2 homozygous cancer
      patients or healthy donors expanded but failed to kill autologous or KIR-matched
      MEL and RCC cells yet had significant cytotoxicity (more than 50% lysis at 20:1
      effector-target [E/T] ratio) against allogeneic KIR-mismatched tumor lines. These
      data suggest immunotherapeutic strategies that use KIR-incompatible allogeneic NK
      cells might have superior antineoplastic effects against solid tumors compared
      with approaches using autologous NK cells.

PMID- 15016657
TI  - Induction of orphan nuclear receptor Nur77 gene expression and its role in
      cadmium-induced apoptosis in lung.
AB  - Cadmium is an environmentally widely dispersed and highly toxic heavy metal that
      has been classified as a human carcinogen. Using the suppression subtractive
      hybridization technique, we identified previously 29 cadmium-inducible genes,
      primarily involved in inflammation, cell survival and apoptosis. Among these
      genes, we are particularly interested in Nor-1, because this gene belongs to the
      Nur77 family, which plays a key role in the apoptotic processes of a variety of
      cells and tissues, including the lung. In the present study, we characterized the
      induction of the Nur77 family genes in the lungs after cadmium exposure. Nur77,
      Nor-1 and Nurr1 were all induced after cadmium treatment in a dose- and time
      dependent manner in WI-38 and A549 lung cell lines. Treatment with inhibitors of
      signaling pathways, such as PD98059 and H89, almost completely blocked the
      expression of Nur77, indicating that the extracellular signal-regulated kinase
      and protein kinase A signaling pathways are important in cadmium-induced Nur77
      expression. When a plasmid encoding dominant-negative Nur77 was transfected into
      A549 cells, cadmium-induced apoptotic changes, such as chromosomal condensation
      and Bax expression, were significantly reduced, suggesting that the expression of
      Nur77 plays an important role in cadmium-induced apoptosis. Furthermore, the
      number of apoptotic cells and the expression of Nur77 was increased in lung
      tissues collected from cadmium-treated (30 micromol/kg body wt) Wistar rats.
      Taken together, these results demonstrate that cadmium induces the expression of
      Nur77 family genes, leading to apoptosis in lung cells, which may cause pulmonary
      toxicity in response to cadmium exposure.

PMID- 15016658
TI  - Ingestion of an isothiocyanate metabolite from cruciferous vegetables inhibits
      growth of human prostate cancer cell xenografts by apoptosis and cell cycle
      arrest.
AB  - Epidemiological surveys indicate that intake of cruciferous vegetables is
      inversely related to prostate cancer incidence, although the responsible dietary
      factors have not been identified. Our studies demonstrated that exposure of human
      prostate cancer cells in culture to the N-acetylcysteine (NAC) conjugate of
      phenethyl isothiocyanate (PEITC-NAC), the major metabolite of PEITC that is
      abundant in watercress, inhibited proliferation and tumorigenesis. The PEITC-NAC
      is known to mediate cytoprotection at initiation of carcinogenesis. The relevance
      of PEITC-NAC in diets on the growth of prostate tumor cells has been evaluated in
      immunodeficient mice with xenografted tumors of human prostate cancer PC-3 cells.
      The daily PEITC-NAC (8 micromol/g) supplemented diet group showed a significant
      reduction in tumor size in 100% of the mice during the 9-week treatment period.
      Tumor weight at autopsy was reduced by 50% compared with mice on the diet without
      PEITC-NAC (P = 0.05). Mitosis and in vivo 5-bromo-2'-deoxyuridine labeled
      proliferating cells were reduced in these tumors. The PEITC-NAC diet up-regulated
      the inhibitors of cyclin-dependent kinases p21WAF-1/Cip-1 and p27Kip1, and
      reduced the expression of cyclins D and E, indicating they were potential
      molecular targets. As a result, phosphorylated Rb was significantly decreased and
      the G1- to S-phase transition retarded. The treated tumors also showed a
      significant increase in apoptosis as determined by in situ end-labeling, and by
      poly ADP-ribose polymerase cleavage. This study demonstrates the first in vivo
      evidence of dietary PEITC-NAC inhibiting tumorigenesis of prostate cancer cells.
      PEITC-NAC may prevent initiation of carcinogenesis and modulate the post
      initiation phase by targeting cell cycle regulators and apoptosis induction.

PMID- 15016659
TI  - Both suboptimal and elevated vitamin intake increase intestinal neoplasia and
      alter crypt fission in the ApcMin/+ mouse.
AB  - The effects of vitamin deficiency on intestinal cancer are unclear, and even less
      is known about the consequences of excessive intake. We therefore investigated
      the actions of altered vitamin content on intestinal polyp development, cell
      proliferation and crypt fission in a mouse model of neoplasia. Ninety multiple
      intestinal neoplasia (ApcMin/+) mice and 90 wild-type littermates, 4 weeks old,
      were divided into six groups and fed either a control semi-synthetic diet, or the
      semi-synthetic diet with the vitamin content lowered to a third of the RDA or the
      semi-synthetic diet with the vitamin content increased 5-fold (except for retinol
      and folate, which were doubled). The number and size of polyps in the small and
      large intestines were scored after 8 weeks on the diets, as was cell
      proliferation (native mitoses per crypt) and crypt fission. The small intestines
      of the low and high vitamin groups were heavier than the controls. There were
      significantly more polyps and the tumour burden was higher in both the low and
      the high vitamin groups (P < 0.02). Proliferation was slightly reduced by the
      vitamin alteration and crypt fission was significantly increased in the ApcMin/+
      mice when compared with the wild-type (P < 0.001). Fission indices were decreased
      by vitamin alteration in the small intestine, and increased in the colon, but
      only in the ApcMin/+ mice. The effects of vitamin alteration on polyp number were
      most pronounced in the proximal intestine, which is also the site of maximum
      crypt fission. Both vitamin deficiency and over-supplementation can markedly
      enhance polyp number and tumour burden.

PMID- 15016660
TI  - Anthocyanins induce cell cycle perturbations and apoptosis in different human
      cell lines.
AB  - To investigate the mechanistic basis for the biological properties of
      anthocyanins, two aglycone anthocyanins [delphinidin (DY) and cyanidin (CY)] were
      used to examine their effects on cell cycle progression and on induction of
      apoptosis in human cancer cells (uterine carcinoma and colon adenocarcinoma
      cells) and in normal human fibroblasts. These compounds differ in the number and
      position of hydroxyl groups on the beta ring in the molecular structure. Cellular
      uptake of anthocyanins was confirmed by HPLC analysis and no metabolites were
      detected. The clonogenic assay showed that CY induces a dose-dependent growth
      inhibitory effect only in fibroblasts. This effect was confirmed by flow
      cytometric analysis, showing a significant reduction of cells in S phase. In
      contrast, DP inhibited cell growth in normal and tumour cell lines. This event is
      accompanied in fibroblasts by an accumulation of cells in the S phase suggesting
      a block in the transition from S to G2 phase. On the other hand, in tumour cell
      lines we observed a reduction of cells in G1 phase, paralleled by the appearance
      of a fraction of cells with a hypodiploid DNA content, thus demonstrating an
      apoptotic effect by DP. The occurrence of apoptosis induced by DP was confirmed
      by morphological and biochemical features, including nuclear condensation and
      fragmentation, annexin V staining, DNA laddering and poly(ADP-ribose) polymerase
      1-proteolysis. Furthermore, the mitochondrial membrane potential of apoptotic
      cells after treatment with DP was significantly lost. The different effects
      exerted by DP as compared with CY suggest that the presence of the three hydroxyl
      groups on the beta ring in the molecular structure of DP may be important for its
      greater biological activity.

PMID- 15016661
TI  - The use of N-t-butyl hydroxylamine for radioprotection in cultured cells and
      mice.
AB  - Exposure of cells to ionizing radiation leads to formation of reactive oxygen
      species (ROS) that are associated with radiation-induced cytotoxicity. Therefore,
      compounds that scavenge ROS may confer radioprotective effects. Recently, it has
      been shown that the decomposition product of the spin-trapping agent alpha-phenyl
      N-t-butylnitrone (PBN), N-t-butyl hydroxylamine (NtBHA), mimics PBN and is much
      more potent in delaying ROS-associated senescence. We investigated the protective
      role of NtBHA against ionizing radiation in U937 cells and mice. Viability and
      cellular oxidative damage reflected by lipid peroxidation, oxidative DNA damage
      and protein oxidation were significantly lower in the cells treated with NtBHA
      when the cells were exposed to ionizing radiation. The modulation of cellular
      redox status was more pronounced in control cells compared with NtBHA-treated
      cells. The ionizing radiation-induced mitochondrial damage reflected by the
      altered mitochondrial permeability transition, the increase in the accumulation
      of ROS and the reduction of ATP production was significantly higher in control
      cells compared with NtBHA-treated cells. NtBHA administration before irradiation
      at 5 mg/kg daily for 2 weeks provided substantial protection against killing and
      oxidative damage to mice exposed to whole-body irradiation. These data indicate
      that NtBHA may have great application potential as a new class of in vivo, non
      sulfur containing radiation protector.

PMID- 15016662
TI  - Guidelines from the British Hypertension Society.

PMID- 15016663
TI  - Congenital heart disease.

PMID- 15016664
TI  - Intimate partner violence.

PMID- 15016665
TI  - Campaign to revitalise academic medicine kicks off.

PMID- 15016666
TI  - Targets, inspections, and transparency.

PMID- 15016670
TI  - Children say they are not involved enough in their treatment.

PMID- 15016671
TI  - Complaints against doctors in child protection work have increased fivefold.

PMID- 15016673
TI  - Oestrogen only arm of women's health initiative trial is stopped.

PMID- 15016678
TI  - Federal funding for comparative drug studies not in US budget.

PMID- 15016681
TI  - Research groups fail to reach agreement on protocol for treatment trials for CJD.

PMID- 15016684
TI  - US-Australia trade deal strengthens power of Australian drugs industry.

PMID- 15016682
TI  - Regulatory body proposed for acupuncturists and herbalists.

PMID- 15016685
TI  - US stroke legislation is revised after BMJ airs controversy.

PMID- 15016687
TI  - Developing countries could derail global anti-obesity plan.

PMID- 15016691
TI  - Discharge destination and length of stay: differences between US and English
      hospitals for people aged 65 and over.

PMID- 15016692
TI  - Use of hospitals, physician visits, and hospice care during last six months of
      life among cohorts loyal to highly respected hospitals in the United States.
AB  - OBJECTIVE: To evaluate the use of healthcare resources during the last six months
      of life among patients of US hospitals with strong reputations for high quality
      care in managing chronic illness. DESIGN: Retrospective cohort study based on
      claims data from the US Medicare programme. PARTICIPANTS: Cohorts receiving most
      of their hospital care from 77 hospitals that appeared on the 2001 US News and
      World Report "best hospitals" list for heart and pulmonary disease, cancer, and
      geriatric services. MAIN OUTCOME MEASURES: Use of healthcare resources in the
      last six months of life: number of days spent in hospital and in intensive care
      units; number of physician visits; percentage of patients seeing 10 or more
      physicians; percentage enrolled in hospice. Terminal care: percentage of deaths
      occurring in hospital; percentage of deaths occurring in association with a stay
      in an intensive care unit. RESULTS: Extensive variation in each measure existed
      among the 77 hospital cohorts. Days in hospital per decedent ranged from 9.4 to
      27.1 (interquartile range 11.6-16.1); days in intensive care units ranged from
      1.6 to 9.5 (2.6-4.5); number of physician visits ranged from 17.6 to 76.2 (25.5
      39.5); percentage of patients seeing 10 or more physicians ranged from 16.9% to
      58.5% (29.4-43.4%); and hospice enrollment ranged from 10.8% to 43.8% (22.0
      32.0%). The percentage of deaths occurring in hospital ranged from 15.9% to 55.6%
      (35.4-43.1%), and the percentage of deaths associated with a stay in intensive
      care ranged from 8.4% to 36.8% (20.2-27.1%). CONCLUSION: Striking variation
      exists in the utilisation of end of life care among US medical centres with
      strong national reputations for clinical care.

PMID- 15016693
TI  - Getting a grip on clinical variations in hospital services.

PMID- 15016694
TI  - Association between depression and abuse by partners of women attending general
      practice: descriptive, cross sectional survey.
AB  - OBJECTIVE: To explore the association between depression and physical, emotional,
      and sexual abuse by partners or ex-partners of women attending general practice.
      DESIGN: Descriptive, cross sectional survey. SETTING: 30 general practitioners in
      Victoria, Australia. PARTICIPANTS: 1257 consecutive female patients. MAIN OUTCOME
      MEASURES: Some type of abuse in an adult intimate relationship (composite abuse
      scale), depression (Beck depression inventory or Edinburgh postnatal depression
      scale), and physical health (SF-36). RESULTS: 18.0% (218/1213) of women scored as
      currently probably depressed and 24.1% (277/1147) had experienced some type of
      abuse in an adult intimate relationship. Depressed women were significantly more
      likely to have experienced severe combined abuse than women who were not
      depressed after adjusting for other significant sociodemographic variables (odds
      ratio 5.8, 95% confidence interval 2.8 to 12.0). These variables included not
      being married, having a poor education, being on a low income, being unemployed
      or receiving a pension, pregnancy status, or being abused as a child. CONCLUSION:
      Physical, emotional, and sexual abuse are strongly associated with depression in
      women attending general practice. Doctors should sensitively ask depressed women
      about their experiences of violence and abuse in intimate relationships. Research
      into depression should include measures of partner abuse in longitudinal and
      intervention studies.

PMID- 15016695
TI  - Ocular and systemic causes of retinopathy in patients without diabetes mellitus.

PMID- 15016696
TI  - Pitfalls in the diagnosis of phaeochromocytoma.

PMID- 15016697
TI  - Cessation interventions in routine health care.

PMID- 15016699
TI  - Random drug testing in schools fails screening criteria.

PMID- 15016698
TI  - British Hypertension Society guidelines for hypertension management 2004 (BHS
      IV): summary.

PMID- 15016700
TI  - Follow up of hypertension by family practitioners: select sample and absolute
      risk of cardiovascular disease.

PMID- 15016701
TI  - Follow up of hypertension by family practitioners: technique should be taught at
      school.

PMID- 15016702
TI  - Results of eVALuate study of hysterectomy techniques: laparoscopic hysterectomy
      may yet have a bright future.

PMID- 15016703
TI  - Results of eVALuate study of hysterectomy techniques: degree of pain cannot be
      commented on.

PMID- 15016704
TI  - Results of eVALuate study of hysterectomy techniques: conversion to open surgery
      should not be regarded as major complication.

PMID- 15016705
TI  - Biopsy specimens should be legally defined as donations.

PMID- 15016706
TI  - Results of eVALuate study of hysterectomy techniques: high rate of complications
      needs explanation.

PMID- 15016707
TI  - ABC of eyes: Injury to the eye: eye padding is not recommended for corneal
      abrasions.

PMID- 15016708
TI  - ABC of eyes: Injury to the eye: ABC should incorporate evidence based medicine.

PMID- 15016709
TI  - ABC of eyes: Injury to the eye: orbital injuries should not be considered in
      isolation.

PMID- 15016716
TI  - Blowing the whistle on review articles.

PMID- 15016715
TI  - The fallacy of "light" cigarettes.

PMID- 15016717
TI  - Central nervous and metabolic effects of intranasally applied leptin.
AB  - In obesity, due to the resistance of leptin receptors at the blood brain barrier,
      increased peripheral leptin levels cannot act appropriately at brain sites
      relevant for appetite regulation. In this study, we focused on the intranasal
      application of leptin. This mode of administration provides a promising tool for
      a direct access of peptides to the brain by circumventing the blood brain
      barrier. Male Wistar rats were treated daily with 0.1 or 0.2 mg/kg leptin
      intranasally for 4 wk. Compared with controls, leptin-treated animals gained
      significantly less weight and exhibited significantly reduced food and water
      intake. Corticotropin-releasing factor mRNA expression in the paraventricular
      nucleus showed a tendency for up-regulation by leptin; neuropeptide Y mRNA
      expression in the arcuate nucleus was decreased. In the central nucleus of the
      amygdala, corticotropin-releasing factor mRNA was significantly elevated in
      leptin-treated animals, suggesting a role in affective and/or emotional aspects
      of food intake. Serum leptin levels were unchanged, indicating a direct action of
      leptin in the central nervous system without prior access to the periphery. The
      intranasal application thus represents a useful tool to administer leptin in a
      noninvasive way with rapid permeation into the central nervous system.

PMID- 15016718
TI  - Suppression of growth hormone (GH) Janus tyrosine kinase 2/signal transducer and
      activator of transcription 5 signaling pathway in transgenic mice overexpressing
      bovine GH.
AB  - High continuous GH levels in vivo produce desensitization of the Janus tyrosine
      kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5)
      pathway of GH signaling in the liver. To evaluate the mechanisms involved in this
      desensitization, transgenic mice overexpressing bovine GH were used. In these
      animals, GH receptor and membrane-associated JAK2 kinase are increased 4.5- and 6
      fold, respectively. However, JAK2. STAT5a and -5b do not become tyrosine
      phosphorylated in response to GH stimulus, nor are these STAT proteins recruited
      to membranes, suggesting that they cannot bind to the receptor. The content of
      the suppressor cytokine-inducible src homology 2 (SH2)-containing protein (CIS),
      both total and membrane-associated, is markedly increased in the liver of GH
      transgenic mice. This could account for the inhibition of STAT5 activation,
      because CIS competes with STAT5 for GH receptor docking sites. Existence of an
      alternative mechanism of negative regulation of this signaling pathway by
      chronically elevated GH levels is suggested by the low level of JAK2
      phosphorylation that transgenic mice exhibit. Whereas total SH2-containing
      phosphatase 2 (SHP-2) content is the same in both kinds of mice, membrane
      associated SHP-2 protein levels increase 4.5-fold in GH transgenic animals. This
      could explain the dramatic inhibition of JAK2 phosphotyrosine level, thus
      contributing to the suppression of GH signaling observed in these transgenic
      mice.

PMID- 15016719
TI  - The metabolic and cardiovascular effects of hyperthyroidism are largely
      independent of beta-adrenergic stimulation.
AB  - Hyperthyroidism and states of adrenergic hyperactivity have many common clinical
      features, suggesting similar pathogenic mechanisms of action. The widespread use
      of beta-adrenergic receptor (betaAR) antagonists (beta-blockers) to treat
      hyperthyroidism has led to the belief that the physiological consequences of
      thyroid hormone (TH) excess are mediated in part via catecholamine signaling
      through betaARs. To test this hypothesis, we compared the response to TH excess
      in mice lacking the three known betaARs (beta-less) vs. wild-type (WT) mice.
      Although beta-less mice had a lower heart rate at baseline in comparison to WT
      mice, the metabolic and cardiovascular responses to hyperthyroidism were
      equivalent in both WT and beta-less mice. These data indicate that the metabolic
      and cardiovascular effects of TH excess are largely independent of betaARs. These
      findings suggest that the efficacy of clinical treatment of hyperthyroidism with
      beta-blockers is due to antagonism of sympathetic signaling, and that this
      process functions independently of TH action.

PMID- 15016720
TI  - Effect of ageing on hormone secretion and follicular dynamics in sheep with and
      without the Booroola gene.
AB  - It has been suggested that ewes carrying the Booroola gene (Fec(B)) consistently
      ovulate more follicles because they recruit more primordial follicles and/or have
      a lower rate of atresia. If the former is correct, the pool of follicles would be
      depleted sooner in Fec(B) animals. We have studied follicular dynamics and
      endocrine function during follicular and early luteal phases of the estrous cycle
      of older ewes with or without the fecundity gene and compared this data with data
      obtained 6 yr previously in the same animals. Older sheep carrying the Booroola
      gene maintained a significantly higher ovulation rate than noncarrier ewes [4.2
      +/- 0.8 vs. 2.2 +/- 0.6 corpora lutea (CL), respectively; P < 0.05], and in
      keeping with data from young animals, both ovulatory follicles and CL (4.7 +/-
      0.3 vs. 6.9 +/- 0.7 mm and 12.8 +/- 0.5 vs. 16.7 +/- 0.8 mm, respectively) were
      smaller than those of noncarrier ewes (P < 0.05). The interval from luteolysis to
      the onset of the LH surge increased with age in all the animals (from 52.0 +/-
      8.0 to 67.0 +/- 7.5 h in gene carrier sheep and from 56.0 +/- 2.0 to 79.5 +/- 9.6
      h in noncarrier sheep, P < 0.05). The concentration of estradiol and inhibin A in
      the early luteal phase was lower in older noncarrier ewes (P = 0.08 and P < 0.05,
      respectively), and the level of inhibin A was inversely related to the level of
      FSH in aged sheep of both genotypes (P < 0.0001). In contrast, the number of
      developing follicles in older ewes of both genotypes was similar to the number
      found in younger ewes, suggesting that increased ovulation rate in sheep carrying
      the Fec(B) mutation is related to a reduced rate of atresia.

PMID- 15016722
TI  - Ligand-selective dissociation of activation and internalization of the
      parathyroid hormone (PTH) receptor: conditional efficacy of PTH peptide
      fragments.
AB  - G protein-coupled receptors (GPCRs) mediate the action of many hormones,
      cytokines, and sensory and chemical signals. It is generally thought that
      receptor desensitization and internalization require occupancy and activation of
      the GPCR. PTH and PTHrP receptor (PTH1R) belongs to GPCR class B and is the major
      regulator of extracellular calcium homeostasis. Using kidney distal convoluted
      tubule cells transfected with a human PTH1R/enhanced green fluorescent protein
      fusion protein, quantitative, real-time fluorescence microscopy was used to
      analyze receptor internalization. In these cells, which are the target of the
      calcium-sparing action of PTH, PTH(1-34) activated adenylyl cyclase (AC) and
      phospholipase C (PLC) and PTH1R endocytosis. PTH(1-31), however, stimulated AC
      and PLC but not PTH1R endocytosis. Conversely, PTH(7-34) rapidly stimulated PTH1R
      internalization without activating AC or PLC. PTH(2-34) and (3-34) caused PTH1R
      internalization intermediate between PTH(1-34) and (7-34). PTH1R sequestration
      occurred in a dynamin- and clathrin-dependent manner. Directly activating AC
      inhibited PTH1R internalization in response to PTH(7-34). PTH1R endocytosis was
      sensitive to protein kinase C inhibition. PTH(1-34), (7-34), and (1-31) evoked
      PTH1R phosphorylation. Removal of most of the C terminus of the PTH1R eliminated
      receptor phosphorylation and the cAMP/protein kinase C sensitivity of
      internalization. PTH(1-34) and (7-34) internalized the truncated PTH1R with
      identical kinetics, and the response was unaffected by forskolin. Thus, the PTH1R
      C terminus contains regulatory sequences that are involved in, but not required
      for, PTH1R internalization. The results demonstrate that receptor activation and
      internalization can be selectively dissociated.

PMID- 15016721
TI  - Peptide YY3-36 inhibits food intake in mice through a melanocortin-4 receptor
      independent mechanism.
AB  - Peptide YY(3-36) (PYY(3-36)), a peptide released postprandially by the gut, has
      been demonstrated to inhibit food intake. Little is known about the mechanism by
      which PYY(3-36) inhibits food intake, although the peptide has been shown to
      increase hypothalamic proopiomelanocortin (POMC) mRNA in vivo and to activate
      POMC neurons in an electrophysiological slice preparation. Understanding the
      physiology of PYY(3-36) is further complicated by the fact that some laboratories
      have had difficulty demonstrating inhibition of feeding by the peptide in
      rodents. We demonstrate here that, like cholecystokinin, PYY(3-36) dose
      dependently inhibits food intake by approximately 20-45% over a 3- to 4-h period
      post ip administration, with no effect on 12-h food intake. This short-lived
      satiety effect is not seen in animals that are not thoroughly acclimated to
      handling and ip injection, thus potentially explaining the difficulty in
      reproducing the effect. Surprisingly, PYY(3-36) was equally efficacious in
      inducing satiety in wild-type and melanocortin-4 receptor (MC4-R)-deficient mice
      and thus does not appear to be dependent on MC4-R signaling. The expression of c
      Fos, an indirect marker of neuronal activation, was also examined in forebrain
      and brainstem neurons after ip treatment with a dose of PYY(3-36) shown to induce
      satiety. The peptide induced no significant neuronal activation in the brainstem
      by this assay, and only modest activation of hypothalamic POMC neurons. Thus,
      unlike cholecystokinin, PYY(3-36)-induced satiety is atypical, because it does
      not produce detectable activation of brainstem satiety centers and is not
      dependent on MC4-R signaling.

PMID- 15016723
TI  - Ligand-regulated internalization of the opioid receptor-like 1: a confocal study.
AB  - To better understand opioid receptor-like 1 (ORL1) internalization, we fused the
      C terminus of ORL1, the nociceptin (noc) receptor, to the N terminus of a green
      fluorescent protein and used the fusion protein to characterize receptor
      endocytosis in live human embryonic kidney cells. The fusion altered neither the
      affinity of the receptor for noc or other ORL1 receptor ligands nor the ability
      of the receptor to mediate agonist-induced binding of GTPgamma(35)S, i.e.
      coupling with heterotrimeric G protein. Confocal microscopy showed that the
      fluorescent receptor was mostly associated (>75%) with the periplasmic membrane.
      In the presence of 0.1 microm noc, approximately 80% of receptors were
      internalized, and half-maximum internalization was reached in approximately 12
      min at 22 C and approximately 6 min at 37 C. After washing, a normal receptor
      level was recovered within 70 min at 22 C. The lack of internalization in the
      presence of 0.45 m sucrose suggests that noc-induced receptor endocytosis mainly
      occurred via clathrin-coated pits. Coincubation of the recombinant cells with noc
      and tetramethylrhodamine-transferrin showed that ORL1 was mainly internalized
      through the endosome compartment. Lofentanil and Ro64-6198 ([(1S,3aS)-8
      (2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4
      one]) promoted endocytosis of the fluorescent receptor as efficiently as noc.
      Among the two ORL1 receptor antagonists, J-113397 (1-[(3R,4R)-1-cyclooctylmethyl
      3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one), but not
      III-BTD, blocked the noc-induced internalization of the fluorescent receptor. Two
      partial agonists were dramatically less efficient than noc to promote ORL1
      internalization. They recruited very little (the pseudopeptide [Phe(1)psi(CH(2)
      NH)Gly(2)]-noc-(1-13)NH(2)) or no (the hexapeptide Ac-Arg-Tyr-Tyr-Lys-Trp-Arg
      NH(2)) G protein receptor kinase type 2 coupled to red fluorescent protein 1 at
      the membrane, suggesting that subsequent receptor phosphorylation necessary for
      internalization via coated pits is altered. Thus, partial agonists that induce a
      prolonged cell response without causing substantial receptor internalization may
      be good tools for further clinical treatments.

PMID- 15016724
TI  - Centile charts II: alternative nonparametric approach for establishing time
      specific reference centiles and assessment of the sample size required.
AB  - BACKGROUND: Reference intervals, and more generally centile estimates, are used
      to characterize a reference population for the purposes of interpreting an
      individual patient's clinical measurement. We describe methods of calculating
      reference intervals where these centiles vary with a covariate, usually age or
      time. METHODS: The US Food and Drug Administration and the IFCC have made
      recommendations on two approaches: the parametric approach, which models the
      structural characteristics of the data set with a theoretical distribution, and
      the nonparametric approach, which makes no particular assumption about this
      structure. In this report we propose a nonparametric procedure that relies on the
      principles of regression and show how sample size determination can be assessed.
      We also show how the sample size calculation is influenced by the distribution of
      the times measured. RESULTS: We illustrated our method on three data sets and
      compared the results for our proposed nonparametric method with parametric
      estimates. We showed that the bias is reduced and that the nonparametric method
      is less likely to produce fluctuating profiles. CONCLUSIONS: To achieve adequate
      precision the sample size needs to be larger than 120, as has often been
      recommended. If there is doubt about the parametric model, then threshold sample
      sizes may need to be as high as 500.

PMID- 15016725
TI  - Between-method variation in human chorionic gonadotropin test results.
AB  - BACKGROUND: Results on sera and calibrators vary 1.4- to 2.3-fold among
      commercial human chorionic gonadotropin (hCG) assays. The relative contributions
      of calibrators, standards, hCG charge isoforms, and major structural variants to
      this variation have not been quantified. METHODS: Purified hCG was separated by
      isoelectric focusing into four fractions with pI ranges of 3-4, 4-5, 5-6, and 6
      7. These four fractions together with pure hCG, hyperglycosylated hCG, hCG beta
      subunit (hCGb), nicked hCG, and hCGb core fragment (hCGbcf) were tested in nine
      commonly used commercial serum assays for hCG. The compositions of pure hCG
      preparations, standards, and commercial hCG preparations were determined by
      immunoassay. RESULTS: The three pure hCG preparations and the four hCG charge
      isoforms each showed parallel responses in the nine commercial hCG assays.
      Although wide variations were found in the detection of hCG structural variants
      by the nine assays (range for hyperglycosylated hCG, 468-1544 IU/L; for hCGb,
      3187-5535 IU/L; for nicked hCG, 2736-4240 IU/L; and for hCGbcf, <2-130 IU/L),
      this did not correlate with the between-method variation observed in results for
      the three pure hCG preparations. Commercial preparations of hCG and calibrators
      showed great variation in their content of hCG structural variants (from 34% to
      100% intact hCG). CONCLUSIONS: Intermethod differences in hCG results were not
      explained by changes in responses attributable to hCG charge isoforms or to hCG
      structural variants, but wide variation was observed in concentrations of hCG
      structural variants in calibrators and in detection of these structural variants.
      Differences in assay specificity and in composition of the calibrators are the
      most likely sources of between-method variation.

PMID- 15016726
TI  - Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in Albers
      Schonberg disease (type II autosomal dominant osteopetrosis).
AB  - BACKGROUND: Albers-Schonberg disease, or autosomal dominant osteopetrosis type II
      (ADO2), is caused by ineffective osteoclastic bone resorption resulting from
      mutations in the chloride channel 7 (ClCN7) gene. Individuals with ADO2 have
      increased numbers of large ineffective osteoclasts in addition to increased serum
      total tartrate-resistant acid phosphatase (TRACP) activity. METHODS: We
      investigated the serum activity of the osteoclast-derived 5b isoform of TRACP
      (TRACP 5b) and concentrations of the bone formation marker osteocalcin in
      clinically affected individuals, unaffected gene carriers, and healthy controls
      from 10 ADO2 families with known ClCN7 gene mutations. Bone fracture prevalence
      was studied in association with the serum markers. RESULTS: Similar to total
      TRACP, TRACP 5b was significantly increased in clinically affected individuals
      compared with age-matched controls. TRACP 5b correlated significantly with total
      TRACP (r = 0.833; P <0.001), suggesting that most of the TRACP in the serum of
      ADO2 patients is osteoclast-derived TRACP 5b. Osteocalcin was significantly
      increased in affected adults and slightly decreased in affected children. TRACP
      5b and total TRACP were significantly increased in clinically affected
      individuals with severe fractures (P <0.05). CONCLUSIONS: The results indicate
      that in ADO2, serum TRACP 5b reflects the number of osteoclasts and that the
      extremely high serum TRACP 5b activity is a specific indicator of the disease.
      Similar to total TRACP, TRACP 5b appears to be a potentially useful marker to
      stratify individuals with ClCN7 gene mutations into clinically affected and
      unaffected gene carriers. It may also have a prognostic value in the prediction
      of fractures in patients with a ClCN7 gene mutation.

PMID- 15016727
TI  - Centile charts I: new method of assessment for univariate reference intervals.
AB  - BACKGROUND: We introduce a new criterion, the percentile inclusion probability,
      for comparing methods for calculating reference intervals. The criterion is
      compared with a previously published measure of reliability suggested by Linnet
      (Linnet K. Clin Chem 1987;33:381-6), the ratio of the width of the confidence
      interval for the percentile to that of the reference interval. METHODS: Data were
      simulated from a range of theoretical statistical distributions representing the
      shapes of data sets encountered in clinical investigations. The two-stage
      transformation of the data to a gaussian distribution recommended by the IFCC was
      compared with a nonparametric approach. RESULTS: The percentile inclusion
      probability criterion identified that the parametric approach is in some cases
      seriously affected by bias. Using different parametric models, we compared
      nonparametric and parametric methods for two sets of clinical data and showed
      that the parametric approach is susceptible to model choice. CONCLUSIONS: Sample
      sizes significantly greater than those currently recommended are required to
      establish reference intervals, regardless of whether parametric or nonparametric
      methods are used. Parametric methods are preferable when the data are truly
      gaussian, but are only marginally better than nonparametric methods when data
      transformation is needed to achieve a gaussian shape.

PMID- 15016728
TI  - Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac
      ryanodine receptor.
AB  - The cardiac ryanodine receptor (RyR2)/calcium release channel on the sarcoplasmic
      reticulum is required for muscle excitation-contraction coupling. Using site
      directed mutagenesis, we identified the specific Ca2+/calmodulin-dependent
      protein kinase II (CaMKII) phosphorylation site on recombinant RyR2, distinct
      from the site for protein kinase A (PKA) that mediates the "fight-or-flight"
      stress response. CaMKII phosphorylation increased RyR2 Ca2+ sensitivity and open
      probability. CaMKII was activated at increased heart rates, which may contribute
      to enhanced Ca2+-induced Ca2+ release. Moreover, rate-dependent CaMKII
      phosphorylation of RyR2 was defective in heart failure. CaMKII-mediated
      phosphorylation of RyR2 may contribute to the enhanced contractility observed at
      higher heart rates. The full text of this article is available online at
      http://circres.ahajournals.org.

PMID- 15016729
TI  - Myocardin and Prx1 contribute to angiotensin II-induced expression of smooth
      muscle alpha-actin.
AB  - Previous studies demonstrated that angiotensin II (Ang II)-induced hypertrophy of
      smooth muscle cells (SMCs) was associated with increased transcription of SM
      alpha-actin gene. The aim of the present study was to determine whether
      myocardin, a SMC-selective cofactor of serum response factor (SRF), contributed
      to Ang II-induced increases in SM alpha-actin transcription. Results showed that
      Ang II increased myocardin mRNA expression as well as SM alpha-actin mRNA
      expression via the Ang II type 1 receptor in cultured rat aortic SMCs.
      Cotransfection studies revealed that CArG elements were required for Ang II
      induced transcription of SM alpha-actin gene, and a dominant-negative form of
      myocardin or a short interfering RNA (siRNA) specific for myocardin decreased Ang
      II-induced SM alpha-actin transcription. Prx1, a homeodomain protein whose
      expression was increased by Ang II, also increased SM alpha-actin gene
      transcription in part via CArG elements, and siRNA specific for Prx1 markedly
      decreased basal and Ang II-induced SM alpha-actin transcription. Electrophoretic
      mobility shift assay showed that myocardin and Ang II, respectively, increased
      formation of a SMC-specific CArG-SRF-myocardin higher order complex. However, Ang
      II had no effect on binding between myocardin and SRF as determined by a
      mammalian two-hybrid assay, suggesting that Ang II-induced increases in formation
      of CArG-SRF-myocardin complex was the result of increased SRF binding to CArG
      elements and increased myocardin expression. Taken together, these results
      support a model in which Ang II-induced increases in expression of SM alpha-actin
      are mediated through Prx1-dependent increases in SRF binding to CArG elements and
      subsequent recruitment of myocardin.

PMID- 15016731
TI  - Defective lung vascular development and fatal respiratory distress in endothelial
      NO synthase-deficient mice: a model of alveolar capillary dysplasia?
AB  - Endothelium-derived NO plays a critical role in the regulation of cardiovascular
      function and structure, as well as acting as a downstream mediator of the
      angiogenic response to numerous vascular growth factors. Although endothelial NO
      synthase (eNOS)-deficient mice are viable, minor congenital cardiac abnormalities
      have been reported and homozygous offspring exhibit high neonatal mortality out
      of proportion to the severity of these defects. The aim of the present report was
      to determine whether abnormalities of the pulmonary vascular development could
      contribute to high neonatal loss in eNOS-deficient animals. We now report that
      eNOS-deficient mice display major defects in lung morphogenesis, resulting in
      respiratory distress and death within the first hours of life in the majority of
      animals. Histological and molecular examination of preterm and newborn mutant
      lungs demonstrated marked thickening of saccular septae, with evidence of reduced
      surfactant material. Lungs of eNOS-deficient mice also exhibited a striking
      paucity of distal arteriolar branches and extensive regions of capillary
      hypoperfusion, together with misalignment of pulmonary veins, which represent the
      characteristic features of alveolar capillary dysplasia. We conclude that eNOS
      plays a previously unrecognized role in lung development, which may have
      relevance for clinical syndromes of neonatal respiratory distress.

PMID- 15016730
TI  - Upregulation of alveolar epithelial active Na+ transport is dependent on beta2
      adrenergic receptor signaling.
AB  - Alveolar epithelial beta-adrenergic receptor (betaAR) activation accelerates
      active Na+ transport in lung epithelial cells in vitro and speeds alveolar edema
      resolution in human lung tissue and normal and injured animal lungs. Whether
      these receptors are essential for alveolar fluid clearance (AFC) or if other
      mechanisms are sufficient to regulate active transport is unknown. In this study,
      we report that mice with no beta1- or beta2-adrenergic receptors (beta1AR-/
      /beta2AR-/-) have reduced distal lung Na,K-ATPase function and diminished basal
      and amiloride-sensitive AFC. Total lung water content in these animals was not
      different from wild-type controls, suggesting that betaAR signaling may not be
      required for alveolar fluid homeostasis in uninjured lungs. Comparison of
      isoproterenol-sensitive AFC in mice with beta1- but not beta2-adrenergic
      receptors to beta1AR-/-/beta2AR-/- mice indicates that the beta2AR mediates the
      bulk of beta-adrenergic-sensitive alveolar active Na+ transport. To test the
      necessity of betaAR signaling in acute lung injury, beta1AR-/-/beta2AR-/-,
      beta1AR+/+/beta2AR-/-, and beta1AR+/+/beta2AR+/+ mice were exposed to 100% oxygen
      for up to 204 hours. beta1AR-/-/beta2AR-/- and beta1AR+/+/beta2AR-/- mice had
      more lung water and worse survival from this form of acute lung injury than wild
      type controls. Adenoviral-mediated rescue of beta2-adrenergic receptor (beta2AR)
      function into the alveolar epithelium of beta1AR-/-/beta2AR-/- and
      beta1AR+/+/beta2AR-/- mice normalized distal lung beta2AR function, alveolar
      epithelial active Na+ transport, and survival from hyperoxia. These findings
      indicate that betaAR signaling may not be necessary for basal AFC, and that
      beta2AR is essential for the adaptive physiological response needed to clear
      excess fluid from the alveolar airspace of normal and injured lungs.

PMID- 15016732
TI  - FVIIa:TF induces cell survival via G12/G13-dependent Jak/STAT activation and
      BclXL production.
AB  - Tissue factor (TF), apart from activating the extrinsic pathway of the blood
      coagulation, is a principal regulator of embryonic and oncogenic angiogenesis,
      inflammation, leukocyte reverse transmigration, and tumor progression. It has
      become clear that these events are mediated by intracellular signal transduction
      elicited by TF/factor VIIa (FVIIa) interaction, but the details of this signaling
      remain largely obscure. In this study, we show that FVIIa/TF-interaction produces
      STAT5 phosphorylation, STAT5 nuclear translocation and transactivation of a STAT5
      reporter construct. FVIIa-dependent STAT5 activation was dependent on FVIIa
      proteolytic activity but not on generation of the downstream coagulation factors
      Xa and thrombin, nor on the TF cytoplasmic domain. FVIIa-induced STAT5
      phosphorylation was dependent on functional G12/G13 class G proteins and Jak2
      activity, but not Jak1 or Tyk2. Finally, we show that FVIIa leads to cell
      survival through a Jak2/STAT5-dependent production of the antiapoptotic STAT5
      target Bcl(XL) as well as Jak2-dependent activation of the antiapoptotic protein
      PKB. In conclusion, our results show that FVIIa induces cell survival through
      STAT5-dependent Bcl(XL) production and Jak2-dependent activation of PKB. Finally,
      we demonstrated for the first time that TF/FVIIa-signal transduction is dependent
      on G12/G13 class G proteins.

PMID- 15016733
TI  - GIT1 mediates thrombin signaling in endothelial cells: role in turnover of RhoA
      type focal adhesions.
AB  - Thrombin mediates changes in endothelial barrier function and increases
      endothelial permeability. A feature of thrombin-enhanced endothelial
      hyperpermeability is contraction of endothelial cells (ECs), accompanied by
      formation of focal adhesions (FAs). Recently, a G protein-coupled receptor kinase
      interacting protein, GIT1, was shown to regulate FA disassembly. We hypothesized
      that GIT1 modulates thrombin-induced changes in FAs. In human umbilical vein ECs
      (HUVECs), thrombin recruited GIT1 to FAs, where GIT1 colocalized with FAK and
      vinculin. Recruitment of GIT1 to FAs was dependent on activation of the small
      GTPase RhoA, and Rho kinase, as demonstrated by adenoviral transfection of
      dominant-negative RhoA and treatment with Y-27632. Thrombin stimulated GIT1
      tyrosine phosphorylation with a time course similar to FAK phosphorylation in a
      Rho kinase- and Src-dependent manner. Depletion of GIT1 with antisense GIT1
      oligonucleotides had no effect on basal cell morphology, but increased cell
      rounding and contraction of HUVECs, increased FA formation, and increased FAK
      tyrosine phosphorylation in response to thrombin, concomitant with increased
      endothelial hyperpermeability. These data identify GIT1 as a novel mediator in
      agonist-dependent signaling in ECs, demonstrate that GIT1 is involved in cell
      shape changes, and suggest a role for GIT1 as a negative feedback regulator that
      augments recovery of cell contraction.

PMID- 15016734
TI  - Hibernating myocardium: chronically adapted to ischemia but vulnerable to sudden
      death.
AB  - The inability to reproduce spontaneous ventricular fibrillation in an animal
      model of chronic coronary artery disease has limited advances in understanding
      mechanisms of sudden cardiac death (SCD). Swine with hibernating myocardium
      arising from a chronic left anterior descending coronary artery (LAD) occlusion
      have a high rate of SCD that parallels the poor clinical survival of medically
      treated patients with hibernating myocardium. Kaplan-Meier analysis (n=426)
      demonstrated a cumulative mortality of 49% after 5 months that was almost
      entirely attributable to spontaneous SCD. Using implantable loop recorders,
      ventricular fibrillation was documented as the arrhythmic mechanism of death in
      all animals (n=10) and was usually preceded by ventricular tachycardia (n=8).
      Physiological studies before SCD (n=7) demonstrated total LAD occlusion and
      collateral-dependent myocardium (n=5), excluding acute occlusion as a major
      trigger of arrhythmia. The physiological substrate of hibernating myocardium was
      present before SCD, with reductions in LAD perfusion (SCD 0.79+/-0.13 versus
      0.80+/-0.08 mL/min per g) and wall thickening (SCD 28+/-3% versus 22+/-3%) that
      were similar to survivors (n=14). Triphenyltetrazolium chloride infarcts among
      animals with SCD were infrequent (4 of 32) and small, averaging 4.6% of LV mass.
      Histology (n=4) showed postmortem changes but no acute inflammation nor
      contraction band necrosis. These data support the notion that hibernating
      myocardium is a pathophysiological substrate at high risk of SCD. This is
      independent of changes in functional stenosis severity, acute myocardial
      necrosis, or fibrotic scar. Thus, regional adaptations that promote myocyte
      survival in the setting of chronic repetitive ischemia result in a substrate with
      enhanced vulnerability to lethal arrhythmias and SCD.

PMID- 15016735
TI  - Role of calcium cycling versus restitution in the mechanism of repolarization
      alternans.
AB  - T-wave alternans, a powerful marker of arrhythmic events, results from
      alternation in action potential duration (APD). The underlying cellular mechanism
      of APD alternans is unknown but has been attributed to either intracellular
      calcium (Ca2+) cycling or membrane ionic currents, manifested by a steep slope of
      cellular APD restitution. To address these mechanisms, high-resolution optical
      mapping techniques were used to measure action potentials and Ca2+ transients
      simultaneously from hundreds of epicardial sites in the guinea pig model of
      pacing-induced T-wave alternans (n=7). The pacing rates (ie, alternans threshold)
      at which T-wave (369+/-11 bpm), APD (369+/-21 bpm), and Ca2+ (371+/-29 bpm)
      alternans first appeared were comparable. Importantly, the site of origin of APD
      alternans and Ca2+ alternans consistently occurred together near the base of the
      left ventricle, not where APD restitution was steepest. In addition, APD and Ca2+
      alternans were remarkably similar both spatially and temporally during discordant
      alternans. In conclusion, the mechanism underlying T-wave alternans in the intact
      heart is more closely associated with intracellular Ca2+ cycling rather than APD
      restitution.

PMID- 15016736
TI  - Fatigue in chronic cholestasis.
AB  - Fatigue is probably the most intriguing symptom affecting patients with chronic
      cholestatic disorders, in particular those with primary biliary cirrhosis. It is
      postulated that fatigue in patients with primary biliary cirrhosis may be
      associated with morphological abnormalities of the central nervous system
      secondary to accumulation of manganese. However, we are still far from
      understanding this complex issue.

PMID- 15016737
TI  - Management of swallowed razor blades-retrieve or wait and see?

PMID- 15016738
TI  - Gene transfer: Bax to the future for cancer therapy.

PMID- 15016739
TI  - Impairment of intestinal intraepithelial lymphocytes in Id2 deficient mice.
AB  - BACKGROUND: Id2, an inhibitor of basic helix-loop-helix transcription factors,
      regulates cell differentiation. Id2-/- mice exhibit a variety of phenotypes in
      the immune system. AIMS: In this study we investigated whether Id2 plays a role
      in intestinal intraepithelial lymphocytes (IELs), which constitute the main
      defence against pathogens in the intestinal tract. METHODS: Flow cytometry and
      bone marrow transplantation were used to analyse and characterise subsets of IELs
      of Id2-/- mice. Gene expression was analysed by real-time polymerase chain
      reaction. Intestinal barrier function was evaluated by treating mice with 5
      fluorouracil (5-FU). RESULTS: Among the four members of the Id gene family, Id2
      was selectively expressed in all T cell subsets in the small intestinal IELs. Id2
      /- mice showed alteration in the proportions of T cell subsets and a substantial
      reduction in the number of IELs, especially those of the CD4+ and CD8 alpha beta+
      T cell subsets, indicating a more pronounced effect on thymus derived IELs.
      Expression of alphaE integrin was reduced in CD4+ and CD8 alpha beta+ T cell
      subsets in IELs of Id2-/- mice. IELs isolated from C57BL/6 mice reconstituted
      with Id2-/- bone marrow cells showed a similar phenotype to that of Id2-/- mice,
      indicating that the defects are intrinsic to bone marrow derived cells.
      Expression of genes encoding intestinal epithelial cell derived cytokines was
      reduced in Id2-/- mice. The 5-FU treatment revealed impaired intestinal barrier
      function of Id2-/- mice. CONCLUSIONS: The Id2 gene is essential for constituting
      the intestinal mucosal barrier, particularly with respect to IELs. Id2 null
      mutant mice may provide a good experimental model for studying the ontogeny of
      IELs and intestinal inflammation and infection.

PMID- 15016741
TI  - Intestinal B cell hyperactivity in AIDS is controlled by highly active
      antiretroviral therapy.
AB  - BACKGROUND: It is well documented that highly active antiretroviral therapy
      (HAART) restores systemic immunity to human immunodeficiency virus (HIV) but the
      effect of this treatment on the mucosal immune system is less clear. AIMS:
      Because future preventive or therapeutic vaccines against HIV may be administered
      by the mucosal route, we wished to evaluate the effect of HAART on the activation
      level and homeostasis of the intestinal B cell system. PATIENTS AND METHODS:
      Duodenal biopsy specimens were collected consecutively from infection prone HIV
      positive adults (n = 31), mostly with advanced AIDS. In situ two colour
      immunofluorescence staining was performed to quantify mucosal immunoglobulin (Ig)
      class and subclass producing immunocytes (plasmablasts and plasma cells).
      RESULTS: HIV positive patients had, on average, duodenal proportions of IgA
      (74.6%), IgM (19.5%), and IgG (3.4%) immunocytes similar to median values
      recorded in 11 HIV seronegative healthy controls but the total immunocyte number
      per mucosal section length unit (500 microm) was significantly increased in
      patients (median 175 v 120 cells/unit; p<0.008), mainly comprised of IgA (p<0.02)
      and IgG1 (median 81.8% of total IgG; p<0.02) isotypes. Patients receiving a
      successful HAART regimen tended to normalise their IgG1 proportion and showed
      significantly lower total duodenal IgA immunocyte number than those receiving no
      or insufficient antiretroviral treatment (p<0.005). CONCLUSION: Our study
      demonstrated that advanced AIDS patients hyperactivate their intestinal B cell
      system. HAART could significantly reverse this perturbation, suggesting restored
      ability of the mucosal immune system to control intestinal infections.

PMID- 15016742
TI  - Increased antigen and bacterial uptake in follicle associated epithelium induced
      by chronic psychological stress in rats.
AB  - BACKGROUND: Chronic stress affects the course of inflammatory bowel disease and
      experimental colitis, and may also initiate intestinal inflammation in rats. AIM:
      To investigate the effects of stress on the M cell containing follicle associated
      epithelium, specialised in antigen uptake. SUBJECTS AND METHODS: Wistar rats were
      submitted to acute water avoidance stress for one hour or chronic water avoidance
      stress for 1 hour/day for 10 consecutive days. Permeability to (51)Cr-EDTA,
      horseradish peroxidase, and chemically killed Escherichia coli K-12 was studied
      in both villus and follicle associated epithelium in Ussing chambers. Segments
      were further examined by light, electron, and confocal microscopy. RESULTS: Acute
      stress increased horseradish peroxidase flux in villus as well as in follicle
      associated epithelium. Chronic stress further increased permeability to
      horseradish peroxidase in villus and follicle associated epithelium, in the
      latter by almost fourfold. Moreover, chronic stress induced over 30 times
      increased E coli passage in follicle associated epithelium whereas there was no
      significant increase in villus epithelium. Bacterial uptake was confirmed by
      confocal microscopy showing fluorescent bacteria penetrating and passing through
      the epithelial surface. CONCLUSIONS: These results show that the barrier function
      of follicle associated epithelium can be modulated, and that chronic stress
      enhances the uptake of luminal antigens and bacteria via the follicle associated
      epithelium. This can increase antigen exposure in Peyer's patches thereby having
      implications in the initiation of proinflammatory immune responses within the
      intestinal mucosa.

PMID- 15016743
TI  - Neonatal maternal deprivation triggers long term alterations in colonic
      epithelial barrier and mucosal immunity in rats.
AB  - BACKGROUND: Stressful events in the early period of life (for example, maternal
      deprivation) have been shown to modify adult immune and gastrointestinal tract
      functions. The present study aimed to establish whether maternal deprivation
      affects colonic epithelial barrier and the development of an experimental colitis
      in adult rats. METHODS: Male Wistar rat pups were separated during postnatal days
      2-14 or left undisturbed with their dam. At 12 weeks of age, we assessed colonic
      paracellular permeability, bacterial translocation, myeloperoxidase (MPO)
      activity, mucosal mast cell density, cytokine (interleukin (IL)-1 beta, IL-2, IL
      4, IL-10, and interferon gamma (IFN-gamma)) mRNA expression, and macroscopic
      damage. Total gut permeability, MPO activity, and macroscopic damage were also
      assessed four days after intracolonic administration of 2,4,6
      trinitrobenzenesulphonic acid (TNBS). RESULTS: Maternal deprivation triggered a
      significant increase in colonic permeability associated with bacterial
      translocation into the mesenteric lymph nodes, liver, and spleen. These
      alterations were associated with some macroscopic damage and an increase in
      colonic MPO activity, mucosal mast cell density, and cytokine mRNA expression.
      Intracolonic infusion of TNBS induced a significantly higher inflammatory
      reaction in separated animals, as judged by enhanced MPO colonic levels, total
      gut permeability, and macroscopic lesions. CONCLUSIONS: Maternal deprivation
      promotes long term alterations in the colonic epithelial barrier associated with
      an exaggerated immune response to an external immune stimulus. This suggests a
      role for early psychological factors in the regulation of colonic mucosal barrier
      in later life.

PMID- 15016744
TI  - CD55 expression patterns on intestinal neuronal tissue are divergent from the
      brain.
AB  - BACKGROUND: and objectives: In this study, we investigated how enteric plexuses
      protect themselves from complement mediated attack. For this purpose, the
      expression patterns of membrane bound complement regulatory proteins (mCRP) and
      their association with C3 deposition was determined. In addition, mCRP expression
      patterns of enteric plexuses were compared with those in the central nervous
      system (CNS). METHODS: Immunohistochemical stainings were performed to
      discriminate neuronal cells from glial cells and to detect the presence of CD46,
      CD55, CD59, and C3d. RNA in situ hybridisation (RISH) was used to determine the
      cell types that produce CD55 mRNA. RESULTS: Enteric plexuses minimally expressed
      CD46 whereas CD55 and CD59 were highly expressed. CD55 expression was also
      observed in a ring around Auerbach's plexuses which was not observed for CD46 and
      CD59. C3d was deposited around the plexuses but plexus cells themselves did not
      stain for C3d. In contrast with CNS neurones, enteric neurones were shown to
      express CD55 whereas enteric glial cells did not. This was confirmed with CD55
      RISH. Phospholipase C mediated cleavage of CD55 demonstrated that CD55 was most
      likely attached to elastic fibres surrounding the plexus. Attached CD55 might
      protect CD55 negative glial cells from complement mediated injury during
      inflammatory reactions. CD55 on elastic fibres surrounding the plexuses most
      likely originated from enteric neuronal cells. CONCLUSION: In contrast with the
      CNS, enteric neurones express CD55 and enteric glial cells lack CD55 expression.
      CD55, produced by neuronal cells, attached to elastic fibres surrounding the
      plexuses is proposed to protect the CD55 negative glial cells within plexuses.

PMID- 15016745
TI  - Arginine stimulates intestinal cell migration through a focal adhesion kinase
      dependent mechanism.
AB  - BACKGROUND: L-Arginine is a nutritional supplement that may be useful for
      promoting intestinal repair. Arginine is metabolised by the oxidative deiminase
      pathway to form nitric oxide (NO) and by the arginase pathway to yield ornithine
      and polyamines. AIMS: To determine if arginine stimulates restitution via
      activation of NO synthesis and/or polyamine synthesis. METHODS: We determined the
      effects of arginine on cultured intestinal cell migration, NO production,
      polyamine levels, and activation of focal adhesion kinase, a key mediator of cell
      migration. RESULTS: Arginine increased the rate of cell migration in a dose
      dependent biphasic manner, and was additive with bovine serum concentrate (BSC).
      Arginine and an NO donor activated focal adhesion kinase (a tyrosine kinase which
      localises to cell matrix contacts and mediates beta1 integrin signalling) after
      wounding. Arginine stimulated cell migration was dependent on focal adhesion
      kinase (FAK) signalling, as demonstrated using adenovirus mediated transfection
      with a kinase negative mutant of FAK. Arginine stimulated migration was dependent
      on NO production and was blocked by NO synthase inhibitors. Arginine dependent
      migration required synthesis of polyamines but elevating extracellular arginine
      concentration above 0.4 mM did not enhance cellular polyamine levels.
      CONCLUSIONS: These results showed that L-arginine stimulates cell migration
      through NO and FAK dependent pathways and that combination therapy with arginine
      and BSC may enhance intestinal restitution via separate and convergent pathways.

PMID- 15016746
TI  - Identification and quantitation of mucosal and faecal desulfovibrios using real
      time polymerase chain reaction.
AB  - BACKGROUND: Desulfovibrios produce sulphide, which is toxic to colonic epithelial
      cells. These bacteria have previously been linked to ulcerative colitis.
      Traditional methods of culturing these organisms are slow, and often unreliable,
      while molecular approaches are either non-quantitative or lack sensitivity. AIMS:
      To develop a sensitive method for quantitating desulfovibrios in stools and
      biopsy tissue, and to investigate the effects of age and disease on these
      bacteria. METHODS: Rectal biopsies were taken from 10 colitis patients and 10
      healthy controls. Stool samples were obtained from 10 healthy infants (mean age
      1.01 (0.18) years), 10 healthy young adults (26.7 (1.2) years), and 10 healthy
      elderly people (71.7 (1.2) years). Primers were designed and developed for
      analysing Desulfovibrio populations in the bowel using real time polymerase chain
      reaction (PCR). RESULTS: The PCR primers were highly specific for desulfovibrios.
      Large numbers (approximately 10(6)-10(7)/g) occurred in biopsies in colitis
      patients and healthy subjects, and no disease related differences were observed.
      Measurements of mucosal desulfovibrios over 12 months showed marked changes in
      some patients. Infants (10(6)-10(7)/g) and elderly people (10(7)-10(8)/g) had
      significantly higher numbers of desulfovibrios in stools compared with young
      adults (10(5)/g). CONCLUSIONS: Real time PCR analysis of desulfovibrios was an
      efficient and accurate method for studying these potentially harmful
      microorganisms. Desulfovibrios were ubiquitous in the bowel, irrespective of age.
      As rectal mucosae were heavily colonised in health and disease, if these bacteria
      play a role in colitis, some host defect, possibly in sulphide detoxication
      pathways or in bacterial antigen handling, is required for manifestations of
      pathogenicity.

PMID- 15016747
TI  - Dietary fructo-oligosaccharides and inulin decrease resistance of rats to
      salmonella: protective role of calcium.
AB  - BACKGROUND: We have shown recently that rapid fermentable fructo-oligosaccharides
      (FOS) decreased resistance of rats towards salmonella. It is not known whether
      inulin (which is fermented more gradually) has similar effects or whether
      buffering nutrients can counteract the adverse effects of rapid fermentation.
      AIMS: To compare the effects of dietary inulin and FOS on resistance of rats to
      Salmonella enterica serovar Enteritidis and to determine whether calcium
      phosphate counteracts the effects of fermentation. METHODS: Male Wistar rats (n =
      8 per group) were fed a human "Western style diet". Diets with 60 g/kg cellulose
      (control), FOS, or inulin had either a low (30 mmol/kg) or high (100 mmol/kg)
      calcium concentration. After an adaptation period of two weeks, animals were
      orally infected with 2 x 10(9) colony forming units of Salmonella enterica
      serovar Enteritidis. Colonisation of salmonella was determined by quantification
      of salmonella in caecal contents. Translocation of salmonella was quantified by
      analysis of urinary nitric oxide metabolites in time. RESULTS: Inulin and FOS
      decreased intestinal pH and increased faecal lactobacilli and enterobacteria.
      Moreover, both prebiotics increased the cytotoxicity of faecal water and faecal
      mucin excretion. Both prebiotics increased colonisation of salmonella in caecal
      contents and enhanced translocation of salmonella. Dietary calcium phosphate
      counteracted most of the adverse effects of inulin and FOS. CONCLUSIONS: Both
      inulin and FOS impair resistance to intestinal infections in rats. This
      impairment is partially prevented by dietary calcium phosphate. The results of
      the present study await verification in other controlled animal and human
      studies.

PMID- 15016748
TI  - Lymphocytic colitis: a retrospective clinical study of 199 Swedish patients.
AB  - BACKGROUND: Lymphocytic colitis is characterised by chronic diarrhoea and
      specific microscopic changes in a macroscopically normal colonic mucosa. We
      report clinical features and treatment outcome in a large patient cohort.
      METHODS: Patients were searched for in 24 Swedish gastroenterology clinics. The
      biopsy material was reassessed using strict histopathological criteria. Clinical
      data were obtained from medical notes. RESULTS: Lymphocytic colitis was diagnosed
      in 199 cases. The female:male ratio was 2.4:1. Median age at diagnosis was 59 (48
      70) years. The most frequent symptoms were diarrhoea (96%), abdominal pain (47%),
      and weight loss (41%). The course was chronic intermittent in 30% of patients,
      chronic continuous in 7%, and a single attack in 63%, and in these cases the
      disease duration was 6 (4-11) months. Seventy nine (40%) patients reported
      associated diseases, of which thyroid disorders, coeliac disease, and diabetes
      mellitus were the most common. In 34 first or second degree relatives of 24 (12%)
      patients, a family history of ulcerative colitis, Crohn's disease, collagenous
      colitis, or coeliac disease was reported. Drug induced disease was suspected in
      19 (10%) patients. A non-significant peak of disease onset was seen in December
      January. More than 80% of treated patients improved on corticosteroids, including
      budesonide. CONCLUSIONS: A family history of other bowel disorders is a new
      finding. The sudden onset and single attack of limited duration may support a
      possible infectious cause in some cases. Drugs may cause lymphocytic colitis.

PMID- 15016749
TI  - Is inflammatory bowel disease an independent and disease specific risk factor for
      thromboembolism?
AB  - BACKGROUND: Patients with inflammatory bowel disease (IBD) are thought to be at
      increased risk of venous thromboembolism (TE). However, the extent of this risk
      is not known. Furthermore, it is not known if this risk is specific for IBD or if
      it is shared by other chronic inflammatory diseases or other chronic bowel
      diseases. AIMS: To compare the risk of TE in patients with IBD, rheumatoid
      arthritis, and coeliac disease with matched control subjects. PATIENTS AND
      METHODS: Study subjects answered a questionnaire assessing the history of TE, any
      cases of which had to be confirmed radiologically. A total of 618 patients with
      IBD, 243 with rheumatoid arthritis, 207 with coeliac disease, and 707 control
      subjects were consecutively included. All three patient groups were compared with
      control subjects matched to the respective group by age and sex. RESULTS: Thirty
      eight IBD patients (6.2%) had suffered TE. This was significantly higher compared
      with the matched control population with only 10 cases reported (1.6%) (p<0.001;
      odds ratio (OR) 3.6 (95% confidence interval (CI) 1.7-7.8)). Five patients with
      rheumatoid arthritis (2.1%) had suffered TE compared with six subjects (2.5%) in
      the control population matched to patients with rheumatoid arthritis (NS; OR 0.7
      (95% CI 0.2-2.9)). TE had occurred in two patients with coeliac disease (1%)
      compared with four subjects (1.9%) in the control population matched to the
      coeliac disease group (NS; OR 0.4 (95% CI 0.1-2.5)). In 60% of TE cases in the
      IBD group, at least one IBD specific factor (active disease, stenosis, fistula,
      abscess) was present at the time TE occurred. CONCLUSIONS: IBD is a risk factor
      for TE. It seems that TE is a specific feature of IBD as neither rheumatoid
      arthritis, another chronic inflammatory disease, nor coeliac disease, another
      chronic bowel disease, had an increased risk of TE.

PMID- 15016750
TI  - Incidence and management of malignant digestive endocrine tumours in a well
      defined French population.
AB  - BACKGROUND AND AIMS: Little is known about the epidemiology of malignant
      digestive endocrine tumours. The aim of this study was to report on their
      incidence and management in a well defined population. METHODS: Data were
      obtained from the population based Digestive Cancer Registry of Burgundy (France)
      over a 24 year period. Incidence rates were calculated by sex, age groups, and
      period of diagnosis. Treatment and stage at diagnosis were also investigated.
      Prognosis was determined using crude and relative survival rates. A multivariate
      relative survival analysis was performed. RESULTS: Between 1976 and 1999, 229
      cases were recorded. Age standardised incidence rates were 0.76/100,000 for men
      and 0.50/100,000 for women. They increased over time in both sexes. The
      resectability rate was 74.1%. Among recorded cases, 26.6% did not extend beyond
      the organ, 20% had lymph node metastases, and 53.3% had visceral metastases or
      were unresectable. There was no improvement in the resection rate or in the stage
      at diagnosis over the study period. The overall relative survival rate was 66.9%
      at one year, 50.4% at five years, and 40.6% at 10 years. Stage at diagnosis, age
      at diagnosis, and subsite were independent significant prognostic factors.
      CONCLUSIONS: Although their incidence is increasing, malignant digestive
      endocrine tumours remain a rare cancer, representing 1% of digestive cancers.
      Stage at diagnosis and prognosis at a population level are worse than those
      reported in hospital series. In the short term, new therapeutic possibilities
      represent the best way to improve their prognosis.

PMID- 15016752
TI  - Treatment of colorectal and hepatocellular carcinomas by adenoviral mediated gene
      transfer of endostatin and angiostatin-like molecule in mice.
AB  - AIM AND METHOD: In this study, we explored the responsiveness of different tumour
      entities (colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), and the
      murine Lewis lung carcinoma (LLC)) to angiostatic antitumour treatment with two
      recombinant adenoviral vectors encoding angiostatin-like molecule (AdK1-3) and
      endostatin (Adendo). RESULTS: AdK1-3 and Adendo exerted inhibitory biological
      functions on endothelial cell proliferation, migration, and tube formation in
      vitro. AdK1-3 inhibited significantly endothelial cell infiltration in vascular
      endothelial growth factor embedded Matrigel plugs in mice whereas Adendo showed
      only minor effects. Both AdK1-3 and Adendo induced similar antitumour effects in
      the LLC tumour model in immune competent C57BL/6 mice but AdK1-3 had stronger
      inhibitory effects in athymic mice. Furthermore, AdK1-3 inhibited tumour growth
      in a murine CRC and human HCC model but was ineffective in a human CRC model. In
      contrast, Adendo did not reduce tumour progress in either of these tumour models
      although AdK1-3 and Adendo effectively reduced intratumoral microvessel density
      in LLC tumours. CONCLUSION: Our data demonstrate that angiostatic gene therapy
      may form a feasible strategy for the treatment of established hepatocellular
      carcinomas and that in vivo antitumour efficacy of angiostatic proteins is tumour
      specific.

PMID- 15016751
TI  - Molecular therapy for peritoneal dissemination of xenotransplanted human MKN-45
      gastric cancer cells with adenovirus mediated Bax gene transfer.
AB  - BACKGROUND: Gene therapy is an innovative therapeutic approach for cancer. An
      adenoviral vector expressing the tumour suppressor p53 gene (Ad/p53) is currently
      under clinical evaluation for various cancers. We recently developed a binary
      adenoviral vector system that can express the strong proapoptotic gene Bax
      (Ad/PGK-GV16+Ad/GT-Bax: Ad/Bax). AIMS: To evaluate the potential of Bax gene
      therapy for gastric cancer, we assessed its antitumour effect in comparison with
      that of p53. METHODS: The human gastric cancer cell lines MKN-1, MKN-7, MKN-28,
      and MKN-45 were treated with Ad/Bax or Ad/p53, and cell viability, transgene
      expression, and caspase activation were assessed in vitro. To compare the
      antitumour effects of Ad/Bax and Ad/p53 treatment in vivo, subcutaneous tumours
      and peritoneal dissemination of MKN-45 cells were generated in nude mice. Each
      mouse underwent intratumoral or intraperitoneal administration of viruses and the
      growth of implanted tumours was observed after treatment. RESULTS: Treatment with
      Ad/Bax and Ad/p53 resulted in marked Bax and p53 protein expression and effective
      apoptosis induction in MKN-1, MKN-7, and MKN-28 cells in vitro. In contrast, MKN
      45 cells showed resistance to Ad/p53 and only treatment with Ad/Bax resulted in
      activation of caspase 3 expression and massive apoptosis. Ad/Bax treatment was
      more effective in suppressing both subcutaneous and peritoneally disseminated MKN
      45 tumours compared with Ad/p53 treatment. CONCLUSION: Ad/Bax treatment
      significantly inhibited the growth of even p53 resistant gastric cancer in vitro
      and in vivo. Therefore, adenovirus mediated Bax gene transfer may be useful in
      gene therapy for gastric cancers.

PMID- 15016753
TI  - Incidence and recurrence rates of colorectal adenomas estimated by annually
      repeated colonoscopies on asymptomatic Japanese.
AB  - BACKGROUND: Whereas high recurrence rates of colorectal adenomas after
      polypectomy are widely recognised, little is known of the natural incidence in
      those with no neoplastic lesions initially. It is also known that single
      colonoscopy has a significant miss rate. AIMS: To elucidate the incidence and
      recurrence rates of colorectal neoplasms from a large cohort of asymptomatic
      Japanese patients on the basis of annually repeated colonoscopies. METHODS: A
      total of 6225 subjects (4659 men and 1566 women) participating in an annual
      colonoscopic screening programme and completing three or more colonoscopies were
      analysed during the 14 year period between 1988 and 2002. Patients were divided
      into three groups according to the findings of the initial two colonoscopies:
      4084 subjects with no neoplasm, 1818 with small adenomas <10 mm, and 323 with
      advanced lesions, including carcinoma in situ, severe dysplasia, or large
      adenomas > or =10 mm. Mean age at the second colonoscopy was 48.8 years. RESULTS:
      For all types of colorectal neoplasms, the incidence rate in those with no
      initial neoplasm was 7.2%/year whereas recurrence rates in those with small
      adenomas and advanced lesions were 19.3% and 22.9%/year, respectively. For
      advanced colorectal lesions, the incidence rate was 0.21%/year whereas recurrence
      rates in those with small adenomas and advanced lesions were 0.64% and
      1.88%/year, respectively. Colorectal neoplasms were in general more likely to
      develop in males and older subjects. CONCLUSIONS: Although recurrence rates after
      polypectomy were elevated, the incidence rates in subjects with no neoplastic
      lesions initially were quite high.

PMID- 15016754
TI  - Methylation patterns define two types of hyperplastic polyp associated with
      colorectal cancer.
AB  - AIM: Hyperplastic polyps (HP) of the colorectum have traditionally been regarded
      as non-neoplastic lesions. Recent data implicate HP in the pathogenesis of
      colorectal cancers (CRC) characterised by extensive DNA methylation and
      microsatellite instability. The aim of this study was to identify morphological
      and molecular features that may characterise subtypes of HP with potential for
      neoplastic progression. MATERIALS AND METHODS: HP (22) clustering around distal
      CRC (group I) were compared with HP (58) in subjects with hyperplastic polyposis
      (group II). DNA methylation was tested in methylated in tumour (MINT) loci (1, 2,
      12, 31) and genes HPP1, MGMT, p14ARF, p16INK4a, and hMLH1. RESULTS: Group II HP
      showed significantly more methylation than group I HP at all loci except MINT1
      and MGMT. Group I showed the lowest frequency of DNA methylation but the highest
      frequency of K-ras mutation. Group II HP (termed HP variant) had the
      morphological features of the recently described "sessile serrated adenomas".
      Methylation of hMLH1 was found most frequently in group II polyps that included
      foci of dysplasia (7/10) and in no group I lesions. CONCLUSION: The findings
      support the existence of morphological and molecular heterogeneity among HP and
      highlight a subset that is likely to have significant malignant potential.

PMID- 15016755
TI  - Histological categorisation of fibrotic cancer stroma in advanced rectal cancer.
AB  - BACKGROUND AND AIMS: Based on conflicting reports regarding the role of the
      fibrotic stromal response in cancer development--namely, that a desmoplastic
      reaction can favour either the host or the tumour--it is clear that the role of
      the stromal response is varied. We have classified the fibrotic stroma of rectal
      adenocarcinoma penetrating the muscularis propria, based on histologically
      identified stromal components. METHODS: Three categories of stroma were used:
      mature-when the stroma was composed of mature collagen fibres (fine and elongated
      fibres into multiple layers); intermediate-when keloid-like collagen was
      intermingled with mature fibres; and immature-consisting of a myxoid stroma in
      which no mature fibres were included. RESULTS: In a data set of 862 patients, 53%
      of patients had mature fibrotic cancer stroma, 33% had intermediate stroma, and
      15% had immature stroma. Five year survival rates decreased as follows: mature
      stroma (80%), intermediate stroma (55%), and immature stroma (27%). The adverse
      tumour phenotype, tumour cell budding (conspicuous isolated cells or small
      clusters of cancer cells), was observed in the cancer fronts in tumours with
      unfavourable fibrotic stroma (p<0.0001). Based on multivariate analysis,
      categorised fibrotic stroma was selected as an independent prognostic parameter
      (hazard ratio 1.39; 95% confidence interval 1.17-1.64) together with tumour
      differentiation. By immunohistochemical examination, as maturation of the
      fibrotic stroma decreased, stromal T cells became significantly sparser.
      Furthermore, myofibroblasts were distributed extensively in immature fibrotic
      stroma compared with mature and intermediate fibrotic stroma. CONCLUSION: The
      morphological categorisation of fibrotic cancer stroma highlights the role of the
      stromal response in relation to the behaviour and host immune reactions of rectal
      adenocarcinoma and would be a useful tool for predicting patient prognostic
      outcome.

PMID- 15016756
TI  - Fatigue and primary biliary cirrhosis: association of globus pallidus
      magnetisation transfer ratio measurements with fatigue severity and blood
      manganese levels.
AB  - BACKGROUND AND AIM: Fatigue is the commonest symptom in primary biliary cirrhosis
      (PBC), affecting individuals at all stages of disease. The pathogenesis of
      fatigue in PBC is unknown although rat models suggest a central nervous system
      (CNS) cause. We examined the hypothesis that a CNS abnormality related to
      cholestasis, rather than cirrhosis per se, underlies this symptom. PATIENTS AND
      METHODS: Fourteen patients with precirrhotic PBC (stage I-II disease), four
      patients with stage III-IV PBC, and 11 healthy women were studied using cerebral
      magnetisation contrast imaging and proton magnetic resonance spectroscopy (MRS).
      RESULTS: The globus pallidus magnetisation transfer ratio (MTR), a quantifiable
      tissue characteristic that may be abnormal in the presence of normal magnetic
      resonance imaging, was significantly reduced in precirrhotic PBC patients
      compared with healthy controls. These measurements correlated with blood
      manganese levels and were more abnormal in the more fatigued subjects. There were
      no differences in MRS measurements between the three study groups, suggesting
      that the abnormal MTR was not related to hepatic encephalopathy. CONCLUSION: This
      study suggests that impairments in liver function in PBC may adversely affect the
      brain long before the development of cirrhosis and hepatic encephalopathy,
      possibly as a result of altered manganese homeostasis within the CNS.

PMID- 15016757
TI  - Hepatitis C virus among childbearing women in Scotland: prevalence, deprivation,
      and diagnosis.
AB  - OBJECTIVES: (A) To examine the prevalence and demographic characteristics of
      hepatitis C virus (HCV) infection among childbearing women in Scotland; and (B)
      to determine the extent of maternal HCV infection diagnosed prior to birth.
      METHODS: (A) Residual dried blood spot samples from routine neonatal screening,
      collected throughout Scotland during March-October 2000, were unlinked from
      identifiers and tested anonymously for HCV antibodies; and (B) electronic record
      linkage of Scotland's databases of births and diagnosed HCV infections was
      performed. RESULTS: (A) Of 30,259 samples, 121 were enzyme linked immunosorbent
      assay repeat reactive and 88 of these were confirmed as anti-HCV positive in the
      recombinant immunoblot assay, representing a seroprevalence of 0.29-0.40%. HCV
      seroprevalence was high among 25-29 year olds (0.4-0.57%), in high deprivation
      areas (0.92-1.07%), and in Greater Glasgow (0.83-0.96%) and Grampian (0.38
      0.62%). Adjusted relative risk for HCV infection was highest among residents in
      high deprivation areas of Glasgow (7.2 (95% confidence interval 2.0-25.5)). (B)
      Of 121 HCV infections found among women at delivery, 24% and 46% were estimated
      to have been diagnosed prior to pregnancy and birth, respectively. CONCLUSIONS:
      HCV prevalence among Scottish childbearing women is consistent with that expected
      from injecting drug use. Based on reported rates of mother to child transmission,
      8-11 paediatric infections are expected per annum. Diagnosis in only 24% of
      infected women prior to pregnancy indicates the extent to which HCV goes
      unrecognised in the injecting community. The current HCV screening approach-to
      test only those with a history of injecting drug use (or other risk factors for
      infection)-identifies approximately a quarter of previously undetected infections
      among pregnant women.

PMID- 15016758
TI  - Genetics of liver disease: immunogenetics and disease pathogenesis.
AB  - Understanding the genetic basis of "complex disease" has been heralded as one of
      the major challenges of the post genome era. However what are "complex diseases"
      and how will understanding the genetics of such diseases advance medical science?
      There has been a great deal of "hype" about the potential of the human genome
      mapping project. The three major claims are that this information will: (a) be
      used in diagnosis; (b) provide useful prognostic indices for disease management
      (including the development of individualised treatment regimens, based on the
      findings of both immunogenetic and pharmacogenetic studies); and (c) provide
      insight into the pathogenesis of these diseases. Of these three objectives the
      last has the greatest potential and is the least exaggerated claim. In this
      review I shall highlight major associations, discuss some of the practical issues
      that arise, and outline how current knowledge of the immunogenetic basis of
      chronic liver disease is beginning to inform the debate about disease
      pathogenesis.

PMID- 15016759
TI  - Thalidomide for treatment of severe intestinal bleeding.
AB  - Apart from its anti-inflammatory activity, which has been used for the treatment
      of active Crohn's disease, thalidomide is also a potent inhibitor of
      angiogenesis. We therefore studied the effect of thalidomide in six patients with
      severe recurrent intestinal bleeding refractory to standard treatment (three
      patients with Crohn's disease (CD), three patients with obscure intestinal
      bleeding; mean of 56 blood transfusions within the last 24 months). Bleeding
      stopped within two weeks after the start of thalidomide in all patients.
      Haemoglobin normalised without further transfusions for the whole observation
      period (mean follow up 33 months) while patients needed a mean of 2.2 (CD) and
      3.1 (obscure bleeding) blood units/month in the 12 months before treatment. After
      three months of thalidomide therapy, serum levels of vascular endothelial growth
      factor were strongly suppressed compared with pretreatment levels. (CD 818 (82) v
      129 (86) pg/ml; obscure bleeding 264 (68) v 50 (25) pg/ml). All six patients
      reported transient fatigue. Peripheral neuropathy was observed in one patient
      with CD after nine months and was reversible after lowering the dose to 100 mg
      daily. These results indicate that thalidomide might be useful for patients with
      otherwise refractory intestinal bleeding.

PMID- 15016761
TI  - Biallelic genotype distributions in papers published in Gut between 1998 and
      2003: altered conclusions after recalculating the Hardy-Weinberg equilibrium.

PMID- 15016762
TI  - A novel TEAD1 mutation is the causative allele in Sveinsson's chorioretinal
      atrophy (helicoid peripapillary chorioretinal degeneration).
AB  - Sveinsson's chorioretinal atrophy (SCRA), also referred to as helicoid
      peripapillary chorioretinal degeneration or atrophia areata, is an autosomal
      dominant eye disease, characterized by symmetrical lesions radiating from the
      optic disc involving the retina and the choroid. Genome-wide linkage analysis
      mapped the SCRA gene to chromosome 11p15 in 81 patients from a large founder
      pedigree in Iceland. The parametric LOD score obtained was 18.9 using an
      autosomal dominant model with high penetrance. Crossover analysis of the linkage
      region with 51 markers identified a 593 kb segment shared by all patients.
      Sequencing exons of the only gene in this interval, the transcriptional enhancer
      TEAD1, revealed a novel missense mutation (Y421H) carried by all patients and
      none of the 502 controls. The mutation is in a conserved amino acid sequence in
      the C terminal of the protein, a potential binding site for YAP65 one of TEAD1's
      cofactors that is expressed in human retina as well as TEAD1 based on RT-PCR
      experiments. Therefore, we conclude that the mutation in the TEAD1 gene is the
      cause of Sveinsson's chorioretinal atrophy.

PMID- 15016763
TI  - A mouse model for alpha-methylacyl-CoA racemase deficiency: adjustment of bile
      acid synthesis and intolerance to dietary methyl-branched lipids.
AB  - alpha-Methylacyl-CoA racemase (Amacr) deficiency in humans leads to sensory motor
      neuronal and liver abnormalities. The disorder is recessively inherited and
      caused by mutations in the AMACR gene, which encodes Amacr, an enzyme presumed to
      be essential for bile acid synthesis and to participate in the degradation of
      methyl-branched fatty acids. To generate a model to study the pathophysiology in
      Amacr deficiency we inactivated the mouse Amacr gene. As per human Amacr
      deficiency, the Amacr(-/-) mice showed accumulation (44-fold) of C27 bile acid
      precursors and decreased (over 50%) primary (C24) bile acids in bile, serum and
      liver, however the Amacr(-/-) mice were clinically symptomless. Real-time
      quantitative PCR analysis showed that, among other responses, the level of mRNA
      for peroxisomal multifunctional enzyme type 1 (pMFE-1) was increased 3-fold in
      Amacr(-/-) mice. This enzyme can be placed, together with CYP3A11 and CYP46A1, to
      make an Amacr-independent pathway for the generation of C24 bile acids. Exposure
      of Amacr(-/-) mice to a diet supplemented with phytol, a source for branched
      chain fatty acids, triggered the development of a disease state with liver
      manifestations, redefining the physiological significance of Amacr. Amacr is
      indispensable for the detoxification of dietary methyl-branched lipids and,
      although it contributes normally to bile acid synthesis from cholesterol, the
      putative pMFE-1-mediated cholesterol degradation can provide for generation of
      bile acids, allowing survival without Amacr. Based upon our mouse model, we
      propose elimination of phytol from the diet of patients suffering from Amacr
      deficiency.

PMID- 15016764
TI  - Mutations in AAC2, equivalent to human adPEO-associated ANT1 mutations, lead to
      defective oxidative phosphorylation in Saccharomyces cerevisiae and affect
      mitochondrial DNA stability.
AB  - Autosomal dominant and recessive forms of progressive external ophthalmoplegia
      (adPEO and arPEO) are mitochondrial disorders characterized by the presence of
      multiple deletions of mitochondrial DNA in affected tissues. Four adPEO
      associated missense mutations have been identified in the ANT1 gene. In order to
      investigate their functional consequences on cellular physiology, we introduced
      three of them at equivalent positions in AAC2, the yeast orthologue of human
      ANT1. We demonstrate here that expression of the equivalent mutations in aac2
      defective haploid strains of Saccharomyces cerevisiae results in (a) a marked
      growth defect on non-fermentable carbon sources, and (b) a concurrent reduction
      of the amount of mitochondrial cytochromes, cytochrome c oxidase activity and
      cellular respiration. The efficiency of ATP and ADP transport was variably
      affected by the different AAC2 mutations. However, irrespective of the absolute
      level of activity, the AAC2 pathogenic mutants showed a significant defect in ADP
      versus ATP transport compared with wild-type AAC2. In order to study whether a
      dominant phenotype, as in humans, could be observed, the aac2 mutant alleles were
      also inserted in combination with the endogenous wild-type AAC2 gene. The
      heteroallelic strains behaved as recessive for oxidative growth and petite
      negative phenotype. In contrast, reduction in cytochrome content and increased
      mtDNA instability appeared to behave as dominant traits in heteroallelic strains.
      Our results indicate that S. cerevisiae is a suitable in vivo model to study the
      pathogenicity of the human ANT1 mutations and the pathophysiology leading to
      impairment of oxidative phosphorylation and damage of mtDNA integrity, as found
      in adPEO.

PMID- 15016765
TI  - Mitochondrial transcription factor A regulates mtDNA copy number in mammals.
AB  - Mitochondrial DNA (mtDNA) copy number regulation is altered in several human
      mtDNA-mutation diseases and it is also important in a variety of normal
      physiological processes. Mitochondrial transcription factor A (TFAM) is essential
      for human mtDNA transcription and we demonstrate here that it is also a key
      regulator of mtDNA copy number. We initially performed in vitro transcription
      studies and determined that the human TFAM protein is a poor activator of mouse
      mtDNA transcription, despite its high capacity for unspecific DNA binding. Next,
      we generated P1 artificial chromosome (PAC) transgenic mice ubiquitously
      expressing human TFAM. The introduced human TFAM gene was regulated in a similar
      fashion as the endogenous mouse Tfam gene and expression of the human TFAM
      protein in the mouse did not result in down-regulation of the endogenous
      expression. The PAC-TFAM mice thus had a net overexpression of TFAM protein and
      this resulted in a general increase of mtDNA copy number. We used a combination
      of mice with TFAM overexpression and TFAM knockout and demonstrated that mtDNA
      copy number is directly proportional to the total TFAM protein levels also in
      mouse embryos. Interestingly, the expression of human TFAM in the mouse results
      in up-regulation of mtDNA copy number without increasing respiratory chain
      capacity or mitochondrial mass. It is thus possible to experimentally dissociate
      mtDNA copy number regulation from mtDNA expression and mitochondrial biogenesis
      in mammals in vivo. In conclusion, our results provide genetic evidence for a
      novel role for TFAM in direct regulation of mtDNA copy number in mammals.

PMID- 15016766
TI  - Characterization of the G91del CRYBA1/3-crystallin protein: a cause of human
      inherited cataract.
AB  - Congenital cataract is a leading cause of visual disability in children.
      Inherited isolated (non-syndromic) cataract represents a significant proportion
      of cases and the identification of genes responsible for inherited cataract will
      lead to a better understanding of the mechanism of cataract formation at the
      molecular level both in congenital and age-related cataract. Crystallins are
      abundantly expressed in the developing human lens and represent excellent
      candidate genes for inherited cataract. A genome-wide search of a five-generation
      family with autosomal dominant lamellar cataract demonstrated linkage to the
      17p12-q11 region. Screening of the CRYBA1/3 gene showed a 3 bp deletion, which
      resulted in a G91del mutation within the tyrosine corner, that co-segregated with
      disease and was not found in 96 normal controls. In order to understand the
      molecular basis of cataract formation, the mutant protein was expressed in vitro
      and its unfolding and refolding characteristics assessed using far-UV circular
      dichroism spectroscopy. Defective folding and a reduction in solubility were
      found. As the wild-type protein did not refold into the native conformation
      following unfolding, a corresponding CRYBB2 mutant was genetically engineered and
      its refolding characteristics analysed and compared with wild-type CRYBB2. Its
      biophysical properties support the hypothesis that removal of the glycine residue
      from the tyrosine corner impairs the folding and solubility of beta-crystallin
      proteins. This study represents the first comprehensive description of the
      biophysical consequences of a mutant beta-crystallin protein that is associated
      with human inherited cataract.

PMID- 15016767
TI  - Cloning of a new familial t(3;8) translocation associated with conventional renal
      cell carcinoma reveals a 5 kb microdeletion and no gene involved in the
      rearrangement.
AB  - This study describes the molecular cloning of a familial translocation,
      t(3;8)(p14.2;q24.2), that segregates with the conventional renal cell carcinoma
      (conventional RCC). We had previously reported the family history and, through
      loss of heterozygosity and comparative genomic hybridization, detected the loss
      of the 3p chromosome arm and somatic mutation in the retained von Hippel-Lindau
      gene in some members of the family. With the help of array painting and sequence
      tagged site-PCR on flow-sorted derivative chromosomes, we have cloned the
      breakpoints of the translocation. We have studied the junctions on both
      derivative chromosomes at the genomic and expression levels. The analysis of the
      sequence revealed a 5 kb microdeletion at the chromosome 3 breakpoint together
      with a high density of repetitive motifs (Alu, short interspersed nuclear
      element) and an AT-rich region. Both chromosome 3 and 8 rearranged regions were
      very poor in gene content. We tested an expressed sequence tag, two predicted
      genes, one novel gene and LRIG1, a gene located more than 200 kb apart from the
      breakpoint on chromosome 3. None of these genes, except LRIG1, showed expression
      in any of the tested tissues (including normal adult and fetal kidney, sporadic
      kidney tumours and tumour samples from the proband's family). Taken together, all
      these data suggest that, rather than deregulation of specific genes that may be
      rearranged by the translocation, the proposed three-step model of tumour
      development (translocation, loss of the 3p chromosome, and mutation in a tumour
      suppressor gene located within that region) could be the biological mechanism
      that takes place in this familial form of conventional RCC.

PMID- 15016768
TI  - What is the most relevant standard of success in assisted reproduction? Defining
      outcome in ART: a Gordian knot of safety, efficacy and quality.
AB  - In the course of the present Debate series, several new outcome measures for
      assisted reproduction have been proposed to encourage the transfer of fewer
      embryos, in order to diminish the number of multiple pregnancies. The
      implementation of these recommendations, however, is hampered by the perception
      that safety and efficacy are communicating vessels: it is presumed that by
      decreasing the number of embryos transferred, pregnancy rates will decrease as
      well. Data from national and international registries, however, do not confirm
      the assumption of the communicating vessels: pregnancy rates tend to be low in
      countries in which many embryos are transferred, and the highest pregnancy rates
      occur where the number of embryos per transfer is low. Only top-level clinics
      (where treatment efficacy is guaranteed) are able to decrease the number of
      embryos transferred without compromising their pregnancy rate, and to vouch for
      safety in this way. Elective single embryo transfer (eSET) can never be mandatory
      in all patients, but the percentage of eSETs performed by a particular assisted
      reproduction treatment centre does reflect its quality: the ultimate outcome
      measure of efficacy and safety. Therefore, the eSET rate is the most relevant
      qualifier of performance in assisted reproduction.

PMID- 15016769
TI  - Polycystic ovary syndrome in adolescence--a therapeutic conundrum.
AB  - The polycystic ovary syndrome (PCOS) often presents in adolescence with menstrual
      disorders, acne and hirsutism. The early diagnostic signs are sometimes dismissed
      as 'normal' changes of adolescence, and the opportunity to save the teenager from
      the stigmata of the syndrome is missed. The finding that the metabolic syndrome
      is a possible long-term sequela of PCOS now presents a challenge to make an early
      diagnosis, educate patients regarding the importance of weight control and
      exercise, and treat accordingly both symptomatically and prophylactically. The
      use of long-term insulin sensitizers, particularly metformin, for these purposes
      in adolescents is now the subject of an inter-disciplinary debate. Good, hard
      supportive data are not yet forthcoming but, as in the adult, the establishment
      of metformin treatment for the hyperinsulinaemic adolescent with PCOS may precede
      the evidence.

PMID- 15016770
TI  - Endometrial and subendometrial blood flow measured during early luteal phase by
      three-dimensional power Doppler ultrasound in excessive ovarian responders.
AB  - BACKGROUND: Impaired implantation in assisted reproduction cycles with high serum
      estradiol (E(2)) concentrations may be related to suboptimal endometrial
      perfusion. Endometrial and subendometrial blood flow were compared between
      excessive responders (serum E(2) on the day of HCG >20 000 pmol/l) and moderate
      responders (E(2) < or =20 000 pmol/l). METHODS: Three-dimensional (3D) ultrasound
      examination with power Doppler was performed 2, 4 and 7 days after HCG in 32
      patients who did not have embryo transfer in order to measure endometrial
      thickness, pulsatility index (PI)/resistance index (RI) of uterine vessels, and
      endometrial volume, vascularization index (VI)/flow index (FI)/vascularization
      flow index (VFI) of endometrial and subendometrial regions. RESULTS: Excessive
      responders tended to have lower endometrial and subendometrial VI/VFI on HCG +2
      and more absent endometrial/subendometrial blood flow. They had significantly
      higher endometrial FI and subendometrial VFI than moderate responders on HCG +7.
      Only in the excessive responder group, uterine PI/RI declined significantly from
      HCG +2 to HCG +7 and endometrial VI/VFI increased significantly from HCG +4 to
      HCG +7. CONCLUSION: Changes in uterine Doppler flow indices, and endometrial and
      subendometrial 3D power Doppler flow indices during the early luteal phase were
      significantly different between moderate and excessive responders.

PMID- 15016771
TI  - Adrenomedullin and vascular endothelial growth factor production by follicular
      fluid macrophages and granulosa cells.
AB  - BACKGROUND: Human follicular fluid contains several substances, such as cytokines
      and growth factors, which may affect follicular growth and maturation. The
      present study examines the relative contribution of macrophages and granulosa
      cells in the production of vascular endothelial growth factor (VEGF) and
      adrenomedullin in the human ovulatory follicle. METHODS: Both follicular fluid
      samples and blood samples were obtained at the time of oocyte retrieval following
      ovarian stimulation from 20 women undergoing IVF treatment because of male
      infertility. Human follicular fluid macrophages and luteinized granulosa cells
      were obtained from pooled follicular fluid of individual patients. Accumulation
      of VEGF and adrenomedullin in the culture medium of the isolated macrophages and
      human granulosa cells was determined at variable time intervals ranging from 0 to
      48 h. Plasma and follicular fluid concentrations of VEGF and adrenomedullin were
      also measured. RESULTS: The follicular fluid concentrations of VEGF and
      adrenomedullin were significantly higher than those found in plasma. After 48 h,
      accumulation of VEGF in the culture medium of follicular fluid macrophages was
      significantly higher than that released in the culture medium of luteinized
      granulosa cells. In contrast, the production rate of adrenomedullin by follicular
      fluid macrophages was similar to that found in granulosa cells. VEGF secreted by
      follicular fluid macrophages increased progressively within 48 h of cell culture.
      A similar response pattern was observed with the culture medium of luteinized
      granulosa cells, but with lower production rates. CONCLUSIONS: This study
      suggests for the first time that both luteinized granulosa cells and macrophages
      actively secrete VEGF and adrenomedullin into follicular fluid in the human
      ovary.

PMID- 15016772
TI  - 'You are a man because you have children': experiences, reproductive health
      knowledge and treatment-seeking behaviour among men suffering from couple
      infertility in South Africa.
AB  - BACKGROUND: In Africa, infertility traditionally has been viewed as a female
      problem. This study explores reproductive health knowledge, health-seeking
      behaviour and experiences related to involuntary childlessness in men suffering
      from couple infertility. METHODS: Twenty-seven men from a diverse cultural urban
      community in South Africa participated in in-depth interviews at the time of
      their first visit to an infertility clinic in a tertiary referral centre.
      RESULTS: Men had little knowledge about the physiology of human fertility, causes
      of infertility and modern treatment options. Awareness of male factor infertility
      was, however, high. Most men appeared involved in the health-seeking process. Men
      described their emotional reactions to childlessness and the impact of
      infertility on marital stability, and many reported that infertile men suffered
      from stigmatization, verbal abuse and loss of social status. CONCLUSIONS: These
      findings improve our understanding of the reproductive health needs of men
      suffering from couple infertility in Africa. This understanding is essential for
      the effective integration of male partners into modern infertility management.
      The need for appropriate counselling of men and, most particularly, for education
      of the community is recognized.

PMID- 15016773
TI  - DNA integrity and motility of human spermatozoa after standard slow freezing
      versus cryoprotectant-free vitrification.
AB  - BACKGROUND: In contrast to the technique of conventional freezing, the
      vitrification of spermatozoa requires high cooling rates (720 000 degrees K/min),
      which could be damaging for spermatozoa. The aim of our study was to compare
      slowly frozen and vitrified spermatozoa in terms of their post-thaw DNA integrity
      and motility. METHODS: Semen samples were prepared according to the routine swim
      up technique and divided into aliquots for comparison of fresh, conventionally
      frozen and vitrified spermatozoa from the same ejaculate in the presence or
      absence of cryoprotectants. Spermatozoa motility and DNA integrity were
      determined. RESULTS: The motility of spermatozoa conventionally (slowly) frozen
      with a cryoprotectant was similar to that recorded for spermatozoa vitrified in
      the absence of cryoprotectant (47 versus 52%). The DNA integrity was unaffected
      by the cryopreservation method or presence of cryoprotectants. CONCLUSION: The
      vitrification of human spermatozoa in the absence of conventional cryoprotectants
      is indeed feasible. The DNA integrity of vitrified sperm is comparable with that
      shown by standard slow-frozen/thawed spermatozoa, yet the method is quick and
      simple and does not require special cryobiological equipment.

PMID- 15016774
TI  - Hypothalamic-pituitary-gonadal axis function after successful kidney
      transplantation in men and women.
AB  - BACKGROUND: Renal transplantation (RT) is the most common solid organ transplant
      procedure. Several studies have reported on gonadal function in male and female
      RT recipients with controversial results. METHODS: Forty consecutive patients (20
      male, 20 female) with a fully functioning allograft (serum creatinine 0.8-1.3
      mg/dl) for at least 15 months after RT were included in the study. Their ages
      ranged from 23 to 44 years (median 38) and their post-RT follow-up lasted 15-86
      months (median 23). FSH, LH, prolactin, 17-beta-estradiol, testosterone,
      androstenedione and dehydroepiandrostrone were determined in all patients and
      compared with a group of 80 healthy subjects. Pelvic ultrasonography was
      performed in all participants. RESULTS: Testosterone was below the normal range
      in 70% of male patients and within the lowest third in the remainder; a lack of
      LH increase indicated an inhibition of the reproductive axis. Male testosterone
      values were negatively influenced by calcineurine inhibitors treatment (P <
      0.005), but positively influenced by a better graft function (P < 0.0001).
      Testicular and prostate volumes were reduced with respect to controls, with the
      latter related to circulating testosterone levels. Ten of the women (50%) had
      menstrual cycle disorders after RT, three being affected by transient, and three
      by persistent, amenorrhea. Another two patients had had transient polymenorrhea.
      In four women (20%), a premature ovarian failure was diagnosed. No relationship
      was found between female reproductive function and age, graft function or
      duration of the post-transplant period. Prolactin was lower in patients on
      calcineurin inhibitors (P < 0.01). CONCLUSIONS: Abnormalities of the reproductive
      system were frequent after successful RT in both genders.

PMID- 15016775
TI  - 'Over-ripeness ovopathy, sex ratio increase and sex ratio reversal a challenging
      hypothesis for sex ratio modulation': an alternative interpretation.
AB  - It is suggested here that Jongbloet has misinterpreted data on the variation of
      sex ratio with maternal age, social class, placental dysfunction, twinning and
      season. When all these matters are considered, it is not clear whether there is
      any truth in his supposition that male fetuses are generally conceived in
      suboptimal conditions. Finally, it is suggested that there is a circularity in
      his presentation of his concept of sex ratio 'reversal'.

PMID- 15016776
TI  - Endothelial function in post-menopausal women: effect of folic acid
      supplementation.
AB  - BACKGROUND: Higher than normal homocysteine levels are associated with an
      increased incidence of adverse cardiovascular events in post-menopausal women,
      perhaps via hyperhomocysteinaemia-induced vascular endothelial damage. Because
      folic acid supplementation reduces homocysteine levels, we attempted to evaluate
      whether folic acid supplementation may affect endothelial function in post
      menopausal women. METHODS: Brachial artery flow-mediated dilatation (endothelium
      dependent) and nitroglycerin-induced dilatation (endothelium-independent) before
      and after a methionine load were analysed in 15 healthy post-menopausal women.
      Plasma levels of folate, homocysteine, glucose, insulin and lipids were measured,
      as was blood pressure. All studies were repeated after 1 month supplementation
      with 7.5 mg/day of folic acid. RESULTS: After folate, endothelial function rose
      37% over pre-folic acid supplementation value (P < 0.001), and flow-mediated
      dilation before folic acid was reduced by 62% subsequent to methionine loading (P
      < 0.0001); this reduction was still present after folic acid, but was only 19% (P
      < 0.001). Nitroglycerin-induced dilatation did not change in response to
      methionine loading before or after folic acid supplementation. Among the other
      cardiovascular risk factors studied, only high-density lipoprotein (HDL)
      cholesterol and low-density lipoprotein (LDL)-cholesterol showed significant
      changes after folic acid supplementation, with a 6% increase (P < 0.03) and a 9%
      decrease (P < 0.03) respectively. CONCLUSIONS: Although preliminary, these
      results indicate that folic acid supplementation may improve endothelial function
      and lipid profile in post-menopausal women, thus contributing to reduce their
      cardiovascular risk.

PMID- 15016777
TI  - The recombinant subdomain IIIB of human serum albumin displays activity of
      gonadotrophin surge-attenuating factor.
AB  - BACKGROUND: Gonadotrophin surge-attenuating factor (GnSAF) is an as yet
      unidentified ovarian factor that acts on the pituitary to attenuate the pre
      ovulatory LH surge. In a previous study, GnSAF bioactivity was proposed to
      derive, at least in part, from a C-terminal domain (95peptide) of human serum
      albumin (HSA). METHODS AND RESULTS: We employ here the expression-secretion
      system of Pichia pastoris to produce and assay selected recombinant polypeptides
      of HSA for GnSAF activity. We show that the C-terminal 95peptide of HSA (residues
      490-585; subdomain IIIB) can be expressed from P.pastoris in secreted form and
      supernatants from clones expressing this polypeptide reduce the GnRH-induced LH
      secretion of primary rat pituitary cultures by 50-82%. When expressed in the same
      system, HSA domain III (residues 381-585) or full-length HSA (residues 1-585) are
      inactive. The bioactive subdomain IIIB is also separable from either domain III
      or full-length HSA on Blue Sepharose chromatography. CONCLUSIONS: Taken together,
      the findings highlight the putative importance of HSA subdomain IIIB as a GnSAF
      bioactive entity and introduce a unique experimental tool to engineer this
      molecule for structure-function analysis.

PMID- 15016778
TI  - Case report: natural transmission of an AZFc Y-chromosomal microdeletion from
      father to his sons.
AB  - Y-chromosomal microdeletions, associated with oligozoospermia or azoospermia, are
      usually de novo deletions in the affected patients. We report here the rare case
      of an affected father who transmitted a Y-chromosomal microdeletion to at least
      two of his three sons naturally and who also fathered a daughter. The extent of
      the deletion, which was determined with new STS-primers and covers 3.5 Mb, was
      identical in the father and his azoospermic sons. To determine any possibly
      modifying influence of other genes involved in spermatogenesis, we analysed two
      polymorphisms of the DAZL gene, the autosomal homologue of the deleted DAZ gene.
      DAZL and DAZ might be functionally related to each other. However, we found
      identical polymorphisms in exon 2 and 3 of the DAZL gene, in both father and his
      sons, corresponding to the most prevalent genotype in fertile men. Thus, other
      genes or environmental factors must modify spermatogenesis in men with identical
      Y-chromosomal microdeletions.

PMID- 15016780
TI  - Pituitary suppression in ultrasound-monitored frozen embryo replacement cycles. A
      randomised study.
AB  - BACKGROUND: This study was designed to assess the value of using a gonadotrophin
      releasing hormone (GnRH) agonist prior to exogenous steroid supplementation for
      endometrial preparation in frozen-thawed embryo replacement (FER) cycles.
      METHODS: A prospective randomized trial of 234 patients undergoing FER cycles was
      conducted. The study population was randomly divided into two groups according to
      a computer-generated list. In group A (n = 117), a daily dose of 6 mg of oral
      estradiol valerate was initiated on menstrual day 1 following pituitary
      suppression using 400 mcg buserelin acetate daily. In group B (n = 117), the same
      dose of estradiol valerate was initiated on day 1 of bleeding without prior GnRH
      agonist therapy. In both groups, ovulation monitoring was not undertaken and
      progesterone pessaries (800 mg daily) were administrated when the endometrial
      thickness had reached 8 mm or more with embryo transfer taking place 2 days
      later. RESULTS: The two groups were comparable with respect to cause of
      infertility, age at stimulation (32.8 +/- 4 vs 33.2 +/- 3.9 years, P = 0.4),
      basal FSH level (6.3 +/- 1.7 vs 6.4 +/- 2 IU/l, P = 0.5), number of oocytes
      collected (16.9 +/- 7.3 vs 16.5 +/- 7.4, P = 0.7) and fertilized normally in the
      retrieval cycle (11.5 +/- 4.9 vs 11 +/- 4.9, P = 0.4) and number of embryos
      cryopreserved (6.6 +/- 3.6 vs 6.2 +/- 3.6, P = 0.3). There was no significant
      difference between the two groups in age at frozen replacement (33.6 +/- 4.2 vs
      34 +/- 3.9 years, P = 0.4), duration of the proliferative phase (20.7 +/- 8.6 vs
      21 +/- 9.2 days, P = 0.7) and number of thawed embryos replaced (2.3 +/- 0.6 vs
      2.2 +/- 0.6, P = 0.2). However, compared with group B, group A achieved
      significantly higher pregnancy (37.6% vs 24%, OR 1.8, 95%CI 1.1-3.4), clinical
      pregnancy (24% vs 11.3%, OR 2.5, 95%CI 1.2-5.5) and live birth rates (20% vs
      8.5%, OR 2.9, 95%CI 1.2-8). CONCLUSION: Medicated frozen embryo replacement
      cycles timed by endometrial thickness measurement alone without monitoring or
      suppression of ovarian activity are associated with reduced outcome.

PMID- 15016779
TI  - Impact of highly purified urinary FSH and recombinant FSH on haemostasis: an open
      label, randomized, controlled trial.
AB  - BACKGROUND: It has recently been suggested that recombinant FSH administration
      may result in an increased risk of venous thrombosis. An open-label, randomized,
      controlled trial was carried out to compare the impact of urinary and recombinant
      FSH on haemostasis. METHODS: Fifty infertile women were randomized, using a
      random number generator on a personal computer, to receive either highly purified
      urinary FSH (u-hFSH) or recombinant human FSH (r-hFSH); a starting dose of 150
      IU. Human chorionic gonadotrophin 10000 IU was administered once there was at
      least one follicle > or =18 mm. The luteal phase was supported with progesterone
      50 mg/day for at least 15 days. Fifty normally menstruating women were recruited
      as controls. Repeated measurements of estradiol, progesterone, prothrombin time
      (PT) expressed as INR, activated partial thromboplastin time (APTT) ratio,
      fibrinogen (FBG), factor VIII (FVIII), normalized activated protein C ratio (nAPC
      ratio), antithrombin III activity (AT), protein C activity (PC), protein S
      activity (PS), tissue-type plasminogen activator antigen (t-PA), type 1
      plasminogen activator inhibitor (PAI), prothrombin fragments 1+2 (F1+2), were
      performed during both hyperstimulated and natural cycles, and at onset of the
      following menstruation or at 8 weeks of pregnancy. RESULTS: At the end of
      gonadotrophin administration PT INR increased in the u-hFSH group, while AT and t
      PA significantly decreased. In the patients treated with r-hFSH, only F1+2
      significantly decreased. No significant changes were observed in the control
      group. In the luteal phase FBG increased significantly in all groups. In the u
      hFSH group no other significant changes were noted compared to pre-ovulatory
      values, while compared to baseline values AT, PS and t-PA significantly
      decreased. In the r-hFSH group during the luteal phase PT INR significantly
      decreased, but did not differ from baseline levels. Other parameters such as FBG,
      FVIII, t-PA, rose significantly, but only FVIII and FBG values were significantly
      higher than baseline levels. In the women who became pregnant a significant
      increase in t-PA and a significant decrease in PS at the midluteal phase were
      observed. After one month all the haemostatic parameters returned to baseline
      value if pregnancy failed to occur, while in the pregnant women a significant
      increase in FVIII and a significant decrease in PS were observed. CONCLUSIONS:
      Ovarian stimulation with recombinant FSH does not influence coagulation and
      fibrinolysis significantly, as already reported for urinary gonadotrophins. The
      moderate changes induced by both treatments are no longer detectable after 4
      weeks.

PMID- 15016781
TI  - What is the most relevant standard of success in assisted reproduction?: no
      single outcome measure is satisfactory when evaluating success in assisted
      reproduction; both twin births and singleton births should be counted as
      successes.
AB  - The 2002 recommendation of the consensus meeting of the European Society of Human
      Reproduction and Embryology (ESHRE) that the outcome measure of assisted
      reproductive technology (ART) and non-ART should be 'singleton live birth rate'
      could profoundly effect the ability of infertility patients to become pregnant.
      We reviewed published reports and new data concerning elective single embryo
      transfer (eSET) vs. double embryo transfer (DET) and the outcome of twin
      pregnancies in the United States, as well as recommendations of other Societies
      concerning number of embryos to transfer and methods used to measure ART success.
      We found that no single outcome measure of ART is ideal. Mandatory eSET would
      result in 42%-70% fewer births compared to DET. Infertility treatments account
      for only 12% of all twin pregnancies and 4% of all premature births in the United
      States. Twin and singleton births due to ART do not occur earlier than
      spontaneously conceived twins and singletons unless they started as triplet and
      higher order pregnancies. Multiple outcome measures are necessary when evaluating
      ART success. Twin as well as singleton births should be counted as ART successes.
      The essential aim of infertility treatment should be a healthy low order
      (singleton or twin) birth.

PMID- 15016782
TI  - Enrichment and identification of human 'fetal' epidermal stem cells.
AB  - BACKGROUND: Human epidermis, a continuously renewing tissue, is maintained
      throughout life by stem cells that proliferate and replenish worn-out or damaged
      cells in the tissue. Cultured human epidermal stem cells have great potential in
      clinical application. However, isolating and culturing a pure population of
      epidermal stem cells has proven to be challenging. METHODS AND RESULTS: We show
      that p63, a new marker for epidermal stem cells, is expressed in the basal layer
      of human fetal epidermis using immunohistochemistry, and that keratinocytes with
      the characteristics of stem cells can be isolated from the epidermis of aborted
      human fetuses aged >/=20 weeks based on high expression of beta(1) integrins by
      fluorescence-activated cell sorting. Furthermore, the enriched population showed
      the expression of molecular markers of putative human epidermal stem cells under
      a confocal microscope and a high colony formation efficiency when it was cultured
      at a clonal density. Under an electron microscope the sorted stem cells exhibited
      a high nuclear:cytoplasmic ratio and fewer organelles than the transit amplifying
      cells. The cultured epidermal stem cells can also be amplified and induced to
      terminal differentiation by suspension in vitro. CONCLUSIONS: Human 'fetal'
      epidermal stem cells have been successfully isolated and cultured in vitro. The
      cultured human epidermal stem cells could be used as a tool for studying stem
      cell biology and testing stem cell therapy.

PMID- 15016783
TI  - Concentrations of endometrial protein PP 14 and CA-125 in uterine flushings
      performed in natural and stimulated cycles.
AB  - BACKGROUND: Impaired implantation in assisted reproduction cycles with high serum
      estradiol (E(2)) concentrations may be attributed to abnormal endometrial
      development. This study compared concentrations of endometrial proteins in
      uterine flushings of infertile patients between natural and stimulated cycles.
      METHODS: Patients received a standard regimen of ovarian stimulation. Seven days
      after the LH surge in natural cycles or the hCG injection in stimulated cycles,
      uterine flushings were performed by slowly injecting and aspirating normal saline
      through a paediatric Foley catheter. Natural cycles were considered as group A
      whereas stimulated cycles with serum E(2) <20 000 pmol/l and serum E(2) >20 000
      pmol/l were classified as groups B and C respectively. PP 14 and CA-125 in
      uterine flushings were measured and expressed per total protein content. RESULTS:
      Concentrations of the total protein, PP 14 and CA-125 in the uterine flushings
      were similar among the three groups. PP 14 per total protein in the uterine
      flushings was significantly correlated with serum E(2) on the day of hCG (r =
      0.459; P = 0.009) in natural cycles only but not in stimulated cycles.
      CONCLUSION: There was no significant difference between natural and stimulated
      cycles in concentrations of PP 14 and CA-125 in uterine flushings performed in
      the mid-luteal phase.

PMID- 15016784
TI  - Preferential infiltration of large bowel endometriosis along the nerves of the
      colon.
AB  - BACKGROUND: Little is known about the mode and the extent of infiltration of
      endometriotic lesions in the large bowel. METHODS: In 31 patients undergoing
      large bowel resection for severe deep-infiltrating endometriosis of the sigmoid
      and rectum with severe digestive symptoms, we performed a prospective
      morphological, histological and immunohistological study (using the monoclonal
      antibodies S100 for the detection of the nerves and CD10 for the detection of the
      endometriotic stromal cells) on the large bowel resection specimen. The
      evaluation of invasion of the large bowel by endometriosis was performed by
      studying the presence, localization and mean number of lesions in the different
      layers of the colon, the relationship between endometriosis and the nerves of the
      colon, the nerve density in the respective layers of the large bowel and the
      presence of endometriosis on the resection margins. RESULTS: The most richly
      innervated layers of the large bowel are the most intensely involved by
      endometriosis. We found that 53 +/- 15% of endometriotic lesions were in direct
      contact the nerves of the colon by means of perineurial or endoneurial invasion.
      The mean largest diameter of the lesion does not seem to be correlated with the
      depth of infiltration. The margins were positive in 9.7% of cases. In cases of
      positive margins, the endometriotic lesions were in close histological
      relationship with the nerves. CONCLUSIONS: There is a close histological
      relationship between endometriotic lesions of the large bowel and the nerves of
      the large bowel wall. Endometriotic lesions seem to infiltrate the large bowel
      wall preferentially along the nerves, even at distance from the palpated lesion,
      while the mucosa is rarely and only focally involved.

PMID- 15016785
TI  - A successful model to assess embryo development after transplantation of prophase
      nuclei.
AB  - BACKGROUND: Germinal vesicle transplantation (GVT) provides a means of
      investigating interactions between karyoplasts and cytoplasts isolated from
      different cells. Technically, GVT can be accomplished with a high degree of
      efficiency without compromising the maturation of either the human or mouse
      oocyte nucleus. Although maturation, fertilization and preimplantation
      development have been established using GVT, full-term development has been
      reported only after supplementation with fresh mature ooplasm. In this study, we
      assess the ability of immature oocytes collected from gonadotrophin-primed
      ovaries to mature in vitro after GVT and develop to full-term. METHODS: GV
      oocytes were retrieved from either non-stimulated or pregnant mare's serum
      gonadotrophin (PMSG)-primed female mice. Microsurgically isolated GV karyoplasts
      were transplanted into previously enucleated oocytes. Oocytes successfully
      reconstituted by electrofusion were cultured for 14 h to allow nuclear
      maturation. Metaphase II oocytes were subjected to Piezo-ICSI, and those
      fertilized normally were cultured to the blastocyst stage. Some such embryos were
      transferred to pseudopregnant female mice to examine their potential for normal
      development. Cumulus-denuded non-manipulated oocytes that were matured in vitro
      served as controls. RESULTS: The reconstitution and maturation rates were
      comparable in oocytes isolated from PMSG-primed and from unstimulated ovaries.
      The rate of normal fertilization in oocytes from primed ovaries was significantly
      higher than that of their non-primed counterparts (63.5 versus 39.6%; P < 0.01).
      This difference was also confirmed in terms of blastocyst development (31.8
      versus 7.9%; P < 0.01). Of a total of 70 embryos transferred to the oviduct of
      five recipient mice, 21.4% developed to normal live offspring. All developed as
      normal adults and proved to be fertile. The live birth rate was comparable to
      that obtained using non-manipulated control oocytes (22.3%). CONCLUSIONS: Higher
      rates of fertilization and blastocyst formation were obtained after GVT of mouse
      oocytes isolated from PMSG-primed ovaries compared with their non-primed
      counterparts. These represent the first mouse offspring derived from in vitro
      matured, cumulus-denuded oocytes treated by allo-GVT and fertilized by ICSI.
      Thus, GVT appears not to impair oocyte maturation, fertilization and pre- and
      post-implantation development and, after gonadotrophin priming, allows generation
      of healthy mouse offspring without mature ooplasm supplementation.

PMID- 15016787
TI  - A postal survey of hydrosalpinx management prior to IVF in the United Kingdom.
AB  - BACKGROUND: In the last decade, numerous studies have demonstrated concern about
      the presence of hydrosalpinx and its management in patients undergoing IVF. We
      evaluated the current management of hydrosalpinx prior to IVF treatment in the
      UK. METHODS: A total of 117 postal survey, anonymous, sealed questionnaires were
      sent to all IVF centres in the UK, to determine the policy for the management of
      hydrosalpinx in infertile women prior to IVF treatment. RESULTS: There were 88
      (75%) responders, of which 80 (91%) indicated that they discussed the effect of
      hydrosalpinx on IVF outcome. Ten (12%) units did not recommend treatment of
      hydrosalpinx prior to IVF treatment, while 30 (36%), 27 (33%) and 16 (19%)
      recommended treatment weakly, strongly and very strongly respectively. The
      treatment options offered by clinicians were laparoscopic salpingectomy (75%),
      open salpingectomy (45%), salpingostomy (40%), proximal tubal occlusion (34%),
      transvaginal songraphic (TVS) aspiration during oocyte collection (23%) and TVS
      aspiration before oocyte collection (10%). The frequency of use varied from one
      option of treatment to another. Only 28% of the responders had a protocol or
      guidelines for the management of hydrosalpinx. CONCLUSIONS: More attention should
      be given to patients with hydrosalpinx prior to IVF treatment and patients should
      be counselled about the negative effect of hydrosalpinx on IVF outcome. There is
      a wide variation in the management of hydrosalpinx prior to IVF treatment in the
      UK and many treatment options may be questionable, as they are not yet based on
      evidence.

PMID- 15016786
TI  - An elevated basal FSH reflects a quantitative rather than qualitative decline of
      the ovarian reserve.
AB  - BACKGROUND: Many cycling women with elevated basal FSH level have been
      discouraged from undergoing IVF treatment. This is because elevated basal FSH is
      associated with poorer assisted reproduction treatment outcome. It has been
      argued that high FSH reflects not only reduced ovarian reserve but also poor
      oocyte quality. The aim of this study is to assess the value of treating cycling
      women who have elevated basal FSH and to assess the reasons for the reduction in
      both pregnancy rate (PR) and live birth rate (LBR). METHODS: Between January 1997
      and December 2001, 2057 patients underwent 3401 consecutive IVF/ICSI cycles in
      which the basal level of FSH (days 2-4) was determined at an earlier cycle.
      Analysis, however, was only performed for a single cycle per patient. All cases
      were divided into four cohorts according to FSH levels: group A, FSH <10 IU/ml;
      group B, 10.1-15 IU/ml; group C, 15.1-20 IU/ml; and group D, FSH >20 IU/ml. Each
      group was stratified further into subgroups according to age, < or =38 and >38
      years. RESULTS: Both PR (A, 32.3%; B, 19.8%; C, 17.5%; and D, 3%) and LBR (A,
      24.7%; B, 13.2%; C, 13.8%; and D, 3%) were significantly reduced in the higher
      FSH level groups. LBR was significantly higher in the younger subgroups (A,
      32.2%; B, 21.8%; C, 20%; and D, 16.7%) as compared with the older subgroups (A,
      12.1%; B, 8.3%; C, 10.5%; and D, 0%). Higher levels of FSH were significantly
      associated with more cycle cancellation, a larger amount of gonadotrophin
      required to achieve follicular maturity, and a lower number of eggs collected,
      embryos available and embryos transferred. In all cases, however, there was no
      significant correlation between FSH levels and fertilization rate or miscarriage
      rate. Younger cycling women with elevated FSH had significantly higher LBR
      compared with older women with normal FSH (21.2% versus 12.1%). Furthermore, the
      cumulative LBR after three cycles in these younger patients with elevated FSH
      levels was 49.3%. CONCLUSION: Although there is a reduction in both PR and LBR
      associated with higher levels of basal FSH, it is clear that in cycling women,
      high basal FSH is not a contraindication to IVF treatment, and a respectable PR
      and LBR can be achieved especially in young women. The reduction in PR and LBR is
      due to reduced reserve rather than poor oocyte quality. Clinics refusing to treat
      cycling women with elevated basal FSH levels may be denying these women a
      reasonable, albeit low, chance of achieving a birth with their own genetic
      material. Clinicians should use basal FSH levels as a guide to advise patients
      about their chances of achieving a live birth, not to exclude patients with a
      predicted lower success rate from a treatment programme.

PMID- 15016789
TI  - Lower body negative pressure as a model to study progression to acute hemorrhagic
      shock in humans.
AB  - Hemorrhage is a leading cause of death in both civilian and battlefield trauma.
      Survival rates increase when victims requiring immediate intervention are
      correctly identified in a mass-casualty situation, but methods of prioritizing
      casualties based on current triage algorithms are severely limited. Development
      of effective procedures to predict the magnitude of hemorrhage and the likelihood
      for progression to hemorrhagic shock must necessarily be based on carefully
      controlled human experimentation, but controlled study of severe hemorrhage in
      humans is not possible. It may be possible to simulate hemorrhage, as many of the
      physiological compensations to acute hemorrhage can be mimicked in the laboratory
      by applying negative pressure to the lower extremities. Lower body negative
      pressure (LBNP) sequesters blood from the thorax into dependent regions of the
      pelvis and legs, effectively decreasing central blood volume in a similar fashion
      as acute hemorrhage. In this review, we compare physiological responses to
      hemorrhage and LBNP with particular emphasis on cardiovascular compensations that
      both share in common. Through evaluation of animal and human data, we present
      evidence that supports the hypothesis that LBNP, and resulting volume
      sequestration, is an effective technique to study physiological responses and
      mechanisms associated with acute hemorrhage in humans. Such experiments could
      lead to clinical algorithms that identify bleeding victims who will likely
      progress to hemorrhagic shock and require lifesaving intervention(s).

PMID- 15016790
TI  - Microneurography: how the technique developed and its role in the investigation
      of the sympathetic nervous system.
AB  - A historical review is given of the development of microneurography and its
      application for studies of sympathetic nerve activity in humans.

PMID- 15016791
TI  - RhoA expression during recovery from skeletal muscle disuse.
AB  - Functional overload and anabolic steroid administration induce signaling pathways
      that regulate skeletal muscle RhoA expression. The purpose of this study was to
      determine RhoA and associated protein expression at the onset of disuse and after
      a brief period of reloading. Male Sprague-Dawley rats were randomly assigned to
      cage control (Con), 3 days of hindlimb suspension (Sus), or 3 days of hindlimb
      suspension with 12 h of reloading (12-h Reload). The reloading stimuli consisted
      of 12 h of resumed normal locomotion after 3 days of hindlimb suspension.
      Plantaris muscle-to-body weight (mg/g) ratio decreased 17% from Con with Sus but
      returned to Con with 12-h Reload, increasing 13% from Sus. Sus decreased RhoA
      protein concentration 46%, whereas 12-h Reload induced a 24% increase compared
      with Sus. The ratio of cytosolic- to membrane-associated RhoA protein was not
      changed with either Sus or 12-h Reload. RhoA mRNA concentration was decreased 48%
      by Sus, and 12-h Reload induced a 170% increase from Sus. beta(1)-Integrin
      protein, a transmembrane protein associated with RhoA activation, was not altered
      by Sus but increased 155% with 12-h Reload. Although beta(1)-integrin mRNA was
      not altered by Sus, it increased 70% from Con with 12-h Reload. Rho family member
      Cdc42 protein associated with the muscle membrane was decreased 60% with Sus, and
      12-h Reload induced a 172% increase compared with Sus. In conclusion, decreased
      RhoA protein expression and mRNA abundance are early adaptations to disuse but
      recover rapidly after normal locomotion is resumed.

PMID- 15016792
TI  - Historical analysis of the neural control of movement from the bedrock of animal
      experimentation to human studies.
AB  - The history of the investigation of the sensorimotor control of movement is
      outlined from its inception at the beginning of the 19th century. Particular
      emphasis is placed on the opening up of new possibilities by the development of
      new techniques, from chronophotography to magnetic brain stimulation, all of
      which have exploited developments in technology. Extrapolating from history,
      future advance in physiological understanding can be guaranteed to require
      seizing the new tools provided by the physical sciences and refining these to our
      particular need. The ever-present danger is that these are then deployed with
      triumphal optimism rather than critical doubt and earlier methods either
      jettisoned prematurely or used incautiously. The new techniques have enabled
      experimentation to become ever less intrusive, permitting a progressive shift
      from animal to human work, thereby offering the prospect of an increasing
      clinical reward.

PMID- 15016793
TI  - The extraction of neural strategies from the surface EMG.
AB  - This brief review examines some of the methods used to infer central control
      strategies from surface electromyogram (EMG) recordings. Among the many uses of
      the surface EMG in studying the neural control of movement, the review critically
      evaluates only some of the applications. The focus is on the relations between
      global features of the surface EMG and the underlying physiological processes.
      Because direct measurements of motor unit activation are not available and many
      factors can influence the signal, these relations are frequently misinterpreted.
      These errors are compounded by the counterintuitive effects that some system
      parameters can have on the EMG signal. The phenomenon of crosstalk is used as an
      example of these problems. The review describes the limitations of techniques
      used to infer the level of muscle activation, the type of motor unit recruited,
      the upper limit of motor unit recruitment, the average discharge rate, and the
      degree of synchronization between motor units. Although the global surface EMG is
      a useful measure of muscle activation and assessment, there are limits to the
      information that can be extracted from this signal.

PMID- 15016794
TI  - Noninvasive stimulation of the human corticospinal tract.
AB  - Spinal tracts can be stimulated noninvasively in human subjects by passing a high
      voltage stimulus between the mastoids or by magnetic stimulation over the back of
      the head. The stimulus probably activates the corticospinal tract at the
      cervicomedullary junction (pyramidal decussation) and evokes large, short-latency
      motor responses in the arm muscles. These responses have a large monosynaptic
      component. Responses in leg muscles can be elicited by cervicomedullary junction
      stimulation or by stimulation over the cervical or thoracic spine. Because nerve
      roots are more easily activated than spinal tracts, stimulus spread to motor
      axons can occur. Facilitation of responses by voluntary activity confirms that
      the responses are evoked synaptically. Stimulation of the corticospinal tract is
      useful in studies of central conduction and studies of the behavior of
      motoneurons during different tasks. It also provides an important comparison to
      allow interpretation of changes in responses to stimulation of the motor cortex.
      The major drawback to the use of electrical stimulation of the corticospinal
      tract is that each stimulus is transiently painful.

PMID- 15016796
TI  - Muscle fat utilization during exercise: controversial only methodologically.

PMID- 15016797
TI  - Linear relationship between the perception of effort and the duration of constant
      load exercise that remains.

PMID- 15016798
TI  - Respiratory-related evoked activity in CPAP-treated OSAS patients.

PMID- 15016799
TI  - Rb inhibits E2F-1-induced cell death in a LXCXE-dependent manner by active
      repression.
AB  - Rb (retinoblastoma protein) inhibits E2F-1-induced cell death. We now show that
      the ability of Rb to inhibit E2F-1-induced cell death is dependent on a
      functional LXCXE-binding site in Rb, thereby suggesting that proteins that bind
      the LXCXE-binding site in Rb may regulate the anti-apoptotic activity of Rb.
      HDAC1, an LXCXE protein that plays a critical role in Rb-mediated transcription
      repression, abrogates the effect of Rb on E2F-1-induced cell death. In contrast,
      RF-Cp145, another LXCXE protein, cooperates with Rb to inhibit E2F-1-induced cell
      death. Both proteins exert their effect in an LXCXE-dependent manner. Rb
      regulates E2F-induced cell death by acting upstream of p73. Rb represses the p73
      promoter. Our results further suggest a model in which Rb-E2F-1 complexes mediate
      the anti-apoptotic activity of Rb through active repression of target genes
      without recruiting HDAC1.

PMID- 15016800
TI  - CpG oligodeoxynucleotides activate HIV replication in latently infected human T
      cells.
AB  - CpG oligodeoxynucleotides (CpG ODNs) stimulate immune cells via the Toll-like
      receptor 9 (TLR9). In this study, we have investigated the effects of CpG ODNs on
      latent human immunodeficiency virus (HIV) infection in human T cells. Treatment
      of the latently infected T cell line ACH-2 with CpG ODNs 2006 or 2040 stimulated
      HIV replication, whereas no effects were evident when ODNs without the CpG motif
      were used. CpG-induced virus reactivation was blocked by chloroquine, indicating
      the involvement of TLR9. In contrast to the responsiveness of ACH-2 cells, CpG
      ODNs failed to activate HIV provirus in the latently infected Jurkat clone J1.1.
      We also studied the effects of CpG ODNs on productive HIV infection and found
      enhancement of viral replication in A3.01 T cells, whereas again no stimulating
      effects were observed in Jurkat T cells. CpG ODN treatment activated NF-kappaB in
      ACH-2 cells, which was similarly triggered in uninfected A3.01 T cells following
      exposure to CpG ODNs, indicating that TLR9-induced signal transduction was not
      dependent on proviral infection. Our study demonstrates that CpG ODNs directly
      trigger the activation of NF-kappaB and reactivation of latent HIV in human T
      cells. Our results point to a novel role for CpG ODNs as stimulators of HIV
      replication and open new avenues to eradicate the latent viral reservoirs in HIV
      infected patients treated with antiretroviral therapy.

PMID- 15016801
TI  - p53-regulated transcriptional program associated with genotoxic stress-induced
      apoptosis.
AB  - By using a genome-wide approach, we sought the identification of p53-regulated
      genes involved in cellular apoptosis. To this end, we assessed the
      transcriptional response of HCT116 colorectal cancer cells during apoptosis
      induced by the anticancer drug 5-fluorouracil as the function of p53 status, and
      we identified 230 potential targets that are regulated by p53. Previously
      identified p53 targets known to be involved in growth arrest and apoptosis were
      observed to be induced, thus validating the approach. Strikingly, we found that
      p53 regulates gene expression primarily through transcriptional repression (n =
      189) rather than activation (n = 41), and selective blockade of p53-dependent
      gene repression resulted in the reduction in 5-fluorouracil-induced apoptosis.
      Reporter and chromatin immunoprecipitation assays demonstrated that p53 can
      suppress the promoter activities of three further studied candidate genes PLK,
      PTTG1, and CHEK1 but would only bind directly to PTTG1 and CHEK1 promoters,
      revealing that p53 can repress gene expression through both direct and indirect
      mechanisms. Moreover, RNA(i)-mediated knockdown of PLK and PTTG1 expression was
      sufficient to induce apoptosis, suggesting that repression of novel anti
      apoptotic genes by p53 might contribute to a significant portion of the p53
      dependent apoptosis. Our data support the divergent functions of p53 in
      regulating gene expression that play both synergistic and pleiotropic roles in
      p53-associated apoptosis.

PMID- 15016802
TI  - The pro-hypertrophic basic helix-loop-helix protein p8 is degraded by the
      ubiquitin/proteasome system in a protein kinase B/Akt- and glycogen synthase
      kinase-3-dependent manner, whereas endothelin induction of p8 mRNA and renal
      mesangial cell hypertrophy require NFAT4.
AB  - Renal disease is a common complication of diabetes. The initiating events in
      diabetic nephropathy are triggered by hyperglycemia and, possibly, advanced
      glycation end products. Subsequently, excess levels of vasoactive peptides
      (especially endothelin-1 (ET-1)) accumulate in the diabetic kidney, and there is
      evidence that these peptides mediate many of the pathophysiological changes
      associated with diabetic renal disease. These changes include an excess
      deposition of extracellular matrix proteins into the glomerular basement membrane
      and renal mesangial cell hypertrophy. Our transcriptional profiling studies have
      revealed that the p8 gene, which encodes a putative basic helix-loop-helix
      protein, is strongly induced in ET-1-treated renal mesangial cells and in an
      animal model of diabetic nephropathy. RNA interference experiments indicated that
      the p8 gene is required for ET-1-induced mesangial cell hypertrophy. Here, we
      show that the p8 polypeptide is a phosphoprotein subject to constitutive
      degradation by the ubiquitin/proteasome system. This degradation is mediated by
      phosphatidylinositol 3-kinase and protein kinase B/Akt. By contrast,
      stabilization of the p8 protein requires glycogen synthase kinase-3. Finally,
      short interfering RNA-mediated RNA interference experiments indicated that ET-1
      stimulated mesangial cell hypertrophy and p8 mRNA induction require the NFAT4
      transcription factor. Thus, p8 levels in the cell are likely maintained by a
      balance between signal-dependent transcriptional induction and proteolysis.

PMID- 15016803
TI  - Folding of active calcium channel beta(1b) -subunit by size-exclusion
      chromatography and its role on channel function.
AB  - Voltage-gated calcium channels mediate the influx of Ca(2+) ions into eukaryotic
      cells in response to membrane depolarization. They are hetero-multimer membrane
      proteins formed by at least three subunits, the poreforming alpha(1)-subunit and
      the auxiliary beta- and alpha(2)delta-subunits. The beta-subunit is essential for
      channel performance because it regulates two distinct features of voltage-gated
      calcium channels, the surface expression and the channel activity. Four beta
      subunit genes have been cloned, beta(1-4), with molecular masses ranging from 52
      to 78 kDa, and several splice variants have been identified. The beta(1b)
      subunit, expressed at high levels in mammalian brain, has been used extensively
      to study the interaction between the pore forming alpha(1)- and the regulatory
      beta-subunit. However, structural characterization has been impaired for its
      tendency to form aggregates when expressed in bacteria. We applied an on-column
      refolding procedure based on size exclusion chromatography to fold the beta(1b)
      subunit of the voltage gated-calcium channels from Escherichia coli inclusion
      bodies. The beta(1b)-subunit refolds into monomers, as shown by sucrose gradient
      analysis, and binds to a glutathione S-transferase protein fused to the known
      target in the alpha(1)-subunit (the alpha-interaction domain). Using the cut-open
      oocyte voltage clamp technique, we measured gating and ionic currents in Xenopus
      oocytes expressing cardiac alpha(1)-subunit (alpha(1C)) co-injected with folded
      beta(1b)-protein or beta(1b)-cRNA. We demonstrate that the co-expression of the
      alpha(1C)-subunit with either folded-beta(1b)-protein or beta(1b)-cRNA increases
      ionic currents to a similar extent and with no changes in charge movement,
      indicating that the beta(1b)-subunit primarily modulates channel activity, rather
      than expression.

PMID- 15016804
TI  - Activity-dependent expression of inositol 1,4,5-trisphosphate receptor type 1 in
      hippocampal neurons.
AB  - There are several lines of evidence showing that synaptic activity regulates the
      level of expression of inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) in
      neurons. In this study, we examined the effect of chronic activity blockade on
      the localization and level of IP3R1 expression in cultured hippocampal neurons.
      We found that chronic blockade of NMDA receptors (NMDARs), one of the major
      Ca(2+)-permeable ion channels, increased the number of neurons that express a
      high level of IP3R1 without any apparent changes in its intracellular
      localization. Interestingly, this up-regulation was time-dependent; there was no
      clear change in IP3R1 expression level up to day 5 of the NMDAR blockade, but
      expression increased at day 6, and the increased expression level persisted for
      at least a week. The up-regulation of IP3R1 depended on transcription and protein
      synthesis and required cAMP-dependent protein kinase activity. Moreover, although
      most of the control neurons did not respond to the metabotropic glutamate
      receptor (mGluR) stimulation, the 2-amino-5-phosphonopentanoic acid-treated
      neurons with high IP3R1 expression became sensitive to mGluR stimulation.
      Furthermore, we also found that hippocampal neurons transiently overexpressing
      green fluorescent protein-tagged IP3R1 released Ca2+ in response to mGluR and
      muscarinic acetylcholine receptor stimulation. These findings suggested that
      chronic NMDAR blockade increased the IP3R1 expression and enhanced sensitivity to
      mGluR stimulation. The change in IP3R1 expression level in response to alteration
      of synaptic activity may be an important determinant of the sensitivity of Ca2+
      stores to G-protein-coupled receptor stimulation and would help to maintain
      intracellular Ca2+ homeostasis in hippocampal neurons.

PMID- 15016805
TI  - Proteasomes begin ornithine decarboxylase digestion at the C terminus.
AB  - Proteasomes denature folded protein substrates and thread them through a narrow
      pore that leads to the sequestered sites of proteolysis. Whether a protein
      substrate initiates insertion from its N or C terminus or in a random orientation
      has not been determined for any natural substrate. We used the labile enzyme
      ornithine decarboxylase (ODC), which is recognized by the proteasome via a 37
      residue C-terminal tag, to answer this question. Three independent approaches
      were used to assess orientation as follows. 1) The 461-residue ODC protein chain
      was interrupted at position 305. The C-terminal fragment was degraded by purified
      proteasomes, but because processivity requires continuity of the polypeptide
      chain, the N-terminal fragment was spared. 2) A proteasome-inhibitory viral
      sequence prevented degradation when introduced near the C terminus but not when
      inserted elsewhere in ODC. 3) A bulky tightly folded protein obstructed in vivo
      degradation most effectively when positioned near the C terminus. These data
      demonstrate that the proteasome initiates degradation of this native substrate at
      the C terminus. The co-localization of entry site and degradation tag to the ODC
      C terminus suggests that recognition tags determine the site for initiating
      entry. Flexibility of a polypeptide terminus may promote the initiation of
      degradation.

PMID- 15016806
TI  - Gating allosterism at a single class of etomidate sites on alpha1beta2gamma2L
      GABA A receptors accounts for both direct activation and agonist modulation.
AB  - At clinical concentrations, the potent intravenous general anesthetic etomidate
      enhances gamma-aminobutyric acid, type A (GABA(A)) receptor activity elicited
      with low gamma-aminobutyric acid (GABA) concentrations, whereas much higher
      etomidate concentrations activate receptors in the absence of GABA. Therefore,
      GABA(A) receptors may possess two types of etomidate sites: high affinity GABA
      modulating sites and low affinity channel-activating sites. However, GABA
      modulation and direct activation share stereoselectivity for the (R)(+)-etomidate
      isomer and display parallel dependence on GABA(A) beta subunit isoforms,
      suggesting that these two actions may be mediated by a single class of etomidate
      site(s) that exert one or more molecular effects. In this study, we assessed GABA
      modulation by etomidate using leftward shifts of electrophysiological GABA
      concentration responses in cells expressing human alpha1beta2gamma2L receptors.
      Etomidate at up to 100 microm reduced GABA EC(50) values by over 100-fold but
      without apparent saturation, indicating the absence of high affinity etomidate
      sites. In experiments using a partial agonist, P4S, etomidate both reduced EC(50)
      and increased maximal efficacy, demonstrating that etomidate shifts the GABA(A)
      receptor gating equilibrium toward open states. Results were quantitatively
      analyzed using equilibrium receptor gating models, wherein a postulated class of
      equivalent etomidate sites both directly activates receptors and enhances agonist
      gating. A Monod-Wyman-Changeux co-agonist mechanism with two equivalent etomidate
      sites that allosterically enhance GABA(A) receptor gating independently of
      agonist binding most simply accounts for direct activation and agonist
      modulation. This model also correctly predicts the actions of etomidate on
      GABA(A) receptors containing a point mutation that increases constitutive gating
      activity.

PMID- 15016807
TI  - The polo box is required for multiple functions of Plx1 in mitosis.
AB  - Polo-like kinases comprise a family of evolutionarily conserved serine/threonine
      protein kinases that play multiple roles in cell cycle regulation. In addition to
      the N-terminal catalytic domain, polo-like kinases have one or two highly
      conserved C-terminal non-catalytic regions, termed polo boxes. These motifs are
      required for targeting these kinases to subcellular mitotic structures. Here we
      report that kinase-dead Xenopus polo-like kinase (Plx1NA) functions as a
      competitor of endogenous Plx1 for polo box binding site(s) and inhibits the
      activation of Cdc25C and the G(2)-M transition in vivo. However, kinase-dead Plx1
      with a point mutation in the polo box region (Plx1NAWF) did not have inhibitory
      effects. The ability of Plx1NA to block activation of the anaphase-promoting
      complex/cyclosome also requires an intact polo box. Microinjection of Plx1NA but
      not Plx1NAWF mRNA into Xenopus embryos caused cleavage arrest and formation of
      monopolar spindles, an effect previously seen in embryos injected with anti-Plx1
      antibody. Spindle assembly experiments in vitro also showed that only monopolar
      spindles formed in Xenopus egg extracts supplemented with recombinant Plx1NA and
      that the spindle assembly process was delayed. Taken together, these results
      indicate that the polo box is required for Plx1 function in both the G(2)-M and
      the metaphase/anaphase transitions during the cell cycle.

PMID- 15016808
TI  - Mitochondrial respiratory deficiencies signal up-regulation of genes for heat
      shock proteins.
AB  - The consequences of mitochondrial dysfunction are not limited to the development
      of oxidative stress or initiation of apoptosis but can result in the
      establishment of stress tolerance. Using maize mitochondrial mutants, we show
      that permanent mitochondrial deficiencies trigger novel Ca(2+)-independent
      signaling pathways, leading to constitutive expression of genes for molecular
      chaperones, heat shock proteins (HSPs) of different classes. The signaling to
      activate hsp genes appears to originate from a reduced mitochondrial
      transmembrane potential. Upon depolarization of mitochondrial membranes in
      transient assays, gene induction for mitochondrial HSPs occurred more rapidly
      than that for cytosolic HSPs. We also demonstrate that in the nematode
      Caenorhabditis elegans transcription of hsp genes can be induced by RNA
      interference of nuclear respiratory genes. In both organisms, activation of hsp
      genes in response to mitochondrial impairment is distinct from their responses to
      heat shock and is not associated with oxidative stress. Thus, mitochondria-to
      nucleus signaling to express a hsp gene network is apparently a widespread
      retrograde mechanism to facilitate cell defense and survival.

PMID- 15016809
TI  - Multiple structural elements contribute to the slow kinetics of the Cav3.3 T-type
      channel.
AB  - Molecular cloning and expression studies established the existence of three T
      type Ca(2+) channel (Ca(v)3) alpha(1) subunits: Ca(v)3.1 (alpha(1G)), Ca(v)3.2
      (alpha(1H)), and Ca(v)3.3 (alpha(1I)). Although all three channels are low
      voltage-activated, they display considerable differences in their kinetics, with
      Ca(v)3.1 and Ca(v)3.2 channels activating and inactivating much faster than
      Ca(v)3.3 channels. The goal of the present study was to determine the structural
      elements that confer the distinctively slow kinetics of Ca(v)3.3 channels. To
      address this question, a series of chimeric channels between Ca(v)3.1 and
      Ca(v)3.3 channels were constructed and expressed in Xenopus oocytes. Kinetic
      analysis showed that the slow activation and inactivation kinetics of the
      Ca(v)3.3 channel were not completely abolished by substitution with any one
      portion of the Ca(v)3.1 channel. Likewise, the Ca(v)3.1 channel failed to acquire
      the slow kinetics by simply adopting one portion of the Ca(v)3.3 channel. These
      findings suggest that multiple structural elements contribute to the slow
      kinetics of Ca(v)3.3 channels.

PMID- 15016810
TI  - CR1/CR2 interactions modulate the functions of the cell surface epidermal growth
      factor receptor.
AB  - Recent crystallographic data on the isolated extracellular domain of the
      epidermal growth factor receptor (EGFR) have suggested a model for its activation
      by ligand. We have tested this model in the context of the full-length EGFR
      displayed at the cell surface, by introducing mutations in two regions (CR1 and
      CR2) of the extracellular domain thought to be critical for regulation of
      receptor activation. Mutations in the CR1 and CR2 domains have opposing effects
      on ligand binding affinity, receptor dimerization, tyrosine kinase activation,
      and signaling competence. Tyr(246) is a critical residue in the CR1 loop, which
      is implicated in the positioning and stabilization of the receptor dimer
      interface after ligand binding; mutations of Tyr(246) impair or abolish receptor
      function. Mutations in CR2, which weaken the interaction that restricts the
      receptor to the tethered (inactive) state, enhance responsiveness to EGF by
      increasing affinity for the ligand. However, weakening of the CR1/CR2 interaction
      does not result in spontaneous activation of the receptors' kinase. We have used
      an antibody (mAb 806), which recognizes a transition state of the EGF receptor
      between the negatively constrained, tethered state and the fully active back-to
      back dimer conformation, to follow conformational changes in the wild-type and
      mutant EGF receptors after ligand binding. Our results suggest that EGFR on the
      cell surface can be untethered, but this form is inactive; thus, untethering of
      the receptor is not sufficient for activation, and ligand binding is essential
      for the correct positioning of the two receptor subunits to achieve kinase
      activation.

PMID- 15016811
TI  - Heme-ligand tunneling in group I truncated hemoglobins.
AB  - Truncated hemoglobins (trHbs) are small hemoproteins forming a separate cluster
      within the hemoglobin superfamily; their functional roles in bacteria, plants,
      and unicellular eukaryotes are marginally understood. Crystallographic
      investigations have shown that the trHb fold (a two-on-two alpha-helical sandwich
      related to the globin fold) hosts a protein matrix tunnel system offering a
      potential path for ligand diffusion to the heme distal site. The tunnel topology
      is conserved in group I trHbs, although with modulation of its size/structure.
      Here, we present a crystallographic investigation on trHbs from Mycobacterium
      tuberculosis, Chlamydomonas eugametos, and Paramecium caudatum, showing that
      treatment of trHb crystals under xenon pressure leads to binding of xenon atoms
      at specific (conserved) sites along the protein matrix tunnel. The
      crystallographic results are in keeping with data from molecular dynamics
      simulations, where a dioxygen molecule is left free to diffuse within the protein
      matrix. Modulation of xenon binding over four main sites is related to the
      structural properties of the tunnel system in the three trHbs and may be
      connected to their functional roles. In a parallel crystallographic investigation
      on M. tuberculosis trHbN, we show that butyl isocyanide also binds within the
      apolar tunnel, in excellent agreement with concepts derived from the xenon
      binding experiments. These results, together with recent data on atypical CO
      rebinding kinetics to group I trHbs, underline the potential role of the tunnel
      system in supporting diffusion, but also accumulation in multiple copies, of low
      polarity ligands/molecules within group I trHbs.

PMID- 15016812
TI  - Broad spectrum identification of cellular small ubiquitin-related modifier (SUMO)
      substrate proteins.
AB  - Reversible covalent modification of proteins with a small ubiquitin-related
      modifier (SUMO) is emerging as an important system contributing to dynamic
      regulation of protein function. To enhance our understanding of the cell
      regulatory systems impacted by sumoylation, we used affinity chromatography
      coupled high pressure liquid chromatography/tandem mass spectrometry for unbiased
      identification of candidate cellular SUMO substrate proteins. Here we describe
      the identification of 21 candidate sumoylated proteins from whole-cell lysates of
      HEK-293 cells. The nature of the proteins identified is consistent with a role
      for sumoylation in diverse cell regulatory systems but highlights regulation of
      chromatin organization and gene expression as major systems targeted by the
      sumoylation machinery.

PMID- 15016813
TI  - Structural dynamics in the active site of murine neuroglobin and its effects on
      ligand binding.
AB  - We have examined the effects of active site residues on ligand binding to the
      heme iron of mouse neuroglobin using steady-state and time-resolved visible
      spectroscopy. Absorption spectra of the native protein, mutants H64L and K67L and
      double mutant H64L/K67L were recorded for the ferric and ferrous states over a
      wide pH range (pH 4-11), which allowed us to identify a number of different
      species with different ligands at the sixth coordination, to characterize their
      spectroscopic properties, and to determine the pK values of active site residues.
      In flash photolysis experiments on CO-ligated samples, reaction intermediates and
      the competition of ligands for the sixth coordination were studied. These data
      provide insights into structural changes in the active site and the role of the
      key residues His64 and Lys67. His64 interferes with exogenous ligand access to
      the heme iron. Lys67 sequesters the distal pocket from the solvent. The heme iron
      is very reactive, as inferred from the fast ligand binding kinetics and the
      ability to bind water or hydroxyl ligands to the ferrous heme. Fast bond
      formation favors geminate rebinding; yet the large fraction of bimolecular
      rebinding observed in the kinetics implies that ligand escape from the distal
      pocket is highly efficient. Even slight pH variations cause pronounced changes in
      the association rate of exogenous ligands near physiological pH, which may be
      important in functional processes.

PMID- 15016814
TI  - T cell receptor signaling inhibits glucocorticoid-induced apoptosis by repressing
      the SRG3 expression via Ras activation.
AB  - Activation of T cell antigen receptor (TCR) signaling inhibits glucocorticoid
      (GC)-induced apoptosis of T cells. However, the detailed mechanism regarding how
      activated T cells are protected from GC-induced apoptosis is unclear. Previously,
      we have shown that the expression level of SRG3, a murine homolog of BAF155 in
      humans, correlated well with the GC sensitivity of T cells either in vitro or in
      vivo. Intriguingly, the expression of SRG3 decreased upon positive selection in
      the thymus. Here we have shown that TCR signaling inhibits the SRG3 expression
      via Ras activation and thereby renders primary thymocytes and some thymoma cells
      resistant to GC-mediated apoptosis. By using pharmacological inhibitors, we have
      shown that Ras-mediated down-regulation of the SRG3 gene expression is mediated
      by MEK/ERK and phosphatidylinositol 3-kinase pathways. Moreover, TCR signals
      repressed the SRG3 transcription through the putative binding sites for E
      proteins and Ets family transcription factors in the proximal region of the SRG3
      promoter. Introduction of mutations in these elements rendered the SRG3 promoter
      immune to the Ras or TCR signals. Taken together, these observations suggest that
      TCR signals result in GC desensitization in immature T cells by repressing SRG3
      gene expression via Ras activation.

PMID- 15016815
TI  - E2A/HEB and Id3 proteins control the sensitivity to glucocorticoid-induced
      apoptosis in thymocytes by regulating the SRG3 expression.
AB  - The E protein family transcription factors encoded by the E2A and HEB genes are
      known to play critical roles in the coordinate regulation of lymphocyte
      development. Previous studies have shown that T cell receptor (TCR) signals
      rapidly induce Id3, a dominant negative antagonist of E2A activity and allow
      thymocytes to survive selection events in the thymus. Here we show that SRG3 acts
      as a novel downstream target of E2A/HeLa E box-binding (HEB) complex and
      modulates glucocorticoid (GC) susceptibility in thymocytes in response to TCR
      signals. We have identified a putative E box element in the SRG3 promoter that is
      required for optimal promoter activity. The transcription factors E2A and HEB
      specifically associate with the E box element. Moreover, E2A-HEB heterodimers
      cooperated to activate SRG3 transcription, which was inhibited by the expression
      of Id proteins. TCR-mediated signals rapidly induced Id3 via MEK/ERK activation
      and thereby kept the E2A/HEB complex from binding to the E box element in the
      SRG3 promoter. Retroviral transduction of Id3 also repressed the SRG3 expression
      by inhibiting the E box binding activity of the E2A/HEB complex. Intriguingly,
      enforced Id3 expression conferred thymocyte resistance to GCs, which could be
      overcome by the overexpression of SRG3. Taken together, these results suggest
      that Id3 may enhance the viability of immature thymocytes by at least rendering
      them resistant to GCs through SRG3 down-regulation.

PMID- 15016816
TI  - Crystal structure of WbpP, a genuine UDP-N-acetylglucosamine 4-epimerase from
      Pseudomonas aeruginosa: substrate specificity in udp-hexose 4-epimerases.
AB  - The O antigen of lipopolysaccharide in Gram-negative bacteria plays a critical
      role in bacterium-host interactions, and for pathogenic bacteria it is a major
      virulence factor. In Pseudomonas aeruginosa serotype O6 one of the initial steps
      in O-antigen biosynthesis is catalyzed by a saccharide epimerase, WbpP. WbpP is a
      member of the UDP-hexose 4-epimerase family of enzymes and exists as a homo
      dimer. This enzyme preferentially catalyzes the conversion between UDP-GlcNAc and
      UDPGalNAc above UDP-Glc and UDP-Gal, using NAD(+) as a cofactor. The crystal
      structures of WbpP in complex with cofactor and either UDP-Glc or UDP-GalNAc were
      determined at 2.5 and 2.1 A, respectively, which represents the first structural
      studies of a genuine UDP-GlcNAc 4-epimerase. These structures in combination with
      complementary mutagenesis studies suggest that the basis for the differential
      substrate specificity of WbpP is a consequence of the presence of a pliable
      solvent network in the active site. This information allows for a comprehensive
      analysis of the relationship between sequence and substrate specificity for UDP
      hexose 4-epimerases and enables the formulation of consensus sequences that
      predict substrate specificity of UDP-hexose 4-epimerases yet to be biochemically
      characterized. Furthermore, the examination indicates that as little as one
      residue can dictate substrate specificity. Nonetheless, phylogenetic analysis
      suggests that this substrate specificity is an evolutionary and highly conserved
      property within UDP-hexose 4-epimerases.

PMID- 15016817
TI  - A novel salt-tolerant L-myo-inositol-1-phosphate synthase from Porteresia
      coarctata (Roxb.) Tateoka, a halophytic wild rice: molecular cloning, bacterial
      overexpression, characterization, and functional introgression into tobacco
      conferring salt tolerance phenotype.
AB  - l-myo-Inositol-1-phosphate synthase (EC 5.5.1.4, MIPS), an evolutionarily
      conserved enzyme protein, catalyzes the synthesis of inositol, which is
      implicated in a number of metabolic reactions in the biological kingdom. Here we
      report on the isolation of the gene (PINO1) for a novel salt-tolerant MIPS from
      the wild halophytic rice, Porteresia coarctata (Roxb.) Tateoka. Identity of the
      PINO1 gene was confirmed by functional complementation in a yeast inositol
      auxotrophic strain. Comparison of the nucleotide and deduced amino acid sequences
      of PINO1 with that of the homologous gene from Oryza sativa L. (RINO1) revealed
      distinct differences in a stretch of 37 amino acids, between amino acids 174 and
      210. Purified bacterially expressed PINO1 protein demonstrated a salt-tolerant
      character in vitro compared with the salt-sensitive RINO1 protein as with those
      purified from the native source or an expressed salt-sensitive mutant PINO1
      protein wherein amino acids 174-210 have been deleted. Analysis of the salt
      effect on oligomerization and tryptophan fluorescence of the RINO1 and PINO1
      proteins revealed that the structure of PINO1 protein is stable toward salt
      environment. Furthermore, introgression of PINO1 rendered transgenic tobacco
      plants capable of growth in 200-300 mm NaCl with retention of approximately 40
      80% of the photosynthetic competence with concomitant increased inositol
      production compared with unstressed control. MIPS protein isolated from PINO1
      transgenics showed salt-tolerant property in vitro confirming functional
      expression in planta of the PINO1 gene. To our knowledge, this is the first
      report of a salt-tolerant MIPS from any source.

PMID- 15016818
TI  - Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity
      through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes.
AB  - During differentiation, expression of protein phosphatase-2Calpha (PP2Calpha) is
      increased in 3T3-L1 adipocytes. To elucidate the role of PP2Calpha in insulin
      signaling, we overexpressed wild-type (WT) PP2Calpha by adenovirus-mediated gene
      transfer in 3T3-L1 adipocytes. Overexpression of PP2Calpha-WT enhanced the
      insulin sensitivity of glucose uptake without any changes in the early steps of
      insulin signaling. Infection with adenovirus 5 expressing PP2Calpha-WT increased
      phosphatidylinositol 3-kinase (PI3K) activities in the immunoprecipitate using
      antibody against the p85 or p110 subunit under both basal and insulin-stimulated
      conditions, followed by activation of downstream steps in the PI3K pathway, such
      as phosphorylation of Akt, glycogen synthase kinase-3, and atypical protein
      kinase C. In contrast, overexpression of the phosphatase-defective mutant
      PP2Calpha(R174G) did not produce such effects. Furthermore, overexpression of
      PP2Calpha-WT (but not PP2Calpha(R174G)) decreased the (32)P-labeled
      phosphorylation state as well as the gel mobility shift of the p85 subunit,
      suggesting that dephosphorylation of the p85 subunit by PP2Calpha activation
      might stimulate PI3K catalytic activity. Moreover, knockdown of PP2Calpha by
      transfection of small interfering RNA led to a significant decrease in Akt
      phosphorylation. In addition, microinjection of anti-PP2Calpha antibody or
      PP2Calpha small interfering RNA led to decreased insulin-stimulated GLUT4
      translocation. In conclusion, PP2Calpha is a new positive regulator of insulin
      sensitivity that acts through a direct activation of PI3K in 3T3-L1 adipocytes.

PMID- 15016819
TI  - Subpopulation of store-operated Ca2+ channels regulate Ca2+-induced Ca2+ release
      in non-excitable cells.
AB  - Ca2+-induced Ca2+ release (CICR) is a well characterized activity in skeletal and
      cardiac muscles mediated by the ryanodine receptors. The present study
      demonstrates CICR in the non-excitable parotid acinar cells, which resembles the
      mechanism described in cardiac myocytes. Partial depletion of internal Ca2+
      stores leads to a minimal activation of Ca2+ influx. Ca2+ influx through this
      pathway results in an explosive mobilization of Ca2+ from the majority of the
      stores by CICR. Thus, stimulation of parotid acinar cells in Ca2+ -free medium
      with 0.5 microm carbachol releases approximately 5% of the Ca2+ mobilizable by 1
      mm carbachol. Addition of external Ca2+ induced the same Ca2+ release observed in
      maximally stimulated cells. Similar results were obtained by a short treatment
      with 2.5-10 microm cyclopiazonic acid, an inhibitor of the sarco/endoplasmic
      reticulum Ca2+ ATPase pump. The Ca2+ release induced by the addition of external
      Ca2+ was largely independent of IP(3)Rs because it was reduced by only
      approximately 30% by the inhibition of the inositol 1,4,5-trisphosphate receptors
      with caffeine or heparin. Measurements of Ca2+ -activated outward current and
      [Ca2+](i) suggested that most CICR triggered by Ca2+ influx occurred away from
      the plasma membrane. Measurement of the response to several concentrations of
      cyclopiazonic acid revealed that Ca2+ influx that regulates CICR is associated
      with a selective portion of the internal Ca2+ pool. The minimal activation of
      Ca2+ influx by partial store depletion was confirmed by the measurement of Mn2+
      influx. Inhibition of Ca2+ influx with SKF96365 or 2-aminoethoxydiphenyl borate
      prevented activation of CICR observed on addition of external Ca2+. These
      findings provide evidence for activation of CICR by Ca2+ influx in non-excitable
      cells, demonstrate a previously unrecognized role for Ca2+ influx in triggering
      CICR, and indicate that CICR in non-excitable cells resembles CICR in cardiac
      myocytes with the exception that in cardiac cells Ca2+ influx is mediated by
      voltage-regulated Ca2+ channels whereas in non-excitable cells Ca2+ influx is
      mediated by store-operated channels.

PMID- 15016821
TI  - Pil1p and Lsp1p negatively regulate the 3-phosphoinositide-dependent protein
      kinase-like kinase Pkh1p and downstream signaling pathways Pkc1p and Ypk1p.
AB  - The Saccharomyces cerevisiae homologs, Pkh1/2p, of the mammalian 3
      phosphoinositide-dependent protein kinase 1 (PDK1) regulate the Pkc1-MAP kinase
      cascade and the partially parallel Ypk1/2p pathway(s) that control growth and
      cell integrity. Mammalian PDK1 is regulated by 3-phosphoinositides, whereas
      Pkh1/2p are regulated by sphingolipid long-chain bases (LCBs). Recently Pkh1/2p
      were found to complex with two related proteins, Pil1p (Ygr086) and Lsp1p
      (Ypl004). Because these two proteins are not related to any known protein we
      sought to characterize their functions. We show that Pkh1p phosphorylates both
      proteins in vitro in a reaction that is only weakly regulated by LCBs. In
      contrast, LCBs inhibit phosphorylation of Pil1p by Pkh2p, whereas LCBs stimulate
      phosphorylation of Lsp1p by Pkh2p. We find that Pil1p and Lsp1p down-regulate
      resistance to heat stress and, specifically, that they down-regulate the activity
      of the Pkc1p-MAP and Ypk1p pathways during heat stress. Pil1p and Lsp1p are thus
      the first proteins identified as regulators of Pkh1/2p. An unexpected finding was
      that the level of Ypk1p is greatly reduced in pkc1Delta cells, indicating that
      Pkc1p controls the level of Ypk1p. Homologs of Pil1p and Lsp1p are widespread in
      nature, and our results suggest that they may be negative regulators of PDK-like
      protein kinases and their downstream cellular pathways that control cell growth
      and survival.

PMID- 15016822
TI  - Deletion of microsomal prostaglandin E2 (PGE2) synthase-1 reduces inducible and
      basal PGE2 production and alters the gastric prostanoid profile.
AB  - Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible protein recently
      shown to be an important source of inflammatory PGE2. Here we have used mPGES-1
      wild type, heterozygote, and null mice to assess the impact of reduction or
      absence mPGES-1 protein on the production of PGE2 and other prostaglandins in
      lipopolysaccharide (LPS)-treated macrophages and mice. Thioglycollate-elicited
      peritoneal macrophages with mPGES-1 deficiency were found to lose their ability
      to produce PGE2 upon LPS stimulation. Resident mPGES-1(-/-) peritoneal
      macrophages exhibited severely impaired PGE2-releasing activity but retained some
      LPS-inducible PGE2 production capacity. Both macrophage types showed a 50%
      decrease in PGE2 production with removal of one copy of the mPGES-1 gene. In
      vivo, mPGES-1 deletion abolished the LPS-stimulated production of PGE2 in spleen,
      kidney, and brain. Surprisingly, lack of mPGES-1 activity resulted in an 80-90%
      decrease in basal, cyclooxygenase-1 (COX-1)-dependent PGE2 production in stomach
      and spleen, and a 50% reduction in brain and kidney. Other prostaglandins
      (thromboxane B2, PGD2, PGF(2alpha), and 6-keto-PGF(1alpha)) were significantly
      elevated in stomachs of mPGES-1-null mice but not in other tissues. Examination
      of mRNA for several terminal prostaglandin synthases did not reveal changes in
      expression levels associated with mPGES-1 deficiency, indicating that gastric
      prostaglandin changes may be due to shunting of cyclooxygenase products to other
      terminal synthases. These data demonstrate for the first time a dual role for
      mPGES-1 in both inflammatory and COX-1-mediated PGE2 production and suggest an
      interdependence of prostanoid production with tissue-specific alterations of
      prostaglandin levels in the absence of mPGES-1.

PMID- 15016820
TI  - The Ras/cAMP-dependent protein kinase signaling pathway regulates an early step
      of the autophagy process in Saccharomyces cerevisiae.
AB  - When faced with nutrient deprivation, Saccharomyces cerevisiae cells enter into a
      nondividing resting state, known as stationary phase. The Ras/PKA (cAMP-dependent
      protein kinase) signaling pathway plays an important role in regulating the entry
      into this resting state and the subsequent survival of stationary phase cells.
      The survival of these resting cells is also dependent upon autophagy, a membrane
      trafficking pathway that is induced upon nutrient deprivation. Autophagy is
      responsible for targeting bulk protein and other cytoplasmic constituents to the
      vacuolar compartment for their ultimate degradation. The data presented here
      demonstrate that the Ras/PKA signaling pathway inhibits an early step in
      autophagy because mutants with elevated levels of Ras/PKA activity fail to
      accumulate transport intermediates normally associated with this process.
      Quantitative assays indicate that these increased levels of Ras/PKA signaling
      activity result in an essentially complete block to autophagy. Interestingly,
      Ras/PKA activity also inhibited a related process, the cytoplasm to vacuole
      targeting (Cvt) pathway that is responsible for the delivery of a subset of
      vacuolar proteins in growing cells. These data therefore indicate that the
      Ras/PKA signaling pathway is not regulating a switch between the autophagy and
      Cvt modes of transport. Instead, it is more likely that this signaling pathway is
      controlling an activity that is required during the early stages of both of these
      membrane trafficking pathways. Finally, the data suggest that at least a portion
      of the Ras/PKA effects on stationary phase survival are the result of the
      regulation of autophagy activity by this signaling pathway.

PMID- 15016823
TI  - The human nuclear SRcyp is a cell cycle-regulated cyclophilin.
AB  - Cyclophilins of the Moca family (Cavarec, L., Kamphausen, T., Dubourg, B.,
      Callebaut, I., Lemeunier, F., Metivier, D., Feunteun, J., Fischer, G., and
      Modjtahedi, N. (2002) J. Biol. Chem. 277, 41171-41182) are found only in
      organisms of the animal kingdom and share several structural and enzymatic
      features. The presence of serine/arginine (S/R) dipeptide repeats in their C
      terminal tail suggests that these enzymes belong to the SR protein family
      involved in the regulation of gene expression. The function of this group of
      cyclophilins is currently unknown. However, their C-terminal tails contain a
      highly conserved polypeptide signature segment (the moca domain), which may well
      be involved in the functional regulation of these proteins. We report here the
      identification of five Cdc2-type phosphorylation sites gathered in and around the
      moca domain of SRcyp, a human cyclophilin belonging to the Moca family. The
      segment of SRcyp containing the identified sites is specifically phosphorylated
      in mitotic cells. This mitosis-specific phosphorylation was inhibited by
      treatment of the cells with roscovitine, a specific inhibitor of cyclin-dependent
      kinases, suggesting that the unknown activity of the moca domain of SRcyp
      requires mitotic regulation by the Cdc2-cyclin B kinase complex. The Cdc2-cyclin
      B complex was found to phosphorylate four of the five identified phosphorylation
      sites in vitro, providing further support for this possibility. Like many factors
      stored in nuclear speckles and involved in the regulation of gene expression,
      this nuclear cyclophilin displays a predominantly diffuse cytoplasmic
      distribution at the onset of mitosis. Only in late telophase is SRcyp recruited
      to the newly formed nuclei. The transit of SRcyp through mitotic interchromatin
      granule clusters, before re-entering the nucleus, suggests that the timing of the
      appearance of this cyclophilin in the telophasic nuclei is tightly coordinated
      with post-mitotic events. Human SRcyp is the first cell cycle-regulated
      cyclophilin to be described.

PMID- 15016824
TI  - Cell surface adenosine deaminase binds and stimulates plasminogen activation on 1
      LN human prostate cancer cells.
AB  - Adenosine deaminase (ADA) is expressed intracellularly by all cells, but in some
      tissues, it is also associated with the cell surface multifunctional glycoprotein
      CD26/dipeptidyl peptidase IV. By modulating extracellular adenosine, this "ecto
      ADA" may regulate adenosine receptor signaling implicated in various cellular
      functions. CD26 is expressed on the surface of human prostate cancer 1-LN cells
      acting as a receptor for plasminogen (Pg). Since ADA and Pg bind to CD26 at
      distinct but nearby sites, we investigated a possible interaction between these
      two proteins on the surface of 1-LN cells. Human ADA binds to CD26 on the surface
      1-LN cells and immobilized CD26 isolated from the same cells with similar
      affinity. In both cases, ADA binding is diminished by mutation of ADA residues
      known to interact with CD26. ADA was also found to bind Pg 2 in the absence of
      CD26 via the Pg kringle 4 (K4) domain. In the presence of 1-LN cells or
      immobilized CD26, exogenous ADA enhances conversion of Pg 2 to plasmin by 1-LN
      endogenous urinary plasminogen activator (u-PA), as well as by added tissue Pg
      Activator (t-PA), suggesting that ADA and Pg bind simultaneously to CD26 in a
      ternary complex that stimulates the Pg activation by its physiologic activators.
      Consistent with this, in melanoma A375 cells that bind Pg, but do not express
      CD26, the rate of Pg activation was not affected by ADA. Thus, ADA may be a
      factor regulating events in prostate cancer cells that occur when Pg binds to the
      cell surface and is activated.

PMID- 15016825
TI  - The structure of the MAPK scaffold, MP1, bound to its partner, p14. A complex
      with a critical role in endosomal map kinase signaling.
AB  - Scaffold proteins of the mitogen-activated protein kinase (MAPK) pathway have
      been proposed to form an active signaling module and enhance the specificity of
      the transduced signal. Here, we report a 2-A resolution structure of the MAPK
      scaffold protein MP1 in a complex with its partner protein, p14, that localizes
      the complex to late endosomes. The structures of these two proteins are
      remarkably similar, with a five-stranded beta-sheet flanked on either side by a
      total of three helices. The proteins form a heterodimer in solution and interact
      mainly through the edge beta-strand in each protein to generate a 10-stranded
      beta-sheet core. Both proteins also share structural similarity with the amino
      terminal regulatory domains of the membrane trafficking proteins, sec22b and
      Ykt6p, as well as with sedlin (a component of a Golgi-associated membrane
      trafficking complex) and the sigma2 and amino-terminal portion of the mu2
      subunits of the clathrin adaptor complex AP2. Because neither MP1 nor p14 have
      been implicated in membrane traffic, we propose that the similar protein folds
      allow these relatively small proteins to be involved in multiple and simultaneous
      protein-protein interactions. Mapping of highly conserved, surface-exposed
      residues on MP1 and p14 provided insight into the potential sites of binding of
      the signaling kinases MEK1 and ERK1 to this complex, as well as the areas
      potentially involved in other protein-protein interactions.

PMID- 15016826
TI  - Development of high affinity camptothecin-bombesin conjugates that have targeted
      cytotoxicity for bombesin receptor-containing tumor cells.
AB  - Mammalian bombesin (BN) receptors are among those most frequently overexpressed
      by a number of common tumors including prostate, breast, lung, and colon cancers.
      The aim of this study was to develop a camptothecin-bombesin (CPT-BN) conjugate
      that interacts with all classes of BN receptors and possibly functions as a
      prodrug via a labile linker with site-specific cytotoxicity for cancer cells
      bearing these receptors. CPT was coupled to analogs of [D-Tyr6,beta
      Ala11,Phe13,Nle14]BN-(6-14) (BA0) using carbamate linkers (L1 and L2) with built
      in nucleophile-assisted releasing groups for intracellular cleavage of free
      cytotoxic agents. One conjugate, CPT-L2-BA3, bound to all three BN receptor
      classes with high affinity and functioned as a full agonist at each. 125I-CPT-L2
      BA3 was rapidly internalized by cells expressing each BN receptor class and,
      using fluorescent imaging, was found to co-localize with BN receptors initially
      and later to be internalized in cytoplasmic compartments. HPLC analysis of
      internalized ligand showed that 40% was intact, 25% was metabolized by releasing
      free CPT, and 35% was metabolized to other breakdown products. CPT-L2-BA3
      inhibited the growth of NCI-H1299 non-small cell lung cancer cells in 3-(4,5
      dimethylthiazol-2-yl)-2.5-diphenyl-2H-tetrazolium bromide (MTT) and clonal growth
      assays. CPT-L2-BA3 was cytotoxic in an MTT assay for cells transfected with each
      class of BN receptor; however, it had significantly less effect in cells lacking
      BN receptors. These results indicate that CTP-L2-BA3 is a potent agonist that is
      cytotoxic for cells overexpressing any of the three BN receptor classes and
      functions as a prodrug for receptor-mediated cytoxicity. It therefore should be a
      useful prototype to explore the effectiveness of tumor-specific cytotoxicity
      delivery using a receptor-mediated mechanism.

PMID- 15016827
TI  - A protein phosphatase-1gamma1 isoform selectivity determinant in dendritic spine
      associated neurabin.
AB  - Protein phosphatase-1 (PP1) catalytic subunit isoforms interact with diverse
      proteins, typically containing a canonical (R/K)(V/I)XF motif. Despite sharing
      approximately 90% amino acid sequence identity, PP1beta and PP1gamma1 have
      distinct subcellular localizations that may be determined by selective
      interactions with PP1-binding proteins. Immunoprecipitation studies from brain
      and muscle extracts demonstrated that PP1gamma1 selectively interacts with
      spinophilin and neurabin, F-actin-targeting proteins, whereas PP1beta selectively
      interacted with G(M)/R(GL), the striated-muscle glycogen-targeting subunit.
      Glutathione S-transferase (GST) fusion proteins containing residues 146-493 of
      neurabin (GST-Nb-(146-493)) or residues 1-240 of G(M)/R(GL) (GST-G(M)-(1-240))
      recapitulated these isoform selectivities in binding and phosphatase activity
      inhibition assays. Site-directed mutagenesis indicated that this isoform
      selectivity was not due to sequence differences between the canonical PP1-binding
      motifs (neurabin, (457)KIKF(460); G(M)/R(GL), (65)RVSF(68)). A chimeric GST
      fusion protein containing residues 1-64 of G(M)/R(GL) fused to residues 457-493
      of neurabin (GST-G(M)/Nb) selectively bound to and inhibited PP1gamma1, whereas a
      GST-Nb/G(M) chimera containing Nb-(146-460) fused to G(M)-(69-240) selectively
      interacted with and weakly inhibited PP1beta, implicating domain(s) C-terminal to
      the (R/K)(V/I)XF motif as determinants of PP1 isoform selectivity. Deletion of
      Pro(464) and Ile(465) in neurabin (deltaPI) to equally space a conserved cluster
      of amino acids from the (R/K)(V/I)XF motif as in G(M)/R(GL) severely compromised
      the ability of neurabin to bind and inhibit both isoforms but did not affect
      PP1gamma1 selectivity. Further analysis of a series of C-terminal truncated GST
      Nb-(146-493) proteins identified residues 473-479 of neurabin as containing a
      crucial PP1gamma1-selectivity determinant. In combination, these data identify a
      novel PP1gamma1-selective interaction domain in neurabin that may allow for
      selective regulation and/or subcellular targeting of PP1 isoforms.

PMID- 15016828
TI  - Interaction between hex and GATA transcription factors in vascular endothelial
      cells inhibits flk-1/KDR-mediated vascular endothelial growth factor signaling.
AB  - Recent evidence supports a role for GATA transcription factors as important
      signal intermediates in differentiated endothelial cells. The goal of this study
      was to identify proteins that interact with endothelial-derived GATA
      transcription factors. Using yeast two-hybrid screening, we identified
      hematopoietically expressed homeobox (Hex) as a GATA-binding partner in
      endothelial cells. The physical association between Hex and GATA was confirmed
      with immunoprecipitation in cultured cells. Hex overexpression resulted in
      decreased flk-1/KDR expression, both at the level of the promoter and the
      endogenous gene, and attenuated vascular endothelial growth factor-mediated tube
      formation in primary endothelial cell cultures. In electrophoretic mobility shift
      assays, Hex inhibited the binding of GATA-2 to the flk-1/KDR 5'-untranslated
      region GATA motif. Finally, in RNase protection assays, transforming growth
      factor beta1, which has been previously shown to decrease flk-1 expression by
      interfering with GATA binding activity, was shown to increase Hex expression in
      endothelial cells. Taken together, the present study provides evidence for a
      novel association between Hex and GATA and suggests that transforming growth
      factor beta-mediated repression of flk-1/KDR and vascular endothelial growth
      factor signaling involves the inducible formation of inhibitory Hex-GATA
      complexes.

PMID- 15016829
TI  - Interleukin (IL)-6 and IL-10 induce decorin mRNA in endothelial cells, but
      interaction with fibrillar collagen is essential for its translation.
AB  - Decorin, a small multifunctional proteoglycan, is expressed by sprouting
      endothelial cells (ECs) during inflammation-induced angiogenesis in vivo and by
      human ECs co-cultured with fibroblasts in a collagen lattice. To investigate how
      decorin is induced, human EA.hy 926 ECs and/or human umbilical vein ECs were
      treated with interleukin (IL)-10 and IL-6. Both treatments induced decorin mRNA
      in human ECs. IL-6 and IL-10 led to a dose-dependent mRNA increase with a maximum
      at 10 and 50 ng/ml, respectively. The combination of both interleukins together
      had a stronger effect than one alone. Immunostaining demonstrated that both
      interleukins caused decorin synthesis in ECs and the formation of capillary-like
      structures in a collagen lattice. However, immunoprecipitations of interleukin
      treated ECs cultured on plastic were negative. Only interleukin-stimulated ECs
      grown on a collagen type I matrix or growth factor-reduced Matrigel were able to
      synthesize the proteoglycan. Acid-soluble collagen type I did not support decorin
      protein synthesis. The addition of antibodies to alpha(1) or alpha(2) integrins
      or the alpha(2) integrin inhibitor rhodocetin led to an inhibition of synthesis.
      These data show that IL-10 and IL-6 induce decorin mRNA transcription, but
      additional signals from the extracellular matrix are necessary for its
      translation.

PMID- 15016830
TI  - Extracellular matrices of the avian ovarian follicle. Molecular characterization
      of chicken perlecan.
AB  - In egg-laying species, such as the chicken, the mode of transport of lipoprotein
      particles from the capillary plasma to endocytic receptors on the oocyte surface
      is largely unknown. Here we show by molecular characterization that the large
      prominent heparan sulfate proteoglycan of extracellular matrices, termed perlecan
      or HSPG2 (the product of the hspg2 gene), is a component of ovarian follicles
      that may participate in this process. However, although normally a major HSPG of
      basement membranes or basal laminae, in chicken follicles, perlecan is absent
      from the membranous structure between the theca interna and granulosa cell
      layers, which to date has been considered a bona fide basement membrane. Rather,
      the protein is localized in the extracellular matrix of theca externa cells,
      which produce this HSPG. Furthermore, in chicken testes, perlecan is localized in
      the peritubular spaces but in less organized fashion than the classical basement
      membrane components, agrin and laminin. All five domains and structural hallmarks
      of chicken perlecan (4071 residues) have been conserved in its mammalian
      counterparts. We have produced the recombinant domain II (containing low density
      lipoprotein (LDL) receptor-like binding repeats) of chicken perlecan and
      demonstrate its capacity to bind LDL and very low density lipoprotein (VLDL),
      apolipoprotein B-containing lipoproteins ultimately destined for uptake into
      oocytes via members of the low density lipoprotein receptor family. Binding to
      perlecan heparan sulfate side chains may facilitate the interaction of
      lipoproteins with domain II. Based on the current results and on domain-domain
      interactions revealed by recent ultrastructural investigations of the LDL
      receptor, nidogen, and laminin (Rudenko, G., Henry, L., Henderson, K.,
      Ichtchenko, K., Brown, M. S., Goldstein, J. L., and Deisenhofer, J. (2002)
      Science 298, 2353-2358 and Takagi, J., Yang, Y., Liu, J. H., Wang, J. H., and
      Springer, T. A. (2003) Nature 424, 969-974), we propose a novel role of perlecan
      in mediating plasma-to-oocyte surface transport of VLDL particles.

PMID- 15016831
TI  - Hyaluronan cell surface binding is induced by type I collagen and regulated by
      caveolae in glioma cells.
AB  - Hyaluronan (HA) is a component of the brain extracellular matrix environment that
      is synthesized and secreted by glioma cells. The primary cell surface receptor
      for HA is CD44, a membrane glycoprotein that is functionally regulated by a
      membrane type 1 matrix metalloproteinase (MT1-MMP). Both CD44 and MT1-MMP are
      partially located in Triton X-100-insoluble domains, but no functional link has
      yet been established between them. In the present study, we studied the
      regulation of HA cell surface binding in U-87 glioma cells. We show that an MMP
      dependent mechanism regulates the intrinsic cell surface binding of HA as
      ilomastat, a broad MMP inhibitor, increased HA binding to glioma cells. HA
      binding was also rapidly and specifically up-regulated by 3-fold by type I
      collagen in U-87 cells, which also induced a significant morphological
      reorganization associated with the activation of a latent form of MMP-2 through a
      MT1-MMP-mediated mechanism. Interestingly, caveolae depletion with a cell surface
      cholesterol-depleting agent beta-cyclodextrin triggered an additional increase (9
      fold) in the binding of HA, in synergy with type I collagen. On the other hand,
      HA cell surface binding was diminished by the MEK inhibitor PD98059 and by the
      overexpression of a recombinant, wild type MT1-MMP, whereas its cytoplasmic
      deleted form had no effect. Taken together, our results suggest that MT1-MMP
      regulates, through its cytoplasmic domain, the cell surface functions of CD44 in
      a collagen-rich pericellular environment. Additionally, we describe a new
      molecular mechanism regulating the invasive potential of glioma cells involving a
      MT1-MMP/CD44/caveolin interaction, which could represent a potential target for
      anti-cancer therapies.

PMID- 15016832
TI  - Protein kinase Calpha phosphorylates the TRPC1 channel and regulates store
      operated Ca2+ entry in endothelial cells.
AB  - The TRPC1 (transient receptor potential canonical-1) channel is a constituent of
      the nonselective cation channel that mediates Ca2+ entry through store-operated
      channels (SOCs) in human endothelial cells. We investigated the role of protein
      kinase Calpha (PKCalpha) phosphorylation of TRPC1 in regulating the opening of
      SOCs. Thrombin or thapsigargin added to the external medium activated Ca2+ entry
      after Ca2+ store depletion, which we monitored by changes in cellular Fura 2
      fluorescence. Internal application of the metabolism-resistant analog of inositol
      1,4,5-trisphosphate (IP3) activated an inward cationic current within 1 min,
      which we recorded using the whole cell patch clamp technique. La3+ or Gd3+
      abolished the current, consistent with the known properties of SOCs.
      Pharmacological (Go6976) or genetic (kinase-defective mutant) inhibition of
      PKCalpha markedly inhibited IP3-induced activation of the current. Thrombin or
      thapsigargin also activated La3+-sensitive Ca2+ entry in a PKCalpha-dependent
      manner. We determined the effects of a specific antibody directed against an
      extracellular epitope of TRPC1 to address the functional importance of TRPC1.
      External application of the antibody blocked thrombin- or IP3-induced Ca2+ entry.
      In addition, we showed that addithrombin or thapsigargin induced phosphorylation
      of TRPC1 within 1 min. Thrombin failed to induce TRPC1 phosphorylation in the
      absence of PKCalpha activation. Phosphorylation of TRPC1 and the resulting Ca2+
      entry were essential for the increase in permeability induced by thrombin in
      confluent endothelial monolayers. These results demonstrate that PKCalpha
      phosphorylation of TRPC1 is an important determinant of Ca2+ entry in human
      endothelial cells.

PMID- 15016834
TI  - Determination of N- and C-terminal borders of the transmembrane domain of
      integrin subunits.
AB  - Previous studies on the membrane-cytoplasm interphase of human integrin subunits
      have shown that a conserved lysine in subunits alpha(2), alpha(5), beta(1), and
      beta(2) is embedded in the plasma membrane in the absence of interacting proteins
      (Armulik, A., Nilsson, I., von Heijne, G., and Johansson, S. (1999) in J. Biol.
      Chem. 274, 37030-37034). Using a glycosylation mapping technique, we here show
      that alpha(10) and beta(8), two subunits that deviate significantly from the
      integrin consensus sequences in the membrane-proximal region, were found to have
      the conserved lysine at a similar position in the lipid bilayer. Thus, this
      organization at the C-terminal end of the transmembrane (TM) domain seems likely
      to be general for all 24 integrin subunits. Furthermore, we have determined the N
      terminal border of the TM domains of the alpha(2), alpha(5), alpha(10), beta(1),
      and beta(8) subunits. The TM domain of subunit beta(8) is found to be 22 amino
      acids long, with a second basic residue (Arg(684)) positioned just inside the
      membrane at the exoplasmic side, whereas the lipidembedded domains of the other
      subunits are longer, varying from 25 (alpha(2)) to 29 amino acids (alpha(10)).
      These numbers implicate that the TM region of the analyzed integrins (except
      beta(8)) would be tilted or bent in the membrane. Integrin signaling by
      transmembrane conformational change may involve alteration of the position of the
      segment adjacent to the conserved lysine. To test the proposed "piston" model for
      signaling, we forced this region at the C-terminal end of the alpha(5) and
      beta(1) TM domains out of the membrane into the cytosol by replacing Lys-Leu with
      Lys-Lys. The mutation was found to not alter the position of the N-terminal end
      of the TM domain in the membrane, indicating that the TM domain is not moving as
      a piston. Instead the shift results in a shorter and therefore less tilted or
      bent TM alpha-helix.

PMID- 15016833
TI  - A novel marker of tissue junctions, collagen XXII.
AB  - Here we describe a novel specific component of tissue junctions, collagen XXII.
      It was first identified by screening an EST data base and subsequently expressed
      as a recombinant protein and characterized as an authentic tissue component. The
      COL22A1 gene on human chromosome 8q24.2 encodes a collagen that structurally
      belongs to the FACIT protein family (fibril-associated collagens with interrupted
      triple helices). Collagen XXII exhibits a striking restricted localization at
      tissue junctions such as the myotendinous junction in skeletal and heart muscle,
      the articular cartilage-synovial fluid junction, or the border between the anagen
      hair follicle and the dermis in the skin. It is deposited in the basement
      membrane zone of the myotendinous junction and the hair follicle and associated
      with the extrafibrillar matrix in cartilage. In situ hybridization of
      myotendinous junctions revealed that muscle cells produce collagen XXII, and
      functional tests demonstrated that collagen XXII acts as a cell adhesion ligand
      for skin epithelial cells and fibroblasts. This novel gene product, collagen
      XXII, is the first specific extracellular matrix protein present only at tissue
      junctions.

PMID- 15016835
TI  - Alcoholic liver injury in the rat is associated with reduced expression of
      peroxisome proliferator-alpha (PPARalpha)-regulated genes and is ameliorated by
      PPARalpha activation.
AB  - Alcoholic liver disease is associated with a state of hepatic fatty acid
      overload. We examined the effect of ethanol and different types of dietary fat on
      the expression of mRNA for liver fatty acid binding protein (L-FABP), peroxisome
      proliferator-activated receptor-alpha (PPARalpha), and peroxisomal fatty acyl CoA
      oxidase (FACO). Four groups of rats (n = 5) were fed intragastrically, a liquid
      diet with or without ethanol (10-16 g/kg/day) for 4 weeks. Pair-fed controls
      received isocaloric amounts of dextrose. The source of fat was either corn oil or
      fish oil. Ethanolfed rats developed fatty liver, necrosis, and inflammation; the
      changes were more severe in the fish oil-ethanol (FE) rats. PPARalpha mRNA levels
      were not different between groups, although there was a trend toward increased
      levels in ethanol-fed rats. We calculated L-FABP/PPARalpha and FACO/PPARalpha
      ratios as a measure of FACO and L-FABP up-regulation relative to PPARalpha
      expression. Both FACO/PPARalpha and L-FABP/PPARalpha ratios were significantly
      decreased in FE rats. However, only L-FABP/PPARalpha was decreased in corn oil
      plus ethanol rats. Also, the level of L-FABP/mRNA correlated inversely with the
      degree of fatty liver in ethanol-fed rats. Since expression of PPARalpha response
      genes was impaired in ethanol-fed rats, we determined whether activation of
      PPARalpha would normalize the PPARalpha response and prevent the pathological
      changes in ethanol-fed rats. Treatment with clofibrate, a PPARalpha-activating
      ligand, led to a marked decrease in fatty liver and complete abrogation of
      necroinflammatory changes in FE rats. Also, nuclear factor kappaB activation and
      up-regulation of tumor necrosis factor-alpha and cyclooxygenase-2 was also
      abolished in clofibrate-treated rats. We conclude that adaptive gene regulation
      of FACO and L-FABP by PPARalpha is impaired in ethanol-fed rats and that
      treatment with clofibrate, a PPARalpha ligand, prevents alcohol-induced
      pathological liver injury, possibly by reversing the above changes.

PMID- 15016836
TI  - The comparative pharmacology and up-regulation of rat neuronal nicotinic receptor
      subtype binding sites stably expressed in transfected mammalian cells.
AB  - We stably transfected human embryonic kidney cells (HEK 293 cells) with genes
      encoding rat neuronal nicotinic receptor alpha2, alpha3, or alpha4 subunits in
      combination with the beta2 or beta4 subunit to generate six cell lines that
      express defined subunit combinations that represent potential subtypes of rat
      neuronal nicotinic acetylcholine receptors (nAChRs). These cell lines were
      designated KXalpha2beta2, KXalpha2beta4, KXalpha3beta2, KXalpha3beta4,
      KXalpha4beta2, and KXalpha4beta4. The Kd values of [3H](+/-)epibatidine ([3H]EB)
      binding to membranes from these six cell lines ranged from approximately 0.02 to
      0.3 nM. The pharmacological profiles of the agonist binding sites of these
      putative nAChR subtypes were examined in competition studies in which unlabeled
      nicotinic ligands, including 10 agonists and two antagonists, competed against
      [3H]EB. Most nicotinic ligands examined had higher affinity for the receptor
      subtypes containing the beta2 subunit compared with those containing the beta4
      subunit. An excellent correlation (r > 0.99) of the binding affinities of the 10
      agonists was observed between receptors from KXalpha4beta2 cells and from rat
      forebrain tissue, in which [3H]EB binding represents predominantly alpha4beta2
      nAChRs. More important, the affinities (Ki values) for the two tissues were
      nearly identical. The densities of the binding sites of all six cell lines were
      increased after a 5-day exposure to (-)-nicotine or the quaternary amine agonist
      carbachol. These data indicate that these cell lines expressing nAChR subunit
      combinations should be useful models for investigating pharmacological properties
      and regulation of the binding sites of potential nAChR subtypes, as well as for
      studying the properties of nicotinic compounds.

PMID- 15016838
TI  - Equilibrium interactions of corepressors and coactivators with agonist and
      antagonist complexes of glucocorticoid receptors.
AB  - Corepressors and coactivators can modulate the dose-response curve and partial
      agonist activity of glucocorticoid receptors (GRs) complexed with agonist and
      antagonist steroids, respectively, in intact cells. We recently reported that GR
      antagonist complexes bind to the coactivator TIF2, (transcriptional intermediary
      factor 2), which is consistent with the whole-cell effects of coactivators being
      mediated by direct interactions with GR complexes. We now ask whether the whole
      cell modulatory activity of corepressors also entails binding to both GR-agonist
      and -antagonist complexes and whether the association of corepressors and
      coactivators with GR complexes involves competitive equilibrium reactions. In
      mammalian two-hybrid assays with two different cell lines and in cell-free pull
      down and whole-cell immunoprecipitation assays, the corepressors NCoR (nuclear
      receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid
      hormone receptor) associate with agonist and antagonist complexes of GRs. Both N-
      and C-terminal regions of GR are needed for corepressor binding, which requires
      the CoRNR box motifs that mediate corepressor binding to other nuclear/steroid
      receptors. Importantly, whole-cell GR interactions with corepressors are
      competitively inhibited by excess coactivator and vice versa. However, the
      regions of the coactivator TIF2 that compete for GR binding to corepressor and
      coactivator are not the same, implying a molecular difference in GR association
      with coactivators and corepressors. Finally, when the whole-cell ratio of
      coactivators to corepressors is altered by selective cofactor binding to
      exogenous thyroid receptor beta +/- thyroid hormone, the GR dose-response-curve
      and partial agonist activity are appropriately modified. Such modifications are
      independent of histone acetylation. We conclude that mutually antagonistic
      equilibrium interactions of corepressors and coactivators modulate the dose
      response curve and partial agonist activity of GR complexes in a manner that is
      responsive to the intracellular ratio of these two classes of cofactors. This
      modulation provides an attractive mechanism for differential control of gene
      expression during development, differentiation, homeostasis, and endocrine
      therapies.

PMID- 15016839
TI  - Modulation of direct leptin signaling by soluble leptin receptor.
AB  - Soluble leptin receptor (SLR) represents the major leptin binding activity in
      plasma. It is generated by alternative splicing of OB-R mRNA (OB-Re) and/or
      ectodomain shedding of membrane-spanning receptors. To determine the role of SLR
      in leptin activation of its long-form receptor, OB-Rb, we established in vitro
      assays using a cell line stably expressing OB-Rb. Human embryonic kidney 293 cell
      lines stably overexpressing OB-Rb show a dose-dependent leptin-induced signal
      transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation and
      STAT3-responsive luciferase (STAT3-luc) activity. We demonstrate that when SLR is
      incubated with free leptin, binding of leptin to OB-Rb is reduced, with
      corresponding decrease of leptin-induced STAT3 tyrosine phosphorylation and STAT3
      luc activity. However, by preparing leptin/SLR mixtures containing the same
      amount of free leptin but increasing amounts of leptin-SLR complex, we show that
      leptin-SLR complex does not inhibit OB-Rb activation by free leptin. These
      results suggest that in settings in which leptin and SLR coexist, SLR may
      sequester leptin from productive interactions with OB-Rb. Because plasma SLR
      levels are independently regulated by many different physiological and
      pathophysiological conditions, SLR may modulate the actions of leptin in tissues
      in which direct action of leptin has been demonstrated.

PMID- 15016837
TI  - Interrelationship of growth differentiation factor 9 and inhibin in early
      folliculogenesis and ovarian tumorigenesis in mice.
AB  - To investigate the interrelationship of inhibin alpha and growth differentiation
      factor 9 (GDF9) during early folliculogenesis, we generated mice lacking both
      inhibin alpha and GDF9. Our findings on these Inha Gdf9 double-mutant mice are as
      follows: 1). females develop ovarian tumors and a cachexia-like wasting syndrome,
      resembling mice lacking inhibin alpha alone. This indicates that the granulosa
      cells are competent to proliferate despite the lack of GDF9; 2). follicular
      development progresses to multiple-layer follicle stages before tumorigenesis.
      This demonstrates that the up-regulation of inhibin alpha in the Gdf9 knockout
      ovary directly prevents the proliferation of the granulosa cells at the primary
      follicle stage, an effect that is released in the absence of inhibin alpha; 3). a
      morphological theca forms around the preantral follicles with no detectable
      selective theca markers [i.e. 17alpha-hydroxylase (Cyp17), LH receptor (Lhr), and
      Kit]. These results indicate that the theca recruitment can occur independently
      of GDF9, but the differentiation of thecal cells is blocked; and 4).
      inhibin/activin subunits betaA, betaB, and Kit ligand (Kitl) mRNA are highly up
      regulated, suggesting that the increased activins and KITL play functional roles
      in early folliculogenesis. Thus, GDF9 appears to function indirectly to regulate
      early granulosa cell proliferation and theca recruitment in vivo.

PMID- 15016840
TI  - Insight into mutation-induced activation of the luteinizing hormone receptor:
      molecular simulations predict the functional behavior of engineered mutants at
      M398.
AB  - In this study, molecular simulations have been combined with site-directed
      mutagenesis experiments to explore M398(2.43), a LH (lutropin) receptor (LHR)
      site in helix 2 susceptible to spontaneous activating mutations, and to develop a
      computational tool for predicting the functionality (i.e. active or nonactive) of
      LHR mutants.Site-directed mutagenesis experiments engineered 15 different
      substitutions for M389(2.43), which resulted in variable levels of constitutive
      activity, inversely correlated with the size of the replacing amino acid. This
      inverse correlation is suggested to be mediated by I460(3.46), M571(6.37), and
      Y623(7.53), the tyrosine of the NPxxY motif. In fact, size reduction at position
      398(2.43), which is concurrent with constitutive receptor activity, releases the
      van der Waals interactions found in the wild-type LHR between M398(2.43) and
      these three amino acids, resulting in structural modifications in the proximity
      to the E/DRY/W motif. An increment, above a threshold value, in the solvent
      accessibility of the cytosolic ends of helices 3 and 6 is the main structural
      feature shared by the active mutants of the LHR. This feature has been
      successfully used for predicting the functionality of the engineered mutants at
      M398(2.43), proving that molecular simulations can be useful for in silico
      screening of LHR mutants.

PMID- 15016841
TI  - Monitoring RNA release from human rhinovirus by dynamic force microscopy.
AB  - Human rhinoviruses were imaged under physiological conditions by dynamic force
      microscopy. Topographical images revealed various polygonal areas on the surfaces
      of the 30-nm viral particles. RNA release was initiated by exposure to a low-pH
      buffer. The lengths of the RNAs that were released but still connected to the
      virus capsid varied between 40 and 330 nm, whereas RNA molecules that were
      completely released from the virus were observed with lengths up to 1 micro m.
      Fork-like structure elements with 30-nm extensions were sometimes resolved at one
      end of the RNA molecules. They possibly correspond to the characteristic multi
      stem-loop conformation, the internal ribosomal entry site, located at the 5'
      region of the genome. This study demonstrates that dynamic force microscopy can
      be used to study viral RNA release in situ under physiological conditions.

PMID- 15016842
TI  - Azido-containing diketo acid derivatives inhibit human immunodeficiency virus
      type 1 integrase in vivo and influence the frequency of deletions at two-long
      terminal-repeat-circle junctions.
AB  - We previously found that azido-containing beta-diketo acid derivatives (DKAs) are
      potent inhibitors of human immunodeficiency virus type 1 (HIV-1) integrase (IN)
      (X. Zhang et al., Bioorg. Med. Chem. Lett., 13:1215-1219, 2003). To characterize
      the intracellular mechanisms of action of DKAs, we analyzed the antiviral
      activities of two potent azido-containing DKAs with either a monosubstitution or
      a disubstitution of azido groups, using single- and multiple-replication-cycle
      assays. Both azido-containing DKAs significantly inhibited HIV-1 infection in
      293T, CEM-SS, and H9 cells (50% inhibitory concentration = 2 to 13 micro M) and
      exhibited low cytotoxicity (50% cytotoxic concentration = 60 to 600 micro M).
      Inhibition of HIV-1 IN in vivo was demonstrated by the observation that
      previously described L-708,906 resistance mutations in HIV-1 IN (T66I and
      T66I/S153Y) also conferred resistance to the azido-group-containing DKAs. In
      vitro assays and in vivo analysis indicated that the DKAs did not significantly
      inhibit the 3' processing and selectively inhibited the strand transfer reaction.
      In addition, quantitative PCR indicated that two-long-terminal-repeat (2-LTR)
      circles were elevated in the presence of the azido-containing DKAs, confirming
      that HIV-1 IN was the intracellular target of viral inhibition. To gain insight
      into the mechanism by which the DKAs increased 2-LTR-circle formation of 3'
      processed viral DNAs, we performed extensive DNA sequencing analysis of 2-LTR
      circle junctions. The results indicated that the frequency of deletions at the
      circle junctions was elevated from 19% for the untreated controls to 32 to 41% in
      the presence of monosubstituted (but not disubstituted) DKAs. These results
      indicate that the structure of the DKAs can influence the extent of degradation
      of viral DNA ends by host nucleases and the frequency of deletions at the 2-LTR
      circle junctions. Thus, sequencing analysis of 2-LTR-circle junctions can
      elucidate the intracellular mechanisms of action of HIV-1 IN inhibitors.

PMID- 15016843
TI  - Amino acid 324 in the simian immunodeficiency virus SIVmac V3 loop can confer CD4
      independence and modulate the interaction with CCR5 and alternative coreceptors.
AB  - The V3 loop of the simian immunodeficiency virus (SIV) envelope protein (Env)
      largely determines interactions with viral coreceptors. To define amino acids in
      V3 that are critical for coreceptor engagement, we functionally characterized Env
      variants with amino acid substitutions at position 324 in V3, which has
      previously been shown to impact SIV cell tropism. These changes modulated CCR5
      engagement and, in some cases, allowed the efficient usage of CCR5 in the absence
      of CD4. The tested amino acid substitutions had highly differential effects on
      viral infectivity. Eleven of sixteen substitutions disrupted entry via CCR5 or
      the alternative coreceptor GPR15. Nevertheless, most of these variants replicated
      in the macaque T-cell line 221-89 and some also replicated in rhesus macaque
      peripheral blood monocytes, suggesting that efficient usage of CCR5 and GPR15 on
      cell lines is not a prerequisite for SIV replication in primary cells. Four
      variants showed enhanced entry into the macaque sMagi reporter cell line.
      However, sMagi cells did not express appreciable amounts of CCR5 and GPR15 mRNA,
      and entry into these cells was not efficiently blocked by a small-molecule CCR5
      antagonist, suggesting that sMagi cells express as-yet-unidentified entry
      cofactors. In summary, we found that a single amino acid at position 324 in the
      SIV Env V3 loop can modulate both the efficiency and the types of coreceptors
      engaged by Env and allow for CD4-independent fusion in some cases.

PMID- 15016844
TI  - Hierarchical targeting of subtype C human immunodeficiency virus type 1 proteins
      by CD8+ T cells: correlation with viral load.
AB  - An understanding of the relationship between the breadth and magnitude of T-cell
      epitope responses and viral loads is important for the design of effective
      vaccines. For this study, we screened a cohort of 46 subtype C human
      immunodeficiency virus type 1 (HIV-1)-infected individuals for T-cell responses
      against a panel of peptides corresponding to the complete subtype C genome. We
      used a gamma interferon ELISPOT assay to explore the hypothesis that patterns of
      T-cell responses across the expressed HIV-1 genome correlate with viral control.
      The estimated median time from seroconversion to response for the cohort was 13
      months, and the order of cumulative T-cell responses against HIV proteins was as
      follows: Nef > Gag > Pol > Env > Vif > Rev > Vpr > Tat > Vpu. Nef was the most
      intensely targeted protein, with 97.5% of the epitopes being clustered within 119
      amino acids, constituting almost one-third of the responses across the expressed
      genome. The second most targeted region was p24, comprising 17% of the responses.
      There was no correlation between viral load and the breadth of responses, but
      there was a weak positive correlation (r = 0.297; P = 0.034) between viral load
      and the total magnitude of responses, implying that the magnitude of T-cell
      recognition did not contribute to viral control. When hierarchical patterns of
      recognition were correlated with the viral load, preferential targeting of Gag
      was significantly (r = 0.445; P = 0.0025) associated with viral control. These
      data suggest that preferential targeting of Gag epitopes, rather than the breadth
      or magnitude of the response across the genome, may be an important marker of
      immune efficacy. These data have significance for the design of vaccines and for
      interpretation of vaccine-induced responses.

PMID- 15016845
TI  - Ancient coevolution of baculoviruses and their insect hosts.
AB  - If the relationships between baculoviruses and their insect hosts are subject to
      coevolution, this should lead to long-term evolutionary effects such as the
      specialization of these pathogens for their hosts. To test this hypothesis, a
      phylogeny of the Baculoviridae, including 39 viruses from hosts of the orders
      Lepidoptera, Diptera, and Hymenoptera, was reconstructed based on sequences from
      the genes lef-8 and ac22. The tree showed a clear division of the baculoviruses
      according to the order of their hosts. This division highlighted the need to
      reconsider the classification of the baculoviruses to include one or possibly two
      new genera. Furthermore, the specialization of distinct virus lineages to
      particular insect orders suggests ancient coevolutionary interactions between
      baculoviruses and their hosts.

PMID- 15016846
TI  - Inferring the evolutionary history of rice yellow mottle virus from genomic,
      phylogenetic, and phylogeographic studies.
AB  - Fourteen isolates of Rice yellow mottle virus (RYMV) were selected as
      representative of the genetic variability of the virus in Africa from a total set
      of 320 isolates serologically typed or partially sequenced. The 14 isolates were
      fully sequenced and analyzed together with two previously reported sequences.
      RYMV had a genomic organization similar to that of Cocksfoot mottle sobemovirus.
      The average nucleotide diversity among the 16 isolates of RYMV was 7%, and the
      maximum diversity between any two isolates was 10%. A strong conservative
      selection was apparent on both synonymous and nonsynonymous substitutions,
      through the amino acid replacement pattern, on the genome size, and through the
      limited number of indel events. Furthermore, there was a lack of positive
      selection on single amino acid sites and no evidence of recombination events.
      RYMV diversity had a pronounced and characteristic geographic structure. The
      branching order of the clades correlated with the geographic origin of the
      isolates along an east-to-west transect across Africa, and there was a marked
      decrease in nucleotide diversity moving westward across the continent. The
      insertion-deletion polymorphism was related to virus phylogeny. There was a
      partial phylogenetic incongruence between the coat protein gene and the rest of
      the genome. Overall, our results support the hypothesis that RYMV originated in
      East Africa and then dispersed and differentiated gradually from the east to the
      west of the continent.

PMID- 15016847
TI  - Modulation of hepatitis B virus secretion by naturally occurring mutations in the
      S gene.
AB  - Alteration in hepatitis B virus (HBV) secretion efficiency may have pathological
      consequences. Naturally occurring mutations that regulate virion secretion have
      not been defined. We recently identified HBV genomes displaying high (4B),
      substantially reduced (3.4), or negative (4C) virion secretion. In the present
      study, the underlying mutations were mapped. A T552C point mutation in the 4B
      genome was responsible for its enhanced virion secretion, whereas a G510A
      mutation in 3.4 and G660C in 4C impaired virus secretion. The three point
      mutations generate M133T, G119E, and R169P substitutions in the S domains of
      viral envelope proteins, respectively, without modifying the coding capacity of
      the overlapping polymerase gene. The mutated residues are predicted to lie in the
      luminal side of the endoplasmic reticulum (ER) or to be embedded in the ER
      membrane and thus are not involved in contact with core particles during
      envelopment. Of the two mutations inhibitory of virion secretion, G510A greatly
      reduced small envelope protein (hepatitis B surface antigen [HBsAg]) levels both
      inside cells and in culture medium, whereas G660C specifically abolished HBsAg
      secretion. Surprisingly, a T484G mutation in the 4B genome, generating an I110M
      substitution in the S domain, could also reduce HBsAg secretion and block virion
      secretion. However, its inhibitory effect was suppressed in the 4B genome by the
      T552C mutation, the enhancer of virion secretion. T552C can also override the
      inhibitory G510A mutation, but not the G660C mutation. These findings suggest a
      hierarchy in the regulation of virion secretion and a close link between
      defective virion secretion and impaired HBsAg formation or secretion.

PMID- 15016848
TI  - Cleavage of eukaryotic translation initiation factor 4GII within foot-and-mouth
      disease virus-infected cells: identification of the L-protease cleavage site in
      vitro.
AB  - Foot-and-mouth disease virus (FMDV) induces a very rapid inhibition of host cell
      protein synthesis within infected cells. This is accompanied by the cleavage of
      the eukaryotic translation initiation factor 4GI (eIF4GI). The cleavage of the
      related protein eIF4GII has now been analyzed. Within FMDV-infected cells,
      cleavage of eIF4GI and eIF4GII occurs with similar kinetics. Cleavage of eIF4GII
      is induced in cells and in cell extracts by the FMDV leader protease (L(pro))
      alone, generating cleavage products similar to those induced by enterovirus and
      rhinovirus 2A protease (2A(pro)). By the use of a fusion protein containing
      residues 445 to 744 of human eIF4GII, it was demonstrated that the FMDV L(pro)
      specifically cleaves this protein between residues G700 and S701, immediately
      adjacent to the site (V699/G700) cleaved by rhinovirus 2A(pro) in vitro. The
      G700/S701 cleavage site does not correspond, by amino acid sequence alignment, to
      that cleaved in eIF4GI by the FMDV L(pro) in vitro. Knowledge of the cleavage
      sites and the three-dimensional structures of the FMDV L(pro) and rhinovirus
      2A(pro) enabled mutant forms of the eIF4GII sequence to be generated that are
      differentially resistant to either one of these proteases. These results
      confirmed the specificity of each protease and showed that the mutant forms of
      the fusion protein substrate retained their correct sensitivity to other
      proteases.

PMID- 15016850
TI  - The last C-terminal residue of VP3, glutamic acid 257, controls capsid assembly
      of infectious bursal disease virus.
AB  - Infectious bursal disease virus (IBDV) is a nonenveloped virus with an
      icosahedral capsid composed of two proteins, VP2 and VP3, that derive from the
      processing of the polyprotein NH(2)-pVP2-VP4-VP3-COOH. The virion contains VP1,
      the viral polymerase, which is both free and covalently linked to the two double
      stranded RNA (dsRNA) genomic segments. In this study, the virus assembly process
      was studied further with the baculovirus expression system. While expression of
      the wild-type polyprotein was not found to be self-sufficient to give rise to
      virus-like particles (VLPs), deletion or replacement of the five C-terminal
      residues of VP3 was observed to promote capsid assembly. Indeed, the single
      deletion of the C-terminal glutamic acid was sufficient to induce VLP formation.
      Moreover, fusion of various peptides or small proteins (a green fluorescent
      protein or a truncated form of ovalbumin) at the C terminus of VP3 also promoted
      capsid assembly, suggesting that assembly required screening of the negative
      charges at the C terminus of VP3. The fused polypeptides mimicked the effect of
      VP1, which interacts with VP3 to promote VLP assembly. The C-terminal segment of
      VP3 was found to contain two functional domains. While the very last five
      residues of VP3 mainly controlled both assembly and capsid architecture, the five
      preceding residues constituted the VP1 (and possibly the pVP2/VP2) binding
      domain. Finally, we showed that capsid formation is associated with VP2
      maturation, demonstrating that the protease VP4 is involved in the virus assembly
      process.

PMID- 15016849
TI  - N-linked glycosylation of the V3 loop and the immunologically silent face of
      gp120 protects human immunodeficiency virus type 1 SF162 from neutralization by
      anti-gp120 and anti-gp41 antibodies.
AB  - We examined how asparagine-linked glycans within and adjacent to the V3 loop (C2
      and C3 regions) and within the immunologically silent face (V4, C4, and V5
      regions) of the human immunodeficiency virus (HIV) SF612 envelope affect the
      viral phenotype. Five of seven potential glycosylation sites are utilized when
      the virus is grown in human peripheral blood mononuclear cells, with the
      nonutilized sites lying within the V4 loop. Elimination of glycans within and
      adjacent to the V3 loop renders SF162 more susceptible to neutralization by
      polyclonal HIV(+)-positive and simian/human immunodeficiency virus-positive sera
      and by monoclonal antibodies (MAbs) recognizing the V3 loop, the CD4- and CCR5
      binding sites, and the extracellular region of gp41. Importantly, our studies
      also indicate that glycans located within the immunologically silent face of
      gp120, specifically the C4 and V5 regions, also conferred on SF162 resistance to
      neutralization by anti-V3 loop, anti-CD4 binding site, and anti-gp41 MAbs but not
      by antibodies targeting the coreceptor binding site. We also observed that the
      amino acid composition of the V4 region contributes to the neutralization
      phenotype of SF162 by anti-V3 loop and anti-CD4 binding site MAbs. Collectively,
      our data support the proposal that the glycosylation and structure of the
      immunologically silent face of the HIV envelope plays an important role in
      defining the neutralization phenotype of HIV type 1.

PMID- 15016851
TI  - p16(Ink4a) interferes with Abelson virus transformation by enhancing apoptosis.
AB  - Pre-B-cell transformation by Abelson virus (Ab-MLV) is a multistep process in
      which primary transformants are stimulated to proliferate but subsequently
      undergo crisis, a period of erratic growth marked by high levels of apoptosis.
      Inactivation of the p53 tumor suppressor pathway is an important step in this
      process and can be accomplished by mutation of p53 or down-modulation of
      p19(Arf), a p53 regulatory protein. Consistent with these data, pre-B cells from
      either p53 or Ink4a/Arf null mice bypass crisis. However, the Ink4a/Arf locus
      encodes both p19(Arf) and a second tumor suppressor, p16(Ink4a), that blocks cell
      cycle progression by inhibiting Cdk4/6. To determine if p16(Ink4a) plays a role
      in Ab-MLV transformation, primary transformants derived from Arf(-/-) and
      p16(Ink4a(-/-)) mice were compared. A fraction of those derived from Arf(-/-)
      animals underwent crisis, and even though all p16(Ink4a(-/-)) primary
      transformants experienced crisis, these cells became established more readily
      than cells derived from +/+ mice. Analyses of Ink4a/Arf(-/-) cells infected with
      a virus that expresses both v-Abl and p16(Ink4a) revealed that p16(Ink4a)
      expression does not alter cell cycle profiles but does increase the level of
      apoptosis in primary transformants. These results indicate that both products of
      the Ink4a/Arf locus influence Ab-MLV transformation and reveal that in addition
      to its well-recognized effects on the cell cycle, p16(Ink4a) can suppress
      transformation by inducing apoptosis.

PMID- 15016852
TI  - Multistep regulation of membrane insertion of the fusion peptide of Semliki
      Forest virus.
AB  - A prevailing model for virus membrane fusion proteins has been that the
      hydrophobic fusion peptide is hidden in the prefusion conformation, becomes
      exposed once the fusion reaction is triggered, and then either inserts into
      target membranes or is rapidly inactivated. This model is in general agreement
      with the structure and mechanism of class I fusion proteins, such as the
      influenza virus hemagglutinin. We here describe studies of the class II fusion
      protein E1 from the alphavirus Semliki Forest virus (SFV). SFV fusion is
      triggered by low pH, which releases E1 from its heterodimeric interaction with
      the E2 protein and induces the formation of a stable E1 homotrimer. The exposure
      and target membrane interaction of the E1 fusion peptide (residues 83 to 100)
      were followed using a monoclonal antibody (MAb E1f) mapping to E1 residues 85 to
      95. In agreement with the known structure of SFV and other alphaviruses, the
      fusion peptide was shielded in native SFV particles and exposed when E1-E2 dimer
      dissociation was triggered by acidic pH. In contrast, the fusion peptide on
      purified E1 ectodomains (E1(*)) was fully accessible at neutral pH. Functional
      assays showed that MAb E1f binding at neutral pH prevented subsequent low-pH
      triggered E1(*) interaction with target membranes and trimerization. E1(*) was
      not inactivated by low pH when treated either in the absence of target membranes
      or in the presence of fusion-inactive cholesterol-deficient liposomes. Thus, the
      membrane insertion of the E1 fusion peptide is regulated by additional low-pH
      dependent steps after exposure, perhaps involving an E1-cholesterol interaction.

PMID- 15016853
TI  - Preextinction viral RNA can interfere with infectivity.
AB  - When the error rate during the copying of genetic material exceeds a threshold
      value, the genetic information cannot be maintained. This concept is the basis of
      a new antiviral strategy termed lethal mutagenesis or virus entry into error
      catastrophe. Critical for its success is preventing survival of residual
      infectious virus or virus mutants that escape the transition into error
      catastrophe. Here we document that mutated, preextinction foot-and-mouth disease
      virus (FMDV) RNA can interfere with and delay viral production up to 30 h when
      cotransfected in BHK-21 cells with standard RNA. Interference depended on the
      physical integrity of preextinction RNA and was not observed with unrelated RNAs
      or with nonmutated, defective FMDV RNA. These results suggest that this type of
      interference requires large size, preextinction FMDV RNA and is mediated neither
      by small interfering RNAs nor by RNAs that can compete with infectious RNA for
      host cell factors. A model based on the aberrant expression of mutated RNA as it
      is expected to occur in the initial stages of the transition into error
      catastrophe is proposed. Interference mediated by preextinction RNA indicates an
      advantage of mutagenesis versus inhibition in preventing the survival of virus
      escape mutants during antiviral treatments.

PMID- 15016854
TI  - Isolation of human monoclonal antibodies that neutralize human rotavirus.
AB  - A human antibody library constructed by utilizing a phage display system was used
      for the isolation of human antibodies with neutralizing activity specific for
      human rotavirus. In the library, the Fab form of an antibody fused to truncated
      cp3 is expressed on the phage surface. Purified virions of strain KU (G1 serotype
      and P[8] genotype) were used as antigen. Twelve different clones were isolated.
      Based on their amino acid sequences, they were classified into three groups.
      Three representative clones-1-2H, 2-3E, and 2-11G-were characterized. Enzyme
      linked immunosorbent assay with virus-like particles (VLP-VP2/6 and VLP-VP2/6/7)
      and recombinant VP4 protein produced from baculovirus recombinants indicated that
      1-2H and 2-3E bind to VP4 and that 2-11G binds to VP7. The neutralization epitope
      recognized by each of the three human antibodies might be human specific, since
      all of the antigenic mutants resistant to mouse monoclonal neutralizing
      antibodies previously prepared were neutralized by the human antibodies obtained
      here. After conversion from the Fab form of an antibody into immunoglobulin G1,
      the neutralizing activities of these three clones toward various human rotavirus
      strains were examined. The 1-2H antibody exhibited neutralizing activity toward
      human rotaviruses with either the P[4] or P[8] genotype. Similarly, the 2-3E
      antibody showed cross-reactivity against HRVs with the P[6], as well as the P[8]
      genotype. In contrast, the 2-11G antibody neutralized only human rotaviruses with
      the G1 serotype. The concentration of antibodies required for 50% neutralization
      ranged from 0.8 to 20 micro g/ml.

PMID- 15016855
TI  - Qualitative T-helper responses to multiple viral antigens correlate with vaccine
      induced immunity to simian/human immunodeficiency virus infection.
AB  - Evidence is accumulating that CD4(+) T-helper (Th) responses play a critical role
      in facilitating effector responses which are capable of controlling and even
      preventing human immunodeficiency virus (HIV) infection. The present work was
      undertaken to determine whether immunization with multiple antigens influenced
      individual Th responses and increased protection relative to a single antigen.
      Rhesus macaques were primed with DNA and boosted (immune-stimulating complex
      formulated protein) with a combination of regulatory and structural antigens (Tat
      Env-Gag) or with Tat alone. Immunization with combined antigens reduced the
      magnitude of the responses to Tat compared to the single-antigen immunization.
      Interestingly, the Th immune responses to the individual antigens were noticeably
      different. To determine whether the qualitative differences in vaccine-induced Th
      responses correlated with vaccine efficacy, animals were challenged intravenously
      with simian/human immunodeficiency virus (strain SHIV(89.6p)) 2 months following
      the final immunization. Animals that developed combined Th1- and Th2-like
      responses to Gag and Th2 dominant Env-specific responses were protected from
      disease progression. Interestingly, one animal that was completely protected from
      infection had the strongest IFN-gamma and interleukin-2 (IL-2) responses prior to
      challenge, in addition to very strong IL-4 responses to Gag and Env. In contrast,
      animals with only a marked vaccine-induced Tat-specific Th2 response (no IFN
      gamma) were not protected from infection or disease. These data support the
      rationale that effective HIV vaccine-induced immunity requires a combination of
      potent Th1- and Th2-like responses best directed to multiple antigens.

PMID- 15016856
TI  - Differential activation of murine herpesvirus 68- and Kaposi's sarcoma-associated
      herpesvirus-encoded ORF74 G protein-coupled receptors by human and murine
      chemokines.
AB  - Infection of mice with murine gammaherpesvirus 68 (MHV-68) is a well
      characterized small animal model for the study of gammaherpesvirus infection. MHV
      68 belongs to the same herpesvirus family as herpesvirus saimiri (HVS) of New
      World squirrel monkeys and human herpesvirus 8 (HHV-8) (also referred to as
      Kaposi's sarcoma-associated herpesvirus [KSHV]). The open reading frame ORF74 of
      HVS, KSHV, and MHV-68 encodes a protein with homology to G protein-coupled
      receptors and chemokine receptors in particular. ORF74 of KSHV (human ORF74
      [hORF74]) is highly constitutively active and has been implicated in the
      pathogenesis of Kaposi's sarcoma. MHV-68-encoded ORF74 (mORF74) is oncogenic and
      has been implicated in viral replication and reactivation from latency. Here, we
      show that mORF74 is a functional chemokine receptor. Chemokines with an N
      terminal glutamic acid-leucine-arginine (ELR) motif (e.g., KC and macrophage
      inflammatory protein 2) act as agonists on mORF74, activating phospholipase C, NF
      kappaB, p44/p42 mitogen-activated protein kinase, and Akt signaling pathways and
      inhibiting formation of cyclic AMP. Using (125)I-labeled CXCL1/growth-related
      oncogene alpha as a tracer, we show that murine CXCL10/gamma interferon-inducible
      protein 10 binds mORF74, and functional assays show that it behaves as an
      antagonist for this virally encoded G protein-coupled receptor. Profound
      differences in the upstream activation of signal transduction pathways between
      mORF74 and hORF74 were found. Moreover, in contrast to hORF74, no constitutive
      activity of mORF74 could be detected.

PMID- 15016857
TI  - Role of interleukin-4 (IL-4) and IL-10 in serum immunoglobulin G antibody
      responses following mucosal or systemic reovirus infection.
AB  - Mucosal and parenteral immunizations elicit qualitatively distinct immune
      responses, and there is evidence that mucosal immunization can skew the balance
      of T helper 1 and T helper 2 responses. However, a clear picture of the effect of
      the route of infection on the balance of the T helper responses has not yet
      emerged. Our laboratory previously demonstrated that oral reovirus infection
      elicits specific serum immunoglobulin G2a (IgG2a), while parenteral reovirus
      infection elicits the mixed production of specific serum IgG2a and IgG1 in mice
      of the H-2(d) haplotype. Knowing that IgG2a production is indicative of a T
      helper 1 response and IgG1 production is indicative of a T helper 2 response, we
      hypothesized that the route of infection influences the development of T helper 1
      and T helper 2 responses. Using quantitative reverse transcription-PCR, we found
      that mRNA for the T helper 1 cytokines gamma interferon and interleukin-12 (IL
      12) were expressed in draining lymphoid tissues following both oral and
      parenteral infections. However, we observed that mRNA for the T helper 2 cytokine
      IL-10 was suppressed in the Peyer's patches and mesenteric lymph nodes and IL-4
      mRNA was suppressed in the mesenteric lymph nodes compared to noninfected
      controls, following oral infection. Using recombinant cytokines and cytokine
      knockout mice, we confirmed that IL-4 plays a major role in mediating the route
      of-infection-dependent differences in serum IgG subclass responses. Therefore,
      the route of infection needs to be taken into consideration when developing
      vaccines and adjuvant therapies.

PMID- 15016858
TI  - Structure of adeno-associated virus serotype 5.
AB  - Adeno-associated virus serotype 5 (AAV5) requires sialic acid on host cells to
      bind and infect. Other parvoviruses, including Aleutian mink disease parvovirus
      (ADV), canine parvovirus (CPV), minute virus of mice, and bovine parvovirus, also
      bind sialic acid. Hence, structural homology may explain this functional
      homology. The amino acids required for CPV sialic acid binding map to a site at
      the icosahedral twofold axes of the capsid. In contrast to AAV5, AAV2 does not
      bind sialic acid, but rather binds heparan sulfate proteoglycans at its threefold
      axes of symmetry. To explore the structure-function relationships among
      parvoviruses with respect to cell receptor attachment, we determined the
      structure of AAV5 by cryo-electron microscopy (cryo-EM) and image reconstruction
      at a resolution of 16 A. Surface features common to some parvoviruses, namely
      depressions encircling the fivefold axes and protrusions at or surrounding the
      threefold axes, are preserved in the AAV5 capsid. However, even though there were
      some similarities, a comparison of the AAV5 structure with those of ADV and CPV
      failed to reveal a feature which could account for the sialic acid binding
      phenotype common to all three viruses. In contrast, the overall surface
      topologies of AAV5 and AAV2 are similar. A pseudo-atomic model generated for AAV5
      based on the crystal structure of AAV2 and constrained by the AAV5 cryo-EM
      envelope revealed differences only in surface loop regions. Surprisingly, the
      surface topologies of AAV5 and AAV2 are remarkably similar to that of ADV despite
      only exhibiting approximately 20% identity in amino acid sequences. Thus, capsid
      surface features are shared among parvoviruses and may not be unique to their
      replication phenotypes, i.e., whether they require a helper or are autonomous.
      Furthermore, specific surface features alone do not explain the variability in
      carbohydrate requirements for host cell receptor interactions among parvoviruses.

PMID- 15016860
TI  - The poliovirus replication machinery can escape inhibition by an antiviral drug
      that targets a host cell protein.
AB  - Viral replication depends on specific interactions with host factors. For
      example, poliovirus RNA replication requires association with intracellular
      membranes. Brefeldin A (BFA), which induces a major rearrangement of the cellular
      secretory apparatus, is a potent inhibitor of poliovirus RNA replication. Most
      aspects governing the relationship between viral replication complex and the host
      membranes remain poorly defined. To explore these interactions, we used a genetic
      approach and isolated BFA-resistant poliovirus variants. Mutations within viral
      proteins 2C and 3A render poliovirus resistant to BFA. In the absence of BFA,
      viruses containing either or both of these mutations replicated similarly to wild
      type. In the presence of BFA, viruses carrying a single mutation in 2C or 3A
      exhibited an intermediate-growth phenotype, while the double mutant was fully
      resistant. The viral proteins 2C and 3A have critical roles in both RNA
      replication and vesicle formation. The identification of BFA resistant mutants
      may facilitate the identification of cellular membrane-associated proteins
      necessary for induction of vesicle formation and RNA replication. Importantly,
      our data underscore the dramatic plasticity of the host-virus interactions
      required for successful viral replication.

PMID- 15016859
TI  - Dimerization of recombinant tobacco mosaic virus movement protein.
AB  - The p30 movement protein (MP) is essential for cell-to-cell spread of tobacco
      mosaic virus in planta. We used anion-exchange chromatography and preparative
      sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to obtain
      highly purified 30-kDa MP, which migrated as a single band in native PAGE.
      Analytical ultracentrifugation suggested that the protein was monodisperse and
      dimeric in the nonionic detergent n-octyl-beta-D-glucopyranoside. Circular
      dichroism (CD) spectroscopy showed that the detergent-solubilized protein
      contained significant alpha-helical secondary structure. Proteolysis of the C
      tail generated a trypsin-resistant core that was a mixture of primarily monomers
      and some dimers. We propose that MP dimers are stabilized by electrostatic
      interactions in the C terminus as well as hydrophobic interactions between
      putative transmembrane alpha-helical coiled coils.

PMID- 15016861
TI  - Nonnucleoside inhibitor binding affects the interactions of the fingers subdomain
      of human immunodeficiency virus type 1 reverse transcriptase with DNA.
AB  - Site-directed photoaffinity cross-linking experiments were performed by using
      human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) mutants
      with unique cysteine residues at several positions (i.e., positions 65, 67, 70,
      and 74) in the fingers subdomain of the p66 subunit. Since neither the
      introduction of the unique cysteine residues into the fingers nor the
      modification of the SH groups of these residues with photoaffinity cross-linking
      reagents caused a significant decrease in the enzymatic activities of RT, we were
      able to use this system to measure distances between specific positions in the
      fingers domain of RT and double-stranded DNA. HIV-1 RT is quite flexible. There
      are conformational changes associated with binding of the normal substrates and
      nonnucleoside RT inhibitors (NNRTIs). Cross-linking was used to monitor
      intramolecular movements associated with binding of an NNRTI either in the
      presence or in the absence of an incoming deoxynucleoside triphosphate (dNTP).
      Binding an incoming dNTP at the polymerase active site decreased the efficiency
      of cross-linking but caused only modest changes in the preferred positions of
      cross-linking. This finding suggests that the fingers of p66 are closer to an
      extended template in the "open" configuration of the enzyme with the fingers away
      from the active site than in the closed configuration with the fingers in direct
      contact with the incoming dNTP. NNRTI binding caused increased cross-linking in
      experiments with diazirine reagents (especially with a diazirine reagent with a
      longer linker) and a moderate shift in the preferred sites of interaction with
      the template. Cross-linking occurred closer to the polymerase active site for RTs
      modified at positions 70 and 74. The effects of NNRTI binding were more
      pronounced in the absence of a bound dNTP; pretreatment of HIV-1 RT with an NNRTI
      reduced the effect of dNTP binding. These observations can be explained if the
      binding of NNRTI causes a decrease in the flexibility in the fingers subdomain of
      RT-NNRTI complex and a decrease in the distance from the fingers to the template
      extension.

PMID- 15016862
TI  - Coronavirus neurovirulence correlates with the ability of the virus to induce
      proinflammatory cytokine signals from astrocytes and microglia.
AB  - The molecular and cellular basis of coronavirus neurovirulence is poorly
      understood. Since neurovirulence may be determined at the early stages of
      infection of the central nervous system (CNS), we hypothesize that it may depend
      on the ability of the virus to induce proinflammatory signals from brain cells
      for the recruitment of blood-derived inflammatory cells. To test this hypothesis,
      we studied the interaction between coronaviruses (mouse hepatitis virus) of
      different neurovirulences with primary cell cultures of brain immune cells
      (astrocytes and microglia) and mouse tissues. We found that the level of
      neurovirulence of the virus correlates with its differential ability to induce
      proinflammatory cytokines (interleukin 12 [IL-12] p40, tumor necrosis factor
      alpha, IL-6, IL-15, and IL-1beta) in astrocytes and microglia and in mouse brains
      and spinal cords. These findings suggest that coronavirus neurovirulence may
      depend on a novel discriminatory ability of astrocytes and microglia to induce a
      proinflammatory response in the CNS.

PMID- 15016863
TI  - PU.1 binding to ets motifs within the equine infectious anemia virus long
      terminal repeat (LTR) enhancer: regulation of LTR activity and virus replication
      in macrophages.
AB  - Binding of the transcription factor PU.1 to its DNA binding motif regulates the
      expression of a number of B-cell- and myeloid-specific genes. The long terminal
      repeat (LTR) of macrophage-tropic strains of equine infectious anemia virus
      (EIAV) contains three PU.1 binding sites, namely an invariant promoter-proximal
      site as well as two upstream sites. We have previously shown that these sites are
      important for EIAV LTR activity in primary macrophages (W. Maury, J. Virol.
      68:6270-6279, 1994). Since the sequences present in these three binding motifs
      are not identical, we sought to determine the role of these three sites in EIAV
      LTR activity. While DNase I footprinting studies indicated that all three sites
      within the enhancer were bound by recombinant PU.1, reporter gene assays
      demonstrated that the middle motif was most important for basal levels of LTR
      activity in macrophages and that the 5' motif had little impact. The impact of
      the 3' site became evident in Tat transactivation studies, in which the loss of
      the site reduced Tat-transactivated expression 40-fold. In contrast, elimination
      of the 5' site had no effect on Tat-mediated activity. Binding studies were
      performed to determine whether differences in PU.1 binding affinity for the three
      sites correlated with the relative impact of each site on LTR transcription.
      While small differences were observed in the binding affinities of the three
      sites, with the promoter-proximal site having the strongest binding affinity,
      these differences could not account for the dramatic differences observed in the
      transcriptional effects. Instead, the promoter-proximal position of the 3' motif
      appeared to be critical for its transcriptional impact and suggested that the
      PU.1 sites may serve different roles depending upon the location of the sites
      within the enhancer. Infectivity studies demonstrated that an LTR containing an
      enhancer composed of the three PU.1 sites was not sufficient to drive viral
      replication in macrophages. These findings indicate that while the promoter
      proximal PU.1 site is the most critical site for EIAV LTR activity in the
      presence of Tat, other elements within the enhancer are needed for EIAV
      replication in macrophages.

PMID- 15016864
TI  - Human immunodeficiency virus type 1 transductive recombination can occur
      frequently and in proportion to polyadenylation signal readthrough.
AB  - One model for retroviral transduction suggests that template switching between
      viral RNAs and polyadenylation readthrough sequences is responsible for the
      generation of acute transforming retroviruses. For this study, we examined
      reverse transcription products of human immunodeficiency virus (HIV)-based
      vectors designed to mimic postulated transduction intermediates. For maximization
      of the discontinuous mode of DNA synthesis proposed to generate transductants,
      sequences located between the vectors' two long terminal repeats (vector "body"
      sequences) and polyadenylation readthrough "tail" sequences were made highly
      homologous. Ten genetic markers were introduced to indicate which products had
      acquired tail sequences by a process we term transductive recombination. Marker
      segregation patterns for over 100 individual products were determined, and they
      revealed that more than half of the progeny proviruses were transductive
      recombinants. Although most crossovers occurred in regions of homology, about 5%
      were nonhomologous and some included insertions. Ratios of encapsidated
      readthrough and polyadenylated transcripts for vectors with wild-type and
      inactivated polyadenylation signals were compared, and transductive recombination
      frequencies were found to correlate with the readthrough transcript prevalence.
      In assays in which either vector body or tail could serve as a recombination
      donor, recombination between tail and body sequences was at least as frequent as
      body-body exchange. We propose that transductive recombination may contribute to
      natural HIV variation by providing a mechanism for the acquisition of nongenomic
      sequences.

PMID- 15016865
TI  - Coupling of human immunodeficiency virus type 1 fusion to virion maturation: a
      novel role of the gp41 cytoplasmic tail.
AB  - Retrovirus particles are not infectious until they undergo proteolytic maturation
      to form a functional core. Here we report a link between human immunodeficiency
      virus type 1 (HIV-1) core maturation and the ability of the virus to fuse with
      target cells. Using a recently developed reporter assay of HIV-1 virus-cell
      fusion, we show that immature HIV-1 particles are 5- to 10-fold less active for
      fusion with target cells than are mature virions. The fusion of mature and
      immature virions was rendered equivalent by truncating the gp41 cytoplasmic
      domain or by pseudotyping viruses with the glycoprotein of vesicular stomatitis
      virus. An analysis of a panel of mutants containing mutated cleavage sites
      indicated that HIV-1 fusion competence is activated by the cleavage of Gag at any
      site between the MA and NC segments and not as an indirect consequence of an
      altered core structure. These results suggest a mechanism by which binding of the
      gp41 cytoplasmic tail to Gag within immature HIV-1 particles inhibits Env
      conformational changes on the surface of the virion that are required for
      membrane fusion. This "inside-out" regulation of HIV-1 fusion could play an
      important role in the virus life cycle by preventing the entry of immature,
      noninfectious particles.

PMID- 15016866
TI  - Alternative approaches for efficient inhibition of hepatitis C virus RNA
      replication by small interfering RNAs.
AB  - Persistent infection with hepatitis C virus (HCV) is a leading cause of chronic
      hepatitis, liver cirrhosis, and hepatocellular carcinoma. It has recently been
      shown that HCV RNA replication is susceptible to small interfering RNAs (siRNAs),
      but the antiviral activity of siRNAs depends very much on their complementarity
      to the target sequence. Thus, the high degree of sequence diversity between
      different HCV genotypes and the rapid evolution of new quasispecies is a major
      problem in the development of siRNA-based gene therapies. For this study, we
      developed two alternative strategies to overcome these obstacles. In one
      approach, we used endoribonuclease-prepared siRNAs (esiRNAs) to simultaneously
      target multiple sites of the viral genome. We show that esiRNAs directed against
      various regions of the HCV coding sequence as well as the 5' nontranslated region
      (5' NTR) efficiently block the replication of subgenomic and genomic HCV
      replicons. In an alternative approach, we generated pseudotyped retroviruses
      encoding short hairpin RNAs (shRNAs). A total of 12 shRNAs, most of them
      targeting highly conserved sequence motifs within the 5' NTR or the early core
      coding region, were analyzed for their antiviral activities. After the
      transduction of Huh-7 cells containing a subgenomic HCV replicon, we found that
      all shRNAs targeting sequences in domain IV or nearby coding sequences blocked
      viral replication. In contrast, only one of seven shRNAs targeting sequences in
      domain II or III had a similar degree of antiviral activity, indicating that
      large sections of the NTRs are resistant to RNA interference. Moreover, we show
      that naive Huh-7 cells that stably expressed certain 5' NTR-specific shRNAs were
      largely resistant to a challenge with HCV replicons. These results demonstrate
      that the retroviral transduction of HCV-specific shRNAs provides a new
      possibility for antiviral intervention.

PMID- 15016867
TI  - High-resolution phylogenetic analysis of hepatitis C virus adaptation and its
      relationship to disease progression.
AB  - Hepatitis C virus (HCV) persists in the majority of those infected despite host
      immune responses. Evidence has accrued that selectively fixed mutations in the
      envelope genes (E1 and E2) are associated with viral persistence, particularly
      those that occur within the first hypervariable region of E2 (HVR1). However, the
      individual amino acid residues under selection have not been identified, nor have
      their selection pressures been measured, despite the importance of this
      information for understanding disease pathogenesis and for vaccine design. We
      performed a high-resolution analysis of published gene sequence data from
      individuals undergoing acute HCV infection, employing two phylogenetic methods to
      determine site-specific selection pressures. Strikingly, we found a statistically
      significant association between the number of sites selected and disease outcome,
      with the fewest selected sites in fulminant HCV cases and the greatest number of
      selected sites in rapid progressors, reflecting the duration and intensity of the
      arms race between host and virus. Moreover, sites outside the HVR1 appear to play
      a major role in viral evolution and pathogenesis, although there was no
      association between viral persistence and specific mutations in E1 and E2. Our
      analysis therefore allows fine dissection of immune selection pressures, which
      may be more diverse than previously thought. Such analyses could play a similarly
      informative role in studies of other persistent virus infections, such as human
      immunodeficiency virus.

PMID- 15016868
TI  - Molecular evidence for rhesus lymphocryptovirus infection of epithelial cells in
      immunosuppressed rhesus macaques.
AB  - Epstein-Barr virus (EBV) is a human oncogenic herpesvirus associated with
      epithelial cell and B-cell malignancies. EBV infection of B lymphocytes is
      essential for acute and persistent EBV infection in humans; however, the role of
      epithelial cell infection in the normal EBV life cycle remains controversial. The
      rhesus lymphocryptovirus (LCV) is an EBV-related herpesvirus that naturally
      infects rhesus macaques and can be used experimentally to model persistent B-cell
      infection and B-cell lymphomagenesis. We now show that the rhesus LCV can infect
      epithelial cells in immunosuppressed rhesus macaques and can induce epithelial
      cell lesions resembling oral hairy leukoplakia in AIDS patients. Electron
      microscopy, immunohistochemistry, and DNA-RNA in situ hybridization were used to
      identify the presence of a lytic rhesus LCV infection in these proliferative,
      hyperkeratotic, or parakeratotic epithelial cell lesions. These studies
      demonstrate that the rhesus LCV has tropism for epithelial cells, in addition to
      B cells, and is a relevant animal model system for studying the role of
      epithelial cell infection in EBV pathogenesis.

PMID- 15016869
TI  - Primary central nervous system lymphoma expressing the human neurotropic
      polyomavirus, JC virus, genome.
AB  - B lymphocytes are known as a potential site for latency and reactivation of the
      human neurotropic polyomavirus, JC virus (JCV). In light of recent studies on the
      oncogenicity of JCV and the transforming ability of the JCV early protein, T
      antigen, we investigated the association of JCV with B-cell lymphomas of the
      central nervous system. Examination of 27 well-characterized clinical specimens
      by gene amplification and immunohistochemistry revealed the presence of DNA
      sequences corresponding to the JCV early genome and the late Agnoprotein in 22
      samples and the JCV late genome encoding the viral capsid proteins in 8 samples.
      Expression of T antigen and that of Agnoprotein by immunohistochemistry were each
      detected in six specimens. No evidence of the production of viral capsid proteins
      was observed, ruling out productive infection of JCV in the tumor cells. The
      results from laser capture microdissection verified the presence of JCV T-antigen
      sequences in tumor cells with positive immunoreactivity to antibodies against the
      viral proteins T antigen and Agnoprotein. Due to previous reports demonstrating
      an association of the Epstein-Barr virus (EBV) with transformation of B
      lymphocytes, EBV DNA sequences and the EBV transforming protein, latent membrane
      protein 1 (LMP1), were analyzed in parallel. EBV LMP1 DNA sequences were detected
      in 16 of 23 samples, and LMP1 expression was detected in 16 samples, 5 of which
      exhibited positive immunoreactivity to JCV proteins. Double labeling demonstrated
      coexpression of JCV T antigen and EBV LMP1 in the same cells. The detection of
      the JCV genome in large numbers of B-cell lymphomas and its coexistence with EBV
      suggest a potential role for JCV in the pathogenesis of primary CNS lymphoma.

PMID- 15016870
TI  - Spacers increase the accessibility of peptide ligands linked to the carboxyl
      terminus of adenovirus minor capsid protein IX.
AB  - The efficiency and specificity of gene transfer with human adenovirus (hAd)
      derived gene transfer vectors would be improved if the native viral tropism could
      be modified. Here, we demonstrate that the minor capsid protein IX (pIX), which
      is present in 240 copies in the Ad capsid, can be exploited as an anchor for
      heterologous polypeptides. Protein IX-deleted hAd5 vectors were propagated in
      hAd5 helper cells expressing pIX variants, with heterologous carboxyl-terminal
      extensions of up to 113 amino acids in length. The extensions evaluated consist
      of alpha-helical spacers up to 75 A in length and to which peptide ligands were
      fused. The pIX variants were efficiently incorporated into the capsids of Ad
      particles. On intact particles, the MYC-tagged-pIX molecules were readily
      accessible to anti-MYC antibodies, as demonstrated by electron microscopic
      analyses of immunogold-labeled virus particles. The labeling efficiency improved
      with increasing spacer length, suggesting that the spacers lift and expose the
      ligand at the capsid surface. Furthermore, we found that the addition of an
      integrin-binding RGD motif to the pIX markedly stimulated the transduction of
      coxsackievirus group B and hAd receptor-deficient endothelioma cells,
      demonstrating the utility of pIX modification in gene transfer. Our data
      demonstrate that the minor capsid protein IX can be used as an anchor for the
      addition of polypeptide ligands to Ad particles.

PMID- 15016871
TI  - Interactions between viral nonstructural proteins and host protein hVAP-33
      mediate the formation of hepatitis C virus RNA replication complex on lipid raft.
AB  - The lipid raft membrane has been shown to be the site of hepatitis C virus (HCV)
      RNA replication. The mechanism of formation of the replication complex is not
      clear. We show here that the formation of the HCV RNA replication complex on
      lipid raft (detergent-resistant membranes) requires interactions among the HCV
      nonstructural (NS) proteins and may be initiated by the precursor of NS4B, which
      has the intrinsic property of anchoring to lipid raft membrane. In hepatocyte
      cell lines containing an HCV RNA replicon, most of the other NS proteins,
      including NS5A, NS5B, and NS3, were also localized to the detergent-resistant
      membranes. However, when individually expressed, only NS4B was associated
      exclusively with lipid raft. In contrast, NS5B and NS3 were localized to
      detergent-sensitive membrane and cytosolic fractions, respectively. NS5A was
      localized to both detergent-sensitive and -resistant membrane fractions.
      Furthermore, we show that a cellular vesicle membrane transport protein named
      hVAP-33 (the human homologue of the 33-kDa vesicle-associated membrane protein
      associated protein), which binds to both NS5A and NS5B, plays a critical role in
      the formation of HCV replication complex. The hVAP-33 protein is partially
      associated with the detergent-resistant membrane fraction. The expression of
      dominant-negative mutants and small interfering RNA of hVAP-33 in HCV replicon
      cells resulted in the relocation of NS5B from detergent-resistant to detergent
      sensitive membranes. Correspondingly, the amounts of both HCV RNA and proteins in
      the cells were reduced, indicating that hVAP-33 is critical for the formation of
      HCV replication complex and RNA replication. These results indicate that protein
      protein interactions among the various HCV NS proteins and hVAP-33 are important
      for the formation of HCV replication complex.

PMID- 15016872
TI  - Transcriptional response of a common permissive cell type to infection by two
      diverse alphaherpesviruses.
AB  - Pseudorabies virus (PRV) and herpes simplex virus type 1 (HSV-1) are distantly
      related alphaherpesviruses whose natural hosts are pigs and humans, respectively.
      Adult infections of natural hosts are mild and rarely lethal. However, both
      viruses are also able to infect other hosts, often with lethal effects. In this
      report, we use the paradigm of infection of a common permissive cell type and
      microarray analysis to determine if these two diverse alphaherpesviruses engage
      similar or different cellular pathways to obtain a common outcome: productive
      infection. We compared cellular gene expression in growth-arrested, primary rat
      embryonic fibroblasts that were mock infected or infected with either purified
      PRV-Becker or HSV-1(F). Infections by either virus affect the transcription of
      more than 1,500 cellular genes by threefold or more. Few differences are detected
      early, and the majority of changes occur during the late stages of infection.
      Remarkably, the transcripts of about 500 genes are regulated in common, while the
      rest are regulated in a virus-specific manner. Genes whose expression is affected
      by infection fall into a diverse group of functional classes and cellular
      pathways. Furthermore, a comparison of the cellular response to HSV-1 infection
      of primary human and rat fibroblasts revealed unexpected diversity in the
      transcript profiles.

PMID- 15016873
TI  - High-throughput screening of the yeast kinome: identification of human
      serine/threonine protein kinases that phosphorylate the hepatitis C virus NS5A
      protein.
AB  - The hepatitis C virus NS5A protein plays a critical role in virus replication,
      conferring interferon resistance to the virus through perturbation of multiple
      intracellular signaling pathways. Since NS5A is a phosphoprotein, it is of
      considerable interest to understand the role of phosphorylation in NS5A function.
      In this report, we investigated the phosphorylation of NS5A by taking advantage
      of 119 glutathione S-transferase-tagged protein kinases purified from
      Saccharomyces cerevisiae to perform a global screening of yeast kinases capable
      of phosphorylating NS5A in vitro. A database BLAST search was subsequently
      performed by using the sequences of the yeast kinases that phosphorylated NS5A in
      order to identify human kinases with the highest sequence homologies. Subsequent
      in vitro kinase assays and phosphopeptide mapping studies confirmed that several
      of the homologous human protein kinases were capable of phosphorylating NS5A. In
      vivo phosphopeptide mapping revealed phosphopeptides common to those generated in
      vitro by AKT, p70S6K, MEK1, and MKK6, suggesting that these kinases may
      phosphorylate NS5A in mammalian cells. Significantly, rapamycin, an inhibitor
      commonly used to investigate the mTOR/p70S6K pathway, reduced the in vivo
      phosphorylation of specific NS5A phosphopeptides, strongly suggesting that p70S6
      kinase and potentially related members of this group phosphorylate NS5A inside
      the cell. Curiously, certain of these kinases also play a major role in mRNA
      translation and antiapoptotic pathways, some of which are already known to be
      regulated by NS5A. The findings presented here demonstrate the use of high
      throughput screening of the yeast kinome to facilitate the major task of
      identifying human NS5A protein kinases for further characterization of
      phosphorylation events in vivo. Our results suggest that this novel approach may
      be generally applicable to the screening of other protein biochemical activities
      by mechanistic class.

PMID- 15016874
TI  - Purification and crystallization reveal two types of interactions of the fusion
      protein homotrimer of Semliki Forest virus.
AB  - The fusion proteins of the alphaviruses and flaviviruses have a similar native
      structure and convert to a highly stable homotrimer conformation during the
      fusion of the viral and target membranes. The properties of the alpha- and
      flavivirus fusion proteins distinguish them from the class I viral fusion
      proteins, such as influenza virus hemagglutinin, and establish them as the first
      members of the class II fusion proteins. Understanding how this new class carries
      out membrane fusion will require analysis of the structural basis for both the
      interaction of the protein subunits within the homotrimer and their interaction
      with the viral and target membranes. To this end we report a purification method
      for the E1 ectodomain homotrimer from the alphavirus Semliki Forest virus. The
      purified protein is trimeric, detergent soluble, retains the characteristic
      stability of the starting homotrimer, and is free of lipid and other
      contaminants. In contrast to the postfusion structures that have been determined
      for the class I proteins, the E1 homotrimer contains the fusion peptide region
      responsible for interaction with target membranes. This E1 trimer preparation is
      an excellent candidate for structural studies of the class II viral fusion
      proteins, and we report conditions that generate three-dimensional crystals
      suitable for analysis by X-ray diffraction. Determination of the structure will
      provide our first high-resolution views of both the low-pH-induced trimeric
      conformation and the target membrane-interacting region of the alphavirus fusion
      protein.

PMID- 15016875
TI  - The soluble form of human respiratory syncytial virus attachment protein differs
      from the membrane-bound form in its oligomeric state but is still capable of
      binding to cell surface proteoglycans.
AB  - The soluble (Gs) and membrane-bound (Gm) forms of human respiratory syncytial
      virus (HRSV) attachment protein were purified by immunoaffinity chromatography
      from cultures of HEp-2 cells infected with vaccinia virus recombinants expressing
      either protein. Sucrose gradient centrifugation indicated that Gs, which is
      secreted into the culture medium, remains monomeric, whereas Gm is an oligomer,
      probably a homotetramer. Nevertheless, Gs was capable of binding to the surface
      of cells in vitro, as assessed by a flow cytometry-based binding assay. The
      attachment of Gs to cells was inhibited by previous heparinase treatment of
      living cells, and Gs did not bind to CHO cell mutants defective in proteoglycan
      biosynthesis. Thus, Gs, as previously reported for the G protein of intact
      virions, binds to glycosaminoglycans presented at the cell surface as
      proteoglycans. Deletion of a previously reported heparin binding domain from Gs
      protein substantially inhibited its ability to bind to cells, but the remaining
      level of binding was still sensitive to heparinase treatment, suggesting that
      other regions of the Gs molecule may contribute to attachment to proteoglycans.
      The significance of these results for HRSV infection is discussed.

PMID- 15016876
TI  - The binding of histone deacetylases and the integrity of zinc finger-like motifs
      of the E7 protein are essential for the life cycle of human papillomavirus type
      31.
AB  - The E7 oncoprotein of high-risk human papillomaviruses (HPVs) binds to and alters
      the action of cell cycle regulatory proteins such as members of the
      retinoblastoma (Rb) family of proteins as well as the histone deacetylases
      (HDACs). To examine the significance of the binding of E7 to HDACs in the viral
      life cycle, a mutational analysis of the E7 open reading frame was performed in
      the context of the complete HPV type 31 (HPV-31) genome. Human foreskin
      keratinocytes were transfected with wild-type HPV-31 genomes or HPV-31 genomes
      containing mutations in HDAC binding sequences as well as in the C-terminal zinc
      finger-like domain, and stable cell lines were isolated. All mutant genomes,
      except those with E7 mutations in the HDAC binding site, were found to be stably
      maintained extrachromosomally at an early passage following transfection. Upon
      further passage in culture, genomes containing mutations to the Rb binding domain
      as well as the zinc finger-like region quickly lost the ability to maintain
      episomal genomes. Genomes containing mutations abolishing E7 binding to HDACs or
      to Rb or mutations to the zinc finger-like motifs failed to extend the life span
      of transfected keratinocytes and caused cells to arrest at the same time as the
      untransfected keratinocytes. When induced to differentiate by suspension in
      methylcellulose, cells maintaining genomes with mutations in the Rb binding
      domain or the zinc finger-like motifs were impaired in their abilities to
      activate late viral functions. This study demonstrates that the interaction of E7
      with HDACs and the integrity of the zinc finger-like motifs are essential for
      extending the life span of keratinocytes and for stable maintenance of viral
      genomes.

PMID- 15016877
TI  - Mitosis-specific hyperphosphorylation of Epstein-Barr virus nuclear antigen 2
      suppresses its function.
AB  - The Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA-2) is a key gene expressed
      in EBV type III latent infection that can transactivate numerous promoters,
      including those for all the other type III viral latency genes as well as
      cellular genes responsible for cell proliferation. EBNA-2 is essential for EBV
      mediated immortalization of primary B lymphocytes. We now report that EBNA-2, a
      phosphoprotein, is hyperphosphorylated specifically in mitosis. Evidence that the
      cyclin-dependent kinase p34(cdc2) may be involved in this hyperphosphorylation
      includes (i) coimmunoprecipitation of EBNA-2 and p34(cdc2), suggesting physical
      association; (ii) temporal correlation between hyperphosphorylation of EBNA-2 and
      an increase in p34(cdc2) kinase activity; and (iii) ability of purified
      p34(cdc2)/cyclin B1 kinase to phosphorylate EBNA-2 in vitro. Hyperphosphorylation
      of EBNA-2 appears to suppress its ability to transactivate the latent membrane
      protein 1 (LMP-1) promoter by about 50%. The association between EBNA-2 and PU.1
      is also decreased by about 50% in M-phase-arrested cells, as shown by
      coimmunoprecipitation from cell lysates, suggesting that hyperphosphorylation of
      EBNA-2 impairs its affinity for PU.1. Finally, endogenous LMP-1 mRNA levels in M
      phase are around 55% of those in asynchronously growing cells. These results
      suggest that regulation of gene expression during type III latency may be
      regulated in a cell-cycle-related manner.

PMID- 15016878
TI  - The vaccinia virus K1L gene product inhibits host NF-kappaB activation by
      preventing IkappaBalpha degradation.
AB  - Vaccinia virus wild-type strains such as Ankara and WR synthesize proteins
      capable of inhibiting the activation of host NF-kappaB, a family of transcription
      factors that regulate the expression of inflammatory genes. In contrast, an
      infection by the attenuated MVA strain, whose genome lacks many immunoregulatory
      genes present in the DNA of its Ankara parent, induces NF-kappaB activation.
      Insertion of NF-kappaB inhibitory genes into the MVA DNA, then, would alter the
      MVA phenotype. By this method, a 5.2-kb region of Ankara DNA containing the K1L
      gene and two other genes that are absent in the MVA genome that was identified as
      NF-kappaB was inhibited in cells infected with the MVA/5.2kb virus. To determine
      if K1L was responsible, the relevant biological properties of both a recombinant
      MVA containing a copy of the WR strain's K1L (MVA/K1L) and a WR deletion mutant
      lacking the K1L gene (DeltaK1L) were examined. Indeed, unlike its progenitor, the
      altered MVA halted degradation of the host regulatory protein IkappaBalpha-a key
      event in the pathway of transcriptional activation by NF-kappaB factors.
      Moreover, MVA/K1L gained the ability to repress artificially contrived and
      natural NF-kappaB-regulated expression of a transfected luciferase and the
      cellular tumor necrosis factor gene, respectively. In contrast, although these
      functions could also be performed by WR, the DeltaK1L virus lost these abilities.
      Thus, one apparent molecular function of K1L is to prevent IkappaBalpha
      degradation. This impediment to NF-kappaB-induced host proinflammatory gene
      expression, in turn, might enhance virus survival.

PMID- 15016879
TI  - Correlation between env V1/V2 region diversification and neutralizing antibodies
      during primary infection by simian immunodeficiency virus sm in rhesus macaques.
AB  - Evolution of the domain encoding the V1/V2 variable region of the simian
      immunodeficiency virus sm (SIVsm) envelope (env) gene was analyzed in relation to
      route of virus challenge, virus load, and neutralizing antibody (NAb) titers
      during primary infection of rhesus macaques with the pathogenic SIVsmE660
      isolate. In this model system animals are initially infected with multiple
      viruses as evidenced by the presence of multiple V1/V2 genotypic variants that
      could be resolved by using a heteroduplex tracking assay (HTA). Overlapping
      subsets of the multiple variants were established in each animal. There was no
      selection for the establishment of specific variants in comparing intravenous-
      and intrarectal-challenged macaques at week 2 postinfection, suggesting that no
      genotypic selection occurred at the mucosal surface. There was an initial period
      of significant stability of the V1/V2 variants. Macaques challenged intravenously
      displayed subsequent V1/V2 diversification significantly earlier than macaques
      challenged intrarectally and well past the initial resolution of viremia. The
      time when SIVsmE660-specific NAbs reached a threshold titer of 100 was
      significantly correlated with the timing of V1/V2 diversification, even though
      antibodies to the Env protein could be detected much earlier. The time when NAbs
      reached a titer of 400 was significantly correlated with virus load late in
      infection. These results show that the route of infection affects the timing of
      V1/V2 diversification and that this diversification is correlated with the
      maturation of a specific NAb response. However, prior immunization capable of
      priming an anamnestic Env antibody response did not accelerate V1/V2
      diversification. This result suggests that diversification of the SIV env V1/V2
      region is the result of a type-specific antibody response.

PMID- 15016880
TI  - Prior infection and passive transfer of neutralizing antibody prevent replication
      of severe acute respiratory syndrome coronavirus in the respiratory tract of
      mice.
AB  - Following intranasal administration, the severe acute respiratory syndrome (SARS)
      coronavirus replicated to high titers in the respiratory tracts of BALB/c mice.
      Peak replication was seen in the absence of disease on day 1 or 2, depending on
      the dose administered, and the virus was cleared within a week. Viral antigen and
      nucleic acid were detected in bronchiolar epithelial cells during peak viral
      replication. Mice developed a neutralizing antibody response and were protected
      from reinfection 28 days following primary infection. Passive transfer of immune
      serum to naive mice prevented virus replication in the lower respiratory tract
      following intranasal challenge. Thus, antibodies, acting alone, can prevent
      replication of the SARS coronavirus in the lung, a promising observation for the
      development of vaccines, immunotherapy, and immunoprophylaxis regimens.

PMID- 15016881
TI  - Differential tissue-specific regulation of antiviral CD8+ T-cell immune responses
      during chronic viral infection.
AB  - The hallmarks of the immune response to viral infections are the expansion of
      antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs) after they encounter
      antigen-presenting cells in the lymphoid tissues and their subsequent
      redistribution to nonlymphoid tissues to deal with the pathogen. Control
      mechanisms exist within CTL activation pathways to prevent inappropriate CTL
      responses against disseminating infections with a broad distribution of pathogen
      in host tissues. This is demonstrated during overwhelming infection with the
      noncytolytic murine lymphocytic choriomeningitis virus, in which clonal
      exhaustion (anergy and/or deletion) of CTLs prevents immune-mediated pathology
      but allows persistence of the virus. The mechanism by which the immune system
      determines whether or not to mount a full response to such infections is unknown.
      Here we present data showing that the initial encounter of specific CTLs with
      infected cells in lymphoid tissues is critical for this decision. Whether the
      course of the viral infection is acute or persistent for life primarily depends
      on the degree and kinetics of CTL exhaustion in infected lymphoid tissues. Virus
      driven CTL expansion in lymphoid tissues resulted in the migration of large
      quantities of CTLs to nonlymphoid tissues, where they persisted at stable levels.
      Surprisingly, although virus-specific CTLs were rapidly clonally exhausted in
      lymphoid tissues under conditions of chronic infection, a substantial number of
      them migrated to nonlymphoid tissues, where they retained an effector phenotype
      for a long time. However, these cells were unable to control the infection and
      progressively lost their antiviral capacities (cytotoxicity and cytokine
      secretion) in a hierarchical manner before their eventual physical elimination.
      These results illustrate the differential tissue-specific regulation of antiviral
      T-cell responses during chronic infections and may help us to understand the
      dynamic relationship between antigen and T-cell populations in many persistent
      infections in humans.

PMID- 15016882
TI  - Concurrent expression of latent and a limited number of lytic genes with immune
      modulation and antiapoptotic function by Kaposi's sarcoma-associated herpesvirus
      early during infection of primary endothelial and fibroblast cells and subsequent
      decline of lytic gene expression.
AB  - Kaposi's sarcoma-associated herpesvirus (KSHV) infection of in vitro target cells
      is characterized by the expression of the latency-associated open reading frame
      (ORF) 73 gene (LANA-1) and the absence of progeny virus production. This default
      latent infection can be switched into lytic cycle by phorbol ester and by the
      lytic cycle ORF 50 (RTA) protein. In this study, the kinetics of latent and lytic
      gene expression immediately following KSHV infection of primary human dermal
      microvascular endothelial (HMVEC-d) and foreskin fibroblast (HFF) cells were
      examined by real-time reverse transcriptase PCR and whole-genome array. Within 2
      h postinfection (p.i.), high levels of ORF 50 transcripts were detected in both
      cell types, which declined sharply by 24 h p.i. In contrast, comparatively low
      levels of ORF 73 expression were detected within 2 h p.i., increased
      subsequently, were maintained at a steady state, and declined slowly by 120 h
      p.i. The RTA and LANA-1 proteins were detected in the majority of infected cells
      by immunoperoxidase assays. In genome array, only 29 of 94 (31%) KSHV genes were
      expressed, which included 11 immediate-early/early, 8 early, and 5 late lytic
      genes and 4 latency-associated genes. While the expression of latent ORF 72, 73,
      and K13 genes continued, nearly all of the lytic genes declined or were
      undetectable by 8 and 24 h p.i. in HMVEC-d and HFF cells, respectively. Only a
      limited number of RTA-activated KSHV genes were expressed briefly, and the
      majority of KSHV genes involved in viral DNA synthesis and structural proteins
      were not expressed. However, early during infection, the lytic K2, K4, K5, K6,
      and vIRF2 genes with immune modulation functions and the K7 gene with
      antiapoptotic function were expressed. Expression of K5 was detected for up to 5
      days of observation, and vIRF2 was expressed up to 24 h p.i. The full complement
      of lytic cycle genes were expressed when 12-O-tetradecanoylphorbol-13-acetate was
      added to the HMVEC-d cells after 48 h p.i. These data suggest that in contrast to
      alpha- and betaherpesviruses and some members of gammaherpesviruses, gamma-2 KSHV
      in vitro infection is characterized by the concurrent expression of latent and a
      limited number of lytic genes immediately following infection and a subsequent
      decline and/or absence of lytic gene expression with the persistence of latent
      genes. Expression of its limited lytic cycle genes could be a "strategy" that
      evolved in KSHV allowing it to evade the immune system and to provide the
      necessary factors and time to establish and/or maintain latency during the
      initial phases of infection. These are unique observations among in vitro
      herpesvirus infections and may have important implications in KSHV biology and
      pathogenesis.

PMID- 15016883
TI  - Transgenic mice expressing the nucleoprotein of Borna disease virus in either
      neurons or astrocytes: decreased susceptibility to homotypic infection and
      disease.
AB  - The nucleoprotein (N) of Borna disease virus (BDV) is the major target of the
      disease-inducing antiviral CD8 T-cell response in the central nervous system of
      mice. We established two transgenic mouse lines which express BDV-N in either
      neurons (Neuro-N) or astrocytes (Astro-N). Despite strong transgene expression,
      neurological disease or gross behavioral abnormalities were not observed in these
      animals. When Neuro-N mice were infected as adults, replication of BDV was
      severely impaired and was restricted to brain areas with a low density of
      transgene-expressing cells. Notably, the virus failed to replicate in the
      transgene-expressing granular and pyramidal neurons of the hippocampus (which are
      usually the preferred host cells of BDV). When Neuro-N mice were infected within
      the first 5 days of life, replication of BDV was not suppressed in most neurons,
      presumably because the onset of transgene expression in the brain occurred after
      these cells became infected with BDV. Astro-N mice remained susceptible to BDV
      infection, but they were resistant to BDV-induced neurological disorder. Unlike
      their nontransgenic littermates, Neuro-N mice with persistent BDV infection did
      not develop neurological disease after immunization with a vaccinia virus vector
      expressing BDV-N. In contrast to the situation in wild-type mice, this treatment
      also failed to induce N-specific CD8 T cells in the spleens of both transgenic
      mouse lines. Thus, while resistance to BDV infection in N-expressing neurons
      appeared to result from untimely expression of a viral nucleocapsid component,
      the resistance to BDV-induced neuropathology probably resulted from immunological
      tolerance.

PMID- 15016884
TI  - Effects of mutations of the initiation nucleotides on hepatitis C virus RNA
      replication in the cell.
AB  - Replication of nearly all RNA viruses depends on a virus-encoded RNA-dependent
      RNA polymerase (RdRp). Our earlier work found that purified recombinant hepatitis
      C virus (HCV) RdRp (NS5B) was able to initiate RNA synthesis de novo by using
      purine (A and G) but not pyrimidine (C and U) nucleotides (G. Luo et al., J.
      Virol. 74:851-863, 2000). For most human RNA viruses, the initiation nucleotides
      of both positive- and negative-strand RNAs were found to be either an adenylate
      (A) or guanylate (G). To determine the nucleotide used for initiation and control
      of HCV RNA replication, a genetic mutagenesis analysis of the nucleotides at the
      very 5' and 3' ends of HCV RNAs was performed by using a cell-based HCV replicon
      replication system. Either a G or an A at the 5' end of HCV genomic RNA was able
      to efficiently induce cell colony formation, whereas a nucleotide C at the 5' end
      dramatically reduced the efficiency of cell colony formation. Likewise, the 3'
      end nucleotide U-to-C mutation did not significantly affect the efficiency of
      cell colony formation. In contrast, a U-to-G mutation at the 3' end caused a
      remarkable decrease in cell colony formation, and a U-to-A mutation resulted in a
      complete abolition of cell colony formation. Sequence analysis of the HCV
      replicon RNAs recovered from G418-resistant Huh7 cells revealed several
      interesting findings. First, the 5'-end nucleotide G of the replicon RNA was
      changed to an A upon multiple rounds of replication. Second, the nucleotide A at
      the 5' end was stably maintained among all replicon RNAs isolated from Huh7 cells
      transfected with an RNA with a 5'-end A. Third, initiation of HCV RNA replication
      with a CTP resulted in a >10-fold reduction in the levels of HCV RNAs, suggesting
      that initiation of RNA replication with CTP was very inefficient. Fourth, the 3'
      end nucleotide U-to-C and -G mutations were all reverted back to a wild-type
      nucleotide U. In addition, extra U and UU residues were identified at the 3' ends
      of revertants recovered from Huh7 cells transfected with an RNA with a nucleotide
      G at the 3' end. We also determined the 5'-end nucleotide of positive-strand RNA
      of some clinical HCV isolates. Either G or A was identified at the 5' end of HCV
      RNA genome depending on the specific HCV isolate. Collectively, these findings
      demonstrate that replication of positive-strand HCV RNA was preferentially
      initiated with purine nucleotides (ATP and GTP), whereas the negative-strand HCV
      RNA replication is invariably initiated with an ATP.

PMID- 15016885
TI  - Both viral and host factors contribute to neurovirulence of bovine herpesviruses
      1 and 5 in interferon receptor-deficient mice.
AB  - Herpes simplex virus (HSV) type 1 and bovine herpesviruses 1 and 5 (BHV-1 and BHV
      5) can use the same cellular receptor for entry, but only HSV is known to cause
      disease in mice. We hypothesized that components of either the innate or the
      adaptive immune system, or a combination of both, were responsible for curbing
      replication of BHVs in mice. Therefore, wild-type mice as well as mice with
      various combined genetic deficiencies in the alpha/beta interferon receptor or
      gamma interferon receptor and in the ability to produce mature B and T
      lymphocytes (RAG-2 deletion) were infected with BHV-1 and BHV-5 and monitored
      clinically, serologically, histopathologically, and virologically. A functional
      immune system protected the mice from disease and death due to BHV infection, and
      the immune response was Th1 like. BHV-5 was transported to the central nervous
      system by the axonal pathway, whereas viremia was required for this outcome with
      BHV-1. The alpha/beta interferon system was able to obstruct quantitative spread
      of the viruses in the infected organism. The gamma interferon system had a
      protective effect against BHV-1, even in mice with the RAG-2 deletion. In
      contrast, the same mice succumbed to neurological disease and death upon
      infection with BHV-5. Productively infected neurons were detected only in BHV-5
      infected mice with an intact gamma interferon system. We conclude that the
      alpha/beta interferon system had a protective effect, while an intact gamma
      interferon system was required for efficient replication of BHV-5 in mouse
      neurons and for the development of neurological disease.

PMID- 15016886
TI  - Comparative molecular analysis of the abnormal prion protein in field scrapie
      cases and experimental bovine spongiform encephalopathy in sheep by use of
      Western blotting and immunohistochemical methods.
AB  - Since the appearance of bovine spongiform encephalopathy (BSE) in cattle and its
      linkage with the human variant of Creutzfeldt-Jakob disease, the possible spread
      of this agent to sheep flocks has been of concern as a potential new source of
      contamination. Molecular analysis of the protease cleavage of the abnormal prion
      protein (PrP), by Western blotting (PrP(res)) or by immunohistochemical methods
      (PrP(d)), has shown some potential to distinguish BSE and scrapie in sheep. Using
      a newly developed enzyme-linked immunosorbent assay, we identified 18 infected
      sheep in which PrP(res) showed an increased sensitivity to proteinase K
      digestion. When analyzed by Western blotting, two of them showed a low molecular
      mass of unglycosylated PrP(res) as found in BSE-infected sheep, in contrast to
      other naturally infected sheep. A decrease of the labeling by P4 monoclonal
      antibody, which recognizes an epitope close to the protease cleavage site, was
      also found by Western blotting in the former two samples, but this was less
      marked than in BSE-infected sheep. These two samples, and all of the other
      natural scrapie cases studied, were clearly distinguishable from those from sheep
      inoculated with the BSE agent from either French or British cattle by
      immunohistochemical analysis of PrP(d) labeling in the brain and lymphoid
      tissues. Final characterization of the strain involved in these samples will
      require analysis of the features of the disease following infection of mice, but
      our data already emphasize the need to use the different available methods to
      define the molecular properties of abnormal PrP and its possible similarities
      with the BSE agent.

PMID- 15016887
TI  - VP1 sequencing of all human rhinovirus serotypes: insights into genus phylogeny
      and susceptibility to antiviral capsid-binding compounds.
AB  - Rhinoviruses are the most common infectious agents of humans. They are the
      principal etiologic agents of afebrile viral upper-respiratory-tract infections
      (the common cold). Human rhinoviruses (HRVs) comprise a genus within the family
      Picornaviridae. There are >100 serotypically distinct members of this genus. In
      order to better understand their phylogenetic relationship, the nucleotide
      sequence for the major surface protein of the virus capsid, VP1, was determined
      for all known HRV serotypes and one untyped isolate (HRV-Hanks). Phylogenetic
      analysis of deduced amino acid sequence data support previous studies subdividing
      the genus into two species containing all but one HRV serotype (HRV-87). Seventy
      five HRV serotypes and HRV-Hanks belong to species HRV-A, and twenty-five HRV
      serotypes belong to species HRV-B. Located within VP1 is a hydrophobic pocket
      into which small-molecule antiviral compounds such as pleconaril bind and inhibit
      functions associated with the virus capsid. Analyses of the amino acids that
      constitute this pocket indicate that the sequence correlates strongly with virus
      susceptibility to pleconaril inhibition. Further, amino acid changes observed in
      reduced susceptibility variant viruses recovered from patients enrolled in
      clinical trials with pleconaril were distinct from those that confer natural
      phenotypic resistance to the drug. These observations suggest that it is possible
      to differentiate rhinoviruses naturally resistant to capsid function inhibitors
      from those that emerge from susceptible virus populations as a result of
      antiviral drug selection pressure based on sequence analysis of the drug-binding
      pocket.

PMID- 15016888
TI  - Human immunodeficiency virus type 1 subtypes have a distinct long terminal repeat
      that determines the replication rate in a host-cell-specific manner.
AB  - The long terminal repeat (LTR) transcriptional promoters of different human
      immunodeficiency virus (HIV) type 1 subtypes were inserted into the LAI molecular
      clone of subtype B. The viral genotypes represent seven subtypes (A, B, C, D, E,
      F, and G) and one circulating recombinant form (AG). We performed replication
      studies with this isogenic set of viruses across six cellular environments. This
      approach revealed strong cellular environment effects, but the method was not
      sensitive enough to detect small differences in the replication rate between the
      subtypes. By conducting pairwise competition experiments between the virus
      variants in six cellular environments, we could demonstrate significant
      differences in the replication rates of the subtypes and that LTR-determined
      viral fitness depends both on the host cell type and the activation state of the
      cell. In addition, we determined the degree of conservation of the transcription
      factor-binding sites (TFBS) in the different-subtype LTRs by analyzing sequences
      from the HIV sequence database. The sequence analyses revealed subtype-specific
      conservation of certain TFBS. The results indicate that one should consider the
      possibility of subtype-specific viral replication rates in vivo, which are
      strongly influenced by the host environment. We argue that the multidimensional
      host environment may have shaped the genetic structures of the subtype LTRs.

PMID- 15016890
TI  - Movement protein of a closterovirus is a type III integral transmembrane protein
      localized to the endoplasmic reticulum.
AB  - Cell-to-cell movement of beet yellows closterovirus requires four structural
      proteins and a 6-kDa protein (p6) that is a conventional, nonstructural movement
      protein. Here we demonstrate that either virus infection or p6 overexpression
      results in association of p6 with the rough endoplasmic reticulum. The p6 protein
      possesses a single-span, transmembrane, N-terminal domain and a hydrophilic, C
      terminal domain that is localized on the cytoplasmic face of the endoplasmic
      reticulum. In the infected cells, p6 forms a disulfide bridge via a cysteine
      residue located near the protein's N terminus. Mutagenic analyses indicated that
      each of the p6 domains, as well as protein dimerization, is essential for p6
      function in virus movement.

PMID- 15016889
TI  - Characterization of emerging European-like porcine reproductive and respiratory
      syndrome virus isolates in the United States.
AB  - European-like field isolates of porcine reproductive and respiratory syndrome
      virus (PRRSV) have recently emerged in North America. The full-length genomic
      sequence of an index isolate characterized in 1999, strain EuroPRRSV, served as
      the reference strain for further studies of the evolution and epidemiology of
      European-like isolates (type 1) in the United States. Strain EuroPRRSV shared
      90.1 to 100% amino acid identity with the prototype European strain, Lelystad,
      within the structural and nonstructural open reading frames (ORFs) and 95.3%
      overall nucleotide identity. The 5' untranslated region and two nonstructural
      regions within ORF 1 were closely examined due to significant divergence from
      strain Lelystad. A 51-bp deletion in a region within ORF 1a, coding for
      nonstructural protein 2 (NSP2), was observed. Sequence analysis of the structural
      ORFs 2 to 7 of additional European-like isolates indicated that these isolates
      share 93% nucleotide identity with one another and 95 to 96% identity with the
      Lelystad strain but only 70% identity with the North American reference strain VR
      2332. Phylogenetic analysis with published PRRSV ORF 3, 5, and 7 nucleotide
      sequences indicated that these newly emerging isolates form a clade with the
      Lelystad and United Kingdom PRRSV isolates. Detailed analysis of four of these
      isolates with a panel of 60 monoclonal antibodies directed against the structural
      proteins confirmed a recognition pattern that was more consistent with strain
      Lelystad than with other North American isolates.

PMID- 15016891
TI  - The subcellular distribution of multigene family 110 proteins of African swine
      fever virus is determined by differences in C-terminal KDEL endoplasmic reticulum
      retention motifs.
AB  - African swine fever virus (ASFV) is a large double-stranded DNA virus that
      replicates in discrete areas in the cytosol of infected cells called viral
      factories. Recent studies have shown that assembling virions acquire their
      internal envelopes through enwrapment by membranes derived from the endoplasmic
      reticulum (ER). However, the mechanisms that underlie the formation of viral
      factories and progenitor viral membranes are as yet unclear. Analysis of the
      published genome of the virus revealed a conserved multigene family that encodes
      proteins with hydrophobic signal sequences, indicating possible translocation
      into the ER lumen. Strikingly, two of these genes, XP124L and Y118L, encoded
      proteins with KDEL-like ER retention motifs. Analysis of XP124L and Y118L gene
      product by biochemical and immunofluorescence techniques showed that the proteins
      were localized to pre-Golgi compartments and that the KEDL motif at the C
      terminus of pXP124L was functional. XP124L expression, in the absence of other
      ASFV genes, had a dramatic effect on the contents of the ER that was dependent
      precisely on the C-terminal sequence KEDL. The normal subcellular distribution of
      a number of proteins resident to this important, cellular organelle was
      drastically altered in cells expressing wild-type XP124L gene product. PXP124L
      formed unusual perinuclear structures that contained resident ER proteins, as
      well as proteins of the ER-Golgi intermediate compartment. The data presented
      here hint at a role for MGF110 gene product in preparing the ER for its role in
      viral morphogenesis; this and other potential functions are discussed.

PMID- 15016892
TI  - Positive selection detection in 40,000 human immunodeficiency virus (HIV) type 1
      sequences automatically identifies drug resistance and positive fitness mutations
      in HIV protease and reverse transcriptase.
AB  - Drug resistance is a major problem in the treatment of AIDS, due to the very high
      mutation rate of human immunodeficiency virus (HIV) and subsequent rapid
      development of resistance to new drugs. Identification of mutations associated
      with drug resistance is critical for both individualized treatment selection and
      new drug design. We have performed an automated mutation analysis of HIV Type 1
      (HIV-1) protease and reverse transcriptase (RT) from approximately 40,000 AIDS
      patient plasma samples sequenced by Specialty Laboratories Inc. from 1999 to mid
      2002. This data set provides a nearly complete mutagenesis of HIV protease and
      enables the calculation of statistically significant K(a)/K(s) values for each
      individual amino acid mutation in protease and RT. Positive selection (i.e., a
      K(a)/K(s) ratio of >1, indicating increased reproductive fitness) detected 19 of
      23 known drug-resistant mutation positions in protease and 20 of 34 such
      positions in RT. We also discovered 163 new amino acid mutations in HIV protease
      and RT that are strong candidates for drug resistance or fitness. Our results
      match available independent data on protease mutations associated with specific
      drug treatments and mutations with positive reproductive fitness, with high
      statistical significance (the P values for the observed matches to occur by
      random chance are 10(-5.2) and 10(-16.6), respectively). Our mutation analysis
      provides a valuable resource for AIDS research and will be available to academic
      researchers upon publication at http://www.bioinformatics.ucla.edu/HIV. Our data
      indicate that positive selection mapping is an analysis that can yield powerful
      insights from high-throughput sequencing of rapidly mutating pathogens.

PMID- 15016893
TI  - Second sialic acid binding site in Newcastle disease virus hemagglutinin
      neuraminidase: implications for fusion.
AB  - Paramyxoviruses are the leading cause of respiratory disease in children. Several
      paramyxoviruses possess a surface glycoprotein, the hemagglutinin-neuraminidase
      (HN), that is involved in attachment to sialic acid receptors, promotion of
      fusion, and removal of sialic acid from infected cells and progeny virions.
      Previously we showed that Newcastle disease virus (NDV) HN contained a pliable
      sialic acid recognition site that could take two states, a binding state and a
      catalytic state. Here we present evidence for a second sialic acid binding site
      at the dimer interface of HN and present a model for its involvement in cell
      fusion. Three different crystal forms of NDV HN now reveal identical tetrameric
      arrangements of HN monomers, perhaps indicative of the tetramer association found
      on the viral surface.

PMID- 15016894
TI  - Localized changes in the gp120 envelope glycoprotein confer resistance to human
      immunodeficiency virus entry inhibitors BMS-806 and #155.
AB  - BMS-806 and the related compound, #155, are novel inhibitors of human
      immunodeficiency virus type 1 (HIV-1) entry that bind the gp120 exterior envelope
      glycoprotein. BMS-806 and #155 block conformational changes in the HIV-1 envelope
      glycoproteins that are induced by binding to the host cell receptor, CD4. We
      tested a panel of HIV-1 envelope glycoprotein mutants and identified several that
      were resistant to the antiviral effects of BMS-806 and #155. In the CD4-bound
      conformation of gp120, the amino acid residues implicated in BMS-806 and #155
      resistance line the "phenylalanine 43 cavity" and a water-filled channel that
      extends from this cavity to the inner domain. Structural considerations suggest a
      model in which BMS-806 and #155 bind gp120 prior to receptor binding and, upon
      CD4 binding, are accommodated in the Phe-43 cavity and adjacent channel. The
      integrity of the nearby V1/V2 variable loops and N-linked carbohydrates on the
      V1/V2 stem indirectly influences sensitivity to the drugs. A putative binding
      site for BMS-806 and #155 between the gp120 receptor-binding regions and the
      inner domain, which is thought to interact with the gp41 transmembrane envelope
      glycoprotein, helps to explain the mode of action of these drugs.

PMID- 15016895
TI  - Low pH is required for avian sarcoma and leukosis virus Env-induced hemifusion
      and fusion pore formation but not for pore growth.
AB  - Binding of avian sarcoma and leukosis virus (ASLV) to its cognate receptor on the
      cell surface causes conformational changes in its envelope protein (Env). It is
      currently debated whether low pH is required for ASLV infection. To elucidate the
      role of low pH, we studied the association between ASLV subgroup B (ASLV-B) and
      liposomes and fusion between effector cells expressing Env from ASLV-A and ASLV-B
      and target cells expressing cognate receptors. Neither EnvA nor EnvB promoted
      cell-cell fusion at neutral pH, but lowering the pH resulted in quick and
      extensive fusion. As expected for a low-pH-triggered reaction, fusion was a steep
      function of pH. Steps that required low pH were identified. Binding a soluble
      form of the receptor caused ASLV-B to hydrophobically associate with liposome
      membranes at neutral pH, indicating that low pH is not required for insertion of
      Env's fusion peptides into membranes. But both cell-cell hemifusion and fusion
      pore formation were pH dependent. It is proposed that fusion peptide insertion
      stabilizes the conformation of ASLV Env into a form that can be acted upon by low
      pH. At this point, but not before, low pH can induce fusion and is in fact
      required for fusion to occur. However, low pH is no longer necessary after
      formation of the initial fusion pore: pore enlargement does not require low pH.

PMID- 15016896
TI  - A peptide from autoantigen La blocks poliovirus and hepatitis C virus cap
      independent translation and reveals a single tyrosine critical for La RNA binding
      and translation stimulation.
AB  - La, a 52-kDa autoantigen in patients with systemic lupus erythematosus, was one
      of the first cellular proteins identified to interact with viral internal
      ribosome entry site (IRES) elements and stimulate poliovirus (PV) and hepatitis C
      virus (HCV) IRES-mediated translation. Previous results from our laboratory have
      shown that a small, yeast RNA (IRNA) could selectively inhibit PV and HCV IRES
      mediated translation by sequestering the La protein. Here we have identified an
      18-amino-acid-long sequence from the N-terminal "La motif" which is required for
      efficient interaction of La with IRNA and viral 5' untranslated region (5'-UTR)
      elements. A synthetic peptide (called LAP, for La peptide) corresponding to this
      sequence (amino acids 11 to 28) of La was found to efficiently inhibit viral IRES
      mediated translation in vitro. The LAP efficiently enters Huh-7 cells and
      preferentially inhibits HCV IRES-mediated translation programmed by a bicistronic
      RNA in vivo. The LAP does not bind RNA directly but appears to block La binding
      to IRNA and PV 5'-UTR. Competition UV cross-link and translation rescue
      experiments suggested that LAP inhibits IRES-mediated translation by interacting
      with proteins rather than RNA. Mutagenesis of LAP demonstrates that single amino
      acid changes in a highly conserved sequence within LAP are sufficient to
      eliminate the translation-inhibitory activity of LAP. When one of these mutations
      (Y23Q) is introduced into full-length La, the mutant protein is severely
      defective in interacting with the PV IRES element and consequently unable to
      stimulate IRES-mediated translation. However, the La protein with a mutation of
      the next tyrosine moiety (Y24Q) could still interact with PV 5'-UTR and stimulate
      viral IRES-mediated translation significantly. These results underscore the
      importance of the La N-terminal amino acids in RNA binding and viral RNA
      translation. The possible role of the LAP sequence in La-RNA binding and
      stimulation of viral IRES-mediated translation is discussed.

PMID- 15016897
TI  - Patterns of feline immunodeficiency virus multiple infection and genome
      divergence in a free-ranging population of African lions.
AB  - Feline immunodeficiency virus (FIV) is a lentivirus that causes AIDS-like
      immunodeficiency disease in domestic cats. Free-ranging lions, Panthera leo,
      carry a chronic species-specific strain of FIV, FIV-Ple, which so far has not
      been convincingly connected with immune pathology or mortality. FIV-Ple,
      harboring the three distinct strains A, B, and C defined by pol gene sequence
      divergences, is endemic in the large outbred population of lions in the Serengeti
      ecosystem in Tanzania. Here we describe the pattern of variation in the three FIV
      genes gag, pol-RT, and pol-RNase among lions within 13 prides to assess the
      occurrence of FIV infection and coinfection. Genome diversity within and among
      FIV-Ple strains is shown to be large, with strain divergence for each gene
      approaching genetic distances observed for FIV between different species of cats.
      Multiple in fections with two or three strains were found in 43% of the FIV
      positive individuals based on pol-RT sequence analysis, which may suggest that
      antiviral immunity or interference evoked by one strain is not consistently
      protective against infection by a second. This comprehensive study of FIV-Ple in
      a free-ranging population of lions reveals a dynamic transmission of virus in a
      social species that has historically adapted to render the virus benign.

PMID- 15016898
TI  - Generation and characterization of neutralizing human monoclonal antibodies
      against human immunodeficiency virus type 1 Tat antigen.
AB  - The human immunodeficiency virus Tat regulatory protein is essential for virus
      replication and pathogenesis. From human peripheral blood mononuclear cells of
      three Tat toxoid-immunized volunteers, we isolated five Tat-specific human
      monoclonal antibodies (HMAbs): two full-length immunoglobulin G (IgG) antibodies
      and three single-chain fragment-variable (scFv) antibodies. The two IgGs were
      mapped to distinct epitopes within the basic region of Tat, and the three scFvs
      were mapped to the N-terminal domain of Tat. The three scFvs were highly reactive
      with recombinant Tat in Western blotting or immunoprecipitation, but results were
      in contrast to those for the two IgGs, which are sensitive to a particular
      folding of the protein. In transactivation assays, scFvs were able to inhibit
      both active recombinant Tat and native Tat secreted by a transfected CEM cell
      line while IgGs neutralized only native Tat. These HMAbs were able to reduce
      viral p24 production in human immunodeficiency virus type 1 strain IIIB
      chronically infected cell lines in a dose-dependent manner.

PMID- 15016900
TI  - Lipid rafts: feeling is believing.
AB  - In the late 1990s, accumulated evidence led to the proposal that biological
      membranes are composed of microdomains of different lipids, which form functional
      "rafts." Recent work using atomic force microscopy has given us new insights into
      the factors influencing the formation and behavior of these physiological
      microenvironments

PMID- 15016899
TI  - The C-terminal transmembrane domain of hepatitis C virus (HCV) RNA polymerase is
      essential for HCV replication in vivo.
AB  - Hepatitis C virus (HCV) RNA replication is dependent on the enzymatic activities
      of the viral RNA-dependent RNA polymerase NS5B, which is a membrane-anchored
      protein. Recombinant NS5B lacking the C-terminal transmembrane domain (21 amino
      acids) is enzymatically active. To address the role of this domain in HCV
      replication in vivo, we introduced a series of mutations into the NS5B of an HCV
      subgenomic replicon and examined the replication capabilities of the resultant
      mutants by a colony formation assay. Replicons lacking the transmembrane domain
      did not yield any colonies. Furthermore, when Huh-7 cells harboring the HCV
      subgenomic replicon were treated with a synthetic peptide consisting of the NS5B
      transmembrane domain fused to the antennapedia peptide, the membrane association
      of NS5B was completely disrupted. Correspondingly, the HCV RNA titer was reduced
      by approximately 50%. A scrambled peptide used as a control did not have any
      effects. These findings suggest that the membrane association of NS5B facilitates
      HCV RNA synthesis. However, a related transmembrane domain derived from bovine
      viral diarrhea virus could not replace the HCV NS5B transmembrane segment. This
      finding suggests that the C-terminal 21 amino acids not only have a membrane
      anchoring function but also may perform additional functions for RNA synthesis in
      vivo.

PMID- 15016902
TI  - Unorthodox sites and modes of aldosterone action.
AB  - Aldosterone controls electrolyte balance by acting on the renal epithelium.
      However, there is strong evidence that vascular endothelium is another target for
      mineralocorticoids. Endothelial cells gain sensitivity to diuretics when exposed
      to aldosterone. Atomic force microscopy detects such phenomena. It is speculated
      that endothelium and kidney join forces in the regulation of body fluids.

PMID- 15016903
TI  - Comparative physiology of lung complexity: implications for gas exchange.
AB  - Lungs evolved to increase diffusing capacity by compartmentalizing and reducing
      the size of individual gas exchange units. This increased the potential for gas
      exchange limitations from ventilation-perfusion heterogeneity. However,
      comparative studies on reptiles, birds, and mammals show that heterogeneity is
      independent of lung complexity.

PMID- 15016901
TI  - Calcium and TRP channels in pulmonary vascular smooth muscle cell proliferation.
AB  - Ca(2+) is a major trigger for pulmonary vasoconstriction and a stimulus for
      pulmonary vascular smooth muscle cell proliferation. The transient receptor
      potential cation channels participate in regulating intracellular Ca(2+) and thus
      vascular contractility and cell proliferation. Upregulation of genes encoding
      these channels is involved in the development of pulmonary hypertension.

PMID- 15016904
TI  - Molecular mechanisms of epithelial polarity: about shapes, forces, and
      orientation problems.
AB  - In a variety of organs, epithelial cells assemble into networks of cysts and
      tubules. Such structures can be reproduced in vitro. Here the importance of
      plasma membrane compartmentalization and forces that drive morphogenetic events
      during cystogenesis are discussed.

PMID- 15016906
TI  - Central pathways controlling brown adipose tissue thermogenesis.
AB  - Heat production in brown adipose tissue contributes to cold defense, to stress
      induced increases in body temperature, and to energy balance. Elucidating the
      functional organization of the central network controlling the sympathetic
      outflow to brown adipose tissue could provide a framework for understanding how
      dysregulation of thermogenesis contributes to hyperthermia and to obesity.

PMID- 15016907
TI  - A nonconventional look at ionic fluxes in the skin: lessons from genetically
      modified mice.
AB  - The mammalian, highly amiloride-sensitive epithelial sodium channel (ENaC) is
      member of the degenerin/ENaC superfamily of ion channels known to be implicated
      in sodium homeostasis, mechanosensation, and mechanoperception. A novel role for
      ENaC implicated in differentiation processes in skin reshapes our current view of
      this ancient transmembrane channel protein.

PMID- 15016908
TI  - Electrophysiological insights into the mechanism of ion-coupled cotransporters.
AB  - Most ion-coupled cotransporters display, in the absence of organic substrate,
      transient currents resembling the gating currents of voltage-dependent ion
      channels. Detailed comparison of these currents in different ionic and
      temperature conditions with the corresponding steady-state currents when
      translocation of the substrate occurs reveals new insights into the mechanisms of
      the process.

PMID- 15016909
TI  - Putative involvement of the histone acetyltransferase Tip60 in ribosomal gene
      transcription.
AB  - Tip60 is a histone acetyltransferase (HAT) implicated in a wide range of cellular
      functions, including mRNA synthesis and DNA repair. In the present report we
      propose a model based on which Tip60 is actively involved in ribosomal gene
      transcription through acetylation of UBF, a ribosomal specific transcription
      factor, as well as through its direct recruitment to the human ribosomal gene
      promoter, as shown by chromatin immunoprecipitation experiments. Electron
      microscopy studies revealed that Tip60 resides in sites of active rDNA
      transcription within the nucleolus, while it co-localizes with UBF as shown by
      confocal microscopy. In addition, in vivo transcription assays demonstrated that
      the nucleolar fraction of Tip60 localizes to sites of newly synthesized rRNA.
      Finally, functional assays established that Tip60 complexes with, and targets UBF
      for acetylation. The present study underlines the importance of acetylation in
      rDNA transcription and directly implicates Tip60 in the process of ribosomal gene
      transcription.

PMID- 15016910
TI  - RNA conformational classes.
AB  - RNA exhibits a large diversity of conformations. Three thousand nucleotides of
      23S and 5S ribosomal RNA from a structure of the large ribosomal subunit were
      analyzed in order to classify their conformations. Fourier averaging of the six
      3D distributions of torsion angles and analyses of the resulting pseudo electron
      maps, followed by clustering of the preferred combinations of torsion angles were
      performed on this dataset. Eighteen non-A-type conformations and 14 A-RNA related
      conformations were discovered and their torsion angles were determined; their
      Cartesian coordinates are available.

PMID- 15016911
TI  - Metagenes and molecular pattern discovery using matrix factorization.
AB  - We describe here the use of nonnegative matrix factorization (NMF), an algorithm
      based on decomposition by parts that can reduce the dimension of expression data
      from thousands of genes to a handful of metagenes. Coupled with a model selection
      mechanism, adapted to work for any stochastic clustering algorithm, NMF is an
      efficient method for identification of distinct molecular patterns and provides a
      powerful method for class discovery. We demonstrate the ability of NMF to recover
      meaningful biological information from cancer-related microarray data. NMF
      appears to have advantages over other methods such as hierarchical clustering or
      self-organizing maps. We found it less sensitive to a priori selection of genes
      or initial conditions and able to detect alternative or context-dependent
      patterns of gene expression in complex biological systems. This ability, similar
      to semantic polysemy in text, provides a general method for robust molecular
      pattern discovery.

PMID- 15016913
TI  - Capillarity-driven assembly of two-dimensional cellular carbon nanotube foams.
AB  - Capillary forces arising during the evaporation of liquids from dense carbon
      nanotube arrays are used to reassemble the nanotubes into two-dimensional
      contiguous cellular foams. The stable nanotube foams can be elastically deformed,
      transferred to other substrates, or floated out to produce free-standing
      macroscopic fabrics. The lightweight cellular foams made of condensed nanotubes
      could have applications as shock-absorbent structural reinforcements and elastic
      membranes. The ability to control the length scale, orientation, and shape of the
      cellular structures and the simplicity of the assembly process make this a
      particularly attractive system for studying pattern formation in ordered media.

PMID- 15016912
TI  - Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to
      the silencing mediator of retinoid and thyroid hormone receptors.
AB  - Ataxin 1 (Atx1) is a foci-forming polyglutamine protein of unknown function,
      whose mutant form causes type 1 spinocerebellar ataxia in humans and exerts
      neurotoxicity in transgenic mouse and fly expressing mutant Atx1. In this study,
      we demonstrate that Atx1 interacts with the transcriptional corepressor SMRT
      (silencing mediator of retinoid and thyroid hormone receptors) and with histone
      deacetylase 3. Atx1 binds chromosomes and mediates transcriptional repression
      when tethered to DNA. Interaction with SMRT-related factors is a conserved
      feature of Atx1, because Atx1 also binds SMRTER, a Drosophila cognate of SMRT.
      Significantly, mutant Atx1 forms aggregates in Drosophila, and such mutant Atx1
      mediated aggregates sequester SMRTER. Consistently, the neurodegenerative eye
      phenotype caused by mutant Atx1 is enhanced by a Smrter mutation and, conversely,
      is suppressed by a chromosomal duplication that contains the wild type Smrter
      gene. Together, our results suggest that Atx1 is a transcriptional factor whose
      mutant form exerts its deleterious effects in part by perturbing corepressor
      dependent transcriptional pathways.

PMID- 15016916
TI  - Pressure-dissociable reversible assembly of intrinsically denatured lysozyme is a
      precursor for amyloid fibrils.
AB  - Although a diversity of proteins is known to form amyloid fibers, their common
      mechanisms are not clear. Here, we show that an intrinsically unfolded protein
      (U), represented by a disulfide-deficient variant of hen lysozyme with no
      tertiary structure, forms an amyloid-like fibril after prolonged incubation.
      Using variable pressure NMR along with sedimentation velocity, circular
      dichroism, and fluorescence measurements, we show that, before the fibril
      formation, the protein forms a pressure-dissociable, soluble assemblage (U'(n))
      with a sedimentation coefficient of 17 S and a rich intermolecular beta-sheet
      structure. The reversible assemblage is characterized with a Gibbs energy for
      association of -23.3 +/- 0.8 kJ.mol(-1) and a volume increase of 52.7 +/- 11.3
      ml.mol(-1) per monomer unit, and involves preferential interaction of hydrophobic
      residues in the initial association step. These results indicate that amyloid
      fibril formation can proceed from an intrinsically denatured protein and suggest
      a scheme N <==>U <==>U'(n)-->fibril as a common mechanism of fibril formation in
      amyloidogenic proteins, where two-way arrows represent reversible processes, one
      way arrow represents an irreversible process, and N, U, and U'(n)represent,
      respectively, the native conformer, the unfolded monomeric conformer, and the
      soluble assemblage of unfolded conformers.

PMID- 15016915
TI  - DAXX interacts with heat shock factor 1 during stress activation and enhances its
      transcriptional activity.
AB  - DAXX, a modulator of apoptosis and a repressor of basal transcription, was
      identified in a two-hybrid screen as a protein capable of interacting with a
      trimeric form of human heat shock factor 1 (HSF1). In human cells, DAXX
      interacted with HSF1 essentially only during stress, i.e., when factor
      trimerization occurred. Several lines of experimentation suggested that DAXX is
      an important mediator of HSF1 activation: (i) overexpression of DAXX enhanced
      basal transactivation competence of HSF1 in the absence of a stress; (ii) a DAXX
      fragment exerted dominant-negative effects on HSF1 activation by different types
      of stress; (iii) induction of heat shock or stress protein (HSP)70 by heat stress
      was defective in a cell line lacking functional DAXX; and (iv) RNA interference
      depletion of DAXX also substantially reduced heat induction of HSF1 activity and
      HSP70 expression. HSF1 transactivation competence is repressed by an HSP90
      containing multichaperone complex that interacts with trimeric factor.
      Overexpressed HSF1, known to be largely trimeric, only marginally increased HSF1
      activity on its own but potentiated the activating effect of DAXX overexpression.
      Expression of a nonnative protein capable of competing for multichaperone complex
      also synergistically enhanced activation of HSF1 by DAXX. These observations
      suggest a model in which DAXX released from its nuclear stores during stress
      opposes repression of HSF1 transactivation competence by multichaperone complex
      through its interaction with trimerized HSF1. Our identification of DAXX as a
      mediator of HSF1 activation raises the question whether DAXX produces some of its
      pleiotropic effects through modulation of HSP levels.

PMID- 15016917
TI  - Disruption of communication between peripheral and central trigeminovascular
      neurons mediates the antimigraine action of 5HT 1B/1D receptor agonists.
AB  - Triptans are 5HT(1B/1D) receptor agonists commonly prescribed for migraine
      headache. Although originally designed to constrict dilated intracranial blood
      vessels, the mechanism and site of action by which triptans abort the migraine
      pain remain unknown. We showed recently that sensitization of peripheral and
      central trigeminovascular neurons plays an important role in the pathophysiology
      of migraine pain. Here we examined whether the drug sumatriptan can prevent
      and/or suppress peripheral and central sensitization by using single-unit
      recording in our animal model of intracranial pain. We found that sumatriptan
      effectively prevented the induction of sensitization (i.e., increased spontaneous
      firing; increased neuronal sensitivity to intracranial mechanical stimuli) in
      central trigeminovascular neurons (recorded in the dorsal horn), but not in
      peripheral trigeminovascular neurons (recorded in the trigeminal ganglion). After
      sensitization was established in both types of neuron, sumatriptan effectively
      normalized intracranial mechanical sensitivity of central neurons, but failed to
      reverse such hypersensitivity in peripheral neurons. In both the peripheral and
      central neurons, the drug failed to attenuate the increased spontaneous activity
      established during sensitization. These results suggest that neither peripheral
      nor central trigeminovascular neurons are directly inhibited by sumatriptan.
      Rather, triptan action appears to be exerted through presynaptic 5HT(1B/1D)
      receptors in the dorsal horn to block synaptic transmission between axon
      terminals of the peripheral trigeminovascular neurons and cell bodies of their
      central counterparts. We therefore suggest that the analgesic action of triptan
      can be attained specifically in the absence, but not in the presence, of central
      sensitization.

PMID- 15016918
TI  - Bacterial biota in the human distal esophagus.
AB  - The esophagus, like other luminal organs of the digestive system, provides a
      potential environment for bacterial colonization, but little is known about the
      presence of a bacterial biota or its nature. By using broad-range 16S rDNA PCR,
      biopsies were examined from the normal esophagus of four human adults. The 900
      PCR products cloned represented 833 unique sequences belonging to 41 genera, or
      95 species-level operational taxonomic units (SLOTU); 59 SLOTU were homologous
      with culture-defined bacterial species, 34 with 16S rDNA clones, and two were not
      homologous with any known bacterial 16S rDNA. Members of six phyla, Firmicutes,
      Bacteroides, Actinobacteria, Proteobacteria, Fusobacteria, and TM7, were
      represented. A large majority of clones belong to 13 of the 41 genera (783/900,
      87%), or 14 SLOTU (574/900, 64%) that were shared by all four persons.
      Streptococcus (39%), Prevotella (17%), and Veilonella (14%) were most prevalent.
      The present study identified approximately 56-79% of SLOTU in this bacterial
      ecosystem. Most SLOTU of esophageal biota are similar or identical to residents
      of the upstream oral biota, but the major distinction is that a large majority
      (82%) of the esophageal bacteria are known and cultivable. These findings provide
      evidence for a complex but conserved bacterial population in the normal distal
      esophagus.

PMID- 15016919
TI  - Pacific and Atlantic Ocean influences on multidecadal drought frequency in the
      United States.
AB  - More than half (52%) of the spatial and temporal variance in multidecadal drought
      frequency over the conterminous United States is attributable to the Pacific
      Decadal Oscillation (PDO) and the Atlantic Multidecadal Oscillation (AMO). An
      additional 22% of the variance in drought frequency is related to a complex
      spatial pattern of positive and negative trends in drought occurrence possibly
      related to increasing Northern Hemisphere temperatures or some other
      unidirectional climate trend. Recent droughts with broad impacts over the
      conterminous U.S. (1996, 1999-2002) were associated with North Atlantic warming
      (positive AMO) and northeastern and tropical Pacific cooling (negative PDO). Much
      of the long-term predictability of drought frequency may reside in the
      multidecadal behavior of the North Atlantic Ocean. Should the current positive
      AMO (warm North Atlantic) conditions persist into the upcoming decade, we suggest
      two possible drought scenarios that resemble the continental-scale patterns of
      the 1930s (positive PDO) and 1950s (negative PDO) drought.

PMID- 15016920
TI  - Modulation of the bilayer thickness of exocytic pathway membranes by membrane
      proteins rather than cholesterol.
AB  - A biological membrane is conceptualized as a system in which membrane proteins
      are naturally matched to the equilibrium thickness of the lipid bilayer.
      Cholesterol, in addition to lipid composition, has been suggested to be a major
      regulator of bilayer thickness in vivo because measurements in vitro have shown
      that cholesterol can increase the thickness of simple phospholipid/cholesterol
      bilayers. Using solution x-ray scattering, we have directly measured the average
      bilayer thickness of exocytic pathway membranes, which contain increasing amounts
      of cholesterol. The bilayer thickness of membranes of the endoplasmic reticulum,
      the Golgi, and the basolateral and apical plasma membranes, purified from rat
      hepatocytes, were determined to be 37.5 +/- 0.4 A, 39.5 +/- 0.4 A, 35.6 +/- 0.6
      A, and 42.5 +/- 0.3 A, respectively. After cholesterol depletion using
      cyclodextrins, Golgi and apical plasma membranes retained their respective
      bilayer thicknesses whereas the bilayer thickness of the endoplasmic reticulum
      and the basolateral plasma membrane decreased by 1.0 A. Because cholesterol was
      shown to have a marginal effect on the thickness of these membranes, we measured
      whether membrane proteins could modulate thickness. Protein-depleted membranes
      demonstrated changes in thickness of up to 5 A, suggesting that (i) membrane
      proteins rather than cholesterol modulate the average bilayer thickness of
      eukaryotic cell membranes, and (ii) proteins and lipids are not naturally
      hydrophobically matched in some biological membranes. A marked effect of membrane
      proteins on the thickness of Escherichia coli cytoplasmic membranes, which do not
      contain cholesterol, was also observed, emphasizing the generality of our
      findings.

PMID- 15016921
TI  - Comorbidity of asthma and anxiety and depression in Puerto Rican children.
AB  - Studies have reported that childhood asthma is associated with internalizing
      disorders, but most of these studies have used global measures of depressive and
      anxiety symptoms. The Diagnostic Interview Schedule for Children was administered
      to a group of 1891 youth ages 4 to 17 and their caregivers in Puerto Rico to
      determine DSM-IV symptoms and diagnoses. Asthma diagnosis and having had an
      asthma attack were assessed by parental report. A diagnosis of asthma was
      associated with having any depressive disorder and one symptom of separation
      anxiety. An asthma attack was associated with any depressive disorder and any
      anxiety disorder and, more specifically, with separation anxiety disorder, major
      depressive disorder, and symptoms of depression, separation anxiety, and
      generalized anxiety. Possible explanations for the findings are discussed.

PMID- 15016922
TI  - Psychosocial stress, personality, and the severity of chronic hepatitis C.
AB  - This cross-sectional study examined the association between the severity of
      chronic hepatitis C and the type 1 personality, which has been shown by Grossarth
      Maticek to be strongly related to the incidence of cancer and mortality. Sixty
      nine patients with chronic hepatitis C completed the Stress Inventory, a self
      report questionnaire to measure psychosocial stress and personality, and were
      classified into three groups according to hepatitis severity: group A, chronic
      hepatitis C with a normal serum alanine aminotransferase level; group B, chronic
      hepatitis C with an elevated alanine aminotransferase level; and group C, liver
      cirrhosis. Each of four scales related to the type 1 personality--low sense of
      control, object dependence of loss, unfulfilled need for acceptance, and altruism
      -was significantly and positively associated with hepatitis severity. The type 1
      score, calculated as the average of these scales, was also strongly related to
      hepatitis severity (p<0.0001), and adjustment for age, sex, education level,
      smoking, drinking, and duration brought no attenuation into the association.
      Chronic psychosocial stress relevant to the type 1 personality may also influence
      the course of chronic hepatitis C.

PMID- 15016923
TI  - Family-perceived distress from delirium-related symptoms of terminally ill cancer
      patients.
AB  - Delirium is a frequent symptom of terminally ill cancer patients and can cause
      serious distress to family members. To clarify the degree of emotional distress
      of family members concerning terminal delirium, a survey of bereaved families was
      performed. A questionnaire was mailed to 300 bereaved families with a request to
      rate the frequency and level of their distress for 12 delirium-related symptoms.
      A total of 195 responses were analyzed (effective response rate=65%). Seventy
      four percent and 62% of the family members reported that the patients had
      symptoms of physical restlessness and mood lability, respectively. Psychotic
      symptoms, such as hallucinations and delusions, were reported by 35%-37%, and
      somnolence was reported in 92%. The prevalence of cognitive symptoms (e.g.,
      communication difficulty, memory disturbance) ranged between 50% and 72%. More
      than two-thirds of the bereaved family members perceived all delirium-related
      symptoms other than somnolence as distressing or very distressing when they
      occurred "often" or "very often." For physical restlessness, mood lability, and
      psychotic symptoms that occurred "sometimes," 27%-36% of the family members had
      moderate to high levels of distress. The bereaved family members of terminally
      ill cancer patients experienced high levels of distress from both the agitation
      and cognitive symptoms of terminal delirium. Multidisciplinary interventions,
      including the prevention of agitation and the minimization of cognitive
      impairment, pharmacological or medical treatments, and supportive and
      psychoeducational approaches for family members, are needed to alleviate family
      distress.

PMID- 15016924
TI  - Vital exhaustion as a risk indicator for first stroke.
AB  - Fatigue is a common condition after stroke. An unresolved question is whether the
      fatigue is a consequence of the stroke or is one of the precursors. The authors'
      objective was to investigate whether vital exhaustion is a precursor of first
      stroke while controlling for other cardiovascular risk factors. The design was a
      prospective cohort study. Vital exhaustion was diagnosed with the Maastricht
      Interview Vital Exhaustion scale. The authors controlled for age, gender,
      diabetes mellitus, systolic and diastolic blood pressure, total cholesterol, body
      mass index, and smoking habits as possible confounders. Data were analyzed with
      Cox regression analysis. The subjects were adults ages 41-66 in an average Dutch
      village population. Outcome measures included first stroke. Vital exhaustion
      increased the risk of stroke by 13% per vital exhaustion point on the Maastricht
      Interview Vital Exhaustion scale. This value remained statistically significant
      after control for other risk factors. Total cholesterol, diastolic blood
      pressure, systolic blood pressure, diabetes mellitus, and smoking also increased
      the risk of stroke significantly. A state of exhaustion is one of the risk
      indicators for stroke. This means that the fatigue so often seen after stroke was
      already experienced by many patients before the occurrence of the stroke.

PMID- 15016925
TI  - Effects of religiosity on patients' perceptions of do-not-resuscitate status.
AB  - Forty-eight oncology inpatients participated in a survey designed to characterize
      their understanding of and beliefs about do-not-resuscitate (DNR) decisions and
      to identify dimensions of religiosity associated with moral beliefs about DNR
      decisions. Seventy-five percent of the patients believed they understood the
      meaning of "DNR," but only 32% were able to provide an accurate definition.
      Seventeen percent believed that DNR decisions are morally wrong, and 23% believed
      that they are equivalent to suicide. Those who lacked an accurate understanding
      of DNR status were significantly more likely to perceive them as morally wrong.
      Gender, but not religious denomination, was significantly related to patients'
      attitudes about the morality of DNR decisions. The belief that DNR decisions are
      morally wrong was predicted by certain religious practices, including near-daily
      meditation, near-daily thinking about God, and the current practice of
      meditation, and by endorsement of the statement, "My faith sometimes restricts my
      action."

PMID- 15016926
TI  - Heart rate variability in patients with major depression.
AB  - This study compared cardiac autonomic modulation in physically healthy patients
      with major depressive disorder to that in mentally healthy heart transplant
      recipients and physically and mentally healthy comparison subjects by using a
      nonlinear measure and a conventional measure of heart rate variability. No
      significant differences in cardiac autonomic modulation were noted between the
      depressive group and the transplant recipients, but both of those groups had
      significantly lower mean values for heart rate variability measures relative to
      the healthy comparison subjects. The results support the hypothesis that cardiac
      autonomic imbalance (reduced vagal modulation) to the extent of cardiac
      neuropathy is present in depression.

PMID- 15016927
TI  - Olanzapine-associated hypothermia.

PMID- 15016928
TI  - Psychosocial intervention for a geriatric patient to address fears related to
      implantable cardioverter defibrillator discharges.

PMID- 15016930
TI  - Depression during treatment with interferon alpha.

PMID- 15016934
TI  - How to assess epidemiological studies.
AB  - Assessing the quality of an epidemiological study equates to assessing whether
      the inferences drawn from it are warranted when account is taken of the methods,
      the representativeness of the study sample, and the nature of the population from
      which it is drawn. Bias, confounding, and chance can threaten the quality of an
      epidemiological study at all its phases. Nevertheless, their presence does not
      necessarily imply that a study should be disregarded. The reader must first
      balance any of these threats or missing information with their potential impact
      on the conclusions of the report.

PMID- 15016933
TI  - Young onset dementia.
AB  - Young onset dementia is a challenging clinical problem with potentially
      devastating medical and social consequences. The differential diagnosis is wide,
      and includes a number of rare sporadic and hereditary diseases. However, accurate
      diagnosis is often possible, and all patients should be thoroughly investigated
      to identify treatable processes. This review presents an approach to the
      diagnosis, investigation, and management of patients with young onset dementia,
      with particular reference to common and treatable causes.

PMID- 15016936
TI  - Fungal empyema thoracis complicating treatment of oesophageal carcinoma.

PMID- 15016935
TI  - Analgesia for patients with advanced disease: I.
AB  - This series of two articles explores the challenge of managing pain in patients
      with advanced malignant and non-malignant disease. Pain is a common symptom in
      advanced disease. Despite guidance from organisations such as the World Health
      Organisation, cancer pain is often inadequately managed. Managing pain in non
      malignant conditions, such as end stage cardiac failure, presents an even greater
      challenge to healthcare professionals. This first article discusses epidemiology,
      definitions, pathophysiology, assessment, non-pharmacological approaches, the
      analgesic "ladder", and opioids. The second article will examine the use of non
      opioids, anaesthetic techniques, and analgesia in dying patients as well as
      discussing future directions.

PMID- 15016938
TI  - Painful Horner's syndrome caused by carotid dissection.

PMID- 15016937
TI  - Antiplatelet therapy in cardiovascular disease.
AB  - Platelet activation and aggregation are considered to be central to arterial
      thrombus formation. Antiplatelet therapy is therefore important for both the
      treatment and prevention of cardiovascular disease. Aspirin, the most widely used
      antiplatelet agent, inhibits platelet cyclo-oxygenase and the conversion of
      arachidonic acid to the potent platelet agonist thromboxane A(2) but does not
      prevent platelet activation occurring via various signalling pathways that are
      independent of thromboxane A(2) release. Therefore a number of other compounds
      have been developed to complement aspirin's beneficial effect. These include the
      thienopyridines (clopidogrel and ticlopidine), dipyridamole, and the
      alpha(IIb)beta(3) (glycoprotein IIb/IIIa) receptor inhibitors.

PMID- 15016939
TI  - How to avoid being sued in clinical practice.
AB  - Challenges to clinical management are a fact of professional life. Every doctor
      must expect to become embroiled in complaints and claims from time to time and be
      prepared to justify why they managed a particular case in the way that they did.
      Good medical practice is defensible practice, which depends upon staying within
      the limits of your own expertise, keeping up to date and conducting audit,
      ensuring your administration is effective and that patients are not allowed to
      slip through the net, that you communicate effectively with patients, their
      carers and colleagues, and that medical records recall all salient facts relating
      to the patient. If things go wrong, be open, investigate the facts, explain the
      situation fully to the patient, and do not be afraid to apologise.

PMID- 15016940
TI  - Implementation of British Thoracic Society guidelines for acute exacerbation of
      chronic obstructive pulmonary disease: impact on quality of life.
AB  - BACKGROUND: The British Thoracic Society (BTS) guidelines have not been examined
      collectively for their impact on chronic obstructive pulmonary disease (COPD).
      Whether intensive outpatient follow up of COPD patients after acute admission,
      using these guidelines, improved quality of life compared to the "usual practice"
      of primary care follow up was investigated. METHODS: Altogether 103 patients with
      a new diagnosis of COPD were admitted and screened over a four year period.
      Seventy patients were excluded because of another dominant medical condition or a
      mandatory requirement for intervention. Patients were randomised to regular
      primary care (control group, n = 15) or chest clinic follow up (intervention
      group, n = 10). Spirometry, oxygen saturation, St George's Respiratory
      Questionnaire (SGRQ), and Short Form 36 questionnaire were measured at baseline
      and six months. The intervention group was reviewed at least four times in the
      six month period and received spirometry, ambulatory oxygen assessment, smoking
      cessation advice, nebuliser assessment, a steroid trial, advice about
      nutrition/exercise, and introduction to a patient support group. RESULTS: There
      was no significant difference between baseline measurements in the two groups.
      There was a significant mean (SD) improvement in the SGRQ symptom score from
      baseline to six months in the intervention group [20.98 (20.36)] compared with
      the controls [0.23 (12.55)] (p = 0.004). At six months the SGRQ symptom score,
      impact score, and total score was significantly better in the intervention than
      the control group (p = 0.01, 0.02, and 0.02). CONCLUSION: Aggressive
      implementation of BTS guidelines after initial hospitalisation may improve
      respiratory health specific quality of life scores in patients with COPD. Larger
      studies are needed to confirm this finding.

PMID- 15016942
TI  - Breast cancer recurrence: follow up after treatment for primary breast cancer.
AB  - BACKGROUND: Breast cancer will affect one in 12 Australian women in their
      lifetime. After potentially curative treatment, it is usual for patients to be
      followed up for many years. However, controversies surround follow up, and its
      value is uncertain. AIM: This study reviews the evidence and describes the role
      of routine follow up in the management of breast cancer in a tertiary hospital.
      By establishing how recurrence of breast cancer presents and identifying the
      proportion of patients with recurrence who were diagnosed as a consequence of
      regular follow up, the value of this system in detecting recurrence can be
      indirectly assessed. DESIGN: A retrospective review was undertaken of all
      patients attending the radiotherapy outpatient clinic for treatment of invasive
      breast cancer in 1997. Hospital records were reviewed to ascertain patient and
      tumour characteristics, treatment received, site of recurrence and its mode of
      detection, whether patients were symptomatic at the time of recurrence, and
      whether they presented at a scheduled appointment. RESULTS: Out of 286 patients
      who presented to the radiotherapy outpatient clinic, 220 were entered into the
      study. Recurrence was recorded in 42 patients (a complete dataset was available
      for 38 of these patients). In total, 74% (31/42) of recurrences were symptomatic,
      and 76% (32/42) presented at unscheduled appointments, the majority (17/32) of
      which were initiated by the patient. Only seven patients had asymptomatic
      recurrences. CONCLUSION: Based on current evidence, long term routine hospital
      follow up after treatment for breast cancer appears to be inefficient in
      detecting recurrence.

PMID- 15016943
TI  - Are we overusing ultrasound in non-traumatic acute abdominal pain?
AB  - BACKGROUND: Ultrasound is being used increasingly in the assessment of acute non
      traumatic abdominal pain as it is non-invasive and does not carry the risk of
      radiation. However, the inappropriate use of ultrasound can lead to a delayed or
      incorrect diagnosis, more work for the personnel involved, and increased hospital
      costs. METHODS: A prospective study was conducted to analyse the clinical
      indications for requesting an ultrasound in those admitted to a district general
      hospital with acute non-traumatic abdominal pain, and to assess whether there is
      a correlation between clinical and laboratory findings and ultrasound results. A
      total of 110 patients were studied during a three month period. RESULTS: The
      results suggest that ultrasound is useful in the investigation of suspected
      biliary colic and abdominal masses. However, the yield of ultrasound in other
      patients with acute non-traumatic abdominal pain is low. This study also suggests
      that the yield of "positive" reports on ultrasound is significantly higher in
      patients with localised abdominal pain and tenderness and in those with acute
      abdominal pain and a raised white cell count or raised liver function tests. The
      yield of positive reports in patients with acute abdominal pain was found to be
      lower those less than 25 years of age than in older patients.

PMID- 15016945
TI  - Nausea and vomiting in a patient with increased thirst.

PMID- 15016944
TI  - Providing treatment for hepatitis C in an Australian district centre.
AB  - Hepatitis C virus (HCV) poses a major public health problem world wide. The
      introduction of combined therapy (interferon and ribavirin) and the recent
      development of pegylated interferon have offered the opportunity to alter the
      natural history of HCV, potentially reducing morbidity and mortality. Until
      recently, treatment has been confined to larger Australian cities. This paper
      describes the establishment of a clinic for the treatment of HCV in a regional
      Australian city. The facilities of the sexual health clinic were utilised.
      Factors contributing to the success of the clinic include the specialist nurse, a
      multidisciplinary approach, and the service model of shared care with general
      practitioners. The patient population and the outcomes of managing HCV in a
      regional centre are described. The sustained viral response rate is comparable to
      the published data from specialist centres.

PMID- 15016946
TI  - A rare cause of empyema in a non-immunocompromised case and successful combined
      treatment.

PMID- 15016949
TI  - Endometriosis and the neoplastic process.
AB  - Endometriosis is a frequent disorder that commonly presents with infertility and
      pelvic pain. Although the precise aetiology of endometriosis is unclear, it is
      generally considered to involve multiple genetic, environmental, immunological,
      angiogenic and endocrine processes. Genetic factors have been implicated in
      endometriosis but the susceptibility genes remain largely unknown. Although
      endometriosis is a benign disorder, recent studies of endometriosis suggest
      endometriosis could be viewed as a neoplastic process. Evidence to support this
      hypothesis includes the increased susceptibility to develop ovarian clear-cell
      and endometrioid cancers in the presence of endometriosis, and molecular
      similarities between endometriosis and cancer. In this article we discuss (i) the
      evidence suggesting that endometriosis might be viewed as a neoplastic process,
      and (ii) the implications of this hypothesis for elucidating the pathogenesis of
      endometriosis and developing novel methods of diagnostic classification and
      individualised treatments.

PMID- 15016950
TI  - Environmental anti-androgens and male reproductive health: focus on phthalates
      and testicular dysgenesis syndrome.
AB  - The amount of research into endocrine disruption has exploded over the past
      decade and a re-evaluation of the state of research in this area is timely. There
      are debates about whether human male reproductive health is really declining and
      whether endocrine disrupting chemicals play any role in the perceived decline.
      Most data currently conclude that there are wide geographical variations in semen
      quality and in the incidence of testicular cancer, cryptorchidism and
      hypospadias. This review aims to give a brief overview of the issues surrounding
      the perceived decline in human male reproductive health and the importance of the
      hormonal environment for the development of the testis and reproductive tract.
      The consequences for the male reproductive tract of abnormal androgen levels or
      action are discussed with reference to environmental anti-androgenic compounds.
      The in vivo data on several anti-androgenic compounds that have been administered
      to pregnant rodents during the period of male reproductive tract development are
      assessed with attention to the effects on the male offspring. Finally, the data
      on in utero phthalate administration are discussed in detail to illustrate the
      similarities between the effects of some phthalate esters and the human male
      reproductive tract disorders which comprise testicular dysgenesis syndrome (TDS).

PMID- 15016951
TI  - Wildlife conservation and reproductive cloning.
AB  - Reproductive cloning, or the production of offspring by nuclear transfer, is
      often regarded as having potential for conserving endangered species of wildlife.
      Currently, however, low success rates for reproductive cloning limit the
      practical application of this technique to experimental use and proof of
      principle investigations. In this review, we consider how cloning may contribute
      to wildlife conservation strategies. The cloning of endangered mammals presents
      practical problems, many of which stem from the paucity of knowledge about their
      basic reproductive biology. However, situations may arise where resources could
      be targeted at recovering lost or under-represented genetic lines; these could
      then contribute to the future fitness of the population. Approaches of this type
      would be preferable to the indiscriminate generation of large numbers of
      identical individuals. Applying cloning technology to non-mammalian vertebrates
      may be more practical than attempting to use conventional reproductive
      technologies. As the scientific background to cloning technology was pioneered
      using amphibians, it may be possible to breed imminently threatened amphibians,
      or even restore extinct amphibian species, by the use of cloning. In this respect
      species with external embryonic development may have an advantage over mammals as
      developmental abnormalities associated with inappropriate embryonic reprogramming
      would not be relevant.

PMID- 15016952
TI  - Assessment of contraceptive vaccines based on recombinant mouse sperm protein
      PH20.
AB  - Mouse PH20 (mPH20), the mouse homologue to guinea pig hyaluronidase protein PH20
      (gpPH20), was used to produce contraceptive vaccines that target both sexes of
      mice. Previously, immunization with a female gamete antigen (the zona pellucida
      subunit 3 protein) delivered in a recombinant murine cytomegalovirus (MCMV), or
      as a purified recombinant protein, has been shown to induce infertility in female
      mice. There is evidence, however, that sperm protein antigens could provide
      broader contraceptive coverage by affecting both males and females, and the most
      promising has been gpPH20 when tested in a guinea pig model. Mice were therefore
      either inoculated with a recombinant MCMV expressing mPH20 or immunized directly
      with purified recombinant mPH20 protein fused to maltose-binding protein. Mice
      treated with either vaccine formulation developed serum antibodies that cross
      reacted to a protein band of 55 kDa corresponding to mPH20 in Western blots of
      mouse sperm. However, there was no significant reduction in the fertility of
      males or females compared with control animals with either formulation. We
      conclude from our data that recombinant mPH20 is not a useful antigen for
      inclusion in immunocontraceptive vaccines that target mice.

PMID- 15016953
TI  - Sequential development of flagellar defects in spermatids and epididymal
      spermatozoa of selenium-deficient rats.
AB  - In this study cauda epididymal spermatozoa of rats maintained on a selenium
      deficient diet for 5 and 7 months exhibited an array of flagellar defects.
      Spermatids and spermatozoa were analyzed by light and electron microscopy to
      define the appearance of flagellar abnormalities during spermiogenesis and post
      testicular sperm development. Late spermatids of selenium-deficient rats
      displayed normal structural organization of the flagellar plasma membrane,
      axoneme, outer dense fibers, fibrous sheath and annulus, but they exhibited a
      premature termination of the mitochondrial sheath. A comparison of late
      spermatids and caput epididymal spermatozoa revealed that a late step in
      flagellar differentiation was the structural remodeling of the annulus and its
      accompanying fusion with both the fibrous sheath and the mitochondrial sheath. In
      selenium-deficient animals, however, the annulus failed to fuse with the
      mitochondrial sheath, generating an apparent weak point in the flagellum. After
      epididymal passage, cauda epididymal spermatozoa of selenium-deficient animals
      also exhibited extensive flagellar disorganization resulting from the apparent
      sliding and extrusion of specific outer dense fiber-doublet microtubule complexes
      from the proximal and the distal ends of the mitochondrial sheath and the
      accompanying loss of the midpiece plasma membrane. Only fiber complex number 4
      was extruded proximally, whereas fibers 4, 5, 6 and 7 were extruded from the
      mitochondrial sheath-deficient posterior midpiece. Axonemal fibers 8, 9, 1, 2 and
      3 retained their normal geometric relationships. These data suggest that the
      known loss of male fertility in selenium deficiency results from the sequential
      development of sperm defects expressed during both spermiogenesis and maturation
      in the epididymis.

PMID- 15016954
TI  - Partial characterization, sperm association and significance of N- and O-linked
      glycoproteins in epididymal fluid of rhesus monkeys (Macaca mulatta).
AB  - The present study investigated regional modifications of glycosylation status,
      sperm association and functional significance of N- and O-linked glycoproteins in
      epididymal luminal fluid of the rhesus monkey (Macaca mulatta). The predominant
      glycoproteins of the epididymal luminal fluid that increase in the extent of
      glycosylation or unmasking of exposed epitopes in a region-specific, maturation
      dependent manner, included those of 150, 116, 68, 64, 58 (N- and O-linked) and
      170 kDa (O-linked). The higher expression of 40 (N-linked), 38 (N- and O-linked)
      and 60, 56 and 33 kDa (O-linked) glycoproteins in the proximal caput epididymal
      fluid was followed by alteration or reorganization of 60, 38 and 33 kDa (O
      linked) glycoproteins in the distal segments of the epididymis. The association
      of epididymal fluid glycoproteins with maturing spermatozoa was identified by
      generating polyclonal antiserum against monkey caudal sperm membrane in female
      albino rabbits. The antiserum crossreacted strongly with 58 and 33 kDa epididymal
      fluid glycoproteins of monkeys and also reacted with 116, 68, 58, 56 and 33 kDa
      glycoproteins from Triton X-100 extracts of human spermatozoa, indicating the
      presence of antigenically related components in both species. The functional
      significance of epididymal fluid glycoproteins in sperm functions was
      investigated by raising antiserum against a heavily glycosylated 58 kDa
      glycoprotein (MEF1) of caudal epididymal fluid, which crossreacted with the
      Triton X-100 extracts of epididymal spermatozoa of monkey and ejaculated human
      spermatozoa on immunoblots. In an in vitro micro-sperm agglutination assay, anti
      MEF1 serum agglutinated both rat caudal epididymal spermatozoa and human
      spermatozoa. MEF1 seemed to be involved in fertilization as demonstrated by
      inhibition of fertility (100%) in female albino rabbits and rats immunized with
      this protein. A sperm-agglutinating 58 kDa glycoprotein of rhesus monkey
      epididymis with functional significance in fertility was identified, thus
      indicating that it is a potential candidate for contraceptive vaccine
      development.

PMID- 15016955
TI  - Age-induced apoptosis in the male genital tract of the mouse.
AB  - We have examined the effects of ageing on the increase in apoptotic cells numbers
      in the male genital tract of the house mouse (Mus musculus). We have found that
      not all organs have the same response. There is an induction of apoptosis in both
      the epididymis and ventral prostate. However, seminal vesicles and other
      prostatic lobes remain unaffected. Apoptosis was assessed by several methods:
      TUNEL, detection of the active fragment of caspase-3 and the pattern of DNA
      fragmentation on agarose gels. This increase in apoptosis is related to the fall
      in testosterone levels, although there is only a partial decrease in androgen
      receptor (AR). AR is still present in all tissues and only moderately reduced in
      the epididymis and ventral prostate. A more intense increase of lipofuscin
      granules, which may be indicative of oxidative stress, occurred in these tissues.
      Finally, testosterone supplementation reverses the changes (both in apoptosis and
      lipofuscin content in the tissue), suggesting a role of androgens in these
      processes.

PMID- 15016956
TI  - Centromere protein b-null mice display decreasing reproductive performance
      through successive generations of breeding due to diminishing endometrial glands.
AB  - Centromere protein B is a highly conserved constitutive protein found at
      centromeres. Gene knockout studies in mice have unexpectedly identified Cenpb as
      a candidate gene involved in uterine function. The present study further explores
      the role of Cenpb in mice by intermating Cenpb-null mice over several
      generations. Breeding studies and analysis of uterine tissue indicate that Cenpb
      null mice lose reproductive fitness over a number of generations due to a
      significant reduction in endometrial glands. These results suggest that Cenpb may
      play an important function in the short- and long-term maintenance of uterine
      integrity.

PMID- 15016957
TI  - Mast cells degranulation affects angiogenesis in the rat uterine cervix during
      pregnancy.
AB  - During pregnancy, it is essential that sufficient nutrients are supplied by the
      vascular system to support the dramatic modifications of the rat uterine cervix.
      Angiogenesis refers to the growth of new blood vessels from pre-existing
      microcirculation and mast cells have been associated with this process. This
      study examined the modifications of the vascular compartment and the distribution
      of mast cells on cervical tissue during pregnancy. Using disodium cromoglycate as
      a mast cell stabilizer, we determined the effects of the mast cell degranulation
      on cervical angiogenesis. Mast cell distribution and their degranulation status
      were evaluated by immunohistochemistry. Endothelial cell proliferation was
      measured by bromodeoxyuridine incorporation. Vascular areas (absolute and
      relative) and maturation indices were assessed by quantitative
      immunohistochemistry of von Willebrand factor and alpha-smooth muscle actin
      respectively. Mast cells were predominantly observed during the first half of
      pregnancy in the perivascular zones. The values of bromodeoxyuridine
      incorporation, absolute vascular area and vascular maturation index exhibited a
      significant increase throughout pregnancy. All animals that received mast cell
      stabilizer showed more than 40% of non-degranulated mast cells. Treated rats
      exhibited a decrease in endothelial proliferation and in relative vascular area;
      in addition, a large proportion of mature blood vessels was observed, suggesting
      a diminished level of new vessel formation. The effects of the mast cell
      stabilizer were sustained beyond the end of treatment. This is the first report
      that brings evidence that mast cell degranulation could be a necessary process to
      contribute to the normal angiogenesis of the rat cervix during pregnancy. Further
      investigations are needed to elucidate the possible implications of abnormal
      vascular development of the uterine cervix on the physiological process of
      ripening and parturition.

PMID- 15016958
TI  - Minor involvement of somatic growth in the onset of puberty of Hatano high- and
      low-avoidance rats.
AB  - The present study was planned to examine the effects of somatic growth on the
      determination of timing of puberty using Hatano high- and low-avoidance rats
      (HAAs and LAAs); the rats were genetically selected from Sprague-Dawley (SD) rats
      for good or poor performance in a two-way active avoidance-learning test. Since
      these two lines were found to have different characteristics, such as body weight
      at birth, maternal care and timing of male puberty, the present study
      characterized female puberty in Hatano rats and then compared postnatal growth
      and timing of puberty between the two lines of rats when they were nursed by
      foster SD dams. When nursed under biological dams, HAAs became heavier, exhibited
      vaginal opening at a younger age and first ovulation was accompanied by more
      oocytes than LAAs. In all of the HAAs, but none of the LAAs, ovulation was
      induced by a single s.c. injection of 5 IU equine chorionic gonadotropin (eCG) on
      day 22 after birth. An additional treatment with 10 IU human CG revealed that, in
      the ovaries of LAAs, a small number of follicles had developed to an ovulable
      stage as a result of the treatment. The fostering improved somatic growth, and
      weights of LAAs were sustained at a heavier level than those of fostered HAAs.
      The fostering, however, did not eliminate the line difference in the timing of
      puberty of both sexes; it did accelerate the vaginal opening of LAAs but not the
      balanopreputial separation. Thus, there is a phenotypic difference in the timing
      of female puberty in Hatano rats exhibiting a different timing of ovarian
      development in response to gonadotropin. The present study indicates that
      postnatal somatic growth is not the predominant determinant in the onset of
      puberty in Hatano rats.

PMID- 15016959
TI  - The effect of endotoxin on functional parameters of mammary CID-9 cells.
AB  - The effect of endotoxin on mammary CID-9 cells, which differentiate in culture
      and express beta-casein, was investigated. Cells in culture supplemented with
      lactogenic hormones and dripped with EMS-Matrix (EMS-drip), were treated daily
      with endotoxin (0.5-500 microg/ml). Endotoxin at concentrations of less or equal
      to 10 microg/ml did not affect cell growth and viability up to 5 days post
      endotoxin treatment. Endotoxin (0.01-10 microg/ml) was added to the culture
      medium, upon confluence, and functional parameters were examined within 48 h post
      endotoxin treatment. Nuclear factor-kappaB (NF-kappaB) (p52) increased in nuclear
      extracts from endotoxin-stimulated cells within 1 h of treatment, while beta
      casein mRNA and protein expression decreased in a concentration-dependent manner
      at 24 and 48 h post treatment. Zymography showed that the 72 and 92 kDa
      gelatinase activity increased in cells at 24 and 48 h post endotoxin treatment at
      10 and 50 microg/ml. At the latter concentration, the active form of 72 kDa
      gelatinase was induced at 48 h. Interleukin-6 and tumor necrosis factor-alpha
      levels increased at 1-3 h post endotoxin treatment and peaked at 6 h in cells on
      plastic and EHS-drip. Nerve growth factor (NGF) levels increased in control and
      endotoxin-treated cells in a time-dependent manner, and endotoxin increased NGF
      levels in culture at 6 and 9 h post endotoxin treatment. This study shows that
      endotoxin activated NF-kappaB, suppressed beta-casein expression and upregulated
      gelatinases, cytokines and NGF. This model could be used to investigate the role
      of mammary cells in initiating and propagating inflammation and to test candidate
      molecules for potential anti-inflammatory properties.

PMID- 15016960
TI  - Direct spinning of carbon nanotube fibers from chemical vapor deposition
      synthesis.
AB  - Many routes have been developed for the synthesis of carbon nanotubes, but their
      assembly into continuous fibers has been achieved only through postprocessing
      methods. We spun fibers and ribbons of carbon nanotubes directly from the
      chemical vapor deposition (CVD) synthesis zone of a furnace using a liquid source
      of carbon and an iron nanocatalyst. This process was realized through the
      appropriate choice of reactants, control of the reaction conditions, and
      continuous withdrawal of the product with a rotating spindle used in various
      geometries. This direct spinning from a CVD reaction zone is extendable to other
      types of fiber and to the spin coating of rotating objects in general.

PMID- 15016961
TI  - Controlled atomic doping of a single C60 molecule.
AB  - We report a method for controllably attaching an arbitrary number of charge
      dopant atoms directly to a single, isolated molecule. Charge-donating K atoms
      adsorbed on a silver surface were reversibly attached to a C60 molecule by moving
      it over K atoms with a scanning tunneling microscope tip. Spectroscopic
      measurements reveal that each attached K atom donates a constant amount of charge
      (approximately 0.6 electron charge) to the C60 host, thereby enabling its
      molecular electronic structure to be precisely and reversibly tuned.

PMID- 15016962
TI  - Transmembrane segments of syntaxin line the fusion pore of Ca2+-triggered
      exocytosis.
AB  - The fusion pore of regulated exocytosis is a channel that connects and spans the
      vesicle and plasma membranes. The molecular composition of this important
      intermediate structure of exocytosis is unknown. Here, we found that mutations of
      some residues within the transmembrane segment of syntaxin (Syx), a plasma
      membrane protein essential for exocytosis, altered neurotransmitter flux through
      fusion pores and altered pore conductance. The residues that influenced fusion
      pore flux lay along one face of an alpha-helical model. Thus, the fusion pore is
      formed at least in part by a circular arrangement of 5 to 8 Syx transmembrane
      segments in the plasma membrane.

PMID- 15016963
TI  - High frequency of mutations of the PIK3CA gene in human cancers.

PMID- 15016965
TI  - Space physics. Will NASA annihilate station antimatter experiment?

PMID- 15016964
TI  - Stem cells, redux.

PMID- 15016967
TI  - Polar research. Plucky scientists plucked from jaws of death.

PMID- 15016966
TI  - Transgenic crops. Britain opts for brave new GM world.

PMID- 15016968
TI  - Reproductive biology. Textbook rewrite? Adult mammals may produce eggs after all.

PMID- 15016969
TI  - Nonproliferation. New initiatives reach out to Iraq's scientific elite.

PMID- 15016971
TI  - Astronomy. Hubble gazes into the universe's uncharted depths.

PMID- 15016970
TI  - Biodefense. U.S. agencies unveil plan for biosecurity peer review.

PMID- 15016972
TI  - Optics. Lens once deemed impossible now rules the waves.

PMID- 15016973
TI  - Astronomy. Galactic stripling gives a glimpse of the universe's raw youth.

PMID- 15016974
TI  - Science publishing. Japan ponders starting a global journal.

PMID- 15016975
TI  - Climate change. All downhill from here?

PMID- 15016976
TI  - Space exploration. Moon's 'abundant resources' largely an unknown quantity.

PMID- 15016977
TI  - Emerging infectious diseases. A global fire brigade responds to disease
      outbreaks.

PMID- 15016978
TI  - Plant biology. Remembrance of winter past.

PMID- 15016979
TI  - Outing the conflicted: et tu, NIH?

PMID- 15016980
TI  - Dietary restriction in Drosophila.

PMID- 15016981
TI  - Support for a colleague.

PMID- 15016982
TI  - Environment. Avoiding destructive remediation at DOE sites.

PMID- 15016983
TI  - Neuroscience. Seeing the world in the same way.

PMID- 15016984
TI  - Geochemistry. What biogenic minerals tell us.

PMID- 15016986
TI  - Physics. Electron spin polarization in nanoscale constrictions.

PMID- 15016985
TI  - Neuroscience. Blocking plasticity in the visual cortex.

PMID- 15016987
TI  - Oceanography. Microbes, molecules, and marine ecosystems.

PMID- 15016988
TI  - Immunology. Keeping the gut microflora at bay.

PMID- 15016989
TI  - Mobile elements: drivers of genome evolution.
AB  - Mobile elements within genomes have driven genome evolution in diverse ways.
      Particularly in plants and mammals, retrotransposons have accumulated to
      constitute a large fraction of the genome and have shaped both genes and the
      entire genome. Although the host can often control their numbers, massive
      expansions of retrotransposons have been tolerated during evolution. Now mobile
      elements are becoming useful tools for learning more about genome evolution and
      gene function.

PMID- 15016990
TI  - Chlorophyll d in an epiphytic cyanobacterium of red algae.

PMID- 15016991
TI  - Intersubject synchronization of cortical activity during natural vision.
AB  - To what extent do all brains work alike during natural conditions? We explored
      this question by letting five subjects freely view half an hour of a popular
      movie while undergoing functional brain imaging. Applying an unbiased analysis in
      which spatiotemporal activity patterns in one brain were used to "model" activity
      in another brain, we found a striking level of voxel-by-voxel synchronization
      between individuals, not only in primary and secondary visual and auditory areas
      but also in association cortices. The results reveal a surprising tendency of
      individual brains to "tick collectively" during natural vision. The intersubject
      synchronization consisted of a widespread cortical activation pattern correlated
      with emotionally arousing scenes and regionally selective components. The
      characteristics of these activations were revealed with the use of an open-ended
      "reverse-correlation" approach, which inverts the conventional analysis by
      letting the brain signals themselves "pick up" the optimal stimuli for each
      specialized cortical area.

PMID- 15016993
TI  - Elastomeric transistor stamps: reversible probing of charge transport in organic
      crystals.
AB  - We introduce a method to fabricate high-performance field-effect transistors on
      the surface of freestanding organic single crystals. The transistors are
      constructed by laminating a monolithic elastomeric transistor stamp against the
      surface of a crystal. This method, which eliminates exposure of the fragile
      organic surface to the hazards of conventional processing, enables fabrication of
      rubrene transistors with charge carrier mobilities as high as approximately 15
      cm2/V.s and subthreshold slopes as low as 2nF.V/decade.cm2. Multiple relamination
      of the transistor stamp against the same crystal does not affect the transistor
      characteristics; we exploit this reversibility to reveal anisotropic charge
      transport at the basal plane of rubrene.

PMID- 15016994
TI  - Dissipationless anomalous Hall current in the ferromagnetic spinel CuCr2Se4-xBrx.
AB  - In a ferromagnet, an applied electric field E invariably produces an anomalous
      Hall current JH that flows perpendicular to the plane defined by E and M (the
      magnetization). For decades, the question of whether JH is dissipationless
      (independent of the scattering rate) has been debated without experimental
      resolution. In the ferromagnetic spinel CuCr2Se4-xBrx, the resistivity rho (at
      low temperature) may be increased by several decades by varying x (Br) without
      degrading M. We show that JH/E (normalized per carrier, at 5 kelvin) remains
      unchanged throughout. In addition to confirming the dissipationless nature of JH,
      our finding has implications for the generation and study of spin-Hall currents
      in bulk samples.

PMID- 15016992
TI  - The wheat VRN2 gene is a flowering repressor down-regulated by vernalization.
AB  - Plants with a winter growth habit flower earlier when exposed for several weeks
      to cold temperatures, a process called vernalization. We report here the
      positional cloning of the wheat vernalization gene VRN2, a dominant repressor of
      flowering that is down-regulated by vernalization. Loss of function of VRN2,
      whether by natural mutations or deletions, resulted in spring lines, which do not
      require vernalization to flower. Reduction of the RNA level of VRN2 by RNA
      interference accelerated the flowering time of transgenic winter-wheat plants by
      more than a month.

PMID- 15016995
TI  - Glass formation at the limit of insufficient network formers.
AB  - Inorganic glasses normally exhibit a network of interconnected, covalent-bonded,
      structural elements that has no long-range order. In silicate glasses, the
      network formers are based on SiO4 tetrahedra interconnected through oxygen atoms
      at the corners. Conventional wisdom implies that alkaline and alkaline-earth
      orthosilicate materials cannot be vitrified, because they do not contain
      sufficient network-forming SiO2 to establish the needed interconnectivity. We
      studied a bulk magnesium orthosilicate glass obtained by containerless melting
      and cooling. We found that the role of network former was largely taken on by
      corner and edge sharing of highly distorted, ionic Mg-O species that adopt 4-, 5
      , and 6-coordination with oxygen. The results suggest that similar glassy phases
      may be found in the containerless environment of interstellar space.

PMID- 15016996
TI  - X-ray diffraction study of the ultrathin Al2O3 layer on NiAl110.
AB  - Ultrathin Al2O3 layers on alloys are used as templates for model catalysts,
      tunneling barriers in electronic devices, or corrosion-resistant layers. The
      complex atomic structure of well-ordered alumina overlayers on NiAl110 was solved
      by surface x-ray diffraction. The oxide layer is composed of a double layer of
      strongly distorted hexagonal oxygen ions that hosts aluminum ions on both
      octahedral and tetrahedral sites with equal probability. The alumina overlayer
      exhibits a domain structure that can be related to characteristic growth defects
      and is generated during the growth of a hexagonally ordered overlayer (Al2O3) on
      a body-centered cubic (110) substrate (NiAl).

PMID- 15016997
TI  - Microbial polysaccharides template assembly of nanocrystal fibers.
AB  - Biological systems can produce extraordinary inorganic structures and
      morphologies. The mechanisms of synthesis are poorly understood but are of great
      interest for engineering novel materials. We use spectromicroscopy to show that
      microbially generated submicrometer-diameter iron oxyhydroxide (FeOOH) filaments
      contain polysaccharides, providing an explanation for the formation of akaganeite
      pseudo-single crystals with aspect ratios of approximately 1000:1. We infer that
      the cells extrude the polysaccharide strands to localize FeOOH precipitation in
      proximity to the cell membrane to harness the proton gradient for energy
      generation. Characterization of organic compounds with high spatial resolution,
      correlated with mineralogical information, should improve our understanding of
      biomineralization mechanisms.

PMID- 15016998
TI  - Identification of polymers as major components of atmospheric organic aerosols.
AB  - Results from photooxidation of aromatic compounds in a reaction chamber show that
      a substantial fraction of the organic aerosol mass is composed of polymers. This
      polymerization results from reactions of carbonyls and their hydrates. After
      aging for more than 20 hours, about 50% of the particle mass consists of polymers
      with a molecular mass up to 1000 daltons. This results in a lower volatility of
      this secondary organic aerosol and a higher aerosol yield than a model using
      vapor pressures of individual organic species would predict.

PMID- 15016999
TI  - Induction of protective IgA by intestinal dendritic cells carrying commensal
      bacteria.
AB  - The enormous number of commensal bacteria in the lower intestine of vertebrates
      share abundant molecular patterns used for innate immune recognition of
      pathogenic bacteria. We show that, even though commensals are rapidly killed by
      macrophages, intestinal dendritic cells (DCs) can retain small numbers of live
      commensals for several days. This allows DCs to selectively induce IgA, which
      helps protect against mucosal penetration by commensals. The commensal-loaded DCs
      are restricted to the mucosal immune compartment by the mesenteric lymph nodes,
      which ensures that immune responses to commensal bacteria are induced locally,
      without potentially damaging systemic immune responses.

PMID- 15017000
TI  - Force-clamp spectroscopy monitors the folding trajectory of a single protein.
AB  - We used force-clamp atomic force microscopy to measure the end-to-end length of
      the small protein ubiquitin during its folding reaction at the single-molecule
      level. Ubiquitin was first unfolded and extended at a high force, then the
      stretching force was quenched and protein folding was observed. The folding
      trajectories were continuous and marked by several distinct stages. The time
      taken to fold was dependent on the contour length of the unfolded protein and the
      stretching force applied during folding. The folding collapse was marked by large
      fluctuations in the end-to-end length of the protein, but these fluctuations
      vanished upon the final folding contraction. These direct observations of the
      complete folding trajectory of a protein provide a benchmark to determine the
      physical basis of the folding reaction.

PMID- 15017001
TI  - Columnar architecture sculpted by GABA circuits in developing cat visual cortex.
AB  - The mammalian visual cortex is organized into columns. Here, we examine cortical
      influences upon developing visual afferents in the cat by altering intrinsic
      gamma-aminobutyric acid (GABA)-mediated inhibition with benzodiazepines. Local
      enhancement by agonist (diazepam) infusion did not perturb visual responsiveness,
      but did widen column spacing. An inverse agonist (DMCM) produced the opposite
      effect. Thus, intracortical inhibitory circuits shape the geometry of incoming
      thalamic arbors, suggesting that cortical columnar architecture depends on
      neuronal activity.

PMID- 15017002
TI  - Specific GABAA circuits for visual cortical plasticity.
AB  - Weak inhibition within visual cortex early in life prevents experience-dependent
      plasticity. Loss of responsiveness to an eye deprived of vision can be initiated
      prematurely by enhancing gamma-aminobutyric acid (GABA)-mediated transmission
      with benzodiazepines. Here, we use a mouse "knockin" mutation to alpha subunits
      that renders individual GABA type A (GABA(A)) receptors insensitive to diazepam
      to show that a particular inhibitory network controls expression of the critical
      period. Only alpha1-containing circuits were found to drive cortical plasticity,
      whereas alpha2-enriched connections separately regulated neuronal firing. This
      dissociation carries implications for models of brain development and the safe
      design of benzodiazepines for use in infants.

PMID- 15017003
TI  - De novo crypt formation and juvenile polyposis on BMP inhibition in mouse
      intestine.
AB  - Little is known about the signaling mechanisms that determine the highly regular
      patterning of the intestinal epithelium into crypts and villi. With the use of
      mouse models, we show that bone morphogenetic protein (BMP)-4 expression occurs
      exclusively in the intravillus mesenchyme. Villus epithelial cells respond to the
      BMP signal. Inhibition of BMP signaling by transgenic expression of noggin
      results in the formation of numerous ectopic crypt units perpendicular to the
      crypt-villus axis. These changes phenocopy the intestinal histopathology of
      patients with the cancer predisposition syndrome juvenile polyposis (JP),
      including the frequent occurrence of intraepithelial neoplasia. Many JP cases are
      known to harbor mutations in BMP pathway genes. These data indicate that
      intestinal BMP signaling represses de novo crypt formation and polyp growth.

PMID- 15017006
TI  - Prothrombin fragment 1+2 is associated with carotid intima-media thickness in
      subjects free of clinical cardiovascular disease.
AB  - BACKGROUND AND PURPOSE: Thrombin, a central enzyme in the clotting cascade, plays
      a role not only in thrombosis but also in the progression of atherosclerosis. We
      studied the relationship between prothrombin fragment 1+2 (F1+2), a specific
      marker of thrombin generation in vivo, and carotid intima-media thickness (IMT),
      an index of subclinical atherosclerosis. METHODS: We examined 181 asymptomatic
      middle-aged subjects (mean age 55.6 years, 76.7% men) free of overt clinical
      atherosclerotic disease. F1+2 was measured by enzyme-linked immunosorbent assay
      and IMT by duplex ultrasonography of carotid artery. Multiple linear regression
      analysis was used to assess the relationship between the 2 parameters. RESULTS:
      Compared with individuals in the lowest tertile of F1+2, those in the upper
      tertile (>0.55 nmol/L) showed significantly higher IMT (P<0.01). In correlation
      analysis, a positive relationship was found between plasma F1+2 and carotid IMT.
      F1+2 also correlated positively with cholesterol (P<0.008) and low-density
      lipoprotein cholesterol (P<0.005), but not with blood pressure or body mass
      index. In the multivariate analysis, the association of F1+2 with carotid IMT
      remained significant (P<0.001) after adjustment for age, sex, body mass index,
      systolic blood pressure, cholesterol, diabetes, and smoking. CONCLUSIONS: In a
      population sample of adults without clinically overt atherosclerotic disease, the
      plasma levels of F1+2 were significantly associated with carotid IMT, suggesting
      a relationship between thrombin generation and the development atherosclerosis.

PMID- 15017007
TI  - Morphometry of medial gaps of human brain artery branches.
AB  - BACKGROUND AND PURPOSE: The bifurcation regions of the major human cerebral
      arteries are vulnerable to the formation of saccular aneurysms. A consistent
      feature of these bifurcations is a discontinuity of the tunica media at the apex
      of the flow divider. The objective was to measure the 3-dimensional geometry of
      these medial gaps or "medial defects." METHODS: Nineteen bifurcations and 2
      junctions of human cerebral arteries branches (from 4 male and 2 female subjects)
      were formalin-fixed at physiological pressure and processed for longitudinal
      serial sectioning. The apex and adjacent regions were examined and measurements
      were made from high-magnification photomicrographs, or projection microscope
      images, of the gap dimensions at multiple levels through the bifurcation.
      RESULTS: Plots were made of the width of the media as a function of distance from
      the apex. The media at each edge of the medial gap widened over a short distance,
      reaching the full width of the media of the contiguous daughter vessel. Medial
      gap dimensions were compared with the planar angle of the bifurcation, and a
      strong negative correlation was found, ie, the acute angled branches have the
      more prominent medial gaps. CONCLUSIONS: A discontinuity of the media at the apex
      was seen in all the bifurcations examined and was also found in the junction
      regions of brain arteries. We determined that the gap width is continuous with
      well-defined dimensions throughout its length and average length-to-width ratio
      of 6.9. The gaps were generally centered on the prominence of the apical ridge.

PMID- 15017008
TI  - Alcohol consumption and risk of stroke among middle-aged men: the JPHC Study
      Cohort I.
AB  - BACKGROUND AND PURPOSE: The impact of light-to-moderate alcohol consumption on
      risk of stroke has not been well examined in a single study, although the effect
      is hypothesized to differ among stroke subtypes from meta-analyses. METHODS: A
      total of 19 544 men aged 40 to 59 years living in communities were followed-up
      from 1990 to 1992 to the end of 2001 in the Japan Public Health Center-based
      Prospective Study on Cancer and Cardiovascular Disease (JPHC Study). RESULTS:
      After 214 504 person-years of follow-up, 694 incident strokes were documented, of
      which 611 were confirmed by imaging studies or autopsy, including 219
      intraparenchymal hemorrhages, 73 subarachnoid hemorrhages, and 319 ischemic
      strokes. Alcohol consumption was positively associated with age-adjusted risk of
      total stroke with a 68% excess risk among drinkers of > or =450 g ethanol per
      week compared with occasional drinkers. This excess risk was confined primarily
      to hemorrhagic stroke, which remained statistically significant even after
      controlling for hypertension and other cardiovascular risk factors (RR: 2.15; 95%
      CI: 1.22 to 3.79). There was a lower risk of ischemic stroke, more specifically
      lacunar infarction, a higher risk of hemorrhagic stroke, and no excess risk of
      total stroke among drinkers of 1 to 149 g ethanol per week compared with
      occasional drinkers; the respective multivariate RR (95% CI) was 0.59 (0.37 to
      0.93), 0.43 (0.22 to 0.87), 1.73 (0.98 to 3.07), and 0.98 (0.71 to 1.36).
      CONCLUSIONS: We found differential effects of light-to-moderate alcohol
      consumption on risks of hemorrhagic and ischemic strokes among middle-aged men.
      Light-to-moderate alcohol consumption, ie, < or =2 drinks per day, does not raise
      the risk of total stroke.

PMID- 15017009
TI  - Prehospital neuroprotective therapy for acute stroke: results of the Field
      Administration of Stroke Therapy-Magnesium (FAST-MAG) pilot trial.
AB  - BACKGROUND AND PURPOSE: To demonstrate that paramedic initiation of intravenous
      magnesium sulfate (Mg) in the field in focal stroke patients is feasible, safe,
      and yields significant time-savings compared with in-hospital initiation of
      neuroprotective therapy. METHODS: We performed an open-label clinical trial.
      Inclusion criteria were: (1) likely stroke as identified by the Los Angeles
      Prehospital Stroke Screen; (2) age 45 to 95; and (3) treatment initiation within
      12 hours of symptom onset. Paramedics initiated 4 g Mg loading dose in the field,
      followed by 16 g over 24 hours in hospital. RESULTS: Twenty patients were
      enrolled, with mean age 74 (range 44 to 92), and 50% were male. Final diagnosis
      was acute cerebrovascular disease in all (ischemic 80%, hemorrhagic 20%). Study
      agent infusion began a median of 100 minutes after symptom onset (range 24 to
      703), and 70% received study agent within 2 hours of onset. The interval from
      paramedic arrival on scene to study agent start was: field-initiated, 26 minutes
      (range 15 to 64) versus in-hospital initiated (historic controls), 139 minutes
      (range 66 to 300; P<0.0001). Paramedics rated patient status on hospital arrival
      as improved 20%, worsened 5%, and unchanged 75%. Median NIHSS on hospital arrival
      was 11 in all patients and 16 in patients unchanged since field treatment start.
      Good functional outcome at 3 months (Rankin < or = 2) occurred in 60%. No serious
      adverse events were associated with field therapy initiation. CONCLUSIONS: Field
      initiation of Mg sulfate in acute stroke patients is feasible and safe.
      Prehospital trial conduct substantially reduces on-scene to needle time and
      permits hyperacute delivery of neuroprotective therapy.

PMID- 15017010
TI  - Volume-regulated anion channels are the predominant contributors to release of
      excitatory amino acids in the ischemic cortical penumbra.
AB  - BACKGROUND AND PURPOSE: Release of excitatory amino acids (EAA) is considered a
      cause of neuronal damage in ischemia. We investigated the sources and mechanisms
      of EAA release using microdialysis in regions of incomplete ischemia where
      perfusion was reduced by 50% to 80%, by applying inhibitors of volume-regulated
      anion channels (VRACs) and the GLT-1 glutamate transporter. METHODS: Reversible
      middle cerebral artery occlusion (rMCAo) was induced in anesthetized rats using
      the intraluminal suture technique. Microdialysate concentrations of glutamate,
      aspartate, and taurine were measured before, during 2 hours of rMCAo, and for 2
      hours after rMCAo. Vehicle, dihydrokainate (DHK, 1 mmol/L), a GLT-1 inhibitor, or
      tamoxifen (50 micromol/L), a VRAC inhibitor, were administered continuously via
      the dialysis probes starting one hour prior to ischemia. RESULTS: During
      incomplete ischemia, dialysate glutamate levels averaged 1.74+/-0.31 micromol/L
      (SEM) in the control group (n=8), 2.08+/-0.33 micromol/L in the DHK group (n=7),
      and were significantly lower at 0.88+/-0.30 micromol/L in the tamoxifen group
      (n=9; P<0.05). As perfusion returned toward baseline levels, EAA levels declined
      in the vehicle and tamoxifen-treated animals but they remained elevated in the
      DHK-treated animals. CONCLUSIONS: In contrast to previous results in severely
      ischemic regions, DHK did not reduce EAA release in less severely ischemic brain,
      suggesting a diminished role for transporter reversal in these areas. These
      findings also support the hypothesis that in regions of incomplete ischemia,
      release of EAAs via VRACs may play a larger role than reversal of the GLT-1
      transporter.

PMID- 15017011
TI  - Mechanical thrombolysis in acute ischemic stroke with endovascular photoacoustic
      recanalization.
AB  - BACKGROUND AND PURPOSE: We present the results of endovascular photoacoustic
      recanalization (EPAR) treatment for acute ischemic stroke from the Safety and
      Performance Study at 6 centers in Europe and North America. The objectives of
      mechanical thrombolysis are rapid vessel recanalization and minimal use of
      chemical thrombolysis. METHODS: This study was a prospective, nonrandomized
      study. The National Institutes of Health Stroke Scale (NIHSS) score and the
      modified Rankin Scale (mRS) score were recorded before treatment. The presence of
      recanalization was assessed by angiography. To measure outcome, follow-up
      examinations were performed at 24 hours, 7 days, and 30 days after stroke onset.
      RESULTS: Thirty-four patients (median NIHSS 19) were enrolled. Ten patients had
      internal carotid artery occlusion, 12 patients had middle cerebral artery
      occlusion, 11 patients had vertebrobasilar occlusion, and 1 patient had posterior
      cerebral artery occlusion. The overall recanalization rate was 41.1% (14/34).
      Complete EPAR treatment was possible in 18 patients (median NIHSS 18), with
      vessel recanalization in 11 patients (61.1%) after EPAR. The average lasing time
      was 9.65 minutes. Incomplete EPAR treatment (16/34, median NIHSS 19) was defined
      as intention to treat with EPAR and that the EPAR microcatheter entered the
      patient. Additional treatment with intraarterial application of rTPA occurred in
      13 patients. An adverse event associated with use of the device occurred in 1
      patient. Symptomatic hemorrhages occurred in 2 patients (5.9%). The mortality
      rate was 38.2%. CONCLUSIONS: This study demonstrates the safety and technical
      feasibility of EPAR. This new technique may provide another treatment option in
      the therapeutic armamentarium for patients with acute ischemic stroke.

PMID- 15017012
TI  - Positron emission tomography examination of cerebral blood flow and glucose
      metabolism in young CADASIL patients.
AB  - BACKGROUND AND PURPOSE: CADASIL causes repeated ischemic strokes leading to
      subcortical vascular dementia. The purpose of this study was to assess whether
      cerebral blood flow (CBF) and regional cerebral metabolic rates of glucose
      (rCMR(gluc)) in CADASIL patients are affected in early adulthood. METHODS: CBF
      and rCMR(gluc) were examined with positron emission tomography in correlation
      with magnetic resonance imaging (MRI) in 14 adult (19 to 41 years) CADASIL
      patients with the Notch3 R133C mutation. Seven patients had experienced transient
      ischemic attack and 3 had experienced > or =1 strokes. RESULTS: The mean CBF in
      the CADASIL patients was significantly lower in both frontal (P=0.019) and
      occipital (P=0.009) white matter (WM) than those in the controls. CBF decreased
      significantly with increased severity of the disease. The patients had lower mean
      rCMR(gluc) values than the controls, although differences were not statistically
      significant. Sum scores of semiquantitative MRI rating scale (Scheltens)
      correlated significantly with WM CBF but not with rCMR(gluc). CONCLUSIONS: In
      CADASIL, there is an early and significant decrease in the CBF of WM associated
      with simultaneous MRI changes. These are obviously caused by the arteriopathy in
      long penetrating arteries and indicate early tissue damage, also expressed as
      impaired rCMR(gluc) in the WM.

PMID- 15017013
TI  - Leukocyte count as an independent predictor of recurrent ischemic events.
AB  - BACKGROUND AND PURPOSE: Inflammatory markers predict first-time ischemic events.
      We investigated whether leukocyte and differential counts predict recurrent
      events and ischemic events in high-risk populations, and whether such events are
      preceded by acutely exacerbated inflammation. METHODS: We studied 18 558 patients
      with ischemic stroke, myocardial infarction, or peripheral arterial disease who
      participated in the trial of Clopidogrel versus Aspirin in Patients at Risk of
      Ischemic Events (CAPRIE), a study that compared the occurrence of ischemic
      stroke, myocardial infarction, or vascular death under randomized treatment with
      aspirin or clopidogrel. Leukocyte counts were frequently assessed during
      followup. RESULTS: Compared with the quartile with lowest leukocyte counts at
      baseline (<5.9x10(9)/L), patients in the top quartile (>8.2x10(9)/L) had higher
      risks for ischemic stroke (relative risk 1.30; P=0.007), myocardial infarction
      (relative risk 1.56, P<0.001), and vascular death (relative risk 1.51; P<0.001)
      after adjustment for other risk factors. Neutrophil counts contributed most to
      increased risk. Assessments of regression dilution effects based on replicate
      measurements show that these risk associations may underestimate the real
      associations by 30 to 50%. Treatment with aspirin or clopidogrel did not
      influence predictive effects by leukocytes. In the week before a recurrent event,
      but not at earlier time points, the leukocyte count was significantly increased
      over baseline levels (n=211; mean difference +0.46x10(9)/L; P=0.005).
      CONCLUSIONS: Leukocyte counts and mainly neutrophil counts are independently
      associated with ischemic events in these high-risk populations. An increase of
      leukocyte counts over baseline levels heralds a period of increased risk lasting
      about one week.

PMID- 15017014
TI  - How much should one rely on computed tomography in patients with TIA in the era
      of diffusion-weighted magnetic resonance imaging?

PMID- 15017015
TI  - Smoking, estrogen, and membrane microviscosity in women.

PMID- 15017016
TI  - Imaging the ischemic penumbra with 18F-fluoromisonidazole in a rat model of
      ischemic stroke.
AB  - BACKGROUND AND PURPOSE: The ischemic penumbra is a major focus of stroke
      research. 18F-fluoromisonidazole (18F-FMISO), a positron emission tomography
      (PET) marker of hypoxic cells, has shown promise as a technique to image the
      penumbra in humans. Our aim was to delineate the pattern of 18F-FMISO binding in
      a rat middle cerebral artery transient thread-occlusion model, and correlate this
      with tissue outcome at 24 hours. We hypothesized that the pattern of 18F-FMISO
      binding would mimic that seen in humans. METHODS: Thirty-eight rats underwent 2
      hours transient middle cerebral artery (MCA) occlusion, and then received 18F
      FMISO at time points from 0.5 to 22 hours post-MCA occlusion and were killed 2
      hours later. Autoradiographic assessment of 18F-FMISO binding and assessment
      (triphenyltetrazolium chloride) of the area of infarction were performed on
      tissue slices. RESULTS: Until 1 hour after MCA occlusion, 18F-FMISO binding was
      increased in the entire MCA territory, with little or no infarction visible. Over
      the next 5 hours, the pattern of binding evolved to a small rim of intensely
      binding tissue surrounding the infarct core, which itself showed reduced binding
      compared with the contralateral hemisphere. By 24 hours, there was minimal
      accumulation of 18F-FMISO binding and a large area of infarction. CONCLUSIONS:
      The pattern of 18F-FMISO binding rats reproduced the pattern seen in humans,
      consistent with this tracer being a marker of the ischemic penumbra in both
      species. This technique may have application in studying the ischemic penumbra in
      animal models, and correlating this with similar studies in humans.

PMID- 15017017
TI  - Hypoxia/ischemia modulates G protein-coupled receptor kinase 2 and beta-arrestin
      1 levels in the neonatal rat brain.
AB  - BACKGROUND AND PURPOSE: Neurotransmitters, neuropeptides, chemokines, and many
      other molecules signal through G protein-coupled receptors (GPCRs). GPCR kinases
      (GRKs) and beta-arrestins play a crucial role in regulating the responsiveness of
      multiple GPCRs. Reduced expression of GRK and beta-arrestins leads to
      supersensitization of GPCRs and will thereby increase the response to
      neuropeptides and neurotransmitters. We analyzed GRK and beta-arrestin expression
      after cerebral hypoxia/ischemia (HI). MATERIALS AND METHODS: Twelve-day-old rat
      pups were exposed to 90 minutes of hypoxia (fraction of inspired oxygen [FiO2]
      0.08) after ligation of the right carotid artery, a procedure that induces
      unilateral damage in the right hemisphere. At 6, 12, 24, and 48 hours after HI,
      the left (hypoxic) and right (hypoxic/ischemic) hemispheres were analyzed for GRK
      and beta-arrestin protein and mRNA expression by Western blotting and real-time
      polymerase chain reaction, respectively. In addition, we analyzed GRK2 expression
      in the hippocampus by immunohistochemistry. RESULTS: HI downregulated GRK2
      protein expression in both hemispheres at 24 to 48 hours after HI, and the effect
      was more pronounced in the ipsilateral hemisphere. HI induced no global change in
      GRK6 protein expression. However, GRK2 was markedly decreased in the hippocampal
      region of the ipsilateral hemisphere that will be severely damaged after HI. No
      changes in global mRNA levels for GRK2 were detected. In contrast, HI increased
      beta-arrestin-1 protein expression as well as mRNA levels at 6 to 12 hours after
      HI. CONCLUSIONS: Neonatal HI-induced brain damage is associated with specific
      changes in the GPCR desensitization machinery. We hypothesize that these changes
      result in supersensitization of multiple GPCRs and might therefore contribute to
      HI-induced brain damage.

PMID- 15017018
TI  - Combined intravenous and intra-arterial recanalization for acute ischemic stroke:
      the Interventional Management of Stroke Study.
AB  - BACKGROUND AND PURPOSE: To investigate the feasibility and safety of a combined
      intravenous (IV) and intra-arterial (IA) approach to recanalization in patients
      with ischemic stroke. MATERIALS AND METHODS: Subjects ages 18 to 80 with an NIH
      Stroke Scale (NIHSS) > or =10 at baseline had IV recombinant tissue plasminogen
      activator (rt-PA) started (0.6 mg/kg, 60 mg maximum over 30 minutes) within 3
      hours of onset. Additional rt-PA was then administered via microcatheter at the
      site of the thrombus up to a total dose of 22 mg over 2 hours of infusion or
      until thrombolysis. Primary comparisons were with similar subsets of placebo and
      rt-PA-treated subjects from the NINDS rt-PA Stroke Trial. RESULTS: The 80
      subjects had a median baseline NIHSS score of 18. The median time to initiation
      of IV rt-PA was 140 minutes as compared with 108 minutes for placebo and 90
      minutes for rt-PA-treated subjects in the NINDS rt-PA Stroke Trial. The 3-month
      mortality in Interventional Management Study (IMS) subjects (16%) was numerically
      lower but not statistically different than the mortality of placebo (24%) and rt
      PA-treated subjects (21%) in the NINDS rt-PA Stroke Trial. The rate of
      symptomatic intracerebral hemorrhage (6.3%) in IMS subjects was similar to that
      of rt-PA-treated subjects (6.6%) but higher than the rate in placebo-treated
      subjects (1.0%, P=0.018) in the NINDS rt-PA Stroke Trial. IMS subjects had a
      significantly better outcome at 3 months than NINDS placebo-treated subjects for
      all outcome measures (odds ratios > or =2). CONCLUSIONS: A randomized trial of
      standard IV rt-PA as compared with a combined IV and IA approach is needed.

PMID- 15017019
TI  - Measurement of carotid plaque volume by 3-dimensional ultrasound.
AB  - BACKGROUND AND PURPOSE: Measurement of carotid plaque volume and its progression
      are important tools for research and patient management. In this study, we
      investigate the observer variability in the measurement of plaque volume as
      determined by 3-dimensional (3D) ultrasound (US). We also investigate the effect
      of interslice distances (ISD) and repeated 3D US scans on measurement
      variability. Materials and Methods Forty 3D US patient images of plaques (range,
      37.43 to 604.1 mm3) were measured by manual planimetry. We applied ANOVA to
      determine plaque volume measurement variability and reliability. Plaque volumes
      were measured with 9 ISDs to determine the effect of ISD on measurement
      variability. Additional plaque volumes were also measured from multiple 3D US
      scans to investigate repeated scan acquisition variability. Results Intraobserver
      and interobserver measurement reliabilities were 94% and 93.2%, respectively.
      Plaque volume measurement variability decreased with increasing plaque volume
      (range, 27.1% to 2.2%). Measurement precision was constant for ISDs between 1.0
      and 3.0 mm, whereas plaque volume measurement variability increased with ISD.
      Repeated 3D US scan measurements were not different from single-scan measurements
      (P=0.867). Conclusions The coefficient of variation in the measurement of plaque
      volume decreased with plaque size. The volumetric change that must be observed to
      establish with 95% confidence that a plaque has undergone change is approximately
      20% to 35% for plaques <100 mm3 and approximately 10% to 20% for plaques >100
      mm3. Measurement precision was unchanged for ISDs <3.0 mm, whereas measurement
      variability increased with ISD. Repeated 3D US scans did not affect plaque volume
      measurement variability.

PMID- 15017020
TI  - Atrial natriuretic peptide gene polymorphisms and risk of ischemic stroke in
      humans.
AB  - BACKGROUND AND PURPOSE: A precise definition of genetic factors responsible for
      common forms of stroke is still lacking. The purpose of the present study was to
      investigate the contributory role of the genes encoding atrial natriuretic
      peptide (ANP) and type A natriuretic peptide receptor (NPRA) in humans'
      susceptibility to develop ischemic stroke. METHODS: Allele and genotype
      frequencies of ANP and NPRA were characterized in an Italian case-control study
      with patients affected by vascular disease or risk factors. Subjects were
      recruited from the island of Sardinia (206 cases, 236 controls). RESULTS: A
      significant association between the ANP/TC2238 polymorphic site and stroke
      occurrence was found when a recessive model of inheritance was assumed. The risk
      conferred by this mutant genotype, when estimated by multivariate logistic
      regression analysis, was 3.8 (95% confidence interval, 1.4 to 10.9). A
      significantly increased risk of stroke recurrence was observed among cases
      carrying the ANP/CC2238 genotype compared with cases carrying the ANP/TT2238
      genotype (P=0.04). No direct association of NPRA with stroke occurrence was
      detected. However, a significant epistatic interaction between the ANP/CC2238
      genotype and an allelic variant of NPRA led to a 5.5-fold increased risk of
      stroke (95% confidence interval, 1.5 to 19.4). CONCLUSIONS: Our findings support
      a direct contributory role of ANP to stroke in humans. A significant interaction
      between ANP and NPRA on stroke occurrence was found.

PMID- 15017021
TI  - Molecular pathology of severe combined immunodeficiency in mice, horses, and
      dogs.
AB  - Severe combined immunodeficiency (SCID) is an inherited disorder of humans, mice,
      horses, and dogs, in which affected individuals are incapable of generating
      antigen-specific immune responses. It occurs when lymphocyte precursors fail to
      differentiate into mature lymphocytes because of mutations within recombinase
      activating genes 1 and 2 or within the genes encoding deoxyribonucleic acid (DNA)
      dependent protein kinase (DNA-PK). It also occurs when differentiated lymphocytes
      are incapable of completing signal transduction pathways because of defects in
      cell surface receptors for interleukins (IL). A spontaneous mutation in DNA-PKcs
      of BALB/c mice results in SCID, as do experimentally induced mutations in RAG1
      and RAG2. SCID in horses results from a spontaneous mutation in DNA-PKcs. Two
      molecular mechanisms account for SCID in dogs. Jack Russell Terriers have a
      mutation within the DNA-PKcs gene, whereas Cardigan Welsh Corgi and Basset Hound
      have different defects in the gene encoding the gamma chain that is common to the
      receptors for IL-2, -4, -7, -9, -15, and -21. The location of the mutation within
      target genes influences the spectrum of diseases observed in affected animals.

PMID- 15017022
TI  - The vagus nerve is one route of transneural invasion for intranasally inoculated
      influenza a virus in mice.
AB  - Intranasally inoculated neurotropic influenza viruses in mice infect not only the
      respiratory tract but also the central nervous system (CNS), mainly the brain
      stem. Previous studies suggested that the route of invasion of virus into the CNS
      was via the peripheral nervous system, especially the vagus nerve. To evaluate
      the transvagal transmission of the virus, we intranasally inoculated unilaterally
      vagectomized mice with a virulent influenza virus (strain 24a5b) and examined the
      distribution of the viral protein and genome by immunohistochemistry and in situ
      hybridization over time. An asymmetric distribution of viral antigens was
      observed between vagal (nodose) ganglia: viral antigen was detected in the vagal
      ganglion of the vagectomized side 2 days later than in the vagal ganglion of the
      intact side. The virus was apparently transported from the respiratory mucosa to
      the CNS directly and decussately via the vagus nerve and centrifugally to the
      vagal ganglion of the vagectomized side. The results of this study, thus,
      demonstrate that neurotropic influenza virus travels to the CNS mainly via the
      vagus nerve.

PMID- 15017023
TI  - Cervical and vaginal epithelial neoplasms in cynomolgus monkeys.
AB  - Papillomavirus-associated cervical cancer is the second most common neoplasm in
      women but has rarely been reported in animals. This report describes cervical and
      vaginal intraepithelial neoplasms identified in routine histologic specimens
      obtained from 20 (5.2%) of 385 female cynomolgus macaques (Macaca fascicularis)
      being used in long-term studies. Lesion incidence was similar in both control and
      hormonally treated animals (4.7% and 5.5%, respectively). Neoplasms included
      benign vaginal papillomas, mild to severe intraepithelial dysplasias, and two
      invasive cervical carcinomas. Common morphologic features included koilocytosis,
      nuclear atypia, and expansion of the basal epithelium. Selective staining of
      lesions with at least one of three papillomavirus antibodies was observed in all
      cases (20 of 20). In contrast, immunostaining of lesions was negative for Epstein
      Barr-related virus proteins (0 of 20). The unique similarities between the
      observed lesions and those seen in women suggest that macaques may provide a
      suitable animal model for study of papillomavirus oncogenesis.

PMID- 15017024
TI  - Cyclooxygenase-2 expression in the cornea of dogs with keratitis.
AB  - Cyclooxygenase-2 (COX-2) can be overexpressed at inflammatory sites, leading to
      the generation of proinflammatory prostanoids. Selective inhibitors of COX-2 have
      potential use in treating inflammatory conditions including ophthalmic diseases
      in veterinary medicine. Keratitis is considered the most common inflammatory eye
      disease in dogs. In this study we evaluated the expression of COX-2 in normal dog
      eyes and in dog eyes with keratitis by immunohistochemistry using isoform
      specific antibodies. In the normal eye (n = 4), no COX-2 immunoreactivity was
      observed in the cornea. In keratitis, COX-2 (n = 12) expression was observed in
      all corneal layers (epithelium, stromal cells, and endothelium). COX-2
      immunoreactivity was also noted in the stromal and epithelial cells of the iris
      and the stromal cells of the trabecular meshwork. These data indicate that COX-2
      may play a pathophysiologic role in keratitis and suggest potential therapeutic
      implications of prostaglandin modulation in inflammatory eye diseases.

PMID- 15017025
TI  - Granulomatous uveitis associated with vaccination in the atlantic salmon.
AB  - This study addressed histologic and immunopathologic changes in ocular tissues
      and investigated the distribution of major histocompatibility class II (MHC class
      II)-positive cells in Atlantic salmon (Salmo salar) suffering from severe
      postvaccination disease. Twenty-nine fish with generalized inflammation, probably
      a result of vaccination, were investigated. One individual that had escaped
      vaccination was included in the study. Material was investigated by cultivation
      methods for fungi and bacteria. Histology using conventional staining procedures
      and immunohistochemistry with antisera against MHC class II beta chain were
      performed. No growth was observed from the cultivation investigations. Histology
      revealed occlusion of the lumen in the larger choroid vessels and in the
      choriocapillaris, inflammatory infiltrations and loss of structure in the choroid
      rete, and, in some cases, aggregations of multinucleated giant cells (MGC) and
      Splendore-Hoeppli material. Immunohistochemistry demonstrated massive MHC class
      II+ cellular infiltrations in the uveal tract. Such infiltrations were also seen
      in the ventral ciliary cleft, a condition that is associated with glaucoma.
      Immunoreactive cells included dendritelike cells, epithelioid cells, and MGCs.
      The endothelia of smaller vessels were frequently MHC class II+, and
      immunoreactive infiltrations were seen in the optic nerve in several individuals.
      No pathologic changes were detected in the unvaccinated individual. In
      conclusion, generalized inflammatory reactions in fish may lead to severe ocular
      inflammation, occlusion of uveal vessels, and perivascular changes with MHC class
      II+ upregulation in cells in the uveal tract and optic nerve.

PMID- 15017027
TI  - Characterization of lymphocytes in canine gastrointestinal lymphoma.
AB  - Primary canine gastrointestinal lymphoma has been believed to be of B-cell origin
      based on the morphology and behavior of the neoplastic cells and the evidence
      from the human medical field. However, the neoplasms have not to date been
      characterized as to the origin of the cell population. Forty-four cases diagnosed
      as canine gastrointestinal lymphoma were retrieved from the records of the
      Veterinary Teaching Hospitals at the University of Minnesota and the University
      of Wisconsin-Madison. Four of the cases have been previously identified as
      epitheliotropic T-cell gastrointestinal lymphoma. Twenty-three of the dogs were
      female, with 11 intact and 12 neutered, and 21 of the dogs were male, with 12
      intact and nine neutered. Sixteen breeds as well as individuals of mixed breeding
      were represented. The Boxer and the sharpei were the most commonly represented
      breeds with six individuals each. The age range of the dogs was 1.5-14.66 years,
      with two dogs identified as adult and two of unknown age. Archived tissue blocks
      of gastrointestinal samples were sectioned in duplicate and prepared for
      immunohistochemical staining with CD3 (T-cell marker) and CD20 (B-cell marker).
      In 75% of the cases examined under light microscopy, 50-95% of the neoplastic
      cells stained positively with CD3 and exhibited marked epitheliotropic behavior.
      In three of the cases, from 10% up to 50% of the neoplastic cells stained
      positively with CD20, with widely scattered CD3(+) cells. In the remainder of the
      cases, few to none of the neoplastic cells stained with either of the markers.
      This retrospective study shows that canine primary gastrointestinal lymphoma is
      more commonly of T-cell origin, rather than B-cell origin.

PMID- 15017026
TI  - Canine prostate carcinomas express markers of urothelial and prostatic
      differentiation.
AB  - Prostate carcinoma and transitional cell carcinoma (TCC) occur in the prostate
      gland of older dogs and have morphologic similarities when evaluated by light
      microscopy. The dog is a commonly used animal model for studying human prostate
      carcinoma; therefore, it is important to accurately differentiate canine prostate
      carcinomas from TCCs. We investigated whether keratin 7 (K7) and arginine
      esterase (AE) would aid differentiation of canine prostate carcinoma from TCC. K7
      expression was evaluated in normal and neoplastic canine prostate and bladder
      tissues using immunohistochemistry. The expression of AE messenger ribonucleic
      acid (mRNA) in normal and neoplastic canine prostate and bladder was detected
      using northern blots and reverse transcriptase-polymerase chain reaction (RT
      PCR). In addition, AE enzyme activity was measured in normal and neoplastic
      canine prostate and bladder tissues. We found marked similarities in K7
      expression in prostate carcinomas and TCCs. AE mRNA was present in high levels in
      normal prostatic tissue but was reduced in prostate carcinoma by northern blot
      assay. Nested RT-PCR detected AE mRNA both in TCCs (13 of 15) and in prostate
      carcinomas (13 of 13). Enzymatic activity of AE was high in normal prostate gland
      and in some prostate carcinomas, whereas normal bladder and TCCs produced lower
      levels of AE. In conclusion, K7 and AE cannot be used to differentiate TCC from
      prostate carcinoma in dogs.

PMID- 15017028
TI  - Hepatic lesions in cetaceans stranded in the Canary Islands.
AB  - This article describes the gross, histopathologic, and ultrastructural findings
      of the livers of cetaceans stranded on the coast of the Canary Islands between
      1992 and 2000. A total of 135 cetaceans were included in the study, among which
      25 were common dolphins (Delphinus delphis), 23 Atlantic spotted dolphins
      (Stenella frontalis), 19 striped dolphins (Stenella coeruleoalba), and 15 other
      species of dolphins and whales. The most common lesion observed in these animals
      was a nonspecific chronic reactive hepatitis (47/135), followed by hyaline
      intracytoplasmic inclusions in hepatocytes (33/135). Parasitic cholangitis was
      detected in 8/135 animals, whereas hepatic lipidosis was presented in 7/135
      animals. The ultrastructure of hyaline hepatocytic cytoplasmic inclusions is
      described, and possible causes of these inclusions are discussed.

PMID- 15017029
TI  - Expression of bone morphogenetic protein-6 and bone morphogenetic protein
      receptors in myoepithelial cells of canine mammary gland tumors.
AB  - To study the ectopic chondrogenesis in canine mammary mixed tumors, the
      expression of bone morphogenetic protein-6 (BMP-6) and specific BMP receptors
      (BMPRs), BMPR-IA, BMPR-IB, and BMPR-II, was examined using immunohistochemical
      and immunoblot analysis in 39 canine mammary gland tumors. Immunohistochemically,
      BMP-6 and all three types of BMPRs were coexpressed in the myoepithelial cells
      and chondrocytes in six of eight benign mixed tumors. In complex adenomas,
      myoepithelial cells showed an expression pattern of BMP-6, BMPR-IA, and BMPR-II
      similar to those in benign mixed tumors, whereas immunoreactivity for BMPR-IB was
      very mild. The myoepithelial cells proliferating within the basement membrane
      showed more intense immunoreactivity for BMP-6 and all BMPRs as compared with
      those proliferating in the interstitial areas. Western blotting analysis revealed
      immunopositive bands at 40-45 kDa for BMP-6 in the samples from simple and
      complex adenomas and benign mixed tumors. The BMPR-IB-specific bands at 45 kDa
      were most detected in benign mixed tumors. Because among BMPRs, BMPR-IB is
      thought to be the major receptor for BMP-6 for primary chondrogenesis, these
      findings suggest that the expression of BMP and its receptors on the
      myoepithelial cells might play a role in the ectopic cartilage formation in
      canine mammary gland tumors, especially in benign mixed tumors.

PMID- 15017030
TI  - Abomasal emptying defect of sheep may be an acquired form of dysautonomia.
AB  - Abomasal emptying defect (AED) is a disease syndrome that primarily affects
      Suffolk sheep and is characterized by distension and impaction of the abomasum.
      No histologic lesion has been consistently associated with this condition. There
      is no known etiology. In this study, nine cases of AED were identified by
      necropsy, including three rams and six ewes between 2 and 6 years of age. Four of
      the cases occurred sporadically, and five ewes were submitted on the same day
      from a single flock. Histologic examination of celiacomesenteric ganglia from six
      of the affected sheep revealed scattered chromatolytic or necrotic neurons,
      without inflammation. Chromatolytic neurons were observed more frequently in AED
      affected sheep than in seven healthy Suffolk sheep (P < 0.08, weak statistical
      support). Neuronal necrosis was not observed in any of the healthy sheep. Lineage
      records of the flock that suffered an outbreak were incompatible with the
      possibility of a simple inheritance pattern for this disease; furthermore, the
      very occurrence of AED in outbreak form is inconsistent with transmission solely
      by inheritance. Only one of the six tested sheep showed concurrent
      immunohistochemical evidence of scrapie. The lesion pattern in celiacomesenteric
      ganglia is suggestive of a neurotoxicosis. Neuronal lesions of AED resemble
      dysautonomic diseases of humans and other animals.

PMID- 15017031
TI  - Chronic eosinophilic dermatitis associated with persistent feline herpes virus
      infection in cheetahs (Acinonyx jubatus).
AB  - A chronic ulcerative and eosinophilic dermatitis occurred in 20 captive cheetahs
      (Acinonyx jubatus) with persistent feline herpes virus 1 (FHV1) infection.
      Affected animals had erythematous, ulcerated plaques primarily on the face and
      forelegs in sites of contact with lachrymal and salivary secretions. The
      dermatitis was characterized by dense infiltrates of eosinophils and plasma cells
      and pseudoepitheliomatous hyperplasia. Rare keratinocytes within the lesions had
      nuclei with marginated chromatin and small eosinophilic inclusions composed of
      herpes virus nucleocapsids. Virus isolated from lesions was confirmed to be FHV1.
      Lesions persisted and progressed unless removed by cryoexcision. The occurrence
      of this unusual reaction to FHV1 in approximately 5% of captive North American
      cheetahs suggests a species propensity for a Th2-dominant response to herpes
      virus infection. This atypical immune reaction may indicate a heritable trait or
      modulation of the immune response by other factors such as chronic stress.

PMID- 15017032
TI  - Solitary retinal astrocytoma in a dog.
AB  - An intraocular mass from a 13-year old Husky-mix dog was diagnosed as retinal
      astrocytoma. The mass arose from the ganglion layer of the retina and occupied
      50% of the vitreous space. The mass was immunoreactive for neuron-specific
      enolase, S-100, vimentin, and glial fibrillary acidic protein. The neoplasm had
      characteristics similar to solitary retinal astrocytomas of humans but lacked the
      marked vascularity.

PMID- 15017033
TI  - Cystic endometrial hyperplasia in elephants.
AB  - Most captive female elephants are nulliparous and aged and many have endometrial
      disease, factors that may hinder fertility. This study characterized the
      pathologic features and demographic distribution of endometrial lesions from 27
      captive Asian (Elephas maximus) and 13 African elephants (Loxodonta africanus),
      12- to 57-years of age. The principal lesion was marked cystic and polypoid
      endometrial hyperplasia (CEH), present in 67% of Asian and 15% of African
      elephants ranging from 26 to 57 years. The lower prevalence in African elephants
      likely reflects their younger age range in this study. Fourteen of 15 affected
      elephants with breeding information were nulliparous. These results suggest that
      CEH and polyps are common in aged nulliparous elephants, and the severity of
      these lesions may impair fertility. These findings will be useful in the
      interpretation of ultrasonographic findings during reproductive examinations of
      potential breeding cows. Also, breeding programs should focus on younger animals.

PMID- 15017034
TI  - Malignant ameloblastic fibro-odontoma in a dog.
AB  - An 11-year-old male Collie was presented with a swelling of the face caused by
      tumor masses arising from the gingiva. Postmortem examination revealed metastases
      to the lymph nodes, lung, liver, and orbital cavity. Histologically, the tumor
      represented a combination of fibrosarcomatous proliferation, pulpal mesenchyme,
      and undifferentiated odontogenic epithelium, with a follicular or plexiform
      growth pattern. In addition, the follicular areas of the tumor showed a biphasic
      character, and there were numerous apoptotic cells in plexiform areas.
      Furthermore, acidophilic material resembling dysplastic dentine or enamel matrix
      was observed in the metastatic lesion in the lung. Based on the histological
      characters, the present case was diagnosed as malignant ameloblastic fibro
      odontoma. This study is the first known description of a possible malignant
      ameloblastic fibro-odontoma in a dog with metastasis to distant organs.

PMID- 15017035
TI  - Extramedullary hematopoiesis in the mandibular lymph node of simian-human
      immunodeficiency virus-infected rhesus monkeys (Macaca mulatta): a report of
      three cases.
AB  - Three cases of extramedullary hematopoiesis (EMH) in the mandibular lymph nodes
      of rhesus monkeys, experimentally infected intravenously with a chimeric simian
      human immunodeficiency virus, are described. On histopathologic evaluation,
      multiple sections of mandibular lymph node from all animals showed evidence of
      EMH, which included erythroid, myeloid, or megakaryocytic precursor cells (or
      all) within the medullary sinuses. Immunohistochemistry was used for positive
      identification of multiple cell types. Evidence of EMH was not observed in
      numerous sections of axillary, inguinal, cervical, hilar, or mesenteric lymph
      nodes or in any other tissues examined. To our knowledge, this is the first
      report on EMH within the lymph nodes of rhesus monkeys without an obvious
      underlying disease process or stringent blood-sampling schedule warranting the
      need for increased hematopoiesis outside the confines of the bone marrow.

PMID- 15017036
TI  - Bovine viral diarrhea virus type 2-induced meningoencephalitis in a heifer.
AB  - The brain from a 15-month-old, black female Angus, with a 48-hour history of
      central nervous system disease, was submitted to the Oklahoma Animal Disease
      Diagnostic Laboratory. Microscopic findings consisted of acute, multifocal
      meningoencephalitis, with neuronal degeneration and necrosis and gliosis. Viral
      isolation yielded noncytopathic bovine viral diarrhea virus (BVDV). Virus
      genotyping classified the virus as BVDV type 2. Immunohistochemical labeling for
      BVDV antigens with BVD MAb 3.12F1 clone was prominent in the cytoplasm of
      neurons, glial cells, ependymal epithelium, perivascular macrophages and spindle
      cells, smooth muscle cells, and intravascular monocytes of the cerebrum and brain
      stem. Laboratory results support that tissue alterations occurred as a result of
      BVDV type 2 infection. In the absence of other clinical signs related to BVDV
      infection and using the microscopic and laboratory evidence presented, we propose
      that the BVDV type 2 isolated from this case may represent a neurovirulent strain
      of the virus. To the best of our knowledge, this is the first report of brain
      lesions and neuronal viral antigen localization in BVDV genotype 2 viral
      infection, acquired either congenitally or postnatally.

PMID- 15017038
TI  - Ribozyme- and siRNA-mediated mRNA degradation: a general introduction.

PMID- 15017037
TI  - Pathologic and immunohistochemical findings in a feline aortic body tumor.
AB  - The presence of a heart-base tumor was diagnosed by ultrasound imaging in a 10
      year-old, female, domestic shorthaired cat presenting with dyspnea and pleural
      effusion because of the presence of a modified transudate. Hematology and
      clinical chemistry were unremarkable. The owner elected euthanasia. At necropsy,
      a locally extensive, firm, multilobulated nodule surrounded the pulmonary vein.
      The tumor was composed of lobules of large polygonal cells separated by a fine
      fibrovascular stroma. Tumor cells infiltrated the myocardium, and neoplastic
      emboli were present, but no metastases were macroscopically detectable. Tumor
      cells were immunohistochemically positive for chromogranin A, for synaptophysin
      and, faintly, for neuron-specific enolase and negative for vimentin, cytokeratin,
      alpha smooth muscle actin, glial fibrillary acidic protein, thyreoglobulin, and
      calcitonin. Based on histologic and immunohistochemical findings, the diagnosis
      of chemodectoma was made.

PMID- 15017039
TI  - Combination of chemical and enzymatic RNA synthesis.
AB  - The potential of standard in vitro transcription reactions can be dramatically
      expanded, if chemically synthesized low-mol-wt compounds are used as building
      blocks in combination with standard nucleotide 5' triphosphates (NTPs). Short
      oligonucleotides that terminate in guanosine effectively compete with guanosine
      5' triphosphate (GTP) as starter building blocks, and they are incorporated at
      the 5'-end of transcripts. Applications include production of RNAs with
      "unfriendly 5'-ends" (they do not begin with G), variations of the 5'-sequence
      are possible with the same DNA template, site-specific insertion of nucleotide
      modifications, and addition of 5'-labels, such as fluorescein for detection or
      biotin for capture. Clearly, chemically synthesized, modified NTPs are inserted
      at internal sites. The combination with phosphorothioate linkages for detection
      has been developed into a powerful high-throughput method to study site-specific
      interference of modifications with RNA function.

PMID- 15017040
TI  - Determination of kinetic parameters for hammerhead and hairpin ribozymes.
AB  - The application of conventional enzymological methods to the study of hairpin and
      hammerhead ribozymes has led to valuable insights into the mechanisms by which
      these small RNAs catalyze phosphodiester cleavage and ligation reactions. Here,
      protocols are presented for measuring rate constants for simple cleavage and
      ligation reactions mediated by minimal hammerhead and hairpin ribozymes under
      standard experimental conditions. Information is also provided to help
      researchers recognize and interpret more complex reaction kinetics that can be
      observed for ribozyme-sequence variants under a variety of reaction conditions.

PMID- 15017042
TI  - Quantification of ribozyme target RNA using real-time PCR.
AB  - An important part of the ribozyme efficiency-screening process is to have a fast
      and accurate way to measure steady-state levels of the target RNA. Here, we
      describe the use of real-time polymerase chain reaction (PCR) for quantification
      of ribozyme target transcripts. In contrast to classical quantitative PCR, real
      time PCR does not require extensive manipulation or generation of relatively
      complex reagents, thus reducing the risk of contamination. PCR products generated
      by Taq polymerase in the presence of SYBR Green dye I can be monitored each cycle
      by collecting fluorescence signals emitted only as the double-stranded DNA is
      formed. The temperature at which the fluorescent data used for quantification are
      collected is based on the melting-curve analysis of the amplified product. After
      constructing a standard curve by plotting the log of the standards' copy number
      vs their fractional cycle number, the copy number of the unknown samples is
      automatically determined by interpolation of this curve. However it is very
      important to validate the melting curve profile with standard gel
      electrophoresis, particularly while setting up the technique. Real-time PCR is
      fast and reproducible. Excluding the isolation of RNA and synthesis of cDNA, the
      results can be obtained in less than 1 h. The coefficient of variance is 15% in
      the range of 104-106 gene copies.

PMID- 15017041
TI  - Real-time monitoring of RNA and DNA reactions by fluorescence detection.
AB  - Conventional analysis of nucleic acid reactions (cleavages, ligations) is
      performed with a (radioactive) labeled substrate, and reaction products (one
      aliqout for each time-point) are analyzed by gel electrophoresis followed by
      detection (X-ray film + densitometer or phosphoimager). This is a cumbersome
      approach, and involves frequent preparation of fresh labeled substrate, and
      rather limited time resolution. Real-time monitoring with non-decaying
      fluorescent labels overcomes these problems. Two analysis methods are presented
      here. Fluorescence polarization with a very broad range of applications, can be
      used for any type of RNA or DNA conversion with significant change of mol wt
      (including "gel shift"). FRET (fluorescence resonance energy transfer) depends on
      intramolecular interaction (or in a multimolecular complex) of a fluorescent dye
      ("reporter") with a quencher moiety (a guanine base or a second dye).
      Applications include detailed kinetic studies and optimizing reactions with a
      wide range of conditions and highly specific nucleic acid sequence detections,
      challenging other hybridization-based methods. Special applications are the
      introduction of catalytic nucleic acids for real-time monitoring of nucleic acid
      amplification reactions such as NASBA and PCR.

PMID- 15017043
TI  - Analysis of ribozyme structure and function by nucleotide analog interference
      mapping.
AB  - Nucleotide analog interference mapping (NAIM) is a quick and effective method to
      define concurrently, yet singly, the importance of specific functional groups at
      particular nucleotide residues in relation to the structure and function of an
      RNA. NAIM can be utilized on virtually any RNA with an assayable function,
      including catalytic RNAs. The method hinges on the ability to successfully
      incorporate, within an RNA transcript, various 5'-O-(1-thio)nucleoside analogs
      randomly via in vitro transcription. This can be achieved by using wild-type or
      Y639F mutant T7 RNA polymerase, thus creating a pool of analog-doped RNAs. When
      subjected to a selection step to separate the active transcripts from the
      inactive ones, the pool helps to identify functional groups that are crucial for
      RNA activity. The technique can be used to study ribozyme structure and function
      via monitoring of cleavage or ligation reactions, or define functional groups
      that are critical for RNA folding, RNA-RNA interactions, and RNA interactions
      with proteins, metals, or other small molecules. All major classes of catalytic
      RNAs have been examined by NAIM. This is a generalized approach that should
      provide the scientific community with the tools to better understand the RNA
      structure-activity relationship (SAR).

PMID- 15017044
TI  - Analysis of global conformational transitions in ribozymes.
AB  - The nucleolytic ribozymes are small, autonomously folding RNA species that
      require metal ions to adopt their active conformations. Three of these ribozymes
      contain one or more helical junctions, that act as key architectural elements in
      the structures. A combination of comparative gel electrophoresis and fluorescence
      resonance energy transfer (FRET) can be used to analyze the global conformation
      in solution, and to study the ion-induced folding processes. The FRET approach
      can also be extended into the time domain to analyze conformational equilibria,
      and increasingly to the single-molecule level.

PMID- 15017046
TI  - Identification of efficient cleavage sites in long-target RNAs.
AB  - In this chapter, we describe a procedure for identification of efficient
      hammerhead ribozyme (hRz) cleavage sites in target RNAs. An active hRz library,
      containing randomized recognition sequences flanked by fixed 5' and 3' regions,
      is designed to generate enormous diversity. The library is incubated with target
      RNA at an elevated temperature in the absence of magnesium, and bound library
      pools are isolated, reamplified, and rebound to target RNA. After two rounds, the
      active preselected library pool is incubated at 37 degrees C with target RNA in
      the presence of magnesium, and cleavage products are directly identified on
      sequencing gels. The protocol identifies highly active hRz, which typically have
      Kms of 20-80 nM, and kcat/Km values of 10(6).

PMID- 15017045
TI  - In vivo detection of ribozyme cleavage products and RNA structure by use of
      terminal transferase-dependent PCR.
AB  - Terminal transferase-dependent PCR (TDPCR) can be used after reverse
      transcription to analyze RNA. This method (RT-TDPCR) is able to provide in vivo
      information at nucleotide-level resolution, and has been used for study of
      ribozymes, RNA size, RNA structure, and RNA-protein interactions. A detailed
      protocol of RT-TDPCR is presented here with examples of its use in detecting
      ribozyme cleavage intermediates in yeast and a RNA transcription start site in
      mammalian cells.

PMID- 15017047
TI  - Selection in vitro of allosteric ribozymes.
AB  - The capacities of RNA for both catalysis and molecular recognition have been
      appreciated for some time. Recently, a number of studies have shown that these
      distinct functional classes may be combined to generate multipartite ribozymes in
      which the catalytic and ligand-binding elements act coordinately. In this
      chapter, we describe a procedure known as allosteric selection, in which an RNA
      catalyst in conjunction with a random sequence domain is subjected to iterative
      in vitro selection in order selectively to recover ligand-dependent ribozymes.

PMID- 15017048
TI  - Regulation of ribozyme cleavage activity by oligonucleotides.
AB  - Here, we describe allosteric ribozymes, which are activated by the addition of a
      short regulator oligonucleotide. The allosteric hammerhead ribozyme, which
      contains a single-stranded loop instead of stem II, exhibited minimal cleavage of
      the target RNA; however, it becomes active by the addition of oligonucleotides
      that bind to the ribozyme. We have also carried out in vitro selection to obtain
      an allosteric hairpin ribozyme, which is activated with a short oligonucleotide.
      The ribozyme contains the characteristic hairpin loop with the structure that
      changes upon regulator oligonucleotide binding. Since both regulations are
      sequence-specific, ribozymes containing different sequences can be positively and
      independently controlled by a specific oligonucleotide. Furthermore, these
      allosteric hairpin loops have the ability to control the activities of other
      functional RNAs.

PMID- 15017050
TI  - Ribozyme expression systems.
AB  - We have succeeded in constructing an effective system for the expression of
      ribozymes under the control of a human tRNAVal promoter, which ensures a high
      level of production of ribozymes in vivo. The engineered tRNAVal-driven
      ribozymes, based on computer-predicted secondary structure, were relatively
      stable and were transported to the cytoplasm, where they could be colocalized
      with their target RNA. The activity of the exported ribozymes was significantly
      higher than that of ribozymes that remained in the nucleus. This chapter examines
      the methods for construction of the appropriate vector that can produce tRNA
      driven ribozymes with high-level intracellular activity and for analysis of the
      constructs in cells.

PMID- 15017049
TI  - Tetracycline-regulated expression of hammerhead ribozymes in vivo.
AB  - A major obstacle to achieving constitutive ribozyme expression in cells is that
      expression or elimination of the target gene may provide either a growth
      advantage or disadvantage to the cells that express ribozyme. Many approaches
      have been used to overcome this problem, mostly based on the effort to create
      conditional or inducible expression systems. In this chapter, we describe the
      most common choice for overcoming this problem, tetracycline-regulated ribozyme
      expression. This system consists of two central components: transcriptional
      transactivators that interact specifically with bacterial cis-regulatory elements
      and antibiotics that can modulate the binding of the transactivators at low and
      nontoxic doses. Here, we summarize protocols to generate cell lines expressing
      tetracycline-regulated ribozyme constructs.

PMID- 15017051
TI  - Design and expression of chimeric U1/ribozyme transgenes.
AB  - The U1snRNA/ribozyme/antisense construct (designated U1/ribozyme) is a chimeric
      transgene that has proven to be very useful for inhibiting the expression of
      targeted genes in vitro and in vivo. It consists of a combination of hammerhead
      ribozyme flanked by target-specific antisense sequences that are in turn flanked
      by the loops and promoter of U1 snRNA. To construct U1/ribozymes,
      antisense/ribozyme sequences are first designed corresponding to ribozyme
      cleavage consensus "GUC" sequences that are present in the targeted mRNA.
      Antisense/ribozyme sequences are then inserted between the U1 snRNA loops, and
      the conceptual secondary structure of the encoded regulatory RNA is analyzed to
      ensure proper folding. Appropriate antisense/ribozymes are then synthesized as
      oligonucleotides, annealed, and ligated into the pU1 vector containing the U1
      snRNA promoter and loops to yield the pU1/ribozyme expression vector. Constructs
      can then be transiently or stably expressed in vitro and in vivo to inhibit the
      expression of target genes. U1/ribozymes can also be expressed in viral vectors
      for more efficient transfection, or complexed to liposomes for systemic delivery.

PMID- 15017052
TI  - Design and validation of therapeutic hammerhead ribozymes for autosomal dominant
      diseases.
AB  - Hammerhead ribozymes are small, catalytic RNAs that can be designed to
      effectively inhibit gene expression in an allele-specific manner. It is the high
      level of sequence discrimination, coupled with the minimal cleavage-site
      requirements of hammerhead ribozymes, that makes these catalytic RNAs so amenable
      for use as therapeutic agents for autosomal dominant diseases. Here, we present a
      detailed set of protocols for the design and validation of hammerhead ribozymes
      for the treatment of autosomal dominant disease, with specific examples of
      hammerhead ribozymes targeted against human P23H rod opsin mRNA, a major cause of
      dominant retinitis pigmentosa.

PMID- 15017053
TI  - Helicase-attached novel hybrid ribozymes.
AB  - Ribozymes have potential as therapeutic agents and in functional studies of genes
      of interest. The activities of ribozymes in vivo depend on the accessibility of
      ribozymes to a cleavage site in the target RNA. At present, the selection of a
      target site for ribozymes is often based on a computer-aided structural analysis
      of the target RNA or trial-and-error experiments in which vast numbers of
      ribozymes are tested systematically. To overcome this problem, we have engineered
      intracellularly produced ribozymes with unwinding activity in vivo. We found that
      attachment to ribozymes (hybrid ribozymes) of an RNA motif with the ability to
      interact with intracellular RNA helicases, which create hybrid ribozymes,
      enhances ribozyme activity significantly in vivo. Thus, hybrid ribozymes can
      catalyze cleavage at the specified target site within an RNA in vivo almost
      independently of the secondary or tertiary structure of the target RNA around the
      cleavage site.

PMID- 15017054
TI  - Functional gene discovery using hybrid ribozyme libraries.
AB  - Hybrid ribozymes that couple the cleavage activity of hammerhead ribozymes with
      the unwinding activity of RNA helicases are powerful tools in the study of cell
      genetics and pharmaceutical drug development. They are useful for targeting a
      specific gene as well as screening functional genes to show phenotypic
      alterations. By randomizing the binding arms within the ribozymes, we can create
      a library of ribozymes that are capable of cleaving any mRNA. After introducing
      the library into cells and recovering the sequence information of ribozymes that
      alter the cell phenotype of interest, genes that are responsible for the specific
      phenotype can be identified. This chapter describes a method known as the gene
      discovery system to identify novel functional genes related to a specific
      phenotype. Our gene-discovery system should be a powerful tool for post-genome
      research.

PMID- 15017055
TI  - Maxizyme technology.
AB  - Ribozymes are small and versatile nucleic acids that can cleave RNAs at specific
      sites. These molecules have great potential to be used as effective gene
      therapeutic agents. However, because of the limitation for cleavable sequences
      within the target mRNA, in some cases conventional ribozymes have failed to
      exhibit precise cleavage specificity. A maxizyme is the dimer of minimized
      ribozymes (minizymes), which can specifically cleave two distinct target sites.
      The maxizyme also has an allosteric function in that it can form an active
      conformation and cleave the two target sites only when it recognizes two distinct
      target sites. We demonstrated previously that an allosterically controllable
      maxizyme was a powerful tool in the disruption of an abnormal chimeric RNA (bcr
      abl) in cells and in mice. Furthermore, more than five custom-designed maxizymes
      have clearly demonstrated these allosteric functions in vitro and in vivo. Thus,
      maxizyme technology is not limited to one specific case, but may have broad
      general applicability in molecular biology and in molecular gene therapy.

PMID- 15017056
TI  - Target-site selection for the 10-23 DNAzyme.
AB  - The 10-23 DNAzyme is capable of cleaving RNA with high sequence specificity at
      sites that contain purine-pyrimidine (R-Y) junctions. Although they are abundant
      in mRNA, many of these potentially cleavable junctions are protected from DNAzyme
      activity by secondary structure. To optimise the process of target-site selection
      in long RNA substrates, a multiplex assay was developed for simultaneous
      comparative analysis of 50 or more different DNAzymes in one reaction. Using this
      approach, the efficiency of 80 DNAzyme sites within the E6 component of a full
      length HPV16 E6/E7 transcript was examined. The activity of molecules selected in
      this system was then compared in a conventional assay with DNAzymes of
      intermediate and low performance. This confirmed the results observed in the
      multiplex reactions, with 10% of DNAzymes inducing substantial cleavage of the
      long transcript. These DNAzyme-sensitive regions are potentially accessible to
      other RNA directed agents such as ribozymes or antisense oligonucleotides.
      Therefore, in addition to finding the most effective DNAzymes for a particular
      target mRNA, this method may also be applicable to locating accessible sites for
      other nucleic acid-based gene suppression strategies.

PMID- 15017057
TI  - In vitro selected RNA-cleaving DNA enzymes from combinatorial libraries.
AB  - The selective inactivation of a target gene by antisense mechanisms is an
      important biological tool in the delineation of gene functions. Ribozymes and RNA
      cleaving DNA enzymes-mediated approaches are more attractive because of their
      ability to catalytically cleave the target RNA. DNA enzymes have recently gained
      great importance because they are short DNA molecules with simple structures that
      are expected to be stable to the nucleases present inside a mammalian cell. We
      have designed a strategy to identify accessible cleavage sites in human
      immunodeficiency virus-1 (HIV-1) gag RNA from a pool of random DNA enzymes, and
      for isolation of DNA enzymes. A pool of random sequences 29 nucleotides long that
      contained the previously identified 10-23 catalytic motif were tested for their
      ability to cleave the target RNA. When the pool of random DNA enzymes was
      targeted to cleave between A and U nucleotides, a DNA enzyme 1836 was identified.
      Although several DNA enzymes were identified using a pool of DNA enzyme that was
      completely randomized with respect to its substrate-binding properties, DNA
      enzyme-1810 was selected for further characterization. Both the DNA enzymes
      showed target-specific cleavage activities in the presence of Mg2+ only. These
      strategies could be applied for the selection of desired target sites in any
      target RNA.

PMID- 15017058
TI  - Nucleic acid sequence analysis using DNAzymes.
AB  - The sequence specificity of the "10-23" RNA-cleaving DNA enzyme can be utilized
      to discriminate between subtle differences in nucleic acid sequence. We examined
      this potential by comparing the cleavage activity of DNAzymes that target
      sequences derived from a relatively conserved segment of the L1 gene from
      different human papillomavirus (HPV) genotypes. DNAzyme activity was found to be
      highly sensitive to mismatches between its binding domain and substrate sequences
      containing polymorphisms. Type-specific DNAzyme-cleavable substrates can also be
      generated by genomic PCR using a chimeric primer containing three bases of RNA.
      The RNA component enables each amplicon to be cleavable in the presence of its
      matching DNAzyme. In this format, the specificity of DNAzyme cleavage is defined
      by Watson-Crick interactions between one substrate-binding domain (arm I) and the
      polymorphic sequence that is amplified during polymerase chain reaction (PCR).
      DNAzyme-mediated cleavage of amplicons generated by this method was used to
      examine the HPV status of genomic DNA derived from Caski cells, which are known
      to be positive for HPV16. This method is applicable to many types of nucleic acid
      sequence variation, including single-nucleotide polymorphisms (SNPs).

PMID- 15017059
TI  - Crystallization of the hairpin ribozyme: illustrative protocols.
AB  - Conditions and techniques that result in successful crystallization differ from
      RNA to RNA. However, there are some general principles that facilitate
      crystallization of most RNAs. Three procedures that were instrumental in
      obtaining well-ordered crystals of the hairpin ribozyme are described in this
      chapter. These are: i) the design of a series of candidate crystallization
      constructs; ii) the evaluation of conditions to obtain monodisperse RNA; and iii)
      the use of seeding techniques to separate nucleation and growth events during
      crystallization. These procedures can be usefully adapted for the crystallization
      of other RNAs.

PMID- 15017060
TI  - An experimental method for selecting effective target sites and designing hairpin
      ribozymes.
AB  - The proper selection of target sites and the correct design of specific ribozymes
      are decisive initial steps in any attempt to perform ribozyme-mediated gene
      silencing. Combinatorial methodologies can be used to improve ribozyme targeting
      and design. The in vitro selection strategy described in this chapter uses a
      combinatorial library of potentially self-cleaving RNA molecules. The hairpin
      ribozyme is attached to the target mRNA, and is adequately randomized to generate
      a population representing all possible substrate specificities. The selection
      procedure yields information on the best target sites, and provides information
      about optimal ribozyme sequences. Thus, this method helps in the rational design
      of efficient hairpin ribozymes for targeting purposes, and avoids trial-and-error
      assays usually associated with theoretical ribozyme design.

PMID- 15017061
TI  - Design and optimization of sequence-specific hairpin ribozymes.
AB  - The hairpin ribozyme belongs to a group of small catalytic RNAs that have been
      extensively used to trans-cleave RNA molecules. Many efforts have been made to
      elucidate its reaction mechanism, and there is great interest in designing
      hairpin ribozymes with improved catalytic activity for use in the development of
      agents that specifically inactivate RNA molecules. This chapter summarizes the
      general principles in the design of hairpin ribozymes for targeting purposes, and
      provides a brief overview of the well-characterized modifications of the ribozyme
      sequences and structural domains that are necessary for optimal activity. The
      main features of the target sequence are also examined and other procedures or
      modifications of interest are also discussed.

PMID- 15017062
TI  - Design, targeting, and initial screening of sTRSV-derived hairpin ribozymes for
      optimum helix 1 length and catalytic efficiency in vitro.
AB  - Hairpin ribozymes derived from the negative strand of satellite RNAs from the
      tobacco ringspot virus (sTRSV) can be engineered to target and cleave a variety
      of heterologous RNAs from both cellular and viral transcripts. Attention to
      design and targeting rules and optimization of helix 1 length and catalytic
      efficiency in vitro may increase the efficacy of hairpin ribozymes in reducing
      the expression of targeted transcripts. Here, principles for the design and
      targeting of sTRSV-derived hairpin ribozymes are described, as well as methods
      and materials for optimizing helix 1 length, and for conducting an initial screen
      of catalytic efficiency to identify promising candidates for further evaluation.
      Examples are provided for hairpin ribozymes that target human and mouse
      transforming growth-factor beta (TGF-beta), as well as human polycystic kidney
      disease gene 1 (PKD1) and JC virus large T-antigen. The tetraloop modification of
      the sTRSV hairpin ribozyme is considered superior to designs based on the native
      sTRSV hairpin ribozyme, given its potential to yield considerable improvements in
      stability and catalytic efficiency.

PMID- 15017063
TI  - Optimization and application of the group I ribozyme trans-splicing reaction.
AB  - Group I ribozymes are naturally occurring catalytic RNAs that are able to excise
      themselves as introns (group I introns) from a precursor RNA, and to ligate the
      flanking exons. Group I ribozymes can be engineered to act in trans by
      recognizing a separate RNA molecule in a sequence specific manner, and to
      covalently link an RNA sequence to this separate RNA molecule. This ribozyme
      transesterification reaction has potential in molecular biology and in medicine
      as a new approach to gene therapy. Here we describe detailed optimized protocols
      where trans-splicing group I ribozymes are applied in mapping accessible sites in
      target messenger RNA, and in messenger RNA-repair by correcting mutations.

PMID- 15017064
TI  - Repair of myotonic dystrophy protein kinase (DMPK) transcripts by trans-splicing
      ribozymes.
AB  - The Tetrahymena group I intron ribozyme is an RNA molecule of approx 400 bases
      that is capable of base-specific RNA trans-splicing. These properties can be
      applied to repair mutations at the RNA level, and therefore can restore normal
      cellular functions in diseased cells. The purpose of this chapter is to present
      the methodology that can be used to repair mutations responsible for myotonic
      dystrophy. The design and construction of group I intron ribozymes and their
      transfection in myotonic dystrophy cells will be among the sections described in
      this chapter.

PMID- 15017065
TI  - General design and construction of RNase P ribozymes for gene-targeting
      applications.
AB  - RNase P ribozyme, such as M1 RNA, the catalytic RNA subunit of RNase P from
      Escherichia coli, cleaves an RNA helix that resembles the acceptor stem and T
      stem structure of its natural ptRNA substrate. When covalently linked with a
      guide sequence, the M1 ribozyme can function as a sequence-specific endonuclease,
      M1GS RNA, and cleave any target RNA sequences that basepair with the guide
      sequence. Using the mRNA coding for the major transcription regulatory protein
      ICP4 of herpes simplex virus 1 (HSV-1) as the model target, we describe in this
      chapter the general design and construction of M1GS ribozymes for gene-targeting
      applications. Specifically, methods are described in detail to determine ideal
      target regions of an mRNA for M1GS ribozymes and to construct highly active RNase
      P ribozymes that target these regions. Extensive protocols for in vitro synthesis
      of the ribozymes and for the cleavage assay of the ribozyme activity are also
      included. These methods are intended to provide general guidelines for the design
      and construction of M1GS ribozymes for gene-targeting applications.

PMID- 15017066
TI  - In vitro selection of RNase P ribozymes that efficiently cleave a target mRNA.
AB  - An in vitro selection procedure for identifying highly efficient RNase P ribozyme
      (M1GS RNA) variants is presented as a model system for engineering ribozymes to
      improve their catalytic efficiency. Detailed protocols as well as the rationale
      for setting up such a system are included, using the mRNA sequence that encodes
      the thymidine kinase (TK) of herpes simplex virus 1 (HSV 1) as a target substrate
      of choice. Using the selection system, we have successfully generated M1GS RNA
      variants that more efficiently cleave the TK mRNA in vitro and more effectively
      inhibit the TK expression in cultured cells than the ribozyme derived from the
      wild-type RNase P ribozyme sequence. The in vitro selection system represents a
      novel and effective approach for engineering highly active RNase P ribozymes that
      can be used in both basic research and clinical therapeutic settings.

PMID- 15017067
TI  - In vitro selection of external guide sequences for directing human RNase P to
      cleave a target mRNA.
AB  - External guide sequences (EGSs) are oligonucleotides that consist of a sequence
      that is complementary to a target mRNA and recruit intracellular RNase P for
      specific degradation of the target RNA. Recent studies indicate that increasing
      the targeting activity of EGSs in directing human RNase P to cleave an mRNA in
      vitro can lead to better efficacies of the EGSs in inducing RNase P-mediated
      inhibition of the expression of the target mRNA in cultured cells. This chapter
      will describe the procedure for the generation of highly functional EGSs by in
      vitro selection. We also describe protocols for in vitro evaluation of the
      activity of the EGSs. These methods should provide general guidelines for using
      in vitro selection for generating highly active EGSs for gene-targeting
      applications.

PMID- 15017068
TI  - RNase P-mediated inhibition of viral growth by exogenous administration of short
      oligonucleotide external guide sequence.
AB  - The use of external guide sequence (EGS) in directing endogenous ribonuclease P
      (RNase P) for inhibition of viral propagation is described in this chapter, with
      an emphasis on chemically modified EGSs and their extracellular delivery.
      Targeting of the mRNA-encoding human cytomegalovirus (HCMV) protease by DNA-based
      EGSs is presented as an example of how to design chemically modified EGSs for
      antiviral applications. General information about the EGS-based technology is
      included, followed by detailed protocols for EGS design, human RNase P
      purification, in vitro assay of EGS activity, liposome-mediated delivery of
      chemically modified EGSs and detection of their distribution in cells, and an
      assay of EGS activity for blocking growth of HCMV in cultured cells.

PMID- 15017069
TI  - RNase P ribozyme as an antiviral agent against human cytomegalovirus.
AB  - Human cytomegalovirus (HCMV) represents one of the most medically important human
      viruses and causes a wide spectrum of human diseases, including birth defects and
      mental retardation in newborns, common opportunistic infections in acquired
      immunodeficiency syndrome (AIDS) patients (e.g., CMV-associated retinitis and
      pneumonia), and possibly cardiovascular diseases such as atherosclerosis. This
      chapter describes the utilization of RNase P ribozyme-specifically, M1GS
      ribozyme, as a gene-targeting agent for blocking HCMV gene expression and growth.
      The target for the RNase P ribozyme is the overlapping region of the mRNAs that
      code for HCMV major transcription factors IE1 and IE2, which are essential for
      viral gene expression and replication. The methods described in this chapter
      focus primarily on i) construction of the retroviral vector for expression of
      M1GS ribozymes in cultured cells, ii) generation of stable cell lines expressing
      ribozymes, iii) determination of the expression of M1GS RNAs in human cells, and
      iv) evaluation of the efficacy of ribozymes in inhibiting HCMV IE1/IE2 expression
      and viral growth. Using these methods, we successfully constructed M1GS RNAs
      against the IE1/IE2 mRNA sequence and recently showed that a reduction of up to
      150- to 3000-fold in HCMV growth is found in cells that express the ribozymes.

PMID- 15017070
TI  - Inhibition of gene expression by nucleic acid enzymes in rodent models of human
      disease.
AB  - Nucleic acid enzymes have emerged as a versatile technique for sequence-specific
      gene silencing in a wide range of cells. However, the question remains as to
      whether, for example, DNA enzymes and ribozymes are functional in animals. In
      this chapter, we describe two different rodent models of human diseases--namely,
      leukemia and chronic heart failure. We specifically reduced Raf-1 expression in
      leukemic mice using an anti-Raf-1 DNA enzyme. A continuous supply of this
      catalytic molecule led to a substantial reduction in leukemic-cell burden and
      survival. Rats with postinfarction heart failure were treated with a DNA enzyme
      targeting TNFa, and this led to a substantial improvement of cardiac function
      concomitant with a restoration of the hemodynamic status of the animals. The
      described protocols should facilitate the in vivo evaluation of other
      oligonucleotide-based therapy such as small interfering RNAs (siRNAs).

PMID- 15017071
TI  - Potential design rules and enzymatic synthesis of siRNAs.
AB  - Small interfering RNAs (siRNAs) have emerged as a powerful technique for sequence
      specific gene silencing in a wide variety of organisms. However, the base
      composition of the siRNA sequence is not the only determinant of efficacy.
      Intrinsic factors related to mRNA structures are likely to be crucial
      determinants for siRNA activity. Indeed, placing the recognition site of an
      active siRNA into a structured mRNA region has abrogated the siRNA activity.
      Therefore, a successful gene-targeting project may require the design of many
      distinct siRNAs at a high cost. Here, potential design rules, cost-effective
      strategies for producing siRNAs by T7 RNA polymerase, and expression cassettes
      for in vivo testing are described.

PMID- 15017072
TI  - RNA interference (RNAi) with RNase III-prepared siRNAs.
AB  - Small interfering RNA (siRNA) has become a powerful tool for selectively
      silencing gene expression in cultured mammalian cells. Because different siRNAs
      of the same gene have varying silencing capacities, several different siRNAS
      typically must be screened to obtain a region that will effectively silence the
      gene of interest. However, RNA interference with synthetic siRNA is inefficient
      and cost-intensive, especially for large, functional genomic studies. Here, we
      describe the use of E. coli endoribonuclease III to cleave double-stranded RNA
      (dsRNA) into esiRNA (endoribonuclease-prepared siRNA) that can target multiple
      sites within an mRNA. EsiRNA mediates effective RNA interference with no apparent
      nonspecific effects in cultured mammalian cells. Since the whole gene can be used
      at once, screening for an active siRNA for an individual gene is eliminated.
      Because of its simplicity and potency, this approach is useful for large-scale
      analysis of mammalian gene function.

PMID- 15017073
TI  - RNAi expression vectors in mammalian cells.
AB  - RNA interference (RNAi) is a recently developed technique for gene silencing by
      introducing dsRNA into cells, and it is shown to work in mammalian cells when
      siRNAs are used. Several groups have developed vector-based siRNA expression
      systems that can induce RNAi in living cells. These vector systems use a pol III
      promoter, such as U6 or H1, and are classified into two groups based on the form
      of expressed RNAs: tandem-type and hairpin-type. Here, we describe how to
      generate these siRNA expression vectors and outline the experimental procedure
      for suppressing the expression of a reporter gene by transient transfection of a
      siRNA expression vector.

PMID- 15017074
TI  - Gene-array analysis of glioma cells after treatment with an anti-PKCalpha siRNA:
      a general protocol.
AB  - Post-transcriptional gene silencing is a powerful tool to reveal gene function.
      In this chapter, we have used gene-array technology to analyze changes in gene
      expression after specific targeting of the protein kinase Calpha isoform with
      small interfering RNAs (siRNAs). Expression profiles were investigated on a human
      gene array of 588 key genes involved in DNA synthesis, apoptosis, cell-cell
      communication, intracellular signal-transduction pathways, cell-surface molecules
      and transcription factors. The data indicate that siRNAs are an ideal tool for
      target validation, and show that RNA-dependent RNA polymerase is not required for
      RNAi in mammalian cells.

PMID- 15017075
TI  - RNAi in living mice.
AB  - By introducing double-stranded RNAs (dsRNAs), it was shown that mRNAs that share
      sequences are destroyed, and that the translation step is severely downregulated
      (RNAi). This technique was demonstrated to be a very powerful tool for reverse
      genetics in Caenorhabditis elegans. However, studies have shown that RNAi can be
      achieved in living mice. In this chapter, we used "green mice" and "green rats"
      as model animals to demonstrate silencing of green fluorescent protein (GFP)
      expression by RNAi. In order to silence the gene, we produced transgenic mouse
      lines that produce dsRNA that is driven by the H1 promoter. It was demonstrated
      that the transgenically expressed, double stranded RNA could silence the GFP
      throughout the body of the mouse or rat and throughout the lifetime.

PMID- 15017076
TI  - Construction and transfection of PCR products expressing siRNAs or shRNAs in
      mammalian cells.
AB  - In mammalian cells, the RNA interference (RNAi) effect has been observed through
      expression of 21-23 base transcripts capable of forming duplexes, or via
      expression of short hairpin RNAs. Here, we describe a facile polymerase chain
      reaction (PCR)-based strategy for rapid synthesis and evaluation of small
      interfering RNAs (siRNA) expression units in mammalian cells. The siRNA
      expression constructs are constructed by PCR, and the PCR products are directly
      transfected into mammalian cells for functional testing. This method is fast and
      inexpensive, allowing several different siRNA gene candidates to be rapidly
      screened for efficacy.

PMID- 15017077
TI  - Systemic delivery of synthetic siRNAs.
AB  - The ability to regulate endogenous gene expression by cleaving mRNA is important
      in basic and applied biological research. This is now driven predominantly by
      small interfering RNAs (siRNAs) as they induce sequence-specific gene silencing.
      However, the major obstacle to the use of siRNAs as therapeutics is the
      difficulty involved in effective in vivo delivery. This chapter describes the
      liposomal delivery of siRNAs into adult mice.

PMID- 15017078
TI  - Adenovirus-delivered siRNA.
AB  - RNA interference is the process that double-stranded RNA (dsRNA) induces the
      homology-dependent degradation of cognate mRNA mediated by 21- to 23-nt small
      interfering RNA (siRNA). Successful application of RNAi in functional genomics
      and proteomics, cancer gene therapy, and virus protection depends on the
      efficient delivery of siRNA into mammalian cells. The availability of high virus
      titer, infection of a broad spectrum of cell types, and independence on active
      cell division makes adenovirus the vector of choice for siRNA delivery. To this
      end, we developed a new adenovirus shuttle vector designated as pShuttle-H1 to
      host H1-RNA promoter and unique BglII and HindIII sites for insertion of oligos
      for expression of siRNA. In this chapter, we describe an adenovirus system that
      uses a commercially available adenovirus system and pShuttle-H1 to deliver siRNA
      expressing cassette into cells to silence a specific gene in mammalian cells.

PMID- 15017079
TI  - RNAi expression vectors in plant cells.
AB  - Suppression by double-stranded RNA (dsRNA) of expression of a target gene is
      known as RNA interference (RNAi). Tobacco BY-2 cell suspension has been used as a
      model cultured plant cell, because it is possible to produce populations of
      tobacco BY-2 cell suspensions that are uniform and divide synchronously for
      functional gene analysis. Here, we describe a method to induce RNAi by
      introducing a hairpin-type dsRNA expression vector into BY-2 cells via
      electroporation. This methodology should facilitate the analysis of individual
      gene function in plant cells.

PMID- 15017080
TI  - Delivery agents for oligonucleotides.
AB  - This chapter provides a basic overview of most of the oligonucleotide delivery
      systems available for an in vitro use. Two major classes are described: systems
      that act through an endocytosis process (e.g., lipid-based vectors,
      nanoparticles, and polycations) and systems that by-pass this endocytosis process
      (e.g., peptides and pore-forming agents). Each technique is briefly described to
      allow a critical choice of the best delivery systems suitable for specific
      purposes in cultured cells.

PMID- 15017081
TI  - Selection of peptides for specific delivery of oligonucleotides into cancer
      cells.
AB  - In this chapter, phage-display peptide technology has been used to select
      peptides that internalize into breast-cancer cells. The used biopanning procedure
      provides information on the best peptide to be used. When one of the selected
      peptides was conjugated to an antisense oligonucleotide against the ErbB2
      receptor, specific delivery to breast-cancer cells was demonstrated. The
      established biopanning procedure should help in the rational selection of cancer
      targeting peptides for specific delivery of DNA and RNA oligonucleotides into
      cancer cells.

PMID- 15017082
TI  - Clinical gene therapy research utilizing ribozymes: application to the treatment
      of HIV/AIDS.
AB  - Antiretroviral drug therapy can effectively reduce the viral load, and is
      associated with a degree of immune reconstitution in human immunodeficiency virus
      (HIV)-infected patients. However, the presence of a latent viral reservoir, the
      development of drug resistance, drug toxicity, and compliance problems are
      obstacles that impede full eradication of HIV through drug therapy. The cellular
      introduction of genetic elements that are capable of inhibiting HIV replication
      is conceptually appealing as a potential new treatment paradigm for acquired
      immunodeficiency syndrome (AIDS). In theory, this approach can lead to the
      development of regenerated hematopoiesis with cells that inhibit viral
      replication and are protected from the pathogenic effects of HIV. Ribozymes are
      catalytic RNA molecules that can efficiently and selectively cleave target RNA.
      By ex vivo retroviral transduction, we have introduced a HIV-1 tat gene-targeted
      ribozyme (RRz2) and a control construct (LNL6) into granulocyte-colony
      stimulating factor (G-CSF) mobilized CD34+ hematopoietic progenitor cells (HPC).
      Transduced autologous CD34+ cells (an approximately equal mix of RRz2 and LNL6)
      were infused in 10 patients in this Phase I study. After a median follow-up of
      2.5 yr, gene presence and expression were detected by a sensitive polymerase
      chain reaction (PCR) assay in a transduced-CD34+ cell dose-dependent manner. In
      this chapter, we describe general considerations related to HIV hematopoietic
      progenitor-cell gene therapy trial design, implementation, and safety, with an
      emphasis on the critical steps of this process, namely vector production and
      characterization, target-cell selection, transduction, final product release
      testing, and evaluation of vector presence.

PMID- 15017083
TI  - Critical steps in the implementation of hematopoietic progenitor-cell gene
      therapy using ribozyme vectors: a laboratory protocol.
AB  - The implementation of a hematopoietic progenitor-cell gene-therapy program
      involves the performance of laboratory procedures and compliance with the current
      code of Good Manufacturing Practices. This chapter explains the multiple
      laboratory steps used in our recent Phase I gene transfer study for HIV. This
      study employed a retroviral vector to deliver an anti-HIV ribozyme to CD34+
      hematopoietic progenitor cells.

PMID- 15017084
TI  - Structure of incommensurate ammonium tetrafluoroberyllate studied by structure
      refinements and the maximum entropy method.
AB  - Incommensurately modulated ammonium tetrafluoroberyllate (AFB) occurs in a narrow
      temperature interval between the paraelectric room-temperature phase with space
      group Pnma (Ti = 178 K) and the ferroelectric low-temperature phase with space
      group Pna2(1) (Tc = 173 K). The structure is determined from accurate single
      crystal X-ray diffraction data collected with synchrotron radiation at 175 K. The
      superspace group of the structure is Pnma(alpha00)0ss with alpha = 0.4796 (4).
      Both structure refinements and the maximum entropy method lead to the same
      structure model, which involves only single harmonic modulations. The building
      units of the structure are BeF4(2-) and NH4+ complex ions with approximately
      tetrahedral point symmetry. They are relatively rigid and the modulations consist
      mainly of translations of the tetrahedra and their rotations around a fixed axis.
      The modulation is related to changes in the network of the hydrogen bonds. The
      low-temperature superstructure can be described as a commensurately modulated
      structure with the same superspace symmetry. The first harmonic modulations of
      the low-temperature and incommensurate phases are related by a scale factor with
      a value of approximately two. In addition, the low-temperature phase exhibits a
      second harmonic modulation that is responsible for shifts along c and the
      ferroelectricity in this phase. The experimental data of the incommensurate phase
      do not contain any evidence for the presence of a second harmonic in the
      modulation functions. This suggests that the development of the second harmonic,
      i.e. the development of the spontaneous polarization, is responsible for the lock
      in transition.

PMID- 15017085
TI  - Calcium-lead fluoro-vanadinite apatites. I. Disequilibrium structures.
AB  - The synthetic vanadinites (Pb(x)Ca(10-x))(VO4)6F2delta, 1 < x < 9, adopt a
      P6(3)/m apatite structure with 9.7590 (1) < or = a < or = 10.1179 (1) A and
      7.0434 (3) < or = c < or = 7.4021 (1) A. The partitioning of calcium and lead
      over the AI(4f) and AII(6h) positions is nonstoichiometric with lead
      preferentially entering the larger AII site. High-resolution electron microscopy
      showed that samples annealed for 10 h at 1073 K are in disequilibrium with
      calcium- and lead-rich microdomains co-existing at unit-cell scales. For
      (Pb5Ca5)(VO4)6F2delta, sintering in excess of 2 weeks is required for the metals
      to order macroscopically. As annealing progresses, c/a, the partitioning
      coefficient kPb(AI/AII) and the AIO6 metaprism twist angle (phi) adjust
      cooperatively to enlarge the apatite channel, and thereby accommodate higher lead
      content. These results demonstrate that phi is a sensitive measure of
      disequilibrium and a useful device for monitoring changes in apatite topology as
      a function of composition.

PMID- 15017086
TI  - Calcium-lead fluoro-vanadinite apatites. II. Equilibrium structures.
AB  - The synthetic vanadinites (Pb(x)Ca(10-x))(VO4)6(F(1-2y)O(y) (y))2, 0.57 < x < 9
      and 0.10 < y < 0.47, adopt the P6(3)/m apatite structure with 9.7835 (3) < or = a
      < or = 10.0531 (1) A and 7.0318 (2) < or = c < or = 7.3033 (1) A. The calcium
      endmember is monoclinic, space group P2(1)/m, with a = 9.7370 (3), b = 9.7358
      (4), c = 7.00572 (9) A, gamma = 120.002 (5) degrees. For mixed metal compounds (x
      not equal to 0) the partitioning of calcium and lead over the AI(4f) and AII(6h)
      positions is nonstoichiometric, with lead preferentially favouring the larger AII
      site at a partitioning coefficient kPb(AI/AII) approximately 0.33 for all x < 7.
      A miscibility gap exists for 2 < x < 3. Trends in crystallographic parameters can
      be correlated through consideration of the AIO6 metaprism twist angle (phi) that
      can be used to derive ideal cell parameters from triangular anion networks.

PMID- 15017087
TI  - The surprisingly elusive crystal structure of sodium metabisulfite.
AB  - The crystal structure of Na2S2O5, a simple and common ionic compound, is reported
      here for the first time. The crystals form non-merohedral twins, with the twin
      domains related by a twofold axis which bisects the angle between the a and c
      axes of each unit cell. The structure was determined from a single-crystal
      fragment of a twinned crystal that had undergone cleavage along the twin
      boundary. In addition to the problems associated with twinning, space-group
      determination proved difficult as well, with the structure initially determined
      in the P2(1) space group appearing to be disordered with two rotational
      conformers of the metabisulfite ion occupying equivalent sites in the lattice. An
      analysis at low temperature provided new weak reflections which were inconsistent
      with the original unit cell, but indexed to the correct unit cell, allowing for
      space group and crystal structure determination. The apparent structure, which
      appeared disordered in P2(1), seems to have resulted from an apparently
      fortuitous superposition of two conformationally inequivalent S2O5(2-) anions in
      the asymmetric unit of the correct structure in the P2(1)/n space group. The
      metabisulfite ions in this structure do not adopt the C(s) geometry observed in
      previously determined crystal structures containing S2O5(2-). The structures of
      both ions in the asymmetric unit are effectively conformational mirror images of
      one another with two of the O atoms on each S atom in the ion approaching an
      eclipsed geometry. This observation provides further evidence that the structures
      of sulfur-oxy anions in the solid state are dictated mainly by interionic
      coulombic forces rather than by intraionic bonding interactions

PMID- 15017088
TI  - Pressure and temperature effects on the degree of symmetry and chirality of the
      molecular building blocks of low quartz.
AB  - We establish quantitative correlations between pressure and temperature (PT)
      changes, and the degree of symmetry and of chirality of the main molecular
      building blocks of low quartz that these PT changes induce. The distortion from
      ideal tetrahedral symmetry, from helicity (deviation from C2 symmetry), and the
      level of chirality are evaluated quantitatively using the continuous-symmetry and
      chirality-measures approach. These measures are global and reflect all changes in
      bond angles and bond lengths. The specific molecular building blocks analyzed are
      the SiO4 elementary building block (which is found to be chiral!), the Si(OSi)4
      unit, the second-shell SiSi4 tetrahedron [composed of the five Si atoms of
      Si(OSi)4] and the four-tetrahedra helix fragment, -O(SiO3)4-. The temperature and
      pressure effects on symmetry and chirality were found to mirror each other in all
      building blocks. By employing this quantitative approach to symmetry and
      chirality we were able to combine the pressure effects and temperature effects
      into a unified picture. Furthermore, the global nature of the symmetry measure
      allows the comparison of the behavior of isostructural materials such as germania
      and quartz. For these crystals it has been shown that the symmetry/chirality
      behavior of germania at low pressures is a predictor for the behavior of these
      structural properties in quartz at higher pressures. Finally, given that the
      rigid SiO4 unit undergoes only minor structural changes, it has been a useful
      observation that the symmetry/chirality of the small SiSi4 tetrahedron is a very
      sensitive probe for the symmetry and chirality changes in quartz as a whole.

PMID- 15017089
TI  - New bond-valence parameters for lanthanides.
AB  - The bond-valence method, especially the valence-sum rule, is very useful for
      checking if the structures formed by trivalent lanthanides are correct. In this
      work bond-valence parameters (Rij), which connect bond valences and bond lengths,
      have been computed for a large number of bonds taken from the Cambridge
      Structural Database, Version 5.24 (2002) [Allen (2002). Acta Cryst. B58, 380
      388]. The calculated values of bond-valence parameters for metal-organic
      compounds decrease with an increase in lanthanide atomic number; the Rij values
      are also smaller than bond-valence parameters calculated for inorganic compounds.
      A summary of bond-valence sums calculated for Rij given in this work and reported
      in the literature, and a functional correlation between lanthanide-oxygen
      distances and coordination number are presented.

PMID- 15017090
TI  - An investigation of H-atom positions in sulfuric acid crystal structures.
AB  - Hydrogen conformations in crystalline H2SO4.8H2O and H2SO4.6.5H2O have been
      studied using a system developed by Hirsch [(2003), Z. Anorg. Allg. Chem. 629,
      666-672]. New H-atom coordinates, as estimated from DFT calculations, are given
      for these structures.

PMID- 15017092
TI  - Two tautomers in one crystal: 4(5)-nitro-5(4)-methoxyimidazole.
AB  - The case of prototropic annular tautomerism in an imidazole derivative has been
      found. The crystal structure contains a 50:50 mixture of two tautomers: 4-nitro-5
      methoxyimidazole and 5-nitro-4-methoxyimidazole. The X-ray experiment actually
      shows the superposition of these compounds; it appears as if the structure is
      centrosymmetric and the N-H hydrogen atoms are disordered over two ring N atoms.
      Owing to the hydrogen-bond pattern, the values of their site occupation factors
      have to be exactly equal to 1/2. The molecules are connected into a three
      dimensional network by means of N-H...N and C-H...O hydrogen bonds.

PMID- 15017091
TI  - Atomic volumes and charges in a system with a strong hydrogen bond: L-tryptophan
      formic acid.
AB  - A high-resolution X-ray diffraction data set was collected within 48 h at 100 K
      with synchrotron radiation and area detection. A full topological analysis was
      applied to the resulting electron-density model. This analysis was followed by a
      Bader partitioning making use of the zero-flux surfaces of the electron-density
      gradient vector field. The atomic and bonding properties obtained were compared
      with the results of previous experimental studies, and with theoretical
      calculations for the title complex and free tryptophan as reported in the
      literature. The agreement between experiment and theory is similar to the
      agreement between different theoretical calculations. There is no charge transfer
      via the strong hydrogen bond; however, its strength is indicated by the very
      small atomic volume of the H atom involved.

PMID- 15017093
TI  - 2-Biphenylol revisited.
AB  - The substantially disordered structure of 2-biphenylol [Perrin et al. (1987).
      Acta Cryst. C43, 980-982; Kapon & Reisner (1988). Acta Cryst. C44, 2039] has been
      reinvestigated as a function of temperature. The structure was determined at 305,
      294, 145 and 90 K; crystals were taken to the lowest temperature both rapidly and
      slowly (0.1 K min(-1)). The results of the previous room-temperature study were
      confirmed and no important structural change was found down to 90 K. Comparisons
      with structures known for other simple 2- and 2,2'-substituted biphenyl
      derivatives suggest that the molecular stacks found for 2-biphenylol are probable
      for related molecules. The disorder in 2-biphenylol allows the formation of some
      O-H...O bonds, but packing efficiency is a more important factor in this
      structure than is hydrogen bonding.

PMID- 15017094
TI  - Crystal structure of the supramolecular linear polymer formed by the self
      assembly of mono-6-deoxy-6-adamantylamide-beta-cyclodextrin.
AB  - Mono-6-deoxy-6-adamantylamide-beta-cyclodextrin-dimethylformamide-15H2O,
      C53H85NO35.C3H7NO.15H2O, crystallizes in the orthorhombic space group
      P2(1)2(1)2(1). The adamantyl group is inserted into the cyclodextrin cavity of
      the adjacent molecule, entering by the side of the secondary hydroxy rim, thus
      forming a supramolecular linear polymer by self-assembly. Adjacent macrocycles
      are linked into columns by hydrogen bonds involving the nearest glucose residues,
      and the structure is further stabilized by their involvement in hydrogen bonding
      with water molecules which reside in channels surrounding the polymer columns,
      thus acting as bridges between the cyclodextrin units. The centroid of the
      adamantyl group lies below the plane formed by the seven glycosidic O atoms of
      the host cyclodextrin, excluding water molecules from the secondary side of beta
      cyclodextrin (beta-CD). Between the adamantyl group and the primary hydroxy rim
      of the cyclodextrin cavity lies a dimethylformamide molecule, which shields the
      hydrophobic adamantyl group from the primary hydroxy rim of its carrying beta-CD
      and excludes water molecules from the primary side of the beta-CD cavity.

PMID- 15017095
TI  - Structural studies of (N-phenylthioureidoalkyl- and -aryl)phosphonates.
AB  - The crystal structures of three (N-phenylthioureidoalkyl- and -aryl)phosphonates,
      i.e. diphenyl [(3-phenylthioureido)phenylpropyl]phosphonate, diphenyl [1-(3
      phenylthioureido)benzyl]phosphonate and diphenyl [2,2-dimethyl-1-(3
      phenylthioureido)propyl]phosphonate, have been determined by X-ray diffraction.
      The conformations of the title molecules, the geometry of the thioureide
      fragments and molecular packing arrangements are analyzed and compared with
      literature data.

PMID- 15017096
TI  - Structures of piperazine, piperidine and morpholine.
AB  - The crystal structures of piperazine, piperidine and morpholine have been
      determined at 150 K. All three structures are characterized by the formation of
      NH...N hydrogen-bonded chains. In piperazine these are linked to form sheets, but
      the chains are shifted so that the molecules interleave. In morpholine there are
      in addition weak CH...O interactions. Topological analyses show that these three
      structures are closely related to that of cyclohexane-II, which can be described
      in terms of a pseudo-cubic close-packed array of molecules in a familiar ABC
      layered arrangement. While the positions of the molecules within each layer are
      similar, hydrogen bonding occurs between the ABC layers and in order to
      accommodate this the molecules are rotated relative to those in cyclohexane-II.
      Piperidine and morpholine also adopt layered structures, with hydrogen-bonding or
      CH...O interactions between the layers. In these cases, however, the layering
      more resembles a hexagonal close-packed arrangement.

PMID- 15017097
TI  - Model for the crystal packing and conformational changes of biphenyl in
      incommensurate phase transitions.
AB  - Standard atom-atom potentials for hydrocarbons and a torsional potential to
      account for the pi-electron conjugation energy were used to model the crystal
      structures and phase transitions of biphenyl. The model describes the high
      temperature phase (I) with its planar molecule as a stationary point of the
      energy hypersurface. Phase I represents a low-energy barrier between the symmetry
      minima of the ground state (phase III), in which the molecule is twisted with
      torsion angles of opposite sign. Global-energy minimization was carried out by
      considering both regular structures, with one or two independent molecules, and
      quasi-one-dimensional superstructures built of N cells (N up to 16) of the high
      temperature structure. The various energy-minimized biphenyl structures
      demonstrate remarkable similarity in their crystal packing; in particular, there
      are characteristic rows of cooperatively twisted molecules parallel to the
      superstructure dimension b. The structures built of centrosymmetric rows (P1, Z =
      4 and 8) are almost as low in energy as the basic structure (an N = 2
      superstructure, Pa, Z = 4); moreover, one of them is isostructural with the low
      temperature p-quaterphenyl structure. With N > 8, structures of lower energy than
      that of the basic structure (N = 2) were found; their common feature is an M-fold
      modulation of the twist angle over the supercell period, with M smaller than N
      and generally not a simple fraction of it. The global minimum was found to
      conform to the ratio k = M/N = 6/14, which is close to the experimentally
      observed k = 6/13 in the incommensurate phase III. Enthalpy minimization showed
      an overall decrease in the magnitude of the twist angle down to tau approximately
      0 degrees, as well as the evolution of the modulated structures towards the high
      temperature structure with increasing pressure, in agreement with evidence for
      the high-pressure limit of the incommensurate biphenyl phases.

PMID- 15017098
TI  - Hydrogen-bonded adducts of triphenylsilanol with diamines: a finite ten-molecule
      aggregate, and chain, sheet and framework structures built from O-H...O, O-H...N
      and C-H...pi(arene) hydrogen bonds.
AB  - The structures of five hydrogen-bonded adducts of triphenylsilanol, Ph3SiOH, with
      diamines have been determined. In the 4:1 adduct formed with 1,4
      diazabicyclo[2.2.2]octane, (Ph3SiOH)4.C6H12N2 (I) (triclinic, P1, Z' = 2), there
      are two independent five-component aggregates built from O-H...N and O-H...O
      hydrogen bonds, in one of which the diamine exhibits orientational disorder:
      these two aggregates are linked into a cyclic ten-molecule unit by means of two
      independent C-H...pi(arene) hydrogen bonds. The 4:1 adduct formed with 1,2-bis(4
      pyridyl)ethene, (Ph3SiOH)4.C12H10N2 (II) (triclinic, P1, Z' = 0.5), forms a
      similar five-component aggregate which lies across a centre of inversion: a
      single C-H...pi(arene) hydrogen bond links these aggregates into a molecular
      ladder. With N,N'-dimethylpiperazine, triphenylsilanol forms a 2:1 adduct,
      (Ph3SiOH)2.C6H14N2 (III) (monoclinic, P2(1)/c, Z' = 0.5), in which a three
      component aggregate built from O-H...N hydrogen bonds lies across a centre of
      inversion: two independent C-H...pi(arene) hydrogen bonds link these aggregates
      into sheets. In the hydrated 2:1 adduct formed with 1,2-bis(4'-bipyridyl)ethane,
      (Ph3SiOH)2.C12H12N2.H2O (IV) (triclinic, P1, Z' = 1), a combination of two
      independent O-H...O and two independent N-H...O hydrogen bonds links the five
      molecular components into a centrosymmetric eight-molecule aggregate, and six
      independent C-H...pi(arene) hydrogen bonds link these chains into a continuous
      three-dimensional framework structure. In the dihydrated 2:1 adduct formed with
      4,4'-bipyridyl, (Ph3SiOH)2.C10H8N2.(H2O)2 (V) (triclinic, P1, Z' = 1), a
      combination of four independent O-H...O and two independent N-H.O hydrogen bonds
      links the five molecular components into a chain of rings, and four independent C
      H...pi(arene) hydrogen bonds link these chains into a continuous three
      dimensional framework structure.

PMID- 15017099
TI  - Structure for perovskites with layered ordering of A-site cations.
AB  - The structure of La(1/3)NbO3 is that of a perovskite with La3+ cations ordered
      into alternate layers of perovskite A-sites. This is the description of a
      tetragonal structure and yet the room-temperature structure shows an orthorhombic
      distortion. The structure of La(2/3)TiO3 shows similar features. It has been
      recognized only very recently that the orthorhombic distortion in both these
      compounds is due to octahedral tilting. It seems clear from the literature that
      Ce(2/3)TiO3, Pr(2/3)TiO3, Nd(2/3)TiO3 and Ce(1/3)NbO3 adopt the same structure.
      Structures of other perovskites, such as Ln(2/3)TiO3, Ln(1/3)NbO3 and Ln(1/3)TaO3
      (Ln = lanthanoid), when orthorhombically distorted, may be similar.

PMID- 15017100
TI  - Space group Cc: an update.
AB  - A recent survey of the Cambridge Structural Database, CSD [Allen (2002). Acta
      Cryst. B58, 380-388], shows that the percentage of incorrect assignments of the
      space group Cc has remained at about 10% since the last survey in 1997.

PMID- 15017101
TI  - Cross-linking of human amniotic membrane by glutaraldehyde.
AB  - PURPOSE: The transplantation of cryopreserved human amniotic membrane has been
      introduced recently for the reconstruction of the ocular surface. However, in
      some diseases the transplant usually dissolves rather quickly and early
      detachment may occur. Therefore, we tried to stabilize the amniotic transplant by
      applying glutaraldehyde for collagen cross-linking of the membrane. METHODS: 18
      human amnions were prepared. 4 x 4 cm pieces of amnion were treated with 0.1%
      glutaraldehyde solution for 30 min. Biomechanical force-elongation measurements
      were performed and resistance to enzymatic digestion by 0.1% collagenase solution
      was tested and compared to cryopreserved and untreated fresh amnion. 8 patients
      with various ocular surface defects were treated with cross-linked amnion and
      compared to 5 patients with cryopreserved amnion. RESULTS: The force of the
      amnion cross-linked with glutaraldehyde at 2.5 mm elongation was increased
      statistically significant by 175% versus fresh amnion and 76.8% versus the
      cryopreserved amnion. Glutaraldehyde-treated membranes were virtually completely
      resistant to enzymatic digestion, while fresh and cryopreserved amnions were
      dissolved completely by day 7. In patients, the cross-linked membrane was
      preserved for up to 90 days without any signs of dissolution of the membrane and
      good transparency. CONCLUSIONS: Collagen cross-linking using glutaraldehyde leads
      to a significant increase in the biomechanical strength and enzymatic resistance
      of amnion, better transparency and less wrinkling. The cross-linked membrane does
      not dissolve for months and is well suited for the surface reconstruction of the
      cornea.

PMID- 15017102
TI  - Exophthalmos in obesity.
AB  - AIMS: To establish the relationship between exophthalmos and obesity. METHODS: A
      group of 19 obese patients (body mass index, BMI >/=30 kg/m(2)) was compared with
      a control group of 45 nonobese individuals (26 > BMI >/= 20 kg/m(2)). Both groups
      underwent Hertel's exophthalmometry, Goldmann applanation tonometry and
      measurement of the medial rectus muscle by echography. RESULTS: Obese patients
      had higher Hertel values and enlarged medial rectus muscle diameter (p < 0.05).
      Indeed, bilateral exophthalmos was observed in 33% of obese subjects. However,
      this did not cause any ocular morbidity. In some cases the difference in
      intraocular pressure was enlarged but together with the exophthalmos not
      statistically significant. CONCLUSIONS: Standard values for exophthalmometry and
      orbital echography may have to be adapted for obese individuals. In several cases
      the eye signs had a remarkable resemblance to patients with Graves' orbitopathy.
      So in each patient with bilateral exophthalmos and eye signs suspicious of
      Graves' orbitopathy obesity should be considered as a possible cause.

PMID- 15017104
TI  - Diquafosol elicits increases in net Cl- transport through P2Y2 receptor
      stimulation in rabbit conjunctiva.
AB  - The purpose of the present study was to understand the mechanisms of action of
      diquafosol, a stable derivative of uridine 5'-triphosphate, on Cl(-) transport
      across the isolated rabbit conjunctiva. Rabbit conjunctivas were isolated and
      mounted in a modified Ussing chamber. Under short-circuit conditions, the effects
      were determined of mucosal (tear) side diquafosol application on the short
      circuit current (Isc). Diquafosol rapidly and dose-dependently increased the Isc
      at concentrations ranging from 0.1 to 968 microM when added to the mucosal side
      of the conjunctiva. In the absence of the serosal Cl(-), the Isc induced by 10
      microM diquafosol was substantially reduced. On the contrary, in the absence of
      mucosal side Na(+), the diquafosol-induced increases in Isc were unchanged.
      Following 45-min preincubation, the P2Y(2) antagonist suramin inhibited the
      diquafosol-induced increases in the Isc whereas the P2Y(1) antagonist pyridoxal
      phosphate-6-azophenyl-2'4'-disulfonic acid had no effect. These studies suggest
      that diquafosol stimulates net Cl(-) secretion from the serosal to the mucosal
      side via stimulation of P2Y(2) receptors in the rabbit conjunctiva.

PMID- 15017103
TI  - Association of a homozygous nonsense mutation in the ABCA4 (ABCR) gene with cone
      rod dystrophy phenotype in an Italian family.
AB  - Genetic variation in the ABCA4 (ABCR) gene has been associated with several
      distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus
      (STGD/FFM), cone-rod dystrophy (CRD), retinitis pigmentosa (RP) and age-related
      macular degeneration. The current model of genotype/phenotype association
      suggests that patients harboring deleterious mutations in both ABCR alleles would
      develop RP-like retinal pathology. Here we describe ABCA4-associated phenotypes,
      including a proband with a homozygous nonsense mutation in a family from Southern
      Italy. The proband had been originally diagnosed with STGD. Ophthalmologic
      examination included kinetic perimetry, electrophysiological studies and
      fluorescein angiography. DNA of the affected individual and family members was
      analyzed for variants in all 50 exons of the ABCA4 gene by screening on the
      ABCR400 microarray. A homozygous nonsense mutation 2971G>T (G991X) was detected
      in a patient initially diagnosed with STGD based on funduscopic evidence,
      including bull's eye depigmentation of the fovea and flecks at the posterior pole
      extending to the mid-peripheral retina. Since this novel nucleotide substitution
      results in a truncated, nonfunctional, ABCA4 protein, the patient was examined in
      depth for the severity of the disease phenotype. Indeed, subsequent
      electrophysiological studies determined severely reduced cone amplitude as
      compared to the rod amplitude, suggesting the diagnosis of CRD. ABCR400
      microarray is an efficient tool for determining causal genetic variation,
      including new mutations. A homozygous protein-truncating mutation in ABCA4 can
      cause a phenotype ranging from STGD to CRD as diagnosed at an early stage of the
      disease. Only a combination of comprehensive genotype/phenotype correlation
      studies will determine the proper diagnosis and prognosis of ABCA4-associated
      pathology.

PMID- 15017105
TI  - Autoclavable two-piece noncased wide-angle contact lens system for vitrectomy.
AB  - PURPOSE: To describe an autoclavable wide-angle two-piece noncased contact lens
      system (two lenses: equatorial and wider-angle lens) for vitrectomy. DESIGN: The
      inferior lens is made of an autoclavable plastic with a concave contact surface
      of 7.7 mm and the superior lens is a convex glass lens. The superior lens is
      mounted on the inferior one to make the lens assembly. RESULT: The equatorial
      lens has a power of +81 D and a field of view of 80-96 degrees, while the wider
      angle lens power is +151 D and the field 110-120 degrees. The lens is kept on the
      cornea upon a drop of viscoelastic substance. An assistant holds it with a
      conventional lens holder. The lens is easy to sterilize by autoclaving and does
      not require expensive gas sterilization or potentially injurious chemical
      sterilization. CONCLUSION: This lens system provides a panoramic wide-angle view
      of the retina during vitreous surgery. The autoclaving makes this lens system
      cost-effective and fast to reuse.

PMID- 15017106
TI  - Suppression of N-methyl-N-nitrosourea-induced photoreceptor apoptosis in rats by
      docosahexaenoic acid.
AB  - We evaluated the effects of dietary intake of docosahexaenoic acid (DHA) on
      photoreceptor cell apoptosis caused by N-methyl-N-nitrosourea (MNU). Five-week
      old female Sprague-Dawley rats were fed basal diet (AIN-76A) or DHA diet
      (modified AIN-76A containing 9.5% DHA) for 2 weeks, and then received a single
      intraperitoneal injection of 60 mg/kg body weight MNU at 50 days of age. Then,
      rats continued to receive the same diet or were switched to the opposite diet:
      group 1, basal diet before and after MNU injection; group 2, DHA diet before MNU
      injection and basal diet after MNU injection; group 3, basal diet before MNU
      injection and DHA diet after MNU injection; group 4, DHA diet before and after
      MNU injection (10 rats in each group). Rats were starved for 24 h, then
      sacrificed 3 or 7 days after MNU. Morphologically, at 3 days after MNU injection,
      photoreceptor cell apoptosis was advanced in group 1 compared with group 4. At
      this time point, as evaluated by retinal damage ratio [(length of retina less
      than 4 photoreceptor cells thick/whole retinal length) x100], retinal damage was
      highest in group 1 (82.4 +/- 5.1%), followed by group 2 (41.1 +/- 7.3%), group 3
      (24.7 +/- 11.5%), and group 4 (6.6 +/- 6.6%); severity tended to be inversely
      correlated with serum DHA composition. At 7 days after MNU injection, active
      signs of photoreceptor cell apoptosis ended in all MNU-treated groups, and
      retinal damage ratio was high in group 1 (88.4 +/- 2.8%), whereas it remained low
      in groups 2, 3 and 4 (38.4 +/- 15.2, 45.7 +/- 9.8 and 46.9 +/- 11.2%,
      respectively). High DHA composition during induction/signaling phase and/or
      effector phase of photoreceptor cell apoptosis can delay the onset of apoptosis
      and counteract progression of MNU retinotoxicity in rat retina. DHA may play a
      role in the suppression of MNU-induced photoreceptor cell apoptosis in rat
      retina.

PMID- 15017107
TI  - The multifocal pattern electroretinogram in chloroquine retinopathy.
AB  - PURPOSE: Optimal screening for ocular toxicity caused by chloroquine and
      hydroxychloroquine is still controversial. With the multifocal pattern
      electroretinogram (mfPERG), a new electrophysiological technique has recently
      become available to detect early changes of ganglion cells. In this study this
      new technique is applied to a series of 10 patients seen consecutively receiving
      long-term chloroquine medication. METHODS: In 10 patients receiving chloroquine
      medication, clinical examination, Amsler visual field testing and computerized
      color vision testing were performed. If toxicity was suspected, automated
      perimetry was carried out. In addition, in all patients conventional pattern
      electroretinogram (PERG) and mfPERG testing were performed. RESULTS: On clinical
      examination 8 patients showed no chloroquine-associated maculopathy, while 2
      patients did. Of these 2, only 1 reported abnormalities when viewing the Amsler
      chart, while automated perimetry showed typical, ring-like paracentral scotomas
      in both affected patients and color vision was significantly abnormal. In the
      normal patients, 4 of 8 had a mild color vision disturbance, which correlated to
      age-related macular changes. The amplitudes of the PERG and the central
      (approximately 10 degrees ) responses of the mfPERG were markedly reduced in
      chloroquine maculopathy, while the latencies were unchanged. The peripheral rings
      of mfPERG (ranging to 48 degrees ) were not affected by chloroquine toxicity.
      Both PERG and mfPERG were less affected by age-related macular changes.
      CONCLUSIONS: The reduction of PERG and central mfPERG responses in chloroquine
      maculopathy may help with the early detection of toxicity.

PMID- 15017108
TI  - Transcript expression of matrix metalloproteinases in the conjunctiva following
      glaucoma filtration surgery in rabbits.
AB  - PURPOSE: To determine the changes in the expression of transcripts of matrix
      metalloproteinases (MMPs) and their tissue inhibitor (TIMP) in the conjunctiva
      following glaucoma filtration surgery (GFS). METHODS: The reverse transcription
      polymerase chain reaction method was performed on tissue specimens obtained from
      adult rabbits undergoing GFS at various postoperative time points. RESULTS: MMP 1
      decreased more than 7-fold from its baseline level during the first 2 weeks
      following surgery. MMP 2 decreased on the 1st postoperative day, but increased on
      day 2, and remained elevated for 2 weeks. The postoperative level of MMP 14 did
      not change much from baseline except that noted on day 9. The TIMP 1 expression
      showed an early biphasic pattern. MMP 3 and MMP 9 were not detected in all the
      specimens. CONCLUSIONS: The transcript expression of MMPs and TIMP 1 in the
      conjunctiva is altered following GFS, with each gene product demonstrating a
      unique temporal pattern.

PMID- 15017109
TI  - Retinal antigens are recognized by antibodies present in sera of patients with
      multiple sclerosis.
AB  - Multiple sclerosis (MS) is frequently accompanied by visual symptoms including
      those related to retinal disorders. Since they may be a consequence of an
      autoimmune reaction, we examined whether sera of patients with diagnosed MS and
      changes in visual-evoked potentials contain antibodies against retinal antigens
      (retAgs). Immunoblot analysis revealed that MS sera recognized mainly a 46-kD
      antigen, a 41-kD antigen, retinal arrestin, to a smaller extent also 70-, 56-, 43
      , and 36-kD proteins. Patients whose sera showed the highest reactivity with 41-
      and 46-kD antigens had deficiencies in visual acuity, visual fields,
      ophthalmoscopy, and electroretinograms. Our observation suggests that antibodies
      to these retAgs may play a role in the origin of ophthalmologic impairment in MS.

PMID- 15017110
TI  - Content of kynurenic acid and activity of kynurenine aminotransferases in
      mammalian eyes.
AB  - The present study investigated the kynurenic acid (KYNA) contents and kynurenine
      aminotransferase (KAT I and II) activity in structures of the human, monkey,
      rabbit and bovine eye. KYNA levels were investigated with HPLC and detected
      fluorimetrically. The activity of KAT I and II was assayed as quantitative
      analysis of newly synthesized KYNA in vitro. Mean KYNA levels (+/-SD) in the
      human retina and vitreous body were 36.8 +/- 7.6 and 33.1 +/- 6.2 pmol/g wet
      tissue weight, respectively. In human eyes, KAT I activity in the vitreous body
      was 0.57 +/- 0.28, that of KAT II was 2.56 +/- 0.69. KAT I activity in the retina
      was 3.42 +/- 1.17 and that of KAT II 10.75 +/- 9.2. (KAT activity is expressed as
      KYNA synthesis in picomoles per gram wet tissue weight per hour.) The values of
      KYNA and KAT observed in other mammalian species tested were in the same range.
      In conclusion, KYNA and KAT enzymatic activity are present in the structures of
      human and other mammalian eyes.

PMID- 15017111
TI  - Activation of resistance arteries with endothelin-1: from vasoconstriction to
      functional adaptation and remodeling.
AB  - Remodeling of resistance arteries is a key feature in hypertension. We studied
      the transition of vasoconstriction to remodeling in isolated rat skeletal muscle
      arterioles. Arterioles activated with 10 nM endothelin-1 showed functional
      adaptation when kept at low distension in a wire myograph setup, where
      contractile properties shifted towards a smaller lumen diameter after 1 day.
      Pressurized arteries kept in organoid culture showed physical inward remodeling
      after 3-day activation with 10 nM endothelin-1, characterized by a reduction in
      relaxed diameter without a change in the wall cross-sectional area (eutrophic
      remodeling). The relaxed lumen diameter (at 60 mm Hg) decreased from 169 +/- 5
      (day 0) to 155 +/- 4 microm (day 3). An antibody directed to the beta(3)-integrin
      subunit (but not one directed to the beta(1)-integrin subunit) enhanced
      remodeling, from a reduction in relaxed diameter at 60 mm Hg of 15 +/- 2.4 to 22
      +/- 1.8 microm (both on day 3). Collagen gel contraction experiments showed that
      the antibody directed to the beta(3)-integrin subunit enhanced the compaction of
      collagen by smooth muscle cells, from 83 +/- 1.5 to 68 +/- 1.5% of the initial
      gel diameter. In conclusion, these data show that inward eutrophic remodeling is
      a response to sustained contraction, which may involve collagen reorganization
      through beta(3)-integrins.

PMID- 15017112
TI  - Tissue-to-blood transport of radiolabelled immunoglobulin injected into the web
      spaces of the hands of normal subjects and patients with breast cancer-related
      lymphoedema.
AB  - AIM: The ability to return interstitial protein to central blood is key to the
      defence against oedema. The aim of this study was to quantify this ability by
      measuring the rate at which radiolabelled human immunoglobulin (HIgG) accumulated
      in blood following injection into the subcutis of the hand in normal volunteers
      and in patients with breast cancer-related lymphoedema (BCRL). METHODS: A total
      of 37 control subjects (healthy normal volunteers or breast cancer patients prior
      to treatment) and 18 women with BCRL were studied with dual-isotope
      lymphoscintigraphy. Each received bilateral subcutaneous depot injection in the
      dorsal web space of HIgG labelled with Tc-99m on one side and In-111 on the
      other. Activities remaining at the depot and accumulating in blood were measured
      at regular intervals for 3 h. Clearance from the depot was exponential and
      expressed as the rate constant k(depot) (min(-1)). Accumulation in blood was
      essentially linear and, using an estimate of blood volume based on height and
      weight, was expressed as the linear constant b(blood) (% administered activity x
      min(-1)). The time axis intercept of this linear fit was recorded as an index of
      the minimum time to arrival of radioprotein in blood. The efficiency with which
      radioprotein that has left the depot (extra-depot activity) is transported into
      blood [tissue-to-blood (T-B) transport] was quantified (1) as the quotient
      b(blood)/k(depot), and (2) as a function of time after injection by comparing the
      total amount of radioprotein in blood at any time with the total amount of
      radioprotein that was no longer in the depot at the same time. RESULTS: Tc-99m
      HIgG and In-111-HIgG behaved similarly and are interchangeable. At all times
      between 60 and 180 min in controls, about 50% of protein that had left the depot
      was present in blood. T-B transport was reduced to about 20% in BCRL arms in
      which the hand was involved in swelling (p < 0.001 versus controls), but remained
      unchanged in patients in whom the hand was spared. The minimum time to arrival of
      radioprotein in blood was not reduced in BCRL; on the contrary, there appeared to
      be a small proportion of injected activity that arrived rapidly in blood in BCRL
      patients but not in controls. CONCLUSION: We conclude that T-B transport is only
      impaired in BCRL when radioprotein is injected into swollen tissue. Significant
      quantities of radioprotein may escape from the arm via local access to blood.
      Individual variation in this capacity may explain the regional sparing observed
      in BCRL.

PMID- 15017113
TI  - Fcgamma receptors on mast cells: activatory and inhibitory regulation of mediator
      release.
AB  - Mast cell activation and subsequent release of proinflammatory mediators are
      primarily a consequence of aggregation of the high affinity receptors for IgE
      (FcepsilonRI) on the mast cell surface following antigen-dependent ligation of
      FcepsilonRI-bound IgE. However, data obtained from rodent and human mast cells
      have revealed that IgG receptors (FcgammaR) can both promote and inhibit mast
      cell activation. These responses appear to be species and/or mast cell phenotype
      dependent. In CD34+-derived human mast cells exposed to interferon-gamma,
      FcgammaRI is upregulated, FcgammaRII is expressed but not upregulated, and
      FcgammaRIII is not expressed. In contrast, in mouse mast cells, FcgammaRII and
      FcgammaRIII receptors are expressed, whereas FcgammaRI is not. Aggregation of
      FcgammaRI on human mast cells promotes mediator release in a manner generally
      similar to that observed following FcepsilonRI aggregation. Aggregation of
      FcgammaRIIb in mouse mast cells fails to influence cellular processes; however,
      when coligated with FcepsilonRI, signaling events thus activated downregulate
      antigen-dependent mediator release. These divergent responses are a consequence
      of different motifs contained within the cytosolic tails of the signaling
      subunits of these receptors and the specific signaling molecules recruited by
      these receptors following ligation. The studies described imply that data
      obtained in rodent models regarding the influence of FcgammaRs on mast cells may
      not be directly translatable to the human. The exploitation of FcgammaRs for a
      potential therapy for the treatment of allergic disorders is discussed in this
      context.

PMID- 15017114
TI  - Sensitization to fig with cross-sensitization to weeping fig and natural rubber
      latex.

PMID- 15017115
TI  - Effects of glucose on blood pressure and production of vascular aldosterone and
      corticosterone.
AB  - OBJECTIVE: The aims of this study were to search for the role of glucose in the
      regulation blood pressure of rats and to investigate the effects of glucose on
      the production of vascular aldosterone and corticosterone in rats. METHODS: Male
      Wistar rats received glucose 15.0 g x kg(-1) x d(-1) (glucose-treated group 1) or
      25.0 g x kg(-1) x d(-1) (glucose-treated group 2) or 35.0 g x kg(-1) x d(-1)
      (glucose-treated group 3), orally, for 3 months, and blood pressure was monitored
      by a pressure transducer. Mesenteric artery perfusion ex vivo was performed and
      pressor responses to norepinephrine were determined in Wistar rats. 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. Reverse transcriptase polymerase chain reaction was used to
      measure the expression of 11beta-HSD2 and CYP11B2 mRNA in mesenteric arteries.
      RESULTS: Blood pressure increased in Wistar rats treated with glucose compared to
      control rats. The pressor responses to norepinephrine in mesenteric arteries
      treated with glucose were significantly increased. Levels of aldosterone were
      decreased but those of corticosterone increased in the perfusate from arteries
      treated with glucose. Reverse transcriptase polymerase chain reaction showed that
      glucose inhibited the expression of 11beta-HSD2 and CYP11B2 mRNA in mesenteric
      arteries. CONCLUSION: These results reveal that glucose able to induce
      hypertension and provide evidence that glucose inhibits the transcriptions of
      both 11beta-HSD2 and CYP 11B2 in vasculature, leading to lower aldosterone and
      higher corticosterone production in vessels, and increased vasoconstrictor
      responses to norepinephrine.

PMID- 15017116
TI  - Predicting nonepileptic seizures utilizing seizure frequency, EEG, and response
      to medication.
AB  - The objective was to develop criteria that would prompt evaluation with video EEG
      monitoring in order to shorten the time to diagnosis of nonepileptic seizures.
      Over a period of 3 consecutive years, all patients being seen for seizures or the
      consideration of seizures meeting the following criteria were admitted for video
      EEG monitoring: (1) at least two events per week, (2) refractory to at least two
      medications, and (3) no prior EEG studies with epileptiform abnormalities after
      at least two attempts. A total of 13 patients met all three criteria, 11 of these
      patients had nonepileptic seizures, yielding a positive predictive value of 0.85.
      The median time from onset of symptoms until referral to the study institution
      was 3 years, with a range of 0-15 years. The median time from the first patient
      visit to a definitive diagnosis on video EEG monitoring was 1 month, with a range
      of 0-7 months. Patients meeting these three criteria frequently have nonepileptic
      seizures. These patients should undergo video EEG monitoring in a timely fashion
      to clarify the diagnosis.

PMID- 15017117
TI  - Pentoxifylline does not prevent hypoxia/reoxygenation-induced necrotizing
      enterocolitis. An experimental study.
AB  - Hypoxia/reoxygenation (H/R)-induced intestinal injury plays a significant role in
      the development of necrotizing enterocolitis (NEC). We experimentally explored
      the effect of pentoxifylline (PTX) on an NEC model. Twenty-one newborn rabbits
      were divided into three groups: group 1 (control), group 2 (H/R) and group 3 (H/R
      + PTX). Five minutes of reoxygenation following 5 min of hypoxia was performed
      three times a day during 3 days. Before each H/R procedure in the H/R + PTX
      group, the rabbits were treated with PTX 25 mg/kg intraperitoneally. Animals were
      sacrificed on the third day and ileum samples were taken for histopathological
      examination and biochemical enzyme studies [superoxide dismutase (SOD),
      glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S
      transferase (GST)]. There was a significant difference in the grade and number of
      the intestinal lesions between controls and the H/R and H/R + PTX groups (p <
      0.001), but no significant difference was found between the H/R and the H/R + PTX
      groups (p > 0.05). Intestinal SOD, GR and GST activities in the H/R and H/R + PTX
      groups were significantly higher than in the control group (p < 0.05); however,
      there was no significant difference between the H/R and H/R + PTX groups (p >
      0.05). Significantly reduced GPx activity was found in the H/R and H/R + PTX
      groups compared with the controls (p < 0.05). No significant difference in GPx
      activity existed between the H/R group and the H/R + PTX group (p > 0.05).
      Ischemia/reperfusion injury was responsible for mediating hypoxia-induced
      intestinal necrosis in NEC and PTX pretreatment did not have a protective effect
      on NEC.

PMID- 15017118
TI  - Effect of epidermal growth factor on the developing rat renal papilla.
AB  - BACKGROUND: Apoptosis plays an important role in the morphogenesis of the renal
      papilla. During kidney development, ATL is derived from the TAL in the inner
      medulla by apoptotic deletion of a fraction of TAL cells and the transformation
      of the remaining TAL cells. EGF is an important regulator of apoptosis in the
      kidney. HYPOTHESIS: Exogenously administered EGF in postnatal rat affects renal
      papilla growth with cell proliferation and apoptosis in the loop of Henle.
      METHODS: Rat pups received subcutaneous injections of EGF (0.3 microg/g body
      weight) or saline four times a day from after birth. Rats were sacrificed and the
      kidneys were preserved for immunohistochemistry on day 4 and day 7. The TAL was
      identified with antibody directed against Na-K-ATPase or BSC1, and type A
      intercalated cells were identified with antibody to anion exchanger 1 (AE1).
      Apoptosis was detected with TUNEL method, and cell proliferation with
      immunostaining for PCNA. RESULTS--PRIMARY AND SECONDARY: EGF treatment resulted
      in the following: (1) reduced kidney weight; (2) shortened length of renal
      papilla; (3) delayed transformation of the cuboidal epithelium into the squamous
      epithelium of the ATL; (4) delayed elimination of type A intercalated cells in
      the medullary collecting duct; (5) decreased both apoptotic index and PCNA
      positive cells in the TAL and the collecting duct of the renal medulla.
      CONCLUSION: These findings suggest that exogenous EGF delays the development of
      loop of Henle in the renal papilla by reducing both apoptosis and cell
      proliferation.

PMID- 15017119
TI  - Lipoprotein(a)-associated atherothrombotic risk in hemodialysis patients.
AB  - BACKGROUND: Hemodialysis patients show a considerably higher risk of
      atherothrombotic disease than the general population. We investigated both
      lipoprotein(a) [Lp(a)] plasma levels and apolipoprotein(a) [apo(a)] phenotypes in
      relation to occurrence of atherothrombotic events in hemodialysis patients
      compared with subjects showing a normal kidney function. METHODS: Lp(a) levels
      and apo(a) isoforms were determined in 118 hemodialysis patients, including 59
      with prior atherothrombotic events, and in 182 subjects with normal creatinine
      clearance, including 82 who experienced a prior atherothrombotic event. RESULTS:
      Lp(a) levels in hemodialysis patients (median; 20 mg/dl) were higher (p < 0.01)
      than in age- and sex-matched subjects with normal renal function without a
      history of atherothrombosis (11.3 mg/dl). Among hemodialysis patients, median
      Lp(a) levels were higher in subjects with than in those without prior
      atherothrombosis (34 vs. 15 mg/dl, p < 0.05). In hemodialysis patients and in
      subjects without nephropathy, the percentage of low-molecular-weight apo(a)
      phenotypes were significantly higher in patients with than in those without a
      history of prior atherothrombotic events (56.9% vs. 33.9%, p < 0.05; 62.2% vs.
      25%, p < 0.00001,respectively). Stepwise regression analysis indicated that the
      presence of at least one apo(a) isoform of low molecular weight was an
      independent predictor of atherothrombosis in hemodialysis patients (p < 0.05).
      CONCLUSIONS: Elevated Lp(a) plasma levels appear to be associated with
      atherothrombosis, independent of their origin due to genetic factors or related
      to the impaired kidney function. Low-molecular-weight apo(a) isoforms are
      reliable genetic markers of atherothrombosis both in patients with impaired
      kidney function and in subjects without nephropathy.

PMID- 15017120
TI  - Proteomics in pancreatic disease.
AB  - Proteomics represents a novel methodological approach to investigate the
      expression of all proteins by a cell or organism in its entireness, similar to
      global strategies for DNA (genomics) and RNA (transcriptomics). This review
      focuses on the history of protein analysis, which made up the golden age of
      pancreatic physiology, the current methodology for proteomics (2D gel
      electrophoresis, mass spectrometry) and the few published experiences with
      proteomics in the field of pancreatology until now. Finally, potential
      applications of proteomics for the pancreas, in concert with other techniques,
      are cited.

PMID- 15017121
TI  - Clinical significance of intraportal endovascular ultrasonography for the
      diagnosis of extrapancreatic nerve plexus invasion by pancreatic carcinoma.
AB  - BACKGROUND/AIMS: The extrapancreatic nerve plexus (PL) invasion is a common
      feature of pancreatic cancer and affects the outcome of the patients after
      surgical resection. IPEUS with high-resolution probes can visualize the PL
      invasion with high overall accuracy rate. The aim of this study is to evaluate
      the clinical significance of the PL invasion diagnosed intraoperatively by
      intraportal endovascular ultrasonography (IPEUS). METHODS: IPEUS was performed in
      64 patients who underwent the pancreatic resection. Several clinicopathological
      factors were studied in patients with or without PL invasion. RESULTS: There were
      18 cases in which PL invasion was confirmed pathologically. IPEUS showed 94%
      sensitivity, 98% specificity and 97% accuracy for the diagnosis of the PL
      invasion with the false-positive rate of 5.6%. The 1-, 2- and 3-year survival in
      18 patients with PL invasion was 30, 6 and 0% in comparison to 52, 32 and 18% in
      those 46 patients without PL invasion and the difference was statistically
      significant (p = 0.008). A significant correlation was found between PL invasion
      and the portal vein invasion, invasion of the margins or pTNM stage. CONCLUSIONS:
      According to current results, the prognosis of the cases with PL invasion is very
      poor and indication for resection is doubtful. We conclude that the cases in
      which PL invasion is diagnosed by IPEUS are not indicated for extended resection
      and correct diagnosis of PL invasion is important not only to predict the outcome
      but also to decide the surgical procedure for obtaining negative margins while
      improving the quality of life after surgery.

PMID- 15017122
TI  - A prospective study of induced abortion and breast cancer in African-American
      women.
AB  - OBJECTIVE: There continues to be controversy about whether induced abortion
      influences the risk of breast cancer. Because case-control studies of this
      relation are subject to recall bias, there is a need for prospective data.
      Further, there has been little study of abortion and breast cancer in African
      American women. We assessed the relation of abortion to risk of breast cancer in
      a prospective follow-up study of African-American women. METHODS: Black Women's
      Health Study participants have been followed by mailed questionnaires every two
      years since enrollment in 1995. Participants reported 348 incident breast cancers
      during 205,983 person-years of follow-up. Women who had an induced abortion were
      compared with women who had never had one, with nulliparous and parous women
      analyzed separately. Incidence rate ratios (IRR) with two-sided 95% confidence
      intervals (CI) were derived from Cox regression models that controlled for age,
      age at first birth, number of births, history of spontaneous abortion, and other
      factors. RESULTS: Among nulliparous women, the IRR for any induced abortion
      relative to none was 0.9 (95% CI = 0.5-1.4), and among parous women, the
      comparable IRR was 1.1 (95% CI = 0.8-1.4). Risk did not vary by number of
      abortions, age at first abortion, age at diagnosis or a family history of breast
      cancer in either nulliparous or parous women. CONCLUSIONS: Our findings indicate
      that induced abortion does not increase breast cancer risk in African-American
      women.

PMID- 15017123
TI  - Does folate intake decrease risk of postmenopausal breast cancer among women with
      a family history?
AB  - BACKGROUND: Several recent studies suggest that adequate dietary folate may
      attenuate the risk of breast cancer associated with intake of alcohol. We
      examined whether the putative benefit extends to women with a family history (FH)
      of breast cancer using a cohort of 33,552 postmenopausal women aged 55-69 years
      in 1986. METHOD: Folate and alcohol intake was estimated from a food frequency
      questionnaire completed at baseline. Folate was categorized as upper 50th, 31st
      50th, 11th-30th, and <10th percentiles. Alcohol use was initially classified into
      three levels; never drinkers, less than the median and greater than the median.
      Subsequent models collapsed levels of intake to any versus none. Occurrence of
      breast cancer was determined through linkage to the Iowa SEER registry.
      Multivariate-adjusted relative risks (RR) and 95% confidence intervals (CI) were
      estimated through Cox proportional hazards regression, stratified on FH using non
      drinkers with high folate and no FH as the referent group. RESULTS: Through 14
      years, 1823 incident cases were identified, 308 among FH+ women. Among FH- women,
      low folate was not a risk factor among non-drinkers (RR = 0.96, CI = 0.73-1.26),
      but was among drinkers (RR = 1.40, CI = 1.05-1.86). Drinkers with high folate
      were not at elevated risk (RR = 1.03, CI = 0.89-1.19). Among FH+ women, low
      folate was a risk factor among drinkers (RR = 2.21, CI = 1.43-3.41) and non
      drinkers (RR = 2.39, CI = 1.36-4.20). Further, drinkers with high folate remained
      at increased risk (RR = 1.67, CI= 1.30-2.14). However, FH+ women with high folate
      who did not drink alcohol had no elevated risk. CONCLUSION: These results suggest
      that folate may attenuate the risks of postmenopausal breast cancer associated
      with family history, but only if alcohol use is avoided or minimized.

PMID- 15017124
TI  - Effectiveness of a community-based oral cancer awareness campaign (United
      States).
AB  - OBJECTIVE: The purpose of this study was to provide the first systematic
      evaluation in the United States of a community-based oral cancer awareness
      campaign. METHODS: We used a non-equivalent control group design and random-digit
      dialing methods to examine billboard effectiveness and pre- and post-billboard
      impact between intervention and control counties in adult probability samples in
      Florida, USA. RESULTS: Respondents in the intervention county were more likely
      than controls to correctly identify the billboard message to get tested for oral
      cancer, and less likely than controls to report ever having an oral cancer
      examination, or to have heard of oral cancer. Results of pre-post analyses within
      each county showed that oral cancer examinations were significantly more frequent
      in both counties after the campaign. There were no significant differences
      between counties on the proportion of individuals who reported having seen the
      campaign or on any other item measuring billboard awareness or impact.
      CONCLUSIONS: Results suggest the Florida billboard campaign had limited success
      in increasing public awareness. Future cancer awareness campaigns should
      incorporate theoretical models, target high-risk groups and the broader community
      and provide culturally relevant messages as part of a multi-media campaign.

PMID- 15017125
TI  - Prostate cancer screening and mortality: a case-control study (United States).
AB  - OBJECTIVE: We performed a case-control study at Kaiser Permanente Northwest to
      assess the association between digital rectal examination (DRE) and prostate
      specific antigen (PSA) testing, separately and together, and prostate cancer
      mortality. METHODS: We identified 171 KPNW members who died as a result of
      prostate cancer from 1992 to 1999 and 342 randomly-selected KPNW members matched
      to the cases on age, sex, and length of plan membership. History of screening was
      determined from medical records and laboratory databases for cases and controls.
      RESULTS: DRE and/or PSA screening at any time up to and including the case
      diagnosis date had taken place among 69.0% of cases and 74.6% of controls. After
      using logistic regression analysis to adjust for matching variables and a
      provider diagnosis of benign prostatic hypertrophy (BPH), we found an inverse
      association between receipt of a prostate cancer screening test and prostate
      cancer mortality (odds ratio (OR): 0.70, 95% confidence interval (CI): 0.46 -
      1.1). Most of the screening tests were DREs, and it was not possible to assess
      the separate influence of PSA screening. CONCLUSIONS: The results of this study
      suggest that men who have been screened for prostate cancer have a reduced risk
      of dying as a result of this disease.

PMID- 15017126
TI  - Smoking-adjusted incidence of lung cancer by occupation among Norwegian men.
AB  - OBJECTIVE: To use aggregated data on smoking habits and lung cancer incidence in
      occupations assumed to carry no lung cancer risk to control for confounding in
      other occupational groups. METHODS: Lung cancer incidence was observed from 1971
      to 1991 for 53 occupational groups and a group of economically inactive men in a
      national cohort study. Data on occupation and smoking habits were collected from
      national surveys during 1965-1980. The relationship between smoking habits and
      lung cancer incidence was estimated on aggregated level using data from 12
      occupational groups that were initially assumed not to be exposed to occupational
      lung carcinogens. The estimated relationship was used to control confounding from
      smoking in the other groups. The results were presented as smoking-adjusted
      incidence ratios. RESULTS: A significant excess risk was found for 26 groups. It
      was estimated that about 20% of all lung cancer among men could be related to
      occupation after adjusting for the effect of smoking. CONCLUSIONS: Our method
      provided a clearer picture of the occupational risk and could be useful in other
      situations where individual information on smoking habits is lacking.

PMID- 15017127
TI  - Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and
      prostate cancer (Norway).
AB  - OBJECTIVE: To investigate whether prognosis of breast-, colon- and prostate
      cancer may be related to vitamin D(3), induced from solar ultra-violet (UV)
      radiation, through studies on geographical and seasonal variations in UV
      radiation. METHODS: This study includes 115,096 cases of breast-, colon- or
      prostate cancer, diagnosed between 1964 and 1992. Among these, 45,667 deaths due
      to the cancer were registered. On the basis of a north-south gradient in solar UV
      radiation and geographical climatic differences, Norway was divided into eight
      residential regions. According to seasonal variations in UV radiation, four
      periods of diagnosis during the year were used. Case fatality according to
      residential region and to season of diagnosis was estimated using Cox regression.
      The effects of occupational sun exposure, childbearing pattern and educational
      level were also evaluated. RESULTS: No geographic variation in case fatality was
      observed for the three cancer types studied. A significant variation in prognosis
      by season of diagnosis was observed. Diagnoses during summer and fall, the
      seasons with the highest level of vitamin D(3), revealed the lowest risk of
      cancer death. CONCLUSION: The results suggest that a high level of vitamin D(3)
      at the time of diagnosis, and thus, during cancer treatment, may improve
      prognosis of the three cancer types studied.

PMID- 15017128
TI  - Breast cancer screening practices among women in the United States, 2000.
AB  - Results from recent studies indicate that many women in the US undergo routine
      screening for breast cancer, but some groups of women are under-screened. In this
      study, we examined the breast cancer screening practices of white and black women
      in the United States, according to Hispanic ethnicity and other factors, using
      data from the 2000 National Health Interview Survey. Among women aged > or =40
      years, 71.2% (95% confidence interval, CI: 70.0-72.4%) of the 8201 white women
      and 67.6% (95% CI: 64.5-70.6%) of the 1474 black women in this sample reported
      having a mammogram in the past two years. About 60.3% (95% CI: 56.7-70.3%) of 970
      Hispanic women (including those who reported they were white or black) and 71.5%
      (95% CI: 70.3-72.7%) of 8705 non-Hispanic women reported having a mammogram in
      the past two years. About 74.8% (95% CI: 73.8-76.8%) of 8176 white women and
      73.8% (95% CI: 71.1-76.6%) of 1471 black women aged > or =40 years had received a
      clinical breast examination in the past two years. About 60.1% (95% CI: 56.1
      64.0%) of 969 Hispanic women (including those who reported they were white or
      black) and 75.6% (95% CI: 74.6-76.6%) of 8678 non-Hispanic women had received a
      clinical breast examination in the past two years. Women with lower incomes,
      those with less education, and recent immigrants were less likely to be screened.
      Women who had a usual source of health care and those with health insurance
      coverage were more likely to have been screened. These results underscore the
      need for continued efforts to ensure that uninsured women and those who are
      medically underserved have access to cancer screening services.

PMID- 15017129
TI  - Arsenic level in drinking water and mortality of lung cancer (Taiwan).
AB  - OBJECTIVE: Lung cancers have been observed among patients of arsenic intoxication
      since the 1950s, but data on the dose-response relationship were limited. In
      order to obtain such data, a study was conducted in ten townships in Taiwan.
      METHODS: Measurements of arsenic levels in drinking water were available for 138
      villages from a census survey conducted by the government. Certificates of deaths
      that occurred in the villages between January 1, 1971 and December 31, 1990 were
      reviewed, and 673 male and 405 female mortality cases of lung cancer were
      identified. Multi-variate regression models were applied to assess associations
      between arsenic levels in drinking water and mortality of lung cancer using
      village as the unit. RESULTS: After adjusting for age, arsenic levels above 0.64
      mg/l were associated with a significant increase in the mortality of lung cancer
      in both genders, but no significant effect was observed at lower levels. Post-hoc
      analyses confirmed such a dose-response relationship. CONCLUSIONS: The results
      indicate a prominent carcinogenic effect of high arsenic levels in drinking water
      on the lung and suggest the new 'maximum contaminant level' of 10 micro g/l
      published by the US Environmental Protection Agency provides sufficient
      protection against lung cancer. Nonetheless, further studies with exposure data
      on individuals are warranted to confirm these findings.

PMID- 15017130
TI  - The sensitivity of Medicare data for identifying incident cases of invasive
      melanoma (United States).
AB  - BACKGROUND: The completeness of Medicare claims for identifying patients with
      melanoma for purposes of conducting population-based studies of melanoma is
      unknown. METHODS: Using a linked Surveillance, Epidemiology, and End Result
      (SEER) tumor registry-Medicare database, the sensitivity of Medicare claims for
      identifying 5372 patients age > or =65 years diagnosed with invasive melanoma
      between 1992 and 1996 was determined. Sensitivity was calculated as the
      proportion of incident cases of melanoma reported by SEER that was also captured
      by Medicare claim diagnostic codes. RESULTS: The overall sensitivity of combined
      Part A and Part B Medicare for incident cases of melanoma was 90.1%. Part B
      Medicare and Part A Medicare alone had 89.5% and 16.5% sensitivity respectively.
      Sensitivity was lower for patients with unrecorded Breslow depth and for patients
      with unstaged or distant stage melanoma. CONCLUSIONS: Medicare Part B claims have
      a high sensitivity for detecting melanoma incidence; Medicare Part A has low
      sensitivity. This sharply contrasts with published studies of other cancers, for
      whom Part A rather than Part B Medicare captures the predominant portion of
      incident cases. Medicare Part B or combined Part A and Part B administrative data
      is a potentially valuable resource for population-based melanoma research in the
      elderly. Further research characterizing the specificity and predictive value of
      Medicare data is needed to assess the potential implications of false positive
      melanoma diagnostic codes.

PMID- 15017131
TI  - Variation in breast cancer counts using SEER and IARC multiple primary coding
      rules.
AB  - OBJECTIVE: To determine breast cancer case counts, on a given data set, using
      both Surveillance, Epidemiology, and End Results (SEER) program and International
      Agency for Research on Cancer (IARC) multiple primary coding rules and to
      describe differences, if any, by age at diagnosis, histology, stage at diagnosis,
      laterality, and grade. METHODS: SEER and IARC multiple primary coding rules were
      applied to a dataset provided by the North American Association of Central Cancer
      Registries. Only registries whose data met high quality data standards for the
      time period studied (1994-1998) and whose permission was obtained were included.
      Percentage differences were calculated using IARC counts as the base. RESULTS:
      Using IARC multiple primary rules resulted in 2.4% fewer cases. Among females,
      the highest percent changes by category were: age group - 80-84 year-olds (3.4%);
      histology - inflammatory breast cancer (4.6%); stage - distant (3.1%); grade -
      well differentiated (3.0%). Among males, the highest percent changes by category
      were: age group - 80-84 year-olds (1.7%); histology - for intraductal and lobular
      breast carcinoma in combination (4.8%); stage - distant (3.0%); grade - well
      differentiated (1.8%). Overall differences were generally unaffected when
      examined by laterality. CONCLUSION: Breast cancer case counts are dependent on
      the multiple primary coding rules used.

PMID- 15017132
TI  - A population-based study of survival among elderly persons diagnosed with
      colorectal cancer: does race matter if all are insured? (United States).
AB  - OBJECTIVES: Racial disparities in colorectal cancer (CRC) outcomes exist.
      Insurance coverage might impact access to care and thus processes and outcomes of
      care. We examined the effect of race on CRC outcomes in a population-based study
      of elderly Tennesseeans who had identical healthcare coverage - simultaneous
      enrollment in both Medicaid and Medicare. METHODS: The study cohort consisted of
      all persons dually enrolled in both Tennessee Medicaid and Medicare who were
      hospitalized with an incident CRC between 1984 and 1994 and whose medical records
      were available for review. Information confirming the diagnosis and staging was
      obtained by review of hospital records. Administrative data from the Tennessee
      Medicaid database identified important medical co-morbidities and determined
      which patients received chemotherapy and radiotherapy. We ascertained vital
      status though 2001 by a search of state and national death certificates using the
      National Death Index. RESULTS: 697 white patients and 272 black patients were
      identified with incident CRC. Blacks were slightly less likely to be diagnosed
      with localized disease than whites (45.2% versus 56.1%, p < 0.01). In a Cox
      regression model that controlled for stage and co-morbidities, there was no
      racial difference in overall mortality (HR for blacks 0.95, 95% CI: 0.81-1.11).
      Blacks were less likely to have surgery (86% versus 91%, p = 0.02). Chemotherapy
      (for stage III or greater) or radiation therapy for rectal cancer was not used as
      frequently as expected in this elderly population. CONCLUSIONS: In this
      population-based study of elderly Tennesseans covered by both Medicaid and
      Medicare, there were no significant differences in outcomes, raising the
      possibility that 'equal coverage*rsquo; leads to more equal outcomes.

PMID- 15017133
TI  - Alcohol and ovarian cancer risk: results from the Netherlands Cohort Study.
AB  - OBJECTIVE: To study alcohol consumption in relation to ovarian cancer risk in a
      prospective cohort study. METHODS: The Netherlands Cohort Study on diet and
      cancer was initiated in 1986. A self-administered questionnaire on dietary habits
      and other risk factors for cancer was completed by 62,573 postmenopausal women.
      Follow-up for cancer was established by annual record linkages with the
      Netherlands Cancer Registry. After 9.3 years of follow-up, 214 incident invasive
      epithelial ovarian cancer cases and 2211 subcohort members with complete data on
      alcohol intake were available for analysis. All incidence rate ratios (RRs) were
      corrected for age, use of oral contraceptives, parity, height, body mass index,
      energy intake and current cigarette smoking. RESULTS: The RRs of ovarian cancer
      for women who consumed up to 5, 15 and >15 g of alcohol per day were 1.13 (95%
      confidence interval, 95% CI = 0.79-1.63), 0.85 (95% CI = 0.53-1.37) and 0.92 (95%
      CI = 0.55-1.54), respectively, compared to non-drinkers. Alcohol consumption in
      the form of wine, beer or liquor was not associated with ovarian cancer risk.
      CONCLUSION: These data do not suggest a major association between alcohol intake
      and ovarian cancer risk in this population.

PMID- 15017134
TI  - Insulin-like growth factor binding protein-3: relationship to the development of
      gastric pre-malignancy and gastric adenocarcinoma (United Kingdom).
AB  - IGF family proteins play a pivotal role in regulating cell growth and apoptosis
      in normal and tumour tissues. IGFBP-3 is the major binding protein of IGFs and
      modulates the bioactivity of IGFs. To examine the role of IGFBP-3 in gastric
      cancer, an IGFBP3 promoter polymorphism, and serum and gastric mucosal levels of
      IGFBP-3 were assessed in two independent groups of patients (396 and 117
      patients, respectively) with gastroduodenal diseases. There was no significant
      association between IGFBP-3 polymorphism and different gastroduodenal diseases (
      p = 0.6), but a significantly higher frequency of CC, a genotype related to lower
      levels of serum IGFBP-3 previously, were observed in patients with antral
      intestinal metaplasia when compared with those without this pre-malignancy ( p =
      0.04). Similarly, data from another independent group of patients further showed
      that patients with antral or corpus intestinal metaplasia had significantly lower
      serum levels of IGFBP-3 than those without these changes ( p = 0.03 and 0.04,
      respectively). Furthermore, the percentage of positive IGFBP-3 staining in tumour
      tissue was significantly higher in patients with well or moderately
      differentiated tumours than those with poorly differentiated tumours ( p = 0.04),
      indicating that IGFBP-3 may be associated with a better prognosis. In conclusion,
      our study suggests that IGFBP-3 may be protective against the development of
      gastric adenocarcinoma by preventing the formation of intestinal metaplasia and
      improve the prognosis of gastric cancer.

PMID- 15017135
TI  - Assignment of protein backbone resonances using connectivity, torsion angles and
      13Calpha chemical shifts.
AB  - A program is presented which will return the most probable sequence location for
      a short connected set of residues in a protein given just (13)C(alpha) chemical
      shifts (delta((13)C(alpha))) and data restricting the phi and psi backbone
      angles. Data taken from both the BioMagResBank and the Protein Data Bank were
      used to create a probability density function (PDF) using a multivariate normal
      distribution in delta((13)C(alpha)), phi, and psi space for each amino acid
      residue. Extracting and combining probabilities for particular amino acid
      residues in a short proposed sequence yields a score indicative of the
      correctness of the proposed assignment. The program is illustrated using several
      proteins for which structure and (13)C(alpha) chemical shift data are available.

PMID- 15017136
TI  - Dipolar assisted rotational resonance NMR of tryptophan and tyrosine in
      rhodopsin.
AB  - Two dimensional (2D) solid-state (13)C.(13)C dipolar recoupling experiments are
      performed on a series of model compounds and on the visual pigment rhodopsin to
      establish the most effective method for long range distance measurements in
      reconstituted membrane proteins. The effects of uniform labeling, inhomogeneous
      B(1) fields, relaxation and dipolar truncation on cross peak intensity are
      investigated through NMR measurements of simple amino acid and peptide model
      compounds. We first show that dipolar assisted rotational resonance (DARR) is
      more effective than RFDR in recoupling long-range dipolar interactions in these
      model systems. We then use DARR to establish (13)C-(13)C correlations in
      rhodopsin. In rhodopsin containing 4'-(13)C-Tyr and 8,19-(13)C retinal, we
      observe two distinct tyrosine-to-retinal correlations in the DARR spectrum. The
      most intense cross peak arises from a correlation between Tyr268 and the retinal
      19-(13)CH(3), which are 4.8 A apart in the rhodopsin crystal structure. A second
      cross peak arises from a correlation between Tyr191 and the retinal 19-(13)CH(3),
      which are 5.5 A apart in the crystal structure. These data demonstrate that long
      range (13)C em leader (13)C correlations can be obtained in non-crystalline
      integral membrane proteins reconstituted into lipid membranes containing less
      than 150 nmoles of protein. In rhodopsin containing 2-(13)C Gly121 and U-(13)C
      Trp265, we do not observe a Trp-Gly cross peak in the DARR spectrum despite their
      close proximity (3.6 A) in the crystal structure. Based on model compounds, the
      absence of a (13)C em leader (13)C cross peak is due to loss of intensity in the
      diagonal Trp resonances rather than to dipolar truncation.

PMID- 15017137
TI  - Interpretation of NMR relaxation properties of Pin1, a two-domain protein, based
      on Brownian dynamic simulations.
AB  - Many important proteins contain multiple domains connected by flexible linkers.
      Inter-domain motion is suggested to play a key role in many processes involving
      molecular recognition. Heteronuclear NMR relaxation is sensitive to motions in
      the relevant time scales and could provide valuable information on the dynamics
      of multi-domain proteins. However, the standard analysis based on the separation
      of global tumbling and fast local motions is no longer valid for multi-domain
      proteins undergoing internal motions involving complete domains and that take
      place on the same time scale than the overall motion. The complexity of the
      motions experienced even for the simplest two-domain proteins are difficult to
      capture with simple extensions of the classical Lipari-Szabo approach.
      Hydrodynamic effects are expected to dominate the motion of the individual
      globular domains, as well as that of the complete protein. Using Pin1 as a test
      case, we have simulated its motion at the microsecond time scale, at a reasonable
      computational expense, using Brownian Dynamic simulations on simplified models.
      The resulting trajectories provide insight on the interplay between global and
      inter-domain motion and can be analyzed using the recently published method of
      isotropic Reorientational Mode Dynamics which offer a way of calculating their
      contribution to heteronuclear relaxation rates. The analysis of trajectories
      computed with Pin1 models of different flexibility provides a general framework
      to understand the dynamics of multi-domain proteins and explains some of the
      observed features in the relaxation rate profile of free Pin1.

PMID- 15017138
TI  - A complete set of novel 2D correlation NMR experiments based on heteronuclear J
      cross polarization.
AB  - A suite of multiple-purpose sensitivity-enhanced 2D correlation NMR experiments
      based on heteronuclear J-cross polarization (HCP) techniques are introduced for
      isotropic liquid samples. Several pulse sequences using an adaptable
      heteronuclear TOCSY mixing building block are proposed for different types of
      effective coherence-order-selective (COS) heteronuclear coherence-transfer
      mechanisms. They are based on the anisotropic behaviour of the involved HCP
      process that is easily described and analysed in terms of cartesian product
      operator formalism. A number of different versions are given for in-phase to in
      phase (II-COS: S (-) ?? to I (-)), in-phase to anti-phase (IA-COS: S (-) ?? to 2
      I (-) S (z)), in-phase to spin-state-selective (IS(3)-COS: S (-) ?? to 2 I (-) S
      (alpha /beta)), anti-phase to in-phase (AI-COS: 2 I (z) S (-) ?? to I (-)), anti
      phase to anti-phase (AA-COS: 2 I (z) S (-) ?? to 2 I (-) S (z)), anti-phase to
      spin-state-selective (AS(3)-COS: 2 I (z) S (-) ?? to 2 I (-) S (alpha /beta)) and
      spin-state-selective to spin-state-selective (S(3)S(3)-COS: 2 I (alpha /beta) S (
      ) ?? to 2 I (-) S (alpha /beta )) coherence transfers. The combination of the
      echo/anti-echo approach, heteronuclear gradient echoes and the preservation of
      equivalent pathways (PEP) methodology affords a general approach to obtain
      sensitivity-enhanced pure-absorption 2D spectra that can be used as interesting
      alternatives to conventional pulse-interrupted free-precession INEPT-based pulse
      schemes, such as HSQC-type and TROSY-type experiments.

PMID- 15017139
TI  - Combined frequency- and time-domain NMR spectroscopy. Application to fast protein
      resonance assignment.
AB  - A simple and general method is presented to simplify multi-dimensional NMR
      spectra of isotope-labeled bio-molecules. The approach is based on band-selective
      Hadamard-type frequency encoding, which disperses the correlation peaks into
      different sub-spectra. This makes it possible to apply low-dimensionality-based
      NMR techniques to larger molecular systems. Here we demonstrate the use of band
      selective Hadamard frequency labeling for fast protein resonance assignment,
      based on our recently proposed suite of 2D experiments (Bersch et al., 2003).

PMID- 15017140
TI  - Trans-hydrogen bond deuterium isotope effects of A:T base pairs in DNA.
AB  - The chemical shifts of (13)C2 of adenosine residues of DNA were observed to
      experience a through-space or trans-hydrogen bond isotope effect as a result of
      deuterium substitution at the imino hydrogen site of base-paired thymidine
      residues. NMR measurements of several self-complementary DNA duplexes at natural
      abundance (13)C in 50% H(2)O, 50% D(2)O solvent mixtures yielded an average trans
      hydrogen bond isotope effect, (2h)Delta(13)C2, of -47 ppb. The data suggest that
      stronger hydrogen bonds have more negative (2h)Delta(13)C2 values, which means
      that A:T N1.H3 hydrogen bonds increase the anharmonicity of the effective
      vibrational potential of H3. However, (2h)Delta(13)C2 values do not correlate
      with intra-residue (2)Delta(13)C4 values of thymidine observed here and earlier
      (Vakonakis et al., 2003), which suggests that (2h)Delta(13)C2 is not determined
      entirely by hydrogen bond strength. Instead, the variations observed in
      (2h)Delta(13)C2 values suggest that they may also be sensitive to base pair
      geometry.

PMID- 15017141
TI  - NMR structural characterization of the N-terminal domain of the adenylyl cyclase
      associated protein (CAP) from Dictyostelium discoideum.
AB  - Cyclase-associated proteins (CAPs) are highly conserved, ubiquitous actin binding
      proteins that are involved in microfilament reorganization. The N-termini of CAPs
      play a role in Ras signaling and bind adenylyl cyclase; the C-termini bind to G
      actin. We report here the NMR characterization of the amino-terminal domain of
      CAP from Dictyostelium discoideum (CAP(1-226)). NMR data, including the steady
      state (1)H-(15)N heteronuclear NOE experiments, indicate that the first 50 N
      terminal residues are unstructured and that this highly flexible serine-rich
      fragment is followed by a stable, folded core starting at Ser 51. The NMR
      structure of the folded core is an alpha-helix bundle composed of six
      antiparallel helices, in a stark contrast to the recently determined CAP C
      terminal domain structure, which is solely built by beta-strands.

PMID- 15017142
TI  - Solution structures of reduced and oxidized bacteriophage T4 glutaredoxin.

PMID- 15017144
TI  - Sequence-specific 1H, 13C and 15N resonance assignments of Ara h 6, an allergenic
      2S albumin from peanut.

PMID- 15017145
TI  - Sequence specific 1H, 13C and 15N resonance assignments of the hath-domain of
      human hepatoma-derived growth factor.

PMID- 15017146
TI  - 1H, 13C and 15N backbone resonance assignments of the hyaluronan-binding domain
      of CD44.

PMID- 15017143
TI  - Sequence-specific backbone NMR assignments for the C-terminal globular domain of
      EMILIN-1.

PMID- 15017147
TI  - NMR assignment of TM1442, a putative anti-sigma factor antagonist from Thermotoga
      maritima.

PMID- 15017148
TI  - NMR assignment of the hypothetical protein HI0004 from Haemophilus influenzae--a
      putative essential gene product.

PMID- 15017149
TI  - Sequential resonance assignments of the extracellular domain of the human TGFbeta
      type II receptor in complex with monomeric TGFbeta3.

PMID- 15017150
TI  - Differences in the symptoms associated with unstable angina and myocardial
      infarction.
AB  - The purpose of this study was to examine whether the symptoms experienced by
      patients with unstable angina (UA) differed from the symptoms experienced by
      patients with myocardial infarction (MI). Data were obtained from two studies:
      one examining the symptoms of MI (n=238) and one examining the symptoms of UA
      (n=100). Interviews were conducted after hospital admission at three medical
      centers in the Midwest. There were no differences between patients with MI or UA
      in age, gender, or race. The patients experiencing MI reported significantly more
      nausea (46% vs. 32%), vomiting (19% vs. 2%), indigestion (42% vs. 16%), and
      fainting (9% vs. 2%). The patients experiencing UA reported significantly more
      chest discomfort (97% vs. 87%), lightheadedness (52% vs. 39%), numbness in the
      hands (43% vs. 28%), and neck discomfort (31% vs. 13%). Patients with MI rated
      the peak intensity of the chest discomfort higher than patients with UA (mean 8.4
      vs. mean 7.7).

PMID- 15017151
TI  - Differences between frontier and urban elders with chronic heart failure.
AB  - The purpose of this study was to compare 136 frontier and 148 urban patients with
      chronic heart failure who were aged 60 years and older. Medical records from 2000
      to 2002 were reviewed from a regional tertiary hospital in Montana. While the two
      groups did not differ with respect to New York Heart Association functional class
      and number of comorbid conditions, the frontier sample was more likely to be
      male, married, and younger. Frontier patients were more depressed and scored
      significantly lower on quality-of-life measures. Among those who had died,
      frontier patients survived an average of 7.7 months, in contrast to urban
      patients who survived an average of 13.4 months following index hospitalization.
      Frontier patients have few available health care services and providers may not
      treat patients as expertly or aggressively as urban providers. Frontier patients
      tend to be isolated due to illness, lack of transportation, travel distances, and
      weather-related barriers. Many may be falling through the cracks.

PMID- 15017152
TI  - Sleep-disordered breathing and the association with cardiovascular risk.
AB  - Breathing-related sleep disorders, particularly obstructive sleep apnea, have
      been largely undiagnosed in people with cardiovascular disease, probably due to
      limited health care provider awareness of the association between the two
      conditions. Solid evidence is emerging that the apneic events that occur during
      sleep lead to acute and chronic hemodynamic changes during wake time, including
      elevated sympathetic tone, decreased stroke volume and cardiac output, increased
      heart rate, and changes in circulating hormones that regulate blood pressure,
      fluid volume, vasoconstriction, and vasodilation. Obstructive sleep apnea is
      associated with known cardiovascular risk factors such as obesity and
      hyperlipidemia, and is considered by many sleep clinicians to be an independent
      risk factor for hypertension. Additionally, sleep apnea has been implicated in
      the pathogenesis of heart failure and stroke. Treatment with positive airway
      pressure during sleep eliminates the apneic events and the ensuing acute
      hemodynamic changes. Improvements in daytime blood pressure and left ventricular
      function also have been noted in persons with hypertension and heart failure.
      Because effective treatment is available for sleep apnea, this condition needs to
      be diagnosed and treated in persons with cardiovascular disease.

PMID- 15017153
TI  - Adherence to long-term therapies management: a call for cardiovascular nursing
      managers and policymakers.

PMID- 15017154
TI  - How sweet it is.

PMID- 15017155
TI  - Left ventricular diastolic dysfunction: risks, identification, and treatment.
AB  - Risk factors of cardiovascular disease, such as hypertension, diabetes, and
      myocardial infarction, if left untreated, will increase the risk of the
      development of chronic heart failure. Much is known about the pathophysiology and
      effective treatments of chronic heart failure from left ventricular systolic
      dysfunction; however, little clinical trial evidence exists concerning benefits
      of treating patients with chronic heart failure and preserved systolic function,
      also known as left ventricular diastolic dysfunction. Rather, an understanding of
      the pathophysiology and patient signs and symptoms has usually dictated choice of
      treatments. With the results of ongoing trials, as well as the Candesartan in
      Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)
      Preserved and the Digitalis Investigation Group (DIG) trials, clinical evidence
      is accumulating to support effective treatments in patients with left ventricular
      diastolic dysfunction. The focus of this review is to discuss the risks of,
      identification of, and rationale for therapeutic choices being employed for
      treating left ventricular diastolic dysfunction and implications from studies
      that may support these choices.

PMID- 15017156
TI  - When three ECGs tell the story.

PMID- 15017174
TI  - Limitations of the Panoramic 200 Optomap.

PMID- 15017175
TI  - Glenn Fry award lecture 2002: wavefront sensing, ideal corrections, and visual
      performance.

PMID- 15017176
TI  - Spasm of the near reflex triggered by disruption of normal binocular vision.
AB  - A 26-year-old healthy female was referred by her optometrist to the binocular
      vision clinic of our institution for the investigation of an accommodative spasm
      occurring during monocular conditions. Corrected binocular visual acuity was
      20/20 (6/6), with normal pupils and good ocular alignment. When the fellow eye
      was covered, visual acuity was <20/200 (6/60) in each eye, miosis was present in
      both eyes, and the occluded eye was in esodeviation, indicating a spasm of the
      near reflex. The spasm disappeared when a translucent occluder was used instead
      of an opaque black occluder. Further investigation permitted us to establish that
      dioptric and nondioptric blur, as well as reduced light transmission, also
      triggered the spasm of the near reflex, but only for specific power, opacity, or
      density. Cycloplegia did not eliminate the spasm. Comparisons are made with the
      single other similar case found in the literature. Assumptions are made as to the
      possible causes of that intermittent spasm.

PMID- 15017178
TI  - Contact lens-induced corneal swelling and surface changes measured with the
      Orbscan II corneal topographer.
AB  - PURPOSE: The purpose of this study was to measure central and topographical
      corneal swelling in response to contact lens wear and eye closure, to determine
      whether the swelling induced by soft and polymethyl methacrylate (PMMA) lenses is
      different, and to determine whether the anterior and/or posterior corneal shape
      alters with corneal swelling. METHODS: An Orbscan II corneal topographer was used
      to measure corneal swelling and the shape of the anterior and posterior corneal
      surfaces of 16 neophytes before and after wearing soft and PMMA contact lenses
      with near-zero oxygen transmissibility. The lens-wearing eye was patched for 3 h.
      RESULTS: The mean 15.1% +/- 3.8% (+/- SD) central corneal swelling with soft
      lenses was significantly >12.6% +/- 4.1% with PMMA lenses. Topographical corneal
      swelling was significantly greater with soft vs. PMMA lenses. However, the
      difference between central and peripheral corneal swelling was much greater with
      PMMA lenses. With both lenses, the cornea swelled significantly more in the
      center than the periphery. The anterior best-fit sphere radius remained unchanged
      in response to soft lenses (0.00 +/- 0.04 mm) and steepened slightly but
      significantly with PMMA lenses (-0.04 +/- 0.05 mm). The posterior best-fit sphere
      radius flattened significantly with both lenses (0.12 +/- 0.07 mm with soft and
      0.14 +/- 0.08 mm with PMMA lenses). CONCLUSIONS: Corneal swelling (greater
      centrally than peripherally) flattens the posterior surface of the cornea and is
      independent of lens type. Although the anterior best-fit sphere radius steepened
      with PMMA, the magnitude is probably clinically unimportant. Both lens types
      produced greater central vs. peripheral corneal swelling. However, the soft lens
      induced significantly greater overall swelling than PMMA. Because their oxygen
      transmission was the same, these results suggest that there is lateral diffusion
      of oxygen from the peripheral area of the cornea (that is not covered by the
      lens) toward the center.

PMID- 15017179
TI  - Effect of contact lens materials on tear physiology.
AB  - PURPOSE: This study measured evaporation rate, thinning characteristics, and
      lipid layer changes in the prelens tear film (PLTF) associated with wearing of
      different soft contact lens materials, in an attempt to determine the
      biocompatibility of the material with the PLTF. METHODS: Twenty habituated
      contact lens wearers wore five different soft materials in a random order on the
      left eye at visits separated by at least 24 h. The soft contact lens materials
      were polymacon (Optima 38), omafilcon A (Proclear Compatibles), phemfilcon A
      (DuraSoft 2), balafilcon A (PureVision), and etafilcon A (Acuvue). Tear film
      evaporation rate was measured by a modified Servo Med Evaporimeter and tear
      thinning time by HirCal grid. Tear film structure, elimination rate, and lens
      wetting ability were recorded dynamically with a Doane tear film video
      interferometer and graded according to a new system developed for the study.
      Baseline measurements were taken of the precorneal tear film before lens
      insertion, and PLTF was determined 30 min after commencing lens wear. RESULTS: No
      statistically significant differences were found for any of the baseline
      (precorneal tear film) data. There was also no significant difference in
      evaporation rate change (analysis of variance) and in tear thinning time
      (Friedmann) between the five contact lenses. In the PLTF structure grading,
      omafilcon A had significantly more stable grades than phemfilcon A (Friedmann, p
      = 0.0033) and polymacon (p = 0.004). In PLTF observation of tear thinning and
      elimination rate, there was a significantly slower rate of elimination observed
      for omafilcon A than phemfilcon A (Friedmann, p = 0.0023) and polymacon (p =
      0.0023). There was no significant difference in the overall PLTF wetting ability
      grading between any of the lenses worn. CONCLUSION: Generally, all soft contact
      lens materials significantly and adversely affected tear physiology by increasing
      the evaporation rate and decreasing tear thinning time. The surface wetting
      ability of all contact lens materials exhibited no significantly difference
      irrespective of the special surface treatments. Only in PLTF structure and in
      PLTF elimination rate were differences found from the conventional low water
      content materials; omafilcon A was better in PLTF structure and in PLTF
      elimination.

PMID- 15017177
TI  - Variables affecting rigid contact lens comfort in the collaborative longitudinal
      evaluation of keratoconus (CLEK) study.
AB  - PURPOSE: To identify factors associated with rigid contact lens comfort in
      keratoconus. METHODS: Baseline data from the 16 Collaborative Longitudinal
      Evaluation of Keratoconus (CLEK) Study clinical sites were analyzed for all
      patients wearing a rigid contact lens in their more severely keratoconic eye (as
      determined by steep keratometry). Corneal transplant patients, patients who did
      not wear a rigid contact lens in either eye, patients who did not wear a rigid
      lens in their worse eye, and patients with missing contact lens comfort data were
      excluded from the sample. A total of 751 eyes were included. Variables assessed
      included measures of disease severity, visual acuity through the patients'
      habitual rigid contact lenses, contact lens wearing time, the apical fitting
      relationship of the contact lens, the degree of peripheral clearance, and the
      presence of corneal scarring and staining. Comfort was measured by asking the
      patients "In general, how comfortable are your contact lenses?" (1 = very
      comfortable through 5 = very irritating). RESULTS: Measures of disease severity
      (steep keratometry and the first definite apical clearance lens) were not
      associated with lens comfort. There was no difference in self-reported contact
      lens comfort between patients fitted with apical touch vs. apical clearance.
      Patients with a peripheral clearance rating of "minimal unacceptable" (more
      common among patients with milder keratoconus) were approximately half as likely
      to report good contact lens comfort compared with patients with "average"
      peripheral clearance (unadjusted odds ratio, 0.39; 95% confidence interval, 0.19
      to 0.79). There was no association between contact lens comfort and the other
      peripheral clearance ratings compared with ratings of average. CONCLUSIONS: There
      does not appear to be an association between decreasing patient-reported rigid
      lens comfort and increasing disease severity as measured by steep keratometry or
      first definite apical clearance lens in this sample. The apical fitting
      relationship (flat vs. steep) does not appear to be associated with patient
      reported comfort. Minimal peripheral clearance may contribute to decreased rigid
      contact lens comfort in keratoconus.

PMID- 15017180
TI  - Preferred retinal locus and reading rate with four dynamic text presentation
      formats.
AB  - BACKGROUND: Electronic display devices hold the potential to improve access to
      written material by people with low vision. For those with central field loss,
      the optimal form of electronic text presentation may vary according to the
      location of the preferred retinal locus, but this has never been investigated. In
      this study, we examined the relationship between preferred retinal locus location
      and reading rate for four electronic display formats (rapid serial visual
      presentation, horizontal scroll, vertical scroll, and page). METHODS: Short
      sentences were presented in each format to 35 low-vision (most with central field
      loss) and 14 age-matched control subjects. Subjects read aloud to determine
      maximum oral reading rate and read silently to determine preferred silent reading
      rate. RESULTS: With the exception of page format, maximum oral reading rates were
      faster than silent preferred reading rates for both groups of subjects. For the
      low-vision group, there was no significant difference in maximum oral reading
      rates between the four display formats; and when reading at a preferred silent
      rate, page format was faster than the other three formats. Though page format was
      read more quickly, half of the low-vision subjects preferred the horizontal
      scroll format. Contrary to our predictions, there was no significant effect of
      preferred retinal locus location (vertical vs. lateral) on reading rate and no
      significant interaction between preferred retinal locus location and display
      format. CONCLUSIONS: The differences between maximum oral and preferred silent
      reading rates and the lack of a relationship between reading rates and preferred
      display format reinforce the importance of patient preference in the evaluation
      and selection of a device or display format during rehabilitation.

PMID- 15017181
TI  - Neuroretinal function during systemic hyperoxia and hypercapnia in humans.
AB  - PURPOSE: Breathing pure oxygen (O2) or carbogen is known to have differential
      effects on the retinal and choroidal blood flow. Our objective was to evaluate
      the effects these hemodynamic changes have on various retinal neurons receiving
      their vital nutrients from these two vascular beds. To that effect, we recorded
      the photopic flash electroretinogram (fERG) and oscillatory potentials (OP's) in
      man. METHODS: Eighteen adults participated in two test sessions to examine the
      effects of breathing pure O2 or carbogen on the fERG's and OP's. The retinal
      potentials were recorded at the end of each of the following breathing phases:
      (1) room air for 5 min, (2) pure O2 or carbogen for 5 min, (3) immediately after
      the flow of gas was stopped, and (4) 10 min after the flow of gas was stopped.
      The heart rate, respiratory rate, oxygen saturation (Sao2), and end-tidal carbon
      dioxide (Etco2) were monitored. The blood pressure and intraocular pressure were
      measured to derive the ocular perfusion pressure. RESULTS: Breathing pure O2
      increased Sao2, decreased heart rate and Etco2, but did not alter respiratory
      rate and ocular perfusion pressure. Breathing carbogen increased Sao2, Etco2, and
      ocular perfusion pressure, decreased respiratory rate but did not alter heart
      rate. The fERG's and OP's were not detrimentally affected by breathing either
      pure oxygen or carbogen. Only OP4 was delayed at the end of testing in the O2
      session. CONCLUSION: Our results show that the neural generators of the photopic
      fERG's and OP's in man are largely unaltered by the degree of systemic hyperoxia
      and hypercapnia induced and their reported effects on retinal and choroidal
      hemodynamics. These results, combined with earlier studies showing that some
      components of the scotopic fERG's and OP's were altered during similar testing
      conditions, suggest that the photopic system is more resistant than the scotopic
      system to altered ocular hemodynamics.

PMID- 15017184
TI  - The contemporary management of prostate cancer in the United States: lessons from
      the cancer of the prostate strategic urologic research endeavor (CapSURE), a
      national disease registry.
AB  - PURPOSE: The epidemiology and treatment of prostate cancer have changed
      dramatically in the prostate specific antigen era. A large disease registry
      facilitates the longitudinal observation of trends in disease presentation,
      management and outcomes. MATERIALS AND METHODS: The Cancer of the Prostate
      Strategic Urologic Research Endeavor (CaPSURE) is a national disease registry of
      more than 10000 men with prostate cancer accrued at 31 primarily community based
      sites across the United States. Demographic, clinical, quality of life and
      resource use variables are collected on each patient. We reviewed key findings
      from the data base in the last 8 years in the areas of disease management trends,
      and oncological and quality of life outcomes. RESULTS: Prostate cancer is
      increasingly diagnosed with low risk clinical characteristics. With time patients
      have become less likely to receive pretreatment imaging tests, less likely to
      pursue watchful waiting and more likely to receive brachytherapy or hormonal
      therapy. Relatively few patients treated with radical prostatectomy in the
      database are under graded or under staged before surgery, whereas the surgical
      margin rate is comparable to that in academic series. CaPSURE data confirm the
      usefulness of percent positive biopsies in risk assessment and they have further
      been used to validate multiple preoperative nomograms. CaPSURE results strongly
      affirm the necessity of patient reported quality of life assessment. Multiple
      studies have compared the quality of life impact of various treatment options,
      particularly in terms of urinary and sexual function, and bother. CONCLUSIONS:
      The presentation and management of prostate cancer have changed substantially in
      the last decade. CaPSURE will continue to track these trends as well as
      oncological and quality of life outcomes, and will continue to be an invaluable
      resource for the study of prostate cancer at the national level.

PMID- 15017185
TI  - Alpha-linolenic acid and the risk of prostate cancer. What is the evidence?
AB  - PURPOSE: Several studies have examined the association between polyunsaturated
      fatty acids and prostate cancer risk. We evaluated the evidence on the
      association between the essential polyunsaturated fatty acid, known as alpha
      linolenic acid, and the risk of prostate cancer in humans. MATERIALS AND METHODS:
      We comprehensively reviewed published studies on the association between alpha
      linolenic acid and the risk of prostate cancer using MEDLINE. RESULTS: A number
      of studies have shown a positive association between dietary, plasma or red blood
      cell levels of alpha-linolenic acid and prostate cancer. Other studies have
      demonstrated either no association or a negative association. The limitations of
      these studies include the assumption that dietary or plasma alpha-linolenic acid
      levels are positively associated with prostate tissue alpha-linolenic acid
      levels, and measurement errors of dietary, plasma and red blood cell alpha
      linolenic acid levels. CONCLUSIONS: More research is needed in this area before
      it can be concluded that there is an association between alpha-linolenic acid and
      prostate cancer.

PMID- 15017186
TI  - Ballistics for physicians: myths about wound ballistics and gunshot injuries.
AB  - PURPOSE: Wound ballistics is a difficult subject. The behavior of all bullets is
      unpredictable but the specific effect of high velocity projectiles has been a
      particular source of confusion in the literature. This confusion has resulted in
      the likely incorrect conclusion that all high velocity wounds require massive
      debridement. We reviewed the entirety of the literature on this subject and
      concluded that high velocity weapons do not reliably create massive wounds, and
      judicious debridement and staged explorations may be the best treatment method
      for these patients. MATERIALS AND METHODS: A MEDLINE search and retrieval were
      done of all pertinent references from 1966 to May 2003 concerning the field of
      wound ballistics. Articles initially missed in this search were obtained from the
      bibliography of retrieved studies. More than 70 articles and book chapters were
      reviewed. RESULTS: Five common myths about the tissue effects of gunshot wounds
      were reviewed as well as the data that dispel these myths. Information on the
      effects of different bullet types, and the intended and actual effect of military
      rifle wounds were assessed. CONCLUSIONS: For the majority of high velocity
      gunshot wounds, especially military rifles that generally fire a projectile that
      is meant to stay intact after impact, wound severity can be limited, even much
      less than that from a civilian rifle, shotgun or handgun. Judicious use of
      debridement during surgical exploration limits the extent of iatrogenic injury in
      the surgical care of these patients.

PMID- 15017187
TI  - Nostrums in urology.

PMID- 15017188
TI  - Early identification of individuals with prostate cancer in negative biopsies.
AB  - PURPOSE: The use of prostate specific antigen (PSA) to screen individuals for
      prostate cancer has changed the management of the disease, permitting early
      detection in men. Repeat biopsies for persistently increased PSA are not uncommon
      with prostate cancer never being detected in many of the men. The novel prostate
      cancer marker, EPCA, is expressed throughout the prostate of individuals with
      prostate cancer but not in those without the disease. MATERIALS AND METHODS: The
      expression of ECPA was studied to identify those men with initially negative
      biopsies who were ultimately found to have prostate cancer. Negative biopsies,
      subsequent biopsies and prostatectomy specimens were evaluated by quantitative
      immunohistochemistry. RESULTS: The EPCA staining intensity in the samples
      analyzed from the patient cohort with prostate carcinoma were significantly
      different compared to controls (p <0.001) with almost no overlap in staining
      results. Sensitivity of the EPCA immunohistochemistry is 84% and specificity is
      85%. CONCLUSIONS: An immunohistochemical test for EPCA could serve as an adjunct
      to the current diagnostic approach to a patient who undergoes prostate needle
      biopsy, and could identify individuals with prostate cancer as much as 5 or more
      years earlier than the current diagnostic approach and algorithms. In addition,
      this test might also help limit the numbers of biopsies performed as part of
      subsequent routine evaluation for increased PSA.

PMID- 15017189
TI  - Evaluation and selection of potential live kidney donors.
AB  - PURPOSE: Renal transplantation is an optimal therapy for patients with end stage
      kidney disease. A thorough evaluation of potential donors is necessary to provide
      the best functional outcome for recipients and ensure no or minimal morbidity for
      donors. MATERIALS AND METHODS: Between 1992 and 2001, 1661 ABO compatible
      potential living donors were evaluated clinically as well as by laboratory and
      imaging studies. RESULTS: Of 1661 potential donors 814 (49%) were excluded. The
      reasons for elimination were general medical reasons in 34.4% of cases,
      nephrological disorders in 25.6%, urological diseases in 11.7% and immunological
      causes in 16.2%. Exclusion on an ethical basis accounted for 12.2% of cases.
      CONCLUSIONS: Although kidneys from living donors provide the best functional
      outcome, 50% of potential candidates must be excluded.

PMID- 15017190
TI  - Clinical and urodynamic evaluation after ureterocystoplasty and kidney
      transplantation.
AB  - PURPOSE: We assessed clinical and surgical results in renal transplantation
      candidates with voiding dysfunction and end stage renal disease who underwent
      bladder augmentation. MATERIALS AND METHODS: We analyzed 8 patients 3 to 30 years
      old with dilated ureters, voiding dysfunction and end stage renal disease who
      underwent renal transplantation following bladder augmentation from 1995 to 2003.
      The etiology of bladder dysfunction was neurogenic bladder in 3 patients,
      posterior urethral valves in 3 and vesicoureteral reflux in 2. All cases were
      assessed by ultrasonography, voiding cystourethrography and urodynamic studies.
      RESULTS: Mean followup was 50 months (range 4 to 93). Previous urodynamic
      evaluation revealed a bladder capacity of 75 to 294 ml (mean +/- SD 167.38 +/-
      77.32) and an intravesical pressure of 28 to 100 mm H2O (mean 51.25 +/- 22.17).
      Urodynamic study after augmentation and kidney transplantation showed a bladder
      capacity of 191 to 400 ml (mean 335.25 +/- 99.01) and an intravesical pressure of
      15 to 35 mm H2O (mean 28 +/- 9.45). Mean serum creatinine was 1.65 mg/dl (range
      0.8 to 2.5). All patients remained continent. Three patients with neurogenic
      bladder empty the bladder by clean intermittent catheterization and the others
      empty by the Valsalva maneuver. None of the grafts were lost and the most common
      complication was asymptomatic urinary tract infection. CONCLUSIONS: Bladder
      augmentation is a well-known procedure for low capacity and poorly compliant
      bladders even in candidates for a renal transplant. Ureterocystoplasty combines
      the benefits common to all enterocystoplasties without adding to complications or
      risks.

PMID- 15017191
TI  - Rapid elimination by glomerular filtration of free prostate specific antigen and
      human kallikrein 2 after renal transplantation.
AB  - PURPOSE: The low molecular mass and short half-life of free (f) prostate specific
      antigen (PSA) implies elimination from blood by glomerular filtration. In
      addition, patients with terminal renal failure have increased fPSA in serum but
      there have been sparse data reported on the rates and pathways of elimination of
      PSA complexes and human kallikrein 2 (hK2). We studied glomerular filtration
      dependent elimination of fPSA and hK2 in patients with renal insufficiency
      undergoing successful renal transplantation. MATERIALS AND METHODS: We studied 14
      patients with immediate onset of renal function after renal transplantation.
      Blood samples were obtained before and at regular intervals up to 160 hours after
      transplanted kidney reperfusion. Measurements of fPSA, total PSA and hK2 were
      performed with immunofluorometric assays and complexed PSA was determined by a
      chemiluminiscence assay. Glomerular filtration rates were monitored by analyzing
      serum creatinine and cystatin C. NONMEM, a multivariate pharmacokinetic approach,
      was used to determine the elimination rates of fPSA and hK2 after renal
      transplantation. RESULTS: Serum fPSA and hK2 but not PSA complexes, decreased
      rapidly after renal transplantation. Significant reductions in fPSA and hK2 were
      observed after only 16 and 8 hours, respectively. fPSA and hK2 showed similar
      elimination patterns, decreasing to 42% and 44% of their original levels compared
      to cystatin C, which was at 44% after 160 hours. The median half-lives of fPSA
      and hK2 were 17.4 and 11.5 hours, respectively. CONCLUSIONS: These results verify
      the hypothesis that fPSA and hK2 are eliminated from the blood circulation by
      glomerular filtration and severe renal failure influences the levels of the 2
      proteins in serum.

PMID- 15017192
TI  - A computer model to predict the outcome and duration of ureteral or renal
      calculous passage.
AB  - PURPOSE: We developed a computer model to predict the outcome and the duration
      until passage of ureteral/renal calculi. MATERIALS AND METHODS: A retrospective,
      randomized study was performed of the outcome in 301 patients presenting to the
      emergency room for renal colic. Presenting characteristics of those diagnosed
      with a single calculus by computerized tomography were recorded for analysis.
      Predictors of stone passage and passage duration were identified and then used to
      create a logistic regression model. The algorithm was trained on 141 randomly
      selected patients and then tested on a separate 160 patients. Model accuracy was
      compared to predictions from 10 experienced urologists and 9 urology residents in
      77 randomly selected patients. The model was tested further in 30 randomly
      selected patients at a private hospital to assess its general applicability.
      RESULTS: The model prediction accuracy in 160 patients was 86.3% for passage and
      87.3% for duration (less or greater than 2 weeks). In the comparison group the
      model, the 10 experienced urologists and the 9 urology residents had an overall
      prediction accuracy of 88.3%, 70.5% (p = 0.006) and 72% (p = 0.007) for passage,
      and 87.1%, 71.6% (p = 0.007) and 81% (p = 0.075) for duration, respectively.
      Prediction accuracy was 93.3% for passage and 90.3% for duration when tested at a
      private hospital. CONCLUSIONS: Our model provides outcome and duration of passage
      predictions for patients presenting acutely in the emergency room with a single
      ureteral/renal calculus. It performs better than experienced urologists and
      urology residents. It can be applied to a private practice setting with equal
      accuracy.

PMID- 15017193
TI  - Is antegrade stenting superior to retrograde stenting in laparoscopic
      pyeloplasty?
AB  - PURPOSE: We describe a simple and timesaving technique of antegrade stenting. We
      compared it with retrograde stenting in laparoscopic pyeloplasty. MATERIALS AND
      METHODS: From December 2002 to August 2003, 24 patients with mean age of 24.29
      years (range 5 to 57) had a Double-J (Medical Engineering Corp., New York, New
      York) stent placed laparoscopically after finishing the posterior suture line.
      The stent and ureteral catheter straightened over the guide wire were introduced
      through the lumen of a 5 mm hook or suction canula via a subcostal port. This
      technique was compared with retrograde stenting in 21 consecutive patients with
      mean age of 24.45 years (range 6 to 65) in terms of stenting time and failure to
      stent leading to conversion. RESULTS: In 23 of 24 cases laparoscopic stenting
      could be completed in a mean time of 5.2 minutes. In case 1 the stent was lying
      outside the pelvis because it was placed after ureteropelvic anastomosis was
      completed. The stent was retrieved after placing the ports again and reinserted
      with retrograde technique. In subsequent cases the stent was inserted
      successfully after completing the posterior suture line and visualizing the
      ureteral lumen. Mean time of retrograde stenting was 39.35 minutes. One case was
      converted to open pyeloplasty after retrograde stenting failed and in another 5Fr
      ureteral catheter was left instead. However, this patient required percutaneous
      stenting on postoperative day 5. With retrograde stenting stent severance and
      upward migration into the ureter occurred in 1 patient each, while none of the
      patients with laparoscopic stenting showed such problems. CONCLUSIONS:
      Laparoscopic stenting is a simple technique that obviates the need for an
      additional procedure and decreases the risk of the stent being cut or migrating
      upward. It also provides better anatomical delineation and dissection around the
      ureteropelvic junction since the pelvis remains distended. In addition, it makes
      suture placement and knot tying easy.

PMID- 15017194
TI  - Hand assisted laparoscopic partial nephrectomy for peripheral and central
      lesions: a review of 30 consecutive cases.
AB  - PURPOSE: We reviewed our first 30 hand assisted laparoscopic partial
      nephrectomies and compared the results of 8 centrally located vs 22 peripherally
      located tumors. MATERIALS AND METHODS: Tumors were classified by computerized
      tomography as central (less than 5 mm from the pelvicaliceal system or hilar
      vessels) or peripheral. The hand assisted technique consisted of mobilization and
      manual parenchymal compression without vascular occlusion or ureteral stent
      placement. Argon beam coagulation and a fibrin glue bandage were used for
      hemostasis. RESULTS: Mean tumor size was 2.6 cm (range 1.0 to 4.7). Mean
      operative time was 199 and 271 minutes, and estimated blood loss was 240 and 894
      ml for peripheral and central lesions, respectively. No case required open
      conversion. The final diagnoses were renal cell carcinoma in 21 patients,
      angiomyolipoma in 4, benign or hemorrhagic cyst in 3 and oncocytoma in 2. Initial
      positive margins were found in 5 of 30 specimens (16.7%) (1 central and 4
      peripheral) and all final resection margins were negative. Four central (50%) and
      2 peripheral (9.1%) tumor cases required transfusion. Drain creatinine was
      elevated in 6 patients (20%) postoperatively, of whom 3 had a central and 3 had a
      peripheral lesion. All responded to conservative management except 1 patient
      (3.3%) who required stent placement. Postoperative bleeding in a central tumor
      case required transfusion of 4 units. There were no short-term local recurrences
      and 1 patient had an asynchronous tumor. CONCLUSIONS: Hand assisted laparoscopic
      partial nephrectomy is safe with excellent immediate cancer control. Careful
      dissection and frozen section analysis are mandatory to ensure a negative tumor
      margin. Blood loss and transfusion rates were higher in patients with centrally
      located tumors and renal hilar vascular control should be considered for central
      lesions.

PMID- 15017195
TI  - Complications of laparoscopic nephrectomy: the Mayo clinic experience.
AB  - PURPOSE: We present the incidence of complications and conversions during
      laparoscopic nephrectomy performed for various indications and discuss methods to
      help prevent future complications. MATERIALS AND METHODS: From June 1999 to
      February 2003 at our institution 285 laparoscopic nephrectomy cases were
      performed, consisting of 113 radical nephrectomies, 101 donor nephrectomies, 27
      simple nephrectomies, 23 partial nephrectomies and 21 nephroureterectomies. We
      reviewed the data base of patients who underwent laparoscopic nephrectomy to
      examine complications and analyze factors related to conversion to an open
      surgical procedure. RESULTS: Major complications occurred in 16 patients (5.6%).
      Major complications were surgical in 12 patients and medical in 4. Of the major
      surgical complications 3, 6, 1, 1 and 1 occurred during laparoscopic radical
      nephrectomy, donor nephrectomy, nephroureterectomy, simple nephrectomy and
      partial nephrectomy, respectively. The predominant major surgical complication
      was bleeding requiring conversion to an open surgical procedure. The overall
      conversion rate was 4% (12 patients), consisting of 6 emergency and 6 elective
      conversions. The remaining 27 patients experienced minor surgical or
      postoperative medical problems, such as urinary retention or wound infection. The
      mortality rate in our series was 0%. CONCLUSIONS: Laparoscopic renal surgery is
      becoming a routine procedure in the armamentarium of many urologists.
      Complications that are unique to laparoscopy exist but they should decrease with
      time with repetition and experience. We have learned many different precautions
      and procedures that should help decrease the risk of future complications
      associated with laparoscopic renal surgery.

PMID- 15017196
TI  - Thoracic complications during urological laparoscopy.
AB  - PURPOSE: We documented thoracic related complications during urological
      laparoscopic surgery. MATERIALS AND METHODS: A total of 1129 patients underwent
      major urological laparoscopic procedures in a 5-year period. Operative reports
      and postoperative radiographic reports were retrospectively reviewed to identify
      patients with thoracic related medical and surgical sequelae. Of the patients 619
      (55%) underwent at least 1 chest x-ray in the immediate or early postoperative
      period. In the remaining 510 patients (45%) there was no clinical indication to
      perform chest x-ray. RESULTS: Of 619 patients undergoing chest x-ray 438 (71%)
      were completely normal. Medical pulmonary complications, surgical thoracic
      complications and subclinical, incidentally detected gas collections in the chest
      were identified in 12.6%, 0.5% and 5.5% of patients, respectively. Medical
      complications in 12.6% of cases included pulmonary infiltrate/atelectasis in
      9.7%, pleural effusion in 4.8% and pulmonary embolus in 0.3%. Surgical
      complications included symptomatic pneumothorax in 4 patients (0.35%), hemothorax
      in 1 (0.08%) and chylothorax in 1 (0.08%). Subclinical abnormal thoracic gas
      collections were radiographically noted in 34 of the 619 patients (5.5%) on chest
      x-ray, including pneumomediastinum in 19 (3.1%), pneumothorax in 10 (1.6%) and
      pneumopericardium in 5 (0.8%). Overall 36 of 40 (90%) thoracic surgical
      complications (3) and subclinical, incidentally detected gas collections (33)
      occurred during retroperitoneal laparoscopy. Re-intervention was necessary in 6
      patients (0.5%), namely pulmonary embolus requiring vena caval filter placement
      in 3 (0.3%), pneumothorax requiring a chest tube in 2 (0.17%) and hemothorax
      requiring emergency open thoracotomy in 1 (0.08%). No patient underwent open
      conversion to complete the initial proposed operation. CONCLUSIONS: Due to its
      high solubility the expectant management of incidental CO2 pneumothorax,
      pneumopericardium and pneumomediastinum is recommended initially in the
      clinically stable patient. Inadvertent diaphragmatic entry can be satisfactorily
      repaired laparoscopically without open conversion. Although it is rare, surgical
      thoracic complications are potentially life threatening, requiring prompt
      identification and management.

PMID- 15017197
TI  - Prospective comparison of the immunological and stress response following
      laparoscopic and open surgery for localized renal cell carcinoma.
AB  - PURPOSE: We prospectively compared the systemic immune and stress response of
      patients who underwent laparoscopic total nephrectomy (LRN) (14) and open
      nephrectomy (ON) (10) for renal cell carcinoma. The ON group comprised open
      radical (4), open total (2) and open partial (4) nephrectomy cases. MATERIALS AND
      METHODS: Only patients with no history of cancer or autoimmune disease and
      American Society of Anesthesiologists score 2 or less who were not using
      immunosuppressive drugs were selected. Peripheral venous blood was collected
      preoperatively and intraoperatively, and 24 hours, 2 weeks, 4 weeks and 3 months
      postoperatively. Blood was analyzed for stress markers (adrenalin, noradrenalin
      and cortisol), inflammatory response markers (C-reactive protein, white blood
      count and leukocyte count), lymphocytic response markers (CD3, CD4 and CD8),
      cytokines interleukin-2 and 4, interferon-alpha and tumor necrosis factor-alpha),
      HLA-DR expression and the proliferative response to mitogen stimulation using
      concanavalin A, phytohemagglutinin 10, and pokeweed mitogen. RESULTS: Mean tumor
      size +/- SD for ON and LRN was 5.6 +/- 2.4 and 4.5 +/- 1.6 cm, respectively (p =
      0.21). The trends with time for all measured postoperative parameters were
      similar in the 2 groups. Inflammatory and stress response markers were
      statistically similar for in the groups at all time points. A significant
      difference between the groups was noted for the percentage of CD4+ and CD8+
      lymphocytes. However, this difference was present preoperatively and there was no
      significant absolute change in these 2 parameters. The cytokine response and HLA
      DR expression were similar in the 2 groups at all time points. Likewise, the
      lymphocytic stimulation index for concanavalin A, phytohemagglutinin and pokeweed
      mitogen were statistically similar for LRN and ON at all time points.
      CONCLUSIONS: The immunological and stress response after LRN and ON for renal
      cell carcinoma is similar. The few differences observed in measured parameters
      likely reflect preoperative differences in baseline and/or the contributory
      effect of anesthesia.

PMID- 15017198
TI  - Value of reverse transcription polymerase chain assay in peripheral blood of
      patients with urothelial cancer.
AB  - PURPOSE: The nested reverse transcription polymerase chain reaction (RT-PCR)
      method was used to determine expression of uroplakin II (UP II) or cytokeratin 20
      (CK-20) in cells separated from the peripheral blood of patients with urothelial
      cancer. We examine whether UP II or CK-20 expression can be used as a urothelial
      cancer marker for urothelial cancer in cells isolated from peripheral blood.
      MATERIALS AND METHODS: Peripheral blood was taken from 20 healthy volunteers
      without a history of urothelial cancer, from 10 patients with a negative bladder
      biopsy for urothelial cancer and from 108 patients with urothelial cancer.
      Results of a nested RT-PCR assay were compared with pathological stage and
      recurrence. RESULTS: None of the peripheral blood samples from the control
      subjects revealed a positive polymerase chain reaction result. Among 108 patients
      with transitional cell carcinoma of the bladder nested RT-PCR for UP II was
      positive in 25 (23%) versus 31 (29%) for CK-20 (p >0.05). Nested RT-PCR for UP II
      was positive in 5 (8%) patients with superficial stage disease (pTa and pT1)
      versus 8 (11%) positive for CK-20. Nested RT-PCR for UP II was positive in 15
      (58%) patients with a stage of pT2 or advanced stages versus 17 (65%) positive
      for CK-20. Nested RT-PCR for UP II was positive in 13 (20%) and 10 (56%) patients
      with grades 2 and 3, respectively, versus 17 (27%) and 12 (67%) nested RT-PCR
      positive for CK-20. A significant difference in the Kaplan-Meier recurrence-free
      actuarial curve was noted among patients with superficial stage who were positive
      and negative on nested RT-PCR for UP II and CK-20 in peripheral blood,
      respectively, but not in the invasive stage. On multivariate analysis nested RT
      PCR for UP II and CK-20 in peripheral blood were independent prognostic factors
      in patients with superficial stage disease but not with invasive stage disease.
      Lung and/or liver metastasis developed in 5 (80%) of 6 patients whose results
      after chemotherapy (consisting of cisplatin, doxorubicin hydrochloride,
      vinblastine sulfate and methotrexate) for nested RT-PCR for UP II and CK-20
      remained positive. CONCLUSIONS: These results seem to indicate that UP II and CK
      20 mRNA in the blood may be useful tumor markers for predicting patient survival
      and the extent of urothelial cancer.

PMID- 15017199
TI  - Adjuvant chemotherapy with paclitaxel and carboplatin in patients with advanced
      bladder cancer: a study by the Hellenic Cooperative Oncology Group.
AB  - PURPOSE: Radical cystectomy represents the treatment of choice for muscle
      infiltrative bladder carcinoma. Adjuvant chemotherapy has been used to improve
      outcome after cystectomy. We report results in a prospective cohort of patients
      at high risk for relapse who were treated with the combination of paclitaxel and
      carboplatin as adjuvant treatment following cystectomy for muscle invasive
      bladder cancer. MATERIALS AND METHODS: A total of 92 patients with extravesical
      tumor extension (pT 3b or greater) or lymph node involvement (N+) were treated
      with 4 cycles of paclitaxel at 175 mg/m and carboplatin (area under the curve 5
      according to the Calvert formula) every 3 weeks following radical cystectomy.
      Patients were followed every 6 months thereafter. RESULTS: Median followup was
      36.6 months. Chemotherapy was well tolerated with 62% of patients receiving 100%
      of the expected chemotherapy doses without delays. Grade 3 or 4 neutropenia was
      reported in 19% of patients, while neutropenic fever was reported in 7%. Five
      year overall, cause specific and disease-free survival was 28.9% (95% CI 14.8 to
      43.0), 36.6% (95% CI 24.4 to 49.7) and 29% (95% CI 16.3 to 42.4), respectively.
      CONCLUSIONS: Adjuvant chemotherapy with paclitaxel and carboplatin is feasible
      and could be used as adjuvant treatment for high risk bladder carcinoma. Its true
      value should be assessed in prospective, randomized trials.

PMID- 15017200
TI  - Histology in mixed germ cell tumors. Is there a favorite pairing?
AB  - PURPOSE: Mixed germ cell tumors account for approximately 30% to 50% of
      testicular tumors. To our knowledge a systematic review with statistical analysis
      of the associations of histological subtypes in mixed germ cell tumors has not
      been done previously. It was our impression that such associations exist.
      Delineating concordant histological types may provide insight into the ontogeny
      of testicular tumors and also have important clinical implications. MATERIALS AND
      METHODS: We retrospectively reviewed the testis cancer data base at our
      institution. The primary tumor of orchiectomy specimens was examined in 2589
      patients. Of these patients mixed histology was noted in 1765 (68.2%). ORs were
      calculated for all possible combinations of teratoma, embryonal carcinoma, yolk
      sac tumor, choriocarcinoma and seminoma. In addition, we evaluated the
      association of various histological types with teratoma at post-chemotherapy
      retroperitoneal lymph node dissection. RESULTS: Of 10 possible combinations of
      histological types in the primary tumor, positive correlations were noted in 4.
      The strongest correlation was found between teratoma and yolk sac tumor (OR 2.58,
      p <0.001). Teratoma or yolk sac tumor in the testis was associated with teratoma
      in the pathology specimen at post-chemotherapy retroperitoneal lymph node
      dissection. CONCLUSIONS: The strongest associations of histological subtypes in
      mixed germ cell tumors were seen between yolk sac tumor and teratoma. Similar
      associations are seen in late relapse and in some cases of prepubertal tumors.
      Further study of these associations may prove valuable in understanding the
      biology and clinical behavior of germ cell tumors.

PMID- 15017201
TI  - Impact of unnecessary exploratory laparotomy on the treatment of patients with
      metastatic germ cell tumor.
AB  - PURPOSE: Patients with testicular germ cell tumors (GCTs) may undergo unnecessary
      diagnostic or surgical procedures when this diagnosis is not considered. In a
      cohort of patients who underwent exploratory laparotomy for unsuspected
      metastatic GCT we determined the impact of this surgery on morbidity, therapeutic
      delay and cancer therapy. MATERIALS AND METHODS: Between 1980 and 2001, 40
      patients who underwent exploratory laparotomy for unsuspected metastatic GCT were
      later referred to our department for management. Patient records were reviewed
      retrospectively. RESULTS: Mean patient age at exploratory laparotomy was 34
      years. All patients had a midline retroperitoneal mass and 14 had disease at
      other sites. At the time of evaluation at our institution abnormalities on
      physical examination and testicular sonogram were identified in 8 (20%) and 22
      (55%) patients, respectively. Elevated serum alpha-fetoprotein and/or beta-human
      chorionic gonadotropin were identified in 26 patients (65%). Eight patients (22%)
      experienced complications from exploratory surgery. The median interval from
      laparotomy to chemotherapy was 29 days and in 48% of patients the delay in
      therapy was 30 days or greater. Of patients with a delay of 30 days or greater
      60% required intensive chemotherapy (multiple regimens, or high dose or salvage
      chemotherapy) compared to 26% with a delay of less than 30 days (p = 0.01).
      CONCLUSIONS: Exploratory laparotomy contributes to therapeutic delay in a
      substantial number of patients and it complicates cancer therapy. At presentation
      evidence to suggest GCT was present in all patients, which highlights the
      importance of physician awareness in making a prompt diagnosis.

PMID- 15017202
TI  - Complication rate of transrectal ultrasound guided prostate biopsy: a comparison
      among 3 protocols with 6, 10 and 15 cores.
AB  - PURPOSE: We assessed the complication rate of ultrasound guided prostate biopsies
      performed at a single center in a screening population. Moreover the impact of
      different biopsy protocols comprising varying numbers of biopsy cores on the
      complication rate was evaluated. MATERIALS AND METHODS: A total of 5957 biopsies
      performed in 4303 clinically healthy men between January 1993 and August 2002 was
      evaluated retrospectively. Due to changes in the biopsy protocol, the number of
      biopsies obtained increased with time from 6 cores (January 1993 to October 1995)
      to 10 (November 1995 to March 2000) to 15 cores (March 2000 to August 2002).
      RESULTS: Minor complications such as hematospermia (36.3%), hematuria (14.5%) and
      rectal bleeding persisting for up to 2 days (2.3%) were noted frequently, while
      major complications requiring further treatment were far less common. Post-biopsy
      fever was seen in 48 patients (0.8%), rectal bleeding requiring surgical
      intervention or persisting for more than 2 days occurred in 36 patients (0.6%)
      and urinary retention was observed in 12 patients (0.2%). The increase in biopsy
      cores with time did not result in increased post-biopsy morbidity. Prostate
      cancer at biopsy was not associated with a higher complication rate. CONCLUSIONS:
      Prostate specific antigen screening has led to an increase in the number of
      patients undergoing prostate biopsy which, in turn, has increased the incidence
      of post-biopsy complications. However, most of the complications are minor and
      self-limiting. In this large study population the increased number of biopsy
      cores did not result in an increased incidence of major post-biopsy
      complications.

PMID- 15017203
TI  - Endorectal magnetic resonance imaging and spectroscopy for the detection of tumor
      foci in men with prior negative transrectal ultrasound prostate biopsy.
AB  - PURPOSE: We determined the ability of combined endorectal magnetic resonance
      imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) to detect
      prostate cancer foci prospectively in men with prior negative transrectal
      ultrasound (TRUS) prostate biopsy. MATERIALS AND METHODS: Endorectal MRI with
      spectroscopy was performed in 24 consecutive patients with 1 or more prior
      negative TRUS prostatic biopsies for persistently increased prostate specific
      antigen and/or abnormal digital rectal examination. All studies were interpreted
      by a dedicated radiologist who reported areas of interest in the peripheral zone
      as normal, equivocal or suspicious on MRI and MRSI separately. Equivocal and
      suspicious areas were then correlated with a 3-dimensional prostate model. All
      patients underwent a standard TRUS 10-core peripheral zone biopsy with up to 4
      additional biopsies targeted at the equivocal or suspected sites. RESULTS:
      Prostate cancer was detected in 7 of 24 subjects (29.2%). Considering the
      equivocal category as test negative the sensitivity, specificity, positive and
      negative predictive values, and the accuracy of MRI, MRSI and combined MRI/MRSI
      for the detection of prostate cancer were 57.1%, 57.1% and 100.0%, 88.2%, 82.4%
      and 70.6%, 66.7%, 57.1% and 58.3%, 83.3%, 82.1% and 100%, and 79.2%, 75.0% and
      79.2%, respectively. The site of positive biopsy correlated correctly in 50% and
      28.6% of MRI and MRSI labeled suspicious cores, respectively. CONCLUSIONS: MRI
      and MRSI have the potential to identify cancer foci and direct TRUS in patients
      with a previous negative TRUS biopsy. Further, larger studies are required to
      quantify the amount of benefit.

PMID- 15017205
TI  - Diclofenac suppository analgesia for transrectal ultrasound guided biopsies of
      the prostate: a double-blind, randomized controlled trial.
AB  - PURPOSE: A significant proportion of men undergoing transrectal ultrasound (TRUS)
      and prostate biopsy report pain during the procedure. A number of different
      methods of pain relief have been suggested in the literature. We prospectively
      evaluated the effect of diclofenac suppositories on pain experienced by men
      undergoing TRUS and prostate biopsy. MATERIALS AND METHODS: A prospective,
      randomized, double-blind, placebo controlled study was performed in 72 patients
      requiring prostate biopsy. Patients were randomly assigned to receive 100 mg
      diclofenac or placebo 1 hour prior to the procedure. They were asked to indicate
      on a 10 cm visual analogue scale the degree of discomfort during the procedure.
      The patients were then seen 2 weeks later and any morbidity, including infection
      and bleeding, was assessed. RESULTS: Patients given diclofenac had significantly
      lower pain scores than those given placebo (2.8 vs 4.9, p <0.001). The 2 groups
      were similar in regard to age, prostate volume, biopsy number, prostate specific
      antigen, histological diagnosis and complication rate. CONCLUSIONS: Rectal
      administration of diclofenac 1 hour prior to TRUS and prostate biopsy is a simple
      procedure that significantly relieves the pain experienced with no increase in
      morbidity. With the trend toward more core samples, screening for prostate cancer
      and the younger age of patients undergoing biopsy we urge urologists to provide
      analgesia for this painful procedure.

PMID- 15017204
TI  - Biopsy of the prostate--an ongoing evolution.

PMID- 15017206
TI  - Percent of cores positive for cancer is a better preoperative predictor of cancer
      recurrence after radical prostatectomy than prostate specific antigen.
AB  - PURPOSE: We examined the prognostic significance of clinical and pathological
      variables on outcome following radical retropubic prostatectomy (RRP) in a cohort
      of patients in the post-prostate specific antigen (PSA) era. MATERIALS AND
      METHODS: We reviewed the clinical and pathological data on a cohort of 476
      patients who underwent RRP for localized prostate cancer between January 1990 and
      July 2001 by 1 urologist (WCD). Median age, preoperative PSA and followup were 61
      years, 5.8 ng/ml and 49 months, respectively. We used Cox proportional hazard
      modeling to evaluate the prognostic significance of clinical and pathological
      variables for cancer recurrence, defined as 2 successive PSA determinations 0.3
      ng/ml or greater. RESULTS: Of the 476 patients 53 (11%) had recurrence. Estimated
      cancer nonprogression probability was 86% (95% CI 83 to 90) and 76% (95% CI 68 to
      86) at 5 and 10 years, respectively. Two multivariate analyses were performed.
      The first analysis, using only preoperative indicators, found that the percent of
      biopsy cores positive for cancer and biopsy Gleason score were the best
      predictive indicators of recurrence. The second multivariate analysis, using
      preoperative and postoperative indicators, found that the percent of biopsy cores
      positive for cancer, RRP Gleason score and the combined pathological stage/margin
      status variable were the best predictive indicators of recurrence. PSA was not
      found to be an important predictor of recurrence on either multivariate analysis.
      Patients with a percent of biopsy cores in the upper half of the distribution
      (greater than 28% positive) were at significantly increased risk for recurrence
      compared with those in the lower half of the distribution (28% or less positive)
      (HR 3.86, p <0.001). CONCLUSIONS: The percent of cores positive for cancer was a
      better predictor of cancer recurrence than PSA in this post-PSA era RRP series.
      In addition, surgical Gleason score and pathological stage/surgical margins were
      also independent predictors of cancer recurrence after RRP. These 3 predictors
      are displayed in a nomogram-type format to summarize estimated 5 and 10-year
      recurrence-free probabilities.

PMID- 15017207
TI  - The risk of finding focal cancer (less than 3 mm) remains high on re-biopsy of
      patients with persistently increased prostate specific antigen but the clinical
      significance is questionable.
AB  - PURPOSE: We evaluated the significance of focal prostate cancer found in sextant
      biopsies in men participating in a biennial prostate specific antigen (PSA) based
      screening program. MATERIALS AND METHODS: In 1995, 10000 men 50 to 65 years old
      were randomized to biennial screening with PSA testing. Sextant biopsies were
      recommended when total PSA was 3 ng/ml or greater at screening rounds 1 and 2,
      and 2.54 ng/ml or greater at subsequent screening rounds. Focal cancer was
      defined as total a core cancer length of less than 3 mm in the biopsy specimen.
      Low volume cancer was defined as a total tumor volume of less than 0.5 cm in the
      radical retropubic prostatectomy specimen. RESULTS: The number of men who
      underwent biopsy and the number of cancers detected in the 5 possible sets of
      biopsies were 1725 and 402, 706 and 124, 307 and 36, 103 and 9, and 13 and 0,
      respectively. The risk of detecting focal cancer was 7.9%, 10.2%, 7.5%, 5.8% and
      0%, respectively, but the relative ratio (focal-to-all cancers) increased 34%,
      58%, 64%, 67% and, not applicable, respectively. In men with a total core cancer
      length of less than 10 mm there was no correlation between core cancer length and
      total tumor volume, as measured in the prostatectomy specimen. Two-thirds of men
      with a total core cancer length of less than 3 mm had a tumor volume of greater
      than 0.5 cm, while the risk of low volume cancer was less than 5% only in men
      with a total core cancer length of greater than 10 mm. CONCLUSIONS: In a repeat
      PSA based screening program sextant biopsies are of little or no value for
      predicting tumor volume.

PMID- 15017208
TI  - Racial/ethnic disparities in the treatment of localized/regional prostate cancer.
AB  - PURPOSE: Racial/ethnic disparities in the utilization of definitive therapy for
      prostate cancer are well recognized in the United States. The effect of race on
      the use of contemporary definitive therapies, including brachytherapy, and the
      assessment of Hispanic men with regard to racial/ethnic disparity has not been
      fully characterized. MATERIALS AND METHODS: We evaluated treatment patterns using
      Surveillance, Epidemiology and End Results registry data on 142340
      localized/regional stage cases between 1992 and 1999 in white, black and Hispanic
      American men. Definitive therapy was defined as radical prostatectomy, external
      beam radiation, brachytherapy or combinations thereof. Logistic regression models
      were constructed to determine the odds of receiving definitive treatment,
      adjusting for age, marital status, tumor grade, and Surveillance, Epidemiology
      and End Results site. RESULTS: Black and Hispanic men were less likely to receive
      definitive therapy than white men (p <0.001). Higher tumor grade was associated
      with decreasing odds of definitive therapy for black and Hispanic men (p <0.001)
      compared to white men. The racial/ethnic disparities in the use of definitive
      therapy decreased between 1992 and 1999 with the greatest decrease in Hispanic
      men. CONCLUSIONS: Hispanic and black men were less likely than white men to
      receive definitive therapy. The disparity in the use of definitive therapy
      between 1992 and 1999 decreased significantly in Hispanic men, although a
      significant disparity in the use of definitive therapy persisted in black men.
      Our observation of an association between tumor grade and the racial/ethnic
      disparity in definitive therapy ties together relevant biological and social
      factors that may contribute to the observed racial/ethnic disparity in mortality.

PMID- 15017209
TI  - The effect of race/ethnicity on prostate cancer treatment outcome is conditional:
      a review of Wayne State University data.
AB  - PURPOSE: The mortality rate for prostate cancer in black American men (AAMs) is 2
      times greater than that in other ethnic groups. However, there is considerable
      controversy as to whether race/ethnicity is an independent predictor of survival
      outcome. We present conditions in which race/ethnicity is and is not an
      independent predictor of survival outcomes. MATERIALS AND METHODS: We examined
      the conditions of age, stage and year of diagnosis, and the role of
      race/ethnicity on disease-free survival in men who underwent consecutive radical
      prostatectomy as monotherapy from 1990 to 1999. Data were collected from 229 AAMs
      and 562 white American men prospectively in the Karmanos Cancer Institute
      Prostate cancer data bases. RESULTS: When the majority of the cohort had
      pathologically organ confined disease, race/ethnicity was not an independent
      predictor of disease-free survival. When the majority of the cohort had a mean
      age of 70 years or greater, race/ethnicity was not an independent predictor. In
      studies done in the late 1990s, when the stage of radical prostatectomy cases had
      shifted toward pathologically organ confined disease as the dominant stage,
      race/ethnicity was not an independent predictor. However, if the cohort was
      diagnosed at younger age and/or with more advanced prostate cancer,
      race/ethnicity became an independent predictor. In the early 1990s there was
      pathologically advanced disease in the majority of our cohort. CONCLUSIONS:
      Race/ethnicity as an independent predictor of prostate cancer is conditional and
      dependent on age, stage and year of diagnosis. Year of diagnosis is associated
      with a stage shift to earlier staged prostate cancer from the early to late
      1990s. In general, study cohorts are often subranges of the entire spectrum of
      prostate cancer that are limited by these factors, especially stage at diagnosis
      and treatment. If diagnosed and treated early enough, although there is evidence
      suggesting that AAMs have more aggressive disease biologically, the role of race
      as a factor in outcome is significantly decreased. The age factor is more complex
      and must be discussed in more detail.

PMID- 15017210
TI  - Long-term survival probability in men with clinically localized prostate cancer:
      a case-control, propensity modeling study stratified by race, age, treatment and
      comorbidities.
AB  - PURPOSE: We used a propensity risk scoring approach to model long-term survival
      for men with clinically localized prostate cancer. We developed comprehensive
      lookup tables for estimating survival probability stratified by patient age,
      race, readily available clinical variables, comorbidities and treatment type.
      MATERIALS AND METHODS: We retrospectively identified a cohort of 1611 men with
      clinically localized prostate cancer (patients) and 4538 age, race and
      comorbidity matched controls. Based on demographic and clinical variables
      propensity risk scoring was used to develop smoothed survival prediction models
      for patients and controls. Based on these models tables were created to provide
      10-year overall survival estimates. The tables are stratified by patient age,
      race, comorbidity, prostate specific antigen, cancer grade, and treatment type
      when applicable. RESULTS: Mean patient age was 67.0 years and median baseline
      prostate specific antigen was 8.5 ng/ml. Of the patients 68% had biopsy cancer
      grade 2, 39% were black, 29% received conservative treatment, 43% underwent
      radical prostatectomy and 27% were treated with radiation therapy. Crude and
      cancer specific 10-year survival rates were 67% and 93%, respectively. Validation
      C-index values were 0.63 for the cancer specific model and 0.69 for the overall
      survival model. CONCLUSIONS: These lookup tables provide physicians and patients
      with realistic estimates of 10-year survival and allow them to compare the impact
      of cancer vs noncancer factors on patient mortality.

PMID- 15017211
TI  - An analysis of men with clinically localized prostate cancer who deferred
      definitive therapy.
AB  - PURPOSE: We evaluated expectant management of prostate cancer with definitive
      treatment deferred until evidence of cancer progression in men with low risk,
      localized cancers. MATERIALS AND METHODS: We retrospectively reviewed
      prospectively entered data base records. Patients with low risk cancer who were
      eligible for definitive therapy but chose deferred management between 1984 and
      2001 composed the cohort. Followup included regular evaluations to detect
      progression by prostate specific antigen (PSA), digital rectal examination,
      transrectal ultrasound and prostate biopsy. Objective progression was defined by
      a point scale of changes in prognostic factors. Definitive treatment was
      recommended in patients with objective progression. RESULTS: The cohort comprised
      88 patients with clinical stages T1-2, NX0, M0 prostate cancer, a mean age of
      65.3 years and a mean initial PSA of 5.9 ng/ml. Systematic biopsy, which was
      repeated after the initial diagnostic biopsy, showed no cancer in 61% of cases.
      During a median followup of 44 months 22 patients had progression. Factors that
      predicted progression were repeat biopsy showing cancer (p = 0.004) and initial
      PSA (p = 0.014). Actuarial 5 and 10-year progression-free probabilities were 67%
      and 55%, respectively. Of the 31 patients treated 17 underwent radical
      prostatectomy, 13 received radiation therapy and 1 received androgen ablation.
      Seven men who did not show objective progression were treated because of anxiety.
      Only 1 patient, who was treated with radiation therapy, had biochemical
      recurrence. CONCLUSIONS: Deferred therapy may be a feasible alternative to
      curative treatment in select patients with favorable, localized prostate cancer.
      About half of these patients remain free of progression at 10 years and
      definitive treatment appeared effective in those with progression. Absent cancer
      on repeat needle biopsy identified cases highly unlikely to progress.

PMID- 15017212
TI  - Survival of patients with hormone refractory prostate cancer in the prostate
      specific antigen era.
AB  - PURPOSE: The historically reported 12 to 18-month duration of survival of
      patients with hormone refractory prostate cancer is not consistent with current
      clinical experience. Furthermore, to our knowledge patient survival after serum
      prostate specific antigen (PSA) progressively increases from a nadir despite
      castrate testosterone has not been previously reported. For this reason we
      studied overall survival and the clinical variables that influence survival in
      patients with hormone refractory prostate cancer. MATERIALS AND METHODS: The
      study focused on 254 patients with prostate cancer on androgen deprivation
      therapy. Hormone refractory prostate cancer was defined as the first in a series
      of PSA elevations despite castrate levels of testosterone. The duration of
      survival in the hormone refractory phase was calculated from the date of the
      first PSA elevation to the date of death. RESULTS: Median survival after hormone
      refractory prostate cancer developed in patients initially staged with and
      without skeletal metastasis was 40 and 68 months, respectively. Six of more than
      25 input variables were retained as significant in the final Cox model. Variables
      associated with longer survival were lower nadir PSA, younger age, higher
      pretreatment testosterone, no history of obstructive uropathy, no history of
      tobacco use (past or current) and lower alkaline phosphatase. CONCLUSIONS:
      Historical reports of survival in hormone refractory prostate cancer
      underestimate current survival observations. The likely explanations of this
      observation include delayed enrollment in clinical trials from which most
      survival data are derived, PSA lead time in staging and improved supportive care.
      Models predicting survival in patients with hormone refractory prostate cancer
      should consider multiple variables.

PMID- 15017213
TI  - The impact of polymorphism on prostate specific antigen gene on the risk, tumor
      volume and pathological stage of prostate cancer.
AB  - PURPOSE: A single nucleotide polymorphism with adenine (A) to guanine (G)
      substitution is identified at position -158 in the androgen response elements
      region of the prostate specific antigen (PSA) gene. We evaluated the relationship
      between the PSA -158A/G polymorphism and the risk, tumor volume and pathological
      stage of prostate cancer. MATERIALS AND METHODS: Peripheral venous blood samples
      were obtained from 122 patients with prostate cancer and 84 controls with benign
      prostatic hyperplasia. The diagnosis, tumor volume and pathological stage of
      prostate cancer were all determined according to the pathological reports of
      transrectal ultrasound guided prostate biopsy, transurethral prostate resection
      and radical prostatectomy. The PSA -158A/G polymorphism was determined by
      polymerase chain reaction based restriction fragment length polymorphism methods.
      RESULTS: Patients with prostate cancer had significantly greater frequencies of
      the G allele (87.3% vs 77.4%) and GG genotype (78.7% vs 61.9%) than the control
      group (p = 0.008 and 0.028, respectively). The OR of GG to AG and AA was 2.27 (p
      = 0.008). In the prostate cancer group the GG genotype was also associated with
      larger tumor volume (2.34 vs 0.82 ml) and higher pathological stage (organ
      confined cancer 68.2% vs 31.8% and extracapsular extension 100% vs 0%) than the
      GA and AA genotypes (p = 0.013 and 0.036, respectively). CONCLUSIONS: The PSA 
      158A/G polymorphism is associated with prostate cancer. The G allele increases
      the risk of prostate cancer and the GG genotype is associated with larger tumor
      volume and higher pathological stage.

PMID- 15017214
TI  - Oxidative DNA damage in patients with prostate cancer and its response to
      treatment.
AB  - PURPOSE: We evaluated the significance of oxidative DNA damage in patients with
      prostate cancer based on the measurement of urinary 8-OHdG (8-hydroxy-2'
      deoxyguanosine) and analyzed changes in urinary 8-OHdG before and after initial
      treatment. MATERIALS AND METHODS: A total of 82 patients with prostate cancer
      were included in this study. Of these 82 patients 42 underwent radical
      prostatectomy and the remaining 40 received hormonal therapy as initial
      treatment. Urinary 8-OHdG and creatinine (Cr), and serum prostate specific
      antigen (PSA) in these 82 patients were assessed before and 2 months after the
      initiation of treatment. RESULTS: The ratio of urinary 8-OHdG-to-Cr (8-OHdG/Cr)
      in patients with prostate cancer was significantly higher than in age matched
      healthy controls. Only age was significantly associated with 8-OHdG/Cr in
      prostate cancer cases among several clinicopathological factors, including serum
      PSA clinical T stage, metastasis and Gleason score. There was no significant
      difference in urinary 8-OHdG/Cr in 42 patients before and after radical
      prostatectomy, while urinary 8-OHdG/Cr in 40 patients after hormonal therapy was
      significantly lower than before hormonal therapy. In addition, changes in PSA
      after initial treatment were not related to changes in urinary 8-OHdG/Cr in
      either treatment group. CONCLUSIONS: These findings suggest that oxidative stress
      may be involved in an early event in prostate cancer development and androgen
      suppression is capable of decreasing oxidative stress. Accordingly androgen
      withdrawal therapy combined with antioxidative agents may inhibit the progression
      of prostate cancer.

PMID- 15017215
TI  - Cost-effectiveness of zoledronic acid for the prevention of skeletal
      complications in patients with prostate cancer.
AB  - PURPOSE: We estimated the cost-effectiveness of zoledronic acid vs placebo for
      decreasing skeletal complications in men with prostate cancer. MATERIALS AND
      METHODS: We performed a cost-effectiveness analysis alongside a multinational
      clinical trial of zoledronic acid. Cost estimation was based on prospectively
      collected resource use data for 85.3% of enrolled patients. Cost-effectiveness
      ratios were based on within-trial data on clinical outcomes, quality of life and
      study medication cost. RESULTS: Patients receiving zoledronic acid experienced
      fewer hospital days during a mean followup of 9 months (average 5.6 vs 8.0 days;
      p = 0.1910). Mean direct costs excluding study medication were US dollars 5365
      for patients receiving zoledronic acid and US dollars 5689 for patients receiving
      placebo, a difference of US dollars 324 (95% CI US dollars 1781 to US dollars
      1146). The global average cost of zoledronic acid plus its administration during
      the trial was US dollars 5677 (US dollars 450 per dose). The nominal cost per
      skeletal complication avoided was US dollars 112300 (95% CI US dollars 6900 to US
      dollars 48700) and the cost per additional patient free of skeletal complications
      was US dollars 51400 (95% CI US dollars 26900 to US dollars 243700). Nominal
      within-trial cost per quality adjusted life-year was US dollars 159200, which
      varied widely in sensitivity analyses. CONCLUSIONS: The nominal base case
      estimate of the cost per quality adjusted life-year for zoledronic acid in the
      prevention of skeletal complications of prostate cancer is consistent with that
      of bisphosphonates in breast cancer. However, the cost-effectiveness ratios for
      bisphosphonates are higher than commonly cited thresholds for conferring cost
      effectiveness.

PMID- 15017216
TI  - The effect of smoking on outcome following external radiation for localized
      prostate cancer.
AB  - PURPOSE: We investigated whether a smoking habit affects biochemical and survival
      outcome after curative external beam radiation therapy (EBRT) for localized
      prostate cancer. MATERIALS AND METHODS: The study population comprised 601 men
      treated with curative EBRT between 1994 and 1997 who had a smoking history
      available. Pretreatment prognostic factors were examined and high risk was
      defined as any of prostate specific antigen greater than 20, Gleason greater than
      7 or stages T3-4. Biochemical outcome (bNED) was assessed by American Society for
      Therapeutic Radiology and Oncology, and Houston criteria. Biochemical, clinical,
      prostate cancer and nonprostate cancer death rates were examined by univariate
      and multivariate statistics. RESULTS: Of the men 15% were current smokers, 55%
      were former smokers and 31% were nonsmokers. Current smokers were younger than
      former smokers or nonsmokers by a mean of 2.5 years (p <0.001). Current smokers
      had higher risk cancers than former smokers or nonsmokers (high risk 60%, 40% and
      43%, respectively, p = 0.017). Five-year bNED rates for smokers were
      significantly worse than for former smokers or nonsmokers (55%, 69% and 73%, p =
      0.01 and 0.0019, respectively). Median followup was 59 months. Multivariate
      analysis confirmed smoking as an independent adverse factor for bNED (p = 0.013)
      even when controlling for prostate specific antigen (p <0.0001), Gleason score (p
      <0.0001), stage (not significant), radiation dose (not significant) and
      neoadjuvant hormone use (p = 0.0014). Local and metastatic failure did not differ
      among the groups. Prostate cancer specific mortality was nonsignificantly worse
      in smokers but overall mortality was much greater. CONCLUSIONS: Smokers present
      with higher risk prostate cancers. Outcomes following EBRT are poorer, even when
      accounting for differences in known pretreatment factors.

PMID- 15017217
TI  - Initial experience with fibrin sealant in pendulous urethral reconstruction. Is
      early catheter removal possible?
AB  - PURPOSE: We assessed whether fibrin sealant promotes early catheter removal after
      pendulous urethral reconstruction. MATERIALS AND METHODS: Between 1997 and 2003,
      43 men with complex stricture disease underwent pendulous urethral reconstruction
      by a single surgeon (AFM). In 18 consecutive cases with a mean stricture length
      of 7.24 cm from 2000 to 2003 fibrin sealant was applied over a ventral onlay
      anastomosis performed with running 5-zero polydiaxanone suture. Results were
      compared with those in 25 men who underwent the procedure without fibrin sealant
      from 1997 to 2000, who served as a control group (mean stricture length 8.30 cm,
      p = 0.418). Catheter duration was recorded after anastomosis integrity was
      radiographically confirmed. RESULTS: All 18 patients with sealant were completely
      healed within 14 days, which was significantly shorter than in controls (p
      <0.001). In the sealant group increased stricture length was associated with
      longer catheter time (p = 0.677). Our impressions were that patient satisfaction
      was enhanced by early catheter removal, and postoperative penile edema and
      ecchymosis were decreased in the fibrin sealant group. CONCLUSIONS: Fibrin
      sealant appears to promote early catheter removal and enhanced wound healing
      after pendulous urethral reconstruction.

PMID- 15017218
TI  - Is seminal vesiculitis a discrete disease entity? Clinical and microbiological
      study of seminal vesiculitis in patients with acute epididymitis.
AB  - PURPOSE: To our knowledge direct evidence of inflammatory involvement of the
      seminal vesicles has not previously been reported in patients with acute
      epididymitis. We verified the discrete disease entity of seminal vesiculitis
      associated with acute epididymitis. MATERIALS AND METHODS: The study included 13
      patients who were clinically diagnosed with acute epididymitis. We report
      imaging, cytological and bacteriological findings in the seminal vesicles of
      patients with acute epididymitis. RESULTS: On transrectal ultrasonography 12 of
      the 13 patients (92.3%) had dilatation of the seminal vesicle on the side
      ipsilateral to epididymitis. Dilatation of the contralateral side was found in
      only 4 patients. Seminal vesicle fluid from the ipsilateral side showed
      inflammatory findings in all patients. In patients 40 years and younger Chlamydia
      trachomatis was detected in seminal vesicle fluid in 7 of the 8 patients with
      epididymitis with results positive for the microorganism on first voided urine.
      CONCLUSIONS: Inflammatory responses were found in the seminal vesicles of
      patients with acute epididymitis. Chlamydia trachomatis was the causative
      pathogen most frequently detected in seminal vesicle fluid. Seminal vesiculitis
      is clearly associated with acute epididymitis and it may be a discrete disease
      entity.

PMID- 15017219
TI  - Abnormal expression of molecular markers for bladder impermeability and
      differentiation in the urothelium of patients with interstitial cystitis.
AB  - PURPOSE: Despite a lack of consensus concerning the etiology of interstitial
      cystitis (IC) the loss of impermeability and other abnormalities of the
      urothelium are features of the disease. In this study the distribution of
      proteins involved with epithelial adhesion, cellular differentiation and bladder
      impermeability in urothelial biopsies were explored by the immunohistochemical
      assessment of E-cadherin, ZO-1, uroplakin and chondroitin sulfate. MATERIALS AND
      METHODS: Biopsies obtained from 27 patients with IC and 7 controls were
      immediately fixed in formalin, immunohistochemically labeled for the described
      proteins and scored for protein expression, morphology and differentiation.
      RESULTS: Only 3 IC samples appeared completely normal, while 24 of the 27 showed
      an abnormality in at least 1 marker and in 6 all 4 markers were abnormal. In
      patients vs controls findings were abnormal for uroplakin in 13 of 27 vs 1 of 7
      (p = 0.085), for E-cadherin (over expressed) in 18 of 27 vs 0 of 7 (p = 0.0021),
      for ZO-1 in 11 of 27 vs 0 of 7 (p = 0.046) and for chondroitin sulfate in 15 of
      27 vs 0 of 7 (p = 0.0054). The morphology/polarity score significantly correlated
      with ZO-1 (Pearson r = 0.3935, p = 0.0423) and chondroitin sulfate (Pearson r =
      0.7079, p <0.0001) expression. Chondroitin sulfate and ZO-1 showed a high
      correlation with each other (Pearson r = 0.5587, p = 0.0025). Uroplakin and E
      cadherin expression were independent of all other markers. CONCLUSIONS: The
      findings reported strongly suggest abnormal differentiation in the IC bladder.
      The disruption of ZO-1 is similar to that reported in feline IC. Elevated E
      cadherin may represent an adaptation to increased bladder permeability.

PMID- 15017220
TI  - Urinary conduit formation using a retubularized bowel from continent urinary
      diversion or intestinal augmentations: ii. Does it have a role in patients with
      interstitial cystitis?
AB  - PURPOSE: Interstitial cystitis (IC) may require surgical treatment in a minority
      of patients in whom conservative treatment failed. This treatment includes
      enterocystoplasty (ECP), or continent or incontinent urinary diversion with or
      without cystourethrectomy. Patients with IC who underwent ECP or continent
      urinary diversion (CUD) occasionally have recurrent pain in the augmented bladder
      or continent pouch. In these patients a new ileal conduit is frequently
      constructed. Using part of the continent urinary diversion or bladder
      augmentation patch to make the ileal conduit has been reported. However, there
      may be some concern with performing the procedure in patients with IC because of
      the theoretical risk of continued pain in the converted ileal segment. We
      evaluated the role of conduit formation using retubularized bowel from ECP or CUD
      in patients with IC. MATERIALS AND METHODS: A total of 11 patients with a mean
      age of 45 years underwent conduit formation using the augmentation patch of ECP
      or part of the continent urinary reservoir. Patients were followed by history,
      physical examination, laboratory tests and urography. RESULTS: Followup was 20 to
      80 months. One patient continued to have pelvic pain. None of the patients had
      residual pain in the conduit. One patient had intermittent pain in the conduit 32
      months after conversion. Two patients had ureteral obstruction requiring ureteral
      reimplantation revision. No patient complained of new gastrointestinal problems.
      CONCLUSIONS: Retubularization of a previously used bowel segment from ECP or CUD
      to form a urinary conduit seems to be an acceptable alternative in patients with
      IC.

PMID- 15017222
TI  - Normality of bladder filling studied in symptom-free middle-aged women.
AB  - PURPOSE: Data from cystometry and frequency volume charts were evaluated
      prospectively in symptom-free, middle-aged female volunteers. MATERIALS AND
      METHODS: A total of 32 women of the 60 who volunteered could be included with no
      history, symptoms or signs of urological/neurological disease. They had a mean
      age +/-SD of 49 +/- 6 years. They completed frequency volume charts during 3
      consecutive days and underwent cystometry, including filling sensation evaluation
      as well as determination of electrosensation thresholds performed using standard
      techniques. RESULTS: Four more women had to be excluded because of clearly
      pathological findings on sensory evaluation. Large bladder capacity and high
      compliance were seen in the normal group. Data on filling sensation and the
      electrical sensation threshold were in the normal range. CONCLUSIONS: To compose
      a study group of normal volunteers of middle age requires strict inclusion and
      exclusion. Even then some volunteers must be excluded if pathological examination
      results are found. Middle-aged women have bladders with large capacity and high
      compliance, which can be the consequence of retaining urine during daily
      activities.

PMID- 15017221
TI  - Assessment of bladder and urethral sphincter function before and after radical
      retropubic prostatectomy.
AB  - PURPOSE: In a prospective study we analyzed the effects of radical retropubic
      prostatectomy (RRP) on detrusor and urethral sphincter function by comparing
      urodynamic status preoperatively with that during longitudinal followup.
      MATERIALS AND METHODS: A total of 49 consecutive patients underwent urodynamics
      with pressure flow studies and Valsalva leak point pressure measurements 3 to 7
      days before RRP (baseline), and then 1 and 8 months after surgery. We assessed
      bladder compliance, detrusor overactivity, detrusor contractility and intrinsic
      sphincter deficiency (ISD). RESULTS: There was no significant change in detrusor
      overactivity at 1 and 8 months of followup. Decreased bladder compliance was
      observed in 20.4% of patients at baseline, and in 38.7% and 30.6% at 1 and 8
      months, respectively. De novo decreased compliance was detected in 18.4% and
      10.2% of patients at the same points. Impaired bladder compliance was comparable
      to that before surgery in 20% of cases. Impaired detrusor contractility was
      detected in 42.8% of patients at baseline, and in 61.2% (p <0.05) and 42.8% at 1
      and 8 months, respectively. De novo hypocontractility was observed in 28.6% and
      10.2% of patients at 1 and 8 months, respectively. A strong association between
      detrusor overactivity and ISD was observed at 1 and 8 months (p <0.01).
      CONCLUSIONS: Following RRP detrusor hypocontractility and decreased bladder
      compliance represent de novo transient dysfunction probably due to bladder
      denervation and an established condition not influenced by the operation. The
      strong association between overactivity and ISD suggests that stress urinary
      incontinence increases urethral afferent nerve activity and induces involuntary
      detrusor contractions.

PMID- 15017223
TI  - Urodynamic and clinical evaluation of 91 female patients with urinary
      incontinence treated with perineal magnetic stimulation: 1-year followup.
AB  - PURPOSE: We evaluate the perineal magnetic stimulation (PMS) effect on continence
      and quality of life in women with urinary incontinence. MATERIALS AND METHODS: We
      prospective studied 91 women with demonstrable urinary incontinence treated with
      16 sessions of PMS. Pretreatment and posttreatment evaluation was done by
      clinical history, physical examination, voiding diary, validated quality of life
      survey (I-QOL) and urodynamic study (UDS). Patients with no leakage after
      treatment were evaluated at 3, 6 and 12 months. RESULTS: Mean patient age +/- SD
      was 60.5 +/- 10.1 years. Immediately after treatment the I-QOL score increased
      35% (p <0.001), the number of pads daily decreased 40% (p <0.001), the number of
      leaks daily decreased 54% (p <0.001) and 34 patients (37%) became dry. Of the 91
      patients 41 were evaluated before and after treatment by UDS. The average
      increase in vesical leak point pressure (VLPP) was 24.3% (p = 0.001) and initial
      VLPP in patients who became dry was greater than 80 cm H2O. After treatment 77%
      of patients with initial low pressure detrusor overactivity on UDS became free of
      this condition. One year after discontinuing PMS 94% of patients who became dry
      immediately after treatment had recurrence. CONCLUSIONS: Immediately after 16
      sessions of PMS women with urinary incontinence have significant improvement in
      the I-QOL score with decreased daily pad use and leakage episodes but 63% had
      failure. Therapy is more effective in patients with a VLPP of greater than 80 cm
      H2O. The beneficial effect is temporary with high and early recurrence after
      discontinuing treatment.

PMID- 15017224
TI  - The Rosti sling: a new, minimally invasive, tension-free technique for the
      surgical treatment of female urinary incontinence-the first 217 patients.
AB  - PURPOSE: We evaluated the outcome of a new, innovative, inexpensive tension-free
      technique, the Rosti sling (RS), for female urinary incontinence. MATERIALS AND
      METHODS: RS was performed in 217 patients under local (45%), spinal (52%) or
      general (3%) anesthesia. A 1.5 x 33 cm strip of polypropylene mesh was inserted
      under the mid urethra from above through small suprapubic stabs down and out
      through a 1.5 cm midline vaginal incision using the Stamey needle. Of the women
      76% had stress urinary incontinence and 24% had mixed incontinence. Patient age
      was 24 to 90 years (mean 56) and parity was 0 to 6 (mean 2). The diagnosis of
      incontinence was based on history and physical examinations with a cough stress
      test. Mean followup was 23 months. RESULTS: Mean operative time was 25 minutes
      (range 15 to 45) and mean hospital stay was 3 days (range 1 to 12). Perioperative
      complications were bladder and urethral perforations in 2 and 1 cases,
      respectively (1.4%), and hematoma in 3 (1.4%). There was postoperative retention
      with a variable duration in 49 patients (23%), of whom 41 underwent Hegar
      dilation. Altogether 186 of 215 patients (86.5%) were cured of incontinence. Two
      patients were lost to followup and 14 (16.3%) had de novo urge incontinence. The
      cure rates were 87% for stress urinary incontinence and 91% for mixed
      incontinence. The cure rate in patients treated under local and spinal anesthesia
      were 82% and 91%, respectively (p = 0.1084). The rates for RS with recurrent vs
      primary incontinence were 84% vs 87% (p = 0.5800) and for RS with vs without
      Hegar dilation 80% vs 88% (p = 0.2094). CONCLUSIONS: The technique described is
      simple, safe and inexpensive. The cure rates are comparable to those of tension
      free vaginal tape. However, because of the relatively high rate of postoperative
      voiding difficulties compared to tension-free vaginal tape, this technique can be
      criticized. To avoid these problems special attention should be focused on
      applying the mesh without tension and with precision.

PMID- 15017225
TI  - Porcine dermis interposition graft for repair of high grade anterior compartment
      defects with or without concomitant pelvic organ prolapse procedures.
AB  - PURPOSE: Recent literature suggests that graft interposition may decrease the
      incidence of cystocele recurrence. We describe our experience with porcine dermis
      interposition grafts for the repair of high grade cystoceles. MATERIALS AND
      METHODS: We retrospectively reviewed the charts of all women who underwent
      surgical repair of high grade cystocele. Prolapse was graded with the Baden
      Walker and Pelvic Organ Prolapse Quantitation systems, and all patients were
      evaluated with multichannel videourodynamics. Concomitant stress urinary
      incontinence was corrected with a pubovaginal sling and vault prolapse was
      corrected with iliococcygeus vault suspension. Postoperatively patients were
      evaluated at 2 weeks, 2 months, 6 months and annually thereafter. RESULTS: A
      total of 70 patients underwent cystocele repair with a porcine dermis
      interposition graft. Concomitant procedures included a pubovaginal sling in 65
      patients and vaginal vault suspension in 50. Mean followup was 24 months. There
      were no intraoperative complications. Of the patient 59 (91%) are currently dry.
      One patient had recurrent vault prolapse without cystocele (C -2), which was
      successfully repaired with abdominal sacral colpopexy. Six patients (8.6%)
      experienced recurrent grade II (Ba 0) cystocele but continued to be asymptomatic.
      Three others (4.3%) had recurrence of grade III (Ba +2) cystocele and elected not
      to undergo reoperation. Two of 6 de novo rectoceles (grade II, Ap and -1 and Bp
      0) were repaired with site specific repairs. Superficial vaginal wound separation
      in 1 case was successfully treated conservatively. CONCLUSIONS: In cases of high
      grade cystocele interposition of porcine dermis represents a successful and safe
      treatment option. Cystocele recurrence is typically low grade and it frequently
      may not require additional surgery.

PMID- 15017226
TI  - Orthotopic bladder substitution in women: nontraditional applications.
AB  - PURPOSE: Orthotopic urinary diversion is a feasible and optimal technique for
      many women undergoing cystectomy. Although successful outcomes have been
      achieved, groups at most centers have strict selection criteria. We evaluated our
      experience with female orthotopic diversion in traditional and nontraditional
      candidates. MATERIALS AND METHODS: From September 1, 1995 to February 6, 2003 53
      females with a mean age of 62 years underwent orthotopic bladder substitution.
      Median followup was 24 months. Clinicopathological parameters were evaluated in
      traditional and nontraditional patients. The nontraditional subset comprised 22
      women older than 70 years (12) or had a history of pelvic radiation (2),
      neoadjuvant chemotherapy (6) or stress incontinence (2). RESULTS: The entire
      group had a mean operative time, blood loss and hospital stay of 6.2 hours, 1,135
      ml and 8.2 days, respectively. Tumor was organ confined in 38 and extravesical in
      14 patients with bladder cancer. Complications were detected in 20 patients,
      including 9 who were traditional (23%) and 11 who were nontraditional (50%).
      Daytime and nighttime continence was reported by 46 (87%) and 45 (85%) patients,
      respectively, of whom 11 (21%) required intermittent catheterization. Of the
      patients with cancer 42 were disease-free, 2 were alive with disease and 6 died
      of disease. The nontraditional subset was older (p <0.0003) and had shorter
      followup (p = 0.05), a higher American Society of Anesthesiologists score (p =
      0.01) and a shorter overall survival (p = 0.001) than the traditional group.
      Continence was seen in 19 of 22 nontraditional patients (86%) and 4 (18%)
      required intermittent catheterization. CONCLUSIONS: Orthotopic neobladder
      diversion offers excellent clinical and functional results, and should be the
      diversion of choice in most women following cystectomy. A subset of less
      favorable candidates can also successfully undergo orthotopic substitution with a
      tolerable toxicity profile.

PMID- 15017227
TI  - Fimch antiserum inhibits the adherence of Escherichia coli to cells collected by
      voided urine specimens of diabetic women.
AB  - PURPOSE: With the increasing problem of resistance in pathogenic microorganisms
      the development of nonantimicrobial therapies is important. Diabetes mellitus
      (DM) is associated with an increased incidence of urinary tract infections. The
      majority of Escherichia coli strains, which is the most prevalent uropathogen,
      have type 1 fimbriae that bind to uroplakin in the bladder, as mediated by the
      adhesin FimH. A vaccine is being developed based on FimH adhesion. MATERIALS AND
      METHODS: The sequence of FimH adhesion of 29 E. coli strains isolated from women
      with DM was determined. For adherence experiments we used E. coli isolated from
      women with DM and a T24 bladder cell line as well as the 2 well-defined type 1
      fimbriated E. coli strains Ctrl 39 and NU14, and uroepithelial cells from women
      with DM. RESULTS: The fimH sequence of E. coli strains isolated from women with
      DM was highly homologous to the known fimH sequence of E. coli from patients
      without DM. Adherence assays in a T24 bladder cell line showed that adherence of
      these E. coli strains from women with DM could be inhibited by pre-incubation
      with antiserum raised against the chaperone-adhesin complex FimC-FimH. AntiFimCH
      antiserum also inhibited the adherence of the 2 well-defined E. coli strains
      expressing type 1 fimbriae, NU14 and Ctrl 39, but not of the FimH mutant strain
      NU14 H-, to uroepithelial cells from women with DM. CONCLUSIONS: These findings
      suggest that a vaccine based on FimH adhesin of type 1 fimbriated E. coli is a
      potential method of preventing urinary tract infection in women with DM.

PMID- 15017228
TI  - Treatment of chronic prostatitis/chronic pelvic pain syndrome with tamsulosin: a
      randomized double blind trial.
AB  - PURPOSE: We compared the efficacy of tamsulosin with placebo for the treatment of
      chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). MATERIALS AND
      METHODS: In a double blind phase II trial, 58 patients 55 years old or younger
      with moderate to severe CP/CPPS were randomized to receive 0.4 mg tamsulosin or
      placebo for 6 weeks. Patients were assessed on days -14 and -1 during a 2-week
      washout, and on days 15 and 45. The primary end point was the change from
      baseline in total National Institutes of Health Chronic Prostatitis Symptom Index
      (NIH-CPSI) score on day 45. Secondary end points were the change from baseline in
      total NIH-CPSI score on day 15 and the change from baseline in pain, urinary
      symptoms and quality of life/impact domains of the NIH-CPSI on days 15 and 45.
      Analyses of responders were performed post hoc. RESULTS: On day 45 the treatment
      effect (difference between treatment groups in change from baseline) was -3.6 (p
      = 0.04) in favor of tamsulosin. The overall effect of tamsulosin was a function
      of the baseline total NIH-CPSI score. Treatment effect increased significantly as
      the baseline score increased (for total NIH-CPSI p <0.01). Tamsulosin efficacy
      was superior to placebo at the 75th percentile of baseline score for the total
      NIH-CPSI score (-8.3, p <0.01), the pain domain (-2.9, p = 0.02), the urinary
      symptoms domain (-2.3, p <0.01) and the impact/quality of life domain (-2.1, p =
      0.02). The efficacy of tamsulosin increased with time (no significant treatment
      difference at 15 days) and tamsulosin was well tolerated. CONCLUSIONS: Tamsulosin
      was superior to placebo in providing symptomatic relief in men with CP/CPPS,
      particularly in those with more severe symptoms.

PMID- 15017229
TI  - Sexual function in ankylosing spondylitis: a study of 65 men.
AB  - PURPOSE: We evaluated sexual function in male patients with ankylosing
      spondylitis (AS) using the validated International Index of Erectile Function
      (IIEF). We also assessed the frequency and association of erectile dysfunction
      with patient age, disease duration, morning stiffness, laboratory activity,
      disease severity, depression status and medication use in this patient group.
      MATERIALS AND METHODS: We evaluated sexual function, in particular erectile
      dysfunction (ED), using the IIEF in male patients with AS followed regularly at
      the outpatient clinic of rheumatology and compared results with those in healthy
      controls. Patient age, disease duration, morning stiffness, laboratory activity,
      disease severity and medication use were obtained by reviewing the medical
      record. Affective patient and control states were measured by the Beck Depression
      Inventory. The Bath AS Functional Index was used to measure functional status in
      AS cases. RESULTS: To our knowledge this is the first study of the frequency of
      ED in men with AS (8 of 65 or 12%). Compared to healthy controls patients with AS
      had significantly lower erectile function, orgasmic function, intercourse
      satisfaction and overall satisfaction scores according to the IIEF, whereas
      sexual desire scores were also lower, although not significantly. According to
      self-reported patient data ED was a prominent characteristic of our population.
      We were not able to relate any clinical features or laboratory findings to ED
      except the duration of morning stiffness. The 22 men with a high degree of
      morning stiffness (greater than 4 hours) had lower erectile function scores
      compared to the 12 with AS and a low degree of morning stiffness (less than 2
      hours) (18.3 +/- 1.6 vs 26.5 +/- 2.4, p <0.05). Of 65 patients with AS 25 (38%)
      were depressed in our study group according to the Beck Depression Inventory,
      while no healthy controls were depressed when a score of greater than 13 was used
      as the cutoff. CONCLUSIONS: ED can be seen in the course of AS. The pathogenesis
      of ED in patients with AS is thought to be multifactorial with disease and
      treatment related factors. Thus, male patients with AS, in particular those with
      a high degree of morning stiffness, should be encouraged to talk about their
      sexuality.

PMID- 15017230
TI  - Endothelial cell activation in men with erectile dysfunction without
      cardiovascular risk factors and overt vascular damage.
AB  - PURPOSE: Endothelial cell activation (ECA) is an initiating event in
      atherosclerosis. Biochemical measures of ECA were evaluated in patients with
      erectile dysfunction (ED) associated or not associated with cardiovascular risk
      factors (VRFs) to assess whether ED is a sentinel of atherosclerosis. MATERIALS
      AND METHODS: Circulating soluble P-selectin, intercellular adhesion molecule-1,
      vascular cell adhesion molecule-1 and endothelin-1 concentrations were assessed
      in 45 men with ED but no VRFs, 45 men with ED associated with VRFs and 25 healthy
      men. Ultrasound intima-media thickness of carotid arteries and pharmacologically
      stimulated peak systolic velocity of cavernous arteries were used to assess
      vascular damage. RESULTS: Measures of ECA were higher in men with ED but no VRFs
      than in controls (p <0.01) and all were comparable among groups of men with ED.
      Levels of endothelin-1 in men with ED and no VRFs versus healthy men of the same
      age resulted in the best independent predictor for ED after adjusting for the
      confounding effect of increased body mass index and smoking (OR 5.37, 95% CI 2.12
      to 19.70). Intima-media thickness of carotid arteries was comparable in controls
      and in men with ED but no VRFs, and ruled out the bias of overt damage of large
      arteries in the latter. Peak systolic velocity of cavernous arteries excluded
      vasculogenic ED in the majority of patients with no VRFs. CONCLUSIONS: Increased
      biochemical measures of ECA were associated with ED independent of coexisting
      VRFs and overt vascular damage, suggesting that ED is a sentinel of early
      atherosclerosis.

PMID- 15017231
TI  - A prospective, randomized study using transdermal electromotive administration of
      verapamil and dexamethasone for Peyronie's disease.
AB  - PURPOSE: Uncontrolled studies with intraplaque electromotive administration of
      verapamil and dexamethasone have demonstrated objective improvements in
      Peyronie's disease. We performed a prospective controlled study to assess the
      efficacy of intraplaque electromotive verapamil/dexamethasone vs electromotive
      lidocaine. MATERIALS AND METHODS: Patients with Peyronie's disease were
      randomized into a study group (47 patients) and a control group (49 patients).
      For each treatment session an electrode receptacle was sited over the plaque and
      filled with either 5 mg verapamil and 8 mg dexamethasone (study group) or 2%
      lidocaine (control group), and a 2.4 mA electric current was applied for 20
      minutes. All patients were scheduled for 4 sessions per week for 6 weeks.
      Assessment before and after treatment included measurements of plaque volume and
      penile curvature, and pain on erection (from questionnaire). RESULTS: A total of
      37 patients in the study group and 36 in the control group completed treatment
      courses. In the study group there were significant decreases in median plaque
      volume from 824 to 348 mm, and in penile curvature from 43 to 21 degrees. In the
      control group median volume and curvature were unchanged. The difference in
      results after treatment between the 2 groups was also significant. Significant
      pain relief occurred in both groups, transient in the control group and permanent
      in the study group. All patients experienced temporary erythema at the electrode
      site. There were no other side effects. CONCLUSIONS: Intraplaque electromotive
      verapamil and dexamethasone induce substantial objective improvement in
      Peyronie's disease compared to electromotive lidocaine administration.

PMID- 15017232
TI  - Exploring cause and effect relationships in male sexual dysfunction.

PMID- 15017233
TI  - Efficacy of antibiotic impregnation of inflatable penile prostheses in decreasing
      infection in original implants.
AB  - PURPOSE: We compared infection rates in original inflatable penile prostheses
      implants between prostheses impregnated with InhibiZone (American Medical
      Systems, Minnetonka, Minnesota), an antibiotic surface treatment, and prostheses
      without antibiotic treatment. MATERIALS AND METHODS: We retrospectively reviewed
      patient information forms filed with the manufacturer following original
      implantation in the United States to implant AMS 700 series penile prostheses
      (American Medical Systems) between May 1, 2001 and April 30, 2003. We compared
      results in 4205 men, including 2261 with a mean age of 60.71 years who received
      prostheses with InhibiZone, a surface treatment combining rifampin and
      minocycline hydrochloride, and a control group of 1944 with a mean age of 61.04
      years who received untreated prostheses. Followup in the treatment and control
      groups was 0 to 11.5 months (mean 5 and 8, respectively). In the treatment group
      only implants in which all components were treated were included. RESULTS: The
      reported incidence of infection after 60 days was 0.28% in the treated group and
      1.59% in the control group (p = 0.0034). After 180 days the infection rate in the
      treated and control groups was 0.68% and 1.61%, respectively (p = 0.0047). The
      treated group had an infection rate that was 82.4% lower than in the control
      group after 60 days and 57.8% lower after 180 days. Erectile dysfunction
      etiologies occurred at statistically similar rates in the 2 groups and did not
      impact infection rate results. CONCLUSIONS: The use of InhibiZone to target
      postoperative infections results in a statistically significant decrease in
      penile prosthesis infection rates in original implants. Infection rates in the
      control group were consistent with those in the published literature.

PMID- 15017234
TI  - Attitudes of adult 46, XY intersex persons to clinical management policies.
AB  - PURPOSE: We surveyed a clinic sample of adult 46,XY intersex patients regarding
      attitudes to clinical management policies. MATERIALS AND METHODS: All adult
      former patients of 1 pediatric endocrine clinic in the eastern United States
      whose addresses could be obtained and who consented to participation were
      surveyed by a comprehensive written followup questionnaire. Three questions on
      attitudes concerning the desirability of a third gender category and the age at
      which genital surgery should be done were presented in the context of ratings of
      satisfaction with gender, genital status and sexual functioning. RESULTS: A total
      of 72 English speaking patients with 46,XY, including 32 men and 40 women 18 to
      60 years old, completed the questionnaire. The majority of respondents stated
      that they were mainly satisfied with being the assigned gender, did not have a
      time in life when they felt unsure about gender, did not agree to a third gender
      policy, did not think that the genitals looked unusual (although the majority of
      men rated their penis as too small), were somewhat or mainly satisfied with
      sexual functioning, did not agree that corrective genital surgery should be
      postponed to adulthood and stated that their genital surgeries should have been
      performed before adulthood, although there were some significant and important
      differences among subgroups. CONCLUSIONS: The majority of adult patients with
      intersexuality appeared to be satisfied with gender and genital status, and did
      not support major changes in the prevailing policy. However, a significant
      minority was dissatisfied and endorsed policy changes.

PMID- 15017235
TI  - Pilot experience with real-time ultrasound guided percutaneous renal mass
      cryoablation.
AB  - PURPOSE: We describe our pilot experience with percutaneous cryoablation of renal
      masses using real-time sonography. MATERIALS AND METHODS: Three patients
      presented with 4 renal masses in 4 kidneys, which enhanced with contrast
      administration by computerized tomography or magnetic resonance imaging criteria.
      Renal neoplasm cryoablation was performed using general anesthesia with 17 gauge
      cryoneedles percutaneously placed into the renal tumor under real-time
      sonographic guidance. Followup cross-sectional imaging was performed 6 to 7 weeks
      following cryoablation in all patients. RESULTS: No perioperative complications
      were noted. All patients were discharged home within 24 hours of the procedure
      and postoperative pain was controlled with oral nonnarcotic medications. Followup
      cross-sectional imaging indicated that the lesions shrank an average 63% +/- 15%
      from initial pretreatment volume. Importantly none of the lesions showed contrast
      enhancement by computerized tomography or magnetic resonance imaging criteria.
      CONCLUSIONS: Our initial experience shows that percutaneous, sonographically
      guided renal neoplasm cryoablation can be a safe method for treating renal
      masses.

PMID- 15017236
TI  - Benign intratesticular tumor.

PMID- 15017237
TI  - Diffuse fibrous pseudotumor of the tunica vaginalis testis, epididymis and
      spermatic cord.

PMID- 15017238
TI  - Fatal acute tumor lysis syndrome, hepatic encephalopathy and flare phenomenon
      following combined androgen blockade.

PMID- 15017239
TI  - Recurrent scrotal arteriovenous malformation.

PMID- 15017241
TI  - Raynaud's phenomenon of the penis.

PMID- 15017240
TI  - Obturator infected hematoma and urethral erosion following transobturator tape
      implantation.

PMID- 15017242
TI  - High flow priapism secondary to internal urethrotomy treated with embolization.

PMID- 15017243
TI  - Testicular ischemia following open prostatectomy.

PMID- 15017244
TI  - Shortening of tension-free vaginal tape for the treatment of recurrent
      incontinence.

PMID- 15017245
TI  - Re: variation in continence and potency by definition.

PMID- 15017247
TI  - Re: comparative assessment of maximal bladder capacity, 0.9% NaCl versus 0.2 M
      KCl, for the diagnosis of interstitial cystitis: a prospective controlled study.

PMID- 15017248
TI  - Re: comparative assessment of maximal bladder capacity, 0.9% NaCl versus 0.2 M
      KCl, for the diagnosis of interstitial cystitis: a prospective controlled study.

PMID- 15017250
TI  - Re: treatment of radiation induced hemorrhagic cystitis with hyperbaric oxygen.

PMID- 15017252
TI  - Re: spontaneous slow wave and contractile activity of the guinea pig prostate.

PMID- 15017254
TI  - Re: optimizing treatment for diabetes mellitus induced erectile dysfunction.

PMID- 15017255
TI  - Magnetic resonance urography: a new gold standard for the evaluation of solitary
      kidneys and renal buds?
AB  - PURPOSE: We evaluated the diagnostic potential of magnetic resonance urography
      (MRU) in pediatric patients with a solitary kidney and/or dysplastic orthotopic
      or ectopic renal buds. We present our evolving experience with this imaging
      procedure. MATERIALS AND METHODS: A total of 30 patients with a mean age of 43.8
      months with a known or suspected solitary kidney with or without clinical
      symptoms underwent ultrasound of the urinary tract as well as voiding
      cystourethrogram, renal static dimercapto-succinic acid (DMSA) scintigraphy and
      MRU. The results of these diagnostic imaging studies were then compared with each
      other and set against the results of the final diagnosis established at surgery
      and by histology, if available. RESULTS: Dysplastic orthotopic or dystopic renal
      buds suspected on ultrasound in 11 of the 30 patients were confirmed in all 11 by
      MRU. While accompanying ectopic ureteral insertions were shown in only 3 patients
      by ultrasound, they were visualized in all 4 by MRU. The other 7 patients with
      dysplastic renal buds had orthotopic ureteral orifices. DMSA scintigraphy failed
      to detect 10 renal buds. CONCLUSIONS: The diagnostic value of MRU appears to be
      superior to that of other imaging tests, even to that of DMSA scintigraphy, which
      with voiding cystourethrography is currently considered the gold standard for
      evaluating sonographically suspected solitary kidneys with contralateral
      orthotopic or ectopic renal buds and ectopic ureteral insertion.

PMID- 15017256
TI  - Latex allergy in children with urological malformation and chronic renal failure.
AB  - PURPOSE: Children with spina bifida, bladder exstrophy and anorectal anomalies
      are at risk for latex allergy. Severe intraoperative anaphylaxis in a boy treated
      with kidney transplantation prompted this study to evaluate the prevalence of
      latex allergy in a cohort of children with chronic renal failure (CRF). MATERIALS
      AND METHODS: Between 1996 and 2002, 57 boys and 28 girls were investigated at a
      median age of 10.5 years (range 1.3 to 22.9). Urological malformations were the
      underlying cause of CRF in 33 patients (39%). Of the patients 39 were on
      conservative treatment, 20 were on dialysis and 26 had a functioning renal graft.
      Latex reaction was assessed by a careful history, specific serum latex IgE and
      skin prick test. RESULTS: A total of 19 patients (22%) showed latex reaction, of
      whom 8 had allergy (clinical symptoms included severe intraoperative anaphylaxis
      in 1) and 11 had sensitivity (positive IgE or prick test without symptoms). Of
      these 19 patients 11 had urological malformations. The number of surgical
      procedures, young age at operation and atopy were significant risk factors. When
      operations were analyzed separately, ie urological vs nonurological surgery, only
      urological surgery was significantly associated with latex reaction. A
      significant correlation was also found between the overall number of operations
      and latex radioallergosorbent class. CONCLUSIONS: All children with CRF who
      undergo early and multiple urological surgery are at high risk for latex
      reaction. Primary latex prevention, ie the routine use of latex-free gloves,
      tubes and catheters, should be implemented in all children with complex
      urological malformations.

PMID- 15017257
TI  - The anterior sagittal transrectal approach for traumatic urethrovaginal fistula
      closure.

PMID- 15017259
TI  - Eosinophilic cystitis in a child presenting with a bladder mass.

PMID- 15017258
TI  - Laparoscopic appendicovesicostomy (Mitrofanoff procedure) in a child using the da
      Vinci robotic system.

PMID- 15017260
TI  - Desmopressin for the treatment of nocturnal bedwetting in patients with neural
      tube closure defects.
AB  - PURPOSE: We evaluated desmopressin (DDAVP) treatment in patients with neuropathic
      bladder secondary to neural tube closure defects (NTDs) and nocturnal
      incontinence. MATERIALS AND METHODS: We selected 25 patients, that is 10 males
      (40%) and 15 females (60%), between ages 7 and 16 years (mean 9.8) with
      neuropathic bladder secondary to NTDs without a ventricular-peritoneal shunt. All
      had a low pressure bladder and presented with daytime continence between
      catheterizations but had persistent nocturnal urine loss 7 nights weekly. They
      underwent treatment with oral DDAVP according to a certain design, namely an
      initial dose of 0.2 mg for 3 weeks, which was increased to 0.3 or 0.4 mg for
      another 3 weeks in nonresponders. The average dose was 0.2 mg. At the effective
      minimal dose (bedwetting decrease greater than 50%) patients continued for 6
      months and then decreased by intervals of 0.05 mg every 2 weeks. In the event of
      recurrence treatment continued for 1 year. RESULTS: All patients responded to
      treatment during the nighttime hours except 1 who suspended treatment after 4
      weeks. There were no adverse effects from DDAVP. CONCLUSIONS: Treating nocturnal
      bedwetting with DDAVP in patients with NTDs was effective and safe. Nevertheless,
      to our knowledge treatment duration has not yet been determined.

PMID- 15017261
TI  - Impact of urinary incontinence on self-concept in children with spina bifida.
AB  - PURPOSE: Low self-concept and self-esteem are thought to be the main predictors
      of psychological problems in children and adolescents. Children with spina bifida
      are thought to be at an increased risk for low self-concept and self-esteem given
      their disabilities. We examined the impact of urinary continence on self-concept
      in children with myelomeningocele. MATERIALS AND METHODS: A total of 50 patients
      7 to 19 years old with spina bifida were evaluated using the Hartner self
      perception profile. Each patient was asked to self-rate on a scale of 1 to 4
      using specific domains of self-concept, including scholastic competence, social
      acceptance, athletic competence, physical appearance, behavioral conduct and
      global self-worth. Continence and several other factors, namely ambulatory
      status, family situation and insurance status, were reviewed simultaneously.
      RESULTS: There were no statistically significant differences between continent
      patients with spina bifida and controls. Overall children with spina bifida rated
      lower in scholastic competence, social acceptance and behavioral conduct than
      controls. Girls with spina bifida scored lower in perceived athleticism, physical
      appearance and global self-worth than boys with spina bifida. Continent girls
      were self-rated higher in social acceptance and global self-worth than
      incontinent girls. Continent boys were self-rated higher in scholastic
      competence, social acceptance, physical appearance and behavior compared to
      incontinent boys. CONCLUSIONS: Continence is associated with better self-concept
      in children with spina bifida and incontinent girls are at particularly high risk
      for poor self-esteem. Urologists' efforts to promote continence are likely to
      have a positive effect on self-concept in boys and girls with spina bifida.

PMID- 15017262
TI  - Family history and behavioral abnormalities in girls with recurrent urinary tract
      infections: a controlled study.
AB  - PURPOSE: We evaluated the role of family history, infrequent voiding, poor fluid
      intake, functional stool retention and inadequate anogenital hygiene or toilet
      habits in girls with recurrent urinary tract infections. MATERIALS AND METHODS:
      The possible occurrence of these risk factors was assessed in 90 Swiss girls with
      recurrent urinary tract infections and in a control group of 45 girls. RESULTS:
      Family history was positive in 42% of patients and in 11% of controls (p <0.001).
      Behavioral abnormalities were also more frequently noted in girls with recurrent
      urinary tract infections than in the control group (81% vs 56%, p <0.01). There
      were 137 abnormalities in 73 girls with recurrent urinary tract infections and 30
      abnormalities in 25 controls. Two or more abnormalities each, that is 2 in 32
      girls and 3 in 16, were noted in 48 girls with recurrent urinary tract infections
      and in 5 control girls. No controls presented with more than 2 abnormalities.
      Infrequent voiding (54% vs 24%, p <0.001), poor fluid intake (53% vs 16%, p
      <0.001) and functional stool retention (30% vs 13%, p <0.05) were more frequently
      disclosed in girls with recurrent urinary tract infections than in control girls.
      In contrast, the frequency of inadequate stool hygiene or toilet habits was
      similar in patients and controls (14% and 13%, respectively). CONCLUSIONS: The
      evaluation of girls with recurrent urinary tract infections should focus on
      identifying behavioral aspects, including infrequent voiding, poor fluid intake
      and functional stool retention.

PMID- 15017263
TI  - Long-term outcome of Fowler-Stephens orchiopexy in boys with prune-belly
      syndrome.
AB  - PURPOSE: Intra-abdominal testes in boys with prune-belly syndrome have been
      conventionally managed by 1 or 2-stage orchiopexy with division of the gonadal
      vessels. We reviewed a series of adults with prune-belly syndrome to assess the
      morphological and functional outcome of orchiopexy in childhood with specific
      reference to the spontaneous onset of puberty, hormonal profiles and sexual
      function. MATERIALS AND METHODS: A total of 41 boys were divided into 3 groups
      depending on the type of orchiopexy performed, namely group 1-20 with bilateral 1
      stage orchiopexy, group 2-10 with unilateral 1-stage and contralateral 2-stage
      orchiopexy, and group 3-11 with bilateral 2-stage orchiopexy. RESULTS: In group 1
      9 of 20 patients had good scrotal testes bilaterally, 6 had a good scrotal testis
      on 1 side and 3 had small testes on each side. Two boys required testosterone
      supplementation but 18 had normal hormonal and sexual function. In group 2 6 of
      10 patients had good scrotal testes bilaterally and 4 had a good scrotal testis
      on 1 side. All patients underwent spontaneous puberty with good sexual function.
      In group 3 7 of 11 boys had good scrotal testes bilaterally and 3 had 1 good
      testis with normal puberty and sexual function. These 10 patients underwent
      spontaneous puberty with good sexual function. CONCLUSIONS: The majority of boys
      with prune-belly syndrome had a satisfactory outcome after orchiopexy with
      division of the gonadal vessels with testicular function sufficient to induce
      puberty and maintain satisfactory sexual function in adult life.

PMID- 15017265
TI  - The cell cycle and its relevance to the urologist.
AB  - PURPOSE: We surveyed fundamental concepts of the cell cycle to help the average
      urologist better understand the molecular basis for specific aspects of
      urological disease. MATERIALS AND METHODS: Important publications that have
      shaped our current understanding of the cell cycle were selected for review.
      Definitions of key terms are provided in a glossary. RESULTS: Cell proliferation,
      survival and programmed cell death (apoptosis) are the net result of a complex
      interaction of molecular signals that regulate DNA and protein synthesis. Many of
      the abnormal patterns of cell behavior that contribute to the pathology of
      malignant urological disease arise from disruptions in the molecular controls
      that normally regulate the cell cycle. Benign urological conditions, including
      cystic diseases and hypertrophy, also reflect abnormal growth that results from
      the disruption of cell cycle controls. CONCLUSIONS: This review is designed for
      the clinician and for the nonspecialist who is interested in the science of the
      cell cycle and its regulation as it broadly pertains to urological disease.
      Recent advances in the understanding of cell cycle regulation are presented with
      clinical correlations illustrating how these processes are involved in
      coordinating cell growth and cell death at the molecular level.

PMID- 15017267
TI  - A new candidate vaccine for Escherichia coli pyelonephritis.

PMID- 15017266
TI  - Antibody responses and protection from pyelonephritis following vaccination with
      purified Escherichia coli PapDG protein.
AB  - PURPOSE: A critical early step in the establishment of Escherichia coli
      pyelonephritis is bacterial attachment via the tip protein of P fimbriae. This
      adhesin, PapG, binds to glycolipid receptors present on vaginal and kidney
      epithelial surfaces. In this study we investigated the efficacy of vaccination
      with purified PapDG protein complex in preventing pyelonephritis caused by E.
      coli. MATERIALS AND METHODS: Mature cynomolgus monkeys were intraperitoneally
      vaccinated with 100 microg purified PapDG protein. Following 3 identical boosters
      serum antibody titers to PapDG were measured by enzyme-linked immunosorbent
      assay. Vaccinated and unvaccinated animals were urethrally inoculated with 1 x 10
      cfu of E. coli strain DS17, which was isolated from a child with acute
      pyelonephritis. The infection course was monitored by catheterized urine
      cultures, and by histological examination of the kidneys, bladder and kidney
      tissue culture 28 days after infection. RESULTS: Intraperitoneal administration
      of purified PapDG vaccine resulted in the development of specific antibody
      responses in cynomolgus monkeys. In contrast to control monkeys, vaccinated
      monkeys did not show histological evidence of pyelonephritis after subsequent
      urethral challenge with pyelonephritogenic E. coli expressing P fimbriae.
      CONCLUSIONS: Purified PapDG is a tractable vaccine candidate that in our small
      study demonstrated the ability to elicit adequate serum antibody levels to
      prevent E. coli mediated pyelonephritis.

PMID- 15017268
TI  - Sensitivity of renal cell carcinoma to aminoflavone: role of CYP1A1.
AB  - PURPOSE: The aminoflavone analogue (AF) exhibits antitumor activity in vitro,
      particularly against neoplastic cells of renal origin. We identified cellular
      correlates of responsiveness to AF in continuous human tumor renal cell carcinoma
      lines and in tumor cell isolates, termed renal carcinoma cell strains, from
      patients with clear cell and papillary renal neoplasms. MATERIALS AND METHODS: In
      vitro antiproliferative activity of AF was evaluated using the sulforhodamine B
      protein dye assay. In vivo antitumor activity of the drug was determined in mice
      bearing xenografts. Covalent binding of AF/metabolite(s) was assessed following
      exposure of cells to AF for 16 hours. CYP1A1 and CYP1B1 mRNA and apoptosis were
      quantitated by reverse transcriptase-polymerase chain reaction and enzyme-linked
      immunosorbent assay, respectively. RESULTS: AF produced total growth inhibition
      in vitro in 3 of 6 human tumor renal cell lines at concentrations of 90 to 400
      nM. In vivo treatment of mice bearing xenografts of the Caki-1 renal cell
      carcinoma, sensitive to AF in vitro, resulted in significant antitumor activity,
      including tumor-free survivors. Studies in 13 renal cell strains isolated from
      patients with clear cell (9) or papillary (4) renal cell carcinoma indicated that
      3 of 4 papillary strains were sensitive to AF compared with 2 of 9 clear cell
      strains. AF sensitive renal cell lines and strains exhibited induction of CYP1A1
      and CYP1B1 gene expression, increased covalent binding of AF metabolite(s) and
      apoptosis. CONCLUSIONS: AF has noteworthy antitumor activity against certain
      human tumor renal cell lines in vitro and in vivo, which correlates with drug
      metabolism to covalently binding metabolites after CYP1A1 and CYP1B1 gene
      expression. We hypothesize that it leads to apoptosis induction. AF sensitive
      renal cell strains are predominantly of the papillary histological type. These
      results are limited by the small numbers of cell lines and cell strains but they
      are suggestive of the need for further testing in larger collections of cell
      strains.

PMID- 15017269
TI  - Substance P induced release of macrophage migration inhibitory factor from rat
      bladder epithelium.
AB  - PURPOSE: Substance P (SP), a neuropeptide mediator of neurogenic inflammation,
      induces vasodilatation, plasma extravasation and hypersensitivity in the bladder.
      SP induced inflammation is enhanced and maintained by the release of additional
      mediators. The rat urothelium contains pre-formed macrophage migration inhibitory
      factor (MIF), a known proinflammatory cytokine, suggesting that it may mediate
      bladder neurogenic inflammation. We documented the time course of SP effects on
      rat bladder inflammation. MATERIALS AND METHODS: Subcutaneous SP administration
      induced neurogenic inflammation. The bladder, urine and serum were removed 15,
      30, 60 and 120 minutes following treatment, and changes in MIF, nerve growth
      factor (NGF), c-fos and cox-2 were determined. RESULTS: SP induced significant
      MIF and NGF release from the bladder following 30 minutes of exposure. cox-2
      protein was detected at significant levels following 60 minutes of SP exposure.
      Basal c-fos protein could be detected in control bladders with significant
      increases following 60 minutes of SP exposure. Histological examination of
      bladder tissue showed increased edema in SP treated bladders. CONCLUSIONS: SP
      stimulated early release of urothelial MIF as well as increased MIF gene
      expression in this model of neurogenic inflammation. SP also increased expression
      of the proinflammatory mediator NGF. In addition, increases in cox-2 enzyme and c
      fos transcription factor were noted. The early release of MIF suggests that it is
      an immediate proinflammatory regulator in the bladder and it establishes MIF as
      candidate proinflammatory mediator of SP induced neurogenic inflammation. These
      data continue to support our hypothesis that MIF is a new target for intervention
      in bladder inflammation.

PMID- 15017270
TI  - Reliable visceromotor responses are evoked by noxious bladder distention in mice.
AB  - PURPOSE: A mouse model of bladder distension (UBD) induced acute visceral
      nociception was characterized. Murine models of nociception may allow for the
      investigation of mechanisms of pain and analgesia through the use of genetic
      models. MATERIALS AND METHODS: Isoflurane anesthetized, spontaneously breathing
      female C3H/J mice had 24 gauge intravesical catheters transurethrally placed and
      electrodes implanted in the abdominal musculature and in upper limbs for
      electromyograms and electrocardiograms. RESULTS: UBD (10 to 80 mm Hg for 20
      seconds, phasic air distention) produced reliable, reproducible visceromotor
      responses (VMRs), that is increased abdominal muscle activity, which were graded
      with graded UBD. Heart rate and respiratory responses were reliable but not
      reproducible. Subcutaneous morphine (1 to 4 mg/kg) and intravesical lidocaine
      (500 microg) produced reversible VMR inhibition. Inflammation produced by
      intravesical mustard oil (2.5% for 15 minutes with an olive oil control) produced
      a marked increase in sensitivity to UBD with more robust responses evoked by
      lower UBD intensities. VMRs were present in decerebrate but not in spinal cord
      transected mice. Unanesthetized mice had similar responses to UBD but with lower
      pressure thresholds for VMRs. CONCLUSIONS: These findings suggest the usefulness
      of the current model system for the study of bladder nociception. In mice UBD
      evoked VMRs are spinobulbospinal reflexes that are reliable and reproducible,
      graded in relation to the stimulus, inhibited by analgesics and augmented by the
      presence of inflammation. Together these data strongly support the use of this
      model because it may allow the assessment of pharmacogenetic differences among
      murine strains and the use of transgenic technologies.

PMID- 15017271
TI  - Role of glutamate receptors in the development and maintenance of bladder
      overactivity after cerebral infarction in the rat.
AB  - PURPOSE: To investigate the role of glutamate receptors in overactive bladder
      (OAB) caused by cerebral infarction (CI) we examined the effects of 2 different
      types of receptors antagonists on OAB induced by left middle cerebral artery
      (MCA) occlusion. MATERIALS AND METHODS: Female rats were intravenously injected
      with dizocilpine, an NMDA (N-methyl-D-aspartate) receptor antagonist, or NBQX
      (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide), an AMPA
      (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist,
      before or after MCA occlusion. Awake rats were cystometrically examined for 8
      hours. Detrusor strips were evaluated for force development in response to
      dizocilpine and NBQX. RESULTS: In CI rats without pretreatment bladder capacity
      (BC) was significantly decreased after MCA occlusion and remained consistently
      below half that of pre-occlusion capacity. Dizocilpine (0.5 mg/kg intravenously)
      administered before MCA occlusion blocked the decrease in BC in awake rats 5 to 8
      hours after MCA occlusion. In CI rats pretreated with NBQX (10 or 30 mg/kg
      intravenously) BC was not different from that in rats without pretreatment.
      Increasing doses of dizocilpine (0.01 to 10 mg/kg) or NBQX (0.1 to 30 mg/kg)
      increased rat BC 2 hours after MCA occlusion. NBQX did not change the BC of sham
      operated rats. No differences in the contractile response to dizocilpine or NBQX
      of detrusor strips from sham operated and CI rats were observed. CONCLUSIONS:
      These results indicate that NMDA receptor has an essential role in the
      development of OAB after CI. AMPA receptor antagonist cannot block the
      development of OAB. However, AMPA receptor antagonist temporally inhibits OAB
      after it is established by CI.

PMID- 15017272
TI  - Restoration of external urethral sphincter function after pudendal nerve end-to
      end anastomosis in the male rabbit.
AB  - PURPOSE: In this study we rehabilitated external urethral sphincter function by
      pudendal nerve end-to-end anastomosis after experimental pudendal nerve axotomy
      in male rabbits. MATERIALS AND METHODS: A total of 17 animals were included in
      this study, including group 1-a control group of 5 (29.4%), group 2-6 (35.3%) and
      group 3-6 (35.3%). Animals from group 2 underwent bilateral axotomy and group 3
      underwent pudendal nerve end-to-end anastomosis. In all groups we performed
      urodynamic investigations prior to axotomy, after axotomy or anastomosis, and 14,
      42 and 90 days after axotomy or nerve anastomosis. RESULTS: In untreated group 1
      control sphincter pressure was 28.5 cm H2O. In group 2 average urethral sphincter
      pressure was 5.6 cm H2O 14 days after axotomy with only a slight increase to
      11.05 cm H2O by day 90. In group 3 external urethral pressure increased to 8.26
      cm H2O after 14 days and to 21.32 cm H2O by postoperative day 90. CONCLUSIONS:
      External urethral sphincter deficiency after bilateral pudendal nerve axotomy
      demonstrates the primacy of the pudendal nerve in the innervation of the external
      urethral sphincter. We were able to rehabilitate external urethral sphincter
      function by performing pudendal nerve end-to-end anastomosis.

PMID- 15017273
TI  - Robotic microsurgical vasovasostomy and vasoepididymostomy: a prospective
      randomized study in a rat model.
AB  - PURPOSE: Microsurgical vasovasostomy and vasoepididymostomy remain technically
      challenging procedures. Refinements in technique have continually improved
      patency and pregnancy rates for the 2 procedures in experienced hands. Advances
      in surgical robotics produced the Da Vinci robot (Intuitive Surgical, Inc.,
      Sunnyvale, California) with motion reduction and no tremor, features that may
      improve outcomes in microsurgery. We report a randomized prospective study of
      vasoepididymostomy and vasovasostomy using the Da Vinci robot in rats. MATERIALS
      AND METHODS: A total of 24 adult male Wistar rats underwent vasectomy through a
      midline abdominal incision. Two weeks later the animals were randomized to
      microsurgical multilayer vasovasostomy, longitudinal vasoepididymostomy or
      robotic vasovasostomy and vasoepididymostomy groups. Outcomes measured included
      surgical time, complications, patency and sperm granuloma formation at 9 weeks.
      RESULTS: Animals were sacrificed 9 weeks after microsurgery. There were no
      significant differences in complications among the groups. Robotic vasovasostomy
      was significantly faster than the conventional microsurgical technique (68.5 vs
      102.5 minutes, p = 0.002). The robotic and microsurgical vasoepididymostomy
      groups did not differ significantly in time. Patency rates were 100% for the
      robotic vasovasostomy and vasoepididymostomy groups, and 90% in the microsurgical
      vasovasostomy and vasoepididymostomy groups. These differences were not
      significant. Sperm granulomas were found in 70% of microsurgical vasovasostomy
      anastomoses and 27% of robotic vasovasostomy anastomoses (p = 0.001). No
      significant difference in the sperm granuloma rate was found between the robotic
      or microsurgical vasoepididymostomy groups (42% and 50%, respectively, p = 0.37).
      CONCLUSIONS: To our knowledge we report the first randomized prospective study
      using the Da Vinci robot for microsurgery. We believe that the improved stability
      and motion reduction during microsurgical suturing with the robot helped achieve
      excellent patency rates for vasovasostomy and vasoepididymostomy. The robot may
      also allow experienced microsurgeons to perform microsurgical procedures in
      patients at remote locations where no experienced microsurgeons are available.

PMID- 15017280
TI  - Brachyspira research - special issue on colonic spirochaetes of medical and
      veterinary significance.

PMID- 15017281
TI  - Differences in lymphocyte subpopulations and cell counts before and after
      experimentally induced swine dysentery.
AB  - The aim of this study was to examine the levels of circulating leukocytes and
      lymphocyte subpopulations before and immediately after experimentally induced
      swine dysentery. Twenty-one healthy crossbred pigs (approximately 22 kg) were
      orally inoculated with Brachyspira hyodysenteriae. Blood was sampled before
      inoculation and when clinical signs of swine dysentery occurred. Pigs that
      remained healthy were sampled when killed. Total and differential white blood
      cell counts were performed, and lymphocyte subpopulations were analysed using
      flow cytometry. Following a mean incubation period of 13 days, 12 pigs developed
      swine dysentery, whereas nine remained healthy throughout the study. Before
      inoculation, pigs that subsequently developed swine dysentery displayed higher
      levels of circulating gamma delta T cells (mean +/- se; 30.7 +/- 3.5 %) compared
      with pigs that remained healthy (14.9 +/- 1.4 %). Sick animals also displayed
      lower levels of CD8 cells (24.6 +/- 1.5 %), cytotoxic/suppressor T cells (10.9 +/
      1.3 %) and CD4 CD8 T cells (8.1 +/- 1.0 %) than the pigs that remained healthy
      (34.9 +/- 3.1 %; 17.6 +/- 2.0 %; 13.6 +/- 2.3 %). No difference was observed in
      leukocyte counts before inoculation. At onset of swine dysentery, there was an
      increase in monocytes (from 1.5 +/- 0.2 x 10 to 3.8 +/- 0.5 x 10 l) and CD4 CD8 T
      cells (from 5.8 +/- 0.9 to 8.9 +/- 0.7 %). In conclusion, gamma delta T cells and
      CD8 cells may be associated with susceptibility to experimentally induced swine
      dysentery, whereas monocytes and CD4 CD8 T cells appear to be the major
      responding leukocytes during the disease.

PMID- 15017282
TI  - Experimental swine dysentery: comparison between infection models.
AB  - The aim of the present study was to develop a reproducible porcine infection
      model with Brachyspira hyodysenteriae. The influence of different factors was
      evaluated, namely, age, a diet containing large quantities of soybean meal,
      housing and administration of cortisol or antacids. Furthermore, the synergistic
      effect of additional bacteria (Escherichia coli O141, Bacteroides vulgatus or a
      mixture of Bacteroides fragilis, a field isolate of Bacteroides and Fusobacterium
      necrophorum) was studied. Experimental infection resulted in an increase in the
      serum concentrations of the acute-phase proteins serum amyloid A and haptoglobin
      and the percentages of neutrophils and monocytes. These alterations were
      specifically related to haemorrhagic diarrhoea. Inoculation combined with feeding
      of large quantities of soybean meal and group-housing induced swine dysentery in
      all experimental animals. If the pigs were fed soybean meal, kept in single pens
      and circulated between the pens, five out of nine developed disease.

PMID- 15017283
TI  - Further characterization of porcine Brachyspira hyodysenteriae isolates with
      decreased susceptibility to tiamulin.
AB  - Brachyspira hyodysenteriae is the causative agent of swine dysentery, a severe
      diarrhoeal disease in pigs. Few drugs are available to treat the disease, owing
      to both antimicrobial resistance and withdrawal of drugs authorized for use in
      pigs. Tiamulin is the drug of choice in many countries, but isolates with
      decreased susceptibility have recently been reported. The mechanism of tiamulin
      resistance in B. hyodysenteriae is not known and this facet is essential to
      understand the dissemination of the trait. To study the resistance epidemiology
      of B. hyodysenteriae, further characterization of a set of isolates from Germany
      (n = 16) and the UK (n = 6) with decreased susceptibility to tiamulin was
      performed. The relatedness between the isolates was studied by comparing PFGE
      patterns, and the in vitro susceptibility to five other antimicrobials (aivlosin,
      doxycycline, salinomycin, chloramphenicol and avilamycin) was also determined.
      For comparison of the antimicrobial-susceptibility pattern, Swedish (n = 20) and
      British (n = 4) tiamulin-susceptible isolates were tested. The German isolates
      represented several different PFGE patterns, indicating that tiamulin usage has
      been sufficient to select clones with decreased tiamulin susceptibility at
      different farms in Germany. The PFGE pattern for the six British isolates with
      decreased tiamulin susceptibility was identical to that of the German isolates,
      and they had a similar antimicrobial-susceptibility pattern, except for
      resistance to aivlosin, which was only found in a few German isolates. No other
      co-resistance with tiamulin was found.

PMID- 15017284
TI  - Decreased susceptibility to tiamulin and valnemulin among Czech isolates of
      Brachyspira hyodysenteriae.
AB  - The agar dilution method was used to investigate the sensitivity to
      pleuromutilins of 100 isolates of Brachyspira hyodysenteriae isolated from 63 pig
      farms between 1997 and 2001. In the period under investigation, MICs to both
      tiamulin and valnemulin increased, with differences between the periods 1997-98
      and 1999-2001 being statistically significant (P < 0.001 for tiamulin and P <
      0.0001 for valnemulin). Between 1997 and 2001, the MIC50 and MIC90 of tiamulin
      increased from 0.062 and 0.25 microg ml, respectively, to 1.0 and 4.0 microg ml.
      Valnemulin MIC50 and MIC90 were < or = 0.031 microg ml in 1997 and by 2001 were
      respectively, 2.0 and 8.0 microg ml. The increase in MICs of tiamulin and
      valnemulin demonstrated in this study reflect the intensity of pleuromutilin use
      in the treatment of swine dysentery in the Czech Republic.

PMID- 15017285
TI  - Brachyspira hyodysenteriae and other strongly beta-haemolytic and indole-positive
      spirochaetes isolated from mallards (Anas platyrhynchos).
AB  - The aims of the current study were to collect intestinal spirochaetes (genus
      Brachyspira) from farmed and wild mallards (Anas platyrhynchos) and to identify
      and classify those isolates that phenotypically resembled Brachyspira
      hyodysenteriae, an enteric pathogen of pigs. The isolation rate of Brachyspira
      spp. was high from both farmed (93 %) and wild mallards (78 %). In wild mallards,
      it appeared that Brachyspira spp. were more likely to be found in migratory birds
      (multivariate analysis: RR = 1.8, 95 % CI 1.1-3.1) than in mallards sampled in a
      public park. Pure cultures of putative B. hyodysenteriae were obtained from 22
      birds. All five isolates from farmed mallards and ten randomly selected isolates
      with this phenotype were used for further studies. All isolates from farmed
      mallards and two of the isolates from wild mallards were PCR-positive for the
      tlyA gene of B. hyodysenteriae. Two isolates from farmed mallards were selected
      for pulsed field gel electrophoresis (PFGE) and randomly amplified polymorphic
      DNA (RAPD) analysis. These isolates clustered with the type and reference strains
      of B. hyodysenteriae. 16S rDNA sequence analysis performed on 11 of the strains
      showed that they were all closely related to each other and to the B.
      hyodysenteriae-Brachyspira intermedia cluster. Three of the mallard isolates had
      16S rDNA sequences that were identical to those of B. hyodysenteriae strains R1
      and NIV-1 previously isolated from common rheas (Rhea americana). To conclude,
      the isolates from farmed mallards and two isolates from wild mallards were
      classified as B. hyodysenteriae based on the fact that they could not be
      differentiated by any of the applied methods from type, reference and field
      strains of B. hyodysenteriae. The remaining isolates could not be assigned
      irrefutably to any of the presently recognized Brachyspira species. These results
      point to a broader host spectrum of B. hyodysenteriae than is generally
      recognized, and to the presence in mallards of strongly beta-haemolytic and
      indole-producing spirochaetes that possess many, but not all, of the currently
      recognized characteristics of B. hyodysenteriae.

PMID- 15017286
TI  - Immunomagnetic separation of the intestinal spirochaetes Brachyspira pilosicoli
      and Brachyspira hyodysenteriae from porcine faeces.
AB  - Porcine intestinal spirochaetes are fastidious anaerobic organisms and, as a
      consequence, it has been necessary to develop various protocols to enhance their
      isolation from or detection in faeces. Immunomagnetic separation (IMS) is a
      method developed recently to improve separation of target cells from mixed cell
      suspensions. The purpose of the present study was to compare the relative
      sensitivity of IMS for isolation of Brachyspira pilosicoli and Brachyspira
      hyodysenteriae with current routine diagnostic methods (culture on selective
      media and PCR) for detection of these micro-organisms in pig faeces. Neither
      direct nor indirect IMS methods enhanced the sensitivity of detection of either
      organism when performed with the recommended washings during sample processing.
      Performance of the IMS procedure without washing gave sensitivity at levels
      similar to direct culture onto selective medium. Further development of IMS
      techniques is required to improve isolation rates of Brachyspira species from
      faecal samples.

PMID- 15017287
TI  - Extensive intestinal spirochaetosis in pigs challenged with Brachyspira
      pilosicoli.
AB  - A field isolate of Brachyspira pilosicoli, the aetiological agent of porcine
      intestinal spirochaetosis, was inoculated by stomach tube into six 6-week-old
      pigs. All animals developed loose to watery faeces and were killed successively
      on days 8, 14 or 17 post-inoculation (day 17 being the end of the study). Mild
      mucosal reddening and flecks of pus characterized the gross lesions, while
      diffuse, catarrhal colitis was revealed microscopically in all animals.
      Intestinal spirochaetosis with moderate to densely packed end-attached B.
      pilosicoli organisms was revealed extensively on the mucosal surface of the large
      intestines by light microscopy and fluorescent in situ hybridization. This study
      is the first to report extensive intestinal spirochaetosis in pigs challenged
      with B. pilosicoli.

PMID- 15017288
TI  - Brachyspira pilosicoli colonization in experimentally infected mice can be
      facilitated by dietary manipulation.
AB  - The purpose of this study was to determine whether defined dietary manipulations
      would enhance colonization of mice experimentally challenged with the intestinal
      spirochaete Brachyspira pilosicoli. Weanling C3H/HeJ mice (n = 48) were fed
      either a standard balanced mouse diet or a diet supplemented with 50 p.p.m. zinc
      bacitracin (ZnB), with 50 % (w/w) lactose or with both supplements. Eight mice
      from each group were challenged orally with a human strain of B. pilosicoli
      (WesB), whilst four in each group acted as uninfected controls to evaluate the
      effects of the diets alone. The mice were kept for 40 days following challenge
      and faeces were collected every 3-4 days and subjected to culture and PCR for B.
      pilosicoli. Feeding ZnB reduced total volatile fatty acid production in the
      caecum. Feeding lactose alone doubled the weight of the caecum and its contents
      compared with control mice, and resulted in a relatively greater production of
      acetate, but a reduction in propionate and isovalerate production. These effects
      were negated by the addition of ZnB with the lactose. None of the mice fed the
      standard diet or receiving ZnB alone became colonized following experimental
      challenge. One of the mice receiving lactose was culture and PCR positive for B.
      pilosicoli on one sampling 1 week after inoculation, and one was positive on
      three samplings taken 20, 25 and 29 days after inoculation. All mice receiving
      both lactose and ZnB became colonized and remained so, with all samples being
      positive over the last seven samplings. The colonization was not associated with
      an end-on attachment of the spirochaete to the epithelial cells of the caecum,
      but colonized mice developed a specific humoral antibody response to the
      spirochaete.

PMID- 15017289
TI  - Biochemical properties of membrane-associated proteases of Brachyspira pilosicoli
      isolated from humans with intestinal disorders.
AB  - A membrane-associated, subtilisin-like, serine protease activity was found in
      both pathogenic and non-pathogenic strains of Brachyspira species in a previous
      study, but the biochemical properties of the enzyme were not investigated. The
      purpose of the present study was to characterize further the biochemical
      properties, including substrate specificity, of the membrane-associated protease
      of Brachyspira pilosicoli isolated from humans with intestinal disorders.
      Protease activity of detergent-enriched membrane protein extracts of B.
      pilosicoli was assessed using fluorescent dye-labelled synthetic peptides as
      substrates and determination of electrophoretic mobility of cleavage products in
      agarose gels. Each activity was further confirmed with class-specific protease
      inhibitors and thermal denaturation. The presence of a hydrophilic membrane
      associated thermolabile serine endopeptidase with specificity for Leu was
      confirmed. Two additional hydrophilic membrane-associated thermostable
      proteolytic activities were identified, one with a putative Ala specificity, and
      one a carboxypeptidase. Taken together, these data suggest that, in addition to a
      previously described membrane-associated subtilisin-like serine protease, the
      membrane of B. pilosicoli contains proteins with at least two other proteolytic
      activities.

PMID- 15017290
TI  - Prevalence, risk factors and molecular epidemiology of Brachyspira pilosicoli in
      humans on the island of Bali, Indonesia.
AB  - The purpose of this study was to investigate the prevalence and epidemiology of
      the anaerobic intestinal spirochaete Brachyspira pilosicoli amongst Indonesians
      living in rural and urban settings on the island of Bali. Faecal samples (n =
      992) were collected on two occasions, 4 months apart, from people living in four
      traditional farming villages, one peri-urban location and one urban area. Samples
      were cultured anaerobically on selective agar and intestinal spirochaete isolates
      were confirmed to be B. pilosicoli by using a species-specific PCR. Forty-eight
      of the 121 isolates obtained were typed by using PFGE. A questionnaire was
      administered to participants and analysed in order to identify potential risk
      factors for colonization. Overall prevalence of carriage on the two visits was
      11.8 and 12.6 %, respectively. Prevalence at different locations varied from 3.3
      to 23.4 %, with the highest prevalence occurring in the peri-urban location.
      Considerable strain diversity was found, with the 48 isolates being divided into
      44 PFGE types. There was no significant association between colonization and
      ownership of animals, contact with animals, farming, age or gender. On the first
      visit, colonization was significantly more common in people who used well water
      compared to those who used tap water. On the second visit, colonization was
      significantly more common in people with wet faeces than in those with normal
      faeces.

PMID- 15017292
TI  - Demonstration of Brachyspira aalborgi lineages 2 and 3 in human colonic biopsies
      with intestinal spirochaetosis by specific fluorescent in situ hybridization.
AB  - Sequences of known 16S rRNA genes, derived from sequence analysis of cloned 16S
      rDNA, were used to design a specific oligonucleotide probe targeting spirochaetes
      of Brachyspira aalborgi lineages 2 and 3. The probe was used with fluorescent in
      situ hybridization to study the involvement of these organisms in human
      intestinal spirochaetosis. Seventeen human colonic biopsies from Norway and
      Denmark with intestinal spirochaetosis caused by Brachyspira-like organisms
      different from the type strain of B. aalborgi (lineage 1) were examined.
      Application of the probe gave a positive signal in two Norwegian biopsies,
      whereas the 15 other biopsies were hybridization-negative. The positive reaction
      visualized the spirochaetes as a fluorescent, 3-5 microm-high fringe on the
      surface epithelium, extending into the crypts. The study verified the presence of
      B. aalborgi lineages 2 and 3 and identified the bacteria as an aetiological agent
      of human intestinal spirochaetosis.

PMID- 15017291
TI  - Analysis of genetic variation in Brachyspira aalborgi and related spirochaetes
      determined by partial sequencing of the 16S rRNA and NADH oxidase genes.
AB  - The purpose of this study was to investigate genetic variation in the anaerobic
      intestinal spirochaete Brachyspira aalborgi by partial sequencing of the 16S rRNA
      and NADH oxidase genes. The spirochaete is poorly cultivable; hence, only six
      isolates were available for analysis. Additional sequences were amplified from
      DNA extracted from fixed colorectal biopsies from 26 patients with histological
      evidence of intestinal spirochaetosis, and from the faeces of six non-human
      primates (NHP). Multiple biopsies from sites along the large intestine were
      tested from three of the 26 patients. Sequences from two biopsies were closely
      related to those of the spirochaete Brachyspira pilosicoli. Eight B. aalborgi
      like 16S rDNA sequences were generated from the biopsies from the other 24
      patients, and four from the NHP faeces. The B. aalborgi 16S rDNA sequences were
      divided into three clusters, 1, 2 and 4, with individual sequence similarities to
      the type strain ranging from 97.49 to 100 %. All human isolates of B. aalborgi
      were located in cluster 1, as was the sequence of the so-called 'Brachyspira
      ibaraki'. All four 16S rDNA sequences from the NHP faeces and the two NHP
      isolates of B. aalborgi were located in cluster 4, which was distinct. Cluster 4
      may represent a novel Brachyspira species. Evidence for multiple strains of B.
      aalborgi or other Brachyspira species was found in biopsies from two patients. In
      the three individuals from whom multiple biopsies were amplified, the sequences
      at each intestinal site were the same, indicating the presence of one dominant
      strain.

PMID- 15017293
TI  - Identification of three clusters of canine intestinal spirochaetes by biochemical
      and 16S rDNA sequence analysis.
AB  - It has been suggested that canine intestinal spirochaetes consist of Brachyspira
      pilosicoli and a group of strains that has been provisionally designated
      'Brachyspira canis'. The purpose of the present study was to compare 22
      spirochaete isolates that were obtained from intestinal specimens of dogs in
      Sweden (n = 12), Norway (n = 4), the United States (n = 3), Australia (n = 2) and
      Germany (n = 1) with type and reference strains, as well as field isolates, of
      Brachyspira species by five biochemical tests and determination of almost
      complete 16S rDNA sequences. In an evolutionary tree derived from 16S rDNA
      sequences, the canine isolates grouped into three clusters. One cluster included
      the type strain of porcine B. pilosicoli, whereas a second larger cluster, which
      was monophyletic, contained a canine strain that was identified previously as 'B.
      canis'. The third cluster consisted of three canine isolates of Scandinavian
      origin, which grouped together with the type strain of the species Brachyspira
      alvinipulli (pathogenic to chicken). These three genotypes, which were identified
      on the basis of 16S rDNA sequences, corresponded to four phenotypic groups based
      on biochemical testing. Two biochemical tests, hippurate hydrolysis and alpha
      galactosidase production, were sufficient for rapid identification of each canine
      cluster.

PMID- 15017294
TI  - The speed limit.

PMID- 15017298
TI  - Implant dentistry and patient financing.

PMID- 15017299
TI  - Treatment options of untreatable traumatized anterior maxillary teeth for future
      use of dental implantation.
AB  - The anterior maxilla is the most traumatized region during childhood.
      Posttraumatic complications occasionally lead to tooth loss as well as the need
      for future implants. Unfortunately, it is contraindicated to place dental
      implants during childhood. A waiting period of approximately 8 to 10 years before
      completion of growth is required. For this patient to become a candidate for
      future dental implants, it is necessary to ensure the continuous growth and to
      preserve the dimensions of the alveolar process until growth has ceased from time
      of injury until joint maturation. To achieve these goals, it is essential to
      coordinate the treatment sequence at the time of trauma. After loss of a
      traumatized anterior permanent maxillary incisor in young adults, treatment
      options are limited: orthodontic closure of the gap and reshaping the adjacent
      teeth, or tooth extraction and maintaining the gap with a temporary restoration.
      Orthodontic space closure has limited indications and requires prosthetic
      restoration of at least 2 teeth. Extraction and temporary restoration will
      usually lead to bone augmentation before implantation. Other possible treatment
      options include orthodontic extrusion of the root remnant (in cases of
      untreatable root fracture or complicated crown-root fracture) and a temporary
      crown to serve the patient until the completion of growth and development,
      autogenous tooth transplantation, intentional extraction and immediate tooth
      replantation, distraction osteogenesis, and decoronation. Because general rules
      do not apply, individual treatment plans are necessary.

PMID- 15017300
TI  - Creation of interimplant papillae through a split-finger technique.
AB  - PURPOSE: The purpose of this pilot study is to propose a technique, the split
      finger approach, to preserve/promote papillae formation. MATERIALS AND METHODS:
      Twenty-one patients with 39 implants consecutively placed in the maxillary
      anterior region were evaluated at 6 months to 1 year after prosthodontic
      restoration. The implants evaluated included 16 single-tooth implants, 1 2-unit
      implant prosthesis, 2 4-unit tooth implants, 1 6-unit prostheses, and 1 7-unit
      restoration. The papillae were recorded as 0 = no papillae; 1 = < or =50% of the
      gingival embrasure height; 2 = >50% but <100% of embrasure height; 3 = 100%
      closure of the proximal space; and 4 = overgrowth of the interproximal tissue.
      RESULTS: Data from this pilot study showed no class 0, class 1, or class 4
      interproximal papillae after the final restoration. The 16 single-tooth
      restorations and 32 papillae had an average mesial papilla score of 3 and an
      average of 2.82 for the distal interproximal space. The average papilla score of
      the other implant papillae sites were 2.7 at 6 months to 1 year. A lower papilla
      score was noted in interimplant papillae. CONCLUSIONS: The proposed split-finger
      technique could serve as a clinically useful alternate procedure to
      promote/augment papillae formation around dental implants.

PMID- 15017301
TI  - Maxillary sinus floor elevation: review of anatomy and two techniques.
AB  - A review of maxillary sinus floor elevation as an integral part of restoring the
      posterior maxilla is discussed. The related anatomy of the area and the current
      techniques available are reviewed. The classic lateral antrostomy pioneered by
      Tatum appears to be the most common sinus lift procedure. The more conservative
      crestal approach, advocated by Summers, provides another effective way of
      allowing implant fixture placement in the atrophic maxilla.

PMID- 15017302
TI  - Soft tissue closure over immediate implants: classification and review of
      surgical techniques.
AB  - Despite the different opinions regarding the success of implants and guided bone
      regeneration membranes, with and without establishing primary wound closure at
      the time of surgical placement, primary closure logically seems to be the ideal
      surgical protocol. It prevents bacterial invasion to the wound and prevents wound
      disruption. In immediate implantation, lack of keratinized tissue available to
      achieve this surgical goal is a problem. Various surgical techniques are
      described to overcome this surgical difficulty, each having its advantages and
      drawbacks. Sound clinical judgment must be exercised when selecting a method,
      because it will influence the treatment result both esthetically and functionally
      by altering adjacent soft tissue and bony topography.

PMID- 15017303
TI  - Immediate Dental Implant Placement in Sockets Augmented With HTR Synthetic Bone.
AB  - PURPOSE: The purpose of this article is to present the results of using immediate
      implant placement in combination with HTR synthetic bone socket grafting to
      achieve a predictable restorative result. MATERIAL AND METHODS: Twenty-three
      hydroxylapatite-coated cylinder implants (Spline, CenterPulse Dental, Carlsbad,
      CA) were placed into fresh extraction sockets in 19 patients. In each case, HTR
      synthetic bone (Bioplant, Inc., South Norwalk, CT) was used to fill any voids
      remaining in the sockets and to augment the facial aspect of the ridge. The
      restorative phase was initiated approximately 6 months after implant placement.
      Conventional impression techniques were used and porcelain-fused-to-metal crowns
      were selected as the final restorations. RESULTS: The prosthetic outcome was
      evaluated as generally favorable. Only 4 (17%) of the dental implants required an
      angled abutment. The gingival contour was excellent in 61% and good in 35% of the
      cases. The emergence profile was evaluated as class I (full papilla) in 37% and
      class II, III, and IV in 21% each. CONCLUSIONS: The clinical results of this
      study demonstrate that immediate implant placement in combination with HTR
      synthetic bone grafting of residual socket voids and crestal deformities is a
      predictable procedure and provides a good base for successful prosthetic
      reconstruction. Adequate gingival contour and favorable emergence profile can be
      expected when combining immediate implant placement and HTR grafting material.

PMID- 15017304
TI  - Biomechanical aspects of monoblock implant bridges for the edentulous maxilla and
      mandible: concepts of occlusion and articulation.
AB  - The knowledge of forces that influence implants and suprastructure is important
      for the restorative dentist to realize the surface areas and vertical dimension
      of fixed restorations. The purpose of the concepts of occlusion is to respect the
      protection of implants that receive stress transmission and being aware of
      destructive forces. In cases in which the edentulous maxilla and mandible are
      provided with large monoblock implant bridges, the author recommends a bilateral
      balanced group guidance. If biomechanical principles are not respected, implant
      loss and restoration failure will result. For the first adjustment of occlusion
      and articulation patterns immediately after implantation, fixed temporaries are
      placed on the implants. Another 40 to 60 days later, the temporaries are
      exchanged for definitive implant bridgework.

PMID- 15017305
TI  - Reimplantation and immediate loading of an accidentally avulsed beaded implant:
      case report.
AB  - We present a case of reimplantation of an accidentally avulsed beaded Endopore
      (Innova Corp., Toronto, Canada) implant. The technique of immediate splinting and
      pharmacotherapy is described together with the clinical and radiologic evaluation
      for reosseointegration. This single case of reimplantation with immediate
      functional loading would suggest that, contrary to the manufacturer's
      recommendation, the Endopore implants can be successfully loaded immediately,
      functionally or nonfunctionally.

PMID- 15017306
TI  - The use of acupuncture in implant dentistry.
AB  - This article aims to review how acupuncture can provide complimentary treatments
      to patients through implant rehabilitation. The following topics are discussed:
      control of gagging reflex, control of postoperative vomiting, control of
      postoperative pain, enhance anesthetic effects, control of anxiety, increase
      saliva production, enhance immune responses, management of temporomandibular
      dysfunction, smoking cessation, control diabetic mellitus, stimulation of
      peripheral nerve regeneration, and adverse effects.

PMID- 15017307
TI  - Platelet-rich plasma for bone graft enhancement in sinus floor augmentation with
      simultaneous implant placement: patient series study.
AB  - The use of autologous platelet-rich plasma (PRP) as a source for growth factors
      in bone grafting is a relatively new and promising technique. Early controlled
      studies indicate that combining PRP with autologous bone grafts significantly
      enhances the rate of bone formation and maturation. The study consisted of 105
      patients who required sinus augmentation with crestal bone height of less than 5
      mm in the posterior maxilla. All patients received a composite bone graft that
      consisted of 30% to 40% autogenous bone harvested from the lateral wall of the
      maxilla zygomatic-maxillary buttress and the tuberosity and 60% to 70% xenograft.
      A total of 50 mL of blood was obtained from each patient before the surgical
      treatment for preparation of 10 mL of PRP. The graft-PRP mixture was activated by
      human thrombin. All sinus augmentations were carried out simultaneously with
      dental implants. At 6 months postoperatively, implants were exposed showing no
      clinical evidence of crestal bone loss around the implants both clinically and
      radiographically. All implants were clinically osseointegrated and loaded with
      fixed porcelain fused to metal prosthesis. The use of PRP in augmenting the
      severely atrophic posterior maxilla has obvious clinical benefits in terms of
      reducing the healing period of bone maturation, better graft handling, and
      accelerated soft tissue healing.

PMID- 15017308
TI  - Effect of platelet-rich plasma on the peri-implant bone response: an experimental
      study.
AB  - Platelet-rich plasma (PRP) is used as a source of growth factors to stimulate and
      accelerate bone formation and soft tissue healing. The use of PRP in bone
      regeneration, both around dental implants and in periodontic treatments, has
      become particularly appealing. The aim of this study was to evaluate the effect
      of PRP in an experimental model of osteogenesis around laminar implants. Fifteen
      male Wistar rats, weighing 90 +/- 10 g, were used in this study. One milliliter
      of blood was obtained from each animal by intracardiac puncture and transferred
      into Eppendorf tubes containing 10% sodium citrate. The tubes were centrifuged at
      1500 rpm for 15 minutes and PRP was prepared. The laminar test was used to
      evaluate the bone peri-implant response. PRP and a titanium laminar implant were
      introduced into the right tibia (Ti/PRP group), whereas the left tibia (control)
      received only a laminar implant (Ti group). Thirty days postimplantation, the
      tibiae were resected, radiographed, and processed for embedding in acrylic resin.
      Ground sections (50 microm) were stained with toluidine blue. The peri-implant
      bone volume was evaluated histomorphometrically. Statistical analysis of the data
      was performed. The amount of newly formed bone in the Ti/PRP group (30 +/- 7 cm)
      was significantly greater than in the Ti group (16 +/- 3 cm). A greater volume of
      peri-implant bone was observed when PRP was used in the laminar implant test
      model.

PMID- 15017309
TI  - Examination of the bone-implant interface in experimentally induced osteoporotic
      bone.
AB  - The objective of this study was to explore the hypothesis that osteoporotic-like
      (OP) conditions have a negative effect on osseointegration (OI) of dental
      implants. Using an ovariectomized (OVX) rat model, the extent of OI using
      histologic and histomorphometric analysis (HMA) under a variety of OVX conditions
      was assessed. Five experimental groups (n = 7 rats per group) were used: 1) OP
      control, 2) OI control, () OI followed by OVX treatment to induce OP (OI-->OP),
      4) OP induction followed by OI (OP-->OI), and 5) OP induction simultaneously with
      OI (OI = OP). Using undecalcified plastic-embedded cross-sections of the implant
      site, HMA was performed to determine the percent of bone contact (BC) at the
      implant-tissue interface and percent of bone area (BA) immediately (1.5-mm
      diameter) surrounding the implant site. The presence of Bone Sialoprotein (BSP),
      an important extracellular matrix component of bone, was evaluated using
      immunohistochemical staining procedures. The implant control resulted in the
      highest level of OI (BC = 79%; BA = 87%), whereas all groups in which OVX was
      performed resulted in a significant reduction in BA (70-75%). High levels of BC
      were observed in established OP conditions (OP-->OI; BC = 79%); however,
      following OI, induction of OP conditions (OI-->OP) led to a significant reduction
      in BC (50%). In each of the OP treatment groups, a diminution of cortical bone,
      increased trabecularization of the host bone site, and loss of staining of BSP
      was observed. The results of this work indicate that although OI is possible
      under a variety of OP-like conditions simulating implant placement, the long-term
      biomechanical stability of implants under these conditions could be compromised
      and remains unclear. Further research to understand implant use in the complex
      bone environment under OP-like conditions is encouraged.

PMID- 15017310
TI  - In vitro evaluation of horizontal implant micromovement in bone specimen with
      contact endoscopy.
AB  - Primary stability of dental implants is mandatory for their osseointegration. A
      method is described that allows objective measurements of implant displacement in
      bone sites during lateral loading. Ten samples of bovine bone (2 cm x 2 cm) with
      bone type II, III, and IV according to Lekholm and Zarb were used for the
      experiment. Ten Semados dental implants of 15-mm length and 3.75-mm diameter were
      placed. All implants were loaded with lateral forces of 5, 10, 20, and 30 N
      through 8-mm abutments for 2 seconds each. Lateral displacement was observed by
      means of contact endoscopy. Micromovement was detected with the help of a
      transmitter strip attached to the abutment. Endoscopic images were processed
      digitally and microdisplacement was calculated relative to the reference body
      (microscrew) placed adjacent to the implant. Micromovement observed varied with
      the force applied. Lateral force of 5 N resulted in a mean displacement of 39
      microm; for 30 N, the mean displacement was 157 microm. Bone type also influenced
      the amount of movement. Contact endoscopy represents a new method for direct
      observation of implant movement relative to the bone surface in vitro. In
      combination with support immersion technique, contact endoscopy could be used as
      an office procedure to evaluate intraoperatively implant stability during
      functional loading.

PMID- 15017314
TI  - M0100: Reason for Assessment.

PMID- 15017311
TI  - Early failure of dental implants and TNF-alpha (G-308A) gene polymorphism.
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a potent inflammatory mediator with
      bone resorption activity. Polymorphisms in the promoter region of the human TNF
      alpha gene have been shown to affect the levels of this cytokine and have been
      associated with a variety of diseases. The aim of this study was to investigate
      the possible relationship between early implant failure and a single nucleotide
      polymorphism (SNP) in the -308 promoter region of the TNF-alpha gene. A sample of
      66 nonsmokers was divided into 2 groups: a test group comprising 28 patients
      (mean age, 52.7 years) with one or more early failed implants and a control group
      consisting of 38 individuals (mean age, 43.2 years) with one or more healthy
      implants. Genomic DNA from buccal mucosa was amplified by the polymerase chain
      reaction (PCR), analyzed by restriction fragment length polymorphism (RFLP), and
      submitted to polyacrylamide gel electrophoresis to distinguish allele G and
      allele A of the TNF-alpha (-308) gene polymorphism. Differences in the allele and
      genotype frequencies between control and test groups were assessed by chi-squared
      test (P <0.05). No significant difference was observed in the allele (P = 0.4635)
      and genotype (P = 0.4445) distribution of the polymorphism when control and
      failure groups were compared. The results indicate that the TNF-alpha (G-308A)
      gene polymorphism is not associated with early implant failure, suggesting that
      its presence alone does not constitute a genetic risk factor for implant loss in
      the Brazilian population.

PMID- 15017315
TI  - Preparing for CHAP Accreditation.
AB  - Many organizations are considering or have chosen to seek accreditation from the
      Community Health Accreditation Program (CHAP). This article presents information
      about the program and strategies on preparing the organization and staff for
      accreditation. Look for a follow-up article on preparing for the accreditation
      site visit.

PMID- 15017316
TI  - The effectiveness of a nurse-led transitional care model for patients with
      congestive heart failure.
AB  - This research brief reports on a study that evaluated the effectiveness of a
      transitional care model for patients with congestive heart failure (CHF). The
      model focused on improving the transition from hospital to home care by upgrading
      traditional discharge practices and implementing an evidence-based educational
      program. It used usual care nurses, rather than specialist nurses, to carry out
      the intervention. The study found that health-related quality of life improved
      and the number of emergency room visits was reduced.

PMID- 15017317
TI  - American College of Obstetricians and Gynecologists releases new guidelines for
      Papanicolaou (Pap) tests.

PMID- 15017318
TI  - Culturally appropriate end-of-life care for the Black American.

PMID- 15017319
TI  - Herbal remedies: the other drugs your patients take.

PMID- 15017321
TI  - Of blood, bones, and broccoli: warfarin-vitamin K interactions.

PMID- 15017324
TI  - Burnout and the power of one.

PMID- 15017323
TI  - Pain control in the home: what have we learned?

PMID- 15017325
TI  - Wound assessment: tips and techniques.

PMID- 15017326
TI  - Johns Hopkins Leadership Academy for End-of-Life Nursing.

PMID- 15017328
TI  - A blessing close at hand.

PMID- 15017329
TI  - Mitochondrial ribosomal proteins: candidate genes for mitochondrial disease.
AB  - Most of the energy requirement for cell growth, differentiation, and development
      is met by the mitochondria in the form of ATP produced by the process of
      oxidative phosphorylation. Human mitochondrial DNA encodes a total of 13
      proteins, all of which are essential for oxidative phosphorylation. The mRNAs for
      these proteins are translated on mitochondrial ribosomes. Recently, the genes for
      human mitochondrial ribosomal proteins (MRPs) have been identified. In this
      review, we summarize their refined chromosomal location. It is well known that
      mutations in the mitochondrial translation system, i.e., ribosomal RNA and
      transfer RNA cause various pathologies. In this review, we suggest possible
      associations between clinical conditions and MRPs based on coincidence of genetic
      map data and chromosomal location. These MRPs may be candidate genes for the
      clinical condition or may act as modifiers of existing known gene mutations (mt
      tRNA, mt-rRNA, etc.).

PMID- 15017330
TI  - Detection of deletions in de novo "balanced" chromosome rearrangements: further
      evidence for their role in phenotypic abnormalities.
AB  - PURPOSE: The purpose of this study was to test the hypothesis that deletions of
      varying sizes in de novo apparently balanced chromosome rearrangements are a
      significant cause of phenotypic abnormalities. METHODS: A total of fifteen
      patients, with seemingly balanced de novo rearrangements by routine cytogenetic
      analysis but with phenotypic anomalies, were systematically analyzed. We
      characterized the breakpoints in these fifteen cases (two of which were
      ascertained prenatally), using a combination of high-resolution GTG-banding,
      fluorescence in situ hybridization (FISH) with bacterial artificial chromosomes
      (BACs), and data from the Human Genome Project. RESULTS: Molecular cytogenetic
      characterization of the 15 patients revealed nine with deletions, ranging in size
      from 0.8 to 15.3 Mb, with the number of genes lost ranging from 15 to 70. In five
      of the other six cases, a known or putative gene(s) was potentially disrupted as
      a result of the chromosomal rearrangement. In the remaining case, no deletions
      were detected, and no known genes were apparently disrupted. CONCLUSIONS: Our
      study suggests that the use of molecular cytogenetic techniques is a highly
      effective way of systematically delineating chromosomal breakpoints, and that the
      presence of deletions of varying size is an important cause of phenotypic
      abnormalities in patients with "balanced" de novo rearrangements.

PMID- 15017331
TI  - Cystathionine beta-synthase deficiency: effects of betaine supplementation after
      methionine restriction in B6-nonresponsive homocystinuria.
AB  - PURPOSE: For treatment of cystathionine beta-synthase (CbetaS) deficiency, we
      determined the effect of betaine (N,N,N-trimethylglycine) therapy and examined
      the genotype-phenotype relationships to betaine. METHODS: In five patients with
      B6-nonresponsive homocystinuria, we defined the CbetaS genotypes and determined
      metabolic responses to betaine as an additive to traditional dietary methionine
      restriction. RESULTS: After betaine therapy, tHcy declined (mean 47.4 micromol/L;
      range: -21.2 to -104.0 micromol/L; P=0.02), whereas total plasma cysteine and
      methionine did not change. Plasma methionine/tHcy ratios increased by 5.45
      (range: +1.5 to 15.3; P=0.05) inpatients with B6-nonresponsive alleles.
      CONCLUSION: Betaine improves metabolic control in B6-nonresponsive patients with
      homocystinuria after optimum dietary control.

PMID- 15017332
TI  - Iron status of children with phenylketonuria undergoing nutrition therapy
      assessed by transferrin receptors.
AB  - PURPOSE: The purpose of the study was to determine the incidence of iron
      deficiency in children undergoing therapy for phenylketonuria using serum
      transferrin receptor and ferritin concentrations. METHODS: A 1-year study was
      conducted in 37 children 2 <13 years old with phenylketonuria (8 fed Periflex
      [Group I], 15 fed Phenex-2 Amino Acid-Modified Medical Food [Group II], and 14
      fed Phenyl-Free [Group III]). Hemoglobin, hematocrit, serum transferrin receptor,
      and ferritin concentrations were assessed at baseline and 12 months and intakes
      of protein, iron, and vitamin C were evaluated at baseline and at 3-month
      intervals. Transferrin receptor and ferritin concentrations were analyzed for
      group differences by analysis of variance. RESULTS: Mean protein, iron, and
      vitamin C intakes of all 3 groups of children were greater than Recommended
      Dietary Intakes for age. Only 2 of 60 3-day diet diaries of Group II children
      failed to contain 100% of Recommended Dietary Intakes for iron during study. The
      following number of children had iron status indices outside reference ranges at
      study end: 7 children, transferrin receptor/ferritin ratios; 4 children,
      transferrin receptors; 2 children, hematocrit; 1 child, ferritin. No correlation
      was found between iron intake and any index of iron status. CONCLUSIONS: The
      transferrin receptor/ferritin ratio appeared to be the most sensitive index of
      iron deficiency in this study. Reasons for iron deficiency with greater than
      recommended iron intakes by children with phenylketonuria may be multiple. Early
      assessment and therapy of iron deficiency may improve cognitive and behavioral
      outcomes of children with PKU.

PMID- 15017333
TI  - Mutations in exon 14 of dihydropyrimidine dehydrogenase and 5-Fluorouracil
      toxicity in Portuguese colorectal cancer patients.
AB  - PURPOSE: Dihydropyrimidine dehydrogenase is a critical enzyme in the catabolism
      of 5-Fluorouracil, a drug frequently used in cancer therapy. Patients with
      deficient dihydropyrimidine dehydrogenase activity are at risk of developing
      severe 5-Fluorouracil-associated toxicity. Genetic analysis of the gene coding
      for dihydropyrimidine dehydrogenase has shown that mutations in exon 14,
      especially the splice-site mutation IVS14+1G-->A, were associated with
      dihydropyrimidine dehydrogenase enzymatic deficiency. METHODS: We evaluated the
      frequency of mutations in exon 14 of dihydropyrimidine dehydrogenase (DPYD) gene
      in 73 unselected colorectal cancer patients treated with 5-Fluorouracil after
      surgery at a Portuguese Cancer Institute. RESULTS: Sequencing the entire exon 14
      allowed the detection of mutations in two of the 73 patients (2.7%), namely two
      of the eight (25%) patients who presented grade 3-4 toxicity after 5-Fluorouracil
      chemotherapy. One patient was heterozygous for the splice-site mutation IVS14+1G-
      >A, whereas the second patient was heterozygous for a novel missense mutation
      1845G-->T (E615D) in exon 14 of DPYD gene. CONCLUSION: We conclude that mutations
      in exon 14 of DPYD gene are responsible for a significant proportion of life
      threatening toxicity to 5-Fluorouracil, and should therefore be excluded before
      its administration to cancer patients.

PMID- 15017337
TI  - Maternal mortality: the need for global participation.

PMID- 15017334
TI  - Frequency of the cystic fibrosis 3199del6 mutation in individuals heterozygous
      for I148T.
AB  - PURPOSE: To determine the carrier frequency of the 3199del6 cystic fibrosis (CF)
      mutation in individuals heterozygous for I148T in a large-scale CF testing
      population. METHODS: DNA samples from 439 consecutive I148T-heterozygous
      individuals were screened for the 3199del6 mutation using a laboratory-developed
      test. RESULTS: Genotyping revealed four samples heterozygous for the 3199del6
      mutation (0.9%). The four samples positive for 3199del6 had an IVS 8 genotype of
      7T/9T. The 3199del6 mutation was not observed after genotyping of 348 random,
      anonymous samples. CONCLUSION: The 3199del6 mutation occurs in 0.9% of
      individuals positive for the I148T mutation and <0.07% of chromosomes that are
      wild type for the ACMG panel mutations.

PMID- 15017338
TI  - Drugs used in hypertensive diseases in pregnancy.
AB  - PURPOSE OF REVIEW: This review will summarize results derived from the most
      recent publications on the use of drugs in women with hypertensive diseases in
      pregnancy. RECENT FINDINGS: There is consensus that severe hypertension should be
      treated without delay to reduce maternal risks of acute cerebrovascular
      complications. There is no consensus that antihypertensive drugs improve maternal
      or fetal outcome in mild to moderate hypertension. Evidence exists that
      antihypertensive drugs may halve the risk of severe hypertension in pregnancy. No
      proof exists that antihypertensive drugs reduce perinatal mortality or
      development of preeclampsia, and such drugs have not been associated with
      improved fetal growth. Clinical trials indicate non-consistent data concerning
      antihypertensive treatment on antenatal rate of hospitalization, proteinuria at
      delivery and neonatal respiratory distress syndrome. Hydralazine has for many
      years been regarded as the first drug of choice for treatment of severe
      hypertension in pregnancy. Recent findings indicate that the calcium antagonist
      nifedipine might be a better alternative. Angiotensin converting enzyme
      inhibitors and angiotensin II receptor antagonists should be discontinued due to
      fetotoxicity. The beta1-selective adrenoceptor blocker atenolol in the first
      trimester is associated with low birth weight. SUMMARY: Large randomized
      controlled trials are urgently needed to determine whether antihypertensive
      therapy in pregnancy results in greater benefit than risks for mother and fetus.

PMID- 15017340
TI  - Antenatal fetal surveillance.
AB  - PURPOSE OF REVIEW: Antenatal fetal surveillance is a field of increasing
      importance in modern obstetrics, especially as results in perinatal care have
      recently made dramatic progress. It is an evolving field, and it is no longer
      acceptable just to wait and see when problems arise in pregnancy. During the past
      few decades many studies have shown that antenatal surveillance in unselected
      populations is of little value. However, high-risk patients benefit from
      antenatal fetal surveillance, especially women with pregnancy problems associated
      with intrauterine growth restriction. RECENT FINDINGS: This review shows that
      modern antenatal fetal surveillance is based on fetal heart rate monitoring,
      ultrasound biometry and amniotic fluid assessment, Doppler blood flow studies of
      fetal and uteroplacental circulation, and an evaluation of biophysical fetal
      parameters. SUMMARY: Used in combination these methods lead to improvements in
      fetal morbidity and mortality. The aim of future research should be to minimize
      the risks of fetal morbidity and mortality further by the optimal timing of
      delivery. Better organization of healthcare systems may improve our ability to
      identify at-risk patients during pregnancy. There is potential to improve the
      specificity of fetal surveillance tests, e.g. better methods of biometry and
      amniotic volume estimation with three-dimensional ultrasound and measurements of
      subcutaneous tissue. Improved knowledge of fetal physiology can be gained from
      research on fetal circulation with Doppler studies. Computer analysis of the
      fetal heart rate can increase the specificity of that test, and artificial neural
      networks may enhance the ability to evaluate the optimal use of integrated
      testing.

PMID- 15017339
TI  - Neurological disorders in pregnancy.
AB  - PURPOSE OF REVIEW: Neurological disorders are common in women of childbearing age
      and can lead to maternal death, as evident from previous reports of the
      Confidential Enquiry into Maternal Deaths in England and Wales. In the last
      report (1997-1999) alone, there were 34 deaths indirectly caused by neurological
      disorders. RECENT FINDINGS: With the new developments in drugs, investigations
      and research, clinicians are now more able than ever before to diagnose and treat
      some disorders. A recent example is the French Study Group on Stroke in
      Pregnancy. SUMMARY: This paper reviews the current concepts and outlines
      appropriate management of conditions such as epilepsy, headache, benign
      intracranial hypertension, myasthenia gravis, multiple sclerosis, Bell's palsy
      and cerebrovascular disorders.

PMID- 15017341
TI  - Antiphospholipid syndrome in pregnancy.
AB  - PURPOSE OF REVIEW: Antiphospholipid syndrome is widely recognized as a risk
      factor for numerous obstetric complications including miscarriage, intrauterine
      growth restriction, preeclampsia, fetal death and preterm labour. The many recent
      changes in concept regarding this syndrome, the role of the relevant antibodies,
      mechanism of action, diagnosis and treatment are assessed in this review. RECENT
      FINDINGS: In recent years, our understanding of antiphospholipid syndrome has
      grown. The antigen has become better defined and is now thought to be beta2
      glycoprotein 1. The 'classical' antibodies, lupus anticoagulant and
      anticardiolipin antibody are known to be pathogenic even when passively
      transferred to animal hosts. It seems, however, that the pathogenic antibodies
      are those directed towards beta2 glycoprotein 1, and that those which are
      directed to phospholipids without binding to beta2 glycoprotein 1 may not be
      pathogenic, but merely epiphenomena. The treatment of this condition has also
      been changed due to the influence of randomized trials in which heparin or low
      molecular weight heparin has replaced the use of steroids. SUMMARY: There are
      numerous pitfalls in managing this condition. As beta2 glycoprotein 1 antibodies
      are not usually tested, the condition may be over diagnosed or misdiagnosed.
      Similarly, the results of treatment are not usually corrected for confounding
      factors such as fetal chromosomal aberrations. In the absence of other
      confounding factors low molecular weight heparins are probably the treatment of
      choice.

PMID- 15017342
TI  - Clinical risk management in obstetrics.
AB  - PURPOSE OF REVIEW: Over recent years there has been a growing appreciation that a
      small but significant proportion of patients experience (sometimes serious)
      adverse events in the hands of health care workers. Although research in this
      area is very much in its infancy there has been an increasing move towards
      applying principles of risk management from industry to health care
      organizations. With the particularly disastrous and costly nature of adverse
      outcomes in obstetrics it is appropriate to review clinical risk management
      issues in maternity. RECENT FINDINGS: This review explores the appropriateness of
      applying lessons learned in industry to maternity. The classification of errors
      into individual and latent, or organizational, is examined. Furthermore, the way
      in which these errors can be identified and subsequently analysed, with examples
      from maternity units in the UK and USA, is discussed. The importance of an
      educational and supportive environment, rather than a blame culture, for both
      reporting of incidents and learning from adverse outcomes is emphasized. SUMMARY:
      Improvement in patient experience of health care rests not just with improved
      treatments, but also with a reduction in the adverse events which occur in health
      care institutions. The principles by which risk can be identified prospectively
      and retrospectively, and the mechanisms for both local risk management and
      regional/national reporting and learning are considered.

PMID- 15017345
TI  - Fetal anemia: new technologies.
AB  - PURPOSE OF REVIEW: The purpose of this review is to summarize recently published
      studies on noninvasive diagnosis of fetal anemia in order to give recommendations
      for the use of these new tools. RECENT FINDINGS: Red cell alloimmunization
      remains one of the most common causes of fetal anemia. Amniocentesis and
      cordocentesis have been used for many years to diagnose fetal anemia due to red
      cell aloimmunization. These techniques, however, are invasive and many
      complications are associated with their use. Noninvasive diagnosis of fetal
      anemia has been performed with Doppler ultrasonography. Based on robust data,
      several authors recommend the use of middle cerebral artery peak systolic
      velocity in the management of fetuses at risk for anemia because of red cell
      alloimmunization. This Doppler parameter can also diagnose fetal anemia due to
      other conditions. SUMMARY: Middle cerebral artery peak systolic velocity appears
      to be the best test for the noninvasive diagnosis of fetal anemia. It is
      important to emphasize that training of sonographers and sonologists is the
      'conditio sine qua non' for the correct sampling of the middle cerebral artery.

PMID- 15017343
TI  - Current strategies for the prevention of postpartum haemorrhage in the third
      stage of labour.
AB  - PURPOSE OF REVIEW: Despite evidence that active management of the third stage of
      labour reduces the incidence of postpartum haemorrhage, expectant management is
      still widely practised. Factors accounting for this situation include the desire
      for a more natural experience of childbirth, the philosophy that active
      management is unnecessary in low-risk women, and avoidance of the adverse effects
      of conventional uterotonic agents. This review will evaluate the various
      strategies currently used for the prevention of primary postpartum haemorrhage.
      RECENT FINDINGS: Since publication of the first systematic review comparing
      active with expectant management in 1988, active management of the third stage
      using oxytocics has become increasingly adopted. Recent surveys, however, show
      that there are still wide variations in practice around the world. Recent
      interest has focused on the use of misoprostol for the prevention of postpartum
      haemorrhage. Carbetocin, an oxytocin receptor agonist, shows promise but has not
      been evaluated for use after vaginal births. SUMMARY: Active management of the
      third stage of labour is superior to expectant management in terms of blood loss,
      postpartum haemorrhage and other serious complications, but is associated with
      unpleasant side effects and hypertension when ergometrine is included.
      Intramuscular oxytocin results in fewer side effects. Oral and rectal misoprostol
      has been extensively assessed and found to be less effective than conventional
      oxytocics with more side effects. Until alternative regimes of misoprostol are
      studied in large controlled trials, misoprostol is not recommended for routine
      use in the third stage of labour. Of the remaining uterotonic agents evaluated,
      intramuscular carbetocin appears the most promising.

PMID- 15017346
TI  - Invasive fetal testing.
AB  - PURPOSE OF REVIEW: Research on prenatal diagnosis and invasive fetal testing has
      continued at a rapid pace. Several studies that will have a profound impact on
      the way prenatal care will be provided to pregnant women have been published in
      the literature during the last year. These publications will be reviewed and
      their impact described. RECENT FINDINGS: The main areas of interest in the recent
      literature covered in this review are first-trimester screening for aneuploidy,
      recent information on loss rates due to amniocentesis and chorionic villus
      sampling, and current work on invasive fetal therapy. SUMMARY: It appears that
      first-trimester screening is at least comparable if not superior in efficacy to
      second-trimester serum screening. This will be a test that will be utilized
      increasingly by both low and high-risk patients for aneuploidy. Of utility to a
      much smaller number of patients, invasive fetal therapy for meningomyelocele
      repair, twin-to-twin transfusion syndrome and fetal cardiac malformations is
      being evaluated in a scientifically more rigorous manner.

PMID- 15017347
TI  - Diagnosis of fetal infections.
AB  - PURPOSE OF REVIEW: The purpose of this review is to present recent developments
      in the prenatal diagnosis of the most clinically relevant congenital infections.
      RECENT FINDINGS: Immunoglobin G avidity testing can help to differentiate between
      recent or prior infection. A combination of tests, including serology, avidity
      and polymerase chain reaction, may be necessary to improve accuracy of diagnosis.
      The interval between exposure to an infectious agent and prenatal testing can be
      critical to the interpretation of the test result. SUMMARY: This review
      reinforces the need for accurate testing to guide appropriate counseling and
      individual fetal risk assessment. The findings of viral-specific antibodies or
      sonographic abnormalities do not accurately predict the severity or outcome of
      fetal infection. Further research is necessary to determine the pathogenesis of
      transplacental viral transmission and thereby allow us to target prevention
      strategies.

PMID- 15017348
TI  - Post-genome molecular diagnostics in obstetrics.
AB  - PURPOSE OF REVIEW: The intention of this review is to familiarize the practicing
      clinician with the current status and future direction of molecular testing in
      obstetrics. As a discipline, obstetrics and gynecology is unique in that it deals
      with the full spectrum of molecular genetic testing. This spectrum includes
      infectious disease, neoplasia and inherited diseases. This review will focus on
      inherited conditions and complex diseases, as it is in this context that we may
      fully realize the true promise of the human genome and its application to the
      practice of medicine. RECENT FINDINGS: Despite the successful sequencing of the
      human genome, very few new molecular genetic tests have become available. The
      apparent reason for this lies in the relative paucity of information gleaned from
      examining the genes themselves. Two new avenues of investigation are presently
      underway to improve the 'infirmity' of this information archive. Rather than
      merely looking at differential gene expression, clinician scientists have begun
      to examine genetic polymorphisms of single and multiple genes within and between
      individuals in an attempt to explain biologic processes, including disease
      states. The second avenue involves the characterization of the products of gene
      expression--proteins. Proteomics, in conjunction with high throughput
      polymorphism analysis, may enable us to diagnose and treat complex multifactorial
      diseases. SUMMARY: Molecular diagnostics for multifactorial diseases will become
      conceptually and technologically more complex than present DNA testing
      modalities. The development and ultimate acceptance of these tests will require
      greater coordination between the medical and scientific communities to ensure
      that the right technologies are applied to the highest quality samples to answer
      the most relevant questions.

PMID- 15017349
TI  - First trimester prenatal diagnosis.
AB  - PURPOSE OF REVIEW: The recent developments in first trimester sonography promise
      to greatly enhance our diagnostic capabilities for detection of aneuploidies.
      Collateral benefits of nuchal translucency measurements include the prediction of
      non-chromosomal adverse outcomes. These advances will fundamentally change
      clinical practices. All obstetricians must therefore have a working knowledge of
      the expanding literature in this field. RECENT FINDINGS: The review covers
      developments in nuchal translucency based first trimester detection of
      chromosomal anomalies and discusses the recent literature on the use of fetal
      nasal bone measurements to further improve diagnostic accuracy. Emerging data on
      the relationship between nuchal fluid measurement and the risk of cardiac anomaly
      will also be presented. SUMMARY: It is likely that the emphasis in obstetric
      clinical care will shift substantially towards the first trimester. With the
      enhanced diagnostic capabilities, greater research emphasis will inevitably need
      to be placed on the first trimester treatment of fetal disorders.

PMID- 15017350
TI  - Bibliography. Current world literature. Maternal-fetal medicine.

PMID- 15017352
TI  - Nutrigenomics and nutrigenetics.
AB  - PURPOSE OF REVIEW: Nutritional genomics has tremendous potential to change the
      future of dietary guidelines and personal recommendations. Nutritional genomics
      covers nutrigenomics, which explores the effects of nutrients on the genome,
      proteome and metabolome, and nutrigenetics, the major goal of which is to
      elucidate the effect of genetic variation on the interaction between diet and
      disease. Nutrigenetics has been used for decades in certain rare monogenic
      diseases such as phenylketonuria, and it has the potential to provide a basis for
      personalized dietary recommendations based on the individual's genetic makeup in
      order to prevent common multifactorial disorders decades before their clinical
      manifestation. RECENT FINDINGS: Preliminary results regarding gene-diet
      interactions in cardiovascular diseases are for the most part inconclusive
      because of the limitations of current experimental designs. Success in this area
      will require the integration of various disciplines, and will require
      investigators to work on large population studies that are designed to
      investigate gene-environment interactions. SUMMARY: Based on the current
      knowledge, we anticipate that in the future we will be able to harness the
      information contained in our genomes to achieve successful aging using behavioral
      changes, with nutrition being the cornerstone of this endeavor.

PMID- 15017353
TI  - Ethnic differences in atherosclerosis, cardiovascular disease and lipid
      metabolism.
AB  - PURPOSE OF REVIEW: Comparison of risk factors and cardiovascular disease among
      racial and ethnic groups is a powerful approach to study genetics and lifestyle,
      or environmental interactions. RECENT FINDINGS: Most, mean or median,
      cardiovascular risk factor levels are similar among black and white people. There
      are much greater differences in the distribution of risk factor level within a
      specific race and ethnic group than between US populations. There are also very
      large differences in levels of risk factors for coronary heart disease between
      specific ethnic migrant populations such as comparing black people in Africa with
      those in the US, or Japanese people in Japan with those in Hawaii and California.
      Differences in distribution of risk factors and disease between race and ethnic
      group are a function of the frequency of specific genotypes and interaction with
      environmental factors. Several of the most important differences between racial
      groups are higher blood pressure, lower triglycerides and higher HDL cholesterol
      among blacks, higher prevalence of diabetes and insulin resistance among Mexican
      Americans and American Indians, and higher triglyceride levels among the
      Japanese. SUMMARY: Further studies of racial and ethnic differences should focus
      on unique phenotypes and genotypic differences, international and migrant studies
      and large enough sample sizes to provide robust results. The sprinkling of a
      percentage of minority participants in each study is worthless. The study of
      racial and ethnic differences in disease and detection of risk factor levels must
      be based on solid hypotheses that can evaluate the interaction of lifestyle and
      possible genetic attributes. Many of the reported ethnic differences in risk
      factors and disease in US populations are primarily a function of differences in
      education, socioeconomic variations, and utilization of preventive and clinical
      treatments.

PMID- 15017355
TI  - Commonalities between genetics of cardiovascular disease and neurodegenerative
      disorders.
AB  - PURPOSE OF REVIEW: Numerous epidemiological and clinical data suggest that
      neurodegenerative disorders, such as Alzheimer's disease, may be related directly
      or indirectly to cardiovascular risk. Genetic studies have demonstrated that they
      share at least one common susceptibility gene, encoding apolipoprotein E, a
      modulator of cardiac risk and of cognitive impairment. Several studies have
      suggested that other genes involved in the development of cardiovascular diseases
      may be involved. Previous studies indicated that additional genes contribute to
      Alzheimer's disease, in particular to the sporadic, more common late-onset form.
      In this review, the authors focus on recent findings concerning the modulation of
      the risk of Alzheimer's disease by genes also involved in the development of
      cardiovascular diseases. RECENT FINDINGS: The intensive search conducted in the
      past year gave rise to many publications, more than half of which were related to
      genes common to cardiovascular and neurodegenerative disorders. The majority of
      the genes studied are involved in cholesterol metabolism, hypertension, lipid
      oxidation and detoxication, or inflammatory processes. SUMMARY: In the past year,
      approximately 100 studies concerning the genetics of Alzheimer's disease were
      published around the world. Results suggest that the risk of Alzheimer's disease
      is modulated by various genes encoding proteins involved in cholesterol
      metabolism, in the detoxication of lipoprotein oxidation or encoding cytokines.

PMID- 15017354
TI  - Gene variants, insulin resistance, and dyslipidaemia.
AB  - PURPOSE OF REVIEW: Both insulin resistance and dyslipidaemia are determined by
      genetic and environmental factors. Depending on their expression and their
      function, gene variants (mutations, polymorphisms) can primarily regulate either
      insulin action or dyslipidaemia. The purpose of this review is to give some
      examples from recent studies on gene variants regulating primarily insulin
      signalling or lipoprotein metabolism. RECENT FINDINGS: Common polymorphisms in
      the PC-1, insulin receptor substrate 1 and 2, and PPAR-gamma 2 genes have been
      linked to insulin resistance and dyslipidaemia, although the results have not
      been consistent. However, the Pro12Pro genotype of the PPAR-gamma 2 gene has been
      consistently associated with insulin resistance and the risk of type 2 diabetes.
      Promoter polymorphisms in the hepatic lipase gene, the 54Thr allele of the fatty
      acid binding protein 2 gene, and genes regulating LDL particle size have been
      associated with lipid metabolism, but on the other hand their association with
      insulin resistance is not consistent. SUMMARY: Although results have not always
      been consistent, gene variants affecting primary insulin action or dyslipidaemia,
      and particularly their interaction with the environment, are important modulators
      of glucose and lipoprotein metabolism.

PMID- 15017356
TI  - Genetics of thrombophilia: impact on atherogenesis.
AB  - PURPOSE OF REVIEW: The goal of this review is to present an update on basic and
      epidemiological findings associating variants in prothrombotic genes with
      atherogenesis and atherothrombotic disease. RECENT FINDINGS: The relation between
      atherosclerosis and thrombosis has long been recognized but only recently has it
      been understood that certain hemostatic factors affect not only thrombus
      formation, but also have a direct atherogenic role. Atherosclerosis is a complex
      disorder that results from the interaction of multiple genetic and environmental
      factors. Numerous polymorphisms and mutations in genes related to the hemostatic
      system and to vascular redox determinants that modulate nitric oxide
      bioavailability have been identified in the past decade; their role in
      atherogenesis and the risk of cardiovascular disease, however, remain uncertain.
      We will discuss the functional implications and association with disease risk of
      polymorphisms in coagulation factors (fibrinogen, prothrombin, and factor V);
      fibrinolytic factors (plasminogen activator inhibitor 1 and lipoprotein(a));
      platelet surface receptors; and vascular redox determinants
      (methylenetetrahydrofolate reductase, endothelial nitric oxide synthase, and the
      antioxidant enzymes cellular glutathione peroxidase and paraoxonase). SUMMARY:
      Overall, these genetic variants have a modest effect on risk when considered
      individually but gain potency when acting synergistically with other genetic or
      environmental risk factors. We conclude that a better characterization of these
      interactions, in addition to the identification of potential novel genetic
      determinants, constitute key issues in the future understanding of the
      pathogenesis of atherothrombosis.

PMID- 15017357
TI  - The role of chemokines in atherosclerosis: recent evidence from experimental
      models and population genetics.
AB  - PURPOSE OF REVIEW: Atherosclerosis is an inflammatory disease process. This
      review discusses the recent genetic evidence from animal models and human
      populations that highlight the importance of chemokines in atherosclerosis.
      RECENT FINDINGS: CC-chemokine/CC-chemokine receptors (CCR), including CCR2/ MCP-1
      (monocyte chemoattractant protein-1) and CCR5/RANTES (regulated on activation,
      normal T-cell expressed and secreted), have been shown in animal knockout and
      transgenic studies to have significant effects on atherosclerotic lesion size and
      macrophage recruitment. More recently fractalkine (CX3C1) and its receptor
      (CX3CR1) have emerged as another important pathway in atherosclerosis. For
      example, fractalkine is present in human atherosclerotic lesions and is able to
      stimulate platelet activation and adhesion. CX3CR1 is expressed on human aortic
      smooth muscle cells and CX3CR1/apolipoprotein E double knockout mice have
      significantly reduced atherosclerotic lesion size and macrophage recruitment.
      Human population genetic studies have tried to assess the importance of
      chemokines in human atherosclerosis. Currently, there is conflicting evidence
      regarding an association between polymorphisms in CCR2/MCP-1 and CCR5/RANTES and
      coronary artery disease. There is evidence, however, for an association between
      the fractalkine receptor polymorphism (CX3CR1-I249) and coronary artery disease
      in both human population and function studies. SUMMARY: Recent transgenic and
      gene knockout studies in murine models of atherosclerosis have highlighted the
      importance of chemokines and their receptors in atherosclerosis. Genetic evidence
      for a role of chemokines and their receptors in human population studies remains
      under investigation. Identifying chemokine polymorphisms could help to determine
      pathways that are important in atherosclerosis disease pathology and that may
      suggest novel therapeutic targets.

PMID- 15017358
TI  - Probing the pathways of chylomicron and HDL metabolism using adenovirus-mediated
      gene transfer.
AB  - PURPOSE OF THE REVIEW: This review clarifies the functions of key proteins of the
      chylomicron and the HDL pathways. RECENT FINDINGS: Adenovirus-mediated gene
      transfer of several apolipoprotein (apo)E forms in mice showed that the amino
      terminal 1-185 domain of apoE can direct receptor-mediated lipoprotein clearance
      in vivo. Clearance is mediated mainly by the LDL receptor. The carboxyl-terminal
      261-299 domain of apoE induces hypertriglyceridemia, because of increased VLDL
      secretion, diminished lipolysis and inefficient VLDL clearance. Truncated apoE
      forms, including apoE2-202, have a dominant effect in remnant clearance and may
      have future therapeutic applications for the correction of remnant removal
      disorders. Permanent expression of apoE and apoA-I following adenoviral gene
      transfer protected mice from atherosclerosis. Functional assays, protein cross
      linking, and adenovirus-mediated gene transfer of apoA-I mutants in apoA-I
      deficient mice showed that residues 220-231, as well as the central helices of
      apoA-I, participate in ATP-binding cassette transporter A1-mediated lipid efflux
      and HDL biogenesis. Following apoA-I gene transfer, an amino-terminal deletion
      mutant formed spherical alpha-HDL, a double amino- and carboxyl-terminal deletion
      mutant formed discoidal HDL, and a carboxyl-terminal deletion mutant formed only
      pre-beta-HDL. The findings support a model of cholesterol efflux that requires
      direct physical interactions between apoA-I and ATP-binding cassette transporter
      A1, and can explain Tangier disease and other HDL deficiencies. SUMMARY: New
      insights are provided into the role of apoE in cholesterol and triglyceride
      homeostasis, and of apoA-I in the biogenesis of HDL. Clearance of the lipoprotein
      remnants and increase in HDL synthesis are obvious targets for therapeutic
      interventions.

PMID- 15017359
TI  - Structure-function relationships in apolipoprotein(a): insights into
      lipoprotein(a) assembly and pathogenicity.
AB  - PURPOSE OF REVIEW: Lipoprotein(a) is a structurally and functionally unique
      lipoprotein consisting of the glycoprotein apolipoprotein(a) covalently linked to
      LDL. Lipoprotein(a) is assembled extracellularly by a two-step mechanism, still
      incompletely understood, in which initial non-covalent interactions between
      apolipoprotein(a) and apolipoprotein B precede specific disulfide bond formation.
      Elevated concentrations of plasma lipoprotein(a) are a risk factor for a variety
      of vascular diseases, including coronary heart disease, ischaemic stroke and
      venous thrombosis. Whereas many pathogenic mechanisms have been proposed for
      lipoprotein(a), it remains to be conclusively demonstrated which mechanisms are
      relevant to human disease. RECENT FINDINGS: Structural and functional studies
      have verified that apolipoprotein(a) kringle 4 types 6-8 contain lysine binding
      sites of a weaker affinity for lysine analogues than kringle 4 type 10. Recent
      evidence has conclusively shown a role for kringle 4 types 7 and 8 in
      lipoprotein(a) assembly. Moreover, apolipoprotein(a) has been shown to undergo a
      conformational change, from a closed to an open form, which accelerates the rate
      of covalent lipoprotein(a) assembly. Functional studies in vitro have identified
      the domains in apolipoprotein(a) that mediate its inhibitory effects on fibrin
      clot lysis, binding to fibrin and other biological substrates, and pro
      inflammatory and anti-angiogenic properties. SUMMARY: Extensive structure
      function studies of apolipoprotein(a) have begun to yield important insights into
      the domains in apolipoprotein(a) that mediate lipoprotein(a) assembly and the
      pathogenic effects of this lipoprotein. Continued investigations of these
      relationships will contribute critically to unravelling the many outstanding
      questions about lipoprotein(a) metabolism and pathophysiology.

PMID- 15017360
TI  - Lipoprotein receptors in the vascular wall.
AB  - PURPOSE OF REVIEW: We will discuss the diverse roles of lipoprotein receptors
      that contribute to the maintenance and integrity of the vascular wall. RECENT
      FINDINGS: Lipoprotein receptors function not only as transporters for cholesterol
      and other lipids. They also act as sensors and signal transducers through which
      the endothelium, macrophages and smooth muscle cells communicate with their
      environment. SUMMARY: Traditionally, lipoprotein receptors were thought of merely
      as transporters of cholesterol and triglycerides to specific target cells, either
      for the purpose of delivery and redistribution of nutrients, or for the
      destruction or clearance of modified (oxidized) lipids by macrophages. Only
      recently have we begun to appreciate that the same receptors engage in a much
      more sophisticated and multi-faceted interaction with their environment.
      Inasmuch, they not only act as mere transporters, but as surprisingly versatile
      and adaptive signal transducers and modulators throughout the vessel wall. These
      recent findings now begin to reshape our thinking of how such structurally
      different and evolutionarily unrelated lipoprotein receptors orchestrate the
      response of the vessel wall to mechanical or metabolic damage.

PMID- 15017361
TI  - Endothelial lipase and HDL metabolism.
AB  - PURPOSE OF REVIEW: In the past year, several laboratories taking independent
      approaches have provided compelling evidence that endothelial lipase, a
      relatively recent addition to the triglyceride lipase gene family, is a major
      determinant of HDL metabolism. This review summarizes recent findings from
      experiments in mice with altered levels of endothelial lipase, from an
      examination of endothelial lipase catalytic and non-catalytic functions in vitro,
      and from human genetic studies. RECENT FINDINGS: An analysis of lipids and
      lipoproteins in endothelial lipase knockout and transgenic mice and in mice with
      adenovirus-driven hepatic overexpression of endothelial lipase shows, without
      exception, that total cholesterol, phospholipid and HDL-cholesterol all vary
      inversely with the endothelial lipase gene dosage, and primarily depend on
      endothelial lipase catalytic activity. Endothelial lipase participates in HDL
      metabolism by promoting the turnover of HDL components and increasing the
      catabolism of apolipoprotein A-I. The measurement of lipase activity on
      lipoprotein substrates in vitro demonstrates that endothelial lipase is distinct
      from other triglyceride lipases in showing the highest activity on HDL.
      Endothelial lipase gene polymorphisms in humans appear to be associated with HDL
      cholesterol or HDL3-cholesterol concentrations. SUMMARY: A low HDL-cholesterol
      level in humans is a risk factor for coronary heart disease. Although not yet
      demonstrated, it is possible that the action of endothelial lipase on HDL may
      promote atherogenesis, in which case endothelial lipase may represent an
      attractive target for pharmaceutical intervention.

PMID- 15017362
TI  - The intracellular transport of chylomicrons requires the small GTPase, Sar1b.
AB  - PURPOSE OF REVIEW: The transport of lipoproteins through the secretory pathways
      of enterocytes and hepatocytes is pivotal for whole-body lipid homeostasis. This
      review focuses on the assembly and structural evolution of COPII (coat protein)
      transport carriers that are essential for the transport of chylomicrons from the
      endoplasmic reticulum to the Golgi apparatus. RECENT FINDINGS: The assembly of
      endoplasmic reticulum to Golgi transport carriers commences with the coating of
      specific areas of the endoplasmic reticulum membrane with Sar1-GTP and the
      Sec23/24 heterodimer. An important advance has been the crystallographic analysis
      of the Sar1-Sec23/24 complex. The proteins form a bow-tie shaped structure, with
      a concave face that seems to match the curvature of transport carriers. Mammalian
      cells produce two isoforms of Sar1, designated Sar1a and Sar1b, both of which are
      expressed in enterocytes. Sar1b is defective in chylomicron retention disease and
      Anderson disease, two rare recessive disorders characterized by severe fat
      malabsorption and a failure to thrive in infancy. Patients with chylomicron
      retention disease and Anderson disease selectively retain chylomicron-like
      particles within membrane-bound compartments. By analogy with procollagen,
      chylomicrons may drive the formation of endoplasmic reticulum to Golgi transport
      carriers from endoplasmic reticulum sites close to, but separate from, domains of
      the endoplasmic reticulum coated with Sar1-Sec23/24. The COPII machinery also
      mediates the transport of VLDL to the Golgi. SUMMARY: New insights into the role
      of the COPII machinery in the intracellular transport of cargo, including
      chylomicrons and VLDL, may suggest new drug targets for ameliorating the lipid
      abnormalities of the metabolic syndrome.

PMID- 15017363
TI  - Zinc finger protein ZNF202 structure and function in transcriptional control of
      HDL metabolism.
AB  - PURPOSE OF REVIEW: The zinc finger protein ZNF202 is a transcriptional repressor
      controlling promoter elements predominantly found in genes involved in lipid
      metabolism and energy homeostasis. Here we summarize the structure, regulation
      and modulation of ZNF202 function by protein interactions. RECENT FINDINGS: We
      review recent data and discuss the importance of the steadily growing list of
      ZNF202 target genes, defining a central role for ZNF202 as a key transcriptional
      regulator in metabolic disorders. Furthermore, we provide an interlink between
      transcriptional repression by ZNF202 and enhancement of gene activation via
      nuclear receptor coactivation by SCAN domain protein 1. SUMMARY: The novel
      findings suggest that ZNF202 together with other SCAN domain proteins
      orchestrates a complex transcriptional regulatory network, which justifies a
      further exploration of its potential as a therapeutic target in lipid disorders
      such as atherosclerosis and associated metabolic syndromes.

PMID- 15017364
TI  - Bibliography. Current world literature. Genetics and molecular biology.

PMID- 15017365
TI  - Nutrition and metabolism.

PMID- 15017366
TI  - Genetics and molecular biology.

PMID- 15017367
TI  - Lipid metabolism.

PMID- 15017368
TI  - Inflammation, oxidative stress, and atherosclerosis.

PMID- 15017369
TI  - Atherosclerosis: cell biology and lipoproteins.

PMID- 15017370
TI  - Clinical therapy and trials.

PMID- 15017372
TI  - Acute idiopathic pulmonary hemorrhage among infants. Recommendations from the
      Working Group for Investigation and Surveillance.
AB  - This report presents CDC's recommended case definitions and surveillance
      practices for Acute Idiopathic Pulmonary Hemorrhage (AIPH). In 1994 and 1997, CDC
      reported clusters of acute pulmonary hemorrhage (APH) among infants in Cleveland,
      Ohio. Subsequent reviews of these investigations identified shortcomings in the
      conduct of the studies and concluded that the investigations did not prove an
      association between APH among infants and exposure to molds. In response to
      recommendations from these reviews, with assistance of external consultants, CDC
      staff developed a plan to conduct surveillance for and investigation of AIPH. In
      developing this response, CDC recommends a definition for a clinically confirmed
      case of AIPH among infants on the basis of evidence of blood in the airway, age
      </=1 year, absence of medical conditions related to pulmonary hemorrhage, and
      severe acute respiratory distress or respiratory failure. CDC recommends that
      pediatric intensive care units (PICUs) report cases that meet the CDC case
      definition to state health departments. CDC staff will study the number of
      reported cases of AIPH among infants and also review the Cleveland and Chicago
      case series to determine the degree to which the present case definition applies
      to them. If these reviews establish that AIPH among infants is a public health
      problem, on the basis of its magnitude or geographic or temporal distribution,
      targeted case surveillance will be initiated based on the distribution of cases.
      CDC staff will work with state and local health departments to investigate
      reported clusters of cases of AIPH among infants.

PMID- 15017373
TI  - Use of carbon monoxide alarms to prevent poisonings during a power outage--North
      Carolina, December 2002.
AB  - Each year in the United States, approximately 500 persons die from unintentional
      carbon monoxide (CO) poisoning, often during electric power outages caused by
      severe storms. Use of residential CO alarms has been recommended to reduce the
      incidence of CO poisoning. In September 2000, Mecklenburg County, North Carolina
      (2002 population: 722,367), adopted a public health ordinance requiring a CO
      alarm in the majority of residences; all-electric residences without attached
      garages (35.4% of all homes) were exempt. The ordinance also permitted use of
      alarms without battery back-up. On December 4, 2002, an ice storm caused 78.9% of
      county households to lose power. During the next 9 days, 124 cases of symptomatic
      CO poisoning were reported. To characterize these poisonings and the
      effectiveness of the CO alarm ordinance, local emergency physicians, fire
      department authorities, and CDC conducted an investigation. This report
      summarizes the results of that investigation, which determined that 96.2% of the
      severe poisonings occurred in homes with no reported functioning CO alarm. As a
      result of these findings, on October 8, 2003, Mecklenburg County officials
      amended the ordinance to require alarms with battery back-ups in all residences.
      Officials in other communities should consider enacting such alarm ordinances to
      prevent CO poisonings.

PMID- 15017374
TI  - Mycobacterium chelonae infections associated with face lifts--New Jersey, 2002
      2003.
AB  - In March 2003, the New Jersey Department of Health and Senior Services (NJDHSS)
      was notified about three patients who acquired surgical-site infections caused by
      Mycobacterium chelonae after having face lifts (i.e., rhytidectomies) performed
      at an outpatient surgical center. NJDHSS learned subsequently of another patient
      with M. chelonae infection who had a rhytidectomy performed at a second surgical
      center. The four patients received diagnoses of M. chelonae infection during
      March 2002-February 2003. NJDHSS conducted an epidemiologic, environmental, and
      microbiologic investigation. This report summarizes the results of that
      investigation, which identified contaminated methylene blue used as a tissue
      marking agent as the source of infection. Surgeons should use only sterile,
      single-use, tissue-marking agents during procedures that require aseptic
      technique, and clinicians should consider M. chelonae when evaluating surgical
      site infections.

PMID- 15017375
TI  - Silicosis in dental laboratory technicians--five states, 1994-2000.
AB  - Silicosis is a debilitating, sometimes fatal, yet preventable occupational lung
      disease caused by inhaling respirable crystalline silica dust. Although
      crystalline silica exposure and silicosis have been associated historically with
      work in mining, quarrying, sandblasting, masonry, founding, and ceramics, certain
      materials and processes used in dental laboratories also place technicians at
      risk for silicosis. During 1994--2000, occupational disease surveillance programs
      in five states identified nine confirmed cases of silicosis among persons who
      worked in dental laboratories; four persons resided in Michigan, two in New
      Jersey, and one each in Massachusetts, New York, and Ohio. This report describes
      three of the cases and underscores the need for employers of dental laboratory
      technicians to ensure appropriate control of worker exposure to crystalline
      silica.

PMID- 15017377
TI  - Manufacturer's recall of rapid cartridge assay kits on the basis of false
      positive Cryptosporidium antigen tests--Colorado, 2004.
AB  - The Colorado Department of Public Health and Environment (CDPHE) has determined
      that a fourfold increase in the number of reported cryptosporidiosis cases in
      Colorado during January-February 2004 might be attributed primarily to false
      positive test results. Since January 1, 2004, a total of 13 in-state cases and
      one out-of-state case were reported to CDPHE. During the previous 7 years, an
      average of three cases were reported during January-February. In eight of 14
      patients, rapid testing was performed by using the ImmunoCard STAT!
      Cryptosporidium/Giardia Rapid Assay (Meridian Bioscience, Inc., Cincinnati,
      Ohio). This assay is a solid-phase qualitative immunochromatographic assay
      designated to detect and distinguish between Giardia intestinalis (lamblia) and
      Cryptosporidium parvum in aqueous extracts of human fecal specimens. Seven of
      these samples were tested by using lot no. 081093 (expires August 11, 2004). Of
      the seven samples that tested positive initially for Cryptosporidium with this
      lot number, four were retested by using other, more specific tests. One patient
      sample was positive by direct microscopy, one was negative by direct microscopy,
      and two were negative by direct fluorescent-antibody testing, suggesting that
      results for three of the four samples were false positive. The results of testing
      for Giardia intestinalis (lamblia) with these kits are unclear. Several other
      states have noted increases in the number of reported cryptosporidiosis cases
      that also might be associated with use of these rapid assays.

PMID- 15017376
TI  - Azithromycin treatment failures in syphilis infections--San Francisco,
      California, 2002-2003.
AB  - The San Francisco Department of Public Health (SFDPH) is investigating several
      clinical failures in syphilis patients treated with the macrolide antibiotic
      azithromycin. This report describes the use of azithromycin for syphilis
      treatment, recent treatment failures in San Francisco, and CDC recommendations
      for syphilis treatment. Clinicians should exercise caution in using azithromycin
      for treating incubating syphilis or syphilis infection until the risk and
      mechanism of failure are better understood.

PMID- 15017378
TI  - BIGH3 mutation in a Bangladeshi family with a variable phenotype of LCDI.
AB  - AIMS: To report a Bangladeshi family displaying intrafamilial phenotypic
      heterogeneity of lattice corneal dystrophy type I (LCDI) and to identify the
      causative mutation. METHODS: Molecular genetic analysis was performed on DNA
      extracted from all members of the family. Exons of BIGH3 gene were amplified by
      polymerase chain reaction. Gene mutation and polymorphisms were identified by
      heteroduplex and sequence analyses. Segregation of the mutation in the family was
      confirmed by restriction digestion of amplified gene fragments. RESULTS: A
      heterozygous C --> T transition at the first nucleotide position of codon 124 of
      the BIGH3 gene was detected in the three affected members and not in the
      unaffected members of the family. CONCLUSIONS: This is the first report of BIGH3
      gene mutation in a Bangladeshi family with phenotypic heterogeneity. This study
      confirms that BIGH3 gene screening should be undertaken for proper classification
      of corneal dystrophy, especially in the absence of histopathological examination.

PMID- 15017379
TI  - Disorders of the blood-aqueous barrier after phacoemulsification in diabetic
      patients.
AB  - PURPOSE: To evaluate the function of the blood-aqueous barrier after
      phacoemulsification with implantation of a foldable intraocular lens (IOL) in
      diabetic patients. METHODS: All patients were enrolled from those scheduled for
      phacoemulsification with intraocular lens implantation in Zhongshan Ophthalmic
      Center Guangzhou from March 2002 to June 2002. The classification on diabetic
      retinopathy (DR) was based on the fundus examination after cataract surgery. The
      blood-aqueous barrier function was examined using the laser flare cell meter
      (Kowa FC-2000) preoperatively and on postoperative days 1, 7, 30, and 90 by an
      independent examiner who was masked to the DR classification. Patients were
      operated by one experienced surgeon as per standard clinical protocol and were
      provided the same postoperative medical care. A linear regression and Wilcoxon
      test were used for the analysis. RESULTS: A total of 112 patients were divided
      into three groups: patients without diabetic mellitus as normal control (n=56),
      diabetic patients without diabetic retinopathy (n=2), with nonproliferation
      diabetic retinopathy (NPDR) (n=37), and diabetic patients with proliferation
      diabetic retinopathy (PDR) (n=17). All patients were examined and successfully
      followed up for 3 months after cataract surgery. Aqueous flare mean photon counts
      in PDR, NPDR, and control eyes were 8.94+/-0.57, 7.03+/-0.27, and 6.94+/-0.34
      before surgery and increased to 32.42+/-0.67, 26.07+/-0.83, 26.27+/-1.37 on the
      first day after surgery (P<0.05), then decreased to 19.86+/-0.78, 14.08+/-0.54
      and 13.96+/-1.05 at 7 days after surgery (P<0.05), 13.24+/-0.29, 9.86+/-0.33, and
      9.07+/-0.43 at 30 days after surgery (P<0.05); eventually, the counting decreased
      to 11.25+/-0.31, 7.24+/-0.67, and 7.16+/-0.27 at 90 days after surgery (P<0.05).
      Linear regression model suggested that other potential variables, such as age,
      sex, eye (left/right), phaco time, phaco energy, and hypertension were not
      related to the outcome. For patients without diabetes mellitus and diabetic
      patients with NPDR, highly statistically significant differences (P<0.05) were
      found between preoperative flare value and those measured on days 1, 7, and 30
      after surgery, but no statistically significant differences (P>0.05) were found
      between the preoperative flare value and those measured on postoperative days 90.
      However, patients with PDR still had a higher flare value even on postoperative
      day 90. The patients with intraoperative iris prolapse had a higher flare value
      between days 1 and 7 postoperatively. CONCLUSION: Phacoemulsification with a
      foldable intraocular lens implantation affects the blood-aqueous barrier more
      severely in diabetic patients with PDR than patients with NPDR and nondiabetic
      patients.

PMID- 15017380
TI  - Transcriptional targeting of tumors with a novel tumor-specific survivin
      promoter.
AB  - It has been demonstrated that survivin, a novel member of the inhibitor of
      apoptosis (IAP) protein family, is expressed in human cancers but is undetectable
      in normal differentiated tissues. We employed a recombinant adenoviral vector
      (reAdGL3BSurvivin) in which a tumor-specific survivin promoter and a luciferase
      reporter gene were inserted into the E1-deleted region of adenovirus vector.
      Luciferase activity was measured in both multiple tumor cell lines and two
      primary melanoma cells infected with reAdGL3BSurvivin. Human fibroblast and
      mammary epithelial cell lines were used as negative controls. A reAdGL3CMV,
      containing the CMV promoter and luciferase gene, was used as a positive control
      to normalize the luciferase activity generated by the survivin promoter. Our data
      revealed that the survivin promoter showed high activity in both established
      tumor cell lines and the primary melanoma cells. In contrast, the in vivo studies
      indicated that the activities of survivin promoter were extremely low in the
      major mouse organs. The survivin promoter appears to be a promising tumor
      specific promoter exhibiting a "tumor on" and "liver off" profile, and therefore,
      it may prove to be a good candidate for transcriptional targeting of cancer gene
      therapy in a wide variety of tumors.

PMID- 15017381
TI  - Hepatic gene expression of NK4, an HGF-antagonist/angiogenesis inhibitor,
      suppresses liver metastasis and invasive growth of colon cancer in mice.
AB  - Hepatocyte growth factor (HGF) is involved in malignant behavior of cancer cells
      by enhancing invasion and metastasis. We earlier found that NK4, a four-kringle
      fragment of HGF, functions as both an HGF antagonist and an angiogenesis
      inhibitor. We have now carried out studies to determine if hydrodynamics-based
      delivery and expression of the NK4 gene would inhibit liver metastasis and
      invasive growth of colon carcinoma cells in mice. When the naked plasmid for NK4
      was introduced into mice by hydrodynamics-based gene delivery, a high level of
      expression of NK4 was predominant in the liver. After intrasplenic inoculation of
      MC-38 murine colon carcinoma cells, the cells formed numerous metastatic nodules
      in the liver and showed invasive growth behavior. On the other hand, when mice
      were given the NK4 plasmid, hepatic gene expression of NK4 inhibited the liver
      metastasis and subsequent growth associated with a decrease in microvessel
      density. Likewise, intrahepatic invasion of cancer cells was inhibited by NK4
      gene expression, and this anti-invasive effect was associated with in situ
      inhibition of c-Met receptor tyrosine phosphorylation. Moreover, NK4 gene
      expression prolonged survival of these mice. Taken together with the knowledge
      that the majority of deaths from colon cancer are due to liver metastasis, the
      potential therapeutic use of hepatic gene expression of NK4 for metastatic colon
      cancer treatment can be given consideration.

PMID- 15017382
TI  - HIV-Tat down-regulates telomerase activity in the nucleus of human CD4+ T cells.

PMID- 15017383
TI  - Intracellular acidification by inhibition of the Na+/H+-exchanger leads to
      caspase-independent death of cerebellar granule neurons resembling paraptosis.
AB  - Potassium withdrawal is commonly used to induce caspase-mediated apoptosis in
      cerebellar granule neurons in vitro. However, the underlying and cell death
      initiating mechanisms are unknown. We firstly investigated potassium efflux
      through the outward delayed rectifier K+ current (Ik) as a potential mediator.
      However, tetraethylammoniumchloride, an inhibitor of Ik, was ineffective to block
      apoptosis after potassium withdrawal. Since potassium withdrawal reduced
      intracellular pH (pHi) from 7.4 to 7.2, we secondly investigated the effects of
      intracellular acidosis. To study intracellular acidosis in cerebellar granule
      neurons, we inhibited the Na+/H+ exchanger (NHE) with 4-isopropyl-3
      methylsulfonylbenzoyl-guanidine methanesulfonate (HOE 642) and 5-(N-ethyl-N
      isopropyl)-amiloride. Both inhibitors concentration-dependently induced cell
      death and potentiated cell death after potassium withdrawal. Although inhibition
      of the NHE induced cell death with morphological criteria of apoptosis in light
      and electron microscopy including chromatin condensation, positive TUNEL staining
      and cell shrinkage, no internucleosomal DNA cleavage or activation of caspases
      was detected. In contrast to potassium withdrawal-induced apoptosis, cell death
      induced by intracellular acidification was not prevented by insulin-like growth
      factor-1, cyclo-adenosine-monophosphate, caspase inhibitors and transfection with
      an adenovirus expressing Bcl-XL. However, cycloheximide protected cerebellar
      granule neurons from death induced by potassium withdrawal as well as from death
      after treatment with HOE 642. Therefore, the molecular mechanisms leading to cell
      death after acidification appear to be different from the mechanisms after
      potassium withdrawal and resemble the biochemical but not the morphological
      characteristics of paraptosis.

PMID- 15017385
TI  - Apoptosis-inducing factor (AIF): caspase-independent after all.

PMID- 15017384
TI  - Osteoclast formation, survival and morphology are highly dependent on exogenous
      cholesterol/lipoproteins.
AB  - Osteoporosis is associated with both atherosclerosis and vascular calcification.
      No mechanism yet explains the parallel progression of these diseases. Here, we
      demonstrate that osteoclasts (OCL) depend on lipoproteins to modulate cellular
      cholesterol levels and that this controls OCL formation and survival. Removal of
      cholesterol in OCL via high-density lipoprotein or cyclodextrin treatment dose
      dependently induced apoptosis, with actin disruption, nuclear condensation and
      caspase-3 activation. One mechanism linked to the induction of OCL apoptosis was
      the cell-type-specific failure to induce HMG-CoA reductase mRNA expression,
      suggesting an absence of feedback regulation of de novo cholesterol biosynthesis.
      Furthermore, cyclodextrin treatment substantially suppressed essential M-CSF and
      RANKL-induced survival signaling pathways via Akt, mTOR and S6K. Consistent with
      these findings, cholesterol delivery via low-density lipoprotein (LDL)
      significantly increased OCL viability. Interestingly, OCLs from the LDL receptor
      (LDLR)-/- mouse exhibited reduced size and lifespan in vitro. Remarkably, LDLR+/+
      OCL in lipoprotein-deficient medium phenocopied LDLR-/- OCL, while fusion and
      spreading of LDLR-/- OCL was rescued when cholesterol was chemically delivered
      during differentiation. With hyperlipidemia being associated with disease of the
      vascular system and bone, these findings provide novel insights into the
      selective lipoprotein and cholesterol dependency of the bone resorbing cell. Cell
      Death and Differentiation (2004) 11, S108-S118. doi:10.1038/sj.cdd.4401399
      Published online 12 March 2004

PMID- 15017386
TI  - Modifications and intracellular trafficking of FADD/MORT1 and caspase-8 after
      stimulation of T lymphocytes.
AB  - The adaptor protein FADD/MORT1 is essential for apoptosis induced by 'death
      receptors', such as Fas (APO-1/CD95), mediating aggregation and autocatalytic
      activation of caspase-8. Perhaps surprisingly, FADD and caspase-8 are also
      critical for mitogen-induced proliferation of T lymphocytes. We generated novel
      monoclonal antibodies specific for mouse FADD and caspase-8 to investigate
      whether cellular responses, apoptosis or proliferation, might be explained by
      differences in post-translational modification and subcellular localisation of
      these proteins. During both apoptosis signalling and mitogenic activation, FADD
      and caspase-8 aggregated in multiprotein complexes and formed caps at the plasma
      membrane but they did not colocalise with lipid rafts. Interestingly, mitogenic
      stimulation, but not Fas ligation, induced a unique post-translational
      modification of FADD. These different modifications may determine whether FADD
      and caspase-8 induce cell death or proliferation.

PMID- 15017387
TI  - E2FBP1/hDril1 modulates cell growth through downregulation of promyelocytic
      leukemia bodies.
AB  - Promyelocytic leukemia nuclear bodies (PML-NBs) comprise multiple regulatory
      factors and play crucial roles in the maintenance of cellular integrity, while
      unregulated activation of PML-NBs induces death and premature senescence. Hence,
      the function of PML-NBs must be directed properly; however, the mechanism that
      regulates PML-NBs remains unclear. In this paper, we show that PML-NBs are
      disintegrated by an AT-rich interaction domain family protein E2FBP1/hDril1
      through specific desumoylation of promyelocytic leukemia protein (PML) in vivo
      and in vitro. RNA interference-mediated downregulation of E2FBP1/hDril1 results
      in hyperplasis of PML-NBs and consequent commitment to PML-dependent premature
      senescence. Thus, the function of E2FBP1/hDril1 is required for maintenance of
      survival potential of the cells. Our data suggest a novel mechanism to govern
      cellular integrity through the modulation of nuclear depots.

PMID- 15017388
TI  - Glucocorticoid receptor heterozygosity combined with lack of receptor auto
      induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia
      cells.
AB  - Glucocorticoids (GC) induce apoptosis in malignant lymphoblasts, but the
      mechanism of this process as well as that of the clinically important GC
      resistance is unknown. We investigated GC resistance in Jurkat T-ALL cells in
      which ectopic GC receptor (GR) restores GC sensitivity, suggesting deficient GR
      expression. Jurkat cells expressed one wild-type and one mutated (R477H) GR
      allele. GR(R477H) ligand-binding-dependent nuclear import, as revealed by live
      cell microscopy of YFP-tagged GR, was unaffected. Transactivation and
      transrepression were markedly impaired; however, GR(R477H) did not act in a
      dominant-negative manner, that is, did not prevent cell death, when introduced
      into a GC-sensitive cell line by retroviral gene transfer. Contrary to another GR
      heterozygous, but GC-sensitive, T-ALL model (CCRF-CEM), Jurkats expressed lower
      basal GR levels and did not auto-induce their GR, as revealed by 'real-time' RT
      PCR and immunoblotting. Absent GR auto-induction could not be restored by
      transgenic GR and, hence, was not caused by reduced basal GR levels. Thus,
      inactivation of one GR gene results in haploinsufficiency if associated with lack
      of GR auto-induction.

PMID- 15017390
TI  - Revalidation.

PMID- 15017389
TI  - The telomeric region is excluded from nucleosomal fragmentation during apoptosis,
      but the bulk nuclear chromatin is randomly degraded.
AB  - Characteristic steps during cellular apoptosis are the induction of chromatin
      condensation and subsequent DNA fragmentation, finally leading to the formation
      of oligomers of nucleosomes. We have examined the kinetics and local distribution
      of this nucleosomal fragmentation within different genomic regions. For the
      induction of apoptosis, HL60 cells were treated with the water-soluble
      camptothecin derivative topotecan (a topoisomerase I inhibitor). The genomic
      origin of the fragments was analysed by Southern blot hybridisation of the
      cleaved DNA. In these experiments we observed similar hybridisation patterns of
      the fragmented DNA, indicating a random and synchronous cleavage of the nuclear
      chromatin. However, hybridisation with a telomeric probe revealed that, in
      contrast to the other analysed genomic regions, the telomeric chromatin was not
      cleaved into nucleosomal fragments despite our observation that the telomeric DNA
      in HL60 cells is organised in nucleosomes. We determined just a minor shortening
      of the telomeric repeats early during apoptosis. These observations suggest that
      telomeric chromatin is excluded from internucleosomal cleavage during apoptosis.

PMID- 15017392
TI  - Abstract issue.

PMID- 15017393
TI  - Training pathways.

PMID- 15017391
TI  - Oral health care.

PMID- 15017394
TI  - Super bugs.

PMID- 15017395
TI  - Legal loophole.

PMID- 15017397
TI  - What's in a name?

PMID- 15017396
TI  - Postgraduate complexity.

PMID- 15017398
TI  - What's in a name?

PMID- 15017408
TI  - Orthodontics. Part 9: anchorage control and distal movement.
AB  - Anchorage is an important consideration when planning orthodontic tooth movement.
      Unwanted tooth movement known as loss of anchorage can have a detrimental effect
      on the treatment outcome. Anchorage can be sourced from the teeth, the oral
      mucosa and underlying bone, implants and extra orally. If extra-oral anchorage is
      used, particularly with a facebow then the use of at least two safety devices is
      mandatory.

PMID- 15017409
TI  - The role of orthodontics and oral and maxillofacial surgery in the management of
      obstructive sleep apnoea - a single case report.
AB  - Obstructive sleep apnoea (OSA) is a potentially fatal breathing disorder, yet is
      widely under-diagnosed. It is a multi-factorial condition associated with high
      morbidity, a degree of mortality and is associated with an increase risk of car
      crashes. A case is presented which demonstrates the inter-disciplinary approach
      to this condition and the successful treatment through mandibular advancement by
      orthodontic means followed by orthognathic surgery. The experience of this
      patient illustrates the importance of the disciplines of orthodontics and oral
      and maxillofacial surgery in the multi-disciplinary management of these patients.

PMID- 15017416
TI  - Appropriate consent and referral for general anaesthesia - a survey in the
      Paediatric Day Care Unit, Barnsley DGH NHS Trust, South Yorkshire.
AB  - BACKGROUND: In November 1998 the General Dental Council introduced guidelines for
      dental practitioners when referring a patient for general anaesthesia (GA). The
      practitioner is required to explain the risks associated with GA and the
      alternatives, give a detailed medical history and a clear justification for
      providing GA in the letter of referral. METHOD: A survey was administered on 202
      parents or guardians, which aimed to investigate whether they felt that their
      dental practitioners had advised them of any risks of GA prior to referral. A
      record was also made if any reasons were given for the provision of GA in the
      letter of referral. RESULTS: The majority of the parents or guardians (66%) felt
      that they were not informed of any of the risks of GA and 25% felt that they
      were. From the letters of referral, 37% contained a reason for GA and 63% did not
      give any reason or justification for GA. CONCLUSION: There is evidence that
      referring practitioners do not adequately explain the risks of the anaesthetic to
      parents or guardians of children undergoing GA. There is also a lack of clear
      justification in the letters of referral for providing GA. PRACTICE IMPLICATION:
      It is essential that the alternatives and the risks of GA are discussed and if GA
      is still required, a clear justification should be contained in the letter of
      referral as part of informed consent. More importantly the referring practitioner
      should keep a contemporaneous record of this, preferably with a signature from
      the parent or guardian on agreement of referral.

PMID- 15017417
TI  - The prevalence of tooth erosion in 12-year-old children.
AB  - OBJECTIVES: To establish the prevalence of tooth erosion in a representative
      sample of 12-year-old children in Leicestershire and Rutland. To determine if
      gender, ethnic group, deprivation or caries experience influences the prevalence
      of erosion. METHODS: A random sample of 1,753 12-year-olds resident in
      Leicestershire and Rutland were examined in 62 schools; 906 were boys and 847
      girls; 1,379 were Caucasian and 316 Asian. Tooth erosion was assessed using the
      index employed in the survey of Children's Dental Health in England and Wales
      (1993). The Townsend index was used to record deprivation. RESULTS: Tooth erosion
      was found in 59.7% of the children, with 2.7% exhibiting exposed dentine.
      Significantly more boys than girls; Caucasian than Asian children; and those with
      caries experience, had erosion present (chi-square for all P<0.01). Overall no
      significant difference was found between deprivation categories, however socio
      economically advantaged Caucasian children had significantly less tooth erosion
      than other groups. CONCLUSIONS: There was a high prevalence of tooth erosion in
      12-year-old children. Significantly more erosion occurred in boys than girls, and
      culture appeared to influence prevalence. Children with caries experience had a
      higher prevalence of erosion than those without caries, which may reflect a lower
      level of dietary care. Deprivation seemed to affect the prevalence of tooth
      erosion in Caucasian children.

PMID- 15017418
TI  - A multifactorial analysis of factors associated with dental erosion.
AB  - OBJECTIVES: This study prospectively examines the relationship of possible
      aetiological factors to the presence of tooth erosion in a cohort of children.
      PATIENTS AND METHODS: A random sample of 1,753 children was examined at age 12
      and 1,308 of the same children were re-examined at age 14 years. The children
      were asked to complete questionnaires on both occasions, 1,149 subjects gave
      usable replies. The erosion index used was based upon the 1993 Survey of
      Children's Dental Health. Results were analysed using logistic regression.
      RESULTS: At age 12 significant positive associations were found between erosion
      and decay experience (odds ratio [OR] = 1.48), drinking fruit juice (OR = 1.42)
      or fizzy pop (OR = 1.59-2.52, depending on amount and frequency). The presence of
      calculus (OR 0.48) or eating fruit other than apples or citrus fruit (OR 0.48)
      reduced the chances of erosion. High consumption of carbonated drinks increased
      the odds of erosion being present at 12 years by 252% and was a strong predictor
      of the amount of erosion found at age 14. CONCLUSIONS: Of the factors
      investigated, a history of dental caries and a high consumption of carbonated
      drinks were most closely related to the presence of dental erosion. The risk of
      erosion bore a strong relationship to the amount and frequency of carbonated
      drink consumption.

PMID- 15017432
TI  - Success in crown and bridge work.
AB  - All practitioners wish for success in their restorative work mainly due to their
      desire to do the best for their patients, but increasingly the achievement of
      success, ie the avoidance of failure, is felt to be necessary to avoid the
      spectre of litigation. The number of patient-led litigation cases is on the
      increase and the majority involve crown and bridge work.

PMID- 15017419
TI  - The specification of learning outcomes in dentistry.
AB  - Increasing emphasis is being placed in dentistry, as in other areas, on outcome
      based education and on the specification of learning outcomes. This paper
      describes the adaptation for dentistry of the medical three circle model as
      described by Harden to specify learning outcomes. The model offers an effective
      and user-friendly format based on the three dimensions of the work of a dentist.
      What the dentist is able to do ('doing the right thing'), how the dentist
      approaches their practice ('doing the thing right'), and the dentist as a
      professional ('the right person doing it'). The model also facilitates curriculum
      and examination planning, reconciles tensions between vocational and academic
      education and is readily understood and accepted by students and teachers.

PMID- 15017433
TI  - Chromosomal gains and genomic loss of p53 and p16 genes in Barrett's esophagus
      detected by fluorescence in situ hybridization of cytology specimens.
AB  - Endoscopic brush cytology is a promising surveillance technique for Barrett's
      esophagus. Ancillary markers are sought to increase the sensitivity of cytology
      and allow identification of patients at increased risk for disease progression.
      To determine if there are specific genetic changes in Barrett's esophagus with
      associated high-grade dysplasia/intramucosal adenocarcinoma compared to those
      without dysplasia, we performed fluorescence in situ hybridization (FISH) on
      cytologic specimens using probes to chromosomes and genomic regions previously
      described as altered in this disease. We studied archival brush cytology slides
      from 40 Barrett's esophagus patients: 21 with biopsy-proven high-grade
      dysplasia/carcinoma and 19 with no dysplasia and a minimum 5 years of negative
      follow-up. Centromeric enumeration probes (CEP) for chromosomes 6, 7, 11, and 12,
      and locus-specific probes (LSI) for 9p21 (p16 gene), and 17p13.1 (p53 gene) loci
      along with their corresponding CEP (9 and 17, respectively) were used in this
      study. A positive FISH result was defined as the presence of cells with >2 CEP
      signals or with a loss of the LSI signals relative to their corresponding CEP.
      p53 locus loss and/or aneusomy of chromosomes 6, 7, 11, and 12 abnormalities
      could be detected by FISH in routinely processed endoscopic brush cytology
      specimens from 95% of biopsy-positive cases with a specificity of 100%.
      Interestingly, all five cases with cytologic changes classified as indefinite for
      dysplasia from patients with a positive biopsy showed changes by FISH. Loss of
      the p16 locus was seen commonly in patients both with and without
      dysplasia/carcinoma. Selected biomarkers from this study merit further
      investigation to determine their potential to detect genetic changes in patients
      with Barrett's esophagus prior to the development of high-grade dysplasia.

PMID- 15017434
TI  - Bilateral carcinomas of the breast with local recurrence: analysis of genetic
      relationship of the tumors.
AB  - Local recurrence of bilateral breast carcinomas is rare, but of biological
      interest, since it is unclear as to which tumor the local recurrence is related
      to, the ipsilateral or the contralateral, or whether it is an independent
      neoplasm. The aim of this study was to investigate the genetic relationship of
      bilateral breast carcinomas to each other and to their local recurrences. Eight
      cases of bilateral breast carcinomas, five with and three without local
      recurrence were analyzed using a microsatellite assay for 13 microsatellite loci.
      The presence of loss of heterozygosity and microsatellite instability in the
      various tumors was used for clonal analysis. All eight bilateral breast
      carcinomas showed divergent alterations in at least two microsatellite loci,
      which ruled out a genetic relationship. Four of five local recurrences were
      genetically related to the ipsilateral tumor and unrelated to the contralateral
      tumor. Only one local recurrence that occurred 11.8 years after the surgery of an
      infiltrative lobular carcinoma simultaneously with distant metastases was
      genetically related to the contralateral breast carcinoma. Although the number of
      cases in our study is limited, there is evidence that local recurrence of
      bilateral breast carcinoma frequently arises from the ipsilateral tumor.

PMID- 15017435
TI  - Mucinous carcinoma of the colon: correlation of loss of mismatch repair enzymes
      with clinicopathologic features and survival.
AB  - Colorectal carcinoma with microsatellite instability (MSI-H) has a characteristic
      clinicopathologic profile, typically forming right-sided, lymphocyte-rich tumors
      that are often mucinous. Mucinous histology in general has been linked to adverse
      prognosis in some studies, but not in others. MSI-H carcinoma, in contrast, has a
      better prognosis than microsatellite stable carcinoma in most studies. We
      assessed the relationship between MSI status, clinicopathologic features and
      outcome for 248 consecutive patients with resected mucinous carcinoma. All cases
      were reviewed to confirm mucinous histology. Immunohistochemical stains for DNA
      mismatch repair enzymes hMLH1, hMSH2 and hMSH6 were performed on a representative
      block from each case. Tumors lacking expression of a mismatch repair enzyme were
      designated MSI-H; all others were classified as microsatellite stable. Age, sex,
      tumor size, site, grade, stage, growth pattern, Crohn's-like reaction, vascular
      invasion and number of tumor-infiltrating lymphocytes were evaluated without
      knowledge of MSI status or patient outcome. 72 (29.3%) mucinous carcinomas were
      MSI-H. Compared to microsatellite stable mucinous cancers, they were more likely
      to be right-sided (83.3 vs 48.6%, P<0.001), have a Crohn's -like reaction (65.7
      vs 29.8%, P<0.001) and have many tumor infiltrating lymphocytes (72.2 vs 20.8%,
      P<0.001). MSI-H mucinous cancers presented more often as localized disease (66.7
      vs 38.1%, P<0.001) and less often with lymph node (26.4 vs 44.9%) or distant (4.2
      vs 16.5%) metastases. In univariate analysis, MSI had a favorable effect on age
      adjusted survival (hazard ratio 0.597, P=0.02). In multivariate analysis, age,
      grade, Crohn's-like reaction and stage were independent predictors of survival,
      but MSI status was not. In conclusion, MSI-H mucinous carcinomas are right-sided,
      low-stage tumors with Crohn's-like reaction and tumor-infiltrating lymphocytes.
      The outcome for MSI-H mucinous carcinoma is better than that of microsatellite
      stable mucinous carcinoma, but MSI status is not an independent predictor of
      survival.

PMID- 15017436
TI  - NTP technical report on the toxicity studies of Butanal oxime (CAS No. 110-69-0)
      administered in drinking water and by gavage to F344/N rats and B6C3F1 mice.
AB  - Butanal oxime is used as a volatile antiskinning agent in paints, inks, and
      similar products. Butanal oxime was chosen for toxicology testing as a
      representative of the aldoxime class. Male and female F344/N rats and B6C3F1 mice
      received butanal oxime (99 percent pure) in drinking water for 15 days or by
      gavage in 0.5 percent methylcellulose for 14 weeks. Animals were evaluated for
      clinical pathology, reproductive system effects, and histopathology. Genetic
      toxicology studies were conducted in Salmonella typhimurium, cultured Chinese
      hamster ovary cells, and mouse peripheral blood erythrocytes. In the 15-day
      studies, groups of five male and five female rats and mice received 0, 312, 625,
      1,250, 2,500, or 5,000 ppm butanal oxime in drinking water, resulting in average
      daily doses of approximately 40, 70, or 100 mg butanal oxime/kg body weight to
      male and female rats; 45, 90, 130, 200, or 300 mg/kg to male mice; and 45, 85,
      100, 130, or 170 mg/kg to female mice. Due to body weight loss and lack of water
      consumption, all male and female rats receiving 2,500 or 5,000 ppm were removed
      from the study on day 9; average daily doses were not calculated for these
      groups. All other rats and mice survived until the end of the studies. Mean body
      weights of 1,250 ppm male and female rats and 2,500 and 5,000 ppm male and female
      mice were significantly less than those of the controls. Male mice receiving
      5,000 ppm and females receiving 2,500 or 5,000 ppm lost weight during the study.
      Water consumption by rats and mice receiving 1,250 ppm or greater was less than
      that by the controls. Thinness in 2,500 and 5,000 ppm rats and mice was the only
      clinical finding of toxicity. Spleen weights were significantly decreased in
      2,500 and 5,000 ppm female mice. No chemical-related lesions were observed
      grossly; histologic examinations were not performed. In the 14-week studies,
      groups of 10 male and 10 female rats and mice received butanal oxime by gavage at
      doses of 0, 25, 50, 100, 200, or 600 mg/kg, 5 days per week for 14 weeks. All 600
      mg/kg rats died or were killed moribund during the first week of the study; in
      the 600 mg/kg mouse groups, seven males and nine females died, were killed
      moribund, or were killed accidentally before the end of the study. Mean body
      weights of 100 and 200 mg/kg male rats, 600 mg/kg male mice, and female mice
      administered 50 mg/kg or greater were less than those of the controls. Clinical
      findings of toxicity in 600 mg/kg rats included loss of coordination, wobbly
      gait, shaking, blinking, constant grooming and scratching of the face, head
      weaving, burying of the face in bedding, lethargy, and prostration; in 600 mg/kg
      mice, clinical findings included ataxia, loss of balance after rearing,
      squinting, and burying of the face in the bedding. Hematology results of the 14
      week gavage studies indicate that butanal oxime induces a methemoglobinemia and a
      responsive anemia in rats and mice. Spleen weights of 100 and 200 mg/kg male
      rats, female rats administered 50 mg/kg or greater, and 200 and 600 mg/kg male
      mice were increased, as were the liver weights of 200 mg/kg female rats and mice.
      In animals that died early due to butanal oxime administration, hepatocellular
      necrosis was the primary pathologic finding. Degeneration of the nasal olfactory
      epithelium was observed in dosed rats and mice that died early as well as in
      animals that survived to the end of the studies. Additional chemical-related
      nasal findings were respiratory epithelial changes in male rats and suppurative
      exudate in male and female mice. Increased incidences and/or severities of
      splenic hematopoietic cell proliferation and pigmentation (hemosiderin) as well
      as bone marrow hyperplasia were also observed in dosed groups, particularly in
      the 200 and 600 mg/kg groups, and were indicative of erythrocyte damage. Butanal
      oxime (3 to 10,000 ug/plate) was mutagenic in S. typhimurium strain TA1535 in the
      presence of 5 percent or 10 percent rat liver S9; an equivocal response was seen
      in TA100 with 30 percent rat S9, and no mutagenic activity was seen in TA98, with
      or without rat or hamster liver S9. Butanal oxime induced chromosomal aberrations
      in cultured Chinese hamster ovary cells, with and without S9. Significant
      increases in the frequencies of micronucleated normochromatic erythrocytes were
      observed in vivo in peripheral blood of male and female mice administered 25 to
      600 mg/kg butanal oxime for 14 weeks by gavage. Synonyms: Butanaloxime;
      butylaldoxime; butyraldehyde oxime; n-butyraldehyde oxime; butyraldoxime; n
      butyraldoxime Trade names: Exkin 1, Exkin No. 1 Anti-Skinning Agent, Skino #1,
      Troykyd Anti-Skin BTO

PMID- 15017437
TI  - It's the law.

PMID- 15017438
TI  - Symptom clusters in elderly patients with lung cancer.
AB  - PURPOSE/OBJECTIVES: To identify the number, type, and combination (cluster) of
      symptoms experienced by patients with lung cancer. DESIGN: A secondary analysis
      of data collected as part of a larger study. SETTING: 24 sites that included
      community hospitals, medical clinics, oncology clinics, and radiation-oncology
      clinics. SAMPLE: 220 patients newly diagnosed with lung cancer, ranging in age
      from 65-89 years (mean = 72 years, SD = 5.02), 38% with early-stage and 62% with
      late-stage lung cancer. METHODS: Subject self-report. FINDINGS: Factor analysis
      found that the symptoms of fatigue, nausea, weakness, appetite loss, weight loss,
      altered taste, and vomiting form a cluster. Initial staging of cancer, the number
      of comorbid conditions, and being treated with chemotherapy emerged as
      significant predictors of the symptoms reported. Few differences were noted
      between men and women. Correlation was found among the numbers of symptoms
      reported, symptom severity, and limitations attributed to symptoms. CONCLUSIONS:
      Patients with lung cancer report multiple distressing symptoms related to symptom
      severity and limitations. IMPLICATIONS FOR NURSING: Assessment of multiple
      symptoms is recommended in patients with lung cancer.

PMID- 15017439
TI  - Advanced practice nursing outcomes: a review of selected empirical literature.
AB  - PURPOSE/OBJECTIVES: To review selected empirical literature examining outcomes of
      advanced practice nursing with a specific focus on the work of oncology advanced
      practice nurses (APNs). DATA SOURCES: Published articles (descriptive and data
      based) and books. DATA SYNTHESIS: Well-designed, methodologically sound
      investigations offer clear and compelling evidence that APNs are effective in
      improving outcomes in diverse populations and settings. Data on outcomes of
      oncology APNs are more limited but do demonstrate statistically significant
      improvements in clinical outcomes in the homecare and ambulatory settings. The
      increase in oncology APNs and the evolution of viable roles for oncology APNs
      across cancer practice settings offer opportunities to further assess the
      outcomes of advanced practice nursing. CONCLUSIONS: Understanding the effects of
      oncology advanced practice nursing on clinical, cost, and satisfaction outcomes
      is critical. These data will help to explain how APNs can be used most
      effectively in the healthcare system to ensure the delivery of quality cancer
      care. IMPLICATIONS FOR NURSING: Assessing the outcomes of advanced practice
      nursing care has been identified as a priority by the Oncology Nursing Society.
      Expansion of APN roles in oncology creates myriad opportunities to investigate
      this issue. APNs should be cognizant of the work that has been done in this area
      and use this knowledge as a foundation from which to launch further
      investigations.

PMID- 15017440
TI  - Prevention and treatment of acute radiation dermatitis: a literature review.
AB  - PURPOSE/OBJECTIVES: To review historical and current research data on prevention
      and treatment of acute radiation dermatitis. DATA SOURCES: 18 research trials and
      1 case report published from 1967-2001 and 1 unpublished research trial from
      1972. DATA SYNTHESIS: Washing the skin with mild soap and water and the hair with
      mild shampoo is safe during radiation therapy. Biafine (Medix Pharmaceuticals,
      Inc., Largo, FL), chamomile cream, almond ointment, topical vitamin C, and
      gentian violet have not been proven effective and should not be used.
      Transparent, hydrocolloid, and hydrogel dressings have been beneficial, as have
      sucralfate cream and corticosteroid cream. Aloe vera may be beneficial and is not
      harmful. CONCLUSIONS: The existing scientific data are lacking in quantity and
      quality. The current body of evidence is unable to provide clinicians with
      comprehensive guidelines for prevention and management of acute radiation
      dermatitis. IMPLICATIONS FOR NURSING: Nurse clinicians and nurse scientists must
      partner to conduct further research to add to the limited resources about the
      prevention and management of acute radiation dermatitis and develop comprehensive
      evidence-based clinical practice guidelines.

PMID- 15017441
TI  - Risks and benefits of soy isoflavones for breast cancer survivors.
AB  - PURPOSE/OBJECTIVES: To present state-of-the-art information about the risks and
      benefits of soy isoflavones for breast cancer survivors. DATA SOURCES: Published
      research articles, pertinent articles and books, and computerized databases. DATA
      SYNTHESIS: Some epidemiologic data suggest that soy isoflavones play an important
      role in preventing breast cancer in Asian women and promoting women's health in a
      variety of ways. However, the use of soy isoflavones in women with breast cancer
      is controversial. Risks and benefits exist regarding the use of soy isoflavones
      by breast cancer survivors. CONCLUSIONS: The use of soy isoflavones to promote
      health in breast cancer survivors remains controversial because of scant
      scientific data. IMPLICATIONS FOR NURSING: Nurses should not only provide updated
      information to the public but also interpret research results carefully. More
      clinical trials need to be conducted on a longitudinal basis with the enrollment
      of breast cancer survivors.

PMID- 15017442
TI  - Factors related to persistent fatigue following completion of breast cancer
      treatment.
AB  - PURPOSE/OBJECTIVES: To verify the predictive capacity of the stress-process
      theory to emeanplain persistent fatigue following completion of breast cancer
      treatments; to verify the relationship between interleukin-1b and fatigue.
      DESIGN: Correlational. SETTING: Tertiary medical center in Quebec City, Canada.
      SAMPLE: A systematic sample of 103 women in remission from breast cancer was
      recruited. The mean age was 54 years. Participants with a depressive mood,
      insomnia, or stage IV cancer were emeancluded. METHODS: Participants were met
      during their follow-up appointment after the end of radiation therapy.
      Questionnaires on fatigue, stress variables, and other confounding variables were
      completed by telephone interview. Blood samples also were collected to measure
      the serum level of interleukin-1b. MAIN RESEARCH VARIABLES: Fatigue, several
      variables from the stress-process theory, pain, menopausal symptoms, and
      demographic and medical variables. FINDINGS: Fatigue was related theoretically
      and coherently to many stress-process variables. By controlling for pain, the
      final regression model included cancer stressors and passive and active coping as
      predictors, which accounted for 41% of the variance in fatigue. No relationship
      was found between fatigue and interleukin-1b. CONCLUSIONS: The results supported
      the relevance of the stress-process theory for emeanplaining cancer-related
      fatigue. IMPLICATIONS FOR NURSING: Nursing interventions based on this
      theoretical framework could be developed. In addition, further clinical research
      that tests the efficacy of these psycho-educative interventions in preventing
      persistent fatigue and improving the quality of life of women with breast cancer
      is recommended.

PMID- 15017443
TI  - Shifting perspectives: adolescent-focused oncology nursing research.
AB  - PURPOSE/OBJECTIVES: To describe contextual features of the experience of
      adolescents with cancer in the United States; to relate these features to a
      different theoretical perspective, the Shifting Perspectives Model of Chronic
      Illness; and to derive implications from that model for conducting research with
      adolescents who have cancer. DATA SOURCES: 64 qualitative and quantitative
      studies and clinical anecdotes. DATA SYNTHESIS: Unique features of adolescents
      with cancer related to person, disease, and treatment indicate that existing
      theories on adolescence do not adequately guide research efforts with this
      patient population, nor do they adequately assist in explaining study findings.
      CONCLUSIONS: The Shifting Perspectives Model of Chronic Illness is useful in
      generating potentially important hypotheses about adolescents and their
      experiences with cancer and has the promise of guiding research design and method
      selection for studies involving adolescents with cancer. The model also
      highlights a moral responsibility for researchers who conduct studies with this
      patient population. IMPLICATIONS FOR NURSING: Nurse researchers who use this
      model to guide their research will create a purposeful balance in methods that
      allows adolescents with cancer to choose the amount of time and detail they will
      give to illness-related or to wellness-related responses in studies, particularly
      those that rely on self-report methods.

PMID- 15017444
TI  - Shifting perspectives: family-focused oncology nursing Research.
AB  - PURPOSE/OBJECTIVES: To analyze five common assumptions about a family's
      adjustment to breast cancer and to suggest needed future directions for family
      focused research. DATA SOURCES: Published research in nursing, psychiatry,
      behavioral medicine, and psycho-oncology about families' functioning with breast
      cancer. DATA SYNTHESIS: Evidence from published research is that family members
      do not modify their coping behavior in response to illness-related pressures, do
      not appear to learn over time how to manage illness-related concerns, are not
      responsive to each other's thoughts and feelings about cancer, experience tension
      in the marriage from cancer, and neither understand nor assist children affected
      by a mother's breast cancer. CONCLUSIONS: Current assumptions about how families
      function with breast cancer need to be replaced with a more informed, data-based
      view that guides the development of better programs and services for assisting
      families. IMPLICATIONS FOR NURSING: Future research and interventions need to
      address the impact of breast cancer on the primary relationships in a household,
      the impact of the illness on the family's core functions, and the family members'
      competencies to manage the illness.

PMID- 15017445
TI  - Shifting perspectives: gero-oncology nursing research.
AB  - PURPOSE/OBJECTIVES: To analyze the development of gero-oncology research through
      a critical review of nursing and other relevant research as well as the present
      state of practice. DATA SOURCES: Journal articles, book chapters, and personal
      experience. DATA SYNTHESIS: Cancer in older adults is viewed through two
      investigative perspectives. The assumptions, questions, theoretical frames, and
      research design that follow from these investigative perspectives do not
      adequately meet the need to examine the interplay of responses to aging, cancer,
      and nursing practice. The mismatch of need, knowledge, and resources marks older
      adults with cancer as a special population in need of far more sophisticated
      research. With the synthesis of a new perspective, gero-oncology nursing research
      becomes age focused, more precisely shaping theoretical, methodologic, and
      analytic approaches. CONCLUSIONS: Uniform attachment of chronologic age or other
      simple age-related variables to investigations, which is the primary
      consideration of age-related research, is irrelevant for older adults who are
      diagnosed with, treated for, live with, survive, and die from cancer. Shaping the
      next phase of gero-oncology research with a focus on age precisely integrates
      theoretical, methodologic, and analytic approaches through language specific to
      older adults and cancer. IMPLICATIONS FOR NURSING: Shifting perspectives in gero
      oncology nursing research will better inform future practice.

PMID- 15017446
TI  - Knowledge, attitudes, beliefs, and practices regarding breast and cervical cancer
      screening in selected ethnocultural groups in Northwestern Ontario.
AB  - PURPOSE/OBJECTIVES: To examine the knowledge, attitudes, beliefs, and practices
      regarding breast and cervical cancer screening in selected ethnocultural groups
      (i.e., Italian, Ukranian, Finnish, and the native population) in Northwestern
      Ontario, Canada. DESIGN: Descriptive, exploratory. SETTING: Rural and urban
      settings in Northwestern Ontario. SAMPLE: 105 women aged 40 and older who were
      residents of Northwestern Ontario and members of selected ethnic groups,
      including Italian, Ukranian, Finnish, Ojibwa, and Oji-Cree. METHODS: An interview
      guide was designed specifically for this study to gather information regarding
      knowledge, attitudes, beliefs, and practices about breast self-examination (BSE),
      clinical breast examination (CBE), mammography, and cervical cancer screening
      procedures. Data were obtained through face-to-face interviews (two or three
      hours) in English or the language spoken. Interviews in other languages were
      transcribed into English. FINDINGS: Ojibwa and Oji-Cree women were more likely
      than any other group to not have practiced BSE, to have refused CBE or mammogram,
      to not have been told how to perform BSE, to not have received written
      information about breast examination, and to be uncomfortable and fearful about
      cervical cancer screening procedures (33% refused internal examination as
      compared to 0-8% in the other ethnic groups). Four issues emerged from the
      findings: (a) using multimedia sources to inform women about screening programs,
      (b) educating women regarding breast and cervical cancer screening, (c) reminding
      women when they are due for screening, and (d) identifying that Pap tests are
      uncomfortable and frightening. CONCLUSIONS: Cultural beliefs, attitudes, and
      practices of marginal populations (e.g., native women) are important to consider
      when developing strategies to address barriers to effective breast and cervical
      screening. IMPLICATIONS FOR NURSING: Educational programs that are culturally
      sensitive to participants are imperative.

PMID- 15017447
TI  - Patients' need for information about cancer therapy.
AB  - PURPOSE/OBJECTIVES: To obtain detailed information about the preferences of
      patients with cancer and their need for information about side effects of cancer
      treatment to design an interactive multimedia educational program. DESIGN:
      Qualitative. SETTING: Regional rural academic medical center. SAMPLE: 51 patients
      and 14 spouses of patients who either currently were undergoing or recently had
      completed chemotherapy or radiation therapy for cancer. METHODS: Focus groups.
      MAIN RESEARCH VARIABLES: Information needs and common and distressing symptoms.
      FINDINGS: Patients wanted information about the process of getting treatment,
      specific side effects that might occur, and the impact of treatment on their
      lives. Patients sought information from a variety of sources, but many found that
      other patients were the most helpful source. Although most patients wanted as
      much information as possible so they would be prepared for whatever happened,
      some patients preferred to avoid information about possible side effects. Several
      obstacles related to information were reported, including access to providers,
      communication difficulties with providers, informational overload, and problems
      with retention. CONCLUSIONS: Several aspects regarding information needs
      confirmed previous findings, and new aspects were illuminated. This led to a
      conclusion that multimedia technology offered many advantages to meet these
      informational needs. IMPLICATIONS FOR NURSING: New approaches to patient
      education that will meet the needs of patients as well as clinicians and
      educators need to be developed.

PMID- 15017448
TI  - Israeli oncology nurses' religiosity, spiritual well-being, and attitudes toward
      spiritual care: a path analysis.
AB  - PURPOSE/OBJECTIVES: To investigate the relationship among the antecedent factors
      of age, ethnicity, and education and the mediating variables of intrinsic
      religiosity, extrinsic religiosity, and spiritual well-being on Israeli oncology
      nurses' attitudes toward spiritual care. DESIGN: A correlational, explanatory
      study. SAMPLE: Members (N = 155) of the Israeli Oncology Nursing Society. METHOD:
      Subjects completed a mailed research package. A path model guided the testing of
      the hypotheses. MAIN RESEARCH VARIABLES: Spiritual well-being, intrinsic
      religiosity, extrinsic religiosity, age, ethnicity, and education. RESULTS:
      Variables of interest accounted for a small but significant amount of the total
      variance in attitudes toward spiritual care. However, only spiritual well-being,
      extrinsic religiosity, and education demonstrated direct relationships with these
      attitudes. In addition, intrinsic and extrinsic religiosity, mediated through
      spiritual well-being, demonstrated indirect relationships with attitudes.
      CONCLUSION: Nurses' attitudes toward spiritual care are influenced by their
      education, intrinsic and extrinsic religiosity, and spiritual well-being.
      IMPLICATIONS FOR NURSING: Because spiritual well-being is a good predictor of
      nurses' positive attitudes toward spiritual care, nurses' spiritual well-being
      should be supported. In addition, nursing education needs to examine ways that
      may support more positive attitudes toward spiritual care. Future research also
      should be conducted on other nursing populations and across cultures and
      religious affiliations.

PMID- 15017449
TI  - A qualitative study of the experiences during radiotherapy of Swedish patients
      suffering from lung cancer.
AB  - PURPOSE/OBJECTIVES: To describe experiences during radiotherapy of patients
      suffering from lung cancer. DESIGN: Inductive, qualitative. SETTING: A
      radiotherapy department in the south of Sweden. SAMPLE: 15 patients with lung
      cancer undergoing their second week of radiotherapy. METHODOLOGIC APPROACH:
      Interviews were conducted in a hospital setting, transcribed, and content
      analyzed. MAIN RESEARCH VARIABLES: Experiences during radiotherapy. FINDINGS: The
      patients' experiences fall into four categories: fatigue, physical distress,
      managing disease- and treatment-related issues, and obstacles to managing.
      Fatigue was a major experience expressed in terms of low energy levels and low
      fitness, sometimes leading to social isolation. CONCLUSIONS: Nurses need to
      implement interventions to minimize side effects of radiotherapy and maximize
      patients' abilities to manage the disease and the treatment. INTERPRETATION:
      Informing and educating patients about pretreatment and assessing fatigue as well
      as implementing interventions (e.g., nurse-patient interaction, support,
      information, encouragement, focus on the patients' own resources) may lead to
      improved comprehensive care during radiation therapy.

PMID- 15017450
TI  - Telephone social support and education for adaptation to prostate cancer: a pilot
      study.
AB  - PURPOSE/OBJECTIVES: To evaluate the feasibility of an intervention of telephone
      social support and education to increase the physical, emotional, functional, and
      interpersonal adaptation of men to prostate cancer. DESIGN: Prospective, random
      assignment to experimental or control treatments. SETTING: Urban New Jersey.
      SAMPLE: 17 men diagnosed with prostate cancer within four weeks of study entry.
      Mean age was 66 years (range = 51-78); 59% were Caucasian, 35% were African
      American, and 6% were American Indian. METHODS: Subjects in the experimental
      group received telephone social support over a 12-month period in addition to
      education via mailed resource kits. The control group received education through
      mailed resource kits only. The Functional Assessment of Cancer Therapy Scale
      General Physical, Emotional, Functional, and Social/Family Well-Being subscales;
      Symptom Experience Scale-Prostate; and the Relationship Change Scale were
      administered initially and at the end of each of the three phases; the
      International Index of Erectile Function Scale was administered at the end of
      each of the three phases. Qualitative information was gathered throughout and at
      the conclusion of the study. MAIN RESEARCH VARIABLES: Physiologic, emotional,
      functional, and social adaptation to prostate cancer. FINDINGS: Results were
      somewhat more favorable for the experimental group on all outcome measures;
      however, differences were not statistically significant. Structured interviews
      with 14 of 17 subjects revealed that telephone social support and education were
      effective in increasing adaptation to prostate cancer. CONCLUSIONS: Despite the
      lack of a significant difference between the experimental and treatment groups in
      this small sample of men, analysis of trends and interview feedback indicated
      that telephone social support, in addition to education through a mailed resource
      kit, has the potential to be beneficial by increasing access to supportive
      services. IMPLICATIONS FOR NURSING: Telephone social support when supplementing
      patient education may assist men in adapting during the year following a prostate
      cancer diagnosis.

PMID- 15017451
TI  - Resolution of spiritual disequilibrium by women newly diagnosed with breast
      cancer.
AB  - PURPOSE/OBJECTIVES: To describe the experience of restoring and maintaining
      spiritual equilibrium over a 14-month period by women newly diagnosed with breast
      cancer. RESEARCH APPROACH: Qualitative approach, longitudinal design. SETTING:
      Urban breast cancer resource center. PARTICIPANTS: 10 women initially one to five
      months from diagnosis, 5 of whom attended an eight-week self-transcendence theory
      based breast cancer support group. METHODOLOGIC APPROACH: Audiotaped interviews
      conducted within five months of diagnosis, two to three months later, and one
      year after that. Narratives were analyzed using Colaizzi's phenomenologic
      approach. MAIN RESEARCH VARIABLES: Spiritual disequilibrium resolution, breast
      cancer, self-transcendence. FINDINGS: Spiritual disequilibrium characteristics,
      as described in several studies of women with breast cancer, were fear of dying
      and a sense of aloneness in a struggle to maintain self-identity. Disequilibrium
      triggered all participants to reach outwardly for information and support from
      other people and faith resources and to reach inwardly to examine life values.
      Shortly after diagnosis, and continuing throughout the study period, most
      participants also reached outwardly to support others and conduct breast cancer
      advocacy work. CONCLUSION: Resolving spiritual disequilibrium for women with
      newly diagnosed breast cancer means restoring a sense of connection to self,
      others, and/or a higher power. Self-transcendence views and behaviors evolving
      over time help women to restore their sense of connectedness, maintain hope for a
      future, and find renewed purpose and meaning. INTERPRETATION: An initial breast
      cancer diagnosis may be associated with spiritual disequilibrium that can be as
      problematic as the physical effects of cancer and cancer treatment. Women restore
      equilibrium through resolving their sense of disconnectedness and regaining a
      positive self-identity.

PMID- 15017452
TI  - Cancer nursing research short course: long-term follow-up of participants, 1984
      1998.
AB  - PURPOSE/OBJECTIVES: To describe research activities of cancer nurses following
      participation in the Oncology Nursing Society (ONS)/National Cancer Institute
      Cancer Nursing Research Short Course from 1984-1989. DESIGN: Descriptive survey.
      SETTING: National survey of course participants. SAMPLE: 128 cancer nurses who
      attended the courses presented from 1984-1998. METHODS: Mailed survey. MAIN
      RESEARCH VARIABLES: Demographic characteristics, current job titles,
      participation in research since course attendance, sources and amounts of
      research support, research roles, and publications. FINDINGS: The course provided
      new investigators with a unique research experience not available at their own
      institutions and helped them launch their research careers. The participants'
      commitment to research is illustrated in their response rate to the survey,
      record of studies, funding sources, and research roles. CONCLUSIONS: The short
      course is a valuable resource for increasing the number of committed oncology
      nursing researchers and assisting in the scientific foundation for the care of
      patients with cancer. Findings clearly show the value of the course to
      participants' research careers. IMPLICATIONS FOR NURSING: ONS has a commitment to
      oncology nursing research as the means to increase the scientific foundation for
      cancer nursing care. The Cancer Nursing Research Short Course provides a valuable
      resource for meeting this commitment.

PMID- 15017454
TI  - Australian Neuroscience Society--24th annual meeting. 27-30 January 2004,
      Melbourne, Australia.

PMID- 15017453
TI  - The effects of concrete objective information and relaxation on maintaining usual
      activity during radiation therapy.
AB  - PURPOSE/OBJECTIVES: To examine the effects of concrete objective information
      (COI) and relaxation instruction (RI) on patients undergoing radiation therapy,
      as well as the contribution of symptom uncertainty and body awareness to the
      intervention effects. DESIGN: Three-group randomized trial. Assignment was
      stratified by cancer site. Data collectors were blinded to group assignments.
      SETTING: University medical center radiation therapy department serving both
      urban and rural communities in the southeastern United States. SAMPLE: 76 adults
      having radiation with curative intent for gynecologic, head and neck, or lung
      cancer. Most were Caucasian and had in situ to stage II disease. Mean age was 55
      years. METHODS: COI and RI were delivered by tape recordings. Outcome measures
      were indicators of usual activities and emotions at treatment week 3 and two and
      four weeks post-treatment. MAIN RESEARCH VARIABLES: Intervention group; social,
      household, and recreational activities; anxiety, depression, and anger; body
      awareness; and symptom uncertainty. FINDINGS: Participants receiving either
      intervention reported more social activity during treatment. Those given RI who
      were high in body awareness reported more household activity during treatment. No
      effects were found regarding emotion. Symptom uncertainty partially explained COI
      effects. CONCLUSIONS: The findings provide additional support for the
      effectiveness of COI in helping patients to maintain more of their usual
      activities during radiation therapy. Instruction in progressive muscle relaxation
      also may help in maintaining activities. IMPLICATIONS FOR NURSING: COI helps
      patients to cope with treatment by reducing their uncertainty about symptoms. RI
      effects may vary by activity type and awareness of usual body sensations.

PMID- 15017455
TI  - International Congress of Biological Psychiatry. 8-13 February 2004, Sydney,
      Australia.
AB  - Approximately 1500 psychiatrists, psychologists and basic scientists attended the
      International Congress of Biological Psychiatry with a specialist interest in the
      biological aspects of psychiatry. There was relatively little information on new
      medications for the treatment of psychiatric disorders but the congress
      emphasized approaches to treatment based on medications and physical therapies,
      as well as advances in the understanding of the biological basis of psychiatric
      illnesses. Around 800 abstracts were presented in symposia, sponsored satellite
      sessions, free communications and poster sessions. The poster sessions were
      particularly well attended and provided many lively discussions. Of particular
      interest were sessions devoted to new antipsychotics for the treatment of
      schizophrenia, management of mood and anxiety disorder, Alzheimer's disease and
      bipolar disorder. This report describes information on the new antipsychotic drug
      aripiprazole, novel targets for the treatment of mood disorders and psychoses,
      GABAA receptors in the treatment of panic disorder, and poster presentations on
      bipolar disorder.

PMID- 15017456
TI  - Gastrointestinal Cancers--first symposium. Current status and future directions
      for prevention and management. 22-24 January 2004, San Francisco, CA, USA.

PMID- 15017457
TI  - International Congress on Anticancer Treatment--15th International Congress.
      Fifth Interactive Gastrointestinal Oncology meeting: Shifting paradigms in GI
      oncology. 9-12 February 2004, Paris, France.

PMID- 15017458
TI  - New trends in immunosuppression--sixth international congress. New drug
      candidates. 5-8 February 2004, Salzburg, Austria.

PMID- 15017459
TI  - NF kappa B: biology and pathology--Keystone Symposium. 11-16 January 2004,
      Snowbird, UT, USA.
AB  - This Keystone Symposium, focusing on the transcription factor NFkappaB, was held
      at the Snowbird ski resort. More than 350 academic and pharmaceutical industry
      scientists attended the meeting. Talks and posters ranged from basic science
      (signaling, chromatin modifications and new NFkappaB gene targets) to animal
      models for disease and clinical trials with NFkappaB inhibitors. Drugs that block
      NFkappaB inhibitors include retinoids, IkappaB kinase inhibitors, non-steroidal
      compounds and proteasome inhibitors. These pharmaceutical approaches and their
      disease relevance are discussed below.

PMID- 15017461
TI  - Prevention and treatment of allergy--SMi's second conference. 2-3 February 2003,
      London, UK.

PMID- 15017460
TI  - Signal Transduction Pathways as Therapeutic Targets. 25-28 January 2004,
      Luxembourg.
AB  - The Signal Transduction Pathways as Therapeutic Targets meeting was attended by
      approximately 400 participants from a wide spectrum of backgrounds, including
      basic scientists, pharmaceutical scientists and postdoctoral fellows from many
      fields. The overall focus of the meeting was on the role that signal transduction
      plays in biology and pathophysiology and the design of compounds that can
      modulate these pathways. This report describes several signaling pathways that
      are potential targets for inflammation and cancer, including those that involve
      the following signaling molecules: Jun N-terminal kinase, cyclin-dependent
      kinases, hypoxia-inducible factor, p21-activated kinases, MEK kinase 1,
      phosphoinositide 3-kinases, myc, p53, Smad, hedgehog, nuclear factor-kB and G
      protein. This report also describes various compounds as potential anti
      inflammatory or anticancer agents.

PMID- 15017462
TI  - The viability of DNA vaccines--marcus evans conference. 3-5 February 2004,
      London, UK.
AB  - This DNA vaccines conference was aimed at examining the viability of DNA vaccines
      as a credible prophylactic/therapeutic technology rather than simply as an
      effective research tool. Presentations and panel discussion sessions focused on
      many of the issues facing the sector, including efficacy, manufacturing costs and
      public acceptability of the technology. Clinical trial data were presented for
      DNA vaccines in development for both human and veterinary use, including cancer,
      HIV infection and malaria. Presentations also covered delivery technologies
      (microparticles, electroporation and epidermal 'tattooing'), and the
      manufacturing industry reported on the latest production advances. Issues
      concerning human vaccine development are covered in this review.

PMID- 15017463
TI  - Drug Delivery Partnerships--IIR's Eighth Annual conference. 28-29 January 2004,
      Beverly Hills, CA, USA.

PMID- 15017464
TI  - Antisense and siRNA technologies--SMi's second annual conference. 16-17 February
      2003, London, UK.

PMID- 15017465
TI  - Controlled release--third annual SMi conference. 9-10 February 2004, London, UK.

PMID- 15017466
TI  - Longitudinal changes in plasma glucose values of the 75-g glucose tolerance test
      in triplet pregnancies.
AB  - We evaluated longitudinal changing patterns of 75 g glucose tolerance test (GTT)
      in triplet pregnancies. Eight triplet pregnancies were prospectively studied. All
      triplet pregnancies were fertilized with artificial reproductive techniques;
      patients showed no glucosuria or fasting hyperglycemia > 100 mg/dL before
      pregnancy. The 75-g GTT was performed at first, second, and third trimester, as
      well as at postpartum. Longitudinal changes in glucose levels at fasting, 1 hour,
      and 2 hours were compared by one-way repeated-measure analysis of variance
      (ANOVA) and Bonferroni/Dunn test ( p < 0.05). Values were expressed as mean +/-
      standard deviation. Each of the 3-point values of 75-g GTT decreased after 28
      weeks of gestation in triplet pregnancies. During the third trimester, fasting
      values were significantly decreased compared with postpartum values (65.5 +/-
      13.4 versus 74.6 +/- 4.0 mg/dL), and 2-hour values were significantly decreased
      from those of second-trimester 75-g GTT (116.3 +/- 19.5 versus 99.6 +/- 17.1
      mg/dL). Longitudinal glucose values of 75-g GTT improve during third trimester in
      triplet pregnancies, suggesting that fetoplacental fuel drain may counterbalance
      maternal insulin resistance.

PMID- 15017467
TI  - Gastroesophageal reflux in infants < 32 weeks gestational age at birth: lack of
      relationship to chronic lung disease.
AB  - The objective of this study was to determine the incidence of gastroesophageal
      reflux (GER) as documented by extended esophageal pH monitoring in symptomatic
      premature infants and to identify its relationship with chronic lung disease
      (CLD). This was a retrospective study of 629 infants born < 32 weeks gestational
      age and admitted to the neonatal intensive care unit during the study period.
      Univariate analyses were done on the 137 infants undergoing the test for the
      association of the following risk factors with acid reflux: birth weight,
      gestational age, race, sex, length of stay, bronchopulmonary dysplasia (BPD; O2
      requirement at 28 days), and severe CLD (O2 requirement at 36 weeks postmenstrual
      age). Eighty-seven of 137 infants were positive for GER. There was no association
      of GER with the risk factors studied, nor were there correlations with BPD or
      severe CLD. GER is common (63%) in premature infants < 32 weeks gestational age
      but clinical symptoms and CLD are poorly correlated with this diagnosis.

PMID- 15017468
TI  - The 30-minute decision-to-incision interval for emergency cesarean delivery: fact
      or fiction?
AB  - The objective of this study was to evaluate the effect of the current guideline
      of 30-minute decision-to-incision interval (D-I) in emergent cesarean delivery
      (ECD) on neonatal and maternal outcomes. A retrospective chart review was
      conducted of pregnant women who underwent ECDs between January 1999 and December
      2001. The overall median D-I was 20 minutes (range, 5 to 57 minutes). In 83 women
      (group I), D-I was < or = 30 minutes, and in 28 women (group II), it exceeded 30
      minutes. Group I had more neonates with cord pH < 7.00, seizures, encephalopathy,
      and lower Apgar scores at 1 and 5 minutes than group II, but were not
      statistically significant. There was no significant difference in neonatal
      admission to the neonatal intensive care unit or length of stay between the two
      groups. Maternal complications were higher in group I, but not statistically
      significant. Although it was achieved in most of the ECDs, the guideline of 30
      minute D-I does not seem to improve neonatal nor worsen maternal outcomes.

PMID- 15017469
TI  - A dysmorphic newborn infant with a complex rearrangement involving chromosomes 2,
      4, and 6 detected by fluorescence in situ hybridization (FISH).
AB  - A newborn female infant with multiple congenital anomalies was found to have an
      unusual and abnormal karyotype. Cytogenetic studies revealed an apparent balanced
      translocation between chromosome 4q31.3 and chromosome 6q25.1. Additional
      material on chromosome 2p was identified and determined to be from chromosome 6q
      by analysis with fluorescence in situ hybridization (FISH). The karyotype is
      46,XX,der(2)t(2;6)(p23;q25.1), t(4;6)(q31.3;q25.1). Her mother has a normal
      female karyotype. The father was unavailable for physical examination or
      cytogenetic analysis.

PMID- 15017471
TI  - Sudden unexpected death of a term fetus in an anticardiolipin-positive mother.
AB  - A term male fetus suddenly and unexpectedly died in utero at the 40th week of
      gestation. The mother had a regular and unremarkable pregnancy except for an
      anticardiolipin antibodies positivity. The histological examination of the
      cardiac conduction system showed islands of conduction tissue in the central
      fibrous body, known as persistent fetal dispersion. The brainstem examination
      revealed a severe bilateral hypoplasia of the arcuate nucleus. This morphological
      finding has been described in more than 35% of our stillborn as well as sudden
      infant death syndrome (SIDS) cases, independently from the presence of
      anticardiolipin antibodies. Some authors have given emphasis to the possible
      lethal association of maternal autoantibodies and QT prolongation. Our findings
      emphasize the need of an accurate postmortem examination including the study of
      brainstem and cardiac conduction system in every case of unexpected late
      intrauterine death, following the same standardized autopsy protocol adopted in
      SIDS cases.

PMID- 15017470
TI  - Extended interval dosing of gentamicin in preterm infants.
AB  - Conventional interval dosing (CID) and extended interval dosing (EID) of
      gentamicin were compared in preterm infants. Gentamicin peak and trough levels,
      serum creatinine, urine output, and hearing screens were obtained in 40 preterm
      infants. Results suggest that EID is safe, provides gentamicin levels in
      desirable ranges (peak, 5 to 12 microg/mL; trough < 2 microg/mL), and reduces
      dosage adjustments.

PMID- 15017472
TI  - Esophageal pH study and symptomatology of gastroesophageal reflux in newborn
      infants.
AB  - A retrospective study was undertaken to assess the association between esophageal
      pH monitoring variables and signs such as regurgitation, vomiting, apnea,
      bradycardia, and cyanotic episodes attributable to gastroesophageal reflux (GER)
      in neonates. One hundred thirty-four infants with one or more of the above
      described signs underwent 24-hour distal esophageal pH monitoring in the neonatal
      intensive care unit, and were divided into 2 groups by gestational age. Group 1
      (preterm infant group) consisted of infants aged 25 to 36 weeks of gestation ( n
      = 45) and group 2 (term infant group) consisted of infants aged 37 to 42 weeks
      gestation ( n = 89). Esophageal pH monitoring variables were compared by
      gestational age group and within preterm infants by theophylline treatment and,
      separately, by nasogastric tube using the Mann-Whitney U test. Comparisons of
      nominal data were made using the chi square test. Logistic regression analysis
      was used to assess the net effect of each independent variable on the risk of
      developing GER. The prevalence of GER was not influenced by gestational age. The
      prevalence of gastrointestinal signs did not differ between groups.
      Cardiorespiratory signs attributed to GER were more frequent in preterm infants
      than in term infants. The number of episodes with pH < 4 in 24 hours was greater
      in the term compared with the preterm infant groups. Logistic regression analysis
      failed to detect an association between acid GER and gestational age, apnea,
      bradycardia, cyanotic episodes, vomiting, or regurgitation. Theophylline
      treatment and the presence of a nasogastric tube did not significantly affect the
      esophageal pH monitoring variables in preterm infants. Preterm infants have a
      smaller number of reflux episodes compared with term infants. In addition,
      treatment with theophylline for apnea of prematurity and the presence of a
      nasogastric tube in preterm infants did not significantly affect pH-monitoring
      variables in preterm infants.

PMID- 15017473
TI  - The role of umbilical cord alpha fetoprotein as a screening tool for neonatal
      hyperbilirubinemia.
AB  - Our aim was to test whether alpha fetoprotein (AFP) might serve as a marker of
      hepatic immaturity sufficient to predict an increased risk for neonatal
      hyperbilirubinemia (NHB) in term babies. We checked umbilical cord AFP (UC AFP)
      levels in 174 healthy full-term infants (male/female ratio 1.26:1) at birth.
      Bilirubin levels were measured upon discharge from the nursery on day 3 of life
      (mean, 57 +/- 10 hours of life). Mean UC AFP was 60.2 +/- 45.9 mg/L. UC AFP
      levels were linearly correlated with subsequent bilirubin levels, and
      significantly higher bilirubin levels were found in neonates whose UC AFP levels
      were 100 mg/L or more. Although statistically significant correlation between UC
      AFP and subsequent NHB exists, UC AFP cannot currently be recommended for use in
      clinical practice because of its inability to serve as a screening tool for
      significant NHB in the individual newborn.

PMID- 15017474
TI  - The relationship between paternal age and early mortality of triplets in the
      United States.
AB  - We sought to determine the impact of advanced paternal age on the birth outcomes
      of triplets in a retrospective cohort study on 15,156 triplets born in the United
      States from 1995 to 1997. The study group comprised fathers aged > or = 40 years.
      Two control groups consisting of mature (30 to 39 years) and younger (20 to 29
      years) fathers were constructed for comparison of main end points. We applied the
      generalized estimating equation framework to obtain relative risk estimates after
      capturing the effect of sibling correlations within triplet clusters. Stillbirths
      were 35% and 26% higher among triplets of mature and older men, respectively,
      whereas neonatal mortality was 28% and 23% lower among infants of mature and
      older fathers, respectively, using younger fathers as the referent category.
      Although only the relative risk for neonatal mortality comparing triplets of
      mature and younger fathers was statistically significant, these results
      constitute high indices that represent an important burden of excess early
      mortality at the population level. Our findings demonstrate a "shifting
      phenomenon" whereby a higher level of intrauterine demise was compensated by a
      higher rate of extrauterine survival among triplets born to older fathers.

PMID- 15017475
TI  - The effect of antenatal corticosteroids on fetal growth, survival, and
      neurodevelopmental outcome in triplet pregnancies.
AB  - Triplet pregnancies have increased as a result of infertility therapy. The
      objectives of this study are to review the outcome of triplet pregnancies and to
      determine the effect of different antenatal corticosteroid treatments on fetal
      growth, survival, and neurodevelopmental outcome. A retrospective case note
      review of infant and maternal records from a single tertiary neonatal unit was
      performed from January 1, 1986, through December 31, 1999; 173 live births from
      60 triplet pregnancies were divided into groups according to maternal antenatal
      corticosteroid exposure. Logistic regression model showed only gestation had a
      significant effect on survival. There was no adverse effect of steroid exposure
      on weight or head circumference at birth. Ninety percent of live births survived
      to discharge. Of 143 survivors, only five infants had documented
      neurodevelopmental problems. Survival rate in triplet pregnancy is high. In this
      analysis of cohort data repetitive antenatal steroids were not associated with
      adverse outcome.

PMID- 15017476
TI  - The morbidity of the 34- to 35-week gestation: should we reexamine the paradigm?
AB  - Algorithms for the management of preterm labor avoid the use of tocolysis beyond
      34 weeks' gestation, based in large part on low respiratory morbidity found at
      this gestational age. We sought to delineate the morbidities, not just
      respiratory, of this age group in a modern neonatal intensive care unit setting.
      We prospectively looked at hospital resource use and general morbidity in a
      consecutive 2-year cohort of 34-weekers at our hospital. The concurrent
      consecutive 35-week cohort was used as a control. Data were prospectively
      collected from obstetricians and bedside records. Compared with 35-weekers, the
      34-week group had similar obstetric characteristics. Significant differences were
      seen in use of oxygen, nasal continuous positive airway pressure,
      methylxanthines, home apnea monitoring, antibiotics, and phototherapy. The 34
      week group took longer to come off intravenous lines and were discharged later.
      Overall, they used approximately twice the resources of the 35-week group. To
      stop or not use tocolysis at 34 weeks' gestation based mainly on low respiratory
      morbidity ignores the significant other morbidities. These findings suggest a
      reconsideration of the paradigm regarding 34-week gestation as a cutoff point in
      decision making.

PMID- 15017477
TI  - Contralateral cerebral infarction following vacuum extraction.
AB  - Cerebral infarction is a rare complication following a vacuum-assisted delivery
      occurring on the side of the vacuum application and often accompanied by a
      cephalhematoma. We report a case of cerebral infarction that was contralateral to
      the side of the vacuum application in a term baby. The baby presented with
      seizures in the immediate neonatal period. There was no fracture of the skull to
      account for a contusion injury. We discuss the mechanisms of intracranial
      vascular injuries during the process of natural and assisted birth.

PMID- 15017478
TI  - High-frequency ventilation in the management of very-low-birth-weight infants
      with pulmonary hemorrhage.
AB  - Severe hypoxic respiratory failure secondary to massive pulmonary hemorrhage
      (MPH) in preterm infants could be fatal. The aim of this study was to assess the
      efficacy of high-frequency ventilation (HFV) as a rescue therapy for respiratory
      failure secondary to MPH in very-low-birth-weight (VLBW) infants. Prospectively
      we followed up all VLBW infants with pulmonary hemorrhage between January 1993
      and December 1996 in our neonatal intensive care unit at King Khalid University
      Hospital. Seventeen VLBW infants with severe hypoxic respiratory failure
      secondary to MPH were treated with HFV. Ten (59%) infants responded to HFV and
      survived, while the other 7 (41%) did not respond and expired. Patent ductus
      arteriosus was considered the most common associated condition in 10 infants
      (59%). There were no statistically significant differences between the responders
      and the nonresponders in regard to gestational age, birth weight, sex ratio, %
      inborn, and primary diagnosis. However, preintervention peak inspiratory pressure
      (pip), arterial-alveolar ratio (a/A ratio) and oxygenation index (OI) were higher
      in the nonresponders ( p = 0.02, p = 0.03, and p = 0.003, respectively), while
      pip, F IO(2), pa CO(2), a/A ratio and OI were significantly lower than the
      nonresponders 3 hours postintervention ( p = 0.008, p = 0.006, p = 0.0002, p =
      0.0005, and p = 0.0007, respectively). In conclusion, HFV might be an effective
      and lifesaving mode of treatment in VLBW infants with respiratory failure
      secondary to MPH; therefore, prospective randomized controlled trials are needed
      to confirm these findings.

PMID- 15017479
TI  - Maternal stressors during prolonged antepartum hospitalization following transfer
      for maternal-fetal indications.
AB  - Our objective was to identify stressors in women requiring prolonged
      hospitalization following maternal-fetal transfer to a tertiary care center.
      Using a modified version of the previously validated Antepartum Hospital
      Stressors Inventory (AHSI), all women transferred to our university-based
      maternal-fetal service between May 2000 and June 2002 and hospitalized for
      greater than 1 month completed a semi-structured interview. The AHSI uses Likert
      scales to evaluate environment, health factors, communication with health care
      providers, family separation, self-image, and emotional and family status issues
      as stressors. Nine consecutive women met inclusion criteria and all agreed to
      participate. Median maternal age was 27 years (range 19 to 33), and gestational
      age at transfer was 25 weeks (range 20 to 31). Parity ranged from 0 to 3 and
      educational level ranged from grade 2 to graduate degrees. The women were from
      Caucasian, Hispanic, and Asian racial-ethnic backgrounds; all were married.
      Median distance from transferring hospital was 20 miles (range 10 to 275 miles).
      All patients reported separation from family, sleeping alone, anxiety about the
      pregnancy and the baby's health, boredom, and eating hospital meals as the
      greatest stressors. Stress was relieved in all women by ultrasounds, family
      members staying in the room, cable television, and internet access. Routine
      beauty maintenance, massage, physical therapy, and continued contact with
      referring physician were also cited as stress alleviators. Following maternal
      fetal transfer, prolonged antepartum hospitalization is associated with stress
      that may be alleviated by access to the outside world via television and the
      internet, liberal visitation, access to health and beauty maintenance, and
      ongoing contact with the referring physician.

PMID- 15017480
TI  - Are maternal serum troponin I levels affected by vaginal or cesarean delivery?
AB  - Our objective was to describe the change in the level of troponin I in patients
      who undergo a vaginal or cesarean delivery. We obtained troponin I levels on
      admission and 1 hour after delivery in women undergoing vaginal and cesarean
      deliveries. Exclusion criteria included <37 weeks' gestation, a history of
      cardiac disease, hypertension, or cardiac symptoms. The troponin I level used to
      indicate myocardial ischemia was 2.0 ng/mL; levels were analyzed using the
      Wilcoxon test. The median age of women in the vaginal versus the cesarean group
      were 25.6 years and 34.4 years, and the median gestational age for both groups
      was 39.6 weeks. The median troponin I level before and after vaginal delivery was
      <0.3 ng/mL and before and after cesarean was <0.3 ng/mL. The highest level of
      troponin I in either group was 0.3 ng/mL. Troponin I is not elevated as a result
      of undergoing a vaginal or cesarean delivery. We conclude that troponin I may be
      used as a reliable marker to diagnose myocardial ischemia in postpartum women.

PMID- 15017481
TI  - Cord blood lipids concentrations and their relation to body size at birth:
      possible link between intrauterine life and adult diseases.
AB  - Umbilical plasma levels of lipoproteins-cholesterol were measured in 480 normal
      newborns delivered by spontaneous vaginal delivery at 39 to 40 weeks of
      gestation. Plasma concentrations of lipids were related to fetal weight,
      abdominal and head circumference, and ponderal index at birth. Plasma
      concentration of low-density lipoprotein cholesterol (LDL-C) correlated
      negatively with abdominal circumference (AC), birth weight, and head
      circumference of newborns (p < 0.021, p < 0.023, p < 0.044, respectively). The
      baby with the smallest AC had the highest plasma concentration of LDL-C (p <
      0.015). In the 165 neonates with ponderal index < 10th percentile, LDL-C was
      substantially elevated (p < 0.018). These findings suggest that disproportionate
      size at birth is associated with altered lipid metabolism. These abnormalities,
      if they persist, might lead to metabolic diseases in adulthood.

PMID- 15017483
TI  - A grid to assess the nutritional status of low-birth-weight infants in the
      neonatal period.
AB  - Growth curves of low-birth-weight infants updated over the past 50 years accept
      many exclusions and do not provide a standard way to assess the nutritional
      status of these infants regardless of their diseases in the neonatal period. A
      new way for assessment is proposed. It is based on the excess time expressed in
      percent beyond the allocated time for an infant to gain his birth weight and the
      excess drop in weight expressed in percent beyond the allowed drop of weight.
      This method delineates one zone of adequate nutrition and three zones of
      malnutrition: mild, moderate, and severe.

PMID- 15017482
TI  - Congenital contractural arachnodactyly and femoral fracture in a newborn infant:
      a causal relationship or a coincidence?
AB  - Congenital contractural arachnodactyly (CCA, Beals syndrome) is an autosomal
      dominant connective tissue disorder characterized by multiple flexion
      contractures, arachnodactyly, severe kyphoscoliosis, abnormal pinnae, and
      muscular hypoplasia. Although it is a connective tissue disorder affecting bone
      structure and formation, coexistence of bony fractures in CCA patients have not
      been reported before. In this article we report a newborn infant diagnosed with
      CCA who developed a femoral fracture possibly due to abnormal bone structure and
      birth injury in spite of cesarean delivery.

PMID- 15017484
TI  - The challenges of academic physician-scientists in gastroenterology and
      hepatology: from managing indebtedness, securing grants, to managing conflicts.

PMID- 15017485
TI  - SSRIs in IBS: sensing a dash of disappointment.

PMID- 15017486
TI  - Ulcerative ileitis encountered at ileo-colonoscopy: likely role of nonsteroidal
      agents.
AB  - BACKGROUND & AIMS: Ileoscopy is increasingly practiced, but it is unclear what
      diagnostic and management decisions should ensue if ulcerations are encountered.
      METHODS: The lead author identified 40 patients with ulcerative ileitis during
      1900 consecutive ileoscopies in a community practice. We analyzed the clinical,
      endoscopic, and histopathologic findings in these patients and related them to
      drug usage. RESULTS: Although most patients were asymptomatic, ileitis likely
      contributed to blood loss in 14 and to right lower quadrant pain in one.
      Endoscopy revealed multiple, discrete, fibrin-covered ulcerations in the
      prevalvular segment with patches of erythematous stippling, normal intervening
      mucosa, and occasional mucosal scars or webs. Histologic findings included focal
      superficial neutrophilic infiltrates, edema, mucosal hemorrhage, lymphatic
      dilatation, fibromuscular hyperplasia, prominence of the muscularis mucosae, and
      antral and Paneth cell metaplasia. Granulomas, fissure ulcers, and apoptosis were
      notably absent. No specific disease process developed in a median follow-up of
      3.2 years. Thirty-three patients admitted recently taking nonsteroidal anti
      inflammatory drugs (NSAIDs), notably: enteric-coated aspirin at 325 mg/day or
      less (19), selective cyclooxygenase-2 inhibitors (5), and nonacetylated
      salicylates (3). Three fourths of nonsteroidal users were taking agents with low
      or intermediate gastroduodenal toxicity. Lesions disappeared after drug
      withdrawal, and reappeared on resumption. CONCLUSIONS: Ileoscopy during
      colonoscopy may identify an ulcerative ileitis. This lesion likely contributes to
      gastrointestinal blood loss and other clinical manifestations, and likely is
      caused by NSAID use, including those usually associated with low toxicity or at
      low doses. Features of NSAID-ileitis overlap with Crohn's ileitis, but
      differentiation of the 2 entities is critical for appropriate management.

PMID- 15017487
TI  - A pilot feasibility study of once daily versus conventional dosing mesalamine for
      maintenance of ulcerative colitis.
AB  - BACKGROUND & AIMS: This study was conducted to assess, in a small sample, the
      short-term outcomes of once-daily mesalamine versus conventional dosing in
      maintaining quiescent ulcerative colitis (UC) and to assess adherence rates with
      both regimens. METHODS: Consecutive patients were randomly assigned to either a
      once-daily regimen, or they continued current conventional regimen (twice daily
      or 3 times daily). Patients were assessed at 3 months and 6 months. At each
      point, a clinical symptom disease score was obtained using patient
      questionnaires, and medication rates via pharmacy data. Adherence was defined as
      consumption of >80% of prescribed medication. Information was collected by an
      investigator blinded to treatment regimen. RESULTS: Twenty-two patients were
      enrolled in the study, 12 in the once-daily group (QD) and 10 in the conventional
      group (CD). At 3 months, no patients had experienced a relapse. All of the
      patients in the QD group and 70% of patients in the CD group were adherent (P =
      0.04). The average amount of medication consumed in the QD group was
      significantly higher than in the CD group (90% vs. 75%, P = 0.02). At 6 months, 2
      patients (1 patient from each group) experienced a clinical relapse (P = 0.76).
      Seventy-five percent vs. 70% of patients were adherent (P = 0.8); the amount of
      medication taken approached significance (90% vs. 76%, P = 0.07). All patients in
      the QD group reported being either "very satisfied" or "satisfied" with their
      regimen. CONCLUSIONS: In this randomized pilot trial, patients taking once-daily
      mesalamine had outcomes similar to those for patients on conventional regimens. A
      larger trial is warranted to assess whether true differences between regimens
      exist.

PMID- 15017488
TI  - Esophageal function testing with combined multichannel intraluminal impedance and
      manometry: multicenter study in healthy volunteers.
AB  - BACKGROUND & AIMS: Combined multichannel intraluminal impedance and manometry
      (MII-EM) assesses esophageal function by simultaneous measurement of both
      pressure and bolus transit. Normative data for this method have not been
      published. The aim of this study was to establish normative data for combined MII
      EM and to correlate liquid and viscous bolus transit by impedance with esophageal
      contractions by manometry. METHODS: Forty-three normal volunteers recruited from
      4 centers (15 women, 28 men; age range, 21-72 years) underwent combined MII-EM
      with a catheter containing 4 impedance-measuring segments and 4 solid-state
      pressure transducers. Each center recruited and analyzed subjects independently,
      according to pre-established criteria. Each subject received 20 x 5 mL swallows,
      10 liquid and 10 viscous material. Tracings were analyzed manually for bolus
      presence time, bolus head advance time, segmental transit times, total bolus
      transit time, contraction amplitude, duration, and onset velocity. RESULTS:
      Ninety-seven and four-tenths percent of manometrically normal liquid and 96.1% of
      manometrically normal viscous swallows had complete bolus transit by impedance.
      Almost half (47.2%) of manometrically ineffective liquid and 34.7% of ineffective
      viscous swallows had complete bolus transit, whereas 91.7% of manometric
      simultaneous liquid swallows and 54.5% of simultaneous viscous swallows had
      complete bolus transit. More than 93% of normal individuals had at least 80%
      complete liquid or at least 70% complete viscous bolus transit. CONCLUSIONS: This
      study establishes normative data for combined MII-EM. Combined MII-EM may be a
      more sensitive tool in assessing esophageal function compared to standard
      manometry because impedance can distinguish different bolus transit patterns.
      Studies in patients with manometrically defined esophageal motility abnormalities
      should help clarify the functional importance of manometric ineffective and
      simultaneous swallows.

PMID- 15017489
TI  - Endoscopic management of postoperative biliary complications in donors for living
      donor liver transplantation.
AB  - BACKGROUND & AIMS: Biliary leakage and stricture are serious complications that
      occur in donors whose liver is resected for living donor transplantation. We
      assessed the usefulness of endoscopic nasobiliary drainage and endoscopic biliary
      stenting, respectively, in repairing biliary leakage and stricture. METHODS:
      Between July 1999 and December 2001, a total of 276 donors underwent liver
      resection (left side, 118; right side, 158) for living donor transplantation at
      Kyoto University Hospital. Seven (2.5%) donors developed biliary leakage, which
      required endoscopic nasobiliary drainage; 3 of these donors also had biliary
      stricture. RESULTS: All 7 patients who developed biliary leakage were the right
      lobe donors. Endoscopic retrograde cholangiography identified the site of the
      biliary leakage in all 7 of the donors. In 6 of these donors, the biliary leakage
      resolved within an average of 15 days after an endoscopic nasobiliary drainage
      tube was placed. In the seventh donor, the biliary leakage resolved after
      percutaneous transhepatic biliary drainage was performed. Three patients
      developed biliary stricture that required endoscopic biliary stenting. The angles
      between common hepatic duct and the left hepatic duct were more acute in patients
      with stricture than in those without stricture (62 degrees vs. 119 degrees).
      CONCLUSIONS: Biliary complications requiring endoscopic treatment developed
      exclusively in donors for right-lobe living donor transplantation. Endoscopic
      retrograde cholangiography is a favorable modality for diagnosing and treating
      postoperative biliary complications in donors for living donor liver
      transplantation.

PMID- 15017490
TI  - An endoscopic pancreatic function test with cholecystokinin-octapeptide for the
      diagnosis of chronic pancreatitis.
AB  - BACKGROUND & AIMS: Current pancreatic function tests are cumbersome and
      unavailable to the clinical gastroenterologist. We have developed a function test
      that can be modified to a purely endoscopic collection method (ePFT). The aim of
      this study was to compare the endoscopic and traditional Dreiling tube collection
      methods. METHODS: Two separate groups of healthy subjects and patients with
      chronic pancreatitis underwent pancreatic function testing. One group underwent
      the endoscopic collection method (ePFT). Intravenous cholecystokinin (CCK 40 ng x
      kg(-1) x h(-1)) was started in preprocedure area. Duodenal fluid was collected
      with upper endoscope during endoscopy at 30, 40, 50, and 60 minutes during
      infusion. Another group underwent the traditional Dreiling collection method.
      Intravenous CCK was started in postprocedure area after endoscopic tube
      placement. Duodenal fluid was collected at 0, 20, 40, 60, and 80 minutes during
      infusion. Lipase concentration was determined (IU/L) on laboratory autoanalyzer.
      RESULTS: Seventy-three patients were studied. Thirty-four underwent endoscopic
      collection and 39 underwent Dreiling collection. The mean peak lipase
      concentrations (+/- standard deviation) for healthy subjects and patients with
      chronic pancreatitis in the endoscopic collection method group were 1612500 +/-
      556152 IU/L and 369594 +/- 281624 IU/L, respectively (P < 0.001). The mean peak
      lipase concentrations (+/- standard deviation) for healthy subjects and patients
      with chronic pancreatitis in the Dreiling tube collection method group were
      1670324 +/- 786731 IU/L and 478956 +/- 406061 IU/L, respectively (P < 0.001).
      There was no statistical difference between collection methods at distinguishing
      healthy subjects and patients with chronic pancreatitis. Receiver operating
      characteristic curves (ROC) for the endoscopic and Dreiling collection methods
      were 0.993 (standard error of mean, 0.009) and 0.921 (standard error of mean,
      0.041). A lipase concentration cut point of 810600 IU/L distinguishes healthy
      subjects from patients with chronic pancreatitis with a sensitivity and
      specificity of 92% and 95%, respectively. The ePFT was safe, short in duration,
      minimized costs (US dollars 1890 vs. US dollars 2659), required small amounts of
      fluid for analysis (1-3 mL), and eliminated radiation exposure. CONCLUSIONS:
      Analysis of timed endoscopic aspirations of pancreatic juice after hormonal
      stimulation can distinguish healthy subjects from patients with chronic
      pancreatitis. This new endoscopic collection method (ePFT) is less cumbersome and
      more time efficient, when compared to traditional collection methods. The ePFT
      broadens the availability of function testing to the practicing clinical
      gastroenterologist.

PMID- 15017492
TI  - Cigarette smoking and colorectal cancer: long-term, subsite-specific risks in a
      cohort study of postmenopausal women.
AB  - BACKGROUND & AIMS: Cigarette smoking is a putative risk factor for colorectal
      cancer (CRC). However, long-term CRC risk estimates among female smokers remain
      limited and inconsistent. The goal of this prospective study was to assess
      cigarette smoking and CRC risk, overall and by anatomic subsite, among
      postmenopausal women. METHODS: Data were drawn from a large population-based
      cohort (n = 41836) of randomly selected women, age 55-69 years at baseline (Iowa
      Women's Health Study). Cigarette smoking and other CRC risk factors were
      characterized at baseline (1986). Incident (n = 869) and fatal (n = 249) CRC
      cases were identified through December 31, 1999. CRC risks were estimated using
      Cox proportional hazards regression models. RESULTS: Compared with never smokers,
      ever smokers had slightly increased risks for both incident (relative risk [RR],
      1.17; 95% confidence interval [CI], 1.00-1.36) and fatal (RR, 1.31; 95% CI, 0.98
      1.74) CRC in multivariate analyses. Incident CRC risks increased progressively by
      lengthening induction period (P trend=0.01), reaching a 30% increase (RR, 1.30;
      95% CI, 1.04-1.63) after age 45 years. By anatomic subsite, ever smoked
      cigarettes and induction period were more strongly associated with incident
      proximal CRC (P = 0.03 and P trend = 0.03, respectively) than incident distal CRC
      (P=0.44 and P trend=0.10, respectively). CONCLUSIONS: In this long-term cohort
      study of postmenopausal women, cigarette smoking was positively associated with
      CRC risk. Onset of smoking in the distant past appeared to confer the greatest
      risk, especially for incident proximal CRC. These data support a potential
      subsite-specific role for cigarette smoking in colorectal carcinogenesis, at
      least among women. Based on emerging data, an epigenetic pathway for smoking
      induced CRC is proposed.

PMID- 15017491
TI  - Predictive value of diminutive colonic adenoma trial: the PREDICT trial.
AB  - BACKGROUND & AIMS: Diminutive adenomas (1-9 mm in diameter) are frequently found
      during colon cancer screening with flexible sigmoidoscopy (FS). This trial
      assessed the predictive value of these diminutive adenomas for advanced adenomas
      in the proximal colon. METHODS: In a multicenter, prospective cohort trial, we
      matched 200 patients with normal FS and 200 patients with diminutive adenomas on
      FS for age and gender. All patients underwent colonoscopy. The presence of
      advanced adenomas (adenoma >or= 10 mm in diameter, villous adenoma, adenoma with
      high grade dysplasia, and colon cancer) and adenomas (any size) was recorded.
      Before colonoscopy, patients completed questionnaires about risk factors for
      adenomas. RESULTS: The prevalence of advanced adenomas in the proximal colon was
      similar in patients with diminutive adenomas and patients with normal FS (6% vs.
      5.5%, respectively) (relative risk, 1.1; 95% confidence interval [CI], 0.5-2.6).
      Diminutive adenomas on FS did not accurately predict advanced adenomas in the
      proximal colon: sensitivity, 52% (95% CI, 32%-72%); specificity, 50% (95% CI, 49%
      51%); positive predictive value, 6% (95% CI, 4%-8%); and negative predictive
      value, 95% (95% CI, 92%-97%). Male gender (odds ratio, 1.63; 95% CI, 1.01-2.61)
      was associated with an increased risk of proximal colon adenomas. CONCLUSIONS:
      Diminutive adenomas on sigmoidoscopy may not accurately predict advanced adenomas
      in the proximal colon.

PMID- 15017494
TI  - The selective serotonin reuptake inhibitor fluoxetine does not change rectal
      sensitivity and symptoms in patients with irritable bowel syndrome: a double
      blind, randomized, placebo-controlled study.
AB  - BACKGROUND & AIMS: Although widely prescribed, the evidence for the use of
      antidepressants for the treatment of irritable bowel syndrome (IBS) is limited.
      In this study, we hypothesized that fluoxetine (Prozac), a selective serotonin
      reuptake inhibitor, has visceral analgesic properties, leading to increased
      sensory thresholds during rectal distention and improvement of symptoms, in
      particular in IBS patients with visceral hypersensitivity. METHODS: Forty non
      depressed IBS patients underwent a rectal barostat study to assess the
      sensitivity to rectal distention before and after 6 weeks of treatment with
      fluoxetine 20 mg or placebo. Abdominal pain scores, individual gastrointestinal
      symptoms, global symptom relief, and psychologic symptoms were assessed before
      and after the intervention. RESULTS: At baseline, 21 of 40 patients showed
      hypersensitivity to rectal distention. Fluoxetine did not significantly alter the
      threshold for discomfort/pain relative to placebo, either in hypersensitive (19
      +/- 3 vs. 22 +/- 2 mm Hg above MDP) or in normosensitive (34 +/- 2 vs. 39 +/- 4
      mm Hg above MDP) IBS patients. Overall, 53% of fluoxetine-treated patients and
      76% of placebo-treated patients reported significant abdominal pain scores after
      6 weeks (not significant). In contrast, in hypersensitive patients only,
      fluoxetine significantly reduced the number of patients reporting significant
      abdominal pain. Gastrointestinal symptoms, global symptom relief, and psychologic
      symptoms were not altered. CONCLUSIONS: Fluoxetine does not change rectal
      sensitivity in IBS patients. Possible beneficial effects on pain perception need
      to be confirmed in larger trials.

PMID- 15017495
TI  - An evidence-based approach to studies of the natural history of gastrointestinal
      diseases: recurrence of symptomatic Crohn's disease after surgery.

PMID- 15017493
TI  - Effects of venlafaxine, buspirone, and placebo on colonic sensorimotor functions
      in healthy humans.
AB  - BACKGROUND & AIMS: We have shown that venlafaxine-XR, a serotonin (5-HT) and
      norepinephrine reuptake inhibitor, enhanced gastric accommodation, whereas
      buspirone, a 5-HT(1A) receptor agonist, reduced postprandial symptoms after a
      fully satiating meal. Our aim was to compare the effects of venlafaxine,
      buspirone, and placebo on colonic sensorimotor functions in healthy adults.
      METHODS: In this randomized, double-blind, parallel-group, placebo-controlled
      trial of 60 healthy adults, we assessed the effects of oral venlafaxine, 150 mg;
      buspirone, 20 mg; and placebo on colonic sensorimotor functions. RESULTS:
      Venlafaxine increased colonic compliance relative to placebo; thus it decreased
      the intracolonic balloon pressure at half-maximum volume (P = 0.001) and altered
      the overall shape of the compliance curve, beta (P = 0.01). Venlafaxine also
      decreased fasting colonic tone (P = 0.02) and the tonic response to a meal (P =
      0.003) compared with placebo; no differences in high amplitude phasic contractile
      events were observed. Pressure thresholds for first sensation (P = 0.1) and gas
      (P = 0.07) were not statistically significant with venlafaxine. The increase in
      pain scores per unit pressure during phasic distentions were affected by
      treatment (P = 0.02), with smallest changes on venlafaxine and highest on
      placebo. Buspirone did not significantly alter colonic compliance, tone, or
      sensation relative to placebo. CONCLUSIONS: Venlafaxine alters colonic compliance
      and tone, and tends to reduce sensation during colonic distention in healthy
      humans. These data support the need for further clinical and physiologic studies
      of venlafaxine in colonic disorders affecting motor and possibly sensory
      functions.

PMID- 15017496
TI  - Update on codes and reimbursements for GI practice.

PMID- 15017497
TI  - Does family history still matter in the era of screening colonoscopy?

PMID- 15017498
TI  - Postoperative ileus: etiologies and interventions.
AB  - This article will review the pathophysiology of postoperative ileus, with
      emphasis on potential therapeutic targets, and examine the efficacy of
      pharmacologic and nonpharmacologic interventions. Proposed mechanisms include
      actuation of spinal and local sympathetic neural reflexes, inflammatory
      mediation, and exacerbation by anesthetic or surgical procedures. Some procedures
      or agents have shown clinical benefit, and these include use of laparoscopic
      surgery, thoracic epidurals, nonsteroidal anti-inflammatory drugs, and opiate
      antagonists. Other procedures may be helpful with low risk of adverse effects.
      These include early feeding and ambulation, laxatives, and possibly neostigmine.

PMID- 15017499
TI  - Medical or invasive therapy for GERD: an acidulous analysis.
AB  - This review critically appraises the evidence on the benefits and costs of the
      available treatments for gastroesophageal reflux disease (GERD) and concludes
      that antireflux surgery has no clear advantages over medical therapy for efficacy
      of healing, prevention of complications, safety, side effects, and cost. Indeed,
      medical therapy is safer and, probably, more cost-effective. Compared with
      medically treated patients, those who have successful fundoplication may be less
      inconvenienced by GERD because they are less likely to need to take pills on a
      daily basis. The patient and physician must judge whether that benefit justifies
      the risks of surgery for a benign condition. There is not yet sufficient data
      available on the endoscopic antireflux procedures to make meaningful conclusions
      regarding their safety and efficacy.

PMID- 15017500
TI  - When is liver biopsy needed in the diagnosis of primary biliary cirrhosis?
AB  - BACKGROUND & AIMS: Liver biopsy has been largely replaced by less invasive
      measurements applied to mathematical models in defining the prognosis of patients
      with primary biliary cirrhosis (PBC). The need for liver biopsy in the diagnosis
      of patients with positive antimitochondrial antibodies (AMAs) in the setting of
      biochemical cholestasis remains uncertain. This study was undertaken to determine
      which variables indicate the need for liver biopsy in patients with positive AMA
      and suspected PBC. METHODS: A total of 3198 patients that were tested for AMA in
      1999 and 2000 were identified. Of these, 198 (6.2%) were AMA positive. Forty-two
      patients were excluded because of unavailable laboratory data or liver biopsy
      specimens. Data on the remaining 156 patients were analyzed to determine which
      variables among patients with positive AMA with and without a histopathologic
      diagnosis of PBC indicate the need for liver biopsy. RESULTS: In 131 of 156
      (84.6%) patients, a diagnosis of PBC was established by liver biopsy. The
      histological diagnosis of PBC was associated with a cholestatic biochemical
      profile (alkaline phosphatase [AP] >1.5 times the upper limits of normal [ULN]
      and aspartate aminotransferase [AST] <5 times ULN) in 112 of 131 (85.5%)
      patients. The combination of AP >1.5 times the ULN and AST <5 times the ULN
      yielded a 98.2% positive predictive value of PBC diagnosis on liver biopsy in AMA
      positive subjects. These results were corroborated by cross-validation in an
      independent set of patients. CONCLUSIONS: In patients with positive AMA, a
      cholestatic biochemical profile (AP >1.5 times the ULN), and absence of markedly
      elevated AST (<5 times the ULN), liver biopsy is rarely required to establish the
      diagnosis of PBC. Liver biopsy would be beneficial to establish the diagnosis of
      PBC in only a minority of AMA-positive patients with AP <1.5 times the ULN or AST
      >5 times the ULN.

PMID- 15017501
TI  - First-degree relatives of patients with advanced colorectal adenomas have an
      increased prevalence of colorectal cancer.
AB  - BACKGROUND & AIMS: The risk of colorectal cancer in relatives of patients with
      adenomatous colonic polyps is not well defined. This study assessed whether
      finding colonic neoplasia during screening colonoscopy was related to the family
      history of colorectal cancer among the participants' parents and siblings.
      METHODS: Self-reported family history of colorectal cancer was recorded for all
      participants in a screening colonoscopy study. The size and location of all
      polyps were recorded before their removal and histologic examination.
      Participants were grouped according to the most advanced lesion detected.
      RESULTS: Three thousand one hundred twenty-one patients underwent complete
      colonoscopic examination. Subjects with adenomas were more likely to have a
      family history of colorectal cancer than were subjects without polyps (odds ratio
      [OR], 1.36; 95% confidence interval [CI], 1.09-1.70). The finding of a small (<1
      cm) tubular adenoma as the most advanced lesion was associated with only a modest
      increase in the OR of colorectal cancer in family members (OR, 1.26; 95% CI, 0.99
      1.61), but the presence of an advanced adenoma was associated with a higher OR
      (OR, 1.62;5% CI, 1.16-2.26). Younger age of adenoma diagnosis was not related to
      a higher prevalence of a family history of colorectal cancer. CONCLUSIONS:
      Relatives patients with advanced colorectal adenomas have an increased risk of
      colorectal cancer. Individuals with advanced colorectal adenomas should be
      counseled about the increased risk of colorectal cancer among their relatives.

PMID- 15017502
TI  - Predictors of advanced proximal neoplasia in persons with abnormal screening
      flexible sigmoidoscopy.
AB  - BACKGROUND & AIMS: The relationship between distal and proximal colonic findings
      is uncertain. Thus, there is no consensus on which findings on screening flexible
      sigmoidoscopy should trigger colonoscopy. METHODS: We analyzed data from the
      Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial to assess the
      relationship between distal and proximal colonic findings. RESULTS: A total of
      8802 subjects had an abnormal baseline sigmoidoscopy and colonoscopy follow-up.
      Subjects with <10-mm single or multiple tubular adenomas had similar risks for
      advanced proximal neoplasia as subjects with hyperplastic polyps or other benign
      lesions (3%-5%). Subjects with large (>or=10 mm), villous, or severely dysplastic
      distal adenomas had similarly elevated risks for advanced proximal neoplasia (11%
      12%). Multivariate logistic modeling showed a significantly increased risk for
      advanced proximal neoplasia associated with the presence of a large tubular (odds
      ratio [OR], 2.6; 95% confidence interval [CI], 2.0-3.4) or villous distal adenoma
      (OR, 2.7; 95% CI, 2.1-3.5) but not with the presence of one (OR, 1.05; 95% CI,
      0.8-1.3) or multiple (OR, 0.8; 95% CI, 0.5-1.2) <10-mm tubular distal adenomas.
      CONCLUSIONS: Among subjects with a polypoid lesion on screening flexible
      sigmoidoscopy, those with small tubular distal adenomas are at similar risk for
      advanced proximal neoplasia as those without distal adenomas. Subjects with a
      large, villous, or dysplastic distal adenoma are at increased risk. A strategy
      that encourages individuals with small tubular adenomas on sigmoidoscopy to
      undergo follow-up colonoscopy and excludes those with nonadenomatous lesions is
      of questionable validity, because both groups are at similar risk for advanced
      proximal neoplasia.

PMID- 15017503
TI  - A randomized, controlled exploratory study of clonidine in diarrhea-predominant
      irritable bowel syndrome.
AB  - BACKGROUND & AIMS: The aim of this study was to evaluate the efficacy and
      tolerability of the alpha-2 adrenoreceptor agonist, clonidine, in patients with
      diarrhea-predominant irritable bowel syndrome (D-IBS) in a double-blind,
      randomized, parallel-group, placebo-controlled trial. METHODS: A 2-week run-in
      evaluated baseline symptoms. Patients received 0.05, 0.1, or 0.2 mg clonidine or
      placebo twice a day for 4 weeks. We evaluated satisfactory relief of IBS by
      weekly question and stool parameters with a daily diary. Satisfactory relief and
      overall bowel function were primary end points. Secondary end points were stool
      frequency, consistency, and ease of passage; gut transit; and fasting and
      postprandial gastric volumes. Analysis followed intention-to-treat principles.
      RESULTS: Forty-four D-IBS patients participated; there were 4 treatment-related
      dropouts: 2/2 in the 0.2-mg and 2/12 in the 0.05-mg clonidine groups. Proportion
      with satisfactory relief of IBS was 0.46, 0.42, and 0.67 with placebo, 0.05 mg,
      and 0.1 mg clonidine, respectively. Relief was sustained through 4 weeks of
      treatment, and bowel dysfunction (firmer stools and easier stool passage [P <
      0.05]) was reduced with clonidine, 0.1 mg twice a day. Clonidine did not
      significantly alter gastrointestinal transit or gastric volumes. Drowsiness,
      dizziness, and dry mouth were the most common adverse events with the 0.1-mg
      dose; severity of adverse effects subsided after the first week of treatment. A
      trial to replicate 20% or more responders with clonidine will require 95 patients
      per treatment arm. CONCLUSIONS: Clonidine, 0.1 mg twice a day for 4 weeks,
      relieves bowel dysfunction and appears promising for relief of D-IBS; these
      effects are unassociated with significant alterations in transit.

PMID- 15017505
TI  - Idiopathic tumefactive chronic pancreatitis: clinical profile, histology, and
      natural history after resection.
AB  - BACKGROUND & AIMS: Little is known about subjects with idiopathic tumefactive
      chronic pancreatitis (TCP), that is, chronic pancreatitis whose clinical
      presentation, usually with a mass or obstructive jaundice, suggests cancer.
      METHODS: We independently reviewed clinical data and histology of 45 TCP (27
      idiopathic, 18 alcohol induced) resected at Mayo Clinic (January 1985-March
      2001). Follow-up data were obtained from medical records and mailed
      questionnaires. RESULTS: Compared with alcoholic subjects, idiopathic TCP
      patients were older (58 +/- 2 vs. 48 +/- 3 yr, P < 0.001), had shorter symptom
      duration (median 3 vs. 24 wk, P < 0.001), were more likely to have no or mild
      abdominal pain (70% vs. 17%, P = 0.001), and were more often jaundiced (67% vs.
      33%, P = 0.02). Three distinct histologic patterns were identified in TCP.
      Typical CP (n = 19) showed lobular atrophy, fat necrosis, and ductal changes
      (dilatation, protein plugs, and stones). Lymphoplasmacytic sclerosing
      pancreatitis (LPSP) (n = 14) was characterized by periductal lymphoplasmacytic
      infiltration, obliterative phlebitis, and cholangitis with edema. Idiopathic duct
      centric CP (IDCP) (n = 12) had neutrophil-predominant lobular inflammation,
      without phlebitis. On correlation of clinical and histologic diagnosis, 17 of 18
      (94%) patients with alcohol-induced TCP had typical CP, and 25 of 27 (93%) with
      idiopathic TCP had LPSP or IDCP. LPSP and IDCP were indistinguishable clinically
      except for higher incidence of jaundice in LPSP (93% vs. 42%, P = 0.005). In
      idiopathic TCP no recurrence of symptoms was observed after resection (median
      follow-up 49 mo). CONCLUSIONS: Idiopathic TCP is clinically and histologically
      distinct from alcohol-induced TCP. It is unclear whether LPSP and IDCP, 2 unique
      patterns of histologic injury observed in idiopathic TCP, are part of the
      spectrum of the same disease or represent 2 or more different entities. Resection
      of mass prevents recurrence of symptoms in idiopathic TCP.

PMID- 15017504
TI  - Budesonide versus mesalamine for maintaining remission in patients refusing other
      immunomodulators for steroid-dependent Crohn's disease.
AB  - BACKGROUND & AIMS: To compare the efficacy of controlled-release budesonide
      capsules with that of mesalamine for maintaining remission and improving quality
      of life (QOL) in patients with steroid-dependent Crohn's disease. METHODS: Fifty
      seven patients (25 men; mean age, 32 +/- 10.1 yr) with quiescent steroid
      dependent Crohn's ileitis, ileocolitis, or colitis (Crohn's disease activity
      index <150) entered a prospective, investigator-blind trial. Patients were
      eligible for treatment with azathioprine but had not consented or had developed
      side effects. Patients were randomized to receive budesonide 6 mg/day (n = 29) or
      mesalamine 1 g 3 times/day (n = 28). Follow-up assessments were made every 2
      months for up to 1 year or until relapse. At each visit, quality of life (QOL)
      was assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS:
      There were no significant differences in baseline clinical characteristics
      between the study groups. The 1-year relapse rate was significantly lower in the
      budesonide group than in the mesalamine group (55% vs. 82%; 95% confidence
      interval, 12.4%-41%; P = 0.045). Patients assigned to budesonide also remained in
      remission longer (241 +/- 114 days vs. 147 +/- 117 days; 95% confidence interval,
      32.7-155.3 days; P = 0.003). Compared with mesalamine, budesonide treatment also
      was associated with a better QOL throughout the study (mean total IBDQ scores 165
      +/- 36 vs. 182 +/- 28, respectively; 95% confidence interval, -0.4 to 34.4, P =
      0.0001). This advantage was confirmed in patients' self-assessed QOL scores.
      CONCLUSIONS: Over a 1-year period, controlled-release budesonide was
      significantly more effective than mesalamine for maintaining remission and
      improving the QOL of patients with steroid-dependent Crohn's disease.

PMID- 15017506
TI  - An evidence-based medicine approach to studies of diagnostic tests: assessing the
      validity of virtual colonoscopy.

PMID- 15017510
TI  - Optimal dosing of 5-aminosalicylic acid: 5 decades of choosing between
      politicians.

PMID- 15017507
TI  - Effect of digestive health care services integration on resource use and outcomes
      in patients with digestive disorders.
AB  - BACKGROUND & AIMS: Academic medical centers are under pressure to contain
      resources. The University of Virginia Digestive Health Service Center (DHSC) is a
      fully integrated inpatient service combining gastroenterology, hepatology,
      surgery, pathology, radiology, and nutritional services. The aim of this study
      was to evaluate whether integration of digestive health services can contain
      resource use among gastrointestinal (GI) inpatient admissions. METHODS: This is a
      cohort study of 2934 inpatient cases admitted to a referral academic medical
      center between January 1, 1998, and June 30, 2000, with a primary diagnosis of an
      esophageal disorder, appendicitis, abdominal hernia, intestinal obstruction,
      diverticulitis, biliary tract disease, liver disease, a pancreatic disorder, or
      GI hemorrhage. Cases were grouped by admitting service (DHSC vs. other
      nonintegrated inpatient services). Total cost, length of stay, and 30-day
      readmission rate were adjusted for differences in baseline patient
      characteristics and compared. RESULTS: DHSC admission was associated with
      significant cost savings (P = 0.0363) and reduced length of stay (P < 0.0001).
      Cost savings were attributable to patients admitted for liver disease (P =
      0.0077), GI hemorrhage (P = 0.0031), and diverticulitis (P = 0.0497); reductions
      in length of stay were seen for patients with liver disease (P = 0.0314), GI
      hemorrhage (P = 0.0212), diverticulitis (P = 0.0017), esophageal disorders (P =
      0.0006), and abdominal hernia (P = 0.0458). DHSC patients with pancreatic
      disorders had increased total cost (P = 0.0247), but no difference in length of
      stay (P = 0.7504) and a lower 30-day readmission rate (P = 0.0478). CONCLUSIONS:
      Integration of digestive health services reduces resource use for patients with
      digestive diseases and may improve outcomes for patients with pancreatic
      disorders. A multidisciplinary service center may represent a more efficient
      model for health care delivery for these patients.

PMID- 15017511
TI  - The CARD15 (also known as NOD2) gene in Crohn's disease: are there implications
      for current clinical practice?

PMID- 15017512
TI  - Treatment of hepatocellular carcinoma.

PMID- 15017513
TI  - Trends in the identification and clinical features of celiac disease in a North
      American community, 1950-2001.
AB  - BACKGROUND AND AIMS: Celiac disease is considered rare in North America. However,
      an increasing incidence and widening clinical spectrum have been reported in many
      countries, and serologic screening suggests a higher prevalence of minimally
      symptomatic disease. This study reports temporal trends in the incidence of
      celiac disease in Olmsted County, Minnesota. METHODS: All county residents
      diagnosed with celiac disease between 1950 and 2001 were identified through the
      Rochester Epidemiology Project. Incidence rates were calculated assuming a
      Poisson distribution, and changes in incidence by calendar year, age, and gender
      were assessed by using Poisson regression. RESULTS: Altogether, 82 new cases of
      celiac disease were identified during the 50-year period. There was a marked
      female predominance (P < 0.005), and the incidence rates increased with age (P <
      0.001) and calendar period (P < 0.001). The overall annual incidence of celiac
      disease was 2.1 per 100,000 (95% confidence interval [CI], 1.7-2.6) but increased
      from 0.9 per 100,000 (CI, 0.5-1.2) in 1950-1989 to 3.3 per 100,000 (95% CI, 2.2
      4.4) in the 1990s. The incidence was 9.1 per 100,000 (95% CI, 5.2-13.0) in the
      final 2 years of the study. Serology prompted biopsy in a substantial proportion
      of recent diagnoses. Clinical features also changed over time, with less diarrhea
      and weight loss at presentation. CONCLUSIONS: Celiac disease has increased
      recently in this well-characterized population. Milder clinical features and use
      of serology suggest an increased detection rate, although a true increase in
      incidence may have also occurred. Celiac disease is not rare in North America.

PMID- 15017514
TI  - Leukocyte adsorptive apheresis for the treatment of active ulcerative colitis: a
      prospective, uncontrolled, pilot study.
AB  - BACKGROUND AND AIMS: Active ulcerative colitis (UC) is characterized by
      infiltration of activated granulocytes and monocytes/macrophages (GM) within the
      large bowel mucosa. GM are major sources of inflammatory cytokines, and in UC
      they are elevated with increased survival time. We investigated the possibility
      that reducing the level of these cells might promote remission of active UC.
      METHODS: Thirty-one patients with active corticosteroid refractory (refractory)
      UC, mean age of 42 years, duration of UC 6 years, clinical activity index (CAI)
      of 15, disease activity index (DAI) of 10, and 8 corticosteroid naive patients
      (naive), mean age of 36 years, duration of UC 2 years, CAI of 11, DAI of 8 were
      recruited. Each patient was treated with up to 11 cycles of granulocyte and
      monocyte adsorptive apheresis over 11 weeks by using a 335-mL capacity column
      filled with cellulose acetate beads that adsorb GM. RESULTS: At week 12, 81% of
      refractory (CAI, 3; P < 0.001 and DAI, 4; P < 0.001) and 88% of naive (CAI, 1; P
      = 0.012 and DAI, 3; P = 0.011) patients achieved remission. Early relapse was not
      a feature, and at 12 months, 26 of 33 patients had maintained their remission.
      The treatment was well tolerated, and no severe side effects were observed.
      CONCLUSIONS: The outcome of this study suggests that reduction of circulating
      granulocytes and monocytes results in alleviation of inflammation and promotes
      clinical remission in patients with severe active UC that has not responded to
      intensive corticosteroid treatment. These data suggest that formal controlled
      studies are warranted.

PMID- 15017516
TI  - Endoscopic clip application as an adjunct to closure of mature esophageal
      perforation with fistulae.
AB  - BACKGROUND AND AIMS: Esophageal perforation is associated with high morbidity and
      mortality. Surgery and drainage are considered primary management. Conservative
      management is an option in a select group. Conservative treatment requires
      drainage, control of infection, nutritional support, and considerable patience.
      METHODS: We describe 3 cases in which endoscopic metallic clips were placed to
      close mature perforations with associated fistulae. All 3 patients underwent
      mucosal approximation of the defects under direct endoscopic visualization.
      RESULTS: A review of the literature revealed only 4 other reports of the use of
      endoclipping for esophageal perforation, one diagnosed immediately, a second
      within 24 hours, a third diagnosed after 2 days and endoclipped after prolonged
      mediastinal drainage, and a fourth believed to be chronic. The cases presented
      here represent well-established, mature defects. CONCLUSIONS: Endoscopic
      treatment of mature esophageal perforation with metallic clips can be performed
      to promote closure. In combination with other conservative medical efforts, this
      method can be used safely and effectively for selected patients.

PMID- 15017515
TI  - The optimal dose of 5-aminosalicylic acid in active ulcerative colitis: a dose
      finding study with newly developed mesalamine.
AB  - BACKGROUND AND AIMS: 5-Aminosalicylate is the gold standard for inducing
      remission in patients with mildly to moderately active ulcerative colitis. The
      optimal dose is as yet not defined. Despite some recent developments, the ideal
      formulation for 5-aminosalicylic acid is still awaited. A new pellet preparation
      was designed combining slow and delayed release properties. Aims of the study
      were to find the optimal dose and to test efficacy and safety of a new 5
      aminosalicylic acid formulation. METHODS: Three hundred twenty-one patients were
      included in a double-blind multicenter trial. Inclusion criteria were active
      ulcerative colitis (Clinical Activity Index [CAI] and Endoscopic Index [EI]
      according to Rachmilewitz, CAI 6-12; EI >/=4). Three different doses of 5
      aminosalicylic acid (0.5 g 3 times a day, 1.0 g 3 times a day, and 1.5 g 3 times
      a day) were studied for 8 weeks. RESULTS: Clinical remission rate (CAI </=4) was
      highest in the 1.0 g 3 times a day group (66 %), 50% in the 0.5 g 3 times a day
      group, and 55% in the 1.5 g 3 times a day group. Hierarchical testing showed no
      significance, indicating a lack of dose response across the 3 mesalamine doses.
      In addition, times to first clinical response were similar: 26.5 days (1.0 g 3
      times a day), 27.5 days (0.5 g 3 times a day), and 21.5 days (1.5 g 3 times a
      day). Endoscopic improvement was better with 1.0 g mesalamine 3 times a day than
      with 0.5 g 3 times a day, but overall endoscopic and histologic improvement was
      not different between treatment groups. Baseline activity, duration, and
      localization of ulcerative colitis did have some influence on the therapeutic
      activity, but there was no significant interaction with the dose of the study
      drug. Safety, with special focus on kidney function, was excellent in all 3
      groups. CONCLUSIONS: There is no significant dose response between mesalamine 1.5
      g/day, 3.0 g/day, and 4.5 g/day. The optimal dose to induce remission of
      ulcerative colitis is 0.5 g 5-aminosalicylic acid 3 times a day. Patients failing
      with this dose may benefit from an increase of the dose up to 1.0 g 3 times a
      day, but should also be considered for alternative treatment. A newly developed
      pellet formulation of 5-aminosalicylic acid has promising efficacy and excellent
      safety.

PMID- 15017517
TI  - Sucralfate therapy in NSAID bleeding gastropathy.
AB  - BACKGROUND AND AIMS: A randomized, double-blind, placebo-controlled, multicenter
      study was conducted to assess the efficacy of 2 g sucralfate suspension in
      treating gastric mucosal lesions caused by long-term treatment with nonsteroidal
      anti-inflammatory drugs (NSAIDs). METHODS: Only patients given NSAIDs
      continuously for at least 2 months with positive fecal occult blood (FOB) and
      endoscopically confirmed mild to moderate mucosal lesions (Lanza scale, grades 2
      4) were included. After 1-week run-in phase, patients were stratified into 2
      groups according to gastropathy-related symptoms during the preceding 7 days
      (symptomatic vs. asymptomatic) and randomized to 2 g (10 mL) of sucralfate
      suspension or placebo twice a day over a 6-week period. NSAIDs were given
      according to each patient's dosage schedule and always after meals. RESULTS:
      Twenty-five patients received sucralfate and 25 received placebo. At the end of
      the study, 68% (17/25) of patients given sucralfate had no lesions (Lanza grade
      0) on endoscopy compared with 35% (8/23) in controls (P = 0.042). The Lanza
      grades in patients given sucralfate were significantly improved compared with the
      placebo patients (P = 0.022). CONCLUSIONS: In this target population selected
      according to positive FOB test and endoscopic evidence of mucosal injury, chronic
      administration of sucralfate significantly decreased NSAID-induced gastric
      erosions.

PMID- 15017518
TI  - An evidence-based approach to studies of gastrointestinal therapies.
AB  - This article provides an evidence-based medicine framework to critically assess
      the validity of study design and clinical significance of study results in the
      context of gastrointestinal therapies for a common clinical scenario. Without
      systems for critically appraising and applying clinical research, we may become
      dependent on outdated information. When used in conjunction with clinical
      judgment, critical appraisal of clinical research facilitates the provision of
      the very best care to patients. This article, which examines a trial about the
      gastrointestinal safety of cyclooxygenase (COX)-II-selective nonsteroidal anti
      inflammatory drugs (NSAIDs), follows the format of other evidence-based medicine
      articles in the Canadian Medical Association Journal, the Journal of the American
      Medical Association, and Gastroenterology. The evidence-based medicine concepts
      have been expanded from previous articles and examples from the gastrointestinal
      literature have been used.

PMID- 15017519
TI  - Knowledge base evaluation of medicine residents on the gastroenterology service:
      Implications for competency assessments by faculty.
AB  - BACKGROUND AND AIMS: Clinician educators are asked to provide both formative and
      summative evaluations on the medical knowledge of residents. This study evaluated
      the accuracy of these evaluations and the perception of residents regarding the
      ability of faculty to assess medical knowledge. METHODS: Gastroenterology
      knowledge ratings provided by 15 faculty gastroenterologists on 49 internal
      medicine residents during a required gastroenterology rotation were correlated
      with performance on the gastroenterology subsection of the In-Training
      Examination for Internal Medicine. Residents also were surveyed regarding their
      perception of the ability of faculty to judge their knowledge of medical
      gastroenterology. RESULTS: The mean correlation (Kendall's tau b) of faculty
      ratings with performance on the ITE was 0.30 (P < 0.01). The range of correlation
      values for individual faculty (-0.39 to 0.80) indicated that some faculty were
      able to assess the medical knowledge of residents better than others. Residents,
      as well as the faculty themselves, perceived that faculty were able to rate their
      medical knowledge relatively well. CONCLUSIONS: The ability of faculty
      gastroenterologists to judge the knowledge of gastroenterology in their resident
      trainees was quite limited. Residents, as well as faculty, inaccurately perceive
      the ability of gastroenterologists to render professional judgments on their
      knowledge base as good. An end-of-rotation written examination would appear to be
      required to provide an accurate assessment of the medical knowledge of residents.

PMID- 15017521
TI  - AT1 and AT2 receptor in the kidney: role in health and disease.
AB  - The renin angiotensin system plays an important role in the control of body fluid
      and electrolyte homeostasis and blood pressure regulation. Angiotensin II is the
      most effector hormone of this system and functions mainly through stimulation of
      its subtype receptors, namely, the AT1 and AT2 receptors. Most of the known
      physiological and pathologic effects of angiotensin II are mediated through
      stimulation of the AT1 receptor. The knowledge about the involvement of the AT2
      receptor in physiological and pathologic processes is still evolving. In the
      kidney, both the AT1 and AT2 receptors contribute to the regulation of renal
      hemodynamic and tubular functions. Also, these receptors regulate renal cellular
      growth and matrix formation. However, AT2 receptor possesses functions that
      counteract the effects of the AT1 receptor. The balance between the AT1 and AT2
      receptors can determine the renal status in health and disease.

PMID- 15017522
TI  - Oxidative stress in hypertension and chronic kidney disease: role of angiotensin
      II.
AB  - Angiotensin II, via the type 1 (AT1) receptor, stimulates oxidative stress. The
      vasculature, interstitium, juxtaglomerular apparatus, and the distal nephron in
      the kidney express nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
      that generates superoxide anion, which is an important component of angiotensin
      II-induced oxidative stress. The angiotensinogen gene is stimulated by NF-kappaB
      activation, which is sensitive to the redox ratio, providing a positive feedback
      loop that can upregulate angiotensin II production. Oxidative stress can
      accompany hypertension in many models, including the spontaneously hypertensive
      rat (SHR), angiotensin II-infused rats, renovascular hypertension, and the
      deoxycorticosterone acetate (DOCA) salt model of hypertension. AT1 receptor
      antagonists can abrogate the effects of angiotensin II on oxidative stress, thus
      providing an important mechanistic insight onto the renal protective effects of
      these agents in conditions associated with angiotensin II excess.

PMID- 15017523
TI  - AT1 receptor heterodimers and angiotensin II responsiveness in preeclampsia.
AB  - Preeclampsia is a pregnancy-specific hypertensive disorder with unknown etiology,
      which affects 5% to 10% of all pregnancies. Increased sensitivity to the
      vasoconstrictor angiotensin II is a common feature of preeclampsia, although
      underlying mechanisms are barely understood. Recent data reveal a potential
      mechanism for the increased angiotensin II responsiveness in preeclampsia:
      increased levels of heterodimers between the vasopressor receptor AT1 and the
      vasodepressor receptor B2. The receptor heterodimers display increased
      sensitivity toward angiotensin II and are found in platelets and in omental
      vessels of preeclamptic women. Moreover, AT1/B2 receptor heterodimers are
      resistant to inactivation by reactive oxygen species, which is elevated in normal
      and preeclamptic pregnancies. Thus, a major symptom of preeclampsia is the result
      of complex formation between two G-protein-coupled receptors.

PMID- 15017524
TI  - Angiotensin II receptor type 1 expression in erythroid progenitors: Implications
      for the pathogenesis of postrenal transplant erythrocytosis.
AB  - Under normal physiological conditions red blood cell production is controlled
      primarily by erythropoietin, although multiple additional stimulatory factors are
      likely to be involved. One of these factors, angiotensin II, can modulate
      erythropoiesis directly via its type 1 receptor, as well as indirectly through
      multiple secondary mediators. We propose that angiotensin II exerts its
      stimulatory effect during the early stages of erythropoiesis, and that this
      effect serves as an important compensatory mechanism if erythropoietin production
      is chronically inadequate. We speculate that if this compensatory stimulation
      continues to be abnormally high after restoration of erythropoietin production
      following renal transplantation, erythrocytosis ensues.

PMID- 15017525
TI  - Changes in glomerular perm-selectivity induced by angiotensin II imply podocyte
      dysfunction and slit diaphragm protein rearrangement.
AB  - Molecular mechanisms governing the loss of glomerular membrane perm selectivity
      during progression of proteinuric kidney diseases are so far poorly defined.
      Discovery of the proteins of the podocyte slit diaphragm, including the nephrin
      CD2AP-podocin complex, has represented a major breakthrough in understanding the
      crucial role of the glomerular epithelial layer in the pathogenesis of
      proteinuria in human congenital disorders. A number of studies have tried to
      address the role of nephrin in acquired proteinuric disorders with conflicting
      results. In human diabetic nephropathy a defect of nephrin gene and protein
      expression has been consistently reported, which translates in profound changes
      of filtration slit ultrastructural architecture. The exclusive effect of
      angiotensin II inhibitors of restoring deficient nephrin expression in
      proteinuric diseases underlines a close interaction between angiotensin II and
      podocyte proteins and indicates a fresh way to look at the renoprotective
      properties of these molecules.

PMID- 15017526
TI  - Impact of renin angiotensin system blockade on renal function in health and
      disease: an end or a beginning?
AB  - Substantial reduction of functioning nephrons from any origin is followed by a
      relentless progression to chronic renal failure. This progression continues long
      after the acute nephropathy and its initiating events have subsided. Glomerular
      hypertension and hyperfiltration are the major contributors to this progressive
      nephron loss. Studies on the adverse effects of hemodynamic changes and attempts
      to define the modalities that slow the rate of progression of renal disease have
      been among the dominant trends in modern nephrology. Numerous animal studies as
      well as recent clinical trials indicate that blockade of the renin angiotensin
      system effectively retards progression of nephropathy from diverse origins.

PMID- 15017527
TI  - Angiotensin receptor blockers in diabetic nephropathy: renal and cardiovascular
      end points.
AB  - The activity of the renin-angiotensin-aldosterone system (RAAS) is elevated both
      in the circulation and in the renal tissue of diabetic and nondiabetic
      nephropathies. The increased RAAS activity plays an important role in the
      hemodynamic and nonhemodynamic pathogenetic mechanisms involved in kidney
      disease. Previous studies have demonstrated that albuminuria is not only a marker
      of glomerular lesions, but also a progression promoter, and finally a powerful
      predictor of the long-term beneficial effect of blood pressure-lowering therapy.
      Randomized crossover and parallel blind studies in patients with diabetic
      nephropathy have demonstrated that angiotensin II receptor blockers (ARB) induce
      favorable changes in systemic blood pressure, renal hemodynamics, and proteinuria
      similar to those induced by angiotensin-converting enzyme (ACE) inhibition.
      Studies have revealed the optimal renoprotective dose for some ARBs; however,
      additional dose titration studies are urgently needed to obtain the maximum
      benefit of this valuable new class of compounds. The combination of ARB and ACE
      inhibition is well tolerated and even more effective than monotherapy in reducing
      systemic blood pressure and albuminuria in diabetic nephropathy. In addition,
      dual RAAS blockade is safe and well tolerated. Impaired autoregulation of
      glomerular filtration rate (GFR); demonstrated with some blood pressure-lowering
      agents implies disturbances in the downstream transmission of the systemic blood
      pressure into the glomerulus, leading to capillary hypertension or hypotension
      depending of the level of blood pressure. ARB does not interfere with GFR
      autoregulation in hypertensive diabetic patients. In contrast to previous
      observational studies with ACE inhibition, long-term treatment with ARB has
      similar beneficial renoprotective effect on progression of diabetic kidney
      disease in hypertensive diabetic patients with ACE II and DD genotypes. ARB can
      prevent/delay development of diabetic nephropathy independently of its beneficial
      blood pressure-lowering effect in patients with type 2 diabetes and
      microalbuminuria. Recently, two landmark studies led to the following conclusion:
      "Losartan and Irbesartan conferred significant renal benefit in patients with
      type 2 diabetes and nephropathy. This protection is independent of the reduction
      in blood pressure it causes. The ARB is generally safe and well tolerated." A
      recent metaanalysis indicates that ARBs reduce cardiovascular events mainly
      because of reduction in first hospitalization for congestive heart failure in
      hypertensive type 2 diabetic patients with albuminuria. The studies mentioned
      here suggest that ARB represents a beneficial treatment of hypertension and
      proteinuria in incipient and overt diabetic nephropathy.

PMID- 15017528
TI  - Angiotensin-converting enzyme inhibition and angiotensin II antagonism in
      nondiabetic chronic nephropathies.
AB  - Angiotensin II (A II), the main effector of the renin angiotensin system (RAS),
      plays a central role in the hemodynamic and nonhemodynamic mechanisms of chronic
      renal disease and is currently the main target of interventions aimed to prevent
      the onset and progression of chronic nephropathies to end-stage renal disease
      (ESRD). In addition, to ameliorate glomerular hyperfiltration and size
      selectivity, reduce protein traffic and prevent glomerular and tubulointerstitial
      toxicity of ultrafiltered proteins, RAS inhibitors also limit the direct
      nephrotoxic effects of A II. Thus, both angiotension-converting enzyme (ACE)
      inhibitors (ACEi) and A II antagonists (ATA) exert a specific nephroprotective
      effect in both experimental and human chronic renal disease. This effect is time
      dependent and is observed across degrees of renal insufficiency. Forced ACEi or
      ATA uptitration above doses recommended to control arterial hypertension and
      combined treatment with both agents allow optimization of A II inhibition and
      maximization of renoprotection. Multifactorial interventions combining RAS
      inhibition to treatments targeted also to non-RAS mechanisms could even achieve
      regression of glomerulosclerosis and chronic tubulointerstitial injury. Studies
      are needed to assess whether renal damage can be reverted to such a point that
      renal function could be fully prevented from worsening, and possibly improvement.
      The economic impact of even a partial improvement would be enormous. Moreover,
      chronic renal insufficiency is an independent risk factor for cardiovascular
      disease, and effective nephroprotection could also decrease the excess
      cardiovascular morbidity and mortality associated with chronic nephropathies. In
      patients with renal insufficiency, ACEi are even more cardioprotective than in
      those without and are well tolerated. Thus, RAS inhibitor therapy should be
      offered to all renal patients without specific contraindications, including those
      closer to renal replacement therapy.

PMID- 15017529
TI  - Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in
      chronic renal disease: safety issues.
AB  - Reducing the actions of the renin-angiotensin-aldosterone system with angiotensin
      converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers
      (ARBs) slows nephropathy progression in patients with or without diabetes. These
      drug classes have proven therapeutic benefits, particularly in patients with
      renal insufficiency (ie, serum creatinine level 133-265 micromol/L [1.5-3.0
      mg/dL]). This class of drugs could also provide renoprotective effects that are
      nonblood pressure-dependent when used as part of combination antihypertensive
      therapy in patients with more advanced renal disease. Although many studies
      demonstrate the use of ACE inhibitors and ARBs to delay the decline in renal
      function and reduce proteinuria, many physicians fail to use these drug classes
      in patients with renal insufficiency for fear that either serum creatinine or
      potassium levels will rise. Thus, because of these issues, patients are deprived
      of known strategies that delay progression of renal disease. A strong association
      exists between acute increases in serum creatinine of up to 30% to 35% after
      initiating ACE inhibitor therapy and long-term preservation of renal function.
      This association is predominantly present in people with a baseline serum
      creatinine of up to 3 mg/dL and usually stablizes within 2 to 3 months of therapy
      given blood pressure is reduced to goal. Moreover, the appropriate use of
      diuretics mitigates against profound increases in serum potassium. Thus,
      withdrawal of an ACE inhibitor in such patients should occur only when the rise
      in creatinine exceeds this threshold over a shorter period of time or
      hyperkalemia develops, ie, serum potassium level of 5.6 mmol/L or greater.

PMID- 15017533
TI  - The good old days.

PMID- 15017534
TI  - Robert E. Gross Lecture. Making health care safe: are we up to it?

PMID- 15017535
TI  - The surgical management of congenital hyperinsulinemic hypoglycemia in infancy.
AB  - BACKGROUND: Congenital hyperinsulinism (CHI) is characterized by profound
      hypoglycaemia caused by inappropriate insulin secretion. CHI is a heterogeneous
      disorder with at least 2 histologic lesions and several implicated genes. If CHI
      is caused by a focal lesion, elective surgery is the only treatment because it
      leads to complete recovery without diabetes; on the contrary, diffuse CHI can
      only be cured by near-total pancreatectomy, and medical treatment, if efficient,
      is preferable. It is therefore mandatory to distinguish the 2 forms of CHI, and
      the surgeon has to fullfill his role in the multidisciplinary team that deals
      with CHI. METHODS: A total of 134 patients with CHI were investigated both
      radiologically and with molecular biology. Pathology was the only proof of focal
      or diffuse lesions, and the pancreatic tissue could be studied by
      electrophysiology (Katp and Ca channels) and gene study. RESULTS: In 59 infants
      with CHI, a focal lesion was suspected by radiology and proved by extemporaneous
      pathology; partial pancreatectomy (33 tail +/- body, 19 head, 5 isthmus
      resections) was performed, and molecular biology and histochemistry confirmed the
      genetic lesion specific to the focal disease; 75 near-total pancreatectomies were
      necessary in diffuse disease to prevent brain damage. CONCLUSIONS: CHI is a
      severe brain-threatening disease. Surgery is indicated in all focal diseases,
      providing they are diagnosed preoperatively. In diffuse disease with resistance
      to medical treatment, near-total pancreatectomy is a last resort option that
      hopefully will be improved in the future with culture of beta cells and genetic
      modification of the beta cell disease before autograft.

PMID- 15017536
TI  - A multidisciplinary approach to the focal form of congenital hyperinsulinism
      leads to successful treatment by partial pancreatectomy.
AB  - BACKGROUND/PURPOSE: Congenital hyperinsulinism (HI) causes severe hypoglycemia in
      neonates and infants. Recessive mutations of the beta-cell K(ATP) channel genes
      cause diffuse HI, whereas loss of heterozygosity together with inheritance of a
      paternal mutation cause focal adenomatous HI. Although these 2 forms of HI are
      clinically identical, focal HI can be cured surgically. The authors reviewed
      their experience with partial pancreatectomy for focal HI. METHODS: From December
      1998 to January 2003, 38 patients (ages 2 weeks to 14 months; median age, 10
      weeks) were treated with partial pancreatectomy for focal HI. Before surgery,
      patients had localization studies using selective arterial calcium stimulation
      with venous sampling or transhepatic portal venous sampling. At operation, the
      focal lesion was found using the preoperative localization data and multiple
      pancreatic biopsies with frozen section analysis, followed by partial
      pancreatectomy. A complete response at follow-up was defined as no requirement
      for glycemic medications, no continuous tube feedings, and no diabetes mellitus.
      RESULTS: Nineteen pancreatic focal lesions were in the head; 15 were in the neck,
      body, or tail; and 4 had more extensive involvement. Lesions that required
      substantial resection of the pancreatic head underwent Roux-en-Y
      pancreaticojejunostomy to preserve the normal body and tail. Lesions of the body
      or tail were usually treated with partial distal pancreatectomy. Ninety-two
      percent (35 of 38) of patients had a complete response to surgery. Three patients
      have required glycemic medications. No patient is diabetic. Surgical
      complications included additional resection for residual disease (3), small bowel
      obstruction requiring laparotomy and enterolysis (2), and chylous ascites (3)
      that resolved with medical management. CONCLUSIONS: A multidisciplinary approach
      to patients with the focal form of congenital hyperinsulinism can distinguish
      focal from diffuse disease, localize focal lesions, and permit partial
      pancreatectomy with cure in most patients.

PMID- 15017537
TI  - Gastric transposition in children--a 21-year experience.
AB  - PURPOSE: The purpose of this study was to analyze the outcome in 173 children
      (104 M, 69 F) undergoing transposition since 1981. METHODS: The most common
      indications for esophageal replacement included failed repair of different
      varieties of esophageal atresia (127), caustic injury (23), and peptic strictures
      (8). A total of 81% of the patients were referred from other hospitals (50% from
      other countries). Age at operation ranged from 7 days to 17 years. The gastric
      transposition was performed using blunt mediastinal dissection only in 90
      patients with an additional 81 patients undergoing lateral thoracotomy. The
      retrosternal position was used in 2 patients. RESULTS: There were no graft
      failures including those who had previously failed gastric tube or Scharlilike
      operations. Anastomotic leakage occurred in 12% (all but 1 resolved
      spontaneously). Anastomotic stricture requiring dilatation occurred in 19.6%.
      Half of these patients had previous caustic esophageal injury. There were 9
      deaths in the group (5.2%). One death occurred intraoperatively, 5 in the early
      postoperative period, and there were 3 late deaths. In more than 90% of our
      patients, the outcome was considered good to excellent in terms of absence of
      swallowing difficulties or other gastrointestinal symptoms. Many, however,
      preferred to eat small frequent meals. Poor outcome was particularly associated
      with multiple previous attempts at esophageal salvage. There was no deterioration
      in the function of the gastric transposition in those patients followed up for
      more than 10 years. CONCLUSIONS: Gastric transposition for esophageal
      substitution is an acceptable procedure. It is attended by 5% mortality and a 12%
      leak rate. A total of 19.6% of the patients needed anastomotic dilatation for
      stricture. In the long term, good function has been maintained. Gastric
      transposition compares favorably with alternative methods of esophageal
      replacement.

PMID- 15017538
TI  - Use of radiofrequency ablation of the lower esophageal sphincter to treat
      recurrent gastroesophageal reflux disease.
AB  - PURPOSE: Recurrent gastroesophageal reflux disease (GERD) after gastroesophageal
      surgery is a troublesome problem. Reoperative surgery often is complicated by
      adhesions and recurrence. Radiofrequency ablation or energy delivery (RF or the
      Stretta procedure) is a new method for treating GERD. This study is the first
      report describing the use of the Stretta procedure in pediatric patients.
      METHODS: Six patients who underwent previous gastroesophageal surgery presented
      with recurrent GERD. Medical records were reviewed and the severity of reflux
      graded using a modified scoring system. All underwent RF and were graded for GERD
      at 6 months postprocedure. RESULTS: Mean operating time was 80 +/- 12 minutes.
      Mean age at initial operation was 12 +/- 4 years and for the RF, 18.0 +/- 3.4
      years. All patients were discharged as outpatients. Early complications occurred
      in one child with self-resolving acute gastric distension. Five of 6 patients
      were completely asymptomatic at 3 months after the procedure, and 3 stopped anti
      secretory agents. One patient was improved but still symptomatic and needed a
      redo fundoplication. Another required a repeat application of RF 10 months after
      the initial one. Mean GERD score pre-Stretta was 5.2 +/- 1.0, which improved to
      1.6 +/- 1.9 at 6 months postprocedure (P <.05; paired t test). CONCLUSIONS: Use
      of RF treatment of the lower esophageal sphincter is a potentially successful
      modality to treat recurrent GERD in children. Long-term follow-up is required.

PMID- 15017540
TI  - Comparison of the incidence of complications in open and laparoscopic
      pyloromyotomy: a concurrent single institution series.
AB  - PURPOSE: The purpose of this study was to compare the incidence and type of
      technical complications seen in a concurrent series of pyloromyotomies done open
      and laparoscopically. METHODS: The medical records of all patients who underwent
      pyloromyotomy for congenital hypertrophic pyloric stenosis over a 66-month period
      were reviewed (n = 457). Information obtained included age, sex, weight,
      operating time, and intraoperative and postoperative complications. RESULTS: Four
      hundred fifty-seven pyloromyotomies were equivalently divided between the 2
      techniques (232 laparoscopic, 225 open). Demographic characteristics and
      operating times were similar. There were no deaths in the series. The overall
      incidences of complications were similar in the 2 groups (open, 4.4%;
      laparoscopic, 5.6%). There was a greater rate of perforation with the open
      technique and a higher rate of postoperative problems including incomplete
      pyloromyotomy in the laparoscopic group. CONCLUSIONS: The open and laparoscopic
      approaches have similar overall complication rates. The distribution and the type
      of complications differ, however.

PMID- 15017539
TI  - Esophagogastric separation for failed fundoplication in neurologically impaired
      children.
AB  - PURPOSE: Recurrent gastroesophageal reflux (GER) after a fundoplication in
      severely neurologically impaired children is a frustrating problem without an
      effective solution: redo fundoplications carry a significant recurrence rate and
      gastrojejunostomy (GJ) tube feedings are associated with frequent tube
      dislodgment. The authors report a series of esophagogastric separation (EGS)
      procedures aimed at the management of failed fundoplication in neurologically
      impaired children. METHODS: Medical records of 10 patients who underwent EGS for
      recurrent GER were reviewed retrospectively. Variables examined included
      diagnosis, preoperative problems, operative and perioperative data, and outcomes.
      RESULTS: None of the patients were feeding orally and all were dependent on tube
      feedings. A median of 1.5 (range, 1 to 3) fundoplications had been performed
      previously and failed. All had preoperative emesis and feeding intolerance. Eight
      had failure to thrive and 5 recurrent pneumonias. Median age at the time of the
      procedure was 7.5 years (range, 2 to 22). Median postoperative length of stay was
      9 days (range, 5 to 17), and there were no leaks from the anastomosis. Salivary
      secretion intolerance was the most common postoperative problem (5 of 10
      patients). Repeat exploration was required for perforation of the colon in one
      and paraesophageal hernia in another. Recurrent GER was not noted. All 9
      currently surviving children are tolerating bolus gastrostomy feedings, which was
      an advantage to the parents. CONCLUSIONS: EGS is an attractive alternative for
      failed fundoplication in severely neurologically impaired children.

PMID- 15017541
TI  - Pyloric atresia: a new operation to reconstruct the pyloric sphincter.
AB  - BACKGROUND/PURPOSE: The standard method of surgical correction of pyloric atresia
      "solid segment" type is a gastroduodenostomy that can in the long term cause
      bilious duodenogastric reflux. The authors report 2 cases of pyloric atresia in
      which the pyloric sphincter was reconstructed by a new technique of
      gastroduodenal mucosal advancement anastomosis. METHODS: Two premature babies
      with "solid segment"-type pyloric atresia, one with an associated junctional
      epidermolysis bullosa, underwent surgery for reconstruction of the pyloric
      sphincter. By a longitudinal incision of the atretic pylorus, the cul-de-sacs of
      gastric and duodenal mucosa were isolated in the respective gastric and duodenal
      sides, advanced into the opened pyloric canal, and sutured together using end-to
      end anastomosis. The longitudinal pyloromyotomy then was closed above the
      reconstructed mucosal pyloric neocanal. RESULTS: The postoperative course was
      normal. At 7 years (patient 1) and 2 years (patient 2) after the operation, both
      are well, and no gastrointestinal disorders are present. Good competence of the
      pyloric sphincter has been confirmed by x-ray barium meal in both cases, and by
      HIDA technetium 99m hepatic scintiscan and esophagogastroduodenoscopy (EGD) with
      biopsy in patient 1. CONCLUSIONS: Our technique of surgical correction of pyloric
      atresia allows preservation of the pyloric sphincter, whose muscular layer,
      although hypoplastic, is present in these cases.

PMID- 15017542
TI  - Genetic polymorphisms of angiotensin system genes in congenital diaphragmatic
      hernia associated with persistent pulmonary hypertension.
AB  - BACKGROUND/PURPOSE: The renin-angiotensin system plays an important role in
      pulmonary artery remodelling. Several polymorphisms of genes encoding for
      components of the renin angiotensin system such as the angiotensin converting
      enzyme (ACE), the angiotensinogen (AGT) gene, and the angiotensin II type 1
      receptor (ATIR) have been associated with the development of pulmonary
      hypertension. The aim of this study was to investigate the ACE I/D genotype, the
      M235 T polymorphism of the AGT gene and the A1166 C polymorphism of AT1R in the
      lungs of congenital diaphragmatic hernia (CDH) complicated by persistent
      pulmonary hypertension (PPH) in the newborn. METHODS: Genomic DNA was extracted
      from archival paraffin-embedded lung tissue from 13 newborns with CDH complicated
      by PPH and from 9 controls. Genotyping for the I/D-ACE, the M235 T-AGT, and the
      A1166 C-ATIR gene polymorphisms were determined by a polymerase chain reaction
      based method with appropriate restriction digest when required. RESULTS: In
      controls, ACE genotype distribution of DD, ID, and II was 11%, 33%, and 55%,
      respectively, whereas in CDH it was 70%, 15%, and 15%, respectively. The ACE-DD
      genotype was significantly higher in CDH compared with controls (P <.05). In CDH
      samples, the prevalence of AGT-MM genotype was lower (8% v. 33%; P <.05), whereas
      the AGT-TT genotype was higher (61% v. 22%; P <.05) compared with controls. There
      were no differences in allele frequencies of AT1R between CDH patients and
      controls. CONCLUSIONS: These data suggest that D allele of the ACE gene
      insertion/deletion polymorphism and angiotensinogen M235 T polymorphism may be
      associated with PPH in newborns with congenital diaphragmatic hernia.

PMID- 15017543
TI  - The relationship of pulmonary artery pressure and survival in congenital
      diaphragmatic hernia.
AB  - BACKGROUND/PURPOSE: Pulmonary hypertension is an integral part of the
      pathophysiology of the respiratory failure associated with congenital
      diaphragmatic hernia. Hypothesizing that the evolution of the pulmonary
      hypertension would determine clinical outcome, the authors examined pulmonary
      artery pressures in relation to survival in their CDH patients. METHODS: The
      authors performed a retrospective chart review of all neonates with the CDH from
      1991 to 2002 at their institution eliminating infants with complex congenital
      heart disease, prematurity, or limited treatment. Cardiac ECHO data were used to
      estimate pulmonary artery pressures as a ratio to systemic pressure. Statistical
      analyses of estimated pulmonary pressure ratios stratified by survival status and
      time were performed using chi2 and Fisher's Exact Test methods. RESULTS: Forty
      seven full-term CDH infants with 428 cardiac ECHO evaluations were studied. Long
      term survival rate was 74%. Forty-nine percent of patients had normal pulmonary
      artery pressure estimates within the first 3 weeks of life. All patients
      survived. Seventeen percent had persistent systemic or suprasystemic pressure
      estimates unrelieved by treatment interventions resulting in 100% mortality rate.
      Thirty-four percent had intermediate reductions in pressure estimates over time
      with 75% survival rate. Systemic pulmonary artery pressures were associated with
      decreased survival at all time-points when compared with normal-pressure
      survivors: week 1, 60% (P <.003); week 3, 38% (P <.007); week 6, 0% (P <.02).
      CONCLUSIONS: The evolution of pulmonary hypertension is a critical determinant of
      survival in CDH patients with current treatment strategies. Three groups can be
      modeled with markedly different clinical performance patterns. Using serial
      cardiac ECHO examinations, pulmonary artery pressure estimations can be used to
      predict clinical outcome.

PMID- 15017544
TI  - Impact of a current treatment protocol on outcome of high-risk congenital
      diaphragmatic hernia.
AB  - BACKGROUND: There is considerable debate regarding the optimal management of
      congenital diaphragmatic hernia (CDH) in high-risk infants (those cases
      presenting with respiratory distress within 2 hours of birth or those diagnosed
      prenatally). The aim of this study was to analyze patient outcomes using a new
      treatment protocol for CDH in a tertiary care non-extracorporeal membrane
      oxygenation (ECMO) neonatal unit. METHODS: The records of 78 consecutive neonates
      with CDH presenting to Bambino Gesu Children's Hospital from 1996 to 2001 were
      analyzed retrospectively. Of these infants, 70 high-risk patients were identified
      (prenatal diagnosis or respiratory distress requiring intubation and assisted
      ventilation within 2 hours after birth), regardless of associated anomalies,
      medical condition on presentation, or degree of pulmonary hypoplasia. A prenatal
      diagnosis was made in 46 of 70 (66%) patients. Associated lethal malformations
      were present in 6 of the children (8.5%). The patients were placed in 3
      historical groups: group 1, 19 patients from 1996 to 1997, group 2, 22 patients
      from 1998 to 1999, and group 3, 29 patients from 2000 to 2001. In the first 2
      groups, a new protocol was introduced using inhaled nitric oxide (iNO) and high
      frequency oxygen ventilation (HFOV). In the third group, gentle ventilation and
      permissive hypercarbia were also used routinely. Mortality and severe morbidity-
      defined as O2 requirement at discharge, need for a tracheostomy, neurologic
      impairment, or bilateral hearing loss-were evaluated when the patients were at 6
      months old. Univariate analysis was performed. RESULTS: The 3 groups were
      comparable with respect to predictive risk factors such as side of hernia,
      prenatal diagnosis, polyhydramnios, stomach and liver in the thorax, associated
      lethal malformations, and patch. Overall survival rate significantly increased
      from 47% (9 of 19) in group 1 and 50% (11 of 22) in group 2 to 90% (26 of 29) in
      group 3 (P =.02). None of the 19 patients in group 1 had severe morbidity
      compared with 2 of 22 (9%) patients in group 2 and 2 of 29 (7%) patients in group
      3. Hearing loss was observed in 4 patients. Mortality rate and preoperative
      pneumothorax significantly decreased in group 3 compared with groups 1 and 2 (P
      =.03 and P =.00, respectively). CONCLUSIONS: (1) The application of new treatment
      protocol for CDH, using gentle ventilation and permissive hypercarbia, produced a
      significant increase in survival with concomitant decrease in morbidity. (2) The
      rate of pneumothorax was significantly decreased by the introduction of
      permissive hypercarbia and gentle ventilation. (3) As more infants survive CDH
      without the use of ECMO, severe long-term sequelae of CDH can be recognized in
      these children.

PMID- 15017545
TI  - Right congenital diaphragmatic hernia: Prenatal assessment and outcome.
AB  - PURPOSE: To understand the natural history of right congenital diaphragmatic
      hernia (CDH), the authors retrospectively reviewed 27 cases of right CDH that
      presented for prenatal evaluation or postnatal treatment. METHODS: Between 1995
      and September 2002, a total of 194 cases of fetal CDH were evaluated and included
      22 right-sided defects. The authors reviewed prenatal diagnostic studies
      (ultrasound scan, magnetic resonance imaging [MRI] echocardiography) and pre- and
      postnatal outcomes in these 22 cases of right CDH. Five additional cases of right
      CDH without a prenatal diagnosis were reviewed. RESULTS: The mean gestational age
      at evaluation was 26.1 weeks. The lung area to head circumference ratio (LHR)
      ranged from 0.32 to 2.5. In all cases, the fetal liver was herniated into the
      right chest. Associated anomalies were common. There were no karyotype
      abnormalities (17 of 22 tested). There were 4 terminations. Nine of the 18 (50%)
      continuing pregnancies had polyhydramnios, premature rupture of membranes, or
      preterm labor. The mean gestational age at birth was 36.8 weeks. One patient
      underwent tracheal occlusion at 27 weeks, and 2 patients died before postnatal
      repair. Overall survival rate (22 prenatal plus 5 postnatal diagnoses) was 19 of
      27 (70%). Postnatal survival rate was 19 of 23 (83%). A Gore-tex (W. L. Gore and
      Associates, Flagstaff, AZ) patch was utilized in 14 of 21 neonates undergoing
      surgery. Twelve of 23 (52%) required extracorporeal membrane oxygenation (ECMO)
      with a 75% survival rate. Significant morbidity occurred in 10 of 19 survivors
      and included neurologic sequelae in 6 of 19 (32%). CONCLUSIONS: MRI was helpful
      in the determination of liver position and confirmation of diagnosis. The high
      incidence of preterm complications, frequent need for ECMO, and high prevalence
      of comorbidities are indicative of the severity of this CDH population and
      warrant close prenatal surveillance and delivery at a tertiary care center with
      ECMO capability.

PMID- 15017546
TI  - Hyperoncotic enhancement of pulmonary growth after fetal tracheal occlusion: a
      comparison between dextran and albumin.
AB  - BACKGROUND/PURPOSE: This study was aimed at comparing albumin and dextran as
      intrapulmonary hyperoncotic enhancers of fetal lung growth after tracheal
      occlusion. METHODS: Fetal lambs (n = 27) were divided proportionally into 5
      groups: group I consisted of sham-operated controls; group II underwent tracheal
      occlusion (TO); groups III, IV, and V underwent TO and intratracheal infusion of
      60 mL of either saline, 6% dextran-70, or 25% albumin, respectively. Multiple
      fetal lung analyses were performed near term. Statistical analysis was by 1-way
      analysis of variance (ANOVA) and post-hoc analyses by the Bonferroni correction
      for multiple comparisons (P <.05). RESULTS: The lung volume-to-body weight ratio
      was significantly higher in groups IV and V than in all other groups with no
      differences between groups II and III, nor between groups IV and V. Airspace
      fraction was not significantly different among the groups, nor was there any
      evidence of alveolar cellular damage. Type-II pneumocyte density was higher in
      group I than in groups II, IV, and V, with no differences among the latter 3
      groups. Lung liquid biochemical profile was normal in all groups. CONCLUSIONS:
      Albumin is as effective as dextran as an intrapulmonary hyperoncotic booster of
      lung growth acceleration after fetal tracheal occlusion, with no lasting effects
      on its fetal lung liquid levels. As a naturally occurring oncotic agent, albumin
      may be a safer option in the clinical application of this therapeutic concept.

PMID- 15017547
TI  - Perinatally diagnosed asymptomatic congenital cystic adenomatoid malformation: to
      resect or not?
AB  - BACKGROUND: Management of asymptomatic congenital cystic adenomatoid malformation
      (CCAM) is controversial. The natural history of untreated asymptomatic CCAM is
      unknown, although most surgeons recommend resection of these lesions to prevent
      future infection. The aim of this study was to determine the relative surgical
      risk of resection compared with the risk of observation for these patients.
      METHODS: A retrospective review of hospital records between 1996 and 2002 in a
      tertiary care pediatric referral center was conducted. All perinatally (prenatal
      or neonatal) diagnosed CCAMs were included. In addition, patients presenting with
      late diagnosis of CCAM were also reviewed. RESULTS: Forty-eight children had CCAM
      diagnosed perinatally. Thirteen of these were symptomatic and required surgery
      within 6 months; these were excluded from the analysis. Of the 35 asymptomatic
      infants, 6 were operated on electively before 6 months of age (median age, 4.5
      months). The other 29 asymptomatic infants were followed up for more than 6
      months. Of these, 9 remained asymptomatic and were eventually operated on
      electively (median age, 13 months). Three (10%) had CCAM infections at 7, 8, and
      11 months of age and required resection. The remaining 17 children have not
      undergone resection and are still asymptomatic (median follow-up, 3 years). An
      additional 12 patients presented with a late diagnosis of CCAM. All of these
      presented with complications (infection or pneumothorax) and underwent resection
      (median age, 6 years). Overall, the complication rate after resection of an
      asymptomatic CCAM was not significantly different from those of resected CCAM
      that had already developed infection or pneumothorax (P =.64). CONCLUSIONS: Ten
      percent of perinatally diagnosed asymptomatic patients had 5 complications
      requiring surgery during follow-up. The true incidence is probably higher given
      the relatively short follow-up in our series. Morbidity after resection of a
      complicated CCAM was not statistically significantly higher than after elective
      resection for an asymptomatic CCAM. Although conservative management of
      asymptomatic CCAM may be warranted, a more extended period of follow-up is
      necessary before this approach can be recommended.

PMID- 15017548
TI  - Results of growth trophic therapy in children with short bowel syndrome.
AB  - PURPOSE: In addition to the structural, ultrastructural, and functional changes
      that occur after extensive enterectomy or in utero bowel loss that results in
      short bowel syndrome (SBS), a complex array of humoral responses take place that
      may also affect adaptation of the remaining small intestine as well as
      nutritional status or growth. These include alterations in the levels of
      circulating hormones and trophic substances such as growth hormone (GH) and
      insulinlike growth factors (IGF-1 and IGFBP-3). The purpose of this investigation
      is to report on the management/treatment of 3 children with SBS (>4 years in
      duration) and growth failure. METHODS: Serum measures of growth factors and the
      response to GH stimulation after an arginine insulin tolerance test (AITT) were
      determined. Weight and height z-scores as well as linear growth velocity were
      calculated annually pre- and postinitiation of medication therapy. RESULTS:
      Patient 1 (boy, 8.5 years old, midgut volvulus, 18-cm bowel) was found to be GH
      deficient, whereas patients 2 (girl, 12.5 years old, gastroschisis, 70-cm bowel)
      and 3 (boy, 9 years old, jejunal atresia, 21 cm bowel) were found to have limited
      GH responsiveness. Subsequently, treatment with GH (1) and growth releasing
      factor (GRF; 2 & 3) was prescribed. Z-scores for both weight and height improved
      over time. Positive linear growth velocity was observed from initiation of
      therapy (<0.5 cm/yr for all) to more than 3 years of treatment (mean 1, 4.7
      cm/yr; 2, 8.7 cm/yr; 3, 5.0 cm/yr [age adjusted normals >4.5, >8.5, and >4.9
      cm/yr, respectively]). All patients received a regular diet with oral
      supplements, whereas 2 received parenteral nutrition support for about 1 year.
      CONCLUSIONS: In children with medically refractory SBS, it is not only important
      to offer trophic factors but also essential that sufficient nutrient substrate be
      provided to achieve adequate growth.

PMID- 15017549
TI  - Functional liver recovery parallels autologous gut salvage in short bowel
      syndrome.
AB  - BACKGROUND/PURPOSE: Parenteral nutrition (PN) is life saving in short bowel
      syndrome. However, long-term parenteral nutrition is frequently complicated by a
      syndrome of progressive cholestatic liver disease that is considered to be
      irreversible beyond the early stages of cholestasis, particularly in the presence
      of any degree of fibrosis in the liver. The purpose of this study was to examine
      apparent improvement in PN-associated liver dysfunction in a cohort of children
      with short bowel syndrome. METHODS: A retrospective case-record review of all
      patients managed within a dedicated Intestinal Rehabilitation Program (IRP)
      identified 13 patients with short bowel who had PN-associated liver dysfunction,
      defined for this purpose as hyperbilirubinemia or an abnormal liver biopsy.
      RESULTS: At referral, 12 of the 13 patients were exclusively on PN, and one was
      on 50% PN. At current follow-up, 3 patients have achieved complete enteral
      autonomy from PN, and 7 patients have had smaller decrements in PN requirements.
      Specific operative procedures to improve intestinal function were undertaken in
      11 patients; 4 patients also underwent cholecystectomies with biliary irrigation
      at the time of intestinal reconstruction. The median highest bilirubin level in
      these 13 patients was 10.7 mg% (range, 3.2 to 24.5 mg%). Liver biopsy results
      indicated that 5 patients were cirrhotic, 3 had bridging fibrosis, and 4 had
      severe cholestasis or lesser degrees of fibrosis. Of 10 survivors in this series,
      9 patients currently have a serum bilirubin less than 1 mg% with a median
      bilirubin in the group of 0.6 mg% (range, 0.3 to 6.4 mg%). Twelve of the 13
      patients in this series were initially referred for liver-small bowel
      transplantation. CONCLUSIONS: This preliminary experience suggests that PN
      dependent patients with advanced liver dysfunction in the setting of the short
      bowel syndrome may, in some instances, experience functional and biochemical
      liver recovery. The latter appears to parallel autologous gut salvage in most
      cases. As a corollary, the authors believe that even advanced degrees of liver
      dysfunction should not preclude attempts at autologous gut salvage in very
      carefully selected patients. Such a policy of "aggressive conservatism" may help
      avoid the need for liver/intestinal transplantation in some patients who appear
      to be not responding to PN.

PMID- 15017550
TI  - Transanal one-stage endorectal pull-through for Hirschsprung's disease: a
      multicenter study.
AB  - BACKGROUND/PURPOSE: Transanal endorectal pull-through (TEPT) is the latest
      development in treatment of Hirschsprung's disease (HD). This prospective study
      was designed to evaluate the safety and efficacy of 1 stage TEPT technique in the
      management of patients with HD. METHODS: One hundred forty-nine children (116
      boys and 33 girls) aged 8 days to 14 years underwent 1 stage TEPT procedure over
      an 18-month period at 5 Egyptian academic pediatric surgical centers and
      affiliated hospitals. Median follow-up was 12 months (range, 3 to 21 months).
      These patients were evaluated with regard to age, sex, length of the aganglionic
      segment, intraoperative details, and postoperative functional results or
      complications. An electromyogram (EMG), endorectal ultrasound scan, and lower
      gastrointestinal (GI) motility studies were reserved for patients with
      postoperative problems with bowel control. RESULTS: Mean operating time was 120.2
      +/- 27.8 minutes (range, 60 to 210 minutes). The average length of resected bowel
      was 26.8 +/- 12.4 cm (range, 15 to 45 cm). Thirteen patients required laparotomy
      because of extension of aganglionic segment beyond the sigmoid colon in 9, tear
      in the mesenteric vessels in 2, and difficulties in getting to the submucosal
      plane in 2. Three deaths (2%) occurred 3 days, 4 days, and 4 weeks
      postoperatively, respectively. Postoperative complications included transient
      perianal excoriation in 48 patients (30 were <3 months of age), enterocolitis (n
      = 26), anastomotic stricture (n = 7), recurrent constipation (n = 6),
      hypoganglionosis at distal end of pulled through segment (n = 2), cuff abscess (n
      = 3), anastomotic leak (n = 1), adhesive bowel obstruction (n = 1), and rectal
      prolapse (n = 1). Complete anorectal continence was noted in 35 of 42 (83.3%)
      children older than 3 years, whereas soiling and frequent accidents still occur
      in 7, who showed a steady improvement in their continence status. CONCLUSIONS:
      One-stage TEPT technique is both feasible and safe technique in properly selected
      children with rectosigmoid HD in all ages. The technique is easily learned and is
      associated with excellent clinical results.

PMID- 15017551
TI  - A pilot study using total colonic manometry in the surgical evaluation of
      pediatric functional colonic obstruction.
AB  - BACKGROUND/PURPOSE: Total colonic manometry (TCM) can directly measure
      intraluminal pressures and contractile function of the entire colon. The utility
      of TCM to guide the surgical management of functional colonic obstruction has not
      been reported. METHODS: Total colonic manometry was performed on all patients
      referred for surgical evaluation of refractory functional colonic obstruction.
      Manometric tracings were obtained while fasting, after feeding, and after
      pharmacologic stimulation. RESULTS: Nine patients were referred for refractory
      colonic obstruction. The mean age was 4.8 years, and the mean duration of follow
      up was 29 months. Two patients had functional obstruction after repair of
      Hirschsprung's disease, and 7 patients had idiopathic functional obstruction. In
      the idiopathic group, 4 distinct motility patterns were identified: (1) normal
      colonic motility, (2) dysmotility with massive distension, (3) persistent
      segmental dysmotility, and (4) global neuropathy/myopathy. Both Hirschsprung's
      patients showed globally abnormal motility. Surgical management was guided by TCM
      results. There was significant improvement in bowel function and weight gain
      after manometry-guided intervention. An unnecessary laparotomy was avoided in 2
      patients. CONCLUSIONS: TCM can be valuable in deciding the need for and timing of
      diversion, the extent of resection required, and the suitability of the patient
      for restoring bowel continuity in refractory functional obstruction.

PMID- 15017552
TI  - Fibroblast growth factor 10 (Fgf10) invalidation results in anorectal
      malformation in mice.
AB  - BACKGROUND/PURPOSE: Anorectal malformations occur in 1 per 4,000 live births and
      represent a surgical challenge. Although critically important, the basic
      mechanisms of normal anorectal union are incompletely understood. Fgf10 signaling
      is known to serve a key role in mesenchymal/epithelial interactions in many organ
      systems including the gastrointestinal tract (GIT). The authors therefore
      hypothesized that Fgf10 signaling has a central role in normal anorectal
      development. METHODS: Fgf10 expression in wild-type (Wt) embryos was evaluated
      using whole-mount in situ hybridization. Wt and Fgf10-/- embryos were harvested
      from timed pregnant mothers at E12.5 through E17.5 and were analyzed for
      anorectal phenotype. RESULTS: Wt development of union between anorectal
      structures is completed between E12.5 and E13.5 with luminal communication
      between distal rectal epithelium and anus. Fgf10 is discretely expressed at E12.5
      in the distal rectum. Fgf10-/- mutants show failure of union of the rectum and
      anus at an early stage (E13.5) and near term (E17.5). CONCLUSIONS: Fgf10 is
      expressed in the rectum at the time when anorectal continuity is established,
      indicating a role in normal anorectal development. Fgf10 invalidation (Fgf10-/-
      mutant) results in a genetically reproducible anorectal malformation phenotype.
      Fgf10 function is critical for normal anorectal development.

PMID- 15017553
TI  - Fetal gastrointestinal motility in a rabbit model of gastroschisis.
AB  - PURPOSE: Gastrointestinal (GI) dysmotility occurs frequently in full-term infants
      with gastroschisis (GS). Although controversial, preterm delivery of infants with
      GS has been advocated to prevent the development of GI dysmotility, and
      understanding the etiology of gestational-related bowel injury may lead to
      prenatal therapies. Using a fetal rabbit model, the authors assessed in vivo and
      in vitro GI motility in preterm GS fetuses. METHODS: On gestation day 24 (term,
      31), surgery was performed in maternal rabbits and GS induced in fetuses, whereas
      control fetuses underwent sham procedures. On gestation day 29, both groups of
      fetuses received ultrasound-guided intragastric injection of fluorescein and
      colored microspheres. Two hours after injection, fetuses were delivered by
      cesarean section and stomach and small intestine harvested intact. "GI motility"
      was calculated as the distance traveled by fluorescein divided by total length.
      In vitro studies of fetal gastric muscle strips contractility responses to
      bethanechol, a cholinergic agonist, were assessed in an organ bath system. Data
      were analyzed as paired and unpaired t tests and expressed as means +/- SEM.
      RESULTS: GS reduced fetal body weight and intestinal length compared with
      controls (28.4 +/- 1.4 v. 33.5 +/- 1.5 g, 36.9 +/- 1.8 v. 25.9 +/- 1.2 cm; P
      <.05, respectively). Fetuses with GS showed markedly reduced in vivo GI motility
      (51.4 +/- 2.9 v 24.8 +/- 2.7%; P <.05) and in vitro gastric contractile tension
      (769 +/- 53 v 396 +/- 26 mNcm2; P <.05). CONCLUSIONS: GI exposure to amniotic
      fluid reduces intestinal motility and gastric contractility functions in the
      preterm rabbit fetus. The results suggest that GS-associated impairment of GI
      neuromuscular functions occurs in utero, before term, and may be responsive to
      manipulation of amniotic fluid content or other therapeutic interventions.

PMID- 15017554
TI  - A novel approach to the management of late-onset liver failure in biliary
      atresia.
AB  - PURPOSE: Late-onset hyperbilirubinemia in patients who have undergone a
      successful portoenterostomy (PE) for biliary atresia (BA) is usually considered
      evidence of ongoing severe liver failure. The authors recently have treated 2
      patients who had acute hyperbilirubinemia years and months after a successful PE
      and had dilated intrahepatic cysts. A combined operative and percutaneous
      approach reestablished drainage and a reduction in their bilirubin levels.
      METHODS: Data from 2 cases of BA and late-onset hyperbilirubinemia from
      obstruction were reviewed and analyzed. RESULTS: Two patients (15-year-old boy
      and a 2.5-year-old girl) presented with increasing serum bilirubin after a PE for
      BA in infancy. Both had extensive preoperative workup, which showed intrahepatic
      biliary dilatation in one and a large bile lake in the other. They underwent
      attempted percutaneous transhepatic cholangiography and stenting, followed by an
      intraoperative transhepatic approach in which the dilated ducts were connected to
      the PE. A rapid and sustained reduction in the serum bilirubin level was noted in
      these patients. CONCLUSIONS: When patients with BA after a successful PE present
      with sudden onset of hyperbilirubinemia, imaging for biliary obstruction should
      be carried out. If biliary dilatation is found, then a combined radiologic and
      operative approach may help improve the bile flow and delay the need for liver
      transplant.

PMID- 15017555
TI  - The ex utero intrapartum treatment procedure: Looking back at the EXIT.
AB  - PURPOSE: The ex utero intrapartum treatment (EXIT) procedure was developed
      originally for management of airway obstruction after fetal surgery, and
      indications have continued to expand for a variety of fetal anomalies. The
      authors review their single-institution experience with EXIT. METHODS:
      Retrospective review of all patients who underwent an EXIT procedure from 1993 to
      2003 (n = 52) was performed. Variables evaluated include indication for EXIT,
      gender, gestational age at EXIT, birth weight, maternal blood loss, operative
      complications, operative time, and survival rate. Technique, personnel, and
      anesthesic management were reviewed. RESULTS: Long-term follow-up was available
      for all patients. Fifty-one of 52 patients were born alive; currently, 27 of 52
      patients (52%) are alive. All deaths have been in patients with congenital
      diaphragmatic hernia. Forty-five patients underwent EXIT for reversal of tracheal
      occlusion for congenital diaphragmatic hernia. Of these patients, 30 underwent
      tracheal clip removal. Two patients had repair of tracheal injury from clipping
      at EXIT. Fifteen patients underwent bronchoscopy and tracheal balloon removal.
      Five patients underwent EXIT procedure for neck masses. Tracheostomy was
      performed in 3 of these patients. One patient was intubated successfully, and 1
      patient underwent resection of the neck mass while on placental support. Two
      patients underwent EXIT procedure and tracheostomy for congenital high-airway
      obstruction syndrome. Average gestational age at delivery was 31.95 +/- 2.55
      weeks. Average birth weight was 1,895 +/- 653 g. Average maternal blood loss was
      970 +/- 510 mL. Average operating time on placental support was 45 +/- 25 minutes
      with a maximum of 150 minutes. CONCLUSIONS: EXIT procedures can be performed with
      minimal maternal morbidity and with good outcomes. It is an excellent strategy
      for establishing an airway in a controlled manner, avoiding "crash" intubation or
      tracheostomy. Longer procedures on placental support allowing for definitive
      management of neck masses and airway obstruction have been realized. EXIT
      procedures have evolved from an adjunct to fetal surgery to a potentially life
      saving procedure in fetuses with airway compromise at birth.

PMID- 15017556
TI  - Does VATS provide optimal treatment of empyema in children? A systematic review.
AB  - PURPOSE: The surgical literature is replete with studies describing methods of
      treatment for pediatric empyema. The purpose of this report was to perform an
      evidence-based review of the literature to determine the most effective and
      appropriate treatment for empyema in infants and children. METHODS: The MEDLINE
      database was searched for English- and Spanish-language articles published from
      1987 through 2002 on the treatment of thoracic empyema in children. Additional
      unpublished data were obtained by contacting individual study authors. There were
      no multiinstitutional prospective studies; all were retrospective, institutional
      series. A true meta-analysis could not be performed because of inherent
      institutional bias and variability in outcome measures among studies. A Kruskal
      Wallis nonparametric test was used to compare methods detailed in the individual
      studies. RESULTS: Forty-four retrospective studies with a total of 1,369 patients
      were available for analysis. Four treatment strategies were compared: chest tube
      drainage alone (16 studies, 611 patients), chest tube drainage with fibrinolytic
      instillation (10 studies, 83 patients), thoracotomy (13 studies, 226 patients),
      and video-assisted thoracoscopic decortication (VATS; 22 studies, 449 patients).
      Outcome measures common to the majority of studies included length of stay, fever
      duration, l of antibiotic therapy duration, and duration of chest tube drainage.
      Patients undergoing early VATS or thoracotomy had shorter length of stay (P
      =.003). There was a trend for shorter duration of postoperative fever compared
      with chest tube alone or with fibrinolytic therapy, but this did not reach
      statistical significance (P =.055). There was no statistical difference in chest
      tube duration between methods. There was no trend correlating antibiotic use with
      treatment methods, length of hospital stay, duration of fever, or length of chest
      tube requirement. CONCLUSIONS: Early VATS or thoracotomy leads to shorter
      hospitalization. The duration of chest tube placement and antibiotic use is
      variable and does not correlate with treatment method. A carefully designed,
      multiinstitutional, randomized study would lead to the development of evidence
      based standards that may optimize the treatment of thoracic empyema in children.

PMID- 15017557
TI  - Quantitation of lung sealing in the survival swine model.
AB  - PURPOSE: Small intercostal spaces and limited pleural space significantly limits
      the use of 12-mm stapling devices in pediatric thoracoscopic surgery. The goal of
      this study was to compare sealing of lung tissue by the 5-mm Ligasure (Valley
      Lab, Boulder, CO) device to a standard 12-mm Endo-GIA stapler (US Surgical,
      Norwalk, CT). METHODS: Institutional Animal Care and Use Committee (IACUC)
      approval was obtained (#A3-02). Sixteen 10-kg female swine were divided between 2
      survival surgical groups. Lung biopsy sections of the lingula were taken by 2
      methods: group A, left anterolateral thoracotomy employing a 12-mm Endo-GIA
      stapler and group B, left thoracoscopy employing the Ligasure 5-mm instrument.
      After a 7-day survival period, lung burst pressures were measured by flow
      controlled insufflation into the trachea. RESULTS: Burst pressure measurement
      reflects the first air leak. By Student's t test analysis there were no
      statistically significant differences between the burst pressures, biopsy
      weights, or operating times. Fifty percent (4 of 8) of the animals in group A
      (Endo-GIA), and 50% (4 of 8) of the animals in group B (Ligasure) developed the
      first air leak in the nonoperative lung. Two animals, one from each group, had
      evidence of intrapleural infections at the time of necropsy. These were
      asymptomatic and did not appear to affect burst pressure measurement.
      CONCLUSIONS: After 7 days of healing, lung biopsy sites created with both the
      Ligasure and the Endo-GIA stapler have burst strengths equal to or greater than
      that of normal lung tissue in the swine survival model.

PMID- 15017558
TI  - Complications associated with the Nuss procedure: analysis of risk factors and
      suggested measures for prevention of complications.
AB  - PURPOSE: Because the Nuss procedure for the correction of pectus excavatum is in
      its early stage, there have been problems that need to be solved. The authors
      examined complications in a single-institute experience of the Nuss technique to
      develop possible solutions to prevent them. METHODS: A total of 335 consecutive
      patients who underwent the Nuss procedure between August 1999 and September 2002
      were studied retrospectively. Median age was 8 years (range, 1 to 46). Two
      hundred sixty-four patients (78.8%) were in the pediatric group (age < or = 15)
      and 71 patients (21.2%) were in adult group (age > 15). One hundred ninety-three
      patients (57.6%) had symmetric and 142 patients (42.4%) had asymmetric pectus
      configurations. Risk factors predicting postoperative complications were analyzed
      using multivariate logistic regression. RESULTS: Postoperative complication rate
      was 16.1% (54 of 335) in total patients. Early complications (within a month)
      were pneumothorax (n = 23; 6.9%), wound seroma (n = 11; 3.3%), and bar
      displacement (n = 8; 2.4%). Late complications (after a month) were pericarditis
      and pericardial effusion (n = 5; 1.5%), bar displacement (n = 4; 1.2%), and
      hemothorax (n = 3; 0.9%). Techniques were modified to prevent complications
      especially in bar shaping and fixation, which led to decrease of complication
      rate in later experience (operation date 1, 29.4%; 15 of 51 v. operation date 2,
      12.0%; 34 of 284; P =.004). Grand Canyon type (eccentric long canal type) showed
      a higher complication rate than other types (40%, 12 of 30 v. 12.1%, 37 of 305; P
      <.001). Risk factors were analyzed in each group. CONCLUSIONS: Major
      complications were related to severe eccentric type of pectus configuration
      (Grand Canyon type) and lack of surgeon's experience (earlier date of operation).
      Complication rate was reduced with accumulation of experience and advancement of
      surgical techniques. The Nuss procedure can be performed at a low risk of
      complications with the current technique.

PMID- 15017559
TI  - Thyroglossal duct infections and surgical outcomes.
AB  - PURPOSE: Thyroglossal duct cysts (TGDC) are the most common head and neck
      congenital anomalies in children and often present as infected neck masses. The
      authors reviewed their experience with TGDC to determine if preoperative
      infection was related to postoperative complications, including recurrence and
      postoperative infection. METHODS: The medical records of 99 patients undergoing
      excision of TGDC from January 1991 to July 2002 were reviewed. Factors thought to
      be associated with recurrence (age, history of infection, drainage, abscess, and
      operative procedure) were analyzed. RESULTS: Ninety-nine patients made up the
      study group. The mean age at operation was 5.0 years (range, 6 months to 16
      years) with a male to female ratio of 1.6:1. TGDC recurred in 12.1% (12 of 99) of
      these patients. There was no gender difference for those with and without
      recurrence. The presence of an abscess or cellulitis preoperatively (22 of 99
      patients) did not correlate with recurrence (NS). In addition, postoperative
      infection occurred in 13 of 99 patients and also was independent of preoperative
      infection. However, postoperative infection clearly was associated with an
      increased risk of TGDC recurrence. Seven of 87 patients without recurrence had a
      postoperative infection, whereas 6 of 12 of those who had a recurrence had a
      postoperative infection (P <.001). The mean follow-up was 3.7 years and was
      comparable for the 2 groups (recurrence v. resolution). Twelve patients
      successfully underwent a second procedure for recurrence. CONCLUSIONS: In this
      large series of TGDC, preoperative infection occurred in approximately 1 of 5
      patients and was not predictive of recurrence. Although postoperative infection
      did not correlate with the presence of preoperative infection, it was clearly
      associated with a statistically significant incidence of recurrent disease.

PMID- 15017560
TI  - Biomolecular markers and involution of hemangiomas.
AB  - BACKGROUND/PURPOSE: Vascular anomalies are a diverse set of lesions with distinct
      clinical behaviors, whose biomolecular characteristics are largely undefined.
      Common hemangiomas proliferate during the first year of life, then involute at a
      variable pace over several years. Other vascular tumors may involute much more
      quickly (rapidly involuting congenital hemangiomas [RICH]), not at all (lymphatic
      malformation), or display malignant behavior (angiosarcoma). Key cytokines
      driving angiogenesis include vascular endothelial growth factor (VEGF) family
      members/receptors (placental growth factor [PIGF], VEGF-A, and VEGF-C) and
      angiopoietins. The authors hypothesized that involuting hemangiomas would display
      biologic markers distinctly different from noninvoluting vascular lesions.
      METHODS: Six patient samples were analyzed: (1) RICH, (2) proliferating
      hemangioma, (3) involuting hemangioma, (4) tufted angioma, (5) hepatic
      angiosarcoma, and (6) lymphatic malformation. Detailed examination of
      endothelial/vascular mural cell status was performed by fluorescent double-label
      immunostaining using specific markers (PECAM-1, alphaSMA) in combination with
      markers of proliferation (anti-phospho-histone H3) or apoptosis (TUNEL).
      Expression of PIGF, VEGF-A, VEGF-C, and Ang-1 was localized by in situ
      hybridization. RESULTS: Involuting/proliferating common hemangiomas demonstrated
      vasculature with abundant vascular mural cells (alphaSMA+); in contrast,
      alphaSMA(+) cells were rare in RICH vessels. Endothelial apoptosis was increased
      dramatically, but proliferation was unchanged during involution. VEGF-A was
      expressed in all lesions except lymphatic malformation, which displayed VEGF-C
      and Ang-1 upregulation. Strikingly, PIGF expression was increased markedly in the
      lesions predicted to involute/actively involuting but was virtually absent from
      noninvoluting tumors. CONCLUSIONS: Vessel architecture and endothelial/vascular
      mural cell status differed between lesions, differentiating even common versus
      rapidly involuting hemangioma and corresponded to clinical involution. VEGF-A
      expression characterized endothelial-derived lesions, whereas VEGF-C marked
      lymphatic-derived cells. PIGF expression occurred only in vascular anomalies
      predicted to involute or actively involuting, a pattern potentially linked to
      PIGF function as a conditional antagonist of VEGF-A. Thus, distinct patterns of
      morphology and angiogenic factor expression characterize vascular anomalies with
      different clinical behaviors.

PMID- 15017561
TI  - Endostatin-mediated concomitant resistance in neuroblastoma.
AB  - PURPOSE: Concomitant resistance, the phenomenon whereby a primary malignancy
      inhibits the growth of metastatic lesions, is likely caused by the production of
      endogenous anti-angiogenic factors. The purpose of this study was to evaluate the
      influence of the angiogenesis inhibitor, endostatin, expressed by primary sites
      of neuroblastoma, on synchronous disease. METHODS: Two neuroblastoma models were
      used. In one, the growth of a second primary tumor in mice with an already
      established primary tumor was compared with tumor growth in nave mice. In the
      other, the growth of liver metastases arising spontaneously from a subcutaneous
      tumor was compared in mice in which the primary tumor was either excised or left
      in place. Systemic endostatin levels and endothelial cell density, vascularity,
      and degree of apoptosis in the secondary tumors and liver metastasis were
      evaluated. RESULTS: Subcutaneous tumors in mice with preexisting neuroblastoma
      were significantly smaller than in mice without an established primary tumor;
      systemic endostatin levels at the time of tumor implantation in mice with
      preexisting tumors were nearly 3 times that of nave mice. Decreased angiogenesis
      and increased apoptosis were seen in the secondary tumors of mice with
      preexisting tumors. Similarly, the weight of liver metastases was significantly
      less in mice in which the primary tumor was left in place as compared with those
      in which the primary tumor had been excised. Systemic endostatin levels in this
      model paralleled the status of the primary tumor; levels decreased with primary
      tumor excision but increased when the primary tumor was retained and allowed to
      grow. Although no difference in microvessel density was seen between groups in
      the liver metastasis, more tumor cell apoptosis was seen in liver metastasis when
      the primary tumor was retained. Thus, the presence of an established primary
      neuroblastoma had a significant inhibitory effect on the growth of secondary
      disease in both models and was associated with elevated systemic endostatin
      levels. CONCLUSIONS: Concomitant antitumoral resistance occurred in these
      experimental murine models of neuroblastoma and appears to be caused, at least in
      part, by angiogenesis inhibition mediated by endostatin elaborated from primary
      tumors.

PMID- 15017562
TI  - The impact of gross total resection on local control and survival in high-risk
      neuroblastoma.
AB  - BACKGROUND/PURPOSE: Gross total resection of the primary tumor in treatment of
      high-risk neuroblastoma remains controversial. Furthermore, there are few reports
      of the effect of primary tumor resection on local control as opposed to overall
      survival. The authors reviewed their institutional experience to assess the
      effect of primary tumor resection on local control and overall survival. METHODS:
      A total of 141 patients were treated on protocol between November 1, 1979 and
      June 25, 2002 and are the subject of this report. Gross total resection was
      assessed by review of operative notes, postoperative computerized axial
      tomograms, and postoperative meta-iodobenzyl guanidine (MIBG)1 scans when
      available. RESULTS: The median age was 3.3 years, and all patients were
      International Neuroblastoma Staging System (INSS) stage 4 with 79% having
      metastases to cortical bone. The primary site was the adrenal gland in 74%, the
      central abdominal compartment in 13%, the posterior mediastinum in 7%, and other
      sites in 6%. Gross total resection was accomplished in 103 (73%) but was more
      than 90% for the last 3 protocols. Five kidneys were lost overall. The
      probability of local progression was 50% in unresected patients compared with 10%
      in patients undergoing gross total resection (P <.01). Overall survival rate in
      resected patients was 50% compared with 11% in unresected patients (P <.01).
      CONCLUSIONS: Our data indicate that local control and overall survival rate are
      correlated with gross total resection of the primary tumor in high-risk
      neuroblastoma. Gross total resection should be part of the management of stage 4
      neuroblastoma in patients greater than 1 year of age.

PMID- 15017563
TI  - Surgical management and outcome of osteosarcoma patients with unilateral
      pulmonary metastases.
AB  - PURPOSE: The surgical management of osteosarcoma patients with unilateral
      pulmonary nodules is controversial. The authors reviewed their institutional
      experience to evaluate the incidence of occult contralateral metastases. METHODS:
      Data were obtained retrospectively on all consecutive osteosarcoma patients from
      1980 to 2002. Eighty-four patients with pulmonary nodules were identified. Forty
      one had bilateral disease, and 43 had unilateral involvement by computed
      tomography (CT) scan. RESULTS: All 43 patients with unilateral nodules underwent
      ipsilateral thoracotomies. Fifteen patients had negative exploration findings,
      and only 1 had pulmonary relapse. Of the 28 patients with metastases confirmed at
      initial thoracotomies, 14 had extensive pleural or extrapulmonary disease at
      initial thoracotomy followed by disease progression. The other 14 are separated
      into early versus late metastases, using 2 years from diagnosis as the cutoff
      point. Seven of the 9 (78%) patients with early metastases had or subsequently
      had contralateral disease; 6 were identified at staged contralateral thoracotomy
      and 1 had relapsed in the unexplored lung a year later. Only 1 of the 5 patients
      with late unilateral metastases had relapse in the contralateral side.
      CONCLUSIONS: Our data indicate that there is a high rate of contralateral
      involvement in osteosarcoma patients with unilateral nodules diagnosed by CT
      scan. Staged bilateral thoracotomies should be considered in osteosarcoma
      patients presenting with unilateral pulmonary disease on imaging studies within 2
      years of diagnosis.

PMID- 15017564
TI  - Outcome and staging evaluation in malignant germ cell tumors of the ovary in
      children and adolescents: an intergroup study.
AB  - PURPOSE: The aim of this study was to perform an evaluation of outcome and the
      role of surgical staging components in malignant germ cell tumors (GCT) of the
      ovary in children and adolescents. METHODS: From 1990 to 1996, 2 intergroup
      trials for malignant GCT were undertaken by Pediatric Oncology Group (POG) and
      Children's Cancer Study Group (CCG). Stage I-II patients were treated with
      surgical resection and 4 cycles of standard dose cisplatin (100 mg/m2/cycle),
      etoposide, and bleomycin (PEB) chemotherapy. Stage III-IV patients were treated
      with surgical resection and randomly assigned to chemotherapy with PEB or high
      dose cisplatin (200 mg/m2/cycle) with etoposide and bleomycin (HDPEB). Patients
      unresectable at diagnosis had second-look operation after 4 cycles of
      chemotherapy if residual tumor was seen on imaging studies. IRB approval of the
      protocols was obtained at each participating institution. An analysis of outcome
      data, operative notes, and pathology reports in girls with ovarian primary site
      was done for this report. RESULTS: There were 131 patients with ovarian primary
      tumors of 515 entered on these studies. Mean age was 11.9 years (range, 1.4 to 20
      years). Six-year survival rate was stage, I 95.1%; stage II, 93.8%; stage III,
      98.3%; stage IV, 93.3%. In only 3 of 131 patients were surgical guidelines
      followed completely. Surgical omissions resulting in protocol noncompliance
      resulted from failure to biopsy bilateral nodes (97%), no omentectomy (36%), no
      peritoneal cytology (21%), no contralateral ovary biopsy (59%). More aggressive
      procedure than recommended by guidelines included total hysterectomy and
      bilateral salpingo-oophorectomy in 6 patients and retroperitoneal node dissection
      in 10 patients. Correlation of gross operative findings with pathology results
      was carried out for ascites, lymph nodes, implants, omentum, and contralateral
      ovary. CONCLUSIONS: Pediatric ovarian malignant GCT (stages I-IV) have excellent
      survival with conservative surgical resection and platinum-based chemotherapy.
      Survival appears to have been unaffected by deviations from surgical guidelines.
      New surgical guidelines are proposed based on correlation of gross findings,
      histology, and outcome in these intergroup trials.

PMID- 15017565
TI  - Sacrococcygeal teratoma: prenatal assessment, fetal intervention, and outcome.
AB  - PURPOSE: To understand the natural history and define indications for fetal
      intervention in sacrococcygeal teratoma (SCT), the authors reviewed all cases of
      fetal SCT presenting for evaluation. METHODS: Prenatal diagnostic studies
      including ultrasound scan, magnetic resonance imaging (MRI), echocardiography and
      pre- and postnatal outcomes were reviewed in 30 cases of SCT that presented
      between September 1995 and January 2003. RESULTS: The mean gestational age (GA)
      at presentation was 23.9 weeks (range, 19 to 38.5) with 3 sets of twins (10%).
      Overall outcomes included 4 terminations, 5 fetal demises, 7 neonatal deaths, and
      14 survivors. Significant obstetric complications occurred in 81% of the 26
      continuing pregnancies: polyhydramnios (n = 7), oligohydramnios (n = 4), preterm
      labor (n = 13), preeclampsia (n = 4), gestational diabetes (n = 1), HELLP
      syndrome (n = 1), and hyperemesis (n = 1). Fetal intervention included cyst
      aspiration (n = 6), amnioreduction (n = 3), amnioinfusion (n = 1), and open fetal
      surgical resection (n = 4). Indications for cyst aspiration and amnioreduction
      were maternal discomfort, preterm labor, and prevention of tumor rupture at
      delivery. Although 15 SCTs were solid causing risk for cardiac failure, only 4
      fetuses met criteria for fetal debulking based on ultrasonographic and
      echocardiographic evidence of impending high output failure and favorable anatomy
      at 21, 23.6, 25, and 26 weeks' gestation. Intraoperative events included maternal
      blood transfusion (n = 1), fetal blood transfusion (n = 2), chorioamniotic
      membrane separation (n = 2), and fetal arrest requiring successful
      cardiopulmonary resuscitation (CPR) (n = 1). In the fetal resection group, 3 of 4
      survived with mean GA at delivery of 29 weeks (range, 27.6 to 31.7 weeks), mean
      birth weight of 1.3 kg, hospital stay ranging from 16 to 34 weeks, and follow-up
      ranging from 20 months to 6 years. Postnatal complications in the fetal surgery
      group included neonatal death (n = 1, secondary to premature closure of ductus
      arteriosus with cardiac failure), embolic event (n = 1, resulting in unilateral
      renal agenesis, jejunal atresia), chronic lung disease (n = 1), and tumor
      recurrence (n = 1). CONCLUSIONS: For fetal SCT, the rapidity at which cardiac
      compromise can develop and the high incidence of obstetric complications warrant
      close prenatal surveillance. Amnioreduction, cyst aspiration, and surgical
      debulking are potentially life-saving interventions.

PMID- 15017566
TI  - Contouring buttock reconstruction after sacrococcygeal teratoma resection.
AB  - PURPOSE: Massive sacrococcygeal teratomas are typically resected and closed in a
      "chevron" fashion. The resultant scar may leave protuberant "dog ears" and extend
      across and below the infragluteal creases down onto the posterior thighs, causing
      undesirable buttock deformity. Given the redundant skin often available, the
      authors sought to develop a closure technique to minimize deformity and
      unpleasant scars. METHODS: At the time of resection of 2 sacrococcygeal
      teratomas, attention was directed to minimizing redundant skin, restoring normal
      buttock contour, and avoiding scars crossing the infragluteal crease. After
      properly securing the anal location, serial polygonal skin excisions were
      performed, working the excess tissue centrally rather than peripherally, leaving
      2 right-angled scars on each buttock. RESULTS: Each infant underwent successful
      reconstruction with a normal buttock contour without redundancy. All scars on the
      buttocks can be easily covered by bathing attire. CONCLUSIONS: The excess skin
      expanded by large sacrococcygeal teratomas affords an opportunity to apply
      straightforward tissue rearrangement principles to reconstruct the buttocks with
      a normal contour and hidden scars.

PMID- 15017567
TI  - A multidisciplinary approach to the adolescent bariatric surgical patient.
AB  - PURPOSE: Pediatric obesity is an epidemic in the United States. As of yet, no
      surgical programs specifically dedicated to the management of clinically severely
      obese adolescents exist. The purpose of this report was to describe the
      establishment and early experience of a multidisciplinary Comprehensive Weight
      Management Center (CWMC) in a free-standing children's hospital. METHODS: With
      input from an ethicist, gastroenterologist, pulmonologist, endocrinologist, and
      adolescent medicine physician, guidelines for patient selection, evaluation, and
      bariatric surgical management were developed and implemented. Roux-en-Y gastric
      bypass (RYGBP) surgery has been performed using open and laparoscopic techniques.
      RESULTS: The average age and body mas index (BMI) for 79 patients referred to the
      CWMC has been 16 years and 54 kg/m2, for boys and 17 years and 51 kg/m2 for
      girls. Twenty-five percent have been considered appropriate for RYGBP, 25% have
      not met criteria for surgery, and 50% are being evaluated. Ten patients who have
      undergone RYGBP had comorbidities of their obesity, including type 2 diabetes
      mellitus (DM), obstructive sleep apnea syndrome (OSAS), pulmonary embolism,
      hypertension, dyslipidemias, and depression. Clinically significant weight loss
      with resolution of comorbidities has occurred in all patients. Significant
      complications have included leak from the gastric remnant, DVT, partial roux limb
      obstruction, and micronutrient deficiency. CONCLUSIONS: RYGBP is an effective
      means to treat obesity-related morbidity in the adolescent. A multidisciplinary
      team of pediatric specialists is needed for optimal preoperative decision making
      and postoperative management. Results have been satisfactory and justify a
      clinical trial to confirm the safety and efficacy of bariatric surgery in the
      adolescent population.

PMID- 15017568
TI  - Glucagonlike peptide-2 analogue: a possible new approach in the management of
      inflammatory bowel disease.
AB  - BACKGROUND/PURPOSE: Glucagonlike peptide-2alpha (GLP-2alpha) has been shown to be
      a growth factor for the small intestine. This study investigated the benefits of
      intravenous and intraluminal administration of GLP-2alpha using a rat model of
      inflammatory bowel disease (IBD). METHODS: Normal Fisher rats and HLA-B27 (IBD)
      rats were treated for 14 days as follows: Fisher, intravenous saline (n = 6); HLA
      B27, intravenous saline (n = 6); HLA-B27, intravenous GLP-2alpha (50 microg/kg/d;
      n = 5); Fisher, intraluminal saline (n = 5); HLA-B27, intraluminal saline (n =
      5); or intraluminal GLP-2alpha (50 microg/kg/d; n = 5). Rats were evaluated for
      frequency of diarrhea, and the bowel was analyzed for gross and microscopic
      lesions. Statistical evaluations were determined using analysis of variance
      (ANOVA). A P value of.05 was significant. RESULTS: Intravenous GLP-2alpha
      decreased diarrhea and the number of bowel lesions (P <.05). Microscopic
      inflammation was reduced by 24% but was not statistically significant.
      Intraluminal GLP-2alpha decreased the number of small intestine lesions (P <.05)
      and the microscopic inflammation (P <.05) but did not significantly reduce
      diarrhea or the overall number of bowel lesions. CONCLUSIONS: GLP-2alpha
      ameliorates the signs of IBD in HLA-B27 rats. Intravenous GLP-2alpha reduces
      diarrhea more effectively than intraluminal administration, and both routes are
      equally effective in ameliorating inflammation. GLP-2alpha potentially provides a
      new modality for the treatment of IBD.

PMID- 15017569
TI  - Rotavirus-associated necrotizing enterocolitis: an insight into a potentially
      preventable disease?
AB  - PURPOSE: The aim of this study was to test the hypothesis that rotavirus
      associated necrotizing enterocolitis (NEC + RV) differs from NEC associated with
      other organisms (NEC-RV). METHODS: Neonates with modified Bell stage II or higher
      NEC were identified. Demographic, clinical, and outcome information was collected
      prospectively. Fecal specimens from all infants were tested for confirmation of
      rotavirus infection (RVI) by immunoelectron microscopy (IEM). RESULTS: Of 2,444
      admissions in the neonatal intensive care unit (NICU), 129 (5.3%) had NEC. Thirty
      eight (29%) were rotavirus positive. The 2 groups did not differ in maternal or
      neonatal characteristics. Stage III or higher NEC was more common in the NEC-RV
      infants (62% v. 39%; P =.032), whereas recurrence was more common in NEC + RV
      group (P <.0001). The predominant distribution of nondiffuse pneumatosis (n = 52)
      was right sided in NEC-RV group and left sided in NEC + RV group (P <.0001).
      Surgical intervention (SI) did not differ between the 2 groups. The complications
      and mortality rates also were similar. Severe pneumatosis (P =.009) and severe
      thrombocytopenia (Platelet count < 50,000/mm3; P <.0001) increased, while human
      milk feedings decreased (P =.022) the odds for surgery. The annual distribution
      of NEC + RV paralleled RVI in the community. CONCLUSIONS: Generally, NEC + RV is
      a less severe disease than NEC - RV as classified by modified Bell staging.
      However, it can reach advanced stages obscuring distinction from NEC - RV.
      Indications for surgery should not be altered by identification of RVI in these
      infants. Monitoring RVI in the community, adhering to infection control measures,
      human milk feedings, and improving neonatal immunity against RVI may reduce the
      incidence of NEC + RV.

PMID- 15017570
TI  - Diagnosis of acute appendicitis in children using a clinical practice guideline.
AB  - PURPOSE: In October 2000, our institution implemented a clinical practice
      guideline (CPG) utilizing selective computed tomography (CT) and ultrasound scan
      (US) for the evaluation of children with suspected appendicitis. The authors
      sought to determine surgical outcomes and diagnostic accuracy in the CPG period.
      METHODS: The authors retrospectively analyzed the medical records of patients
      evaluated under the CPG at their institution between January 1 and December 31,
      2001. Depending on a patient's clinical presentation, the CPG recommends
      immediate surgery or further evaluation with CT or US. CPG patients were
      identified if they received an appendectomy or a CT or US for suspected
      appendicitis. Negative appendectomy and perforation rates, as well as admissions
      for inpatient observation were compared with control patients treated for
      suspected appendicitis at our hospital in 1997, before frequent utilization of
      imaging studies. RESULTS: In the CPG period, 571 patients were evaluated for
      acute appendicitis, with 272 undergoing an appendectomy. Whereas 513 patients
      (90%) received a CT or US, only 34 patients (6%) were admitted to the surgical
      service for serial examinations. Patients with a histologically normal appendix
      decreased from 27 of 255 (10.6%) in 1997 to 15 of 272 (5.5%) in 2001 (P =.03).
      Fifty-seven patients (22.2%) in 2001 had a perforated appendix compared with 65
      (28.5%) in 1997 (P =.11). The CPG, incorporating clinical judgment and selected
      imaging, had a sensitivity of 98.8%, a specificity of 95.2%, and positive and
      negative predictive values of 94.4% and 99.0%, respectively. CONCLUSIONS: A
      clinical practice guideline selectively utilizing CT and US is highly accurate in
      the diagnosis of acute appendicitis, minimizing the need for inpatient admission
      for serial examinations.

PMID- 15017571
TI  - Delayed versus immediate surgery in acute appendicitis: do we need to operate
      during the night?
AB  - BACKGROUND/PURPOSE: Over the last 4 years, the authors changed their management
      of acute nonperforated appendicitis from emergent surgery within the first 2 to 6
      hours of admission to initiation of antibiotic therapy with operation within 24
      hours of admission in those seen in the late evening or early morning. They
      examined, therefore, whether a delay in operation for acute appendicitis would
      affect outcome measures of patient morbidity and resource use. METHODS: The
      medical records of 126 patients with acute appendicitis occurring between 1998
      and 2001 were retrospectively reviewed. Incidence of perforation at surgery,
      length of stay (LOS), hospital charges, operating time, and complications as a
      function of duration between emergency room (ER) triage and operation (ER-OR) or
      admission and operation (Admit-OR) were analyzed by Student's t test, and
      regression analysis with P less than.05 considered significant. RESULTS: Thirty
      eight children (26%) were operated on within 6 hours of ER triage, whereas the
      remaining 88 children (74%) were operated on between 6 and 24 hours from ER
      triage. No significant difference was noted in perforation rate, LOS, costs, or
      operative time, nor were substantial changes in complications noted between those
      with an ER-OR < or =6 hours and greater than 6 hours. Likewise, no significant
      differences in these outcome measures were noted for Admit-OR greater than 6 when
      compared with < or =6 hours. Only costs with ER-OR greater than 12 hours and LOS
      with Admit-OR greater than 6 hours were significantly (without Bonferroni
      correction) different than < or = 6 hours. Multivariable linear regression
      analysis identified only LOS as a significant predictor of time to OR.
      CONCLUSIONS: In children with acute appendicitis, delaying surgery until the
      daytime hours did not significantly affect operating time, perforation rate, or
      complications. Delayed management allows greater efficiency and effective use of
      physician and hospital resources, including decreased resident involvement in
      operations during the night.

PMID- 15017572
TI  - Surgical management of cloacal malformations: a review of 339 patients.
AB  - BACKGROUND/PURPOSE: The aim of this study was to describe lessons learned from
      the authors' series of patients with cloaca and convey the improved understanding
      and surgical treatment of the condition's wide spectrum of complexity. METHODS:
      The medical records of 339 patients with cloaca operated on by the authors were
      retrospectively reviewed. RESULTS: A total of 265 patients underwent primary
      operations, and 74 were secondary. All patients were approached posterior
      sagittally; 111 of them also required a laparotomy. The average length of the
      common channel was 4.7 cm for patients that required a laparotomy and 2.3 cm for
      those that did not. Vaginal reconstruction involved a vaginal pull-through in 196
      patients, a vaginal flap in 38, vaginal switch in 30, and vaginal replacement in
      75 (36 with rectum, 31 with ileum, and 8 with colon). One hundred twenty-two
      patients underwent a total urogenital mobilization. Complications included
      vaginal stricture or atresia in 17, urethral strictures in 6, and urethro-vaginal
      fistula in 19, all of which occurred before the introduction of the total
      urogenital mobilization. A total of 54% of all evaluated patients were continent
      of urine and 24% remain dry with intermittent catheterization through their
      native urethra and 22% through a Mitrofanoff-type of conduit. Seventy-eight
      percent of the patients with a common channel longer than 3 cm require
      intermittent catheterization compared with 28% when their common channel was
      shorter than 3 cm. Sixty percent of all cases have voluntary bowel movements (28%
      of them never soiled, and 72% soiled occasionally). Forty percent are fecally
      incontinent but remain clean when subjected to a bowel management program. Forty
      eight patients born at other institutions with hydrocolpos were not treated
      correctly during the neonatal period. The surgeons failed to drain the dilated
      vaginas, which interfered with the drainage of the ureters and provoked urinary
      tract infections, pyocolpos, and/or vaginal perforation. In 24 patients, the
      colostomy was created too distally, and it interfered with the pull-through.
      Twenty-three patients suffered from colostomy prolapse. All of these patients
      required a colostomy, revision before the main repair. Thirty-six patients
      underwent reoperation because they had a persistent urogenital sinus after an
      operation done at another institution, and 38 patients underwent reoperation
      because they suffered from atresia or stenosis of the vagina or urethra. The
      series was divided into 2 distinct groups of patients: group A were those with a
      common channel shorter than 3 cm (62%) and group B had a common channel longer
      than 3 cm (38%). CONCLUSIONS: The separation of these groups has important
      therapeutic and prognostic implications. Group A patients can be repaired
      posterior sagittally with a reproducible, relatively short operation. Because
      they represent the majority of patients, we believe that most well-trained
      pediatric surgeons can repair these type of malformations, and the prognosis is
      good. Group B patients (those with a common channel longer than 3 cm), usually
      require a laparotomy and have a much higher incidence of associated urologic
      problems. The surgeons who repair these malformations require special training in
      urology, and the operations are prolonged, technically demanding, and the
      functional results are not as good as in group A. It is extremely important to
      establish an accurate neonatal diagnosis, drain the hydrocolpos when present, and
      create an adequate, totally diverting colostomy, leaving enough distal colon
      available for the pull-through and fixing the colon to avoid prolapse. A correct
      diagnosis will allow the surgeon to repair the entire defect and avoid a
      persistent urogenital sinus. Cloacas comprise a spectrum of defects requiring a
      complex array of surgical decisions. The length of the common channel is an
      important determinant of the potential for urinary control, and predicts the
      extent of surgical repair.

PMID- 15017573
TI  - The parental perspective regarding the contralateral inguinal region in a child
      with a known unilateral inguinal hernia.
AB  - PURPOSE: The management of the contralateral region in a child with a known
      inguinal hernia has been debated by surgeons for more than 50 years. However, the
      perspective of the child's parents has not been sought, and this study was
      designed to evaluate parental views on this topic. METHODS: After IRB approval,
      all patients less than 10 years of age with a unilateral inguinal hernia seen by
      the senior surgeon were studied prospectively from November 2001 through February
      2003. A study sheet was given to the parents about the nature of an inguinal
      hernia, the incidence of 20% to 40% of a contralateral patent processus vaginalis
      (CPPV), and the possible surgical options (perform repair of the unilateral
      inguinal hernia only, repair the unilateral inguinal hernia with contralateral
      exploration and repair if indicated, or unilateral inguinal hernia repair with
      laparoscopy through the ipsilateral hernia sac and repair of a CPPV if
      discovered). The parents of the last 113 patients requesting contralateral
      inspection were asked their motives (convenience or anesthesia concerns)
      regarding their decision. RESULTS: One hundred sixty-seven patients comprise the
      study group. Twelve parents chose unilateral repair alone, 13 chose bilateral
      incisions with contralateral repair if a CPPV was found, and 142 chose unilateral
      hernia repair with laparoscopic contralateral inspection followed by repair if
      needed. Regarding their motives, 90 of the last 113 parents requesting
      contralateral inspection indicated that convenience was the primary motive.
      Surprisingly, only 21 exhibited concerns about their child undergoing a second
      anesthesia. CONCLUSIONS: When presented options regarding management of a
      unilateral inguinal hernia, parents preferred laparoscopic inspection and repair
      of the contralateral region, if needed, more for convenience than for concerns
      about a second procedure and anesthesia.

PMID- 15017575
TI  - Application of the APSA evidence-based guidelines for isolated liver or spleen
      injuries: a single institution experience.
AB  - PURPOSE: In 1998, the American Pediatric Surgical Association (APSA) recommended
      evidence-based guidelines for the management of hemodynamically stable patients
      with isolated liver or spleen injuries. A clinical practice guideline (CPG) was
      developed using the APSA guidelines. This study analyzes the impact of the CPG on
      the care of these children in a single institution. METHODS: Patients treated
      with the CPG between September 1998 and June 2002 were compared with a similar
      cohort admitted from February 1992 to October 1997, before the CPG was
      instituted. Groups were analyzed for age, computerized tomographic organ injury
      grade, hematocrits obtained, Injury Severity Score (ISS), length of intensive
      care unit (ICU) and hospital stay, follow-up imaging studies performed, and
      outcome. RESULTS: CPG patients had a shorter ICU length of stay (0.4 +/- 0.6 v
      1.4 +/- 0.6 days; P <.001), shorter hospital stay (3.8 +/- 1.2 v 7.2 +/- 1.4
      days; P <.001), fewer hematocrits obtained (4.7 +/- 2.2 v 9.2 +/- 3.1; P <.001),
      and fewer follow-up imaging studies (0.3 +/- 0.4 v 2.1 +/- 1.1; P <.001). One
      patient in the CPG group was readmitted for delayed hemorrhage. No urgent
      operations were performed in either group. CONCLUSIONS: Application of an APSA
      based CPG resulted in decreased length of ICU stay, decreased hospital stay, and
      decreased resource utilization without any noted effect on outcome.

PMID- 15017574
TI  - Effect of age on cervical spine injuries in children after motor vehicle
      collisions: effectiveness of restraint devices.
AB  - PURPOSE: Despite the devastating consequences of cervical spine (C-spine) injury
      in children after motor vehicle collisions (MVC), the factors leading to the
      injury and the appropriateness of protective restraints remain undefined. The
      authors hypothesized that age-related anatomic factors contribute to inadequate
      restraints and therefore increase injury severity after MVC. METHODS: Data on
      children (<18 years, 1997 to 2002) admitted to a level 1 pediatric trauma center
      were prospectively collected and retrospectively reviewed. Those with C-spine
      injuries caused by MVC were extracted and divided into 2 groups: young (0 to 8
      years) and old (9 to 18 years). Statistical comparison was by Student's t test or
      Z-test, with P less than.05 accepted as significant. RESULTS: Of 5,117 trauma
      admissions, 94 had C-spine injuries with a mean age of 11 +/- 5 years, 66% of
      which were boys. Among 1,124 patients who had sustained MVC there were 27 C-spine
      injuries (2.4% incidence), of which, 12 were less than 8 and 15 were older than 8
      years. Restraint devices were utilized at least as frequently in younger children
      (young, 58% v. old, 43%; not significant). However, younger children had an
      increased incidence of permanent cord deficit (young, 57% v. old, 13%; P <.05)
      and closed head injury (young, 50% v. old, 7%; P <.05) even while wearing
      restraint devices, suggesting that restraint devices are inadequate or improperly
      used in younger patients. This is supported by the increased injury severity
      scores of the younger group (young, 37.7 +/- 8.5 v. old, 16.5 +/- 4.6; P <.05).
      CONCLUSIONS: Younger children suffer more sever cervical spine injuries after
      motor vehicle collisions than their older counterparts, in part because of the
      inadequacy of currently existing restraint devices. Design modifications to
      current restraints, including the use of head straps, might improve outcome after
      MVC in younger patients.

PMID- 15017576
TI  - The significance of contrast blush on computed tomography in children with
      splenic injuries.
AB  - PURPOSE: Most children and adults with blunt splenic injuries are treated
      nonoperatively by well-established management protocols. The "blush sign" is an
      active pooling of contrast material within or around the spleen seen during
      intravenous enhanced computed tomography (CT) scan. Adult treatment algorithms
      often include the "blush sign" as an indication for embolization or surgical
      intervention. This study was designed to evaluate the implications of the "blush
      sign" in children with blunt splenic injuries. METHODS: A review was performed of
      all children with blunt splenic injuries treated between January 1996 and
      December 2001 at a level I pediatric trauma center using an established solid
      organ injury protocol. The demographic, CT imaging, and outcome data were
      recorded. Treatment was categorized as operative or nonoperative. A single
      pediatric radiologist retrospectively reviewed all available CT scans to confirm
      injury grade and the presence or absence of a "blush sign." RESULTS: There were
      133 eligible children admitted with blunt splenic trauma, with a mean age of 9.1
      years (range, 1 to 15), including 86 children with an abdominal CT available for
      review. A "blush sign" on initial CT scan was noted in 6 children, all with grade
      3 or above splenic injuries, 5 of who were treated nonoperatively. In this
      series, the single child with a "blush sign" who did not respond to nonoperative
      treatment had a severe polytrauma requiring urgent splenectomy and left
      nephrectomy. None of the children died of their splenic injury. CONCLUSIONS:
      Although associated with higher grades of injury, the blush sign did not mandate
      embolization or surgical intervention in children with blunt splenic trauma in
      this series. Severe splenic injuries with a blush sign on the initial CT scan may
      be successfully treated nonoperatively when using an established treatment
      protocol. Management should be based primarily on physiological response to
      injury rather than the radiologic features of the injury.

PMID- 15017577
TI  - Nitrous oxide analgesia for minor pediatric surgical procedures: an effective
      alternative to conscious sedation?
AB  - BACKGROUND/PURPOSE: Minor surgical procedures in children, while usually not
      requiring general anesthesia, need effective control of pain, anxiety, and
      motion. Certain techniques of conscious sedation may result in loss of protective
      airway reflexes. Nitrous oxide, however, when inhaled at levels below 50%
      maintains protective reflexes and does not require fasting or postprocedure
      monitoring. This study prospectively examines the efficacy of nitrous oxide
      analgesia in children undergoing outpatient surgical procedures. METHODS: Over a
      2-year period (2000 to 2002), 150 consecutive children were given nitrous oxide
      analgesia as an alternative to a general anesthetic, sedation, or local
      anesthetic alone. Nitrous oxide (<50%) was administered by our practice's
      sedation-certified nurse practitioner without an anesthesiologist present. The
      children used the Wong-Baker Faces Scale (0-5) to score pain at different
      intervals (preprocedure, at injection, during procedure, and postprocedure) and
      event memories were tabulated. RESULTS: Of 150 children, 5 were uncooperative and
      could not participate. One hundred forty-five children, ages 1 to 20 years (Mean,
      9.83 +/- 4.92 years) successfully underwent procedures (58 cyst/nevus excisions,
      49 abscess drainages, 38 other) using nitrous. Two patients were too young to
      score pain. Pre- and postprocedure pain scores were significantly higher in the
      abscess group (P <.0001); during the procedures, however, all groups reported
      pain scores less than 1, with parents citing 100% satisfaction with the
      technique. Of 128 children receiving local anesthesia, 107 (84%) had no recall of
      the injection. Complications were limited to 4 patients; 2 experienced nausea,
      and 2 vomited. All resolved without interrupting the procedure. CONCLUSIONS:
      Nitrous oxide analgesia is a cost-effective and efficacious alternative to
      conscious sedation or general anesthesia for minor pediatric surgical procedures.
      In the office or outpatient setting, the technique provides for almost
      pain/anxiety-free surgery, no postoperative monitoring, and a high degree of
      satisfaction for patients, parents, and staff.

PMID- 15017578
TI  - Herbal medication use in the pediatric surgical patient.
AB  - PURPOSE: The aim of this study was to determine the prevalence of herbal
      medication use in the pediatric surgical patient population, because herbal
      medications can cause major perioperative complications. METHODS: A questionnaire
      on all drug use before surgery was given to the parents of 1,100 consecutive
      pediatric surgical patients operated on at a metropolitan children's hospital
      between June 14, 2002 and August 14, 2002. RESULTS: Eighty-three percent of the
      surveys were returned. Twenty-one percent of the parents were herbal medication
      users, but only 4% of patients utilized herbal medications. An average of 2.4
      different herbal medicines were in use by each child, and the most common herbal
      medications were echinacea, chamomile, and aloe. Forty-two percent of herbal
      medication-using patients were taking prescription medicines concurrently.
      Fifteen herbal medications-using patients underwent major surgery, and the
      average preoperative herbal cessation interval was 3.5 days. Children of parents
      who were herbal medication users and children reported to have chronic diseases
      were more likely to use herbal medicines (P <.05). Ten percent of parents
      reported that the surgeon inquired about patient herbal medication use.
      CONCLUSIONS: This is the first report on herbal medication use in the pediatric
      surgical patient. The prevalence of herbal medication use is significantly higher
      in children of parents who use herbal medications and children whose parents
      consider them to be chronically ill. Surgeons need to specifically inquire about
      the use of herbal medication in their patients to prevent possible harmful
      interactions and perioperative complications.

PMID- 15017580
TI  - Amniotic fluid beta-endorphin: a prognostic marker for gastroschisis.

PMID- 15017581
TI  - Cerebral Abeta amyloidosis and postmenopausal hormone deficiency: roles in the
      genesis of Alzheimer's disease.

PMID- 15017582
TI  - Colocalization and alteration of estrogen receptor-alpha and -beta in the
      hippocampus in Alzheimer's disease.
AB  - The human hippocampus is severely affected in Alzheimer's disease (AD). Because
      postmenopausal estrogen use may decrease the risk and delay the onset and
      progression of AD, possibly by a direct action on the hippocampal neurons, we
      used fluorescence immunocytochemistry to examine the colocalization of estrogen
      receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) in the hippocampus
      of elderly human controls and AD patients. Double-labeling cells (DLCs) of
      ERalpha and ERbeta can be divided into 3 types: double-cytoplasm-staining cells
      (DCCs), double-nucleus-staining cells (DNCs), and ERalpha nucleus-staining and
      ERbeta cytoplasm-staining cells (NCCs). There was no difference in the percentage
      of DLCs in total ERalpha-positive cells or in total ERbeta-positive cells in the
      CA1 to CA4 subfields of the hippocampus between controls and AD patients.
      Interestingly, the ratio of DNCs to the total ERalpha-positive cells (2.6% +/-
      0.5%) or to the total ERbeta-positive cells (1.8% +/- 0.3%) in the CA1 subfield
      of the AD hippocampus was significantly decreased in comparison with controls
      (5.0% +/- 0.7% and 3.9% +/- 0.6%, respectively; P<0.001), suggesting that changes
      in the compartmentalization of these receptors could play a role in the
      pathogenesis of AD.

PMID- 15017583
TI  - Use of interphase fluorescence in situ hybridization in prostate needle biopsy
      specimens with isolated high-grade prostatic intraepithelial neoplasia as a
      predictor of prostate adenocarcinoma on follow-up biopsy.
AB  - Isolated high-grade prostatic intraepithelial neoplasia (HGPIN) on needle biopsy
      confers an increased risk of prostate carcinoma (CaP) on follow-up biopsy. The
      aim of this study is to determine whether paraffin-section fluorescence in situ
      hybridization (FISH) of specific chromosome/oncogene copy number abnormalities
      (CNAs) in biopsy specimens with isolated HGPIN increases the predictive value for
      CaP on repeat biopsy. Cases were divided into 3 groups: controls (n=8) and
      sextant biopsy specimens with isolated HGPIN without CaP (group A; n=11) and with
      CaP (group B; n=14) on follow-up biopsy. Dual-color FISH assessing c-myc, HER
      2/neu, chromosome region 7q31 (D7S486), and corresponding chromosome centromeres
      was performed. An amplification ratio (AR) for each marker centromere was derived
      for each biopsy specimen, with AR ranges designated as no/low, low-intermediate,
      and high. Also calculated for each marker were the percentage of cells with
      marker amplification, hyperdiploidy, and monosomy. A composite score for each
      biopsy specimen was calculated based on these parameters, with a possible range
      of 0 to 15. The specific chromosomal oncogene CNAs were as follows: for
      chromosome 7/7q31, 2 of 11 (18%) in group A and 6 of 14 (43%) in group B; for
      chromosome 8/c-myc, 4 of 11 (36%) in group A and 9 of 13 (69%) in group B; and
      for chromosome 17/HER-2/neu, 10 of 10 (100%) in group A and 13 of 14 (93%) in
      group B. The mean composite score was 0 for controls, 2.5 for group A, and 4.7
      for group B. Composite scores > or =4 for the 3 groups were 0 of 9 (0%) for
      controls, 1 of 11 (12%) for group A, and 8 of 14 (57%) for group B. These
      differences were statistically significant (P=0.015). One group A patient with a
      high composite score (6) had atypical small glands on follow-up biopsy at <1
      year. Chromosome/oncogene CNAs are uncommon in control patients, occurring with
      increasing frequency and magnitude in patients with isolated HGPIN without and
      with follow-up CaP. Chromosome/oncogene CNAs in HGPIN are mostly of the low to
      intermediate level and display intercellular heterogeneity. HER-2/neu
      amplification is common in HGPIN with and without follow-up CaP. Chromosome 7 and
      8 aneusomy and 7q31 and c-myc amplification are greater in HGPIN with follow-up
      CaP. Patients with isolated HGPIN and high composite score without follow-up CaP
      are uncommon; these patients may have a small, unsampled CaP. Although patients
      with HGPIN without CaP are more likely to have a low composite score, a subset of
      patients with follow-up CaP have low composite score, suggesting (1) mutational
      pathways independent of chromosomes 7, 8, and 17 and HER-2/neu, c-myc, and
      chromosome region 7q31 CNAs; (2) CaP derived from an independent, unsampled focus
      of HGPIN; or (3) CaP not derived from HGPIN.

PMID- 15017584
TI  - Apoptosis incidence and protein expression of p53, TGF-beta receptor II, p27Kip1,
      and Smad4 in benign, premalignant, and malignant human prostate.
AB  - Deregulation of apoptosis is involved in prostate cancer development and
      progression. This study involved an immunohistochemical "profiling" of prostate
      tissue specimens from patients who underwent prostatectomy for localized prostate
      cancer, to identify apoptosis-specific alterations associated with premalignant
      precursor lesions. Prostate tissue was pathologically evaluated, and areas of
      benign acini, high-grade prostate intraepithelial neoplasia (HGPIN), and prostate
      cancer were identified. Immunohistochemical analysis was performed to determine
      the expression of p27Kip1, a key cell cycle regulator, transforming growth factor
      (TGF)-beta receptor II (TbetaRII), a critical signaling effector of TGF-beta;
      Smad4, a downstream intracellular effector of TGF-beta signaling; p53, a key
      apoptosis regulator; and prostate-specific antigen (PSA), a clinical marker of
      prostate cancer. The apoptotic index of the same cell populations was determined
      using the transferase-mediated digoxigenin-tagged 16-desoxy-uridine-triphosphate
      nick end labeling assay. Our findings indicate a significant reduction in p27Kip1
      immunoreactivity in HGPIN (P<0.0001) and prostate cancer (P<0.0001) compared with
      the benign tissue. A significant down-regulation was detected in TbetaRII
      expression in HGPIN and prostate cancer compared with benign prostatic
      hyperplasia (BPH)(P<0.001). A significant decrease was also observed in Smad4
      levels in HGPIN and prostate cancer compared with BPH (P<0.001). Evaluation of
      the incidence of apoptosis revealed a significant decrease in the apoptotic index
      among the epithelial cell populations in HGPIN and a further decrease in prostate
      carcinoma (P<0.01). This reduced apoptotic index correlated with a significant
      increase in p53 immunoreactivity in the prostatic carcinoma foci. Prostate cancer
      cells exhibited strong nuclear staining for p53 compared with adjacent HGPIN
      (P<0.05) and the benign lesions of the same prostate specimens (P<0.05). A
      significant reduction in PSA immunostaining was detected in HGPIN and prostate
      carcinoma foci compared with the benign glandular epithelia (P<0.001). These
      results further define deregulation of TGF-beta signaling effectors as a
      molecular basis for loss of apoptotic control contributing to the development of
      prostate tumors. Identification of apoptotic regulators in precursor premalignant
      lesions may have prognostic significance in disease progression as well as
      therapeutic value for targeting prostate cancer.

PMID- 15017585
TI  - Histological characteristics of tumor in vessels and lymph nodes are significant
      predictors of progression of invasive ductal carcinoma of the breast: a
      prospective study.
AB  - Invasive ductal carcinomas (IDCs) of the breast are composed of primary invasive
      tumors as well as tumor cells in blood vessels and lymph nodes. The purpose of
      this study was to determine whether the histological characteristics of tumor in
      the vessels and nodes are significantly associated with outcome. In a series of
      393 patients, multivariate analyses showed that in IDCs without nodal metastasis
      and with fibrotic focus dimension, lymph vessel tumor emboli with >6 apoptotic
      figures and those invading >3 mm from the tumor margin had significantly higher
      hazard rates (HRs) for recurrence (P<0.05). In IDCs with 1 to 3 nodal metastases,
      >2 apoptotic figures in tumor emboli in blood vessels and >5 invaded lymph
      vessels were associated with significantly higher HRs for tumor recurrence and
      death (P<0.005). In IDCs with 4 or more nodal metastases, nodal tumors with >5
      mitotic figures and >5 nodes with extranodal extension were associated with
      significantly higher HRs for tumor recurrence or death (P<0.05). We conclude that
      several histological characteristics of tumors in vessels and nodes have
      significant implications for the progression of IDCs.

PMID- 15017586
TI  - Chromosomal aberrations in esophageal squamous cell carcinoma among Chinese: gain
      of 12p predicts poor prognosis after surgery.
AB  - Sixty primary esophageal squamous cell carcinomas (ESCCs) were evaluated for
      cytogenetic changes by comparative genomic hybridization (CGH). Recurrent
      chromosomal aberrations were correlated with stage and clinical outcome after
      esophagectomy to identify cytogenetic changes that are of prognostic
      significance. Chromosomal aberrations were found in 52 (86.7%) cases. The most
      frequently detected chromosomal gains involved 3q (67.3%), 8q (57.7%), 5p
      (51.9%), 7q (28.8%), 15q (28.8%), 20p (21.2%), 20q (28.8%), 1q (26.9%), 7p
      (26.9%), 2p (23.1%), and 12p (23.1%). Chromosome 12p was most frequently involved
      in high-level amplification. Six of the 12 cases with gain in 12p showed high
      level amplification and the minimum overlapping region localized to 12pter-p13.
      The most frequently detected chromosomal loss involved 3p (46.2%), 4q (26.9%), 4p
      (23.1%), 3q (19.2%), 9p (17.3%), 19p (17.3%), and whole 13 (15.4%). No
      significant correlation was found between the recurrent chromosomal aberrations
      and pathological stage of ESCC. Univariate analysis demonstrated that late
      pathological stage (III and IV), gain in 12p, and loss in 3p are associated with
      poor relapse-free survival. Multivariate analysis confirmed gain in 12p as
      independent prognosticator for relapse-free survival after esophagectomy besides
      pathological stage. We conclude that chromosomal aberrations are common in ESCC.
      Gain in 12p is indicative of poor prognosis after esophagectomy, and combined
      modality therapy would be indicated in these patients.

PMID- 15017587
TI  - Cyclooxygenase-2, Bcl-2, and chromosome 1p analysis in protoplasmic astrocytomas.
AB  - Protoplasmic astrocytomas are rare gliomas whose nosology remains enigmatic. This
      study retrospectively reviews the clinicopathologic features of eight tumors,
      including evaluation of these neoplasms for chromosome 1p loss, Bcl-2
      immunoreactivity, and cyclooxygenase-2 immunoreactivity. Patients ranged in age
      from 3 to 49 years (median 25.5 years) and included six males and two females.
      All patients presented with a period of seizures (median duration of period, 54
      months) before surgery. Five tumors were either totally or partially based in the
      temporal lobe. In the six patients for whom follow-up information was available,
      there was no evidence of recurrence at last known follow-up (range 5 to 171
      months; median 134 months). Histologically, all tumors were marked by a
      proliferation of cells with rounded to oval nuclear contours and a paucity of
      cytoplasmic processes, arranged against a microcystic background. A rare mitotic
      figure was observed in only one tumor. Vascular proliferative changes and
      necrosis were not seen in any of the tumors. None of the tumors showed allelic
      loss on chromosome 1p by fluorescent in situ hybridization (FISH) analysis.
      Cyclooxygenase-2 (an enzyme involved in the conversion of arachidonate to
      prostaglandin H2 and G2) immunoreactivity was observed in two tumors. Bcl-2 (an
      anti-apoptotic protein) immunoreactivity was also confined to two tumors. In
      conclusion, protoplasmic astrocytomas appear to be low-grade neoplasms, as
      evidenced by their relatively benign clinical course. Although they
      histologically resemble microcystic oligodendrogliomas, none of the tumors showed
      allelic loss on chromosome 1p, a finding that has been described in the majority
      of low-grade oligodendrogliomas. This suggests that the protoplasmic astrocytoma
      is a distinct entity from low-grade oligodendroglioma. Similar to other low-grade
      astrocytomas, only a minority of tumors show evidence of cyclooxygenase-2 and Bcl
      2 immunoreactivity.

PMID- 15017588
TI  - Loss of heterozygosity analysis shows monoclonal evolution with frequent genetic
      progression and divergence in esophageal carcinosarcoma.
AB  - Carcinosarcoma (spindle cell carcinoma) of the esophagus is a rare neoplasm that
      shows squamous cell carcinoma (SCC) with a variable component of spindle cell
      sarcoma. Clinical and pathologic features of this neoplasm have been well
      documented, but the histogenesis has long been a matter of speculation and
      dispute. In an attempt to clarify the clonality and genetic relationships in the
      evolution of this neoplasm, we microdissected a total of 36 carcinomatous and
      sarcomatous foci from six esophageal carcinosarcoma (CS) and analyzed the allelic
      status with 25 microsatellite markers on chromosomal arms 3p, 5q, 6q, 8p, 9p,
      11q, 13q, 17p, and 18q. In all cases, we found multiple and homogenous allelic
      losses in both the carcinomatous and sarcomatous components, strongly supporting
      the concept of monoclonal origin for this neoplasm. Homogeneous allelic losses
      were detected most frequently on 17p (5 cases), a chromosomal arm that included
      the p53 locus, followed by 3p, 11q, and 13q (3 cases); 9p (2 cases); and 8p and
      18q (1 case). Moreover, five of the six cases showed additional or divergent
      allelic losses at more than one chromosomal locus at some of the microdissected
      foci, indicating genetic progression (2 cases) or genetic progression and
      divergence (3 cases). In four cases, the genetic changes indicated that an
      original clone of a pure SCC apparently acquired carcinosarcomatous or
      sarcomatous phenotype by successive genetic changes. On the other hand, we saw no
      evidence for tumors in which a sarcoma appeared to give rise to a
      carcinosarcomatous or carcinomatous subclone in the examined cases. In
      conclusion, our data support the concept that esophageal CS is derived from a
      single clone originating from a SCC. Furthermore, we showed genetic heterogeneity
      to accompany the phenotypic divergence, with patterns of genetic alterations that
      are consistent with both progression and divergence within individual tumors.

PMID- 15017589
TI  - Immunohistochemical evaluation of adenomatous polyposis coli, beta-catenin, c
      Myc, cyclin D1, p53, and retinoblastoma protein expression in syndromic and
      sporadic fundic gland polyps.
AB  - Syndromic and sporadic fundic gland polyps are morphologically indistinguishable
      but may arise via different pathogenetic mechanisms involving mutations of the
      adenomatous polyposis coli (APC) and its downstream target beta-catenin genes.
      Although a higher frequency of dysplasia has been reported in syndromic forms,
      the risk of developing invasive carcinoma is exceedingly low. The current study
      was designed to investigate whether syndromic and sporadic fundic gland polyps
      differ in protein expression of a number of genes that are thought to be
      important in the control of neoplastic transformation. A total of 262 fundic
      gland polyps, including 155 syndromic polyps obtained from 35 patients with
      familial adenomatous polyposis or Gardner's syndrome and 107 sporadic polyps
      randomly selected from 45 patients with gastroesophageal reflux disease or
      Barrett's esophagus, were included in this study. Immunohistochemical evaluation
      showed that loss of immunoreactivity to the antibody against the carboxyl
      terminus of the APC protein, presumably resulting from APC gene mutations, was
      more frequent in syndromic than in sporadic cases (40% versus 6.7%, P<0.001).
      However, immunostaining failed to show aberrant nuclear localization of beta
      catenin, a protein regulated by APC, in any of the polyps, irrespective of
      syndromic or sporadic types. Instead, positive membranous staining for beta
      catenin was observed in all the cases. In addition, the expression
      characteristics of 2 other proteins, c-Myc and cyclin D1, whose genes have been
      reported to be transcriptionally regulated by the APC/beta-catenin pathway, were
      similar in these two types of polyps. Furthermore, all cases, including those
      harboring dysplasia, showed negative nuclear staining for p53 and positive
      nuclear staining for retinoblastoma (RB). Taken together, these data show a lack
      of dysregulation in the APC/beta-catenin signaling pathway and in the expression
      of p53 and RB in fundic gland polyps despite a high frequency of somatic
      mutations of the APC and beta-catenin genes reported in these polyps. These
      findings may explain at least in part why fundic gland polyps show a negligible
      malignant potential even in the presence of dysplasia.

PMID- 15017591
TI  - Acute cellular rejection grading scheme for human gastric allografts.
AB  - The control of acute cellular rejection (ACR) in multivisceral transplantation
      improves long-term survival, but monitoring this process can be challenging
      because different allografts can display varying forms and degrees of rejection.
      Criteria for ACR of small bowel and liver have been established, but a systematic
      analysis for ACR in stomach is lacking. For this reason we have developed a
      comprehensive grading scheme for the evaluation of gastric allograft rejection.
      The grading scheme was designed to individually grade a variety of changes in the
      surface epithelium, lamina propria, and glandular structures. The individual
      values are cumulated, and the final score determines assignment of the rejection
      grade. The ACR grades range from no evidence of acute cellular rejection to
      severe rejection. We performed a retrospective study based on 70 gastric
      allograft biopsies from 20 patients who received multivisceral transplantation
      from 1995 to 2001. We found that the scoring system showed no significant
      interobserver variability and allowed for an accurate designation of the ACR
      grade to the gastric allografts. We found with this grading system that neither
      clinical symptoms nor gastric endoscopic findings could serve as specific
      indicators of gastric ACR. Our results also showed that there were differences in
      the occurrence and intensity of acute rejection between the stomach and other
      transplanted organs, suggesting that ACR can occur independently among different
      allografts of the same host. In conclusion, we find that this scheme for grading
      ACR in gastric transplants is objective and reproducible. This grading system
      will likely allow for improved correlation between gastric ACR grade and clinical
      symptoms, as well as improve interobserver uniformity within and between
      institutions.

PMID- 15017590
TI  - Standardized approach for microsatellite instability detection in gastric
      carcinomas.
AB  - Microsatellite instability (MSI) defines a specific type of genetic instability.
      Although consensus diagnostic criteria for MSI definition in colorectal cancer
      have been established, their utility in other tumor types remain to be proven.
      Previously we developed a mathematical model for MSI definition in colorectal
      cancer. The aim of this study was to establish diagnostic criteria for MSI
      evaluation in human gastric cancer. We designed an algorithm for the efficient
      characterization of MSI and used it to analyze data on 7 microsatellite markers
      in 35 gastric carcinomas. Theoretical models considering 1, 2, or 3 populations
      were tested against the data collected. Also, hypermethylation of hMLH1 gene
      promoter and hMLH1 protein expression were studied. The observed frequencies of
      MSI in our series of samples best fit a 2-population model: stable and unstable,
      defined by instability in 2 or more of a minimum of 7 markers analyzed. MSI was
      observed in 29% of the tumors. Misclassification rate was <4% when any 7 loci
      were analyzed. MSI(+) tumors inversely associated with p53 protein
      overexpression. A good correlation between hMLH1 status (either protein or
      promoter hypermethylation) and MSI classification was observed. We have developed
      a simple, sensitive, and specific approach to assess the presence of MSI in
      gastric cancer that may have clinical applications.

PMID- 15017592
TI  - Loss of p53 transcriptional activity in hepatocellular carcinoma evaluated by
      yeast-based functional assay: comparison with p53 immunohistochemistry.
AB  - We studied the transcriptional activity of p53 protein in 50 tissues of
      hepatocellular carcinoma (HCC) using a yeast functional assay. In this assay, red
      yeast colonies indicate that p53 protein cannot bind to its specific domain and
      has lost its transcriptional activity. We also clarified whether mutant p53
      protein could inactivate wild-type p53 protein in a transdominant manner using a
      modified yeast assay. In addition, we examined whether immunohistochemically
      detectable p53 protein was functionally inactive. The incidence of p53
      inactivation was significantly higher in tumors with capsular invasion. Out of 21
      tumors diagnosed with p53 mutations, 11 exhibited >75% red colonies, and all
      contained missense mutations. In these tumors, p53 function was lost because
      there was supposedly no intact p53 gene on either allele. One missense mutant
      produced <60% red colonies, but it was also considered inactive as a p53 protein
      heterotetramer because of its transdominant activity. In 7 of the remaining 9
      tumors, p53 was considered to be mutated on one allele and intact on the other.
      All of these 7 tumors contained nonsense or frameshift mutations and had no
      transdominant activity, which suggested that p53 function remained intact.
      Alternately, immunohistochemical analysis demonstrated that all of the tumors
      with missense mutations were positively immunostained, whereas those that
      contained nonsense or frameshift mutations were negatively stained. Consequently,
      positively immunostaining tumors mostly coincided with p53-inactive tumors. These
      yeast-based assays suggested that p53 function was retained in some mutant cases.
      Immunohistochemistry was helpful in screening functionally inactive p53 protein
      in HCCs.

PMID- 15017593
TI  - Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue
      microarrays.
AB  - Using global gene expression analyses, multiple novel tumor markers overexpressed
      in infiltrating ductal adenocarcinomas of the pancreas have recently been
      identified. However, the expression of these markers in morphologically similar
      adenocarcinomas of the biliary tree has not been investigated. The purpose of the
      present study was 3-fold. First, we used 8 markers that have been shown to be
      overexpressed in whole tissue sections of pancreatic adenocarcinomas to validate
      tissue microarrays (TMAs) created from a series of pancreatic adenocarcinomas
      (n=68). The labeling patterns of 6 epithelial markers (fascin, mucin 4, 14-3
      3sigma, prostate stem cell antigen, topoisomerase IIalpha, and cdc2/p34) were
      concordant with previously published studies on whole tissue sections, yet
      required far fewer slides and reagents. Mesothelin, an epithelial marker, and
      heat shock protein 47, a marker of peritumoral desmoplasia, showed lower levels
      of expression in the TMAs when compared with whole tissue sections. Second, we
      examined the previously unknown expression of the same 8 novel tumor proteins in
      cancers of the biliary tree by using TMAs created from a series of intrahepatic
      cholangiocarcinomas, gallbladder adenocarcinomas, and adenocarcinomas of the
      distal common bile duct (n=38). Each of the 8 markers was overexpressed in the
      biliary cancers, ranging from 14% demonstrating at least focal labeling with
      prostate stem cell antigen to 100% labeling with cdc2/p34. Most of the markers
      showed lower frequencies of expression in the biliary tract carcinomas in
      comparison to the pancreatic adenocarcinomas. In addition, expression patterns
      varied with location in the biliary system (intrahepatic versus gallbladder
      versus distal common bile duct). These differences were statistically significant
      (P<0.05) for mesothelin, mucin 4, and heat shock protein 47. Finally, the
      expression of selected markers in neoplastic progression of gallbladder cancer
      was examined. Two markers, fascin and mesothelin, showed up-regulation of
      expression with transition from carcinoma in situ to invasive adenocarcinoma,
      implicating a role for these markers in neoplastic progression. The results of
      this study indicate that TMA technology provides valid and cost-effective means
      to screen large numbers of novel tumor markers, even in tumors such as pancreatic
      and biliary adenocarcinomas that characteristically have abundant desmoplastic
      stroma. In addition, novel tumor markers of pancreatic adenocarcinomas show
      similar, yet not identical, expression patterns in biliary carcinomas. Therefore,
      these markers are potentially useful in developing diagnostic tests and treatment
      paradigms for tumors involving the biliary system.

PMID- 15017594
TI  - Glomerular changes in BK virus nephropathy.
AB  - This study seeks to define the glomerular changes that are associated with human
      BK virus nephropathy (BKVN). It is based on histopathologic review of 124
      biopsies showing light-microscopic changes of viral nephropathy. The diagnosis of
      BKVN was confirmed by immunohistochemistry or by in situ hybridization.
      Histological lesions were scored by the Banff 97 criteria for renal allograft
      pathology and were correlated with clinical parameters. Viral cytopathic effect
      in the parietal Bowman's capsular epithelium was seen in 21/124 (17%) biopsies.
      Immunohistochemistry showed infection of Bowman's capsular epithelium in an
      additional 15/124 (12%) biopsies. Crescents were found in 15/124 (12%) samples.
      Glomerulitis exceeding grade Banff g1 was only occasionally shown (4/124=3%
      biopsies). Other pathologic lesions documented include mild increase in mesangial
      matrix in 23% biopsies, aneurysmal dilatation of glomerular capillaries in 28%,
      ischemic glomerulopathy in 62%, and chronic transplant glomerulopathy graded as
      mild (cg1) in 62% of biopsies and as moderate (cg2) in 2/124 (1.9%) biopsies.
      These findings show that infection of the glomerular epithelium cells can occur
      in a subset of patients with BKVN, most often in biopsies with high viral load in
      the tubular epithelium. Isolated crescents can occur in BKVN biopsies, but
      rapidly progressive glomerulonephritis is not observed. Two biopsies showed
      electron-dense deposits on ultrastructural examination, but a cause and effect
      relationship to BK virus infection could not be established.

PMID- 15017595
TI  - Distinction between intestinal metaplasia in the cardia and in Barrett's
      esophagus: the role of histology and immunohistochemistry.
AB  - Intestinal metaplasia in Barrett's esophagus (BIM) is a precancerous condition,
      whereas the carcinogenic potential of intestinal metaplasia of the cardia (CIM)
      is uncertain. Although clinically important, histological distinction between
      both conditions by endoscopic biopsies is considered problematic. In the present
      study, 4-mm samples of BIM (n=31) and CIM (n=9) were selected from esophagectomy
      specimens that had been resected for esophageal cancer. Slides were coded and
      stained with hematoxylin and eosin (H&E), Alcian blue-periodic acid-Schiff (PAS),
      cytokeratins (CK) 7 and 20, and CD10, which labels the intestinal brush border.
      The predictive value of these stains for the recognition of BIM and CIM was
      evaluated independently by two senior pathologists. With the use of H&E-stained
      slides exclusively, BIM samples were categorized correctly in 93.5% and 83.9% of
      cases (pathologists 1 and 2, respectively), and CIM samples, in 100% and 88.9% of
      cases. Alcian blue-PAS-positive goblet cells were identified by both
      investigators in all BIM and CIM samples. BIM-typical CK 7 and 20 immunostaining
      pattern was identified in 90.3%/83.9% of BIM but only in 11.1%/11.1% of CIM. CD10
      positive brush border was present in 32.3%/25.8% of BIM and in 88.9%/88.9% of
      CIM. When HE-stained slides and immunohistologically stained slides were used
      together for tissue recognition, BIM were categorized correctly in 90.3%/80.6% of
      cases, and CIM, in 88.9%/88.9% of cases. In conclusion, BIM and CIM can be
      usually distinguished on the basis of HE sections. CK 7 and CK 20 expression
      pattern analysis discriminates correctly between BIM and CIM in the majority of
      cases. CD10-positive intestinal brush border is present in the majority of CIM
      but only in a minority of BIM. However, immunohistochemical investigations could
      not improve the diagnostic accuracy of HE histology alone.

PMID- 15017596
TI  - Primary villoglandular adenocarcinoma of cloacogenic origin of the vulva.
AB  - Primary villoglandular adenocarcinomas of the vulva are rare, and only seven
      cases have been described to date. Hypotheses about the origin of this neoplasm
      remain highly speculative. We report the case of a 58-year-old woman who
      developed this very uncommon malignant tumor. Immunohistochemical studies of the
      tumor revealed positive staining for cytokeratins 7 and 20 and a negative
      staining for estrogen and progesterone receptors. Special stains showed the
      presence of intracellular mucin. No other primary lesion was found on clinical
      evaluation and extensive investigation. The patient was first treated by radical
      hemivulvectomy, followed by ipsilateral inguinal lymph node dissection and
      laparoscopic right salpingo-oophorectomy for an incidental finding of an ovarian
      cyst. The patient remained free of disease 16 months after the initial surgery.

PMID- 15017597
TI  - A case of metastatic breast cancer with outgrowth of HER2-negative cells after
      eradication of HER2-positive cells by humanized anti-HER2 monoclonal antibody
      (trastuzumab) combined with docetaxel.
AB  - A 38-year-old woman with cancer of the left breast underwent a modified radical
      mastectomy with lymph node dissection. Twenty-one months later, massive liver
      metastases and pleural carcinomatosis occurred. The liver metastases responded
      completely to chemotherapy with trastuzumab combined with docetaxel, but the
      pleural carcinomatosis was refractory to the therapy. Fluorescence in situ
      hybridization showed that both the primary tumor and the metastatic tumors of the
      lymph nodes were composed of HER2 amplification-positive and HER2 amplification
      negative cancer cells. This analysis also detected a single cell with HER2
      amplification in the pleural effusion that was taken at the completion of the
      chemotherapy, but four follow-up tests showed no amplified cells. It is
      speculated that in the liver metastases, the trastuzumab was cytotoxic to both
      HER2-amplified and nonamplified cancer cells and may have acted through its
      antiangiogenic effect. However, in the pleural effusion, the effect of
      trastuzumab was more specific to HER2-amplified cells and caused outgrowth of
      cancer cells lacking expression of HER2 receptors.

PMID- 15017598
TI  - Mixed micropapillary and trophoblastic carcinoma of bladder: report of a first
      case with new immunohistochemical evidence of urothelial origin.
AB  - The micropapillary variant of urothelial carcinoma has a reported incidence of
      0.7%. Trophoblastic urinary carcinoma is very rare, with roughly 30 cases
      reported during the last century. This is the first report of mixed
      micropapillary and trophoblastic bladder carcinoma. A 45-year-old man presented
      with gross hematuria. His tumor contained choriocarcinomatoid areas with
      syncytiotrophoblasts, classic micropapillary carcinoma, conventional high-grade
      urothelial carcinoma, and flat carcinoma in situ. He underwent radical surgery;
      tumor stage was T4N2M0. Despite postoperative combination chemotherapy, he
      developed pulmonary and retroperitoneal metastases and died 20 months after
      presentation. The tumor was immunopositive for human chorionic gonadotropin and
      human placental lactogen in trophoblast and for cytokeratin 20 and high-molecular
      weight cytokeratin in all tumor components. Because high-molecular-weight
      cytokeratin is expressed by urothelium but is rarely found in placental
      trophoblast or germ-cell choriocarcinoma, its presence in trophoblastic bladder
      carcinoma is new evidence that the latter is a transformed neoplasm of urothelial
      origin.

PMID- 15017599
TI  - Acute vascular humoral rejection in a sensitized cardiac graft recipient:
      diagnostic value of C4d immunofluorescence.
AB  - A 37-year-old female patient had a cardiac transplantation for dilated
      cardiomyopathy. She was sensitized by two pregnancies showing anti-human
      leukocyte antigen I and II antibodies. The pretransplantation crossmatch was
      negative, but she developed acute humoral rejection characterized by vascular C4d
      deposits, arteriolitis, and intravascular leukocyte accumulation and adhesion in
      venules. Although C4d deposits disappeared in 4 weeks, she had persistent
      endothelial cell activation (endothelial expression of ELAM-1, VCAM-1, or human
      leukocyte antigen class II) throughout the 6 months of follow-up. Although she
      received intensive immunosuppression, she presented three episodes of acute
      cellular rejection during that period of time. This case shows that C4d deposits
      represent a sensitive marker of acute humoral rejection in cardiac
      transplantation. Therefore, C4d immunofluorescence should be more frequently
      assessed in endomyocardial biopsies.

PMID- 15017601
TI  - Controversies in the management of hepatitis C patients with advanced fibrosis
      and cirrhosis.

PMID- 15017602
TI  - Chronic diarrhea: a review on pathophysiology and management for the clinical
      gastroenterologist.

PMID- 15017603
TI  - Analog diagnosis in a digital world: the quest to improve endoscopic tissue
      acquisition and diagnostic sensitivity in malignant biliary stricture.

PMID- 15017604
TI  - Endoscopic ultrasound-guided fine needle aspiration biopsy of suspected
      cholangiocarcinoma.
AB  - BACKGROUND AND AIMS: Despite advances in endoscopic techniques for sampling bile
      duct strictures, the diagnosis of cholangiocarcinoma remains a challenge. The
      purpose of this study was to evaluate the yield of EUS-FNA and its impact on
      patient management for patients with suspected cholangiocarcinoma. METHODS: All
      patients undergoing EUS for the evaluation of suspected malignant biliary
      strictures were prospectively evaluated over a 23-month period. A single
      gastroenterologist performed all EUS-FNAs in the presence of a cytopathologist.
      Reference standard for final diagnosis included surgery, death from disease, and
      clinical and/or imaging follow-up. RESULTS: Twenty-eight patients (mean age 67
      years [SD +/- 11], 72% male) were evaluated. Most patients (91%) presented with
      obstructive jaundice, and all except 1 had nondiagnostic sampling of the biliary
      lesions either at ERCP (88%), percutaneous transhepatic cholangiogram (n = 2),
      and/or computed tomography-guided biopsy (n = 1). Sixty-seven percent (14/21) had
      no definitive mass seen on prior abdominal imaging studies. The mean tumor size
      by EUS was 19 mm x 16 mm with a median number of passes to diagnosis of 3 (range
      1-7). The sensitivity, specificity, positive predictive value, negative
      predictive value, and accuracy were 86%, 100%, 100%, 57%, and 88%, respectively.
      EUS-FNA had a positive impact on patient management in 84% of patients:
      preventing surgery for tissue diagnosis in patients with inoperable disease (n =
      10), facilitating surgery in patients with unidentifiable cancer by other
      modalities (n = 8), and avoiding surgery in benign disease (n = 4). CONCLUSIONS:
      Given the apparent accuracy and safety of EUS with FNA for imaging bile duct mass
      lesions and for obtaining a tissue diagnosis in patients with suspected
      cholangiocarcinoma, this technology may represent a new approach to diagnosis
      especially when other methods fail. The ability to obtain a definite diagnosis
      has a significant impact on patient management.

PMID- 15017605
TI  - A prospective comparison of digital image analysis and routine cytology for the
      identification of malignancy in biliary tract strictures.
AB  - BACKGROUND & AIMS: Digital image analysis (DIA) allows quantification of nuclear
      DNA content and may help distinguish benign and malignant strictures of the
      biliary tract. METHODS: One hundred ten consecutive patients undergoing
      endoscopic retrograde cholangiography for suspicious biliary tract strictures
      were enrolled in a prospective study comparing the accuracy of DIA and routine
      cytology (RC). Standard brush cytology sampling was performed twice by using 2
      cytology brushes per patient. Both brushes were fixed in a single-specimen vial.
      Each specimen was formed into 1 pellet, and the sample was equally divided for
      evaluation by DIA and RC. DNA histograms were generated for ploidy analysis. The
      DIA criterion for malignancy was demonstration of aneuploidy. RESULTS: Two
      patients had inadequate samples obtained for DIA analysis, 7 benign patients were
      excluded because of inadequate follow-up of less than 75 days, and 1 patient was
      lost to follow-up to clarify malignant versus benign disease. Of the remaining
      100 patients, 56 strictures were malignant and 44 were benign. The sensitivities
      of DIA and RC were 39.3% and 17.9%, respectively (P = 0.014). The specificities
      of DIA and RC were 77.3% and 97.7%, respectively (P = 0.003). The accuracy of DIA
      (56.0%) was equivalent to RC (53.0%). CONCLUSIONS: DIA is a valuable adjunct to
      RC for detecting malignant strictures of the biliary tract.

PMID- 15017606
TI  - Risk factors for esophagitis in extreme acid hypersecretors with and without
      Zollinger-Ellison syndrome.
AB  - BACKGROUND & AIMS: Whereas severe duodenal ulcer is the hallmark of acid
      hypersecretion in Zollinger-Ellison syndrome (ZE) and similar states, the
      esophagus also is at high risk. We quantified the incidence of esophagitis and
      various risk factors that might contribute to it. METHODS: Sixty-eight acid
      hypersecretors (basal acid output >15 mmol/h), 50 patients with ZE, and 18
      patients without ZE with normal gastrin levels were studied by gastric analysis,
      serum gastrin levels, and endoscopy. In 44 of 68 patients, esophageal manometry
      was performed after the esophagus had healed. RESULTS: Erosive esophagitis, grade
      2 or worse, was found in 65%; an additional 15% had heartburn only, for a total
      reflux disease incidence of 80%. ZE accounted for 95% of severe esophagitis.
      Patients with and without esophagitis had the same high overnight fasting gastric
      residual volume and acidity, as well as basal and peak acid and pepsin outputs.
      However, patients with esophagitis had a lower median lower esophageal sphincter
      pressure (LESP) of 15.5 vs. 23 mm Hg in those without symptoms; the critical
      discriminator threshold was 16 mm Hg. Multivariate analysis further identified
      frequent vomiting and obesity as positive predictors of esophagitis, whereas
      Helicobacter pylori was a strong negative predictor (odds ratio, 0.16), possibly
      related to an elevated LESP in patients infected with H. pylori. CONCLUSIONS:
      Erosive esophagitis is very common in acid hypersecretors. Identified risk
      factors that could promote abnormal esophageal exposure to the high acid and
      pepsin levels in our population of hypersecretors were vomiting, LESP < 16 mm Hg,
      and obesity, whereas H. pylori appeared to protect the esophagus not by reduced
      acid, but through an elevated LESP.

PMID- 15017607
TI  - Clarification of the esophageal function defect in patients with manometric
      ineffective esophageal motility: studies using combined impedance-manometry.
AB  - BACKGROUND & AIMS: Combined multichannel intraluminal impedance (MII) and
      manometry (MII-EM) recently became available as an esophageal function test.
      Initial studies in healthy volunteers have shown that a proportion of ineffective
      contractions actually have complete bolus transit. The aim of our study is to
      evaluate esophageal bolus transit in patients with manometric patterns of
      ineffective esophageal motility (IEM). METHODS: All patients referred for
      esophageal function testing during a 9-month period underwent combined MII-EM
      studies, including 10 liquid and 10 viscous swallows. IEM is defined as >or=30%
      liquid swallows with contraction amplitude <30 mm Hg in the distal esophagus.
      Diagnosis of esophageal transit abnormalities is defined as abnormal bolus
      transit if >or=30% of liquid and >or=40% of viscous swallows had incomplete bolus
      transit. RESULTS: Seventy patients (35 women; mean age, 54 yr; range, 17-86 yr)
      with a manometric diagnosis of IEM were identified of a total of 350 combined MII
      EM studies. In these patients, 68% of liquid and 59% of viscous swallows showed
      normal bolus transit, and almost one third of patients received an overall
      diagnosis of normal bolus transit for both liquid and viscous swallows.
      CONCLUSIONS: Our experience with combined MII-EM in patients with a manometric
      diagnosis of IEM confirms the suspicion that "effectiveness" should only be
      determined by using a test of esophageal function. Furthermore, we believe our
      results support a conclusion that a higher level of esophageal diagnostic
      information is best obtained by combined MII-EM. Future outcome studies should
      establish its value in patients with nonobstructive dysphagia and in
      prefundoplication assessment.

PMID- 15017608
TI  - Clinical "cytokine storm" as revealed by monocyte intracellular flow cytometry:
      correlation of tumor necrosis factor alpha with severe gut graft-versus-host
      disease.
AB  - BACKGROUND & AIMS: Gut graft-versus-host disease (GVHD) contributes significantly
      to lethality after allogeneic hematopoietic stem-cell transplantation (HSCT). In
      murine models, macrophage secretion of interleukin 1alpha (IL-1alpha) and tumor
      necrosis factor alpha (TNF-alpha) contributes to gut GVHD pathogenesis. To help
      characterize whether human gut GVHD has similar biological characteristics,
      monocyte IL-1alpha and TNF-alpha production were evaluated after HSCT. METHODS:
      Patients with refractory hematologic malignancy (n = 17) underwent reduced
      intensity conditioning, HLA-matched sibling HSCT, and cyclosporine A GVHD
      prophylaxis. After HSCT, monocyte IL-1alpha and TNF-alpha levels were measured
      using intracellular flow cytometry (IC-FCM), and results were correlated with
      clinical GVHD. RESULTS: Incidences of acute GVHD were none (n = 3), grades I-II
      (n = 9), or grades III-IV (n = 5; each case with stage 2-3 gut GVHD).
      Posttransplantation monocyte IL-1alpha production (percentage of CD14(+)IL-1(+)
      cells) increased significantly from 8.7% +/- 3.7% (week 2) to 40.3% +/- 7.3%
      (week 4; P = 0.0065) and was not associated with GVHD severity (P = 1.00).
      Conversely, increases in monocyte TNF-alpha were quantitatively reduced and
      temporally delayed, from 0.6% +/- 0.2% (week 2) to 3.6% +/- 1.4% (week 6; P =
      0.076). Most importantly, elevation of monocyte TNF-alpha level correlated with
      increased gut GVHD severity (P = 0.0041); increases in monocyte TNF-alpha levels
      typically preceded the onset of gut GVHD symptoms. CONCLUSIONS: Human gut GVHD
      after reduced-intensity allogeneic HSCT is associated with monocyte cytokine
      secretion initially involving IL-1alpha, followed by TNF-alpha. Serial
      measurement of monocyte cytokines, in particular, TNF-alpha, by IC-FCM may
      represent a noninvasive method for GVHD monitoring, potentially allowing the
      identification of patients appropriate for early-intervention strategies.

PMID- 15017609
TI  - Small early tubular adenomas and mixed colonic polyps found on screening flexible
      sigmoidoscopy do not predict proximal neoplasia in males.
AB  - BACKGROUND & AIMS: Distal colonic adenomas found on flexible sigmoidoscopy are
      associated with proximal neoplasias, thus requiring a complete colonoscopic
      examination, but data regarding the association of distal mixed polyps with
      proximal neoplasia are lacking. We conducted this study to elucidate the
      significance of distal mixed colonic polyps in predicting proximal neoplasia.
      METHODS: We retrospectively analyzed data from patients who underwent a flexible
      sigmoidoscopic examination for colorectal cancer screening and a follow-up
      colonoscopic examination because of distal colonic polyps. Distal index polyps
      were classified by a pathologist as early tubular adenoma (ETA), serrated, or
      true mixed categories. Index polyps also were immunostained with a monoclonal
      antibody, Adnab-9, a marker for the colorectal adenoma carcinoma sequence.
      RESULTS: In 636 patients with distal index polyps, 6% were malignant, 55% were
      adenomas, 13% were ETAs, 6% were serrated, 4% were true mixed, and 17% were
      hyperplastic. Compared with distal hyperplastic index polyps, distal malignant
      polyps (P = 0.0006) and adenomas (P = 0.001) were associated with a significantly
      increased number of synchronous proximal neoplasia, but the small distal mixed,
      serrated, or ETA did not predict the increased incidence of proximal neoplasia.
      Large distal polyps of each category were significantly associated with an
      increased number of synchronous proximal neoplasias. In support of these
      findings, immunostaining of distal polyps with Adnab-9 showed predictability for
      proximal neoplasia only in the adenoma category (P < 0.05). CONCLUSIONS: Small
      ETAs, serrated, or mixed polyps found on flexible sigmoidoscopic examination do
      not increase the probability of synchronous proximal neoplasia.

PMID- 15017610
TI  - Clinical and genetic characteristics of hereditary pancreatitis in Europe.
AB  - BACKGROUND & AIMS: Hereditary pancreatitis is an autosomal dominant disease that
      is mostly caused by cationic trypsinogen (PRSS1) gene mutations. The aim was to
      determine phenotype-genotype correlations of families in Europe. METHODS:
      Analysis of data obtained by the European Registry of Hereditary Pancreatitis and
      Pancreatic Cancer was undertaken using multilevel proportional hazards modelling.
      RESULTS: There were 112 families in 14 countries (418 affected individuals): 58
      (52%) families carried the R122H, 24 (21%) the N29I, and 5 (4%) the A16V
      mutation, 2 had rare mutations, and 21 (19%) had no PRSS1 mutation. The median
      (95% confidence interval [CI]) time to first symptoms for R122H was 10 (8, 12)
      years of age, 14 (11, 18) years for N29I, and 14.5 (10, 21) years for mutation
      negative patients (P = 0.032). The cumulative risk (95% CI) at 50 years of age
      for exocrine failure was 37.2% (28.5%, 45.8%), 47.6% (37.1%, 58.1%) for endocrine
      failure, and 17.5% (12.2%, 22.7%) for pancreatic resection for pain. Time to
      resection was significantly reduced for females (P < 0.001) and those with the
      N29I mutation (P = 0.014). The cumulative risk (95% CI) of pancreatic cancer was
      44.0% (8.0%, 80.0%) at 70 years from symptom onset with a standardized incidence
      ratio of 67% (50%, 82%). CONCLUSIONS: Symptoms in hereditary pancreatitis start
      in younger patients and endpoints take longer to be reached compared with other
      forms of chronic pancreatitis but the cumulative levels of exocrine and endocrine
      failure are much higher. There is an increasingly high risk of pancreatic cancer
      after the age of 50 years unrelated to the genotype.

PMID- 15017611
TI  - Nonalcoholic fatty liver disease in patients with type 2 diabetes.
AB  - BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is reported commonly
      in patients with type 2 diabetes mellitus (DM), which has been suggested as a
      risk factor for the progressive form of NAFLD, or nonalcoholic steatohepatitis.
      The aim of this study was to assess the outcome of patients with NAFLD and DM.
      METHODS: A cohort of patients with NAFLD was identified, and patients with other
      causes of liver disease (alcohol, medication, etc.) were excluded. Clinical,
      pathological, and mortality data were available for this cohort. Patients were
      categorized and compared according to the presence or absence of DM. RESULTS: Of
      132 patients with NAFLD, 44 patients (33%) had an established diagnosis of DM.
      Patients with DM were older and had greater serum glucose and triglyceride levels
      and a greater aspartate aminotransferase-alanine aminotransferase ratio. Liver
      biopsy specimens from patients with DM showed more vacuolated nuclei and
      acidophilic bodies. Cirrhosis (histological or clinical) occurred in 25% of
      patients with DM (11 of 44 patients) and NAFLD compared with only 10.2% (9 of 88
      patients) of patients without DM with NAFLD (P = 0.04). After adjusting for
      potential confounders (age, body mass index, and the presence of cirrhosis), both
      overall mortality (risk ratio [RR], 3.30; 95% confidence interval [CI], 1.76
      6.18; P = 0.002) and mortality related to liver disease (RR, 22.83; 95% CI, 2.97
      175.03; P = 0.003) were greater in diabetic patients with NAFLD. Markers of
      hepatic dysfunction (low albumin level, high total bilirubin level, and prolonged
      prothrombin time) were the only independent predictors of increased mortality.
      CONCLUSIONS: Patients with NAFLD and DM are at risk for the development of an
      aggressive outcome, such as cirrhosis and mortality. This study supports the
      potential role of insulin resistance in the development of poor clinical outcomes
      in patients with NAFLD.

PMID- 15017612
TI  - Tenofovir disoproxil fumarate for the treatment of lamivudine-resistant hepatitis
      B.
AB  - BACKGROUND & AIMS: Lamivudine resistance occurs in patients with chronic
      hepatitis B at rates of 16%-32% after 1 year and 49% after 3 years. Adefovir
      dipivoxil, a nucleotide analogue recently approved by the Food and Drug
      Administration for the treatment of chronic hepatitis B, is effective against
      hepatitis B virus (HBV) but has been associated with renal toxicity at high
      doses. Tenofovir disoproxil fumarate is another nucleotide analogue with
      demonstrated antiviral activity against both wild-type and lamivudine-resistant
      HBV. Tenofovir, at its licensed dose, has not been associated with renal
      dysfunction. METHODS: We describe a series of 9 patients with lamivudine
      resistant hepatitis B treated with tenofovir, 300 mg, once daily before the
      availability of adefovir. Levels of HBV DNA, alanine aminotransferase (ALT),
      hepatitis B e antigen (HBeAg), and antibody to HBeAg (anti-HBe) were monitored.
      RESULTS: The addition of tenofovir to the existing regimen of lamivudine resulted
      in a median decline of 4.5 log(10) copies/mL in HBV DNA levels (range, 3.2-6.3
      log(10) copies/mL) after a median treatment duration of 12 months (range, 6-16
      mo). HBeAg seroconversion was observed in 2 patients, with a third patient
      undergoing HBeAg loss while remaining anti-HBe negative. In 4 of 7 patients with
      elevated ALT levels at baseline, ALT levels normalized. No significant adverse
      events were encountered during treatment. CONCLUSIONS: In patients with
      lamivudine-resistant hepatitis B, treatment with tenofovir is well tolerated and
      results in significant virological, serological, and biochemical improvements on
      par with those seen with high-dose adefovir (30 mg/day) therapy, without the
      complication of renal toxicity.

PMID- 15017614
TI  - Liver abnormalities in celiac disease.
AB  - Celiac disease is an intolerance of the small bowel to gluten. Although most
      symptomatic patients have symptoms related to the gastrointestinal tract, many
      extra-intestinal manifestations have been described. A wide spectrum of
      hepatobiliary diseases have been described, including asymptomatic elevations of
      liver enzyme levels, nonspecific hepatitis, nonalcoholic fatty liver disease, and
      autoimmune and cholestatic liver disease. In addition, celiac disease may be the
      underlying cause of unexplained elevations of liver enzyme levels. Because most
      patients do not have overt gastrointestinal symptoms, a high index of suspicion
      is required. Moreover, in the majority of patients, liver enzyme levels will
      normalize on a gluten-free diet. We review the literature pertaining to hepatic
      abnormalities that may be seen in association with celiac disease. We also
      suggest an approach to the investigation and management of these patients.

PMID- 15017613
TI  - A treatment algorithm for the management of chronic hepatitis B virus infection
      in the United States.
AB  - BACKGROUND AND AIMS: Chronic hepatitis B is an important public health problem
      worldwide and in the United States. A treatment algorithm for chronic hepatitis B
      virus (HBV) infection was developed by a panel of US hepatologists based on new
      developments in the understanding of the virology of HBV, availability of more
      sensitive molecular diagnostic testing, and advantages and disadvantages of
      currently approved therapies. METHODS: This algorithm is based on available
      evidence, but where data are lacking, the panel relied on clinical experience and
      consensus expert opinion. RESULTS: Serum HBV DNA can be detected at levels as low
      as 100-1000 copies/mL by using molecular assays and should be determined to
      establish a baseline level before treatment, monitor response to antiviral
      therapy, and survey for the development of drug resistance. The primary aim of
      antiviral therapy is durable suppression of serum HBV DNA to the lowest level
      possible. The threshold level of HBV DNA for determination of candidacy for
      therapy is >/=10(5) copies/mL for patients with hepatitis B e antigen (HBeAg)
      positive chronic hepatitis B. A lower serum HBV DNA threshold is appropriate for
      patients with HBeAg-negative chronic hepatitis B and those with decompensated
      cirrhosis, and the panel recommends thresholds of 10(4) copies/mL and 10(3)
      copies/mL, respectively. CONCLUSIONS: Interferon alfa-2b, lamivudine, and
      adefovir dipivoxil are all approved as initial therapy for chronic hepatitis B
      and have certain advantages and disadvantages. Issues for consideration include
      efficacy, safety, incidence of resistance, method of administration, and cost.
      Studies are under way to explore the safety and efficacy of combination therapy,
      which may prove to be more effective than monotherapy in suppressing viral
      replication and may decrease or delay the incidence of drug resistance.

PMID- 15017615
TI  - Pharmacology and gastrointestinal safety of lumiracoxib, a novel cyclooxygenase-2
      selective inhibitor: An integrated study.
AB  - BACKGROUND AND AIMS: Lumiracoxib is a structurally novel, acidic selective
      inhibitor of cyclooxygenase (COX)-2. We coordinated existing methodologies in a
      single study to evaluate potency, selectivity, and effect on the human
      gastrointestinal tract. METHODS: Twenty four healthy subjects (aged 18-45 years,
      12 female) received high dose lumiracoxib (800 mg every day), standard dose
      naproxen (500 mg twice a day), or placebo for 8 days in a double-blind randomized
      crossover study. At the start and end of each dosing period, COX-2 selectivity
      was assessed by ex vivo serum thromboxane B(2) (COX-1) and lipopolysaccharide
      stimulated prostaglandin (PG) E(2) (COX-2), mucosal injury by endoscopy, and
      small and large bowel permeability by 0- to 5-hour and 5- to 24-hour (51)Cr-EDTA
      absorption. Plasma lumiracoxib was measured 2 hours after dosing on day 8 and
      vortex-stimulated ex vivo gastric mucosal PGE(2) synthesis at the end of each
      treatment period by enzyme immunoassay. RESULTS: Lumiracoxib was well absorbed
      and demonstrated similar potency to naproxen as a COX-2 inhibitor (77% and 66%
      inhibition, respectively, vs. placebo), but it differed in being more selective
      (24% and 97% inhibition of thromboxane B(2) vs. placebo). Gastric PGE(2) was
      reduced by 69% by naproxen (P < 0.001 vs. placebo) and 29% by lumiracoxib (P <
      0.01 vs. placebo and naproxen). No subjects developed gastroduodenal erosions on
      lumiracoxib (vs. 75% on naproxen and 12.5% on placebo). (51)Cr-EDTA absorption
      increased significantly with naproxen but not lumiracoxib. CONCLUSIONS:
      Lumiracoxib is a potent selective inhibitor of COX-2 that causes little or no
      endoscopically detected stomach or duodenal injury or changes in bowel
      permeability.

PMID- 15017616
TI  - Perceptions of physicians and patients with organic and functional
      gastrointestinal diagnoses.
AB  - BACKGROUND AND AIMS: We studied patient after-hours telephone calls to
      gastrointestinal (GI) fellows at a university program to determine requests made,
      physicians' responses, and perceptions of patients and physicians to these
      requests. METHODS: During a 4-month period, 4 GI fellows taking call were asked
      about reasons for patient-initiated after-hours telephone calls, actions taken,
      and their perceptions about the nature of the request, the illness impact, and
      their role in the care administered. Patients were telephoned within 1 week and
      asked the same questions about their perceptions of the call. RESULTS: Patients
      (N = 102) made 103 telephone calls, averaging 8.7 minutes, for symptoms (56%),
      procedure-related concerns (19%), and medications (18%). Physicians usually
      referred the patient to the clinic or emergency room (40%) or provided discussion
      and reassurance (36%). Patients' perceptions differed from physicians'
      perceptions: patients believed their problems to be more severe and more
      disabling and requests were more reasonable than perceived by the physician.
      Furthermore, their interactions with physicians (physician helpfulness,
      satisfaction with the recommendation, and likeability of the physician) were more
      positive than believed by physicians. Physicians believed phone calls from
      patients with functional disorders were less serious and less reasonable, that
      these patients were less disabled, and also that these patients were less liked
      than patients with an organic diagnosis. CONCLUSIONS: In this study, physicians
      carried a lower perception of the importance of telephone requests, the impact of
      the disorder, and their perceived helpfulness to patients than did patients
      making these requests. Physician perceptions were significantly lower for all
      these factors for patients with functional GI diagnoses. Additional studies are
      needed to understand the reasons for differing perceptions between physicians and
      patients.

PMID- 15017617
TI  - Stratification of bone fracture risk in patients with celiac disease.
AB  - BACKGROUND AND AIMS: Our objective in this cross-sectional, case-control study
      was to gain insight into celiac osteopathy by examining a well-defined cohort of
      patients with a wide clinical spectrum of the disease. METHODS: We studied 148
      unselected celiac patients and 296 (1:2) age- and sex-matched controls diagnosed
      with functional gastrointestinal disorders. Based on the clinical history, 53%
      were classically symptomatic, 36% had subclinical celiac disease, and 11% were
      silent, detected by screening. The fracture information was obtained through an
      in-person interview using a pre-designed questionnaire. RESULTS: Classically
      symptomatic patients had an increased number of fractures in the peripheral
      skeleton (47%) compared with age- and sex-matched controls (15%; odds ratio, 5.2;
      95% confidence interval, 2.8-9.8). However, fractures in subclinical/silent
      celiac cases (20%) were no different from those in controls (14%; odds ratio,
      1.7, 0.7-4.4). Compared with the subclinical/silent group, a significantly
      greater prevalence of fractures was detected in classically symptomatic patients
      (odds ratio, 3.6, 1.7-7.5). Compared with controls, celiac disease patients had
      significantly more fractures produced by mild trauma (P < 0.01), but there were
      no differences in the severity of trauma events that induced fractures. Mean bone
      density femoral neck z score was higher for subclinical/silent cases compared
      with classically symptomatic patients (P < 0.05). CONCLUSIONS: Celiac patients
      show a very wide variation in fracture risk, with increased risk in classically
      symptomatic patients. Diagnostic and therapeutic strategies to prevent bone loss
      and fracture should be preferentially used in the subgroup of patients with
      classic clinical disease.

PMID- 15017618
TI  - Enteroaggregative Escherichia coli diarrhea in travelers: response to rifaximin
      therapy.
AB  - BACKGROUND AND AIMS: We have recently shown that enteroaggregative Escherichia
      coli (EAEC) strains commonly cause travelers' diarrhea. The study was designed to
      determine whether U.S. travelers with EAEC diarrhea responded to rifaximin
      therapy. METHODS: In a multicenter placebo-controlled clinical trial of
      travelers' diarrhea without non-EAEC pathogens we evaluated 2 doses of rifaximin.
      EAEC was sought in stool samples in enrolled subjects by HEp-2 cell assay.
      Response to rifaximin (both groups combined) and placebo were evaluated in EAEC
      positive and EAEC-negative patient groups. RESULTS: Compared with placebo,
      rifaximin shortened the postenrollment illness in travelers with EAEC diarrhea
      (median, 22 vs. 72 hours; P = 0.03). In subjects with EAEC-negative diarrhea, the
      median duration of post-treatment diarrhea was shorter with rifaximin (33 hours)
      than with placebo (52 hours), but this difference was not significantly different
      (P = 0.14). CONCLUSIONS: Improvement of EAEC-mediated diarrhea with antibiotic
      treatment supports the pathogenicity of this organism in travelers to developing
      countries. The study provides information on the value of the poorly absorbed
      drug rifaximin in therapy of travelers' diarrhea.

PMID- 15017619
TI  - Utility of serum antibodies in determining clinical course in pediatric Crohn's
      disease.
AB  - BACKGROUND AND AIMS: The utility of serial measurements of anti-Saccharomyces
      cerevisiae (ASCA) and perinuclear antineutrophil cytoplasmic (p-ANCA) antibodies
      in Crohn's disease (CD) evolution is unknown. We aimed to study the pattern of
      antibody change and the prognosis of selected outcomes by baseline (at time of
      diagnosis) and serial antibody measurements in pediatric CD patients. METHODS:
      Serum ASCA and p-ANCA antibodies were measured at baseline (n = 154) and repeated
      during follow-up (n = 61) using standard techniques in a cohort of patients
      identified at Hopital Sainte-Justine between 1996 and 1998. Clinical information
      was abstracted from medical charts. Antibody patterns were examined using mixed
      modeling techniques. The prognostic ability of antibodies for selected outcomes
      was evaluated using logistic regression. RESULTS: Fifteen (24.5%), 18 (29.5%),
      and 11 (18%) patients with serial antibody measurements changed their ASCA-IgA,
      ASCA-IgG, and p-ANCA status (positivity), respectively. No distinct patterns in
      the evolution of antibody titers were noted. Baseline ASCA-IgA positivity
      significantly predicted relapses during disease course (IgA: odds ratio [OR],
      2.9; 95% confidence interval [CI], 1.33-6.35). Serial antibody measurements did
      not predict the occurrence of clinical outcomes. CONCLUSIONS: Baseline serum
      antibodies were predictive of a more relapsing disease course in pediatric CD.
      However, the limited variability in the antibodies over time and the inability of
      serial measurements to predict clinical outcomes may limit their use in the
      establishment of intervention strategies.

PMID- 15017620
TI  - Extensive but hemiallelic methylation of the hMLH1 promoter region in early-onset
      sporadic colon cancers with microsatellite instability.
AB  - BACKGROUND AND AIMS: Methylation of the hMLH1 promoter region is frequently
      observed in microsatellite instability (MSI)-positive sporadic colorectal
      carcinomas. We studied hMLH1 promoter methylation in peripheral blood lymphocytes
      of 87 index patients representing 29 cases of hereditary nonpolyposis colorectal
      cancers (HNPCCs), 28 cases of atypical HNPCCs, and 30 sporadic cases of the
      development of early-onset colorectal carcinomas or multiple primary cancers.
      METHODS: Methylation of the hMLH1 promoter region was analyzed by Na-bisulfite
      polymerase chain reaction/single-strand conformation polymorphism analysis or
      methylation-specific polymerase chain reaction. MSI, allelic status of the hMLH1
      locus, and loss of hMLH1 protein expression were examined in cases for which
      tumor tissues were available. RESULTS: Extensive methylation of the hMLH1
      promoter was detected in peripheral blood lymphocytes of 4 of 30 patients with
      sporadic early-onset colon cancer, among whom multiple primary cancers (1 colon
      and 1 endometrial cancer) developed in 2 cases. This methylation was not detected
      in analyses of HNPCC or atypical HNPCC groups or healthy control subjects. MSI
      was positive, and extensive methylation was detected in both cancers (colon and
      endometrial cancer) and normal tissues (colon, gastric mucosa, endometrium, and
      bone marrow) in all of the examined cases (3 of 3). Analysis of a polymorphic
      site in the hMLH1 promoter in 2 informative cases showed that methylation was
      hemiallelic. In 1 case, the unmethylated allele was lost in the colon cancer but
      not in the metachronous endometrial cancer. CONCLUSIONS: Constitutive,
      hemiallelic methylation of the hMLH1 promoter region was shown to be associated
      with carcinogenesis in sporadic, early-onset MSI-positive colon cancers.

PMID- 15017621
TI  - Determinants of health-related quality of life in patients with chronic liver
      diseases.
AB  - BACKGROUND AND AIMS: The study aims to assess influence of the liver disease,
      active medical and psychiatric comorbidities, and sociodemographic variables in
      the determination of health-related quality of life (HRQOL) measured by a generic
      and a liver-specific instrument in unselected patients with chronic liver
      disease. METHODS: Two hundred four of 255 consecutive patients (80%) with all
      stages of various liver diseases attending a tertiary-care center completed the
      following self-report questionnaires: sociodemographic questionnaire of the
      Competence Network Bowel Disease, morbidity list of the German Pain
      Questionnaire, the German version of the Hospital Anxiety and Depression Scale
      (HADS-D), and Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) as
      generic instruments; and the German version of the Chronic Liver Disease
      Questionnaire (CLDQ) as a disease-specific HRQOL-instrument. RESULTS: Stepwise
      multiple regression showed that cause of liver disease, severity of disease
      (cirrhosis vs. no cirrhosis, Child-Pugh score), sex, age, and social class had no
      effect on HRQOL. Anxiety resp. depression scores >/= 11 in the German version of
      the HADS, indicating a probable psychiatric disorder, contributed independently
      to the impaired HRQOL in the total score of the CLDQ and the Physical and Mental
      Summary Scores of the SF-36 (P < 0.0001). Number of active medical comorbidities
      contributed independently to the reduced HRQOL in the total score of the CLDQ and
      the Physical Summary Score of the SF-36 (P < 0.0001). Furthermore, the SF-36
      Mental Summary Score was influenced negatively by active cardiovascular
      comorbidity (P < 0.003). CONCLUSIONS: Psychiatric comorbidity and active medical
      comorbidity, and not severity of the liver disease according to Child-Pugh score,
      determine reduced HRQOL in patients with chronic liver diseases.

PMID- 15017622
TI  - Assessing quality of life in primary biliary cirrhosis.
AB  - BACKGROUND AND AIMS: Assessment of health-related quality of life (HRQOL) is not
      routinely reported in the literature on chronic liver disease (CLD). Few studies
      have examined quality of life (QOL) in patients with primary biliary cirrhosis
      (PBC) despite its significant functional impact. One of the reasons for the lack
      of HRQOL measurement in patients with PBC may be the absence of a well-recognized
      and widely used measure that clinicians can use in ordinary clinical practice.
      The aim of this study is to evaluate HRQOL measures used in patients with PBC and
      examine the suitability of the measures for these patients. METHODS: A literature
      search identified reports that focused on any aspect of QOL in patients with PBC.
      Key texts were identified containing generic, domain-specific, and condition
      specific measures. The identified measures were systematically evaluated for
      appropriateness, acceptability, reliability, validity, precision, and
      responsiveness. RESULTS: Twenty measures were identified from 9 key texts. Six of
      the measures were previously validated generic measures; 10 were domain-specific
      measures previously used to measure fatigue, depression, and psychological
      distress in general and psychiatric populations; and 4 measures had been
      developed in patients with CLD. Reporting of reliability and validity generally
      was consistent for all measures used. However, reporting of the remaining
      criteria was variable, particularly in relation to responsiveness over time and
      acceptability of the measures to patients with PBC. CONCLUSIONS: A clearer and
      more rigorous approach is needed in reporting the properties of HRQOL measures
      used in patients with PBC to help clinicians decide which measures are most
      suitable for these patients.

PMID- 15017623
TI  - BK virus colonic ulcerations.

PMID- 15017624
TI  - Strategies to address increased demand for colonoscopy: Guidelines in an open
      endoscopy practice.
AB  - BACKGROUND AND AIMS: Since Medicare approval for reimbursement of screening
      colonoscopies, the number of colonoscopy requests has increased. Physician
      resources have often been inadequate to meet the demand. We sought to reduce the
      demand for colonoscopy in an open endoscopy system by using a guideline-based
      triage system to eliminate inappropriate procedures and to align the timing of
      surveillance colonoscopies with recommendations made by national organizations.
      METHODS: This was a cohort study with primary care outpatients. From October 2002
      to February 2003, 498 consecutive patients on a waiting list of 2400 awaiting
      colonoscopy for all indications were triaged and are the focus of the study.
      Selection of patients for appropriate colonoscopy was based on consensus
      guidelines developed for institutional use by using established published
      guidelines for appropriate colonoscopy indications. RESULTS: Of the 498
      consecutive patients triaged, 139 (28%) were deemed inappropriate. The most
      common reason was inappropriate referral for surveillance of colorectal polyps.
      The percentage of inappropriate referrals by the 3 largest referring specialties
      (internal medicine, family medicine, and gastroenterology) combined was also 28%
      with no statistically significant differences between specialties. CONCLUSIONS:
      Most referrals for colonoscopy in an open-access endoscopy system were
      appropriate, although about 1 in 4 were not. Use of triage and further education
      of physicians regarding colonoscopy may optimize colonoscopy utilization.

PMID- 15017625
TI  - Hyperplastic polyps and colorectal cancer: is there a link?
AB  - Most colorectal cancers (CRCs) are thought to arise in preexisting polyps called
      adenomas. A second type of colorectal polyp known as a hyperplastic polyp has
      been regarded as harmless for decades. Patients with hyperplastic polyps are
      therefore not thought to be at any increased risk of CRC, and best-practice
      guidelines indicate that these polyps do not require surveillance colonoscopy.
      Recently, it has become clear that CRC is not a single disease. One type of CRC
      (30%) shows a chemical alteration in DNA known as methylation, and a proportion
      of these also show genetic instability at the level of DNA. There is now strong
      evidence that the hyperplastic polyp is not harmless, but it might serve as the
      precursor of CRC with DNA methylation and deficient DNA mismatch repair. This
      novel pathway applies particularly to the subset of hyperplastic polyps that
      occurs in the proximal colon. If this premise is correct, it would be unsafe to
      ignore these polyps. There is now a need to define the genetic steps that explain
      the evolution of CRCs that develop within hyperplastic polyps. At the clinical
      level, it will be necessary to identify biomarkers for hyperplastic polyps that
      are especially prone to malignant conversion. Screening can then be targeted more
      selectively toward patients who are at significantly increased risk of malignant
      transformation of hyperplastic polyps.

PMID- 15017626
TI  - Gastrointestinal basic science 2002-2003: the year in review.
AB  - The Board of Editors of Gastroenterology identified 6 topics in basic
      gastroenterology research in which exciting advancements have been made during
      the past year. These topics are (1) NOD2 variants in Crohn's disease, (2)
      Heliobacter pylori and CagA and VacA pathogenesis, (3) beta-catenin function in
      normal colonic epithelia and colon cancer, (4) DNA methylation in colonic cancer,
      (5) the HCV replicon, and (6) the use of small interfering RNA in somatic cell
      genetics. Basic research in gastroenterology has been characterized during the
      past year by the rapid translation from fundamental research into
      pathophysiological systems. New technological advances are being applied to
      difficult areas of gastrointestinal research. Well-defined patient populations
      are critical to extend the knowledge derived from the human genome to
      gastrointestinal diseases.

PMID- 15017627
TI  - Capsule endoscopy for Crohn's disease: ready for prime time?

PMID- 15017628
TI  - Self-selection and use patterns of over-the-counter omeprazole for frequent
      heartburn.
AB  - BACKGROUND AND AIMS: The Food and Drug Administration approval and subsequent
      launch of over-the-counter (OTC) omeprazole raises the question whether consumers
      would use OTC omeprazole appropriately in a "real world" setting. METHODS: A 3
      month observational study was conducted in an OTC setting to determine whether
      consumers could (1) correctly self-select to use omeprazole for frequent
      heartburn, (2) comply with a product label that calls for 14 consecutive days of
      once-daily dosing, and (3) use more than 14 doses of medication only under the
      advice of a physician. Consumers were interviewed at 5 shopping malls in
      geographically distinct areas of the United States and asked whether they had
      heartburn. Of the 1999 self-reported heartburn sufferers, 866 determined the
      product was appropriate for their condition and purchased the product; of these,
      758 (88%) returned diaries documenting product usage and physician contact.
      RESULTS: OTC consumers accurately self-selected; more than 90% of participants
      had heartburn 2 or more days/week. Analysis of diary data showed a high degree of
      compliance to label use directions; only 3% of subjects took more than 14 doses
      without consulting a physician. After 3 months, 43% of subjects did not have
      recurrence of heartburn. Overall, 75% of subjects had contact with a physician
      about heartburn before, during, or soon after the study (26% contacted a
      physician during the 3-month study). Of the 758 subjects, only 1 subject took
      more than 14 tablets without consulting a physician and had recurrence of
      heartburn. CONCLUSIONS: Actual use data support that consumers accurately self
      select if an OTC proton pump inhibitor is appropriate for use, comply with a 14
      day regimen in the OTC setting, and appropriately seek physician involvement for
      longer-term management of frequent heartburn.

PMID- 15017629
TI  - Polymorphism of interleukin-1beta affects the eradication rates of Helicobacter
      pylori by triple therapy.
AB  - BACKGROUND AND AIMS: Polymorphism in interleukin-1beta (IL-1beta) is associated
      with intragastric pH levels in Helicobacter pylori-positive subjects.
      Intragastric pH levels affect the activity of antibiotics against H. pylori in
      the stomach. The aim of this study was to investigate whether IL-1beta
      polymorphism is associated with eradication rates of H. pylori by triple therapy
      with a proton pump inhibitor (PPI), amoxicillin, and clarithromycin. METHODS:
      Three hundred thirty-six patients infected with H. pylori completed treatment
      with omeprazole, 20 mg, or lansoprazole, 30 mg twice daily; clarithromycin, 200
      mg 3 times daily; and amoxicillin, 500 mg 3 times daily, for 1 week. IL-1beta-511
      and CYP2C19 genotypes of patients and sensitivity of H. pylori to clarithromycin
      and amoxicillin were determined. RESULTS: Logistic regression analysis showed
      that the IL-1beta-511 polymorphism, as well as CYP2C19 genotype of patients and
      clarithromycin-resistance of H. pylori, was associated with successful
      eradication. Eradication rates for H. pylori were 77.3% (75 of 97; 95% confidence
      interval, 67.5-84.6), 89.6% (147 of 164; 95% confidence interval, 83.9-93.1), and
      94.7% (95% confidence interval, 86.9-98.5) in patients with the C/C, C/T, and T/T
      genotypes of IL-1beta-511, respectively (P = 0.0014). CONCLUSIONS: IL-1beta-511
      polymorphism is one of the determinants of successful eradication of H. pylori
      using triple therapy with a PPI, amoxicillin, and clarithromycin, together with
      CYP2C19 genotype and bacterial resistance to clarithromycin.

PMID- 15017630
TI  - Initial experience with wireless capsule enteroscopy in the diagnosis and
      management of inflammatory bowel disease.
AB  - BACKGROUND AND AIMS: Wireless capsule enteroscopy (WCE) offers the potential to
      directly visualize the entire small bowel and identify superficial lesions not
      detected by traditional endoscopy and radiography. The aim of this study is to
      assess the clinical utility of WCE in the evaluation of patients with known or
      suspected inflammatory bowel disease (IBD). METHODS: Fifty patients with ongoing
      symptoms underwent Given M2A endoscopic capsule examinations. Indications
      included: (1) evaluation for small-bowel involvement in patients with IBD with
      isolated colitis (n = 22), (2) determination of the extent of small-bowel disease
      in patients with Crohn's disease (CD; n = 20), and (3) workup of suspected IBD (n
      = 8). Outcome measures were classified as diagnostic when multiple ulcerations
      were present, suspicious when </=3 ulcerations were seen, and nonspecific or
      normal. RESULTS: WCE findings were diagnostic for CD in 20 patients and
      suspicious for small-bowel CD in 10 patients. Seventeen of 20 patients with
      diagnostic WCE findings improved with increased IBD-directed medical therapy, as
      did 7 of 10 patients with suspicious study results. WCE was normal or showed
      nonspecific findings in the remaining 20 patients. Notably, identification of
      small-bowel lesions in 5 patients with a previous history of isolated colitis
      resulted in a change in diagnosis to CD after confirmatory ileoscopy with biopsy.
      CONCLUSIONS: Results of this preliminary study suggest that WCE is a novel and
      potentially clinically useful method of directly visualizing and diagnosing small
      bowel lesions in patients with IBD that can be missed by traditional endoscopic
      and radiological procedures.

PMID- 15017631
TI  - Gender differences in the response of colitis to smoking.
AB  - BACKGROUND AND AIMS: The aim of this study was to examine in parallel the effect
      of smoking on ulcerative colitis and Crohn's colitis and assess the effect of
      gender on the response of colitis to smoking. METHODS: Medical charts of 1784
      adult consecutive patients (978 patients, ulcerative colitis; 118 patients,
      indeterminate colitis; and 688 patients, Crohn's colitis), whose smoking habits
      were specified by direct interview, were reviewed. RESULTS: The proportion of
      ever smokers was 42% in ulcerative colitis, 43% in indeterminate colitis, and 61%
      in Crohn's colitis. Smoking cessation preceded the onset of colitis in 279
      patients with ulcerative colitis or indeterminate colitis (61%) and only 52
      patients (12%) with Crohn's colitis. In ulcerative colitis and indeterminate
      colitis, current smoking delayed mean age at disease onset in men (from 32 to 41
      yr; P < 0.001), but not women (from 33 to 33 yr), and decreased the need for
      immunosuppressants in men (10-yr cumulative risk, 26% +/- 4% in nonsmokers vs. 8%
      +/- 4% in smokers; P < 0.01), but not significantly in women. Conversely, in
      Crohn's colitis, current smoking hastened disease onset in women (from 35 to 29
      yr; P < 0.001), but not men (from 32 to 31 yr), and increased the need for
      immunosuppressants in women (10-yr cumulative risk, 48% +/- 5% in nonsmokers vs.
      58% +/- 4% in smokers; P < 0.01), but not men. CONCLUSIONS: The dual effects of
      smoking in colitis, beneficial in ulcerative colitis and harmful in Crohn's
      colitis, are modulated importantly by gender, with women having more disadvantage
      than men.

PMID- 15017633
TI  - Calcifying obstructive pancreatitis: a study of intraductal papillary mucinous
      neoplasm associated with pancreatic calcification.
AB  - BACKGROUND AND AIMS: We have observed intraductal papillary mucinous neoplasm
      (IPMN) associated with pancreatic calcification. The aim of this study is to
      describe the profile of IPMN associated with calcification and gain insights into
      the pathogenesis of calcification in IPMN. METHODS: We identified 10 patients
      with IPMN with pancreatic calcification, of whom 7 underwent pancreatic
      resection. We reviewed demographic data, history of previous pancreatitis, and
      radiological and histological features of these patients. RESULTS: In patients
      with IPMN with calcification (mean age, 65 +/- 12 yr; 50% men), a diagnosis of
      chronic calcifying pancreatitis was entertained in 5 of 10 patients; 2 patients
      had undergone previous endoscopic therapy for stone removal. There was no
      previous history of pancreatitis in 9 of 10 patients. Radiologically,
      calcifications were seen diffusely throughout the gland in 8 of 10 patients and
      interpreted as chronic calcific pancreatitis. Although 1 of the 7 patients who
      underwent resection had diffuse IPMN throughout the gland, 6 patients had IPMN
      confined to the head or uncinate process (mean size, 2.75 cm; range, 1.1-5 cm).
      Histologically, 6 of 7 IPMNs were adenomas, and 1 patient had invasive cancer. No
      patient had intratumoral calcification. All 7 patients had calcification within
      the main pancreatic duct and/or side branches, often within inspissated mucus.
      CONCLUSIONS: IPMN associated with pancreatic calcification can lead to
      misdiagnosis and inappropriate treatment for chronic calcifying pancreatitis. In
      the absence of intratumoral calcification or a previous history of long-standing
      chronic pancreatitis, calcification in IPMN likely represents a unique and
      hitherto unrecognized form of calcifying obstructive pancreatitis caused by
      prolonged partial obstruction of the pancreatic duct.

PMID- 15017632
TI  - Rectal hyperreactivity to distention in patients with irritable bowel syndrome:
      role of distention rate.
AB  - BACKGROUND AND AIMS: Rectal motor hyperreactivity to distention may be involved
      in the pathophysiological course of defecatory symptoms in patients with
      irritable bowel syndrome (IBS), but results of patient studies are conflicting,
      possibly because of differences in the applied distention rate. Because a fast
      rate of distention increases the rectal motor response in healthy subjects, it
      also may show hyperreactivity in patients with IBS. The aim of this study is to
      compare the effects of 2 distention rates on rectal motor responses and
      sensations in 16 patients with IBS and 12 healthy subjects. METHODS: Rectal
      distensibility and the frequency of rectal contractions and sensations were
      recorded during volume-controlled rectal distentions at 2 distention rates (10
      and 100 mL/min). RESULTS: Recta of patients with IBS were significantly less
      distensible than those of healthy subjects during fast distention (P = 0.0006),
      but this difference was not statistically significant during slow distention (P =
      0.07). The frequency of rectal contractions and sensations, the majority of which
      were sensations of gas and a desire to defecate, were significantly greater in
      patients with IBS during both slow and fast distentions (both P < 0.025).
      CONCLUSIONS: Recta of patients with IBS are hyperreactive to distention, and fast
      distention magnifies this abnormal motor response. A greater frequency of
      sensations during a fixed-time distention period may help to characterize the
      patients.

PMID- 15017634
TI  - Hepatitis B genotypes correlate with tumor recurrence after curative resection of
      hepatocellular carcinoma.
AB  - BACKGROUND AND AIMS: Hepatitis B virus (HBV) genotype C is associated with the
      development of hepatocellular carcinoma (HCC), compared with genotype B. This
      study aims to investigate whether HBV genotypes influence the clinicopathologic
      features and long-term prognosis of patients after curative resection of HCC.
      METHODS: Stored serum samples from 62 patients with HBV-related HCC were tested
      for HBV genotype using a molecular method. RESULTS: Sixty of 62 patients (96.8%)
      undergoing curative resection of HCC were infected with genotype B or C.
      Concomitant cirrhosis was encountered more frequently in patients with genotype
      C. During a mean follow-up period of 26.3 +/- 9.8 months, patients with genotype
      B had a lower overall tumor recurrence rate than those with genotype C (22% vs.
      46%; P = 0.04). Stepwise multiple Cox proportional hazards regression analysis
      showed that multiplicity of tumor (hazard ratio, 6.84; 95% confidence interval
      [CI], 1.45-32.2; P = 0.02) was associated with tumor recurrence, whereas genotype
      C and age were associated with borderline significance (P = 0.06). Stratified
      analysis showed that genotype C was still associated with tumor recurrence in
      cirrhotic patients with borderline significance by univariate analysis (hazard
      ratio, 3.8; 95% CI, 0.84-17.6; P = 0.07). However, cumulative 2-year survival
      rates were similar between patients with genotype B and C (92% vs. 85%; P =
      0.23). CONCLUSIONS: Our data suggest that patients with HCC with genotype C have
      a greater tumor recurrence rate after curative resection of HCC compared with
      those with genotype B. Prolonged follow-up is needed to clarify the impact of HBV
      genotype on postoperative outcome.

PMID- 15017635
TI  - Colonoscopy practice patterns since introduction of medicare coverage for average
      risk screening.
AB  - BACKGROUND AND AIMS: Recent legislation passed in July 2001 provides coverage for
      all Medicare beneficiaries for average-risk screening colonoscopy. METHODS: We
      analyzed the Clinical Outcomes Research Initiative national endoscopic database
      to characterize colonoscopy practice patterns before and after the introduction
      of this coverage. RESULTS: Between January 1998 and May 2002, 205,638 patients
      underwent colonoscopy, of whom 8.3% underwent average-risk colon cancer
      screening. The proportion of procedures performed for average-risk screening has
      increased dramatically from 4.6% (before July 2001) to 14.2% (after July 2001).
      With the increased volume of average-risk screening examinations, colonic lesion
      detection (masses and polyps greater than 9 mm) has declined (4.9% before July
      2001 to 3.8% after July 2001). CONCLUSIONS: There has been a dramatic increase in
      the rates of screening colonoscopy during the past 4 years. If rates continue to
      increase, optimal resource utilization will assume increasing importance.

PMID- 15017636
TI  - Recombinant-activated factor VII as hemostatic therapy in eight cases of severe
      hemorrhage from esophageal varices.
AB  - BACKGROUND AND AIMS: There are several treatment options for gastroesophageal
      variceal hemorrhage. In severe cases, bleeding persists and is associated with a
      dismal outcome. The coagulation disorders might be correlated with risk of
      bleeding in patients with portal hypertension. The administration of activated
      recombinant factor VII corrects prothrombin time transiently in nonbleeding
      patients with cirrhosis as well as in bleeding ones. The aim of this study was to
      assess the hemostatic efficacy of activated recombinant factor VII in bleeding
      esophageal varices. METHODS: Between May 2001 and September 2002, 112 patients
      with cirrhosis and an episode of acute esophageal variceal bleeding were
      admitted. On an open basis with a single intravenous dose of 4.8 mg of
      recombinant factor VII, we treated 8 patients experiencing severe and active
      hemorrhage from esophageal varices unresponsive to pharmacologic therapy,
      endoscopic therapy, or balloon tamponade. RESULTS: Eight (7%) of 112 patients met
      entry criteria. Hemostasis was achieved in all the cases after recombinant
      activated factor VII therapy. Rebleeding and mortality rates were 25% and 50% (2
      and 4 patients), respectively. CONCLUSIONS: In our experience, recombinant
      activated factor VII achieves hemostasis in bleeding esophageal varices
      unresponsive to standard treatment.

PMID- 15017637
TI  - Pretreatment antimicrobial susceptibility testing is not cost saving in the
      standard eradication of Helicobacter pylori.

PMID- 15017638
TI  - GI clinical research 2002-2003: the year in review.

PMID- 15017640
TI  - Collaborative health for IBS.

PMID- 15017639
TI  - Autoimmune chronic pancreatitis: a plea for simplification and consistency.

PMID- 15017641
TI  - Propofol versus midazolam/fentanyl for outpatient colonoscopy: administration by
      nurses supervised by endoscopists.
AB  - BACKGROUND & AIMS: Propofol is under evaluation as a sedative for endoscopic
      procedures. We compared nurse-administered propofol to midazolam plus fentanyl
      for outpatient colonoscopy. METHODS: One hundred outpatients undergoing
      colonoscopy were randomized to receive propofol or midazolam plus fentanyl,
      administered by a registered nurse and supervised only by an endoscopist.
      Endpoints were patient satisfaction, procedure and recovery times,
      neuropsychologic function, and complications. RESULTS: The mean dose of propofol
      administered was 277 mg; mean doses of midazolam and fentanyl were 7.2 mg and 117
      microg, respectively. Mean time to sedation was faster with propofol (2.1 vs. 6.1
      min; P<0.0001), and depth of sedation was greater (P<0.0001). Patients receiving
      propofol reached full recovery sooner (16.5 vs. 27.5 min; P=0.0001) and were
      discharged sooner (36.5 vs. 46.1 min; P=0.01). After recovery, the propofol group
      scored better on tests reflective of learning, memory, working memory span, and
      mental speed. Six minor complications occurred in the propofol group: 4 episodes
      of hypotension, 1 episode of bradycardia, and 1 rash. Five complications occurred
      with the use of midazolam and fentanyl: one episode of oxygen desaturation
      requiring mask ventilation and 4 episodes of hypotension. Patients in the
      propofol vs. midazolam and fentanyl groups reported similar degrees of overall
      satisfaction using a 10-cm visual analog scale (9.3 vs. 9.4, P>0.5). CONCLUSIONS:
      Nurse-administered propofol resulted in several advantages for outpatient
      colonoscopy compared with midazolam plus fentanyl, but did not improve patient
      satisfaction.

PMID- 15017642
TI  - Endoscopy in eosinophilic esophagitis: "feline" esophagus and perforation risk.
AB  - BACKGROUND & AIMS: Idiopathic eosinophilic esophagitis is an underdiagnosed
      disease with typical endoscopic findings, which have not been well described.
      METHODS: Charts and pathology reports at two tertiary care centers from June 1993
      to April 2002 were reviewed to describe the endoscopic findings of this disease
      and to correlate them with clinical characteristics. Eight patients were
      identified as having eosinophilic esophagitis based on clinical symptoms and
      pathology reports. RESULTS: Soft and subtle ring(s) in the esophagus were found
      in 7 of 8 patients. In 3 of 8 patients, the esophagus appeared rigid. Mucosal
      rents occurred with simple passage of the endoscope in 5 of 8 patients. One
      patient developed a perforation after simple passage of the endoscope. Endoscopic
      findings can be normal or very subtle in these patients, and the findings can
      easily be missed during endoscopy. Tearing of the esophagus can occur with simple
      passage of the endoscope or biopsy even in the absence of overt rings. A minimum
      of 8 weeks of medical therapy (proton pump inhibitor, histamine antagonists,
      immunosuppressants) should be undertaken before considering dilation because of
      the high risk involved with the procedure and the good response to medical
      therapy. CONCLUSIONS: We recommend considering dilation only in patients with
      eosinophilic esophagitis who do not respond to medical therapy and have rings
      that appear to be obstructing the lumen.

PMID- 15017643
TI  - Expression of epidermal growth factor receptor in gastric carcinomas.
AB  - BACKGROUND & AIMS: Epidermal growth factor receptor belongs to the family of type
      I receptor tyrosine kinases. Overexpression of epidermal growth factor receptor
      has been observed in a variety of cancers with or without amplification of the
      gene. Novel chemotherapies targeting receptor tyrosine kinases might be effective
      for the treatment of cancers in which overexpression of this protein is a
      feature. The aim of this study was to assess the potential efficacy of epidermal
      growth factor receptor-targeted therapy in gastric cancer. This was achieved by
      determining the frequency of increased epidermal growth factor receptor
      expression in gastric cancers and investigating the relationship between protein
      overexpression and gene amplification. METHODS: Immunohistochemical evaluation of
      413 gastric cancers was carried out by using a monoclonal antibody to the
      epidermal growth factor receptor. The intensity of reactivity was scored by using
      a 4-tier system (negative, 1+, 2+, and 3+). All positive staining (>1+) tumors
      overexpressing the protein were then analyzed for gene amplification by
      fluorescence in situ hybridization by using a gene-specific probe. RESULTS: High
      levels of overexpression (2+ or 3+ staining) were found in 9 of 413 (2.2%)
      patients, whereas low levels of overexpression (1+) were found in 34 (8.2%) of
      the study cohort. Fluorescence in situ hybridization analysis showed that more
      than 10 copies of the gene were recognized in all 5 cancers with 3+ staining and
      in 2 of the 4 tumors with 2+ staining. CONCLUSIONS: Although a high level of
      overexpression of epidermal growth factor receptor is uncommon in gastric
      carcinomas, it almost exclusively occurs by gene amplification.

PMID- 15017644
TI  - A collaborative health care model for the treatment of irritable bowel syndrome.
AB  - BACKGROUND & AIMS: There have been few reports of successful treatment of
      chronically symptomatic patients with irritable bowel syndrome. We performed a
      preliminary single center study to evaluate a new collaborative treatment model
      that used both gastroenterologist and psychologist working together, compared to
      medical treatment or psychological treatment alone. A second goal was to
      determine the sample size that would be necessary to definitively demonstrate
      efficacy of such a collaborative treatment program. METHODS: Forty-one patients
      with irritable bowel syndrome, seen in a tertiary setting, were randomly assigned
      to the 3 treatment groups. The research design was weighted toward collaborative
      treatment, which consisted of 3 biweekly visits. A series of questionnaires,
      including a 2-week daily diary as well as measures of quality of life, anxiety,
      depression, and relationships, were administered before treatment, after
      treatment, and again 3 months later. At termination of the study, patients
      completed a global assessment scale. RESULTS: Sixteen patients completed the
      collaborative program, 8 completed medical treatment directed at gastrointestinal
      function, and 6 completed psychological therapy. Eleven patients dropped out of
      the study; 2 had organic disease. Intent to treat and per protocol analyses
      showed that global self-assessment improved significantly at long-term follow-up
      in the collaborative treatment group (P<0.0002). Abdominal pain, diarrhea, and
      constipation also improved significantly in the collaborative treatment group
      (P<0.001). Collaborative treatment was statistically superior to medical
      treatment alone (P<0.05). The psychological treatment group had 50% improvement
      in global score. There was no significant improvement in the medically treated
      group. CONCLUSIONS: We have demonstrated that short-term treatment with
      gastroenterologist and psychologist working together is more effective than
      medical treatment in relieving symptoms in patients with chronic irritable bowel
      syndrome. Attributes of a collaborative approach are discussed. These pilot data
      suggest that collaborative treatment programs should be explored in further
      studies, and they show the importance of dealing with both mind and body in these
      patients.

PMID- 15017646
TI  - Risk of fracture in ulcerative colitis: a population-based study from Olmsted
      County, Minnesota.
AB  - BACKGROUND & AIMS: Osteopenia is common in patients with ulcerative colitis (UC),
      but less is known about fracture risk. Previously we were unable to demonstrate
      increased fractures in a population-based cohort with Crohn's disease. METHODS:
      Medical records of 273 Olmsted County, Minnesota residents initially diagnosed
      with UC in 1940-1993 were reviewed for evidence of subsequent fractures, as were
      records of a control cohort of county residents matched on age and gender.
      Cumulative fracture incidence after diagnosis was estimated by using the Kaplan
      Meier method. The hazard ratio of fracture in cases relative to control subjects
      was estimated by Cox proportional hazards regression, which was also used to
      evaluate potential risk factors for fracture. RESULTS: Median follow-up was 13
      years (range, 1 day-53 years). The cumulative incidence of any fracture from time
      of diagnosis was 40% at 25 years versus 42% in control subjects (P=0.615). The
      hazard ratio in cases compared to control subjects was 1.1 (95% confidence
      interval, 0.8-1.6) for any fracture and 1.3 (95% confidence interval, 0.6-2.8)
      for any osteoporotic fracture (hip, spine, or wrist as a result of moderate
      trauma). Other causes of secondary osteoporosis were associated with increased
      fracture risk, whereas estrogen use was protective. One hundred three cases
      received any corticosteroids (38%), and 34 (12%) had taken corticosteroids for 6
      months or longer. Corticosteroids and bowel resection were not associated with
      fracture risk. CONCLUSIONS: In this population-based cohort of patients with UC,
      fracture risk was not elevated relative to matched community control subjects.
      Use of corticosteroids did not appear to significantly influence the risk of
      fracture.

PMID- 15017645
TI  - Involvement of the biliary system in autoimmune pancreatitis: a follow-up study.
AB  - BACKGROUND & AIMS: The aim of this study was to define the bile duct changes
      associated with autoimmune pancreatitis. METHODS: Eight patients with autoimmune
      pancreatitis were followed for a mean of 4 years. The clinical features of these
      patients, including extrapancreatic bile duct changes, were examined by using
      biochemical parameters and several imaging modalities. Pathologic features of the
      pancreas and liver were examined by using the biopsy specimens of 7 patients.
      RESULTS: Diffuse or focal narrowing of the main pancreatic duct was observed in
      all patients. Histologic examination of the pancreas showed lymphoplasmacyte
      infiltration with severe fibrosis and acinar cell depletion. In 6 patients
      extrapancreatic bile duct changes such as stricture of the bile duct at hilus or
      intrahepatic area were observed. In 2 patients abnormalities in the bile duct and
      pancreas were detected simultaneously at diagnosis, and changes in the bile duct
      were observed later in 4 patients. Lymphoplasmacyte infiltration and fibrosis
      were observed in the portal area of all 7 liver biopsy samples. Five of the
      patients with bile duct changes received steroid therapy, and the pathological
      changes improved. CONCLUSIONS: Extrapancreatic bile duct changes are frequently
      associated with autoimmune pancreatitis. Similar pathogenic mechanism might
      produce the biliary tract and pancreatic abnormalities in autoimmune pancreatitis
      resulting in a similar histopathology in the liver and pancreas and response to
      steroid therapy.

PMID- 15017647
TI  - An evidence-based approach to studies in cirrhosis and portal hypertension:
      medical management of mild to moderate ascites.
AB  - Previous articles in this series have examined the critical appraisal of isolated
      structured clinical questions using the framework of evidence-based medicine.
      When patients are identified with a disease-specific process, however, an
      integrated approach for addressing multiple questions is required. This article,
      the sixth in the evidence-based medicine series for this journal, integrates
      critical appraisal techniques to examine the decision-making process used when
      evaluating a patient with cirrhosis and new-onset mild to moderate ascites. In
      the following clinical scenario, an approach is described for determining
      prognosis after the development of ascites and whether salt restriction and oral
      diuretics are effective therapies. The format is similar to other evidence-based
      medicine articles published in the Journal of the American Medical Association.
      The evidence-based medicine concepts have been expanded from previous articles,
      and examples from the hepatology literature have been used.

PMID- 15017648
TI  - Cholestatic jaundice as a paraneoplastic manifestation of prostate
      adenocarcinoma.
AB  - Malignancies may cause cholestatic jaundice through well-recognized mechanisms
      (e.g., bile duct obstruction or widespread hepatic infiltration). Paraneoplastic
      syndromes associated with malignancy, particularly with renal cell carcinoma
      (Stauffer's syndrome) and malignant lymphoproliferative diseases, can induce a
      reversible form of cholestasis through an unclear pathogenetic mechanism.
      Prostate cancer presenting initially with cholestatic jaundice without any
      obvious cause (i.e., obstruction or infiltration) has been reported in 2 cases in
      the medical literature. We report a patient who presented with pruritus and
      cholestatic jaundice. During the diagnostic work-up, prostate cancer was
      diagnosed. Conjugated bilirubin and alkaline phosphatase levels were increased
      markedly with modest increases of gamma-glutamyltranspeptidase and transaminase
      levels. The results of appropriate investigations performed during the patient's
      hospitalizations indicated no evidence of hepatic metastases or extrahepatic
      biliary obstruction. After treatment with flutamide and leuprolide, the patient's
      symptoms and the laboratory abnormalities reversed rapidly. We regard the
      cholestatic jaundice of this patient as part of a paraneoplastic syndrome; the
      cause of cholestasis remains an enigma. Patients with unexplained cholestasis
      should be investigated for malignancies, including prostate cancer.

PMID- 15017651
TI  - Laryngeal signs and symptoms and gastroesophageal reflux disease (GERD): a
      critical assessment of cause and effect association.
AB  - Gastroesophageal reflux disease (GERD) has been associated increasingly with ear,
      nose, and throat (ENT) signs and symptoms. However, the cause and effect
      relationship between these two clinical entities are far from established. Many
      patients diagnosed initially with GERD as the cause of laryngeal signs do not
      symptomatically or laryngoscopically respond to aggressive acid suppression and
      do not have abnormal esophageal acid exposure by pH monitoring. This has resulted
      in frustration on the part of both gastroenterologists and ENT physicians and
      confusion on the part of patients. In this article we discuss the reasons for
      this controversy and highlight the recent data attempting to clarify this complex
      area.

PMID- 15017652
TI  - Exercise and gastrointestinal function and disease: an evidence-based review of
      risks and benefits.
AB  - BACKGROUND & AIMS: Exercise is beneficial to health because it reduces the risk
      of cardiovascular and endocrine diseases, improves bone and muscle conditioning,
      and lessens anxiety and depression. However, the impact of exercise on the
      gastrointestinal system has been conflicting. This systematic literature review
      evaluates the effect of the different modes and intensity levels of exercise on
      gastrointestinal function and disease using an evidence-based approach. Although
      more applicable to trained athletes and individuals who are highly active and, as
      such, at risk to experience the side-effects of exercise, an effort was made to
      state the level or degree of exercise or the lack of such evidence. RESULTS:
      Light and moderate exercise is well tolerated and can benefit patients with
      inflammatory bowel disease and liver disease. Physical activity can also improve
      gastric emptying and lower the relative risk of colon cancer in most populations.
      Severe, exhaustive exercise, however, inhibits gastric emptying, interferes with
      gastrointestinal absorption, and causes many gastrointestinal symptoms, most
      notably gastrointestinal bleeding. CONCLUSIONS: This knowledge will enable
      physicians to prescribe physical exercise in health and disease and to better
      manage patients with exercise-related gastrointestinal disorders. Our
      understanding of exercise and its gastrointestinal manifestations as well as
      risks and benefits warrants further investigation.

PMID- 15017653
TI  - Fluctuating transglutaminase autoantibodies are related to histologic features of
      celiac disease.
AB  - BACKGROUND & AIMS: Asymptomatic children at risk for celiac disease (CD) and
      seropositive for immunoglobulin A anti-TG autoantibodies (TGAA) may lack small
      intestinal mucosal changes characteristic of CD. We have followed a group of
      children with serial testing for TGAA. METHODS: Subjects were a group of at-risk
      children comprised of infants expressing HLA-DR3 on newborn screening, those with
      type 1A diabetes, or a first-degree relative of someone with type 1 diabetes. All
      children participating in the prospective study for development of CD underwent
      serial testing for TGAA. Data from clinical evaluation and small intestinal
      biopsy were compared to the TGAA levels followed over time. RESULTS: In 42
      children, serial TGAA determinations while on a gluten-containing diet showed
      levels fluctuating 10-100-fold over 3-12 months. A TGAA index more than 0.5 had a
      positive predictive value (PPV) for histologic confirmation of CD of 96% (22/23).
      A TGAA index above the usual cutoff for positivity (0.05) had a PPV of only 76%
      (28/37). CONCLUSIONS: In children with TGAA seropositivity, the TGAA level varied
      over time and a higher titer predicted an abnormal biopsy characteristic of CD. A
      threshold for biopsy for diagnosis of CD could be set higher for screening
      identified cases than for clinically identified cases to decrease the frequency
      of performing "normal" biopsies.

PMID- 15017654
TI  - Gastric mucosal mast cells are increased in Helicobacter pylori-negative
      functional dyspepsia.
AB  - BACKGROUND & AIMS: Mast cells might be involved in pathogenesis of functional
      dyspepsia because they can release a wide range of potent mediators, capable of
      altering gastric nerve and muscle function. This study aimed to determine whether
      mast cell numbers were increased in the gastric mucosa of patients with
      functional dyspepsia compared to control subjects. METHODS: Biopsy samples were
      taken from the antrum and corpus of 111 patients: 20 asymptomatic control
      subjects, 62 patients with Rome criteria functional dyspepsia (33 Helicobacter
      pylori positive, 29 H. pylori negative), and 29 inflammatory control subjects (H.
      pylori positive). Mast cells were detected immunohistochemically by using a mouse
      monoclonal antibody specific for tryptase. Quantification was performed with
      light microscopy, and results were expressed as mast cells/mm(2) +/- standard
      error of mean. RESULTS: Mast cells were significantly increased in H. pylori
      negative functional dyspepsia samples compared to normal control samples in the
      antrum (230.1 +/- 11.3 vs. 94.8 +/- 8.4, P < 0.001) and corpus (264.1 +/- 27.1
      vs. 123.9 +/- 11.5, P = 0.001). Mast cells were also significantly increased in
      the antrum of patients with H. pylori positive functional dyspepsia compared to
      asymptomatic control subjects (166.5 +/- 17.0 vs. 94.8 +/- 8.4, P < 0.03).
      However, there was no significant difference between mast cell numbers in
      patients with H. pylori positive functional dyspepsia compared to inflammatory
      control subjects. CONCLUSIONS: Mast cells are increased in functional dyspepsia,
      independently of inflammation. This might contribute to the pathogenesis of
      functional dyspepsia by altering signaling in the brain-gut axis.

PMID- 15017655
TI  - Klebsiella oxytoca as an agent of antibiotic-associated hemorrhagic colitis.
AB  - BACKGROUND & AIMS: Klebsiella oxytoca has been isolated from stools and colonic
      biopsy specimens of patients with Clostridium difficile-negative antibiotic
      associated hemorrhagic colitis (AAHC), but the pathogenic role of the germ has
      not been established. The purpose of this study was to investigate the presence
      of K. oxytoca in patients with AAHC from a prospective cohort of patients with
      acute colitis, and to test the cytotoxicity on HEp-2 cells of K. oxytoca strains
      from patients with AAHC and healthy carriers. METHODS: Colonic biopsy specimens
      and a sample of colonic fluid from 93 consecutive patients with acute colitis
      were cultured on selective media for 7 established pathogens and K. oxytoca. The
      2 K. oxytoca strains isolated in the 4 patients with C. difficile-negative AAHC
      of this cohort and 105 additional K. oxytoca strains from patients with C.
      difficile-negative AAHC (n = 15) and healthy carriers (n = 90) were tested for
      cytotoxicity using a HEp-2 cell culture assay. RESULTS: K. oxytoca was isolated
      in 50% (2 of 4) of the patients of the prospective cohort with C. difficile
      negative AAHC compared with 2% (1 of 41) of the patients with acute colitis
      caused by established pathogens (P = 0.02). The rate of cytotoxic strains of K.
      oxytoca was higher in patients with AAHC (82%) than in healthy carriers (42%, P =
      0.003). CONCLUSIONS: We conclude that K. oxytoca is isolated with a significant
      high rate in patients with C. difficile-negative AAHC, and that K. oxytoca
      strains from patients with AAHC are cytotoxic more frequently on HEp-2 cells than
      strains from healthy carriers. These results strengthen the hypothesis of a
      causative role of K. oxytoca in some of the patients with AAHC.

PMID- 15017656
TI  - Fecal multiple molecular tests to detect colorectal cancer in stool.
AB  - BACKGROUND & AIMS: Evaluation of molecular alterations in fecal DNA is a
      potential, noninvasive, alternative tool for the detection of colorectal cancer.
      We analyzed a large panel of molecular alterations involved in tumor
      transformation and progression to define their single diagnostic contribution in
      terms of sensitivity, cost, and time required to carry out the different tests.
      METHODS: DNA was analyzed in stool from 38 healthy individuals and in paired
      stools and primary lesions from 56 patients with colorectal cancer. p53 exons 5
      8, K-ras exons 1-2, four fragments of adenomatous polyposis coli (APC) exon 15,
      and 5 microsatellite loci were analyzed. Moreover, DNA amplification was
      evaluated for 4 exons of both p53 and APC. RESULTS: K-ras (34%) and p53 (34%)
      mutations were the most frequent alterations in tumors, followed by
      microsatellite instability (13%) and APC mutations (13%). The most frequent event
      in stool was DNA amplification (51%), followed by alterations of K-ras (11%), p53
      and microsatellite instability (6%), and APC (2%). K-ras and p53 gene mutations
      increased the capacity of DNA amplification to detect tumor cells by 8%.
      CONCLUSIONS: K-ras and p53 gene mutations were the most frequent alterations
      observed in stool from patients with colorectal cancer, but DNA amplification was
      even more frequent, being present in more than half of patients. If these
      preliminary results are confirmed in a prospective study on a larger case series,
      this approach could be used for noninvasive colon cancer diagnosis in screening
      programs.

PMID- 15017657
TI  - Effect of pioglitazone on biochemical indices of non-alcoholic fatty liver
      disease in upper body obesity.
AB  - BACKGROUND & AIMS: The aim of our study is to report our observations on the
      change in liver function tests of volunteers receiving pioglitazone as part of a
      study of its effects on fatty acid metabolism. Treatment with other
      thiazolidinediones has been reported to ameliorate non-alcoholic fatty liver
      disease (NAFLD) in obese and diabetic humans, but whether pioglitazone has
      similar effects has not been reported. METHODS: Five of 20 upper body obese
      volunteers (10 men, 10 premenopausal women) had abnormal baseline liver enzymes
      (3 had ultrasonographic evidence of hepatic steatosis). All volunteers were
      treated with 30 mg pioglitazone per day for 18 +/- 0.4 weeks. Body composition,
      blood lipids, and insulin sensitivity (intravenous glucose tolerance test) were
      assessed at baseline and after pioglitazone treatment. RESULTS: During
      pioglitazone treatment, the liver enzyme abnormalities uniformly improved in
      subjects with evidence of NAFLD, primarily during the first 2 months. Some
      parameters of insulin sensitivity improved when measured after 18 weeks of
      pioglitazone treatment. Liver function tests remained normal in the 15 volunteers
      without evidence of NAFLD. CONCLUSIONS: Liver function studies improved in obese
      volunteers with NAFLD during pioglitazone treatment. Although the nature of our
      observations does not prove a cause and effect relationship between pioglitazone
      treatment and improvement in liver enzymes, the time course and magnitude of
      improvement we observed may facilitate future research into thiazolidinedione
      treatment of NAFLD.

PMID- 15017658
TI  - Natural history of the C282Y homozygote for the hemochromatosis gene (HFE) with a
      normal serum ferritin level.
AB  - BACKGROUND & AIMS: The discovery of a genetic test for hereditary hemochromatosis
      has identified many individuals who are homozygous for the C282Y mutation of the
      HFE gene with a normal transferrin saturation and serum ferritin level. The long
      term prognosis, rate of iron accumulation, and surveillance guidelines for these
      individuals are unknown. METHODS: To determine the degree of iron accumulation
      over time, an updated serum ferritin level was obtained in patients initially
      identified as homozygous for the C282Y mutation with a normal serum ferritin
      level. RESULTS: Twenty-two asymptomatic untreated C282Y homozygotes with a normal
      serum ferritin level were identified, 10 through population screening, 9 through
      pedigree analysis, and 3 through a general medical work-up. There were 18 women
      (4 postmenopausal) and 4 men with a median age of 46 years, range 28-76 years.
      The median follow-up interval was 4 years, range 2-23 years. The serum ferritin
      levels of 20 of 22 patients remained below the upper limit of normal during the
      follow-up period. A decline in serum ferritin level was observed in 13 of 22
      patients. Three patients had an increase in serum ferritin level of greater than
      50%, with only 1 male patient exceeding the upper limit of normal by having a
      serum ferritin level increase from 295 to 344 microg/L during a 3-year period.
      CONCLUSIONS: In C282Y homozygotes with a normal ferritin level at the time of
      diagnosis, 20 of 22 patients failed to show any significant increase in serum
      ferritin level during a median follow-up of 4 years. This has clinical and
      economic implications for follow-up and surveillance of this selected population.

PMID- 15017660
TI  - Rapid endoscopic secretin stimulation test and discrimination of chronic
      pancreatitis and pancreatic cancer from disease controls.
AB  - BACKGROUND & AIMS: The cholecystokinin (CCK)/secretin pancreatic function tests
      to diagnose pancreatic exocrine insufficiency are time consuming and invasive.
      Our aim was to develop a rapid pancreatic function test performed during upper
      endoscopy that could discriminate between patients with normal from impaired
      exocrine pancreatic secretion. METHODS: We prospectively evaluated 412 patients
      for possible pancreatic diseases. During upper endoscopy, 1 CU/kg of secretin was
      given intravenously and duodenal juice (collected for 10 min) was assayed for
      concentrations of bicarbonate and lipolytic and trypsin activity. Final diagnosis
      was by histology, imaging, and a previously validated scoring system (for chronic
      pancreatitis). Of 412 patients, 117 patients had normal pancreas, 72 patients had
      chronic pancreatitis, and 116 patients had pancreatic adenocarcinoma. The
      remaining 107 patients had miscellaneous disease of the peripancreatic region. In
      28 patients we also validated the secretin test with the standard CCK pancreatic
      function test. RESULTS: There was no difference between bicarbonate or trypsin
      concentrations among the groups. Lipolytic concentration was significantly lower
      in chronic pancreatitis (115 +/- 18) and in pancreatic adenocarcinoma (87 +/- 10)
      compared with patients with normal pancreas (229 +/- 23; P < 0.03 and P < 0.0001,
      respectively). The overall accuracy of the endoscopic secretin test was 79%, with
      positive and negative predictive values of 73% and 85%, respectively. The
      concentration of lipolytic activity obtained by the endoscopic secretin test in
      28 patients correlated moderately well (r = 0.41, P < 0.03) with lipolytic output
      obtained by the CCK pancreatic function test. CONCLUSIONS: Lipolytic
      concentration in duodenal juice after intravenous secretin collected for 10
      minutes during upper endoscopy was significantly lower in chronic pancreatitis
      and pancreatic adenocarcinoma compared with patients with normal pancreas, but
      was not accurate enough for routine clinical use.

PMID- 15017659
TI  - Recovery from severe hepatitis caused by mushroom poisoning without liver
      transplantation.
AB  - BACKGROUND & AIMS: Toxic mushroom poisoning leads to a variety of clinical
      outcomes ranging from self-limited gastrointestinal symptoms to fulminant hepatic
      failure requiring orthotopic liver transplantation. We reviewed the outcomes of
      patients with severe acute hepatitis secondary to mushroom poisoning, treated
      with contemporary modalities. METHODS: We retrospectively reviewed patients
      admitted to our institution over a 5-year period with elevated transaminase
      levels (>1000 IU/L) attributed to recent mushroom ingestion. The patients'
      clinical course, laboratory data, and treatment regimen were recorded and
      analyzed. RESULTS: Eight patients who presented with severe hepatitis after
      mushroom ingestion qualified for analysis. The mean peak serum levels were:
      aspartate transaminase 5488 IU/L, alanine transaminase 7618 IU/L, and total
      bilirubin 10.5 mg/dL. The mean peak prothrombin time was 31 seconds. One patient
      developed acute renal failure requiring hemodialysis. Three patients developed
      encephalopathy ranging from grade I to III. All 8 patients survived without
      significant morbidity or need for liver transplantation. Subgroup analysis
      revealed that older patients spent more days in the intensive care unit and
      subsequently had longer hospital stays. The older group also had a trend toward
      more severe laboratory abnormalities. CONCLUSIONS: Patients with severe hepatitis
      from mushroom poisoning are thought to have a poor prognosis and frequently need
      liver transplantation for survival. We suggest that with early and aggressive
      multidisciplinary care, such patients have improved outcomes and may avoid liver
      transplantation.

PMID- 15017661
TI  - An evidence-based medicine approach to economic studies: assessing the cost
      effectiveness of competing strategies for colorectal cancer screening.
AB  - Cost-effectiveness analysis aims to quantitatively compare the expected outcomes
      of competing management strategies in environments with limited economic
      resources. A valid economic study models all relevant strategies from an
      appropriate perspective. The model must use costs that are accurately measured
      and strategies that have established clinical effectiveness, and appropriately
      integrate these data. The results should include the incremental cost
      effectiveness ratio, which quantifies the resources required to achieve greater
      benefit with one strategy compared to another. A sensitivity analysis is required
      to determine whether uncertainty in assumptions alters the conclusions. Final
      interpretation of a cost-effectiveness analysis relies on whether costs and
      outcomes in the study can be realized in one's own health care environment.

PMID- 15017662
TI  - Endoluminal therapy for Barrett's with high-grade dysplasia and early esophageal
      adenocarcinoma.

PMID- 15017663
TI  - Iron, HFE mutations, and hepatocellular carcinoma: is hepatic iron a carcinogen?

PMID- 15017664
TI  - Studying pruritus in the 21st century.

PMID- 15017665
TI  - Combined endoscopic mucosal resection and photodynamic therapy versus
      esophagectomy for management of early adenocarcinoma in Barrett's esophagus.
AB  - BACKGROUND & AIMS: Although esophagectomy is the standard of care for treating
      early adenocarcinoma in Barrett's esophagus, the procedure is associated with
      significant morbidity and mortality. For these patients, the multimodal approach
      of endoscopic mucosal resection and photodynamic therapy (EMR/PDT) may be a
      viable, less invasive option. METHODS: A retrospective review (1996-2001) of all
      patients undergoing either combined EMR/PDT group or esophagectomy (SURG) for
      early-stage Barrett's adenocarcinoma was performed. Data were collected on
      patient demographics, tumor staging, procedure-related morbidity and mortality,
      persistence or recurrence of cancer, and cancer-related deaths after therapy.
      Differences in outcomes between the 2 groups were assessed. RESULTS: Twenty-four
      patients were identified in the EMR/PDT group and 64 in the SURG group. The SURG
      group was found to have a significantly higher procedure-related complication
      rate compared with the EMR/PDT group (31 vs. 4; P < 0.01). There were no
      procedure-related deaths in the EMR/PDT group, whereas one death occurred in the
      SURG group as a result of complications. Eighty-three percent of patients (20 of
      24) in the EMR/PDT group and all patients in the SURG group remained free of
      cancer over a follow-up of 12 +/- 2 and 19 +/- 3 months, respectively. Four
      patients in the EMR/PDT group failed to respond to therapy; 2 of them underwent
      alternate therapies and are free of disease, whereas the other 2 died of
      unrelated causes. CONCLUSIONS: The combination of EMR/PDT seems to be a viable
      and less morbid alternative to standard esophagectomy in patients presenting with
      early Barrett's esophageal adenocarcinoma. A prospective randomized, controlled
      trial of EMR/PDT compared with esophagectomy for managing early adenocarcinoma in
      Barrett's esophagus may be warranted.

PMID- 15017666
TI  - Argon beam plasma coagulation as therapy for high-grade dysplasia in Barrett's
      esophagus.
AB  - BACKGROUND & AIMS: Patients with high-grade dysplasia in Barrett's esophagus have
      a high chance of developing adenocarcinoma. Previously these patients have
      undergone resection, however, the management of patients unsuitable for surgical
      resection is unclear. We have studied the long-term outcome of patients who have
      undergone endoscopic Argon ablation for high-grade dysplasia in Barrett's.
      METHODS: Twenty-nine patients (median age, 64 yr; range, 43-85 yr) with high
      grade dysplasia in Barrett's, who were unfit or had declined surgery, underwent
      Argon ablation and received follow-up evaluation over 7 years (mean follow-up, 37
      mo; range, 7-78 mo). Treatment was stopped once there was no further histologic
      evidence of dysplasia. The patients then went on to receive a surveillance
      endoscopy at 3, 6, and 12 months after ablation, then annually thereafter.
      RESULTS: High-grade dysplasia responded to treatment in 25 patients (86%); 22 of
      these had complete regression to neosquamous esophageal mucosa. During follow-up
      evaluation, no patients died of esophageal adenocarcinoma. Four patients
      developed cancer, 3 of whom continue with ablation therapy. The fourth patient
      died of unrelated causes. A single esophageal perforation was the only
      significant adverse event attributable to therapy. No esophageal strictures
      occurred and patients returned to normal activity after 24 hours in the majority
      of cases. Patients who received Argon ablation showed no difference in survival
      to that of the general population. CONCLUSIONS: Argon beam ablation for high
      grade dysplasia in Barrett's esophagus is an effective and safe treatment,
      especially in patients unfit for surgical resection.

PMID- 15017667
TI  - Gastric accommodation and emptying in evaluation of patients with upper
      gastrointestinal symptoms.
AB  - BACKGROUND & AIMS: Endoscopy-negative dyspepsia is a common symptom that often is
      difficult to define in pathophysiologic terms. The aim of this study was to
      assess the frequency of disordered gastric accommodation and emptying in patients
      referred with unexplained upper gastrointestinal symptoms. METHODS: A
      computerized diagnostic index was used to identify all patients, 18-70 years old,
      who underwent single-photon emission computed tomography (SPECT) to assess
      gastric accommodation at Mayo Clinic Rochester over a 3-year period.
      Demographics, clinical features, and results of diagnostic testing, including
      scintigraphic gastric emptying, were extracted from the electronic record.
      RESULTS: A total of 214 patients were identified; the primary clinical diagnoses
      were functional dyspepsia, postfundoplication syndromes, rumination syndrome, and
      diabetic dyspepsia. Gastric accommodation was impaired in 43% of the whole group:
      47% of functional dyspepsia, 44% of postfundoplication syndromes, and 33% of
      diabetic dyspepsia. Delayed gastric emptying was most prevalent in diabetic
      dyspepsia, and was accelerated in postfundoplication syndromes groups. Thirty
      seven percent of patients had abnormal gastric emptying. The highest prevalence
      of delayed gastric emptying was in the diabetic dyspepsia and accelerated gastric
      emptying in postfundoplication syndromes groups. Twenty-five percent of patients
      with normal gastric emptying had impaired accommodation. Upper-gastrointestinal
      symptoms were not different in groups based on gastric accommodation or emptying
      results. CONCLUSIONS: Impaired gastric accommodation is common in patients with
      unexplained dyspepsia. Symptoms alone cannot predict physiologic disturbances.
      These noninvasive tests identify single or combined pathophysiologic disturbances
      and may help to identify subgroups of patients as candidates for more selective
      pharmacotherapy in the future.

PMID- 15017668
TI  - Pretreatment antimicrobial susceptibility testing is cost saving in the
      eradication of Helicobacter pylori.
AB  - BACKGROUND & AIMS: The major obstacle to 100% effective eradication of
      Helicobacter pylori infection is represented by antimicrobial-resistant H. pylori
      strains. This randomized study was designed to evaluate whether regimens based on
      pretreatment susceptibility testing were more effective and cost saving compared
      with standard nonsusceptibility testing-based therapy in the eradication of H.
      pylori infection. METHODS: We studied 150 consecutive H. pylori-infected
      dyspeptic subjects. Patients were randomly assigned to omeprazole 20 mg twice
      daily, clarithromycin 500 mg twice daily, and metronidazole 500 mg twice daily
      for 7 days or to omeprazole 20 mg twice daily and 2 antimicrobials chosen based
      on susceptibility testing. H. pylori status was reevaluated 12 weeks after the
      end of treatment by the (13)C-urea breath test. RESULTS: Susceptibility testing
      based regimens led to the following results. (1) Eradication rates were 97.3%
      (95% confidence interval [CI], 91.2%-99.5%) (71 of 73) and 94.6% (95% CI, 87.6%
      98.3%) (71 of 75) in the per-protocol and intention-to-treat analysis,
      respectively. These were significantly higher (P < 0.005) than eradication rates
      obtained without susceptibility testing, that is, 79.4% (95% CI, 69.1%-87.6%) (58
      of 73) and 77.3% (95% CI, 66.9%-85.7%) (58 of 75) in the per-protocol and
      intention-to-treat analyses, respectively. (2) There were savings of
      approximately $5 U.S. per patient compared with standard triple therapy.
      CONCLUSIONS: Pretreatment antimicrobial susceptibility testing is more effective
      and cost saving and, in health systems that confirm cost advantage, microbial
      susceptibility testing should be routinely used for eradication of H. pylori
      infection.

PMID- 15017669
TI  - HFE C282Y heterozygosity in hepatocellular carcinoma: evidence for an increased
      prevalence.
AB  - BACKGROUND & AIMS: Iron overload is observed frequently in chronic liver disease,
      and some studies have suggested that chronic iron overload may contribute to the
      pathogenesis of hepatocellular carcinoma (HCC). Heterozygosity for hereditary
      hemochromatosis (HH) is associated with increased body iron stores. The discovery
      of the HH gene HFE has enabled identification of the heterozygote status. The aim
      of this study was to evaluate if heterozygosity for HH is a risk factor for HCC.
      METHODS: The C282Y and the H63D mutation of the HFE gene were analyzed in 137
      patients with HCC and no history of HH, 107 patients with cirrhosis without HCC
      and 126 healthy controls. Hepatic iron content was measured by using a
      semiquantitative histologic score. RESULTS: Seventeen of 137 HCC patients (12.4%)
      were C282Y heterozygote, compared with only 4 of 107 (3.7%) cirrhotic patients
      without HCC and 6 of 126 (4.8%) healthy controls (P < 0.05). The frequency of the
      H63D mutation showed no significant differences. C282Y heterozygote HCC patients
      had significantly higher levels of serum ferritin and transferrin saturation than
      C282Y wild-type patients (793 +/- 122 vs. 355 +/- 23 ng/mL, and 42.3% +/- 7.3%
      vs. 29.2% +/- 1.7%, respectively), and significantly higher iron deposition in
      HCC as well as in nontumorous liver tissue. CONCLUSIONS: The C282Y heterozygous
      genotype is significantly more common in HCC patients and is associated with
      significantly increased intrahepatic iron deposition and systemic iron stores.
      These results suggest that C282Y heterozygosity plays a role in liver iron
      deposition and could contribute to hepatocarcinogenesis via the accumulation of
      potentially carcinogenic iron. These findings may have implications for HCC
      screening and prevention strategies.

PMID- 15017670
TI  - Prostaglandin E receptors in bile ducts of hepatolithiasis patients and the
      pathobiological significance for cholangitis.
AB  - BACKGROUND & AIMS: In hepatolithiasis, chronic proliferative cholangitis may
      influence the progression of the disease. Prostaglandin (PG) E(2) experimentally
      causes morphologic changes to intrahepatic bile ducts, analogous to the changes
      found in cholangitis. This study was designed to gain an understanding of the
      involvement of PGE(2) and PGE receptor (EP) subtypes in the development of
      cholangitis. METHODS: The expression levels of secretory-type group IIA
      phospholipase A(2) (sPLA(2)-IIA) and cyclooxygenase (COX)-2 as well as EP
      subtypes were determined in the bile ducts with change of cholangitis. In in
      vitro experiments, growth promotion and mucin secretagogue properties of biliary
      epithelial cells in response to EP-selective agonists or antagonists were
      studied. RESULTS: The messenger RNA (mRNA) level of sPLA(2)-IIA and the protein
      and mRNA levels of COX-2 were significantly increased in the bile ducts of
      patients with hepatolithiasis compared with the levels of the bile ducts of
      control subjects. These changes were associated with a concomitant increase in
      PGE(2) and total mucin concentrations in the bile. The mRNAs of EP subtypes
      EP(2), EP(3), and EP(4) but not EP(1) were amplified in the bile ducts. Treatment
      with an EP(4)-selective agonist (ONO-AE1-329) caused a dose-dependent increase in
      DNA synthesis, colony number, and mucin secretion in the cells. Conversely,
      treatment with an EP(4)-selective antagonist (ONO-AE3-208) abolished the
      biological effects of PGE(2) on the cells. CONCLUSIONS: In hepatolithiasis, an
      enhanced synthesis of sPLA(2)-/COX-2-derived PGE(2) and its actions mediated via
      the EP(4) receptor in the bile ducts may be of pathobiological significance for
      chronic proliferative cholangitis.

PMID- 15017672
TI  - Sex-specific risks for pediatric onset among patients with Crohn's disease.
AB  - BACKGROUND & AIMS: Increases in the incidence of pediatric Crohn's disease might
      reflect increases in incidence for onset at all ages or diagnostic improvement.
      Alternatively, there might be etiologic differences between adult and pediatric
      onset disease with different risks for pediatric disease. Differences in sex
      ratio between adult and pediatric disease suggest etiologic differences might
      exist and also suggest differences in sex-specific susceptibility during
      childhood. This study seeks to identify whether factors previously associated
      with overall risk of Crohn's disease (number of siblings and maternal age) are
      associated with pediatric as opposed to adult onset among patients with Crohn's
      disease and whether these associations vary by sex. METHODS: A nested case
      control study of patients with Crohn's disease was designed to compare pediatric
      with adult-onset disease. The participants were all patients with Crohn's disease
      in the Swedish Inpatient Register born between 1960 and 1998; 46.6% of the 4826
      patients were male. RESULTS: A notable association between mother's age at
      pregnancy and pediatric Crohn's disease was observed in female but not male
      patients. Compared with those whose mothers were younger than 21 years, female
      patients with older mothers, coded into ordered 5-year age categories, were at a
      higher risk of pediatric disease with adjusted odds ratios (95% confidence
      intervals) of 1.42 (0.85-2.37), 2.08 (1.19-3.66), 3.50 (1.83-6.69), 3.02 (1.35
      6.75), and 12.64 (3.63-43.98). No statistically significant independent
      associations were observed for father's age or number of siblings. CONCLUSIONS:
      Females might be more susceptible or more often exposed to factors associated
      with older maternal age at pregnancy that increase their risk of pediatric-onset
      Crohn's disease.

PMID- 15017671
TI  - Natural history of pruritus in primary biliary cirrhosis.
AB  - The natural history of pruritus in primary biliary cirrhosis (PBC) remains poorly
      defined. The aim of this investigation was to evaluate outcomes of pruritus in
      clinical trials for ursodeoxycholic acid (UDCA). In a UDCA-placebo trial begun in
      1988 (n = 180), a 55% prevalence rate for pruritus was observed. Serum alkaline
      phosphatase level and Mayo risk score were independent risk factors for pruritus
      (P < 0.0001). Among placebo-treated patients (n = 91), the annual risks for
      development or improvement/resolution of pruritus were 27% and 23%, respectively.
      For UDCA-treated patients (n = 89), a trend toward improvement in pruritus was
      observed after 1 year compared to placebo (30% vs. 23%, P = 0.08) but not at 2 or
      3 years. In a 3-dose UDCA trial begun in 1995 (n = 155), the overall prevalence
      of pruritus was significantly lower at 37% when compared to UDCA-placebo
      participants (P < 0.001). Baseline serum alkaline phosphatase level and Mayo risk
      score were again independent risk factors for pruritus (P < 0.0001). Among 13
      (3.9%) patients with refractory pruritus, symptom resolution (n = 5) or
      improvement (n = 8) was associated with the use of oral rifampin (300 or 600 mg
      daily). Two patients treated with rifampin developed biochemical evidence for
      hepatotoxicity necessitating drug withdrawal. Although less prevalent among
      recently diagnosed individuals, more than one third of PBC patients develop
      pruritus. No significant risk reduction in developing pruritus with UDCA therapy
      was observed compared to placebo-treated patients. The long-term administration
      of rifampin for refractory pruritus is associated with occasional hepatotoxicity.

PMID- 15017673
TI  - Colonoscopic surveillance of patients with a family history of colon cancer and a
      history of normal colonoscopy: is a five-year interval between colonoscopies
      appropriate?
AB  - BACKGROUND & AIMS: Patients with a family history of colon cancer are advised to
      undergo surveillance colonoscopy 5 years after a normal screening colonoscopy. No
      prospective study has evaluated the prevalence of adenomas found at surveillance
      colonoscopy in these patients. The aims of this trial were (1) to determine the
      percentage of these patients with adenomas; (2) to determine the percentage of
      these patients with advanced adenomas (i.e., villous adenomas, adenomas > or = 10
      mm, adenomas with high grade dysplasia); and (3) to assess risk factors for
      adenomas in these patients. METHODS: Consecutive patients with a family history
      of colorectal cancer and a normal screening colonoscopy 5 years earlier were
      offered a surveillance colonoscopy. Patients also completed a questionnaire about
      potential risk factors for adenomas. Multiple logistic regression analysis
      assessed associations between risk factors and adenomas. RESULTS: One hundred
      patients completed the trial. The male/female ratio was 54/46, the mean age was
      56.2 +/- 8.8 years, and 91% were white. Eight percent (8 of 100) of patients had
      advanced adenomas at surveillance colonoscopy, and 33% (33 of 100) had adenomas.
      Among patients with adenomas, 39% (13 of 33) had no adenomas in the left side of
      the colon (i.e., distal to the splenic flexure). Among patients with advanced
      adenomas, 25% (2 of 8) had no adenomas in the left side of the colon. Multiple
      logistic regression analysis showed a significant negative association between
      adenomas and NSAID use (odds ratio, 0.26 [95% confidence interval, 0.09-0.79]),
      and male gender had a positive association with adenomas (odds ratio, 2.79 [95%
      confidence interval, 1.01-7.74]). CONCLUSIONS: These data support a 5-year
      interval between screening and surveillance colonoscopy for patients with a
      family history of colorectal cancer and a normal screening colonoscopy.

PMID- 15017674
TI  - Nutrition in the management of necrotizing pancreatitis.
AB  - Comparative trials have shown that enteral feeding (EN) is better than total
      parenteral nutrition (TPN) in acute pancreatitis. However, the following case
      report of a 64-year-old man with necrotizing pancreatitis suggests that EN may
      cause complications in patients with ductular damage. In the second week, this
      patient with acute pancreatitis developed >50% pancreatic necrosis, resulting in
      gastroduodenal obstruction and pain, leading to the use of TPN. A trial of EN
      delivered past the obstruction was associated with increased abdominal pain,
      leukocytosis, and pancreatic fluid accumulation. Measurement of the pancreatic
      response to feeding showed a 90% reduction in enzyme secretion compared to
      healthy volunteers, but no change in the uptake of stable isotope labeled amino
      acids into secreted trypsin. This suggests that enzymes were being synthesized by
      the remaining pancreatic tissue, but that some of the secretions were leaking
      into the inflammatory mass. Symptoms resolved after reinstitution of TPN and
      bowel rest. A further trial of EN was successful when the tube was advanced to
      the distal jejunum to avoid pancreatic stimulation. After 3 weeks of home EN, he
      was readmitted for surgical evacuation of an infected fluid collection. Although
      enteral feeding is generally better than TPN in the nutritional management of
      acute pancreatitis, there may be a subgroup of patients with ductular damage due
      to necrotizing disease in whom TPN and pancreatic rest may be safer.

PMID- 15017675
TI  - An evidence-based approach to clinical practice guidelines: diagnosis and
      treatment of irritable bowel syndrome.

PMID- 15017676
TI  - The economics of laparoscopic Nissen fundoplication.
AB  - BACKGROUND & AIMS: A major impetus for laparoscopic Nissen fundoplication (LNF)
      is its purported cost savings compared with medical therapy, but few studies have
      examined these economic outcomes. The aim was to analyze health care costs and
      use among a cohort of patients undergoing LNF and compare them with patients with
      medically treated gastroesophageal reflux disease (GERD). METHODS: Comparison of
      health care use and direct costs from the third-party payer perspective using 13
      United HealthCare Plans. Sixty-one patients who underwent LNF from January 1994
      to June 1998 and 178 matched controls were used for this study. Outcome variables
      included the cost of hospital and outpatient visits, hospitalizations, related
      endoscopic procedures, and pharmacy claims for proton pump inhibitors, H(2)
      receptor antagonists, and prokinetics. Cost of LNF or index
      esophagogastroduodenoscopy was not included. RESULTS: Sixty-one LNF patients and
      178 controls were studied. No differences were seen for the costs of office
      visits and hospital admissions or the number of gastrointestinal procedures. LNF
      patients had significantly lower gastrointestinal medication costs. Median total
      health care costs were significantly lower in the LNF group but mean total costs
      were not different. This was attributable to $201,000 in costs for managing
      complications in one patient that skewed total health care cost in the LNF group.
      CONCLUSIONS: For the 12 months after surgery, LNF reduced costs for
      gastrointestinal medications but not total costs for the cohort. LNF cost is
      impacted greatly by the cost of associated complications. Based on these data,
      LNF does not appear to significantly reduce the direct cost of health care for
      GERD patients on a population basis.

PMID- 15017677
TI  - Virtual colonoscopy to screen for colorectal cancer.

PMID- 15017678
TI  - Virtual colonoscopy to screen for colorectal cancer.

PMID- 15017679
TI  - Virtual colonoscopy to screen for colorectal cancer.

PMID- 15017680
TI  - Lp(a) lipoprotein, vascular disease, and mortality in the elderly.

PMID- 15017681
TI  - Conditions associated with ST-segment elevation.

PMID- 15017682
TI  - Conditions associated with ST-segment elevation.

PMID- 15017683
TI  - Conditions associated with ST-segment elevation.

PMID- 15017685
TI  - Rx: Canadian drugs.

PMID- 15017684
TI  - Conditions associated with ST-segment elevation.

PMID- 15017686
TI  - Infection control during construction.

PMID- 15017687
TI  - [Effects of aminoguanidine on the expression of NOS in facial nerve and
      surrounding tissues of traumatic facial paralysis rats].
AB  - OBJECTIVE: To study the effects of inducible NOS inhibitor aminoguanidine on the
      expression of NOS in facial nerve and surrounding tissue of traumatic facial
      paralysis rats. METHODS: A small dose of aminoguanidine were intraperitoneally
      injected into rats before and after facial paralysis. The facial nerve and
      surrounding tissues were cut at different time point. Immunohistochemical ABC
      method was used to study the changes of NOS expression in facial nerve and
      surrounding tissues. RESULTS: The inducible NOS immunoreactivity was obvious
      inhibited in the facial nerve and surrounding tissues in aminoguanidine group.
      CONCLUSION: Aminoguanidine chronic treatment can obvious inhibit the inducible
      NOS expression in the facial nerve and surrounding tissues. Aminoguanidine can
      improve the regeneration of facial nerve and the recovery of traumatic tissues.

PMID- 15017688
TI  - [Expression of GBD gene of Streptococcus mutans glucan binding protein A in
      mammalian cells].
AB  - OBJECTIVE: To evaluate the expression of recombinant plasmid pcDNA3.1/GBD of
      glucan binding protein of Streptococcus mutans in mammalian cells COS-7. METHODS:
      Eukaryotic plasmid carrying encoding gene of GBD of Streptococcus mutans gbpA was
      constructed and the plasmid was introduced into COS-7 cells by Lipofectamine
      reagent. The transient expressed protein in COS-7 cells was detected by
      immunochemistry technique. RESULTS: The positive expression was detected in
      plasma of the cells which were transfected with recombinant plasmid pcDNA3.1/GBD.
      The cells which were transfected with pcDNA3.1 were negative. CONCLUSION: GBD can
      translate and express in COS-7 cells after transfected with recombinant plasmid
      pcDNA3.1/GBD. The expressed protein locates in the plasma and the protein is able
      to combine with anti-GbpA antibody. The expressed protein has the antigenicity
      and is a candidate gene vaccine.

PMID- 15017689
TI  - [The influence to maxillary growth by exposed bone wound in hard palate of rat].
AB  - OBJECTIVE: To confirm if denuded bone on lateral aspects of the hard palate of
      surgical repairs of the cleft palate is the main reason of causing disturbance of
      facial growth and to investigate the mechanism. METHODS: 48 SD rats were employed
      in the study. Among them 40 animals were divided into normal control and
      experimental group randomly. Normal control was not operated. Hard palate
      mucoperiosteum on the left side in experimental group were excised. Left hard
      palate mucoperiosteum in another 8 female three-week-old SD rats were excised
      with same method and were sacrificed at 2nd, 5th, 8th, and 12th day,
      respectively. The 8 rats were used for histological research. RESULTS: The width
      of all left sides hard palates in experimental group was significantly narrower
      than right side, and demonstrated statistical difference. Chronic osteomyelitis
      on the denuded hard palate was observed. CONCLUSION: The denuded bone wound might
      be a principal factor for the following maxillary growth deformity in cleft
      palate patients who received palatoplasty in childhood. The mechanism of causing
      the deformity might be wound and scar contraction, decreased blood flow and
      nutrition plus chronic osteomyelitis.

PMID- 15017690
TI  - [Mandibular condensability and length contraction: an animal experimental study].
AB  - OBJECTIVE: To investigate the condensability of mandibular length. METHODS: In
      six goats were used in the study. Corticotomy at right mandibular angles was
      performed via extral-oral accession. Special devices were applied to shorten the
      mandible by 0.5 mm per three days respectively. RESULTS: 1. Mandibular angles of
      the six goats were shorten by 0.8 cm to 1.3 cm respectively in 48 days to 78
      days; 2. In spite of the lower ascending ramus moving forward and angles being
      blunt, the occlusion scarcely varied because of contralateral bite-lock; 3. X-ray
      demonstrated that, at first, bone density in contracted areas declined, and then
      increased gradually to almost normal density; 4. Under microscope there were
      three tissues layers from central to lateral within the bone gap: fiber layer,
      cartilage layer and bone layer, and fiber layer gradually transform into
      cartilage layer with the fixed time. At the end of fixation they all transform
      into bone tissue. CONCLUSION: Contraction osteogenesis is actually a process of
      compression, absorption and rebuilding. It is feasible that using contraction
      osteogenesis to shorten the mandible via cortcotomy.

PMID- 15017691
TI  - [Establishment of cultivating technology of dental follicle cells of rat and
      their identifying].
AB  - OBJECTIVE: To establish a method for culturing dental follicle cells of rat and
      observe the growth characteristics of the cultured cells in vitro. METHODS:
      Dental follicle and associated enamel organs were dissected from the first and
      second mandibular molars of 6-7-day-old rats, and then cultured in vitro.
      Purified dental follicle cells derived from the third or the fourth passage cells
      were utilized in the following experiments. The shape and ultrastructure of
      dental follicle cells were observed by light-microscopy and transmission electron
      microscopy. Immunocytochemistry was used to detect the expression of vimentin,
      type I collagen and fibronectin. RESULTS: The cultured cells were fibroblastic in
      shape, elongate with processes, and transmission electron microscopy revealed
      that they contained electron-dense granules, an abundant rough endoplasmic
      reticulum, but did not form desmosomes. Vimentin, type I collagen and fibronectin
      were present in dental follicle cell. CONCLUSION: The dental follicle cells of
      rat could be successfully cultured in vitro and the cultured cells had the same
      characteristics of dental follicle cells of normal rat.

PMID- 15017692
TI  - [Expression and implication of Pgp, MRP, LRP, GST-pi, Topo II alpha in tongue
      squamous cell carcinoma].
AB  - OBJECTIVE: To explore the correlation of chemotherapy efficacy in tongue squamous
      cell carcinoma(SCC) with expression level of P-glycoprotein(Pgp), multidrug
      resistance-associated protein (MRP), lung resistance-related protein (LRP),
      glutathiones-tranferase (GST-pi), DNA topo-isomerase II alpha (Topo II alpha).
      METHODS: The expression patterns of Pgp, MRP, LRP, GST-pi and Topo II alpha in 40
      patients (pre and post-chemotherapy, respectively) with tongue SCC were examined
      by immunohistochemically labelled streptavidin bioein method (LsAB). RESULTS: The
      expression ratios of Pgp, MRP, LRP, GST-pi and Topo II alpha in pre-chemotherapy
      cases were 47.5%, 50%, 35%, 45%, 82.5%, respectively. No relations between
      expression of Pgp, MRP, LRP, GST-pi, Topo II alpha and clinic indexes were
      established (P > 0.05). Expression ratios of Pgp, MRP in post-chemotherapy cases
      were higher than that in pre-chemotherapy cases (P < 0.05). Expression of Pgp and
      MRP showed relevance with drug resistance (P < 0.05). The co-expression was
      common, the ratios of co-expression of Pgp, MRP, GST-pi and MRP, GST-pi in
      chemotherapy non-responders were 40% and 50%, respectively, but 0 in responders.
      CONCLUSION: The intrinsic multidrug resistance of tongue SCC is relevant to the
      effects of Pgp, MRP, GST-pi.

PMID- 15017693
TI  - [Expression of matrixmetalloproteinase-8 on the bell-stage in human and rat tooth
      development].
AB  - OBJECTIVE: To study the expression of MMP-8 in human and rat tooth development.
      METHODS: Immunohistochemistry was used to detect the localization of MMP-8
      protein while in situ hybridization was used to examine the expression of MMP-8
      mRNA. RESULTS: The expression of MMP-8 protein was localized in odontoblast and
      dentin matrix at the later bell stage in human tooth germ. The dentin was denser
      close to the pulp cavity. The expression of MMP-8 mRNA was found in very few
      polarized odontoblast at the early bell stage and all polarized odontoblast at
      the later bell stage in rat tooth germ. CONCLUSION: The results suggested that
      MMP-8 involved in dentin matrix rebuilding in the process of dentin formation in
      human and rat dental development.

PMID- 15017694
TI  - [Expression of testosterone in the rapid growing rat condylar cartilage and the
      expression changes after the function mandibular advancement].
AB  - OBJECTIVE: To investigate the expressions of Testosterone in the condylar
      cartilage of rapid growing rats. METHODS: The mimic functional appliances were
      used in experiment groups and rats were killed after 3 days, 1 week, 2 weeks, 3
      weeks and 4 weeks. Immunohistochemical technique was used to detect the
      expression of T. RESULTS: T was expressed throughout the condylar cartilage. The
      Highest expressions were in mature layers of both experiment and control groups.
      Along with the maturation, the expressions of T in the condylar cartilage were
      changed respectively, and the immunostain levels in the mature layer of
      experiment groups 2 and 3 weeks were higher than those of control groups (P <
      0.05). CONCLUSION: 1. T is a member of cartilage growth and development control
      system. 2. The orthopedic mechanism of functional appliance may be conducted by
      T.

PMID- 15017695
TI  - [Clinical study of hyaluronic acid in the treatment of chronic periodontitis].
AB  - OBJECTIVE: Clinical effects in local application of hyaluronic acid (HA)
      adjunctive to scaling and root planing (SRP) were evaluated. METHODS: In this
      cross over design study 20 patients with chronic periodontitis were included.
      Plaque index, sulcus-fluid-flow-rate (SFFR), sulcus bleeding index, probing
      pocket depth and attachment level were monitored. All patients were treated with
      full mouth SRP, in addition a HA gel was administered subgingivally in the test
      site every week for 6 weeks. RESULTS: A statistically significant improvement of
      all clinical test parameters was observed in both groups (P < 0.05). Clinically,
      no significant difference between test and control group could be found. However,
      the SFFR decreased significantly faster in the test group. CONCLUSION: No post
      inflammatory tissue regeneration could be achieved by the adjunctive use of HA
      gel to SRP in the patients with chronic periodontitis. Due to SFFR a control of
      local inflammation can be achieved quickly.

PMID- 15017696
TI  - [The prevalence analysis of cleft palate in Chinese perinatals: 1996-2000].
AB  - OBJECTIVE: To study the epidemiological features of cleft palate (CP) in Chinese
      perinatals. METHODS: Data from 1996 to 2000 were collected through Chinese Birth
      Defects Monitoring Network a hospital based congenital malformation registry
      system. During that period all live or still births with 28 weeks of gestation or
      more were assessed within 7 days after delivery. RESULTS: 499 perinatals with CP
      were identified among 2,218,616 births, then the overall prevalence rates of CP
      were 2.25/10,000, rates in isolated and syndromic CP were 1.75/10,000,
      0.50/10,000 respectively. The rates in urban and rural area, in male and female
      births were 2.27/10,000 and 2.19/10,000, 1.93/10,000 and 2.57/10,000
      respectively. The highest but nonsignificant rate (2.84/10,000) was found in
      maternal age group of more than 35 years. An increased trend was found both in
      overall CP and syndromic CP during that period. Geographic variation was found
      among provinces. The perinatal mortality rate of CP was 14.9%, and the rate of
      isolated forms was 7.3%, while the rate of syndromic CP was as high as 41.4%.
      CONCLUSION: The increasing prevalence rate of syndromic CP can account for the
      secular trend of overall CP. Female predominance was only observed in isolated
      forms of CP among Chinese perinatals. Geographic variation was identified too.
      Due to poor birth quality, perinatals suffering from syndromic CP had poor
      prognosis.

PMID- 15017697
TI  - [Expression of nucleolar organizer regions associated proteins of T lymphocytes
      in the patients with oral and maxillofacial tumors].
AB  - OBJECTIVE: To study the Ag-NORs expressive character of T lymphocyte in patients
      with oral and maxillofacial tumor and evaluate its diagnostic value for the
      patients. METHODS: Nucleolar organizer regions(NORs) of T lymphocyte from 86
      normal adults, 102 patients with oral and maxillofacial benign tumors and 87
      patients with oral and maxillofacial malignant tumors were analyzed through KL
      imaging system. RESULTS: There was significant difference among normal adults,
      benign and malignant patients (P < 0.01). Their average I.S% values were 7.87 +/-
      0.12, 5.72 +/- 0.14, 4.19 +/- 0.13, respectively. CONCLUSION: The expression of
      Ag-NORs of T lymphocyte has definite relation with oral and maxillofacial tumors;
      detection of Ag-NORs might play valuable in diagnosis of oral and maxillofacial
      tumors.

PMID- 15017698
TI  - [Treatment of the asymmetric prominent mandibular angle].
AB  - OBJECTIVE: To investigate the causes and treatment of the asymmetric prominent
      mandibular angle. METHODS: From 1996 to 2001, mandibular angle osteotomy,
      mandibular outer cortex osteotomy, mandible, genioplasty and buccal pad excision
      were selected to treat 70 patients. RESULTS: All the patients had satisfactory
      results with complications of bleeding, infection and labial scar in three
      patients. CONCLUSION: Asymmetric prominent mandibular angle should be treated
      according to the characteristics of the deformity. Mandibular angle osteotomy,
      osteotomy of outer cortex of the mandible, genioplasty and bucal pad excision can
      provide satisfactory result.

PMID- 15017699
TI  - [A study of oral colonization of mutans streptococci and feeding habits in
      infants].
AB  - OBJECTIVE: To study the correlation of prime colonization time of Mutans
      Streptococci and feeding habits in infants. METHODS: One hundred and eighty
      children (aged 6-24 months) from Shenyang city were examined for the colonization
      of MS Related items were registered by completed questionnaires. RESULTS: The
      study showed a correlation between prime colonization time and feeding mode,
      breast feeding, feeding frequency during bedtime, asleep habits. CONCLUSION:
      Advocating reasonable feeding mode and asleep habits is effective to interdict or
      delay MS's colonization and transmission in child to prevent caries.

PMID- 15017700
TI  - [Treatment effects of headgear-Herbst appliance].
AB  - OBJECTIVE: Skeletal and dental changes during treatment and six months post
      treatment with the headgear-Herbst appliance were evaluated quantitatively.
      METHODS: The sample comprised of 22 treated patients and 31 controls. Lateral
      cephalograms were obtained at start, after 6 months and end of active treatment,
      and after 6 months of retention. RESULTS: The restraint effect on the maxilla was
      significant in both initial and late phases, the enhanced growth of the mandible
      was significant during the initial phase only, while there was effect of reduced
      increase in lower facial height during the late phase only. During retention
      period the jaw base relationship was maintained and the effect on the lower
      facial height was reinforced. CONCLUSION: The Headgear Herbst was effective
      orthopedic devise.

PMID- 15017701
TI  - [Effect of microwave thermocoagulation on oral benign tumor].
AB  - OBJECTIVE: The purpose of this article was to observe the effect of by microwave
      thermocoagulation on oral benign tumor and to provide theoretical basis for
      clinic treatment of oral benign tumor. METHODS: 165 patients with oral benign
      tumor were included. There were 83 patients with oral bursa cyst, 42 patients
      with hemangioma, 19 patients with papilloma, 14 patients with fibrous hyperplasia
      and 7 patients with epulis. All the patients were treated by WB-100 microwave
      thermocoagulation. RESULTS: 144 patients were effective after the first treatment
      and 21 patients were effective after the second treatments. No side effect and
      reoccurrence were found after 3 years. CONCLUSION: Microwave thermocoagulation is
      an effective and safe method in clinic treatment of oral benign tumor.

PMID- 15017702
TI  - [Study on endotoxin levels of acute and chronic periapical periodontitis].
AB  - OBJECTIVE: To compare the endotoxin levels between acute and chronic periapical
      periodontitis with different clinical symptoms. METHODS: 10 cases of acute
      periapical priodontitis(Group 1), 10 cases of chronic periapical periodontitis
      (group 2, the diameter of apical radiolucency area was less than 2 mm), 10 cases
      of chronic periapical periodontitis with sinus(group 3, the diameter of apical
      radiolucency area was greater than 2 mm), 10 cases of chronic periapical
      periodontitis without sinus (group 4, the diameter of apical radiolucency area
      was greater than 2 mm), were included in the study. Chromogenic substrate method
      of limulus amebocyte lysate(LAL) test was used to measure the endotoxin level.
      RESULTS: Endotoxin concentrations in group 2 were significantly lower than those
      in group 1, group 3 and group 4(P < 0.01). CONCLUSION: Endotoxin plays a very
      important role in the initiation and development of periapical periodotitis and
      is closely associated with clinical symptoms and apical radiolucency degree.

PMID- 15017703
TI  - [Characterization of Notch gene involved in genetic regulatory networks in dental
      pulp stem cells].
AB  - OBJECTIVE: To investigate the characterization of Notch gene involved in genetic
      regulatory networks in dental pulp stem cells. METHODS: The pulp tissue was
      separated from mouse teeth and digested by collagenase type I. Single-cell
      suspensions of dental pulp were seeded into 6-well plates with alpha modification
      of Eagle's medium supplemented with ES cell qualified Fetal Bovine Serum. Colony
      forming efficiency was assessed in 14ds culture. Transcripts for Notch were
      detected by reverse transcription-PCR by using total RNA isolated from cells.
      RESULTS: There were clonogenic cells in dental pulp cell and the incidence of
      colony-forming cells derived from mouse dental pulp cells was 1.6-2.5
      colonies/10(4) plate. Mouse-specific Notch mRNA expressed in colony-forming
      cells. CONCLUSION: Notch mRNA expressing in colony-forming cells provided a more
      detailed understanding of mouse dental pulp stem cell biology.

PMID- 15017704
TI  - [The effect of Redix Scutellariae on butyrate of Porphyromonas endodontalis in
      vitro].
AB  - OBJECTIVE: To study the effect of Radix Scutellariae on the growth, metabolism of
      Porphyromonas endodontalis (P.e), as a preparation for studying the mechanism of
      Radix Scutellariae in treating pulp and periapical diseases. METHODS: P.e was
      chosen as the experimental bacteria. Radix Scutellariae was extracted by means of
      reflux with 80% ethanol. The value of MIC of Radix Scutellariae was measured by
      minute amount serial dilusion test, and the production of butyrate was measured
      by high liquid chromatograph(HPLC). RESULTS: Radix Scutellariae could inhibit the
      growth of P.e, of which the MIC was 100 mg/L. Following the increase in
      concentration of Radix Scutellariae, the amount of butyrate decreased to (3.527
      +/- 0.009) mg/L, (3.048 +/- 0.005) mg/L, (2.490 +/- 0.011) mg/L, (2.209 +/-
      0.016) mg/L, respectively (P < 0.05). CONCLUSION: Radix Scutellariae could
      inhibit the growth and metabolism of P.e and might be an effective agent in
      treating pulp and periapical diseases.

PMID- 15017705
TI  - [The effect of bFGF on proliferation of periodontal fibroblast-like cells of
      dogs].
AB  - OBJECTIVE: To evaluate the effects of basic fibroblast growth factor(bFGF) on
      proliferation of periodontal fibroblast-like cells in vivo. METHODS: A U-shaped
      osseous defect was produced on the buccal side of the mesial root. Four posterior
      teeth were conducted in four quadrants. Each quadrant included 4 groups: control,
      bFGF, expanded polytetrafluoroethylene(ePTFE) membrane, bFGF + ePTFE. Each time
      the 4 teeth sites in one quadrant were operated weekly and each dog experienced 4
      times of operations. Bromodeoxyuridine(BrdU) was injected 1 hour prior to
      sacrificing the dogs at 4 weeks after first surgery. Immunohistochemical method
      was applied to count the BrdU-labeled fibroblast-like cells. RESULTS: The number
      of BrdU-labeled cells reached the maximum at the 2nd week among all groups and
      then, decreased with time. Both bFGF and bFGF + ePTFE treated group had
      significantly more BrdU+ cells than remained control or ePTFE groups (P < 0.05)
      at 1st, 2nd weeks after surgery. CONCLUSION: 2 weeks after periodontal surgery is
      active phase of proliferation of periodontal fibroblasts. bFGF enhances
      fibroblast proliferation in early periodontal wound healing, and in turn
      accelerate periodontal regeneration.

PMID- 15017706
TI  - [Mechanical property analysis of polyethylene fiber reinforced polymethyl
      methacylate].
AB  - OBJECTIVE: To investigate if the Ribbond polyethylene fiber has the effect of
      reinforcing polymethyl methacylate. METHODS: 28 specimens were fabricated and
      divided into 3 groups: group of chemical-cured PMMA, group of chemical-cured PMMA
      reinforced by stainless steel wire and group of chemical-cured PMMA reinforced by
      Ribbond polyethylene fiber. A three-point bending test was used to measure the
      flexural strength and flexural modulus of specimens. Then the data were analyzed
      with a one-way analysis of variance. RESULTS: The flexural strength of chemical
      cured PMMA group was (51.383 +/- 2.761) MPa, the flexural modulus was (1791.2 +/-
      113.760) MPa; The flexural strength of stainless steel wire reinforced group was
      (58.725 +/- 1.218) MPa, the flexural modulus was (2092.76 +/- 120.28) MPa; The
      flexural strength of Ribbond polyethylene fiber reinforced group was (80.975 +/-
      2.58) MPa, the flexural modulus was (2866.53 +/- 107.51) MPa. The one-way
      analysis of variance showed that the results were significant (P < 0.001). Newman
      Keuls method showed that the differences among all groups were significant (P <
      0.05). CONCLUSION: The Ribbond polyethylene fiber can raise the flexural strength
      and flexural modulu of polymethyl methacylate.

PMID- 15017707
TI  - [The effect of casting techniques on the accuracy of titanium crown and bridge].
AB  - OBJECTIVE: To investigate the method of enhancing the accuracy of titanium crowns
      by improving the casting method. METHODS: A self-assembled die was used to
      fabricate 48 standardized wax crowns. The dies were averagely divided into two
      groups. 21 crowns were successfully fabricated from one group according to the
      improved techniques. 18 crowns were fabricated by traditional method. A reference
      mark was scribed 90 degrees apart at four sites on the margin of each wax pattern
      and respective die. The distance between the margins of the wax pattern and the
      die was measured under a stereomicroscope. Similar method was also applied to
      measure the margin of castings. The castings were longitudinally split through
      midline. The distance between the 4 points(B',C',D',E') selected in the inner
      part of the crown and the die was respectively examined. RESULTS: Castings
      acquired by the improved method were more complete and had smoother surface.
      Marginal discrepancy value had significant difference between the two groups.
      Value in experimental group was smaller. Distance from B',E' to die between the
      two groups had no significant difference, but the distance from C',D' to the die
      was significantly different. The experimental group was smaller. CONCLUSION:
      Standardized crowns fabricated by the improved titanium casting technique were
      more accurate, but special investment for titanium crowns and bridges should be
      developed to compensate the casting shrinkage of metal.

PMID- 15017708
TI  - [Intracellular calcium ion release stimulated by 1,25(OH)2D3 and influenced with
      mechanical pressure in mandibular condylar chondrocytes of rabbit].
AB  - OBJECTIVE: To investigate the intracellular calcium ion release and the system of
      calcium channel by 1,25 (OH)2D3 stimulus, and the effect of mechanical pressure
      on it in rabbit mandibular condylar chondrocytes (MCC) in vitro. METHODS: In
      vitro cultured MCC from two-week-old New Zealand rabbits were incubated under 20
      g/L heparin, 1 g/L procaine, continuous pressure of 90 kPa for 60 min and 360 min
      in a hydraulic pressure controlled cellular strain unit. With the Fluo-3/AM probe
      loaded, 1,25(OH)2D3 was added to the medium and then the intracellular calcium
      level was detected by a laser confocal scanning microscope. RESULTS:
      Intracellular calcium concentration increased in MCC treated with 1,25(OH)2D3,
      1,25(OH)2D3 and procaine, while it didn't change in heparin treated group.
      Calcium in group under continuous pressure of 90 kPa for 60 min was also
      increased, even higher than the group stimulated only with 1,25(OH)2D3.
      Intracellular calcium in group treated with continuous pressure of 90 kPa for 360
      min showed no significant difference compared to the control and even decreased
      at the end of the recording period. CONCLUSION: 1,25(OH)2D3 could stimulate the
      intracellular calcium release channel of inositol triphosphate (IP3) receptor
      open in MCC in vitro and increases the level of intracellular calcium
      concentration. Pretreatment of definite mechanical pressure could modulate the
      sensitivity of IP3 channel to 1,25(OH)2D3 stimulus.

PMID- 15017709
TI  - [The expression of TGF-beta 1 mRNA in pubescent rhesus monkeys' condyle under
      Class III intermaxillary functional orthopedic force].
AB  - OBJECTIVE: To investigate the expression of TGF-beta 1 mRNA in pubescent Rhesus
      monkeys' condylar under Class III intermaxillary functional orthopedic force for
      different lengths of time. METHODS: Six pubescent Rhesus monkey were divided into
      two test groups and a control group. Monkeys in the test groups were TMAIII while
      the control groups did not. Histological method (HE staining) and in situ
      hybridization were employed in this study. RESULTS: 1. The histological results
      showed that, compared with the control group, the anterior part of the condyle
      became thicker while the median part and the posterior part became thinner in 3
      months group. However, in 6 months group, the change was similar to 3 months
      group. 2. The results of in situ hybridization showed that, in control group, TGF
      beta 1 mRNA mildly expressed in the anterior part of the condyle while
      extensively in the median and posterior parts. In 3 months group, TGF-beta 1 mRNA
      expressed in all parts of condyle; the most intensive expression was in the
      anterior part. Compared with 3 months group, the expression of TGF-beta 1 mRNA
      decreased in 6 months group, but the expression in anterior part was stronger
      than in median and posterior parts. CONCLUSION: Under Class III Orthopedic
      therapy, TGF-beta 1 mRNA probably participated in the endochrondral bone
      remodeling in the condyle, and the expression was closely related to loading
      time. In 3 months group, the expression of TGF-beta 1 mRNA was stronger than that
      in 6 months group. It was inferred that the remodeling of endochrondral bone was
      more active in 3 months group.

PMID- 15017711
TI  - [The role of 18F-FDG in hypopharyngeal cancer].
AB  - OBJECTIVE: To evaluate the function of fluorine-18-fluorodeoxyglucose (18F-FDG)
      in the diagnose of hypopharyngeal cancer. METHOD: Twenty patients with
      hypopharyngeal cancer were entered in the research. Every clinical information
      was collected carefully, including 18F-FDG, CT scanner and panendoscopy (pharyngo
      laryngo-broncho-oesophagien), compared and analysed with each other. RESULT: The
      study showed 18 positive 18F-FDG reactions among these 20 patients, including 5
      ectopia reactions. Compared with the clinical and pathology exam, we found that
      18F-FDG exam had a good correspondance, with such good sensitivity and
      specificity. CONCLUSION: 18F-FDG reaction is useful in the diagnose of
      hypopharyngeal cancer, especially for the detection of the secondary secret
      cancer; also useful for the follow-up exam.

PMID- 15017710
TI  - [Integrated methods for assessing auditory nerve-auditory pathway integrity].
AB  - OBJECTIVE: To evaluate the feasibility and value of integrated methods to assess
      auditory pathway integrity. METHOD: Twenty-four cases of bilateral profoundly
      deafened individuals who were considered as the candidates of cochlear
      implantation were included in this study. Auditory pathway integrity from these
      candidates of cochlear implantation were assessed with the integrated methods
      established by our team, which consist of 5 categories including 1. audiological
      test; 2. radiological imaging study; 3. ear-canal electric audiometry; 4.
      response to sound in daily life; and 5. speech development. RESULT: Twenty-three
      candidates who meet the criteria of auditory nerve-auditory pathway integrity
      received cochlear implantation with improved hearing and speech development
      postoperatively. The remainder one of the 24 candidates was diagnosed as
      bilateral absence of auditory nerve. The fault of cochlear implantation was
      avoided. CONCLUSION: The integrated methods for assessing auditory pathway
      integrity is feasible and valuable. Auditory nerve-auditory pathway integrity
      should be considered and included as one of the most important criteria for
      cochlear implantation candidate.

PMID- 15017712
TI  - [The clinical analysis of cervical lymph node metastases from squamous cell
      carcinoma of the larynx and hypopharynx treated with total laryngectomy].
AB  - OBJECTIVE: To detect the distribution and characteristics of lymph nodes
      metastasis in patients of laryngeal and hypopharyngeal cancer. METHOD: A
      retrospective review of 129 patients who had radical neck dissection, including
      first recurrence in cervical lymph nodes after laryngectomy, was performed to
      analyze the cervical lymph node metastases of different types of laryngeal and
      hypopharyngeal cancer treated by total laryngectomy. RESULT: The patients of the
      hypopharyngeal and supraglottic cancer had a tendency of cervical lymph nodes
      metastasis in their early stage. The rate of the fusional lymph nodes was high in
      hypopharyngeal cancer, and so as to the rate of the positive lymph nodes in their
      level IV. In our study the percentage of the poor-differentiated squamous cell
      carcinoma was relatively high in hypopharyngeal and supraglottic cancer than in
      glottic cancer. And there was no statistical difference in stages of the primary
      tumour between groups of neck dissection with laryngectomy simultaneously and of
      first recurrence in lymph nodes after laryngectomy. CONCLUSION: The latent lymph
      nodes metastasis and preventive neck dissection should be considered in patients
      of hypopharyngeal and supraglottic cancer in or above stages of T2, especially in
      patients with poor-differentiated squamous cell carcinoma, though the sign of
      positive lymph nodes was not evident.

PMID- 15017713
TI  - [Long-term follow-up result of near-total laryngectomy in senile patients with
      laryngeal carcinoma].
AB  - OBJECTIVE: To study the long-term follow-up result of near-total laryngectomy in
      senile patients with laryngeal carcinoma. METHOD: Twelve patients who were above
      65 years old and underwent near-total laryngectomy from 1990 to 1996 were
      summarized. Twelve patients with quamous cell carcinoma of larynx were conformed.
      We adopted and improved Parson's operation, remained normal side cricoid
      cartilage plate, cricoarytenoid joint and recurrent laryngeal nerve. RESULT:
      Three year and five year survival rates were 75.0% and 66.7% respectively. All
      patients had good swallowing founction in two weeks after operation. Ten patients
      obtained good speech function. CONCLUSION: The authors believed that near total
      laryngectomy was safe and beneficial to senile patients with laryngeal cancers
      who suffered from foundermental disease in heart, lung or brain.

PMID- 15017714
TI  - [The surgical treatment of cancer in the base of tongue].
AB  - OBJECTIVE: To seek for a better approach for the resection of carcinoma of the
      base of tongue. METHOD: From 1991 to 2000, all 21 cases of tongue base carcinoma
      had been removed by transhyoid pharyngotomy(11 cases), mandibulectomy(7 cases)
      and step-liked mandibulotomy (3 cases). RESULT: Three patients with step-liked
      mandibulotomy had speech disorder and dysphagy. The rest had satisfactory speech
      and swallowing functions. During followed-up of 2-5 years, 2 cases lost follow
      up, 18 cases were alive at 2 years, 13 cases were alive at 3 years, 5 cases 5
      years. CONCLUSION: Transhyoid pharyngotomy provides good exposure to resect those
      tumors that involve the base of tongue, epiglottis, hypopharynx and larynx.

PMID- 15017715
TI  - [Surgical treatment for patients with late-stage thyroid carcinoma].
AB  - OBJECTIVE: To explore the value of surgical treatment for patients with late
      stage thyroid carcinoma. METHOD: Eleven cases of late-stage thyroid carcinoma
      underwent radical neck lymphnode dicission of the affected side plus functional
      neck lymphnode dicission on the opposite side. Three of them received lobectomy
      of the affected sides and excission of the isthmus. Six cases received lobectomy
      of affected sides, excission of isthmus and subtotal thyroidectomy of the
      opposite side; 2 of them received total thyroidectomy and parathyroid
      transpiantation. RESULT: With 9 cases followed up, 8 cases survived without
      recurrence and advancing. One for 6 years, 1 for 5 years, 2 for 3 years, 3 for 2
      years and 1 for 1 year. The other one died, suffered from papillary
      adenocarcinoma combined with metastatic adenocarcinoma. CONCLUSION: For patients
      with late-stage thyroid carcinoma, operation should be performed as possible.
      Postoperative thyroid hormone administration could inhibit the development of the
      primary and metastatic lesions effectively. Preservation of parathyroid glands
      could improve the patient's life quality.

PMID- 15017716
TI  - [Lateral thyrotomy approach on the paraglottic space disease].
AB  - OBJECTIVE: To discuss the feasibility and superiority of lateral thyrotomy
      approach on the paraglottic space operation. METHOD: Five case mucocele of larynx
      located at paraglottic space were resected the cyst completely by a U-shaped
      lateral thyrotomy approach. One cases of laryngeal trauma foreign body in
      paraglottic space was taken out by approach through vertical split of the thyroid
      lamina. RESULT: Three cases mucocele of larynx located did not recurrent during
      follow-up 1 year and their phonation were recoverd normally. The other two cases
      are during follow-up. One cases of laryngeal trauma foreign body has been
      oprated, her vocal cords moved normally and the glottic could be closed
      completely. CONCLUSION: Through lateral thyroid lamina split or partial resection
      approach, the paraglottic space can be exposed clearly and the cyst or foreign
      body can be easily removed under direct visualization. The operation provides
      minimal trauma without deformity in laryngeal framework, and postoperative
      complication to enter the laryngeal mucosa. It proves to be an effective approach
      to benign lesion at paraglottic space.

PMID- 15017717
TI  - [The pathogenesis and treatment exploration of vocal cord paralysis].
AB  - OBJECTIVE: To investigate the causes and effective treatment of vocal cord
      paralysis(VCP). METHOD: Sixty-five patients with VCP in our hospital in recent 10
      years were analyzed. All the patients underwent examination by indirect
      laryngoscope, stroboscopy or electrolaryngostroboscopy, of which, 31 cases were
      operated by stiring arytenoid cartilage. RESULT: Fourteen cases with VCP were
      caused by neck and thoracic tumor; Nine cases were caused by infectations;
      sixteen cases were caused by neck, thoracic, abdominal openations; twelve cases
      were caused by trachea intubation; Three cases were caused by gastric intubation;
      Eleven cases were caused without obvious reason. All the symptoms of VCP were
      cured after treatment in 37 cases. The improvement rate of hoarseness was 58.46%.
      CONCLUSION: Patients with hoarseness should be routinely examinated by indirect
      laryngoscope, stroboscopy or electrolaryngostroboscopy. Arytenoid cartilage of
      patients with VCP should be stired by indirect laryngoscope or direct
      laryngoscope or self-retaining laryngoscope as early as possible.

PMID- 15017718
TI  - [Analysis on clinical and immunohistochemical characteristics of primary
      extranodular non-Hodgkin's lymphoma in otolaryngol head and neck].
AB  - OBJECTIVE: To study the characteristic of clinical manifestation and cell
      immunophenotype in cases with primary extra-nodular non-Hodgkin's lymphoma (PE
      NHL) in otolaryngol head and neck for early diagnosis and treatment. METHOD:
      Clinical manifestation of one hundred and fifty five patients with PE-NHL in
      otolaryngol head and neck from 1991 to 2000 were analyzed and restudied by
      pathological sections with immunohistochemical technology. RESULT: The age of
      twenty six to fifty years old was the most common age range in the group of
      patients with PE-NHL. Waldeyer's ring was the most commonly involved site (92
      cases), the rest were in sinonasal (57 cases), in laryngopharynx (2 cases) and in
      larynx (4 cases). There were no characteristic symptoms of primary lesion
      located. The lump or fester signs were mostly observed on primary position. Cell
      immunophenotype result displayed 46.4% of the PE-NHL originating from T cells,
      while 53.6% originating from B cell. Most of waldeyer's PE-NHL originating from B
      cell, while most of sinonasal PE-NHL originating from T cell. CONCLUSION: The
      clinical behavior in patients with the PE-NHL is complicated and lacks
      characterisic symptoms, so the diagnosis is difficult. Doctor should be alert and
      the repeated exact biopsy may be needed. The diagnosis can be definite by
      pothological and immunohistochemical approaches with clinical manifestation.

PMID- 15017719
TI  - [The study of autonomic nervous activities in patients with obstructive sleep
      apnea syndrome].
AB  - OBJECTIVE: To explore the nocturnal variation of autonomic nervous system (ANS)
      in patients with obstructive sleep apnea syndrome (OSAS) and the transformation
      after surgery. METHOD: Sixty-one subjects with OSAS were recruited to undergo 7
      hour nocturnal polysomnography(PSG) in sleep lab. Sixteen subjects with OSAS were
      performed PSG before and after UPPP. Sixteen subjects without OSAS were included
      as controls. Power spectrum analysis of heart rate variability (HRV) was
      performed in each subject. RESULT: The nocturnal of ANS activities were abnormal
      in patients with OSAS, especially the enhancement of sympathetic nervous
      activity. It increased gradually along with aggravating condition. The activities
      of sympathetic and vagus nerve were decreased significantly. CONCLUSION: There
      are abnormal ANS activities in patients with OSAS. Effective treatment of OSAS by
      surgery will significantly reduce the parameters of ANS, and redress the
      abnormality of heart rate and blood pressure.

PMID- 15017721
TI  - [Surgical treatment for the chronic severe aspiration].
AB  - OBJECTIVE: To find out the best surgical treatment for chronic severe aspiration
      with different pathogenesis. METHOD: Eight patients with severe aspiration were
      treated by 3 surgical methods. Six of 8 cases were perfomed tracheotomy. The
      cannula had a gasbag and the gasbag was inflated before eating food every time.
      Epiglottic flap closure for one patient with intractable aspiration. Stomach
      stomy for the case with tracheoasophageal fistula. RESULT: There did not found
      aspiratory pneumonia in all cases after following up for 9 months to 4.5 years.
      The six cases with tracheotomy could eating normally and their phonation were
      reserved. Only one case has a slight aspiration. The patient with epiglottic flap
      closure hadn't aspirated when eating. The stomach-stomy could prevent the
      aspiration in having meal. CONCLUSION: Tracheotomy, epiglottic flap closure and
      stomach-stomy are all the effective surgical treatment for chronic severe
      aspiration. Any of 3 surgical methods should be selected according to the
      etiology, the degree of aspiration and the patient's condition, so as to improve
      the quality of the patient's life.

PMID- 15017720
TI  - [Vocal cord polypectomy of patient with thick and short neck using
      laryngostroscope under direct vision].
AB  - OBJECTIVE: To seek a new operation and objective assessment of curative effect
      for the patients with polyp of vocal cord while with thick and short neck.
      METHOD: The polypectomy in 42 cases was conducted using bent forceps by
      pharyngeal area under direct vision with laryngostroscope. The symmetry,
      regularity, mucosal wave, and glotta closure was surveyed by endo-stroboscope in
      the process of the operation. If vestigial polyp was present, repair and
      removement could be promptly finished again. RESULT: All operations were
      successful at one time. On the basis of comparative analysis with pre and post
      operation electroglottograms, its curative effect was objectively evaluated.
      Elapse was not found by post-operation follow-up survey, and euphonia was
      listened. CONCLUSION: The operation method has clinical application value for the
      vocal cord polypectomy in patients with thick and short neck.

PMID- 15017722
TI  - [A preliminary study of reducing bleeding procedure during endoscopic sinus
      surgery].
AB  - OBJECTIVE: To explore the method and the feasibility of reducing bleeding
      procedure(RBP) during endoscopic sinus surgery. METHOD: The focuses and tissue
      being removed in nasal cavity were coagulated by bipolar radiofrequency in order
      to reduce bleeding during operation in 53 patients with nasal disease. The
      bleeding places were coagulated in the same way after operation. RESULT: The
      nasal cavities without stuffed qauze to control bleeding after operation was in
      37 cases (69.8%) of 53 patients operated. The average volume of bleeding during
      the surgery was 39.67 ml in 37 patients with chronic sinusitis and nasl polyp.
      CONCLUSION: The RBP during endoscopic sinus surgery is well worth researching and
      discussing further.

PMID- 15017723
TI  - [The expression of cell adhesion molecule Syndecan-1 and E-candherin in laryngeal
      cancer].
AB  - OBJECTIVE: To observe Syndecan-1 and E-candherin expression and their
      relationship with clinico-pathologic factors in primary laryngeal squamous cell
      carcinoma(LSCC). METHOD: Syndecan-1 and E-candherin proteins were determined with
      immunohistochemical technique. RESULT: In invasive LSCC the expression of these
      two adhesion molecules were very similar. Both diminished with decreasing cell
      differentiation, lacked often in poorly differentiated tumors. And their
      expression were significantly correlated with each other. CONCLUSION: Our results
      suggest that Syndecan-1 and E-candherin expression correlates significantly with
      the histological differentiation grade of the tumors and the tumors size. They
      may play important roles in the pathogensis and the development of LSCC.

PMID- 15017724
TI  - [Expression and correlation of apoptosis-related gene c-IAP2 and caspase-4 in
      head and cervical undifferentiation squamous cell carcinoma].
AB  - OBJECTIVE: To examine the expression of apoptosis-related genes c-IAP2 and
      caspase-4 in head and cervical undifferentiation cell carcinoma, as well as to
      investigate the role and mechanism of the two apoptosis-related genes in head and
      cervical undifferentiation squamous cell carcinoma. METHOD: Sixty-six historily
      confirmed specimen of head and cervical undifferentiation squamous cell carcinoma
      were subjected for immunohistochemical staining to analyze the expression of c
      IAP2 and caspase-4, in addition 5 cases of normal nasal mucosa tissue were
      selected as control. RESULT: 1. Higher level expression of c-IAP2 protein was
      detected in the head and cervical undifferentiation squamous cell carcinoma
      specimen compared with normal nasal mucosa(P < 0.05), and the expression of
      caspase-4 was more deletion in it than in normal nasal mucosa(P < 0.05). 2. The
      expression of c-IAP2 protein was positive correlation with clinical prognosis,
      not correlated with clinical staging. The expression of caspase-4 protein was
      negative correlated with clinical prognosis, not correlated with clinical
      staging, too. 3. The expression of c-IAP2 was negative correlated with the
      expression of caspase-4. CONCLUSION: It indicates that in tissue of head and
      cervical undifferentiation squamous cell carcinoma, c-IAP2 is activated while
      caspase-4 is restrained. The signal transduction pathway of apoptosis is
      arrested, leading to surviving of the tumor cells, which maybe directly
      associated with the developing of head and cervical undifferentiation squamous
      cell carcinoma, and also with the failure of tumor treatment.

PMID- 15017725
TI  - [Expression of NO and NOS in nasal polyps].
AB  - OBJECTIVE: To investigate the expression of nitric oxide synthase(NOS) in nasal
      polyps tissue and also to study the function of nitric oxide in the pathology of
      nasal polyps. METHOD: Investigating the expression of iNOS, eNOS with
      immunohistochemical staining, and the expression of iNOS mRNA with hybridization
      in situ. Analysing the production of nitric oxide in the nasal polyps through
      nitrate reductase technique. RESULT: In the polyps group, eNOS located in gland
      cells, epithelial and vascular endothelial cells, the staining of which was a
      little stronger than those of controls. The staining of iNOS was fairly strong in
      the epithelial cells, and it expressed mostly in the inflammatory cells inside
      the tissue. CONCLUSION: eNOS may play a role in glandular secretion and vascular
      dilatation. The increase of eNOS might respond to the enhanced nasal secretion
      and edema of nasal mocusa. Large amount of NO produced by iNOS may deteriorate
      the inflammation process of nasal polyps.

PMID- 15017726
TI  - [Treatment of rectal cancer in Denmark--how can it be improved?].

PMID- 15017727
TI  - [Ultrasonography in rheumatic diseases. Gray scale ultrasound].

PMID- 15017729
TI  - [Hereditary angioedema].

PMID- 15017728
TI  - [Recurrent abdominal pain in children].

PMID- 15017730
TI  - [3-month colic].

PMID- 15017731
TI  - [Treatment of rectal cancer in Denmark 1994-1999].

PMID- 15017732
TI  - [Doppler ultrasonography in rheumatic diseases].

PMID- 15017733
TI  - [Air: a suitable contrast agent in musculoskeletal ultrasonography].

PMID- 15017734
TI  - [Psychosocial consequences of first myocardial infarction. A prospective study].

PMID- 15017735
TI  - [Increased rate of hospitalization and improved survival after acute myocardial
      infarction].

PMID- 15017736
TI  - [Allergy to chlorhexidine--an important differential diagnosis].

PMID- 15017737
TI  - [Primary clubbing of fingers and toes].

PMID- 15017738
TI  - [Treatment with ACE inhibitors in acute apoplexy].

PMID- 15017739
TI  - [Labor pain 1].

PMID- 15017740
TI  - [Labor pain 2].

PMID- 15017741
TI  - [Quality assurance, professional secrecy and the National Board of Health and
      Welfare].

PMID- 15017742
TI  - [Transplantation between monozygotic twins].

PMID- 15017743
TI  - [Prenatal diagnosis 2].

PMID- 15017744
TI  - [Health services and alternative therapy].

PMID- 15017745
TI  - Unicorns, obstetricians, neurosurgeons--three things hard to find in Missouri.

PMID- 15017746
TI  - We will rescue tort reform this session!

PMID- 15017750
TI  - Suggestions to avoid discrimination lawsuits.

PMID- 15017749
TI  - Lead, follow--or keep an open mind.

PMID- 15017748
TI  - The future of medical education: a crisis brewing?

PMID- 15017751
TI  - Management of abnormal bleeding in adolescents.
AB  - Menstrual dysfunction is a common gynecologic problem for adolescents. While the
      majority of abnormal uterine bleeding is the result of dysfunctional ovulatory
      patterns, other illnesses or conditions can be underlying problem bleeding.
      Successful diagnosis and management of these conditions in adolescents requires a
      firm understanding of the normal menstrual process. Professionals who treat
      adolescents must develop specialized strategies and skills to optimize history
      taking, examination, and treatment in this group.

PMID- 15017753
TI  - The Manchester Procedure.
AB  - This article describes the historical development for the Manchester Surgical
      Procedure for the correction of genital prolapse.

PMID- 15017752
TI  - The adnexal mass in pregnancy.
AB  - The management of the adnexal mass in pregnancy can place the patient and/or
      fetus at risk. Adnexal masses occur in approximately one in 600 pregnancies, of
      which the risk of malignancy is up to 5%. The decision to proceed with
      conservative versus operative intervention is discussed in this article.

PMID- 15017755
TI  - The role of obstetricians-gynecologists in the prevention and treatment of
      osteoporosis.
AB  - This manuscript reviews the time course and components of osteoporosis and the
      diagnostic tools and medication available for treatment; as well as discusses the
      role of the obstetrician-gynecologis in detection, prevention, and treatment of
      osteoporosis in the pre- and postmenopausal patient. It also updates a review
      that appeared in this journal.

PMID- 15017754
TI  - Vulvar dysesthesia.
AB  - Chronic vulvar pain is a significant and misunderstood factor in women's health.
      Recent new definitions of chronic vulvar dysesthesia have helped to clarify the
      issue, however the etiology and effective treatment options remain elusive. A
      systematic approach to the diagnosis and treatment of vulvar dysesthesia is
      necessary for this difficult and challenging condition.

PMID- 15017756
TI  - Diverticular bleeding: novel treatment with band ligation.
AB  - Diverticulosis accounts for 50% of adult cases of lower gastrointestinal
      bleeding. Recurrent or persistent bleeding usually is treated surgically. Recent
      studies suggest that 20% of patients with diverticular bleeding can have the site
      identified and treated endoscopically. Treatment modalities include injection
      techniques, thermal therapy and hemoclips. This paper reports three cases
      successfully treated with band ligation, after initial epinephrine injection
      therapy had failed.

PMID- 15017758
TI  - Psychic reality and the analytic relationship.
AB  - In this article I have argued that the more linear transformations or
      desymbolized expressions of one's earliest relationships are always a part of
      psychic reality and represent a unique opportunity in the analytic situation to
      transform a person's emotional orientation to the world. A necessary condition
      for this to come about is the analyst's capacity for sustained interest in the
      patient. This interest, which goes well beyond an intellectual one, can be
      threatened by countertransference as well as certain assumptions the analyst has
      about the nature of the analytic process. The analyst's belief in the analytic
      process, a belief that can only come from his or her own analysis, is seen as
      crucial in helping the transformational process that occurs in a successful
      analysis.

PMID- 15017757
TI  - Prehospital dispatch assessment of stroke.
AB  - This study is to determine the assessment accuracy for the diagnosis of stroke by
      EMS dispatchers and paramedics compared to emergency physicians (EPs). Of the 191
      patients who met inclusion criteria, dispatchers assessed 133 as having a stroke;
      EPs agreed in 67 (50%) cases. Paramedics assessed 100 patients as having stroke;
      EPs agreed in 70 (70%) cases. Dispatcher and paramedic sensitivity for diagnosing
      stroke was 61% and 64%, respectively; specificity was 20% and 63% respectively.
      Sensitivity for the detection of acute stroke was nearly identical between EMS
      dispatchers and on-scene paramedics; overall agreement with emergency physician
      diagnosis was moderate.

PMID- 15017759
TI  - Male mothers and cannibal women: a Kleinian interpretation of male initiation in
      the New Guinea Highlands.

PMID- 15017760
TI  - Between tomboys and butch lesbians: gender nonconformity viewed through clinical
      psychoanalysis and lesbian and gay theory.

PMID- 15017761
TI  - My psychoanalytic journey.

PMID- 15017762
TI  - Attack of the inward eye: self-observing and aggression.

PMID- 15017763
TI  - Freud, Hitler, and National Socialism.

PMID- 15017764
TI  - Repairing worlds: an exploration of the psychoanalytical and Kabbalistic concepts
      of reparation and Tikkun.

PMID- 15017765
TI  - Obsessive drawing: I can't stop thinking about.

PMID- 15017766
TI  - [Andrei Vasil'evich Khodin -- founder and editor-in-chief of the first Russian
      journal "Annals of Ophthalmology"].

PMID- 15017767
TI  - ["Annals of Ophthalmology" celebrates its 120th anniversary].

PMID- 15017769
TI  - [Present-day positions of the clinical-and-social ophthalmology].
AB  - Outlined in the paper are the basic trends and tasks of clinical-and-social
      ophthalmology--research and practice related with the medical-and-social
      consequences of disabling visual impairments as well as of blindness and
      disability due to vision. They comprise: 1) A study of the epidemiological,
      social-and-hygienic and clinical-and-ophthalmologic aspects of blindness and
      disability; 2) Scientific elaboration of methodological, clinical, social and
      managerial positions and criteria of ophthalmologic and of medical-and-social
      expertise; 3) A theoretical definition of the methodological principles for
      medical-and-social rehabilitation of the disabled due to vision. Data are
      presented of the rate of blindness and disability due to ophthalmic pathologies
      in the Russian Federation. The modern standpoints of ophthalmologic medical-and
      social expertise and rehabilitation of persons with visual lesions are
      elucidated.

PMID- 15017768
TI  - [Some significant events that occurred in ophthalmology during the last 20
      years].

PMID- 15017771
TI  - [Clinical and epidemiological features of uveitis in children].
AB  - The structure, dynamic morbidity and clinical specificity of endogenous uveitis
      have been studied in different-age children in a Moscow district for as long as
      30 years. The frequency of uveitis was determined for Moscow; it went up in the
      city, during the recent 15 years, 5-fold. On the basis of complex examinations of
      1573 children with uveitis, the age-related, clinical-and-morphological and
      etiological specific features of uveitis were investigated. The rate and nature
      of complications after uveitis leading to the disablement due to blindness and
      poor vision were defined. Lipid peroxidation, body antioxidant protection,
      corticosterones and hydrocortisones as well as metabolism of acid
      glycosaminoglycans were found, according to biochemistry results, to be important
      in uveitis pathogenesis, which is a fundamental in working out the pathogenetic
      therapy and prognostication of uveitis. The thus elaborated system of clinical
      and-laboratory and of therapeutic measures enhanced the efficiency of the early
      and differential diagnostics of uveitis and of the complex therapeutic treatment
      of the discussed severe pathology, which brought about a 2-fold cut of stay in
      hospital, improved the functional outcomes and reduced the complications' rate.

PMID- 15017770
TI  - [Priority trends in the sphere of eye injuries].
AB  - Comprehensive recent research of eye traumatism is described, aspects related
      with changes in the trauma structure are defined and advanced methods of
      diagnostics as well as of therapeutic and surgical treatment in eye trauma are
      elucidated in the paper. It is pointed out that the above study results are
      valuable for rehabilitation of victims during peacetime, in emergency situations
      and in calamities; the contribution of civil ophthalmologic institutions to
      rendering a specialized medical care to victims of military conflicts is equally
      important. The case study comprises extensive research findings that can be used
      in the below cases requiring a specialized medical care: penetrating eye
      injuries, contusion, burn injuries of the eye, splintered trauma etc.; the
      current micro-surgery standards must be adhered to and the latest technologies
      must be used. Finally, the important role of and valuable contributions to the
      above research made by the Calamity Medicine Center ("Zashchita") are underlined.

PMID- 15017773
TI  - [The organ-saving treatment of intraocular tumors (development trends)].
AB  - A trend towards an increase of malignant tumors observed during the recent 30-40
      years, an unsatisfactory efficiency of enucleation as of a method applicable to
      treating such tumors and the designing of a modern technical basis stimulated a
      new trend in ophthalmooncology, i.e. organ-saving treatment. Outlined in the
      paper is an analysis of achievements of modern radiation treatment techniques and
      of local surgical extraction of tumors suggested both by Russian and foreign
      researchers; the methods are shown to be promising for future development.

PMID- 15017772
TI  - [Current aspects of correction of refractive disorders].
AB  - The key issues associated with correcting the refractive derangements are
      analyzed in the paper; they are: 1) the frequency of refractive defects; 2) a
      need in preparatory measures targeted at a better diagnostics and an adequate
      correction choice; and 3) possibilities of full-value correction involving the
      achievements of modern ophthalmology. The key criteria that can be used to
      enhance the efficiency of ametropia correction method are described. Advantages
      and disadvantages of different corrections methods (spectacles and contact lenses
      and refractive surgeries) were analyzed with regard for the above criteria.

PMID- 15017774
TI  - [Retinoschisis. 1. Diagnosis, classification, examination methods].
AB  - Extensive clinical data (595 patients) were made use of to work out a clinical
      classification and to isolate 2 groups of patients, i.e. one with primary
      retinoschisis and the other with secondary retinoschisis. According to
      etiopathogenesis, primary retinoschisis is subdivided into the inherited
      (congenital) variation and the acquired one. Congenital retinoschisis comprises,
      in its turn, juvenile and linked with X-chromosome variants as well as
      retinoschisis observed in Goldman-Favre and Wagner syndromes. The group of
      acquired retinoschisis is made up of degenerative (senile) and myopic variants,
      which are triggered by the typical or cystic peripheral retinal degeneration.
      Secondary retinoschisis is observed in different eye diseases like trauma,
      diabetes, uveitis, angiomatosis etc. The central, peripheral and combined
      retinoschisis variations are distinguished according to localization; two
      variations are distinguished according to the disease clinical course, i.e.
      stationary with demarcation and complicated progressing without demarcation and
      with uneven borders. The study results show that retinoschisis of any variation
      begins at the extreme periphery; lamination of the flat type develops primarily
      in the lower-external quadrant and the one of the bullous type--in the upper
      external quadrant.

PMID- 15017775
TI  - [Local express auto-cytokine therapy (a complex of cytokines) in the treatment of
      viral and nonviral eye lesions].
AB  - The method of local express-autocytocinetherapy (LEACCT) consists in using an
      experimentally tested autologous complex of cytokines (alpha- beta- gamma
      interferons, interleukins 2.8, tumor necrosis factor gamma etc.), which is
      produced by joining the autoblood of patients with immune-modulator poludan
      (complex poly A:poly U). The external LEACCT and the intrachamber LEACCT are
      distinguished. The former presupposes the administration (subconjunctivally and
      in installations) of the autoblood-poludan mixture. This method is used in herpes
      and adenovirus keratoconjunctivitis, slow re-epithelization after laser
      keratectomy and in eye burns (178 patients). The latter comprises, apart from the
      external LEACCT procedures, a 1-4-time introduction of the mentioned mixture into
      patient's anterior chamber. It was used in endothelial herpetic
      keratoiridocyclitis, initial bullous keratopathy, severe keratoconus and in
      injuries of the anterior lens capsule (117 patients). The clinical-study results
      (main group--295 patients) show that the designed method based on poludan has
      pronounced anti-inflammatory and regenerative effects in different viral and
      virus-free lesions of the eye tissues; it is simple and can be applied in
      clinical settings. An increased visual acuity ranging from 0.05 to 1.0 was
      registered in 85% of cases. The action of the complex of cytokines is as close as
      possible to the physiological mechanism, which provides for avoiding the side
      effects and for applying the treatment scheme in situations when the
      administration of other drugs is limited or their efficiency is not sufficient.

PMID- 15017776
TI  - [Results of the examination of hemodynamics of the eye and brain in patients with
      primary open-angle glaucoma].
AB  - The paper contains the results of examinations of hemodynamics of the eye and
      brain in patients with primary open-angle glaucoma (POAG) obtained by the authors
      also by means of rheoophthalmography made to determine the functional status of
      intraocular vessels. New methods are suggested for diagnostic interpretation,
      which enhance the importance of rheography in examinations of hemodynamics of the
      eye and brain in patients with glaucoma. The authors used self-learning
      artificial neuron networks to process Fourie- and wavelet factors, obtained in
      novel rheoophthalmograms processing, which made it possible to recommend the
      described method for an early diagnosis of POAG.

PMID- 15017778
TI  - [A morphological pattern of the aqueous humor in the evaluation of
      pathophysiological mechanisms of involutional cataract genesis].
AB  - The method of wedge-type dehydration was made use of to study the specificity of
      the systemic structure of 496 samples of aqueous humor obtained in the course of
      surgical interventions in 62 patients for senile cataract. The results were
      analyzed with respect to a cataract stage and it was established that the
      systemic structure of aqueous humor reflects different-phase impairments in the
      system of the intermolecular interaction of aqueous-humor components, which is
      mainly related with activated processes of organic products' mineralization as
      observed in senile cataract progression.

PMID- 15017777
TI  - [Clinical-immunological and ecological research in diabetic retinopathy].
AB  - Two hundred and ninety-six patients with diabetic retinopathy (DR) were examined:
      conservative therapy and laser coagulation of the retina were applied in 120 and
      176 of them, respectively. The ecological situation in the residence region and
      its impact on the morbidity and immune status of DR patients were analyzed. The
      comfort degree of the environment and the level of anthropogenic contamination
      affect the morbidity and immunogram results. Immune-correctors, i.e. T-activin,
      sodium nucleinate and laser blood irradiation (LBI), were used within treatment
      schemes in DR. Laser coagulation of the retina is advisable to assign in
      combination with sodium nucleinate and LBI in the aftercare of patients
      concurrently with complex therapy; T-activin is used, within conservative
      therapy, to correct the unfavorable ecological impact exerted on patient's body.

PMID- 15017779
TI  - [From scattering to wavefront. Healing optics].
AB  - The purpose of this report, made within research in progress, was to discuss the
      optical effect of irregular surface structures that might be associated with
      complicated refractive procedures related with the retinal image quality. We
      concentrated our discussion on the range of surface structures between the known
      scattering effects and wavefront aberrations of higher orders. The case study
      demonstrates that the surface irregularities of the cornea might induce, after
      refractive laser surgery, significant optical aberrations that are much too
      different from the classical wavevront or scattering errors. Such optical errors,
      however, cannot be correctly measured by current commercial wavefront sensors.
      Finally, the influence of the healing process on Strehl ratio is under
      discussion.

PMID- 15017780
TI  - [Clinical forms of acanthamoeba keratitis as viewed from the standpoint of
      biomicroscopy and confocal microscopy].
AB  - Clinical cases of 60 patients with acanthamebic keratitis examined by
      biomicroscopy and of 22 patients largely examined by confocal microscopy are
      generalized. Acanthamebic keratitis is a slowly progressing infectious lesion of
      the cornea, which is caused by acanthamebas freely residing in soil and water.
      Contaminated contact lenses are the key risk factor. The main clinical features
      of acanthamebic keratitis are defined; they are presence of risk factors; a
      unilateral lesion in young, healthy and immune-competent persons; a typical
      clinical pattern of surface keratitis mainly of the ring shape; corneal neuritis
      without corneal neovascularization but with a severe pain in the eye; and a slow
      chronic clinical course, i.e. lasting for several weeks and months. Confocal
      microscopy is the most effective and fast diagnostic tool because it ensures the
      detection of acanthamebic cysts and trophozoids in all strata of the corneal
      stroma. The authors isolate, within the clinical course of acanthamebic
      keratitis, 5 stages; they are surface epithelial keratitis; surface epithelial
      punctate keratitis; stromal ring-shaped keratitis; ulcerous keratitis; and
      keratoscleritis.

PMID- 15017782
TI  - [An age-functional approach to ametropia compensation].

PMID- 15017781
TI  - [Isolated aplasia of the optic nerve].
AB  - The results of ophthalmologic examinations, including ophthalmoscopy, ultrasound
      Doppler-graphy as well as neuroradiological and electrophysiological
      investigations, of a 6-month boy with bilateral isolated aplasia of the optic
      nerve are described. The discussion comprises a literature survey dedicated to
      pathogenesis and diagnostics of optic-nerve aplasia in children.

PMID- 15017783
TI  - [Clinical features of coronary artery ectasia].
AB  - OBJECTIVES: To investigate the clinical significance of coronary artery ectasia
      in Japanese patients. METHODS: Coronary artery ectasia was found in 54 of 3,778
      (1.4%) consecutive patients who underwent coronary angiography. The clinical
      characteristics and the coronary angiographic findings of these patients were
      studied. Follow-up data were obtained for 49 patients, who were separated into
      two groups: Group A subsequently suffered a follow-up major cardiac event, and
      Group B did not develop such an event. RESULTS: Among the coronary artery ectasia
      patients, 65% had myocardial infarction, 91% had coronary artery disease, and 48%
      had single-vessel disease. Seventy-six percent had single-vessel involvement with
      coronary artery ectasia. Eighteen patients (37%) suffered 22 follow-up major
      events. Seventy-two percent of the first follow-up event cases occurred within 4
      years after the first cardiac event. The follow-up event in 78% of cases was
      acute coronary syndrome. There were no significant differences in age and
      prevalence of each coronary artery risk factor between Groups A and B. There were
      no significant differences in the incidence of follow-up event between the
      patients with single-vessel disease and the patients with multi-vessel disease,
      nor between the patients with single-vessel involvement with coronary artery
      ectasia and the patients with multi-vessel involvement with coronary artery
      ectasia. There was no significant difference in the percentage of patients in
      whom the culprit vessel of the cardiac event was the same as the ectatic vessel
      between the first cardiac event and follow-up cardiac events (41% vs 62%).
      CONCLUSIONS: Coronary artery ectasia is not benign and must be carefully
      monitored. Coronary atherosclerosis may contribute to the occurrence of
      subsequent cardiac events.

PMID- 15017784
TI  - [Effects of acute administration of beraprost sodium on parameters related to
      atherosclerotic vascular damage in coronary artery disease].
AB  - OBJECTIVES: The present study was conducted to examine the effects of acute
      administration of prostacyclin derivatives on plasma levels of adhesion
      molecules, endothelial function, and pulse wave velocity in patients with
      coronary heart disease. METHODS: In 20 patients with coronary heart disease,
      plasma levels of vascular cell adhesion molecule-1, P-selectin, and beta
      thromboglobulin, endothelial function, and pulse wave velocity were assessed
      before and after the cold pressor test. These assessments were performed again 2
      hr after the oral administration of prostacyclin derivatives (beraprost sodium 40
      micrograms) or placebo. Endothelial function was assessed by changes in forearm
      blood flow before and after reactive hyperemia. Pulse wave velocity was
      determined by the volume rendering method. RESULTS: Prostacyclin derivatives
      significantly improved endothelial function and decreased plasma beta
      thromboglobulin level, but did not affect blood pressure and pulse wave velocity.
      Prostacyclin derivatives did not prevent the elevations of blood pressure and
      pulse wave velocity induced by the cold pressor test, but did prevent the
      elevations of P-selectin and beta-thromboglobulin induced by the cold pressor
      test. CONCLUSIONS: Prostacyclin derivatives improved endothelial function and
      prevented platelet activation induced by the cold pressor test. Prostacyclin
      apparently has an anti-atherogenic effect.

PMID- 15017786
TI  - [Premature ventricular contraction during myocardial contrast echocardiography:
      relationship with imaging method, acoustic power and dose of contrast agent].
AB  - OBJECTIVES: This study investigated the influence of imaging method, acoustic
      power, and dose of contrast agent on the occurrence of premature ventricular
      contraction during myocardial contrast echocardiography. METHODS: Myocardial
      contrast echocardiography was performed with a Toshiba POWER VISION 6000 and
      YM454 (Definity in USA) contrast agent. Myocardial contrast echocardiography in
      the short-axis view at the mid-papillary muscle level and electrocardiography in
      lead II were recorded on videotape in nine awake beagles. The imaging method was
      continuous, using 1:1 and 1:4 intermittent end-systolic triggered mode. Acoustic
      power was low, middle and high (as mechanical index, 0.4, 0.8 and 1.0 at
      continuous mode and 0.6, 1.0 and 1.4 at intermittent mode). YM454 was given
      intravenously at doses of 1, 10, 30, 50 and 100 microliters/kg/min. Premature
      ventricular contractions were counted on the videotape for each experimental
      condition. The examination was repeated on a separate day to ascertain the
      reproducibility. RESULTS: At low and middle acoustic power, no premature
      ventricular contraction was induced with any combinations of YM454 doses and
      trigger intervals. The highest incidence of premature ventricular contraction was
      5.1% of all ultrasound pulses at the combination of high acoustic power, 1:4
      intermittent and 30 microliters/kg/min of YM454. All premature ventricular
      contractions induced by trigger mode were observed concomitantly to the end
      systolic phase. Reproducibility was low at 0.9%. CONCLUSIONS: Although high
      acoustic power, intermittent myocardial contrast echocardiography with high dose
      of contrast agent induced premature ventricular contractions, the incidence of
      premature ventricular contractions was low. Low acoustic power or low dose of
      contrast agent induced no premature ventricular contractions.

PMID- 15017787
TI  - [Tako-tsubo-like transient left ventricular dysfunction with apical thrombus
      formation: a case report].
AB  - A 76-year-old woman with oppressive chest pain was admitted to our hospital.
      Initial electrocardiography revealed normal sinus rhythm with ST-segment
      elevation in leads V2-V5. The patient underwent emergent coronary angiography,
      which demonstrated no significant coronary stenosis. Left ventriculography
      revealed marked hypokinesis and akinesis of the mid and distal segments of all
      ventricular walls, with hyperkinesis of the base. Six days after admission,
      transthoracic echocardiography revealed immobile apical thrombus. The thrombus
      disappeared without any embolic episode after 2 weeks of anticoagulant therapy
      with heparin and warfarin. Left ventricular walls returned to normal 3 months
      after the attack. Tako-tsubo-like cardiomyopathy with apical thrombus has only
      been reported in three cases. Left ventricular function normalizes within several
      days or weeks in most cases of tako-tsubo-like transient left ventricular
      dysfunction. Therefore, if the thrombus remains within the left ventricle, the
      risk of embolism might be relatively high. Careful management must be required in
      patients with tako-tsubo-like transient left ventricular dysfunction.

PMID- 15017785
TI  - Relations between strength and endurance of leg skeletal muscle and
      cardiopulmonary exercise testing parameters in patients with chronic heart
      failure.
AB  - OBJECTIVES: The relations between muscle strength, muscle endurance, and
      cardiopulmonary parameters were investigated in patients with chronic heart
      failure. METHODS: The subjects comprised 33 outpatients with stable chronic heart
      failure (27 men, 6 women, mean age 60.3 +/- 12.7 years). A pedal-type isokinetic
      device was used throughout the study. The safety of the study protocol was
      examined first. Maximum muscle power (peak power), an index of muscle strength,
      was measured for 6 consecutive revolutions(3 revolutions of each leg). The
      strength decrement index (SDI) was measured for 20 consecutive maximal
      revolutions (10 revolutions in each leg). The SDI is an index of muscle endurance
      and compares the mean power for revolutions 9 and 10 with that for revolutions 2
      and 3. Each subjects underwent symptom-limited cardiopulmonary exercise testing
      with a cycle ergometer on another day. RESULTS: No subject experienced continuous
      abnormal heart rate or blood pressure response, chest pain, ischemic ST-T change,
      or severe arrhythmia. The peak power and the SDI were correlated with the
      anaerobic threshold (r = 0.42, 0.52, respectively), with peak oxygen uptake (r =
      0.66, 0.61), and with the increase in oxygen uptake per unit increase in work
      rate (r = 0.43, 0.63). However, the slope of the ventilation equivalent to carbon
      dioxide output was correlated only with the SDI (r = -0.54) and the time constant
      for the oxygen uptake decrease was correlated only with the peak power (r = 
      0.46). CONCLUSIONS: Peak functional capacity depends on both muscle strength and
      endurance, and subjective symptoms in daily activity, especially dyspnea on
      exertion, depend mainly on muscle endurance in patients with chronic heart
      failure.

PMID- 15017788
TI  - [Usefulness of dobutamine stress echocardiography in a patient with aortic valve
      stenosis and left ventricular dysfunction: a case report].
AB  - A 76-year-old man with previous antero-septal myocardial infarction and aorto
      coronary bypass surgery developed exertional dyspnea. Echocardiography revealed
      diffuse left ventricular hypokinesis and aortic stenosis with a mean pressure
      gradient of 29 mmHg. Coronary angiography showed no significant lesions in the
      bypass grafts and total occlusions of the proximal left anterior descending
      artery and mid circumflex artery. Dobutamine stress echocardiography was
      performed to evaluate the severity of aortic stenosis and left ventricular
      functional reversibility. Administration of dobutamine increased the mean
      pressure gradients to 48 mmHg and increased the stroke volume by 28% without
      change in aortic valve area of about 0.5 cm2. We considered that our patient had
      severe aortic stenosis with contractile reserve. After aortic valve replacement,
      he improved with better left ventricular function.

PMID- 15017789
TI  - [An 85-year-old man with diabetes mellitus presenting with edema of the
      extremities].

PMID- 15017791
TI  - Starting a student-focused teaching revolution.

PMID- 15017792
TI  - The recent tragic events surrounding the Charles Cullen case.

PMID- 15017793
TI  - Developing abstracts for workshops and conferences: improve your chance of
      acceptance.

PMID- 15017794
TI  - Standardized patient experiences: evaluation of clinical performance and nurse
      practitioner student satisfaction.
AB  - Standardized Patients (people trained to accurately portray a specific patient)
      have been widely used by medical schools and, to a lesser degree, by schools of
      nursing as a method for evaluating clinical performance. These trained patients
      provide a viable method for teaching and evaluating nurse practitioner students
      as they progress through their educational programs toward clinical competency.
      Evaluation using Standardized Patient Experiences provides objective and valid
      information regarding students' synthesis of didactic information and abilities
      to apply knowledge in the clinical setting. The purpose of this article is to
      describe the implementation of Standardized Patient Experiences across a
      curriculum for family nurse practitioner and adult geriatric nurse practitioner
      students. Students evaluated the experiences throughout the curriculum and
      overwhelmingly found them to be realistic, challenging, and of value to their
      programs of study.

PMID- 15017795
TI  - Clinical education initiative in the community: caring for patients with
      congestive heart failure.
AB  - With greater numbers of chronically ill clients cared for in their homes rather
      than in acute care hospitals, nursing schools need to create and implement
      innovative strategies for experiences in the community setting. A telephone
      intervention program was initiated in the last semester of the medical-surgical
      clinical course to promote the health of patients with congestive heart failure
      and provide meaningful community experiences for senior nursing students.
      Students' journals from this semester-long clinical experience were analyzed and
      showed outcome benefits to both patients and students.

PMID- 15017796
TI  - Comfort levels of nursing students regarding clinical assignment to a patient
      with AIDS.
AB  - For educators, preparing nursing students for the care of persons with AIDS is an
      important responsibility. A review of the literature suggests that many nursing
      students are fearful of occupational transmission of HIV and that educational
      interventions may improve the students' attitudes toward caring for patients with
      AIDS. The author administered Form A of the Nursing Care Comfort scale to a
      sample of 122 baccalaureate students. Findings revealed variations in comfort
      levels relative to specific nursing skills.

PMID- 15017797
TI  - TNEEL workshop. Interactive methods for teaching end-of-life care.
AB  - Nurse educators have identified lack of end-of-life content as a serious deficit
      in undergraduate nursing education. TNEEL, a new software program with tools for
      teaching end-of-life topics, was created to help educators overcome this problem.
      The authors implemented an experiential workshop to help educators learn how to
      use TNEEL's wide variety of educational tools. Trainers provided information
      about TNEEL and coached participants (N = 94) as they practiced using laptop
      computers to increase their familiarity and comfort in using the toolkit.
      Workshop participants completed pre- and posttest evaluations addressing their
      opinions and beliefs about using this computer tool. Findings support the
      workshop as an effective way to facilitate adoption of this innovative
      educational resource and support the development of a nation-wide training plan
      for TNEEL with experiential workshops.

PMID- 15017798
TI  - Curriculum evaluation. Who, when, why, how?
AB  - The faculty of a large, Midwestern, public university implemented a community
      based baccalaureate curriculum to prepare students for the changing health care
      environment. Evaluation was planned as the curriculum was developed. The
      constituents of the School of Nursing were determined to be the students, alumni,
      employers, clinical agencies, and faculty. Surveys, focus groups, questionnaires,
      and meetings with agency representatives were some of the methods used to gather
      data from the constituents. Information gathered during a three-year period
      resulted in further curriculum revision, increased community partnerships, and
      more positive feedback from students.

PMID- 15017799
TI  - Innovation in nursing education: a call to reform.

PMID- 15017800
TI  - It's time for a change, one way or another.

PMID- 15017801
TI  - Vegetable oil sprinkling as a dust reduction method in swine confinement.
AB  - The aim of this project was evaluate the effectiveness of an oil sprinkling
      system as a dust-reduction method for swine production facilities. This article
      presents the results of the second-year experiment of a multi-year study. The
      first-year experiment demonstrated that a 5% oil-water emulsion automatically
      applied at the rate of 3 and 5 g/pig/day achieved a 23% to 34% reduction in total
      dust. The modifications for the second year experiment included: (1) increasing
      oil application rate to 7 and 8 g/pig/day, (2) replacing sprinkler heads to
      achieve a smaller droplet size and a more direct spray pattern on pen-floor
      surfaces, and (3) more closely matching the treatment and control rooms by stage
      in the pig production cycle. Four swine finishing rooms were used for this study;
      two were treatment rooms (soybean oil at 7 g/pig/day, and canola oil 8 g/pig/day)
      and two were control rooms. The treatment rooms had a low-pressure oil-sprinkling
      system, which sprinkled 5% oil-to-water mixture 12 times per day, 12 s each time.
      Concentrations of several environmental contaminants were measured. The average
      total dust concentration in the control rooms was 1.39 mg/m3. The average total
      dust concentration in the treatment rooms was 0.65 mg/m3. The treatment reduced
      dust by an average of 52%, (p = 0.0001). There was no difference in the degree of
      dust control between soybean oil and canola oil. The respirable dust
      concentrations were very low in all rooms, and there were no significant
      differences between rooms in ammonia, carbon dioxide, temperature, or humidity.

PMID- 15017803
TI  - On-farm falls among youth less than 20 years old in the U.S.
AB  - This article examines the magnitude and characteristics of fall-related injuries
      on U.S. farms for youth less than 20 years old for work and non-work exposures at
      a national level. To examine the problem, data from the Childhood Agricultural
      Injury Survey (CAIS) and Census of Fatal Occupational Injuries (CFOI) were used.
      Findings indicate that falls are an important contributor to on-farm injuries,
      with youth appearing to be at considerable risk. Thus, a reduction of the
      exposure of youth to fall-related hazards on farms is needed. Strategies such as
      providing safe play areas for young children and continuing efforts to prevent
      extra riders on farm equipment will help in reducing these hazardous fall
      exposures.

PMID- 15017802
TI  - Operational characteristics of tractors driven by children on farms in the United
      States and Canada.
AB  - Farm tractors are an important source of traumatic injury for children on farms.
      There is, however, no documentation about the age and size of tractors that
      children are operating and little information about the frequency with which
      rollover protective structures (ROPS) are used. This study described tractors
      that children on farms in the U.S. and Canada were operating by age, horsepower,
      and the presence of ROPS, according to the age and gender of the farm children
      involved. As a sub-analysis of data compiled during a randomized controlled
      trial, a descriptive analysis was completed on work exposure data collected by
      telephone interview. Of the 1,113 children involved in the trial, 522 (47%) were
      reported to perform at least one job that involved the operation of a farm
      tractor, and 408 (36.7%) were operating tractors of at least 20 horsepower. The
      majority of these children were male. There was a wide range of ages and sizes of
      tractors operated. However, the majority of tractors were between 20 and 70
      horsepower and manufactured after 1970. Nearly one-half of the tractors were
      equipped with ROPS, and these tended to be newer and larger tractors. This
      analysis provides new data about the broad range of tractors driven by farm
      children in the U.S. and Canada. The findings point to a need to re-examine the
      reliance on a single voluntary standard to mitigate the hazard of tractor
      rollovers and the need for an enhanced safety policy requiring all tractors
      operated by children be equipped with ROPS.

PMID- 15017804
TI  - Management as a risk factor for farm injuries.
AB  - The organizational injury theory focusing on management issues could provide new
      viewpoints on causes and prevention of injuries in agriculture. The objective of
      this study was to test whether the quality of farm management is associated with
      farm injuries. A cohort of 134 farms was used to examine the relationship between
      farm injuries and selected management, farm, and farm operator characteristics.
      The number of machines and musculoskeletal disorders were found to be risk
      factors for injuries (RR = 2.34, 95% CI 1.27-4.31, and RR = 1.75, 95% CI 1.14
      2.69). Management quality (significant work delays) was associated with injuries
      (RR = 1.59, 95% CI 1.00-2.52) in univariable analysis but not in the
      multivariable model. Although the results for the association between injury and
      management quality were not conclusive, this line of research should be
      continued.

PMID- 15017805
TI  - Injuries in the Iowa Certified Safe Farm Study.
AB  - The aims of this article are to assess injury characteristics and risk factors in
      the Iowa Certified Safe Farm (CSF) program and to evaluate the effectiveness of
      CSF for reducing injuries. This intervention program includes a health screening,
      on-farm safety review, education, and monetary incentives. Cohorts of farmers in
      an intervention group (n = 152) and control group (n = 164) in northwestern Iowa
      were followed for a three-year period. During the follow-up, there were 318
      injuries (42/100 person-years), of which 112 (15/100 person-years) required
      professional medical care. The monetary cost of injuries was $51,764 ($68 per
      farm per year). There were no differences in the self-reported injury rates and
      costs between the intervention and control groups. Raising livestock, poor
      general health, and exposures to dust and gas, noise, chemicals and pesticides,
      and lifting were among risk factors for injury. Most injuries in this study were
      related to animals, falls from elevation, slips/trips/falls, being struck by or
      struck against objects, lifting, and overexertion. Machinery was less prominent
      than generally reported in the literature. Hurry, fatigue, or stress were
      mentioned as the primary contributing factor in most injuries. These findings
      illustrate the need for new interventions to address a multitude of hazards in
      the farm work environment as well as management and organization of farm work.

PMID- 15017806
TI  - Agenda for Change update.

PMID- 15017807
TI  - Is image important?

PMID- 15017808
TI  - Sense of purpose.

PMID- 15017809
TI  - Birth rights.

PMID- 15017810
TI  - Post-transplant challenge.

PMID- 15017811
TI  - Better than you think.

PMID- 15017812
TI  - Screen saver.

PMID- 15017813
TI  - Hard to measure.

PMID- 15017814
TI  - Primary Sjogren's syndrome.
AB  - This article aims to raise awareness of the chronic autoimmune rheumatological
      disorder Sjogren's syndrome. It describes the main symptoms, diagnosis and
      management of patients with primary Sjogren's syndrome. It is applicable to
      nurses working in primary and secondary care settings and offers advice on how
      they can support such patients with protective and preventive measures.

PMID- 15017815
TI  - Quality in colposcopy.
AB  - This article analyses the colposcopy service, which is a crucial part of the
      National Health Service Cervical Screening Programme (NHSCSP), to assess how
      quality is measured and delivered. It highlights the role of the nurse
      colposcopist and discusses where improvements to the service could be made.

PMID- 15017816
TI  - Cardiomyopathy.
AB  - Cardiomyopathy is a disease of the heart muscle. There are four main types of
      cardiomyopathy and each can affect people differently. This article discusses the
      signs and symptoms, diagnosis and treatment for the different types of  the
      disease, the importance of genetic screening and risk stratification, and the
      nurse'a role in patient management.

PMID- 15017817
TI  - Squaring the circle.

PMID- 15017818
TI  - Prescription drugs uses and effects. Non-steroidal anti-inflammatory drugs.

PMID- 15017819
TI  - To err is human. Developing safer health care delivery systems.

PMID- 15017820
TI  - Dietary strategies for cholesterol reduction--do they work?

PMID- 15017822
TI  - Giving voice to important social issues through the performing arts.

PMID- 15017821
TI  - Molecular medicine: a primer for clinicians. Part XIV: Stem cells.
AB  - Earlier papers in this series have described many of the tools of molecular
      biology that are finding practical bedside applications. We have reviewed how
      molecular diagnostics, genetic testing, and DNA and protein microarrays all have
      become part of clinical medicine. We have also described the potential of the
      human genome project to impact the practice of medicine. Finally, we have
      discussed several ethical issues, including genetic screening, forensic DNA
      testing, and gene therapy. In this paper, and the next, we will discuss two
      topical areas in which molecular biology may influence how medicine is practiced
      in the future; stem cell research and cloning technology.

PMID- 15017823
TI  - Psychopathy and sexual deviance in treated rapists: association with sexual and
      nonsexual recidivism.
AB  - This study examined the role of the Psychopathy Checklist-Revised (PCL-R; R. D.
      Hare, 1991) and sexual deviance scores in predicting recidivism in a sample of 94
      convicted rapists involuntarily admitted to a Dutch forensic psychiatric hospital
      between 1975 and 1996. The predictive utility of grouping offenders based on the
      combination of psychopathy and sexual deviance was also investigated. Measures
      were coded from pre-release institutional records. Recidivism (reconviction) data
      were retrieved from the Judicial Documentation Register of the Ministry of
      Justice and were related to PCL-R and sexual deviance scores. The follow-up
      period after release ranged up to 23.5 years (M = 11.8 years). Base rates for
      sexual, violent nonsexual, violent (including sexual), and general recidivism
      were 34%, 47%, 55%, and 73%, respectively. For all types of offending, offenders
      scoring high on the PCL-R (> or = 26) were significantly more often reconvicted
      than other offenders. The sexual deviance score was found to be a significant
      predictor of sexual reconviction. Survival analyses provided considerable
      evidence that psychopathic sex offenders with sexual deviant preferences are at
      substantially greater risk of committing new sexual offenses than psychopathic
      offenders without deviant preferences or nonpsychopathic offenders with or
      without sexual deviance. The findings are discussed in terms of their practical
      and clinical implications.

PMID- 15017824
TI  - Stability of the interpretative risk percentages for the RRASOR and Static-99.
AB  - Current procedures to estimate sex offender recidivism risk typically involve
      actuarial instruments, either alone or in combination with adjustments based on
      other considerations. Two of the most commonly employed actuarial instruments for
      the assessment of sexual recidivism risk are the Rapid Risk Assessment for Sex
      Offender Recidivism (RRASOR; R. K. Hanson, 1997) and the Static-99 (R. K. Hanson
      & D. Thornton, 2000). Although multiple studies of the interrater reliability and
      predictive validity of these instruments have been completed, with very
      supportive results, there have to date not been any studies of the degree to
      which the specific risk percentages attached to each instruments score replicate
      and remain stable despite changes in underlying samples' recidivism base rates.
      This study, using data from multiple sources, investigated this issue. The
      findings indicated that the 5-year risk percentages for the RRASOR were
      replicated and were remarkably stable despite changes in the samples underlying
      recidivism base rate. The Static-99 5-year risk percentages were mostly
      replicated and were stable across varying base rates, but to a lesser degree than
      was found for the RRASOR. Implications of these results are discussed.

PMID- 15017825
TI  - A comparison of relational attitude and personality disorders in the explanation
      of child molestation.
AB  - This study examined parental sensitivity, relational attitude (i.e., trust,
      friendship, adult romantic attachment), and personality disorders in the
      aetiology of sexual offences among a group of 84 child molesters and a matched
      normal control group (n = 80). The child molesters were selected from either a
      community-based, educational training program (n = 51), or a Belgium prison (n =
      33). Analyses using structural equation modeling found that both relational
      attitude and personality disorders differentiated between the child molesters and
      the comparison group. Implications for the aetiology and treatment of child
      molesting is discussed.

PMID- 15017826
TI  - Engagement, denial, and treatment progress among sex offenders in group therapy.
AB  - This study investigates the relationship between engagement, denial, and
      treatment progress among a sample of 61 male sex offenders in outpatient group
      therapy. Three hypotheses were posed: (1) that denial is inversely related to
      engagement in group therapy; (2) that denial is inversely related to treatment
      progress, and (3) that engagement is correlated with treatment progress. Results
      revealed a strong correlation between engagement in group therapy, measured by
      the Group Engagement Measure, and sex offender treatment progress, assessed by
      the Sex Offender Treatment Rating Scale. Denial, measured by the Facets of Sexual
      Offender Denial Scale, demonstrated a strong inverse relationship to treatment
      progress. Engagement and denial were also strongly inversely related. Together,
      engagement and denial explained a significant amount of the variance in treatment
      progress. The findings provide support for current standards of practice that
      maintain that admitting to a sex crime is a necessary condition for progress and
      engagement in treatment. Strategies for increasing engagement and treatment
      progress, and reducing denial, are discussed.

PMID- 15017827
TI  - Approach versus avoidance goals in relapse prevention with sexual offenders.
AB  - Relapse prevention (RP) plays a major role in the vast number of treatment
      programs for sexual offenders. However, despite its widespread application,
      questions have been raised regarding the uncritical adoption of the approach (R.
      K. Hanson, 1996). More specifically, the way in which it is presented to sexual
      offenders has been criticized for being unhelpfully negative in focus (Mann,
      2000) and it has been suggested that treatment should adopt a broader focus on
      improving quality of life (T. Ward and C. A. Stewart, 2003), with the expectation
      that recidivism would reduce as a side-effect. The current study evaluated two
      orientations to relapse prevention, comparing a deliberately positively-focused
      orientation, focusing on creating a "good life," to the more traditional approach
      that focuses on avoiding and controlling risk factors. Twenty-four participants
      completed an approach-focused RP intervention and 23 completed an avoidance
      focused RP intervention. Results indicated that participants who completed the
      approach-focused intervention had a greater engagement in treatment as measured
      by homework compliance and willingness to disclose lapses. Furthermore,
      participants within the approach-focused intervention were rated by therapist to
      be more genuinely motivated to live life without offending by the end of
      treatment. However, differences between the groups in terms of self-esteem change
      following treatment were not very marked. These results are discussed in terms of
      their implications for treatment delivery.

PMID- 15017828
TI  - A comment on the first report.

PMID- 15017829
TI  - ACHE's corporate partners. ACHE's program provides a forum in which provider
      supplier partnerships flourish.

PMID- 15017830
TI  - Interview with ACHE's incoming chairman. Interview by Ellen Lanser May.

PMID- 15017831
TI  - Aligning the stars: creating dialogue within healthcare teams.

PMID- 15017832
TI  - Spiritual leadership: a new model.
AB  - Recent unethical business practices of some corporations and the overall loss of
      confidence by the public in corporate leadership have given rise to a unique
      leadership model--one that focuses on spirituality. "Ninety percent of our
      diverse American population and health-care workforce have spiritual and
      religious beliefs. While these beliefs may be mystical, religious, or secular,
      there are many common patterns that influence change and leadership within our
      organizations." So says Gary Strack, CHE, president and chief executive officer
      of Boca Raton (FL) Community Hospital. Strack presented a seminar on the topic at
      ACHE's 2003 Congress on Healthcare Management.

PMID- 15017833
TI  - Leadership. The tasks of collaborative leaders.

PMID- 15017834
TI  - Executive skills. How to negotiate effectively.

PMID- 15017835
TI  - Why good people behave badly. An organization's culture and values can influence
      behavior.

PMID- 15017836
TI  - Optimizing your technology investment. How can you obtain the best or quickest
      return on your investment?

PMID- 15017837
TI  - Today's crusader for tomorrow's leaders. Texas Children's Leadership University
      hones skills via a unique forum.

PMID- 15017838
TI  - Specialized teams complement nursing. Patient satisfaction begins with satisfied
      professional and support teams.

PMID- 15017839
TI  - Membership card fosters communication. A hospital connects with residents of its
      rural Maine community.

PMID- 15017840
TI  - The new Medicare drug law. Analysts provide a "view from Washington" on this far
      reaching initiative.

PMID- 15017841
TI  - Recovering from a career setback. A mistake doesn't have to derail your career
      plans.

PMID- 15017842
TI  - Mission complete. Organizing supplies is DreamWeaver's quest.

PMID- 15017843
TI  - The choice is yours.

PMID- 15017844
TI  - The ups and downs of inventory management.

PMID- 15017845
TI  - [Variants of human immunodeficiency virus type 1, detected in Russia among those
      infected by the sexual route].
AB  - We analyzed 52 blood samples obtained independently from among individuals, who
      had never practiced the intravenous administration of drugs, for the purpose of
      detecting the subtypes of HIV-1 that circulated during 1999-2002. The study
      materials were analyzed by the methods of gag/env heteroduplex mobility assay and
      by env gp120 C2-V3 sequencing. Four viral subtypes (A,B,C and G) and a
      recombinant gagA/envB were detected in subjects contaminated through heterosexual
      contacts. Noteworthily, HIV-1 variations of subtype A, which were found in 22
      (73.3%) of 30 analyzed samples, were predominant in this risk group. An analysis
      of nucleotide sequences exposed a high degree of homology between the viruses,
      detected previously among drug-addicts, and the isolates detected by us in
      subjects contaminated heterosexually. However, HIV-1, subtype B, detected by us
      in all 16 studied cases, still continue to circulate among the males infected
      through homosexual contacts with men.

PMID- 15017846
TI  - [Role of stabilizing and splitting selection in evolution of of viruses from the
      Parvoviridae and Astroviridae families].
AB  - We had previously collected and analyzed, by phylogenetic methods, all genetic
      data available now for the Parvoviridae and Astroviridae families, which made it
      possible to define the evolutionary relations between the viruses as well as to
      depict a variety of events in the evolutionary history of the two families. The
      offered case study is dedicated to investigating the stabilizing and splitting
      selection types in the evolution of the discussed viral families. We analyzed the
      number of synonymous and non-synonymous nucleotide substitutions in the coding
      genomes' regions of the viruses. Finally, the stabilizing selection was shown to
      be a key factor in the evolution of parvoviruses and astroviruses.

PMID- 15017847
TI  - [Subtypes of HBsAg of the hepatitis B virus in Western Siberia].
AB  - HBs antigens were subtyped in blood samples of intravenous drug-addicts (IDA) and
      of donors from as many as 10 cities of Western Siberia by using the immune-enzyme
      assay with 6 high-specific monoclonal antibodies. Two HBsAg subtypes were found,
      in a ratio of 3% ayw2: 97% ayw3 (varA and varB), in IDA blood samples from
      Novosobirsk. Three HBsAg subtypes were found, in a ratio of 57% ayw2: 42% ayw3
      (varA and varB): 1% adw2, in the donors' blood samples. The obtained data are
      sufficient for developing the first national sera panel containing different
      HBsAg subtypes of hepatitis B virus typical of Russia.

PMID- 15017848
TI  - [Evaluation of morbidity and etiological structure of acute and chronic viral
      hepatitis in the Sakha Republic (Yakutiia)].
AB  - The morbidity of viral hepatitis was epidemiologically analyzed and the
      etiological structure of severe and chronic viral hepatitis was studied in the
      Republic of Sakha (Yakutia). Acute viral hepatitis B, whose portion is 43.5%, was
      found to be of the key significance within the structure of acute viral hepatitis
      (AVH). Acute viral hepatitis C (with 4.7% in the AVH structure) is by far more
      rare. The latter is close to the value registered in other Russia's regions.
      Apart from the prevalence of viral hepatitis B (32.4%) an exceptionally high
      share of chronic hepatitis delta (24.5%) was established for the etiological
      structure of chronic viral hepatitis, which is a specificity of the discussed
      region. The epidemic situation in the Republic of Sakha (Yakutia) was stated to
      be linked with the mentioned extra dangerous diseases, which requires appropriate
      emergency measures with the prevention vaccination program against hepatitis B
      being a priority.

PMID- 15017850
TI  - [Cytokine status of patients with ophthalmic herpes].
AB  - Data are reported on the content of pro- and antiinflammatory cytokines in blood
      serum and lachrymal fluid of 62 patients with ophthalmoherpes. It was concluded
      that the cytokine profiles are subject to changes in the eye herpes: the IL-6 and
      IL-4 contents were increasing in blood serum, while IL-1 beta and TNF-alpha were
      increasing in lachrymal fluid. The content of cytokine in blood serum is
      different from such content in lachrymal fluid in surface-type and profound
      variations of ophthalmoherpes. Disbalance of inflammatory IL-1 beta, IL-6, TNF
      alpha and IL-4 are typical of the latter case, which can be used clinically to
      evaluate a disease severity degree.

PMID- 15017849
TI  - [Polymorphism of herpes simplex virus type 1 and 2 DNA from laboratory strains
      and clinical material from patient with genital herpes].
AB  - Polymerase chain reaction (PCR), that can amplify a fragment of the DNA
      polymerase gene of 4 herpes viruses, i.e. herpes simplex viruses, type 1 (HSV-1),
      herpes simplex viruses, type 2 (HSV-2), Epstein-Barr virus and cytomegalovirus,
      was made use of to study the genetic polymorphism of HSV-1 and HSV-2 strains. The
      obtained amplicons were analyzed by the method of restriction-size fragments'
      polymorphism (RSFP) with restrictases Rsal, Taql and Hinfl. Four HSV-1 strains
      had an identical restriction profile. Strain G (HSV-2) also displayed the
      expected restriction profiles, however, contradictory results were obtained for
      strain BH (HSV-2): the restriction profiles with restrictases Hinfl and Rsal
      corresponded to HSV-2, and the restriction profile with Taql corresponded to HSV
      1. The sequencing of appropriate fragments of strains G and BH revealed a dot
      type mutation localized in Taql restriction site. The thus worked out PCR was
      used jointly with RSFP in the genotyping of 75 urogenital samples obtained from
      women with genital herpes who were treated at Moscow patient-care facilities. HSV
      1 and HSV-2 were detected in 18 (24%) and 57 (76%) of samples, respectively. No
      changes were registered in the restriction profile for HSV-2 among the
      investigated samples and all of them had the restriction profile similar to that
      of strain G. The conclusion is that genital herpes associated with HSV-2 is
      genetically stable within its Moscow population.

PMID- 15017851
TI  - [Outbreak of enteroviral infection in Vitebsk during pollution of water supply by
      enteroviruses].
AB  - The conducted virologic, serological and molecular-and-biological investigations
      showed that virus Coxsakie B4, isolated from cerebrospinal fluid and
      rhinopharyngeal lavages of patients, was the main etiological agent, which caused
      mainly an outbreak of enterovirus infection in the city of Vitebsk in 2001.
      Coxsakie B4 viruses were found in 30% of samples by using the cultural method and
      in 76.9% of samples--by polymerase chain reaction (PCR) while carrying out the
      sanitary-and-virologic investigations in drinking water, including in infection
      foci. Besides, we found infectious non-cytolitic enteroviruses (EV) with changed
      biological properties (which could not be detected by the classic cultural
      method) in drinking water by using the method of PCR integrated with cell culture
      in the "-" strand of EV RNA. Peculiar clinical-and-epidemiological
      characteristics of the disease outbreak, i.e. "explosive" onset, multiple
      clinical forms, mixed EV infections and disease decay after drinking-water
      chlorination, as well as the isolation of one and the same EV serotype from
      patients and from water testify to a possible water origin of the outbreak.

PMID- 15017852
TI  - [Algorithm for predicting development of HIV infection].
AB  - Described in the paper are the results of a 15-year monitoring (1986-2001) of HIV
      patients at the Clinic of the Institute of Immunology, Federal Department
      "Medbioextreme", Russia's Health Ministry. The gathered experimental data,
      including the immunologic, biochemical and general-clinical parameters, were
      comprehensively analyzed. Optimal schemes of complex HIV monitoring were designed
      to ensure a comparative and dynamic study of different clinical-and-laboratory
      indices for the purpose of defining the HIV-induced pathogenesis specificity and
      adequate therapeutic approaches.

PMID- 15017853
TI  - [Typing of cattle leukemia virus circulating in the Ukraine].
AB  - Bovine leucosis virus (BLV), circulating in the Ukrainian territory, was
      characterized through the definition of its subspecies affiliation. The pro-viral
      BLV DNA was isolated from peripheral-blood lymphocytes of naturally-HIV-infected
      black-variegate animals taken from leucosis-affected farms in the Kharkov Region.
      The env-gene fragment of pro-viral DNA was amplified, sequenced and analyzed
      after the amplicon had been treated by three restriction enzymes, i.e. BamH I,
      Bcl I and Pvu II. According to the analysis of restriction-fragments' length
      polymorphism, the Ukrainian BLV isolate can be classified as belonging to the
      Australian subspecies, i.e. to one of the 3 known subspecies. Multiple alignment
      and phylogenetic analysis of the env-gene fragment of BLV isolates from the EMBL
      database showed that evolutionally the Ukrainian isolate is distantly located
      from the isolates' clusters of the Belgian, Japanese and Australian subspecie and
      has the biggest quantity (4) of non-coinciding nucleotides for the analyzed
      highly conservative locus of the BLV env-gene with a length of 444 pair of
      nucleotides.

PMID- 15017854
TI  - [Production of full length DNA copies of genomic segments of influenza virus
      using DNA recombination in the process of polymerase chain reaction].
AB  - The case study comprises a description of a method used for producing the full
      length cDNA complementary to influenza virus segments made through the
      recombination of homologous DNA fragments in the process of polymerase chain
      reaction (PCR). The detailed protocol of the method is presented alongside with a
      discussion of the advantages of the suggested approach.

PMID- 15017856
TI  - [Controversies in the treatment of shock].
AB  - In last years there are still dilemmas about the starting of prompt resuscitation
      by volume restoring in haemorrhagic shock in penetrant, non-penetrant and
      vascular injuries. Will massive fluid administration before surgical control of
      bleeding, because of destroying the primary thromb, induce excessive bleeding and
      worse outcome, in regard to postponed resuscitation until the control of
      haemorrhage? What means that less fluid should be given, less than optimal, but
      in the quantity with which progressive circulatory shock will be avoided.
      According to some authors this should be followed in the treatment of non
      penetrant injuries, what has been shown positive in animal models. There is also
      dilemma about the kind of fluid, crystalloids and what crystalloids, or colloids?
      Crystalloids are preferred, especially to Ringer lactat, except in the cases of
      traumatic brain injury when saline is better, because of mild hyperosmolarity.
      Hypertonic solutions 7.5% NaCl and 3% NaCl have advantages for prehospital
      resuscitation. As the advantages of colloids in regard to crystalloids were not
      proven, they should be used together with crystalloids, if the blood products are
      not available at the moment, and they should be given. It is considered that
      about 25% of overall colloid used is not justified. In the assessment of shock,
      i.e. tissue perfusion which is the most important parameter of shock, modern
      technologies measure systemic oxygenation SO2 as a balance of oxygen delivery DO2
      and oxygen consumption DO2 and mixed venous blood PCO2. Noninvasive monitoring
      replaces invasive, and it can be even more precise and more accurate in parameter
      assessment. Sublingual capnography is new monitoring as indirect indicator of gut
      mucose perfusion and impedance monitoring which functions by means of measuring
      the changes of electrical impedance of thorax which are proportional to the pulse
      wave in aorta during systole and diastole.

PMID- 15017858
TI  - Creating effective clinical audit in anaesthesia.
AB  - Audit or simply quality control concept has been introduced for more than 10-15
      years in the UK. A brief introduction about its characters and importance will be
      discussed with more stress on the practical aspects of it. To achieve clinical
      effectiveness in Anesthesia or in ITU more than one issue should be addressed.
      The following are examples of issues that could be audited for a better
      performance: Admission selection (polices), The length of stay Management
      guidelines, Responsibilities, Daily assessment and plan, Discharge policies,
      Readmission prevention, Interhospital transfer, Bed blockers prevention. Two
      audit examples from theatre and ITU will be discussed in details. Theatre audit
      deals with causes of delays in theatre and over running lists. ITU audit
      addresses the time lagged between admission and first assessment by the admitting
      firm from the day of admission onward. Lessons to be learned from these two
      audits are: Address something you are not happy with, Meeting standards (what if
      there are no standards), Agree audit methodology in advance, A real life problem
      justifiably taken even for the first time, Even if no successful outcome at least
      people are aware or there is a trial to solve the problem. Solution may be by:
      protocol, identifying responsibilities, rota changes. Finally the importance of
      selecting what should be audited and monitoring these audits will be highlited.

PMID- 15017857
TI  - Prevention of nosocomial infections in ICU. What is really effective?
AB  - In South East of France, about 20% of the ICU patients with a length of stay > or
      = 2 days will develop a nosocomial infection (NI) related to an invasive device.
      This elevated rates of NI (the most elevated in the hospital) are related to the
      usual severity of patients, the use of invasive devices such as indwelling
      arterial catheter, central venous catheter, intubation and bladder catheter.
      These two characteristics are associated with an important antimicrobial
      consumption and a subsequent selection of resistant bacteria. The techniques
      which could be used in the prevention of NI have now proved to be effective. They
      are hand disinfection, non sterile gloves utilization and a rationale use of
      mask, gowns. The application of these measures are known as Standard Precautions,
      recommended by the CDC. The specificity of prevention in ICU is questionable,
      since many measures can be applied in ICU, anesthesia or surgery. In the
      prevention of NI in ICU, without any doubt, the most important (but the most
      difficult to achieve) is the strict respect of standard precautions. To achieve
      this goal, the best investment is alcoholic hand rub. Among the specific
      measures, maximum barrier precaution for CVC insertion, reduction of indication
      and duration of invasive device exposure. The real challenge is to apply few
      effective measures, but accepted, associated with behavioural changes and whose
      compliance is measured.

PMID- 15017860
TI  - [Effect of surgical trauma on patient nutritional status].
AB  - The acute phase response to sudden illness or trauma is one of the most basic
      features of the body's defenses against injury. This response includes:
      alterations in amino acid distribution and metabolism, an increase in acute phase
      globulin synthesis, increased gluconeogenesis, reductions in serum iron and zinc
      levels, increased serum copper and ceruloplasmin levels, as well as negative
      nitrogen balance. Changes in the nutritive status follow as a consequence of
      these changes. Phylogenetically, this response could be considered the most
      primitive, even though new reports from literature suggest that the nutritive
      status of patients is an important medical category due to several reasons. It is
      known that 30%-60% of the patients have changes in the nutritive status, when
      admitted in a hospital. It is also known that 30%-45% of the patients will
      develop changes in the nutritive status during hospitalization. The aim of this
      study is to analyse the influence of operative trauma on the nutritive status of
      the patients through evaluation of the following nutritive markers: body weight
      and mass, albumin and total protein levels in serum, level of transferine and
      haptoglobine, and loss of nitrogen and proteins. The subjects were surgical
      patients (at the age of 16 to 60) divided into three groups according to the
      severity of the operative trauma (small, medium severe and heavily severe
      trauma). The results indicated the following: the loss of body weight, nitrogen
      and proteins is dependent upon the severity of the operative trauma and the
      transverine and haptoglobine levels are in positive significant correlation with
      the severity of the operative trauma.

PMID- 15017859
TI  - [Combined spinal epidural and general anesthesia in abdominal surgery].
AB  - Almost ten years has past since Eldor described combined spinal-epidural-general
      anaesthesia (CSEOGA) as a new concept in anaesthesia in which all of these
      components can be used, with sub-anaesthetic doses of drugs, due to its sinergist
      effect. The clinics studies has not demonstrated crucial advantages CSEGA
      comparing with combined epidural-general anaesthesia (CEDGA), in sense of
      analgesia, pulmonary function and neuro-hormomal inhibition. However we have been
      routinely practising our technique CSEGA in big abdominal and thoraco-abdominal
      surgery, since 1997. This study is a retrospective analysis of our technique and
      clinic observations, during 4.5 years, which include 293 patients. Their
      demographic characteristics can be seen in table 2. We perform combined spinal
      epidural anaesthesia (CSE) in one or two interspinal spaces, depending on the
      type of surgery, but always before induction in general anaesthesia (GA). For
      preemptive and intraoperative analgesia we use 0.25% plain bupivacaine (B), both
      for spinal (SA) and epidural (ED) blockade. The most important detail in our
      technique, despite precise order to administrate drugs, is analgesic solution
      (AS) which contain B 4.5 mg, fentanyl (Fe) 50 mcg and morphine hydrochloride (Mo)
      0.2 mg, in total volume of 3 ml, in SA. After the ED test dose with 2% lidocaine
      60 mg (3 ml), before the induction in GA, we inject more 10 ml B, but
      intraoperative analgesia is almost performed with B 3 to 5 ml in intermittent
      bolus doses. This ED bolus dosis is particularly important, partly to
      sufficiently cephalic migration of the SA somatosensorieblock, as well as for
      intraoperative analgesia. For very light GA only artificial ventilation with 66%
      N2O in O2 and muscle relaxation with paneuronium is needed. Co analgesia with
      intravenous (i.v.) Fe, was exceptionally seldom needed, except for induction.
      Intraoperative drugs consumption was very small as we see in table 5. With
      adequate liquid compensation, this technique achieve exceptionally intraoperative
      homodynamic stability in patients, despite to long and big operations.
      Postoperative analgesia are supplied by SA the first 24 hours, but the next 72
      ours is performed with intermittent ED bolus doses of 0.12% B with 2 mg Mo in
      total volume of 15 ml and 10 ml, depending on the epidural catheter (EDK)
      position in lumbar or thoracic part of spine. The break through of postoperative
      pain was between 20% to 34%, which was suppressed with metamisol. According to
      the verbal rating scale (VRS < 1) 90% patients were satisfied with this
      analgesia, which gave possibilities to mobilization and rehabilitation even the
      first postoperative day. All clinical sings show that thanks to inhibition of
      spinal and supraspinal sensitization, all principles of the preemptive analgesia
      (PA), inhibition of neuro-hormonal stress reaction are met and postoperative
      outcome is improved and satisfied. The complications we had were insignificant,
      in time observed and without any consequences.

PMID- 15017861
TI  - [Administration of Voluven, a plasma expander, in emergency medicine].
AB  - HAES 130/04 Voluven is a new coloid plasma expander with better farmacokinetic
      properties as other well-known HAES solutions. It's reflected with quick volume 1
      effect, plato takes about 4 and its clinical effect lasts for 6 hours. Voluven is
      metabolised by alfa-amilase and eliminated through kidney in 24 hours.
      Anafilactoid reactions are very rare, pruritus appears only with extensive long-
      term use. Voluven interferes with haemostasis less than other HAES solutions.
      With its use needs for homologic blood transfusion are diminished. Activated
      FVIII, PTT and time for tromb formation reach the preoperative values
      significantly earlier when Voluven is used. Voluven does not accumulate in plasma
      and tissue if used frequently. That's why greater daily amounts (50-70 ml/kg/day)
      are recommended. Voluven is not contraindicated in renal insufficiency until
      there is urine production. Recent studies show that, in severe head trauma,
      there're less complications with sudden ICP rise, less second haemorrhagic and
      mechanical ventilation is abbrevated with Voluven. Greater tissue pO2 values on
      the first postoperative day prove better microperfussion and less oedema of
      endothelial cells in shock with Voluven application. Owing to these distinguished
      properties Voluven has a role in treatment of traumatic and haemorrhagic shock.

PMID- 15017862
TI  - [Local anesthesia in ophthalmologic surgery].
AB  - Operations of the anterior segment of the eye are dominant in ophthalmic surgery.
      It is a lesser known fact that these are the most common elective surgical
      procedures of all. There has been a dramatic change of anaesthetic practice for
      ophthalmic surgery over the last twelve years. LA is the anaesthetic of choice
      nowadays unless contraindicated. These changes were brought about due to the fact
      that anaesthetists initially became involved and then took over the performance
      of LA in ophthalmology. Peribulbar technique was introduced in 1986 as a safer
      alternative to retrobulbar anaesthesia. The needle tip is placed outside the
      muscle cone (in the peribulbar space). Adequate eyelid blockade and good hypotony
      of the eye is achieved. Perforation of the eyebulb is extremely rare
      complication. Sub-Tenon's anaesthesia is a new method of direct infiltration of
      local anaesthetic into sub-Tenon's space using a blunt cannula. Sub Tenon blocks
      avoid blind sharp needle penetration into space of the orbit. Although still a
      relatively new technique, sub-Tenon's anaesthesia is becoming increasingly
      popular. Day care intraocular surgery under local anaesthetic is the option of
      choice. Patients are admitted, operated on and discharged within few hours.

PMID- 15017863
TI  - [Postoperative thromboembolic complications and preventive measures].
AB  - Modern surgical procedures become very extensive and aggressive in every surgical
      branch. Due to expressive development of anesthesia techniques with large
      monitoring systems support is provided to patients for broad spectrum of
      disorders. Therefore, we need to protect patients from imminent complications, as
      development of deep venous thrombosis and embolic pulmonary incidents. The main
      target in prophylaxis is to divide patients by risk and the type of surgical
      procedures during the time of "bed recovery". Today, current farmacological
      treatment is prone to control and prevent such events and to decrease mortality.
      Patients are divided in three groups: low risk (small operations with early
      mobilization); medium risk (surgery with risk in patients history); high risk
      (severe patients and long surgery, prolonged recovery). The best solutions in
      current medicine is to prevent most of complications, by administration of low
      molecular heparin (LMWH). Advantages of that treatment are: no need of intensive
      monitoring, long-time treatment, safe usage in "day case surgery" Beside LMWH, we
      still use heparin, although we tend to trial newer treatments and supports for
      prevention of complications. For special groups of patients recent trials examine
      heparinoid like drug-hyrudin, provided by chemical engeneering. That drug is
      metabolised in liver. Current therapy and prevention of DVT and pulmonary embolia
      is LMWH. It entered in every alghorythm of surgical and anaesthetic procedures
      and become CONDITIO SINE QUA NON.

PMID- 15017864
TI  - [Incidence of ARDS in patients with multiple injuries].
AB  - Adult respiratory distress syndrome (ARDS) is common complication and cause of
      death in some patients with polytrauma. Twenty patients with polytrauma were in
      test group and have had revised trauma score (RTS) nine or less. The aim of this
      study is to establish an incidence of ARDS, mortality rate and significance of
      Lung injury score (LIS) in assessment of damage of the lung function. In test
      group, 20% (4 patients) tested have developed ARDS with mortality rate of 25%
      (one patient dead). LIS is important for quantification and qualification of
      damage of the lung function. In patients who survived, value of LIS has been
      decreasing within three days. In patient who deceased, LIS has been continuously
      more than 2.5 within three days. LIS does not have significance as mortality
      predictor in cases of non-pulmonary complications such as renal, hepatic and
      cardiac dysfunction.

PMID- 15017866
TI  - [Prevention of secondary brain injuries].
AB  - Neurologic complications after severe brain injuries are the result of primary
      injuries in the moment of impact and secondary injuries which evolve over the
      minutes and days later. According to statistics, secondary injuries were
      documented in about 90 percent of patients who died after traumatic brain injury.
      Low oxygen delivery in hypotension, hypoxia, oedema, intracranial hypertension or
      changes in cerebral blood flow all account for development of secondary injuries.
      Primary injuries are more or less complete, but secondary injuries could be
      prevented with adequate therapy. Understanding mechanisms of secondary injuries
      could help identify potentially beneficial therapies. Important elements of
      therapy are: head position, normoglycemia, osmotherapy, normal body temperature,
      optimal blood pressure, adequate oxygenation, barbiturate therapy. Neutral head
      and neck position is recommended to prevent intracranial hypertension.
      Hyperglycemia with less ATP leads to ishaemic acidosis, hypoglycemia enhances
      decomposition of phospholipids and release of fat acids, what makes the cellular
      damage worse. Normocapnia is recommended and adequate oxygenation (PaO2 higher
      than 90%). To prevent dehydration and electrolyte imbalance, serum electrolytes
      should be examined every 4-6 h as well as osmolarity. Moderate therapeutic
      hypothermia could be of benefit, and maintaining of optimal blood pressure (MAP
      above 90 mmHg), especially in the first period after injury. As these have a lot
      of adverse effects, barbiturates are recommended only when conventional therapies
      show no effect. Patients should be hydrated well before induction of
      barbiturates. In organized trauma centers and with adequate intensive care the
      mortality from traumatic brain injury decreased from 50% in 1970, to about 30%
      now days.

PMID- 15017865
TI  - [To what extent does Trasylol decrease the need for blood and blood derivatives
      in postoperative acetylsalicylic acid (ASA)-induced hemorrhage in CABG surgery?].
AB  - ASA is commonly used for many years as pain relief drug, anti-inflammatory and
      against temperature, as well as antiaggregatory agent in coronary disease
      therapy. Aprotinin (Trasylol) has antifibrinolytic properties, among other
      actions, inhibits intrinsic coagulation cascade, and it has been demonstrated to
      reduce blood loss. Can be given in different doses and by different protocols. It
      is frequently used in cardiosurgery to reduce postoperative bleeding in the cases
      when ASA is not stopped at the right time before surgery. We evaluated the
      effects of therapeutic ASA doses on postoperative bleeding in patients undergoing
      coronary bypass grafting (CABG) compared with usage of Trasylol in CABG, bleeding
      and blood and fresh frozen plasma (FFP) requirements. This is a retrospective
      study, period October 1998-March 2002. Out of total CABG patients 75 fulfilled
      criteria (elective surgery, first CABG)--they were divided into following groups:
      ASA group of 25 patients (ASA withdrawn 1-3 days before surgery), Non ASA group
      of 25 patients (ASA withdrawn 10 or more days before surgery) and Trasylol group
      of 25 patients (ASA till surgery plus Trasylol intraoperatively). Average
      bleeding in ASA group 24 hours postoperatively was 1600 ml, Non ASA group had
      average bleeding 900 ml, while Trasylol group had average drainage of 700 ml
      after 24 hours. ASA average blood requirement was 1800 ml, 250 ml FFP and 250 ml
      5% albumin, Non ASA group has less need for blood and FFP--250 ml blood, 50 ml
      FFP and 30 ml 5% albumin. Our Trasylol group had quite profound bleeding and high
      requirements for blood and FFP--average 850 ml blood, 200 ml FFP and 150 ml 5%
      albumin. We recommend discontinuation of ASA therapy sufficiently early for all
      elective CABG, because in our case Trasylol did not give satisfactory decrease in
      postoperative bleeding and blood and FFP requirements. That all increase
      possibility of postoperative complication occurrence and increase CABG costs.

PMID- 15017867
TI  - [Metabolic response to trauma and stress].
AB  - Trauma, surgery, burns and infection are accompanied with catabolic response
      which is characterized by enhanced protelysis, enhanced excretion of nitrogen,
      neoglucogenesis and resistance of peripheral tissues to insulin. This catabolic
      response is mediated through neural pathways and neuroendocrine axis. The purpose
      of this response is restoration of adequate perfusion and oxygenation and
      releasing of energy and substrates for the tissues, organs and systems which
      functions are essential for the survival. Metabolic response to injury and severe
      infection leads to decomposition of skeletal muscle proteins to amino acids,
      intensive liver gluconcogenesis from lactate, glycerol and alanin with enhanced
      oxidation of aminoacids. These substrates are necessary for synthesis of various
      mediators of protein or lipid nature, which are important for the defense and
      tissue regeneration. The changes result in negative balance of nitrogen, loss of
      body weight, and lower plasma concentration of all aminoacids. Patients who were
      unable to develop this hypercatabolic response have poor prognosis, and the
      patients with hypercatabolic response rapidly lose their body cell mass and
      without metabolic and nutritive support have more complications and higher
      mortality. Although neoglucogenesis, proteolysis and lipolysis are resistant to
      exogenous nutrients, metabolic support in critical illness improves the chances
      for survival until the healing of the disease. Casual therapy in such conditions
      is elimination of "stressors" which maintain abnormal endocrine and metabolic
      response. Adequate oxygenation, hemostasis, infection control and control of
      extracellular compartment expansion and low flows, are essential for the efficacy
      of nutritive support and that is the only way to convalescence and wound healing.

PMID- 15017869
TI  - [On the implementation of Federal Law No. 52-F3 "On sanitary and epidemiological
      well-being of the population" dated March 30, 1999 and measures for its better
      application].

PMID- 15017868
TI  - [Regional anesthesia in children].
AB  - Regional anaesthesia is today a well established method for providing pain
      control in children. We must consider two kinds of problems: problems unique to
      paediatric population and problems that are the same in adults. A good knowledge
      of paediatric anatomy is mandatory for regional anaesthesia. Physiology in
      newborn and infants differ from older children and adults; metabolism and
      clearance of drugs, local anaesthetic included, are reduced so that we have a
      narrow therapeutic window and an increased toxicity. Moreover, the risk of
      inadvertent intravascular injection exists and can be minimized only with
      adequate monitoring along the performance of block. The availability of new local
      anaesthetics enantiomers such as ropivacain and levobupivacain, can add safety to
      regional anaesthesia and the addition of adjuvants like clonidine and ketamine
      contribute to the reduction of risks connected with toxicity. Performance of a
      block during anaesthesia is safer than when performed in an awake child.

PMID- 15017871
TI  - [Evaluation of the impact of emissions from the oil-refining plants on human
      health].
AB  - The entry of complexes of organic compounds, the components of the emissions from
      petrochemical and oil-refining plants into the environment leads to its quality
      and can have an adverse impact on the health status of the population in the area
      adjacent to the petrochemical plant. This paper deals with the formation of an
      evidence base for evaluating the etiopathogenetic role of the chemical components
      of emissions from a petrochemical plant in the development of diseases in the
      population under environmental conditions. The files of data accumulated in the
      period of 1994-2001 were analytically generalized in the electron database in
      accordance with the content of the priority chemical components of emissions in
      the body of 250 children living in the industrial area where the study plant is
      situated. The estimation of the level and time course of changes in toxicants in
      the blood of children identified health indicators to optimize monitoring and to
      evaluate the efficiency of environment-protective and therapeutic-and
      prophylactic programs. The findings suggest that the elevated level of some
      organic compounds that exert a polytropic toxic effect on the vital organs and
      systems is a risk factor for diseases and requires a systemic monitoring.

PMID- 15017870
TI  - [Combined use of active chlorine and coagulants for drinking water purification
      and disinfection].
AB  - The authors made an experimental study of the efficiency of water purification
      procedures based on the combined use of active chlorine and coagulants and
      hygienically evaluated the procedures. The study included the evaluation of water
      disinfection with various coagulants and active chlorine; the investigation of
      the processes of production of deleterious organic chlorine compounds; the
      assessment of the quality of water after its treatment. The coagulants
      representing aluminum polyoxychloride: RAX-10 (AQUA-AURATE 10) and RAX-18 (AQUA
      AURATE 18), and aluminum sulfate, technically pure grade were tested. The
      treatment of river water with the coagulants RAX-10 and RAX-18, followed by
      precipitation, filtration, and chlorination under laboratory conditions, was
      shown to result in water disinfection to the levels complying with the
      requirements described in SanPiN 2.1.4.1074-01. RAX-18 showed the best
      disinfecting activity against total and heat-tolerant coliform bacteria, but also
      to the highly chlorine-resistant microrganisms--the spores of sulfite-reducing
      Clostridia, phages, and viruses. Since the coagulants have an increased sorptive
      capacity relative to humus and other organic substances, substitution of primary
      chlorination for coagulant treatment may induce a reduction in the risk of
      formation of oncogenically and mutagenically hazardous chlorinated hydrocarbons.

PMID- 15017872
TI  - [Prevention of endemic goiter in areas jointly exposed to natural and industrial
      chemical factors].
AB  - The present paper deals with the sanitary evaluation of goiter endemia and with a
      rationale for principles in its prevention in areas exposed to natural and
      industrial chemical factors (in case of the Perm Region). The findings suggest
      that the elevated levels of some toxic metals and organic compounds in the body
      and zinc deficiency are strumogenic factors that maintain and aggravate the
      severity of goiter endemia in the presence of iodine deficiency. Comprehensive
      programs for prevention and correction of goiter endemia should be worked out
      differentially, by taking into account a combined influence of natural and
      industrial chemical factors on the population.

PMID- 15017873
TI  - [Impact of man-made load on patients' life quality].
AB  - The present prospective study included 70 females with uterine myoma indicated
      for surgery. The patients lived in the city districts having different industrial
      loads. Life quality was studied before and different periods after surgery. The
      poor environment was ascertained to affect life quality in patients with uterine
      myoma. Testing the life quality of a patient can significantly alter our views of
      preparation for surgery and of postoperative rehabilitation.

PMID- 15017874
TI  - [The role of mineral composition of drinking water in the development of non
      communicable diseases among the population].

PMID- 15017875
TI  - [Efficiency of sanitary measures in oil-producing areas].
AB  - The paper presents the results of an analysis of the efficiency of sanitary and
      environment-protective measures relating the ambient atmosphere in the oil
      producing areas of the Republic of Tatarstan. It characterizes the environment
      protective activity of the PJSC "Tatneft", gives a sanitary evaluation of the
      quality of the ambient air in the oil-producing areas. It has been ascertained
      that the improvement of manufacturing technology and the construction of gas and
      dust catching units on the oil-producing facilities reduce atmospheric pollutant
      emissions. The levels of hydrocarbons, nitric oxide, and hydrogen sulfide have
      been substantially decreased. At present, the influence of oil-producing
      facilities on the quality of the ambient air is 17-19%; the main source of
      atmospheric pollution is motor transport (its influence on atmospheric pollution
      is 40-56%). At present versus 1989-1995, the degree of pollution and the
      mutagenic potential of the ambient air are reduced, which suggests the efficiency
      of sanitary and environment-protective measures implemented by the PJSC
      "Tatneft".

PMID- 15017876
TI  - [Lead pollution of some environmental areas].
AB  - The levels of lead were determined in snow water, soil, and sludge. Its highest
      concentration was found in the deposits of the eastern and central areas of the
      region. These are areas with elevated technogenic loads. The concentration of
      lead in the snow cover was compared with its levels in the sludge and soil.

PMID- 15017877
TI  - [Prevalence of bronchial asthma in poor environmental areas].
AB  - Among patients with bronchial asthma, there are predominantly females who live in
      an industrial area. In this area, patients with severe bronchial asthma are 2.4
      times more and those with a severe exacerbation are twice more. Bronchial asthma
      may serve as a marker of the poor environment.

PMID- 15017878
TI  - [Evaluation of the influence of chemical factors of petroleum organic synthesis
      enterprises on the health status of their workers].
AB  - Recent studies conducted by a number of authors have given a good idea of the
      toxic effects of petroleum and its products on man. The combined effects of
      chemical and physical factors are known to potentiate their toxic effects and to
      cause an increase in morbidity among the workers of oil-refining plants. The
      paper substantiates the basic health indices to reduce the risk of industrial
      influences of the chemical components of emissions from an oil-producing plant on
      its workers' health. The workers were examined in accordance with the developed
      algorithm of hygienic evaluation under the influence of a combination of chemical
      factors, which makes it possible to define health indicators to optimize
      monitoring and to evaluate the efficiency of therapeutic-and-prophylactic
      programs. The results of the study suggest that in the workers, the elevated
      blood level of organic compounds exerting a polytropic toxic effect on the vital
      organs and systems is a risk factor for diseases and requires a systemic
      monitoring. Thus, program-specific planning of therapeutic and prophylactic
      measures implemented at an oil-producing plant should be accomplished by taking
      into account the optimum complex of diagnostic studies to evaluate the workers'
      health status.

PMID- 15017879
TI  - [Health promotion in gas industrial workers].
AB  - Health promotion in the workers of the limited liability company
      "Astrakhangazprom" in their working places (without discontinuing work) with the
      complexes of nutrients (including omega-3) enriched with vitamins, macro- and
      microelements, made in Russia yielded a positive therapeutic effect in improving
      the health status, in normalizing and improving laboratory and instrumental data,
      and in reducing sick cases with temporary disability. The duration of a health
      promotion course was 2 months.

PMID- 15017880
TI  - [Central hemodynamics in seamen during trans-latitudinal voyage].
AB  - The present study has analyzed a cardiovascular response in the sailors of a
      ship's crew (n = 23) on board the large self-reacting trawler "Konstantin
      Dushenov" during a fish-catching translatitudinal voyage for 5 months (181 days).
      The nonspecific mechanisms of adaptation in the seamen during long-term voyages
      are found to form by activating the central outlines of controlling. With the
      general trend for the activity of the sympathetic nervous system to decrease
      during the voyage, latter manifested itself under loads in a working cycle, by
      demonstrating the preserved responsiveness of the body in the sailors. By
      analyzing the results of the study, the authors show that there are the
      correlations between the parameters kept in mind, which allow the mechanisms of
      adjustment to be studied. The paper presents the results of informational
      simulation of correlation matrices with their high level of generalization where
      the time of course of adaptive changes to working conditions is demonstrated.

PMID- 15017881
TI  - [Evaluation of a chemical factor during fires].
AB  - The working conditions of firemen during active service cannot be assessed
      without characterizing the degree of ambient gas contamination with toxic
      substances. Firemen extinguish fires and liquidate accidents under difficult
      conditions, which presents a threat to their life and health. Fire-induced
      combustion products can emit as high as 100 types of chemical compounds. Of them,
      the most common and well-studied compounds are carbon oxide, sulfur dioxide and
      nitric dioxide, formaldehyde, hydrogen chloride, saturated hydrocarbons (C2-C10),
      acetone, benzene, toluene, and some chlorohydrocarbons (vinyl chloride,
      chloroform, and tetrachloromethane). These compounds are hazard classes II and
      III, they have been detected in the air samples in the foci of a fire in the
      amenity and industrial premises, during combustion of motor transport, garbage,
      etc. Toxicological exposure to these compounds is accelerated under elevated
      temperatures.

PMID- 15017882
TI  - [Health status in children with diffuse thyroid enlargement under man-made
      pollution].
AB  - The paper presents data on lipid and protein metabolic parameters, hormonal
      profile, physical development, and the cardiovascular system in school children
      with and without diffuse thyroid enlargement from the industrial centers of the
      Irkutsk Region. The study has revealed changes in metabolic processes, physical
      development, and blood circulation in the population of children, which are
      considered to be manifestations of adaptive processes to environmental factors,
      primarily chemical ambient air pollution and iodine deficiency.

PMID- 15017883
TI  - [The cardiovascular system in students born in the Middle Ob region].
AB  - The students of a northern pedagogical institute, whose age was 17-20 years, who
      had been born and permanently lived under uncomfortable climatic conditions of
      the Middle Ob Region, were examined. For evaluation of the cardiovascular system,
      hemodynamic parameters were determined, ECG readings were recorded and the values
      of cardiointervalogms were analyzed. The findings suggest that there are specific
      features in the status and performance of the cardiovascular system of young
      males and females aged 17-20 years, the natives of the Middle Ob Region. These
      include no age-related lower heart rate; a predominance of sympathetic effects on
      cardiovascular regulation; and myocardial functional changes.

PMID- 15017884
TI  - [The health status of children under poor ecological and social conditions].
AB  - In the Republic of Altai, the past decades are marked by poor trends in the
      children's health status: lower birth rates, a rise in general and infantile
      mortality and morbidity and worse physical development. The districts and areas
      that differ in environmental and social characteristics have been identified.
      Their comparison has determined the influence of environmental and social factors
      on the health status of children. There is a relationship of the children's
      health to environmental and social factors. It has been found that social factors
      much more influence than do environmental ones. A combination of environmental
      and social factors exerts the greatest impact on the basic health indices. In the
      area exposed to a combination of negative effects of these factors where natives
      predominantly live, there are negative changes in the children's health status.
      The leading social factors are maternal working conditions, familial financial
      position, a child's dietary habits, and living conditions.

PMID- 15017886
TI  - [Formation of healthy life style in a young generation].
AB  - The paper shows how to promote human health, by using pedagogical aids based on
      the concept of meeting the requirements a human being made at either stage of
      maturation.

PMID- 15017885
TI  - [Gender differences in health status and life quality of students].
AB  - The study has revealed that the leading hygienic risk factor of disorders and low
      life quality in medical students are an excess educational load at the expense of
      lecture and extra lecture hours, which is not characteristic of engineering
      students for whom the organization of a training process mostly meets the
      sanitary requirements. Gender differences have been found in life quality
      assessed by young males and females. Social factors have been proved to be the
      most significant parameters modifying the student's life quality. Moreover, the
      students of both institutes show decreased mental capacity by the third year of
      studies, by the fourth year, there are signs of its enhancement irrespective of
      gender.

PMID- 15017887
TI  - [Methodological features of sanitary standardization of water pesticides].

PMID- 15017889
TI  - [Individual health: essence, mechanisms, manifestations].
AB  - The paper provides evidence for that it is necessary to enhance the efficiency of
      prevention of chronic non-communicable diseases by applying the new strategy--the
      individual's health controlling strategy. To characterize the controlled object-
      individual health--its essence, mechanisms, and manifestations are considered. On
      this basis it is stated that a positive health scale can be constructed.

PMID- 15017888
TI  - [Red blood cell system in albino rats exposed to long-term nitrite intoxication].
AB  - The long-term intake of nitrates at a concentration of 0.2 g/l in animals affects
      erythrocytic parameters. The nature of this effect depends on the duration of
      intoxication. There are three-phase changes in the concentrations of red blood
      cells and hemoglobin, which accompany the substantial changes of the functional
      characteristics of erythrocytic membranes. The intensification of erythropoiesis
      developing under such conditions is based on erythroidal hyperplasia of the red
      bone marrow and spleen and it is of compensatory significance, by ensuring the
      recovery of the parameters of the erythrocytic composition by the end of the
      experiment.

PMID- 15017890
TI  - [Experience in teaching sanitary-and-epidemiological legislation in the
      postgraduate training of physicians].

PMID- 15017891
TI  - [Rapid method for water bio-testing in the field conditions].

PMID- 15017892
TI  - [Diagnostic aspects of identification of the hazard of aliphatic chlorinated
      hydrocarbons for children's health].

PMID- 15017894
TI  - A study of gabapentin in the treatment of tonic-clonic seizures of alcohol
      withdrawal syndrome.
AB  - In this study for thirty (30) patients with alcohol withdrawal syndrome, the
      response to anticolvusant gabapentin was assessed. Thirty (30) patients with
      median age of 57.0 years and median body weight of 79.1 kg were treated with
      gabapentin 3 x 300 mg daily for up 30 days. The preliminary findings of this
      study suggest that gabapentin is very effective against tonic-clonic seizures in
      alcohol withdrawal syndrome. Gabapentin was safe and well tolerated. For twenty
      (20) patients no side effect were observed.

PMID- 15017893
TI  - [Effect of alcohol on aminotransferase activity in adolescents].
AB  - The objective of research were consolidate the correlation the greatest values
      ALT and AST, and consummation alcohol. To the group of 302 adolescents, male sex
      of 18, 19 and 20 years is measured the activity of ALT and AST. The examines are
      questionned to the consummation of alcohol. Had to the significant increased
      values AST, and only mildly increased values in relation to the upper referent
      values.

PMID- 15017895
TI  - [Complications in the posterior eye segment after Nd-YAG laser capsulotomy].
AB  - After the Nd-YAG laser posterior capsulotomy can be develop complications on the
      posterior eye segment. Aims of the research is showed the frequency of the
      complications which developed during six months, and to analyze the influence of
      total laser energy on them. Number complications is raised on the time. Rupture
      of the anterior hyaloid face in 7.5% of the cases, rupture retina in 4.1%,
      rupture macule in 2.5%, retinal detachment in 2.5%, cystoid macular edema in
      4.1%, macular fibrose in 10.8%, changes in the corpus vitrei in 10.8% of the
      eyes. The influence total laser energy on the complications is statistically
      significant, and the collerative connections are positive and strong.

PMID- 15017896
TI  - [Effectiveness of gemcitabine in combination with cisplatin in a randomized study
      of untreated patients with advanced non-small-cell lung carcinoma].
AB  - Lung cancer is the leading cause of cancer death in men worldwide. It accounts
      for 29 percent of all cancer deaths in men in the European community; the
      corresponding figure for woman is 9 percent. AIMS: The evaluation Response Rate
      (RR) and one-year survival in inoperable locally advanced Non-Small cell Lung
      Cancer (NSCLC) treated with Gemcitabine (Gemzar/kappa) plus Cisplatin and
      fractionated chest radiation. The evaluation RR and one-year survival in
      metastatic NSCLC treated with Gemcitabine plus Cisplatin. PATIENTS AND METHODS:
      Retrospective clinical study on two years clinical material (2000 and 2001). In
      first group number of evaluated patients was 74 with stage IIIa (N2) and IIIb;
      mean age 52.5; male 56, female 18; WHO performance status 0-2. Second group was
      14 patients with stage IV and next characteristics: mean age 50.3; male 10,
      female 4; WHO performance status 0-2. Treatment schedule for patients with stage
      IIIa (N2) and IIIb: Cisplatin 75 mg/m2 plus Gemcitabin 1250 mg/m2, day first, and
      Gemcitabin 1250 mg/m2, day 8, every 3 weeks, total 3 cycles. After third cycle
      chemotherapy, in period from 7-14 days started with fractionated radiation
      therapy. Usually it was 40-46 Gy on tumor and mediastinum during 30 days.
      Patients with metastatic NSCLC (stage IV) treated with the same schedule, every
      three weeks, total 4 cycles but without fractionated radiation therapy. RESULTS:
      Overall RR for stage IIIa (N2) and stage IIIb was 46.6% and one-year survival
      42.5%. RR for stage IV was in the form of partial response at the eight patients
      (57%) with one-year survival 7.3% (one patient) and median time to disease
      progression 1.3 months. CONCLUSION: In our two years clinical sample we treated
      74 patients with NSCLC stage IIIa (N2) and stage IIIb with schedule--Cisplatin 75
      mg/m2 plus Gemcitabin 1250 mg/m2, day first, and Gemcitabin 1250 mg/m2, day 8,
      every 3 weeks, total 3 cycles and fractionated radiation therapy with 40-46 Gy
      during 30 days on tumor and mediastinum. It's very effective regime with overall
      response rate 46.6% and one-year survival 42.5%. For stage IV it's not so
      effective regime, because, even now, it's so expensive regime for us.

PMID- 15017897
TI  - [Excretion of hepatitis A virus antigen in feces in acute and prolonged hepatitis
      A infection].
AB  - The excretion of the antigen hepatitis A virusa (Ag HAV) in stool in the acute
      phase develops in the course of the incubation and the early symptomatic illness
      phase, what amounts maximally to 60 days. In the available literature there are
      no data regarding to the length of the excretion of Ag HAV in the stored forms of
      the illness (PTHA). AIM: Of this paper was to examine the relation of the
      excretion length Ag-HAV in stool according to the maintenance length of the
      pathologic activities the alaninaminotranspherase (ALT), the persistence of the
      antibodies to Ag-HAV IgM class (anti-HAV IgM) and the maintenance of the
      increased values of the circulating immune complex (CiC) in the serum of the ill
      become with PTHA. MATERIAL AND METHODS: In the three year prospective study of
      the values of the circulating immune complex in stool of 10 suffering from acute
      hepatitis A, and 39 ill become with the protrahirated form of HAV-infection. Ag
      HAV in stool is determined by the method the flow through immunoelectroosmophores
      (IOEP). IgM anti-HAV was determined by ELISA method. CiC have determined
      photometrically in the sediment polictilenglycole. RESULTS: Of the researches
      show that FALI Ag HAV u obje grupe pacijenata izlucuje prvo permanentno, potom
      intermitentno. In the group with acute HAV infection svi pacijenti su imali
      pozitivan nalaz Ag-HAV in stool. In PTH group in 61% examina was found Ag-HAV,
      and in 39% was not found either stool sample. The longest excretion of Ag-HAV in
      stool was verified during the third recrudescence, 5.5 month from the beginning
      of HAV-infection, that is on the 159-th day of the illness. CONCLUSIONS: The
      results of the researches has shown that the excreation of Ag-HAV in stool
      approximately equally to the maintenance of the increased values ALT, and three
      fold shorter than the maintenance of IgM anti-HAV and the patologic values CiC in
      patient serum with PTHA.

PMID- 15017898
TI  - [Comparative parameters of myelotoxicity in patients treated with simultaneous
      chemotherapy and radiotherapy or only radiotherapy].
AB  - BACKGROUND: The Modern oncological treatment usually consists of the different
      kind of the therapies. Improvement of survival and local control of disease could
      be possible with combined treatments: surgery, radiotherapy, chemotherapy, etc.
      However if these treatments are given concomitantly one can expect higher
      toxicity. AIM: Comparation of parameters of miclotoxicity: red blood cell count,
      white blood cell count, platelets and hemoglobin in patients with advanced
      cervical carcinoma treated with concomitant chemo-radiotherapy versus
      radiotherapy alone. PATIENTS AND METHODS: From 1997-1999, we performed
      prospective, by randomised, study, and 80 patients were divided in two groups:
      Group A--40 patients treated with concomitant chemo-radiotherapy versus, Group B-
      40 patients treated with radiotherapy alone. Red blood cell count, white blood
      cell count, platelets and hemoglobin were evaluated before enrollement, during
      the theraphy, after 3 and 6 months, according to CTC toxicity criteria. RESULTS:
      We perform statistical analysis using H2 test, and we found no significant
      difference in mild nad severe toxicity in red blood cell count, white blood cell
      count, platelets and hemoglobin among groups.

PMID- 15017899
TI  - The relationship between circulating carcinoembryonic antigen (CEA) levels and
      parameters of primary tumor and metastases in breast cancer patients.
AB  - AIM: The Carcinoembryonic antigen (CEA) is used as a tumor marker for breast
      cancer (BC). In order to better define clinical usefulness of CEA in breast
      cancer patients (BCP) we determined its baseline pre-treatment levels and
      correlated them with main parameters of primary tumor and metastases. PATIENTS
      AND METHODS: The main experimental group consisted of 47 female patients with
      histologically confirmed diagnosis of BC. The obtained results have been compared
      with those of two control groups: clinically healthy women, and patients with
      other types and locations of cancer. In both cancer groups the parameters of
      primary tumor (size, grade) and metastases (time interval to metastases,
      location, size) have been determined. Circulating levels of CEA were measured by
      the means of immunoradiometric assay. Results were processed by means of t-test,
      two way analysis of variance in F-test, and logistic general linear model with
      calculations of Pearson's correlation coefficient. RESULTS: Baseline levels of
      CEA in BCP were significantly higher than in healthy women (p < 0.0001), and in
      patients with other types and locations of cancer (p < 0.007). There also was
      significant difference (p < 0.001) between serum CEA in other cancer patients and
      healthy women. Baseline CEA levels were in significant positive correlation with
      the size of primary tumor both in all BCP (p < 0.03) and in hyperCEA BCP (p <
      0.002), while in other cancer patients such a correlation did not exist. There
      was no correlation between CEA and degree of differentiation of primary tumor
      either in BCP or in other cancer patients. The average circulating levels of CEA
      in metastatic BCP were significantly higher (p < 0.03) in comparison to non
      metastatic patients, while in other cancer patients such a difference did not
      show up. There was significant correlation (p < 0.0001) between circulating CEA
      and the size of metastases in all BCP and in subgroup of hyperCEA BCP, while in
      other cancer patients it was not a case. There was no correlation between serum
      CEA and other two metastatic parameters either in BCP or in other cancer
      patients. CONCLUSIONS: CEA does not have high tumor specificity for BC since its
      baseline levels may be elevated in other types of cancer. Circulating levels of
      CEA in BCP are directly dependable on the size of both primary and metastatic
      tumor. CEA is a tumor antigen of less differentiated cancer cells. Circulating
      CEA is a good prognostic marker for patients with metastatic BC.

PMID- 15017900
TI  - [Occupational exposure and prevention of viral hepatitis B in health care
      personnel in the Canton of Sarajevo].
AB  - Health workers are exposed to the accidental injuries with blood, so that
      increasing of HBsAg among inhabitants in Bosnia and Herzegovina and professional
      risk for VHB is increased in this risk group. Among 6.712 health workers in
      Canton Sarajevo, it's expected that 1.217 health workers will be exposed to the
      professional accidental injury with the blood, but it's expected annually 44
      professionally infected health workers with HBV. With introduction of vaccine
      against HBV it would come to very important decreasing of the diseases among
      health workers (p < 0.001), but the risk for the disease HBV would decrease 45
      times.

PMID- 15017901
TI  - [Correlation between levels of blood glucose and cerebrospinal fluid glucose and
      proteins in diabetes mellitus].
AB  - Patient with diabetes mellitus is prone to develop the vascular lesion of blood
      vessels of all kinds. Microangiopathy and atherosclerosis are progressive during
      the illness. Also with this study blood brain barrier change in the diabetes
      mellitus patients was observed. In patients with diabetes mellitus the level of
      glucose and total proteins increased in the cerebrospinal fluid. During diabetes
      mellitus the change of permeability blood brain barrier is evident. Blood brain
      barrier permeability changes in the patients with ICV as well as in the patients
      without ICV correlate with the values of diabetes mellitus in blood.

PMID- 15017902
TI  - [Erectile dysfunction--incidence, causes and risk factors].
AB  - The inability of a male to attain and maintain an erection sufficient to allow
      vaginal penetration is called erectile dysfunction. It is a part of general male
      sexual dysfunction called impotence, which also includes libidinal, orgasmic and
      ejaculatory dysfunction. Erectile dysfunction affects millions of men and
      although it may not mean a total loss of sexual satisfaction, it often creates a
      mental stress that affects the man's quality of life. Knowledge of erectile
      dysfunction has increased remarkably over the past decade. Nowadays, about 50-85%
      of erectile dysfunction patients can be shown to have a somatic cause by modern
      methods of examination. Erectile dysfunction may also occur as a result of
      specific illness or medical treatment, and it is often multifactorial in
      etiology. Erectile dysfunction increases with age.

PMID- 15017903
TI  - [Criteria for work capacity evaluation in rheumatoid arthritis].
AB  - The Rheumatoid arthritis (RA) causes early retirement and great number of working
      day losses. According to our investigation, retirement of patient in our country
      comes even earlier then in other countries. Possible causes for that are limited
      possibilities of application of contemporary therapy, which result in severer
      clinical course of the diseases as well as of the different criteria of the
      physicians for evaluation of the working ability. The aim of this work was to
      propose the criteria, which would help physicians to evaluate temporary or
      permanent working ability. For the purpose of forming the proposal of criteria,
      functional tests, parameters from our own research as well as the suggestions of
      the top world's institutions OMERACT, EULAR) are used. In order to assess working
      ability one should need: pain assessment, Ritchie articular index, the number of
      painful and swollen joints, morning stiffness duration, index of joint motion,
      functional ability measured by HAQ, ESR, CRP, Disease Activity Score (DAS), and
      rtg of both hands. Decision of working ability should not be made based on the
      current status of some parameters; it should be made by the analysis of the
      disease's progression. If the index of joint motion, functional status and rtg
      changes are severer every year, the retirement should be considered. The
      appropriate evaluation of current activity and follow up of its progression with
      the usage of the proposed criteria should help primary care physicians to
      evaluate temporary and permanent working disability.

PMID- 15017904
TI  - [Initial experience with human rights laws related to care of individuals with
      mental disorders].
AB  - This paper will review the patients in compulsory admission to treatment at the
      Intensive Care Unit of the Psychiatric Clinic in Sarajevo in the period from
      October 01 st, 2002 to October 01, 2003, following the adoption of the Law on
      Protection of Persons with Mental Disturbances. All the outstanding issues
      related to the enforcement of the law require caution and special attention and
      consultations with the incumbent Municipal courts responsible for the enforcement
      of the law.

PMID- 15017906
TI  - [Tumor of the sacroiliac region].
AB  - We present case of a 13 y. girl who has admitted with hard symptoms on our
      Department after back injury in school. Clinical presentation and complete
      radiological tests were pointed to inflammatory process of sacroiliac region.
      Hard general condition has forced us to indicate operative procedure. Diagnosis
      was established after surgical intervention-incapsulated tumor-lipoma, which has
      been extirpated without visible inflammatory signs. After this intervention local
      and general condition were improved-clinically and laboratory. Girl was sent to
      home as a completely cured patient.

PMID- 15017905
TI  - [Unilateral pheochromocytoma and adrenal gland hyperplasia].
AB  - Woman, forty two years old, has been hospitalized because of frequent headache,
      palpitation and tremor of lips with paroxysmal increase of blood pressure. The
      adrenals have examined. The status of the hormones has checked many times but
      showed increased values of VMA and 17-OH steroids only once. There is no
      possibility to measure the catcholamines. Analysis of other hormones has showed
      normal values except of paradoxal hGH increase during suppressive hGH test and
      hypoglycemia in OGTT test. The changes of the left adrenal, which size was 25x18
      and 30x25 mm, have diagnosed by MRI of adrenals. It has been suspected
      microadenoma by MRI of pituitary gland. The left adrenalectomy has been done.
      During the surgery hypertension and tachyarrhythmia has occurred and treated by
      fentolamin and propranolol. No complications have been noticed after the surgery.
      The status of the adrenals hormones are in the normal range. Patohystological
      analysis has proved phcochromocytoma and hyperplasy.

PMID- 15017907
TI  - [Inverted papilloma of the urinary bladder].
AB  - The inverted papilloma is relatively rare urothelial benign tumor. In 1980 was
      described only 108 cases of this benign proliferative lesions of bladder.
      Papillary fronds project into the fibrovascular stroma of the bladder rather than
      into the bladder lumen. The lesion is usually covered by a thin layer of normal
      urothelium. In Our case, tumor was found during the open adenomectomy, although
      patient was examined by ultrasound, before surgical treatment. One year after
      surgical treatment, control cystoscopic examine shows no recidive benign lesion.

PMID- 15017908
TI  - [Hemothorax caused by bleeding inside extralobar pulmonary sequestration in a
      patient on anticoagulation therapy].
AB  - Extralobar pulmonary squestration is a rare anomaly of abnormal pulmonary tissue
      without any communication to the bronchial tree and that receives blood supply
      from anomalous systemic arteries. We presented a case of massive hemothorax
      caused by bleeding inside extralobar pulmonary sequestration in an 34-year young
      man on anti-coagulation therapy because of built-in mechanic aortic valve.
      Surgical treatment was decortication and sequestrectomy after ligature of the
      aberrant vessels. We reviewed the literature on this topic and did not found any
      report about similar case.

PMID- 15017910
TI  - [Retinal and pineal melatonin--from a circadian signal to therapeutic use].
AB  - Melatonin, the major product of the pincal gland, is also synthesized in the
      retina of several vertebrate species. Retinal melatonin levels show a marked
      daily variation, with high levels at night and low levels during the light
      period. Melatonin rhythm generating system includes photodetector, circadian
      clock and melatonin synthesis machinery and they are located in pincal organ and
      retina. In both, light regulates daily variations in melatonin secretion by
      controlling the activity of arylalkylamine N-acetyltransferase (AANAT). In
      mammals, circadian system is comprised of three major components: the eyes, the
      hypothalamic suprachiasmatic nucleus (SCN) and the pincal gland. The SCN harbours
      the endogenous oscillator that is entrained every day to the ambient lighting
      conditions via retinal input. Among the many circadian rhythms in the body that
      are driven by SCN output, the synthesis of melatonin in the pincal gland
      functions as a hormonal message encoding for the duration of darkness.
      Dissemination of this circadian information relies on the activation of melatonin
      receptors, which are most prominently expressed in the SCN, and the hypophysical
      pars tuberalis (PT), but also in many other tissues. Melatonin is essential for
      rhythmic signaling in the PT. Here, melatonin acts in concert with adenosine to
      elicit rhythms in clock gene expression. By sensitizing adenylyl cyclase,
      melatonin opens a temporally-restricted gate and thus lowers the threshold for
      adenosine to induce cAMP-sensitive genes. This interaction, which regulates gene
      expression and pituitary output (by endocrine-endocrine interaction) represents
      general mechanism by which the master clock in the brain synchronizes clock cells
      in peripheral tissues that require unique phasing of output signals.

PMID- 15017909
TI  - [Modern approach to diagnosis and therapy in childhood leukemias].
AB  - Leukemias are the most common malignancies in children. More than 80% leukemias
      in childhood are acute (non mature) lymphoblastic leukemias (ALL), and the rest
      are acute myeloid leukemias (AML). Chronic leukemias are very rare, and they are
      almost always chronic myclogeneous leukemia (CML). Owning to good diagnostic
      procedures and using very aggressive treatment protocols, usually life
      threatening, thereis significant progress in curing of this severe disease.
      Today, about 70% children suffering from acute lymphoblastic leukemia and about
      55% children with acute mycloid leukemia could be cured. In this paper we present
      diagnostic procedures, classification and treatment protocols for leukemias in
      childhood.

PMID- 15017911
TI  - Neonatal nursing: the first six weeks.

PMID- 15017912
TI  - Soaring to new heights as a flight nurse.

PMID- 15017913
TI  - Nurse attorney: an oxymoron?

PMID- 15017914
TI  - Take a critical look at progressive care.

PMID- 15017915
TI  - The other "C". Getting your calcium.

PMID- 15017916
TI  - Just for teens. Need for control.

PMID- 15017917
TI  - Diabetes essentials. Insulin administration.

PMID- 15017918
TI  - Disability program. Social Security provides safety net.

PMID- 15017919
TI  - Type 2 & insulin. Overcoming the fear.

PMID- 15017920
TI  - Steak & potatoes. Here's the kind of old-fashioned meal that brings everyone
      hurrying to the table.

PMID- 15017921
TI  - How to shop for shoes. If you have diabetes, footwear is more than a fashion
      statement. Here are some tips for buying the right pair of shoes.

PMID- 15017922
TI  - Research profile. Foot ulcer risk. The role of circulation. .

PMID- 15017923
TI  - A new and improved diabetes.org. Today, a click to www.diabetes.org delivers more
      than ever.

PMID- 15017924
TI  - Light-emitting foot pads improve neuropathy.

PMID- 15017926
TI  - Low back pain sufferers shouldn't shun exercise.

PMID- 15017925
TI  - Mood improves after menopause, but transition is difficult.

PMID- 15017927
TI  - Food choices may affect diabetes risk. Coffee and magnesium-rich foods may
      deflect diabetes, while red meat may promote it.

PMID- 15017928
TI  - Moderate exercise, without dieting, can prevent further weight gain.

PMID- 15017929
TI  - Fitness fends off death among diabetics.

PMID- 15017930
TI  - Dodging MS and RA with vitamin D.

PMID- 15017931
TI  - Where should your omega-3s come from? The fish scare is overblown. Eating omega-3
      rich fish twice a week does far more good than harm.

PMID- 15017932
TI  - Heart attack? Ambulance is better than a car.

PMID- 15017933
TI  - High blood sugar, homocysteine boost artery-reclogging risks.

PMID- 15017934
TI  - FDA evaluating new angina drug.

PMID- 15017935
TI  - Heart bypass grafts compared.

PMID- 15017936
TI  - Tuning out arthritis pain.

PMID- 15017937
TI  - Strontium strengthens some bones.

PMID- 15017938
TI  - Planning for the unexpected: do it now. Health proxies and living wills
      communicate your healthcare wishes if you are unable to. Yet fewer than 20
      percent of Americans have such plans in place.

PMID- 15017939
TI  - How now, mad cow?

PMID- 15017940
TI  - Americans committed to cancer screening.

PMID- 15017941
TI  - Ulcers from NSAIDs can be prevented.

PMID- 15017942
TI  - The kidney-heart disease connection. One in nine American adults has chronic
      kidney disease and is therefore at increased risk of cardiovascular disease.

PMID- 15017943
TI  - Depression: therapy or medication? Therapy and antidepressants may affect the
      brain differently, but both are effective.

PMID- 15017944
TI  - What's the difference between bacterial and viral meningitis?

PMID- 15017945
TI  - When is it appropriate to use over-the-counter  antidiarrheal medication, and
      when does diarrhea call for a doctor's visit?

PMID- 15017946
TI  - Managing conflict in an urban health care setting: what do "experts" know?

PMID- 15017947
TI  - Mediating disputes in managed care: resolving conflicts over covered services.

PMID- 15017948
TI  - Conflict in health care organizations.

PMID- 15017949
TI  - Regulation of research with children: the evolution from exclusion to inclusion.

PMID- 15017950
TI  - (Women and) children first: applicable to lifeboats? Applicable to human
      experimentation?

PMID- 15017951
TI  - Pediatric priorities: legislative and regulatory initiatives to expand research
      on the use of medicines in pediatric patients.

PMID- 15017952
TI  - Ethical issues in conducting behavioral genetics research: the case of smoking
      prevention trials among adolescents.

PMID- 15017953
TI  - The lead-based paint abatement repair and maintenance study in Baltimore:
      historic framework and study design.

PMID- 15017954
TI  - Whose duty is it anyway?: the Kennedy Krieger opinion and its implications for
      public health research.

PMID- 15017956
TI  - Parental consent for children's participation in biomedical research: the
      ethical, regulatory, and judicial framework of Grimes v. Kennedy Krieger
      Institute, Inc.

PMID- 15017955
TI  - The Kennedy Krieger case: judicial anger and the research enterprise.

PMID- 15017957
TI  - Reproductive genetics 1991-2002: a selected annotated legal bibliography of
      genetic testing, gene transfer and reproductive cloning.

PMID- 15017958
TI  - Biotechnology and human dignity, a necessary and compatible union.

PMID- 15017959
TI  - Contrary to first impression, genes are patentable: should there be limitations?

PMID- 15017960
TI  - Data-sharing and data-withholding in genetics and the life sciences: results of a
      national survey of technology transfer officers.

PMID- 15017961
TI  - Public access versus proprietary rights in genomic information: what is the
      proper role of intellectual property rights?

PMID- 15017962
TI  - The potential impact of genetic sequencing on the American health insurance
      system.

PMID- 15017963
TI  - Nonsexual boundary violations: sauce for the gander.
AB  - Numerous articles in the mental health literature concern sexual contact between
      therapists and patients, which is explicitly prohibited by all four mental health
      professions' ethical codes. There is relatively little about nonsexual boundary
      violations, which are often covert and much more difficult to recognize
      (particularly in their early stages) than sexual violations; what little there is
      assumes that the clinician has the power in the relationship and uses that power
      for personal advantage. In this article the authors discuss the situation, rare
      in civil mental health facilities but common in correctional and forensic mental
      health facilities, in which personality-disordered patients manipulate and coerce
      clinicians to cross appropriate professional nonsexual boundaries for the
      patients' benefit; this reversal of the usual power dynamics between treaters and
      patients requires recognition of the role reversals present and requires
      different strategies for preventing such violations (hence "sauce for the
      gander").

PMID- 15017965
TI  - Genetic engineering and our human nature.

PMID- 15017966
TI  - A manager asks: motivational implications. Is sick time used "because it's
      there"?

PMID- 15017964
TI  - Having one child to save another: a tale of two families.

PMID- 15017967
TI  - Homeric psychology [1922].

PMID- 15017968
TI  - Medical and religious aspects of mummification in ancient Egypt.

PMID- 15017969
TI  - Sources of controversy in blood sedimentation tests. Perspectives of the Edmund
      Biernacki's method.

PMID- 15017970
TI  - Perspectives on the evolution of Japanese medicine.

PMID- 15017971
TI  - [A combination of clinical medicine and social welfare activities of the
      Ophthalmic Rehabilitation Clinic at Juntendo University].
AB  - I intend to analyze in this paper tha activities of the Ophthalmic Rehabilitation
      Clinic at Juntendo University in order to clarify how social welfare is
      incorporated with medical care in rehabilitation. The patients who feel little
      hope of recovery often suffer a great sense of emptiness until they finally
      manage to rehabilitate themselves in society. The clinic was founded for them in
      1964 inside the Department of Ophthalmology, Juntendo University. The Department
      has been providing consultation with the visually handicapped. The program
      consists of counseling, educational guidance, daily training, etc. It is quite
      remarkable that the rehabilitation program, in addition to the medical
      examination, has been introduced to the outpatients who have visual handicaps.

PMID- 15017972
TI  - [A study of Bo-Juyi's disease].
AB  - Hitherto, Bo-Juyi has been known as a sickly poet. But analysis of his disease
      according to the traditional Chinese medicine had not been until this paper. So
      many factors affected his illness; especially the weak life power which he was
      given from his mother and the heavy load of stress he suffered were worsening
      factors. His habits of heavy drinking of alcohol and tea weakened his
      constitution by creating bad waters in his body-which normally would have
      protected the flow of Qi, blood and fluids. Therefore, he was susceptible to many
      diseases.

PMID- 15017973
TI  - Cell of the month. Dendritic cell sensing a lymphocyte.

PMID- 15017974
TI  - Viral ion channels as models for ion transport and targets for antiviral drug
      action.

PMID- 15017975
TI  - The threatened trade in human ova.

PMID- 15017976
TI  - Redox regulation of PTEN and protein tyrosine phosphatases in H(2)O(2) mediated
      cell signaling.
AB  - Protein tyrosine phosphatase (PTP) is a family of enzymes important for
      regulating cellular phosphorylation state. The oxidation and consequent
      inactivation of several PTPs by H(2)O(2) are well demonstrated. It is also shown
      that recovery of enzymatic activity depends on the availability of cellular
      reductants. Among these redox-regulated PTPs, PTEN, Cdc25 and low molecular
      weight PTP are known to form a disulfide bond between two cysteines, one in the
      active site and the other nearby, during oxidation by H(2)O(2). The disulfide
      bond likely confers efficiency in the redox regulation of the PTPs and protects
      cysteine-sulfenic acid of PTPs from further oxidation. In this review, through a
      comparative analysis of the oxidation process of Yap1 and PTPs, we propose the
      mechanism of disulfide bond formation in the PTPs.

PMID- 15017977
TI  - Regulation of the cholinergic gene locus by the repressor element-1 silencing
      transcription factor/neuron restrictive silencer factor (REST/NRSF).
AB  - The cholinergic gene locus is comprised of two genes, the choline
      acetyltransferase gene and the vesicular acetylcholine transporter gene. The
      vesicular acetylcholine transporter gene is located within the first intron of
      the choline acetyltransferase gene. This arrangement permits coordinate
      regulation of the locus. Protein kinase A regulates expression of the cholinergic
      gene locus in PC12 cells. This regulation was found to be dependent on the
      presence of a 21-bp DNA sequence known as the repressor element- (RE- 1)/neuron
      restrictive silencer element(NRSE). Repressor element-I silencing transcription
      factor (REST)/ neuron-restrictive silencer factor (NRSF), which binds to the RE
      I/NRSE, is a zinc finger containing transcriptional repressor that blocks the
      expression of many neuronal RE-I/NRSE containing genes in nonneuronal cells.
      However, REST/NRSF expression has also been observed in neurons as well as the PC
      12 cell line used in these studies. REST/NRSF truncated isoforms were expressed
      in neuronal cells, suggesting they also function in regulating neuronal gene
      expression. A study of REST4, one of the REST/NRSF isoforms, suggests that it
      regulates transcription of the cholinergic gene locus by blocking the repressor
      activity of REST/NRSF. Protein kinase A regulation of the cholinergic gene locus
      in PC 12 cells can thus be attributed, at least in part, to increased synthesis
      of REST4, which in turn derepresses the repressor activity of REST/NRSF.

PMID- 15017978
TI  - Avian influenza: the whole world's business.

PMID- 15017979
TI  - Weapons of mass vaccination.

PMID- 15017980
TI  - Clinicians await end to HIV trial ordeal in Libya.

PMID- 15017981
TI  - Compensation for victims of contaminated blood.

PMID- 15017982
TI  - Canadian hospital recalls patients for HIV testing.

PMID- 15017983
TI  - Infectious diseases surveillance update.

PMID- 15017985
TI  - [Ephedra products from the Internet: dangerous herb].

PMID- 15017984
TI  - [Gene chips--soon routine in diagnosis of causative agents?].

PMID- 15017986
TI  - Cancer Vaccine Collaborative 2002. September 30 - October 1, 2002, New York, USA.
      Abstracts.

PMID- 15017987
TI  - Boutiques reborn in 2003.

PMID- 15017988
TI  - ScanBalt coordinates intellectual property in Northern Europe.

PMID- 15017989
TI  - Ireland launches regenerative medicine research center.

PMID- 15017990
TI  - Converting biotech scientists into managers.

PMID- 15017991
TI  - Endocrine-related resources from the National Institutes of Health.

PMID- 15017993
TI  - [A famous trio of anaesthetists, yesterday in Paris: Ernest Kern, Jean Lassner
      and Guy Vourc'h].

PMID- 15017992
TI  - An extremely sensitive species-specific ARMs PCR test for the presence of tiger
      bone DNA.
AB  - The survival of the tiger (Panthera tigris) is seriously threatened by poaching
      to provide raw materials for Traditional Chinese Medicines (TCMs). Most highly
      prized are the tiger's bones, which are used in combination with other animal and
      plant derivatives in pills and plasters for the treatment of rheumatism and other
      ailments. Hundreds of patent remedies have been produced which claim to contain
      tiger bone, but proof of its presence is needed, if legislation prohibiting the
      trade in endangered species is to be enforced. A highly sensitive tiger-specific
      real-time PCR assay has been developed to address this problem. Using primers
      specific to the tiger mitochondrial cytochrome b gene, successful amplification
      has been reliably achieved from blood, hair and bone as well as from a range of
      TCMs spiked with 0.5% tiger bone. Although capable of detecting fewer than 10
      substrate molecules, the seven varieties of TCM pills and plasters tested showed
      no detectable trace of tiger DNA before spiking. Furthermore, sequencing several
      "tiger bone" fragments seized from TCM shops has shown that they actually
      originated from cattle and pigs. The potential effects of traditional bone
      preparation methods, evidence that much lower concentrations are used than
      alleged on TCM packaging, and substitution of bones from other species all
      suggest a low likelihood of detecting tiger DNA in patent medicines. Despite
      this, the basic methods have been thoroughly proven and can be readily applied to
      derivatives from other CITES protected species providing a rapid and highly
      sensitive forensic test for species of origin. Potential applications to the
      monitoring of wild populations are demonstrated by the successful identification
      of shed hairs and faecal samples.

PMID- 15017994
TI  - Time for progress.

PMID- 15017995
TI  - Molecular markers in gastrointestinal cancer: targeted therapy and tailored
      chemotherapy.

PMID- 15017998
TI  - [Medical and engineering cooperation in otorhinolaryngology: speech synthesis].

PMID- 15017997
TI  - [Achievements of Dr. Peter Agre, a winner of the 2003 Nobel Prize in Chemistry].

PMID- 15017999
TI  - Consumer preferences for general practitioner services.
AB  - This study focuses on segmenting the market for General Practitioner services in
      a regional setting. Using factor analysis, five main service attributes are
      identified. These are clear communication, ongoing doctor-patient relationship,
      same gender as the patient, provides advice to the patient, and empowers the
      patient to make his/her own decisions. These service attributes are used as a
      basis for market segmentation, using both socio-demographic variables and cluster
      analysis. Four distinct market segments are identified, with varying degrees of
      viability in terms of target marketing.

PMID- 15017996
TI  - [Laparoscopic colon surgery. Indications and technique].

PMID- 15018001
TI  - Cost-effective advertising through TV and newspaper "banner" ads.
AB  - Banner ads, small strip ads in newspapers used to specifically promote an
      information piece, were introduced into one newspaper in the Connecticut market
      in 1999 by Yale-New Haven Hospital (YNHH). Based on their success, the concept
      was expanded to six additional newspapers in late 2000 and to TV in the summer of
      2001. Between 2000-2002, even as the overall marketing/advertising budget
      declined 30%, switching advertising dollars from image/display ads to banner ads
      resulted in consumer awareness of YNHH increasing from 29% to 42%. Perception of
      YNHH as "the advanced medicine" hospital grew from 22% to 40% during the same
      period. The specific strategic and operational actions generated since the
      implementation of the program are detailed and the advantages and disadvantages
      of this banner advertising approach are discussed. Banner ads may offer an
      alternative approach for organizations to advertise their products and programs.

PMID- 15018000
TI  - From attitude formation to behavioral response in organ donation: using marketing
      to increase consent rates.
AB  - This article presents a theoretical analysis of attitude formation and the
      relationship to stated behavioral intentions as it relates to the decision to
      donate organs. This analysis reveals the presence of three distinct paths to
      behavior of potential donors, groups differing in their involvement with organ
      donation. Promotional objectives and campaign strategies designed to influence
      attitudes and behaviors should differ according to the behavioral path in
      operation and the involvement of the audience. Mass media campaigns are likely to
      reach high involvement groups only. Therefore, personal selling, underutilized in
      previous donation campaigns, should be brought into the donation strategy to
      appeal to low involvement groups. By recognizing differences in audience
      involvement and implementing different strategies, overall donation rates could
      substantially increase.

PMID- 15018002
TI  - Determinants of the use of health plan information in formulating health plan
      selection decisions.
AB  - This study seeks to identify the impact of information on employees' health plan
      selection decision-making. Surveys were administered to 1,722 Federal employees
      working in the Department of Health and Human Services (DHHS) enrolled in the
      Federal Employees Health Benefits Program (FEHBP). This study focuses on the
      enrollees' access to and use of three types of health plan information: print
      information issued by the Federal government (in particular, The Guide to Federal
      Employees Health Benefit Plans), print information issued by the health plans,
      and web-based information. Literature from health plans was utilized to a greater
      degree than The Guide. Web-based information was the least accessed and used.
      Major positive predictors of the use of health plan information from any source
      were: race, time in Federal employment, whether the employee was considering a
      plan change, employees with less time in current plan, employees who search for
      information to make decisions, and spouses' health status. Younger and more
      educated employees were more likely to access web-based information. Implications
      for management, policy, and future research are discussed.

PMID- 15018003
TI  - A descriptive narrative of healthy eating: a social marketing approach using
      psychographics in conjunction with interpersonal, community, mass media and new
      media activities.
AB  - This paper explores the profile of healthy and unhealthy eating consumers in
      terms of demographic, psychographic and communicative variables. Data from 3,388
      respondents to the 1999 DDB Needham Life Style Study were analyzed. The results
      show the healthy eaters to be environmentally conscious and health-oriented,
      suggesting an underlying theme of personal and social responsibility. The
      communicative activities of healthy eaters demonstrate an information orientation
      while unhealthy eaters are more entertainment oriented. Practical and social
      implications are discussed for social marketers regarding target segmentation and
      message design.

PMID- 15018004
TI  - Eczematous diseases of the geriatric population.
AB  - Geriatric patients must endure many medical challenges within and from without
      the integumental system. Clinicians should be comprehensive in treatment and
      thorough in investigation of any and all dermatologic concerns. Many of these
      concerns begin with an eczematous lesion and the differential is broad. Knowledge
      of the structure and anatomy of the skin, and how time and external forces
      combine with internal processes to manifest lesional findings, is the key. The
      dermatologist may have to sift through the entire dermatologic differential each
      and every time he or she encounters a lesion with eczematous characteristics.
      Complete examination of patients and careful attention to their history is the
      best starting point to help patients achieve the most quality from life and the
      least morbidity from disease.

PMID- 15018005
TI  - Scabies and pediculosis.
AB  - Although scabies and pediculosis are difficult and widespread problems, there are
      many effective treatments available. Dermatologists play a major role in
      educating the public in prevention and diagnosis. Although patients are more
      aware and well informed of the infections because of the Internet and other
      sources, practitioners are often the most important source of information and
      treatment in helping to eradicate this worldwide problem.

PMID- 15018007
TI  - Cutaneous manifestations of endocrine-metabolic disease and nutritional
      deficiency in the elderly.
AB  - This article explores cutaneous manifestations of endocrine-metabolic disease and
      nutritional deficiency in the elderly. Topics covered include the following:
      diabetes mellitus, thyroid disorders, adrenal dysfunction, pituitary disorders,
      parathyroid disease, nutritional deficiencies, menopause, and HIV.

PMID- 15018006
TI  - Skin diseases of the lower extremities in the elderly.
AB  - Routine care of the legs and feet in the elderly is important in helping to
      prevent infections, malignancies, and further deterioration. The lower
      extremities are of particular interest because of the increasing amount of
      diseases and disorders involving the legs and feet. Foot disorders in the elderly
      are associated with poor choices in footwear, structural changes, brought on by
      aging, and inadequate knowledge about prevention and treatment. Conservative
      treatments along with gait modification provide positive long-term results,
      although sometimes surgery is necessary for severe foot disorders. Onychomycosis
      and other nail disorders commonly infect the elderly despite the wide variety of
      treatment options. The increase in malignancy formation in the elderly is caused
      by the increase in the elderly population and inadequate treatment of leg ulcers
      and other chronic lesions. Aging is associated with many dermatologic changes;
      many of the disorders and diseases of the lower extremities can be managed if
      detected and treated early. Proper awareness of the signs, symptoms, and care is
      important.

PMID- 15018008
TI  - Cutaneous fungal infections in the elderly.
AB  - Because of impaired host defenses and a favorable environment at specific
      anatomic sites, there is an increased prevalence of seborrheic dermatitis,
      mucosal and cutaneous candidiasis, tinea pedis, and onychomycosis in the
      geriatric population compared with other age groups. Both KOH and fungal culture
      are timely, convenient, and cost-effective methods of diagnosis. Sensitivity of
      these tests depends on proper technique for specimen collection and experience.
      KOH 20% with DMSO and DTM are highly recommended. Treatment should be tailored to
      the diagnosis and the individual patient. This includes the targeted spectrum of
      coverage (dermatophyte or yeast); topical versus systemic therapy; review of the
      patient's medication list for potential drug interactions; and likelihood of
      compliance. Checking baseline laboratories and routine monitoring of complete
      blood count and liver function tests in healthy patients, without a history of
      liver disease or active hepatitis, and without potential drug interactions, seems
      unwarranted for rare adverse events. Successful management requires adequate
      patient education, correction of underlying predisposing factors, and
      prophylactic measures against recurrence.

PMID- 15018009
TI  - Skin infections in the elderly.
AB  - The diagnosis and management of viral diseases of the skin are significant issues
      in the elderly population. With advances in these areas, there are new tools to
      combat these diseases and limit morbidity. It is important for clinicians to
      monitor and treat these diseases aggressively in the elderly because of the
      potential for immunosuppression in this population. Further advances in antiviral
      therapy and the potential for the development of antiviral vaccines will aid in
      the therapy of these diseases. Onychomycosis is found more frequently in the
      elderly. In this population, the most common clinical presentations are distal
      and lateral subungual onychomycosis (which usually affects the great or first
      toe) and white superficial onychomycosis (which generally involves the third or
      fourth toes). Over the past several years, new treatments for this disorder have
      emerged that offer shorter courses of therapy and greater efficacy than previous
      therapies. The treatment of bacterial skin and skin structure infections in the
      elderly is an important issue. There has been an alarming increase in the
      incidence of gram-positive infections, including resistant bacteria, such as MRSA
      and drug-resistant pneumococci. Although vancomycin has been considered the drug
      of last defense against gram-positive multidrug-resistant bacteria, the late
      1980s saw a rise in vancomycin-resistant bacteria, including VRE. With treatment
      options limited, it has become critical to identify antibiotics with novel
      mechanisms of activity. Several new drugs have emerged as possible therapeutic
      alternatives, including linezolid and quinupristin-dalfopristin.

PMID- 15018010
TI  - Antimicrobial therapy and resistance in dermatologic pathogens of the elderly.
AB  - Dermatologic infections are treated to improve the elderly patient's quality of
      life and prevent disability and death. Pharmacokinetic changes, social issues,
      and the risk for adverse effects and drug interactions, however, increase the
      challenge to achieve successful treatment of those over age 65 as compared with
      younger patients. This challenge grows ever larger when coupled with the
      increasing trends of resistance among bacteria and fungi. The clinician can
      effectively face this challenge through careful consideration of diagnosis,
      patient risk factors, antimicrobial pharmacology, and resistance patterns.

PMID- 15018011
TI  - Blistering diseases in the elderly: diagnosis and treatment.
AB  - This article discusses the major blistering diseases in the geriatric population.
      The diagnosis of both immune- and non-immune-mediated blistering disorders can be
      confirmed with the help of histologic and immunopathologic studies. Various
      serologic assays, which are more specific, also can be used to confirm the
      diagnosis of autoimmune blistering diseases. These techniques have facilitated
      the diagnosis and allowed the institution of early treatment. The treatment of
      blistering disorders has included both localized and systemic treatments.
      Localized treatment involves topical care including the following measures: the
      prevention of trauma; soaking of blisters in antiseptic (potassium permanganate
      or aluminum subacetate) solutions; topical and intralesional corticosteroids; and
      the prevention and early treatment of infections with local or systemic
      antibiotics. Conventional oral systemic therapies that have proved to be
      beneficial include systemic corticosteroids, anti-inflammatory agents, and
      immunosuppressive agents. Because the elderly are more prone to the side effects
      of these systemic agents, it is crucial that routine hematologic tests be done
      and monitored until the treatments have been discontinued. Recently, newer
      alternative treatment modalities have proved to be successful in patients who
      failed to respond or developed multiple side effects to the conventional oral
      systemic agents. In conclusion, as clinicians gain a greater understanding into
      the pathogenesis of these diseases, more specific molecular-targeted treatments
      will most likely become available.

PMID- 15018012
TI  - Controversies about the decubitus ulcer.
AB  - Knowledge of the decubitus ulcer has made great progress in recent decades. No
      longer is the diagnosis of a bedsore, as it was in the iron lung days, almost a
      death warrant. One cannot cause to heal a patient who is in organ failure, nor
      can one necessarily prevent ulcers in a new spinal cord-injured patient.
      Reflecting on the common cold, one realizes that prevention is limited to
      covering the face when sneezing, and treatment is symptomatic. There is no way of
      eradicating the virus of the common cold, nor is there an appropriate treatment.
      The decubitus ulcer should be conceived of in a similar vein, until understanding
      is more complete and specific treatments are available.

PMID- 15018013
TI  - Skin cancer in elderly patients.
AB  - The role of the dermatologist who provides care to the geriatric patient assumes
      the care for the integument system. The ability to diagnose and treat cancerous
      lesions effectively with special care given to the needs of the geriatric patient
      is considered indispensable. The clinician should accept the responsibility of
      skin cancers and obtain biopsies with empathy and care.

PMID- 15018014
TI  - Cutaneous oncologic and cosmetic surgery in geriatric patients.
AB  - A wide array of surgical procedures is available to geriatric patients. These
      interventions can enhance the appearance of patients and facilitate the removal
      of skin cancers. Pre-existing medical conditions of geriatric patients must be
      considered comprehensively when selecting and performing cutaneous surgical
      procedures. Many older patients suffer from a variety of diseases and take a
      variety of medications and herbal supplements to ameliorate the consequences of
      such diseases. In general, skin surgery can be performed safely on even very old
      patients, provided precautions are followed. The biopsychosocial well-being and
      essence of patients must also be addressed when performing dermatologic surgery.
      If patients are treated holistically and comprehensively, their surgical
      experience can be enhanced and their health and appearance improved.

PMID- 15018015
TI  - Clinicopathologic attributes of common geriatric dermatologic entities.
AB  - Certain dermatologic lesions may initially present or be more commonly ascribed
      to the elderly. These disorders encompass a diverse array of etiologically
      unrelated degenerative, autoimmune, idiopathic, and neoplastic conditions that
      may dramatically impact the quality of life and produce significant morbidity and
      mortality. As the population ages, a more complete understanding of the clinical
      and histopathologic features unique to the geriatric dermatologic patient is
      essential.

PMID- 15018016
TI  - Benefical effects of reteplase in combination with abciximab: platelet/leukocyte
      interactions and coagulation system.
AB  - Pathophysiological aspects of acute myocardial infarction include altered
      hemostatic and fibrinolytic systems as well as platelet activation. Treatment
      with thrombolytics and GP IIb/IIIa antagonists has been described as having an
      additional influence on these systems. We investigated the effects of a new
      thrombolytic regimen with half-dose double-bolus reteplase (2 x 5 IU, 20
      patients) combined with abciximab versus full dose reteplase (2 x 10 IU, 18
      patients) on platelet-granulocyte complexes and on thrombin-antithrombin III
      complexes in patients with acute ST-segment elevation myocardial infarction. In
      vivo, the thrombolytic regimen with half-dose reteplase in combination with
      abciximab caused fewer platelet-granulocyte aggregates (measured as percentage of
      CD41-positive granulocytes) and a lower paradoxical activation of the coagulation
      system (measured as thrombin-antithrombin III complex) compared with the
      reteplase regimen. The combination regimen could therefore have benefical effects
      on platelet-induced leukocyte activation and leukocyte-mediated
      proinflammatory/cytotoxic effects as well as on granulocyte-induced effects on
      endothelium, tissue damage and coagulation. This could be, at least in part, a
      possible explanation for the significantly lower rates of reinfarction, recurrent
      ischaemia and percutaneous coronary interventions observed during the early phase
      after an acute myocardial infarction in the combination group in the GUSTO-V
      trial.

PMID- 15018017
TI  - Low-dose schema of isotretinoin in acne vulgaris.
AB  - In severe papulopustular and in nodulocystic/conglobate acne, oral isotretinoin
      is the treatment of choice. It is also required for patients with moderate to
      severe acne, especially when acne scars start to occur A new therapeutic approach
      consists of a low-dose regimen of isotretinoin. We performed a comparative study
      of high- and low-dose schemas of isotretinoin per os for the treatment of acne.
      The purpose of this study was to assess the therapeutic effect and tolerability
      of low doses of isotretinoin in the treatment of acne vulgaris and compare low
      dose with high-dose regimens. Sixty-four patients (35 women and 29 men) with
      different types and grades of acne vulgaris were divided into two treatment
      groups of 32 patients, in a trial that compared a low dose of 0.15-0.40 mg/kg per
      day with a high dose of 0.5-1.0 mg/kg per day. These regimens were analyzed with
      reference to clinical history of acne, baseline investigations, dose and response
      to isotretinoin, clinical and laboratory adverse effects, relapses and cost of
      therapy. The mean success rate of the low-dose schema was 69%. The total dose up
      to 120 mg/kg should be followed for optimal results (success rate of 91%) and
      avoidance of relapses. The low-dose schema produced fewer adverse effects and
      offered a very beneficial effect on pre-existing scarring. Our results confirm
      the beneficial effect of the low-dose schema. We recommend a total dose > or =
      120 mg/kg, as this therapeutic regimen of isotretinoin has proven to be the most
      successful in preventing relapses and scarring.

PMID- 15018018
TI  - Calcipotriol ointment versus cream in psoriasis vulgaris.
AB  - Psoriasis is a multifactorial, chronically relapsing, inflammatory skin disease
      occurring in 1-3% of the world's population. Vitamin D3 analogs have effects on
      proliferation and differentiation, as well as on the infiltration and activation
      of neutrophils and immunocytes in psoriatic skin lesions. This study aims to
      assess the efficacy and safety of topical calcipotriol and to compare ointment
      and cream formulations in the treatment of psoriasis vulgaris. A total of 41
      patients with mild to moderate psoriasis vulgaris (18 men and 23 women aged
      between 5 and 63 years) were enrolled in the study. Each patient was instructed
      to apply the treatment twice daily over the psoriatic lesions. Routine blood
      tests and serum calcium were performed prior to and at the end of treatment.
      Treatment assessment was carried out on weeks 2, 4 and 6 and was based on the
      Psoriasis Area and Severity Index (PASI) score. Of the 41 patients included in
      our study, only 29 completed the treatment course. Their PASI before treatment
      ranged from 1.2 to 43 (mean: 12.1). Both groups, calcipotriol 50 microg/g
      ointment (11 patients) and calcipotriol 50 microg/g cream (18 patients) showed
      time-dependent improvement and after 6 weeks there was excellent improvement with
      a marked reduction in the total mean PASI from 12.1 to 1.02. There was a
      significant reduction of PASI in the ointment group in comparison with the cream
      group (mean PASI from 12.7 to 0.8 and 11.1 to 1.15, respectively). No significant
      adverse effects were observed in either group, except for mild irritation in a
      few patients in the calcipotriol cream group. In conclusion, calcipotriol was
      effective, safe and well tolerated in the treatment of psoriasis vulgaris and
      better results were observed with the ointment formulation. Longer treatment
      courses could be advised.

PMID- 15018019
TI  - The acute effects of cilazapril on pulmonary function tests and arterial blood
      gas changes in patients with pulmonary hypertension.
AB  - The aim of the present study was to evaluate pulmonary function tests and
      arterial oxygen transport in patients with pulmonary hypertension due to
      congestive heart failure before and after cilazapril treatment. Thirty patients
      (16 men and 14 women, mean age, 65 +/- 18 years) with congestive heart failure
      and 30 healthy volunteers (20 men and 10 women, mean age 59 +/- 12 years, p >
      0.05) were included in the study. All patients underwent evaluation of pulmonary
      function by spirometry and arterial blood gas analysis. Arterial oxygen
      saturation and arterial oxygen transport changed significantly after treatment
      (81 +/- 7 to 87 +/- 8 and 317 +/- 74 to 392 +/- 8, respectively). Forced
      expiration volume in 1 second, vital capacity and total lung capacity were
      increased after cilazapril treatment (2.55 +/- 0.7 to 2.61 +/- 0.8, 3.2 +/- 0.9
      to 3.3 +/- 1.0 and 3.6 +/- 0.9 to 4.1 +/- 1.1, respectively, p < 0.05). In
      conclusion, short-term cilazapril administration improved pulmonary function and
      arterial oxygen transport because it increased cardiac output, produced pulmonary
      vasodilatation, improved the pulmonary hemodynamics and removed interstitial
      fluid.

PMID- 15018020
TI  - Evaluating pain in osteoarthritis of the hands: the effect of patient
      information.
AB  - The evaluation of osteoarthritis pain is principally based on a subjective rating
      scale. Accuracy in recording pain score is obviously important. In the present
      study we evaluated the effect of better standardization of information given to
      patients in determining the visual analog scale (VAS) score. Fifty-three
      consecutive male and female outpatients aged 18-65 years (40 women and 13 men)
      fulfilling the criteria for osteoarthritis of the hands were included in the
      study. Eligible patients attended the Rheumatology Center on three occasions: day
      1, day 3 and day 6 of the study. Two information cards were prepared. On the
      first card, given to the patient at the end of the first visit, osteoarthritis of
      the hands was described as a less dangerous disease than rheumatoid arthritis. On
      the second card, given to patients at the end of the second visit, greater
      emphasis was placed on anatomo-pathological description of the destructive
      lesions. VAS score was recorded on days 1, 3 and 6 of observation. ANOVA for
      repeated measures demonstrated a significant reduction of VAS score between the
      first and the second assessment and a significant increase between the second and
      the third assessment. A further significant difference was found in the
      comparison between the first and third assessment. These results show that
      different standards of information given to patients may modify VAS score.

PMID- 15018021
TI  - Interindividual variation in the ratio between plasma morphine and its
      metabolites in cancer patients.
AB  - In 25 cancer patients treated with slow-release oral morphine and in 10 cancer
      patients treated with continuous infusion of morphine, plasma steady-state
      concentrations of morphine (M), morphine-3-glucuronide (M-3-G) and morphine-6
      glucuronide (M-6-G) were determined by high-performance liquid chromatography.
      Blood samples were withdrawn at 0, 2 and 6 h after oral administration in
      patients treated with slow-release oral morphine and once or twice a day in
      patients treated with continuous infusion of morphine. In four cancer patients
      treated with continuous infusion of morphine, in order to analyze
      chronopharmacokinetic variability, the M-3-G/M ratio was observed at 12:00 h and
      24:00 h. No significant changes were observed in M-3-G/M ratios and M-6-G ratios
      at 0, 2, and 6 h after oral administration of morphine. The M-3-G/M ratio (38.6
      +/- 25.7) in the oral morphine group was significantly higher than that (15.3 +/-
      12.9) in the continuous infusion group (p < 0.01). There was an approximately 10
      fold interindividual variation in the M-3-G/M ratio both in the continuous
      infusion group and in the oral morphine group. These results suggest that the
      activity of UDP glucuronosyltransferase 2B7 in the intestinal metabolism of
      morphine may play an active part in a large interindividual variation in the
      ratio of metabolites to morphine. Further studies are needed to clarify this
      hypothesis.

PMID- 15018022
TI  - Eggshell calcium in the prevention and treatment of osteoporosis.
AB  - In this paper the most significant biological and clinical aspects of a
      biopreparation made of chicken eggshells are reviewed. Eggshell powder is a
      natural source of calcium and other elements (e.g. strontium and fluorine) which
      may have a positive effect on bone metabolism. Experimental and clinical studies
      performed to date have shown a number of positive properties of eggshell powder,
      such as antirachitic effects in rats and humans. A positive effect was observed
      on bone density in animal models of postmenopausal osteoporosis in ovariectomized
      female rats. In vitro eggshell powder stimulates chondrocyte differentiation and
      cartilage growth. Clinical studies in postmenopausal women and women with senile
      osteoporosis showed that eggshell powder reduces pain and osteoresorption and
      increases mobility and bone density or arrests its loss. The bioavailability of
      calcium from this source, as tested in piglets, was similar or better than that
      of food grade purified calcium carbonate. Clinical and experimental studies
      showed that eggshell powder has positive effects on bone and cartilage and that
      it is suitable in the prevention and treatment of osteoporosis.

PMID- 15018023
TI  - Genetic biomarkers and occupational epidemiology--recollections, reflections and
      reconsiderations.

PMID- 15018024
TI  - Relationship between silicosis and lung function.
AB  - In an examination of the relationship between silicosis and lung function,
      relevant studies of silica-exposed workers were reviewed. Smoking, dust exposure,
      and emphysema are three important factors that can confound the association
      between silicosis and lung function. Despite the importance of smoking in
      relation to lung function, some studies did not control for smoking, or smoking
      was controlled inadequately. The data suggest a weak association between lung
      function (mainly obstruction) and dust exposure, although some studies had crude
      measures of exposure. In general, the lung function of those with radiographic
      silicosis in category 1 was indistinguishable from those in category 0. Those in
      category 2 had small reductions in lung function relative to those with category
      0 and little difference in the prevalence of emphysema. There were slightly
      greater decrements in lung function with category 3 and more significant
      reductions with progressive massive fibrosis. Emphysema was related to higher
      categories of silicosis, as well as to smoking. Silica exposure was often
      inadequately controlled in studies examining silicosis and lung function. A few
      studies suggested that emphysema is an independent risk factor associated with
      significant reductions in lung function.

PMID- 15018025
TI  - Effects on the peripheral nervous system of tunnel workers exposed to acrylamide
      and N-methylolacrylamide.
AB  - OBJECTIVES: This study evaluates the possible toxic effects on the peripheral
      nervous system of tunnel workers exposed to acrylamide and N-methylolacrylamide
      during grouting work. METHODS: Symptoms and nerve conduction velocities (NCV)
      were recorded for 24 tunnel workers 4 and 16 months after the cessation of
      exposure during grouting operations. Fifty tunnel workers not involved in
      grouting operations served as referents. Exposure was assessed by questionnaires,
      qualitative exposure indices, and measurements of hemoglobin adducts after the
      cessation of exposure. RESULTS: The exposed workers reported a higher prevalence
      of symptoms during grouting work than they did in an examination 16 months later.
      A statistically significant reduction in the mean sensory NCV of the ulnar nerve
      was observed 4 months postexposure when compared with the values of the reference
      group (52.3 versus 58.9 m/s, P = 0.001), and the mean ulnar distal delay was
      prolonged (3.1 versus 2.5 ms, P = 0.001). Both measures were significantly
      improved when measured 1 year later. Exposure-related improvements were observed
      from 4 to 16 months postexposure for both the median (motor and sensory NCV and F
      response) and ulnar (sensory NCV, F-response) nerves. A significant reversible
      reduction in the mean sensory amplitude of the median nerve was also observed,
      while the mean sensory amplitude of the sural nerve was significantly reduced
      after 16 months. CONCLUSIONS: The results indicate demyelinating and axonal
      changes in peripheral nerves of tunnel workers in relation to exposure to N
      methylolacrylamide and acrylamide during grouting operations. The changes were
      slight, mostly subclinical, and most of the effects were reversible, with
      normalization after 1 year.

PMID- 15018026
TI  - Exposure to persistent organochlorine compounds through fish consumption and the
      incidence of osteoporotic fractures.
AB  - OBJECTIVES: Animal studies have shown that persistent organochlorine compounds
      (POC) impair normal bone metabolism and result in increased bone fragility. These
      findings may have health implications for POC-exposed human populations. The aim
      of the present study was to assess the impact of POC-contaminated fish on the
      self-reported fracture incidence of Swedish fishermen and their wives. METHODS: A
      postal questionnaire was sent to 2096 fishermen and 1602 fishermen's wives from
      the Swedish east (exposed) coast and 4584 fishermen and 4217 fishermen's wives
      from the west (unexposed) coast. Self-reported fractures, together with specified
      current fish consumption and information about potential confounders, were
      registered. The response rates varied between 50% and 59%. The age distributions
      of the nonrespondents and respondents were almost identical. Hip, vertebral, and
      wrist fractures were classified as osteoporotic. The fracture incidence rates for
      specific skeletal locations were based on allocated fractures and person-years
      under risk from the age of 25 years until the time of fracture or the end of
      follow-up. RESULTS: No differences in fracture incidence were observed between
      the east and west-coast cohorts. East-coast wives with more than one meal of
      fatty fish from the Baltic Sea per month had, however, an increased fracture
      incidence as compared with that of the east-coast wives who ate, at most, one
      such meal per month (age-adjusted incidence rate ratio 1.68, 95% confidence
      interval 1.00-2.84). No such exposure-response association was found for the
      fishermen. CONCLUSIONS: The present study only minimally supports an association
      between POC exposure through contaminated fish and an increased risk of
      osteoporotic fractures.

PMID- 15018027
TI  - Costs, benefits and effectiveness of worksite physical activity counseling from
      the employer's perspective.
AB  - OBJECTIVES: This study evaluated the impact of worksite physical activity
      counseling using cost-benefit and cost-effectiveness analyses. METHODS: Civil
      servants (N = 299) were randomly assigned to an intervention (N = 131) or control
      (N = 168) group for 9 months. The intervention costs were compared with the
      monetary benefits gained from reduced sick leave. In addition, the intervention
      costs minus the monetary benefits from sick leave reduction were compared with
      the effects (percentage meeting the public health recommendation for moderate
      intensity physical activity, energy expenditure, cardiorespiratory fitness, and
      upper extremity symptoms). RESULTS: The intervention costs were EUR 430 per
      participant, and the benefits were EUR 125 due to sick leave during the
      intervention period, for net total costs of EUR 305 for the intervention. During
      the same 9-month period the year after the intervention, the benefits from sick
      leave reduction were EUR 635. No statistically significant differences in costs
      and benefits were found between the groups. As to the cost-effectiveness,
      improvement in energy expenditure and cardiorespiratory fitness was observed at
      higher costs. The point estimates of the cost-effectiveness ratios were EUR 5.2
      (without imputation of effect data) and EUR 2.7 (with imputation of effect data)
      per extra kilocalorie of energy expenditure per day and EUR 235 (without
      imputation of effect data) and EUR 45.9 (with imputation of effect data) per beat
      per minute of decrease in submaximal heart rate. CONCLUSIONS: This study does not
      provide a financial reason for implementing worksite counseling intervention on
      physical activity on the short-term. However, positive effects were shown for
      energy expenditure and cardiorespiratory fitness.

PMID- 15018028
TI  - Psychosocial job factors and the one-year evolution of back-related functional
      limitations.
AB  - OBJECTIVES: This 1-year prospective study aimed at assessing the association
      between some psychosocial job characteristics and back-related functional
      limitations. METHODS: The participants were 849 workers who sought medical
      consultation for nonspecific back pain in primary care settings of the Quebec
      City area. Information on job decision latitude, psychological demands, and
      social support at work was collected during a telephone interview conducted after
      the medical consultation. Back-related functional limitations were measured at
      baseline and 1 year later with the Roland-Morris Disability Questionnaire. The
      analyses were stratified by gender. Social support at work and the type of back
      pain were considered potential effect modifiers. Several potential confounders
      were also considered in the multiple regression analyses that were conducted to
      isolate the effect of the job psychological demands and decision latitude on the
      1-year level of back-related functional limitations. RESULTS: A modest difference
      in the 1-year Roland-Morris average scores was found only among the women and
      only for the association between job decision latitude with back-related
      functional limitations, according to the level of social support at work. This
      difference was of limited clinical significance. Analyses by type of back pain
      showed, however, a clinically significant association between the combination of
      high psychological demands and low decision latitude and back-related functional
      limitations only for subjects with persistent pain. CONCLUSIONS: Job
      psychological demands and decision latitude have little influence on the 1-year
      evolution of back-related functional limitations for one-time and recurrent back
      pain problems. However, our results suggest that this association could be
      important for workers with persistent pain.

PMID- 15018029
TI  - Different risk factors for musculoskeletal complaints and musculoskeletal
      sickness absence.
AB  - OBJECTIVES: The aim of this study was to investigate whether individual, work
      related physical and psychosocial risk factors involved in the occurrence of
      musculoskeletal complaints also determine musculoskeletal sickness absence.
      METHODS: This cross-sectional study used a self-administered questionnaire to
      collect data on individual and work-related risk factors and the occurrence of
      musculoskeletal complaints and musculoskeletal sickness absence among 373
      employees of laundry-works and dry-cleaning establishments (response rate 87%).
      Logistic regression models were used to determine associations between risk
      factors and the occurrence of musculoskeletal complaints and sickness absence due
      to these complaints. RESULTS: Both work-related physical and psychosocial factors
      showed strong associations with low-back pain and upper-extremity complaints.
      Work-related physical factors did not influence sickness absence, whereas
      psychosocial factors showed some associations with sickness absence. Sickness
      absence was associated with The Netherlands as the country of birth [odds ratio
      (OR) 0.3, 95% confidence interval (95% CI) 0.2-0.6], and female workers had an
      episode of sickness absence due to low-back pain less often (OR 0.5, 95% CI 0.3
      0.9), but more often due to upper-extremity complaints (OR 2.2, 95% CI 1.14.5).
      CONCLUSIONS: Work-related physical and psychosocial factors largely determine the
      occurrence of low-back pain and upper-extremity complaints, whereas individual
      factors predominantly determine whether persons with these musculoskeletal
      complaints take sick leave.

PMID- 15018031
TI  - Some implications of genetic biomarkers in occupational epidemiology and
      practice.
AB  - This paper addresses the use of genetic biomarkers in occupational epidemiology
      and some of the scientific, ethical, and social implications for epidemiologists
      and practitioners to consider, including issues involving individual risk
      estimation, the communication of epidemiologic results, and the translation of
      epidemiologic data into clinical or occupational health practice. Three scenarios
      from the occupational setting illustrate some of these issues and implications.
      The scenarios involve glutathione-S-transferase theta 1 (GSTT1) and hematopoietic
      cancer in hospital workers, human leukocyte antigen coding for glutamic acid in
      the 69th position (HLA DPB1(E69)) and chronic beryllium disease in beryllium
      workers, and peripheral myelin protein 22 (PMP22) deletion and carpal tunnel
      syndrome in railroad track workers. Epidemiologic research involving genetic
      biomarkers requires the application of genetic tests and can be considered on a
      continuum between basic sciences and clinical and occupational and public health
      practice for which questions of test relevance, validity, and utility become
      important.

PMID- 15018030
TI  - Cancer mortality and morbidity among Lithuanian asbestos-cement producing
      workers.
AB  - OBJECTIVES: This study investigated the incidence of cancer and cause-specific
      mortality among workers in the two Lithuanian asbestos-cement factories. METHODS:
      The study included 1887 asbestos-cement workers, 1285 men and 602 women, and
      37000 person-years. The two factories were active from 1956 (A) and 1963 (B), and
      the workers were observed from 1978 to 2000. The analysis was based on a
      comparison between the observed and expected numbers of cancer and causes of
      death. The observed numbers of cancer were obtained through linkage with the
      national cancer registry. The date and causes of death were obtained from two
      different sources. The expected numbers were calculated on the basis of gender-
      and age-specific incidence and mortality rates in 5-year periods from the whole
      country. Standardized incidence ratios (SIR) and standardized mortality ratios
      (SMR) and 95% confidence intervals (95% CI) were calculated. Duration of
      employment and time since first exposure were used as indicators of exposure.
      RESULTS: During the follow-up, 1978-2000. 473 deaths were observed versus 489
      expected. There was no excess risk of deaths from nonmalignant respiratory
      diseases, except for an elevated risk of mortality in relation to the digestive
      organs other than cancer, 18 observed versus 12.2 expected (95% CI 0.9-2.3).
      There was no excess risk for any types of cancer, except for colorectal cancer in
      men, 17 observed cases (SIR 1.6, 95% CI 1.6-2.6) and one case of mesothelioma in
      a woman. CONCLUSIONS: This study on asbestos-exposed workers did not show any
      excess risk of respiratory cancer or deaths of pneumoconiosis.

PMID- 15018032
TI  - Use of surname models in human population biology: a review of recent
      developments.
AB  - Since 1985, when a bibliography concerning studies on surnames and genetic
      structure appeared, the number of publications on this subject has increased a
      thousandfold. New topics and uses have been added, but large gaps in knowledge
      remain. Only studies on isonymy in cities of nation states for recent times are
      well covered, and most studies are on populations that were selected because they
      are isolated and not because they are typical. This review, although not
      exhaustive, covers the literature published since 1985.

PMID- 15018033
TI  - Mitochondrial DNA variation and the origins of the Aleuts.
AB  - The mitochondrial DNA (mtDNA) variation in 179 Aleuts from five different islands
      (Atka, Unalaska, Umnak, St. Paul, and St. George) and Anchorage was analyzed to
      better understand the origins of Aleuts and their role in the peopling of the
      Americas. Mitochondrial DNA samples were characterized using polymerase chain
      reaction amplification, restriction fragment length polymorphism analysis, and
      direct sequencing of the first hypervariable segment (HVS-I) of the control
      region. This study showed that Aleut mtDNAs belonged to two of the four
      haplogroups (A and D) common among Native Americans. Haplogroup D occurred at a
      very high frequency in Aleuts, and this, along with their unique HVS-I sequences,
      distinguished them from Eskimos, Athapaskan Indians, and other northern
      Amerindian populations. While sharing several control region sequences (CIR11,
      CHU14, CIR60, and CIR61) with other circumarctic populations, Aleuts lacked
      haplogroup A mtDNAs having the 16265G mutation that are specific to Eskimo
      populations. R-matrix and median network analyses indicated that Aleuts were
      closest genetically to Chukotkan (Chukchi and Siberian Eskimos) rather than to
      Native American or Kamchatkan populations (Koryaks and Itel'men). Dating of the
      Beringian branch of haplogroup A (16192T) suggested that populations ancestral to
      the Aleuts, Eskimos, and Athapaskan Indians emerged approximately 13,120 years
      ago, while Aleut-specific A and D sublineages were dated at 6539 +/- 3511 and
      6035 +/- 2885 years, respectively. Our findings support the archaeologically
      based hypothesis that ancestral Aleuts crossed the Bering Land Bridge or
      Beringian platform and entered the Aleutian Islands from the east, rather than
      island hopping from Kamchatka into the western Aleutians. Furthermore, the Aleut
      migration most likely represents a separate event from those responsible for
      peopling the remainder of the Americas, meaning that the New World was colonized
      through multiple migrations.

PMID- 15018034
TI  - Genetics and population history of Caucasus populations.
AB  - We describe aspects of genetic diversity in several ethnic populations of the
      Caucasus Mountains of Daghestan using mitochondrial DNA sequences and a sample of
      100 polymorphic Alu insertion loci. The mitochondrial DNA (mtDNA) sequences are
      like those of Europe. Principal coordinates and nearest neighbor statistics show
      that there is little detectable structure in the distances among populations
      computed from mtDNA. The Alu frequencies of the Caucasus populations suggest that
      they have undergone more genetic drift than most other groups since the dispersal
      of modern humans. Genetic differences among these populations are not large;
      instead, they are of the same order as distances among populations of Europe. We
      compare two methods of inference about the demography of ancient colonizing
      populations from Africa, one based on conventional FST statistics and one based
      on mean Alu insertion frequencies. The two approaches agree reasonably well if we
      assume that there was demographic growth in Africa before the diaspora of
      ancestors of contemporary regional human groups outside Africa.

PMID- 15018035
TI  - Beta-globin gene cluster haplotypes in the Corsican and Sardinian populations.
AB  - The distribution of beta-globin cluster haplotypes has been studied in the
      populations of Corsica (France) and Sardinia (Italy). The analysis was carried
      out using five restriction fragment length polymorphism markers on chromosome 11
      inside the beta-globin cluster using the restriction enzymes HincII and HindIII.
      The results show a remarkable heterogeneity within the two islands. However, the
      presence of rare haplotypes common to the most conservative areas (Nuoro and
      Corte) of the two islands is particularly interesting. These data support the
      hypothesis of a common origin of the populations of Sardinia and Corsica during
      the middle and upper Paleolithic periods and could be interpreted as a founder
      effect.

PMID- 15018036
TI  - Insertion/deletion polymorphisms in tribal populations of southern India and
      their possible evolutionary implications.
AB  - India has the unique distinction of having perhaps the largest diversities, both
      biological and cultural. The Nilgiri Hills of southern India, a home for several
      tribal pockets representing different genetic isolates, provides a genetic wealth
      to understand human evolution. We have analyzed eight widely distributed
      polymorphic insertion/deletion loci (AluAPO, AluACE, AluDI, AluPLAT, AluPV92,
      AluFXIIIB, CD4 del and mtNUC) in 250 unrelated individuals from five tribal
      populations (Badaga, Irula, Kota, Kurumba, and Toda). All loci were highly
      polymorphic except the CD4 del locus, at which the deletion allele was fixed in
      Kotas and Kurumbas. The levels of average heterozygosities were found to be high
      in all the populations. In most populations, they were also higher than those
      predicted by the island model of population structure. The gene diversity (GST =
      8.3%) was found to be higher than that in populations of most global regions with
      the exception of Africa. It is clear from the present study that drift effects
      could have accentuated the process of genetic differentiation of the tribal
      populations. The possibility of an early demographic expansion of modern humans
      within south India also cannot be ruled out.

PMID- 15018037
TI  - Angiotensin-converting enzyme gene (ACE) insertion/deletion polymorphism in
      Mexican populations.
AB  - The angiotensin-converting enzyme gene (ACE) insertion/deletion polymorphism was
      determined in 211 Mexican healthy individuals belonging to different Mexican
      ethnic groups (98 Mestizos, 64 Teenek, and 49 Nahuas). ACE polymorphism differed
      among Mexicans with a high frequency of the D allele and the D/D genotype in
      Mexican Mestizos. The D/D genotype was absent in Teenek and present in only one
      Nahua individual (2.0%). When comparisons were made, we observed that Caucasian,
      African, and Asian populations presented the highest frequencies of the D allele,
      whereas Amerindian (Teenek and Pima) and Australian Aboriginals showed the
      highest frequencies of the I allele. The distribution of I/D genotype was
      heterogeneous in all populations: Australian Aboriginals presented the lowest
      frequency (4.9%), whereas Nahuas presented the highest (73.4%). The present study
      shows the frequencies of a polymorphism not analyzed previously in Mexican
      populations and establishes that this polymorphism distinguishes the Amerindian
      populations of other groups. On the other hand, since ACE alleles have been
      associated with genetic susceptibility to developing cardiovascular diseases and
      hypertension, knowledge of the distribution of these alleles could help to define
      the true significance of ACE polymorphism as a genetic susceptibility marker in
      the Amerindian populations.

PMID- 15018038
TI  - God, faith, and death: the impact of biological and religious correlates on
      mortality.
AB  - Marked denominational mortality differentials have been documented for various
      time periods and geographic locations. From a historical perspective, death rates
      among Catholics are often found to be higher than those among Protestants or
      Jews. Using a conceptual model based on the life history approach, biomedical and
      sociocultural factors of causation are extrapolated. In total, 5513 historical
      entries from family reconstitution were available. Selection of data was guided
      by the inclusion of information about religious affiliation. Only married couples
      with children as well as single mothers were considered. Of these, 1855 entries
      were of Roman Catholic (C), 1143 of Lutheran/Protestant (L/P), and 609 of
      Reformed Calvinist (R) denomination. With a focus on both adult and subadult
      mortality, this study attempted to document that the cultural patterns associated
      with religious behavior are merely proximate determinants, while the ultimate
      causes are biological in nature. Survival prospects depended on demographic and
      familial characteristics such as age-at-first-birth, spacing and stopping
      behavior, infant care, and targeted sibship size, rather than religiosity.

PMID- 15018039
TI  - Achieving women and declining sex ratios.
AB  - Professionally written biographies of 353 women selected for inclusion in two
      volumes of a dictionary of biography were analyzed separately for data on family
      structure, occupation, and personality characteristics. Findings from Volume 4
      (1921-1940) were similar to those from Volume 5 (1941-1960). Results showed that
      55.2% of women biographees had no children. They were either unmarried or, if
      married, childless. Of those who did have children, biographees had a
      significantly high ratio of sons to daughters compared with the norm (0.514)
      (Vol. 4: males = 106, females = 76; Vol. 5: males = 115, females = 80; totals:
      males = 221, females = 156; chi2 = 7.87; p = 0.005). These data, interpreted
      according to the maternal dominance hypothesis (Grant 1998) and set in the
      context of increased workforce participation by women and declining fertility,
      suggest another possible explanation for the contemporary decline in the
      secondary sex ratio.

PMID- 15018040
TI  - Population structure of Sao Miguel Island, Azores: a surname study.
AB  - The knowledge of a population structure may constitute a powerful tool for
      mapping genes underlying susceptibility to Mendelian and complex diseases. To
      obtain a better understanding of the population structure of Sao Miguel Island
      (Azorean Archipelago, Portugal), we carried out a surname survey using the
      surnames listed in the most recent telephone book (2001). We identified 1315
      different surnames in a total of 27,621 subscribers. The frequency of the
      different surnames was used to calculate the following parameters: isonymy (I),
      random component of inbreeding (FST), genetic diversity according to Fisher
      (alpha), migration rate according to Karlin-McGregor (v) and Nei's genetic
      distance. Eleven localities were selected, according to population size and
      geographic distribution, for analysis using the above parameters. Our results
      show that 51% of Salga's population and 52% of Sete Cidades's population are
      represented by six and eight surnames, respectively. These figures demonstrate
      the effective isolation of these two small places, which are located at opposite
      ends of Sao Miguel Island. Salga, Achada, and Sete Cidades present the lowest
      values of Fisher's alpha, indicating less genetic diversity. In contrast, the
      capital, Ponta Delgada, presents the highest value of alpha (78.13), indicating
      more genetic diversity. Our data indicate that the clustering of the localities
      corresponds to the geographic features of the island, where localities close
      together tend to share similar surnames. In conclusion, the population of Sao
      Miguel is relatively homogeneous and may constitute an ideal model for genetic
      mapping studies.

PMID- 15018041
TI  - A 9.1-kb insertion/deletion polymorphism suggests a common pattern of genetic
      diversity in Island Melanesia.
AB  - Earlier reports suggest a distinct pattern of genetic variation linked to both
      language and geographic distance in Island Melanesia. Inland Papuan-speaking
      populations from different islands tend to share one allelic profile, while shore
      based or more cosmopolitan populations share another, related to Southeast Asian
      influence over the past 3000 years. In the present paper, we report the genotypes
      and allele frequencies of an informative 9.1-thousand-base-pairs (kb)
      insertion/deletion polymorphism in 19 populations living in Island Melanesia. The
      populations studied inhabit the islands of New Britain, New Ireland, New Hanover,
      and Mussau in the Bismarck Archipelago, and speak either Austronesian or Papuan
      languages. We also include for reference a collection from New Guinea and
      Bougainville. The data show a marked fluctuation in the allele frequency among
      the different isolates, with the 9.1-kb(-) allele frequency ranging from 0.67 to
      0.98. The deletion allele reaches fixation in some Papuan-speaking interior
      populations of New Britain, as well as in the interiors of New Guinea and
      Bougainville. However, certain inland Austronesian-speaking populations also
      share a similar high frequency of the deletion. Our data suggest that language
      distinctions are generally, but not invariably, indicative of diverse allelic
      patterns in this complex region, where inland groups on large islands tend to be
      often distinctive from shore-based populations.

PMID- 15018042
TI  - Betacyanins and phenolic compounds from Amaranthus spinosus L. and Boerhavia
      erecta L.
AB  - Stem bark extracts of Boerhavia erecta L. (erect spiderling) and Amaranthus
      spinosus L. (spiny amaranth), two wild growing weed plants used in traditional
      African medicine, were characterized with respect to their phenolic profile
      including the betalains. While the main betalains in A. spinosus were identified
      as amaranthine and isoamaranthine, the major betacyanins in B. erecta were
      betanin, isobetanin together with neobetanin. The latter showed higher betalain
      concentrations amounting to 186 mg/100 g, while the former contained 24 mg
      betacyanins in 100 g of the ground plant material. Extracts of A. spinosus were
      found to contain hydroxycinnamates, quercetin and kaempferol glycosides, whereas
      catechins, procyanidins and quercetin, kaempferol and isorhamnetin glycosides
      were detected in B. erecta. The amounts of these compounds ranged from 305 mg/100
      g for A. spinosus to 329 mg/100 g for B. erecta.

PMID- 15018043
TI  - Verbenacine and salvinine: two new diterpenes from Salvia verbenaca.
AB  - Two new diterpenes namely verbenacine (1) and salvinine (2) have been isolated
      from the aerial parts of Salvia verbenaca. Their structures have been elucidated
      on the basis of chemical and spectral data as 3alpha-hydroxy-19-carboxykaur-15
      ene and 19-hydroxy-12,14-dioxo labda-15,17-diene.

PMID- 15018044
TI  - Chemical constituents of Euphorbia marschalliana Boiss.
AB  - Acetone extract of aerial parts of Euphorbia marschalliana collected from Iran
      has been subjected to different chromatography techniques for fractionation and
      purification. The stereo-structures of the myrsinol esters 15-O-acetyl-3-O
      propionyl-5-O-butanoyl-7-O-nicotinoylmyrsinol (1) and 15-O-acetyl-3,5-O
      dibutanoyl-7-O-nicotinoylmyrsinol (2) have been probed using ROESY spectroscopy
      and modified for the stereochemistry at C-6, C-12 and C-13. Beta-sitosterol (3),
      29-norcycloart-5-ene (4), 5,8-lanostadiene-3beta-ol (5), 3beta,24(S),25
      trihydroxycycloartane (6), 3beta,24(R),25-trihydroxycycloartane (7) and 24
      methylenecycloartan-3beta-ol (8) were identified for the first time in this
      plant.

PMID- 15018045
TI  - Sesquiterpenes and a phenylpropanoid from Cordia trichotoma.
AB  - Two new secondary metabolites, the phenylpropanoid 3-(2',4',5'
      trimethoxyphenyl)propanoic acid (1) and the sesquiterpene (+)-1beta,4beta,6alpha
      trihydroxyeudesmane (2) were isolated from the heartwood of Cordia trichotoma
      Vell., along with the known sesquiterpenes (-)-1beta,4beta,7alpha
      trihydroxyeudesmane (3) and (+)-1beta,4beta,11-trihydroxyoppositane (4). Their
      structures were elucidated by means of spectroscopic data interpretation, mainly
      1D and 2D NMR and mass spectrometry.

PMID- 15018046
TI  - Dorycnioside, a new phenylbutanone glucoside from Dorycnium pentaphyllum subsp.
      herbaceum.
AB  - A new phenylbutanone glucoside, dorycnioside, was isolated from the methanol
      extract of the aerial parts of Dorycnium pentaphyllum subsp. herbaceum Vill.
      (Rouy) and identified as 4-(4'-O-beta-D-glucopyranosyl-3',5'-dimethoxyphenyl)-2
      butanone (1). In addition, two known phenylbutanone glucosides, five flavonoids,
      one cyanogenic glucoside, one cyclitol and one hydroquinone glucoside were also
      isolated and identified. The major constituent of the methanol extract was found
      to be myricitrin. The structure of 1 was elucidated on the basis of its
      spectroscopic data. It is the first time that derivatives of phenylbutanone are
      isolated from the Leguminosae family.

PMID- 15018047
TI  - Determination of aucubin and catalpol in Plantago species by micellar
      electrokinetic chromatography.
AB  - Micellar electrokinetic chromatography (MEKC) was used for the separation and
      determination of two iridoid glycosides, aucubin and catalpol, in several
      Plantago species growing in Croatia: P. altissima L., P. argentea Chaix, P.
      coronopus L., P. holosteum Scop. (subsp. depauperata, subsp. holosteum and subsp.
      scopulorum), P. lagopus L., P. lanceolata L., and P. maritima L. Hot water
      extraction (HWE) was applied for the isolation of iridoid substances. Significant
      differences appeared between the iridoid contents in the examined species. The
      yield of aucubin and catalpol was up to 0.27% and 1.81% of the dry mass of the
      leaves, respectively. Besides aucubin and catalpol, two related compounds were
      determined in the plant samples.

PMID- 15018048
TI  - Aromatic components of the leaves of the New Zealand lemonwood tree Pittosporum
      eugenioides.
AB  - The major aromatic components of the essential leaf oil of the New Zealand
      lemonwood tree Pittosporum eugenioides are octyl acetate (33%), terpinen-4-ol
      (13%), decanol (6%) and (Z)-hex-3-enol (5%). These products are responsible for
      the characteristic Citrus-like aroma which is detected when the leaves are
      crushed, a phenomenon which provided the species with its common name. The major
      component of the oil, octyl acetate is also an abundant component of the
      essential oils of Heracleum and Boswellia species.

PMID- 15018049
TI  - Essential oils of the leaves of the Raukaua genus (Araliaceae).
AB  - The Raukaua genus of the family Araliaceae consists of 3 species, R. anomalus, R.
      edgerleyi and R. simplex, all endemic to New Zealand. The essential oil of R.
      edgerleyi and R. simplex consisted largely of monoterpenes. Limonene was the most
      abundant (23%) in R. edgerleyi and myrcene the most abundant (34%) in R. simplex.
      The oil of R. simplex lacked any significant sesquiterpenoids whereas
      bicyclogermacrene constituted 12% of the oil of R. edgerleyi. The oil of R.
      anomalus contained monoterpenes in low abundance and the sesquiterpenoids
      germacrene-B (15%) and gamma-muurolene (16%) dominated the composition of this
      oil. The oil of R. edgerleyi had a pleasant fresh green aroma but the low yields
      of all three oils excluded them from potential commercial use.

PMID- 15018050
TI  - Essential oils from the leaves of three New Zealand species of Pseudopanax
      (Araliaceae).
AB  - Essential oils from three of the eleven endemic New Zealand species of
      Pseudopanax, P. arboreus, P. discolor and P. lessonii, were found to have a
      fairly uniform composition which was different from that of the oils of Raukaua
      species that were formerly classified in the Pseudopanax genus. Oils of the three
      Pseudopanax species all contained significant proportions of viridiflorol and a
      closely related unidentified hydroazulene alcohol in common. In addition, the oil
      of P. arboreus contained bicyclogermacrene, linalool and long chain hydrocarbons.
      The oil of P. discolor contained nerolidol in abundance (36.3%) together with
      linalool and epi-alpha-muurolol. The oil of P. lessonii contained a complex
      mixture of sesquiterpene alcohols including epi-alpha-muurolol and a mixture of
      long chain hydrocarbons. Nerolidol and linalool provided the oil of P. discolor
      with a pleasant floral aroma, but the yield of oil was very low (0.01%).

PMID- 15018051
TI  - Flavonoids from the genus Taxus.
AB  - From the needles of Taxus baccata the following flavonoids were isolated: 3-O
      rutinosides quercetin, myricetin and kaempferol, 7-O-glucosides kaempferol and
      quercetin, kaempferol, quercetin, myricetin. The composition of flavonols and
      biflavones in some of the species of the genus Taxus, namely T. celebica, T.
      cuspidata, T. media and cultivar varieties T. baccata 'Aurea', T. baccata 'Aurea
      decora', T. baccata 'Elegantissima', T. baccata 'Fastigiata', T. baccata
      'Pyramidalis', T. media 'Hatfieldii' were compared by HPLC separation.

PMID- 15018052
TI  - Secondary metabolite content in Fabiana imbricata plants and in vitro cultures.
AB  - A rapid in vitro propagation system leading to the formation of shoots, calli,
      roots, cell suspensions and plantlets was developed for the Andean medicinal
      plant Fabiana imbricata (Solanaceae). Massive propagation of shoots and roots was
      achieved by the temporary immersion system (TIS), morphogenesis and maintenance
      of cell suspensions by standard in vitro culture techniques. Oleanolic acid (OA),
      rutin, chlorogenic acid (CA) and scopoletin content in aerial parts of wild
      growing Fabiana imbricata plants as well as in plantlets regenerated in vitro,
      callus cultures, cell suspensions and biomass, obtained by the TIS system was
      assessed by HPLC. On a dry weight basis, the OA content in the aerial parts of
      the plant ranged between 2.26 and 3.47% while in vitro plantlets, callus and root
      cultures presented values ranging from not detected up to 0.14%. The rutin
      content of the samples presented a similar trend with maxima between 0.99 and
      3.35% for the aerial parts of the plants to 0.02 to 0.20% for plantlets, 0.12%
      for cell suspensions and 0.28% for callus. Rutin was not detected in the roots
      grown by the TIS principle. The CA and scopoletin content in the aerial parts of
      F. imbricata ranged between 0.22-1.15 and < 0.01-0.55%, respectively. In the
      plantlets, the concentration of CA was 0.29 to 1.48% with scopoletin in the range
      0.09 to 0.64% while in the callus sample, the CA and scopoletin content were 0.46
      and 0.66%, respectively. A very different result was found in roots grown by TIS,
      where both OA and rutin were not detected and its main secondary metabolite,
      scopoletin was found between a range of 0.99 and 1.41% with CA between of 0.11
      and 0.42%.

PMID- 15018053
TI  - Fatty acids profile of Spirulina platensis grown under different temperatures and
      nitrogen concentrations.
AB  - The influence of culture temperature and the concentration of sodium nitrate
      (NaNO3) on the gas-chromatographic profile of the fatty acids of the filamentous
      cyanobacterium Spirulina platensis was evaluated. We found that temperature was
      the most important factor and that the greatest amount of gamma-linolenic acid
      (GLA) was obtained at 30 degrees C, the fatty acid profile of the Spirulina
      cultivated showing that (in order of abundance) palmitic, linolenic and linoleic
      acids were most prevalent.

PMID- 15018054
TI  - Influence of temperature on phytohormone interactions with monolayers obtained
      from phospholipids of wheat calli.
AB  - The effect of temperatures (15 and 5 degrees C) on adsorption parameters of
      phytohormones at monolayers prepared from a mixture of phospholipids extracted
      from non-embryogenic (NE) and embryogenic (E) winter wheat calli initiated from
      inflorescences (inf) and embryos (emb) was studied. The surface parameter values,
      i.e. limiting area and collapse pressure, were determined using the Langmuir
      method. Phytohormones 2,4-dichlorophenoxyacetic acid (2,4-D), indole-3-acetic
      acid (IAA), kinetin, zeatin and zearalenone were investigated. The phytohormones,
      at a concentration of 0.2 microg/ml dissolved in water, were injected into the
      subphase. Phospholipids, at the concentration of 2 mg/ml, were spread at the
      water surface and the monolayer was compressed. The anomalous temperature effect
      was observed, especially, in non-embryogenic systems. In monolayers obtained from
      E phospholipids, the temperature effect was dependent on the kind of tissue from
      which the callus was initiated. Among all the examined phytohormones, the
      greatest changes (monolayer expansion) were found for IAA and zearalenone.
      However, this activity depended strongly on the kind of tissue from which the
      phospholipid mixture was extracted.

PMID- 15018055
TI  - Alkaloids in Bulgarian Pancratium maritimum L.
AB  - A GC/MS analysis of alkaloids from leaves, bulbs and roots of Pancratium
      maritimum was performed. From the identified 16 alkaloids, 5 alkaloids were
      reported for the first time for this plant. Several compounds with
      pharmacological activity were found. Haemanthamine was main alkaloid in the
      leaves and bulbs whereas galanthane was found to be main alkaloid in roots.

PMID- 15018056
TI  - Rhamnolipid biosurfactants produced by Renibacterium salmoninarum 27BN during
      growth on n-hexadecane.
AB  - A new strain Renibacterium salmoninarum 27BN was isolated for its capacity to
      utilize n-hexadecane as sole substrate. Growth on n-hexadecane was accompanied
      with the production of glycolipid surface active substances detected by surface
      pressure lowering and emulsifying activity. Glycolipid detection by thin layer
      chromatography and infrared spectra analyses showed for the first time that
      Renibacterium salmoninarum 27BN secretes the two rhamnolipids RLL and RRLL
      typical for Pseudomonas aeruginosa. Growth of Renibacterium salmoninarum 27BN on
      n-hexadecane depended on the bioavailability of the substrate and the secreted
      rhamnolipids appeared to be efficient in increasing hexadecane availability for
      the cells.

PMID- 15018057
TI  - Composition and the in vitro antimicrobial activities of the essential oils of
      some Thymus species.
AB  - The genus Thymus (Lamiaceae) is represented by 38 species (64 taxa) in Turkey,
      and 24 of which are endemic to Turkey. Aerial parts of Thymus longicaulis subsp.
      chaubardii var. chaubardii, T. zygioides var. lycaonicus, T. longicaulis subsp.
      longicaulis var. subisophyllus and T. pulvinatus collected from three different
      localities in Balikesir province were subjected to hydrodistillation to yield
      essential oils which were subsequently analysed by GC and GC/MS. The main
      constituents of the oils were identified, and antimicrobial bioassay was applied.
      Thymol (56.6%, 42.8%, 36.9%) was the main component in the oils of T. longicaulis
      subsp. chaubardii var. chaubardii (chemotype I), T. longicaulis subsp. chaubardii
      var. chaubardii (chemotype II) and T. zygioides var. lycaonicus respectively. The
      oil of T. longicaulis subsp. longicaulis var. subisophyllus contained carvacrol
      (60.0%) and the oil of T. pulvinatus borneol (27.9%) as main constituents.

PMID- 15018058
TI  - New steroidal saponins from rhizomes of Costus spiralis.
AB  - Two new steroidal saponins were isolated from the rhizomes of Costus spiralis
      Rosc. Their structures were established as (3beta,25R)-26-(beta-D
      glucopyranosyloxy)-22-hydroxyfurost-5-en-3-yl O-D-apio-beta-D-furanosyl-(1-->2)-O
      [alpha-L-rhamnopyranosyl-(1-->4)]-beta-D-glucopyranoside (1) and (3beta,25R)-26
      (beta-D-glucopyranosyloxy)-22-hydroxyfurost-5-en-3-yl O-D-apio-beta-D-furanosyl
      (1-->4)-O-[alpha-L-rhamnopyranosyl-(1-->2)]-beta-D-glucopyranoside (2). Their
      structural identifications were performed using detailed analyses of 1H and 13C
      NMR spectra including 2D NMR spectroscopic techniques (DEPT, COSY, HETCOR and
      COLOC) and chemical conversions. The steroidal saponins were evaluated for anti
      inflammatory activity.

PMID- 15018059
TI  - Prolyl endopeptidase inhibitors from Syzygium samarangense (Blume) Merr. & L. M.
      Perry.
AB  - Compounds isolated from the hexane extract of the leaves of Syzygium samarangense
      (Blume) Merr. & L. M. Perry were tested for inhibitory activity against the
      following serine proteases: trypsin, thrombin and prolyl endopeptidase. The
      compounds were identified as an intractable mixture of alpha-carotene and beta
      carotene (1), lupeol (2), betulin (3), epi-betulinic acid (4), 2',4'-dihydroxy-6'
      methoxy-3'-methylchalcone (5), 2'-hydroxy-4',6'-dimethoxy-3'-methylchalcone (6),
      2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (7), 2',4'-dihydroxy-6'-methoxy
      3'-methyldihydrochalcone (8) and 7-hydroxy-5-methoxy-6,8-dimethylflavanone (9).
      Hydrogenation of compounds 5, 6 and 7 yielded compound 8, 2'-hydroxy-4',6'
      dimethoxy-3'-methyldihydrochalcone (10) and 2',4'-dihydroxy-6'-methoxy-3',5'
      dimethyldihydrochalcone (11), respectively. The hydrogenated products of
      compounds 6 and 7 were also tested for enzyme inhibitory activity. In addition,
      beta-sitosterol (12) and beta-D-sitosterylglucoside (13) were also isolated. This
      is the first report of the isolation of compounds 1-6, 8 and 13 from this plant.
      Compounds 3-8 and 10 exhibited significant and selective inhibition against
      prolyl endopeptidase among three serine proteases. This is the first report of
      this kind of activity for all these compounds.

PMID- 15018060
TI  - In situ assessment of porphyrin photosensitizers in Propionibacterium acnes.
AB  - Porphyrins are known to be efficient photosensitizer molecules and the combined
      action of light and porphyrins in Propionibacterium acnes have a lethal action on
      the cells. Identification and quantification of in situ porphyrins in P. acnes
      have been done using an integrating sphere connected to an ordinary absorption
      spectrophotometer, and the amounts of porphyrins in the cells were quantified by
      measuring scattering free absorption spectra of the cell suspensions. The
      concentration of porphyrins in P. acnes cells were increased in either of two
      ways; by the addition of delta-aminolevulinic acid (ALA), which lead to the
      formation of coproporphyrin III under the incubation conditions used in these
      experiments, or by the addition of protoporphyrin IX (PPIX) to the cell
      suspension. In the latter case, PPIX molecules are taken up by the cells in a
      membrane-mediated uptake mechanism, and accumulate in the cells either on a
      monomeric or a particular aggregate form. The fraction of porphyrins on aggregate
      form increased with increasing PPIX additions. In the case of ALA induced
      porphyrin production, only monomeric porphyrins were stored in the cells. In both
      cases, the cells have a limited binding capacity of monomeric porphyrins, which
      is estimated to be 3 x 10(5) molecules/cell, or one porphyrin molecule to every
      100st lipid molecule in the cell membrane.

PMID- 15018061
TI  - Improvement of carotenoid-synthesizing yeast Rhodotorula rubra by chemical
      mutagenesis.
AB  - A mutant Rhodotorula rubra with enhanced carotenoid-synthesizing activity for
      synthesizing total carotenoids and beta-carotene was obtained by N-methyl-N'
      nitro-N-nitrosoguanidine mutagenesis. When co-cultivated with yogurt starter
      bacteria (Lactobacillus bulgaricus + Streptococcus thermophilus) in whey
      ultrafiltrate it produced 15.7 mg total carotenoids l(-1) culture fluid or 946
      microg total carotenoids g(-1) dry cells of which 71% was beta-carotene. Grown as
      a monoculture in glucose substrate, the mutant shown 1.4 times lower carotenoid
      synthesizing activity, and the relative share of beta-carotene in the total
      carotenoids was lower (63%). The individual pigments torulene and torularhodin
      were identified, whose mass fractions were (29% and 7%) and (24% and 4%),
      respectively, for the mutant grown as a monoculture and as a mixed culture with
      the yogurt bacteria.

PMID- 15018062
TI  - Analysis of insecticidal Azadirachta indica A. Juss. fractions.
AB  - As a result of chemical investigation on the ethanolic extract of fresh fruit
      coatings of Azadirachta indica A. Juss. (neem), twenty-seven compounds were
      identified in non-polar to less polar fractions which showed pesticidal activity
      determined by WHO method against Anopheles stephensi Liston. These
      identifications were basically made through GC-EIMS and were further supported by
      other spectroscopic techniques, including 13C NMR, UV and FTIR as well as
      retention indices. Thus sixteen n-alkanes, 1-16; three aromatics 2,6-bis-(1,1
      dimethylethyl)-4-methyl phenol (17), 2-(phenylmethylene)-octanal (20), 1,2,4
      trimethoxy-5-(1Z-propenyl)-benzene (27); three benzopyranoids 3,4-dihydro-4,4,5,8
      tetramethylcoumarin (18), 3,4-dihydro-4,4,7,8-tetramethylcoumarin-6-ol (19),
      1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl-cyclopenta[g]-2-benzopyran (22); one
      sesquiterpene methyl-3,7,11-trimethyl-2E,6E,10-dodecatrienoate (21); three esters
      of fatty acids methyl 14-methyl-pentadecanoate (23), ethyl hexadecanoate (24),
      ethyl 9Z-octadecenoate (25) and one monoterpene 3,7-dimethyl-1-octen-7-ol (26)
      were identified. Except 6, 8, 24 and 25 all these compounds were identified for
      the first time from the pericarp and fifteen of these, 1-3, 7, 9, 10, 17-23, 26,
      27, are hitherto unreported previously from any part of the tree. Although this
      tree is a rich source of various natural products, it is the first report of
      identification of mono- and sesquiterpenes 26 and 21 and a potent antioxidant,
      17.

PMID- 15018064
TI  - Putative L-triiodothyronine receptors in the liver nuclei of mature tropical
      toad, Bufo melanostictus.
AB  - Thyroid hormones exert a major role in growth and differentiation of almost all
      types of tissues in animals, particularly in amphibian metamorphosis, through its
      specific nuclear receptor activation followed by gene expression. However, its
      function in mature tropical amphibians is less studied. The present study
      revealed the existence of a single class of specific nuclear receptor(s) in the
      liver nuclei of mature tropical toad, Bufo melanostictus, with a dissociation
      constant of (3.7 +/- 0.9) x 10(-10) molar and maximum binding capacity of 0.074
      +/- 0.013 pmol/mg DNA. The percentage of relative binding affinities for the
      specific nuclear L-T3 binding site in the liver nuclei of toad were L
      triiodothyronine (L-T3) > triiodothyroacetic acid (TRIAC) > L-thyroxine (L-T4) =
      tetraiodothyroacetic acid (TETRAC) > 3,3',5'-triiodothyronine (r-T3) >
      Diiodothyrtonine (L-T2) (100 > 75 > 19.4 = 19.4 > 3.7 > 0.39) and the relative
      ED50 values (in nanomolar) were 0.33 < 0.44 < 1.7 = 1.7 < 9 < 83.

PMID- 15018063
TI  - Chemical defense of Mediterranean sponges Aplysina cavernicola and Aplysina
      aerophoba.
AB  - The Mediterranean sponges Aplysina aerophoba and A. cavernicola accumulate
      brominated isoxazoline alkaloids including aplysinamisin-1 (1), aerophobin-2 (2),
      isofistularin-3 (3) or aerothionin (4) at concentrations up to 10% of their
      respective dry weights. In laboratory feeding experiments employing the
      polyphagous Mediterranean fish Blennius sphinx crude extracts of both Aplysina
      sponges were incorporated into artificial fish food at their physiological
      concentrations (based on volume) and offered to B. sphinx in choice feeding
      experiments against untreated control food. In addition to the Aplysina sponges,
      extracts from nine other frequently occurring Mediterranean sponges were likewise
      included into the experiments. Both Aplysina species elicited strong feeding
      deterrence compared to the other sponges tested. Bioassay-guided fractionation of
      A. cavernicola yielded the isoxazoline alkaloids aerothionin (4) and
      aplysinamisin-1 (1) as well as the 3,4-dihydroxyquinoline-2-carboxylic acid (8)
      as major deterrent constituents when tested at their physiological concentrations
      as present in sponges. Aeroplysinin-1 (5) and dienone (6), however, which are
      formed in A. aerophoba and A. cavernicola from isoxazoline precursors through
      bioconversion reactions upon tissue injury showed no or only little deterrent
      activity. Fractionation of a crude extract of A. aerophoba yielded aerophobin-2
      (2) and isofistularin-3 (3) as major deterrent constituents against B. sphinx. We
      propose that the isoxazoline alkaloids 1-4 of Mediterranean Aplysina sponges as
      well as the 3,4-dihydroxyquinoline-2-carboxylic acid (8) (in the case of A.
      cavernicola) act as defensive metabolites against B. sphinx and possibly also
      against other predators while the antibiotically active bioconversion products
      aeroplysinin-1 (5) and dienone (6) may protect sponges from invasion of bacterial
      pathogens.

PMID- 15018065
TI  - Inhibition of vesicular stomatitis virus replication by prostaglandin A1 in Aedes
      albopictus cells.
AB  - Cyclopentenone prostaglandins (PGs) exhibit antiviral activity against RNA and
      DNA viruses in mammalian cell lines, and this effect has been associated with the
      induction of a heat shock protein (hsp70). We investigated the effect of
      prostaglandin A1 (PGA1) on the replication of vesicular stomatitis virus (VSV) in
      Aedes albopictus (mosquito) cells. PGA1 was found to inhibit VSV replication dose
      dependently. Virus yield was reduced to 50% (3 microg PGA1/ml) and to 95% with 8
      microg PGA1/ml. Even with the dramatic reduction of virus production observed in
      cells treated with PGA1, VSV-specific protein synthesis was unaltered. Treatment
      of cells with PGA1 (5 microg/ml) stimulated the synthesis of a polypeptide
      identified as a heat-shock protein (hsp) by immunoblot analysis. PGA1 induced
      hsp70 synthesis in uninfected cells. However, in VSV-infected cells the induction
      of hsp70 by PGA1 was reduced. This is the first report of antiviral effects of
      PGs affecting the replication of VSV in a mosquito cell line.

PMID- 15018066
TI  - Protein and lipid composition of a vitellin isolated from eggs of Sparus aurata.
AB  - The protein and lipid composition of a vitellin isolated from eggs of Sparus
      aurata were characterized by SDS PAGE, N-terminal sequence analysis and lipid
      analysis by thin layer chromatography and gas chromatography. The lipoprotein
      complex contains proteins with apparent molecular weights of 69, 59, 23, 21 and
      12 kDa and were characterized as vitellinogenin fragments by N-terminal
      sequencing. Lipid extraction and analysis indicate an association of cholesterol
      and phospholipids with the protein subunits. The phospholipids contain fatty
      acids with 14, 16 and 18 carbon atoms as determined by GC/MS.

PMID- 15018068
TI  - Potential for biodegradation of hydrocarbons by microorganisms isolated from
      Antarctic soils.
AB  - Seventeen pure aerobic microbial isolates were obtained from soil samples of
      three regions of Antarctica: Casey Station, Dewart Island and Terra Nova Bay.
      Most of them were gram positive coryneform bacteria. Isolates were tested for
      their ability to grow on mineral salt agar plates supplemented with one of the
      following model n-alkanes or aromatic hydrocarbons: hexane, heptane, paraffin,
      benzene, toluene, naphthalene and kerosene. Cell hydrophobicity, the ability to
      produce anionic glycolipids and extracellular emulsifying activity were also
      determined and assessed on the basis of growth of soil isolates on hydrocarbons.
      This study revealed degraders with broader abilities to grow on both types of
      hydrocarbons, good production of glycolipids and emulsifying activity. On this
      basis, a mixed culture of strains is proposed, which may find application for
      bioremediation at temperate temperature of soil environments polluted with
      different hydrocarbons.

PMID- 15018067
TI  - Cuticular hydrocarbons of Heterotermes tenuis (Isoptera: Rhinotermitidae):
      analyses and electrophysiological studies.
AB  - Termites have become an important pest of Eucalyptus and Pinus reforestations,
      sugarcane and other cultures. An alternative for the control of this pest would
      be the use of attractive traps that take in account the social behavior of these
      insects. Diverse factors are important for the insects in the localization of the
      habitat and the choice of the food and specific odors can facilitate this.
      Studies referring to Heterotermes tenuis (Isoptera: Rhinotermitidae) are scarce.
      The objective of this work was to analyze the tergal cuticular extract of H.
      tenuis and determine the selectivity and sensitivity of its antennae to the
      components of this extract by electroantennography (EAG). The composition of the
      cuticular extract was determined by GC-MS analysis. The hydrocarbons found were
      restricted to linear alkanes, being most abundant C24 to C27 that comprises ca.
      65% of the total. Olefins were not detected. EAG and behavioral test responses to
      the cuticular hydrocarbons were greater and significantly different from the
      control and the high selectivity of the antennae to the extract indicates its
      potential as chemical messenger. Cuticular hydrocarbons mixture is species
      specific and can be used to identify a given taxon without the diagnostic castes,
      soldiers or imagoes Difference in the composition appears to relate with the type
      of habitat of specie.

PMID- 15018069
TI  - Decomposition of aqueous diphenyloxide by ozonolysis and by combined gamma-ray
      ozone processing.
AB  - Diphenyloxide (DPO) is one of many, rather toxic pollutants produced by
      combustion of fossil fuels, which are emitted to the atmosphere with flue gases
      and brought to ground water by rain and snow. Its decomposition is investigated
      by ozonolysis at room temperature and the major products like phenol, resorcinol,
      hydroquinone, dihydroxy-benzoic acid as well as the total yield of aldehydes and
      carboxylic acids were determined as a function of applied ozone concentration. In
      addition, the DPO-degradation was studied by a combined action of gamma-ray under
      continuous bubbling of a known ozone concentration. In this case the formation of
      the same products is observed, but their yields differ from the above ones. Based
      on the synergistic action of ozone and gamma-ray the DPO-radiolysis is rather
      efficient, leading to an initial-G-value of 11.3. Some probable reaction
      mechanisms are presented for explanation of the degradation process.

PMID- 15018070
TI  - Lower limit to the size of the primeval amino acid alphabet.
AB  - Here I systematically examine the information complexity of all primary sequences
      of natural proteins deposited in the Swiss-Prot database. The sequence complexity
      is assessed by determining the frequency of occurrence of each amino acid type on
      sequence windows of fixed length, calculating the Shannon entropy of the window
      and then averaging over all windows covering the sequence. The minimum value in
      information content obtained from the present-day record imposes a lower limit in
      the number of letters that a primeval amino acid alphabet must have had.

PMID- 15018071
TI  - [Reflections from an experimental clinical ethics center at Cochin Hospital
      (Paris)].

PMID- 15018072
TI  - [Chemopreventive agents in colorectal cancer].

PMID- 15018074
TI  - [Prostate cancer. Progress and controversies].

PMID- 15018073
TI  - [Fabry disease in 2004].
AB  - Fabry disease is a hereditary metabolic disease, with an X-linked transmission,
      that is due to the deficit of alpha-galactosidase A, a lysosomal enzyme. The
      enzyme deficiency is responsible for an accumulation of neutral
      glycosphingolipids in the organism with a consequent disease of overload that is
      responsible for pain, dermatological, renal, cardiac, gastro-intestinal, cochlear
      and neurological manifestations. Fabry disease starts during childhood but the
      diagnosis is often made too late. An early diagnosis is nevertheless essential in
      order to commence a treatment before the occurrence of morbid cardio or cerebro
      vascular accidents, or the development of end-stage chronic renal failure. Some
      phenotypic variants of Fabry disease are probably under-diagnosed among patients
      with so-called idiopathic hypertrophic cardiomyopathy on haemodialysis. Treatment
      by substitution of the enzyme with a recombinant alpha-galactosidase has been
      recently validated in breakthrough controlled clinical trials. Substitutive
      enzyme treatment represents a major therapeutic development. At the same time, it
      raises numerous questions such as the ideal age for initiation of treatment, the
      dose and the optimal frequency of enzyme administration, the reversibility of
      certain histopathological lesions and the determination of the best markers for
      the assessment and follow-up of the efficacy of treatment. Monitoring of the
      plasma levels of the enzyme substrate and the antibody titre seem to be
      essential. The documentation of short-term clinical benefits could require the
      use of sophisticated investigation methods such as the study of the myocardial
      function by tissue Doppler imaging.

PMID- 15018075
TI  - [The epidemiology of prostate cancer].
AB  - Prostate cancer is a public health problem. Currently, it is the most frequent
      cause of cancer, and the second most common cause of cancer mortality, in men in
      most developed countries. Its incidence in France in 2000 is close to 40 000 new
      cases, a consistent increase of 7,9% per year. One man in 8 in France will be
      diagnosed with prostate cancer in the course of his life. More than half of these
      cancers are diagnosed before 75 years, most often at a localized stage accessible
      to a curative treatment. The increasing practice of PSA testing and systematic
      prostatic biopsies are responsible for this rise in incidence. The mortality is
      stable at around 10 000 per year in France. Hereditary risk factors permit a
      definition of a target population for screening. Environmental factors are little
      known, but a diet rich in fat seems to be associated with a more elevated risk.

PMID- 15018076
TI  - [Prostate specific antigen and diagnosis of prostate cancer].
AB  - Prostate cancer had a development predominantly at peripheral gland and stay for
      a long time asymptomatic without clinical symptoms. When the cancer is
      symptomatic, it is often translate an advanced stage. The symptoms of prostate
      cancer are not specifics: urinary troubles, compression of iliac vessels or bone
      metastases pain. The digital rectal examination highlight an induration nodule,
      irregular and painless. The probability to have a cancer increase with the rate
      of the prostate specific antigen (PSA). Some others situations can increase the
      rate of PSA: benign prostatic hyperplasia, prostatitis, bladder catheterisation,
      urinary retention, endoscopic examination. The ratio of free-PSA/total-PSA
      (fPSA/tPSA) permits a best discrimination between benign prostatic hyperplasia
      and prostate cancer The more fPSA/tPSA ratio is low, the more the risk of
      prostate cancer is high. Prostate cancer is suspected with the digital rectal
      examination and the rate of PSA but the diagnosis is made by histological
      examination (the tissue samples are took by transrectal ultrasound-guided
      biopsies). The staging of disease must be realised according to the risk of
      metastasis appreciated by clinical stage, rate of PSA and Gleason score.

PMID- 15018077
TI  - [Imaging of cancer prostate].
AB  - Imaging of prostate cancer relies mainly on ultrasonography (US) and magnetic
      resonance imaging (MRI). It plays a diagnostic role in detecting and staging
      prostate carcinomas. Prostate biopsies are performed under endorectal US guidance
      at best with additional colour Doppler information. US also may provide useful
      information regarding the significance of an abnormal digital rectal examination
      sometimes related to some benign prostate alterations that can mimic a neoplastic
      nodule. In all cases imaging studies need to be interpreted in light of clinical
      and biological data including the results of biopsy especially in staging
      carcinoma with MR. Finally, CT and scintigraphy are helpful in screening for
      distant metastases.

PMID- 15018078
TI  - [Surgery of prostate cancer].
AB  - Radical prostatectomy is one of the standard treatment of localised prostate
      cancer. It is considered that cure is obtain if PSA value is undetectable (< 0,1
      ng/mL) for at least 5 to 7 years post surgery. 8 to 9 men out of 10 are currently
      cured by prostatectomy if the cancer is detected at organ confined stage, with
      PSA < 10 ng/mL. Major technical progress related to patient setting, surgical
      approach, instrumentation, periprostatic fascial exposure and surgical strategy
      clearly decreased perioperative morbidity and late effects (erectile dysfunction
      and incontinence). Laparoscopic approach was described mainly by French teams
      since 1997 and represents a validated alternative to the gold standard suprapubic
      open approach.

PMID- 15018079
TI  - [External beam radiotherapy and brachytherapy in prostate cancer].
AB  - For the last 10 years, along with surgery, radiotherapy has become a major issue
      in the curative treatment of prostate cancer. Several radiotherapy techniques can
      be used. In good prognosis cancers, when the prostate is small, brachytherapy is
      one of the therapeutic options. By implanting radioactive seeds within the
      prostate, this technique permits strictly limited intraprostatic irradiation.
      Conformal external beam (3D) radiotherapy adapts to individual morphology
      according to dosimetric CT scan data. This is particularly useful to deliver a
      high dose in the target volume while limiting the dose in surrounding organs. It
      is indicated either for localised tumours as an alternative solution to surgery,
      or for tumours with more aggressive patterns or locally advanced that will in
      both cases require adjuvant hormotherapy; conventional (2D) radiotherapy can be
      used in case of isolated clinical or biological relapse after prostatectomy.
      These last two techniques induce two main types of late toxicity: radio-induced
      rectitis and sexual impotence. Last but not least, radiotherapy as well as
      nuclear medicine can be used with palliation intent and may be of great help to
      relieve pain in case of bone metastases.

PMID- 15018080
TI  - [Metastatic prostate cancer].
AB  - Metastatic prostate cancer is an uncurable disease. Treatment is only palliative.
      Median survival of patients is 3 years. Prostate cancer is an hormonodependent
      cancer, androgen blockade is the most active treatment. However hormone
      resistance occurs after a median interval of 2 years. The major symptom is pain,
      others are urinary obstruction, neurological complications of bone metastases and
      hematological disorders. Androgen deprivation is the first-line treatment,
      impotency and osteoporosis being the main side effects. Other treatments are
      radiotherapy, radiopharmaceutics and chemotherapy. The most important treatment
      issue is quality of life.

PMID- 15018081
TI  - [Therapeutic options and controversies in the management of prostate cancer].
AB  - Many improvements have been made regarding the management of prostate cancer. The
      standard therapeutic options for localised prostate cancer remain radical
      prostatectomy, external beam radiation therapy, and brachytherapy. However, some
      minimally invasive treatments are being investigated, including high intensity
      focused ultrasound and cryotherapy. In the future these therapies may replace
      standard treatments in selected patients. On the other hand, only few advances
      have been made in the treatment of non-localised prostate cancer. Locally
      advanced cancer is treated with combination of radiotherapy and hormonotherapy,
      and metastatic cancer is treated with hormone therapy. Docetaxel may improve
      patient survival in hormone-refractory disease.

PMID- 15018082
TI  - [Prostate cancer and quality of life].
AB  - Faced with equivalent treatments in terms of control of localised prostate
      cancer, by treatments as different as radical prostectomy and radiotherapy, the
      analysis of the physical and psychosocial consequences of each treatment is
      indispensable in determining the therapeutic options proposed to a patient.
      Current information on the quality of life after treatment of localised and
      metastatic prostate cancer show effects after treatment that are specific to this
      pathology (urinary, sexual and digestive problems) and general (physical state
      and functional capacity, capacity to accomplish all forms of work, capacity to
      maintain social relations...). These effects nevertheless differ depending of the
      stage of the disease and the type of treatment.

PMID- 15018083
TI  - [Already ten years!].

PMID- 15018084
TI  - [Fits, faints and blackouts in the adult].

PMID- 15018085
TI  - [Work accidents and work-related illness: definitions].

PMID- 15018086
TI  - [Broncho-pulmonary infections in the adult].

PMID- 15018087
TI  - [Rachialgia].

PMID- 15018089
TI  - Chronobiology meets sleep research.

PMID- 15018088
TI  - [Medical travel at the beginning of the XIXth century].

PMID- 15018090
TI  - The role of chronobiology in sleep disorders medicine.
AB  - This review is concerned with circadian (approximately 24 h) aspects of
      chronobiology, and how they relate to sleep disorders medicine. We begin with an
      introduction to the key concepts and paradigms of circadian rhythms research in
      general, including a description of homeostatic and circadian determinants of
      sleep timing. This is followed by a brief history of chronobiology in relation to
      sleep disorders medicine. Both animal and human circadian rhythm studies are
      considered. We trace historical changes in the relative emphasis placed on social
      contacts, light, and melatonin in human circadian rhythms research. Special
      attention is given to free-running, forced desynchrony, and ultra-short
      sleep/wake cycle findings of particular relevance to sleep disorders medicine.
      The latter part of the review comprises a description of the circadian rhythm
      sleep disorders, highlighting insights derived from basic circadian rhythms
      research, including recent advances in molecular genetics. We conclude that the
      role of chronobiology in sleep disorders medicine is profound and pervasive, and
      that the two disciplines will move ever closer as a natural function of important
      new insights into sleep and sleep disorders provided by basic circadian rhythms
      research.

PMID- 15018091
TI  - Do circadian rhythms in respiratory control contribute to sleep-related breathing
      disorders?
AB  - Sleep-related respiratory dysfunction compromises the health and quality of life
      of millions of people worldwide, underscoring the need for a full understanding
      of the mechanisms by which the respiratory control system is altered at night.
      This paper suggests the hypothesis that the circadian timing system may play a
      role in the pathogenesis of some types of sleep-related breathing disorders.
      Recent studies have provided evidence that the circadian timing system has an
      influence on respiration and respiratory control, even in the absence of sleep.
      These new data are reviewed and potential mechanisms underlying the circadian
      modulation of breathing are outlined, identifying important gaps in our
      knowledge. It is proposed that circadian rhythms in respiratory control may
      increase the propensity for nocturnal respiratory instability and recurrent
      apnea. Importantly, circadian and sleep mechanisms appear to have additive
      effects on breathing, suggesting that the circadian timing system can potentially
      amplify or suppress sleep-related breathing abnormalities, depending upon the
      characteristics of the circadian output and the time of day at which sleep
      occurs.

PMID- 15018092
TI  - Understanding adolescents' sleep patterns and school performance: a critical
      appraisal.
AB  - The present paper reviews and critiques studies assessing the relation between
      sleep patterns, sleep quality, and school performance of adolescents attending
      middle school, high school, and/or college. The majority of studies relied on
      self-report, yet the researchers approached the question with different designs
      and measures. Specifically, studies looked at (1) sleep/wake patterns and usual
      grades, (2) school start time and phase preference in relation to sleep habits
      and quality and academic performance, and (3) sleep patterns and classroom
      performance (e.g., examination grades). The findings strongly indicate that self
      reported shortened total sleep time, erratic sleep/wake schedules, late bed and
      rise times, and poor sleep quality are negatively associated with academic
      performance for adolescents from middle school through the college years.
      Limitations of the current published studies are also discussed in detail in this
      review.

PMID- 15018093
TI  - The hazards and prevention of driving while sleepy.
AB  - In the present paper the literature bearing on the association between sleepiness
      and driving is reviewed and the current state of prevention is discussed.
      Sleepiness may be a factor in about 20% of motor vehicle accidents and studies
      carried out in controlled environments suggest that the most common changes in
      driving performance attributable to sleepiness include increased variability of
      speed and lateral lane position. Higher-order functions including judgement and
      risk taking may also deteriorate. Moreover, prolonging wakefulness even by a few
      hours may produce deterioration in driving performance comparable to that seen in
      drivers with blood alcohol concentrations at levels deemed dangerous by
      legislation. The majority of prevention efforts to date have focussed on short
      term solutions that only mask underlying sleepiness and it is suggested that more
      emphasis be directed toward primary prevention efforts such as educating drivers
      about the importance of getting sufficient sleep and avoiding circadian
      performance troughs. Finally, the important role that health professionals can
      play in the identification, treatment, and education of sleepy drivers is
      highlighted.

PMID- 15018094
TI  - Insomnia, alcoholism and relapse.
AB  - Insomnia and alcoholism are significantly associated in community surveys and
      patient samples. Insomnia occurs in 36-72% of alcoholic patients and may last for
      weeks to months after initiating abstinence from alcohol. Some correlates of
      insomnia in alcoholic patients are identical to those observed in non-alcoholic
      insomniacs, including anxiety and depression, tobacco smoking, and the use of
      alcohol to aid sleep. Other studies suggest that as the severity of alcoholism
      increases, so does the likelihood of insomnia in alcoholic patients. In the sleep
      laboratory, alcoholic patients who complain of insomnia have disrupted sleep
      continuity when compared to alcoholic patients without insomnia complaints.
      Recently sober alcoholics are also more likely than non-alcoholics to have sleep
      disordered breathing and increased periodic leg movements, which might contribute
      to insomnia in some alcoholic patients. The co-occurrence of insomnia and
      alcoholism is clinically significant because alcoholism can exacerbate the
      adverse consequences of insomnia (e.g. mood changes and performance decrements)
      and because insomnia among patients entering treatment for alcoholism has been
      significantly associated with subsequent alcoholic relapse. Baseline
      polysomnographic correlates of subsequent relapse include prolonged sleep
      latency, decreased sleep efficiency and total sleep time, increased rapid eye
      movement sleep pressure, and decreased slow wave sleep. Whether treatment of
      insomnia in alcoholic patients reduces relapse rates is unknown, but preliminary
      treatment guidelines that accommodate the special characteristics of alcoholic
      patients are provided, with a goal to reduce daytime impairment and psychological
      distress.

PMID- 15018095
TI  - Interaction of two Bacillus thuringiensis delta-endotoxins with the digestive
      system of Lygus hesperus.
AB  - The active-toxin form of CrylAc (65 kDa) or Cry2Ab was fed to a non-susceptible
      insect, Lygus hesperus, in an artificial diet. Biochemical and immunocytochemical
      methods were used to determine the distribution of ingested toxin. The toxins did
      not elicit a feeding deterrent response. CrylAc and Cry2Ab were ingested; small
      amounts were absorbed into the hemolymph as holoproteins, but most was excreted.
      SDS-PAGE analysis of CrylAc and Cry2Ab incubations with salivary gland homogenate
      showed a small decrease in the molecular weight of the active toxins. Proteolytic
      processing of the toxins also occurred in vivo, within the digestive system of L.
      hesperus. Excreted CrylAc and Cry2Ab retained activity toward lepidopteran
      larvae. Immunocytochemical in vivo localization studies showed negligible
      association of CrylAc with L. hesperus tissues. In contrast, strong extracellular
      association of Cry2Ab was observed with L. hesperus midgut brush border
      microvilli and basement membrane, as well as with cellular outlines within the
      hemolymph and fat body.

PMID- 15018096
TI  - Biodegradation of DDT by a Pseudomonas species.
AB  - A bacterial strain capable of degrading 1,1,1-trichloro-2,2-bis(4
      chlorophenyl)ethane (DDT) was isolated from insecticide-contaminated soil by
      biphenyl enrichment culture and identified as a Pseudomonas species. The organism
      degraded DDT through the intermediate formation of 2,3-dihydroxy-DDT, which
      undergoes meta-ring cleavage, ultimately yielding 4-chlorobenzoic acid as a
      stable metabolite.

PMID- 15018097
TI  - A novel two-component system amrB-amkB involved in the regulation of central
      carbohydrate metabolism in rifamycin SV-producing Amycolatopsis mediterranei U32.
AB  - A novel two-component signal transduction system amrB-amkB was cloned from
      rifamycin SV-producing Amycolatopsis mediterranei U32, and their biochemical
      functions as a response regulator and a histidine protein kinase, respectively,
      were proven. The amrB disruption mutant was generated by insertional inactivation
      with the aparmycin resistance gene. The metabolic response to the absence of amrB
      gene was determined by a biochemical profiling technique in which the
      concentration changes of metabolic intermediates were measured by gas
      chromatography with time-of-flight mass spectrometry (GC/TOF-MS). Although the
      phenotype analyses of the amrB gene disruption mutant showed no significant
      change with respect to rifamycin SV production and morphological differentiation,
      the global metabolomic analyses found the concentration levels of some key
      intermediates in the TCA cycle and glycolysis pathway were affected by an amrB
      gene disruption event. The primary results suggested that amrB-amkB genes might
      be involved in the regulation of central carbohydrate metabolism in A.
      mediterranei U32.

PMID- 15018098
TI  - Isolation and identification of hyper-ammonia producing bacteria from swine
      manure storage pits.
AB  - Storage of swine manure is associated with the microbiological production of a
      variety of odorous compounds, including ammonia, organic acids, and alcohols,
      phenolics, and sulfides. Until recently, little was known about the
      microorganisms responsible for their production. Results from our laboratory have
      demonstrated that the predominant microbial populations of stored swine manure
      are anaerobic, low (G + C), Gram-positive bacteria. However, studies on pure
      cultures isolated from manure have found few microorganisms that produce
      appreciable ammonia concentrations. Therefore, selective and enrichment
      techniques were employed to isolate ammonia-producing bacteria from stored swine
      manure by using media containing peptone and amino acids as carbon and energy
      sources. We now report on the isolation of 40 bacterial cultures, a number of
      which are capable of producing at least 40 mM ammonia in peptone-amino acid
      medium, concentrations similar to those produced by hyper-ammonia producing (HAP)
      bacteria isolated from the rumen of cattle. The manure HAP isolates are
      phylogenetically distinct from the ruminal isolates and may prove to be
      intimately involved in the production of ammonia during storage of swine manure.

PMID- 15018099
TI  - Effects of DL-malate on in vitro forage fiber digestion by mixed ruminal
      microorganisms.
AB  - The objective of this study was to evaluate the effects of 0, 4, 8, and 12 mM DL
      malate on the in vitro mixed ruminal microorganism fermentation of alfalfa hay
      and Coastal bermudagrass hay. When alfalfa hay was the substrate, 4 and 8 mM DL
      malate numerically increased propionate concentration, and 12 mM DL-malate
      increased (P < 0.10) propionate. All three concentrations of DL-malate decreased
      (P < 0.05) the acetate:propionate ratio. In Coastal bermudagrass hay
      fermentations, all three DL-malate concentrations increased (P < 0.05) propionate
      and decreased (P < 0.05) the acetate:propionate ratio, while 4 and 12 mM DL
      malate numerically increased in vitro dry matter disappearance. When mixed
      ruminal microorganisms were incubated with 6.25 mM DL-lactic acid and alfalfa
      hay, 8 and 12 mM DL-malate increased (P < 0.05) final pH, and 12 mM DL-malate
      increased (P < 0.10) propionate and decreased (P < 0.10) the acetate:propionate
      ratio. DL-Malate treatment had little effect on in vitro dry matter
      disappearance. Addition of 8 and 12 mM DL-malate to Coastal bermudagrass hay plus
      DL-lactic acid fermentations increased (P < 0.05) final pH, and 8 mM DL-malate
      increased (P < 0.10) in vitro dry matter disappearance. Even though DL-malate
      treatment consistently increased final pH values in fermentations that included
      DL-lactic acid, there was not a corresponding increase in in vitro dry matter
      disappearance of either alfalfa hay or Coastal bermudagrass hay in the 48-h batch
      culture incubations.

PMID- 15018100
TI  - Identification and initial characterization of a putative Mycoplasma gallinarum
      leucine aminopeptidase gene.
AB  - Aminopeptidases (APN) may play a role in host colonization of M. gallinarum.
      Characterization of endogenous APN activity suggests that the leucine APN (LAP)
      of M. gallinarum is a metallo-aminopeptidase activated by Mn2+ and is present in
      the cytosol and possibly associated with the inner leaflet of the membrane. A
      1.36-kb open reading frame (ORF) identified from overlapping genomic phage clones
      showed 68% nucleotide identity and 51% amino acid identity with the M. salivarium
      LAP gene. This ORF is expressed as a 1.5-kb monocistronic transcript and is
      present as a single copy in M. gallinarum. This gene sequence was modified to
      account for codon usage, and expression in E. coli produced a 51-kDa protein,
      which compares well with the product predicted from the ORF. This ORF is a strong
      candidate for contributing the LAP activity of M. gallinarum protein extracts.

PMID- 15018101
TI  - Comparative genomic analysis of the sigB operon in Listeria monocytogenes and in
      other Gram-positive bacteria.
AB  - The stress-responsive, alternative sigma factor sigmaB has been described in
      members of three Gram-positive genera, Bacillus, Listeria, and Staphylococcus. In
      these bacteria, sigmaB appears to play an important role in facilitating rapid
      adaptation to and survival in stressful environments. sigmaB activity is
      regulated through a complex system of phosphatases and kinases encoded by rsb
      (regulator of sigma B) genes. We describe the sigB operon structure for the
      facultative intracellular pathogen Listeria monocytogenes and apply this sequence
      as well as other previously described sigB operon sequences to probe the
      evolution and functional conservation of the sigmaB stress response system among
      different Gram-positive bacteria. While sigmaB as well as two Rsbs (RsbS and
      RsbT) are highly conserved (73%, 84%, and 79% average amino acid [aa] identities,
      respectively), the predicted aa sequences of the other Rsb proteins showed less
      conservation (62-71% aa identities). Furthermore, the sigB operon structure
      varies among bacterial species. Bacterial species differ in the numbers and
      identities of rsb genes encoded in their genomes. We thus conclude that the
      sigmaB stress-response system as represented by the sigB operon has diverged in
      both its overall components as well as in the sequences of its individual
      proteins, even among closely related bacterial species. Differential evolution of
      this stress response system among various genera may represent a strategy that
      enables bacteria to adapt cellular response and survival systems to a variety of
      stress conditions.

PMID- 15018102
TI  - Isolation and characterization of a strain of Bacillus thuringiensis subsp.
      morrisoni PG-14 encoding delta-endotoxin Cry1Ac.
AB  - Bacillus thuringiensis 656-3, isolated from a soil sample collected at mushroom
      houses, showed high toxicity to mushroom flies, Lycoriella mali and Coboldia
      fuscipes. B. thuringiensis 656-3 produced bipyramidal inclusions and reacted with
      the H antiserum of B. thuringiensis subsp. morrisoni (H8a8b). The plasmid and
      protein profiles of B. thuringiensis 656-3 were similar to those of its reference
      strain, subsp. morrisoni PG-14. However, PCR analysis using cry gene primers
      showed that B. thuringiensis 656-3, unlike its reference strain, had cry4A,
      cry4B, cry10A, cry11A, and cry1Ac genes, suggesting that B. thuringiensis 656-3
      was a unique strain with respect to gene type. In addition, B. thuringiensis 656
      3 showed a high level of toxicity against mushroom flies, L. mali and C.
      fuscipes.

PMID- 15018104
TI  - Evaluation of OxoPlate for real-time assessment of antibacterial activities.
AB  - We have evaluated the OxoPlate OP96F for its usefulness in the characterization
      of antibacterial compounds. Each well of the plate carries two different
      fluorescent dyes, an oxygen-sensitive indicator dye and a reference dye.
      Fluorescence intensity is proportional to the amount of dissolved oxygen in the
      medium. Growth of bacterial cells is measured indirectly via the gradual
      depletion of oxygen. In this study, Bacillus subtilis was treated with 14
      different antibacterials of various modes of action. The OxoPlate was not only
      useful to deduce MIC values directly from the oxygen-depletion curves, but was
      also able to discriminate bactericidal from bacteriostatic compounds. Oxygen
      levels of cultures treated with bactericidal compounds dropped initially and then
      increased after the cells had died. In contrast, oxygen levels remained low when
      cultures were treated with bacteriostatic compounds. The system described herein
      gives valuable insight into the kinetics of growth inhibition and killing, and we
      conclude that the OxoPlate is highly useful for the initial characterization of
      antibacterials.

PMID- 15018103
TI  - Identification of an iron-binding protein of the Dps family expressed by
      Streptococcus thermophilus.
AB  - Streptococcus thermophilus PB18 can grow between 20 degrees and 52 degrees C and
      is resistant to various stresses such as heat, acidic or cold shock. During cold
      shock, a protein of 21.5 kDa was previously shown to be induced in S.
      thermophilus. In addition to its cold-shock induction, 2D-PAGE revealed that the
      21.5-kDa protein was also expressed during the stationary phase of growth. The
      recent access to the genome sequence of S. thermophilus LMG18311 allowed the
      identification of a 173-amino acid protein displaying a strong homology between
      the 21.5-kDa protein and members of the Dps family of proteins. Specific staining
      of non-denaturing polyacrylamide gel electrophoresis (ND-PAGE) followed by two
      dimensional PAGE (2D-PAGE) showed that the 21.5-kDa protein was an iron-binding
      protein.

PMID- 15018105
TI  - Identification and immunochemical location of UMP kinase from Bacillus subtilis.
AB  - Phosphorylation of CMP and UMP is accomplished in Bacillus subtilis, as in
      Escherichia coli, by two different enzymes exhibiting characteristic structural
      and catalytic properties. UMP kinase from B. subtilis is an oligomer whose
      activity is strictly dependent on GTP. The B. subtilis enzyme is unstable in the
      absence of UTP, which acts as an allosteric inhibitor. Antibodies raised against
      recombinant B. subtilis UMP kinase recognized the protein both in soluble extract
      and in immunoelectron microscopy. UMP kinase from B. subtilis has a peripheral
      distribution which is related most probably to its role in the synthesis of
      membrane sugar components and its putative role in cell division.

PMID- 15018106
TI  - NADP-glutamate dehydrogenase activity is increased under hyperosmotic conditions
      in the halotolerant yeast Debaryomyces hansenii.
AB  - Glutamate plays an important role in osmoprotection in various bacteria. In these
      cases, increased intracellular glutamate pools are not attributable to the NADP
      dependent glutamate dehydrogenase (NADP-GDH) or the glutamate synthase, which do
      not increase their activities under hyperosmotic conditions, but rather to
      changes in other enzymes involved in glutamate metabolism. We performed a study
      which indicates that, as opposed to what happens in bacteria, the activity of
      NADP-GDH is fivefold higher when the halotolerant yeast Debaryomyces hansenii is
      grown in the presence of 1 M NaCl, compared with growth in media with no added
      salt. Since purified NADP-GDH activity in vitro was not enhanced by the presence
      of salt and was more sensitive to ionic strength than the two isoenzymes from S.
      cerevisiae, increased enzyme synthesis is the most plausible mechanism to explain
      our results. We discuss the possibility that increased NADP-GDH activity in D.
      hansenii plays a role in counteracting the inhibitory effect of high ionic
      strength on the activity of this enzyme.

PMID- 15018107
TI  - Isolation and phylogenetic analysis of Xylella fastidiosa from its invasive
      alternative host, porcelain berry.
AB  - A strain of Xylella fastidiosa was isolated from an invasive alternative host
      species, porcelain berry. Its genetic relationship with strains isolated from a
      native alternative host, wild grape; a nonnative alternative host, mulberry; and
      other economically important hosts including cultivated grape, peach, plum, oak,
      maple and oleander was determined by using sequence analysis of the 16S-23S rRNA
      intergenic spacer region. Our phylogenetic analysis revealed that the porcelain
      berry strain is most closely related to the wild grape strain. These two strains
      are more closely related to the oak, peach, and plum strains than to the mulberry
      and oleander strains. They are separated from the maple and cultivated grape
      strains. Our data suggest that suppression of porcelain berry, wild grape, and
      mulberry in the vicinity of susceptible economically important hosts such as oak,
      peach, and plum may provide an important control measure for diseases caused by
      X. fastidiosa.

PMID- 15018108
TI  - Sequence analysis of DNA fragments from the genome of the primary endosymbiont of
      the whitefly Bemisia tabaci.
AB  - The whitefly Bemisia tabaci contains a primary prokaryotic endosymbiont housed
      within specialized cells in the body cavity. Two DNA fragments from the
      endosymbiont, totaling 33.3 kilobases, were cloned and sequenced. In total, 37
      genes were detected and included the ribosomal RNA operon and genes for ribosomal
      RNA proteins. The guanine plus cytosine of the DNA was 30.2 mol%, different from
      that of endosymbionts of other plant sap-sucking insects.

PMID- 15018109
TI  - Functional MR imaging: paradigms for clinical preoperative mapping.
AB  - Clinical applications of functional MR imaging include mapping of brain functions
      in relationship to intracranial tumors, seizure foci, or vascular malformations
      to determine the risk for performing surgical excision, the need for
      intraoperative mapping during excision, and selecting the optimal surgical
      approach to a lesion. A variety of paradigms are used to produce a blood-oxygen
      level-dependent response in various brain regions, which can be identified with
      functional MR imaging. The paradigms used include active motor, language, or
      cognitive tasks, and passive tactile, auditory, or visual stimuli. Activation
      usually indicates the location of eloquent cortex. Lack of function in a region
      cannot be assumed when functional MR imaging shows absence of activation within
      the region.

PMID- 15018110
TI  - MR myelography of the spine and MR peripheral nerve imaging.
AB  - MRM is a useful imaging technique that can be incorporated into routine spine MR
      imaging protocols without a significant increase in imaging time or patient
      discomfort. When combined with high quality, sequential (no inter-slice gap),
      axial images of the spine, the authors have found that it decreases the surgeon's
      need for conventional contrast enhanced myelography by showing the etiology of
      compression and degree of compressive effect, particularly in cases of
      degenerative spine disease. In select cases where greater bone detail is desired,
      an unenhanced CT is often sufficient. MRPNI also is a useful imaging technique
      that is primarily used in the evaluation of patients with radicular symptoms not
      explained by spine MR imaging findings. Selective MRPNI is performed based on
      clinical and electrodiagnostic results to evaluate extra-spinal causes of
      peripheral neuropathy. It is easily performed using phase array coils and is
      primarily used to detect traumatic axonal disruption and compressive neuropathy.

PMID- 15018111
TI  - MR angiography of the spine: update.
AB  - The role of MRA, as an adjunct to conventional MR imaging of the spine and spinal
      cord, is evolving. The older MRA methods that have been applied to spinal
      vascular imaging include 2D and 3D phase contrast techniques and a derivative of
      3D time-of-flight techniques with data acquired for about several minutes after
      gadolinium contrast injection (standard 3D CE MRA). Newer 3D gradient-echo
      techniques, which allow the acquisition of each volume of data in tens of seconds
      as a contrast bolus traverses the region of interest (fast 3D CE MRA), offer the
      possibility of temporally resolving intradural arteries and veins. The appearance
      of normal and abnormal intradural vessels, primarily veins, on the standard 3D CE
      MRA method has been described for the thoracolumbar region. Normal intradural
      arteries have been more difficult to detect, although preliminary results with
      the fast 3D CE MRA method, are promising. Only by establishing the MRA appearance
      of normal arteries and veins, can one begin to define "abnormal" with greater
      confidence (presuming that the variability in the appearance of normal vessels is
      not so great as to preclude differentiation). In striving for this goal, MRA has
      already encountered competition from CT angiography. In the characterization of
      spinal vascular lesions, the value of MRA has been demonstrated most convincingly
      for dural AVF. This lesion is more accurately localized and more sensitively
      detected (by neuroradiolologists and others experienced in spine imaging) with
      combined MR imaging and standard 3D CE MRA than with MR imaging alone.
      Preliminary results suggest that sensitivity and specificity may be further
      improved if fast 3D CE MRA is combined with conventional MR imaging. Although
      less well documented, the value of MRA in characterizing other lesions, such as
      AVMs and vascular tumors, has been reported in recent publications. In the
      future, the role of MRA will depend on technical advances, such as parallel
      acquisition techniques and possibly implantable RF coils, which permit improved
      detection of, and differentiation between, intradural arteries and veins. With
      these improvements, MRA may play an expanded role in the characterization of
      spinal vascular abnormalities, encompassing trauma and degenerative spine disease
      and vascular malformations and tumors.

PMID- 15018112
TI  - MR angiography of the extracranial circulation.
AB  - In this article, the authors present a brief history of MR angiography (MRA) of
      the neck with emphasis on the techniques developed, particularly recent ones, to
      improve image quality. The goal of MRA is to eventually replace catheter
      angiography. The use of MRA, particularly contrast enhanced MRA with regards to
      pathology (atherosclerotic disease/plaque formation, dissection and post
      traumatic aneurysm) involving the extra-cranial carotid and vertebral arteries is
      addressed. The authors also comment on computed tomographic angiography and
      sonography and how they compare with contrast enhanced MRA when pertinent.

PMID- 15018113
TI  - Contrast-enhanced MR angiography of the intracranial circulation.
AB  - NCE MRA can provide the authors with useful diagnostic information in patients
      suffering from intracranial vascular disease, often leading to improved or
      altered treatment decisions. Most centers have used 3D TOF for evaluation of
      stroke-the most common cerebral vascular disease. Because of slow and disturbed
      flow, conventional 3D TOF MRA tends to overestimate stenotic lesions and occluded
      arteries and this can confound neurovascular assessment in stroke patients. Post
      contrast 3D TOF techniques provide a more robust and more specific method for
      imaging the intracranial circulation that overcomes the drawbacks of conventional
      3D TOF. In the setting of acute ischemic stroke, the authors have found that the
      combination of conventional and CE 3D TOF MRA improves their overall diagnostic
      ability. Dynamic and time-resolved CE MRA techniques have evolved rapidly. Time
      resolved CE MRA, in particular, is emerging as a useful technique for imaging
      dynamic vascular pathologies such as AVMs. Unfortunately, time-resolved MRA of
      the intracranial circulation provides images with low spatial resolution and is
      currently limited to subsecond frame rate 2D acquisitions, and less than 2
      seconds frame rates for 3D acquisitions. Nevertheless, like in other vascular
      regions, CE MRA represents a milestone for non-invasive intracranial vascular
      imaging. The continuing development of CE MRA techniques and of new contrast
      agents will lessen the need for intra-arterial angiography in the future.

PMID- 15018114
TI  - Practical consideration for 3T imaging.
AB  - In the past 10 to 15 years, 1.5T has been one of the most commonly used field
      strengths for day-to-day clinical operations. However, recent advances in high
      field technology and the increased availability of high field (> 1.5T) human
      scanners have opened the doors for a variety of exciting improvements in clinical
      and research applications of MR imaging. In particular, 3T has continued to gain
      wide acceptance as one of the main field strengths for clinical and research
      studies. Therefore, in this article the authors focus on the pros and cons of 3T
      imaging and comparisons between results obtained at 3T and 1.5T.

PMID- 15018115
TI  - MR microscopy of normal human brain.
AB  - MR microscopy at 9.4T depicts the architecture of the brain in exquisite detail,
      including the individual laminae of the cortex, the individual nuclei of the
      basal ganglia, the thalami, subthalami and metathalami, and the orientations and
      relationship among the dominant nuclei and white matter tracts of the brain. The
      authors believe that these anatomic relations will ultimately be displayed in
      vivo as clinical MR scanners begin to operate at field strengths of 4.7T, 7T, and
      8T. Then, those familiar with this anatomy will be able to interpret patient
      images with far greater sophistication.

PMID- 15018116
TI  - Vanek's tumor (inflammatory fibroid polyp). Report of 18 cases and comparison
      with three cases of original Vanek's series.
AB  - Eighteen cases of Vanek's tumors are presented. The patients included nine men
      and nine women between the ages of 45 and 93 years (mean, 66.2 years). Nine cases
      were clinically diagnosed as polyps of the gastric antrum, five cases as polyps
      of the stomach (not otherwise specified), one polyp was located in the ileum and
      the three remaining polyps in the small intestine (not otherwise specified). The
      thirteen polyps with available size information measured from 0.4 to 5 cm in the
      greatest diameter (mean, 2.2 cm). Immunohistochemically, the affections were
      positive for vimentin (18/18) and CD34 (15/18). All the cases negative for CD34
      also lacked concentric onion skin-like formations of the spindle cells around
      glands and vessels. The different immunophenotype and absence of concentric
      formations could be explained by the existence of two different lesions commonly
      designated as Vanek's tumor (inflammatory fibroid polyp) or by the hypothesis of
      various evolutional stages. In the differential diagnosis, it is important to
      distinguish namely eosinophilic gastroenteritis, gastrointestinal stromal tumor,
      inflammatory pseudotumor, hemangioendothelioma, and hemangiopericytoma. In
      contrast to gastrointestinal stromal tumors, genetically no substitution,
      deletion, or insertion occurred in c-kit exon 11 in all analyzed samples.
      Likewise, no deletion or insertion in part of c-kit exon 9 was observed.

PMID- 15018117
TI  - Clear cells and thyroid transcription factor I reactivity in sclerosing
      mucoepidermoid carcinoma of the thyroid gland.
AB  - Clear cells have been described in mucoepidermoid carcinoma of the salivary
      glands, but to our knowledge these cells have not been recognized as a
      distinctive component of sclerosing mucoepidermoid carcinoma with eosinophilia of
      the thyroid gland. We report four examples in which sclerosing mucoepidermoid
      carcinoma of the thyroid gland contained a minor component (10% to 30%) of clear
      cells. The four tumors occurred in women with Hashimoto's thyroiditis whose ages
      ranged from 38 to 52 years. All four patients presented with thyroid nodules, but
      two also had enlarged cervical lymph nodes. Although two tumors metastasized to
      multiple cervical lymph nodes and one recurred in the soft tissues of the neck,
      all four patients are disease-free 6 months to 6 years after surgical treatment.
      The locally aggressive behavior of the first three tumors was probably related to
      their size, rather than to the presence of clear cells. Microscopically, these
      tumors showed the classical features of sclerosing mucoepidermoid carcinoma with
      eosinophilia, as well as nests of clear cells that appeared to be glycogen-rich
      squamous cells. Although the four tumors were thyroglobulin negative, two were
      immunoreactive to thyroid transcription factor 1 (TTF-1), supporting the idea
      that they originated from squamous metaplasia of follicular epithelium rather
      than from solid cell nests of the ultimobranchial body.

PMID- 15018118
TI  - Nasal glial heterotopia: a clinicopathologic and immunophenotypic analysis of 10
      cases with a review of the literature.
AB  - Nasal glial heterotopia (also known as "nasal glioma"), is a rare developmental
      abnormality seen in a wide age group but typically presenting at birth or in
      early childhood. Failure to recognize the entity is the principle difficulty in
      diagnosis. Ten cases of nasal glial heterotopic diagnosed between 1970 and 2000
      were identified. Histologic and immunohistochemical features were evaluated and
      patient follow-up was obtained. The patients included five females and five males
      with a mean age at presentation of 8.6 years (range, birth to 44 years). Most
      patients presented clinically with a polypoid mass in the nasal cavity, although
      two patients had a mass on the nasal bridge. Symptoms were present for an average
      of 2 to 3 months. A connection to the central nervous system was identified in
      one case. Masses ranged in size from 1 to 7 cm in greatest dimension (mean, 2.4
      cm). Histologically, the masses were composed of astrocytes (including
      gemistocytic type) and neuroglial fibers intermixed with a fibrovascular
      connective tissue stroma. Neurons and ependymal cells were noted in two cases.
      Focal calcifications and inflammatory cells were identified occasionally. Masson
      trichrome stains the collagen intensely blue, while the neural population stains
      magenta. Immunohistochemical reactivity with glial fibrillary acidic protein and
      S-100 protein will help to confirm the histologic diagnosis, while collagen type
      IV and laminin can highlight the reactive fibrosis. All cases were managed by
      surgery. All patients were alive without complications at last follow-up (mean,
      26.8 years), except for the single fetus included in the study. Nasal glial
      heterotopia typically involves the nasal cavity and usually presents perinatally,
      although three patients presented in adulthood. The subtle glial component on
      routine microscopy can be accentuated with a trichrome stain or by
      immunoreactivity with glial fibrillary acidic protein and S-100 protein. Imaging
      studies must be performed before surgery to exclude an encephalocele, which
      requires different surgery. Complete surgical excision of nasal glial
      heterotopias is curative.

PMID- 15018119
TI  - Epiphyseal osteoblastoma of tibia with xanthomatous stromal reaction.
AB  - Osteoblastoma occurring in long bones has a distinctive predilection for the
      metaphysis and the diaphysis. Epiphyseal location is rare. Although variation in
      histologic patterns is a well-known feature of this tumor, xanthomatous stromal
      reaction has not yet been described. We report a case of a 34-year-old man who
      developed an osteoblastoma primarily located in the epiphysis of his left tibia
      with extension into the metaphysis. The striking histologic features included a
      prominent xanthoma-like stroma consisting of foamy histiocytes in addition to
      focal areas with classical configuration of an osteoblastoma. The significance of
      this finding is discussed.

PMID- 15018120
TI  - Fine-needle aspiration cytology of giant cell tumor of soft tissue (soft tissue
      giant cell tumor of low malignant potential).
AB  - Giant cell tumor of soft tissue is an uncommon neoplasm. To our knowledge, its
      cytopathology obtained using the fine-needle aspiration biopsy technique has not
      been previously described. We report an example of the fine-needle aspiration
      cytology of giant cell tumor of soft tissue in a 40-year-old woman, and correlate
      it with the corresponding tissue specimen.

PMID- 15018121
TI  - Atypical fibrous histiocytoma of the scrotum.
AB  - Atypical fibrous histiocytoma is a rare neoplasm. A scrotal location for this
      tumor is even more unusual. We report a case of a 90-year-old man with scrotal
      atypical fibrous histiocytoma. Our case had histologic features consistent with
      those cases previously reported in the literature. The tumor consists of cells
      with large hyperchromatic irregular nuclei, bizarre multinucleated cells (monster
      cells), and xanthomatous cells with large prominent nuclei set in a background of
      classic fibrous histiocytoma. Rare mitotic figures are identified.
      Immunohistochemical studies showed the tumor cells to be positive for vimentin,
      smooth muscle actin, desmin, KP-1, factor XIIIa, and MIB-1 (less than 10%). In
      addition to the expected immunohistochemical studies, the tumor stained diffusely
      positive for CD117. To our knowledge, this is the first report of atypical
      fibrous histiocytoma of the scrotum.

PMID- 15018123
TI  - Endometrial atypical hyperplasia with clear cell change spreading throughout the
      endometrium.
AB  - An unusually rare case of atypical endometrial hyperplasia with clear cell change
      (metaplasia) spreading through almost the whole endometrium of a 37-year-old
      woman with infertility and abnormal bleeding is reported.

PMID- 15018122
TI  - Triple synchronous neoplasms in one kidney: report of a case and review of the
      literature.
AB  - We report the case of a patient with three synchronous but histologically
      different primary renal tumors that were all in the same kidney. Two tumors were
      different subtypes of renal cell carcinoma (RCC), and the third was a variant
      form of angiomyolipoma. The patient was a 62-year-old man who was receiving
      antihypertensive drugs and came to our hospital for a regular check-up.
      Ultrasonography performed during the visit revealed a left renal mass, but the
      patient had no related symptoms. Subsequent computed tomography revealed two
      round, high-density masses, one in the mid-portion and the other in the lower
      pole of the left kidney, and multiple cysts in the right kidney and the liver.
      The mass in the mid-portion measured 3.3 x 3.0 x 2.8 cm, and the mass in the
      lower pole measured 1.7 x 1.1 x 0.9 cm. A left radical nephrectomy was performed.
      On gross examination, an additional ovoid nodule (0.6 cm in the greatest
      dimension) was found in the lower pole. Microscopically, the largest tumor
      consisted of a broad alveolar arrangement of large round cells with abundant
      eosinophilic or clear cytoplasm, distinct cell borders, and perinuclear halos,
      features consistent with chromophobe RCC. The smallest tumor was a conventional
      (clear-cell) RCC. The third tumor was composed solely of atypical epithelioid
      cells with prominent nucleoli and yellowish-brown to black pigments. The tumor
      cells were positive for melanin (Fontana-Masson stain), the melanoma marker
      HMB45, vimentin, smooth-muscle actin, and the macrophage marker CD68 and were
      negative for cytokeratin. This tumor was considered a pigmented epithelioid type
      of angiomyolipoma. The histologic, histochemical, and immunohistochemical
      features in this case confirmed the presence of three synchronous primary tumors,
      a chromophobe and a clear-cell type RCC and a pigmented epithelioid
      angiomyolipoma, all of which were in the same kidney. This case is the first of
      its type reported in the literature.

PMID- 15018124
TI  - Primitive neuroectodermal tumors, embryonal tumors, and other small cell and
      poorly differentiated malignant neoplasms of the central and peripheral nervous
      systems.
AB  - Many different types of small cell, embryonal, and poorly differentiated
      neoplasms originate within the central and peripheral nervous systems. Because
      appropriate treatment is based on a correct diagnosis, the surgical pathologist
      must be familiar both with basic characteristics of each of the numerous entities
      as well as the spectrum of morphologic features that each may display. The
      nosology and nomenclature of these tumors have a rich and varied history. One
      basic distinction is between primitive neuroectodermal tumors of the central
      nervous system (cPNETs) and primitive neuroectodermal tumors of the peripheral
      nervous system (pPNETs), which are clinicopathologically and genetically
      distinct. Among the cPNETs are medulloblastoma, pineoblastoma, cerebral
      neuroblastoma, ependymoblastoma, medulloepithelioma, primary rhabdomyosarcoma,
      and atypical teratoid/rhabdoid tumor, whereas the pPNETs comprise the more
      differentiated end of a spectrum of neoplasms that include skeletal and
      extraskeletal Ewing's sarcoma.

PMID- 15018125
TI  - Overview on SARS in Asia and the world.
AB  - Severe Acute Respiratory Syndrome (SARS) is the first major novel infectious
      disease to hit the international community in the 21st century. It originated in
      southern China in November 2002, reached Hong Kong in February 2003 and spread
      rapidly thereafter to 29 countries/regions on five continents. At the end of the
      epidemic, the global cumulative total was 8098 with 774 deaths. Seven Asian
      countries/regions were among the top ten on the list. Mainland China and Hong
      Kong, SAR, accounted for 87% of all cases and 84% of all deaths. Severe acute
      respiratory syndrome is caused by a novel coronavirus. It has alarmed the world
      with its infectivity and significant morbidity and mortality, its lack of a
      rapid, reliable diagnostic test and lack of effective specific treatment and
      vaccination. The adverse impact on travel and business around the world,
      particularly in Asia, has been enormous. Some lessons learnt from this epidemic
      included: (1) any outbreak of infectious disease can rapidly spread around the
      world by air travel; (2) early reporting of the outbreak to neighbouring
      countries/regions and the World Health Organization is essential to prevent
      international spread; and (3) infection control, tracing and quarantine of
      contacts are essential to control the epidemic. Many questions remain unanswered,
      including the origin and pathogenesis of the novel coronavirus, the natural
      history and the best specific treatment of the disease. The SARS-CoV has probably
      jumped from an animal host to humans. There is an urgent need to evaluate the
      human-animal habitat in southern China and to remove animal reservoirs if found.

PMID- 15018126
TI  - SARS: clinical virology and pathogenesis.
AB  - Severe acute respiratory syndrome (SARS) is caused by a novel coronavirus, called
      the SARS coronavirus (SARS-CoV). Over 95% of well characterized cohorts of SARS
      have evidence of recent SARS-CoV infection. The genome of SARS-CoV has been
      sequenced and it is not related to any of the previously known human or animal
      coronaviruses. It is probable that SARS-CoV was an animal virus that adapted to
      human-human transmission in the recent past. The virus can be found in
      nasopharyngeal aspirate, urine and stools of SARS patients. Second generation
      reverse transcriptase polymerase chain reaction assays are able to detect SARS
      CoV in nasopharyngeal aspirates of approximately 80% of patients with SARS within
      the first 3 days of illness. Seroconversion for SARS-CoV using immunofluorescence
      on infected cells is an excellent method of confirming the diagnosis, but
      antibody responses only appear around day 10 of the illness. Within the first 10
      days the histological picture is that of acute phase diffuse alveolar damage
      (DAD) with a mixture of inflammatory infiltrate, oedema and hyaline membrane
      formation. Desquamation of pneumocytes is prominent and consistent. After 10 days
      of illness the picture changes to one of organizing DAD with increased fibrosis,
      squamous metaplasia and multinucleated giant cells. The role of cytokines in the
      pathogenesis of SARS is still unclear.

PMID- 15018127
TI  - SARS: epidemiology.
AB  - Severe acute respiratory syndrome (SARS) originated in Southern China in November
      2002, and was brought to Hong Kong in February 2003. From Hong Kong, the disease
      spread rapidly worldwide but mostly to Asian countries. At the end of the
      epidemic in June, the global cumulative total was 8422 cases with 916 deaths
      (case fatality rate of 11%). People of all ages were affected, but predominantly
      females. Health care workers were at high risk and accounted for one-fifth of all
      cases. Risk factors for death included old age and comorbid illnesses, especially
      diabetes. The disease is caused by a novel coronavirus and is transmitted by
      droplets or direct inoculation from contact with infected surfaces. Contaminated
      sewage was found to be responsible for the outbreak in a housing estate in Hong
      Kong affecting over 300 residents. The mean incubation period was 6.4 days (range
      2-10). The duration between onset of symptoms and hospitalisation was from 3 to 5
      days. The relatively prolonged incubation period allowed asymptomatic air
      travellers to spread the disease globally. The number of individuals infected by
      each case has been estimated to be 2.7. Effective control of nosocomial
      transmission included early detection of disease, strict isolation of patients,
      practice of droplet and contact precautions and compliance with the use of
      personal protective equipment. Effective control of disease spread in the
      community included tracing and quarantine of contacts. Development of a validated
      diagnostic test and an effective vaccine as well as elimination of possible
      animal reservoirs are measures needed to prevent another epidemic.

PMID- 15018128
TI  - SARS: radiological features.
AB  - Air-space disease is typical in severe acute respiratory syndrome (SARS) and may
      be indistinguishable from pneumonia of other causes. In the majority of patients,
      ground glass opacities on chest radiographs progress rapidly to focal, multifocal
      or diffuse consolidation. Unilateral involvement is common in the early acute
      phase, becoming bilateral at maximal lung involvement. Generally, radiographic
      opacities peak between 8 and 10 days after onset of illness, with radiographic
      scores reflecting temporal changes in clinical and laboratory parameters such as
      oxygen saturation (SaO2) and liver transaminases. Pleural effusions, cavitating
      consolidation and mediastinal lymphadenopathy are not typical radiographic
      features. Pneumomediastinum and pneumothoraces are complications that are
      associated with extensive disease, with or without assisted ventilation. The
      utility of high resolution computed tomography (HRCT) and CT scans lies in the
      confirmation of airspace opacities in cases with normal initial chest radiographs
      that have strong contact history and signs and symptoms highly suspicious of SARS
      during the outbreak, allowing early treatment and prompt isolation. The
      characteristic HRCT feature in the acute phase is ground-glass opacities with
      smooth interlobular septal thickening, sometimes with consolidation in a
      subpleural location, which progress rapidly to involve other areas of the lungs.
      Temporal lung changes documented on HRCT suggest that some residual opacities
      found may not be reversible.

PMID- 15018129
TI  - SARS: clinical features and diagnosis.
AB  - Severe acute respiratory syndrome (SARS) is a highly infectious disease with a
      significant morbidity and case fatality. The major clinical features include
      persistent fever, chills/rigor, myalgia, malaise, dry cough, headache and
      dyspnoea. Less common symptoms include sputum production, sore throat, coryza,
      dizziness, nausea, vomiting and diarrhoea. Older subjects may present with
      decrease in general well-being, poor feeding, fall/fracture and delirium, without
      the typical febrile response. Common laboratory features include lymphopenia with
      depletion of CD4 and CD8 lymphocytes, thrombocytopenia, prolonged activated
      partial thromboplastin time, elevated D-Dimer, elevated alanine transminases,
      lactate dehydrogenase and creatinine kinase. The constellation of compatible
      clinical and laboratory findings, together with the rather characteristic
      radiological features especially on HRCT and the lack of clinical response to
      broad-spectrum antibiotics, should quickly arouse suspicion of SARS. The
      positivity rates of urine, nasophargyngeal aspirate and stool specimen have been
      reported to be 42%, 68% and 97%, respectively, on day 14 of illness, whereas
      serology for confirmation may take 28 days to reach a detection rate above 90%.
      Recently, quantitative measurement of blood SARS CoV RNA with real-time RT-PCR
      technique has been developed with a detection rate of 80% as early as day 1 of
      hospital admission but the detection rates drop to 75% and 42% on day 7 and day
      14, respectively.

PMID- 15018130
TI  - SARS: pharmacotherapy.
AB  - The pharmacotherapy for severe acute respiratory syndrome (SARS) is controversial
      and largely anecdotal. Most patients with suspected SARS should initially be
      treated with potent antibiotics before proceeding to 'anti-SARS' therapy. There
      is a spectrum of severity and rate of progression in SARS, and the stages of
      viral replication, inflammatory pneumonitis and residual pulmonary fibrosis are
      clinically non-distinct. Although now considered lacking in efficacy, ribavirin
      was used extensively in Hong Kong for treatment of SARS. Retrospective data
      suggest that the use of Kaletra (ritonavir and lopinavir), an anti-protease,
      could reduce mortality and improve outcomes, although the adverse reactions are
      also worrisome. Anecdotal experience strongly supports the use of steroid, at
      least in a subset of SARS patients, particularly with 'critical SARS' who display
      continued clinical instability or deterioration and progressive radiographic or
      HRCT deterioration. A retrospective study carried out of 72 probable SARS
      patients has shown that cases who received pulse methylprendisolone did not
      differ in cumulative steroid dosage or adverse reactions, although the former
      patients had less oxygen requirement, better radiographic outcome, and less
      likelihood of requiring rescue pulse steroid therapy than their counterparts.
      Nevertheless, lower dosage of steroid as initial therapy in SARS had also been
      associated with good clinical outcomes. Poor responders to initial therapy might
      benefit from rescue steroid therapy or intravenous Pentaglobin. Other drug
      treatments had also been tried in desperate patients, including the use of
      convalescence serum and plasmapheresis. Secondary infections could be
      troublesome, particular for patients with prolonged hospitalization and
      mechanical ventilation.

PMID- 15018131
TI  - SARS: ventilatory and intensive care.
AB  - Severe acute respiratory syndrome (SARS) is an emerging infection caused by a
      novel coronavirus. It is characterised by a highly infectious syndrome of fever
      and respiratory symptoms, and is usually associated with bilateral lung
      infiltrates. The clinical syndrome of SARS often progresses to varying degrees of
      respiratory failure, with about 20% of patients requiring intensive care. Despite
      concern about potential aerosol generation, non-invasive ventilation (NIV) has
      been reported to be efficacious in the treatment of SARS-related ARF without
      posing infection risks to health care workers (HCW). Spontaneous
      pneumomediastinum and pneumothorax in SARS is common. The incidence of NIV
      associated barotrauma ranged from 6.6% to 15%. Patients who fail to tolerate NIV
      or fail NIV with progressive dyspnoea, tachypnoea and hypoxaemia should be
      intubated and mechanically ventilated. Mortality rates in intensive care units
      for SARS patients were high: 34-53% at 28 days, when some patients were still
      being ventilated. Strict adherence to infection control measures including
      isolation, use of appropriate personal protective equipment and negative pressure
      environment had been reported to eliminate cross-infection to HCW.

PMID- 15018132
TI  - SARS: prognosis, outcome and sequelae.
AB  - Severe acute respiratory syndrome (SARS) is associated with considerable
      morbidity and mortality in the acute phase. Worldwide case fatality rate is 11%
      (range 7 to 27%) for the most severely affected regions. Several adverse
      prognostic factors have been identified, including advanced age, presence of
      comorbidity, higher lactose dehydrogenase levels and initial neutrophil count,
      but the impact of viral and other host factors on outcome is unknown. Published
      data on sequelae of SARS are limited. Clinical follow-up of patients who
      recovered from SARS has demonstrated radiological, functional and psychological
      abnormalities of varying degrees. In the early rehabilitation phase, many
      complained of limitations in physical function from general weakness and/or
      shortness of breath. In a small series of subjects who underwent CT scan of the
      chest, over half showed some patchy changes consistent with pulmonary fibrosis.
      Lung function testing at 6-8 weeks after hospital discharge showed mild or
      moderate restrictive pattern consistent with muscle weakness in 6-20% of
      subjects. Mild decrease in carbon monoxide diffusing capacity was detected in a
      minority of subjects. Preliminary evidence suggests that these lung function
      abnormalities will improve over time. Psychobehavioural problems of anxiety
      and/or depression were not uncommon in the early recovery phase, and improved
      over time in the majority of patients. Avascular necrosis of the hip has been
      reported as another complication. The long-term sequelae of SARS are still
      largely unknown. It is important to follow up these patients to detect and
      appropriately manage any persistent or emerging long-term sequelae in the
      physical, psychological and social domains.

PMID- 15018133
TI  - SARS: hospital infection control and admission strategies.
AB  - Nosocomial clustering with transmission to health care workers, patients and
      visitors is a prominent feature of severe acute respiratory syndrome (SARS).
      Hospital outbreaks of SARS typically occurred within the first week after
      admission of the very first SARS cases when the disease was not recognized and
      before isolation measures were implemented. In the majority of nosocomial
      infections, there was a history of close contact with a SARS patient, and
      transmission occurred via large droplets, direct contact with infectious material
      or by contact with fomites contaminated by infectious material. In a few
      instances, potential airborne transmission was reported in association with
      endotracheal intubation, nebulised medications and non-invasive positive pressure
      ventilation of SARS patients. In all SARS-affected countries, nosocomial
      transmission of the disease was effectively halted by enforcement of routine
      standard, contact and droplet precautions in all clinical areas and additional
      airborne precautions in the high-risk areas. In Hong Kong, where there are few
      private rooms for patient isolation, some hospitals have obtained good outcome by
      having designated SARS teams and separate wards for patient triage, confirmed
      SARS cases and step-down of patients in whom SARS had been ruled out. In
      conclusion, SARS represents one of the new challenges for those who are involved
      in hospital infection control. As SARS might re-emerge, all hospitals should take
      advantage of the current SARS-free interval to review their infection control
      programmes, alert mechanisms, response capability and to repair any identified
      inadequacies.

PMID- 15018134
TI  - SARS: public health measures in Hong Kong.
AB  - As there are no validated and rapid diagnostic tests nor specific treatment for
      severe acute respiratory syndrome (SARS) at the initial stage of the outbreak,
      public health measures are vital for the control of the disease. These included
      an enhanced disease surveillance system, expanded laboratory diagnostic capacity,
      heightened infection control in hospitals and residential institutions for the
      elderly, intensive contact tracing coupled with medical surveillance at
      designated medical centres, quarantine of close contacts by way of home
      confinement, formation of multidisciplinary investigation and response teams, and
      public education and communication. The above measures were implemented in many
      countries during the outbreak. To prevent spread in the region and beyond, port
      health measures targeted at both entry and exit health screenings were also
      carried out together with regional and international liaison.

PMID- 15018135
TI  - Zinc deficiency in men with Crohn's disease may contribute to poor sperm function
      and male infertility.
AB  - In Great Britain, married couples were reported to have between 1.9 and 2.1
      children, while men with Crohn's disease had a mean of 1.2 and of 0.4 children
      before and after diagnosis, respectively. The role of zinc for male fertility is
      essential. Although lack of zinc in Crohn's disease is well established in up to
      70% of patients, a possible relation between zinc deficiency and male
      subfertility in Crohn's disease remains unclear. This study is aimed at examining
      a possible link between zinc deficiency in men with Crohn's disease and male
      subfertility in this group of patients.

PMID- 15018136
TI  - Establishing of two in vitro models of epithelial cells from the apocrine
      secreting rat coagulating gland.
AB  - Apocrine secretion is an alternative export pathway for proteins and was
      described especially for accessory sex glands of rodents and men. This mechanism
      is not as well characterized as the classical merocrine (eccrine) export. In the
      rat coagulating gland both secretion modes were observed, and several proteins
      were identified to be released by these two pathways. To obtain more data on the
      apocrine secretion mode, we established two culture models of the rat coagulating
      gland: primary epithelial cells and an organ culture system. The in vitro models
      were characterized with immunocytochemistry, electron microscopy and RT-PCR. The
      polarity of primary and passaged epithelial cells (passage 8) was proven by the
      detection of occludin, E-cadherin and beta-actin. The gland tissue pieces showed
      good maintenance after 1-week culture. Finally we demonstrated that the
      epithelial cells of both culture models are still expressing and producing
      apocrine and merocrine proteins. Using these two culture models for the rat
      coagulating gland, it is now possible to initiate studies on the apocrine
      secretion mechanism in vitro.

PMID- 15018137
TI  - Serum reproductive hormone levels and sperm production in male adult rats after
      treatment with arresting, a fraction obtained from seminiferous tubules
      conditioned medium.
AB  - This study used seminiferous tubule (ST) segments from adult rats to condition
      culture medium that had been concentrated, size fractioned and administered 10-84
      days to adult rats by subcutaneous or intratesticular injection and the effects
      on testes weight, testosterone, luteinizing hormone (LH) and FSH levels and
      (homogenization-resistant) epididymal sperm count were determined. The
      conditioned medium obtained 2 days after culture of ST was fractionated in a 30
      100 kDa component. The fraction was injected subcutaneously or intratesticularly.
      This factor(s), named arresting, decreases sperm count in the epididymis from 13
      days to 84 days of treatment without changes in serum LH or testosterone levels.
      The results of the present study suggest that arresting acts on
      spermiogenesis/spermiation and/or the entry of sperm into the epididymis from the
      efferent ductules.

PMID- 15018139
TI  - Effect of high altitude exposure on spermatogenesis and epididymal sperm count in
      male rats.
AB  - The present study was designed to determine the effect of exposure to high
      altitude on spermatogenesis using transillumination technique and sperm count in
      male rats. In addition, the effect of oral intubation for intragastric
      administration of vehicle on testicular parameters in adult male rats in a
      schedule of 42 days was assessed. Male rats were exposed to Cerro de Pasco (Peru)
      at 4340 m for 3, 7, 14, 21, 28, 35 and 42 days resulting in a modification of the
      pattern of the seminiferous tubule stages. At day 3, stages I, IV-V, VI, VII and
      IX-XI were relatively shorter at high altitude than at sea level. At day 7,
      stages VIII, IX-XI, XII and XIII-XIV were reduced. At day 14, stages VII, VIII
      and IX-XI were reduced. At day 21 and 28, stages VIII, XII and XIII-XIV were
      significantly increased at high altitude. At day 35 an increase in stage XIII-XIV
      was observed. At day 42, stages II-III, IX-XI and XII were significantly
      increased at high altitude. Epididymal sperm count was significantly reduced at
      day 7 of exposure to high altitude and maintained low levels with respect to sea
      level up to 42 days. In conclusion, high altitude exposure affects
      spermatogenesis, particularly onset of mitosis and spermiation. This in turn
      affects epididymal sperm count.

PMID- 15018138
TI  - Morphological and morphometric attributes of epididymal and testicular
      spermatozoa following surgical sperm retrieval for obstructive and nonobstructive
      azoospermia.
AB  - Whilst the morphological (shape) and morphometric (sperm head size) attributes of
      ejaculated spermatozoa have been well studied, the morphological and morphometric
      qualities of testicular and epididymal spermatozoa retrieved from males with
      obstructive and nonobstructive azoospermia is much less documented. We wished to
      examine the effect of aetiology of azoospermia and site of retrieval on the
      attributes of retrieved spermatozoa. This was a prospective observational study
      of 30 consecutive successful sperm retrievals, six for nonobstructive azoospermia
      and 24 for obstructive, of which five were retrieved from the epididymis and the
      remainder from the testis. The proportion of morphologically normal testicular
      spermatozoa in patients with obstructive and nonobstructive azoospermia was not
      significantly different (7% versus 7.6%, P = 0.97). Testicular spermatozoa from
      males with obstructive azoospermia showed an increase in frequency of sperm with
      small heads [47/180 (26%) versus 97/909 (11%), P = 0.036] as well as small
      acrosome and increasing vacuole formation over nonobstructive spermatozoa.
      Similarly, there was a significant increase in tail deformities and decreases in
      tail lengths in sperm from males with nonobstructive azoospermia. Epididymal
      spermatozoa showed significantly greater proportion of morphologically normal
      spermatozoa than testicular (20% versus 13%, P = 0.001) as well as a significant
      increase in acrosome vacuoles. Furthermore, morphometrically epididymal
      spermatozoa displayed with smaller head length, width and area than testicular
      spermatozoa. Testicular spermatozoa from obstructive azoospermia displayed
      significantly less tail defects (35% versus 57%, P = 0.003) as well as
      significantly longer tail lengths (30.6 microm versus 10.7 microm). These
      morphological and morphometric differences between epididymal and testicular and
      obstructive and nonobstructive spermatozoa may represent part of the natural
      maturation process. There were no associations between any morphological or
      morphometric abnormality with any significant parameter in subsequent use in
      ICSI.

PMID- 15018140
TI  - Men born in the region of Leipzig (Saxony, Germany) between 1960 and 1970 showed
      a significantly decreased sperm count (examination of 3432 individuals).
AB  - The routine spermiogram parameters of 3432 patients born between 1952 and 1971 in
      the region of Leipzig were determined between January 1975 and March 2000. The
      patient group aged 24-35 years was characterized by low mobility and relocation
      living in the main centre of chemical industry with enormous environmental
      pollution in Eastern Germany up to 1990. Sperm concentrations and total sperm
      counts were found to be significantly reduced in men born between 1960 and 1970
      compared with men born before this period (52.38 +/- 1.21 versus 70.79 +/- 2.15
      millions ml(-1) 139.51 +/- 3.66 versus 176.31 +/- 6.04 millions; mean +/- SEM; P
      < 0.01; 2410 versus 1022 patients) independently of the year of semen
      examination.

PMID- 15018141
TI  - Formation and organization of the mammalian sperm head.
AB  - The formation and organization of a mammalian sperm head occurs through diverse
      cellular and molecular processes during spermiogenesis. Such cellular events
      include sequential changes in the nucleus and the acrosome-which is derived from
      the Golgi apparatus-in concert with prominent bundles of microtubules, the
      manchette. However, these complex processes are readily impaired by a variety of
      intrinsic and extrinsic factors, eventually causing various types of male
      infertility--such as teratozoospermia--which include the deformation of the
      acrosome and nucleus. In order to comprehend such idiopathic male infertility
      syndromes, it is important to clarify the mechanism involved in sperm head
      formation and organization. In addition to the manchette, two key structures in
      these events are the acroplaxome and the perinuclear theca. The acroplaxome forms
      the acrosome plate with periodic intermediate filament bundles of the marginal
      ring at the leading edge of the acrosome, and its nature has recently been
      characterized. The perinuclear theca, which is located in the perinuclear region
      in the sperm head, contains not only a cytoskeletal element to maintain the shape
      of the sperm head but also functional molecules leading to oocyte activation
      during fertilization. This review discusses recent developments regarding the
      formation and organization of the mammalian sperm head in relation to its
      relevant functions.

PMID- 15018142
TI  - Localization of lymphocyte apoptosis in murine lymphoid tissues after stimulation
      of natural killer T cells with alpha-galactosylceramide.
AB  - Alpha-galactosylceramide (alpha-GalCer) has been reported to induce activation
      induced cell death (AICD) in natural killer T (NKT) cells. We undertook this
      study to demonstrate the distribution of AICD of NKT cells in the lymphoid
      tissues and differences in frequency between the central and peripheral lymphoid
      tissues, histologically and quantitatively analyzing the apoptotic figure in the
      murine spleen, lymph node, and thymus after alpha-GalCer treatment. Lymphocyte
      apoptosis was identified as a cluster of nuclei with chromatin condensation in
      hematoxylin-eosin-stained sections, and was confirmed by TUNEL staining, double
      staining for TUNEL and CD4, and electron microscopy. In the spleen, it appeared
      at 12 h after alpha-GalCer administration, increased in number, reaching a peak
      at 24 h, and then falling to a normal level at 72 h. It was preferentially found
      in the white pulp, especially in the periarterial lymphoid sheath, but was sparse
      in the red pulp. Alpha-GalCer-induced lymphocyte apoptosis was seen in tumor
      necrosis factor (TNF)-deficient mice as well, but was not in lpr/lpr (Fas
      deficient) or gld/gld (Fas ligand-deficient) mice. As for the tissue
      distribution, lymphocyte apoptosis was frequently seen in the paracortex of the
      lymph node, whereas it was rare in the thymus. These data indicate that alpha
      GalCer-induced AICD of NKT cells takes place in the T-cell area of peripheral
      lymphoid tissues (i.e., the spleen and lymph node) through the Fas/Fas ligand,
      but not the TNF pathway.

PMID- 15018143
TI  - The ultrastructure of periductal connective tissue and distinctive populations of
      collagen fibrils associated with ductal epithelia of exocrine glands.
AB  - The ultrastructure of the connective tissue around the intraglandular ducts was
      observed in rat exocrine glands. Connective tissue with a dense population of
      collagen fibrils was found either around the ducts and blood vessels
      (perivasculoductal connective tissue; PVDCT) as in the lacrimal and salivary
      glands and liver, or solely surrounding the ducts (periductal connective tissue;
      PDCT) as in the exocrine pancreas, whereas the interlobular and intralobular
      interstitium of the glands-except for the liver-contained substantially fluid
      filled spaces without collagen fibrils. The PVDCT and PDCT of these glands
      contained two populations of collagen fibrils-fibroblast-associated and
      epithelium-associated-although the development and density of these fibrils
      varied considerably in individual glands. Both populations of collagen fibrils
      were most developed in the lacrimal glands, in which the basal aspects of the
      ductal epithelium and the basement membrane showed considerable undulation
      associated with a distinctive peribasement membrane zone with amorphous matter
      and a small population of the fibrils. In the parotid and submandibular glands,
      both populations were distinct, though poorly developed. In the exocrine pancreas
      and hepatic Glisson's sheath, the two populations of collagen fibrils were
      moderately developed, and the basal aspects of the ductal epithelium were
      characterized by prominent invaginations in which the multilaminar basement
      membranes and the epithelium-associated collagen fibrils were frequently
      engulfed. These observations provide evidence that the two populations of
      collagen fibrils around the ducts are found universally in exocrine glands, and
      support the hypothesis of the collagen fibril-synthesizing and -secreting ability
      of ductal epithelial cells.

PMID- 15018144
TI  - Extracellular matrix-regulated p53 expression and nuclear localization in
      cultured Detroit 562 cells derived from pharyngeal carcinoma.
AB  - Tumor suppressor p53 functions as a transcriptional factor that regulates the
      cell cycle and apoptosis. A mutated p53 gene can result in decreased sequence
      specific DNA binding and transcriptional activity of the p53 protein. In this
      study, we examined the regulatory role of the extracellular matrix components in
      p53 expression and nuclear localization in a Detroit 562 cell line derived from a
      pharyngeal carcinoma. When cultured on a polystyrene surface, type I collagen
      gel, or Matrigel containing basement membrane components, Detroit 562 cells
      showed a distinct response to extracellular matrix components morphologically. As
      shown by Western blotting, Detroit 562 cells cultured on Matrigel displayed an
      increased expression of p53 protein as well as an elevated nuclear p53 level, as
      compared with the cells cultured on the polystyrene surface or type I collagen
      gel. When cultured on Matrigel, nuclear p53-positive cells were exclusively
      localized to the outer surface layer of the cell clusters, whereas most of the
      inner cells showed no p53 expression. In Detroit 562 cell clusters on Matrigel,
      proliferative activities, as evaluated by proliferationcell nuclear antigen
      staining and bromo-deoxyuridine incorporation assay, were evenly distributed;
      virtually no apoptotic cells, as evaluated by the fluorescence TUNEL assay, were
      detected in the cell clusters, suggesting that the peculiar localization of
      nuclear p53-positive cells was not directly related to cell proliferation or
      apoptosis. These results indicate that p53 expression and its localization in
      Detroit cells were modulated by extracellular matrix signals, particularly by the
      basement membrane components in Matrigel.

PMID- 15018145
TI  - Selective expression of L-serine synthetic enzyme 3PGDH in schwann cells,
      perineuronal glia, and endoneurial fibroblasts along rat sciatic nerves and its
      upregulation after crush injury.
AB  - Non-essential amino acid L-serine functions as a highly potent, glia-derived
      neurotrophic factor, because it is a precursor for syntheses of proteins, other
      amino acids, membrane lipids, and nucleotides, and also because its biosynthetic
      enzyme 3-phosphoglycerate dehydrogenase (3PGDH) is preferentially expressed in
      particular glial cells within the brain. Here we pursued 3PGDH expression in
      peripheral nerves and its change after crush injury. In the pathway of rat
      sciatic nerves, 3PGDH was selectively expressed in non-neuronal elements: Schwann
      sheaths and endoneurial fibroblasts in sciatic nerves, satellite cells in dorsal
      root ganglia, and astrocytes and oligodendrocytes in the spinal ventral horn. In
      contrast, 3PGDH was immunonegative in axons, somata of spinal motoneurons and
      ganglion cells, and endoneurial macrophages. One week after crush injury, 3PGDH
      was upregulated in the distal segment of injured nerves, where 3PGDH was
      intensified in activated Schwann cells and fibroblasts. 3PGDH was still negative
      in activated macrophages, which were instead associated or surrounded by
      activated Schwann cells with intensified 3PGDH. These results suggest that in the
      peripheral nervous system, these non-neuronal cells synthesize and may supply L
      serine to satisfy metabolic demands for maintenance and regeneration of
      peripheral nerves and for proliferation and activation of macrophages upon nerve
      injury.

PMID- 15018147
TI  - Localization and expression of chondromodulin-I in the rat cornea.
AB  - The localization and expression in the rat cornea of chondromodulin-I (ChM-I), an
      inhibitory angiogenesis factor, were examined by immunohistochemistry, Western
      blot analysis, ribonuclease protection assay, and real-time PCR assay. We found
      immunoreactivity for ChM-I in the epithelial layer but not the stromal layer or
      endothelial layer in the cornea, in addition to the positive ChM-I
      immunoreactivity in other sites in the eye such as the sclera, retina, and
      ciliary body. The ChM-I immunoreactivity was most intense at the outside of the
      basal cells and in their cytoplasm while the intensity of the immunoreactivity
      decreased gradually from the wing cells to the superficial cells in the corneal
      epithelial layer. No reactivity however, was detected in the Bowman's membrane or
      conjunctival epithelial cells which had continuity with the corneal epithelial
      cells. The expression of ChM-I mRNA was demonstrated in the cornea at one-third
      less intensity than that in the sclera with choroids and retinal pigment
      epithelium by ribonuclease protection assay and real-time PCR. ChM-I in the
      corneal epithelial layer may prevent neovascularization and maintain avascularity
      in the cornea.

PMID- 15018148
TI  - Embryonic development of the myenteric nerve plexus in the rat small intestine as
      revealed by light and scanning electron microscopy.
AB  - This study was performed to clarify developmental changes in the structure of the
      myenteric nerve plexus in the rat small intestine. The small intestines of fetal
      and neonatal rats were examined by light microscopic immunohistochemistry for
      protein gene product 9.5 (PGP-9.5) and alpha-smooth muscle actin (alpha-SMA).
      Direct observation of the three-dimensional structure of the neuronal and
      muscular elements was accomplished by scanning electron microscopy of tissues
      after KOH treatment. At the embryonic day 14 (E14), PGP-9.5 immunopositive
      (neuronal) cells first appeared in the mesenchymal tissue outside an alpha-SMA
      positive (muscle) cell layer. These cells increased in number to form a thin and
      continuous sheet, which was sandwiched between the inner and outer muscular
      layers at E17. This neuronal layer consisted of immature ganglion cells
      associated with supportive (enteroglial) cells, and was gradually segregated into
      groups by incomplete separation through slit-like interruptions at E18. With the
      widening of these slits at E19, the neuronal sheet was observed as a ladder
      composed of transversely elongated ganglia and their connecting nerve strands,
      resulting in the typical structure of the myenteric nerve plexus. Fibroblastic
      cells of a peculiar shape appeared on the outer surface of the myenteric plexus
      at E19. These cells (presumably interstitial cells) interconnected their long
      branching projections to form a cellular network on the myenteric plexus until
      birth.

PMID- 15018146
TI  - The expression of cytokeratin in hepatic stellate cells of the cod.
AB  - In the current study, we examined the cytoskeletal architecture of cod hepatic
      stellate cells. We found that the cod hepatic stellate cells contain abundant
      cytoplasmic filaments. Deep-etch electron microscopy showed that the major
      component of the cytoplasmic filaments was intermediate filaments, although
      microtubules and microfilaments were also found in the cytoplasmic filament
      bundles. Immunoelectron microscopy revealed the presence of beta-tubulin, alpha
      smooth muscle actin, smooth muscle type myosin, desmin and cytokeratin but not
      vimentin or glial fibrillar acidic protein. These results demonstrate that the
      cytoplasmic filaments of cod hepatic stellate cells are composed of desmin and
      cytokeratin intermediate filaments, acto-myosin complexes and microtubules,
      suggesting that the cod hepatic stellate cells have both contractile and
      structural functions. The expression of cytokeratin in cod hepatic stellate cells
      indicates that they serve for mechanical support in the extremely soft liver
      tissues of cods with their abundant lipids.

PMID- 15018149
TI  - Human blood group antigen H is not the specific marker for type I cells in the
      taste buds.
AB  - We examined the localization of human blood antigen H (AbH) and its correlation
      with other cell type markers in the taste buds of circumvallate papillae of the
      adult rat. Immunoreactivity for AbH was localized in the membrane of two cell
      populations in the taste buds: in spindle-shaped cells extending from base to the
      apical portion of the taste buds as well as in round-shaped cells at the basal
      portion of the taste buds. Quantitative analysis revealed that approximately
      47.8%, 24.4%, and 14.6% of cells within the taste buds displayed AbH-, alpha
      gustducin- or protein gene product 9.5 (PGP 9.5)-immunoreactivity, respectively.
      Approximately 16.3% and 6.6% of AbH-immunoreactive taste bud cells displayed
      alpha-gustducin- or PGP 9.5-immunoreactivity, respectively. Although previous
      studies proposed that AbH immunoreactivity was specific for type I cells (dark
      cells or supporting cells), the present results indicate that AbH
      immunoreactivity is also present in some type II cells (alpha-gustducin
      immunoreactive cells) and type III cells (PGP 9.5-immunoreactive cells).

PMID- 15018151
TI  - Blood coagulation tests in toxicological studies--review of methods and their
      significance for drug safety assessment.
AB  - In general toxicological studies, prothrombin time and activated partial
      thromboplastin time are routinely measured to assess blood coagulation. Special
      (problem-driven) tests for blood coagulation are of significance to detect
      abnormalities and investigate the mechanism of toxicity in detail. In this
      review, we compiled widely scattered information on blood coagulation testing
      from different fields in the biological area, and reviewed the methods available
      and their significance in toxicological studies. The relevant literature cited
      here reports large species differences in platelet aggregation, coagulation
      factors or fibrinolysis, and technical limitations. However, the following tests
      are basically applicable to laboratory animals; (1) assays for individual
      coagulation factors and protein induced by vitamin K absence or antagonists
      (PIVKA) to investigate coagulation factor abnormalities; (2) platelet aggregation
      , platelet adhesion-, platelet release-tests and von Willebrand factor assay to
      screen and/or investigate platelet dysfunction; (3) fibrin/fibrinogen degradation
      products (FDP), D-dimer and thromboelastogram to detect fibrinolitic
      abnormalities, and assays for plasminogen, plasmin and their activator/inhibitor
      to investigate fibrinolysis in detail; and (4) bleeding-time to grossly evaluate
      blood coagulation capability in vivo. An appropriate battery of these tests
      provides significant information for risk assessment of drugs.

PMID- 15018150
TI  - Hepatocarcinogenesis by peroxisome proliferators.
AB  - It is well known that various kinds of hypolipidemic drugs induce marked changes
      in the livers of rats and mice. The initial hepatic responses in rodents are
      marked hepatomegaly, proliferation of peroxisomes in association with changes in
      peroxisome structure and enzyme composition. Furthermore, since many of
      hypolipidemic peroxisome proliferators induce hepatocellular carcinomas in both
      rats and mice, the relationship between peroxisome proliferation and
      hepatocarcinogenicity of these drugs has become extremely important. However, it
      has not yet been established whether there are any direct relationships among
      pharmacological action, peroxisome proliferation and carcinogenicity of these
      drugs. In order to clarify this task, we have studied the involvement of HGF in
      hepatocarcinogenesis caused by peroxisome proliferators. After male F-344 rats
      were orally given Wy-14,643, hepatocarcinomas and (pre) neoplastic nodules were
      observed in the livers. At that time, the content of HGF and the expression of
      HGF mRNA were significantly decreased in the liver tumors. These findings may
      indicate that decreases in hepatic HGF levels are specific events induced by
      peroxisome proliferators but not by genotoxic carcinogenesis, and that those
      changes play an important role in the promotion of neoplastic or preneoplastic
      cell growth induced by peroxisome proliferators. Decrease in HGF induced by
      peroxisome proliferators such as Wy-14,643 would inhibit the growth of normal
      hepatocytes and then lend an advantageous circumstance for the selective growth
      of neoplastic or preneoplastic cells, resulting in the development of growth of
      tumors.

PMID- 15018152
TI  - Oral glucose tolerance test and determination of serum fructosamine level in
      beagle dogs.
AB  - The present communication deals with information regarding the practice of the
      oral glucose tolerance test and determination of serum fructosamine in laboratory
      beagles. In the oral glucose tolerance test, a 180-min level was found to be
      crucial following a gavage administration of 50% glucose solution at 5 mL/kg per
      body weight under fasting conditions. Serum fructosamine concentration as
      'determined by enzymatic assay ranged between 82 and 123 micromol/L (mean of 104
      micromol/L), which was about 0.285 to 0.25 times the value obtained by the
      chemical method described by Johnson and colleagues. Reasons for differences are
      ascribed to the presence of substances with reducing potential other than
      fructosamine in the serum.

PMID- 15018153
TI  - Renal effects of 26-week administration of olmesartan
      medoxomil/hydrochlorothiazide in rats.
AB  - The combination of an angiotensin II type 1 receptor blocker (ARB) and a diuretic
      is effective clinically in treatment of hypertension. As a non-clinical safety
      evaluation of a combination of the ARB olmesartan medoxomil (OM) and the diuretic
      hydrochlorothiazide (HCTZ), male and female normotensive rats were administered
      OM/HCTZ (fixed ratio of 8 : 5) orally by gavage for 26 weeks at dose levels of 0,
      4.88, 16.25, 48.75, 162.5, 487.5, or 1625 mg/kg/day. Additional groups were given
      1000 mg/ kg/day OM or 625 mg/kg/day HCTZ. Statistically significant and marked
      decreases in urinary protein excretion were observed in males and females given
      doses of 16.25 mg/kg/day or higher compared to vehicle-control groups. Increases
      in blood urinary nitrogen (BUN) were observed in males and females given doses of
      16.25 and 162.5 mg/kg/day or higher, respectively. Increased incidence of chronic
      progressive nephropathy (CPN), a rat-specific spontaneous renal lesion, was
      observed in males and females given doses of 48.75 mg/kg/day or higher. An
      additional mechanistic study, consisting of male and female rats given 0, or
      162.5 mg/kg/day OM/HCTZ, was conducted to clarify the toxicological significance
      of the increases in BUN and the increased incidence of CPN described above. This
      additional study clearly demonstrated that saline-supplementation through free
      access to saline in the drinking water ameliorated the elevation in BUN and also
      ameliorated the incidence of CPN. Consequently, the effects on BUN and CPN
      observed in the first study can be explained by the hemodynamic disturbances
      caused by the large doses and an exaggerated pharmacological action in volume
      depleted normotensive animals. Importantly, the marked decreases in urinary
      protein were not affected by the saline-supplementation, and indicated that
      OM/HCTZ elicited a renoprotective effect, probably by an effect on the glomeruli.
      An additional toxicokinetic study revealed no drug interactions between OM and
      HCTZ. In conclusion, OM/HCTZ induced a renoprotective effect as well as changes
      probably attributed to the exaggerated pharmacological action of the ARB with
      diuretic in normotensive rats. These results suggest that OM/HCTZ may have
      renoprotective effects in clinical treatment of hypertensive patients.

PMID- 15018154
TI  - Cellular toxicity of catechin analogues containing gallate in opossum kidney
      proximal tubular (OK) cells.
AB  - A variety of catechins exist in green tea and Chinese rhubarb. It is also known
      that the green tea tannin mixture and its individual tannin components such as (
      )-epicatechin 3-O-gallate (ECG) and (-)-epigallocatechin 3-O-gallate (EGCG)
      suppress renal failure in animals and inhibit the growth of mesangial cells. In
      addition, gallic acid (GA), a structural constituent of these catechins, induces
      apoptosis in tumor cell lines. However, the effects of catechins on renal tubular
      cells have not been investigated. In this experiment, the growth of opossum
      kidney proximal tubular (OK) cells was inhibited by GA (36.9 +/- 9.5%, p < 0.01)
      and EGCG (48.6 +/- 16.7%, p < 0.01) at 50 microM, and was almost completely
      inhibited by these compounds at concentrations over 100 microM. Furthermore, ECG
      inhibited the growth of OK cells at concentrations over 200 microM (52.6 +/-
      16.5%, p < 0.01). The numbers of in situ end-labeled (ISEL) cells in cultures
      treated with GA at 25 and 50 microM, ECG at 100 and 200 microM, or EGCG at 25
      microM were significantly less than those in the cultures treated with high
      concentration EGCG (50 microM). In addition, exposure to 50 microM EGCG or 400
      microM GA for 24 hr led to a significant increase in fragmented DNA, but ECG did
      not significantly induce DNA fragmentation compared to the control. These results
      suggest that EGCG induces mostly apoptosis in OK cells, but the cellular toxicity
      of GA involves both apoptosis and other mechanisms. Finally, ECG inhibits the
      growth largely via some mechanism other than apoptosis. This chemical-specific
      difference of cytotoxic pattern may be dependent on the combination of GA and
      basal catechin structures, or NADH oxidase (NOX) activity on the OK cell surface.

PMID- 15018155
TI  - Automated measurement of freezing time to contextual and auditory cues in fear
      conditioning as a simple screening method to assess learning and memory abilities
      in rats.
AB  - In fear-conditioning paradigms, rats display a freezing response not only upon
      presentation of a conditioned stimulus (usually tone), but also when returned to
      a conditioning chamber (context) in which they received an unconditioned stimulus
      (usually a foot shock). These paradigms have intrinsic advantages for screening
      effects of chemicals on learning and memory, although the time-consuming
      monitoring of freezing time by human observers may be problematic. In this study,
      an automated apparatus was developed to optimize a fear-conditioning paradigm for
      screening. We developed an apparatus that records freezing time measured from
      body movements detected by passive infrared (PIR) sensors. The apparatus detected
      freezing time as accurately as the human scoring method, and these data were used
      to determine learning parameters (freezing time to context or to tone) and a non
      learning parameter (freezing time to novel context) in the rats. Rats orally
      administered the neurotoxic compound trimethyltin (TMT) exhibited decreased
      freezing levels to context, but not to tone or to novel context. These results
      suggest that this automated method can be an effective part of a screening
      program.

PMID- 15018156
TI  - Comparative assessment of prurifloxacin, sparfloxacin, gatifloxacin and
      levofloxacin in the rabbit model of proarrhythmia.
AB  - The administration of certain quinolone antibiotics has been associated with a
      prolongation of the QT interval on electrocardiogram, and in rare cases
      ventricular arrhythmias such as torsades de pointes. In this in vivo study using
      a rabbit arrhythmia model, we assessed the proarrhythmic effects and changes in
      the QT interval elicited by the administration of NM394 (UFX), an active
      metabolite of the new quinolone antibiotic prulifloxacin, and three
      representative quinolones, sparfloxacin (SPFX), gatifloxacin (GFLX) and
      levofloxacin (LVFX). Chloralose-anesthetized rabbits were co-administered a
      continuous infusion of methoxamine (15 microg/kg/min) together with NaOH
      (vehicle, 0.2 mol/L), SPFX (2, 3, 4 mg/kg/min), GFLX (4 mg/kg/min), LVFX (4
      mg/kg/min) or UFX (4 mg/kg/min) via the ear vein, and then the effects on
      electrocardiogram were examined. SPFX and GFLX both prolonged the QT and QTc
      intervals. GFLX also induced premature ventricular contractions in all 6 rabbits
      that received it, and subsequently it induced torsades de pointes (TdP) in 3 of
      the 6 rabbits. SPFX infused at the dose of 4 mg/ kg/min induced conduction blocks
      without inducing TdP, whereas that infused at the lower dose of 3 mg/ kg/min
      induced both conduction blocks and TdP. The infusions with LVFX and UFX did not
      elicit remarkable prolongations in the QT interval, and none of the animals
      infused with the agents developed arrhythmia. These findings suggested that LVFX
      and UFX were less potent than SPFX and GFLX in prolonging the QT interval and
      inducing life-threatening arrhythmias.

PMID- 15018157
TI  - Thirteen-week repeated dose toxicity of rice bran glycosphingolipid in Wistar
      Hannover (GALAS) rats.
AB  - Rice bran glycosphingolipid (RBGSL), one of the glycosphingolipids (GSLs), has
      been widely used as a food additive, a base of cosmetics, and so on. As a part of
      the safety assessment of RBGSL, a 13-week repeated dose toxicity study was
      performed in Wistar Hannover (GALAS) rats. Male and female rats were divided into
      4 groups consisting of 8 animals and were given 0, 60, 250, and 1000 mg/kg BW of
      RBGSL orally 5 times weekly for 13 weeks. During the experiment, no deaths were
      observed in any groups, and there were no remarkable changes in general
      appearance, body weight, food and water consumption, hematological and serum
      biochemical parameters, organ weight and histopathological findings between the
      control and treated groups. On the basis of these data, the no-observed-adverse
      effect level (NOAEL) of RBGSL in Wistar Hannover rats was considered to be 1000
      mg/kg BW/ day or more.

PMID- 15018158
TI  - Role of magnetic resonance imaging for evaluation of tumors in the cardiac
      region.
AB  - The aim of this study was to review the role of MRI in the assessment of heart
      neoplasm, 25 cases with heart neoplasm (10 myxoma, 6 rhabdomyoma, 5 angiosarcoma,
      2 mesothelioma, 1 lymphoma, and 1 fibroma) were examined with MRI and
      echocardiography. Multislice T1- and T2-weighted spin-echo images and static
      gradient-echo images were taken in appropriate directions with electrocardiogram
      gating. Gadolinium enhancement was performed in 21 cases. Transthoracic
      echocardiography was performed in all cases. Except for the 5 patients with
      rhabdomyoma, the pathological diagnosis was obtained. MRI proved to be useful for
      tissue characterization of myxoma, angiosarcoma, mesothelioma, and fibroma in
      cases with tuberous sclerosis. MRI also proved to be useful for detection of the
      tumor, depiction of contour, relation with other cardiac structures, in cases
      with myxoma, angiosarcoma, mesothelioma, lymphoma, and fibroma. In the
      differential diagnosis, MRI provided important information in cases with myxoma,
      rhabdomyoma, angiosarcoma, and fibroma. In cases with tumors expanding into the
      mediastinum, such as mesothelioma and fibroma in this report, MRI was useful in
      determining the location and border. In cases with tumors adjacent to
      pericardium, MRI was useful in detecting pericardial invasion. Gadolinium
      enhancement added useful information in cases with myxoma, rhabdomyoma,
      angiosarcoma, and mesothelioma. The role of MRI with and without Gd enhancement
      differs somewhat in individual types of heart neoplasm, and adaptation must be
      considered in each kind of neoplasm. On the other hand, MRI is an essential
      examination in all cases with a cardiac mass, which has not been diagnosed, since
      it may provide useful information for the differential diagnosis.

PMID- 15018159
TI  - A case of missing mitral valve leaflet: radiological detection.
AB  - Intravascular foreign bodies may be introduced into the circulation as a
      complication of minimally invasive or interventional techniques, or during
      cardiac valve surgery. Prosthetic heart valve leaflets have been rarely described
      as intravascular foreign bodies. Herein we report a case of prosthetic heart
      valve leaflet embolization to the aortic bifurcation with computed tomography and
      ultrasonography findings, and the importance of radiographic imaging in the
      localization of missing leaflet fragment is pointed out.

PMID- 15018160
TI  - MRI and CT revealing carcinoid heart disease.
AB  - Carcinoid heart disease is a frequent complication of the carcinoid syndrome,
      usually presenting as right-sided valvular heart disease. Although the diagnosis
      is most often made with cardiac ultrasound, MRI and CT are valuable techniques
      for diagnosing carcinoid heart disease.

PMID- 15018161
TI  - Combined PET/CT with iodine-124 in diagnosis of spread metastatic thyroid
      carcinoma: a case report.
AB  - Iodine-124 positron emission tomography (PET) is a useful 3D imaging technique
      for diagnosis and management of thyroid diseases. The difficulty in
      interpretation of the PET scans with highly selective tracers, such as iodine
      124, is the lack of identifiable anatomical structures, so an accurate anatomical
      localization of foci presenting abnormal uptake is problematic. Consequently, a
      combined PET/CT scanner can resolve these difficulties by co-registering PET and
      CT data in a single session allowing a correlation of functional and morphologic
      imaging. A case is presented where iodine-124 produced by a clinical cyclotron
      and FDG were used to acquire images with a combined PET/CT scanner for clinical
      staging. On the basis of the PET/CT exams the treatment of the patient was
      modified.

PMID- 15018162
TI  - Parotid tumors: MR imaging with pathological correlation.
AB  - Most parotid tumors grow slowly, whether benign or malignant; thus, it is
      difficult to predict the malignant or benign nature of a tumor clinically.
      Magnetic resonance imaging may have a place in the diagnostic work-up of parotid
      tumors. The purpose of this article is to illustrate the MR imaging findings of
      parotid tumors and to correlate them to pathologic findings. The MR imaging may
      be helpful in differentiation of benign and malignant tumors of the parotid
      gland, and can provide important clues in the diagnosis of their histologies.

PMID- 15018163
TI  - Cystic angiomatosis with splenic involvement: unusual MRI findings.
AB  - Cystic angiomatosis is a rare disorder with a poor prognosis. We describe a case
      of a 33-year-old woman who presented with long-standing bone pain, hemolytic
      anemia, and an enlarged spleen. Radiologically, multiple osseous lesions with a
      mixed pattern of lytic and sclerotic areas were seen within the shoulders, spine,
      and pelvis. On CT and MRI of the abdomen, the spleen was markedly enlarged, with
      internal hyperdense foci on non-contrast CT scan, corresponding to low signal
      intensity areas on all MR pulse sequences. After administration of contrast, a
      mottled enhancement pattern throughout the entire spleen was seen both on CT and
      MRI. Cystic angiomatosis was proven by histological analysis of a biopsy specimen
      of an involved vertebra and histopathological examination of the spleen after
      subsequent splenectomy. This is the first report of a patient with disseminated
      cystic angiomatosis with splenic involvement in which the MRI features differ
      from the previous reports. Instead of the usual pattern consisting of multiple
      well-defined cystic lesions, a diffuse involvement replacing the entire spleen,
      with heterogeneous signal intensities on T2-weighted images and heterogeneous
      enhancement pattern, was seen in our patient.

PMID- 15018164
TI  - Peliosis hepatis presenting as a multifocal hepatic pseudotumor: MR findings in
      two cases.
AB  - Two cases of pseudotumoral peliosis hepatis are presented with emphasis on MRI
      findings. One patient had four individual lesions, the other had two. Image
      characteristics in both were: heterogeneic signal intensity on T1-weighted images
      (T1WI) with areas of high-, intermediate, and low signal intensity; heterogeneic
      signal intensity on T2WI with presence of numerous intralesional "cystic"
      hyperintense areas with a hypointense border. Signal intensities on T1WI were iso
      to hypointense in one case and mild central hyperintensities were demonstrated
      in the other case, probably due to intra-lesional hemorrhage or diffuse
      accumulation of fresh clotting within the sinusoids. One case demonstrated early
      enhancement of the peripheral borders in the arterial phase, and both
      demonstrated enhancement in the portovenous and late phases. One case was studied
      with Gd-BOPTA and iron oxides and demonstrated enhancement with both products,
      suggestive for the presence of hepatocytes and Kupffer cells. This is the first
      report of the use of hepato-specific contrast agents in this entity. Spontaneous
      regression of the lesions was demonstrated on a follow-up MR examination in one
      case.

PMID- 15018165
TI  - Hepatocellular carcinoma in an ectopic liver: CT findings.
AB  - Hepatocellular carcinoma (HCC) in an ectopic liver is very rare and its CT
      findings have never been reported. We present an ectopic HCC between the spleen
      and left diaphragm, mimicking a splenic neoplasm on the CT scan. A follow up CT
      at seven months postoperatively revealed multiple recurrent HCCs in the mother
      liver.

PMID- 15018166
TI  - Pancreatic Castleman's disease: MR findings.
AB  - Castleman's disease can involve a number of organs/tissues but generally affects
      the mediastinum. Occurrence of Castleman's disease in the pancreas in either form
      of the disease, the hyaline vascular or the plasma-cell type, is very rare, with
      only a few case reports in which the imaging findings were described. The MR
      imaging of pancreatic Castleman's disease has not been previously reported, to
      our knowledge. We submit the MRI findings in a patient with the plasma-cell-type
      of Castleman's disease, which presented as an isolated smoothly marginated
      pancreatic mass, hypointense on T1-weighted fat-suppressed images, isointense on
      T2-weighted sequences, and that after contrast material injection showed
      peripheral rim enhancement during the arterial phase.

PMID- 15018167
TI  - Diseases of the cecum: a CT pictorial review.
AB  - Cecal pathology is commonly encountered and may represent a diagnostic challenge
      in patients with either acute or chronic clinical presentations. Although
      appendicitis accounts for the majority of surgical conditions presenting with
      right lower quadrant pain, readers should be aware of the broad spectrum of cecal
      pathologies and characteristic CT findings, which can be useful in establishing
      the correct diagnosis.

PMID- 15018168
TI  - Diverticular disease in CT colonography.
AB  - The aim of this study was to evaluate findings on CT colonography (CTC) in
      patients with diverticular disease. In a retrospective analysis of 160
      consecutive patients, who underwent CTC and conventional colonoscopy (CC),
      patients with diverticular disease were retrieved. The CTC images were compared
      with CC and, if possible, with pathology. Findings on both 2D and 3D images are
      illustrated with emphasis on diagnostic problems and the possible solutions to
      overcome these problems. Several aspects of diverticulosis were detected:
      prediverticulosis (3%); global (55.6%); and focal wall thickening (4%) caused by
      thickened haustral folds, fibrosis, inflammation and adenocarcinoma; diverticula
      (52%); pseudopolypoid lesions caused by diverticular fecaliths (39%); inverted
      diverticula (1.2%); and mucosal prolapse (0.6%). Solutions to overcome pitfalls
      are described as abdominal windowing, content of the pseudopolypoid lesion,
      comparison of 2D and 3D images, prone-supine imaging and the aspect of the
      pericolic fat. In this series there were equivocal findings in case of mucosal
      prolapse (0.6%) and focal wall thickening (4%). Diverticulosis is a challenge for
      CTC to avoid false-positive diagnosis of polypoid and tumoral disease. Knowledge
      of possible false causes of polypoid disease and comparison of 2D and 3D images
      are necessary to avoid false-positive diagnosis. In case of equivocal findings
      additional conventional colonoscopy should be advised whenever a clinically
      significant lesion (> or = 1 cm) is suspected.

PMID- 15018169
TI  - Rectal inflammation as first manifestation of graft-vs-host disease: radiologic
      pathologic findings.
AB  - Graft-vs-host disease (GVHD) is a common, life-threatening complication of bone
      marrow transplantation that frequently involves the gastrointestinal tract. Since
      symptoms are typically nonspecific, radiologic examination is often performed to
      reach a diagnosis. To the best of our knowledge, this is the first reported
      radiologic description of a case of rectal involvement as the first manifestation
      of GVHD. The differential diagnosis of segmental rectal wall thickening in a
      patient following bone marrow transplantation should include GVHD.

PMID- 15018170
TI  - Percutaneous thrombin injection for the treatment of a post-pancreatitis
      pseudoaneurysm.
AB  - Visceral artery pseudoaneurysms are often treated surgically or by transcatheter
      embolisation. We report a case of a pseudoaneurysm in a patient with chronic
      pancreatitis, which was successfully occluded by percutaneous injection of
      thrombin into the pseudoaneurysmal sac as a first-line management.

PMID- 15018171
TI  - Hemolysis, hemorrhage, headache, and hidden abortion: imaging findings in
      antiphospholipid syndrome.
AB  - Antiphospholipid antibodies are associated with arterial and venous thromboses,
      recurrent pregnancy loss, and organ infarction. Any vascular region can be
      affected. We present a 20-year-old woman suffering from secondary
      antiphospholipid syndrome with a unique combination of multifocal venous
      thromboses, pulmonary embolism, spontaneous abortion, and splenic infarction.
      Diversity of clinical symptoms and diagnostic imaging modalities are discussed
      with emphasis on cross-sectional imaging. The syndrome should be suspected in
      patients with thromboses and organ infarctions of otherwise undetermined
      etiology.

PMID- 15018173
TI  - MR findings of prostatic urethral polyp in an adult.
AB  - We report MR imaging characteristics of a prostatic urethral polyp in a 35-year
      old man. Traditionally, the methods of diagnosis include computed tomography,
      transrectal sonography, voiding cystourethrography, intravenous pyelography,
      urethroscopy, and cystoscopy. To our knowledge, MR findings have not been
      previously described. In this case, MR imaging clearly demonstrated a polypoid
      tumor located in the prostatic urethra with a stalk connected to the bladder
      neck. A pathological study revealed the polyp consisted of a fibrovascular core
      covered with a double layered, prostatic-type epithelium.

PMID- 15018172
TI  - Ovarian cancer: the clinical role of US, CT, and MRI.
AB  - This article presents an overview of ovarian cancer, which addresses the clinical
      roles of imaging studies, including US, CT, and MR imaging in the course of
      diagnosis and treatment of this important disease. US is the modality of choice
      in the evaluation of patients with suspected adnexal masses. Although its
      accuracy is not sufficient to avert surgery, morphological analysis of adnexal
      masses with US helps narrow the differential diagnosis, determining the degree of
      suspicion for malignancy, usually in concert with a serum CA-125 level. Combined
      morphological and vascular imaging obtained by US appear to further improve the
      preoperative assessment of adnexal masses. For uncertain or problematic cases, MR
      imaging helps to distinguish benign from malignant, with an overall accuracy for
      the diagnosis of malignancy of 93%. The accuracy of MR imaging in the confident
      diagnosis of mature cystic teratoma, endometrial cysts, and leiomayomas is very
      high. CT is not indicated for differential diagnosis of adnexal masses because of
      poor soft tissue discrimination, except for fatty tissue and for calcification,
      and the disadvantages of irradiation. In the staging of ovarian cancer, CT, US,
      and MR imaging all have a similarly high accuracy. Although it is difficult to
      suggest a simple algorithm for evaluating the state of women with adnexal masses,
      the correct preoperative diagnosis and staging of ovarian cancer with the use of
      any of these imaging studies will lead to an appropriate referral to a specialist
      in gynecologic oncology and offer a significant survival advantage for patients
      with ovarian cancer.

PMID- 15018174
TI  - Primary localized amyloidosis of the urinary bladder.
AB  - We report a rare case of localized form of primary amyloidosis (amyloidoma) of
      the urinary bladder with CT and MR findings. Clinically, it is difficult to
      distinguish from invasive transitional cell carcinoma and inflammatory lesion. We
      think that the MR intensity on T2-weighted images is helpful in making the
      diagnosis.

PMID- 15018175
TI  - Transient partial amnesia complicating cardiac and peripheral arteriography with
      nonionic contrast medium.
AB  - The aim of this study was to present a case of disruption of the blood-brain
      barrier during the coronary and lower extremity angiographies with radiological
      and clinical findings. This condition was secondary to intraarterial use of a
      nonionic, monomeric contrast medium. A total of 450 cc contrast media was used.
      Computed tomography examination showed contrast enhancement of the right
      occipital and frontoparietal cortical regions, which returned to normal one day
      after. The patient also fully recovered from the neurological symptoms within 24
      h. We discussed the possible mechanism for blood-brain barrier disruption in this
      case.

PMID- 15018177
TI  - Bilateral congenital absence of the internal carotid artery.
AB  - Bilateral congenital absence of the internal carotid artery was incidentally
      found in an 11-year-old boy. Magnetic resonance imaging showed a normal-appearing
      brain that was entirely supplied by the vertebrobasilar system, and CT confirmed
      the absence of the bony carotid canals. Although most reported patients with
      agenesis of both internal carotid arteries presented with cerebrovascular
      lesions, this case demonstrates that this rare malformation may be asymptomatic.

PMID- 15018176
TI  - Imaging of renal tumours in infancy and childhood.
AB  - There is a large range of benign and malignant renal neoplasms. This article
      lists the most benign, indeterminate and malignant renal tumours that occur
      during infancy and childhood. It briefly describes the most important entities,
      including their imaging features, and important complications. Differential
      diagnosis and pitfalls are discussed, and a brief suggestion for a standardised
      imaging algorithm is proposed. Although modern imaging techniques, including
      colour Doppler sonography, helical or multidetector CT, and MR have significantly
      improved imaging potential, the definite diagnosis on tumour entity still is
      established only by histology.

PMID- 15018178
TI  - MRI findings of hypoxic cortical laminar necrosis in a child with hemolytic
      anemia crisis.
AB  - We present magnetic resonance imaging findings of a 5-year-old girl who had a
      rapidly installing hemolytic anemia crisis induced by trimethoprim
      sulfomethoxazole, resulting in cerebral anoxia leading to permanent damage.
      Magnetic Resonance imaging revealed cortical laminar necrosis in arterial border
      zones in both cerebral hemispheres, ischemic changes in subcortical white matter
      of left cerebral hemisphere, and in the left putamen. Although cortical laminar
      necrosis is a classic entity in adulthood related to conditions of energy
      depletions, there are few reports available in children. A wide review of the
      literature is also presented.

PMID- 15018179
TI  - Colonic arteriovenous malformation in a child misinterpreted as an idiopathic
      colonic varicosis on angiography: remarks on current classification of childhood
      intestinal vascular malformations.
AB  - A case of lower gastrointestinal hemorrhage in a child caused by an arteriovenous
      malformation (AVM) of the colon is presented. On diagnostic angiography, the
      lesion was misinterpretated as an idiopathic colonic varicosis because none of
      the characteristic features of an AVM were present. The role of angiography and
      shortcomings in nomenclature and classification of intestinal vascular anomalies
      in childhood are discussed.

PMID- 15018181
TI  - Scimitar syndrome: morphological diagnosis and assessment of hemodynamic
      significance by magnetic resonance imaging.
AB  - Scimitar syndrome has a variable presentation depending on the age at which the
      diagnosis is made. We report a case of a young woman (age 18 years) with
      suspected right pulmonary hypoplasia in whom a scimitar syndrome was diagnosed.
      Using MRI morphological findings and hemodynamic significance of the syndrome
      were assessed. Left-to-right shunt was calculated from blood flow measurements
      performed in the ascending aorta, the main pulmonary artery, and the aberrant
      scimitar vein.

PMID- 15018180
TI  - High-resolution real-time compound ultrasound imaging of transient protein-losing
      gastropathy of childhood.
AB  - We report the case of a 1.5-year-old girl with transient protein-losing
      gastropathy with hypertrophic gastric folds (PLGH). The diagnosis of PLGH was
      made by abdominal ultrasound (US) and not by an upper gastrointestinal (UGI)
      study as reported in many previous publications. Real-time compound ultrasound
      imaging showed in high detail the echogenic thickening of the mucosal gastric
      layer and associated hyperaemia on colour Doppler US. These ultrasonic findings
      highly correlated with the endoscopic US findings and microscopic changes of the
      gastric wall in PLGH. An awareness of the high-resolution abdominal ultrasound
      appearances of PLGH may facilitate earlier diagnosis and obviate the need for an
      upper GI contrast series.

PMID- 15018183
TI  - Accessory ossicles and sesamoid bones of the ankle and foot: imaging findings,
      clinical significance and differential diagnosis.
AB  - Accessory ossicles and sesamoid bones are frequent findings in routine
      radiographs of the ankle and foot. They are commonly considered fortuitous and
      unrelated to the patient's complaint; however, they may eventually cause painful
      syndromes or degenerative changes in response to overuse and trauma. They may
      also suffer or simulate fractures. Our aim was to review, illustrate and discuss
      the imaging findings of some of the more frequent accessory ossicles and sesamoid
      bones of the ankle and foot region, with particular emphasis on those that may be
      of clinical significance or simulate fractures.

PMID- 15018182
TI  - Neoplastic transformation and tumour-like lesions in Paget's disease of bone: a
      pictorial review.
AB  - The development of a sarcoma is the most serious complication of Paget's disease
      of bone. Although its incidence is <1% of those with the underlying disease, it
      is important to recognise the imaging features of these tumours as Paget's
      disease of bone is relatively common in the ageing population in certain parts of
      the world. The purpose of this pictorial review is to present the imaging
      features of Paget's sarcoma based on one orthopaedic oncology centres experience
      in 49 patients; however, not all masses or destructive lesions arising in
      association with Paget's disease are sarcomas and not all the tumours are
      malignant. This review also includes other malignancies which may arise in
      pagetic bone as well as tumour-like manifestations of Paget's disease.

PMID- 15018184
TI  - Sacral pseudotumor complicating iliac bone harvest: radiographic, CT and MRI
      appearances.
AB  - We present the imaging appearances of a lytic pseudotumor in the right sacral ala
      presenting with referred pain to the right thigh. Subsequent imaging revealed the
      presence of a cystic lesion arising at the site of previous bone graft harvest;
      CT-guided aspiration yielded synovial fluid presumed to arise from the contiguous
      sacroiliac joint.

PMID- 15018185
TI  - Reversed double PCL sign: unusual location of a meniscal fragment of the knee
      observed by MR imaging.
AB  - A 36-year-old woman with tears of the anterior cruciate ligament and medial
      meniscus received a meniscectomy. The MR images obtained prior to the partial
      meniscectomy showed a bucket-handle meniscal tear with centrally displaced
      fragment lying anterior to the posterior cruciate ligament (PCL), representing a
      "double PCL sign"; however, after the meniscectomy, MR images demonstrated a
      fragment in the space posterior to the PCL where no structure is generally
      recognized except for the ligament of Wrisberg. This article reports a "reversed"
      double PCL sign, caused by inadequate surgical clearance of a bucket-handle tear
      of the medial meniscus.

PMID- 15018186
TI  - Unusual skeletal metastases from myxoid liposarcoma only detectable by MR
      imaging.
AB  - We present two cases of skeletal metastases from myxoid liposarcoma, occurring
      several years after treatment of the primary tumors in the lower limb. The
      present two case reports have unusual radiological features only detectable by MR
      imaging and not by plain radiographs or bone scans. From the present two cases,
      we found that a negative plain radiograph of the spine or a negative bone scan
      could not exclude skeletal metastases from myxoid liposarcoma, and MRI was a more
      sensitive screening procedure for their detection, especially in T1-weighted
      images. Unusual radiological features of skeletal metastases from myxoid
      liposarcoma are not well documented and only a few cases have been previously
      reported. Our aim is to document two more patients exhibiting the unusual
      radiological features of skeletal metastases from myxoid liposarcoma to improve
      their early detection and management.

PMID- 15018187
TI  - Abnormal hyperintensity within the subarachnoid space evaluated by fluid
      attenuated inversion-recovery MR imaging: a spectrum of central nervous system
      diseases.
AB  - A variety of central nervous system (CNS) diseases are associated with abnormal
      hyperintensity within the subarachnoid space (SAS) by fluid-attenuated inversion
      recovery (FLAIR) MR imaging. Careful attention to the SAS can provide additional
      useful information that may not be available with conventional MR sequences. The
      purpose of this article is to provide a pictorial essay about CNS diseases and
      FLAIR images with abnormal hyperintensity within the SAS. We present several CNS
      diseases including subarachnoid hemorrhage, meningitis, leptomeningeal
      metastases, acute infarction, and severe arterial occlusive diseases such as moya
      moya disease. We also review miscellaneous diseases or normal conditions that may
      exhibit cerebrospinal fluid hyperintensity on FLAIR images. Although the
      detection of abnormal hyperintensity suggests the underlying CNS diseases and
      narrows differential diagnoses, FLAIR imaging sometimes presents artifactual
      hyperintensity within the SAS that can cause the misinterpretation of normal SAS
      as pathologic conditions; therefore, radiologists should be familiar with such
      artifactual conditions as well as pathologic conditions shown as hyperintensity
      by FLAIR images. This knowledge is helpful in establishing the correct diagnosis.

PMID- 15018189
TI  - Lethal subarachnoid bleeding under immunosuppressive therapy due to mycotic
      arteritis.
AB  - A subarachnoid haemorrhage (SAH) occurred 67 days after cardiac transplantation
      in a 10-year-old girl with consecutive immunocompromising therapy. Neither
      digital subtraction angiography (DSA) nor computed tomographic angiography showed
      signs of intracranial vascular malformations. One month before the lethal SAH
      occurred, she had developed arterial hypertension and attacks of severe headache
      with cerebrospinal fluid (CSF) pleocytosis while CT scans showed an infarct of
      the left thalamus. Pathologic findings established the rare diagnosis of SAH due
      to aspergillosis-related mycotic arteritis. Imaging characteristics are
      presented.

PMID- 15018188
TI  - CT and MR imaging of central nervous system effects of therapy in patients
      treated for hematological malignancies.
AB  - The purpose of this article is to present the imaging appearance of central
      nervous system effects of therapy that may occur in patients treated for
      hematological malignancies. Imaging in these patients relates to complications of
      high-dose therapy, bone marrow transplantation, infections occurring in
      immunocompromised patients, central nervous system dysfunction due to failure of
      other organ systems, or cerebral hemorrhages due to platelet refractoriness.
      Rapid and accurate diagnosis is essential but often difficult, as neurological
      manifestations are rarely disease specific. Neurological imaging, in combination
      with electrophysiological studies as well as blood and cerebrospinal fluid
      investigations, may be helpful for diagnosing most of these complications, as
      well as in differentiating between the manifestations of the underlying disease
      and complications of the treatment.

PMID- 15018190
TI  - Giant cavernoma of the brain stem: value of delayed MR imaging after contrast
      injection.
AB  - Cavernous angiomas are vascular malformations composed of slowly perfused,
      sinusoidal vessels which can be located in any part of the central nervous
      system. Whereas diagnosis is mostly straightforward in typical cases, some
      lesions may present in unusual locations or with unusual imaging characteristics.
      Because of the slow perfusion, contrast enhancement is not regarded as a
      characteristic imaging feature of cavernomas. We report a large brain stem
      cavernoma with signs of recent bleeding, in which the differential diagnosis
      against other mass lesions was facilitated by the demonstration of slow, but
      intense, contrast enhancement on MRI 1 h after contrast injection. We conclude
      that contrast enhancement in delayed images may contribute to a safe diagnosis of
      cavernous haemangiomas and should be performed in atypical cases.

PMID- 15018191
TI  - Diffusion MRI findings in phenylketonuria.
AB  - Two patients with phenylketonuria were studied who were under dietary control
      since infancy, and who were mentally normal. Diffusion MRI was obtained using a
      spin-echo, echo-planar sequence with a gradient strength of 30 mT/m at 1.5 T. A
      trace sequence (TR=5700 ms, and TE=139 ms) was used, acquired in 22 s. Heavily
      diffusion-weighted (b=1000 mm2/s) images, and the apparent diffusion coefficient
      (ADC) values from automatically generated ADC maps were studied. There were two
      different patterns in these two patients, restricted and increased diffusion
      patterns. Restricted diffusion pattern consisted of high-signal on b=1000 s/mm2
      images with low ADC values ranging from 0.46 to 0.57x10(-3) mm2/s. Increased
      diffusion pattern consisted of normal b=1000 s/mm2 images with high ADC values
      ranging from 1.37 to 1.63x10(-3) mm2/s. It is likely that these values reflected
      presence of two different histopathological changes in phenylketonuria or
      reflected different stages of the same disease.

PMID- 15018192
TI  - Diffuse spinal and intercostal nerve involvement in chronic inflammatory
      demyelinating polyradiculoneuropathy: MRI findings.
AB  - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an uncommon
      demyelinating disorder with a relapsing and remitting or continuously progressive
      course. Hypertrophic nerve roots, sometimes associated with gadolinium
      enhancement, has been reported more commonly in lumbar spine and less commonly in
      the brachial plexus and cervical roots; however, diffuse involvement of
      intercostal nerves bilaterally has never been reported previously. We present MRI
      findings which include diffuse enlargement and mild enhancement of roots and
      extraforaminal segments of nerves in all segments except a short segment between
      T12-L2 as well as all the intercostal nerves in a case of CIPD with a 10-year
      history.

PMID- 15018193
TI  - Spontaneous intrahepatic portosystemic venous shunt in leptospirosis: is it a
      rare association or coincidence?

PMID- 15018194
TI  - Extremely tortuous superior cerebellar artery.

PMID- 15018195
TI  - Targeted tumour biopsy under contrast-enhanced ultrasound guidance.

PMID- 15018196
TI  - Dermal spindle cell lipoma of the posterior neck: CT and MR findings.

PMID- 15018197
TI  - Safety of the long-time monthly triple dose of a Gd-based contrast agent.

PMID- 15018199
TI  - Cholangiographic magnetic resonance findings in post-radiation therapy
      extrahepatic biliary stricture.

PMID- 15018198
TI  - MR findings of renal malignant fibrous histiocytoma.

PMID- 15018200
TI  - CT features of uterine torsion.

PMID- 15018201
TI  - Detection of portal venous gas on sonography, but not on CT.

PMID- 15018202
TI  - Withdrawal of artificial life support.

PMID- 15018204
TI  - Crime and adverse medical treatment events: professional responses.

PMID- 15018203
TI  - Consenting to shared electronic health records: the proposed HealthConnect
      system.

PMID- 15018205
TI  - Alexander v Heise.

PMID- 15018206
TI  - The medical provision of hydration and nutrition: two very different outcomes in
      Victoria and Florida.
AB  - Decisions to withhold or withdraw medical hydration and nutrition are amongst the
      most difficult that confront patients and their families, medical and other
      health professionals all over the world. This article discusses two cases
      relating to lawful withdrawal and withholding of a percutaneous endoscopic
      gastrostomy tube (PEG) from incompetent patients with no hope of recovery.
      Victoria and Florida have statutory frameworks that provide for advance
      directives, however in both Gardner; Re BWV and Schindler v Schiavo; Re Schiavo
      the respective patients did not leave documented instructions. The article
      analyses the two cases and their outcomes from legal, medical and ethical
      perspectives.

PMID- 15018207
TI  - Gardner; Re BWV: resolved and unresolved issues at end of life.
AB  - The Medical Treatment Act 1988 (Vic) gives statutory recognition to a patient's
      (or their agent or guardian if incompetent) right to refuse medical treatment.
      The case of Gardner; Re BWV confirmed that medical treatment as defined under the
      Act included artificial nutrition and hydration and as such could be withdrawn,
      notwithstanding that this would result in the patient's death. This article
      analyses Gardner; Re BWV and argues that, by deliberately dealing narrowly with
      the issues at hand, both the Victorian Civil and Administrative Tribunal at first
      instance and the Victorian Supreme Court knowingly left BWV to die from
      dehydration over a period of weeks. By not addressing these issues, the tribunal,
      and more particularly the Supreme Court, lost an opportunity for a reform of the
      law, so urgently needed at end of life, which would have allowed for "mercy
      killing", thus sparing BWV and her family the lingering death she was given.

PMID- 15018208
TI  - The Dutch Euthanasia Act and related issues.
AB  - In 2002 the Dutch Euthanasia Act came into force. This Act is the result of a
      lengthy developmental process. It codifies the requirements that have evolved in
      case law and medical ethics since 1973. Empirical data indicate that the Dutch
      euthanasia practice is stabilising. Euthanasia and assisted suicide occur in 2.7%
      of all deaths. Now that the Act has been passed, the focus is on improving the
      quality of medical decision-making. From an international perspective, the Dutch
      legislation is exceptional. However, it appears that other countries and
      international organisations are considering euthanasia legislation as well. It
      remains to be seen how influential the Dutch model will prove to be.

PMID- 15018209
TI  - Reforming the relationship between medicine and the law of tort.
AB  - The Australian Government's medical indemnity package is predicated on the belief
      that the current crisis is primarily one of insurance. However, an examination of
      the fault-based tort system illustrates that, irrespective of their insurance
      status, doctors are profoundly affected by the adversarial process and their
      response to it is leading to sub-optimal patient care. This article argues that
      the adversarial system of medical negligence fails to satisfy the main aims of
      tort law, those being equitable compensation of plaintiffs, correction of
      mistakes and deterrence of negligence. Instead, doctors experience litigation as
      a punishment and, in order to avoid exposure to the system, have resorted not to
      corrective or educational measures but to defensive medicine, a practice which
      the evidence indicates both decreases patient autonomy and increases iatrogenic
      injury. This is unacceptable and suggests that the package has missed the point.
      This article proposes an alternative medico-legal tort scheme which attempts to
      overcome some of these problems.

PMID- 15018211
TI  - Nursing culpability: a proposal for change in nursing regulation.
AB  - Nurses make mistakes. They work in a complex environment which can sometimes be a
      contributory factor to a mistake being made. At present, Nurses' Boards in
      Australia have no mandate to investigate the circumstances in which a mistake is
      made. Their jurisdiction is limited to investigation of the individual nurse.
      This article sets out the argument for change in nursing legislation to allow for
      a broadening of the role of Nurses' Boards. It argues that an extension of their
      jurisdiction explicitly to allow them to investigate inadequacies in the health
      system would be a constructive development.

PMID- 15018210
TI  - Tissue donation: ethical guidance and legal enforceability.
AB  - The legal and ethical framework regulating the use of tissue donated for medical
      research in Australia provides clear direction on the appropriate use of donated
      tissue in many instances. However, this article argues that the current framework
      may be inadequate to address some of the problems that may arise from misuse of
      such tissue. It argues that the Human Tissue Acts do not provide a sufficiently
      broad system of regulation and require updating. It also notes that as much of
      Australian research practice is regulated through ethics guidelines, which do not
      have the status of law, in some cases this approach may fail to provide remedies
      for those whose tissue is used inappropriately.

PMID- 15018212
TI  - The inadequacies of absolute prohibition of reproductive cloning.
AB  - This study reviews debates on human cloning and its benefits, considers
      international and domestic laws, and argues that the choice of reproductive means
      is a human right. In exercise of this right, a balanced approach should be
      adopted, in order to benefit human society while protecting human dignity
      adequately. The immaturity of cloning techniques indicates that at the present
      time human reproductive cloning is too risky. Thus a temporary ban on such
      cloning is appropriate, but the ban on relevant scientific research and animal
      experimentation is inappropriate as it denies the spirit of freedom of scientific
      inquiry, and hinders making the benefits of scientific advancement available to
      human society as a whole.

PMID- 15018213
TI  - "Sufficiency" for living organism inventions under the Patents Act 1990 (Cth).
AB  - The Patents Act 1990 (Cth) requires a complete specification to describe the
      invention. This description is central to the policy objective that the statutory
      rights under the Patents Act 1990 (Cth) are exchanged for disclosure of the
      invention, including how to make the invention. In addressing these requirements
      for "micro-organisms", the Patents Act 1990 (Cth) adopted the Budapest Treaty on
      the International Recognition of the Deposit of Micro-organisms for the Purposes
      of Patent Procedure (Budapest Treaty) recognising that the "invented" organism
      itself may be necessary to make and use the invention, and that a formal
      description may be of limited value or practicability. The scope of the Budapest
      Treaty does not, however, extend to a significant class of living organisms
      outside the class defined by the term "micro-organism". This article reviews the
      application of the description requirements for living organism inventions under
      the Patents Act 1990 (Cth) and concludes that some form of public availability or
      deposit requirements are necessary for invented living organisms that are outside
      the scope of the Budapest Treaty's "micro-organisms".

PMID- 15018214
TI  - The co-regulation of medical discipline: challenging medical peer review.
AB  - The medical profession has always fiercely defended its right to self-regulation
      on the basis of peer review. However, in New South Wales, Australia, the
      profession has willingly surrendered these rights in favour of a disciplinary
      system known as co-regulation or collaborative regulation, under which
      disciplinary processes are shared with a "lay" body, the Health Care Complaints
      Commission. The system constitutes a unique situation in the history of medical
      regulation. This article examines the origin and operations of co-regulation and
      comes to the conclusion that its successful operation over the last decade raises
      questions about whether peer review is indispensable as the basis of medical
      regulation.

PMID- 15018215
TI  - Health risks of electromagnetic fields. Part I: Evaluation and assessment of
      electric and magnetic fields.
AB  - Exposure to electric and magnetic fields (EMF) emanating from the generation,
      distribution, and utilization of electricity is widespread. The major debate in
      recent years has focused on the possibility that exposure to EMF may result in
      adverse health consequences, including the development of cancer. This article
      provides a review and evaluation of potential health risks associated with
      residential and occupational exposure to EMF. In addition to reviewing data from
      laboratory, epidemiology, and clinical studies, we examine exposure data from
      field measurement surveys and exposure guidelines that have been established for
      EMF. Currently, the evidence in support of an association between EMF and
      childhood cancer is limited, although this issue warrants further investigation.
      Evidence of an association between EMF exposure and adult cancers, derived
      largely from occupational settings, is inconsistent, precluding clear
      conclusions. There is little evidence of an association between EMF and noncancer
      health effects. Epidemiological studies of EMF and population health are limited
      by exposure measurement error and the lack of a clear dose/response relationship
      in studies suggesting possible health risks. Further research is needed to
      clarify the ambiguous findings from present studies and to determine if EMF
      exposure poses a health risk.

PMID- 15018216
TI  - Health risks of electromagnetic fields. Part II: Evaluation and assessment of
      radio frequency radiation.
AB  - The increasing use of different radio frequency (RF)-emitting devices in
      residential and occupational settings has raised concerns about possible health
      effects of RF energy emitted by such devices. The debate about the potential
      risks associated with RF fields will persist with the prevalent network-connected
      wireless products and services targeting the marketplace for all kinds of
      consumer use. The aim of this article is to provide biomedical researchers with a
      review and critical evaluation of the current literature on acute and long-term
      health risks associated with RF radiation (RFR). Issues examined include safety
      standards for RFR; dosimetry and measurement surveys; and toxicological,
      epidemiological, and clinical studies of health outcomes that may be associated
      with RFR. Overall, the existing evidence for a causal relationship between RFR
      and adverse health effects is limited. Additional research is needed to clarify
      possible associations between RFR and biological effects noted in some studies.
      Particular attention should be directed toward long-term, low-level exposure to
      RFR.

PMID- 15018217
TI  - IOM calls for universal health care coverage by 2010.

PMID- 15018218
TI  - VA pharmacy technicians step up in status.

PMID- 15018219
TI  - Massachusetts moves ahead with patient safety initiatives.

PMID- 15018220
TI  - States, safety net providers recover millions from Medicaid fraud schemes.

PMID- 15018221
TI  - ASHP resident matching program: how does it work?

PMID- 15018222
TI  - Sirolimus-eluting coronary stent.
AB  - PURPOSE: The mechanism of action and pharmacokinetics of sirolimus when used as
      part of a drug-eluting stent (DES) and the efficacy and cost of using DESs versus
      bare-metal stents are discussed. SUMMARY: The use of balloon angioplasty with or
      without coronary artery stenting is limited by the phenomenon of in-stent
      restenosis (ISR). Until very recently, most efforts to overcome ISR had been
      ineffective. The search to prevent or reduce the frequency of ISR has led to the
      recent development of novel coronary artery stents designed to deliver a drug
      that acts locally. The first DES was approved by FDA in April 2003. This stent
      releases sirolimus, an agent that inhibits vascular smooth-muscle-cell
      proliferation. To date, four major clinical trials have demonstrated the
      sirolimus-eluting stent to be safe and effective in preventing restenosis in de
      novo coronary artery lesions. CONCLUSION: The sirolimus-eluting coronary stent is
      associated with less ISR than non-drug-containing stents, but further
      investigation is needed to determine its exact place in the treatment of coronary
      artery occlusion.

PMID- 15018223
TI  - ASHP national survey of pharmacy practice in hospital settings: monitoring and
      patient education--2003.
AB  - PURPOSE: Results of the 2003 ASHP national survey of pharmacy practice in
      hospital settings that pertain to monitoring and patient education are presented.
      METHODS: A stratified random sample of pharmacy directors at 1173 general and
      children's medical-surgical hospitals in the United States was surveyed by mail.
      SMG Marketing Group, Inc., supplied data on hospital characteristics; the survey
      sample was drawn from SMG's hospital database. RESULTS: The response rate was
      47.1%. Virtually all hospitals (95.3%) had pharmacists regularly monitoring
      medication therapy in some capacity. Patient monitoring has improved since 2000;
      fewer respondents reported monitoring less than 25% of patients in the hospital,
      and most hospitals reported an increase in the amount of time pharmacists devoted
      to monitoring activities. Pharmacists were provided computer access to laboratory
      information in 78% of hospitals to facilitate this function. Detection and
      reporting of adverse drug events (ADEs) have substantially increased since 1999,
      with an increase of 42% in events reported internally. Strategies to improve ADE
      reporting were in place in 84% of hospitals, indicating that pharmacists are
      adopting the widely recommended philosophy of learning from errors. Errors were
      less widely reported externally, limiting the value of aggregated data for
      improving the medication-use process. Most hospitals (85.5%) had an
      interprofessional infrastructure in place to discuss and learn from voluntary
      reports of ADEs. Medication counseling continued to be relatively infrequent,
      with nearly three fourths of hospitals reporting fewer than 26% of inpatients
      received medication education. Pharmacist staffing in hospitals has risen
      significantly, from an average of 8.6 full-time equivalents (FTEs) in 2002 to 9.4
      FTEs per hospital. Vacancy rates for pharmacists decreased from 7.3% in 2002 to
      43%. It is now estimated that there are 1846 vacancies in hospital pharmacies.
      CONCLUSION: Notable improvements in hospital pharmacy practice have been made.
      The percentage of patients whose medication therapy is monitored by pharmacists
      has increased, and most hospitals reported that the amount of time pharmacists
      spent monitoring patients' medication therapy had increased. Internal and
      external reporting of ADEs has increased, and pharmacist vacancies have decreased
      from 2002. Staffing has also improved, suggesting an abatement of the critical
      shortage of pharmacists in the hospital setting.

PMID- 15018224
TI  - Establishment and outcomes of a model primary care pharmacy service system.
AB  - PURPOSE: The establishment and outcomes of a model primary care pharmacy service
      system are described. SUMMARY: A primary care pharmacy practice model was
      established at a government health care facility in March 1996. The original
      objective was to establish a primary pharmacy practice model that would
      demonstrate improved patient outcomes and maximize the pharmacist's contributions
      to drug therapy. Since its inception, many improvements have been realized and
      supported by advanced computer and automated systems, expanded disease state
      management practices, and unique practitioner and administrative support. Many
      outcomes studies have been performed on the pharmacist-initiated and -managed
      clinics, leading to improved patient care and conveying the quality-conscious and
      cost-effective role pharmacists can play as independent practitioners in this
      environment. These activities demonstrate cutting-edge leadership in health
      system pharmacy. Redesign has been used to improve consistent access to a
      medication expert and has significantly improved the quality of patient care
      while easing physicians' workload without increasing health care costs.
      CONCLUSION: A system using pharmacists as independent practitioners to promote
      primary care has achieved high-quality and cost-effective patient care.

PMID- 15018225
TI  - Impact of nurse case manager-pharmacist collaboration on adverse-drug-event
      reporting.

PMID- 15018226
TI  - Clinical pharmacology services: a pharmacist-based consulting service for the
      developmentally disabled.

PMID- 15018228
TI  - Measuring performance indicators in clinical pharmacy services with a personal
      digital assistant.

PMID- 15018227
TI  - Pharmacist-run lipid management program in rural Alabama.

PMID- 15018229
TI  - Strategies for pharmacy integration and pharmacy information system interfaces,
      Part 1: History and pharmacy integration options.

PMID- 15018230
TI  - Strategies for pharmacy integration and pharmacy information system interfaces,
      Part 2: Scope of work and technical aspects of interfaces.

PMID- 15018231
TI  - Strategies for the prevention and treatment of statin-induced myopathy: is there
      a role for ubiquinone supplementation?

PMID- 15018232
TI  - Vascular access in apheresis: part II.

PMID- 15018233
TI  - Therapeutic apheresis in Japan.

PMID- 15018234
TI  - Microsurgery in children for creation of arteriovenous fistulas in renal and non
      renal diseases.
AB  - Microsurgery for angioaccess in children includes the use of a surgical
      microscope, microsurgical instruments, prophylactic tourniquet-induced hemostasis
      and no-touch surgery. In the recent publications concerning angioaccess in
      children, the percentages of grafts versus arteriovenous fistulas (AVF) varied
      from 54 to 76% without microsurgery, and from 0 to 14% with microsurgery.
      Similarly, the percentages of AVF which failed to mature varied from 30 to 33%
      without microsurgery, and from 5 to 10% with microsurgery. In a personal series
      of 380 children receiving hemodialysis, 434 microsurgical angioaccesses were
      created, 78% being distal autologous AVF. Eighty-five percent of the distal
      radial-cephalic AVF were patent after 2 years and 60% after 4 years. These
      results of microsurgically created AVF are probably responsible, at least in
      part, for the high percentage of end-stage renal disease (ESRD) children treated
      by hemodialysis on 1 February 2003 in Paris using an autologous fistula (70% of
      33 children), while only 24% were hemodialyzed via a central venous catheter and
      6% were on peritoneal dialysis. This compares favorably with the annual
      publication of the North American Pediatric Renal Transplant Cooperative Study in
      1996 reporting that two-thirds of the dialysis population were maintained on
      peritoneal dialysis and that the majority of hemodialysis accesses were external
      percutaneous catheters. Microsurgical AVF are also created successfully in non
      ESRD children requiring frequent blood access for various chronic diseases. It
      has been possible to create a distal AVF in 68% of cases and the long-term
      patency rate was just below 60% after 10 years. Microsurgery is mandatory for
      creation of arteriovenous fistulas, the best form of angioaccess for children
      treated by hemodialysis or requiring repeated access to blood in various non
      renal diseases.

PMID- 15018235
TI  - Silver coating of dialysis catheters to reduce bacterial colonization and
      infection.
AB  - Complications resulting from infection remain a major problem for hemodialysis
      catheters, with significant numbers of catheters being removed due to catheter
      related sepsis. Numerous strategies have been employed to reduce the occurrence
      of infection and improve long-term outcomes, with varying degrees of success. One
      promising approach is coating the external surface of catheters with silver using
      physical vapor deposition processes. This article reviews results of animal and
      clinical experiments conducted to assess efficacy and biocompatibility of silver
      coated dialysis catheters. It is concluded that silver coatings can reduce
      bacterial colonization and occurrence of infection associated with these devices.

PMID- 15018236
TI  - Transluminal removal of an embolized venous catheter fragment with simple means:
      a case report.
AB  - Vascular catheters are associated with complications like infection, thrombosis
      and stenosis. The embolization of a venous catheter fragment is a rare
      complication. This report presents a successful transluminal removal of an
      embolized catheter fragment in a 87-year-old patient who underwent on operative
      revision with renewed resection and postoperative multiorgan failure. The patient
      needed a large-bore catheter due to acute renal failure. By replacing the central
      venous catheter using the Seldinger technique a catheter fragment embolized in
      the right ventricle. This catheter fragment was removed with a Dormia basket.

PMID- 15018237
TI  - Immunomodulation effects and clinical evidence of apheresis in renal diseases.
AB  - This article overviews the immunomodulation effects and clinical evidence of
      apheresis in renal diseases, in particular primary and secondary
      glomerulonephritis. A considerable permeability factor(s) derived from
      circulating T cells is speculated to have a crucial role in the proteinuria of
      nephrotic syndrome (NS). Plasma exchange (PE), immunoadsorption using Protein A
      sepharose cartridges, low-density lipoprotein apheresis and lymphocyte apheresis
      (LCAP) were tried to remove such factors or pathogenic T cells. Other glomerular
      diseases induced by specific antibodies such as antiglomerular basement membrane
      antibodies, antineutrophil cytoplasmic antibodies and immune-complexes such as
      lupus nephritis were also treated with PE, double filtration plasma apheresis.
      IAPP and LCAP. Many reports suggested that apheresis might have beneficial
      immunomodulation effects for the treatment of glomerular diseases: however, the
      recommendations based on evidence from small cohorts remain at low-level in most.

PMID- 15018238
TI  - Therapeutic apheresis therapy for ABO-incompatible renal transplantations.
AB  - The most important transplantation antigen system for organ transplantation is
      the ABO blood group system. Crossing the blood barrier is usually not done except
      in emergency cases such as liver transplantations for fulminant hepatitis. Early
      experiences of allograft transplantations across the blood barriers were
      discouraging. In the 1970s, clinical trials were started transplanting kidneys of
      subgroup A2 into blood group O recipients because the tissues of the A2 subgroup
      express a lower amount of A antigens compared with subgroup A1. The recipients
      required no special treatment and received the standard immunosuppressive regimen
      as used in blood group identical cases. Many early graft loses immediately after
      transplantations were experienced, but these trials resulted in an excellent
      graft survival rate. A few centers have adapted the concept of A2 kidneys to non
      A recipient transplantations with successful results by reducing anti-A blood
      type titers prior to transplantations. In the early 1980s, the possibility of
      bridging the ABO barrier was tested by several groups. A1 and B kidneys from
      living donors were also successfully transplanted across the blood barrier using
      quadruple immunosuppressive drugs and splenectomy. Since 1989, the largest number
      of ABO-incompatible renal transplantations have been performed in Japan because
      of the limited numbers of cadaveric donors. Approximately 400 cases have been
      successfully transplanted across the blood barrier at many centers in Japan.
      Owing to novel immunosuppressive drugs, the ABO-incompatible allografts exhibited
      a level of function comparable with that of ABO-matched allografts even though
      anti-A or anti-B antibodies had returned to the circulation of the recipients. In
      this article, we describe the historical background, the current therapeutic
      strategies including apheresis therapy for the ABO-incompatible transplantations,
      and the experiences at our institution.

PMID- 15018239
TI  - Plasmapheresis in C4d-positive acute humoral rejection following kidney
      transplantation: a review of 4 cases.
AB  - Acute and chronic rejection after kidney transplantation has long been
      exclusively attributed to cellular and vascular mechanisms. Modern
      immunosuppressive therapy, therefore, addresses the cellular immune system.
      Rising experiences in kidney transplantation in the last few decades have
      revealed that some types of rejection are refractory to the conventional
      immunosuppressive treatment. Humoral rejection. which has previously been
      reported as a crucial factor in hyperacute rejection, is now suspected to play
      also an important role in acute and chronic rejection. Acute humoral rejection
      (AHR) is characterized by immunohistochemical detection of C4d deposits in
      peritubular capillaries. As shown for other antibody-mediated diseases, such as
      some autoimmune diseases, plasmapheresis has been suggested to be an efficient
      therapeutic approach in AHR. We present four patients with C4d-positive AHR in
      the early phase after kidney transplantation. In three of the four patients,
      humoral graft rejection was successfully treated by plasmapheresis. Graft
      function was significantly improved with a stable long-term outcome. One patient
      lost the graft. Although the number of patients with C4d-positive AHR treated by
      plasmapheresis is limited, plasma exchange appears to be an efficient and
      powerful therapeutic approach to control humoral rejection.

PMID- 15018240
TI  - Successful treatment of ulcerative colitis with leukocytapheresis using non-woven
      polyester filter.
AB  - Ulcerative colitis is a chronic inflammatory disease of the rectum and colon.
      Although the pathogenesis of ulcerative colitis is not fully elucidated, cell
      mediated immunity plays an important role in disease pathogenesis.
      Leukocytapheresis is a newly emerging therapy to eliminate activated leukocyte
      from systemic circulation. We have studied the effects of leukocytapheresis on
      patients with ulcerative colitis who had failed to respond to conventional
      therapy. A total of 51 patients with ulcerative colitis were treated with
      apheresis using a non-woven polyester fiber filter (Finecell, Asahi Medical
      Co.,Tokyo, Japan) originally developed as a microcoagulation elimination filter
      for massive transfusion. Of the 51 patients, 33 (64.7%) achieved clinical
      remission manifested by clinical activity and colonoscopic findings without any
      adverse effects. This result suggested that leukocytapheresis using Finecell
      might serve as an alternative therapy for ulcerative colitis as other
      leukocytapheresis using centrifugation or column.

PMID- 15018241
TI  - Plasma exchange treatment improves prognosis of antineutrophil cytoplasmic
      antibody-associated crescentic glomerulonephritis: a case-control study in 26
      patients from a single center.
AB  - Twenty-six patients with Antineutrophil cytoplasmic antibody (ANCA)-associated
      crescentic glomerulonephritis (GN) were divided into two groups according to the
      acute phase treatment: drug therapy consisting of steroids and oral
      cyclophosphamide plus a plasma exchange (PE) course (group A, 13 patients) or
      drug therapy alone (group B, 13 patients). Group A patients had a more severe
      clinical picture and higher serum creatinine than group B (12.7 +/- 6.9 vs. 8.5
      +/- 5.3 mg%); nine patients from group A (69%) and five from group B (38%)
      required dialysis. At follow up (mean 35 months) all patients treated with PE
      were alive: four of them were in end-stage renal disease. Among group B patients,
      three (23%) died in the acute phase; 6 (46%) needed renal replacement therapy at
      follow up. Of the dialysis-dependent patients, five out of nine from group A were
      free of dialysis, while in group B two out of five patients had died, two had
      entered a regular dialysis treatment and one had received a cadaver graft. These
      data suggest that PE may significantly improve the prognosis of patients with
      ANCA-associated crescentic GN even if they are not dialysis-dependent at the time
      of diagnosis.

PMID- 15018242
TI  - Granulocyte and monocyte adsorptive apheresis for patients with chronic hepatitis
      C virus infection: a report on six cases with high plasma viremia.
AB  - Granulocytes and monocytes/macrophages (GM) are known to constitute extra-hepatic
      sites for hepatitis C virus (HCV) replication and dissemination. Accordingly, we
      thought that selective GM adsorptive apheresis (GMA) might contribute to the
      treatment of HCV in patients with high viremia (HCV-RNA > 100 kIU/mL). Of six
      patients (three males and three females), mean age 62.2 years, five had not
      responded to interferon-alpha (INF-alpha) and one was INF-alpha naive. Each
      patient received five GMA sessions, once a week for 5 weeks. The two antecubital
      veins were used as blood access and return lines and the apheresis was performed
      at 30 mL/min for 60 min. Treatment efficacy was assessed by monitoring changes in
      plasma HCV-RNA and aminotransferase. Granulocyte and monocyte/macrophage
      adsorptive apheresis was well tolerated. During each GMA, there was on average a
      52.9% fall in plasma HCV-RNA, but HCV-RNA increased again during the time before
      the next GMA. There was no marked change in either aminotransferase during GMA.
      Furthermore, beyond the last GMA, HCV-RNA increased together with worsening
      aminotransferase in three of six patients. In conclusion, it would appear that
      GMA can partially reduce plasma HCV and GMA at a frequency of one session/week
      for 5 consecutive weeks but that this was inadequate to induce a sustained
      decrease in plasma HCV-RNA in patients with high viremia without simultaneous
      administration of antiviral medications. The most effective frequency of GMA
      needs to be determined in future clinical studies.

PMID- 15018243
TI  - Introduction. Hormone replacement therapy and the cardiovascular system:
      targeting the RAAS.

PMID- 15018244
TI  - Cardiovascular disease in postmenopausal women.
AB  - Cardiovascular disease is a major cause of death in both sexes. Women suffer
      almost as many myocardial infarctions as men, although they tend to occur at a
      greater age. Prevention programs for heart disease have impacted more positively
      on men than women and relatively young women aged 35-54 years may have fared
      worse. Hypertension is more prevalent amongst younger men than women, but above
      65 years of age it becomes more common in women. Adequate treatment of
      hypertension has many rewards, but is only received by a minority of
      hypertensives. Heart failure, too, is a major burden of cardiovascular disease,
      particularly in older women. Approximately 30% of all cardiac surgery is
      performed on women, who have a worse short-term postoperative prognosis than men,
      although the two sexes fare equally in long-term survival. Hypertension, heart
      failure and diabetes have been identified as key preoperative factors determining
      a poorer prognosis for cardiac surgery amongst women. The renin-angiotensin
      aldosterone system is thought to be central to the development of cardiovascular
      disease, with elevated levels of angiotensin II hypothesized as the factor which
      stimulates the formation of large insulin-resistant adipocytes, en route to
      diabetes. At the cellular level, estrogens have many effects on cardiovascular
      cells capable of being interpreted as beneficial in terms of cardiovascular
      disease. New studies demonstrate that approximately 5% of proteins produced by
      human myocardial cells are modulated by estrogens, estrogens receptors are
      modulated by age and disease, and estrogens modulate expression of receptors for
      endothelin-1, a neurohormone implicated in cardiovascular disease.

PMID- 15018245
TI  - Hormone therapy and the cardiovascular system: the critical role of progestins.
AB  - In broad support of the findings of the Heart and Estrogen/progestin Replacement
      Study (HERS) and other trials, the recently published preliminary findings of the
      Women's Health Initiative (WHI) study buttress the view that hormone replacement
      therapy (HRT) with a combination of 0.625 mg/day conjugated equine estrogens
      (CEE) and 2.5 mg/day medroxyprogesterone acetate (MPA) increases risks of
      coronary heart disease. Also, on the basis of outcomes for a range of other
      diseases and adverse events, it was concluded that such treatment had no overall
      global benefit. In contrast, interim analysis of results for the CEE-only arm of
      WHI did not suggest an excess of adverse outcomes. Such studies are important in
      the understanding of the relationships between hormone therapy and cardiovascular
      disease, but they have not established that all forms of combined HRT, using
      different progestins and different modes of delivery, necessarily have adverse
      outcomes for coronary heart disease and related diseases. Animal models provide
      evidence that MPA--and hence the HERS and WHI--may have unique features,
      differing from progesterone, that incline it to oppose potentially some
      beneficial effects of estrogens. Progestins in general, particularly the newer
      molecules (such as drospirenone, dienogest, Nestorone, nomegestrol acetate and
      trimegestone), vary widely in their non-progestogenic properties (including
      anti/androgenic, anti/mineralocorticoid and glucocorticoid actions), and further
      studies are required to test the implications of HERS and WHI against a range of
      different HRT combinations and modes of delivery.

PMID- 15018247
TI  - Potassium: more beneficial effects.
AB  - Over 70 years ago, potassium was found to have a natriuretic effect and was used
      in patients with heart failure. However, it took many years for its role in the
      control of blood pressure to be recognized. Recently, epidemiological and
      clinical studies in man and experimental studies in animals have shown that
      increasing potassium intake towers blood pressure and that communities with a
      high potassium intake tend to have lower population blood pressures. Several
      studies have shown an interaction between salt intake and potassium intake.
      However, the recent DASH-Sodium (Dietary Approaches to Stop Hypertension) study
      demonstrates an additive effect of a low salt and high potassium diet on blood
      pressure. Increasing potassium intake may have other beneficial effects, for
      example, reducing the risk of stroke and preventing the development of renal
      disease independent of its effect on blood pressure. A high potassium intake
      reduces calcium excretion and could play an important role in the management of
      hypercalciuria and kidney stone formation, as well as bone demineralization.
      Potassium intake may also play an important role in carbohydrate intolerance. A
      reduced serum potassium increases the risk of lethal ventricular arrhythmias in
      those at risk, i.e. patients with ischemic heart disease, heart failure or left
      ventricular hypertrophy, and increasing potassium intake may prevent this. In
      this article, we address the evidence for the important role of potassium intake
      in regulating blood pressure and other beneficial effects of potassium which may
      be independent of and additional to its effect on blood pressure.

PMID- 15018246
TI  - Cardiovascular benefits of aldosterone receptor antagonists.
AB  - There is considerable evidence in the setting of cardiovascular disease to
      suggest that, in addition to the classic effects of aldosterone on sodium
      retention, blood volume, blood pressure and potassium homeostasis, aldosterone is
      involved in fibrotic end-organ damage by means of intermediate mechanisms
      involving an interplay between the mineralocorticoid receptor, sodium intake and
      a variety of molecular messengers. Such processes may help to explain the
      reduction in mortality that can be achieved in patients with severe heart failure
      and post-myocardial infarction by the addition of an aldosterone receptor
      antagonist to standard therapy. Studies in animal models treated with the nitric
      oxide inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), angiotensin II
      and salt, with and without adrenalectomy, have demonstrated that myocardial
      damage can be eliminated by adrenalectomy or by administering an aldosterone
      receptor antagonist and is induced by adding back aldosterone to adrenalectomized
      animals. Importantly, at least a modest salt intake is an obligate co-factor.
      Other animal studies have established that an early stage in aldosterone
      associated myocardial damage involves the release of proinflammatory molecules,
      including cyclo-oxygenase type 2, osteopontin and monocyte chemoattractant
      protein-1. Taken together, these findings suggest that aldosterone in the
      presence of salt intake is a major cardiovascular risk factor mediated by
      inflammatory and fibrotic processes. Thus, mineralocorticoid receptor antagonists
      are likely to be effective additional agents to treat a broad range of
      cardiovascular diseases.

PMID- 15018248
TI  - Drospirenone: a new cardiovascular-active progestin with antialdosterone and
      antiandrogenic properties.
AB  - Drospirenone (DRSP) is a novel progestogen derived from 170alpha-spirolactone.
      Its pharmacodynamic profile is closer to progesterone than any other currently
      available progestogen. DRSP has progestational, antialdosterone and
      antiandrogenic properties, but is devoid of any estrogenic, androgenic,
      glucocorticoid, antiglucocorticoid or mineralocorticoid activities. The affinity
      of DRSP for the mineralocorticoid receptor makes it an antagonist of aldosterone,
      which is not only important in the renin-angiotensin-aldosterone system (RAAS),
      but also acts directly on the cardiovascular system. DRSP (1, 2 or 3 mg) in
      combination with 1 mg 17beta-estradiol (E2) is being developed by Schering AG as
      a continuous combined product for hormone replacement therapy (HRT). Phase II/III
      trials of E2/DRSP combinations have demonstrated clinical efficacy for the
      treatment of hot flushes, as well as improvement of bone density in the hip.
      Within 1 year of treatment with E2/DRSP, more than 80% of recipients regained
      amenorrhea. E2/DRSP at all three doses of DRSP is associated with a highly
      favorable safety profile, with excellent endometrial protection after 1 and 2
      years (no cases of hyperplasia or cancer), favorable lipid profiles, with no
      evidence of attenuation of the beneficial effects on lipids of E2, probably due
      to DRSP's lack of androgenicity. Recipients of E2/DRSP combinations showed a
      small decrease in body weight, probably due to DRSP's antialdosterone properties.
      Adverse events with E2/DRSP did not differ significantly from those observed with
      standard HRT preparations. Phase III studies with E2/DRSP show that DRSP does not
      antagonize the well-documented reductions of blood pressure associated with E2;
      rather, small DRSP dose-related reductions in systolic and diastolic blood
      pressures were observed, which should be beneficial for recipients, especially
      those who are mildly hypertensive. These effects on blood pressure are probably
      due to DRSP displaying aldosterone receptor antagonism, a property which, in
      other settings, has been shown to convey benefits in terms of cardiovascular
      disease. Further studies of the cardiovascular effects of E2/DRSP combinations
      are anticipated.

PMID- 15018249
TI  - e-Health in Europe.

PMID- 15018250
TI  - Is it time to change diabetic disease nomenclature?
AB  - The study explored the confusion in diabetes terminology as illustrated by the
      use of insulin in NIDDM. It is proposed that a new terminology for both types of
      diabetes be introduced. In order to investigate this proposal, we invited a total
      of 84 medical professionals to contribute their views via a one-page
      questionnaire, personally handed to the participants. Considering the variety of
      terms in the sample polled for this study, and the fact that patients with type 2
      diabetes might need insulin management at any stage of their life, some
      professionals persist in using the old names, a fact that seems to fly in the
      face of logic. Most pharmacists will be aware that not only are the professionals
      confused by the current situation but that patients are also perplexed when, for
      example, receiving treatment with insulin after being told that they have non
      insulin dependent diabetes.

PMID- 15018251
TI  - Massive nasal bleeding and hemodynamic instability associated with clopidogrel.
AB  - A 58-year-old woman was brought to our emergency department with massive nasal
      bleeding and hemodynamic instability. The patient had been on clopidogrel
      treatment (75 mg/day) for 2 years, which was started after an episode of
      transitory ischemic attack. Blood pressure normalized following the
      administration of intravenous fluids, and the bleeding stopped after nasal
      tamponade and desmopressin therapy.

PMID- 15018252
TI  - Clostridium difficile colitis associated with valaciclovir.
AB  - OBJECTIVE: To report a case of Clostridium difficile colitis associated with
      valaciclovir treatment. CASE SUMMARY: A 73-year-old man with lumbar herpes-zoster
      started valaciclovir 1 g tid. After three days he began vomiting and developed
      diarrhea, three to four stools per day. Symptoms worsened over the following days
      and he was admitted. Valaciclovir was stopped and fluid and electrolyte
      replacement was started. He continued 6 days later with diarrhea of 7 to 13
      stools per day and a stool test for diagnosis of C. difficile infection was
      performed with a positive result. The patient received oral metronidazole (500
      mg/t.i.d. for 10 days) and rapid improvement and eventual resolution of his
      diarrhea was observed after 3 days of therapy. DISCUSSION: Although no conclusive
      reports of this reaction exist, we think this is a case of C difficile colitis
      that appeared three days after valaciclovir was initiated. Colitis improved with
      metronidazole. Other causes of diarrhea were excluded, such as diabetes mellitus,
      renal failure, intestinal surgery and intestinal obstruction. Infection was
      confirmed by a positive test for C. difficile. The application of Naranjo's
      algorithm asserts the reaction as 'probable'. CONCLUSIONS: Valaciclovir
      associated C. difficile colitis, although rare, can have severe consequences for
      the patient's health. It should be included as a possible adverse effect of
      valaciclovir treatment by health professionals.

PMID- 15018253
TI  - Medication error due to ambiguous labelling of a commercial product.
AB  - Medication errors may involve prescribing, dispensing, preparation and
      administration of drugs. We report a case in which an administration error
      occurred due to ambiguous labelling of a commercial drug. Tablets were packed in
      sets of two tablets per blister with the print on the blister 'Zelitrex 500',
      making the amount of drug per tablet unclear. A short survey among nurses and
      pharmacy technicians showed that the majority interpreted the strength of the
      tablets incorrectly. This case shows that, despite regulations for controlling
      and accepting labelling before marketing, ambiguous labelling may occur and can
      lead to medication errors.

PMID- 15018254
TI  - The nature of informal pain questioning by nurses--a barrier to post-operative
      pain management?
AB  - OBJECTIVE: The aim of this study was to explore the nature of nurses' informal
      pain-related questioning. METHODS: Non-participant observations were performed on
      one vascular and one urology surgery ward, involving 26 nurses in 402 patient
      contacts on eight days (total observation time: 39 hours). A questionnaire survey
      of 180 (of 335 = 53.7% response rate) nurses working on the same two types of
      surgery wards in 14 UK hospitals was also undertaken. Instruments (observation
      sheet & questionnaire) were based on initial qualitative work and developed
      alongside each other to enable complementation of data. RESULTS: Both methods
      identified routine drug administration rounds as the predominant time for
      informal pain questioning. Observed nurses asked about one third of patients at
      those times. The majority of pain questions were closed, and interactions were
      generally brief and task-orientated, often involving one question. CONCLUSION:
      This study has shown the need for a more systematic way to assess patients' pain
      in routine practice. Suggestions are made about how pain questioning could be
      improved even if it continues to take place during drug rounds. These may provide
      a good opportunity for efficient pain questioning within a work environment
      acknowledging pressures of time and workload. Furthermore, within the current
      climate of increased multidisciplinary collaboration, the relevance of this study
      to medicines management and pharmacy are discussed.

PMID- 15018255
TI  - Pharmaceutical care model for patients with type 2 diabetes: integration of the
      community pharmacist into the diabetes team--a pilot study.
AB  - OBJECTIVE: To evaluate the feasibility and impact of a structured approach for
      community pharmacist input as a member of the multidisciplinary team caring for
      patients with type-2 diabetes and health professional providing advice on
      medication. METHODS: Prospective pretest-posttest single group study. Sixty-two
      patients on oral hypoglycaemic therapy, identified as regular customers of four
      Scottish (UK) community pharmacies, were recruited. Each patient underwent an
      initial assessment: review of medical general practice notes/community pharmacy
      PMR (Patient medication record) system and structured interview. Standardised
      documentation was completed, a pharmaceutical care plan (PCP) prepared, peer
      reviewed and then discussed face-to-face with patients' GPs (general
      practitioners). A second (final) assessment was conducted 24 to 28 weeks from the
      initial interview. MAIN OUTCOME MEASURES: Pharmaceutical care issues (PCIs)
      throughout study period; change in parameters from initial to final assessment:
      patient knowledge of oral hypoglycaemic and anti-hypertensive therapy; HbA1c;
      blood pressure; total cholesterol; medication compliance. RESULTS: A total of 178
      PCIs were identified (mean [range] 2.9 [1-5] per patient) and categorised: drug
      therapy problems (n = 76); monitoring (n = 21); and patient knowledge (n = 81).
      Drug therapy problems discussed with the GPs were agreed for 74 (97%) and
      resolved for 55 (72%) at final assessment. Biological outcome measures were
      assessed for 59 patients (3 drop-outs). A reduction (P < 0.05) in HbA1 c, blood
      pressure and total cholesterol was observed over the study period. Patients
      knowledge was poor for oral hypoglycaemic therapy but improved (initial-51 %,
      final-72%, P < 0.05). CONCLUSION: This study demonstrated a feasible
      pharmaceutical care model for diabetes patients in an European country. The
      results have shown the pharmacist to be effective and well accepted by GPs and
      patients.

PMID- 15018256
TI  - Unclaimed prescriptions after automated prescription transmittals to pharmacies.
AB  - OBJECTIVE: To assess the extent of and the reasons for unclaimed prescriptions,
      primary non-compliance, after automated transmittals to pharmacies. METHODS:
      Cross-sectional study in 3 health care districts (population 240,000) in the
      southernmost of Sweden on unclaimed electronic prescriptions (e-prescriptions),
      transmitted to 21 pharmacies during the period of 3 months (2000) and semi
      structured interview study with patients not claiming their e-prescriptions
      transmitted to 4 pharmacies during a period of 3 weeks (2001). MAIN OUTCOME
      MEASURE: Proportion of unclaimed e-prescriptions of total number of (dispensed
      and unclaimed) e-prescriptions and reasons for primary non-compliance. RESULTS:
      In total, 2171 (2.4%) e-prescriptions remained unclaimed at the pharmacies. The
      peak non-redemption rate was observed for those 15-24 years old (5.5%). The
      lowest rate was observed for those 65-74 years old. Men had a higher non
      redemption rate than women. The highest rate for men was observed 25-34 years old
      (6.6%). Drugs for the musculoskeletal system (ATC group M) had higher non
      redemption rates than expected (3.9%), and antibiotics (ATC-group J) lower
      (1.7%). Adolescents and young adults, 15-24 years old, had high non-compliance
      rates for drugs for the musculoskeletal system (14%) and anti-asthmatic drugs
      (11%). Of 78 interviewed patients, not claiming their e-prescriptions, 61%
      reported no need to have the prescription dispensed. However, unintentional non
      compliance was reported by 28%, most of them were not aware that a prescription
      had been transmitted to the pharmacy. Thirteen percent reported that non
      redemption had given further medical problems or made obtaining a new
      prescription necessary. CONCLUSION: Primary non-compliance was generally low, but
      there were differences related to age, gender and type of drugs. The most common
      reason reported for non-redemption was that the prescription was not needed, but
      some patients were unaware that prescriptions were issued and transmitted to the
      pharmacy.

PMID- 15018257
TI  - Simulated patients in the community pharmacy setting. Using simulated patients to
      measure practice in the community pharmacy setting.
AB  - BACKGROUND: Performance measurement and quality of care in community pharmacy
      settings is problematic because of the lack of formal patient registration and
      the resultant risk of selection bias. Although simulated patients have been used
      for teaching and education purposes, particularly in medical settings, their use
      as a research tool requires exploration in other health settings. The purpose of
      this paper is to describe how we used simulated patients to measure professional
      performance of community pharmacy staff. METHOD: Sixty pharmacies participated in
      a randomised controlled trial (RCT) to evaluate the effectiveness and efficiency
      of two guideline implementation strategies in the community pharmacy setting. The
      primary outcome measure for the study was derived from assessment forms completed
      by simulated patients following covert visits to participating pharmacies.
      RESULTS: Of the 420 simulated patient visits scheduled, 384 (91%) were completed.
      Nine visits were reported by pharmacy staff using reply-paid postcards, four of
      which concurred with known SP visits. Each detected visit was made by a different
      SP. In a post-intervention survey, 26 (52%) pharmacists stated they had been
      apprehensive about the use of simulated patients as part of the study, however,
      41 (82%) pharmacists agreed that SP visits were an acceptable research method to
      use in a community pharmacy setting. DISCUSSION: Simulated patients are a
      feasible method of assessing professional performance in community pharmacy
      settings and overcome the methodological problems of other measurement methods.
      Further research is needed to assess the reliability and validity of simulated
      patients.

PMID- 15018258
TI  - Tirofiban and eptifibatide treatment of patients presenting with acute coronary
      syndrome with non-ST segment elevation.
AB  - OBJECTIVE: This retrospective study was conducted to determine the usage patterns
      and tolerability of tirofiban and eptifibatide during the first year of their
      use. METHODS: We have assessed the appropriate use of these drugs according to
      the criteria implemented by the Clinical Institute of Cardiovascular Disease as
      part of a protocol for treating acute coronary syndrome with non-ST segment
      elevation. RESULTS: 37 patients received tirofiban and 19 patients received
      eptifibatide. These patients were at high risk of poor outcomes such as
      myocardial infarction or death. Tirofiban and eptifibatide were used according to
      the indication criteria: only one case fell outside them. Dosing, time for drug
      initiation (from last chest pain) and time of infusion were considered
      appropriate. Tirofiban was involved in two cases of minor bleeding complications
      and eptifibatide in one case of thrombocytopenia (80,000 platelets per
      millimeter). These mild adverse drug reactions were reversible with the early
      withdrawal of the drugs. CONCLUSIONS: This study shows that tirofiban and
      eptifibatide have been used optimally, with a close adherence to the pre
      established protocol. Both drugs have shown a good level of tolerability.

PMID- 15018259
TI  - The effectiveness of hospital pharmacy in the UK: methodology for finding the
      evidence.
AB  - OBJECTIVE: To describe the methodology used to identify United Kingdom (UK)
      hospital pharmacy practice research work from the last two decades. METHOD: A
      comprehensive search for citations that appeared to contribute to the overall
      evidence or in some way measure, demonstrate or evaluate the effectiveness of UK
      hospital pharmacy practice. This involved a search of thirteen electronic
      databases covering a wide variety of UK, European and international publications,
      hand searching of selected UK journals and conference proceedings, a written
      request for details sent to all UK Chief Pharmacists and Directors of Pharmacy
      and a bibliography search of each reference identified. All appropriate
      references were then added to a single computer database. MAIN OUTCOME MEASURE:
      Number of references identified by each strand of the search strategy. RESULTS:
      The search initially highlighted a total of 10,099 articles from the thirteen
      reference databases, but only 281 were considered suitable for inclusion in the
      final review. Hand searching of the selected journals and conference proceedings
      yielded another 173 references and the written requests to hospital chief
      pharmacists resulted in another 128 references being identified. Finally,
      bibliography searches of the articles identified by the above three methods
      resulted in another 242 references, bringing the total number of references to
      824. CONCLUSION: This paper describes a strategy to identify a comprehensive
      collection of citations supporting the evidence for the effectiveness of hospital
      pharmaceutical services in the UK. The large number of references identified
      demonstrate that hospital pharmacists in the UK make significant contributions to
      both the research literature and to patient care. However, database searches
      alone highlighted just 34% of the total references finally included in this
      study, demonstrating that pharmacy practice research work may be difficult to
      access by conducting database searches alone. The results from this project
      provide a resource for the profession and can be utilised as a foundation for
      future developments in both the delivery and research of hospital pharmacy
      practice.

PMID- 15018261
TI  - Preface: Fatigue and Performance Modeling Workshop, June 13-14, 2002.

PMID- 15018260
TI  - Dispensing glucose test materials in Dutch community pharmacies.
AB  - OBJECTIVE: To assess the proportion of diabetic patients who collect self
      monitoring equipment for glucose testing in Dutch community pharmacies. METHODS:
      Data were used from the PHARMO-Record Linkage System, containing pharmacy
      dispensing records from 1991 to 1998. The study population consisted of patients
      who received at least two prescriptions of insulin and/or oral hypoglycemic
      agents. Information was collected on patient demographics, antidiabetic drug use
      and self-monitoring equipment (blood glucose meters and test strips). Type of
      diabetes was determined for all incident users of antidiabetic drugs. MAIN
      OUTCOME MEASURE: The proportion of patients per community pharmacy, who were
      dispensed self-monitoring equipment at least once. RESULTS: The study population
      consisted of 11,358 diabetic patients. The number of incident patients was 5,050,
      of whom 91.7% had type 2 diabetes. Twenty-nine pharmacies were included. The mean
      proportion of patients per pharmacy who received test strips at least once was
      30.1% (SD = 6.7%), range 19-46%. The proportion of patients who were dispensed
      test strips was almost three times higher among type 1 than among type 2 patients
      (54% vs. 17%). CONCLUSION: In comparison to other countries' published data,
      Dutch community pharmacies dispense relatively few glucose test materials to
      diabetic patients. There are substantial differences between pharmacies in
      dispensing test strips. Further research is needed into the determinants
      governing the use of test strips at both patient and pharmacy level.

PMID- 15018262
TI  - Summary of the key features of seven biomathematical models of human fatigue and
      performance.
AB  - BACKGROUND: Biomathematical models that quantify the effects of circadian and
      sleep/wake processes on the regulation of alertness and performance have been
      developed in an effort to predict the magnitude and timing of fatigue-related
      responses in a variety of contexts (e.g., transmeridian travel, sustained
      operations, shift work). This paper summarizes key features of seven
      biomathematical models reviewed as part of the Fatigue and Performance Modeling
      Workshop held in Seattle, WA, on June 13-14, 2002. The Workshop was jointly
      sponsored by the National Aeronautics and Space Administration, U.S. Department
      of Defense, U.S. Army Medical Research and Materiel Command, Office of Naval
      Research, Air Force Office of Scientific Research, and U.S. Department of
      Transportation. METHODS: An invitation was sent to developers of seven
      biomathematical models that were commonly cited in scientific literature and/or
      supported by government funding. On acceptance of the invitation to attend the
      Workshop, developers were asked to complete a survey of the goals, capabilities,
      inputs, and outputs of their biomathematical models of alertness and performance.
      Data from the completed surveys were summarized and juxtaposed to provide a
      framework for comparing features of the seven models. RESULTS: Survey responses
      revealed that models varied greatly relative to their reported goals and
      capabilities. While all modelers reported that circadian factors were key
      components of their capabilities, they differed markedly with regard to the roles
      of sleep and work times as input factors for prediction: four of the seven models
      had work time as their sole input variable(s), while the other three models
      relied on various aspects of sleep timing for model input. Models also differed
      relative to outputs: five sought to predict results from laboratory experiments,
      field, and operational data, while two models were developed without regard to
      predicting laboratory experimental results. All modelers provided published
      papers describing their models, with three of the models being proprietary.
      CONCLUSIONS: Although all models appear to have been fundamentally influenced by
      the two-process model of sleep regulation by Borbely, there is considerable
      diversity among them in the number and type of input and output variables, and
      their stated goals and capabilities.

PMID- 15018263
TI  - Comparison of mathematical model predictions to experimental data of fatigue and
      performance.
AB  - As part of the "Fatigue and Performance Modeling Workshop," six modeling teams
      made predictions for temporal profiles of fatigue and performance in five
      different scenarios. One scenario was based on a laboratory study of fatigue and
      performance during 88 h of extended wakefulness with or without nap
      opportunities. Another scenario was based on a field study of alertness in
      freight locomotive engineers. Two scenarios were based on laboratory studies with
      various conditions of chronic sleep restriction and recovery. There was a
      theoretical scenario for future ultra-long-range flight operations as well.
      Experimental data were available for all scenarios except the latter. The model
      predictions were compared with the experimental data; after linear scaling using
      mixed-effects regression, mean square errors were computed to quantify goodness
      of-fit. The six models were also compared among each other on the basis of these
      mean square errors. The present paper provides detailed information about the
      results of these comparisons. The models were capable of predicting the data for
      some scenarios fairly well. However, predicting the data for the two scenarios
      involving chronic sleep restriction was more problematic. Differences among the
      predictions from the six models were relatively small, suggesting that these
      models have a broad common basis. More experimental research is needed to yield
      new insights for the further development of fatigue and performance models.

PMID- 15018264
TI  - The two-process model of sleep regulation revisited.
AB  - The two-process model of sleep regulation posits that the interaction of its two
      constituent processes, a sleep/wake dependent homeostatic Process S and a
      circadian Process C, generates the timing of sleep and waking. The time course of
      Process S was derived from a physiological variable, EEG slow-wave activity. In
      addition to the timing of sleep, changes of daytime vigilance are accounted for
      by the interaction of the two processes. The attractiveness of the model derives
      from its physiological basis and its mathematical simplicity. The two-process
      model stimulated the establishment of other models of neurobehavioral functions.
      The background of the model is reviewed and simulations of alertness and
      sleepiness are discussed.

PMID- 15018266
TI  - A model to predict work-related fatigue based on hours of work.
AB  - Several research groups have developed models for estimating the work-related
      fatigue associated with shiftworkers' duty schedules. In June 2002, invited
      members of seven of these groups attended the Fatigue and Performance Modeling
      Workshop in Seattle, WA. At the workshop, each group described the background and
      conceptual basis of their model, and an independent party compared the models'
      predictions with performance and sleepiness data from five laboratory- and
      workplace-based scenarios. One of these models, the Fatigue Audit InterDyne
      (FAID), can be used to quantify the work-related fatigue associated with any duty
      schedule using hours of work (i.e., start/end times of work periods) as the sole
      input. The objectives of the current paper were to: 1) describe the background
      and conceptual basis of FAID; 2) present FAID-based predictions for four of the
      scenarios; and 3) discuss the advantages of, and possible improvements to, FAID.
      The analyses conducted to compare the predictive power of each model are
      described in detail by Van Dongen elsewhere in this issue.

PMID- 15018265
TI  - Fatigue models for applied research in warfighting.
AB  - The U.S. Department of Defense (DOD) has long pursued applied research concerning
      fatigue in sustained and continuous military operations. In 1996, Hursh developed
      a simple homeostatic fatigue model and programmed the model into an actigraph to
      give a continuous indication of performance. Based on this initial work, the Army
      conducted a study of 1 wk of restricted sleep in 66 subjects with multiple
      measures of performance, termed the Sleep Dose-Response Study (SDR). This study
      provided numerical estimation of parameters for the Walter Reed Army Institute of
      Research Sleep Performance Model (SPM) and elucidated the relationships among
      several sleep-related performance measures. Concurrently, Hursh extended the
      original actigraph modeling structure and software expressions for use in other
      practical applications. The model became known as the Sleep, Activity, Fatigue,
      and Task Effectiveness (SAFTE) Model, and Hursh has applied it in the
      construction of a Fatigue Avoidance Scheduling Tool. This software is designed to
      help optimize the operational management of aviation ground and flight crews, but
      is not limited to that application. This paper describes the working fatigue
      model as it is being developed by the DOD laboratories, using the conceptual
      framework, vernacular, and notation of the SAFTE Model. At specific points where
      the SPM may differ from SAFTE, this is discussed. Extensions of the SAFTE Model
      to incorporate dynamic phase adjustment for both transmeridian relocation and
      shift work are described. The unexpected persistence of performance effects
      following chronic sleep restriction found in the SDR study necessitated some
      revisions of the SAFTE Model that are also described. The paper concludes with a
      discussion of several important modeling issues that remain to be addressed.

PMID- 15018267
TI  - Predictions from the three-process model of alertness.
AB  - This paper summarizes a computer model for predicting alertness/performance in
      daily life. The model uses the timing of work hours (and/or sleep hours) as input
      and uses both a circadian and a homeostatic component (amount of prior wake and
      amount of prior sleep) that are summed to yield predicted subjective alertness
      (on a scale between 1 and 21). The model also includes prediction of psychomotor
      performance on various tasks, an identification of levels at which the risk of
      performance/alertness impairment start, as well as a prediction of sleep latency
      and time of awakening from sleep. The model is currently being used to evaluate
      work/rest schedules for navy, airline and railway applications. It is also used
      for teaching sleep/wake regulation and for generating research hypotheses.

PMID- 15018268
TI  - Commentary on the three-process model of alertness and broader modeling issues.

PMID- 15018269
TI  - Commentary on the interactive neurobehavioral model.

PMID- 15018270
TI  - Modeling performance and alertness: the QinetiQ approach.
AB  - The basis of the QinetiQ alertness model used at the heart of the System for
      Aircrew Fatigue Evaluation (SAFE) free-standing software tool is described. A
      number of extensions to the basic model that are applicable to the civil aviation
      environment are outlined, based on the analysis of eight studies involving sleep
      diaries gathered from pilots undertaking a range of duty schedules. The
      relationship between subjective alertness and performance of laboratory tasks is
      described and it is concluded that different tasks are affected differentially by
      fatigue. In general, there is a larger impact on the incidence of errors than on
      response time. The implementation of the full model in the Integrated Performance
      Modeling Environment is described and the application of both the alertness and
      performance models to two scenarios provided by the workshop organizers is
      outlined. It is concluded that further work is needed in three areas: cumulative
      fatigue, the impact of sleep architecture, and the prediction of performance for
      complex tasks in systems.

PMID- 15018271
TI  - Circadian alertness simulator for fatigue risk assessment in transportation:
      application to reduce frequency and severity of truck accidents.
AB  - The Circadian Alertness Simulator (CAS) was developed as a practical tool for
      assessing the risk of diminished alertness at work. Applications of CAS include
      assessment of operational fatigue risk, work schedule optimization, and fatigue
      related accident investigation. Based on the documented work schedules of
      employees, sleep and alertness patterns are estimated and a cumulative fatigue
      score is calculated. The risk assessment algorithms are based on physiological
      sleep/wake principles including homeostatic and circadian processes. The free
      parameters of the algorithms were optimized using over 10,000 d of sleep and
      alertness data sets collected from transportation workers performing their
      regular jobs. The validity and applicability of the CAS fatigue score was then
      tested using work/rest and accident data from three trucking operations. Heavy
      truck drivers involved in DOT-recordable or high-cost accidents were found to
      have significantly higher CAS fatigue risk scores than accident-free drivers.
      Implementing a risk-informed, performance-based safety program in a 500 power
      unit trucking fleet, where dispatchers and managers were held accountable for
      minimizing driver CAS fatigue risk scores, significantly reduced the frequency
      and severity of truck accidents. Further examination of CAS risk assessment
      validity using scenarios provided in a fatigue modeling workshop indicated that
      the CAS Model also performed well in estimating alertness with a real-world
      transportation scenario of railroad locomotive engineer work/rest patterns.

PMID- 15018272
TI  - Fatigue and performance models: general background and commentary on the
      circadian alertness simulator for fatigue risk assessment in transportation.
AB  - Mathematical models of fatigue and performance are potentially powerful tools to
      predict the effects of duty-rest schedules in many situations. Most current
      models, including the Circadian Alertness Simulator (CAS), derive from the two
      process theory of sleep regulation. In these models, performance and fatigue are
      determined by a homeostatic process that depends solely on sleep/wake history,
      and a circadian process, driven by the biological clock. These models assume: 1)
      performance capability recovers in an exponential manner during sleep; 2) the
      homeostatic and circadian processes are additive. Current evidence suggests that
      both assumptions require modification. An attractive feature of the CAS is that
      it computes alertness curves for individuals, based on individual sleep/wake
      histories and other data. However, statistical evaluation is usually based on
      group data, with few performance metrics. As in other models, there is no
      substantive theory to connect the alertness computation with specific cognitive
      or psychomotor functions.

PMID- 15018273
TI  - Comparison of model predictions to experimental data: rectifying false
      impressions.

PMID- 15018274
TI  - SLEEP (Sleep Loss Effects On Everyday Performance) Model.
AB  - Sleep management affects human productivity, safety, health, and efficiency in
      the performance of various tasks. Most people seem to be unaware of the value and
      role of sleep and the various risks that can occur when less than desired amounts
      of sleep are obtained. People especially seem to be unaware of the dangers
      associated with the long-term accumulation of reduced sleep. Thus, a need exists
      to provide tools to enhance sleep education. This paper presents an overview of a
      sleep simulation and sleep education tool, the SLEEP (Sleep Loss Effects on
      Everyday Performance) Model. The SLEEP Model includes alcohol and caffeine along
      with sleep as variables that affect performance. Assumptions and modeling
      concepts are discussed, and the major mathematical functions are presented as
      part of this paper. The unique features of the SLEEP Model are: 1) it is based on
      conservation of REM sleep; 2) it uses a ratio of current day's sleep to sleep
      need for the day to adjust performance predictors; 3) it is designed for easy
      input and output of information; and 4) it has a wide range of applications,
      including sleep, alcohol, and caffeine management. Generally the mathematical
      functions used in the SLEEP Model fit the calibration data set with an R2 of 0.8
      or better and have statistical significance at least at the 0.05 probability
      level. Several figures of simulated results are presented with a discussion of
      references that report similar measured results. The SLEEP Model appears to be a
      practical tool to teach people the value of proper sleep management.

PMID- 15018275
TI  - Nonlinear mixed-effects modeling: individualization and prediction.
AB  - The development of biomathematical models for the prediction of fatigue and
      performance relies on statistical techniques to analyze experimental data and
      model simulations. Statistical models of empirical data have adjustable
      parameters with a priori unknown values. Interindividual variability in estimates
      of those values requires a form of smoothing. This traditionally consists of
      averaging observations across subjects, or fitting a model to the data of
      individual subjects first and subsequently averaging the parameter estimates.
      However, the standard errors of the parameter estimates are assessed inaccurately
      by such averaging methods. The reason is that intra- and inter-individual
      variabilities are intertwined. They can be separated by mixed-effects modeling in
      which model predictions are not only determined by fixed effects (usually
      constant parameters or functions of time) but also by random effects, describing
      the sampling of subject-specific parameter values from probability distributions.
      By estimating the parameters of the distributions of the random effects, mixed
      effects models can describe experimental observations involving multiple subjects
      properly (i.e., yielding correct estimates of the standard errors) and
      parsimoniously (i.e., estimating no more parameters than necessary). Using a
      Bayesian approach, mixed-effects models can be "individualized" as observations
      are acquired that capture the unique characteristics of the individual at hand.
      Mixed-effects models, therefore, have unique advantages in research on human
      neurobehavioral functions, which frequently show large inter-individual
      differences. To illustrate this we analyzed laboratory neurobehavioral
      performance data acquired during sleep deprivation, using a nonlinear mixed
      effects model. The results serve to demonstrate the usefulness of mixed-effects
      modeling for data-driven development of individualized predictive models of
      fatigue and performance.

PMID- 15018276
TI  - Modulating the homeostatic process to predict performance during chronic sleep
      restriction.
AB  - BACKGROUND: In most current sleep/performance models, the homeostatic process is
      generally conceived as a simple reservoir in which performance capacity increases
      exponentially during sleep and decays either linearly or exponentially during
      wakefulness. Models that include this notional homeostatic process have been
      successful for describing sleep-performance data under conditions of irregular
      sleep schedules, jet lag, and short periods of total sleep loss. However,
      recently described data from sleep restriction studies indicate that recovery
      following chronically restricted sleep is considerably slower than would be
      predicted by these models. These findings suggest that chronic sleep restriction
      induces relatively long-term, slow-recovering changes in brain physiology that
      affect alertness and performance. METHODS: This paper describes, both
      conceptually and mathematically, a generic modification to sleep/performance
      models that facilitates the ability to predict the rate at which alertness and
      performance restoration occurs during recovery sleep following chronic sleep
      restriction. Weighted nonlinear least-squares methods were used to compare the
      proposed modulated homeostatic model with recent sleep/performance observations
      during chronic sleep restriction and recovery. RESULTS: When compared with the
      classical Walter Reed homeostatic model, this proposed model was found to provide
      a better description of sleep restriction and recovery observations. The proposed
      model was also found to be consistent with the data from a recent University of
      Pennsylvania study. CONCLUSIONS: These two models make significantly different
      predictions of performance during both the recovery phase and the chronic sleep
      restriction phase.

PMID- 15018277
TI  - Dealing with inter-individual differences in the temporal dynamics of fatigue and
      performance: importance and techniques.
AB  - Inter-individual differences in performance impairment from sleep loss are
      substantial and consistent, as demonstrated and quantified here by means of the
      intraclass correlation coefficient (ICC) in two laboratory-based sleep
      deprivation studies. There is an urgent need, therefore, to consider inter
      individual variability in biomathematical models of fatigue and performance,
      which currently treat individuals as being all the same. Traditional regression
      techniques do not handle inter-individual variability, but cutting-edge mixed
      effects modeling techniques have recently become available to deal with inter
      individual differences in the temporal dynamics of fatigue and performance. The
      standard two stage (STS), restricted maximum likelihood (REML), and non-linear
      mixed-effects modeling (NMEM) approaches to mixed-effects models are compared
      here using data from a chronic partial sleep deprivation experiment. Mixed
      effects modeling can be incorporated in the two distinct steps (the direct and
      inverse problems) of biomathematical model development in order to deal with
      inter-individual differences. This paper demonstrates that inter-individual
      variability accounts for a large percentage of observed variance in
      neurobehavioral responses to sleep deprivation, and describes tools that model
      developers will need to produce a new generation of fatigue and performance
      models capable of incorporating inter-individual variability and useful for
      subject-specific prediction.

PMID- 15018278
TI  - On the importance of countermeasures in sleep and performance models.

PMID- 15018279
TI  - Intermittent exposure to bright light in field conditions.
AB  - The Interactive Neurobehavioral Model integrates Kronauer's and Jewett's latest
      mathematical model of the resetting effect of light on the human circadian
      pacemaker. This model is based on several lines of experimental evidence and
      considers the endogenous circadian pacemaker as a complex oscillatory system that
      responds dynamically to the resetting effect of light. This model can help us
      understand the results of an experiment using intermittent bright light exposure
      in the workplace environment. Intermittent exposure to bright light was
      effectively used as part of an intervention to promote circadian re-entrainment
      of a group of nurses to their permanent night work schedule. Regular exposure to
      lower light levels and darkness also provided a significant phase delay of
      endogenous circadian rhythms, although the adaptation was incomplete in this
      group of workers. These last results are consistent with the intensity-dependent
      component of the model. The development of better tools to measure retinal
      exposure to light throughout the 24-h day is required to adequately test modeling
      predictions under field conditions.

PMID- 15018280
TI  - Trends in the risk of accidents and injuries and their implications for models of
      fatigue and performance.
AB  - Models based on measures of fatigue and performance make the implicit assumption
      that they will be successful in predicting risk. The present paper reviews the
      available literature on shiftwork safety in which real measures of accidents or
      injuries could be pinpointed in time and in which the a priori risk appeared to
      be constant. Three main problems for the models emerged from this review: 1) risk
      was significantly higher on the afternoon shift than on the morning shift; 2) the
      dominant peak in risk over the course of the night shift occurred at about
      midnight; and 3) risk increased substantially over spans of four successive
      nights. It is suggested that the relationship between risk and fatigue may be non
      linear, that models may have overestimated the recovery during short sleeps, and
      that day sleeps between night shifts may be less recuperative than normally timed
      night sleeps of the same length.

PMID- 15018281
TI  - Fatigue models as practical tools: diagnostic accuracy and decision thresholds.
AB  - Human fatigue models are increasingly being used in a variety of industrial
      settings, both civilian and military. Current uses include education, awareness,
      and analysis of individual or group work schedules. Perhaps the ultimate and
      potentially most beneficial use of human fatigue models is to diagnose if an
      individual is sufficiently rested to perform a period of duty safely or
      effectively. When used in this way, two important questions should be asked: 1)
      What is the accuracy of the diagnosis for duty-specific performance in this
      application; and 2) What decision threshold is appropriate for this application
      (i.e., how "fatigued" does an individual have to be to be considered "not safe").
      In the simplest situation, a diagnostic fatigue test must distinguish between two
      states: "fatigued" and "not fatigued," and the diagnostic decisions are "safe"
      (or "effective") and "not safe" (or "not effective"). The resulting four decision
      outcomes include diagnostic errors because diagnostic tests are not perfectly
      accurate. Moreover, since all outcomes have costs and benefits associated with
      them that differ between applications, the choice of a decision criterion is
      extremely important. Signal Detection Theory (SDT) has demonstrated usefulness in
      measuring the accuracy of diagnostic tests and optimizing diagnostic decisions.
      This paper describes how SDT can be applied to foster the development of fatigue
      models as practical diagnostic and decision-making tools. By clarifying the
      difference between accuracy (or sensitivity) and decision criterion (or bias) in
      the use of fatigue models as diagnostic and decision-making tools, the SDT
      framework focuses on such critical issues as duty-specific performance,
      variability (model and performance), and model sensitivity, efficacy, and
      utility. As fatigue models become increasingly used in a variety of different
      applications, it is important that end-users understand the interplay of these
      factors for their particular application.

PMID- 15018282
TI  - Alternative methods for modeling fatigue and performance.
AB  - The use of nonparametric approaches and semiparametric approaches for modeling
      fatigue and performance are analyzed. Nonparametric approaches in the form of
      stand-alone artificial neural networks and semiparametric (hybrid) approaches
      that combine neural networks with prior process knowledge are explored and
      compared with existing parametric approaches based on the two-process model of
      sleep regulation. Within the context of a military application, we explore two
      notional semiparametric approaches for real-time prediction of cognitive
      performance on the basis of individualized on-line measurements of physiologic
      variables. Initial analysis indicates that these alternative modeling approaches
      may address key technological gaps and advance fatigue and performance modeling.
      Most notably, these approaches seem amenable to predicting individual performance
      and quantitatively assessing the reliability of model predictions through
      estimation of statistical error bounds, which have eluded researchers for the
      last two decades.

PMID- 15018283
TI  - Critical research issues in development of biomathematical models of fatigue and
      performance.
AB  - This article reviews the scientific research needed to ensure the continued
      development, validation, and operational transition of biomathematical models of
      fatigue and performance. These models originated from the need to ascertain the
      formal underlying relationships among sleep and circadian dynamics in the control
      of alertness and neurobehavioral performance capability. Priority should be given
      to research that further establishes their basic validity, including the accuracy
      of the core mathematical formulae and parameters that instantiate the
      interactions of sleep/wake and circadian processes. Since individuals can differ
      markedly and reliably in their responses to sleep loss and to countermeasures for
      it, models must incorporate estimates of these inter-individual differences, and
      research should identify predictors of them. To ensure models accurately predict
      recovery of function with sleep of varying durations, dose-response curves for
      recovery of performance as a function of prior sleep homeostatic load and the
      number of days of recovery are needed. It is also necessary to establish whether
      the accuracy of models is affected by using work/rest schedules as surrogates for
      sleep/wake inputs to models. Given the importance of light as both a circadian
      entraining agent and an alerting agent, research should determine the extent to
      which light input could incrementally improve model predictions of performance,
      especially in persons exposed to night work, jet lag, and prolonged work. Models
      seek to estimate behavioral capability and/or the relative risk of adverse events
      in a fatigued state. Research is needed on how best to scale and interpret
      metrics of behavioral capability, and incorporate factors that amplify or
      diminish the relationship between model predictions of performance and risk
      outcomes.

PMID- 15018284
TI  - Research requirements for operational decision-making using models of fatigue and
      performance.
AB  - Sustained human performance is critical to job and mission success in many
      federal agencies including national defense, aerospace exploration, and
      transportation. For the responsible agencies, applications of the basic
      biomedical and applied human factors science provide the best available solutions
      to help individuals perform more effectively and with increased safety. Key
      products of this research are biomathematical models that predict periods of
      impaired performance, with applications in planning tools, real time monitoring,
      and intervention decision aids. Since it is difficult to quantify the number of
      judgment errors or accidents averted, metrics of success for fatigue management
      systems must be largely based on the accuracy of performance predictions derived
      from laboratory-based research studies and the extent to which such results can
      be generalized to the field environment. Performance metrics must, at a minimum,
      be correlated with occupational task performance to demonstrate relevance to real
      world applications. This paper outlines broad goals for human effectiveness
      research related to fatigue, alertness, and performance. To advance from the
      present state of knowledge to useful predictive models requires a well
      coordinated commitment from federal agencies. Users should be made aware that
      current models and tests are not likely to encompass all of the aspects of human
      performance that are relevant to field environments and occupations.

PMID- 15018285
TI  - Initiatives in space medicine.

PMID- 15018286
TI  - Locomotion in simulated zero gravity: ground reaction forces.
AB  - BACKGROUND: Exercise is likely to be an important countermeasure to bone
      demineralization, which remains a concern for astronauts during long-duration
      spaceflight. However, loads on the feet during exercise with 1 G equivalent
      gravity replacement are not known. The purpose of this study was to compare
      ground reaction forces (GRFs) during over-ground and simulated zero gravity (0 G)
      locomotion. HYPOTHESIS: It was hypothesized that sufficient gravity replacement
      loading could be applied to the subjects such that GRF profiles similar to those
      seen in 1 G would occur during locomotion in a zero-gravity locomotion simulator
      (ZLS). METHODS: GRFs were measured during overground walking and running, and
      during locomotion in two restraint harness designs in the ZLS with an initial
      loading of 1 body weight. Load cells measured the gravity replacement load (GRL)
      in the ZLS. Joint angles at the hip and knee were also measured by goniometers.
      RESULTS: Peak forces were greater in overground locomotion than in the ZLS;
      however, loading rates were greater in the ZLS running conditions than in
      overground running. The knee joint was more flexed at key times in the support
      phase during running in the ZLS compared with overground. CONCLUSIONS: Large
      loads and loading rates can be generated at the feet during simulated 0 G
      exercise although peak forces during running in the ZLS are less than overground
      running at the same speed. The refinement of the gravity replacement system to
      provide a constant 1 G load should be considered.

PMID- 15018287
TI  - Detection of leukocyte activation in pigs with neurologic decompression sickness.
AB  - BACKGROUND: In a porcine model of neurological decompression sickness (DCS),
      perivascular leukocyte activation was a consistent finding in biopsies of
      associated cutaneous DCS. This prompted examination of other organs for similar
      changes; multifocal leukocyte activation was found in the lungs (pneumonitis) and
      liver (hepatitis). HYPOTHESIS: DCS in pigs induces leukocyte aggregation and
      activation in the liver and lungs. METHODS: Male Yorkshire swine, trained to run
      on a modified treadmill, were compressed to 200 ft of seawater (fsw) in a dry,
      air-filled compression chamber. Decompression varied according to the profile
      under study. RESULTS: In 106 pigs, evidence for association of leukocyte
      aggregation and activation with the clinical diagnosis of neurologic DCS was
      sought. The incidence of pneumonitis (20/68, 29% with DCS; 4/38, 10% without DCS)
      and hepatitis (23/68, 33% with DCS; 4/38, 10% without DCS) were strongly
      correlated with the incidence of neurologic DCS via Pearson Chi-squared analysis
      (p = 0.026 pneumonitis and p = 0.008 hepatitis). Additionally, Kruskal-Wallis
      rank analysis for numbers of organs involved and incidence of neurologic DCS
      showed a strong correlation between the increasing occurrence of neurologic DCS
      and the involvement of both the liver and lungs (p = 0.004). CONCLUSIONS: The
      results imply that, at least in pigs, DCS induces leukocyte aggregation and
      activation in the liver and lungs. These organs are not normally considered
      targets of DCS. Leukocyte aggregation in these organs may be related to their
      roles as highly perfused organs. Leukocyte aggregation may be a marker for DCS,
      providing further evidence for wider, systemic effects of DCS.

PMID- 15018288
TI  - Kinetics of rotavirus infection in mice are not altered in a ground-based model
      of spaceflight.
AB  - INTRODUCTION: The effect of simulated spaceflight conditions using the hindlimb
      unloading model on mucosal immune responses has not been examined. Therefore, we
      determined whether clearance, protection, and the antibody responses to an
      enteric pathogen, rotavirus, were altered under simulated spaceflight conditions.
      METHODS: Groups of mice were either restrained and hindlimb unloaded, restrained
      without hindlimb unloading, or housed under standard conditions for either 4 or
      14 d prior to and an additional 10 d following inoculation with ECwt murine
      rotavirus. An additional group of mice previously infected with rotavirus was
      housed under the three conditions for either 4 or 14 d prior to a rotavirus
      challenge. RESULTS: Hindlimb unloading of mice did not alter clearance of a
      primary rotavirus infection compared with controls nor were there differences in
      protection from rotavirus challenge 42 d later between the three groups, all
      housed under standard conditions. There were no differences in protection from
      rotavirus challenge in mice that were hindlimb unloaded during the challenge
      infection compared with controls. The generation of rotavirus-specific fecal
      antibodies, as measured by enzyme-linked immunosorbent assay (ELISA), was not
      significantly different between any of the groups following either primary or
      challenge rotavirus infection. However, serum rotavirus-specific IgG1 antibody
      was not induced in mice housed under normal conditions and challenged under
      hindlimb unloading conditions compared with controls. DISCUSSION: These data are
      the first examination of the mucosal immune response to an enteric viral pathogen
      under simulated spaceflight conditions and indicate that rotavirus immunity was
      not impacted in this model.

PMID- 15018289
TI  - Comparison of lower- vs. upper-body cooling during arm exercise in hot
      conditions.
AB  - INTRODUCTION: Studies examining cooling strategies and exercise have generally
      employed lower-body exercise despite the fact that arm exercise is an important
      mode for many industrial tasks and disabled populations. The aim of this study
      was to determine the effects of two cooling strategies during arm exercise in the
      heat. METHODS: There were eight male subjects (mean +/- SD age 24.5 +/- 4.0 yr,
      weight 81.0 +/- 7.8 kg, upper-body VO2peak 3.13 +/- 0.50 L x min(-1)) who
      volunteered for this study. Subjects undertook arm crank exercise for 30 min (50%
      VO2peak) in a hot environment (40.2 +/- 0.4 degrees C, 38.7 +/- 7.4% RH) on three
      occasions (no cooling control, CON; lower-body cooling, LC; upper-body cooling,
      UC). RESULTS: No differences were observed between trials for oxygen consumption,
      respiratory exchange rate (RER), or blood lactate. Heart rate (HR) was greatest
      during CON (151 +/- 11 bpm) when compared with UC and LC (148 +/- 16 and 138 +/-
      13 bpm; p < 0.05). Mean skin temperature was warmer during CON (36.3 +/- 0.5
      degrees C) when compared with UC (31.2 +/- 1.4 degrees C, p < 0.05), which was
      warmer than during LC (28.5 +/- 1.3 degrees C, p < 0.05). No differences were
      observed for rectal or aural temperatures between trials. At the end of exercise,
      heat storage was hyperthermic (3.04 +/- 0.68 J x g(-1)), thermoneutral (0.18 +/-
      1.21 J x g(-1)), and hypothermic (-2.37 +/- 0.81 J x g(-1)) during CON, UC, and
      LC, respectively (p < 0.05). Perceived exertion was lowest during LC and greatest
      during CON (p < 0.05). CONCLUSIONS: The results of this study suggest that
      cooling the lower body during arm exercise in hot conditions is more effective in
      reducing physiological and thermal strain than cooling the upper body.

PMID- 15018290
TI  - Efficacy of acupressure and acustimulation bands for the prevention of motion
      sickness.
AB  - INTRODUCTION: The purpose of this study was to examine whether acupressure and
      acustimulation prevent motion sickness, taking into consideration whether or not
      the acupressure and acustimulation are administered properly. These techniques
      claim to reduce nausea through stimulation of the P6/Neiguan acupuncture point by
      applying acupressure or electrical acustimulation. METHODS: The Acuband and
      ReliefBand were used to administer acupressure and acustimulation, respectively.
      There were 77 subjects who were assigned to 1 of 5 conditions: Acuband trained or
      untrained; ReliefBand trained or untrained; or placebo. Subjects were exposed to
      a 20-min baseline and a maximum of 20 min of optokinetic drum rotation. Untrained
      subjects read the device directions, used it as they deemed appropriate, and
      completed a usability analysis following drum exposure. Trained subjects read the
      device directions and were trained to use the device appropriately prior to drum
      exposure. Symptoms and gastric myoelectric activity were monitored during
      baseline and rotation. RESULTS: In all conditions, symptoms of motion sickness
      and gastric tachyarrhythmia increased, and 3 cpm gastric myoelectric activity
      decreased, during drum exposure. The only difference found between conditions was
      a potential delay in symptom onset for the ReliefBand compared with the Acuband.
      While the Acuband was found difficult to use (0 untrained subjects used it
      correctly) and only a few minor usability issues were identified for the
      ReliefBand, usability had no impact on efficacy. DISCUSSION: Neither band nor
      placebo prevented the development of motion sickness, regardless of whether the
      bands were used correctly or incorrectly.

PMID- 15018291
TI  - Fludrocortisone does not prevent orthostatic hypotension in astronauts after
      spaceflight.
AB  - BACKGROUND: During stand/tilt tests after spaceflight, 20% of astronauts
      experience orthostatic hypotension and presyncope. Spaceflight-induced
      hypovolemia is a contributing factor. Fludrocortisone, a synthetic
      mineralocorticoid, has been shown to increase plasma volume and orthostatic
      tolerance in Earth-bound patients. The efficacy of fludrocortisone as a treatment
      for postflight hypovolemia and orthostatic hypotension in astronauts has not been
      studied. Our purpose was to test the hypothesis that astronauts who ingest
      fludrocortisone prior to landing would have less loss of plasma volume and
      greater orthostatic tolerance than astronauts who do not ingest fludrocortisone.
      METHODS: There were 25 male astronauts who were randomized into 2 groups: placebo
      (n = 18) and fludrocortisone (n = 7), and participated in stand tests 10 d before
      launch and 2-4 h after landing. Subjects took either 0.3 mg fludrocortisone or
      placebo orally 7 h prior to landing. Supine plasma and red cell volumes, supine
      and standing HR, arterial pressure, aortic outflow, and plasma norepinephrine and
      epinephrine were measured. RESULTS: On landing day, 2 of 18 in the placebo group
      and 1 of 7 in the fludrocortisone group became presyncopal (chi2 = 0.015, p =
      0.90). Plasma volumes were significantly decreased after flight in the placebo
      group, but not in the fludrocortisone group. During postflight stand tests,
      standing plasma norepinephrine was significantly less in the fludrocortisone
      group compared with the placebo group. CONCLUSIONS: Treatment with a single dose
      of fludrocortisone results in protection of plasma volume but no protection of
      orthostatic tolerance. Fludrocortisone is not recommended as a countermeasure for
      spaceflight-induced orthostatic intolerance.

PMID- 15018292
TI  - The role of blood glucose availability and fatigue in the development of
      cognitive impairment during combat training.
AB  - INTRODUCTION: The aim of this study was to determine whether inadequate nutrition
      would produce a reduction in the blood glucose concentration and impair cognitive
      function. METHODS: Energy intake, blood glucose, and cognitive function were
      measured in 18 male subjects during a 4-d military field exercise. Baseline
      measures of fasting blood glucose, body mass, cognitive function, and mood were
      taken before the start of combat training. Measurements of blood glucose,
      cognition, and well-being were then repeated during every subsequent 24 h period.
      Activity levels were monitored continuously using wrist-worn activity monitors.
      RESULTS: Subjects experienced an increase in symptoms relating to hypoglycemia
      after 24 h in the field (p < 0.01), vigor decreased (p < 0.001), and fatigue
      increased (p < 0.001). After 48 h, subjects reported feelings of depression (p <
      0.05), anger (p < 0.01), and confusion (p < 0.001). Delayed memory recall was
      significantly impaired after 48 h (p < 0.05), and there was a decrease in
      vigilance (p < 0.01). Between 48 and 72 h, there was a decrease in immediate
      memory recall (p < 0.05). Delayed memory recall and vigilance remained impaired,
      but did not deteriorate further. When subjects were extracted from the field
      after 96 h, nude BM had decreased by 2% (p < 0.05). CONCLUSION: Although it was
      possible to reproduce the symptoms and cognitive impairment associated with
      hypoglycemia, there was no change in blood glucose concentration throughout the 4
      d period. The impairment in cognitive function is likely to have been the result
      of significant sleep deprivation.

PMID- 15018293
TI  - Cockpit seat and pilot helmet vibration during flight operations on aircraft
      carriers.
AB  - INTRODUCTION: Human vibration exposure data relative to military tactical and
      strategic aircraft operations are required for assessing the potential health
      risks and performance consequences when using helmet-mounted equipment. The
      objective of this study was to characterize cockpit seat and pilot helmet
      vibration in a jet aircraft during aircraft carrier flight operations. METHODS:
      The Remote Vibration Environment Recorder (REVER) was used to measure triaxial
      accelerations at the seat base, seat pan, seat back, and helmet in the F/A-18C
      (Hornet) jet aircraft. Data were collected during flight operations on 2 aircraft
      carriers for a total of 11 catapult launches (CATs), 9 touch-and-goes (TGs), and
      4 arrested landings (TRAPs). Helmet pitch acceleration and displacement were
      estimated from the helmet translational acceleration data. RESULTS: Of particular
      interest was the substantial low frequency seat and helmet vibration observed
      during the catapult launch. During the stroke period, seat and helmet vertical
      (Z) accelerations reached 6 and 8 g peak-to-peak, respectively, and occurred in
      the frequency range of 3-3.5 Hz. The associated helmet pitch reached peak-to-peak
      displacements ranging between 90 and 18 degrees. DISCUSSION: The large helmet
      rotations may be associated with helmet slippage that can cause partial or
      complete loss of the projected image on a helmet-mounted display (HMD)
      (vignetting). This is highly undesirable when using the HMD as the primary flight
      reference. The aircraft operational vibration can be regenerated in the
      laboratory for investigating this specific concern. The goal is to develop helmet
      mounted equipment design guidelines that consider hostile vibratory environments.

PMID- 15018294
TI  - Changes in cervical spine bone mineral density in response to flight training.
AB  - BACKGROUND: High magnitude loads and unusual loading regimes are two important
      determinants for increasing bone mass. Past research demonstrated that positive
      Gz-induced loading, providing high loads in an unaccustomed manner, had an
      osteogenic effect on bone. Another determinant of bone mass is that the bone
      response to loading is site specific. This study sought to further investigate
      the site specific bone response to loading, examining the cervical spine
      response, the site suspected of experiencing the greatest loading, to high
      performance flight. METHODS: Bone mineral density (BMD) and bone mineral content
      (BMC) was monitored in 9 RAAF trainee fighter pilots completing an 8-mo flight
      training course on a PC-9 and 10 age-height-weight-matched controls. RESULTS: At
      completion of the course, the pilots had a significant increase in cervical spine
      BMD and total body BMC. No significant changes were found for the control group.
      CONCLUSIONS: This study demonstrated that the physical environment associated
      with flight training may have contributed to a significant increase in cervical
      spine bone mass in the trainee PC-9 pilots. The increase in bone mass was
      possibly a response to the strain generated by the daily wearing of helmet and
      mask assembly under the influence of positive sustained accelerative forces.

PMID- 15018295
TI  - Flight safety and medical incapacitation risk of airline pilots.
AB  - BACKGROUND: This paper examines the use of quantitative incapacitation risk
      assessment for aeromedical decision-making in determining the medical fitness of
      multicrew airline pilots, and estimates the effect on flight safety should
      medical standards be relaxed. The use of the "1% rule" for setting limits for
      aircrew incapacitation risk is re-examined. Human failure (medical
      incapacitation) is compared with acceptable failure rates in another safety
      critical system, the aircraft engines. METHODS: The expected number of
      cardiovascular incapacitations occurring in flight was modeled by applying an age
      related cardiovascular incapacitation risk to the pilot population. The effect on
      flight safety of relaxing the maximum acceptable incapacitation risk on estimated
      incapacitation rates in two-pilot operations was also modeled, taking into
      account a likely increase in the number of pilots who would be allowed to
      continue to fly with a known medical condition. RESULTS: The model overestimates
      cardiovascular incapacitation risk and, therefore, provides a cautious estimate.
      If the maximum acceptable cardiovascular risk is increased, the model predicts a
      disproportionately small increase in the number of such incapacitations in
      flight. CONCLUSIONS: The evidence suggests that the incapacitation risk limits
      used by some states, particularly for cardiovascular disease, may be too
      restrictive when compared with other aircraft systems, and may adversely affect
      flight safety if experienced pilots are retired on overly stringent medical
      grounds. States using the 1% rule should consider relaxing the maximum acceptable
      sudden incapacitation risk to 2% per year.

PMID- 15018296
TI  - Submarine escape from depths of 30 and 60 feet: 41,183 training ascents without
      serious injury.
AB  - INTRODUCTION: In the case of a submerged, disabled submarine, survivors may be
      forced to escape by entering the water and ascending rapidly to the surface. The
      large pressure changes involved may produce pulmonary barotrauma, arterial gas
      embolism, or barotrauma. To assess the likelihood of such injuries, we
      retrospectively evaluated medical problems due to submarine escape training among
      military personnel. METHODS: We evaluated 41,183 controlled ascents performed
      over the past 21 yr in the escape training tank at Golcuk-Kocaeli, Turkey. Each
      trainee performed two free ascents from 30 ft and two hooded ascents from 60 ft.
      Before participating, candidates were screened by physical examination,
      spirometry, and chest X-rays; ear examinations for barotrauma were made after
      ascents. If a trainee failed to exhale properly during ascent, an instructor
      aborted the ascent and took him to a bell or side recess of the tank. RESULTS: No
      record of pulmonary barotrauma or other major complications were found. Middle
      ear barotrauma was observed following 1,643 of the ascents (4.1%), with rupture
      of the tympanic membrane in 35 cases. DISCUSSION: Submarine escape ascents can be
      safely performed provided that subjects are medically screened and well trained.

PMID- 15018297
TI  - Sonographic detection of pneumothorax and hemothorax in microgravity.
AB  - INTRODUCTION: An intrathoracic injury may be disastrous to a crew-member aboard
      the International Space Station (ISS) if the diagnosis is missed or delayed.
      Symptomatic or clinically suspicious thoracic trauma is treated as a surgical
      emergency on Earth, usually with immediate stabilization and rapid transport to a
      facility that is able to deliver the appropriate medical care. A similar approach
      is planned for the ISS; however, an unnecessary evacuation would cause a
      significant mission impact and an exorbitant expense. HYPOTHESIS: The use of
      ultrasound imaging for the detection of pneumothorax and hemothorax in
      microgravity is both possible and practical. METHODS: Sonography was performed on
      anesthetized pigs in a ground-based laboratory (n = 4) and microgravity
      conditions (0 G) during parabolic flight (n = 4). Aliquots of air (50-500 ml) or
      saline (10-200 ml) were introduced into the pleural space to simulate
      pneumothorax and hemothorax, respectively. RESULTS: The presence of "lung
      sliding" excluded pnemothorax. In microgravity, a loss of "lung sliding" was
      noted simultaneously in the anterior and posterior sonographic windows after 100
      ml of air was introduced into the chest, indicating pneumothorax. The presence of
      the fluid layer in simulated hemothorax was noted in the anterior and posterior
      sonographic windows after 50 ml of fluid was injected into the pleural space.
      During the microgravity phase, the intrapleural fluid rapidly redistributed so
      that it could be detected using either anterior or posterior sonographic windows.
      CONCLUSION: Modest to severe pneumothorax and hemothorax can be diagnosed using
      ultrasound in microgravity.

PMID- 15018299
TI  - The maintenance of wakefulness test as a predictor of alertness in aircrew
      members with idiopathic hypersomnia.
AB  - Aviators are required to maintain a high level of alertness during their
      missions. Two conditions that may disrupt this alertness are fatigue and
      hypersomnia. Fatigue is a physiological state, while hypersomnia is a pathologic
      state, also termed excessive daytime sleepiness (EDS), which is manifested by the
      tendency to fall asleep in inappropriate places or situations, such as during
      flight or driving. Hypersomnolence may be diagnosed by subjective measurements,
      such as the Epworth sleepiness scale, but the diagnosis is established by two
      objective tests: the Multiple Sleep Latency Test (MSLT) and the Maintenance of
      Wakefulness Test (MWT). The first consists of four 20-min sessions used to
      determine the time it takes the patient to fall asleep when given the opportunity
      and is considered positive when the sleep latency time is shorter than 5 min,
      although some authors use 8 min as the cut-off for the diagnosis. The Maintenance
      of Wakefulness Test (MWT) consists of four 40-min sessions during which the
      patient attempts to maintain wakefulness while seated in a dark, quiet room
      during the day. Herein we report 2 cases of aviators who were returned to flying
      duty despite a pathologic MSLT. These aviators were waivered based on a normal
      MWT and safety history obtained from their commanders.

PMID- 15018298
TI  - Resources for inflight medical care.
AB  - With the anticipated growth of air travel, inflight illness and injury are
      expected to increase as well. This is because more elderly people and people with
      preexisting disease are taking to the air. Although inflight medical events and
      deaths are uncommon, physician passengers are occasionally called upon to render
      care. Resources for the physician may include emergency medical kits, automatic
      external defibrillators (AEDs), ECG monitors, portable oxygen bottles, and first
      aid kits. Most airlines provide around-the-clock air-to-ground radio consultation
      either with their own medical department personnel or contracted medical
      consultants. Furthermore, some flight attendants are trained in cardiopulmonary
      resuscitation, first-aid, and operation of AEDs. This paper describes those
      inflight resources available to a physician who is called upon to treat an ill or
      injured passenger. In a broader sense, it is also providing advice to physicians
      who administer inflight medical care. The Aviation Medical Assistance Act of 1998
      ("Good Samaritan act") is also discussed.

PMID- 15018300
TI  - Renal artery dissection associated with Gz acceleration.
AB  - A 55-yr-old male presented with flank pain and nausea minutes after intensive
      aerobatic flight maneuvers. An initial diagnosis of acute appendicitis was made.
      Computed axial tomography and renal arteriography showed a right kidney with two
      renal arteries, a right upper pole infarction, and a dissection in the upper
      renal artery which had a more vertical trajectory than the usual main renal
      artery. No signs of diseases known to be associated with renal artery dissection
      were present. The patient recovered without residual hypertension. Heavy positive
      G loads may have potential to cause renal arterial injury, particularly when
      renal vascular anatomical variations exist. The postulated mechanism is similar
      to fall injuries in which the subjects landed on their feet, with inertia causing
      caudal renal dislodgement and stretch of the renal vessels.

PMID- 15018301
TI  - Cases in space medicine.

PMID- 15018302
TI  - This month in aerospace medicine history--March 2004.

PMID- 15018304
TI  - Nifedipine inhibits apoptotic cell death of cultured endothelial cells induced by
      tumor necrosis factor-alpha.
AB  - Impaired endothelial cell (EC) growth and function have been suggested to be an
      initial event that leads to the development of atherosclerosis. We have very
      recently found that nifedipine, one of the most popularly used dihydropyridine
      based calcium antagonists, prevented EC monocyte chemoattractant protein-1
      production elicited by tumor necrosis factor-alpha (TNF-alpha through its
      antioxidative properties. However, the effects of nifedipine on EC growth and
      apoptosis are not fully understood. In this study, we investigated whether
      nifedipine could inhibit tumor necrosis factor (TNF)-alpha-induced growth
      retardation and apoptotic cell death in human umbilical vein ECs (HUVECs). TNF
      alpha inhibited EC proliferation, which was significantly blocked by nifedipine
      or antioxidant N-acetylcysteine (NAC). Nifedipine or NAC was also found to
      significantly inhibit apoptotic cell death of TNF-alpha-exposed HUVECs. Our
      present study suggests that nifedipine may play a protective role against the
      development and progression of atherosclerosis by promoting EC repair through its
      antioxidative properties.

PMID- 15018303
TI  - Synthesis and anti-inflammatory activities of N-benzoylamino-1,2,3,6
      tetrahydropyridine analogs.
AB  - The anti-inflammatory activity of N-benzoylamino-1,2,3,6-tetrahydropyridine (Fig.
      1) has been previously described. Further structural modification of 1 indicated
      that anti-inflammatory activities were greatly influenced by the position and
      nature of substituents on the tetrahydropyridine ring moiety. Analogs of 1 with
      benzyl group at position 4 of the tetrahydropyridine ring moiety and substituents
      on the benzene moiety were synthesized (9a-90). The effect of these substituents
      on pharmacological activity was screened in vivo using the carrageenan-induced
      paw edema assay in male Sprague-Dawley rats. Analogs with electron-donating
      substituents at position 4 and 2 of the benzene moiety 9f, 90 and 9d exhibited
      significant anti-inflammatory activities, similar to that observed for the
      reference compound, indomethacin. In summary, at an early stage of efforts to
      establish structure-activity relationship within this series, we found that 9f is
      a promising lead compound chosen for further investigation.

PMID- 15018305
TI  - Nifedipine inhibits tumor necrosis factor-alpha-induced monocyte chemoattractant
      protein-1 overexpression by blocking NADPH oxidase-mediated reactive oxygen
      species generation.
AB  - There is a growing body of evidence that dihydropyridine-based calcium
      antagonists (DHPs) improve endothelial function, thus slowing the development and
      progression of atherosclerosis. However the molecular mechanisms by which DHPs
      normalize endothelial dysfunction, an initial step in atherosclerosis, are not
      fully understood. Monocyte recruitment and firm adhesion to endothelial cells
      play a central role in the pathogenesis of atherosclerosis. In this study, we
      investigated whether nifedipine, one of the most popular DHPs, could inhibit
      tumor necrosis factor-alpha (TNF-alpha)-induced reactive oxygen species (ROS)
      generation and subsequent monocyte chemoattractant protein-1 (MCP-1) expression
      in human umbilical vein endothelial cells (HUVEC). TNF-alpha significantly
      increased intracellular ROS generation in HUVEC, which was completely blocked by
      nifedipine. Nifedipine completely inhibited TNF-alpha-induced nicotinamide
      adenine dinucleotide phosphate (NADPH) oxidase activity in HUVEC. Furthermore,
      nifedipine was found to significantly inhibit upregulation of MCP-1 messenger RNA
      levels in TNF-alpha-exposed HUVEC. The results demonstrate that nifedipine could
      inhibit TNF-alpha-induced MCP-1 overexpression in HUVEC by suppressing NADPH
      oxidase-mediated ROS generation. Our present study suggests that nifedipine may
      play a protective role in the development and progression of atherosclerosis
      through its antioxidative properties.

PMID- 15018306
TI  - Characteristics of anaerobes from skin specimens.
AB  - Anaerobes isolated from skin specimens from 1999 to 2001 were examined. The most
      common type was Peptostreptococcus spp., especially P. magnus and P.
      assaccharolyticus and Bacteroides fragilis. Dominance was seen for P. magnus, P.
      acnes and P. prevotii. Peptostreptococcus spp. and P. acnes showed high
      susceptibility to four antimicrobial agents. Prevotella spp. and B. fragilis
      showed low or no susceptibility to ampicillin, while B. fragilis showed low
      susceptibility to ceftizoxime. Evaluation of anaerobes is important for the
      balance of skin flora as well as for the choice of antimicrobial agents, when the
      anaerobes are pathogenic.

PMID- 15018307
TI  - Propionibacterium acnes lipase in seborrheic dermatitis and other skin diseases
      and Unsei-in.
AB  - We examined Propionibacterium acnes lipase in skin diseases and Unsei-in. Butyric
      acid production in axillary seborrheic dermatitis (ASD) was higher than in other
      dermatitis, and that in acne vulgaris (AV) was significantly higher than in
      controls. P. acnes lipase is the pathogenic factor in AV and fatty acids produced
      by lipase might be the pathogenic factor in ASD. Unsei-in suppressed P. acnes
      lipase probably because some ingredients have antimicrobial and anti-inflammatory
      activities.

PMID- 15018308
TI  - Risk factors of adverse drug reaction caused by nimesulide in Shanghai patients
      with osteoarthropathy.
AB  - The aim of this study was to investigate the risk factors for adverse drug
      reactions (ADRs) to nimesulide in patients from Shanghai with osteoarthropathy. A
      retrospective epidemiological study was performed to obtain information
      (observational variables) on demographics, primary disease, family history of
      disease, quality of life, dietary habits, lifestyle, use of nonsteroidal anti
      inflammatory drugs (NSAIDs) and ADR history of NSAIDs. Univariate and
      multivariate analyses were performed to establish the relationship between these
      observational variables and the occurrence of ADRs caused by nimesulide. Among
      the 726 variables, five risk factors for ADRs to nimesulide were identified. The
      study showed an increased risk for ADR occurrence with increased scoring of the
      following four factors: (i) "Concomitant drug therapy" (odds ratio [OR]: 4.66,
      95% confidence intervals [CI]: 1.26-17.26, p < 0.05); (ii) "Compared with six
      months ago, how would you rate your health in general now?" (OR: 1.38, 95% CI:
      1.03-1.84, p < 0.05); (iii) "General feeling of health status" (OR: 1.27, 95% CI:
      1.03-1.56, p < 0.05) and (iv) "1 expect my health to get worse" (OR: 2.05, 95%
      CI: 1.22-3.44, p < 0.01). There was a decreased risk for ADR occurrence with
      increased scoring of the factor "Have you ever suffered from depression that
      impacted on your life?" (OR: 0.15, 95% CI: 0.03-0.66, p < 0.05). The predictive
      model for the overall incidence rate of ADRs caused by nimesulide was then
      established. In conclusion, the predictive model helps to indicate the risk of
      ADRs to nimesulide and provides clinicians with an alternative method for
      decision making when prescribing this drug.

PMID- 15018309
TI  - Uncertainties in physical and biological targeting with radiation therapy.
AB  - Advances in radiation therapy over the past decade have resulted from increased
      accuracy of imaging and highly conformal three dimensional treatment planning and
      delivery of radiation therapy. Three-dimensional conformal radiation therapy (3D
      CRT) with higher doses than previously considered tolerable is now standard for
      many types of cancer. Intensity modulated radiation therapy (IMRT) with x-rays,
      proton beam treatments and intensity modulated proton therapy (IMPT) are major
      areas of research. Tumor motion between and even during radiation treatments
      represents a major uncertainty. Tumor heterogeneity results in additional
      uncertainties affecting tumor control with radiation therapy. Imaging the
      heterogeneous targets within tumors offers new opportunities for tumor
      delineation. Molecular therapeutic agents enhance the effects of ionizing
      radiations in murine systems. Clinical trials combining molecular targeting
      agents with conformal radiation therapy are being initiated.

PMID- 15018310
TI  - Selection and delineation of target volumes in head and neck tumors: beyond ICRU
      definition.
AB  - Implementation of three-dimensional conformal radiotherapy (3D-CRT) and intensity
      modulated radiation therapy (IMRT), which permits far greater control of dose
      distribution, requires proper selection and delineation of target volumes, and
      adequate control of setup uncertainties. The present manuscript intends to review
      available data on selection and delineation of target volumes for primary tumor
      and neck nodes. Setup uncertainties and how they influence the PTV delineation
      are also discussed.

PMID- 15018311
TI  - Target definition and contouring in carcinoma of the lung and esophagus.
AB  - The optimal treatment for intrathoracic tumors such as lung and esophageal cancer
      requires an improvement of therapeutic ratio to increase efficacy of the cancer
      cell kill and decrease the normal-cell kill. This is not an easy task because
      sensitive normal cells such as alveoli and epithelial cells in the esophagus and
      bronchus surround these tumors. How to minimize the damage of such sensitive
      normal cells within irradiated fields without sparing cancer cells is a major
      issue for radiation oncologists, especially as concurrent chemoradiotherapy has
      become more standard treatment. One way to achieve this task is accurate
      delineation of the target volume, which will be emphasized here. Some other ways
      to achieve it are biological protection by ethyol, keratinocyte growth factors,
      biologically targeted treatments such as C225 and celecoxib, and anti
      angiogenesis, which have been briefly addressed in Dr. Cox's article in this
      Journal. Molecular imaging is a new diagnostic and therapeutic modality that
      offers great potential for accuracy of target definition, although it is not
      quite ready for routine clinical use at the present time. Accurate target
      definition and contouring in cases of carcinoma of the lung and esophagus depend
      on expertise of diagnostic and therapeutic medical teams. There we review the
      normal anatomy, diagnostic methods, and tumor delineation of cancer of the lung
      and esophagus.

PMID- 15018312
TI  - Target delineation and treatment planning in breast conserving therapy.
AB  - The increased utilization of computed tomography based treatment planning and
      intensity modulated radiation therapy for treatment of breast cancer has yielded
      many potential advantages. Yet, a complete understanding of at risk tissues and
      avoidance structures is necessary to appropriately utilize such a conformal
      treatment design. Designing a treatment that maximizes dose homogeneity to the
      whole breast while minimizing dose to the lung parenchyma, coronary vessels, and
      myocardium has the potential to improve long-term morbidity and cosmetic outcome.
      In this review we discuss the utilization of three dimensional treatment planning
      and intensity modulation for the treatment of breast cancer. We focus on the
      delineation of target and avoidance structures in the setting of breast
      conserving therapy and the techniques utilized to maximize the therapeutic ratio.

PMID- 15018313
TI  - Uncertainties in radiation therapy: target definition in carcinoma of the uterine
      cervix.
AB  - In treatment of patients with carcinoma of the cervix, as in any other malignant
      tumor, accurate identification of target volumes is critical to enhance precision
      of radiation therapy planning and delivery. These results in improved
      locoregional tumor control lead to lower incidence of distant metastases and
      improved survival. Also, radiation therapy morbidity is decreased, enhancing
      quality of life. Various imaging techniques are available to achieve better
      target delineation and this can be enhanced with image fusion. Available
      innovative treatment techniques to optimize the use of radiation therapy for
      these patients are illustrated.

PMID- 15018314
TI  - Uncertainties in radiation therapy: target volume definition in prostate cancer.
AB  - Accurate definition of target volumes and pelvic organs at risk is critical to
      improve the outcome in patients treated with irradiation for localized carcinoma
      of the prostate. Precise delineation of these structures will assist in more
      rational therapeutic decisions and optimized radiation therapy treatment planning
      and delivery. Increased conformity in radiation dose distribution allows delivery
      of higher doses of irradiation and dose escalation studies and results in
      improved tumor control, lower incidence of distant metastasis, improved survival
      and better quality of life. Multiple imaging methods are available and
      significant advances have been made in image fusion to enhance target volume
      definition. An exhaustive review of the literature is presented.

PMID- 15018315
TI  - Uncertainties in contemporary treatment of aggressive lymphomas.
AB  - Contemporary treatment of malignant lymphomas relies on systemic chemotherapy.
      The role of radiation therapy is often debated. Randomized clinical trials have
      shown that the addition of radiation therapy, following complete response (CR) to
      several cycles of combination chemotherapy for early stage diffuse large B-cell
      and immunoblastic lymphoma, increases disease-free survival. The dose required to
      achieve consistent control after complete response is uncertain, but the
      available data suggest a dose-response for tumor control after CR. The role of
      radiation therapy after partial response (PR) is uncertain as many such patients
      are advised to undergo high dose chemotherapy followed by bone marrow
      reconstitution. Involved field radiation therapy after PR is able to achieve
      durable freedom-from-relapse. The role of radiation therapy for peripheral T-cell
      lymphomas and mediastinal T-cell lymphoblastic lymphomas is also uncertain.
      Finally, in the era of combination chemotherapy and conformal irradiation, a
      uniform understanding of what constitutes "involved field" treatment volume is
      lacking. This issue is even more complex now that intensity-modulated irradiation
      has become widely available. It is unlikely that these questions will be
      addressed in randomized clinical trials.

PMID- 15018316
TI  - Virtual simulation: fifteen years later.
AB  - In the last two decades there was a radical change in radiotherapy setup. The
      growing availability of CT equipment and console for computer-aided treatment
      planning setup enabled the use of advanced technologies as conformal 3D radiation
      therapy in most centers. In particular in 1987 virtual simulation was proposed
      for setup. During its use a number of application modalities appeared. Virtual
      simulation in some centers is applied alone while in others it is associated with
      conventional simulation. However, from numerous reports published in last years
      it seems that virtual simulation significantly improves treatment quality
      independently of radical or palliative intent and of the size of treated volumes
      (high doses to small volumes or wide shaped fields). Some studies stressed that
      virtual simulation could significantly shorten treatment planning times with
      consequent cost reduction. The use of virtual simulation evidenced associated
      problems and in particular setup limitations due to the CT gantry size, the need
      to up-date the conventional modalities of setup verification according to the new
      technologies and more generally to up-date quality assurance procedures in an
      advanced technological setting. Finally there was the self-evident need of a
      better knowledge of the anatomy on axial sections, of tumor spread routes in
      particular.

PMID- 15018317
TI  - Lymphatic drainage, CTV and molecular imaging in non-small cell lung cancer.
AB  - Prognosis for non-small cell lung cancer (NSCLC) patients who have locally
      advanced unresectable disease is poor for persistent thoracic disease and
      development of distant metastasis. In view of the poor rate of local control
      following conventional radiation therapy, there is a great need for methods to
      improve its efficacy. Three-dimensional conformal radiation therapy (3DCRT) is a
      high precision radiotherapy able to deliver higher doses with smaller doses to
      the surrounding normal tissues. However, the real problem is: "what do I want to
      treat?" This question is addressed based on the clinical and biological target
      volume definition. Selection of the CTV is therefore basically the clinical
      compromise between the most radical possible CTV and the critical normal tissue
      tolerance. The clinical target volume includes the GTV plus a margin to encompass
      subclinical or microscopic malignant disease immediately adjacent to it. Standard
      radiation therapy consists of a dose of 40 Gy to the entire mediastinum,
      supraclavicular fossa, and ipsilateral hilum, even if there is no evidence of
      disease in these areas. Despite the high risk of nodal spread in lung cancer, the
      benefit of additional elective nodal irradiation (ENI) is not proven while it
      seems to significantly increase the rate of radiation morbidity. Several studies
      have been published where ENI was systematically omitted. The main arguments for
      omitting ENI and the principal clinical experiences, are discussed.

PMID- 15018318
TI  - Lymphatic drainage and CTV in breast cancer.
AB  - Conformal radiotherapy has improved the technique and favored the solution of the
      problem of limiting cardiac and pulmonary irradiation. However new uncertainties
      have arisen especially with regard to treatment reproducibility. Passing from the
      clinical concept of CTV to the geometric concept of PTV, the anatomic
      identification of the different structure becomes of major importance together
      with the knowledge of the clinical evolution of breast cancer. The irradiation of
      breast lymph nodes now requires, if possible, 3D conformal processing of the
      treatment. Treatment parameters should be selected as to ensure adequate
      irradiation of target volumes while sparing healthy tissues as much as possible.
      In a near future, IMRT should be able to markedly improve the dose homogeneity to
      target with consequent lower cardiopulmonary toxicity.

PMID- 15018319
TI  - Lymphatic drainage and CTV in pancreatic carcinoma.
AB  - CTV definition in exclusive or adjuvant radiation therapy of pancreatic carcinoma
      is essentially based on the opinion of "expert" authors and on the knowledge of
      lymphatic pathways. The subject has been widely debated. Radiotherapy treatments
      of the entire upper abdomen (liver and pancreatic region), pancreas and lymph
      node stations, to volumes focused on macroscopic tumor only, have been proposed.
      Carcinoma of exocrine pancreas is characterized by the frequent, early appearance
      of metastasis via the lymphatic route. Most commonly involved lymph node stations
      include those of the celiac trunk, superior mesenteric, peripancreatic,
      lumboaortic lymph nodes, those of the hepatic portal (the latter in particular
      for pancreatic head tumors) and of the hilum of spleen (the latter in particular
      for pancreatic tail tumors). The possible multicentricity of pancreatic
      carcinoma, most likely due to intraductal spread, should lead to the inclusion in
      the CTV of the entire pancreatic parenchyma. This should be considered also for
      the frequent perineural intra- or extrapancreatic spread of pancreatic carcinoma
      present also in small tumors (T1). In extrapancreatic spread the retropancreatic
      adipose tissue should be included in the CTV at least at the GTV level. At the
      present state of knowledge, in the absence of pattern of failure analysis and of
      comparison of different treatment approaches, in terms of the definition of
      volumes of interest, CTV definitions which include lymphatic drainage stations,
      most part of pancreatic parenchyma and retropancreatic adipose tissue seem
      justified especially in treatments for cure. In palliation, the CTV may be
      limited to the GTV and the adipose tissue behind it.

PMID- 15018320
TI  - Preoperative radiotherapy in gastric cancer: CTV definition for conformal therapy
      according to tumor location.
AB  - In the past radiation oncologists had not a major interest in the treatment of
      gastric cancer, but the positive outcomes of the Intergroup Study (INT-0116)
      supported the role of locoregional control in promoting better survival. To
      reduce the toxicity and the risk of residual disease in locally advanced tumors
      after surgery,a preoperative approach was tentatively considered. The aim of this
      manuscript is to define the location of nodal area at risk for cancer involvement
      according to the tumor location (cardias, corpus, antrum) on CT images to help
      the radiotherapist in the contouring process of the CTV for preoperative
      conformal treatment of gastric cancer. The analysis of both the percentage of
      nodal involvement detected at surgery and of the site of recurrence after radical
      surgery can direct to the areas to be considered at risk with its contouring on
      CT. Preoperative conformal-three dimensional radiotherapy of gastric cancer
      requires clear and well defined contouring guide-lines to allow the evaluation of
      clinical outcomes and the analysis if the area at risk for recurrence has changed
      after the preoperative approach.

PMID- 15018321
TI  - Underlying anatomy for CTV contouring and lymphatic drainage in rectal cancer
      radiation therapy.
AB  - Despite the low local recurrence rate that can be achieved by adequate surgery
      (total mesorectal excision--TME), radiation therapy was shown to play a
      significant role in reducing this risk. The widespread use of TME in many
      European Centers has introduced a new terminology and the need to identify the
      area at major risk for local failure using this surgical procedure. In the
      surgical series where extended extra-mesorectal surgery was performed, the role
      of lymphatic spread was evidenced, especially for low rectal cancer, through the
      pelvic parietal fascia and lateral pelvic spaces. The aim of this study was to
      better define some anatomic concepts and the main risk factors which impact on
      CTV contouring and field conformation in rectal cancer treatment. This
      information helps formulating guidelines for CTV contouring in daily radiotherapy
      practice, in order to define the best therapy, according to the tumor stage and
      location.

PMID- 15018323
TI  - Clinical target volume definition in the elderly patient.
AB  - Elderly age is one of the main risk factors to be associated with the onset of
      different tumors. The tumor in the elderly almost always appears at a late,
      advanced stage for the lack of an accurate attention to symptoms-signs, as well
      as for the absence of involvement in mass screening campaigns. In the choice of a
      radiotherapy treatment in the elderly, the healthy tissues adjacent to the tumor
      may show a different ability for repair; this should be kept in mind in the
      definition of the target volume together with the possible presence of
      comorbidities specific to the elderly age.

PMID- 15018322
TI  - Lymphatic drainage and CTV in carcinoma of the prostate.
AB  - The prostate lymphatics drain into the periprostatic subcapsular network, from
      which 3 groups of ducts originate: the ascending ducts from the cranial prostate
      draining into the external iliac lymph nodes, the lateral ducts running to the
      hypogastric lymph nodes and the posterior ducts draining from the caudal prostate
      to the subaortic sacral lymph nodes of the promontory. Internal, external iliac
      and obturator lymph nodes are the most frequently involved by prostate carcinoma.
      Metastases to presacral and common iliac lymph nodes are rare. For the limited
      staging accuracy, present indications for seminal vesicle irradiation and pelvic
      node prohylactic irradiation are essentially based on risk categories and
      estimation algorithms; the latter while are widely used in international studies
      are not free of limitations as stressed since they were introduced. A method to
      deliver high doses to the tumor while limiting the irradiation of critical organs
      might be the delivery of a boost to the tumor only. This approach could become
      increasingly feasible with the diffusion of imaging procedures able to better
      define tumor extension.

PMID- 15018324
TI  - Tissue plasminogen activator levels after single intracisternal injection in
      patients with subarachnoid hemorrhage.
AB  - Tissue plasminogen activator (tPA) levels were investigated in the cisternal
      fluid of patients with subarachnoid hemorrhage treated with single intracisternal
      injection of recombinant tPA during radical surgery for ruptured aneurysms. Seven
      patients received different doses of tPA: two of 400 microg/ml, three of 500
      microg/ml, one of 700 microg/ml, and one of 800 microg/ml in a total amount of 20
      ml distilled water at pH 7. Cerebrospinal fluid samples were taken directly from
      the cisternal fluid at 15-minute incubation after injection, immediately after
      irrigation during surgery, and by lumbar tap 2 days after surgery. Cisternal tPA
      levels decreased to about 60% of the mean injected doses after 15-minute
      incubation. Simple linear regression analysis showed these tPA levels after
      incubation correlated with the initial doses. After copious irrigation with
      Ringer solution at pH 8, tPA levels decreased rapidly without correlation with
      the initial doses. After spinal drainage for 2 days, tPA levels further decreased
      by an order of 10(-4) to 10(-6) from the initial dose. These values were still
      greater than normal controls. The final values of tPA levels were not related to
      the initial dose. None of the patients suffered from systemic or wound
      complications. Cisternal tPA injection with increased doses and irrigation may be
      beneficial for the selective rapid removal of blood clots with controllable
      safety.

PMID- 15018325
TI  - Interlaminar fixation using the atlantoaxial posterior fixation system (3XS
      system) for atlantoaxial instability: surgical results and biomechanical
      evaluation.
AB  - This study evaluated the surgical results for patients with atlantoaxial
      instability due to various lesions treated using the atlantoaxial posterior
      fixation system (3XS system; Kisco DIR, Paris, France), together with a
      biomechanical study of this system. The strength of the 3XS system during torsion
      was examined using a biomechanical simulation model. The 3XS system consists of a
      transverse unit, hooks, and rods. The lower part of the biomechanical simulation
      machine was rigidly fixed and the upper part was movable, allowing torsion to be
      applied until the point of failure. The test was started at 1.5 newton-meters,
      thought to be the maximum load on the upper cervical spine. The 3XS system
      tolerated torsion of up to 20 newton-meters, but became deformed. The instrument
      was fractured at 30 newton-meters. Fifteen patients, four with atlantoaxial
      instability, seven with os odontoideum, and four with odontoid fractures,
      underwent surgery using the 3XS system and an iliac bone fragment inserted
      between the C-1 and C-2 laminae. Postoperative rigid fixation of the lesion and
      optimal cervical alignment was obtained in all patients, and the patients were
      discharged within 2 weeks after surgery. Follow-up radiography showed bony fusion
      between C-1 and C-2 in all patients. Posterior fixations between C-1 and C-2
      using the 3XS system were easy to perform and no surgical complications were
      encountered. The biomechanical study showed the 3XS system can tolerate torsions
      unlikely to occur during rotation movements in the atlantoaxial region in humans.
      The surgical use of the 3XS system for the treatment of atlantoaxial instability
      has several advantages.

PMID- 15018326
TI  - Arteriovenous malformation surrounding the trigeminal nerve--case report.
AB  - A 57-year-old man presented with subarachnoid hemorrhage due to the rupture of an
      arteriovenous malformation (AVM) located at the base of the root of the right
      trigeminal nerve. In contrast to previous similar cases, his history included no
      evidence of trigeminal neuralgia or sensory loss. Right vertebral artery
      angiography revealed a doubled superior cerebellar artery feeding the angioma
      nidus. The patient refused radiotherapy and preferred surgical treatment.
      Intraoperatively, a close relationship between arterial feeders and rootlets of
      the trigeminal nerve was observed. Complete removal of the malformation was
      achieved and confirmed angiographically. The postoperative course was complicated
      by subdural hygroma that required repeated drainage and eventually a shunting
      procedure. This case demonstrates that microsurgical treatment of a trigeminal
      AVM is feasible. However, stereotactic radiosurgery may be the preferred
      treatment option considering the potential for postoperative complications.

PMID- 15018327
TI  - Ampulla (takotsubo) cardiomyopathy associated with subarachnoid hemorrhage
      worsening in the late phase of vasospasm--case report.
AB  - A 66-year-old woman presented with subarachnoid hemorrhage(SAH) caused by a
      ruptured aneurysm of the left middle cerebral artery. Electrocardiography (ECG)
      disclosed abnormalities resembling acute myocardial infarction. She underwent
      neck clipping of the aneurysm uneventfully. Sixteen days after admission, ECG
      again disclosed abnormalities resembling acute myocardial infarction, and
      echocardiography suggested heart failure. Coronary angiography showed no
      abnormalities, but left ventriculography showed severe hypokinesia in the apex of
      the heart consistent with so-called ampulla (takotsubo) cardiomyopathy. The heart
      failure was treated with catecholamines and her heart function gradually
      recovered. Ampulla (takotsubo) cardiomyopathy associated with SAH requires
      careful management of heart function.

PMID- 15018328
TI  - Idiopathic interdural hematoma looking like a "Chinese dumpling"--case report.
AB  - A 79-year-old man presented with an interdural hematoma manifesting as headache.
      Computed tomography revealed a right parietal intracranial hematoma. Magnetic
      resonance imaging revealed the hematoma had divided the dura mater into two
      layers. Craniotomy was performed and a dural pouch containing a solid hematoma
      was totally removed. Histological examination showed the hematoma had divided the
      meningeal dura into two layers. This case confirms the location of interdural
      hematoma.

PMID- 15018329
TI  - Ischemic basilar artery dissecting aneurysm treated by stenting only--case
      report.
AB  - A 45-year-old man presented with enlargement of basilar artery dissecting
      aneurysm 10 months after suffering brain stem infarction. Combined stenting and
      placement of Guglielmi detachable coils (GDCs) was planned to obliterate the
      aneurysm sac. Stent deployment was performed but the procedure was halted to
      avoid overdosing with contrast material. Cerebral angiography 10 days later
      showed thrombosis of the aneurysm sac and normalization of the blood flow in the
      basilar artery. The patient has been followed up for 2 years and showed good
      clinical and angiographic outcome. Stenting results in obliteration of the
      aneurysm sac, so a two-stage procedure is recommended.

PMID- 15018330
TI  - Cerebellar hemorrhage secondary to cranial metastasis of prostate cancer--case
      report.
AB  - A 77-year-old man with a 9-year history of prostate cancer presented with high
      fever and dysphagia. The initial diagnosis was aspiration pneumonia, but the
      patient became comatose 2 days after admission, and neuroradiological workup
      revealed cerebellar hemorrhage, obstructive hydrocephalus, and extensive
      destruction of the occipital bone secondary to cranial metastasis. The diagnosis
      was cerebellar hemorrhage secondary to cranial metastasis of prostate cancer.
      Tumor resection was abandoned because of the patient's poor health. Shunt surgery
      and palliative radiotherapy were temporarily effective in restoring his
      consciousness, but he died of systemic infection 3 weeks after surgery.
      Metastasis of prostate cancer to the cranium, particularly to the skull base,
      rarely causes lower cranial nerve paresis, and awareness of this sign may lead to
      earlier detection of the cranial metastasis and prevention of cerebellar
      hemorrhage.

PMID- 15018331
TI  - Prolactinoma with a high adrenocorticotropic hormone level caused by meningitis-
      case report.
AB  - A 69-year-old man was admitted semicomatose with high-grade fever and meningeal
      signs. Magnetic resonance imaging showed a supra- and intrasellar lesion. Hormone
      studies on admission showed increased serum prolactin, adrenocorticotropic
      hormone (ACTH), and cortisol titers. However, the serum ACTH and cortisol levels
      returned to normal after treatment of meningitis with an antimicrobial agent. The
      histological diagnosis was pituitary adenoma. Immunohistological staining showed
      positive reaction for prolactin but not for ACTH. This is a rare case of
      prolactinoma with a high serum ACTH level caused by meningitis.

PMID- 15018332
TI  - Supra- and infratentorial subdural empyema secondary to septicemia in a patient
      with liver abscess--case report.
AB  - An 81-year-old man presented with subdural empyema in the left parietotemporal
      convexity 2 months after treatment under diagnoses of liver abscess and
      septicemia. Systemic investigation found no evidence of otorhinological or other
      focal infection except for liver abscess. Emergency drainage of pus was performed
      via a single burr hole and additional intravenous antibiotics were administered.
      Six weeks later, magnetic resonance imaging revealed subdural empyema in the
      right cerebellopontine angle in addition to recurrence of pus in the left
      parietotemporal subdural space. Ischemic changes were also shown in the right
      cerebellar hemisphere and brainstem. Although subdural empyema secondary to
      septicemia is rare, the possibility of this type of intracranial infection must
      be kept in mind, especially in compromised patients with septicemia.

PMID- 15018333
TI  - Microvascular decompression of cranial nerves using sheets of a dural substitute-
      technical note.
AB  - Several types of prosthesis are used for microvascular decompression (MVD)
      surgery for neurovascular compression syndrome. However, most prostheses adhere
      to the surrounding neuronal structures and occasionally cause granulomas. The
      present study evaluated a dural substitute made of expanded
      polytetrafluoroethylene, the Gore-Tex EPTFE patch, as a prosthesis for MVD.
      Twelve patients with trigeminal neuralgia, 19 patients with hemifacial spasm
      (HFS), and two patients with glossopharyngeal neuralgia underwent MVD using the
      dural substitute. In most cases, one or two sheets of the dural substitute were
      inserted between the offending artery and the compression site covering the
      cranial nerve and the brainstem. Thirty of the 33 patients experienced complete
      relief of the symptoms that lasted for at least 10-75 months after the surgery.
      HFS recurred one month post-surgery in a patient who underwent MVD using two
      small sheets. Varied grades of hearing disturbance were observed in three
      patients with HFS. MVD using dural substitute is an easy and efficient method
      because it is not necessary to move the offending arteries away from the
      compression site. Large sheets should be positioned over the compression site for
      sufficient decompression. However, this technique needs to be improved so that
      the prosthesis does not affect cranial nerve VIII, as three of 19 patients with
      HFS showed hearing disturbances despite intraoperative monitoring of the auditory
      brainstem response.

PMID- 15018334
TI  - National profile: overview of capabilities and core functions of local public
      health jurisdictions in 47 states, the District of Columbia, and 3 U.S.
      territories, 2000-2002.
AB  - This is the first nationally conducted survey targeting the full population of
      all local public health jurisdictions to assess the three core functions of
      public health: assessment, policy development, and assurance, as well as overall
      capabilities. Data were analyzed from 2,007 local public health jurisdictions in
      47 states, the District of Columbia, and 3 U.S. territories (American Samoa,
      Northern Mariana Islands, and Puerto Rico) between July 2000 and April 2002, in a
      collaborative effort between the Centers for Disease Control and Prevention and
      the Department of Justice. An unweighted overall mean summary score of 65.4% (on
      a scale of 0% to 100%) was calculated from the responses to the 20-question
      survey. The mean summary scores across all 2,007 local public health
      jurisdictions for assessment, policy development, and assurance were 66.8%,
      67.4%, and 63.0%, respectively. Also, data was analyzed by the population size of
      jurisdiction and the type of jurisdiction. The results provide national
      population baseline data for estimates of local public health jurisdiction
      capabilities and core functions that may be useful in identifying areas for
      improvement, in building a stronger U.S. public health system to better serve
      each community, and in educating the public about the core functions of public
      health to help ensure that public health agencies are accountable to those they
      serve.

PMID- 15018335
TI  - Managing complex systems: performance management in public health.
AB  - The complexity of mobilizing and managing systems-wide public health responses
      has prompted Turning Point's Performance Management National Excellence
      Collaborative, funded by the Robert Wood Johnson Foundation, to develop a
      conceptual framework for performance management in public health. The framework
      has four integrated parts: (1) performance standards, (2) performance measures,
      (3) reporting of progress, and (4) a quality improvement process. The
      Collaborative based its framework on evidence gathered through a survey of
      current state performance management practices, a literature review, and its
      investigation of current practice models. This balanced and cohesive management
      model can be constructively used by public health programs, organizations, and
      community and state public health systems.

PMID- 15018336
TI  - Minimum public health standards as a basis for secure public health funding.

PMID- 15018337
TI  - Performance contracting for public health: the potential and the implications.

PMID- 15018338
TI  - Pennsylvania partners in pursuit of good health: building a shared-responsibility
      model for state health improvement.
AB  - Over the last decade, much attention has focused on the reorganization of the
      roles and functions of public health to improve the health of communities. The
      Pennsylvania State Health Improvement Plan (SHIP) offers one example of how
      national, state, and local components of the public health system can effectively
      integrate their strategies and resources to improve responsiveness to local
      public health needs. This article reviews the policy action and planning process
      used to develop a community partnership, shared-responsibility model and the
      strategies and implementation plans that have been adopted to achieve
      substantial, measurable improvement in community health status.

PMID- 15018339
TI  - Survey of restaurants regarding smoking policies.
AB  - The New Hampshire Indoor Smoking Act was implemented in 1994 to protect the
      public's health by regulating smoking in enclosed places. A survey was conducted
      of New Hampshire restaurants to determine smoking policies, to determine
      restaurant characteristics associated with smoking policies, and to evaluate
      compliance with the Indoor Smoking Act. A list of New Hampshire restaurants was
      obtained from a marketing firm. Establishments were selected randomly until 400
      had completed a 22-question telephone survey. Forty-four percent of restaurants
      permitted smoking. Characteristics positively associated with permitting smoking
      were being a non-fast-food restaurant, selling alcohol, selling tobacco, and
      having greater than the median number of seats. Of restaurants permitting
      smoking, 96.1% had a designated smoking area, 87.0% had a ventilation system to
      minimize secondhand smoke, 83.6% had a physical barrier between smoking and
      nonsmoking areas, and 53.1% exhibited signs marking the smoking area. Forty
      percent of restaurants permitting smoking met all four requirements of the Indoor
      Smoking Act. Smoking policies differ, by type of restaurant. Compliance with the
      Indoor Smoking Act is low.

PMID- 15018340
TI  - Public education campaign heightens awareness that youth model authorities'
      tobacco use.
AB  - To evaluate whether people changed their views about acceptability of authority
      figures smoking after an anti-tobacco initiative, randomly selected southeastern
      U.S. voters (801 in 2001; 806 in 2002) responded to a 20-minute telephone
      interview. Acceptability attitudes held steady: most (80.8%) said that any
      authority figures' smoking in front of youth is unacceptable, with women,
      minorities, and never-smokers even surer than their counterparts. However, there
      was a change in 2002, with respondents more strongly recognizing that youth model
      adults' tobacco behaviors and attitudes. An implication is that media campaigns
      may benefit from emphasizing that youth model adults' tobacco use.

PMID- 15018341
TI  - Public education strategies for delivering breast and cervical cancer screening
      in American Indian and Alaska Native populations.
AB  - A 1993 amendment to the authorizing legislation for the Center of Disease Control
      and Prevention's National Breast and Cervical Cancer Early Detection Program
      allows direct funding to tribal organizations and urban Native health centers.
      This study examined tribal programs' implementation of the public education and
      outreach component utilizing a multisite case study design implemented in
      partnership with tribal programs. Data were collected from 141 semistructured
      interviews with key informants and 16 focus groups with program-eligible women.
      Innovative strategies built on native iconography and personal encounters have
      encouraged participation and made the programs culturally relevant, providing
      insights for other communities with little experience in providing early
      detection services.

PMID- 15018342
TI  - Comparing telephone and written surveys to assess local adolescent immunization
      coverage rates.
AB  - To identify adolescent hepatitis B coverage levels, a survey was conducted of
      seventh grade parents in San Diego County, California, using a random digit-dial
      telephone survey. A written survey was fielded also that was distributed at
      selected schools. Results were validated using data from a mandated report from
      all schools. Both survey methods overestimated the proportion completing the
      hepatitis B series by about 10%. Parents accurately reported immunization shot
      dates from the child's parent-held immunization shot record on the telephone and
      written surveys. The written survey, in addition to having a somewhat lower cost,
      may be useful when focusing on a localized area, whereas the telephone survey
      permits a more representative sample of a larger county-wide population.

PMID- 15018343
TI  - Effects of interdisciplinary rounds on length of stay in a telemetry unit.
AB  - Interdisciplinary rounds (IRs) have been proposed to improve staff communication
      and reduce LOS. There have been no studies of IRs on an inpatient telemetry ward.
      Patients on a telemetry unit of a community hospital were randomly assigned to
      either an IR intervention or standard care. Charts were reviewed to determine
      LOS, patient characteristics, and indirect indices of quality of care.
      INTERVENTION: Daily work rounds, in which resident physicians, nurses, and
      ancillary staff meet to discuss patients on the team. RESULTS: 84 patients were
      enrolled, 42 randomized to the intervention and 42 to standard care. There was no
      significant difference in LOS. Indirect measures of quality of care (dietician,
      pharmacist, or physical therapist visit) did not differ. In a multiple linear
      regression model, only abnormal laboratory data, the presence of dementia, and
      the presence of a home health aid significantly predicted LOS. CONCLUSION: IRs
      did not decrease LOS in a telemetry ward. Whereas a potential benefit of IRs in
      other settings cannot be ruled out, this study emphasizes the importance of
      rigorous testing of strategies to enhance the quality or reduce the costs of
      inpatient care.

PMID- 15018344
TI  - Security aspects of electronic data interchange between a state health department
      and a hospital emergency department.
AB  - Electronic emergency department reporting provides the potential for enhancing
      local and state surveillance capabilities for a wide variety of syndromes and
      reportable conditions. The task of protecting data confidentiality and integrity
      while developing electronic data interchange between a hospital emergency
      department and a state public health department proved more complex than
      expected. This case study reports on the significant challenges that had to be
      resolved to accomplish this goal; these included application restrictions and
      incompatibilities, technical malfunctions, changing standards, and insufficient
      dedicated resources. One of the key administrative challenges was that of
      coordinating project security with enterprise security. The original project has
      evolved into an ongoing pilot, with the health department currently receiving
      secure data from the emergency department at four-hour intervals. Currently,
      planning is underway to add more emergency departments to the project.

PMID- 15018346
TI  - The need for federal involvement.

PMID- 15018345
TI  - Evaluation of the Washington State National Pharmaceutical Stockpile dispensing
      exercise, part II--dispensary site worker findings.
AB  - On January 24, 2002, the Washington State Department of Health, in collaboration
      with local and federal agencies, conducted an exercise of the Centers for Disease
      Control and Prevention's National Pharmaceutical Stockpile dispensing portion of
      the Washington State plan. This exercise included predrill planning, training,
      and the orchestration of services of more than 40 dispensary site workers. These
      workers provided education and post-exposure prophylaxis for over 230 patient
      volunteers in the aftermath of a simulated exposure to B. anthracis. This article
      discusses findings of a postdrill questionnaire completed by 90% of these
      dispensary site workers who provided triage, education, dispensary, security and
      other services during this exercise. In general, this dispensing drill promoted
      confidence in the worker participants and provided an opportunity for these
      participants to coordinate their activities. This mock bioterrorist preparedness
      exercise allowed worker participants and observers to review and evaluate the
      Washington State plan for dispensing the National Pharmaceutical Stockpile. This
      article is apparently the first published account of dispensary site workers'
      subjective impressions and quantitative analysis of their postdrill opinions
      following a simulated bioterrorist post-exposure chemoprophylaxis dispensing
      exercise.

PMID- 15018347
TI  - Codes, principles, laws, and other sources of authority in public health.

PMID- 15018348
TI  - cDNA cloning of rabbit thrombomodulin and characterization of gene expression in
      cardiovascular tissue.
AB  - Thrombomodulin (TM), a component of the protein C anticoagulant pathway, is
      critical for the maintenance of vascular thromboresistance. To facilitate the
      study of in vivo TM regulation, we cloned and sequenced the cDNA encoding full
      length rabbit TM. Translation of the open reading frame predicts a 580 amino acid
      protein that contains a 19 amino acid signal peptide, one lectin-like and six EGF
      like extracellular domains, a 23 amino acid transmembrane domain and a 36 amino
      acid cytoplasmic domain. In addition, there are three potential N-linked and six
      O-linked glycosylation sites. Comparison of the predicted rabbit TM protein with
      those of human, mouse and rat reveals 67-72% primary sequence conservation with
      identical domain homology. TM gene expression was quantified in rabbit
      cardiovascular tissue by real-time PCR using primers and probe based on the
      derived cDNA sequence and found to correlate with protein expression as
      determined by Western blot analysis.

PMID- 15018349
TI  - Cloning and partial characterization of a beta-1,3-glucanase gene from
      strawberry.
AB  - Plant pathogenesis-related proteins, including beta-1,3-glucanses, are believed
      to be involved in plant defense mechanisms. We have cloned a beta-1,3-glucanse
      gene from strawberry (Fragaria x ananassa Duch). This gene, designated FaBG2-1,
      is a Class II glucanase gene composed of two exons and one intron. The location
      of a 397-base intron in the gene was confirmed by sequencing a partial cDNA clone
      obtained by using a rapid amplification of cDNA ends procedure. Also, based on
      the cDNA sequence, the transcription start site of FaBG2-1 was assigned to a -54G
      residue. Genomic Southern blot analysis indicated that FaBG2-1 is a member of a
      multi-gene family. Reverse transcriptase-polymerase chain reaction analysis
      revealed that this beta-1,3-glucanase gene is expressed constitutively in
      strawberry leaves.

PMID- 15018350
TI  - cDNA cloning and molecular characterization of a cysteine-rich gene from
      Campoletis chlorideae polydnavirus.
AB  - Polydnavirus (PDV) of Campoletis chlorideae (CcIV) is very important for the
      successful development of the parasitoid progenies. Previous study revealed that
      the persistence and expression of CcIV in parasitized Helicoverpa armigera larvae
      continued for 5 days, and the 1.0 kb gene (CcIV 1.0) was most abundantly
      expressed. In this report, a cDNA library was constructed using the SMART cDNA
      Synthesis Method, and the CcIV 1.0 was cloned and identified by PCR, Southern
      blot hybridization and 5' end amplification, this gene is 936 bp long and encodes
      207 amino acids with a signal peptide and a cysteine motif. Sequence comparison
      shows CcIV 1.0 has high identity with VHv 1.4, VHv 1.1 genes (86%, 88%) and WHv
      1.6, WHv 1.0 genes (89%, 87%) of Campoletis sonorensis PDV, which might suggest
      that they have arisen from a common ancestral gene; the homology between CcIV and
      other PDV genes is not significant.

PMID- 15018352
TI  - An exact formula for the number of alignments between two DNA sequences.
AB  - Given two DNA sequences, one is usually interested in measuring their similarity.
      For this purpose we have to consider different alignments of both the sequences.
      The number of alignments grows rapidly with the length of the sequences. In this
      short communication, we give an exact formula for the number of possible
      alignments using the theory of difference equations.

PMID- 15018351
TI  - Cloning and characterization of two novel lipid transfer protein I genes in Vigna
      radiata.
AB  - Two full-length lipid transfer protein (LTP) cDNAs were isolated from mungbean
      (Vigna radiata) and designated Vrltp1 and Vrltp2. The deduced amino acid
      sequences contain the two highly conserved pentapeptides characteristic of plant
      LTPIs suggesting these Vrltps belong to the LTPI gene family. Vrltp1 mRNA was
      detected in developing seeds, but Vrltp2 mRNA was not. Within the vegetative
      tissues, the Vrltp1 and Vrltp2 mRNAs were present only in leaves and stems, but
      not root tips. Salt and dehydration stresses and exogenous abscisic acid (ABA)
      treatments resulted in increased mRNA levels of both Vrltps in leaves. We suggest
      that these unique Vrltps are specific to growing shoot tissues, and may play an
      important role in plant acclimation to water stress.

PMID- 15018353
TI  - Isolation, expression pattern of a novel human RAB gene RAB41 and
      characterization of its intronless homolog RAB41P.
AB  - Small GTPases form a big family including Ras, Rho, Rac, Rab, Sar1/Arf
      subfamilies and Ran homologs, playing important roles in diverse cellular
      processes. Through data mining, a novel human RAB41 gene was predicted and
      subsequently isolated from human testis. The open reading frame of RAB41 is 636bp
      in length. RAB41 was composed of three exons, and it was mapped to chromosome
      3q21.3 by comparing with the human genomic data. RAB41 protein contains a RAB
      domain. Similarity analysis indicated that RAB41 is closely similar to RAB19. The
      results of PCR amplification indicated that human RAB41 is widely expressed in
      brain, testis, lung, heart, ovary, colon, kidney, uterus and spleen but not in
      liver. By genomic searching, an intronless pseudogene homologous to RAB41 at
      chromosome 16--RAB41P was identified at human chromosome 16q11.2. Flanking the
      pseudogene RAB41P in human genome, there exist some transposable elements LINEs-
      L1, whose contribution in the generation of this intronless homolog is discussed.

PMID- 15018354
TI  - Identification of a novel splice variant: human SGT1B (SUGT1B).
AB  - We identified a novel splice variant of human SGT1 (SUGT1), a suppressor of the
      G2 allele of SKP1, by analysis of 8 human EST clones whose open reading frame
      encoded 365 amino acids. We termed this variant SGT1B (SUGT1B) and the original
      SGT1A (SUGT1A). The putative SGT1B and SGT1A proteins are 91% identical, and both
      contain a tetratricopeptide repeat (TPR) domain, two variable regions, a CS
      domain, and a SGS domain. The NCBI human genome database showed that SGT1B and
      SGT1A are located on chromosome band 13q14.13. SGT1B contains an additional 33
      amino acids encoded by a region between exons 5 and 6 of SGT1A and lacks Ser110
      of SGT1A. Immunoblotting using antibodies to N-terminal (amino acids 1-157) and C
      terminal (amino acids 182-333) regions of SGT1A detected 2 bands whose sizes
      corresponded to those predicted for SGT1A and SGT1B. Overexpression experiments
      confirmed this finding. Additional immunoblot analysis demonstrated that both are
      highly expressed in human brain, liver, lung, and testis.

PMID- 15018355
TI  - Isolation and sequencing a genomic DNA encoding for phenylalanine ammonia-lyase
      from Phalaenopsis.
AB  - The enzyme L-phenylalanine ammonia-lyase is universally present in higher plants
      and it catalyzes the first committed reaction for a central pathway that
      generates hundreds of different phenylpropanoid metabolites including
      anthocyanin, the main pigments in flowers. In this study, we have successfully
      isolated and analyzed a phenylalanine ammonia-lyase gene from Phalaenopsis. The
      gene spans 3265bp and consists of two exons and one intron and encodes a
      polypeptide of 703 amino acid residues.

PMID- 15018356
TI  - Online cognitive engagement of boys with ADHD.
AB  - The present study was designed to examine the role that attentional problems may
      play in accounting for difficulties in story comprehension experienced by
      children with ADHD. A secondary task methodology was used to examine whether or
      not online variations in cognitive engagement with a televised story were related
      to the continuity of central or incidental information. Twenty-two 9- to 11 -year
      old boys with ADHD and 36 of their nonreferred peers watched a television program
      and responded to auditory probes presented at preselected points during
      continuous sequences of central or incidental information. The reaction times to
      the probes for nonreferred boys showed the expected linear increase in cognitive
      engagement (i.e., the RTs increased) as central, plot-relevant sequences
      continued. In contrast, boys with ADHD showed the expected increase in RTs
      relatively late in the central sequences. The results were discussed in terms of
      how delays in engaging with central information may contribute to the academic
      difficulties experienced by boys with ADHD.

PMID- 15018357
TI  - Boredom proneness and sleep disorders as predictors of adult attention deficit
      scores.
AB  - This study examined the extent to which boredom proneness and sleep disturbances
      were related to attention deficit scores in college-aged adults. In a sample of
      148 college students, Attention scores on the Adult Behavior Checklist were best
      predicted by Boredom Proneness (BP) subscale scores, which assess one's inability
      to maintain internal stimulation and feelings of constraint, and scores on the
      Epworth Daytime Sleepiness Scale and Athens Insomnia Scale (R2 = .57).
      Hyperactivity scores were best predicted by the BP subscales, which assess one's
      need for a stimulating environment, the perception of time passing slowly, and
      feelings of constraint, and the Epworth Scale (R2 = .51). The findings contribute
      to the understanding of the symptomatology of attention deficit in adults and
      provide further evidence of the validity of this measure.

PMID- 15018358
TI  - Persistence of Attention-Deficit/Hyperactivity Disorder into adulthood: what have
      we learned from the prospective follow-up studies?
AB  - OBJECTIVES: Longitudinal studies of children with Attention-Deficit/Hyperactivity
      Disorder (ADHD) into adolescence have all reported high rates of ADHD. However,
      findings from studies into adulthood are inconsistent. This article reviews
      factors that may account for disparate rates found in adult follow-ups, and
      recommends optimal methodologies for prospective studies of children with ADHD in
      particular and childhood mental disorders in general. METHOD: Follow-up studies
      of children with ADHD into adulthood are critically reviewed to identify factors
      that influence adult ADHD prevalence estimates. RESULTS: Four factors are
      identified: (1) ascertainment procedure, (2) attrition rate, (3) reporting
      source, and (4) disorder criteria. CONCLUSIONS: Estimates of the proportion of
      children with ADHD who will experience symptoms of the childhood syndrome in
      adulthood are likely to vary considerably, as a function of multiple factors.
      Several recommendations are made for designing future follow-up investigations.

PMID- 15018359
TI  - Child and familial pathways to academic achievement and behavioral adjustment: a
      prospective six-year study of children with and without ADHD.
AB  - This longitudinal study examined familial and child predictors of academic
      achievement and behavioral adjustment. Participants included 115 children with
      ADHD and 59 normative comparisons. Data analyses spanned three assessment waves
      from elementary- through secondary-school grades. We evaluated the degree to
      which child and familial factors present during middle school mediated
      relationships between childhood ADHD, subsequent academic achievement, and
      behavioral adjustment during high school. We found that emotional and behavioral
      well-being of ADHD children during middle school mediated relations between
      childhood ADHD and adverse academic and behavioral outcomes during high school.
      In addition, familial factors in middle school years predicted the behavioral
      adjustment of children in both the ADHD and non-ADHD groups. Academic achievement
      during high school was strongly associated with previous achievement levels. Our
      results provide support for tailoring preventive interventions to the unique
      needs of children with ADHD and their parents at various stages of adolescent
      development.

PMID- 15018360
TI  - Billing basics for physician assistants and nurse practitioners.
AB  - In recent years, physicians have increasingly looked to nonphysician
      practitioners (NPPs) as a resource for delivering care to patients. While
      historically more prevalent in primary care groups, nonphysician practitioners
      have expanded their presence within medical subspecialty and surgical groups as
      well. Along with planning for appointment scheduling, credentialing, and
      introducing the nonphysician provider to patients and referring physicians, the
      savvy practice will thoroughly review how services for a nonphysician can and
      should be billed. In this article, we focus our attention on basic Medicare
      billing parameters for physician assistants and nurse practitioners, two types of
      nonphysician practitioners.

PMID- 15018361
TI  - Selecting managed care plans: getting the most for your practice through the use
      of evaluation tools.

PMID- 15018362
TI  - Employee discharge liability: the straw that broke the camel's back.
AB  - Employers are frequently confronted with workers who do not perform adequately.
      It is important to document and communicate dissatisfaction with an employee's
      performance as failings become evident. Efforts at remediation of the
      deficiencies must also be recorded. This article outlines the pitfalls of
      employee discharge without such documentation and strategies to avoid litigation
      and achieve an equitable outcome for both parties.

PMID- 15018363
TI  - Recruitment, retention, and revenue: the three Rs of successful group practice
      management.
AB  - Recruiting a physician to your medical practice can be an expensive proposition.
      But what is the cost of losing a physician, or of failing to fill a vacancy? This
      article examines the ramifications of physician recruitment and retention, from
      the perspective of its financial impact, by providing the framework for a
      strategy meant to increase the odds of successfully recruiting a new physician.
      The article also offers suggestions to help the medical practice manager retain
      productive doctors by considering physician retention as an extension of the
      recruitment effort.

PMID- 15018364
TI  - Special considerations for hiring an office manager.
AB  - Medical practice office managers come in many varieties. They can be hired from
      the outside or promoted from within. They can have a great deal of experience
      working in medical practices or practically none. Which type of office manager is
      the best choice for your practice? This article will help you decide. It
      describes three types of office managers and considers the pros and cons of each.
      It explores the characteristics, advantages, and disadvantages of lay
      administrators hired from the outside, office managers promoted from the ranks,
      and "super-aides" who are asked to manage while doing their old jobs. This
      article also offers a list of 10 characteristics to look for in office manager
      candidates, as well as six areas of overall responsibility for your office
      manager. Finally, it includes a quick checklist of 20 required duties of typical
      medical practice office managers that can help you shape your office manager's
      job description.

PMID- 15018366
TI  - Computer briefs: wireless networking--802.11?

PMID- 15018365
TI  - Saving nurses, saving patients: responses to the labor crisis.
AB  - While numerous task forces have spent enormous time and energy studying the size
      and scope of the nursing shortage, other organizations have been hard at work
      solving the difficulties faced by nurses and reducing the effects of the labor
      shortages on patient care. These efforts range from national legislative
      activities to grassroots innovations. Many of these efforts have already produced
      tangible results and take the form of major investments in professional
      development and improvements to the workplace environment. Physicians play an
      important role in the hospital work environment and can affect teamwork, a clear
      driver of nurse satisfaction.

PMID- 15018367
TI  - Ten myths about the Stark statute debunked.
AB  - The Stark statute was enacted in 1995, but final regulations were not published
      until January 2001 and even then did not address all the Stark exceptions. Many
      people are confused about how to apply the exceptions and what the Stark statute
      means. This article identifies 10 of the most common myths about Stark and
      explains and corrects the misconceptions.

PMID- 15018368
TI  - Managed-care physician class-action suits on pay issues.

PMID- 15018369
TI  - Health literacy: adverse implications for patients and physicians.
AB  - An astounding portion of the American adult population lacks a level of literacy
      to comply with effective delivery of health care. This article outlines the
      concerns and some measures that practices may adopt to help remedy the problem.

PMID- 15018370
TI  - Planning for the future.

PMID- 15018372
TI  - Evaluation of activity-based costing versus resource-based relative value
      costing.
AB  - Activity-based costing (ABC) and relative value units costing (RVU) are two
      approaches that a practice manager can use to determine the cost of physician
      services. Each costing approach has features that provide distinction as well as
      differentiation in the cost estimates that are estimated. This paper will provide
      cost estimates under each approach along with cost estimates under a hybrid
      approach that merges features from each costing approach known as the ABC-RVU
      costing technique. A comparison of the results will be provided.

PMID- 15018371
TI  - Trends in the consumer price index.

PMID- 15018373
TI  - Sexual abuse and eating disorders: clinical cases.
AB  - The aim of this analysis of five clinical cases is to show how an experience of
      sexual abuse can contribute towards increasing individual vulnerability and
      become one of several factors that come together to aggravate and complicate the
      symptoms characterising eating disorders. It is also intended to enhance the
      importance of a "multifactorial" model for approaching this kind of
      psychopathology.

PMID- 15018374
TI  - Maladaptive eating attitudes of elite and amateur Turkish dancers: are they at
      risk?
AB  - The aims of this study were to investigate whether Turkish dancers are at risk of
      eating disorders, and to identify any gender and elite vs. amateur differences.
      The study involved 100 participants (64 females and 36 males) divided into three
      groups: 6lite dancers, amateur dancers and controls. The elite dancers were the
      members of the State Conservatoire; the amateur dancers were university students
      attending university dance clubs; the control group consisted of university
      students who were not members of dance clubs. All of the participants completed
      the Eating Attitude Test and a questionnaire about eating habits. Both the elite
      and amateur dancers had more pathological eating attitudes than the controls.
      Females had more problematic eating attitudes than males. Both elite and amateur
      female Turkish dancers may be at risk for disordered eating. The implications for
      prevention are discussed.

PMID- 15018375
TI  - The effects of 5-HT on feeding behaviour in mianserin- or cyproheptadine
      pretreated rats.
AB  - We examined the effects of 5-HT on the feeding behaviour patterns of rats
      pretreated with mianserin (5-HT(1B/2A/1D receptor antagonist) or cyproheptadine
      (a 5-HT(2c) receptor antagonist), injected into the pariventricular hypothalamus
      nucleus (PVN). The animals were kept at 21 +/- 1 degrees C with a 12 h light and
      12 h dark cycle on a self-selected feeding paradigm, and provided with freely
      available and separate sources of proteins, carbohydrates, fats and water. The
      results indicate that the suppressive effect of 5-HT on carbohydrate intake can
      be blocked by mianserin and cyproheptadine even at the onset of the natural
      (dark) feeding period; however, this is a distinct blockade in the paradigm of
      feeding behavior. All of the meal patterns of fat intake and rest remained
      unaffected.

PMID- 15018377
TI  - "Before and after" diet advertisements escalate weight stigma.
AB  - The stigma-producing effects of "before and after" diet advertisements on a
      healthy weight sample were examined. Subjects (n = 59) were exposed to a
      presentation containing either a "before and after" diet ad, or solely the
      "before" or "after" picture embedded in a different ad. Subjects were then given
      measures to assess negative attitudes and endorsement of stereotypes about
      overweight people. Across all subjects, strong implicit anti-fat bias was
      present. Subjects in the Before and After condition indicated that weight is more
      easily controllable than did subjects in either the Before Picture Only or the
      After Picture Only conditions. There were two moderating variables for this
      effect. Subjects who reported greater life satisfaction endorsed fewer anti-fat
      stereotypes, and those who enjoyed an emotionally close relationship with an
      overweight person were less biased. These results suggest that "before and after"
      diet ads enhance weight stigma and perpetuate damaging stereotypes.

PMID- 15018376
TI  - Self-reported competencies and problems among Swedish girls with eating disorders
      and a control sample, using the youth self-report.
AB  - OBJECTIVE: To study self-reported competencies and problems in adolescent girls
      with eating disorders, anorexia nervosa (AN), bulimia nervosa (BN), and eating
      disorder not otherwise specified (EDNOS) compared to matched normal controls.
      METHOD: The Youth Self-Report (YSR) was completed by 211 girls between 13 and 17
      years of age with eating disorders and 211 controls matched for age, sex, and
      geographical area. RESULTS: Girls with eating disorders scored lower on all
      competence scales and higher on most problem 'scales compared to controls. Type
      of diagnosis had no effect on competence scales, but BN-patients scored higher
      than AN- and EDNOS-patients on many problem scales. AN-bingers/purgers reported
      more problems than restrictors on somatic complaints, delinquent behaviour, and
      the externalizing dimension. DISCUSSION: We conclude that the YSR gives important
      information concerning self-reported competencies and concomitant symptoms of
      general psychopathology in eating disordered adolescent girls.

PMID- 15018378
TI  - Weight satisfaction and self-esteem among teenagers in Helsinki, Moscow and
      Tallinn.
AB  - OBJECTIVE: Information on weight satisfaction in Eastern Europe is limited. This
      study compares relative weight, weight satisfaction and self-esteem of teenagers
      living in two post-Soviet capitals, Moscow and Tallinn, and a western capital
      Helsinki. METHOD: Classroom surveys including data about weight and height,
      weight satisfaction and self-4 esteem among 15-18-year-old girls (n = 911) and
      boys (n = 650) collected in 1994-95. RESULTS: Body mass index and self-esteem
      were highest in Helsinki. Nevertheless, feelings of over-weight were most common
      among Tallinn girls and feelings of over- and underweight among Muscovite girls.
      Boys were mostly satisfied with their current weight with no differences between
      cities. Low self-esteem was associated with feelings of overweight among girls
      and underweight among boys. DISCUSSION: Somewhat unexpectedly, girls grown in non
      western cultures were more dissatisfied with their weight than girls in Helsinki.
      These findings may partly be attributable to rapid economic and cultural
      transformations that were occurring in these countries during the study period.

PMID- 15018379
TI  - Psychometric properties of Eating Disorder Inventory for Children (EDI-C) in
      Swedish girls with and without a known eating disorder.
AB  - OBJECTIVE: To evaluate the Swedish version of the Eating Disorder Inventory (EDI
      C) for the internal consistency, factor structure and ability to discriminate
      between adolescent girls with and without a known eating disorder (ED). METHODS:
      Completely answered EDI-C questionnaires were available from 201 girls diagnosed
      with an ED and from 2073 schoolgirls. The girls were adolescents attending grade
      7-12. RESULTS: Internal consistency was 0.70-0.91 for the ED group. Eleven
      factors with eigenvalue > 2.2 explained 56% of the variance and showed satisfying
      correspondence to the proposed constructs of EDI-C. A discriminant analysis
      classified 85.6% of the cases correctly. The three most important discriminating
      subscales were Drive for Thinness, Asceticism and Body Dissatisfaction. All
      subscales except Maturity Fears showed significantly higher mean values for the
      ED group. CONCLUSIONS: The results indicate that the psychometric properties of
      EDI-C are comparable to the properties of EDI-2. EDI-C should be preferred for
      adolescents since its statements suit this age group.

PMID- 15018380
TI  - Screening of males with eating disorders.
AB  - The purpose of this study was to evaluate two different questionnaires for
      screening of eating disorders (ED) in males; the Eating Disorders Inventory (EDI)
      and the Survey for Eating Disorders (SEDs). The study sample consisted of 1196
      Norwegian males serving as compulsory military recruits (mean age 19.9, SD =
      1.4). The best predictors for having a SEDs-based diagnosis of ED were the EDI
      scales Drive for thinness (D7), bulimia (B), ineffectiveness (I) and
      interpersonal awareness (IA). When we classified men with an EDI sum score of 40
      or higher as having an ED, the sensitivity was 47% and the specificity was 91%,
      compared to the SEDs diagnosis of ED. Our results suggest modest agreement
      between the ability of the EDI and that of the SEDs to identify men with ED. Our
      results indicate the need of further studies including clinical samples to
      validate the EDI against the SEDs.

PMID- 15018381
TI  - Differential diagnoses to consider at an eating disorders clinic.
AB  - OBJECTIVE: To determine the reasons for referral of patients without eating
      disorders who were within a cohort of patients referred to an adult tertiary care
      eating disorders program. METHODS: Cases were obtained by retrospectively
      reviewing all the charts of patients who had been referred to a single eating
      disorders program over a 20-year period from 1981 to 2000. All referred cases had
      been screened by a nurse using a telephone or written questionnaire. RESULTS:
      Thirty-three out of 987 patients (3.3%) were identified as having no eating
      disorders. Four subjects were males (12.1%) and 29 were females (87.9%). After
      investigation, 16 were found to have a psychiatric diagnosis, 8 had a medical
      diagnosis, and 8 had no identifiable diagnosis. CONCLUSIONS: This study shows
      that the screening process for referral to a tertiary care eating disorders
      program is highly reliable and suspicion for a patient without an eating disorder
      should be low; in comparison with the eating disorder population, these patients
      are more likely to be male and psychiatric illnesses are twice more likely than
      medical disorders to be diagnosed.

PMID- 15018382
TI  - Psychopathological differences between morbidly obese binge eaters and non-binge
      eaters after bariatric surgery.
AB  - AIMS: To determine the psychological characteristics of a group of morbidly obese
      patients with binge eating disorders and to investigate whether the
      psychopathological status of binge eaters is different from that of other
      morbidly obese patients. METHODS: We used the Binge Eating Scale, the Three
      Factor Eating Questionnaire and the Millon Clinical Multiaxial Inventory-II (MCMI
      II) to interview 140 morbidly obese patients 18 months after bariatric surgery
      (vertical banded gastroplasty), and compared the results obtained in binge eaters
      (n = 25) and non-binge eaters (n = 115). RESULTS: The binge eaters had more
      eating disturbances (more binge eating, less restriction, more disinhibition,
      more hunger) and psychopathological characteristics (passive-aggressive traits,
      aggressive-sadistic traits, manic disorders, alcohol dependence and major
      depression) than the non-binge eaters. They were also younger and achieved a
      lower percentage of weight loss. CONCLUSIONS: After bariatric surgery, our obese
      binge eaters reported significantly more psychiatric symptoms, especially those
      relating to eating disorders, depression, alcohol dependence and personality
      disturbances. Their weight loss was less satisfactory, and they sought bariatric
      surgery at a younger age.

PMID- 15018383
TI  - Quantification of sub-clinical anxiety and depression in essentially obese
      patients and normal-weight healthy subjects.
AB  - The aim of this study was to quantify the degree of sub-clinical anxiety and
      depression in essentially obese patients (EOP) and normoponderal healthy subjects
      (NHS) in order to identify quantitative differences based on mean scores and
      percentages (the latter in cases showing a tendency towards pathological anxiety
      and depression indicated by a score of > or = 8). The study involved 69 EOP (age:
      13-72 years; BMI: > 25.0 and < 35.0 kg/m2) and 66 NHS (age: 18-68 years; BMI: >
      18.5 and < or = 25.0 kg/m2). The scores, expressed in Anxiety Units (AU) and
      Depression Units (DU), were computed using ad hoc questionnaires (the ASQ and
      CDQ) validated for the Italian population. The mean scores of sub-clinical
      anxiety and depression in the EOP were significantly higher (both p = 0.001) than
      those of the NHS (6.33 +/- 2.38 vs 5.02 +/- 2.22 AU; 6.42 +/- 2.42 vs 5.02 +/-
      2.03 DU), as were the percentages of cases with a tendency towards pathological
      anxiety and depression (42% vs 18%, and 43% vs 12%) (both p = 0.001). The
      significantly higher mean sub-clinical anxiety and depression score in the EOP
      indicate that a worse mood status is associated with obesity in a non-random
      manner. The significantly higher percentages of EOP with a tendency towards
      pathologic anxiety and depression indicate that obesity is a clinical condition
      that predisposes to the development of clinically relevant affective disorders.

PMID- 15018384
TI  - Body uneasiness in overweight and obese Italian women seeking weight-loss
      treatment.
AB  - OBJECTIVE: It is known that the psychopathology of eating disorders is associated
      with body image disturbances, but little is known concerning the body image of
      obese subjects. The aim of this study was to assess body uneasiness in overweight
      and obese women in relation to their age, degree of obesity, the percentage and
      distribution of body fat mass, and eating disordered behaviours. METHOD: The
      study population consisted of 99 overweight and obese women with a mean age of
      34.3 +/- 10.1 years and a mean body mass index (BMI) of 31.3 +/- 5.4 kg/m2, who
      completed two self-report questionnaires: the Bulimic Investigation Test
      Edinburgh (BITE) to assess disordered eating behaviours and the Body Uneasiness
      Test (BUT) to assess body image uneasiness. Pearson correlations were used to
      determine the associations between the BUT scores and age, anthropometric
      measures (BMI, waist and hip circumferences, waist/hip ratio, percentage of body
      fat mass) and the BITE scores. The most significant determinants of the BUT
      scores were also determined using a multiple linear regression model. RESULTS:
      Disordered eating behaviours were found in 7.1% of the patients. Neither BUT nor
      BITE scores correlated with age, but BITE scores correlated with BMI and hip
      circumference (p < 0.05). The overall BUT score increased with increasing BITE
      scores and higher indices of all of the anthropometric measures (p < 0.001)
      except for the percentage of body fat mass. Multiple linear regression analyses
      showed that, among the considered parameters, the only significant determinants
      of body uneasiness were disordered eating behaviours. CONCLUSIONS: Our results
      confirm that body uneasiness in an obese clinical population is closely
      associated with disordered eating behaviours, and suggest that it is not
      dependent on age, the degree of obesity, or the percentage or distribution of
      body fat mass.

PMID- 15018385
TI  - Clinical course and short-term outcome of hospitalized adolescents with eating
      disorders: the success of combining adolescents and adults on an eating disorders
      unit.
AB  - Although significant controversy exists regarding the appropriate setting for
      treating adolescents with eating disorders, empirical studies have been lacking.
      This study aimed to evaluate, and compare with adults, the clinical course and
      short-term outcome of adolescents with eating disorders hospitalized on an adult
      eating disorders unit. One hundred forty-four consecutive inpatient admissions on
      a weight gain protocol (28% minors and 72% adults) completed psychometric
      measures and were assessed on clinical indices. No differences between minors and
      adults were demonstrated for weight gain per week on either inpatient or partial
      hospitalization admissions. Whereas inpatient length of stay was equivalent,
      adolescents stayed significantly longer in partial hospitalization than adults.
      Minors did not differ from adults on the presence of problematic eating
      disordered behaviors or most psychometric measures, although they had less
      functional interference due to their eating disorders. Results suggest that an
      adult eating disorders specialty program can be an appropriate and efficacious
      setting for adolescents.

PMID- 15018386
TI  - Kidney stones in anorexia nervosa: a case report and review of the literature.
AB  - Nephrolithiasis (kidney stones) is a recognized complication of anorexia nervosa
      (AN). We present the case of a 41-year-old woman with a 25-year history of AN.
      Between 1978 and 1986, she had two episodes of calcium oxalate kidney stones.
      Proper management of kidney stones in AN requires collection of the stone,
      laboratory analysis of the stone to determine its composition, and laboratory
      evaluation of the urine and blood to determine what treatment is necessary to
      prevent recurrent kidney stone formation.

PMID- 15018387
TI  - Self-phlebotomy in eating disorders.
AB  - We present the case of a health-care professional with anorexia nervosa who used
      self-phlebotomy as a form of purge. Self-phlebotomy is most prevalent in young
      females employed in medical or paramedical professions. The occurrence in eating
      disorders of severe, unexplained, or rapidly appearing anemia; unexplained needle
      tracks, or past or present employment as a health-care worker should raise
      suspicion of self-phlebotomy.

PMID- 15018388
TI  - [Emergencies in hematology].
AB  - In this review common and important causes of hematologic emergencies are
      discussed. Upon cause, four groups for classification of the emergency are
      formed. Among these are hyperviscosity syndromes of different origin, impaired
      immun-response and neutropenia, thrombocytopenia of different causes and, last
      but not least, severe acute hemolysis. It is emphasized that rapid diagnosis with
      the help of a few common laboratory tests and immediate transfer to a tertiary
      care center are necessary to reduce morbidity and mortality.

PMID- 15018390
TI  - [Garbage in-garbage out: influence of preanalytical variables on hematological
      analysis].
AB  - Preanalytical factors have a significant impact on the quality of hematological
      analyses and must not be disregarded during clinical interpretation of laboratory
      data. Besides unchangeable physiological variables such as age, sex, race,
      patient preparation, an expert phlebotomy, rapid transport to the laboratory as
      well as many other variable factors play a crucial role in obtaining correct
      laboratory results. More advanced tests (erythrocyte enzymes, evaluation of
      hemoglobinopathies, molecular biology, flowcytometric characterization of
      leucocytes etc.) performed by specialized centers require special preanalytical
      measures. The centers should be consulted about the preanalytical conditions
      before blood sampling is performed or--if possible--the patient should be sent to
      these centers for phlebotomy.

PMID- 15018389
TI  - [Classification of neoplastic disorders of the haematopoietic system].
AB  - The present article is written in an attempt to illustrate the ongoing diagnostic
      progress by presenting some examples of pre-existing and newly defined entities.
      The World Health Organisation proposed in 2001 a "Classification of Tumours of
      the Haematopoietic and Lymphoid Tissues". Relying on the broadest consensus
      possible, it received high acclamation by both clinicians and pathologists. The
      approach is based on cell lineage assignment including morphology and
      immunophenotype, but also relies on cytogenetic and clinical features in order to
      define disease entities to an extent as far as possible. The diagnostic criteria
      for myeloid, lymphoid and histiocytic neoplasms have been compiled by an
      international group of 51 experts assembled in ten disease-related committees. In
      order to cover the interests of daily haematological practice, selected topics
      are focussed including chronic and acute myeloid neoplasias, precursor lymphoid
      neoplasias, mature B-, T- and NK-cell lymphomas, Hodgkin lymphoma as well as
      histiocytic and dendritic cell neoplasias.

PMID- 15018391
TI  - [Genetic analysis and immunophenotyping in the diagnosis of hematological
      disease].
AB  - The developments in the fields of genetics and immunology and the application of
      these informations have significant consequences for the diagnosis of
      hematological diseases. The present article gives an introduction into the
      principles of several modern diagnostic techniques, which are applied in the
      diagnosis of hematological diseases. In addition, it summarizes the application
      of these techniques in the diagnosis of several acquired and inherited diseases.
      The most important method of immunophenotyping is FACS (fluorescence activated
      cell sorting) analysis, which is based on the automated recognition of
      fluorescently labelled monoclonal antibodies bound to specific antigens on the
      surface or in the cytoplasm of different cell populations of the immune system.
      Techniques from molecular biology and from cytogenetics are also relevant for the
      diagnosis of hematological diseases: they allow the identification of changes of
      the genetic material on the level of DNA (molecular biology) and chromosomes
      (cytogenetics). Molecular biological and cytogenetic methods coalesce in the
      field of molecular cytogenetics, which renders possible the identification of
      chromosome mutations, which are invisible by the classical cytogenetical
      approach, and difficult to detect by routine molecular biological analysis. Most
      hematological malignancies are associated with genomic changes, which can be
      identified by cytogenetic and/or molecular biological methods. These genetic
      changes usually correspond with a specific pattern of surface antigens of the
      tumour cells, which can be identified by FACS. The different mutations in
      different genes causing a large number of inherited hematological diseases can
      often be found by molecular analysis, too. For hematological neoplasias, the
      exact definition of the causative mutations is increasingly important for
      therapeutic decisions and follow-up analysis of minimal residual disease. For
      inherited diseases, the identification of mutations is often the basis for a
      correct genetic counselling of the family.

PMID- 15018392
TI  - [Conventional and new laboratory parameters in the evaluation of hematologic
      disease].
AB  - Laboratory investigation plays a crucial role in the workup of hematological
      disease. The well established method of morphological analysis of blood
      components has been continuously complemented by other methods. On one hand,
      these consist of considerable improvements of methods employed for automated cell
      enumeration allowing for early and accurate detection of cell subpopulations, and
      quantification of valuable red cell parameters, which are of use in the
      differential diagnosis of anemia. On the other hand, several parameters for the
      differentiation of microcytic anemia have become available often allowing for the
      sometimes difficult diagnosis of anemia of chronic disease, iron deficiency
      anemia, or thalassemia (ferritin, soluble transferrin receptor, transferrin
      saturation, RDW, zinc protoporphyrin, as well as reticulocyte indices CHr, Ret-Y
      Hypo%). In macrocytic anemia, introduction of methods to measure methylmalonic
      acid (MMA), homocystein, holotranscobalamin (holo-TC), complement the
      determinations of vitamin concentrations (vitamin B12, folic acid in serum and
      erythrocytes). Employing these newer parameters in addition to the well
      established ones allows for detection of early or combined disease. The clinician
      has to know the diagnostic characteristics not only of the old but also of the
      newer parameters.

PMID- 15018394
TI  - [Myelodysplastic syndromes--an overview for the practitioner].
AB  - Myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematological
      diseases deriving from a clonally expanded precursor bone marrow cell. MDS are
      characterized by ineffective hematopoiesis, peripheral cytopenias of various
      degrees and increased risk for transformation into acute myeloid leukemia. The
      incidence is highest in elderly people. Diagnosis is based on morphology,
      exclusion of reactive causes of dyshematopoiesis and cytogenetics/FISH.
      Allogeneic stem cell transplantation, the only curative therapy so far, is not
      feasible for most of the patients. Other therapeutic options include supportive
      therapy such as blood transfusions and antibiotics, hematopoietic growth factors
      (rHuEPO, G-CSF), immunomodulating agents and chemotherapy. It is important to
      install iron chelation therapy in cases with long term transfusion dependency.

PMID- 15018393
TI  - [Differential diagnosis of anemia].
AB  - Anemia is often encountered in clinical practice. It has to be noted that anemia
      is only a symptom of an underlying disease. Early, correct and consequent
      diagnosis is crucial in order to prevent late detection of fatal disease or to
      prescribe contraindicated therapy. The combined use of a morphologic and
      physiologic classification allows for understanding and correct classification of
      anemia in a specific patient. In this respect, the determination of reticulocyte
      counts is of special importance. Further targeted biochemical, morphological and
      immunological analysis leads to the definitive diagnosis of anemia. A large
      proportion of the anemias can be diagnosed and treated by the general
      practitioner. However, involvement of a haematologist is recommended in several
      clinical situations, such as newly diagnosed haemolytic anemia, as well as in
      patients with complex, equivocal or therapy-refractory anemia or certain
      normocytic hyporegenerative anemias. This paper presents a differentiated
      stepwise approach in diagnosing anemic disorders.

PMID- 15018395
TI  - [Blast cells in peripheral blood smear].
AB  - Despite modern technologies such as immunophenotyping and molecular probing
      cytomorphological examination of stained peripheral blood smears by microscopy
      remains the mainstay of diagnosis in a large variety of diseases. Although
      technically simple morphological analysis requires considerable skill. Early
      diagnosis in several hematological diseases is important (for example acute
      promyelocytic leukaemia associated frequently with disseminated intravascular
      coagulation), in order to initiate adjusted therapy. Further, referral of the
      patient to tertiary care centers is only justified after a solid diagnosis is
      obtained. Many disorders can be diagnosed by pathognomonic blood smears. The
      present article is a short overview of important hematological disorders, which
      are associated with blast cells in the peripheral blood. Important morphological
      cell characteristics are illustrated by microscopic pictures.

PMID- 15018396
TI  - [Myeloproliferative disorders].
AB  - Myeloproliferative disorders are caused by abnormalities of hematopoietic stem
      cells leading to uncontrolled proliferation of one or more cell lines in the
      blood. Besides sharing common clinical and hematologic features they are
      characterized by clonal hematopoiesis and genetic instability, resulting in a
      disease-specific rate of transformation into acute leukemia. This review
      discusses relevant clinical and prognostic aspects as well as current diagnostic
      and therapeutic procedures of polycythemia vera, essential thrombocythemia and
      chronic idiopathic myelofibrosis.

PMID- 15018397
TI  - [Chronic myeloid leukemia--update].
AB  - Chronic myeloid leukemia (CML) is a clonal stem cells disorder and belongs to the
      myeloproliferative diseases. Over the past decades seminal discoveries in the
      field of CML research have greatly contributed to our knowledge of
      leukemogenesis. The hallmark of the disease is the presence of the Philadelphia
      chromosome, the first described acquired non-random cytogenetic abnormality in
      human malignancies. This chromosomal abnormality is the result of a reciprocal
      translocation between chromosomes 9 and 22, t(9;22). At the molecular level this
      involves the fusion of the ABL protooncogene on chromosome 9 with the BCR
      (breakpoint cluster region) gene on chromosome 22. The fusion protein has
      increased tyrosine kinase activity and is a key event in the malignant
      transformation of a given progenitor cell in the bone marrow. Diagnosis of CML is
      based on the peripheral blood smear, bone marrow examination, the presence of the
      Philadelphia chromosome and its molecular correlate, the BCR-ABL transcript.
      Remarkable progress has been made in the treatment options over the last years
      which as a result rendered the therapeutic choices more complex and challenging.
      The current knowledge of treatment options is reviewed with particular emphasis
      on the newly introduced tyrosine kinase inhibitor Imatinib which opened an as yet
      unexpected promising avenue in the treatment of CML.

PMID- 15018398
TI  - [Chronic lymphocytic leukemia--the old and the new].
AB  - Chronic Lymphocytic Leukemia (CLL) is the most frequent lymphoproliferative
      disease and leukaemia in western countries. CLL occurs more frequently in men
      than women, the median age at diagnosis is 65 years. CLL is defined as a
      persisting chronic lymphocytosis > 5 G/l with classical morphological features
      (small lymphocytic cells with round nuclei, dense chromatin and small cytoplasmic
      rim) and a classical immunophenotype (CD5+, CD19+, CD20+, CD23+); however,
      deviations from classical morphology are frequent. In cases with classical
      diagnostic features in the peripheral blood, a bone marrow biopsy is not
      necessary for diagnosis. Prognostic features comprise the stage of the disease
      according to the Rai or Binet systems, laboratory markers such as LDH, beta-2
      microglobulin, lymphocyte doubling time and CD38 expression by flow cytometry
      (and ZAP-70 expression if available) as well as the status on IgV(H)
      hypermutations and cytogenetic analysis. Up to 2/3 of patients do not need
      treatment at the time of diagnosis and can initially be followed using a watch
      and wait strategy. If therapy becomes necessary, initial standard treatment still
      is chlorambucil. Later, purine analogues and Alemtuzumab are treatment options
      for refractory or relapsing disease. Therapies with antibodies such as
      Alemtuzumab and Rituximab in combination with purine analogues are currently
      under clinical investigation. With recurrent or atypical infections,
      hypogammaglobulinemia should be searched for and immunoglobulins should be
      substituted if necessary. However, their prophylactic use is not recommended.

PMID- 15018399
TI  - [Differential diagnosis of absolute lymphocytosis].
AB  - The differential diagnosis of absolute lymphocytosis is variegated. In general,
      reactive (secondary) lymphocytosis can be well differentiated from a
      lymphoproliferative disease (primary lymphocytosis). Together with correspondent
      clinical characteristics, an absolute lymphocytosis often suggests a potential
      diagnosis and the further diagnostic process. Reactive lymphocytosis is usually
      self limiting and normalizes after cessation of the inflammatory stimulus. If a
      lymphoproliferative disorder is suspected further diagnostic procedures (i.e.
      cytometry, bone marrow examinations, biopsies of other organs if needed and
      molecular analyses) should be performed. If the distinction between malignant
      lymphoproliferation and reactive lymphocytosis cannot be done immediately, a
      watch and wait strategy may be implemented. In case of persistent lymphocytosis
      for longer than six months or occurrence of additional symptoms earlier on,
      diagnosis should be forced.

PMID- 15018400
TI  - [Monoclonal gammopathies--from MGUS to myeloma].
AB  - Monoclonal gammopathies are characterized by the overproduction of a monoclonal
      immunoglobulin (M-Protein), which may be detected in serum or urine by protein
      electrophoresis and immunofixation. The presence of an M-Protein results from the
      proliferation of a single abnormal clone of differentiated B lymphocytes or
      plasma cells, and is associated with a variety of clinical conditions, ranging
      from asymptomatic to malignant disease. Recent years have witnessed considerable
      advances in the treatment of plasma cell myeloma, the most common malignant
      disorder of the monoclonal gammopathies. As compared with conventional-dose
      treatments, high-dose chemotherapy with autologous stem-cell transplantation
      increases response rates and overall survival of patients with myeloma who are
      younger than 65 years of age. Progress in supportive therapies and the
      development of promising new drugs such as proteasome inhibitors and thalidomide
      analogues may provide further benefits for myeloma patients in the future.

PMID- 15018401
TI  - [Idiopathic thrombocytopenic purpura in children].
AB  - In children the rate of acute, transient ITP is much higher than the chronic form
      of ITP. Often acute childhood ITP is a para- or postinfectious event.
      Pathophysiologically bleeding symptoms mainly depend on the ratio between normal
      or increased platelet production and early destruction of platelets. The
      management of ITP has to be focused on the individual bleeding symptoms rather
      than to the platelet count (see staging system). Today's treatments are directed
      against the disturbed immune response. As recent guidelines and surveys
      demonstrate opinion based recommendations have to be challenged by evidence based
      clinical research in ITP (see www.unibas.ch/itpbasel).

PMID- 15018402
TI  - [Etiology and treatment of thrombocytopenia].
AB  - Thrombocytopenia has many causes. History, clinical examination of the patient,
      and a careful analysis of the peripheral blood smear may already lead to the
      etiology of cytopenia. The aim of the treatment is the correction of the
      underlying disease. In the management of immune thrombocytopenic purpura, the
      most common form of thrombocytopenia in adults, the goal is to avoid hemorrhages
      and not to increase the platelet value to normal.

PMID- 15018403
TI  - [Aquired immune hemolytic anemias].
AB  - Aquired immune hemolytic anemias are classified in autoimmune hemolytic anemia
      (AIHA) of warm type, cold agglutinine disease, paroxysmal cold hemoglobinuria,
      drug-induced immune hemolytic anemia, and paroxysmal nocturnal hemoglobinuria.
      The autoantibodies in AIHA of warm type react most strongly at 37 degrees C (warm
      autoantibodies). They are of the IgG, less commonly of the IgM and IgA classes.
      The cause of autoimmunization remains obscure in 50% of the patients (idiopathic
      AIHA). In the remaining cases, the AIHA is associated with other diseases.
      Corticosteroids are the mainstay of therapy, but most patients with AIHA of warm
      type require additional treatment with azathioprine or other drugs. Cold
      agglutinins are the cause of hemolysis in about 10% of patients with AIHA.
      Paroxysmal cold hemoglobinuria (Donath-Landsteiner) is less common and occur in
      children following infections. Drugs are the cause of hemolysis in about 10% of
      all cases with AIHA. The true incidence of alloimmune hemolytic anemias including
      neonatal immune hemolytic anemias is unknown. The paroxysmal nocturnal
      hemoglobinuria is rare. It is caused by complement activation due to aquired
      membrane defects.

PMID- 15018404
TI  - Laparoscopic staging of gastrointestinal tumours.

PMID- 15018405
TI  - [Gastric lymphomas: surgical indications].
AB  - Primary gastric lymphoma (PGL) are lymphomas with an exclusive gastric
      localization. Histologically they are B-like non-Hodgkin lymphomas. Aim of
      Authors' study is to define the role of surgery in the treatment of PGL, on the
      basis of their series casistics and a review of the more recent literature data.
      The Authors observed 41 patients (23 F and 18 M) in a period of 10 years: 35
      patients underwent to surgical operation associated in 18 of them to
      chemotherapic treatment; in 6 cases medical eradication of Helicobacter Pylori
      (H.P.) was performed as unique treatment. Antibiothic treatment allows the
      eradication of H.P. in 97% of the patients and a histologic decreasing of MALT
      lymphoma in 70% of the patients in about 6 months. That represents the first
      therapeutic choice for the low grade of malignancy MALT PGL at I and II stages.
      In the cases of partial decreasing or progression of PGL, the Authors consider
      opportune surgical operation. In the majority of the cases the surgical option
      represents, according to our advise, the best choice for the high percentage of
      definitive recoveries, allowing a 10 or more years of surviving of the 90%, if it
      is done in the first stages of the disease. The results of the association with
      neoadjuvant or aduvant chemotherapy are still controversial. On the basis of
      their experience total gastrectomy can be considered the elective choice
      operation, with IID level lymphadenectomy and possible splenectomy.

PMID- 15018406
TI  - [Parathyroid carcinoma: clinical aspects and therapy].
AB  - Parathyroid carcinoma is a rare entity with an 0,5-1% of incidence on primary
      hyperparathyroidism (HPP) in literature. The very high values of calcium and
      parathormone (PTH) and the clinical aspects of hypercalcemia are the
      characteristics findings in these patients. We present our experience on 6 pts on
      153 cases with HPP treated (3,9%). The clinical and diagnostic suspects are
      frequently intraoperative findings and the decision making for the surgeon is not
      always easy (parathyroidectomy with or without hemithyroidectomy,
      lymphadenectomy, surgical resection of other tissues). The mortality rate is high
      and we have registered three deaths at 8,14 and 64 months.

PMID- 15018407
TI  - [Is the Lauren classification an independent parameter for the prognostic
      evaluation of surgically treated gastric cancer patients? Analysis of a case
      series].
AB  - The Authors highlight the efficacy of the Lauren's classification in 28
      surgically treated gastric cancer patients. Lauren's classification allows a
      prognostic evaluation corresponding to the effective gastric cancer natural
      history. Present histo-morphological classification criteria appear not to
      coincide with the clinical evolution; as a matter of fact over- or understaging
      is possible in gastric cancer patients. 64,28% of the Lauren's classification
      intestinal type patients survive after a four year follow up vs. 42,85% of the
      diffuse type patients. The Authors discuss about new biomolecular knowledge in
      gastric cancer oncogenesis.

PMID- 15018408
TI  - [Dermatofibrosarcoma protuberans: therapeutical and clinical considerations].
AB  - Taking the starting point from their own experience and looking at the most
      recent literature, the Authors report the prospects about the surgical treatment
      of dermatofibrosarcoma protuberans.

PMID- 15018409
TI  - [Rectosigmoid junction neoplasms: our experience].
AB  - The Authors report their experience with 25 patients operated for colorectal
      junction neoplasms from January 1998 to December 2002 in the Section of
      Oncological Surgery, at Perugia University. According to the international
      literature, the Authors maintain the absolute functional and anatomical
      individuality of this part of the large bowel, underlining the peculiarity of the
      sigmoidal junction neoplasms respect all the others colic sites regarding
      clinical manifestations, symptoms developing and biological behaviour. The
      characteristics seem also capable of changing the surgical choice as well as the
      prognosis of the disease.

PMID- 15018410
TI  - [Desmoid tumor of rectus muscle of abdomen in a woman of childbearing age: what
      can we do?].
AB  - The desmoid tumor (DT) is a soft tissue neoplasm most frequently localized in the
      anterior abdominal wall typically in females of childbearing age. Because its
      particular incidence in women who had recently been pregnant, it was correlated
      with delivery's trauma stimulating proliferation of muscolo-aponeurotic tissues.
      Complete surgical resection is the recommended treatment approach to prevent
      recurrence. Many authors emphasize the role of radiotherapy in regression of DT
      and in controlling local recurrence in patient who had incomplete resection. Many
      others emphasize the role of chemotherapy or antiestrogenic compounds, even
      though tumour does not express estrogen receptors. DT, otherwise, is neoplasm
      with high rates of recurrence after surgery but it never develops distant
      metastases, so that function and structure-sparing surgery may be a reasonable
      choice in young women when possible without leaving macroscopic residual disease.
      Furthermore literature data suggest that the presence of incomplete histological
      surgical resection does not correlate with local recurrence and that pregnancy
      does not represent a risk factor. In women of childbearing age, even after non
      radical histological DT primary resection, adjunctive radiotherapy, chemotherapy
      or antiestrogen therapy could be avoided and clinical observation alone may be
      considered.

PMID- 15018411
TI  - [Management of the neoplastic stenosis of the left colon with self-expandable
      endoprosthesis].
AB  - Malignant tumors of the large bowel develop colonic obstruction in 10-30% cases.
      Recently many authors have employed self-expandable stents to resolve the colonic
      obstruction. During 2002, seven patients affected by neoplastic malignant
      stenosis of the left colon underwent endoscopic placement of self-expandable
      enteral stent. The technique succeeded in relieving the obstruction in 6
      patients, while in a woman affected by malignant tumor of the splenic flexure,
      colonic stenting was unsuccessful. The Authors didn't observe any procedure
      related complications; sign and symptoms of intestinal obstruction resolved
      within 24-72 hours from placement. Four patients needed hydro-electrolitemic
      correction, intestinal cleaning and R0 resection with one stage anastomosis
      within 5 and 9 days. Bowel decompression of the neoplastic stenosis relieved by
      self expandable metallic stents is useful to avoid emergency surgery and provide
      time for a complete preoperative staging, a metabolic correction and a mechanical
      bowel preparation. Complications of stent placement are common in many reports
      and include minor rectal bleeding (2%) and perforations (4%). Stenting is
      contraindicated in cases of enlarged colon with diameter superior to 8 cm or in
      flogistic lesions.

PMID- 15018412
TI  - [Milligan-Morgan haemorrhoidectomy with ultrasonic scalpel].
AB  - INTRODUCTION: Milligan-Morgan haemorrhoidectomy is considered the best treatment
      for hemorrhoidal disease. Although this, many patients complaint post-operative
      pain that remain the worse complication. For this reason different are the trials
      performed in order to reduce his intensity. In this report we want to evaluate if
      the use of ultrasonic scalpel to perform Milligan-Morgan hemorrhoidectomy,
      compared with conventional surgery, could reduce post-operative pain. MATERIALS
      AND METHODS: 30 patients with III and IV degree of haemorrhoids were included in
      this study and divided in two groups. In the first group Milligan-Morgan
      haemorrhoidectomy was performed with conventional instruments, while in the
      second group the some procedure was performed with ultrasonic scalpel. The
      duration of intervention, time hospitalization, the time to open alvus to stools,
      the time to return to normal activity, the complications, pain and the amount of
      analgesic consumption were evaluated. RESULTS: In the II group's patients, it was
      observed a reduced time to healing with reduced spread of necrosis and
      inflammatory pattern, associated with reduced post-operative pain and the lower
      analgesic consumption. CONCLUSIONS: The use of ultrasonic scalpel to perform
      Milligan-Morgan haemorrhoidectomy, compared with conventional instruments, reduce
      post-operative pain making a more short time to healing and a precocious time to
      return to normal activity. For this reason we believe that the use of ultrasonic
      scalpel, although a more elevated costs, seems to be advantageous.

PMID- 15018413
TI  - [Diagnosis and treatment of Crohn's disease].
AB  - The Authors state their ideas and report their experience about diagnosis and
      treatment of Crohn's disease. After having treated risk and etiological factors,
      they discuss typical anatomo-pathological lesions. Then they explain clinical
      diagnostic and surgical choices extensively: they prefer laparotomic approach.
      The Author's conclude that timely diagnosis spare heavy complications.

PMID- 15018414
TI  - [Care for and maintenance of the quality life in oncological surgery: from
      psychological reaction to pain control].
AB  - Life care and quality life control would be considered as important as diagnostic
      and therapeutic steps. Surgical phase has a particular aspect in oncology, as the
      patient himself requires a curative intent from surgery (it's generally well
      known that alternative therapies for solid tumors, such as chemotherapy and
      radiotherapy, are thought to be extreme remedies during advanced study); in fact
      surgeons first, focused their attention upon life quality either of hospitalized
      or discharged patients. The aim of this article is to illustrate themes of
      clinical practice such as the complex emotional reaction of the patient and the
      pharmacological support for pain control.

PMID- 15018415
TI  - Impact of HIV/AIDS on education in the sub-Saharan Africa.

PMID- 15018416
TI  - Morbidity and mortality of neonates admitted in general paediatric wards at
      Kenyatta National Hospital.
AB  - BACKGROUND: Neonatal morbidity and mortality is high in developing countries.
      Facilities for specific neonatal care are limited in Kenya with no neonatal
      intensive care unit in the public health institutions. The new born unit at
      Kenyatta National Hospital (KNH) cannot accommodate all neonates so a number of
      these are admitted to the general paediatric wards. OBJECTIVES: To establish the
      morbidity and mortality of neonates admitted to the general wards at KNH and to
      review the medical interventions applied in the management and make
      recommendations that will improve on this. DESIGN: A retrospective study.
      SETTING: Kenyatta National Hospital general paediatric wards-Nairobi, Kenya.
      SUBJECTS: All babies who were admitted to the general paediatric wards at KNH
      from January to December 2000. RESULTS: A total of 308 records of neonates
      admitted to the general paediatric wards at KNH in the year of study were found
      and retrieved. The mortality was 315/1000 neonates admitted. Of the 308
      admissions, 33.4% were low birth weight (LBW), 5% being very low birth weight
      (VLBW). The common diagnoses at admission or discharge were suspected sepsis 71%
      (confirmed sepsis 8.4%), jaundice 35%, pneumonia 32%, omphalitis 28%, dehydration
      14%, apnoec attacks 13%, and hypothermia 6%. Eighty nine (29%) of the infants
      were not investigated at all. The mean duration of stay was nine days for those
      who lived to discharge and four days for those who died. Of those who died, 49%
      died within 24 hours of admission. The frequently cited cause of death was
      suspected sepsis, pneumonia, dehydration and hypothermia. There were only six
      admissions to the general purpose intensive care unit referred from the wards.
      The independent predictors of mortality were low birth weight, apnoec attacks,
      hypothermia and dehydration(p < 0.05). CONCLUSION: The mortality rate for
      neonates admitted to the general paediatric wards is high with almost half the
      deaths occurring in the first twenty four hours of admission. While the wards are
      doing commendable work, they need support by improving laboratory back up for
      improved diagnostic ability and to improve supportive care such as maintenance of
      fluid electrolyte balance, temperature regulation and access to intensive care
      facilities.

PMID- 15018417
TI  - Diphtheria seroprevalence in children living in the eastern Turkey.
AB  - OBJECTIVES: To determine the seroprevalence of diphtheria in 767 children aged 0
      6 years and to identify the relationship between diphtheria seroprevalence and
      several sociodemographic characteristics of the study subjects in the Erzurum,
      Erzincan and Kars cities situated in Eastern Turkey. DESIGN: A cross sectional
      study. SETTING: The subjects were recruited from three cities (Erzurum, Erzincan,
      Kars). The sampling method of 30 clusters recommended for field studies was used
      for a predetermined number of selecting subjects in the rural and urban areas in
      each city. SUBJECTS: Of the 767 children included in this study, 423 were from
      Erzurum, 187 from Kars and 157 from Erzincan. Diphtheria serology was used to
      examine the blood samples by ELISA method. RESULTS: Positive diphtheria
      seroprevalence was detected in 77.9% of 767 subjects in Eastern Turkey.
      Seroprevalence was 74.5% in children younger than one year of age, increased to
      84% at the age of 3-4 years, and reduced to 80% at the age of 4-5 years and 69.8%
      at the age of 5-6 years. The seroprevalence rates were similar in sex and number
      of siblings. Seroprevalence of diphtheria increased with educational level of
      parents in the rural area. CONCLUSION: Positive seroprevalence against diphtheria
      in eastern Turkey is disturbingly low.

PMID- 15018418
TI  - Domestic accidental deaths in the Niger Delta Region, Nigeria.
AB  - BACKGROUND: Domestic accidental deaths constitute a public health burden in the
      Niger Delta Region of Nigeria. This study is aimed at highlighting this public
      health burden. OBJECTIVE: This is study is aimed at highlighting this public
      health burden. DESIGN: A six year retrospective study using mortuary records.
      SETTING: University of Port Harcourt Teaching Hospital, Port Harcout, Nigeria.
      PATIENTS AND METHODS: Coroner's forms data were used from University of Port
      Harcout Teaching Hospital, Anatomical Pathology Department, which is the foremost
      health institution in the region serving a core population of about six million
      people. RESULTS: Eighty three domestic accidental deaths seen at the University
      of Port Harcourt Teaching Hospital in the Niger Delta Region of Nigeria between
      January 1995 and December 2001 were analysed. The 83 deaths occurred in 63 males
      and 20 females, giving a ratio of 3:1, between the ages of six months and 86
      years. There was a bimodal age distribution, with 20 cases (24.1%) occurring in
      preschool age children, and 22 cases (26.5%) occurring in the elderly over 70
      years. Fifty one deaths (61.4%) occurred in the urban areas, while 32 cases
      (36.8%) occurred in the rural areas. Seventeen cases (20.5%) occurred from falls
      from height or same level, thereby, constituting the commonest mechanism of
      injuries that lead to death in the elderly. In children, the commonest mechanism
      of injuries leading to death was poisoning. The yearly incidence of these deaths
      is decreasing with the peak of 26.5% in 1995, and 6.0% in 1999. CONCLUSION:
      Enforceable legislation by government coupled with public education to reduce
      occurrence should be encouraged. Safety at home must be taken very seriously.

PMID- 15018419
TI  - Infectivity of Plasmodium falciparum gametocytes in patients attending rural
      health centres in western Kenya.
AB  - BACKGROUND: Experimentally studying the transmission of the malaria parasite and
      its regulating factors requires availability of human blood donors carrying
      infectious gametocytes. The difficulty of identifying gametocyte carriers from
      the community is often limited due to financial and human resources constraints.
      The available alternative is rural health centres where malaria patients go for
      treatment. In this study, the potential of recruiting volunteers and acquiring
      infectious blood for experimental infections from rural health centers in malaria
      endemic area was examined through routine patient diagnosis. OBJECTIVE: To
      examine the patients presenting at rural health centers for the potential to
      carry sexual stage malaria parasite and test their infectivity to Anopheles
      gambiae mosquitoes. SETTING: Mbita Health Centre, Mbita Town Ship, Suba District,
      western Kenya. METHODOLOGY: Routine survey of all patients attending Mbita Health
      Centre with suspected malaria. Patients were examined for Plasmodium falciparum
      trophozoites and gametocytes. Gametocyte-positive volunteers were recruited for
      their potential to infect Anopheles mosquitoes via membrane feeding. RESULTS:
      Three thousand nine hundred and eighty seven patients were screened between May
      2000 and April 2001. Plasmodium falciparum was the predominant parasite species
      and P. malariae being the only minor species, accounting for 0.9% of malaria
      cases. Clinical malaria varied with age and prevailed throughout the year with a
      slight seasonality. Gametocyte prevalence was low (0.9-6.6%), and gametocyte
      densities were generally very low with a geometric mean of 39 gametocytes per
      microl blood. Children aged > 5 years constituted 67% of all gametocyte carriers.
      Only 22 volunteers with mean gametocytes density of 39.62 per microl blood
      (range: 16-112) were recruited for study of parasite infectiousness to laboratory
      reared mosquitoes. Only two patients infected 1% of 1099 mosquitoes with one or
      two oocysts. CONCLUSION: The low gametocyte densities or other possible host and
      vector related factors regulating infectivity of gametocyte carriers to
      mosquitoes may have caused the poor infections of mosquitoes. This study
      indicates that rural health centers in malaria-endemic areas may not be suitable
      for recruiting infectious gametocyte donors for studies of vector competence.
      They are suitable for passive clinical case surveillance and for evaluation of
      the effects of control measures.

PMID- 15018420
TI  - Leprosy in Nkhotakota District Hospital.
AB  - OBJECTIVE: To study the profile of leprosy cases at Nkhotakota District Hospital
      in Central Region of Malawi. DESIGN: Retrospective cross-sectional study of all
      registered cases of leprosy from records over a nine year period (January 1992 to
      April 2001) SETTING: Nkhotakota District Hospital-Central Region of Malawi.
      RESULTS: In total 526 cases of leprosy were identified from the records. The
      prevalence rates gradually increased from 0.998 per 10,000 cases in 1992 to 3.39
      cases per 10,000 in 1995. There was however a gradual decline of prevalence rates
      from 1997/1998 that had 3.17 cases per 10,000 to 1.3 cases per 10,000 in 2001.
      1996 registered 2.34 cases per 10,000. Fifty seven cases (10.8%) were found with
      children of the age of 14 or below and 469 (89.2%) cases were of adults.
      Paucibacillary leprosy presented with more cases than multibacillary leprosy (p <
      0.0000001). There were 80 (15.2%) cases of multibacillary leprosy compared to 446
      (84.8%) cases of paucibacillary leprosy. In addition more males were affected by
      multibacillary leprosy than females (p < 0.0001) and females were more affected
      by paucibacillary leprosy (p < 0.01) than males. CONCLUSION: The results show
      that paucibacillary leprosy though minor in Malawi can become endemic as
      paucibacillary leprosy is a reflection of leprosy contacts in the population. We
      therefore recommend continued epidemiological surveys of leprosy. Training in
      leprosy detection should be encouraged so that this disease can be totally
      eradicated in Malawi.

PMID- 15018421
TI  - Prevalence and clinical presentation of HIV infection among newly hospitalised
      surgical patients at Muhimbili National Hospital, Dar es Salaam, Tanzania.
AB  - BACKGROUND: In Tanzania information is lacking on the prevalence of HIV infection
      in surgical patients in tertiary care facilities, in whom there are many points
      of special interest. OBJECTIVE: To determine the prevalence of HIV infection and
      associated clinical and demographic features among hospitalised surgical patients
      at Muhimbili National Hospital (MNH). SETTING: Muhimbili National Hospital.
      MATERIALS AND METHODS: Consecutive newly admitted patients were tested for HIV
      antibodies after pre-test counselling. Sera were tested using a dual ELISA
      algorithm. The data were analysed to determine the prevalence of HIV infection
      and relationships of serostatus with clinical and socio-demographic
      characteristics. RESULTS: Of 1,534 patients admitted during the study,
      1,031(67.2%) consented to HIV testing following pre-test counselling. The
      prevalence of AIDS-related clinical features in patients who declined to be HIV
      tested was similar to that of seronegative patients, but significantly lower than
      that of seropositive patients. The overall age-adjusted HIV prevalence was 10.5%
      (95% CI = 9.9-14.0). The highest age-specific HIV prevalence was in the age group
      35-44 years at 27.9%. No one was infected in the age group 0-4 years (n = 111).
      Differences in prevalence between age groups were statistically significant (p <
      0.0001). Patients with granulomatous and suppurative infections had HIV
      prevalence of 28.3%. Twenty of 124 seropositive patients (16.1%) died in hospital
      compared to 58 of 907(6.4%) of seronegative patients (p = 0.0001). CONCLUSION: At
      Muhumbili National Hospital overall HIV prevalence in hospitalised surgical
      patients were 10.5%, compared to an overall national prevalence of 6.7%. Patients
      in the age groups 25 to 34 and 35 to 44 years had HIV seroprevalence of 26.8% and
      27.9% respectively. Patients with infective conditions had the highest HIV
      prevalence. HIV seropositive patients were associated with higher hospital
      mortality than seronegative patients.

PMID- 15018422
TI  - Partner notification in the management of sexually transmitted infections in
      Nairobi, Kenya.
AB  - OBJECTIVE: To assess utilization of partner notification as a tool in prevention
      and control of Sexually transmitted infections in Nairobi City Council clinics.
      DESIGN: A cross-sectional study carried out between April and September 2000.
      SETTING: Nairobi City Council health clinics were stratified into eight
      administrative divisions and a total of 16 out of 54 primary health clinics with
      at least four STIs patients per day were selected. A standard questionnaire was
      administered to every fourth patient with clinical diagnosis of STIs who gave
      consent on exist. Sexual partners referred by index cases during the five day
      period from each clinic were also enrolled into the study. An additional
      questionnaire was administered to HCP who were managing STIs patients and their
      sex partners. RESULTS: Of 407 STIs patients recruited between April and September
      2000, 20.6% were primary and 2% were secondary referrals giving an average
      referral rate of 23%. Respondents with multiple sex partners were less likely to
      refer their partners compared to those who had one partner (17.9% vs 82.1%, p <
      0.005). Counseling of STI patients on the importance of partner referral was more
      effective than issuing referral cards alone (72.8% vs 56.8% % p = < 0.006).
      Barriers to partner notification included partners being out of town (44.6%) fear
      of quarrels and violence from partners (32.5%) and casual partners (15.1%) whose
      sex partners were unknown. CONCLUSION: Counseling and understanding of STIs
      patients on the need to treat all sexual partners is pivotal to the success of
      partner referral.

PMID- 15018423
TI  - Prevalence of rotavirus, adenovirus and astrovirus infection in young children
      with gastroenteritis in Gaborone, Botswana.
AB  - OBJECTIVE: To determine the prevalence of three enteric viruses, namely
      rotavirus, adenovirus and astrovirus, as agents of diarrhoea in and around
      Gaborone, Botswana. DESIGN: The sample were categorised into four groups
      according to the age of the patient: 0-3 months, 4-6 months, 7-12 months and 25
      60 months. Total monthly samples across age groups formed basis for calcultating
      seasonal prevalence of rotavirus infection. SETTING: Stool samples were collected
      from three medical laboratories in Gaborone and one in the town of Mochudi. These
      were collected from children under the age of five years with gastroenteritis.
      SUBJECTS: Stool samples were collected between March 2001 and February 2002 from
      346 children less than five years of age suffering from gastroenteritis. These
      samples had been sent to medical laboratories for microbiological examination.
      METHODS: The samples were screened for rotavirus (RV), adenovirus (Ad) and
      astrovirus (AsV) antigens using commercially available ELISA kits. The Ad
      positive samples were further analysed by commercially available group specific
      Ad type 40/41 Enzyme Immuno Assays (EIA). RESULTS: Shedding of RV was detected in
      9.2%, Ad in 7.8% and AsV in 2.7% of the samples analysed. The enteric Ad (types
      40 and 41) were detected in 2% of the samples and the remaining 5.8% of Ad
      positive samples were non-enteric Ad. An increase of RV was noted in the autumn
      winter season but no seasonal pattern was observed in Ad shedding. Seasonal
      prevalence of AsV could not be determined. The average age of children infected
      with these agents was less than one year. CONCLUSION: The incidence of rotavirus
      infection amongst children in Botswana appears to be relatively low. The
      prevalence rate of adenovirus and astrovirus is similar to other studies in parts
      of Southern Africa. However, continued enteric virus surveillance and
      epidemiology amongst this group is required.

PMID- 15018424
TI  - Enterotoxigenicity and drug sensitivity of staphylococci from children aged five
      years and below with sporadic diarrhoea.
AB  - OBJECTIVE: To investigate the incidence of enterotoxigenic strains of
      staphylococci in children aged five years and below suffering from sporadic
      diarrhoea and their antibiotic susceptibility pattern. DESIGN: Collection of
      stool samples from children with sporadic diarrhoea and laboratory based
      microbiological analysis. SETTING: Microbiology Research Laboratory, Department
      of Veterinary Microbiology and Parasitology, University of Ibadan, Ibadan,
      Nigeria. RESULTS: Out of one thousand seven hundred and sixty one diarhoeic
      faecal specimens collected, one hundred and seven strains of staphylococci were
      isolated as pure culture. Seventy two of these 107 staphylococci were coagulase
      positive S. aureus, 33 strains were S. epidermidis and two strains were S.
      saprophyticus. Sixty one (84.7%) of 72 isolates of S. aureus produced
      enterotoxins. Staphylococcal enterotoxins A was produced singly by 37(60.7%) of
      the toxigenic strain, while 12(19.7%) produced enterotoxin D alone. Two strains
      produced both enterotoxins A and C, six strains produced both enterotoxins A and
      D, one strain produced enterotoxins A, C and D while two strains produced
      enterotoxins A, B, and D. Most strains were resistant to pennicilin, with minimum
      inhibitory concentrations (MIC) within the range of 1-16 microg/ml. CONCLUSION:
      Enterotoxigenic strains of S. aureus were recovered from children aged five years
      and below suffering from sporadic diarhoea. The incidence rate was 3.5% of the
      samples investigated. Results of their antibiogram revealed that chloramphenicol,
      gentamicin, cephalothin and clindamycin would be appropriate for treatment of
      such diarrhoea after the clinical value of the antibiotics in young children has
      been evaluated.

PMID- 15018425
TI  - Congenital syphilis in an immunocompromised neonate: case report.
AB  - Syphilis is a notifiable and preventable disease, congenital syphilis more so.
      Consequently, attention has been recently focused on prenatal diagnosis of foetal
      syphilis by the use of ultrasonography apart from the conventional serologic
      screening. Congenital syphilis has not been reported from the Kingdom of Lesotho.
      We report the case of a 3.0 kg male neonate with florid joint and bone lesions of
      congenital syphilis associated with HIV infection seen at the Queen Elizabeth II
      Hospital, Maseru, Kingdom of Lesotho. Co-existing HIV infection influences the
      clinical manifestation of syphilis, the progression of neurosyphilis and the
      response to standard therapy. The baby had the recommended standard treatment
      with good response and he was followed-up for a period of twelve months with
      serologic screening and radiographic evaluation.

PMID- 15018426
TI  - A national survey of alcohol screening and referral in college health centers.
AB  - To determine the extent and nature of alcohol screening and referral services
      provided by college health centers, the authors conducted a state-stratified,
      random sampling of 25% of 327 4-year accredited US colleges and universities with
      health centers. Of the 249 survey respondents, 32% routinely screened students
      for alcohol use. Urban, public, and large institutions were most likely to screen
      routinely. Only 11.7% of the sample reported they used standardized instruments,
      predominantly the CAGE. The health centers used an average of 3.4 referral
      options, but only 27.5% offered students access to campus programs specifically
      designed for students who are substance abusers. Findings suggest that the
      majority of college health centers are not providing routine alcohol screening
      for students or using standardized screening instruments. In addition, students
      are often referred to services that may be inappropriate or ineffective in
      addressing the needs of college drinkers.

PMID- 15018427
TI  - Colleges respond to student binge drinking: reducing student demand or limiting
      access.
AB  - Administrators at 68% of 4-year colleges nationwide (N = 747) responded to a
      survey concerning the types of programs and policies they used in response to
      students' heavy drinking. Most schools conducted targeted alcohol education and
      invested in institutional prevention efforts; half conducted social norms
      campaigns; a sizeable minority restricted alcohol on campus. Schools that focused
      on demand reduction were less likely to ban alcohol use. One in 3 schools
      received funding for these programs from governmental agencies, and 1 in 5 from
      the alcohol industry. Such schools were more likely to conduct targeted alcohol
      education and social norms programs and were less likely to restrict alcohol use
      on campus or at college events. Colleges may want to reconsider prevention
      initiatives that focus exclusively on demand or supply. They may also want to
      examine the extent to which funding is the driving force shaping the direction of
      their alcohol initiatives.

PMID- 15018428
TI  - Condom use among Latino college students.
AB  - Recent reports indicate that Latinos, the largest racial/ethnic minority group in
      the United States, are disproportionately affected by HIV and AIDS. College
      health professionals, therefore, should understand current sexual behaviors and
      risk factors among Latino youth. The authors assessed students' condom use at
      their most recent sexual encounter by using data from those students who reported
      oral, vaginal, or anal sex during the last 30 days. Fewer than half of recently
      sexually active Latino students had used condoms during their last oral (4.9%),
      vaginal (41.3%), or anal (27.8%) sexual encounter. Predictors of condom use
      varied according to the type of sexual activity. Findings from this exploratory
      study offer current information about condom use and sexual behaviors among
      Latino college students and suggest that prevention interventions and messages
      should be tailored to students' gender and types of sexual activity.

PMID- 15018429
TI  - Transition to university and vigorous physical activity: implications for health
      and psychological well-being.
AB  - The authors investigated vigorous physical activity and psychological well-being
      during transition from high school to first-year university in a sample of 145
      Canadian undergraduates. Participants completed retrospective measures assessing
      vigorous physical activity during their first 2 months at university and their
      last 2 months at high school as well as measures assessing psychological well
      being. According to nationally recommended (US Department of Health and Human
      Services) standards, two thirds (66.2%) of students reported adequate levels of
      vigorous activity in high school, whereas significantly fewer (44.1%) met the
      standard during their first 8 weeks at university. One third of students were
      active in high school but became insufficiently active once at university; 33%
      were active at both times; 23% consistently fell short of recommended levels; and
      only 11% became active once at university. Students who had become insufficiently
      active reported higher levels of fatigue and lower levels of vigor compared with
      those who continued to be active.

PMID- 15018430
TI  - Service learning, social justice, and campus health.
AB  - Healthy campuses are critical so that students can learn and actively participate
      in shaping and maintaining a strong educational environment. This Viewpoint
      describes the commonalities between service learning, social justice, campus
      health, and the goals of Healthy Campus 2010, which was developed from the larger
      Healthy People 2010 objectives proposed by the US Department of Health and Human
      Services. The values, methods, and intended results of service learning are
      closely related to effective health promotion and disease prevention. Service
      learning focuses on personal and civic responsibility, thus providing students
      with opportunities for enhancing individual and community health. Service
      learning also espouses social justice and provides a vehicle for students to
      learn about, reflect on, and address health disparities. The author cites
      research concerning the effect of service learning on students in institutions of
      higher education and their social justice-related behaviors.

PMID- 15018431
TI  - Immunohistochemical evaluation of the c-kit proto-oncogene in sarcomas of the
      uterus: a case series.
AB  - OBJECTIVE: To evaluate the incidence of c-kit expression in uterine sarcomas.
      STUDY DESIGN: Immunohistochemical evaluation for expression of c-kit was
      performed on specimens from 11 patients with pathologically documented uterine
      sarcomas. Histologic subtypes included 5 carcinosarcomas, 3 leiomyosarcomas and 3
      endometrial stromal sarcomas. Histologic sections of formalin-fixed, paraffin
      embedded hysterectomy specimens from patients with uterine sarcomas were
      immunostained with c-kit (CD117) antibody. Overall staining intensity was graded
      as strong, intermediate or weak. RESULTS: In all 11 patients with uterine
      sarcoma, c-kit immunostaining was positive. Four specimens demonstrated stronger
      staining intensity than did the gastrointestinal stromal tumor control. Five
      specimens demonstrated intermediate staining intensity. Two specimens
      demonstrated weak staining intensity. Furthermore, in the carcinosarcoma
      specimens both the epithelial and sarcomatous elements were positive for c-kit
      staining. CONCLUSION: In this case series, c-kit expression was demonstrated in
      all sarcomas of the uterus regardless of histologic type. These results suggest
      that such drugs as imatinib mesylate, which inhibit the c-kit tyrosine kinase,
      should be investigated for these mesenchymal neoplasms.

PMID- 15018432
TI  - Complications of outpatient LLETZ procedures.
AB  - OBJECTIVE: To determine the rates and types of acute complications occurring
      within 14 days of large loop excision of the transformation zone of the cervix.
      STUDY DESIGN: A retrospective chart review was performed for patients who
      underwent a loop excision procedure between July 1999 and July 2001. Extracted
      information included age, parity, ethnicity, indication for the procedure, risk
      factors for cervical intraepithelial neoplasia, histologic classification of the
      specimen, and type and incidence of complications. Length of follow-up was also
      recorded. Statistical analysis was performed utilizing Wilcoxon sum analysis.
      RESULTS: Five hundred fifty-seven charts were re- viewed; 74.8% of the patients
      were < or = 40 years old. Ethnicity was 59% Hispanic. The most common indication
      for loop excision was high grade squamous intraepithelial lesions on a Pap smear.
      Of the patients, 40% used tobacco, and 30% had a sexually transmitted disease.
      The overall complication rate was 9.7%, with a major complication rate of 0.6%
      and minor complication rate of 9.1%. Minor complications included 14 cases of
      abdominal pain and 26 of vaginal bleeding, 7 of which required treatment with
      Monsel solution or placement of Surgicel (Ethicon, Albuquerque, New Mexico).
      There were 6 cases of vaginal discharge and 1 of bladder spasm. Major
      complications included 1 patient with a bowel injury who returned to the
      operating room, 1 who returned to the operating room for hemorrhage and 1 with
      prolonged observation for chest pain. There was no association between age,
      parity, risk factors for cervical dysplasia, indication for procedure or
      pathology of specimen with acute complications. CONCLUSION: Any surgical
      procedure may cause acute complications. While acute complications are not
      frequent with loop excision, the procedure is not entirely risk free.

PMID- 15018433
TI  - Diagnosing and managing thyroid disorders during pregnancy: a survey of
      obstetrician-gynecologists.
AB  - OBJECTIVE: To document the knowledge and clinical practice of obstetrician
      gynecologists regarding their diagnosis and management of thyroid disorders
      during pregnancy. STUDY DESIGN: We surveyed 1,392 practicing obstetrician
      gynecologists about their knowledge and clinical practice of treating thyroid
      disorders during pregnancy; 569 of the surveys were returned. Of those, 441
      respondents treated pregnant women and completed the entire survey. RESULTS: A
      majority of respondents had treated patients for hypothyroidism (88.7%) and
      hyperthyroidism (60.5%) within the previous year. In general, respondents
      appeared to be well versed in the symptoms of hypothyroidism and hyperthyroidism.
      Most respondents correctly predicted the likely results for thyroid-stimulating
      hormone, free thyroxine and total thyroxine for pregnant euthyroid, hyperthyroid
      and hypothyroid women, but about 50% appeared uncertain of the meaning of free
      thyroxine index. A majority (53.1%) of respondents considered their training
      during residency concerning thyroid disorders during pregnancy to be adequate,
      but few (7.5%) considered it to be comprehensive, and the remainder considered it
      barely adequate at best. Self-assessment of training and confidence regarding
      diagnosing and managing thyroid disorders during pregnancy were in concordance (r
      = .462 and r = .464, respectively; P < .001 in both cases). CONCLUSION: Thyroid
      disorders are commonly treated by obstetrician-gynecologists, and in general
      their practices for diagnosis and management conform to accepted practices. A
      sizable minority of responding obstetrician-gynecologists indicated that they
      considered their training to be inadequate and their confidence in diagnosing and
      managing thyroid disorders to be low.

PMID- 15018434
TI  - Vaginal distribution of miconazole nitrate suspension from administration of a
      single vaginal insert.
AB  - OBJECTIVE: To perform a phase IV, open-label study of OVULE (Personal Care
      Products, Skillman, New Jersey) using magnetic resonance imaging (MRI) to
      describe the release, vaginal distribution and retention of a suspension
      containing miconazole nitrate in healthy female volunteers. STUDY DESIGN: Three
      parous and 3 nulligravid women were enrolled. Each subject self-inserted the
      OVULE on the MRI table and remained recumbent after insertion. MRI images were
      obtained every 15 minutes for 1 hour and then at predetermined intervals
      following suspension insertion until the suspension was no longer identified.
      RESULTS: Placement of the OVULE was in the upper vagina in 4 subjects and in the
      lower vagina in 1 subject, and the Ovule was expelled in 1 subject. Average time
      to capsule shell dissolution was 36 minutes. Average time to maximum vaginal
      mucosal coverage by the suspension was 49 minutes. The average time at which the
      suspension was last seen in the vagina was 5 hours and 53 minutes. CONCLUSION:
      MRI can be used to noninvasively quantify the intravaginal spread of a
      therapeutic antifungal agent. Understanding the intravaginal spread of antifungal
      agents may lead to further optimization of antifungal preparations as well as to
      better patient instructions.

PMID- 15018435
TI  - Maternal serum free beta-hCG levels in uncomplicated pregnancies at the 10th-15th
      week of gestation and the development of obstetric complications.
AB  - OBJECTIVE: To determine if free beta-human chorionic gonadotropin (hCG) serum
      levels at the 10th-14th week of gestation were different in groups of women who
      had experienced pregnancy complications. STUDY DESIGN: The obstetric records of
      women who had uncomplicated pregnancies when they consented to donate blood for
      biochemical research purposes early in pregnancy were reviewed. Two hundred
      thirteen of these women had donated blood at the 10th-14th week of gestation. Of
      these, 135 had uneventful pregnancies and delivered at term, 19 delivered before
      37 weeks'gestation, 10 had fetuses small for gestational age, 4 developed
      pregnancy-induced hypertension, 7 developed gestational diabetes, 10 aborted
      spontaneously, 4 had an intrauterine fetal death after 20 weeks' gestation, and
      24 were lost to follow-up. After the clinical groups had been identified, the 213
      maternal serum stored samples were thawed and free beta-hCG measured by enzyme
      linked immunosorbent assay. After normalization of the data, ANOVA was used to
      compare mean gestational age and mean free beta-hCG levels within groups.
      RESULTS: The overall mean gestational age at maternal blood sampling was 12.5
      weeks. All groups had similar gestational ages at blood sampling (P = .18). The
      overall mean free beta-hCG serum level was 18.05 mIU/mL. Only the group of women
      who went on to experience spontaneous abortions had significantly lower free beta
      hCG lev- els (mean, 10.45 mIU/mL; P < .03) CONCLUSION: Our data suggest that of
      the groups with obstetric complications evaluated, only the group of women who
      experienced spontaneous abortions had significantly different serum levels of
      free beta-hCG at the 10th-14th week of gestation.

PMID- 15018436
TI  - Human chorionic gonadotropin for in vitro oocyte maturation: does it improve the
      endometrium or implantation?
AB  - OBJECTIVE: To determine the effect of human chorionic gonadotropin (hCG) priming
      on endometrial receptivity in women with polycystic ovary syndrome undergoing in
      vitro maturation. STUDY DESIGN: The study was a randomized, controlled trial.
      After a withdrawal bleed, on day 8-10 of the cycle, women were randomized to
      receive 10,000 IU hCG or none 36 hours before immature oocyte retrieval. Oocytes
      were matured and fertilized, and up to 3 embryos were transferred. Prior to
      transfer, endometrial thickness, uterine artery pulsatility index and
      subendometrial bloodflow were determined. RESULTS: There was no difference in
      endometrial thickness (10.1 vs. 10.4 mm), uterine artery pulsatility index (2.45
      vs. 2.65) or absent subendometrial bloodflow (23% vs. 18%) between the treatment
      and control groups. Higher numbers of embryos were produced in the treatment
      group (7.0 vs. 3.6), resulting in more pregnancies, although the implantation
      rates (16.7 vs. 16.0%) were similar. CONCLUSION: Preretrieval hCG priming does
      not improve the ultrasound parameters of endometrial receptivity or the
      implantation rate, although more embryos are generated.

PMID- 15018437
TI  - Effect of a shorter clerkship on third-year obstetrics and gynecology final
      examination scores.
AB  - OBJECTIVE: To determine if either a shorter third-year obstetrics and gynecology
      (Ob/Gyn) student clerkship or the semester of rotation results in differences in
      a student's objective or subjective performance. STUDY DESIGN: Five hundred
      twenty-one students from 1995-1998 (8-week clerkship) and 112 students from 1998
      1999 (6 weeks) in their third year of medical school were included. Final
      examination scores, subjective assessments for the Ob/Gyn clerkship, final grades
      and United States Medical Licensure Examination (USMLE) Step 1 scores were
      obtained (first attempts only). Student t tests, chi2 and univariate analysis
      (using USMLE Step 1 scores as a control) were used (P <. 05) to compare the
      Ob/Gyn clerkship scores/grades by both clerkship length and semester of rotation.
      RESULTS: The 8-week and 6-week clerkship mean final examination scores were 69.5
      and 69.7, respectively; the USMLE Step 1 scores were 205.1 and 215.1,
      respectively (P < .001). After univariate analysis, lower examination scores were
      seen for students clerking on the 6-week rotation (P < .001) as well as for those
      clerking in the first semester (first semester, 68.1; second, 71.3; P < .001).
      Based upon these results, the 8-week clerkship scores were calculated to be
      approximately 3.4 points higher than those of the 6-week clerkship, potentially
      lowering the final grades of 15.2% of the 6-week students. No significant
      differences were seen with the comparisons of a student's subjective assessments.
      CONCLUSION: A shorter third-year Ob/Gyn student clerkship appears to lower Ob/Gyn
      final examination scores. Lower examination scores are also seen for students
      with a first-semester clerkship. These lower scores could lead to lower final
      grades.

PMID- 15018438
TI  - Are patch tests useful in plasma cell vulvitis?
AB  - OBJECTIVE: To evaluate eventual contact sensitization in 7 patients with plasma
      cell vulvitis (PCV). STUDY DESIGN: Seven women with PCV underwent patch tests
      with the Italian standard series and with additional batteries of allergens
      (perfumes, preservatives, emulsifiers, medicaments and corticosteroid series).
      RESULTS: One patient experienced a positive reaction t o balsam of Peru and wool
      alcohol. CONCLUSION: Patch testing is not normally necessary in the management of
      PCV. However, when a patient with PCV complains of burning or pruritus after
      application of topical products, patch tests could prove useful.

PMID- 15018439
TI  - Early and midluteal phase blood estradiol levels after ovum pickup and pregnancy
      rates after ICSI cycles.
AB  - OBJECTIVE: To examine whether blood estradiol level tendencies during the late
      follicular and early luteal phases and the 11 days after embryo transfer have any
      association with the outcome of intracytoplasmic sperm injection-embryo transfer
      (ICSI-ET) cycles. STUDY DESIGN: This prospective study involved 38 assisted
      reproductive technology cycles in 35 infertile patients treated with assisted
      reproductive technologies in which blood samples taken on the 4th, 7th, 9th and
      11th days following ET were tested for progesterone, estradiol and hCG levels
      using an enzyme-linked immunoassay. The estradiol blood levels were compared with
      the maximal follicular phase blood estradiol. The data were analyzed using
      Microsoft Excel (Redmond, Washington) and SPSS 10.0 (Chicago, Illinois). The
      chi2, Mann-Whitney U, Wilcoxon and Pearson tests were usedfor statistical
      analysis. RESULTS: Average maximum estradiol blood level, number of oocytes
      produced,fertilization rates and cleavage rates did not show any significant
      difference between pregnant and nonpregnant cycles. The lower the ratios of
      estradiol levels measured on posttransfer days 4, 7 and 9 to the
      maximumfollicular phase level, the lower the probability of pregnancy (P < .01, P
      < .01 and P < .01, respectively). CONCLUSION: The steeper the decline in blood
      estradiol levels (affecting the periimplantation period) following ovum pickup
      relative to the maximum follicular phase estradiol levels, the lower the chance
      of pregnancy in ICSI-ET cycles.

PMID- 15018440
TI  - Quality of life in Brazilian women with endometriosis assessed through a medical
      outcome questionnaire.
AB  - OBJECTIVE: To assess the quality of life in women with pelvic pain associated
      with endometriosis through the 36-item Short Form Health Survey (SF-36). STUDY
      DESIGN: The study was cross-sectional and conducted at a tertiary care center.
      Sixty women diagnosed surgically with endometriosis were interviewed during the
      first half of 2001. RESULTS: In general, a poor quality of life was observed
      among the women interviewed. No correlation was found between the quality of life
      and intensity of pain, use of medications and/or living with a partner. Women
      with moderate or severe endometriosis scored better on the emotional aspects of
      the questionnaire. Among those who exercised regularly, better scores on mental
      health were observed. CONCLUSION: According to the SF-36 questionnaire, this
      cohort study of Brazilian women with endometriosis showed a poor quality of life.

PMID- 15018442
TI  - Endometrial adenocarcinoma within a single horn of a didelphic uterus: a report
      of 2 cases.
AB  - BACKGROUND: Didelphic uterus results from incomplete fusion of the mullerian
      ducts. CASES: In 2 cases, endometrial adenocarcinoma arose in 1 horn of a
      didelphic uterus. CONCLUSION: Clinicians should be aware of mullerian anomalies,
      which may go undetected, resulting in diagnostic delay.

PMID- 15018441
TI  - Intravenous methotrexate for treatment of interstitial pregnancy: a case report.
AB  - BACKGROUND: Ectopic pregnancy is the leading cause of first-trimester maternal
      death, accounting for 9% of pregnancy-related deaths. Interstitial (cornual)
      pregnancies represent 6% of all ectopics but account for a disproportionately
      higher mortality rate. Surgical management has been the treatment of choice for
      interstitial pregnancies. A very limited number of articles pre have explored the
      use of intravenous methotrexate to treat cornual pregnancy as a possible
      conservative first-line therapy in selected, hemodynamically stable patients.
      CASE: A patient with a confirmed interstitial pregnancy was treated with
      intravenous methotrexate. The patient's beta-hCG levels decreased to zero within
      9 weeks. CONCLUSION: Intravenous methotrexate was used successfully in the
      treatment of an interstitial pregnancy without complications.

PMID- 15018444
TI  - Acute urinary retention caused by a uterine leiomyoma: a case report.
AB  - BACKGROUND: Large uterine leiomyomas may cause acute urinary retention from
      bladder outlet obstruction. CASE: A 46-year-old, premenopausal, multiparous woman
      presented to a large, urban, university emergency department, where a diagnosis
      of acute urinary retention from uterine prolapse was made. An indwelling Foley
      catheter was placed. A week later the patient presented to an urogynecologist's
      office for evaluation of the prolapse and urinary retention. Physical examination
      showed an 18-20-week-sized uterus with a posterior lower uterine segment
      leiomyoma displacing the cervix anteriorly, causing bladder outlet obstruction,
      and no evidence of pelvic organ prolapse. The obstruction was relieved by total
      abdominal hysterectomy with bilateral salpingo-oophorectomy. CONCLUSION: A large
      uterine leiomyoma obstructed the bladder neck and presented as urinary retention.

PMID- 15018443
TI  - Birth of healthy neonates after intracytoplasmic injection of ejaculated or
      testicular spermatozoa from men with nonmosaic Klinefelter's syndrome: a report
      of 2 cases.
AB  - BACKGROUND: Klinefelter's syndrome is one of the major causes of azoospermia,
      cryptozoospermia and severe oligozoospermia with either a nonmosaic (47,XXY) or
      mosaic (47,XXY/46,XY) ICSI treatment with cryopreserved testicular spermatozoa
      failed, but after the third attempt, 6 of 8 oocytes injected with cryopreserved
      sperm were fertilized and karyotype. Men with Klinefelter's syndrome generally
      have difficulty having children. CASES: Patient 1 had motile spermatozoa in the
      ejaculate, which were injected into 3 oocytes, resulting in fertilization and
      cleavage. Two good-quality embryos were transferred into his wife's uterine
      cavity. She conceived and, following a normal pregnancy, delivered a healthy
      female infant. Two years later she conceived for the second time with motile
      spermatozoa in the ejaculate and delivered a healthy male infant uneventfully. To
      our knowledge, this was the first case in which a nonmosaic Kleinefelter's
      syndrome patient fathered 2 children through intracytoplasmic sperm injection
      (ICSI) using motile spermatozoa in the ejaculate. Patient 2, with azoospermia,
      was subjected to testicular biopsy to collect spermatozoa. The first 2 attempts
      at ICSI treatment with cryopreserved testicular spermatozoa failed, but after the
      third attempt, 6 of 8 oocytes injected with cryopreserved sperm were fertilized
      and cleaved. Two of these embryos were transferred into the wife's uterine
      cavity. She conceived and, following a normal pregnancy, delivered a healthy male
      infant. In all cases, amniocentesis followed by genetic analysis showed a normal
      karyotype. CONCLUSION: Two infertile men with nonmosaic Klinefelter's syndrome
      successfully fathered normal children after intracytoplasmic injection of
      ejaculated or testicular spermatozoa.

PMID- 15018445
TI  - Fine needle aspiration of the gestational sac for termination of early pregnancy
      in cervical stenosis: a case report.
AB  - BACKGROUND: First-trimester abortion in women with cervical stenosis results in
      difficult or impossible suction curettage. We present the case of an early
      pregnancy in a woman with cervical stenosis after cone biopsy in which the
      pregnancy was terminated by transvaginal needle aspiration of the gestational sac
      under echographic guidance. CASE: A 31-year-old woman, gravida 6, para 3, abortus
      2, with a history of grade 3 cervical intraepithelial neoplasia after cervical
      conization, presented at 6 weeks' gestation and requested pregnancy termination.
      A cervical examination disclosed that the cervix was difficult to outline and
      that the external os could not be identified. Under the guidance of endovaginal
      sonography, a 16-gauge needle was introduced into the gestational sac through the
      anterior portion of the vagina. Intracardiac injection of potassium chloride was
      first attempted to stop fetal cardiac activity. The sac tissue was then
      aspirated, followed by repeated normal saline irrigation. The patient's
      postoperative course was smooth and was monitored in the outpatient department.
      CONCLUSION: For termination of early pregnancy complicated by cervical stenosis,
      whether due to blighted ovum, intrauterine fetal death or elective abortion,
      needle aspiration under the guidance of transvaginal sonography is safe and
      effective.

PMID- 15018446
TI  - Single umbilical artery and associated hydronephrosis: a report of 2 cases.
AB  - BACKGROUND: A single umbilical artery (SUA) in a fetus may be associated with
      hydronephrosis. CASES: We describe 2 cases of SUA, one of which had severe
      hydronephrosis with ascites and was stillborn. The other case was born alive with
      a unilateral hydroureter and is being managed with close monitoring. CONCLUSION:
      Detection of SUA on antenatal ultrasound should prompt a careful search for
      urinary tract abnormalities, as associated severe hydronephrosis may lead to a
      poor outcome.

PMID- 15018447
TI  - Pediatric celiac disease: clinicopathologic and genetic aspects.
AB  - Evaluation for celiac disease (CD), an autoimmune enteropathy triggered by grain
      proteins in wheat, barley, rye, and possibly oats, is a common indication for
      pediatric endoscopy and biopsy. Duodenal or jejunal biopsy remains key for the
      initial diagnosis of CD. Small intestinal pathology may be diffuse or focal in
      CD, and histologic findings are nonspecific and must be interpreted in
      conjunction with clinical and serologic findings. A standardized grading system
      for CD biopsies is recommended. This review article summarizes the epidemiology,
      clinical manifestations, genetics, pathogenesis, and serologic and histologic
      findings of CD. Clinical management of CD and general handling of small
      intestinal biopsies are also addressed.

PMID- 15018448
TI  - Amniotic sac infection syndrome features fetal lung neuroendocrine cell
      hyperfunction.
AB  - Neuroendocrine cells (NEC) are abundant in fetal and neonatal lungs, but reduced
      in infants with hyaline membrane disease. Perinatal neuroendocrine cell
      hyperplasia (NCH) has been reported in the hypoplastic lung in diaphragmatic
      hernia, bronchopulmonary dysplasia, and Wilson-Mikity syndrome. Since we are
      unaware of any reports on NCH in fetal inflammatory conditions, this report
      addresses the NEC in fetuses with congenital pneumonia. Twenty-one
      fetuses/neonates with congenital pneumonia, autopsied between 1995 and 2001, were
      compared to 21 fetuses without a congenital infection matched for gestational
      age. Lung sections were immunostained for chromogranin, bombesin, calcitonin, and
      synaptophysin. Proportions of immunopositive cells lining 20 consecutive
      bronchioles calculated from digital images were significantly higher in the study
      than the control group for chromogranin (1.8 vs. 0.8%, P = 2.4 E-06), calcitonin
      (1.2 vs. 0.7%, P = 0.005), and bombesin (1.1 vs. 0.7%, P = 0.005). There was no
      difference in synaptophysin (11.7% vs. 12.6%, P = 0.07). The absence of
      significant differences in the synaptophysin ratio excludes simple NCH in the
      study group. The synchronous increase in three neurohormones is indicative of NEC
      hyperfunction, due to either altered enzymatic inactivation by neutral
      endopeptidase, known to be reduced in adult lung inflammation, or by an increase
      in expression of the neurohormone genes. These data indicate that NEC
      hyperfunction may be responsible for the deranged fetal/neonatal lung function
      and circulatory adaptation, and contribute to the lethality of the amniotic sac
      infection syndrome.

PMID- 15018449
TI  - Rapidly involuting congenital hemangioma: clinical and histopathologic features.
AB  - We define the histopathologic findings and review the clinical and radiologic
      characteristics of rapidly involuting congenital hemangioma (RICH). The features
      of RICH are compared to the equally uncommon noninvoluting congenital hemangioma
      (NICH) and common infantile hemangioma. RICH and NICH had many similarities, such
      as appearance, location, size, and sex distribution. The obvious differences in
      behavior served to differentiate RICH, NICH, and common infantile hemangioma.
      Magnetic resonance imaging (MRI) of the three tumors is quite similar, but some
      RICH also had areas of inhomogeneity and larger flow voids on MRI and arterial
      aneurysms on angiography. The histologic appearance of RICH differed from NICH
      and common infantile hemangioma, but some overlap was noted among the three
      lesions. RICH was composed of small-to-large lobules of capillaries with
      moderately plump endothelial cells and pericytes; the lobules were surrounded by
      abundant fibrous tissue. One-half of the specimens had a central involuting
      zone(s) characterized by lobular loss, fibrous tissue, and draining channels that
      were often large and abnormal. Ancillary features commonly found were
      hemosiderin, thrombosis, cyst formation, focal calcification, and extramedullary
      hematopoiesis. With one exception, endothelial cells in RICH (as in NICH) did not
      express glucose transporter-1 protein, as does common infantile hemangioma. One
      RICH exhibited 50% postnatal involution during the 1st year, stopped regressing,
      was resected at 18 months, and was histologically indistinguishable from NICH. In
      addition, several RICH, resected in early infancy, also had some histologic
      features suggestive of NICH. Furthermore, NICH removed early (2-4 years), showed
      some histologic findings of RICH or were indistinguishable from RICH. We conclude
      that RICH, NICH, and common infantile hemangioma have overlapping clinical and
      pathologic features. These observations support the hypothesis that these
      vascular tumors may be variations of a single entity ab initio. It is unknown
      whether the progenitor cell for these uncommon congenital vascular tumors is the
      same as for common infantile hemangioma.

PMID- 15018450
TI  - Expression of glial cell line-derived neurotrophic factor and neurturin in mature
      kidney, nephrogenic rests, and nephroblastoma: possible role as differentiating
      factors.
AB  - Kidney development involves a series of complex interactions between the ureteric
      bud and undifferentiated mesenchyme, resulting in the production of the nephron
      unit. Among locally derived soluble factors, a particular relevance has been
      recognized to glial cell line-derived neurotrophic factor (GDNF) and neurturin
      (NTN) for the mesenchyme-to-epithelial conversion of a metanephron.
      Nephroblastoma is a developmental tumor of the kidney deriving from metanephric
      blastema that mimics renal development and may offer an adequate model of human
      nephrogenesis. We investigated the immunohistochemical expression of GDNF, NTN,
      and their receptors (GFRalpha1, 2, and 3, and Ret) in normal human kidney and in
      42 nephroblastomas, 20 of which were associated with nephrogenic rests (group A)
      and 22 were not (group B). We compared the immunostaining pattern in group A vs.
      group B and correlated clinical course with stage, grade, presence of nephrogenic
      rests, and immunohistochemical findings. GDNF, NTN, and their receptors were
      expressed in mature kidney and in 67% (GDNF) and 33% (NTN) of tumors,
      particularly in the epithelial component; precursor lesions were negative. No
      significant differences of expression were observed between groups A and B
      tumors. Low stage (P = 0.012), absence of nephrogenic rests (P = 0.016), intense
      expression of GDNF (P = 0.034), and NTN (P = 0.05) were associated with a more
      favorable outcome. Besides inductive activity in nephrogenesis, GDNF and NTN may
      play a role in maintaining differentiation and survival functions in mature
      kidney and may contribute to induce differentiation of nephroblastoma cells
      toward the less aggressive epithelial component. The pathway of activation seems
      to follow an autocrine/paracrine mechanism, as neurotrophic factors, GFRalpha1-2
      3 receptors and Ret are coexpressed.

PMID- 15018451
TI  - Malformations in acardiac twins are consistent with reversed blood flow: liver as
      a clue to their pathogenesis.
AB  - Because of the uncertainty concerning the origin of the malformations in the
      acardiac twin, its structure was studied to see if the malformations were random
      or with a pattern related to the twinning process. Included were 18 cases of
      dysmorphic twins in which an autopsy demonstrated a rudimentary or absent heart,
      and in which some polarity was evident. The organs and long bones with
      alterations were tabulated according to the embryonal-fetal circulation of blood
      from and to the placenta. Malformations were more often encountered in the
      superior limbs and organs; the number of altered organs decreased in a cranio
      caudal direction. The liver was the exception being affected in 89% of the cases
      vs. an average of 54% for the other abdominal organs. As the liver lies first in
      the circulatory path from the placenta to the fetus, the pattern of the
      malformations was in accordance with the "twin reversed arterial perfusion
      sequence" (TRAP). The more frequent absence of distal bones (P = 0.0007) is
      compatible with reduced perfusion in each limb. The malformations found in the
      acardiac twins involved brain, esophagus and trachea, liver, other abdominal
      organs, diaphragm, vertebrae, limbs, anus, and omphalocele; vascular disruption
      may be the common pathogenesis for the acardiac twins as well as other dysmorphic
      infants with similar anomalies.

PMID- 15018452
TI  - Dermoid cysts of the tongue: report of five cases and review of the literature.
AB  - Dermoid cysts of the tongue are uncommon. To date, there have been nine reported
      cases in the English language literature. In this article, we describe five cases
      accessioned at our institution over a 12-year period, two of which have
      previously been reported. The prevalence of dermoid cysts at our institution over
      this period was quite low. Of 324,042 surgical cases, 0.24% (765 cases) were
      dermoid cysts. Of these, five were from the tongue, representing only 0.7% of the
      dermoid cysts accessioned and 0.0015% of the total surgical specimens. The
      literature is reviewed and the possible origin of these lesions is discussed.

PMID- 15018453
TI  - Lung pathology in patients with congenital diaphragmatic hernia treated with
      fetal surgical intervention, including tracheal occlusion.
AB  - Fetal intervention for congenital diaphragmatic hernia was developed to lessen
      the high morbidity and mortality of pulmonary hypoplasia. Lung pathology and
      morphometry in patients treated with fetal intervention have not been described.
      We report clinical and autopsy findings, as well as basic lung morphometry in 16
      cases of congenital diaphragmatic hernia with fetal intervention (12 cases
      tracheal occlusion; 4 cases hernia repair), and 19 cases of congenital
      diaphragmatic hernia without fetal intervention. All patients who underwent fetal
      intervention were born premature. Lung enlargement with increased lung-to-body
      weight ratio was observed with fetal tracheal occlusion, accompanied by lower
      than normal radial alveolar counts and increased alveolar size. Patients treated
      with tracheal occlusion also had early alveolar development (at 29.8, 30.6, and
      30.9 wk postconceptual age) as well as mucous fluid pooling in airways and
      alveoli. All cases showed severe alveolar septal widening, more extensive in
      patients without fetal intervention. When grouped by postconceptual age, no
      statistically significant difference was found between patients with and without
      fetal intervention with respect to lung-to-body weight ratio, radial alveolar
      count, mean alveolar length, and relative arteriolar media thickness. Lung
      enlargement has been observed with fetal tracheal occlusion sonographically; our
      studies suggest that this is due in part to emphysema and mucous fluid pooling.
      The lung remains abnormal with low radial alveolar counts and increased alveolar
      size. Tracheal occlusion did not prevent development of lung pathology associated
      with pulmonary hypoplasia.

PMID- 15018455
TI  - Concurrent infantile hemangioendothelioma and mesenchymal hamartoma in a
      developmentally arrested liver of an infant requiring hepatic transplantation.
AB  - A newborn female underwent a surgical resection for a hepatic mass discovered
      prenatally by ultrasonography, and diagnosed pathologically as a mesenchymal
      hamartoma. Within 4 months after surgery, multiple cutaneous hemangiomas
      developed and a multinodular mass was detected in the liver. A liver biopsy
      showed an infantile hemangioendothelioma with type I features. An orthotopic
      liver transplant was performed due to the extensive nature of the hepatic
      involvement and progressive respiratory compromise. Virtually the entire liver
      was involved by a large infantile hemangioendothelioma. A multicystic mesenchymal
      hamartoma was also found on the left side. In addition, the uninvolved hepatic
      parenchyma had features recapitulating the fetal liver. This simultaneous
      involvement of the liver by a mesenchymal hamartoma and infantile
      hemangioendothelioma is unique. A review of the literature revealed only one
      incompletely characterized case with similar findings.

PMID- 15018454
TI  - Quercetin, an over-the-counter supplement, causes neuroblastoma-like elevation of
      plasma homovanillic acid.
AB  - A 22-month-old boy, who regularly consumed the oral dietary supplement,
      quercetin, was suspected erroneously of having a catecholamine-producing tumor,
      based on elevated serum and urine levels of the dopamine metabolite, homovanillic
      acid (HVA). Subsequent studies of healthy adult volunteers showed that
      significant elevations in plasma HVA are a consequence of quercetin ingestion.

PMID- 15018456
TI  - Acute lymphoblastic leukemia with hypereosinophilia: report of a case with 5q
      deletion and review of the literature.
AB  - Peripheral blood eosinophilia as a presentation of acute lymphoblastic leukemia
      (ALL) has only rarely been reported. The eosinophilia is thought to be a
      nonneoplastic reaction to the neoplastic lymphoblasts. We present the case of a 5
      year-old girl who developed peripheral hypereosinophilia with no circulating
      blasts prior to her diagnosis of B-cell lineage ALL. Cytogenetic study showed a
      hyperdiploid blast population with 5q deletion. Persistent peripheral
      hypereosinophilia should always be fully investigated, the possibility of a
      malignancy including ALL needs to be excluded, even in the absence of peripheral
      cytopenias and circulating blasts.

PMID- 15018457
TI  - Well-differentiated fetal adenocarcinoma: rare tumor in the pediatric population.
AB  - Well-differentiated fetal adenocarcinoma (WDFA) is a rare tumor of the lung,
      which has gone by many names over the years. The lesion was first described by
      Kradin et al., in 1982, who called it "pulmonary blastoma with argyrophil cells
      and lacking sarcomatous features (pulmonary endodermal tumor resembling fetal
      lung)." Since then, there have been at least 65 cases reported in the literature.
      Although there has been no consensus in the literature as to the best
      pathological term for this entity, the most recent World Health Organization
      classification of lung and pleural tumors uses the term well-differentiated fetal
      adenocarcinoma. Characteristically, this lesion consists of an epithelium, which
      recapitulates fetal lung at 3-5 months of gestation and demonstrates
      neuroendocrine differentiation. Although the classic age range is 30-40 years,
      there have been seven reports of WDFA in the pediatric age. We report an
      additional pediatric case of this tumor and review the pediatric cases in the
      existing literature.

PMID- 15018458
TI  - Renal tubular dysgenesis in an hydropic fetus with trisomy 21: a case report with
      literature review.
AB  - Renal tubular dysgenesis (RTD) is a rare form of noncystic renal disease
      characterized by paucity or absence of proximal renal tubules. Always lethal in
      the perinatal period, it has been associated with Potter sequence and with other
      congenital malformations. An autosomal recessive inheritance has been suggested.
      We present a case of renal tubular dysgenesis associated with fetal hydrops and
      trisomy 21, with a review of relevant literature.

PMID- 15018460
TI  - Chronic granulomatous disease.

PMID- 15018459
TI  - Molecular basis of the brain tumor-polyposis (Turcot) syndrome.

PMID- 15018461
TI  - Fatal cardiac failure in a 7-month-old child.

PMID- 15018463
TI  - Massive perivillous histiocytosis in twins.

PMID- 15018462
TI  - Genetic basis of congenital nephrotic syndrome.
AB  - A young girl presented at 1 month of age with nephrotic syndrome. By
      incorporating clinical and pathologic data, the diagnosis of congenital nephrotic
      syndrome, Finnish type, was made. The differential diagnosis of early onset
      nephrotic syndrome, as it pertains to this patient is discussed. This article
      highlights recently discovered glomerular filtration proteins and their
      relationship to the pathophysiology of inherited kidney disease.

PMID- 15018464
TI  - Features described and illustrated in 1684 suggesting Meckel-Gruber syndrome.
AB  - In 1684, Mr. Christopher Krahe described a monstrous child, born in Denmark on
      Friday, February 29, 1684. The description is suggestive of a diagnosis of Meckel
      Gruber syndrome (dysencephalia splanchnocystica). This may represent the oldest
      description and illustration of the syndrome, of which the first detailed
      description is attributed to Johann Friedrich der Jungere in 1822.

PMID- 15018465
TI  - Introductory remarks. Focus on hospital-acquired infections in Italy.

PMID- 15018466
TI  - Hospital infection control in Italy.
AB  - In 1998, the National Health Plan identified the reduction of hospital infection
      (HI) incidence as a priority. This article reviews the main activities set up in
      Italy on infection control in the hospital setting. In 1983, the first national
      prevalence survey reported 6.8% and 7.6% prevalence rates of patients with HI and
      of HIs, respectively. The high point prevalence found in the intensive care units
      (ICU) (12.5%), prompted a national incidence study in 1985. This study found an
      incidence of 29.5 HIs per 100 patients in the ICUs: lower respiratory tract
      infections (LRTI) were the most common HIs (47.8%), followed by urinary tract
      infections (UTI) (19.9%) and blood stream infections (BSI) (4.8%). A 1999 survey
      showed that in 463 Italian hospitals only 40.5% had protocols on the use of
      disinfectants, 32.3% on sterilization, 30.8% on occupational risk management,
      18.3% on isolation measures, 17.7% on hand-washing, 14.3% on antibiotic
      prophylaxis in surgery, 9.4% on the prevention of surgical site infections and
      8.5% on the management of CVC. A national forum to consider surveillance systems
      using standardized definitions and methodologies is urgently needed.

PMID- 15018467
TI  - Prevalence of nosocomial infections in 15 Italian hospitals: first point
      prevalance study for the INF-NOS project.
AB  - BACKGROUND: The aim of our study was to assess the magnitude of nosocomial
      infections (NI) in 15 Italian hospitals. PATIENTS AND METHODS: A multicenter
      point prevalence study of NI was carried out in October 2001 among eight medical,
      surgical and intensive care units in hospitals with more than 400 beds, after a
      pilot phase performed in April 2001. RESULTS: Of the 2,165 surveyed patients, 163
      had a total of 179 NIs. The global prevalence rate of patients with NI and of NI
      was respectively 7.5% (95% CI 6.4-8.6) and 8.3% (95% CI 7.1-9.4), ranging from
      5.5% (95% CI 4.2-6.8) in medical wards to 34.2% (95% CI 25.7-42.7) in intensive
      care units (ICUs). The NI prevalence was higher in: hospitals that did not have
      an infection control committee (ICC) compared to hospitals with an ICC (10.3%,
      95% CI 6.4-10.1 versus 7.2, 95% CI 6.0-8.3, p = 0.08); university hospitals
      compared with non-teaching hospitals (9.4%, 95% CI 4.5-14.2 versus 7.4%, 95% CI
      6.3-8.5, p = 0.4) and; hospitals with 1,000 or more beds compared to lower volume
      hospitals (9.5%, 95% CI 7.3-11.7 versus 6.6%, 95% CI 5.3-7.8, p = 0.02). The most
      prevalent infections found were lower respiratory tract infections, urinary tract
      infections and surgical-site infections, representing 38.0%, 20.1% and 12.8%,
      respectively, of all NI. Among 1,674 patients without any infection, 575 (34.3%)
      of them had been undergoing antibiotic treatment at the time of the survey.
      CONCLUSION: The high rate of NI, particularly in ICUs, and the high number of
      improper procedures emphasize the need to develop clinically-oriented guidelines,
      tailor active infection control programs and implement an active ICU surveillance
      system.

PMID- 15018468
TI  - Prevalence and patterns of antibiotic prescribing in Italian hospitals.
AB  - Use of antimicrobial drugs is associated with the emergence of resistant
      bacteria, increasing hospital expenditures and requires an assessment of
      appropriateness. The aim of this study was to investigate prevalence and patterns
      of antibiotic prescribing and expenditures in Italian hospitals. A prevalence
      survey was performed in 15 Italian hospitals. Data on antimicrobial use and
      expenditures in the year 2000 and 1-day point prevalence information on
      antibiotic prescription, type and sources of infections and expenditures were
      obtained through a review of pharmacy records and charts of 2,165 inpatients.
      45.5% of the patients surveyed were receiving at least one antibiotic: 148 for
      hospital-acquired infections (HAI), 262 for community-acquired infections (CAI).
      No active infection was recorded for 575 patients (58.4%). 57.3% of prescriptions
      for HAI and 65.9% for CAI were based on empiric and presumptive criteria, while
      39% of HAI and 15.8% of CAI were oriented by microbiology and susceptibility
      testing results. Guidelines were followed in choosing the antimicrobial drugs for
      22.8% of therapeutic and 46.8% of prophylactic courses. High rates of antibiotic
      usage were observed in Italian hospitals. Areas for improvement, both for the use
      of diagnostic resources and the prescribing habits, were identified. The 1-day
      prevalence survey of antimicrobial use may be a tool of feedback to prescribers
      for more appropriate drug selection.

PMID- 15018469
TI  - Risk of hepatitis C virus transmission following percutaneous exposure in
      healthcare workers.
AB  - BACKGROUND: We wanted to determine the incidence of anti-hepatitis C virus (HCV)
      seroconversion after percutaneous exposure to infectious fluids of an anti-HCV
      positive source in healthcare workers (HCW) and to investigate related risk
      factors. PATIENTS AND METHODS: Prospective observation in 55 Italian hospitals of
      anti-HCV-negative exposed HCW were followed clinically and serologically for at
      least 6 months. RESULTS: Of 4,403 exposed HCW, 14 seroconverted (0.31%; 95% CI
      0.15-0.48) after an injury with a hollow-bore, blood-filled needle
      (14/1,876=0.74%; 95% CI 0.41-1.25). Deep injuries increased the seroconversion
      risk (OR 6.53; 95% CI 2.01-20.80). Exposure to an HIV co-infected source was
      associated with an higher, though not yet statistically significant, risk (OR
      2.76, 95% CI 0.49-10.77). Source's HCV viremia was available in 674 cases, 566 of
      whom tested positive, including the nine seroconversion cases for whom this
      information was available. CONCLUSION: The risk of acquiring HCV after
      percutaneous exposure seems to be lower than previously reported. Deep injury,
      injury with a blood-filled needle and HIV co-infection of source seem to be
      associated with occupational transmission. Needlestick prevention devices could
      decrease the risk of infection with HCV and other bloodborne pathogens in HCW.

PMID- 15018470
TI  - Nosocomial infections in HIV-positive patients: an overview.
AB  - Nosocomial infections (NIs) constitute a significant public health problem and
      contribute to prolonged hospitalization, additional healthcare costs and excess
      morbidity and mortality. NIs appear to be more common in patients with acquired
      immunodeficiency syndrome (AIDS) as a result of some degree of immunosuppression,
      prior antiobiotics treatment and greater exposure to invasive devices such as
      indwelling intravenous catheters. The objective of this article is to give an
      insight into the main NIs occurring in HIV-infected patients. Literature
      pertaining to NIs in HIV-infected patients was reviewed. According to the leading
      studies in the literature, the incidence of NI ranges from 7.9 to 15 per 100
      admissions. Bloodstream infections are the most frequent infections, mainly due
      to intravascular catheters, followed by urinary and respiratory tract infections.
      Colonization seems to have an important role in the development of NIs among this
      immunocompromised population. CLinicians need to be aware of the risk of NIs in
      HIV-infected patients, and must always take these infections into account in
      their overall management.

PMID- 15018471
TI  - The impact of nosocomial infections on hospital care costs.
AB  - Estimating costs due to nosocomial infection (NI) requires the incremental costs
      associated with NI diagnosis and treatment must be distinguished from those
      attributable to the management of the original healthcare problems. We carried
      out a review of the analyses of additional costs resulting from NIs and the
      evaluation of the methods used to estimate these costs, in order to perform a
      cost benefit analysis of NI prevention activities. Characteristics of additional
      costs for main NIs were initially considered. Secondly, a review of methods for
      estimating the incremental costs was performed. Finally, a cost effectiveness
      analysis of NI prevention activities was performed. Few studies estimated the
      incidence of NLs and assessed the economic burden they cause. Investigators
      generally estimated only direct additional costs. Implicit physician assessment,
      unmatched group comparison, matched control and appropriateness evaluation
      protocol (AEP)-based methods are the methodologies used to estimate incremental
      days of stay due to NIs. Different studies show possible benefits, in terms of
      health and cost savings, when hospital-acquired infections are prevented.
      However, there is a need for further studies to evaluate in greater detail the
      variables related to costs attributable to these infections and to enhance the
      control strategies. Moreover, a structured surveillance and control program of NI
      is the single most effective tool for prevention.

PMID- 15018472
TI  - Benchmarking for prevention: the Centers for Disease Control and Prevention's
      National Nosocomial Infections Surveillance (NNIS) system experience.
AB  - Healthcare-associated infections are a major cause of morbidity and mortality at
      hospitals in the United States. Surveillance of these infections identifies
      secular trends and provides data upon which prevention interventions can be based
      in order to improve patient safety. National surveillance of healthcare
      associated infections was initiated in the United States in 1970. Since that
      time, the Centers for Disease Control and Prevention's (CDC) National Nosocomial
      Infections Surveillance (NNIS) system has provided standardized methods for
      collecting and comparing healthcare-associated infection rates and the national
      benchmark infection rate data for inter- and intra-hospital comparisons. The
      surveillance methods used and results of the implementation of these methods are
      reviewed. The number of hospitals participating in the CDC's national
      surveillance of healthcare-associated infections has grown from approximately ten
      to 20 hospitals in 1970 to over 300 hospitals in 2002. Over the years, NNIS
      system participants have used standardized definitions, standardized surveillance
      component protocols, risk stratification for calculation of infection rates and
      provided national benchmark infection rates for inter- and intra-hospital
      comparisons. These methods have resulted in a significant reduction in
      bloodstream infections, urinary tract infections and pneumonia in intensive care
      unit (ICU) patients and surgical site infections in surgical patients. The NNIS
      data show that national surveillance of healthcare-associated infections combined
      with an intervention prevention program can reduce infection rates, reduce
      morbidity and mortality and improve patient safety. Establishment of such
      healthcare-associated infection surveillance and prevention systems in countries
      throughout the world should be a priority.

PMID- 15018473
TI  - Changing perspectives in the nutritional management of disease.
AB  - There have been substantial changes in the nutritional management of many
      diseases in the last 20 years, which have been accompanied by a growing
      recognition of its importance. Many of the changes in clinical nutrition have
      been associated with the introduction of standards, clinical audit and the
      implementation of evidence-based practice, which has led to a re-evaluation of
      some established dietary interventions using a hierarchy-of-evidence approach.
      Although there are few randomised controlled trials on which to base such work,
      the examination of other, often less-robust, evidence has led to some traditional
      dietary interventions being modified. Examples in gastroenterology include the
      use of low-fat diets in gall bladder disease and the restriction of protein in
      hepatic encephalopathy, where the current evidence suggests that neither should
      be used routinely in clinical practice. Where therapeutic dietary restrictions
      are required, as with low-Na diets in ascites, there is very little information
      on how these restrictions influence total nutrient intake and, if intake is
      impaired, how the detrimental effects of an inadequate intake should be balanced
      with the therapeutic effects of restriction. Studies are required to ensure that
      nutritional interventions are not only effective but also free from undesirable
      side effects. The mode and timing of the delivery of nutritional support has also
      been re-evaluated and the benefits of early enteral feeding have been recognised.
      The delivery of dietary advice is a new area that is being considered, with
      practitioners in clinical nutrition using behaviour-change skills to facilitate
      optimum nutrition rather than simply providing patients with advice. For such
      developments to continue in clinical nutrition it is essential that all practice
      should be systematically evaluated and, where necessary, modified in the light of
      sound current research findings, and that gaps in our present knowledge base are
      identified and addressed.

PMID- 15018474
TI  - Searching the evidence: the clinically-effective nutritionist.
AB  - As a clinically-effective nutritionist faced with needing to find the answer to a
      clinical question quickly it is necessary to search the best evidence
      efficiently. The requirements are to: (1) avoid having lots of papers to read;
      (2) be able to access this information at one's place of work; (3) restrict
      reading to trials and systematic reviews of trials. If a decision has to be made
      while on the ward, the best resource is probably an easy-to-use book, Clinical
      Evidence. This resource is also available on-line, but there may not be access to
      the Internet on the ward. If a little more time is available, and access to the
      Internet, the following plan is suggested: (1) work out what the question is and
      highlight the search terms; (2) using the best search engine available, search
      MEDLiNE from 1990 for titles and abstracts of papers containing the search terms,
      this is the search strategy (limit the search by publication type by requesting
      randomised controlled trials only, English language only and human only); (3) if
      more or less than approximately ten hits are obtained, alter the limits of the
      search (not the search strategy); (4) read the abstract, or full paper where
      available, of the relevant hits and appraise this evidence.

PMID- 15018475
TI  - Nutritional demands in acute and chronic illness.
AB  - Common to both acute and chronic disease are disturbances in energy homeostasis,
      which are evidenced by quantitative and qualitative changes in dietary intake and
      increased energy expenditure. Negative energy balance results in loss of fat and
      lean tissue. The management of patients with metabolically-active disease appears
      to be simple; it would involve the provision of sufficient energy to promote
      tissue accretion. However, two fundamental issues serve to prevent nutritional
      demands in disease being met. The determination of appropriate energy
      requirements relies on predictive formulae. While equations have been developed
      for critically-ill populations, accurate energy prescribing in the acute setting
      is uncommon. Only 25-32% of the patients have energy intakes within 10% of their
      requirements. Clearly, the variation in energy expenditure has led to
      difficulties in accurately defining the energy needs of the individual. Second,
      the acute inflammatory response initiated by the host can have profound effects
      on ingestive behaviour, but this area is poorly understood by practising
      clinicians. For example, nutritional targets have been set for specific disease
      states, i.e. pancreatitis 105-147 kJ (25-35 kcal)/kg; chronic liver disease 147
      168 kJ (35-40 kcal)/kg, but given the alterations in gut physiology that
      accompany the acute-phase response, targets are unlikely to be met. In cancer
      cachexia attenuation of the inflammatory response using eicosapentaenoic acid
      results in improved nutritional intake and status. This strategy poses an
      attractive proposition in the quest to define nutritional support as a clinically
      effective treatment modality in other disorders.

PMID- 15018476
TI  - Nutritional modulation as part of the integrated management of chronic
      obstructive pulmonary disease.
AB  - Weight loss is a frequent complication in patients with chronic obstructive
      pulmonary disease (COPD) and is a determining factor for functional capacity,
      health status and mortality. Weight loss in COPD is a consequence of an inbalance
      between increased energy requirements and dietary intake. Both metabolic and
      mechanical inefficiency may contribute to elevated energy expenditure during
      physical activity, while systemic inflammation has been associated with
      hypermetabolism at rest. Disease-specific symptoms and systemic inflammation may
      impair appetite and dietary intake. Altered intermediary metabolism may cause
      disproportionate wasting of fat-free mass in some patients. A combination of
      nutritional support and exercise as an anabolic stimulus appears to be the best
      approach to obtaining marked functional improvement. Patients responding to this
      treatment even demonstrated a decreased mortality. The effectiveness of anti
      catabolic modulation requires further investigation.

PMID- 15018477
TI  - Can nutrition counselling be more behavioural? Lessons learned from dietary
      management of cystic fibrosis.
AB  - Cystic fibrosis (CF) is a genetically-inherited disorder that results in energy
      imbalance. Undernutrition is common in children with CF and associated with poor
      health outcomes. To ensure optimal growth and nutrition, children with CF are
      recommended to consume 120-150% of the recommended daily allowance (RDA) for
      energy, but most studies show they typically are only able to achieve 100% of the
      RDA. While biological factors clearly contribute to poor dietary adherence,
      recent studies have documented behavioural and environmental barriers to
      adherence that includes parent-child interaction at mealtimes. While not
      'abnormal', parent behaviours such as paying increased attention to the child in
      the form of coaxing, commanding and feeding when the child is engaged in
      behaviours incompatible with eating (food refusal, talking, leaving the meal) may
      serve to reinforce these child non-eating behaviours. Thus, dietary counselling
      alone, albeit necessary, is typically insufficient because of failure to
      specifically address these behavioural and environmental barriers to dietary
      treatment. Behavioural intervention that targets both nutrition education and
      behavioural management has been found to be effective in achieving an average
      increased energy intake of 4200 kJ (1000 kcal)/d and weight gain of 1.48 kg over
      9 weeks in children with CF. This intervention utilizes self-monitoring, goal
      setting and shaping to structure the delivery of treatment. It also teaches
      parents to utilize child behaviour-management techniques to motivate children to
      increase their energy intake. These behavioural strategies include differential
      attention (praising and ignoring), contingency management and behavioural
      contracting. The potential application of these techniques to dietary counselling
      is suggested.

PMID- 15018478
TI  - Oral protein-energy supplements for children with chronic disease: systematic
      review.
AB  - Growth failure and poor nutritional status are features of children with chronic
      disease. Oral protein-energy supplements are one of a number of interventions
      provided with the aim of improving nutritional status in these children. The
      present paper describes a Cochrane systematic review assessing the efficacy of
      these products in children with chronic disease. The objective was to examine the
      evidence that in children with chronic disease oral protein-energy supplements
      alter nutrient intake, nutritional indices, survival and quality of life. All
      randomised controlled trials of the use of oral protein-energy supplements in
      children with chronic disease were identified through searching electronic
      databases and hand searching the abstract books of nutrition conferences. Studies
      identified were independently assessed for eligibility and methodological
      quality, and data on outcomes of interest were combined in a meta-analysis where
      possible. Two trials were eligible for inclusion in the review, both of which
      were undertaken with children with cystic fibrosis. No statistical differences
      could be found between treatment and control groups when data from both studies
      were combined. Oral protein-energy supplements are widely used to improve the
      nutritional status of children with chronic disease. No conclusions can be drawn
      on the efficacy of these products based on the limited data available. Further
      randomised controlled trials are required to investigate the use of these
      products in children with chronic disease. Until further data are available,
      these products should be used with caution.

PMID- 15018479
TI  - The nutritional management of surgical patients: enhanced recovery after surgery.
AB  - Malnutrition has long been recognised as a risk factor for post-operative
      morbidity and mortality. Traditional metabolic and nutritional care of patients
      undergoing major elective surgery has emphasised pre-operative fasting and re
      introduction of oral nutrition 3-5 d after surgery. Attempts to attenuate the
      consequent nutritional deficit and to influence post-operative morbidity and
      mortality have included parenteral, enteral and oral sip feeding. Recent studies
      have emphasised that an enhanced rate of recovery can be achieved by a multi
      modal approach focused on modulating the metabolic status of the patient before
      (e.g. carbohydrate and fluid loading), during (e.g. epidural anaesthesia) and
      after (e.g. early oral feeding) surgery. Using such an approach preliminary
      results on patients undergoing elective colo-rectal surgery indicate a
      significant reduction in hospital stay (traditional care, n 48, median stay 10 d
      v. enhanced recovery programme, n 33, median stay 7d; P<0.01) can be achieved.
      Such findings emphasise the potential role of multi-modal care programmes in the
      promotion of early recovery from major surgical trauma.

PMID- 15018480
TI  - Geographical differences in vitamin D status, with particular reference to
      European countries.
AB  - Vitamin D is produced endogenously when the skin is exposed to sunlight and can
      be obtained exogenously from a few natural food sources, from food fortification
      and from supplements. Generally, vitamin D intake is low < or = 2-3 microg/d in
      Europe. Casual exposure to sunlight is thought to provide most of the vitamin D
      requirement of the human population. However, skin synthesis of vitamin D may not
      compensate for the low nutritional intake in Europe, even in countries with high
      supplies from food fortification and supplements. For assessment of vitamin D
      nutritional status the concentration of 25-hydroxyvitamin D (25(OH)D) in serum is
      considered to be an accurate integrative measure reflecting an individual's
      dietary intake and cutaneous production. A substantial percentage of the elderly
      and adolescents in Europe have a low concentration of 25(OH)D; in the elderly
      this percentage ranges from approximately 10 in the Nordic countries to
      approximately 40 in France. Low vitamin D status seems to be aggravated by
      disease and immobility, and by a low frequency of supplement use.

PMID- 15018481
TI  - Vitamin D and bone health in early life.
AB  - Prolonged vitamin D deficiency resulting in rickets is seen mainly during rapid
      growth. A distinct age distribution has been observed in the Copenhagen area
      where all registered hospital cases of rickets were either infants and toddlers
      or adolescents from immigrant families. Growth retardation was only present in
      the infant and toddler group. A state of deficiency occurs months before rickets
      is obvious on physical examination. Growth failure, lethargy and irritability may
      be early signs of vitamin D deficiency. Mothers with low vitamin D status give
      birth to children with low vitamin D status and increased risk of rickets.
      Reports showing increasing rates of rickets due to insufficient sunlight exposure
      and inadequate vitamin D intake are cause for serious concern. Many countries
      (including the USA from 2003) recommend vitamin D supplementation during infancy
      to avoid rickets resulting from the low vitamin D content of human milk. Without
      fortification only certain foods such as fatty fish contain more than low amounts
      of vitamin D, and many children will depend entirely on sun exposure to obtain
      sufficient vitamin D. The skin has a high capacity to synthesize vitamin D, but
      if sun exposure is low vitamin D production is insufficient, especially in dark
      skinned infants. The use of serum 25-hydroxyvitamin D to evaluate vitamin D
      status before development of rickets would be helpful; however, there is no
      agreement on cut-off levels for deficiency and insufficiency. Furthermore, it is
      not known how marginal vitamin D insufficiency affects children's bones in the
      long term.

PMID- 15018482
TI  - The effect of physical activity and its interaction with nutrition on bone
      health.
AB  - Physical activity (PA) is a popular therapy for the prevention and treatment of
      bone loss and osteoporosis because it has no adverse side effects, it is low
      cost, and it confers additional benefits such as postural stability and fall
      prevention. Bone mass is regulated by mechanical loading, and is limited but not
      controlled by diet. The mechanism by which strain thresholds turn bone
      remodelling 'on' and 'off' is known as the mechanostat theory. Research in
      animals has shown that optimal strains are dynamic, with a high change rate, an
      unusual distribution and a high magnitude of strain, but the results of
      randomized controlled trials in human subjects have been somewhat equivocal. In
      the absence of weight-bearing activity nutritional or endocrine interventions
      cannot maintain bone mass. Biochemical markers of bone turnover predict bone mass
      changes, and findings from our research group and others have shown that both
      acute and chronic exercise can reduce bone resorption. Similarly, Ca intervention
      studies have shown that supplementation can reduce bone resorption. Several
      recent meta-analytical reviews concur that changes in bone mass with exercise are
      typically 2-3%. Some of these studies suggest that Ca intake may influence the
      impact of PA on bone, with greater effects in Ca-replete subjects. Comparative
      studies between Asian (high PA, low Ca intake) and US populations (low PA, high
      Ca intake) suggest that PA may permit an adaptation to low Ca intakes. Whether Ca
      and PA interact synergistically is one of the most important questions unanswered
      in the area of lifestyle-related bone health research.

PMID- 15018483
TI  - Vitamin K and bone health.
AB  - Vitamin K, originally recognised as a factor required for normal blood
      coagulation, is now receiving more attention in relation to its role in bone
      metabolism. Vitamin K is a coenzyme for glutamate carboxylase, which mediates the
      conversion of glutamate to gamma-carboxyglutamate (Gla). Gla residues attract
      Ca2+ and incorporate these ions into the hydroxyapatite crystals. There are at
      least three Gla proteins associated with bone tissue, of which osteocalcin is the
      most abundant and best known. Osteocalcin is the major non-collagenous protein
      incorporated in bone matrix during bone formation. However, approximately 30% of
      the newly-produced osteocalcin stays in the circulation where it may be used as
      an indicator of bone formation. Vitamin K deficiency results in an increase in
      undercarboxylated osteocalcin, a protein with low biological activity. Several
      studies have demonstrated that low dietary vitamin K intake is associated with
      low bone mineral density or increased fractures. Additionally, vitamin K
      supplementation has been shown to reduce undercarboxylated osteocalcin and
      improve the bone turnover profile. Some studies have indicated that high levels
      of undercarboxylated osteocalcin (as a result of low vitamin K intake?) are
      associated with low bone mineral density and increased hip fracture. The current
      dietary recommendation for vitamin K is 1 microg/kg body weight per d, based on
      saturation of the coagulation system. The daily dietary vitamin K intake is
      estimated to be in the range 124-375 microg/d in a European population. Thus, a
      deficiency based on the hepatic coagulation system would be unusual, but recent
      data suggest that the requirement in relation to bone health might be higher.

PMID- 15018484
TI  - Is vitamin A consumption a risk factor for osteoporotic fracture?
AB  - Severe vitamin A toxicity is known to have adverse effects on skeletal health.
      Studies involving animal models and case reports have documented that
      hypervitaminosis A is associated with bone resorption, hypercalcaemia and bone
      abnormalities. More recently, some epidemiological studies have suggested that
      high habitual intake of vitamin A could contribute to low bone mineral content
      and fracture risk. The evidence relating to the possible deleterious role of
      vitamin A in bone health is of variable quality and is potentially confounded by
      collinearity of nutrient intake and difficulties in assessing vitamin A exposure.
      Furthermore, because intake of vitamin A varies between studies it is not
      possible to define an intake threshold associated with harm.

PMID- 15018485
TI  - The role of dietary calcium in bone health.
AB  - Approximately 99% of body Ca is found in bone, where it serves a key structural
      role as a component of hydroxyapatite. Dietary requirements for Ca are determined
      by the needs for bone development and maintenance, which vary throughout the life
      stage, with greater needs during the periods of rapid growth in childhood and
      adolescence, during pregnancy and lactation, and in later life. There is
      considerable disagreement between expert groups on the daily Ca intake levels
      that should be recommended, reflecting the uncertainty in the data for
      establishing Ca requirements. Inadequate dietary Ca in early life impairs bone
      development, and Ca supplementation of the usual diet for periods of < or = 3
      years has been shown to enhance bone mineral status in children and adolescents.
      However, it is unclear whether this benefit is long term, leading to the
      optimisation of peak bone mass in early adulthood. In later years inadequate
      dietary Ca accelerates bone loss and may contribute to osteoporosis. Ca
      supplementation of the usual diet in post-menopausal women and older men has been
      shown to reduce the rate of loss of bone mineral density at a number of sites
      over periods of 1-2 years. However, the extent to which this outcome reduces
      fracture risk needs to be determined. Even allowing for disagreements on
      recommended intakes, evidence indicates that dietary Ca intake is inadequate for
      maintenance of bone health in a substantial proportion of some population groups,
      particularly adolescent girls and older women.

PMID- 15018486
TI  - Dietary sodium as a risk factor for osteoporosis: where is the evidence?
AB  - Na-induced calciuria has been well documented and provides a physiological basis
      for the proposed role of dietary Na (or salt) as a risk factor for osteoporosis.
      However, the evidence is based primarily on acute salt-loading studies, and there
      are insufficient data on the effects of high salt intake on net Ca retention to
      predict long-term effects on bone health. Results of investigations on salt and
      bone turnover, as assessed by bone biomarkers, are inconsistent, but the large
      variations in inter-individual response to acute and chronic Na loading may be
      related to salt sensitivity. Results of cross-sectional and prospective
      investigations on high salt intake and long-term bone health are inconclusive,
      probably reflecting the difficulty of conducting such studies in free-living
      populations. However, the mean urinary Ca loss of 1 mmol/100 mmol Na suggests
      that chronic changes in salt intake may have large effects on Ca and bone
      balance, especially in individuals with a reduced capacity to compensate for Na
      induced Ca loss. Investigating the relationship between salt intake and bone
      health requires a greater focus on whole diets (including components such as K,
      Mg, P and protein), reliable measures of salt intake, appropriate bone health
      outcome measures, and improved subject characterisation (e.g. salt sensitivity).
      The reasons for inter-individual variability should be explored using post
      genomic techniques.

PMID- 15018487
TI  - Dietary protein and bone health.
AB  - The effects of dietary protein on bone health are paradoxical and need to be
      considered in context of the age, health status and usual diet of the population.
      Over the last 80 years numerous studies have demonstrated that a high protein
      intake increases urinary Ca excretion and that on average 1 mg Ca is lost in
      urine for every 1 g rise in dietary protein. This relationship is primarily
      attributable to metabolism of S amino acids present in animal and some vegetable
      proteins, resulting in a greater acid load and buffering response by the
      skeleton. However, many of these early studies that demonstrated the calciuric
      effects of protein were limited by low subject numbers, methodological errors and
      the use of high doses of purified forms of protein. Furthermore, the cross
      cultural and population studies that showed a positive association between animal
      protein intake and hip fracture risk did not consider other lifestyle or dietary
      factors that may protect or increase the risk of fracture. The effects of protein
      on bone appear to be biphasic and may also depend on intake of Ca- and alkali
      rich foods, such as fruit and vegetables. At low protein intakes insulin-like
      growth factor production is reduced, which in turn has a negative effect on Ca
      and phosphate metabolism, bone formation and muscle cell synthesis. Although
      growth and skeletal development is impaired at very low protein intakes, it is
      not known whether variations in protein quality affect the achievement of optimal
      peak bone mass in adolescents and young adults. Prospective studies in the
      elderly in the USA have shown that the greatest bone losses occur in elderly men
      and women with an average protein intake of 16-50 g/d. Although a low protein
      intake may be indicative of a generally poorer diet and state of health, there is
      a need to evaluate whether there is a lower threshold for protein intake in the
      elderly in Europe that may result in increased bone loss and risk of osteoporotic
      fracture.

PMID- 15018488
TI  - Dietary phyto-oestrogens and bone health.
AB  - The use of dietary phyto-oestrogens as a possible option for the prevention of
      osteoporosis has raised considerable interest because of the increased concern
      about the risks associated with the use of hormone-replacement therapy. However,
      the evidence in support of a bone-sparing effect in post-menopausal women is
      still not sufficiently convincing. Most studies have been performed on soyabean
      isoflavones (genistein and daidzein), either in the purified form or as a
      soyabean-based product or extract. In vitro studies using primary cell cultures
      or stabilised cell lines indicate that treatment with genistein may lead to a
      reduction in bone resorption, but effects on bone formation have also been shown.
      Investigations using animal models have provided convincing evidence of major
      improvements in bone mass or bone turnover following soyabean feeding. Cross
      sectional observations in South-East Asian populations with moderately high
      intakes of soyabean isoflavones (50 mg/d) have shown that women in the high
      quartile of intake have higher bone mineral density (BMD) and reduced bone
      turnover, an effect that has not been shown in populations with low average
      intakes. Human trials have given an indication of a possible effect on lumbar
      spine BMD, although they have been either short term (<6 months) or
      methodologically weak. Unresolved issues are: the optimal dose compatible with
      safety; the individual differences in response that can be related to diet and
      genotypes; the duration of exposure. Furthermore, there needs to be an evaluation
      of the relative biological effects of phyto-oestrogens other than isoflavones
      (lignans, resorcylic acid lactones, flavanols, coumestans) that are also present
      in European diets.

PMID- 15018489
TI  - Intake of fruit and vegetables: implications for bone health.
AB  - 'These famous words by Mencken in the early 20th century about the meaning of
      life and death, may also apply to the struggle of the healthy skeleton against
      the deleterious effects of retained acid!' (Kraut & Coburn, 1994). The health
      related benefit of a high consumption of fruit and vegetables and the influence
      of this food group on a variety of diseases has been gaining increasing
      prominence in the literature over a number of years. Of considerable interest to
      the osteoporosis field is the role that bone plays in acid-base balance. Natural,
      pathological and experimental states of acid loading and acidosis have been
      associated with hypercalciuria and negative Ca balance, and more recently the
      detrimental effects of 'acid' from the diet on bone mineral have been
      demonstrated. Suprisingly, consideration of the skeleton as a source of 'buffer'
      contributing to both the preservation of the body's pH and defence of the system
      against acid-base disorders has been ongoing for over three decades. However, it
      is only more recently that the possibility of a positive link between a high
      consumption of fruit and vegetables and indices of bone health has been more
      fully explored. A number of population-based studies published in the last decade
      have demonstrated a beneficial effect of fruit and vegetable and K intake on
      axial and peripheral bone mass and bone metabolism in men and women across the
      age-ranges. Further support for a positive link between fruit and vegetable
      intake and bone health can be found in the results of the Dietary Approaches to
      Stopping Hypertension (DASH) and DASH-Sodium intervention trials. There is now an
      urgent requirement for the implementation of: (1) fruit and vegetable and alkali
      administration-bone health intervention trials, including fracture risk as an end
      point; (2) re-analysis of existing dietary-bone mass and metabolism datasets to
      look specifically at the impact of dietary 'acidity' on the skeleton.

PMID- 15018490
TI  - Impact of genetic variation on metabolic response of bone to diet.
AB  - There is compelling evidence to suggest that both the development of bone to peak
      bone mass at maturity and subsequent loss depend on the interaction between
      genetic, hormonal, environmental and nutritional factors. The major part (< or =
      80%) of the age-specific variation in bone turnover and bone density is
      genetically determined. However, the notion of genetic determinant is of little
      value unless the specific genes that are involved can be identified. Most work in
      this area of osteoporosis research has focused on the candidate gene approach,
      which has identified several candidate genes for osteoporosis, including genes
      encoding the vitamin D receptor (VDR), oestrogen receptors (alpha and beta),
      apolipoprotein E, collagen type I alpha 1 and methylenetetrahydrofolate
      reductase, amongst many others. However, in general, findings from numerous
      studies of the association between such genes and various bone variables have
      been inconsistent. In addition to possible gene-gene interactions it is likely
      that there are interactions between these genes and certain environmental
      factors, especially nutrition, that may mediate expression of bone-related
      phenotypes. While these potential interactions add a level of complexity to our
      understanding of these apparent genetic effects on bone, identification of a role
      for genetic factors without knowledge of their interaction with nutrients can do
      little to advance prevention and treatment of osteoporosis. This information is
      especially important because, unlike genotype, diet and nutrition can be
      modified. The aim of the present review is to critically evaluate current
      knowledge relating to candidate genes for osteoporosis, with particular emphasis
      on their interaction with nutrients and dietary factors in determining bone
      health.

PMID- 15018491
TI  - Amino acid templating of inorganic networks: synthesis and structure of L
      asparagine zinc phosphite, C4N2O3H8.ZnHPO3.
AB  - C(4)N(2)O(3)H(8).ZnHPO(3) is the first zincophosphite framework to be templated
      by an amino acid (l-asparagine), which bonds to Zn via a carboxyl O atom. It
      contains infinite, homochiral, helical 4-ring chains of ZnO(4) and HPO(3) groups,
      stabilized by intra- and interchain N-H.O hydrogen bonds. Crystal data:
      C(4)N(2)O(3)H(8).ZnHPO(3), M(r) = 277.49, orthorhombic, P2(1)2(1)2(1) (No. 19), a
      = 5.0349(2) A, b = 9.4539(4) A, c = 18.6092(8) A, V = 885.79 (6) A(3), Z = 4.

PMID- 15018492
TI  - Polyhapto-aromatic interactions in lead(II) coordination.
AB  - In its crystalline form, the Pb(II) complex of 1,3-diphenylpropane-1,3-dionate
      (dibenzoylmethanide, DBM(-)) can be regarded as containing polymeric chains of
      centrosymmetric, dimeric Pb(2)(DBM)(4) units linked through hexahapto
      interactions of the Pb atoms with phenyl groups from adjacent units. Each Pb atom
      also appears to be involved in intraunit dihapto-aromatic interactions, thus
      attaining a total hapticity of thirteen. Comparison with the analogous Sn(II)
      compound indicates that the unusually high coordination number may reflect the
      capacity of Pb(II) to act as both a Lewis acid and a Lewis base.

PMID- 15018493
TI  - An unusual mixed-valence Cu(I)-Cu(II) 3-D framework.
AB  - The reaction of Cu(CH(3)CN)(4)ClO(4) with 2-pyridylacrylic acid (2-HPYA) affords
      an unusual mixed-valence Cu(I)-Cu(II) 3-D framework ([Cu(II)(2
      PYA)(2)](3).[Cu(I)(2-PYA)](2).(H2O)(2))n (1) with a novel topology which features
      Cu(II) dimeric units (or paddle-wheel unit). The almost perpendicular
      coordinating direction between the N atom of pyridyl and the O atom of
      carboxylate groups may be responsible for the formation of such a novel network.

PMID- 15018494
TI  - An unprecedented uranyl phosphate framework in the structure of
      [(UO2)3(PO4)O(OH)(H2O)2](H2O).
AB  - The new uranyl phosphate [(UO2)3(PO4)O(OH)(H2O)2](H2O) (1) with an unprecedented
      framework structure has been synthesized at 150 and 185 degrees C. The structure
      (tetragonal, P4(2)/mbc, a = 14.015(1) A, c = 13.083(2) A, V = 2575.6(4) A(3), Z =
      8) contains uranyl phosphate chains composed of uranyl pentagonal and hexagonal
      bipyramids and phosphate tetrahedra linked by sharing of polyhedral edges. The
      uranyl phosphate chains are aligned both along [100] and [010] and are linked
      into a novel framework structure involving channels along [001]. Topologically
      identical chains occur linked into sheets in more than a dozen uranyl phosphate
      minerals, but these chains have never been observed in opposing orientations and
      linked into a framework as in 1.

PMID- 15018495
TI  - Lanthanide/ATP interaction in water mediated by luminescent hemispherical-shaped
      complexes.
AB  - Ligand LH(2), composed of two bipyridylcarboxylate fragments linked to an amino
      butyl chain, reacts with europium and terbium to form luminescent complexes in
      water at neutral pH. When testing these unsaturated complexes as anion sensors
      with NO(3)(-), HPO(4)(2)(-), AMP, ADP, and ATP, a marked selectivity is observed
      for HPO(4)(2)(-) and ATP(4)(-) at pH = 7.0. The interaction of these anions with
      the complex was investigated by means of absorption and emission spectroscopies.
      With ATP(4)(-), ES-MS and (31)P NMR experiments revealed the formation of a
      [Ln.L.(ATP)](3)(-) ternary species.

PMID- 15018496
TI  - Structure of two azide salts of a copper(II) macrocycle and magnetic properties
      of Cu(14ane)Cu(N3)4.
AB  - Synthesis of azide complexes with the copper(II) macrocycle complex Cu(14ane)(2+)
      (where 14ane = 1,4,8,11-tetraazacyclothetradecane) has yielded two compounds.
      Cu(14ane)Cu(N(3))(4) contains micro(1,3)-azido bridged chains of Cu(14ane)(2+)
      cations and Cu(N(3))(4)(2)(-) anions. Magnetic studies reveal the presence of
      ferromagnetic interactions within the chains with J/k = 0.635(4) K.
      [Cu(14ane)N(3)]BF(4) contains [Cu(14ane)N(3)]+ cations with elongated square
      pyramidal geometry. The BF(4)(-) anions are weakly coordinated in the sixth
      coordination site of the cations.

PMID- 15018497
TI  - Axial ligation of Fe(II)-bleomycin probed by XANES spectroscopy.
AB  - Full multiple scattering calculations of the Fe K-edge X-ray absorption near edge
      structure of bleomycin have been performed. Structural insight is based on the
      comparison between experimental and theoretical data calculated for different
      active site models coming from NMR-informed molecular dynamic simulations. In all
      models considered, the equatorial ligands (secondary amine in beta-aminoalanine,
      pyrimidine and imidazole rings and the beta-hydroxyhistidine) were left
      unchanged. Seven models with two axial ligands (the primary amine in beta
      aminoalanine and the carbomoyl group of the mannose or a solvent molecule) were
      tested. The best agreement between theoretical and experimental spectra is
      achieved for the model of bleomycin with the primary amine and the oxygen of the
      mannose sugar occupying the axial positions. The coordination environment is
      characterized by serious distortions of the Fe octahedron, including the presence
      of one ligand with a very short bond length and significant angular distortions.

PMID- 15018498
TI  - Spacer flexibility in bis(pyridyl) ligands: chelating organosilicon
      pyridylethynyl ligands.
AB  - Two new bis(pyridylethynyl) ligands with organosilicon spacers have been
      synthesized. The ligands react readily with silver(I) to form crystalline
      complexes, both of which are revealed to be triflate-bridged dimers by X-ray
      crystallographic analysis. The complex with the flexible siloxane-based ligand
      possesses considerably less bond angle distortion.

PMID- 15018499
TI  - (Salen)CrIIIX catalysts for the copolymerization of carbon dioxide and epoxides:
      role of the initiator and cocatalyst.
AB  - The copolymerization of CO(2) and cyclohexene or propylene oxide has been
      examined employing (salen)Cr(III)Nu complexes (Nu = Cl or N(3)) as catalysts. The
      addition of various cocatalysts, including phosphines and PPN+ or Bu4N+ Cl- salts
      serves to greatly enhance the rate of copolymer production. In these instances,
      the mechanism of the initiation step appears to be unimolecular in catalyst
      concentration, unlike the bimolecular process cocatalyzed by N-methylimidazole.
      The copolymers were produced with >95% carbonate linkages with TOFs in the range
      39-494 mol epoxide consumed/mol Cr.h. In the presence of phosphine cocatalysts,
      no cyclic carbonate was produced as a byproduct.

PMID- 15018500
TI  - Tricarbonylrhenium(I) complexes with thiosemicarbazone derivatives of 2
      acetylpyridine and 2-pyridine formamide showing two unusual coordination modes of
      tridentate thiosemicarbazone ligands.
AB  - [NEt(4)](2)[Re(CO)(3)Br(3)] reacts with 2-acetylpyridine phenylthiosemicarbazone
      (HL(1)) and 2-pyridine formamide thiosemicarbazone (HL(2)) under formation of air
      stable, neutral rhenium(I) complexes of the compositions [Re(CO)(3)(L(1)-N,N,S)]
      and [Re(CO)(3)Br(HL(2)-N,N)]. Spectroscopic studies and X-ray crystallography
      show that the potentially tridentate thiosemicarbazones adopt unusual
      coordination modes. Whereas HL(1) deprotonates and binds to the metal in a
      nonplanar fashion, HL(2) acts as neutral N,N donor ligand. The bond lengths
      inside the chelate rings are almost uninfluenced by the overall bonding
      situation.

PMID- 15018501
TI  - Alkynylxenon(II) fluorides.
AB  - Alkynylxenon(II) fluorides, RCC(triple bond)XeF, have been prepared from the
      reactions of the corresponding trimethyl(alkynyl)silanes, Me3(-)SiC(triple
      bond)CR, and XeF2 in the presence of [NMe4F in common organic solvents at low
      temperature. The existence of the linear unit C(triple bond)C-Xe-F was proved for
      PhC(triple bond)CXeF by the 19F-13C NMR correlation method using the HMBC pulse
      sequence.

PMID- 15018502
TI  - The first enantiomerically pure helical noncovalent tripod for assembling nine
      coordinate lanthanide(III) podates.
AB  - Decomplexation of the trivalent lanthanide, Ln(III), from the racemic bimetallic
      triple-stranded helicates [LnCr(L8)(3)](6+) provides the inert chiral tripodal
      nonadentate receptor [Cr(L8)(3)](3+). Elution of the latter podand with
      Na(2)Sb(2)[(+)-C(4)O(6)H(2)](2).5H(2)O through a cation exchange column allows
      its separation into its inert helical enantiomers M-(+)(589)-[Cr(L8)(3)](3+) and
      P-(-)(589)-[Cr(L8)(3)](3+), whose absolute configurations are assigned by using
      CD spectroscopy and exciton theory. Recombination with Ln(III) restores the
      original triple-stranded helicates [LnCr(L8)(3)](6+), and the associated
      thermodynamic parameters unravel the contribution of electrostatic repulsion and
      preorganization to the complexation process. Combining M-(+)(589)-[Cr(L8)(3)](3+)
      with Eu(III) produces the enantiomerically pure d-f helicate MM-(-)(589)
      [EuCr(L8)(3)](CF(3)SO(3))(6).4CH(3)CN, whose X-ray crystal structure
      (EuCrC(113)H(111)N(25)O(21)S(6)F(18), monoclinic, P2(1), Z = 2) unambiguously
      confirms the absolute left-handed configuration for the final helix. The
      associated ligand-centered and metal-centered chiro-optical properties recorded
      for the complexes MM-[LnCr(L8)(3)](6+) and PP-[LnCr(L8)(3)](6+) (Ln = Eu, Gd, Tb)
      show a strong effect of helicity on specific rotary dispersions, CD and CPL
      spectra.

PMID- 15018503
TI  - Syntheses, structures, and photoluminescence of a novel class of d10 metal
      complexes constructed from pyridine-3,4-dicarboxylic acid with different
      coordination architectures.
AB  - Two novel d(10) metal coordination polymers [Zn(PDB)](n)() (1) and
      [Cd(3)(PDB)(2)(OH)(2)(H(2)O)(2)](n)() (2) (H(2)PDB = pyridine-3,4-dicarboxylic
      acid) have been synthesized under hydrothermal conditions and characterized by
      elemental analysis, IR, TG analysis, and single-crystal X-ray diffraction.
      Crystal data for 1: C(7)H(3)NO(4)Zn, orthorhombic Pna2(1), a = 8.423(17) A, b =
      6.574(13) A, c = 12.899(3) A, Z = 4. Crystal data for 2:
      C(14)H(12)N(2)O(12)Cd(3), monoclinic C2/c, a= 20.130(4) A, b = 6.692(13) A, c =
      13.081(3) A, beta = 102.78(3) degrees, Z = 4. Both compounds exhibit novel three
      dimensional frameworks. Compound 1 not only possesses a one-dimensional
      rectangular channel but also contains infinite double-stranded helical chains.
      Compound 2 has two different types of channels, one being built up from pyridine
      rings and [CdO(5)N] and [CdO(6)] building units and the other being constructed
      from pyridine rings and [CdO(5)N] building units. Furthermore, both compounds
      show strong photoluminescence properties at room temperature.

PMID- 15018504
TI  - 2D-3D transformation of layered perovskites through metathesis: synthesis of new
      quadruple perovskites A2La2CuTi3O12 (A = Sr, Ca).
AB  - We describe the synthesis of two new quadruple perovskites,
      Sr(2)La(2)CuTi(3)O(12) (I) and Ca(2)La(2)CuTi(3)O(12) (II), by solid-state
      metathesis reaction between K(2)La(2)Ti(3)O(10) and A(2)CuO(2)Cl(2) (A = Sr, Ca).
      I is formed at 920 degrees C/12 h, and II, at 750 degrees C/24 h. Both the oxides
      crystallize in a tetragonal (P4/mmm) quadruple perovskite structure (a =
      3.9098(2) and c = 15.794(1) A for I; a = 3.8729(5) and c = 15.689(2) A for II).
      We have determined the structures of I and II by Rietveld refinement of powder
      XRD data. The structure consists of perovskite-like octahedral CuO(4/2)O(2/2)
      sheets alternating with triple octahedral Ti(3)O(18/2) sheets along the c
      direction. The refinement shows La/A disorder but no Cu/Ti disorder in the
      structure. The new cuprates show low magnetization (0.0065 micro(B) for I and
      0.0033 micro(B) for II) suggesting that the Cu(II) spins are in an
      antiferromagnetically ordered state. Both I and II transform at high temperatures
      to 3D perovskites where La/Sr and Cu/Ti are disordered, suggesting that I and II
      are metastable phases having been formed in the low-temperature metathesis
      reaction. Interestingly, the reaction between K(2)La(2)Ti(3)O(10) and
      Ca(2)CuO(2)Cl(2) follows a different route at 650 degrees C, K(2)La(2)Ti(3)O(10)
      + Ca(2)CuO(2)Cl(2) --> CaLa(2)Ti(3)O(10) + CaCuO(2) + 2KCl, revealing multiple
      reaction pathways for metathesis reactions.

PMID- 15018505
TI  - Intermolecular magnetic couplings in the dinuclear copper(II) complex mu-chloro
      mu-[2,5-bis(2-pyridyl)-1,3,4-thiadiazole] aqua chlorocopper(II)
      dichlorocopper(II): synthesis, crystal structure, and EPR and magnetic
      characterization.
AB  - Mu-chloro-mu-[2,5-bis(2-pyridyl)-1,3,4-thiadiazole] aqua chlorocopper(II)
      dichlorocopper(II) is the first characterized dimeric complex of a transition
      metal and this hetero ligand [C(12)H(10)Cl(4)Cu(2)N(4)OS; triclinic; space group
      P; a = 9.296(3) A, b = 9.933(3) A, c = 10.412(3) A; alpha = 79.054(5) degrees,
      beta = 82.478(6) degrees, gamma = 67.099(5) degrees; Z = 2 at room temperature].
      The Cu(II) ions are bridged by the N-N thiadiazole bond and a chloride ion [Cu1
      Cu2 = 3.7800(8) A]. Thermogravimetric analysis shows this structure to be stable
      at temperatures up to 348 K. At higher temperatures, the successive loss of a
      water molecule and one chloride of the dimeric unit is identified. From room
      temperature to 125 K, half of the Cu(2+) ions are progressively engaged in
      intermolecular dinuclear antiferromagnetic exchanges, while the other half remain
      paramagnetic. At lower temperatures, both susceptibility and electron
      paramagnetic resonance measurements show the paramagnetic-only couplings of this
      half of the Cu(2+) ions, involving a singlet ground state for interacting Cu(2+).
      This unusual behavior has been satisfactorily explained on the basis of
      intermolecular Cu-Cu interactions (J = -180 cm(-1)), involving the magnetic d(z)2
      orbital perpendicular to the molecular plane, on which are seen the conjugate
      effects of the bridging chloride and the planar thiadiazole. It is noteworthy
      that the behavior of the title compound is original, compared to the systematic
      in-plane intramolecular antiferromagnetic coupling of other thiadiazole
      containing binuclear complexes.

PMID- 15018506
TI  - Octanuclear and nonanuclear supramolecular copper(II) complexes with linear
      "tritopic" ligands: structural and magnetic studies.
AB  - The structures and magnetic properties of self-assembled copper(II) clusters and
      grids with the "tritopic" ligands 2poap (a), Cl2poap (b), m2poap (c), Cl2pomp
      (d), and 2pomp (e) are described [ligands derived by reaction of 4-R-2,6
      pyridinedicarboxylic hydrazide (R = H, Cl, MeO) with 2-pyridinemethylimidate (a
      c, respectively) or 2-acetylpyridine (d, R = Cl; e, R = H)]. Cl2poap and Cl2pomp
      self-assemble with Cu(NO(3))(2) to form octanuclear "pinwheel" cluster complexes
      [Cu(8)(Cl2poap-2H)(4)(NO(3))(8)].20H(2)O (1) and [Cu(8)(Cl2pomp
      2H)(4)(NO(3))(8)].15H(2)O (2), built on a square [2 x 2] grid with four pendant
      copper arms, using "mild" reaction conditions. Similar reactions of Cl2pomp and
      2pomp with Cu(ClO(4))(2) produce pinwheel clusters [Cu(8)(Cl2pomp
      2H)(4)(H(2)O)(8)](ClO(4))(8).7H(2)O (3) and [Cu(8)(2pomp
      2H)(4)(H(2)O)(8)](ClO(4))(8) (4), respectively. Heating a solution of 1 in
      MeOH/H(2)O produces a [3 x 3] nonanuclear square grid complex, [Cu(9)(Cl2poap
      H)(3)(Cl2poap-2H)(3)](NO(3))(9).18H(2)O (5), which is also produced by direct
      reaction of the ligand and metal salt under similar conditions. Reaction of
      m2poap with Cu(NO(3))(2) produces only the [3 x 3] grid [Cu(9)(m2poap
      H)(2)(m2poap-2H)(4)](NO(3))(8).17H(2)O (6) under similar conditions. Mixing the
      tritopic ligand 2poap with pyridine-2,6-dicarboxylic acid (picd) in the presence
      of Cu(NO(3))(2) produces a remarkable mixed ligand, nonanuclear grid complex
      [Cu(9)(2poap-H)(4)(picd-H)(3)(picd-2H)](NO(3))(9).9H(2)O (7), in which aromatic
      pi-stacking interactions are important in stabilizing the structure. Complexes 1
      3 and 5-7 involve single oxygen atom (alkoxide) bridging connections between
      adjacent copper centers, while complex 4 has an unprecedented mixed micro-(N-N)
      and micro-O metal ion connectivity. Compound 1 (C(76)H(92)N(44)Cu(8)O(50)Cl(4))
      crystallizes in the tetragonal system, space group I, with a = 21.645(1) A, c =
      12.950(1) A, and Z = 2. Compound 2 (C(84)H(88)N(36)O(44)Cl(4)Cu(8)) crystallizes
      in the tetragonal system, space group I, with a = 21.2562(8) A, c = 12.7583(9) A,
      and Z = 2. Compound 4 (C(84)H(120)N(28)O(66)Cl(8)Cu(8)) crystallizes in the
      tetragonal system, space group I4(1)/a, with a = 20.7790(4) A, c = 32.561(1) A,
      and Z = 4. Compound 7(C(104)H(104)N(46)O(56)Cu(9)) crystallizes in the triclinic
      system, space group P, with a = 15.473(1) A, b = 19.869(2) A, c = 23.083(2) A,
      alpha = 88.890(2) degrees, beta = 81.511(2) degrees, gamma = 68.607(1) degrees,
      and Z = 2. All complexes exhibit dominant intramolecular ferromagnetic exchange
      coupling, resulting from an orthogonal bridging arrangement within each
      polynuclear structure.

PMID- 15018507
TI  - Diastereoselective assembling of 21-C-alkylated nickel(II) complexes of inverted
      porphyrin on a platinum(II) template.
AB  - Reaction of 21-C-methyl and 21-C-benzyl nickel(II) complexes of inverted meso
      tetratolylporphyrin with platinum(II) dichloride or its bis(benzonitrile) complex
      yields a chloroplatinum(II) species containing two nickel(II) carbaporphyrinoids
      in a cis arrangement. One of the carbaporphyrinoids coordinates to the platinum
      ion with the external nitrogen while the other is bound with the external
      nitrogen and one ortho-carbon of the adjacent meso-aryl ring. The reaction is
      highly chemoselective. (1)H and (13)C NMR experiments in solution show the
      diastereoselectivity of the reaction. Single-crystal X-ray data confirm the
      presence of the diastereomer with opposite configurations of the Ni(II)
      coordinated carbons in the subunits of the dimer. Cyclovoltammetric measurements
      reveal an anodic shift of the nickel(II) oxidation potentials of dimers with
      respect to those of the parent monomers and two different reduction couples.
      Reaction of unsubstituted inverted porphyrin with Pt(PhCN)(2)Cl(2) in
      chlorobenzene yields a monomeric platinum(II) complex of inverted porphyrin. This
      complex displays a markedly upfield (195)Pt NMR shift compared to
      tetraphenylporphyrinatoplatinum(II). Under strongly basic conditions
      deprotonation of the external nitrogen of inverted porphyrin and both
      electrochemical and chemical oxidation of platinum(II) center are observed.

PMID- 15018508
TI  - Irreversible but noncovalent Ru(II)-pyridine bond: its use for the formation of
      [2]-catenanes.
AB  - The reaction between ligand 1, which consists of two terminal pyridines attached
      to a central 1,10-phenanthroline (phen), and the complex Ru(phen)2(CH3CN)2(PF6)2
      has been studied. A new ruthenium containing metallamacrocycle has been obtained
      and fully characterized. Despite the relatively poor yield for the cyclization
      process involving the ruthenium center (20%), this strategy led to the synthesis
      of two different kinds of [2]-catenane. The first example reported in this
      article is a bimetallic Cu(I)/Ru(II) catenane 5(3+) consisting of a purely
      organic ring interlocked with the ruthenium(II)-incorporating metallacycle.
      Complex 5(3+) was selectively demetalated at the Cu(I) center to lead to the free
      Ru(II)-containing catenane. A trimetallic Ru(II)/Cu(I)/Ru(II) catenane 8(5+) was
      also synthesized showing that this approach is reliable and promising for the
      elaboration of photoactive multicomponent systems.

PMID- 15018509
TI  - Cyanide-melt synthesis of reduced molybdenum selenide clusters.
AB  - The tightly cross-linked Mo(3n)Se(3n+2) (n = 2, 3,... infinity) cluster compounds
      react with alkali metal cyanide or cyanide salt mixtures at temperatures of 450
      675 degrees C to yield cyanide-terminated molybdenum chalcogenide clusters,
      [Mo6Se8(CN)6]n- (1n-) (n = 6, 7) and [Mo4Se4(CN)12](8-) (2(8-)). The process by
      which discrete 1(n-) clusters are excised from a CN-linked intermediate chain
      compound, K6Mo6Se8(CN)5 (3), was investigated, and the cubane cluster 2(7-) plays
      an essential role. An efficient one-step synthesis for Na8[2(8-)] is presented.
      These clusters are stable in basic aqueous solutions. Cyclic voltammetric (CV)
      measurements in basic aqueous media show multiple reversible redox waves
      corresponding to 1(6-/7-), 1(7-/8-), and 1(8-/9-) redox couples with half-wave
      potentials of E(1/2) = -0.442, -0.876, and -1.369 V, respectively, versus SHE.
      Half-wave potentials (E(1/2)) for the [Mo4Se4)(CN)12](6-/7-) and [Mo4Se4(CN)12](7
      /8-) couples are 0.233 and -0.422 V, respectively, versus SHE. The 2(8-)
      compounds are K7Na[2(8-)].5H2O.MeOH, Cs7Na4[2(8-)]Cl3, Na8[2(8-)], and K4Na4[2(8
      )].12H2O. The products were characterized by X-ray crystallography, cyclic
      voltammetry, and UV-vis spectroscopy. Reduction potentials measured by
      voltammetry are consistent with conditions needed for isolating reduced species
      on a preparative scale but are much more negative than previously reported
      values. Na8[1(8-)].20H(2)O was isolated by reduction of 1(7-) with Zn in aqueous
      NaCN solution. Reduction potentials measured in basic NaCN solutions of 2(8-)
      also differ widely from previous reported values.

PMID- 15018510
TI  - Synthesis and structure of five Sc3CuyZn18-y-type compositions (0 < or = y < or =
      approximately 2.2), 1/1 crystalline approximants of a new icosahedral
      quasicrystal. Direct example of tuning on the basis of size effects and Hume
      Rothery concepts.
AB  - The newly reported icosahedral quasicrystalline phase approximately
      Sc(3)Cu(2.1)Zn(12.9) was approached through four synthetic, structural, and EDX
      analyses of the range of approximants formed by systematic substitutions of 0-4
      Zn by Cu in the reported Sc(3)Zn(17) as well as for the corrected Sc(3)Zn(18)
      (ScZn(6)) composition. Structures of high yield products of the 0, 1, 2, 3 Cu
      atom steps all refined as isotypic Sc(3)Cu(y)Zn(18-y) phases (Im(-)3, Z = 8, a =
      13.8311(5) to 13.7528(5) A for 0 < or = y < or =2.2), basically isostructural
      with RCd(6) phases known for many rare-earth elements. The present phases all
      exhibit the novel feature of disordered zinc tetrahedra in the center of four
      concentric polyhedral clusters: pentagonal dodecahedron (Zn/Cu), icosahedron
      (Sc), icosidodecahedron (Zn), and triacontahedron (Zn). The Cu tuning process
      reduces both the average electron count per atom (e/a) to 2.04 and the average
      atom size until major amounts of the zinc-poorer quasicrystal separate along with
      the present normal crystalline phase near four added Cu. The Cu is an important
      neighbor to the disordered Zn atoms. The approximant structure repeatedly
      exhibits components with pseudo-icosahedral symmetry.

PMID- 15018511
TI  - X-ray diffraction and NMR studies on a series of Binap-based Ru(II)
      hydroxyphosphine pi-arene complexes.
AB  - A series of new Ru(II) arene phosphine complexes derived from Binap have been
      prepared. Specifically, reaction of Ru(OAc)(2)(Binap) with 3,5
      (CF(3))(2)C(6)H(3))(4)B (BArF).H(OEt(2))(2), is shown to afford new mono- and
      dinuclear Ru(II) hydroxyphosphine pi-arene complexes via a series of P-C bond
      cleavage reactions. The dinuclear Ru(II) pi-arene complexes contain bridging
      P(O)(OH)(2) ligands. Crystal structures of five new complexes are reported and
      suggest an eta(4)-arene rather than an eta(6)-arene coordination mode. However,
      in solution, their (13)C NMR data are more consistent with a strongly distorted
      eta(6)-coordination mode. PGSE (1)H and (19)F diffusion measurements on the
      dinuclear complexes suggest hydrogen bonding of the triflate anion and ion
      pairing of the BArF(-) anion.

PMID- 15018512
TI  - Crystal engineering through face interactions between tetrahedral and octahedral
      building blocks: crystal structure of [epsilon
      Al13O4(OH)24(H2O)12]2[V2W4O19]3(OH)2).27H2O.
AB  - A new intercluster salt crystal [epsilon
      Al13O4(OH)24(H2O)12]2[V2W4O19]3(OH)2).27H2O (1) was synthesized from the reaction
      of octahedral Lindqvist-type polyoxometalate [V2W4O19](4-) and truncated
      tetrahedral Keggin-type [epsilon-Al13O4(OH)24-H2O)(12)](7+) cluster ions. The
      crystal structure shows that the oppositely charged cluster ions are arranged
      alternately and have their contacting faces parallel to each other for maximal
      interactions, both electrostatic and hydrogen bonding. The face-to-face
      interaction mode of the clusters allows analysis of the crystal structure in an
      analogy to the bond directionality of conventional inorganic crystals. Therefore,
      the packing of clusters in 1 is that of As2O3 (Claudetite-II). With the bond
      directionality, the crystal has large one-dimensional channels with a cross
      sectional area of 14.17 x 13.88 A(2) that are filled by lattice water and charge
      balancing OH-.

PMID- 15018513
TI  - Reactions of arachno-6,8-C2B7H12- with electron deficient olefins: syntheses of
      cyano-substituted carboranes.
AB  - The syntheses of new cyano-substituted derivatives of arachno-6,8-C(2)B(7)H(13)
      have been achieved through the addition reactions of the arachno-6,8
      C(2)B(7)H(12)(-) (1-) anion with cyano-activated olefins. The reaction of PSH+1-
      with tetracyanoethylene (TCNE) yielded the unusual bridging compound PSH(+)endo-6
      endo-7-[micro(2)-(C(CN)(2))(2)]-arachno-6,8-C(2)B(7)H(12)(-) (PSH+2-)) resulting
      from cycloaddition of the TCNE at the C6-B7 edge of the anion. Consistent with
      its hypho skeletal electron count, an X-ray crystallographic study and DFT/GIAO
      calculations confirm 2(-) has a more open structure than 1-. The reaction of 1-
      with acrylonitrile resulted in the formation of endo-6-(NCCH(2)CH(2))-arachno-6,8
      C(2)B(7)H(11)(-) (3-), which, upon acidification, afforded endo-6-(NCCH(2)CH(2))
      arachno-6,8-C(2)B(7)H(12) (3) in high yield. X-ray crystallographic and DFT/GIAO
      studies established that the cyanoethyl fragment in 3 is substituted at the endo
      position of the C6 cage-carbon. Heating 3 in THF at 50 degrees C or in toluene at
      110 degrees C resulted in the quantitative isomerization of the cyanoethyl
      substituent from the endo- to the exo-position at C6 to yield exo-6
      (NCCH(2)CH(2))-arachno-6,8-C(2)B(7)H(12) (4). This is the first example of an
      endo to exo isomerization to be observed at a cage-carbon of a carborane. While
      heating 3 resulted in isomerization to 4, heating 3- in the presence of a small
      amount of 3 yielded the new ethylene-bridged 10-vertex tricarbaborane micro(6,9)
      (CH(2)CH(2))-arachno-5,6,9-C(3)B(7)H(11) (5) resulting from reduction of the 3-
      pendant nitrile group, followed by deammination and carbon insertion.

PMID- 15018514
TI  - Experimental and theoretical investigation on the relative stability of the PdS2-
      and pyrite-type structures of PdSe2.
AB  - Under ambient condition PdSe2 has the PdS2-type structure. The crystal structure
      of PdSe2 under pressure (up to 30 GPa) was investigated at room temperature by X
      ray diffraction in an energy-dispersive configuration using a diamond anvil cell
      with a mixture of water/ethanol/methanol as a pressure transmitting medium. A
      reversible structural transition from the PdS2-type to the pyrite-type structure
      occurs around 10 GPa, and the applied pressure reduces the spacing between
      adjacent 2/proportional to [PdSe2] layers of the PdS2-type structure to form the
      three-dimensional lattice of the pyrite-type structure. First principles and
      extended Huckel electronic band structure calculations were carried out to
      confirm the observed pressure-induced structural changes. We also examined why
      the isoelectronic analogues NiSe2 and PtSe2 adopt structures different from the
      PdS2-type structure on the basis of qualitative electronic structure
      considerations.

PMID- 15018515
TI  - Iridium cyclometalated complexes with axial symmetry. Synthesis and photophysical
      properties of a trans-biscyclometalated complex containing the terdentate ligand
      2,6-diphenylpyridine.
AB  - The first example of an iridium biscyclometalated complex with a C wedge N wedge
      C 2,6-diphenylpyridine (dppy)-type ligand, [(4'-(4-bromophenyl)-2:2',6':2' '
      terpyridine)Ir(2,6-diphenyl-4-(4-tolyl)pyridine)](NO(3)) (1), has been
      synthesized and characterized by various techniques such as X-ray
      crystallography, mass spectrometry, (1)H and (13)C NMR, cyclic voltammetry, and
      both steady-state and time-resolved emission and absorption studies. Preliminary
      density functional theory calculations have also been conducted. 1 crystallizes
      in the monoclinic space group P2(1)/n. The crystallographic data are as follows:
      C(45)H(31)BrN(4)IrO(3).2H(2)O, a = 17.4308(4) A, b = 9.0312(2) A, c = 26.7601(7)
      A, beta = 104.496(1) degrees, V = 4078.5(2) A(3), Z = 4. The relatively long Ir-C
      distances (2.122 and 2.094 A) reflect the strong mutual trans effect of the
      cyclometalating carbons. The complex exhibits strong visible absorption and long
      lived (1.7 micros) emission (lambda(max), 690 nm) in room temperature solution.
      The inherent asymmetry of the coordination environment offers a unique
      directional character to the emitting excited state, which is predominantly
      ligand-to-ligand charge transfer (dppy --> 2,2':6',2' '-terpyridine) in nature.

PMID- 15018517
TI  - A novel organic-inorganic hybrid based on an 8-electron-reduced Keggin
      polymolybdate capped by tetrahedral, trigonal bipyramidal, and octahedral zinc:
      synthesis and crystal structure of
      (CH3NH3)(H2bipy)[Zn4(bipy)3(H2O)2MoV8MoVI4O36)(PO4)].4H2O.
AB  - Hydrothermal reaction of H(3)PO(3), CH(3)NH(2), zinc(II) acetate, 4,4'-bipyridine
      (bipy), and (NH(4))(6)Mo(7)O(24).4H(2)O at 180 degrees C led to a novel organic
      inorganic layered hybrid,
      [CH(3)NH(3)][H(2)bipy][Zn(4)(bipy)(3)(H(2)O)(2)Mo(V)(8)Mo(VI)O(36)(PO(4))].4H(2)O
      (1). Its structure was established by single-crystal X-ray diffraction. It
      crystallizes in the monoclinic space group P2(1)/c with cell parameters of a =
      17.3032(2), b = 17.8113(3), and c = 23.4597 (4) A, beta = 106.410(1) degrees, V =
      6935.6(2) A(3), and Z = 4. The structure of compound 1 features a novel 2D layer
      built from the 8e-reduced tetracapped Keggin [Zn(4)Mo(12)O(36)(PO(4))](3)(-)
      anions, which are further interconnected by bridging bipy ligands. The four
      zinc(II) ions are in tetrahedral, trigonal bipyramidal, and octahedral
      coordination geometries, respectively.

PMID- 15018518
TI  - Inter-string arrays of bimetallic assemblies with alternative Cu2+-Cl-Cu2+ and Cu
      NC-M (M = Co3+, Fe+3, Cr+3) bridges: syntheses, crystal structure, and magnetic
      properties.
AB  - Three bimetallic assemblies with alternate homometallic bridges through chloride
      ligands and heterometallic bridges through cyanide ligands of formula
      [(323)(2)Cu(2)(Cl)M(CN)(6)](n).2n(H(2)O), where 323 = N,N'-bis(3
      aminopropyl)ethylenediamine and M = Co(3+) for 1, Fe(3+) for 2, and Cr(3+) for 3,
      were synthesized. They have been characterized structurally, analytically,
      spectroscopically, and magnetically. All three assemblies crystallize in the
      monoclinic system in the same space group P2(1)/n, with a = 11.642(2) A, b =
      10.285(3) A, c = 13.622(2) A, beta = 95.69(3) degrees, V = 1623.1(6) A(3), and Z
      = 4 for 1; a = 11.681(4) A, b = 10.315(3) A, c = 13.567(5) A, beta = 95.62(3)
      degrees, V = 1626.8(9) A(3), Z = 4 for 2, and a = 11.782(4) A, b = 10.386(2) A, c
      = 13.755(4) A, beta = 95.51(3) degrees, V = 1657.4(8) A(3), Z = 4 for 3. Crystal
      structure analyses reveal that one-dimensional zigzag chains propagate in two
      different crystallographic directions (a and b) which are held together during
      the course of their propagation. All three assemblies have a homometallic Cu-Cl
      Cu core in common. Assembly 1 exhibits metamagnetic behavior and shows weak
      antiferromagnetic interactions between Cu(2+) paramagnetic centers, through the
      chloride bridges. The Neel temperature, T(N), is 3.5 K, and the critical field is
      4 T. In the presence of a magnetic field larger than 4 T, the local spin doublets
      of Cu(2+) in the assembly 1 remain in parallel arrangements. Assemblies 2 and 3
      may be described as an alternative repetition of the antiferromagnetically
      coupled Cu-Cl-Cu fragment and ferromagnetically coupled Cu-CN
      Fe(3+)/Cr(3+)fragment. The overall magnetic character of the strings in
      assemblies 2 and 3 are antiferromagnetic. Ferromagnetic interaction evidenced by
      the (Cu-CN-Fe(3+)/Cr(3+)) fragment was masked by the antiferromagnetic
      interaction between the Cu(2+) centers through the chloride bridge. The magnetic
      properties agree well with those expected for two [323 Cu(2+)] and a [Fe(CN)](3+)
      unit with spin-orbit coupling effect of the low-spin iron(III) ions for 2 and for
      two [323 Cu(2+)] and a [Cr(CN)](3+) unit for 3. In aqueous solution, trinuclear
      [(323)(2)Cu(2)M(CN)(6)](+) and dinuclear [(323)CuM(CN)(6)](-) species were
      observed.

PMID- 15018516
TI  - The reaction of dimethyltin(IV) dichloride with thiamine diphosphate (H2TDP):
      synthesis and structure of [SnMe2(HTDP)(H2O)]Cl.H2O, and possibility of a
      hitherto unsuspected role of the metal cofactor in the mechanism of vitamin-B1
      dependent enzymes.
AB  - The complex [SnMe(2)(HTDP)(H(2)O)]Cl.H(2)O, synthesized by reaction between
      dimethyltin(IV) dichloride and thiamine diphosphate hydrochloride (H(3)TDPCl) in
      water, was characterized by X-ray diffractometry and IR and Raman spectroscopy in
      the solid state, and by electrospray mass spectrometry (ESMS) and NMR
      spectroscopy ((1)H, (13)C, (31)P, (119)Sn and inverse-detection (1)H,(15)N HMBC)
      in aqueous solution. In the solid state the HTDP(-) anion chelates the metal via
      one oxygen atom of each phosphate group [Sn-O = 2.062(3), 2.292(3) A], and
      another oxygen atom belonging to the terminal phosphate links the SnMe(2)(2+)
      cations into chains. The tin atom has distorted octahedral coordination involving
      the trans methyl groups, the above-mentioned diphosphate oxygen atoms, and the
      oxygen atom of the coordinated water molecule. The thiamine moiety has F
      conformation. NMR studies suggest that the interaction between the organometallic
      cation and the HTDP(-) ligand persists in D(2)O solution, which is in keeping
      with the ESMS spectrum showing a peak corresponding to [SnMe(2)(HTDP)]. Both in
      the solid state and in solution, the acidic HTDP(-) proton in the complex is
      located on the N(1') atom of the pyrimidine ring. The enzymatic behavior of
      native pyruvate decarboxylase (EC 4.1.1.1, PDC), obtained from baker's yeast, was
      compared in a coupled assay with that shown by the "SnMe(2)-holoenzyme" created
      by incubation of apoPDC with [SnMe(2)(HTDP)(H(2)O)]Cl.H(2)O. The SnMe(2)
      holoenzyme exhibited about 34% of the activity of the native enzyme (with a
      Michaelis-Menten constant of 2.7 microM, as against 6.4 microM for native PDC),
      so confirming the very low specificity of PDC regarding the identity of its metal
      ion cofactor. In view of the observed protonation of N(1'), it is suggested that
      the role of divalent cations in the mechanism of thiamine-diphosphate-dependent
      enzymes may be not only to anchor the cofactor in its binding site but also to
      shift the acidic proton of HTDP(-) from the diphosphate group to N(1');
      protonation of N(1') is widely believed to be important for enzyme function, but
      the origin of the proton has never been clarified.

PMID- 15018519
TI  - Ion chemistry of OV(OCH3)3 in the gas phase: molecular cations and anions and
      their primary fragmentations.
AB  - Trimethyl vanadate(V), OV(OCH(3))(3) (1), is examined by various mass
      spectrometric means. Photoionization experiments yield an ionization energy of
      IE(OV(OCH(3))(3)) = 9.54 +/- 0.05 eV for the neutral molecule. The primary
      fragmentation of the molecular cation 1(+), i.e., loss of neutral formaldehyde,
      can occur via two independent routes of hydrogen migrations to afford the formal
      V(IV) compounds HOV(OCH(3))(2)(+) and OV(OCH(3))(CH(3)OH)(+), respectively. These
      two pathways are associated with low-lying activation barriers of almost
      identical height. At elevated energies, direct V-O bond cleavage of 1(+) allows
      for expulsion of a methoxy radical concomitant with the generation of the
      cationic fragment OV(OCH(3))(2)(+), a formal V(V) compound. Trimethyl vanadate
      can also form a molecular anion, 1(-), whose most abundant dissociation channel
      involves loss of a methyl radical, thereby leading to the formal V(V) compound
      OV(OCH(3))(2)O(-). Various mass spectrometric experiments and extensive
      theoretical studies provide detailed insight into the ion structures and the
      relative energetics of the primary dissociation reactions of the molecular
      cations and anions of 1.

PMID- 15018520
TI  - Ferromagnetic ordering in bis(benzene)chromium(+) Bis(4,5-dimethoxybenzene-1,2
      dithiolato)nickel(-).
AB  - The compound bis(benzene)chromium(+) bis(4,5-dimethoxy-1,2
      benzenedithiolato)nickel(-), [Cr(bz)(2)](+)[Ni(dmox)(2)](-), was prepared as well
      defined crystals by a metathesis reaction. X-ray single-crystal structure
      confirms the expected symmetries of the cations (D6h) and anions (D2h). The Ni-S
      bond length is typical for a monoanionic bis(arene)-1,2-dithiolato nickel complex
      thus confirming the ascribed charges. The structure reveals interpenetrating
      cation and anion sublattices where all ions are well separated from other ions of
      the same charge and with almost perpendicular symmetry planes of cations and
      anions. Above ca. 10 K the compound is paramagnetic and follows the Curie-Weiss
      law for S = 1/2 on each ion with a Weiss temperature of 8.5 K. Magnetic
      susceptibility and magnetization studies reveal the transition to a
      ferromagnetically ordered phase at 3.4 K. The ferromagnetic interaction is likely
      to occur through short contacts between anion heteroatoms (O and Ni) and cation H
      atoms, forming a 2-D network. A third dimension is possible through somewhat
      longer interionic S-H contacts. The Curie-Weiss law behavior can be modeled for 1
      D chains with a ferromagnetic interaction of J = 11.6 K.

PMID- 15018522
TI  - DFT-based pseudo-Jahn-Teller coupling studies on the steric and energetic lone
      pair effect of four- and five-coordinate halide molecules and complexes with
      central ions from the fifth, sixth, and seventh main groups.
AB  - The energetical and stereochemical effect of the s(2) lone pair in the title
      molecules and complexes is investigated using a pseudo-Jahn-Teller coupling model
      with parameters adjusted to energies and wave functions from DFT calculations.
      Vibronic coupling parameters were calculated and compared with those of the
      coordination number (CN) 3. Inspecting the correlation between the chemical
      hardness and the vibronic coupling energy (hardness rule), it is found that the
      tendency to distort decreases with increasing CN. While all considered molecules
      AX(3) (A(III) = P to Bi; X(-) = F to I) undergo lone pair deformations (D(3h)--->
      C(3v)), only part of the AX(4)(-) and BX(4) species (B(IV) = S to Po) do so (T(d)
      --> C(2v)-and even less the ones with CN = 5 (D(3h)---> C(2v) (congruent with
      C(4v)), AX(5)(2-), BX(5)(-), and CF(5) (C(V); Cl to I). The distorted polyhedra
      of minimum energy possess usually the butterfly C(2v) shape (CN = 4, tau(2)(zeta)
      displacement path) and a C(2v) = C(4v)geometry (CN = 5, epsilon' (epsilon)
      distortion path). A further symmetry lowering to C(s) occurs, if the central ion
      becomes too small with respect to the ligands (ionic size influence, PCl(Br)(4)(
      ), PCl(5)(2-)), with the tendency to reduce the CN toward 3 + 1 and 4 + 1,
      respectively. For CN = 4 the various stationary points of, for example,
      compressed and elongated C(3v), C(4v), etc. in the multidimensional ground-state
      potential surface have been characterized. Though of higher energy than the
      absolute C(2v) minimum, they are shown to govern the dynamics and reactivity of
      the CN = 4 species to a large extent. To simulate the chemical environment
      (positively charged counterions, polar solvents), the DFT calculations were
      performed using the polarizable continuum model COSMO (conductor-like screening
      model). Though the electronic energy gain upon distortion is not significantly
      affected by the solvent, the total stabilization energy is distinctly enhanced,
      frequently leading to lone pair deformations of otherwise electronically stable
      species. All results obtained by the combined vibronic/DFT approach are well in
      accord with available experimental data.

PMID- 15018521
TI  - The role of sequestering agents in the formation and structure of germanium anion
      cluster polymers.
AB  - Large blue-green, transparent crystalline needles of [K-(2,2)diaza-[18]-crown
      6]KGe(9).3en are prepared, in high yield, from the reaction of (2,2)diaza[18]
      crown-6 in toluene with a solution of "KGe(4)" in ethylenediamine (en). The
      compound crystallizes in the orthorhombic space group Pnma (a = 10.9763(12) A, b
      = 27.265(3) A, c = 13.880(1) A; Z = 4). The crystal structure of [K-(2,2)diaza
      [18]-crown-6]KGe(9).2en features one-dimensional [KGe(9)](-) bare intermetallic
      chains formed from the linking, via exo-bonds, of nido-Ge(9)(2-) clusters.
      Uncomplexed K atoms effectively cap the square bases of the monocapped square
      antiprismatic [Ge(9)](2-) clusters. The optical band gap of the title compound is
      1.25 eV. The use of weaker sequestering agents in the isolation of Ge cluster
      anions from en solutions provides an additional handle in a controlled molecular
      route to preparing new low-dimensional Zintl phases.

PMID- 15018523
TI  - Characterization and purification of supramolecular metal complexes using gel
      permeation chromatography.
AB  - Gel-permeation chromatography (GPC) has been used to analyze transition-metal
      based squares, triangles, and related supramolecular complexes. Using rhenium
      containing molecular squares of different sizes, a linear calibration curve has
      been established, which was used for confirming the relative sizes of other
      assemblies. GPC can also discriminate cyclic trimers and tetramers of a dirhodium
      building block. Preparative GPC has been used to resolve macroscopic samples of a
      rhenium-based supramolecular mixture into pure syn and anti isomers. A mixture of
      "triangle" and "square" has also been successfully separated.

PMID- 15018524
TI  - An improved method for the synthesis of [closo-B12(OH)12]-2.
AB  - The dicesium salt of the icosahedral borane anion dodecahydroxy-closo
      dodecaborate(2-), closo-Cs(2)B(12)(OH)(12), Cs(2)4, was prepared using an
      improved synthetic pathway. Heating cesium dodecahydro-closo-dodecaborate, closo
      Cs(2)B(12)H(12), Cs(2)1, with 30% hydrogen peroxide added in successive
      increments at 105-110 degrees C provided Cs(2)4 in 95% yield. Reaction progress
      was monitored using (1)H-decoupled (11)B NMR while (17)O NMR provides the most
      reliable way to detect the presence of peroxides in the reaction solution. The
      reaction may be safely increased in scale to afford Cs(2)4 in multigram
      quantities.

PMID- 15018525
TI  - Spectroscopic investigation of interactions between dipeptides and vanadate(V) in
      solution.
AB  - The reaction of vanadate(V) with a series of dipeptides (Val-Gln, Ala-Gln, Gly
      Gln, Gly-Glu, and Ala-Gly) was investigated by UV-visible spectroscopy and
      multinuclear ((51)V, (14)N, (13)C) NMR spectroscopy in solution. It was possible
      to evaluate the formation constants of the corresponding complexes for which a
      molecular structure was proposed. Complex formation is favored by the presence of
      a functionalized or a sterically demanding side chain. The Val-Gln dipeptide
      which combines both properties exhibits one of the highest formation constant
      reported so far for dipeptides.

PMID- 15018526
TI  - The weakly coordinating trichloromethanesulfonate anion: NQR comparison of its
      coordinating abilities via oxygen with those of the chloroacetate ions.
AB  - Ionic and covalent derivatives of the chlorine analogue of the nonbasic, weakly
      coordinating triflate ion, Cl3CSO3(-) or "trichlate" ion, have been prepared and
      compared with the corresponding more strongly coordinated chloroacetates,
      Cl(x)CH(3-x)CO(2)M (x = 1-3), using 35Cl NQR (nuclear quadrupole resonance)
      spectroscopy. The (35)Cl NQR frequencies of all types of derivatives are
      sensitive to the nature of the metal ion or Lewis acid and are most sensitive in
      the case of monochloroacetates. In covalent (including zirconocene) derivatives,
      the average NQR frequencies fall as the Pauling electronegativity of M falls. The
      results for ionic derivatives contrast with previous results for ionic
      hexachlorometalates: the average (35)Cl NQR frequencies drop sharply as the ionic
      radius of the group 1 cation increases. Ab initio Gaussian 98 computations at the
      B3LYP/6-311++G(3df,3pd) level on isolated XCH2CO2M (M = Li, Na, K; X = F, Cl)
      molecules duplicate this trend, showing increasing polarization of the C-Cl bond
      and smaller electric field gradients for larger group 1 ions; the relevance of
      this to the solid state polymerization of chloroacetates (Herzberg, O.; Epple, M.
      Eur. J. Inorg. Chem. 2001, 1395-1406) is discussed. We have prepared the
      dihydrate and monohydrate of trichlic acid, Cl3CSO3H. Although trichlates have
      the highest average NQR frequencies of any of these salts, the NQR frequencies of
      trichlic acid dihydrate are anomalously lower than those of trichloroacetic acid,
      which suggests that it is a strong acid, ionized in the solid state to H5O2+ and
      Cl3CSO3(-) ions.

PMID- 15018527
TI  - Photoswitchable luminescence of rhenium(i) tricarbonyl diimines.
AB  - The synthesis, characterization, and X-ray crystal structures of
      [Re(diimine)(CO)(3)(dpe)](PF(6)) (dpe = 1,2-di(4-pyridyl)ethylene) compounds are
      reported. The cis-dpe complexes exhibit yellow luminescence after UV excitation,
      whereas the trans-dpe counterparts are nonluminescent. The luminescence quantum
      yields of the cis-dpe complexes are strongly dependent on the identity of the
      diimine ligand. Irradiation (350 nm) of the trans-dpe complexes induces trans -->
      cis dpe-ligand isomerization with quantum yields on the order of 0.2, and this
      process leads to an on-switching of yellow luminescence. After long 350-nm
      irradiation times, a steady state composed of roughly 70% cis- and 30% trans-dpe
      complexes is reached. The reverse cis --> trans photoisomerization reaction is
      induced by irradiating the cis-dpe complexes at 250 nm, switching off the yellow
      luminescence. For 250-nm excitation, photodecomposition of the
      [Re(diimine)(CO)(3)(dpe)](+) complexes competes efficiently with
      photoisomerization.

PMID- 15018528
TI  - Synthesis, crystal structure, and physical properties of (BEDT-TTF)[Ni(tdas)2]
      (BEDT-TTF = bis(ethylenedithio)tetrathiafulvalene; tdas = 1,2,5-thiadiazole-3,4
      dithiolate): first monomeric [Ni(tdas)2]- monoanion.
AB  - We report the synthesis, structure, and physical properties of (BEDT
      TTF)[Ni(tdas)2] [BEDT-TTF, or ET, is bis(ethylenedithio)tetrathiafulvalene; tdas
      is 1,2,5-thiadiazole-3,4-dithiolate], which is the first example of a salt
      containing monomeric [Ni(tdas)2]- monoanions. This salt, which crystallizes in
      the monoclinic space group P2(1)/c with a = 17.2324(6) A, b = 13.2740(5) A, c =
      10.9467(4) A, beta = 96.974(2) degrees, and V = 2485.5(2) A(3), forms a layered
      structure. One layer contains dimerized BEDT-TTF electron donor molecules and
      isolated [Ni(tdas)2]- monoanions, while the second layer contains chains of
      [Ni(tdas)2]- monoanions. Conductivity measurements show that (BEDT
      TTF)[Ni(tdas)2] has a semiconductor-to-semiconductor transition near 200 K, while
      magnetic measurements indicate that it is an S = 1/2 paramagnet with weak
      antiferromagnetic coupling. Reflectance spectra reveal bands in the near-infrared
      region (6.6 x 10(3) and 10.6 x 10(3) cm(-1)) which are typical of (BEDT-TTF)2(2+)
      dimers. From these data, we can conclude that the unpaired electron lies on the
      [Ni(tdas)2]- anions. Tight-binding band structure calculations were used to
      analyze the electronic structure of this salt.

PMID- 15018529
TI  - Insertion of SO2 into a sulfide-bridged M-Ge bond: synthesis, characterization,
      and reactivity of the O-germyl-S-sulfoxylate.
AB  - Addition of SO(2) to [formula: see text](1) results in the insertion of SO(2)
      into the Pd-Ge bond to give the O-germyl-S-sulfoxylate insertion isomer
      (Et3P)2Pd(mu-S)S(O)OGe[N(SiMe3)2]2 (2). Heating solutions of 2 results in the
      formation of (Et3P)Pd(SGe[N(SiMe3)2]2OSOGe[N(SiMe3)2]2S) (3) and a LnPd(0)
      fragment. X-ray crystal structures of 2 and 3 are reported.

PMID- 15018530
TI  - From calcium interaction to calcium electrochemical detection by
      [(C5H5)Fe(C5H4COCH=CHC6H4NEt2)] and its two novel structurally characterized
      derivatives.
AB  - [(C(5)H(5))Fe(C(5)H(4)COCH=CHC(6)H(4)NEt(2))] (1) has been electrochemically
      evaluated toward different cations in solution. Calcium sensing by this compound
      and its two new derivatives [(C(5)H(5))Fe(C(5)H(4)CO(CH=CH)(2)C(6)H(4)NMe(2))]
      (2) and [(C(5)H(5))Fe(C(5)H(4)CH=CHCOCH=CHC(6)H(4)NEt(2))] (3) that exhibit a
      conjugated link between the ferrocene unit and the nitrogen atom has been
      thoroughly examined. Compounds 2 and 3 have been structurally characterized by
      single-crystal X-ray diffraction studies. The three related protonated species
      [1H][BF(4)] (4), [2H][BF(4)] (5), and [3H][BF(4)] (6) have been isolated in a
      good yield. NMR experiments clearly established that calcium interaction occurs
      in the vicinity of the carbonyl group, and mass spectrometry studies confirmed
      that this interaction, which involves several ligand-Ca(2+) adducts, is complex.
      A combination of electrochemical and NMR experiments highlighted an original salt
      influence on the electrochemical calcium sensing result.

PMID- 15018531
TI  - Substituent effects on the site of electron transfer during the first reduction
      for gold(III) porphyrins.
AB  - Gold(III) porphyrins of the type (P-R)AuPF(6), where P = 5,10,15,20-tetrakis(3,5
      di-tert-butylphenyl)porphyrin and R is equal to H (1), NO(2) (2), or NH(2) (3)
      which is substituted at one of the eight beta-pyrrolic positions of the
      macrocycle, were investigated as to their electrochemistry and
      spectroelectrochemistry in nonaqueous media. Each compound undergoes three
      reductions, the first of which involves the central metal ion to give a Au(II)
      porphyrin or a Au(III) porphyrin pi-anion radical depending upon the nature of
      the porphyrin ring substituent. A similar metal-centered reduction also occurs
      for compounds 1, 3, and Au(III) quinoxalinoporphyrin, (PQ)AuPF(6) (4), where PQ =
      5,10,15,20-tetrakis(3,5-di-tert-butylphenyl)quinoxalino[2,3-b]porphyrin, and
      these results on the three Au(III) porphyrins overturn the long held assumption
      that reductions of such complexes only occur at the macrocycle. In contrast, when
      a NO(2) group is introduced on the porphyrin ring to give (P-NO(2))AuPF(6) (2),
      the site of electron transfer is changed from the gold metal to the macrocycle to
      give a porphyrin pi-anion radical in the first reduction step. This change in the
      site of electron transfer was examined by electrochemistry combined with thin
      layer UV-vis spectroelectrochemistry and ESR spectroscopy of the singly reduced
      compound produced by chemical reduction. The reorganization energy (lambda) of
      the metal-centered electron transfer reduction for (P-H)AuPF(6) (1) in
      benzonitrile was determined as lambda = 1.23 eV by analyzing the rates of
      photoinduced electron transfer from the triplet excited states of an organic
      electron donor to 1 in light of the Marcus theory of electron transfer. The
      lambda value of the metal-centered electron transfer of gold porphyrin (1) is
      significantly larger than lambda values of ligand-centered electron transfer
      reactions of metalloporphyrins.

PMID- 15018532
TI  - Head-to-head (HH) and head-to-tail (HT) conformers of cis-bis guanine ligands
      bound to the [Re(CO)3]+ core.
AB  - We have prepared four complexes of the type [Re(guanine)(2)(X)(CO)(3)] (guanine =
      9-methylguanine or 7-methylguanine, X = H(2)O or Br) in order to understand the
      factors determining the orientation of coordinated purine ligands around the
      [Re(CO)(3)](+) core. The 9-methylguanine ligand (9-MeG) was chosen as the
      simplest N(9) derivatized guanine, and 7-methylguanine (7-MeG) was chosen because
      metal binding to N(9) does not impose steric hindrance. Two types of structures
      have been elucidated by X-ray crystallography, an HH (head-to-head) and HT (head
      to-tail) conformer for each of the guanines. All complexes crystallize in
      monoclinic space groups: [Re(9-MeG)(2)(H(2)O)(CO)(3)]ClO(4) (2) in P2(1)/n with a
      = 12.3307(10) A, b = 16.2620(14) A, c = 13.7171(11) A, and beta = 105.525(9)
      degrees, V = 2650.2(4) A(3), with the two bases in HT orientation and its
      conformer [Re(9-MeG)(2)(H(2)O)(CO)(3)]Br (3) in P2(1)/n with a = 15.626(13) A, b
      = 9.5269(5) A, c = 15.4078(13) A, and beta = 76.951(1) degrees, V = 2234.5(3)
      A(3), and the two bases in an HH orientation. Similarly, [Re(7
      MeG)(2)(H(2)O)(CO)(3)]ClO(4) (4) crystallizes in P2(1)/c with a = 13.0708(9) A, b
      = 15.4082(7) A, c = 14.316(9) A, and beta = 117.236(7) degrees, V = 2563.5(3)
      A(3), and exhibits an HT orientation and [ReBr(7-MeG)(2)(CO)(3)] (5) in P2/c with
      a = 17.5117(9) A, b = 9.8842(7) A, c = 15.3539(1) A, and beta = 100.824(7)
      degrees, V = 2610.3(3) A(3), and shows an HH orientation. When crystals of any of
      these complex pairs are dissolved in D(2)O, the (1)H NMR spectrum shows a single
      peak for the H(8) resonance of the respective coordinated purine indicating a
      rapid equilibrium between HH and HT conformations in solution. DFT calculations
      simulating the rotation of one ligand around its Re-N bond showed energetic
      barriers of less than 8.7 kcal/mol. We find no hypochromic effect in the Raman
      spectrum of 3, which showed base stacking in the solid state. Neither steric
      interactions nor hydrogen bonding are important in determining the orientation of
      the ligands in the coordination sphere.

PMID- 15018533
TI  - Experimental and theoretical investigations of structural trends for selenium(IV)
      imides and oxides: X-ray structure of Se3(NAd)2.
AB  - The thermal decomposition of Se(NAd)(2) (Ad = 1-adamantyl) in THF was monitored
      by (77)Se NMR and shown to give the novel cyclic selenium imide Se(3)(NAd)(2) as
      one of the products. An X-ray structural determination showed that Se(3)(NAd)(2)
      is a puckered five-membered ring with d(Se-Se) = 2.404(1) A and |d(Se-N)| =
      1.873(4) A. On the basis of (77)Se NMR data, other decomposition products include
      the six-membered ring Se(3)(NAd)(3), and the four-membered rings AdNSe(micro
      NAd)(2)SeO and OSe(micro-NAd)(2)SeO. The energies for the cyclodimerization of
      E(NR)(2) and RNEO (E = S, Se; R = H, Me, (t)Bu, SiMe(3)), and the cycloaddition
      reactions of RNSeO with E(NR)(2), RNSO(2) with Se(NR)(2), and S(NR)(2) with
      Se(NR)(2) have been calculated at MP2, CCSD, and CCSD(T) levels of theory using
      the cc-pVDZ basis sets and B3PW91/6-31G* optimized geometries. Sulfur(IV) and
      selenium(IV) diimide monomers are predicted to be stable, the sole exception
      being Se(NSiMe(3))(2) that shows a tendency toward cyclodimerization. The
      cyclodimerization energy for RNSeO and the cycloaddition reaction energies of
      RNSeO with Se(NR)(2) as well as that of RNSO(2) with Se(NR)(2) are negative,
      consistent with the observed formation of OSe(micro-N(t)Bu)(2)SeO, OSe(micro
      N(t)Bu)(2)SeN(t)Bu, and O(2)S(micro-N(t)Bu)(2)SeN(t)Bu, respectively.
      Cycloaddition is unlikely when one of the reactants is a sulfur(IV) diimide.

PMID- 15018534
TI  - Iron(II) carboxylate complexes based on a tetraimidazole ligand as models of the
      photosynthetic non-heme ferrous sites: synthesis, crystal structure, and
      Mossbauer and magnetic studies.
AB  - The preparations, X-ray structures, and detailed physical characterization are
      presented for new complexes involving an iron(II) center, a tetraimidazole ligand
      (TIM), and different carboxylates. [Fe(TIM)(C(6)H(5)CH(2)CO(2))](ClO(4)) (1)
      crystallizes in the Pbca space group with a = 10.8947(13), b = 20.343(2), and c =
      22.833(3) A, Z = 8, and V = 5060.6(11) A(3). [Fe(TIM)(CH(3)CO(2))](ClO(4)) (2)
      crystallizes in the Ia space group with a = 17.117(2), b = 10.3358(12), and c =
      25.658(3) A, beta = 90.301(13) degrees, Z = 8, and V = 4539.5(9) A(3). In both
      structures, the iron(II) is hexacoordinated to the four N(imidazole) donors of
      the TIM ligand and the two O donors of a bidentate carboxylate. The flexibility
      of the carboxylate bidentate coordination, symmetrical or more or less
      asymmetrical, associated with the steric demand of the TIM ligand results in a
      remarkable versatility of the Fe(II)N(4)O(2) coordination geometry. The diversity
      in carboxylate bidentate coordination modes has allowed us to clearly show the
      importance of the structural and electronic effects, through IR and Mossbauer
      spectroscopy, of this apparently tenuous carboxylate shift. Comparison of the
      structural and Mossbauer properties of these complexes with the non-heme ferrous
      site of photosynthetic systems (i) shows that the metric parameters of site 2b,
      including the symmetrically chelated bidentate carboxylate, are closer to those
      of the non-heme ferrous site in the bacterial reaction centers of
      Rhodopseudomonas viridis and R. sphaeroides and (ii) suggests that the ligand
      environment of the non-heme ferrous center of PS 2 is close to the axially
      distorted octahedral symmetry resulting from an asymmetrical bidentate
      coordination of the -CO(2) motif, as in complex 1.

PMID- 15018535
TI  - Coordination complexes of molybdenum with 3,6-di-tert-butylcatechol. Addition
      products of DMSO, pyridine N-oxide, and triphenylarsine oxide to the putative
      [MoVIO(3,6-DBCat)2] monomer and self-assembly of the chiral [(MoVIO(3,6
      DBCat)2)4] square.
AB  - Molybdenum complexes of 3,6-di-tert-butylcatechol have been prepared from the
      reaction between [Mo(CO)(6)] and 3,6-di-tert-butyl-1,2-benzoquinone. A putative
      "[MoO(3,6-DBCat)(2)]" monomer is assumed to form initially by reaction with trace
      quantities of oxygen. Condensation of the reaction mixture leads to the formation
      of oligomeric products, including the [(MoO(3,6-DBCat)(2))(4)] chiral square
      isolated by chromatographic separation. Molybdenum centers at the corner of the
      square are bridged by oxo ligands centered along edges. Four-fold and inversion
      crystallographic symmetry gives tetramers as either LambdaLambdaLambdaLambda or
      DeltaDeltaDeltaDelta isomers, and the crystal structure consists of parallel
      columns of squares with the same chirality. Addition of O-Subst (O-Subst = dmso,
      pyridine N-oxide, triphenylarsine oxide) ligands to [MoO(3,6-DBCat)(2)] occurs
      selectively to give cis-[MoO(O-Subst)(3,6-DBCat)(2)] products. All three addition
      complexes are fluxional in solution. The temperature-dependent stereodymanic
      behavior of [MoO(dmso)(3,6-DBCat)(2)] has been shown to occur via a trigonal
      prismatic intermediate (Bailar twist) that conserves the cis disposition of oxo
      and dmso ligands. Electrochemical and chemical reduction reactions have been
      investigated for [MoO(dmso)(3,6-DBCat)(2)] with interest in displacement of
      SMe(2) with formation of cis-[MoO(2)(3,6-DBCat)(2)](2-). Cyclic voltammetry shows
      an irreversible two-electron reduction for the complex at -0.852 V (vs Fc/Fc(+)).
      Chemical reduction using CoCp(2) was observed to give a product with an
      electronic spectrum that is generally associated with cis-[MoO(2)(Cat)(2)](2-)
      complexes. Structural characterization revealed that the product was
      [CoCp(2)][MoO(3,6-DBCat)(2)], possibly formed as the product of dmso displacement
      upon one-electron reduction of [MoO(dmso)(3,6-DBCat)(2)].

PMID- 15018536
TI  - Electron transfer and CO addition to polynitrido cobalt carbonyl clusters:
      parallel pathways for conversion of the [Co10N2(CO)19]4- anion to the novel
      [Co11N2(CO)21]3- anion.
AB  - The redox aptitude of the dinitrido anion [Co10N2(CO)19]4- has been tested from
      both chemical and electrochemical points of view, together with its reactivity
      toward CO that induces disproportionation. In any case, through a remarkable
      overlapping of intermediate steps, the new anion [Co11N2(CO)21]3- (4) is
      eventually obtained. A detailed study of the pathways to 4 allowed the
      identification of three labile intermediates by their characteristic IR spectra
      as well as their electrochemical and paramagnetic properties. The unprecedented
      structure of trianion 4 has been studied in details in two different crystalline
      salts.

PMID- 15018537
TI  - Oxamidate-bridged dinuclear five-coordinate nickel(II) complexes: a magneto
      structural study.
AB  - The preparation, spectroscopic characterization, and magnetic study of three new
      oxamidate-bridged nickel(II) dinuclear complexes of formulas
      ([Ni(Me3[12]aneN3)]2(mu-oa))(PF6)2 (1), ([Ni(Me3[12]aneN3)]2(mu-dmoa))(PF6)2 (2),
      and ([Ni(Me3[12]aneN3)]2(mu-dpoa))(PF6)2 (3) (Me3[12]aneN3 = 2,4,4-trimethyl
      1,5,9-triazacyclododec-1-ene, oa = oxamidate, dmoa = N,N'-dimethyloxamidate, and
      dpoa = N,N'-diphenyloxamidate) are reported. The crystal structures of two of
      them (1 and 3) have been determined. 1 and 3 crystallize in the monoclinic
      system, space group P2(1)/c, with Z = 2 and a = 7.901(4) A, b = 13.597(6) A, c =
      17.565(10) A, and beta = 96.46(4) degrees for 1 and a = 13.854(3) A, b =
      17.469(4) A, c = 12.543(3) A, and beta = 116.22(3) degrees for 3. The structures
      of 1 and 3 consist of dinuclear ([Ni(Me3[12]aneN3)]2(mu-oa))2+ and
      ([Ni(Me3[12]aneN3)]2(mu-dpoa))2+ cations and hexafluorophosphate anions. Each
      nickel in 1-3 is five-coordinate, and the substitution of the hydrogen atom of
      the amidate nitrogen of 1 by a methyl (2) or a phenyl (3) group causes a
      significant modification of the stereochemistry of the nickel(II) ions from
      square pyramidal toward trigonal bipyramidal (tau values of 0.12 and 0.48 for 1
      and 3, respectively). The NOESY spectrum of 3 has allowed us to achieve the
      assignment of the phenyl protons of the N,N'-diphenyloxamidate. The value of
      magnetic coupling between the two nickel(II) ions across the oxamidate bridge [J
      = -57.0 (oa, 1), -38.0 (dmoa, 2) and -30.5 cm(-1) (dpoa, 3)] is very sensitive to
      this stereochemical change, and its variation is explained on the basis of
      orbital considerations. DFT type calculations have been performed to analyze and
      substantiate the trend of the magnetic coupling in 1-3.

PMID- 15018538
TI  - Mechanistic studies on the formation and reactivity of dioxygen adducts of diiron
      complexes supported by sterically hindered carboxylates.
AB  - Dioxygen activation by enzymes such as methane monooxygenase, ribonucleotide
      reductase, and fatty acid desaturases occurs at a nonheme diiron active site
      supported by two histidines and four carboxylates, typically involving a
      (peroxo)diiron(III,III) intermediate in an early step of the catalytic cycle.
      Biomimetic tetracarboxylatodiiron(II,II) complexes with the familiar
      "paddlewheel" topology comprising sterically bulky o-dixylylbenzoate ligands with
      pyridine, 1-methylimidazole, or THF at apical sites readily react with O(2) to
      afford thermally labile peroxo intermediates that can be trapped and
      characterized spectroscopically at low temperatures (193 K). Cryogenic stopped
      flow kinetic analysis of O(2) adduct formation carried out for the three
      complexes reveals that dioxygen binds to the diiron(II,II) center with
      concentration dependences and activation parameters indicative of a direct
      associative pathway. The pyridine and 1-methylimidazole intermediates decay by
      self-decomposition. However, the THF intermediate decays much faster by oxygen
      transfer to added PPh(3), the kinetics of which has been studied with double
      mixing experiments in a cryogenic stopped-flow apparatus. The results show that
      the decay of the THF intermediate is kinetically controlled by the dissociation
      of a THF ligand, a conclusion supported by the observation of saturation kinetic
      behavior with respect to PPh(3), inhibition by added THF, and invariant
      saturation rate constants for the oxidation of various phosphines. It is proposed
      that the proximity of the reducing substrate to the peroxide ligand on the diiron
      coordination sphere facilitates the oxygen-atom transfer. This unique
      investigation of the reaction of an O(2) adduct of a biomimetic
      tetracarboxylatodiiron(II,II) complex provides a synthetic precedent for
      understanding the electrophilic reactivity of like adducts in the active sties of
      nonheme diiron enzymes.

PMID- 15018539
TI  - One-dimensional cobalt diphosphonates exhibiting weak ferromagnetism and field
      induced magnetic transitions.
AB  - This paper reports two new cobalt phosphonate compounds
      [NH3(CH2)nNH3]Co2(hedpH)2.2H2O [n = 4 (1), 5 (2)], where hedp is (1
      hydroxyethylidene)diphosphonate [CH3C(OH)(PO3)2]. Both contain ladderlike chains
      with the same composition [Co2(hedpH)2](n)(2n-), where edge-shared [CoO6]
      octahedra are each bridged by O-P-O units. The chains are linked by very strong
      hydrogen bonds to form a three-dimensional open network with channels in which
      the diammonium counterions and lattice water reside. Magnetic studies reveal
      dominant antiferromagnetic interactions between the Co centers within the chain
      in both compounds. The field dependent magnetization confirms the occurrence of
      the field-induced magnetic transitions, with the critical fields ca. 25 kOe for 1
      and 27.5 kOe for 2, respectively. In the case of compound 2, weak ferromagnetism
      is also observed at very low temperatures, possibly arising from spin canting of
      the antiferromagnetically coupled Co(II) ions in the chain. Crystal data: 1,
      monoclinic, P2(1)/c, a = 5.4868(8), b = 12.9116(18), and c = 15.251(2) A, beta =
      98.843(2) degrees, V = 1067.6(3) A(3), Z = 2; 2, monoclinic, P2(1)/c, a =
      5.4757(7), b = 12.7740(16), and c = 15.794(2) A, beta = 98.797(2) degrees, V =
      1091.7(2) A(3), Z = 2.

PMID- 15018541
TI  - Aluminum complexes incorporating bidentate amido phosphine ligands.
AB  - A series of aluminum complexes supported by o-phenylene-derived amido phosphine
      ligands, N-(2-diphenylphosphinophenyl)-2,6-dimethylanilide ([Me-NP]-) and N-(2
      diphenylphosphinophenyl)-2,6-diisopropylanilide ([iPr-NP]-), have been prepared.
      The reactions of trialkylaluminum with H[Me-NP] and H[iPr-NP], respectively, in
      refluxing toluene produced the corresponding dialkyl complexes [Me-NP]AlR(2) and
      [iPr-NP]AlR(2) (R = Me, Et). Deprotonation of H[Me-NP] with n-BuLi in THF at -35
      degrees C followed by addition of AlCl(3) in toluene at -35 degrees C afforded
      [Me-NP]AlCl(2), which was subsequently reacted with 2 equiv of
      trimethylsilylmethyllithium in toluene to give [Me-NP]Al(CH(2)SiMe(3))(2). The
      aluminum complexes were all characterized by (1)H, (13)C, (31)P, and (27)Al NMR
      spectroscopy. The solid-state structures of monomeric, four-coordinate [Me
      NP]AlEt(2) and [iPr-NP]AlMe(2) and five-coordinate [Me-NP]AlCl(2)(THF) were
      determined by X-ray crystallography. The (1)H NMR studies of [Me-NP]AlEt(2), [Me
      NP]Al(CH(2)SiMe(3))(2), and [iPr-NP]AlEt(2) indicate diastereotopic alpha
      hydrogen atoms in these molecules. Heteronuclear COSY and NOE experiments suggest
      that the phosphorus donor in [Me-NP]Al(CH(2)SiMe(3))(2) and [iPr-NP]AlEt(2) is
      coupled to only one of the diastereotopic alpha-hydrogen atoms that is virtually
      antiperiplanar with respect to the phosphorus atom.

PMID- 15018540
TI  - (Bis(1,2,4-triazol-1-yl)methane)silver(I) phosphino complexes: structures and
      spectroscopic properties of mixed-ligand coordination polymers.
AB  - Adducts of the ligand bis(1,2,4-triazol-1-yl)methane (tz(2)(CH(2))) of the form
      AgX:tz(2)(CH(2)):ER(3):MeCN (1:1:1:x) (X = NO(3), R = Ph, E = P, As, or Sb, x = 1
      or 2; X = NO(2), ClO(4), O(3)SCF(3), E = P, R = Ph, x = 0, 1 or 2; X = NO(3),
      ClO(4), E = P, R = cy, x = 1; X = ClO(4), E = As, R = Ph, x = 2) and
      AgNO(3):tz(2)(CH(2)):P(o-tolyl)(3) (2:2:1) have been synthesized and
      characterized in the solid state and in solution by analyses, spectral (IR, far
      IR, (1)H and (13)C NMR, ESI MS data) data, and conductivity measurements. In the
      one-dimensional polymers (characterized by X-ray studies)
      AgNO(3):tz(2)(CH(2)):PPh(3):CH(3)CN (1:1:1:1),
      AgClO(4):tz(2)(CH(2)):PPh(3):CH(3)CN (1:1:1:2), AgNO(3):tz(2)(CH(2)):AsPh(3):
      CH(3)CN (1:1:1:2), and AgNO(3):tz(2)(CH(2)):SbPh(3):CH(3)CN (1:1:1:2), the silver
      atom can be regarded as four-coordinate, the tz(2)(CH(2)) ligands behaving as
      bridging groups rather than chelates, with no pair of ligands being dominant,
      quasi-trans, in their interactions. The AgNO(3):tz(2)(CH(2)):P(o-tolyl)(3)
      (2:2:1) adduct is a two-dimensional polymer containing two independent silver
      atoms, one four-coordinated unsymmetrically by a pair of triazolyl rings, one P(o
      tolyl)(3), and a unidentate nitrate and the second by a quasi-symmetrical O(2)NO
      chelate and a pair of equivalent triazolyl rings.

PMID- 15018542
TI  - Toward a catalytic cycle for the Mn-salen mediated alkene epoxidation: a
      computational approach.
AB  - BP86 density functional calculations for the title reaction are presented, where
      a model catalyst with hypochlorite as oxygen-containing counter ligand,
      (ClO)(O)Mn(acacen') (acacen' = -O(CH)3N-C2H4-N(CH)3O-), is employed. The
      epoxidation reaction on potential energy surfaces corresponding to an overall
      spin-density of two and four unpaired electrons is investigated. The presence of
      the hypochlorite ligand is found to cause the reaction to proceed under
      conservation of spin. Further, the oxygen-containing counter ligand causes
      reoxidation of the Mn-center, thus closing the catalytic cycle. A catalytic
      scheme is therefore proposed, which includes a step of regeneration of the
      catalytically active species. Energetic estimates including corrections for
      solvent effects are presented for the relevant steps constituting the proposed
      catalytic scheme.

PMID- 15018543
TI  - Metal-induced coordination inversion and carbon-nitrogen bond rearrangement.
      Structurally characterized phenyl isocyanate inserted into aluminum methyl
      compounds and O- and N-bound aluminum compounds.
AB  - [C(4)H(3)N(CH(2)NMe(2))-2]AlMe(2) (1) is prepared in 88% yield by the reaction of
      substituted pyrrole [C(4)H(4)N(CH(2)NMe(2))-2] with 1 equiv of AlMe(3) in
      methylene chloride. Reaction of compound 1 with 1 equiv of phenyl isocyanate in
      toluene generates a seven-membered cycloaluminum compound
      [C(4)H(3)N[CH(2)NPh(CONMe(2))]-2] AlMe(2) (2). The phenyl isocyanate was inserted
      into the aluminum and dimethylamino nitrogen bond and induced an unusual
      rearrangement which results in C-N bond breaking and formation. A control
      experiment shows that the reaction of substituted pyrrole [C(4)H(4)N(CH(2)NMe(2))
      2] with 1 equiv of phenyl isocyanate in diethyl ether yields a pyrrolyl attached
      urea derivative [C(4)H(3)N(CH(2)NMe(2))-2-[C(=O)NHPh]-1] (3). The demethanation
      reaction of AlMe(3) with 1 equiv of 3 in methylene chloride at 0 degrees C
      afforded O-bounded and N-bounded aluminum dimethyl compounds
      [C(4)H(3)N(CH(2)NMe(2))-2-[C(=O)NPh]-1]AlMe(2) (4a) and [C(4)H(3)N(CH(2)NMe(2))-2
      [CO(=NPh)]-1]AlMe(2) (4b) in a total 78% yield after recrystallization. Both 4a
      and 4b are observed in (1)H NMR spectra; however, the relative ratio of 4a and 4b
      depends on the solvent used. Two equivalents of AlMe(3) was reacted with 3 in
      methylene chloride to yield a dinuclear aluminum compound
      AlMe(3)[C(4)H(3)N(CH(2)NMe(2))-2-[C(=O)NPh]-1] AlMe(2) (5). Reaction of 5 with
      another equivalent of ligand 3 results in the re-formation of compounds 4a and
      4b.

PMID- 15018544
TI  - Investigation of hydrothermal routes to mixed-metal cerium titanium oxides and
      metal oxidation state assignment using XANES.
AB  - The reaction between TiF(3) or TiO(2) and Ce(3+) in sodium hydroxide solutions
      yields highly crystalline NaCeTi(2)O(6) at room temperature and under mild
      hydrothermal conditions (T < or = 240 degrees C). There is no evidence for the
      formation of ternary Ce-Ti-O materials by this method, and the use of bases other
      than NaOH always produces poorly crystalline materials. The material
      NaCeTi(2)O(6) has a distorted perovskite structure with sodium and cerium ions
      randomly occupying the A sites: Pnma, a = 5.4517(8) A, b = 7.7292(6) A, c
      =5.4573(3) A. XANES spectroscopy at the Ti K edge and Ce L(III) edge, with
      reference to crystalline model compounds, reveals that cerium is found solely as
      Ce(III) and titanium as Ti(IV) in NaCeTi(2)O(6). Isomorphous substitution of
      Ce(3+) by Nd(3+) or Ti(4+) by V(4+) is found to be very facile under hydrothermal
      conditions (at a temperature of 240 degrees C), by addition of appropriate
      amounts of metal salts to the hydrothermal reaction mixtures. The series NaCe(1
      x)Nd(x)Ti2O6 (0 < or = x < or = 1) and NaCeTi(2-x)V(x)O6 (0 <or = x < or = 1.8)
      can be formed directly in one step, and all materials were characterized by
      powder X-ray diffraction. The oxidation states of the substituent elements were
      determined using XANES spectroscopy, which further demonstrates that isomorphous
      substitution has taken place, with all vanadium present as V(IV) when the B site
      is substituted. Scanning electron microscopy analysis of the solids shows them to
      be made up of irregularly shaped particles made up of clusters of submicron-sized
      crystallites but that on firing in excess of 1000 degrees C the particle size is
      increased to approximately 10 microm and the particles have distinct, sharp
      edges.

PMID- 15018545
TI  - Synthesis and characterization of ionic liquids incorporating the nitrile
      functionality.
AB  - A series of imidazolium salts with the nitrile functional group attached to the
      alkyl side chain, viz. [CnCNmim][X] (where CnCNmim is the 1-alkylnitrile-3
      methylimidazolium cation and Cn= (CH2)(n), n = 1-4; X = Cl, PF(6), and BF(4)) and
      [C3CNdmim][X] (where CnCNdmim is the 1-alkylnitrile-2,3-dimethylimidazolium
      cation and C(n) = (CH2)(n), n = 3; X = Cl, PF(6), and BF(4)), have been prepared
      and characterized using spectroscopic methods. The majority of the nitrile
      functionalized imidazolium salts can be classed as ionic liquids since they melt
      below 100 degrees C. Four of the imidazolium salts have been characterized in the
      solid state using single-crystal X-ray diffraction analysis to reveal an
      extensive series of hydrogen bonds between H atoms on the cation and the anion.
      The relationship between the solid-state structure and the melting point is
      discussed. Key physical properties (density, viscosity, and solubility in common
      solvents) of the low melting ionic liquid have been determined and are compared
      with those of the related 1-alkyl-3-methylimidazolium and 1-alkyl-2,3
      dimethylimidazolium ionic liquids. It was envisaged that these ionic liquids
      could act as both solvent and ligand for catalyzed reactions, and this
      application is demonstrated in hydrogenation reactions, which show that retention
      of the catalyst in the ionic liquid during product extraction is extremely high.

PMID- 15018546
TI  - First characterization of the ammine-ammonium complex [(NH4(NH3)4)2(mu-NH3)2]2+
      in the crystal structure of [NH4(NH3)4][B(C6H5)4].NH3 and the [NH4(NH3)4]+
      complex in [NH4(NH3)4][Ca(NH3)7]As3S6.2NH3 and [NH4(NH3)4][Ba(NH3)8]As3S6.NH3.
AB  - The compound [NH4(NH3)4][B(C6H5)4].NH3 (1) was prepared by the reaction of
      NaB(C(6)H(5))(4) with a proton-charged ion-exchange resin in liquid ammonia.
      [NH(4)(NH(3))(4)][Ca(NH(3))(7)]As(3)S(6).2NH(3) (2) and
      [NH4(NH3)4][Ba(NH3)8]As3S6.NH3 (3) were synthesized by reduction of As(4)S(4)
      with Ca and Ba in liquid ammonia. All ammoniates were characterized by low
      temperature single-crystal X-ray structure analysis. They were found to contain
      the ammine-ammonium complex with the maximal possible number of coordinating
      ammonia molecules, the [NH4(NH3)4]+ ion. 1 contains a special dimer, the
      [(NH4(NH3)4)2(mu-NH3)2]2+ ion, which is formed by two[NH4(NH3)4]+ ions linked by
      two ammonia molecules. The H(3)N-H...N hydrogen bonds in all three compounds
      range from 1.82 to 2.20 A (DHA = Donor-H... Acceptor angles: 156-178 degrees). In
      2 and 3, additional H(2)N-H...S bonds to the thioanions are observed, ranging
      between 2.49 and 3.00 A (DHA angles: 120-175 degrees). Two parallel phenyl rings
      of the [B(C(6)H(5))(4)](-) anion in 1 form a pi...pi hydrogen bond (C...C
      distance, 3.38 A; DHA angles, 82 degrees), leading to a dimeric [B(C6H5)4]2(2-)
      ion.

PMID- 15018547
TI  - Carbene complexes of rhodium and iridium from tripodal N-heterocyclic carbene
      ligands: synthesis and catalytic properties.
AB  - Two tripodal trisimidazolium ligand precursors have been tested in the synthesis
      of new N-heterocyclic carbene rhodium and iridium complexes. [Tris(3
      methylbenzimidazolium-1-yl)]methane sulfate gave products with coordination of
      the decomposed precursor. [1,1,1-Tris(3-butylimidazolium-1-yl)methyl]ethane
      trichloride (TIMEH(3)(Bu)) coordinated to the metal in a chelate and bridged
      chelate form, depending on the reaction conditions. The crystal structures of two
      of the products are described. The compounds resulting from the coordination with
      TIME(Bu) were tested in the catalytic hydrosilylation of terminal alkynes.

PMID- 15018550
TI  - Ion "threshing": collisionally activated dissociation in an external octopole ion
      trap by oscillation of an axial electric potential gradient.
AB  - We have implemented efficient and rapid collisionally activated dissociation
      (CAD) external to an ICR cell by use of a novel axial electric potential gradient
      mounted in an external ion accumulation octopole. The gradient is produced by
      eight tilted (in the axial direction) wires mounted between the rods of the
      octopole. Rapid switching of the wire potential between a positive and negative
      value drives the ion axial motion back and forth and, in the presence of nitrogen
      gas at suitable pressure, induces dissociation. A fragmentation period on the
      order of tens of milliseconds is typical. Precursor ion isolation is achieved in
      a quadrupole mass filter mounted between the electrospray source and the
      accumulation octopole. A scan rate of >1 Hz is possible with resolving power and
      mass accuracy equivalent to direct infusion experiments (for equivalent detection
      period for 1 scan). The method is thus sufficiently rapid for MS/MS with on-line
      LC sample introduction. Moreover, compared to CAD in the ICR cell, external CAD
      improves mass accuracy, producing thermal on-axis fragment ions for detection.

PMID- 15018551
TI  - Tissue molecular ion imaging by gold cluster ion bombardment.
AB  - The use of gold cluster focused ion beams produced by a liquid metal ion gun in a
      TOF-SIMS mass spectrometer is shown to dramatically enhance secondary ion
      emission of phospholipids and peptides. The method has been successfully tested
      with cells grown onto plastic slips and with mouse brain slices, without any
      treatment of the samples. Very reliable time-of-flight mass spectra are acquired
      with a low primary ion dose of a few 10(7) ions, and high lateral resolution
      molecular ion images are obtained for heavy ions of great biological interest.
      This approach offers new opportunities in pharmacological and biological research
      fields by localizing compounds of interest such as drugs or metabolites in
      tissues.

PMID- 15018553
TI  - Dielectrophoretic concentration and separation of live and dead bacteria in an
      array of insulators.
AB  - Insulator-based (electrodeless) dielectrophoresis (iDEP) is an innovative
      approach in which the nonuniform electric field needed to drive DEP is produced
      by insulators, avoiding problems associated with the use of electrodes. Live and
      dead Escherichia coli were concentrated and selectively released by applying
      stepped DC voltages across a microchannel containing an array of insulating posts
      etched in glass. The only electrodes present were two platinum wires placed in
      the inlet and outlet reservoirs, producing mean electric fields of up to 200 V/mm
      across the insulators. The cells were labeled with Syto 9 and propidium iodide
      and imaged through a fluorescent microscope. Cell trapping and release were
      controlled by modifying the relative responses of electrokinesis and DEP by
      adjusting the magnitude of the applied voltage. Dead cells were observed to have
      significantly lower dielectrophoretic mobility than live cells, whereas the
      electrokinetic mobilities of live and dead cells were indistinguishable. The
      locations of the bands of differentially trapped cells were consistent with
      predictions. In addition, cells were selectively trapped and concentrated against
      backgrounds of 1- and 0.2-microm carboxylate-modified polystyrene particles. This
      first application of iDEP for simultaneous live/dead bacteria separation and
      concentration illustrates its potential as a front-end method for bacterial
      analysis.

PMID- 15018552
TI  - Serum peptide profiling by magnetic particle-assisted, automated sample
      processing and MALDI-TOF mass spectrometry.
AB  - Human serum contains a complex array of proteolytically derived peptides (serum
      peptidome) that may provide a correlate of biological events occurring in the
      entire organism; for instance, as a diagnostic for solid tumors (Petricoin, E.
      F.; Ardekani, A. M.; Hitt, B. A.; Levine, P. J.; Fusaro, V. A.; Steinberg, S. M.;
      Mills, G. B.; Simone, C.; Fishman, D. A.; Kohn, E. C.; Liotta, L. Lancet 2002,
      359, 572-577). Here, we describe a novel, automated technology platform for the
      simultaneous measurement of serum peptides that is simple, scalable, and
      generates highly reproducible patterns. Peptides are captured and concentrated
      using reversed-phase (RP) batch processing in a magnetic particle-based format,
      automated on a liquid handling robot, and followed by a MALDI TOF mass
      spectrometric readout. The protocol is based on a detailed investigation of serum
      handling, RP ligand and eluant selection, small-volume robotics design, an
      optimized spectral acquisition program, and consistent peak extraction plus
      binning across a study set. The improved sensitivity and resolution allowed
      detection of 400 polypeptides (0.8-15-kDa range) in a single droplet
      (approximately 50 microL) of serum, and almost 2000 unique peptides in larger
      sample sets, which can then be analyzed using common microarray data analysis
      software. A pilot study indicated that sera from brain tumor patients can be
      distinguished from controls based on a pattern of 274 peptide masses. This, in
      turn, served to create a learning algorithm that correctly predicted 96.4% of the
      samples as either normal or diseased.

PMID- 15018554
TI  - Mouse embryonic stem cell sorting for the generation of transgenic mice by
      sedimentation field-flow fractionation.
AB  - Mouse embryonic stem (ES) cells are an important tool for generation of
      transgenic mice and genetically modified mice. A rapid and efficient separation
      of ES cells that respects cell integrity, viability, and their developmental
      potential while also allowing purified ES fraction collection under sterile
      conditions might be of great interest to facilitate the generation of chimeric
      animals. In this study, we demonstrated for the first time the effectiveness of a
      sedimentation field-flow fractionation (SdFFF) cell sorter to provide, with a
      characteristic DNA content, a purified ES cell fraction and with a high in vivo
      developmental potential to prepare transgenic mice by generation of chimeras
      having a high percentage of chimerism.

PMID- 15018555
TI  - X-ray fluorescence tomography of individual municipal solid waste and biomass fly
      ash particles.
AB  - Information about Cd distribution inside single municipal solid waste and biomass
      fly ash particles is fundamental since it affects its leachability. The internal
      2D distributions of the main and trace elements in such highly inhomogeneous
      matrixes were successfully determined by means of the combined synchrotron
      radiation induced micro X-ray fluorescence (micro-SRXRF) and tomography (micro
      SRXRFT) techniques. Scanning micro-SRXRF measurements show Cd elemental
      distribution within single fly ash particles to be inhomogeneous, but no
      information can be obtained about its internal distribution. During micro-SRXRFT
      analysis, single fly ash particles are successively measured by a rotational
      translational scan in a VH=2 x 5 microm2 microbeam. The 2D internal elemental
      distribution images, obtained by the modified simultaneous algebraic
      reconstruction technique algorithm, provide the size and the location of Cd
      containing areas together with the location of other measurable elements. Results
      showed Cd concentration to be higher in the core of the fly ash particles
      analyzed rather than on the surface of the particles. Moreover, in both ashes, Ca
      containing matrixes are found to be the main Cd-bearing phases. A possible
      mechanism for Cd adsorption on the fly ash particles is proposed based on the
      obtained results.

PMID- 15018556
TI  - Microextended X-ray absorption fine structure studies of cadmium speciation
      within single municipal solid waste fly ash particles.
AB  - The local chemical structure of trace amounts of cadmium within microvolumes of
      highly inhomogeneous municipal solid waste fly ash particles was successfully
      monitored by means of micro-EXAFS. A new quantification procedure was developed
      for the evaluation of the micro-EXAFS data sets obtained from each individual
      particle based on a reverse Monte Carlo simulation. Evidence has been presented
      for the existence of cadmium silicate and cadmium chloride, with the cadmium
      silicate being the dominant form, and it has been demonstrated that the cadmium
      exists in both crystalline and amorphous states within the microspots analyzed.

PMID- 15018557
TI  - In situ electrochemical-NMR spectroscopy. Reduction of aromatic halides.
AB  - A three-electrode, two-compartment cylindrical electrochemical cell has been
      constructed for in situ operation in a 500 MHz 1H NMR spectrometer. The cell was
      designed around a standard 10-mm sample tube holder and is lowered into position
      within the magnet by height-adjustable aluminum rods that support the wires
      connecting the potentiostat to the working, auxiliary and reference electrodes.
      The electrochemical cell functions under diffusion-controlled conditions in
      nonspinning mode and is able to operate under variable temperature and oxygen
      free regimes. The working electrode consists of a 10-nm-thick gold film deposited
      onto the surface of a 7.49-mm-o.d. glass NMR tube that is located directly within
      the radio frequency coils of the NMR probe. The NMR spectra were collected
      simultaneously to the current flowing during the electrolysis with typical NMR
      line widths being approximately 2 Hz. The highly symmetrical nature of the cell
      design meant that probe tuning and gradient shimming changed minimally between
      experiments, which allowed standard shim sets to be saved and recalled for later
      use, thereby greatly reducing the time taken for tuning processes. Insertion and
      removal of the cell from within the magnet is achieved within a few seconds,
      which combined with the rapid shimming process makes the cell suitable for
      routine operation. The cell was used to study the in situ reduction of 9
      bromoanthracene, 9-chloroanthracene, and 4-bromobenzophenone in deuterated
      acetonitrile with tetrabutylammonium hexafluorophosphate as the supporting
      electrolyte.

PMID- 15018559
TI  - Focal volume confinement by submicrometer-sized fluidic channels.
AB  - Microfluidic channels with two lateral dimensions smaller than 1 microm were
      fabricated in fused silica for high-sensitivity single-molecule detection and
      fluorescence correlation spectroscopy. The effective observation volumes created
      by these channels are approximately 100 times smaller than observation volumes
      using conventional confocal optics and thus enable single-fluorophore detection
      at higher concentrations. Increased signal-to-noise ratios are also attained
      because the molecules are restricted to diffuse through the central regions of
      the excitation volume. Depending on the channel geometries, the effective
      dimensionality of diffusion is reduced, which is taken into account by simple
      solutions to diffusion models with boundaries. Driven by electrokinetic forces,
      analytes could be flowed rapidly through the observation volume, drastically
      increasing the rate of detection events and reducing data acquisition times. The
      statistical accuracy of single-molecule characterization is improved because all
      molecules are counted and contribute to the analysis. Velocities as high as 0.1
      m/s were reached, corresponding to average molecular residence times in the
      observation volume as short as 10 micros. Applications of these nanofabricated
      devices for high-throughput, single-molecule detection in drug screening and
      genomic analysis are discussed.

PMID- 15018558
TI  - Amperometric detection of nucleic acid at femtomolar levels with a nucleic
      acid/electrochemical activator bilayer on gold electrode.
AB  - Cationic redox polymers containing osmium-bipyridine complexes strongly interact
      with anionic enzymes, such as glucose oxidase and peroxidases, and
      electrochemically "activate" the enzymes. On the basis of these observations,
      attempts were made to develop an ultrasensitive nucleic acid biosensor. A mixed
      monolayer of single-stranded oligonucleotide capture probe and 16
      mercaptohexadecanoic acid was formed on a gold electrode through self-assembly.
      Following hybridization with a complementary nucleic acid and glucose oxidase
      labeled oligonucleotide detection probe, a cationic redox polymer
      (electrochemical activator) overcoating was applied to the electrode through
      layer-by-layer electrostatic self-assembly. The formation of an anionic-cationic
      bilayer brought the glucose oxidase in electrical contact with the redox polymer,
      making the bilayer an electrocatalyst for the oxidation of glucose. Thus, nucleic
      acid molecules were quantified amperometrically at femtomolar levels. The effect
      of experimental variables on the amperometric response was investigated and
      optimized to maximize the sensitivity and speed up the assay time. A detection
      limit of 1.0 fmol/L in 1.0-microL droplets and a linear current-concentration
      relationship up to 800 fmol/L were attained following a 30-min hybridization. The
      biosensor was applied to the detection of the 16S gene in a mixture of
      Escherichia coli 16S + 32S rRNA and a full-length rat housekeeping gene,
      glyceraldehyde-3-phosphate dehydrogenase (GAPDH), of a RT-PCR product.

PMID- 15018560
TI  - Adenosine-dependent assembly of aptazyme-functionalized gold nanoparticles and
      its application as a colorimetric biosensor.
AB  - Previous work has shown that DNAzyme-directed assembly of gold nanoparticles can
      be utilized to make effective colorimetric biosensors. However, the method is
      restricted to analytes that are directly involved in phosphodiester cleavage. To
      expand the methodology to a broader range of analytes, a colorimetric adenosine
      biosensor based on the aptazyme-directed assembly of gold nanoparticles is
      reported here. The aptazyme is based on the 8-17 DNAzyme with an adenosine
      aptamer motif that can modulate the DNAzyme activity through allosteric
      interactions depending on the presence of adenosine. In the absence of adenosine,
      the aptazyme is inactive and the substrate strands can serve as linkers to
      assemble DNA-functionalized 13-nm-diameter gold nanoparticles, resulting in a
      blue color. However, the presence of adenosine activates the aptazyme, which
      cleaves the substrate strand, disrupting the formation of nanoparticle
      aggregates. A red color of separated gold nanoparticles is observed.
      Concentrations of adenosine of up to 1 mM can be measured semiquantitatively by
      the degree of blue to red color changes or quantitatively by the extinction ratio
      at 520 and 700 nm. Under the same conditions, 5 mM guanosine, cytidine, or
      uridine resulted in a blue color only, indicating good selectivity of the sensor.
      The color difference can be clearly observed by the naked eye by spotting the
      resulting sensor solution onto an alumina TLC plate. Since aptamers that can
      target many classes of important analytes have already been selected, they can be
      adapted into aptazyme systems through rational design or further selection. Thus,
      colorimetric biosensors for many analytes of interest can be designed using the
      method presented here, regardless of whether the analytes are directly involved
      in the cleavage reaction or not.

PMID- 15018561
TI  - Multiparameter microscopy and spectroscopy for single-molecule analytics.
AB  - The ability to monitor several parameters simultaneously from distinct individual
      fluorescent reporter molecules facilitates the disentanglement of complex and
      interacting systems and opens new perspectives in areas from basic science to
      biopharmaceutical technology. By combining annular illumination microscopy, time
      correlated single-photon counting, and multichannel detection, we were able to
      determine 14 independent parameters from one individual fluorophore. The whole
      set of parameters was deduced from the few properties of the fluorescence
      photons, i.e., arrival time, wavelength, and polarization. With this approach,
      the intensity, the polarization, and the spectral dynamics can be analyzed on a
      nanosecond time scale and the mean values can be monitored with submillisecond
      time resolution. Nanosecond spectral dynamics of single molecules has been
      observed, to the best of our knowledge, for the first time. From our experience,
      we can determine all parameters for more than 30% of the illuminated fluorophores
      in biological samples and for more than 80% in doped polymeric films.

PMID- 15018562
TI  - Microcontact printing of DNA molecules.
AB  - The controlled placement of DNA molecules onto solid surfaces is the first step
      in the fabrication of DNA arrays. The sequential deposition of tiny drops
      containing the probe DNA fragments using arrays of spotting needles or ink jet
      nozzles has become a standard. However, a caveat of liquid spotting is the drying
      of the deposited drop because this creates the typical inhomogeneities, i.e.,
      rims around the spot. Another drawback is that each DNA array is an original and
      has to be fabricated individually. Microcontact printing is a versatile technique
      to place proteins onto different target surfaces in uniformly patterned
      monolayers with high lateral resolution. Here, we show for the first time that
      DNA can also be printed with equally high resolution in the submicrometer range
      using an elastomeric stamp with chemically tailored surface. Two regimes for the
      transfer of the molecules were observed. Finally, microcontact printing of an
      array of DNA probes onto a solid support and its use in a subsequent
      hybridization assay was demonstrated.

PMID- 15018563
TI  - Microanalysis by laser-induced plasma spectroscopy in the vacuum ultraviolet.
AB  - A new setup for microanalysis by laser-induced plasma spectroscopy in the VUV
      range is presented and described in detail. The system features an integrated
      ablation and detection module with a newly designed VUV echelle system. The
      echelle permits a full spectral coverage between 150 and 300 nm with a resolving
      power lambda/Deltalambda between 11,000 and 15,000. At present, the ablation
      module permits a microanalysis with a crater size of 25 microm and a nominal
      depth resolution with an ablation rate of 150 nm/pulse. The VUV performance was
      demonstrated for bulk analysis of steel; detection limits for sulfur, carbon, and
      phosphorus were in the lower milligram per kilogram range. The VUV scanning and
      mapping performance for heterogeneous matrixes was illustrated for mineral bottom
      ash samples from a waste incineration process.

PMID- 15018564
TI  - In situ MALDI-TOF MS regional analysis of neutral phospholipids in lens tissue.
AB  - Phospholipids (PLs) are important sources of lipid second messengers that
      participate in cell signaling pathways. Consequently, their analysis in
      biological tissues has received increased attention. Current approaches for PL
      analysis include an extraction step and subsequent identification of the main PL
      classes by either 31P NMR spectroscopy or chromatographic separation followed by
      mass spectrometric detection. Previous in vitro studies revealed regional changes
      in the PL composition of mammalian lenses at different growth stages. In this
      report, we demonstrate the feasibility of direct in situ analysis of two relevant
      PL classes, phosphatidylcholines (PCs) and sphingomyelins (SMs), in slices of
      fresh or fixed (2.5% formaldehyde) mammalian lenses. The chosen matrix was p
      nitroaniline, as it generated superior sensitivity when compared to 2,5
      dihydroxybenzoic acid, the compound most commonly used for in vitro analysis of
      PLs by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF)
      mass spectrometry (MS). Regional differences in the relative amounts of PCs and
      SMs were in agreement with trends demonstrated by previous in vitro studies.
      Fresh and fixed tissue of the same lens gave comparable relative levels of PCs
      and SMs. In situ analysis of PLs by MALDI-TOF MS offers a rapid and sensitive
      tool for the mapping of PLs in biological tissues.

PMID- 15018565
TI  - Statistical models for protein validation using tandem mass spectral data and
      protein amino acid sequence databases.
AB  - The purpose of this work is to develop and verify statistical models for protein
      identification using peptide identifications derived from the results of tandem
      mass spectral database searches. Recently we have presented a probabilistic model
      for peptide identification that uses hypergeometric distribution to approximate
      fragment ion matches of database peptide sequences to experimental tandem mass
      spectra. Here we apply statistical models to the database search results to
      validate protein identifications. For this we formulate the protein
      identification problem in terms of two independent models, two-hypothesis
      binomial and multinomial models, which use the hypergeometric probabilities and
      cross-correlation scores, respectively. Each database search result is assumed to
      be a probabilistic event. The Bernoulli event has two outcomes: a protein is
      either identified or not. The probability of identifying a protein at each
      Bernoulli event is determined from relative length of the protein in the database
      (the null hypothesis) or the hypergeometric probability scores of the protein's
      peptides (the alternative hypothesis). We then calculate the binomial probability
      that the protein will be observed a certain number of times (number of database
      matches to its peptides) given the size of the data set (number of spectra) and
      the probability of protein identification at each Bernoulli event. The ratio of
      the probabilities from these two hypotheses (maximum likelihood ratio) is used as
      a test statistic to discriminate between true and false identifications. The
      significance and confidence levels of protein identifications are calculated from
      the model distributions. The multinomial model combines the database search
      results and generates an observed frequency distribution of cross-correlation
      scores (grouped into bins) between experimental spectra and identified amino acid
      sequences. The frequency distribution is used to generate p-value probabilities
      of each score bin. The probabilities are then normalized with respect to score
      bins to generate normalized probabilities of all score bins. A protein
      identification probability is the multinomial probability of observing the given
      set of peptide scores. To reduce the effect of random matches, we employ a
      marginalized multinomial model for small values of cross-correlation scores. We
      demonstrate that the combination of the two independent methods provides a useful
      tool for protein identification from results of database search using tandem mass
      spectra. A receiver operating characteristic curve demonstrates the sensitivity
      and accuracy level of the approach. The shortcomings of the models are related to
      the cases when protein assignment is based on unusual peptide fragmentation
      patterns that dominate over the model encoded in the peptide identification
      process. We have implemented the approach in a program called PROT_PROBE.

PMID- 15018566
TI  - Liquid chromatography with mass spectrometry in tandem mode applied for the
      identification of wine markers in residues from ancient Egyptian vessels.
AB  - Presented in this paper is a new method for the identification of tartaric acid
      as a wine marker in archaeological residues from Egyptian vessels using liquid
      chromatography with mass spectrometry in tandem mode (LC/MS/MS). Owing to the
      special characteristics of these samples, such as the dryness and the small
      quantity available for analysis, it was necessary to have a very sensitive and
      highly specific analytical method to detect tartaric acid at trace levels in the
      residues. Furthermore, an alkaline fusion was carried out to identify syringic
      acid derived from malvidin as a red wine marker, in a deposit residue from a wine
      jar found at the tomb of king Tutankhamun. Malvidin-3-glucoside, the main
      anthocyanin that gives young wines their red color, polymerizes with aging into
      more stable pigments. However, the presence of malvidin in ancient residues can
      be proved by alkaline fusion of the residue to release syringic acid from the
      pigment, which has been identified, here for the first time, by using the
      LC/MS/MS method revealing the red grape origin of an ancient Egyptian wine
      residue.

PMID- 15018567
TI  - A feasibility study of solid supported enhanced microdialysis.
AB  - For the first time, a solid supported enhanced microdialysis methodology for
      analysis of neuropeptides is described. The microdialysis samples were, in this
      study, subsequently collected in fractions, dissolved from the solid particles,
      dried, and resolved in a formic acid buffer in order to make them suitable for
      capillary liquid chromatography-mass spectrometry. Different microdialysis flow
      profiles were evaluated where air-gapped continuous flow was considered most
      suitable for the solid supported microdialysis mode. Six endogenous neuropeptides
      were initially used to investigate the feasibility of this enhanced microdialysis
      methodology. The improved relative recovery obtained from the solid supported
      enhanced microdialysis was varying from no effect to 10 times higher as compared
      to ordinary microdialysis. The most efficient enrichment was obtained for
      luteinizing hormone releasing hormone, which was the largest but also the most
      hydrophilic of the peptides. In contrast, no significant difference in recovery
      was observed for Leu-enkephalin being the smallest and the most hydrophobic
      peptide tested. These results indicate an increased flux and selective uptake of
      hydrophilic peptides across the membrane and enrichment on the particles in solid
      supported microdialysis.

PMID- 15018568
TI  - Simultaneous quantification of human cardiac alpha- and beta-myosin heavy chain
      proteins by MALDI-TOF mass spectrometry.
AB  - We have developed a novel method for quantifying protein isoforms, in both
      relative and absolute terms, based on MALDI-TOF mass spectrometry. The utility of
      the approach is demonstrated by quantifying the alpha and beta protein isoforms
      of myosin heavy chain (MyHC) in human atrial tissue. Alpha-MyHC (726-741) and
      beta-MyHC (724-739) were identified as isoform-specific tryptic peptides. A
      calibration curve was constructed by plotting ion current ratios against molar
      ratios of the two peptides prepared synthetically. MyHC was digested by trypsin
      and the ion current ratio determined for the two tryptic peptides. The ion
      current ratio was converted to the peptide ratio and hence the isoform ratio by
      reference to the standard curve. The accuracy of the method was confirmed by a
      comparison between these results and those determined by an established method of
      MyHC isoform ratio determination. So that the molar ratio could be converted to
      absolute values, a third peptide, an analogue of the two peptides being measured,
      was synthesized for use as an internal standard (IS). The measured ion current
      ratios of synthetic alpha-MyHC (726-741), beta-MyHC (724-739), and IS peptides
      were used to generate standard curves. A known quantity of the IS was added to
      the MyHC digests. The measured ion current ratios were converted to the actual
      quantities of the isoform-specific peptides and hence the actual quantity of each
      protein isoform by reference to the standard curves. This method is of general
      applicability, especially when isoform quantification is required.

PMID- 15018569
TI  - Apparatus and initial results for pressurized planar electrochromatography.
AB  - Pressurized planar electrochromatography (PPEC) is a new planar chromatographic
      technique in which the mobile phase is driven by electroosmotic flow, while the
      sorbent layer is pressurized in a manner that allows heat to flow from the layer
      through an electrically insulating, thermally conducting, sheet of aluminum
      nitride ceramic. A prototype apparatus for performing PPEC is described.
      Separation by PPEC is faster than by conventional TLC, and an example is
      presented of a 24-fold enhancement in the speed of separation. PPEC was performed
      on both regular and high-performance C18 layers, and the latter yield
      substantially faster separation. The sorbent layer requires conditioning at
      elevated temperature before use, and solute migration velocity increases with
      this temperature. The flow rate increases in a linear manner with increasing
      voltage and diminishes in a nonlinear manner with increasing pressure. Both
      electrical current and Joule heating diminish with increasing pressure, and the
      diminution of flow at high pressure can be compensated by an increase in voltage.
      PPEC is more efficient than classical TLC. Theoretical plate heights diminish
      with increasing Rf and are in the range 29-21 and 55-27 microm for the high
      performance and regular plates, respectively. PPEC retains the advantages of
      classical TLC but has the ability to separate a substantially higher number of
      samples simultaneously. An example is presented on the separation of nine samples
      in 1 min on a 2.5 cm x 10 cm sorbent layer.

PMID- 15018570
TI  - Inability of unpacked gooseneck liners to stop the sample liquid after injection
      with band formation (fast autosampler) into hot GC injectors.
AB  - With the introduction of the fast autosampler, the rules on how to perform
      splitless injection should have been revisited: the fast autosampler releases the
      sample liquid as a band that is no longer nebulized by solvent vapors as in
      previous injection techniques. In empty gooseneck liners, the sample liquid is
      shot to the bottom of the injector and jumps around in a largely uncontrolled
      manner. Visual experiments showed that the liquid is partially rejected. Another
      portion passes by the column inlet into the column attachment region, while the
      last part may directly enter the column. The impact on chromatography was
      investigated by using a mixture of n-alkanes: the higher boiling components
      passing by the column entrance into the zone of the column attachment were
      largely lost, i.e., were discriminated against the volatile components. It was
      concluded that empty gooseneck liners are not suitable for injection by fast
      autosamplers.

PMID- 15018571
TI  - Selective detection of volatile aromatic compounds using a compact laser
      ionization detector with fast gas chromatography.
AB  - We report results for a new gas chromatography detector that is comparatively
      sensitive and far more selective for aromatic compounds than the traditional
      photoionization detector. The detection means is multiphoton ionization at
      atmospheric pressure. The ionization source in these experiments is a diode
      pumped passively Q-switched microchip laser operating at 266 nm. Experiments were
      conducted with the detector interfaced to a fast gas chromatograph. For <20 s
      elution time, limits of detection were <1 pg for toluene, ethylbenzene, xylenes,
      and isopropylbenzene; the limit of detection for benzene is approximately 10 pg.
      Detector response was linear over 5 orders of magnitude, including these low
      levels. Negligible signals were observed for nonaromatic ketones, aldehydes,
      ethers, and cycloalkanes at levels as high as 0.1 microg (10 mg/L concentration).
      Detector efficiency after fast GC separation was 0.002% when using a detector
      cell with a radius of 1.1 cm and a purge gas flow of 500 mL/min. The advantages
      of this detector are further illustrated by the fast GC analysis of fuel samples.

PMID- 15018572
TI  - Determination of shapes and maximums of analyte peaks based on solute mobilities
      in capillary electrophoresis.
AB  - In capillary electrophoresis, the relative orders of mobilities of analyte,
      additive, and the complex formed determine the analyte peak shape in a way
      similar to the way the binding isotherms determine the peak shapes in
      chromatography. The three mobilities allow six possible orders; each produces a
      characteristic peak shape in CE. Equations describing the analyte migration in a
      CE system with the presence of mobility-changing additives can be implemented
      into computer programs to predict the migration times of the analyte peak
      maximums, and the predicted migration times agree well with the experimental
      results.

PMID- 15018573
TI  - Use of external magnetic fields to reduce reaction times in an immunoassay using
      micrometer-sized paramagnetic particles as labels (magnetoimmunoassay).
AB  - The paper presents a rapid immunoassay system capable of quantifying analyte in
      complex biological and environmental media. Antibody-coated micrometer-sized
      paramagnetic particles are used as labels in an assay in which they bind
      quantitatively with an analyte and capture antibody molecules immobilized on a
      polyester disk to form a sandwich assay. The assay is performed in a simple
      reaction vessel, and reactions between labels, analyte, and antibodies are
      accelerated by positioning magnets alternately above and below the vessel. The
      bound paramagnetic particles are quantified using a simple flat, spiral, coil
      located just below the polyester disk. The electronic circuitry associated with
      the coil uses components that are inexpensive and readily available. The coil has
      been designed to respond only to particles bound on the disk and not to unbound
      particles still in the test solution. Unbound particles are pulled away from the
      disk by the magnet before readings are taken. The use of the reaction vessel with
      the cardiac markers CRP and CKMB is described. No sample preparation or washing
      step is used in the assays, and results can be obtained in less than 3 min after
      introducing the sample into the vessel with sensitivities in the normal clinical
      range.

PMID- 15018574
TI  - Activation of phosphorothionate pesticides based on a cytochrome P450 BM-3
      (CYP102 A1) mutant for expanded neurotoxin detection in food using
      acetylcholinesterase biosensors.
AB  - A novel enzymatic in vitro activation method for phosphorothionates has been
      developed to allow their detection with acetylcholinesterase (AChE) biosensors.
      Activation is necessary because this group of insecticides shows nearly no
      inhibitory effect toward AChE in their pure nonmetabolized form. In contrast,
      they exert a strong inhibitory effect on AChE after oxidation as it takes place
      by metabolic activation in higher organisms. Standard chemical methods to oxidize
      phosphorothionates showed inherent disadvantages that impede their direct use in
      food analysis. In contrast, a genetically engineered triple mutant of P450 BM-3
      (CYP102 A1) could convert the two frequently used insecticides parathion and
      chlorpyrifos into their oxo variants as was confirmed by GC/MS measurements. The
      wild-type protein was unable to do so. In the case of chlorpyrifos, the enzymatic
      activation was as good as the chemical oxidation. In the case of parathion, the
      P450 activation was more efficient than the oxidation by NBS but neither
      activation method yielded an AChE inhibition that was as high as with paraoxon.
      The application of the method to infant food in combination with a disposable
      AChE biosensor enabled detection of chlorpyrifos and parathion at concentrations
      down to 20 microg/kg within an overall assay time of 95 min.

PMID- 15018575
TI  - Artificial neural network analysis for evaluation of peptide MS/MS spectra in
      proteomics.
AB  - The aim of the work was to explore usefulness of artificial neural network (ANN)
      analysis for the evaluation of proteomics data. The analysis was applied to the
      data generated by the widely used protein identification program Sequest,
      completed with several structural parameters readily calculated from peptide
      molecular formulas. Proteins from yeast cells were identified based on the MS/MS
      spectra of peptides. The constructed ANN was demonstrated to classify
      automatically as either "good" or "bad" the peptide MS/MS spectra otherwise
      classified manually. An appropriately trained ANN proves to be a high-throughput
      tool facilitating examination of Sequest's results. ANNs are recommended as a
      means of automatic processing of large amounts of MS/MS data, which normally must
      be considered in the analysis of complex mixtures of proteins in proteomics.

PMID- 15018576
TI  - High-throughput comprehensive analysis of human plasma proteins: a step toward
      population proteomics.
AB  - A high-throughput (HT) comprehensive analysis approach was developed for assaying
      proteins directly from human plasma. Proteins were selectively retrieved, by
      utilizing antibodies immobilized within affinity pipet tips, and eluted onto
      enzymatically active mass spectrometer targets for subsequent digestion and
      structural characterization. Several parameters, including uniform parallel
      protein elution from 96 affinity pipet tips, proper buffering for on-target
      digestion, termination of the digestion, and MALDI matrix (re)introduction, were
      evaluated and optimized. The approach was validated via parallel, high-throughput
      analysis of transthyretin (TTR) and transferrin (TRFE) from 96 identical plasma
      samples. The 96 parallel analyses for each protein were completed in less than 90
      min, measured from protein extraction to insertion in the mass spectrometer.
      Virtually identical mass spectra were obtained from the 96 TTR analyses,
      characterized by the presence of 14 tryptic fragments that allowed TTR sequence
      mapping with 100% coverage. Database search returned TTR as the best match for
      all 96 data sets. In regard to the TRFE analyses, database searching using data
      from the 96 spectra returned TRFE as the best match for all but 1 of the spectra.
      TRFE was mapped with 47-69% sequence coverage, with gaps in the sequence coverage
      corresponding to the carbohydrate-containing peptide fragments and large and
      small trypsin fragments that fell outside the window of mass analysis. Overall,
      the combined high-throughput affinity capture-protein digestion approach showed
      high reproducibility and speed and yielded an exceptional level of protein
      characterization, suggesting its use in future population proteomics endeavors.

PMID- 15018577
TI  - A strategy for identifying differences in large series of metabolomic samples
      analyzed by GC/MS.
AB  - In metabolomics, the purpose is to identify and quantify all the metabolites in a
      biological system. Combined gas chromatography and mass spectrometry (GC/MS) is
      one of the most commonly used techniques in metabolomics together with 1H NMR,
      and it has been shown that more than 300 compounds can be distinguished with
      GC/MS after deconvolution of overlapping peaks. To avoid having to deconvolute
      all analyzed samples prior to multivariate analysis of the data, we have
      developed a strategy for rapid comparison of nonprocessed MS data files. The
      method includes baseline correction, alignment, time window determinations,
      alternating regression, PLS-DA, and identification of retention time windows in
      the chromatograms that explain the differences between the samples. Use of
      alternating regression also gives interpretable loadings, which retain the
      information provided by m/z values that vary between the samples in each
      retention time window. The method has been applied to plant extracts derived from
      leaves of different developmental stages and plants subjected to small changes in
      day length. The data show that the new method can detect differences between the
      samples and that it gives results comparable to those obtained when deconvolution
      is applied prior to the multivariate analysis. We suggest that this method can be
      used for rapid comparison of large sets of GC/MS data, thereby applying time
      consuming deconvolution only to parts of the chromatograms that contribute to
      explain the differences between the samples.

PMID- 15018578
TI  - Prediction of MS/MS data. 1. A focus on pharmaceuticals containing carboxylic
      acids.
AB  - Metabolite identification is a necessary step in developing safe and effective
      drugs. Metabolite analysis typically involves rapid identification of the
      chemical composition of the metabolite by automated HPLC-MS methods, followed by
      the laborious process of identifying the structure of the metabolite. Since MS is
      typically utilized to identify the metabolite, it is logical to utilize MS/MS to
      structurally characterize the sample. However, interpretation of MS/MS data may
      not provide sufficient information, as fragmentation pathways are not well
      understood or predictable. Therefore, other more time-consuming methods of
      analysis are often undertaken. If the dissociation rules for low-energy MS/MS
      experiments were clearly defined for all classes of compounds, more information
      would be obtained from MS/MS data, and metabolite identification would proceed
      more rapidly. We are currently developing methods to define these fragmentation
      rules. By screening approximately 100 carboxylic acids at a time and applying
      knowledge of physical-organic chemistry, predictive rules are under development
      that describe how compounds dissociate under low-energy collision-induced
      dissociation conditions. Studies of carboxylic acid dissociation demonstrate that
      this approach is practical and reliable. Dissociation rules were predicted with a
      90% success rate, when tested on acid-containing pharmaceuticals. This predictive
      power cannot be matched by any commercially available software. This study, and
      others like it, will be used to develop algorithms that more rapidly identify
      drug metabolites and degradation products, based on MS/MS data. Such algorithms
      will benefit drug development for all types of pharmaceuticals.

PMID- 15018579
TI  - Collisional cooling of large ions in electrospray mass spectrometry.
AB  - Collisional cooling of ions in the rf-only multipole guides has become a method
      of choice for coupling electrospray sources to various mass analyzers. Normally
      parameters of such ion guides (length, pressure) provide enough thermalization
      and focusing for ions in a wide mass range. Noncovalent complexes, however, have
      more compact conformations than denatured biomolecules of similar mass and,
      therefore may not be transmitted efficiently through standard ion guides, as
      demonstrated by theoretical analysis, simulations, and experiments. Several
      methods of improving collisional cooling for large compact ions have been
      developed on a quadrupole time-of-flight instrument, which include operating the
      ion guides at higher pressure and trapping ions to increase the cooling time.
      Improved transmission of heavy ions obtained with those methods is studied in
      experiments with proteasome 20S, an oligomeric protein noncovalent complex with
      molecular weight around 692,000, and a few other compounds.

PMID- 15018580
TI  - Enzymatic tissue digestion as an alternative sample preparation approach for
      quantitative analysis using liquid chromatography-tandem mass spectrometry.
AB  - Compound extraction from biological tissue often presents a challenge for the
      bioanalytical chemist. Labor-intensive homogenization or sonication of whole or
      powdered tissue is performed before compounds can be extracted and analyzed.
      Enzymatic digestion is commonly used for tissue dissociation and cell harvesting
      and offers the advantages of unattended sample preparation, potential automation,
      and low cost. The feasibility of enzymatic digestion as an alternate tissue
      preparation technique was evaluated for bioanalysis of drugs in conjunction with
      LC/MS/MS. Two different enzymes (collagenase and proteinase K) that are known to
      degrade connective tissues to allow tissue dissolution were chosen for
      evaluation, employing well-known antidepressants desipramine and fluoxetine as
      test compounds in dog and rat brain tissue. Comparison between enzymatic
      digestion and conventional homogenization tissue preparation was performed,
      including investigation of matrix ionization suppression of both methods using a
      postcolumn infusion system. Results showed that enzymatic digestion has
      extraction efficiency comparable to homogenization. Matrix ionization suppression
      was not observed for either the test compounds evaluated or the sample extraction
      method. Test compound levels of incurred tissue samples prepared by enzymatic
      digestion were in good agreement with the values obtained by the conventional
      homogenization tissue preparation, indicating that enzymatic digestion is an
      appropriate tissue sample preparation method.

PMID- 15018581
TI  - Effect of nonionic fluorosurfactant on the electrogenerated chemiluminescence of
      the tris(2,2'-bipyridine)ruthenium(II)/tri-n-propylamine system: lower oxidation
      potential and higher emission intensity.
AB  - Fluorosurfactants are commercially available, and their applications in
      electrochemical systems have been the interest of many studies. Here, we describe
      a novel effect of a nonionic fluorosurfactant (Zonyl FSN) on the electrogenerated
      chemiluminescence (ECL) of the tris(2,2'-bipyridine)ruthenium(II)/tri-n
      propylamine (TPrA) system at gold and platinum electrodes. Compared with its
      hydrocarbon analogue (Triton X-100), the adsorbed fluorosurfactant species not
      only rendered the electrode surfaces more hydrophobic but also significantly
      retarded the growth of the electrode oxide layers. As a result, more facile
      direct oxidation of TPrA was achieved, which led to the appearance of a low
      oxidation potential ECL signal (below 1.0 V vs SCE). At the gold electrode, the
      ECL peak appeared at 0.82 V, approximately 400 mV more negative than usual; while
      its intensity was approximately 50 times higher. The generation of the intense
      ECL signal at low oxidation potential may lead to the development of more
      efficient ECL analysis.

PMID- 15018582
TI  - Mass transfer and gas-phase calibration of implanted oxygen sensors.
AB  - A protocol is described for validation of implanted oxygen sensors, in which
      sensors are calibrated in the gas phase where concentration boundary layers are
      absent. Calibration prior to sensor implantation and confirmation after sensor
      explantation allows separation of tissue mass transfer effects from sensor
      variance and drift. A model is given here that describes the oxygen-dependent
      signal current in terms of oxygen mass transfer to the sensor, permeability of
      the sensor membrane, and electrode area. The parameter used in the model to
      describe mass transfer to implanted sensors is consistent with experimental
      observations and allows comparisons with nonimplanted sensors. This method
      provides a bridge between the complementary approaches of empirical calibration
      and model-based calculation for determining oxygen concentration from the sensor
      response.

PMID- 15018583
TI  - A microfluidic platform using molecular beacon-based temperature calibration for
      thermal dehybridization of surface-bound DNA.
AB  - This work presents a simple microfluidic device with an integrated thin-film
      heater for studies of DNA hybridization kinetics and double-stranded DNA melting
      temperature measurements. The heating characteristics of the device were
      evaluated with a novel, noninvasive indirect technique using molecular beacons as
      temperature probes inside reaction chambers. This is the first microfluidic
      device in which thermal dehybridization of surface-bound oligonucleotides was
      performed for measurement of double-stranded DNA melting temperatures with +/- 1
      degrees C precision. Surface modification and oligonucleotide immobilization were
      performed by continuously flowing reagents through the microchannels. The
      resulting reproducibility of oligonucleotide surface densities, at 9% RSD, was
      better than for the same modification chemistries on glass slides in unstirred
      reagent solutions (RSD=20%). Moreover, the surface density of immobilized DNA
      probe molecules could be varied controllably by changing the concentration of the
      reagent solution used for immobilization. Thus, excellent control of surface
      characteristics was made possible, something which is often difficult to achieve
      with larger devices. Solid-phase hybridization reactions, a fundamental aspect of
      microarray technologies often taking several hours in conventional systems, were
      reduced to minutes in this device. It was also possible to determine forward rate
      constants for hybridization, k. These varied from 820,000 to 72,000 M(-1) s(-1),
      decreasing as surface densities increased. Surface densities could therefore be
      optimized to obtain rapid hybridization using such an approach. Taken together,
      this combined microfluidic/small-volume heating approach represents a powerful
      tool for surface-based DNA analysis.

PMID- 15018584
TI  - Sub-parts-per-quadrillion-level graphite furnace atomic absorption
      spectrophotometry based on laser wave mixing.
AB  - Nonlinear laser wave mixing in a common graphite furnace atomizer is presented as
      a zeptomole-level, sub-Doppler, high-resolution atomic absorption
      spectrophotometric method. A nonplanar three-dimensional wave-mixing optical
      setup is used to generate the signal beam in its own space. Signal collection is
      efficient and convenient using a template-based optical alignment. The graphite
      furnace atomizer offers advantages including fast and convenient introduction of
      solid, liquid, or gas analytes, clean atomization environment, and minimum
      background noise. Taking advantage of the unique features of the wave-mixing
      optical method and those of the graphite furnace atomizer, one can obtain both
      excellent spectral resolution and detection sensitivity. A preliminary
      concentration detection limit of 0.07 parts-per-quadrillion and a preliminary
      mass detection limit of 0.7 ag or 8 zmol are determined for rubidium using a
      compact laser diode as the excitation source.

PMID- 15018585
TI  - Modulation of the sensitive temperature range of fluorescent molecular
      thermometers based on thermoresponsive polymers.
AB  - Fluorescent molecular thermometers based on polymers showing a temperature
      induced phase transition and labeled with polarity-sensitive fluorescent
      benzofurazans are the most sensitive known. Here we show a simple and effective
      method for modulating the sensitive temperature ranges of fluorescent molecular
      thermometers based on such temperature-responsive polymers. 4-N-(2
      acryloyloxyethyl)-N-methylamino-7-N,N-dimethylaminosulfonyl-2,1,3-benzoxadiazole
      was adopted as a polarity-sensitive fluorescent benzofurazan, and nine copolymers
      of two kinds of acrylamide derivative (N-n-propylacrylamide, N
      isopropylacrylamide, and/or N-isopropylmethacrylamide) with a small amount of DBD
      AE were obtained. The fluorescence intensities of these copolymers in aqueous
      solution sharply increased with increasing temperature over a small range (6-7
      degrees C). In contrast, these fluorescent molecular thermometers differed from
      one another in the sensitive temperature range (between 20 and 49 degrees C).
      Moreover, the sensitive temperature ranges were well related to the acrylamide
      ratios in feed. In addition, the responses from these fluorescent molecular
      thermometers to the change in temperature were reversible and exactly repeatable
      during 10 cycles of heating and cooling (relative standard deviation of the
      fluorescence intensity, 0.44-1.0%).

PMID- 15018586
TI  - Immunosensor for detection of Yersinia enterocolitica based on imaging
      ellipsometry.
AB  - An immunosensor for the detection of pathogens was developed using imaging
      ellipsometry (IE) as a detection method. Yersinia enterocolitica was selected as
      the target pathogen in this study. A gold surface deposited with a self-assembled
      layer of 11-mercaptoundecanoic acid (11-MUA) was used as a substrate. For the
      fabrication of the immunosensor, protein G spots were made on the substrate using
      an inkjet-type microarrayer, and monoclonal antibody (Mab) was adsorbed onto the
      protein G spots. Deposition of each layer onto the substrate was confirmed by the
      measurement of surface plasmon resonance. The ellipsometric image of the protein
      G spot and the Mab-adsorbed protein G spot were acquired using an off-null
      ellipsometry type of imaging ellipsometry system. By measuring the ellipsometric
      angles of the protein layers, the surface concentration of each protein layer was
      calculated. The change in the mean optical intensity of the protein spot to the
      various concentrations of Y.enterocolitica was estimated. The immunosensor using
      imaging ellipsometry could successfully detect Y. enterocolitica in
      concentrations varying from 10(3) to 10(7) cfu/mL. The proposed immunosensor
      system has the advantage of allowing label-free detection, high sensitivity, and
      operational simplicity.

PMID- 15018587
TI  - Improved mass analysis of oligoribonucleotides by 13C, 15N double depletion and
      electrospray ionization FT-ICR mass spectrometry.
AB  - 13C, 15N doubly depleted 32-ribonucleotide was synthesized enzymatically by in
      vitro transcription from nucleoside triphosphates isolated from E. coli grown in
      a minimal medium containing 12C, 14N-enriched glucose and ammonium sulfate.
      Following purification and desalting by reversed-phase HPLC, buffer exchange with
      Microcon YM-3, and ethanol precipitation, electrospray ionization Fourier
      transform ion cyclotron resonance mass spectra revealed greatly enhanced
      abundance of monoisotopic ions (by a factor of approximately 100) and a narrower
      isotopic distribution with higher signal-to-noise ratio. The abrupt onset and
      high magnitude of the monoisotopic species promise to facilitate accurate mass
      measurement of RNA's.

PMID- 15018588
TI  - Gonadotropin-releasing hormone antagonists for assisted reproductive techniques:
      are there clinical differences between agents?
AB  - Gonadotropin-releasing hormone (GnRH) antagonists have been tested extensively in
      ovarian stimulation protocols for assisted reproductive techniques (ART). GnRH
      antagonists immediately and rapidly inhibit gonadotropin release by the anterior
      pituitary gland by competitive blockage of the GnRH receptor, preventing and
      interrupting luteinising hormone surges in controlled ovarian hyperstimulation
      for infertility treatment. A review of the available literature on GnRH
      antagonists for ART is presented, focusing on the pharmacological and clinical
      properties of the two compounds available on the market, cetrorelix and
      ganirelix. Both cetrorelix and ganirelix are well tolerated and effective drugs
      for controlled ovarian hyperstimulation and are of comparable value for
      infertility treatment. Cetrorelix is available as a 0.25mg preparation for daily
      injections and as a 3mg intermediate depot preparation. Ganirelix is available as
      a 0.25mg preparation for daily injections.Currently, two treatment protocols are
      used in clinical practice: the GnRH antagonist multiple-dose protocol and the
      GnRH antagonist single-dose protocol. Both protocols are effective and well
      tolerated. Cetrorelix and ganirelix have not yet been directly compared in a
      clinical trial; nor have the single-dose and the multiple-dose approaches been
      compared in a randomised, controlled trial. Data to compare these compounds in
      clinical terms can be extrapolated only from results of phase II dose-finding
      studies and phase III studies comparing GnRH agonist cycles with GnRH antagonists
      in single- and multiple-dose protocols. Therefore, all conclusions on clinical
      differences between cetrorelix and ganirelix should remain tentative, as they are
      based on a limited amount of available data.Randomised, controlled trials
      comparing cetrorelix and ganirelix are warranted to further evaluate benefits and
      drawbacks of individual GnRH antagonists. Furthermore, more data are needed to
      determine the efficacy and safety of cetrorelix and ganirelix in established
      treatment protocols in patients other than those included in clinical trials
      investigating new drugs, such as "poor responders", patients with polycystic
      ovaries, patients with a history of allergy or overweight patients.

PMID- 15018591
TI  - Current issues in the management of urinary tract infections: extended-release
      ciprofloxacin as a novel treatment option.
AB  - Symptomatic urinary tract infections (UTIs) are a major public health concern in
      the developed world, accounting for almost 8 million annual outpatient and
      emergency department visits in the US alone, while also representing one of the
      most common hospital-acquired infections. The vast majority of uncomplicated UTIs
      are caused by the Gram-negative bacillus Escherichia coli, with other pathogens
      including enterococci, Staphylococcus saprophyticus, Klebsiella spp. and Proteus
      mirabilis. Effective management of UTIs in both the inpatient and outpatient
      settings has been complicated by the fact that many uropathogenic strains have
      developed resistance to antimicrobials, including cotrimoxazole
      (trimethoprim/sulfamethoxazole), the current first-line treatment for
      uncomplicated UTIs in the US and many other countries. In some countries, other
      antimicrobial therapies, such as trimethoprim and nitrofurantoin, are also used
      for treatment of uncomplicated UTIs. Antimicrobial resistance has been associated
      with an increased rate of clinical failure, and reports from Canada and the US
      indicate that the prevalence of cotrimoxazole resistance exceeds 15% and can be
      as high as 25%.The emergence and dissemination of antimicrobial resistance can be
      reduced with the use of agents that have favourable
      pharmacokinetic/pharmacodynamic profiles and convenient dose administration
      regimens that facilitate patient adherence and, therefore, pathogen eradication.
      Fluoroquinolones have been used successfully to treat a wide range of community-
      and hospital-acquired infections, and the rates of fluoroquinolone resistance
      have remained low. Use of fluoroquinolones is recommended for uncomplicated UTIs
      in areas where the incidence of cotrimoxazole resistance exceeds 10%, as well as
      for the treatment of complicated UTIs and acute pyelonephritis. Ciprofloxacin is
      a widely used fluoroquinolone with high bactericidal activity against
      uropathogens and well established clinical efficacy in the treatment of UTIs. A
      new, extended-release formulation of ciprofloxacin (Cipro XR) provides systemic
      drug exposure comparable with that achieved with twice-daily administration of
      conventional, immediate-release ciprofloxacin, while also attaining higher
      maximum plasma concentrations with less interpatient variability. Therapeutic
      drug concentrations with extended-release ciprofloxacin are established
      immediately after dose administration and maintained throughout the 24-hour
      dosage interval, permitting convenient, once-daily treatment. Clinical trial
      results confirm that extended-release ciprofloxacin is as safely used and
      effective as the conventional, immediate-release formulation of ciprofloxacin in
      patients with uncomplicated UTIs, complicated UTIs or acute uncomplicated
      pyelonephritis. These findings support the use of extended-release ciprofloxacin
      as a well tolerated, effective and convenient therapy for UTIs, which may improve
      patients' adherence to therapy and, thereby, reduce the risk of infection
      recurrence and emergence of antimicrobial resistance.

PMID- 15018592
TI  - What is the role of NSAIDs in pre-emptive analgesia?

PMID- 15018590
TI  - Guillain-Barre syndrome: epidemiology, pathophysiology and management.
AB  - Guillain-Barre syndrome (GBS) is clinically defined as an acute peripheral
      neuropathy causing limb weakness that progresses over a time period of days or,
      at the most, up to 4 weeks. GBS occurs throughout the world with a median annual
      incidence of 1.3 cases per population of 100 000, with men being more frequently
      affected than women. GBS is considered to be an autoimmune disease triggered by a
      preceding bacterial or viral infection. Campylobacter jejuni, cytomegalovirus,
      Epstein-Barr virus and Mycoplasma pneumoniae are commonly identified antecedent
      pathogens. In the acute motor axonal neuropathy (AMAN) form of GBS, the infecting
      organisms probably share homologous epitopes to a component of the peripheral
      nerves (molecular mimicry) and, therefore, the immune responses cross-react with
      the nerves causing axonal degeneration; the target molecules in AMAN are likely
      to be gangliosides GM1, GM1b, GD1a and GalNAc-GD1a expressed on the motor
      axolemma. In the acute inflammatory demyelinating polyneuropathy (AIDP) form,
      immune system reactions against target epitopes in Schwann cells or myelin result
      in demyelination; however, the exact target molecules in the case of AIDP have
      not yet been identified. AIDP is by far the most common form of GBS in Europe and
      North America, whereas AMAN occurs more frequently in east Asia (China and
      Japan). The prognosis of GBS is generally favourable, but it is a serious disease
      with a mortality of approximately 10% and approximately 20% of patients are left
      with severe disability. Treatment of GBS is subdivided into: (i) the management
      of severely paralysed patients with intensive care and ventilatory support; and
      (ii) specific immunomodulating treatments that shorten the progressive course of
      GBS, presumably by limiting nerve damage. High-dose intravenous immunoglobulin
      (IVIg) therapy and plasma exchange aid more rapid resolution of the disease. The
      predominant mechanisms by which IVIg therapy exerts its action appear to be a
      combined effect of complement inactivation, neutralisation of idiotypic
      antibodies, cytokine inhibition and saturation of Fc receptors on macrophages.
      Corticosteroids alone do not alter the outcome of GBS.

PMID- 15018589
TI  - Prevention of venous thromboembolism following orthopaedic surgery: clinical
      potential of direct thrombin inhibitors.
AB  - Patients undergoing total hip or total knee replacement are at high risk of
      venous thromboembolism (VTE), and are therefore considered to be populations well
      suited for the evaluation and dose optimisation of new anticoagulants. Deep vein
      thrombosis may lead to life-threatening pulmonary embolism, disabling morbidity
      in the form of the post-thrombotic syndrome, and risk of recurrent thrombotic
      events. There is increasing evidence that anticoagulant treatment for the
      prevention of VTE should be extended from 1 to at least 4 weeks after surgery.
      Anticoagulation with vitamin K antagonists (such as warfarin), low molecular
      weight heparin or unfractionated heparin effectively lowers the risk of VTE, but
      these anticoagulants have limitations such as the need for coagulation monitoring
      and subsequent dose adjustment (vitamin K antagonists), difficulty of continuing
      prophylaxis out of hospital because of the requirement for parenteral
      administration, and risk of heparin-induced thrombocytopenia. The development of
      new anticoagulants has been pursued with the aim of finding more effective, safer
      and/or more convenient therapies. Thrombin is a central regulator in the
      coagulation and inflammation process and several direct thrombin inhibitors
      (DTIs) with distinct pharmacological profiles, as well as pharmacological
      differences from the conventional anticoagulants, are currently in clinical use
      for certain indications or are under development. Clinical experience with
      parenterally administered DTIs has accumulated since the mid 1990s, although only
      desirudin (a recombinant hirudin) is currently approved for use in patients
      undergoing orthopaedic surgery. Two oral DTIs, ximelagatran and dabigatran
      etexilate, are in clinical development. Dabigatran etexilate has recently been
      evaluated in phase II clinical trials in patients undergoing total hip
      replacement. Several large phase III trials have now demonstrated the efficacy
      and safety of ximelagatran in the prevention of VTE following total hip or knee
      replacement. Ximelagatran can be used with an oral fixed dose without the need
      for coagulation monitoring or dose adjustment. Hence, it offers significant
      potential to facilitate the management of anticoagulation in or out of hospital.

PMID- 15018594
TI  - Is omapatrilat a novel therapy of the past rather than the future?

PMID- 15018596
TI  - Fulvestrant: a review of its use in hormone receptor-positive metastatic breast
      cancer in postmenopausal women with disease progression following antiestrogen
      therapy.
AB  - Fulvestrant (Faslodex) is a novel estrogen receptor (ER) antagonist that
      competitively binds to the ER with a much greater affinity than that of
      tamoxifen. The downregulation of cellular levels of the ER protein results in
      complete abrogation of estrogen-sensitive gene transcription. This distinct
      mechanism of action ensures a lack of cross resistance with other hormonal agents
      and, in contrast to tamoxifen, fulvestrant has no known estrogen-agonist effects.
      Fulvestrant is administered via monthly intramuscular injections (250mg) and is
      recommended for the treatment of hormone receptor-positive metastatic breast
      cancer in postmenopausal women with disease progression following antiestrogen
      therapy. The efficacy of fulvestrant was similar to that of the aromatase
      inhibitor anastrozole (1 mg/day) in two, well designed studies in postmenopausal
      women with locally advanced or metastatic breast cancer that had progressed
      during prior antiestrogen therapy. Time to disease progression (primary endpoint)
      and treatment failure, rates of objective response and clinical benefit, overall
      survival and quality of life were similar in patients treated with fulvestrant or
      anastrozole. In retrospective noninferiority analyses, fulvestrant was at least
      as effective as anastrozole in all randomised patients, and in those with or
      without visceral metastases. Fulvestrant is generally well tolerated and was
      tolerated as well as anastrozole in clinical trials. Treatment-related adverse
      events were mostly mild to moderate and led to treatment withdrawal in about 1%
      of patients who received fulvestrant or anastrozole. The main adverse effects
      associated with therapy are nausea, asthenia, pain, vasodilation and headache.In
      conclusion, monthly intramuscular injections of fulvestrant are at least as
      effective and as well tolerated as oral anastrozole once daily in the treatment
      of postmenopausal women with advanced breast cancer that has progressed on prior
      antiestrogen therapy. Because of a different mode of action to that of other
      hormonal agents, fulvestrant is effective in the treatment of tamoxifen-resistant
      disease and, unlike tamoxifen, has no known estrogen agonist effects. Thus,
      fulvestrant provides an effective and well tolerated option for the treatment of
      hormone receptor-positive metastatic breast cancer in postmenopausal women with
      disease progression following antiestrogen therapy.

PMID- 15018598
TI  - Disenrollment from a state child health insurance plan: are families jumping
      S(c)HIP?
AB  - BACKGROUND: Colorado's Child Health Plan Plus (CHP+) is a non-Medicaid state
      child health plan that began enrollment in April 1998. Families are disenrolled
      12 months after enrollment if they fail to re-enroll. OBJECTIVE: To assess
      insurance coverage before and 1 year after initial enrollment in CHP+; reasons
      for disenrollment; and factors associated with re-enrollment. DESIGN/METHODS: We
      interviewed 480 randomly selected families 2 months after initial enrollment into
      CHP+ (September 1999 through January 2000) and 1 year later. RESULTS: Prior to
      CHP+, 38% of families had Medicaid (MK), 35% were privately insured (PI), 6% were
      uninsured (UI), and 20% had other/unknown insurance. After the 12 months, 34%
      were re-enrolled, 16% got other insurance (6% MK, 10% PI/other), 4% had children
      older than 18 years, and 46% were UI (9% had intentionally and 37% had
      unintentionally disenrolled from CHP+). All unintentionally disenrolled families
      were planning to re-enroll and 90% still appeared eligible. In multivariate
      analysis, having a primary care provider prior to enrollment was associated with
      re-enrollment (odds ratio [OR] 1.7, 95% confidence interval [CI] 1.1 to 2.6), but
      having problems with the application process impeded re-enrollment (OR 0.7, 95%
      CI 0.6 to 0.9). CONCLUSIONS: Only about a third of families eligible for State
      Children's Health Insurance Program successfully re-enrolled before their
      termination date. Institution of a passive renewal process would decrease
      unnecessary disenrollment in eligible families.

PMID- 15018599
TI  - Assessing age-related risk for gonococcal and chlamydial infections among females
      in Hawaii, 2001: a comparison of morbidity rates with screening test positivity.
AB  - OBJECTIVE: National and state public health officials generally present sexually
      transmitted disease (STD) surveillance information in terms of overall cases and
      population-based rates. Because many adolescents (especially in the younger ages)
      are not sexually active, the use of population-based denominators leads to the
      calculation of low age-specific STD rates. This study compared morbidity rates
      with screening test positivity for gonorrhea and chlamydia to better define age
      related STD risk among females in Hawaii. METHODS: All female gonorrhea and
      chlamydia cases reported to the Hawaii State Department of Health (HDOH) during
      2001 were grouped by age. Population estimates were used to calculate age
      specific morbidity rates. Age-specific screening test positivity was calculated
      by dividing the number of positive tests identified through the HDOH STD
      screening programs by the number of screening tests performed in each age
      category (x100). RESULTS: Although morbidity rates for both chlamydia and
      gonorrhea were low among 10-14 year olds, this group had the highest screening
      test positivity. Screening test positivity decreased incrementally with
      increasing age. CONCLUSIONS: Screening test positivity may provide a more
      accurate estimate of STD risk for sexually active adolescents than population
      based rates. Physicians should obtain sexual histories from their adolescent
      patients and provide STD prevention counseling and screening to those found to be
      sexually active. In addition, expanded STD screening and treatment services
      should be made available and accessible to young, sexually active adolescents
      because they appear to be at greatest risk.

PMID- 15018597
TI  - Ximelagatran/Melagatran: a review of its use in the prevention of venous
      thromboembolism in orthopaedic surgery.
AB  - Ximelagatran (Exanta), the first available oral direct thrombin inhibitor, and
      its active form, melagatran, have been evaluated in the prevention of venous
      thromboembolism (VTE) in patients undergoing hip or knee replacement. After oral
      administration ximelagatran is rapidly bioconverted to melagatran. Melagatran
      inactivates both circulating and clot-bound thrombin by binding to the thrombin
      active site, thus, inhibiting platelet activation and/or aggregation and reducing
      fibrinolysis time. The efficacy of subcutaneous melagatran followed by oral
      ximelagatran has been investigated in four European trials and the efficacy of an
      all oral ximelagatran regimen has been investigated in five US trials. In a dose
      ranging European study, preoperatively initiated subcutaneous melagatran 3 mg
      twice daily followed by oral ximelagatran 24 mg twice daily was significantly
      more effective than subcutaneous dalteparin sodium 5000IU once daily in
      preventing the occurrence of VTE, including deep vein thrombosis (DVT) and
      pulmonary embolism (PE), in patients undergoing hip or knee replacement. In one
      study, there were no significant differences in VTE prevention between
      subcutaneous melagatran 3 mg administered after surgery followed by ximelagatran
      24 mg twice daily and enoxaparin sodium (enoxaparin) 40 mg once daily. Compared
      with enoxaparin, significantly lower rates of proximal DVT and/or PE (major VTE)
      and total VTE were observed when melagatran was initiated preoperatively (2mg)
      then postoperatively (3mg) and followed by ximelagatran 24 mg twice daily. In the
      US, four studies showed that postoperatively initiated ximelagatran 24 mg twice
      daily was of similar efficacy to enoxaparin or warfarin in the prevention of VTE
      in patients undergoing hip or knee replacement. However, ximelagatran 36 mg twice
      daily was superior to warfarin (target international normalised ratio of 2.5) at
      preventing the incidence of VTE in patients undergoing total knee replacement in
      two studies.Ximelagatran alone or after melagatran was generally well tolerated.
      Overall, the incidence of bleeding events and transfusion rates were not markedly
      different from those documented for comparator anticoagulants. In a post-hoc
      analysis of one study, transfusion rates were lower in ximelagatran than
      enoxaparin recipients. CONCLUSIONS: Oral ximelagatran alone or in conjunction
      with subcutaneous melagatran has shown good efficacy and was generally well
      tolerated in the prevention of VTE in patients undergoing orthopaedic surgery.
      Furthermore, patients receiving ximelagatran/melagatran do not require
      anticoagulant monitoring. The drug has a low potential for drug interactions and
      can be administered either by subcutaneous injection or orally. Thus, on the
      basis of available evidence, ximelagatran/melagatran appears poised to play an
      important role in the prophylaxis of VTE in patients undergoing orthopaedic
      surgery.

PMID- 15018600
TI  - Parent's language of interview and access to care for children with special
      health care needs.
AB  - OBJECTIVE: To examine the association between the parent's language of interview
      and the access to care for children with special health care needs (CSHCN).
      METHODS: We used the 2001 National Survey of Children with Special Health Care
      Needs to compare socio-demographic characteristics and health care access
      variables among CSHCN with parents who interviewed in English and another
      language. Additional multivariate analyses explored the effect of language of
      interview on access to health care for the subgroup of Hispanic respondents.
      RESULTS: CSHCN with non-English-speaking parents were from less-educated and
      lower-income families and were more likely to lack insurance and have conditions
      that greatly affected their activities. These children were also more likely to
      have inadequate insurance (odds ratio [OR]=11.29), have an unmet need for family
      support services (OR=1.88), lack a personal doctor or nurse (OR=1.98), lack a
      usual source of care (OR=1.89), and lack family-centered care (OR=1.74). Non
      English-speaking parents were more likely to report having employment
      consequences (OR=1.94) and spending over $500 out-of-pocket annually on the
      child's health care needs (OR=1.49). The likelihood of Hispanic children
      experiencing health care access barriers compared with non-Hispanic children was
      reduced when language was controlled for and several disparities between Hispanic
      children and other children became insignificant. CONCLUSIONS: CSHCN with non
      English-speaking parents were more likely to be from disadvantaged families and
      to experience barriers to access than were CSHCN with English-speaking parents.
      Systems of care for CSHCN should consider the needs and challenges experienced by
      families whose primary language is not English.

PMID- 15018601
TI  - The discipline survey: a new measure of parental discipline.
AB  - OBJECTIVES: To develop a new measure of parental discipline of children
      encompassing a broad array of types of discipline and modes of administration.
      METHODS: Parents of 12- to 19-month-old children were interviewed using a new 45
      item structured survey about discipline in general pediatric clinics in North
      Carolina and Alabama. Demographic data describing the population studied were
      linked from another study in which these families were participating. Principal
      component analysis and confirmatory reliability analysis were used to define
      subscales and determine which items were retained in the survey. RESULTS: One
      hundred eighty-two parents were interviewed about disciplinary practices.
      Disciplinary subscales were robust for a number of disciplinary types
      (monitoring, verbal communication, modeling behavior, corporal punishment, and
      ignoring) and modes of administration (follow-through, consistency, positive
      demeanor, negative demeanor). CONCLUSIONS: The Discipline Survey is a promising
      new measure of parental discipline. A survey instrument to assess disciplinary
      practices like the one developed fills a gap and can enhance research methodology
      for those interested in the effects of interventions on parental discipline.

PMID- 15018602
TI  - Use of medical services by methylphenidate-treated children in the general
      population.
AB  - OBJECTIVES: To examine selected medical services for children treated for
      attention-deficit/hyperactivity disorder (ADHD) in a general population setting
      with universal health insurance. DESIGN: Retrospective analysis of administrative
      prescription and health services databases spanning from 1990 to 1996. SETTING:
      British Columbia, Canada. PATIENTS: Children (<19 years of age) who had received
      the psychostimulant methylphenidate (MPH; Ritalin) on a chronic basis (chronic
      MPH group), who had received MPH on any other basis (nonchronic-MPH group), and
      who were in a no-MPH comparison group. MAIN OUTCOME MEASURES: The number of
      individuals who received any of the following services based on claims submitted
      by qualified practitioners: 1) emergency care, 2) critical care, 3) injury
      related diagnostic and treatment services, 4) complementary and alternative
      medical (CAM) care, and 5) other diagnostic and treatment services (audiometry
      and allergy testing). RESULTS: Prevalence of services users was higher among MPH
      treated than nontreated children for all types of services (except critical care
      services in the chronic-MPH group) after adjusting for effects of age, sex,
      socioeconomic status, and geographic setting, with odds ratios ranging from 1.49
      to 3.17. There were no differences between the 2 MPH-treated groups. CONCLUSIONS:
      Children treated with MPH for ADHD or presumed ADHD are more frequent users of a
      wide range of medical services than are other children. Findings support and
      extend existing evidence of increased use of medical services by this population
      of children. Findings have implications for service planning, including injury
      prevention, with these children. High utilization of audiometric, allergy, and
      CAM services warrants further scrutiny.

PMID- 15018604
TI  - The Medical Home Index applies primarily to children with special health care
      needs.

PMID- 15018603
TI  - Assessment of pediatric residents' otoscopic interpretive skills by videotaped
      examinations.
AB  - BACKGROUND: Accurate diagnosis of otitis media is essential to facilitate
      appropriate management. Few residency programs assess formally their residents'
      competency in diagnosing middle ear disease. OBJECTIVE: To evaluate the
      performance of pediatric residents' otoscopic interpretive skills by level of
      training, with a videotaped otoendoscopic examination (VOE). METHODS: A VOE was
      used to assess and compare the performance of a cross-sectional sample of 141
      residents with one another by level of training as well as with novice and expert
      groups. Total score, sensitivity, specificity, and kappa coefficients were
      calculated for each subject by comparing the subject's answers on the 50-ear test
      with the VOE's expert panel-derived answers, and averages were determined for
      each training level. RESULTS: Each pediatric resident training group had moderate
      agreement (mean kappa coefficient range: .45-.56) with the VOE answers, compared
      with the novice group (mean kappa: .31, fair) and expert group (mean kappa: .80,
      substantial). Twenty-eight residents (20%) had fair or less agreement (kappa<.41)
      with the VOE answers. The mean total scores of all pediatric resident training
      levels were significantly (P<.05) lower than the expert group and significantly
      (P<.05) higher than the novice group (with exception of the early postgraduate
      year-1 group). Subjects with more training had higher kappa levels (r=.33,<.001,
      Spearman) when results were compared among novice, residents, and experts.
      CONCLUSIONS: We found the VOE to be a feasible and reliable instrument to
      accurately distinguish novice, resident, and expert level skills in the
      determination of middle ear effusion status.

PMID- 15018605
TI  - Health care for children and youth in the United States: 2002 report on trends in
      access, utilization, quality, and expenditures.
AB  - OBJECTIVE: To examine changes in insurance coverage, health care utilization,
      perceived quality of care, and expenditures for children and youth in the United
      States using data from 1987-2001. METHODS: Three national health care databases
      serve as the sources of data for this report. The Medical Expenditure Panel
      Survey (1996-2001) provides data on insurance coverage, utilization,
      expenditures, and perceived quality of care. The National Medical Expenditure
      Survey (1987) provides additional data on utilization and expenditures. The
      Nationwide Inpatient Sample (1995-2000) from the Healthcare Cost and Utilization
      Project provides information on hospitalizations. RESULTS: The percent of
      children uninsured for an entire year declined from 10.4% in 1996 to 7.7% in
      1999. Most changes in children's health care occurred between 1987 and the late
      1990s. Overall utilization of hospital-based services has declined significantly
      since 1987, especially for inpatient hospitalization. Several of the observed
      changes from 1987 varied significantly by type of health insurance coverage,
      poverty status, and geographic region. Quality of care data indicate some
      improvement between 2000 and 2001, which varies by insurance coverage. Overall,
      mean length of stay of hospitalizations did not change significantly from 1995 to
      2000, but changes in the prevalence of hospitalizations and the length of stay
      associated with age-specific diagnoses were evident during this time period.
      CONCLUSIONS: Health care for children and youth has changed significantly since
      1987, with most of the changes occurring between 1987 and 1996. Insurance
      coverage has improved, the site of care has shifted toward ambulatory sites,
      hospital utilization has declined, and expenditures on children as a proportion
      of total expenditures have decreased. Variation in these changes is evident by
      insurance status, poverty, and region.

PMID- 15018607
TI  - Whither public health insurance for children and youth (and families).

PMID- 15018608
TI  - Regulation of expression of the stress response gene, Osp94: identification of
      the tonicity response element and intracellular signalling pathways.
AB  - Osp94 (osmotic stress protein of 94 kDa) is known to be up-regulated by
      hypertonic and heat-shock stresses in mouse renal inner medullary collecting duct
      (mIMCD3) cells. To investigate the molecular mechanism of transcriptional
      regulation of the Osp94 gene under these stresses, we cloned and characterized
      the 5'-flanking region of the gene. Sequence analysis of the proximal 4 kb 5'
      flanking region revealed a TATA-less G/C-rich promoter region containing a
      cluster of Sp1 sites. We also identified upstream sequence motifs similar to the
      consensus TonE/ORE (tonicity-response element/osmotic response element) as well
      as the consensus HSE (heat-shock element). Luciferase activities in cells
      transfected with reporter constructs containing a TonE/ORE-like element (Osp94
      TonE; 5'-TGGAAAGGACCAG-3') and HSE enhanced reporter gene expression under
      hypertonic stress and heat-shock stress respectively. Electrophoretic gel
      mobility-shift assay showed a slowly migrating band binding to the Osp94-TonE
      probe, probably representing binding of TonEBP (TonE binding protein) to this
      enhancer element. Furthermore, treatment of mIMCD3 cells with MAPK (mitogen
      activated protein kinase) inhibitors (SB203580, PD98059, U0126 and SP600125) and
      a proteasome inhibitor (MG132) suppressed the increase in Osp94 gene expression
      caused by hypertonic NaCl. These results indicate that the 5'-flanking region of
      Osp94 gene contains a hypertonicity sensitive cis -acting element, Osp94-TonE,
      which is distinct from a functional HSE. Furthermore, the MAPK and proteasome
      systems appear to be, at least in part, involved in hypertonic-stressmediated
      regulation of Osp94 through Osp94-TonE.

PMID- 15018609
TI  - Effect of thyroid hormone binding proteins on insulin receptor binding of B1
      thyronine-insulin analogues.
AB  - Certain thyronine-insulin analogues, which form non-covalent complexes with
      plasma proteins, have been shown to act preferentially in the liver. We
      hypothesized that this property may be dependent on the ability of the analogue
      to bind to the insulin receptor without prior dissociation from the binding
      protein. NaB1-L-thyroxyl-insulin, NaB1-3,3',5'-triiodothyronine-insulin, NaB1-D
      thyroxyl-insulin and NaB1-L-thyroxyl-aminolauroyl-insulin were compared with
      insulin for their capacity to inhibit the binding of [125I]TyrA14-insulin to rat
      liver plasma membrane in albumin-free buffer. Effective doses at 50% maximum
      inhibition of binding (ED50) were calculated with and without addition of the
      thyroid hormone binding proteins transthyretin, thyroxine binding globulin and
      human serum albumin. The binding of thyronine-insulin analogues to insulin
      receptors was inhibited in a dose-dependent manner by the addition of thyroid
      hormone binding proteins at concentrations in the physiological range. Complexes
      of thyronine-insulin analogues with thyroid hormone binding proteins exhibit
      impaired insulin receptor binding affinities compared with those of the analogues
      in their free form. Hepatoselectivity in vivo may not depend on binding of the
      intact complexes to hepatocytes. These results have implications for the
      physiological role of hormone binding proteins and the in vivo properties of
      other insulin analogues which bind to plasma proteins.

PMID- 15018610
TI  - Senescence-associated changes in respiration and oxidative phosphorylation in
      primary human fibroblasts.
AB  - Limitation of lifespan in replicative senescence is related to oxidative stress,
      which is probably both the cause and consequence of impaired mitochondrial
      respiratory function. The respiration of senescent human diploid fibroblasts was
      analysed by high-resolution respirometry. To rule out cell-cycle effects,
      proliferating and growth-arrested young fibroblasts were used as controls.
      Uncoupled respiration, as normalized to citrate synthase activity, remained
      unchanged, reflecting a constant capacity of the respiratory chain. Oligomycin
      inhibited respiration, however, was significantly increased in mitochondria of
      senescent cells, indicating a lower coupling of electron transport with
      phosphorylation. In contrast, growth-arrested young fibroblasts exhibited a
      higher coupling state compared with proliferating controls. In intact cells,
      partial uncoupling may lead to either decreased oxidative ATP production or a
      compensatory increase in routine respiration. To distinguish between these
      alternatives, we subtracted oligomycin-inhibited respiration from routine
      respiration, which allowed us to determine the part of respiratory activity
      coupled with ATP production. Despite substantial differences in the respiratory
      control ratio, ranging from 4 to 11 in the different experimental groups, a fixed
      proportion of respiratory capacity was maintained for coupled oxidative
      phosphorylation in all the experimental groups. This finding indicates that the
      senescent cells fully compensate for increased proton leakage by enhanced
      electron-transport activity in the routine state. These results provide a new
      insight into age-associated defects in mitochondrial function and compensatory
      mechanisms in intact cells.

PMID- 15018611
TI  - Participation of the proteasomal lid subunit Rpn11 in mitochondrial morphology
      and function is mapped to a distinct C-terminal domain.
AB  - Substrates destined for degradation by the 26 S proteasome are labelled with
      polyubiquitin chains. Rpn11/Mpr1, situated in the lid subcomplex, partakes in the
      processing of these chains or in their removal from substrates bound to the
      proteasome. Rpn11 also plays a role in maintaining mitochondrial integrity,
      tubular structure and proper function. The recent finding that Rpn11 participates
      in proteasome-associated deubiquitination focuses interest on the MPN+ (Mpr1,
      Pad1, N-terminal)/JAMM (JAB1/MPN/Mov34) metalloprotease site in its N-terminal
      domain. However, Rpn11 damaged at its C-terminus (the mpr1-1 mutant) causes
      pleiotropic effects, including proteasome instability and mitochondrial
      morphology defects, resulting in both proteolysis and respiratory malfunctions.
      We find that overexpression of WT (wild-type) RPN8, encoding a paralogous subunit
      that does not contain the catalytic MPN+ motif, corrects proteasome conformations
      and rescues cell cycle phenotypes, but is unable to correct defects in the
      mitochondrial tubular system or respiratory malfunctions associated with the mpr1
      1 mutation. Transforming mpr1-1 with various RPN8-RPN11 chimaeras or with other
      rpn11 mutants reveals that a WT C-terminal region of Rpn11 is necessary, and more
      surprisingly sufficient, to rescue the mpr1-1 mitochondrial phenotype.
      Interestingly, single-site mutants in the catalytic MPN+ motif at the N-terminus
      of Rpn11 lead to reduced proteasome-dependent deubiquitination connected with
      proteolysis defects. Nevertheless, these rpn11 mutants suppress the mitochondrial
      phenotypes associated with mpr1-1 by intragene complementation. Together, these
      results point to a unique role for the C-terminal region of Rpn11 in
      mitochondrial maintenance that may be independent of its role in proteasome
      associated deubiquitination.

PMID- 15018613
TI  - Kinetic and structural characterization of a product complex of 6-hydroxymethyl
      7,8-dihydropterin pyrophosphokinase from Escherichia coli.
AB  - HPPK (6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase) catalyses the transfer
      of pyrophosphate from ATP to HMDP (6-hydroxymethyl-7,8-dihydropterin), to form
      AMP and DHPPP (6-hydroxymethyl-7,8-dihydropterin pyrophosphate). This
      transformation is a key step in the biosynthesis of folic acid, and HPPK is
      consequently a target for antimicrobial drugs. The substrates are known to bind
      to HPPK in an ordered manner, with ATP binding first followed by HMDP. In the
      present study we show by isothermal titration calorimetry that the product,
      DHPPP, can bind to the HPPK apoenzyme with high affinity (equilibrium
      dissociation constant, K(d)=0.2 microM), but without the enhancement of pterin
      fluorescence that occurs on binding of HMDP. The transient kinetics of the enzyme
      can be monitored by measuring the change in the fluorescence of the pterin ring
      using stopped-flow methods. The fluorescence exhibits a pronounced biphasic
      behaviour: it initially rises and then declines back to its original level. This
      behaviour is in agreement with a two-state kinetic model, with the first phase of
      fluorescence increase associated with HMDP binding to the enzyme, and the second
      phase with a slow event that occurs after the reaction has taken place. The HPPK
      DHPPP and HPPK-DHPPP-AMP complexes were examined by NMR, and the binding site for
      DHPPP partially mapped from changes in chemical shifts identified from two
      dimensional 1H/15N heteronuclear single-quantum coherence spectra. The results
      demonstrate that DHPPP, in contrast to HMDP, is able to bind to the HPPK
      apoenzyme and suggest that the pyrophosphate moieties on the ligand play an
      important role in establishment of a high affinity binding site for the pterin
      ring.

PMID- 15018612
TI  - Contribution of the active-site metal cation to the catalytic activity and to the
      conformational stability of phosphotriesterase: temperature- and pH-dependence.
AB  - Phosphotriesterase (PTE) detoxifies nerve agents and organophosphate pesticides.
      The two zinc cations of the PTE active centre can be substituted by other
      transition metal cations without loss of activity. Furthermore, metal-substituted
      PTEs display differences in catalytic properties. A prerequisite for engineering
      highly efficient mutants of PTE is to improve their thermostability. Isoelectric
      focusing, capillary electrophoresis and steady-state kinetics analysis were used
      to determine the contribution of the active-site cations Zn2+, Co2+ or Cd2+ to
      both the catalytic activity and the conformational stability of the corresponding
      PTE isoforms. The three isoforms have different pI values (7.2, 7.5 and 7.1) and
      showed non-superimposable electrophoretic titration curves. The overall
      structural alterations, causing changes in functional properties, were found to
      be related to the nature of the bound cation: ionic radius and ion
      electronegativity correlate with Km and kcat respectively. In addition, the pH
      dependent activity profiles of isoforms were different. The temperature-dependent
      profiles of activity showed maximum activity at T < or =35 degrees C, followed by
      an activation phase near 45-48 degrees C and then inactivation which was
      completed at 60 degrees C. Analysis of thermal denaturation of the PTEs provided
      evidence that the activation phase resulted from a transient intermediate.
      Finally, at the optimum activity between pH 8 and 9.4, the thermostability of the
      different PTEs increased as the pH decreased, and the metal cation modulated
      stability (Zn2+-, Co2+- and Cd2+-PTE showed different T (m) values of 60.5-67
      degrees C, 58-64 degrees C and 53-64 degrees C respectively). Requirements for
      optimum activity of PTE (displayed by Co2+-PTE) and maximum stability (displayed
      by Zn2+-PTE) were demonstrated.

PMID- 15018616
TI  - Development of an adsorption procedure for the direct separation and purification
      of prodigiosin from culture broth.
AB  - A novel procedure for the direct separation and purification of prodigiosin based
      on adsorption chromatography is provided. A surfactant (Tween 80; 0.1%, w/v) was
      used to improve prodigiosin release from the cell envelope. An adsorbent (X-5
      resin) with high loading capacity (7.3 mg/g) was selected for the direct recovery
      of prodigiosin from culture broth by static adsorption or in situ separation.
      This technology not only simplified the separation process, but also made the
      recovery yield (83%) much higher when compared with the conventional method
      (50%). As a result, it will be particularly suited for large-scale separation and
      purification of prodigiosin.

PMID- 15018614
TI  - Ceramide 1-phosphate enhances calcium entry through voltage-operated calcium
      channels by a protein kinase C-dependent mechanism in GH4C1 rat pituitary cells.
AB  - Sphingomyelin derivatives modulate a multitude of cellular processes, including
      the regulation of [Ca2+]i (the intracellular free calcium concentration).
      Previous studies have shown that these metabolites often inhibit calcium entry
      through VOCCs (voltage-operated calcium channels). In the present study, we show
      that, in pituitary GH4C1 cells, C1P (C2-ceramide 1-phosphate) enhances calcium
      entry in a dose-dependent manner. The phospholipase C inhibitor U73122 attenuated
      the response. C1P invoked a small, but significant, increase in the formation of
      inositol phosphates. Pre-treatment of the cells with pertussis toxin was without
      an effect on the C1P-evoked increase in [Ca2+]i. The effect of C1P was critically
      dependent on extracellular calcium, since no increase in [Ca2+]i was observed
      when cells in a calcium-free buffer were stimulated with C1P. Furthermore, if the
      cells were retreated with 300 nM of the VOCC inhibitor nimodipine, the effect of
      C1P was almost totally abolished. In addition, ceramide C8-1-phosphate evoked an
      increase in [Ca2+]i, but the onset of the response was slow compared with that of
      C1P. In cells treated with 1 mM thapsigargin for 15 min, C1P still evoked an
      increase in [Ca2+]i. In patch-clamp experiments in the whole-cell mode, C1P
      enhanced calcium entry through the VOCCs compared with vehicle-treated cells.
      Dialysis of the cells with C1P did not enhance the calcium current. On-cell patch
      clamp experiments showed an enhanced probability of the VOCCs being open
      (P(open)) in the presence of C1P. Inhibition of PKC (protein kinase C) with
      GF109203X and down-regulation of PKC with PMA attenuated the C1P-evoked increase
      in [Ca2+]i. Furthermore, down-regulation of PKC abolished the effect of C1P on
      P(open). This is the first report showing that a sphingomyelin derivative
      enhances calcium entry through VOCCs.

PMID- 15018618
TI  - Correlation between imaging and pathology in ductal carcinoma in situ of the
      breast.
AB  - BACKGROUND: It is helpful in planning treatment for patients with ductal
      carcinoma in situ (DCIS) if the size and grade could be reliably predicted from
      the mammography. The aims of this study were to determine if the type of
      calcification can be best used to predict histopathological grade from the
      mammograms, to examine the association of mammographic appearance of DCIS with
      grade and to assess the correlation between mammographic size and pathological
      size. METHODS: Mammographic films and pathological slides of 115 patients treated
      for DCIS between 1986 and 2000 were reviewed and reclassified by a single
      radiologist and a single pathologist respectively. Prediction models for the
      European Pathologist Working Group (EPWG) and Van Nuys classifications were
      generated by ordinal regression. The association between mammographic appearance
      and grade was tested with the chi2-test. Relation of mammographic size with
      pathological size was established using linear regression. The relation was
      expressed by the correlation coefficient (r). RESULTS: The EPWG classification
      was correctly predicted in 68%, and the Van Nuys classification in 70% if DCIS
      was presented as microcalcifications. High grade was associated with presence of
      linear calcifications (p < 0.001). Association between mammograhic- and
      pathological size was better for DCIS presented as microcalcifications (r = 0.89,
      p < 0.001) than for DCIS presented as a density (r = 0.77, p < 0.001).
      CONCLUSIONS: Prediction of histopathological grade of DCIS presenting as
      microcalcifications is comparable using the Van Nuys and EPWG classification.
      There is no strict association of mammographic appearance with histopathological
      grade. There is a better linear relation between mammographic- and pathological
      size of DCIS presented as microcalcifications than as a density, although both
      relations are statistically significant.

PMID- 15018615
TI  - Differential signalling for enhanced hexose uptake by interleukin (IL)-3 and IL-5
      in male germ cells.
AB  - We studied the expression and function of the IL (interleukin)-3 and IL-5 family
      of receptors in male germ cells. RT (reverse transcription)-PCR showed expression
      of mRNAs encoding the alpha and beta subunits of the IL-3 and IL-5 receptors in
      human testis, and the presence of IL-3 and IL-5 receptors alpha and beta proteins
      was confirmed by immunoblotting with anti-alpha and anti-beta antibodies. The
      immunolocalization studies showed expression of these receptors in the germ line
      in the human testis and in human and bovine ejaculated spermatozoa. Functional
      studies with bull spermatozoa indicated that IL-3 signalled for increased uptake
      of hexoses in these cells at picomolar concentrations compatible with expression
      of functional high-affinity IL-3 receptors in these cells. In contrast, IL-5
      failed to induce increased hexose uptake in bull spermatozoa. Experiments using
      HL-60 eosinophils that express functional IL-3 and IL-5 receptors confirmed that
      IL-3, but not IL-5, signalled for increased hexose uptake. Our findings suggest
      that differential signalling for increased hexose uptake by heteromeric high
      affinity IL-3 and IL-5 receptors in mammalian spermatozoa is a property that
      depends on the identity of the alpha-subunit forming part of the alphabeta
      complex and is not a property specific to the germ cells.

PMID- 15018619
TI  - Bronchial hyperreactivity and spirometric impairment in polysensitized patients
      with allergic rhinitis.
AB  - BACKGROUND: We previously demonstrated in a group of patients with perennial
      allergic rhinitis alone impairment of spirometric parameters and high percentage
      of subjects with bronchial hyperreactivity (BHR). The present study aimed at
      evaluating a group of polysensitized subjects suffering from allergic rhinitis
      alone to investigate the presence of spirometric impairment and BHR during the
      pollen season. METHODS: One hundred rhinitics sensitized both to pollen and
      perennial allergens were evaluated during the pollen season. Spirometry and
      methacholine bronchial challenge were performed. RESULTS: Six rhinitics showed
      impaired values of FEV1 without referred symptoms of asthma. FEF 25-75 values
      were impaired in 28 rhinitics. Sixty-six patients showed positive methacholine
      bronchial challenge. FEF 25-75 values were impaired only in BHR positive patients
      (p < 0.001). A significant difference was observed both for FEV1 (p < 0.05) and
      FEF 25-75 (p < 0.001) considering BHR severity. CONCLUSIONS: This study evidences
      that an impairment of spirometric parameters may be observed in polysensitized
      patients with allergic rhinitis alone during the pollen season. A high percentage
      of these patients had BHR. A close relationship between upper and lower airways
      is confirmed.

PMID- 15018620
TI  - Task-oriented evaluation of electronic medical records systems: development and
      validation of a questionnaire for physicians.
AB  - BACKGROUND: Evaluation is a challenging but necessary part of the development
      cycle of clinical information systems like the electronic medical records (EMR)
      system. It is believed that such evaluations should include multiple
      perspectives, be comparative and employ both qualitative and quantitative
      methods. Self-administered questionnaires are frequently used as a quantitative
      evaluation method in medical informatics, but very few validated questionnaires
      address clinical use of EMR systems. METHODS: We have developed a task-oriented
      questionnaire for evaluating EMR systems from the clinician's perspective. The
      key feature of the questionnaire is a list of 24 general clinical tasks. It is
      applicable to physicians of most specialties and covers essential parts of their
      information-oriented work. The task list appears in two separate sections, about
      EMR use and task performance using the EMR, respectively. By combining these
      sections, the evaluator may estimate the potential impact of the EMR system on
      health care delivery. The results may also be compared across time, site or
      vendor. This paper describes the development, performance and validation of the
      questionnaire. Its performance is shown in two demonstration studies (n = 219 and
      80). Its content is validated in an interview study (n = 10), and its reliability
      is investigated in a test-retest study (n = 37) and a scaling study (n = 31).
      RESULTS: In the interviews, the physicians found the general clinical tasks in
      the questionnaire relevant and comprehensible. The tasks were interpreted
      concordant to their definitions. However, the physicians found questions about
      tasks not explicitly or only partially supported by the EMR systems difficult to
      answer. The two demonstration studies provided unambiguous results and low
      percentages of missing responses. In addition, criterion validity was
      demonstrated for a majority of task-oriented questions. Their test-retest
      reliability was generally high, and the non-standard scale was found symmetric
      and ordinal. CONCLUSION: This questionnaire is relevant for clinical work and EMR
      systems, provides reliable and interpretable results, and may be used as part of
      any evaluation effort involving the clinician's perspective of an EMR system.

PMID- 15018622
TI  - The prevalence, patterns of usage and people's attitude towards complementary and
      alternative medicine (CAM) among the Indian community in Chatsworth, South
      Africa.
AB  - BACKGROUND: The purpose of this study was to determine, among the Indian
      community of Chatsworth, South Africa, the prevalence and utilisation patterns of
      complementary and alternative medicine (CAM), attitudes associated with CAM use
      and communication patterns of CAM users with their primary care doctors. METHODS:
      Face-to-face structured interviews were conducted in Chatsworth, a suburb of
      Durban in which South Africans of Indian origin predominantly reside.
      Participants were 200 randomly selected adult English-speaking Indian residents.
      RESULTS: The prevalence of CAM usage for period 2000/2001 was 38.5% (95%
      confidence interval 31.7% to 45.6%). Spiritual healing and herbal/natural
      medicines, including vitamins were the most common types of CAM used, accounting
      for 42.8% and 48.1% respectively of overall CAM usage. People used CAM to treat
      conditions including diabetes mellitus, headaches, arthritis and joint pains,
      stress, skin disorders, backaches, hypertension and nasal disorders. Half of the
      CAM users used allopathic medicines concurrently. The cost of CAM utilization
      over this 1-year period, incurred by 80.5% of users for the duration of therapy
      for their most troublesome condition was below R500 (approximately US50 dollars).
      Age, sex, marital status, religion, level of education and income were shown not
      to influence the use of CAM. Greater than half (51.9%) of CAM users did so either
      upon the advice of someone they knew, or after noticing a CAM advertisement in
      the local press. Seventy-nine percent of CAM users indicated that they had
      positive outcomes with their treatments. Fifty four percent of CAM users
      (excluding those using spiritual healing only) failed to inform their doctors
      that they used CAM. The main reason given by half of this group was that
      informing their doctors did not seem necessary. CONCLUSION: The prevalence of CAM
      in Chatsworth is similar to findings in other parts of the world. Although CAM
      was used to treat many different ailments, this practice could not be attributed
      to any particular demographic profile. The majority of CAM users were satisfied
      with the effects of CAM. Findings support a need for greater integration of
      allopathic medicine and CAM, as well as improved communication between patients
      and caregivers regarding CAM usage.

PMID- 15018621
TI  - The effects of ethanol and silymarin treatment during gestation on spatial
      working memory.
AB  - BACKGROUND: Using a rat model we have found that the bioflavonoid silymarin (SY)
      ameliorates some of the negative consequences of in utero exposure to ethanol
      (EtOH). In the current study our aim was to determine if spatial working memory
      (SWM) was impaired in offspring whose mothers were maintained on a liquid diet
      containing EtOH during different gestational weeks. We also determined if SWM was
      altered with a concomitant administration of SY with EtOH during specific
      gestational weeks. METHODS: We provided pregnant Fischer/344 rats with liquid
      diets containing 35% EtOH derived calories (EDC) during specific weeks of the
      gestational period. A silymarin/phospholipid compound containing 29.8% silybin co
      administered with EtOH was also administered during specific weeks of the
      gestational period. We tested SWM of the offspring with a radial arm maze on
      postnatal day (PND) 60. After testing the rats were sacrificed and their brains
      perfused for later analysis. RESULTS: We observed SWM deficits, as well as a
      significantly lower brain weight in female offspring born of mothers treated with
      EtOH during the third week of gestation in comparison to mothers treated during
      either the first or second weeks of gestation. Rats from any group receiving EtOH
      in co-administration with SY showed no significant deficits in SWM. CONCLUSION:
      EtOH treatment during the last week of gestation had the greatest impact on SWM.
      The addition of SY to the EtOH liquid diet appeared to ameliorate the EtOH
      induced learning deficits.

PMID- 15018624
TI  - The outcome of kidney transplants with multiple renal arteries.
AB  - BACKGROUND: The use of grafts with multiple renal arteries has been considered a
      relative contraindication because of the increased incidence of vascular and
      urologic complications The aim of this study is to determine whether the kidney
      grafts with multiple arteries have any adverse effect upon post-transplant graft
      and patient survival. METHODS: We reviewed the records of 225 adult kidney
      transplants done consecutively at our institution. Twenty-nine patients (12.8%)
      had grafts with multiple renal arteries. We analyzed the incidence of post
      transplant hypertension and vascular complications, mean creatinine levels,
      patient and graft survival. In 17 cases reconstruction was done as conjoined
      anastomosis between two arteries of equal size, and in 6 cases as end-to-side
      anastomosis of smaller arteries to larger arteries. Multiple anastomoses were
      performed in 6 cases. RESULTS: In one patient postoperative bleeding occurred.
      Mean systolic blood pressures, creatinine levels at first year and last follow-up
      and complication rates were all in acceptable ranges. There was no significant
      difference in graft and patient survival between multiple and single renal artery
      allografts. CONCLUSION: Although the kidney grafts with multiple renal arteries
      have been considered a relative contraindication because of the increased risk of
      complications, in our study allografts with multiple arteries were used
      successfully in kidney transplantation.

PMID- 15018623
TI  - Complementary and conventional medicine: a concept map.
AB  - BACKGROUND: Despite the substantive literature from survey research that has
      accumulated on complementary and alternative medicine (CAM) in the United States
      and elsewhere, very little research has been done to assess conceptual domains
      that CAM and conventional providers would emphasize in CAM survey studies. The
      objective of this study is to describe and interpret the results of concept
      mapping with conventional and CAM practitioners from a variety of backgrounds on
      the topic of CAM. METHODS: Concept mapping, including free sorts, ratings, and
      multidimensional scaling was used to organize conceptual domains relevant to CAM
      into a visual "cluster map." The panel consisted of CAM providers, conventional
      providers, and university faculty, and was convened to help formulate conceptual
      domains to guide the development of a CAM survey for use with United States
      military veterans. RESULTS: Eight conceptual clusters were identified: 1) Self
      assessment, Self-care, and Quality of Life; 2) Health Status, Health Behaviors;
      3) Self-assessment of Health; 4) Practical/Economic/ Environmental Concerns; 5)
      Needs Assessment; 6) CAM vs. Conventional Medicine; 7) Knowledge of CAM; and 8)
      Experience with CAM. The clusters suggest panelists saw interactions between CAM
      and conventional medicine as a critical component of the current medical
      landscape. CONCLUSIONS: Concept mapping provided insight into how CAM and
      conventional providers view the domain of health care, and was shown to be a
      useful tool in the formulation of CAM-related conceptual domains.

PMID- 15018626
TI  - Massive right-sided hemorrhagic pleural effusion due to pancreatitis; a case
      report.
AB  - BACKGROUND: Hemorrhagic pleural effusion, especially in the right hemithorax
      rarely occurs as the sole presentation of pancreatitis. CASE PRESENTATION: This
      article reports massive right-sided hemorrhagic pleural effusion as the sole
      manifestation of pancreatitis in a 16-year-old Iranian boy. The patient referred
      to Nemazee Hospital, the main hospital of southern Iran, with right-sided
      shoulder and chest pain accompanied with dyspnea. His chest x-ray showed massive
      right-sided pleural effusion. The pleural fluid amylase was markedly elevated
      (8840 U/L), higher than that in the serum (3318 U/L). Abdominal CT scan showed a
      cystic structure measuring about 5.2 cm in the head of pancreas, highly
      suggestive of a pancreatic pseudocyst. Pleural effusion resolved after 3 weeks of
      chest tube insertion but not completely. After this period of conservative
      therapy another CT scan showed that pseudocyst was still in the head of pancreas.
      So, external drainage was done with mushroom insertion and the patient was
      discharged after 40 days of hospitalization. The cause of pancreatitis could not
      be identified. CONCLUSION: Pancreatitis should be taken into consideration when
      hemorrhagic pleural effusion, especially in the right hemithorax occurs.

PMID- 15018625
TI  - Use of botulinum toxin-A for musculoskeletal pain in patients with whiplash
      associated disorders [ISRCTN68653575].
AB  - BACKGROUND: Whiplash associated disorder is commonly linked to motor vehicle
      accidents and sports injuries. Cervical injury is attributed to rapid extension
      followed by neck flexion. The exact pathophysiology of whiplash is uncertain but
      probably involves some degree of aberrant muscle spasms and may produce a wide
      range of symptoms. The most commonly prescribed pharmacological agents for
      initial treatment of whiplash-associated pain are oral muscle relaxants and
      nonsteroidal anti-inflammatory drugs. However, potential systemic adverse effects
      limit these agents. Physical interventions such as mobilization, manipulation,
      and exercises have proved beneficial for pain and dysfunction but only on a time
      limited basis. Little evidence suggests that physical therapy specifically aimed
      at the musculature (e.g., transcutaneous electrical nerve stimulation,
      ultrasonography, heat, ice, and acupuncture) improves prognosis in acute whiplash
      associated disorder. A new approach to treatment is the use of botulinum toxin,
      which acts to reduce muscle spasms. METHODS/DESIGN: This is a prospective,
      randomized, controlled clinical trial and botulinum toxin-A (Botox) injections
      will be compared with placebo injections. The primary objective is to determine
      the efficacy of Botox in the management of musculoskeletal pain in whiplash
      associated disorders. DISCUSSION: Botulinum toxin type-A toxin has been studied
      in small trials on whiplash associated disorder patients and has generally been
      found to relieve pain and improve range of motion. Specifically, we seek to
      assess the efficacy of Botox in reducing pain and to improve the cervical spine
      range of movement, during the 6-month trial period.

PMID- 15018627
TI  - Prevalence of obsessive-compulsive disorder in Iran.
AB  - BACKGROUND: Estimates of the annual prevalence for Obsessive Compulsive Disorder
      (OCD) were consistent across the international sites range, 1.9%-2.5%. The nine
      population surveys, which used Diagnostic Interview Schedule, estimated a six
      month prevalence of OCD ranging from 0.7% to 2.1%. This study performed in order
      to determine the prevalence of OCD in a population-based study among Iranian
      adults aged 18 and older and to study the association of them with factors such
      as sex, marital status, education, type of occupation and residential area.
      METHODS: A cross-sectional nationwide epidemiological study of the Iranian
      population aged 18 and older was designed to estimate the prevalence of
      psychiatric disorders and their association with the above mentioned factors.
      25180 individuals were selected and interviewed through a randomized systematic
      and cluster sampling method from all Iranian households. Schedule for Affective
      Disorders and Schizophrenia (SADS) and Diagnostic and Statistical Manual of
      Mental Disorders-IV (DSM-IV) criteria were used in diagnosis of OCD. 250 clinical
      psychologists interviewed the selected subjects face to face at their homes.
      RESULTS: The prevalence of OCD in Iran is 1.8% (0.7% and 2.8% in males and
      females; respectively). 50.3% of the survey sample were men, 49.9% women, 29.1%
      single, 67.45% married, 0.4% separated or divorced, 2.5% widow/widower and 4%
      undetermined. All of the above-mentioned factors were examined in the univariate
      and multivariate logistic regression models. Although the data did not fit the
      models well, but in univariate models, sex, the category "single" of marital
      status, age, the categories "business" and "housewife" and residential areas
      showed significant effect adjusting for the factors, but the models didn't fit
      the data properly. CONCLUSION: The study suggests that the prevalence of OCD is
      not rare in the community of Iran and is within the range of other countries.
      Similar to prior studies in other communities, OCD is more common in females than
      males.

PMID- 15018628
TI  - Toxoplasma seropositivity and depression: a case report.
AB  - BACKGROUND: The association between toxoplasmosis and psychiatric disorders has
      been reported in a few anecdotal reports. CASE PRESENTATION: A case of depression
      with toxoplasma seropositivity is presented. The patient with depression showed
      poor response to antidepressants, for which he was investigated and was found
      positive on the serological test for the toxoplasma. The response to
      antidepressant treatment improved only after adequate treatment for toxoplasma.
      CONCLUSIONS: The case suggests a probable association between toxoplasmosis and
      depression.

PMID- 15018629
TI  - Infant mortality trends in a region of Belarus, 1980-2000.
AB  - BACKGROUND: The Chernobyl disaster in 1986 and the breakup of the former Soviet
      Union (FSU) in 1991 challenged the public health infrastructure in the former
      Soviet republic of Belarus. Because infant mortality is regarded as a sensitive
      measure of the overall health of a population, patterns of neonatal and
      postneonatal deaths were examined within the Mogilev region of Belarus between
      1980 and 2000. METHODS: Employing administrative death files, this study utilized
      a regional cohort design that included all infant deaths occurring among persons
      residing within the Mogilev oblast of Belarus between 1980 and 2000. Patterns of
      death and death rates were examined across 3 intervals: 1980-1985 (pre
      Chernobyl), 1986-1991 (post-Chernobyl & pre-FSU breakup), and 1992-2000 (post
      Chernobyl & post-FSU breakup). RESULTS: Annual infant mortality rates declined
      during the 1980s, increased during the early 1990s, and have remained stable
      thereafter. While infant mortality rates in Mogilev have decreased since the
      period 1980-1985 among both males and females, this decrement appears due to
      decreases in postneonatal mortality. Rates of postneonatal mortality in Mogilev
      have decreased since the period 1980-1985 among both males and females. Analyses
      of trends for infant mortality and neonatal mortality demonstrated continuous
      decreases between 1990, followed by a bell-shaped excess in the 1990's. Compared
      to rates of infant mortality for other countries, rates in the Mogilev region are
      generally higher than rates for the United States, but lower than rates in
      Russia. During the 1990s, rates for both neonatal and postneonatal mortality in
      Mogilev were two times the comparable rates for East and West Germany.
      CONCLUSIONS: While neonatal mortality rates in Mogilev have remained stable,
      rates for postneonatal mortality have decreased among both males and females
      during the period examined. Infant mortality rates in the Mogilev region of
      Belarus remain elevated compared to rates for other western countries, but lower
      than rates in Russia. The public health infrastructure might attempt to assure
      that prenatal, maternal, and postnatal care is maximized.

PMID- 15018630
TI  - Variability of wavefront aberration measurements in small pupil sizes using a
      clinical Shack-Hartmann aberrometer.
AB  - BACKGROUND: Recently, instruments for the measurement of wavefront aberration in
      the living human eye have been widely available for clinical applications.
      Despite the extensive background experience on wavefront sensing for research
      purposes, the information derived from such instrumentation in a clinical setting
      should not be considered a priori precise. We report on the variability of such
      an instrument at two different pupil sizes. METHODS: A clinical aberrometer (COAS
      Wavefront Scienses, Ltd) based on the Shack-Hartmann principle was employed in
      this study. Fifty consecutive measurements were performed on each right eye of
      four subjects. We compared the variance of individual Zernike expansion
      coefficients as determined by the aberrometer with the variance of coefficients
      calculated using a mathematical method for scaling the expansion coefficients to
      reconstruct wavefront aberration for a reduced-size pupil. RESULTS: Wavefront
      aberration exhibits a marked variance of the order of 0.45 microns near the edge
      of the pupil whereas the central part appears to be measured more consistently.
      Dispersion of Zernike expansion coefficients was lower when calculated by the
      scaling method for a pupil diameter of 3 mm as compared to the one introduced
      when only the central 3 mm of the Shack - Hartmann image was evaluated. Signal-to
      noise ratio was lower for higher order aberrations than for low order
      coefficients corresponding to the sphero-cylindrical error. For each subject a
      number of Zernike expansion coefficients was below noise level and should not be
      considered trustworthy. CONCLUSION: Wavefront aberration data used in clinical
      care should not be extracted from a single measurement, which represents only a
      static snapshot of a dynamically changing aberration pattern. This observation
      must be taken into account in order to prevent ambiguous conclusions in clinical
      practice and especially in refractive surgery.

PMID- 15018631
TI  - HFE C282Y and H63D in adults with malignancies in a community medical oncology
      practice.
AB  - BACKGROUND: We sought to compare frequencies of HFE C282Y and H63D alleles and
      associated odds ratios (OR) in 100 consecutive unrelated white adults with
      malignancy to those in 318 controls. METHODS: Data from patients with more than
      one malignancy were analyzed according to each primary malignancy. For the
      present study, OR > or =2.0 or < or =0.5 was defined to be increased or
      decreased, respectively. RESULTS: There were 110 primary malignancies (52
      hematologic neoplasms, 58 carcinomas) in the 100 adult patients. Allele
      frequencies were similar in patients and controls (C282Y: 0.0850 vs. 0.0896,
      respectively (OR = 0.9); H63D: 0.1400 vs. 0.1447, respectively (OR = 0.9)). Two
      patients had hemochromatosis and C282Y homozygosity. With C282Y, increased OR
      occurred in non-Hodgkin lymphoma, myeloproliferative disorders, and
      adenocarcinoma of prostate (2.0, 2.8, and 3.4, respectively); OR was decreased in
      myelodysplasia (0.4). With H63D, increased OR occurred in myeloproliferative
      disorders and adenocarcinomas of breast and prostate (2.4, 2.0, and 2.0,
      respectively); OR was decreased in non-Hodgkin lymphoma and B-chronic lymphocytic
      leukemia (0.5 and 0.4, respectively). CONCLUSIONS: In 100 consecutive adults with
      malignancy evaluated in a community medical oncology practice, frequencies of HFE
      C282Y or H63D were similar to those in the general population. This suggests that
      C282Y or H63D is not associated with an overall increase in cancer risk. However,
      odds ratios computed in the present study suggest that increased (or decreased)
      risk for developing specific types of malignancy may be associated with the
      inheritance of HFE C282Y or H63D. Study of more patients with these specific
      types of malignancies is needed to determine if trends described herein would
      remain and yield significant differences.

PMID- 15018632
TI  - Chromosomal amplifications, 3q gain and deletions of 2q33-q37 are the frequent
      genetic changes in cervical carcinoma.
AB  - BACKGROUND: Carcinoma of uterine cervix is the second most common cancers among
      women worldwide. Combined radiation and chemotherapy is the choice of treatment
      for advanced stages of the disease. The prognosis is poor, with a five-year
      survival rate ranging from about 20-65%, depending on stage of the disease.
      Therefore, genetic characterization is essential for understanding the biology
      and clinical heterogeneity in cervical cancer (CC). METHODS: We used a genome
      wide screening method--comparative genomic hybridization (CGH) to identify DNA
      copy number changes in 77 patients with cervical cancer. We applied categorical
      and survival analyses to analyze whether chromosomal changes were related to
      clinico-pathologic characteristics and patients survival. RESULTS: The CGH
      analysis revealed a loss of 2q33-q37 (57.1%), gain of 3q (54.5%) and chromosomal
      amplifications (20.77%) as frequent genetic changes. A total of 15 amplified
      chromosomal sites were detected in 16 cases that include 1p31, 2q32, 7q22, 8q21.2
      q24, 9p22, 10q21, 10q24, 11q13, 11q21, 12q15, 14q12, 17p11.2, 17q22, 18p11.2, and
      19q13.1. Recurrent amplified sites were noted at 11q13, 11q21, and 19q13.1. The
      genomic alterations were further evaluated for prognostic significance in CC
      patients, and we did not find any correlation with a number of clinical or
      histological parameters. The tumors harboring HPV18 exhibited higher genomic
      instability compared to tumors with HPV 16. CONCLUSIONS: This study demonstrated
      that 2q33-q37 deletions, 3q gains and chromosomal amplifications as
      characteristic changes in invasive CC. These genetic alterations will aid in the
      identification of novel tumor suppressor gene(s) at 2q33-q37 and oncogenes at
      amplified chromosomal sites. Molecular characterization of these chromosomal
      changes utilizing the current genomic technologies will provide new insights into
      the biology and clinical behavior of CC.

PMID- 15018633
TI  - Amyloidosis in familial Mediterranean fever patients: correlation with MEFV
      genotype and SAA1 and MICA polymorphisms effects.
AB  - BACKGROUND: Familial mediterranean fever (FMF) is a recessively inherited disease
      characterized by recurrent crises of fever, abdominal, articular and/or thoracic
      pain. The most severe complication is the development of renal amyloidosis. Over
      35 mutations have been discovered so far in the gene responsible for the disease,
      MEFV. This article aims at determining a correlation between the MEFV genotype
      and the occurrence of amyloidosis in FMF patients, in addition to the study of
      the modifying effects of the SAA1 (type 1 serum amyloid A protein) and MICA
      (Major Histocompatibility Complex (MHC) class-I-chain-related gene A) genes on
      this severe complication. METHODS: Fourteen MEFV mutations were screened and the
      SAA1 and MICA polymorphisms tested in 30 FMF patients with amyloidosis and 40 FMF
      patients without amyloidosis. RESULTS: The M694V and V726A allelic frequencies
      were, respectively, significantly higher and lower in the group with amyloidosis,
      compared to the control FMF group. The beta and gamma SAA1 alleles were more
      frequently encountered in the group without amyloidosis, whereas the alpha allele
      was significantly more observed in FMF patients with amyloidosis (p < 0.025). All
      the MICA alleles were encountered in both patients' groups, but none of them was
      significantly associated with amyloidosis. CONCLUSIONS: The results suggest a
      protective effect of the SAA1 beta and gamma alleles on the development of
      amyloidosis and show the absence of a MICA modifying effect on amyloidosis
      development. Testing these polymorphisms on a larger sample will lead to more
      definite conclusions.

PMID- 15018634
TI  - Novel and de novo PKD1 mutations identified by multiple restriction fragment
      single strand conformation polymorphism (MRF-SSCP).
AB  - BACKGROUND: We have previously developed a long RT-PCR method for selective
      amplification of full-length PKD1 transcripts (13.6 kb) and a long-range PCR for
      amplification in the reiterated region (18 kb) covering exons 14 and 34 of the
      PKD1 gene. These have provided us with an opportunity to study PKD1 mutations
      especially in its reiterated region which is difficult to examine. In this
      report, we have further developed the method of multiple restriction fragment
      single strand conformation polymorphism (MRF-SSCP) for analysis of PKD1 mutations
      in the patients with autosomal dominant polycystic kidney disease (ADPKD). Novel
      and de novo PKD1 mutations are identified and reported. METHODS: Full-length PKD1
      cDNA isolated from the patients with ADPKD was fractionated into nine overlapping
      segments by nested-PCR. Each segment was digested with sets of combined
      restriction endonucleases before the SSCP analysis. The fragments with aberrant
      migration were mapped, isolated, and sequenced. The presence of mutation was
      confirmed by the long-range genomic DNA amplification in the PKD1 region,
      sequencing, direct mutation detection, and segregation analysis in the affected
      family. RESULTS: Five PKD1 mutations identified are two frameshift mutations
      caused by two di-nucleotide (c. 5225_5226delAG and c.9451_9452delAT) deletions, a
      nonsense (Q1828X, c.5693C>T) mutation, a splicing defect attributable to 31
      nucleotide deletion (g.33184_33214del31), and an in-frame deletion (L3287del,
      c.10070_10072delCTC). All mutations occurred within the reiterated region of the
      gene involving exons 15, 26, 15, 19 and 29, respectively. Three mutations (one
      frameshift, splicing defect, and in-frame deletion) are novel and two (one
      frameshift and nonsense) known. In addition, two mutations (nonsense and splicing
      defect) are possibly de novo. CONCLUSION: The MRF-SSCP method has been developed
      to analyze PCR products generated by the long RT-PCR and nested-PCR technique for
      screening PKD1 mutations in the full-length cDNA. Five mutations identified were
      all in the reiterated region of this gene, three of which were novel. The
      presence of de novo PKD1 mutations indicates that this gene is prone to
      mutations.

PMID- 15018635
TI  - Association of Atopobium vaginae, a recently described metronidazole resistant
      anaerobe, with bacterial vaginosis.
AB  - BACKGROUND: Bacterial vaginosis (BV) is a polymicrobial syndrome characterized by
      a change in vaginal flora away from predominantly Lactobacillus species. The
      cause of BV is unknown, but the condition has been implicated in diverse medical
      outcomes. The bacterium Atopobium vaginae has been recognized only recently. It
      is not readily identified by commercial diagnostic kits. Its clinical
      significance is unknown but it has recently been isolated from a tuboovarian
      abcess. METHODS: Nucleotide sequencing of PCR amplified 16S rRNA gene segments,
      that were separated into bands within lanes on polyacrylamide gels by denaturing
      gradient gel electrophoresis (DGGE), was used to examine bacterial vaginal flora
      in 46 patients clinically described as having normal (Lactobacillus spp.
      predominant; Nugent score < or = 3) and abnormal flora (Nugent score > or = 4).
      These women ranged in age from 14 to 48 and 82% were African American. RESULTS:
      The DGGE banding patterns of normal and BV-positive patients were recognizably
      distinct. Those of normal patients contained 1 to 4 bands that were focused in
      the centre region of the gel lane, while those of BV positive patients contained
      bands that were not all focused in the center region of the gel lane. More
      detailed analysis of patterns revealed that bands identified as Atopobium vaginae
      were present in a majority (12/22) of BV positive patients, while corresponding
      bands were rare (2/24) in normal patients. (P < 0.001) Two A. vaginae isolates
      were cultivated from two patients whose DGGE analyses indicated the presence of
      this organism. Two A. vaginae 16S rRNA gene sequences were identified among the
      clinical isolates. The same two sequences were obtained from DGGE bands of the
      corresponding vaginal flora. The sequences differed by one nucleotide over the
      short (approximately 300 bp) segment used for DGGE analysis and migrated to
      slightly different points in denaturing gradient gels. Both isolates were strict
      anaerobes and highly metronidazole resistant. CONCLUSION: The results suggest
      that A. vaginae may be an important component of the complex bacterial ecology
      that constitutes abnormal vaginal flora. This organism could play a role in
      treatment failure if further studies confirm it is consistently metronidozole
      resistant.

PMID- 15018636
TI  - Primary care physicians' approach to diagnosis and treatment of hepatitis B and
      hepatitis C patients.
AB  - BACKGROUND: Infections caused by hepatitis B virus (HBV) and hepatitis C virus
      (HCV) are considered to be important health problems worldwide. The purpose of
      this study was to measure the general practitioners (GPs)' basic knowledge on HBV
      and HCV risk factors in determining their practice about this subject. METHODS: A
      cross-sectional type questionnaire survey was carried out at all of 32 primary
      healthcare centers (PHCCs) in Samsun, Turkey, between March 1 and April 31, 2002.
      The questionnaires were sent to 160 GPs and 129 (80.6%) of them answered the
      questionnaires. Knowledge, role responsibility, self-efficacy and attitudes and
      beliefs regarding to viral hepatitis B and hepatitis C were asked. RESULTS: Most
      of the GPs had adequate knowledge about transmission of HBV and HCV and also
      about risk factors for transmission of viruses. Most of the GPs (83.7%) were
      aware of recommendations for approach to a baby, born from HBsAg positive mother.
      They have limited facilities in diagnosis of viral hepatitis. Of the
      participants, 108 (83.7%) expressed that they could not diagnose HBV infections
      and 126 (97.7%) of them stated that they could not make the diagnoses of HCV
      infection in their local healthcare centers. The knowledge about treatment of
      chronic viral hepatitis B (21.8%) and C patients (17.8%) with elevated ALT is not
      sufficient. CONCLUSION: GPs' knowledge about risks of viral hepatitis was
      adequate in this study. They were not able to diagnose and follow up of these
      infections at PHCCs because of limited knowledge about chronic viral hepatitis
      and diagnostic facilities. GPs should be informed about current advice in
      diagnosis and treatment of chronic of HBV and HCV infections.

PMID- 15018637
TI  - Can the caged bird sing? Reflections on the application of qualitative research
      methods to case study design in homeopathic medicine.
AB  - BACKGROUND: Two main pathways exist for the development of knowledge in clinical
      homeopathy. These comprise clinical trials conducted primarily by university
      based researchers and cases reports and homeopathic "provings" compiled by
      engaged homeopathic practitioners. In this paper the relative merits of these
      methods are examined and a middle way proposed. This consists of the "Formal Case
      Study" (FCS) in which qualitative methods are used to increase the rigour and
      sophistication with which homeopathic cases are studied. Before going into design
      issues this paper places the FCS in an historical and academic context and
      describes the relative merits of the method. DISCUSSION: Like any research, the
      FCS should have a clear focus. This focus can be both "internal", grounded in the
      discourse of homeopathy and also encompass issues of wider appeal. A selection of
      possible "internal" and "external" research questions is introduced. Data
      generation should be from multiple sources to ensure adequate triangulation. This
      could include the recording and transcription of actual consultations. Analysis
      is built around existing theory, involves cross-case comparison and the search
      for deviant cases. The trustworthiness of conclusions is ensured by the
      application of concepts from qualitative research including triangulation,
      groundedness, respondent validation and reflexivity. Though homeopathic case
      studies have been reported in mainstream literature, none has used formal
      qualitative methods--though some such studies are in progress. SUMMARY: This
      paper introduces the reader to a new strategy for homeopathic research. This
      strategy, termed the "formal case study", allows for a naturalistic enquiry into
      the players, processes and outcomes of homeopathic practice. Using ideas from
      qualitative research, it allows a rigorous approach to types of research question
      that cannot typically be addressed through clinical trials and numeric outcome
      studies. The FCS provides an opportunity for the practitioner-researcher to
      contribute to the evidence-base in homeopathy in a systematic fashion. The FCS
      can also be used to inform the design of clinical trials through holistic study
      of the "active ingredients" of the therapeutic process and its clinical outcomes.

PMID- 15018638
TI  - Individual patient meta-analysis of single-dose rofecoxib in postoperative pain.
AB  - BACKGROUND: Individual patient meta-analysis to determine the analgesic efficacy
      and adverse effects of single-dose rofecoxib in acute postoperative pain.
      METHODS: Individual patient information was available from 14 trials; 13 in
      dental and one in postsurgical pain. For each patient the percentage of maximum
      possible pain relief (%maxTOTPAR) was determined at different time points. The
      proportion of patients with at least 50% maxTOTPAR, and number-needed-to-treat
      (NNT) for at least 50% maxTOTPAR, were then calculated, with time when 50% of
      patients had remedicated (TTR50) and number-needed-to-harm (NNH) for adverse
      effects. RESULTS: In dental pain, for rofecoxib 50 mg (1330 patients) compared
      with placebo (570 patients) the NNT was 1.9 (95% confidence interval 1.8 to 2.1)
      for six hours, 2.0 (1.8 to 2.1) at eight, 2.4 (2.2 to 2.6) at 12, and 2.8 (2.5 to
      3.1) at 24 hours. The TTR50 was 15.5 hours. Adverse effects were uncommon, though
      post-extraction alveolitis (dry socket) occurred more often with rofecoxib 50 mg
      than with placebo, NNH 24 (14 to 80). For postsurgical pain in one trial (163
      patients), the NNT for rofecoxib 50 mg for six hours was 3.9 (2.6 to 7.8), the
      TTR50 was 5.8 hours, and multiple-dose adverse effects over five days occurred at
      similar rates with rofecoxib 50 mg and placebo. CONCLUSIONS: Single-dose
      rofecoxib 50 mg is an effective treatment with long-lasting analgesia and few
      adverse effects in dental pain. More information is required to confirm efficacy
      in postsurgical pain.

PMID- 15018639
TI  - In vivo analysis of interactions between GFP-labeled microfilaments and plastid
      stromules.
AB  - BACKGROUND: Plastid stromules are stroma-filled tubules that extend from the
      surface of plastids in higher plants and allow the exchange of protein molecules
      between plastids. These structures are highly dynamic; stromules change both
      their shape and position in the cytoplasm very rapidly. Previous studies with
      microfilament inhibitors indicated that stromule shape and movement are dependent
      on the actin cytoskeleton. To learn more about the nature of the interactions of
      stromules and the cytoskeleton, we imaged fluorescently-labeled microfilaments
      and plastids. RESULTS: We have used Arabidopsis thaliana plants expressing green
      fluorescent protein fused to the human actin-binding protein talin to observe
      microfilaments and their relationship to stromules in vivo. Microfilaments were
      observed in close contact with stromules and plastid bodies of hypocotyl
      epidermis. Time-lapse confocal microscopy revealed that microfilament
      rearrangements were associated with changes in plastid and stromule morphology
      and position. We also observed close interactions between mitochondria and
      stromules in double-labeled cells. CONCLUSION: Our results indicate a correlation
      between the rearrangement of microfilaments and changes in the shape and position
      of plastids and stromules. Stromules interact with microfilaments that may also
      be utilized by mitochondria and other organelles. The interaction of
      microfilaments and plastids is likely to be mediated by actin-binding proteins on
      the plastid envelope membrane.

PMID- 15018640
TI  - Relationship between PPARalpha activation and NO on proximal tubular Na+
      transport in the rat.
AB  - BACKGROUND: Nitric oxide (NO) regulates renal proximal tubular (PT) Na+ handling
      through modulation of Na+-K+ ATPase. Peroxisome Proliferator Activated Receptor
      alpha (PPARalpha), a nuclear transcription factor, is expressed in PTs and has
      been reported to influence NO generation/activity in renal tissues. This study
      tested the hypothesis that PPARalpha interacts with NO and thereby affects renal
      tubular Na+ transport. Urinary excretion of nitrite (UNOXV) and Na+ (UNaV) and PT
      Na+ transport (Na+-K+ ATPase activity) were determined in rats treated with
      clofibrate (250 mg/kg i.p) or WY14643 (45 mg/kg; i.p.), a PPARalpha ligand, 2%
      NaCl (orally), clofibrate/NaCl, L-NAME, an inhibitor of NO production (100 mg/kg;
      orally), L-NAME/Clofibrate. RESULTS: Clofibrate or WY14643 increased PPARalpha
      expression by 106 +/- 7% (p < 0.05) and 113 +/- 8% (p < 0.05), respectively.
      Similarly, clofibrate and WY14643 increased expression of MCAD, a downstream
      target protein of PPARalpha by 123 +/- 8% (p < 0.05) and 143 +/- 8% (p < 0.05),
      respectively. L-NAME attenuated clofibrate-induced increase in PPARalpha
      expression by 27 +/- 2% (p < 0.05) but did not affect MCAD expression. UNOXV
      excretion increased 3-4 fold in rats treated with clofibrate, WY14643 or NaCl
      from 44 +/- 7 to 170 +/- 15, 144 +/- 18 or 132 +/- 11 nmol/24 hr, respectively (p
      < 0.05). Similarly, clofibrate, WY14643 or NaCl elicited a 2-5 fold increase in
      UNaV. L-NAME significantly reduced basal UNOXV and UNaV and abolished the
      clofibrate-induced increase. Clofibrate, WY14643, NaCl or clofibrate + NaCl
      treatment reduced Na+-K+-ATPase activity in the PT by 89 +/- 23, 62 +/- 10, 43 +/
      9 and 82 +/- 15% (p < 0.05), respectively. On the contrary, L-NAME or ODQ,
      inhibitor of sGC, abolished the inhibition of Na+-K+-ATPase activity by
      clofibrate (p < 0.05). Clofibrate either alone or with NaCl elicited
      approximately 2-fold increase in the expression of the alpha1 subunit of Na+-K+
      ATPase in the PT while L-NAME abolished clofibrate-induced increase in Na+-K+
      ATPase expression. CONCLUSION: These data suggest that PPARalpha activation,
      through increased NO generation promotes renal excretion of Na+ through reduced
      Na+-K+ ATPase activity in the PT probably via post translational modification of
      Na+-K+-ATPase.

PMID- 15018641
TI  - Differential inhibition of postnatal brain, spinal cord and body growth by a
      growth hormone antagonist.
AB  - BACKGROUND: Growth hormone (GH) plays an incompletely understood role in the
      development of the central nervous system (CNS). In this study, we use transgenic
      mice expressing a growth hormone antagonist (GHA) to explore the role of GH in
      regulating postnatal brain, spinal cord and body growth into adulthood. The GHA
      transgene encodes a protein that inhibits the binding of GH to its receptor,
      specifically antagonizing the trophic effects of endogenous GH. RESULTS: Before
      50 days of postnatal age, GHA reduces spinal cord weight more than brain weight,
      but less than body weight. Thereafter, GHA ceases to inhibit the increase in body
      weight, which approaches control levels by day 150. In contrast, GHA continues to
      act on the CNS after day 50, reducing spinal cord growth to a greater extent and
      for a longer duration than brain growth. CONCLUSIONS: Judging from its inhibition
      by GHA, GH differentially affects the magnitude, velocity and duration of
      postnatal growth of the brain, spinal cord and body. GH promotes body enlargement
      more than CNS growth early in postnatal life. Later, its CNS effects are most
      obvious in the spinal cord, which continues to exhibit GH dependence well into
      adulthood. As normal CNS growth slows, so does its inhibition by GHA, suggesting
      that reduced trophic effects of GH contribute to the postnatal slowing of CNS
      growth. GHA is a highly useful tool for studying the role of endogenous GH on
      organ-specific growth during aging.

PMID- 15018642
TI  - C. trachomatis-infection accelerates metabolism of phosphatidylcholine derived
      from low density lipoprotein but does not affect phosphatidylcholine secretion
      from hepatocytes.
AB  - BACKGROUND: Chlamydia trachomatis is a prevalent sexually transmitted disease and
      the leading cause of infectious blindness in developing nations. It was not known
      if C. trachomatis-infection influenced metabolism of lipoprotein-derived
      phospholipids. Nor was it known if C. trachomatis-infection altered
      phosphatidylcholine (PC) secretion from hepatocytes. In the current study, low
      density lipoprotein (LDL)-derived [methyl-3H]PC metabolism was examined in L929
      cells infected with C. trachomatis to determine if PC derived from LDL could
      serve as a potential source of PC trafficked to C. trachomatis. In addition,
      release of endogenously synthesized [methyl-3H]PC into the medium was examined in
      rat liver hepatocytes infected with C. trachomatis to determine if infection
      altered PC secretion. RESULTS: L929 cells 20 h post infection exhibited a 39% (p
      < 0.05) reduction in radioactivity in PC but total radioactivity incorporation
      was unaltered compared to controls. Lysophosphatidyl [methyl-3H]choline (LPC) and
      aqueous [methyl-3H]choline metabolites were elevated 3.6-fold (p < 0.05) and 16.5
      fold (p < 0.05), respectively, in C. trachomatis-infected cells and this was due
      to a 51% increase (p < 0.05) in calcium-dependent phospholipase A2 activity.
      Hepatocytes 22 h post infection then incubated for 16 h with [methyl-3H]choline
      showed elevated [methyl-3H]PC biosynthesis but [methyl-3H]PC secreted into the
      medium was unaltered compared to controls. In contrast, both cellular and medium
      lyso [methyl-3H]PC were elevated in C. trachomatis-infected cells. CONCLUSION:
      This study is the first to show that metabolism of LDL-derived PC is accelerated
      in C. trachomatis infection and to support the notion that LDL-delivered PC may
      potentially serve as a source of PC trafficked to Chlamydia. In addition, C.
      trachomatis-infection does not inhibit PC secretion from hepatocytes indicating
      that the pool of newly synthesized PC destined for lipoprotein secretion may
      differ from the pool of PC used for C. trachomatis membrane biosynthesis.

PMID- 15018643
TI  - Immune response to Mycoplasma pneumoniae P1 and P116 in patients with atypical
      pneumonia analyzed by ELISA.
AB  - BACKGROUND: Serology is often used for the diagnosis of Mycoplasma pneumoniae. It
      is important to identify specific antigens that can distinguish between the
      presence or absence of antibodies against M. pneumoniae. The two proteins, P116
      and P1, are found to be immunogenic. By using these in ELISA it is possible to
      identify an immune response against M. pneumoniae in serum samples. RESULTS: A
      recombinant protein derived from the P116 protein and one from the P1 protein
      were used in two ELISA tests, rP116-ELISA and rP1-ELISA. Human serum samples from
      patients with atypical pneumonia were tested and compared to the results of the
      complement fixation test. There was a good agreement between the two tests but
      the rP1-ELISA showed the best discrimination between positive and negative
      samples. CONCLUSION: Two ELISA tests based on recombinant proteins have been
      analysed and compared to the complement fixation test results. The two ELISA
      tests were found suitable for use in serodiagnostics of M. pneumoniae infections.
      The use of specific antigens eliminates the risk of cross reaction to an immune
      response against other bacteria.

PMID- 15018644
TI  - Bacillus subtilis GlcK activity requires cysteines within a motif that
      discriminates microbial glucokinases into two lineages.
AB  - BACKGROUND: Bacillus subtilis glucokinase (GlcK) (GenBank NP_390365) is an ATP
      dependent kinase that phosphorylates glucose to glucose 6-phosphate. The GlcK
      protein has very low sequence identity (13.7%) to the Escherichia coli
      glucokinase (Glk) (GenBank P46880) and some other glucokinases (EC 2.7.1.2), yet
      glucose is merely its substrate. Our lab has previously isolated and
      characterized the glcK gene. RESULTS: Microbial glucokinases can be grouped into
      two different lineages. One of the lineages contains three conserved cysteine (C)
      residues in a CXCGX(2)GCXE motif. This motif is also present in the B. subtilis
      GlcK. The GlcK protein occurs in both monomer and homodimer. Each GlcK monomer
      has six cysteines. All cysteine residues have been mutated, one-by-one, into
      alanine (A). The in vivo GlcK enzymatic activity was assayed by functional
      complementation in E. coli UE26 (ptsG ptsM glk). Mutation of the three motif
      specific residues led to an inactive enzyme. The other mutated forms retained, or
      in one case (GlcKC321A) even gained, activity. The fluorescence spectra of the
      GlcKC321A showed a red shift and enhanced fluorescence intensity compare to the
      wild type's. CONCLUSIONS: Our results emphasize the necessity of cysteines within
      the CXCGX(2)GCXE motif for GlcK activity. On the other hand, the C321A mutation
      led to higher GlcKC321A enzymatic activity with respect to the wild type's,
      suggesting more adequate glucose phosphorylation.

PMID- 15018645
TI  - Triple-target microarray experiments: a novel experimental strategy.
AB  - BACKGROUND: High-throughput, parallel gene expression analysis by means of
      microarray technology has become a widely used technique in recent years. There
      are currently two main dye-labelling strategies for microarray studies based on
      custom-spotted cDNA or oligonucleotides arrays: (I) Dye-labelling of a single
      target sample with a particular dye, followed by subsequent hybridisation to a
      single microarray slide, (II) Dye-labelling of two different target samples with
      two different dyes, followed by subsequent co-hybridisation to a single
      microarray slide. The two dyes most frequently used for either method are Cy3 and
      Cy5. We propose and evaluate a novel experiment set-up utilising three
      differently labelled targets co-hybridised to one microarray slide. In addition
      to Cy3 and Cy5, this incorporates Alexa 594 as a third dye-label. We evaluate
      this approach in line with current data processing and analysis techniques for
      microarrays, and run separate analyses on Alexa 594 used in single-target, dual
      target and the intended triple-target experiment set-ups (a total of 18
      microarray slides). We follow this by pointing out practical applications and
      suitable analysis methods, and conclude that triple-target microarray experiments
      can add value to microarray research by reducing material costs for arrays and
      related processes, and by increasing the number of options for pragmatic
      experiment design. RESULTS: The addition of Alexa 594 as a dye-label for an
      additional--third--target sample works within the framework of more commonplace
      Cy5/Cy3 labelled target sample combinations. Standard normalisation methods are
      still applicable, and the resulting data can be expected to allow identification
      of expression differences in a biological experiment, given sufficient levels of
      biological replication (as is necessary for most microarray experiments).
      CONCLUSION: The use of three dye-labelled target samples can be a valuable
      addition to the standard repertoire of microarray experiment designs. The method
      enables direct comparison between two experimental populations as well as
      measuring these two populations in relation to a third reference sample, allowing
      comparisons within the slide and across slides. These benefits are only offset by
      the added level of consideration required in the experimental design and data
      processing of a triple-target study design. Common methods for data processing
      and analysis are still applicable, but there is scope for the development of
      custom models for triple-target data. In summary, we do not consider the triple
      target approach to be a new standard, but a valuable addition to the existing
      microarray study toolkit.

PMID- 15018646
TI  - Utilization of a labeled tracking oligonucleotide for visualization and quality
      control of spotted 70-mer arrays.
AB  - BACKGROUND: Spotted 70-mer oligonucleotide arrays offer potentially greater
      specificity and an alternative to expensive cDNA library maintenance and
      amplification. Since microarray fabrication is a considerable source of data
      variance, we previously directly tagged cDNA probes with a third fluorophore for
      prehybridization quality control. Fluorescently modifying oligonucleotide sets is
      cost prohibitive, therefore, a co-spotted Staphylococcus aureus-specific
      fluorescein-labeled "tracking" oligonucleotide is described to monitor
      fabrication variables of a Mycobacterium tuberculosis oligonucleotide microarray.
      RESULTS: Significantly (p < 0.01) improved DNA retention was achieved printing in
      15% DMSO/1.5 M betaine compared to the vendor recommended buffers. Introduction
      of tracking oligonucleotide did not effect hybridization efficiency or introduce
      ratio measurement bias in hybridizations between M. tuberculosis H37Rv and M.
      tuberculosis mprA. Linearity between the mean log Cy3/Cy5 ratios of genes
      differentially expressed from arrays either possessing or lacking the tracking
      oligonucleotide was observed (R2 = 0.90, p < 0.05) and there were no significant
      differences in Pearson's correlation coefficients of ratio data between
      replicates possessing (0.72 +/- 0.07), replicates lacking (0.74 +/- 0.10), or
      replicates with and without (0.70 +/- 0.04) the tracking oligonucleotide. ANOVA
      analysis confirmed the tracking oligonucleotide introduced no bias. Titrating
      target-specific oligonucleotide (40 microM to 0.78 microM) in the presence of 0.5
      microM tracking oligonucleotide, revealed a fluorescein fluorescence inversely
      related to target-specific oligonucleotide molarity, making tracking
      oligonucleotide signal useful for quality control measurements and
      differentiating false negatives (synthesis failures and mechanical misses) from
      true negatives (no gene expression). CONCLUSIONS: This novel approach enables
      prehybridization array visualization for spotted oligonucleotide arrays and sets
      the stage for more sophisticated slide qualification and data filtering
      applications.

PMID- 15018648
TI  - Profound influence of microarray scanner characteristics on gene expression
      ratios: analysis and procedure for correction.
AB  - BACKGROUND: High throughput gene expression data from spotted cDNA microarrays
      are collected by scanning the signal intensities of the corresponding spots by
      dedicated fluorescence scanners. The major scanner settings for increasing the
      spot intensities are the laser power and the voltage of the photomultiplier tube
      (PMT). It is required that the expression ratios are independent of these
      settings. We have investigated the relationships between PMT voltage, spot
      intensities, and expression ratios for different scanners, in order to define an
      optimal scanning procedure. RESULTS: All scanners showed a limited intensity
      range from 200 to 50 000 (mean spot intensity), for which the expression ratios
      were independent of PMT voltage. This usable intensity range was considerably
      less than the maximum detection range of the PMTs. The use of spot and background
      intensities outside this range led to errors in the ratios. The errors at high
      intensities were caused by saturation of pixel intensities within the spots. An
      algorithm was developed to correct the intensities of these spots, and, hence,
      extend the upper limit of the usable intensity range. CONCLUSIONS: It is
      suggested that the PMT voltage should be increased to avoid intensities of the
      weakest spots below the usable range, allowing the brightest spots to reach the
      level of saturation. Subsequently, a second set of images should be acquired with
      a lower PMT setting such that no pixels are in saturation. Reliable data for
      spots with saturation in the first set of images can easily be extracted from the
      second set of images by the use of our algorithm. This procedure would lead to an
      increase in the accuracy of the data and in the number of data points achieved in
      each experiment compared to traditional procedures.

PMID- 15018647
TI  - Combined subtractive cDNA cloning and array CGH: an efficient approach for
      identification of overexpressed genes in DNA amplicons.
AB  - BACKGROUND: Activation of proto-oncogenes by DNA amplification is an important
      mechanism in the development and maintenance of cancer cells. Until recently,
      identification of the targeted genes relied on labour intensive and time
      consuming positional cloning methods. In this study, we outline a straightforward
      and efficient strategy for fast and comprehensive cloning of amplified and
      overexpressed genes. RESULTS: As a proof of principle, we analyzed neuroblastoma
      cell line IMR-32, with at least two amplification sites along the short arm of
      chromosome 2. In a first step, overexpressed cDNA clones were isolated using a
      PCR based subtractive cloning method. Subsequent deposition of these clones on a
      custom microarray and hybridization with IMR-32 DNA, resulted in the
      identification of clones that were overexpressed due to gene amplification. Using
      this approach, amplification of all previously reported amplified genes in this
      cell line was detected. Furthermore, four additional clones were found to be
      amplified, including the TEM8 gene on 2p13.3, two anonymous transcripts, and a
      fusion transcript, resulting from 2p13.3 and 2p24.3 fused sequences. CONCLUSIONS:
      The combinatorial strategy of subtractive cDNA cloning and array CGH analysis
      allows comprehensive amplicon dissection, which opens perspectives for improved
      identification of hitherto unknown targeted oncogenes in cancer cells.

PMID- 15018650
TI  - Acetylcholinesterase alterations reveal the fitness cost of mutations conferring
      insecticide resistance.
AB  - BACKGROUND: Insecticide resistance is now common in insects due to the frequent
      use of chemicals to control them, which provides a useful tool to study the
      adaptation of eukaryotic genome to new environments. Although numerous potential
      mutations may provide high level of resistance, only few alleles are found in
      insect natural populations. Then, we hypothesized that only alleles linked to the
      highest fitness in the absence of insecticide are selected. RESULTS: To obtain
      information on the origin of the fitness of resistant alleles, we studied
      Drosophila melanogaster acetylcholinesterase, the target of organophosphate and
      carbamate insecticides. We produced in vitro 15 possible proteins resulting from
      the combination of the four most frequent mutations and we tested their catalytic
      activity and enzymatic stability. Mutations affected deacetylation of the enzyme,
      decreasing or increasing its catalytic efficiency and all mutations diminished
      the stability of the enzyme. Combination of mutations result to an additive
      alteration. CONCLUSION: Our findings suggest that the alteration of activity and
      stability of acetylcholinesterase are at the origin of the fitness cost
      associated with mutations providing resistance. Magnitude of the alterations was
      related to the allelic frequency in Drosophila populations suggesting that the
      fitness cost is the main driving force for the maintenance of resistant alleles
      in insecticide free conditions.

PMID- 15018649
TI  - Complex genetic predisposition in adult and juvenile rheumatoid arthritis.
AB  - BACKGROUND: Rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) are
      complex multifactorial diseases caused by environmental influences and an unknown
      number of predisposing genes. The present study was undertaken in order to
      investigate association of polymorphisms in candidate genes with RA and JRA in
      German subjects. RESULTS: Up to 200 unrelated German RA and JRA patients each and
      300-400 healthy controls have been genotyped for HLA-DRB1, TNFa, TNFA -238a/g,
      TNFA -308a/g, TNFA -857c/t, TNFR1 -609g/t, TNFR1 P12P, TNFR2 del 15bp, IKBL 
      332a/g, IKBL -132t/a, IKBL C224R, CTLA4 -318c/t, CTLA4 T17A, PTPRC P57P, MIF 
      173g/c, the MIF and IFNG microsatellites as well as for D17S795, D17S807,
      D17S1821 by polyacrylamide gel electrophoresis, single-strand conformation
      polymorphism analysis, restriction fragment length polymorphism analysis or
      allele specific hybridization. None of the investigated genetic markers is
      associated with both, RA and JRA, but there are some statistically significant
      differences between patients and controls that have to be discussed sensibly.
      CONCLUSIONS: The difficulty in investigating the genetics of complex disorders
      like RA and JRA may arise from genetic heterogeneity in the clinically defined
      disease cohorts (and generally limited power of such studies). In addition,
      several to many genes appear to be involved in the genetic predisposition, each
      of which exerting only small effects. The number of investigated patients has to
      be increased to establish the possibility of subdivison of the patients according
      their clinical symptoms, severity of disease, HLA status and other genetic
      characteristics.

PMID- 15018651
TI  - Mutations of acetylcholinesterase which confer insecticide resistance in
      Drosophila melanogaster populations.
AB  - BACKGROUND: Organophosphate and carbamate insecticides irreversibly inhibit
      acetylcholinesterase causing death of insects. Resistance-modified
      acetylcholinesterases(AChEs) have been described in many insect species and
      sequencing of their genes allowed several point mutations to be described.
      However, their relative frequency and their cartography had not yet been
      addressed. RESULTS: To analyze the most frequent mutations providing insecticide
      resistance in Drosophila melanogaster acetylcholinesterase, the Ace gene was
      cloned and sequenced in several strains harvested from different parts of the
      world. Sequence comparison revealed four widespread mutations, I161V, G265A,
      F330Y and G368A. We confirm here that mutations are found either isolated or in
      combination in the same protein and we show that most natural populations are
      heterogeneous, composed of a mixture of different alleles. In vitro expression of
      mutated proteins showed that combining mutations in the same protein has two
      consequences: it increases resistance level and provides a wide spectrum of
      resistance. CONCLUSION: The presence of several alleles in natural populations,
      offering various resistance to carbamate and organophosphate compounds will
      complicate the establishment of resistance management programs.

PMID- 15018652
TI  - Dppa3 / Pgc7 / stella is a maternal factor and is not required for germ cell
      specification in mice.
AB  - BACKGROUND: In mice, germ cells are specified through signalling between layers
      of cells comprising the primitive embryo. The function of Dppa3 (also known as
      Pgc7 or stella), a gene expressed in primordial germ cells at the time of their
      emergence in gastrulating embryos, is unknown, but a recent study has claimed
      that it plays a central role in germ cell specification. RESULTS: To test Dppa3's
      role in germ cell development, we disrupted the gene in mouse embryonic stem
      cells and generated mutant animals. We were able to obtain viable and fertile
      Dppa3-deficient animals of both sexes. Examination of embryonic and adult germ
      cells and gonads in Dppa3-deficient animals did not reveal any defects. However,
      most embryos derived from Dppa3-deficient oocytes failed to develop normally
      beyond the four-cell stage. CONCLUSION: We found that Dppa3 is an important
      maternal factor in the cleavage stages of mouse embryogenesis. However, it is not
      required for germ cell specification.

PMID- 15018654
TI  - Array-A-Lizer: a serial DNA microarray quality analyzer.
AB  - BACKGROUND: The proliferate nature of DNA microarray results have made it
      necessary to implement a uniform and quick quality control of experimental
      results to ensure the consistency of data across multiple experiments prior to
      actual data analysis. RESULTS: Array-A-Lizer is a small and convenient stand
      alone tool providing the necessary initial analysis of hybridization quality of
      an unlimited number of microarray experiments. The experiments are analyzed for
      even hybridization across the slide and between fluorescent dyes in two-color
      experiments in spotted DNA microarrays. CONCLUSIONS: Array-A-Lizer allows the
      expedient determination of the quality of multiple DNA microarray experiments
      allowing for a rapid initial screening of results before progressing to further
      data analysis. Array-A-Lizer is directed towards speed and ease-of-use allowing
      both the expert and non-expert microarray researcher to rapidly assess the
      quality of multiple microarray hybridizations. Array-A-Lizer is available from
      the Internet as both source code and as a binary installation package.

PMID- 15018653
TI  - Protein-trap version 2.1: screening for expressed proteins in mammalian cells
      based on their localizations.
AB  - BACKGROUND: "Protein-trap" is a method that allows epitope-tagging of endogenous
      proteins. This method allows for the identification of endogenously expressed
      proteins that exhibit specific localization of interest. This method has been
      recently reported for its application in the study of Drosophila development by
      using a relatively large epitope, green-fluorescent-protein (GFP). RESULT:
      Herein, we report a new "protein-trap" vector for mammalian cells. This new
      method utilizes a much smaller epitope-tag and also allows for drug-selection
      prior to the epitope-tagging. Pre-selection by drug resulted in the highly
      efficient protein-trapping frequency. CONCLUSION: The "protein-trap" method based
      on this new vector is expected to serve as a complimentary approach to the
      previously reported GFP-based method.

PMID- 15018655
TI  - MuTrack: a genome analysis system for large-scale mutagenesis in the mouse.
AB  - BACKGROUND: Modern biological research makes possible the comprehensive study and
      development of heritable mutations in the mouse model at high-throughput. Using
      techniques spanning genetics, molecular biology, histology, and behavioral
      science, researchers may examine, with varying degrees of granularity, numerous
      phenotypic aspects of mutant mouse strains directly pertinent to human disease
      states. Success of these and other genome-wide endeavors relies on a well
      structured bioinformatics core that brings together investigators from widely
      dispersed institutions and enables them to seamlessly integrate data,
      observations and discussions. DESCRIPTION: MuTrack was developed as the
      bioinformatics core for a large mouse phenotype screening effort. It is a
      comprehensive collection of on-line computational tools and tracks thousands of
      mutagenized mice from birth through senescence and death. It identifies the
      physical location of mice during an intensive phenotype screening process at
      several locations throughout the state of Tennessee and collects raw and
      processed experimental data from each domain. MuTrack's statistical package
      allows researchers to access a real-time analysis of mouse pedigrees for aberrant
      behavior, and subsequent recirculation and retesting. The end result is the
      classification of potential and actual heritable mutant mouse strains that become
      immediately available to outside researchers who have expressed interest in the
      mutant phenotype. CONCLUSION: MuTrack demonstrates the effectiveness of using
      bioinformatics techniques in data collection, integration and analysis to
      identify unique result sets that are beyond the capacity of a solitary
      laboratory. By employing the research expertise of investigators at several
      institutions for a broad-ranging study, the TMGC has amplified the effectiveness
      of any one consortium member. The bioinformatics strategy presented here lends
      future collaborative efforts a template for a comprehensive approach to large
      scale analysis.

PMID- 15018656
TI  - Aggregation of topological motifs in the Escherichia coli transcriptional
      regulatory network.
AB  - BACKGROUND: Transcriptional regulation of cellular functions is carried out
      through a complex network of interactions among transcription factors and the
      promoter regions of genes and operons regulated by them. To better understand the
      system-level function of such networks simplification of their architecture was
      previously achieved by identifying the motifs present in the network, which are
      small, overrepresented, topologically distinct regulatory interaction patterns
      (subgraphs). However, the interaction of such motifs with each other, and their
      form of integration into the full network has not been previously examined.
      RESULTS: By studying the transcriptional regulatory network of the bacterium,
      Escherichia coli, we demonstrate that the two previously identified motif types
      in the network (i.e., feed-forward loops and bi-fan motifs) do not exist in
      isolation, but rather aggregate into homologous motif clusters that largely
      overlap with known biological functions. Moreover, these clusters further
      coalesce into a supercluster, thus establishing distinct topological hierarchies
      that show global statistical properties similar to the whole network. Targeted
      removal of motif links disintegrates the network into small, isolated clusters,
      while random disruptions of equal number of links do not cause such an effect.
      CONCLUSION: Individual motifs aggregate into homologous motif clusters and a
      supercluster forming the backbone of the E. coli transcriptional regulatory
      network and play a central role in defining its global topological organization.

PMID- 15018658
TI  - Cytokines and costimulatory molecules in the immune response to murine
      gammaherpesvirus-68.
AB  - Murine gammaherpesvirus 68 (MHV-68) infection of mice provides a useful small
      animal model for studying gammaherpesvirus pathogenesis and immunity. Recent work
      has elucidated the cytokine and chemokine profiles during MHV-68 infection and
      has identified some of the costimulatory interactions that are important for an
      effective immune response to this virus. Several themes emerge from this work.
      There is a differential requirement for certain cytokines and costimulatory
      molecules in the acute and long-term control of MHV-68, and for control of the
      virus in different anatomical sites. CD4 T cell help is not required for short
      term control of MHV-68 in the lung by cytotoxic CD8 T cells, but is essential for
      effective long-term control. Stimulation via CD40 is an important component of
      this CD4 T cell help, and interestingly, some of its effects appear to be
      independent of CD28. MHV-68 infection also increases the expression of several
      chemokines, which could potentially play important roles in leukocyte trafficking
      to sites of infection. However, to counter this response, MHV-68 has evolved
      strategies that enable it to evade or subvert the host chemokine system. Studying
      the role of cytokines and costimulatory molecules in immunity to MHV-68 may
      provide useful insights for the development of agents to control
      gammaherpesviruses that cause human disease.

PMID- 15018659
TI  - Induction of T lymphocytes specific for bovine viral diarrhea virus in calves
      with maternal antibody.
AB  - Passive antibody to bovine viral diarrhea virus (BVDV) acquired through colostrum
      intake may interfere with the development of a protective immune response by
      calves to this virus. The objective of this study was to determine if calves,
      with a high level of maternal antibody to bovine viral diarrhea virus (BVDV),
      develop CD4(+), CD8(+), or gammadelta T lymphocyte responses to BVDV in the
      absence of a measurable humoral immune response. Colostrum or milk replacer fed
      calves were challenged with virulent BVDV at 2-5 weeks of age and/or after
      maternal antibody had waned. Calves exposed to BVDV while passive antibody levels
      were high did not mount a measurable humoral immune response to BVDV. However,
      compared to nonexposed animals, these animals had CD4(+), CD8(+), and gammadelta
      T lymphocytes that were activated by BVDV after exposure to in vitro BVDV. The
      production of IFNgamma by lymphocytes after in vitro BVDV exposure was also much
      greater in lymphocytes from calves exposed to BVDV in the presence of maternal
      antibody compared to the nonexposed calves. These data indicate that calves
      exposed to BVDV while maternal antibody levels are high can develop antigen
      specific CD4(+), CD8(+), and gammadelta T lymphocytes in the absence of an active
      antibody response. A manuscript presented separately demonstrates that the calves
      with T lymphocytes specific for BVDV in this study were also protected from
      virulent BVDV genotype 2 challenge after maternal antibody became undetectable.

PMID- 15018660
TI  - Impact of immunizations with porcine reproductive and respiratory syndrome virus
      on lymphoproliferative recall responses of CD8+ T cells.
AB  - The objective of this study was to investigate the immune responses elicited by
      either a modified-live (MLV) or a killed virus (KV) porcine reproductive and
      respiratory syndrome virus (PRRSV) vaccine. Specifically, we investigated the
      effects of multiple vaccinations on antigen-specific cellular and antibody
      responses against PRRSV. Twelve sows were obtained from herds with either a
      history of repeated MLV or KV PRRSV vaccination and a non-vaccinated, PRRSV
      negative herd. Within herd, sows were divided into three groups and vaccinated
      with MLV, KV, or injected with saline. On day 0, 27, and 38, recall responses of
      peripheral blood mononuclear cells (PBMC) to the parent strains of the vaccines
      (e.g., MLV-VR2332 or KV-ISUP) were examined. The concentrations of total PRRSV
      specific and virus-neutralizing serum antibodies were determined by ELISA and
      serum neutralization assays. Following immunization, the antigen-specific
      proliferation of CD8alphabeta(+), CD4(+)CD8alphaalpha(+) T cells in the naive
      sows was greater than in sows repeatedly vaccinated with KV or MLV. This
      diminished lymphoproliferative responses of CD8alphabeta(+) and
      CD4(+)CD8alphaalpha(+) T cells could be partially overcome by heterologous
      immunization. However, B cell proliferation, PRRSV antibody concentrations and
      virus neutralizing antibody titers were not enhanced by heterologous immunization
      and only KV vaccination increased antibody levels in previously immunized (MLV or
      KV) sows.

PMID- 15018661
TI  - T cells from a high proportion of apparently naive cattle can be activated by
      modified vaccinia virus Ankara (MVA).
AB  - Modified vaccinia virus Ankara (MVA) was used as a vector to express genes from
      bovine respiratory syncytial virus (BRSV). Using these recombinant viruses as
      recall antigens for cells from BRSV-immuned cattle proved to be problematic
      because non-recombinant MVA itself frequently stimulated high levels of T
      lymphocyte activation. This phenomenon was observed in a high percentage of
      cattle from multiple herds. Gamma delta TCR(+) T cells were more sensitive to
      activation by MVA than other classes of T cells. A serological assay for MVA
      neutralization detected low, fluctuating titers of serum virus neutralizing (SVN)
      activity toward MVA in some cattle, but these were lower titers than those
      observed in cattle that underwent MVA vaccination. T cell reactivity in non
      vaccinated cattle did not correlate significantly (p > 0.05) with SVN activity,
      undermining the notion that any adaptive immune response was responsible for the
      observed T cell sensitivity. More probable explanations are that MVA has
      mitogenic or superantigenic properties, or that the virus induces gammadelta
      TCR(+) T cell activation through interactions with innate pattern recognition
      receptors.

PMID- 15018662
TI  - Segments of puumala hantavirus nucleocapsid protein inserted into chimeric
      polyomavirus-derived virus-like particles induce a strong immune response in
      mice.
AB  - Insertion of a short-sized epitope at four different sites of yeast-expressed
      hamster polyomavirus major capsid protein VP1 has been found to result in the
      formation of chimeric virus-like particles. Here, we demonstrate that the
      insertion of 45 or 120 amino acid-long segments from the N-terminus of Puumala
      hantavirus nucleocapsid protein into sites 1 (amino acids 80-89) and 4 (amino
      acids 288-295) of VP1 allowed the highly efficient formation of virus-like
      particles. In contrast, expression level and assembly capacity of fusions to
      sites 2 (amino acids 222-225) and 3 (amino acids 243-247) were drastically
      reduced. Immunization of BALB/c mice with chimeric virus-like particles induced a
      high-titered antibody response against the hantavirus nucleocapsid protein, even
      in the absence of any adjuvant. The strongest response was observed in mice
      immunized with virus-like particles harboring 120 amino acids of hantavirus
      nucleocapsid protein. According to the immunoglobulin subclass distribution of
      nucleocapsid protein-specific antibodies a mixed Th1/Th2 response was detected.
      The VP1 carrier itself also induced a mixed Th1/Th2 response, which was found to
      be reduced in mice immunized with virus-like particles harboring 120 amino acid
      long inserts. In conclusion, hamster polyomavirus VP1 represents a promising
      carrier moiety for future vaccine development.

PMID- 15018664
TI  - Neurological disorder after Borna disease virus infection in the absence of
      either interferon-gamma, Fas, inducible NO synthase, or chemokine receptor CXCR3.
AB  - Borna disease virus (BDV) can induce severe neurological disorder in Lewis rats
      and MRL mice. Antiviral CD8 T cells have been shown to be the mediators of
      disease in these animals. To define molecules involved in the disease process, we
      performed infection studies in MRL mice lacking either interferon-gamma, a
      functional Fas/FasL system, chemokine receptor CXCR3, or inducible NO synthase.
      We further used transgenic MRL mice expressing interferon-gamma-inducible, T cell
      attracting chemokine CXCL10 in brain astrocytes. After intracerebral infection
      with BDV, wild-type and mutant mice developed CD8 T cell responses and
      neurological disease at similar frequency and with similar kinetics, suggesting
      that these factors are not required for initiation and maintenance of the
      immunopathological process. Similarly, the course of disease could not be altered
      by treating infected MRL mice or Lewis rats with the drug L-N(6)-(1-iminoethyl)
      lysine (L-NIL) that specifically blocks the activity of the inducible NO
      synthase. We therefore have excluded a number of important factors that have been
      demonstrated to be crucial in the pathogenesis of a broad number of pathologic
      conditions. Thus, BDV-induced disease may not result from the action of a single
      dominant T cell-dependent effector molecule. Disease rather reflects a combined
      influence of several as yet undefined factors from CD8 T cells.

PMID- 15018663
TI  - Mouse strain differences in the chemokine response to acute lung infection with a
      murine gammaherpesvirus.
AB  - Numerous mouse strain-based differences in the immune response and in
      susceptibility to numerous pathogens have been described, but it is not known if
      these differences extend to chemokine responses to viral infection of the lungs.
      To define mouse strain-based differences in the host chemokine response and
      susceptibility to infection with murine gammaherpesvirus-68 (MHV-68), we compared
      the induced chemokine response to MHV-68 infection in the lungs of BALB/c and
      C57BL/6 mice at 1-15 days post-infection. CC and CXC chemokines were induced in
      both BALB/c and C57BL/6 following infection but the level of chemokine induction
      was significantly higher in the BALB/c mice for all chemokines measured. In
      addition, interferon-gamma (IFN-gamma) was also induced to a significantly higher
      level in the lungs of BALB/c infected mice compared to C57BL/6 mice.
      Interestingly, viral gene expression was lower in the lungs of C57BL/6 mice
      during the acute phase of replication. Titers of infectious virus were also
      greater in BALB/c lungs, although they did not achieve statistical significance.
      In contrast, latent viral load in the spleen, as measured by quantitative real
      time PCR, did not significantly differ between mouse strains, suggesting that the
      establishment of latency is not affected by the amount of virus present during
      acute infection. This data suggests that robust chemokine response and expression
      of IFN-gamma in the lungs of infected BALB/c mice does not correlate with
      increased resistance to infection. In addition, the significant differences in
      chemokine responses observed will be important factors to consider in future
      studies of viral pathogenesis using mouse models.

PMID- 15018665
TI  - Rubella virus does not induce apoptosis in primary human embryo fibroblast
      cultures: a possible way of viral persistence in congenital infection.
AB  - Congenital rubella is a persistent infection that contrasts with acute postnatal
      infection. Basis of the Rubella virus (RV) persistence still remain unknown,
      though several hypotheses have been postulated. RV induces apoptosis in cell
      lines, maybe as a way of cell-autonomous defense mechanism against virus.
      Considering the pattern of c-oncogenes expression during embryogenesis, which
      promotes proliferation while it inhibits apoptosis in specific cells, at certain
      times, it can be proposed that when RV infection establishes early in gestation,
      embryo cells that are proliferating have their apoptotic pathways shut down; then
      infected proliferating embryo cells cannot execute their apoptotic death program.
      We here report that RV induces apoptosis in human normal-term placenta chorionic
      villi explants (CVE) and in monolayers of cytotrophoblasts (CTB), but does not
      induce apoptosis in primary human embryo fibroblasts (HEF) cultures. These
      results suggest distinct responses to RV infection when comparing differentiated
      cells, as CTB, to cells with high proliferating potential, as HEF. RV shoots
      apoptosis in the former, whereas in fibroblastic dividing cells derived from
      embryo, RV appears not to be enough stimulus to activate the genetic program of
      cell death.

PMID- 15018667
TI  - Increased plasma transforming growth factor-beta1 is associated with disease
      progression in HIV-1-infected patients.
AB  - Transforming growth factor-beta(1) (TGF-beta(1)) is a pleiotropic cytokine with a
      variety of effects on a wide range of cells in the immune system. Evidence
      suggests that TGF-beta(1) is also involved in the pathogenesis of human
      immunodeficiency virus type 1 infections. The aim of this study was to explore
      possible relationships between circulating TGF-beta(1) and immune as well as
      clinical HIV infection parameters with special impact on disease progression. TGF
      beta(1) concentrations were measured by ELISA in the plasma of 66 patients in
      different stages of HIV infection and 20 healthy controls. HIV infection resulted
      in a significant increase of plasma TGF-beta(1) concentration compared to healthy
      individuals (11.4 +/- 6.8 vs. 6.1 +/- 1.5 ng/mL, p < 0.01). TGF-beta(1) values
      showed a significant negative correlation with CD4 cells count (r = -0.42, p =
      0.001), as well as with CD8 cells count (r = -0.031, p < 0.05). Moreover,
      patients with the symptomatic phase of HIV infection presented an almost twofold
      increase of plasma TGF-beta(1) concentration in comparison to asymptomatic
      patients and healthy individuals. Our results demonstrate the relationship
      between TGF-beta(1) concentrations and HIV infection advancement with marked
      elevation in the late stages of the disease. These findings support in vitro
      observations suggesting an important, immunosuppressive role of TGF-beta(1) in
      HIV infection pathogenesis.

PMID- 15018666
TI  - Avidity of antibodies to cytomegalovirus in HIV-seropositive patients with and
      without CMV retinitis.
AB  - Antibodies of high avidity may protect the fetus from CMV infection, but the
      association of avidity with other CMV infections is unknown. To determine if anti
      CMV antibody avidity is altered in HIV-seropositive patients, either untreated or
      treated with HAART, and to determine if alterations in avidity are associated
      with CMV retinitis, we obtained sera from 164 CMV-seropositive adults: 68 were
      HIV-seronegative healthy adults and 96 were HIV seropositive. Of the HIV
      positive, 57 had no current or prior evidence of CMV retinitis (29 were being
      treated with HAART, and 28 were receiving no therapy when sampled), and 39 had
      either active CMV retinitis or were immunorestored by HAART with quiescent CMV
      retinitis. IgG antibody avidity was determined for each serum run in duplicate
      using an EIA assay and 5M urea as a dissociating agent. After correction for the
      significantly higher levels of IgG antibodies to CMV in the HIV-seropositive sera
      as compared to the normal healthy individuals, both HIV-infected and HIV
      uninfected individuals had nearly identical average avidity indices (avidity
      index = 76). There was also no significant difference in average avidity index
      between HAART-treated and untreated patients, or between patients with active and
      immunorestored, quiescent CMV retinitis). These results indicate antibody avidity
      is unaltered in HIV disease and does not play an important role in the
      pathogenesis of AIDS-related CMV disease.

PMID- 15018669
TI  - HLA-G expression in Guillain-Barre syndrome is associated with primary infection
      with cytomegalovirus.

PMID- 15018670
TI  - Conceiving the past and future.
AB  - The authors compared people's views of their histories and futures by asking them
      to recall and anticipate personally significant episodes. It was hypothesized and
      found in Study 1 that individuals spontaneously recall an affectively mixed past,
      containing both "highs" and "lows," whereas they anticipate homogeneously ideal
      futures. It was further hypothesized that people devote little thought to
      negative futures, and this was tested directly in Studies 2 and 3 by assessing
      how quickly past and likely future events came to mind. Asked to report positive
      and negative episodes from the past and future, participants took longer to
      generate future negative than positive events. Speed of recall was unaffected by
      the valence of past episodes. In Study 4, the response latency difference was
      again replicated for future events and it was demonstrated that people are slower
      in both generating negative future events and judging those events as likely.

PMID- 15018668
TI  - Yeast-expressed hantavirus Dobrava nucleocapsid protein induces a strong, long
      lasting, and highly cross-reactive immune response in mice.
AB  - In Europe, Dobrava virus (DOBV) carried by the yellow-necked field mouse Apodemus
      flavicollis is one of the hantaviruses that can cause severe hemorrhagic fever
      with renal syndrome in humans. For several hantaviruses, the nucleocapsid (N)
      protein has proven to be very immunogenic in humans and rodents and even can
      protect rodents against a virus challenge. To investigate the immunogenicity of
      DOBV N protein, BALB/c and C57BL/6 mice were immunized three times with a DOBV
      recombinant N (rN) protein expressed in yeast Saccharomyces cerevisiae together
      with complete Freund's, with incomplete Freund's, and without adjuvant,
      respectively. Mice of both strains elicited N-specific antibodies with end-point
      titers being as high as 1:1,000,000 in C57BL/6 mice. The antibodies induced by
      DOBV rN protein were highly cross-reactive to the rN proteins of hantaviruses
      Puumala and Hantaan. In both mice strains, DOBV rN protein induced N-specific
      antibodies of all IgG subclasses (IgG1, IgG2a, IgG2b, and IgG3), suggesting a
      mixed Th1/Th2 immune response. Taken together, yeast-expressed DOBV rN protein
      represents a promising vaccine candidate.

PMID- 15018671
TI  - Interpersonal distance in immersive virtual environments.
AB  - Digital immersive virtual environment technology (IVET) enables behavioral
      scientists to conduct ecologically realistic experiments with near-perfect
      experimental control. The authors employed IVET to study the interpersonal
      distance maintained between participants and virtual humans. In Study 1,
      participants traversed a three-dimensional virtual room in which a virtual human
      stood. In Study 2, a virtual human approached participants. In both studies,
      participant gender, virtual human gender, virtual human gaze behavior, and
      whether virtual humans were allegedly controlled by humans (i.e., avatars) or
      computers (i.e., agents) were varied. Results indicated that participants
      maintained greater distance from virtual humans when approaching their fronts
      compared to their backs. In addition, participants gave more personal space to
      virtual agents who engaged them in mutual gaze. Moreover, when virtual humans
      invaded their personal space, participants moved farthest from virtual human
      agents. The advantages and disadvantages of IVET for the study of human behavior
      are discussed.

PMID- 15018673
TI  - Self-consistency for low self-esteem in dissonance processes: the role of self
      standards.
AB  - The self-consistency revision of cognitive dissonance theory predicts that people
      with low self-esteem are less likely to experience dissonance arousal compared to
      people with high self-esteem. Two experiments investigated how the accessibility
      of different self-standards in the context of a dissonant act activates the
      consistency role of self-esteem in the process of cognitive dissonance arousal.
      In Experiment I, after participants wrote a counter-attitudinal essay, priming
      personal self-standards caused more attitude change for those with high compared
      to low self-esteem, whereas priming no standards or priming normative self
      standards caused the same level of attitude change among both self-esteem groups.
      Experiment 2 showed that the self-consistency effect for low self-esteem
      participants only occurred among those who were high in self-certainty when
      personal self-standards were primed. The importance of self-standards for
      understanding the role of self-esteem in dissonance processes is discussed.

PMID- 15018672
TI  - When communications collide with recipients' actions: effects of post-message
      behavior on intentions to follow the message recommendation.
AB  - Two experiments investigated the processes through which post-message behavior
      (e.g., noncompliance) influences resistance to the message. Participants in
      Experiment 1 read preventive, consumer-education messages that either opposed the
      consumption of an alcohol-like product or recommended moderation. Half of the
      participants then tried the product, whereas the remaining participants performed
      a filler task. In the absence of trial, the two messages had the same effect.
      However, recipients of the abstinence-promoting preventive message who tried the
      product had stronger intentions to use the product in the future than recipients
      of the moderation message. This finding suggests that assessments of message
      impact may be inadequate unless an opportunity for trial is also provided.
      Results are interpreted in terms of self-perception and cognitive dissonance and
      contrasted from psychological reactance.

PMID- 15018674
TI  - Predicting change in self-reported and interviewer-assessed adult attachment:
      tests of the individual difference and life stress models of attachment change.
AB  - The study tested the key assumption of the individual difference model of adult
      attachment change: that people who have experienced certain vulnerability factors
      will be prone to change attachment styles because they have developed unclear
      models of self and others that render their attachment models unstable. This
      model was compared to a life stress model, which states that change occurs as an
      adaptation to new, interpersonally relevant life circumstances. Changes in self
      reported and interviewer-assessed attachment were examined among 94 young adults
      who were followed over 1 year. Analyses yielded support for the individual
      difference model for change in both self-reported and interviewer-assessed
      attachment. The life stress model was supported for change in interviewer
      assessed attachment only. Implications for differential change processes for self
      reported versus interviewer-assessed aspects of adult attachment are discussed.

PMID- 15018675
TI  - Physical, emotional, and behavioral reactions to breaking up: the roles of
      gender, age, emotional involvement, and attachment style.
AB  - Associations between gender, age, emotional involvement, and attachment style and
      reactions to romantic relationship dissolution were studied in a survey of more
      than 5,000 Internet respondents. It was hypothesized that individual reactions to
      breakups would be congruent with characteristic attachment behaviors and affect
      regulation strategies generally associated with attachment style. Attachment
      related anxiety was associated with greater preoccupation with the lost partner,
      greater perseveration over the loss, more extreme physical and emotional
      distress, exaggerated attempts to reestablish the relationship, partner-related
      sexual motivation, angry and vengeful behavior, interference with exploratory
      activities, dysfunctional coping strategies, and disordered resolution.
      Attachment-related avoidance was weakly and negatively associated with most
      distress/proximity-seeking reactions to breakups and strongly and positively
      associated with avoidant and self-reliant coping strategies. Security (low scores
      on the anxiety and avoidance dimensions) was associated with social coping
      strategies (e.g., using friends and family as "safe havens"). Attachment
      insecurity, particularly anxiety, was associated with using drugs and alcohol to
      cope with loss.

PMID- 15018676
TI  - Narcissists as "Victims": the role of narcissism in the perception of
      transgressions.
AB  - Narcissism is a set of traits that are motivated by the desire to establish and
      maintain a grandiose self-image. Consistent with this conceptualization, the
      authors hypothesized that narcissistic people perceive themselves to be the
      victims of other people's inter-personal transgressions more frequently than do
      less narcissistic people. In a 14-day diary study, the authors found that
      narcissism (particularly in its exploitiveness/entitlement dimension) was
      associated positively with the number and frequency of transgressions that
      respondents reported. The narcissism-victimization relationship appears to
      result, at least in part, from biased recall or self-presentation. The
      exploitiveness/entitlement dimension of narcissism may be particularly useful for
      explaining why narcissistic people report higher rates of interpersonal
      transgressions in their daily lives.

PMID- 15018678
TI  - Identification and the commitment shift: accounting for gender differences in
      relationship illusions.
AB  - Previous work revealed gender differences in relationship illusions. Women, and
      not men, perceived their dating partners more favorably than their partners' self
      perceptions. In two studies, the authors replicated these findings and showed
      they are moderated by relationship commitment but not by relationship
      satisfaction. Dating men low in commitment devalued their partners' virtues,
      whereas those high in commitment exaggerated their partners' virtues compared to
      their partners' self-perceptions. In contrast, dating women showed relationship
      illusions irrespective of their commitment. In Study 2, similar results were
      obtained with relationship-specific identification. Moreover, men's commitment
      mediated the effect of identification with the relationship. This suggests that
      gender differences in relationship identities exist at a general level and that
      men need to identify with and then commit to a specific relationship before they
      exhibit pro-relationship thinking, which women exhibit as general dispositions.

PMID- 15018677
TI  - Mechanisms of self-control failure: motivation and limited resources.
AB  - Research has found that individuals who are lower in self-control strength
      because of previous self-control exertions perform more poorly on subsequent
      tests of self-control. The present studies suggest that this effect may be
      moderated by motivation. In particular, depletion and motivation jointly
      determine self-control performance. Individuals who were depleted and believed
      that the task would help others (Experiment 1) or believed that their efforts
      could benefit them (Experiment 2) performed better on a subsequent test of self
      control than individuals who were depleted and lower in motivation. The results
      of Experiment 3 replicated these findings and suggested that depletion only
      affects performance on tasks that require self-control; tasks that are difficult
      but do not require self-control are immune to the effects of depletion. Hence,
      depleted individuals may compensate for their lack of self-control resources when
      sufficiently motivated. The results may help explain the nature of self-control
      strength.

PMID- 15018679
TI  - Self-esteem maintenance processes: why low self-esteem may be resistant to
      change.
AB  - If most people desire to maximize feelings of self-worth, how do we explain the
      persistence of low self-esteem? Results from four studies suggest that people
      with low self-esteem may be less likely to accept positive feedback from
      themselves than from an outside source but equally likely to accept negative
      feedback from the self and an outsider. When the self was the source of positive
      feedback, people high, but not low, in self-esteem incorporated the feedback into
      their self-views; in contrast, when positive feedback came from a knowledgeable
      external source, both high and low self-esteem people accepted it. Finally, when
      self-generated feedback was negative, participants low in self-esteem accepted
      it. The authors discuss how these findings shed light on the maintenance of low
      self-esteem.

PMID- 15018680
TI  - Mapping the intimate relationship mind: comparisons between three models of
      attachment representations.
AB  - This study compared three models of how attachment working models might be
      cognitively represented. Model 1 posits that attachment representations consist
      of a single global working model summarizing attachment across specific
      relationships and domains. Model 2 proposes three independent working models for
      the relationship domains of family, platonic friendships, and romantic partners.
      Model 3 postulates that specific relationship models are nested under
      relationship domain representations that are, in turn, nested under an
      overarching global working model. Participants completed standard attachment
      scales for the relationship domains of family, platonic friendships, and romantic
      partners and also provided attachment ratings for three specific relationships
      within each domain. As expected, confirmatory factor analyses showed that Model 3
      attained the best fit, regardless of analysis strategy, measurement strategy,
      gender, and relationship status. Implications are discussed.

PMID- 15018681
TI  - Adaptive self-regulation of unattainable goals: goal disengagement, goal
      reengagement, and subjective well-being.
AB  - Three studies examined associations between goal disengagement, goal
      reengagement, and subjective well-being. In Study 1, 115 undergraduates reported
      on the extent to which they were able to abandon unattainable goals and reengage
      their efforts in alternative goals. Study 2 examined the importance of goal
      disengagement and goal reengagement in groups of young adults and older adults (N
      = 120). In Study 3, a sample of parents of children with cancer and parents of
      medically healthy children was examined (N = 45). The findings confirmed that
      goal disengagement and goal reengagement can be associated with ratings of high
      subjective well-being. In addition, the results showed that goal disengagement
      and goal reengagement can have interactive effects on subjective well-being. The
      importance of the findings for effective self-regulation and successful
      development are discussed.

PMID- 15018682
TI  - Social categorization and fear reactions to the September 11th terrorist attacks.
AB  - Two experiments were run in The Netherlands and Belgium 1 week after the
      terrorist attacks against the World Trade Center in New York on September 11,
      2001. The aim was to investigate whether social categorization affected emotional
      reactions, behavioral tendencies, and actual behaviors. Results showed that
      focusing participants' attention on an identity that included American victims
      into a common ingroup led them to report more fear and stronger fear-related
      behavioral tendencies and to engage more often in fear-related behaviors than
      when victims were categorized as outgroup members. Results are discussed with
      respect to appraisal theories of emotion and E. R. Smith's model of group-based
      emotions.

PMID- 15018684
TI  - American and Japanese women use different coping strategies during normal
      pregnancy.
AB  - In this longitudinal study, pregnant women in Japan and the United States
      reported on three coping strategies. Two are individually phrased: personal
      influence over outcomes and acceptance of outcomes. The third, social assurance,
      is grounded in relationships, noting that close others can influence outcomes. A
      European American sample rated acceptance highest as a strategy, whereas Japanese
      women rated social assurance highest. For Americans, acceptance correlated with
      better pregnancy outcomes (less distress over time, better prenatal care, and
      less weight gain). For Japanese women, social assurance predicted a more positive
      maternal relationship. Acceptance correlated with less Time 1 distress in both
      samples. Surprisingly, personal influence generally did not predict positive
      outcomes in either sample, perhaps because normal pregnancy is a time-limited
      event with a positive prognosis. The findings are consistent with the view that
      well-being is related to individual variables in the United States but also to
      features of social relationships in Japan.

PMID- 15018683
TI  - Optimism, promotion pride, and prevention pride as predictors of quality of life.
AB  - The relationship between optimism and two potential sources of optimistic beliefs
      -promotion pride (based on a history of success in promotion regulation) and
      prevention pride (based on a history of success in prevention regulation)--was
      explored. Optimism was more strongly related to promotion pride than prevention
      pride (controlling for neuroticism), consistent with past work showing that
      anticipating success increases eagerness motivation but decreases vigilance
      motivation. This suggests that the psychology of prevention regulators is not
      captured well by the existing literature on optimism. Although prevention pride
      does not predict self-reports of well-being, it does predict adaptive functioning
      independent of optimism, neuroticism, and promotion pride. Promotion pride
      uniquely predicted a sense of purpose in life or goal directedness. Both
      promotion and prevention pride predicted active coping. It is argued that
      promotion and prevention pride tell us something unique and important about the
      role of successful self-regulation in determining quality of life.

PMID- 15018685
TI  - Putting personality in social context: extraversion, emergent leadership, and the
      availability of rewards.
AB  - The present research tested relations between extraversion and emergent
      leadership among men in situations that differed in potential reward
      availability. Four-person groups of men engaged in a Leaderless Group Discussion
      (LGD) task and were randomly assigned to be evaluated by an attractive female
      observer, an attractive male observer, or not be evaluated. Evolutionary theories
      suggest that impressing a female evaluator in an intrasexually competitive
      situation should hold greater reward potential for men than impressing either a
      male evaluator or no evaluator. Accordingly, more extraverted men (who are more
      sensitive to reward cues) should display more group leadership when being
      evaluated by a woman than either a man or no one. Self-and peer ratings confirmed
      that more extraverted men were significantly more likely to emerge as leaders,
      but only in the female-evaluator condition. The results are discussed in terms of
      the interplay between personality, situational factors, and evolutionary
      principles.

PMID- 15018686
TI  - What you think is what you get: comparative evaluations of close relationships.
AB  - Three studies tested the hypothesis that focus of comparison moderates the
      influence of comparison standards on relationship satisfaction. Participants were
      asked to evaluate either their current relationships or their alternative
      relationships relative to an external comparison standard: a romantic stereotype
      (Study 1) or others' relationships (Studies 2 and 3). Consistent with the
      focusing hypothesis, the results show that people are more satisfied when they
      assimilate their relationship outcomes to a high standard or when they contrast
      them away from a low standard. Satisfaction, however, also increases when
      alternative relationships are contrasted away from a high standard or when they
      are assimilated to a low standard of comparison. Perceived quality of
      alternatives partially mediated the impact of focus of comparison on
      satisfaction. This finding is consistent with interdependence theory's
      distinction between a comparison level and a comparison level for alternative
      relationships, which are not completely independent from each other.

PMID- 15018687
TI  - On the investigation of primed and chronic autonomous and heteronomous
      motivational orientations.
AB  - Four studies examined primed and chronic autonomous and heteronomous motivations.
      Study 1 showed that autonomy and heteronomy can be primed and influence
      perceptions and behavior in a way consistent with consciously regulated motives.
      In Study 2, a measure of chronic motivation was developed and its construct
      validity and reliability were assessed. In Study 3, the chronicity measure
      predicted behavior while consciously regulated motives predicted intention but
      not behavior. Results of Study 4 replicated results of the priming manipulation
      in Study 1. However, this effect was moderated by level of motivational
      chronicity. The priming effect was found to be stronger for non-chronics than for
      chronics. Overall, the findings suggest that autonomous and heteronomous
      motivations can be regulated automatically as well as consciously.

PMID- 15018688
TI  - Gender-typical responses to sexual and emotional infidelity as a function of
      mortality salience induced self-esteem striving.
AB  - The authors propose that gender-differentiated patterns of jealousy in response
      to sexual and emotional infidelity are engendered by the differential impact of
      each event on self-esteem for men and women. Study 1 demonstrated that men derive
      relatively more self-esteem from their sex lives, whereas women's self-esteem is
      more contingent on romantic commitment. Based on terror management theory, it is
      predicted that if gender-differentiated responses to infidelity are motivated by
      gender-specific contingencies for self-esteem, they should be intensified
      following reminders of mortality. In Study 2, mortality salience (MS) increased
      distress in response to sexual infidelity for men and emotional infidelity for
      women. Study 3 demonstrated that following MS, men who place high value on sex in
      romantic relationships exhibited greater distress in response to sexual
      infidelity, but low-ex-value men's distress was attenuated. The authors discuss
      the implications for evolutionary and self-esteem-based accounts of jealousy as
      well as possible integration of these perspectives.

PMID- 15018689
TI  - Culture-specific patterns in the prediction of life satisfaction: roles of
      emotion, relationship quality, and self-esteem.
AB  - This study was conducted to explore the culture-specific roles of emotion,
      relationship quality, and self-esteem in determining life satisfaction. It was
      hypothesized that maintaining good interpersonal relationships would make
      individuals in collectivistic cultures not only feel good about their lives but
      also feel better about themselves. Furthermore, two emotion variables--emotional
      expression and emotion differentiation--were proposed as possible determinants of
      relationship quality. It was hypothesized that emotional expressiveness would be
      more important for maintaining good interpersonal relationships in
      individualistic societies but emotion differentiation would be more important in
      collectivistic cultures. These hypotheses were tested with Euro-American, Asian
      American, Korean, and Chinese groups using multigroup analyses in a structural
      equation model. Results supported all proposed hypotheses and indicated that
      emotion differentiation contributes to maintaining good interpersonal
      relationships in collectivistic cultures, which contributes to self-esteem and
      satisfaction with life.

PMID- 15018690
TI  - Clinical characteristics and length of hospital stay among older adults with
      bipolar disorder, schizophrenia or schizoaffective disorder, depression, and
      dementia.
AB  - Although many older adults with serious psychiatric illnesses share common
      concerns, such as medical comorbidity, personal loss, greater propensity for
      adverse medication effects, and greater dependence on others for basic needs such
      as transportation, individualized treatment needs must be differentiated by
      underlying psychiatric disorders. This retrospective study evaluated clinical
      characteristics and resource use among 137 older adults with bipolar disorder,
      schizophrenia or schizoaffective disorder, depression, and dementia who were
      discharged from an urban, academic medical center's inpatient geropsychiatric
      unit. The authors found women to be significantly overrepresented among
      individuals with schizophrenia or schizoaffective disorder compared to those with
      bipolar disorder, depression, and dementia (P=.034). Among those with bipolar
      disorder, anticonvulsant medications were predominantly used as mood stabilizers,
      with only the rare use of lithium. Individuals with schizophrenia or
      schizoaffective disorder were the youngest group of patients; individuals with
      dementia were the oldest group (P<.001). This shows significant differences in
      clinical characteristics among hospitalized older adults with serious mental
      illnesses. Additional studies are needed on outcomes of serious chronic
      psychiatric illnesses in later life to optimize care environments for older adult
      psychiatric patients.

PMID- 15018692
TI  - Pathological gambling among elderly veterans.
AB  - The purpose of the present study was to examine elderly patients, aged 60 and
      older, admitted to a residential gambling treatment program and to compare them
      to a younger cohort on a variety of mental health factors and measures. A
      retrospective chart review was performed for 37 elderly gamblers consecutively
      admitted to the Gambling Treatment Program of a VA center between December 1999
      and December 2002. These elderly subjects were compared with a younger cohort of
      98 gamblers. On intake, the gamblers completed the Addiction Severity Index (ASI)
      and a variety of mental health questionnaires. Compared to the younger cohort,
      elderly gamblers were more likely to be retired but demonstrated similar
      impairment on the ASI composite employment severity score. Elderly gamblers were
      just as likely as the younger gamblers to have a lifetime history of serious
      suicidal ideation. They were equally likely as the younger cohort to carry a
      psychiatric diagnosis, and depression was the most common diagnosis.

PMID- 15018691
TI  - Pharmacotherapy outcome in older pathological gamblers: a preliminary
      investigation.
AB  - Although pharmacotherapy is often effective for pathological gambling, little is
      known about how it affects older populations. The present study examines the
      response to pharmacotherapy in a series of pathological gamblers age 60 years and
      older. Fourteen older patients who fulfilled DSM-IV criteria for pathological
      gambling were treated in an outpatient clinic. Subjects were assessed
      retrospectively with the Clinical Global Impressions scale (both severity and
      improvement measures) using information collected on gambling symptoms during
      clinic visits. Eight (57.1%) older patients achieved sustained response to
      pharmacotherapy. The present findings indicate that many older pathological
      gamblers respond to "off-label" use of pharmacotherapy. The present findings are
      preliminary. Further studies with larger samples are needed to confirm these
      findings.

PMID- 15018693
TI  - Sleep/wake disruption in Alzheimer's disease: APOE status and longitudinal
      course.
AB  - Disturbed sleep is a major clinical problem in Alzheimer's disease (AD).
      Apolipoprotein epsilon4 (APOE epsilon4) carrier status may increase risk of AD,
      yet there are no data on relations between APOE status and progression of sleep
      disturbance in AD. The objective of this study was to determine if sleep
      parameters in AD patients change over time as a function of APOE carrier status.
      Forty-four community-dwelling AD patients with diagnosis of probable AD were
      followed from early stages of disease. Their sleep/wake parameters were compared
      according to APOE status. For APOE epsilon4 carriers, only wake after sleep onset
      (WASO) increased in association with lower cognitive function as indicated by the
      Mini-Mental State Examination (MMSE); for non-epsilon4 subjects, increases in
      WASO and declines in total sleep time, sleep efficiency, and the amplitude of the
      rest/activity circadian rhythm over time were associated with lower performance
      on the MMSE. In these data, APOE status was associated with the progression of
      sleep/wake disturbances in AD. Overall, there was greater deterioration on sleep
      parameters in patients negative for the epsilon4 allele.

PMID- 15018694
TI  - Herbal products and other supplements: use by elderly veterans with depression
      and dementia and their caregivers.
AB  - The use of herbal products and other "natural" supplements among the US
      population is on the rise. Limited data suggest that such use among the elderly
      may correlate with higher education levels as well as psychiatric symptoms. The
      authors examined herbal/supplement use among elderly veterans with depression
      and/or dementia (n = 82) and their primarily elderly caregivers (n = 56).
      Eighteen percent of subjects and 16% of caregivers used herbals/supplements.
      Seventy-five percent of subjects who used these products during the study period
      were also taking potentially interacting medications. Given the prior association
      of herbal/supplement use with higher education levels, a surprising number of
      elderly veterans with depression and/or dementia (the majority of whom had high
      school or less education) used these products. As evidenced by missing
      documentation in many physician notes, subjects may not have discussed their
      usage of herbals/supplements with their physicians. In light of the possibility
      of potentially harmful drug interactions, physicians who treat elderly patients
      should regularly inquire about the use of these products.

PMID- 15018695
TI  - Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI).
AB  - The Neuropsychiatric Inventory (NPI) is used to assess neuropsychiatric symptoms
      in dementia patients. To reduce clinicians' time taken to administer the NPI, the
      authors studied a caregiver-administered NPI (CGA-NPI), in which caregivers
      completed the written form of the NPI worksheet. After a brief presupervision
      session, the caregivers of 61 dementia patients completed the CGA-NPI by reading
      through the worksheet. This was followed by a postsupervision session to check if
      the caregivers had completed the form appropriately. The correlation between the
      prevalence rates of each neuropsychiatric symptom obtained by the CGA-NPI and
      those obtained by the NPI was fair to good (kappa = 0.57-0.90) in all domains.
      All frequency, severity, and caregivers' distress scores of the CGA-NPI
      correlated significantly with those of the NPI (r> 0.6, P<.001). Total CGA-NPI
      scores also correlated highly with total NPI scores (r= 0.86, P<.001). These
      results suggest that the CGA-NPI can substitute for the NPI, saving
      administration time.

PMID- 15018696
TI  - Use of a VA pharmacy database to screen for areas at high risk for disease:
      Parkinson's disease and exposure to pesticides.
AB  - The purpose of this study was to assess whether pharmacy database information
      from US Department of Veterans Affairs (VA) medical centers could be used to
      screen for areas of higher Parkinson's disease prevalence in patients exposed to
      pesticides. The authors used pharmacy data sets and compared the use of
      antiparkinsonian medications at 2 VA medical centers in California: one in Palo
      Alto, near the ocean, and one in Fresno, downwind from extensively farmed parts
      of the Central Valley. They found that patients at Fresno had higher odds ratios
      (1.5-1.8) for the use of Parkinson's disease medications than patients at Palo
      Alto. These data are consistent with the observations of prior epidemiologic
      studies and suggest that VA pharmacy databases can prioritize locations for
      further epidemiologic research. However, a thorough exploration of alternative
      explanations is needed to reach definitive conclusions regarding the findings
      suggested by this method.

PMID- 15018697
TI  - Parkinsonism in a nursing home: underrecognition.
AB  - Parkinsonism is a very common condition in the elderly, particularly the elderly
      demented. The authors' experience in both the in-and outpatient settings
      suggested that parkinsonism was generally underdiagnosed in the elderly. They
      evaluated the residents at a local nursing home to assess for parkinsonian signs.
      They then compared the findings to those noted in the charts. Blinded assessment
      of all nursing home residents for signs of parkinsonism was performed. A
      standardized evaluation instrument was used, followed by a chart review to
      determine if patients were taking medications that might induce the parkinsonism
      and whether the parkinsonism had been recognized. The authors looked separately
      at those patients receiving antipsychotics because of their increased risk.
      Twenty-seven out of 100 residents had "probable" parkinsonism, 12 of whom were
      severe, and 33 had "possible" parkinsonism. Of 27 residents on antipsychotics, 23
      showed parkinsonian features versus 43 of 73 not on such drugs (P<.02). Only 1
      patient with drug-induced parkinsonism and 3 residents with previously diagnosed
      Parkinson's disease had chart notes indicating that parkinsonism had been
      recognized.

PMID- 15018698
TI  - Decisional capacity of depressed elderly to consent to electroconvulsive therapy.
AB  - The purpose of this article is to determine the abilities of severely depressed
      elderly to consent to electroconvulsive therapy (ECT) and to investigate the
      impact of educational intervention on their capacity. Forty severely depressed
      adults referred for ECT, with Mini-Mental State Examination scores greater than
      20, were recruited. Using the MacArthur Competence Assessment Tool for Treatment
      (MacCAT-T), decisional capacities were assessed at baseline and reassessed after
      education. Between the 2 assessments, all subjects received standard education,
      and half of the group was subsequently randomized to receive further education.
      At baseline, the geriatric group scored lower on understanding, reasoning, and
      choice and higher on appreciation. After education, all MacCAT-T scores increased
      for both age groups. Depressed elderly in the sample, as a group, had adequate
      decisional capacities to consent to ECT. They showed greater improvement in
      decisional capacity with education. The findings highlight the importance of
      providing education to the elderly to optimize their ability to give informed
      consent.

PMID- 15018699
TI  - Peripheral T cell lymphoma with cytotoxic phenotype: an emerging disease in HIV
      infected patients?
AB  - Recently, a 15-fold increased risk of T cell lymphomas has been estimated in HIV
      infected populations. This increase has been observed for all T cell lymphoma
      subtypes. In the present report we describe clinical and pathological features of
      three consecutive cases of peripheral T cell lymphoma (PTCL) with cytotoxic
      phenotype in HIV-positive patients that came to our attention in May-September
      2002. The diagnosis of PTCL was made in lymph node (two cases) and in needle
      biopsies from liver and bone marrow of the same patient. The patients were two
      females (31 and 45 years old) and one male (49 years old). The risk factor for
      each patient was heterosexual, injecting drug user, and homosexual, respectively.
      CD4 cell counts were low (79-81 cells/mm3). Two patients were naive for
      antiretroviral therapy. At histological examination, all the involved tissues
      were effaced by a neoplastic proliferation of CD3+/CD8+ medium to large
      pleomorphic cells containing TIA-1+ cytotoxic granules and a few granzyme B+
      granules. Neoplastic cells were not infected by EBV or by HHV-8. They were
      negative for the B cell antigens CD20 and CD79a, for CD30 and for CD56. Clonal T
      cell receptor-g (TCR-g) rearrangements were demonstrated in the three cases.

PMID- 15018700
TI  - Characterization of a naphthalene derivative inhibitor of retroviral integrases.
AB  - The retroviral integrase protein (IN) is essential for virus replication and,
      therefore, an attractive target for the development of inhibitors to treat human
      immunodeficiency virus (HIV) infection. Diverse classes of compounds that are
      active against this protein have been discovered using in vitro assays. Here we
      describe the synthesis of a novel compound, 3,8-dibromo-7-amino-4-hydroxy-2
      naphthalenesulfonic acid (2BrNSA), which inhibits the in vitro activities of the
      full-length HIV-1 and avian sarcoma virus (ASV) integrases, and the isolated
      catalytic core fragment of the ASV protein (residues 52-207). The compound also
      inhibits retroviral reverse transcriptase in vitro, but the IC(50) for the HIV-1
      enzyme is almost two orders of magnitude higher than for HIV-1 integrase. The
      inhibitor was found to be active in cell culture, preventing reporter gene
      transduction of HeLa cells by both ASV and HIV-1 vectors. Neither viral
      attachment nor uptake into cells appeared to be affected in these transfections,
      whereas accumulation of vector DNA and its joining to host DNA were both
      drastically reduced in the presence of the inhibitor. Propagation of two
      different strains of replication-competent HIV-1 in human peripheral blood
      mononuclear cells (PBMCs) was also reduced by the inhibitor, allowing survival of
      a substantial number of cells in the treated cultures. Based on these and other
      results we speculate that binding of 2BrNSA to integrase in infected cells
      interferes not only with its catalytic activity but also with critical
      interactions that are required for the formation or function of the reverse
      transcriptase complex. Its activity in cell culture suggests that this inhibitor
      may provide a valuable new lead for further development of drugs that target
      early steps in the HIV life cycle.

PMID- 15018701
TI  - A potent anti-HIV immunotoxin blocks spreading infection by primary HIV type 1
      isolates in multiple cell types.
AB  - Although several immunotoxins that selectively kill HIV-1-infected cells have
      been described, their clinical utility is limited by low potency against
      spreading viral infection. We show here that changing the carboxyterminal
      sequence of an anti-HIV-1 envelope immunotoxin to the consensus endoplasmic
      reticulum retention sequence KDEL substantially improves its ability to block
      infection of peripheral blood mononuclear cells by primary HIV-1 isolates without
      increasing nonspecific toxicity. Polychromatic flow cytometry of peripheral blood
      mononuclear cells (PBMC) infected with an HIV-1-GFP reporter virus demonstrated
      that the improved immunotoxin is active against a variety of primary cell types
      including memory T cells, NK-T cells, and monocyte/macrophages. The subnanomolar
      potency of this agent suggests that it could be clinically useful either as an
      adjuvant to highly active antiretroviral therapy (HAART) in drug-resistant
      patients or to reduce the reservoir of latently infected cells that is implicated
      in HIV-1 persistence.

PMID- 15018703
TI  - Graves' disease during immune reconstitution after highly active antiretroviral
      therapy for HIV infection: evidence of thymic dysfunction.
AB  - A patient with HIV infection who experienced immune reconstitution after highly
      active antiretroviral therapy (HAART) [increase in CD4 T cell count from
      <1/microl to >600/microl] presented with severe Graves' disease 32 months after
      commencing HAART. A comprehensive clinical and laboratory study demonstrated
      pronounced regional lymphadenopathy and thymic enlargement at presentation, and
      that the onset of thyrotropin receptor antibody production was associated with
      increased production of soluble CD30 (a marker of type 2 immune responses). Blood
      naive CD8 T cell counts and TREC levels in both CD4 and CD8 T cells were
      increased at multiple time points compared with carefully selected controls. We
      conclude that the Graves' disease in this patient was associated with abnormally
      high blood counts of thymus-derived T cells, and propose that Graves' disease
      after HAART in this and other HIV patients may result from failure to delete
      autoreactive T cell clones in the regenerating thymus.

PMID- 15018702
TI  - Detecting alcohol problems in HIV-infected patients: use of the CAGE
      questionnaire.
AB  - The HIV epidemic has been consistently associated with injection drug use and
      crack cocaine, but alcohol problems in HIV-infected persons are less well
      described. Our objectives were 2-fold: (1) to assess the prevalence of alcohol
      problems in HIV-infected patients initiating medical care; and (2) to determine
      the positive predictive value of the CAGE questionnaire for alcohol abuse or
      dependence in HIV-infected patients. Between July 1997 and October 2000, we
      assessed a consecutive series of patients who were establishing primary care for
      HIV infection (clinic sample), using an established alcohol screening test, the
      CAGE questionnaire. In addition, we enrolled other HIV-infected patients,
      including some of the clinic sample, who had two or more positive responses to
      the CAGE questionnaire into a longitudinal cohort (cohort sample), performed a
      diagnostic interview for lifetime history of alcohol abuse and dependence, and
      determined the positive predictive value of CAGE for alcohol diagnoses. In the
      clinic sample (n = 664), 42% (276 of 664) had two or more positive responses to
      the four CAGE questions. In the cohort sample (n = 141), 95% (134 of 141) met DSM
      IV criteria for diagnosis of lifetime alcohol abuse or dependence. For patients
      initiating HIV primary care, a history of alcohol problems is very common. The
      CAGE questionnaire identifies a lifetime history of alcohol abuse or dependence
      in HIV-infected patients. Routine screening for alcohol problems should be
      performed in all patients entering HIV medical care and the CAGE questions are
      useful in this setting.

PMID- 15018704
TI  - Envelope glycoprotein determinants of increased entry in a pathogenic simian
      human immunodeficiency virus (SHIV-HXBc2P 3.2) passaged in monkeys.
AB  - Passage of a nonpathogenic simian-human immunodeficiency virus (SHIV-HXBc2) in
      monkeys resulted in changes in the viral envelope glycoproteins that are
      responsible for a dramatic increase in replication and pathogenicity in vivo.
      Here, we show that the envelope glycoproteins of the pathogenic SHIV-HXBc2P 3.2
      mediate virus entry into rhesus monkey peripheral blood mononuclear cells (PBMC)
      more efficiently than the parental SHIV-HXBc2 envelope glycoproteins, and study
      the basis for this increase. Both parental and pathogenic SHIVs exclusively use
      CXCR4 as a coreceptor. The determinants of the increased entry associated with
      the SHIV-HXBc2P 3.2 envelope glycoproteins are located in both the gp120 and gp41
      subunits. Changes in the gp120 V3 variable loop specify a decreased sensitivity
      to SDF-1, consistent with an increase in the affinity of the HXBc2P 3.2 gp120
      glycoprotein for CXCR4. Thus, multiple changes in the gp120 variable loops and
      the gp41 ectodomain of a pathogenic SHIV cooperate to allow enhanced replicative
      capacity, which in part results from increased chemokine receptor binding.

PMID- 15018705
TI  - HIV type 1-infected dendritic cells induce apoptotic death in infected and
      uninfected primary CD4 T lymphocytes.
AB  - In addition to their essential role in adaptive immunity, dendritic cells (DCs)
      participate in innate immunity. In the context of measles virus (MV) or
      cytomegalovirus infections, they develop cytotoxic functions that may contribute
      in vivo to the elimination of virus-infected cells, but that also kill infected
      and noninfected T lymphocytes. Because the human immunodeficiency virus (HIV)
      induces T cell depletion through mechanisms that are still obscure, we
      investigated its ability to trigger DC cytotoxicity. When incubated with HIV,
      monocyte-derived DCs induced apoptosis in MDA-231 cells, which are sensitive to
      MV-induced DC cytotoxicity, and in uninfected as well as HIV-infected H9 CD4+ T
      cell lines. This apoptosis was inhibited by a mixture of FasL, TRAIL, TNF-alpha,
      and TWEAK inhibitors. Indeed, HIV infection induced or enhanced sensitivity to
      TRAIL, TNF-alpha, and TWEAK in H9 cells. Moreover, dendritic cells incubated with
      HIV-1 BAL or a wildtype HIV-1 isolate induced apoptosis in autologous primary
      CD4+ T lymphocytes, infected or not with a wild-type HIV-1 isolate. Therefore,
      induction of DC cytotoxicity by HIV may be relevant to in vivo HIV infection.
      Induction of cytotoxicity in DCs by HIV might contribute to HIV-associated T cell
      depletion through induction of apoptosis, especially in the early stages of
      infection. It may also contribute to elimination of infected cells in vivo,
      thereby enhancing cross-presentation of HIV by DCs. Therefore this new cytotoxic
      function of DCs may play an important role in innate and adaptive immunity during
      HIV infection.

PMID- 15018706
TI  - Chronic HIV type 1 infection down-regulates expression of DAP kinase and p19ARF
      p53 checkpoint and is associated with resistance to CD95-mediated apoptosis in
      HUT78 T cells.
AB  - Death-associated protein kinase (DAP kinase) is a proapoptotic serine/threonine
      kinase that has been shown to play a role in both death-receptor signaling and
      mitochondrial signaling pathways of apoptosis. DAP kinase activates the p19ARF
      p53 apoptotic checkpoint. In this study we report that the expression of DAP
      kinase, p19ARF, p53, and p21WAF1 was significantly down-regulated in the
      chronically HIV-1SF2-infected HUT78 T cells (HUT78/HIV-1SF2) as compared to
      uninfected HUT78 cells. An increased proportion of HUT78/HIV1SF2 cells was
      detected in S phase and a decreased proportion in G0/G1 phase indicating that
      more HUT78/HIV1SF2 cells progressed through the G1/S transition. Furthermore,
      HUT78/HIV-1SF2 cells showed increased resistance to CD95-mediated apoptosis as
      compared to HIV-1SF2-uninfected HUT78 cells and activation of caspase-3, -8, and 
      9 was significantly reduced in HUT78/HIV-1SF2 cells. These data suggest that down
      regulation of DAP kinase and downstream signaling factors may be one of the
      mechanism that HIV-1 may employ to protect the infected host cells from cell
      death and to allow persistent HIV-1 replication.

PMID- 15018707
TI  - Mutations conferring drug resistance affect eukaryotic expression of HIV type 1
      reverse transcriptase.
AB  - Mutations in reverse transcriptase (RT) confer high levels of HIV resistance to
      drugs. However, while conferring drug resistance, they can lower viral
      replication capacity (fitness). The molecular mechanisms behind remain largely
      unknown. The aim of the study was to characterize the effect of drug-resistance
      mutations on HIV RT expression. Genes encoding AZT-resistant RTs with single or
      combined mutations D67N, K70R, T215F, and K219Q, and RTs derived from drug
      resistant HIV-1 strains were designed and expressed in a variety of eukaryotic
      cells. Expression in transiently transfected cells was assessed by Western
      blotting and immunofluorescent staining with RT-specific antibodies. To compare
      the levels of expression, mutated RT genes were microinjected into the nucleus of
      the oocytes of Xenopus laevis. Expression of RT was quantified by sandwich ELISA.
      Relative stability of RTs was assessed by pulse-chase experiments. Xenopus
      oocytes microinjected with the genes expressed 2-50 pg of RT mutants per cell.
      The level of RT expression decreased with accumulation of drug-resistance
      mutations. Pulse-chase experiments demonstrated that poor expression of DR-RTs
      was due to proteolytic instability. Instability could be attributed to additional
      cleavage sites predicted to appear in the vicinity of resistance mutations.
      Accumulation of drug-resistance mutations appears to affect the level of
      eukaryotic expression of HIV-1 RT by inducing proteolytic instability. Low RT
      levels might be one of the determinants of impaired replication fitness of drug
      resistant HIV-1 strains.

PMID- 15018708
TI  - Spliced human immunodeficiency virus type 1 RNA is reverse transcribed into cDNA
      within infected cells.
AB  - Both the full-length and spliced RNA species of HIV-1 possess the necessary cis
      acting elements including the primer binding site (PBS), the polypurine tract
      (PPT), as well as the 5' R and 3' R regions that are needed for their conversion
      to double-stranded cDNA through reverse transcription. Since measurable amounts
      of spliced viral RNA molecules can be detected within virus particles, we have
      examined the potential for reverse transcription of such virion-associated
      spliced viral RNA upon infection of permissive cells. Analysis of viral cDNA
      species by PCR and DNA sequencing not only led to the identification of viral DNA
      molecules that were reverse transcribed from full-length viral RNA, but also DNA
      molecules that displayed the same nucleotide sequences as those found in spliced
      viral RNA, except that the former harbored the complete long terminal repeats
      (LTR), a feature that distinguishes proviral DNA from viral genomic RNA. Further
      studies revealed various types of cDNA species that resemble the spliced viral
      RNA encoding each of the env, tat, rev, or nef genes, of which the nef cDNA
      represents the majority. Therefore, spliced HIV-1 RNA molecules must have been
      reverse transcribed along with full-length viral RNA during infection.

PMID- 15018709
TI  - The N-terminal of the V3 loop in HIV type 1 gp120 is responsible for its
      conformation-dependent interaction with cell surface molecules.
AB  - The V3 loop of HIV-1 gp120 plays an important role in the interaction of the
      viral envelope with cellular coreceptors and/or with other cell surface
      molecules. To clarify this interaction we used a panel of monoclonal antibodies
      (MAbs) against V3 loop and synthetic looped V3 peptides V3-BH10, V3-ADA, and V3
      89.6, derived from the V3 regions of the BH10 clone of IIIB (X4-tropic), ADA (R5
      tropic), and 89.6 (R5X4-tropic), respectively. A linear mutant peptide, V3
      BH10/CA, was also synthesized as a control. Biotinylated V3-BH10, -BH10/CA, and
      ADA were also made. The binding abilities of the biotinylated and nonbiotinylated
      peptides to various types of cells were investigated by using flow cytometry.
      Subsequently, the principal region of the V3 loop involved in cell surface
      binding was analyzed by using MAbs against the tip (447-52D and 694-98D), N
      termini (IIIB-V3-21) or C-termini (IIIB-V3-01) of the V3 loop in flow cytometry
      and enzyme-linked immunoabsorbent assay. We demonstrate that looped V3 peptides
      of both X4 and R5X4 HIV (V3-BH10 and V3-89.6) can bind to various types of cells
      irrespective of their CD4 and/or coreceptor expression in a conformation
      dependent manner. In contrast, the V3 loop of R5 HIV (V3-ADA) can scarcely bind
      to the cells. Using MAbs whose epitopes cover the entire V3 loop we found that
      MAb IIIB-V3-21 can react with platebound but not cell-bound peptides, and the MAb
      blocked biotin-V3-BH10 binding suggesting that the N-terminal of the V3 loop
      interacts directly with cell surface molecule(s).

PMID- 15018710
TI  - Selective CD27+ (memory) B cell reduction and characteristic B cell alteration in
      drug-naive and HAART-treated HIV type 1-infected patients.
AB  - To investigate HIV-1-related B cell disorders, the quantity of CD27 positive
      (CD27+) B cells and their CD38, CD95, and bcl-2 intensities were examined by flow
      cytometry analysis in 16 drug-naive patients, 27 highly active antiretroviral
      therapy (HAART)-treated patients, and 20 uninfected controls. CD27+ B cells have
      been recognized as memory B cells. The mean percentage of CD27+ B cells was
      significantly lower in drug-naive patients (11.9%) and in HAART-treated patients
      (16.1%) than in controls (31.4%) (p < 0.01). The intensities of CD38 and CD95 on
      CD27+ B cells were higher in drug-naive patients than in controls (p < 0.01 in
      CD95). The intensity of CD95 on CD27+ B cells in HAART-treated patients was lower
      than that of drug-naive patients, but significantly higher than that of controls
      (p < 0.01). The intensity of bcl-2 on CD27+ B cells was equivalent among the
      three groups. These findings suggest that disturbance of peripheral B cell
      composition, exemplified by CD27+ B cell reduction, exists in both drug-naive and
      HAART-treated HIV-1-infected patients. In addition, the augmented apoptotic state
      of CD27+ B cells found in HAART-treated patients with undetectable viral loads,
      indicated by CD95 elevation, suggests that some HIV-1-related B cell disorders
      last for years after effective antiviral therapy.

PMID- 15018711
TI  - CD38 expression on CD8 T lymphocytes as a marker of residual virus replication in
      chronically HIV-infected patients receiving antiretroviral therapy.
AB  - The level of CD8+ CD38+ T lymphocytes in blood correlates with disease
      progression in HIV-infected individuals, independently of the CD4 count.
      Effective antiretroviral therapy reduces this lymphocyte subset in parallel with
      plasma viremia, although CD38 expression on CD8+ cells does not normalize
      completely in most subjects, and might reflect residual HIV replication. The
      expression of CD38 on CD8+ cells (as number of CD38 molecules per CD8+ cell) was
      measured quantitatively by flow cytometry in 200 individuals, of whom 170 were
      HIV positive and 30 were HIV-uninfected controls. Forty-six HIV-infected subjects
      were on antiretroviral therapy and had undetectable viral load. The remaining 124
      HIV-positive persons were not on therapy and had detectable plasma viremia. The
      mean level of CD38 on CD8+ cells was higher in HIV-positive, untreated patients
      than in subjects on antiviral therapy and controls (5023, 2029, and 1978
      molecules per CD8+ cell, respectively, p < 0.01). In HIV-positive, untreated
      subjects, the higher CD38 expression mainly occurred on CD45RO+ CD8+ cells. The
      level of CD38 strongly correlated with plasma HIV-RNA (r = 0.63, p < 0.001). The
      levels of CD38 on CD8+ cells declined steadily in HIV-positive subjects after
      beginning antiretroviral therapy. A few individuals presented viral blips whereas
      being on antiviral treatment, levels of CD38 on CD8+ cells increased transiently
      in parallel with episodes of viral replication. Levels of CD38 on CD8+ cells are
      increased in chronic HIV infection, and strongly correlate with plasma viremia.
      The slow decline of CD38 expression on CD8+ cells over time in subjects with
      undetectable plasma viremia while being on antiretroviral therapy suggests that
      CD38 expression on CD8+ cells could be used as a marker of residual virus
      replication.

PMID- 15018712
TI  - Evaluation of combination DNA/replication-competent Ad-SIV recombinant
      immunization regimens in rhesus macaques.
AB  - Combination vaccine regimens in which priming with recombinant DNA is followed by
      boosting with recombinant viral vectors have been shown in previous studies to
      effectively enhance cellular immunity. However, no information exists concerning
      possible synergy of the cellular immune response when DNA immunization is
      followed by administration of a recombinant vector able to replicate. As our
      approach makes use of replication-competent Ad HIV and SIV recombinants, we
      performed a pilot experiment in six rhesus macaques in which we compared
      immunogenicity resulting from priming with one or two DNA recombinants encoding
      the SIVsmH4 env and rev genes with that elicited by a single replication
      competent Ad5hr-SIV env/rev priming immunization. All macaques were subsequently
      administered an Ad5hr-SIV env/rev booster immunization followed by two
      immunizations with SIV gp120 protein. The choice of the env gene as target
      immunogen allowed comparison of induced cellular immune responses as well as
      binding and neutralizing antibodies elicited in serum and mucosal secretions. We
      report here that all immunized monkeys developed strong cellular immunity to the
      SIV envelope as shown by secretion of interferon-gamma, lysis of envelope
      expressing target cells, and/or proliferation in response to gp120 or inactivated
      SIV. Similarly, all macaques developed anti-gp120 binding antibodies and
      neutralizing antibodies in serum and IgG and IgA binding antibodies in mucosal
      secretions. We did not observe consistently enhanced immune responses in any
      immunization group. We conclude that two sequential immunizations with the same
      replication-competent Ad5hr-SIV recombinant is as effective as priming with one
      or two recombinant DNA vaccines followed by a single Ad5hrSIV recombinant
      immunization.

PMID- 15018713
TI  - Rapid epidemic spread of HIV type 1 subtype A1 among intravenous drug users in
      Latvia and slower spread of subtype B among other risk groups.
AB  - To investigate the rapid HIV epidemic in Latvia, 97 newly detected individuals
      were sampled in 2000-2001. To establish the molecular epidemiology we sequenced
      the env V3 and gag p17 regions of the HIV genome and compared them with reference
      sequences using phylogenetic analyses. As expected, the vast majority (n = 88;
      91%) were intravenous drug users (IDUs) from the Riga region. Also, the majority
      of the investigated individuals (n = 93; 96%) were found to carry a subtype A1
      virus that may have entered the Latvian IDU population several times. In
      addition, one IDU was infected with CRF03_AB and three other individuals, who had
      been infected through sexual contacts, carried subtype B virus. Thus, subtype A1
      dominates the Latvian epidemic and is strongly associated with the IDU risk
      group. Although some spread of subtype A1 has occurred in the heterosexual group,
      subtype B dominates among homosexually and heterosexually infected individuals.

PMID- 15018714
TI  - Detection of HIV type 1 non-B subtypes in Sicily, Italy.
AB  - To evaluate the presence of HIV-1 non-B subtypes in Sicily, we sequenced and
      genotyped HIV-1 PR and RT regions of the pol gene using plasma from 169 HIV-1
      infected adult patients. All samples were obtained from a study of antiretroviral
      associated resistance mutations resulting in virological failure during highly
      active antiretroviral therapy (HAART). Eight (4.7%) patients had the non-B HIV-1
      subtype including some circulating recombinant forms (CRFs). All of these
      individuals acquired the infection by heterosexual transmission. The detection of
      HIV-1 non-B strains was significantly associated with younger age of HIV-1
      acquisition. Our findings indicate, for the first time, the presence of HIV-1 non
      B subtypes in Sicily in patients who experienced virological failure during
      HAART, and highlight the need for implementing a network for the epidemiological
      surveillance of HIV-1 subtypes in Southern Europe.

PMID- 15018716
TI  - Self-reported health in Poland and the United States: a comparative analysis of
      demographic, family and socioeconomic influences.
AB  - This study compares the social determinants of individual health between the
      United States, a capitalist society, and Poland, a 'post-communist' society. The
      effects of demographic factors, family characteristics and socioeconomic status
      on self-reported health are estimated with OLS regression using data from the
      1994 American and Polish General Social Surveys. The results show lower self
      reported health and more rapid declines in health for people over 60 in Poland
      than in the United States. Also, in Poland, women report worse health than do men
      while the opposite is found for the United States. The relationships between
      education, income and health were stronger in the United States than in Poland.
      Age, gender and SES may operate differently in the two countries because of a gap
      in social development (e.g. varying living standards and styles, health care
      systems and cultural attitudes) between the West and the former Eastern Europe.

PMID- 15018715
TI  - Active generation and selection for HIV intersubtype A/D recombinant forms in a
      coinfected patient in Kenya.
AB  - To investigate the in vivo evolution of recombinant HIV, we followed up on a
      mother who was initially coinfected with subtypes A and D in Kenya. Blood samples
      were obtained in 1996 and 2002, and HIV pol and env genes were amplified by PCR,
      cloned, sequenced, and phylogenetically analyzed. As for the 1996 sample most of
      the clones generated from the pol and env genes clustered either with subtypes A
      and D reference strains. However, two clones from the pol gene were found to be
      independent recombinants between subtypes A and D by RIP analysis, suggesting
      active generation of recombinant forms. As for the 2002 sample, all the clones
      from the pol gene clustered only with the subtype A reference strain, while all
      the env clones clustered only with subtype D, denoting a dominance of an A/D
      recombinant form. These results indicate that in patients dually infected with
      subtypes A and D there is an ongoing generation and selection for A/D recombinant
      forms.

PMID- 15018717
TI  - Illness and Internet empowerment: writing and reading breast cancer in
      cyberspace.
AB  - The Internet is now a site where women with breast cancer both read and write
      about the illness, and in doing so negotiate identity and definitions of
      situation in disembodied space. Cyberspace has been imagined as a liberatory
      realm where women can transgress gender roles, invent selves and create new forms
      of knowledge. This study explores the personal web pages of women with breast
      cancer with an interest in exploring the issue of 'cyber-agency' or empowerment
      in cyberspace. I suggest here that women's web pages might offer potentially
      critical opportunities for women's knowledge-making in relation to what are often
      highly political aspects of the body, gender and illness. However, the Internet
      is not an inherently empowering technology, and it can be a medium for affirming
      norms of femininity, consumerism, individualism and other powerful social
      messages.

PMID- 15018718
TI  - Medicalization, ambivalence and social control: mothers' descriptions of
      educators and ADD/ADHD.
AB  - Conrad notes that non-medical personnel often accomplish the routine, everyday
      work of medicalization. This is particularly so in the case of Attention Deficit
      (Hyperactivity) Disorder, where teachers, special educators and school
      psychologists identify, assess and administer medication to 'problematic'
      children. Drawing on data from interviews with Canadian and British mothers of
      ADD/ADHD children, this article explores mothers' perceptions of educators' roles
      in medicalizing children who are different, comparing medicalization in two
      divergent sites. In Canada, where ADD/ADHD is a highly medicalized phenomenon,
      and teachers have few alternative forms of social control available to them in
      classrooms, it appears that educators are prepared to identify problem children
      and press for medical treatment with remarkable vigor. In Britain, where
      medicalization remains incomplete, and where teachers and special educators have
      more stringent alternative forms of social control available to them, educators
      were often described as gatekeepers who will refuse the label or to administer
      medication.

PMID- 15018719
TI  - Giving birth, going home: influences on when low-income women leave hospital.
AB  - The US Newborns' and Mothers' Health Protection Act of 1996 ('The Two-Day Law')
      mandates insurance coverage for women who have just given birth to remain in
      hospital for two days post-partum. However, many women are being discharged from
      hospital after 24 hours. To assess why early discharge is still occurring, a
      study of 406 new mothers was conducted at an urban metropolitan hospital in the
      USA. The women were aware of the new law (95%) but decision making was often
      relinquished to hospital authorities. Patients who stayed longer tended to be
      more assertive in decision making, and used the Two-Day Law as leverage in
      discussions about going home. The study concluded that the nurses were
      authoritative and often influential agents in the decision-making process, and
      that patients were likely to interpret specific interactions with hospital staff
      as a signal to leave.

PMID- 15018720
TI  - 'Am I being over-sensitive?' Women's experience of sexual harassment during
      medical training.
AB  - Despite larger numbers of women in medicine and strong statements against gender
      discrimination in written policies and the medical literature, sexual harassment
      persists in medical training. This study examines the everyday lives of women and
      men resident physicians to understand the context within which harassment
      unfolds. The narratives explored here reveal how attention is deflected from the
      problem of sexual harassment through a focus on women's 'sensitivity'. Women
      resist by refusing to name sexual harassment as problematic, and by defining
      sexual harassment as 'small stuff' in the context of a rigorous training program.
      Ultimately, both tactics of resistance fail. Closer examination of the relations
      shaping everyday actions is key, as is viewing the rigid hierarchy of authority
      and power in medical training through a gender lens. I conclude with a discussion
      of how reforms in medical education must tend to the gendered, everyday realities
      of women and men in training.

PMID- 15018722
TI  - Community health psychology: promoting analysis and action for social change.
AB  - Community health psychology is concerned with the theory and method of working
      with communities to combat disease and to promote health. This introductory
      article outlines key assumptions and debates underlying this area of research and
      practice-in the interests of framing the papers in this special edition of the
      Journal of Health Psychology. Attention is given to the value of emphasizing the
      community level of analysis and action; the role of collective action in
      improving health; psycho-social mediatiors between community participation and
      health; and the potential role of partnerships in creating 'healthy communities'.
      A distinction is made between 'accommodationist' and 'critical' perspectives, and
      the authors consider whether or not significant social change can come from
      community-level action.

PMID- 15018723
TI  - The 'Voices' project: capacity-building in community development for youth at
      risk.
AB  - We report three cycles of an 'action research' project aimed at increasing the
      capacities of young people at risk in a rural Australian town. Drawing on an
      'experience-based' approach to risk assessment and the concept of collective
      efficacy, we aimed to provide a group of 10 young people with a safe and
      uncensored space within which to voice their own concerns about the risks and
      problems confronting them. Their stories were then made public through theatrical
      performance. The purpose of the article is to demonstrate the dynamics of
      capacity-building in marginalized communities as a means of producing the
      political changes required for improving health outcomes in a setting previously
      opposed to such a strategy.

PMID- 15018724
TI  - Partnerships and participation of community residents in health promotion and
      prevention: experiences of the highfield community enrichment project (better
      beginnings, better futures).
AB  - We provide a description and analysis of the role of partnerships between
      community residents and service-providers in planning and implementing a health
      promotion/prevention programme for children and families. The context for this
      study is the Highfield Community Enrichment Project, a multi-component, community
      based promotion/prevention project operating in Toronto, Ontario, Canada. The
      nature and amount of resident participation in this project are described, as
      well as barriers to resident participation and strategies to reduce those
      barriers. The findings are interpreted in terms of empowerment and partnership
      theory, and the implications of these findings for involving citizens from low
      income communities in planning promotion/prevention programmes are discussed.

PMID- 15018725
TI  - Exploring the potential of the theory of social representations in community
      based health research--and vice versa?
AB  - This article seeks to demonstrate the importance of developing a dialogue between
      social representations theory and community approaches to researching issues of
      health. We show how we have used the theory within our own research to ground our
      findings at the level of community. The article is divided into three sections:
      the recognition of competing systems of knowledge; the role of representations in
      maintaining stigmatizing practices; and the impact of representations on
      identities. Each section is illustrated with material drawn from Foster's
      research on mental illness and Dorrer's research on women's representations of
      healthy eating. We conclude by arguing that, while social representations theory
      is a valuable tool for community-based health research, the theory would benefit
      from developing a more participatory methodology.

PMID- 15018726
TI  - 'We Will Never Ever Forget.': the Swissair flight 111 disaster and its impact on
      volunteers and communities.
AB  - In collaboration with a Community Advisory Group we examined the impact of the
      1998 Swissair Flight 111 disaster on volunteer responders and surrounding
      communities. We conducted qualitative interviews and administered a set of
      structured questionnaires to 13 volunteer disaster workers and conducted a focus
      group with community leaders. Community silence and limited help-seeking
      behaviour were typical reactions to the SA 111 disaster. The nature and duration
      of the disaster response efforts contributed to a probable 46 per cent PTSD rate
      in the community volunteers. Community-based, culturally appropriate followup, as
      well as the development of volunteer protocols for future disaster response
      efforts, are necessary to minimize long-term health impacts and to promote
      resilience among community residents and volunteers exposed to a major disaster.

PMID- 15018728
TI  - Making 'Context' concrete: a dialogical approach to the society-health relation.
AB  - To understand the role of context in constituting health is recognized as a key
      challenge facing contemporary health psychology. However, few models or theories
      are available which pinpoint the processes linking individual health with
      community or societal contexts. This article draws on dialogical and
      sociocultural psychological theory, to make context concrete by proposing the
      concepts of 'mediating moments' and 'reflected mediating moments'. These concepts
      are further developed through their application to the empirical case of the
      constitution of condom use in sex-worker-client interactions in Calcutta.
      Interviews and group discussions with sex workers and other 'red light area'
      residents are interpreted to examine at what moments the societal phenomena of
      poverty and gender relations come to mediate condom use behaviour.

PMID- 15018727
TI  - Evaluation of HIV/AIDS prevention in South African schools.
AB  - This article reports on the implementation of a school-based HIV/AIDS and life
      skills training program to prevent the spread of HIV/AIDS among the young people
      in secondary schools in South Africa. The implementation of the program was
      evaluated for a period of two years, using process and outcome evaluation and a
      systems approach to understand the higher-order feedback processes that
      obstructed the implementation and effectiveness of the intervention. Although
      HIV/AIDS is a medical condition, this article emphasizes that HIV/AIDS prevention
      is interrelated with the psychosocial context within the community. Interventions
      should therefore be conceptualized and implemented in terms of the various levels
      of interaction in the community.

PMID- 15018729
TI  - Strengthening quality and continuity of diabetes care in rural ghana: a critical
      social psychological approach.
AB  - Adopting critical social psychology and community psychology perspectives, this
      article examines the links between shared social knowledge of diabetes, illness
      experience and illness action through semi-structured individual and group
      interviews with diabetes sufferers and lay healthy individuals in two rural
      Ghanaian communities. Analysis highlights that both groups make sense of diabetes
      and illness experience by drawing interchangeably from four shared knowledge
      modalities: common-sense, scientized, religious and emotional. Common-sense
      notions of health and illness and scientized understandings of diabetes frame
      illness action goals that merge with biomedical goals. These goals are
      compromised by structural, community/family and emotional dynamics. Findings
      suggest that the best immediate solutions lie in addressing availability and cost
      of biomedical care and quality food, with concomitant attention to community
      education and self-help groups as negotiators of psychosocial and economic
      support.

PMID- 15018730
TI  - Participation, health and the development of community resources in Southern
      Brazil.
AB  - This article seeks to contribute to the debate about participation and health by
      presenting a framework for psychosocial interventions in primary health care. It
      highlights the social psychological dimensions of participation and the role it
      plays in improving conditions of living and thus health. The Freirean concepts of
      dialogue, recognition and conscientization, combined with understanding of local
      knowledge are suggested as guiding notions for psychosocial interventions seeking
      to enhance community participation and develop the local level. The article
      discusses the challenges as well as the potential gains experienced in the
      process of participation presented. It concludes by reaffirming the importance of
      participation and empowerment in health interventions struggling against health
      inequalities and seeking health for all.

PMID- 15018731
TI  - Assumptions and values of community health psychology.
AB  - There is a need to widen the practice of health psychologists to include the
      theories and methods of community psychology and an awareness of contemporary
      issues in community health. The aim of such a community health psychology would
      be both to deepen our understanding of the aetiology of health and illness in
      society and to develop strategies that will contribute to a reduction in human
      suffering and an improvement in quality of life. The aim of this article is to
      review the background and assumptions of community health psychology and to
      consider some values that would underlie such an approach.

PMID- 15018732
TI  - Pronounced antitumor efficacy by extracellular activation of a doxorubicin
      glucuronide prodrug after adenoviral vector-mediated expression of a human
      antibody-enzyme fusion protein.
AB  - Tumor-specific activation of the glucuronide prodrug of doxorubicin, N-[4
      doxorubicin-N-carbonyl(oxymethyl)phenyl]-O-beta-glucuronyl carbamate (DOX-GA3),
      by beta-glucuronidase present in necrotic tumor areas might be improved after
      transduction of tumor cells to secrete a targeted form of beta-glucuronidase. To
      that end, we constructed an adenovirus vector, designated Ad/C28-GUSh, encoding
      human beta-glucuronidase fused to a human single-chain Fv (scFv) against the
      epithelial cell adhesion molecule (EpCAM), C28, and preceded by a signal sequence
      for secretion. Antibody specificity and enzyme activity were retained in the
      fusion protein secreted by tumor cells infected with Ad/C28-GUSh. Diffusion of
      fusion protein from transduced tumor cells within MCF-7 multicellular spheroids
      was visualized by immunohistochemistry. Treatment of spheroids with Ad/C28-GUSh
      and DOX-GA3 resulted in growth inhibition comparable to treatment with
      doxorubicin alone. Treatment of well-established FMa human ovarian cancer
      xenografts with intravenous injection of DOX-GA3 (500 mg/kg) resulted in a tumor
      volume-doubling time of 23.8 days compared to 8.0 days for phosphate-buffered
      saline (PBS)-treated mice. Intratumoral administration of Ad/C28-GUSh before DOX
      GA3 enhanced the growth inhibition and increased the tumor volume-doubling time
      to 43.1 days (p < 0.01), while virus alone had no effect. Thus, we have
      successfully shown that an adenovirus vector encoding a secreted, targeted form
      of human beta-glucuronidase can further improve DOX-GA3 monotherapy.

PMID- 15018733
TI  - Redox regulation of pancreatic cancer cell growth: role of glutathione peroxidase
      in the suppression of the malignant phenotype.
AB  - Pancreatic cancer has low levels of antioxidant enzymes including manganese
      superoxide dismutase (MnSOD), which converts superoxide radical (O(2)(*-)) into
      hydrogen peroxide (H(2)O(2)), and glutathione peroxidase (GPx), which converts
      H(2)O(2) into water. Recent studies have demonstrated that overexpression of
      MnSOD has a tumor-suppressive effect in pancreatic cancer. However, GPx
      overexpression has been shown to reverse the tumor cell growth inhibition caused
      by MnSOD overexpression in other types of cancer. Our aims were to determine if
      overexpression of GPx alters in vitro pancreatic cancer cell behavior and if
      delivering the GPx gene directly to tumor xenografts alters growth and survival.
      In vitro, AdGPx slowed tumor growth by 39% and AdMnSOD slowed tumor growth by
      35%. AdGPx also decreased plating efficiency and growth in soft agar. The
      combination of AdGPx and AdMnSOD had the greatest effect on tumor cell growth
      suppression with a 71% reduction in cell growth compared to controls. In vivo,
      either AdGPx or AdMnSOD alone slowed tumor growth by 51% and 54%, respectively,
      while the combination of AdGPx and AdMnSOD potentiated tumor growth suppression
      by 81% of controls and increased animal survival. GPx may be a tumor suppressor
      gene in pancreatic cancer. Delivery of the GPx gene alone or in combination with
      the MnSOD gene may prove beneficial for treatment of pancreatic cancer.

PMID- 15018735
TI  - Potential of atelocollagen-mediated systemic antisense therapeutics for
      inflammatory disease.
AB  - To study the possibility of using atelocollagen as an oligonucleotide (ODN)
      delivery carrier in vivo, the activity of formulated antisense ODN targeted
      against the intercellular adhesion molecule-1 (ICAM-1) mRNA was investigated in
      an allergic dermatitis model in mice. The allergic dermatitis was elicited in one
      ear of animals sensitized by treatment with 2,4-dinitrofluorobenzene. Antisense
      ODN was given to the animals as a single intravenous injection of formulation
      containing atelocollagen. Antisense activity was determined by measurement of ear
      thickness, histopathology, and immunohistochemistry 24 hr after the initiation of
      the dermatitis. Antisense activity was found to increase according to the
      concentration of atelocollagen in the formulation. The effect mediated by the ODN
      formulated with 0.05% atelocollagen was more than 50 times greater than that
      provided by ODN infusion, although the levels of ODN formulated with
      atelocollagen dropped below that of the 24-hr infusion group within 30 min. The
      formulated ODN could suppress inflammatory progression by treatment at 8 hr after
      the ear challenge when inflammation had already commenced at the challenged site.
      Moreover, antisense activity was noted even when the formulated ODN was injected
      3 days before the initiation of inflammation. These data demonstrate that
      atelocollagen can enhance antisense activity remarkably and that the sustainable
      antisense activity mediated by the formulation of ODN with atelocollagen could
      completely change the strategy of antisense therapeutics.

PMID- 15018734
TI  - Anti-human immunodeficiency virus hematopoietic progenitor cell-delivered
      ribozyme in a phase I study: myeloid and lymphoid reconstitution in human
      immunodeficiency virus type-1-infected patients.
AB  - A phase I gene transfer clinical study was undertaken to examine the ability to
      introduce a potential anti-human immunodeficiency virus (HIV) gene therapeutic
      into hematopoietic progenitor cells (HPC), thereby contributing to multilineage
      engraftment. The potential therapeutic effect of genetically modifying HPC with
      protective genes in HIV-infected adults depends in part on the presence of adult
      thymic activity and myeloid capacity in the setting of HIV replication. Herein we
      report the presence and expression of a retroviral vector encoding an anti-HIV-1
      ribozyme in mature hematopoietic cells of different lineages, and de novo T
      lymphocyte development ensuing from genetically engineered CD34(+) HPC. Sustained
      output of vector-containing mature myeloid and T-lymphoid cells was detected even
      in patients with multidrug-resistant infection. In addition, the study showed
      that the degree of persistence of gene-containing cells was dependent on
      transduced HPC dose. These novel findings support the concept of gene therapy as
      a modality to effect immune reconstitution with cells engineered to inhibit HIV
      replication and this report represents the first demonstration of long-term
      maintenance of a potential therapeutic transgene in HIV disease.

PMID- 15018736
TI  - Pseudomonas aeruginosa-induced neutrophilic lung inflammation is attenuated by
      adenovirus-mediated transfer of the heme oxygenase 1 cDNA in mice.
AB  - Heme oxygenase (HO) is well known as the rate-limiting enzyme in the oxidative
      degradation of heme to biliverdin, carbon monoxide (CO), and iron. Based on
      recent evidence that overexpression of HO-1 confers protection against various
      types of cell and tissue injury by regulating apoptotic cell death or cytokine
      expression profiles, the present study was performed to examine whether the
      transfer of exogenous HO-1 cDNA in the lung would provide therapeutic effect in a
      murine model of lung inflammation induced by Pseudomonas aeruginosa. HO-1
      overexpression clearly attenuated neutrophil influx and decreased numbers of
      apoptotic bronchial epithelial cells. Interestingly, the overexpression of Bcl-2,
      a known antiapoptotic factor, was observed and thought to be the mechanism that
      inhibits bronchial epithelial cellular apoptosis. It is thus suggested that HO-1
      overexpression is useful for treating P. aeruginosa-associated lung inflammation
      by attenuating neutrophil influx and apoptotic cell death.

PMID- 15018737
TI  - Direct exposure of mouse spermatozoa to very high concentrations of a serotype-2
      adeno-associated virus gene therapy vector fails to lead to germ cell
      transduction.
AB  - In a clinical safety trial involving an adeno-associated virus (AAV) gene therapy
      vector encoding human factor IX, intrahepatic administration of the vector was
      associated with the finding of vector DNA in semen that persisted for several
      weeks. Uncertainty remains as to the route by which the vector reached semen, but
      the finding raised the prospect that mature sperm could be exposed to the vector
      and sustain integration of vector DNA. To provocatively test for the ability of
      AAV vectors to transduce mature sperm, we exposed mouse sperm to concentrations
      of the same vector used in clinical studies at concentrations ranging from 840 to
      3400 particles per sperm cell, performed in vitro fertilization and embryo
      transfer, and evaluated newborn pups by Southern analysis for the presence of
      vector sequences. Of 102 pups analyzed, none showed evidence of vector DNA
      integration. We conclude from these studies that exposure of mature sperm to AAV
      gene therapy vectors is highly unlikely to lead to germline transduction.

PMID- 15018738
TI  - Quantitative adenovirus neutralization assays based on the secreted alkaline
      phosphatase reporter gene: application in epidemiologic studies and in the design
      of adenovector vaccines.
AB  - Replication-defective recombinant adenoviruses (rAd) are used as vectors for
      vaccines as well as for gene therapy. To determine type-specific antibodies to
      adenovirus (Ad) serotypes 2, 5, 24, 34, and 35, we developed quantitative
      neutralization assays using recombinant adenoviruses with the secreted alkaline
      phosphatase (SEAP) reporter gene. Among the standardized parameters, the
      concentration of infectious and noninfectious adenoviral particles used in the
      assay is critical for a reliable comparison of data from different studies. The
      usefulness of this assay was demonstrated in a pilot epidemiologic study of 40
      healthy individuals. In this study, the highest prevalence of antiadenovirus
      antibodies was found for the Ad2 serotype (82.5%), followed by Ad5 (35%). The
      prevalence of antiadenovirus antibodies for the serotypes 24, 34, and 35 was low
      (7.5%, 2.5%, and 0%, respectively). In addition, epidemiologic parameters such as
      gender and age were statistically evaluated. A positive association was found
      between age and the presence of anti-Ad5 antibodies. The assay was also useful
      for evaluating the presence of antiadenovirus antibodies in the design of
      vaccines using a rhesus monkey model. In this animal model, it was possible to
      determine differential dose and time responses, and the specificity for the
      detection of neutralizing antibodies was assessed. The evaluation of serotype
      specific neutralizing antibodies can be of both clinical and epidemiologic
      importance as a means of selecting the appropriate serotype adenovector(s).

PMID- 15018739
TI  - Mobilized blood CD34+ cells transduced and selected with a clinically applicable
      protocol reconstitute lymphopoiesis in SCID-Hu mice.
AB  - We developed a clinically applicable gene transfer procedure into mobilized
      peripheral blood (MPB) CD34(+) hematopoietic progenitor cells, based on single
      viral exposure and selection of engineered cells. CD34(+) cells were transduced
      with a retroviral vector carrying the truncated form of the nerve growth factor
      receptor (Delta NGFR) marker gene, and immunoselected for Delta NGFR expression.
      Optimal time and procedure for viral exposure, length of culture, and transgene
      expression of MPB CD34(+) cells were determined using in vitro assays. The
      multipotent capacity of MPB CD34(+)-transduced cells was demonstrated in the SCID
      hu bone/liver/thymus mouse model. Transduced Delta NGFR(+) cells retained 50% of
      long-term culture-colony forming cells (LTC-CFC) compared to unmanipulated
      CD34(+) cells. In SCID-hu mice, 52% of CD45(+) cells, 27% of CD34(+) cells, 49%
      of B cells, and more than 50% of T cells were derived from transplanted
      CD34(+)/Delta NGFR(+) cells. Furthermore, transplantation of purified transduced
      cells greatly reduced the competition with untransduced progenitors occurring in
      unselected grafts. These data demonstrate that MPB CD34(+) cells, transduced with
      a single viral exposure and selected by transgene expression, retain multilineage
      reconstitution capacity and remarkable transgene expression.

PMID- 15018742
TI  - Twenty years of biliopancreatic diversion: what is the goal of the surgery?
AB  - BACKGROUND: Comparative evaluation of weight loss after bariatric surgery is
      difficult without definition of success and without a norm for presenting
      results. We explored the pertinence of defining success: a residual BMI <40 or
      <35 kg/m(2), and the need for reporting results with stratification by initial
      obesity and length of follow-up. METHODS: Results of 1,271 consecutive
      biliopancreatic diversion (BPD) patients were compared when presented with or
      without stratification, and we searched for landmarks of success which would be
      shared by patients themselves. RESULTS: Presented globally, after a mean follow
      up of 7.9 +/- 4.2 years, BMI decreased from 48.4 +/- 9.4 to 31.3 +/- 6.5, and
      only 10% and 26% of patients would have been considered failures with a residual
      BMI >or= 40 or >or= 35 respectively. Because heavier patients were losing less in
      terms of percentage ( P <0.0001) and regained weight faster ( P <0.0001), global
      and cumulative results failed to show a failure-rate doubling every 5 years and a
      very high failure-rate in heavier patients. The landmarks of BMI 40 and 35 were
      the same unconsciously used by patients to express their own perception of
      failure. For patients with an initial BMI <50, a residual BMI of 35 caused a
      significant drop in the degree of satisfaction from 90 to 40%. For super-obese,
      the same critical point was found at a BMI of 40 where satisfaction dropped from
      91 to 57%. CONCLUSION: Landmarks of success at BMI 40 and 35 were realistic,
      reasonable and coincided with patients' own expectations. Since initial obesity
      and duration after surgery made so much difference in results, a comparison of
      different surgical approaches was useless without stratification for both factors
      together.

PMID- 15018740
TI  - A phase I vaccine safety and chemotherapy dose-finding trial of an allogeneic GM
      CSF-secreting breast cancer vaccine given in a specifically timed sequence with
      immunomodulatory doses of cyclophosphamide and doxorubicin.

PMID- 15018743
TI  - A comparison of laparoscopic adjustable gastric banding and biliopancreatic
      diversion in superobesity.
AB  - BACKGROUND: Controversy exists regarding the best surgical treatment for
      superobesity (BMI >50 kg/m(2)), and a comparison of the 2 most commonly performed
      procedures in Europe, namely biliopancreatic diversion (BPD) and laparoscopic
      adjustable gastric banding (LAGB), has not yet been reported. METHODS: BPD has
      been performed in 134 morbidly obese patients since 1996, and as the primary
      bariatric procedure in 23 superobese patients. 23 sex-matched patients who most
      closely resembled the age and BMI of the 23 BPD patients were chosen from 1319
      patients who had undergone LAGB since 1996. These groups were compared using
      appropriate statistical tests. RESULTS: BPD was performed laparoscopically in 12
      patients. Median excess weight loss at 24 months was 64.4% following BPD and
      48.4% following LAGB. Hospital stay and complication rate were significantly
      greater with BPD, although the majority of complications were related to the
      laparotomy wound in patients undergoing open BPD. Rate of resolution of
      obstructive sleep apnea, hypertension and diabetes mellitus following LAGB was
      similar to BPD. CONCLUSION: BPD results in significantly greater weight loss than
      LAGB in superobese patients, but is associated with a longer hospital stay and a
      higher complication rate in patients undergoing open BPD.

PMID- 15018744
TI  - Outcome following gastric bypass surgery: impact of past sexual abuse.
AB  - BACKGROUND: This study examined gastric bypass (GBP) outcome in 2 groups of
      morbidly obese females: those with a history of sexual abuse (SA) and those
      without a history of sexual abuse (NSA). METHODS: Subjects were assessed
      preoperatively and at one of two time points following surgery: either 5 to 9
      months or 10 to 14 months. Outcome measures included BMI, level of depression as
      measured through the Beck Depression Inventory (BDI), and level of self-esteem as
      measured through the Rosenberg Self-Esteem Scale (RSE).T-tests were conducted for
      pre and post scores between the 2 groups on each of the variables. RESULTS: Of
      the 12 tests conducted, the only statistically significant difference was on BDI
      scores for the 5 to 9 month post-surgery groups, with the SA groups showing a
      significantly higher level of depression than the NSA group. CONCLUSIONS: The
      results suggest that females with a history of sexual abuse are as successful
      with weight loss following GBP as those without a history of abuse. While females
      with a history of sexual abuse show significantly more depression 5 to 9 months
      after surgery, they are indistinguishable from those without a history of abuse 1
      year following GBP.Thus, sexual abuse does not appear to be a negative prognostic
      indicator for GBP.

PMID- 15018745
TI  - Severe protein-calorie malnutrition after bariatric procedures.
AB  - BACKGROUND: Serious nutritional complications after Roux-en-Y gastric bypass
      (RYGBP) are infrequent. In a retrospective study of patients operated during a 68
      month period, malnutrition was investigated to analyze circumstances associated
      with nutritional failure. METHODS: In 236 consecutive RYGBPs, 11 patients with
      severe malnutrition were identified (4.7%) with age 45.1 +/- 10.6 years (10
      females/1 male) and initial BMI 54.6 +/- 8.4 kg/m(2). RESULTS: In these 11
      patients, the derangement was diagnosed 17.9 +/- 15.8 months after RYGBP,
      following defined events in 63.6% (gastric stenosis, associated diseases ) or
      mostly exaggeration of expected symptoms in 36.4% (vomiting without endoscopic
      abnormalities). BMI then was 31.4 +/- 8.6 kg/m(2) (42.5 +/- 9.9% total reduction,
      or 2.4 +/- 2.1% decrease/month), and serum albumin and hemoglobin were 24.0 +/-
      8.2 g/L and 97.0 +/- 23.0 g/L respectively. Edema was present in 45.4% (5/11),
      hospitalization was required in 54.5% (6/11), and 18.2% (2/11) eventually died.
      CONCLUSIONS: Serious malnutrition was unusual but not exceedingly rare in this
      series. Exogenous precipitating factors were clearly identified in 63.6% of the
      patients. Careful clinical and nutritional follow-up is recommended to prevent
      these uncommon but potentially dangerous complications.

PMID- 15018746
TI  - Acute post-gastric reduction surgery (APGARS) neuropathy.
AB  - BACKGROUND: A variety of neurologic complications have been reported after weight
      loss surgery. Recently, a new term was introduced to describe cases of
      postoperative polyneuropathy - acute post-gastric reduction surgery (APGARS)
      neuropathy, a polynutritional, multisystem disorder characterized by protracted
      postoperative vomiting, hyporeflexia, and muscular weakness. The incidence,
      associations, and prognosis of this disorder have not been precisely defined.
      METHODS: A questionnaire about features of APGARS was mailed to all members of
      the ASBS. Surgeons were asked about their surgical and bariatric experience.
      Respondents were asked to report on specific cases where APGARS may have been
      present. They were also asked to report the patient's diagnosis and which
      operation the patient had undergone. RESULTS: Of the 808 questionnaires, 257 were
      returned for a response-rate of 31.8%. The mean years in general surgical
      practice and in bariatric surgery were 15.3 +/- 10.3 and 7.5 +/- 7.4. A total of
      168010 bariatric cases were performed by all respondents. 109 cases of neuropathy
      were described. 99 cases were believed to represent APGARS (weakness with
      hyporeflexia and/or vomiting). Vitamin B and/or thi12 amine deficiency were
      present in 40 (40%); 18 cases resolved. 9 of 17 cases with B(12) deficiency
      resolved; 12 of 29 cases with thiamine deficiency resolved; and 3 of 6 cases with
      both deficiencies resolved. Vitamin deficiencies were not noted in 59 (60%), of
      which 30 resolved. The most common diagnoses were Wernicke's encephalopathy,
      thiamine deficiency, and Guillain-Barre Syndrome. The most common operation
      performed was gastric bypass. CONCLUSIONS: The incidence of APGARS in this survey
      was 5.9 cases per 10000 operations. Given the potentially reversible nature of
      APGARS, surgeons should be aware of the findings and treatment.

PMID- 15018747
TI  - Bowel obstruction after laparoscopic Roux-en-Y gastric bypass.
AB  - BACKGROUND: Bowel obstruction has been frequently reported after laparoscopic
      Roux-en-Y gastric bypass (LRYGBP). The aim of this study was to review our
      experience with bowel obstruction following LRYGBP, specifically examining its
      etiology and management and to strategize maneuvers to minimize this
      complication. METHODS: We retrospectively reviewed the charts of 9 patients who
      developed postoperative bowel obstruction after LRYGBP. Each chart was reviewed
      for demographics, timing of bowel obstruction from the primary operation,
      etiology of obstruction, and management. RESULTS: 9 of our initial 225 patients
      (4%) who underwent LRYGBP developed postoperative bowel obstruction. The mean age
      was 46 +/- 12 years, with mean BMI 47 +/- 9 kg/m(2). 6 patients developed early
      bowel obstruction, and 3 patients developed late bowel obstruction. The mean time
      interval for development of early bowel obstruction was 16 +/-16 days. The causes
      for early bowel obstruction included narrowing of the jejunojenunostomy
      anastomosis (n=3), angulation of the Roux limb (n=2), and obstruction of the Roux
      limb at the level of the transverse mesocolon (n=1). The mean time interval for
      development of late bowel obstruction was 7.4 +/- 0.5 months. The causes for late
      bowel obstruction included internal herniation (n=2) and adhesions (n=1). 6 of 9
      bowel obstructions (66%) were considered technically related to the learning
      curve of the laparoscopic approach. Eight of the 9 patients required operative
      intervention, and 6 of the 8 reoperations were managed laparoscopically.
      Management included laparoscopic bypass of the jejunojejunostomy obstruction site
      (n=5), open reduction of internal hernia (n=2), and laparoscopic lysis of
      adhesion (n=1). CONCLUSIONS: Bowel obstruction is a frequent complication after
      LRYGBP, particularly during the learn ing curve of the laparoscopic approach.
      Specific measures should be instituted to minimize bowel obstruction after LRYGBP
      as most of these complications are considered technically preventable.

PMID- 15018748
TI  - Laparoscopic Roux-en-Y gastric bypass for morbid obesity: results of our learning
      curve in 100 consecutive patients.
AB  - BACKGROUND: Morbid obesity requires life-long treatment, and bariatric surgery
      provides the best results. Among the bariatric procedures, laparoscopic Roux-en-Y
      gastric bypass (LRYGBP) has been considered to be superior. However, it requires
      advanced laparoscopic skills and a learning curve. We analyzed our results in an
      initial series of 100 patients. METHODS: Data of 100 consecutive patients who
      underwent LRYGBP for morbid obesity in a 2.5-year period were prospectively
      collected and analyzed with emphasis on results and complications. RESULTS: Mean
      age was 31+/-5 years. There were 63 woman and 37 men. Preoperative BMI was 50+/-9
      kg/m(2). 33 patients were considered super-obese (BMI>50). Mean operative time
      was 3.8 +/- 0.7 hours. Two patients required conversion to open surgery. Mean
      hospital stay was 6 days. Complications occurred in 10 patients. Mortality rate
      was 2%. Excess body weight loss was as follows: 33 +/- 8% at 3 months (n=92), 47
      +/- 2% at 6 months (n=82), 62 +/- 4% at 1 year (n= 70), 66 +/- 5% at 18 months
      (n= 63) and 67 +/- 8% at 2 years (n= 35). There was significant improvement in
      several co-morbid conditions, such as diabetes and hypertension. CONCLUSION:
      LRYGBP is a reproducible technique. It requires the combination of bariatric and
      laparoscopic expertise.

PMID- 15018749
TI  - Is routine cholecystectomy required during laparoscopic gastric bypass?
AB  - BACKGROUND: Routine cholecystectomy is often performed at the time of gastric
      bypass for morbid obesity. The aim of our study was to determine the incidence of
      gallstone formation requiring cholecystectomy following a laparoscopic Roux-en-Y
      gastric bypass (LRYGBP). METHODS: 289 LRYGBP were performed between November 1999
      and May 2002. 60 patients (21%) who had prior cholecystectomy were excluded. If
      gallstones were identified by intra-operative ultrasound (IOUS), simultaneous
      cholecystectomy was performed. Patients without gallstones were prescribed
      ursodiol for 6 months and scheduled for follow-up with transabdominal ultrasound.
      RESULTS: During LRYGBP, gallstones were detected in 40 patients using IOUS (14%)
      and simultaneous cholecystectomy was performed. Of 189 patients with no stones
      identified by IOUS, 151 patients (80%) had a postoperative ultrasound after 6
      months. 39 patients developed gallstones (22%) and 12 developed sludge (8%), as
      demonstrated by ultrasound at the time of follow-up. 11 patients had gallstone
      related symptoms and subsequently underwent cholecystectomy (7%). 106 patients
      (70%) were gallstone-free at the time of ultrasound follow-up. Ursodiol
      compliance was found to be significantly lower for patients developing stones
      than for gallstone-free patients (38.9% vs 58.3%, z =-2.00, P = 0.045).
      CONCLUSIONS: There is a low incidence of symptomatic gallstones requiring
      cholecystectomy after LRYGBP. Prophylactic ursodiol is protective. Routine IOUS
      and selective cholecystectomy with close patient follow-up is a rational approach
      in the era of laparoscopy.

PMID- 15018750
TI  - The effects of pneumoperitoneum on respiratory mechanics during general
      anesthesia for bariatric surgery.
AB  - BACKGROUND: The effects of pneumoperitoneum (PPM) on respiratory mechanics during
      bariatric surgery were investigated. PATIENTS AND METHODS: 10 patients with BMI
      50.5+/-8 kg/m(2) (range 40.9- 66.8) who underwent laparoscopic adjustable gastric
      banding with the Swedish band under general anesthesia were studied. Besides
      routine monitoring of vital signs and lung volumes, respiratory mechanics
      (compliance and resistance) were measured during positive pressure ventilation
      using an anesthesia delivery unit (Datex Ohmeda type A_Elec). Data were recorded
      at the following stages: 1). before PPM, 2). during PPM, and 3). after gas
      deflation. One-way analysis of variance was used for analysis of data. P <0.05
      was considered significant. RESULTS: The airway, peak inspiratory and plateau
      pressures increased significantly during PPM. Dynamic lung compliances were
      44.6+/-7.8 SD, 31.8+/-5.5 and 44.5+/-8.3 cm/H(2)O before, during and after PPM
      respectively with significant differences (P <0.05). CONCLUSIONS: Although
      significant decrease in lung mechanics was found in the present study,these
      variations were well tolerated in morbidly obese patients with PPM pressure of 15
      mmHg.

PMID- 15018751
TI  - Reduction in co-morbidities 4 years after laparoscopic adjustable gastric
      banding.
AB  - BACKGROUND: We investigated the reduction in co-morbidities following
      laparoscopic adjustable silicone gastric banding (LAGB). METHODS: Between
      December 1996 and October 2002, 295 patients with mean BMI 45 kg/m(2) were
      operated (79% women, average age 41 years). Mean follow-up was 44 months.
      Reduction in co-morbidity was scaled relative to the preoperative co-morbidity
      level as having been cured, improved, unchanged, or worsened. Patients needing
      reoperations were analyzed separately. RESULTS: The preoperative frequencies of
      co-morbidities were as follows: hypertension 52%, diabetes 20%, dyspnea 85%,
      peripheral edema 63%, sleep apnea 36%, arthralgia 89%, reflux 57%, reduced self
      esteem 95%, reduced general physical performance 96%, hyperlipidemia 39%,
      hyperuricemia 36%, and menstrual problems 22%. Excess weight loss after 1 year
      was 40%, after 2 years 46%, after 3 years 47%, and after 4 years 54%. After 4
      years, the rate of cure/improvement of the co-morbiditites were: hypertension 58%
      / 42%, diabetes 75% / 8%, dyspnea 85% / 12%, arthralgia 52% / 24%, reflux 79% /
      11%, self-esteem 45% / 39%, and general physical performance 58% / 33%. We also
      found an improvement in stress incontinence, sleep apnea, peripheral edema, and
      regulation of menstruation. Greater weight loss was associated with greater
      reduction in dyspnea, arthralgia, self-esteem, and physical performance.
      Hypertension, diabetes, reflux, and edema improved independent of the amount of
      weight loss. Reoperated patients undergoing either rebanding or biliopancreatic
      diversion with duodenal switch had similar weight loss and reduction in co
      morbidities as did patients treated with LAGB only. CONCLUSION: With moderate
      weight loss following LAGB, co-morbidities were cured in 50-80% or improved in 10
      40% of all patients.

PMID- 15018752
TI  - Laparoscopic adjustable banding in pregnancy: safety, patient tolerance and
      effect on obesity-related pregnancy outcomes.
AB  - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is increasingly
      recommended to women of reproductive age. For continued use, LAGB needs to be
      proven to be safe and well-tolerated during pregnancy. Maternal obesity is a well
      recognized risk factor for gestational diabetes, maternal hypertension and is
      more likely to result in instrumental delivery or caesarean section. Weight
      control with the LAGB may reduce the incidence of these complications. METHODS:
      An observational study was conducted of the LAGB in pregnancy, including a study
      comparing outcomes of LAGB pregnancies with previous non-LAGB pregnancies. Women
      who had had successful LAGB pregnancies were identified from a computerized
      database. A telephone questionnaire was used to collect the additional outcome
      data needed and was administered by an independent medical practitioner. RESULTS:
      49 LAGB and 31 previous non-LAGB pregnancies were included. 2 LAGBs (4%) required
      removal during pregnancy. Mean maternal weight gain was significantly reduced in
      the LAGB group, 3.7 kg vs 15.6 kg (P <0.0001), with no effect on fetal weight,
      3.31 vs 3.53 kg, or neonatal complications, 4% and 3%. The incidence of
      gestational diabetes, 8 and 27% (P =0.048), and hypertension, 8 and 22.5% (P
      =0.06) was significantly reduced in the LAGB group. The overall complication rate
      during pregnancy for LAGB was 20.4% and 52% for non-LAGB (P =0.0037) CONCLUSION:
      LAGB is safe and well-tolerated during pregnancy with a lower incidence of
      gestational diabetes and maternal hypertension. LAGB can be safely recommended to
      morbidly obese women of childbearing age.

PMID- 15018753
TI  - Initial experience with laparoscopic adjustable gastric banding in Hungary.
AB  - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) was started in Hungary
      in 1998. We used Lap-Band and SAGB devices. In this study we present our
      experience through the learning curve. METHODS: From Jan 1999 to Dec 2002, 54
      patients underwent laparoscopic surgery for morbid obesity in our department,
      using the Lap-Band and SAGB. There were 33 men and 21 women, with median age 42
      (range 20-64), and preoperative BMI 50 kg/m(2) (range 41-66). All underwent LAGB,
      except one patient who had laparoscopic vertical banded gastroplasty. The
      procedures used the 4-trocar technique. RESULTS: The first patient required
      reoperation because of gastric rupture from drinking sparkling mineral water
      despite of our advice. Excluding this, we had no intraoperative or short-term
      postoperative complications. Mean operating time was 82 minutes (range 55-192),
      and hospital stay was 3 days. Followup ranges from 1 to 36 months. Mean weight
      loss was 47 kg at 12 months and 67 kg at 36 months. Mean BMI fell to 29 kg/m(2).
      CONCLUSION: With its safety and effectiveness, LAGB has been a good choice for
      handling morbidly obese patients in our early experience.

PMID- 15018754
TI  - Effects of laparoscopic gastric banding on body composition, metabolic profile
      and nutritional status of obese women: 12-months follow-up.
AB  - BACKGROUND: Obesity is frequently associated with metabolic and cardiovascular co
      morbidities and high mortality rates. Besides, because of the increasingly
      recognized fact that conservative therapy for morbid obesity is associated with
      an almost 90-95% failure rate in the long term, and probably because of the
      development of laparoscopic surgery,the demand for bariatric surgery is
      increasing rapidly. The significant weight loss observed during the first 6-12
      months after gastric banding is related to the severe food restriction, related
      hypercatabolism, and has a potential risk of mineral and vitamin deficiencies.
      The aim of this study was to evaluate the effects of gastric banding on total
      body composition, metabolic profile and nutritional status. METHODS: 31 women
      were studied with median age 36 years (range 25-52), body weight 118.6 kg (range
      98-156), BMI 43.6 kg/m(2) (range 36-56 kg/m(2)), percentage of excess body weight
      (%EW) of 107% (range 72- 166%), waist 115 cm (range 98-132) and hip 138 cm (range
      119-155). Total body composition was measured before, 6 and 12 months after
      laparoscopic gastric banding, using dual-energy x-ray absorptiometry. Metabolic
      and nutritional profile were evaluated before and 1, 3, 6, 9 and 12 months
      postoperatively. RESULTS: There was a 23.3% reduction of total body weight and
      36.8% reduction of body fat. Unfortunately we also observed a reduction of Fat
      Free Mass (FFM) of 9.6%. In addition, the major determinants of weight loss were
      the initial body weight and abdominal distribution of fat mass. Reduction of FFM
      was positively correlated with the rapidity of weight loss. A significant
      improvement of glucidic profile was observed, with disappearance of impaired
      fasting glucose, and normalization of the values of triglycerides in all
      patients. The prevalence of the metabolic syndrome decreased from 89% in
      preoperative conditions to 15% 1 year after gastric banding. No major nutritional
      deficiencies was found following gastric banding. CONCLUSIONS: This prospective
      study suggests that the first 6 months postoperatively are crucial for weight
      loss and changes in body composition. Furthermore, the significant reduction of
      body weight is accompanied by an important improvement of biological
      abnormalities.

PMID- 15018755
TI  - The effects of gastric bands of different synthetic materials on the gastric and
      esophageal mucosa: an experimental study.
AB  - BACKGROUND: Gastric and mucosal changes were studied when different synthetic
      materials were used for gastric banding. METHODS: 60 Wistar-Albino rats (weight
      200-250 g, age 12 weeks) were classified into 5 groups. Gastric banding was
      carried out with different materials: group 1 - polytetrafluoroethylene (PTFE),
      group 2 - polythylene (PE), group 3 - polypropylene (PP), group 4 - silicone; and
      group 5 - controls. Histopathological examination of proximal and distal gastric
      mucosa and esophagus were evaluated for foreign body reaction, lymphocytic
      infiltration, neutrophil infiltration, gastric wall invasion, and
      gastroesophageal reflux. RESULTS: PE and PP caused a much more severe foreign
      body reaction that PTFE and silicone. Lymphocytic infiltration (chronic
      inflammation) was not significantly different between PP, PE, and PTFE, and was
      present in 80% of rats with these materials (P >0.05); in the silicone group,
      lymphocytic reaction was minimal. There was no neutrophilic infiltration in the
      silicone group (P =0.001), but this sign of acute inflammation was present in the
      other groups. However, the neutrophilic infiltration showed no difference between
      PE, PTFE and PP. PP, PE and PTFE migrated into the gastric wall at similar rates
      (no significant difference, P >0.05); in the silicone group, however,
      intragastric migration was not observed. With regard to gastroesophageal reflux,
      no significant difference was found between all the groups (P>0.05). In all
      groups, no histopathologic change was observed in the gastric mucosa proximal and
      distal to the bands. CONCLUSION: Silicone was the ideal material for banding,
      because it had good tissue adaptation and caused no inflammatory response.

PMID- 15018756
TI  - Mechanical evaluation of a ruptured Swedish adjustable gastric band.
AB  - BACKGROUND: Leakage of a laparoscopically placed Swedish adjustable gastric band
      (SAGB) was observed 2 1/2 years after placement. The band was evaluated for
      mechanical inaccuracies by a laboratory. METHODS: The ruptured SAGB was
      investigated microscopically and wall thicknesses were measured. An unused SAGB
      was tested, both empty and filled, for mechanical deformity after exposure to
      saline solution. RESULTS: A permanent transformation of the silicone rubber was
      found, caused by bowing of the device. 2 tears were present at the end of a kink.
      The mean wall thickness was within acceptable limits. Exposure of the gastric
      band to saline solution did not cause any sign of permanent deformity of the
      silicone rubber. CONCLUSION: The rupture of the gastric band did not seem to be
      caused by a production error. Long-term deformity, in combination with a
      continuous dynamic load, may increase the risk of tearing. Long-term follow up is
      recommended for patients treated with this device.

PMID- 15018757
TI  - Literature review of comparative studies of complications with Swedish band and
      Lap-Band.
AB  - BACKGROUND: Gastric restriction is a treatment option for morbid obesity.
      Currently there are several types of adjustable gastric bands available, with two
      leading but conceptionally different systems, not just from a technical point of
      view but also from the long-term complication rates. METHODS: A literature search
      of articles published from January 1997 to December 2002 dealing with prospective
      or restrospective studies comparing results of treatment with the Swedish band
      and Lap-Band was carried out. RESULTS: 7 comparative studies fulfilled inclusion
      criteria, with a total of 1031 patients in the Swedish band (41-597) and 1305
      patients in the Lap-band groups (34-821). Pouch dilatation/slippage and/or
      erosion in Swedish vs Lap-band were reported in the studies as follows: 1 vs 2 in
      study group 1, 0 vs 9 in study group 2, 0 vs 3 in 3, 3 vs 38 in 4, 0 vs 64
      (slippages) and 4 vs 4 (erosions) in group 5. In study 6, 3 vs 3 dilatations and
      0 vs 1 erosions were reported. Study 7 found 12 vs 42 long-term complications of
      this origin. Port-site infections, total reoperation rates and length of hospital
      stay were also compared. CONCLUSION: The results of this meta-analysis reveal
      that fall in BMI is similar with both laparoscopic bands. Long-term complication
      rates, despite the fact that they have been defined in a similar way in all the
      included studies, may be higher with more reoperation rates in Lap-band(R)
      patients.

PMID- 15018758
TI  - Hand-assisted laparoscopic revision of previous restrictive operations to
      vertical banded gastroplasty.
AB  - BACKGROUND: Revision of failed gastric restrictive procedures to proximal Roux-en
      Y gastric bypass (RYGBP) is the standard for many bariatric surgeons. Where the
      patient is not a suitable candidate or simply refuses gastric bypass, an
      alternative is herewith proposed. METHODS: 3 patients had undergone a gastric
      banding as the original operation and 1 patient had had a vertical banded
      gastroplasty (VBG). 1 patient presented with insufficient weight loss, 1 with
      regain of weight and 2 with complaints of food intolerance and vomiting. The
      gastric bands were removed by hand-assisted laparoscopy (HALS), with conversion
      to a VBG. In the patient with stomal stenosis after a VBG, HALS interposition of
      PTFE was performed to enlarge the collar. RESULTS: In 2 patients, further weight
      reduction was achieved. In the other 2 patients, relief of symptoms was achieved.
      There were no complications during or after the revisional surgery. CONCLUSION:
      HALS conversion of a gastric banding to a VBG, or PTFE interposition in the case
      of stomal stenosis after a VBG, can be a valuable alternative for patients
      unsuitable for or refusing proximal RYGBP.

PMID- 15018759
TI  - Improvement of vertical banded gastroplasty by strict dietary management.
AB  - BACKGROUND: Vertical banded gastroplasty (VBG) has been found to reduce BMI
      significantly during the first postoperative year. However, the same trend in
      weight loss has not been established thereafter. The purpose of this study was to
      evaluate the effects of our dietary program on morbidly obese patients treated
      with VBG. METHODS: A prospective evaluation of 40 obese patients (25 female, 15
      male) undergoing VBG over a 3-year period was undertaken. RESULTS: The age range
      was 24-57 (median 38) years, mean weight 133+/-2 SD kg, and mean BMI 45+/-6.4 SD
      kg/m2. After VBG, a special follow-up program was applied to patients. All
      patients (100%) were available for follow-up. Operative mortality was zero. 4
      patients developed an early postoperative complication, and 1 patient was re
      operated because of staple-line disruption 8 months after VBG. BMI decreased to
      34+/-3.2 after 12 months, 27+/-1.3 after 24 months, and 28+/-1.4 after 36 months.
      All patients showed weight loss after VBG, and the weight loss continued with the
      strict follow-up program during a 3-year period, except in 1 patient who regained
      the weight lost despite an intact staple-line and stoma. CONCLUSION: Our policy
      for patients after VBG appears to be effective.

PMID- 15018760
TI  - Pre- and postoperative esophageal and gastric pH levels in morbidly obese
      patients undergoing vertical gastroplasty.
AB  - BACKGROUND: The aim of this study was to determine whether the
      anatomicofunctional changes induced by vertical gastroplasty lead to pH
      alterations in the esophagus and body and antrum of the stomach. MATERIALS AND
      METHODS: 23 non-smoking volunteers (3 men, 20 women) mean age 35.29 +/- SD 6.85
      years, mean weight 163.17 +/- 52.11 kg and mean BMI 56.06 +/- 14.01 kg/m2 were
      studied. The pH of the esophagus, body and antrum of the stomach were measured
      preoperatively and 18 months postoperatively (after excess weight loss). Data was
      analyzed statistically using paired student t-test. RESULTS: The pH values before
      (pH(1)) and after (pH(2)) the operation were: for the esophagus pH(1e) +/- SD =
      6.12 +/- 0.31 and pH(2e) +/- SD = 5.92 +/- 0.37 (P =0.38), for the body of the
      stomach pH(1b) +/- SD = 2.2 +/- 0.30 and pH(2b) +/- SD = 2.56 +/- 0.34 (P =0.30),
      and for the antrum pH(1a) +/- SD = 1.78 +/- 0.28, and pH(2a) +/- SD = 1.65 +/-
      0.36 (P =0.011). CONCLUSIONS: Vertical gastroplasty does not affect the pH levels
      in the esophagus and in the body of the stomach. However, there is acidification
      in the antrum, which could lead to pH-related diseases.

PMID- 15018762
TI  - Gastric wall necrosis from organo-axial volvulus as a late complication of
      laparoscopic gastric banding.
AB  - We present a case of massive gastric wall necrosis associated with volvulus of
      the stomach occurring 17 months after laparoscopic gastric banding. The 19- year
      old female was admitted to our hospital with acute abdominal pain with rapid
      deterioration from massive necrosis of a distended stomach which perforated
      distal to the gastric band, accompanied by splenic infarction. Total gastrectomy
      and spenectomy were required. We present this very rare complication which should
      be recognized and treated early, so that a less drastic operation is possible.

PMID- 15018761
TI  - A potential complication of bi-level positive airway pressure after gastric
      bypass surgery.
AB  - BACKGROUND: Bi-level positive airway pressure (BIPAP) is a common treatment
      modality for patients with obstructive sleep apnea (OSA), especially in the
      morbidly obese population. To our knowledge, there have been no reports of any
      adverse effects of BIPAP on patients who undergo weight loss surgical procedures.
      METHODS: We report 2 patients who were treated with BIPAP in the postoperative
      period following open Roux-en-Y gastric bypass (RYGBP). Their clinical courses
      and outcomes are presented. RESULTS: The patients developed massive bowel
      distention following treatment with BIPAP and subsequently developed anastomotic
      leaks. CONCLUSION: BIPAP following RYGBP may not be a completely benign treatment
      modality. We advise caution and careful monitoring during the use of BIPAP after
      gastric bypass surgery.

PMID- 15018769
TI  - A twelve-month study of West Nile virus antibodies in a resident and a migrant
      species of kestrels in Israel.
AB  - Two species of kestrel, the common and lesser, were caught each month at three
      geographically defined locations in Israel over a 12-month period, and a total of
      306 blood samples were examined for West Nile virus neutralizing antibodies. The
      prevalences and mean antibody titers were analyzed statistically by the multiple
      linear regression model and were shown to be significantly affected by two of the
      independent variables, location and age of the bird. The season had no overall
      effect on prevalence and titer but a comparison of the mean monthly titers
      revealed that April was highest and July and August the lowest statistically for
      the common kestrel which is a resident species. In contrast, the migrating lesser
      kestrel was caught only in the spring months and principally at the Jerusalem
      location, where eight out of 29 birds were seropositive. By comparing the
      serology of the non-migrating, common kestrel with the migrating, lesser kestrel,
      the effect of seasonality was evaluated in relation to their ecological patterns
      and yielded evidence for the entry in April of a small number of previously
      infected common kestrels into Israel. This serological approach based on
      continuous sampling over an extended period could be used to forecast in the
      coming years the timing and dispersion of West Nile virus in both Old and New
      Worlds if surveys are based on a limited number of informative (flag) species.

PMID- 15018768
TI  - Longitudinal studies of West Nile virus infection in avians, Yucatan State,
      Mexico.
AB  - Following the introduction of West Nile virus (WNV) into North America in 1999,
      surveillance for evidence of infection with this virus in migratory and resident
      birds was established in Yucatan State, Mexico in March 2000. Overall, 8611 birds
      representing 182 species and 14 orders were captured and assayed for antibodies
      to WNV. Of these, 5066 (59%) birds were residents and 3545 (41%) birds were
      migrants. Twenty-one (0.24%) birds exhibited evidence of flavivirus infection. Of
      these, 8 birds had antibodies to WNV by epitope-blocking enzyme-linked
      immunosorbent assay. Five (0.06%) birds (gray catbird, brown-crested flycatcher,
      rose-breasted grosbeak, blue bunting and indigo bunting) were confirmed to have
      WNV infections by plaque reduction neutralization test. The WNV-infected birds
      were sampled in December 2002 and January 2003. The brown-crested flycatcher and
      blue bunting presumably were resident birds; the other WNV seropositive birds
      were migrants. These data provide evidence of WNV transmission among birds in the
      Yucatan Peninsula.

PMID- 15018770
TI  - Density of questing Ixodes ricinus nymphs and adults infected by Borrelia
      burgdorferi sensu lato in Switzerland: spatio-temporal pattern at a regional
      scale.
AB  - Lyme borreliosis, the most important vector-borne disease in the Northern
      hemisphere, causes health problem for populations in endemic areas. In the
      present study, the density of questing Ixodes ricinus ticks and their infection
      with Borrelia burgdorferi sensu lato (sl) was examined in 11 areas located on the
      Swiss Plateau and in an alpine valley. From 1999 to 2001, free-living I. ricinus
      ticks were collected on a monthly basis by flagging vegetation in these areas.
      Each tick was examined for the presence of B. burgdorferi sl using direct
      fluorescent antibody assay, and for isolation of the bacteria. Borreliae were
      characterized by PCR followed by RFLP. Density of questing ticks varied greatly
      between studied areas. Borreliae were observed in ticks collected in all
      investigated sites. However, the prevalence of infection differed significantly
      among areas. Infection prevalence varied from 9% to 40% in nymphs and from 22% to
      47% in adults. Adult ticks were significantly more infected (129/366, 35%) than
      nymphs (109/552, 20%). There was no correlation between nymphal density and
      infection prevalence as well as between adult density and infection prevalence,
      but there was a correlation between density of ticks and density of infected
      ticks. During the spring peak of questing tick density, a range of 2-30.3
      infected ticks per 100 m(2) was observed. B. burgdorferi sl isolates (n = 129)
      were obtained from ticks collected in 10/11 areas. Five Borrelia species were
      identified: B. garinii, B. burgdorferi sensu stricto, B. afzelii, B. valaisiana,
      B. lusitaniae, and six mixed infections were also obtained. Borrelia species were
      heterogeneously distributed in the different areas.

PMID- 15018771
TI  - Mapping Rift Valley Fever vectors and prevalence using rainfall variations.
AB  - High activity of the Rift Valley Fever (RVF) virus is related to a tremendous
      increase of associated mosquito vectors, which follows periods of high rainfall.
      Indeed, rainfall creates an ecologically humid environment that insures the
      proliferation of breeding sites and the development of RVF vectors. Data
      collected by Fontenille et al. (1998) from 1991 to 1996 in the Barkedji area in
      the northern Senegal are employed to discuss and quantify the incidence of
      rainfall upon the abundances of RVF vectors. We have constructed a non-linear
      mapping of vector abundances versus rainfall variations, and developed a
      stochastic model and a corresponding algorithm allowing on output the simulation
      of RVF mosquito vectors as a function of rainfall trajectories in the course of
      time. This stochastic mapping of vector abundance is subsequently used to assess
      the prevalence of RVF in a population of susceptible hosts as a consequence of
      rainfall.

PMID- 15018772
TI  - Occurrence of Borrelia afzelii and Borrelia garinii in Ixodes ricinus ticks from
      southern Moravia, Czech Republic.
AB  - During the years 1996-2000, a total of 2398 Ixodes ricinus ticks were collected
      in three areas of southern Moravia and eastern Bohemia, Czech Republic, and
      examined by dark-field microscopy for the presence of spirochetes. The prevalence
      of B. burgdorferi sensu lato in Ixodes ricinus ticks varied and depended upon the
      year. In 1996, the prevalence 6.8% was observed, during 1997 and 1998, it
      increased to 8.4% and 12.3%, respectively. The lowest prevalence was observed in
      1999 (3.6%), and in 2000 it increased to 4.0%. The mean rate of infection was
      6.5%, and the proportions of infected ticks were 12.2% in 263 male ticks, 8.3% in
      289 female ticks, 6.0% in 1621 nymphs, and 1.3% in 225 larvae. From the total of
      156 highly infected ticks (>100 spirochetes per sample) transferred into BSK-H
      medium for isolation attempts, 13 isolates were obtained. PCR-RFLP and
      electrophoresis (SDS-PAGE) were used for the identification and characterization
      of Borrelia strains. Ten tick isolates were identified as Borrelia afzelii, and
      the other three isolates were found to be Borrelia garinii. The results indicate
      the epidemiological importance of B. afzelii and B. garinii in central Europe,
      and emphasize the role of I. ricinus in the ecology of B. burgdorferi and in the
      epidemiology and epizootiology of Lyme disease.

PMID- 15018773
TI  - Acquisition of different isolates of Anaplasma phagocytophilum by Ixodes
      scapularis from a model animal.
AB  - The prevalence of etiologic agents in ticks reflects the intensity of their
      transmission in natural cycles and is an important measure of their potential to
      cause human disease. The distribution of Anaplasma phagocytophilum within the
      range of its primary vectors is patchy. Even nearby sites differ dramatically in
      the prevalence of Anaplasma in questing ticks. We hypothesized that this
      irregular distribution may be due in part to variations in acquisition rates of
      different isolates of A. phagocytophilum by I. scapularis ticks from infected
      animals. BALB/c mice were infected with seven isolates of A. phagocytophilum from
      different geographical regions: four isolates from the Northeastern United States
      (Bridgeport, Dawson, Gaillard, NY-8), two from the Midwest (Webster, Sp-Is), and
      one from California (MRK). Larval ticks were placed on infected mice for 16
      consecutive weeks and allowed to feed to repletion. The prevalence of infection
      in the freshly molted nymphs was then determined by PCR. The proportion of ticks
      that became infected with either isolate fluctuated over the duration of
      infection. Mice harboring the isolate Sp-Is were most infectious for ticks at 3
      weeks postinfection. Mice infected with the other six isolates exhibited several
      peaks of infectivity. Timing and relative heights of these peaks differed between
      isolates. Geographical proximity of the studied isolates did not predetermine
      their similarity, and isolates originating from the same region differed more in
      their ability to infect ticks than isolates from different regions. However, it
      appears unlikely that described differences in agent acquisition by ticks alone
      are sufficient to account for the irregular distribution of A. phagocytophilum in
      vector populations.

PMID- 15018774
TI  - The epidemic of West Nile virus in the United States, 2002.
AB  - Since 1999, health officials have documented the spread of West Nile virus across
      the eastern and southern states and into the central United States. In 2002, a
      large, multi-state, epidemic of neuroinvasive West Nile illness occurred. Using
      standardized guidelines, health departments conducted surveillance for West Nile
      virus illness in humans, and West Nile virus infection and illness in non-human
      species. Illnesses were reported to the Centers for Disease Control and
      Prevention (CDC) through the ArboNET system. In 2002, 39 states and the District
      of Columbia reported 4,156 human West Nile virus illness cases. Of these, 2,942
      (71%) were neuroinvasive illnesses (i.e., meningitis, encephalitis, or
      meningoencephalitis) with onset dates from May 19 through December 14; 1,157
      (28%) were uncomplicated West Nile fever cases, and 47 (1%) were clinically
      unspecified. Over 80% of neuroinvasive illnesses occurred in the central United
      States. Among meningitis cases, median age was 46 years (range, 3 months to 91
      years), and the fatality-to-case ratio was 2%; for encephalitis cases (with or
      without meningitis), median age was 64 years (range, 1 month to 99 years) and the
      fatality-to-case ratio was 12%. Neuroinvasive illness incidence and mortality,
      respectively, were significantly associated with advanced age (p = 0.02; p =
      0.01) and being male (p < 0.001; p = 0.002). In 89% of counties reporting
      neuroinvasive human illnesses, West Nile virus infections were first noted in non
      human species, but no human illnesses were reported from 77% of counties in which
      non-human infections were detected. In 2002, West Nile virus caused the largest
      recognized epidemic of neuroinvasive arboviral illness in the Western Hemisphere
      and the largest epidemic of neuroinvasive West Nile virus ever recorded. It is
      unknown why males appeared to have higher risk of severe illness and death, but
      possibilities include higher prevalence of co-morbid conditions or behavioral
      factors leading to increased infection rates. Several observations, including
      major, multi-state West Nile virus epidemics in 2002 and 2003, suggest that major
      epidemics may annually reoccur in the United States. Non-human surveillance can
      warn of early West Nile virus activity and needs continued emphasis, along with
      control of Culex mosquitoes.

PMID- 15018775
TI  - Host feeding patterns of established and potential mosquito vectors of West Nile
      virus in the eastern United States.
AB  - An important variable in determining the vectorial capacity of mosquito species
      for arthropod-borne infections is the degree of contact of the vector and the
      vertebrate reservoir. This parameter can be estimated by examining the host
      feeding habits of vectors. Serological and polymerase chain reaction based
      methods have been used to study the host-feedings patterns of 21 mosquito species
      from New York, New Jersey, and Tennessee, 19 of which previously have been found
      infected with West Nile virus. Mammalophilic mosquito species in New Jersey and
      New York fed primarily upon white-tailed deer, while those from Memphis,
      Tennessee, fed mainly upon domestic dogs. A total of 24 different avian host
      species were detected among the avian-derived blood meals. American Robin,
      Northern Cardinal, Northern Mockingbird, Tufted Titmouse, and Brown-headed
      Cowbird were common avian hosts, while blood meals derived from the American Crow
      were relatively rare. Although the majority of common host species were
      potentially among the most abundant birds at each location, the proportion of
      blood meals from the most commonly fed upon avian species was greater than was
      predicted based upon the likely abundance of these species alone. These findings
      suggest that vector species for West Nile virus may preferentially feed upon
      certain avian hosts.

PMID- 15018776
TI  - An interview with Lyle Petersen, M.D., M.P.H. Interview by Vicki Glaser.

PMID- 15018777
TI  - Fertility of mice following receipt of ovaries slow cooled in dimethyl sulphoxide
      or ethylene glycol is largely independent of cryopreservation equilibration time
      and temperature.
AB  - Cryopreservation procedures generally depend on both the cryoprotectant used and
      the equilibration conditions to which the material is exposed. The aim of the
      present study was to examine the effect of cryoprotectants (dimethyl sulphoxide
      (DMSO) and ethylene glycol (EG)) and equilibration conditions (0, 30 or 120 min
      at 0 degrees C or 120 min at room temperature) on the fertility of mice receiving
      cryopreserved mouse ovaries. The study compared the fertility of cryopreserved
      Day 14 mouse pup ovaries following grafting to adult recipient mice for 4 months.
      There was no effect of the cryoprotectant or equilibration condition used on the
      interval to the first plugging/mating or on the interval to the birth of the
      first litter, the size of litters, the number of litters produced or the total
      number of offspring produced. Despite this, when compared with control females
      (untreated, sham and fresh transplant) the cryopreservation and transplantation
      procedures delayed fertility. However, the size of litters was equivalent for all
      cryopreserved and control groups (P > 0.05). The results show that, for the
      equilibration conditions examined, DMSO and EG are equally efficient
      cryoprotective agents for mouse ovarian tissue.

PMID- 15018778
TI  - Ultrastructural localisation of calcium deposits in the mouse ovary.
AB  - Follicle-enclosed mouse oocytes contain numerous calcium deposits. The
      ultrastructural distribution of calcium deposits in the nuclei, mitochondria and
      cytoplasm of mouse oocytes and granulosa cells of primary, secondary and antral
      follicles was examined using the combined oxalate-pyroantimonate method. The
      mitochondria of oocytes from all types of follicles had the highest levels of
      calcium deposits of all oocyte compartments, with the exception of primary
      follicles, in which oocyte nuclei contained the same level of calcium deposits as
      the mitochondria. Calcium deposits in the cytoplasm of oocytes from primary
      follicles were significantly lower than those in the cytoplasm of oocytes from
      secondary and antral follicles. Calcium deposits in the cytoplasm of granulosa
      cells were significantly lower than calcium deposits in the mitochondria of
      granulosa cells and this difference persisted throughout all categories of
      follicles. Calcium deposits in the nuclei of granulosa cells did not differ from
      levels in the mitochondria in primary and secondary follicles. In contrast, the
      nuclei of granulosa cells from antral follicles had lower levels of calcium
      deposits than the mitochondria. The differences observed in calcium deposits in
      various cellular compartments in oocytes and granulosa cells in the follicles of
      ovaries of adult mice can be attributed to their acquisition of meiotic
      competence and follicular development.

PMID- 15018779
TI  - Interferon-alpha-like biological activity in human seminal plasma, follicular
      fluid, embryo culture medium, amniotic fluid and fetal blood.
AB  - Interferons (IFNs) are a group of cytokines exhibiting antiviral,
      antiproliferative and immunoregulatory properties. The principal stimulus for the
      synthesis of IFNs is the presence of viral double-stranded RNA, although rare
      examples of constitutive synthesis have also been described. The aim of the
      present study was to determine IFN-alpha-like biological activity in the seminal
      plasma, follicular and amniotic fluid, embryo culture medium, and fetal blood
      obtained from patients without apparent viral or bacterial infections. Interferon
      alpha-like biological activity was determined by a standard cytopathic effect
      inhibition bioassay. The study included two groups of patients. The first group
      consisted of 30 married couples participating in the programme for assisted
      reproduction and the second group consisted of 23 patients scheduled for prenatal
      diagnosis (15 for amniocentesis and eight for cordocentesis). The seminal plasma
      of infertile men (asthenozoospermia, oligoasthenozoospermia) contained a high
      titre of IFN-alpha-like antiviral activity. Asthenozoospermia was diagnosed in
      men with a normal sperm concentration but less than 50% progressively motile
      sperm and oligoasthenozoospermia was diagnosed in men with a sperm count less
      than 1 x 10(6) mL(-1). Despite slightly higher antiviral titres in the seminal
      plasma obtained from asthenozoospermic patients, no clear association between IFN
      alpha-like biological activity and sperm concentration was found. Interferon
      alpha-like biological activity was found in all samples of follicular and
      amniotic fluid and in fetal blood of patients with intrauterine growth
      retardation and trisomy 18. Antiviral titres from seminal plasma and follicular
      fluids were significantly higher compared with amniotic fluids and fetal blood.
      Embryo culture medium did not contain IFN-alpha-like biological activity. Our
      results demonstrate that IFN-alpha-like activity in biological fluids is relevant
      for reproduction, even in the absence of infection.

PMID- 15018780
TI  - Immune response of the tammar wallaby (Macropus eugenii) to sperm antigens.
AB  - In the present study, male and female tammar wallabies were immunised with whole
      tammar wallaby sperm in adjuvant. An assay for sperm antibodies using a live
      sperm ELISA has been developed to detect sperm surface antigens and used to
      validate an assay using a 3-[(3-cholamidopropyl) dimethylammonio]-1
      propanesulfonate (CHAPS) membrane extract of whole tammar wallaby sperm. The
      tests were used to monitor the immune response to whole sperm in both male and
      female tammar wallabies. Antisera with a limited array of specificities were
      generated, with those locating to the midpiece region of the sperm appearing the
      most likely candidates for targets for fertility perturbation based on
      immunofluorescence of fixed and non-fixed sperm. These systemically generated
      antibodies were demonstrated to have access to both the female and male tammar
      reproductive tracts and were found on ejaculated sperm and antibodies from female
      sera and follicular fluid-labelled fresh ejaculated sperm from non-immunised
      males. Preliminary sequencing of these proteins has identified some possibilities
      for further investigation.

PMID- 15018781
TI  - Development of in-vitro-derived bovine embryos in protein-free media: effects of
      amino acids, glucose, pyruvate, lactate, phosphate and osmotic pressure.
AB  - In experiment 1, the effects of a group of either 20 (i.e. glutamine + essential
      + non-essential) or 11 (i.e. hamster embryo culture medium (HECM)-6) amino acids
      were evaluated in modified potassium simplex optimised medium (mKSOM) or basic
      medium (BM)-3. In experiment 2, the effects of glucose, pyruvate, lactate,
      phosphate or all four substrates were evaluated in low- or high-osmotic pressure
      BM-3 (255 and 275 mOsmol respectively) containing 20 amino acids (BM-3-20aa). In
      experiment 1, mKSOM containing 20 amino acids (mKSOM-20aa) supported the highest
      frequency of total, expanded (Days 7, 8 and 9) and hatched blastocysts. In
      experiment 2, supplement type affected the frequency of development to at least
      the morula stage (Day 7), expanded (Day 8), hatched (Day 9) or total blastocysts
      and cell number per blastocyst. Osmotic pressure affected the frequency of
      expanded blastocysts (Day 7) and blastocyst cell number. Regardless of the
      osmotic pressure, BM-3-20aa containing glucose (0.2 mM) supported the highest
      frequency of blastocyst development. The interaction between supplement type and
      osmotic pressure was not significant; however, treatment mean differences were
      more marked in high- than in low-osmotic pressure medium. In conclusion, the
      beneficial effects of amino acids on in vitro embryo development are influenced
      by the base medium. Moreover, glucose-containing media supported a higher
      frequency of embryonic development than pyruvate- and/or phosphate-supplemented
      media, indicating that glucose plays more important roles in non-energy
      generating pathways.

PMID- 15018782
TI  - Effect of a gonadotrophin-releasing hormone antagonist on luteinising hormone
      secretion and early pregnancy in gilts.
AB  - The aims of the present study were: (1) to determine the duration of suppression
      of luteinising hormone (LH) following a single treatment with a gonadotrophin
      releasing hormone (GnRH) antagonist (BIM-21009; Biomeasure) at a dose of 100
      microg kg(-1); (2) to block LH pulses only for certain days of pregnancy; and (3)
      to determine the period of early pregnancy most susceptible to suppression of LH.
      Three groups of gilts were injected with 100 microg kg(-1) on Day 16 (n = 5), 14
      (n = 6) or 19 (n = 4) of pregnancy. Blood for LH analysis was collected at 20-min
      intervals for 12 h on the day before treatment and during varying stages of early
      pregnancy. Blood for progesterone analysis was collected daily and development of
      pregnancy was followed using real-time ultrasound. Prior to treatment, gilts had
      2.6 +/- 0.7 LH pulses per 12 h. The GnRH antagonist abolished LH pulses for a
      period of 2.7 +/- 1.8 days and, thereafter, suppressed the resumed LH pulses (P <
      0.05). Pregnancy was disrupted in three pigs (20%) with a mean treatment-to
      abortion period of 4.7 days concurrent with a mean treatment-to-progesterone
      decline interval of 4.3 days. In a proportion of pigs, short-term LH suppression
      may cause early disruption of pregnancy.

PMID- 15018783
TI  - Fast detection of fluoroacetamide in body fluid using gas chromatography-mass
      spectrometry after solid-phase microextraction.
AB  - A novel method for fast determination of fluoroacetamide, a kind of organic
      fluorine pesticide, in blood and urine samples was developed with acetamide as an
      internal standard using gas chromatography/mass spectrometry (GC/MS) after solid
      phase microextraction (SPME) technique. The SPME was performed by immersing a
      PDMS fiber of 100 microm coating thickness in a sample solution for 25 min at 70
      degrees C with (CH(3)CH(2))(4)NBr to improve the extraction efficiency. After a
      GC sample injection, the extracted fluoroacetamide was desorbed from the fiber
      for 4 min to perform the GC/MS detection with a HP-PLOT Q capillary column. The
      analytical conditions were optimized by examining systematically, the effects of
      experimental parameters on the ratio of characteristic ion peak areas of
      fluoroacetamide to acetamide. Under optimal conditions, the ratio was
      proportional to the concentration of fluoroacetamide ranging from 5.0 to 90
      microg/ml with a detection limit of 1.0 microg/ml. The average recovery of
      fluoroacetamide in blood sample was 92.2%. The established method could be used
      for the fast and convenient measurement of fluoroacetamide in poisoned sample.

PMID- 15018784
TI  - Systematic study of long-term stability of 3,4-dihydroxyphenylglycol in plasma
      for subsequent determination with liquid chromatography.
AB  - The effect of three storage temperature levels (i.e. +4, -20 and -80 degrees C)
      and time intervals from sampling (3, 6 and 9 months) on the degradation of 3,4
      dihydroxyphenylglycol (DHPG) and norepinephrine (NE) was investigated in a
      systematic study. Extracted human plasma samples and acidified standard solutions
      were stored for long periods (up to 9 months) without the addition of any
      stabilizing agent. DHPG and NE values, determined using a ion-pair reversed-phase
      high-performance liquid chromatography method with electrochemical detection of
      coulometric type (IP-RP-HPLC-CD), remained constant over time in those plasma
      samples and standard solutions that had been stored at the lowest storing
      temperature (i.e. -80 degrees C). The expected degradation was observed at higher
      temperature levels. Plasma and standard DHPG degradation can, therefore, be
      prevented by storing samples at a lower temperature than previously suggested
      with no need to add any stabilizing agent.

PMID- 15018785
TI  - Simultaneous determination of clozapine, olanzapine, risperidone and quetiapine
      in plasma by high-performance liquid chromatography-electrospray ionization mass
      spectrometry.
AB  - Clozapine (CLZ), olanzapine (OLZ), risperidone (RIP) and quetiapine (QTP) have
      been widely used in the treatment of schizophrenia. However, no study (or little
      study) has been conducted to determine the four drugs simultaneously by the use
      of high-performance liquid chromatography-electrospray ionization mass
      spectrometry (HPLC-MS/ESI). OBJECTIVE: To develop a sensitive method for
      simultaneous determination of CLZ, OLZ, RIP and QTP in human plasma by HPLC
      MS/ESI. METHODS: The analytes were extracted twice by ether after samples had
      been alkalinized. The HPLC separation of the analytes was performed on a MACHEREY
      NAGEL C(18) (2.0 mm x 125 mm, 3 microm, Germany) column, using water (formic
      acid: 2.70 mmol/l, ammonium acetate: 10 mmol/l)-acetonitrile (53:47) as mobile
      phase, with a flow-rate of 0.16 ml/min. The compounds were ionized in the
      electrospray ionization (ESI) ion source of the mass spectrometer and were
      detected in the selected ion recording (SIR) mode. RESULTS: The calibration
      curves were linear in the ranges of 20-1000 ng/ml for CLZ and QTP, 1-50 ng/ml for
      OLZ and RIP, respectively. The average extraction recoveries for all the four
      analysts were at least above 80%. The methodology recoveries were higher than 91%
      for the analysts. The intra- and inter-day R.S.D. were less than 15%. CONCLUSION:
      The method is accurate, sensitive and simple for routine therapeutic drug
      monitoring (TDM) and for the study of the pharmacokinetics of the four drugs.

PMID- 15018786
TI  - Measurement of the anticancer agent gemcitabine and its deaminated metabolite at
      low concentrations in human plasma by liquid chromatography-mass spectrometry.
AB  - A liquid chromatography/mass spectrometry (LC-MS) method has been developed and
      validated for the determination of the anticancer agent gemcitabine (dFdC) and
      its metabolite 2',2'-difluoro-2'-deoxyuridine (dFdU) in human plasma. An
      Oasis((R)) HLB solid phase extraction cartridge was used for plasma sample
      preparation. Separation of the analytes was achieved with a YMC ODS-AQ (5 microm,
      120 A, 2.0 mm x 150 mm) column. The initial composition of the mobile phase was
      2% methanol/98% 5mM ammonium acetate at pH 6.8 (v/v), and the flow rate was 0.2
      ml/min. An isocratic gradient was used for 3min, followed by a linear gradient
      over 4 min to 30% methanol/70% 5mM ammonium acetate at pH 6.8. The gradient
      returned to the initial conditions over 2 min and remained there for 6 min. The
      retention times of dFdC, dFdU, and the internal standard 5'-deoxy-5-fluorouridine
      (5'-DFUR) were 11.46, 12.63, and 13.58 min. The mass spectrometer was operated
      under negative electrospray ionization conditions. Single-ion-monitoring (SIM)
      mode was used for analyte quantitation at m/z 262 for [dFdC-H](-), m/z 263 for
      [dFdU-H](-), and m/z 245 for [5'-DFUR-H](-). The average recoveries for dFdC,
      dFdU, and 5'-DFUR were 88.4, 84.6, and 99.3%, respectively. The linear
      calibration ranges were 5-1000 ng/ml for dFdC, and 5-5000 ng/ml for dFdU. The
      intra- and inter-assay precisions (%CV) were </=3 and </=7% at three
      concentration levels (50.0, 500, and 5000 ng/ml). The limits of quantitation
      (defined as 10 times of signal-to-noise ratio) were 3.16 ng/ml for dFdC, and 1.35
      ng/ml for dFdU with 50-microl sample injections. This method has been used for
      measuring plasma concentrations of dFdC and dFdU in samples from adult cancer
      patients in a Phase I trial of weekly dFdC given as 150 (or lower) mg/(m(2) 24-h)
      infusion. The average plasma dFdC concentrations at 22- and 23-h into the
      infusion were 18.3 and 16.8 ng/ml at 150 and 100mg/m(2), respectively; the values
      for dFdU averaged 2950 and 1372 ng/ml.

PMID- 15018787
TI  - Quantitation of Valdecoxib in human plasma by high-performance liquid
      chromatography with ultraviolet absorbance detection using liquid-liquid
      extraction.
AB  - A simple, sensitive and specific HPLC method with UV detection (210 nm) was
      developed and validated for quantitation of Valdecoxib in human plasma, the
      newest addition to the group of non-steroidal anti-inflammatory drugs-a highly
      selective cyclooxygenase-2 inhibitor. The analyte and an internal standard
      (Rofecoxib) were extracted with diethyl ether/dichloromethane (70/30 (v/v)). The
      chromatographic separation was performed on reverse phase ODS-AQ column with an
      isocratic mobile phase of water/methanol (47/53 (v/v)). The lower limit of
      quantitation was 10 ng/ml, with a relative standard deviation of <20%. A linear
      range of 10-500 ng/ml was established. This HPLC method was validated with
      between-batch and within-batch precision of 1.27-7.45 and 0.79-6.12%,
      respectively. The between-batch and within-batch bias was 0.74-7.40 and -0.93 to
      7.70%, respectively. Frequently coadministered drugs did not interfere with the
      described methodology. Stability of Valdecoxib in plasma was excellent, with no
      evidence of degradation during sample processing (autosampler) and 30 days
      storage in a freezer. This validated method is suitable for bioequivalence
      studies following single dose in healthy volunteers.

PMID- 15018788
TI  - Determination of paeoniflorin in rat hippocampus by high-performance liquid
      chromatography after intravenous administration of Paeoniae Radix extract.
AB  - A rapid and simple high-performance liquid chromatographic (HPLC) assay for the
      determination of paeoniflorin in rat hippocampus was developed in this study. The
      chromatographic analysis was carried out using reversed-phase isocratic elution
      with a Zorbax SB-C(18) column, a mobile phase of methanol-water (32:68, v/v), and
      detection by ultraviolet (UV) absorption at 233 nm. The lower limits of
      quantitation (LLQ) were 1 microg/ml for paeoniflorin. The calibration curve for
      paeoniflorin was linear (r = 0.9999) over the concentration range of 1-50
      microg/ml. The coefficients of variation of intra- and inter-day assays were
      7.00, 0.58, 1.46% and 5.48, 1.79, 1.70% at concentrations of 1, 10, 50 microg/ml,
      respectively. The recoveries of paeoniflorin from rat hippocampus were 98.28 +/-
      2.14, 98.96 +/- 1.48, and 95.34 +/- 0.92 at concentrations of 1, 10 and 50
      microg/ml, respectively. Stability studies showed that paeoniflorin was stable at
      temperatures of 2-8 degrees C in methanol for at least 20 days. The method was
      applied to determine the time course of paeoniflorin in rat hippocampus,
      following the administration of a 60 mg/kg i.v. dose of paeoniflorin in Paeoniae
      Radix extract to a male Wistar rat.

PMID- 15018789
TI  - Analysis of glycerophosphoinositol by liquid chromatography-electrospray
      ionisation tandem mass spectrometry using a beta-cyclodextrin-bonded column.
AB  - Glycerophosphoinositol (GroPIns) has been demonstrated to have important roles in
      many intracellular regulatory processes. GroPIns has been analysed for many years
      by anion-exchange HPLC after radiolabelling of cells in culture, but no method
      has been developed, to our knowledge, for the direct detection and quantitation
      of the unlabelled compound in such biological samples. Here is reported a liquid
      chromatography-tandem mass spectrometry (LC-MS/MS) method for the direct
      quantitative analysis of GroPIns that can indeed be applied to cell extracts.
      Analyses were performed on a beta-cyclodextrin-bonded HPLC column using a binary
      mobile phase of acetonitrile and 20 mM ammonium formate in water, which allowed
      direct on-line detection by tandem mass spectrometry in negative electrospray
      ionisation (ESI) mode. The method was applied to the quantitative analysis of
      GroPIns in selected rat cell lines after a two-phase acid extraction of cultured
      cells using external calibration. The potential matrix signal suppression effects
      were investigated by the parallel quantitation of GroPIns in extracts of selected
      cultured cell lines with both external calibration and the standard additions
      method. The accuracy data obtained demonstrated the feasibility of external
      calibration, so allowing a simpler and less time-consuming approach than that of
      the standard additions method.

PMID- 15018790
TI  - Determination of nimodipine in human plasma by a sensitive and selective liquid
      chromatography-tandem mass spectrometry method.
AB  - A sensitive and highly selective liquid chromatography-tandem mass spectrometry
      (LC-MS-MS) method was developed to determine nimodipine in human plasma. The
      analyte and internal standard nitrendipine were extracted from plasma samples by
      n-hexane-dichloromethane-isopropanol (300:150:4, v/v/v), and chromatographed on a
      C(18) column. The mobile phase consisted of methanol-water-formic acid (80:20:1,
      v/v/v). Detection was performed on a triple quadrupole tandem mass spectrometer
      by selected reaction monitoring (SRM) mode via atmospheric pressure chemical
      ionization (APCI) source. The method has a limit of quantification of 0.24 ng/ml.
      The linear calibration curves were obtained in the concentration range of 0.24-80
      ng/ml. The intra- and inter-day precisions were lower than 4.4% in terms of
      relative standard deviation (R.S.D.), and the accuracy ranged from 0.0 to 5.8% in
      terms of relative error (RE). This validated method was successfully applied for
      the evaluation of pharmacokinetic profiles of nimodipine tablets administered to
      18 healthy volunteers.

PMID- 15018791
TI  - Simultaneous determination of levodopa and 3-O-methyldopa in human plasma by
      liquid chromatography with electrochemical detection.
AB  - A simple and rapid assay is described for the simultaneous analysis of levodopa
      (l-DOPA) and 3-O-methyldopa (3-OMD) in human plasma samples, applying an ion-pair
      reversed-phase liquid chromatographic method with electrochemical detection,
      designed for clinical trials performed to study the effect of peripheral catechol
      O-methyltransferase inhibitors on the metabolism of l-DOPA. After protein
      precipitation of 100 microl plasma sample aliquots with perchloric acid, the
      analytes are directly injected, separated within 10 min and simultaneously
      quantified down to 20 ng/ml by an electrochemical detector equipped with a dual
      electrode system operating in redox mode eliminating effectively potential
      endogenous and exogenous interferences. The intra-assay precision for l-DOPA and
      3-OMD was 1.34-6.54 and 3.90-5.50%, whereas the inter-assay precision was 2.09
      7.69 and 4.16-9.90%, respectively. The recoveries were close to 90% for l-DOPA
      and almost 100% for 3-OMD. Satisfactory storage stability was achieved for up to
      16 weeks at -70 degrees C by stabilizing plasma samples with antioxidants.

PMID- 15018792
TI  - Validation of a gas chromatography-mass spectrometry method for the determination
      of pg/ml levels of 17beta-estradiol and 17beta-trenbolone in bovine serum.
AB  - A method for the quantitation of pg/ml levels of 17beta-estradiol and 17beta
      trenbolone in bovine serum by gas chromatography/electron-capture mass
      spectrometry has been developed and validated. Using the area ratios of the
      integrated molecular-ion peaks of the analytes to their corresponding deuterated
      internal standards, [2,4,16,16-2H4] 17beta-estradiol (17beta-estradiol-d(4)) and
      [16,16-2H2] 17beta-trenbolone (17beta-trenbolone-d(2)), and non-weighted linear
      regression, two calibration curves per analyte; 5-50 and 50-500 pg/ml for 17beta
      estradiol in sera, and 25-250 and 250-2500 pg/ml for 17beta-trenbolone in sera,
      respectively, were constructed. Splitless injection of 200 fg 17beta-estradiol
      and 1000 fg 17beta-trenbolone could be detected and quantified. Tested batches of
      control bovine sera did not exhibit interference for 17beta-trenbolone, and
      showed expected background presence of endogenous 17beta-estradiol. Intra-day
      residual errors did not exceed 20%, and regression correlations were greater than
      0.99. Intra-day precision data was similar to inter-day precision data. Using
      this method, 16 samples can be processed within one working day.

PMID- 15018793
TI  - Simple chromatography method for simultaneous determination of dextromethorphan
      and its main metabolites in human plasma with fluorimetric detection.
AB  - Dextromethorphan, the innocuous non-narcotic antitussive agent, is the most
      widely used probe drug to assess CYP2D6 function both in vivo and in vitro. For
      this reason a simple and selective high performance liquid chromatography method
      with fluorimetric detection for simultaneous quantitation of dextromethorphan,
      and its main metabolites in human plasma was developed and validated. The method
      involved a simple and rapid protein precipitation protocol, using a mixture of
      ZnSO(4) and methanol. The analysis was performed on a 3 microm, C(18) Tracer
      Excel 15 cm x 0.4 cm i.d. column by gradient elution in which Mobile phase A
      consisted of potassium dihydrogen phosphate buffer (pH = 3, 0.01
      M):methanol:tetrahydrofuran (68.5:31:0.5), and mobile phase B consisted of
      methanol:tetrahydrofuran (93.25:6.75). Linear calibration curves were obtained in
      the range of 10-500 ng/ml for dextromethorphan, dextrorphan and hydroxymorphinan.
      The limit of quantitation (LOQ) was 10 ng/ml for each compound. The maximum
      within and between days precisions were 7.4 and 7.8%, respectively. The
      accuracies at four different concentration levels ranged from 88.2 to 111.5%. The
      recoveries were between 88.0 and 108.6%. The assay method was successfully
      applied to determine dextromethorphan metabolic ratio after an oral dose of 30 mg
      of dextromethorphan hydrobromide.

PMID- 15018794
TI  - Determination of nicotine and cotinine in tobacco harvesters' urine by solid
      phase extraction and liquid chromatography.
AB  - A solid-phase extraction method using Drug Test-1 column containing chemically
      modified silica as a solid support for sample clean up and reversed phase ion
      paired high-pressure liquid chromatography method have been developed for the
      simultaneous determination of nicotine and its metabolite cotinine from the urine
      samples. Mobile phase was consisted of acetate buffer (containing 0.03 M sodium
      acetate and 0.1 M acetic acid) pH 3.1 and acetonitrile (78:22% (v/v)) containing
      0.02 M sodium octanosulfonate as an ion pair agent. pH of the mobile phase was
      adjusted to 3.6 with triethylamine for better resolution and to prevent peak
      tailing. The linearity was obtained in the range of 0.5-10 microg/ml
      concentrations of nicotine and cotinine standards. The correlation coefficients
      were 0.998 for cotinine and 0.999 for nicotine. The recoveries were obtained in
      the range of 79-97% with average value of 85% for nicotine and in the range of 82
      98% with average value of 88% for cotinine. The limit of detection was 2 ng/ml
      for cotinine and 5 ng/ml for nicotine with 2 ml urine for extraction, calculated
      by taking signal to noise ratio 10:3. The intra-day co-efficient of variation
      (CV) were <4 and 7% and inter-day CV were <9 and 7% for nicotine and cotinine,
      respectively. The method was applied to the urine samples of tobacco harvesters,
      who suffer from green tobacco sickness (GTS) to check the absorption of nicotine
      through dermal route during the various processes of tobacco cultivation due to
      its good reproducibility and sensitivity.

PMID- 15018795
TI  - Determination of the glucocorticoids prednisone, prednisolone, dexamethasone, and
      cortisol in human serum using liquid chromatography coupled to tandem mass
      spectrometry.
AB  - Glucocorticoids are an important component of immunosuppressive therapy for solid
      organ transplantation. A method to quantitate prednisone, prednisolone,
      dexamethasone and cortisol in human serum has been developed. Analysis is
      performed utilizing reversed-phase liquid chromatography coupled to tandem mass
      spectrometry. The method was validated to a lower limit of quantitation of 5.4
      ng/ml for prednisone and cortisol, and 10.7 ng/ml for dexamethasone and
      prednisolone, with error below 7% at the lower limits. The between-day relative
      standard deviations ranged 2.9-7.1%. Comparison of cortisol analysis to an
      established method using clinical samples yielded differences below 15% for 26 of
      28 determinations.

PMID- 15018796
TI  - Determination of picogram levels of midazolam, and 1- and 4-hydroxymidazolam in
      human plasma by gas chromatography-negative chemical ionization-mass
      spectrometry.
AB  - Midazolam is a widely accepted probe for phenotyping cytochrome P4503A. A gas
      chromatography-mass spectrometry (GC-MS)-negative chemical ionization method is
      presented which allows measuring very low levels of midazolam (MID), 1-OH
      midazolam (1OHMID) and 4-OH midazolam (4OHMID), in plasma, after derivatization
      with the reagent N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide. The
      standard curves were linear over a working range of 20 pg/ml to 5 ng/ml for the
      three compounds, with the mean coefficients of correlation of the calibration
      curves (n = 6) being 0.999 for MID and 1OHMID, and 1.0 for 4OHMID. The mean
      recoveries measured at 100 pg/ml, 500 pg/ml, and 2 ng/ml, ranged from 76 to 87%
      for MID, from 76 to 99% for 1OHMID, from 68 to 84% for 4OHMID, and from 82 to
      109% for N-ethyloxazepam (internal standard). Intra- (n = 7) and inter-day (n =
      8) coefficients of variation determined at three concentrations ranged from 1 to
      8% for MID, from 2 to 13% for 1OHMID and from 1 to 14% for 4OHMID. The percent
      theoretical concentrations (accuracy) were within +/-8% for MID and 1OHMID,
      within +/-9% for 4OHMID at 500 pg/ml and 2 ng/ml, and within +/-28% for 4OHMID at
      100 pg/ml. The limits of quantitation were found to be 10 pg/ml for the three
      compounds. This method can be used for phenotyping cytochrome P4503A in humans
      following the administration of a very low oral dose of midazolam (75 microg),
      without central nervous system side-effects.

PMID- 15018797
TI  - Characterisation and quality assessment of binding sites on a propazine-imprinted
      polymer prepared by precipitation polymerisation.
AB  - In this paper, the Langmuir-Freundlich isotherm (LF) is used to characterise a
      propazine-imprinted polymer obtained by precipitation polymerisation (MIP-P).
      Different rebinding studies were carried out allowing to explain the different
      interactions taking place between the molecularly imprinted polymer and six
      triazinic herbicides (desisopropylatrazine, desethylatrazine, simazine, atrazine,
      propazine and prometryn). The LF fitting parameters obtained (total number of
      binding sites, heterogeneity index and mean binding affinity) were compared to
      those obtained in a previous work for a propazine-imprinted polymer prepared by
      bulk polymerisation (MIP-B). From that study, it was concluded that precipitation
      polymerisation yielded polymers with a more homogeneous binding site distribution
      and higher affinity constants.

PMID- 15018798
TI  - Liquid chromatography method for determination of bivalirudin in human plasma and
      urine using automated ortho-phthalaldehyde derivatization and fluorescence
      detection.
AB  - A high-performance liquid chromatographic (HPLC) method was developed using solid
      phase extraction, o-phthalaldehyde (OPA) derivatization and fluorescence
      detection for the determination of the direct thrombin inhibitor bivalirudin in
      human plasma and urine. The use of this assay will facilitate the study of the
      pharmacodynamics of bivalirudin in studies of special patient populations. A
      C(18) bioanalytical column at a flow rate of 1 ml/min with an aqueous
      trifluoroacetic acid (0.1% TFA in deionized water, pH 2.2, v/v) mobile phase and
      methanol gradient was used. The assay demonstrated linearity from 3 to 20
      microg/ml bivalirudin in plasma, with a detection limit of 1 microg/ml. The
      method was utilized in a study evaluating the pharmacokinetic and pharmacodynamic
      effects of bivalirudin in patients undergoing percutaneous coronary interventions
      (PCIs).

PMID- 15018799
TI  - Development of a gas chromatographic test for the quantification of the biomarker
      3-bromopropionic acid in human urine.
AB  - An accurate and precise method was developed for the detection and quantification
      of 3-bromopropionic acid (3-BPA), a metabolite and biomarker for exposure to 1
      bromopropane (1-BP). 1-BP is used as an industrial solvent and exposure is a
      health concern for industrial workers due to its toxicity. It has been associated
      with neurological disorders in both animals and humans. Urine sample preparation
      for the determination of 3-BPA consisted of liquid-liquid extraction (LLE) with
      ethyl acetate and silylation with N-methyl-N-[tert
      butyldimethylsilyl]trifluoroacetamide (MTBSTFA). Quantification was by means of a
      gas chromatograph (GC) equipped with a mass selective detector (MSD) using a
      dimethylpolysiloxane (HP-1) capillary column and 3-chloropropionic acid was used
      as an internal standard in the procedure. Demonstrated accuracy and precision
      during this method's validation was good; recovery varied between 93 and 98% with
      relative standard deviations (R.D.S.) of 5.7% or less. The limit of detection
      (LOD) for the procedure was approximately 0.01microg/ml 3-BPA in urine. These
      data and other factors of the development and validation of this test method will
      be discussed.

PMID- 15018800
TI  - Determination of myo-inositol in biological samples by liquid chromatography-mass
      spectrometry.
AB  - Due to the absence of HPLC methods to determine myo-inositol using mass detection
      and considering its sensitivity and selectivity, a high performance liquid
      chromatography-mass spectrometry method for the analysis of myo-inositol is
      described and applied to its direct determination in urine and saliva samples.
      Successful resolution of myo-inositol and its related substances was achieved
      with a stationary phase Aminex HPX-87C Column with milli-Q water as mobile phase
      and 5 mM ammonium acetate added post-column. The detector counted positive ions
      by monitoring m/z = 198, which corresponds to the myo-inositol adduct with
      ammonium cation. Urine and saliva samples were previously purified by passing
      through an anion-exchange resin. Concentrations as low as 138 and 461 microg/l in
      saliva and urine could be respectively quantified. Intra-day R.S.D. ranged from
      0.83 to 1.02%, whereas inter-day R.S.D. was between 1.54 and 3.58%.

PMID- 15018801
TI  - Electron ionization gas chromatography-mass spectrometric determination of
      residues of thirteen pyrethroid insecticides in whole blood.
AB  - A new rapid and sensitive electron ionization gas chromatography-mass
      spectrometry method in selective ion monitoring mode (SIM) was developed for the
      determination of l3 synthetic pyrethroid insecticide molecules and their stereo
      isomers in whole blood. The pyrethroid insecticides investigated are allethrin,
      bifenthrin, cypermethrin, cyphonothrin, cyfluthrin, lambda-cyhalothrin,
      deltamethrin, fenvalerate, fenpropathrin, imiprothrin, permethrin, prallethrin
      and transfluthrin. The residues of pyrethroids are extracted from the whole blood
      using hexane and acetone mixture (80 + 20%) as solvent. All the pyrethroid
      residues were separated by using a gas chromatography-mass spectrometry operated
      in electron ionization mode and quantified in selective ion monitoring mode. The
      method can detect the residues of different pyrethroids down to the level 0.05-2
      ng/ml. Recovery experiments conducted in whole blood samples at the fortification
      level 1-1000 ng/ml showed 91-103% recovery. The applications of the analytical
      method for the determination of pyrethroid residues in real samples were tested
      by analyzing 45 human blood samples collected from the population exposed
      continuously to different pyrethroid based formulations. The results are
      confirmed by spiking the known quantity of pyrethroids and subsequently their
      positive detection.

PMID- 15018802
TI  - Rapid determination of metformin in human plasma by liquid chromatography-tandem
      mass spectrometry method.
AB  - A rapid, sensitive and specific liquid chromatography-tandem mass spectrometry
      method is described for quantitation of metformin in human plasma. After a
      simple, one-step protein precipitation using acetonitrile, metformin and the
      internal standard diphenhydramine were chromatographed on a C(8) column and
      detected by tandem mass spectrometry. An atmospheric pressure chemical ionization
      interface was chosen to reduce ion suppression from sample matrix components and
      provide high sensitivity. The method has a chromatographic total run time of 3.4
      min and was linear within the range 2-2000 ng/ml. Intra- and inter-day precision,
      expressed as the relative standard deviation (R.S.D.), ranged from 4.4 to 5.7%
      and from 1.3 to 2.8%, respectively. Assay accuracy was less than 1% in terms of
      %RE (relative error). The assay was used to evaluate the pharmacokinetics of
      metformin after an oral administration of multicomponent formulation containing
      500 mg metformin and 2.5 mg glyburide to 20 healthy volunteers.

PMID- 15018803
TI  - A novel mRNA expressed along brain ventricles.
AB  - The present descriptive study shows the expression pattern of an mRNA, IIIG9,
      whose most striking expression is seen along the lining of all four ventricles of
      the adult rat brain. Lower levels of expression are evident in other areas of the
      brain, notably in cortex, hippocampus, and various thalamic, hypothalamic and
      brainstem nuclei where it seems to be primarily neuronal, with little or no
      expression in white matter tracts. However, expression in cells on both sides of
      the basement membrane of the ependyma suggests expression in other cell types
      such as astrocytes, neuroblasts and putative precursors (subependyma), as well as
      ependymal cells and tanycytes. In the periphery, ovary had an expression level
      similar to the brain, whereas testes had a much higher level of expression.

PMID- 15018804
TI  - Microarray analysis of brain RNA in mice with methylenetetrahydrofolate reductase
      deficiency and hyperhomocysteinemia.
AB  - Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common genetic
      cause of hyperhomocysteinemia, which is associated with increased risk for
      cardiovascular disease, stroke and possibly other neurological disorders.
      Microarray analysis of brain RNA from day 14 Mthfr(-/-) mice revealed several
      genes with altered expression. Expression changes in inositol 1,4,5-triphosphate
      receptor, type 1 (Itpr1), proteolipid protein (Plp), neurogenic differentiation
      factor 1 (Neurod1), S100 calcium binding protein A8 (S100a8), and
      methylenetetrahydrofolate dehydrogenase (NAD+ dependent),
      methenyltetrahydrofolate cyclohydrolase (Mthfd2) were confirmed by RT-PCR. We
      propose that neuronal damage by hyperhomocysteinemia may involve disruption of
      intracellular calcium.

PMID- 15018805
TI  - A new UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase mRNA exhibits
      predominant expression in the hypothalamus, thalamus and amygdala of mouse
      forebrain.
AB  - Protein glycosylation is a common and important process that can alter the
      stability, half-life, biological activity and receptor recognition of target
      molecules. We have identified a new putative mouse UDP-GalNAc:polypeptide N
      acetylgalactosaminyltransferase family member, termed GalNAc-T10/ppGaNTase-T10
      (gene symbol Galnt10), and determined its expression pattern in mouse CNS using
      in situ hybridization analysis. Results demonstrated predominant expression of
      Galnt10 in several distinct hypothalamic, thalamic and amygdaloid nuclei. The
      most abundant hybridization levels were observed in the paraventricular,
      ventromedial and arcuate nuclei of the hypothalamus, the anterodorsal and
      parafascicular nuclei of the thalamus and the central, basomedial and medial
      nuclei of the amygdala. Expression of Galnt10 was also detected in cerebral
      cortex, lateral septum, habenula and hippocampus. The localization of this
      putative glycosyltransferase in distinct regions within the CNS indicates the
      specificity for complex protein modifications and suggests that region-specific
      glycosylation represents an essential process in basic biological functions.

PMID- 15018806
TI  - In vivo CREB phosphorylation mediated by dopamine and NMDA receptor activation in
      mouse hippocampus and caudate nucleus.
AB  - The pattern of CREB phosphorylation was investigated in the caudate nucleus and
      hippocampus 10 min or 3 h after i.p. injection of dopamine or NMDA receptor
      agonists alone, or in combination with antagonists. Ten minutes after C57BL/6 J
      mice were injected with either the dopamine D1 receptor agonist SKF-38393
      hydrobromide or NMDA, immunoreactivity of phosphorylated CREB (pCREB) was
      significantly increased in all parts of the caudate nucleus but not in
      hippocampal regions. However, 3 h after the injection of SKF-38393, pCREB levels
      in the caudate nucleus did not differ significantly from the pCREB levels in
      control animals, whereas pCREB levels were still elevated 3 h after NMDA
      injection. Except for the D1 receptor antagonist SCH-23390, which induced CREB
      phosphorylation in the caudate nucleus, dopamine and NMDA receptor antagonists
      had little effect on pCREB levels by themselves. However, the NMDA receptor
      antagonist CGS-19755 injected i.p. blocked both the NMDA- and SKF-38393-induced
      rise of pCREB levels in the caudate nucleus. Similarly, the D1 receptor
      antagonist SCH-23390 inhibited the effects produced by SKF-38393 or NMDA.
      Interestingly, the D2 receptor antagonist sulpiride also blocked the SKF-38393
      triggered rise of pCREB. The results demonstrated that NMDA and dopamine
      receptors modulate pCREB levels in the caudate nucleus and suggest mutual
      permissive roles for both receptors.

PMID- 15018807
TI  - Expression of Apc2 during mouse development.
AB  - APC2 (previously known as APCL), a molecule closely related to the adenomatous
      polyposis coli (APC) tumor suppressor, can deplete cytoplasmic beta-catenin, like
      APC itself. Recently, it has been shown that APC2 may regulate the localization
      of p53 and the microtubule stability and/or extension. Although it has been
      reported that APC2 mRNA is expressed in human brain, the anatomical and ontogenic
      expression patterns remain unclear. The purpose of this study was to investigate
      the distribution of mouse Apc2 during mouse development. In the adult brain, Apc2
      is expressed predominantly in neurons and throughout the brain. Northern blot
      analysis demonstrated a high level of Apc2 expression in embryonic and early
      postnatal brain. Ontogenic analysis has indicated that Apc2 is expressed in
      neural tissue, including the peripheral nervous system. During development of
      cortex, retina and cerebellum, Apc2 is expressed in post-mitotic cells. These
      findings suggest that Apc2 may contribute to the development of neuronal cells.

PMID- 15018808
TI  - Expression of the bHLH transcription factor Tcf12 (ME1) gene is linked to the
      expansion of precursor cell populations during neurogenesis.
AB  - In this study, we focused on the potential function of the murine gene Tcf12
      (also known as ME1 or HEB) encoding the bHLH E-protein ME1 during brain
      development. An exencephaly phenotype of low penetrance has consistently been
      observed in both Tcf12 null mice and Tcf12(dm) homozygous mice. Thus, to address
      the possible underlying mechanism of the Tcf12 gene during the early steps of
      brain development, we performed a detailed analysis of its spatio-temporal
      expression pattern at distinct steps of gastrulation and neurogenesis. We found
      that Tcf12 transcripts are detected in the embryonic ectoderm prior to neural
      induction during gastrulation. During neurulation, Tcf12 transcripts are evident
      at high levels in the proliferating neuroepithelium of the neural folds and the
      cephalic mesenchyme. Thus, Tcf12 gene expression coincides with the massive
      proliferation occurring in the forming neuroepithelium and cephalic mesenchyme
      during neural tube formation, which is consistent with the exencephaly phenotype
      of Tcf12 null mice. In the developing cortex and spinal cord, Tcf12 expression is
      restricted to the proliferative ventricular zones, indicating that Tcf12
      expression is down regulated when these neuronal cells undergo their final
      differentiation. Interestingly, we found that the postnatal Tcf12 expression
      parallels the ongoing adult neurogenesis in the mitotically active subventricular
      zone. Thus, the timing and location of Tcf12 expression combined with this severe
      neurulation defect support our hypothesis that the Tcf12 gene may be involved in
      the control of proliferating neural stem cells and progenitor cells and that it
      may be critical to sustain their undifferentiated state during embryonic and
      adult neurogenesis.

PMID- 15018810
TI  - ProSAAS and prohormone convertase 1 are broadly expressed during mouse
      development.
AB  - ProSAAS (encoded by mouse gene Pcsk1n) is a recently described neuroendocrine
      secretory pathway protein that is cleaved into smaller peptides that may function
      in cell-cell signalling. ProSAAS and its processing intermediates are also potent
      inhibitors of prohormone convertase 1 (PC1), which is encoded by mouse gene
      Pcsk1. In order to gain insight into the function of proSAAS, we have examined
      the distribution of several proSAAS-derived peptides and PC1 by
      immunohistochemistry throughout mouse development. The distribution patterns of
      both SAAS and PC1 are broad from E9 to E11, with some enrichment in neural tube
      derived tissues. By E15, the expression of SAAS is largely restricted to
      neuroendocrine tissues known to produce bioactive peptides. In general, the
      expression pattern of PC1 overlaps with that of SAAS and other proSAAS-derived
      peptides, consistent with the hypothesis that proSAAS functions as an endogenous
      PC1 inhibitor.

PMID- 15018811
TI  - Distribution of neuromedin U receptor subtype 2 mRNA in the rat brain.
AB  - Neuromedin U (NMU) is a family of peptides found in the gut and the central
      nervous system [Neuroscience 25 (1988) 797; Biochem. Biophys. Res. Commun. 130
      (1985) 1078]. While several peripheral activities such as uterus stimulating and
      hypertensive effects have been described for NMU [Biochem. Biophys. Res. Commun.
      130 (1985) 1078], its role in the CNS remains poorly understood. Recently, we
      reported the identification of two receptors for NMU (NMU1R and NMU2R), and
      demonstrated that NMU may play a role in regulating feeding behavior. The central
      effect of NMU is likely mediated primarily via NMU2R, since NMU1R is detectable
      only in the periphery, but not in the brain [Nature 406 (2000) 70]. In this
      report, we describe detailed mapping of NMU2R mRNA expression in the rat brain by
      in situ hybridization. The most intense signals were observed in the ependymal
      cell layer along the wall of the third ventricle in the hypothalamus, CA1 region
      of the hippocampus, indusium griseum and septohippocampal nucleus. Moderate
      expression was detected in the hypothalamic paraventricular nucleus, dorsal raphe
      nucleus as well as a number of other brain structures. The presence of NMU2R in
      the hypothalamus is consistent with its role in energy balance. Significant
      levels of expression of NMU2R elsewhere in the brain may suggest additional
      physiological functions for this neuropeptide.

PMID- 15018809
TI  - Localization of mRNAs for phosphatidylinositol phosphate kinases in the mouse
      brain during development.
AB  - The gene expression for seven phosphatidylinositol phosphate kinases (PIPKs)
      types Ialpha, Ibeta, Igamma, types IIalpha, IIbeta, IIgamma, and type III-was
      examined using in situ hybridization histochemistry, in the mouse brain during
      normal development. In the embryonic mouse brain, positive expression signals
      were detected only for the genes encoding PIPK Igamma and PIPK IIbeta in both the
      cerebral ventricular and mantle zones, with weaker signals in the former zone. On
      the other hand, the genes encoding all PIPKs were essentially detected in the
      external granule cell layer which represents the germinal zone for the neuronal
      granule cells. In the postnatal brain, among the seven PIPKs, the expression for
      genes encoding PIPK Igamma and IIbeta is evident in most gray matter, while the
      expression for the other five types was weak in the cortical gray matter and
      negligible in most non-cortical gray matter such as the diencephalon and brain
      stem nuclei. While the expression for most PIPKs in the mature hippocampus was
      distinct, the expression in the CA3 and the dentate gyrus was less definite for
      the genes encoding PIPK Ialpha and IIgamma, respectively. The distinct expression
      for the gene encoding PIPK IIalpha was detected in the postnatal white matter
      such as the cerebellar medulla, the corpus callosum, the hippocampal fimbriae,
      and the internal capsule.

PMID- 15018812
TI  - Plasminogen.
AB  - Plasminogen activator inhibitor-2 (PAI-2) specifically inhibits plasminogen
      activators, extracellular fibrinolytic serine proteases that are also implicated
      in brain plasticity and toxicity. Primarily localized intracellularly, PAI-2 is
      thought to also counteract apoptosis mediated by a currently undefined
      intracellular protease. Here we localized PAI-2 mRNA through in situ
      hybridization in brain cryosections derived from normal adult mice or after
      kainate excitation. We found that in the normal brain PAI-2 mRNA was confined to
      an area within the accumbens nucleus shell. After kainate was injected (i.p.),
      PAI-2 mRNA was substantially and rapidly (within 2 h) induced in neuron-like
      cells primarily in layers II-III of the neocortex; the cingulate, piriform,
      entorhinal and perirhinal cortices; the olfactory bulb, nucleus and tubercle; in
      the accumbens nucleus, shell and core; throughout the caudate putamen and the
      amygdaloid complex; in the CA1 and CA3 areas of the hippocampus, and in the
      parasubiculum. These findings suggest that PAI-2 could play a role in the
      accumbens nucleus as well as in activity-related events associated with
      olfactory, striatal, and limbic structures.

PMID- 15018813
TI  - Gpr85, a novel member of the G-protein coupled receptor family, prominently
      expressed in the developing mouse cerebral cortex.
AB  - The G-protein coupled receptors (GPCRs) characterized by seven transmembrane
      domains represent the largest receptor superfamily to date and are implied in
      diverse cell signaling events, its members being present in a diversity of organs
      and tissues. Here we report the expression of Gpr85, a novel member of this gene
      family during mouse embryonal development and in the adult brain. Transcripts of
      Gpr85 were detected predominantly in tissues of neuroectodermal origin. In the
      central nervous system Gpr85 was expressed during phases of early neuronal
      differentiation. Highest transcript levels were observed in the developing
      cerebral cortex, pointing to a specific function of this gene for differentiation
      processes in the cerebral cortex. In addition, expression was also detected in
      derivatives of the neural crest and developing teeth.

PMID- 15018814
TI  - Reduced neuropeptide Y mRNA levels in the frontal cortex of people with
      schizophrenia and bipolar disorder.
AB  - To study the change of gene expression in the brain tissues of schizophrenia, we
      used the gene expression monitoring technology and compared two sets of pools
      each containing four RNA samples of frontal cortex that were randomly selected
      from the control or schizophrenia group. We found that the expression of two
      genes were commonly altered in four pairwise comparisons; the expression of DEAD
      box protein p72 (p72) gene was increased and neuropeptide Y (NPY) gene expression
      was decreased in the schizophrenia group compared with the control group. To
      substantiate these results, we estimated their mRNA levels by the real time
      TaqMan method in the 15 samples of each frontal or temporal cortex of four
      matched groups of schizophrenia, bipolar disorder, major depression and normal
      controls. A statistically significant decrease was observed for NPY in the
      frontal, but not in the temporal cortex, in the schizophrenia group (P=0.003). A
      decrease was also observed in the frontal cortex of the bipolar disorder group
      (P=0.031). In contrast, p72 gene expression showed no significant difference
      among the four groups. In conclusion, by novel technology of DNA array and TaqMan
      PCR analyses, we found that neuropeptide Y mRNA levels were significantly reduced
      in the frontal cortex in both schizophrenia and bipolar disorder.

PMID- 15018815
TI  - Nasal embryonic LHRH factor (NELF) expression within the CNS and PNS of the
      rodent.
AB  - A novel protein (NELF) was identified screening embryonic luteinizing hormone
      releasing hormone (LHRH) neurons at different migrational states. Experiments in
      vitro revealed that NELF functions in olfactory axon outgrowth and subsequently
      alters LHRH neuronal migration. NELF was not restricted to LHRH neurons in the
      developing rodent. Multiple CNS and PNS tissues expressed this gene. To
      characterize the specific regions that express NELF in situ hybridization
      histochemistry was performed. Within the CNS, cells in the cortex, hippocampus,
      thalamus and olfactory regions express NELF pre- and postnatally.

PMID- 15018816
TI  - A molecular explanation of interactions between photic and non-photic circadian
      clock-resetting stimuli.
AB  - Non-photic clock-resetting events (arousal and locomotor activity) in the
      subjective day reduced expression of Period genes in the suprachiasmatic nucleus
      of hamsters. This decrease was attenuated by a 30-min light pulse occurring
      during the last 0.5 h of 3.5 h of confinement to a novel running wheel. This
      provides an example at the molecular level of an interaction between different
      modalities of synchronizing agents.

PMID- 15018817
TI  - A database for regional gene expression in the human brain.
AB  - Alterations in gene expression levels have been widely studied for various
      neurological diseases, but few studies have sought to characterize genome-wide
      gene expression patterns from various regions of the normal brain. A sensitive
      method for quantifying transcript levels, Serial Analysis of Gene Expression
      (SAGE), was used to assay expression levels in white matter, thalamus, and
      cerebellum from the same normal brain, obtained by rapid autopsy. The complete
      dataset for these SAGE libraries are posted on the Cancer Genome Anatomy Project
      sponsored SAGEmap website where library comparisons can be made, or the data
      downloaded for local analysis. The expression of several region-specific genes-
      neurogenic differentiation 1 (cerebellum), cocaine- and amphetamine-regulated
      transcript (thalamus), and neurogranin (white matter)--was confirmed using
      quantitative fluorescent real-time RT-PCR. Further informatics analysis of the
      data yielded a list of brain-specific genes. The database formed by this analysis
      provides a means to investigate the expression status of genes involved in the
      region specific functions of the normal brain. These normal brain gene expression
      levels also are useful for comparison to pathological expression levels and a
      sensitive means to determine gene expression in a normal adult brain prior to
      formulating therapeutic strategies.

PMID- 15018818
TI  - Investigation of differentially expressed genes during the development of mouse
      cerebellum.
AB  - Before the discovery of DNA microarray and DNA chip technology, the expression of
      only a small number of genes could be analyzed at a time. Currently, such
      technology allows us the simultaneous analysis of a large number of genes to
      systematically monitor their expression patterns that may be associated with
      various biological phenomena. We utilized the Affymetrix GeneChip Mu11K to
      analyze the gene expression profile in developing mouse cerebellum to assist in
      the understanding of the genetic basis of cerebellar development in mice. Our
      analysis showed 81.6% (10,321/12,654) of the genes represented on the GeneChip
      were expressed in the postnatal cerebellum, and among those, 8.7% (897/10,321)
      were differentially expressed with more than a two-fold change in their maximum
      and minimum expression levels during the developmental time course. Further
      analysis of the differentially expressed genes that were clustered in terms of
      their expression patterns and the function of their encoded products revealed an
      aspect of the genetic foundation that lies beneath the cellular events and neural
      network formation that takes place during the development of the mouse
      cerebellum.

PMID- 15018819
TI  - The expression of chicken NOV, a member of the CCN gene family, in early stage
      development.
AB  - The nephroblastoma overexpressed gene, NOV, is a member of the CCN gene family.
      We investigated the NOV gene expression pattern in the chicken during early stage
      embryogenesis. Several embryonic structures showed a distinct expression pattern.
      The initial expression was detected in Hensen's node (Hamburger and Hamilton
      stage (HH) 5). The expression was noted in the presumptive notochord and floor
      plate forming cells. The expression on the left side was more elongated
      posteriorly, a type of left-right asymmetry. Chicken NOV gene expression in the
      forming notochord and floor plate was observed until HH 18. The expression was
      also detected in the ventral area of the mesencephalon and isthmus at HH 14-16.

PMID- 15018820
TI  - Expression of cellular retinoic acid-binding protein I is specific to neurons in
      adult transgenic mouse brain.
AB  - Cellular retinoic acid binding protein I (CRABP-I) plays a role in retinoic acid
      (RA) metabolism or transport. This report shows specific neuronal expression of
      CRABP-I in adult transgenic mouse brain using CRABP-I promotor-driven lac-Z and
      neuron- and astrocyte-markers. Double staining indicates that CRABP-I is
      expressed in neurons and large cells (>12 microm) but to much lesser degree the
      astrocytes. CRABP-I-lac-Z(+) neurons were distributed throughout the brain, but
      in a very discreet pattern in each brain region. CRABP-I expression in specific
      populations of brain neurons suggests that RA is extensively metabolized in
      mature brains, mostly in neurons. Additionally, the genetic basis of its specific
      expression in these brain areas is located in the 5' regulatory region of this
      gene.

PMID- 15018821
TI  - Drosophila cholinergic neurons and processes visualized with Gal4/UAS-GFP.
AB  - Using 7.4 kb of 5' flanking DNA from the Drosophila cholinergic gene locus to
      drive Gal4 expression we can visualize essentially all cholinergic neurons and
      neuropiles after genetic recombination with a UAS-GFP (S65T) reporter gene. In
      contrast to previous methods somata and neuropiles can be observed in the same
      samples. Fluorescence intensity is strong enough to allow observations in live
      animals at all developmental stages. Three-dimensional reconstructions made from
      confocal sections of whole-mount preparations reveal the extensive cholinergic
      connections among various regions of the nervous system.

PMID- 15018822
TI  - Differentiation of benign vs. malignant mass in a postirradiation cerebral
      arteriovenous malformation by 2-deoxy-2-[18F] fluoro-D-glucose positron emission
      tomography.
AB  - This report demonstrates the findings on two 2-deoxy-2-[(18)F]fluoro-D-glucose
      positron emission tomography (FDG-PET) brain scans of a 16-year-old girl with
      previous radiation therapy for an arteriovenous malformation (AVM) that was
      transformed by radiation therapy to a mass in a deep and relatively inaccessible
      cerebral location. Clinical neurologic examination, brain CT without and with
      contrast, 1.5 T MRI of the brain without and with contrast, magnetic resonance
      angiography (MRA), (1)H magnetic resonance spectroscopic imaging (MRSI) of the
      brain, and two FDG brain PET scans were performed to characterize the lesion.
      Magnetic resonance imaging (MRI) and (1)H MR spectroscopic findings showed a mass
      and surrounding vasogenic edema in the deep left parietal lobe suggestive of
      malignant angiosarcoma. However, an FDG-PET scan of the brain identified a large
      area of hypometabolism involving the left parietal lobe. The PET findings were
      unchanged compared to a FDG-PET scan performed one year prior, suggesting that
      the lesion was benign. In addition, an MRI performed six months after the second
      PET scan was also consistent with a benign lesion, and was unchanged from the MRI
      performed two years prior. We present the first detailed imaging characteristics
      of a mass of high clinical suspicion for malignancy resulting from transformation
      of an arteriovenous malformation after radiosurgery treatment. Two FDG-PET scans
      performed for a one-year time interval provided a noninvasive method to establish
      that the lesion had nonmalignant characteristics.

PMID- 15018823
TI  - 2-Deoxy-2-[18F]fluoro-D-glucose positron emission tomography uptake in systemic
      lupus erythematosus-associated adenopathy.
AB  - Systemic lupus erythematosus (SLE) and lymphoma are disease entities that often
      have similar presenting signs and symptoms that can complicate or delay
      definitive diagnosis. 2-Deoxy-2-[(18)F]fluoro-D-glucose positron emission
      tomography (FDG-PET) has become a valuable tool in the diagnosis, staging, and
      evaluation of response to therapy in lymphoma patients. However, its utility in
      patients with SLE has been limited to the central nervous system. Significant FDG
      uptake has not been previously reported in lymphadenopathy associated with SLE.
      The case presented is an example of histologically proven benign adenopathy in a
      16-year-old female with SLE that was hypermetabolic on FDG-PET imaging. It
      highlights the importance of recognizing that widespread inflammatory adenopathy
      in SLE can mimic the pattern of FDG uptake seen with lymphoma at PET imaging.

PMID- 15018824
TI  - Acute no-effect dose for in ova exposure to C3F7 tagged 5-hydroxytryptophan, a
      novel probe for investigating neural development.
AB  - PURPOSE: To create a probe for investigating neural development in chicks using
      magnetic resonance, a C(3)F(7) tag was bonded to the indole ring of 5
      hydroxytryptophan (5-HTP). Immunoassays indicate that a low dose (5 microg/egg)
      administered in ova results in 0.5-1.0 microg accumulating in a 250 microL
      midbrain. PROCEDURES: Given the potential for developmental neurotoxicity of a
      compound that replaces an endogenous neurotransmitter, we investigated the
      effects of acute exposure during development. RESULTS: No qualitative differences
      were observed between treatment groups. Differences in mortality rates between
      treatment groups were not statistically significant [X(2)(obs)=2.30, X(2)(crit)
      (df=2)=5.99, P>.05]. CONCLUSION: The no-effect dose for in ova administration of
      C(3)F(7) tagged5-HTP is 5 microg/egg on Day 17.

PMID- 15018825
TI  - The pyridinyl-6 position of WAY-100635 as a site for radiofluorination--effect on
      5-HT1A receptor radioligand behavior in vivo.
AB  - PURPOSE: We aimed to evaluate radiofluorination at the pyridinyl-6 position of
      the selective 5-HT(1A) receptor antagonist, WAY-100635 [N-(2-(1-(4-(2
      methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide)], on 5
      HT(1A) receptor radioligand behavior in vivo. PROCEDURES: The pyridinyl-6
      [(18)F]fluoro derivative of WAY-100635 ([(18)F]6FPWAY) was obtained by direct
      nucleophilic substitution with [(18)F]fluoride ion in a bromo precursor. After
      intravenous injection of [(18)F]6FPWAY into Cynomolgus monkey, the uptake of
      radioactivity into brain regions was assessed with positron emission tomography
      (PET) and blood samples analyzed by high performance liquid chromatography (HPLC)
      for parent radioligand and radioactive metabolites. The experiment was repeated
      after pretreatment of the monkey with a dose of WAY-100635 that blocks brain 5
      HT(1A) receptors. RESULTS: After intravenous injection of [(18)F]6FPWAY into
      Cynomolgus monkey, the uptake of radioactivity into whole brain reached 4.33% of
      injected dose at 7.5 min. Uptake was highest in 5-HT(1A) receptor-rich regions.
      Pretreatment with WAY-100635 reduced uptake in these regions to near the levels
      in receptor-devoid cerebellum. [(18)F]6FPWAY was rapidly metabolized in vivo, as
      evidenced by the rapid appearance of radioactive metabolites in plasma.
      CONCLUSION: [(18)F]6FPWAY is selective and moderately useful for imaging brain 5
      HT(1A) receptors in vivo. The pyridinyl-6 position is resistant to defluorination
      and may be an attractive site for the (18)F-labeling of 6FPWAY analogs that
      resist hydrolysis.

PMID- 15018826
TI  - In vivo sampling for pharmacokinetic studies in small experimental animals: a
      combination of microdialysis, planar chromatography and digital autoradiography.
AB  - PURPOSE: We describe a method for measuring the pharmacokinetics of positron
      emission tomography (PET) tracers during rat studies using microdialysis (MD) in
      combination with planar chromatography and digital autoradiography with a
      phosphoimager plate (DAR). PROCEDURES: An MD probe was inserted into the jugular
      vein of the rat and perfused with physiological buffer solution (n>/=3). An (18)F
      labeled radiopharmaceutical was injected intravenously, and dialysate fractions
      were collected, measured for radioactivity, and applied on a chromatography
      plate. This plate was exposed with an imaging plate for radioactivity imaging.
      RESULTS: Time activity curves for unbound, unchanged tracer and metabolites were
      determined. The amount of unchanged tracer in the last MD fraction was compared
      with the amount in the plasma sample collected after sacrifice of the animal.
      CONCLUSION: MD continuously samples and monitors the amount of unbound tracer in
      the blood from one single experimental animal. MD combined with planar
      chromatography and DAR is a highly sensitive and linear method for simultaneous
      analysis of PET tracers and their metabolites in blood.

PMID- 15018827
TI  - Investigation of a new input function validation approach for dynamic mouse
      microPET studies.
AB  - PURPOSE: Image-derived input functions are desirable for quantifying biological
      functions in dynamic mouse micro positron emission tomography (PET) studies, but
      the input function so derived needs to be validated. Conventional validation
      using serial blood samples is difficult in mice. We introduced the theoretical
      basis and used computer simulations to show the capability of a new approach that
      requires only a small number of blood samples per mouse but uses multiple
      animals. PROCEDURES: 2-Deoxy-2-[(18)F]fluoro-D-glucose (FDG) kinetics (60
      minutes) were simulated for 10 to 20 animals with three to six blood samples
      available per animal. Various amounts/types of noise/errors in the blood
      measurements were assumed, and different amounts/types of errors were added to
      the true input function to simulate image-derived input function. Deviations
      between blood samples and the derived input function were examined by statistical
      techniques to evaluate the capability of the approach for detecting the simulated
      errors in the derived input function. RESULTS: For a total of 60 blood samples
      and a 10% measurement noise, a 5% contaminating error in image-derived input
      function can be detected with a statistical power of approximately 0.9 and with a
      95% confidence. The power of the approach is directly related to the error
      magnitude in the image-derived input function, and is related to the total number
      of blood samples taken, but is inversely related to the measurement noise of the
      blood samples. CONCLUSION: The new validation approach is expected to be useful
      for validating input functions derived with image-based methods in dynamic mouse
      microPET studies.

PMID- 15018828
TI  - Conventional imaging and 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission
      tomography for predicting the clinical outcome of patients with previously
      treated Hodgkin's disease.
AB  - PURPOSE: The aim of this study was to determine the ability of 2-deoxy-2
      [(18)F]fluoro-d-glucose positron emission tomography (FDG-PET) to predict the
      clinical outcome of previously treated patients with Hodgkin's Disease (HD).
      PATIENTS AND METHODS: Thirty-two patients were studied with PET within a median
      interval of 5.2 months after treatment. Conventional imaging (CI) performed
      within two months before PET included 2.9+/-1.2 imaging tests/patient. To
      determine the independent ability of FDG-PET to predict the clinical outcome, PET
      images were reread without knowledge of CI and clinical history. Study end points
      were disease-free survival, or clinical evidence of disease or death. PET and CI
      stages were also compared for each patient. RESULTS: Using the clinical outcome
      as gold standard after a median follow-up of 14 months, 21 of 32 patients (65%)
      were considered disease-free while 11 of 32 patients (35%) had evidence for
      disease or had died. The predictive accuracy of PET was 91% vs. 66% for
      conventional imaging (P<0.05). The positive predictive value (PPV) was also
      significantly higher for PET (79% vs. 50%, P<0.05), while its negative predictive
      value (NPV) tended to be higher than that of CI (100% vs. 86%, P=0.08). Kaplan
      Meier analysis for disease-free survival showed a significant difference between
      PET-negative and -positive results. No such difference was observed between CI
      positive and -negative results (P=0.35). CONCLUSION: Whole-body FDG-PET imaging
      modified the clinical stage in 28% of patients. Moreover, FDG-PET predicted
      patient outcome with a higher predictive accuracy than CI. This superior
      prognostic accuracy was achieved with a single FDG-PET study vs. 2.9+/-1.2 CI
      procedures/patient.

PMID- 15018829
TI  - Positron emission tomography with 2-deoxy-2-[(18)F]fluoro-D-glucose for
      evaluating local and distant disease in patients with cervical cancer.
AB  - PURPOSE: To assess the accuracy of positron emission tomography (PET) with 2
      deoxy-2-[(18)F]fluoro-D-glucose (FDG) for evaluating local and distant disease in
      patients with cervical cancer. METHODS: The PET imaging database maintained at
      our institution was used to identify patients who received FDG-PET scans for the
      clinical indication of cervical cancer for the past four years. Patients were
      followed for a minimum of six months following the PET study. Results of the FDG
      PET studies were correlated with surgical pathology, biopsy results, and/or
      clinical follow up to assess the accuracy of FDG-PET in evaluating local and
      distant disease. RESULTS: A total of 61 FDG-PET studies performed in 41 patients
      were included in this retrospective study. Nine FDG-PET studies were performed
      for initial staging of cervical cancer, and 52 PET scans were performed in 35
      different patients as restaging studies following therapy. For the initial
      staging, the local primary disease was identified in all nine FDG-PET studies,
      and PET distinguished the patients which had localized disease (four patients)
      from those with distant metastases on follow-up (five patients) with 100%
      accuracy. For restaging cervical cancer, FDG-PET had a sensitivity of 0.82 and
      specificity of 0.97 (accuracy 0.92) for evaluation of local recurrence. For
      evaluating distant disease in these patients, PET had a sensitivity of 1.00 and
      specificity of 0.90 (accuracy 0.94). In the evaluation of local disease, focal
      rectal activity caused false-positive results in two cases. Three false-positive
      studies for distant disease were caused by inflammatory adenopathy. CONCLUSION:
      FDG-PET is an accurate modality both for initial staging and restaging of
      patients with cervical cancer. PET is particularly sensitive for detecting
      distant metastases, allowing stratification of patients into those with locally
      confined disease and those with distant disease. These results were achieved by
      using a standardized PET imaging protocol without the use of bowel preparations,
      lasix administration, or Foley catheter drainage. Evaluation of local disease can
      be challenging due to adjacent rectal and bladder activity, and the use of hybrid
      PET/computed tomography (CT) scanners in the future may further improve
      evaluation of local disease.

PMID- 15018830
TI  - Positron emission tomography/computed tomography of a rare xanthogranulomatous
      process: Erdheim-Chester disease.
AB  - Erdheim-Chester disease (ECD) is a disseminated xanthogranulomatous infiltrative
      disease of unknown etiology due to infiltration of different organs and bones by
      foamy histiocytes. A 37-year-old male with cerebral and periorbital lesions was
      diagnosed with this rare disease and was evaluated with magnetic resonance
      imaging (MRI) and 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) with positron emission
      tomography/computed tomography (PET/CT) imaging at baseline and following
      therapy. FDG-PET imaging allowed accurate evaluation of the extent of the disease
      at baseline, as well as assessment of response to therapy.

PMID- 15018832
TI  - AMPA receptor modulators as cognitive enhancers.
AB  - AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate
      receptors mediate fast excitatory transmission throughout the central nervous
      system. Positive modulation of these receptors can potentially enhance cognition
      by, firstly, offsetting losses of glutamatergic synapses; secondly, promoting
      synaptic plasticity; and thirdly, increasing the production of trophic factors.
      The advent of small molecules that selectively enhance AMPA receptors in the
      brain made it possible to test these hypotheses. Preclinical experiments indicate
      that the compounds accelerate the encoding of memory and have positive effects on
      models of cognitive dysfunction. Initial results with human subjects are also
      positive. AMPA receptor modulators thus represent an entirely new approach to
      cognitive enhancement and the treatment of diverse brain disorders.

PMID- 15018833
TI  - The kynurenine pathway of tryptophan degradation as a drug target.
AB  - In mammalian cells, the essential amino acid tryptophan is degraded primarily by
      the kynurenine pathway, a cascade of enzymatic steps containing several
      biologically active compounds. Metabolites of this pathway, collectively termed
      'kynurenines', have been shown to be involved in many diverse physiological and
      pathological processes. In particular, fluctuations in the levels of kynurenines
      have discrete effects on the nervous and immune systems. A considerable number of
      pharmacological tools have recently become available to probe the kynurenine
      pathway experimentally. Some of these 'kynurenergic' agents can be envisioned to
      be of therapeutic value, especially in the treatment of diseases that are
      associated with impaired kynurenine pathway metabolism.

PMID- 15018834
TI  - Metabotropic glutamate 2/3 receptors as drug targets.
AB  - Metabotropic glutamate receptors are a family of class III G-protein-coupled
      receptors comprising eight members (mGluR1-8), which are an attractive target in
      the central nervous system because of the widespread use of glutamate as the
      principal excitatory amino acid transmitter. The unique pharmacology of class III
      G-protein coupled receptors, their forebrain localization in key limbic-related
      cortical/thalamic/striatal/amygdaloid circuits, and the promise of subtle
      modulation of glutamatergic neurotransmission make these receptors intriguing
      targets for a wide variety of neuropsychiatric disorders.

PMID- 15018835
TI  - Glutamate systems in cocaine addiction.
AB  - All addictive drugs facilitate dopamine transmission, and determining the role of
      dopamine has been the predominant focus of biomedical research in addiction for
      20 years. Newer data and hypotheses have begun to shift our focus to involvement
      of cortex and corticofugal glutamate projections. The rationale for shifting
      focus to glutamate ranges from evidence showing that cortical activity is altered
      in addicts to data from animal models demonstrating drug-induced changes in the
      function of proteins that regulate pre- and postsynaptic glutamate
      neurotransmission. Recent studies have particularly focused on involvement of a
      circuit that includes glutamate projections from the prefrontal cortex to the
      nucleus accumbens.

PMID- 15018836
TI  - Neurotransmitter transporters: why dance with so many partners?
AB  - Plasma membrane transporters terminate the actions of several small molecule
      neurotransmitters, including glutamate, gamma-aminobutyric acid, glycine,
      dopamine, serotonin and norepinephrine. The fact that anti-depressants, cocaine
      and amphetamines can have such profound behavioral effects by inhibiting the
      activity of some of these transporters underscores the importance of these
      molecules. Recent studies have begun to define the mechanisms that regulate these
      transporters. As these studies progress, it is becoming clear that the
      transporters form complexes both with themselves and with many other proteins
      that can regulate either transporter localization or activity. In most cases, the
      physiological and/or pathological relevance of these interactions is only
      beginning to emerge.

PMID- 15018837
TI  - Effects of nicotinic stimulation on cognitive performance.
AB  - Recent advances in studies of nicotinic agents in humans have begun to more
      carefully define cognitive operations that can be influenced by nicotinic
      stimulation and/or blockade. Careful separation of the cognitive domains affected
      by nicotinic stimulation has identified attentional performance as the most
      likely candidate to be positively influenced by nicotinic receptor activation.
      Studies of the effects of nicotinic systems and/or nicotinic receptor stimulation
      in pathological disease states such as Alzheimer's disease, Parkinson's disease,
      attention deficit/hyperactivity disorder and schizophrenia show the potential for
      therapeutic utility of nicotinic drugs. In contrast to studies in pathological
      states, studies of nicotine in normal-non-smokers tend to show deleterious
      effects. This contradiction can be resolved by consideration of cognitive and
      biological baseline dependency differences between study populations in terms of
      the relationship of optimal cognitive performance to nicotinic receptor activity.
      Although normal individuals are unlikely to show cognitive benefits after
      nicotinic stimulation except under extreme task conditions, individuals with a
      variety of disease states can benefit from nicotinic drugs. Attentional
      function/dysfunction may serve as an endophenotypic therapeutic target for
      nicotinic drug development.

PMID- 15018838
TI  - Cotransmission.
AB  - After some early hints, cotransmission was proposed in 1976 and the 'chemical
      coding' gradually established for sympathetic, parasympathetic, sensory-motor,
      enteric and some invertebrate nerves. More recently, cotransmission has been
      recognised in the central nervous system. ATP appears to be a primitive
      signalling molecule that has been retained as a cotransmitter in every nerve type
      in both peripheral and central nervous systems, although the relative role of ATP
      varies considerably in different species and pathological conditions. In the past
      two years, interest has focused on the mechanisms underlying cotransmission,
      plasticity and differential control of cotransmitter expression.

PMID- 15018839
TI  - What's atypical about atypical antipsychotic drugs?
AB  - Atypical antipsychotic drugs, by definition, differ from typical antipsychotic
      agents in producing significantly fewer extrapyramidal symptoms and having a
      lower risk of tardive dyskinesia in vulnerable clinical populations at doses that
      produce comparable control of psychosis. The atypical drugs differ from the
      typicals in their mechanism of action, but not all share the same mechanism.
      Many, but not all, atypicals have been found to improve cognitive function, which
      could be their most important advantage with regard to efficacy. Clozapine, the
      prototype of these agents, has been found to improve delusions and hallucinations
      in patients who fail to respond to other antipsychotic drugs, and to reduce the
      risk of suicide. These agents have been found to increase cortical dopamine and
      acetylcholine release, as well as have a variety of effects on the glutamatergic
      system not shared by the typical agents. Effects on neuronal survival and
      plasticity, together with decreased neurotoxicity, might also contribute to their
      clinical advantage over typical neuroleptic drugs.

PMID- 15018840
TI  - Neurotrophic effects of antidepressant drugs.
AB  - The past decade has witnessed a growing interest in the trophic effects of
      antidepressant drugs. Antidepressants stimulate the production and signaling of
      plasticity-related proteins such as neurotrophins and cAMP response element
      binding protein, and neurotrophin signaling appears to be both sufficient and
      necessary for antidepressant action in rodents. Furthermore, several different
      antidepressant treatments increase neurogenesis in rodent hippocampus and this
      effect correlates with the behavioral effects produced by these drugs. These data
      suggest that antidepressants facilitate activity-dependent selection of
      functional synaptic connections in brain and, through their neurotrophic effects,
      improve information processing within neuronal networks compromised in mood
      disorders.

PMID- 15018841
TI  - Drug exposure early in life: functional repercussions of changing
      neuropharmacology during sensitive periods of brain development.
AB  - Exposure to drugs early in life can have long-lasting implications for brain
      structure and function. Effects on the developing nervous system, before
      homeostatic regulatory mechanisms are properly calibrated, differ from those on
      mature systems. Recent studies show that permanent alterations in brain
      pharmacology and cell signaling are induced by early drug exposure, producing
      hypo- or hyperresponsiveness to environmental or pharmacological challenges later
      in life. As a result, children exposed to drugs pre- or postnatally might respond
      abnormally to therapeutics used to treat the very disorders that they later
      exhibit as a result of their previous drug exposure.

PMID- 15018842
TI  - Pharmacogenetics and psychopharmacology.
AB  - Genetic factors play a major role in the differential responses to treatment or
      the incidence of adverse drug effects in psychopharmacotherapy. The aim of
      pharmacogenetics is to elucidate this variability caused by hereditary
      differences. From hypotheses on the mechanisms of drug action, several mutations
      in genes coding for neurotransmitter receptors, neurotransmitter-degrading
      enzymes, transport proteins or enzymes of the drug metabolizing system have been
      identified and investigated. Although there exists some controversy among the
      results, many studies are supportive of the hypothesis that
      psychopharmacogenetics will be helpful in predicting an individual's drug
      response while minimizing the rate of side effects. The inclusion of functional
      genomics, which investigates the complex gene and/or protein expression in
      response to a given drug, could help lead to the development of novel and safer
      drugs.

PMID- 15018843
TI  - Mutant genes responsible for Parkinson's disease.
AB  - Recent progress has documented the presence of at least 10 disease-related genes
      or loci linked to Parkinson's disease. Analysis of the genotypes and phenotypes
      of these mutant genes has revealed a broad spectrum of clinical and pathological
      presentations, many of which share a common feature of alteration in the
      ubiquitin proteasome system. Further understanding of the pathogenesis of these
      inherited cases of Parkinson's disease and development of transgenic animal
      models bearing these mutations should provide novel insight into the causes of
      nigral cell death and meaningful strategies for future therapy.

PMID- 15018844
TI  - Mechanisms of cell death in polyglutamine expansion diseases.
AB  - Abnormal protein aggregation is a hallmark of many neurodegenerative diseases.
      However, the mechanism by which protein aggregates induce neurodegneration
      remains controversial. Recently proposed mechanisms of neuronal death in
      polyglutamine expansion diseases include activation of caspases and associated
      cell death pathways, interference with transcriptional regulation, downregulation
      of survival pathways and obstruction of axonal transport. Because the expression
      of expanded polyglutamine in selected neuronal populations can adversely affect
      multiple aspects of neuronal survival and function, we propose that effective
      therapeutic approaches might have to target the upstream mechanism of
      neurotoxicity by selectively inhibiting the formation of intraneuronal aggregates
      and increasing the degradation of mutant proteins.

PMID- 15018846
TI  - Stem cells as a potential treatment of neurological disorders.
AB  - The ability of stem cells to participate in brain repair has been increasingly
      demonstrated in recent studies. Most investigations have aimed to replace damaged
      neurons and glia by direct transplantation or recruitment of newly generated
      cells in the adult. However, functional improvements were often a result of stem
      cell-induced self-repair and neuroprotection, rather than cell replacement. Thus,
      a far more pragmatic approach in the short term might be to use stem cells as
      chaperones for degenerating nervous tissues. Additionally, targeted delivery of
      therapeutic agents could be achieved by modifying stem cells to release specific
      drugs at the site of transplantation. Elucidation and exploitation of this new
      'stem cell pharmacology' has the potential to revolutionise treatment of
      neurological diseases.

PMID- 15018845
TI  - Recent advances in the pharmacology of neurological gene therapy.
AB  - The choice of vectors, transgenes, regulatory elements, delivery approaches and
      the capacity to transduce the appropriate target cell type all influence the
      effectiveness of gene therapy for neurological diseases. Furthermore, even if
      many strategies are sound and effective in experimental animals, issues relating
      to side effects of gene therapy, longevity of therapeutic transgene expression
      and diffusion throughout the brain can limit the clinical potential of gene
      therapy. During the past 12-18 months, there have been significant advances in
      the following areas: the capacity to target vectors to predetermined cells types;
      the development of gene therapy approaches for the treatment of dominant
      inherited and neurodegenerative diseases; the capacity to achieve systemic
      delivery of viral vectors to the brain; and the development of viral vectors to
      model neurological diseases.

PMID- 15018847
TI  - Incidence and routes of transmission of hepatitis B virus in England and Wales,
      1995-2000: implications for immunisation policy.
AB  - BACKGROUND: The incidence of hepatitis B virus (HBV) infection in the UK is low.
      Since the infection can have serious sequelae, there is a continuing need to
      examine its epidemiology so as to inform control measures. OBJECTIVES: We aimed
      to describe the current HBV incidence and patterns of transmission in the UK, to
      estimate the rate of new carrier infections, and to discuss implications for the
      control of HBV through immunisation. STUDY DESIGN: We analysed routine England
      and Wales laboratory surveillance data of acute HBV infection (1995-2000) and
      data on migration and global HBsAg prevalence. RESULTS: The estimated annual
      incidence of HBV infection in England and Wales was 7.4 per 100,000. Injecting
      drug use was the most frequently reported route of transmission. The number of
      cases attributed to heterosexual contact was fairly stable, whereas the number of
      cases in men having sex with men decreased. These observations continue trends
      reported for the early 1990s. Transmission during childhood was rarely reported,
      but was more frequent among South Asians. The incidence in South Asians is
      relatively high, and their main risk factors are medical treatment overseas and
      heterosexual contact. For about a third of cases of acute HBV infection no route
      of transmission is reported, but analysis of secular trends and age distribution
      suggest that many of these may be related to injecting drug use. Endemic
      transmission gives rise to only a small proportion of all new chronic infections,
      with the vast majority arising from immigration of established HBV carriers.
      CONCLUSIONS: The incidence of acute HBV infection in England and Wales has
      remained low, with a similar pattern of reported routes of transmission compared
      to the early 1990s. The UK prevalence of HBV infection is dependant on global
      rather than national immunisation policy. Endemic transmission may be reduced by
      improving immunisation coverage among injecting drug users, which is expected to
      also reduce the number of cases without a risk factor reported. In addition,
      immunisation options that better suit the needs of ethnic minorities need to be
      explored.

PMID- 15018848
TI  - No evidence of hepatitis B virus activity in patients with anti-HBc antibody
      positivity with or without anti-hepatitis C virus antibody positivity.
AB  - BACKGROUND: The serological pattern of anti-HBc antibody positivity without both,
      HBsAg and anti-HBs antibody positivity may be present in up to 4% of the
      population of Europe and the United States. OBJECTIVES: The aim of the present
      study was to determine the hepatitis B virus (HBV) activity by detection of serum
      HBV DNA in patients with anti-HBc antibody positivity only and with confirmed
      anti-hepatitis C virus (anti-HCV) antibody positivity or without anti-HCV
      antibody positivity. STUDY DESIGN: A total of 141 patients positive for anti-HBc
      antibodies only, were investigated on serum HBV DNA load. Patients were
      classified into two groups: patients with confirmed positive anti-HCV antibodies
      (group 1) and patients without anti-HCV antibodies (group 2). RESULTS:
      Demographic data of patient groups were similar. In 66 of 70 patients with anti
      HBc antibodies and anti-HCV antibodies (group 1), serum HCV RNA was detected; the
      remaining 4 patients were HCV RNA negative but the presence of anti-HCV
      antibodies was confirmed by the line probe assay. In none of the patients, with
      anti-HBc antibodies and without anti-HCV antibodies (group 2), serum HCV RNA was
      detected. In none of the patients, serum HBV DNA was detected. CONCLUSION: In
      this study, serum HBV DNA could not be detected in patients with anti-HBc
      antibodies only. There seems to be no need for determination of serum HBV DNA in
      patients without clinical evidence of chronic liver disease. Nevertheless, it
      would be useful to test patients with progressive liver disease and those, which
      belong to high-risk groups such as hemophiliacs, intravenous drug abusers,
      patients on hemodialysis, and immunocompromised patients.

PMID- 15018849
TI  - Detection of BK virus and JC virus DNA in urine samples from immunocompromised
      (HIV-infected) and immunocompetent (HIV-non-infected) patients using polymerase
      chain reaction and microplate hybridisation.
AB  - BACKGROUND: The majority of the human population is infected with two human
      polyomaviruses BK virus (BKV) and JC virus (JCV) during childhood. After initial
      infection both viruses persist within renal system. Reactivation of both viruses
      may be linked with immunodeficiency or immunosuppressive therapy. OBJECTIVE: To
      evaluate the relationship between immunodeficiency and viruria, prevalence of BK
      and JC viruria over time was investigated in a cohort of HIV seropositive
      individuals at different stages of disease. The excretion in this group was
      compared with virus excretion in their HIV seronegative partners and in an
      unselected cohort of patients attending a Genito-Urinary Medicine (GUM) clinic.
      STUDY DESIGN: The excretion of BKV and JCV DNA in multiple urine samples from HIV
      infected patients at different stages of disease and their HIV-negative partners,
      and in single samples from a cohort of patients at a GUM clinic was investigated.
      A microplate hybridisation method was developed to increase both the sensitivity
      and specificity of detection of the PCR product. The method was also applied to
      estimate the DNA copy numbers of BKV and JCV in urine samples. RESULTS: Within
      the HIV group, the level of immunosuppression (CD4+ category) was not associated
      with JCV viruria. By contrast, there was a modest correlation between
      immunodeficiency as indicated by a decline in CD4+ count and BKV viruria.
      Shedding of both BKV and JCV DNA together in urine samples of HIV-infected
      patients was much higher than in control groups (P = 0.02), indicating that HIV
      infection may associate with polyomavirus reactivation. The incidence of flu-like
      syndrome was much higher in HIV-infected asymptomatic individuals than acquired
      immunodeficiency syndrome (AIDS)-related complex (ARC)/AIDS patients. In general,
      the concentration of BKV DNA viruria (DNA copy number) was dependent to CD4+
      counts (P = 0.008) while concentration of JCV DNA was independent to CD4+ cell
      count (P = 0.54). The prevalence of BKV and JCV DNA in patients who were infected
      with C. trachomatis was 9/50 (18%) and 11/50 (22%), respectively. BKV and JCV DNA
      was detected in 3/19 (15%) and 2/19 (10%) of patients who were infected with N.
      gonorrhoea. Results suggested that persons infected with C. trachomatis were more
      likely to show BKV and JCV viruria. CONCLUSION: These results confirm that
      shedding of BK and JC viruses in urine is not exclusively found in
      immunosupression, it may also occur in healthy individuals. The frequency of
      virus excretion is however, apparently increased in HIV-infected patients,
      although no firm statistical difference could be established. One of the
      interesting aspects of these findings was the relatively high incidence of BKV
      and JCV viruria in both control groups, i.e. HIV-negative partners of HIV
      infected patients and patients attending a GUM clinic.

PMID- 15018850
TI  - Optimization of PCR based detection of human papillomavirus DNA from urine
      specimens.
AB  - BACKGROUND: Human papillomavirus (HPV) causes cervical cancer. Current screening
      requires a yearly pelvic exam and Pap smear. However, these procedures are
      impractical for screening all women at risk for disease. Urine sampling has been
      successfully utilized to screen for Chlamydia trachomatis (CT) and Neisseria
      gonorrhoreae (NG) infections and has been considered for HPV DNA detection by
      several investigators. However, no study to date has been performed to
      specifically optimize HPV detection in urine. OBJECTIVES: To compare handling and
      extraction techniques in order to optimize the HPV specific PCR system in urine
      specimens. STUDY DESIGN: Examination of 10 characteristics that may contribute to
      PCR inhibition in urine was performed utilizing 10SG mulitstixs. Five different
      DNA extraction methods were compared in spiked specimens and in 10 clinical
      specimens. After the optimal extraction technique was identified, concentration
      of the sample with and without prior dilution was compared to the original
      protocol. Lastly, specimen handling was compared between immediate processing,
      refrigerating overnight, or freezing overnight. RESULTS AND CONCLUSIONS: the
      presence of protein in urine enhanced amplification while nitrites decreased
      amplification. Of the extraction methods tested, the QIAamp DNA Mini Kit
      demonstrated the best amplification from urine samples spiked with HPV DNA and
      clinical specimens. The addition of a dilution step and a concentration step
      before applying the Qiagen protocol further increased amplification of beta
      globin (from 50 to 63%) and the HPV L1 gene (from 13 to 33%). Lastly,
      refrigerating the specimens at 4 degrees C overnight appears to produce better
      amplification (62% beta-globin and 17% HPV positive) than either immediate
      processing (46% beta-globin and 13% HPV+) or freezing the specimen for 24h prior
      to processing (46% beta-globin and 10% HPV+). In these studies, amplification was
      low despite optimization. Additional improvements are required prior to clinical
      application of a urine-based HPV DNA detection system.

PMID- 15018852
TI  - Once, twice, or three times daily famciclovir compared with aciclovir for the
      oral treatment of herpes zoster in immunocompetent adults: a randomized,
      multicenter, double-blind clinical trial.
AB  - BACKGROUND: Famciclovir, the well absorbed oral pro-drug of penciclovir, is
      effective in the treatment of herpes zoster when given three times daily. Because
      the intracellular half-life of penciclovir triphosphate in varicella-zoster virus
      (VZV)-infected cells (7h) is considerably longer than that of aciclovir
      triphosphate (1h), it may be possible to administer famciclovir less frequently
      than three times daily for herpes zoster: aciclovir is administered five times
      daily. METHODS: 559 immunocompetent adults presenting with herpes zoster whose
      skin lesions were present for less than 72 h were randomized to receive
      famciclovir 750 mg once daily (od), 500 mg twice daily (bid), or 250 mg three
      times daily (tid), or aciclovir 800 mg five times daily. All treatments were
      given for 7 days. Participants were evaluated until complete healing or for 4
      weeks, whichever occurred first. RESULTS: There were no significant differences
      between the four treatment groups with respect to times to full crusting; loss of
      vesicles, ulcers and crusts; cessation of new lesion formation; a 50% reduction
      in the area of affected skin; and the loss of acute pain. CONCLUSIONS:
      Famciclovir 750 mg once daily, 500 mg twice daily and 250 mg daily, and aciclovir
      800 mg five times daily are three times comparable in efficacy with respect to
      the cutaneous healing of herpes zoster. The current study was not designed to
      assess the effects of the treatments on postherpetic neuralgia (PHN).

PMID- 15018851
TI  - Comparison of sequential cytomegalovirus isolates in a patient with lymphoma and
      failing antiviral therapy.
AB  - BACKGROUND: Long-term anti-cytomegalovirus (CMV) treatments in immunocompromised
      patients are hampered by resistance to antiviral drugs. Longitudinal changes in
      the resistance genotype may depend on changes in selective pressure and the
      complexity of CMV isolates. OBJECTIVE: To evaluate longitudinal changes in the
      CMV resistance genotype and phenotype along with strain-specific variability in a
      patient with non-Hodgkin's lymphoma in whom successive anti-CMV treatments
      failed. STUDY DESIGN: The resistance phenotype and genotype of seven CMV isolates
      collected from one patient during a 2-year follow-up period were retrospectively
      analysed. In parallel, we used glycoprotein B (gB) genotyping, and a- and UL10-13
      sequence analysis to study CMV interstrain variability. RESULTS: The patient was
      infected by at least three CMV strains plus variants of the parental strains.
      Resistance to ganciclovir, cidofovir and foscarnet was successively detected
      during the follow-up period. UL97 protein kinase changes responsible for
      resistance to ganciclovir were initially detected at residues 591 and 592, and
      then at position 594. Decreased sensitivity to foscarnet coincided with the
      appearance of amino acid substitution N495K in DNA polymerase, whereas cross
      resistance to ganciclovir and cidofovir was due to the L501I substitution.
      CONCLUSIONS: The CMV isolates obtained from our patient were complex mixtures of
      strains. Changes in resistance genotypes depended on resistance selective
      pressure and were not linked to interstrain variation.

PMID- 15018853
TI  - Detection of hepatitis A virus RNA in serum during the window period of
      infection.
AB  - BACKGROUND: Hepatitis A virus (HAV) infection is the leading cause of clinically
      apparent viral hepatitis in many parts of the world, including developed and
      developing countries. Only limited information is available regarding the
      seronegative viremic window that follows HAV infection, and no systematic search
      has been reported for HAV RNA positive, IgM anti-HAV negative serum samples
      during hepatitis A outbreaks. OBJECTIVES: To determine the proportion of HAV
      infected individuals among (i) children who were tested negative for anti-HAV
      antibodies during hepatitis A outbreaks which occurred in a public school (n =
      157) and a child care center (n = 38); (ii) subjects (n = 46) initially
      classified as acute non-A-C hepatitis patients after clinical examination and
      serological tests (sporadic cases). STUDY DESIGN: Reverse transcription (RT)-PCR
      was performed to detect the presence of HAV genome in serum samples collected
      from anti-HAV negative, susceptible subjects. RESULTS: HAV RNA was detected in
      19/157 (12%) and 5/38 (13%) anti-HAV negative children from the public school and
      child care center, respectively. Twelve (26%) out of the 46 acute hepatitis
      patients (sporadic cases) were also HAV RNA positive. From nine of these 12
      patients, a second blood sample was obtained 18-34 days after the first one: all
      nine had seroconverted to IgM anti-HAV, and their serum transaminases had reached
      elevated levels (mean ALT, 418; mean AST, 241). CONCLUSIONS: Detection of HAV RNA
      before IgM anti-HAV seroconversion may be used as an early diagnosis method
      during hepatitis A outbreaks. HAV RNA testing should also help to elucidate acute
      hepatitis cases of unknown etiology.

PMID- 15018854
TI  - Insight into the intrinsic sensitivity of the PCR assay used to detect CMV
      infection in amniotic fluid specimens.
AB  - BACKGROUND: PCR detection of human cytomegalovirus (HCMV) DNA in amniotic fluid
      (AF) is the most sensitive tool for diagnosis of fetal infection, but has sub
      optimal sensitivity. It has been suggested that inhibition by AF reduces the
      sensitivity of this assay, however this assumption has never been thoroughly
      studied. Several PCR assays have been shown to improve sensitivity, but
      comparative studies are insufficient to choose the optimal approach. OBJECTIVES:
      To assess the effect of AF inhibition on PCR sensitivity and to determine the
      most sensitive assay for diagnosing fetal infection. STUDY DESIGN: Plasmid
      containing HCMV DNA was tested by PCR, in water and in non-infected AF, to assess
      the inhibitory effect of AF. Twenty-three AF-infected samples were tested by
      various PCR protocols. AF supernatant, with or without DNA extraction, and AF
      cells, were assayed by single-round and semi-nested PCR. Viral load was measured
      in the supernatant by a commercial quantitative PCR kit. RESULTS: The plasmid
      model demonstrated that single-round PCR was 2000-fold less sensitive in AF
      compared with water. Semi-nested PCR was only 10-fold less sensitive. Single
      round PCR was 30% sensitive in HCMV-infected AF supernatants, and detected viral
      loads higher than 2.3 x 10(6) viral copies/ml. Extraction of DNA from the
      supernatant increased the sensitivity of this assay to 89% and the detection
      limit to 5.2 x 10(4) copies/ml. Semi-nested PCR performed on supernatant, with
      and without DNA extraction, was 96% and 100% sensitive, respectively, with a
      detection threshold of 3.8 x 10(3) copies/ml. Single-round and semi-nested PCR
      were 89% and 100% sensitive, respectively, in cells. The commercial quantitative
      PCR assay was 100% sensitive. CONCLUSIONS: AF supernatant is inhibitory to PCR.
      The two most sensitive assays were semi-nested PCR performed on DNA extracted
      from the supernatant and the commercial quantitative PCR kit. Of these two, the
      latter is standardized, non-labor-intensive, and allows minimal opportunity for
      contamination, thereby making it the preferred method for diagnosis.

PMID- 15018855
TI  - Multiple HPV genotypes in cervical carcinomas: improved DNA detection and typing
      in archival tissues.
AB  - BACKGROUND: Human papillomaviruses (HPV) have been considered to be the necessary
      and central agents of cervical carcinoma. OBJECTIVE: The aim of this study was to
      determine the prevalence and genotypes of HPV in archival cervical carcinomas.
      STUDY DESIGN: The study included 152 paraffin-embedded, formaldehyde-fixed
      cervical carcinoma specimens. To improve the detection and typing of HPV in
      archival tissues, we conducted a comprehensive study in which, polymerase chain
      reaction (PCR)-based methods using E7 type-specific (TS) and L1 modified general
      primers (MY11/GP6+ and GP5+/GP6+) were employed. RESULTS: Overall HPV prevalence
      was 98% in the cervical carcinomas. HPV 16 was detected in 66% of the tumors, HPV
      18 in 22%, HPV 31 in 13%, HPV 33 in 9%, and HPV 58 in 9%. Notably, multiple HPV
      types were present in 44 (28.9%) of the 152 cervical carcinomas. The most common
      co-infections were HPV types 16/18 (12 cases), followed by HPV types 16/31 (7
      cases). Additionally, HPV 18 was more frequent in adenocarcinomas and
      adenosquamous carcinomas (86%) than in squamous cell carcinomas (15.8%) (P =
      0.0002). CONCLUSIONS: The combination of L1 general primers and E7 type-specific
      primers can be of use in detecting HPV DNA in archival tissues. The present study
      showed a high frequency of multiple HPV infections in cervical carcinomas. Hence,
      relevant HPV typing information in cervical carcinoma is very important for
      further HPV vaccine design and application.

PMID- 15018856
TI  - Detection of transfusion transmitted virus DNA by real-time PCR.
AB  - BACKGROUND: Little is known about the pathogenic role and the endemic situation
      of transfusion transmitted virus (TTV). OBJECTIVES: In this study, a molecular
      assay for detection of TTV based on automated nucleic acid extraction and real
      time PCR was developed and evaluated. The new assay includes an internal control.
      STUDY DESIGN: After optimization of the molecular assay, 103 clinical samples
      were studied retrospectively. All sera had been tested for anti-HCV and anti-HIV
      1 antibodies earlier. RESULTS: The amplification efficiency was found to be 102%.
      When clinical specimens were tested, 79 of 103 serum samples were found to be
      positive for TTV. There was no significant difference between various groups of
      patients. The internal control was detected in all negative and weak positive
      samples. CONCLUSIONS: This molecular assay proved to be suitable for routine
      detection of TTV in clinical samples. Moreover, a relative statement on the TTV
      serum load can be done.

PMID- 15018857
TI  - Quantitative detection of human immunodeficiency virus type 1 (HIV-1) proviral
      DNA in peripheral blood mononuclear cells by SYBR green real-time PCR technique.
AB  - BACKGROUND: The persistence of proviral human immunodeficiency virus type 1 (HIV
      1) DNA reservoir represents one of the major drawbacks to the total eradication
      of HIV-1. The quantitative determination of proviral HIV-1 DNA load offers
      significant therapeutic information, especially when the HIV-1 RNA levels drop
      below the detectable limits during the highly active retroviral therapy (HAART)
      treatment. Moreover, the detection of HIV-1 proviral DNA is an important
      diagnostic marker in the evaluation of HIV-1 infection of newborns of HIV-1
      seropositive women. OBJECTIVE: We evaluated a real-time PCR based on LightCycler
      technology revealed through SYBR green fluorochrome (SYBR green real-time PCR) to
      quantify the HIV-1 proviral DNA load in peripheral blood mononuclear cells (PBMC)
      of HIV-1 seropositive patients. STUDY DESIGN: Firstly, we assessed the SYBR green
      real-time quantitative PCR for HIV-1 proviral DNA load detection determining the
      specificity and sensitivity of the assay using the LightCycler system. Secondly,
      we tested the performance of our SYBR green real-time PCR on 50 HIV-1
      seropositive patients under HAART and 20 blood donors. RESULTS/CONCLUSIONS: The
      results of this study showed that our SYBR green real-time PCR is able to detect
      five copies of the HIV-1 genome. Moreover, our method revealed HIV-1 proviral DNA
      in all the 50 HIV-1 seropositive patients ( 627 +/- 1068 HIV-1 proviral DNA
      copies per 10(6) PBMC, with a range of 30-6300 copies), whereas no positive
      signal was observed in any PBMC blood donors. Our SYBR green real-time PCR
      represents a sensitive and useful approach that could be applied both in HIV-1
      proviral DNA reservoir determination and in HAART monitoring, particularly when
      the HIV-1 plasmatic RNA is undetectable.

PMID- 15018858
TI  - Evaluation of a broadly reactive nucleic acid sequence based amplification assay
      for the detection of noroviruses in faecal material.
AB  - A recently described nucleic acid sequence based amplification (NASBA) assay for
      the detection of genogroup I (GI) and genogroup II (GII) norovirus RNA in faecal
      samples was evaluated against a reverse transcription polymerase chain reaction
      (RT-PCR). Both assays were used to screen a panel of 38 faecal samples known to
      contain 17 different norovirus strains and 131 clinical samples collected from 60
      gastroenteritis outbreaks of unknown aetiology. The NASBA assay detected 13 out
      of the 17 strains of norovirus in the characterised panel, failing to detect a
      single GII strain and three GI strains. There was 90% agreement between the two
      assays used to detect norovirus in clinical samples from outbreaks. NASBA
      detected norovirus RNA in all 64 samples positive by RT-PCR and also detected
      norovirus RNA in additional 13 samples that were negative by RT-PCR. The
      sensitivity and specificity of NASBA was 100% and 80%, respectively, compared to
      RT-PCR results. The norovirus NASBA assay was shown to be highly sensitive and
      specific, and its ease of use and rapid turnaround time makes it a favourable
      alternative to RT-PCR for the investigation of norovirus outbreaks.

PMID- 15018859
TI  - Monitoring of human cytomegalovirus (HCMV)-specific CD4+ T cell frequency by
      cytokine flow cytometry as a possible indicator for discontinuation of HCMV
      secondary prophylaxis in HAART-treated AIDS patients.
AB  - OBJECTIVE: Absolute CD4+ T cell count and human cytomegalovirus (HCMV)-specific
      CD4+ T cell frequency (as determined by cytokine flow cytometry, CFC) were
      compared for their ability to predict HCMV disease and safe discontinuation of
      HCMV secondary prophylaxis. STUDY DESIGN: Three groups of AIDS patients with
      previous nadir CD4+ T cell count <100/microl were studied. Group A included 48
      HAART-treated patients with no HCMV disease. Group B included 11 HAART-treated
      patients with previous HCMV disease who discontinued HCMV prophylaxis. Group C
      included 23 HAART-treated (n = 16) or -naive (n = 7) patients with previous HCMV
      disease either continuing or starting HCMV prophylaxis. Patients underwent follow
      up for detection of HCMV viremia or disease (groups A and B) and for
      discontinuation of HCMV secondary prophylaxis on the basis of either HCMV
      specific or absolute CD4+ T cell count (group C). RESULTS: During follow-up,
      while some patients showed a stable HCMV-specific CD4+ T cell response, others
      had a fluctuating response (unstable responders) or showed no response at all. In
      detail, 13/48 group A patients were either HCMV non-responders or unstable
      responders and 2 of them developed HCMV viremia; 3/11 group B patients were
      unstable responders, none developing either HCMV viremia or disease; finally, 9
      group C patients discontinued HCMV prophylaxis based on absolute CD4+ T cell
      count > 150 cells/microl, but in 2 of them lacking HCMV-specific response HCMV
      retinitis relapsed. None of the seven group C patients discontinuing HCMV
      prophylaxis on the basis of CFC showed HCMV disease relapse. CONCLUSIONS: CFC may
      support absolute CD4+ T cell count for both guiding HCMV prophylaxis
      discontinuation and better monitoring HCMV infection in AIDS patients with no
      previous HCMV disease or having discontinued HCMV prophylaxis.

PMID- 15018860
TI  - Human cytomegalovirus (HCMV)-specific CD4+ T lymphocyte response in AIDS patients
      with no past or current HCMV disease following HAART.
AB  - BACKGROUND: The incidence of Human Cytomegalovirus (HCMV) end-organ disease has
      dramatically decreased since the implementation of highly active antiretroviral
      therapies (HAARTs), but the precise immune mechanism whereby HCMV is controlled
      remains to be elucidated. OBJECTIVES: To investigate the effect of (HAART) on
      CD4+ T-cell immunity to HCMV in AIDS patients with no past or current HCMV
      disease. STUDY DESIGN: Seventeen patients were prospectively examined for CD4+
      (CD45RO+ and CD45 RA+) T-cell counts (flow cytometry), HIV RNA load (Amplicor HIV
      test), HCMV leukoDNAemia and HCMV DNA in urine (nested PCR), lymphoproliferative
      response (LPR) to HCMV, phytohemagglutinin (PHA) and purified protein derived
      from Mycobacterium tuberculosis (PPD) by measurement of 5-bromo-2'-deoxyuridine
      incorporation to DNA (ELISA) and cytokine secretion (IFN-gamma, IL-4 and IL-10)
      by HCMV-stimulated peripheral blood mononuclear cell (PBMC) cultures (ELISA).
      RESULTS: Fifteen patients responded favorably to HAART (virologically,
      immunologically, or both). Of these, six patients presented LPR to HCMV at least
      once during follow-up, whereas most displayed detectable LPRs to PHA. IFN-gamma
      was detected at least once in supernatants of HCMV-stimulated PBMC cultures from
      14 of the 17 patients. All but one patient tested negative for HCMV leukoDNAemia
      and HCMV DNA in urine, and none developed HCMV disease during the observation
      period. CONCLUSIONS: Control of HCMV replication and the absence of HCMV disease
      are not consistently associated with recovery and/or maintenance of LPR to HCMV
      in AIDS patients under HAART and with no prior HCMV disease. Whether detection of
      IFN-gamma by PBMCs upon HCMV antigenic stimulation may serve as a surrogate
      marker for protection against HCMV disease requires further investigation.

PMID- 15018861
TI  - The value of virus serology in epidemiological studies of acute otitis media in
      children.
AB  - BACKGROUND: Acute otitis media (AOM) is a major health problem in young children.
      There is a general conception that AOM is a bacterial disease but with the
      availability of sensitive diagnostic methods, it has gradually become evident
      that viruses play an important role in the pathogenesis of AOM. Paired blood
      samples are seldom taken from infants although valuable information could be
      obtained by serological methods. During the recent Finnish Otitis Media (FinOM)
      Cohort Study, in addition to nasopharyngeal aspirates (NPA) and middle ear fluids
      (MEF), paired acute and convalescent serum samples were collected from children
      with AOM. OBJECTIVES: To establish the diagnostic value of serological methods in
      etiological and epidemiological studies of AOM. STUDY DESIGN: A complete set of
      NPA, MEF, and paired sera was collected during 447 events of AOM experienced by
      179 children between 2 months and 2 years of age. Antigens of respiratory
      syncytial virus (RSV), adenoviruses, influenza A and B, and parainfluenza types 1
      3 in NPAs and MEFs were detected by time-resolved fluoroimmunoassay (TR-FIA), and
      antibody titers were determined by complement fixation test (CFT) or by enzyme
      immunoassay. RESULTS: A total of 163 virus-positive events were identified. Of
      those, only 34 were positive by TR-FIA and by serology. From 48 events a positive
      result was obtained only by TR-FIA and from 81 only by serology. CONCLUSION:
      Although serological methods are usually of little use in clinical practice,
      epidemiological studies clearly gain value if serology is included. The number of
      virus-positive findings dramatically increased by including serological tests in
      the diagnostic work-up of these AOM events.

PMID- 15018862
TI  - Parainfluenza virus 3 infection pre- and post-haematopoietic stem cell
      transplantation: re-infection or persistence?
AB  - BACKGROUND: A 5-year-old boy with acute lymphoblastic leukaemia (ALL) received a
      haematopoietic stem cell transplant (HSCT) from his father and was monitored for
      the presence of respiratory viruses. STUDY DESIGN: Nasal washes were taken during
      the transplant period and tested by culture and real-time PCR. RESULTS: Fifteen
      days prior to transplant parainfluenza virus 3 (PIV3) was isolated by culture and
      confirmed by immunofluoresence (IF) from a nasal wash specimen. Subsequent
      samples were negative by both IF and culture so the pre-transplant conditioning
      was started. One week after the HSCT the patient developed respiratory symptoms
      which progressively deteriorated. The IF and culture for PIV3 became positive
      again only after the symptoms deteriorated. However, retrospectively, a real-time
      PCR assay showed that the PIV3 was detectable throughout the conditioning phase
      and the amount of virus increased at the time of reappearance of respiratory
      symptoms post-HSCT. CONCLUSIONS: Management of PIV3 infection is important in
      HSCT. The use of this real-time PCR assay could improve diagnosis and management
      of PIV3 infection.

PMID- 15018863
TI  - Catheter ablation of atrial fibrillation: still investigational or already an
      established therapy?

PMID- 15018864
TI  - How to perform pulmonary vein isolation.

PMID- 15018865
TI  - How to perform pulmonary vein isolation for the treatment of atrial fibrillation:
      use of the LocaLisa catheter navigation system.

PMID- 15018866
TI  - Computerized high-density mapping of the pulmonary veins: new insights into their
      electrical activation in patients with atrial fibrillation.
AB  - AIM: To report the method and findings of computerized high-density mapping of
      pulmonary veins (PVs) in patients undergoing their electrical isolation for
      atrial fibrillation (AF). METHODS AND RESULTS: In 17 consecutive patients (8 M,
      age 55+/-11 years), a 64 electrode basket catheter was placed in the target PVs
      and 56 bipolar electrograms were recorded, analyzed and isochronal maps were
      generated. PVs were mapped during sinus rhythm, left-sided pacing and ectopic
      activity. The sites of earliest activation at the veno-atrial junction were
      defined as the atrium to vein conduction breakthroughs. PV activation pattern was
      classified as predominantly longitudinal or transverse, according to the
      direction of the impulse from the breakthroughs. The ectopic pattern was defined
      as multifocal, when distant areas in the PV had activation times within 10ms.
      Thirty-one PVs were mapped. The activation pattern was predominantly longitudinal
      in 13 PVs and transverse in 18 PVs. Two breakthroughs were identified in 22 PVs
      and three in nine. All the breakthroughs were evident simultaneously in sinus
      rhythm and left-sided pacing changed only the predominance of the breakthrough.
      Ectopies were mapped in 10 PVs: eight showed a multifocal and two a monofocal
      pattern; six ectopies originated from the proximal tract of the PV. CONCLUSION:
      High-density mapping of PV identifies a typical activation pattern. Multiple and
      discrete breakthroughs are simultaneously identified in sinus rhythm. The
      majority of the mapped ectopies has a multifocal pattern and proximal origin.

PMID- 15018867
TI  - Detection by intracardiac echocardiography of early formation of left atrial
      thrombus during pulmonary vein isolation.

PMID- 15018868
TI  - ECG signs mimicking acute inferior wall myocardial infarction are associated with
      elevated myocardial enzymes during isolation of pulmonary vein for focal atrial
      fibrillation.
AB  - In this study, we report an intraprocedural incident in patients undergoing
      ablation for atrial fibrillation. During left atrial manipulation our patients
      suffered from acute chest pain, showed ECG signs of an acute inferior wall
      myocardial infarction, and increased levels of cardiac Troponin I (cTnI). We
      strongly recommend being aware of unexpected reactions during isolating pulmonary
      veins for focal atrial fibrillation, especially when passing the dorsal part of
      the left atrium. If pericardial effusion is ruled out and ECG signs as well as
      symptoms disappear, the ablation procedure should proceed. We think patients
      undergoing pulmonary vein ablation for atrial fibrillation should be informed of
      this threatening complication.

PMID- 15018869
TI  - Ice mapping during cryothermal ablation of accessory pathways in WPW: the role of
      the temperature time constant.
AB  - AIM: Cryothermal energy has the ability reversibly to demonstrate loss of
      function with cooling, ice mapping, at less deep temperatures. The purpose of
      this study was to investigate the time course of the temperature during ice
      mapping of accessory pathways. METHODS AND RESULTS: Thirteen patients with the
      Wolff-Parkinson-White (WPW) syndrome underwent cryoablation. After identification
      of a prospective ablation site, ice mapping was performed by cooling the tip to a
      minimum of -30 degrees C. Successful ice mapping was defined by loss of accessory
      pathway (AP) conduction. A total of 104 ice maps were analyzed. Successful ice
      mapping was demonstrated in 17 attempts. There was no significant difference in
      mapping temperature between successful and unsuccessful ice mapping (-29.4+/-3.2
      degrees Celsius vs -30.4+/-1.7 degrees Celsius). The temperature time constant
      tau during successful ice mapping was significantly shorter compared with
      unsuccessful ice mapping (7.0+/-1.1 s vs 10.1+/-1.3 s; P<0.0001). The response
      time (RT) to mapping temperature of -30 degrees C was significantly prolonged in
      unsuccessful ice mapping attempts (35.8+/-4.5 s vs 53.5+/-11.0 s; P<0.0001).
      Significant correlations were found between successful ice mapping and the
      temperature time constant, and between RT and the temperature time constant
      (P<0.001). CONCLUSION: The ability to identify prospective ablation sites by ice
      mapping was demonstrated. Successful ice mapping attempts were characterized by a
      short temperature time constant and a short response time to mapping temperature
      with a sudden disappearance of pathway conduction.

PMID- 15018870
TI  - Prognostic significance of right ventricular extrasystoles.
AB  - Extrasystoles (RVES) from the right ventricular outflow tract (RVOT) are a common
      arrhythmia in routine ECGs. METHODS: In this prospective study 56 consecutive
      patients with RVES (22 males, 34 females) were examined for morphological and/or
      functional right ventricular (RV) abnormalities by 12-lead, Holter, exercise
      ECGs, transthoracic echocardiography and signal averaging. The follow-up time was
      3.1-15.8 years (arithmetic mean +/- SD = 7.2 +/- 1.6 years; median, 6.9 years).
      Patients with hyperthyroidism, structural cardiovascular and/or lung diseases
      were excluded. RESULTS: A total of 57.1% of the patients with RVES presented with
      echomorphologic abnormalities of the right ventricle (RV). In 26.8% the
      echomorphologic right ventricular abnormalities progressed in 33.3% of patients
      with normal RVs at baseline (group I) and in 21.9% of those with abnormal RVs at
      baseline (group II). No significant differences were found between the 2 patient
      groups in terms of age at onset, family history, ECG changes, late potentials and
      malignant right ventricular outflow tract arrhythmias on 24-h and exercise ECGs.
      While females predominated in group I, males were numerous in group II (p =
      0.006). Sustained ventricular tachycardia, syncope or sudden death were absent
      throughout the follow-up. CONCLUSION: Patients with RVES carry a good prognosis
      in terms of morbidity and mortality no matter whether echomorphologic
      abnormalities are present or not.

PMID- 15018872
TI  - Radiofrequency catheter ablation of an accessory pathway through an anomalous
      inferior vena cava with azygos continuation.
AB  - A 59-year-old man with Wolff-Parkinson-White syndrome and an infrahepatic
      interruption of his inferior vena cava with an azygos continuation underwent a
      successful ablation of a right anteroseptal accessory pathway with a femoral
      approach through the azygos vein and superior vena cava.

PMID- 15018871
TI  - Electrical storm in Brugada syndrome successfully treated using isoprenaline.
AB  - A case of an electrical storm occurring in a patient implanted with a
      cardioverter-defibrillator for Brugada syndrome is reported. Recurrent
      ventricular fibrillation was initiated by short-coupled isolated monomorphic
      ventricular premature beats probably originating from the right ventricular
      outflow tract, associated with a manifest electrocardiographic pattern of Brugada
      syndrome. Infusion of atropine accelerated the heart rate but did not prevent
      ventricular fibrillation, however, low doses of isoprenaline quickly obviated any
      recurrence of ventricular fibrillation. This was associated with the
      disappearance of the short-coupled premature beats together with a normalization
      of the electrocardiographic pattern. Possible mechanisms are discussed according
      to the accepted pathophysiological hypothesis.

PMID- 15018873
TI  - Multifocal cardiac Purkinje cell tumor in infancy.
AB  - Cot death is the commonest form of death among babies in the first year of life.
      The authors report the unusual case of a 2-month-old female infant dying suddenly
      and unexpectedly in whom a postmortem histological examination demonstrated a
      cardiac multifocal Purkinje cell tumor. Necroscopy studies of sudden infant death
      should always include an accurate histological examination of the cardiac
      conduction system and brainstem using serial sections.

PMID- 15018874
TI  - The DATAS rationale and design: a controlled, randomized trial to assess the
      clinical benefit of dual chamber (DDED) defibrillator.
AB  - Single chamber (SC) implantable cardioverter defibrillators (ICDs) have several
      limitations that might be relevant during follow-up, like atrial pacing
      requirements, inadequate therapies, sustained atrial tachyarrhythmias and
      difficulties to achieve an accurate diagnosis of the arrhythmia. Dual chamber
      (DC) ICDs offer an attractive and rational solution, although controversy remains
      if the costs and complexity of these devices offer a real clinical advantage. The
      Dual Chamber & Atrial Tachyarrhythmias Adverse Events Study (DATAS) was designed
      to analyze the ability of DC ICD, DDED, to reduce clinically significant adverse
      events compared with SC ICD in a non-selected population with conventional
      indications for ICD implantation. This is a prospective, multicentre, randomized,
      open labelled study, with three arms: two of them (simulated SC ICD and true DC
      ICD) cross-over, and the third (true SC ICD) parallels the other two. The
      composite primary end point comprises four Clinically Significant Adverse Events
      (CSAE): (1) all-cause mortality, (2) invasive intervention, hospitalization or
      prolongation of hospitalization due to cardiovascular cause, (3) inappropriate
      shocks, and (4) sustained symptomatic atrial tachyarrhythmias that (a) require
      urgent termination or (b) last more than 48h leading to therapeutic intervention.
      Secondary end points constitute each of the individual components of CSAE,
      cardiovascular status, quality of life and a detailed analysis of atrial and
      ventricular arrhythmias. To date (June 2003) there have been 343 patients enroled
      from 947 screened patients. The projected enrollment includes 360 patients and
      the conclusion of the study is expected at the beginning of 2005.

PMID- 15018876
TI  - Clinical value of routine predischarge testing after ICD-implantation.
AB  - AIMS: After implantation of a cardioverter/defibrillator (ICD) predischarge
      testing is often performed to ensure appropriate therapy function. Nevertheless
      there is no proven evidence for the necessity of this examination. In this
      retrospective single-centre analysis we investigated the clinical value of
      routine predischarge testing. METHODS AND RESULTS: Predischarge testing was
      performed in 161 patients 6+/-2 days after primary implantation of an ICD. There
      were no complications related to ICD-testing. In 17 of 161 patients (11%) there
      was at least one pathological finding. In 4 of 17 patients we observed a
      defibrillation energy requirement (DER) with a safety margin of less than 10J. In
      two of these patients an early lead repositioning was undertaken and in two
      patients reversal of the shock polarity was used to achieve an adequate DER. In
      13 of 17 patients we detected a distinct deviation of pacing thresholds or R-wave
      sensing amplitudes. In two of these patients an early electrode repositioning was
      performed because of lead displacement. In the remaining 11 patients we found an
      adequate DER at first, whereas in two patients a further lead repositioning was
      still necessary during follow-up. In 144 of 161 patients (89%) predischarge
      testing was without pathological findings. None of these patients needed revision
      of the ICD-lead during a mean follow-up of 24+/-13 months. CONCLUSIONS: Abnormal
      measurements during predischarge testing are not rare findings in ICD-recipients.
      Noninvasive methods cannot rule out inadequate defibrillation function. A normal
      predischarge test seems to be a reliable predictor for a stable electrode
      function during the first years of follow-up.

PMID- 15018877
TI  - Adverse effects of direct current cardioversion on cardiac pacemakers and
      electrodes Is external cardioversion contraindicated in patients with permanent
      pacing systems?
AB  - Use of pacing in sick sinus syndrome and recent developments in pacemaker therapy
      for intermittent atrial fibrillation raise the question of whether external
      electrical cardioversion should be used for termination of atrial fibrillation.
      This paper analyzes three cases of pacemaker and/or electrode dysfunction
      appearing after direct current (DC) cardioversion for termination of atrial
      fibrillation. Despite similar conditions during cardioversion in all cases,
      different dysfunctions reflecting damage to the pulse generator and/or a rise of
      the stimulation threshold in both, atrial and ventricular leads, have been
      observed. The possible mechanisms for these effects are discussed and
      recommendations for the management of cardioversion in patients with permanent
      pacemaker systems are given.

PMID- 15018875
TI  - Mortality of patients with implanted cardioverter/defibrillators in relation to
      episodes of atrial fibrillation.
AB  - AIMS: This study was undertaken to evaluate if a history of episodes of atrial
      fibrillation (AF) has an effect on survival in patients (pts) with implanted
      cardioverter defibrillators (ICD). METHODS AND RESULTS: Retrospective analysis of
      baseline characteristics, medication and endpoints in pts receiving a dual
      chamber ICD comparing pts without (group 1: n = 291) and with a history of AF
      (group 2: n = 68). Pts in groups 1 and 2 did not differ with regard to baseline
      characteristics. Forty-one pts (8.7%) experienced a detected episode of AF.
      During the study period (mean follow-up 9.5 months) 25 pts died (5.8% of group 1
      vs 11.8% of group 2). Patient survival was found to be 97.9% vs 91.2% ( n = 279
      vs 63) at 3 months after implantation, 97.5% vs 89.7% ( n = 244 vs 54) at 6
      months, and 93.7% vs 86.5% ( n = 96 vs 28) at 12 months in group 1 vs group 2 (p
      = 0.005). The risk of death increased after a first episode of AF was experienced
      during follow-up (RR = 5.0, p = 0.0007). Independent predictors of mortality are
      NYHA class (p = 0.002, history of AF (p = 0.009 for predicting early mortality),
      and detected episodes of AF during follow-up (p = 0.001). CONCLUSION: ICD
      patients with a history of AF had a higher than average risk of death early after
      implantation and after device-detected episodes of AF.

PMID- 15018878
TI  - Radioiodine ablation of the thyroid to prevent recurrence of amiodarone-induced
      thyrotoxicosis in patients with resistant tachyarrhythmias.
AB  - Amiodarone-induced thyrotoxicosis (AIT) is a common complication of amiodarone
      therapy. Although permanent withdrawal of amiodarone is recommended due notably
      to the risk of worsening of tachyarrhythmias, some patients may require the
      reintroduction of amiodarone several months after normalizing their thyroid
      function. We, retrospectively, assessed the effects of (131)I therapy to prevent
      recurrence of AIT in euthyroid patients requiring reintroduction of amiodarone.
      SUBJECTS AND METHODS: Amiodarone was required in 10 cases of recurrent
      symptomatic paroxysmal atrial fibrillation (AF) and in 5 cases of ventricular
      tachycardia (VT) (M = 12, F = 3, mean age: 63 +/- 14). The underlying heart
      disease was dilated cardiomyopathy (n = 4), ischaemic heart disease (n = 4),
      hypertensive heart disease (n = 2), arrhythmogenic right ventricular dysplasia (n
      = 27) and valvulopathy (n = 1). Two patients had idiopathic paroxysmal AF.
      RESULTS: A mean (131)I dose of 579 +/- 183 MBq was administered 34 +/- 37 after
      the episode of AIT. Amiodarone was reintroduced in 14 of 15 patients after a mean
      interval of 103 +/- 261 d. Fourteen patients developed definite hypothyroidism
      necessitating l-thyroxine but we observed no late recurrence of AIT. After a mean
      follow-up of 22 +/- 16 months, tachyarrhythmias were controlled in 12 of 14
      patients. CONCLUSION: (131)I therapy appears to be an effective and safe approach
      to prevent the recurrence of AIT in a patient requiring the reintroduction of
      amiodarone for tachyarrhythmias.

PMID- 15018879
TI  - Anthrax vaccination and self-reported symptoms, functional status, and medical
      conditions in the National Health Survey of Gulf War Era Veterans and Their
      Families.
AB  - PURPOSE: To evaluate the health status of Gulf War veterans who reported receipt
      of anthrax vaccination and a small group of Gulf War veterans for whom
      documentation of anthrax vaccination exists. METHODS: Among the 11,441 Gulf War
      veterans who completed a health survey, 4601 reported receiving the anthrax
      vaccine during the war; 2979 veterans reported not receiving it; 3861 were
      uncertain. Also, 352 of these respondents were documented by the Department of
      Defense as having received anthrax vaccination. We compared the medical history
      of these groups of veterans using multivariate analyses. Finally, we analyzed
      perception of exposure and its relation to reporting bias. RESULTS: There were
      statistically significant differences in prevalence for almost all outcomes
      studied between those who reported having received anthrax vaccination and those
      who did not so report. However, when we compared the veterans for whom
      vaccination records exist to the group who self-reported that they had not
      received the vaccine, the significant differences in prevalence for almost all of
      the outcomes disappeared. CONCLUSIONS: The extent of a reporting bias should be
      carefully considered when one evaluates the health consequences of anthrax
      vaccination based on self-reported data.

PMID- 15018880
TI  - Association between residence on Cape Cod, Massachusetts, and breast cancer.
AB  - PURPOSE: Massachusetts cancer registry and case-control data suggest that breast
      cancer incidence is elevated on Cape Cod relative to other parts of the state. We
      examined the association between length of residence on Cape Cod and breast
      cancer, since residential history could be acting as a surrogate for unidentified
      environmental risk factors. METHODS: We computed odds ratios (OR) and 95%
      confidence limits (CL) for 1121 cases occurring between 1988 and 1995 on Cape Cod
      and 992 controls, according to categories of residence time on Cape Cod, after
      adjusting for age, family history, parity and age at first live or stillbirth,
      education, body mass index, and breast cancer history. RESULTS: Breast cancer
      risk was elevated among women living on Cape Cod 5 or more years with a peak
      occurring in the 25 to less than 30 year category (adjusted OR=1.72; 95% CL,
      1.12, 2.64). Adjusting for confounding strengthened the associations. Odds ratios
      did not increase monotonically over categories of longer residence. CONCLUSIONS:
      Our results suggest that longer residence on Cape Cod is associated with elevated
      breast cancer risk, however inconsistency in the pattern of association limits
      conclusions that might be drawn about it. Suspected environmental exposures
      include pesticides and drinking water contaminated by industrial, agricultural,
      and residential land use.

PMID- 15018881
TI  - The specificity of the CDC-1994 criteria for chronic fatigue syndrome: comparison
      of health status in three groups of patients who fulfill the criteria.
AB  - PURPOSE: The Centers for Disease Control (CDC)-1994 definition of chronic fatigue
      syndrome (CFS) is very broad, and there have been suggestions that it lacks
      specificity. To test this, we have compared three groups of patients, all of whom
      fulfill the criteria but self-report different etiologies. METHODS: Patients with
      self-reported symptoms which developed sporadically (sCFS, n=48); after Gulf War
      service (GW, n=24); and following exposure to organophosphate insecticides (OP,
      n=25) underwent a clinical examination, completed the MOS SF-36 quality of life
      and Hospital Anxiety and Depression scales, and were assessed for major and minor
      criteria for CDC-1994 CFS. RESULTS: Significant differences in simple clinical
      measures and outcome measures were observed between groups. The GW group had
      significantly more severe physical symptoms-fatigue, muscle and multi-joint pain
      than OP or sCFS, and the sCFS group was significantly less impaired than the
      other two groups in terms of role emotional and mental health. In all three
      groups, a majority of patients exhibited muscle weakness in the lower limbs, and
      significant numbers of patients had absent or abnormal reflexes. CONCLUSIONS:
      Differences in simple, easily performed clinical outcome measurements can be
      observed between groups of patients, all of whom fulfill the CDC-1994 criteria
      for CFS. It is likely that their response to treatment may also vary. The
      specificity of the CFS case definition should be improved to define more
      homogeneous groups of patients for the purposes of treatment and research.

PMID- 15018882
TI  - Long-term consequences of body mass index for cardiovascular mortality: the
      Chicago Heart Association Detection Project in Industry study.
AB  - PURPOSE: This report: 1) examines the importance of long-term follow-up (25
      years) in BMI-cardiovascular mortality associations in eight age-gender
      subcohorts from the Chicago Heart Association Detection Project in Industry; and
      2) addresses the impact of previously identified methodologic problems in studies
      on weight-mortality associations, which include no adjustment for cigarette
      smoking, adjustment for physiological effects of obesity, and no exclusion of
      early deaths. METHODS: Associations were adjusted for age and ethnicity only,
      then for cigarettes/day, and for systolic blood pressure, serum cholesterol, and
      diabetes, for three periods of follow-up, 0 to 15, 6 to 15, and 16 to 25 years.
      RESULTS: In 25-year follow-up with exclusion of deaths for 0 to 15 years, there
      was a positive association in all subcohorts, with seven significant, both with
      and without adjustment for smoking or obesity-related risk factors. In contrast,
      with adjustment for obesity-related risk factors and no exclusion of early deaths
      in shorter-term (15-year) follow-up, there were two non-significant positive,
      three non-significant inverse, one significant positive, and one significant
      quadratic association. CONCLUSION: Failure to address potential methodologic
      problems can substantially alter associations in BMI-mortality studies and may
      contribute to observed differences among studies. The long-term outlook with
      overweight or obesity is adverse and deserves concerted efforts in prevention and
      treatment.

PMID- 15018884
TI  - Comparison of methods for collection of DNA samples by mail in the Black Women's
      Health Study.
AB  - PURPOSE: The authors compared approaches to participants and methods of
      collecting buccal cell samples by mail in the Black Women's Health Study, a
      follow-up study of geographically dispersed African-American women. Outcomes of
      interest were within group participation rates, yield of DNA, and PCR success.
      METHODS: Six hundred fifty six participants were randomized to four groups:
      Groups 1 and 2 used the cheek swab method and Groups 3 and 4 used the mouthwash
      swish method. Groups 1 and 3 were mailed collection kits together with consent
      forms, whereas Groups 2 and 4 were mailed a kit only after returning a signed
      consent. RESULTS: Participation rates were similar regardless of the method used
      for sample collection or mailing of the kits: samples were returned by 40% of
      Group 1, 37% of Group 2, 36% of Group 3, and 35% of Group 4. The median DNA yield
      was 3693 ng/sample for the swab method and 10,077 ng/sample for the mouthwash
      swish method (p<0.001). PCR analyses were successful in 98% of mouthwash samples
      and 94% of swab samples. CONCLUSION: Because of its higher yield of DNA, the
      mouthwash swish method is preferable for collection of buccal cell samples by
      mail.

PMID- 15018883
TI  - Conception and pregnancy during the Persian Gulf War: the risk to women veterans.
AB  - PURPOSE: To enumerate Gulf-War (GW) exposed conceptions and to compare
      reproductive outcomes of GW-exposed pregnancies with postwar conceptions of women
      Gulf War veterans (GWV) and women nondeployed veterans (NDV). METHODS: Deployment
      data and inpatient records from 153 military hospitals identified servicewomen
      who were pregnant between August 1990 and May 1992 and belonged to military units
      that were deployed to the Gulf War. Postal surveys were used in 1997 and 1998 to
      elicit reproductive history; responses were validated against military
      hospitalization records. Reproductive outcomes of GW-exposed pregnancies were
      compared with postwar conceptions of women GWVs and NDVs. RESULTS: 3285 women had
      a pregnancy-related admission; of these, 1558 completed the questionnaire. Self
      reported reproductive outcomes and dates, gestational data, and individual
      deployment dates identified 415 Gulf War-exposed pregnancies, 298 GWV postwar
      conceptions, and 427 NDV conceptions. Compared with NDV conceptions, adverse
      reproductive outcomes were similar among GW-exposed pregnancies. However,
      spontaneous abortions [NDV: 9.1%, GWV postwar: 22.8%, adjusted odds ratio
      (OR)=2.92, 95% confidence interval (CI): 1.9, 4.6] and ectopic pregnancies (NDV:
      1.4%, GWV postwar: 10.7%, adjusted OR=7.70, 95% CI, 3.0, 20) were elevated for
      GWV postwar conceptions. CONCLUSION: GW-exposed conceptions and nondeployed
      conceptions had similar outcomes. However, GWV postwar conceptions were at
      increased risk for ectopic pregnancies and spontaneous abortions.

PMID- 15018885
TI  - Hypertensive patients from two rural Chinese counties respond differently to
      benazepril: the Anhui Hypertension Health Care Study.
AB  - PURPOSE: Essential hypertension, as a complex disorder with unknown etiology
      cause, is a major public health problem worldwide. Patients need constant drug
      therapy to maintain their blood pressure in a normal range. However, the current
      facts suggest that the treatment is not optimized in a large number of patients,
      and as a result they are at risk for compliance resulting in uncontrolled blood
      pressure. Genetic and environmental factors associated with individual variation
      in response to anti-hypertensive drug remain largely unknown. METHODS: In order
      to illustrate the existence and to attempt to identify the factors modifying drug
      effect, we conducted a large-scale follow-up study in two Chinese rural counties
      differing in both genetic background and residential environment. Hypertensive
      patients were treated with benazepril, a commonly used angiotensin converting
      enzyme inhibitor, for 15 days, and the end-point effect was evaluated. RESULTS:
      We found that there were large and significant differences in drug response
      between subjects from two counties, even after adjustment for known factors. The
      responses to benazepril, measured in diastolic blood pressure drop, in male
      patients from Yuexi was twice as effective as their counterparts from Huoqiu.
      CONCLUSIONS: These results suggest that adjustment of treatment regimen is
      necessary to improve efficacy, and it could be done at the population level to
      make it more feasible and affordable.

PMID- 15018886
TI  - Serological evidence of Cryptosporidium infections in a Russian city and
      evaluation of risk factors for infections.
AB  - PURPOSE: Assess the relative frequency of Cryptosporidium infections and risk
      factors for infection in Cherepovets, Russia. METHODS: In June 1999, data on
      demographic, socioeconomic, hygienic characteristics, and recent gastrointestinal
      illness were collected on 50 community-recruited adults and 50 blood donors. The
      community group then maintained daily diaries of exposures and gastrointestinal
      symptoms for 5 months. Sera samples at the inception and conclusion of the study
      were tested for antibody responses to the 15/17 kDa and 27 kDa Cryptosporidium
      antigens using mini-immunoblots. RESULTS: At the inception, 68% and 88% of study
      participants had detectable serological responses to 15/17 kDa and 27 kDa
      antigens. Older age was associated with stronger antibody responses to both
      antigens. Attendance at swimming pools was associated with stronger responses to
      both antigens in predominantly male blood donors. Over the follow-up period,
      drinking non-boiled water from shallow draw-wells was associated with an increase
      in serological response to the 27 kDa antigen. Self-reported gastrointestinal
      illness was not associated with an increase in serological response. CONCLUSIONS:
      The prevalence of positive serological responses in Cherepovets was higher than
      in most prior Cryptosporidium serosurveys in non-outbreak communities. Drinking
      water is an important pathway for infection.

PMID- 15018887
TI  - Recurrent gastroenteritis among infants in Western Australia: a seven-year
      hospital-based cohort study.
AB  - PURPOSE: To investigate factors that affect the frequency of recurrent
      gastroenteritis among infants in Western Australia (WA). METHODS: A 7-year
      retrospective cohort study was undertaken on all infants born in 1995 who were
      admitted for gastroenteritis during their first year of life (n=514). Linked
      hospitalization records of the cohort were retrieved to derive the number of
      readmissions, microbiologic diagnoses, patient demographics, and co-morbidities
      at the index episode. A negative binomial regression model adjusting for inter
      hospital variations was used to determine the prognostic factors influencing
      recurrent gastroenteritis. RESULTS: Diarrhea with no specific etiology accounted
      for 54.7% of the cases presented at index admission and 55.8% of the total 676
      admissions for the cohort. Of the 514 infants, 119 (23%) experienced repeated
      episodes of gastroenteritis. The lowest proportion of recurrences was 15.4% for
      patients initially admitted for bacterial or viral diarrhea. Over 85% of the
      recurrences from either bacterial and viral diarrhea or etiology unspecified were
      readmitted under the same category. Aboriginality and dehydration were
      significantly associated with the recurrence frequency, the adjusted incidence
      rate ratio being 2.86 (95% CI, 1.92-4.26) and 0.66 (95% CI, 0.49-0.88),
      respectively. Aboriginal infants contributed to 58% of those patients in the
      cohort who sustained repeated episodes of gastroenteritis. The proportion of
      patients with the recurrent disease was also significantly higher for Aboriginals
      (39%) than for non-Aboriginals (15%). The effect of dehydration was evident after
      accounting for within hospital correlations. CONCLUSIONS: Hospitalizations for
      recurrent gastroenteritis were more frequent among Aboriginal children than non
      Aboriginal children in WA. Readmissions were also related to the presence of
      dehydration at the index episode. These findings have implications for preventive
      strategies to reduce the burden of gastroenteritis.

PMID- 15018888
TI  - Less affluent area of residence and lesser-insured status predict an increased
      risk of death or myocardial infarction after angiographic diagnosis of coronary
      disease.
AB  - PURPOSE: Low socioeconomic status (SES) predicts coronary artery disease (CAD)
      onset, but its value among patients with CAD is uncertain. Geographic measures
      (e.g., residential neighborhood) may predict risk, but this requires further
      evaluation. METHODS: A cohort of 3410 patients with significant, angiographically
      defined CAD (> or =1 lesion of > or =70% stenosis) joined a registry during the
      period between 1993 and 2000 and was followed for 6.7 years (median 3.7 years). A
      geographic SES measure-residential economic status (RES)-and insurance type were
      examined for association with mortality or myocardial infarction (MI). RESULTS:
      In Cox regression adjusting for 17 covariates, lower RES quartile was associated
      with increased death/MI (p-trend<0.001), death (p-trend=0.001), and MI (p
      trend=0.07). First RES quartile (vs. fourth) predicted death/MI (hazard ratio
      [HR]=1.32, 95% confidence interval [CI]=1.07-1.62, p=0.01) and death (HR=1.46,
      CI=1.12-1.91, p=0.006), but not MI (HR=1.18, p=0.31). Compared with private
      insurance, self-pay (HR=1.88, p=0.053), charity care (HR=1.71, p<0.001), and
      Medicaid (HR=1.43, p=0.24), but not Medicare (HR=0.95, p=0.68), were associated
      with death/MI. CONCLUSIONS: Both geographic (RES) and economic (insurance)
      measures of SES independently predicted risk of death/MI in a large population
      with angiographically-defined CAD. This suggests that SES remains a significant
      predictor of health outcomes after CAD has developed, and that geographic
      measures of SES deserve further evaluation.

PMID- 15018889
TI  - Regarding "Persistent organochlorine compounds and birth weight".

PMID- 15018892
TI  - Molecular regulation of angiogenesis and tumorigenesis by signal transduction
      pathways: evidence of predictable and reproducible patterns of synergy in diverse
      neoplasms.
AB  - A large number of oncogenes, tumor suppressor genes, and signal transduction
      pathways have been described. Currently, a framework that allows prediction of
      tumor behavior based upon oncogenes, tumor suppressors, and signal transduction
      pathways is lacking. In 1869, Mendeleev published a periodic table of elements
      which allowed prediction of properties of elements based upon atomic weights that
      allowed prediction of chemical and physical properties of elements yet to be
      discovered. In this paper, I will discuss recurrent patterns of synergy found in
      the literature and our laboratory between tumor suppressor genes, oncogenes, and
      signaling pathways that allows one to predict the signaling pathway in a given
      tumor based upon the inactivation of a tumor suppressor gene. These patterns can
      be found in multiple different human neoplasms. Conversely, one can predict the
      inactivation of a tumor suppressor based upon the activation status of a
      signaling pathway. This knowledge can be used by a clinician or pathologist with
      access to immunohistochemistry to make predictions based upon simple technologies
      and determine the signaling pathways involved in a patient's tumor. These
      strategies may be useful in the design of prevention and treatment strategies for
      cancer.

PMID- 15018893
TI  - Oncogenes and tumor angiogenesis: the question of vascular "supply" and vascular
      "demand".
AB  - Among novel promising approaches that have recently entered the scene of anti
      cancer therapy angiogenesis inhibition and targeting cancer-causing genes (e.g.
      oncogenes) are of particular interest as potentially highly synergistic. One
      reason for this is that transforming genetic lesions driving cancer progression
      (e.g. mutations of ras and/or p53) are thought to be causative for the onset of
      tumor angiogenesis and thereby responsible for build up of vascular supply which
      is essential for cancer cell survival, malignant growth, invasion and metastasis.
      However, many of the same genetic alterations that emerge during disease
      progression and repeated rounds of mutagenic and/or apoptosis causing therapy
      could alter cellular hypoxia-, growth factor- and apoptotic pathways in such a
      manner, as to also render cancer cells (partially) refractory to the detrimental
      consequences of poor blood vessel accessibility (density), ischemia, hypoxia and
      growth factor deprivation. As recent experimental evidence suggests, such cancer
      cells could therefore display a reduced vascular demand and remain viable even in
      poorly perfused regions of the tumor as well as possess an overall
      growth/survival advantage. The latter circumstance may lead to (predict)
      diminished efficacy of anti-angiogenic agents in certain malignancies. Therefore,
      we propose that analysis of oncogenic pathways and gene expression profiling of
      cancer cells may lead to important clues as to potential efficacy of anti
      angiogenic therapies, the direct target of which is the host vasculature, but
      which are ultimately aimed at (indirect) destruction/control of the cancer cells
      population. We also suggest that oncogene (tumor suppressor)-directed therapies
      may help reverse diminished vascular demand of highly transformed cancer cells
      and thereby facilitate (sensitize tumors to) therapies directed against vascular
      supply of cancers and their metastases.

PMID- 15018894
TI  - Oncogenic Ras and its role in tumor cell invasion and metastasis.
AB  - The processes by which cancer cells leave the tumor and enter adjacent tissue is
      known as invasion, whereas metastasis refers to secondary tumor colonization of
      tissue at a distance from the primary lesion. These two events are the most
      lethal of cancer phenomena and the signaling mechanisms that govern them are
      complex. The Ras signaling pathways are well represented in their involvement in
      tumor initiation, but considerably less is known about their contribution to
      invasion and metastasis. In this review, we discuss the current evidence for
      mutant Ras proteins as significant players in these aspects of cancer
      progression.

PMID- 15018895
TI  - Autocrine signaling in carcinoma: VEGF and the alpha6beta4 integrin.
AB  - This review highlights an emerging function for vascular endothelial growth
      factor (VEGF) in carcinoma and discusses mechanisms involved in the elaboration
      of VEGF autocrine loops. Evidence is provided that autocrine VEGF contributes to
      the two major components of invasive carcinoma: survival and migration. Moreover,
      the findings discussed support the hypothesis that carcinoma progression selects
      for cells that depend on VEGF as a survival factor. Furthermore, a related
      hypothesis, which is developed, is that the function of the alpha6beta4 integrin,
      which has been implicated in carcinoma progression, is linked to its ability to
      regulate VEGF translation and, consequently, autocrine VEGF signaling. The
      findings reviewed challenge the notion that the function of VEGF in cancer is
      limited to angiogenesis and suggest that VEGF and VEGF receptor-based
      therapeutics, in addition to targeting angiogenesis, may also impair tumor cell
      survival and invasion directly.

PMID- 15018896
TI  - Multiple regulatory pathways of vascular permeability factor/vascular endothelial
      growth factor (VPF/VEGF) expression in tumors.
AB  - VPF/VEGF is a multi-functional cytokine with important roles in both
      vasculogenesis and angiogenesis. Its production is generally regulated by local
      oxygen concentration. Hypoxia stimulates VPF/VEGF production by increasing its
      gene transcription and the stability of its mRNA. The increase in transcription
      in hypoxia occurs mainly through the stabilization and activation of the
      transcription factor, Hypoxia Inducible Factor (HIF). Cellular oxygen
      concentration is not the only regulator of VPF/VEGF synthesis. Some cancer cells
      can produce high levels of VPF/VEGF even in normoxia. Clear cell renal carcinoma
      cell line (RCC) like 786-0, pancreatic carcinoma cell line, ASPC-1,
      fibrocarcinoma cell line, HT1080, ovarian cancer cells, etc. produce an elevated
      level of VPF/VEGF, which is not dependent on hypoxia. In this article, we discuss
      different regulatory pathways in tumor cells comprised of oncogenes, tumor
      suppressor genes etc. that play important roles, in both the transcription and
      stability of VPF/VEGF mRNA.

PMID- 15018897
TI  - UVA-mediated activation of signaling pathways involved in skin tumor promotion
      and progression.
AB  - Each year more than 1,000,000 cases of non-melanoma skin cancer (NMSC) are
      diagnosed in the Unites States. Solar radiation has been described as an
      important etiological factor in the development of NMSC. UVA comprises the
      largest portion of solar radiation reaching the surface of the earth (90-99%) and
      has been described to lead to benign tumor formation as well as malignant
      cancers, squamous cell carcinomas (SCCs). While much research has focused upon
      the effects of UVB radiation, little is known about UVA-induced signaling
      pathways and their role in tumor promotion. Here we focus on UVA-mediated
      activation of mitogen-activated protein kinase (MAPK) pathways and their role in
      activator protein-1 (AP-1) mediated transcription and cyclooxygenase-2 (COX-2)
      expression. AP-1 and COX-2 have been found to play a role in angiogenesis in
      other tissues. We propose UVA-mediated increases in AP-1 and COX-2 may play a
      role in tumor promotion through increases in interleukin-8 (IL-8) and vascular
      endothelial growth factor (VEGF). Since MAPKs, specifically p38 and JNK, appear
      to play a major role in the expression of UVA-induced AP-1 and COX-2,
      pharmacological inhibitors may be of benefit in the chemoprevention of non
      melanoma skin cancer.

PMID- 15018899
TI  - Synthetic ion channels.

PMID- 15018898
TI  - Antiangiogenic cancer therapy.
AB  - Like most embryonic tissues, tumors have the ability to build up their own blood
      vessel networks. However, the architecture of tumor vessels is fundamentally
      different from that found in healthy tissues. Tumor vessels are usually
      irregular, heterogeneous, leaky, and poorly associated with mural cells.
      Endothelial cells in tumor vessels are also disorganized and express imbalanced
      surface molecules. These unusual features may provide some molecular and
      structural basis for selective inhibition or even destruction of tumor vessels by
      angiogenesis inhibitors. In animal tumor models, several angiogenesis inhibitors
      seem to inhibit tumor angiogenesis specifically without obvious effects on the
      normal vasculature. As a result, these inhibitors produced potent antitumor
      effects in mice. Excited by these preclinical studies, more than 60 angiogenesis
      inhibitors are being evaluated for their anticancer effects in human patients.
      Although the ultimate outcome of antiangiogenic clinical trials remains to be
      seen, several early observations have reported some disappointing results. These
      early clinical data have raised several important questions. Can we cure human
      cancers with angiogenesis inhibitors? Have we found the ideal angiogenesis
      inhibitors for therapy? What is the difference between angiogenesis in an
      implanted mouse tumor and in a spontaneous human tumor? What are the molecular
      mechanisms of these angiogenesis inhibitors? Should angiogenesis inhibitors be
      used alone or in combinations with other existing anticancer drugs? In this
      review, we will discuss these important issues in relation to ongoing
      antiangiogenic clinical trials.

PMID- 15018900
TI  - Design, synthesis, and characterization of peptide nanostructures having ion
      channel activity.
AB  - We report the synthesis and the functional studies of multiple crown alpha
      helical peptides designed to form artificial ion channels. The approach combines
      the versatility of solid phase peptide synthesis, the conformational
      predictability of peptidic molecules, and the solution synthesis of crown ethers
      with engineerable ion-binding abilities. Several biophysical methods were
      employed to characterize the activity and the mode of action of these crown
      peptide nanostructures. The 21 residue peptides bearing six 21-EC-7 turned out to
      facilitate the translocation of ions in a similar fashion to natural ion
      channels.

PMID- 15018901
TI  - Functional, synthetic organic chemical models of cellular ion channels.

PMID- 15018902
TI  - Water molecules in hydroxy/acid networks as a competition between dynamics and
      bonding. Synthesis of a wet hydrophobic pore.
AB  - In a model formed by hydroxy acids with a general structure (+/-)-1, we found
      that solid-state structures depend on steric interactions. Thus, with the
      exception of molecules 1b and 1e, compounds (+/-)-1a-(+/-)-1m, which possess
      bulky and conformationally rigid substituents, aggregate by forming tapes and
      sheets by alternating (+) and (-) subunits held together via carboxylic acid to
      alcohol hydrogen bonds. Homologue (+/-)-1n with conformationally flexible
      substituents, which allow conformational deformation gives, by way of the
      incorporation of water molecules, an efficient hexagonal assembly, which extends
      to the third-dimension to form tubular H-bonding networks. Each puckered channel
      can be described as being interconnected by closely packed hexagons in chair-like
      conformations. The ethyl groups presented in (+/-)-1n provided the volume
      required to lock the inner hexagonal wall into a rigid structure.

PMID- 15018904
TI  - Outer surface modification of synthetic multifunctional pores.
AB  - The characteristics of pores formed by p-octiphenyl beta-barrels with LWV triads
      at the outer surface are reported in comparison with the conventional rigid-rod
      beta-barrels with all-L outer surface. Maintained multifunctionality of
      tetrameric pores with external LWV triads (inversion of ion selectivity,
      molecular recognition and transformation) is implicative for intact barrel
      interior. Increased pore activity supports dominance of high bilayer affinity for
      W over low affinity for V. Transmembrane p-octiphenyl orientation (from
      fluorescence depth quenching) supports barrel-stave (rather than toroidal) pores
      and dominance of transmembrane preference of rigid rods over interfacial
      preference of W. Destabilization of beta-barrel pores in membranes (from short
      single-channel lifetimes) and in the media (from 4th-power dependence on monomer
      concentration) by LWV triads supports dominance of low beta-propensity for W over
      high beta-propensity for V. The relation between the stability of supramolecular
      (pre)pores and dependence of activity on monomer concentration is discussed in a
      more general context.

PMID- 15018903
TI  - Electrochemical release from gold-thiolate electrodes for controlled insertion of
      ion channels into bilayer membranes.
AB  - A proof-of-principle experiment to inject a sub-attomole amount of a channel
      compound into a bilayer membrane is described. The system is based on reductive
      cleavage of a self-assembled gold-thiol monolayer. In 'macroscopic' experiments,
      11-biphenyloxyundecane thiol formed well-ordered monolayers by open-circuit or
      controlled potential deposition. The products of reductive release were
      determined by chromatographic analysis. In DMF, the sole reduction product is the
      corresponding disulfide. In acetonitrile and water, only the thiol is detected.
      The current efficiency is low due to competing electrolysis of water, and to the
      low solubility of the released thiol or disulfide layer. On a 'microscopic'
      scale, the half ester of dithiodibutyric acid with gramicidin was deposited on a
      gold microelectrode under open circuit conditions. The thoroughly washed
      microelectrode, placed in proximity to a bilayer, released gramicidin only
      following a 100 ms pulse of reducing potential. The transfer efficiency of this
      method for controlled positioning of ion channels is estimated to be better than
      1 part in 10(5).

PMID- 15018906
TI  - Gramicidin-based channel systems for the detection of protein-ligand interaction.
AB  - To detect protein-ligand interaction a gramicidin-based sensor was developed.
      Biotin was tagged to the C-terminus of gramicidin (Gram-bio 1). The biotin
      moiety, which faces the electrolyte, gave little effect on single-channel
      conductance. Streptavidin added to the electrolyte was detected by Gram-bio 1
      through the monitoring channel current using the planar bilayer system. The
      suppression of macroscopic currents and the acceleration of their decaying time
      course were observed in a concentration dependent manner. In the single-channel
      level, however, no significant effect on the single-channel conductance and the
      open dwell time was observed upon addition of streptavidin. Therefore,
      streptavidin neither blocked the open channel nor changed the stability of the
      conducting dimer. Insertion of a linker between gramicidin and biotin did not
      change the streptavidin-sensitivity of the current reduction. We conclude that
      the binding of streptavidin to the Gram-bio 1 shifted the distribution of the
      complex from the membrane to the electrolyte and, thus, reduced the formation of
      conducting dimer of Gram-bio 1 in the membrane. Interaction of biotin with an
      anti-biotin antibody was also observed using this system, indicating that this
      system is applicable for the detection of protein-ligand interaction having a
      binding constant of approximately 10(8-9) M(-1) or more. Both the adamantane
      tagged gramicidin for detection of beta-cyclodextrin and the Strep Tag-II-tagged
      gramicidin for detection of streptavidin (binding constant: approximately 10(5)
      M(-1) or less) failed to respond. Thus, high-affinity ligands upon tagging to
      gramicidin render the gramicidin-based sensor able to execute as a real-time
      monitoring system for protein-ligand interaction.

PMID- 15018907
TI  - Toward an HDAC6 inhibitor: synthesis and conformational analysis of cyclic
      hexapeptide hydroxamic acid designed from alpha-tubulin sequence.
AB  - A cyclic hexapeptide hydroxamic acid inhibitor for HDAC6 has been designed and
      synthesized on the basis of the facts that alpha-tubulin is the substrate of
      HDAC6 and of the excellent inhibitory activity of cyclic tetrapeptide hydroxamic
      acids (CHAPs) for HDACs. Unexpectedly, cyclic hexapeptide hydroxamic acid showed
      very low HDAC inhibitory activity. To explain the low activity, we have carried
      out conformation analysis and compared it to the crystal structure of alpha
      tubulin. The conformation around the acetylated lysine of the cyclic hexapeptide
      substrate or the aminosuberate hydroxamic acid [Asu(NHOH)] of cyclic hexapeptide
      inhibitor is different from that around alpha-tubulin's lysine-40. The difference
      in the conformation seems to cause some steric hindrance at the capping site
      resulting in poor binding capacity.

PMID- 15018905
TI  - Engineering charge selectivity in model ion channels.
AB  - Most ion channel proteins exhibit some degree of charge selectivity, that is, an
      ability to conduct ions of one charge more efficiently than ions of the opposite
      charge. The structural origins of charge selectivity remain incompletely
      understood despite recent advances in the determination of cation-selective and
      anion-selective channel protein structures. Helix bundle channels formed via self
      assembly of the peptide alamethicin provide a tractable model system for
      exploring the structural basis of charge selectivity. We synthesized covalently
      linked alamethicin dimers, with amino acid substitutions at position 18 [lysine
      (Lys), arginine (Arg), glutamine (Gln), 2,3-diaminopropionic acid (Dpr)] in each
      helix, to assess the role of this position as a charge-selectivity determinant in
      alamethicin channels. Of the position 18 substitutions investigated, the Lys
      derivative exhibited the greatest degree of anion selectivity. Arg-containing
      channels were slightly less anion-selective than Lys. Interestingly, Dpr channels
      showed cation selectivity nearly equivalent to that exhibited by the neutral Gln
      derivative. We suggest that this result is due to a wider pore diameter that
      permits a greater number of counter-ions leading to enhanced charge screening and
      a lower effective side-chain positive charge.

PMID- 15018908
TI  - Synthesis and selective cyclooxygenase-2 (COX-2) inhibitory activity of a series
      of novel bicyclic pyrazoles.
AB  - Novel series of pyrazolo[5,1-b]1,3-oxazolidines, pyrazolo[5,1-b]1,3-oxazines and
      imidazolidino[1,2-d]pyrazoles were synthesized. These compounds were evaluated in
      vitro for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2
      (COX-2) in human whole blood (HWB). Several of the compounds were found to be
      novel and selective COX-2 inhibitors, the most potent and selective being 1-(5
      cyclohexyl (2H,3H-pyrazolo[5,1-b]-1,3-oxazolidin-6-yl)-4-(methylsulfonyl)benzene,
      7a (IC(5o) for COX-1>100 microM; for COX-2=1.3 microM).

PMID- 15018909
TI  - Design of N-acetyl-6-sulfo-beta-d-glucosaminide-based inhibitors of influenza
      virus sialidase.
AB  - Biological activity of N-acetyl-6-sulfo-beta-d-glucosaminides (6-sulfo-GlcNAc 1)
      having a structural homology to N-acetylneuraminic acid (Neu5Ac 2) and 2-deoxy
      2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en 3) was examined in terms of
      inhibitory activity against influenza virus sialidase (influenza, A/Memphis/1/71
      H3N2). pNP 6-Sulfo-GlcNAc 1a was proved to show substantial activity to inhibit
      the virus sialidase (IC(50)=2.8 mM), though p-nitrophenyl (pNP) GlcNAc without 6
      sulfo group and pNP 6-sulfo-GlcNH(3)(+) 1b without 2-NHAc showed little activity
      (IC(50) >50 mM). The activity was enhanced nearly 100-fold when the pNP group of
      1a was converted to p-acetamidophenyl one 5 (IC(50)=30 microM) or replaced with 1
      naphthyl 6 (IC(50)=10 microM) or n-propyl one 8 (IC(50)=11 microM).

PMID- 15018910
TI  - QSPR/QSAR in N-[(dimethylamine)methyl] benzamides substituents groups influence
      upon electronic distribution and local anesthetics activity.
AB  - It was determined, with a systematic mode, the carbonyl group frequency in the
      region of the infrared of N-[(dimethylamine)methyl] benzamides 4-substituted (set
      A) and their hydrochlorides (set B), that had its local anesthetical activity
      evaluated. The application of the Hammett equation considering the values of the
      absorption frequency of carbonyl group, nu(C=O,) using the electronic constants
      sigma, sigma(I), sigma(R), I and R leads to meaningful correlation. The nature
      and the contribution of substituent group electronic effects on the polarity of
      the carbonyl group was also analyzed. The use of the nu(C=O) as an experimental
      electronic parameter for QSPR studies was validated.

PMID- 15018911
TI  - 2,3-disubstituted 6-azabicyclo[3.2.1]octanes as novel dopamine transporter
      inhibitors.
AB  - A series of cis and trans 3beta-aryl-2-carbomethoxy-6-azabicyclo[3.2.1]octanes,
      with different substitution at the para-position of the aryl group, were
      synthesized and examined for reuptake inhibition at the dopamine transporter
      (DAT). The potency for inhibition of DA reuptake was compared with that of
      cocaine to determine the significance of the replacement of the 8
      azabicyclo[3.2.1]octane (tropane nucleus), displayed in cocaine, for the 6
      azabicyclo[3.2.1]octane (normorphan framework). This bicyclic core structure
      constitutes a novel chemical scaffold in DAT inhibitor design, which may provide
      new insights into the 3D structure of the DAT and its interaction with cocaine
      and DA. Among these compounds, the trans-amine series 8 were the most potent
      ligands at the DAT. In particular, the normorphan analogue 8c (bearing a p-chloro
      substituent at the beta-aryl group, IC(50)=452 nM) displayed a potency that is in
      the same range as cocaine (IC(50)=459 nM) itself.

PMID- 15018912
TI  - Synthesis and in vitro evaluation of S-acyl-3-thiopropyl prodrugs of Foscarnet.
AB  - A new enzyme-labile group called S-acyl-3-thiopropyl group (SATP) has been
      synthesized from allylic esters of phosphonate. After demonstration of the enzyme
      labile character of the SATP in cellular extracts, it has been introduced onto
      the phosphonate moiety of PFA (Foscarnet) to obtain potential lipophilic
      prodrugs. To ponder the lipophilicity of the triesters of PFA, esters of
      monomethylether of polyethyleneglycols and of thioglycerol were introduced on the
      PFA carboxylate moiety. The SATP groups were introduced in an attempt to deliver
      PFA after bioactivation inside the cells. The PFA prodrugs were evaluated in
      vitro for their activity against human immunodeficiency viruses (HIV-1 and HIV
      2).

PMID- 15018913
TI  - 8,9-dihydroxy-1,2,3,11b-tetrahydrochromeno[4,3,2,-de]isoquinoline (dinoxyline), a
      high affinity and potent agonist at all dopamine receptor isoforms.
AB  - The synthesis and preliminary pharmacological evaluation of 8,9-dihydroxy
      1,2,3,11b-tetrahydrochromeno[4,3,2,-de]isoquinoline (5, now named dinoxyline) is
      described. This molecule was designed as a potential bioisostere that would
      conserve the essential elements of our beta-phenyldopamine D(1) pharmacophore
      (i.e., position and orientation of the nitrogen, hydroxyls, and phenyl rings).
      Previously, we have rigidified these elements using alkyl bridges, as exemplified
      in the dopamine D(1) full agonist molecules dihydrexidine (1) and dinapsoline
      (2). This approach has been modified and we now show that it is possible to
      tether these elements using an ether linkage. Preliminary pharmacology has
      revealed that 5 is a potent full D(1) agonist (K(0.5) <10 nM; EC(50)=30 nM), but
      also has high affinity for brain D(2)-like and cloned D(2) and D(3) receptors.
      Interestingly, whereas 1 and 2 and their analogues have only moderate affinity
      for the human D(4) receptor, 5 also has high affinity for this isoform. Moreover,
      although N-alkylation of 1 and 2 increases D(2) affinity, the N-allyl (15) and N
      n-propyl (17) derivatives of 5 had decreased D(2) affinity. Therefore, 5 may be
      engaging different amino acid residues than do 1 and 2 when they bind to the D(2)
      receptor. This is the first example of a ligand with high affinity at all
      dopamine receptors, yet with functional characteristics similar to dopamine.
      These rigid ligands also will be useful tools to determine specific residues of
      the receptor transmembrane domains that are critical for agonist ligand
      selectivity for the D(4) receptor.

PMID- 15018914
TI  - 5-N-Substituted-2-(substituted benzenesulphonyl) glutamines as antitumor agents.
      Part II: synthesis, biological activity and QSAR study.
AB  - Cancer is a major killer disease throughout human history. Thus, cancer becomes a
      major point of interest in life science. It was proved that cancer is a nitrogen
      trap and tumor cells are avid glutamine consumers. The non-essential amino acid
      glutamine, which is a glutamic acid derivative, supplies its amide nitrogen to
      tumor cells in the biosynthesis of purine and pyrimidine bases of nucleic acids
      as well as takes part in protein synthesis. Based on these and in continuation of
      our composite programme of development of new potential anticancer agents through
      rational drug design, 17 new 5-N-Substituted-2-(substituted benzenesulphonyl)
      glutamines were selected for synthesis. These compounds as well as 36 earlier
      synthesized glutamine analogues were screened for antitumor activity using
      percentage inhibition of tumor cell count as the activity parameter. QSAR study
      was performed with 53 compounds in order to design leads with increased
      effectiveness for antitumor activity using both physicochemical and topological
      parameters. QSAR study showed that steric effect on the aromatic ring is
      conducive to the activity. n-butyl substitution on aliphatic side chain and atom
      no 12 is important for antitumor activity of glutamine analogues.

PMID- 15018916
TI  - 1,4-dihydroxyxanthone modulates the adhesive property of endothelial cells by
      inhibiting intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion
      molecule-1 (VCAM-1) and E-selectin.
AB  - Cell adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1),
      vascular cell adhesion molecule (VCAM-1) and E-selectin, play important roles in
      the recruitment of leukocytes to the site of inflammation. Blocking the
      expression of these molecules or preventing their interaction with the receptors
      has been shown to be important in controlling various inflammatory diseases.
      These cell adhesion molecules are induced on endothelial cells by various
      proinflammatory cytokines like IL-1beta and TNF-alpha and also by bacterial LPS.
      We demonstrate here that 1,4-Dihydroxyxanthone (1,4 DHX) inhibits the expression
      of cell adhesion molecules, such as ICAM-1, VCAM-1 and E-selectin, on endothelial
      cells in a concentration and time dependent manner. The inhibition by 1,4 DHX is
      reversible. On further analysis, our results also show that 1,4 DHX inhibits the
      adhesion of peripheral neutrophils to the endothelial cell monolayers. 1,4 DHX,
      therefore, could be used as a novel target for controlling various pathological
      conditions associated with upregulation of endothelial leukocyte adhesion
      molecules.

PMID- 15018915
TI  - Synthesis and biological evaluation of 6-substituted purine and 9-beta-d
      ribofuranosyl purine analogues.
AB  - 6-Substituted purine and 9-beta-d-ribofuranosyl purine analogues were synthesized
      and their biological activities were evaluated. CD Spectra and thermal melting
      studies showed that compounds 8, 9, 10 could interact with RNA and DNA in
      solution. Compound 8 and 10 may bind with RNA single strand and interfere the
      formation of RNA duplex. Among of these compounds, compound 8 showed middle
      inhibition on the growth of HeLa cells (70.21%) and HL-60 cells (70.85%) at 10
      microM. Comparing to the structures of these synthetic compounds, it may indicate
      that the sugar moiety and the 6-amino side chain of nucleoside 8 play an
      important role in the biological activities.

PMID- 15018918
TI  - Antimycobacterial compounds. New pyrrole derivatives of BM212.
AB  - We have identified BM212 as a lead compound among a series of pyrrole derivatives
      with good in vitro activity against mycobacteria and candidae. First studies led
      us to synthesize some pyrrole compounds in which the thiomorpholine fragment was
      present. Some compounds revealed very active and these findings prompted us to
      prepare new pyrrole derivatives 2-15 in the hope of increasing the activity. The
      microbiological data showed interesting in vitro activity against Mycobacterium
      tuberculosis and atypical mycobacteria.

PMID- 15018917
TI  - Synthesis and structure/NMDA receptor affinity relationships of 1-substituted
      tetrahydro-3-benzazepines.
AB  - A novel synthesis of 1-substituted tetrahydro-1H-3-benzazepines 4 is described.
      Starting with (2-bromophenyl)acetaldehyde acetal 5, the nitrostyrene 9 was
      prepared in three steps allowing the addition of various nucleophiles to yield
      the nitroacetals 10. The one-pot Zn/HCl reductive cyclization of the nitroacetals
      10 provided the 3-benzazepines 4, which were investigated for their affinity to
      the phencyclidine binding site of the NMDA receptor. A one-atomic spacer between
      the 3-benzazepine system and the phenyl residue in position 1 seems to be
      favorable for high NMDA receptor binding. In this series the benzazepine 4l
      substituted with the conformationally restricted and H-bond accepting acetanilide
      substituent in position 1 displays the highest NMDA receptor affinity (K(i)=89
      nM).

PMID- 15018919
TI  - Synthesis of novel 4- and 5-substituted benzyl ether derivatives of vesamicol and
      in vitro evaluation of their binding properties to the vesicular acetylcholine
      transporter site.
AB  - Detection of the central cholinergic deficits, a consistent feature of
      Alzheimer's disease, is essential to allow preventive measures and/or symptomatic
      treatment already at a very early stage of the disease. The vesicular
      acetylcholine transporter (VAChT) represents an appropriate target to establish
      PET radiotracer that are adequate for brain imaging the loss of cholinergic
      terminals. Here we describe the synthesis and binding characteristics of novel
      derivatives of vesamicol, known to represent a specific antagonist of VAChT
      sites. Novel benzyl ether derivatives of vesamicol either 4- or 5-substituted at
      the cyclohexylring have been synthesized by different regioselective ring opening
      reactions of a same epoxide precursor. The affinity and selectivity of the novel
      compounds to VAChT sites were analyzed by competitive radioligand binding studies
      in rat brain and liver membrane preparations using tritium labeled radioligands.
      The 4-substituted fluorobenzylether of vesamicol 10b was shown to exhibit a high
      affinity to VAChT sites (K(i)-value(10b)=10.7+/-1.7 nM), but demonstrated also
      binding capacities to sigma receptors (K(i-)value(10b)=18.5+/-6.9 nM, [(3)H]DTG;
      K(i)-value(10b)=30.6+/-9.6 nM, [(3)H]haloperidol). The data suggest the potential
      of vesamicol derivatives to design appropriate radiotracer for PET imaging of
      central cholinergic deficits.

PMID- 15018920
TI  - Further insights on the structural aspects of PLA(2) inhibition by gamma
      hydroxybutenolide-containing natural products: a comparative study on
      petrosaspongiolides M-R.
AB  - Petrosaspongiolides M-R (PM-PR, 1-5) are marine sesterterpenes structurally
      characterised by a gamma-hydroxybutenolide moiety. They have shown an in vitro
      and in vivo potent anti-inflammatory activity, mediated by specific inhibition of
      secretory phospholipase A(2) (sPLA(2) enzymes). The molecular mechanism
      underlying the sub-micromolar irreversible inhibition of the bee-venom PLA(2)
      (bvPLA(2)) by PM has been clarified combining mass spectrometry (MS) and
      molecular modelling approaches. The N-terminal amino group (Ile-1 residue),
      recently identified as the unique PM covalent binding site on this enzyme,
      selectively delivers a nucleophilic attack onto the masked aldehyde at C-25 of
      the pharmacophoric gamma-hydroxybutenolide ring of PM, giving rise to a Schiff
      base. In the attempt of broadening the knowledge of the mechanism at molecular
      level of PLA(2) inactivation by this family of compounds, we performed a
      comparative analysis on petrosaspongiolides M-R, whose results are discussed in
      this paper. Firstly, the amount of bvPLA(2) enzyme covalently modified after
      incubation with each of petrosaspongiolides M-R was measured and resulted to be
      in good agreement with pharmacological in vitro data. Then, a full
      characterisation of the bvPLA(2) adduct with PR, one of the least active and most
      structurally different among petrosaspongiolides, by LC-MS, MS(n), and
      computational methods, confirmed the same inhibition mechanism and covalent
      binding site already found for PM. Finally, extensive molecular docking studies
      performed in comparison on the PM-PLA(2) and PR-PLA(2) complexes provided
      critical insight on how the balance between non-covalent and covalent inhibitor
      enzyme interactions may affect the final potency exhibited by the various
      compounds of the petrosaspongiolide family.

PMID- 15018921
TI  - Deoxynucleic guanidine; synthesis and incorporation of purine nucleosides into
      positively charged DNG oligonucleotides.
AB  - The synthesis of purine nucleosides capable of making the guanidinium linkage is
      described for the first time starting from the corresponding 2'-deoxynucleosides.
      The positively charged mixed base DNG oligomer containing guanine was synthesized
      on solid-phase using CPG as support from 3' to 5' direction using the precursor
      building block nucleosides.

PMID- 15018922
TI  - Synthesis and biological evaluation of 2-(4-fluorophenoxy)-2-phenyl-ethyl
      piperazines as serotonin-selective reuptake inhibitors with a potentially
      improved adverse reaction profile.
AB  - Three new 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines, 1-(3-chlorophenyl)-4-[2
      (4-fluorophenoxy)-2-phenylethyl]-piperazine 7, 1-[2-(4-fluorophenoxy)-2
      phenylethyl]-4-(2-methoxyphenyl)-piperazine 8, and 1-[2-(4-fluorophenoxy)-2
      phenylethyl]-4-(3-trifluoromethylphenyl)-piperazine 9, modeled after the potent
      antidepressant fluoxetine and coupled with several functionalized piperazines,
      have been prepared by chemical synthesis as selective serotonin reuptake
      inhibitors (SSRIs) with a potentially improved adverse reaction profile. Typical
      SSRIs, although very effective in the treatment of depression, still face the
      troublesome side effect of sexual dysfunction. A number of pharmacological agents
      notably, drugs in the piperazine class-have been used to reverse SSRI-induced
      sexual dysfunction, and evidence for developing an improved SSRI by coupling a
      fluoxetine congener with the pharmacophore of a reversal agent holds promise.
      Preliminary data indicates that the hydrochloride (HCl) salts 10, 11, and 12 each
      exhibit single-site binding at the site of the serotonin reuptake transporter
      (SERT). However, each of the three compounds are much less potent than typical
      SSRIs, showing micromolar (microM) affinity for the SERT with IC(50) values of
      1.45 microM, 3.27 microM, and 9.56 microM, respectively. Further biological
      evaluation of compounds 10, 11, and 12 is needed before definitive conclusions
      can be made with regard to each compound's potential for use as an SSRI-type
      candidate which is devoid of sexual side effects. Nevertheless, the initial
      findings are quite encouraging, thus lending credence to the idea of hybridizing
      an SSRI congener with that of the pharmacophore of an agent known to reverse or
      treat SSRI-induced sexual dysfunction.

PMID- 15018923
TI  - QSAR study on some anti-HIV HEPT analogues using physicochemical and topological
      parameters.
AB  - A Quantitative Structure-Activity Relationship (QSAR) study has been carried out
      using topological indices, physicochemical and indicator parameters on a series
      of HEPT analogues for their HIV reverse transcriptase inhibitory activity.
      Correlation analysis and multiple linear regression (MLR) method were used to
      find out the best QSAR model. The results clearly explained that decreased
      hydrophobicity of substituents at R(1) and R(2) positions are favorable for the
      activity and presence of di-substitution at phenyl ring as well as i-Pr at R(1)
      position have detrimental effect but presence of OH group at R(2) position
      increases the activity. The atoms numbered as 1, 2, 3, 4, 5, 6 and 11 may
      constitute pharmacophore moiety of the HEPT analogues for their anti-HIV
      activity. Leave one out (LOO-) cross validation method was used to judge the
      predictive power of final equations. From the study one can propose that atom or
      fragmental level descriptors are more useful to interpret drug-receptor
      interactions in these analogues. The potentiality of ETSA index to recognize
      these atoms (Pharmacophoric atoms) was established.

PMID- 15018924
TI  - Synthesis and SAR of tetracyclic pyrroloquinolones as phosphodiesterase 5
      inhibitors.
AB  - The synthesis of the fused tetracyclic pyrroloquinolones 9a-i in four steps is
      described. The PDE5 inhibitory activities of these compounds, their selectivities
      against PDE1, PDE2, PDE3, PDE4 and PDE6, the preclinical pharmacokinetic
      assessments and the in vivo efficacy in increasing intracavernosal pressure are
      presented and discussed.

PMID- 15018925
TI  - Synthesis and duplex DNA recognition studies of oligonucleotides containing a
      ureido isoindolin-1-one homo-N-nucleoside. A comparison of host-guest and DNA
      recognition studies.
AB  - In an effort to construct non-natural bases to be used in triplex-based antigene
      DNA recognition strategies, a uriedo-isoindolin-1-one homo-N-nucleoside base was
      designed to bind the cytosine-guanine (CG) base pair. An organic soluble analogue
      of this base was shown to effectively complex CG (K(assoc)=740M(-1)) in
      chloroform through formation of three hydrogen bonds (Mertz, E.; Mattei, S.;
      Zimmerman, S. C. Org. Lett. 2000, 2, 2931-2934). The novel nucleoside base was
      synthesized and successfully incorporated into oligonucleotides which were used
      in triple helix melting temperature studies. Low melting temperatures were
      observed when the isoindolin-1-one base was paired opposite CG as well as GC, TA,
      and AT, thus indicating that despite favorable recognition in model studies, the
      artificial base did not effectively recognize duplex DNA to form pyrimidine
      purine-pyrimidine type triple helices.

PMID- 15018926
TI  - Design, synthesis, and alpha(1)-adrenoceptor binding properties of new
      arylpiperazine derivatives bearing a flavone nucleus as the terminal heterocyclic
      molecular portion.
AB  - Following our research project aimed at obtaining new compounds with high
      affinity and selectivity toward alpha(1)-adrenoceptors (AR), a new class of
      piperazine derivatives was designed, synthesized and biologically tested. The new
      compounds 1-13 are characterized by a flavone system linked, through an ethoxy or
      propoxy spacer, to a phenyl- or pyridazinone-piperazine moiety. Biological data
      showed an interesting profile for the phenylpiperazine subclass found to have a
      nanomolar affinity toward alpha(1)-AR, and less pronounced affinity for alpha(2)
      AR and the 5-HT(1A) serotoninergic receptor. A discussion on the structure
      activity relationship (SAR) of such compounds is also reported, on the basis of
      the flavone substitution pattern, length and functionalization of the spacer, and
      disruption of the phenylpiperazine system.

PMID- 15018927
TI  - Kinetic and structural consequences of the leaving group in substrates of a class
      C beta-lactamase.
AB  - The class C beta-lactamase of Enterobacter cloacae P99 is known to catalyze the
      hydrolysis of certain acyclic (thio)esters. Previous experiments have employed
      thioglycolate, m-hydroxybenzoate, and phenylphosphate leaving groups. The
      relative effectiveness of these leaving groups has now been quantitatively
      assessed by employment of a series of compounds with common acyl groups, and
      found to rank in the order phenylphosphate >m-hydroxybenzoate >thioglycolate.
      Structural models suggest that these leaving groups interact during acylation
      principally with Tyr 150, Lys 315, and Thr 316 of the beta-lactamase active site.
      The positions of the leaving group carboxylates in these models is compared with
      those in published crystal structures of complexes of class C beta-lactamases
      with beta-lactams. The particular effectiveness of the acyl phosphate indicates
      the positions of two oxyanions that strongly interact with the active site. This
      information should be useful in the design of inhibitors of class C beta
      lactamases.

PMID- 15018928
TI  - Synthesis of bicyclic biaryls as glucose-6-phosphatase inhibitors.
AB  - Biaryls, 7-naphthyl-5-s-amino-2,3-dihydrobenzo[b]thiophene-4-carbonitriles (3a
      e), 8-(1-naphthyl)-6-s-amino-isothiochroman-5-carbonitriles (6a-d), 4-(1
      naphthyl)-2-s-aminobezocycloalkene-1-carbonitriles (6e-j), 8-naphthyl-6-s-amino-2
      ethyl-1,2,3,4-tetrahydro-isoquinoline-5-carbonitrle (6k-n), 1-naphthyl-3-s-amino
      10H-9-thia-phenantherene-4-carbonitriles (8a-e) and 1-(1-naphthyl)-3-s-amino-9,10
      dihydrophenantherene-4-carbonitriles (8f-i) have been prepared through carbanion
      induced ring transformation reactions of 6-naphthyl-3-cyano-4-s-amino-2H-pyran-2
      ones (1) from respective ketones (2, 5, and 7). These compounds have been
      evaluated for their glucose-6-phosphatase inhibitory activity and only 6a, c, j,
      m, c, d, h displayed significant inhibition of the glucose-6-phosphatase.

PMID- 15018929
TI  - Synthesis and structure-activity relationships of a new model of arylpiperazines.
      Part 7: Study of the influence of lipophilic factors at the terminal amide
      fragment on 5-HT(1A) affinity/selectivity.
AB  - The influence of lipophilic factors at the amide fragment of a new series of (+/
      )-7a-alkyl-2-[4-(4-arylpiperazin-1-yl)butyl]-1,3-dioxoperhydropyrrolo[1,2
      c]imidazoles 2 and of (+/-)-7a-alkyl-2-[(4-arylpiperazin-1-yl)methyl]-1,3
      dioxoperhydropyrrolo[1,2-c]imidazoles 3 has been studied. Variations of logP have
      been carried out by introducing different hydrocarbonated substituents (R(1)) at
      the position 7a of the bicyclohydantoin, namely the non-pharmacophoric part. All
      the new compounds exhibit high potency for the 5-HT(1A) receptor; however,
      affinities for the alpha(1) receptor are high for compounds 2a-l while compounds
      3a-f are selective over this adrenergic receptor. On the other hand, differences
      in logP do not notably affect the K(i) values for the above receptors.

PMID- 15018930
TI  - Equol, a natural estrogenic metabolite from soy isoflavones: convenient
      preparation and resolution of R- and S-equols and their differing binding and
      biological activity through estrogen receptors alpha and beta.
AB  - Equol is a metabolite produced in vivo from the soy phytoestrogen daidzein by the
      action of gut microflora. It is known to be estrogenic, so human exposure to
      equol could have significant biological effects. Equol is a chiral molecule that
      can exist as the enantiomers R-equol and S-equol. To study the biological
      activity of racemic (+/-)-equol, as well as that of its pure enantiomers, we
      developed an efficient and convenient method to prepare (+/-)-equol from
      available isoflavanoid precursors. Furthermore, we optimized a method to separate
      the enantiomers of equol by chiral HPLC, and we studied for the first time, the
      activities of the enantiomers on the two estrogen receptors, ERalpha and ERbeta.
      In binding assays, S-equol has a high binding affinity, preferential for ERbeta
      (K(i)[ERbeta]=16 nM; beta/alpha=13 fold), that is comparable to that of genistein
      (K(i)[ERbeta]=6.7 nM; beta/alpha=16), whereas R-equol binds more weakly and with
      a preference for ERalpha (K(i)[ERalpha]=50 nM; beta/alpha=0.29). All equol
      isomers have higher affinity for both ERs than does the biosynthetic precursor
      daidzein. The availability and the in vitro characterization of the equol
      enantiomers should enable their biological effects to be studied in detail.

PMID- 15018931
TI  - Development.

PMID- 15018932
TI  - Asymmetric localization and function of cell-fate determinants: a fly's view.
AB  - One mechanism to generate daughter cells with distinct fates is the asymmetric
      inheritance of regulatory proteins, leading to differential gene regulation in
      the daughter cells. This mode of cell division is termed 'asymmetric cell
      division.' The nervous system of the fly employs asymmetric cell division, both
      in the central nervous system, to generate neural precursors, neurons and glial
      cells; and in the peripheral nervous system, to create sensory organs that are
      composed of multiple cell types. These cell lineages are excellent models to
      examine the gene expression program that leads to fate acquisition, the cell-fate
      determinants that control these programs and how these determinants, in turn, are
      distributed through cell polarity machinery.

PMID- 15018933
TI  - Cell fate decisions and patterning in the vertebrate retina: the importance of
      timing, asymmetry, polarity and waves.
AB  - The differentiation of distinct cell populations in the retina is a multi-step
      process that involves cell cycle exit, migration, and dramatic changes of cell
      morphology. All these steps are tightly controlled by multiple regulatory
      pathways, which involve both cell-autonomous networks of transcription factors
      and cell-cell signaling events. Additional regulatory inputs into cell fate
      decisions have been recently suggested: accumulating evidence shows that the
      timing of cell cycle exit, the orientation of the mitotic spindle during the last
      cell division, and the polarity of neuronal progenitor cells could play important
      roles in cell fate determination.

PMID- 15018934
TI  - Specification of chemosensory neuron subtype identities in Caenorhabditis
      elegans.
AB  - Cellular diversity in the nervous system arises from the presence of multiple
      neuronal subtypes, each of which is specialized to perform a unique function.
      Work in Caenorhabditis elegans has begun to reveal the pathways that are
      essential for the specification of identities of neuronal subtypes in its
      chemosensory system. The functions of each chemosensory neuron subtype are
      specified by distinct developmental cascades, using molecules from well-conserved
      transcription factor families. Additional cellular complexity is generated by
      novel mechanisms that further diversify the identities of the left and right
      members of a bilateral sensory neuron pair.

PMID- 15018935
TI  - Odorant receptor gene choice in olfactory sensory neurons: the one receptor-one
      neuron hypothesis revisited.
AB  - Designed for general chemical recognition, the mammalian olfactory system shares
      many similarities with the immune system. Among these is the popular notion that
      a single olfactory sensory neuron expresses a single odorant receptor gene, while
      all other approximately 1000 genes of this type remain silent. Here, I examine
      the evidence supporting the one receptor-one neuron hypothesis. I conclude that,
      contrary to widespread belief, it is far from being proven. I propose an
      hypothesis of a developmental phase of oligogenic expression that is followed by
      positive and negative selection resulting usually in cells with one expressed
      receptor. Curiously, selective processes are well established and widely accepted
      for lymphocytes, but these concepts are essentially ignored for olfactory sensory
      neurons, despite the analogies that are frequently made between these two
      systems. More attention must be paid to odorant receptor gene choice and
      expression during development and neuronal differentiation.

PMID- 15018936
TI  - Mechanisms of glial development.
AB  - Glial cells comprise most of the non-neuronal cells of the brain and peripheral
      nervous system, and include the myelin-forming oligodendrocytes and Schwann
      cells, radial glia and astrocytes. Their functions are diverse and include almost
      every aspect of nervous system function, from the birth and death of cells to the
      migrations and cell-cell interactions that connect and integrate the working
      elements of the nervous system. Recent studies have provided exciting insights
      into the mechanisms that drive the conversion into a glial cell and the
      developmental signals that guide the behavior of these multifunctional cells. An
      emerging theme is the so-called glial lineage being more diverse and more plastic
      than was previously thought. Here, we highlight some recent insights into glial
      development.

PMID- 15018937
TI  - Secreted cell signaling molecules in axon guidance.
AB  - The growth cones of developing neurons respond to specific guidance cues in their
      extracellular environment. Recent studies have shown that secreted signaling
      molecules from protein families that are best known for their roles as morphogens
      in specifying cell fate can function as axon guidance molecules. These signaling
      molecules seem to act directly on the growth cone and thus are likely to activate
      non-canonical signaling pathways that are coupled to the cytoskeleton.

PMID- 15018938
TI  - The optic chiasm as a midline choice point.
AB  - The mouse optic chiasm is a model for axon guidance at the midline and for
      analyzing how binocular vision is patterned. Recent work has identified several
      molecular players that influence the binary decision that retinal ganglion cells
      make at the optic chiasm, to either cross or avoid the midline. An ephrin-B
      localized to the midline, together with an EphB receptor and a zinc-finger
      transcription factor expressed exclusively in the ventrotemporal retina where
      ipsilaterally projecting retinal ganglion cells are located, comprise a molecular
      program for the uncrossed pathway. In addition, the mechanisms for axon
      divergence in the optic chiasm are discussed in the context of other popular
      models for midline axon guidance.

PMID- 15018939
TI  - Retinal axon guidance: novel mechanisms for steering.
AB  - Axons from the retina traverse different molecular territories as they navigate
      to the tectum. A single territory might span only a few cell diameters and
      harbour multiple guidance cues, many of which are beginning to be characterized.
      Also present in the pathway are 'modulators' that influence a growth cone's
      response to a coincident signal but do not guide growth directly. An emerging
      principle is that the growth cone, itself, changes molecularly as it journeys
      through the visual pathway. Growing retinal axons contain mRNAs, ubiquitinating
      and apoptotic enzymes, translation and degradation machinery. Guidance cues can
      trigger rapid and local synthesis, degradation and endocytosis of proteins,
      providing a fast and flexible way for growth cones to respond to cues in their
      microenvironment and to alter their responsiveness. The data raise the idea that
      the localized synthesis and downregulation of proteins might help to steer
      retinal axon growth and, further, might contribute to the changing character of a
      growth cone as it ages.

PMID- 15018940
TI  - Development of the zebrafish lateral line.
AB  - The lateral line system is simple (comprising six cell types), its sense organs
      form according to a defined and reproducible pattern, and its neurons are easily
      visualized. In the zebrafish, these advantages can be combined with a wealth of
      genetic tools, making this system ideally suited to a combined molecular,
      cellular and genetic analysis. Recent progress has taken advantage of these
      various qualities to elucidate the mechanism that drives the migration from head
      to tail of the sense organ precursor cells, and to approach the questions
      surrounding axonal guidance and target recognition.

PMID- 15018941
TI  - Dendritic development: lessons from Drosophila and related branches.
AB  - Dendrites show remarkable diversity in morphology and function, but the
      mechanisms that produce the characteristic forms is poorly understood. Insect
      systems offer a unique opportunity to manipulate and study identified neurons in
      otherwise undisturbed environments. Recent studies in Drosophila show that
      dendritic targeting, branching patterns, territories, and metamorphic remodeling
      are controlled in specific ways, by intrinsic genetic programs and extrinsic
      cues, with important implications for function. Here, we review some recent
      advances in our understanding of dendritic development in insects, focusing
      primarily on insights that have been gained from studies of Drosophila.

PMID- 15018942
TI  - Molecular mechanisms of target specificity during synapse formation.
AB  - Neurons are connected with a high degree of specificity in neuronal circuits.
      Axon guidance mechanisms are responsible for directing axons to their approximate
      target region. It is not well understood how precise synaptic connections form
      between specific pre- and postsynaptic neurons within the target area. Recent
      analysis of a group of cell surface proteins in different systems has shed light
      on the diverse cellular and molecular mechanisms that generate the precise
      patterns of connectivity.

PMID- 15018943
TI  - Synaptic basis for developmental plasticity in somatosensory cortex.
AB  - Sensory experience drives plasticity of the body map in developing and adult
      somatosensory cortex, but the synaptic mechanisms underlying such plasticity are
      not well understood. Recently, several mechanisms that are likely to contribute
      to map plasticity have been directly observed in response to altered experience
      in vivo. These mechanisms include long-term potentiation and long-term depression
      at specific excitatory synapses, competition between lemniscal (barrel) and non
      lemniscal (septal) processing streams, and regulation of the number of inhibitory
      synapses.

PMID- 15018944
TI  - Activity-dependent organization of inhibitory circuits: lessons from the auditory
      system.
AB  - In contrast to our detailed knowledge about the development and plasticity of
      excitatory neuronal circuits, little is known about the development of inhibitory
      circuits. Recent studies from the developing mammalian auditory system have
      revealed the presence of substantial activity-dependent synaptic reorganization
      in several inhibitory pathways. These studies importantly shed some new light on
      the general rules and cellular mechanisms that manage the organization of precise
      inhibitory circuits in the developing brain.

PMID- 15018945
TI  - Structural dynamics of synapses in living animals.
AB  - Recently, there has been increasing interest in the use of in vivo imaging
      approaches in the study of the way that synaptic circuits become established and
      the degree to which they stabilize in mature brains. We review progress since the
      first efforts, two decades ago, at in vivo synaptic imaging and highlight the
      more recent advances in molecular biology, optics and neurobiological imaging
      that have fueled a mini-renaissance in this line of inquiry. Many of the
      technical problems that limited early efforts still remain, but the rapid pace of
      molecular and optical innovation might soon transform this specialized field into
      one that is more 'mainstream'.

PMID- 15018946
TI  - Human microcephaly.
AB  - Microcephaly is defined as a reduction in head circumference and this clinical
      finding infers that an individual has a significant diminution in brain volume.
      Microcephaly can be usefully divided into primary microcephaly, in which the
      brain fails to grow to the correct size during pregnancy, and secondary
      microcephaly, in which the brain is the expected size at birth but subsequently
      fails to grow normally. Current work suggests that primary microcephaly is caused
      by a decrease in the number of neurones generated during neurogenesis, but that
      in secondary microcephaly it is the number of dendritic processes and synaptic
      connections that is reduced. Important insights into human neurogenesis are being
      revealed by the study of rare genetic diseases that involve primary microcephaly,
      illustrated by the identification of the Microcephalin, abnormal spindle in
      microcephaly and ataxia-telangiectasia and Rad3-related genes. Furthermore, these
      findings facilitate the search for the evolutionary changes that have lead to the
      human brain being so much larger than that of any other primates.

PMID- 15018947
TI  - Nogo and axon regeneration.
AB  - Nogo-A is one of several neurite growth inhibitory components present in
      oligodendrocytes and CNS myelin membranes. Nogo has a crucial role in restricting
      axonal regeneration and compensatory fibre growth in the injured adult mammalian
      CNS. Recent studies have shown that in vivo applications of Nogo neutralizing
      antibodies, peptides blocking the Nogo receptor subunit NgR, or blockers of the
      postreceptor components Rho-A and ROCK induce long-distance axonal regeneration
      and compensatory sprouting, accompanied by an impressive enhancement of
      functional recovery, in the rat and mouse spinal cord.

PMID- 15018948
TI  - Disguising adult neural stem cells.
AB  - A description of adult neural stem cells has remained somewhat elusive. With no
      unique and definitive markers to label stem cells in general, neural stem cells
      are difficult to identify definitively and one is forced to examine cell behavior
      - leading to the retrospective identification of a stem cell. The most prevalent
      view in the literature describes the adult forebrain neural stem cell as a
      relatively quiescent subependymal cell that expresses glial fibrillary acidic
      protein. In this review we summarize some of the recent studies that have
      supported or challenged this conception of the nature of the adult forebrain
      neural stem cell. We highlight and compare the experimental paradigms that have
      led to our current state of knowledge and conclude that there is no reason at
      present to abandon the prevailing view of adult neural stem cell identity.

PMID- 15018949
TI  - The use of yeast and moulds as sensing elements in biosensors.
AB  - Whole cell biosensors are able to provide information that sensors based on
      single and multiple types of molecules are unable to do. For example, broad
      spectrum catabolite analysis, cell toxicity and genotoxicity are best detected in
      the context of a functioning cell. Most whole cell sensors have used bacterial
      cells as the sensing element. Fungal cells, however, can provide all of the
      advantages bacterial cells offer but in addition they can provide information
      that is more relevant to other eukaryote organisms. These cells are easy to
      cultivate, manipulate for sensor configurations and are amenable to a wide range
      of transducer methodologies. An overview of the use of yeast and filamentous
      fungi as the sensing element of some biosensors is presented here.

PMID- 15018951
TI  - Cholesterol amperometric biosensor based on cytochrome P450scc.
AB  - A screen-printed enzyme electrode based on flavocytochrome P450scc (RfP450scc)
      for amperometric determination of cholesterol has been developed. A one-step
      method for RfP450scc immobilization in the presence of glutaraldehyde or by
      entrapment of enzyme within a hydrogel of agarose is discussed. The sensitivity
      of the biosensor based on immobilization procedures of flavocytochrome P450scc by
      glutaric aldehyde is 13.8 nA microM(-1) and the detection limit is 300 microM
      with a coefficient of linearity 0.98 for cholesterol in the presence of sodium
      cholate as detergent. The detection limits and the sensitivity of the agarose
      based electrode are 155 microM and 6.9 nA microM(-1) with a linearity coefficient
      of 0.99. For both types of electrodes, the amperometric response to cholesterol
      in the presence of detergent was rather quick (1.5-2 min).

PMID- 15018950
TI  - Immobilization of hemoglobin on zirconium dioxide nanoparticles for preparation
      of a novel hydrogen peroxide biosensor.
AB  - Direct electrochemistry and thermal stability of hemoglobin (Hb) immobilized on a
      nanometer-sized zirconium dioxide (ZrO2) modified pyrolytic graphite (PG)
      electrode were studied. The immobilized Hb displayed a couple of stable and well
      defined redox peaks with an electron transfer rate constant of (7.90 +/- 0.93)s(
      1) and a formal potential of -0.361 V (-0.12 V versus NHE) in 0.1M pH 7.0 PBS.
      Both nanometer-sized ZrO2 and dimethyl sulfoxide (DMSO) could accelerate the
      electron transfer between Hb and the electrode. Spectroscopy analysis of the
      Hb/ZrO2/DMSO film showed that the immobilized Hb could retain its natural
      structure. This modified electrode showed a high thermal stability up to 74
      degrees C and an electrocatalytic activity to the reduction of hydrogen peroxide
      (H2O2) without the aid of an electron mediator. The electrocatalytic response
      showed a linear dependence on the H2O2 concentration ranging from 1.5 to 30.2
      microM with a detection limit of 0.14 microM at 3sigma. The apparent Michaelis
      Menten constant KMapp for H2O2 sensor was estimated to be (0.31 +/- 0.02) mM,
      showing a high affinity.

PMID- 15018952
TI  - Construction and characterization of novel dual stress-responsive bacterial
      biosensors.
AB  - Using the genes for the green fluorescence protein and Xenorhabdus luminescens
      luciferase operon and the promoters for the recA and katG genes, two stress
      responsive Escherichia coli biosensor strains have been constructed that can
      individually or concurrently respond to oxidative and genotoxic conditions.
      Strain DUO-1 carries the pRGDK1 plasmid, which has the recA::GFPuv4 and
      katG::luxCDABE fusion genes oriented divergently with each other, while in DUO-2,
      i.e., pRGDK2, they are in a tandem orientation, with the recA promoter showing
      run-though transcription of the katG::luxCDABE fusion. These two strains and
      their responses were characterized using several known hydroxyl radical-forming
      chemicals, e.g., hydrogen peroxide and cadmium chloride, along with some
      genotoxins, e.g., mitomycin C and methyl-N-nitro-N-nitrosoguanidine, and some
      general toxicants. Both strains showed an induction of green fluorescent protein
      (GFP) and bioluminescence when they experienced DNA and oxidative damage,
      respectively, while the tandem orientation of the two fusion genes within DUO-2
      allowed it to also sensitively respond to genotoxins via the production of
      bioluminescence. However, the characteristics of DUO-2's bioluminescent response
      to each stress were easily distinguishable, making it useful for the detection of
      both stresses. Furthermore, tests with mixtures of chemicals showed that both DUO
      1 and DUO-2 were responsive when chemicals causing oxidative or genotoxic stress
      were present as a single chemical or within complex chemical mixtures.

PMID- 15018953
TI  - A novel nanolayer biosensor principle.
AB  - A method for eliminating the mass transport limitation on biosensor surfaces is
      introduced. The measurement of macromolecular binding kinetics on plane surfaces
      is the key objective of many evanescent wave (e.g. total internal reflection
      fluorescence (TIRF)), and surface plasmon resonance (SPR) based biosensor
      systems, allowing the determination of binding constants within minutes or hours.
      However, these methods are limited in not being rigorously applicable to large
      macromolecules like proteins or DNA, since the on-rates are transport limited due
      to a Nernst diffusion layer of 5-10 microm thickness. Thus, for the binding of
      fibrinogen (340 kDa) to a surface current SPR biosensors will show a mass
      transport coefficient of ca. 2 x 10(-6) m/s. In a novel approach with an
      immiscible fluid vesicle (e.g. air bubble), it has been possible to generate
      nanoscopic fluid films of ca. 200 nm thickness on the sensor surface of an
      interfacial TIRF rheometer system. The thickness of the liquid film can be can be
      easily probed and measured by evanescent wave technology. This nanofilm technique
      increases the mass transport coefficient for fibrinogen to ca. 1 x 10(-4) m/s
      eliminating the mass transport limitation, making the binding rates reaction-rate
      limited. From the resulting exponential kinetic functions, lasting only 20-30s,
      the kinetic constants for the binding reaction can easily be extracted and the
      binding constants calculated. As a possible mechanism for the air bubble effect
      it is suggested that the aqueous fluid flow in the rheometer cell is separated by
      the air bubble below the level of the Nernst boundary layer into two independent
      laminar fluid flows of differing velocity: (i) a slow to stationary nanostream
      ca. 200 nm thick strongly adhering to the surface; and (ii) the bulk fluid
      streaming over it at a much higher rate in the wake of the air bubble. Surprising
      properties of the nanofluidic film are: (i) its long persistence for at least 30
      60s after the air bubble has passed (2.5s); and (ii) the absence of solute
      depletion. It is suggested that a new liquid-liquid interface (i.e. a "vortex
      sheet") between the two fluid flows plays a decisive role, lending metastability
      to the nanofluidic film and replenishing its protein concentration via the
      vortices-thus upholding exponential binding kinetics. Finally, the system relaxes
      via turbulent reattachment of the two fluid flows to the original velocity
      profile. It is concluded that this technique opens a fundamentally novel approach
      to the construction of macromolecular biosensors.

PMID- 15018955
TI  - Application of a miniature biochip using the molecular beacon probe in breast
      cancer gene BRCA1 detection.
AB  - We report for the first time the application of a biochip using the molecular
      beacon (MB) detection scheme. The usability of this biochip novel detection
      system for the analysis of the breast cancer gene BRCA1 is demonstrated using
      molecular beacon probes. The MB is designed for the BRCA1 gene and a miniature
      biochip system is used for detection. The performance of the biochip-MB detection
      system is evaluated. The optimum conditions for the MB system for highest
      fluorescence detection sensitivity are investigated for the detection system. The
      detection of BRCA1 gene is successfully demonstrated in solution and the limit of
      detection (LOD) is estimated as 70 nM.

PMID- 15018954
TI  - Development of an immunosensor for human ferritin, a nonspecific tumor marker,
      based on surface plasmon resonance.
AB  - A direct human ferritin immunosensor was developed using anti-human ferritin
      monoclonal antibodies (MAbs) immobilized on the gold surface of a self-assembled
      surface plasmon resonance (SPR) apparatus. A kind of self-assembled monolayer
      (SAM) prepared by cystamine-glutaraldehyde method was applied to immobilize the
      MAbs. The reusability of the sensor chip adopting the SAM was found to be better
      than the other immobilization methods including adsorption, protein A,
      concanavalin A method. Ten cycles of measurements could be performed on the same
      chip regenerated with a 0.1M HCl solution. A linear relationship existed between
      the angle shifts (millidegrees) and the log values of ferritin concentrations in
      the range from 0.2 to 200 ng/ml in buffer and human serum. When used for 15 days,
      the angle shifts were all >95% of those on the response at the first day. A 10 M
      NaOH solution was used for clearing nonspecific binding in human serum.
      Correlation coefficient was 0.991 between this SPR method and chemiluminescent
      immunoassay for determination of ferritin in clinical human serum samples. The
      SPR sensor offers advantages of simplicity of immobilization, high sensitivity,
      high specificity, low sample requirement, high reusability, no label and no
      pretreatment etc.

PMID- 15018956
TI  - Direct electrical detection of hybridization at DNA-modified silicon surfaces.
AB  - Electrochemical impedance spectroscopy was used to investigate the changes in
      interfacial electrical properties that arise when DNA-modified Si(111) surfaces
      are exposed to solution-phase DNA oligonucleotides with complementary and non
      complementary sequences. The n- and p-type silicon(111) samples were covalently
      linked to DNA molecules via direct Si?C linkages without any intervening oxide
      layer. Exposure to solutions containing DNA oligonucleotides with the
      complementary sequence produced significant changes in both real and imaginary
      components of the electrical impedance, while exposure to DNA with non
      complementary sequences generated negligible responses. These changes in
      electrical properties were corroborated with fluorescence measurements and were
      reproduced in multiple hybridization-denaturation cycles. The ability to detect
      DNA hybridization is strongly frequency-dependent. Modeling of the response and
      comparison of results on different silicon bulk doping shows that the sensitivity
      to DNA hybridization arises from DNA-induced changes in the resistance of the
      silicon substrate and the resistance of the molecular layers.

PMID- 15018957
TI  - Ultrasonic deposition of cells on a surface.
AB  - Bacteria in water have been driven to a glass surface by an ultrasonic standing
      wave. On an antibody coated surface capture of Bacillus subtilis var niger (BG)
      spores (6.6 x 10(6) ml(-1)) was increased more than 200-fold over above the
      efficiency in the absence of ultrasound. In microfluidic (non-turbulent) systems
      detection of particles by sensors operating at a surface is diffusion limited.
      This results in very low detection abilities particularly for particles with
      diameters greater than 1 microm. Ultrasound is used here to drive bacterial
      spores to a wall and overcome this limitation. The results confirm: (1) pressure
      nodes can be formed close to the water-glass interface when the glass thickness
      is near half the ultrasonic wavelength; (2) the antibody used was able to capture
      spores in the presence of an ultrasonic standing wave.

PMID- 15018958
TI  - Novel biosensors for quantitative phytic acid and phytase measurement.
AB  - Phytase (EC 3.1.3.26) and phytic acid (myo-inositol hexaphosphate) play an
      important environmental role in poultry industry and have a health aspect in food
      industry. Novel biosensors have been developed for simple, one step quantitative
      phytic acid and phytase detection. A system based on the sequentially acting
      enzyme phytase and pyruvate oxidase (POD) was employed for the development of
      phytase and phytic acid biosensors. Poly(carbamoylsulphonate) (PCS) hydrogel
      immobilized POD electrode was applied for the detection of phytase. It was based
      on the indication of phosphate ions produced by the hydrolysis of phytic acid.
      The phytase biosensor showed a linear response ranging from 0.5 to 6.0 units/ml.
      A bi-enzyme sensor based on co-immobilization of phytase and POD was developed
      for the detection of phytic acid on the basis of amperometric detection of the
      enzymatically-generated hydrogen peroxide at 0.6 V versus Ag/AgCl. It showed a
      linear response ranging from 0.2 to 2.0 mM with a detection limit of 0.002 mM.

PMID- 15018959
TI  - Poly(ethylene glycol) interfaces: an approach for enhanced performance of
      microfluidic systems.
AB  - Microfluidic systems are extensively used platform for analytical and therapeutic
      applications. One of the major problems encountered in these systems is the loss
      of material due to non-specific surface interactions. When biological solutions
      are flowed through microchannels, they tend to adsorb on the surface due to the
      negative charge of the surface. This results in a reduced efficiency of the
      system which can be critical in sensitive biological analysis. Poly(ethylene
      glycol) (PEG) is known to form non-fouling interfaces on silicon and glass which
      are common materials used in microfluidic systems. The most common approach for
      modifying silicon/glass with PEG involves a solution phase protocol. Since the
      micro/nanofluidic systems have channel sizes ranging from hundreds of microns to
      submicron with variety of complicated network, this surface modification approach
      is not sufficient in forming uniform, conformal, and ultrathin films on the
      surface. Due to the enclosed features in these systems, the properties of liquids
      such as viscosity and surface tension play an important role in the clogging and
      eventually biofouling of these microchannels. Hence, we have developed a solvent
      free vapor deposition protocol for modifying silicon/glass surfaces with PEG.
      Various concentrations of protein solutions were flowed through unmodified and
      PEG-modified glass microcapillaries of different lengths at different flow rates.
      PEG surfaces formed on silicon have shown 80% reduction in protein adsorption in
      static conditions.

PMID- 15018960
TI  - Real-time analysis of protein adsorption to a variety of thin films.
AB  - The ability of a fluorescence-based array biosensor to screen surfaces for the
      adsorption of biomolecules in real-time is demonstrated. Glass microscope slides
      were coated with silanes, including 3-mercaptopropyl-triethoxysilane, 3
      glycidyloxypropyltrimethoxysilane, 3-aminopropyltrimethoxy-silane, octadecyl
      trichlorosilane, and 2-methoxy((polyethylenoxy)propyl)tri-methoxysilane, or with
      polymer thin films, including polystyrene, polyimide, sol-gel,
      poly(dimethylsiloxane), and agarose. The adsorption of Cy5-labeled proteins,
      bovine serum albumin, fibrinogen, and lysozyme onto these surfaces was measured
      using total internal reflection spectroscopy over a period of 50 min. The
      majority of the modified surfaces, apart from notable exceptions including the
      thiol silane and PDMS, behaved as expected upon protein adsorption, and the
      observations could be related to the properties of both the individual surfaces
      and proteins. This study highlights the complex nature of the mechanisms involved
      when a protein interacts at a solid-liquid interface. However, it also
      demonstrates a comparatively generic method with which to screen surfaces for
      their protein resistant properties and to measure surface interactions in real
      time. Furthermore, since the array biosensor can perform multiple measurements
      simultaneously, the interactions of a variety of proteins with a single surface
      can be monitored.

PMID- 15018961
TI  - Determination of beta-D-glucose using flow injection analysis and composite-type
      amperometric tubular biosensors.
AB  - An amperometric tubular cell involving composite biosensors for the determination
      of beta-d-glucose in a flow injection analysis (FIA) system is proposed. Diverse
      configurations and parameters are evaluated to improve the system's response. The
      configuration producing less noise resulted when the biosensor was located closer
      to the auxiliary electrode, which also required coupling both electrodes within
      the system under a continuous flow regime. Further, we report on the influence of
      the active area of the biosensor and of the flow rate used. Statistical analyses
      of the data revealed two regions with a linear response range for the
      determination of beta-d-glucose, with a detection limit of 4.7 x 10(-4) M and in
      the low concentration region a sensitivity of 17.46 +/- 0.12 microAM(-1). At the
      beta-d-glucose concentrations studied there was no evidence of enzymatic
      saturation. An increment on the ionic strength of the sample and carrier passing
      through the analysis system decreases its sensitivity. The reproducibility of the
      analytical system in terms of its standard deviation was 2.9% with a 95%
      confidence level, having a lifetime that lasted at least 100 days. beta-d-Glucose
      was determined in different commercial medical glucose-containing solutions, the
      experimental results are in good agreement with those reported by the
      manufacturer.

PMID- 15018962
TI  - Opto-electrical processes in a conducting polymer-bacteriorhodopsin system.
AB  - In this report, we highlight the opto-electrical processes at a conducting
      polymer-bacteriorhodopsin (bR) interface in presence of a voltage bias. Oriented
      bR on a conducting polymer substrate forms a unique hybrid system where the
      oxidation state of the polymer controls the optically activated proton gradient
      in the bR side. The internal conversion of the intermediate deprotonated M-state
      and the proton transfer/transport of bR at the interface can be controlled by the
      electrostatic environment and leads to interesting device features in this
      process.

PMID- 15018963
TI  - Characterization of 3-D collagen hydrogels for functional cell-based biosensing.
AB  - To address the growing demand for functional cell-based assay technologies with
      accelerated drug discovery applications, we have proposed the use of human
      neuroblastoma cells (IMR-32) immobilized in three-dimensional (3-D) collagen
      hydrogel matrices. The gel protects weakly adherent cells from fluid mechanical
      forces while providing a more physiologically relevant 3-D environment. Hydrogels
      made up of collagen, between 0.5 and 1.0mg/ml, exhibited mechanical stability
      adequate to withstand fluid mechanical forces (<0.11 mN) typical of automated
      commercial fluid transfer equipment. Collagen-entrapped cells visualized with the
      aid of confocal microscopy and a potentiometric-sensitive dye, TMRM, exhibited
      round morphology in comparison to flat morphology typical of cells in two
      dimensional (2-D) monolayer cultures. Morphological differentiation characterized
      by neurite extension and cell aggregation was observed for both 2-D and 3-D
      cultures. Differentiated IMR-32 cells failed to develop a resting membrane
      potential typical of excitable cells. Free intracellular calcium was monitored
      with Calcium Green-1. Depolarization-induced Ca 2+influx was only observed with
      differentiated 3-D cells unlike 2-D cells, where calcium flux was observed in
      both differentiated and undifferentiated cells. Taken together, the results
      revealed that collagen hydrogels (0.5 mg/ml collagen) were suitable structural
      supports for weakly adherent cells. However, for voltage-dependent calcium
      channel function applications, further investigations are needed to explain the
      difference between 2-D monolayer and 3-D collagen-entrapped cells.

PMID- 15018964
TI  - Development of novel conductometric biosensors based on immobilised whole cell
      Chlorella vulgaris microalgae.
AB  - A novel biosensor based on immobilised whole cell Chlorella vulgaris microalgae
      as a bioreceptor and interdigitated conductometric electrodes as a transducer has
      been developed and tested for alkaline phosphatase activity (APA) analysis. These
      sensors were also used for the detection of toxic compounds, namely cadmium ions,
      in aquatic habitats. Algae were immobilised inside bovine serum albumin (BSA)
      membranes cross-linked with glutaraldehyde vapours. The detection of the local
      conductivity variations caused by algae enzymatic reactions could be achieved.
      The inhibition of C. vulgaris microalgae Alkaline phosphatase activities in
      presence of cadmium ions was measured. These results were compared with
      measurements in bioassays. It finally appeared that conductometric biosensors
      using algae seemed more sensitive than bioassays to detect low levels of cadmium
      ions (the detection limit for the first experiments was 1 ppb of Cd2+). The main
      advantages of these alkaline phosphatase biosensors consist of their high
      specificity in regard to the toxic compounds they enable to detect, but also on
      their high stability since contrary to enzymatic biosensors, they use whole algae
      cells with APs on their walls.

PMID- 15018965
TI  - Model development and numerical simulation of electric-stimulus-responsive
      hydrogels subject to an externally applied electric field.
AB  - Based on a multi-phasic mixture theory with consideration of ionic diffusion and
      convection, a multi-physic model, called the multi-effect-coupling electric
      stimulus (MECe) model, is developed for simulation of responsive behavior of the
      electric-sensitive hydrogels when they are immersed into a bathing solution
      subject to an externally applied electric field. In the developed model, with
      chemo-electro-mechanical coupling effects, the convection-diffusion equations for
      concentration distribution of diffusive ions incorporate the influence of
      electric potential. The electroneutrality condition is replaced by the Poisson
      equation for distribution of electric potential. The steady and transient
      analyses of hydrogel deformation are easily carried out by the continuity and
      momentum equations of the mixture phase. Further, the computational domain of the
      present model covers both the hydrogel and the surrounding solution. In order to
      solve the present mathematical model consisting of multi-field coupled nonlinear
      partial differential governing equations, a hierarchical iteration technique is
      proposed and a meshless Hermite-Cloud method (HCM) is employed. The steady-state
      simulation of the electric-stimulus responsive hydrogel is numerically conducted
      when it is subjected to an externally applied electric field. The hydrogel
      deformation and the ionic concentrations as well as electric potentials of both
      the hydrogel and external solution are investigated. The parameter influences on
      the swelling behaviors of the hydrogel are also discussed in detail. The
      simulating results are in good agreement with the experimental data and they
      validate the presently developed model.

PMID- 15018966
TI  - Use of micromachined probes for the recording of cardiac electrograms in isolated
      heart tissues.
AB  - Micromachined probes, with iridium (Ir) microelectrodes on silicon shanks, were
      evaluated to assess their suitability for cardiac electrogram recording. The
      electrochemical activation (anodic oxidation) procedure for the circular Ir
      microelectrode was investigated using the square wave potential according to the
      electrode size, number of cycles, and cathodic-anodic potential level of the
      square wave. Increase in the charge storage capacity was pronounced either in
      smaller electrodes or with higher potential level of the square wave. The
      electrode impedance reduced in a similar manner with increasing number of cycle
      irrespective of the electrode size. With either lower potential level (
      0.70/+0.60 V) or smaller number of cycle (200 cycles) than those for the
      activation of stimulating electrode, the likelihood of overactivation of the
      recording microelectrode can be minimized. These anodic IrOx film (AIROF)
      microelectrodes were used for the recording of extracellular electrograms in two
      different ex vivo cardiac tissue preparations. A single-shank microprobe was
      applied to the left ventricle of a mouse heart. Both the spontaneous and paced
      transmural responses propagating between epicardium and endocardium were
      obtained. Longitudinal cardiac wavefronts propagating along the rabbit papillary
      muscle were also recorded with a unique multiple-shank design. The measured mean
      amplitude and the propagation velocity of the extracellular voltage were 12.2 +/-
      1.8 mV and 58.9 +/- 2.2 cm/s, respectively (n = 27). These microprobes with
      precisely defined electrode spacing make a useful tool for the spatial and
      temporal mapping of electrical properties in isolated heart tissues ex vivo.

PMID- 15018967
TI  - A novel method to construct a third-generation biosensor: self-assembling gold
      nanoparticles on thiol-functionalized poly(styrene-co-acrylic acid) nanospheres.
AB  - A novel method for fabrication of horseradish peroxidase (HRP) biosensor has been
      developed by self-assembling gold nanoparticles on thiol-functionalized
      poly(styrene-co-acrylic acid) (St-co-AA) nanospheres. At first, a cleaned gold
      electrode was immersed in thiol-functionalized poly(St-co-AA) nanosphere latex
      prepared by emulsifier-free emulsion polymerization of St with AA and function
      with dithioglycol to assemble the nanospheres, then gold nanoparticles were
      chemisorbed onto the thiol groups. Finally, horseradish peroxidase was
      immobilized on the surface of the gold nanoparticles. The sensor displayed an
      excellent electrocatalytical response to reduction of H2O2 without the aid of an
      electron mediator. The sensor was highly sensitive to hydrogen peroxide with a
      detection limit of 4.0 micromoll(-1), and the linear range was from 10.0
      micromoll(-1) to 7.0 mmoll(-1). The biosensor retained more than 97.8% of its
      original activity after 60 days of use. Moreover, the studied biosensor exhibited
      good current repeatability and good fabrication reproducibility.

PMID- 15018968
TI  - The construction of endothelial cellular biosensing system for the control of
      blood pressure drugs.
AB  - In order to assess blood pressure control drugs, the endothelial cellular
      biosensing system for assessing blood pressure control drugs was constructed.
      This system consists of human umbilical vein endothelial cells (HUVEC) on a
      polyion-coated gold electrode, a platinum counter electrode and an Ag/AgCl
      reference electrode. Nitric oxide (NO) as an indicator of blood vessel relaxation
      was detected with a polyion-coated electrode in the system. The NO detection
      limit of this electrode was 8.4 nM by differential pulse voltammetry (DPV). The
      drugs of blood pressure control (acetylcholine chloride (AcChCl), NOC 7 and NG
      monomethyl-L-arginine (L-NMMA)) were assessed with this endothelial cellular
      biosensing system. One milli molar of AcChCl make NO released from HUVEC
      stimulated by activating endothelial nitric oxide synthase (eNOS) in HUVEC. In
      the case of 5 mM of L-NMMA, NO releasing was inhibited by inhibiting eNOS
      activation by 1 mM of AcChCl. NOC 7 immediately released NO regardless of eNOS
      activation in endothelial cells.

PMID- 15018970
TI  - Effect of cationic lipid and matrix lipid composition on solid lipid nanoparticle
      mediated gene transfer.
AB  - This investigation is focused on the enhancement of in vitro transfection
      activity by optimizing cationic lipid and matrix lipid composition of solid lipid
      nanoparticles (SLN). For this purpose SLN were formulated by using two different
      matrix lipids and six different cationic detergents. These 12 formulations were
      tested for physical parameters such as particle size, zeta potential and DNA
      binding capacity, and also for their biological properties such as cytotoxicity
      and in vitro transfection efficiency. The SLN were produced by hot high-pressure
      homogenization, all formulations were physically stable and showed a highly
      positive surface charge (+34 to +45 mV). In vitro cytotoxicity measurements on
      COS-1 cells revealed that cytotoxicity is strongly dependent on the cationic
      lipid used. SLN made from one-tailed cationic detergents were highly cytotoxic.
      In contrast the two-tailed cationic lipids were all well tolerated. Transfection
      activity seems to be determined by both the cationic lipid and the matrix lipid
      used. Here, the combination of cetylpalmitate and N-[1-(2,3-dioleoyloxy)propyl]
      N,N,N-trimethylammonium chloride led to significantly higher transfection
      efficiencies than in all other tested combinations. These results indicate that
      well tolerated and highly efficient in vitro transfection could be achieved with
      SLN whenever selecting good combinations of two-tailed cationic lipids and matrix
      lipids.

PMID- 15018971
TI  - Development of acrylic-based copolymers for oral insulin delivery.
AB  - We developed nanospheres of crosslinked networks of methacrylic acid grafted with
      poly(ethylene glycol), and acrylic acid grafted with poly(ethylene glycol)
      nanospheres for use as oral insulin delivery devices. The copolymer nanospheres
      were synthesized via free-radical precipitation/dispersion. The average particle
      diameter of the copolymer gel nanospheres at various physiologically relevant pH
      values was characterized using photon correlation spectroscopy. Their size
      increased dramatically as the surrounding pH rose above the pK(a) of the network.
      The nanospheres ranged in diameters from 200 nm at pH of 2.0 to 2 microm at pH
      around 6.0. Insulin was loaded into the copolymers at levels of 9.33 and 9.54 mg
      per 140 mg solid sample, by partitioning from concentrated insulin solutions. In
      vitro studies were performed to study the passage of the insulin-loaded copolymer
      samples in the gastrointestinal tract. Insulin was entrapped at low pH (pH=3.0)
      but released at more neutral pH (pH=7.0). Animal studies were performed to
      investigate the abilities of insulin-loaded copolymer samples to influence the
      serum glucose levels of rats. In studies with diabetic rats, the serum glucose
      level was lower than control values for the animals that received the insulin
      loaded copolymers and lasted for at least 6 h. The insulin loaded copolymer
      nanospheres caused a significant reduction of serum glucose with respect to that
      of a control animal.

PMID- 15018973
TI  - Thiomers: development and in vitro evaluation of a peroral microparticulate
      peptide delivery system.
AB  - The aim of this study was to develop a peroral mucoadhesive microparticulate
      delivery system for peptide drugs. Microparticles containing either the
      mucoadhesive polymer poly(acrylic acid)-cysteine (PAA-Cys) or unmodified PAA, 15%
      insulin used as model peptide drug and 0, 30, 50 and 70% Eudragit RS (MP-RS0, MP
      RS30, MP-RS50 and MP-RS70) were prepared by the emulsification solvent
      evaporation technique. Particle size distribution, release of incorporated
      insulin, mucoadhesive and swelling properties were examined. During preparation
      inter- and intramolecular cross-linking occurred, which could be quantified by
      the amount of disulfide bonds within the resulting particles; this was determined
      to be 69.2% of the total amount of thiol groups. This cross-linking led to a
      higher stability of the particles. Microparticles were spherical displaying a
      rough surface. The particle diameter was in the range of 1-110 microm in the
      following rank order beginning with the largest: MP-RS30>MP-RS50>MP-RS70=MP-RS0.
      The higher the ratio of Eudragit RS in the microparticles, the more prolonged was
      the release of insulin. In the case of MP-RS70, a sustained release over a time
      period of at least 60 min was achieved. Mucoadhesive properties and the capacity
      of water uptake followed the rank order: MP-RS0>MP-RS30>MP-RS50>MP-RS70. Compared
      to particles comprising unmodified PAA, the mucoadhesive properties of the
      thiolated microparticulate systems were up to 14-fold improved. According to
      these results PAA-Cys-Eudragit RS microparticles might be a promising tool for
      the peroral administration of peptide drugs.

PMID- 15018972
TI  - Evidence for restrictive parameters in formulation of insulin-loaded
      nanocapsules.
AB  - Poly(isobutylcyanoacrylate) nanocapsules with an oily core were originally
      proposed for lipophilic drug encapsulation [Int. J. Pharm. 28 (1986) 125] but
      insulin, a hydrosoluble protein, has also been successfully encapsulated by Damge
      et al. [Diabetes 37 (1988) 246]. The aim of this work was to understand if
      several parameters were restrictive for the encapsulation of insulin into the
      oily core of the nanocapsules prepared by interfacial polymerization. The
      encapsulation efficiency of insulin was not affected by the type of insulin since
      the peptides adopted the same association state after their addition to the
      organic phase. Formulation parameters mainly affected the size of the
      nanocapsules obtained but did not influence the insulin encapsulation efficiency.
      In contrast, the order of introduction of insulin and of the monomer in the
      organic phase was shown to control the formation and the characteristics of the
      nanocapsules. The key parameters, which were found to clearly influence the
      encapsulation efficiency of insulin, were the pH of the aqueous insulin solution
      and the origin of the monomer. Both of these parameters can affect the rate of
      the interfacial polymerization. Consequently, the ability of insulin to be
      entrapped into the oil containing nanocapsules appeared to be governed more by
      the rate of the monomer polymerization.

PMID- 15018974
TI  - Development of novel 5-FU-loaded poly(methylidene malonate 2.1.2)-based
      microspheres for the treatment of brain cancers.
AB  - In order to treat malignant brain tumors by local delivery of antineoplastic
      agents, the feasibility of 5-fluorouracil (5-FU)-sustained release biodegradable
      microspheres with a novel material, poly(methylidene malonate 2.1.2), was
      investigated using an emulsion/extraction method. This polymer was expected to
      present a slow degradation rate, thus leading to a long term local delivery
      system. Microparticles were successfully obtained and characterized in terms of
      drug loading, size, morphology and release profile. The size of the particles was
      between 40 and 50 microm, which was compatible with a stereotactic injection
      through a needle. Sufficient drug loadings were obtained (i.e. compatible with
      the preparation of therapeutic 5-FU doses in a minimal volume of injection), and
      perfectly spherical microspheres were observed. The respective influences of the
      polymer molecular weight, the polymer concentration, and the emulsion time on the
      release profiles were studied using a 2(3) factorial design. In the same
      objective, the solvent extraction time was extended while keeping all the
      previous parameters fixed at their optimal values. The in vitro study of these
      different parameters allowed a reduction of the initial burst release, with a
      percentage of 5-FU released after 24 h that was lowered from 90 to 65%, and the
      achievement of a long term drug delivery system, since the release was still
      ongoing after 43 days. Moreover, the microparticles could be gamma-sterilized (25
      kGy) without modification of the release kinetics. Thus, the requested
      specifications to perform animal experiments were attained.

PMID- 15018975
TI  - Association complexes between ovalbumin and cyclodextrins have no effect on the
      immunological properties of ovalbumin.
AB  - Delivery systems are designed to deliver necessary amounts of drugs without
      modifying their biological features. Cyclodextrins (CD) are potential candidates
      for such a role due to their ability to alter physical and chemical properties of
      guest molecules by the formation of inclusion/association complexes. They have
      already been used to stabilize and solubilize peptides and proteins of biological
      importance. However, no systematic study has been reported on their immunological
      effects upon coupling to such proteins. Herein, we prepared and characterized the
      association complexes between alpha-, beta- and hydroxypropyl-beta-cyclodextrin
      and ovalbumin (Ova). Afterward we tested the effect of CD coupling in the Ova
      antigenicity and the immunological effects of CD coupling on Ova oral and
      subcutaneous administration. Our results clearly show that CD-coupled Ova elicits
      the same immunological activities as uncoupled Ova. Therefore, we conclude that
      CDs are immunologically safe for use as delivery systems in animals.

PMID- 15018976
TI  - PLGA microspheres for the ocular delivery of a peptide drug, vancomycin using
      emulsification/spray-drying as the preparation method: in vitro/in vivo studies.
AB  - The aim of this study was an in vitro/in vivo investigation on poly(lactide-co
      glycolide) (PLGA) microspheres as carriers for the topical ocular delivery of a
      peptide drug vancomycin (VA). The microspheres were prepared by an
      emulsification/spray-drying technique that can be proposed as an alternative to
      the double emulsion method for preparation of peptide-loaded microparticles. The
      drug encapsulation efficiencies were close to the theoretical values (84.2
      99.5%); the average particle size, expressed as dvs, was about 11 microm. The
      microspheres were able to modulate the in vitro drug release of VA with a
      behavior dependent on their composition: the highest drug content corresponded to
      the highest release rate. In vivo studies were carried out by assessing the
      pharmacokinetic profile of VA in the aqueous humor of rabbits after topical
      administration of aqueous suspensions of microspheres. High and prolonged VA
      concentrations and increased AUC values (2-fold) with respect to an aqueous
      solution of the drug were observed. Increasing the viscosity of the microsphere
      suspension by addition of a suspending-viscosizing agent (hydroxypropylcellulose)
      did not produce an increase of the ocular bioavailability. PLGA microspheres can
      be proposed as a system for ocular delivery of peptide drugs.

PMID- 15018977
TI  - Preparation and in vitro characterization of amifostine biodegradable
      microcapsules.
AB  - The purpose of this project was to develop sustained release microcapsules of
      amifostine. The microcapsules were prepared using solvent evaporation technique.
      The effect of several formulation variables on the characteristics of the
      microcapsules was studied. The formulation variables studied were drug loading,
      polymer (polylactide-co-glycolide) (PLGA) concentration, and the amount of
      gelatin in the initial aqueous phase. The drug loading was studied at three
      different levels (5, 10, and 25 mg); the PLGA concentration was studied at two
      levels (500 and 1000 mg); and the amount of gelatin used ranged from 2 to 14 mg.
      In general, the microcapsules were less than 155 microm in diameter with median
      size between 50 and 80 microm. While the use of higher amounts of PLGA
      significantly increased the median size of the microcapsules, using higher
      amounts of amifostine had no significant effect, irrespective of the amount of
      PLGA. The use of gelatin, within the range 2-14 mg, did not show any significant
      effect on the particle size distribution. Scanning electron microscopy (SEM) of
      the microcapsules revealed that all nine formulations yielded spherical
      particles. The use of 500 mg PLGA with 10 or 25 mg amifostine yielded
      microcapsules with porous surfaces. The surface pores, however, were not present
      in microcapsules prepared using 1000 mg PLGA. The efficiency of encapsulation
      decreased significantly from 63 to 24% when the amount of amifostine increased
      from 5 to 25 mg in the formulations using 500 mg PLGA. Similarly, the efficiency
      of encapsulation decreased from 87 to 23% when the amount of PLGA was doubled to
      1000 mg. An increase in the amount of amifostine in the formulation using 500 mg
      PLGA also resulted in a significant increase in initial drug release (from 20 to
      62%) within the first hour. These results were consistent with the porous
      morphology of these microcapsules. In general, all batches of microcapsules
      showed 24-96 h sustained drug release.

PMID- 15018978
TI  - Preparation and characterisation of thiolated poly(methacrylic acid)-starch
      compositions.
AB  - The development of mucoadhesive polymer systems, which start swelling in the
      intestine after oral administration without an enteric coating, might be the key
      for drug delivery systems exhibiting a prolonged intestinal residence time. The
      preparation and characterisation of such polymeric excipients was therefore the
      aim of this study. A poly(methacrylic acid)-cysteine conjugate (thiolated PMAA)
      exhibiting 747.8+/-30.9 micromol thiol groups per gram polymer was co
      precipitated with starch at pH 3. The resulting thiolated PMAA-starch composition
      consisting of 24% thiolated PMAA and 76% starch was lyophilised and analysed with
      regard to its swelling behaviour as well as to its cohesive and mucoadhesive
      properties. Results demonstrated that the thiolated PMAA-starch composition does
      not swell at all in a simulated gastric fluid. In contrast, a 4- and 6-fold
      increase in weight by water uptake was observed at pH 5 and 7, respectively.
      Disintegration studies demonstrated improved cohesive properties due to the
      immobilisation of thiol groups on PMAA, which are involved in the formation of
      stabilising inter- and/or intrachain disulfide bonds. Tensile studies
      demonstrated a total work of adhesion of 90.2+/-15.2 and 27.5+/-2.9 microJ for
      thiolated PMAA-starch and PMAA-starch, respectively. These results were confirmed
      by mucoadhesion studies utilising the rotating cylinder method. Thiolated PMAA
      starch represents therefore a promising novel mucoadhesive excipient, which might
      provide a prolonged residence time of various delivery systems in the intestine.

PMID- 15018979
TI  - Cytarabine release from comatrices of albumin microspheres in a poly(lactide-co
      glycolide) film: in vitro and in vivo studies.
AB  - Cytarabine (ara-C) was included in albumin microspheres and these microspheres
      were immersed in a poly(lactide-co-glycolide) (PLGA) film to constitute a
      comatrix system to develop a prolonged form of release. Cytarabine-loaded albumin
      microspheres were synthesized by emulsion, and 25 or 50 mg of drug were included
      in the disperse phase. Thus, microspheres with 46+/-4 microg drug/mg microspheres
      and 50+/-5 microg drug/mg microspheres were obtained, which means a percentage of
      incorporation efficiency of 42+/-4% and 25+/-2%, respectively. These cytarabine
      loaded microspheres were used to prepare PLGA-comatrices. Kinetic release studies
      indicated that total cytarabine release only takes place in the presence of
      protease, probably due to the fact that glutaraldehyde establishes covalent links
      with the amine side group of the drug and cross-links it with the protein matrix.
      A slower kinetic release of the drug was obtained from PLGA-comatrices, although
      only 80% of the included cytarabine was released on day 7. The comatrices were
      subcutaneously implanted in the back of rats and in both cases the ara-C
      administered dose was 36 mg of ara-C per kg of body weight. The drug was detected
      in plasma 10 days. The mean residence time (MRT) of the drug administered by
      these comatrices was 87-91 times larger when compared to the value obtained when
      the drug was administered in solution by intraperitoneal injection. The
      histological studies show that a degradative process of the comatrices takes
      place. The comatrices do not damage surrounding tissue; a normal regeneration of
      the implanted zone was observed.

PMID- 15018980
TI  - In vitro evaluation of floating and drug releasing behaviors of hollow
      microspheres (microballoons) prepared by the emulsion solvent diffusion method.
AB  - Hollow microspheres (microballoons) floatable in JPX III No.1 solution were
      developed as a dosage form characterized by excellent buoyant properties in the
      stomach. Microballoons were prepared by the emulsion solvent diffusion method
      utilizing enteric acrylic polymers codissolved with drug in a mixture of
      dichloromethane and ethanol. The release properties of five different drugs
      exhibiting distinct water solubilities (aspirin, salicylic acid, ethoxybenzamide,
      indomethacin and riboflavin) entrapped within microballoons were investigated.
      Buoyancy of the microballoons decreased with increasing drug release rate. In the
      case of aspirin, salicylic acid and ethoxybenzamide, the drug release profiles of
      microballoons proved a linear relationships by Higuchi plotting. However,
      indomethacin and riboflavin release profiles did not follow the Higuchi equation.
      When the loading amount of riboflavin was higher than the solubility in the
      mixture of dichloromethane and ethanol, the drug release profiles of the
      microballoons displayed an initial burst release. The insoluble riboflavin in the
      mixture of dichloromethane and ethanol adsorbed on to the microballoon surface in
      the crystal state. Such riboflavin crystals were released preferentially at the
      initial stage of the release test, which was attributable to the initial burst.
      In addition, by incorporating a polymer such as hydroxypropylmethylcellulose
      within the shell of microballoons, the release rate of riboflavin from the
      microballoons could be controlled while maintaining high buoyancy.

PMID- 15018981
TI  - Polycomplexes of poly(acrylic acid) with streptomycin sulfate and their
      antibacterial activity.
AB  - Complex formation between streptomycin sulfate and poly(acrylic acid) has been
      studied in aqueous solutions by turbidimetric, potentiometric and viscometric
      methods as well as by FTIR spectroscopy. It was shown that these polycomplexes
      are stabilized by electrostatic interactions. The solubility of polycomplexes was
      examined as a function of pH and it was found that at pH values below 3.1 the
      polycomplexes undergo complete dissociation or dissolution. The antimicrobial
      activity of the drug and its polycomplex was evaluated using Sarcina sp. as a
      model organism. It was demonstrated that the polycomplexes have an antimicrobial
      activity on the same level as the free drug.

PMID- 15018982
TI  - Preparation and evaluation of drug-loaded gelatin nanoparticles for topical
      ophthalmic use.
AB  - Gelatin nanoparticles encapsulating pilocarpine HCl or hydrocortisone as model
      drugs were produced using a desolvation method. The influence of a number of
      preparation parameters on the particle properties was investigated. For the
      pilocarpine HCl-loaded spheres, an influence of the pH during particle
      preparation on the size was observed. Slightly negative zeta potential values
      were measured for all samples. In the case of pilocarpine HCl-loaded spheres, no
      influence of the gelatin type or the pH level was observed, which could be
      attributed to the shielding effect of ions present in the dispersion medium. When
      hydrocortisone was entrapped, a difference in zeta potential value between
      gelatin type A and gelatin type B particles was measured. A high pilocarpine HCl
      entrapment was established. Hydrocortisone was complexed with cyclodextrins in
      order to increase its aqueous solubility. The drug encapsulation was lower than
      in the case of pilocarpine HCl, but still amounted to approximately 30-40%.
      Compared to the aqueous drug solutions, a sustained release for both drugs was
      observed. The release kinetics of pilocarpine HCl are close to zero order, and no
      significant differences were measured between the various preparations. In the
      case of hydrocortisone, the release data suggests a difference in release rate
      depending on the type of cyclodextrin employed.

PMID- 15018983
TI  - Solubility enhancement of celecoxib using beta-cyclodextrin inclusion complexes.
AB  - Celecoxib has very low water solubility. It forms a complex with beta
      cyclodextrin (betaCD) both in aqueous and in solid state. It was observed that
      due to formation of the inclusion complex, the solubility and dissolution rate of
      celecoxib were enhanced. The formation of 1:1 complex with betaCD in solution was
      confirmed by phase solubility and spectral shift studies. The apparent stability
      constants calculated by these techniques were 881.5 and 341.5 M(-1),
      respectively. The solid inclusion complexes of celecoxib and betaCD were prepared
      by the kneading method using different molar proportions of betaCD, and formation
      of solid inclusion complexes of celecoxib and betaCD at different molar ratios
      were confirmed by differential scanning calorimetry. Enhancement of dissolution
      rates with increasing quantity of betaCD in the complex was observed. It was also
      observed that the complexes exhibit higher dissolution rates than the pure drug
      and physical mixture.

PMID- 15018984
TI  - The ophthalmic lyophilisate carrier system (OLCS): development of a novel dosage
      form, freeze-drying technique, and in vitro quality control tests.
AB  - The ophthalmic lyophilisate carrier system (OLCS) is a novel dosage form for
      delivery of pharmacologically active ingredients or other substances improving
      the structure of the tear film to the eye. A drop of lyophilisate containing the
      drug and bulk forming water-soluble or swelling excipients is attached to a
      flexible hydrophobic carrier. Placebo OLCS and OLCS containing several drugs
      commonly used in ophthalmology were compared to conventional eye drops containing
      the same ingredients. A novel lyophilization procedure for the production of this
      dosage form is described, which allows stricter control of the freezing and
      drying conditions and shortens the production cycle by at least an order of
      magnitude. In clinical studies it was found that OLCS are easy to administer and
      well tolerated if the force of adhesion between lyophilisates and carrier strips
      and the structural firmness of the lyophilisates themselves are well controlled.
      These parameters are critical for convenient administration and complete delivery
      of the dose of active ingredients incorporated, therefore suitable in vitro tests
      were developed with which their values can be determined for the purpose of
      process validation. A study of fluorescein OLCS in humans indicated that
      concentration profiles in the cornea and anterior chamber are significantly
      higher than after administration of equal doses of the diagnostic in conventional
      eye drops.

PMID- 15018985
TI  - Tableting and stability evaluation of enteric-coated omeprazole pellets.
AB  - In this study, fluidized-bed manufactured enteric-coated omeprazole pellets were
      compressed into tablets. The stability of the pellets and those of compressed
      tablets were evaluated for remaining omeprazole and for degradation products
      under an accelerated stability protocol. The data were analyzed using the
      artificial neural network (ANN) and analysis of variance (ANOVA). It was found
      that enteric-coated omeprazole pellets could be compressed into quickly
      disintegrating tablets using microcrystalline cellulose granules as the pressure
      absorbing matrix. The ANN, using the multilayer perceptron model, predicted that
      there was a positive correlation between tablet crushing strength and
      microcrystalline cellulose concentration. Microcrystalline cellulose matrix
      showed a strong plastic deformation and all the pellets inside the tablet
      maintained their integrity with no significant change in their surface
      properties. Omeprazole degradation in acid medium was mainly dependent on
      microcrystalline cellulose concentration. A 90-day accelerated stability test in
      brown glass bottles with a desiccant showed that all prototype formulations would
      result in an acceptable stability profile for both remaining omeprazole, and also
      for the increase of impurity concentrations.

PMID- 15018986
TI  - Iron(II) sulfate release from drop-formed lipophilic matrices developed by
      special hot-melt technology.
AB  - Iron(II) sulfate-containing lipophilic matrices were developed by a special hot
      melt technology (melt solidification in drops), using stearin, white wax and
      their mixture as conventional bed materials. The special technology resulted in
      spherical particles which can be filled directly into capsules; these store iron
      as a depot and ensure a slow and uniform release, whereby the irritation of the
      gastric mucosa by the iron can be decreased. The rates of dissolution of the
      iron(II) sulfate from the various lipophilic matrices were different, but
      fundamentally low. Kinetic calculations demonstrated that the rate of dissolution
      of the iron(II) sulfate was of approximately zero kinetic order. The results of
      in vivo experiments on rabbits correlated well with the in vitro data. The plasma
      curves for the animals treated with the iron(II) sulfate preparations varied with
      the excipients in the depot products. The properties and ratio of the bed
      materials influenced the release of the iron(II) sulfate. In all probability, the
      release of the active agent can be regulated through the use of a melt of stearin
      and white wax in different ratios. The development products functioned as a
      sustained-release system and ensured elimination of the irritation of the gastric
      mucosa. At the same time, the results justified the applicability of the special
      hot-melt technology in the development of the solid dosage form.

PMID- 15018987
TI  - Feasibility of a bioadhesive drug delivery system targeted to oesophageal tissue.
AB  - This contribution examines the feasibility of utilising an oesophageal-adhesive
      alginate layer to support model drug particles. Such a bioadhesive system offers
      the prospect of local drug delivery to the oesophagus, which in turn has
      applications in the treatment of conditions including gastro-oesophageal reflux
      disease and oesophageal cancer. Surface-modified (amine, carboxylate and sulfate)
      as well as neutral fluorescent beads were investigated as model drug particles. A
      fluorescence assay technique was utilised to quantify the extent and duration of
      adhesion of a fixed dose of these particles to excised porcine oesophageal
      tissue. Retention of the particles was investigated both from aqueous systems and
      within an adhesive alginate solution. After 30 min significantly higher adhesion
      of neutral beads was recorded from the alginate solution as compared to the
      aqueous suspension (n = 6, P < 0.05). The beads that possessed a negative charge
      showed significantly greater retention within the alginate carrier (n = 6, P <
      0.05). However, the amine-modified beads showed retention profiles that were
      similar both within the alginate carrier and within the aqueous suspension (n =
      6, P > 0.05).

PMID- 15018988
TI  - A simple, high throughput method for the quantification of sodium alginates on
      oesophageal mucosa.
AB  - Sodium alginate is a potential bioadhesive, but the lack of a convenient and
      suitable method for its quantification on the mucosal surface complicates the
      evaluation of its mucosal retentive properties. This paper develops and evaluates
      a spectrophotometric method for the rapid quantification of a range of sodium
      alginates differing in chemical composition, and investigates how quantification
      was influenced by the presence of oesophageal mucosa. The method, based on dye
      complexation with 1,9-dimethyl methylene blue (DMMB) was sensitive to alginate
      molecular weight and uronic acid composition, however, no significant
      correlations between assay performance and alginate molecular characteristics
      were demonstrated. The assay was also influenced by complexation time, calcium
      ions and mucin, but was unaffected by the presence of oesophageal tissue
      scrapings. The assay proved to be capable of quantifying sodium alginate with
      excellent linearity (r = 0.999), reproducibility (CV < 3%) and sensitivity (0.3 g
      l(-1)) and proved to be a precise, high-throughput method that may be used for
      quantifying the retention of sodium alginate on oesophageal mucosa.

PMID- 15018990
TI  - Enhanced paclitaxel bioavailability after oral administration of paclitaxel or
      prodrug to rats pretreated with quercetin.
AB  - The aim of this study was to investigate the effect of quercetin on the
      bioavailability of paclitaxel after the oral administration of paclitaxel or a
      prodrug to rats pretreated with quercetin. Paclitaxel (40 mg/kg) and prodrug (280
      mg/kg, 40 mg/kg as the paclitaxel) were administered orally to rats pretreated
      with quercetin (2, 10, 20 mg/kg). The plasma concentrations of paclitaxel
      pretreated with quercetin were increased significantly (P < 0.01 for paclitaxel;
      P < 0.05 for prodrug) compared to the control. The areas under the plasma
      concentration-time curve (AUC) and the peak concentrations (Cmax) of paclitaxel
      pretreated with quercetin were significantly higher (P < 0.01) than the control.
      The half-life (t(1/2)) and mean residence times were significantly (P < 0.05)
      longer compared to the control. The absolute bioavailability (AB%) of paclitaxel
      pretreated with quercetin was significantly higher (P < 0.01) than the control.
      The AUC of paclitaxel after administration of the prodrug to rats pretreated with
      quercetin was significantly (P < 0.05) higher than the prodrug control. The
      relative bioavailability of paclitaxel after administration of the prodrug to
      rats pretreated with quercetin was 1.25- to 2.02-fold higher than the prodrug
      control. The AB% of paclitaxel was increased significantly (P < 0.05) by
      quercetin from 8.0 to 10.1 and 16.2%. The bioavailability of paclitaxel
      administered as a prodrug with or without pretreatment of quercetin was
      remarkably higher than the control. AUC, AB% and Cmax of paclitaxel after
      administration of the paclitaxel or prodrug pretreated with quercetin for 3 days
      were much higher than those administered after 20 min. It might have resulted
      from the physicochemical properties of the prodrug, which is a water-soluble
      compound and passes through the gastrointestinal mucosa more easily than
      paclitaxel without obstruction of P-gp and cytochrome P-450 in the
      gastrointestinal mucosa. It seems that the development of oral paclitaxel
      preparations as a prodrug or with quercetin is feasible, which is more convenient
      than the i.v. dosage forms.

PMID- 15018989
TI  - Influence of phloretin on the skin permeation of lidocaine from semisolid
      preparations.
AB  - The purpose of the present study was to determine the significance of phloretin
      on the topical permeation of lidocaine using different semisolid preparations as
      delivery systems. One hydrophilic and three lipophilic formulations were used.
      After estimation of the solubility of phloretin and lidocaine in the vehicles and
      analysis of the viscoelastic properties, standard diffusion experiments with
      Franz type diffusion cells through porcine skin were performed. Results indicate
      a general lidocaine enhancement by phloretin in the tested vehicles. The
      permeation was enhanced 1.39-fold in the hydrophilic formulation and between 1.25
      and 1.76-fold in the lipophilic formulations.

PMID- 15018991
TI  - Characterization of Caco-2 cell monolayer drug transport properties by cassette
      dosing using UV/fluorescence HPLC.
AB  - Cassette dosing is commonly used in pharmacokinetic studies to decrease time,
      labor and expenditures. Cassette dosing (having several compounds in a mixture)
      has been used to screen in vitro permeabilities in Caco-2 cell monolayers. The
      cassette dosing method has accelerated both transport experiments and sample
      analyses, which are both part of Caco-2 permeability screening. In this study, a
      cassette dosing method was used for a mixture of heterogeneous test drugs, which
      are transported by various mechanisms across the Caco-2 cell monolayer. To
      characterize the Caco-2 cell monolayer absorption properties, we developed a new
      UV/fluorescence HPLC method for nine heterogeneous drugs. This new analytical
      method is fast and specific for high throughput analysis. Fluorescence detection
      was used to analyze the low concentration of drugs while UV detection was
      suitable for higher concentrations. The permeability results of single drugs and
      the mixture of drugs showed a high degree of similarity for each individual
      compound. All drugs can be applied to the Caco-2 cell culture as a mixture, and
      the cassette dosing method is suitable for permeability studies.

PMID- 15018992
TI  - Phloretin and 6-ketocholestanol: membrane interactions studied by a
      phospholipid/polydiacetylene colorimetric assay and differential scanning
      calorimetry.
AB  - The aim of this study was to investigate membrane interactions of phloretin and 6
      ketocholestanol using different methods. A previously reported colorimetric assay
      with phospholipid/polydiacetylene (PDA) vesicles was used to examine a possible
      interaction of phloretin and 6-ketocholestanol with this target. During this
      interaction the used aggregates of lipids and conjugated PDA undergo a visible
      and quantifiable blue to red color transition. A positive result is indicative
      for a reaction response with membrane lipids of a simplified bilayer structure
      instead of the complex bilayer system of the stratum corneum. Results of this
      test confirm previous proposed membrane interactions by skin diffusion studies.
      Additional differential scanning calorimetry studies with 1,2-dimyristoyl-sn
      glycero-3-phosphocholine (DMPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine
      (DPPC) liposomes confirm a membrane interaction and indicates that phloretin and
      6-ketocholestanol interact with the lipid layer and change structural parameters.
      They strongly decrease the lipid phase transition temperature of DMPC and DPPC
      liposomes by at least about 6.6 degrees C and maximally about 13.9 degrees C
      which refers to a higher fluidity of the membrane.

PMID- 15018993
TI  - Functional characterization of sodium- and chloride-dependent taurine transport
      in human keratinocytes.
AB  - In the skin, taurine acts as an important osmolyte required for keratinocyte
      hydration. It has antioxidant effects, protects cells from UV-induced stress and
      has effects on cell proliferation, inflammation and collagenogenesis. This study
      was performed to find and characterize functionally a taurine transport system in
      keratinocytes and to establish a cell culture model for skin taurine transport
      studies. Uptake of [(3)H]taurine was studied both in the human adult low calcium
      high temperature (HaCaT) cell line and in human native epidermal keratinocytes.
      Uptake of [(3)H]taurine in HaCaT cells was strictly dependent on extracellular
      sodium and chloride. The taurine uptake rate was saturable and indicated
      participation of a single transport system with kinetic parameters of Kt = 5.1 +/
      0.2 microm and Vmax = 320.5 +/- 2.8 pmol/10 min per mg of protein. Uptake was
      strongly inhibited by beta-amino acids (taurine, beta-alanine, hypotaurine, beta
      guanidinopropionic acid), whereas alpha- and gamma-amino acids had little or no
      effect. Taurine uptake in normal keratinocytes was very similar to that in HaCaT
      cells with respect to substrate specificity and affinity. We conclude that
      keratinocytes express the Na(+) and Cl(-) dependent, high-affinity taurine
      transporter. This system accepts beta- and certain gamma-amino acids as
      substrates.

PMID- 15018994
TI  - Chemical and enzymatic stability evaluation of lipoamino acid esters of
      idebenone.
AB  - Lipophilic conjugates of idebenone (IDE) with short-chain alkylamino acids were
      previously synthesized and evaluated in vitro for their antioxidant properties.
      In this study, their susceptibility to chemical and enzymatic hydrolysis was
      evaluated. Results indicated that these derivatives release the parent drug
      quantitatively via enzymatic hydrolysis by serum and liver esterases, with a
      cleavage rate related to the length of the alkyl side chain. Consequently, the
      present lipoamino acid conjugates of IDE are prodrugs and their in vivo effects
      are mediated through the parent compound released in the body.

PMID- 15018995
TI  - Usage of radiopharmaceuticals in the development of pharmaceutical drug delivery
      systems: validation of [99mTc]DTPA and [99mTc]ECD.
AB  - Tablets containing drugs of different lipophilicity, ranitidine and cinarizine,
      and placebo were prepared and their in vitro behaviour was studied by dissolution
      and disintegration tests. [(99m)Tc]Diethylenetriamine-pentaacetic acid
      ([(99m)Tc]DTPA) and [(99m)Tc]ethyl cysteinate dimer ([(99m)Tc]ECD) were used as
      tracers of the process. Both of them were added to tablets during wet
      granulation. Dissolution and disintegration profiles were assessed at different
      pH values (1, 4 and 7). Radioactivity was evaluated in filtered samples and
      scintigraphic studies were carried out in gamma camera. Stability in dissolution
      media was confirmed for both tracers under these conditions. Dissolution and
      disintegration velocity constants were calculated. [(99m)Tc]DTPA proved to be an
      appropriate tracer for polar drugs such as ranitidine. Nevertheless, it was not a
      suitable tracer for lipophilic active drugs such as cinarizine. On the other
      hand, the most lipophilic tracer, [(99m)Tc]ECD, exhibited the opposite behaviour.
      Scintigraphic studies of the disintegration process did not show significant
      differences between placebos and tablets containing active drugs. As
      disintegration is a physical process it does not discriminate between chemical
      differences in tablet formulations. Both methods complement each other because
      the dissolution process can be followed when a suitable radiotracer is chosen
      according to the physicochemical characteristics of the active drug.

PMID- 15018996
TI  - Extension of in-use stability of preservative-free nasalia.
AB  - Nasal drops and nasal sprays are commonly supplied in multi-dose containers that
      usually include suitable levels of an appropriate preservative in order to kill
      or prevent growth of any microorganisms which might enter the dispensing system.
      Preservatives should both protect the patient from infection and prevent spoilage
      of the product. Unfortunately, preservatives often cause unwanted side effects;
      in particular, the nasal mucosa is irritated frequently. Consequently, the use of
      preservatives in nasal preparations should be avoided. The technical design of
      the 3K system, a new multi-dose container, combines several microbiological
      safety features and therefore allows use without preservatives. Earlier tests
      have shown its safety for 6 weeks after the first opening. In order to test the
      microbiological safety of this multi-dose system over longer time periods, an in
      use stability test was designed. The results revealed that the first dose as well
      as the contents complied with the requirements of the European Pharmacopoeia.
      Therefore, from a microbiological point of view for the tested nasalia in the 3K
      system, the stability after opening could be extended from 6 weeks up to several
      months without loss of microbiological quality.

PMID- 15018997
TI  - Kinetic spectrophotometric method for the determination of norfloxacin in
      pharmaceutical formulations.
AB  - A simple and sensitive kinetic spectrophotometric method is described, based on
      the oxidation of norfloxacin with alkaline potassium permanganate. The reaction
      is followed spectrophotometrically by measuring the rate of change of absorbance
      at 603 nm. The initial rate and fixed time (at 3 min) methods are utilized for
      constructing the calibration graphs to determine the concentration of the drug.
      The calibration graphs are linear in the concentration ranges 2.0-20 microg ml(
      1) and 1.0-20 microg ml(-1) using the initial rate and fixed time methods,
      respectively. The results are validated statistically and through recovery
      studies. The method has been successfully applied to the determination of
      norfloxacin in commercial dosage forms. Statistical comparison of the results
      with the reference method shows excellent agreement and indicates no significant
      difference in accuracy and precision.

PMID- 15018998
TI  - Comparison of scanning electron microscopy, dynamic light scattering and
      analytical ultracentrifugation for the sizing of poly(butyl cyanoacrylate)
      nanoparticles.
AB  - Nanoparticles represent promising carriers for controlled drug delivery. This
      work focuses on the size and molecular mass characterization of
      polyalkylcyanoacrylate nanoparticles formed by anionic emulsion polymerization of
      butylcyanoacrylate in the presence of poloxamer 188 as a stabilizer. Three
      different methods were used to determine the size and size distribution of the
      particle populations: scanning electron microscopy (SEM), dynamic light
      scattering (DLS), and analytical ultracentrifugation (ANUC). SEM on freeze-dried
      and Au-shadowed samples showed a relatively narrow distribution of virtually
      spherical particles with a mean diameter of 167 nm. DLS yielded a monomodal
      distribution with hydrodynamic diameters around 199 nm (in the absence of
      additional stabilizer) or 184 nm (in the presence of 1% poloxamer 188). The size
      distribution determined by ANUC using sedimentation velocity analysis was
      somewhat more complex, the size of the most abundant particles being around 184
      nm. Molar particle mass distributions centered around 2.3x10(9) g/mol. The
      advantages and disadvantages of the three sizing techniques are discussed.

PMID- 15018999
TI  - Evaluation of ophthalmic suspensions using surface tension.
AB  - Uniformity and precision of single dose are required for ophthalmic suspensions
      including water-insoluble ingredients. Solid sediments formed after standing
      still must be immediately re-dispersible and distributed homogeneously before
      use. However, selection of an appropriate water-soluble polymer as suspending
      agent is a challenging problem. In this report, the relationship between the
      surface tension and the re-dispersibility of suspensions was investigated. The
      surface tension of 0.1 w/v% fluorometholone suspensions began to decline from 74
      mN/m at 0.0001 w/v% of hydroxypropylmethylcellulose (HPMC) and became almost
      constant at 52 mN/m at 0.01 w/v% of HPMC. Re-dispersion time was less than 4 s
      when HPMC was present at concentrations between 0.0001 w/v% and 0.01 w/v%. At
      these concentrations, aggregation of suspended particles was not observed. When
      indomethacin suspensions at 1.0 w/v% concentration were used, the surface tension
      began to decline from 73 mN/m at 0.0005 w/v% HPMC and became constant at 50 mN/m
      at 0.005 w/v% HPMC. The suspension also showed good re-dispersibility, and a
      uniform suspension was obtained between 0.0005 w/v% and 0.005 w/v% of HPMC. The
      time required for re-dispersion was less than 17 s. The change of surface tension
      showed a good correlation with the concentration of HPMC in ophthalmic
      suspensions having good re-dispersibility. Measurement of the surface tension of
      suspensions provided the optimal concentration of the water-soluble polymers for
      the suspensions of well re-dispersible characteristics. Evaluation of ophthalmic
      suspension using surface tension is a good strategy for formulation of suspending
      pharmaceutical products in the ophthalmic area.

PMID- 15019000
TI  - Determination of the physical state of norethindrone acetate containing
      transdermal drug delivery systems by isothermal microcalorimetry, X-ray
      diffraction, and optical microscopy.
AB  - Transdermal drug delivery systems (TDDS) enable a controlled drug delivery to the
      skin. The low permeability of the stratum corneum necessitates a high drug
      concentration of the polymeric matrix and often requires supersaturation. This,
      however, promotes crystallisation of supersaturated systems. Isothermal
      microcalorimetry at 25 degrees C, polarisation light microscopy, and X-ray powder
      diffraction (XRPD) were used to characterise the crystal growth of norethindrone
      acetate (NEA). The solubility of NEA in the patches determined by these methods
      is about 4%. The crystallisation process could be measured reliably and with a
      high accuracy by microcalorimetry and microscopy. XRPD was considerably less
      sensitive but was the only method allowing a semi-quantitative determination of
      the amounts of crystals formed. The drug-associated heat measured by
      microcalorimetry increased proportionally with increasing NEA concentration in
      the concentration range of 4-10% demonstrating a constant crystallisation rate.
      At a higher supersaturation, such as 12% drug content, the crystallisation
      process was accelerated. The application of Johnson-Mehl-Avrami kinetics for the
      analysis of nucleation and crystal growth of the punched patches indicated a site
      saturated nucleation mechanism and a one-dimensional crystal growth. The
      crystallisation enthalpy of NEA was -22.8+/-2.6 kJ/mol. The most specific method
      to observe the crystal formation is polarisation light microscopy. However, the
      microscopic analysis requires much longer storage times than microcalorimetry to
      detect crystallisation.

PMID- 15019001
TI  - Use of isothermal heat conduction microcalorimetry, X-ray diffraction, and
      optical microscopy for characterisation of crystals grown in steroid combination
      containing transdermal drug delivery systems.
AB  - The combined application of the steroids estradiol (E2) hemihydrate and
      norethindrone acetate (NEA) is desirable for hormone replacement therapy.
      Transdermal drug delivery systems (TDDS) enable a controlled delivery of these
      drugs to the skin. However, in order to attain high skin permeation rates the
      concentration of the dissolved drugs in the TDDSs has to be high. This often
      results in supersaturated systems with a high crystallisation tendency. The
      combination of NEA and E2-hemihydrate in the acrylic matrix of patches yields
      crystals that are different from single drug systems. A new crystal phase showing
      additional X-ray powder diffraction peaks and a new feather-like crystal shape
      appeared. The crystal formation was considerably accelerated and enhanced by
      increasing E2 contents in the patches. The new crystal phase seems to be
      kinetically favoured compared with crystals appearing from pure E2-hemihydrate or
      NEA. A crystallisation enthalpy of -7.9+/-0.95 kJ/mol in the matrix containing a
      1:3 mixture of E2-hemihydrate and NEA was determined by isothermal
      microcalorimetry. The crystallisation rate increased with higher drug
      concentrations. In addition, the influence of patch pre-treatment at 80 degrees C
      prior to storage on crystallisation was investigated. This treatment enabled a
      slight reduction of the crystallisation in the TDDSs. Microcalorimetry enabled
      the classification of various additives according to their influence on the
      crystallisation process.

PMID- 15019003
TI  - The new look and focus of JCE.

PMID- 15019004
TI  - Adherence to long-term therapies: recent WHO report provides some answers but
      poses even more questions.

PMID- 15019002
TI  - Thermodynamics of solutions III: comparison of the solvation of (+)-naproxen with
      other NSAIDs.
AB  - Naproxen was studied by classical thermoanalytical methods, namely sublimation
      calorimetry, solution calorimetry and the solubility method. Temperature
      dependence of a saturated vapor pressure was obtained and the sublimation
      enthalpy, deltaHsub(0) and entropy, deltaSsub(0) and their relative fraction of
      the total process were calculated. These parameters yielded for naproxen were
      compared to the respective data of other naphthalene derivatives. The crystal
      lattice energy of naproxen was calculated by two force fields (Gavezzotti et al.
      and Mayo et al.) and compared to the experimental data. Contributions of
      different motifs of the naproxen molecule to the total packing energy were
      analyzed. The Gibbs energy of solvation as well as enthalpic and entropic terms
      thereof in aliphatic alcohols have been studied for naproxen, and compared to
      model substances and other non-steroid anti-inflammatory drugs (benzoic acid,
      diflunisal and flurbiprofen). The major driving force of the solvation process is
      the enthalpy. The respective contributions of the specific and the non-specific
      solvation interactions in terms of absolute and relative values have been
      investigated.

PMID- 15019005
TI  - Bayes without priors.
AB  - BACKGROUND AND OBJECTIVES: Classical statistical inference has attained a
      dominant position in the expression and interpretation of empirical results in
      biomedicine. Although there have been critics of the methods of hypothesis
      testing, significance testing (P-values), and confidence intervals, these methods
      are used to the exclusion of all others. METHODS: An alternative metaphor and
      inferential computation based on credibility is offered here. RESULTS: It is
      illustrated in three datasets involving incidence rates, and its advantages over
      both classical frequentist inference and Bayesian inference, are detailed.
      CONCLUSION: The message is that for those who are unsatisfied with classical
      methods but cannot make the transition to Bayesianism, there is an alternative
      path.

PMID- 15019006
TI  - Providing more up-to-date estimates of patient survival: a comparison of standard
      survival analysis with period analysis using life-table methods and proportional
      hazards models.
AB  - OBJECTIVE: Standard survival methods can yield out-of-date estimates of long-term
      survival. Period analysis, based on life-table methodology, provides more up-to
      date survival estimates by exploring survival during a restricted recent period
      of interest. It excludes the short-term survival of patients recruited at the
      start of the study. We use statistical models to further develop the method of
      period analysis, providing more up-to-date estimates of survival and the ability
      to explore differences in survival by covariates and adjust for case mix.
      METHODS: We use cancer registry data for colorectal cancer in Leicestershire, UK,
      to illustrate the use of Cox proportional hazards (CPH) models to estimate period
      and standard survival. We compare these estimates with those obtained using life
      table methodology. RESULTS: Period estimates were slightly higher than the
      standard estimates as they reflect recent improvements in short-term survival.
      The results for period analysis using the life-table approach and using CPH
      models were similar. However, CPH models allowed further investigation of other
      risk factors and the ability to control for potential confounding variables.
      CONCLUSION: Using period survival estimates, more up-to-date information is
      available to clinicians and others with an interest in monitoring survival.
      Period CHP models offer all the advantages of statistical modeling, and are
      straightforward to fit in standard statistical packages.

PMID- 15019008
TI  - The value of the CAGE in screening for alcohol abuse and alcohol dependence in
      general clinical populations: a diagnostic meta-analysis.
AB  - OBJECTIVE: To perform a meta-analysis to assess diagnostic characteristics of the
      CAGE in screening for alcohol abuse or dependence in a general clinical
      population and to test a new method for pooling of ROC curves. METHODS: Medline
      search performed over the period 1/1/1974 to 31/12/2001. MEASUREMENT: Calculation
      of diagnostic values. RESULTS: We identified 35 articles using the DSM criteria
      as the gold standard to test the diagnostic value of the CAGE. Only 10 studies
      could be included for the meta-analysis. With a cutoff point > or =2, the pooled
      sensitivity is far better in inpatients (0.87) than in primary care patients
      (0.71) or ambulatory patients (0.60). The pooled specificity also differs for
      each group. The likelihood ratios seem to be relatively constant over the
      populations (overall LR+:3.44;LR-:0.18). We calculated a pooled AUC of 0.87 (95%
      CI 0.85-0.89). At low specificity values, the sensitivity was homogeneous over
      the studies, and at a low sensitivity, the specificity was heterogeneous.
      CONCLUSION: The diagnostic value of the CAGE is of limited value using this test
      for screening purposes at his recommended cutpoint of > or =2.

PMID- 15019007
TI  - Linking hospital discharge and death records--accuracy and sources of bias.
AB  - BACKGROUND AND OBJECTIVE: The aim of this study was to develop and apply an
      automated linkage algorithm to 10 years of California hospitalization discharge
      abstracts and death records (1990 to 1999), evaluate linkage accuracy, and
      identify sources of bias. METHODS: Among the 1,858,458 acute hospital discharge
      records with unique social security numbers (SSNs) from 1 representative year of
      discharge data (1997), which had at least 2 years of follow-up, 66,410 of 69,757
      deaths occurring in the hospital (95%) and 66,998 of 1,788,701 of individuals
      discharged alive (3.7%) linked to death records. Linkage sensitivity and
      specificity were estimated as 0.9524 and 0.9998 and positive and negative
      predictive values as 0.994 and 0.998 (corresponding to 400 incorrect death
      linkages among out-of-hospital death record linkages and 3,300 unidentified
      record pairs among unlinked live discharges). RESULTS: Based upon gold standard
      linkage rates, discharge records for those of age 1 year and older without SSNs
      may have 2,520 additional uncounted posthospitalization deaths at 1 year after
      admission. Gold standard comparison for those with SSNs showed women, the
      elderly, and Hispanics and non-Hispanic Blacks had more unlinked hospital death
      records, although absolute differences were small. The concentration of
      unidentified linkages among discharge records of traditionally vulnerable
      populations may result in understating mortality rates and other estimates (i.e.,
      events with competing hazard of death) for these populations if SSN is
      differentially related to a patient's disease severity and comorbidities.
      CONCLUSION: Because identification of cases of out-of-hospital deaths has
      improved over the past decade, observed improvements in patient survival over
      this time are likely to be conservative.

PMID- 15019009
TI  - Distribution-based criteria for change in health-related quality of life in
      Parkinson's disease.
AB  - BACKGROUND AND OBJECTIVE: To be useful, results from health-related quality of
      life (HRQoL) measures must be interpretable. The objective of this article is to
      examine statistical (distributional) approaches to interpretability. The standard
      error of measurement (SEM) and the standard error of the difference (S(diff)) are
      used in data on individuals with Parkinson's disease to calculate the minimum
      change scores required to be statistically meaningful for each dimension of an
      instrument to assess HRQoL in Parkinson's disease, the PDQ-39. METHODS: Data was
      collected from both a community and a clinic study; in both studies the PDQ-39
      was administered at baseline and follow-up. RESULTS: The patterns of SEMs and
      S(diff)s were similar both across time periods and between samples, for all
      dimensions except Social Support. CONCLUSIONS: The results suggest that, for
      example, six points change on a 0-100 transformed scoring of the Mobility
      dimension may be considered on distributional grounds a minimum meaningful
      change. The demonstrated consistency across occasions and types of sample of SEMs
      and S(diff) for the majority of the dimensions of the PDQ-39, is evidence of the
      theoretically claimed advantage of this measure of sample independence, and
      supports use of this distributional approach to minimum meaningful change.

PMID- 15019010
TI  - Different methods to assess quality of life from multiple follow-ups in a
      longitudinal asthma study.
AB  - BACKGROUND AND OBJECTIVE: Serial measurements obtained during observational
      longitudinal studies offer the opportunity to describe the effects of chronic
      diseases on patient-centered outcomes such as quality of life. The purpose of
      this study was to assess serial Asthma Quality of Life Questionnaire (AQLQ) and
      SF-36 scores against a transition item using three methods of data analysis-final
      minus initial scores, maximum minus minimum scores, and regression line slopes
      through all scores. METHODS: Using receiver operating characteristic (ROC)
      curves, each method of analysis was compared against patients' responses to a
      global transition question about change in asthma status with responses
      dichotomized as "stayed the same or got worse" or "improved." A total of 185
      patients, mean age 41+/-11 years, 83% women, completed the AQLQ and SF-36 three
      to seven times at approximately 8-month intervals over a mean of 24.8+/-3.9
      months. For the AQLQ, all three methods of data analysis performed well against
      the transition item with ROC areas highest for the symptoms, activities, and the
      summary AQLQ scores (0.74-0.78). RESULTS: Overall, ROC areas increased as the
      number of observations increased, ranging from 0.78 to 0.93 for the AQLQ summary
      score for patients with three to six or more assessments, respectively (P =.02).
      As part of the AQLQ, patients cited specific activities in which they were
      limited because of asthma. A total of 66 different activities were cited,
      including limitations in stair climbing, walking, interacting with others,
      sleeping, and working. In ROC analysis, serial measurements of these items also
      performed well against the transition item with areas ranging from 0.72 to 0.75
      for all three methods of analysis. In contrast, ROC areas for the SF-36 Physical
      and Mental Component Summary scores were significantly lower, ranging from 0.59
      to 0.66 compared to the AQLQ areas, indicating that the generic scale was less
      responsive than the disease-specific scale (P< or = .01). The three different
      methods of analysis also provided unique information about the cohort. The final
      minus initial analysis showed that 63% of patients had clinically important
      improvements, the maximum minus minimum analysis showed that over 90% of patients
      had fluctuations in scores that were clinically important, and the slope analysis
      showed that 79% of patients had an overall trend of improvement. CONCLUSIONS:
      This study described possible methods to analyze and present serial data.
      Additional techniques to assess and interpret serial longitudinal data are needed
      to comprehensively describe long-term effects of chronic diseases on quality of
      life.

PMID- 15019011
TI  - Comorbidity of somatic chronic diseases and decline in physical functioning:; the
      Longitudinal Aging Study Amsterdam.
AB  - OBJECTIVE: To assess the association of decline in physical functioning with
      number of chronic diseases and with specific comorbidity in different index
      diseases. METHODS: A longitudinal design was employed using data from 2,497 older
      adults participating in the Longitudinal Aging Study Amsterdam. Logistic
      regression analyses were used to determine influence of chronic diseases on
      change in physical functioning, operationalized using the Edwards-Nunnally index.
      RESULTS: Decline in physical functioning was associated with number of chronic
      diseases (adjusted ORs from 1.58 for 1, to 4.05 for > or =3 diseases).
      Comorbidity of chronic nonspecific lung disease and malignancies had the
      strongest exacerbating influence on decline. An exacerbating effect was also
      found for arthritis in subjects with diabetes or malignancies and for stroke in
      subjects with chronic nonspecific lung disease or malignancies. A weaker effect
      than expected was observed for diabetes in subjects with stroke, malignancies,
      cardiac disease, or peripheral atherosclerosis. CONCLUSION: Comorbidities
      involving chronic diseases that share etiologic factors or pathophysiologic
      mechanisms appear to have a weaker negative influence on decline in physical
      functioning than expected. Results indicate that combinations of diseases that
      both influence physical functioning, but through different mechanisms (locomotor
      symptoms vs. decreased endurance capacity) may be more detrimental than other
      combinations.

PMID- 15019012
TI  - Scaling the sickness impact profile using item response theory: an exploration of
      linearity, adaptive use, and patient driven item weights.
AB  - BACKGROUND AND OBJECTIVE: The objective of the study was to enhance the clinical
      interpretation and practicality of the widely used comprehensive Sickness Impact
      Profile. METHOD: Item Response Theory (extension of the Rasch model) was used to
      calibrate the severity of the SIP items, to assess item bias and to construct
      equally severe short forms of the SIP that can be used interchangeably. The
      scores of 1507 subjects were analyzed. RESULTS: Of the 127 SIP items, 82 items
      fitted the extended Rasch model, i.e., the observed proportions of sickness level
      groups endorsing the items corresponded to the proportions expected by the model.
      The item severity hierarchy allowed a more straightforward interpretation of the
      calibrated SIP-82 scores. Some items showed bias in age, gender, or diagnosis
      groups. The equivalent short forms agreed sufficiently well with the calibrated
      SIP-82 item pool to be used interchangeably. We observed a moderate correlation
      between the original SIP item severity weights and the Rasch item severity
      calibrations (r=0.53). CONCLUSION: The interpretability and practicality of the
      SIP was enhanced by the IRT calibration. Using the item calibrations, short forms
      can be assembled that can be used interchangeably.

PMID- 15019013
TI  - A randomized crossover trial of PAPNET for primary cervical screening.
AB  - OBJECTIVE: To develop and demonstrate efficient methods to estimate the relative
      true positive and false positive rates of two cervical screening tests
      (conventional cytology and PAPNET). METHODS: We designed the study to meet
      stringent methodologic criteria for comparison of two tests while simultaneously
      minimizing the numbers requiring reference standard verification. We used a
      cytology reference standard and also assessed histology when available. For the
      primary analysis, slides with discordant results around the test threshold (CIN
      1) were reviewed by a panel of two cytopathologists, blind to previous results,
      to establish the reference standard result (reference standard threshold for
      abnormality CIN2). Where histology was available, a secondary analysis was
      conducted with the reference standard based on the highest grade lesion (either
      cytology or histology). RESULTS: Among 21,747 Pap smears, 372 were discordant
      around the test threshold, requiring verification. In the primary analysis PAPNET
      detected four more true positives than conventional reading; difference in
      sensitivity 1.29% (95%CI -5.79 to 8.36%, P=.40). There were two extra false
      positives using PAPNET; difference in the false positive rate 0.0097% (95%CI 
      0.122 to 0.142%, P=.47). The results of the combined cytology and histology
      analysis were similar; difference in true positive rate 0.29% (95%CI -6.76 to
      7.34%, P=.50) and difference in false positive rate 0.024% (95%CI -0.098 to
      0.15%, P=.39). CONCLUSION: This is an efficient and valid study design where the
      objective is to examine the comparative accuracy of two tests. The design
      provides an efficient means of estimating the difference between true positive
      and false positive detection by the two tests, which often is sufficient
      information for policy decisions.

PMID- 15019014
TI  - Impact of cardiovascular diseases on activity limitations and need for help among
      older persons.
AB  - BACKGROUND AND OBJECTIVE: The aim of this study was to estimate the importance of
      specific chronic cardiovascular diseases (CVDs) as determinants of disability.
      METHODS: One thousand two hundred eighty-eight (86%) participants from a random
      population sample of 1,500 individuals (from two geographical regions of Finland)
      aged 65-74 years were interviewed and clinically examined in 1997. RESULTS: CVDs
      were strongly associated with disability. However, mental disorders were the
      strongest determinant of disability. Of specific CVDs, cerebrovascular diseases
      in men, and myocardial infarction, heart failure, and cerebrovascular diseases in
      women were significantly associated with disability after adjustment for age and
      comorbidity. In men 33% and in women 24% of disability was attributable to CVD,
      excluding lone hypertension. CONCLUSION: CVDs are important determinants of
      disability among Finns aged 65-74 years. Due to the growing number of elderly
      people with CVDs, disability associated with these diseases is likely to become a
      growing social and health burden to the community.

PMID- 15019015
TI  - Disease progression in HIV-infected patients treated with stavudine vs.
      zidovudine.
AB  - BACKGROUND AND OBJECTIVES: This prospective, observational study compared disease
      progression and death in HIV-1 patients treated with stavudine vs. zidovudine in
      the Collaborations in HIV Outcomes Research/U.S. (CHORUS) cohort. METHODS:
      Patients with a first occurrence of CD4 count <500 cells/microL (n=3301) were
      grouped as: no nucleoside reverse transcriptase inhibitor (NRTI) use; other NRTI
      without stavudine or zidovudine; stavudine with no zidovudine, with or without
      other NRTIs; and zidovudine with no stavudine, with or without other NRTIs. The
      risk for death or disease progression was evaluated in unadjusted analyses and
      using a Cox proportional hazards model, adjusting for: study site, age, gender,
      race, route of HIV infection, previous AIDS-defining conditions, number of
      previous antiretroviral regiments, CD4 count, HIV-1 RNA, and treatment variables.
      Sensitivity analyses were conducted to determine the sensitivity of the results
      to major modeling assumptions. A landmark analysis was conducted to determine the
      absolute difference in time to event. RESULTS: During a median follow-up of 2.4
      years, there were 57 deaths and 348 AIDS-defining conditions in 405 patients.
      Stavudine treatment compared with zidovudine resulted in a greater percentage of
      patients with AIDS-defining events (14.5 vs. 10.9%; P=.013), and an increased
      risk of disease progression (HR=1.30; 95% CI: 1.01,1.7; P=.04). This result was
      not sensitive to modeling assumptions. Landmark analysis demonstrated an absolute
      difference in time to 95% event-free survival of 2.7 months for those with a CD4<
      or =200 cells/microL and 11 months for those 6 months after model entry.
      CONCLUSIONS: In unadjusted and adjusted analyses of 3301 HIV-1 infected patients,
      stavudine containing combination therapy was associated with an increased risk of
      disease progression or death compared to therapy containing zidovudine. Most of
      the difference was attributable to new cases of wasting.

PMID- 15019016
TI  - The incidence of sudden cardiac death in the general population.
AB  - BACKGROUND AND OBJECTIVES: To determine the incidence of sudden cardiac death in
      a general (Dutch) population. METHODS: Cohort study in the Integrated Primary
      Care Information (IPCI) project, a database with all medical data from 150
      general practices in The Netherlands. The study population comprised 249,126
      subjects with a mean follow-up of 2.54 years. RESULTS: In this period 4,892
      deaths were identified, 582 of which were classified as (probable) sudden cardiac
      death. The overall incidence of sudden cardiac death in this population was 0.92
      cases per 1,000 person-years (95%CI: 0.85-0.99). The risk was 2.3-fold higher in
      men than in women, and increased with age. The incidence of sudden cardiac death
      peaked in October and was lowest in August. CONCLUSIONS: The incidence of sudden
      cardiac death in the general Dutch population was almost 1 per 1,000 person-years
      per year during the period 1 January, 1995 to 1 April, 2001. Most of the cases
      occurred at home.

PMID- 15019017
TI  - Risk of hospitalization for upper gastrointestinal tract bleeding.
AB  - OBJECTIVE: This study evaluates the hospitalization risk for upper
      gastrointestinal bleeding (UGIB) with reference to the clinical characteristics
      of patients and drugs taken before admission. METHODS: This study is based on the
      GIFA (Italian Group for the Pharmacosurveillance in the Elderly) database. Cases
      with an ICD-9 code of esophagus, stomach or duodenum bleeding, or acute esophago
      gastroduodenal disease associated with anemia have been classified as UGIB. Sex,
      age, year of observation, drugs taken at home, comorbidity, smoking, alcohol, and
      use of gastroprotectants have been also taken into account. Statistical analysis
      has been conducted using multivariate logistic regression models. RESULTS: 32,388
      patients have been enrolled, 940 of which presented UGIB. Age, comorbidity, use
      of smoke and alcohol, hospitalization duration, and mortality during
      hospitalization were significantly higher in UGIB than nonUGIB patients.
      Increased UGIB risk has been found in patients taking NSAIDs (both when aspirin
      was included or excluded), acetaminophen, constipating agents, iron, ethacrynic
      acid, propranolol. Reduced UGIB risk has been found in patients taking nitrates.
      CONCLUSIONS: UGIB risk appears to correlate with clinical characteristics of the
      patient: it increases with age, comorbidity, and smoke and alcohol consumption.
      Among drugs, NSAIDs are associated with the highest UGIB risk, while nitrates
      with a reduction of risk.

PMID- 15019018
TI  - Structural identification of extractables from rubber closures used for pre
      filled semisolid drug applicator by chromatography, mass spectrometry, and
      organic synthesis.
AB  - Extractables or leachables from rubber closures used for drug products can
      potentially be detrimental since some of these rubber extractables are known to
      be toxic and pyrogenic. In addition, these extractables could interfere with
      analysis or even affect the stability profile of the active ingredients. For
      these reasons, it became necessary to identify structures of the possible
      extractables or leachables from rubber closures so that their potential impact on
      the drug products that are in direct contact with rubber closures could be
      evaluated. In this report, five species, 4-(1,1-dimethyl-propyl)-phenol (1),
      sulfur (2), 2,6-di-tert-butyl-[1,4] benzoquinone (3), furan-2-yl-(5-hydroxymethyl
      furan-2-yl)-methanol (4), and 2-bromo-4-(1,1-dimethyl-propyl)-phenol (5), were
      found to be possible extractables from the rubber closures which were used in a
      selected pre-filled semisolid drug applicator. A strategy combining HPLC, GC,
      mass spectrometry, and organic synthesis was utilized.

PMID- 15019019
TI  - Fractionation of peptides in proteomics with the use of pI-based approach and
      ZipTip pipette tips.
AB  - The aim of the work was to explore the utility of the in-solution isoelectric
      focusing (sIEF) fractionation method. That method was proved to be the
      alternative separation method of mixtures of protein tryptic digests in
      proteomics. Analysis of the identification of peptides was performed with the use
      of matrix-assisted laser desorption ionization time-of-flight mass spectrometry
      (MALDI-TOF/TOF-MS). For that research, previously designed the miniaturized multi
      chamber fractionation sIEF device (75 microl volume for each chamber) based on
      polyacrylamide gel membranes with immobilines technology was utilized. To
      evaluate the efficiency and accuracy of sIEF fractionation combined with MS/MS
      peptides identification, bovine serum albumin (BSA) digest and mixture of five
      proteins digest were used. First, fractionation of bovine serum albumin digest
      sample was performed using sIEF method. Studies performed for that simple mixture
      of peptides proved the ability of the sIEF device to focus peptides mostly in one
      chamber. Additionally performed the correlation analysis between pI(calc) and
      pI(exp) values for identified peptides proved the possibility to obtain
      experimentally useful high correlation. That information was found to have a
      potential value for construction of additional constraint during false positives
      evaluation process among identified proteins. Next, studies on the sIEF
      fractionation were combined with the evaluation of practical use of ZipTip
      pipette tips to fractionate peptides in the case of simple mixture of proteins.
      For this, five proteins digest samples were used. The analysis without prior any
      fractionation enabled to identify very limited number of proteins. The
      significant improvement was obtained when one used sIEF alone or with combination
      with ZipTips fractionation prior to MS analysis. The proposed approach based on
      in-solution isoelectric focusing proved to be an efficient and accurate
      alternative fractionation method of protein digests and can be considered as the
      first useful dimension in two-dimensional proteomics separations. Moreover,
      analytical information from that pI-based fractionation method can be considered
      as the additional source of database matching constraint. It can also be a
      valuable tool for analytical and bioinformatic studies of peptides fractionation
      in proteomics.

PMID- 15019020
TI  - Investigating the potential of erythromycin and derivatives as chiral selector in
      capillary electrophoresis.
AB  - Macrocyclic antibiotics are present in an increasing number of chiral separation
      applications. In this study, erythromycin and some derivatives, belonging to the
      group of macrolide antibiotics, were investigated for their potential as chiral
      selector. Erythromycin A itself and five related substances namely erythromycin A
      N-oxide, anhydroerythromycin A, anhydroerythromycin A N-oxide, erythralosamine
      and erythralosamine N-oxide were included. Twenty-one chiral compounds with a
      wide difference in physico-chemical properties were used to test the chiral
      activity of the erythromycins. The chiral compounds were analysed using capillary
      zone electrophoresis with the erythromycins dissolved in the running buffer at
      different concentrations ranging from 0.1 to 10mM, with three different BGEs:
      sodium phosphate pHs 3.0 and 7.0 and sodium borate pH 9.2. The erythromycins
      showed more interactions with the acidic compounds (as observed with leucovorin,
      dopa, carbidopa, ketoprofen, indoprofen and warfarin) than with the neutral or
      weakly basic ones, especially in acidic medium. Unfortunately, no chiral
      separations were obtained for any of the 21 racemic mixtures. The complexation
      constants were calculated for the compounds showing interaction, based on the
      variation of electrophoretic mobility of the compounds in the presence of
      different concentrations of erythromycins. Finally, the size of erythromycin A
      was calculated using computational modelling. It was shown that the aglycone ring
      is only half as big as the beta-cyclodextrin cavity, giving a possible
      explanation for the negative response of erythromycin in this study.

PMID- 15019021
TI  - Effects of EDTA on signal stability during electrochemical detection of
      acetaminophen.
AB  - The use of EDTA in the medium to avoid the passivation of a solid electrode
      during electrochemical analysis of acetaminophen is presented in this work. The
      performance of this system was investigated with respect to pH, applied potential
      and supporting electrolyte concentration. The major advantage in using EDTA in
      the supporting electrolyte is the significant increase in sensitivity, precision
      and stability of the measurements, when compared to the system in absence of the
      chelating agent. The sensitivity increases 5.5 times (21.5 and 3.9 mA l mol(-1)
      in the presence and the absence of EDTA, respectively), the repeatability (n=20)
      is 3.5 times better, expressed by within-run-precision of 4.0% for 6.0 x 10(-5)
      mol l(-1) acetaminophen in the presence of EDTA while, in its absence, the within
      run-precision was higher than 14%. Moreover, the system showed excellent
      stability, allowing more than 120 measurements with no significant changes.

PMID- 15019022
TI  - Osteryoung square wave stripping voltammetry at mercury film electrode for
      monitoring ultra trace levels of Tarabine PFS and its interaction with ssDNA.
AB  - The electrochemical oxidation and reduction behaviour of adsorbed species of
      antimetabolic antineoplastic agent Tarabine PFS (Cytosar-U) in Sorensen buffer
      solution of different pH values at an in situ-mercury film electrode (MFE) is
      studied using cyclic voltammetry (CV) and Osteryoung square-wave stripping
      voltammetry (OSWSV). Optimal experimental and operational parameters have been
      selected for the drug preconcentration and determination in aqueous medium. Based
      on the adsorption and accumulation of Tarabine PFS using Osteryoung square-wave
      anodic stripping voltammetry (OSWASV) at MFE, the drug is easily detected as
      0.134 ng/ml (5.51 x 10(-10) M). Calibration plots have been constructed at
      different accumulation times. The standard deviation (n=10) at a concentration
      level of 6 x 10(-8) M Tarabine PFS is 0.062. The interaction of ssDNA with the
      drug under the optimal conditions at pH 7.7 has been studied. The formal
      potentials E degrees and E degrees ' and the equilibrium constants K(1) and K(2)
      have been calculated for the free form of Tarabine PFS and the bonded form with
      ssDNA, respectively. It was found that K(2) value for the bonded oxidized form is
      298 times than that of K(1) for the bonded reduced form. Therefore, ssDNA has
      been found to interact strongly with the oxidized form of the drug. The method
      has been used for the nanogram determination of ssDNA with 1.9% variation
      coefficient. Detection limit of 3 ng/ml ssDNA has been achieved. Possible
      interfering organic compounds, cations and anions have been tested. The method
      has been applied for the drug determination in urine samples, down to 0.23 ng/ml
      could be easily achieved in such samples.

PMID- 15019023
TI  - Development and validation of a quantitative assay for raloxifene by capillary
      electrophoresis.
AB  - The migration behavior of raloxifene was investigated by capillary
      electrophoresis (CE). The influence of different parameters (nature and
      concentration of the running buffer, pH and applied voltage) on migration time,
      peak symmetry and efficiency was systematically investigated. A buffer consisting
      of 20mM acetate buffer of pH 4.5 was found to provide a very efficient and stable
      electrophoretic system for the analysis of raloxifene. The optimized method was
      validated with respect to precision, linearity, limits of detection and
      quantification, accuracy and robustness. The applicability of the assay was
      demonstrated by analyzing this drug in human plasma and pharmaceutical
      preparations.

PMID- 15019024
TI  - Electrochemical behavior and determination of amiloride drug in bulk form and
      pharmaceutical formulation at mercury electrodes.
AB  - The polarographic behavior of amiloride hydrochloride has been studied in Britton
      Robinson buffers of pH 1.9-11. In acidic medium at Ph< or =2, the dc-polarograms
      exhibited a single 4-electron cathodic irreversible wave, while at pH values >2,
      a second two-electron irreversible cathodic wave appeared at a more negative
      potential. The single or first wave may be attributed to the cleavage of the
      double bond of the -CH=NH of the imidino amide group with the release of NH(3).
      While the second wave may be due to the saturation of the C=O of the carboxamide
      moiety. A polarographic procedure of suffocate sensitivity for the determination
      of bulk amiloride drug in Britton-Robinson buffer at pH 2 is described. The
      calibration graph was obtained over the concentration range 2.5 x 10(-5) to 2.5 x
      10(-4) M amiloride. The limits of detection (LOD) and quantitation (LOQ) of the
      procedure were 1 x 10(-5) and 3.3 x 10(-4) M bulk amiloride, respectively.
      Moreover, a differential-pulse adsorptive cathodic stripping voltammetric
      procedure has been described to assay of the drug at lower concentration levels.
      The optimal conditions were: E(acc) = -0.9V, t(acc)=30 s, scan rate=20mV, pulse
      height=90 mV and Britton-Robinson buffer of pH 8. The calibration graph was
      obtained over the concentration range 2 x 10(-8) to 1 x 10(-6) M for bulk
      amiloride. Both procedures were successfully applied to the determination of
      amiloride in tablets without the necessity for sample pretreatment or any time
      consuming extraction or evaporation steps prior to the drug analysis.

PMID- 15019025
TI  - Application of the HPLC method for benzalkonium chloride determination in aerosol
      preparations.
AB  - Benzalkonium chloride (BAC) is a bacteriostatic agent used in the pharmaceutical
      industry as a preservative. BAC is a mixture of alkylbenzyldimethylammonium
      chlorides, the three most important of which being those with alkyl substituents
      C12, C14, C16 at the quaternary ammonium salt. The purpose of this study was to
      develop a method for determining benzalkonium chloride identity and content in
      aerosol preparations in which protein or steroid hormones are the active
      components. The high performance liquid chromatography (HPLC) method was used for
      this purpose. In the performed comparison of the influence of selected factors on
      the process of the separation of BAC homologues, a column with packing modified
      with cyan groups and mobile phase containing 0.075 M acetate buffer with
      acetonitrile (45:55), in an isocratic elution, was used for qualitative and
      quantitative determinations and for method validation. The developed method may
      be used for the assessment of the identity and content of BAC homologues in
      various pharmaceutical preparations. It is simple and it does not require
      particular sample preparation for the tests. It is characterized by good
      selectivity and high precision of the determinations.

PMID- 15019026
TI  - Model lipophilic formulations of retinyl palmitate: influence of conservative
      agents on light-induced degradation.
AB  - Vitamin A is widely employed in pharmaceuticals and cosmetics. The all-trans (AT)
      isomer (100% of biological potency) is sensible to different factors, such as
      light, heat and formulation components, leading to its degradation or
      isomerization. The main objective of this work was to study, in model cosmetic
      lipophilic vehicles, the degradation of retinyl palmitate (RetP) to the less
      active cis-isomers in presence of widely used conservative agents (propyl gallate
      and Vitamin E). Two lipophilic phases were used (liquid paraffin and almond oil)
      because liquid paraffin, almost composed of satured hydrocarbons, is not degraded
      by light exposure, while almond oil, containing several double bonds, could
      interfere with light-induced degradative process of RetP. In the first phase, the
      more suitable analytical method was chosen between normal and reverse phase HPLC
      to follow the degradation of RetP. In the second phase, RetP light-induced
      degradation was studied to simulate storage condition effect on cosmetic products
      ageing. The results showed that: (a) the reverse phase HPLC technique, unable to
      separate the all-trans from the 13-cis and 9-cis isomers, derived by Vitamin A
      isomerization, leads to an incorrect quantitation of RetP; (b) the lipophilic
      vehicle influences the isomerization-degradation process; (c) the conservative
      agents do not protect from degradation.

PMID- 15019027
TI  - Application of near-infrared spectroscopy to the determination of the sites of
      manufacture of proprietary products.
AB  - Reflectance near-infrared (NIR) spectroscopy has been investigated as a method to
      distinguish between the sites of manufacture of a number of proprietary tablets.
      As test samples, parallel imports which are pharmaceutically equivalent products
      manufactured at different sites have been used. Three products: Aremis/Besitran,
      Renitec and Voltarol Retard originating from two or more sites and Adalat from a
      single site were examined. The principal component analysis (PCA) score plots
      showed that spectra of tablets originating from different sites of manufacture
      often gave rise to statistically different populations. PCA loadings indicated
      that the differences were related to moisture content and excipients. Spectra
      were used to construct a library for the classification of tablets to predict the
      site of manufacture based on the method of residual variance of the principal
      components. Where a large data set was available (Aremis/Besitran tablets)
      prediction rates for the successful identification of the two sites of
      manufacture, Madrid and Barcelona, were 95.7 and 98.1%, respectively for the
      validation set with all errors encountered of Type I.

PMID- 15019028
TI  - Penciclovir solubility in Eudragit films: a comparison of X-ray, thermal,
      microscopic and release rate techniques.
AB  - The solubility of penciclovir (C(10)N(5)O(3)H(17)) in a novel film formulation
      designed for the treatment of cold sores was determined using X-ray, thermal,
      microscopic and release rate techniques. Solubilities of 0.15-0.23, 0.44, 0.53
      and 0.42% (w/w) resulted for each procedure. Linear calibration lines were
      achieved for experimentally and theoretically determined differential scanning
      calorimetry (DSC) and X-ray powder diffractometry (XRPD) data. Intra- and inter
      batch data precision values were determined; intra values were more precise.
      Microscopy was additionally useful for examining crystal shape, size distribution
      and homogeneity of drug distribution within the film. Whereas DSC also determined
      melting point, XRPD identified polymorphs and release data provided relevant
      kinetics.

PMID- 15019029
TI  - Concerning the stability of benzyl alcohol: formation of benzaldehyde dibenzyl
      acetal under aerobic conditions.
AB  - An impurity in benzyl alcohol was identified as benzaldehyde dibenzyl acetal
      (BDBA). The component BDBA is reversibly formed by the reaction of benzyl alcohol
      with benzaldehyde, an oxidative degradation product of benzyl alcohol. Whereas,
      BDBA is a known chemical entity, it is not typically controlled in commercial
      benzyl alcohol since it cannot be formed in the absence of benzaldehyde, which is
      itself generally controlled. However, once commercial benzyl alcohol is exposed
      to the atmosphere, formation of BDBA is possible. The synthesis and
      characterization of BDBA is reported. The ability of BDBA to react with alcohols
      to form other types of acetals, and the impact of low levels of BDBA on the
      quantitative analysis of pharmaceutical products, are considered.

PMID- 15019030
TI  - Development and validation of a HPLC method for routine quantification of the
      decapeptide Cetrorelix in liposome dispersions.
AB  - The development and validation of an HPLC method for the quantification of the
      decapeptide Cetrorelix (acetyl-D-2-naphthylalanyl-D-4-chlorphenylalanyl-D-3
      pyridylalanyl-seryl-tyrosyl-D-citrullyl-leucyl-arginyl-prolyl-d-alaninamide), a
      potent antagonist of the luteinising hormone-releasing hormone in liposome
      dispersions is described. An isocratic reversed phase method with UV-detection
      appeared most appropriate. Several detergents were tried to disrupt liposomes.
      Furthermore, detergents turned out to be useful, because they minimised unwanted
      loss of Cetrorelix due to adsorption to the vial surfaces. Triton X-100 was found
      most effective, while sodium cholate led to quantification problems. In the
      presence of 2.5% Triton X-100 calibration curves with a high degree of linearity
      were achieved in the desired range of 0.2-10 microg/ml. The limits of detection
      and quantification of Cetrorelix were calculated from the peak-to-noise ratio to
      be 11 and 37 ng/ml, respectively. The repeatability of the method in presence of
      phospholipid and Triton was good with relative standard deviations (R.S.D.)
      ranging from 0.8% (at 0.05 microg/ml) to 1.5% (at 0.2 microg/ml). The presence of
      liposomes at phospholipid contents of up to 0.25mg/ml did not significantly
      affect the slope or linearity of the calibration curve, nor the peak-to-noise
      ratio.

PMID- 15019031
TI  - HPLC with programmed wavelength fluorescence detection for the simultaneous
      determination of marker compounds of integrity and P-gp functionality in the Caco
      2 intestinal absorption model.
AB  - A high sensitivity reversed-phase HPLC method is presented for the simultaneous
      determination of marker compounds of paracellular transport (atenolol),
      transcellular transport (propranolol) and P-gp functionality (talinolol) in the
      Caco-2 system. The Caco-2 system is presently commonly accepted as an in vitro
      cell culture model of the intestinal mucosa. A programmed wavelength fluorescence
      detection method was used to optimise the response of the marker compounds. This
      marker compound mixture and the corresponding HPLC assay can be used for in house
      validation of the Caco-2 system or to evaluate simultaneously the effect of test
      compounds or absorption enhancing strategies on monolayer integrity and P-gp
      functionality. The method can easily be adapted to determine the concentration of
      atenolol, propranolol and talinolol in blood, thus allowing to use the same
      compounds in the in situ rat perfusion system with blood sampling from the
      mesenteric vein.

PMID- 15019032
TI  - Development and validation of a new HPLC analytical method for the determination
      of alprazolam in tablets.
AB  - A new analytical method is developed together with its latter validation study,
      by means of a high resolution liquid chromatography (HPLC) of reverse phase to
      quantify alprazolam (8-chloro-1-methyl-6-phenyl-4H-[1,2,4] triazole [4,3,-alpha]
      [1,4] benzodiazepine) in tablets. Determination is carried out by means of an ODS
      C18 column (200 mm x 4.6 mm i.d., 5 microm particle size); the mobile phase
      consisted of a mixture of 0.02 M buffer solution of phosphates (pH 6.0) and
      acetonitrile (45:55, v/v). It is pumped through the chromatographic system at a
      flow rate of 0.50 ml min(-1). The UV detector is operated at 254 nm. The
      validation study is carried out fulfilling the ICH guidelines in order to prove
      that the new analytical method, meets the reliability characteristics, and these
      characteristics show the capacity of an analytical method to keep, throughout the
      time, the fundamental criteria for validation: selectivity, linearity, precision,
      accuracy and sensitivity. The method is applied during the working day for the
      quality control of commercial alprazolam tablets in order to quantify the drug
      and its degradation products and to check the content uniformity test.

PMID- 15019033
TI  - Automated high throughput ADME assays for metabolic stability and cytochrome P450
      inhibition profiling of combinatorial libraries.
AB  - Early determinations of pharmaceutical properties can serve as predictors of a
      compound's likely development success. Our laboratory has implemented high
      throughput in vitro absorption, distribution, metabolism and excretion (ADME)
      assays which address absorption, metabolism, and physico-chemical properties in
      an effort to identify potential development liabilities early, thereby minimizing
      discovery to market attrition. In response to the throughput demands of parallel
      synthesis, we have incorporated a SAGIAN core robotics system for the
      determination of both metabolic stability in human liver microsomes (HLMs) and
      cytochrome P450 (CYP450) inhibition. This automated solution has led to an
      increase in capacity, throughput and reliability for both in vitro assays. The
      SAGIAN core robotics system integrates devices such as liquid handlers, plate
      hotels and incubators through the use of an ORCA robotic arm. The HLM stability
      assay utilizes a Multimek 96-channel pipettor for liquid handling. The incubation
      plates are transferred off-line for final semi-quantitative analysis using high
      throughput parallel LC/MS. The CYP inhibition method combines both liquid
      handlers and an integrated fluorescence plate reader to perform single
      concentration percent inhibition assays for 88 compounds. Cytochrome P450
      inhibition is measured for both CYP3A4 and CYP2D6 isozymes. This system
      represents a fully integrated approach to high throughput ADME evaluation in
      support of drug discovery. The core system concept creates a plug-and-play
      approach, which combines a series of modular stations to build a robotic
      platform, which is flexible, upgradable, and easily reconfigured when assays
      change or are newly developed. The application of these strategies as a means of
      assessing metabolic stability and CYP inhibition of synthetic libraries is
      discussed.

PMID- 15019034
TI  - Fast liquid chromatographic-tandem mass spectrometric (LC-MS-MS) determination of
      metformin in plasma samples.
AB  - Liquid chromatographic-tandem mass spectrometric (LC-MS-MS) methods for the
      determination of metformin in plasma from different species are presented. The
      first method employed a YMC cyano 2mm x 50 mm, 3 microm analytical column. For
      minimum sample preparation direct injection of samples after protein
      precipitation was performed. The polar column used with highly organic mobile
      phases provided a normal phase retention mechanism. The elution conditions were
      optimized to obtain reproducible peak areas and good peak shape. A step gradient
      from 100% acetonitrile to acetonitrile-water 80:20 (v/v) containing 10mM ammonium
      acetate and 1% acetic acid was applied, leading to a sample-to-sample cycle time
      of 2 min. In a second method, a column-switching LC-MS-MS assay for on-line
      trapping was developed. The analyte and internal standard were trapped on a YMC
      cyano 2 mm x 10 mm, 5 microm column using acetonitrile-methanol 95:5 (v/v).
      Elution was performed isocratically in back-flush mode on to the analytical
      column (YMC cyano 2 mm x 50 mm, 3 microm) using 10 mM ammonium acetate in
      acetonitrile-water 80:20 (v/v) with 1% formic acid. With this approach, the
      signal-to-noise ratio was improved and the run time could be shortened to 1 min.
      Calibration samples were prepared in the matrix to be assayed in the range of 10
      10,000 ng/ml. Quality control (QC) samples were prepared at 40, 400 and 4000
      ng/ml and interspersed with the unknown study samples in the assays. Deviations
      for precision and accuracy were less than 20% for the lower limit of
      quantification (LLOQ) and low QC sample and less than 15% for other calibrators
      and QCs.

PMID- 15019035
TI  - High-performance liquid chromatographic method for the bioequivalence evaluation
      of desloratadine fumarate tablets in dogs.
AB  - A simple HPLC method was developed for the determination of desloratadine in dog
      plasma and was used for evaluating the bioequivalence of desloratadine fumarate
      tablets and desloratadine tablets in dogs. Chromatographic separation was
      performed on a Hypersil CN column (150 mm x 5.0 mm, 5 microm) using a mixture of
      methanol, acetonitrile and phosphate buffer (pH 5.5; 0.01 mol/l) (35:35:30,
      v/v/v) as mobile phase delivered at a flow rate of 0.8 ml/min. The detection was
      set at 241 nm. The limit of quantitation was 5.0 ng/ml. The calibration range was
      from 5.0 to 800.0 ng/ml. Inter- and intra-day precision ranged from 1.8 to 3.8%
      and from 2.2 to 9.0%, respectively. The recovery of desloratadine from dog plasma
      ranged from 78.8 to 82.0%. The developed method was applied to the bioequivalence
      studies of desloratadine fumarate tablets (test preparation) and desloratadine
      tablets (reference preparation) in five dogs. Pharmacokinetic parameters t(max),
      C(max), AUC(0-t), AUC(0- infinity ), t(1/2) were determined from plasma
      concentration-time profiles of both preparations. The analysis of variance
      (ANOVA) did not show any significant difference between the two preparations and
      90% confidence intervals fell within the acceptable range for bioequivalence.
      Based on these statistical inferences it was concluded that the two preparations
      exhibited comparable pharmacokinetic profiles and that desloratadine fumarate
      tablets was bioequivalent to desloratadine tablets.

PMID- 15019036
TI  - Selective kinetic determination of amikacin in serum using long-wavelength
      fluorimetry.
AB  - A simple and rapid method for the determination of the antibiotic amikacin,
      involving the use of a long-wavelength fluorophor, namely indocyanine green,
      (ICG) is presented. The dye is oxidised by cerium(IV) in acidic medium, resulting
      in a sharp decrease of the fluorescence, but this fluorescence quenching is
      inhibited in the presence of amikacin, which can be ascribed to the formation of
      an ion pair between the fluorophor and the analyte. The initial rate of the
      system is monitored at lambda(ex): 765 nm and lambda(em): 812 nm as excitation
      and emission wavelengths, respectively, using the stopped-flow mixing technique,
      which makes the method applicable to automatic routine analysis. Each measurement
      is obtained in only 2-3s. The method presents a detection limit of 0.02 microg
      m1(-1) in standard solutions, which corresponds to 2.5 microg ml(-1) in serum
      samples. The precision is in the range 4.8-6%. The good selectivity of the method
      allows amikacin to be determined in the presence of other antibiotics, including
      other aminoglycoside antibiotics, in serum. The recoveries obtained from the
      analysis of different samples were in the range 89.4-104.7%.

PMID- 15019037
TI  - Analysis of volatile components from Cortex cinnamomi with hyphenated
      chromatography and chemometric resolution.
AB  - In this paper, the combination of hyphenated chromatography and chemometric
      resolution was investigated as a method to qualitatively and quantitatively
      determine volatile components in Cortex cinnamomi from four main producing areas.
      With the help of chemometric resolution approaches, whether the chromatographic
      elution of chemical components is featured by "first-in-first-out" or embedded
      peaks could be determined. Upon this useful information obtained, the matrix data
      generated by hyphenated chromatography could be uniquely resolved into pure
      chromatogram and spectrum of each chemical component involved followed by
      qualitative and quantitative analysis. The results obtained in this work showed
      that, 94, 88, 93 and 89 volatile components were separated and 63, 60, 60 and 58
      of them qualitatively and quantitatively determined representing about 93.39,
      93.62, 92.03 and 92.59% of the total relative content, respectively. The
      combination of hyphenated chromatography with chemometric resolution could
      greatly enhance the chromatographic separation and spectral qualitatively
      determination ability so as to qualitatively and quantitatively detect many more
      volatile components and improve the analysis accuracy.

PMID- 15019038
TI  - Separation and determination of synthetic impurities of norfloxacin by reversed
      phase high performance liquid chromatography.
AB  - A simple and rapid high performance liquid chromatographic method for the
      separation and determination of synthetic impurities of norfloxacin was
      developed. The separation was achieved on a reversed-phase C(18) column using
      0.01 M potassium dihydrogen orthophosphate and acetonitrile (60:40, v/v, pH 3.0)
      as mobile solvent at a flow rate of 1.0 ml/min at 40 degrees C and a UV detection
      at 260 nm. The method was used not only for quality assurance but also for
      monitoring the chemical reactions during the process development work in the
      laboratory. It was found to be specific, precise and reliable for determination
      of unreacted levels of raw materials, intermediates and the finished products of
      norfloxacin.

PMID- 15019039
TI  - A cytochrome c-enhanced peroxidation reaction with potential use in screening
      dietary antioxidants.
AB  - Reactive oxygen species (ROS) that result from events such as cellular
      respiration can cause damage to biological molecules and tissues. A variety of
      endogenous and dietary antioxidants function in moderating the extent of
      oxidative damage in the body. In this report, a pro-oxidant system is presented
      as an assay for screening possible antioxidant activities of dietary factors. The
      assay reaction involves peroxidatic oxidation of the redox indicator N,N,N',N'
      tetramethyl-1,4-phenylenediamine (TMPD). It is shown that the reaction rate is
      enhanced by up to 10-fold in the presence of cytochrome c (cyt c), a
      mitochondrial electron transport protein. The extent to which selected dietary
      antioxidant factors inhibit the cytochrome c-enhanced peroxidatic oxidation of
      TMPD is also reported. Considering the known pathological consequences of
      mitochondrial membrane disruption and cytochrome c release in the cell, this
      reaction and assay may be of pathological and therapeutic relevance.

PMID- 15019040
TI  - Assay for nipecotic acid in small blood samples by gas chromatography-mass
      spectroscopy.
AB  - An analytical method for nipecotic acid quantification in rat blood was developed
      utilizing a stable isotope internal standard and capillary gas chromatography
      mass spectroscopy. The method involves a solid phase extraction step followed by
      a two-step derivatization. The analytes are separated by capillary gas
      chromatography and detected by selected ion monitoring of their base peaks at 180
      and 185 m/z, respectively. The assay has a limit of detection (LOD) of 10 ng/ml
      and a limit of quantification of 26 ng/ml in 200 microl of rat whole blood. The
      linear range of the assay covers from 26 to 6500 ng/ml (r2=0.9996, n=9). The
      coefficient of variation was less than 10% at concentrations of 50, 1000 and 5000
      ng/ml. The assay was used to characterize the pharmacokinetics of R-(-)-nipecotic
      acid in a rat. R-(-)-nipecotic acid clearance was 4.2 ml/min, its half-life was
      1.5h and its volume of distribution at steady state was 325 ml.

PMID- 15019041
TI  - Stereoselective metabolism of silybin diastereoisomers in the glucuronidation
      process.
AB  - A separation method for the hepatoprotective drug silybin and its metabolites by
      RP-HPLC was described. Based on this separation, the stereoselectivity of the
      metabolism of silybin was investigated by incubation of the drug and its two
      diastereoisomers with bovine liver microsomes. Information about the structures
      of these metabolites was obtained, using UV, HPLC/MS and NMR spectra. Four major
      metabolites (M(1), M(4) of silybin A and M(2), M(5) of silybin B), were prepared
      by preparative HPLC, and their configurations were accomplished by NMR spectra. A
      HPLC method was used to quantify the metabolites. The results showed that silybin
      was extensively metabolized and the major sites for glucuronidation were the C
      20, C-7, at phenolic OH groups. Furthermore, the results obtained reveal that
      there was significant stereoselectivity in the glucuronidation process of
      silybin. Silybin B was glucuronidated at a more efficient rate than its
      diastereoisomer, and glucuronidation of silybin B was much preferred at the 20
      position, while that of silybin A was similar at both 7 and 20 position.

PMID- 15019042
TI  - Identification of BVT.2938 metabolites by LC/MS and LC/MS/MS after in vitro
      incubations with liver microsomes and hepatocytes.
AB  - The metabolism of the 5HT2c agonist BVT.2938, 1-(3-[2-[(2-ethoxy-3
      pyridinyl)oxy]ethoxy]-2-pyrazinyl)-2(R)-methylpiperazine, was studied in vitro by
      incubation with rat, monkey and human liver microsomes as well as cryopreserved
      hepatocytes, followed by liquid chromatography/mass spectrometry (LC/MS) and
      LC/MS/MS analysis on a quadrupole-time of flight mass spectrometer for structural
      elucidation. Deuterium exchange on column was used to differentiate between
      hydroxylation and N-oxidation. Liver microsomes were incubated in two different
      buffer systems with optimum conditions for cytochrome P450 activity or UDP
      glucuronosyltransferase activity. The major phase I metabolites of BVT.2938
      originated from O-deethylation of the pyridine ring, O-dealkylation of the
      ethylene bridge, pyrazine ring hydroxylation, hydroxylation of pyridine ring and
      piperazine ring N-hydroxylation. When a hydrogen carbonate buffer system was
      supplemented with UDPGA, the piperazine carbamoyl-glucuronide from the parent
      compound was identified together with several glucuronides of the phase I
      metabolites. The metabolite pattern in hepatocytes was similar to microsomes
      except that the sulphate at the N-position of the piperazine ring of BVT.2938 was
      identified, while the carbamoyl-glucuronide was missing. Excellent correlation
      was obtained between radioactivity detection and the chemiluminescent nitrogen
      detector when the nitrogen content of the analytes was taken into account.

PMID- 15019043
TI  - Spectroscopic and chromatographic evidences of NADPH in human placental extract
      used as wound healer.
AB  - An aqueous extract of human placenta, which is used as wound healer, has been
      investigated in terms of fluorescence properties. When excited at 340 nm, it
      results in fluorescence emission having maxima around 436 nm, which is fairly
      specific for nicotinamide adenine dinucleotide, reduced form (NADH) and
      nicotinamide adenine dinucleotide phosphate, reduced form (NADPH). The excitation
      spectra, having emission at 440 nm, show patterns comparable to these
      nucleotides. Thin layer chromatography and reversed-phase (RP) HPLC confirm
      presence of only NADPH in the extract. The emission and excitation patterns of
      NADPH purified after HPLC resemble exactly with the reference compound. Its
      content has been estimated to be 0.018 +/- 0.003 mg/ml based on fluorescence
      emission with respect to a standard calibration curve (n=6). Biological
      functionality of NADPH in the extract has been confirmed by glutathione reductase
      assay (n=5).

PMID- 15019044
TI  - High performance liquid chromatographic determination of some co-administered
      anticancer drugs in pharmaceutical preparations and in spiked human plasma.
AB  - Two HPLC methods are introduced in this paper for the simultaneous determination
      of doxorubicin hydrochloride (DOX) and 5-fluorouracil (5-FU), combination I, and
      of cytarabine (CYT) and etoposide (ETO), combination II, as co-administered
      drugs. In both combinations, a [250 mm x 4.6 mm C-18 column is used. The mobile
      phase for combination I consists of a mixture of acetonitrile and 0.05 M disodium
      hydrogenphosphate (50:50, v/v) containing 0.1% sodium laurylsulfate (SLS)
      adjusted to pH 3.7 at a flow rate 1 ml/min, with UV detection at 260 nm and
      ambient temperature. For combination II, the mobile phase consists of a mixture
      of 0.02 M sodium dihydrogenphosphate aqueous solution adjusted to pH 6.0 (with
      0.2 M orthophosphoric acid or sodium hydroxide) and acetonitrile in a ratio of
      (7:3) at a flow rate 1 ml/min, with UV detection at 254 nm and ambient
      temperature. The methods also permitted the determination of methyl
      hydroxybenzoate (MHB) which is used as a preservative in DOX vials, combination
      I, and of benzyl alcohol (BZA) preservative in ETO vials, combination II. The
      proposed HPLC methods were successfully applied to the determination of the
      investigated drugs, of the two combinations, both in injection solutions and
      spiked human plasma samples with high precision and accuracy. Linearity,
      validation, accuracy, precision, limits of detection, limits of quantitation, and
      other aspects of analytical validation are presented in the text.

PMID- 15019045
TI  - Behavior and quantification studies of amiloride drug using cyclic and square
      wave adsorptive stripping voltammetry at a mercury electrode.
AB  - The cyclic voltammograms of amiloride at the hanging mercury drop electrode
      showed a single well-defined four-electron irreversible cathodic peak in Britton
      Robinson (B-R) buffer of pH 2. At higher pH values (pH > or =3), two irreversible
      cathodic peaks corresponding to the transfer of four (first peak) and two (second
      peak) electrons, were obtained The peak potentials were shifted to more negative
      values on the increase of pH of the medium, implying the involvement of protons
      in the electrode reaction and that the proton-transfer reaction precedes the
      proper electrode process. The 4-electron single peak (pH 2) or the first peak (pH
      > or = 3) may be attributed to the cleavage of the -CH=NH double bond of the N
      imidino amide group with the release of NH(3) molecule. While the second peak may
      be due to the saturation of the C?O double bond of the carboxamide moiety. Based
      on the interfacial adsorptive character of the drug onto the mercury electrode
      surface, a simple, sensitive and low cost square-wave adsorptive cathodic
      stripping (SWAdCS) voltammetric procedure was optimized for analysis of the drug.
      The optimal operational conditions of the proposed procedure were: accumulation
      potential E(acc)= -0.7 V, accumulation time t(acc)= 60-65s, scan increment= 10
      mV, pulse-amplitude = 50-60 mV, frequency =120 Hz using a B-R buffer of pH 8 as a
      supporting electrolyte. The linear concentration range was found to be 2 x 10(-9)
      to 2 x 10(-7) M amiloride with limits of detection (LOD) and quantitation (LOQ)
      of 1.9 x 10(-10) and 6.3 x 10(-10) M, respectively. The procedure was
      successfully applied for determination of amiloride in pharmaceutical formulation
      and spiked in human serum. The LOD and LOQ of amiloride spiked in human serum
      were 5.7 x 10(-10) and 1.9 x 10(-9) M amiloride, respectively. The procedure did
      not require sample pretreatment or any time-consuming extraction or evaporation
      steps, other than deproteinization and then centrifugal separation of protein
      from serum sample prior to analysis of the drug.

PMID- 15019046
TI  - Liquid chromatography-tandem mass spectrometric method for the analysis of
      fluconazole and evaluation of the impact of phenolic compounds on the
      concentration of fluconazole in Candida albicans.
AB  - A bioanalytical method using liquid chromatography-tandem mass spectrometry was
      developed for the analysis of fluconazole in Candida albicans after incubation
      with phenolic compounds, which have been proved possessing antifungal properties
      and have synergetic activity against C. albicans when in combination with
      fluconazole. Samples of C. albicans thallus obtained by centrifuging the mixed
      culture after 24 h incubation were saponified and centrifuged. The supernatant
      was evaporated to dryness, reconstituted, and injected on a C18 column using an
      organic-aqueous mobile phase. The chromatographic run time was 3.5 min per
      injection, with retention times of 2.4 min for fluconazole. The detection was by
      monitoring fluconazole at m/z 305-->191. The standard curve range was 1.0-100.0
      ng ml(-1) with a mean correlation coefficient 0.9992. The precision and accuracy
      of the quality control (QC) samples were R.S.D < 5.5%, R.E. <3% for intra-day and
      R.S.D. <6.2%, R.E. <4% for inter-day. The concentration of fluconazole in C.
      albicans was found to be increased with the increment of the tested compounds
      concentration when they were in combination.

PMID- 15019047
TI  - Structural identification and characterization of impurities in moxifloxacin.
AB  - In the synthesis of Moxifloxacin four prominent impurities were detected in HPLC
      analysis. These impurities were detected in gradient HPLC method. They were
      isolated from enriched mother liquors and were characterized as 1-cyclopropyl-6
      fluoro-1,4-dihydro-8-methoxy-7-[(S,S)-N-methyl-2,8-diazabicyclo (4,3,0) non-8yl]
      4-oxo-3-quinoline carboxylic acid (Impurity-1), methyl-1-cyclopropyl-6-fluoro-1,4
      dihydro-8-methoxy-7-[(S,S)-2,8-diazabicyclo(4,3,0)non-8-yl]-4-oxo-3-quinoline
      carboxylate (impurity-2), and 1-cyclopropyl-6-fluoro-1,4 dihydro-8-hydroxy-7
      [(S,S)-2,8-diazobicyclo(4,3,0)non-8-yl]-4-oxo-3-quinoline carboxylicacid
      (impurity-3), 1-cyclopropyl-6,7-difluoro-8-hydroxy-4-oxo-1,4 dihydro-3-quinoline
      carboxylicacid (impurity-4) by means of 1H, 13C NMR, DEPT, IR and mass spectral
      data. Structural elucidation by spectral data was discussed.

PMID- 15019048
TI  - Prediction of isotope patterns for partially deuterated analytes in HPLC/MS.
AB  - A probability model is given which accurately predicts the electrospray mass
      patterns of substance P arising from full or incomplete deuterium exchange in
      solution. For accurate determination of the number of exchangeable protons the
      solvent should have a deuterium purity of at least 98%. At 25 degrees C several
      minutes are required before the degree of exchange reaches the equilibrium value.

PMID- 15019049
TI  - Polarographic determination of diazepam with its parallel catalytic wave in the
      presence of persulfate.
AB  - A new method for the determination of diazepam was proposed based on its
      polarographic catalytic wave in the presence of persulfate. In 0.20 M NaAc-HAc
      (pH 4.7)-1.0 x 10(-2) M K(2)S(2)O(8) supporting electrolyte, the reduction wave
      of diazepam with peak potential -0.89 V (versus SCE) was catalyzed, producing a
      parallel catalytic wave. The peak current of the catalytic wave was 15 times
      higher than that of the corresponding reduction wave for 4.0 x 10(-6) M diazepam,
      and was rectilinear to diazepam concentration in the range of 5.6 x 10(-8) to 8.9
      x 10(-6) and 8.8 x 10(-6) to 2.0 x 10(-4) M. The detection limit was 9.6 x 10(-9)
      M. The mechanism of the parallel catalytic wave of diazepam was discussed.

PMID- 15019051
TI  - Immunoaffinity solid-phase extraction for pharmaceutical and biomedical trace
      analysis-coupling with HPLC and CE-perspectives.
AB  - Immunoaffinity solid-phase extraction (SPE) technique is based upon a molecular
      recognition mechanism. The high affinity and the high selectivity of the antigen
      antibody interactions allow the specific extraction and the concentration of the
      analytes of interest in one step. In pharmaceutical and biological fields, where
      most often matrices are complex and analytes at trace-levels, this approach
      constitutes a unique tool for fast and solvent-free sample preparation. This
      review presents a general description of this extraction technique and gives
      numerous examples of its applications in pharmaceutical and biomedical fields. It
      emphasizes the on-line coupling with chromatographic and electrophoretic
      separation techniques and introduces new developments. The future directions,
      especially with regards to the current development of analytical microsystems,
      are discussed.

PMID- 15019052
TI  - Recent developments for SPIE-IA, a new sandwich immunoassay format for very small
      molecules.
AB  - Recent publications describing new elegant approaches to assay small analytes
      using noncompetitive format were briefly reviewed. Among these methods, we have
      developed a new protocol, named SPIE-IA, which involves a cross-linking step
      achieved using chemical hombifunctional reagents, UV irradiation or free
      radicals. This new method proved to be useful to detect naturally occurring
      analyte/antibody complexes or to protect the analytes against degradation by
      peptidases. On the other hand, SPIE-IA could allow to study the adverse
      biological effects of UV and some aspects of free radical chemistry or to
      evaluate the antioxidant activity of molecules.

PMID- 15019053
TI  - Detection methods of microsphere based single-step bioaffinity and in vitro
      diagnostics assays.
AB  - Microspheres provide a solid phase substrate for bioaffinity binding similar to
      the walls of traditional test tubes and the wells of microtiter plates. The
      coated microsphere concentrates analyte molecules in the reaction volume on its
      surface. When the bioaffinity binding reaction has reached an equilibrium, the
      local concentration of the analyte in close proximity of the microsphere is
      orders of magnitude higher than the concentration of the analyte in the total
      reaction volume. The preparation and quality control of microspheres coated with
      bioactive material is less costly and labour intensive when compared to test tube
      or microwell plate coating procedures. In addition, the cost for logistics and
      transportation of microsphere reagents is lower than that of coated tubes or
      plates. Moreover, microspheres can be easily used in miniaturised assay formats
      and several different detection schemes can be employed in the measurement of
      microsphere-based assays. Several different types of microspheres are
      commercially available. The microspheres can be manufactured in different sizes
      from many materials, such as polystyrene, acrylate, and glass. The surface of the
      microspheres can be activated to enable covalent binding of biomolecules.
      Further, the microspheres may contain internal fluorochrome or magnetic material,
      for identification or separation purposes. In this paper we review different
      assay formats for single-step measurement of bioaffinity assays employing
      microspheres. The term single-step is used to describe assays where all reagents
      and the sample are mixed, incubated and measured without separate washing steps.

PMID- 15019054
TI  - Sequential oligopeptide carriers, SOCn, as scaffolds for the reconstitution of
      antigenic proteins: applications in solid phase immunoassays.
AB  - A new class of helicoid type sequential oligopeptide carriers (SOC), for
      anchoring antigenic epitopes, has been modeled from the repetitive Lys-Aib-Gly
      (SOC(n)-I) and Aib-Lys-Aib-Gly (SOC(n)-II) units aiming to the development of
      scaffolds with predetermined 3D structures. Conformational analysis showed that
      the SOC(n) carriers adopt 3(10)-helical structures, while the SOC(n)-conjugates
      retain their original active conformations and they interact neither to the
      carriers nor to each other. It is concluded that the helicoid structure of SOC(n)
      helps the reconstitution and/or mimicking of the native forms of the epitopes so
      that potent antigens are generated for developing specific, sensitive and
      reproducible immunoassays.

PMID- 15019055
TI  - Solid phase assays in glycoconjugate research: applications to the analysis of
      proteoglycans, glycosaminoglycans and metalloproteinases.
AB  - Glycoconjugates are a class of macromolecules consisting of different
      constituents, one of which is sugar moieties. Glycoconjugates comprise the
      majority of tissue constituents, both intracellular and extracellular.
      Extracellular glycoconjugates (glycoproteins and proteoglycans) participate in a
      wide variety of interactions, through which they maintain tissue integrity.
      Therefore, their analysis or the study of their possible interactions would give
      evidence for the state of tissues. Since the amounts of some of the extracellular
      glycoconjugates are usually low or the amounts of tissue to be examined come from
      biopsies, specific analytical systems are developed for their study, the most
      familiar being solid phase assays, which have the advantages of analysis of
      multiple samples on the same time, cheap instrumentation and high specificity.

PMID- 15019057
TI  - A sandwich ELISA for the estimation of human syndecan-2 and syndecan-4 in
      biological samples.
AB  - Syndecans are integral membrane proteoglycans containing both chondroitin and
      heparan sulphate side chains. Syndecans are shed from the cell surface, and may
      be detected in cellular supernatant or body fluids. In this study, we wished to
      design ELISA methods for syndecan-2 and syndecan-4, with the future aim of
      analyzing syndecans in large number of patient materials. Briefly, sandwich
      ELISAs for human syndecan-2 and syndecan-4 were designed employing monoclonal
      mouse antibodies as capture and commercially available polyclonal rabbit anti
      syndecan as secondary antibodies. Although no quantified standard was available,
      relative estimation of syndecan-2 and syndecan-4 levels was possible in a small
      pilot material. The paper presents the ELISA method for these proteoglycans. We
      suggest that this may be a useful tool in the analysis of patient materials and
      in the detection of syndecans during proteoglycan purification.

PMID- 15019056
TI  - Analysis of fluorophore-labelled hyaluronan and chondroitin sulfate disaccharides
      in biological samples.
AB  - In this report, we describe a polyacrylamide gel electrophoresis for the analysis
      of fluorophore-labelled hyaluronan (HA) and chondroitin sulfate (CS) Delta
      disaccharides. The method utilizes derivatization of reducing ends of hyaluronan
      and the variously sulfated chondroitin sulfate Delta-disaccharides with 2
      aminoacridone (AMAC), followed by electrophoresis in Tris-HCl buffer (pH 8.8),
      and polyacrylamide gel (T 25%/C 3.75%). The method was applied to the analysis of
      GAGs secreted into the culture medium of human aortic smooth muscle cells and the
      obtained results were compared with those analysed by fluorophore assisted
      carbohydrate electrophoresis (FACE). The described method is a useful and
      sensitive tool for the rapid monitoring of GAGs in high number of biologic
      samples.

PMID- 15019058
TI  - Potential use of solid phase immunoassays in the diagnosis of coagulase-negative
      staphylococcal infections.
AB  - Staphylococcus epidermidis is a major nosocomial pathogen, even though it is a
      member of the normal bacterial flora of skin and the mucous membranes. A major
      complication is the development of biofilms on implanted medical devices.
      Diagnosis of coagulase-negative staphylococcal infections relies on the presence
      of clinical manifestation of infections and on microbiologic evidence, usually
      obtained after the removal of the biomaterial. Solid-phase immunoassays have not
      yet been used for routine diagnosis of coagulase-negative staphylococcal
      infections and distinction between pathogenic and normal cocci. The enzyme
      immunoassays developed in the last decade are presented in this review article.
      Serodiagnosis has been attempted by determining antibodies against bacterial
      cells, mixtures of S. epidermidis slime antigens and discrete slime antigens.
      Detection or typing of staphylococcal cells has been performed by specific
      antibodies and lectins. There is still a long way until the application of such
      assays in the routine clinical laboratory and large clinical studies are
      necessary.

PMID- 15019059
TI  - Serological detection of hepatitis B viral infection by a panel of solid-phase
      enzyme-linked immunosorbent assays (ELISA).
AB  - Immunoassays for the detection of hepatitis B virus (HBV) in biological samples
      were developed. Using recombinant HBV antigens (Ags) and HBV-specific antibodies
      (Abs), we designed and evaluated a panel of enzyme-linked immunosorbent assays
      (ELISAs) detecting the main hepatitis B-related viral markers, namely HBV surface
      Ag (HBsAg), HBV e Ag (HBeAg), Abs to HBsAg (anti-HBs), Abs to HBV core Ag (anti
      HBc) and Abs to HBeAg (anti-HBe), in blood serum. The ELISAs were validated using
      a panel of prescreened, by commercial tests, serum samples. In principle, HBV Ags
      or anti-HBV monoclonal antibodies (mAbs) were immobilised on microplate wells.
      Horseradish peroxidase (HRP) or biotin were used to prepare labeled Abs.
      Specifically for the determination of HBsAg and HBeAg, two-site sandwich
      immunoenzymometric assays were developed. The useful range was estimated at 20
      500 ng/ml and human serum samples assayed were diluted 10- and 4-fold for HBsAg
      and HBeAg, respectively, with phosphate buffered saline (PBS) containing Tween 20
      and gelatin. For the detection of Abs to HBs an indirect ELISA was formulated.
      Sera were similarly 4-fold diluted in the same buffer. Finally, competitive
      ELISAs were used for detecting anti-HBc and anti-HBe and sera tested were diluted
      20- and 5-fold, respectively. All selected dilutions resulted in the accurate and
      reliable determination of HBV Ags and anti-HBV Abs. Taken altogether, these
      ELISAs are highly specific and equally sensitive to the circulating tests.
      However, their design could be very useful for research and/or preclinical
      studies of selected HBV-infected individuals.

PMID- 15019060
TI  - Clara cell secretory protein: determination of serum levels by an enzyme
      immunoassay and its importance as an indicator of bronchial asthma in children.
AB  - Clara cell secretory protein (CC16) is a 16kDa protein secreted by Clara cells in
      the lining fluid of bronchiolar and bronchial epithelium. CC16 presents several
      biologic properties, and has been shown to have immunomodulatory and anti
      inflammatory activity. It may play a role in controlling inflammation in the
      airway. There is some evidence that the CC16 level is primarily lower in adult
      individuals with bronchial asthma, thus contributing to its pathophysiology. This
      study was designed to examine CC16 serum levels of children, healthy and with
      asthma. An enzyme solid phase immunoassay utilizing monoclonal antibody to CC16
      was the analytical method to determine the protein concentration in blood sera.
      The method showed excellent linearity, high sensitivity (detection limit: <50
      ng/l) and precision. It was found that asthmatic children appear significantly
      lower levels (P < 0.001) of CC16 in serum as compared to healthy ones. It is,
      therefore, concluded that CC16 may be a useful diagnostic index of bronchial
      asthma in the early child-age.

PMID- 15019061
TI  - Determination and biological relevance of serum cross-linked type I collagen N
      telopeptide and bone-specific alkaline phosphatase in breast metastatic cancer.
AB  - Bone metastasis is a frequent complication of cancer disease. The metastatic
      spread of cancer to bone is common to many different malignancies, particularly
      breast (ca. 73%), prostate (ca. 68%) and lung (ca. 36%) cancers. Metastases to
      bone cause increased bone resorption both from direct effects of the tumor itself
      and thought osteoclastic activation. The diagnosis and follow-up of bone
      metastatic cancer patients usually relies on skeletal X-ray and bone
      scintigraphy. However, the development of biochemical markers, used as indicators
      of bone metabolism, provides data useful in the clinical practice. The most
      important markers for bone remodeling process, bone formation and resorption, are
      bone-specific alkaline phosphatase (BAP) and N-telopeptide of type I collagen
      (NTx), respectively. In this report, we applied two solid-phase immunoassays used
      for the determination of BAP and NTx in serum of breast cancer (BC) post
      menopausal women with bone metastasis and healthy individuals. BAP level in
      patients was found to be 45.72 +/- 12.92 U/l, while the normal range for healthy
      individuals was 14.2 - 42.7 U/l. The respective level of serum NTx was 19.20 +/-
      8.87 nM bone collagen equivalents (BCE) for patients and 15.9 +/- 3.8 nM BCE for
      healthy women. Correlation of the obtained data showed elevated levels for both
      markers indicating high rate of bone degradation in breast metastatic cancer.

PMID- 15019062
TI  - A heterogeneous enzymatic assay for quantification of Plasmepsin II activity and
      the evaluation of its inhibitors.
AB  - The emergence and worldwide spreading of Plasmodium falciparum strains that shown
      to be resistant to traditional drugs is considered a very serious health problem,
      given the high mortality and morbidity rate of Malaria. In the search for new
      drugs against this parasite, Hb hydrolyzing enzymes, such as Plasmepsin II (Plm
      II), have been classified as very promising targets for therapeutic attacks. In
      this work, it is developed a cheap and high-throughput heterogeneous enzymatic
      assay for measuring Plasmepsin II activity in order to use it as a tool in the
      discovery of new inhibitors of this enzyme. In this assay, Plasmepsin II acts
      upon a solid-phase bound synthetic peptide (DU2) whose sequence comprises the
      cleavage site F(33)-L(34) present in Hb alpha-chain. The peptide surface density
      is quantified by means of a classical ELISA-based procedure. In order to estimate
      the kinetic constants of the system and to quantify both, enzymatic and
      inhibitory activity, it was used a model for the kinetics of enzyme quasi
      saturable systems previously developed by our group, that fitted very well to the
      experimental data. It was used Pepstatin as a model inhibitor of Plasmepsin II
      and the resulting dose-response relation agreed with the expected behavior for
      the Pepstatin-Plasmepsin II pair under the employed experimental conditions.

PMID- 15019063
TI  - Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation
      and supercritical methods.
AB  - This study compares the physicochemical properties of carbamazepine (CBZ) solid
      dispersions prepared by either a conventional solvent evaporation versus a
      supercritical fluid process. Solid dispersions of carbamazepine in
      polyvinylpyrrolidone (PVP) K30 with either Gelucire 44/14 or Vitamin E TPGS, NF
      (d-alpha-tocopheryl polyethylene glycol 1000 succinate) were prepared and
      characterized by intrinsic dissolution, differential scanning calorimetry, powder
      X-ray diffraction and Fourier transform infrared spectroscopy. CBZ/PVP K30 and
      CBZ/PVP K30/TPGS solid dispersions showed increased dissolution rate. The best
      intrinsic dissolution rate (IDR) was obtained for supercritically processed
      CBZ/PVP K30 that was four-fold higher than pure CBZ. Thermograms of various solid
      dispersions did not show the melting peak of CBZ, indicating that CBZ was in
      amorphous form inside the carrier system. This was further confirmed by X-ray
      diffraction studies. Infrared spectroscopic studies showed interaction between
      CBZ and PVP K30 in solid dispersions. The amorphous state of CBZ coupled with
      presence of interaction between drug and PVP K30 suggests fewer, if any,
      stability problems. Because the supercritical-based process produced solid
      dispersions with IDR better than conventional solid dispersions augmented with
      amphiphilic carriers, stability issues associated with lipid carriers do not
      apply, which, in turn, implies easier scale up under current Good Manufacturing
      Practice for this technique.

PMID- 15019064
TI  - Evaluation of carboxymethyl guar films for the formulation of transdermal
      therapeutic systems.
AB  - Carboxymethyl guar (CMGS), an anionic semisynthetic guar gum derivative was
      evaluated for its suitability of use in transdermal drug-delivery systems.
      Terbutaline sulfate (TS) was used as a model drug. The diffusion of terbutaline
      sulfate from CMGS solution was relatively slower at pH 5 than at pH 10. It is
      most likely that the interaction between CMGS and terbutaline sulfate at pH 5 is
      physical, involving static interaction. The ability of such interactions in
      modifying the release kinetics of drug from the CMGS transdermal films was
      studied. The release was exponential from pH 5 formulations whereas the release
      rate followed zero or Higuchian order from pH 10 formulations. However, the
      diffusion kinetics of both pH 5 and pH 10 formulations followed zero order across
      human cadaver epidermis. Such an interaction was also found to alter the
      pharmacokinetic parameters of the drug. The steady-state concentration of TS was
      relatively consistent and the bioavailability was approximately 50% higher in pH
      5 formulations than pH 10. The elimination rate constant/half-life was
      significantly different between pH 5 and pH 10 formulations.

PMID- 15019065
TI  - Sustained release of acetaminophen from a heterogeneous mixture of two
      hydrophilic non-ionic cellulose ether polymers.
AB  - This study examined the release of acetaminophen (APAP) from hydroxypropyl
      methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) matrices. The effect of
      pseudoephedrine (PE) as a co-active, HPMC:HPC ratio, polymer loading, pH of the
      dissolution media, and compression force on APAP release were studied. Granules
      formulated with APAP or both APAP and PE, and various blends of HPMC and HPC were
      compressed into tablets at different compression forces. APAP release from the
      matrix tablets was not considerably influenced by changes in HPMC:HPC ratio or
      compression force. The rate of drug release was significantly affected by pH of
      the dissolution media, total polymer loading, and the presence of PE. Drug
      release from the formulations containing both APAP and PE was slower than those
      containing only APAP. Drug release from tablets formulated with APAP only showed
      an initial burst at pH 1.16 or 7.45. Formulations containing both APAP and PE
      showed slower drug release at pH 1.16 than at pH 7.4. The drug release data
      showed a good fit to the Power Law Model. The mechanism of drug release is
      consistent with a complex behavior. The results of the tablet erosion studies
      indicated that the amount of APAP released was linearly related to the percentage
      of tablet weight loss. The kinetics of tablet water uptake was consistent with a
      diffusion and stress relaxation mechanism.

PMID- 15019066
TI  - The effect of solubilization on the oral bioavailability of three benzimidazole
      carbamate drugs.
AB  - The effect of solubilization by complexation with povidone on the oral
      bioavailability of three anthelmintic benzimidazole carbamate drugs: mebendazole
      (MBZ), albendazole (ABZ) and ricobendazole (RBZ), was studied in mice. The
      following in vitro characteristics of the initial raw materials and the drug
      povidone complexes were evaluated: melting point (MP); mean dissolution time
      (MDT); solubility constants (Cs) in n-octanol, acid (pH 1.2) and neutral (pH 7.4)
      aqueous media; apparent partition coefficients (P) and capacity factors (k'W)
      determined by HPLC. The following in vivo parameters were also evaluated: AUC(0
      infinity), C(max), T(max) and MRT. The possible relationship between in vitro
      characteristics and in vivo parameters was explored and it was found that an
      increase in solubility, especially in acidic medium, leads to an increase in AUC
      and C(max) and a decrease in T(max). Therefore, dissolution seems to be the
      absorption limiting step for these drugs. For the in vivo parameters related to
      the amount of absorbed drug (AUC and C(max)), the best correlation was obtained
      with the in vitro characteristics related to solubility which are Cs, MP and MDT.
      On the other hand, there were good linear correlations between T(max) which is an
      in vivo parameter related to the rate of drug absorption, and the
      lipophilia/hydrophilia (logP and log k'W) relation-parameters.

PMID- 15019067
TI  - Intranasal administration of melatonin starch microspheres.
AB  - Using melatonin as model drug, starch microspheres for intranasal administration
      were prepared by an emulsification-crosslinking technique using a uniform design
      to optimize preparation conditions. The entrapment ratio of melatonin in the
      microspheres was 11.0% and particle sizes ranged from 30 to 60 microm. Melatonin
      was released from the microspheres in a sustained manner in vitro. Nasal
      clearance of 99mTC labeled starch microspheres was investigated using gamma
      scintigraphy. It was revealed that >80% of the starch microspheres could be
      detected in the nasal tissue 2h after administration, compared to 30% for a
      solution. The pharmacokinetics of melatonin starch microspheres was investigated
      after intranasal administration. The absorption rate was rapid (T(max) min), and
      the absolute bioavailability was high, 84.07%. A good correlation was found
      between in vitro release and in vivo absorption data.

PMID- 15019068
TI  - Influence of encapsulation on the in vitro percutaneous absorption of octyl
      methoxycinnamate.
AB  - The purpose of this study was to evaluate the in vitro transdermal permeation and
      skin accumulation of one ultraviolet (UV) absorber-octyl methoxycinnamate (OMC)
      through pig skin and to determine the quantity of OMC in the skin surface and
      different pig skin layers (stratum corneum, viable epidermis, dermis, and
      receptor fluid). Four cases have been considered: the application of oil-in-water
      (O/W) and water-in-oil (W/O) emulsions containing the same filter free and
      encapsulated in nanocapsules (NC). The influence of the carrier on the
      percutaneous penetration was studied. Data showed that UV absorber exhibited
      increases in skin accumulation when is formulated in emulsions in free form. Skin
      accumulation of OMC-free in the emulsions was significantly (P < 0.05) greater
      than that of OMC-encapsulated for all formulations investigated. OMC-free skin
      accumulation ranged from 127.8 +/- 22.8 microg/cm(2) (O/W emulsion) to 172.1 +/-
      12.9 microg/cm(2) (W/O emulsion). OMC-encapsulated skin accumulation ranged from
      50.3 +/- 13.1 microg/cm(2) to 43.0 +/- 6.5 microg/cm(2) at NC-O/W and NC-W/O,
      respectively. No significant differences were found in the transdermal permeation
      of cinnamate for any of the formulations tested. The results of this study
      demonstrate that the inclusion of OMC-encapsulated in sunscreen formulations
      decreases the skin accumulation of the cinnamate since the in vitro release
      mechanism of OMC-nanocapsules is governed by hydrophobicity and crystallinity of
      the polymer and by the high lipophilicity of the drug. The crystallinity of the
      polymer have the ability of reflecting and scattering UV radiation on their own
      thus leading to photoprotection without the need for molecular sunscreens.

PMID- 15019069
TI  - Micellar solutions of triblock copolymer surfactants with pilocarpine.
AB  - Solutions of surface active triblock copolymer Pluronic F127 in the vicinity of
      the critical micellar concentration (cmc) were prepared with or without
      pilocarpine (either as the hydrochloride salt or the free base) in water and
      phosphate buffer. The characteristics parameters of the surface activity (cmc,
      Gamma and a) were determined for F127 solutions. Additionally, it was found that
      the pilocarpine solutions without F127 in water exhibits a certain surface
      activity. The solutions containing F127 (2 wt.%) well above the cmc and
      pilocarpine (2 wt.% for the salt, or equimolar 1.7 wt.% for the base) were
      further tested in vivo (miotic response) on rabbit eye. Though the entrapment
      efficiency of the drug in the micelles was rather low (maximal 1.9%) the
      pharmacokinetic parameters (duration of miotic response and the area under miotic
      curve) were improved when compared to the standard pilocarpine solutions. The
      best results were obtained for the micellar pilocarpine base solution which
      exhibits significant prolongation of miotic activity and an increase of AUC for
      64%.

PMID- 15019070
TI  - Therapeutic efficacy of sustained drug release from chitosan gel on local
      inflammation.
AB  - The model anti-inflammatory drug prednisolone (PS) was retained in chitosan (CS)
      gel beads, which were prepared in a 10% aqueous amino acid solution (pH 9.0).
      Sustained release of PS from the CS gel beads was observed. Carrageenan solution
      was injected into air pouches (AP), which were prepared subcutaneously on the
      dorsal surface of mice, in order to induce local inflammation. CS gel beads
      retaining PS were then implanted into the AP to investigate the therapeutic
      efficacy of sustained PS release against local inflammation. In vivo PS release
      from CS gel beads was governed by both diffusion of the drug and degradation of
      the gel matrix. Sustained drug release by CS gel beads allowed the supply of the
      minimum effective dose and facilitated prolonged periods of local drug presence.
      Inflammation indexes were significantly reduced after implantation of CS gel
      beads when compared with injection of PS suspension. Thus, extension of the
      duration of drug activity by CS gel beads resulted in improved therapeutic
      efficacy. These observations indicate that CS gel beads are a promising
      biocompatible and biodegradable vehicle for treatment of local inflammation.

PMID- 15019072
TI  - Improvement of the ocular bioavailability of timolol by sorbic acid.
AB  - The ocular bioavailability of timolol increased in sorbic acid solution due to
      ion pair formation. Its octanol/water partition coefficient also increased,
      suggesting the formation of a more lipophilic complex. The concentration of
      timolol in rabbit aqueous humor was determined after instillation of timolol
      ophthalmic solution containing sorbic acid. When the molar ratio of sorbic acid
      to timolol was two or higher, the concentration of timolol in the aqueous humor
      was higher than with timolol alone. In the presence of sorbic acid the maximal
      aqueous humor concentration and the area under the curve were more than two-fold
      higher than those of Timoptol, a timolol maleate ophthalmic solution, and similar
      in value to TIMOPTIC-XE, a gel-forming ophthalmic solution. To investigate the
      transcorneal absorption mechanism, in vitro permeation profiles across the intact
      and de-epithelialyzed cornea were analyzed on the basis of the bilayer diffusion
      model. The partition coefficient in the epithelium was about twice as high in the
      presence of sorbic acid than with timolol alone, although the diffusion
      coefficient in the epithelium did not change. We conclude that the improved
      ocular bioavailability in the presence of sorbic acid is due to increased
      partitioning of timolol in the corneal epithelium.

PMID- 15019071
TI  - Development of parenteral formulation for a novel angiogenesis inhibitor, CKD-732
      through complexation with hydroxypropyl-beta-cyclodextrin.
AB  - The effect of hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) on the aqueous
      solubility and chemical stability of O-(4-Dimethylaminoethoxycinnamoyl)fumagillol
      (CKD-732), a new angiogenesis inhibitor, was investigated with an aim of
      preparing a stable and effective parenteral formulation. The CKD-732/HP-beta-CyD
      inclusion complex was obtained in solid state by freeze-drying and characterized
      in solution by proton nuclear magnetic resonance (1H NMR). Then, the
      pharmacokinetic profile in rats and the in vivo tumor growth inhibitory activity
      in mice following the parenteral administration of aqueous CKD-732/HP-beta-CyD
      complex were compared to those of CKD-732.hemioxalate solution having an
      equivalent concentration. The aqueous solubility of CKD-732 was markedly
      increased by the combination of pH adjustment and HP-beta-CyD complexation
      through a soluble 1:1 inclusion complex formation, which was supported by NMR
      spectroscopy. The hydrolysis of CKD-732 following pseudo first-order kinetics was
      decelerated moderately but significantly in acidic and basic solutions in the
      presence of HP-beta-CyD. The stability of lyophilized CKD-732/HP-beta-CyD complex
      was also drastically improved after storage in various conditions. The
      intravenous pharmacokinetic profile and the subcutaneous in vivo tumor growth
      inhibitory activity of aqueous CKD-732/HP-beta-CyD complex were not significantly
      different from those of CKD-732.hemioxalate solution with the favorable reduction
      of irritation. These results demonstrate that the CKD-732/HP-beta-CyD complex is
      an attractive formulation for use in the parenteral delivery of CKD-732.

PMID- 15019073
TI  - Stomach-specific anti-H. pylori therapy; part III: effect of chitosan
      microspheres crosslinking on the gastric residence and local tetracycline
      concentrations in fasted gerbils.
AB  - The main objective of the present study was to examine the effect of chemical
      crosslinking of chitosan microspheres on the gastric residence and local
      tetracycline concentrations following oral administration in fasted gerbils.
      Radioiodinated [125I] glyoxal-crosslinked chitosan microsphere suspension in
      deionized distilled water was administered for the gastric residence studies. At
      different time points, the animals were sacrificed and the radioactivity in
      tissues and fluids was measured. Stomach tetracycline concentrations were
      determined using tritiated-[3H]-tetracycline-loaded crosslinked chitosan
      microspheres. The radioactivity, measured with a liquid scintillation analyzer,
      was used to determine the microgram of drug per gram of tissues or fluids. After
      2 h in the fasted stomach, approximately 10% of the non-crosslinked chitosan
      microspheres remained. On the other hand, 17% of the crosslinked chitosan
      microspheres remained in the fasted stomach after the same time period. The
      microspheres were predominantly found in the colon after 6 h of administration.
      There was no detectable radioactivity in the plasma, urine, small intestine,
      liver, and kidneys. Tetracycline concentration profile in the stomach from the
      crosslinked microsphere formulation was higher than that of the aqueous solution
      and the non-crosslinked microsphere formulation. While the area-under-the-curve
      (AUC(0.5-->10 h)) for tetracycline solution and non-crosslinked chitosan
      microspheres was 447.3 and 358.2 microg h/g of tissue, respectively, the AUC(0.5-
      >10 h) for the crosslinked chitosan microspheres was 868.9 microg h/g of tissue.
      The drug was predominantly found in the colon and urine after 6 h of
      administration. Results of this study show that chitosan microspheres prepared by
      chemical crosslinking provide a longer residence time in the fasted gerbil
      stomach than either tetracycline solution or microspheres prepared by ionic
      precipitation.

PMID- 15019074
TI  - Prolongation of epidural bupivacaine effects with hyaluronic acid in rabbits.
AB  - To assess the prolongation of epidural bupivacaine by hyaluronic acid viscous
      formulations we designed a cross-over study in rabbits. Different doses of
      bupivacaine (3 or 6 mg) either as a solution (bupivacaine hydrochloride), or as
      viscous formulations with hyaluronic acid (bupivacaine base and bupivacaine
      hydrochloride) were administered in a rabbit model of epidural anesthesia. In the
      first part of the study, in vitro release characteristics were determined. Then
      pharmacodynamic effects and pharmacokinetic profiles of each bupivacaine
      formulation were studied. The rank order release rate of bupivacaine in vitro was
      always hydrochloride solution >> viscous physical mixture of bupivacaine with
      hyaluronic acid > viscous ionic complex of bupivacaine base with hyaluronic acid.
      Onset time of epidural anesthesia was similar whatever the formulation of
      bupivacaine used. We did not find any blockade prolongation when 3mg bupivacaine
      was administered, but significant blockade prolongations were observed with
      viscous formulations incorporating 6 mg bupivacaine. The observed reduction in
      the absorption rate of bupivacaine into the systemic circulation for both viscous
      hyaluronic formulations after 6 mg of bupivacaine may explain the prolongation of
      spinal effects. Drug release and duration of action were found to be viscosity
      controlled as linear relationships were found between pharmacodynamic effects and
      viscosity. Our results were in accordance with those reported with bupivacaine
      cyclodextrin complex, another formulation with a molecular dispersion of the
      drug, resulting in a moderate prolongation of action.

PMID- 15019075
TI  - The use of inverse gas chromatography to assess the acid-base contributions to
      surface energies of cefditoren pivoxil and methacrylate copolymers and possible
      links to instability.
AB  - It is known that acids and bases when mixed together have the potential to react,
      however, there is complexity when materials are in the solid state, as the
      surface of the solids may not have all functional groups of the molecule
      expressed in equal proportions. Conceptually a drug that is acidic when in
      solution could have a crystal surface that is largely basic (if the acid groups
      are aligned away from the surface). The interaction of cefditoren pivoxil (a
      basic drug when dissolved) and various Eudragit polymers was studied. The drug
      was chemically unstable with Eudragit EPO (basic) and stable with Eudragit L100
      or S100 (both acidic). Thus, the hypothesis of this work was that the surface of
      these materials had a different nature to the dissolved molecules, such that
      solid state reactions do not proceed in line with the expectation from the
      solution state. Inverse phase gas chromatography (IGC) was used to investigate
      the cefditoren pivoxil and the Eudragits. The basic to acidic parameter ratios
      (K(D)/K(A)) on the powder surface of the samples by IGC revealed that surface
      nature was in keeping with the tendency to react, such that the incompatibility
      could be due to the acid-base interaction between any carbonyl groups having an
      amphoteric nature on the surface of cefditoren pivoxil crystal and
      dimethylaminoethyl groups having a basic nature on the powder surface of Eudragit
      EPO. This study indicated that IGC would be suitable to elucidate the cause of
      incompatibility between two different solids.

PMID- 15019076
TI  - Preparation and in vitro synergistic anticancer effect of vitamin K3 and 1,8
      diazabicyclo[5,4,0]undec-7-ene in poly(ethylene glycol)-diacyllipid micelles.
AB  - Polymeric micelles consisting of poly(ethylene glycol)-distearoyl
      phosphoethanolamine conjugates (PEG-DSPE) loaded with Vitamin K3 (VK3) to 0.2 mg
      of drug/mg of carrier and with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) to 0.06
      mg of drug/mg of carrier were prepared. These micelles were stable for as long as
      6 months during storage at 4 degrees C and did not change their size or release
      the incorporated drugs. Co-encapsulation of VK3 and DBU into PEG-DSPE micelles
      resulted in synergistic anticancer effects against both murine and human cancer
      cells in vitro. The synergism may be explained by the fact that the presence of
      DBU promotes the escape of drug-loaded micelles from the endosomes of cancer
      cells directly into the cytoplasm as demonstrated by fluorescent microscopy.

PMID- 15019077
TI  - Power consumption measurement and temperature recording during granulation.
AB  - This study was performed to elucidate the influences of process and formulation
      design using power consumption and temperature measurements during granulation.
      Power consumption was recorded "in process" using a previously introduced
      computer program for optimal end-point detection at an early stage. The
      temperature increase (DeltaT) during granulation was recorded using a temperature
      sensor. The temperature increase in the wet powder bed expresses the friction
      forces at interparticle contacts occurring during granulation. The maxima of
      temperature profile occurred at 130% saturation, whereas the maxima of power
      consumption were determined at 100% saturation. The ratio of temperature and
      power consumption (TPR factor) is introduced as a signature of formulation
      design. TPR factor was found to be dependent on particle size, particle surface,
      water absorption capacity and solubility of the excipient and model drug,
      respectively. However, TPR factor was found to be independent of process design,
      such as the filling level of the mixer. Understanding and controlling the
      granulation process is a key factor in robust dosage form design. The "in
      process" control fits ideally the prerequisites of a drug quality system for the
      21st century and FDA's Process Analytical Technology (PAT) initiative. The
      results of previous and present works of our research group will be used in a
      following step to develop an artificial neural network for granulation "in
      process" control.

PMID- 15019078
TI  - Effect of drug solubility and different excipients on floating behaviour and
      release from glyceryl monooleate matrices.
AB  - Glycerol monooleate (GMO) matrix was found to be a gastro-retentive carrier
      system suitable for both polar and as well as non-polar drugs. Chlorpheniramine
      maleate (CPM) and diazepam (DZP) were used as model drugs. Effect of PEG 4000,
      PEG 10000, and stearic acid on floatability and release profile was studied.
      Water uptake increased with increase in the loading of polar drug (CPM) and
      decreased with non-polar drug (DZP). Similar effect was found to occur in case of
      drug release. PEGs increased the release up to certain concentration and
      decreased thereafter. Drug release decreased linearly with concentration of
      stearic acid. The type and extent of mesophases formed were significantly
      affected by the nature of drug, excipients and their concentration. Thus the
      selection of suitable excipients depending on polarity of drug, could help to
      modulate the floatability and release profile from GMO matrices.

PMID- 15019079
TI  - Transport characteristics of 9-nitrocamptothecin in the human intestinal cell
      line Caco-2 and everted gut sacs.
AB  - The intestinal absorptive characteristics and the efflux mechanisms of 9
      nitrocamptothecin (9-NC), a novel water-insoluble camptothecin (CPT) derivative,
      were investigated. The Caco-2 cells and the everted gut sacs were used as models
      of the intestinal mucosa to assess transepithelial transport of 9-NC. The
      determination of 9-NC was performed by HPLC. In the Caco-2 cells, the absorptive
      transport of 9-NC was pH dependent and the transport was enhanced at weakly
      acidic pH on the apical side. No concentration dependence and saturation were
      observed for the absorptive transport of 9-NC at concentrations up to 250 microM,
      while secretory transport were concentration dependent and saturable process
      (K(m) was 49.8 +/- 1.2 microM, V(max) was 38.28 +/- 0.8 ng/cm(2)/min). In the
      presence of verapamil (100 microM) and CsA (10 microM), potent inhibitors of P
      glyprotein (P-gp)/MRP2 (cMOAT), the P(appBL-AP)/P(appAP-BL) ratio was decreased
      from 3.4 to 1.4 and 1.3, respectively, and permeation of apical to basolateral
      was enhanced approximately two-fold. In the everted gut sacs, the absorption of 9
      NC was passive diffusion and had no significant difference in different gut
      regions. Adding verapamil in the everted gut sacs over a concentration ranging
      from 10 to 100 microM, the absorption of 9-NC was significantly enhanced,
      especially more markedly in lower small intestine (P < 0.05). Overall, the
      current study suggests that pH and efflux transporters are capable of mediating
      the absorption and efflux of 9-NC, and they may play significant roles in
      limiting the oral absorption of 9-NC.

PMID- 15019080
TI  - The influence of buffer composition on tissue integrity during permeability
      experiments "in vitro".
AB  - A well-balanced incubation saline is necessary for permeability experiments with
      the rat jejunal tissue in the diffusion chambers. At the same time the
      investigated substance must be chemically stable and sufficiently soluble in this
      incubation saline. To investigate whether the absence of some ions in incubation
      salines influences the tissue viability and integrity or the diffusional
      characteristics of the epithelial membrane the electrical parameters were
      monitored and the permeability of fluorescein and acyclovir was evaluated during
      the experiments in side-by-side diffusion chambers. Our results show that the
      tissue integrity and viability are seriously impaired when Ca(2+) and Mg(2+)-free
      conditions are applied on both sides of the diffusion chambers, but not when only
      mucosal or only serosal side is Ca(2+) and Mg(2+)-free. Bicarbonate-free
      incubation salines can also alter the measured apparent permeability coefficients
      even though the tissue viability and integrity do not change. This change in the
      apparent permeability is most likely due to a change in the pH of the mucosal
      surface and can be prevented if the buffer capacity of the incubation saline is
      increased.

PMID- 15019081
TI  - Study of the phase behavior of polyethylene glycol 6000-itraconazole solid
      dispersions using DSC.
AB  - The aim of the present study was to investigate the phase behavior of solid
      dispersions made up of PEG 6000 and itraconazole using DSC. Solid dispersions
      were prepared by solvent evaporation. DSC analysis of pure PEG 6000 showed three
      endothermic events, representing the melting transitions of the three different
      crystal modifications. It was shown that itraconazole decreased the formation of
      the polymer modifications with melting transitions at 56 and 59 degrees C but
      promoted the formation of the modification with a melting transition at 63
      degrees C. All dispersions investigated showed the presence of crystalline
      itraconazole indicating that the drug is not molecularly dispersed in the polymer
      matrix. However, the presence of an endothermic peak in DSC curves of all solid
      dispersions at approximately 85-90 degrees C showed that at least a second phase
      of pure itraconazole is present also: glassy itraconazole. The protective effect
      of the polymer is clear at low concentration of drug since no recrystallisation
      exotherm can be detected. However, at drug concentrations at or above 80%, a
      recrystallization exotherm at approximately 117 degrees C can be detected. At
      least three different phases can be distinguished at room temperature: a polymer
      phase, crystalline itraconazole and glassy itraconazole. The findings of the
      present study thus demonstrate the coexistence of multiple drug phases in a solid
      dispersion.

PMID- 15019082
TI  - Successful in silico predicting of intestinal lymphatic transfer.
AB  - The possibility of developing a quantitative relationship between molecular
      structure and lymphatic transfer of lipophilic compounds co-administered with a
      long-chain triglyceride vehicle was examined. Molecular descriptors were
      calculated using the computer program VolSurf, and lymphatic transfer data were
      derived from the literature. A significant structure-property relationship was
      established using partial least squares, projection to latent structures
      statistics (PLS). R(2)X was 0.77, R(2)Y was 0.83 and the prediction power of Q(2)
      was 0.73 in the two-component PLS model. A number of descriptors contributed to
      the prediction leading to a complex model, but the prediction power was improved
      with the PLS model when compared to the frequently used method by relating logP
      values (LogKow) with lymphatic transfer.

PMID- 15019083
TI  - Low hepatic glutathione S-transferase and increased hepatic DNA adduction
      contribute to increased tumorigenicity of aflatoxin B1 in newborn and partially
      hepatectomized mice.
AB  - Low levels of hepatic glutathione S-transferase and increased formation of
      aflatoxin B1 (AFB1)-DNA adducts correlate with hepatocyte proliferation and
      increased hepatocarcinogenesis in both newborn mice and partially hepatectomized
      adult mice, as compared to normal, adult C57BL/6J mice. Newborn mice, which are
      highly susceptible to the hepatocarcinogenic effects of AFB1, have active
      proliferation of hepatocytes until 3 weeks of age, when hepatocyte proliferation
      abruptly ceases. At about this time, the mice become highly resistant to AFB1. In
      adult mice, AFB1 carcinogenicity is increased after stimulation of liver
      proliferation by partial hepatectomy. To become carcinogenic, AFB1 is activated
      in the liver by the P450 enzyme system to electrophilic intermediates, some of
      which form DNA adducts believed to be responsible for mutations leading to
      cancer. The most carcinogenic intermediate, AFB(1)-8,9-epoxide, is detoxified by
      glutathione S-transferase-mediated conjugation to glutathione. Glutathione
      levels, glutathione S-transferase levels, and AFB1-DNA adduct formation were
      measured at 4, 10, 30, 120, 245 and 365 days of age in C57BL/6J mice. There was a
      5-fold increase in hepatic glutathione S-transferase levels and 13-fold decrease
      in hepatic AFB1-DNA adduct formation over these ages. Induction of hepatocyte
      proliferation following partial hepatectomy of 120-day-old mice lowered hepatic
      glutathione S-transferase levels and increased the extent of hepatic AFB1-DNA
      formation to levels similar to those measured in 4-day-old mice. These results
      indicate that increased susceptibility to AFB1 hepatocarcinogenesis in newborn
      mice, and in adult mice following partial hepatectomy, is due to decreased GST
      and increased adduct formation in proliferating liver.

PMID- 15019084
TI  - alpha1-Microglobulin as a promising marker of cadmium-induced tubular
      dysfunction, possibly better than beta2-microglobulin.
AB  - The purpose of the present study was to evaluate the validity of alpha1
      microglobulin (alpha1-MG) in comparison with popularly used beta2-microglobulin
      (beta2-MG). A database on 8975 cases of never-smoking adult women was revisited;
      the data were based on spot urine samples from the women in 10 prefectures all
      over Japan. The validity of alpha1-MG was examined following essentially the same
      protocol as beta2-MG was examined in a previous study. Comparisons were made for
      alpha1-MG as observed (e.g. alpha1-MG(ob)), as corrected for creatinine (CR or
      cr) (e.g. alpha1-MGcr) and as corrected for a specific gravity (SG or sg) of
      1.016 (e.g. alpha1-MGsg). A cut-off value of 5.0 mg alpha1-MG/g cr or l was
      deduced from 400 microg beta2-MG/g cr taking advantage of the regression equation
      between alpha1-MG and beta2-MG. The prevalence of alph1-microglobulinuria as
      corrected for a specific gravity of 1.016 (or alpha1-MGsg-uria in short) was
      essentially unchanged irrespective of SG, except for in very dense or very thin
      urine samples. alpha1-MGcr-uria prevalence decreased at higher CR. Comparison of
      the present observation with previous findings on beta2-MG-uria prevalence showed
      that the variation in prevalence of MG-uria as a function of urine density was
      smaller for alpha1-MGsg whereas it was substantially larger for beta2-MGcr, and
      thus it appeared prudent to consider alpha1-MGsg rather than beta2-MGcr as a
      marker of tubular dysfunction.

PMID- 15019085
TI  - Effects of acute lindane intoxication and thyroid hormone administration in
      relation to nuclear factor-kappaB activation, tumor necrosis factor-alpha
      expression, and Kupffer cell function in the rat.
AB  - Nuclear factor-kappaB (NF-kappaB) DNA binding, tumor necrosis factor-alpha (TNF
      alpha) expression, and parameters related to liver oxidative stress and Kupffer
      cell function were assessed in control rats and in animals given 3,3',5
      triiodothyronine (T3) (0.1 mg T3/kg) and/or lindane (50 mg/kg; 4 h after T3).
      Liver NF-kappaB DNA binding and serum TNF-alpha levels were enhanced by the
      combined T3-lindane administration after 16-22 h, effects that were lower than
      those elicited by the separate treatments and coincided with increased hepatic
      TNF-alpha mRNA levels. Thyroid calorigenesis occurred independently of lindane,
      whereas T3, lindane and T3-lindane groups showed liver glutathione (GSH)
      depletion, with higher protein carbonyl levels in lindane and T3-lindane groups.
      Carbon-induced O2 consumption/carbon uptake ratios were not altered by T3 or
      lindane compared to controls, whereas combined T3-lindane administration elicited
      a 92% diminution with enhancement in the sinusoidal efflux of lactate
      dehydrogenase (LDH). In conclusion, depression of T3- or lindane-induced liver NF
      kappaB activation and TNF-alpha expression occurred after their combined
      treatment, effects that correlate with the impairment of the respiratory burst
      activity of Kupffer cells and exacerbation of liver injury.

PMID- 15019086
TI  - Acute exposure to aroclor 1016 or 1260 differentially affects dopamine
      transporter and vesicular monoamine transporter 2 levels.
AB  - Polychlorinated biphenyls (PCBs) have been shown to specifically target the
      dopaminergic nervous system, resulting in long-term reduction of striatal
      dopamine (DA) levels. However, the mechanism(s) by which PCBs exert this effect
      is not known. Here we report that decreased striatal dopamine levels are observed
      1, 7, and 14 days after acute exposure to the common PCB mixtures Aroclor 1016 or
      1260. Dopamine transporter (DAT) levels were decreased at all time points in
      Aroclor 1016 treated animals, and on Days 1 and 7 in Aroclor 1260 treated
      animals. Vesicular monoamine transporter 2 (VMAT2) levels were not affected by
      Aroclor 1016, but were significantly decreased 14 days after exposure to Aroclor
      1260. Tyrosine hydroxylase expression, a marker of dopamine neuron integrity, was
      not significantly affected by PCB exposure at any time. These data suggest that
      PCB-induced reductions in striatal dopamine may be mediated by alterations in DAT
      and VMAT2 expression.

PMID- 15019088
TI  - Microcystin-LR and nodularin induce intracellular glutathione alteration,
      reactive oxygen species production and lipid peroxidation in primary cultured rat
      hepatocytes.
AB  - Microcystin-LR (MCYST-LR) and nodularin (NOD) produced by cyanobacteria are
      potent specific hepatotoxins. However, the mechanisms of their hepatotoxicity
      have not been fully elucidated. In the present study the effect of non cytotoxic
      low concentrations of MCYST-LR and NOD on intracellular reduced glutathione (GSH)
      alteration, reactive oxygen species (ROS) production and lipid peroxidation was
      investigated in primary cultured rat hepatocytes. Cell viability was determined
      by the methylthiazoltetrazolium (MTT) dye assay, reduced GSH was evaluated by
      enzymatic methods, ROS were evaluated by the dichlorofluorescein diacetate (H2DCF
      DA) fluorescent probe and lipid peroxidation by dosing malondialdehyde (MDA) by
      the thiobarbituric acid method. The 24 h LC50 values of MCYST-LR and NOD were 48
      and 62 ng/ml, respectively. Exposure of freshly isolated rat hepatocytes to MCYST
      LR or NOD at non cytotoxic low concentrations (2, 10 ng/ml) for 3, 24 and 48 h
      periods resulted in a significant rise of GSH levels and production of ROS. NOD
      significantly induced in a time- and concentration-dependent lipid peroxidation.
      However, MCYST-LR treatment did result in a significant decrease in MDA levels
      compared with controls. Although MCYST-LR and NOD are closely related in terms of
      structure and inhibition of protein phosphatases, they induce differently the
      oxidative stress at non cytotoxic low concentrations. Therefore, the results
      indicate that oxidative stress mediated by reactive intermediates may be a
      mechanism by which these cyanotoxins induce their hepatotoxic effect.

PMID- 15019087
TI  - The role of mdr2 in manganese-bilirubin induced cholestasis in mice.
AB  - The pathogenesis of manganese-bilirubin (Mn-BR) induced cholestasis has only been
      studied in rats and is associated with alteration in the hepatic homeostasis of
      cholesterol and phospholipids. Multidrug resistance-2 (mdr2) transporter, which
      mediates excretion of these lipids, is suggested to be involved in this
      phenomenon. The present study was undertaken to examine if Mn-BR induced
      cholestasis is reproducible in mice, then to clarify the role of mdr2 in its
      pathogenesis, using mice with disrupted mdr2 gene (mdr2 (-/-)). Results showed
      that Mn-BR combination decreased bile flow in mice. This reduction in bile flow
      was similar in mdr2 (-/-) and the wild type mdr2 (+/+). Furthermore, the change
      in biliary lipid excretion was comparable in both genotypes. These data indicate
      that Mn-BR induced cholestasis is reproducible in mice and provide evidence that
      mdr2 alteration is not a primary event in this form of cholestasis.

PMID- 15019089
TI  - Detoxication of the environmental pollutant acrolein by a rat liver aldo-keto
      reductase.
AB  - Acrolein is a highly reactive hazardous air pollutant of human health concern,
      particularly as it is a component of cigarette smoke. It can be metabolized by
      enzymes including the aldo-keto reductase (AKR) family of enzymes. AKR7A1 is a
      member of the AKR7 sub-family and can catalyse the reduction of toxic aldehydes,
      including alpha-unsaturated carbonyl compounds, to alcohols [Biochem. J. 312
      (1995) 535]. In this study, the role of AKR7A1 in protecting against acrolein
      toxicity has been assessed by stably-expressing a cDNA encoding AKR7A1 in Chinese
      hamster V79 cells. Cells expressing AKR7A1 showed over 2-fold increased
      resistance to acrolein compared to V79 cells alone, as measured by 3-[4,4
      dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays. IC50
      increased from 45 microM in control V79-pCI-neo cells to 125microM for V79-AKR7A1
      cells. Cells expressing AKR7A1 were also found to be less susceptible to DNA
      damage, showing a decrease in mutation rate in the presence of acrolein as
      measured by hypoxanthine guanine phosphoribosyl transferase (HGPRT) mutagenicity
      assays. The mutation rate for acrolein-exposed control cells was 20-fold higher
      than for acrolein-exposed AKR7A1-expressing cells. These results indicate that
      AKR7A1 has the potential to protect against acrolein-induced damage in vivo.

PMID- 15019090
TI  - Fatty acid alterations in liver and milk of cadmium exposed rats and in brain of
      their suckling offspring.
AB  - Fatty acid composition was studied in milk at day 14 and in liver at day 24 after
      parturition of lactating rats exposed to 0 ppm, 5 ppm or 25 ppm cadmium (Cd) via
      drinking water for 17 days during lactation, and in the brain of their offspring
      at day 19 after birth. In the liver phospholipid fraction, 22:5(n-3) was
      significantly higher, while in the triacylglycerol fraction 22:6(n-3)/20:5(n-3)
      ratio was significantly lower in the 25 ppm group compared to the controls.
      Significantly higher proportions of 16:0 and lower proportions of medium-chain
      fatty acids, 8:0-14:0, were observed in milk of dams in the 25 ppm group,
      indicating decreased enzymatic activity of thiotransferase II in the mammary
      gland. Slightly increased levels of 20:3(n-6) were observed in brains of pups in
      the 25 ppm group compared to control. The results indicate that Cd exposure
      influences fatty acid metabolism in lactating rats.

PMID- 15019091
TI  - Mono(2-ethylhexyl)phthalate exhibits genotoxic effects in human lymphocytes and
      mucosal cells of the upper aerodigestive tract in the comet assay.
AB  - Phthalic acid esters such as di(2-ethylhexyl)phthalate (DEHP) are widely used as
      plasticizers in PVC products manufactured for commercial, medical, and consumer
      purposes. Humans are exposed to phthalates originating, e.g., from blood storage
      bags, tubing materials, and from food-wrapping. While xenoestrogenic and chronic
      toxic effects of phthalates have been extensively discussed, there is little data
      on genotoxic effects in human cells. The alkaline comet assay was used to detect
      single-strand breaks and alkali labile sites of DNA after incubation of human
      nasal mucosal cells (n = 11) and peripheral lymphocytes (n = 11) with mono(2
      ethylhexyl)phthalate (MEHP), the principal hydrolysis product of DEHP. MEHP
      showed a dose-dependent enhancement of DNA migration both in human mucosal cells
      and in lymphocytes. This effect indicates a genotoxic potential of MEHP in human
      mucosal cells. It confirms previous data obtained on the effect of MEHP on
      lymphocytes.

PMID- 15019092
TI  - Primary cultures of microglial cells for testing toxicity of anticancer drugs.
AB  - Toxicity of anticancer agents on normal neural cells during chemotherapy of
      primary or secondary brain tumors is a clinical problem of increasing relevance
      and concern. In this perspective, here we used primary cultures of rat cortical
      microglia as an in vitro paradigm of normal glia to investigate the neurotoxicity
      of anticancer agents. The effects of two compounds frequently used for treatment
      of brain tumors, methotrexate (MTX) and temozolomide (TMZ), were compared to
      those of a known microglial activator, bacterial lipopolysaccharide (LPS); cell
      viability and metabolism was assessed by the MTS assay. We found that LPS, in the
      low-intermediate range of concentrations, strongly activates microglia cells, but
      a highly significant decrease in viability was observed from 100 ng/ml onward.
      TMZ has no effect at concentrations of clinical interest, whereas MTX
      significantly increases cell metabolism at 30 microM, a phenomenon possibly
      reflecting MTX neurotoxicity observed in patients.

PMID- 15019094
TI  - The mechanism of indole acetic acid cytotoxicity.
AB  - The cytotoxic effect of IAA (1 mM) was examined in rat neutrophils and
      lymphocytes by: loss of membrane integrity (necrosis), DNA fragmentation,
      chromatin condensation and mitochondrial transmembrane potential (apoptosis). The
      following conditions were studied: (1) rat neutrophils (high peroxidase activity;
      (2) rat lymphocytes in the absence and presence of horseradish peroxidase; and
      (3) rat lymphocytes co-cultivated with rat neutrophils. Incubation of neutrophils
      with IAA induced loss of membrane integrity, chromatin condensation and DNA
      fragmentation. The same was observed in lymphocytes incubated with HRP and IAA or
      co-cultivated with neutrophils in the presence of IAA. Neutrophils and
      lymphocytes incubated with IAA presented a more pronounced depolarization of
      mitochondrial transmembrane potential after 12 h treatment. Incubation for 24 h
      in the presence of IAA (1 mM) showed increase in the activities of superoxide
      dismutase (SOD), catalase (CAT) and glutathione peroxidase. The addition of
      exogenous antioxidant enzymes (SOD and CAT) prevented the loss of cell membrane
      integrity induced by IAA. Therefore, the process of cell death induced by IAA
      involves ROS production.

PMID- 15019093
TI  - The role of nitric oxide in the particulate matter (PM2.5)-induced NFkappaB
      activation in lung epithelial cells.
AB  - NFkappaB is one of key transcription factors that are involved in the
      inflammatory responses to the particulate matter (PM) in the lungs. In order to
      further understand the molecular mechanism, the effects of antioxidants and an
      inducible nitric oxide synthase (iNOS) inhibitor on PM-induced NFkappaB
      activation were examined in A549 lung epithelial cells. NFkappaB activation by
      2.5 microm particulates (PM2.5) was evident from the degradation of an NFkappaB
      inhibitory protein, IkappaBalpha, and a luciferase reporter assay for NFkappaB
      activity. In these experiments, a pre-treatment of the cells with antioxidants N
      acetyl-l-cysteine (NAC) and dimethylthiourea (DMTU) or an iNOS inhibitor l-N6-1
      iminoethyl-lysine (L-NIL) clearly inhibited the NFkappaB activation by PM2.5. The
      inhibitory effect of L-NIL was also observed on the PM2.5-induced interleukin-8
      (IL-8) gene expression both at the transcriptional and protein levels. These
      results suggest that PM2.5 induces NFkappaB activity via the pathways involving
      ROS and/or RNS generation. Considering the fact that NFkappaB also induces NO
      generation via iNOS expression, they might make a positive feedback loop that
      amplifies the downstream responses.

PMID- 15019096
TI  - Changes in the spontaneous and stimulus-evoked activity in the somatosensory
      cortex of rats on acute manganese administration.
AB  - In this work, acute effects of inorganic manganese exposure on nervous electrical
      activity of rats were investigated. Young adult male Wistar rats were prepared
      for recording in anaesthesia and spontaneous cortical as well as stimulus-evoked
      cortical and peripheral nervous activity was recorded before and after i.p.
      administration of 25 and 50 mg/kg Mn2+. The alterations found resulted possibly
      from several known neuronal effects of manganese. The frequency shift of
      spontaneous cortical activity, and increased latency and decreased amplitude of
      the peripheral nerve action potential, were probably due to the Mn(2+)-induced
      impairment of the mitochondria, whereas the increased amplitude of the evoked
      cortical response, to the effect on glutamatergic transmission.

PMID- 15019095
TI  - Distribution and disposition of benzalkonium chloride following various routes of
      administration in rats.
AB  - Benzalkonium chloride (BZK) is a cationic surfactant used widely as a
      disinfectant, preservative and sanitizer in hospitals, at home and many public
      places. The toxicity of BZK is not well established although several human
      fatalities have been reported over the years. In this study, distribution and
      disposition of BZK following oral administration (PO) and intravascular (jugular
      vein (JV), femoral artery (FA), femoral vein (FV) and jugular artery (JA))
      administration in rats were investigated along with pathological examinations.
      Toxic doses of 250 and 15 mg/kg of BZK were used for PO and intravascular
      administration, respectively. The fatal effects of BZK appeared soon in JV-, FV-
      or JA-rats, but took hours in PO or FA-rats. No rat receiving BZK via FA survived
      longer than 1 day. The PO-rats that aspirated BZK into their lungs had some
      systemic symptoms and higher blood and tissue concentrations of BZK. The blood
      BZK levels and kinetics were similar among the different routes of intravascular
      administration, but the lung and kidney levels were higher in JV-rats.
      Pathological examinations confirmed severe congestion and edema in the lungs and
      kidneys. These results suggest that (1) the toxic effects of BZK varied depending
      on the route of administration, (2) the degree of toxicity correlated with peak
      blood and tissue concentrations in orally dosed rats, (3) different toxicological
      progressions and manifestations were observed in FA- and JV-dosed rats even
      though these groups had similar blood concentration profiles, and (4) lung and
      kidney are reservoirs for BZK and considered to be the target organs of BZK.

PMID- 15019097
TI  - Induction of hepatic metallothionein synthesis by endoplasmic reticulum stress in
      mice.
AB  - Metallothionein (MT) is a small sulfhydryl-rich protein whose levels are elevated
      by various inducers of organelle stresses, such as nuclear stress (cisplatin),
      mitochondrial stress (antimycin A, 2,4-dinitrophenol) and lysosomal stress
      (paraquat). Although abnormal folding of protein in the endoplasmic reticulum
      (ER) causes ER stress, induction of MT synthesis by ER stress has never been
      investigated. In this study, we examined the induction of MT by an inducer of ER
      stress, tunicamycin (Tun), which induces ER stress by inhibiting N-linked
      glycosylation of protein in the ER. Administration of Tun (0.5-1.5 mg/kg, sc)
      increased hepatic MT levels in C57BL/6J mice (3.1-fold). The maximal increase in
      hepatic MT was observed 48-96 h after the administration of Tun (1.0 mg/kg).
      Expressions of MT-I, II and glucose-regulated protein 78 (Bip/GRP78), which is a
      molecular chaperone induced by ER stress, mRNA were also detected by
      administration of Tun. Thapsigargin (Thap), a generator of ER stress by
      inhibiting ER Ca(2+)-ATPase, also increased both hepatic MT levels and expression
      of MT-I and -II mRNA. The level of expression of Bip/GRP78 mRNA induced by Tun
      administration in MT-null mice was greater than that in wild-type mice. Taken
      together, these findings suggest that inhibitors of ER are potent inducers of MT.

PMID- 15019098
TI  - Identification of principal cytochrome P-450 in triphenyltin metabolism in rats.
AB  - The in vivo and in vitro metabolism of triphenyltin using rat hepatic cytochrome
      P-450 (CYP) systems was investigated to confirm the specific CYP that is closely
      related to triphenyltin metabolism. No significant sex differences occurred
      between the in vivo and in vitro metabolic patterns of the chemical, indicating
      that the principal CYP for triphenyltin metabolism in rats is not a sex-specific
      form of CYP. In addition, seven types of complementary DNA (cDNA)-expressed rat
      CYPs, typical phenobarbital (PB)-inducible forms and the CYP2C subfamily were
      tested to determine the activity of triphenyltin metabolism. Among the CYP
      isoforms studied, although CYP2B1 had a small metabolic capacity, a marked
      dearylation of the chemical was induced by CYP2C6. Furthermore, anti-rat CYP2C6
      antibodies and cimetidine, a selective CYP2C6 inhibitor, inhibited triphenyltin
      dearylation activity in the hepatic microsomes of rats. Taken together, these
      findings suggest that CYP2C6 is the principal CYP for the triphenyltin metabolism
      in rats.

PMID- 15019099
TI  - Genetic characterization of orf viruses isolated from various ruminant species of
      a zoo.
AB  - In the present study, an outbreak of proliferative dermatitis in musk ox (Ovibos
      moschatus), Sichuan takin (Budorcas taxicolor tibetana) and domestic Shetland
      sheep (Ovis aries) in a zoo is described. Skin lesions consisted of severe,
      persistent, multifocal, proliferative dermatitis in musk ox, and mild, transient,
      focal, dermatitis in the Sichuan takin and Shetland sheep. Parapoxviruses were
      isolated from skin lesions, and characterized by restriction enzyme analysis and
      partial gene sequencing. The results of this investigation indicate that the
      outbreak of proliferative dermatitis was due to infection by a single
      parapoxvirus, which is genetically closely related to other orf virus (ORFV)
      strains but distant to bovine papular stomatitis virus (BPSV) and pseudocowpox
      virus (PCPV).

PMID- 15019100
TI  - Comparable sensitivity and specificity in three commercially available ELISAs to
      differentiate between cattle infected with or vaccinated against foot-and-mouth
      disease virus.
AB  - Three commercially available ELISAs for the detection of antibodies to the non
      structural proteins of foot-and-mouth disease virus (FMDV) were evaluated, using
      sera from uninfected, vaccinated, infected, inoculated, first vaccinated and
      subsequently infected, and first vaccinated and subsequently inoculated cattle.
      We compared antibody kinetics to non-structural proteins, sensitivity, and
      specificity. One of the ELISAs had a higher sensitivity and much lower
      specificity than the other two, therefore we established standardised cutoff
      values for the compared assays using receiver operated characteristic (ROC)
      curves. Using the standardised cutoff values, all three ELISAs produced
      comparable results with respect to sensitivity and specificity. Antibody
      development to non-structural proteins after infection and after
      vaccination/infection was not significantly different. Development of antibodies,
      however, both neutralising and directed to non-structural proteins, was
      significantly delayed after intranasal inoculation as compared to
      intradermolingual infection. Based on results of sera obtained after vaccination
      and experimental infection all three assays can be used for testing sera
      collected between 4 weeks and 6 months after infection. More information is
      needed on the prevalence of positive reactors in a situation where emergency
      vaccination has been used and FMD transmission was still observed.

PMID- 15019101
TI  - Pasteurella multocida contains multiple immunogenic haemin- and haemoglobin
      binding proteins.
AB  - Iron-dependent outer membrane proteins (IROMPs) play an important role in
      bacterial pathogenesis and present several attributes of potential vaccine
      candidates. TBLASTN analysis of the Pasteurella multocida Pm70 genome using the
      same molecules of other bacterial pathogens as a query identified eight putative
      haemin and haemoglobin receptors for this organism. Quantitative binding assays
      have demonstrated that the proteins PM0040, PM0236, PM0741, PM1081, PM1428,
      PM0592 and HgbA bind both haemin and haemoglobin, whereas PM0576 and PM1282 ORFs
      only bind either haemoglobin or haemin, respectively. Furthermore, Western blot
      analysis showed that P. multocida-infected mice generate specific antibodies
      against PM0040, PM0236, PM0741, PM1081, PM1428, PM0592 and HgbA proteins.
      Nevertheless, inoculation of mice with any single one of these receptors alone
      did not protect against P. multocida infection.

PMID- 15019102
TI  - Detection of specific antibodies against deflagellated Salmonella Enteritidis and
      S. Enteritidis FliC-specific 9kDa polypeptide.
AB  - Specific antibody levels of laying hens and young chickens experimentally
      infected with Salmonella Enteritidis and vaccinated farm flocks were evaluated by
      enzyme-linked immunosorbent assays (ELISAs) with two different antigens,
      deflagellated S. Enteritidis whole cell (DEWC) and S. Enteritidis FliC-specific
      9kDa polypeptide (SEP9). Infected laying hens excreted S. Enteritidis throughout
      the experimental period, and the specific antibody titers in DEWC-ELISA, were
      significantly higher than the uninfected group. It suggests that this DEWC
      specific antibody will serve as an effective indicator of S. Enteritidis
      infection, especially for non-vaccinated laying flocks. SEP9-specific antibodies
      were detected in spray-inoculated young chickens but not in oral-inoculated young
      chickens. Compared with greatly high SEP9-specific antibody levels of vaccinated
      farm flocks, no response was observed in orally infected hens. These results
      indicate that S. Enteritidis discontinues expressing SEP9 once it has crossed the
      intestinal barrier, and that SEP9-ELISA will serve as a valuable monitoring tool
      for the status of S. Enteritidis vaccination on a flockwide basis, independent of
      stable S. Enteritidis infections.

PMID- 15019103
TI  - Pseudomonas aeruginosa from canine otitis externa exhibit a quorum sensing
      deficiency.
AB  - Pseudomonas aeruginosa LasB elastase gene (lasB) transcription depends on cell
      density-dependent quorum-sensing mechanisms of gene activation. Previously, we
      collected several non-mucoid P. aeruginosa veterinary isolates and showed that
      the total matrix protease phenotype was similar for isolates regardless of host
      and site of isolation. In contrast, isolates from chronic canine ear infections
      (otitis externa) were significantly more likely to exhibit less elastase activity
      as measured by elastin Congo red than from any other site [Clin. Diag. Lab.
      Immun. 8 (2001) 632]. In this study, we found that the elastase deficiency
      phenotype is stable upon passage in broth culture. Transcript amplification
      analyses indicated that the elastase deficiency appears to be strain-specific,
      with each isolate exhibiting a unique expression profile relative to strain PAO1.
      Although a number of strain-specific transcriptional differences were observed,
      the overall pattern that emerges is a quorum sensing deficiency among canine ear
      P. aeruginosa isolates.

PMID- 15019104
TI  - Bovine viral diarrhea virus 1 is classified into different subgenotypes depending
      on the analyzed region within the viral genome.
AB  - Phylogenetic analyses of bovine viral diarrhea virus (BVDV) were performed based
      on the nucleotide sequences of the 5' untranslated region (5'-UTR) and E2-coding
      gene. Thirty-six BVDV detected from naturally infected cattle in the northern
      region of Japan were divided into three genotypes, BVDV1a, BVDV1b and BVDV2, in a
      5'-UTR phylogenetic tree. In a phylogenetic tree constructed from the E2-coding
      gene, BVDV1c was identified and the viruses classified in BVDV1c were included in
      BVDV1a in the 5'-UTR phylogenetic tree. Moreover, BVDV1a and BVDV1b in the E2
      phylogenetic tree clustered closer together than in the 5'-UTR tree. These
      results suggested that phylogenetic analysis of the E2 gene was more useful for
      identification of subgenotypes within BVDV1.

PMID- 15019105
TI  - Pulsed-field gel electrophoresis-based subtyping of DNA degradation-sensitive
      Salmonella enterica subsp. enterica serovar Livingstone and serovar Cerro
      isolates obtained from a chicken layer farm.
AB  - Salmonella enterica serovar subsp. enterica Livingstone and serovar Cerro
      isolates from a commercial egg-producing farm, which had previously been
      untypeable by pulsed-field gel electrophoresis (PFGE) because of DNA degradation
      during the PFGE process, successfully gave banding patterns using electrophoresis
      buffer supplemented with 50 microM thiourea. By PFGE in the presence of thiourea,
      DNA degradation-sensitive S. enterica serovar Cerro isolates from the commercial
      egg-producing farm were found to be genetically unrelated to S. enterica serovar
      Cerro isolates that gave the patterns in the absence of thiourea. Forty-five of
      50 (90%) S. enterica serovar Livingstone isolates from the farm showed
      arbitrarily designated XbaI-digested patterns X1 and X2 that were distinguished
      by one-band difference and had an identical BlnI-digested pattern. In one of the
      two layer houses in the farm, the numbers of isolates having the pattern X2
      increased from 57% in 1997 to 89% in 1998, whereas virtually all the isolates
      obtained from the other house in the same period showed the profile X1. This
      suggests that strains having the pattern X2 might have an advantage to
      preferentially colonize in the former house.

PMID- 15019106
TI  - Characterisation of bovine strains of Pasteurella multocida and comparison with
      isolates of avian, ovine and porcine origin.
AB  - One hundred and fifty-three bovine Pasteurella multocida strains recovered
      primarily from cases of pneumonia and mastitis in England and Wales over an 11
      year period were characterised by capsular PCR typing, comparison of outer
      membrane protein (OMP) profiles, and multilocus sequence analysis. All of the
      strains were of capsular type A with the exception of a single capsular type F
      isolate. Thirteen distinct OMP profiles (OMP-types) were identified based mainly
      on molecular mass heterogeneity of the heat-modifiable (OmpA) and porin (OmpH)
      proteins. However, 85% of the isolates were represented by just five OMP-types
      and 39% of the strains were of a single OMP-type. Multilocus sequence analysis
      revealed a limited degree of genetic diversity among bovine P. multocida
      isolates; strains of the same OMP-type have identical genetic backgrounds and
      represent distinct clones. Analysis of OMP variation was more discriminating than
      multilocus sequence analysis because strains of different OMP-types had the same,
      or similar, genetic backgrounds. The association of a small number of clones with
      the majority of cases of bovine pneumonia suggests that these clones have an
      increased capacity to cause disease compared to less frequently recovered clones.
      Molecular mass heterogeneity of OmpA and OmpH, in strains of the same or similar
      genetic background, suggests that these proteins are subject to diversifying
      selection within the host and might play important roles in host-pathogen
      interactions. Comparison of the OMP profiles of bovine isolates with those of
      avian, ovine and porcine strains showed that a high proportion of the respiratory
      tract infections in each of these species are caused by different strains of P.
      multocida. However, the presence of small numbers of closely related strains in
      more than one host species suggests that transmission of bacteria between
      different host species is also a factor in the population biology of P.
      multocida.

PMID- 15019107
TI  - Haemophilus parasuis: new trends on diagnosis, epidemiology and control.
AB  - Haemophilus parasuis is a commensal organism of the upper respiratory tract of
      conventional pigs, but under appropriate conditions can invade and cause severe
      systemic disease, characterized by fibrinous polyserositis, arthritis and
      meningitis. Factors involved in systemic invasion by H. parasuis remain largely
      unknown. However, major advances in our knowledge of H. parasuis include (1)
      development of a species-specific PCR test to detect H. parasuis in clinical
      samples, (2) study of molecular epidemiology within and between herds, by use of
      a repetitive element-based PCR, (3) the proposal of an alternative serotyping
      technique, (4) development and testing of a new in vivo model for pathogenesis
      and virulence studies, and (5) use of controlled exposure of young pigs to low
      doses of live, virulent H. parasuis strains to reduce nursery mortality in
      affected swine herds.

PMID- 15019108
TI  - Revised definition of Actinobacillus sensu stricto isolated from animals. A
      review with special emphasis on diagnosis.
AB  - The taxonomy of the members of the genus Actinobacillus associated with animals
      has been reviewed with focus on classification and identification including
      molecular based characterization, typing and identification. Out of the 22
      species or species like taxa reported as Actinobacillus, 19 are associated with
      animals. When classified on the basis of 16S rRNA sequence based phylogenetic
      analysis, DNA-DNA hybridizations and phenotypic analysis, Actinobacillus sensu
      stricto is restricted to include A. lignieresii, A. pleuropneumoniae, A. equuli
      subsp. equuli, A. equuli subsp. haemolyticus (taxon 11 of Bisgaard), A. hominis,
      A. suis, A. ureae, A. arthritidis (taxon 9 of Bisgaard), Actinobacillus
      genomospecies 1 and 2 and the taxa 8 and 26 of Bisgaard. The remaining 11 species
      of Actinobacillus are unrelated to A. sensu stricto and should consequently be
      grouped with other genera or be renamed as new genera depending on new data.
      Identification of members of Actinobacillus at species level is possible through
      phenotypic characterization combined with information on host of isolation. PCR
      tests are available for specific detection of A. pleuropneumoniae. Only A.
      pleuropneumoniae is presently considered as a primary pathogen. Based on
      different types of RTX genes it is possible to PCR type A. pleuropneumoniae to
      serotype level. PCR might also be used for the specific detection of A. equuli
      subsp. haemolyticus. Epidemiological investigations and surveillance have so far
      included serotyping, multilocus enzyme electrophoresis (MLEE), ribotyping and
      restriction fragment length profiling.

PMID- 15019109
TI  - Prevalence of feline coronavirus types I and II in cats with histopathologically
      verified feline infectious peritonitis.
AB  - Feline coronaviruses (FCoV) vary widely in virulence causing a spectrum of
      clinical manifestations reaching from subclinical course to fatal feline
      infectious peritonitis (FIP). Independent of virulence variations they are
      separated into two different types, type I, the original FCoV, and type II, which
      is closely related to canine coronavirus (CCV). The prevalence of FCoV types in
      Austrian cat populations without FIP has been surveyed recently indicating that
      type I infections predominate. The distribution of FCoV types in cats, which had
      succumbed to FIP, however, was fairly unknown. PCR assays have been developed
      amplifying parts of the spike protein gene. Type-specific primer pairs were
      designed, generating PCR products of different sizes. A total of 94 organ pools
      of cats with histopathologically verified FIP was tested. A clear differentiation
      was achieved in 74 cats, 86% of them were type I positive, 7% type II positive,
      and 7% were positive for both types. These findings demonstrate that in FIP cases
      FCoV type I predominates, too, nonetheless, in 14% of the cases FCoV type II was
      detected, suggesting its causative involvement in cases of FIP.

PMID- 15019111
TI  - Prevalence and epidemiological features of bovine viral diarrhoea virus infection
      in Lithuania.
AB  - The objectives of the present work were to estimate the level of bovine viral
      diarrhoea virus (BVDV) infection in cattle herds at the different Lithuanian
      districts and to determine factors influencing the course of BVDV infection. The
      studies were explored in 147 intensive dairy cattle breeding herds from 27
      different Lithuanian regions in 1997-2001. BVDV infection was diagnosed in all
      investigated regions. The existing variations in the structure of cattle
      population determined different distribution patterns of BVDV infection. The
      number of seropositive animals ranged from 11.9 to 100%. It must be pointed out
      that 29.9% of the herds were not infected with BVDV and in 32.7% of the herds
      from 70 to 100% of cattle were seropositive to BVDV. A positive correlation
      between the number of seropositive cattle, and the size of herds and age of
      animals was determined. Sex of animal had no influence on the prevalence of BVDV.
      It was estimated that the annual incidence risk of infection with BVDV decreases
      with the animal age.

PMID- 15019110
TI  - Safety and efficacy of a modified-live canine coronavirus vaccine in dogs.
AB  - The safety and the efficacy of a modified-live (ML) canine coronavirus (CCoV)
      vaccine strain 257/98-3c was evaluated in 14 dogs seronegative and virus negative
      for CCoV. For the safety test, four dogs were inoculated, two by intramuscular
      and two by oronasal route, with 10 times the vaccinal dose. During the
      observation period (28 days) all dogs did not display any local or systemic
      reaction. For the efficacy test, eight dogs were vaccinated by intramuscular
      (four dogs-group A) or by oronasal route (four dogs-group B). Two dogs were
      maintained as non-vaccinated controls. In the dogs of group A, vaccinal virus was
      not detected in faecal samples by virus isolation (VI) and by PCR assay, while in
      the dogs of group B, the virus was revealed for six median days only by PCR.
      Twenty-eight days later, the vaccinated and control dogs were challenged with a
      field CCoV strain. After the challenge, the vaccinated dogs did not display
      clinical signs and the dogs of group A shed virus for 5.5 median days, evaluated
      by VI, and for 10 median days evaluated by PCR. Virus shedding was not observed,
      both by VI and PCR assay, in the dogs of group B. The two control dogs displayed
      moderate clinical signs and the virus was detected by VI for 14.5 median days
      starting from day 3 post-challenge (dpc 3) and by PCR assay for 23 median days
      starting from dpc 1.

PMID- 15019112
TI  - Immunoblotting, ELISA and culture evidence for Chlamydiaceae in sows on 258
      Belgian farms.
AB  - The prevalence of Chlamydiaceae infections on 258 closed pig breeding farms in
      Belgium was examined. For this purpose, 258 farms were randomly selected in the
      provinces West-Vlaanderen (44%), Oost-Vlaanderen (20%), Antwerpen (10%) and
      Vlaams-Brabant (6%). Of all farms examined, 96.5% were positive for Chlamydia
      specific antibodies in ELISA and most were moderately to strongly positive. ELISA
      results revealed only 9 (3.5%) sero-negative farms. None of the ELISA negative
      sera reacted in immunoblotting. Only 212 of 249 ELISA positive sera reacted
      positive in immunoblotting. Additionally, 23 autopsy samples were examined by
      isolation in Vero cells. The major outer membrane sequence of the one isolate
      obtained showed 98.6% amino acid homology to the one of Chlamydophila psittaci
      strain CP3, formerly isolated from a pigeon. Present observations indicate that
      chlamydial infections are nearly endemic in the Belgian pig population and that
      Belgian pigs can become infected with C. psittaci. Nevertheless, the role and
      significance of Chlamydiaceae as pathogens in pigs remain unsolved and require
      further investigation.

PMID- 15019113
TI  - Identification of an alkaline ceramidase gene from Dermatophilus congolensis.
AB  - A random amplified polymorphic DNA (RAPD) procedure was used to identify a
      specific 0.6 kb DNA fragment unique to Dermatophilus congolensis. This 0.6 kb
      fragment was evaluated as a specific DNA probe and used to design oligonucleotide
      primers for polymerase chain reaction (PCR) amplification. The nucleotide
      sequences adjacent to this DNA fragment were determined by inverse PCR allowing
      the identification of a 4.1 kb sequence. Analysis of this revealed a complete
      open reading frame (ORF) with a high similarity to an alkaline ceramidase from
      Pseudomonas aeruginosa. The molecular weight of the enzyme derived from the
      predicted amino acid sequence is 74,662 Da, its pI is 9.81. The predicted N
      terminal sequence of the enzyme contains a signal sequence indicating that the
      enzyme is exported by the bacterium. Since ceramides have important protective
      and cell regulatory roles in the epidermis we suggest that this ceramidase may
      have a role in the pathogenesis of dermatophilosis. It is the first completely
      sequenced gene described for D. congolensis.

PMID- 15019114
TI  - Prior infection with Bordetella bronchiseptica increases nasal colonization by
      Haemophilus parasuis in swine.
AB  - The objective of this study was to determine whether Bordetella bronchiseptica
      would predispose to colonization or disease with Haemophilus parasuis. Three
      experiments were completed. In the first experiment, three groups of pigs (10
      pigs/group) were inoculated intranasally with either B. bronchiseptica, H.
      parasuis, or with B. bronchiseptica followed by H. parasuis 1 week later. A
      fourth group of 10 pigs served as a non-infected control group. The second
      experiment was like the first, except that there were only five pigs per
      experimental group. The third experiment consisted of only two groups (10
      pigs/group), one of which was inoculated intranasally with H. parasuis, whereas
      the other was inoculated with B. bronchiseptica followed by H. parasuis 1 week
      later. Pigs were necropsied 1-2 weeks after inoculation with H. parasuis. Mean
      nasal colonization by H. parasuis was significantly higher in the coinfected
      groups compared to the groups infected with H. parasuis alone. Pneumonia was
      present in 9/25 pigs coinfected with B. bronchiseptica and H. parasuis, 5/25 pigs
      infected with H. parasuis alone, 1/15 pigs infected with B. bronchiseptica alone,
      and in none of the pigs in the non-inoculated groups. Thus, B. bronchiseptica
      increased colonization of the upper respiratory tract with H. parasuis.

PMID- 15019116
TI  - Skin elasticity meter or subjective evaluation in scars: a reliability
      assessment.
AB  - Various methods are available for evaluating the elasticity of scars. However,
      the reliability and validity of these methods have been sparsely examined. The
      aim of this study was to examine the reliability of the subjective evaluation of
      scar pliability, while at the same time testing the reliability of the
      measurements of a non-invasive suction device (Cutometer Skin Elasticity Meter
      575) on scars. Four observers assessed 49 scar areas of 20 patients with a
      subjective assessment of pliability. Subsequently, each observer measured the
      scar areas with the Cutometer. The intraclass correlation coefficients (ICC) of
      the elasticity (Ue) and extension (Uf) parameters of the Cutometer were
      acceptable (r = 0.76 and 0.74, respectively) when a single observer carried out
      the measurements. The subjective assessment of pliability needs to be completed
      by two or more observers to make the evaluation reliable (r = 0.79). The
      concurrent validities between the subjective pliability-assessment and each of
      the Cutometer parameters were statistically significant and ranged from r = 0.29
      0.53. The correlations between each of the Cutometer parameters were high and
      statistically significant (r > or = 0.71). CONCLUSION: A single observer can
      reliably use the Cutometer for the elasticity measurements of scars. Furthermore,
      either Ue or Uf, instead of all five elasticity values provided by the Cutometer,
      can be adequately used for the elasticity measurements of scars. The subjective
      assessment of pliability of scars can only be assessed reliably when completed by
      two or more observers. The concurrent validity showed that all Cutometer
      parameters, except for visco-elasticity (Uv), and the subjective assessment of
      pliability measured the same characteristic of a scar.

PMID- 15019115
TI  - Colour evaluation in scars: tristimulus colorimeter, narrow-band simple
      reflectance meter or subjective evaluation?
AB  - The evaluation of scar colour is, at present, usually limited to an assessment
      according to a scar assessment scale. Although useful, these assessment scales
      only evaluate subjectively the degree of scar colour. In this study, the
      reliability of the subjective assessment of scar colour by observers is compared
      to the reliability of the measurements of two objective colour measurement
      instruments. Four independent observers subjectively assessed the vascularisation
      and pigmentation of 49 scar areas in 20 patients. The degree of vascularisation
      and pigmentation was scored according to a scale ranging from '1', when it
      appeared to be like healthy skin, to '10', which corresponds to the worst
      imaginable outcome of vascularisation or pigmentation. The observers also scored
      the pigmentation categories of the scar (hypopigmention, hyperpigmention or mixed
      pigmentation). Finally, each observer measured the scar areas with a tristimulus
      colorimeter (Minolta Chromameter) and a narrow-band simple reflectance meter
      (DermaSpectrometer). A single observer could reliably carry out measurements of
      the DermaSpectrometer and the Minolta Chromameter for the evaluation of scar
      colour (r = 0.72). The vascularisation of scars could also be assessed reliably
      with a single observer (r = 0.76) whereas for a reliable assessment of
      pigmentation at least three observers were necessary (r > or = 0.77). The
      agreement between the observers for the pigmentation categories also turned out
      to be unacceptably low (k = 0.349). This study shows that an overall evaluation
      of scar colour with the DermaSpectrometer and the Minolta Chromameter is more
      reliable than the evaluation of scar colour with observers. Of both instruments
      for measuring scar colour, we prefer, because of its feasibility, the
      DermaSpectrometer.

PMID- 15019117
TI  - Establishing a baseline for organisation and outcome in burn care-basic data
      compiled by German burn centres, 1991-2000.
AB  - From the years 1991 to 2000, basic data from patients admitted to the intensive
      care unit of burn centres in Germany, Austria and Switzerland, participating in
      the German Speaking Association for Burn Treatment, were collected prospectively.
      Starting in 1991 with 7 hospitals and 618 patients included in the study; in the
      year 2000, 19 hospitals representing nearly 1500 patients submitted their data.
      Over a period of 10 years, a total number of 10,259 patients could be included in
      the study. The majority of patients were adult, the male/female ratio was 70/30.
      Most of the patients suffered from household accidents, only 25% were
      occupational accidents. Medium total burn surface area (TBSA) and Abbreviated
      Burn Severity Index (ABSI) score were quite similar in the participating
      hospitals, while the medium length of stay in the ICU ranged from 6 to 24 days.
      The overall mortality was 17.5% and showed no decrease over the period of time.

PMID- 15019118
TI  - The effect of CAPE on lipid peroxidation and nitric oxide levels in the plasma of
      rats following thermal injury.
AB  - Both experimental and clinical studies have shown that oxygen-derived free
      radicals rise in the plasma after thermal injury and participate in the
      pathogenesis of tissue damage. Hence, various antioxidant molecules have been
      used in treatment of burn injury both experimentally and clinically. Caffeic acid
      phenethyl ester (CAPE), an active component of propolis from honeybee hives, is
      known to have potent antioxidant property. The purpose of the present study was
      to investigate the effects of CAPE on oxidative stress in plasma of burned rats.
      Experiment was designed in three groups of rats with 20% full-thickness burn: (a)
      sham burn (n = 7); (b) burn only (n = 22); (c) burn + treatment with CAPE (n =
      22). Plasma levels of malondialdehyde (MDA), nitric oxide (NO) and the activities
      of xanthine oxidase (XO), and superoxide dismutase (SOD) were used as both bio
      indicators of oxidant status and determinant of antioxidant effect of CAPE. They
      were assessed by biochemical methods at 1st, 3rd, 7th, and 14th post-burn days.
      In conclusion, CAPE was shown to possess antioxidant activity by saving SOD
      activity, preventing XO activity and decreasing the levels of MDA, and NO. Our
      study showed that CAPE may be beneficial in burn injury.

PMID- 15019119
TI  - The zinc finger protein A20 protects endothelial cells from burns serum injury.
AB  - Burn injuries as well as skin damages are often associated with immune
      suppression and often cause multiple organ failures. The monolayer endothelium is
      vulnerable to injuries from circulating factors resulting from remote wounds.
      Endothelial cell activation and apoptosis can alter microvascular permeability
      and intensify organ damage. A20, as a physiological cytoprotective gene is
      essential for preventing spontaneous innate immune cell-mediated inflammation and
      tissue destruction. It is not known whether A20 has the function to protect
      endothelial cells from the effect of burns serum challenge on endothelial
      function in vitro. This study shows that A20 can express in endothelial cells
      after burns serum stimulation and inhibit endothelial cell activation and
      apoptosis induced by burns serum. These results suggest that A20 may be
      beneficial in limiting the response to burn injuries.

PMID- 15019120
TI  - Effects of enteral supplementation with glutamine granules on intestinal mucosal
      barrier function in severe burned patients.
AB  - Glutamine is an important energy source in intestinal mucosa, the small intestine
      is the major organ of glutamine uptake and metabolism and plays an important role
      in the maintenance of whole body glutamine homeostasis. The purpose of this
      clinical study is to observe the protection effects of enteral supplement with
      glutamine granules on intestinal mucosal barrier function in severe burned
      patients. Forty-eight severe burn patients (total burn surface area 30-75%, full
      thickness burn area 20-85%) were randomly divided into two groups: burn control
      group (B group, 23 patients) and glutamine treated group (Gln group, 25
      patients). Glutamine granules 0.5 g/kg were supplied orally for 14 days in Gln
      group, and the same dosage of placebo were given for 14 days in B group. The
      plasma level of glutamine, endotoxin and the activity of diamine oxidase (DAO),
      as well as intestinal mucosal permeability were determined. The results showed
      that the levels of plasma endotoxin, activity and urinary lactulose and mannitol
      (L/M) ratio in all patients were significant higher than that of normal control.
      After taking glutamine granules for 14 days, plasma glutamine concentration was
      significantly higher in Gln group than that in B group (607.86+/-147.25 microM/l
      versus 447.63 +/- 132.28 microM/l, P < 0.01). On the other hand, the levels of
      plasma DAO activity and urinary L/M ratio in Gln group were lower than those in B
      group. In addition, the wound healing was better and hospital stay days were
      reduced in the Gln group (46.59 +/- 12.98 days versus 55.68 +/- 17.36 days, P <
      0.05). These results indicated that glutamine granules taken orally could abate
      the degree of intestine injury, lessen intestinal mucosal permeability,
      ameliorate wound healing and reduce hospital stay.

PMID- 15019121
TI  - In vitro cytotoxity of silver: implication for clinical wound care.
AB  - In this study, we look at the cytotoxic effects of silver on keratinocytes and
      fibroblasts. We have assessed the viability of monolayer cultures using the MTT
      and BrdU assays. The composition of the culture medium and also the culture
      technique were modified to assess the effects of culture 'environment' on the
      susceptibility of the cells to the toxic action of silver. Further in vitro,
      experiments were performed using tissue culture models to allow cellular behavior
      in three dimensional planes which more closely simulated in vivo behavior. The
      silver source was both silver released from silver nitrate solution but also
      nanocrystalline silver released from a commercially available dressing. The
      results show that silver is highly toxic to both keratinocytes and fibroblasts in
      monolayer culture. When using optimized and individualized culture the
      fibroblasts appear to be more sensitive to silver than keratinocytes. However,
      when both cell types were grown in the same medium their viability was the same.
      Using tissue culture models again indicated an 'environmental effect' with
      decreased sensitivity of the cells to the cytotoxic effects of the silver.
      Nevertheless in these studies the toxic dose of skin cells ranging from 7 x 10(
      4) to 55 x 10(-4)% was similar to that of bacteria. These results suggest that
      consideration of the cytotoxic effects of silver and silver-based products should
      be taken when deciding on dressings for specific wound care strategies. This is
      important when using keratinocyte culture, in situ, which is playing an
      increasing role in contemporary wound and burn care.

PMID- 15019123
TI  - Firework-related childhood injuries in Greece: a national problem.
AB  - During a 5-year period, out of 110066 children with injuries recorded in the
      Greek Emergency Department Injury Surveillance System (EDISS), 91 had firework
      related injuries. Descriptive analyses and the Barrell matrix were used to
      determine risk factors and extrapolated national firework childhood injury
      figures were calculated. The estimated annual incidence of childhood firework
      injuries treated in the emergency departments of hospitals countrywide, was 7 per
      100000 children years. Seventy percent of injuries concerned older children (10
      14 years), mostly boys with self-inflicted injuries, whereas girls suffered
      injuries as bystanders. A sharp peak in spring was noted, when the Greek Orthodox
      Easter is celebrated. Illicitly sold fireworks caused most injuries, but in eight
      instances homemade firecrackers were responsible.

PMID- 15019122
TI  - Burn injuries in children with attention-deficit/hyperactivity disorder.
AB  - PURPOSE: Children with attention-deficit/hyperactivity disorder (ADHD) are at
      increased risk for traumatic injury than non-ADHD-children. Burn injuries in ADHD
      children have not been studied. This study was conducted to determine differences
      in burn injuries between these groups. METHODS: The charts of all children ages 5
      18, admitted over a 7-year period to a single regional pediatric burn center,
      were reviewed. ADHD-children were compared to non-ADHD-children regarding age and
      gender, type and extent of burn, and burn injury outcome. FINDINGS: There were
      278 children included, 35 (13%) having ADHD. ADHD-children were more likely male
      but did not differ in age compared to non-ADHD-children. ADHD-children were more
      likely to experience a thermal rather than flame burn (83% versus 58% thermal, P
      < 0.01) and had more extensive burn injury (10% versus 5% median TBSA, P = 0.03).
      The ADHD group had a longer length of stay (11 versus 7 days, P = 0.05) and was
      less likely to be discharged to home (86% versus 93%, P = 0.17). CONCLUSIONS:
      ADHD-children do differ from non-ADHD-children in their pattern and extent of
      burn injury. The impulsivity and vigilance deficits that characterize ADHD may
      place these children at higher risk for specific types of burn injuries.

PMID- 15019124
TI  - Thermal injuries due to paint thinner.
AB  - This study was designed to evaluate the epidemiology and outcome of burn injuries
      due to paint thinner in a local burn center. During a 10-year period, 32 patients
      were admitted to our Burn Unit for paint thinner thermal burn. Patients were
      reviewed regarding the age, sex, etiologic factors, extent and localization of
      burn, treatment methods, length of hospitalization, and results. There were 30
      males and 2 females. The mean age of patients was 25.9 +/- 11 years. The most
      common etiologic factor was kindling a fire with paint thinner. The mean extent
      of burn was 33.6 +/- 24% of the total body surface area. All patients sustained
      burn injury on the face, arms, and hands and five patients among them had
      extended burn areas on the trunk and/or lower extremity. The mean length of
      hospitalization for the survivors was 34.5 +/- 21.6 days. Twenty-eight patients
      were treated by early excision and split-thickness skin grafting. In four
      patients, burn wounds were healed by conservative management. Five patients with
      burn size of over 75% of the total body surface area died. In conclusion, paint
      thinner may be the cause of a catastrophic thermal injury and should not be used
      for the purpose of kindling fire.

PMID- 15019125
TI  - Hydrofluoric acid burns.
AB  - OBJECTIVE: The purpose of this article is to report our experience with
      hydrofluoric acid (HF) burns and to present our management guidelines for these
      burns, which include a novel way of delivering calcium combined with dimethyl
      sulphoxide (DMSO) for cutaneous burns. METHOD: We reviewed our institutional
      experience from 1977 to 1999 for patients presenting with burns caused by
      hydrofluoric acid and collected data on age, sex, burn size, anatomical site,
      method of contact, surgical procedure, and outcome. RESULTS: Of a total of 2310
      admissions, 42 HF burns patients were identified during the study period. The
      average age was 34 years. There were 35 males and 7 females. Seventy-four percent
      of cases received burns to the upper limb. Median burn size was 1% of the total
      body surface area. Seventeen percent of patients required a surgical procedure.
      In 24% of cases, the method of contact was work related and 40% were injured
      using cleaning products at home or on boats. No deaths were recorded. CONCLUSION:
      HF injury is uncommon but problematic burns often requiring surgery. RECOMMENDED
      MANAGEMENT: In cases of cutaneous exposure, treatment should commence immediately
      with 30 min lavage followed by application dimethyl sulphoxide 50% + calcium
      gluconate 10% in surgical jelly. If hand or forearm is affected, regional
      intravenous calcium 'Bier's block' using 40 ml 10% calcium gluconate with 5000 U
      heparin in total final volume of 40 ml may be indicated. Subcutaneous
      infiltration may be indicated for elsewhere at 0.5 ml/cm(2) burn of 10% calcium
      gluconate. Persisting pain may require nail removal or arterial calcium infusion.

PMID- 15019126
TI  - Emergency department management of minor burn injuries in Ontario, Canada.
AB  - Many thermal injuries are minor and can be effectively treated in a primary care
      setting. A cross-sectional survey was conducted to examine how emergency
      department physicians care for minor burns in the Canadian province of Ontario.
      Respondents were provided with a colour photograph of a patient with a minor burn
      and asked to comment about history, physical examination, investigations,
      treatment plan and follow-up care. A 37% response rate was attained (141/380). Of
      all respondents, 70% failed to record the burn extent, and 45% failed to discuss
      analgesia. No significant differences existed between emergency physicians in
      teaching and non-teaching hospitals (P > 0.05), with the exception that teaching
      hospital physicians referred significantly more to burn centres (P = 0.013). This
      suggests that educational interventions focussing on burn extent, pain control
      and referral criteria may be beneficial to emergency physicians.

PMID- 15019127
TI  - Virtual bronchoscopy for diagnosis of inhalation injury in burnt patients.
AB  - Virtual bronchoscopy using a multislice CT scanner, is a new non-invasive imaging
      technique and its utility in the diagnosis of inhalation injury in burnt patients
      has not been reported in literature yet. Initial experience of technique is
      encouraging and it merits more interest. It overcomes many of the limitations of
      the presently established procedure of fibreoptic bronchoscopy. Ten burned
      patients with clinical suspicion of inhalation injury underwent this
      investigation and in eight of these the diagnosis was confirmed.

PMID- 15019129
TI  - Toxic shock syndrome in a scald burn child treated with an occlusive wound
      dressing.

PMID- 15019128
TI  - Delayed primary closure of the burn wounds.
AB  - 'Early closure' of burn wounds by excising the burned tissues and promptly
      covering it with skin-grafts or its substitutes within first 'five' post-burns
      day is a standard technique of burn-wound-management in the burn-units of the
      "developed" world. But lack of education in general, and health-education in
      particular amongst the common people in the "developing" countries could hinder
      acceptance of this procedure. Lack of well-trained and motivated burns-surgeons
      could worsen the situation. The Sultanate of Oman is one of the developing gulf
      countries in the middle-east, where at Khoula hospital, the National Burns-Center
      in the capital city of Muscat, 'early' surgery was introduced in November 1997 to
      soon become a routine protocol for burn-wound-management. But delay in getting
      consent for surgery from unwilling patients or in transferring them from the
      peripheral hospitals were often the reasons for delaying the burn-wound excision
      and closure 'beyond 6 days to 11th or 12th' day post-burn. Hence, instead of the
      term "early", the authors prefer to call it "delayed primary" burn-wound closure
      because, it still offers "primary intention healing" of the burn-wounds. The aim
      of this article is to analyze retrospectively the results of the "delayed
      primary" closure of the burn-wounds done in the Khoula Hospital Burns-Unit of the
      Sultanate of Oman. During a period of 50 months from November 1997 to December
      2001, carefully selected 143 patients out of a total of 592 admissions in burns
      unit were subjected to burn-wound excision and auto-skin-grafting (STSG), of whom
      about 87% patients had "delayed primary" and 13% had "early" surgery. There was
      no mortality or post-operative morbidity in these operated patients. However, due
      to the non-availability of skin substitutes the excision and auto-grafting could
      not be done in extensive burns with inadequate skin-donor-area. The maximum
      percentage of burns treated by delayed primary surgery (DPS) was 50% in children
      and 55% in adults. Follow-up results were good functionally as well as
      cosmetically. The authors conclude that "delayed primary" is the second best
      alternative to the "early" burn-wound excision and closure with similar
      advantages of reducing risk of septicemia, mortality, and morbidity, hospital
      stay and cost of treatment. It should be preferred over "secondary" skin-grafting
      of granulating wounds. Thus, in the developing countries, the indications of
      delayed primary burn surgery could be (1) patients unstable or unfit for surgery
      during the first post-burn week; (2) delay in transferring in the patients; (3)
      delay in getting patient's consent for surgery; (4) very major burns without
      availability of skin substitutes; and (5) lack of operating time in a busy burns
      unit. The contraindications for delayed primary surgery are any sign of invasive
      sepsis or organ failure.

PMID- 15019130
TI  - Fatal possible toxic shock syndrome in an adult following 15% scald burn.

PMID- 15019131
TI  - Acute osteomyelitis after a minor, 2nd degrees burn of the finger.

PMID- 15019132
TI  - Late residual pulmonary sequel following kerosene burns.

PMID- 15019133
TI  - Initial optimal continuous distension pressure in prone HFOV in a paediatric
      burn: case report.

PMID- 15019135
TI  - An unusual case of intra-oral frostbite.

PMID- 15019134
TI  - Congenital burns.

PMID- 15019136
TI  - A mobile electrode for EGG monitoring.

PMID- 15019137
TI  - A multi purpose, self-adjustable aeroplane splint for the splinting of axillary
      burns.

PMID- 15019138
TI  - Seroprevalence of Toxoplasma gondii in American free-ranging or captive pumas
      (Felis concolor) and bobcats (Lynx rufus).
AB  - Toxoplasma gondii is a major zoonotic agent infecting a wide range of mammals,
      including wild felids. Like domestic cats, wild felids are involved in the
      complete infective cycle of T. gondii, as they can host in their gastrointestinal
      tract sexually mature parasites and shed infective oocysts in their feces. In
      order to evaluate the importance of this wildlife reservoir, 438 serum samples
      collected between 1984 and 1999 from 438 pumas (Felis concolor) and from 58
      bobcats (Lynx rufus) from North America, Central America and South America were
      screened for antibodies to T. gondii. The overall prevalence of T. gondii
      antibodies was 22.4% in pumas and 51.7% in bobcats, with regional variations.
      Adults were more likely to be seropositive than juveniles and kittens (prevalence
      ratio (PR) = 2.61; confidence interval (CI) = 1.15, 4.04). In the US, pumas from
      the southwestern states (Arizona, California and New Mexico) were more likely to
      be seropositive for T. gondii ( PR = 2.61; 95% CI = 1.32-5.18 ) than pumas from
      the northwestern and mountain states (Colorado, Idaho, Oregon, Utah and Wyoming).
      Male pumas from the US were more likely to be seropositive than females (PR =
      2.08; 95% CI = 1.11-3.92), whereas female pumas from Mexico, Central America and
      South America were more likely to be seropositive than female pumas from Canada
      and the US (PR = 2.49; 95% CI = 1.09-5.69). Captive pumas were also more likely
      to be seropositive (21.7%, 29/92) for T. gondii than free-ranging animals (19.9%,
      69/346) (PR = 1.85; 95% CI = 1.06, 3.17).

PMID- 15019139
TI  - Comparison and standardisation of serological methods for the diagnosis of
      Neospora caninum infection in bovines.
AB  - Various existing serological tests were compared with a standard panel of 523
      sera in a multicentred study across Europe. Well characterised sera from animals
      that were experimentally or naturally infected with Neospora caninum as well as
      sera from cattle deemed uninfected with N. caninum were provided by the
      participants of the study and analysed in several commercial (CHEKIT Dr.
      Bommeli/Intervet, CIVTEST BOVIS NEOSPORA Hipra, Cypress Diagnostics C.V., Herd
      Check IDEXX, Mastazyme MAST Diagnostics, P38-ELISA Animal Welfare and Food Safety
      GmbH (AFOSA)) as well as in-house assays (five ELISAs and one IFAT). Most tests
      showed a high level of agreement in the interpretation of the test results
      (positive or negative). A further distinct increase in agreement between tests
      was obtained after the application of standardised cut-offs offered by a two
      graph receiver operating characteristic analysis. This procedure allows a
      standardised interpretation of results obtained with different tests used in
      independent, parallel seroepidemiological studies.

PMID- 15019141
TI  - Efficacy of alpha-cyclodextrin against experimental cryptosporidiosis in neonatal
      goats.
AB  - The efficacy of orally administered tablets containing alpha-cyclodextrin, an
      excipient used in the pharmaceutical industry with demonstrated
      anticryptosporidial activity in vitro and in neonatal mice, was evaluated in
      neonatal goat kids. The formulation was evaluated for hardness and was subjected
      to in vitro drug release studies. Twenty goat kids were orally inoculated with
      10(6) oocysts of C. parvum within the first 6 days of age. Half of the animals
      were treated by oral administration of four tablets of alpha-cyclodextrin/day
      (500 mg/kg of body weight) for six consecutive days, the treatment beginning on
      the day of inoculation. Infection was monitored by daily examination of faecal
      samples from the first day to 25 days post-inoculation. The criteria studied in
      evaluating efficacy were: oocyst shedding, presence of diarrhoea and weight gain
      at 15 and 25 days post-inoculation. alpha-cyclodextrin was effective when given
      at the beginning of infection: there was a longer pre-patent period, a reduction
      in the patent period and a decrease in the intensity of infection, these
      differences being statistically significant (P < 0.05) compared with untreated
      neonatal kids. Moreover, except in one animal, the diarrhoea was prevented in
      infected neonatal kids. Animals from both groups increased the body weight and no
      significant differences were seen between the two groups.

PMID- 15019140
TI  - PCR amplification of RoTat 1.2 VSG gene in Trypanosoma evansi isolates in Kenya.
AB  - A direct card agglutination test for Trypanosoma evansi, CATT/T. evansi based on
      the predominant variable antigen-type (pVAT) RoTat 1.2 was evaluated previously
      in the field in Isiolo District, Kenya. Sixteen out of 51 (31.4%)
      parasitologically positive camels were negative by the antibody detection test.
      In the present study, trypanosomes isolated from the camels were analysed in an
      attempt to determine the cause of the false negative results of CATT/T. evansi. A
      total of 20 field isolates comprised 16 stocks from camels that were negative by
      CATT/T. evansi, and 4 from CATT/T. evansi-positive camels. In addition, 15 known
      T. evansi and four T. brucei were used as reference. Purified DNA samples were
      tested using an established RoTat 1.2-based polymerase chain reaction (PCR) that
      yields a 488 bp product for the specific detection of T. evansi. Antibodies to
      RoTat 1.2 variant surface glycoprotein (VSG) were used in Western blotting to
      detect RoTat 1.2 VSG linear epitopes. Results of PCR and Western blot showed that
      the 16 stocks isolated from CATT/T. evansi-negative camels fell into three
      groups. In Group 1, both the RoTat 1.2 VSG gene and the VSG were absent in three
      stocks. In five trypanosome stocks in Group 2, the RoTat 1.2 VSG gene was
      detected, but Western blot was negative indicating absence of the expressed VSG.
      Five other stocks containing the RoTat 1.2 VSG gene were also in this group. The
      RoTat 1.2 VSG gene was detected and Western blot was positive in all four
      trypanosome stocks in Group 3. All four stocks from CATT/T. evansi-positive
      camels contained the RoTat 1.2 VSG gene and the expressed VSG. The reference T.
      evansi KETRI 2479 lacked the RoTat 1.2 VSG gene and there was no immune
      reactivity detected by Western blot. The rest of the reference T. evansi stocks
      examined contained the RoTat 1.2 VSG gene. All the four T. brucei samples
      examined were negative by PCR and Western blot. In conclusion, this study showed
      that the RoTat 1.2 VSG gene was absent from some T. evansi trypanosomes in Kenya.

PMID- 15019142
TI  - Epidemiological factors that influence time-to-treatment of trypanosomosis in
      Orma Boran cattle raised at Galana Ranch, Kenya.
AB  - Four thousand nine hundred and seventy-one trypanosomosis-surveillance records
      from an open population of Orma Boran cattle raised under natural trypanosomosis
      challenge in Galana Ranch, Kenya between the years 1990 and 2000 were analysed.
      The objective of the analysis was to identify epidemiological factors that
      influenced time-to-treatment of trypanosomosis cases. Under the surveillance
      programme, blood was being examined fortnightly for trypanosomosis using buffy
      coat technique. Infected animals were treated when their packed cell volumes
      (PCV) fell to 25% or lower. The number of days between the first diagnosis and
      treatment of trypanosomosis cases was obtained from the difference between
      diagnosis and treatment dates. Days-to-treatment clustered around the screening
      periods; therefore, time-to-treatment was represented by a series of time points
      0-8 at 14-day intervals. Factors postulated to affect the outcome (time-to
      treatment) were age of an animal at time of diagnosis, sex, number of trypanosome
      infections, trypanosome species and season of the year. Five animal generations
      were generated from birth dates and treated as nuisance parameters. Conditional
      logistic regression and Cox proportional hazards models were fitted to the data,
      the former to analyse factors that influenced treatment after time 0 (outcome
      dichotomised as time 0 or >0) and the latter to analyse factors that influenced
      time-to-treatment for cases that were treated after time 0, excluding all cases
      treated on time 0. The majority of the cases (89.5%) were treated on the same day
      of diagnosis. Trypanosome infections were more likely to be treated after time 0
      in dry than in wet season. Similarly, the rate of treatment was lower in the dry
      than the wet season. An increase in number of previous trypanosome infections
      reduced the odds of an animal being treated after time 0. Animals that had been
      exposed to many infections before had higher rates of treatment than those that
      had minimal experiences. We offer possible reasons for these observations and
      conclude that selection of animals for breeding purposes in programmes geared
      towards improving trypanotolerance should take into consideration the
      environmental factors that affect classification of an animal as being resistant
      or susceptible.

PMID- 15019143
TI  - Adaptation of a commercial ELISA for the detection of antibodies against Neospora
      caninum in bovine milk.
AB  - The aim of the present study was to determine whether a commercially available
      ELISA could be used to examine bovine milk for antibodies against Neospora
      caninum. In an initial titration experiment, a milk dilution of 1:2 was found
      optimal to obtain milk results that were linearly correlated to those obtained
      with corresponding sera. This dilution was then used to examine 791 milk samples
      from N. caninum infected herds in the commercial ELISA. Milk results of
      individual animals were compared with those obtained by the same ELISA for the
      corresponding serum samples. The linear correlation between milk and serum
      antibody results of individual animals was characterized by R2 = 0.702. Multiple
      linear regression indicated that the later the stage of lactation at which an
      animal was sampled, the higher the milk ELISA result was as compared to the serum
      ELISA result. The examination of the two-graph receiver operating characteristics
      revealed an optimal cut-off of 0.261 to obtain similar results in the examination
      of milk and serum. With this cut-off, the test had a sensitivity and specificity
      relative to the serum results of 90%. The milk-based commercial ELISA classified
      more aborting dams as positive than the serum-based ELISA with this cut-off. The
      milk ELISA may be a valuable tool to assess the herd status with regard to
      abortion caused by N. caninum.

PMID- 15019144
TI  - Determination of the effective dose of an experimental fasciolicide in naturally
      and experimentally infected cattle.
AB  - The aim of the present study was to determine the effective dose of an
      experimental fasciolicide called compound alpha or 5-chloro-2-methylthio-6-(1
      napthyloxy)1H-benzimidazole in experimentally and naturally infected cattle. In
      the first experiment, 24 fluke-free heifers were each infected with 800
      metacercariae of Fasciola hepatica and re-infected on day 45 with other 600 cysts
      per animal. On day 75, when the animals had 4- and 10-week-old flukes
      respectively, they were divided into four groups (G) of six animals each
      according to fluke egg counts. Groups 1-3 received compound alpha at 10, 12 and
      14 mg/kg/p.o., respectively. G4 remained as an untreated control. Twenty days
      after treatment, the animals were sacrificed for the recovery of flukes. Efficacy
      was assessed as a percentage of egg or fluke reduction relative to the untreated
      control. In the second experiment (naturally infected cattle), 24-year-old steers
      positive to F. hepatica eggs were blocked into four groups of five animals each.
      Groups 1-3 received compound alpha at 10, 12 and 14 mg/kg/p.o., respectively.
      Group 4 served as a non-treated control. All procedures to determine efficacy
      were carried out as mentioned in the first experiment. The results in the first
      study showed a percentage on egg reduction of 97.3, 100 and 100 and overall fluke
      reduction of 94.3, 100 and 100 for Groups 1-3, respectively. In the second study,
      the percentage of egg reduction was of 87.5, 99.1 and 100 and overall efficacy
      regarding fluke reduction was of 84.2, 99.6, and 100 for Groups 1-3,
      respectively. It is concluded that the effective dose selected for compound alpha
      was of 12 mg/kg/p.o. in cattle having an induced or natural F. hepatica
      infection.

PMID- 15019145
TI  - Characterisation of Fasciola species from Mainland China by ITS-2 ribosomal DNA
      sequence.
AB  - Isolates of Fasciola (Platyhelminthes: Trematoda: Digenea) from different host
      species and geographical locations in Mainland China were characterised
      genetically. The second internal transcribed spacer (ITS-2) of nuclear ribosomal
      DNA (rDNA) was amplified from individual trematodes by polymerase chain reaction
      (PCR), and the representative amplicons were cloned and sequenced. The length of
      the ITS-2 sequences was 361-362bp for all Chinese Fasciola specimens sequenced.
      While there was no variation in length or composition of the ITS-2 sequences
      among multiple specimens from France, Sichuan and Guangxi, sequence difference of
      1.7% (6/362) was detected between specimens from France and Sichuan, and those
      from Guangxi. Based on ITS-2 sequence data, it was concluded that the Fasciola
      from Sichuan represented Fasciola hepatica, the one from Guangxi represented
      Fasciola gigantica and the one from sheep from Heilongjiang may represent an
      "intermediate genotype", as its ITS-2 sequences were unique in that two different
      ITS-2 sequences exist in the rDNA array within a single Fasciola worm. One of the
      sequences is identical to that of F. hepatica, and the other is almost identical
      to that of F. gigantica in that nucleotides at five of the six polymorphic
      positions represent F. gigantica. This microheterogeneity is possibly due to
      sequence polymorphism among copies of the ITS-2 array within the same worm. Based
      on the sequence differences, a PCR-linked restriction fragment length
      polymorphism (PCR-RFLP) assay was established for the unequivocal delineation of
      the Fasciola spp. from Mainland China using restriction endonuclease Hsp92II or
      RcaI. This assay should provide a valuable tool for the molecular identification
      and for studying the ecology and population genetic structures of Fasciola spp.
      from Mainland China and elsewhere.

PMID- 15019146
TI  - Detection of Fasciola gigantica infection in snails by polymerase chain reaction.
AB  - Polymerase chain reaction (PCR) was used to detect Fasciola gigantica infection
      in the snail intermediate host. Fasciola specific primers amplified a 124 bp
      fragment in PCR when the genomic DNA isolated from F. gigantica infected Lymnaea
      auricularia snails was used as template. In addition to the 124 bp amplicon, a
      ladder of DNA fragments representing amplification of the 124 bp repetitive
      sequences was observed. Genomic DNA of the parasite was used as a positive
      control, which also gave an amplification of the 124 bp fragment. DNA isolated
      from non-infected snails was used as a negative control and no amplification of
      this sequence was observed. This technique is highly specific and sensitive and
      possesses fairly good prospects of its utility as an epidemiological tool for
      ascertaining the infectivity status in ubiquitous snail populations.

PMID- 15019147
TI  - Resistance of Santa Ines, Suffolk and Ile de France sheep to naturally acquired
      gastrointestinal nematode infections.
AB  - A study was conducted to assess the breed resistance against nematode infections
      in Santa Ines, Ile de France and Suffolk male lambs over a 9-month period in Sao
      Paulo state, Brazil. Lambs were born during the winter (year 2000) and were
      weaned at 2 months of age. The animals were then housed and treated with
      anthelmintics to eliminate natural infections by gastrointestinal nematodes. In
      late October 2000, lambs were placed in a paddock, where they stayed until August
      of the following year. Fecal and blood samples were taken from each animal every
      2 weeks. On the same day, a pasture sample was collected to determine the number
      of infective larvae on the herbage. To prevent deaths, individual treatment with
      anthelmintics was provided to lambs with fecal egg counts (FEC) higher than 4000
      eggs per gram (EPG) or with a packed cell volume (PCV) lower than 21%. In August
      2001, all animals were slaughtered and the worms present in samples of the
      gastrointestinal contents were identified and counted. Most of the Suffolk and
      Ile de France sheep received three to six anthelmintic treatments over a period
      of 7 months, while most of the Santa Ines were not treated. Reductions in PCV and
      plasma protein values associated with high FEC and worm burdens were recorded,
      particularly, in Suffolk and Ile de France lambs. Haemonchus contortus and
      Oesophagostomum columbianum burdens and number of nodular lesions caused in the
      large intestine by O. columbianum larvae were significantly lower in Santa Ines
      sheep. All three breeds showed similar Trichostrongylus colubriformis worm
      burdens. The relative resistance of Santa Ines young male sheep was superior to
      that of Suffolk and Ile de France sheep.

PMID- 15019148
TI  - Efficacy of benzimidazole anthelmintics in goats and sheep in the Philippines
      using a larval development assay.
AB  - The negative effects of nematodes in small ruminants can be reduced by use of
      dewormers but their effectiveness is increasingly limited by the emergence of
      anthelmintic resistance. The efficacy of benzimidazole (BZ) anthelmintics in the
      Philippines was estimated by an in vitro larval development assay using worm eggs
      recovered from faeces collected from goats and sheep. Two hundred and eighteen
      farms were selected to represent areas of the country with high goat and sheep
      populations and the full range of farm sizes, from smallholders with just a few
      animals to commercial and institutional farms with several hundred. Initial
      surveys of worm control advisers indicated that BZs have been in continuous
      widespread use for up to 20 years with little use of other chemical groups. A
      larval development assay (LDA: DrenchRite) was modified for use with BZs alone to
      allow up to five samples to be analysed on a single microtitre plate. The assay
      was validated by comparison with the faecal egg count reduction test (FECRT). The
      dominant nematode genera were Haemonchus and Trichostrongylus with small numbers
      of Oesophagostomum. The range of BZ efficacy estimated from the LDA results was 0
      100% and the distribution of efficacy levels was continuous, with mean efficacy
      of 82 and 64% for goats and sheep, respectively. There were significant
      associations between efficacy and parameters measured to characterize the sampled
      farms: size of animal management group, FEC of sample, recent importation of
      stock and no access to common grazing were all correlated with decreased
      efficacy. Likewise, low efficacy was associated with reported frequency and
      number of years that BZ drenches had been used. The LDA was found to be highly
      suited to estimate efficacy in nematode populations from small farms where
      performance of a FECRT for even one chemical would be impractical. Using a larval
      development assay, we have demonstrated a wide efficacy range for BZs against
      nematodes from all sizes of goat and sheep farms in the tropics.

PMID- 15019149
TI  - Ectoparasitic species from Canis familiaris (Linne) in Buenos Aires province,
      Argentina.
AB  - Several arthropods that live as ectoparasites on domestic dogs can cause severe
      dermatitis or act as vectors of pathogenic agents, resulting in serious diseases
      not only in dogs, but also in humans. We studied ectoparasites found on Canis
      familiaris sampled in five areas in Buenos Aires province, Argentina. The
      prevalence of fleas, ticks and lice was analyzed, as well as their seasonal
      variations through the different sites studied. The kind of infestation found in
      each host was determined and the intensity of natural infestation was estimated.
      The study was carried out from October 2001 to July 2002, with 116 dogs that
      lived in rural areas and did not receive control treatments. In order to remove
      the ectoparasites, the dogs' skin was rubbed with a piece of cotton soaked in
      ether. All dogs had at least one species of ectoparasites. A total number of 5193
      ectoparasites were found corresponding to four species, 15.7% Ctenocephalides
      canis, 73% Rhipicephalus sanguineus, 1.8 Linognathus setosus and 9.4% Heterodoxus
      spiniger. R. sanguineus was the most abundant species, and C. canis was the only
      flea species found. This may be due to the dogs being exclusively rural animals.
      Within the zones sampled, Magdalena showed the greatest prevalence, maybe as a
      consequence of having the highest relative humidity in relation to the other
      areas. Triple infestation (ticks-fleas-lice) was observed in 56.9% of the dogs;
      39.6% presented double infestation, most being ticks-fleas, and only 3.4% showed
      simple infestation (lice). Female hosts were the most affected. Even though there
      were records of ectoparasites throughout all the year, a higher intensity was
      observed during the spring months, most likely as a result of the increase in
      temperature after the winter months.

PMID- 15019150
TI  - A comparison between ethanol-induced chemical ablation and ivermectin plus
      prednizolone in the treatment of symptomatic esophageal spirocercosis in the dog:
      a prospective study on 14 natural cases.
AB  - This study included a total of 14 dogs with spontaneous esophageal spirocercosis.
      Historical and clinical evidence of esophageal dysphagia, detection of parasitic
      ova in fecal samples and endoscopic documentation of esophageal nodules were the
      inclusion criteria. The animals were randomly assigned into two groups: group A
      (n = 6 ) dogs received two intranodular injections of absolute ethanol (96%) via
      a through-the-endoscope injector, at weekly intervals; group B (n = 8) dogs were
      put on ivermectin (600 microg/kg BW, subcutaneously, twice, 14 days apart) and
      oral prednisolone (0.5mg/kg BW, every 12h, for a total of 3 weeks, tapering the
      dose accordingly). Clinical and fecal examination as well as endoscopy, were
      performed on admission and at 20, 60 and 180 days from the beginning of the
      treatment. One group A dog responded poorly and died of pyothorax during the
      trial and another developed esophagitis due to accidental intraluminal ethanol
      infusion, only to experience an uneventful recovery. At different times during
      the 6-month follow-up period, there was a complete disappearance of the clinical
      signs in 4/6 group A dogs. However, full nodular regression was achieved only in
      one dog, and parasitic ova were still found in the feces of 4/6 dogs. At the same
      period of time in five group B dogs still available for evaluation, resolution of
      the clinical signs and complete nodular regression were seen in four and five
      animals, respectively, while negative fecal results were obtained in all dogs
      (8/8) of the same group 2 months from the beginning of the treatment. No
      significant difference was found between the groups, regarding the resolution of
      clinical signs, though group B dogs demonstrated a significantly higher rate of
      regression of esophageal nodules as well as negative fecal results, compared to
      group A dogs. The combination of ivermectin and prednizolone may be considered an
      effective treatment in the symptomatic and evidently asymptomatic esophageal
      spirocercosis of the dog.

PMID- 15019151
TI  - Seroepidemiology of neosporosis in dairy cattle in Uruguay.
AB  - A seroepidemiological survey of Neospora caninum was done in a dairy farm in
      Uruguay employing indirect fluorescent antibody test (IFAT). Sera from 217 cattle
      (155 cows, 31 heifers and 31 calves) were tested for N. caninum antibodies in
      July 2000 and it was found that abortions were significantly associated with the
      seropositivity of the cows by chi(2)-test (P = 0.025). The cows with an IFAT
      titre of 1:3200 were at a significantly higher risk of abortion than seronegative
      cows (P = 0.0013). Neospora organisms were detected in the brains of two aborted
      foetuses by immunohistochemical examination. The infection of N. caninum was
      considered postnatal because of the even distribution of seropositive cows (60%),
      low seroprevalence (20%) in calves and no significant correlation in the
      serostatus between calves and their dams (P = 0.43). A fitted binomial
      generalised linear model revealed that there was an increasing risk of abortion
      with increasing IFAT titre and increasing age between 2 and 6 years.

PMID- 15019152
TI  - Failure to establish infection with Tetratrichomonas sp. in the reproductive
      tracts of heifers and bulls.
AB  - Experimental infection of the reproductive tracts of heifers and bulls with
      Tetratrichomonas sp. isolated from preputial smegma of virgin bulls was
      attempted. Nine heifers and four bulls were challenged by inoculation of 7 x
      10(6) Tetratrichomonas sp. into the vaginal lumen and preputial cavity,
      respectively. Vaginal mucus and preputial smegma samples were collected and
      cultured for Tetratrichomonas sp. Heifers were slaughtered in groups of three at
      2, 9 and 21 days after inoculation. Two heifers and two bulls infected with
      Tritrichomonas foetus and two uninfected heifers were used as controls for the
      model infection. Tetratrichomonas sp. were only isolated in vaginal mucus of 7/9
      inoculated heifers at 6h post-inoculation, and genital secretions taken at
      slaughter time from vagina, uterus and oviduct were cultural negative. Bulls
      challenged with Tetratrichomonas sp. remained cultural negative. Since
      Tetratrichomonas sp. survived only a few hours in the female genitalia and did
      not survive in the male genitalia after experimental challenge, Tetratrichomonas
      sp. did not colonize the genital tract. These were likely trichomonads from the
      digestive tract. Collection of clean samples without fecal contamination from the
      reproductive tract is proposed as a measure to avoid Tetratrichomonas sp.
      transitory genital infection.

PMID- 15019153
TI  - An outbreak of neurofilariosis in young goats.
AB  - An outbreak of cerebrospinal microfilariosis in 23 kids, representing a whole kid
      crop, occurred on a farm in Qassim, Central Saudi Arabia. The morbidity and
      mortality rates were 100%. Clinical signs, in kids from the fourth to sixth week
      of age, manifested as weakness in the hind legs followed by incoordination of
      movement and feet dragging. Seven to ten days later, the hind legs were
      completely paralyzed, and within a week the front legs were also paralyzed. The
      animals continued to feed, drink and suckle normally, and were in good health.
      Paralyzed kids were helped to suckle by the farm attendants. With time, loss of
      control of motor functions occurred and the ability to hold the head in upright
      position was lost, ability to eat or drink was lost. The infected kids health
      deteriorated and they eventually died. Two dead kids were postmortemed. With the
      exception of a meningeal haemorrhage seen in one kid, no obvious macroscopic
      lesions were seen in any of the autopsied animals. Histopathological examination
      of the spinal cord and brain showed different microfilaria of different sizes
      between the meninges and the nervous tissue. This indicated that development of
      the parasite occurred in the nervous tissue. The larger microfilaria contained
      black deposits, most likely to be digested blood, in their guts. It is likely
      that the parasites are haematophagus. The main lesions caused by the microfilaria
      were migratory traumatic haemorrhagic tracts in the spinal cord and the brain.
      These sometimes contained parts of the microfilariae. In the brain malacic
      lesions and sporadic aggregates of lymphocytes were also noted.

PMID- 15019154
TI  - Inhibition of the development of hepatocellular carcinomas by phenyl N-tert-butyl
      nitrone in rats fed with a choline-deficient, L-amino acid-defined diet.
AB  - Effects of phenyl N-tert-butyl nitrone (PBN), a spin-trapping agent, on the
      development of frank cancers were examined in male Wistar rats fed with a choline
      deficient, l-amino acid-defined (CDAA) diet for 70 weeks. PBN (0.065% in the
      drinking water) reduced incidences, multiplicities and possibly sizes of both
      hepatocellular adenomas and carcinomas when administered for all 70 weeks or only
      for the first 26 weeks, and those of carcinomas but not adenomas, when
      administered only for the last 44 weeks. These results indicate that PBN can
      prevent the development of frank HCCs in the CDAA diet model. The anti
      carcinogenic effect of PBN may be ascribed to the prevention of both the
      development of HCAs and their malignant conversion to HCCs. If such findings can
      be generalized, PBN may be able to serve as a good tool to investigate molecular
      mechanisms underlying carcinogenic processes.

PMID- 15019155
TI  - Revised rat multi-organ carcinogenesis bioassay for whole-body detection of
      chemopreventive agents: modifying potential of S-methylcysteine.
AB  - The DMBDD rat multi-organ carcinogenesis model based on two-stage carcinogenesis
      theory was revised to make more suitable assay system for detecting
      chemopreventive effects of chemical substances by increasing the doses of two
      carcinogens, 1,2-dimethylhydrazine dihydrochloride (DMH) and N-butyl-N-(4
      hydroxybutyl)nitrosamine (BBN). The revised bioassay resulted in increasing
      preneoplastic or neoplastic lesions in the colon, urinary bladder and liver. S
      Methylcysteine (SMC), a water-soluble organosulfur compound, was used as a test
      chemical in the new initiation regimen. Though SMC did not express clear-cut
      inhibitory effects in tumor levels, it showed modifying effects on the
      development of lung hyperplastic and colon preneoplastic lesions. In conclusion,
      the present model featuring high yields of preneoplastic and neoplastic lesions
      with low mortality in a short period (30 weeks), might be suitable for testing
      the efficacy of possible chemopreventive chemicals at the whole-body level.

PMID- 15019157
TI  - Apoptotic and anti-adhesion effect of ajoene, a garlic derived compound, on the
      murine melanoma B16F10 cells: possible role of caspase-3 and the alpha(4)beta(1)
      integrin.
AB  - In this study we evaluated the hypothesis that the antitumor activity of ajoene
      could be associated with its apoptosis-inducing effect, and with its ability to
      block the expression of the alpha(4)beta(1) integrin, in the murine melanoma
      B16F10 cells. Ajoene induced a significant reduction in B16F10 viability
      (IC(50)=62 microM), in a dose-dependent manner. Flow cytometric analysis showed
      that the cytotoxic effect of this compound was associated with caspase-3
      activation. Ajoene at 25 microM altered the alpha(4)beta(1) integrin expression
      on B16F10, and induced a significant reduction in the adhesion of these cells to
      an endothelial cell monolayer.

PMID- 15019156
TI  - Folic acid reduces nuclear translocation of beta-catenin in rectal mucosal crypts
      of patients with colorectal adenomas.
AB  - We have demonstrated that folic acid inhibits cell proliferation and epidermal
      growth factor receptor (EGFR) activation in colon cancer cell lines. We examined
      the effect of one year supplemental folic acid (5 mg/day) on the rectal mucosal
      expression of beta-catenin and pGSK3beta, known to be affected by EGF-R, in
      patients with colorectal adenomas. Folic acid treatment significantly reduced
      nuclear expression of beta-catenin (P < 0.05) and cellular expression of
      pGSK3beta (P < 0.01) when compared to placebo. Folic acid may exert its
      chemopreventive effect, at least in part, through inhibition of nuclear
      translocation of beta-catenin.

PMID- 15019158
TI  - Brusatol-induced HL-60 cell differentiation involves NF-kappaB activation.
AB  - Brusatol, a quassinoid isolated from the fruit of Brucea javanica, induces cell
      differentiation with various leukemic cell lines in the concentration range of 5
      25 ng/ml. To investigate its mechanism of action, cultured HL-60 cells were
      treated with brusatol (25 ng/ml) for various periods of time and qualitatively
      analyzed for differential gene expression using a cDNA macroarray. As suggested
      by these preliminary data, we investigated the effect of brusatol on the
      Rel/nuclear factor-kappa B (NF-kappaB) family members and their role in HL-60
      cell differentiation. When cells were treated with brusatol (25 ng/ml), p100/p52,
      p105/p50 and p65 mRNA were found to be up-regulated with a maximum after 8 h. As
      determined by electrophoretic mobility shift assays (EMSA), NF-kappaB was
      activated, involving p50 and p65. Moreover, immunoblots showed a decrease of
      IkappaBalpha and generation of the phosphorylated form of IkappaBalpha in whole
      cell lysates. Cell differentiation induced by brusatol was inhibited by SN50, a
      NF-kappaB translocation inhibitor. These results strongly suggest that brusatol
      induces activation of NF-kappaB and the activation and translocation of NF-kappaB
      into the nucleus is responsible for promoting HL-60 cell differentiation.

PMID- 15019159
TI  - Polymorphisms of DNA repair gene XRCC3 Thr241Met and risk of gastric cancer in a
      Chinese population.
AB  - Mammalian cells are constantly exposed to a wide variety of genotoxic agents from
      both endogenous and exogenous sources. Genetic variability in DNA repair may
      contribute to human cancer risk. In this population-based case-control study in
      China, we tested the hypothesis that a C to T variant (Thr241Met) of DNA repair
      gene XRCC3 (X-ray repair cross-complementing group 3) is associated with risk of
      developing gastric cancer. We genotyped for this variant using polymerase chain
      reaction-restriction fragment length polymorphisms (PCR-RFLP) in 188
      histologically confirmed gastric cancer patients and 166 frequency-matched cancer
      free controls. The XRCC3 genotype and allele frequencies were not significantly
      different between cases and controls (P = 0.99 for genotype; P = 0.76 for
      allele). The XRCC3 241Met allele frequency (4.8%) was significantly lower in
      healthy Chinese controls than previously reported healthy US Caucasian controls
      (38.9%). Compared with the XRCC3 241Thr/Thr genotype, the variant XRCC3241Thr/Met
      and Met/Met genotypes were not associated with an increased risk of gastric
      cancer (adjusted odds ratio (OR(a)), 1.06; 95% confidence interval (CI), 0.52
      2.16). These findings suggest that polymorphisms of XRCC3 Thr241Met may not play
      a role in the etiology of gastric cancer. Further studies with a larger number of
      subjects and simultaneous measurement of different polymorphisms in DNA repair
      genes in the same pathway are needed to confirm these findings.

PMID- 15019160
TI  - The 825C>T polymorphism of the G-protein beta-3 subunit gene (GNB3) and breast
      cancer.
AB  - The 825C>T polymorphism in the gene for the G-protein beta3 subunit (GNB3) has
      been linked to the occurrence of a splice variant of GNB3 and distinct cellular
      and metabolic features and may be associated with malignant disease. 500 patients
      with histologically confirmed breast cancer and 500 female age-matched healthy
      control subjects were genotyped for the GNB3 polymorphism to analyze its role for
      breast cancer. Prevalences of GNB3 CC, CT and TT genotypes were similar among
      patients (49.7, 39.8, 10.5%) and controls (50.1, 42.4, 7.5%, P = 0.25). The GNB3
      genotype was furthermore not linked to tumor size, histological grading, estrogen
      or progesterone receptor status and age at diagnosis. In an exploratory analysis,
      carriage of a 825-T allele was associated with a longer metastasis-free period in
      patients with primary low-grade breast cancer, but not in those with primary high
      grade breast cancer (Cox regression, P = 0.025). We conclude that the GNB3 825C>T
      polymorphism does not appear to be associated with breast cancer risk, but may
      influence development of metastasis in low-grade tumors.

PMID- 15019161
TI  - Inhibition of transforming growth factor-beta and matrix metalloproteinases by
      estrogen and prolactin in breast cancer cells.
AB  - Hormones, estrogen and prolactin, transforming growth factor-beta (TGF-beta), and
      matrixmetalloproteinases (MMPs) may modulate breast cancer progression. The goal
      of this research was to examine the regulation of expression of TGF-beta and MMPs
      (MMP-1, 2, 9) by estrogen and prolactin, independently and in combination, at
      physiological doses, and at doses stimulating cancer cell (T47D) proliferation in
      vitro. Prolactin, and estrogen synergistically, and similarly, inhibited the
      expression of TGF-beta and MMPs at physiological concentrations without altering
      cell proliferation, indicating a beneficial role of the hormones. The growth
      stimulating concentration of prolactin, but not estrogen, also inhibited the TGF
      beta and MMP expression.

PMID- 15019162
TI  - Mitotic instability associated with late genomic changes in bone and soft tissue
      tumours.
AB  - One source of genomic instability in tumours is abnormal mitotic segregation of
      chromosomes. Evaluation of chromosome segregation and cytogenetic aberrations in
      28 bone and soft tissue neoplasms revealed few mitotic disturbances in benign
      lesions, whereas most of the malignant tumours, except for chondrosarcomas,
      showed anaphase bridges and/or multipolar mitoses. Only cases with chromosomal
      imbalances exhibited these defects and they were not present in any of the cases
      with sole primary changes, indicating that mitotic instability is established
      relatively late in mesenchymal tumour development. Most cases with multipolar
      mitoses exhibited abnormal centrosome configurations. However, induction of
      supernumerary centrioles in vitro failed to produce mitotic abnormalities in
      normal cells, indicating that additional disturbances of the cell division
      machinery are required for the generation of mitotic multipolarity.

PMID- 15019163
TI  - Loss of heterozygosity and p53 expression in Pterygium.
AB  - While the pathogenesis of pterygium is still not well understood, environmental
      factors such at UV light, appear to play an important role in its development. UV
      radiation can cause mutations in genes such as the p53 tumor suppressor gene,
      that when inactivated through mutation and loss of heterozygosity can lead to
      cell proliferation and genomic instability. However, aside from mutations in the
      gene, other mechanisms have been identified that can lead to loss of p53
      function. These include the interaction of the p53 protein with cellular or viral
      gene products that lead to the inactivation of p53 or to its rapid degradation as
      well as the silencing of transcription of the p53 gene through the aberrant
      expression of factors that control p53 expression. We have analyzed the status
      and expression of the p53 gene in epithelial cells derived from pterygium and
      have demonstrated that the p53 gene has undergone a monoallelic deletion. Assays
      for both p53 protein and mRNA revealed that the remaining allele in these cells
      is not expressed at detectable levels. Furthermore, the remaining allele, by DNA
      sequence analysis appears to remain wild type. The mechanism of silencing the p53
      gene and the loss of p53 expression in these cells is currently under
      investigation.

PMID- 15019164
TI  - Autocrine inhibition of chemotherapy response in human liver tumor cells by
      insulin-like growth factor-II.
AB  - Insulin-like Growth Factor (IGF)-II is frequently overexpressed in experimental
      and human hepatocellular carcinomas (HCCs) and has been correlated with increased
      tumor growth. We have analyzed, whether IGF-II affects chemotherapy response and
      apoptosis in human liver tumor cells. Three liver tumor cell lines highly
      expressed IGF-II and supported their growth in an autocrine manner by secreting
      excessive amounts of IGF-II. Neutralization of IGF-II significantly increased
      response to the chemotherapeutic agents cisplatin and etoposide especially at
      lower, cytostatic doses. While blocking of IGF-II did not increase spontaneous
      cell death in exponentially growing cultures, increased cell death was found
      under conditions of confluent growth and chemotherapy. Thus in HCC cells, IGF-II
      is a relevant protumorigenic growth factor that significantly reduces
      susceptibility to apoptosis and chemotherapeutic treatment. Therefore
      interference with IGF-II activity may improve response of HCCs to otherwise
      inefficient chemotherapeutic agents.

PMID- 15019165
TI  - Analysis of potential prognostic factors in 111 patients with ovarian cancer.
AB  - The aim of this study was to assess the correlation of survival with clinical,
      surgical, histopathological, and biochemical parameters in patients with ovarian
      cancer. Age, surgical and histopathological data, the concentrations of estrogen
      and progesterone receptors, Her-2 neu, p53, U-PA, PAI-1, and Cathepsin D, DNA-and
      S-phase indexes of 111 ovarian cancer patients have been analyzed and correlated
      to survival. Progesterone receptors were correlated with prolonged survival. FIGO
      staging at the time of diagnosis is an independent prognostic factor for the
      patient's survival. Endometrioid and serous ovarian cancers have a better
      prognosis than mucinous and clear cell ovarian cancers. Survival of optimally
      debulked patients was substantially longer than that of not optimally debulked
      patients. This study shows, that an accurate clinical and surgical staging with
      an according histopathological assessment combined with optimal cytoreduction is
      of importance for the prognosis of ovarian cancer patients.

PMID- 15019166
TI  - Wnt inhibitory factor-1: a candidate for a new player in tumorigenesis of
      intestinal epithelial cells.
AB  - Using cDNA-Representational Difference Analysis it was found that expression of
      Opg, Ctse, Krt2-4, Fut-2, 24p3 and Wif-1 genes was elevated in intestinal
      adenomas as compared to normal epithelial cells of Apc(Min/+) mutant mice.
      Expression of Wif-1, which encodes Wnt inhibitory factor-1 was also detected in a
      number of tumor cell lines of epithelial cell origin including two human colon
      adenocarcinoma cell lines. The possible role of Wif-1 over-expression in the
      etiology of colorectal cancer is discussed.

PMID- 15019167
TI  - The attentional selection of spatial and non-spatial attributes in touch: ERP
      evidence for parallel and independent processes.
AB  - To investigate the functional relationship between spatial and non-spatial
      attentional selectivity in somatosensory processing, event-related potentials
      (ERPs) were recorded to mechanical tactile stimuli, which were delivered to the
      right or left hand, and were low or high in frequency (Experiment 1), or soft or
      strong in intensity (Experiment 2). Participants' task was to attend to a
      specific combination of one stimulus location and one non-spatial attribute.
      Spatial attention was reflected in enhanced N140 components followed by a
      sustained attentional negativity. ERP effects of non-spatial attention (enhanced
      negativities to the attended frequency or intensity) were observed in the same
      latency range, suggesting that the attentional selection of relevant spatial and
      non-spatial attributes occurs in parallel. Most importantly, ERP correlates of
      attention directed to stimulus frequency and intensity were unaffected by the
      current focus of spatial attention. In contrast to vision, where the selective
      processing of non-spatial attributes is hierarchically dependent on selection by
      location, but similar to auditory attention, spatial and non-spatial attentional
      selectivity appear to operate independently in touch.

PMID- 15019168
TI  - P300 from inspiratory occlusion reflects orienting but not startle.
AB  - Sudden onset inspiratory occlusion stimuli elicit large amplitude P300 components
      and also startle blinks. The primary purpose of this study was to assess the
      influence of the startle reflex on the respiratory related P300. A secondary
      purpose was to assess changes in P300 scalp topography as a function of stimulus
      familiarity. Young adults (n=12) were exposed to 200 inspiratory occlusion
      stimuli, and EEG was recorded from 29 A1/A2 referenced sites. Data from the
      occlusions were divided into four consecutive blocks of 50 trials to assess blink
      and P300 habituation effects. Results showed that 40% of the occlusion stimuli
      elicited a blink response, and that blink amplitude showed significant
      habituation across the experimental session. Change in P300 amplitude across the
      experimental session varied according to scalp site. At central and parietal
      locations, P300 amplitude showed an initial decrease but then remained stable.
      Frontally, P300 amplitude decreased over each of the four trial blocks. P300
      scalp topography showed a classic centro-parietal maximum, however, a more
      frontally orientated scalp focus was seen for the first trial block. P300 was not
      significantly different when derived from averages of responses containing and
      not containing blinks. These data indicate that the previously studied centro
      parietal P300 is not related to a startle reflex. However, when occlusions are
      first presented, a scalp topography similar to that previously noted for novel
      stimuli is observed.

PMID- 15019169
TI  - Extraversion-related differences in response organization: evidence from
      lateralized readiness potentials.
AB  - Research utilizing a mental-chronometry approach to examine individual
      differences in extraversion suggests that extraversion-related individual
      differences may involve stimulus analysis, response organization, and peripheral
      motor processes. In a sample of 14 introverted and 14 extraverted female
      volunteers event-related potentials (ERP) and lateralized readiness potentials
      (LRPs) were recorded concurrently with reaction time (RT) measures as
      participants performed a two-choice go/no-go task. Although there were no
      extraversion-related differences in mean reaction time, introverts showed higher
      N1 amplitudes and shorter P3 latencies compared to extraverts. Furthermore,
      response-locked LRP latencies were reliably shorter for extraverts than for
      introverts. The latter finding provides first direct evidence for the
      contribution of central processes related to motor activation to account for
      extraversion-related individual differences.

PMID- 15019170
TI  - Emotion and motivated behavior: postural adjustments to affective picture
      viewing.
AB  - Thirty-six participants (18 female, 18 male) viewed affective pictures to
      investigate the coupling between emotional reactions and motivated behavior.
      Framed within the biphasic theory of emotion, the three systems approach was
      employed by collecting measures of subjective report, expressive physiology, and
      motivated behavior. Postural adjustments associated with viewing affective
      pictures were measured. Results indicated sex-differences for postural responses
      to unpleasant pictures; an effect not found for pleasant and neutral picture
      contents. Females exhibited increased postural movement in the posterior
      direction, and males exhibited increased movement in the anterior direction, for
      unpleasant pictures. Subjective report of valence and arousal using the self
      assessment manikin (SAM), and the startle eye-blink reflex were collected during
      a separate session, which replicated previous picture-viewing research.
      Specifically, participants rated pleasant pictures higher in valence and
      exhibited smaller startle responses compared to unpleasant pictures. Females also
      reported lower valence ratings compared to males across all picture contents.
      These findings extend our knowledge of motivated engagement with affective
      stimuli and indicate that postural responses may provide insight into sex-related
      differences in withdrawal behavior.

PMID- 15019171
TI  - Reactions to facial expressions: effects of social context and speech anxiety on
      responses to neutral, anger, and joy expressions.
AB  - Male and female participants (n=19) high or low in speech fear viewed pictures of
      faces posed in anger, neutral, and joyful expressions for 8s each. Zygomaticus
      major and corrugator supercilii EMG, skin conductance, and heart rate were
      measured during picture viewing, and subjective ratings were made after each
      picture. Compared to anger expressions, joy expressions were responded to with
      greater zygomatic EMG, less corrugator EMG, and greater heart rate and skin
      conductance. Physiological response to neutral expressions was similar to
      response to anger expressions. Expressions posed by women were responded to
      physiologically more negatively than expressions posed by men. More fearful
      participants exhibited more negative and less positive facial expressions, and
      skin conductance responses suggesting greater attention when viewing negative
      expressions. Results suggest that reactions to facial expressions are influenced
      by social context, and are not simple mimicry.

PMID- 15019172
TI  - A method for estimating long-range power law correlations from the
      electroencephalogram.
AB  - Recent research has found long-range electroencephalogram (EEG) power law
      correlations, indicating time scale invariance. However, the EEG is also rather
      noisy, displaying short-term decorrelation like white noise--i.e., what is scale
      invariant at one time period may disappear in the next. The paradoxical
      combination of short-range divergence, but long-range correlations, suggests that
      any long-range correlations detected in one sample may be spurious, since they
      could be related to amplitude fluctuations. To overcome this problem, this paper
      suggests a new technique for analysing EEG signals segmented by zero-crossings,
      using detrended fluctuation analysis (DFA), evaluated across two time periods
      (TIME) and different sites (SITE). A mean scaling exponent across all subjects
      and sites of alpha = 0.67 was observed. MANOVA analysis indicates no significant
      main effect for TIME or interaction with SITE, suggesting that the zero-crossing
      method may be successful in determining the fractal nature of EEG dynamics across
      relatively long time scales.

PMID- 15019173
TI  - Reductions in secretory immunoglobulin A to cold pressor stress are not
      influenced by timing of saliva sampling.
AB  - Acute psychological stress has been shown to alter secretory immunity,
      principally secretory immunoglobulin A (S-IgA). Most acute stress tasks result in
      increases in S-IgA, but decreases have been reported in response to the cold
      pressor. However, the evidence is mixed, with increases and no changes in S-IgA
      in response to the cold pressor also being reported. It was hypothesised that
      differences in the timing of saliva sampling may provide an explanation for these
      discrepant results. Participants completed two 4-min cold pressor tasks, each
      preceded by a rest period in which baseline S-IgA was measured. In one condition,
      S-IgA was assessed during the final 2 min of the cold pressor; in the other, it
      was measured immediately after completion of the task. S-IgA decreased from
      baseline to task, regardless of timing of saliva sampling. It was concluded that
      differences in timing of sampling do not account for the mixed reports in the
      literature.

PMID- 15019174
TI  - Cell cycle regulation of neuronal apoptosis in development and disease.
AB  - Apoptosis of neurons is indispensable to the normal development of the nervous
      system and contributes to neuronal loss in neurologic injury and disease. Life
      and death decisions are imposed upon neurons by extracellular and intracellular
      stimuli including the lack of trophic support, exposure to neurotoxins, oxidative
      stress, and DNA damage. These stimuli induce signaling pathways that are
      integrated at the mitochondrial apoptotic machinery culminating in cell survival
      or death. Growing evidence suggests that cell cycle proteins are expressed in
      dying neurons in the developing and adult brain. However, the role and mechanisms
      by which re-activation of cell cycle pathways in postmitotic neurons propagates
      an apoptotic signal to the cell death machinery are just beginning to be
      characterized. Here, we will review the molecular mechanisms of neuronal cell
      death and survival with a focus on recent findings on cell cycle regulation of
      neuronal apoptosis in primary cultures of neurons, mouse models of neuronal
      diseases, and human neurodegenerative diseases.

PMID- 15019175
TI  - The characteristics and neuronal substrate of saccadic eye movement plasticity.
AB  - Saccadic eye movements are shifts in the direction of gaze that rapidly and
      accurately aim the fovea at targets of interest. Saccades are so brief that
      visual feedback cannot guide them to their targets. Therefore, the saccadic motor
      command must be accurately specified in advance of the movement and continually
      modified to compensate for growth, injury, and aging, which otherwise would
      produce dysmetric saccades. When a persistent dysmetria occurs in subjects with
      muscle weakness or neural damage or is induced in normal primates by the
      surreptitious jumping of a target forward or backward as a saccade is made to
      acquire the target, saccadic amplitude changes to reduce the dysmetria.
      Adaptation of saccadic amplitude or direction occurs gradually and is retained in
      the dark, thus representing true motor plasticity. Saccadic adaptation is more
      rapid in humans than in monkeys, usually is incomplete in both species, and is
      slower and less robust for amplitude increases than decreases. Adaptation appears
      to be motor rather than sensory. In humans, adaptation of saccades that would
      seem to require more sensory-motor processing does not transfer to saccades that
      seem to require less, suggesting the existence of distributed adaptation loci. In
      monkeys, however, transfer from more simple to more complex saccades is robust,
      suggesting a common adaptation site. Neurophysiological data from both species
      indicate that the oculomotor cerebellum is crucial for saccadic adaptation. This
      review shows that the precise, voluntary behaviors known as saccadic eye
      movements provide an alternative to simple reflexes for the study of the neuronal
      basis of motor learning.

PMID- 15019176
TI  - Emergent properties of CNS neuronal networks as targets for pharmacology:
      application to anticonvulsant drug action.
AB  - CNS drugs may act by modifying the emergent properties of complex CNS neuronal
      networks. Emergent properties are network characteristics that are not
      predictably based on properties of individual member neurons. Neuronal membership
      within networks is controlled by several mechanisms, including burst firing, gap
      junctions, endogenous and exogenous neuroactive substances, extracellular ions,
      temperature, interneuron activity, astrocytic integration and external stimuli.
      The effects of many CNS drugs in vivo may critically involve actions on specific
      brain loci, but this selectivity may be absent when the same neurons are isolated
      from the network in vitro where emergent properties are lost. Audiogenic seizures
      (AGS) qualify as an emergent CNS property, since in AGS the acoustic stimulus
      evokes a non-linear output (motor convulsion), but the identical stimulus evokes
      minimal behavioral changes normally. The hierarchical neuronal network,
      subserving AGS in rodents is initiated in inferior colliculus (IC) and progresses
      to deep layers of superior colliculus (DLSC), pontine reticular formation (PRF)
      and periaqueductal gray (PAG) in genetic and ethanol withdrawal-induced AGS. In
      blocking AGS, certain anticonvulsants reduce IC neuronal firing, while other
      agents act primarily on neurons in other AGS network sites. However, the NMDA
      receptor channel blocker, MK-801, does not depress neuronal firing in any network
      site despite potently blocking AGS. Recent findings indicate that MK-801 actually
      enhances firing in substantia nigra reticulata (SNR) neurons in vivo but not in
      vitro. Thus, the MK-801-induced firing increases in SNR neurons observed in vivo
      may involve an indirect effect via disinhibition, involving an action on the
      emergent properties of this seizure network.

PMID- 15019177
TI  - Toxicity and human health risk of hair dyes.
AB  - Hair dyes and their ingredients have moderate to low acute toxicity. Human
      poisoning accidents are rare and have only been reported following oral
      ingestion. Contact sensitisation to hair dyes has been a safety issue, mainly as
      a consequence of unprotected professional exposure. Although the use of hair dyes
      has dramatically increased in industrialised countries during the last decades,
      the prevalence of sensitisation to hair dyes in the general and professional
      populations has stabilised or declined. In vitro genotoxicity tests on hair dye
      ingredients frequently had positive results, although their correlation with in
      vivo carcinogenicity for the chemical class of oxidative hair dye ingredients
      (aromatic amines) is uncertain. Positive in vivo genotoxicity results on hair
      dyes are rare. Studies in man found no evidence of genotoxic effects of hair dyes
      or their ingredients. On the basis of mechanistic studies, some in vivo positive
      hair dye ingredients (p-aminophenol, Lawsone) have been shown to pose no or
      negligible risk to human health. Although a recent case-control epidemiology
      study suggested an association of hair dye use and bladder cancer, a number of
      other studies, including prospective investigations on large populations, found
      no or negative correlations for bladder or other cancers. Although in vivo
      topical carcinogenicity studies on hair dye ingredients or commercial
      formulations yielded no evidence for systemic toxicity or carcinogenicity, oral
      carcinogenicity studies on hair dye ingredients at oral doses up to the maximum
      tolerated dose (MTD) suggested that some ingredients are carcinogenic in rodents.
      Human systemic exposure to various (14)C-labelled oxidative hair dyes under
      conditions of use was below 1.0% of the amount applied. Conservative risk
      assessments suggested no or negligible cancer risk, including for ingredients
      that were found to be positive in oral carcinogenicity studies. The results of
      reproductive toxicity studies and epidemiological investigations suggested that
      hair dyes and their ingredients pose no risk of adverse reproductive effects. In
      conclusion, the weight of evidence suggests that consumer or professional
      exposure to hair dyes poses no carcinogenic or other human health risks.

PMID- 15019178
TI  - Amnesic shellfish poison.
AB  - Amnesic shellfish poisoning (ASP) is caused by consumption of shellfish that have
      accumulated domoic acid, a neurotoxin produced by some strains of phytoplankton.
      The neurotoxic properties of domoic acid result in neuronal degeneration and
      necrosis in specific regions of the hippocampus. A serious outbreak of ASP
      occurred in Canada in 1987 and involved 150 reported cases, 19 hospitalisations
      and 4 deaths after consumption of contaminated mussels. Symptoms ranged from
      gastrointestinal disturbances, to neurotoxic effects such as hallucinations,
      memory loss and coma. Monitoring programmes are in place in numerous countries
      worldwide and closures of shellfish harvesting areas occur when domoic acid
      concentrations exceed regulatory limits. This paper reviews the chemistry,
      sources, metabolism and toxicology of domoic acid as well as human case reports
      of ASP and discusses a possible mechanism of toxicity.

PMID- 15019179
TI  - The formation of AFB(1)-macromolecular adducts in rats and humans at dietary
      levels of exposure.
AB  - The levels of aflatoxin B(1)-DNA and aflatoxin B(1)-albumin adducts were
      investigated by accelerator mass spectrometry (AMS) in humans and rats following
      exposure to a known, dietary relevant amount of carbon-14 labeled aflatoxin B(1)
      ([(14)C]AFB(1)). The aims of the study were to: (a) investigate the dose
      dependent formation of DNA and protein adducts at very low doses of AFB(1) (0.16
      ng/kg-12.3 microg/kg) in the rat; (b) measure the levels of AFB(1)-albumin and
      AFB(1)-DNA adducts at known, relevant exposures in humans (c) study rat to human
      extrapolations of AFB(1)-albumin and DNA adduct levels. The results in the rat
      showed that both AFB(1)-albumin adduct and AFB(1)-DNA adduct formation were
      linear over this wide dose range. The order of adduct formation within the
      tissues studied was liver>kidney>colon>lung=spleen. Consenting volunteers
      received 1 microg ( approximately 15 ng/kg) of [(14)C]AFB(1) in a capsule
      approximately approximately 3.5-7 h prior to undergoing colon surgery. The mean
      level of human AFB(1)-albumin adducts was 38.8+/-19.55 pg [(14)C]AFB(1)/mg
      albumin/microg AFB(1)/kg body weight (b.w.), which was not statistically
      different to the equivalent dose in the rat (15 ng/kg) 42.29+/-7.13 pg
      [(14)C]AFB(1)/mg albumin/microg AFB(1)/kg b.w. There was evidence to suggest the
      formation of AFB(1)-DNA adducts in the human colon at very low doses. Comparison
      of the linear regressions of hepatic AFB(1)-DNA adduct and AFB(1)-albumin adduct
      levels in rat found them to be statistically similar suggesting that the level of
      AFB(1)-albumin adducts are useful biomarkers for AFB(1) dosimetry and may reflect
      the DNA adduct levels in the target tissue. [(14)C]AFB(1)-DNA and [(14)C]AFB(1)
      albumin adducts were hydrolysed and analysed by HPLC to confirm that the [(14)C]
      measured by AMS was derived from the expected [(14)C]AFB(1) adducts.

PMID- 15019180
TI  - Effects of inorganic mercury on reproductive performance of mice.
AB  - Effects of mercuric chloride (MC) on the reproductive performance of mice were
      evaluated. Both male and female mice were divided into four groups that were
      subsequently exposed to 0.00, 0.25, 0.50, and 1.00 mg/kg/day of MC, respectively.
      At the end of pre-mating dosing, males were paired with females receiving the
      same dose. Dosing continued for males throughout mating, while dosing in females
      continued throughout mating, gestation, and lactation. The males were necropsied
      at the conclusion of mating and the females were necropsied at the conclusion of
      lactation. Fertility indices, parturition, gestation, live birth litter size,
      survival indices, and implantation efficiency were recorded. Subsequently, these
      data were statistically analyzed. Fertility and survival indices were
      significantly reduced in the treated groups. Exposure of mice to MC did not
      affect their litter size. No evidence of mercury induced target organ toxicity
      was seen in either the clinical pathology parameters or histomorphologic
      evaluations. However, in MC treated females, ovary weights were significantly
      different from the control. There were no histomorphologic or clinical pathology
      effects induced by MC. These results suggested that oral exposure to 0.25-1.00
      mg/kg/day of MC produced adverse effects on the reproductive performance of mice
      in the absence of overt mercury toxicity.

PMID- 15019181
TI  - 1,8-cineole (eucalyptol), a monoterpene oxide attenuates the colonic damage in
      rats on acute TNBS-colitis.
AB  - The monoterpene oxide, 1,8-cineole (cineole, eucalyptol) was examined for its
      possible influence on the acute phase of trinitrobenzene sulfonic acid (TNBS)
      induced colitis in rats. The test compound, 1,8-cineole (200 and 400 mg/kg) or
      vehicle (1 ml, 2% Tween 80) was instilled rectally, 24, and 2 h before (pre
      treatment) or 2 and 24 h after (post-treatment) the induction of colitis by
      intracolonic administration of TNBS (0.25 ml of 25 mg of TNBS in 50% ethanol).
      Rats were killed 48 h after colitis induction and colonic segments were analysed
      for gross damage scores, changes in wet weights, myeloperoxidase activity, an
      indicator of neutrophilic infiltration and glutathione level, a major cellular
      antioxidant. TNBS induced an extensive inflammation and ulceration in the colon.
      Colonic damage was associated with an increase in myeloperoxidase activity and by
      a decrease in glutathione. When compared to vehicle-treated TNBS controls, a
      marked reduction in gross damage scores and wet weights (mg/cm) of colonic
      segments were evident in animals pre-treated but not post-treated with 1,8
      cineole. Cineole also significantly reduced the myeloperoxidase activity, and
      caused repletion of glutathione. These results confirm the anti-inflammatory
      action of 1,8-cineole and suggest its potential value as a dietary flavoring
      agent in the prevention of gastrointestinal inflammation and ulceration.

PMID- 15019182
TI  - Toxicological evaluation of the ethanolic extract of Artemisia dracunculus L. for
      use as a dietary supplement and in functional foods.
AB  - TARRALIN is an ethanolic extract of Artemisia dracunculus (Russian tarragon), a
      common medicinal and culinary herb with centuries of use. Artemisia dracunculus
      is a close relative of the French or cooking tarragon and contains components
      common to many herbs that are routinely consumed without reported adverse
      effects. Since safety information of Artemisia dracunculus and its extract is
      limited to historical use, TARRALIN was examined in a series of toxicological
      studies. Complete Ames analysis did not reveal any mutagenic activity either with
      or without metabolic activation. TARRALIN was tested in an acute limit test at
      5000 mg/kg with no signs of toxicity noted. In a 14 day repeated dose oral
      toxicity study, rats appeared to well tolerate 1000 mg/kg/day. Subsequently,
      TARRALIN was tested in an oral subchronic 90-day toxicity study (rat) at doses of
      10, 100 and 1000 mg/kg/day. No noteworthy signs of toxicity were noted in feeding
      or body weight, functional observational battery or motor activity. Gross
      necropsy and clinical chemistry did not reveal any effects on organ mass or blood
      chemistry and microscopic examinations found no lesions associated with
      treatment. Therefore, TARRALIN appears to be safe and non-toxic in these studies
      and a no-observed adverse effect level in rats is established at 1000 mg/kg/day.

PMID- 15019183
TI  - Cadmium, mercury and lead in medicinal herbs in Brazil.
AB  - Samples of herbal medicine used in Brazil were analyzed, after nitric digestion,
      for the content of cadmium, mercury and lead, by atomic absorption
      spectrophotometry. Fifteen samples of ginkgo biloba (Ginkgo biloba), 13 of
      celastraceae (Maytenus ilicifolia), 14 of cascara buckthorn (Rhamnus purshiana),
      13 of eggplant (Solanum melongena), 15 of horse chestnut (Aesculus
      hippocastanum), 13 of Brazilian ginseng (Pffafia glomerata), 17 of centella
      asiatic (Hydrocotyle asiatica), 13 of guarana (Paullinia cupana), 12 of artichoke
      (Cynara scolymus) and five samples of chlorella (Chlorella pyrenoidosa) were
      analyzed. Cadmium, mercury and lead were not detected (limit of quantifications
      of 0.20, 0.01 and 2.0 mg/kg, respectively) in any sample of artichoke, eggplant
      and guarana. Cadmium was found in samples of the other medicinal herbs at levels
      up to 0.74 microg/g and mercury up to 0.087 microg/g. Three samples of horse
      chestnut contained 153, 156 and 1480 microg Pb/g, while the highest concentration
      found in the other samples analyzed was 22 microg Pb/g. The estimated lead intake
      through the consumption of horse chestnut reached 440% of Provisional Tolerable
      Weekly Intake (PTWI), and might be of concern to consumers if the medicine was
      taken on a long-term basis. Cadmium and mercury exposure through the herbal
      medicines does not appear to be of health concern.

PMID- 15019184
TI  - Protective effect of diltiazem on cyanide-induced neurotoxicity in Wistar strain
      rats.
AB  - Cyanide is a well-established poison known for its rapid lethal action and
      toxicity. The central nervous system is one of the main target sites for cyanide
      toxicity. Cyanide not only alters brain biogenic amine levels but also the
      intracellular calcium levels in the neuronal cells. In the present study the role
      of calcium channel blocker diltiazem (DIL) in cyanide induced biogenic amine
      changes was evaluated in the Wistar strain rats. The protective effect of
      diltiazem pretreatment and diltiazem treatment along with cyanide on the
      dopaminergic system and the serotonergic system in the corpus striatum were
      studied. Diltiazem pretreatment was found to prevent cyanide induced changes in
      both the amines in the corpus striatum. These results suggest that diltiazem may
      mitigate the harmful effects of cyanide by interfering with influx of calcium
      ions and release of the biogenic amines.

PMID- 15019185
TI  - Hepatoprotective and antioxidant effects of Bupleurum kaoi Liu (Chao et Chuang)
      extract and its fractions fractionated using supercritical CO(2) on CCl(4)
      induced liver damage.
AB  - Fractionation with supercritical CO(2) is employed to divide ethanolic extract
      (E) of B. kaoi into four fractions (R, F1, F2 and F3). To assess the selectivity
      of the fractionation, extracts of the four fractions were characterized in terms
      of the hepatoprotective capacity and activity of antioxidant enzymes to against
      CCl(4)-induced damage. The in vitro study revealed that pretreatment with B. kaoi
      extract or its fractions, except F3, significantly protected primary hepatocytes
      against damage by CCl(4) (P<0.05). The R and F1 fractions had the highest
      saikosaponins content (175 and 200 mg/g dry weight, respectively) and most
      effectively protected the liver from damage by CCl(4). This study demonstrated
      that the oral pretreatment of B. kaoi (100 and 500 mg/kg), except F3, three days
      before a single dose of CCl(4) (CCl(4)/olive oil=1:1, 3 ml/kg, sc) was
      administered significantly lowered the serum levels of hepatic enzyme markers
      (AST and ALT) (P<0.05). A pathological examination showed that lesions, including
      ballooning degeneration, necrosis, hepatitis and portal triaditis were partially
      healed by treatment with B. kaoi extract and fractions. Oxidative stress induced
      by CCl(4) led to lipid peroxidation (MDA) and changes in the levels of the
      antioxidant enzymes in the liver. However, all the fractions, except F3, markedly
      suppressed lipid peroxidation and reversed the activities of the antioxidant
      enzymes to the normal levels.

PMID- 15019186
TI  - Comparative cytotoxicity of deoxynivalenol, nivalenol, their acetylated
      derivatives and de-epoxy metabolites.
AB  - The cytotoxicity of the de-epoxy metabolites of trichothecenes nivalenol (NIV)
      and deoxynivalenol (DON) was determined and compared with the cytotoxicity of the
      respective toxin with an intact epoxy group and their acetylated derivatives. The
      cytotoxic effects was determined by using the 5-bromo-2'-deoxyuridine (BrdU)
      incorporation assay assessing DNA-synthesis. The toxicity of NIV and DON
      expressed as the concentration inhibiting 50% of the DNA synthesis (IC(50)), was
      occurring at similar micromolar concentrations (1.19+/-0.06 and 1.50+/-0.34
      microM). The toxicity of fusarenon X (4-acetyl NIV) in the assay was similar to
      the toxicity of NIV, and the toxicity of 15-AcDON was equal to the toxicity of
      DON. 3-AcDON was less toxic than DON and 15-AcDON. The IC(50) value for de-epoxy
      DON was 54 times higher in the assay than the IC(50) for DON, while the IC(50) of
      de-epoxy NIV was 55 times higher than the IC(50) for NIV. The results verify
      previous findings that the de-epoxidation is a detoxification reaction.

PMID- 15019188
TI  - Toxicological evaluation of expanded shredded tobacco stems.
AB  - A tiered testing strategy has been developed to evaluate the potential of tobacco
      processes, ingredients, or technological developments to change the biological
      activity resulting from burning tobacco. The strategy is based on comparative
      chemical and biological testing. Expanded shredded tobacco stems (ESS) constitute
      an example of a common tobacco components expansion process currently used in the
      manufacture of cigarettes to increase the tobacco blend filling capacity. As part
      of the toxicological evaluation of ESS, test cigarettes containing 9.5%, 18.5%,
      and 25% ESS were compared to control cigarettes containing 0% ESS. Testing
      included mainstream cigarette smoke chemistry studies, genotoxicity studies (Ames
      and sister chromatid exchange), a 13-week inhalation study in Sprague-Dawley
      rats, and a 30-week dermal tumor promotion study in SENCAR mice. Collectively,
      data indicated that cigarettes with and without ESS had a similar toxicological
      profile in this test battery.

PMID- 15019187
TI  - Subacute toxicity assessment of annatto in rat.
AB  - Increased human use of annatto (Bixa orellana L), a red yellow food colorant,
      demands generation of toxicity data. The toxic effects of annatto powder (bixin
      27%) have been assessed following administration of a subacute regimen (4 weeks,
      20 doses) in Wistar male and female rats. A full study with three dose levels was
      considered unnecessary since no sign of toxicity had been noted in a preliminary
      experiment with 1000 mg/kg body weight/day as was recommended by the OECD
      guideline. In this study, annatto administered by gavage at a dose level of 2000
      mg/kg/day decreased male body weight gain, but had no effect on either food
      intake or food conversion efficiency. Haematological and plasma biochemical
      examination as well necropsy performed at the end of administration (29th day)
      and observation (43rd day) periods revealed no alterations related with annatto
      administration. Kidney apoptosis occurred in 20% treated female rats in
      restricted areas without proliferation or tubular segments modification. The
      precise nature of apoptosis was not investigated in the present study. These
      findings suggest that annatto was no toxic to the rat.

PMID- 15019189
TI  - Absorption and elimination of D and C Red No. 28 in male F-344 rats.
AB  - D and C Red No. 28 (Red 28) is a US certified color additive used in drugs and
      cosmetics. Little is known about the extent of systemic absorption and
      pharmacokinetic behavior of Red 28. Therefore, these studies were performed to
      determine oral bioavailability and pharmacokinetic parameters of Red 28 in male F
      344 rats following single and repeated oral dosing. Rats were administered either
      a single i.v. dose (50 mg/kg), a low oral gavage dose (50 mg/kg), or a high oral
      gavage dose (500 mg/kg) of Red 28. Plasma, urine and feces samples were subjected
      to solid phase extraction (SPE) and analyzed by HPLC for Red 28. Regardless of
      the dose or route of administration, the terminal t(1/2) of Red 28 was 2.5 h. The
      major route of elimination was fecal excretion, with 88% (i.v.) and 98% (50 mg/kg
      p.o.) of the dose recovered by 96 h. Urinary excretion of Red 28 accounted for 1%
      of the dose following i.v. administration. No Red 28 was detected in urine after
      p.o. administration. Biliary excretion was determined experimentally to be the
      primary route of elimination for systemically available Red 28. Bioavailability
      following p.o. administration was very low (1-2%) and was not altered
      significantly by 14 days of dietary pretreatment with Red 28.

PMID- 15019190
TI  - Extract of the seed coat of Tamarindus indica inhibits nitric oxide production by
      murine macrophages in vitro and in vivo.
AB  - The seed coat extract of Tamarindus indica, a polyphenolic flavonoid, has been
      shown to have antioxidant properties. The present studies investigated the
      inhibitory effect of the seed coat extract of T. indica on nitric oxide
      production in vitro using a murine macrophage-like cell line, RAW 264.7, and in
      vitro and in vivo using freshly isolated B6C3F1 mouse peritoneal macrophages. In
      vitro exposure of RAW 264.7 cells or peritoneal macrophages to 0.2-200 microg/mL
      of T. indica extract significantly attenuated (as much as 68%) nitric oxide
      production induced by lipopolysaccharide (LPS) and interferon gamma (IFN-gamma)
      in a concentration-dependent manner. In vivo administration of T. indica extract
      (100-500 mg/kg) to B6C3F1 mice dose-dependently suppressed TPA, LPS and/or IFN
      gamma induced production of nitric oxide in isolated mouse peritoneal macrophages
      in the absence of any effect on body weight. Exposure to T. indica extract had no
      effect on cell viability as assessed by the MTT assay. In B6C3F1 mice,
      preliminary safety studies demonstrated a decrease in body weight at only the
      highest dose tested (1000 mg/kg) without alterations in hematology, serum
      chemistry or selected organ weights or effects on NK cell activity. A significant
      decrease in body weight was observed in BALB/c mice exposed to concentrations of
      extract of 250 mg/kg or higher. Oral exposure of BALB/c mice to T. indica extract
      did not modulate the development of T cell-mediated sensitization to DNFB or HCA
      as measured by the local lymph node assay, or dermal irritation to nonanoic acid
      or DNFB. These studies suggest that in mice, T. indica extract at concentrations
      up to 500 mg/kg may modulate nitric oxide production in the absence of overt
      acute toxicity.

PMID- 15019191
TI  - Antimutagenic, antioxidant and free radical scavenging activity of ethyl acetate
      extracts from white, yellow and red onions.
AB  - The beneficial effects of red, yellow and white onion extracts have been assessed
      by antioxidant activity and antimutagenic activity. And the effects compared to
      BHT and ascorbic acid. Total phenolic compounds and flavonoids in onion extracts
      were determined. Yellow onion extract had more organic acid and free sugar than
      those detected in the white and red onion extract. The scavenging activity of
      DPPH radical and H(2)O(2) were increased depending on the concentration. The
      antioxidant activities using beta-carotene-linoleate system and reducing power
      were increased but the effect was small to that of BHT and ascorbic acid. After
      digested, extracts showed antimutagenic activities, and it seems that they
      inhibit the mutagenicity for digesting. This study demonstrated that the
      antimutagenicities and antioxidant properties of ethyl acetate extract against
      mutagens were related to their phenols and flavonoids, which are heat stable and
      losses digestive juices are relatively low.

PMID- 15019192
TI  - Lack of toxicity or carcinogenicity of S-170, a sucrose fatty acid ester, in F344
      rats.
AB  - A chronic combined toxicity and carcinogenicity study of S-170, a sucrose fatty
      acid ester, was performed in male and female F344 rats. S-170 was given ad
      libitum in the diet at levels of 0, 1.25, 2.5 or 5% to 10 rats/sex/group for 12
      months to determine chronic toxicity and 0, 2.5 or 5% to 50 rats/sex/group for
      two years in the carcinogenicity study. Treatment with S-170 exerted no effect on
      survival in either sex. In the 12-month chronic toxicity study, no treatment
      related effects on body weights, or hematological, blood biochemical, urinary and
      pathological parameters were demonstrated in any of the treated groups. In the
      carcinogenicity study, S-170 did not cause any dose-related significant increase
      in the incidences of tumors in any organs or tissues. Taken together, the results
      clearly demonstrate that S-170 has neither toxic nor carcinogenic activity in
      F344 rats under the conditions of the study. No observed adverse effect levels
      (NOAELs) calculated from the 12-month chronic toxicity and carcinogenicity study
      were 2.37 g/kg/day in males and 2.80 g/kg/day in females, and 2.12 g/kg/day in
      males and 2.42 g/kg/day in females, respectively.

PMID- 15019193
TI  - Dietary estimated intake of intense sweeteners by Italian teenagers. Present
      levels and projections derived from the INRAN-RM-2001 food survey.
AB  - In a previous study, Italian female teenagers regular consumers of sugar free
      soft drinks and table-top sweeteners were suggested to have a higher intake of
      intense sweeteners than other teenagers. A food frequency questionnaire designed
      to identify adolescents who were high consumers of these food products was filled
      in by a randomly extracted sample of teenagers (n=3982) living in the District of
      Rome (Italy) in year 2000. A consumer survey was then carried out in a randomly
      extracted sub-sample of males and females and in all females who reported high
      consumption of sugar-free soft drinks and/or table-top sweeteners. A total of 362
      subjects participated in a detailed food survey by recording, at brand level, all
      foods and beverages ingested over 12 days. For each sugar-free product, producers
      provided the concentration of intense sweeteners (saccharin, aspartame,
      acesulfame K and cyclamate). No intake in excess of the Acceptable Daily Intake
      (ADI) was observed. Also medicines and supplements were taken into account and
      these did not result in a large impact on chronic exposure to intense sweeteners.
      The intake levels did not exceed the ADI even under a worst case scenario which
      was performed to take into consideration a hypothetical future substitution of
      all regular food products with their sugar-free version. It can be concluded
      that, with the observed current consumption patterns and occurrence levels, the
      risk of an excessive intake of intense sweeteners by Italian teenagers is
      extremely low.

PMID- 15019194
TI  - Subchronic toxicity study of dietary N-acetylglucosamine in F344 rats.
AB  - A subchronic toxicity study of N-acetylglucosamine (GlcNAc), a monomeric form of
      chitin, was conducted in groups of 10 male and 10 female F344 rats fed pelleted
      diets containing 0, 0.625, 1.25, 2.5 or 5% concentrations for 13 weeks. All
      animals survived until the end of the experiment. Slight, non-significant
      increase in body weights was observed in males receiving 0.625, 1.25 or 2.5% from
      week 4 until the end of the experiment, when significant elevation was found for
      the males receiving 0.625, 1.25 or 2.5% at the terminal sacrifice to result in
      decreased relative weights of many organs in these cases. However, there were no
      obvious indications of toxicity in any group receiving GlcNAc in terms of
      clinical signs, food intake, hematology, serum biochemistry, and
      histopathological findings. Thus, it was concluded that orally administered
      GlcNAc exerts no obvious toxicity to F344 rats at concentrations up to 5% in the
      diet for 13 weeks. Based on the present toxicity data, > or =5% was determined to
      be a no-observed-adverse-effect level, translated into 2476 and 2834 mg/kg/day
      for male and female rats, respectively.

PMID- 15019195
TI  - Gene-encoded antimicrobial peptides. Introduction.

PMID- 15019196
TI  - Evolution of primate theta-defensins: a serpentine path to a sweet tooth.
AB  - Retrocyclins (ancestral human theta-defensins) are cyclic antimicrobial
      octadecapeptides that interfere with viral uptake and protect human cells from
      infection by T- and M-tropic strains of HIV-1 in vitro. As are other theta
      defensins, retrocyclins are lectins that bind gp120, CD4, and galactosylceramide
      all of which are implicated in HIV-1 uptake. Although theta-defensin mRNA
      transcripts are present in human bone marrow, spleen, thymus, testis, and
      skeletal muscle, a premature stop codon aborts their translation. We found six
      theta-defensin (DEFT) genes in the human genome; five on chromosome 8p23 and one
      on chromosome 1. All six of these pseudogenes, as well as their homologues in
      chimpanzees and gorillas, contained the same premature stop codon mutation.
      Whereas we found intact DEFT genes in DNA from several Old World Monkeys,
      Hylobates syndactylus (a lesser ape) and orangutans, no homologues were present
      in DNA from six New World Monkeys and five prosimians. We conclude that DEFT
      genes and theta-defensins arose in Old World Monkeys by mutation of a pre
      existing alpha-defensin gene. Although intact DEFT genes survive in some nonhuman
      primates, our hominid ancestors lost their ability to produce theta-defensins
      after the orangutan and hominid lineages diverged. It is possible (but may be
      difficult to prove) that this mutation rendered our species more susceptible to
      infection by HIV-1.

PMID- 15019197
TI  - Hagfish intestinal antimicrobial peptides are ancient cathelicidins.
AB  - Three potent broad-spectrum antimicrobial peptides (HFIAP-1, -2, and -3) isolated
      from intestinal tissues of Myxine glutinosa (Atlantic hagfish) are identified as
      ancient members of the cathelicidin family of antimicrobial peptides, hitherto
      known only from mammals. In situ hybridization reveals that HFIAPs are produced
      in nests of myeloid cells within the loose connective tissue of the gut wall, a
      tissue reminiscent of both gut-associated lymphoid tissue (GALT) and vertebrate
      spleen. We suggest that this tissue organization provides local defense of the
      hagfish gastrointestinal tract via innate immunity and possibly served as the
      architectural plan upon which the adaptive immune system evolved.

PMID- 15019198
TI  - Molecular strategies in biological evolution of antimicrobial peptides.
AB  - Gene-encoded antimicrobial peptides that protect the skin of hylid and ranin
      frogs against noxious microorganisms are processed from a unique family of
      precursor polypeptides with a unique pattern of conserved and variable regions
      opposite to that of conventional secreted peptides. Precursors belonging to this
      family, designated the preprodermaseptin, have a common N-terminal preproregion
      that is remarkably well conserved both within and between species, but a
      hypervariable C-terminal domain corresponding to antimicrobial peptides with very
      different lengths, sequences, charges and antimicrobial spectra. Each frog
      species has its own distinct panoply of 10-20 antimicrobial peptides so that the
      5000 species of ranids and hylids may produce approximately 100,000 different
      peptide antibiotics. The strategy that these frogs have evolved to generate this
      enormous array of peptides includes repeated duplications of a 150 million years
      old ancestral gene, focal hypermutation of the antimicrobial peptide domain maybe
      involving a mutagenic DNA polymerase similar to Escherichia coli Pol V, and
      subsequent actions of positive (diversifying) selection. The hyperdivergence of
      skin antimicrobial peptides can be viewed as the successful evolution of a multi
      drug defense system that provides frogs with maximum protection against rapidly
      changing microbial biota and minimizes the chance of microorganisms developing
      resistance to individual peptides. The impressive variations in the expression of
      frog skin antimicrobial peptides may be exploited for discovering new molecules
      and structural motifs targeting specific microorganisms for which the therapeutic
      armamentarium is scarce.

PMID- 15019199
TI  - The relationship between peptide structure and antibacterial activity.
AB  - Cationic antimicrobial peptides are a class of small, positively charged peptides
      known for their broad-spectrum antimicrobial activity. These peptides have also
      been shown to possess anti-viral and anti-cancer activity and, most recently, the
      ability to modulate the innate immune response. To date, a large number of
      antimicrobial peptides have been chemically characterized, however, few high
      resolution structures are available. Structure-activity studies of these peptides
      reveal two main requirements for antimicrobial activity, (1) a cationic charge
      and (2) an induced amphipathic conformation. In addition to peptide conformation,
      the role of membrane lipid composition, specifically non-bilayer lipids, on
      peptide activity will also be discussed.

PMID- 15019200
TI  - Can we predict biological activity of antimicrobial peptides from their
      interactions with model phospholipid membranes?
AB  - Cationic antibacterial peptides are produced in all living organisms and possess
      either selective activity toward a certain type of cell or microorganism, or a
      broad spectrum of activity toward several types of cells including prokaryotic
      and mammalian cells. In order to exert their activity, peptides first interact
      with and traverse an outer barrier, e.g., mainly LPS and peptidoglycan in
      bacteria or a glycocalix layer and matrix proteins in mammalian cells. Only then,
      can the peptides bind and insert into the cytoplasmic membrane. The mode of
      action of many antibacterial peptides is believed to be the disruption of the
      lipidic plasma membrane. Therefore, model phospholipid membranes have been used
      to study the mode of action of antimicrobial peptides. These studies have
      demonstrated that peptides that act preferentially on bacteria are also able to
      interact with and permeate efficiently anionic phospholipids, whereas peptides
      that lyse mammalian cells bind and permeate efficiently both acidic and
      zwitterionic phospholipids membranes, mimicking the plasma membranes of these
      cells. It is now becoming increasingly clear that selective activity of these
      peptides against different cells depends also on other parameters that
      characterize both the peptide and the target cell. With respect to the peptide's
      properties, these include the volume of the molecule, its structure, and its
      oligomeric state in solution and in membranes. Regarding the target membrane,
      these include the structure, length, and complexity of the hydrophilic
      polysaccharide found in its outer layer. These parameters affect the ability of
      the peptides to diffuse through the cell's outer barrier and to reach its
      cytoplasmic plasma membrane.

PMID- 15019201
TI  - Interactions of antifungal plant defensins with fungal membrane components.
AB  - Plant defensins are small, basic, cysteine-rich peptides that are generally
      active against a broad spectrum of fungal and yeast species at micromolar
      concentrations. Some of these defensins interact with fungal-specific lipid
      components in the plasmamembrane. Structural differences of these membrane
      components between fungal and plant cells probably account for the selective
      activity of plant defensins against fungal pathogens and their nonphytotoxic
      properties. This review will focus on different classes of complex lipids in
      fungal membranes and on the selective interaction of plant defensins with these
      complex lipids.

PMID- 15019202
TI  - A peptidylprolyl cis/trans isomerase from Xenopus laevis skin: cloning,
      biochemical characterization and putative role in the secretion.
AB  - In amphibian skin secretions, a peptidylprolyl cis/trans isomerase activity was
      detected. A Xenopus laevis skin cDNA coding for this protein was cloned,
      sequenced and over-expressed in Escherichia coli. The primary structure of the
      protein shows extensive similarity with members of the cyclophilin A family.
      Catalytic parameters of the recombinant protein are similar to those of the human
      enzyme. The enzymatic activity is inhibited by cyclosporin A. Data suggesting
      that peptidylprolyl isomerization influences the biological activity of
      antibacterial peptides of amphibian origin are presented, and its putative role
      in the defence mechanism discussed.

PMID- 15019203
TI  - In vitro and in vivo antimicrobial activity of two alpha-helical cathelicidin
      peptides and of their synthetic analogs.
AB  - Two alpha-helical antimicrobial peptides (BMAP-27 and -28) and four synthetic
      analogs were compared for in vitro and in vivo antimicrobial efficacy. All
      peptides proved active in vitro at micromolar concentrations against a range of
      clinical isolates, including antibiotic-resistant strains. BMAP-27 and two
      analogs were more effective towards Gram-negative, and BMAP-28 towards Gram
      positive organisms. In addition, BMAP-28 provided some protection in vitro
      against human herpes simplex virus type 1 (HSV-1). The parent peptides and mBMAP
      28 analog protected mice from lethal i.p. infections in an acute peritonitis
      model at peptide doses significantly lower than those toxic to the animals,
      suggesting a satisfactory therapeutic index.

PMID- 15019204
TI  - Two different propionicins produced by Propionibacterium thoenii P-127.
AB  - The bacteriocin GBZ-1 was purified from the growth media of Propionibacterium
      thoenii P-127 and was found to have a molecular weight of 6000Da. P. thoenii P
      127 also known as the producer of the bacteriocin PLG-1 (MW 10kDa). Under
      specific growth conditions, on semi-solid media, P. thoenii P-127 produced both
      PLG-1 and GBZ-1. The N-terminal of GBZ-1 was microsequenced, the gene was cloned
      and the DNA sequence was determined and identified. GBZ-1 is highly homologous to
      a protease-activated antimicrobial peptide (PAMP). In contrast to PAMP, it was
      purified in its active form and no protease digestion was required for its
      activation. The survival curve of indicator bacteria Lactobacillus delbrueckii
      subsp. lactic ATCC 4797 showed two phases. The fast phase of 20min was followed
      by a slow phase. While bacterial survival was reduced by 2logs during the fast
      phase, bacterial survival was reduced by additional 3logs up to 200min during the
      slow phase. GBZ-1 activity was affected by magnesium and its activity was
      completely abolished at 50mM magnesium chloride. Other divalent cations had no
      effect on GBZ-1 activity of GBZ-1. To the best of our knowledge this is the first
      report of a bacterium producing two different bacteriocins under different growth
      conditions.

PMID- 15019205
TI  - Susceptibility of Treponema pallidum to host-derived antimicrobial peptides.
AB  - LL-37 displays potent broad-spectrum activity against a number of pathogenic
      bacteria and is the only cathelicidin thus far identified in humans. In this
      study, we examined the capacity of human LL-37 and the similar CAP-18-derived
      peptide from rabbits to exert antimicrobial activity against the causative agent
      of syphilis, Treponema pallidum. We found that both peptides, as well as a
      truncated version of human LL-37 that contains its bactericidal domain, could
      exert rapid, but salt-sensitive antimicrobial activity against T. pallidum.
      Infectivity of T. pallidum in a rabbit model could effectively be blocked with
      the synthetic truncated LL-37-derived peptide WS22-N-amide.

PMID- 15019206
TI  - Antiendotoxin activity of protegrin analog IB-367 alone or in combination with
      piperacillin in different animal models of septic shock.
AB  - The therapeutic efficacy of protegrin peptide IB-367 was investigated in three
      rat models of septic shock: (i) rats injected intraperitoneally with 1mg
      Escherichia coli 0111:B4 lipopolysaccharide, (ii) rats given an intraperitoneal
      injection of 2 X 10(10) CFU of E. coli ATCC 25922, and (iii) rats in which intra
      abdominal sepsis was induced via cecal ligation and puncture. All animals were
      randomized to receive parenterally isotonic sodium chloride solution, 1mg/kg of
      IB-367, 60mg/kg piperacillin and 1mg/kg of IB-367 plus 60mg/kg piperacillin. The
      peptide demonstrated lower level of antimicrobial activity than piperacillin,
      nevertheless it exhibited the dual properties of antimicrobial and antiendotoxin
      agent. Finally IB-367 and piperacillin association showed to be the most
      effective therapeutic approach.

PMID- 15019207
TI  - Membrane binding and permeation by indolicidin analogs studied by a biomimetic
      lipid/polydiacetylene vesicle assay.
AB  - Membrane binding and relative penetration of indolicidin analogs were studied
      using lipid/polydiacetylene (PDA) chromatic biomimetic membranes. Colorimetric
      and fluorescence analyses determined that an indolicidin analog with a proline
      and tryptophan residue substituted with lysines showed more pronounced bilayer
      surface interactions, while indolicidin and particularly an indolicidin analog in
      which all prolines were replaced with alanine residues exhibited deeper insertion
      into the lipid bilayer. The colorimetric data demonstrated that more pronounced
      blue-red transitions were observed when the chromatic vesicles incorporated
      lipopolysaccharide (LPS) within the lipid bilayer, indicating that LPS promoted
      preferred binding and incorporation of the peptides at the lipid/water interface.
      The fluorescence quenching experiments further confirmed this outcome. The
      results indicate that the antibacterial activity of indolicidin most likely
      requires initial binding to the LPS moieties within bacterial membranes, as well
      as disruption of the bilayer interface. The degree of hemolysis induced by the
      analogs, on the other hand, correlated to the extent of penetration into the
      hydrophobic core of the lipid assembly.

PMID- 15019208
TI  - Antimicrobial polypeptides of the human colonic epithelium.
AB  - The lumen of the human colon is heavily colonized with microbes, but infections
      across its epithelial surface are infrequent. To address the hypothesis that
      antimicrobial polypeptides contribute to the barrier function of colonic
      epithelial cells, we examined cellular extracts from non-inflamed colonic mucosa
      using an antimicrobial assay. This approach yielded five polypeptides: three
      antimicrobials were previously identified as ribosomal polypeptides (L30, S19 and
      ubiquicidin), and two were members of the histone family (H1.5 and H2B). All
      exhibited bactericidal activity against Escherichia coli, and with the exception
      of S19, had been isolated by others based on their potent antimicrobial activity
      in other cells and tissues. These polypeptides normally reside inside cells and
      are proposed to contribute to the formation of the functional antimicrobial
      barrier of the colonic epithelium.

PMID- 15019209
TI  - Functional characterisation of the 1-18 fragment of esculentin-1b, an
      antimicrobial peptide from Rana esculenta.
AB  - Esculentin-1 is a 46-amino acid residue peptide isolated from skin secretions of
      Rana esculenta, displaying the most potent antimicrobial activity among the
      bioactive molecules found in the secretion, with negligible effects on eukaryotic
      cell membranes. From skin secretions, the 19-46 fragment of esculentin-1, devoid
      of antibacterial activity, was also isolated. We studied in detail the activity
      of the N-terminal fragment (1-18) of esculentin-1 using a synthetic amidated
      analogue. The results show that this fragment is highly active against most
      bacterial and fungal species, although at a lower extent than the full-length
      peptide, being four-fold more potent against Phytophthora nicotianae. It has a
      reduced activity against human erythrocytes with respect to the full-length
      peptide. The killing curves in liquid medium are similar for the two molecules
      and the shorter peptide is able to increase the bacterial outer and inner
      membrane permeability. Overall these data indicate that the antimicrobial
      properties of esculentin-1 are exerted by its N-terminal 1-18 region and that the
      positively charged residue distribution as well as peptide length represent
      important determinants for cell selectivity.

PMID- 15019210
TI  - The antibacterial peptide ceratotoxin A displays alamethicin-like behavior in
      lipid bilayers.
AB  - Ceratotoxin A (CtxA), a 36-residue alpha-helical cationic peptide isolated from
      the medfly Ceratitis capitata, exhibits strong antibacterial activity. To
      determine its mode of action against bacteria, we investigated the behavior of
      ceratotoxin A by incorporating it into planar lipid bilayers. Macroscopic and
      single channel conductance experiments showed that ceratotoxin A forms voltage
      dependent ion channels in bilayers according to the barrel-stave model. The
      characteristics of the channel suggest that the C-terminal regions form bundles
      of five or six helices embedded in the membrane, such that the N-terminal
      moieties lie on the polar side of the lipid bilayer.

PMID- 15019211
TI  - Detection of HBD1 peptide in peripheral blood mononuclear cell subpopulations by
      intracellular flow cytometry.
AB  - Production of human beta-defensin1 (HBD1) in response to LPS in monocytes,
      myeloid dendritic cells and plasmacytoid dendritic cells (PDC) was examined.
      Since PDC make up only 0.1-0.5% of the peripheral blood mononuclear cell
      population, we developed a method to determine HBD1 peptide levels using four
      color flow cytometry, which can examine several cell surface or intracellular
      markers at once. Coupled with intracellular flow cytometry, we determined that
      PDC and monocytes only made significant amounts of HBD1 when exposed to >50ng/ml
      LPS for 2h. This response was limited to monocytes when ultrapure LPS was used,
      and was inhibited in PDC by chloroquine treatment.

PMID- 15019212
TI  - Quantitative interactions between cryptdin-4 amino terminal variants and
      membranes.
AB  - Paneth cells secrete alpha-defensins into the lumen from the base of small
      intestinal crypts, and cryptdin-4 (Crp4) is the most potent mouse alpha-defensin
      in vitro. Purified recombinant Crp4 and Crp4 variants with (des-Gly)-, (Gly1Val)
      , (Gly1Asp)-, and (Gly1Arg)-substitutions were all bactericidal with Crp4 and
      (Gly1Arg)-Crp4 being slightly more active than other variants. Bactericidal
      activities correlated directly with permeabilization of live Escherichia coli,
      with equilibrium binding to E. coli membrane phospholipid bilayers and vesicles,
      and with induced graded fluorophore leakage from phospholipid vesicles. The Crp4
      peptide N-terminus affects bactericidal activity modestly, apparently by
      influencing peptide binding to phospholipid bilayers and subsequent
      permeabilization of target cell membranes.

PMID- 15019213
TI  - Prevention of lethal murine candidiasis using HP (2-20), an antimicrobial peptide
      derived from the N-terminus of Helicobacter pylori ribosomal protein L1.
AB  - Peptide HP (2-20), A(2)KKVFKRLEKLFSKIQNDK(20), is a cationic antimicrobial
      peptide derived from the N-terminus of Helicobacter pylori ribosomal protein 1,
      HpRpL1. Native peptide HP (2-20) and its synthetic derivatives have been shown in
      vitro to exhibit potent killing activity against Gram-positive, Gram-negative and
      yeast cells, thus, making them promising candidates for treatment of
      polymicrobial infections. However, the therapeutic potential of peptide HP (2-20)
      or its synthetic derivatives in any animal model of either bacterial or fungal
      diseases has not yet been investigated. In this study, we demonstrate that
      synthetic peptide amide HP (2-20), administered in six doses (300microg each; one
      intraperitoneal dose at the time of the infection, followed by five intravenous
      doses at 12h intervals) to CBA/J male mice experimentally infected with a lethal
      inoculum ( [Formula: see text] CFU) of Candida albicans, delayed the onset of
      disease, suppressed disease progression, and greatly increased survival rate and
      time (16.6% by day 14), as compared with the untreated infected control mice
      (100% mortality by day 5). Further, using isotonic buffer systems differing in
      ionic strength, peptide HP (2-20) was shown in vitro to exhibit an ionic strength
      dependent hemolytic activity, previously not detected. Repeated intravenous
      administration of uninfected control CBA/J male mice with peptide HP (2-20),
      however, caused neither morbidity nor mortality. These findings strongly evidence
      the therapeutic efficacy and safety values of peptide HP (2-20) as a lead drug
      for the treatment of acquired candidiasis.

PMID- 15019214
TI  - Activity of dermaseptin K4-S4 against foodborne pathogens.
AB  - Dermaseptin S4 and its substituted derivative K(4)-S4 were investigated against
      various food-related pathogenic bacteria in culture media. K(4)-S4, but not the
      native peptide displayed significant growth inhibitory activity against all
      bacteria tested. Next, activity of K(4)-S4 against Escherichia coli O157:H7 was
      defined in terms of milieu dependencies. Salt-dependent kinetic studies in growth
      medium indicated that the peptide's antibacterial activity is maintained at
      fairly high (up to 600mM) NaCl concentrations but inhibited at higher
      concentrations. Similarly, antibacterial activity was reduced at high but not low
      pH conditions. Importantly, antibacterial activity was significantly maintained
      at temperatures lower than 37 degrees C and significantly enhanced at 42 degrees
      C. With respect to bactericidal kinetics, negative cultures were obtained in LB
      as well as in commercial apple juice, respectively, within 1 and 2h treatment, at
      twice the minimal inhibitory concentration (MIC) value. Overall, the data
      collected is indicative of a certain interest for dermaseptin derivatives as
      potential food preservatives.

PMID- 15019216
TI  - Treatment efficacy of the lead RNAIII-inhibiting peptide YSPWTNF-NH2 in acquired
      Staphylococcus aureus sepsis: a histopathological assessment.
AB  - The quorum-sensing interfering RNAIII-inhibiting peptide (RIP) YSPXTNF and its
      synthetic analogues YSPWTNF and YSPITNF have been shown to prevent and suppress
      diseases caused by Staphylococcus aureus at different body sites in different
      animal models. This study was designed to investigate histopathologically the
      therapeutic efficacy of lead peptide RIP YSPWTNF-NH(2) in the subcutaneous air
      sac murine model of acquired S. aureus sepsis. Two experimental protocols were
      evaluated: an infection/therapy protocol, for which twenty BALB/c mice per group
      were infected with a subcutaneous inoculum of S. aureus strain ATCC 25923 (
      [Formula: see text] colony forming units) that were either pretreated or not with
      150microg of peptide RIP, and a safety protocol, for which three uninfected mice
      per group received treatment with either 150microg of peptide RIP or saline.
      Therapeutic efficacy was assessed by clinical examination for a period of 20 days
      and histopathology at 12, 24, 36, 48, 96 and 168h after inoculation. Treatment
      safety was assessed histopathologically at 24, 48 and 264h after inoculation.
      Subcutaneous administration of uninfected control mice with a single dose of
      peptide RIP YSPWTNF caused no significant histopathology in most organs examined,
      except for slight to moderate lung and liver congestions. In contrast to the
      situation with the untreated infected control group mice that presented with
      histopathological alterations consistent with the diagnosis of rapidly
      progressive and highly erosive disease (100% mortality by day 3), treatment of
      infected animals with peptide RIP YSPWTNF had a profound therapeutic effect on
      survival rate (67% by day 20) and on disease progression. The histopathological
      examination confirmed the clinical findings showing that extensive tissue damage
      at the site of the infection and in organs were greatly suppressed in the peptide
      RIP-treated animals.

PMID- 15019215
TI  - Inhibition of Staphylococcus aureus pathogenesis in vitro and in vivo by RAP
      binding peptides.
AB  - Staphylococcus aureus cause many diseases by producing toxins, whose synthesis is
      regulated by quorum-sensing mechanisms. S. aureus secretes a protein termed
      RNAIII activating protein (RAP) which autoinduces toxin production via the
      phosphorylation of is target protein TRAP. Mice vaccinated with RAP were
      protected from S. aureus infection, suggesting that RAP is an useful target for
      selecting potential therapeutic molecules to inhibit S. aureus pathogenesis. We
      show here that RAP (native and recombinant) was used to select RAP-binding
      peptides (RBPs) from a random 12-mer phage-displayed peptide library. Two RBPs
      were shown to inhibit RNAIII production in vitro (used a marker for
      pathogenesis). The peptide WPFAHWPWQYPR, which had the strongest inhibitory
      activity, was chemically synthesized and also expressed in Escherichia coli as a
      GST-fusion. Both synthetic peptide and GST-fusion peptide decreased RNAIII levels
      in a dose-dependent manner. The GST-fusion peptide was also shown to protect mice
      from a S. aureus infection in vivo (tested in a murine cutaneous S. aureus
      infection model). Our results suggest the potential use of RAP-binding proteins
      in treating clinical S. aureus infections.

PMID- 15019217
TI  - Clostridium difficile-the next step in mandatory reporting.

PMID- 15019218
TI  - Ventilation performance in operating theatres against airborne infection: review
      of research activities and practical guidance.
AB  - Surgical site infection risk due to airborne bacteria is a key area of
      consideration in developing operating theatre ventilation design and monitoring
      procedures. This paper reviews the recent extensive research into operating
      theatre ventilation development in relation to the design concepts in operating
      theatre layout, pressurization and ventilation, particularly the evolvement of
      ultra-clean ventilation. The findings that led to the current technical standards
      and the developments of microbial measurements and numerical techniques are
      discussed. Since the late 1980s, computational fluid dynamics has been a fast
      developing tool used in the prediction of room air distribution and contaminant
      dispersion. The basic principles and current practice applying to operating
      theatre ventilation studies are introduced.

PMID- 15019219
TI  - Positive-pressure isolation and the prevention of invasive aspergillosis. What is
      the evidence?
AB  - Positive-pressure ventilation implies a sealed room, usually with an anteroom to
      facilitate the donning of protective clothing, airflows of at least 12 air
      changes per hour and high-efficiency particulate air (HEPA) to prevent infection
      in susceptible patients. Laminar airflow (LAF) involves much greater air changes,
      expense and inconvenience to the patient due to noise and draughts. There are
      few, if any, truly controlled trials on the impact of positive-pressure
      ventilation and the prevention of invasive aspergillosis (IA); most are
      observational studies conducted during an outbreak or retrospective analyses of
      the incidence of IA over periods of time when a variety of preventative
      interventions were introduced. Therefore, it is often difficult to determine the
      specific impact of positive-pressure ventilation with HEPA in leading to a
      reduction in IA. During periods of hospital demolition or construction, HEPA
      significantly reduces the aspergillus spore counts and in many studies, the
      incidence of IA, but other measures such as enhanced cleaning, the sealing of
      windows and the use of prophylactic anti-fungal agents are also important. On
      balance, the additional expense and inconvenience of LAF does not appear to be
      justified. Where positive-pressure ventilation is installed, it is imperative
      that the system be monitored to ensure that the pressure differentials and air
      changes are appropriate. Whilst there is a role for positive-pressure ventilation
      in reducing the incidence of IA, we need a better definition of the importance of
      hospital-acquired IA compared with community-acquired infection and of the
      relationship between strains of Aspergillus species isolated from the environment
      and those strains causing infection.

PMID- 15019220
TI  - Investigation of an outbreak of multidrug-resistant Acinetobacter baumannii in
      trauma intensive care unit.
AB  - Between January and June 2002, an outbreak of multidrug-resistant Acinetobacter
      baumannii occurred in a trauma intensive care unit (TICU) at the Hamad Medical
      Corporation, Qatar. The outbreak involved 21 patients whose
      infection/colonization was hospital acquired. All the strains were resistant to
      all tested antibiotics except amikacin. An A. baumannii strain with a similar
      antibiogram was isolated from the environment, equipment and hands of healthcare
      workers (HCWs). The technique of open suctioning probably resulted in
      aerosilization and contamination of the immediate patient environment. This
      allowed the hands of HCWs to be contaminated with the outbreak strain, with
      subsequent transmission to other patients and their environment. Lack of proper
      hand hygiene between patients and equipment contact facilitated this
      transmission. A review of hand hygiene practices, extensive environmental
      cleaning, a closed suctioning system, education and review of other infection
      control practices, contributed to the termination of the outbreak.

PMID- 15019221
TI  - Role of environmental cleaning in controlling an outbreak of Acinetobacter
      baumannii on a neurosurgical intensive care unit.
AB  - An outbreak of Acinetobacter baumannii colonization and infection occurred in 19
      patients over a 14-month period during 1998-1999 on a neurosurgical intensive
      care unit. During efforts to control the outbreak a significant correlation was
      observed between the number of environmental isolates of A. baumannii obtained
      during each monthly screening and the number of patients with A. baumannii
      colonization/infection in the same calendar month (P < 0.004). Use of 1000 ppm
      hypochlorite solution and the introduction of new cleaning protocols reduced the
      number of environmental isolates. Failure to maintain low levels of environmental
      contamination with A. baumannii resulted in increases in patient colonization.
      This study showed that high standards of cleaning play an integral role in
      controlling outbreaks of A. baumannii in the intensive care unit setting.

PMID- 15019222
TI  - Clinical surveillance of surgical imipenem-resistant Pseudomonas aeruginosa
      infection in a Japanese hospital.
AB  - In order to elucidate any changes in imipenem-resistant Pseudomonas aeruginosa
      (IRPA) infections in Japan, we examined 511 P. aeruginosa stains isolated from
      our surgical ward between 1987 and 2001. These isolates were subjected to
      susceptibility testing against various antipseudomonal agents including imipenem,
      meropenem, ceftazidime, gentamicin and ciprofloxacin. They were serotyped with
      the slide agglutination test and genotyped using pulsed-field gel electrophoresis
      (PFGE). The annual incidences of IRPA infections were particularly high in the
      early 1990s. Epidemiological investigations revealed that these outbreaks were
      due to dissemination of hospital-acquired IRPA isolates. Intensive use of
      imipenem promoted the selection of highly resistant strains. Further study of
      resistance mechanisms revealed that none of the 110 IRPA strains were metallo
      beta-lactamase (MBL) producers. Polymerase chain reaction (PCR) analysis using
      bla(IMP) specific primers confirmed that no IMP-1 type MBL gene-positive strains
      were detected from our ward. Susceptibilities of those IRPA strains against other
      antipseudomonal agents showed relatively low levels, suggesting that imipenem
      resistance was mainly due to impermeability of the OprD porin. In conclusion,
      hospital-acquired outbreaks of IRPA were recently reduced by guidelines for, and
      surveillance of, appropriate use of antimicrobial agents. When the rate of IRPA
      isolation increases, serotyping should be performed initially and PFGE is
      required to confirm outbreaks. A computer-assisted genotyping technique is
      available to perform epidemiological studies of IRPA isolates.

PMID- 15019223
TI  - Iatrogenic meningitis after lumbar puncture-a preventable health hazard.
AB  - Iatrogenic meningitis (IM) is a rare complication of diagnostic and therapeutic
      lumbar puncture (LP). This study includes cases of IM managed in the Departments
      of Neurology, of two referral hospitals, in India between January 1984 and April
      2002. The diagnosis of IM was made when symptoms of meningitis occurred 24 h to
      21 days after LP. All the procedures were performed in the peripheral hospitals
      before they were referred to the two centres. There were 17(63%) women and
      10(37%) men. The age range was 19-50 years with a mean age of 31. The
      precipitating event was spinal anaesthesia for pelvic and intra-abdominal
      surgeries (Caesarean section 11 cases, hysterectomy three cases, herniorraphy two
      cases, appendicectomy two cases, anal fissurectomy one case, varicocelectomy one
      case and hydrocelectomy one case) laminectomy in two and diagnostic myelogram in
      four patients. The cerebrospinal fluid (CSF) culture was positive in six (22%)
      patients. The organisms were Pseudomonas aeruginosa in one case, Staphylococcus
      aureus in three cases, Acinetobacter spp. in one case and Mycobacterium
      tuberculosis in one case. In five individuals, mycotic aneurysms with
      subarachnoid haemorrhage due to invasive aspergillosis was documented at autopsy.
      The mean follow-up was 10.6 months (range 1-18). Seventeen (63%) patients
      received conventional antibiotics alone, while 10 patients received antibiotics
      and anti-tuberculous drugs when the meningitis became chronic. The mortality was
      36%. The poor prognostic factors were women who underwent Caesarean section (P <
      0.04) presence of hemiplegia (P < 0.04) and altered mental status (P < 0.0004).
      This study shows high morbidity and mortality of IM after LP. Simple aseptic
      precautions under- taken before the procedure can prevent IM. The urgent need for
      increasing the awareness among medical personnel in peripheral hospitals of
      developing countries cannot be over emphasized.

PMID- 15019225
TI  - Wound ventilation with carbon dioxide: a simple method to prevent direct airborne
      contamination during cardiac surgery?
AB  - Carbon dioxide (CO2) insufflation in the cardiothoracic wound cavity is used in
      open-heart surgery for prevention of arterial air embolism. The objective of this
      study was to investigate if CO2 insufflation may influence the rate of airborne
      contamination of the cardiothoracic wound. This was studied in a cardiothoracic
      wound cavity model that contained two 9 cm blood agar plates. Contamination rates
      were compared between a control without insufflation and insufflation with: (1) a
      thin open-ended tube or a gas-diffuser, (2) air or CO2, and (3) CO2 flows of 5 or
      10 L/min. CO2 insufflation at 5 L/min with an open-ended tube resulted in a
      contamination rate almost four times that of the control (P = 0.01), whereas with
      the gas-diffuser the contamination rate decreased (P = 0.01). With the gas
      diffuser, air insufflation at 5 L/min markedly reduced the contamination rate
      compared with the control (P < 0.001), but was less protective than CO2
      insufflation at the same flow (P < 0.001). With both gases, the contamination
      rate was particularly low close to the gas-diffuser (P < 0.001). Increasing the
      CO2 flow from 5 to 10 L/min reduced the average contamination rate in the model
      from 30% to 22% (P < 0.001) of the control. At a CO2 flow of 10 L/min the
      contamination rate within 9 cm of the gas-diffuser was 14% of the control.
      Intraoperative wound ventilation with CO2 using a gas-diffuser may not only
      prevent air embolism, but may also significantly reduce the risk of airborne
      contamination and postoperative wound infection in cardiac surgery. In contrast,
      insufflation with an open-ended tube substantially increases these risks.

PMID- 15019224
TI  - Initial stage of hospital contamination with methicillin-resistant Staphylococcus
      aureus in Lao People's Democratic Republic.
AB  - Monitoring drug-resistant Staphylococcus aureus has been carried out in Lao
      People's Democratic Republic (Lao PDR) since 1993. No methicillin-resistant S.
      aureus (MRSA) strains were detected until 2001 when two isolates were found:
      01LP40, which was coagulase type IV, enterotoxin non-productive, and SCCmec
      (staphylococcal chromosome cassette mec) type III; and 01LP63 from a different
      hospital, which was coagulase type II, enterotoxin productive, and the SCCmec
      belonged to a new type. In 2002 four MRSA isolates similar to the latter were
      detected, 02LP211, 02LP214, 02LP217 from the same hospital as 01LP63, and 02LP100
      from a third hospital. This appears to be the initial stage of a MRSA epidemic in
      Lao PDR. Careful monitoring and intensive monitoring and precautions are
      recommended.

PMID- 15019226
TI  - Hand hygiene and aseptic technique in the emergency department.
AB  - Hand hygiene and simple aseptic measures before invasive procedures are effective
      in reducing rates of healthcare-associated infection. The perceived urgency of a
      clinical situation in the emergency department, however, may influence medical
      staff's compliance with good practice in infection control. The aims of this
      prospective, single-blinded, observational study were twofold. First, to assess
      doctors' compliance with good practice in hand hygiene between patient episodes
      and asepsis during invasive procedures in the emergency department. Second, to
      assess the effect of clinical urgency on compliance with good practice in hand
      hygiene and asepsis during invasive procedures. Good practice standards for
      asepsis in invasive procedures and hand hygiene between patient episodes were
      compiled from a literature search. Doctors' compliance with these standards was
      observed in two emergency departments (UK and New Zealand). Observed clinical
      cases were classified as immediate, urgent and non-urgent based on the triage
      system. There was poor compliance with good practice guidelines for asepsis in
      invasive procedures in both centres. Staff achieved high compliance with the
      guidelines in only 27% of cases in the UK and 58% of cases in New Zealand.
      Clinical urgency did not appear to adversely affect compliance with aseptic good
      practice. Hand hygiene between patient consultations was very low at 14% in the
      UK and 12% in New Zealand. Asepsis and hand hygiene was poor in both the UK and
      New Zealand emergency departments. There may be a need for some compromise in
      standards of asepsis in very sick patients due to the urgency of the clinical
      situation. Compliance in all situations especially non-urgent procedures needs to
      be improved.

PMID- 15019227
TI  - Hospital-acquired infections in Italy: a region wide prevalence study.
AB  - Between October and December 2000, a region-wide prevalence study of hospital
      acquired infections (HAI) was conducted in all public hospitals (59 facilities
      with ca. 16000 beds; 560000 admission yearly) in Piemonte Region, Italy, and in
      the one hospital of the neighbouring autonomous region of Valle d'Aosta. The
      study population comprised a total of 9467 patients hospitalized for at least 24
      h. The prevalence of HAI was 7.84%, with marked differences in prevalence among
      the participating hospitals (range: 0-47.8%). The higher relative frequency of
      urinary tract infections (UTI; 52.7%) was due to the inclusion of urine cultures
      obtained on the day of the study from asymptomatic UTI in catheterized patients.
      A significant correlation was found with major risk factors related to medical
      procedures (urinary catheter, mechanical ventilation, surgical drainage,
      intravascular catheters). Patients with HAI were found to be older and to have a
      greater mean length of stay in hospital. Multiple logistic regression analyses
      showed that lack of independence, indwelling urinary catheter and mechanical
      ventilation were the risk factors more significantly associated with HAI. The use
      of antibiotics, in particular prophylactic agents used in surgery
      (cephalosporins, glycopeptides), provided an incentive for corrective
      intervention in antibiotic administration and in training of healthcare workers.

PMID- 15019228
TI  - Three scenarios of clinical claim reimbursement for nosocomial infection: the
      good, the bad, and the ugly.
AB  - We studied the extent to which hospitals can expect to receive reimbursement for
      costs relating to nosocomial infections (NI) under the diagnosis-related groups
      (DRG) system of clinical claims and calculated the loss of reimbursement due to
      missed or incorrect registration of infective complications on hospital discharge
      records (HDR). We calculated clinical claim reimbursement in three scenarios: the
      good, in which all NI are recorded on HDR; the bad, in which a proportion of NI
      recorded on HDR observed at the 41 participating hospitals; the ugly, in which
      none of the NI are recorded on HDR. We analysed in which patients the recording
      of infective complications changed the DRG clinical claim and the economic
      consequences on reimbursements. Compared with the ugly scenario, the bad
      scenario, which is closest to what actually occurs, with only 55.9% of NI
      (180/322) properly recorded, produced an increased DRG clinical claim in 30
      cases, of on average 403 for every NI. Compared with the ugly scenario, the good
      scenario, produced an increased DRG clinical claim in 45 cases with an average
      reimbursement of 618. The difference between the bad and the good scenarios shows
      an average loss of 215 for every case. Our calculated good scenario could cover
      only 3.8% of direct costs per case attributable to NI. Real, tangible benefits in
      health, both social and economic, will only accrue from the monitoring and
      control of NI in hospitals.

PMID- 15019229
TI  - Effectiveness of topical chlorhexidine powder as an alternative to
      hexachlorophane for the control of Staphylococcus aureus in neonates.
AB  - We routinely phage-type Staphylococcus aureus isolates from high-risk inpatients
      each week. This surveillance approach previously identified a five-year outbreak
      of a methicillin-susceptible S. aureus strain (MSSA, PT 53,85), which affected
      202 babies on a regional neonatal unit. We previously reported this outbreak and
      the multiple staged infection control measures that were required to end it.
      These included strict emphasis on hand hygiene, environmental and staff
      surveillance sampling, application of topical triclosan solution and
      hexachlorophane powder, aseptic handling of a skin protectant material, and use
      of topical mupirocin for staff nasal carriers of the endemic MSSA strain and for
      babies colonized or infected with S. aureus. In summer 2000 topical
      hexachlorophane powder became unavailable and we therefore substituted topical 1%
      chlorhexidine powder as part of routine umbilical decontamination. We have
      continued prospective S. aureus surveillance for the past five years to monitor
      the effect of this practice change. We observed a continued decline in the
      numbers of monthly MSSA isolates from neonatal unit babies. Since the
      substitution of chlorhexidine for hexachlorophane, the median monthly number of
      MRSA isolates has been 0.5 (range 0-4). Only sporadic S. aureus PT 53,85 isolates
      were recovered. Control of S. aureus in our regional neonatal unit, in particular
      an endemic MSSA strain, was maintained when topical umbilical hexachlorophane
      powder was substituted with 1% chlorhexidine powder.

PMID- 15019230
TI  - Preoperative screening of elective orthopaedic patients for MRSA.

PMID- 15019231
TI  - Restricting the use of ampicillin-sulbactam.

PMID- 15019232
TI  - Re: Marchetti MG, Finzi G, Cugini P, Manfrini M, Salvatorelli G. Hospital use of
      decontaminating mats. J Hosp Infect 2003;55:68-72.

PMID- 15019233
TI  - Biological significance of the U residue at the -3 position of the mRNA sequences
      of influenza A viral segments PB1 and NA.
AB  - The levels of viral proteins in infected cells are thought to be regulated by a
      variety of mechanisms. The initiation codons for the PB1 and NA proteins of
      A/WSN/33 (H1N1) influenza virus are in a suboptimal Kozak sequence for
      translation. To determine the significance of these suboptimal Kozak sequences,
      model vRNAs, whose coding regions were replaced with the reporter SEAP gene (for
      secreted alkaline phosphatase) and recombinant viruses with optimal Kozak
      sequences for PB1 and NA were constructed. Conversion of the upstream sequence of
      the PB1 and NA initiation codon to an optimal Kozak sequence was reflected in the
      level of reporter protein expression, but not the level of PB1 and NA protein
      expression. The recombinant viruses that had optimal Kozak sequences for PB1, NA,
      or both genes had similar replicative properties, both in cell culture and in
      mice, to those of the wild-type virus. These results suggest that expression of
      the PB1 and NA proteins is regulated by a mechanism other than that controlling
      the initiation of translation of these proteins.

PMID- 15019234
TI  - Alternate circulation of recent equine-2 influenza viruses (H3N8) from two
      distinct lineages in the United States.
AB  - Phylogenetic and antigenic analyses indicate that recent circulating equine-2
      influenza viruses in the United States have been alternating between two genetic
      and antigenic distinct lineages since 1996. The evolution rates for these two
      lineages, the Kentucky and the Florida lineage, are very similar. For the earlier
      isolates in the Kentucky lineage, there are multiple and sequential nonsynonymous
      substitutions at antigenic sites B and D. However, there are no changes at any of
      these antigenic sites for KY98 and OK00. In the Florida lineage, except for NY99
      with one amino acid substitution at antigenic site B, viruses in this lineage do
      not have nonsynonymous substitutions at any of the antigenic sites. The lack of
      amino acid substitutions at these antigenic sites suggests a mechanism other than
      immune selection is responsible for the maintenance of these viral lineages.
      Serological analysis indicates that these two lineages are antigenic distinct,
      and the pattern of reactivity of horse sera towards these two lineages alternates
      in consecutive years, parallel to the "switching" of virus lineage seen in the
      phylogenetic tree. This alternate circulation may play a role in the maintenance
      of these two lineages of equine-2 influenza virus.

PMID- 15019235
TI  - Molecular characterization of noroviruses detected in diarrheic stools of
      Michigan and Wisconsin dairy calves: circulation of two distinct subgroups.
AB  - Noroviruses have emerged as the leading worldwide cause of acute non-bacterial
      gastroenteritis in humans. The presence of noroviruses in diarrheic stool samples
      from calves on Michigan and Wisconsin dairy farms was investigated by RT-PCR.
      Norovirus-positive samples were found on all eight farms studied in Michigan and
      on 2 out of 14 farms in Wisconsin. Phylogenetic analyses of partial polymerase
      and capsid sequences, derived for a subset of these bovine noroviruses, showed
      that these strains formed a group which is genetically distinct from the human
      noroviruses, but more closely related to genogroup I than to genogroup II human
      noroviruses. Examination of 2 full and 10 additional partial capsid (ORF2)
      sequences of these bovine strains revealed the presence of two genetic subgroups
      or clusters of bovine noroviruses circulating on Michigan and Wisconsin farms.
      One subgroup is "Jena-like", the other "Newbury agent-2-like".

PMID- 15019236
TI  - Characterization and phylogenetic analysis of the chitinase gene from the
      Helicoverpa armigera single nucleocapsid nucleopolyhedrovirus.
AB  - A putative chitinase gene was identified within the fragment EcoRI-K of the
      Helicoverpa armigera single-nucleocapsid nucleopolyhedrovirus (HearNPV, also
      called HaSNPV) genome. The open reading frame (ORF) contains 1713 nucleotides
      (nt) and encodes a protein of 570 amino acids (aa) with a predicted molecular
      weight of 63.6 kDa. Transcription started at about 18 h post infection (p.i.) and
      the protein was first detected at 20 h p.i. The times of transcription and
      expression are characteristic of a late baculovirus gene. 5' and 3' RACE
      indicated that transcription was initiated from the adenine residue located at 
      246 nt upstream from the ATG start site and the poly (A) tail was added at 267 nt
      downstream from the stop codon. This is the first report on the molecular
      characterization of a chitinase from a single nucleocapsid NPV. The phylogeny of
      baculoviral chitinase genes were extensively examined in comparison with
      chitinases derived from bacteria, fungi, nematode, actinomycetes, viruses,
      insects and mammals. Neighbor-joining and most parsimony analyses showed that the
      baculoviral chitinases were clustered exclusively within gamma-proteobacteria.
      Our results strongly suggest that baculoviruses acquired their chitinase genes
      from bacteria.

PMID- 15019237
TI  - Comparisons of envelope through 5B sequences of infectious bronchitis
      coronaviruses indicates recombination occurs in the envelope and membrane genes.
AB  - A 1.78 kb sequence, including the E, M, 5a and 5b genes, and the intergenic
      region between the M and 5a genes, of six US strains of infectious bronchitis
      (corona)virus (IBV) were sequenced and compared to the published sequences for
      two additional strains. The overall identities as determined through pairwise
      analyses of nucleotide sequences of the entire 1.78kb region ranged from 90 to
      99%, with the 5b open reading frame (ORF) having the greatest identity (94-99%)
      while the identities of the E, 5a and M ORFs ranged from 87 to 100%. Nucleotide
      sequencing of recent field isolates from Alabama (Ala1) and California (Cal3)
      revealed distinct shifts in homology in the M gene, indicating two apparent
      recombination events between the Holland 52/Mass41-like strain and an Ark-like
      strain, both origins of commonly used vaccine strains. Putative sites of
      recombination could also be identified in both the E and M ORFs of laboratory
      strains of IBV.

PMID- 15019238
TI  - An internal element of the measles virus antigenome promoter modulates
      replication efficiency.
AB  - The cis-acting sequence elements that direct measles virus (MV) genome synthesis
      reside in the 109 base non-coding region at the 5' trailer (3' antigenomic) end
      of MV genome that makes up the antigenomic promoter (AGP). The MV-AGP nucleotides
      79-96, corresponding to nucleotide hexamers 14, 15 and 16 (the C' element), show
      sequence similarity with the equivalent region of many paramyxoviruses and are
      analogous to the three nucleotide hexamers that form the second replication
      control element in the Sendai virus AGP. In this study, results of two
      independent procedures demonstrate that the MV C' element also is a replication
      control sequence. Results of in vivo nucleotide selection experiments show that
      selection pressure for retaining the wild type nucleotides at the first position
      of each of the three hexamers, and for the fifth position of the 14th hexamer was
      relatively high. However, with continued replication, preference for the
      conservation of wild type nucleotides across the entire C' element was clearly
      evident. Results of mutational analysis of individual nucleotides in one or more
      hexamers in a measles-helper-virus driven reporter gene rescue system agreed with
      these results. Substitutions at the first position of the 14th, the 15th or the
      16th hexamers reduced minireplicon activity dramatically. In contrast, changes at
      the other five positions of any one hexamer had little or no effect on
      minireplicon activity, even when all the five bases were changed at the same
      time. However, when minireplicons were analyzed which contained point mutations
      at equivalent positions in all three hexamers, it was evident that the
      nucleotides, particularly those at the 5th position, were also important
      components of the C' element. This pattern of sequence requirement in the C'
      element based on mutational analysis could be described as a distinct motif, 5'
      (GNNNAN)2GNNNCN-3', that is important for MV replication.

PMID- 15019239
TI  - Sequence requirements for the development of a chimeric HCV replicon system.
AB  - The hepatitis C virus (HCV) 3'nontranslated region (3'NTR) is important for virus
      infection and replicon replication. Here, we constructed a panel of chimera
      replicons containing non-structural (NS) and 3'NTR sequences from different HCV
      strains or types, and examined the requirements for stable replication. A
      subgenomic replicon chimera comprising the polymerase and 3'NTR from HCV strain
      Con1, and other non-structural genes from type 1a strain H77, supported stable
      colony formation and replication in Huh7 cells. However, extending the type 1a
      sequence to include 132 amino acids of NS5B resulted in a defective HCV replicon.
      In contrast, a similar chimera containing HCV strain J4 sequences linked in cis
      to Con1 NS5B and 3'NTR supported stable replication suggesting that the
      interaction between the NS proteins and the 3'NTR may represent a critical
      determinant. Lastly, the type 1a 3'NTR from pCV-J4L6S was unable to confer
      replication when paired with non-structural coding sequences from BB7 or J4 and
      the 3'NTR from Con1 was unable to confer replication when paired with J4 or H77
      sequences. These results highlighted the importance of sequence specific
      interaction among 3'NTR and two distinct subdomains of the NS coding region as a
      determinant in supporting stable replication of subgenomic replicons. The results
      underscore the importance of directly cloning 3'NTR sequences from relevant
      clinical samples.

PMID- 15019240
TI  - Prevalence of SEN virus among children in Japan.
AB  - Recently, a novel deoxyribonucleic acid (DNA) virus, designated SEN virus (SENV),
      was discovered and strong associations between the two SENV variants (SENV-D and
      SENV-H) and non-A to E hepatitis were reported. To clarify the character of SENV
      infection in children, we investigated the detection rates of serum SENV DNA by
      polymerase chain reaction (PCR) among children with non-A to C hepatitis, with
      histories of transfusions, with neither histories of transfusions nor liver
      diseases (control), and among pregnant women. SENV-D was detected in 60% of
      fulminant hepatitis, 5% of acute hepatitis, 11% of chronic hepatitis, 13% of
      controls, and 15% of pregnant women. SENV-H was detected in none of fulminant
      hepatitis, 5% of acute hepatitis, none of chronic hepatitis, 2% of controls, and
      12% of pregnant women. No significant difference was found for SENV-D between
      acute or chronic hepatitis and controls, however SENV-D detection rate in
      fulminant hepatitis was significantly higher than that in controls (P < 0.05). No
      significant difference was found for SENV-H between any hepatitis and controls,
      however SENV-H detection rate in pregnant women was significantly higher than
      that in controls (P < 0.05). Neither SENV-D nor SENV-H was associated with acute
      or chronic hepatitis; however, SENV-D might be a risk factor of fulminant
      hepatitis.

PMID- 15019241
TI  - Heterogeneity in Nsp2 of European-like porcine reproductive and respiratory
      syndrome viruses isolated in the United States.
AB  - Recently, isolates of porcine reproductive and respiratory syndrome virus (PRRSV)
      that possess nucleotide sequences similar to European isolates have been reported
      in United States herds. The origin, diversity and prevalence of European-like
      North American PRRSV isolates in the U.S. remain unknown. Nucleotide sequence
      analysis of the 12kb ORF1 of a North American isolate, SDPRRS 01-08 (01-08),
      showed 93.7% identity with Lelystad virus (LV), the prototypic European isolate,
      but only 58% identity with VR-2332, the prototypic North American isolate.
      Comparisons between LV and 01-08 at the peptide sequence level of the predicted
      non-structural proteins (Nsp) showed that Nsp9 (98.9% amino acid identity) was
      the most conserved and the least conserved was Nsp2 at 90.6% identity. For the
      purpose of comparison, GP5, the principal envelope structural protein, showed a
      93.5% identity between 01-08 and LV. The most dramatic differences between the
      Nsp2 proteins of LV and 01-08 were a single 17 amino acid deletion between
      residues 734 and 750, as well as several amino acid differences. The same
      deletion was identified in the Nsp2 in five of seven other EuroPRRSV isolates
      submitted to the South Dakota Animal Disease Research and Diagnostic Laboratory.
      The remaining two isolates contained small deletions, but in other regions of
      Nsp2. Peptide sequence diversity in the form of hypervariability and deletions in
      Nsp2 demonstrate that European-like PRRSV isolates in the USA represent a
      heterogeneous group. Furthermore, areas in Nsp2 with deletions and amino acid
      hypervariability localize to regions that are predicted to be immunologically
      important.

PMID- 15019242
TI  - Receptor specificity of H5 influenza virus escape mutants.
AB  - The binding of viruses to synthetic polyacrylamide (PAA)-based
      sialylglycoconjugates was used to characterize the receptor specificities of
      antibody escape mutants of the influenza virus A/Mallard/Pennsylvania/10218/84
      (H5N2). The sialylglycoconjugates that were used carried identical terminal
      Neu5Acalpha2-3Gal moieties but differed in the structure of the next saccharide
      residue(s). Our data show that mutations in the vicinity of the haemagglutinin
      (HA) receptor-binding site (RBS) effect the recognition of the third saccharide
      residue and change the affinity pattern of binding. The affinity of the majority
      of the escape mutants for sialyl receptors increased compared to the parental
      strain.

PMID- 15019243
TI  - Detection and localization of avian alphaherpesviruses in embryonic tissues
      following in ovo exposure.
AB  - We investigated whether chicken embryonic tissues are susceptible to infection
      with virulent Marek's disease virus (MDV). Groups of embryonic day (ED) 17
      chicken embryos and 1-day-old chicks were compared for tissue sites of viral
      persistence of MDV and herpesvirus of turkeys (HVT) in lungs, thymuses, bursae of
      Fabricius and spleens. MDV DNA was detectable in the lungs and thymuses of
      embryos at 3 days post-inoculation (DPI) by in situ hybridization, while HVT DNA
      was only present in embryonic lungs. The target cells in lungs and thymuses
      appeared non-lymphoid and lymphoid, respectively. By 5 days post-inoculation,
      both viruses were detectable in all organs examined and persisted after hatch.
      Although MDV DNA was present in the embryo, there was little evidence of viral
      replication. These findings demonstrate the differences in pathogenesis of
      embryonic infection with MDV and HVT and provide evidence that the chicken embryo
      is susceptible to infection with a virulent avian herpesvirus.

PMID- 15019244
TI  - Characterization of the Lassa virus matrix protein Z: electron microscopic study
      of virus-like particles and interaction with the nucleoprotein (NP).
AB  - Lassa virus is the causative agent of a hemorrhagic fever endemic in west Africa.
      The RNA genome of Lassa virus encodes the glycoprotein precursor GP-C, a
      nucleoprotein (NP), the viral polymerase L and a small protein Z (11 kDa). Here,
      we analyze the role of Z protein for virus maturation. We have recently shown
      that expression of Z protein in the absence of other viral proteins is sufficient
      for the release of enveloped Z-containing particles. In this study, we examined
      particles secreted into the supernatant of a stably Z protein-expressing CHO cell
      line by electron microscopy. The observed Z-induced virus-like particles did not
      significantly differ in their morphology and size from Lassa virus particles.
      Mutation of two proline-rich domains within Z which are known to drastically
      reduce the release of virus-like particles, had no effect on the cellular
      localization of the protein nor on its membrane-association. Furthermore, we
      present evidence that Z interacts with the NP. We assume that Z recruits NP to
      cellular membranes where virus assembly takes place. We conclude from our data
      that Lassa virus Z protein plays an essential role in Lassa virus maturation.

PMID- 15019245
TI  - Recombinant avian adenovirus CELO expressing the human interleukin-2:
      characterization in vitro, in ovo and in vivo.
AB  - In our study, a recombinant adenovirus based on the avian adenovirus CELO genome,
      has been constructed that contains the human interleukin-2 gene. We have shown
      the production of biologically active recombinant interleukin-2 in vitro (LMH and
      293 cells) and in ovo (chicken embryos) infected with recombinant virus CELO-IL2.
      An increase in the median survival time of C57BL/6 mice carrying B16 melanoma
      tumors has been demonstrated after multiple intra-tumors injections of the
      recombinant adenovirus CELO-IL2.

PMID- 15019246
TI  - Use of multi-photon laser-scanning microscopy to describe the distribution of
      xenobiotic chemicals in fish early life stages.
AB  - To better understand the mechanisms by which persistent bioaccumulative toxicants
      (PBTs) produce toxicity during fish early life stages (ELS), dose-response
      relationships need to be understood in relation to the dynamic distribution of
      chemicals in sensitive tissues. In this study, a multi-photon laser scanning
      microscope (MPLSM) was used to determine the multi-photon excitation spectra of
      several polyaromatic hydrocarbons (PAHs) and to describe chemical distribution
      among tissues during fish ELS. The multi-photon excitation spectra revealed
      intense fluorescent signal from the model fluorophore, pentamethyl-difluoro-boro
      indacene (BODIPY), less signal from benzo[a]pyrene and fluoranthene, and no
      detectable signal from pyrene. The imaging method was tested by exposing newly
      fertilized medaka (Oryzias latipes) eggs to BODIPY or fluoranthene for 6 h,
      followed by transfer to clean media. Embryos and larvae were then imaged through
      5 days post-hatch. The two test chemicals partitioned similarly throughout
      development and differences in fluorescence intensity among tissues were evident
      to a depth of several hundred microns. Initially, the most intense signal was
      observed in the oil droplet within the yolk, while a moderate signal was seen in
      the portion of the yolk containing the yolk-platelets. As embryonic development
      progressed, the liver biliary system, gall bladder, and intestinal tract
      accumulated strong fluorescent signal. After hatch, once the gastrointestinal
      tract was completely developed, most of the fluorescent signal was cleared. The
      MPLSM is a useful tool to describe the tissue distribution of fluorescent PBTs
      during fish ELS.

PMID- 15019247
TI  - A comparative assessment of the adrenotoxic effects of cadmium in two teleost
      species, rainbow trout, Oncorhynchus mykiss, and yellow perch, Perca flavescens.
AB  - Rainbow trout (Oncorhynchus mykiss) and yellow perch (Perca flavescens) have a
      different sensitivity to cadmium (Cd) in vivo (trout < LC50 < perch). Metals and
      particularly Cd impair cortisol secretion by adrenocortical cells in both
      species. The purpose of the present study was to assess in vitro the effect of Cd
      on cortisol secretion by adrenocortical cells of trout and perch, to compare the
      sensitivity of adrenal steroidogenesis in these two teleosts. Adrenocortical
      cells were exposed to Cd for 60 min, then stimulated with ACTH, dbcAMP or with
      pregnenolone, a cortisol precursor. Cd inhibited ACTH-stimulated cortisol
      secretion in a dose-dependent manner in both fish species, however, the EC50s
      (concentration resulting in 50% inhibition of cortisol secretion) was
      significantly lower in trout (EC50 = 0.09 mM) than perch (EC50 = 0.26 mM). To
      test the specificity of Cd to act as an endocrine disrupter, the LC50
      (concentration that kills 50% of the cells) was also evaluated to determine the
      LC50/EC50 ratio ( LC50/EC50(O.mykiss) = 175.6 > LC50/EC50(P.flavescens) = 37.7).
      Adrenocortical cells of trout were more sensitive than those of perch and Cd had
      a higher endocrine-disrupting potential and specificity in trout than in perch.
      However, in both species, Cd had the same effect on ACTH, dbcAMP and pregnenolone
      stimulated cortisol secretion, with pregnenolone maintaining cortisol secretion
      until cell viability was impaired. These results confirm that for both species,
      Cd interferes in the signalling pathway of cortisol synthesis in a step prior to
      the pregnenolone formation. Data provided by the present study revealed important
      differences in vulnerability of adrenal steroidogenesis between rainbow trout and
      yellow perch.

PMID- 15019248
TI  - Application of an immunoperoxidase staining method for detection of 7,8-dihydro-8
      oxodeoxyguanosine as a biomarker of chemical-induced oxidative stress in marine
      organisms.
AB  - 7,8-Dihydro-8-oxodeoxyguanosine (8-oxo-dG) is a typical modification of DNA
      caused by oxygen free radicals and can be an useful biomarker for pollutants
      inducing oxidative stress. An immunoperoxidase method using monoclonal antibody
      1F7 toward 8-oxo-dG was applied to tissues and smeared cells of marine organisms
      for detection and quantification of oxidative DNA damage in such models. The
      assay, previously employed on human cells, was assessed for the first time on
      Mediterranean mussels (Mytilus galloprovincialis) and European eels (Anguilla
      anguilla), exposed to model pro-oxidant chemicals, namely benzo[a]pyrene (B[a]P)
      and copper. Quantification of 8-oxo-dG was microscopically carried out and
      expressed as relative nuclear staining intensity. Higher levels of oxidative DNA
      damage were detected in the digestive glands of treated mussels compared to
      controls, while the effect was less pronounced in haemocytes, characterized by
      more elevated basal levels of 8-oxo-dG. The assay was suitable for detection of 8
      oxo-dG also in fish liver sections indicating consistent damage after B[a]P
      exposure. The main advantage of the immunohistochemical approach is the
      elimination of DNA extraction which considerably reduces the processing of
      biological samples. In addition, the assay requires small amounts of frozen
      tissues or fixed cells for detection of 8-oxo-dG and is potentially able to
      discriminate variable susceptibility to oxidative stress in different cell types.
      Although further investigations are required for the improvement and the
      validation of the assay in field conditions, laboratory exposures provided useful
      indications on the consistency of the approach and the efficacy of antibody 1F7
      in marine organisms for a rapid assessment of pollutant-induced oxidative DNA
      damage.

PMID- 15019249
TI  - Effects of agricultural pesticides on the immune system of Xenopus laevis and
      Rana pipiens.
AB  - Over the last 30 years, there have been mass declines in diverse geographic
      locations among amphibian populations. Multiple causes have been suggested to
      explain this decline. Among these, environmental pollution is gaining attention.
      Indeed, some chemicals of environmental concern are known to alter the immune
      system. Given that amphibians are frequently exposed to agricultural pesticides,
      it is possible that these pollutants alter their immune system and render them
      more susceptible to different pathogens. In this study, we exposed two frog
      species, Xenopus laevis and Rana pipiens, for a short period of time to a mixture
      of pesticides (atrazine, metribuzine, endosulfan, lindane, aldicarb and dieldrin)
      representative in terms of composition and concentrations to what it is found in
      the environment of the southwest region of the province of Quebec. The pesticides
      were known to be present in surface water of many tributaries of the St. Lawrence
      River (Quebec, Canada). Our results demonstrate that the mixture of pesticides
      could alter the cellularity and phagocytic activity of X. laevis and the
      lymphocyte proliferation of R. pipiens. Taken together, these results indicate
      that agricultural pesticides can alter some aspects of the immune response in
      frogs and could contribute to their global decline by rendering them more
      susceptible to certain infections.

PMID- 15019250
TI  - Acetylcholinesterase inhibition as a biomarker of adverse effect. A study of
      Mytilus edulis exposed to the priority pollutant chlorfenvinphos.
AB  - The inhibition of acetylcholinesterase (AChE) activity has been used widely as a
      biomarker of exposure to organophosphorous pesticides (OPs). However, scientific
      uncertainty about the risk assessment implications of data describing inhibition
      of cholinesterases in diverse species and tissues has hampered the use of AChE
      activity as a biomarker of adverse effect. Here, haemolymph AChE activity was
      combined with biomarkers of cellular integrity, immunotoxicity and physiological
      status in order to measure exposure to and the effects of the priority pollutant
      chlorfenvinphos. Laboratory exposures of the blue mussel Mytilus edulis to
      commercial grade chlorfenvinphos (Sapecron) were conducted over 24, 48 and 96 h.
      AChE activity in haemolymph of M. edulis was highly variable and bore no
      relationship to either sublethal effects or lethality over the range 0.003-0.03
      mg/l chlorfenvinphos. In comparison, concentration dependent inhibition was
      evident for each of the remaining biomarkers (phagocytic activity, spontaneous
      cytotoxicity, neutral red retention time, total haemolymph protein). Mussels at
      the highest exposure concentration showed visual signs of neurotoxicity (impaired
      neuromuscular control). Haemocyte phagocytic activity and spontaneous
      cytotoxicity responses were highly sensitive to chlorfenvinphos with significant
      modulation evident after 24 h exposure to environmentally realistic
      concentrations of 0.007 mg/l (P = 0.0003). Thus the immune function and well
      being of the mussels was significantly impacted in the absence of measurable
      inhibition of haemolymph AChE.

PMID- 15019251
TI  - A protective effect of dietary calcium against acute waterborne cadmium uptake in
      rainbow trout.
AB  - The present study examined the interactions between elevated dietary calcium (as
      ionic Ca2+ in the form of CaCl2 x 2H2O) and acute waterborne Cd exposure (50
      microg/l as CdNO3 for 3 h) on whole body uptake and internal distribution of
      newly accumulated Cd, Ca2+, and Na+ in juvenile rainbow trout (Oncorhynchus
      mykiss). Fish were fed with three diets 20 (control), 30 and 60 mg Ca2+/g food:
      for 7 days before fluxes were measured with radiotracers over a 3h period. The
      two elevated Ca2+ diets reduced the whole body uptake of both Ca2+ and Cd by >50%
      and similarly reduced the internalization of both newly accumulated metals in
      most tissues, effects which reflect the shared branchial uptake route for Ca2+
      and Cd. As the Ca2+ concentrations of the fluid phases of the stomach and
      intestinal contents were greatly elevated by the experimental diets, increased
      gastrointestinal Ca2+ uptake likely caused the down-regulation of the branchial
      Ca2+ (and Cd) uptake pathway. Waterborne Na+ uptake and internal distribution
      were not affected. While plasma Ca2+ surged after the first two feedings of the
      60 mg Ca2+/g diet, internal homeostasis was quickly restored. Total Ca2+, Na+,
      and Cl- levels in tissues were not affected by diets. While dietary Ca2+
      protected against waterborne Cd uptake, it did not protect against the relative
      inhibition of waterborne Ca2+ uptake caused by waterborne Cd. Acute exposure to
      50 microg/l Cd reduced the uptake and internalization of newly accumulated Ca2+
      (but not Na+) by 70% or more, regardless of diet. Since elevated dietary Ca2+
      reduces waterborne Cd uptake, fish eating a Ca(2+)-rich invertebrate diet may be
      more protected against waterborne Cd toxicity in a field situation.

PMID- 15019252
TI  - Altered thyroid status in lake trout (Salvelinus namaycush) exposed to co-planar
      3,3',4,4',5-pentachlorobiphenyl.
AB  - Recent studies indicate that co-planar 3,3',4,4',5-pentachlorobiphenyl (PCB)
      congeners or their metabolites may disrupt thyroid function in fishes. Although
      co-planar PCB have been detected at microgram per kilogram levels in fish from
      contaminated areas, few studies have examined mechanisms whereby, co-planar PCBs
      may alter thyroid function in fish. We treated immature lake trout by
      intraperitoneal (i.p.)-injection or dietary gavage with vehicle containing 0,
      0.7, 1.2, 25 or 40 microg 3,3',4,4',5-pentachlorobiphenyl (PCB 126) per kgBW.
      Blood and tissue samples were collected at various times up to 61 weeks following
      exposure. The treatments produced sustained dose-dependent elevations of tissue
      (PCB 126) concentrations. Thyroid epithelial cell height (TECH), plasma thyroxine
      (T4) and 3,3',5-triiodo-l-thyronine (T3) concentrations, hepatic 5'
      monodeiodinase, hepatic glucuronidation of T4 and T3, as well as plasma T4
      kinetics and fish growth were analyzed. Exposure to the highest doses of PCB 126
      caused increased TECH, plasma T4 dynamics and T4-glucuronidation (T4-G). PCB 126
      did not affect 5'-monodeiodinase and T3-glucuronidation (T3-G) and there were no
      effects on fish growth or condition. Because T3 status and growth were
      unaffected, the thyroid system was able to compensate for the alterations caused
      by the PCB 126 exposure. It is clear that concentrations of co-planar PCBs
      similar to those found in predatory fish from contaminated areas in the Great
      Lakes are capable of enhancing metabolism of T4. These changes may be of
      significance when T4 requirements are high for other reasons (e.g. periods of
      rapid growth, warm temperatures, metamorphosis, and parr-smolt transformation).

PMID- 15019253
TI  - Quantitative inter-specific chemical activity relationships of pesticides in the
      aquatic environment.
AB  - Inter-species correlations could be a useful tool for predicting toxicity and for
      establishing sensitivity ratios among species. In this paper, quantitative inter
      specific chemical activity relationships (QICAR) for aquatic organisms were
      developed to verify if such an approach could be utilised for estimating
      toxicological data when no other information is available. Inter-specific
      toxicity relationships on fish, Daphnia and algae were performed for pesticides
      considering a large data set (more than 600 compounds) and grouping the data
      either on a functional (herbicides, fungicides and insecticides) or chemical
      class base. Good correlations were found between several fish species and they
      were improved by excluding, from the data set, highly specific compounds such as
      organophosphorus insecticides. Relationship between fish (rainbow trout) and
      Daphnia was significant for the whole data set, but clearly improves if
      congeneric classes of pesticides are considered. The most significant results
      were found for azoles (fungicides) and for all data set of pesticides with the
      exclusion of organophosphorus and carbamate insecticides. As expected, toxicity
      on algae does not correlate either with fish or with Daphnia on the whole data
      set, but excluding the classes acting specifically toward one organism
      (insecticides and several classes of herbicides), good relationships were found.
      The analysis of the data permits the conclusion that the specificity in the mode
      action of pesticides is the key parameter for expecting or not inter-specific
      relationships. By the relative specificity of action of a group of compounds
      towards two species, the probability of obtaining a QICAR for this group can be
      derived. In general, compounds acting with the same level of specificity towards
      two different species, have a higher probability of showing inter-specific
      relationships and the lower the specificity of the mode of action of the
      compounds (e.g. narcotics or less inert chemicals), then the stronger are the
      relationships.

PMID- 15019254
TI  - Development of a qualitative indirect ELISA for the measurement of rabies virus
      specific antibodies from vaccinated dogs and cats.
AB  - A protocol suitable for the detection of rabies virus-specific antibodies in
      serum samples from companion animals using an enzyme linked immunosorbent assay
      (ELISA) is described. This method has been used successfully for the qualitative
      assessment of rabies virus-specific antibodies in serum samples from a cohort of
      vaccinated dogs and cats. In two initial field studies, a variable population of
      field samples from the Veterinary Laboratories Agency (VLA), United Kingdom were
      tested. In the first study (n = 1000), the number of false-positive and false
      negative results was 11 samples (1.1%) and 67 samples (6.7%), respectively. In
      the second study (n = 920), the number of false-positive and false-negative
      results was 7 samples (0.8%) and 52 samples (5.7%). In a third study, undertaken
      at l'Agence Francaise de Securite Sanitaire des Aliments (AFSSA), Nancy, France
      (n = 440), 1 false-positive sample (0.23%) and 91 (20.7%) false-negative samples
      were identified. Data generated using this prototype ELISA indicate a strong
      correlation for specificity when compared to the gold standard fluorescent
      antibody virus neutralisation (FAVN) test. Although the ELISA has a lower
      sensitivity than the FAVN test, it is a useful tool for rapidly screening serum
      samples from vaccinated companion animals. Using a cut-off value of 0.6 EU/ml,
      the sensitivity (R = % from VLA and 79% from AFSSA) and specificity (R = 97.3%)
      indices between the ELISA compared favourably with data generated using the FAVN
      test. The major advantages of the ELISA test are that it is a qualitative tool
      that can be completed in four hours, does not require the use of live virus and
      can be performed without the need for specialised laboratory containment. This
      contrasts with 4 days using conventional rabies antibody virus neutralisation
      assays. Using the current format, the ELISA assay described would be a valuable
      screening tool for the detection of rabies antibodies from vaccinated domestic
      animals in combination with other Office International des Epizooties (OIE)
      accepted serological tests.

PMID- 15019255
TI  - Flow cytometric quantitation of the protective efficacy of dendritic cell based
      vaccines in a human papillomavirus type 16 murine challenge model.
AB  - A murine model for the assessment of protective immunity to human papillomavirus
      (HPV) type 16, a virus that does not naturally infect mice, is described. In this
      system, protection was tested following intranasal challenge of mice with a
      recombinant vaccinia virus expressing both the selected HPV antigen and a beta
      galactosidase (beta-gal) reporter. The extent of viral infectivity was determined
      by measuring beta-gal positive lung cells using flow cytometry. The efficacy of
      this model to measure protective immunity was evaluated by priming mice with the
      beta-gal vaccinia virus then challenging the mice with the same virus. Vaccinia
      primed mice had negligible numbers of beta-gal positive cells in the lung 5 days
      following viral challenge indicating protection, whereas around 50% of cells were
      infected in immunologically naive, challenged mice. The protective efficacy of
      two dendritic cell vaccines for HPV16 was measured in this model. Both vaccines
      provided some protection to subsequent viral challenge, compared with their
      controls. Although this protection model was applied to HPV in this study, it may
      also have broad application to other viruses that do not infect mice naturally.

PMID- 15019256
TI  - Standardised evaluation of the performance of a simple membrane filtration
      elution method to concentrate bacteriophages from drinking water.
AB  - The bacteriophage elution procedure described further after adsorption to acetate
      nitrate cellulose membrane filters allows better recovery of phages concentrated
      from 1l of water than elution procedures used previously. The improvement is due
      to the combined effect of the eluent (3% (w/v) beef extract, 3% (v/v) Tween 80,
      0.5M NaCl, pH 9.0) and the application of ultrasound instead of agitation or
      swirling. Average recovery of somatic coliphages, 82 +/- 7%, was the greatest,
      and that of phages infecting Bacteroides fragilis, 56 +/- 8%, the lowest, with
      intermediate values for F-specific and F-specific RNA bacteriophages. Thus, the
      method allowed recovery of over 56% for all the phages suggested as surrogate
      indicators. The method was then validated according to an International
      Standardisation Organisation validation standard procedure and implemented in
      routine laboratories, which obtained reproducible results.

PMID- 15019257
TI  - Atypical scrapie cases in Germany and France are identified by discrepant
      reaction patterns in BSE rapid tests.
AB  - The intensified surveillance of scrapie in small ruminants in the European Union
      (EU) has resulted in a substantial increase of the number of diagnosed cases.
      Four rapid tests which have passed the EU evaluation for BSE testing of cattle
      are also recommended currently and used for the testing of small ruminants by the
      EU authorities. These tests include an indirect ELISA (cELISA), a colorimetric
      sandwich ELISA (sELISA I), a chemiluminescent sandwich ELISA (sELISA II), and a
      Western blot (WB). To this point, the majority of samples have been screened by
      using either sELISA I (predominantly in Germany) or WB (predominantly in France).
      In this study, it is shown that a number of the German and French scrapie cases
      show inconsistent results using rapid and confirmatory test methods. Forty-eight
      German sheep, 209 French sheep and 19 French goat transmissible spongiform
      encephalopathy (TSE) cases were tested. All cases were recognised by the sELISA I
      and either one of the confirmatory methods (scrapie-associated fibrils (SAF)
      immunoblot or immunohistochemistry). Surprisingly, three rapid tests failed to
      detect a significant number of scrapie cases (29 in France and 24 in Germany).
      The possible reasons for these inconsistent reaction patterns of scrapie cases
      are discussed. Similar discrepancies have not been observed during rapid testing
      of cattle for BSE, the disease for which all diagnostic methods applied have been
      evaluated.

PMID- 15019258
TI  - Detection of infectious salmon anaemia virus by real-time RT-PCR.
AB  - A one-tube real-time reverse transcription-polymerase chain reaction (RT-PCR)
      using LightCycler technology and SYBR Green chemistry that quantitatively detects
      infectious salmon anaemia virus (ISAV) in biological samples is described. The
      assay utilized primers targeting ISAV RNA segment 8, with ISAV isolate U5575-1 as
      template. The entire optimized assay, including one cycle of reverse
      transcription, 50 cycles of complementary DNA amplification, and data acquisition
      and analysis took only 80min. The melting curve and gel electrophoresis analyses
      of real-time RT-PCR showed harmony with each other as a virus-specific single
      melting peak and a product of the expected size of 211 bp were obtained. A
      regression line between the mean threshold cycle (Ct) values and viral template
      concentrations over a 1:10(5) dilution range with an r(2) value of 0.962 and a
      slope of -3.771 indicated that the assay was highly reproducible. This assay was
      100 times more sensitive than the conventional one-tube RT-PCR assay when
      compared on the same sample. Analysis of different tissues from fish that
      survived an ISAV experimental infection further confirmed that real-time RT-PCR
      was more sensitive than regular RT-PCR for detection of ISAV nucleic acids.
      Temporal analysis of ISAV-infected TO cell cultures showed that the amount of the
      specific viral RNA increased more than 100-fold within 32 h post-inoculation
      (p.i.) and over 1200-fold by 144 h p.i. The melting curve analysis throughout the
      duration of the infection sampled had a single melting peak suggesting that the
      virus population was uniform in the targeted region. Quantitative analysis of
      CHSE-214 cell cultures infected with different ISAV isolates indicated that ISAV
      isolates, based on their ability to replicate and cause cytopathic effects in
      CHSE-214 cells, may be differentiated into three CHSE phenotypes: replicating
      cytopathic, replicating non-cytopathic, and non-replicating. Thus, the SYBR Green
      real-time RT-PCR is a sensitive, rapid, and highly reproducible assay that can be
      used to quantitate ISAV in biological samples.

PMID- 15019259
TI  - Multiplex RT-nested PCR differentiation of gill-associated virus (Australia) from
      yellow head virus (Thailand) of Penaeus monodon.
AB  - A multiplex RT-nested PCR has been developed to detect and differentiate the
      closely related prawn viruses, gill-associated virus (GAV) from Australia and
      yellow head virus (YHV) from Thailand. RT-PCR using primers to conserved
      sequences in the ORF1b gene amplified a 794 bp region of either GAV or YHV.
      Nested PCR using a conserved sense primer and either a GAV- or YHV-specific
      antisense primer to a divergent sequence differentially amplified a 277 bp region
      of the primary PCR amplicon. Multiplexing the YHV antisense primer with a GAV
      antisense primer to another divergent sequence allowed the viruses to be
      distinguished in a single nested PCR. Nested PCR enhanced detection sensitivity
      between 100- and 1000-fold and GAV or YHV RNA was detectable in approximately 10
      fg lymphoid organ total RNA. The multiplex RT-nested PCR was also able to co
      detect GAV and YHV RNA mixed over a wide range of concentrations to simulate
      potential dual-infection states. The robustness of the test was examined using
      RNA samples from Penaeus monodon prawns infected either chronically or acutely
      with GAV or YHV and collected at different locations in Eastern Australia and
      Thailand between 1994 and 1998. GAV- (406 bp) or YHV-specific (277 bp) amplicons
      were differentially generated in all cases, including five YHV RNA samples in
      which no primary RT-PCR amplicon was detected. Sequence analysis of GAV and YHV
      PCR amplicons identified minor variations in the regions targeted by the virus
      specific antisense primers. However, none occurred at positions that critically
      affected the PCR.

PMID- 15019260
TI  - Cloning and expression of two fragments of the S gene of canine coronavirus type
      I.
AB  - Two fragments, S66 and S55, of the S glycoprotein of the newly identified canine
      coronavirus type I (CCoV type I), were expressed in a procariotic system. The
      purified recombinant proteins of 350 and 366 amino acids in length, respectively,
      were employed to develop an enzyme-linked immunosorbent assay (ELISA) for the
      detection of CCoV type I antibodies in dog sera. Four canine sera-positive for
      CCoV type II, four sera-positive for CCoV type I and 10 negative control sera
      were examined. Only the sera-positive for CCoV type I strongly reacted with both
      the proteins, whereas the sera-positive for CCoV type II showed low reactivity in
      the ELISA test. As CCoV type I seems to be not cultivable in cell cultures, the
      recombinant fragments of the S protein represent a unique method to study,
      preliminarily, the immunological and the pathogenetic characteristics of this new
      virus.

PMID- 15019261
TI  - Quantitative real-time PCR on Lightcycler for the detection of human
      immunodeficiency virus type 2 (HIV-2).
AB  - Similar to HIV-1, the viral load in HIV-2 is a marker of the evolution of
      infection and the success of therapy. No approved or commercially distributed
      assay exists to determine the plasma viral load of HIV-2. We therefore developed
      a quantitative real-time PCR to determine the plasma RNA viral load of HIV-2,
      based on the reference strains ROD and EHO, which represent subtypes A and B of
      HIV-2, respectively. After testing several pairs of primers, a set was chosen
      that recognised the 5'-LTR region of a subtypes A and B consensus sequence. The
      quantification of the PCR reaction was done using SYBR-Green I as the fluorescent
      dye in a Lightcycler system and relying on an external standard curve. The method
      was then optimised with reference strains, an validated further using patient
      samples and an inter-laboratory comparison. Good specificity was obtained for
      both subtypes of HIV-2, and a linear range between 10 and 10(6) copies of viral
      RNA. The limit of quantitation was 250 copies per millilitre of plasma. The
      coefficient of variation ranged from 0.7 to 5.6%, depending on the concentration
      of the target sequences.

PMID- 15019262
TI  - Comparison of porcine circovirus type 2 load in serum quantified by a real time
      PCR in postweaning multisystemic wasting syndrome and porcine dermatitis and
      nephropathy syndrome naturally affected pigs.
AB  - Postweaning multisystemic wasting syndrome (PMWS) diagnosis is based on the
      presence of characteristic histopathological lymphoid lesions and porcine
      circovirus type 2 (PCV2) within these lesions. Previous studies indicate that
      PCV2 load is higher in PMWS affected than in PCV2 infected, healthy pigs. On the
      other hand, PCV2 has been suggested to play a role in porcine dermatitis and
      nephropathy syndrome (PDNS) pathogenesis. This study describes a new TaqMan real
      time PCR assay and its use to quantify viral load in serum samples. Serum viral
      loads were related with different degrees of PMWS characteristic lesions and PDNS
      cases. DNA extracted from serum samples from 75 animals with mild, moderate and
      severe PMWS lesions and 12 animals with PDNS was used as template. PCV2 DNA was
      quantified in 69 of 75 PMWS cases and in 11 of 12 PDNS cases. Significant
      differences in PCV2 load were observed between animals with severe, moderate and
      mild PMWS lesions, although variability within each group was high, probably due
      to heterogeneity in disease progression. These results suggest that high viral
      load is a major feature of PMWS affected pigs. PDNS affected animals had lower
      PCV2 loads. No significant differences in viral load were found between animals
      suffering from PDNS and animals with mild PMWS characteristic lesions, which were
      unaffected clinically.

PMID- 15019263
TI  - Amplification refractory mutation system PCR assays for the detection of variola
      and Orthopoxvirus.
AB  - PCR assays that can identify the presence of variola virus (VARV) sequences in an
      unknown DNA sample were developed using principles established for the
      amplification refractory mutation system (ARMS). The assay's specificity utilised
      unique single nucleotide polymorphisms (SNP) identified among Orthopoxvirus (OPV)
      orthologs of the vaccinia virus Copenhagen strain A13L and A36R genes. When a
      variola virus specific primer was used with a consensus primer in an ARMS assay
      with different Orthopoxvirus genomes, a PCR product was only amplified from
      variola virus DNA. Incorporating a second consensus primer into the assay
      produced a multiplex PCR that provided Orthopoxvirus generic and variola-specific
      products with variola virus DNA. We tested two single nucleotide polymorphisms
      with a panel of 43 variola virus strains, collected over 40 years from countries
      across the world, and have shown that they provide reliable markers for variola
      virus identification. The variola virus specific primers did not produce
      amplicons with either assay format when tested with 50 other Orthopoxvirus DNA
      samples. Our analysis shows that these two polymorphisms were conserved in
      variola virus genomes and provide a reliable signature of Orthopoxvirus species
      identification.

PMID- 15019265
TI  - Use of whole blood dried on filter paper for detection and genotyping of measles
      virus.
AB  - PCR, and two different ELISAs were used to detect measles virus on blood dried on
      filter paper samples from Equatorial Guinea. Sensitivity was 40% by PCR, 57.1% by
      indirect ELISA and 86.7% by micro chain capture ELISA. Genotype B3 was found in
      two positive samples by PCR.

PMID- 15019264
TI  - Restriction fragment length polymorphism of L1 amplicon using Rsa 1 detects five
      different human papillomavirus types and their co-infections among women
      attending a gynaecological outpatient department.
AB  - Detection of human papillomavirus (HPV) types 6, 11, 16, 18, and 33 including co
      infections among females attending gynaecological outpatient department and
      cancer clinics, was done by restriction fragment length polymorphism (using Rsa
      1), of approximately 450bp amplicon, obtained by the amplification of the L1
      region of HPV genome with consensus primers MY09/11 [Cancer Cells 7 (1989) 209].
      The results were further tested with HPV type specific primers [J. Med. Virol. 29
      (1989) 20]. The technique was found to be low-cost and less time consuming. The
      advantage of Rsa 1 over other enzymes was that it detects the five most prevalent
      HPV types commonly associated with warts, cervical dysplasia, and cancer.

PMID- 15019266
TI  - Parkinson's disease, pesticides and individual vulnerability.

PMID- 15019267
TI  - Is ethanol a pro-drug? The role of acetaldehyde in the central effects of
      ethanol.

PMID- 15019268
TI  - Do pediatric drugs cause developing neurons to commit suicide?

PMID- 15019269
TI  - The heterogeneous course of drug transit through the body.

PMID- 15019270
TI  - New directions in the treatment of Gaucher disease.

PMID- 15019271
TI  - Immunomodulatory and neuroprotective effects of inosine.

PMID- 15019272
TI  - Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4).

PMID- 15019273
TI  - Is thymus redundant after adulthood?
AB  - Thymus is considered to involute with age with a decline in thymic function.
      However, this generality is not universally and incontrovertibly true. Many
      studies performed in animals and men have proved to the contrary that thymic
      activity and function appear to be well maintained in the old age and may be
      indispensable for T cell reconstitution in different immunological settings.
      During some clinical situations where T cell pool needs to be regenerated,
      renewal of thymic activity and mass has been observed in an otherwise dormant
      thymic remnant. New studies have revealed a dynamic interplay between postnatal
      thymus output and peripheral T cell pool. Moreover, age-related loss of thymic
      function appears to be only quantitative and not qualitative. This review, thus,
      focuses on the different conditions that lead to thymic involution and attempts
      to bring about the emerging notion and the clinical relevance of continuous
      thymic activity well beyond the adulthood to optimise the function of the immune
      system in the context of cancer and infectious diseases.

PMID- 15019275
TI  - Susceptibility of mast cell-deficient W/Wv mice to pristane-induced experimental
      lupus nephritis.
AB  - In many models of organ-specific autoimmune diseases, mast cells provide a
      critical cellular link between autoantibodies and end-organ inflammation, both
      initiating and propagating disease. However, their role in systemic autoimmunity
      remains speculative. We therefore examined the role of mast cells in a murine
      model of systemic immune complex-related autoimmune disease, lupus nephritis,
      expecting to observe the development of humoral autoimmunity in the absence of
      end-organ disease. Surprisingly, not only did mast cell-deficient animals develop
      characteristic humoral features of lupus, including hypergammaglobulinemia and
      autoantibodies, they also developed immune complex glomerulonephritis, as
      evidenced by renal immune deposits, glomerular disease, and proteinuria. These
      findings implicate the presence of distinct effector pathways to end-organ damage
      in humoral autoimmune diseases: one involving the interaction between
      autoantibodies and mast cells to recruit inflammation in organ-specific
      autoimmunity, and another involving a more direct--mast cell-independent-
      interaction between autoantibodies and circulating inflammatory mediators in
      systemic autoimmunity.

PMID- 15019274
TI  - Spironolactone inhibits production of proinflammatory cytokines by human
      mononuclear cells.
AB  - BACKGROUND: The mineralocorticoid receptor antagonist spironolactone (SPIR)
      reduces the mortality and morbidity in patients with congestive heart failure
      (CHF). Overexpression of proinflammatory cytokines contribute to the development
      and progression of CHF. MATERIAL AND METHODS: We examined the effect of SPIR on
      in vitro cytokine production by human peripheral blood mononuclear cells (PBMC).
      PBMC were cultured with 10-1000 microM SPIR and stimulated with
      lipopolysaccharide or phytohaemagglutinin-P. Tumour necrosis factor-alpha (TNF
      alpha), interleukin (IL)-6, IL-1beta, and interferon (IFN)-gamma were measured in
      culture supernatants by enzyme-linked immunosorbent assay and mRNA expression of
      the cytokines was determined by real-time reverse transcriptase polymerase chain
      reaction (PCR). RESULTS: SPIR inhibited the stimulated production of TNF-alpha,
      IL-6, and IFN-gamma, whereas the release of IL-1beta was not significantly
      affected. The SPIR-induced cytokine inhibition occurred at the transcriptional
      level and was independent of antimineralocorticoid and antiandrogen activities.
      CONCLUSION: The findings suggest that inhibited production of proinflammatory
      cytokines may be an extrarenal mechanism that contributes to the beneficial
      effect of SPIR in patients with CHF.

PMID- 15019276
TI  - Distinct mechanisms are involved in tumoristatic and tumoricidal activities of
      monocyte-derived dendritic cells.
AB  - Monocyte-derived dendritic cells (DC) were found to inhibit proliferation of
      different tumor cell lines. LPS-induced maturation of DC strongly increased their
      capacity to inhibit tumor cell growth. We observed that tumoristatic activity of
      LPS-activated DC was independent of their cytotoxic potential. Indeed, LPS
      activated DC were able to inhibit growth of caspase-8-deficient or Bcl-2
      overexpressing Jurkat cells whereas they were not cytotoxic towards the same
      targets. On the other hand, we found that supernatant derived from LPS-activated
      DC exerted a significant anti-proliferative activity against Jurkat cells while
      it did not induce any cytotoxic effect. Tumor necrosis factor (TNF) was shown to
      critically contribute to tumor growth inhibition in this system.

PMID- 15019277
TI  - Contribution of mast cells to bacterial clearance and their proliferation during
      experimental cystitis induced by type 1 fimbriated E. coli.
AB  - Bacterial infections of the urinary bladder are very common, and the role of mast
      cells in these infections is invariably thought of as a detrimental one. However,
      recent studies have shown that mast cells play a key role in host defense against
      various enterobacterial infections. In this manuscript, using mast cell-deficient
      (WBB6F1 - W/Wv) and mast cell-sufficient (WBB6F1 - +/+) mice we have investigated
      the protective role of mast cells in urinary bladder infections in vivo. Our
      findings show that (i) the mast cells are activated by FimH-expressing E. coli,
      and release large amount of histamine in the urinary bladder; (ii) the number of
      surviving bacteria in the urine is dependent on the presence of mast cells, and
      (iii) mast cell number in the bladder increases following uropathogenic infection
      in mice which is likely due to an increase in the mast cell growth-promoting
      cytokine IL-3 in bacteria-activated mast cells. Taken together, these
      observations suggest a beneficial role of mast cells in urinary bladder
      infections in mice.

PMID- 15019279
TI  - Expression of FasL by tumor cells does not abrogate anti-tumor CTL function.
AB  - The effects of Fas-ligand (FasL) expression by tumor cells on their
      tumorigenicity and immunogenicity have been reported as opposite, contradictory
      results. In some systems the killing of Fas positive cytotoxic T-cells (CTL) by
      FasL expressing tumors resulted in increased tumorigenicity while in other
      systems tumors expressing FasL were eliminated by neutrophil mediated
      inflammation. In the present study, we investigated how FasL expression
      influences the low immunogenic Lewis lung carcinoma clone D122 and its highly
      immunogenic MHC I (H-2Kb) and B7-1 (CD80) transfectant 39.5-B7, by transfecting
      the human FasL (FasL) gene into these cells. Despite the fact that FasL
      expressing cells kill effectively appropriate target cells (L1210-fas) compared
      to parental cells (D122) and low expressors (DFasL-33), these tumor cells were
      completely rejected in syngeneic mice (C57BL/6), but not in Fas mutant B6-MRL
      mice, suggesting that functional Fas receptor expression in the host was required
      to induce an anti-tumor mechanism. In addition, although FasL-expressing
      immunogenic tumor cells (39.5-B7-FasL 7) kill effectively target cells in vitro,
      both the transfectant and the mock transfectant (39.5-B7-pBabe) were rejected in
      syngenic mice. The sensitivity of FasL expressing tumor cells to lysis by CTLs
      was similar to that of FasL non-expressors. Therefore, these results indicate
      that FasL expression on immunogenic tumor cells does not affect their
      immunogenicity in vivo, as well as CTL functions in vitro.

PMID- 15019280
TI  - Combined association between IFN-gamma 3,3 homozygosity and DRB1*03 in Lofgren's
      syndrome patients.
AB  - In the present study, short tandem repeats (STR) polymorphism within the first
      intron of IFN-gamma gene in connection with HLA-DRB1*03 specificities was
      analysed in 43 sarcoidosis patients, 14 of which presented with Lofgren's
      syndrome (LS). Four out of 5 known IFN-gamma alleles with 12-15 CA repeats,
      respectively were detected in sarcoidosis patients. IFN-gamma 3,3 homozygosity
      was found to constitute a risk factor associating with LS manifestation (0.50
      versus 0.19, OD = 4.18, P = 0.014). As expected, DRB1*03 prevailed in LS cases
      (9/14 versus 7/29, P = 0.014 LS versus non-LS cases and 9/14 versus 35/162, OD =
      6.20, P = 0.001, LS patients versus controls). However, we also showed the
      presence of a combined association between DRB1*03 and IFN-gamma 3,3 in
      sarcoidosis (P = 0.017) and LS patients (P = 0.001).

PMID- 15019278
TI  - Schistosoma mansoni PIII antigen modulates in vitro granuloma formation by
      regulating CD28, CTLA-4, and CD86 expression in humans.
AB  - We investigated the in vitro responses of peripheral blood mononuclear cells
      (PBMC) from intestinal chronic schistosomiasis patients to PIII, a multivalent
      antigen prepared from Schistosoma mansoni adult worm. PIII decreased cellular
      proliferation and granulomatous reaction. Moreover, induced the reduction of IFN
      gamma levels and increased IL-10 production. To better understand the mechanism
      through which the observed suppression occurs, the present study focused on the
      phenotypic pattern displayed by PBMC treated with PIII in an in vitro granuloma
      assay. Expression of the surface markers CD28, CTLA-4 and CD86 by lymphocytes and
      monocytes were analyzed by flow cytometry. Our results demonstrated a significant
      decrease of CD28+CD4+ and CD28+CD8+ T-cell percentage stimulated by PIII compared
      to its non-infected counterparts. This suppressive effect was related to a
      significant increase in the percentage of T-cells expressing CTLA-4. PIII also
      promoted a significant increase in the percentage of cells expressing CD86.
      Indeed, our results demonstrated that PIII was capable of modulating in vitro
      granuloma reaction, and this event was related to the balance of IL-10, IFN-gamma
      and CD28, CTLA-4, CD86 bringing new insight to the immunoregulation of
      granulomatous hypersensitivity in human schistosomiasis.

PMID- 15019281
TI  - Molecular basis of antigen recognition by insulin specific T cell receptor.
AB  - The TCR alpha/beta chains recognize antigen peptides bound to the groove of the
      MHC class II molecule. The crystal structure analyses of the TCR/peptide/MHC
      class II complexes have revealed that the Valpha chains play a significant role
      in antigen recognition. However, molecular details which amino acid residues of
      the Valpha chain are able to contribute to fine antigen specificity are not
      clearly understood. Previously, we have classified a panel of T hybrids specific
      for insulin isotypes from different species of animals into four groups based on
      response profiles to these antigens. In particular, the group III (pork insulin >
      or = beef insulin hierarchy of responsiveness) and IV (pork insulin >> beef
      insulin hierarchy of responsiveness) T hybrids are interesting, since these TCR
      alpha/beta chains with marked different antigen specificities demonstrate
      identical gene usages and very similar sequences. To specifically address the
      molecular requirements for insulin recognition by TCR, the TCR alpha and beta
      chain genes from these group III and IV T hybrids were transfected into 58 alpha
      beta- T hybrid. The experiments suggested that CDR3alpha dictates the fine
      antigen specificity. Then, we have introduced a series of mutations into position
      95 of CDR3alpha. The mutation experiments clearly indicated that position 95alpha
      determines the antigen specificity of the group III and IV T hybrids.

PMID- 15019282
TI  - Broad-spectrum immunity against superantigens is elicited in mice protected from
      lethal shock by a superantigen antagonist peptide.
AB  - Bypassing the restricted presentation of conventional antigens, superantigens
      trigger an excessive cellular immune response leading to toxic shock. Antagonist
      peptides that inhibit the induction of human Th1 cytokine gene expression by a
      variety of bacterial superantigens protect mice from lethal toxic shock. We show
      that the surviving mice rapidly develop a broad-spectrum, protective immunity
      against further lethal toxin challenges with the same superantigen and even with
      superantigen toxins that they have not encountered before. By blocking the
      induction of a cellular immune response leading to toxic shock, the antagonist
      peptide allows the superantigen to induce a vigorous humoral immune response
      directed against itself, resulting in anti-toxin IgM and IgG that are broadly
      protective. Adoptive transfer of these antibodies to naive mice rendered them
      resistant to lethal superantigen challenge. The appearance of these antibodies
      does not require immunization with an adjuvant and is not elicited by the
      antagonist peptide. Our results show that superantigens are potent immunogens
      when given the opportunity to induce a B cell response, in conditions where a
      deleterious Th1 response is prevented by the superantigen antagonist peptide.

PMID- 15019283
TI  - Mast cells are involved in inflammatory reactions during Complex Regional Pain
      Syndrome type 1.
AB  - BACKGROUND: The Complex Regional Pain Syndrome type 1 (CRPS1) is a complication
      of surgery or trauma but spontaneous development is also described. Although the
      pathogenesis remains debatable, afferent, efferent and central nervous system
      mechanisms are proposed. Recently we showed involvement of the proinflammatory
      cytokines IL-6 and TNFalpha which is direct evidence for an inflammatory process.
      Many types of cells, such as activated T lymphocytes, monocytes, macrophages and
      skin resident cells like mast cells, could contribute to the production of
      cytokines. Involvement of mast cells is relatively easy to detect by measurement
      of tryptase. AIM: To establish whether mast cells are involved in the
      inflammatory reactions during CRPS1. METHODS: Twenty patients fulfilling the
      Bruehl criteria with CRPS1 in one extremity were studied. Impairment was assessed
      by registration of pain and measurement of differences in temperature, volume and
      mobility between the involved and uninvolved extremity. Blisters were made with a
      suction method in order to determine cytokines and mast cell derived tryptase in
      the involved and uninvolved extremity. RESULTS: In the blister fluid a
      significant difference (median +/- interquartile range, Wilcoxon signed-ranks
      test P < 0.05) was found between the involved and uninvolved extremity in IL-6
      [53.5 (17.3-225) versus 6.2 (2-20.3) pg/ml], TNFalpha [31 (15.5-131.5) versus 8
      (4-39) pg/ml], and tryptase [37 (20.5-62.3) versus 12.5 (6.7-23.5) ng/ml]. There
      was a significant correlation (0.455) between the intensity of pain and tryptase
      levels in the involved extremity (Spearman's test, P < 0.05). CONCLUSION: Mast
      cells are involved in inflammatory reactions during the CRPS1. Mast cells could
      play a role in the production of cytokines such as TNFalpha.

PMID- 15019284
TI  - Autologous cytotoxicity of natural killer cells derived from HIV-infected
      patients.
AB  - NK cells recognize target cells with reduced expression of MHC class I molecules.
      Human immunodeficiency virus (HIV) infection decreases MHC class I on the cell
      membrane. The aim of this study was to directly evaluate the role and conditions
      of NK cell effects in HIV seropositive patients ex vivo. Autologous HIV-infected
      CD4+ T cells were exposed to NK cells recognition. We discovered an increased
      lysis of the target cells after infection with human immunodeficiency virus-1
      (HIV-1). The expression of the HIV-1 nef gene or the combined expression of nef
      and tat confers NK susceptibility to autologous CD4+ targets. Downregulation of
      MHC class I but not HLA-C or CD4 correlated with increased recognition by NK
      cells. The specific recognition is correlated with downregulation of MHC class I
      molecules on the infected target cells.

PMID- 15019285
TI  - Association between the interleukin-1beta C(-511)T polymorphism and blood
      pressure in a Chinese hypertensive population.
AB  - The interleukin-1beta (IL-1beta) is an important pro-inflammatory cytokine in a
      broad spectrum of physiological processes. Previous investigations have observed
      that levels of the IL-1beta were higher in essential hypertensive patients and
      the IL-1beta gene polymorphism has been shown to be related to IL-1 production.
      We hypothesized that genetically determined differences in activity or
      responsiveness of cytokine(s) might contribute to hypertension. In this report,
      we utilized a family-based design to test the association between the IL-1beta C(
      511)T polymorphism and blood pressure levels in hypertensive patients chosen from
      rural communities in Anhui, China. In men, carriers of the IL-1beta (-511)*C
      allele were found to have lower systolic (P = 0.049) blood pressure levels
      compared with T homozygotes, which conforms to an additive effect model. By
      contrast, no significant association between the IL-1beta gene and blood pressure
      levels was revealed in women. Our results suggested a significant role of the IL
      1beta C(-511)T polymorphism in the control of blood pressure in Chinese
      hypertensives.

PMID- 15019286
TI  - Isolation of two distinct populations of recombinant antibody molecules specific
      for rat malonyl-CoA decarboxylase from a semi-synthetic human scFv display
      library using Ex-phage system.
AB  - A semi-synthetic human scFv phage display library by randomizing amino acid
      residues at CDR3H was constructed using pIGT3 phagemid vector. Recombinant phages
      were rescued by super-infecting the JS5 E. coli library stock with Ex-phage, the
      mutant M13KO7 helper phage containing amber mutations at gIII. The library was
      composed of 2 x 10(8) independent clones, and selected for the specific binders
      against malonyl-CoA decarboxylase (MCD) by panning. Five soluble scFv clones
      specific for MCD were finally identified and classified into two groups based on
      the difference in their binding pattern to MCD. Two clones (M4 and M8) showed
      good binding reactivity to MCD in ELISA but not in Western blot, whereas, the
      rest three clones (M23, M28 and M41) reacted to the antigen in Western blot but
      not in ELISA implying they bound to somewhat different epitopes on MCD. DNA
      sequencing analysis of M4, M8, M23 and M28 showed that VH of all clones were
      belonged to VH3 subgroup. On the other hand, M4 and M8 utilized VLkappa subgroup
      I, and M23 and M28 used VLkappa subgroup IV, suggesting that difference in
      binding pattern between M4/M8 and M23/M28 against MCD might come from the
      different VL gene utilization. In conclusion, human monoclonal scFv antibodies
      specific for MCD were successfully isolated and we demonstrated that distinct
      populations of recombinant antibodies specific to the target antigen could be
      isolated by Ex-phage system.

PMID- 15019287
TI  - IL-15 induces IFN-beta and iNOS gene expression, and antiviral activity of murine
      macrophage RAW 264.7 cells.
AB  - The effects of interleukine-15 (IL-15) on macrophage activation and antiviral
      activity have been investigated in this study. We have provided evidence that IL
      15 stimulates murine macrophage RAW 264.7 cells to release nitric oxide (NO) and
      inhibit vaccinia virus (VV) replication in bystander human 293 cells in a dose
      dependent manner. The IL-15-induced antiviral activity was partially mediated by
      NO, as blocking NO production by NO synthase (iNOS) inhibitor NG-monomethyl-L
      arginine acetate (L-NMA) partially restored the virus replication. Interferon
      gamma (IFN-gamma) was not detectable by ELISA in the cell supernatant of IL-15
      activated macrophages or in the co-cultures of macrophages and infected bystander
      cells. Neutralizing anti-IFN-gamma, anti-IFN-gamma receptor R2, anti-TNF-alpha,
      or anti-IL-12 antibodies had no effect on NO production or antiviral activity. In
      contrast, neutralizing anti-IFN-alpha/beta antibody completely restored the VV
      replication and reduced the NO level to one third of that in the control.
      Elevated mRNA levels of IFN-beta and iNOS genes were detected in IL-15-activated
      RAW 264.7 cells by RT-PCR. Our data suggest that IL-15 is capable of inducing IFN
      beta, which could participate in NO-mediated antiviral effect.

PMID- 15019288
TI  - Generation and preliminary characterization of an antibody library with
      preferential reactivity to human colorectal cancer cells as compared to normal
      human blood cells.
AB  - We are developing recombinant polyclonal antibody libraries (PCALs) reactive to
      human colorectal cancer cells as an anti-cancer therapeutic approach. To test the
      hypothesis that PCALs with preferential recognition of tumor cells as compared to
      normal cells could be generated, a Fab phage display library reactive to human
      colorectal cancer cell lines was absorbed with normal human blood cells. ELISA
      analysis of the absorbed Fab phage display library showed that 70% of tested
      clones reacted to colorectal cancer cells. Reactivity of the library to blood
      cells was reduced 4-10-fold, with many clones unreactive to one or more of the
      blood cell types. DNA fingerprint analysis of colorectal cancer-binding clones
      showed that the absorbed library remained polyclonal. The H and L chain V region
      gene pairs of the absorbed library were transferred in mass from the Fab phage
      display vector to a mammalian vector and expressed as IgG following transfection
      into Sp2/0 myeloma cells. ELISA analysis showed that 79% of transfectants
      expressed IgG and of those 74% were positive for binding to the SW480 human
      colorectal cancer cell line. A template of 95 SW480-reactive wells was assembled,
      designated Lib-Col2.1, and IgG purified from a consolidated mass culture. The
      purified Lib-Col2.1 IgG was compared to the clinically used anti-colorectal
      cancer mAb 17-1A, by ELISA and flow cytometry, for binding density on SW480
      colorectal cancer cells and on normal human blood cells. The results showed that
      Lib-Col2.1 bound to SW480 cells at higher density than mAb 17-1A and that its
      binding to normal human blood cells was reduced 2.4-24-fold relative to an
      unabsorbed anti-SW480 serum. Furthermore, Lib-Col2.1 was more effective than mAb
      17-1A at inhibiting the growth of SW480 cells in culture. These results suggest
      that a polyclonal antibody library with preferential reactivity to cancer cells
      as compared to normal cells could be generated.

PMID- 15019289
TI  - Suppression of macrophage function in AK-5 tumor transplanted animals: role of
      TGF-beta1.
AB  - Transforming growth factor-beta 1 (TGF-beta1), a multifunctional cytokine
      secreted by various cell types has been implicated in diverse physiologic and
      pathophysiologic functions, including immunological, inflammatory, and neoplastic
      processes. AK-5 tumor cells when injected intraperitoneally grow as ascites,
      causing 100% mortality. Peritoneal macrophages cocultured with AK-5 cells, in
      vitro showed specific suppression of tumoricidal function. We report that AK-5
      cells secrete the latent form of TGF-beta1, which is converted to its active
      homodimeric form, causing suppression of the secretion of cytocidal molecule by
      macrophages thereby inhibiting their cytotoxic capabilities. When macrophages are
      cocultured with AK-5 cells in the presence of antibodies against TGF-beta1 or the
      receptor II for TGF-beta, there is significant recovery in the secretion of
      nitric oxide and macrophage cytotoxic potential. These results suggest a major
      role for TGF-beta produced by the tumor cells, in the immune escape mechanisms
      adopted by the AK-5 tumor cells.

PMID- 15019290
TI  - Inclusion bodies from recombinant bacteria as a novel system for delivery of
      vaccine antigen by the oral route.
AB  - A fragment of non-glycosylated E2 antigen of classical swine fever virus (CSFV),
      lacking the trans-membrane anchor (TM-) of the native glycoprotein, was produced
      in recombinant Escherichia coli strain BL21(DE3) in the form of inclusion bodies.
      These inclusion bodies isolated from the bacteria cells were administrated orally
      to mice twice at either 10 or 50 microg per dose. Each mouse fed with inclusion
      bodies carrying the E2 antigen responded with plasma antibodies and/or fecal IgA
      at least once during the entire investigation. Our study showed the capacity of
      inclusion bodies to induce both systemic and mucosal responses as well as to
      evoke relatively-long mucosal memory when fed to mice at low-number vaccination
      schedule and without any adjuvant. We propose the use of inclusion bodies for
      oral vaccination as an alternative to artificial systems for delivery of
      recombinant antigens by the oral route. Very few steps are needed to obtain an
      antigen ready for use as a vaccine. The procedure is easy and inexpensive and can
      be used for development of vaccine against classical swine fever.

PMID- 15019291
TI  - Beta-galactosylceramide increases and sulfatide decreases cytokine and chemokine
      production in whole blood cells.
AB  - The glycosphingolipid sulfatide and its immediate precursor beta
      galactosylceramide (GalCer) are present in the pancreatic beta-cell in equimolar
      concentrations and may play a role in islet pathology. Previous studies of
      mononuclear cells have shown that sulfatide tends to decrease and GalCer tends to
      increase the production of proinflammatory cytokines. In this study we
      investigated the influence of various isoforms of sulfatide on the production of
      cyto- and chemokines and tested whether the opposing effects of GalCer and
      sulfatide could counter one another in competition assays. PHA-, LPS-, or
      unstimulated whole blood cultures were incubated with 30 microg/ml of native
      sulfatide (isolated from pig brains), C:16:0 and C:24:0 analogues of sulfatide,
      or native GalCer preparations. After 24 h, the supernatant levels of
      proinflammatory cytokines and chemokines were quantitated by ELISA. The general
      trend was for the sulfatides to lower the production of the cytokines, and for
      GalCer to increase it. In competition assays, native sulfatide dampened the
      stimulatory effects of GalCer but did not abolish cytokine release; GalCer, on
      the other hand, nullified the effect of native sulfatide at a ratio of four
      sulfatide molecules to one GalCer molecule. C:16:0 sulfatide appeared to have a
      stronger effect than C:24:0 sulfatide. The C:16:0 analogue decreased IL-1beta, IL
      6, TNF-alpha, MIP-1alpha and IL-8 to 3-56% of control values (P < 0.05-0.01),
      while GalCer increased their production 2- to 10-fold (P < 0.01). In conclusion,
      sulfatide decreases the in vitro production of proinflammatory cytokines, whereas
      GalCer has the opposite effect.

PMID- 15019292
TI  - Two different forms of human CTLA-4 proteins following peripheral T cell
      activation.
AB  - To study expression of human CTLA-4 in peripheral T cells, we developed a new
      anti-peptide (anti-CTLA4pB) antibody. Both denatured and native forms of CTLA-4
      can be recognized by anti-CTLA4pB antibody. After peripheral T cell activation,
      we observed that most of CTLA-4 is localized primarily to intracellular
      compartment rather than to the cell surface. Biochemical study using anti-CTLA4pB
      antibody was revealed two forms of CTLA-4 on activated peripheral T cells. The
      majority of CTLA-4 was detected as a 34 kDa moiety in cytosolic fraction under
      reducing conditions. The presence of a 30 kDa CTLA-4 moiety was observed
      simultaneously in membrane fraction under reducing condition. The post-induction
      ratio of cytosolic:membrane-bound forms of CTLA-4 was approximately 50:1. Further
      analysis was indicated that the 34 kDa moiety in cytosolic fraction is part of a
      250 kDa multi-protein complex. Antibodies raised against this complex recognized
      54 and 75 kDa proteins together with a 34 kDa form of CTLA-4. In contrast,
      membrane-bound forms of CTLA-4 were 60 and 120 kDa under non-reducing condition.
      The molar ratio of 60 and 120 kDa oligomers was approximately 1:1. These results
      may provide evidence for post-translational modification of human CTLA-4 after T
      cell activation.

PMID- 15019293
TI  - In vitro induction of inhibitory macrophage differentiation by granulocyte
      macrophage colony-stimulating factor, stem cell factor and interferon-gamma from
      lineage phenotypes-negative c-kit-positive murine hematopoietic progenitor cells.
AB  - CD11b+Gr-1+ inhibitory macrophages (iMacs) were implicated in profound depression
      of T cell functions sometimes observed during cyclophosphamide treatments and
      overwhelming infections, through a secretion of nitric oxide (NO). Myeloid origin
      and maturation stages of iMacs are still unknown. As tumor necrosis factor-alpha
      (TNF-alpha) and interferon-gamma (IFN-gamma) contributed crucially to the
      activation of inducible NO synthase (iNOS) gene transcription and to the
      differentiation of macrophages, we tested their roles in the induction of iMacs
      differentiation from bone marrow hematopoietic progenitor cells (HPC) of
      uncompromised mice. Lineage phenotypes-negative (lin)) c-kit+ cells of Balb/c
      mice were cultured 6 days with granulocyte-macrophage colony-stimulating factor
      (GM-CSF), stem cell factor (SCF, c-kit ligand) in presence or not of TNF-alpha or
      IFN-gamma. CD11b+Gr-1+ cells only derived in presence of [GM-CSF + SCF + TNF
      alpha] or [GM-CSF + SCF + IFN-gamma] could express iNOS upon in vitro stimulation
      with [IFN-gamma + TNF-alpha] or [IFN-gamma + LPS] known to boost iNOS expression
      in murine macrophages. However, whereas [GM-CSF + SCF + TNF-alpha] induced only
      weakly iMacs generation and contributed also to the differentiation of CD11b+Gr-1
      CD11c+ myeloid dendritic cells, [GM-CSF + SCF + IFN-gamma] induced exclusively
      and importantly iMacs differentiation. Moreover [GM-CSF + SCF + IFN-gamma]
      generated iMacs were more mature than [GM-CSF + SCF + TNF-alpha]-derived iMacs
      since IFN-gamma increased more strongly CD11b+Gr-1+ cells expressing Ly-6C and
      generated lesser cells expressing MHC class II and CD86 molecules. Finally [GM
      CSF + SCF + IFN-gamma]-generated CD11b+ cells showing a powerful suppressive
      activity on T cell proliferations, correlated with NO secretion. In conclusion,
      our study showed, for the first time, that IFN-gamma induced very efficiently the
      differentiation of functional iMacs from lin- c-kit+ murine HPC in vitro, and
      indicated clearly that iMacs progenitors may be present in bone marrow of naive
      mice.

PMID- 15019294
TI  - Effect of PSK on the maturation of dendritic cells derived from human peripheral
      blood monocytes.
AB  - Dendritic cells (DCs) are powerful antigen-presenting cells (APCs) that have
      attracted attention in recent years from the viewpoint of DC vaccine therapy
      against cancer. However, the existence of a strongly immunosuppressed state in
      cancer-bearing individuals inhibits DC maturation, which is one of the problems
      facing anti-cancer DC vaccine therapy. Protein-bound polysaccharide K (PSK),
      which is extracted from the cultured mycelium of Coriolus versicolor (Fr.) Quel,
      is used as an anti-cancer agent in Japan. PSK is reported to improve the
      immunosuppressed state and might be associated with DC maturation directly. We
      examined the effect of PSK on the maturation of DC derived from CD14-positive
      cells obtained from human peripheral blood monocytes using a negative selection
      method. CD14-positive cells cultured in the presence of PSK significantly
      increased the expression of HLA class II antigen and CD40; significantly
      increased the number and expression of CD80-, CD86- and CD83-positive cells;
      decreased Fluorescein isothiocyanate (FITC)-dextran uptake, augmented IL-12
      production; augmented the allogeneic mixed lymphocyte reaction; and induced
      antigen-specific cytotoxicity. These results indicate that PSK promotes both the
      phenotypic and functional maturation of DC derived from human CD14-positive
      mononuclear cells. The clinical significance of the combined use of PSK in DC
      vaccine therapy remains for study.

PMID- 15019296
TI  - A phagemid system enabling easy estimation of the combinatorial antibody library
      size.
AB  - We developed a new phagemid system for the generation of combinatorial antibody
      libraries. This system allows the recombination efficiency to be estimated
      easily, which aids the accurate measurement of the antibody library size. Two
      phagemids were constructed. pRTCB bears the structural tetracycline-resistant
      gene (tetR) and pRTCA bears its promoter region (Ptet). pRTCA and pRTCB were
      constructed so that recombinase-mediated chain exchange (RMCE) in Cre-expressing
      bacteria results in the simultaneous acquisition of Tet resistance and newly
      recombined single chain variable fragment (scFv) genes. PCR and restriction
      enzyme analysis of randomly selected tetR phagemids showed that all Tet-resistant
      phagemids have an active tetR gene and a recombined scFv gene. RMCE efficiency
      was measured by the ratio of the tetR colonies to the total colonies. The scFv
      proteins expressed from the recombined phagemid vectors were functional. Thus,
      our phagemid vector system may be useful for making combinatorial antibody
      libraries.

PMID- 15019295
TI  - Impact of tumor-derived CCL2 on T cell effector function.
AB  - To study the effects of tumor-derived monocyte chemoattractant protein-1 (MCP-1,
      CCL2) on the anti-tumor immune response we used the 4T1 murine mammary carcinoma
      which constitutively expresses CCL2. We generated 4T1 that do not express
      detectable levels of CCL2 and found that the T cell response to the tumors were
      altered. Lymph nodes draining the CCL2- tumor contained CD62Llo cells that
      produced greater levels of INF-gamma in response to the tumor than CD62Llo cells
      from lymph nodes draining a tumor that produced CCL2. Moreover, exposure of
      splenic T cells to recombinant CCL2 in vitro decreased the ability of the T cells
      to produce IFN-gamma. However, despite the enhanced effector function evident in
      the absence of CCL2, vaccination/challenge experiments failed to reveal an
      increase in immunogenicity of the CCL2 null cells relative to the CCL2+ cells.
      Collectively, these data indicate that tumor-derived CCL2 could decrease T cell
      effector function, yet not the overall immunogenicity of the tumor.

PMID- 15019298
TI  - In vivo and in vitro effects of acrylamide on synaptosomal neurotransmitter
      uptake and release.
AB  - Evidence suggests acrylamide (ACR) neurotoxicity is mediated by impaired
      presynaptic transmission. To assess the effects of ACR on nerve terminal
      function, [3H] glutamate release and uptake were determined in brain synaptosomes
      isolated from intoxicated rats (50mg/kg per day x 8 days, i.p. or 21 mg/kg per
      day x 21 days, p.o.). Regardless of ACR dose-rate, a significant reduction in
      synaptosomal K(+)-stimulated, Ca(2+)-dependent release was detected, whereas
      kinetic analysis of Na(+)-dependent uptake did not reveal consistent changes.
      Immunoblot analysis showed normal protein levels (e.g. SNAP-25) in dysfunctional
      synaptosomes isolated from ACR-intoxicated rats. This suggests that defective
      release does not involve changes in protein synthesis and/or anterograde delivery
      of presynaptic constituents. To identify potential targets, synaptosomes were
      exposed in vitro to [ 14C ]-ACR and radiolabeled proteins were separated by gel
      electrophoresis and detected by autoradiography. [14C]-ACR labeling of distinct
      synaptosomal protein bands (10.5-154000 kDa) was blocked by the sulfhydryl
      alkylating agent, N-ethylmaleimide (NEM; 4mM) but not by the non-neurotoxic
      structural analog propionamide (10mM). In vitro characterization of synaptosomal
      [3H] glutamate uptake and release showed that ACR, NEM and iodoacetic acid (IAA)
      produced concentration-dependent decreases in each parameter that were highly
      correlated to reductions in free sulfhydryl content. All three chemicals were
      equiefficacious with respect to reducing sulfhydryl content and neurotransmitter
      uptake/release, although the relative potencies differed; [3H]. Kinetic analysis
      of uptake showed that in vitro exposure to ACR, IAA or NEM at their respective
      IC(50)'s caused similar reductions in V(max). These data suggest that ACR-induced
      synaptic dysfunction involves adduction of presynaptic protein thiol groups and
      subsequent reduction in neurotransmitter release.

PMID- 15019297
TI  - Dopamine transporter binding study in differentiating carbon disulfide induced
      parkinsonism from idiopathic parkinsonism.
AB  - Long-term exposure to carbon disulfide (CS(2)) may induce parkinsonian features.
      There may be confusion in distinguishing between CS(2) parkinsonism and
      idiopathic parkinsonism, especially for workers who developed parkinsonian
      features in viscose rayon plants. We performed clinical examinations, and
      laboratory studies including magnetic resonance imaging (MRI) and dopamine
      transporter (DAT) studies with (99m)Tc-TRODAT-1 brain single photon emission
      computed tomography (SPECT) in three workers who had long-term exposure to CS(2).
      Patient 1 had polyneuropathy, and encephalopathy with tremor; patient 2 had
      polyneuropathy, and encephalopathy with parkinsonian features; and patient 3 had
      pure parkinsonian features without polyneuropathy or cerebellar signs. The
      treatment with l-dopa was effective in patient 3, but non-effective in patient 2.
      Brain MRI revealed multiple high signal intensities over the subcortical white
      matter, basal ganglia, and/or even the brainstem in patients 1 and 2, but normal
      in patient 3. In DAT studies, the bindings were normal in patients 1 and 2 and
      was decreased in patient 3. We conclude that CS(2) exposure may induce
      polyneuropathy, and cerebellar dysfunction in addition to parkinsonian features
      and that brain MRI may show multiple lesions in the cerebral white matter and
      basal ganglia. In addition, DAT with (99m)Tc-TRODAT-1 brain SPECT may provide a
      useful information in differential diagnosis between CS(2) parkinsonism and
      idiopathic parkinsonism.

PMID- 15019299
TI  - Toxicity of a treatment associating dopamine and disulfiram for catecholaminergic
      neuroblastoma SH-SY5Y cells: relationships with 3,4-dihydroxyphenylacetaldehyde
      formation.
AB  - 3,4-Dihydroxyphenylacetaldehyde (DOPAL) is formed by the oxidative deamination of
      dopamine (DA) catalyzed by monoamine oxidases (MAO); then, the aldehyde is
      oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenases
      (ALDH) or reduced to 3,4-dihydroxyphenylethanol (DOPET) by aldose/aldehyde
      reductases. The present work aimed at evaluating the in vitro toxicity of DOPAL
      on catecholaminergic neuroblastoma SH-SY5Y cells which accumulate DA. DOPAL
      synthesis was stimulated by incubating cells with DA and blocking DOPAL oxidation
      by disulfiram, an irreversible inhibitor of ALDH. As evidenced by MTT reduction
      assays, DA and disulfiram treatments produced cell losses which increased with
      time. 10(-2)M DA reduced by 40% cell viability after a 1h treatment, when its
      TC(50) (concentration reducing viability by 50%) value was 7.3 x 10(-5) M after a
      24 h treatment. For the same treatment periods, TC(50) values for disulfiram were
      8 x 10(-5) and 8.7 x 10 (-7) M, respectively. MTT reduction assay performed after
      a 24h treatment followed by a 24h incubation in a drug-free medium evidenced that
      the toxicity of 10(-4)M DA or 10(-6)M disulfiram was potentiated by the second
      drug. HPLC measurements showed that DOPAL was produced at the early stages of the
      treatment by DA and disulfiram. This was evidenced by the significant increase in
      the ((DOPAL + DOPET)/DOPAC ratio observed after a combined 3h treatment by 10(
      4)M DA and 10(-6)M disulfiram. Total contents in DA and DOPAL were greatly
      reduced at the end of a 15 h treatment, and disulfiram did not significantly
      enhanced the (DOPAL + DOPET)/DOPAC ratio. For both treatment durations, DOPAL and
      DOPET were detectable only in the extracellular medium. So, these results suggest
      that an early production of DOPAL could produce delayed toxic effects on SH-SY5Y
      cells. Production of DOPET and release of DOPAL could be important means for
      reducing DOPAL concentrations in dopaminergic neurons.

PMID- 15019300
TI  - 3-monochloropropane-1,2-diol does not cause neurotoxicity in vitro or
      neurobehavioral deficits in rats.
AB  - 3-monochloro-1,2-propanediol (3-MCPD) is a contaminant of acid-hydrolyzed
      vegetable protein. Several reports have suggested that chronic exposure to 3-MCPD
      could produce neurotoxicity in vitro or neurobehavioral effects in experimental
      animals. The present study further explored the in vitro neurotoxic effects of
      0.1-100 microM 3-MCPD on PC12 and N18D3 cell lines. In addition, to investigate
      the effects of repeated ingestion of 3-MCPD on neurobehavioral impairments
      parameters in rats, motor activity, landing foot splay, and grip strength tests
      were performed, following treatment with 3-MCPD at dose levels of 10, 20, and 30
      mg/kg per day for 11 weeks. We demonstrated that no significant neurotoxic
      effects were present in 3-MCPD-treated rats compared to saline-treated control
      rats, whereas, acrylamide, used as a positive control, induced significant
      deficits in all neurobehavioral parameters in both male and female rats. On the
      other hand, body weight gain was significantly decreased in high dose 3-MCPD
      treated male rats as well as in acrylamide-treated rats. Taken together, these
      results suggest that 3-MCPD, at the dose levels used for this study, does not
      produce in vitro neurotoxicity or neuromotor deficits in vivo.

PMID- 15019301
TI  - Increased activity and involvement of caspase-3 in radiation-induced apoptosis in
      neural cells precursors from developing rat brain.
AB  - Using primary cultures of neural precursor cells of cortex from developing rat
      brain, we demonstrated the involvement of caspase-3 in the apoptotic process
      induced by gamma irradiation. The precursor nature of cells was confirmed by
      nestin and GFAP immunoreactivity and by the capacity of differentiation in
      neuronal and glial cells after 5 days in culture. Neural precursors were
      irradiated with single doses ranging from 0.1 to 4Gy. Cellular death, determined
      24 h post-irradiation (pi) was dose-dependent and the induction of apoptosis was
      confirmed by nuclear condensation, DNA fragmentation and hypodiploid DNA peak
      represented by the "sub G1" region. For the higher doses, apoptosis was evident
      after 4-6 h pi and increased during 24 h. Caspase-3 activity increased with doses
      and was maximal at 4-6 h pi with 3Gy and remained similar with 4Gy. The
      protection from radiation-induced apoptosis by caspase-3 inhibitor, zDEVD-fmk,
      confirmed that this enzyme is involved in the apoptotic mechanism in this system.
      The possibility of using this tissue culture system for studying the effects of
      ionizing radiation on morphological and molecular differentiation was considered.

PMID- 15019302
TI  - Methylmercury stimulates arachidonic acid release and cytosolic phospholipase A2
      expression in primary neuronal cultures.
AB  - Cytosolic phospholipase A2 (cPLA2) plays an important role in the stimulus
      dependent hydrolysis of sn-2 ester bond from membrane phospholipids, releasing
      arachidonic acid (AA), which along with its metabolites is involved in a number
      of regulatory functions. The present study examined the effect of methylmercury
      (MeHg; 0, 2.5, 5.0 microM) on cPLA2 activation in primary hippocampal neurons by
      assessing the release of 3H-AA. A significant increase in AA release was observed
      in cultures treated with 5 microM MeHg (10, 30, 60 and 120 min). This effect was
      due to neuronal cPLA2 activation, since it was completely abolished by
      arachidonyl trifluoromethyl ketone (AACOCF3), a specific inhibitor of cPLA2.
      Additional studies confirmed, by means of western blot analysis, that MeHg (5.0
      and 10 microM; 16h) potently increases neuronal cPLA2 protein expression. These
      results suggest that cPLA2-stimulated hydrolysis and release of AA are potential
      mediators of MeHg-induced neurotoxicity.

PMID- 15019303
TI  - Emergency treatment of life-threatening intrathecal methotrexate overdose.
AB  - A male 34-year-old patient with aggressive diffuse malignant lymphoma was
      hospitalized for treatment. Because of high likelihood of CNS involvement,
      intrathecal methotrexate (MTX) 15 mg was administered with hydrocortisone 100mg.
      Shortly after the intrathecal injection the patient became agitated, and
      complained of severe low back pain and 2h later he became confused and developed
      generalized seizures. At this stage, it was realized that the dose contained 1200
      mg of MTX (80-fold overdose). The patient developed ARDS and was comatose; he was
      intubated and transferred to ICU. The patient was immediately treated with
      intravenous leucovorin 1200 mg, and 15 mg every 6h, thereafter, for 72 h. In
      addition, CSF exchange with warm normal saline was initiated via intrathecal
      catheter, and a total of 200 ml of CSF were replaced during 48 h. Finally, at the
      end of the exchange 2 mg of leucovorin with 2 mg of dexamethasone were
      administered intrathecally. MTX levels in CSF 7h post-injection were 770 microM,
      and increased to 1250 microM 2h later. Thereafter, the levels in CSF declined,
      and 48 h post-injection were 47 microM. The plasma levels of MTX 7h post
      injection were 10 microM, and declined to 0.7 microM at 68 h. The patient
      regained consciousness and underwent successful weaning from ventilator after
      tracheostomy. The highest reported intrathecal dose after which the patient
      survived was 625 mg. Due to the rarity of reported cases, there are no clear
      guidelines for treatment of massive intrathecal overdose. There is a controversy
      regarding the toxicity of intrathecal injection of leucovorin. We propose CSF
      exchange and intravenous leucovorin as the mainstay of treatment.

PMID- 15019304
TI  - Transplacental exposure to the DNA demethylating agent, 5-AZA-CdR, affects the
      sexual behavior of CD-1 male mice.
AB  - Intrauterine exposure to 5-AZA-2'-deoxycytidine (5-AZA-CdR) alters gene
      expression causing malformations, abnormal post-natal growth and altered
      reproductive capacity. To elucidate whether the phenomenon observed in 5-AZA-CdR
      in utero exposed male mice was a behavioral alteration, at gestation day (GD) 10,
      CD-1 pregnant mice were administered 1mg/kg i.p. of 5-AZA-CdR or saline solution.
      After parturition, the number and sex of pups were recorded. While litter size
      was not affected, the ratio of male to female offspring was altered in treated
      mice. To determine whether the phenotypic observation of male gender corresponded
      to the appropriate genotype, presence of Sry gene in 5-AZA-CdR F1 males was
      determined. At 3 months of age, the male sexual behavior test outlined by Chubb
      was conducted. Presence of vaginal plug and pregnancy were determined in the
      natural breeding phase. Mount latency and number of mounts per mouse were
      assessed in the behavioral test phase. In utero exposed male mice resulted in
      diminished mating behavior (as measured by vaginal plug presence, mount latency
      and number of mounts) and reduced sexual interest while exposed to a receptive
      female. While normal presence of Sry gene was observed, mating behavior was
      altered in exposed males suggesting that the reproductive alteration could be
      attributed to a behavioral phenomenon.

PMID- 15019305
TI  - Cerebral cortical abnormalities seen in a non-human primate model of prenatal
      cocaine exposure are not related to vasoconstriction.
AB  - In our previous studies [J. Comp. Neurol. 435 (2001) 263] we demonstrated that
      rhesus monkeys born to mothers receiving cocaine orally during the period of
      pregnancy when neurons destined for the cerebral neocortex were generated
      displayed inappropriate positioning of neocortical neurons, loss of normal
      neocortical lamination, and reduction in neocortical volume, density and total
      number of neocortical neurons. In the present paper, we examined whether these
      cytoarchitectural abnormalities were related to the relatively high blood levels
      of the cocaine metabolite, benzoylecgonine, associated with oral cocaine
      administration. We also evaluated the role of vasoconstriction of the
      uteroumbilical and fetal brain vessels in the generation of these abnormalities.
      For these purposes, we compared cerebral neocortical cytoarchitecture in 2-month
      old monkeys from five groups of mothers: (1). a drug-naive group, (2). a cocaine
      treated group, (3). a group treated with benzoylecgonine at doses producing
      higher blood levels of this metabolite and stronger vasoconstriction that those
      in the cocaine-treated group, (4). a group treated with cocaine plus the
      vasodilator, isosorbide dinitrate, which counteracted the vasoconstrictive
      actions of cocaine, and (5). a group exposed to isosorbide dinitrate alone. All
      treatments were carried out from the 45 th through 102 nd day of pregnancy. We
      found that the general appearance of the neocortex and the position and number of
      neocortical neurons in the offspring of benzoylecgonine- and isosorbide dinitrate
      treated mothers were indistinguishable from those in the offspring of drug-naive
      mothers. In contrast, significant alterations in these parameters (similar to
      those seen in our previous studies) were observed in the offspring of cocaine and
      cocaine + isosorbide dinitrate-treated mothers. These findings suggest that it is
      unlikely that either benzoylecgonine or vasoconstriction are responsible for the
      abnormalities seen in the neocortical cytoarchitecture in our non-human primate
      model of prenatal cocaine exposure.

PMID- 15019306
TI  - Manganese distribution in the brain and neurobehavioral changes following
      inhalation exposure of rats to three chemical forms of manganese.
AB  - The central nervous system is an important target for manganese (Mn) intoxication
      in humans; it may cause neurological symptoms similar to Parkinson's disease.
      Manganese compounds emitted from the tailpipe of vehicles using
      methylcyclopentadienyl manganese tricarbonyl (MMT) are primarily Mn phosphate, Mn
      sulfate, and Mn phosphate/sulfate mixture. The purpose of this study is to
      compare the patterns of Mn distribution in various brain regions (olfactory bulb,
      frontal parietal cortex, globus pallidus, striatum and cerebellum) and other
      tissues (lung, liver, kidney, testis) and the neurobehavioral damage following
      inhalation exposure of rats to three Mn species. Rats (n=15 rats per Mn species)
      were exposed 6 h per day, 5 days per week for 13 consecutive weeks to metallic
      Mn, Mn phosphate or Mn phosphate/sulfate mixture at about 3000 microgm(-3) and
      compared to controls. At the end of the exposure period, spontaneous motor
      activity was measured for 36 h using a computerized autotrack system. Mn in
      tissues was determined by instrumental neutron activation analysis (INAA). The Mn
      concentrations in the brain were significantly higher in rats exposed to Mn
      phosphate and Mn phosphate/sulfate mixture than in control rats or rats exposed
      to metallic Mn. Exposure to Mn phosphate/sulfate mixture caused a decrease in the
      total ambulatory count related to locomotor activity. Our results confirm that Mn
      species and solubility have an influence on the brain distribution of Mn in rats.

PMID- 15019307
TI  - Effects of methionine sulfoximine on the glutamine and glutamate content and cell
      volume in rat cerebral cortical slices: involvement of mechanisms not related to
      inhibition of glutamine synthesis.
AB  - Treatment of cerebral cortical slices with 5mM ammonium acetate (ammonia)
      elevated the glutamine (Gln) content and increased cell volume in the slices, in
      agreement with the postulated contribution of glutamine to hyperammonemic brain
      edema [Neurochem. Int. 43 (2003) 299]. In this study we show that, unexpectedly,
      treatment with a glutamine synthetase inhibitor, methionine sulfoximine (MSO)
      (0.1-5.0mM) in the absence of ammonia increases Gln content in the slices in a
      dose-independent manner, to levels higher than those recorded after ammonia
      treatment. MSO (>0.1mM) inhibited (>0.1mM) Gln uptake in crude cerebral cortical
      cell membranes (P2 fraction). Since Gln uptake in this preparation was largely
      facilitated by the Gln efflux-promoting systems ASC and N and less so by the
      uptake promoting system A, MSO-induced accumulation of Gln could result from
      inhibition of Gln efflux. MSO did not affect cell volume in the slices, showing
      that Gln retention is not as a rule a causative factor in cerebral edema. MSO at
      5mM concentration increased cell swelling induced by ammonia, which is consistent
      with earlier observations pointing to the direct excitotoxic action of MSO in
      vivo and in vitro. The results emphasize the limits of applicability of MSO as an
      inhibitor of Gln synthesis in an in vitro system.

PMID- 15019309
TI  - Exocytosis: using amperometry to study presynaptic mechanisms of neurotoxicity.
AB  - The development of carbon fiber microelectrode amperometry enabled detailed
      investigation of the presynaptic response at the single cell level with single
      vesicle resolution. Consequently, amperometry allowed for detailed studies into
      the presynaptic mechanisms underlying neurotoxicity. This review describes the
      results from recent amperometric studies regarding the effects of environmental
      pollutants and drugs of abuse on vesicular catecholamine release. The observed
      alterations in neurotransmitter release are generally believed to affect the
      communication between neurons and to influence their development, maintenance and
      survival. Therefore, the alterations in neurotransmitter release can be used as
      one of many measures for the neurotoxic potential of substances. Hence, it is
      likely that the use of amperometry leads to a better understanding of the
      presynaptic mechanisms of neurotoxicity.

PMID- 15019308
TI  - Manganese distribution across the blood-brain barrier III. The divalent metal
      transporter-1 is not the major mechanism mediating brain manganese uptake.
AB  - Manganese (Mn) is essential for and toxic to the brain. Brain Mn uptake utilizes
      both diffusion and transporter-mediated pathways. The divalent metal transporter
      1 (DMT-1) has been suggested to mediate brain Mn uptake. The b/b Belgrade rat
      does not express significant amounts of functional DMT-1. In the present work,
      brain influx transfer coefficients of (54) Mn ion and (54) Mn transferrin (Mn Tf)
      were determined in b/b and +/b Belgrade and Wistar rats using the in situ brain
      perfusion technique. Brain Mn uptake was not significantly different among the
      three rat strains for either Mn species. We hypothesized that Mn may enter brain
      endothelial cells by a DMT-1-independent process but not be able to distribute
      across those cells into brain tissue due to the absence of DMT-1 activity. To
      test this hypothesis the brain capillary endothelial cells were isolated from b/b
      and +/b Belgrade rats and Wistar rats after in situ brain perfusion. Some animals
      received cerebrovascular washout after in situ brain perfusion to ascertain any
      affect of genotype on (54) Mn adsorption to the endothelial cell luminal surface.
      Less than 30% of the brain (54) Mn after (54) Mn ion or (54) Mn Tf perfusion
      remained associated with endothelial cells, suggesting the majority had
      distributed into brain extracellular fluid (ECF) and/or brain cells. Mn appears
      to distribute across the rat blood-brain barrier (BBB) into the brain by one or
      more carrier-mediated processes other than the DMT-1.

PMID- 15019310
TI  - Neurotoxicity marker profiles in the CSF are not age-dependent but show variation
      in children treated for acute lymphoblastic leukemia.
AB  - BACKGROUND: In children treated for hematological malignancies, a transient
      elevation of the neurodegenerative marker Tau was found in the cerebrospinal
      fluid (CSF). In the first part of this study, CSF-Tau, CSF-Phospho-Tau, and CSF
      Neuromodulin (CSF-NM) were measured in a heterogeneous group of patients
      presenting in the pediatric oncology department. In the second part, the
      neurodegenerative markers were analyzed in a group of children with non-B-cell
      acute lymphoblastic leukemia (nB-ALL) treated according to EORTC protocols 58881
      and 58951. PROCEDURE: CSF was collected from lumbar punctures at diagnosis only
      in the first group, and at diagnosis and during treatment in the second group.
      CSF-proteins were measured with ELISA. RESULTS: There was no age variation in any
      of the markers at diagnosis in the first group of children. After prephase
      induction therapy with one intrathecal (IT) injection of methotrexate (MTX) and 7
      days systemic corticosteroids, an increase in CSF-Tau was observed, and
      accompanied with increase of both CSF-P-Tau and CSF-NM. While CSF-Tau remained
      high during induction treatment, CSF-P-Tau, and CSF-NM decreased. CONCLUSION:
      Neurodegenerative markers do not vary with age. The different protein profiles
      suggest that the neurotoxicity from the prephase, which results in an increase of
      CSF-Tau, CSF-P-Tau, and CSF-NM, may have a different mechanism to the
      neurotoxicity induced later during induction treatment, when only CSF-Tau remains
      high.

PMID- 15019311
TI  - Spine density and dendritic branching pattern of hippocampal CA1 pyramidal
      neurons in neonatal rats chronically exposed to the organophosphate paraoxon.
AB  - The organophosphate cholinesterase (ChE) inhibitor paraoxon is the oxidized
      active metabolite of parathion, a pesticide whose use in agriculture has been
      matter of increasing concern. The present work was aimed at reproducing a
      prolonged exposure to low concentrations of paraoxon and assessing possible
      damage to the hippocampus during the period of most significant cholinergic
      development. Male Wistar rats were given, from P8 to P20, subcutaneous daily
      injections of paraoxon (0.1, 0.15 and 0.2mg/kg). The rate of body weight gain was
      reduced by all doses of paraoxon and brain ChE activity progressively decreased
      up to 60% by P21. Some deaths occurred in the beginning of the treatment, but the
      surviving animals showed neither convulsions nor overt signs of cholinergic
      hyperstimulation. Morphometric analysis of Lucifer Yellow-stained CA1 pyramidal
      neurons in coronal sections of the hippocampus showed that by P21 paraoxon caused
      a decrease in spine density on basal but not on secondary apical dendrites. The
      dendritic arborization and the pyramidal and granular cell body layers were not
      altered by paraoxon. ChE staining decreased in all hippocampal and dentate gyrus
      regions studied, whereas choline acetyltransferase (ChAT) and zinc-positive
      fibers remained as in control. In summary, chronic exposure to low paraoxon
      concentrations during the period of rapid brain development caused significant
      and selective decrease in basal dendritic spine density of the CA1 pyramidal
      neurons. Distinct modulation of the basal tree at the stratum oriens by the
      interplay of cholinergic afferent and GABAergic interneurons, as well as the
      remodeling process in response to a repetitive and rather mild paraoxon insult,
      may account for this selective susceptibility of basal dendritic spines. The
      hippocampal alterations described here occurred in the absence of toxic
      cholinergic signs and may affect brain development and cause functional deficits
      that could continue into adulthood.

PMID- 15019312
TI  - The One-Eye drug trial revisited.

PMID- 15019313
TI  - The uniocular drug trial and second-eye response to glaucoma medications.
AB  - PURPOSE: To determine if the intraocular pressure (IOP) reduction observed in a
      uniocular trial correlates with the IOP reduction seen in the fellow eye when the
      same medication is then administered to the second eye of patients with glaucoma.
      STUDY DESIGN: Observational case series. PARTICIPANTS: Fifty-two patients with
      bilateral glaucoma. METHODS: Glaucoma patients underwent uniocular trials of
      various glaucoma medications, then subsequently received the same drug in the
      fellow eye. The IOP reduction observed in the first eye was compared with that
      observed in the second eye to determine correlation. MAIN OUTCOME MEASURE:
      Intraocular pressure reduction in fellow-eye pairs. RESULTS: Intraocular pressure
      dropped a mean of 5.7+/-3.8 mmHg (mean +/- standard deviation) in the first eye
      after a uniocular trial, and 2.8+/-3.3 mmHg in the second eye after bilateral
      use. Regression analysis demonstrated a poor correlation between first-eye and
      second-eye response to the same medication (r(2) = 0.0174). To minimize possible
      contralateral IOP effects of first-eye therapy, a subset of 26 patients treated
      with latanoprost (which has little if any contralateral IOP effect, due to rapid
      systemic metabolism) was studied, with no improvement in correlation (r(2) = 
      0.0023). CONCLUSION: Uniocular trials of glaucoma medications do not adequately
      predict second-eye IOP responses to the same medications. If both eyes of a
      glaucoma patient require IOP reduction, one should not assume that magnitudes of
      response will be equal in both eyes. The effect of a given medicine must be
      assessed independently for each eye.

PMID- 15019315
TI  - The reliability of frequency-doubling perimetry in young children.
AB  - OBJECTIVE: To evaluate whether healthy young children are able to perform
      automated static perimetry reliably using the frequency-doubling technology (FDT)
      perimeter. DESIGN: Prospective, observational case series. PARTICIPANTS: Forty
      healthy children aged 4 to 14 years. TESTING: Subjects underwent, in 1 randomly
      chosen eye, 2 consecutive visual field (VF) tests using the C-20 full-threshold
      program of the commercially available FDT. MAIN OUTCOME MEASURES: Global measures
      included mean deviation (MD), pattern standard deviation (PSD), test duration and
      reliability indices, including fixation losses and false-positive and false
      negative errors. Fixation losses are checked 6 times throughout the examination,
      rather than being continuously monitored. Two scoring systems, based on the total
      deviation probability plot, classified each VF as normal or abnormal. RESULTS:
      All subjects completed the VF test. The better of 2 examinations (as determined
      by the MD score) was used for analysis. The average test duration was 4.9+/-0.7
      minutes for the entire group. The mean MD and PSD were -0.78+/-4.9 and 6.7+/-6.2,
      respectively. A clear correlation to age was found for MD, PSD, abnormality of
      the VF, and test duration (all P<0.05). Of all VFs, 32.5% were unreliable, such
      that at younger than 8 years of age, 42.9% of the VFs were unreliable, compared
      with 23.1% for those older than 8 years. Younger than 8 years of age, 78.6% of
      VFs were abnormal, whereas for ages 8 years and older, 26.9% of VFs were
      abnormal. CONCLUSIONS: Frequency-doubling technology seems to be a clinically
      feasible VF method for evaluating young children older than approximately 8 years
      of age. The reliability indices, MD, test duration, and the reproducibility of
      the VF test were found to be highly correlated with age, in such a way that these
      parameters all improved with increasing age.

PMID- 15019314
TI  - Intraocular pressure-reducing effects and safety of latanoprost versus timolol in
      patients with chronic angle-closure glaucoma.
AB  - OBJECTIVE: To demonstrate that the intraocular pressure (IOP)-reducing effect of
      latanoprost once daily is at least as good as that of timolol twice daily in
      patients with chronic angle-closure glaucoma (CACG). DESIGN: Randomized, double
      masked, multicenter 12-week study. PARTICIPANTS: In all, 137 patients with
      unilateral or bilateral CACG were treated with latanoprost, and 138 were treated
      with timolol. METHODS: Patients received either latanoprost (9 pm) and a placebo
      (9 am) or timolol (both 9 am and 9 pm). Intraocular pressure was measured at 9 am
      and 5 pm at baseline and weeks 2, 6, and 12. MAIN OUTCOME MEASURES: The
      difference between groups in daily IOP (average of 9 am and 5 pm measures)
      reduction was the primary outcome. Secondary outcomes included differences
      between groups in IOP reductions at 9 am and 5 pm, and in proportions of patients
      reaching specified daily IOP levels. RESULTS: Using repeated measures (analysis
      of covariance: intent to treat), mean changes from baseline in daily IOP levels
      during 12 weeks were -8.2 mmHg and -5.2 mmHg for latanoprost- and timolol-treated
      patients, respectively (difference: -3.0 mmHg [95% confidence interval: -4.0, 
      2.1], P<0.001). Greater reductions in IOP levels at both 9 am and 5 pm were found
      in latanoprost-treated patients (P<0.001 for both), and greater proportions of
      patients receiving latanoprost reached prespecified target daily IOP levels
      (P<0.001 for all 3 target levels tested). Both drugs were well tolerated.
      CONCLUSION: Latanoprost administered once daily provides significantly greater
      IOP reduction in CACG patients than does timolol instilled twice daily.

PMID- 15019316
TI  - Longitudinal study of the normal eyes in unilateral keratoconus patients.
AB  - PURPOSE: To determine the rate at which clinically normal eyes in unilateral
      keratoconus (KC) patients progress to KC and to identify the risk factors that
      might predict the development of KC in a longitudinal study. DESIGN: Prospective
      observational study. PARTICIPANTS: We recruited 778 patients with KC and 252
      normal controls in Los Angeles, California. One hundred sixteen of 778 patients
      (14.9%) were diagnosed with clinically unilateral KC at baseline. METHODS: Both
      eyes of these unilateral KC patients were examined at baseline, and 85 patients
      were followed up with clinical evaluation and videokeratography for a period
      ranging from 6 months to 8 years. MAIN OUTCOME MEASURES: Progression to clinical
      KC from previously normal fellow eyes. Quantitative and qualitative
      videokeratography variables, contact lens wear, and demographic variables were
      analyzed as potential predictive factors for this progression. RESULTS: During
      the follow-up period, 30 of 85 (35.3%) clinically normal fellow eyes had KC
      develop, and 25 of these 30 (83.3%) had KC develop within the first 6 years after
      the initial KC diagnosis. By use of the time period from the patients' first
      diagnosis of unilateral KC to the end of the follow-up period (range, 6 months-41
      years), the median time (estimated from the survival analysis) to the development
      of KC was 16.7 years (95% confidence interval, 11.34, 28.91). Fellow eyes with
      higher inferior-superior dioptric asymmetry value (I-S) or KC percentage index
      (logKISA) values had higher risk for KC developing (I-S, risk ratio [RR] = 1.348,
      P = 0.022; log(KISA), RR = 4.245, P = 0.003). Asymmetric patterns also showed an
      increased risk for KC developing (P = 0.03), especially the asymmetric bowtie
      with skewed radial axes (AB/SRAX) pattern. CONCLUSIONS: Approximately 50% of
      clinically normal fellow eyes will progress to KC within 16 years. The greatest
      risk is during the first 6 years of the onset. Quantitative indices (I-S and KISA
      values) and qualitative patterns (AB/SRAX) might predict this progression.

PMID- 15019317
TI  - Wavefront analysis in post-LASIK eyes and its correlation with visual symptoms,
      refraction, and topography.
AB  - PURPOSE: To evaluate the information assessed with the LADARWave wavefront
      measurement device and correlate it with visual symptoms, refraction, and corneal
      topography in previously LASIK-treated eyes. PARTICIPANTS: One hundred five eyes
      (58 patients) of individuals who underwent LASIK surgery were evaluated. DESIGN:
      Retrospective, noncomparative case series. MAIN OUTCOME MEASURES: Complete
      ophthalmologic examination, corneal topography, and wavefront measurements were
      performed. Correlations were made between the examinations and symptoms. METHODS:
      Wavefront measurements were assessed with the LADARWave device. Manifest,
      cycloplegic refraction, and topographic data were compared with wavefront
      refraction and higher order aberrations. Visual symptoms were correlated to
      higher order aberrations in 3 different pupil sizes (5-mm, 7-mm, and scotopic
      pupil size). Pearson's correlation coefficient and generalized estimating
      equations were used for statistical analysis. RESULTS: In post-LASIK eyes,
      wavefront refraction components were poorly correlated to manifest and
      cycloplegic components. The comparison between manifest, cycloplegic, and
      wavefront refraction with total amount of higher order aberrations showed no
      strong correlation. The comparison between topography and manifest, cycloplegic,
      and wavefront refraction did not show strong correlation. Visual symptoms
      analysis showed correlation of double vision with total coma and with horizontal
      coma for the 5-mm and 7-mm pupil size; correlation between starburst and total
      coma for the 7-mm pupil size; and correlation of double vision with horizontal
      coma, glare with spherical aberrations and with total aberrations, and starburst
      with spherical aberrations for the scotopic pupil size. Scotopic pupil size had a
      positive association with starburst and a negative association with double
      vision. CONCLUSIONS: The LADARWave wavefront measurement device is a valuable
      diagnostic tool in measuring refractive error with ocular aberrations in post
      LASIK eyes. A strong correlation between visual symptoms and ocular aberrations,
      such as monocular diplopia with coma and starburst and glare with spherical
      aberration, suggest this device is valuable in diagnosing symptomatic LASIK
      induced aberrations. Horizontal coma was correlated with double vision, whereas
      vertical coma was not.

PMID- 15019318
TI  - Contrast sensitivity after wave front-guided LASIK.
AB  - PURPOSE: To compare the effects on contrast sensitivity of wave front-guided
      (WFG) versus standard LASIK. DESIGN: Prospective, nonrandomized, comparative
      clinical study. PARTICIPANTS: Twenty-four eyes of 13 consecutive patients (mean
      age, 25.2+/-8.4 years; spherical equivalent, -0.5 to -4.25 diopters [D]) treated
      with WFG LASIK (WaveLight-Allegretto scanning-spot laser and wave front analyzer)
      and 22 eyes of 12 consecutive patients (mean age, 28.4+/-9.1 years; spherical
      equivalent, -0.75 to -4.5 D) treated with standard LASIK (WaveLight-Allegretto
      scanning-spot laser). METHODS: Best-corrected contrast sensitivity was measured
      before and 1 month after surgery in both the WFG LASIK group and the standard
      LASIK group. A sine-wave contrast sensitivity test (functional acuity contrast
      test) was used to measure contrast sensitivity at 5 spatial frequencies (1.5, 3,
      6, 12, and 18 cycles/degree). We compared the LASIK-induced changes in contrast
      sensitivity in each groups at each spatial frequency. MAIN OUTCOME MEASURE: The
      effect on contrast sensitivity of WFG LASIK versus standard LASIK. RESULTS:
      Uncorrected visual acuity of 20/20 or better was achieved by 72% of eyes treated
      with WFG LASIK and by 70% of the eyes treated with standard LASIK. One month
      after LASIK, 88% of the contrast sensitivity measurements improved in the WFG
      LASIK group, whereas in the standard LASIK group, only 40% of the contrast
      sensitivity measurements improved. The contrast sensitivity improvement was
      significantly larger in the WFG LASIK group at all spatial frequencies (P<0.05).
      The WFG LASIK patients had a negative correlation between the changes in contrast
      sensitivity and the preoperative refractive error. CONCLUSIONS: The ability of
      WFG LASIK to correct optical aberrations results in significantly improved
      contrast sensitivity compared with standard LASIK 1 month after surgery.

PMID- 15019319
TI  - Topographically guided excimer laser photorefractive keratectomy to treat
      superficial corneal opacities.
AB  - OBJECTIVE: To demonstrate the efficacy and safety of topographically guided
      excimer laser photorefractive keratectomy (PRK) in treating superficial corneal
      opacities. DESIGN: Prospective, noncomparative interventional case series.
      METHODS: Twenty-six eyes of 24 patients with postinfectious (n = 6), post
      traumatic (n = 18), and post-PRK (n = 2) scars were treated with an excimer laser
      linked to a computerized videokeratography unit with a topographically supported
      customized ablation workstation. MAIN OUTCOME MEASURES: Manifest spectacle
      refraction, best spectacle-corrected visual acuity (BSCVA), uncorrected visual
      acuity (UCVA), change of corneal clarity, and topographic indexes of surface
      regularity. RESULTS: The mean follow-up period was 7.7+/-2.1 months (+/- standard
      deviation) (range = 6-12). Corneal clarity and corneal topography patterns
      improved in all eyes. Uncorrected visual acuity improved from 0.7+/-0.8 logarithm
      of the minimum angle of resolution (logMAR) to 0.4+/-0.5 logMAR (P = 0.008), and
      BSCVA improved from 0.3+/-0.6 logMAR to 0.1+/-0.6 logMAR (P<0.001). The BSCVA
      increased in all eyes (>/=2 lines in 76.9% of eyes and 1 line in 23.1%). The mean
      spherical equivalent refraction changed from -0.125+/-2.77 diopters (D) to
      +1.33+/-1.28 D (P = 0.019). CONCLUSIONS: The use of topographically guided PRK
      with the topographically supported customized ablation method resulted in
      significant increases of UCVA and BSCVA and improved corneal clarity in all
      patients. The technique seems to be safe and effective for treating various
      superficial corneal diseases, including postinfectious, post-traumatic, and post
      PRK scars.

PMID- 15019321
TI  - Viability of limbal epithelium after anterior lamellar harvesting using a
      microkeratome.
AB  - OBJECTIVE: To determine the viability in cold eye bank storage of different
      layers of central and limbal corneal epithelium, including the limbal basal stem
      cell population, on days 0, 3, 6, and 9 after harvest using a large diameter
      microkeratome system. METHODS: Twenty-two human whole globes not suitable for
      transplantation were obtained from an eye bank (San Diego Eye Bank, San Diego,
      California) and used for study. Large-diameter anterior corneal discs were
      prepared using a large diameter microkeratome and stained with calcein AM and an
      ethidium homodimer to differentiate live from dead cells, respectively. A laser
      confocal microscope and digital imaging were used to distinguish live (green)
      from dead (red) cells. Central and limbal epithelial regions were isolated and
      the middle and basal epithelial sections were cell counted by 3 independent
      observers. These sections were stored up to 9 days at 4 degrees C in an eye bank
      corneal storage medium. Differences were tested using nonparametric methods. MAIN
      OUTCOME MEASURES: The percentage of live cells in each of these epithelial layers
      was determined for up to 9 days in cold eye bank corneal storage medium. RESULTS:
      At all time points studied, the better protected basal epithelial layers
      displayed greater mean viability than the overlying middle epithelial layers.
      However, the difference was not statistically significant on all days. When
      comparing the basal epithelial viability of the limbal and central regions, after
      day 0 in 4 degrees C cold organ culture, the observed viability of the limbal
      basal epithelium, the purported location of the limbal epithelial stem cell
      region, was significantly greater than that of the central epithelium. On day 0,
      median limbal basal versus central basal epithelial viability were 100% (range,
      71.7-100%) versus 98.4% (range, 88.9-100%) (P>0.05); on day 3, 100% (range, 64.3
      100%) versus 63.4% (range, 13.6-95.5%) (P<0.0005); on day 6, 95.0% (range, 35.0
      100%) versus 28.0% (range, 0-92.0%) (P<0.0005); and on day 9, 95.0% (range, 3.7
      100%) versus 68.6% (range, 0-100%) (P<0.0005). CONCLUSIONS: After microkeratome
      harvesting, the limbal basal epithelium is significantly longer lived in cold eye
      bank storage than central basal epithelium and the middle layers of limbal and
      central epithelium. This longevity not only bodes well for organ storage of
      limbal grafts, but also confirms the hardiness of the stem cell region.

PMID- 15019320
TI  - Avellino corneal dystrophy after LASIK.
AB  - OBJECTIVE: To report cases of Avellino corneal dystrophy (ACD) exacerbated by
      LASIK for myopia. DESIGN: Retrospective, noncomparative, interventional case
      series and review of the literature. PARTICIPANTS: Seven patients. INTERVENTION:
      Six patients with exacerbation of granular corneal deposits after LASIK were
      examined for TGFBI mutations by polymerase chain reaction sequencing of DNA. One
      previously reported patient who was heterozygous for the ACD gene was followed up
      for 16 months after mechanical removal of granular deposits from the interface
      after LASIK. MAIN OUTCOME MEASURES: Slit-lamp examination, visual acuity,
      manifest refraction, and DNA sequencing analysis. RESULTS: All patients were
      heterozygous for the Avellino dystrophy gene. Corneal opacities appeared 12
      months or more after LASIK. Best spectacle-corrected visual acuity decreased as
      the number and density of the opacities increased. One patient underwent
      mechanical removal of granules from the interface and had a severe recurrence
      within 16 months. Another patient had removal of the granules from the interface
      with PTK, followed by treatment with topical mitomycin C. In this patient, the
      cornea has remained relatively clear for 6 months. CONCLUSIONS: Laser in situ
      keratomileusis increases the deposition of visually significant corneal opacities
      and is contraindicated in patients with ACD. Mechanical removal of the material
      from the interface does not prevent further visually significant deposits.
      Mitomycin C treatment, in conjunction with surgical removal of opacities, may be
      an effective treatment.

PMID- 15019322
TI  - A randomized trial of topical cyclosporin 0.05% in topical steroid-resistant
      atopic keratoconjunctivitis.
AB  - OBJECTIVE: To evaluate the short-term efficacy and safety of topical cyclosporin
      A 0.05% in the treatment of patients with severe, steroid-resistant atopic
      keratoconjunctivitis (AKC). DESIGN: Multicenter, placebo-controlled, double
      masked, randomized trial. PARTICIPANTS: Twenty-two patients with AKC refractory
      to topical steroid treatment. INTERVENTION: Patients were randomly assigned (1:1)
      to treatment with topical 0.05% cyclosporin A eyedrops or a placebo (artificial
      tears) for a period of 28 days, 6 times daily during the first 2 weeks and 4
      times daily during the last 2 weeks. MAIN OUTCOME MEASURES: Symptoms (itching,
      tearing, discomfort, mucous discharge, and photophobia) and signs (bulbar
      conjunctival hyperemia, upper tarsal conjunctival papillae, punctate keratitis,
      corneal neovascularization, cicatrizing conjunctivitis, and blepharitis) of AKC
      recorded on the day of enrollment and at the end of the treatment period.
      RESULTS: A composite score computed by summing the severity grade over all 5
      symptoms and 6 signs of AKC for each patient indicated a greater improvement in
      the cyclosporin A group relative to the placebo at the end of the 4-week
      treatment period (P = 0.048 and P = 0.002, for symptoms and signs, respectively).
      No adverse effects of the treatment with cyclosporin A 0.05% eyedrops were
      observed. CONCLUSIONS: Topical cyclosporin A 0.05% seems to be safe and have some
      effect in alleviating signs and symptoms of severe AKC refractory to topical
      steroid treatment.

PMID- 15019323
TI  - Nine-year incidence of lens opacities in the Barbados Eye Studies.
AB  - OBJECTIVE: To provide 9-year cumulative incidence of age-related lens opacities
      in a predominantly black population. DESIGN: Population-based cohort study, after
      9 years of follow-up (n = 2793; 81% participation). MAIN OUTCOME MEASURES: Nine
      year cumulative incidence and progression of lens opacities, by type, based on
      the Lens Opacities Classification System II at the slit lamp. RESULTS: Black
      participants had a higher 9-year incidence of overall lens changes than white
      participants (age- and gender-adjusted relative risk [RR], 1.8; 95% confidence
      interval [CI], 1.2-2.8), as well as of cortical opacities (RR, 3.2; 95% CI, 1.7
      6.2). In black participants, incidence rates of any cortical and any nuclear
      opacities were 33.8% and 42.0%, respectively, and higher than for any posterior
      subcapsular (PSC) opacities (6.3%). The incidence increased with age for all 3
      types, and women had a higher risk of cortical and nuclear opacities (P<0.05).
      Single cortical opacities were the most frequent type to develop by the 9-year
      follow-up (23.2%), followed by nuclear-only opacities (17.1%) and mixed opacities
      (15.3%). Progression rates of pre-existing opacities were 22.0% for cortical,
      17.8% for nuclear, and 25.8% for PSC opacities. CONCLUSIONS: The 9-year follow-up
      of this cohort indicated a high incidence and progression of cortical and nuclear
      opacities, highlighting the public health importance of cataract in black
      populations.

PMID- 15019324
TI  - Incidence and prevalence of uveitis in Northern California; the Northern
      California Epidemiology of Uveitis Study.
AB  - PURPOSE: To determine the incidence and prevalence of uveitis in a large, well
      defined population in Northern California. DESIGN: Cross-sectional study using
      retrospective database and medical record review. PARTICIPANTS: A group of 2070
      people within 6 Northern California medical center communities (N = 731 898) who
      had a potential diagnosis of uveitis. METHODS: The patient database of a large
      health maintenance organization (2 805 443 members at time of the study) was
      searched for all patients who, during a 12-month period, had the potential
      diagnosis of uveitis. Detailed quarterly gender- and age-stratified population
      data were available. Medical records of patients who potentially had uveitis and
      who were members of the 6 target communities were reviewed by 2 uveitis
      subspecialists to confirm the diagnosis of uveitis and to establish time of
      onset. Demographic and clinical data were gathered for patients meeting the
      clinical definition of uveitis. Incidence rates were calculated by using a
      dynamic population model. Prevalence rates were based on the mid-study period
      population. MAIN OUTCOME MEASURES: Presence and date of onset of uveitis.
      RESULTS: At midstudy, the population for the 6 communities was 731 898. During
      the target period, 382 new cases of uveitis were diagnosed; 462 cases of uveitis
      were diagnosed before the target period. These data yielded an incidence of
      52.4/100 000 person-years and a period prevalence of 115.3/100 000 persons. The
      incidence and prevalence of disease were lowest in pediatric age groups and were
      highest in patients 65 years or older (P<0.0001). The prevalence of uveitis was
      higher in women than in men (P<0.001), but the difference in incidence between
      men and women was not statistically significant. Comparison between the group of
      patients who had onset of uveitis before the target period (ongoing uveitis) and
      the entire cohort of uveitis patients showed that women had a higher prevalence
      of ongoing uveitis than men and that this difference was largest in the older age
      groups (P<0.001). CONCLUSION: In this largest population-based uveitis study in
      the United States to date, the incidence of uveitis was approximately 3 times
      that of previous U.S. estimates and increased with the increasing age of
      patients. Women had a higher prevalence of uveitis than men, and the largest
      differences were in older age groups.

PMID- 15019327
TI  - Asymmetry of choroidal venous vascular patterns in the human eye.
AB  - PURPOSE: To describe the angioarchitecture of choroidal veins in normal subjects
      using indocyanine green (ICG) angiography. DESIGN: Consecutive observational case
      series. PARTICIPANTS: Thirty-six eyes of 33 healthy volunteers ranging in age
      from 21 to 81 years (50.0+/-18.2 [mean +/- standard deviation]). METHODS:
      Indocyanine green angiography was performed with a modified Topcon fundus ICG
      camera. Montage images were obtained during the venous phase of the ICG
      angiogram. MAIN OUTCOME MEASURES: Indocyanine green angiographic montage images
      covering all areas of the observable fundus. RESULTS: Eighteen of 36 eyes
      examined (50%) showed asymmetry of choroidal venous vascular patterns consistent
      with a preferential route of choroidal venous drainage of the macular region.
      Twelve of the 18 eyes with a preferred drainage route drained superotemporally;
      the remaining 6 eyes drained by either an inferotemporal or a superonasal route.
      A preferential choroidal venous drainage route in the macula was identified with
      equal frequency in young and old subjects. Of 36 eyes examined, 27 (75%) lacked
      ICG angiographic evidence of symmetric separation of outer choroidal veins.
      CONCLUSIONS: There is ICG angiographic evidence of asymmetry of choroidal venous
      drainage in one half of normal individuals. The relative frequency of a resulting
      preferential drainage route in a group of normal subjects and the equal
      distribution in young and old subjects indicate that this finding is neither
      pathologic nor attributable to aging. There is also ICG angiographic evidence for
      a lack of symmetric separation in the outer choroidal venous system in the
      majority of normal human subjects tested, indicating that classic watershed zones
      may not be present or are less prominent in this portion of the choroidal
      vasculature.

PMID- 15019326
TI  - Evaluation of patients with scleritis for systemic disease.
AB  - OBJECTIVE: To evaluate the relationship between associated medical conditions and
      scleritis-particularly, the timing of the diagnosis of these diseases. DESIGN:
      Retrospective case series. PARTICIPANTS: Patients with scleritis presenting to a
      single center over an 18-year period. METHODS: Medical records were reviewed for
      the presence of an associated infectious or rheumatic disease and for the timing
      of the diagnosis of the systemic disease relative to the presentation for
      evaluation of the scleritis. MAIN OUTCOME MEASURES: Presence of an associated
      medical condition and timing of diagnosis relative to that of scleritis. RESULTS:
      In a series of 243 patients with scleritis, 44.0% had an associated medical
      condition: 7.0%, an infection, and 37.0%, a rheumatic disease. The most frequent
      infection was herpes zoster, and the most frequent rheumatic disease was
      rheumatoid arthritis, present in 4.5% and 15.2% of patients, respectively. Of the
      107 patients with an underlying disease, 77.6% had a previously diagnosed
      disease, 14.0% had their conditions diagnosed as a result of the initial
      evaluation, and 8.4% developed a systemic disease during follow-up. Systemic
      vasculitis was less likely to have been previously diagnosed than other rheumatic
      diseases (59.1% vs. 83.8%, P = 0.015) and more likely to be diagnosed by the
      initial diagnostic evaluation (27.3% vs. 8.8%, P = 0.027). Ten patients (4.1%)
      had a positive antineutrophil cytoplasmic antibody (ANCA) test result without
      clinical evidence of a systemic vasculitis. Four of 5 patients with a positive
      cytoplasmic ANCA test result but no clinical evidence of systemic vasculitis
      required immunosuppressive drugs for control of the scleritis, whereas 1 of the 5
      patients with a positive perinuclear ANCA test result required immunosuppressive
      drugs. Among patients with no evident systemic disease after the initial
      diagnostic evaluation, the rate of occurrence of a rheumatic disease was 4% per
      person-year. CONCLUSIONS: Although associated systemic diseases are frequent
      among patients with scleritis, the majority are previously diagnosed. Systemic
      vasculitis is less likely than other rheumatic diseases to have been previously
      diagnosed. Because vasculitis is a potentially life-threatening disorder, it
      should be a focus of the diagnostic evaluation.

PMID- 15019328
TI  - Age-related macular degeneration causing visual impairment in people 75 years or
      older in Britain: an add-on study to the Medical Research Council Trial of
      Assessment and Management of Older People in the Community.
AB  - PURPOSE: Age-related macular degeneration (AMD) is the most commonly occurring
      cause of visual loss in people registered as blind or partially sighted. There
      are no nationally representative data on the prevalence of AMD in the British
      population. We aimed to estimate the prevalence of AMD causing visual impairment
      in people 75 years or older in Britain. DESIGN: Population-based cross-sectional
      study. PARTICIPANTS: Thirteen thousand nine hundred people 75 years or older in
      49 practices taking part in the Medical Research Council Trial of the Assessment
      and Management of Older People in the Community. METHODS: Trial nurses tested
      visual acuity in everyone 75 years or older in participating practices. We
      collected data on the cause of visual loss for everyone who was visually
      impaired. We obtained these data from review of the general practice medical
      notes and by sending a questionnaire to the hospital ophthalmologist. Visual
      impairment was defined as a binocular acuity of less than 6/18. MAIN OUTCOME
      MEASURE: Prevalence of AMD causing visual impairment. RESULTS: There were 976
      visually impaired people for whom a cause of visual loss was established. Of
      these, 516 (53%) had AMD as a cause of visual loss. We estimate that 3.7% (95%
      confidence interval, 3.2%-4.2%) of the population 75 years or older and 14.4%
      (11.6%-17.2%) of the population 90 years or older are visually impaired due to
      AMD. There are an estimated 192 000 people 75 years or older visually impaired
      due to AMD in the United Kingdom (95% confidence interval, 144 000-239 000).
      CONCLUSION: Our results, from the largest and most representative study of the
      causes of vision loss in older people in the British population, confirm the
      substantial burden of AMD in people 75 years and older. As the population ages,
      this problem will get worse. The needs of this group for vision aids and other
      support in the community should be addressed; research on the causes of AMD and
      possible preventive measures should be given priority.

PMID- 15019329
TI  - The fellow eye of patients with rhegmatogenous retinal detachment.
AB  - OBJECTIVE: To determine how often the fellow eyes of patients with rhegmatogenous
      retinal detachment (RRD) without proliferative vitreoretinopathy (PVR) harbor
      vision-threatening conditions at presentation and during follow-up. DESIGN:
      Retrospective, observational case series. PARTICIPANTS: Two hundred forty-eight
      patients with RRD without PVR were studied. INTERVENTION: The authors observed
      the fellow eye of patients with RRD for vision-threatening pathology. MAIN
      OUTCOME MEASURE: Detection of vision-threatening pathology in the fellow eye of
      patients with RRD without PVR. RESULTS: Two hundred forty-eight patients were
      observed for an average of 5.2 years. One hundred fifty-seven vision-threatening
      events or diagnoses occurred in the fellow eye, including pre-existing and newly
      diagnosed conditions, 97 (62%) of which were rhegmatogenous in nature. Fifty-six
      patients (23%) had retinal detachments in their fellow eye, including those with
      a history of RRD repair (28 eyes), those presenting with bilateral RRD (4 eyes),
      and those developing new RRD during follow-up (24 eyes). In addition, 1 patient
      developed recurrent retinal detachment in the fellow eye during follow-up.
      Retinal tears were diagnosed and treated with laser retinopexy or cryotherapy in
      30 (12%) fellow eyes (4 before the initial examination, 7 upon initial
      examination, and 19 on follow-up). Lattice degeneration was present in 27 (11%)
      fellow eyes. CONCLUSIONS: Patients who develop RRD are at considerable risk for
      developing vision-threatening events, particularly rhegmatogenous events, in the
      fellow eye.

PMID- 15019330
TI  - Retinal and choroidal biopsies are helpful in unclear uveitis of suspected
      infectious or malignant origin.
AB  - OBJECTIVES: To assess the clinical value of retinal or choroidal biopsy in
      establishing a definitive diagnosis directing subsequent management and to assess
      the risk involved in such surgery. DESIGN: Retrospective noncomparative
      interventional case series. PARTICIPANTS: Thirteen patients with uveitis of
      suspected malignant or infectious origin. One patient had 2 consecutive biopsies
      on the same eye. METHODS: A retrospective review of a 4-year period was
      undertaken of all those cases in which the biopsy was taken for diagnostic
      purposes at a single institution. MAIN OUTCOME MEASURES: Ability of biopsy to
      establish a pathologic diagnosis and guide treatment and surgical complications.
      RESULTS: A transscleral approach was used in 4 and a pars plana vitrectomy
      approach in 10 of the biopsies. The only operative complication was a retinal
      break in 1 case. Postoperative events that might be related to the surgery
      included 1 localized retinal detachment, 2 cataracts, and 1 phthisical eye. The
      pathologic diagnosis differed from the initial clinical diagnosis in 5 of the 13
      cases. The biopsy result directed specific appropriate treatment in 7 of the 13
      cases. In the 6 remaining cases, no specific diagnosis was confirmed, but the
      results of the biopsy were useful in excluding malignancy and in some cases
      allowing a therapeutic trial. CONCLUSIONS: Retinal or choroidal biopsy is a
      valuable investigation that often changes clinical management when carried out
      for specific indications in patients with uveitis of suspected malignant or
      infectious origin. Although it is likely to remain an investigation of last
      resort, it should be considered at an earlier stage when there is diagnostic
      uncertainty if severe visual loss is to be prevented.

PMID- 15019331
TI  - Posterior segment manifestations of Rickettsia conorii infection.
AB  - PURPOSE: To characterize and analyze the posterior segment manifestations of
      Mediterranean spotted fever (MSF), an infectious disease caused by Rickettsia
      conorii. DESIGN: Prospective, noncomparative case series. PARTICIPANTS: Thirty
      patients (60 eyes) with serologically proven MSF at the acute stage. METHODS:
      Patients underwent complete ophthalmic examination, including dilated
      biomicroscopic fundus examination, fundus photography, and fluorescein
      angiography. Sequential follow-up examinations were performed in patients with
      evidence of posterior segment involvement. RESULTS: Of 30 patients, 25 (83.3%)
      had unilateral (n = 5) or bilateral (n = 20) posterior segment involvement
      related to MSF. Of those 25 patients, 16 (64%) had no ocular symptoms, and 9
      (36%) had ocular complaints. Findings included mild vitreous inflammation (45
      eyes [75%]), white retinal lesions (18 eyes [30%]), focal vascular sheathing (5
      eyes [8.3%]), multiple arterial plaques (1 eye [1.7%]), intraretinal hemorrhages
      (14 eyes [23.3%]), white-centered retinal hemorrhages (2 eyes [3.3%]), subretinal
      hemorrhages (2 eyes [3.3%]), serous retinal detachment (3 eyes [5%]), macular
      star (2 eyes [3.3%]), cystoid macular edema (1 eye [1.7%]), optic disc edema (1
      eye [1.7%]), branch retinal artery occlusion (1 eye [1.7%]), optic disc staining
      (30 eyes [50%]), retinal vascular leakage (27 eyes [45%]), delayed filling in a
      branch retinal vein (1 eye [1.7%]), and multiple hypofluorescent choroidal dots
      (10 eyes [16.7%]). One eye (1.7%) had retinal neovascularization at the 6-month
      follow-up examination. All posterior segment findings at the acute stage resolved
      in 3 to 10 weeks, and the final visual acuity was 20/20 in 42 of 45 affected eyes
      (93.3%). Retinal pigment epithelium changes developed in 9 eyes (15%), with
      resolved full-thickness white retinal lesions. No other abnormalities were noted
      in the eye with retinal neovascularization over a further follow-up of 6 months.
      CONCLUSION: Posterior segment involvement, frequently asymptomatic, is common in
      patients with acute MSF. Because the diagnosis can be easily overlooked, a
      careful dilated funduscopic examination, complemented by fluorescein angiography
      in selected cases, is recommended. Mild vitritis, retinal vasculitis, optic disc
      staining, white retinal lesions, retinal hemorrhages, and multiple
      hypofluorescent choroidal dots are the most common manifestations of MSF.
      Posterior segment changes in a patient with fever and/or skin rash living in or
      returning from a specific endemic area, especially during the spring or summer,
      strongly suggest R. conorii infection.

PMID- 15019333
TI  - Sheathotomy to decompress branch retinal vein occlusion: a matched control study.
AB  - PURPOSE: To evaluate the efficacy and safety of arteriovenous sheathotomy surgery
      to decompress branch retinal vein occlusion (BRVO). DESIGN: Prospective,
      nonrandomized, comparative interventional trial with concurrent control group.
      PARTICIPANTS: Twenty eyes with decreased visual acuity secondary to BRVO who
      underwent vitrectomy and surgical decompression by means of arteriovenous
      sheathotomy were compared with 20 control eyes (10 observation and 10 laser
      treated). INTERVENTION: The 20 surgical eyes underwent pars plana vitrectomy and
      arteriovenous sheathotomy with a microvitreoretinal blade. Of the 20 control
      eyes, 10 had no intervention (observation), and 10 had grid laser
      photocoagulation a mean of 9 months after diagnosis. RESULTS: The mean
      preoperative visual acuity was 20/250 in the surgical group and 20/180 in the
      control group (statistically similar in the observation group and laser-treated
      group). The mean 14-month visual acuity was 20/63 in the surgical group and
      20/125 in the control group (P = 0.02). Seventy-five percent of the surgical
      group halved their visual angle compared with 40% of the control group (40%
      observation vs. 40% laser; P = 0.025). Average lines of visual acuity gained were
      4.55 in the surgical group and 1.55 in the control group (P = 0.0226; 1.1 lines
      in observation group and 2.0 lines in laser group). CONCLUSIONS: Surgical
      arteriovenous sheathotomy to decompress BRVO results in significantly better
      visual outcomes than a matched control group of observation and laser-treated
      eyes. A randomized multicenter clinical trial is warranted to determine the
      efficacy of this procedure.

PMID- 15019332
TI  - Waldenstrom's macroglobulinemia-associated retinopathy.
AB  - OBJECTIVE: To report the clinical, electrophysiologic, and immunopathologic
      findings in a patient with progressive retinal degeneration associated with
      Waldenstrom's macroglobulinemia. DESIGN: Case report with immunohistochemical
      studies. METHODS: A 46-year-old female with elevated serum immunoglobulin M (IgM)
      levels complained of photophobia and photopsias. Complete ophthalmic examinations
      including electrophysiologic testing and hematologic evaluations were performed
      over a 3-year period. Immunohistochemical studies to determine the presence of
      serum antiretinal antibodies were evaluated using confocal microscopy. RESULTS:
      Examination of the patient's fundus remained normal, although there was
      deterioration in her visual acuity, visual field, and electroretinogram over the
      follow-up period. Waldenstrom's macroglobulinemia was diagnosed by bone marrow
      biopsy. Indirect immunohistochemistry revealed reactivity of the patient's serum
      against the photoreceptor-connecting cilium. CONCLUSION: The paraneoplastic
      retinopathy associated with Waldenstrom's macroglobulinemia in this patient is
      presumed to result from antibodies of the IgM subtype reacting to proteins in the
      retinal photoreceptors.

PMID- 15019334
TI  - Three families displaying the combination of Stargardt's disease with cone-rod
      dystrophy or retinitis pigmentosa.
AB  - OBJECTIVE: To investigate the clinical spectrum and molecular causes of retinal
      dystrophies in 3 families. DESIGN: Family molecular genetics study. PARTICIPANTS:
      Sixteen patients and 15 relatives in 3 families. METHODS: Members of 3 families
      with multiple ABCA4-associated retinal disorders were clinically evaluated.
      Deoxyribonucleic acid samples of all affected individuals and their family
      members were analyzed for variants in all 50 exons of the ABCA4 gene. MAIN
      OUTCOME MEASURES: ABCA4-associated retinal phenotypes and mutations in the ABCA4
      gene. RESULTS: In family A, 2 sisters were diagnosed with Stargardt's disease
      (STGD); the eldest sister was compound heterozygous for the mild 2588G-->C and
      the severe 768G-->T mutation. Another patient in this family with a severe type
      of retinitis pigmentosa (RP) carried the 768G-->T mutation homozygously. In
      family B, 2 siblings presented with an RP of severity similar to that encountered
      in family A. Both were homozygous for the severe IVS33+1G-->A mutation. Two other
      family members with STGD were compound heterozygous for the 2588G-->C and
      IVS33+1G-->A mutations. In family C, all 5 siblings of generation II demonstrated
      age-related macular degeneration (AMD). In generations III and IV, 2 STGD
      patients and 1 cone-rod dystrophy (CRD) patient were present. In 1 STGD patient
      we identified a heterozygous 768G-->T mutation. Sequence analysis of the entire
      ABCA4 gene did not reveal the remaining 2 mutations. Nevertheless, the 2 patients
      with STGD, the patient with CRD, and 2 of the AMD patients shared a common
      haplotype spanning the ABCA4 gene. CONCLUSIONS: Different mutations in the ABCA4
      gene are the cause of STGD and RP or CRD in at least 2 and, possibly, 3 families.
      Patients with RP caused by ABCA4 mutations are characterized by an early onset
      and rapid progression of their retinal dystrophy, with extensive chorioretinal
      atrophy resulting in a very low visual acuity. Various combinations of relatively
      rare retinal disorders such as STGD, CRD, and RP in one family may not be as
      uncommon as once believed, in view of the relatively high carrier frequency of
      ABCA4 mutations (about 5%) in the general population.

PMID- 15019335
TI  - Nondiagnosed uveal melanomas.
AB  - PURPOSE: To determine the proportion of nondiagnosed uveal melanomas after
      evaluation by optometrists or ophthalmologists. DESIGN: Retrospective
      observational cohort study. PARTICIPANTS: Four hundred thirty-three ophthalmic
      oncology patients with uveal melanoma. METHODS: This was a retrospective study of
      uveal melanoma patients from a single ophthalmic oncology center. We sent
      questionnaires to living patients we had treated between 1980 and 2000 for uveal
      melanoma. Patients were divided into those who had an examination within 1 year
      before diagnosis of a melanoma in which the tumor was not detected, those
      patients who were being observed with a known pigmented uveal tumor, and those
      who had not had an eye examination for at least 10 years. MAIN OUTCOME MEASURE:
      The detection of unsuspected melanomas. RESULTS: We determined that 37% of
      patients referred to us with a newly discovered uveal melanoma had been examined
      within a year, without a uveal melanoma being detected. Of patients whose medical
      records were obtained, 71% had eyes that had been dilated and the tumor not
      found. The patients in whom the tumors were nondiagnosed within 1 year of
      referral to us had a mean tumor thickness of 6 mm and a mean tumor diameter of 12
      mm. Ninety percent of the tumors were partially posterior to the equator.
      Patients who had been observed by their outside ophthalmologist with a choroidal
      pigmented tumor had significantly smaller tumors (P<0.005). CONCLUSIONS: There
      are a notable number of patients seen by general ophthalmologists with
      symptomatic uveal melanomas in whom the diagnosis is not established. It is
      likely that screening efforts for this relatively rare condition are often not
      efficacious.

PMID- 15019336
TI  - Noninvasive in vivo detection of prognostic indicators for high-risk uveal
      melanoma: ultrasound parameter imaging.
AB  - PURPOSE: Primary malignant melanoma of the choroid and ciliary body has
      traditionally been treated without histologic staging, using purely clinical
      indicators. The presence of extravascular matrix patterns (EMP) in histologic
      sections of uveal melanoma has been shown to be an independent indicator of
      metastatic risk. These patterns are of a dimension and physical composition that
      are likely to be detected with ultrasound backscatter analysis. Our aim was to
      determine whether ultrasound parameter imaging could detect the presence of EMP
      at a diagnostically significant level for treatment staging and for planning
      investigational studies of therapeutic modalities. DESIGN: Prospective, masked
      ultrasound-pathologic correlative study. PARTICIPANTS: One hundred seventeen
      patients diagnosed with previously untreated choroidal melanoma were scanned
      within 2 weeks before enucleation. METHODS: Tumors were evaluated histologically
      and divided into high-risk and low-risk groups on the basis of the presence of 2%
      or more histologic cross-sectional area composed of EMP patterns. Digital
      ultrasound data were processed to generate parameter images representing the size
      and concentration of ultrasound scatterers. Histologic and ultrasound images and
      data were correlated, and linear and nonlinear statistical methods were used to
      create multivariate models for noninvasive differentiation of high-risk and low
      risk tumors. MAIN OUTCOME MEASURES: Presence or absence of high-risk EMP and
      associated ultrasound parameter classification models. RESULTS: Of the 117
      tumors, 69 were classified as low risk, and 48 were classified as high-risk with
      histologic analysis. A classification that used ultrasound parameter image
      features with linear discriminant analysis could correctly identify 79.5% of
      cases retrospectively and 75.2% of cases by use of cross-validation, an estimate
      of prospective classification ability. By use of a more powerful classification
      technique (support vector machine), 93.1% of cases were correctly classified
      retrospectively. With a cross-validation procedure, 80.10% of cases were
      correctly classified. CONCLUSIONS: Ultrasound can be used noninvasively to
      classify tumors into high-risk and low-risk groups by detecting the presence of
      EMP patterns. By the use of previous studies that compared the histologic
      presence of EMP patterns with patient survival, estimates of hazard rates
      associated with ultrasound risk groups can be made. The noninvasive ultrasound
      classification is potentially useful as a prognostic variable and as a tool for
      stratification of patient populations for tumor treatment evaluation.

PMID- 15019337
TI  - Radiation retinopathy after fractionated stereotactic radiotherapy for optic
      nerve sheath meningioma.
AB  - PURPOSE: To report a patient with radiation retinopathy after fractionated
      stereotactic radiotherapy for treatment of optic nerve sheath meningioma (ONSM).
      DESIGN: Interventional case report. METHODS: The clinical presentation, radiation
      treatment, and subsequent visual complications of a patient with ONSM are
      described. MAIN OUTCOME MEASURES: Development of radiation retinopathy and
      Snellen visual acuity. RESULTS: A 36-year-old man presented with a left optic
      neuropathy. Magnetic resonance imaging studies showed abnormalities consistent
      with ONSM. Because of progressive vision loss, the patient underwent fractionated
      stereotactic radiotherapy for the lesion. Vision initially improved after
      treatment, but 22 months later, retinal abnormalities consistent with radiation
      retinopathy were noted in the left eye. Visual acuity worsened over the next 24
      months in association with the development of retinal hemorrhages, lipid, and
      retinal edema predominantly within the nasal portion of the posterior pole.
      Fluorescein angiography showed edema associated with microaneurysms, retinal
      telangiectasia, and capillary nonperfusion. Laser photocoagulation was performed
      on several occasions in areas of microaneurysms and retinal telangiectasia;
      however, the retinal edema and lipid remained, associated with persistent
      decreased vision. CONCLUSIONS: Radiation retinopathy and vision loss may occur
      after fractionated stereotactic radiotherapy for ONSM and should be discussed as
      a potential complication.

PMID- 15019338
TI  - Neurofibromatosis type 1 and optic pathway gliomas: follow-up of 54 patients.
AB  - OBJECTIVE: To describe the natural history of optic pathway gliomas (OPGs) in
      patients with neurofibromatosis type 1 (NF1), and to evaluate the current
      recommended guidelines for monitoring and follow-up of OPGs in this population.
      DESIGN: Retrospective case series. PARTICIPANTS: Patients with OPGs and NF1 seen
      in the neurofibromatosis clinic at the Children's Hospital at Westmead in Sydney,
      Australia. METHODS: Patients with definite NF1 and confirmed OPGs were identified
      and their medical records searched to obtain data on demographics, details of the
      OPG diagnosis, and serial ophthalmic examination findings. Patients were
      stratified into groups according to age and mode of presentation. MAIN OUTCOME
      MEASURES: Visual acuity was recorded for each eye and grouped into mild (Snellen
      equivalent > or = 6/12), moderate (Snellen equivalent = 6/15-6/60), and severe
      (Snellen equivalent < 6/60) visual impairment at time of diagnosis, during follow
      up, and at the most recent examination. RESULTS: Data were collected on 54
      patients, the majority of whom (78%) were seen from 1990 to 2002, with an average
      follow-up of 8.6 years. The mean age at the time of OPG diagnosis was 5.2 years,
      with 32 patients having symptoms or signs at the time of diagnosis. Seventeen
      patients were diagnosed after the age of 6 years (range, 7-15). Twenty-two
      patients had tumor progression within 1 year of diagnosis, and a further 6
      patients showed progression after 1 year. Most patients' conditions were managed
      conservatively (68.5%). At follow-up, 17 patients (31.5%) had severe visual
      impairment (<6/60 Snellen equivalent) in their worse eye, and 16.7% had bilateral
      moderate/severe visual impairment. CONCLUSIONS: Contrary to some previous
      reports, our results show that OPGs in patients with NF1 often present in older
      children and may progress some time after diagnosis. Given the potential for
      serious visual consequences, these findings indicate a need for regular
      ophthalmological monitoring of this population for a long duration.

PMID- 15019339
TI  - Surgery for trichiasis by ophthalmologists versus integrated eye care workers: a
      randomized trial.
AB  - OBJECTIVE: To study the outcome of bilamellar tarsal rotation (BTR) trichiasis
      surgery performed by ophthalmologists versus that done by integrated eye care
      workers (IECWs). DESIGN: Randomized prospective interventional trial.
      PARTICIPANTS: Nine hundred eighty-two patients with various degrees of
      trachomatous trichiasis in central Ethiopia. METHODS: Trachomatous trichiasis
      patients in 3 woredas (districts) in central Ethiopia were enrolled. Trichiasis
      severity was graded. Patients were randomly assigned to surgery by 2
      ophthalmologists and 2 IECWs. On the seventh day postoperatively, patients were
      evaluated for undercorrection or other complications. If trichiasis was present,
      it was considered a failure of surgery (technical failure), and patients were
      excluded from the follow-up study, but repeat surgery was performed. Those
      patients with good correction at the seventh day were examined again on the third
      and sixth months. Further follow-up evaluation is planned for the first, second,
      and third years postoperatively. MAIN OUTCOME MEASURES: Recurrence rate,
      recurrence difference in the various grades, and difference between surgeries
      done by ophthalmic surgeons and those done by IECWs. RESULTS: In the third month
      of follow-up, it was possible to locate 713 (73.0%) of the operated patients.
      Eighty-one of 713 (11.4%) individuals and 94 of 1286 (5.4%) operated lids
      developed recurrent trichiasis in this period. There was a linear trend of
      recurrence with grading (severity) at baseline (chi(2) = 22.017, P<0.001), but
      there was no difference in recurrence by age (chi(2) =1.53, P = 0.9 at the third
      month; chi(2) = 1.43, P = 0.9 at the sixth month). There was also no difference
      with regard to gender (0.38 < odds ratio < 1.14, P = 0.1). The recurrence
      observed in the group of individuals operated on by ophthalmologists at the 3
      month follow-up was 47 (12.1%) lids, and the recurrence observed in the group
      operated on by the IECWs was 34 (9.9%) lids, with no statistically significant
      difference (chi(2) =1.38, P = 0.24, 95% confidence interval [CI], -18% to 74%).
      At the 6-month follow-up, 43 (6.2%) persons had recurrence (95% CI, 4.4%-8%).
      There was no statistically significant difference between the 2 groups of
      surgeons at the 6-month point of follow-up examination (chi(2) = 4.46, P = 0.2).
      The overall recurrence was 124 (14.3%) lids within the first 6 months.
      CONCLUSION: Recurrent trichiasis is common, especially in cases where the degree
      of trichiasis is severe at baseline. This suggests that these patients may need
      surgical overcorrection to decrease the recurrence rate. The outcome of BTR
      surgery done by IECWs is similar to that of the ophthalmic surgeons. Because of
      these findings, we recommend that training of IECWs in trichiasis surgery may
      help to ameliorate the effects of the eye care worker shortage in developing
      countries.

PMID- 15019340
TI  - Endoscopically assisted balloon dacryoplasty treatment of incomplete nasolacrimal
      duct obstruction.
AB  - PURPOSE: To report the success rate of endoscopically assisted balloon
      dacryoplasty (EADCP) for treatment of acquired incomplete nasolacrimal duct
      obstructions (NLDOs). DESIGN: Retrospective, noncomparative case series.
      PARTICIPANTS: Records of patients treated for incomplete NLDOs with EADCP by one
      of the authors (WLW) were reviewed. Diagnosis of incomplete NLDO was based upon
      subjective complaints of tearing, dye disappearance testing, clinical evidence of
      epiphora, and nasolacrimal duct irrigation. Endoscopically assisted balloon
      dacryoplasty was performed for incomplete obstructions identified. METHODS: One
      hundred forty-two nasolacrimal systems in 103 patients with incomplete NLDOs
      underwent EADCP for treatment of incomplete obstructions. A 3x15-mm balloon was
      utilized in all procedures, with silicone lacrimal tubes placed in 131 systems.
      Patients received postoperative topical antibiotic-steroid drops for 2 weeks and
      a 1-week tapering dosage of systemic methylprednisolone. MAIN OUTCOME MEASURES:
      Patients were assessed at their last postoperative visit by nasolacrimal system
      irrigation, dye disappearance testing, and subjective complaints of epiphora.
      RESULTS: Eighty systems (56%) experienced complete resolution of symptoms after
      surgery. Forty-eight additional systems (34%) showed improvement but still
      experienced periodic epiphora. Fourteen systems (10%) showed no improvement. The
      average time before follow-up was 7.5 months. CONCLUSION: Endoscopically assisted
      balloon dacryoplasty as a treatment for incomplete NLDOs provides complete relief
      or substantial improvement in a significant percentage of patients. Nasal
      videoendoscopy adds significantly to the understanding of this procedure and its
      potential for success. Endoscopically assisted balloon dacryoplasty should be
      considered an appropriate treatment option for selected patients with incomplete
      NLDOs.

PMID- 15019342
TI  - Head tilt-dependent esotropia associated with trisomy 21.
AB  - OBJECTIVE: To describe a series of patients who used a head tilt to control
      esotropia. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Seven
      children with esotropia that decreased with their compensatory abnormal head
      tilt. Six of the patients had trisomy 21. The patients had no other identifiable
      etiology for their head tilt, including no oblique muscle dysfunction, nystagmus
      that changed with head tilt, or uncorrected refractive error. INTERVENTION: Six
      patients underwent horizontal extraocular muscle surgery. Preoperative evaluation
      in 4 patients included assessment of the change in head position with either
      monocular occlusion or prisms. MAIN OUTCOME MEASURES: Ocular alignment in primary
      position and improvement in abnormal head tilt after surgery. RESULTS: In the 4
      patients who underwent preoperative testing, the abnormal head tilt resolved with
      either monocular occlusion or prisms. The head tilt and esotropia were eliminated
      or improved in all patients who underwent strabismus surgery. CONCLUSIONS:
      Abnormal head tilt may be used as a compensatory maneuver to improve purely
      horizontal strabismus. This finding appears to be associated with trisomy 21.
      Horizontal extraocular muscle surgery may improve the head tilt in such patients.

PMID- 15019343
TI  - Protective eyewear for young athletes.
AB  - American Academy of Pediatrics and the American Academy of Ophthalmology strongly
      recommend protective eyewear for all participants in sports in which there is
      risk of eye injury. Protective eyewear should be mandatory for athletes who are
      functionally one-eyed and for athletes whose ophthalmologists recommend eye
      protection after eye surgery or trauma.

PMID- 15019341
TI  - Orthokeratology lens-related corneal ulcers in children: a case series.
AB  - OBJECTIVE: Orthokeratology is a process by which the corneal curvature is
      flattened by sequentially fitting rigid gas permeable contact lenses of
      decreasing central curvature. There has been a resurgence of interest with the
      recent introduction of reverse geometry lenses. Although promising results have
      been described in reducing the myopic refractive error, the use of these lenses
      can be associated with corneal problems, as reported in this case series. DESIGN:
      Observational case series. PARTICIPANTS: Six children with orthokeratology
      related corneal ulcers. METHODS: Consecutive cases of orthokeratology lens (OKL)
      related corneal ulcers in children presented to a tertiary referral center (March
      1999-June 2001) were reviewed. MAIN OUTCOME MEASURES: Preinfection and
      postinfection visual acuity, refraction, any organisms identified. RESULTS: Six
      children between the ages of 9 and 14 years (mean = 12.1) were treated. The
      male:female ratio was 1:5. All cases were unilateral, with equal numbers of left
      and right eyes. All children wore the OKL at night for a duration of 8 to 12
      hours, with the onset of infection between 3 and 36 months (mean = 16.6) of OKL
      wear. All of the patients suffered a resultant best-corrected visual acuity loss.
      Five of the 6 cases were culture positive for Pseudomonas aeruginosa.
      CONCLUSIONS: In view of the temporary benefits of orthokeratology, together with
      a known increased risk of infection associated with overnight lens wear, parents
      of children considering orthokeratology must be informed and warned of the
      potential for permanent loss of vision. The ophthalmic community should have a
      heightened awareness of the associated complications.

PMID- 15019344
TI  - Screening with photoscreening photographs.

PMID- 15019345
TI  - Monitored anesthesia care.

PMID- 15019347
TI  - Patients with Sturge-Weber syndrome.

PMID- 15019349
TI  - Patchy ischemic retinal whitening.

PMID- 15019351
TI  - Quality of life instrument and retinal diseases.

PMID- 15019353
TI  - Needle tap in the diagnosis of inflammation.

PMID- 15019355
TI  - Preferred practice pattern changes.

PMID- 15019357
TI  - PION after lumbar spine injury.

PMID- 15019359
TI  - PION after lumbar spine injury.

PMID- 15019361
TI  - Videokeratoscopic indices for keratitis sicca.

PMID- 15019363
TI  - Biostatistical education in ophthalmology.

PMID- 15019364
TI  - Temporal variation in diabetic macular edema measured by optical coherence
      tomography.
AB  - PURPOSE: To determine, by optical coherence tomography (OCT), whether there is a
      quantitative decrease in macular edema in diabetic subjects over the course of a
      day. STUDY DESIGN: Observational case series. PARTICIPANTS: Ten subjects with
      diabetic macular edema in 1 or both eyes. METHODS: Subjects were admitted to the
      hospital the evening before the study so that they would remain in the recumbent
      position until immediately before study measurements began. They then underwent 4
      OCT measurements of macular thickness in both eyes, at 8:00 am, 11:00 am, 2:00
      pm, and 5:00 pm. At each of these times, they also had refractions and visual
      acuity measurements using the Early Treatment Diabetic Retinopathy Study
      protocol. Macular thickness measurements determined by the Zeiss-Humphrey
      (Dublin, CA) optical coherence tomograph for each eye of each subject were
      plotted as a function of time. MAIN OUTCOME MEASURES: Temporal changes in retinal
      thickness in each of the 9 macular sectors defined by the OCT protocol and in the
      entire macula of each eye, averaged from all 9 sectors; temporal changes in
      refractive error and visual acuity. RESULTS: Four of the 10 subjects showed
      consistent decreases in macular thickness over the course of the day in 1 or more
      of the retinal sectors in 1 or both eyes. When macular thickness values were
      averaged over all 9 sectors for all subjects, both eyes showed consistent
      declines in mean thickness throughout the day. By t test, the 8 am value in each
      eye was significantly higher (P<0.0005) than any of the 3 later values, which did
      not differ significantly from each other. However, comparison of all 4 values by
      analysis of variance showed no significant differences. With the exception of 1
      subject, there were no consistent changes in refractive error or in best
      corrected visual acuity over the course of the study. CONCLUSIONS: This study,
      using quantitative OCT determinations, seems to confirm the much earlier report
      by Sternberg et al, which used more subjective methods, that macular edema might
      vary over the day. That the 8 am value, obtained just after waking, was higher
      than the 3 later values (highly significant by 1 test) suggests that the decrease
      in macular thickness is most likely due to the shift from recumbent to upright
      body position, although our study protocol did not exclude other possible
      mechanisms. Although changes in macular thickness over the course of the day did
      not occur in all subjects, therapeutic studies for macular edema that use OCT as
      an outcome measure should control for time of day when these measurements are
      carried out.

PMID- 15019365
TI  - Intravitreal triamcinolone acetonide for diabetic diffuse macular edema:
      preliminary results of a prospective controlled trial.
AB  - OBJECTIVE: To evaluate prospectively the efficacy and safety of 1 intravitreal
      injection of 4 mg of triamcinolone acetonide for refractory diffuse diabetic
      macular edema. DESIGN: Interventional case series. PARTICIPANTS: Fifteen patients
      with bilateral diabetic macular edema unresponsive to laser photocoagulation. In
      all patients, one eye received the injection, and the other served as a control.
      INTERVENTION: Intravitreal injection of 4 mg of triamcinolone acetonide under
      subconjunctival anesthesia. MAIN OUTCOME MEASURES: The main outcome measure was
      central macular thickness (CMT) at 1, 3, and 6 months, measured by optical
      coherence tomography. Secondary outcomes were Early Treatment Diabetic
      Retinopathy Study (ETDRS) scores, intraocular pressure, and cataract progression.
      RESULTS: In this preliminary report, we give the results for 12 patients who had
      a follow-up of at least 3 months. Seven of them were followed up for 6 months.
      Before injection, CMT was 509.6+/-143.5 microm (mean +/- standard deviation [SD])
      in injected eyes, versus 474.4+/-82.6 microm in control eyes. Four weeks after
      injection, it was 207.3+/-44.2 microm in injected eyes and 506.7+/-122.4 microm
      in control eyes (P<0.001, bilateral Wilcoxon test for paired samples), and after
      12 weeks, 207+/-96.7 microm and 469.3+/-117.6 microm, respectively (P = 0.005).
      The difference between the CMTs of injected and control eyes was no longer
      significant at 24 weeks because of the recurrence of macular edema in 5 of 12
      injected eyes. Before triamcinolone injection, the ETDRS score was 47.8+/-13
      (mean +/- SD; range, 28-66) in injected eyes, versus 51.9+/-14.6 (range, 31-71)
      in control eyes. Twelve weeks thereafter, the corresponding values were 52.7+/
      10.8 (range, 34-70) and 50.8+/-14.3 (range, 29-69), respectively, and at 24
      weeks, 54.7+/-7.6 (range, 47-68) and 50.6+/-18.4 (range, 28-71). At no time was
      the difference between the ETDRS scores for injected and control eyes
      significant. In 6 of the 12 injected eyes, intraocular pressure exceeded 25 mmHg,
      and was controlled by topical medication. CONCLUSION: Intravitreal injection of
      triamcinolone effectively reduces macular thickening due to diffuse diabetic
      macular edema, at least in the short term. Further studies are required to
      demonstrate that it provides visual benefit.

PMID- 15019367
TI  - Residual vitreous cortex after surgical posterior vitreous separation visualized
      by intravitreous triamcinolone acetonide.
AB  - OBJECTIVE: To visualize the residual vitreous cortex (VC) on the retinal surface
      after surgical posterior vitreous separation (PVS) during a pars plana vitrectomy
      (PPV), especially in patients with diabetic retinopathy. DESIGN: Case-control
      study. PARTICIPANTS: Patients with proliferative diabetic retinopathy (PDR),
      diabetic macular edema (DME), branch retinal vein occlusion (BRVO), and
      rhegmatogenous retinal detachment (RRD). METHODS: A triamcinolone acetonide (TA)
      assisted vitrectomy was performed on patients with the following diseases: PDR
      (40 eyes), DME (26 eyes), BRVO (11 eyes), and RRD (17 eyes). Eyes with no
      apparent preoperative posterior vitreous detachment were enrolled in this study.
      After performance of surgical PVS, the residual VC was visualized as a white gel
      highlighted by TA. Based on this finding, the residual VC pattern was then
      divided into 3 groups: (1) diffuse type (VC was diffusely present in the temporal
      vascular arcade), (2) focal type (a small island of VC was left), and (3) no
      residual VC. A multivariate analysis using analysis of variance was performed
      regarding the residual VC pattern, disease type, age, and the 3 different
      surgeons. MAIN OUTCOME MEASURES: Each surgeon determined the type of residual VC
      during the operation, and the results were confirmed by a postoperative review of
      the videotape records judged by the other 2 surgeons. RESULTS: Eighty percent of
      the PDR eyes demonstrated the diffuse type; 10%, the focal type; and 10%, no
      residual VC. Fifty-eight percent of the eyes with DME demonstrated the diffuse
      type; 19%, the focal type; and 23%, no residual VC. Eighteen percent of the BRVO
      eyes showed the diffuse type; 24%, the focal type; and 59%, no residual VC.
      Thirty percent of the RRD eyes showed the diffuse type; 30%, the focal type; and
      40%, no residual VC. A multivariate logistic regression analysis showed that PDR
      was a predictor of the diffuse type of residual VC in comparison to RRD (odds
      ratio = 8.42, 95% confidence interval = 2.07-34.3). Neither age nor the surgeon
      was a significant factor for a specific type of residual VC. CONCLUSIONS:
      Diabetic eyes more often demonstrated the diffuse type of residual VC, even after
      surgical PVS. This information may be valuable for surgeons performing a PPV on
      patients with diabetic retinopathy.

PMID- 15019368
TI  - Ultrastructure of internal limiting membrane removed during plasmin-assisted
      vitrectomy from eyes with diabetic macular edema.
AB  - PURPOSE: To study the effect of autologous plasmin enzyme (APE) on the adhesion
      of the vitreous cortex to the internal limiting membrane (ILM) in eyes with
      diabetic macular edema. DESIGN: Nonrandomized, comparative, interventional case
      series. PARTICIPANTS: Ten eyes of 10 patients with diabetic macular edema without
      a posterior vitreous detachment (PVD), which were treated with APE as an adjunct
      to conventional pars plana vitrectomy, and 10 eyes of 9 patients without a PVD,
      which underwent pars plana vitrectomy without APE, were studied. METHODS: In the
      APE group, 0.4 IU of APE was injected into the midvitreous cavity in 9 eyes, and
      0.8 IU of APE in 1 eye. Thirty minutes after plasmin injection, the eyes
      underwent pars plana vitrectomy with ILM peeling. All eyes in the control group
      had conventional vitreous surgery with ILM peeling. The removed ILMs were
      investigated for the presence of vitreous and for ultrastructural differences by
      transmission and scanning electron microscopy. MAIN OUTCOME MEASURES: The status
      of the vitreous and induction of a PVD during surgery, and the presence of
      vitreous and ultrastructural differences of the removed ILM by transmission and
      scanning electron microscopy. RESULTS: In APE-treated eyes, the degree of
      liquefaction of the vitreous was graded as high in 4 eyes. Spontaneous PVD
      occurred in 2 eyes, whereas core vitrectomy with a maximum vacuum of 100 mmHg
      induced a PVD in 2 additional eyes. In the control group, 8 eyes required suction
      with a maximum of 200 mmHg to induce the PVD. Scanning electron micrography of
      the removed ILM in the APE-treated eyes showed a smooth surface on the vitreous
      side in 8 eyes and only sparse collagen fibers in 2 eyes. Conversely, in the
      control group, dense vitreous fibers were found in 4 eyes, sparse collagen
      fibrils in 3 eyes, and a smooth retinal surface in 3 eyes. CONCLUSIONS: These
      findings indicate that APE helps separate the vitreous hyaloid from the ILM
      surface and may be a useful adjunct to conventional vitreous surgery for diabetic
      macular edema.

PMID- 15019369
TI  - Peeling of the basal membrane in the human retina: ultrastructural effects.
AB  - PURPOSE: To study the effects of internal limiting membrane (ILM) peeling,
      usually performed in cases of macular hole formation, on the structural integrity
      of the human retina. DESIGN: Experimental study. MATERIAL: Two human donor eyes.
      METHODS: A human donor retina was subjected to ILM peeling shortly after
      enucleation, fixed, and studied by electron microscopy. MAIN OUTCOME MEASURES:
      Electron microscopic findings. RESULTS: Within the peeled area, and even at its
      margins, a substantial number of Muller (glial) cell endfeet and vitreal Muller
      cell processes was severely damaged. However, many glial cells remained intact,
      and the cell bodies of the injured cells showed no signs of destruction.
      CONCLUSIONS: We have shown that ILM peeling results in minor, but demonstrable,
      damage of the adjacent retina. Clinical studies are required to demonstrate
      unequivocally that ILM peeling does not induce functional deficits rather than
      improvement of visual function.

PMID- 15019370
TI  - Risk factors for central serous chorioretinopathy: a case-control study.
AB  - PURPOSE: To identify systemic factors associated with the development of central
      serous chorioretinopathy (CSCR). DESIGN: Retrospective, case-control study.
      PARTICIPANTS AND CONTROLS: 312 cases and 312 controls. RESULTS: By use of a
      multivariate analysis, the previously described risk factors, systemic steroid
      use (odds ratio [OR], 37.1; 95% confidence interval [CI], 6.2-221.8), and
      pregnancy (OR, 7.1; 95% CI, 1.0-50.7), were strongly associated with CSCR.
      Additional risk factors identified by this study include antibiotic use (OR, 6.2;
      95% CI, 1.0-37.9), alcohol use (OR, 4.9; 95% CI, 1.5-16.3), untreated
      hypertension (OR, 3.3; 95% CI, 1.3-8.5), and allergic respiratory disease (OR,
      2.5; 95% CI, 1.2-5.1). CONCLUSIONS: A wide variety of systemic factors are
      associated with CSCR. Prospective studies are warranted to evaluate the nature
      and significance of these associations further.

PMID- 15019371
TI  - Fluorescein angiographic lesion type frequency in neovascular age-related macular
      degeneration.
AB  - OBJECTIVE: To assess the frequency of lesion types using fluorescein angiography
      (FA) in neovascular age-related macular degeneration (nAMD). DESIGN: Cross
      sectional study. PARTICIPANTS: Two hundred cases of nAMD. METHODS: Fluorescein
      angiograms from 908 patients (university-based, tertiary retinal referral
      practice [UP] = 478; comprehensive, community-based eye clinic [CC] = 430) were
      reviewed to identify 200 cases of nAMD (100 from each center). Two graders
      evaluated the frequency of angiographic subtypes. MAIN OUTCOME MEASURES:
      Identifying (1) the frequency of subfoveal nAMD lesions that meet the definition
      of "predominantly classic," "minimally classic," "occult with no classic"; (2)
      lesion location, size, and subtype; and (3) the intergrader agreement (kappa).
      RESULTS: There was little difference in the frequency of lesion type between the
      UP and the CC. Most nAMD lesions were subfoveal (78.5%, 157 of 200), and of
      these, 20% (32 of 157) were predominantly classic; whereas 73% (114 of 157) were
      occult with no classic, and 7% (11 of 157) were minimally classic. Of the 200
      angiograms, 33 (16.5%) were juxtafoveal, and 10 (5%) were extrafoveal. Twenty of
      the 43 juxtafoveal and extrafoveal lesions (47%) were predominantly classic.
      Classic with no occult subfoveal lesions were smaller than minimally classic or
      occult with no classic (1.7 vs. 3.7 and 2.8 mm; P = 0.001 and 0.01,
      respectively). Of 114 subfoveal occult with no classic lesions, 54 (47%) had both
      smaller lesion size <==4 disc areas (DA) and lower visual acuity <20/50, whereas
      107 (94%) had a smaller lesion or lower visual acuity. CONCLUSIONS: Most
      angiographic lesions of patients who undergo FA for nAMD are subfoveal and
      occult. We estimate that 20% of subfoveal lesions are predominantly classic.
      Approximately half of the juxtafoveal and extrafoveal lesions are predominantly
      classic. Nearly 30% of all nAMD lesions have both small occult lesions (size <==4
      DA) and a visual acuity less than 20/50. We found minimal difference in lesion
      type between a UP and a CC.

PMID- 15019372
TI  - Laser trabecular sclerosis for chronic hypotony after vitreoretinal surgery.
AB  - PURPOSE: To perform a pilot study of laser trabecular sclerosis (LTS) for chronic
      ocular hypotony after vitreoretinal surgery. DESIGN: Prospective noncomparative
      case series. PARTICIPANTS: Three patients with chronic hypotony after
      vitreoretinal procedures underwent LTS. All patients had undergone complex
      vitreoretinal surgery with attached retinas postoperatively but with persistent
      hypotony and poor vision. INTERVENTION: Laser trabecular sclerosis was performed
      in a fashion similar to laser trabeculoplasty, using a 100-microm spot, 800 to
      1000 mW power at 0.1 seconds, and applying heavy confluent treatment in >/=1
      sessions throughout the angle where trabecular meshwork was visible. MAIN OUTCOME
      MEASURES: Intraocular pressure (IOP), best spectacle-corrected visual acuity, and
      complications were studied. RESULTS: In 1 patient, a single session of LTS was
      followed by an increase in IOP of approximately 4 mm, with subjective and
      objective improvement in vision. A second patient exhibited improvement in IOP
      and visual acuity after 3 sessions of LTS. A third patient underwent 3 sessions
      of LTS without improvement in IOP or vision. CONCLUSION: Given the limitations of
      this small series, including the lack of a randomized prospective design, it is
      not possible to determine the safety or efficacy of LTS, but this study does
      suggest that this procedure could play a therapeutic role in some patients with
      chronic symptomatic hypotony after complex intraocular surgery. Further study is
      warranted.

PMID- 15019373
TI  - Variable corneal compensation improves discrimination between normal and
      glaucomatous eyes with the scanning laser polarimeter.
AB  - PURPOSE: The presently available scanning laser polarimeter (SLP) has a fixed
      corneal compensator (FCC) that neutralizes corneal birefringence only in eyes
      with birefringence that matches the population mode. A prototype variable corneal
      compensator (VCC) provides neutralization of individual corneal birefringence
      based on individual macular retardation patterns. The aim of this study was to
      evaluate the relative ability of the SLP with the FCC and with the VCC to
      discriminate between normal and glaucomatous eyes. DESIGN: Prospective,
      nonrandomized, comparative case series. PARTICIPANTS: Algorithm-generating set
      consisting of 56 normal eyes and 55 glaucomatous eyes and an independent data set
      consisting of 83 normal eyes and 56 glaucomatous eyes. TESTING: Sixteen
      retardation measurements were obtained with the SLP with the FCC and the VCC from
      all subjects. MAIN OUTCOME MEASURES: Dependency of parameters on age, gender,
      ethnic origin, and eye side was sought. Logistic regression was used to evaluate
      how well the various parameters could detect glaucoma. Discriminant functions
      were generated, and the area under the receiver operating characteristic (ROC)
      curve was determined. RESULTS: Discrimination between normal and glaucomatous
      eyes on the basis of single parameters was significantly better with the VCC than
      with the FCC for 6 retardation parameters: nasal average (P = 0.0003), superior
      maximum (P = 0.0003), ellipse average (P = 0.002), average thickness (P = 0.003),
      superior average (P = 0.010), and inferior average (P = 0.010). Discriminant
      analysis identified the optimal combination of parameters for the FCC and for the
      VCC. When the discriminant functions were applied to the independent data set,
      areas under the ROC curve were 0.84 for the FCC and 0.90 for the VCC (P<0.021).
      When the discriminant functions were applied to a subset of patients with early
      visual field loss, areas under the ROC curve were 0.82 for the FCC and 0.90 for
      the VCC (P<0.016). CONCLUSION: Individual correction for corneal birefringence
      with the VCC significantly improved the ability of the SLP to distinguish between
      normal and glaucomatous eyes and enabled detection of patients with early
      glaucoma.

PMID- 15019374
TI  - Reduction of posterior pole retinal thickness in glaucoma detected using the
      Retinal Thickness Analyzer.
AB  - OBJECTIVES: To report evidence of changes in posterior pole retinal thickness in
      glaucoma and preperimetric glaucoma. DESIGN: Cross-sectional study. PARTICIPANTS:
      One hundred forty participants (140 eyes): 31 normal subjects, 33 with ocular
      hypertension, 43 with primary open-angle glaucoma (POAG), and 33 with
      preperimetric glaucoma. INTERVENTION: Posterior pole retinal thickness
      measurements using the Retinal Thickness Analyzer (RTA; Talia Technology Ltd.,
      Neve-Ilan, Israel). MAIN OUTCOME MEASURES: The mean foveola average thickness
      (VAV), foveola minimum thickness (VMI), perifoveal average thickness (PFAV),
      perifoveal minimum thickness (PFMI), posterior pole average thickness (PPAV), and
      posterior pole minimum thickness (PPMI) were compared among the groups. The
      correlation between RTA values and visual field values was evaluated. The area
      under the receiver operator characteristic (AROC) curve, the optimal cut values,
      and the predictability values were estimated statistically between normal and the
      other groups using RTA values. RESULTS: Results from 91 eyes (65%) were included.
      Perifoveal average thickness values in preperimetric glaucoma (190.4+/-15.6
      microm; mean+/-standard deviation) and POAG (185.7+/-16.8 microm) were
      significantly less than in normal controls (211.4+/-16.8 microm) and in eyes with
      ocular hypertension (211.6+/-15.9 microm). Perifoveal minimum thickness, PPAV,
      and PPMI were significantly less in preperimetric glaucoma and in POAG than in
      normal controls; VAV and VMI were not significantly different among groups.
      Perifoveal average thickness, PFMI, PPAV, and PPMI significantly correlated with
      visual field mean defect (R = -0.38, -0.42, -0.36, and -0.41, respectively) and
      loss of variance (R = -0.29, -0.30, -0.26, and -0.17, respectively). The AROC
      using PFAV, PFMI, PPAV, and PPMI was significantly larger than 0.5 between normal
      and preperimetric glaucoma (0.83, 0.92, 0.82, and 0.87, respectively) and between
      normal and POAG eyes (0.86, 0.97, 0.83, and 0.93, respectively). When using the
      PFMI, the sensitivities at the minimum specificity cutoffs of 90% were highest in
      comparisons between normal and preperimetric glaucoma (sensitivity, 75%) and
      between normal and POAG eyes (sensitivity, 95%). By the logistic regression
      analysis, PFAV, PFMI, PPAV, and PPMI distinguished between normal and
      preperimetric glaucoma (R(2) = 0.30, 0.49, 0.27, and 0.37, respectively) and
      between normal and POAG (R(2) = 0.37, 0.59, 0.31, and 0.51, respectively).
      CONCLUSIONS: Posterior pole retinal thickness decreases in early- and moderate
      stage glaucoma. Reduction of perifoveal retinal thickness is correlated with
      visual field loss. In vivo measurements of posterior pole retinal thickness may
      help distinguish between normal and glaucomatous eyes.

PMID- 15019375
TI  - Efficacy and safety of the fixed combinations latanoprost/timolol versus
      dorzolamide/timolol in patients with elevated intraocular pressure.
AB  - PURPOSE: To compare the efficacy and safety of the fixed combination of
      latanoprost and timolol with those of the fixed combination of dorzolamide and
      timolol in patients with elevated intraocular pressure (IOP). DESIGN: Three
      month, randomized, parallel group, evaluator-masked, multicenter study.
      PARTICIPANTS: Patients with primary open-angle glaucoma or ocular hypertension
      with elevated IOP insufficiently responsive to monotherapy; 253 randomized: 125
      to receive a fixed combination of latanoprost 0.005% and timolol 0.5% once daily,
      and 128 to receive a fixed combination of dorzolamide 2% and timolol 0.5% twice
      daily. METHODS: Visits were at screening (current ocular hypotensive therapy was
      discontinued), 2 weeks (if needed for an IOP-safety check), baseline
      (randomization), and after 1 and 3 months of therapy. Intraocular pressure was
      measured in triplicate at 8 am, 12 pm, and 4 pm at each study visit, and diurnal
      IOP was calculated as the mean value of these recordings. Adverse events were
      recorded at each visit. MAIN OUTCOME MEASURE: The difference between treatment
      groups in the change in mean diurnal IOP from baseline to month 3. RESULTS: Mean
      diurnal IOP levels were similar at baseline. Mean (+/- standard error of the
      mean) reductions in diurnal IOP from baseline to month 3 were 9.4+/-0.27 mmHg in
      the latanoprost/timolol fixed-combination group, versus 8.4+/-0.26 mmHg in
      patients receiving the dorzolamide/timolol fixed combination. The mean difference
      in diurnal IOP reduction between treatments was 1.00 mmHg (95% confidence
      interval, 0.31-1.69; P = 0.005) in favor of the latanoprost/timolol fixed
      combination. Both treatments generally were well tolerated. CONCLUSIONS: The
      fixed combination of latanoprost and timolol was slightly more effective than
      that of dorzolamide and timolol in reducing mean diurnal IOP, and both treatments
      were generally well tolerated.

PMID- 15019376
TI  - Long-term surgical and visual outcomes in Indian children with developmental
      glaucoma operated on within 6 months of birth.
AB  - PURPOSE: To determine the long-term surgical and visual outcomes in Indian
      children with developmental glaucoma operated within 6 months of birth. DESIGN:
      Retrospective consecutive, noncomparative case series. PARTICIPANTS: All children
      with developmental glaucoma who underwent surgery within 6 months of birth over a
      12-year period were included. METHODS: Two hundred ninety-nine eyes of 157
      consecutive patients who underwent primary combined trabeculotomy-trabeculectomy
      for developmental glaucoma from January 1990 through December 2001 by a single
      surgeon were studied. However, for the purpose of statistical analysis, only 1
      randomly chosen eye of patients with a bilateral affliction (142, 90.4%) was
      considered. MAIN OUTCOME MEASURES: The main outcome measures were preoperative
      and postoperative intraocular pressures (IOPs), corneal clarity and diameters,
      visual acuities, refractive errors, success rate, time of surgical failure, and
      complications. RESULTS: The series consisted of 299 primary combined
      trabeculotomy-trabeculectomy surgeries during 157 anesthesias. The intraocular
      pressure was reduced from 26.6+/-6.2 mmHg to 14.4+/-4.9 mmHg, with a mean
      percentage reduction of 41.1+/-28.8 (P<0.0001). The probability of success
      (IOP<21 mmHg) was 94.4%, 92.1%, 86.7%, 79.4%, 72.9%, and 63.1% at first, second,
      third, fourth, fifth, and sixth year, respectively (Kaplan-Meier analysis). The
      mean follow-up period was 26.5+/-25.1 months. Preoperatively, 133 eyes (84.7%)
      had significant corneal edema. Postoperatively, normal corneal clarity was
      achieved in 83 of 133 eyes (62.4%) with corneal edema. There were no major
      intraoperative complications. Postoperatively, 17 eyes (10.8%) had a shallow
      anterior chamber develop; 3 of these eyes (17.6%) required surgical reformation.
      There was no incidence of endophthalmitis or any other sight-threatening
      complication. Data on visual acuity were available in 49 patients (31.2%). At the
      final follow-up visit, 20 patients (40.8%) had normal visual acuity (best
      corrected visual acuity of >/=20/60 in the better eye). CONCLUSIONS: Primary
      combined trabeculotomy-trabeculectomy is safe and effective for developmental
      glaucoma when performed within 6 months of birth. It leads to excellent IOP
      control and moderate visual outcome.

PMID- 15019377
TI  - Tubercular preseptal cellulitis in children: a presenting feature of underlying
      systemic tuberculosis.
AB  - OBJECTIVE: To present the clinical findings in 7 patients with preseptal
      cellulitis caused by tuberculosis. DESIGN: Retrospective noncomparative
      interventional case series. PARTICIPANTS: Seven patients. METHODS: Review of
      clinical findings, course, diagnostic tools, and management of 7 cases with
      tubercular preseptal cellulitis. MAIN OUTCOME MEASURES: Healing of local and
      systemic lesions, cosmetic correction. RESULTS: The presenting features of
      tuberculosis included lid abscess formation in 5 cases, with spontaneous
      fistulization in 2 patients. Two cases were initially seen with a cicatricial
      ectropion of the upper lid. A history of a lid swelling with spontaneous
      fistulization was present in both cases. Nonresponsiveness of the lesions to
      systemic antibiotics led to a detailed evaluation of the patients, and evidence
      of an underlying active or healed systemic focus was present in all the cases.
      Acid-fast bacilli from pus from the discharging sinuses were identified in only 1
      case, and in another patient, a biopsy specimen of the submandibular lymph node
      showed caseation necrosis. In the other cases, the diagnosis was presumptive from
      a strongly reactive Mantoux test, raised erythrocyte sedimentation rate, and the
      presence of a systemic focus. All the patients showed a dramatic response with
      antitubercular treatment, with complete healing of lesions. Two patients had a
      residual cicatricial ectropion, which was corrected surgically in both cases.
      CONCLUSIONS: Preseptal or lid involvement can be the presenting feature of
      tuberculosis and a marker for underlying systemic focus in children. Spontaneous
      fistulization of the abscess, minimal inflammatory signs, nonresponsiveness to
      antibiotic therapy, tethering to the underlying structures and skin, and the
      presence of a cicatricial ectropion should alert the clinician to look for an
      alternate diagnosis. The lid presentation might be a marker of an underlying
      systemic focus; therefore, awareness of the many faces of tuberculosis is
      important for ophthalmologists.

PMID- 15019378
TI  - Sleep disturbances in young subjects with visual dysfunction.
AB  - PURPOSE: To determine whether the type of ophthalmic disease is predictive of
      sleep and wakefulness disturbances in young subjects with visual dysfunction.
      DESIGN: Prospective cohort study. PARTICIPANTS AND CONTROLS: Twenty-five subjects
      (ages 12-20) were recruited from the Missouri School for the Blind. Twelve
      controls with normal sight were recruited from a residential school. METHODS:
      Daily activity was monitored for 14 days using wrist actigraphy. Sleep and
      wakefulness measures were derived from actigraphy records by automated analysis.
      Visually impaired subjects were prospectively stratified by presence or absence
      of optic nerve disease. MAIN OUTCOME MEASURES: Daytime napping and regularity of
      awakening time (wake-up time instability). RESULTS: Subjects with optic nerve
      disease napped in the daytime significantly more than other visually impaired
      children or normal sighted controls: 28.1+/-4.0 minutes per day (mean +/-
      standard error) versus 11.9+/-2.4 minutes per day in equally visually impaired
      subjects with intact optic nerve function versus 6.2+/-2.2 minutes per day in
      subjects with normal sight (P<0.0001). These subjects also showed significantly
      more variable awakening times than the other groups. Logistic regression revealed
      that subjects with optic nerve disease are 9.1 times more likely to demonstrate
      daily napping of more than 20 minutes per day than equally blind subjects without
      optic nerve disease (95% confidence interval [CI] = 1.4-58.7, P = 0.02). Blind
      subjects with optic nerve disease are 21.3 times more likely than children with
      normal sight to nap more than 20 minutes on average per day (95% CI = 1.2-378, P
      = 0.04). CONCLUSIONS: Optic nerve disease is predictive of increased daytime
      napping in young visually impaired subjects, suggesting that the nature and
      presence of ophthalmic disease affect the probability of concomitant sleep timing
      disorders.

PMID- 15019380
TI  - The axial length/disc area ratio in anisometropic hyperopic amblyopia: a
      hypothesis for decreased unilateral vision associated with hyperopic
      anisometropia.
AB  - OBJECTIVE: Hyperopic anisometropia is a risk factor for amblyopia. Disc areas and
      axial lengths are reduced in amblyopic eyes. This study's aim was to investigate
      the differences in the relative size of the optic disc in 5 groups of eyes: (1)
      normal right eyes; (2) smaller eyes of nonamblyopic, anisometropic, bilateral
      hyperopes; (3) larger eyes of nonamblyopic, anisometropic, bilateral hyperopes;
      (4) fellow (nonamblyopic) eyes of eyes of amblyopic, anisometropic, bilateral
      hyperopes; and (5) amblyopic eyes of bilateral hyperopic anisometropes. To
      determine the relative size of the discs, the relationships of axial length to
      disc area in the above groups were evaluated. DESIGN: Case-control study.
      PARTICIPANTS: Nine hundred twenty-seven records from the author's private
      practice, which included axial length measurements and optic disc photographs or
      digital images, were analyzed to form the 5 groups above. METHODS: Disc areas
      were measured using objective techniques developed by Bengtsson and Krakau. Axial
      lengths were determined by ultrasound biometry or with a Zeiss IOL Master. MAIN
      OUTCOME MEASURES: Optic disc areas, corrected for magnification, axial lengths,
      and a derived ratio, axial length/disc area (AXL/DA). RESULTS: The AXL/DA for the
      amblyopic eyes (group 5) was significantly greater than that of all of the other
      groups, indicating that amblyopic eyes have discs that are both absolutely
      smaller and, when adjusted for eyes' size, relatively smaller than those of
      nonamblyopic eyes. CONCLUSION: The relatively small size of the discs of
      amblyopic eyes points to an organic as opposed to a functional amblyopia in these
      patients.

PMID- 15019381
TI  - Initial results of endothelial cell counts after Artisan lens for phakic eyes: an
      evaluation of the United States Food and Drug Administration Ophtec Study.
AB  - PURPOSE: To evaluate the endothelial cell count change in eyes implanted with the
      iris-claw phakic Artisan lens for treatment of moderate to high myopia. DESIGN:
      Prospective, multicenter clinical trial. PARTICIPANTS: The first 765 eyes
      enrolled at 25 North American sites in the United States Food and Drug
      Administration Ophtec clinical trial of the myopic Artisan IOL. Outcome analyses
      of endothelial cell count measurements were based on those obtained before
      surgery and at 6, 12, and 24 months after surgery performed between October 1998
      and December 2001. SETTING: Multiple private and university practices. METHODS:
      Percentage change in endothelial cell count from baseline to 6, 12, and 24 months
      were analyzed using specular microscopy. Upper limit of detecting endothelial
      cell density change was estimated using 3 repeated counts at preoperative and
      postoperative time frames. MAIN OUTCOME MEASURES: Percentage change in
      endothelial cell loss. RESULTS: The mean preoperative endothelial cell count was
      2631+/-442 cells/mm(2). Percentage change from baseline at 6, 12, and 24 months
      was -0.09%+/-16.39%, -0.87%+/-16.35%, and -0.78%+/-17.41%. No statistically
      significative postoperative endothelial cell loss was found. The endothelial cell
      loss rate was higher among patients who wore spectacles before surgery and was
      correlated negatively with preoperative endothelial cell density (P<0.001). No
      relationships were noted between endothelial cell loss and either patient age or
      implant power. A 4.1% repeatability of measurements was found based on the
      average of 3 repeated counts, whereas single cell count estimates were associated
      with a 23% accuracy in detecting endothelial cell density change. In a worst-case
      scenario, adjusting for measurement accuracy, 9% of all eyes were at higher risk
      of a 10% loss of cell density at 12 months after surgery, although eyes at higher
      risk were found to have high preoperative endothelial cell counts (P<0.0001).
      CONCLUSIONS: The Artisan iris-claw phakic intraocular lens did not result in
      significant loss of endothelial cell density up to 2 years after implantation of
      the myopic Artisan phakic lens.

PMID- 15019382
TI  - Comparison of 6-month results of implantation of the 1CU accommodative
      intraocular lens with conventional intraocular lenses.
AB  - OBJECTIVE: To evaluate the clinical results of implantation of the new 1CU
      accommodative intraocular lens (IOL) in cataract patients and to compare results
      with those of conventional IOLs. DESIGN: Nonrandomized comparative trial.
      PARTICIPANTS: Twenty eyes of 20 patients (mean age = 65.8+/-13.3 years) in the
      1CU group and 20 eyes of 20 patients (mean age = 67.4+/-11.6 years) in the
      control group. METHODS: All patients underwent phacoemulsification and IOL
      implantation. The 1CU accommodative lens was used in 20 eyes, and conventional
      IOLs (polymethyl methacrylate, hydrophilic or hydrophobic acrylate) were used in
      the control group. Patients were observed prospectively, and 6-month data were
      analyzed. MAIN OUTCOME MEASURES: Accommodative ranges determined by 3 different
      methods (near point, defocusing, and retinoscopy). Secondary outcome measures
      were (1) increase of anterior chamber depth after topical application of 1%
      cyclopentolate eyedrops and (2) distance-corrected near visual acuity with
      Birkhauser reading charts at 35 cm. RESULTS: We observed a higher accommodative
      range with all 3 methods (mean = 1.83+/-0.49 vs. 1.16+/-0.27 diopters [D] [near
      point], 1.85+/-0.43 vs. 0.64+/-0.21 D [defocusing], and 0.98+/-0.55 vs. 0.17+/
      0.22 D [retinoscopy]), a larger increase of anterior chamber depth after
      cyclopentolate eyedrops (mean = 0.42+/-0.18 vs. 0.11+/-0.06 mm), and better
      distance-corrected near visual acuity (median = 0.4 vs. 0.2) in the 1CU group
      relative to the control group. All differences between the 2 groups were
      statistically highly significant (P<0.001). CONCLUSIONS: In the present study,
      the 1CU accommodative IOL showed increased accommodative range and better near
      visual acuity than a control group with conventional IOLs. Further research is
      necessary to confirm these results in masked, randomized, prospective studies and
      to confirm further the accommodative power of this group of new IOLs.

PMID- 15019384
TI  - Corneal surgery for severe phacoemulsification burns.
AB  - OBJECTIVE: To evaluate the outcome of corneal surgery for the treatment of severe
      corneal phacoemulsification burns. DESIGN: Interventional case series.
      PARTICIPANTS: Four patients with severe intraoperative phacoemulsification burns.
      INTERVENTION: One patient underwent penetrating keratoplasty and 3 underwent
      lamellar keratoplasties for the treatment of their corneal burns. MAIN OUTCOME
      MEASURES: Preoperative and postoperative visual acuities, preoperative and
      postoperative corneal topographies, and clinical observation. RESULTS: The visual
      acuity (VA) after the phacoemulsification burn was counting fingers in all
      patients. One patient had a penetrating keratoplasty, whereas the other 3 had
      lamellar grafts. After the corneal surgery, the corrected postoperative VA was
      20/30 to 20/50 in all patients, with astigmatism ranging from 2.5 to 5.5
      diopters. CONCLUSION: Severe phacoemulsification burns can be safely treated with
      corneal surgery, with acceptable postoperative visual acuities.

PMID- 15019383
TI  - Effect of accommodation and pupil size on the movement of a posterior chamber
      lens in the phakic eye.
AB  - PURPOSE: Although a posterior chamber phakic intraocular lens provides effective
      refractive correction of high myopia and hyperopia, mechanical contact between
      the implantable contact lens (ICL) and the crystalline lens and inadequate
      aqueous circulation in the prelenticular space could cause subcapsular
      opacification. To assess whether and to what extent such mechanical contact
      occurs, changes in the distance between the STAAR Collamer ICL and the
      crystalline lens under various conditions were investigated. DESIGN: Open pilot
      study. PARTICIPANTS: Thirteen eyes of 11 myopic and 2 hyperopic patients with a
      mean age of 38 years (range, 19-53 years) were examined at least 6 months after
      ICL implantation. METHODS: A noninvasive, high-resolution biometry technique,
      partial coherence interferometry, was used to measure distance changes between
      the ICL and the crystalline lens during subjective accommodation, after
      instillation of pilocarpine, and under changing light conditions. MAIN OUTCOME
      MEASURES: Mean distance changes from the posterior corneal surface to the ICL,
      from the posterior corneal surface to the anterior surface of the crystalline
      lens, and the distance between the ICL and the crystalline lens. RESULTS: In the
      nonaccommodated state, the mean distance between the ICL and the crystalline lens
      was 457 microm (range, 123-924 microm). During subjective accommodation, a
      significant (P<0.01) decrease and, after topical application of pilocarpine, a
      nonsignificant (P=0.35) decrease of anterior chamber depth was accompanied by a
      nonsignificant (P = 0.71) reduction of the ICL-crystalline lens distance. Under
      photopic conditions, a significant mean reduction (P<0.01) of the ICL-crystalline
      lens distance of -28 microm (range, -16 to -188 microm) was observed.
      CONCLUSIONS: Partial coherence interferometry biometry enabled noninvasive high
      precision investigation of ICL dynamics. No significant changes between the ICL
      and the crystalline lens were detected during subjective accommodation and after
      application of pilocarpine. However, under photopic conditions, with constriction
      of the pupil, the distance between the ICL and the crystalline lens was
      significantly reduced. This mechanism might cause inadequate aqueous circulation
      in the prelenticular space and might be one of the causes of subcapsular
      opacification in some of the eyes after ICL implantation.

PMID- 15019385
TI  - Neuroretinitis in patients with multiple sclerosis.
AB  - PURPOSE: To present a case series of three patients with neuroretinitis
      associated with multiple sclerosis. DESIGN: Retrospective, noncomparative,
      consecutive, interventional case series. PARTICIPANTS: Thirty-five consecutive
      patients with neuroretinitis. METHODS: The records of 35 consecutive patients
      with neuroretinitis were reviewed for prior, concurrent, or subsequent
      development of multiple sclerosis. MAIN OUTCOME MEASURES: Presentation, clinical
      course, and diagnosis of multiple sclerosis. RESULTS: Three of 35 patients (8.6%)
      with neuroretinitis were diagnosed with multiple sclerosis by the McDonald
      criteria. One of the three patients underwent brain biopsy that further confirmed
      multiple sclerosis. Neuroretinitis in the three patients occurred after the
      diagnosis of multiple sclerosis. All three patients with multiple sclerosis had
      been treated with interferon beta before or concurrently with the development of
      neuroretinitis. CONCLUSIONS: Neuroretinitis can be an associated manifestation of
      multiple sclerosis. The possible association between neuroretinitis and
      interferon beta warrants further investigation.

PMID- 15019387
TI  - Localization of local anesthetic solution by magnetic resonance imaging.
AB  - PURPOSE: The aim of this study was to examine the distribution of local
      anesthetic solution by magnetic resonance imaging (MRI) after combined peribulbar
      and retrobulbar, superomedial retrobulbar, and sub-Tenon's injection in relation
      to clinical akinesia. DESIGN: Randomized clinical trial. PARTICIPANTS: Fifteen
      patients scheduled for cataract surgery, 5 patients in each group. METHODS: Five
      patients received combined peribulbar and retrobulbar anesthesia, 5 patients
      received superomedial retrobulbar injection, and 5 patients had sub-Tenon's
      injection, all with a combination of bupivacaine 0.75%, lidocaine 2%, and
      hyaluronidase. The MRI scans were performed before the injection and up to 35
      minutes after the injection. RESULTS AND CONCLUSIONS: Reliable anesthesia is
      achieved using a combined peribulbar and retrobulbar block and a relatively great
      volume of local anesthetic solution, which spreads throughout the orbit, as
      evidenced by MRI. After superomedial retrobulbar and sub-Tenon's injection, the
      local anesthetic solution accumulates behind the globe. Sub-Tenon's injection
      gives good analgesia and slight akinesia with a very small volume. Superomedial
      retrobulbar injection and combined peribulbar and retrobulbar block provide a
      similar degree of exophthalmos, which seems to be the result of the volume
      injected behind the globe.

PMID- 15019389
TI  - Tumor necrosis factor alpha blockade with infliximab for refractory uveitis and
      scleritis.
AB  - OBJECTIVE: To assess the efficacy and safety of the anti-tumor necrosis factor
      alpha agent infliximab in treatment-resistant uveitis and scleritis. DESIGN:
      Retrospective, noncomparative interventional case series. PARTICIPANTS: Seven
      patients with noninfectious ocular inflammatory disease that was refractory to
      alternative immunosuppression. These included one patient with idiopathic retinal
      vasculitis and panuveitis, one patient with intermediate uveitis, one patient
      with chronic juvenile anterior uveitis, three patients with scleritis, and one
      patient with scleritis and peripheral ulcerative keratitis. Four patients had an
      underlying systemic disease that was in remission in three cases. INTERVENTION:
      Infusions of infliximab, 200 mg, were given at 4-week to 8-week intervals,
      depending on the clinical response. MAIN OUTCOME MEASURES: Clinical response,
      including symptoms, visual acuity, degree of scleral vascular engorgement,
      corneal thinning, anterior chamber activity, and posterior segment inflammation,
      reduction in concomitant immunosuppression, and adverse effects. RESULTS: The
      mean patient age was 47 years (range, 24-78), and four patients were female. The
      mean number of infliximab infusions was seven (range, 2-19), and the mean follow
      up period was 12 months (range, 4-22 months). Six patients experienced a clinical
      improvement, with five achieving remission and significant reduction in
      immunosuppression. One patient showed an initial response but developed a delayed
      hypersensitivity response that precluded further treatment. No other adverse
      effects occurred. CONCLUSIONS: Infliximab seems to be an effective and safe
      treatment for noninfectious uveitis and scleritis and may be indicated as rescue
      therapy for relapses of ocular inflammation or as maintenance therapy when
      conventional immunosuppression has failed. Further investigation of infliximab
      for treatment-resistant scleritis and uveitis is warranted.

PMID- 15019388
TI  - Aeromonas caviae keratitis associated with contact lens wear.
AB  - OBJECTIVE: We report the first case of bilateral contact lens-related Aeromonas
      caviae keratitis associated with A. caviae contamination of the contact lens
      case. The presence of virulence factors produced by Aeromonas species was also
      investigated. DESIGN: Case report. INTERVENTION AND TESTING: Conjunctival swabs
      and corneal scrapings from both eyes were inoculated for culture. The contact
      lens case was also cultured. The isolate was analyzed for the presence of
      virulence properties, such as gelatinase and protease production. The presence of
      virulence genes, such as the cytolytic enterotoxin (AHCYTOEN) and type IV
      Aeromonas pilus (tap) genes, was investigated using polymerase chain reaction.
      The susceptibility of A. caviae to 6 commercial contact lens disinfecting
      solutions was tested. MAIN OUTCOME MEASURES: Culture results, protease activity,
      and gelatinase production were analyzed. Polymerase chain reaction amplification
      products were visualized in ethidium bromide-stained agarose gel. Bacterial
      growth after exposure to contact lens disinfecting solutions was assessed.
      RESULTS: Aeromonas caviae was grown bilaterally from the conjunctiva, cornea, and
      contact lens case. The organism showed protease and gelatinase production.
      Polymerase chain reaction amplification revealed that the A. caviae strain
      contained the AHCYTOEN and tap virulence genes. Incubation for the minimum
      recommended time with all tested disinfecting solutions was effective in killing
      A. caviae. CONCLUSIONS: Aeromonas caviae should be considered a possible
      etiologic agent of contact lens-associated keratitis. The presence of virulence
      factors may be important in determining corneal infection. Commercial contact
      lens disinfecting solutions, along with proper lens case hygiene, may be
      effective in preventing A. caviae keratitis in soft contact lens wearers.

PMID- 15019391
TI  - Progressive enlargement of acquired retinal astrocytoma in 2 cases.
AB  - PURPOSE: To document 2 cases of progressively enlarging retinal astrocytoma that
      caused exudative retinal detachment, vitreous hemorrhage, and tumor seeding,
      simulating retinoblastoma in 1 case and choroidal melanoma in the other. DESIGN:
      Interventional case reports. PARTICIPANTS: Two patients. METHODS: Two patients
      with visual loss from an atypical, enlarging amelanotic retinal mass were
      evaluated. The first patient, a 14 year-old otherwise healthy girl, had a
      noncalcified gelatinous retinal mass with prepapillary involvement and
      surrounding retinal traction, as well as overlying vitreous hemorrhage and
      vitreous seeds. Over 37 months, the tumor grew in basal dimension from 4 mm to 10
      mm. Retinal astrocytoma was suspected, but the presence of tumor enlargement and
      vitreous seeding raised concern for possible retinoblastoma. Fine-needle
      aspiration biopsy was performed. The second patient, a 33-year-old woman, had an
      amelanotic mass develop in the macula of her amblyopic left eye. Over 2 years,
      the mass enlarged to 9.5 mm in basal dimension and 6.3 mm in thickness, and total
      serous retinal detachment developed. Choroidal melanoma with retinal invasion was
      clinically suspected. Enucleation was performed. RESULTS: In patient 1, cytologic
      examination revealed bland spindle cells with fibrillar cytoplasm consistent with
      an astrocytic tumor of the retina. Enucleation was subsequently performed because
      of continued tumor growth, progressive retinal detachment, and visual loss.
      Histopathologic examination confirmed astrocytoma of the retina and optic disc.
      In patient 2, enucleation revealed astrocytoma of the retina and optic disc with
      total retinal detachment. There was no evidence of systemic tuberous sclerosis in
      either patient. CONCLUSIONS: Retinal astrocytoma can show progressive
      enlargement, retinal detachment, and vitreous seeding, findings that can mislead
      the clinician toward the diagnosis of retinoblastoma or choroidal melanoma.

PMID- 15019390
TI  - Demographic-related variations in posterior segment ocular sarcoidosis.
AB  - OBJECTIVE: To compare the frequency of posterior segment involvement (PSI), the
      prevalence of specific posterior segment signs, and visual acuity in ocular
      sarcoidosis by patient race, sex, and age. DESIGN: Retrospective, cross-sectional
      observational study. PARTICIPANTS: Seventy-six consecutive patients with biopsy
      proven or presumed ocular sarcoidosis seen at the Duke University Eye Center
      between 1989 and 2001. METHODS: Medical record review. MAIN OUTCOME MEASURES:
      Patient demographics, presence and laterality of specific posterior segment
      signs, and visual acuity at initial examination. RESULTS: Of the 76 patients, 68%
      were black (34 female and 18 male) and 32% were white (18 female and 6 male). A
      total of 68 patients (89%) had PSI: black patients had 85% and white patients had
      100% (P = 0.05). For patients with PSI, white females had the highest mean age at
      initial examination (58 years compared with 37 years for all others; P = 0.005).
      The most common findings among the 68 patients with posterior segment disease
      were vitritis (69%); choroidal "punched-out" lesions (56%); "snowball" lesions
      (46%); cystoid macular edema (CME; 31%); and periphlebitis, vitreous opacity, and
      posterior vitreous detachment (29% each). There was a significantly higher
      prevalence of "punched-out" lesions and CME in whites (79% and 54%, respectively)
      compared with blacks (43% and 18%, respectively; P = 0.005 each). Additionally,
      the prevalence of CME was highest in white females (61%) compared with all others
      (20%; P = 0.002). Patients with vitreous hemorrhage were more likely to be in the
      youngest age group (P = 0.02). Female patients with posterior segment disease had
      a significantly lower visual acuity compared with males in both the better
      (P<0.001) and worse (P = 0.002) eye. CONCLUSIONS: We have identified variations
      based on patient race, sex, and age in PSI, specific posterior segment signs, and
      visual acuity in cases of ocular sarcoidosis.

PMID- 15019392
TI  - Incidence, associations, and evaluation of sixth nerve palsy using a population
      based method.
AB  - PURPOSE: To determine the incidence of sixth nerve palsy in a population-based
      study, with particular emphasis on associated coexisting medical conditions and
      to use these data to develop a management algorithm. DESIGN: Retrospective,
      population-based case series. PARTICIPANTS: All residents of Olmsted County,
      Minnesota, USA, diagnosed with sixth nerve palsy between January 1, 1978 and
      December 31, 1992. METHODS: All cases were identified by using the Rochester
      Epidemiology Project medical records linkage system, which captures all patient
      physician encounters in Olmsted County. The entire medical record of each patient
      was reviewed to confirm the diagnosis, document county residency, and to
      determine associated medical conditions. We used stringent predetermined criteria
      to define diabetes mellitus and hypertension as associations. Incidence rates
      were adjusted to the age and gender distribution of the 1990 white population in
      the United States. MAIN OUTCOME MEASURES: Etiology or systemic associations of
      the palsy. RESULTS: We identified 137 new cases of sixth nerve palsy over the 15
      year period. The age- and gender-adjusted annual incidence of sixth nerve palsy
      was 11.3/100 000 (95% confidence interval, 9.3-13.2/100 000). Causes and
      associations were: undetermined (26%), hypertension alone (19%), coexistent
      hypertension and diabetes (12%), trauma (12%), multiple sclerosis (7%), neoplasm
      (5%), diabetes alone (4%), cerebrovascular accident (4%), postneurosurgery (3%),
      aneurysm (2%), and other (8%). When sixth nerve palsy was the presenting sign in
      cases of neoplasm (n = 1) and aneurysm (n = 3), history and examination revealed
      the presence of other neurologic symptoms or signs. CONCLUSIONS: We provide
      population-based data on the incidence of sixth nerve palsy with a notably lower
      incidence of neoplasm and higher incidence of diabetes and hypertension than
      previous institution-based series. We suggest that patients with nontraumatic
      neurologically isolated sixth nerve palsy may undergo a focused medical
      evaluation followed by close observation, whereas non-neurologically isolated
      cases warrant a full neurologic evaluation, including prompt neuroimaging.

PMID- 15019393
TI  - Neuro-ophthalmic findings in the visual variant of Alzheimer's disease.
AB  - PURPOSE: To describe the clinical features of a visual variant Alzheimer's
      disease, a disorder that might be seen by the ophthalmologist with visual
      symptoms and signs. DESIGN: Retrospective case series. PARTICIPANTS: Eight
      patients with Alzheimer's disease presenting with predominantly visual
      complaints. METHODS: A retrospective review of patients at a tertiary care
      academic center seen by the authors from 1999 to 2001 with Alzheimer's disease
      and predominantly visual complaints. RESULTS: Eight patients with the visual
      variant of Alzheimer's disease were reviewed. All had seen eye care providers
      before referral to the neuro-ophthalmology clinic for visual complaints but
      without a diagnosis. Four patients had homonymous visual field loss, and two had
      presumed cortical visual impairment. Neuroimaging showed either normal brain (1
      patient) or atrophy of the parietal or occipital areas but no structural lesions
      (7 patients). Fluoro-18-deoxyglucose positron emission tomography scans were
      performed in five of the cases, and all showed hypoperfusion in the
      parietooccipital areas. Neuropsychologic testing revealed visuospatial deficits
      in all 5 patients tested. CONCLUSIONS: Visual symptoms might be the presenting
      (or rarely only) manifestation of Alzheimer's disease. Clinicians should be aware
      of the visual variant of Alzheimer's disease. Neuropsychological testing and
      magnetic resonance imaging (MRI) provide supporting evidence for the diagnosis.
      Positron emission tomography scans might be helpful in selected cases, especially
      those with a normal MRI.

PMID- 15019395
TI  - Orbitotemporal neurofibromatosis. Clinical features and surgical management.
AB  - PURPOSE: To classify the periorbital deformities of adult orbitotemporal
      neurofibromatosis (NF) and describe new clinical findings, and to recommend
      guidelines for surgical treatment and management of surgical complications.
      DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Thirty-three
      patients over age 16 with orbitotemporal NF. METHODS: Retrospective surgical case
      record and serial photographic review recording the laterality and the severity
      of periorbital involvement, the presence of complications from previous surgery,
      the surgical techniques undertaken, and the surgical outcome and complications.
      MAIN OUTCOME MEASURES: Comparison of preoperative and postoperative level of
      deformities. RESULTS: New classification of periorbital deformities: (1) brow
      ptosis, (2) upper lid infiltration with ptosis, (3) lower lid infiltration, (4)
      lateral canthal disinsertion, and (5) conjunctival and lacrimal gland
      infiltration. Two patients had bilateral and 31 patients (94%) had unilateral
      orbitotemporal NF. All patients had upper and 19 patients (58%) had lower lid
      involvement. Six (18%) patients had significant brow infiltration. Fourteen (42%)
      patients had a dropped lateral canthus requiring surgical reattachment, 28 (85%)
      required anterior levator resection for ptosis, and 28 (85%) had lid-debulking
      surgery. New findings included severe brow infiltration, lacrimal gland
      involvement, and functional nasolacrimal duct obstruction. Complications from
      previous surgery included residual ptosis, ptosis overcorrection, poor lid
      contour, dry eye, corneal exposure, and upper and lower lid entropion/ectropion.
      CONCLUSIONS: The periorbital appearance and comfort of patients with NF type 1
      who have orbitotemporal NF can be significantly improved through oculoplastic
      surgery.

PMID- 15019396
TI  - Adrenal suppression and failure to thrive after steroid injections for periocular
      hemangioma.
AB  - PURPOSE: To evaluate the effects of steroid injections for periocular capillary
      hemangioma on adrenal function and body composition. DESIGN: Noncomparative,
      interventional case series. PARTICIPANTS: Four patients with periocular
      hemangioma. METHODS: Four white female infants with sight-threatening periocular
      hemangiomata received a combination of steroid injections of triamcinolone and
      betamethasone. In the first 2 cases, injections were perilesional and in the
      other 2, intralesional. MAIN OUTCOME MEASURES: The infants were monitored by
      serial measurements of basal serum cortisol concentrations, responses to the
      Synacthen stimulation test, measurement of growth and of weight gain, and, in one
      case, more detailed anthropometric measures of body composition. RESULTS:
      Prolonged suppression of circulating serum cortisol concentrations and cortisol
      responses to the Synacthen stimulation test were noted in 3 cases, and marked
      failure to thrive was noted in all 4 cases. CONCLUSIONS: Adrenal suppression
      after steroid injection for periocular capillary hemangioma is a potentially life
      threatening complication. Failure to thrive is also a frequent side effect of
      treatment. Ophthalmologists should undertake the above treatment in consultation
      with a pediatric endocrinologist.

PMID- 15019397
TI  - Confocal microscopy: a report by the American Academy of Ophthalmology.
AB  - OBJECTIVE: To review the available evidence for the use of confocal microscopy in
      diagnosing infectious keratitis and for other applications for ophthalmic
      practice. METHODS: A MEDLINE search of the peer-reviewed literature for the years
      1990 to 2001 yielded 94 citations. The search was limited to studies of human
      subjects published in English with abstracts. The Ophthalmic Technology
      Assessment Committee Cornea Panel evaluated these 94 articles for possible
      clinical relevance and selected 51 (54%) for content review by the panel members.
      Of these 51 articles, 24 were selected for the panel methodologist to review and
      rate according to the strength of evidence. RESULTS: Of the 24 articles, 21
      (87.5%) were classified as case reports or case series and were rated as level
      III evidence. Three articles were classified as independent, masked, or objective
      comparisons performed in a narrow spectrum of patients or in a nonconsecutive
      series of patients and were rated as level II evidence. No studies were rated as
      level I evidence, defined as an independent masked comparison of an appropriate
      spectrum of consecutive patients. CONCLUSION: Confocal microscopy is a new
      technology with clinical applications in ophthalmology. Although confocal
      microscopy has been used in other fields of medicine, the optical transparency of
      the cornea and other structures of the eye provides a unique opportunity to apply
      this technology. The targeted literature review of 24 articles found no level I
      studies to support the use of confocal microscopy in the management of eye
      disorders. Three level II studies pertained to promising clinical applications of
      the confocal microscope and provided evidence that supports the use of confocal
      microscopy as an adjunctive modality for diagnosing Acanthamoeba keratitis. The
      remaining 21 articles, rated as level III evidence, focus on the use of confocal
      microscopy to facilitate the diagnosis of infectious keratitis, including amoebic
      and fungal, but currently there are no definitive studies of its role in the
      differential diagnosis of this condition. There are also level III studies that
      support the use of the confocal microscope in refractive surgery. Facilitating
      the diagnosis of infectious keratitis and applying the confocal microscope to
      refractive surgery may hold the greatest promise of this new technology.

PMID- 15019398
TI  - Munchausen syndrome by proxy.

PMID- 15019400
TI  - Comparison of atropine and patching treatments.

PMID- 15019402
TI  - Coexisting glaucoma and cataract.

PMID- 15019404
TI  - Capsular apposition after cataract surgery.

PMID- 15019406
TI  - Management of myopathic ptosis.

PMID- 15019405
TI  - Brimonidine and latanoprost as adjunctive therapy.

PMID- 15019408
TI  - Management of myopathic ptosis.

PMID- 15019410
TI  - Superior oblique palsy.

PMID- 15019412
TI  - Silent sinus syndrome-new perspectives?

PMID- 15019414
TI  - Nasolacrimal intubation with mitomycin C.

PMID- 15019416
TI  - Children with vernal keratoconjunctivitis.

PMID- 15019419
TI  - LSD, 5-HT (serotonin), and the evolution of a behavioral assay.
AB  - Research in our laboratory, supported by NIDA and facilitated by Roger Brown, has
      indicated that serotonergic neuronal systems are involved in the discriminative
      stimulus effects of LSD. However, the only compounds that fully antagonize the
      LSD cue act at both serotonin (5-HT) and dopamine (DA) receptors. In addition,
      substitution for LSD in standard drug vs. no-drug (DND) discriminations does not
      necessarily predict either similar mechanisms of action or hallucinogenic potency
      because 'false positives' occur when animals are given drugs such as lisuride
      (LHM), quipazine, or, possibly, yohimbine. These effects can be greatly reduced
      by using drug vs. drug (D-D), drug vs. drug vs. no drug (D-ND), or drug vs. '
      other' drug (saline, cocaine, pentobarbital) training procedures. Additional
      studies, in which drugs were administered directly into the cerebral ventricles
      or specific brain areas, suggest that structures containing terminal fields of
      serotonergic neurons might be involved in the stimulus effects of LSD.

PMID- 15019420
TI  - Reward, memory and substance abuse: functional neuronal circuits in the nucleus
      accumbens.
AB  - The firing patterns of neurons in the nucleus accumbens (NA) are examined and
      discussed with respect to different types of rewards and reward conditions.
      Comparisons and contrasts between individually identified NA neuron responses to
      cocaine self-administration and water reinforcement are presented with an
      emphasis on the fact that the same neurons do not respond in a phasic manner to
      both types of rewards. However, the phasic firing patterns, even though
      segregated for each reinforcer, are quite similar, suggesting that the method of
      differentiation between rewarding stimuli in the NA is by sorting cell
      populations into distinct ensembles or networks for each type of reinforcer.
      These neural networks appear to be 'tuned' to respond to particular associative
      behavioral contexts that couple response execution to reward delivery, and in the
      process acquire a reciprocity to firing within reward contexts. This maintains
      the specificity of each reinforcer for the response and associated stimuli that
      produce it and, makes it possible to attach different NA networks to different
      reinforcing circumstances. Comparisons of cocaine and water reinforced NA cell
      firing patterns during rapid switching between these two reinforcers suggests
      that the networks are negatively coupled and mutually inhibit each other to
      maintain accurate encoding of immediately experienced, as well as expected (i.e.
      future) reward contingencies.

PMID- 15019421
TI  - Neurochemical and behavioral studies on ethanol and nicotine interactions.
AB  - The most commonly abused drugs, alcohol and nicotine, are likely also the most
      costly drugs in terms of health and societal costs. A large body of evidence from
      epidemiological studies indicate that smoking and alcohol-intake are positively
      correlated. The mesocorticolimbic dopamine system has been implicated in
      mediating some of the reinforcing effects of ethanol, however, the mechanism(s)
      of action remains to be elucidated; consideration as to ethanol's ability to
      interact with ligand-gated ion channels should be considered. Accumulating
      evidence from electrophysiological, pharmacological and neurochemical studies
      suggest that ethanol may interact with the nicotinic acetylcholine receptor
      (nAChR). Thus, it has been shown that the ethanol-induced stimulation of the
      mesolimbic dopamine system and of locomotor activity as well as ethanol intake
      and preference in rodents may involve central nicotinic acetylcholine receptors.
      Additionally, data has been presented that nAChRs located in the ventral
      tegmental area may be of particular importance for these effects of ethanol.
      Studies aimed at defining the nAChR subpopulation(s) involved in mediating
      ethanol-induced locomotor stimulation and accumbal dopamine overflow as well as
      ethanol-intake have revealed that alpha(3)beta(2) or alpha(6) (using alpha
      Conotoxin MII) but not alpha(4)beta(2) (using dihydro-beta-erythroidine) or
      alpha(7) (using methyllycaconitine), could represent targets for developing new
      drugs in the treatment of alcoholism. These results do not allow any conclusion
      as to whether the involvement nAChRs in mediating the effects of ethanol is
      direct and/or indirect. With regard to an indirect effect, evidence has
      accumulated indicating that the cholinergic excitatory input to the dopaminergic
      neurons in the ventral tegmental area may be an important part of the neuronal
      circuits mediating natural as well as drug-rewarded behavior. The possibility may
      thus be considered that ethanol activates the cholinergic afferents causing a
      release of acetylcholine in the ventral tegemental area leading to a stimulation
      of nAChRs and thereby excite the mesocorticolimbic dopamine system.

PMID- 15019422
TI  - Opponent process properties of self-administered cocaine.
AB  - Over the past decade, data collected in our laboratory have demonstrated that
      self-administered cocaine produces Opponent-Process-like behavioral effects.
      Animals running a straight alley once each day for IV cocaine develop over trials
      an approach-avoidance conflict about re-entering the goal box. This conflict
      behavior is characterized by a stop in forward locomotion (usually at the very
      mouth of the goal box) followed by a turn and 'retreat' back toward the goal box.
      The results of a series of studies conducted over the past decade collectively
      suggest that the behavioral ambivalence exemplified by rats running the alley for
      IV cocaine stems from concurrent and opponent positive (rewarding) and negative
      (anxiogenic) properties of the drug--both of which are associated with the goal
      box. These opponent properties of cocaine have been shown to result from
      temporally distinct affective states. Using a conditioned place preference test,
      we have been able to demonstrate that while the initial immediate effects of IV
      cocaine are reinforcing, the state present 15 min post-injection is aversive. In
      our most recent work, the co-administration of IV cocaine with either oral
      ethanol or IV heroin was found to greatly diminish the development and occurrence
      of retreat behaviors in the runway. It may therefore be that the high incidence
      of co-abuse of cocaine with either ethanol or heroin, stems from the users'
      motivation to alleviate some of the negative side effects of cocaine. It would
      seem then that the Opponent Process Theory has provided a useful conceptual
      framework for the study of the behavioral consequences of self-administered
      cocaine including the notion that both positive and negative reinforcement
      mechanisms are involved in the development and maintenance of cocaine abuse.

PMID- 15019423
TI  - Descending modulation of pain.
AB  - Although interest in descending modulation of spinal cord function dates back to
      the time of Sherrington, the modern era began in the late 1960s when it was shown
      that focal electrical stimulation in the midbrain of the rat produced analgesia
      sufficient to permit surgery. From this report evolved the concept of endogenous
      systems of pain modulation. Initial interest focused on descending inhibition of
      spinal nociceptive processing, but we now know that descending modulation of
      spinal nociceptive processing can be either inhibitory or facilitatory. As our
      understanding of descending facilitatory, or pro-nociceptive influences grows, so
      too has our appreciation of its potential importance. Accumulating evidence
      suggests that descending facilitatory influences may contribute to the
      development and maintenance of hyperalgesia and thus contribute to chronic pain
      states.

PMID- 15019424
TI  - Neurobiological mechanisms in the transition from drug use to drug dependence.
AB  - Drug addiction is a chronic relapsing disorder characterized by compulsive drug
      intake, loss of control over intake, and impairment in social and occupational
      function. Animal models have been developed for various stages of the addiction
      cycle with a focus in our work on the motivational effects of drug dependence. A
      conceptual framework focused on allostatic changes in reward function that lead
      to excessive drug intake provides a heuristic framework with which to identify
      the neurobiologic mechanisms involved in the development of drug addiction.
      Neuropharmacologic studies in animal models have provided evidence for the
      dysregulation of specific neurochemical mechanisms in specific brain reward and
      stress circuits that provide the negative motivational state that drives
      addiction. The allostatic model integrates molecular, cellular and circuitry
      neuroadaptations in brain motivational systems produced by chronic drug ingestion
      with genetic vulnerability, and provides a new opportunity to translate advances
      in animal studies to the human condition.

PMID- 15019425
TI  - Cocaine effects on the developing brain: current status.
AB  - The present paper reports on the results obtained in a rabbit model of prenatal
      cocaine exposure that mimics the pharmacokinetics of crack cocaine in humans, and
      relates these findings to studies in other species including humans. A general
      finding is that prenatal exposure to cocaine during neurogenesis produces
      dysfunctions in signal transduction via the dopamine D(1) receptor and
      alterations in cortical neuronal development leading to permanent morphological
      abnormalities in frontocingulate cortex and other brain structures. Differences
      in the precise effects obtained appear to be due to the dose, route and time of
      cocaine administration. Related to these effects of in utero cocaine exposure,
      animals demonstrate permanent deficits in cognitive processes related to
      attentional focus that have been correlated with impairment of stimulus
      processing in the anterior cingulate cortex. The long-term cognitive deficits
      observed in various species are in agreement with recent reports indicating that
      persistent attentional and other cognitive deficits are evident in cocaine
      exposed children as they grow older and are challenged to master more complex
      cognitive tasks.

PMID- 15019426
TI  - Ventral striatal control of appetitive motivation: role in ingestive behavior and
      reward-related learning.
AB  - The nucleus accumbens is a brain region that participates in the control of
      behaviors related to natural reinforcers, such as ingestion, sexual behavior,
      incentive and instrumental learning, and that also plays a role in addictive
      processes. This paper comprises a review of work from our laboratory that focuses
      on two main research areas: (i). the role of the nucleus accumbens in food
      motivation, and (ii). its putative functions in cellular plasticity underlying
      appetitive learning. First, work within a number of different behavioral
      paradigms has shown that accumbens neurochemical systems play specific and
      dissociable roles in different aspects of food seeking and food intake, and part
      of this function depends on integration with the lateral hypothalamus and
      amygdala. We propose that the nucleus accumbens integrates information related to
      cognitive, sensory, and emotional processing with hypothalamic mechanisms
      mediating energy balance. This system as a whole enables complex hierarchical
      control of adaptive ingestive behavior. Regarding the second research area, our
      studies examining acquisition of lever-pressing for food in rats have shown that
      activation of glutamate N-methyl-d-aspartate (NMDA) receptors, within broadly
      distributed but interconnected regions (nucleus accumbens core, posterior
      striatum, prefrontal cortex, basolateral and central amygdala), is critical for
      such learning to occur. This receptor stimulation triggers intracellular cascades
      that involve protein phosphorylation and new protein synthesis. It is
      hypothesized that activity in this distributed network (including D1 receptor
      activity) computes coincident events and thus enhances the probability that
      temporally related actions and events (e.g. lever pressing and delivery of
      reward) become associated. Such basic mechanisms of plasticity within this
      reinforcement learning network also appear to be profoundly affected in
      addiction.

PMID- 15019427
TI  - Brain-stimulation reward, morphine-induced oral stereotypy, and sensitization:
      implications for abuse.
AB  - Early professionals believed that it was unlikely that anyone but the emotionally
      unstable received pleasure and became addicted to narcotic drugs. This position
      was well entrenched and influenced much of the thinking well into the latter half
      of the last century. Although the discovery of a brain reward system was made
      early in the 1950's it was not until 20 years later that this discovery was
      applied to the study of the mechanisms involved in the rewarding aspects of
      abused substances. Along this vein results will be shown in which opiate
      antagonist block the dopamine agonist activation of the brain reward system as
      well as the corollary. Sensitization of the reward system suggests that a driving
      force for drug use is 'liking' and not just 'wanting.' Basal changes in cerebral
      metabolic rates of glucose are seen in the presence of cues associated with
      morphine experience, giving evidence for the role of drug related cues in
      craving. Finally we asked the question 'Do old rats have as much fun as young
      rats?'

PMID- 15019428
TI  - Aggression and defeat: persistent effects on cocaine self-administration and gene
      expression in peptidergic and aminergic mesocorticolimbic circuits.
AB  - The question of how ostensibly aversive social stress experiences in an
      aggressive confrontation can persistently increase intense drug taking such as
      cocaine 'bingeing' needs to be resolved. The biology of social conflict
      highlights distinctive behavioral, cardiovascular and endocrine profiles of
      dominant and subordinate animals, as seen also in rodents and primates under
      laboratory conditions. In contrast to continuous subordination stress that
      produces chronic pathophysiological consequences and often is fatal, animals
      adapt to brief episodes of social defeat stress, but show enduring functional
      activation in mesocorticolimbic microcircuits. Uncontrollable episodes of social
      defeat stress produce long-lasting tolerance to opiate analgesia and,
      concurrently, behavioral sensitization to challenges with either amphetamine or
      cocaine. One week after a single social defeat stress, cross-sensitization to
      cocaine is evident in terms of enhanced motor activity as well as in terms of
      increased Fos labeling in the periaqueductal grey area, the locus coeruleus, and
      the dorsal raphe nuclei. When challenged with a low amphetamine dose, the
      behavioral and neural effects of repeated brief episodes of social defeat stress
      persist for months. Previous exposure to social defeat stress can (1).
      significantly shorten the latency to acquire cocaine self-administration, (2).
      maintain this behavior at low cocaine unit doses, (3). significantly increase the
      levels of cocaine taking during a 24 h binge of continuous drug availability,
      (4). dysregulate the timing of consecutive infusions, and (5). abolish the
      circadian pattern of self-administration. Amygdaloid modulation, especially
      originating from central and basolateral nuclei, of dopaminergic pathways via
      peptidergic and glutamatergic neurons appears to be a key mechanism by which
      social defeat stress affects cocaine self-administration. Social stress alters
      the feedback from prefrontal cortex and thereby may contribute to the
      dysregulation of dopaminergic activity that is necessary for cocaine self
      administration.

PMID- 15019429
TI  - Sensitization to the reinforcing effects of cocaine following binge-abstinent
      self-administration.
AB  - The process of addiction in humans involves a transition from recreational drug
      use to compulsive drug-taking. To understand or study this behavioral phenomenon
      from a neurobiological perspective, behavioral models that reflect this process
      are necessary. Data from typical (restricted access) self-administration
      procedures demonstrate a stable pattern of responding over time, and thus fail to
      capture the transitional phases of this process. Here we describe the development
      of a model that incorporates self-administration-induced changes in the
      reinforcing efficacy of cocaine, assessed using a progressive ratio schedule of
      reinforcement to probe the 'motivational' state of the animal. To date we have
      identified two necessary conditions for the development of this sensitization:
      extended access to cocaine and a deprivation period. This model, in conjunction
      with recently developed tools to characterize neurochemical and epigenetic
      changes, will provide a better understanding of the neurobiological bases of the
      addiction process.

PMID- 15019430
TI  - The expanding effects of cocaine: studies in a nonhuman primate model of cocaine
      self-administration.
AB  - Although neuroimaging investigations in human cocaine abusers have provided
      important insights into the brain changes that accompany drug use, the
      interpretation of reports in human abusers can be very difficult. Studies in
      nonhuman primates provide a way to systematically evaluate the structural and
      functional adaptations engendered by cocaine self-administration without the
      confounds of human research. Functional activity, measured with metabolic mapping
      methods, and markers of the dopamine system, assessed autoradiographically, were
      evaluated over the course of chronic cocaine self-administration (5 days, 3.3
      months, and 15-22 months). Within the striatum the topography of these responses
      shifts dramatically over time. Changes in functional activity and alterations in
      the dopamine system occupy larger and larger portions of dorsal and ventral
      striatum with increasing durations of cocaine exposure. The growing impact of
      cocaine suggests that the elements of the behavioral repertoire outside of the
      influence of cocaine become smaller and smaller with increasing durations of
      exposure to drug use resulting in cocaine's dominance over all aspects of the
      addict's life.

PMID- 15019431
TI  - Amphetamine neurotoxicity: accomplishments and remaining challenges.
AB  - In addition to the social, cultural and indirect medical complications of
      amphetamine analog abuse, this class of drugs is also known to have the potential
      to damage brain monoaminergic cells directly. Using methamphetamine as a
      prototype, this article provides a brief review of the history of amphetamine
      neurotoxicity research and the progress that has been made toward defining its
      characteristics. Remaining challenges for this line of investigation are
      outlined, and suggested avenues for addressing these challenges are provided.

PMID- 15019432
TI  - Sensitization of midbrain dopamine neuron reactivity and the self-administration
      of psychomotor stimulant drugs.
AB  - Psychostimulant drugs like amphetamine are readily self-administered by humans
      and laboratory animals by virtue of their actions on dopamine (DA) neurons in the
      midbrain. Exposing animals to this drug either systemically or in the cell body
      region of these neurons in the ventral tegmental area leads to long-lasting
      alterations in dopaminergic function. These have most often been assessed as
      increased locomotor activity and enhanced DA overflow in the nucleus accumbens
      (NAcc) after re-exposure to the drug weeks to months later. Evidence is presented
      showing that manipulations that produce this sensitization of midbrain DA neuron
      reactivity enhance the pursuit and self-administration of psychostimulant drugs.
      Procedures known to prevent the induction of sensitization by amphetamine also
      prevent the facilitation of drug taking. Enhanced drug self-administration and
      primed reinstatement of drug seeking are also accompanied by enhanced NAcc DA
      reactivity. Finally, drugs that increase NAcc DA overflow acutely but fail to
      produce sensitization of this effect are not associated with the subsequent
      enhancement of self-administration. These results indicate a direct relationship
      between the sensitization of midbrain dopamine neuron reactivity and the
      excessive pursuit and self-administration of psychostimulant drugs. Understanding
      the neuronal events and adaptations that underlie the induction and expression of
      sensitization may thus help elucidate how drug abuse develops, how it is
      reinstated and ultimately how both may be prevented.

PMID- 15019433
TI  - Involvement of cholinergic neuronal systems in intravenous cocaine self
      administration.
AB  - Recent studies suggest the participation of cholinergic neurons in the brain
      processes underlying reinforcement. The involvement of cholinergic neurons in
      cocaine self-administration has been recently demonstrated in studies using
      muscarinic and nicotinic agonists and antagonists, microdialysis, assessment of
      choline acetyltransferase activity and acetylcholine (ACh) turnover rates. The
      present experiment was initiated to identify subsets of cholinergic neurons
      involved in the brain processes that underlie cocaine self-administration by
      lesioning discrete populations with a selective neurotoxin. Rats were trained to
      self-administer cocaine and the cholinergic neurotoxin 192-IgG-saporin or vehicle
      was then bilaterally administered into the posterior nucleus accumbens (NAcc)
      ventral pallidum (VP). The 192-IgG-saporin induced lesions resulted in a pattern
      of drug-intake consistent with either a shift in the dose intake relationship to
      the left or downward compared to sham-treated controls. A second experiment used
      a self-administration threshold procedure that demonstrated this lesion shifted
      the dose intake relationship to the left compared to the sham-vehicle treated
      rats. The magnitude and extent of the lesion was assessed by measuring the
      expression of p75 (the target for 192-IgG-saporin) and choline acetyltransferase
      (ChAT) in the NAcc, VP, caudate nucleus-putamen (CP) and vertical limb of the
      medial septal nucleus-diagonal band (MS-DB) of these rats using real time reverse
      transcriptase-polymerase chain reaction. Significant reductions in gene
      expression for p75 (a selective marker for basal forebrain cholinergic neurons)
      and ChAT were seen in the MS-DB and VP while only small decreases were seen in
      the NAcc and CP of the 192-IgG-saporin treated rats. These data indicate that the
      overall influence of cholinergic neurons in the MS-DB and VP are inhibitory to
      the processes underlying cocaine self-administration and suggest that agonists
      directed toward subclasses of cholinergic receptors may have efficacy as
      pharmacotherapeutic adjuncts for the treatment of cocaine abuse.

PMID- 15019434
TI  - International Society for the Prevention of Child Abuse and Neglect (ISPCAN) and
      worldwide endeavors to prevent child maltreatment.

PMID- 15019435
TI  - What we can learn from the spectrum of infant physical abuse in Alaska.

PMID- 15019436
TI  - The incidence of infant physical abuse in Alaska.
AB  - OBJECTIVES: To determine the incidence of and risk factors associated with infant
      (< 1 year of age) physical abuse in Alaska. METHODS: A population-based
      retrospective cohort study for the 1994-2000 resident birth cohort was conducted
      by linking data from birth certificates, Child Protective Services, a statewide
      hospital-based trauma registry, hospital discharge data, and the Alaska Infant
      Mortality Review (including death certificates). The main outcome measures were
      the incidences of overall physical abuse and abuse resulting in hospitalization
      or death. A case of child abuse was defined as an instance of substantiated
      physical abuse to an infant identified in the Child Protective Services database
      or an infant death with homicide identified on the death certificate as the
      manner of death. RESULTS: During the 7-year study period, there were 70,842
      births and 325 cases of physical abuse including 72 that led to hospitalization
      (n = 58), death (n = 4), or both (n = 10); respective incidences for all abuse
      and abuse leading to hospitalization or death were 4.6 and 1.0 per 1000 live
      births. Following multivariate analyses, the risk factors with the highest
      population attributable risks were maternal or paternal education < or = 12
      years, unmarried mother, and maternal prenatal substance use. To determine if the
      study methodology was likely to have missed cases of severe abuse, we examined
      information for all 216 infants hospitalized for trauma during the study period
      who did not have identification of abuse in one of the study databases; of these,
      at least 39 had injuries inconsistent with the reported mechanism (a long bone or
      skull fracture that reportedly resulted from a fall of less than 3 feet or from a
      caretaker's arms or for which the caretaker denied a history of trauma).
      CONCLUSIONS: Alaska has one of the highest documented infant physical abuse
      incidences reported in the literature and abuse is associated with potentially
      modifiable-primarily social-risk factors. Despite this high incidence,
      substantial under-reporting of hospitalized cases likely occurs.

PMID- 15019437
TI  - Financing medically-oriented child protection teams in the age of managed health
      care: a national survey.
AB  - OBJECTIVE: The direct and indirect costs to society from child maltreatment are
      estimated to be quite high. The costs related to medical care are of interest to
      professionals serving on medically-oriented child protection teams that conduct
      medical evaluations of alleged abuse. This study was designed to explore a number
      of financially related issues on medically-oriented child protection teams
      specifically examining the team's staffing, funding sources, reimbursement,
      budgeting, perceived impact of managed health care and their perception of
      funding stability. METHOD: Mailed survey of medically-oriented child protection
      teams throughout the United States using a questionnaire that contained 28 items
      focused on a variety of financial issues; 14 items were drawn from a similar
      study done 6 years earlier, which allowed for comparison over time. RESULTS:
      Responses were received from 320 out of 472 organizations, yielding a response
      rate of 68%. Inclusion criteria were met by 153 responses and were included in
      the analysis; 22 of these had also responded to the earlier survey. Median total
      budget was $300,000 and state and local government funding was the largest
      revenue source (Mdn = 30%, range: 0-100%), followed by patient care generated
      revenue (Mdn = 20%, range: 0-100%). The mean charge for an evaluation was $283
      (SD = 196.11, range: $0-$800). Forty percent of teams indicated that managed care
      had no impact where as 49% saw a negative impact. Comparisons between the
      responses to this survey and the one done 1993 demonstrated that teams were
      seeing about the same number of patients and showed trends towards increased
      budget amounts and broader inclusion of various health care and non-health care
      disciplines on the teams. CONCLUSIONS: No single source of funds for such teams
      has emerged as the uniform solution for all teams. Creative patchworks composed
      of various funding sources remain the typical solution to the funding needs of
      medically-oriented child protection teams.

PMID- 15019438
TI  - Which juvenile crime victims get mental health treatment?
AB  - OBJECTIVE: To explore factors that facilitate the receipt of mental health
      treatment among juvenile crime victims. METHOD: Telephone interviews were
      conducted with a national sample of 157 caretakers whose children had suffered a
      serious sexual or physical assault in the previous year. RESULTS: Twenty-two
      percent of caretakers had thought about getting professional counseling for their
      child victims, and 20% of the child victims actually received it. But half of the
      families who thought about it did not follow through on their consideration.
      Moreover, nearly half of those victimized children who actually received
      counseling did so without their families reporting that they had considered it in
      advance. The level of symptoms and parent-child relationship factors were related
      to considering counseling which was in turn strongly related to actually getting
      counseling. Other factors were independently related to receiving counseling,
      such as the victimization occurring at school and the victim being perceived as
      at fault to some degree. Advice to get counseling and medical insurance also
      played roles. CONCLUSIONS: These findings suggested two pathways to counseling.
      One occurred via direct parental concern, and was associated with such variables
      as parental perceptions that the child was depressed or withdrawn or that the
      parent-child relationship had been negatively affected. The other pathway
      occurred independent of parental concern, most likely via school interventions,
      because this counseling was in conjunction with school victimizations.

PMID- 15019439
TI  - The relative influence of childhood sexual abuse and other family background risk
      factors on adult adversities in female outpatients treated for anxiety disorders
      and depression.
AB  - OBJECTIVE: This study from Norway examines the relative influence of child sexual
      abuse (CSA) and family background risk factors (FBRF) on the risk for current
      mental disorders and the quality of current intimate relationships in women with
      CSA treated for anxiety disorders and/or depression. Women with these disorders
      frequently seek treatment, and the place of CSA in therapy is still under debate.
      METHOD: 112 women, who were treated with outpatient psychotherapy by female
      therapists for anxiety disorders and/or depression were included. CSA had been
      admitted at the start of treatment start in 56 women, while no CSA was admitted
      among the 56 women of the comparison group. Systematic and detailed retrospective
      information about childhood as well as data on current functioning and current
      mental disorders were collected by questionnaires and structured interviews done
      by an independent female psychiatrist. RESULTS: The women of the CSA group
      reported significantly more FBRF than the comparisons. CSA increased the risk for
      posttraumatic stress disorder (PTSD), non-suicidal self-inflicted harm, and rape
      after 16 years. Major depression, dysthymia, and their comorbidity were not
      associated with CSA. The five indicators of quality of current intimate
      relationship were not associated with CSA. CONCLUSIONS: Women with CSA who have
      been treated for anxiety disorders and/or depression, also frequently have been
      exposed to FBRF. Increased risk for PTSD, self-inflicted harm before therapy, and
      rape after 16 years of age was influenced by CSA, while mood disorders and the
      quality of current attachment are not associated with CSA, but with FBRF or other
      factors not examined in this study.

PMID- 15019440
TI  - Maltreatment and coping strategies among male adolescents living in the Gaza
      Strip.
AB  - OBJECTIVE: To establish the nature and extent of maltreatment experiences, coping
      strategies, and behavioral/emotional problems, and their relationships, in a
      sample of Palestinian adolescents. METHOD: A study of 97 male adolescents aged 15
      19 years, and attending a vocational training center based in the Gaza Strip.
      Adolescents completed the Child Maltreatment Schedule and the Ways of Coping
      Scale (WAYS). The Strengths and Difficulties Questionnaire (SDQ) was completed by
      adolescents and by their teachers. RESULTS: Findings revealed high rates of
      emotional and physical maltreatment. Reliance on emotion-focused or avoidant
      coping strategies was associated with exposure to maltreatment. Use of
      maladaptive coping also predicted emotional difficulties in the respondents.
      CONCLUSIONS: Coping strategies are an important indicator of psychosocial
      functioning in adolescents who have experienced maltreatment. Identification of
      coping styles can augment the assessment of at-risk adolescents. Emotion-focused
      strategies, in particular, appear to be widely used by young people from non
      Western cultural backgrounds.

PMID- 15019441
TI  - Progress report on the development of child abuse prevention, identification, and
      treatment systems in Eastern Europe.
AB  - PROBLEM: After the Soviet Union dissolved in 1989, it became apparent that there
      was little recognition of the problems of child abuse and neglect,
      professionally, legally, or societally. There were no effective systems or laws
      in place to deal with these problems. METHOD: Beginning in 1995 the Children's
      Mental Health Alliance, in conjunction with the Open Society Institute began
      conducting trainings in Eastern Europe [Journal of the American Academy of Child
      Adolescent Psychiatry 39 (2000) 660]. Originally 18 countries from the Baltics to
      the Balkans participated. A program was elaborated which would proceed in several
      stages: (1) training mental health professionals to deal with child abuse and
      neglect (CAN); (2) teaching multidisciplinary team work and fostering the
      development of multidisciplinary NGOs focused on CAN; (3) promoting the self
      sufficiency of these NGO's which would then facilitate social and legal reform
      and increase public awareness of the problem. Specific methods included multi
      national trainings, assignment of mentors to the developing teams who maintained
      weekly contact with the teams and made yearly site visits to their countries, and
      overseeing project grants from OSI. RESULTS: NGO's had been established and
      registered in 11 countries, many establishing a network of programs within their
      countries. By 2000, over 3800 mental health professional had been trained, either
      directly by the program or by the trainees of the program. By the end of 2000,
      over 17,000 other professionals (lawyers, police, judges, educators, other
      physicians, etc.) had been trained by the network. CONCLUSION: While more work
      needs to be in this region, the teams in 11 countries have made solid starts.

PMID- 15019443
TI  - Acoustic emission analysis of fiber-reinforced composite in flexural testing.
AB  - OBJECTIVES: The aim of this study was to examine the emission of acoustic signals
      from six commercially available fiber-reinforced composites (FRC) used in the
      frameworks of fixed partial dentures in material bending. METHODS: FRC test
      specimens were made of six commercially available fiber products of polyethylene
      or glass and five light-curing resins. FRC test specimens were polymerized with a
      hand light-curing unit or with a light-curing oven. The flexural test for
      determination of ultimate flexural strength of test specimens (n = 6) was based
      on the ISO 10477 standard after the specimens were stored in air or in water for
      two weeks. The acoustic emission (AE) signals were monitored during three-point
      loading test of the test specimens using a test with increasing loading levels
      until the specimens fractured. RESULTS: Generally, stress level required for the
      AE activity initiation ranged from 107 MPa (Ribbond) to 579 MPa (everStick). The
      ultimate flexural strength of FRC specimens were higher, ranging from 132 to 764
      MPa, being highest with everStick and Vectris FRC, and lowest with Ribbond FRC.
      ANOVA showed a statistically significant difference between the initiation of AE
      activity and the ultimate flexural strength according to the brand (p < 0.001)
      storing conditions (p < 0.001) and polymerization procedure (p < 0.001). AE
      activity and ultimate flexural strength correlated significantly (p < 0.010, r =
      0.887). SIGNIFICANCE: The result of this study suggested that AE activity in FRC
      specimens started at a 19-32% lower stress level than occurred at final fracture.

PMID- 15019442
TI  - Cross-cultural comparisons of child-reported emotional and physical abuse: rates,
      risk factors and psychosocial symptoms.
AB  - OBJECTIVES: This study was designed to assess the incidence of child emotional
      and physical abuse, associated risk factors and psychosocial symptoms in a cross
      cultural comparison between post-communist bloc countries. METHOD: One-thousand
      one-hundred forty-five children ages 10-14 from Latvia (N = 297), Lithuania ( N =
      300), Macedonia (N = 302), and Moldova (N = 246) participated in the study. They
      completed questionnaires assessing their experience of emotional or physical
      abuse, and provided information about family risk-factors and psychosocial
      symptoms, including PTSD-related symptoms. RESULTS: Incidence rates of
      maltreatment differed by country, as did levels of reported psychosocial
      symptoms. Incidence of emotional and physical abuse differed by region, with
      higher levels of abuse reported in the rural regions. In all four countries, a
      similar association between emotional/physical abuse and psychosocial symptoms
      was found, with the uniformly largest correlation between emotional abuse and
      anger. When examining the combined scores of emotional and physcial abuse, even
      higher correlation's were found, particularly in relation to anger and
      depression. In all four countries, parental overuse of alcohol was associated
      with emotional and/or physical abuse. CONCLUSIONS: Findings show differences by
      country in child-reported levels of emotional and physical abuse, but similar
      patterns of correlation with psychosocial symptoms and the risk factors of
      parental alcohol overuse and living in a rural area.

PMID- 15019444
TI  - Determination of polymerization shrinkage stress by means of a photoelastic
      investigation.
AB  - OBJECTIVE: This study examined the polymerization stress of different established
      composite resins (Tetric Ceram, Vivadent; EsthetX, Surefil, Dentsply/DeTrey;
      Clearfil AP-X, Clearfil Photo Posterior, Kuraray; Prodigy Condensable, sds Kerr;
      Filtek P 60, 3M ESPE; Solitaire 2, Heraeus-Kulzer) by means of a photo-elastic
      investigation and investigated six new, experimental composite resins, which have
      been claimed to exhibit less polymerization shrinkage (InTen-S, Vivadent; K 112,
      K 051, Dentsply/DeTrey; Compox, Pluto, Hermes 3M ESPE). METHODS: Cylindrical
      cavities (phi 5 mm) in Araldit B epoxide resin plates (40 x 40 x 3 mm3) were
      pretreated with the Rocatec system to ensure bonding of the composite resin. Ten
      composite resin specimens of each material, embedded in the Araldit plates, were
      exposed for 60 s (Elipar TriLight, Standard-mode, 800 mW/cm2). Polymerization
      contraction stress data (MPa) were calculated at 4 min and 24 h after exposure,
      based on the diameter of the isochromatic curves of first order obtained from the
      Araldit-plates. The statistical analysis was carried out with the Wilcoxon test
      (5% level). RESULTS: After 24 h, the calculated mean polymerization stress values
      were 4.4+/-0.1 MPa for Tetric Ceram, 4.6+/-0.1 MPa for EsthetX, 3.7+/-0.1 MPa for
      Z 250, 4.6+/-0.1 MPa for Clearfil AP-X, 4.1+/-0.1 MPa for Prodigy Condensable,
      4.0+/-0.1 MPa for Filtek P 60, 4.5+/-0.1 MPa for Surefil, 4,5+/-0.1 MPa for
      Clearfil Photo Posterior, 5.4+/-0.04 MPa for Solitaire 2, 3.2+/-0.1 MPa for In
      Ten-S, 3.9+/-0.1 MPa for K 112, 3.1+/-0.04 MPa for K 051, 3.2+/-0.1 MPa for
      Compox, and 2.0+/-0.1 MPa for Hermes. CONCLUSIONS: The new and experimental
      composite resins In Ten-S, K 051, Compox, and Hermes showed significantly less
      polymerization shrinkage stress than the controls (p < 0.0005, Bonferroni
      correction). For the experimental material Pluto, no determination of
      isochromatic rings was possible.

PMID- 15019445
TI  - Ultimate tensile strength of tooth structures.
AB  - OBJECTIVE: This study determined the ultimate tensile strength (UTS) of enamel
      (E), dentin (D) and dentin-enamel junction (DEJ) using the microtensile
      technique. It was hypothesized that the UTS of dental structures varies according
      to location and nature. METHODS: Intact occlusal enamel surfaces from extracted
      human third molars were etched with 37% phosphoric acid and bonded with a one
      bottle adhesive system. The bonded occlusal surfaces received a resin composite
      build-up and teeth were serially, vertically sectioned into several 0.7 mm thick
      slabs. Each slab was then trimmed to a dumbbell-shaped specimen with irrigated
      diamond burs to reduce the cross-sectional area to approximately 0.5 mm2 at E, D
      or DEJ. E was tested according to its prismatic orientation (parallel, EP; and
      transversally, ET) and D as function of depth (superficial, DS; middle, DM and
      deep, DD). Specimens were tested in tension in an Instron testing machine at 0.5
      mm/min. Results were analyzed by one-way ANOVA and Duncan's Multiple Range test.
      RESULTS: UTS mean values (N = 20) were, MPa (SD): DEJ, 46.9 (13.7)b; EP, 42.1
      (11.9)b; ET, 11.5 (4.7)d; DS, 61.6 (16.2)a; DM, 48.7 (16.6)b and DD, 33.9 (7.9)c.
      Enamel stressed transversally to its prismatic orientation was significantly
      weaker (p < 0.05) Dentin depth significantly affected its UTS (p < 0.05) DEJ
      presented UTS that was similar to EP and DM (p > 0.05) SIGNIFICANCE: The UTS of
      dental structures varies according to its nature and location.

PMID- 15019446
TI  - New mechanical retention method for resin and gold alloy bonding.
AB  - OBJECTIVE: The purpose of this study was to improve adhesion between dental
      adhesive resins and 14K gold alloy by creating a sponge-like structure on the
      alloy surface which enhanced mechanical bonding. METHODS: The internal oxidation
      particles of Cu oxides precipitated on a 14K gold alloy surface after high
      temperature oxidation at 800 degrees C in air were removed by pickling with an
      acid solution to create a sponge-like structure on the alloy surface. A PMMA
      resin containing 4-META as an adhesive monomer and a self-cured resin without 4
      META were used to examine the effects of mechanical and chemical factors on bond
      strength. A thiophosphate-type metal primer (M-Primer II) was used in combination
      with 4-META resin to strengthen the chemical bonding of 4-META resin to the
      porous alloy surface. The surfaces of the alloy specimen treated by oxidation,
      pickling, and bonding with 4-META resin were analyzed using an electron probe X
      ray micro-analyzer. RESULTS: SEM observation showed many resin tags on the resin
      side of the bond structure after removal of the gold alloy matrix with aqua
      regia. The bond strength of 4-META resin to the porous alloy surface was 38+/-3
      (mean+/-SD) MPa whereas that to a flat alloy surface with the same composition
      was 19+/-1 MPa. The bond strength of a self-cured resin without 4-META to the
      porous alloy surface was 24+/-2 MPa. SIGNIFICANCE: A high bond strength was
      obtained when 4-META resin was bonded to the porous 14K gold alloy surface
      treated with M-Primer II.

PMID- 15019447
TI  - Work of adhesion of resin on treated lithia disilicate-based ceramic.
AB  - OBJECTIVE: This study is to test the hypothesis that chemical etching and silane
      coating of a ceramic surface will influence the work of adhesion (WA) of adhesive
      resin to dental ceramic. METHODS: A hot-pressed lithia disilicate-based ceramic
      was used as a model material to investigate the influence of probing media and
      surface treatments on WA using a dynamic contact angle analyzer. Eighty ceramic
      specimens were randomly divided into eight experimental groups and treated as
      follows: (1 and 3) as polished; (2 and 4) etched with 9.5% hydrofluoric acid (HF)
      for 1 min; (5) etched with 4% acidulated phosphate fluoride (APF) for 2 min; (6)
      silane coated; (7) etched with HF for 1 min and silane coated; (8) etched with
      APF for 2 min and silane coated. Advancing and receding contact angles (theta(a)
      and theta(r)) were measured using high purity water (gamma = 72.6 mN/m) for
      groups 1 and 2, and a liquid resin (gamma = 39.7) for groups 3-8 as probing
      liquids. RESULTS: The liquid resin medium yielded a lower WA than water.
      Silanization produced a significantly lower WA (p < 0.001) than non-silanated
      surfaces. Etching alone consistently yielded a greater WA for all surface
      treatments (p < 0.001). SIGNIFICANCE: The silanated ceramic surface exhibited a
      lower surface energy and did not enhance bonding to the liquid resin by work of
      adhesion.

PMID- 15019448
TI  - Volumetric dimensional change of six direct core materials.
AB  - OBJECTIVES: This study evaluated the influence of water on the volumetric
      dimensional change of six direct placement core build-up materials by using
      Archimedes' principle. METHODS: The effect on dimensional change due to the
      setting reaction was determined through the use of a silicone oil storage medium.
      The materials used were two dual-cured resin composites (CoreStore and Build-It
      FR), two chemically activated resin composites (CorePaste and Ti-Core), one metal
      reinforced glass ionomer cement (Ketac-Silver), and one resin-modified glass
      ionomer (Fuji II LC Core). Using the manufacturers' instructions for each
      material, cylindrical specimens were prepared with dimensions of 7+/-0.1 mm in
      diameter and 2+/-0.1 mm in height. Each material had four groups (n = 5) based on
      storage conditions; silicone oil at 23 and 37 degrees C and distilled water at 23
      and 37 degrees C. A 0.01 mg resolution balance was used to determine volumetric
      dimensional change using an Archimedean equation. Measurements were made 30 min
      after mixing, and at the time intervals of 1, 14, and 56 days. RESULTS: All
      materials exhibited dimensional change. Ketac-Silver had the most shrinkage in
      silicone oil and Fuji II LC showed the highest expansion in distilled water. The
      glass ionomer materials showed more change than did any of the resin composite
      materials. SIGNIFICANCE: Current direct placement core materials show variation
      in the amount of volumetric dimensional change seen over a period of 56 days.

PMID- 15019449
TI  - The effect of recasting on corrosion of a silver-palladium alloy.
AB  - OBJECTIVES: Noble and semi-noble dental casting alloys are often reused by
      recasting. The aim of this study was to determine if repeated casting has a
      detrimental effect on the corrosion behavior of a silver-based dental alloy.
      METHODS: A commercial Ag-Pd-Cu-Au alloy was cast and four times recast.
      Electrochemical tests were performed to determine the effects of recasting on the
      polarization parameters and the corrosion current density in artificial saliva.
      Changes in hardness, chemical composition and microstructure were determined.
      RESULTS: Recasting had little effect on the shape of the polarization curves, but
      the corrosion current density dramatically increased after the fifth cast.
      Hardness increased with recasting and the microstructure showed grain growth.
      Increased subgrain formation was found for the fifth cast. The elemental map
      showed decreased surface concentration of Au for the fifth cast. The bulk
      concentrations of Au, Ag and Pd remained constant, but the copper and zinc
      contents slightly decreased and the content of impurities increased.
      SIGNIFICANCE: Recasting of an Ag-Pd-Cu-Au alloy initially had little effect on
      the corrosion susceptibility in artificial saliva, but a severe degradation of
      properties was observed after the fifth cast. The results indicate that a dental
      alloy of this type can be safely recast only a small number of times.

PMID- 15019450
TI  - The use of acoustic microscopy to study the mechanical properties of glass
      ionomer cement.
AB  - OBJECTIVES: The aim of the study was to investigate the relationship between
      microstructure, acoustic and mechanical properties of hardened dental cement
      samples, prepared with different powder/water ratios. METHODS: Glass-ionomer
      dental cement samples, prepared with a standard amount of cement powder and
      different amounts of water have been examined after being hardened. Surface
      microstructure and ultrasound, longitudinal and shear velocities were obtained
      with a scanning acoustic microscope. Conditional effective elastic modulus and
      Poisson's ratio have been calculated using longitudinal and shear sound velocity
      values. Then on the same samples elastic modulus and microhardness have been
      determined by standard tests. Additional samples have been used to determine
      compressive strength. RESULTS: Density; conditionally instantaneous elastic
      modulus; high-elasticity modulus and compression strength of the samples decrease
      when large amounts of water were used for their preparation. At the same time
      porosity and microhardness of the cement matrix increase. Acoustic parameters and
      parameters of elasticity, calculated on the basis of sound velocity, demonstrated
      changes, similar to those obtained in standard mechanical tests. SIGNIFICANCE:
      The established relation between microstructure, acoustic and mechanical
      parameters demonstrated a high capacity of acoustic microscopy application for
      non-destructive characterization of dental materials. A particular advantage of
      the acoustic microscopy is the opportunity to evaluate microstructure and
      mechanical properties on the same sample.

PMID- 15019451
TI  - Depth of cure and surface microhardness of composite resin cured with blue LED
      curing lights.
AB  - OBJECTIVES: This study examined the depth of cure and surface microhardness of
      Filtek Z250 composite resin (3M-Espe) (shades B1, A3, and C4) when cured with
      three commercially available light emitting diode (LED) curing lights [E-light
      (GC), Elipar Freelight (3M-ESPE), 475H (RF Lab Systems)], compared with a high
      intensity quartz tungsten halogen (HQTH) light (Kerr Demetron Optilux 501) and a
      conventional quartz tungsten halogen (QTH) lamp (Sirona S1 dental unit). METHODS:
      The effects of light source and resin shade were evaluated as independent
      variables. Depth of cure after 40 s of exposure was determined using the ISO
      4049:2000 method, and Vickers hardness determined at 1.0 mm intervals. RESULTS:
      HQTH and QTH lamps gave the greatest depth of cure. The three LED lights showed
      similar performances across all parameters, and each unit exceeded the ISO
      standard for depth of cure except GC ELight for shade B1. In terms of shade, LED
      lights gave greater curing depths with A3 shade, while QTH and HQTH lights gave
      greater curing depths with C4 shade. Hardness at the resin surface was not
      significantly different between LED and conventional curing lights, however,
      below the surface, hardness reduced more rapidly for the LED lights, especially
      at depths beyond 3 mm. SIGNIFICANCE: Since the performance of the three LED
      lights meets the ISO standard for depth of cure, these systems appear suitable
      for routine clinical application for resin curing.

PMID- 15019452
TI  - Influence of dietary simulating solvents on the hardness of provisional
      restorative materials.
AB  - OBJECTIVE: To evaluate the influence of dietary simulating solvents on surface
      hardness of chemical, light and dual-cure provisional restorative materials.
      METHODS: The provisional materials evaluated were Temporary Bridge Resin (TBR)
      (Dentsply), Protemp Garant (PG) (ESPE-3M), Luxatemp Automix (LA) (DMG), Unifast
      LC (UF) (GC), Luxatemp Solar Plus (LS) (DMG) and Provipoint DC (PP) (Vivadent).
      Materials were manipulated according to manufacturers' instructions and placed in
      customized molds. Immediately after setting/light-polymerization, the materials
      were stored in the following dietary simulating solvents at 37 degrees C for 1
      week: (a) heptane, (b) 100% ethanol solution (ES), (c) 75% ES, (d) 50% ES, (e)
      25% ES, and (f) distilled water. Specimens stored in air were used as control.
      After the one-week conditioning period, hardness testing (KHN; n = 6) was carried
      out with a digital microhardness tester (load=100 gf; dwell time=15 s). Hardness
      ratios were plotted against the solubility parameter of the solvents and the
      Environmental Index was subsequently computed. Data were subjected to
      ANOVA/Scheffe's test at significance level 0.05. RESULTS: For all materials,
      conditioning in the various ES resulted in significantly lower KHN values
      compared to conditioning in air and water. TBR, UF and PP were also significantly
      softened by conditioning in heptane. Ranking of Environmental Index was as
      follows: LS>LA>PG>TBR>UF>PP. SIGNIFICANCE: All provisional materials were
      significantly softened by aqueous ethanol solutions. Materials based on bis-acryl
      resins were generally more resistant to damage from dietary solvents.

PMID- 15019454
TI  - Exotherm behavior of the polymer-based provisional crown and fixed partial
      denture materials.
AB  - OBJECTIVES: The objective of this in vitro study was to evaluate the exothermic
      reaction during polymerization of the polymer-based provisional crown and fixed
      partial denture materials. METHODS: Three dimethacrylate-based materials and one
      monomethacrylate-based material were selected. The specimens were pre-conditioned
      to 23 degrees C. Temperature changes of the materials during polymerization were
      recorded in a model test-cavity overlying a type K thermocouple. Peak
      temperature, time to reach peak temperature and total peak area were determined.
      The data were statistically analyzed using one-way ANOVA at a significance level
      of 0.05. RESULTS: All materials exhibited exotherm release ranging from 5.1 to
      12.7 degrees C. Trim gave a peak temperature that was not significantly lower (p
      > 0.05) than those of Protemp 3 Garant and Luxatemp, but fast set Temphase showed
      a significantly higher (p < 0.05) peak temperature than the other materials. All
      materials showed no significant differences (p > 0.05) in the total peak area.
      Trim showed the slowest exotherm reaction; its time to reach the peak temperature
      was ca. 10 min after mixing, while ca. 2 min for the other materials.
      SIGNIFICANCE: The dimethacrylate-based materials (except for fast set Temphase)
      exhibited no significant differences in peak temperature and total peak area from
      the monomethacrylate-based material with slower exotherm reaction. A
      reformulation of the dimethacrylate-based materials could be envisaged to
      generate a material with a slightly slower setting and a reduced peak
      temperature.

PMID- 15019453
TI  - Non-destructive characterization of resin-based filling materials using
      Electronic Speckle Pattern Interferometry.
AB  - OBJECTIVES: The aim of this study was to develop a non-destructive test for
      characterizing the modulus of resin-based filling materials. METHODS: Five
      different visible-light-cured composites (Filtek A110 [AO], Z100 [ZO], Filtek
      Z250 [ZT], F2000 [FT] and Filtek Flow [FF]; 3M-ESPE) were selected for this
      study. An ESPI (Electronic Speckle Pattern Interferometry) apparatus involving
      cantilever beam specimens (28 mm long, 8 mm wide and 2 mm thick) was developed
      for determining modulus. Out-of-plane displacement upon force application was
      measured using two focus region lengths (22 mm [EI1]; 11 mm [EI2]) and modulus (n
      = 7) was subsequently computed based on cantilever beam equations. Data was
      compared to those obtained from three-point-bend flexural testing (n = 7) based
      on ISO4049:2000 specifications [ISO]. Specimens were stored in distilled water at
      37 degrees C for 1 week prior to evaluation for all tests. Results were analyzed
      using ANOVA/Scheffe's post-hoc tests (p < 0.05) and Pearson's correlation (p <
      0.01). RESULTS: Modulus ranged from 5.53 to 13.99, 5.78 to 14.24 and 4.26 to
      11.30 GPa for EI1, EI2 and ISO, respectively. For all three tests, the modulus of
      ZO and FT was significantly greater than ZT, which in turn was significantly
      greater than AO and FF. Correlation of EI1 and EI2 to ISO was significant,
      positive and very strong (r = 0.94 for EI1 and EI2). SIGNIFICANCE: ESPI may be a
      viable method of characterizing the modulus of resin-based filling materials. As
      it is a non-destructive test, time-dependent effects of composites can be
      determined using the same specimens leading to substantial time and material
      savings.

PMID- 15019455
TI  - Critical configuration analysis of four methods for measuring polymerization
      shrinkage strain of composites.
AB  - OBJECTIVES: To compare four methods for measuring polymerization shrinkage strain
      of composites and to develop a rational basis for comparing data from different
      methods and laboratories. METHODS: Dilatometry, modified bonded disk, strain
      gage, and a new linear transducer method were used to measure polymerization
      shrinkage strain of a model composite under similar irradiation conditions. The
      resin consisted of an untinted resin (50:50 BISGMA/TEGDMA, 0.7% CQ, 0.35% DMAEM,
      0.05% BHT) filled with 5% fumed silica and 67 wt% untreated hybrid filler.
      Specimens (n = 10) were exposed for 60 s at 600 mW/cm2 and then monitored for 300
      s. Specimen volumes were 8 mm3 for the strain gage method, 25 mm3 for the linear
      transducer and dilatometer methods and 43 mm3 for the bonded disk method. The
      degree of constraint applied to the specimens by each method was calculated and
      compared. Shrinkage strain values at 60 and 300 s were tested for significance at
      p = 0.05 using one-way ANOVA and Tukey's test. RESULTS: Shrinkage strain
      magnitudes at 60 and 300 s for the four methods were significantly different (p <
      0.01) The modified bonded disk method measured the highest shrinkage value and
      exhibited the highest degree of specimen constraint. There was a 5 s delay after
      light activation before strain was detected by the strain gage. SIGNIFICANCE:
      Specimen constraint differed in all four methods and was linearly correlated with
      shrinkage strain magnitude when the degree of constraint was less than 42%.

PMID- 15019456
TI  - Prediction of composite elastic modulus and polymerization shrinkage by
      computational micromechanics.
AB  - OBJECTIVES: The objective of this study was to simulate the elastic modulus and
      polymerization shrinkage of a light activated polymer matrix composite using a
      generalized method of cells (GMC) micromechanics model. Two hypotheses were
      tested: (1) the micromechanics model provides estimates of elastic modulus vs
      filler fraction with greater accuracy than the rule of mixtures, Hashin-Shtrikman
      and phenomenological models; (2) Micromechanics Analysis Code/Generalized Method
      of Cells accurately simulates experimental benchmarks of polymerization shrinkage
      strain. METHODS: The study applied mathematical algorithms to a representative
      volume element of a model polymer composite to yield value estimates of the
      elastic modulus and contraction strain. Mechanical properties of the composite
      constituents were derived from thermomechanical and dynamic mechanical analysis
      of BisGMA and TEGDMA filled and unfilled resins. Data from the micromechanics
      model were compared to results of other analytical methods as well as
      experimental benchmarks. RESULTS: Predictions of elastic modulus vs filler
      fraction from the micromechanics model provided greater accuracy than the rule of
      mixtures and the Hashin-Shtrikman models. Predictions of polymerization shrinkage
      strain were within 13% of experimental values. SIGNIFICANCE: The elastic
      micromechanics model presented accurately predicted elastic modulus and
      polymerization shrinkage strain as a function of filler fraction, superior to
      other analytical methods.

PMID- 15019457
TI  - Contraction force rate of polymer composites is linearly correlated with
      irradiance.
AB  - OBJECTIVES: The force developed during cure of a composite represents the
      potential loads that can be induced into the dental adhesive and tooth structure
      that in turn affects the integrity of the dental adhesive and tooth. The purpose
      of this study was to evaluate the dependence of polymerization contraction force
      development on light energy density (product of irradiance and time). METHODS:
      Contraction force during polymerization was measured with a low compliance test
      fixture in which the composite specimen was placed between a glass plate and
      steel rod. The steel rod passed through a washer-type load cell that measured
      force development during cure. Six irradiance levels were evaluated as well as a
      'pulse-delay' method. A generic composite consisting of a 1:1 blend of BisGMA and
      TEGDMA resin and 67 wt% unsilanated hybrid filler with 5 wt% fumed silica was
      used for all experiments. Contraction force was collected for 550 s. The first
      derivative of contraction force with respect to time (dF/dt) was calculated. Net
      contraction force at 550 s and max[dF/dt] was statistically analyzed as a
      function of irradiance and energy density (product of irradiance and time) with
      one-way ANOVA and Tukey's post-hoc test at the 0.05 level of significance.
      RESULTS: Contraction force increased most rapidly immediately following light
      activation. Force resulting from the pulse-delay method was significantly
      different from all other methods (p < 0.001). Force resulting from irradiation at
      600 mW/cm2 was significantly different (p < 0.01) from all other methods and 500
      mW/cm2 was significantly different from 100 and 200 mW/cm2. Maximum df/dt
      (max[dF/dt] over full range of time) was linearly related to irradiance, linear
      regression r2 = 0.98. All pairs of irradiance were significantly different except
      pulse-delay and 200-300 mW/cm2 and 300 and 400 mW/cm2. SIGNIFICANCE: The pulse
      delay method demonstrated contraction force rates lower than what would be
      expected using energy considerations and lower force rates at each of the two
      light exposures than their single exposure counterparts. Since the adhesive resin
      and dentin are viscoelastic and thus strain rate dependent, time dependent
      contraction force should be an important consideration.

PMID- 15019458
TI  - The effect of different extenders on post-thaw sperm survival, acrosomal
      integrity and longevity in cryopreserved semen of Formosan Sika deer and Formosan
      Sambar deer.
AB  - This study investigates the efficacy of five extenders in contributing to the
      outcome of semen cryopreservation in Formosan Sika and Sambar deer. Pooled semen
      (n=4) of six males of each breed was used. In Sika deer, semen collection rate
      was 96% (23/24) over all electro-ejaculations. Volume, sperm motility and sperm
      concentration of fresh ejaculates was 0.5+/-0.4 ml, 77+/-6% and 1471.3+/-940.0 x
      10(6) ml(-1), respectively. Post-thaw motility in respective extender was A: 66+/
      16%; B: 71+/-2%; C: 73+/-6%; D: 9+/-4% and E: 26+/-12% (mean+/-S.D.). In extender
      C (74+/-14%) more viable spermatozoa were preserved than in the others (A: 64+/
      10%; B: 48+/-11%; D: 41+/-16%; E: 47+/-6%; P<0.05). Acrosomal integrity was not
      influenced by extender composition. Post-thaw motility did not decrease during a
      4-h incubation period, irrespective of the extender used (P>0.05). In Sambar
      deer, semen collection rate was 88% (21/24) over all electro-ejaculations.
      Volume, sperm motility and sperm concentration of fresh ejaculates was 1.3+/-0.5
      ml, 82+/-4% and 379.1+/-252.2 x 10(6) ml(-1), respectively. Post-thaw motility
      was in respective extenders A: 69+/-2%; B: 74+/-6%; C: 73+/-2%; D: 13+/-6% and E:
      31+/-20%. Extenders B and C were superior (P>0.05) with respect to sperm
      motility. Similarly, post-thaw viability in extenders A (70+/-7%), B (76+/-7%)
      and C (79+/-2%) was higher than that D (25+/-19%) and E (29+/-17%) (P<0.01).
      Sperm acrosomal integrity was better preserved in extenders B (86+/-4%) and C
      (83+/-4%) than in extenders A (54+/-13%), D (39+/-22%) and E (46+/-22%) (P<0.05).
      Post-thaw sperm longevity in extender A reduced from 69 to 16% during incubation
      (P<0.05) whereas only a slight decrease was observed in the other extenders after
      4 h. In conclusion these data show that egg-yolk-Tris-Tes-glycerol based extender
      C containing Equex STM paste is optimal for freezing semen of Formosan Sika deer
      while egg-yolk-Tris-citric acid-glycerol based extender B containing Equex and
      extender C are superior in semen cryopreservation to others for Formosan Sambar
      deer.

PMID- 15019459
TI  - Kinetics of protein tyrosine phosphorylation in sperm selected by binding to
      homologous and heterologous oviductal explants: how specific is the regulation by
      the oviduct?
AB  - Essential steps of the capacitation process take place in the oviductal isthmus.
      A crucial step in the process of capacitation is the phosphorylation of membrane
      proteins. The aims of this work were (1) to study the effect of dog sperm binding
      to oviductal epithelium on tyrosine phosphorylation and (2) to investigate the
      specificity of regulation of molecular changes by the oviduct of different
      species by comparing the numbers of canine sperm bound to heterologous (porcine)
      and homologous epithelium, and the kinetics of tyrosine phosphorylation. Semen
      was collected from four healthy dogs and washed through a Percoll gradient.
      Explants, small pieces of epithelium, were cut from porcine and estrous bitch
      oviducts. During 6 h of coincubation in Tyrode medium, the numbers of bound sperm
      were counted by microvideographic observation, and the state of tyrosine
      phosphorylation was determined immunocytochemically after 3, 30, 90, 180 and 360
      min. Canine sperm bound in similar numbers to homologous and heterologous
      explants. Increasing tyrosine phosphorylation of tail proteins and subsequent
      phosphorylation of sperm head proteins were observed. Binding occurred mainly in
      sperm with non-phosphorylated heads (approximately 2% phosphorylated), while
      higher proportions of head-phosphorylated cells were found in unbound populations
      (approximately 40-60%;P<0.05). The head phosphorylation progressed significantly
      during incubation in unbound spermatozoa (P<0.05), while it was suppressed in
      bound suspensions. The rate of tyrosine phosphorylation of sperm tail proteins
      was higher in cells bound to explants than in unbound cells or in those incubated
      in control medium. There were no significant differences with respect to the
      kinetics of tyrosine phosphorylation between the two coincubation systems. These
      observations support the hypothesis that spermatozoa with non-phosphorylated
      heads preferentially attach to epithelial cells. Tyrosine phosphorylation of
      sperm head proteins and capacitation are delayed in spermatozoa in close contact
      with oviductal epithelium. This mechanism appears to be species-independent, as
      sperm bound similarly to pig and dog oviduct explants, and similar
      phosphorylation kinetics were observed in both types of tissue.

PMID- 15019460
TI  - Ultrasonographic characterization of the ovaries and the uterus in prepubertal
      and pubertal gilts.
AB  - In two experiments (EXP), 44 and 52 crossbred gilts (mean age+/-S.D. and weight+/
      S.D.: 204+/-22 and 203+/-9 days, 114+/-13 and 127+/-12 kg, respectively, in EXP 1
      and 2) from four farms were examined by means of transcutaneous ultrasonography
      (US) to define the characteristics of the ovaries and the uterus (echotexture,
      size) and to investigate the appropriateness of US to determine sexual maturity.
      Gilts were judged as prepubertal [PRE; follicles 2-5 mm (F2-5) only] or pubertal
      [PUB; F7-8, corpora lutea (CL), corpora haemorrhagica (CH)] at the first (PUB-1;
      EXP 1) or a subsequent estrous cycle [PUB-2; additionally corpora albicantia
      (CA); EXP 1] by US, and results were verified by postmortem examination (EXP 1),
      or progesterone analysis and detection of estrous signs (EXP 2). Accuracy of US
      was 100% for PRE and PUB (both EXP) and 77.3% for PUB-1 and PUB-2 (EXP 1). PRE
      and PUB with CL/CH had uteri of homogeneous, PUB with F7-8 of heterogeneous
      echotexture. The size was expressed as the mean sectional area (SAsono) of 2-5
      cross-sections of the uterine horns (calculated by multiplication of 1/2 the
      maximum x the minimum dimension of the cross-sections x pi). SAsono corresponded
      with the sectional area of postmortem dissected transverse uterine segments
      relatively with r=0.92 (P<0.0001; EXP 1). Mean SAsono (both EXP) and mean uterine
      weight (EXP 1) were PRE<PUB (all P<0.0001). SAsono and UW showed a high
      correlation (UW=287x SAsono-66; r=0.92; P<0.0001; EXP 1). In conclusion, the
      diagnosis of sexual maturity is facilitated in prepubertal and pubertal gilts
      based on the characteristics of the ultrasonographic appearance of the ovaries
      and the size of the uteri.

PMID- 15019461
TI  - Effects of adrenocorticotropin stimulation on cortisol dynamics of pregnant gilts
      and their fetuses: implications for prenatal stress studies.
AB  - The effect of adrenocorticotropic hormone (ACTH) administration on plasma
      cortisol concentrations was determined in pregnant gilts and their fetuses. In a
      first experiment, 100 IU ACTH (Synacthen Depot) was administered intramuscularly
      to the gilts every second day from Days 49 to 75 of gestation. ACTH injections
      were carried out at 08:00 h and, thereafter, 10 blood samples were taken within
      the following 8h via jugular catheters. Blood samples were analysed for plasma
      cortisol concentrations, and results were compared with values from animals which
      were treated with physiological saline and untreated animals (blood sampling
      only). The values for plasma cortisol concentrations increased until 3h after
      ACTH applications to a mean maximum level of 276.5+/-17.2 nmol/l in the whole 4
      week stimulation period. Plasma cortisol levels did not return to pre-treatment
      values within the 8 h post-injection. No differences in cortisol levels were
      found between the physiological saline and untreated control, and no habituation
      of the adrenocortical response to ACTH was found during the 4-week stimulation
      period. In a second experiment, 100 IU ACTH were administered to pregnant gilts
      at gestation Day 65. After 3 h, fetuses were recovered under general anaesthesia
      and blood samples were taken from the umbilical vein, artery, and, after
      decapitation, from periphery. Application of ACTH to the sows significantly
      increased their plasma cortisol concentrations (P<0.001), and also increased
      plasma cortisol concentrations in peripheral blood samples from the fetuses
      (P=0.09) and in the umbilical vein (P<0.001) and artery (P<0.01), respectively.
      Plasma ACTH concentrations did not differ in fetuses from ACTH-treated or control
      sows. The results show that in gilts the adrenocortical response to an exogenous
      application of Synacthen Depot is consistent over time during mid-gestation.
      Furthermore, cortisol but not ACTH levels were increased in fetuses from ACTH
      treated sows, indicating that maternal cortisol can cross the placenta during mid
      gestation. The stimulation of maternal cortisol release through exogenous ACTH
      with subsequent elevation of fetal cortisol levels is, therefore, a useful
      approach for studying effects of elevated maternal glucocorticoids in prenatal
      stress studies in pigs.

PMID- 15019462
TI  - Effect of DNA repair inhibitor (3-aminobenzamide) on genetic stability of loach
      (Misgurnus fossilis) embryos derived from cryopreserved sperm.
AB  - Semen cryopreservation is widely used in clinical medicine, agriculture,
      aquaculture and biomedical research, but it is an inefficient technique that
      induces extensive cytoplasmic damage and loss of fertilising ability. Whether any
      genetic damage (i.e. DNA strand breakage or mutation) is also induced is still
      unclear. However, previous data has indicated that this is likely. The present
      study was designed to explore this possibility further by using inhibitors of the
      DNA repair system to block DNA repair in embryos derived from cryopreserved
      spermatozoa. If cryopreservation causes strand breaks in sperm DNA it might be
      expected that inhibition of a repair enzyme such as poly(ADP-ribose) polymerase
      (PARP) would enhance any such negative effect of cryopreservation. To check this
      hypothesis 3-aminobenzamide (3-AB) was used as an inhibitor of PARP. Weather
      loach (Misgurnus fossilis) eggs were fertilised using cryopreserved as well as
      fresh spermatozoa. Embryos derived from cryopreserved spermatozoa were exposed to
      10 mM 3-AB for 2 h after fertilisation. The experiments were carried out using
      43,544 embryos from 5 females and 10 males. Embryo survival was evaluated at
      different stages until the hatching stage. Sperm cryopreservation significantly
      decreased embryo survival (53.6+/-2.79% compared to 76.97+/-2.79% of control;
      P<0.01). The addition of 3-AB to the medium with embryos derived from
      cryopreserved sperm further decreased embryo survival from 53.6+/-2.79% to 46.1+/
      2.79% (P<0.01) whereas there was no adverse effect of 3-AB exposed embryos
      derived from fresh sperm (76.97+/-2.79% of control compared to 74.8+/-2.79% of
      control+3-AB). The effect of 3-AB provides indirect evidence that
      cryopreservation might induce instability in sperm DNA, and that such damage can
      be repaired by the oocyte repair system after fertilisation.

PMID- 15019463
TI  - Mitochondrial aggregation patterns and activity in porcine oocytes and apoptosis
      in surrounding cumulus cells depends on the stage of pre-ovulatory maturation.
AB  - In this study, we evaluated the distribution and oxidative activity of
      mitochondria in ex vivo pre-ovulatory porcine oocytes using the fluorescence
      probe MitoTracker CMTM Ros Orange. Cumulus-oocyte complexes (COCs) were
      classified according to cumulus morphology and time from hCG administration. The
      meiotic configuration of the oocytes and the degree of apoptosis in the
      surrounding cumulus cells were also evaluated. Estrus was synchronized in 45
      crossbred Landrace gilts by feeding altrenogest for 15 days and administering
      1000 IU PMSG on Day 16. The LH peak was simulated by treatment with 500 IU hCG,
      given 80 h after PMSG. Endoscopic oocyte recovery was carried out 2 h before or
      10, 22, or 34 h after hCG administration. Altogether 454 COCs were aspirated from
      follicles with a diameter of more than 5 mm. Cumulus morphology in the majority
      of COCs recovered 2 h before and 10 h after hCG was compact (60.4 and 52.7%,
      respectively; P<0.05). At 22 h after hCG, COC morphology changed significantly
      from 10 h dramatically: 74% of COCs had an expanded cumulus (P<0.01). At 34 h
      after hCG, 100% of recovered COCs had an expanded cumulus. The percentage of
      oocytes with a mature meiotic configuration differed among COC morphologies and
      increased as the interval after hCG administration increased (P<0.05). The type
      of mitochondrial distribution in the oocytes (n=336) changed from homogeneous to
      heterogeneous as the interval after hCG administration increased (P<0.01) and was
      associated with the cumulus morphology. Representative mitochondrial
      distributions were found as follows: -2 h: fine homogeneous in compact and
      dispersed COCs; 10 h: granulated homogeneous in compact and dispersed COCs; 22 h:
      granulated homogeneous in expanded COCs; and 34 h: granulated heterogeneous and
      clustered heterogeneous in expanded COCs (P<0.01). The oxidative activity of
      mitochondria measured by fluorescence intensity (Em: 570 nm) per oocyte after
      Mitotracker CMTM Ros Orange labeling increased in the oocyte as the post-hCG
      interval increased (P<0.01) and depended on the type of mitochondrial
      distribution. Lowest oxidative activity of mitochondria was found in oocytes with
      fine homogeneous distribution (253.1+/-9.4 microA). The oxidative activity
      increased (334.4+/-10.3 microA) in oocytes with granulated homogeneous
      distribution of mitochondria, and reached highest level in oocytes with
      granulated heterogeneous (400.9+/-13.0 microA) and clustered heterogeneous
      distributions (492.8+/-13.9 microA) (P<0.01). Mitochondrial activity in oocytes
      coincided with apoptosis in surrounding cumulus cells which increased in a time
      dependent manner during pre-ovulatory maturation in vivo (P<0.01). These results
      indicate that there is a relationship between meiotic progression, cumulus
      expansion and mitochondrial redistribution and their oxidative activity during
      final pre-ovulatory maturation in pig oocytes. It appears that increased levels
      of mitochondrial activities in oocytes are correlated to increased levels of
      apoptosis in surrounding cumulus cells, in which mitochondria may play a role.

PMID- 15019464
TI  - Influences of FSH and EGF on primordial follicles during in vitro culture of
      caprine ovarian cortical tissue.
AB  - Factors that control the onset of folliculogenesis are critical to female gamete
      production, but poorly understood. The aim of the present study was to
      investigate the effects of FSH and EGF on the activation and growth of goat
      primordial follicles in vitro. To this end, pieces of goat ovarian cortex were
      cultured in vitro for 1, 3 or 5 days, at 39 degrees C in an atmosphere containing
      5% CO(2), in minimum essential medium supplemented with insulin, transferrin,
      selenium, pyruvate, glutamine, hypoxanthine, BSA, penicillin, streptomycin and
      fungizone and with or without FSH (100 ng/ml) and/or EGF (100 ng/ml). At the end
      of the culture periods, the relative proportions of primordial, intermediate,
      primary and secondary follicles were calculated and compared with those in non
      cultured tissue. In addition, mitotic activity of granulosa cells was studied by
      immunohistochemistry for proliferating cell nuclear antigen (PCNA). In brief, it
      was found that goat primordial follicles activate spontaneously during culture in
      vitro and, while neither FSH nor EGF affected the proportion of primordial
      follicles that entered the growth phase, both stimulated an increase in oocyte
      and follicle diameter, especially in intermediate and primary follicles cultured
      for 5 days. On the other hand, there was no significant effect of culture or
      either growth factor on the proportion of PCNA-stained growing follicles.
      Contrary to expectations, neither FSH nor EGF affected follicle viability or
      integrity during culture, since the percentages of intact follicles did not
      differ between control, FSH and/or EGF containing medium. In conclusion, this
      study demonstrated that goat primordial follicles activate spontaneously in
      vitro, and that both FSH and EGF stimulate an increase in follicle size by
      promoting oocyte growth.

PMID- 15019465
TI  - Repeated oocyte pick up in prepubertal swamp buffalo (Bubalus bubalis) calves
      after FSH superstimulation.
AB  - The objective in this study was to investigate the effect of repeated oocyte
      collection by transvaginal, ultrasound-guidance, oocyte pick-up (OPU) in nine,
      prepubertal (8-12 months), swamp buffaloes. Animals were treated with FSH for 3
      days and received GnRH on the third day, 24 h before OPU. This session was
      repeated on five occasions at 2 weekly intervals. Over the five sessions of
      hormone treatment followed by OPU, 39/42 (92.9%) animals responded and had 6.6+/
      3.6 follicles with a follicular diameter of 5.0+/-2.0 mm. The oocyte recovery
      rate was 5.4+/-3.7 and averaged 82.8% oocytes, except for session 4, when oocyte
      recovery was around 75.0%. Most oocytes were denuded (39.5%), whilst 28.8% had a
      substantial cumulus mass. There were no differences in the ovarian responses and
      the recovery rates between the collections. It was concluded that five repeat
      cycles of FSH and OPU did not influence the follicular response to
      superstimulation or the number of oocytes recovered from prepubertal, buffalo
      calves.

PMID- 15019466
TI  - Unilateral hysterectomy (cornuectomy) in the bitch and its effect on subsequent
      fertility.
AB  - During caesarean section of bitches a beginning tissue necrosis of the uterus is
      often encountered. These alterations mostly require ovariohysterectomy that means
      the end of breeding life. The aim of this study was to create a model for
      unilateral hysterectomy during dystocia and to evaluate subsequent fertility.
      Unilateral cornuectomy was performed in 18 clinically healthy bitches of
      different ages, breeds, and at different stages of the sexual cyclus. Four
      bitches were not available for follow-up examinations. Twelve bitches were mated
      at the first obvious estrus period postoperatively and 10 pregnancies were
      diagnosed. Nine bitches delivered one to five puppies (mean 3.8) after a
      gestation period of 63-67 days. The puppies (n=38) were in a very good condition
      and showed high vitality. Unilateral cornuectomy of the uterus had no adverse
      effects and postoperative mating revealed pregnancy without complications and
      normal parturition. In the case of pathological changes in one uterine horn
      during a caesarean section unilateral hysterectomy seems to be an alternative to
      ovariohysterectomy.

PMID- 15019467
TI  - Fertility results after different thawing procedures for ram semen frozen in
      minitubes and mini straws.
AB  - The effect of different thawing procedures for ram semen frozen in minitubes and
      mini straws on the fertility of sheep was tested in a field trial in which 727
      Norwegian crossbred ewes, aged between six months and five-and-a-half years from
      nine farms, were inseminated with frozen-thawed semen in natural estrous.
      Minitubes were thawed at 70 degrees C for 8 s (T70) and mini straws either at 70
      degrees C for 5 s (S70), 50 degrees C for 9 s (S50), or 35 degrees C for 12 s
      (S35). Cervical insemination with 200 x 10(6) spermatozoa resulted in 25-day non
      return rates of 78.7, 69.0, 73.6, and 72.9% (overall 73.6%), respectively, and
      lambing rates of 77.6, 66.1, 71.4, and 68.9% (overall 71.0%), respectively. There
      was a significantly higher lambing rate for T70 compared to S35 (P=0.03) and S70
      (P=0.02), respectively, but not compared to S50 (P=0.29). Age of the ewes
      (P=0.02), farmers (P=0.02) and the interaction between farmer x straw
      type/thawing temperature (P=0.01) had a significant effect on the lambing rate.
      In conclusion, the superior fertility results achieved for minitubes compared to
      mini straws have to be carefully evaluated in relation to the possible
      application of a more rational semen production and simplified semen handling at
      AI, when using mini straws thawed at 35 degrees C.

PMID- 15019468
TI  - Combined ACTH and glucocorticoid treatment improves survival and organ maturation
      in premature newborn calves.
AB  - Glucocorticoids play an important role in prenatal organ maturation in many
      species. In humans, maternal treatment with synthetic glucocorticoids improves
      neonatal adaptation of prematurely born infants. In cows, pre-term calf survival
      is improved following a single maternal glucocorticoid administration. We
      hypothesized that stimulation of endogenous cortisol secretion by
      adrenocorticotropin (ACTH) treatment combined with maternal dexamethasone
      treatment, would be even more efficient in stimulating organ maturation in the
      prematurely delivered calf. Three groups of premature calves were delivered by
      caesarian section at 90% of gestation length from dams which were either
      untreated or injected with dexamethasone before delivery, combined with either
      prenatal or postnatal ACTH treatment to the calf. During the first 24h after
      birth, thermoregulation, blood chemistry, liver values and organ weights were
      recorded. In the untreated calves, survival was significantly correlated with
      blood oxygenation, sodium and calcium levels at the moment of birth. There were
      marked maturational effects of the treatments on body temperature regulation,
      blood acid-base status, oxygenation, glucose, insulin, IGF-1 levels, weight of
      the heart, liver, gastrointestinal tract and thymus weight. For many of the
      measured metabolic, endocrine and organ weight parameters, the intrauterine ACTH
      treatment was associated with improved values relative to the postnatal ACTH
      treatment, which appeared to have no immediate effect on calf viability. In
      conclusion, the premature calf delivered by caesarian section at 90% of gestation
      length showed blood chemistry, metabolic, endocrine and organ growth
      characteristics that indicated severe prematurity. However, the maturation of
      organ function in newborn premature calves following maternal glucocorticoid
      injections was further enhanced if is was preceded by intra-fetal injections of
      ACTH.

PMID- 15019470
TI  - Membrane depolarization is the initial action of crotoxin on isolated murine
      skeletal muscle.
AB  - Although much is known about the pathogenesis of crotoxin-induced muscle damage,
      the initial site and action of the toxin is still not clear. In this study we
      used an electrochromic fluorescent dye, Di-4-ANEPPS, to measure the changes in
      membrane potential of isolated murine omohyoid muscle to determine if
      depolarization could be one of the initial effects of crotoxin. Omohyoid isolates
      were pre-loaded with 1 microM Di-4-ANEPPS, exposed to various crotoxin
      treatments, and the change in fluorescence was recorded using either a dual
      wavelength spectrofluorometer or digital imaging. Spectrofluorometry indicated
      that crotoxin depolarized isolated omohyoid muscles within 4 min as indicated by
      an increase in fluorescence to 122% of control values. Crotoxin also induced
      depolarization of extensor digitorum longus and soleus muscles as indicated by an
      increase in fluorescence of 140 and 110% of the control, respectively.
      Fluorescent images obtained from omohyoid muscle preparations exposed to crotoxin
      and Di-4-ANEPPS revealed localized areas of increased fluorescence, muscle
      contractions, derangement of myofibrils, and differing sensitivity to crotoxin of
      different muscle cells. Light microscopy results confirmed this variable
      disruption of muscle cell integrity and differing sensitivity to crotoxin. An
      increase in creatine kinase release rates confirmed damage to the plasma
      membrane. We conclude that plasma membrane depolarization is most likely the
      earliest indicator of cell damage from crotoxin and is quickly followed by
      hypercontraction of myofilaments, disruption of the plasma membrane, release of
      creatine kinase and necrosis.

PMID- 15019472
TI  - Bites by Australian mygalomorph spiders (Araneae, Mygalomorphae), including
      funnel-web spiders (Atracinae) and mouse spiders (Actinopodidae: Missulena spp).
AB  - A number of mygalomorph spiders cause bites in Australia, including the funnel
      web spiders (Hexathelidae, Atracinae: Hadronyche and Atrax) and mouse spiders
      (Actinopodidae: Missulena). There is ongoing debate about the significance of
      bites by mouse spiders and the frequency of severe envenoming by funnel-web
      spiders. We conducted a prospective cohort study of definite spider bites with
      expert spider identification and include the analysis of mygalomorph spiders
      here. Subjects were recruited prospectively from February 1999 to April 2003 from
      patients presenting to participating hospitals or contacting a state poison
      information centre. Forty-nine cases of bites by mygalomorph spiders were
      included: 16 were by funnel-web spiders, 13 by mouse spiders and 20 by other
      trapdoor spiders (Families Idiopidae and Nemesiidae). Of the 49 bites, 45 (92%)
      occurred on distal limbs (hands and feet). Local effects included severe pain
      (53%), puncture marks (61%) and bleeding (27%), local redness (33%). Itchiness
      did not occur. The following were highly statistically associated with
      mygalomorph spider bites compared to all other spiders (p<0.0001) circumstances
      (gardening at the time (likelihood ratio (LR) 7.9) and distal limb bites (LR
      2.0)) and early clinical features (presence of puncture marks OR bleeding (2.3),
      or severe pain (2.0)). Of 16 funnel-web spider bites, there were 10 cases with
      minor local effects, four with moderate envenoming (non-specific systemic or
      local neurotoxicity) and two with severe envenoming requiring antivenom. In
      addition to local effects, mouse spider bites caused local paraesthesia in three
      cases, local diaphoresis in one case and non-specific systemic effects in five
      cases, but not severe envenoming. True trapdoor spider bites caused only minor
      effects. The data from a mixed species sample of funnel-web spiders confirms
      previous observations suggesting that only a small proportion of funnel-web bites
      cause severe effects. Mouse spider bites are unlikely to cause major envenoming
      but the clinical effects are consistent with neurotoxic venom and are more severe
      than the trapdoor spiders.

PMID- 15019471
TI  - First evidence of Dinophysistoxin-1 ester and carcinogenic polycyclic aromatic
      hydrocarbons in smoked bivalves collected in the Patagonia fjords.
AB  - Diarrhetic shellfish poisoning (DSP) is a gastrointestinal disease caused by fat
      soluble polyether toxins produced by dinoflagellates and accumulated in
      shellfish. Up to the present, only four fat-soluble polyethers have been known as
      diarrhetic shellfish toxins. Among them,*** Okadaic acid, Dinophysistoxin-1,
      Dinophysistoxin-2 and Dinophysistoxin-3. Outbreaks associated with DSP have
      occurred in the Chilean Patagonia fjords since 1970. Native people, who live in
      small communities close to the southern fjords, smoke fresh shellfish. During
      this popular smoking procedure, they impregnate the shellfish with polycyclic
      aromatic hydrocarbons, as incomplete combustion products, which are potent
      carcinogenic compounds, this product is sold in local markets without phycotoxins
      analysis or inclusion in any monitoring program. The present paper shows, DSP
      phycotoxins quantitation, using high performance liquid chromatography with
      fluorescent and mass spectrometric detection and the measurements of polycyclic
      aromatic hydrocarbons by gas chromatography with mass detection, in smoked
      shellfish samples. The presence of Dinophysistoxin-3, the Dinophysistoxin-1 ester
      (7-O-acyl-derivatives of dinophysistoxin-1), was assessed in all shellfish
      samples analyzed. The 7-OH in Dinophysistoxin-1 was esterified with palmitic
      fatty acid. The shellfish meat contains seven polycyclic aromatic hydrocarbons,
      among them fluoranthene, phenanthrene, anthracene, pyrene and benzo[a]pyrene. The
      gas chromatography-mass spectrometry analysis showed four of the six most
      frequent carcinogenic polycyclic aromatic hydrocarbons reported. The content of
      benzo[a]pyrene in the Razor Clam and Ribbed Mussel were 78.61 and 4.94 ng/g of
      shellfish dry weight, respectively. In both cases the benzo[a]pyrene amounts were
      greater than the acceptable tolerance limits of 1 microg/kg of sample. The Razor
      Clam samples also show amount further above the maximum label regulated by
      FAO/WHO (10 microg/kg). The presence of both type of compounds in the smoked
      shellfish samples analyzed, correspond to a dangerous combination, where the
      polycyclic aromatic hydrocarbons are carcinogenic compounds by themselves and DTX
      1, is a potent tumor promoter.

PMID- 15019473
TI  - Effects of microcystin-LR on development of medaka fish embryos (Oryzias
      latipes).
AB  - Chronic and subchronic toxicity from exposure to microcystins, cyclic hepatotoxic
      heptapeptides from cyanobacteria, receives increasing attention as a public human
      health biohazard. So far, the effects of microcystin on fish have been studied
      mainly in adults, rather than during early life stages. Limitations of direct
      ambient exposure experiments to fish egg have resulted from the difficult access
      of microcystin through the egg chorion. Using a microinjection technology, we
      have introduced microcystin-LR (MC-LR) directly into one-cell stage embryos or
      into the vitellus of late neurula embryos (stage 19) or into the vitellus of
      stage 25 embryos of medaka (Oryzias latipes) at the onset of the liver anlage.
      Microinjection (100 pl; stage 1 or 2 nl; stage 19 or 25) of MC-LR resulted in a
      dose dependent mortality of embryos. Survival rates were reduced up to 90% with
      microcystin concentrations of 10 or 1 microg/ml (corresponding to 1-20 pg or 0.1
      2 pg of toxin injected), injected either at stages 1, 19 or 25. Also, a dose
      dependent advanced embryonic hatching processing was observed; hatching being
      brought forward from 2 or 3 days compared to controls in most of the microcystin
      injected groups. In agreement with the known hepatotoxic effects of microcystin,
      injected embryos consistently displayed hepatobiliary abnormalities such as liver
      hypertrophy and hepatic hemorrhage, also evidenced in post-hatching juveniles.
      Thus, the methodology presented in this paper should be valuable tool to analyze
      the effects of toxins on the development of aquatic vertebrate embryos.

PMID- 15019474
TI  - Paralytic shellfish poisoning: post-mortem analysis of tissue and body fluid
      samples from human victims in the Patagonia fjords.
AB  - In July 5, 2002 fishermen working in harvesting sea urchin (Loxechinus albus) in
      the Patagonia Chilean fjords were intoxicated by consumption of filter-feeder
      bivalve Aulacomya ater. After the ingestion of 7-9 ribbed mussel, two fishermen
      died 3-4 h after shellfish consumption. The forensic examination in both victims
      did not show pathological abnormalities with the exception of the lungs
      conditions, crackling to the touch, pulmonary congestion and edema. The toxic
      mussel sample showed a toxicity measured by mouse bioassay of 8575 microg of STX
      (saxitoxin) equivalent by 100 g of shellfish meat. Using post-column
      derivatization HPLC method with fluorescent on line detection was possible to
      measure mass amount of each paralytic shellfish poisoning (PSP) toxin yielding
      individual toxin concentrations. These PSP toxins were identified in the gastric
      content, body fluids (urine, bile and cerebrospinal fluid) and tissue samples
      (liver, kidney, lung, stomach, spleen, heart, brain, adrenal glands, pancreas and
      thyroids glands). The toxin profiles of each body fluid and tissue samples and
      the amount of each PSP toxin detected are reported. The PSP toxins found in the
      gastric content, were STX and the gonyautoxins (GTX4, GTX1, GTX5, GTX3 and GTX2)
      which showed to be the major amount of PSP toxins found in the victims biological
      samples. The PSP toxin composition in urine and bile showed as major PSP toxins
      neoSaxitoxin (neoSTX) and GTX4/GTX1 epimers, both STX analogues with an hydroxyl
      group (-OH) in the N(1) of the tetrahydropurine nucleus. The neoSTX was not
      present in the gastric content sample, indicating that the oxidation of N(1) in
      the STX tetrahydropurine nucleus resulted neoSTX, in a similar way that GTX3/GTX2
      epimers were transformed in GTX4/GTX1 epimers. Beside this metabolic
      transformation, also the hydrolysis of carbamoyl group from STX to form its
      decarbomoyl analogue decarbamoylsaxitoxin was detected in liver, kidney and lung.
      These two findings show that PSP toxins went under metabolic transformation
      during the 3-4 h of human intoxication period, in which PSP toxins showed
      enzymatic oxidation of N(1) in the tetrahydropurine nucleus, producing neoSTX and
      GTX4/GTX1 epimers starting from STX and GTX3/GTX2 epimers, respectively. This
      study conclude, that PSP toxins are metabolically transformed by humans and that
      they are removed from the body by excretion in the urine and feces like any other
      xenobiotic compound.

PMID- 15019475
TI  - Epidemiology of snakebite in Eshowe, KwaZulu-Natal, South Africa.
AB  - Three hundred and thirty-three patients admitted to Eshowe Hospital with
      snakebite were analysed. Forty-one were non-envenomed, 282 exhibited painful
      progressive swelling (PPS), seven showed progressive weakness (PW), and there
      were three cases of minor envenomations that were unclassifiable. Offending dead
      venomous snakes included Naja mossambica (Mozambique spitting cobra), Bitis
      arietans (puff adder), Atractaspis bibronii (stiletto snake), Causus rhombeatus
      (common night adder) and Dendroaspis polylepis (black mamba). Most bites occurred
      on the leg in the wet summer months during the first three decades of the
      patients' lives. The majority of patients used a first-aid measure. The snake was
      most commonly sighted if the patient was bitten on an upper limb or above the
      ankle. Severe envenomation was associated with quicker arrival at hospital, and
      multiple bites occurred more frequently in sleeping patients. Non-envenomation
      following snakebites was more common in winter, in adult females, and if the
      patient was bitten proximally on a limb or on a hand. Patients with PPS developed
      bite site complications (42), compartment syndromes (4), femoral vessel
      entrapment (1), deep vein thrombosis (1), and respiratory complications (4).
      Severe swelling was associated with spring and early summer, proximal limb bites
      and children who were most at risk of necrosis. Fingers and hands were most prone
      to necrosis and permanent disability. Four patients with PW developed respiratory
      failure. Antivenom was administered to 12 patients, five of whom developed an
      acute adverse reaction. There was one death.

PMID- 15019476
TI  - Cross-reactivity and inhibition of haemolysis by polyclonal antibodies raised
      against St II, a cytolysin from the sea anemone Stichodactyla helianthus.
AB  - The immunogenicity of sticholysin II (St II), a pore-forming polypeptide from the
      sea anemone Stichodactyla helianthus, was studied in rabbits using two adjuvants,
      Freund's and aluminium hydroxide. High titres of antibodies were raised against
      St II with Freund's adjuvant (FA). The structural homology between sticholysins I
      and II was also revealed by cross-reactivity assays. Since the oil constituent of
      FA neutralized the St II haemolytic activity, immunizations with St II-Freund's
      emulsions were carried out with the inactivated cytolysin. Purified anti-St II
      IgG also neutralized the St II haemolytic activity.

PMID- 15019477
TI  - Characterisation of major peptides in 'jack jumper' ant venom by mass
      spectrometry.
AB  - The jack jumper ant, Myrmecia pilosula, is endemic to South-Eastern Australia,
      where around 2.7% of the population has a history of systemic allergic reactions
      (anaphylaxis) to its venom. Previous work had indicated that there were several
      allergenic peptides derived from the cDNA Myr p 1, the major expressed allergenic
      product being a 56-residue peptide (Myr p 1 57-->112, 'pilosulin 1',
      approximately 6052 Da). Another major allergen had been described as a 27 residue
      peptide derived from the cDNA Myr p 2 (Myr p 2 49-->75, 'pilosulin 2',
      approximately 3212 Da), possibly existing as part of a disulfide complex. As a
      preliminary step in detailed stability studies of a pharmaceutical product used
      for venom immunotherapy, LC-MS and Edman sequencing analysis of venom collected
      from various locations by both electrical stimulation and venom sac dissection
      was undertaken. More than 50 peptides in the 4-9 kDa range were detected in LC-MS
      analyses. A subsequence of Myr p 2 was found as part of the major peptide present
      in all samples; this was a bis-disulphide linked, antiparallel aligned
      heterodimer consisting of Myr p 2 49-->74, (des-Gly(27)-pilosulin 2,
      approximately 3155 Da) and a previously unreported peptide of approximately 2457
      Da. Pilosulin 1 was found by a combination of tandem mass spectrometry and Edman
      sequencing to exist mainly, and sometimes exclusively, as a previously unreported
      approximately 6067 Da variant, in which the valine at residue 5 is replaced by
      isoleucine. A range of hydrolysis products of [Ile(5)]pilosulin 1 and pilosulin 1
      were also detected in partially degraded venom. Further IgE-binding studies using
      these peptides are warranted and a revision of the nomenclature of allergenic
      components of M. pilosula venom may be required to conform with established IUIS
      guidelines.

PMID- 15019478
TI  - Accumulation and depuration of the cyanobacterial toxin cylindrospermopsin in the
      freshwater mussel Anodonta cygnea.
AB  - Cylindrospermopsin (CYN) is a toxic alkaloid produced by several genera of
      freshwater cyanobacteria. This compound has been implicated in outbreaks of human
      sickness and the death of domestic and wild animals. Given that several of the
      cyanobacterial genera known to produce CYN are common components of the
      phytoplankton of freshwaters including aquaculture facilities, we studied the
      accumulation of CYN in the freshwater mussel (swan mussel) Anodonta cygnea.
      Anodonta were exposed to CYN-producing cultures of the cyanobacterium
      Cylindrospermopsis raciborskii for 16 days and were found to accumulate the toxin
      to concentrations up to 2.52 microg g tissue dry weight(-1). There was
      considerable variation in the concentrations of CYN detected in different parts
      of the body. At the end of a 2-week accumulation period the distribution of CYN
      in the body of Anodonta was as follows: haemolymph (68.1%), viscera (23.3%), foot
      and gonad (7.7%) and mantle (0.9%). No CYN was detected in the gills or adductor
      muscle of any animals. Following a 2-week depuration period, approximately 50% of
      the toxin remained in the tissues. Based on the recently derived guideline value
      for CYN in human drinking water (1 microg l(-1)) and the concentrations of this
      compound in animal tissues reported here, there is a clear need for the increased
      monitoring of this compound in organisms grown for human and animal consumption.

PMID- 15019479
TI  - The loss of PSP toxin production in a formerly toxic Alexandrium lusitanicum
      clone.
AB  - Toxin production has always been considered a constitutive characteristic of
      dinoflagellates in the genus Alexandrium. Here we demonstrate that saxitoxin
      production can be lost by an Alexandrium species during routine culture
      maintenance. This is the first report of any marine saxitoxin-producing alga ever
      to have completely lost the ability to produce toxins. A clonal toxic isolate of
      Alexandrium lusitanicum from Portugal has been maintained in culture since 1962.
      In 1992, a subculture was established and sent to a different laboratory. Recent
      comparisons of the parental strain and the subculture revealed that the former
      had lost its toxicity, whereas the latter still produces saxitoxins. This loss of
      toxicity was confirmed by three independent toxin detection methods: mouse
      bioassay, mouse neuroblastoma assay and HPLC. Sequence analyses of different rRNA
      domains demonstrated that the toxic and non-toxic cultures are genetically
      identical for those markers. Morphological analysis showed that both cultures
      have the same plate tabulation and are A. lusitanicum. These results strongly
      argue that the loss of toxicity is not a result of a culturing artifact or
      mistake, such as mislabeling or contamination. The clonal cultures also show a
      significant difference in growth. Possible explanations for the change include
      genetic mutations or the effects of prolonged treatment of the non-toxic culture
      with antibiotics.

PMID- 15019481
TI  - Bothrops asper metalloproteinase BaP1 is inhibited by alpha(2)-macroglobulin and
      mouse serum and does not induce systemic hemorrhage or coagulopathy.
AB  - The ability of the P-I metalloproteinase BaP1, isolated from the venom of the
      snake Bothrops asper, to induce systemic bleeding, thrombocytopenia and
      defibrinogenation was assessed in an experimental mouse model. Intravenous
      administration of BaP1 caused neither systemic bleeding nor any evidence of
      pathology in lungs, kidneys, liver, heart and brain. Moreover, there were no
      alterations in the whole blood clotting time or in platelet numbers. In addition,
      BaP1 did not inhibit collagen-induced platelet aggregation in vitro. Proteolytic
      and hemorrhagic activities of BaP1 were readily inhibited by the plasma
      proteinase inhibitor, alpha(2)-macroglobulin, and normal mouse serum also
      inhibited hemorrhage. Such inhibition may explain why BaP1 induces multiple local
      tissue-damaging effects, but is largely devoid of systemic toxicity.

PMID- 15019480
TI  - Occurrence of saxitoxins as a major toxin in the ovary of a marine puffer
      Arothron firmamentum.
AB  - Eleven male and 14 female specimens of a marine puffer Arothron firmamentum were
      collected from Oita and Iwate Prefectures, Japan. The toxicity assay using mouse
      showed that only ovary and skin of the female specimens were toxic, the toxicity
      scores being 5-740 as paralytic shellfish poison and <5-30 MU/g as tetrodotoxin
      (TTX), respectively. The toxin extracts from the both tissues were then treated
      with cartridge columns, and subjected to high performance liquid chromatography
      and liquid chromatography-mass spectral analyses. In the analyses, saxitoxin
      (STX) and decarbamoylSTX (dcSTX) were identified as the major toxins in the
      ovary, while the skin contained only TTX.

PMID- 15019482
TI  - Purification and preliminary characterization of a plasma kallikrein inhibitor
      isolated from sea hares Aplysia dactylomela Rang, 1828.
AB  - An inhibitor active against pancreatic trypsin was found in the crude extract
      from the sea hares Aplysia dactylomelaRang, 1828. A stronger inhibitory activity
      against human plasma kallikrein was detectable after treating this extract at 60
      degrees C, for 30 min. The plasma kallikrein inhibitor (AdKI) purification was
      achieved by acetone fractionation (80%) v/v, ion-exchange chromatography on Mono
      Q column and gel filtration chromatography on Superdex 75 column (FPLC system).
      By the latter a molecular mass of 2900 Da was estimated. The purified inhibitor
      strongly inhibits human plasma kallikrein with a K(i) value of 2.2 x 10(-10)M,
      while human plasmin and pancreatic trypsin were inhibited with K(i) values of 1.8
      x 10(-9) and 4.7 x 10(-9)M, respectively. Chymotrypsin, pancreatic elastase,
      pancreatic kallikrein and thrombin are not inhibited. The effect of AdKI on
      plasma kallikrein was confirmed by the prolongation of activated partial
      thromboplastin time, using a clotting time assay. The inhibitor did not affect
      prothrombin time or thrombin time. AdKi is a more specific inhibitor than other
      serine proteinase inhibitors from marine invertebrates.

PMID- 15019483
TI  - A new membrane-attack complex/perforin (MACPF) domain lethal toxin from the
      nematocyst venom of the Okinawan sea anemone Actineria villosa.
AB  - The Okinawan sea anemone Actineria villosa causes severe cases of stinging. We
      isolated the 60 kDa A. villosa toxin (AvTX-60A) as the major toxin from the
      isolated nematocysts of this species. AvTX-60A showed fatal toxicity to mice with
      intraperitoneal injection at a minimum lethal dose of less than 250 microg/kg.
      The N-terminal amino acid sequence was determined and the corresponding cDNA
      encoding AvTX-60A was sequenced. The deduced amino acid sequence of AvTX-60A
      showed high similarity with PsTX-60A, which had been isolated as one of the major
      toxins from the venomous sea anemone Phyllodiscus semoni. These sea anemone
      toxins are new members of the family of proteins containing membrane-attack
      complex/perforin (MACPF) domains, best known in pore forming proteins such as
      perforin. These are the first examples of MACPF domain proteins as toxins for
      prey acquisition or repelling predators in nature.

PMID- 15019485
TI  - Excitement ahead: structure, function and mechanism of snake venom phospholipase
      A2 enzymes.
AB  - Venom phospholipase A2 (PLA2) enzymes share similarity in structure and catalytic
      function with mammalian enzymes. However, in contrast to mammalian enzymes, many
      are toxic and induce a wide spectrum of pharmacological effects. Thus structure
      function relationship of this group of small proteins is subtle, but complex
      puzzle to protein biochemists, molecular biologists, toxinologists,
      pharmacologists and physiologists. This review describes the present status of
      our understanding of their structure, function and mechanism. It was proposed
      that their unique ability to 'target' themselves to a specific organ or tissue is
      due to their high affinity binding to specific proteins which act as receptors
      (more precisely, acceptors). This specific binding of PLA2 is conferred by the
      presence of a 'pharmacological site' on its surface which is independent of the
      catalytic site. The high affinity interaction of PLA2 with its acceptor (or
      target protein) is probably due to the complementarity, in terms of charges,
      hydrophobicity and van der Waal's contact surfaces, between the pharmacological
      site and the binding site on the surface of the acceptor protein. Upon binding to
      the target, the PLA2 can induce its pharmacological effects by mechanisms either
      dependent on or independent of its catalytic activity. Because of the
      unprecedented wide spectrum of specific targeting to various tissues and organs,
      identification of the pharmacological sites has potential for exploitation in
      development of novel systems useful for 'delivering' specific proteins to a
      particular target tissue or organ. Thus research in this field will provide a lot
      of exciting opportunities.

PMID- 15019486
TI  - Molecular evolution of myotoxic phospholipases A2 from snake venom.
AB  - After two decades of study, we draw the conclusion that venom-gland phospholipase
      A2 (PLA2) isozymes, including PLA2 myotoxins of Crotalinae snakes, have evolved
      in an accelerated manner to acquire their diverse physiological activities. In
      this review, we describe how accelerated evolution of venom PLA2 isozymes was
      discovered. This type of evolution is fundamental for other venom isozyme
      systems. Accelerated evolution of venom PLA2 isozyme genes is due to rapid change
      in exons, but not in introns and the flanking regions, being completely opposite
      to the case of the ordinary isozyme genes. The molecular mechanism by which
      proper base substitutions had occurred in the particular sites of venom isozyme
      genes is a puzzle to be solved in future studies. It should be noted that
      accelerated evolution occurred until the isozymes had acquired their particular
      function and, since then, they have evolved with less frequent mutation, possibly
      for functional conservation. We also found that interisland mutations occurred in
      venom PLA2 isozymes. The relationships between mutation and its driving force are
      speculative and the real mechanism remains a mystery.

PMID- 15019487
TI  - Chemical modifications of phospholipases A2 from snake venoms: effects on
      catalytic and pharmacological properties.
AB  - Phospholipases A2 (PLA2s) constitute major components of snake venoms and have
      been extensively investigated not only because they are very abundant in these
      venoms but mainly because they display a wide range of biological effects,
      including neurotoxic, myotoxic, cytotoxic, edema-inducing, artificial membrane
      disrupting, anti-coagulant, platelet aggregation inhibiting, hypotensive,
      bactericidal, anti-HIV, anti-tumoral, anti-malarial and anti-parasitic. Due to
      this functional diversity, these structurally similar proteins aroused the
      interest of many researchers as molecular models for study of structure-function
      relationships. One of the main experimental strategies used for the study of
      myotoxic PLA2s is the traditional chemical modification of specific amino acid
      residues (His, Met, Lys, Tyr, Trp and others) and examination of the consequent
      effects upon the enzymatic, toxic and pharmacological activities. This line of
      research has provided useful insights into the structural determinants of the
      action of these enzymes and, together with additional strategies, supports the
      concept of the presence of 'pharmacological sites' distinct from the catalytic
      site in snake venom myotoxic PLA2s.

PMID- 15019488
TI  - Mapping structural determinants of biological activities in snake venom
      phospholipases A2 by sequence analysis and site directed mutagenesis.
AB  - In addition to their catalytic activity, snake venom phospholipases A2 (vPLA2)
      present remarkable diversity in their biological effects. Sequence alignment
      analyses of functionally related PLA2 are frequently used to predict the
      structural determinants of these effects, and the predictions are subsequently
      evaluated by site directed mutagenesis experiments and functional assays. In
      order to improve the predictive potential of computer-based analysis, a simple
      method for scanning amino acid variation analysis (SAVANA) has been developed and
      included in the analysis of the lysine 49 PLA2 myotoxins (Lys49-PLA2). The SAVANA
      analysis identified positions in the C-terminal loop region of the protein, which
      were not identified using previously available sequence analysis tools. Site
      directed mutagenesis experiments of bothropstoxin-I, a Lys49-PLA2 isolated from
      the venom of Bothrops jararacussu, reveals that these residues are exactly those
      involved in the determination of myotoxic and membrane damaging activities. The
      SAVANA method has been used to analyse presynaptic neurotoxic and anti-coagulant
      vPLA2s, and the predicted structural determinants of these activities are in
      excellent agreement with the available results of site directed mutagenesis
      experiments. The positions of residues involved in the myotoxic and neurotoxic
      determinants demonstrate significant overlap, suggesting that the multiple
      biological effects observed in many snake vPLA2s are a consequence of superposed
      structural determinants on the protein surface.

PMID- 15019489
TI  - An overview of lysine-49 phospholipase A2 myotoxins from crotalid snake venoms
      and their structural determinants of myotoxic action.
AB  - In 1984, the first venom phospholipase A2 (PLA2) with a lysine substituting for
      the highly conserved aspartate 49 was discovered, in the North American crotalid
      snake Agkistrodon p. piscivorus [J. Biol. Chem. 259 (1984) 13839]. Ten years
      later, the first mapping of a 'toxic region' on a Lys49 PLA2 was reported, in
      Bothrops asper myotoxin II [J. Biol. Chem. 269 (1994) 29867]. After a further
      decade of research on the Lys49 PLA2s, a better understanding of their structural
      determinants of toxicity and mode of action is rapidly emerging, with myotoxic
      effector sites identified at the C-terminal region in at least four proteins: B.
      asper myotoxin II, A. p. piscivorus K49 PLA2, A. c. laticinctus ACL myotoxin, and
      B. jararacussu bothropstoxin I. Although important features still remain to be
      established, their toxic mode of action has now been understood in its more
      general concepts, and a consistent working hypothesis can be experimentally
      supported. It is proposed that all the toxic activities of Lys49 PLA2s are
      related to their ability to destabilize natural (eukaryotic and prokaryotic) and
      artificial membranes, using a cationic/hydrophobic effector site located at their
      C-terminal loop. This review summarizes the general properties of the Lys49 PLA2
      myotoxins, emphasizing the development of current concepts and hypotheses
      concerning the molecular basis of their toxic activities.

PMID- 15019490
TI  - A structure based model for liposome disruption and the role of catalytic
      activity in myotoxic phospholipase A2s.
AB  - Venom phospholipase A2s (PLA2s) display a wide spectrum of pharmacological
      activities and, based on the wealth of biochemical and structural data currently
      available for PLA2s, mechanistic models can now be inferred to account for some
      of these activities. A structural model is presented for the role played by the
      distribution of surface electrostatic potential in the ability of myotoxic
      D49/K49 PLA2s to disrupt multilamellar vesicles containing negatively charged
      natural and non-hydrolyzable phospholipids. Structural evidence is provided for
      the ability of K49 PLA2s to bind phospholipid analogues and for the existence of
      catalytic activity in K49 PLA2s. The importance of the existence of catalytic
      activity of D49 and K49 PLA2s in myotoxicity is presented.

PMID- 15019491
TI  - Skeletal muscle degeneration induced by venom phospholipases A2: insights into
      the mechanisms of local and systemic myotoxicity.
AB  - Local and systemic skeletal muscle degeneration is a common consequence of
      envenomations due to snakebites and mass bee attacks. Phospholipases A2 (PLA2)
      are important myotoxic components in these venoms, inducing a similar pattern of
      degenerative events in muscle cells. Myotoxic PLA2s bind to acceptors in the
      plasma membrane, which might be lipids or proteins and which may differ in their
      affinity for the PLA2s. Upon binding, myotoxic PLA2s disrupt the integrity of the
      plasma membrane by catalytically dependent or independent mechanisms, provoking a
      pronounced Ca2+ influx which, in turn, initiates a complex series of degenerative
      events associated with hypercontraction, activation of calpains and cytosolic
      Ca(2+)-dependent PLA2s, and mitochondrial Ca2+ overload. Cell culture models of
      cytotoxicity indicate that some myotoxic PLA2s affect differentiated myotubes in
      a rather selective fashion, whereas others display a broad cytolytic effect. A
      model is presented to explain the difference between PLA2s that induce
      predominantly local myonecrosis and those inducing both local and systemic
      myotoxicity. The former bind not only to muscle cells, but also to other cell
      types, thereby precluding a systemic distribution of these PLA2s and their action
      on distant muscles. In contrast, PLA2s that bind muscle cells in a more selective
      way are not sequestered by non-specific interactions with other cells and,
      consequently, are systemically distributed and reach muscle cells in other
      locations.

PMID- 15019492
TI  - Myotoxic phospholipases A2 and the regeneration of skeletal muscles.
AB  - The review explains why the myotoxic phospholipases A2 and cardiotoxins are such
      important tools in the study of the regeneration and maturation of mammalian
      skeletal muscle. The role of satellite cells as precursors of cell-based
      regeneration is discussed and recent controversies on the origin of myogenic
      cells involved in the regeneration of mature skeletal muscle are addressed. This
      is followed by discussions of sarcomere reconstruction, myosin and sarcoplasmic
      reticulum ATPase expression, the electrophysiological properties of regenerating
      muscle, and the reconstruction of the neuromuscular junction. The emphasis
      throughout is on the plastic changes of major structural and functional proteins
      that occur during regeneration, and on other influences that determine the final
      outcome of regenerative activity such as innervation, thyroid status, mechanical
      work and the functional integrity of the microcirculation. The review closes with
      a discussion of some of the factors--such as active regeneration--that influence
      the success of gene-based therapies applied to inherited muscle disease.

PMID- 15019493
TI  - Inflammatory effects of snake venom myotoxic phospholipases A2.
AB  - Snake venom phospholipases A2 (PLA2) show a remarkable functional diversity.
      Among their toxic activities, some display the ability to cause rapid necrosis of
      skeletal muscle fibers, thus being myotoxic PLA2s. Besides myotoxicity, these
      enzymes evoke conspicuous inflammatory and nociceptive events in experimental
      models. Local inflammation and pain are important characteristics of snakebite
      envenomations inflicted by viperid and crotalid species, whose venoms are rich
      sources of myotoxic PLA2s. Since the discovery that mammalian PLA2 is a key
      enzyme in the release of arachidonic acid, the substrate for the synthesis of
      several lipid inflammatory mediators, much interest has been focused on this
      enzyme in the context of inflammation. The mechanisms involved in the
      proinflammatory action of secretory PLA2s are being actively investigated, and
      part of the knowledge on secretory PLA2 effects has been gained by using snake
      venom PLA2s as tools, due to their high structural homology with human secretory
      PLA2s. The inflammatory events evoked by PLA2s are primarily associated with
      enzymatic activity and to the release of arachidonic acid metabolites. However,
      catalytically inactive Lys49 PLA2s trigger inflammatory and nociceptive responses
      comparable to those of their catalytically active counterparts, thereby
      evidencing that these proteins promote inflammation and pain by mechanisms not
      related to phospholipid hydrolysis nor to mobilization of arachidonic acid. These
      studies have provided a boost to the research in this field and various
      approaches have been used to identify the amino acid residues and the specific
      sites of interaction of myotoxic PLA2s with cell membranes potentially involved
      in the PLA2-induced inflammatory and nociceptive effects. This work reviews the
      proinflammatory and nociceptive effects evoked by myotoxic PLA2s and their
      mechanisms of action.

PMID- 15019494
TI  - Natural phospholipase A(2) myotoxin inhibitor proteins from snakes, mammals and
      plants.
AB  - A renewed interest in the phenomenon of inter- and intra-species resistance
      towards the toxicity of snake venoms, coupled with the search for new strategies
      for treatment of snake envenomations, has prompted the discovery of proteins
      which neutralize the major toxic components of these venoms. Among these emerging
      groups of proteins are inhibitors of toxic phospholipases A2 (PLA2s), many of
      which exhibit a wide range of toxic effects including muscle-tissue damage,
      neurotoxicity, and inflammation. These proteins have been isolated from both
      venomous and non-venomous snakes, mammals, and most recently from medicinal plant
      extracts. The snake blood-derived inhibitors have been grouped into three major
      classes, alpha, beta, and gamma, based on common structural motifs found in other
      proteins with diverse physiological properties. In mammals, DM64, an anti
      myotoxic protein isolated from opossum serum, belongs to the immunoglobulin super
      gene family and is homologous to human alpha1B-glycoprotein and DM43, a
      metalloproteinase inhibitor from the same organism. In plants, a short note is
      made of WSG, a newly described anti-toxic-PLA2 glycoprotein isolated from
      Withania somnifera (Ashwaganda), a medicinal plant whose aqueous extracts
      neutralize the PLA2 activity of the Naja naja venom. The implications of these
      new groups of PLA2 toxin inhibitors in the context of our current understanding
      of snake biology as well as in the development of novel therapeutic reagents in
      the treatment of snake envenomations worldwide are discussed.

PMID- 15019497
TI  - Reactive strategies in indirect reciprocity.
AB  - Evolution of reactive strategy of indirect reciprocity is discussed, where
      individuals interact with others through the one-shot Prisoner's Dilemma game,
      changing their partners in every round. We investigate all of the reactive
      strategies that are stochastic, including deterministic ones as special cases.
      First we study adaptive dynamics of reactive strategies by assuming monomorphic
      population. Results are very similar to the corresponding evolutionary dynamics
      of direct reciprocity. The discriminating strategy, which prescribes cooperation
      only with those who cooperated in the previous round, cannot be an outcome of the
      evolution. Next we examine the case where the population includes a diversity of
      strategies. We find that only the mean 'discriminatoriness' in the population is
      the parameter that affects the evolutionary dynamics. The discriminating strategy
      works as a promoter of cooperation there. However, it is again not the end point
      of the evolution. This is because retaliatory defection, which was prescribed by
      the discriminating strategy, is regarded as another defection toward the society.
      These results caution that we have to reconsider the role of retaliatory
      defection much more carefully.

PMID- 15019495
TI  - Role of Clostridium perfringens phospholipase C in the pathogenesis of gas
      gangrene.
AB  - Gas gangrene is an acute and devastating infection most frequently caused by
      Clostridium perfringens and characterized by severe myonecrosis, intravascular
      leukocyte accumulation, and significant thrombosis. Several lines of evidence
      indicate that C. perfringens phospholipase C (Cp-PLC), also called alpha-toxin,
      is the major virulence factor in this disease. This toxin is a Zn2+ metalloenzyme
      with lecithinase and sphingomyelinase activities. Its three dimensional structure
      shows two domains, an N-terminal domain which contains the active site, and a C
      terminal domain required for the Ca2+dependent interaction with membranes. Cp-PLC
      displays several biological activities: it increases capillary permeability,
      induces platelet aggregation, hemolysis, myonecrosis, decreases cardiac
      contractility, and is lethal. Experiments with genetically engineered Cp-PLC
      variants have revealed that the sphingomyelinase activity and the C-terminal
      domain are required for toxicity. The myotoxicity of Cp-PLC is largely dependent
      on its membrane damaging effect. In addition, it has been suggested that the
      alterations in the blood flow induced by this toxin also contribute to muscle
      damage. In gas gangrene, Cp-PLC dysregulates transduction pathways in endothelial
      cells, platelets and neutrophils leading to the uncontrolled production of
      several intercellular mediators and adhesion molecules. Thus, Cp-PLC alters the
      traffic of neutrophils to the infected tissue and promotes thrombotic events,
      enhancing the conditions for anaerobic growth.

PMID- 15019498
TI  - A new method of solution for the occupancy problem and its application to operon
      size prediction.
AB  - The problem of estimating the expected number of transcription units containing a
      specific number of genes arises in the context of operon size prediction in
      prokaryotic genomes, where operons are defined to be transcription units
      containing two or more genes. It turns out that this problem is identical
      mathematically to the balls in urns occupancy problem in probability theory. In
      that problem, a fixed number of indistinguishable balls are randomly placed in a
      known number of distinguishable urns, subject to the restriction that no urns may
      remain empty, and an estimate is desired for the expected number of urns
      containing a specific number of balls. In this paper we present a new simple
      technique for solving the occupancy problem when empty urns are allowed and
      extend it to the case when each urn must contain the same non-zero minimum number
      of balls. Treating transcription units as equivalent to urns, and genes as
      equivalent to balls, we then use that result to solve the problem of estimating
      the expected number of transcription units that contain a specific number of
      genes, and then apply that result to predicting the expected number of
      transcription units present in an entire genome. Since these predictions can be
      made for any completely sequenced and annotated prokaryotic genome, they provide
      a starting point for the comparison of regulatory complexity across such genomes.

PMID- 15019499
TI  - Apparent 2-D diffusivity in a ruffled cell membrane.
AB  - Most biological cell membranes have a microtopology that increases their surface
      area, including a highly ruffled surface in the case of leukocytes. Thus,
      molecular membrane diffusivities as measured by fluorescence recovery after
      photobleaching or other methods are decreased when projected onto a plane. We use
      a two-dimensional crested cycloid as a parameterized surface to simulate the
      random-walk diffusion of a molecule within a ruffled membrane. The apparent 2-D
      diffusivity was then calculated when the ruffled membrane is projected onto a
      plane. It is shown that the apparent diffusivity decreases as a function of the
      membrane area, to the -1.4 power.

PMID- 15019500
TI  - Emergence of non-random structure in local food webs generated from randomly
      structured regional webs.
AB  - Previous studies have shown that high-resolution, empirical food webs possess a
      non-random network structure, typically characterized by uniform or exponential
      degree distributions. However, the empirical food webs that have been
      investigated for their structural properties represent local communities that are
      only a subset of a larger pool of regionally coexisting species. Here, we use a
      simple model to investigate the effects of regional food web structure on local
      food webs that are assembled by two simple processes: random immigration of
      species from a source web (regional food web), and random extinction of species
      within the local web. The model shows that local webs with non-random degree
      distributions can arise from randomly structured source webs. A comparison of
      local webs assembled from randomly structured source webs with local webs
      assembled from source webs generated by the niche model shows that the former
      have higher species richness at equilibrium, but have a nonlinear response to
      changing extinction rates. These results imply that the network structure of
      regional food webs can play a significant role in the assembly and dynamics of
      local webs in natural ecosystems. With natural landscapes becoming increasingly
      fragmented, understanding such structure may be a necessary key to understanding
      the maintenance and stability of local species diversity.

PMID- 15019501
TI  - Dynamic response of cancer under the influence of immunological activity and
      therapy.
AB  - The dynamical basis of tumoral growth has been controversial. Many models have
      been proposed to explain cancer development. The descriptions employ exponential,
      potential, logistic or Gompertzian growth laws. Some of these models are
      concerned with the interaction between cancer and the immunological system. Among
      other properties, these models are concerned with the microscopic behavior of
      tumors and the emergence of cancer. We propose a modification of a previous model
      by Stepanova, which describes the specific immunological response against cancer.
      The modification consists of the substitution of a Gompertian law for the
      exponential rate used for tumoral growth. This modification is motivated by the
      numerous works confirming that Gompertz's equation correctly describes solid
      tumor growth. The modified model predicts that near zero, tumors always tend to
      grow. Immunological contraposition never suffices to induce a complete regression
      of the tumor. Instead, a stable microscopic equilibrium between cancer and
      immunological activity can be attained. In other words, our model predicts that
      the theory of immune surveillance is plausible. A macroscopic equilibrium in
      which the system develops cancer is also possible. In this case, immunological
      activity is depleted. This is consistent with the phenomena of cancer tolerance.
      Both equilibrium points can coexist or can exist without the other. In all cases
      the fixed point at zero tumor size is unstable. Since immunity cannot induce a
      complete tumor regression, a therapy is required. We include constant-dose
      therapies and show that they are insufficient. Final levels of immunocompetent
      cells and tumoral cells are finite, thus post-treatment regrowth of the tumor is
      certain. We also evaluate late-intensification therapies which are successful.
      They induce an asymptotic regression to zero tumor size. Immune response is also
      suppressed by the therapy, and thus plays a negligible role in the remission. We
      conclude that treatment evaluation should be successful without taking into
      account immunological effects.

PMID- 15019502
TI  - Enrichment and foodchain stability: the impact of different forms of predator
      prey interaction.
AB  - We propose a simple model of an ecological foodchain of arbitrary length. The
      model is very general in nature and describes a whole class of foodchains. Using
      the methods of qualitative analysis the model's stability can be analysed without
      restricting the predator-prey interaction to any specific functional form. The
      model can therefore be used to study the effect of different functional forms on
      the stability of the foodchain. We demonstrate that the stability of steady
      states may strongly depend on the exact functional form of the interaction
      function used. It is shown that a class of interaction functions exists, which
      are similar to the widely used Holling functions but bestow radically different
      stability properties upon the model. An example is shown in which enrichment has
      a stabilizing effect on the foodchain. By contrast enrichment destabilizes steady
      states if Holling functions are used.

PMID- 15019503
TI  - Alternative stable states and regional community structure.
AB  - Many models of local species interactions predict the occurrence of priority
      effects due to alternative stable equilibria (ASE). However, few empirical
      examples of ASE have been shown. One possible explanation for the disparity is
      that local ASE are difficult to maintain regionally in patch dynamic models. Here
      we examine two possible mechanisms for regional coexistence of species engaged in
      local ASE. Biotically generated heterogeneity (e.g., habitat modification that
      favors further invasion by conspecifics) results in regional exclusion of one
      species at equilibrium. In contrast, abiotic heterogeneity due to spatial
      variation in resource supply ratios generates local-scale ASE and ensures
      regional coexistence with sufficiently broad environmental gradients. Abiotic
      heterogeneity can result in a species that is the dominant competitor over some
      of its range being excluded if the area where it is dominant is too small. Biotic
      heterogeneity can lead to alternative stable landscapes or regional priority
      effects, while abiotic heterogeneity results in regional determinism. Broad
      environmental gradients in resource supply favor regional coexistence of species
      that exhibit local ASE.

PMID- 15019504
TI  - Simulating the SARS outbreak in Beijing with limited data.
AB  - We propose a mathematical model to simulate the SARS outbreak in Beijing. The
      model consists of six subpopulations, namely susceptible, exposed, quarantined,
      suspect, probable and removed, as China started to report SARS cases as suspect
      and probable separately from April 27 and cases transferred from suspect class to
      probable class from May 2. By simplifying the model to a two-compartment suspect
      probable model and a single-compartment probable model and using limited data, we
      are able to simulate the SARS outbreak in Beijing. We estimate that the
      reproduction number varies from 1.0698 to 3.2524 and obtain certain important
      epidemiological parameters.

PMID- 15019505
TI  - Folding of small RNAs displaying the GNC base-pattern: implications for the self
      organization of the genetic system.
AB  - Theoretical arguments and statistical analyses of present-day coding sequences
      have long suggested the existence of primitive patterns in RNA sequences, which
      were thought to have been predominant at the time of the origin of the genetic
      code. The main propositions were centered around the base-patterns GNC and RNY,
      where R = A or G , Y = C or U and N = A, G, C or U. A theoretical model of the
      primitive process of translation explaining the origin of this type of pattern
      was recently published in the Journal of Theoretical Biology. On the basis of
      this previous analysis, and on physico-chemical evidence supporting the idea of
      the GNC base-pattern as the most primitive one, the present paper shows the
      results of folding simulations of small RNA strands displaying this pattern,
      which enabled us to specify the characteristics of the suggested primitive form
      of tRNA. This analysis is notably based on a conjecture of Eigen and Schuster of
      an early structural (or pattern) similarity between mRNA and tRNA, and, more
      specifically, of a "joint function of messenger and adaptor". Working with this
      conjecture, we show that the convergence of the primitive pool of RNAs toward a
      system containing a high proportion of sequences displaying the GNC base-pattern
      (according to the evolutionary model) is accompanied by a significant gain in
      stability of the translation process. In particular, it is demonstrated how the
      reading frame would be automatically discriminated without the presence of a
      start codon.

PMID- 15019506
TI  - Evolutionary stability for large populations.
AB  - We present a revision of Maynard Smith's evolutionary stability criteria for
      populations which are very large (though technically finite) and of unknown size.
      We call this the large population ESS, as distinct from Maynard Smith's infinite
      population ESS and Schaffer's finite population ESS. Building on Schaffer's
      finite population model, we define the large population ESS as a strategy which
      cannot be invaded by any finite number of mutants, as long as the population size
      is sufficiently large. The large population ESS is not equivalent to the infinite
      population ESS: we give examples of games in which a large population ESS exists
      but an infinite population ESS does not, and vice versa. Our main contribution is
      a simple set of two criteria for a large population ESS, which are similar (but
      not identical) to those originally proposed by Maynard Smith for infinite
      populations.

PMID- 15019507
TI  - Apparent competition and recovery from infection.
AB  - We use mathematical models to analyse how the recovery rate from infection
      influences the fitness of a host in a setting of interspecific competition. We
      show that sub-optimal immunity against pathogens can be advantageous for the host
      in the presence of cross-species infection. Weaker immunity allows the parasite
      to be used as a biological weapon, and this increases the fitness of the host
      relative to a competitor. A parameter region is observed in which the outcome of
      competition depends on the initial conditions. We extend this model and consider
      the dynamics in a spatial setting and find that the outcome depends on the
      migration rate of the host species. At low migration rates, coexistence of the
      host species is possible across space. For higher migration rates, the host
      species characterized by a lower recovery rate can invade the territory of its
      competitor. Finally, we study these dynamics in an evolutionary setting. Although
      a lower recovery rate from infection can increase the competitive ability of a
      species, we find that evolution maximizes the recovery rate and minimizes
      parasite burden. The models presented are related to the concept of apparent
      competition, and our results are discussed in relation to both theoretical and
      empirical studies.

PMID- 15019508
TI  - Steady-states of receptor-ligand dynamics: a theoretical framework.
AB  - This paper studies aspects of the dynamics of a conventional mechanism of ligand
      receptor interactions, with a focus on the stability and location of steady
      states. A theoretical framework is developed, which is based upon the rich and
      deep formalism of irreducible biochemical networks. When represented in this
      manner, the mass action kinetics of biochemical processes can be clearly seen in
      terms of their component biochemical interactions, their kinetic rate constants,
      and the stoichiometry for the system. A minimal parametrization is provided for
      models for two- or multi-state receptor interaction with ligand, and an "affinity
      quotient" is introduced, which allows an elegant classification of ligands into
      agonists, neutral agonists, and inverse agonists.

PMID- 15019509
TI  - Study of DNA binding sites using the Renyi parametric entropy measure.
AB  - Shannon's definition of uncertainty or surprisal has been applied extensively to
      measure the information content of aligned DNA sequences and characterizing DNA
      binding sites. In contrast to Shannon's uncertainty, this study investigates the
      applicability and suitability of a parametric uncertainty measure due to Renyi.
      It is observed that this measure also provides results in agreement with
      Shannon's measure, pointing to its utility in analysing DNA binding site region.
      For facilitating the comparison between these uncertainty measures, a
      dimensionless quantity called "redundancy" has been employed. It is found that
      Renyi's measure at low parameter values possess a better delineating feature of
      binding sites (of binding regions) than Shannon's measure. The critical value of
      the parameter is chosen with an outlier criterion.

PMID- 15019510
TI  - A phenomenological model for atherosclerotic plaque growth and rupture.
AB  - The objective of this communication is to develop a computer-based framework for
      the overall coupled phenomena leading to growth and rupture of atherosclerotic
      plaques. The modeling is purposely simplified to expose the dominant
      phenomenological controlling mechanisms, and their coupled interaction. The main
      ingredients of the present simplified modeling approach, describing the events
      that occur due to the presence and oxidation of excess low-density lipoprotein
      (LDL) in the intima, are: (i) adhesion of monocytes to the endothelial surface,
      which is controlled by the intensity of the blood flow and the adhesion molecules
      stimulated by the excess LDL, (ii) penetration of the monocytes into the intima
      and subsequent inflammation of the tissue, and (iii) rupture of the plaque
      accompanied with some degree of thrombus formation or even subsequent occlusive
      thrombosis. The set of resulting coupled equations, each modeling entirely
      different physical events, is solved using an iterative staggering scheme, which
      allows the equations to be solved in a computationally convenient decoupled
      fashion. Theoretical convergence properties of the scheme are given as a function
      of physical parameters involved. A numerical example is given to illustrate the
      modeling approach and an a priori prediction for time to rupture as a function of
      arterial geometry, diameter of the monocyte, adhesion stress, bulk modulus of the
      ruptured wall material, blood viscosity, flow rate and mass density of the
      monocytes.

PMID- 15019511
TI  - Meiosis-II and mitosis have different molecular formats.

PMID- 15019512
TI  - The molecular site of action of juvenile hormone and juvenile hormone
      insecticides during metamorphosis: how these compounds kill insects.
AB  - Studies in a variety of insects during the past four decades has deepened our
      understanding of juvenile hormone (JH) physiology, but how this hormone works at
      the molecular level remains elusive. Similarly, the mechanism of toxicity of JH
      analogue insecticides is still in question. There is much evidence from
      laboratory usage that JHAs act as JH agonists and generally show the highest
      toxicity when applied at the onset of metamorphosis. A physiological basis for
      the toxicity and morphogenetic effects has been suggested by recent work linking
      these effects with interference with the expression or action of certain genes,
      particularly the Broad-Complex (BR-C) transcription factor gene, that direct
      metamorphic change. Misexpressed BR-C then leads to improper expression of one or
      more downstream effector genes controlled by BR-C gene products, resulting in
      abnormal developmental and physiological changes that disrupt metamorphosis.
      Therefore, JH is a necessary molecule at certain times in insect development but
      becomes toxic when present during metamorphosis.

PMID- 15019514
TI  - Correlation between concentration of hemolymph nutrients and amount of fat body
      consumed in lightly and heavily parasitized hosts (Pseudaletia separata).
AB  - Two states of parasitization in the Pseudaletia separata-Cotesia kariyai system
      were examined: one that was lightly parasitized and one that was heavily
      parasitized. We predicted that the consumption of fat body and hemolymph
      nutrients depends on the number of parasitoid larvae in the host. Lightly
      parasitized hosts (average clutch size+/-S.E.: 42.5+/-16.2, N=15) and heavily
      parasitized hosts (average clutch size+/-S.E.: 230.2+/-8.8, N=15) were prepared
      artificially. Eight days after parasitization, perivisceral fat body was depleted
      in the heavily parasitized host, although peripheral fat body was not yet
      consumed, but by day 10 most of the peripheral fat body was consumed. In lightly
      parasitized hosts, perivisceral fat body was not consumed by day 10. The
      parasitoid larvae deplete the perivisceral fat body first and then consume the
      peripheral fat body in the heavily parasitized host. The amount of trehalose, the
      major carbohydrate in the hemolymph, was related to the number of parasitoid
      larvae developing in the host. In a heavily parasitized host, trehalose
      concentrations remained low. However, in lightly parasitized hosts, the amount of
      trehalose increased 8 days after parasitization and then decreased by day 10.
      Protein and total lipid concentrations in the hemolymph of the heavily
      parasitized host were significantly lower than in lightly parasitized host on day
      10, suggesting that the large number of parasitoid larvae depleted the fat body
      and hemolymph nutrients by day 10. High concentrations of total lipid on day 8
      and 10 in lightly parasitized hosts and on day 8 in heavily parasitized host are
      likely to be attributed to the teratocytes.

PMID- 15019513
TI  - Commencement of pupal commitment in late penultimate instar and its hormonal
      control in wing imaginal discs of the silkworm, Bombyx mori.
AB  - Pupal commitment of the wing imaginal disc of the silkworm, Bombyx mori, is
      completed shortly after the final (fifth) larval ecdysis. Pupal commitment was
      induced by in vitro culture with 20-hydroxyecdysone (20E). Shortly after the head
      capsule slippage (HCS) that occurs approximately 24 h before the final larval
      ecdysis, the discs become competent to respond to 20E, indicating that the
      process of pupal commitment begins in the late penultimate (fourth) instar. The
      simultaneous presence of methoprene (JHA) with 20E suppressed the pupal
      commitment at 4 ng/ml for the discs at 12 h after HCS and at 240 ng/ml for the
      discs at the ecdysis. Thus, the discs rapidly lose their sensitivity to JH at the
      end of the fourth instar. Day 0 fourth wing discs were not pupally committed by
      20E when freshly dissected discs were exposed to 20E. By contrast, exposure to
      20E after a pre-culture in a hormone free medium induced the pupal commitment. In
      those discs, the effective JHA concentration to suppress the 20E effects was 0.1
      ng/ml. The present data suggest that pupal commitment proceeds through two stages
      from a reversible state that begins at around HCS to an irreversible state early
      in the fifth instar. The loss of sensitivity to JH is the primary impetus to
      begin the process and 20E is the factor that drives the discs to enter the
      reversible state.

PMID- 15019515
TI  - The proximate cue of density-dependent soldier production in a social aphid.
AB  - Tuberaphis styraci is a social aphid that produces 2nd instar soldiers with
      morphological, behavioral and reproductive division. High aphid density was shown
      to induce soldier production in T. styraci, although direct cue of soldier
      induction associated with high density has been unknown. In order to identify the
      proximate environmental cue underlying the density-dependent soldier production,
      a series of experiments was conducted using an artificial diet rearing technique.
      When adult aphids were reared with live normal nymphs, live soldiers, dead normal
      nymphs, shed skins, honeydew globules and excreted wax, only live normal nymphs
      effectively induced soldier production. In order to gain insights into the nature
      of soldier-inducing cue associated with normal aphids, we performed artificial
      diet experiments using partitioned and non-partitioned chambers, in which direct
      contact between aphids was either inhibited or allowed. Induction of soldiers was
      observed only when direct contact was allowed. Therefore, it was shown that the
      soldier-inducing cue is neither volatile in the air nor diffusible through the
      diet, but is transmitted between normal non-soldier aphids via direct contact. On
      the basis of these results, we suggest that the soldier-inducing cue might be
      physical stimulus combined with non-volatile surface chemicals whose properties
      differ between normal aphids and soldiers.

PMID- 15019516
TI  - Metabolic rate and jump performance in seven species of desert fleas.
AB  - We hypothesized that sexual and interspecific differences in jumping performance
      of fleas found in our previous study are correlated with differences in resting
      metabolic rate (RMR) between sexes and among species. To test this hypothesis, we
      measured RMR of seven flea species (Xenopsylla conformis mycerini, Xenopsylla
      ramesis, Xenopsylla dipodilli, Parapulex chephrenis, Synosternus cleopatrae
      pyramidis, Nosopsyllus iranus theodori and Stenoponia tripectinata medialis). We
      compared RMR between sexes and among species and examined whether there is intra-
      and interspecific correlation between RMR and jumping ability. Both mass-specific
      and mass-independent RMR were the highest in female S. t. medialis, whereas mass
      specific RMR was the lowest in male X. dipodilli and mass-independent RMR was the
      lowest in three Xenopsylla species and P. chephrenis. Mass-specific and mass
      independent RMR were significantly higher in females than in males in all fleas
      except S. t. medialis. Differences in jumping ability between males and females
      were found to be correlated with sexual differences in mass-specific or mass
      independent RMR. Interspecific comparison showed that the length of jump in both
      male and female fleas was strongly affected by their mass-specific and mass
      independent RMR.

PMID- 15019517
TI  - Effects of eicosanoid biosynthesis inhibitors on the prophenoloxidase-activating
      system and microaggregation reactions in the hemolymph of Rhodnius prolixus
      infected with Trypanosoma rangeli.
AB  - Investigations on the effects of eicosanoid biosynthesis inhibitors on the
      hemocyte microaggregation and prophenoloxidase (proPO)-activating system in the
      hemolymph, parasitemia and mortality of Rhodnius prolixus infected with
      Trypanosoma rangeli were performed. Hemocoelic injection of live T. rangeli
      epimastigotes into fifth-instar larvae of R. prolixus that previously fed on
      blood containing an inhibitor of phospholipase A(2) (dexamethasone), a specific
      inhibitor of the cyclooxygenase pathway (indomethacin), and a non-selective
      lipoxygenase inhibitor (NDGA) (i) reduced the hemocyte microaggregation, (ii)
      attenuated the proPO system in the hemolymph and (iii) enhanced parasitemia and
      mortality induced by the parasite challenge in these insects. The effects
      obtained by dexamethasone administered orally were counteracted by inoculation of
      the insects with arachidonic acid. We suggest that the infectivity of T. rangeli
      can be increased by interference with the R. prolixus immune system. This is the
      first demonstration that the triatomine's immune responses to a parasite
      infection are modulated by a physiological system that includes eicosanoid
      biosynthesis.

PMID- 15019518
TI  - Two coexisting lines of the endoparasitoid Venturia canescens show differences in
      reproductive success under conspecific superparasitism.
AB  - In a laboratory colony of the endoparasitic wasp Venturia canescens Grav.
      (Hymenoptera: Ichneumonidae), two genetically distinct lines (RP, RM) appear to
      coexist sympatrically. The two lines display pronounced differences in ovarian
      morphology, parasitism behaviour and number of offspring produced under competing
      superparasitism. Since V. canescens is a solitary endoparasitoid, larvae inside
      superparasitised hosts must compete for host possession. We examined the outcome
      of conspecific superparasitism between the wasp lines with different time
      intervals between ovipositions. The results showed that the competitive abilities
      of the two lines were not symmetrical. Further, the RM-line won a significantly
      higher fraction (around 60%) of the overall contests. Dissection of parasitoid
      larvae from their hosts indicated that most contests between competing larvae had
      occurred within the first 24 h of the eggs hatching, suggesting the advantage of
      the RM-line relates to physical combat. It was previously thought that the
      coexistence of the two lines was exclusively due to maternal effects. The results
      of this study indicate for the first time that these differences are based on
      phenotypic variations in both the larval offspring and the mother.

PMID- 15019519
TI  - Bacillus thuringiensis toxin (Cry1Ab) has no direct effect on larvae of the green
      lacewing Chrysoperla carnea (Stephens) (Neuroptera: Chrysopidae).
AB  - Earlier studies have shown that larvae of the green lacewing predator Chrysoperla
      carnea are negatively affected when preying on lepidopteran larvae that had been
      fed with transgenic maize expressing the cry1Ab gene from Bacillus thuringiensis.
      To test whether the observed effects were directly caused by the Cry1Ab toxin, we
      have developed a bioassay which allows us to feed high concentrations of the
      toxin directly to the predator. The results of these feeding studies show no
      direct toxic effect of Cry1Ab on C. carnea larvae. The amount of toxin ingested
      by first instar C. carnea in the present study was found to be a factor 10,000
      higher than the concentration ingested when feeding on Bt-reared lepidopteran
      larvae, a treatment that was previously shown to have a negative impact on the
      predator. In addition, feeding first instar C. carnea with the Cry1Ab toxin did
      not affect the utilisation of subsequently provided prey. Furthermore, the
      quality of the prey provided to first instars did not affect the sensitivity of
      second and third instar C. carnea to the Bt-toxin. The presented results strongly
      suggest that C. carnea larvae are not sensitive to Cry1Ab and that earlier
      reported negative effects of Bt-maize were prey-quality mediated rather than
      direct toxic effects. These results, together with the fact that lepidopteran
      larvae are not regarded as an important prey for C. carnea in the field, led us
      to conclude that transgenic maize expressing Cry1Ab poses a negligible risk for
      this predator.

PMID- 15019521
TI  - Lifetime egg maturation by host-deprived Venturia canescens.
AB  - The study investigated egg maturation and deposition by the endoparasitoid wasp
      Venturia canescens under conditions of host deprivation. Female V. canescens
      maintained without hosts began to deposit eggs onto the sides of the culture
      vessel on the day of eclosion. The maturation of additional eggs was not
      inhibited once the maximum oviduct egg load was reached but rather continued for
      the duration of the experiment (up to 39 days), at a rate of around 5.8% of the
      remaining unmatured eggs per day. Following host access, wasps matured additional
      eggs at an increased rate. Artificial damage to the ovipositor resulted in a
      reduced rate of egg maturation even though the oviducts were partly egg depleted,
      while damage to the auxiliary valvulae had no effect. These results suggest two
      conclusions. Under conditions of host deprivation, the rate at which eggs are
      matured is determined by the rate of synthesis of precursors by the fat body that
      in turn is modified by feedback from the ovipositor, induced by physical
      stimulation. Further, the discarding of eggs is due to the involuntary
      unidirectional movement of eggs down the oviduct, facilitated by the ongoing
      maturation of additional eggs.

PMID- 15019520
TI  - Eastern tent caterpillars (Malacosoma americanum) cause mare reproductive loss
      syndrome.
AB  - A new equine abortigenic disease, mare reproductive loss syndrome (MRLS), was
      recognized and significantly impacted the Ohio Valley in the springs of 2001 and
      2002. MRLS caused approximately 330 million US dollars in losses in 2001. An
      epidemiological investigation of MRLS associated occurrence of the disease with
      exposure to eastern tent caterpillars (M. americanum). This work investigates the
      epidemiological association between M. americanum and MRLS to determine if this
      association was correlative or causative. A pilot study and simulated exposure to
      M. americanum and their excreta on pasture grasses. The pilot study advanced
      exposure of pregnant mares to M. americanum materials and 18 of the 29 mares in
      the study aborted with symptoms of MRLS before other cases were reported in the
      region. In, three of seven mares exposed to M. americanum aborted, while mares in
      control (n=6) and M. americanum frass (n=7) treatments had no losses. In, mares
      were fed frozen insect larvae in feed buckets mixed with oats. Abortions occurred
      in three of five mares receiving frozen M. americanum, while mares that were fed
      autoclaved M. americanum (n=5) or frozen gypsy moth larvae (n=4) had no abortions
      due to MRLS. In, M. americanum larvae were dissected and fractionated.
      Statistically significant numbers of abortions occurred only in the positive
      control group and in association with the M. americanum exoskeleton. All
      abortions induced by exposure to M. americanum exhibited changes in echogenicity
      of fetal fluids and bacteriological findings post abortion that were consistent
      with MRLS. These studies support the hypothesis that ingestion of M. americanum
      larvae induces the MRLS-type equine abortions, and provide experimental evidence
      that this lepidopteran larva can cause an abortigenic disease in a vertebrate
      host.

PMID- 15019522
TI  - Chilling stress effects on corpus allatum proliferation in the Hawaiian
      cockroach, Diploptera punctata: a role for ecdysteroids.
AB  - Endocrine regulation of corpus allatum (CA) cell proliferation in response to
      chilling was studied in mated females of the Hawaiian cockroach, Diploptera
      punctata. Chilling alone, when applied 24 h post-mating, suppressed CA cell
      division, and elevated ecdysteroid levels in Diploptera's haemolymph. Application
      of 20-hydroxyecdysone (20E) at 24 h post-mating similarly suppressed CA cell
      division, but had no effects at 48 h or 72 h post-mating. Severance of the
      ventral nerve cord prior to chilling or to the application of 20E prevented
      suppression of CA cell division, indicating that the effects of either chilling
      or 20E application are mediated by the ventral nerve cord.

PMID- 15019523
TI  - Estimating disease resistance in insects: phenoloxidase and lysozyme-like
      activity and disease resistance in the cricket Gryllus texensis.
AB  - An animal's ability to resist disease is usually estimated by measuring one or
      more components of the immune system. There is an assumption that these assays of
      immunity measure an animal's ability to mount an effective immune response. This
      paper tests this assumption by examining the relationship between two common
      estimates of insect immunocompetence, phenoloxidase and lysozyme-like enzyme
      activity, and resistance to three common insect bacterial pathogens: Serratia
      marcescens, Serratia liquefaciens, and Bacillus cereus. There was a correlation
      (Spearman's rs=0.33, p<0.001, n=190 pairs) between total phenoloxidase and
      baseline lysozyme-like activity within individuals. However, total phenoloxidase
      and baseline lysozyme-like activity levels did not predict which male crickets
      would survive any of the three bacterial challenges. Lysozyme-like activity
      increased after an immune challenge (Friedman, 33.72, p<0.001), and the greater
      the increase, the greater the chance that the cricket would survive S. marcescens
      (slope=0.15, chi 2=8.2, p=0.005) or B. cereus (slope=0.8, chi 2=6.4, p=0.01). The
      crickets with a greater total hemolymph protein concentration were also more
      likely to survive a challenge with any of the three bacterial pathogens than the
      crickets with lower total hemolymph protein concentrations (S. liquefaciens:
      slope=0.02, chi 2=9.2, p=0.002; B. cereus: slope=0.02, chi 2=6.5, p=0.01; S.
      marcescens: slope=0.03, chi 2=7.8, p=0.005). Because of the complexity of the
      immune system, empirical tests of the relationship between assays of immunity and
      resistance to a range of actual pathogens are important for correctly
      interpreting these measures.

PMID- 15019524
TI  - Rank integration in dominance hierarchies of host colonies by the paper wasp
      social parasite Polistes sulcifer (Hymenoptera, Vespidae).
AB  - In multiple-foundress nests of the wasp Polistes dominulus, dominance hierarchies
      are established among foundresses, and only the dominant (=alpha) individual lays
      eggs. The alpha female can be distinguished from subordinate females and workers
      on the basis of the proportions of some hydrocarbons present on the cuticle,
      suggesting that chemical signaling of her reproductive status could occur. P.
      dominulus is also the host species of the obligate social parasite Polistes
      sulcifer. After aggressively usurping host colonies and behaviorally replacing
      the host alpha female, parasites are characterized by a change in the proportions
      of their cuticular hydrocarbons to match that of the host cuticular profile at
      both species and colony levels. In the current study, we demonstrate that P.
      sulcifer queens also modify their cuticular hydrocarbon proportions after
      usurpation to match that of the host alpha female. Parasite females, therefore,
      acquire the dominant rank in host colonies both reproductively and chemically by
      mimicking the typical alpha profile of the host. Parasite females were not able
      to fully inhibit ovary development in host foundresses, and 10 days after
      usurpation, parasites, alpha and beta foundresses show similar chemical profiles
      and ovarian development.

PMID- 15019525
TI  - Intracellular freezing and survival in the freeze tolerant alpine cockroach
      Celatoblatta quinquemaculata.
AB  - The alpine cockroach Celatoblatta quinquemaculata is common at altitudes of
      around 1500 m on the Rock and Pillar range of Central Otago, New Zealand where it
      experiences freezing conditions in the winter. The cockroach is freeze tolerant,
      but only to c. -9 degrees C. The cause of death at temperatures below this is
      unknown but likely to be due to osmotic damage to cells (shrinkage). This study
      compared the effect of different ice nucleation temperatures (-2 and -4 degrees
      C) on the viability of three types of cockroach tissue (midgut, Malpighian
      tubules and fat body cells) and cooling to three different temperatures (-5, -8, 
      12 degrees C). Two types of observations were made (i) cryomicroscope
      observations of ice formation and cell shrinkage (ii) cell integrity (viability)
      using vital stains. Cell viability decreased with lower treatment temperatures
      but ice nucleation temperature had no significant effect. Cryomicroscope
      observations showed that ice spread through tissue faster at -4 than -2 degrees C
      and that intracellular freezing only occurred when nucleated at -4 degrees C.
      From temperature records during cooling, it was observed that when freezing
      occurred, latent heat immediately increased the insect's body temperature close
      to its melting point (c. -0.3 degrees C). This "rebound" temperature was
      independent of nucleation temperature. Some tissues were more vulnerable to
      damage than others. As the gut is thought to be the site of freezing, it is
      significant that this tissue was the most robust. The ecological importance of
      the effect of nucleation temperature on survival of whole animals under field
      conditions is discussed.

PMID- 15019526
TI  - Comparison of the effects of pyrokinins and related peptides identified from
      arthropods on pupariation behaviour in flesh fly (Sarcophaga bullata) larvae
      (Diptera: Sarcophagidae).
AB  - Peptides from the pyrokinin/PBAN family and some structurally related compounds
      identified in various arthropods were tested for acceleration of puparial
      contraction in flesh fly larvae. Modifications of behavioural patterns of
      pupariation were further studied for the active compounds using a behavioural
      analysis based on the recording of changes in tension of the cuticle. Nine
      peptides belonging to the pyrokinin/PBAN family (Lem-PK, Pea-PK-5, Lom-PK II, Hez
      PBAN, Bom-DH-I), identified in five different insect species, two pyrokinin
      peptides derived from the genome of Drosophila melanogaster (capa-3, and hugin),
      and two pyrokinins identified from the white shrimp Penaeus vannamei were very
      active in the pupariation assay, with threshold doses within the range of 0.1-5.0
      pmol larva(-1). High activity was also detected for a related peptide ETH1 from
      Drosophila. All of these peptides share a C-terminal PRLamide, which is essential
      and sufficient for the activity. Interestingly, two other structurally related
      peptides from Drosophila--ETH2 and capa-1--which feature conservative changes
      (Ile and Val, respectively) at the C-terminal Leu position, were inactive within
      a physiological range of concentrations. It is clear that the receptor mediating
      the acceleration of puparial contraction behaviour is sensitive to the
      introduction of greater steric bulk at the C-terminal Leu position. The peptides
      that accelerated pupariation showed very similar patterns of muscular and
      cuticular activity.

PMID- 15019527
TI  - The presence of Drosophila melanogaster sex peptide-like immunoreactivity in the
      accessory glands of male Helicoverpa armigera.
AB  - In this study a highly specific polyclonal antibody to DrmSP was produced and
      used to develop and standardize a sensitive direct ELISA. Structure-activity
      studies revealed that the antiserum is specific to the N-terminal of DrmSP. This
      ELISA was used for the detection of DrmSP-like immunoreactivity in the
      reproductive tissues of male Helicoverpa armigera moths at femtomole levels. Two
      positive immunoreactive peaks were found in HPLC purified extracts of male
      accessory glands. The immunoreactive peak, which contained a higher amount of
      immunoreactivity, was also found to be pheromonostatic in PBAN-injected
      decapitated females as well as in intact female moths during their peak pheromone
      production. Lower levels of DrmSP-like immunoreactivity were found in younger
      males (1-2 day-old) when compared to older males (3-7 day-old).

PMID- 15019528
TI  - Circadian rhythm of behavioural responsiveness to carbon dioxide in the blood
      sucking bug Triatoma infestans (Heteroptera: Reduviidae).
AB  - The temporal modulation of the behavioural response to carbon dioxide and its
      chronobiological basis were investigated in larvae of Triatoma infestans. We
      analysed the orientation towards CO(2) of insects kept under three different
      illumination regimes: (1) 12 h light/12 h darkness cycles (L/D), (2) constant
      darkness (D/D) and (3) constant light (L/L). When maintained under L/D
      conditions, insects exhibited an oriented response towards airstreams added with
      1500 ppm of CO(2) during the first hours of the scotophase only. Bugs maintained
      under D/D also showed a positive orientation response towards CO(2) during the
      first hours of the subjective night, while bugs kept under L/L did not show a
      rhythmic oriented behaviour. Thus, T. infestans displayed a daily rhythm of
      orientation towards CO(2) (i.e. a potential food source) only at the beginning of
      the scotophase. The persistence of the rhythm under constant darkness reveals the
      existence of an endogenous circadian control of this behaviour.

PMID- 15019529
TI  - Ischemic preconditioning: nearly two decades of research. A comprehensive review.
AB  - The phenomenon of "ischemic preconditioning" has been recognized for almost two
      decades. In experimental animals and humans, a brief period of ischemia has been
      shown to protect the heart from more prolonged episodes of ischemia, and reduce
      the degree of impaired ventricular function or subsequent damage. Ischemic
      preconditioning is classified into two distinct components: the classic early
      preconditioning and the delayed or late preconditioning, each with its own
      biologic mechanism of adaptation. A comprehensive understanding of these
      mechanisms and application to clinical scenarios has the promise of providing
      unique opportunities, particularly regarding the development of preconditioning
      mimetic agents. Administration of these mimetic drugs or procedures could
      potentially advance the use of preconditioning as a therapeutic tool and/or
      preventive factor for cardiovascular disease.

PMID- 15019530
TI  - Exclusive expression of transmembrane TNF-alpha in mice reduces the inflammatory
      response in early lipid lesions of aortic sinus.
AB  - We investigated the effect of transmembrane form of tumor necrosis factor-alpha
      (TNF) on atherosclerosis in mice. We compared the development of early
      atherosclerotic lesions in the aortic sinus of (1) TNF-deficient mice that
      express only a non-cleavable transmembrane form of TNF (tmTNF), (2) wild-type
      (WT) C57BL/6 mice, and (3) TNF-deficient mice (TNF(-/-)). All mice were fed an
      atherogenic diet for 20 weeks. Lipid deposition was the most prominent in WT mice
      (25030 +/- 5693 microm2), tended to be lower in tmTNF mice (13640+/- 2190
      microm2, P > 0.05 versus WT mice) and rare in TNF(-/-) mice (1408 +/- 513
      microm2, P < 0.05 versus tmTNF and P < 0.01 versus WT). Macrophage accumulation
      was five-fold lower (P < 0.05) in tmTNF than in WT mice. In addition, the alpha
      actin immuno-reactivity of medial smooth muscle cells remained intact in tmTNF
      mice but not in WT mice. In WT mice, the plasma lipid profile was significantly
      more atherogenic than that of TNF(-/-) mice (P < 0.05), but not significantly
      different from that of tmTNF mice (P > 0.05). These results indicated that in
      contrast to TNF(-/-) mice, mice expressing exclusively tmTNF were not completely
      protected from early atherosclerotic lesion formation, although their lesions
      have a less inflammatory state than those of WT mice, which underlines the
      stronger proinflammatory potential of soluble TNF.

PMID- 15019531
TI  - Fluvastatin inhibits raft dependent Fcgamma receptor signalling in human
      monocytes.
AB  - Statins inhibit HMG-CoA reductase and thus block cholesterol and isoprenoid
      biosynthesis. Since statins also have anti-inflammatory effects, we investigated
      the effect of fluvastatin on monocyte Fcgamma receptor function. Fluvastatin (0.5
      20 microM) inhibited Fcgamma receptor signal transduction at the level of
      tyrosine kinase activation, in a time and dose dependent manner. Initiation of
      tyrosine phosphorylation is not thought to involve prenylated proteins; thus, we
      hypothesised that fluvastatin might disrupt cholesterol and sphingolipid membrane
      rafts to impair signalling. Consistent with this hypothesis, fluvastatin
      decreased (and mevalonate rescued) signalling molecules within membrane rafts in
      parallel with effects on tyrosine phosphorylation events. Raft integrity was
      unaffected by prenyl transferase inhibitors. In addition, Fcgamma receptor
      mediated immune complex trafficking, activation of MAP kinases (ERK and p38), and
      downstream inflammatory mediator release (MMP-1 and IL-6) were blocked by
      fluvastatin. Thus, HMG-CoA reductase inhibition alters immune receptor signalling
      by disrupting membrane rafts essential for the initiation of signal transduction.
      Inhibition of Fcgamma receptor function may limit development and progression of
      atherosclerosis by decreasing monocyte/macrophage inflammatory mediator release.
      Since many receptors utilise cholesterol rich rafts this mechanism may have
      broader significance given the pleiotropic effects of statins.

PMID- 15019532
TI  - Homocysteine enhances superoxide anion release and NADPH oxidase assembly by
      human neutrophils. Effects on MAPK activation and neutrophil migration.
AB  - Hyperhomocysteinaemia has recently been recognized as a risk factor of
      cardiovascular disease. However, the action mechanisms of homocysteine (Hcy) are
      not well understood. Given that Hcy may be involved in the recruitment of
      monocytes and neutrophils to the vascular wall, we have investigated the role of
      Hcy in essential functions of human neutrophils. We show that Hcy increased
      superoxide anion (O2*-) release by neutrophils to the extracellular medium, and
      that this effect was inhibited by superoxide dismutase and diphenyleneiodonium
      (DPI), an inhibitor of NADPH oxidase activity. The enzyme from rat peritoneal
      macrophages displayed a similar response. These effects were accompanied by a
      time-dependent increased translocation of p47phox and p67phox subunits of NADPH
      oxidase to the plasma membrane. We also show that Hcy increased intracellular
      H2O2 production by neutrophils, that Hcy enhanced the activation and
      phosphorylation of mitogen-activated protein kinases (MAPKs), specifically p38
      MAPK and ERK1/2, and that the migration of neutrophils was increased by Hcy.
      Present results are the first evidence that Hcy enhances the oxidative stress of
      neutrophils, and underscore the potential role of phagocytic cells in vascular
      wall injury through O2*- release in hyperhomocysteinaemia conditions.

PMID- 15019533
TI  - The hypolipidemic natural product Commiphora mukul and its component
      guggulsterone inhibit oxidative modification of LDL.
AB  - There is accumulating evidence that LDL oxidation is essential for atherogenesis,
      and that antioxidants that prevent this oxidation may either slow down or prevent
      atherogenesis. In the present study, we found that Commiphora mukul and its
      cholesterol-lowering component, guggulsterone, effectively inhibited LDL
      oxidation mediated by either catalytic copper ions, free radicals generated with
      the azo compound 2,2'-azobis-(2-amidinopropane)dihydrochloride (AAPH), soybean
      lipoxygenase enzymatically, or mouse peritoneal macrophages. This inhibition was
      assessed by the decrease in the following parameters describing LDL oxidation:
      conjugated dienes, relative electrophoretic mobility (REM), thiobarbituric acid
      reactive substances, lipid hydroperoxides, oxidation-specific immune epitopes as
      detected with a monoclonal antibody against oxidized LDL, and the accumulation of
      LDL derived cholesterol esters in mouse peritoneal macrophages. We concluded that
      C. mukul and its lipid-lowering component, guggulsterone, significantly inhibit
      LDL oxidation. The combination of antioxidant and lipid-lowering properties of C.
      mukul and guggulsterone makes them especially beneficial against atherogenesis.

PMID- 15019534
TI  - Inhibition of cholesteryl ester transfer protein increases serum apolipoprotein
      (apo) A-I levels by increasing the synthesis of apo A-I in rabbits.
AB  - BACKGROUND: Inhibition of cholesteryl ester transfer protein (CETP) is an
      effective way to increase HDL levels in animals and humans. The effects of a CETP
      inhibitor, JTT-705, on the in vivo kinetics of apolipoprotein (apo) A-I and apo A
      I gene expression in the liver and intestine were investigated. METHODS: Japanese
      White rabbits were randomly fed normal rabbit chow LRC-4 (n=10, control) or a
      food admixture of LRC-4 and 0.75% JTT-705 (n=10, treated) for 7 months. An in
      vivo kinetics study of apo A-I was performed by injecting rabbit 125I-apo A-I,
      and apo A-I mRNA levels were quantified by RT-PCR. RESULTS: JTT-705 significantly
      inhibited CETP activities, increased serum levels of HDL-cholesterol (C), HDL2-C,
      HDL-phospholipid, and apo A-I, and decreased HDL-triglyceride levels. The
      synthetic rate of apo A-I was higher in the treated rabbits than in control
      rabbits (13.7 +/- 2.6 versus 9.5 +/- 1.3 mg/kg per day, P < 0.05), while the
      fractional catabolic rate was similar in the two groups. JTT-705 increased apo A
      I mRNA levels in the liver without affecting those in the intestine. CONCLUSION:
      Inhibition of CETP activity by JTT-705 increases HDL levels by increasing the
      synthesis of apo A-I, suggesting that it could be a promising therapeutic
      approach for atherosclerosis.

PMID- 15019536
TI  - Serum homocysteine concentrations, gemfibrozil treatment, and progression of
      coronary atherosclerosis.
AB  - The present study aimed to assess the effect of gemfibrozil on serum total
      homocysteine (tHcy) concentration and to evaluate the influence of tHcy on the
      angiographically determined progression of coronary atherosclerosis in a
      randomised, placebo-controlled trial of 395 post-coronary bypass men with low HDL
      cholesterol levels. The baseline levels of tHcy and those after 16 months of
      randomised therapy were measured by high-pressure liquid chromatography. Patients
      were genotyped for the thermolabile variant of N5,N10-methylenetetrahydrofolate
      reductase (MTHFR) (677C > T substitution). Gemfibrozil therapy was associated
      with a median 18% increase in tHcy levels (P < 0.01). In the gemfibrozil group
      increases in tHcy and HDL cholesterol were related (r = 0.217, P = 0.004), but
      changes in tHcy and triglycerides were not. Levels of tHCy were not associated
      with baseline extent or progression of coronary-artery disease. Subjects
      homozygous for the rare MTHFR T allele had 34% higher median tHcy concentrations
      than CC homozygotes or CT heterozygotes, but responses to gemfibrozil did not
      differ significantly among genotypes. The MTHFR genotype was not associated with
      extent or progression of coronary atherosclerosis. We conclude that gemfibrozil
      causes a significant elevation in tHcy levels, but the clinical relevance of this
      is unknown at present.

PMID- 15019535
TI  - Peroxynitrite-mediated oxidative modification of low-density lipoprotein by
      aqueous extracts of cigarette smoke and the preventive effect of fluvastatin.
AB  - Cigarette smoking is known to promote atherosclerosis, possibly through enhanced
      oxidative stress. The aim of the present study was to elucidate the possible
      involvement of peroxynitrite in oxidative modification of low-density lipoprotein
      (LDL) induced by aqueous extract of cigarette smoke (CSE) and the preventive
      effect of fluvastain, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor
      with antioxidative activity, in vitro and in vivo. Modification of LDL was
      monitored by LDL subfraction analysis using anion-exchange HPLC, TBARS formation
      and 3-nitrotyrosine production. Incubation of LDL with CSE caused a marked
      increase in oxidative modification of LDL and nitration of tyrosine residues in
      the apolipoprotein B. These modifications were prevented by treatment with
      fluvastatin as well as Vitamin E in a concentration-related manner. Fluvastatin
      was equal to or more effective than Vitamin E for preventing protein nitration,
      but weaker for preventing oxidative modification. When CSE was injected daily
      into the ear vein of Watanabe heritable hyperlipidemic rabbits for 5 months, both
      oxidative modification and nitration of the plasma LDL noticeably occurred. These
      changes induced by CSE could be effectively prevented by the simultaneous oral
      administration of fluvastatin (10 and 30 mg/kg) or Vitamin E (150 mg/kg).
      Fluvastatin prevented the LDL nitration more effectively than Vitamin E. These
      results suggest that peroxynitrite in CSE is involved in oxidative modification
      of LDL and that fluvastatin can efficiently prevent LDL modification by
      scavenging peroxynitrite. Fluvastatin may be potentially beneficial to
      hypercholesterolemic patients with oxidative stress such as smoking.

PMID- 15019537
TI  - Fenofibrate improves the atherogenic lipid profile and enhances LDL resistance to
      oxidation in HIV-positive adults.
AB  - BACKGROUND: Low HDL-cholesterol, hypertriglyceridemia (HTG) and occurrence of
      small dense LDL could be involved in increased cardiovascular risk in HIV
      infected patients. This study evaluates the effects of fenofibrate and/or Vitamin
      E on lipoprotein profile. DESIGN: Thirty-six HIV-positive adults with fasting
      triglycerides (TGs) > or =2 mmol/l and stable antiretroviral therapy (ART) were
      randomly assigned to receive either micronised fenofibrate (200 mg/day) or
      Vitamin E (500 mg/day) for a first period of 3 months and the association of both
      for an additional 3-month period. METHODS AND RESULTS: Total cholesterol, HDL-C,
      LDL-C, triglycerides, apoA1, apoB, apoCIII, lipoprotein composition, LDL size and
      LDL resistance to copper-induced oxidation were determined before initiation of
      fenofibrate or Vitamin E, and 3 and 6 months thereafter. Three months of
      fenofibrate treatment results in a significant decrease in triglycerides (-40%),
      apoCIII (-21%), total cholesterol (-14%), apoB (-17%) levels, non-HDL-C (-17%),
      TG/apoA1 ratio in HDL (-27%) associated with an increase in HDL-C (+15%) and
      apoA1 (+11%) levels. Moreover, fenofibrate increases LDL size and enhances LDL
      resistance to oxidation. Three months of Vitamin E supplementation only improves
      LDL resistance to oxidation and addition to fenofibrate results in a slightly
      greater effect. CONCLUSION: Fenofibrate therapy improves the atherogenic lipid
      profile in HIV-positive adults with hypertriglyceridemia.

PMID- 15019538
TI  - Third generation oral contraceptive use and cardiovascular risk factors.
AB  - OBJECTIVE: To analyze the relationship between third generation oral
      contraceptive (OC) use and various cardiovascular risk factors--including markers
      of inflammation--in a population-based sample. STUDY POPULATION AND METHODS: Data
      on OC use were obtained from women, aged 25-44 years participating in the MONICA
      Augsburg survey 1994-1995. Complete data were available from 841 women. Third
      generation OCs were defined as OCs containing desogestrel or gestodene, the
      remaining OC products were summarized in the group "other OC." RESULTS: Women
      taking third generation OCs had significantly higher C-reactive protein,
      fibrinogen, plasma viscosity, and HDL-cholesterol concentrations compared to the
      "other OC" group and non-users. In contrast, LDL-cholesterol was identical in the
      three groups. The analyses of interaction between smoking and OC use revealed
      that smoking women taking third generation pills had a less favourable pattern
      concerning inflammatory markers compared to women not on OC or using other
      products. CONCLUSION: Potentially harmful effects of OCs may arise from their
      positive association with the acute phase response. There is a close relationship
      with inflammatory markers in particular in women taking third generation OCs,
      which may, at least in part, contribute to the increased atherothrombotic risk,
      reported specifically in these women.

PMID- 15019539
TI  - Lipoprotein concentrations in newborns are associated with allelic variations in
      their mothers.
AB  - BACKGROUND: Factors determining lipoprotein concentrations in the fetus are not
      yet fully understood. We postulated that an important factor is the genetic make
      up of the mother. In the present study, we examined the associations between the
      cord blood concentrations of lipoproteins of 525 newborns and the polymorphisms
      present in their mothers on the genes of apolipoprotein E (APOE*E2, *E3, *E4),
      apolipoprotein C-III (APOC3*C3238G also called APOC3*S2) and lipoprotein lipase
      (LPL*S447X). RESULTS: Newborns born of mothers with APOE*E2 allele had
      significantly lower cord blood LDL-C (P < 0.01) and apoB (P < 0.01) and
      significantly higher cord blood HDL-C and apoA1 (all P-values < 0.03) compared to
      those born of mothers with APOE*E3E3 genotype. These associations were
      independent of the presence of APOE*E2 allele in the newborns. Similarly,
      APOC3*S2 in mothers was associated with significantly lower (all P < 0.001) cord
      blood LDL-C, apoB, HDL-C and apoA1. In contrast, LPL*S447X in mothers lowered
      significantly cord blood LDL-C and apoB only when LPL*S447X was present in
      newborns. Most of the effects of these maternal polymorphisms on the newborns
      were independent of the changes of maternal lipoproteins generated by these
      polymorphisms. CONCLUSIONS: This is the first evidence that maternal genetic
      variations influence fetal lipoprotein concentrations, independent of the genetic
      status of the fetus and of the variations of maternal lipoprotein concentrations
      generated by these genetic variants. It suggests that proteic components of
      maternal lipoproteins strongly control the metabolism of maternal lipoproteins
      carried out at the surface of the placenta to assure the cholesterol delivery to
      the fetus.

PMID- 15019540
TI  - Biological determinants of serum ICAM-1, E-selectin, P-selectin and L-selectin
      levels in healthy subjects: the Stanislas study.
AB  - BACKGROUND: Circulating levels of adhesion molecules increase in various
      inflammation-related diseases, such as atherosclerosis. However, data about
      factors influencing their concentrations in physiological conditions are scarce.
      METHODS: We have studied the determinants of serum levels of intercellular
      adhesion molecule-1 (ICAM-1), E-selectin, P-selectin and L-selectin in a sample
      of healthy individuals: 303 children (4-17 years) and 493 adults (18-55 years).
      The concentrations of these molecules have been measured by enzyme-linked
      immunosorbant assay. RESULTS: As far as the children are concerned, a decrease in
      the levels of ICAM-1, E-selectin, P-selectin and L-selectin has been noticed for
      both boys and girls aged 4-17 years, without any difference between genders. For
      the adults, no age-related variation has been found for the ICAM-1, E-selectin
      and P-selectin levels, while the L-selectin level decreased until 55 years old.
      In the adult group, no sex-related difference in the concentrations of ICAM-1, E
      selectin and L-selectin has been seen. As to the P-selectin level, men had
      significantly higher levels than women. Multiple regression analysis showed that
      smoking, homeostasis model assessment (HOMA) index, aspartate aminotransferase
      (AST), alkaline phosphatase (ALP) and C-reactive protein (CRP) were significant
      positive determinants of the ICAM-1 concentration, whereas age and apo AI were
      negative ones. The E-selectin level was positively associated with body mass
      index (BMI), leukocyte, platelet and erythrocyte counts, glucose, ALP and tumor
      necrosis factor-alpha (TNF-alpha), and negatively related to the use of oral
      contraceptive (OC). Positive determinants of the P-selectin concentration were
      leukocyte, platelet and erythrocyte counts, whereas sex, the use of oral
      contraceptive, glucose and TNF-alpha were negative determinants of P-selectin.
      Only two determinants have been noticed for the concentration of serum L
      selectin: age, which was negatively correlated, and leukocyte count, which was
      positively associated. CONCLUSION: Our study contributes to the understanding of
      the regulation of adhesion molecules in physiological conditions.

PMID- 15019542
TI  - Is blood donation induced low iron status associated with favourable levels of
      OxLDL, s-ICAM-1, sVCAM-1 and vWF-antigen in healthy men.
AB  - The potential effect of iron depletion by blood donation and its relevance to
      cardiovascular diseases are still under debate. Markers of vascular integrity are
      increasingly applied in investigations of atherothrombotic diseases. In this
      study, we investigated whether a lower iron status through blood donation was
      associated with markers of vascular integrity (circulating oxidised LDL, sICAM-1,
      sVCAM-1 and vWF-antigen) by comparing healthy male voluntary donors to non
      donors, taking into account differences in baseline characteristics. Two fasting
      blood samples were collected within 1 week from 41 donors and 39 non-donors. The
      iron status was estimated by measuring the concentration of plasma iron,
      ferritin, haemoglobin and hematocrit. The markers of iron status were all
      significantly lower in donors compared to non-donors, especially for ferritin
      concentrations. However, the lower iron status by blood donation was not
      reflected in the concentrations of OxLDL, sICAM-1, sVCAM-1 and vWF-antigen in men
      after adjustment for BMI and ratio total/HDL cholesterol. In order to avoid
      possible selection-bias related to donorship, we have additionally investigated
      the difference in marker concentrations within the non-donors, comparing low- and
      high-ferritin concentrations. This analysis suggests that ferritin concentration
      is not associated with in vivo LDL oxidation.

PMID- 15019541
TI  - Familial HDL deficiency due to ABCA1 gene mutations with or without other genetic
      lipoprotein disorders.
AB  - Mutations in ABCA1 have been shown to be the cause of Tangier disease (TD) and
      some forms of familial hypoalphalipoproteinemia (HA), two genetic disorders
      characterized by low plasma HDL levels. Here we report six subjects with low HDL,
      carrying seven ABCA1 mutations, six of which are previously unreported. Two
      mutations (R557X and H160FsX173) were predicted to generate short truncated
      proteins; two mutations (E284K and Y482C) were located in the first extracellular
      loop and two (R1901S and Q2196H) in the C-terminal cytoplasmic domain of ABCA1.
      Two subjects found to be compound heterozygotes for ABCA1 mutations did not have
      overt clinical manifestations of TD. Three subjects, all with premature coronary
      artery disease (pCAD), had a combination of genetic defects. Besides being
      heterozygotes for ABCA1 mutations, two of them were also carriers of the R3500Q
      substitution in apolipoprotein B and the third was a carrier of N291S
      substitution in lipoprotein lipase. By extending family studies we identified 17
      heterozygotes for ABCA1 mutations. Plasma HDL-C and Apo A-I values in these
      subjects were 38.3 and 36.9% lower than in unaffected family members and similar
      to the values found in heterozygotes for Apo A-I gene mutations which prevent Apo
      A-I synthesis. This survey underlines the allelic heterogeneity of ABCA1
      mutations and suggests that: (i) TD subjects, if asymptomatic, may be overlooked
      and (ii) there may be a selection bias in genotyping towards carriers of ABCA1
      mutations who have pCAD possibly related to a combination of genetic and
      environmental cardiovascular risk factors.

PMID- 15019543
TI  - Cardiovascular disease and mortality in statin-treated patients with familial
      hypercholesterolemia.
AB  - Patients with familial hypercholesterolemia (FH) are at an increased risk of
      premature cardiovascular disease (CVD). The benefits of statin therapy are not
      well known since no placebo controlled studies have been performed in these
      patients. The aim of this study was to determine the CVD event and mortality risk
      in statin-treated patients with FH. A total of 345 FH patients were followed
      prospectively for 8 years. Mortality from CVD was compared to that of the general
      population. The absolute risk of CVD in patients without a previous history of
      CVD was 3% per year for men and 1.6% for women. Mortality from CVD in patients
      without a previous history was 1.4-fold (95% CI = 0.6-3.3) increased and
      ischaemic heart disease (IHD) mortality was 2.6-fold (95% CI = 1.1-6.3) higher
      compared to the general population. This mortality risk was highest in patients
      aged 40-59 years. Female FH patients had no increased CVD or IHD mortality risk.
      Over a period of 8 years the event risk of patients with a history of CVD was
      almost 30% per year under age 40 years and 15% in patients aged 60 years and
      over. When compared to the general population, mortality from other causes than
      CVD was lower for patients with FH, the relative risks not reaching statistical
      significance. The relative risk of mortality from all causes was 1.5 (P < 0.05)
      for men and 1.0 for women. In conclusion, male patients with FH, treated from
      middle-age with statins remain at an increased risk of developing CVD.

PMID- 15019544
TI  - Carotid atherosclerosis and cardiovascular risk factors: a comparison of
      residents of a rural area of Okinawa with residents of a typical suburban area of
      Fukuoka, Japan.
AB  - Areas of Japan are known worldwide for the longevity of their residents. Okinawa
      has the highest longevity in Japan and a low rate of death due to cardiovascular
      disease. We investigated carotid atherosclerotic (CA) risk factors in islands of
      I city in Okinawa prefecture and compared them with K town, a suburban area of
      Fukuoka prefecture in Kyushu, to determine the relationship between
      cardiovascular risk factors and carotid atherosclerosis. We investigated
      conventional cardiovascular risk factors in 1078 I city residents (375 men, mean
      age 63.7 and 703 women, mean age 60.0) in 2000 and 2364 K town residents (676
      men, mean age 57.1 and 1688 women, mean age 53.0) in 1999. Carotid
      atherosclerosis was assessed by mean intima-media thickness (IMT) by B-mode
      ultrasound. The mean IMT was significantly lower in the residents of I city than
      in those of K town (P < 0.05). Total cholesterol (TC) and low-density-lipoprotein
      cholesterol (LDL-C) levels and smoking rate were also lower in I city than in K
      town. Body mass index (BMI) and triglyceride (TG) level were higher in I city
      than in K town. In I city, multiple regression analysis found independent
      relationships between carotid atherosclerosis and age, sex (male), hypertension,
      LDL cholesterol, high-density-lipoprotein cholesterol (HDL-C), and diabetes. The
      lower mean IMT is probably related to a lower lifetime burden of atherosclerotic
      risk factors, which may in turn be related to the longevity of Okinawa residents.
      BMI was not a cardiovascular risk factor, although LDL cholesterol was a common
      important risk factor.

PMID- 15019545
TI  - Plasma C-reactive protein, but not protein S, VCAM-1, von Willebrand factor or P
      selectin, is associated with endothelium dysfunction in coronary artery disease.
AB  - Abnormal endothelium-dependent vasodilatation is well documented in coronary
      artery disease (CAD), as are significant increases of acute phase inflammatory
      proteins and other soluble hepatic and endothelium derived proteins. In the
      current study we investigated whether there is a relationship between endothelium
      dependent vasodilatation and the plasma levels of such proteins. Further we
      examined the association between these proteins, together with age, cholesterol
      and endothelium function, and participant status (i.e. healthy, smoker, coronary
      artery disease). Three groups of participants were recruited: healthy controls (n
      = 20), cigarette smokers (n = 20) and patients with coronary artery disease (n =
      20). Forearm vascular dilatation responses to the endothelium-dependent agonist
      acetylcholine were obtained using venous occlusion plethysmography. Blood was
      sampled at the time of study for the measurement of the serological proteins
      described above. Responses to acetylcholine were significantly dampened in
      patients with CAD when compared with control and smoker groups (forearm blood
      flow at acetylcholine 37 microg/min): control, smokers, CAD, 12.14 +/- 2.14,
      12.35 +/- 09.4, 5.12 +/- 0.81, ANOVA, P < 0.05). Responses to acetylcholine were
      not different between controls and smokers. C-reactive protein (C-RP) levels
      (controls, smokers, CAD, 1.40 +/- 0.19, 2.27 +/- 0.71, 4.73 +/- 1.09, P < 0.05)
      and protein S levels were significantly higher in the CAD group compared with the
      other two groups. There was a significant inverse correlation between forearm
      blood flow responses to acetylcholine and C-reactive proteins. Both responses to
      acetylcholine and C-RP levels demonstrated a significant association with
      participant status with the r value increasing from 0.405 for responses to
      acetylcholine to 0.491 for the combination of responses to acetylcholine and C
      RP. We conclude that there is an inverse correlation between C-reactive protein,
      but not protein S, VCAM-1, P-selectin nor von Willebrand factor, levels and
      abnormal endothelium-dependent vasodilation and further that responses to
      acetylcholine together with C-RP protein have a strong association with
      cardiovascular risk and disease.

PMID- 15019546
TI  - Prevalence and correlates of carotid atherosclerosis among elderly Japanese men.
AB  - We determined intima-media thickness (IMT) and diameter of carotid artery and
      estimated their correlations with cardiovascular risk factors in 1129 men aged 60
      74 years, who participated in a cardiovascular risk survey in three Japanese
      communities. The multivariate odds ratios (95% confidence interval) for the
      maximum IMT > or = 1.1 mm in the common carotid artery (CCA) were 1.3 (1.1-1.5)
      per 4 years of age, 1.8 (1.4-2.5) for hypertension, 1.4 (1.2-1.7) for a 34.4
      mg/dl increase in serum total cholesterol, 0.7 (0.6-0.8) for a 14.7 mg/dl
      increase in serum HDL-cholesterol, and 2.4 (1.1-5.0) for history of stroke, while
      the maximum IMT > or = 1.5mm in the internal carotid artery (ICA) were 1.6 (1.4
      1.8) per 4 years of age, 1.9 (1.5-2.4) for hypertension, 1.6 (1.2-2.1) for
      current smoking, and 3.5 (1.6-7.6) for history of stroke. Age, height,
      hypertension, current smoking, ethanol intake and history of coronary heart
      disease were independent determinants of both the outer and inner CCA diameter.
      Maximum IMT correlated positively with the outer diameter and inversely with the
      inner diameter in the CCA. Carotid atherosclerosis suggests to be a risk factor
      for stroke among Japanese elderly men, although future prospective studies are
      required to confirm this finding.

PMID- 15019547
TI  - Haptoglobin phenotype and prevalent coronary heart disease in the Framingham
      offspring cohort.
AB  - BACKGROUND: The haptoglobin (Hp) locus is polymorphic with two major alleles
      denoted 1 and 2. Several recent prospective longitudinal studies have
      demonstrated conflicting results regarding whether there is an increase or
      decrease in the relative risk of coronary heart disease (CHD) conferred on
      individuals homozygous for the haptoglobin 1 allele (Hp 1-1). METHODS: We sought
      to examine the relationship between Hp type and prevalent coronary heart disease
      in a cross-sectional study from a large community-based cohort, the Framingham
      Heart Offspring Study (n = 3273). RESULTS: Overall we found no relation between
      Hp type and CHD prevalence. In secondary analyses we found a different pattern of
      Hp type and CHD prevalence by diabetes status. In nondiabetics, compared with Hp
      1-1, Hp 2-1 (OR 1.71, 95% CI 1.03, 2.83) was associated with excess prevalence of
      CHD. In contrast in diabetic individuals we observed the opposite pattern; Hp 2-1
      (OR 0.49, 95% CI 0.24, 0.99) and Hp 2-2 (OR 0.46, 95% CI 0.22, 0.96) were
      associated with diminished prevalence of CHD. CONCLUSIONS: These data are
      consistent with an interaction between Hp type and diabetes in the prevalence of
      CHD. These findings will need to be confirmed in other cohorts and in
      longitudinal studies.

PMID- 15019548
TI  - Lack of evidence for reduced plasma apo B48 catabolism in patients with
      heterozygous familial hypercholesterolemia carrying the same null LDL receptor
      gene mutation.
AB  - Increasing evidence suggests that remnants of chylomicrons and very low density
      lipoprotein (VLDL) also known as triglyceride-rich lipoproteins (TRL) are
      directly related to the pathogenesis of atherosclerosis. While studies in animals
      suggest that low density lipoprotein (LDL) receptor deficiency delays clearance
      of chylomicron remnants, human data supporting this hypothesis are conflicting.
      The objective of this study was to compare the fractional catabolic rate (FCR)
      and production rate (PR) of TRL apolipoprotein B48, the principal structural
      protein of intestinally derived chylomicron remnants, between familial
      hypercholesterolemic (FH) heterozygotes and non-FH controls. This was achieved by
      examining the kinetics of TRL apo B48 labelled with a stable isotope (L-(5,5,5
      D3)leucine) in five normolipidemic males (age: 24.7 +/- 1.3 years; body mass
      index (BMI): 23.9 +/- 1.4 kg/m2) and six genetically defined FH heterozygous
      males (age: 29.7 +/- 9.9 years; (BMI): 22.0 +/- 4.3 kg/m2) carrying the same null
      LDL receptor gene mutation. All participants were apo E3 homozygotes. During the
      kinetic study, the subjects consumed 1/30 of their daily food intake every 30 min
      over a 15 h period. No significant difference was observed between FH
      heterozygotes and controls for FCR of TRL apo B48 (7.9 +/- 2.1 versus 7.9 +/- 2.6
      pools per day, P = 0.99) while the TRL apo B48 pool size (10.5 +/- 5.4 versus 5.7
      +/- 2.4 mg, P = 0.03) and PR (1.1 +/- 0.3 versus 0.6 +/- 0.3 mg kg(-1) per day, P
      = 0.02) were significantly higher among FH than in controls. In conclusion, this
      study shows no evidence for reduced plasma apo B48 catabolism in patients with
      heterozygous FH carrying the same null LDL receptor gene mutation and suggests
      that the plasma levels of intestinally derived TRL are elevated in FH due to an
      increased production rate.

PMID- 15019549
TI  - Effect of fibrates on postprandial remnant-like particles in patients with
      combined hyperlipidemia.
AB  - We have investigated the effect of standard doses of two fibrates, gemfibrozil
      and fenofibrate, on fasting and postprandial remnant-like particles (RLP) in
      subjects with combined hyperlipidemia. Forty-eight subjects participated; of
      these, 14 underwent a Vitamin A-fat loading test before and after 6 months of
      treatment with gemfibrozil (n = 8) and fenofibrate (n = 6). Blood was drawn every
      2h for 12h after the test meal. The postprandial response was calculated as the
      area under the curve (AUC). There was no difference in fasting levels and pre
      treatment AUC for triglycerides (TG), RLP cholesterol (RLP-C), RLP triglycerides
      (RLP-TG) and retinyl palmitate (RetP) between the two treatment groups. There was
      also no difference in the treatment effect on all parameters between the two
      treatment groups. Combining the two treatment groups, treatment resulted in a
      significant reduction in fasting levels and AUC of all four parameters. Assigning
      the difference observed between pre-treatment AUC of the combined study group and
      AUC of a normolipidemic (NL) control group as 100%, fibrate treatment resulted in
      decreases in AUC for TG, RLP-C, RLP-TG and RetP of 68, 69, 69 and 94%,
      respectively. These results indicate that fibrates are effective agents in
      reducing the postprandial increase in remnant lipoprotein particles.

PMID- 15019550
TI  - Abnormal capillary permeability and endothelial dysfunction in hypertension with
      comorbid Metabolic Syndrome.
AB  - PURPOSE: Metabolic Syndrome as defined by ATP III criteria, a constellation of
      risk factors associated with insulin resistance, predisposes to premature
      atherosclerosis and early coronary events. Whether that negative risk profile is
      associated with endothelial dysfunction remains to be established. MATERIALS AND
      METHODS: Transcapillary escape rate of albumin (TERalb), a measure of capillary
      permeability and integrity of systemic capillary endothelium, and forearm
      vasodilation to intra-arterial acetylcholine (ACH), an index of nitric oxide (NO)
      mediated vasomotor dysfunction, were assessed in 24 non-diabetic, uncomplicated
      hypertensive men with Metabolic Syndrome according to ATP III criteria
      (hypertension with at least two additional traits such as high triglycerides, low
      HDL, abdominal obesity, impaired fasting or post-load plasma glucose). Twelve age
      matched lean normal hypertensive patients with normal lipid and glucose profile
      and nine normotensive subjects were the controls. All patients underwent lipids
      determination and fasting and post-OGTT insulin assessment; HOMA-IR was the index
      of insulin resistance. RESULTS: TERalb was higher in hypertensive patients with
      Metabolic Syndrome, without differences between hypertensive and normotensive
      controls. Blood pressure (BP), lipids, plasma glucose, insulin levels and HOMA-IR
      were unrelated to TERalb. Responses to acetylcholine were selectively attenuated
      in metabolic patients and, on an individual basis, related only to HDL
      cholesterol levels, independent of LDL cholesterol, BP, body size, triglycerides,
      and HOMA-IR values. No relationship existed between responses to acetylcholine
      and TERalb. CONCLUSIONS: Altered systemic capillary permeability characterizes
      insulin-resistant hypertensive patients with Metabolic Syndrome. That defect,
      which may promote early atherosclerosis development, coexists with blunted
      endothelial-mediated vasodilation, indicating a pervasive abnormality of
      endothelial function.

PMID- 15019551
TI  - Influenza--a trigger for acute myocardial infarction.

PMID- 15019552
TI  - Abstract morphemes and lexical representation: the CV-Skeleton in Arabic.
AB  - Overlaps in form and meaning between morphologically related words have led to
      ambiguities in interpreting priming effects in studies of lexical organization.
      In Semitic languages like Arabic, however, linguistic analysis proposes that one
      of the three component morphemes of a surface word is the CV-Skeleton, an
      abstract prosodic unit coding the phonological shape of the surface word and its
      primary syntactic function, which has no surface phonetic content (McCarthy, J.
      J. (1981). A prosodic theory of non-concatenative morphology, Linguistic Inquiry,
      12 373-418). The other two morphemes are proposed to be the vocalic melody, which
      conveys additional syntactic information, and the root, which defines meaning. In
      three experiments using masked, cross-modal, and auditory-auditory priming we
      examined the role of the vocalic melody and the CV-Skeleton as potential
      morphemic units in the processing and representation of Arabic words.
      Prime/target pairs sharing the vocalic melody but not the CV-Skeleton
      consistently failed to prime. In contrast, word pairs sharing only the CV
      Skeleton primed reliably throughout, with the amount of priming being as large as
      that observed between word pattern pairs sharing both vocalic melody and CV
      Skeleton. Priming between morphologically related words can be observed when
      there is no overlap either in meaning or in surface phonetic form.

PMID- 15019553
TI  - The ontogeny of face identity; I. Eight- to 21-week-old infants use internal and
      external face features in identity.
AB  - A paradigm was designed to study how infants identify live faces. Eight- to 21
      week-old infants were seated comfortably and were presented an adult female,
      dressed in a white laboratory coat and a white turtle neck sweater, until
      habituation ensued. The adult then left the room. One minute later either she or
      an identically garbed confederate returned. Looking time did not increase above
      habituation levels when the original experimenter returned, but increased
      substantially when the confederate entered the room. Furthermore, internal
      features alone could serve as the basis of face identity. Looking times of
      infants who had habituated to experimenters with masked outer features of hair,
      ears and neck also markedly increased when a second identically dressed
      experimenter returned. Identity in this instance could only be based on internal
      facial characteristics. A second study assessed the contributions of internal and
      external facial features to identity. Infants were habituated to an experimenter
      in a short wig. One minute later they saw her again, either in the same short wig
      or in a long one. Alternatively, they saw a second experimenter wearing either
      the short wig or the long one. Infants looked longer only to the stranger wearing
      the long wig. Very brief looking times occurred to the familiar adult, regardless
      of wig, and to the stranger wearing the familiar wig. This paradigm provides an
      approach to discover rules used by infants of different ages to process and
      identify adult faces and to establish the bases of face preference.

PMID- 15019554
TI  - Six does not just mean a lot: preschoolers see number words as specific.
AB  - This paper examines what children believe about unmapped number words - those
      number words whose exact meanings children have not yet learned. In Study 1, 31
      children (ages 2-10 to 4-2) judged that the application of five and six changes
      when numerosity changes, although they did not know that equal sets must have the
      same number word. In Study 2, 15 children (ages 2-5 to 3-6) judged that six plus
      more is no longer six, but that a lot plus more is still a lot. Findings support
      the hypothesis that children treat number words as referring to specific, unique
      numerosities even before they know exactly which numerosity each word refers to.

PMID- 15019555
TI  - Semantics, cross-cultural style.
AB  - Theories of reference have been central to analytic philosophy, and two views,
      the descriptivist view of reference and the causal-historical view of reference,
      have dominated the field. In this research tradition, theories of reference are
      assessed by consulting one's intuitions about the reference of terms in
      hypothetical situations. However, recent work in cultural psychology (e.g.
      Nisbett, R. E., Peng, K., Choi, I., & Norenzayan, A. (2001). Culture and systems
      of thought: holistic vs. analytic cognition. Psychological Review, 108, 291-310.)
      has shown systematic cognitive differences between East Asians and Westerners,
      and some work indicates that this extends to intuitions about philosophical cases
      (Weinberg, J., Nichols, S., & Stich, S. (2001). Normativity and epistemic
      intuitions. Philosophical Topics 29(1&2), 429-459.) In light of these findings on
      cultural differences, an experiment was conducted which explored intuitions about
      reference in Westerners and East Asians. The experiment indicated that, for
      certain central cases, Westerners are more likely than East Asians to report
      intuitions that are consistent with the causal-historical view. These results
      constitute prima facie evidence that semantic intuitions vary from culture to
      culture, and the paper argues that this fact raises questions about the nature of
      the philosophical enterprise of developing a theory of reference.

PMID- 15019556
TI  - Assessing automaticity in audiovisual speech integration: evidence from the
      speeded classification task.
AB  - The McGurk effect is usually presented as an example of fast, automatic,
      multisensory integration. We report a series of experiments designed to directly
      assess these claims. We used a syllabic version of the speeded classification
      paradigm, whereby response latencies to the first (target) syllable of spoken
      word-like stimuli are slowed down when the second (irrelevant) syllable varies
      from trial to trial. This interference effect is interpreted as a failure of
      selective attention to filter out the irrelevant syllable. In Experiment 1 we
      reproduced the syllabic interference effect with bimodal stimuli containing
      auditory as well as visual lip movement information, thus confirming the
      generalizability of the phenomenon. In subsequent experiments we were able to
      produce (Experiment 2) and to eliminate (Experiment 3) syllabic interference by
      introducing 'illusory' (McGurk) audiovisual stimuli in the irrelevant syllable,
      suggesting that audiovisual integration occurs prior to attentional selection in
      this paradigm.

PMID- 15019557
TI  - Involvement of prolactin, vasopressin and opioids in post-ictal antinociception
      induced by electroshock in rats.
AB  - The neurochemical mechanisms involved in post-ictal antinociception remain to be
      elucidated. Application of electroconvulsive shock (ECS) to rats results in post
      ictal antinociception. The objective of this study was to identify endogenous
      substances that could participate in antinociception during post-ictal depression
      induced by ECS (70 mA, 60 Hz, 1 s). Antinociception was measured by the rat paw
      pressure test, in which increased sensitivity is induced by intraplantar
      injection of carrageenan. This test proved to be efficient in detecting the
      electroshock-induced antinociception. Intense post-ictal antinociception was
      observed over a period of 30 min after the end of the seizure. It was used
      nonspecific opioid and specific vasopressin antagonists and the prolactin (PRL)
      release inhibitor to test the reversal of antinociception. Administration of
      naloxone (5, 7.5 and 10 mg/kg) blocked the post-ictal antinociception. The V(1)
      (125 microg/kg) and V(2) (250 microg/kg) vasopressin receptor antagonists ([beta
      mercapto-beta,beta-cyclopentamethylenepropionyl(1),O-Et-Tyr(2),Val(4),Arg(8)]
      vasopressin and [adamantaneacetyl(1),O-Et-d-Tyr(2),Val(4),Abu(6),Arg(8,9)]
      vasopressin) also inhibited the nociceptive response. The antinociception
      blockade was more intense after administration of the V(1) receptor antagonist.
      Bromocriptine (4, 8 and 12 mg/kg) was able to reverse antinociception behavior
      during the post-ictal period. Morphine (1, 2 and 4 mg/kg), vasopressin (12.5, 100
      and 400 microg/kg) and prolactin (100, 200 and 400 microg/kg) administration
      promoted a higher nociceptive threshold. It was administered the three substances
      with their respective antagonists to verify the opioidergic pathway and
      vasopressin and prolactin release interactions, and as a positive control. We
      observed that the tested mediators were released in an independent manner,
      indicating no interference in which other.

PMID- 15019558
TI  - The novel antipsychotic aripiprazole is a partial agonist at short and long
      isoforms of D2 receptors linked to the regulation of adenylyl cyclase activity
      and prolactin release.
AB  - Aripiprazole is a novel antipsychotic with a unique mechanism of action, which
      differs from currently marketed typical and atypical antipsychotics. Aripiprazole
      has been shown to be a partial agonist at the D(2) family of dopamine (DA)
      receptors in biochemical and pharmacological studies. To demonstrate
      aripiprazole's action as a partial D(2) agonist in pituitary cells at the
      molecular level, we retrovirally transduced the short (D(2S)) and the long
      (D(2L)) form of the human DA D(2) receptor gene into a rat pituitary cell line,
      GH4C1. [(3)H]-raclopride saturation binding analyses revealed a B(max) value
      approximately four-fold higher at D(2S) receptor-expressing GH4C1 cells than at
      D(2L) receptor-expressing GH4C1 cells, while a K(d) value was similar.
      Aripiprazole inhibited forskolin-stimulated release of prolactin in both D(2S)
      and D(2L) receptor-expressing GH4C1 cells, whereas the maximal inhibition of
      prolactin release was less than that of DA. Similarly, aripiprazole partially
      inhibited forskolin-induced cAMP accumulation in both D(2) receptor-expressing
      cells. Aripiprazole antagonized the suppression attained by DA (10(-7) M) in both
      D(2) receptor-expressing cells and, at the maximal blockade of cAMP, yielded
      residual cAMP levels equal to those produced by aripiprazole alone. These results
      indicate that aripiprazole acts as a partial agonist at both D(2S) and D(2L)
      receptors expressed in GH4C1 cells. These data may explain, at least in part, the
      observations that aripiprazole shows a novel antipsychotic activity with minimal
      potential for adverse events including no significant increase of serum prolactin
      levels in clinical studies.

PMID- 15019559
TI  - Functional coupling of the nociceptin/orphanin FQ receptor in dog brain
      membranes.
AB  - Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ receptor
      (NOP) which is yet to be functionally characterized in dog brain. Ligand binding
      data reports low NOP density (29 fmol mg(-1) protein) in dog. In this study using
      dog brain membranes, we have examined the effects of N/OFQ on [leucyl
      (3)H]N/OFQ(1-17)OH ([leucyl-(3)H]N/OFQ) binding in the presence and absence of
      120 mM NaCl and 100 microM GTPgammaS. Data from standard [(35)S]GTPgammaS binding
      and immunoprecipitation (G(alphai1-3)) assays are also presented, along with data
      from a limited number of control experiments with human NOP expressed in Chinese
      hamster ovary (CHO(hNOP)) cells. N/OFQ displaced [leucyl-(3)H]N/OFQ binding with
      pK(i) and slope values of 9.62+/-0.07 and 0.38+/-0.05, respectively. Addition of
      NaCl/GTPgammaS produced a steepening (slope 0.95+/-0.06, n=3) of the curve. N/OFQ
      stimulated [(35)S]GTPgammaS binding with pEC(50) and E(max) values of 8.21+/-0.17
      and 1.17+/-0.01, respectively (in CHO(hNOP), pEC(50) and E(max) values were
      8.47+/-0.01 and 7.01+/-0.63). N/OFQ stimulated [(35)S]GTPgammaS binding in dog
      and CHO(hNOP) cell membranes could be immunoprecipitated with an anti-G(alphai1
      3) antibody, indicating coupling to a pertussis toxin (PTx)-sensitive G-protein.
      N/OFQ actions were competitively antagonized by the selective NOP antagonists,
      100 nM J-113397, 1 microM [Nphe(1)]N/OFQ(1-13)NH(2) and 1 microM [Phe(1)Psi(CH(2)
      NH)Gly(2)]N/OFQ(1-13)NH(2) (partial agonist) yielding pK(B) values of 8.58+/
      0.21, 7.06+/-0.59 and 7.32+/-0.41, respectively (in CHO(hNOP), a pK(B) for J
      113397 of 8.33+/-0.02 was obtained). Despite relatively low receptor density, we
      were able to detect functional activity of native dog NOP, with pharmacology
      consistent with reports for other species.

PMID- 15019560
TI  - Similar 1H magnetic resonance spectroscopic metabolic pattern in the medial
      temporal lobes of patients with mild cognitive impairment and Alzheimer disease.
AB  - Structures of the medial temporal lobes are recognized to play a central role in
      memory processing and to be the primary sites of deterioration in Alzheimer
      disease (AD). Mild cognitive impairment (MCI) represents potentially an
      intermediate state between normal aging and AD. Proton magnetic resonance
      spectroscopy (MRS) was used to examine brain metabolic changes in patients with
      AD and MCI in the medial temporal lobes (MTLs), parietotemporal cortices (PTCs)
      and prefrontal cortices (PFCs). Fourteen patients with MCI, 14 patients with mild
      AD and 14 age- and sex-matched control subjects were studied. Patients with AD
      and MCI demonstrated significant reductions of NAA/H(2)O and Cho/H(2)O in the
      left MTL relative to control subjects. Patients with AD showed mI/H(2)O increases
      relative to patients with MCI and control subjects in all six regions
      investigated, and a statistically significant mI/H(2)O increase was measured in
      the right PTC. Patients with AD and MCI demonstrated the same metabolic pattern
      in the left MTL, suggesting a similar pathological process underlying memory
      impairment. Increased mI signal appears to be a neurochemical abnormality
      associated mostly with AD and the dementia process. Some interhemispheric
      metabolite asymmetries were increased in AD patients.

PMID- 15019561
TI  - Swim posture of mice does not affect performance in the water maze.
AB  - We quantified swim postures of mice in relation to their cognitive performance.
      After training in a water maze, young (5-6 months) and aged (14-16 months) female
      apolipoprotein E-knockout (apoE0/0) mice and wild type controls were video taped
      while swimming. Subsequently, angles of body points with the water surface were
      calculated. Mice with a more horizontal swim posture (young and aged apoE0/0,
      aged wild type mice) also showed an increased body weight. However, swim posture
      was not related to cognitive performance.

PMID- 15019562
TI  - Pharmacological characterization of SIB-1663, a conformationally rigid analog of
      nicotine.
AB  - SIB-1663 ([+/-]-7-methoxy-2,3,3a,4,5,6,9b-hexahydro-1H-pyrrolo-[3,2h]
      isoquinoline) is a conformationally restricted analog of nicotine (NIC). SIB-1663
      exhibited modest affinities to cholinergic receptors (K(i) values displacing the
      binding of [(3)H]-nicotine (NIC) and [(3)H]-quinuclinidylbenzilate (QNB) binding
      were 1.0+/-0.3 and 2.6+/-0.3 microM, respectively) with no appreciable affinity
      to nearly 40 other receptors. SIB-1663 selectively activated alpha2beta4 and
      alpha4beta4 human recombinant neuronal nicotinic acetylcholine receptors (nAChRs)
      with no appreciable activation of alpha4beta2 nAChRs, the presumed high-affinity
      nAChRs in rodent brain. These properties led us to examine profile of SIB-1663 in
      native preparations. SIB-1663 increased DA release from the rat striatum (STR)
      and olfactory tubercles and NE release from hippocampus, thalamus and prefrontal
      cortex (PFC). SIB-1663 was equiefficacious to NIC in STR-DA and PFC-NE release
      assays and less efficacious than NIC in other release assays. SIB-1663 appeared
      to be partial agonist in the hippocampal NE release assay. SIB-1663-induced
      neurotransmitter release in vitro was relatively insensitive to the nAChR
      antagonists, mecamylamine (MEC) or dihydro-beta-erythroidine (DHbetaE) providing
      equivocal evidence for nAChR activity. SIB-1663 (3-30 mg/kg, s.c.) increased
      locomotor activity in naive rats in a novel environment, increased ipsilateral
      turning in rats with unilateral 6-OHDA nigrostriatal lesion and increased
      withdrawal latencies in the tail-flick assay. The in vivo effects of SIB-1663 in
      these assays showed varying degrees of sensitivity to nAChR antagonists in that
      the locomotor activity and turning behavior of SIB-1663 were partially sensitive
      to MEC, whereas the antinociceptive activity was completely sensitive to MEC. In
      addition, SIB-1663 (s.c. or i.c.v.) attenuated antinociceptive activity NIC given
      by the same route suggesting a partial agonist activity. SIB-1663 also increased
      the retention of avoidance learning in normal rats when administered immediately
      after the acquisition session. These data indicate that SIB-1663, a
      conformationally restricted analog of NIC, with distinct nAChR subtype
      selectivity from NIC exhibits contrasting pharmacology with some of its in vivo
      actions involving nAChRs.

PMID- 15019563
TI  - Morphological differences between planes of section do not influence the
      electrophysiological properties of identified rat dorsal motor nucleus of the
      vagus neurons.
AB  - Recent cytoarchitectonic studies have shown that the dorsal motor nucleus of the
      vagus (DMV) comprises neurons with different morphological features. Our own
      studies, conducted in horizontal brainstem slices, have shown that DMV neurons
      projecting to stomach areas can be distinguished from neurons projecting to the
      intestine on the basis of their electrophysiological as well as morphological
      properties. The majority of the in vitro experimental investigations, however,
      have been conducted on coronal brainstem slices. The aim of the present study was
      to assess whether the electrophysiological properties of DMV neurons are due to
      intrinsic membrane properties of the neurons or are dependent upon the plane of
      section, i.e., coronal vs. horizontal, in which the brainstem is cut. The
      fluorescent retrograde tracer DiI was applied to either the stomach or intestine
      of rats. Whole cell recordings were subsequently made from labeled DMV neurons in
      thin brainstem slices sectioned in either the horizontal or coronal plane. In the
      horizontal plane, both the somata and the dendritic tree of gastric-projecting
      neurons were smaller than intestinal-projecting neurons. In the coronal plane,
      however, apart from a smaller soma diameter in gastric-projecting neurons,
      morphological differences were not found between the groups. The
      electrophysiological differences observed between the groups were, however,
      consistent in both planes of section, that is, intestinal-projecting neurons had
      larger and longer afterhyperpolarization (AHP) as well as slower frequency
      responses to depolarizing stimuli than gastric-projecting neurons. Our data
      suggest that intrinsic rather than morphological features govern the
      electrophysiological characteristics of DMV neurons.

PMID- 15019564
TI  - Evidence for the involvement of metabotropic glutamatergic, neurokinin 1 receptor
      pathways and protein kinase C in the antinociceptive effect of dipyrone in mice.
AB  - This study aimed to investigate further the mechanisms involved in the
      antinociception caused by dipyrone, given by intraperitoneal (i.p.) or
      intrathecal (i.t.) routes. The intraperitoneal administration of dipyrone to mice
      30 min prior resulted in a significant and dose-related inhibition of the biting
      responses induced by i.t. injection of glutamate, trans-ACPD or substance P (SP).
      In addition, dipyrone given by i.t. route, 15 min before glutamate, trans-ACPD or
      SP, also produced a significant reduction in their nociceptive effects. In
      addition, dipyrone given by i.t. route, 15 min before glutamate, trans-ACPD or
      SP, also produced a significant reduction in their nociceptive effects. Dipyrone,
      given either systemically (i.p.) or by i.t. route also caused a dose-dependent
      inhibition of phorbol myristate acetate (PMA)-induced nociception. Given by
      systemic route, dipyrone inhibited PMA-induced paw oedema formation.
      Collectively, these results extend previous data from our group indicating that
      glutamatergic-mediated pain responses, specifically those mediated by
      metabotropic receptor subtype, together with inhibition of neurokinin NK(1)
      mediated response, account for the antinociceptive action of dipyrone in mice.
      Furthermore, we have also produced experimental evidence indicating that the
      activation of the protein kinase C-dependent pathway plays a role in the dipyrone
      antinociceptive action.

PMID- 15019565
TI  - Exercise-induced changes of motor excitability with and without sensory block.
AB  - To explore interactions between the sensory and motor system, we investigated
      motor excitability changes following a motor exercise with and without an
      anesthetic block of cutaneous inputs overlying the target muscle. Transcranial
      magnetic stimulation (TMS) with a focal coil was applied to determine motor
      output maps, intracortical inhibition (ICI) and intracortical facilitation (ICF)
      of the first dorsal interosseous muscle (FDI) on both sides. Twelve subjects
      performed phasic right index finger adductions (frequency: 0.333 Hz) for 30 min.
      TMS measurements were performed before and after the motor task (Experiment 1).
      In Experiment 2, median and radial nerve were blocked with Ropivacaine injections
      at the right wrist prior to the motor exercise. TMS was applied before and after
      induction of anesthesia and after exercise. In Experiment 3, the same anesthetic
      block was applied and TMS was performed before and after induction of anesthesia
      and after additional 30 min of rest. In Experiment 1, right FDI motor output area
      was enlarged, its center of gravity moved posteriorly, and ICI was reduced after
      the exercise. In Experiment 2, anesthesia was associated with a shrinkage of
      right FDI motor output area. After exercise, right FDI motor output area enlarged
      again but was still significantly smaller than pre-anesthesia. In both
      experiments, TMS results of left FDI remained unchanged. In Experiment 3, the
      anesthesia-induced decrease of right FDI motor output area remained unchanged
      after the period of rest. We conclude that a simple motor task enhanced the
      cortical representation of the target muscle and reduced intracortical
      inhibition. An impairment of cutaneous afferents decreased the cortical
      representation of the target muscle. The decrease of motor excitability induced
      by the sensory deficit could only partially be reversed by the motor exercise.

PMID- 15019566
TI  - Nociceptive spinal neurons expressing NK1 and GABAB receptors are located in
      lamina I.
AB  - The nociceptive nature of spinal dorsal horn neurons expressing NK1 and gamma
      aminobutyric acid (GABA)(B) receptors was evaluated in the rat. Immunodetection
      of the Fos protein, induced by noxious mechanical stimulation of the skin, was
      combined with immunocytochemistry for NK1 or GABA(B) receptors (double
      immunostaining study) or both receptors (triple-immunostaining study). Neurons
      double-labeled for Fos and for each receptor largely prevailed in lamina I. The
      proportions of Fos-positive cells immunostained for NK1 or GABA(B) receptors were
      higher in lamina I than in the remaining spinal laminae. More Fos-positive cells
      were immunoreactive (IR) for GABA(B) receptors than for NK1 in all dorsal horn
      laminae. In the triple-immunostaining study, co-localization of NK1 and GABA(B)
      receptors occurred only in lamina I and was higher in neurons expressing Fos. As
      to the morphological lamina I cell class, NK1-positive cells belonged mainly to
      the fusiform type while similar proportions of fusiform, pyramidal and flattened
      NK1 neurons expressed GABA(B) receptors. No differences were found between those
      cell types as to the degree of nociceptive activation. The present results
      suggest that the co-localization of NK1 and GABA(B) receptors is a common feature
      of fusiform, pyramidal and flattened neurons in lamina I. Considering the
      participation of the three cell classes in various ascending systems, it is
      concluded that a simultaneous action of substance P (SP) and GABA may play an
      important role in the modulation of nociceptive input supraspinally transmitted
      from lamina I.

PMID- 15019567
TI  - Inhibition of mixed lineage kinase 3 attenuates MPP+-induced neurotoxicity in SH
      SY5Y cells.
AB  - The neuropathology of Parkinson's Disease has been modeled in experimental
      animals following MPTP treatment and in dopaminergic cells in culture treated
      with the MPTP neurotoxic metabolite, MPP(+). MPTP through MPP(+) activates the
      stress-activated c-Jun N-terminal kinase (JNK) pathway in mice and SH-SY5Y
      neuroblastoma cells. Recently, it was demonstrated that CEP-1347/KT7515
      attenuated MPTP-induced nigrostriatal dopaminergic neuron degeneration in mice,
      as well as MPTP-induced JNK phosphorylation. Presumably, CEP-1347 acts through
      inhibition of at least one upstream kinase within the mixed lineage kinase (MLK)
      family since it has been shown to inhibit MLK 1, 2 and 3 in vitro. Activation of
      the MLK family leads to JNK activation. In this study, the potential role of MLK
      and the JNK pathway was examined in MPP(+)-induced cell death of differentiated
      SH-SY5Y cells using CEP-1347 as a pharmacological probe and dominant negative
      adenoviral constructs to MLKs. CEP-1347 inhibited MPP(+)-induced cell death and
      the morphological features of apoptosis. CEP-1347 also prevented MPP(+)-induced
      JNK activation in SH-SY5Y cells. Endogenous MLK 3 expression was demonstrated in
      SH-SY5Y cells through protein levels and RT-PCR. Adenoviral infection of SH-SY5Y
      cells with a dominant negative MLK 3 construct attenuated the MPP(+)-mediated
      increase in activated JNK levels and inhibited neuronal death following MPP(+)
      addition compared to cultures infected with a control construct. Adenoviral
      dominant negative constructs of two other MLK family members (MLK 2 and DLK) did
      not protect against MPP(+)-induced cell death. These studies show that inhibition
      of the MLK 3/JNK pathway attenuates MPP(+)-mediated SH-SY5Y cell death in culture
      and supports the mechanism of action of CEP-1347 as an MLK family inhibitor.

PMID- 15019569
TI  - Stress and anxious-related behaviors in Lurcher mutant mice.
AB  - Blood corticosterone levels (CORT) were measured before and after the completion
      of the elevated +-maze test in cerebellar Lurcher mutant and control mice.
      Consistent with the existence of a much more pronounced activation of the
      hypothalamo-pituitary-adrenal (HPA) system in the mutants, our results showed
      that while basal CORT were similar in mutants and controls, the surge of this
      stress indicator was enhanced in the Lurcher mice after completion of a
      behavioral test of anxiety. In contrast, at the behavioral level, we also
      observed that Lurcher exhibited significantly reduced anxiety related indices;
      they spent a significant greater amount of time in the aversive places of the
      apparatus and entered them more frequently than non mutant mice. It is proposed
      that rather than less anxious, the Lurcher mice are less inhibited than controls
      when placed in anxiogenic situation and that such poor inhibition could be
      causally related to changes in HPA system regulation. The overall patterns of our
      behavioral and endocrinological results thereby provided the evidence that
      cerebellar circuitry is involved in producing changes in physiological and
      behavioral stress-related emotional responses.

PMID- 15019568
TI  - GABAA, not GABAB, receptor shows subunit- and spatial-specific alterations in the
      hippocampus of seizure prone gerbils.
AB  - In the present study, we investigated site-specific expressions of GABA(A) and
      GABA(B) receptor subunits in the seizure-sensitive (SS) and seizure-resistant
      (SR) gerbil hippocampus to elucidate the function of the gamma-aminobutyric acid
      (GABA) receptor in seizure activity in this animal. There were no differences of
      the immunoreactivities of GABA(B) receptor and some GABA(A) receptor subunits
      (alpha3, alpha4, pan beta and delta) in the hippocampus between SR and SS
      gerbils. The alpha1 subunit expression was mainly detected in interneurons of
      stratum radiatum and hilar region of dentate gyrus in the SR gerbil. However, in
      SS gerbil, interneurons were nearly devoid of alpha1 subunit immunoreactivity and
      mainly detected in the molecular layer of dentate gyrus. In SR gerbil, alpha2
      subunit immunoreactivity was detected in Ammon's horn, particularly in the CA2
      region. In SS gerbil, granule cell layer of the dentate gyrus in SS gerbil showed
      strong alpha2 subunit immunoreactivity. The distribution of alpha5 and gamma2
      subunit immunoreactivity in the hippocampus was similarly detected in SR and SS
      gerbil. However, alpha5 immunodensity of SR gerbil was slightly lower than that
      of SS gerbil in CA1 region and was slightly strong than that of SS gerbil in
      subiculum. These differences in distribution of GABA(A) receptor, not GABA(B)
      receptor, in the SR and SS gerbil hippocampus may indicate that abnormal
      hyperactive neuronal discharges are occurred in SS gerbil, which presumably
      result in spontaneous and repetitive seizure activity in this animal.

PMID- 15019570
TI  - Direct projections from caudal ventrolateral medullary depressor sites to the
      subfornical organ.
AB  - Experiments were performed in the male Wistar rat to investigate the projections
      from cardiovascular responsive sites in the ventrolateral medulla (VLM) to the
      subfornical organ (SFO). Unilateral iontophoretic injections of Phaseolus
      vulgaris leucoagglutinin (PHA-L) were made into either caudal VLM (CVLM) sites at
      which microinjection of l-glutamate (10 nl; 0.25 M) elicited decreases in mean
      arterial pressure or into rostral VLM (RVLM) sites at which l-glutamate
      microinjection elicited increases in arterial pressure. After a survival period
      of 7-10 days, transverse sections of the forebrain and brainstem were processed
      for PHA-L immunoreactivity. After injections of PHA-L into the CVLM, axonal and
      presumptive terminal labeling was found bilaterally throughout the rostrocaudal
      extent of the SFO, although most of the projections were observed within the
      rostral half of the nucleus. Within the SFO, labeling was found primarily in the
      lateral aspects of the nucleus, often in close proximity to blood vessels. In
      addition, CVLM injections resulted in labeling within the organum vasculosum of
      the laminae terminalis (OVLT) and within the ventral and dorsal components of the
      median preoptic nucleus (MnPO) bilaterally, but with an ipsilateral predominance.
      In contrast, PHA-L injections into the RVLM did not result in axonal labeling in
      the SFO or OVLT, although a few labeled axons were found to course through the
      region of the ventral component of MnPO. These data have demonstrated that
      neurons within the cardiovascular responsive region of the CVLM send direct
      axonal projections to the SFO and other structures of the laminae terminalis, and
      suggest that the CVLM may function in the modulation of the activity of neurons
      of circumventricular organs to intra- and extracellular signals of body fluid
      balance.

PMID- 15019571
TI  - Hypothermia-induced changes of afferent sensory transmission to the VPM thalamus
      of rats and hamsters.
AB  - Effects of hypothermia on the afferent somatosensory transmission to the
      ventroposteromedial (VPM) thalamus were determined in anesthetized rats and
      hamsters. Hamsters showed a gradual suppression of afferent sensory transmission
      during cooling (to 18 degrees C) and disinhibition during subsequent warming of
      body temperature (Tb). However, rats exhibited steep inhibition from Tb 26
      degrees C to complete absence of sensory transmission at Tb 20 degrees C and
      abrupt disinhibition during subsequent warming. Species difference at thalamic
      level was quite similar to our previous results in the primary somatosensory (SI)
      cortex, suggesting that changes of sensory transmission observed in the SI cortex
      may have already occurred at thalamic level. Differences between the cortex and
      the thalamus were observed only during deep hypothermia in rat and during the
      final period of warming in hamster. Conduction latencies of thalamocortical
      system of both species were not influenced during Tb lowering until 24 degrees C
      (equivalent to brain temperature 25-26 degrees C). These results suggest
      inherently different adaptability to hypothermia in processing somatosensory
      information between hibernator and non-hibernator, but similar sustainability of
      sensory functions of the thalamocortical system during hypothermia in both
      species.

PMID- 15019572
TI  - Bunazosin hydrochloride reduces glutamate-induced neurotoxicity in rat primary
      retinal cultures.
AB  - To study neuroprotective effects of bunazosin hydrochloride which is an alpha(1)
      adrenoceptor antagonist used as an ocular hypotensive drug compared to other
      alpha(1)-adrenoceptor antagonists, and its mechanism of action. We evaluated the
      neuroprotective effects of bunazosin hydrochloride or seven other alpha(1)
      adrenoceptor antagonists against glutamate-induced cell death in rat primary
      retinal cultures. We also evaluated the binding inhibition of bunazosin
      hydrochloride for 24 different receptors/channels and its effects on the Na(+)
      influx into cells induced by veratridine or glutamate. Bunazosin hydrochloride
      significantly inhibited glutamate-induced cell death at concentrations of 1 and
      10 microM. Cells were also protected when treated with some alpha(1)-adrenoceptor
      antagonists, but not by the others. Bunazosin hydrochloride showed a high
      inhibition for Na(+) channels and inhibited the Na(+) influx induced by
      veratridine or glutamate. These findings indicate that in retinal cultures
      bunazosin hydrochloride has a neuroprotective effect against glutamate-induced
      cell death and that the inhibition of Na(+) channels by bunazosin hydrochloride
      may be partly responsible for this effect.

PMID- 15019573
TI  - Interhemispheric involvement of the anterior cortical nuclei of the amygdala in
      rewarding brain stimulation.
AB  - The amygdaloid complex is one of the structures thought to modulate brain
      stimulation reward (BSR) elicited from the median forebrain bundle (MFB).
      Previous metabolic and behavioral data from our laboratory point to the
      amygdaloid cortical nuclei as key to this process. In this study, thresholds for
      rewarding stimulation of the MFB were determined for 42 days, 21 days following
      an electrolytic lesion to amygdaloid nuclei ipsilateral to the stimulation
      electrode, and 21 days following one applied to the contralateral amygdala. A
      subset of animals showed post-lesion changes in MFB frequency thresholds that
      were maintained if not augmented after the second lesion. These ranged from 26%
      to 150% compared to baseline values, among the largest ever reported to our
      knowledge. Interestingly, damage to anterior sites within the cortical nuclei was
      the most effective in producing modifications to the rewarding value of the
      stimulation. Equally singular was the finding that contralateral lesions tended
      to alter thresholds more than ipsilateral ones, confirming our earlier finding of
      interhemispheric connectivity in amygdaloid modulation of MFB reward signals.
      This interpretation was substantiated by tracking long-term metabolic activity in
      the amygdala using cytochrome oxidase histochemistry. The density of reaction
      product at damaged amygdala sites was negatively correlated (r=-0.90) with the
      increases in thresholds obtained at contralateral MFB loci. Together with the
      fact that such large lesion effects are seldom obtained, our metabolic results
      point to the existence of a relationship between these nuclei and reward signals
      generated at the MFB. Moreover, our data suggest that this communication takes
      place interhemispherically.

PMID- 15019575
TI  - Differential effects of ibogaine on local cerebral glucose utilization in drug
      naive and morphine-dependent rats.
AB  - Ibogaine, a hallucinogenic indole alkaloid, has been proposed as a treatment for
      addiction to opioids and other drugs of abuse. The mechanism for its putative
      anti-addictive effects is unknown. In this study, the effects of ibogaine on
      local cerebral glucose utilization (LCGU) were determined in freely moving, drug
      naive, or morphine-dependent adult, male, Sprague-Dawley rats using the [(14)C]2
      deoxyglucose (2-DG) method. Morphine-dependent rats were treated with increasing
      doses of morphine (5-25 mg/kg, s.c., b.i.d.) and then maintained at 25 mg/kg
      (b.i.d.) for 4-7 days. For the 2-DG procedure, rats were injected with saline or
      ibogaine (40 mg/kg, i.p.). 2-DG was administered 1 h after administration of
      ibogaine. The rate of LCGU was determined by quantitative autoradiography in 46
      brain regions. In drug-naive animals, ibogaine produced significant increases in
      LCGU in the parietal, cingulate, and occipital cortices and cerebellum compared
      to controls consistent with its activity as a hallucinogen and a tremorogen.
      Morphine-dependent rats had only minor alterations in LCGU at the time assessed
      in this experiment. However, in morphine-dependent animals, ibogaine produced a
      global decrease in LCGU that was greatest in brain regions such as the lateral
      and medial preoptic areas, nucleus of the diagonal band, nucleus accumbens shell,
      inferior colliculus, locus coeruleus, and flocculus compared to morphine
      dependent animals treated with saline. These findings indicate that ibogaine
      produces distinctly different effects on LCGU in drug-naive and morphine
      dependent rats. This suggests that different mechanisms may underlie ibogaine's
      hallucinogenic and anti-addictive effects.

PMID- 15019574
TI  - Differential MnSOD and HO-1 expression in cerebral endothelial cells in response
      to sublethal oxidative stress.
AB  - The two inducible enzymes, manganese superoxide dismutase (MnSOD) and heme
      oxygenase-1 (HO-1) may participate in the cellular defense of brain endothelium
      against oxidative stress. The time-dependent expression of MnSOD and HO-1 mRNAs
      and proteins was investigated in vitro in rat cerebral endothelial cells (CEC)
      subjected to sublethal mild or moderate hydroxyl radical-induced oxidative
      stress. Mild oxidative stress induced increases in both MnSOD and HO-1 mRNA and
      protein expression. Moderate oxidative stress resulted in a significant reduction
      in HO-1 mRNA and protein expression, whereas MnSOD expression pattern was similar
      to that observed after mild oxidative stress. A profound protein loss of both
      MnSOD and HO-1 was detected 24 h after exposure of CEC to a moderate oxidative
      stress. The data indicate that cerebral endothelial cells respond by increasing
      the expression of antioxidant defense enzymes in a manner dependent on the
      oxidative stress intensity.

PMID- 15019577
TI  - Differential effects of midazolam on inhibitory postsynaptic currents in CA1
      pyramidal cells and dentate gyrus granule cells of rat hippocampal slices.
AB  - To examine regional differences of synaptic transmission, the effects of
      midazolam were observed on inhibitory postsynaptic currents (IPSCs) in CA1
      pyramidal cells (CA1-PCs) and dentate gyrus granule cells (DG-GCs) in rat
      hippocampal slices. Midazolam is one of the most popular benzodiazepines. The
      monosynaptic IPSCs in the CA1-PCs and DG-GCs were evoked by electrical
      stimulation of GABAergic interneurons and recorded by whole cell patch-clamp
      techniques. The effects of specific concentrations of midazolam (0.3, 1, 10 and
      75 microM) on the IPSCs in CA1-PCs and DG-GCs were examined at particular
      membrane potentials (20 mV steps, from -120 to +40 mV). In all midazolam
      concentrations tested, the conductance of the IPSCs was significantly larger than
      that in control and was increased by increasing the concentration of midazolam in
      CA1-PCs (normalized conductance, 0.3 microM, 121%; 1 microM, 125%; 10 microM,
      147%; 75 microM, 147%). However, midazolam did not significantly change the
      conductance of the IPSCs in DG-GCs (normalized conductance, 0.3 microM, 92%; 1
      microM, 92%; 10 microM, 91%; 75 microM, 115%). The normalized conductance was
      significantly different between the CA1-PCs and DG-GCs in 1 and 10 microM
      midazolam. The results strongly suggest that the differential effects of
      midazolam on IPSCs in CA1-PCs and DG-GCs could be, at least in part, due to the
      different sensitivity to midazolam of the GABA(A) receptor subtypes.

PMID- 15019576
TI  - Cellular mechanisms of serotonin 5-HT2A receptor-mediated cGMP formation: the
      essential role of glutamate.
AB  - The current study explores the mechanisms by which activation of serotonin(2A) (5
      HT(2A)) receptors increase production of cyclic guanosine monophosphate (cGMP) in
      slices of rat frontal cortex. Contrary to results in cortical slices, stimulation
      of 5-HT(2A) receptors in cells stably expressing this serotonin receptor did not
      alter cGMP levels. In cortical slices, stimulation of cGMP formation by 2,5
      dimethoxy-4-methylamphetamine (DOM), a 5-HT(2A/2C) receptor agonist, was blocked
      by tetanus toxin, a substance that prevents vesicular neurotransmitter release.
      However, this stimulation was not altered by tetrodotoxin, an agent that inhibits
      depolarization-induced neurotransmitter release. Addition of an N-methyl-d
      aspartate (NMDA) receptor antagonist, d-AP-7, but not of an AMPA/kainate receptor
      antagonist CNQX, completely inhibited DOM-mediated cGMP production in the slices.
      Combined application of maximally effective concentrations of NMDA and DOM
      elicited a greater increase in cGMP content than either drug alone. The present
      study shows that 5-HT(2A) receptors do not directly stimulate cGMP formation, but
      rather that 5-HT(2A) receptor-mediated cGMP production is dependent on
      extracellular glutamate activating NMDA receptors. The results indicate that 5
      HT(2A) receptor-mediated cGMP production could be at least partially attributed
      to potentiation of NMDA receptor-mediated cGMP formation.

PMID- 15019579
TI  - Paradoxical sleep deprivation potentiates amphetamine-induced behavioural
      sensitization by increasing its conditioned component.
AB  - The effects of paradoxical sleep deprivation (PSD-48 h) on the conditioned and
      unconditioned components of behavioural sensitization to amphetamine (two
      injections of 2.0 mg/kg, separated by 7 days) were studied using locomotion
      frequency of mice observed in an open-field as experimental parameter.
      Behavioural sensitization only occurred in PS deprived mice that were exposed to
      the open-field after the first amphetamine injection. The possible involvement of
      PSD in the development of a Pavlovian association between the stimulant effect of
      amphetamine and environmental as well as interoceptive drug cues is discussed.

PMID- 15019578
TI  - Peripheral inflammation increases phosphoinositide activity in the rat dorsal
      horn.
AB  - Persistent pain leads to changes in the spinal cord that contribute to
      hyperalgesia and allodynia. The effort to characterize these changes has focused
      on neurotransmitters and receptors, while relatively little is known about pain
      associated modulation of second-messenger responses. Nearly all neurotransmitters
      can activate the phosphoinositide (PI) second-messenger system which has been
      investigated using a method that localizes membrane-bound [(3)H]CDP
      diacylglycerol (DAG) produced from the precursor [(3)H]cytidine [Science 249
      (1990) 802]. The present study applied this method in spinal cord slices from
      rats injected with complete Freund's adjuvant in one hindpaw and from uninflamed
      control rats. Two days after the injection, slices were removed and maintained in
      vitro for pharmacological testing. Some slices were exposed to the acetylcholine
      agonist carbachol which is antinociceptive in the spinal cord. Inflammation
      resulted in increased baseline, unstimulated [(3)H]CDP-DAG accumulation,
      especially in superficial dorsal horn layers, as well as enhanced carbachol
      stimulated labeling. These results suggest that persistent pain leads to
      neurochemical changes within the spinal cord that could potentially enhance
      responses to a spectrum of pain-modulating transmitters.

PMID- 15019580
TI  - Kindling of the ventral tegmental area induces supersensitivity in the central
      dopamine system.
AB  - Kindling of the ventral tegmental area (VTA), a major source of the mesolimbic
      dopamine pathway, was examined in rats. We applied two quantitative measurements
      of dopamine sensitivity before and 2 weeks after VTA kindling (20 times
      electrical stimulations (100 microA at 1 min intervals) delivered once per day
      for 14 consecutive days): behavioral responses induced by test VTA stimulation
      and methamphetamine (MAP)-induced locomotor activity. The total amount of MAP
      induced locomotor activity was significantly increased after VTA kindling, while
      the responses to electrical stimulation were unchanged. These results indicate
      that repeated activation of the mesolimbic dopamine system can produce a
      neuroplastic change, which results in dopamine supersensitivity.

PMID- 15019583
TI  - 2004: MEEGID VII and the year of Infection, Genetics and Evolution.

PMID- 15019581
TI  - Reactive astrocytes express PARP in the central nervous system of SOD(G93A)
      transgenic mice.
AB  - In the present study, we used the transgenic mice expressing a human Cu/Zn SOD
      mutation (SOD1(G93A)) as an in vivo model of amyotrophic lateral sclerosis (ALS)
      and performed immunohistochemical studies to investigate the changes of poly(ADP
      ribose) polymerase (PARP) in the central nervous system. In the spinal cord of
      symptomatic transgenic mice, immunohistochemistry showed intensely stained PARP
      immunoreactive glial cells with the appearance of astrocytes, which were
      confirmed as astrocytes by double-immunofluorescences. In the brainstem and
      cerebellum, PARP-immunoreactive astrocytes were observed in the medullary and
      pontine reticular formation, hypoglossal nucleus, vestibular nucleus, cochlear
      nucleus and cerebellar nuclei. On the contrary, no PARP-immunoreactive glial
      cells were observed in control mice although PARP-immunoreactive motor neurons
      were found. In presymptomatic transgenic mice, a few moderately stained neurons
      were observed, whereas PARP-immunoreactive astrocytes were not detected. The
      present study provides the first evidence that PARP-immunoreactive astrocytes
      were found in the central nervous system of symptomatic SOD1(G93A) transgenic
      mice, suggesting that reactive astrocytes may play an important role in the
      pathogenesis and progress of ALS.

PMID- 15019582
TI  - A patch-clamp investigation of membrane currents in a novel mammalian retinal
      ganglion cell line.
AB  - We characterised membrane currents in undifferentiated RGC-5 cells, a cell line
      used in in vitro models of apoptosis and glaucoma. The cells were inexcitable,
      with no voltage-dependent Na(+) currents or action potentials. Some novel
      currents were observed including basal Cl(-) currents, inwardly rectifiying K(+)
      currents and Gd(3+) insensitive stretch-activated currents. Our results highlight
      the differences between the electrophysiological properties of undifferentiated
      RGC-5 cells and retinal ganglion cells.

PMID- 15019584
TI  - Phylogenetic reconstruction of Mycobacterium tuberculosis within four settings of
      the Caribbean region: tree comparative analyse and first appraisal on their
      phylogeography.
AB  - In order to compare phylogenetic methods and to reconstruct the evolutionary
      history of the tubercle bacilli, a set of macro-array-based genotyping data of
      Mycobacterium tuberculosis clinical isolates (called spoligotyping for spacer
      oligonucleotide typing, which assays the variability of the Direct Repeat -DR-
      locus), was analyzed in four settings of the Caribbean region (Guadeloupe,
      Martinique, Cuba and Haiti). A set of 47 alleles, split into 26 shared and 21
      unique alleles) representative of 321 individual M. tuberculosis clinical
      isolates from patients residing in the above regions was studied. The following
      methods (and software in brackets) were investigated: numerical taxonomy distance
      methods (TAXOTRON), maximum parsimony procedure (PAUP), median-joining networks
      (NETWORK), and nested clade analysis (GEODIS). Results using these methods were
      analyzed, compared and discussed. The latter method (GEODIS) was investigated in
      detail by introducing geographical data together with genetic variability results
      to detect a link between population structure and population history, and to test
      the null hypothesis of no association between geography and genotypes.
      Irrespective of the methods used, our findings demonstrate that a core structure
      of four families (or clades) of M. tuberculosis strains is highly prevalent
      within the islands studied, indirectly reflecting passed colonization history of
      these different settings. Specificity of M. tuberculosis genotypes in each of the
      islands is discussed in the light of their respective colonial and contemporary
      histories.

PMID- 15019585
TI  - Evidence from the evolutionary analysis of nucleotide sequences for a recombinant
      history of SARS-CoV.
AB  - The origins and evolutionary history of the Severe Acute Respiratory Syndrome
      (SARS) coronavirus (SARS-CoV) remain an issue of uncertainty and debate. Based on
      evolutionary analyses of coronavirus DNA sequences, encompassing an approximately
      13kb stretch of the SARS-TOR2 genome, we provide evidence that SARS-CoV has a
      recombinant history with lineages of types I and III coronavirus. We identified a
      minimum of five recombinant regions ranging from 83 to 863bp in length and
      including the polymerase, nsp9, nsp10, and nsp14. Our results are consistent with
      a hypothesis of viral host jumping events, concomitant with the reassortment of
      bird and mammalian coronaviruses, a scenario analogous to earlier outbreaks of
      influenzae.

PMID- 15019586
TI  - Comparative proteomics of the Mycobacterium leprae binding protein myelin P0: its
      implication in leprosy and other neurodegenerative diseases.
AB  - Mycobacterium leprae, the causative agent of leprosy invades Schwann cells of the
      peripheral nerves leading to nerve damage and disfigurement, which is the
      hallmark of the disease. Wet experiments have shown that M. leprae binds to a
      major peripheral nerve protein, the myelin P zero (P0). This protein is specific
      to peripheral nerve and may be important in the initial step of M. leprae binding
      and invasion of Schwann cells which is the feature of leprosy. Though the
      receptors on Schawann cells, cytokines, chemokines and antibodies to M. leprae
      have been identified the molecular mechanism of nerve damage and
      neurodegeneration is not clearly defined. Recently pathogen and host
      protein/nucleotide sequence similarities (molecular mimicry) have been implicated
      in neurodegenerative diseases. The approach of the present study is to utilise
      bioinformatic tools to understand leprosy nerve damage by carrying out sequence
      and structural similarity searches of myelin P0 with leproma and other genomic
      database. Since myelin P0 is unique to peripheral nerve, its sequence and
      structural similarities in other neuropathogens have also been noted. Comparison
      of myelin P0 with the M. leprae proteins revealed two characterised proteins,
      Ferrodoxin NADP reductase and a conserved membrane protein, which showed
      similarity to the query sequence. Comparison with the entire genomic database
      (www.ncbi.nlm.nih.gov) by basic local alignment search tool for proteins (BLASTP)
      and fold classification of structure-structure alignment of proteins (FSSP)
      searches revealed that myelin P0 had sequence/structural similarities to the
      poliovirus receptor, coxsackie-adenovirus receptor, anthrax protective antigen,
      diphtheria toxin, herpes simplex virus, HIV gag-1 peptide, and gp120 among
      others. These proteins are known to be associated directly or indirectly with
      neruodegeneration. Sequence and structural similarities to the immunoglobin
      regions of myelin P0 could have implications in host-pathogen interactions, as it
      has homophilic adhesive properties. Although these observed similarities are not
      highly significant in their percentage identity, they could be functionally
      important in molecular mimicry, receptor binding and cell signaling events
      involved in neurodegeneration.

PMID- 15019587
TI  - Identification of trypanosomes in Glossina pallidipes and G. longipennis in
      Kenya.
AB  - The polymerase chain reaction (PCR) was used to identify trypanosomes in Glossina
      pallidipes and G. longipennis caught in Kenya. Of 3826 flies dissected, 188
      (4.9%) were parasitologically positive overall. The infection rate in G.
      pallidipes was 5.7% (187 of 3301 flies), but only one of 525 G. longipennis was
      infected (infection rate 0.2%). There was a higher infection rate in female G.
      pallidipes flies than male flies (chi(2) = 18.5, P < 0.001) and odds ratio = 2.5
      (95% 1.6, 3.7). The infected flies were analysed by PCR using 10 sets of primers
      specific for species and subgroups within the subgenera Nannomonas, Trypanozoon
      and Duttonella. Of 188 parasitologically positive samples, PCR identified 137
      (72.9%), leaving 51 (27.1%) non-identified. We recorded infection rates of 47.2%
      for Trypanosoma congolense savannah, forest and kilifi subgroups, 20.9% for T.
      simiae/T. simiae tsavo/T. godfreyi, 14.9% for T. brucei ssp. and 13.8% for T.
      vivax. Thirty-nine (26.7%) flies had mixed infections, with a minor association
      between T. congolense savannah/T. simiae tsavo/T. godfreyi (chi(2) = 6.93, d.f. =
      1, P < 0.05). The relative proportion of each trypanosome species or subgroup
      varied between fly belts with T. congolense (all subgroups) being the most
      abundant and T. godfreyi the least. Statistical analysis showed that dissection
      method and PCR test classified infections independently (chi(2) = 10.5, d.f. = 1,
      P < 0.05 and kappa = 0.38). This study shows that pathogenic trypanosomes are
      widespread in all sampled testes fly belts with G. pallidipes as the main vector.
      Further, PCR test is more reliable in detecting and identifying trypanosomes than
      dissection method.

PMID- 15019588
TI  - Evidence for aneuploidy and recombination in the human commensal yeast Candida
      parapsilosis.
AB  - Isolates of Candida parapsilosis, including representatives of the three major
      sub-species groups, were screened for single nucleotide polymorphisms (SNPs) by
      sequencing five independent loci totaling 4kb per isolate. Group I isolates were
      highly conserved and in some cases, group I alleles were found in group II and
      III strains. Unique alleles were also associated with groups II and III,
      consistent with earlier observations of intergroup divergence. There was no
      heterozygosity in any strain, and a FACS analysis demonstrated that for all three
      groups nuclei are variant in size, ranging from 0.5 to 1.0 x the size of other
      diploid yeast genomes. This suggests that natural isolates of C. parapsilosis are
      aneuploid, with some isolates being essentially haploid. Taken collectively with
      the observation of group I alleles within group II and III strains, we propose
      that some form of recombination is occurring between groups.

PMID- 15019589
TI  - A phylogenetic reconstruction of the epidemiological history of canine rabies
      virus variants in Colombia.
AB  - Historically, canine rabies in Colombia has been caused by two geographically
      distinct canine variants of rabies virus (RV) which between 1992 and 2002
      accounted for approximately 95% of Colombian rabies cases. Genetic variant 1
      (GV1) has been isolated up until 1997 in the Central Region and the Department of
      Arauca, and is now considered extinct through a successful vaccination program.
      Genetic variant 2 (GV2) has been isolated from the northern Caribbean Region and
      continues to circulate at present. Here we have analyzed two sets of sequence
      data based upon either a 147 nucleotide region of the glycoprotein (G) gene or a
      258 nucleotide region that combines a fragment of the non-coding intergenic
      region and a fragment of the polymerase gene. Using both maximum likelihood (ML)
      and Markov chain Monte Carlo (MCMC) methods we have estimated the time of the
      most recent common ancestor (MRCA) of the two variants to be between 1983 and
      1988. Reconstructions of the population history suggest that GV2 has been
      circulating in Colombia since the 1960s and that GV1 evolved as a separate
      lineage from GV2. Estimations of the effective population size at present show
      the GV2 outbreak to be approximately 20 times greater than that of GV1.
      Demographic reconstructions were unable to detect a decrease in population size
      concurrent with the elimination of GV1. We find a raised rate of nucleotide
      substitution for GV1 gene sequences when compared to that of GV2, although all
      estimates have wide confidence limits. We demonstrate that phylogenetic
      reconstructions and sequence analysis can be used to support incidence data from
      the field in the assessment of RV epidemiology.

PMID- 15019590
TI  - Genetic variability between Trichomonas vaginalis isolates and correlation with
      clinical presentation.
AB  - The random amplified polymorphic DNA (RAPD) technique was used to determine
      genetic differences among isolates of Trichomonas vaginalis and these genetic
      data were correlated with patient records. A panel of 10 random primers was used
      to determine the type and extent of intraspecific polymorphism in 40 isolates of
      T. vaginalis. All primers detected DNA polymorphism among isolates. Numerical
      analysis of 124 RAPD amplified bands generated by these 10 primers were carried
      out with the unweighted pair group methods analysis (UPGMA) using Jaccard's
      Similarity Coefficient and data were used to construct a dendrogram. Four main
      groups can be distinguished by RAPD data, these groups coincide with four
      different patient categories (asymptomatic and symptomatic: light, moderate, and
      severe infection). These patients did not have any concomitant vaginal infection.
      Each of the four groups can be characterized by specific genetic markers, but a
      specific 490bp marker was found to be specific for all symptomatic isolates, not
      the asymptomatic isolates. This is the first description of a possible virulence
      marker for T. vaginalis. Further studies will be necessary to ascertain the
      importance and function of this genetic marker in clinical infection.

PMID- 15019592
TI  - Evolution and immunology of infectious diseases: what's new? An E-debate.

PMID- 15019591
TI  - Genetic characterisation of Cryptosporidium from a wild population of eastern
      grey kangaroos Macropus giganteus inhabiting a water catchment.
AB  - Molecular characterisation of Cryptosporidium oocysts isolated from faeces
      collected from eastern grey kangaroos Macropus giganteus inhabiting an Australian
      water catchment revealed that this host was susceptible to three types of
      Cryptosporidium. Nucleotide sequence analysis of the 18S rDNA, Cryptosporidium
      oocyst wall protein (COWP) and a 70kDa heat shock protein (HSP70) identified an
      isolate identical to the described Cryptosporidium 'marsupial' genotype. A second
      isolate had less than 0.5% variation, compared to the described Cryptosporidium
      'marsupial' genotype, within the sequences of the 18S rDNA, COWP and HSP70 and
      10% variation in the internal transcribed spacer 1 (ITS1). Multilocus analysis of
      the third Cryptosporidium revealed a novel genotype that had a degree of genetic
      variation, at the four loci characterised, which was greater than or equivalent
      to that used to discriminate between currently recognised Cryptosporidium
      species. These findings have increased our current understanding on the molecular
      epidemiology of Cryptosporidium in Australian wildlife and have provided
      information on the types of Cryptosporidium marsupials may shed into the
      environment.

PMID- 15019593
TI  - The relationship between immune-mediated Type 1 diabetes mellitus and ethnicity.
AB  - OBJECTIVE: To determine the proportion of adults with newly diagnosed Type 1
      diabetes that had immune-mediated disease (IMD). SUBJECTS AND METHODS: Two
      hundred fifteen patients with hyperglycemia and symptoms of insulin deficiency
      were screened for antibodies [islet cell antibodies (ICA), insulin autoantibodies
      (IAA), and glutamatic acid decarboxylase antibodies (GADA(65))] and HLA DR/DQ
      markers of IMD. RESULTS: The mean age was 34 years and the mean BMI was 30.0
      kg/m(2); 21.8% were non-Hispanic white (NHW), 27% were Latin American (LA), 47.9%
      were African American (AA), and 3.3% of other (OT) ethnic origins. Sixty
      individuals (28%) had one or more autoantibodies [Ab(+)]: 62% of NHW, 19% of AA,
      and 19% of LA. BMI was significantly lower (P<.01) in Ab(+). At least one HLA-DQ
      allele for susceptibility for IMD was identified in 52% of Ab(+). CONCLUSIONS:
      These results suggest that islet cell autoantibodies and HLA markers of
      susceptibility for IMD are frequent in individuals of varying ethnic backgrounds,
      older age at onset, and higher body weight. Since early insulin therapy could
      delay what may otherwise be rapid progression to complete insulinopenia in
      patients with IMD, screening of adult diabetic patients for IMD at diagnosis may
      be of benefit to long-term management.

PMID- 15019594
TI  - Immune-mediated disease and secondary failure to oral therapy in type 2 diabetes
      mellitus.
AB  - PURPOSE: To determine the proportion of adults with type 2 diabetes, who
      developed secondary failure to oral medications that had immune-mediated diabetes
      (IMD). SUBJECTS AND METHODS: One hundred and eight subjects who failed to oral
      therapy were screened for autoantibodies (ICA, IAA, IA-2A, and GADA(65)) and HLA
      DR/DQ markers of IMD. RESULTS: Mean age was 49 years and mean body mass index
      (BMI) was 31.5 kg/m(2); 21.3% were non-Hispanic White (NHW), 32.3% Latin American
      (LA), and 43.2% African American (AA). Fourteen percent had one or more
      autoantibodies [Ab(+)]: five NHW, three LA, and seven AA. Ab(+) patients were
      younger (P=.03) and had lower body weight (P=.05) than Ab(-) patients. HLA
      markers of susceptibility for IMD were identified in 64% Ab(+) and in 43% Ab(-)
      (chi(2), P=.46). CONCLUSIONS: These results suggest that secondary failure to
      oral therapy can be due to continuing IMD in obese, type 2 diabetic individuals
      of varying ethnic backgrounds than those who have been traditionally associated
      with autoimmune type 1 diabetes. Screening for markers for IMD at diagnosis could
      be a useful way to predict those likely to develop secondary failure to oral
      therapy and may assist in the selection of medical therapy.

PMID- 15019595
TI  - The health care costs of diabetic nephropathy in the United States and the United
      Kingdom.
AB  - PROBLEM: Diabetic nephropathy (DN) is a common microvascular complication of
      diabetes and can result in end-stage renal disease (ESRD) necessitating long-term
      dialysis or kidney transplantation. The costs of these complications are
      relatively high. The aim of this study was to quantify and compare the rates and
      annual costs of DN in the USA and the UK. METHODS: A cost of illness model was
      used to estimate the numbers of people with DN (microalbuminuria, overt
      nephropathy, and ESRD) or a previous kidney transplant at a given point in time
      and the numbers of new kidney transplants during a year. All costs were estimated
      in 2001 currencies. A sensitivity analysis assessed the robustness of the
      national annual cost estimates. RESULTS: In the USA, the total annual medical
      costs incurred by all payers in managing DN were US dollars 1.9 billion for Type
      1 diabetes (range: US dollars 1.0-2.8 billion), US dollars 15.0 billion for Type
      2 diabetes (range: US dollars 7.6-22.4 billion), and US dollars 16.8 billion for
      all diabetes (range: US dollars 8.5-25.2 billion). In the UK, the total annual
      costs to the National Health Service (NHS) of managing DN were US dollars 231
      million ( pound 152 million) for Type 1 diabetes (range: US dollars 190-350
      million [ pound 125-230 million]), US dollars 933 million (pound 614 million) for
      Type 2 diabetes (range: US dollars 809 million-US dollars 1.4 billion [pound 532
      927 million]), and US dollars 1.2 billion ( pound 765 million) for all diabetes
      (range: US dollars 999 million-US dollars 1.8 billion [pound 657 million- pound
      1.2 billion]). CONCLUSIONS: The total annual cost of DN is 13 times greater in
      the USA than in the UK. Controlling for the substantially higher number of people
      at risk, the total cost per person with DN and/or a kidney transplant is 40%
      higher: US dollars 3735 in the USA and US dollars 2672 (pound 1758) in the UK.

PMID- 15019596
TI  - The prevalence of symptoms of sensorimotor and autonomic neuropathy in Type 1 and
      Type 2 diabetic subjects.
AB  - The aim of this study was to analyze the prevalence and severity of sensorimotor
      and autonomic neuropathic symptoms within an outpatients diabetic population. A
      total of 350 consecutive Type 1 (26.9%) and Type 2 diabetic subjects were
      investigated using the Michigan Neuropathy Screening Instrument (MNSI). The
      original questionnaire was extended with questions on autonomic neuropathy and to
      include a six-point scale to rate the severity of symptoms, which were recorded
      accurately in order to avoid overrating. More than one half of Type 2 and nearly
      a third of Type 1 diabetic subjects suffer from at least one neuropathic symptom;
      the former suffered significantly more often from paresthesia (P<.05) and burning
      pain (P=.05). Less than 10% of the study population had autonomic symptoms. The
      prevalence of symptomatic polyneuropathy (PNP), diagnosed by an abnormal MNSI
      together with the presence of any symptom, was 16.0% in Type 1 and 37.5% (P<.001)
      in Type 2 diabetic subjects. Subjects with an abnormal ankle reflex (54.6%) had
      in 48.2% any sensorimotor, in 35.1% any autonomic, and in 25.7% any sensorimotor
      plus autonomic symptoms. The corresponding percentages for subjects with an
      abnormal vibration perception threshold (VPT; 28.9%) were 59.4%, 46.5%, and
      34.7%, respectively. An abnormal ankle reflex was significantly correlated to
      numbness, and to the the sum of sensorimotor and autonomic symptoms. An abnormal
      vibration perception was significantly correlated to numbness, to paresthesia
      pain, and to the sum of sensorimotor and autonomic symptoms. A higher percentage
      of Type 2 diabetic subjects had symptoms of neuropathy and the most frequent
      symptoms were numbness, muscle cramps and postural hypotension.

PMID- 15019597
TI  - HLA-DRB1, -DQA1, and -DQB1 subtypes or ACE gene polymorphisms do not seem to be
      risk markers for severe retinopathy in younger Type 1 diabetic patients.
AB  - The aim of this study was to test the hypothesis that HLA-DRB1, -DQA1, and -DQB1
      subgroups or angiotensin-converting enzyme (ACE) gene polymorphisms are
      associated with severe retinopathy in younger Type 1 diabetic patients. Twenty
      four Type 1 diabetic patients who had received panretinal photocoagulation for
      severe nonproliferative or proliferative diabetic retinopathy were compared with
      24 Type 1 diabetic patients (participating in a photographic screening program
      with regular fundus examinations) with no or minimal retinopathy, matched for age
      at onset and duration of diabetes. The HLA-DRB1-DQA1-B1 haplotype 04-03-0302
      represented 22/48 (46%) in the severe and 21/48 (44%) in the no/minimal
      retinopathy group, respectively (n.s.). The most common genotype, 03-0501-0201/04
      03-0302, occurred in 8/24 (33%) with severe and 10/24 (42%) with no/minimal
      retinopathy, respectively (n.s.). There were no statistical differences between
      patients with severe and no/minimal retinopathy whether DRB1, DQA1, or DQB1
      alleles, haplotypes, or genotypes were analysed. The ACE gene polymorphism was
      almost identical between patients with severe and no/minimal retinopathy, and
      serum ACE levels did not differ. Thus, in the present study on a small group with
      carefully characterised diabetic retinopathy phenotypes, there was no indication
      that HLA-DRB1, -DQA1, and -DQB1 subtypes or ACE gene polymorphisms were
      associated with severe retinopathy in younger Type 1 diabetic patients.

PMID- 15019598
TI  - The effect of glucose levels on fetal birth weight: a study of Chinese gravidas
      in Tianjin, China.
AB  - The relationship between maternal glucose intolerance and fetal birth weight
      remains, to a large extent, unknown in Chinese gravidas. From December 1998 to
      December 1999, 9471[corrected] women in six urban districts of Tianjin, China,
      underwent an initial screening using a 50-g, 1-h glucose load at 26-30
      gestational weeks. Women with a serum glucose reading >or=7.8 mmol/l, were
      followed up for a 75-g, 2-h glucose tolerance test, which was interpreted using
      the 1998 World Health Organization's (WHO) criteria for diabetes. A total of 174
      women had gestational diabetes mellitus. Complete data was collected in 170
      women. Among them, 56 accepted diabetes management including self-home glucose
      monitoring, diet, and physical activity advice, and others received no treatment.
      The comparison group was 302 women with normal glucose tolerance (NGT). Glucose
      levels at the initial screening (partial R(2)=.0343, P<.0001), maternal weight
      gain during pregnancy (partial R(2)=.0915, P<.0001), and gestational week at
      delivery (partial R(2)=.0432, P<.0001) were determinants of fetal birth weight,
      controlling for maternal age, pregravid BMI, maternal stature, and other
      confounders. Both gestational diabetes mellitus (GDM) status and a positive
      screening but normal oral glucose tolerance test (OGTT) result were predictors of
      macrosomia (birth weight >or=4000 g). It concludes that maternal glucose levels
      correlate with fetal birth weight and a glucose level of 7.8 mmol/l or more at
      the initial screening is predictive of macrosomia in Chinese gravidas regardless
      of GDM status.

PMID- 15019599
TI  - Cognitive function in Japanese elderly with type 2 diabetes mellitus.
AB  - The current study was conducted to investigate the cognitive function in Japanese
      elderly with type 2 diabetes mellitus (DM). Participants included 69 diabetic and
      27 nondiabetic subjects (60 to 85 years old). The cognitive functional tests
      conducted were the Mini-Mental State Examination (MMSE), Word Lists Recall
      (immediate, delayed), Digit Symbol Test (Wechsler Adult Intelligence Scale
      Revised [WAIS-R]), and the Stroop Color Word Test. Hemoglobin A1c (HbA1c) was
      measured as the index of glycemic control, and information about recent
      hypoglycemic episodes was gathered by using questionnaires. Student's t test
      showed that DM subjects had significantly lower scores in the MMSE (P<.01) and
      Digit Symbol Test (P<.05) than non-DM subjects. The scores of the Digit Symbol
      Test in diabetes subjects had a significant negative relationship with HbA1c (r=
      .433; P<.001), and insulin-use had a significant relationship with the scores of
      the MMSE and Digit Symbol Test. Subjects in the DM group were further divided by
      insulin use. Comparison of insulin-treated DM subjects, non-insulin-treated DM
      subjects, and nondiabetic subjects by analysis of variance followed by
      Bonferroni's post hoc test showed that insulin-treated DM subjects had
      significantly lower scores in the MMSE and Digit Symbol Tests than both non
      insulin-treated DM subjects (P<.05) and nondiabetic subjects (P<.01). Our study
      suggests that Japanese elderly DM subjects, especially those with insulin
      treatment, have poor cognitive function.

PMID- 15019600
TI  - Markers of endothelial dysfunction in hyperglycaemic Asian Indian subjects.
AB  - OBJECTIVE: The aims of this study were the following: (1). to determine the
      levels of endothelin-1(ET1), soluble adhesion molecules like intracellular
      adhesion molecule-1 (sICAM-1), and vascular cell adhesion molecule-1 (sVCAM-1) in
      different stages of glucose intolerance and to identify a suitable marker of
      endothelial dysfunction and (2). to determine the possible association of these
      biochemical parameters with diabetic complications and with impaired glucose
      tolerance (IGT). RESEARCH DESIGN AND METHODS: In this cross-sectional study,
      plasma ET1, sICAM-1, and sVCAM-1 were measured by enzyme-linked immunosorbent
      assay (ELISA) in 20 nondiabetic subjects, in 15 subjects with IGT, in 21 Type 2
      diabetic subjects without any complication, and in 21 Type 2 diabetic patients
      with nephropathy and retinopathy. RESULTS: Median ET1 levels were significantly
      elevated (P=.004) in IGT subjects (0.31 fmol/ml) when compared with the
      nondiabetic subjects (0.11 fmol/ml). Subjects with nephropathy (0.50 fmol/ml) had
      significantly higher (P=.002) ET1 values when compared with those without
      complications (0.40 fmol/ml). The levels of sICAM-1 and sVCAM-1 did not show any
      significant difference among the groups. ET1 showed correlation with age, body
      mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP),
      fasting plasma glucose (FPG), 2 h post glucose (2hPG), waist-to-hip ratio (WHR),
      total white blood corpuscles count, glycosylated haemoglobin (HbA1c),
      triglycerides (TG), very-low-density lipoprotein cholesterol (VLDLc), and
      hypertension (HTN). In the multiple linear regression analysis, plasma ET1 was
      significantly associated with the presence of Type 2 diabetes either with or
      without complications (P<.0001 and P=.0098, respectively), WHR (P=.0063), and
      sVCAM-1 (P=.0051). The total variance explained by the above-mentioned parameters
      was 55%. CONCLUSION: Elevated levels of ET1 were present in subjects with IGT and
      in Type 2 diabetic subjects. Such associations with sICAM-1 or sVCAM-1 in these
      subjects were not seen. ET1 could be an early marker of endothelial dysfunction,
      which appeared to occur even in the subclinical stages of hyperglycaemia.

PMID- 15019601
TI  - AGE down-regulation of monocyte RAGE expression and its association with diabetic
      complications in type 1 diabetes.
AB  - Advanced glycation end product (AGE) engagement of a cell surface receptor for
      AGE (RAGE) has been implicated in the development of diabetic complications. In
      this study, we determined the RAGE mRNA levels in monocytes from type 1 diabetic
      patients and analyzed their relationship with diabetic vascular complications.
      Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis
      revealed that the monocyte expression of RAGE mRNA was significantly lower in
      patients with retinopathy than in those without retinopathy and was also
      significantly down-regulated in patients with nephropathy in comparison with
      those without nephropathy. Experiments with monocyte-enriched cultures revealed
      that RAGE mRNA and protein levels were down-regulated by the exposure to
      glyceraldehyde-derived AGE-the recently identified high-affinity RAGE ligand.
      Accordingly, we then assayed for the serum levels of glyceraldehyde-derived AGE
      as well as those of carboxymethyllysine (CML)-the known RAGE ligand and related
      them to the monocyte levels of RAGE mRNA. This screen revealed a negative
      correlation between the two parameters. The results thus suggest that the
      decrease in monocyte RAGE expression can be at least partly accounted for by the
      ligand engagement and may be a factor contributing to the development of diabetic
      vascular complications.

PMID- 15019602
TI  - Hypoglycemia as a barrier to glycemic control.
AB  - Diabetes mellitus is associated with significant morbidity and mortality derived
      from long-term microvascular and macrovascular complications of chronic
      hyperglycemia. The Diabetes Control and Complications Trial (DCCT) and the UK
      Prospective Diabetes Study (UKPDS) have clearly shown the benefits of intensive
      glycemic control for preventing or delaying the development and progression of
      long-term complications. However, intensive glycemic control, particularly with
      insulin therapy, is associated with an increased incidence of hypoglycemia, which
      is the major barrier to the implementation of intensive treatment from the
      physician's and patient's perspective. Avoiding the use of intensive treatment
      most often precludes optimal glycemic control. Some of the many underlying causes
      of hypoglycemia are defective and deficient counterregulatory responses, relative
      hyperinsulinization owing to a missed meal, excessive or unplanned exercise,
      erroneous insulin dosages, excessive insulinotropic effects of some oral
      secretagogues, and the failure of traditional insulin preparations to simulate
      the physiologic patterns of endogenous basal insulin secretion found in
      nondiabetic individuals. Additionally, patient involvement is critical to
      intensive glycemic control and should involve frequent self-monitoring of blood
      glucose (SMBG), adherence to treatment regimens, and knowledge of the
      interrelationship among physical activity, diet, and insulin. This review
      summarizes the current knowledge on hypoglycemia with a focus on the improvements
      in insulin therapy (i.e., the mealtime and basal insulin analogs) that may
      produce more normal physiologic insulin profiles with an attendant lower risk of
      hypoglycemia than that currently seen in clinical practice.

PMID- 15019604
TI  - A preliminary molecular and morphological phylogeny of the Antarctic Epimeriidae
      and Iphimediidae (Crustacea, Amphipoda).
AB  - The phylogenetic relationships of 14 species of the Antarctic amphipod families
      Epimeriidae and Iphimediidae were investigated using 553bp of the gene for the
      mitochondrial cytochrome oxidase subunit I (COI) and 98 morphological characters.
      Both families are dominant members of the Antarctic benthic amphipod community.
      In contrast to previous studies, our molecular and morphological data suggest
      that the families Epimeriidae and Iphimediidae may not be sister taxa. Our study
      suggests that Iphimediidae are more closely related to Eusirus (Eusiridae) than
      to Epimeria (Epimeriidae). Phylogenetic analyses based on maximum parsimony (MP)
      and maximum likelihood (ML) indicate that the genera Iphimediella and
      Gnathiphimedia are not monophyletic.

PMID- 15019603
TI  - Proteinuria in African Americans with type 1 diabetes.
AB  - AIMS: African Americans with type 1 diabetes are at a high risk for end-stage
      renal disease (ESRD). Factors associated with the presence of (any) proteinuria
      were examined in this ethnic group. METHODS: Proteinuria and creatinuria were
      measured in both first-voided and 4-h timed urine specimens in African Americans
      with type 1 diabetes (N=717). Other evaluations included clinical interview,
      ocular examination, fundus photography, blood pressure, and glycosylated
      hemoglobin measurements. RESULTS: Of the 717 patients, 357 (49.8%) had any
      proteinuria. Frequency of any proteinuria increased significantly with (a). age,
      from 34.2% of patients 20-30 years of age to 84.7% in those >or=45 years of age,
      and (b). duration of diabetes from 24.1% in those with 0-4 years of diabetes to
      77.5% in those with >or=25 years of diabetes. Multivariate logistic regression
      showed that any proteinuria was significantly and independently associated with
      male sex, systemic hypertension, poor glycemic control, and longer duration of
      diabetes. CONCLUSION: Proteinuria is common in African Americans with type 1
      diabetes. Risk factors include male sex, systemic hypertension, poor glycemic
      control, and longer duration of diabetes. Whether early protection of renal
      function, in addition to glycemic control, may prevent such morbidity in this
      ethnic group requires study.

PMID- 15019605
TI  - Phylogenetic relationships among early-diverging eudicots based on four genes:
      were the eudicots ancestrally woody?
AB  - Based on analyses of combined data sets of three genes (18S rDNA, rbcL, and
      atpB), phylogenetic relationships among the early-diverging eudicot lineages
      (Ranunculales, Proteales, Trochodendraceae, Sabiaceae, and Buxaceae) remain
      unclear, as are relationships within Ranunculales, especially the placement of
      Eupteleaceae. To clarify relationships among these early-diverging eudicot
      lineages, we added entire sequences of 26S rDNA to the existing three-gene data
      set. In the combined analyses of four genes based on parsimony, ML, and Bayesian
      analysis, Ranunculales are strongly supported as a clade and are sister to other
      eudicots. Proteales appear as sister to the remaining eudicots, which are weakly
      (59%) supported as a clade. Relationships among Trochodendraceae, Buxaceae
      (including Didymeles), Sabiaceae, and Proteales remain unclear. Within
      Ranunculales, Eupteleaceae are sister to all other Ranunculales, with bootstrap
      support of 70% in parsimony analysis and with posterior probability of 1.00 in
      Bayesian analysis. Our character reconstructions indicate that the woody habit is
      ancestral, not only for the basal angiosperms, but also for the eudicots.
      Furthermore, Ranunculales may not be ancestrally herbaceous, as long maintained.
      The woody habit appears to have been ancestral for several major clades of
      eudicots, including Caryophyllales, and asterids.

PMID- 15019606
TI  - Phylogenies of the Frigatebirds (Fregatidae) and Tropicbirds (Phaethonidae), two
      divergent groups of the traditional order Pelecaniformes, inferred from
      mitochondrial DNA sequences.
AB  - The frigatebirds (Fregatidae) and Tropicbirds (Phaethonidae) represent the most
      morphologically and behaviorally distinct members of the traditional Order
      Pelecaniformes. Using 1756bp of mitochondrial DNA sequence consisting of the 12S,
      ATPase-6, ATPase-8, and COI genes obtained from all extant species, we derive a
      completely resolved phylogeny for both groups. The inferred relationships among
      these species are robust to the method of phylogenetic estimation used, and all
      branches are well supported, in spite of the relatively recent radiation within
      the frigatebirds. The two families are not closely related either to each other,
      or to any other putative relatives (e.g., pelicans; Pelecanidae).

PMID- 15019607
TI  - Phylogenetic relationships and evolutionary history of the shrimp genus Penaeus
      s.l. derived from mitochondrial DNA.
AB  - Mitochondrial DNA sequences were used to reconstruct the phylogeny of the Penaeus
      s.l. genus of marine shrimp. This phylogeny was used to test the validity of
      hypotheses on the species groupings, in particular the subgenus/genus
      subdivision, and on the species' evolutionary history. Newly derived sequences of
      both 16S rRNA and COI genes from 19 species of Penaeus s.l. and one outgroup were
      combined with previous sequences from seven additional species to allow analysis
      of 26 of the 28 recognised (or nominated) species. Phylogenetic analyses do not
      support the validity of all the previously created six subgenera (or genera) but
      provide evidence for division of the genus into two previously unrecognised
      clades (Melicertus+Marsupenaeus and Penaeus
      s.s.+Fenneropenaeus+Farfantepenaeus+Litopenaeus). A key conclusion from a
      previous molecular study, that the subgenera Farfantepenaeus and Litopenaeus are
      paraphyletic, was rejected. The molecular data support an Indo-West Pacific
      origin of the genus, with a single relatively recent colonisation of the Western
      Hemisphere, and subsequent subdivision into two clades prior to the emergence of
      the Panamanian isthmus.

PMID- 15019608
TI  - Complete mitochondrial genome DNA sequence for two ophiuroids and a holothuroid:
      the utility of protein gene sequence and gene maps in the analyses of deep
      deuterostome phylogeny.
AB  - The complete mitochondrial genome sequences have been determined for the
      holothuroid Cucumaria miniata and two ophiuroid species Ophiopholis aculeata and
      Ophiura lutkeni. In addition, the nucleotide sequence of the mitochondrial
      protein-coding genes for the asteroid Pisaster ochraceus has been completed.
      Maximum-likelihood and LogDet distance analyses of concatenated protein-coding
      sequences produced a series of trees that did not conclusively support generally
      accepted models of echinoderm phylogeny. The ophiuroid data consistently
      demonstrated accelerated nucleotide divergence rates and lack of stationarity.
      This confounds the phylogenetic analyses. Molecular investigations using
      individual protein-coding gene alignments demonstrated that the cytochrome b gene
      exhibits the least deviation in rate and stationarity and generated some trees
      consistent with proposed echinoderm phylogenies. Phylogenies based on echinoderm
      mitochondrial gene rearrangements also proved problematic because of extensive
      variation in gene order between and within classes. A comparison of the two
      distinctive ophiuroid mitochondrial gene orders supports the hypothesis that O.
      lutkeni has a more derived mitochondrial gene order versus O. aculeata. The
      variation in the echinoderm mitochondrial gene maps reinforces the limitations of
      the application of mitochondrial gene rearrangements as a global phylogenetic
      tool.

PMID- 15019609
TI  - Molecular systematics of the damselfishes (Teleostei: Pomacentridae): Bayesian
      phylogenetic analyses of mitochondrial and nuclear DNA sequences.
AB  - Damselfishes in the family Pomacentridae represent one of the few families of
      reef fishes found on coral reefs irrespective of location. At a local scale,
      damselfishes are often the most abundant coral reef fish, and their study has
      provided much of our current understanding of the ecology of tropical reef
      animals. The study of phylogenetic relationships among the Pomacentridae has
      lagged ecological investigation of the group, thus limiting historical
      perspective on the remarkable species richness of the family. In this study, we
      used 1989bp of DNA sequence representing three mitochondrial genes and 1500bp of
      the single copy nuclear RAG1 region to infer hypotheses of relationship for the
      group. Our analysis includes 103 Pomacentridae species in 18 genera, and three of
      the four named subfamilies: Amphriprioninae, Chrominae, and Pomacentrinae. The
      Bayesian method of phylogenetic reconstruction was applied to the data, because
      even with a large number of sequences it is an efficient means of analysis that
      provides intuitive measures of support for tree topologies and for the parameters
      of the nucleotide substitution model. Four Pomacentridae clades were identified
      with high statistical support whether the data were analyzed from a mtDNA, RAG1
      or combined perspective, and in all analyses the current subfamilial
      classification of the Pomacentridae was rejected. At the genus level, Amphiprion,
      Chromis, and Chrysiptera were also rejected as natural groups. Abudefduf,
      Amblyglyphidodon, Dascyllus, Neoglyphidodon, Neopomacentrus, and Pomacentrus were
      each strongly supported as monophyletic genera but the support for monophyly is
      nonetheless compromised by sample size, except in the case of Dascyllus and
      Abudefduf for which we have sampled almost all of the described species.

PMID- 15019610
TI  - Molecular phylogeny of the family Pectinidae (Mollusca: Bivalvia) based on
      mitochondrial 16S and 12S rRNA genes.
AB  - Pectinidae is a large bivalve family characterised by almost circular, flat
      shells. Species are distributed worldwide and fall into three life-styles:
      swimming, byssally attached to hard substrates, and cemented to rocks with one
      valve. Despite these very different life strategies, pectinid shells are highly
      conservative in shape and offer few clues for the unravelling of phylogenetic
      issues. Consequently, phylogenetic studies based on morphological features have
      not yielded conclusive results. We thus set out to analyse partial sequences of
      mitochondrial 12S and 16S rRNA genes from 23 species of 16 genera with molecular
      techniques. The results are largely in contrast, both at the genus and the
      subfamily level, with the systematic classifications based on adult morphological
      characters, whereas they agree with the morphological classifications based on
      the more conserved non-adaptive features.

PMID- 15019611
TI  - Molecular phylogeny and morphological change in the Psittacula parakeets.
AB  - We reconstruct a phylogeny of the African and Asian Psittacula parakeets using
      approximately 800bp of mitochondrial cytochrome b sequence to examine their
      evolutionary relationships in reference to their head plumage and major
      morphological tail innovations. Our phylogeny identifies three groups, whose
      distinctiveness is also apparent from their possession of three different head
      plumage characters: a neck ring, a distinctive colouration of the head, and a
      'moustache'-shaped pattern that extends from the chin to the cheek. We examine
      the extent of sexual dimorphism in tail length across the phylogeny and reveal
      large differences between closely related forms. We apply a range of published
      avian cytochrome b substitution rates to our data, as an alternative to internal
      calibration of a molecular clock arising from incomplete paleontological
      information. An ancestral Psittacula form appears to have evolved during the late
      Miocene-early Pliocene (3.4-9.7MYA), a time when regional geological processes on
      the Asian continent may have promoted subsequent diversity at the species level,
      and many forms diverged relatively early on in the evolutionary history of
      Psittacula (between 2.5 and 7.7MYA). However, others, such as the derbyan and
      moustached parakeets, diverged as recently as 0.2MYA. Our phylogeny also suggests
      that the echo parakeet from Mauritius diverged from the Indian ringneck parakeet
      as opposed to the African ringneck, and may have done so relatively recently. The
      molecular results indicate support for a southwards radiation from India across
      the Indian Ocean to Mauritius, where the arrival-date of the echo parakeet
      appears consistent with the island's volcanic formation.

PMID- 15019612
TI  - Reconstructing an island radiation using ancient and recent DNA: the extinct and
      living day geckos (Phelsuma) of the Mascarene islands.
AB  - Mitochondrial (12SrRNA and cyt b, 1086 bp) and nuclear (c-mos, 374 bp) DNA
      sequences were used to investigate relationships and biogeography of 24 living
      and extinct taxa of Phelsuma geckos. Monophyly of Phelsuma and sister
      relationship to the SW African Rhoptropella is corroborated. Phelsuma originated
      on Madagascar and made multiple long-distance invasions of oceanic islands
      including the Mascarenes, Aldabra, Comores, Seychelles, Andamans, and perhaps
      Pemba. The Mascarenes were probably colonised once, about 4.2-5.1Ma, and here
      Phelsuma rosagularis and Phelsuma inexpectata are newly recognised as species, as
      are three lineages of Phelsuma cepediana. Mascarene relationships are: Phelsuma
      edwardnewtoni, Phelsuma gigas (Phelsuma guentheri ((((P. cepediana A (P.
      cepediana B, C)) P. rosagularis) Phelsuma borbonica) ((Phelsuma ornata, P.
      inexpectata) Phelsuma guimbeaui))). The two recently extinct species, P.
      edwardnewtoni and the giant secondarily nocturnal Phelsuma gigas, differentiated
      on Rodrigues while on Mauritius the large nocturnal P. guentheri separated from a
      small diurnal form that radiated into six species, a likely result of volcanic
      activity. Two small-bodied lineages from Mauritius invaded the more recent island
      of Reunion producing two more species. Outside the Mascarenes, two mainly
      Madagascan assemblages are substantiated: Phelsuma serraticauda (Phelsuma
      lineata, Phelsuma laticauda, Phelsuma quadriocellata); (Phelsuma m. kochi
      (Phelsuma m. grandis, Phelsuma abboti)) (Phelsuma astriata, Phelsuma sundbergi).
      Their relationships to the Mascarene clade, and to Phelsuma mutabilis, Phelsuma
      standingi and Phelsuma andamanensis are unresolved.

PMID- 15019613
TI  - The origin of polynucleotide phosphorylase domains.
AB  - In this report, we document the presence of polynucleotide phosphorylase (PNPase)
      in the animal eukaryotes. These proteins contain several domains, including 2
      RNase PH domains (PNPase 1 and PNPase 2) which are closely related functionally
      and in sequence similarity to ribonuclease PH (RPH) protein. Phylogenetic
      analysis of the gene genealogy of these three domains suggests that PNPase was
      formed via a duplication event that also produced the RNase PH protein. Given the
      current distribution of these domains in the tree of life, these duplication
      events most likely occurred in the common ancestor of the three organismal
      superkingdoms, Archaea, Eukarya, and Bacteria. In particular, PNPase 2 and RPH
      are more closely related to each other than either one is to PNPase 1, suggesting
      a deeper differentiation of PNPase 1 in the common organismal ancestor. In
      addition, while PNPase 1 and PNPase 2 appear to have the same evolutionary signal
      as determined by the incongruence length difference (ILD) test, RPH appears to
      have an incongruent signal with both of the PNPase domains. This result suggests
      that RPH experienced different evolutionary divergence patterns than the PNPase
      domains, consistent with the linked nature of the two PNPase domains.

PMID- 15019614
TI  - Assessing the phylogeny of Frankia-actinorhizal plant nitrogen-fixing root nodule
      symbioses with Frankia 16S rRNA and glutamine synthetase gene sequences.
AB  - Actinomycetes from the genus Frankia induce nitrogen-fixing root nodules on
      actinorhizal plants in the "core rosid" clade of eudicots. Reported here are nine
      partial Frankia 16S rRNA gene sequences including the first from host plants of
      the rosaceous genera Cercocarpus and Chamaebatia, 24 partial glutamine synthetase
      (GSI; glnA) sequences from Frankia in nodules of 17 of the 23 actinorhizal
      genera, and the partial glnA sequence of Acidothermus cellulolyticus.
      Phylogenetic analyses of combined Frankia 16S rDNA and glnA sequences indicate
      that infective strains belong to three major clades (I-III) and that Clade I
      strains consisting of unisolated symbionts from the Coriariaceae, Datiscaceae,
      Rosaceae, and Ceanothus of the Rhamnaceae are basal to the other clades. Clock
      like mutation rates in glnA sequence alignments indicate that all three major
      Frankia clades diverged early during the emergence of eudicots in the Cretaceous
      period, and suggest that present-day symbioses are the result of an ancestral
      symbiosis that emerged before the divergence of extant actinorhizal plants.

PMID- 15019615
TI  - Towards a phylogenetic framework for the evolution of shakes, rattles, and rolls
      in Myiarchus tyrant-flycatchers (Aves: Passeriformes: Tyrannidae).
AB  - A phylogeny of 19 of the 22 currently recognized species of Myiarchus tyrant
      flycatchers is presented. It is based on 842bp of mitochondrial DNA (mtDNA)
      sequences from the ATPase subunit 8 and ATPase subunit 6 genes. Except for the
      morphologically distinct M. semirufus, mtDNAs of the remaining 18 species fall
      into either of two clades. One comprises predominantly Caribbean and Central and
      North American taxa (Clade I), and the other is of predominantly South American
      taxa (Clade II). The phylogeny is only very broadly concordant with some vocal
      characters and also with the limited morphological diversity for which the group
      is well known. Paraphyly in several species (M. swainsoni, M. tuberculifer, M.
      ferox, M. phaeocephalus, M. sagrae, M. stolidus) suggests that morphological
      evolution, albeit resulting in limited morphological diversity, has been more
      rapid than that of mtDNA, or that current taxonomy is faulty, or both. A South
      American origin for Myiarchus is likely. Dispersal and vicariance both appear to
      have been involved in generating the present-day distribution of some species.
      Relatively recent dispersal events out of South America are inferred to have
      brought species of Clades I and II into broad sympatry. Jamaica has been
      colonized independently at least twice by members of Clades I and II. The
      phylogeny brings a historical perspective that in turn suggests that ecological
      study of closely related species from within each major clade where they are
      sympatric will be especially rewarding.

PMID- 15019616
TI  - Comparative analysis of NBS domain sequences of NBS-LRR disease resistance genes
      from sunflower, lettuce, and chicory.
AB  - Plant resistance to many types of pathogens and pests can be achieved by the
      presence of disease resistance (R) genes. The nucleotide binding site-leucine
      rich repeat (NBS-LRR) class of R-genes is the most commonly isolated class of R
      genes and makes up a super-family, which is often arranged in the genome as large
      multi-gene clusters. The NBS domain of these genes can be targeted by polymerase
      chain reaction (PCR) amplification using degenerate primers. Previous studies
      have used PCR derived NBS sequences to investigate both ancient R-gene evolution
      and recent evolution within specific plant families. However, comparative studies
      with the Asteraceae family have largely been ignored. In this study, we address
      recent evolution of NBS sequences within the Asteraceae and extend the comparison
      to the Arabidopsis thaliana genome. Using multiple sets of primers, NBS fragments
      were amplified from genomic DNA of three species from the family Asteraceae:
      Helianthus annuus (sunflower), Lactuca sativa (lettuce), and Cichorium intybus
      (chicory). Analysis suggests that Asteraceae species share distinct families of R
      genes, composed of genes related to both coiled-coil (CC) and toll-interleukin
      receptor homology (TIR) domain containing NBS-LRR R-genes. Between the most
      closely related species, (lettuce and chicory) a striking similarity of CC
      subfamily composition was identified, while sunflower showed less similarity in
      structure. These sequences were also compared to the A. thaliana genome.
      Asteraceae NBS gene subfamilies appear to be distinct from Arabidopsis gene
      clades. These data suggest that NBS families in the Asteraceae family are
      ancient, but also that gene duplication and gene loss events occur and change the
      composition of these gene subfamilies over time.

PMID- 15019617
TI  - Molecular phylogeny of the critically endangered Indochinese box turtle (Cuora
      galbinifrons).
AB  - The Indochinese box turtle Cuora galbinifrons is a polytypic, critically
      endangered species from Vietnam, Laos, and Hainan Island, China. We analyze up to
      1790bp of mitochondrial DNA under maximum parsimony and maximum likelihood
      criteria to test if the five historically recognized subspecies represent
      evolutionary lineages, and to elucidate the relationship of C. galbinifrons to
      other Cuora. C. galbinifrons is composed of three major mitochondrial DNA clades
      corresponding to the three subspecies galbinifrons, bourreti, and picturata.
      These three lineages are also morphologically diagnosable, and consequently we
      recommend elevating each to full species. Cuora galbinifrons hainanensis nests
      within the galbinifrons clade, and we retain it as a synonym of galbinifrons, as
      supported by morphology. Cuora "serrata" is known to be a hybrid of male Cuora
      mouhotii and female C. galbinifrons, and our findings show that C. "serrata"
      originates from both female galbinifrons and bourreti. Little or no mitochondrial
      DNA variation was found among the morphologically distinct species Cuora
      aurocapitata, Cuora pani, and Cuora trifasciata, for which hypotheses are
      proposed. Recognizing galbinifrons, bourreti, and picturata as separate species
      has consequences for ongoing ex situ captive breeding programs and prioritization
      of in situ conservation activities, particularly in Vietnam.

PMID- 15019618
TI  - Ecdysozoan phylogeny and Bayesian inference: first use of nearly complete 28S and
      18S rRNA gene sequences to classify the arthropods and their kin.
AB  - Relationships among the ecdysozoans, or molting animals, have been difficult to
      resolve. Here, we use nearly complete 28S+18S ribosomal RNA gene sequences to
      estimate the relations of 35 ecdysozoan taxa, including newly obtained 28S
      sequences from 25 of these. The tree-building algorithms were likelihood-based
      Bayesian inference and minimum-evolution analysis of LogDet-transformed
      distances, and hypotheses were tested wth parametric bootstrapping. Better
      taxonomic resolution and recovery of established taxa were obtained here,
      especially with Bayesian inference, than in previous parsimony-based studies that
      used 18S rRNA sequences (or 18S plus small parts of 28S). In our gene trees,
      priapulan worms represent the basal ecdysozoans, followed by nematomorphs, or
      nematomorphs plus nematodes, followed by Panarthropoda. Panarthropoda was
      monophyletic with high support, although the relationships among its three phyla
      (arthropods, onychophorans, tardigrades) remain uncertain. The four groups of
      arthropods-hexapods (insects and related forms), crustaceans, chelicerates
      (spiders, scorpions, horseshoe crabs), and myriapods (centipedes, millipedes, and
      relatives)-formed two well-supported clades: Hexapoda in a paraphyletic crustacea
      (Pancrustacea), and 'Chelicerata+Myriapoda' (a clade that we name
      'Paradoxopoda'). Pycnogonids (sea spiders) were either chelicerates or part of
      the 'chelicerate+myriapod' clade, but not basal arthropods. Certain clades
      derived from morphological taxonomy, such as Mandibulata, Atelocerata,
      Schizoramia, Maxillopoda and Cycloneuralia, are inconsistent with these rRNA
      data. The 28S gene contained more signal than the 18S gene, and contributed to
      the improved phylogenetic resolution. Our findings are similar to those obtained
      from mitochondrial and nuclear (e.g., elongation factor, RNA polymerase, Hox)
      protein-encoding genes, and should revive interest in using rRNA genes to study
      arthropod and ecdysozoan relationships.

PMID- 15019619
TI  - Phylogenetic structure of Zacco platypus (Teleostei, Cyprinidae) populations on
      the upper and middle Chang Jiang (=Yangtze) drainage inferred from cytochrome b
      sequences.
AB  - We examined the genetic structure and phylogenetic relationships of some Chinese
      populations from the Chang Jiang (=Yangtze) drainage of the cyprinid Zacco
      platypus. We sequenced the complete mitochondrial cytochrome b gene of 64
      individuals from 6 upper and middle tributaries of the Sichuan and Hunan
      Provinces to assess their population structure and systematics. The combined
      analyses of the phylogenetic information and the population structure suggested
      that Chinese Z. platypus consist of four distinct mtDNA lineages which exhibit
      high genetic variation and haplotypic diversity (Zacco A-D). The high molecular
      divergence observed among Zacco A-D mtDNA lineages (TrN+I (0.76) distance, mean
      8.9%+/-1.7%) and their phylogeographic structure indicate that all four lineages
      have evolved independently. Analysis of molecular variance (AMOVA) indicates that
      most of the genetic variation observed is found among the four Zacco mtDNA
      lineages (thetaCT = 0.94) suggesting restricted gene flow among the Chang Jiang
      populations. Long-term interruption of gene flow was also evidenced by thetaST
      values higher than 0.9 that could be favoured by the discontinuous distributions
      of the lineages inhabiting upper (Sichuan Province) and middle (Hunan Province)
      Chang Jiang tributaries. The significant correlation between the geographic and
      genetic distances provide support for the importance of geographic discontinuity
      in shaping the Zacco genetic structure. Nested clade analysis (NCA) results were
      congruent with phylogenetic relationships recovered and confirm the genetic
      distinctiveness of four independent Zacco groups. These four groups correspond to
      the four Zacco A-D mtDNA lineages recovered in the phylogeny and were defined by
      nucleotide synapomorphies permitting bootstrapped and Bayesian confidence of 95%
      or greater. The high level of mitochondrial sequence divergence separating all
      Zacco mtDNA lineages suggested that the Z. platypus populations from the Chang
      Jiang drainage probably correspond to four different species.

PMID- 15019620
TI  - Phylogenetic comparison of metabolic capacities of organisms at genome level.
AB  - Horizontal gene transfer (HGT) has been shown to widely spread in organisms by
      comparative genomic studies. However, its effect on the phylogenetic relationship
      of organisms, especially at a system level of different cellular functions, is
      still not well understood. In this work, we have constructed phylogenetic trees
      based on the enzyme, reaction, and gene contents of metabolic networks
      reconstructed from annotated genome information of 82 sequenced organisms.
      Results from different phylogenetic distance definitions and based on three
      different functional subsystems (i.e., metabolism, cellular processes,
      information storage and processing) were compared. Results based on the three
      different functional subsystems give different pictures on the phylogenetic
      relationship of organisms, reflecting the different extents of HGT in the
      different functional systems. In general, horizontal transfer is prevailing in
      genes for metabolism, but less in genes for information processing. Nevertheless,
      the major results of metabolic network-based phylogenetic trees are in good
      agreement with the tree based on 16S rRNA and genome trees, confirming the three
      domain classification and the close relationship between eukaryotes and archaea
      at the level of metabolic networks. These results strongly support the hypothesis
      that although HGT is widely distributed, it is nevertheless constrained by
      certain pre-existing metabolic organization principle(s) during the evolution.
      Further research is needed to identify the organization principle and constraints
      of metabolic network on HGT which have large impacts on understanding the
      evolution of life and in purposefully manipulating cellular metabolism.

PMID- 15019621
TI  - Phylogeny of elasmobranchs based on LSU and SSU ribosomal RNA genes.
AB  - The dominant view of the phylogeny of living elasmobranchs, based on
      morphological characters, is that batoids (skates and rays) are derived sharks,
      joined with saw sharks, and angel sharks in the clade Hypnosqualea [S. Shirai,
      Squalean Phylogeny: A New Framework of 'Squaloid' Sharks and Related Taxa,
      Hokkaido University Press, Sapporo, 1992]. By contrast, a recent molecular
      phylogenetic study based on mitochondrial genes for 12S and 16S rRNA and tRNA
      valine [C.J. Douady et al., Mol. Phylogenet. Evol., 26 (2003) 215-221] supported
      the older view that batoids and sharks are separate lineages. Here, we tested
      these two different views using combined, nuclear large-subunit and small-subunit
      rRNA gene sequences ( approximately 5.3kb) from 22 elasmobranchs, two chimeras,
      and two bony fishes. We used maximum likelihood, maximum parsimony, minimum
      evolution, and Bayesian inference for tree reconstruction, and found the large
      subunit rRNA gene to contain far more signal than the small-subunit gene for
      resolving this mostly Mesozoic radiation. Our findings matched those of in
      separating batoids from sharks and in statistically rejecting Hypnosqualea. The
      angel shark (Squatina) was the sister group to squaliforms (dogfish sharks), and
      our findings are consistent with the idea that "orbitostylic" sharks form a
      monophyletic group (squaliforms+the hexanchiform
      Chlamydoselachus+Squatina+Pristiophorus). In the galeomorph sharks, however,
      lamniforms grouped with orectolobiforms, opposing the widely accepted
      'lamniform+carcharhiniform' grouping. A tree based on the mitochondrial gene for
      cytochrome b also supported a separation of sharks and batoids, in contrast to
      Hypnosqualea. Among elasmobranchs, variation in the evolutionary rates of the
      nuclear rRNA genes was higher than that of cytochrome b genes, mainly due to the
      relatively rapid evolution of rRNA in some carcharhiniforms. In conclusion,
      several different molecular studies now refute the Hypnosqualea hypothesis of
      elasmobranch interrelationships.

PMID- 15019622
TI  - From a comb to a tree: phylogenetic relationships of the comb-footed spiders
      (Araneae, Theridiidae) inferred from nuclear and mitochondrial genes.
AB  - The family Theridiidae is one of the most diverse assemblages of spiders, from
      both a morphological and ecological point of view. The family includes some of
      the very few cases of sociality reported in spiders, in addition to bizarre
      foraging behaviors such as kleptoparasitism and araneophagy, and highly diverse
      web architecture. Theridiids are one of the seven largest families in the
      Araneae, with about 2200 species described. However, this species diversity is
      currently grouped in half the number of genera described for other spider
      families of similar species richness. Recent cladistic analyses of morphological
      data have provided an undeniable advance in identifying the closest relatives of
      the theridiids as well as establishing the family's monophyly. Nevertheless, the
      comb-footed spiders remain an assemblage of poorly defined genera, among which
      hypothesized relationships have yet to be examined thoroughly. Providing a robust
      cladistic structure for the Theridiidae is an essential step towards the
      clarification of the taxonomy of the group and the interpretation of the
      evolution of the diverse traits found in the family. Here we present results of a
      molecular phylogenetic analysis of a broad taxonomic sample of the family (40
      taxa in 33 of the 79 currently recognized genera) and representatives of nine
      additional araneoid families, using approximately 2.5kb corresponding to
      fragments of three nuclear genes (Histone 3, 18SrDNA, and 28SrDNA) and two
      mitochondrial genes (16SrDNA and CoI). Several methods for incorporating indel
      information into the phylogenetic analysis are explored, and partition support
      for the different clades and sensitivity of the results to different assumptions
      of the analysis are examined as well. Our results marginally support theridiid
      monophyly, although the phylogenetic structure of the outgroup is unstable and
      largely contradicts current phylogenetic hypotheses based on morphological data.
      Several groups of theridiids receive strong support in most of the analyses:
      latrodectines, argyrodines, hadrotarsines, a revised version of spintharines and
      two clades including all theridiids without trace of a colulus and those without
      colular setae. However, the interrelationships of these clades are sensitive to
      data perturbations and changes in the analysis assumptions.

PMID- 15019623
TI  - Molecular phylogeny and biogeography of the endemic Hawaiian Succineidae
      (Gastropoda: Pulmonata).
AB  - The endemic Hawaiian Succineidae represent an important component of the
      exceptionally diverse land snail fauna of the Hawaiian Islands, yet they remain
      largely unstudied. We employed 663-bp fragments of the cytochrome oxidase I (COI)
      mitochondrial gene to investigate the evolution and biogeography of 13 Hawaiian
      succineid land snail species, six succineid species from other Pacific islands
      and Japan, and various outgroup taxa. Results suggest that: (1) species from the
      island of Hawaii are paraphyletic with species from Tahiti, and this clade may
      have had a Japanese (or eastern Asian) origin; (2) species from five of the
      remaining main Hawaiian islands form a monophyletic group, and the progression
      rule, which states that species from older islands are basal to those from
      younger islands, is partially supported; no geographic origin could be inferred
      for this clade; (3) succineids from Samoa are basal to all other succineids
      sampled (maximum likelihood) or unresolved with respect to the other succineid
      clades (maximum parsimony); (4) the genera Succinea and Catinella are
      polyphyletic. These results, while preliminary, represent the first attempt to
      reconstruct the phylogenetic pattern for this important component of the endemic
      Hawaiian fauna.

PMID- 15019624
TI  - Phylogeny of muroid rodents: relationships within and among major lineages as
      determined by IRBP gene sequences.
AB  - The rodent family Muridae is the single most diverse family of mammals with over
      1300 recognized species. We used DNA sequences from the first exon (
      approximately 1200bp) of the IRBP gene to infer phylogenetic relationships within
      and among the major lineages of muroid rodents. We included sequences from every
      recognized muroid subfamily except Platacanthomyinae and from all genera within
      the endemic Malagasy subfamily Nesomyinae, all recognized tribes of
      Sigmodontinae, and a broad sample of genera in Murinae. Phylogenetic analysis of
      the IRBP data suggest that muroid rodents can be sorted into five major lineages:
      (1) a basal clade containing the fossorial rodents in the subfamilies Spalacinae,
      Myospalacinae, and Rhizomyinae, (2) a clade of African and Malagasy genera
      comprising the subfamilies Petromyscinae, Mystromyinae, Cricetomyinae,
      Nesomyinae, and core dendromurines, (3) a clade of Old World taxa belonging to
      Murinae, Otomyinae, Gerbillinae, Acomyinae, and Lophiomyinae, (4) a clade uniting
      the subfamilies Sigmodontinae, Arvicolinae, and Cricetinae, and (5) a unique
      lineage containing the monotypic Calomyscinae. Although relationships among the
      latter four clades cannot be resolved, several well-supported supergeneric
      groupings within each are identified. A preliminary examination of molar tooth
      morphology on the resulting phylogeny suggests the triserial murid molar pattern
      as conceived by evolved at least three times during the course of muroid
      evolution.

PMID- 15019625
TI  - Phylogeny and evolution of basils and allies (Ocimeae, Labiatae) based on three
      plastid DNA regions.
AB  - A phylogeny of basils and allies (Lamiaceae, tribe Ocimeae) based on sequences of
      the trnL intron, trnL-trnF intergene spacer and rps 16 intron of the plastid
      genome is presented. Several methods were used to reconstruct phylogenies and to
      assess statistical support for clades: maximum parsimony with equally and
      successively weighted characters, bootstrap resampling, and Bayesian inference.
      The phylogeny is used to investigate the distribution of morphological, pericarp
      anatomy, chemical, and pollen characters as well as the geographical distribution
      of the clades. Tribe Ocimeae is monophyletic and easily diagnosable with
      morphological synapomorphies. There are monophyletic clades within Ocimeae that
      broadly correspond to currently recognised subtribes: Lavandulinae, Hyptidinae,
      Ociminae, and Plectranthinae. Only Lavandulinae has clear non-molecular
      synapomorphies. Several currently recognised genera are not monophyletic. Floral
      morphology consistent with sternotribic pollination is most common in Ocimeae,
      but there are independent departures from this model. Buzz pollination is likely
      in some species, the only postulated occurrence of this within Lamiaceae. Quinone
      diterpenoids and flavones in the leaf exudates differ in their distributions
      across the phylogeny and this could contribute to differences in the recorded
      medicinal as well as pesticidal uses of the species in the different clades.
      Mapping geographic distribution on to an ultrametric phylogenetic tree produced
      using non-parametric rate smoothing supports an Asiatic origin for Ocimeae. There
      are several secondary occurrences in Asia arising from the African Ociminae and
      Plectranthinae clades. Colonisation of Madagascar occurred at least five times,
      and New World colonisation occurred at least three times.

PMID- 15019626
TI  - A molecular phylogeny of eurytomid wasps inferred from DNA sequence data of 28S,
      18S, 16S, and COI genes.
AB  - Using partial DNA sequence data from nuclear 28S and 18S genes and mitochondrial
      16S and COI genes, we reconstructed a phylogeny of the family Eurytomidae. Both
      maximum parsimony and Bayesian methods were employed. The analysis revealed a
      significant incongruence between the mitochondrial genes and the nuclear genes,
      and we chose the results from the nuclear genes as our preferred hypothesis. Our
      phylogeny suggested that the family Eurytomidae is not a monophyletic group;
      neither are the genera Eurytoma and Bruchophagus. The monophyly of genera
      Sycophila and Plutarchia was well supported, as was the close association of the
      genera Aiolomorphus, Tenuipetiolus, Bephratelloides, and Phylloxeroxenus. Our
      phylogeny also revealed an anticipated pattern, in which species groups from the
      genera Eurytoma and Bruchophagus are often more closely related to other small
      genera than to other species groups of the same genus. Subsequent taxonomic
      revisions include elevating the subfamily Rileyinae to a family status and the
      divisions of the genera Eurytoma and Bruchophagus.

PMID- 15019627
TI  - Testing alternative vicariance scenarios in Western Mediterranean discoglossid
      frogs.
AB  - Dated molecular phylogenies are often used to interpret evolutionary history with
      respect to paleogeographic events. Where more than one interpretation is
      possible, it is desirable but difficult to assess the alternatives in an
      objective manner. The present work demonstrates a formalized method for testing
      molecular clock calibrations and biogeographic scenarios based on them. We
      assessed the plausibility of several previously published biogeographic
      hypotheses, using the frog genera Alytes, Discoglossus, and Bombina as model
      groups. Our data set comprised ca. 900bp of partial mitochondrial 16S and 12S
      rRNA gene sequences (both genes evolved in a clock-like manner across genera)
      from nearly all the species and subspecies in the three genera. We tested several
      calibrations of a molecular clock, which resulted in competing temporal settings
      for the evolution of taxa. Although only one scenario was in complete accordance
      with paleogeographic data, statistical testing did not reject the alternatives.
      Limitations encountered with the present approach may be overcome by more
      comprehensive analyses in future.

PMID- 15019628
TI  - Molecular phylogeny of Lysimachia (Myrsinaceae) based on chloroplast trnL-F and
      nuclear ribosomal ITS sequences.
AB  - Both nuclear ribosomal ITS and chloroplast trnL-F sequences were acquired for 57
      species (accessions) of Lysimachia and its close relatives, and were analyzed
      together with sequences retrieved from databases. The results of phylogenetic
      analyses based on these data (separately or combined) show that Lysimachia is
      paraphyletic, with the monotypic genus Glaux nested deeply inside. Previous
      suggestions that Anagallis and Trientalis could be ingroups of Lysimachia were
      not corroborated by our results. The molecular phylogenies do not support the
      current infrageneric divisions of Lysimachia. Subgenus Lysimachia contains at
      least five independent lineages. The Hawaii endemic subgenus Lysimachiopsis was
      shown to group with subgenera Palladia and Heterostylandra, instead of subgenus
      Idiophyton as previously suggested. The two North American representatives of
      Lysimachia, subgenus Seleucia and section Verticillatae of subgenus Lysimachia
      are group together as the most basal clade of the genus. Parallel and independent
      evolutions were inferred for morphological characters that were previously used
      as diagnostic criteria. Molecular phylogenies do not offer clear inferences on
      the overall historical biogeography of Lysimachia, but Southeast Asia origins of
      several clades, including the Hawaiian endemic clade and the Iberian Lysimachia
      ephemerum are strongly supported.

PMID- 15019630
TI  - Efficiently resolving the basal clades of a phylogenetic tree using Bayesian and
      parsimony approaches: a case study using mitogenomic data from 100 higher teleost
      fishes.
AB  - Many phylogenetic analyses that include numerous terminals but few genes show
      high resolution and branch support for relatively recently diverged clades, but
      lack of resolution and/or support for "basal" clades of the tree. The various
      benefits of increased taxon and character sampling have been widely discussed in
      the literature, albeit primarily based on simulations rather than empirical data.
      In this study, we used a well-sampled gene-tree analysis (based on 100
      mitochondrial genomes of higher teleost fishes) to test empirically the
      efficiency of different methods of data sampling and phylogenetic inference to
      "correctly" resolve the basal clades of a tree (based on congruence with the
      reference tree constructed using all 100 taxa and 7990 characters). By itself,
      increased character sampling was an inefficient method by which to decrease the
      likelihood of "incorrect" resolution (i.e., incongruence with the reference tree)
      for parsimony analyses. Although increased taxon sampling was a powerful approach
      to alleviate "incorrect" resolution for parsimony analyses, it had the general
      effect of increasing the number of, and support for, "incorrectly" resolved
      clades in the Bayesian analyses. For both the parsimony and Bayesian analyses,
      increased taxon sampling, by itself, was insufficient to help resolve the basal
      clades, making this sampling strategy ineffective for that purpose. For this
      empirical study, the most efficient of the six approaches considered to resolve
      the basal clades when adding nucleotides to a dataset that consists of a single
      gene sampled for a small, but representative, number of taxa, is to increase
      character sampling and analyze the characters using the Bayesian method.

PMID- 15019631
TI  - Evolution and phylogenetic utility of CAD (rudimentary) among Mesozoic-aged
      Eremoneuran Diptera (Insecta).
AB  - We sequenced nearly the entire carbomoylphosphate synthase (CPS) domain of CAD,
      or rudimentary, (ca. 4 kb) from 29 species of flies representing all major clades
      within Eremoneura, or higher flies, and several orthorrhaphous brachyceran
      outgroups. We compared these sequences with orthologs from Anopheles gambiae and
      Drosophila melanogaster to assess structure, compositional bias, and phylogenetic
      utility. CAD is large (6.6+ kb), complex (comprised of three major and myriad
      minor functional domains) and relatively free of introns, extreme nucleotide bias
      (except third codon positions), and large hypervariable regions. The CPS domain
      possesses moderate levels of nonsynonymous divergence among taxa of intermediate
      evolutionary age and conveys considerable phylogenetic signal. Phylogenetic
      analysis of CPS sequences under varying methods and assumptions resulted in well
      resolved, strongly supported trees concordant with many traditional ideas about
      higher dipteran phylogeny and with prior inferences from 28S rDNA. The most
      robustly supported major eremoneuran clades were Cyclorrhapha, Platypezoidea,
      Eumuscomorpha, Empidoidea, Atelestidae, Empidoidea exclusive of Atelestidae,
      Hybotidae s.l., Microphoridae+Dolichopodidae, and Empididae s. str. Because CAD
      is ubiquitous, apparently single copy (at least within holometabolous insects),
      readily obtained from several insect orders using primers described herein, and
      exhibits considerable phylogenetic utility, it should have wide applicability in
      insect molecular systematics.

PMID- 15019629
TI  - Preliminary phylogeny of Valerianaceae (Dipsacales) inferred from nuclear and
      chloroplast DNA sequence data.
AB  - Valerianaceae is a relatively small (ca. 350 species), but morphologically
      diverse angiosperm clade. Sequence data from the entire ndhF gene, the trnL-F
      intergenic spacer region, the trnL intron, the matK region, the rbcL-atpB
      intergenic spacer region and internal transcribed spacer (ITS) region of nuclear
      ribosomal DNA were collected for 21 taxa within Dipsacaceae and Valerianaceae (1
      and 20, respectively). These data were included in several phylogenetic analyses
      with previously published sequences from Dipsacales. Results from these analyses
      (maximum parsimony, maximum likelihood, and Bayesian analysis) are in strong
      agreement with many of the conclusions from previous studies, most importantly:
      (1) Valerianaceae is sister to Dipsacaceae; (2) Triplostegia is more closely
      related to species of Dipsacaceae than to Valerianaceae; and (3) Valeriana
      appears not to be monophyletic, with Valeriana celtica falling outside the
      remainder of the species of Valeriana sampled here (with very strong support).
      With the exception of V. celtica, these data support two major clades within
      Valeriana; one that is exclusively New World and another that is distributed in
      both the Old and New World. Although the species of Valerianaceae and its sister
      group Dipsacaceae plus Triplostegia, are widely distributed in the Northern
      Hemisphere, and the data imply that Valerianaceae diversified initially in Asia
      (the Himalayan Patrinia and Nardostachys falling at the base of the clade), the
      center of modern species diversity for the group is in the Andes of South America
      with as many as 175 species restricted to that region. Although the exclusively
      South American taxa form a clade in the chloroplast and combined ITS and
      chloroplast analyses, support values tend to be low. Future studies will need to
      include additional data, in the form of both characters and taxa, before any
      strong conclusions about the character evolution, diversification, and
      biogeography of the South American valerians can be made.

PMID- 15019632
TI  - Phylogenetic relationships among Passiflora species based on the glutamine
      synthetase nuclear gene expressed in chloroplast (ncpGS).
AB  - This paper presents the first molecular phylogeny of the genus Passiflora
      encompassing almost all sections of this large genus. The nuclear-encoded
      chloroplast-expressed glutamine synthetase gene (ncpGS) was used to examine the
      relationships among Passiflora species (passionflowers), which was then compared
      with the new classification proposed by Feuillet and MacDougal. The resulting
      Bayesian, likelihood, and parsimony trees are congruent and well supported. The
      90 Passiflora species examined apparently split into eight main subgenera:
      Plectostemma, Granadilla, Astrophea, Deidamioides, Polyanthea, Dysosmia,
      Tetrapathea, and Tryphostemmatoides. These results are in overall agreement with
      the Feuillet and MacDougal's classification but here we propose that three
      additional subgenera, Polyanthea, Dysosmia, and Tetrapathea, should be
      maintained. We observe a striking overall correlation between the phylogenetic
      position of the different species and their chromosome number. The first clade
      contains the arborescent species of the subgenus Astrophea, with n=12. The second
      clade, subgenus Plectostemma, includes species from four subgenera of Killip's
      classification with n=6 chromosomes. The last clade, subgenus Granadilla,
      includes species of seven old subgenera with n=9. Subgenus Dysosmia, with a
      variable chromosome number of n=9-11, is considered here as a separate subgenus
      closely related to the subgenus Granadilla.

PMID- 15019633
TI  - Infrageneric phylogenies: a comparison of chloroplast-expressed glutamine
      synthetase, cytosol-expressed glutamine synthetase and cpDNA maturase K in
      Passiflora.

PMID- 15019634
TI  - Changes in coronary endothelial function predict progression of allograft
      vasculopathy after heart transplantation.
AB  - OBJECTIVE: Coronary endothelial dysfunction may be an early marker for cardiac
      allograft vasculopathy (CAV) in orthotopic heart transplant recipients. We used
      serial studies to evaluate changes in coronary endothelial function in patients
      with and without clinically evident CAV. BACKGROUND: In serial studies with
      intravascular ultrasound (IVUS) and Doppler flow wire measurements, we previously
      demonstrated that annual decrements in coronary endothelial function are
      associated with progressive intimal thickening. METHODS: We studied 45 patients
      annually, beginning at transplantation until pre-specified end-points
      (angiographic CAV or cardiac death) were reached. At each study, we measured
      coronary endothelial function using intracoronary infusions of adenosine,
      acetylcholine, and nitroglycerin. We simultaneously recorded IVUS images and
      Doppler velocities. RESULTS: Of the 45 patients studied, 9 reached end-points
      during the study (6 had CAV and 3 died). The mean annual change in area response
      to acetylcholine was -4.5% +/- 3.0% in patients who reached end-points and -0.9%
      +/- 1.5% in those who did not (p = 0.04). The mean annual decrement in flow
      response to acetylcholine was greater in patients who reached end-points (-31% +/
      11% vs -5% +/- 5%, p = 0.08). Responses to adenosine and nitroglycerin did not
      differ. CONCLUSIONS: When serial responses were evaluated, patients with end
      points had more rapid decreases in endothelial function. The rate of disease
      progression may be more important than the absolute degree of intimal thickening
      in early CAV. These data implicate endothelial dysfunction in the development of
      clinically significant vasculopathy and suggest that serial studies of
      endothelial function may provide important prognostic information about the
      development of CAV after heart transplantation.

PMID- 15019635
TI  - Does acute cellular rejection correlate with cardiac allograft vasculopathy?
AB  - BACKGROUND: Previous studies of the association between acute cellular rejection
      and cardiac allograft vasculopathy (CAV) have yielded conflicting conclusions. We
      explored a possible association between acute cellular rejection and the extent
      of CAV, and we found a potential confounding variable that may obscure such an
      association. METHODS: We investigated 140 patients (mean age, 51 +/- 11 years)
      who underwent serial intravascular ultrasound examinations at baseline and at 1
      year after heart transplantation to assess CAV as change in maximal intimal
      thickness (CMIT). Patients were classified according to the presence or absence
      of biopsy-proven myocardial fibrosis. We used a standard biopsy-scoring system
      and a novel biopsy-scoring system, developed in our institution, to assess acute
      cellular rejection. Using univariate analysis, we found that CMIT was not
      associated with acute cellular rejection in the overall patient population (n =
      140). However, we observed a correlation between CMIT and acute cellular
      rejection (standard method, r = 0.30, p = 0.01; novel method, r = 0.51, p <
      0.0001) in patients who had no evidence of ischemic injury or fibrosis in their
      biopsy specimens (n = 57). Step-wise multiple regression showed that the
      rejection score derived from our novel method was associated more closely with
      the CMIT than was that derived from the traditional method. CONCLUSIONS: This
      data indicate that the presence of myocardial fibrosis masks an actuarial
      association between acute cellular rejection and the development of de novo
      allograft vasculopathy. As previously suspected, myocardial fibrosis is a marker
      for non-immune-mediated graft injury independently associated with an increased
      incidence of CAV.

PMID- 15019636
TI  - Donor hepatitis-C seropositivity is an independent risk factor for the
      development of accelerated coronary vasculopathy and predicts outcome after
      cardiac transplantation.
AB  - BACKGROUND: It is possible, but unproven, that hepatitis C (HCV) infection
      accelerates atherosclerosis. We evaluated the hypothesis that donor HCV
      seropositivity predicts mortality and the development of coronary vasculopathy in
      cardiac transplant recipients. METHODS: Thirty-four cardiac transplant recipients
      who were seronegative for HCV at the time of transplantation received hearts from
      HCV-seropositive donors. We compared the mortality and the incidence of
      vasculopathy in this group of patients (study group) with a group of 183
      successive heart transplant recipients (control group) with no evidence of HCV in
      the donor or in the recipient. RESULTS: After transplantation, 75% of the HCV
      seronegative patients who received hearts from HCV-seropositive donors had
      detectable and persistent viremia (presence of HCV-RNA by reverse-transcription
      polymerase chain reaction). After a mean follow-up of 4.2 +/- 1.9 years,
      mortality was 2.8-fold greater in the study group than in controls (95%
      confidence interval [CI], 1.3-5.7; p = 0.006). The risk of having any
      vasculopathy after a mean follow-up of 3.4 +/- 1.6 years and after adjustment for
      other significant risk factors was 3-fold greater (hazards ratio, 3.08; 95% CI
      1.52-6.20; p = 0.001) in the HCV group compared with controls. The risk of
      developing advanced vasculopathy was much greater in the study group compared
      with controls (hazard ratio, 9.4; 97% CI, 3.3-26.6; p = < 0.0001). The risk of
      mortality (p = 0.005) and vasculopathy (p = < 0.0001) was greatest in patients
      with combined donor HCV seropositivity and the presence of antibodies against
      donor B cells by flow cytometry. CONCLUSION: We conclude that donor hepatitis-C
      virus seropositivity is an independent risk factor for increased mortality and
      for the development of accelerated allograft vasculopathy after cardiac
      transplantation. These observations may have implications for the use of HCV
      positive donors in heart transplant recipients.

PMID- 15019637
TI  - Vasoactive peptides during long-term follow-up of patients after cardiac
      transplantation.
AB  - BACKGROUND: Vasoactive peptides are accepted indicators of the degree of heart
      failure and its progression or improvement following medical therapy.
      Normalization of cardiac hemodynamics by cardiac transplantation (HTx) may lead
      to normalization of atrial natriuretic peptide (ANP) and brain natriuretic
      peptide (BNP) plasma levels shortly after the procedure. METHODS: Long-term
      follow-up was done for 14 consecutive patients, 12 men and 2 women, 49 years of
      age (range 24 to 64 years). ANP and BNP were measured by radioimmunoassay (RIA)
      in central venous plasma samples (before breakfast, at steady state) at the
      following intervals after HTx: 7 to 30 (1), 31 to 60 (2), 61 to 90 (3), 120 to
      180 (4) and 210 to 365 (5) days. RESULTS: During follow-up, ANP decreased
      significantly within 2 months after HTx and continued of this level, whereas BNP
      decreased continuously without reaching normal values. The mean ratio of ANP:BNP
      increased from 3.23 to 8.01 during follow-up. Whereas right atrial pressure
      (RAP), right ventricular pressure (RVP), right ventricular end-diastolic pressure
      (RVEDP) and pulmonary capillary wedge pressure (PCWP) did not change during
      follow-up, cardiac output (CO) improved slightly, but significantly from 5.21
      liters/min to 5.9 liters/min (p = 0.035). CONCLUSIONS: Normalization of left
      ventricular function after orthotopic HTx does not induce an early diminution of
      ANP and BNP plasma levels to normal concentrations. Although elevated ANP
      concentrations showed only minimal changes within 1 year, BNP decreased
      significantly as early as 2 months after HTx, without reaching normal values
      during the year of follow-up. Also, the ratio of ANP and BNP increased
      significantly from 3.23 to 8.01. These results demonstrate the contribution of
      other factors beyond cardiac function that determine the levels of these
      peptides.

PMID- 15019639
TI  - Lung transplantation for lymphangioleiomyomatosis.
AB  - BACKGROUND: Lymphangioleiomyomatosis is a rare disease in women leading to
      respiratory failure. We describe a single-institution experience with lung
      transplantation for end-stage lymphangioleiomyomatosis. METHODS: We
      retrospectively reviewed records of patients transplanted for
      lymphangioleiomyomatosis between 1989 and 2001. Follow-up was complete on all
      patients (median 3.5 years). RESULTS: Seven single and 7 bilateral transplants
      were performed on 14 recipients (mean age 41.8 years). Eleven patients suffered
      the following intra-operative complications: dysrhythmia (1); blood loss > 1,000
      ml (7); extensive pleural adhesions (10); hypothermia (1); phrenic nerve injury
      (1); and graft dysfunction (2). The following post-operative complications
      occurred in 11 recipients: dysrhythmia (7); respiratory failure (5); sepsis (3);
      airway dehiscence (2); vocal cord dysfunction (1); cholecystitis (1); deep vein
      thrombosis (1); acute renal failure (1); and pericarditis (1). Post-operative
      chylous fistulas necessitated thoracic duct ligation (1); sclerosis (6); and
      drainage of ascites (1). There were no peri-operative deaths. Late deaths
      occurred due to sepsis in 2 patients and obliterative bronchiolitis in 1 patient.
      Survival rates were 100%, 90% and 69% at (1, 2 and 5 years, respectively.) Mean
      FEV1 (1.77 +/- 1.06 vs 0.60 +/- 0.91) and 6-minute walk (1,519 +/- 379 vs 826 +/-
      293 feet) improved at 1 year as compared with pre-transplant evaluation. Five
      patients reached criteria for bronchiolitis obliterans syndrome. One recipient
      has had a documented recurrence of lymphangioleiomyomatosis in the transplanted
      lung. CONCLUSIONS: Early and late survival after lung transplant are comparable
      in lymphangioleiomyomatosis patients versus patients with other diseases.
      Morbidity is common after transplant for lymphangioleiomyomatosis and is usually
      due to lymphangioleiomyomatosis-related complications. Lymphangioleiomyomatosis
      recurrence in the allograft does not pose a substantial clinical problem.

PMID- 15019638
TI  - Renal insufficiency and end-stage renal disease in the heart transplant
      population.
AB  - BACKGROUND: Renal insufficiency and end-stage renal disease (ESRD) are important
      problems in the cardiac transplant population, and are associated with
      significant morbidity, mortality and financial cost. We undertook this study to
      define pre-operative or early post-operative predictors of subsequent renal
      insufficiency and ESRD. METHODS: We studied 370 patients at Brigham and Women's
      Hospital who received heart transplants between 1984 and 1999, with up to 10-year
      follow-up. We evaluated 2 time-dependent primary outcomes: early reduction in
      GFR, and development of ESRD at any timepoint. Cox proportional hazards modeling
      was used in both univariate and multivariate analyses. RESULTS: The mean
      estimated glomerular filtration rate (GFR) fell 24% within the first post
      transplant year, and remained stable thereafter. By actuarial analysis, 23% of
      patients developed a 50% reduction in GFR by the third year, and 20% developed
      ESRD by the tenth year of follow-up. In Cox multivariate analysis, significant
      predictors of post-transplant ESRD included: GFR <50 ml/min (hazards ratio [HR]
      3.69, p = 0.024); high mean cyclosporine trough in the first 6 months (HR 5.10, p
      = 0.0059); and presence of diabetes (HR 3.53, p = 0.021). Conclusions about renal
      insufficiency outcome were limited by difficulties with accurate estimation of
      GFR and with definition of renal insufficiency. CONCLUSIONS: The results of this
      study underscore the magnitude of the problem of renal insufficiency and ESRD in
      the heart transplant population. In addition, these data suggest that patients at
      high risk for these outcomes can be identified early, even pre-operatively, to
      guide post-operative management.

PMID- 15019641
TI  - Hypercholesterolemia is common after pediatric heart transplantation: initial
      experience with pravastatin.
AB  - BACKGROUND: Coronary allograft vasculopathy (CAV) is a progressive complication
      after cardiac transplantation and limits survival. Hyperlipidemia is a known risk
      factor for CAV, and pravastatin is effective in decreasing cholesterol levels in
      adults after transplantation. However, few data exist regarding lipid profiles
      and statin use after pediatric heart transplantation. We evaluated the prevalence
      of hyperlipidemia in pediatric heart transplant recipients and assessed the
      efficacy and safety of pravastatin therapy. METHODS: We performed a retrospective
      chart review of lipid profiles > or =1 year after surgery in 50 pediatric cardiac
      transplant recipients to assess the incidence of hyperlipidemia. Twenty of these
      patients received pravastatin for hypercholesterolemia. Their primary
      immunosuppression therapy was cyclosporine/prednisone plus either azathioprine or
      mycophenolate mofetil. We reviewed serial lipid profiles, creatinine
      phosphokinase, and liver enzymes. RESULTS: Overall, 36% of the patients (n = 50)
      had total cholesterol (TC) concentrations > 200 mg/dl and 52% had low-density
      lipoprotein (LDL) >110 mg/dL beyond 1 year after transplantation. Of the 20
      treated with pravastatin, TC (236 +/- 51 vs 174 +/- 33 mg/dl) and LDL levels (151
      +/- 32 vs 99 +/- 21 mg/dl) decreased significantly with therapy (p <.0001). We
      found no symptoms; however, 1 patient had increased creatinine phosphokinase.
      Liver enzyme concentrations remained normal in all. CONCLUSIONS:
      Hypercholesterolemia is prevalent in pediatric cardiac transplant recipients.
      Pravastatin therapy is effective in decreasing TC and LDL levels, seems to be
      safe, and is tolerated well. Further studies are necessary to determine whether
      pravastatin treatment is beneficial in decreasing CAV.

PMID- 15019640
TI  - Donor history of asthma is not a contraindication to lung transplantation: 12
      year single-center experience.
AB  - BACKGROUND: Donor asthma has been regarded as a contraindication to lung
      transplantation (LTx) because of concerns that pre-existing airway inflammation
      will predispose to early and late graft dysfunction. The aim of this study was to
      describe LTx outcomes in which lungs had been transplanted from donors with a
      history of asthma. METHODS: A retrospective chart review was undertaken of 743
      consecutive donor lung referrals to the Alfred Hospital between 1990 and
      September 2002. Seventy-four were noted to have a history of asthma, including 18
      in whom asthma was the cause of death. Twenty-seven patients became lung donors,
      of whom 16 were on asthma treatment (on-treatment group) and 11 were not (no
      treatment group). RESULTS: From 27 lung donors, 35 LTx procedures were performed
      (16 double LTx [DLTx], 19 single LTx [SLTx]). Five recipients died at <30 days
      (including 3 of early graft failure in the no-treatment group), and 7 died at >30
      days (only 1 due to BOS). The 30-day, 1-year and 5-year survival rates in the on-
      and no-treatment donor groups were 90% vs 76%, 74% vs 69% and 74% vs 60%,
      respectively, and were not significantly different from our overall LTx survival
      rates. There were no significant differences in percent predicted forced
      expiratory volume in 1 second, ICU stay or hospital stay overall, or when
      analyzed according to on treatment vs no treatment and SLTx vs DLTx. Only 2
      procedures LTx were performed from fatal asthma donors, both of whom had
      subsequent graft dysfunction and died on Days 73 and 484, respectively.
      CONCLUSIONS: The use of lungs from carefully selected lung donors with a history
      of asthma may increase the donor pool with acceptable long-term outcomes. The use
      of fatal asthma donors remains problematic.

PMID- 15019642
TI  - Identifying cardiac transplant rejection in children: diagnostic utility of
      echocardiography, right heart catheterization and endomyocardial biopsy data.
AB  - BACKGROUND: There has been a continued search for alternative diagnostic
      techniques that do not necessitate endomyocardial biopsy for diagnosing rejection
      in cardiac transplant recipients. The purpose of this study is to evaluate the
      role of echocardiography and hemodynamic catheterization data compared with
      endomyocardial biopsy results, in rejection surveillance for the pediatric heart
      transplant recipient. METHODS: A prospective, blinded evaluation was performed
      utilizing echocardiographic and standard right heart catheterization parameters
      to predict acute rejection episodes. RESULTS: Forty-nine patients underwent 281
      biopsies. Two groups were defined: those with Grade <2 rejection and those with
      grade > or =2 rejection. None of the echocardiographic variables showed
      significant differences between the study groups and all group data were within
      normal limits. Mixed venous saturation, mean right atrial pressure, right
      ventricular end-diastolic pressure and mean pulmonary artery pressure were found
      to be statistically significant between groups. Receiver-operator characteristic
      (ROC) curves were constructed to determine the extent to which the various
      parameters were clinically useful. The ROC found little clinical usefulness for
      all variables, including those found to be statistically significant.
      CONCLUSIONS: Differences in both echocardiographic and hemodynamic data were not
      clinically significant between the 2 groups of patients. Although many of the
      catheterization-derived parameters were statistically significant, they did not
      permit effective discrimination between groups. This is the only clinically
      relevant application of such data and may explain the conflicting previous
      reports. It is only through analyses such as ROC that the clinical application
      (or lack thereof) can be appreciated in this population.

PMID- 15019643
TI  - Are non-brain stem-dead cardiac donors acceptable donors?
AB  - BACKGROUND: The deleterious effects of brainstem death (BSD) on donor cardiac
      function and endothelial integrity have been documented previously. Domino
      cardiac donation (heart of a heart-lung recipient transplanted into another
      recipient) is a way to avoid the effects of brainstem death and may confer both
      short- and long-term benefits to allograft recipients. METHODS: This study
      evaluates short- and long-term outcome in heart recipients of BSD donors
      (cadaveric) as compared with domino hearts explanted from patients who underwent
      heart-lung transplantation. RESULTS: Patients having undergone cardiac
      transplantation between April 1989 and August 2001 at Papworth Hospital were
      included (n = 571). Domino donor hearts were used in 81 (14%) of these cases. The
      pre-operative transpulmonary gradient was not significantly different between the
      two groups (p = 0.7). There was no significant difference in 30-day mortality
      (4.9% for domino vs 8.6% for BSD, p = 0.38) or in actuarial survival (p = 0.72).
      Ischemic time was significantly longer in the BSD group (p < 0.001). Acute
      rejection and infection episodes were not significantly different (p = 0.24 vs:
      0.08). Relative to the BSD group, the risk (95% confidence interval) of acute
      rejection in the domino group was 0.89 (0.73 to 1.08). Similarly, the relative
      risk of infection was 0.78 (0.59 to 1.03). The 5-year actuarial survival rates
      (95% confidence interval) were 78% (69% to 87%) and 69% (65% to 73%) in the
      domino and BSD groups respectively. Angiography data at 2 years were available in
      50 (62%) and 254 (52%) patients in the domino and BSD groups, respectively. The
      rates for 2-year freedom from cardiac allograft vasculopathy (CAV) were 96% (91%
      to 100%) and 93% (90% to 96%), respectively. CONCLUSION: Despite the lack of
      endothelial cell activation after brainstem death and a shorter ischemic time,
      the performance of domino donor hearts was similar to that of BSD donor hearts.
      This may indicate a similar pathology (i.e., endothelial cell activation) in the
      domino donors.

PMID- 15019644
TI  - Sustained suppression of peripheral blood immune functions by treatment with
      mycophenolate mofetil correlates with reduced severity of cardiac allograft
      rejection.
AB  - BACKGROUND: We tested the hypothesis that sustained suppression of immune
      functions by mycophenolate mofetil (MMF) throughout the dosing interval reduces
      the severity of rejection. METHODS: Four groups of rat heart allograft recipients
      were treated orally daily through Day 5 with either: "low-dose" MMF, 10 mg/kg
      once daily (QD) or 5 mg/kg twice daily (BID); or "high-dose" MMF, 20 mg/kg QD or
      10 mg/kg BID. The following were determined for all animals on Day 6:
      pharmacokinetics (PK, using high-performance liquid chromatography) of
      mycophenolic acid (MPA); pharmacodynamics (PD, by flow cytometry quantitation of
      whole blood mitogen-stimulated lymphocyte proliferation and expression of diverse
      T-cell surface activation molecules); and histologic graft rejection scores (RS).
      RESULTS: RS correlated with PD for suppression of both lymphocyte proliferation
      and transferrin receptor expression (r2 = 0.85 and 0.81, respectively) more
      highly than with MPA plasma levels (r2 = 0.45), which shows the validity of PD as
      surrogate markers of MMF efficacy. MMF 5 mg/kg BID produced greater (p < 0.001)
      suppression of lymphocyte proliferation (area under the PD effect-time curve, AUE
      = 2,010% inhibition. hour) and sustained trough (E0) PD effect (86% suppression)
      than MMF 10 mg/kg QD (AUE = 1,436% inhibition. hour, E0 = 55%). RS did not differ
      between the 20 mg/kg QD and 10 mg/kg BID "high-dose" groups, because PD was
      maximally suppressed. CONCLUSIONS: PD were surrogate markers for MMF
      immunosuppressive efficacy. MMF 5 mg/kg BID produced more sustained suppression
      of both PD and rejection than MMF 10 mg/kg QD.

PMID- 15019645
TI  - Histidine-tryptophan-ketoglutarate solution maximally preserves endothelium
      derived hyperpolarizing factor-mediated function during heart preservation:
      comparison with University of Wisconsin solution.
AB  - BACKGROUND: The University of Wisconsin (UW) solution is used widely in heart
      preservation but has been demonstrated to be detrimental to the endothelial
      function. The present study compares the effect of histidine-tryptophan
      ketoglutarate (HTK) and UW solutions on endothelium-derived hyperpolarizing
      factor (EDHF)-mediated function in porcine small coronary arteries. METHODS: An
      isometric force study was performed in a myograph and the membrane potential of a
      single smooth muscle cell was measured electrophysiologically. Small coronary
      arteries (diameter 457 +/- 15 microm) were incubated with UW (n = 8), HTK (n = 7)
      or Krebs solution (n = 15) at 4 degrees C for 4 hours. After washout, in the
      presence of indomethacin (Indo; 7 micromol/liter), N(G)-nitro-l-arginine (l-NNA;
      300 micromol/liter) and oxyhemoglobin (HbO; 20 micromol/liter), bradykinin (BK; 
      10 to -6.5 log M)-induced relaxation was compared in U46619 (-8 log M) pre
      contraction. EDHF-mediated hyperpolarization was elicited by BK (-6.5 log M) in
      the presence of Indo, l-NNA and HbO. RESULTS: BK-induced, EDHF-mediated
      relaxation was reduced from 93.6 +/- 2.8% to 79.7 +/- 4.6% after UW preservation
      (p = 0.01 by unpaired t-test and p = 0.005 by 2-way analysis of variance
      [ANOVA]), whereas HTK incubation did not decrease EDHF-mediated relaxation (87.0
      +/- 6.5%, p = 0.3 by unpaired t-test and p = 0.6 by 2-way ANOVA, compared with
      control, and p = 0.001 by 2-way ANOVA, compared with UW). EDHF-mediated
      hyperpolarization (10.3 +/- 1.6 mV) was attenuated by UW exposure (3.4 +/- 0.6
      mV, [p = 0.002] vs control), but not by HTK exposure (8.3 +/- 1.1 mV, [p = 0.3]
      vs control). CONCLUSIONS: HTK is superior to UW solution in protecting EDHF
      mediated endothelial function in porcine small coronary arteries. The present
      findings supports the use of HTK solution in heart preservation.

PMID- 15019646
TI  - Functional status and perceived control influence quality of life in female heart
      transplant recipients.
AB  - BACKGROUND: The purpose of this study was 2-fold: (1) to describe and compare the
      quality of life (QOL) and psychologic well-being of 2 groups of women matched for
      age and functional status (6-minute walk distance), including those who had
      received a heart transplant and those who were candidates on a transplant waiting
      list; and (2) to identify correlates of QOL in female heart transplant
      recipients. METHODS: Data were collected from 50 female recipients (mean age 54.7
      +/- 13.0 years) and 50 female candidates (mean age 56.8 +/- 12.2 years) from a
      major heart transplant facility using the Minnesota Living with Heart Failure
      Questionnaire, the Beck Depression Inventory and the Control Attitude Scale.
      RESULTS: The overall QOL scores were 28.0 +/- 26.4 and 56.3 +/- 26.1 for
      recipients and candidates, respectively (p < 0.01), with lower scores denoting
      higher QOL. The mean physical health (11.3 +/- 11.2 vs 19.9 +/- 12.1, p < 0.01)
      and emotional health (7.5 +/- 8.2 vs 12.8 +/- 7.8, p < 0.001) scores were also
      lower (reflecting higher physical and emotional health) for recipients as
      compared with candidates. Likewise, recipients reported significantly (p < 0.001)
      lower depressive moods (23.2 +/- 8.2 vs 45.8 +/- 16.3) and higher perceived
      control (10.9 +/- 4.3 vs 8.6 +/- 1.9) compared with candidates. Functional
      status, depression and perceived control were significant correlates of QOL among
      female recipients and accounted for 49% variance in overall QOL. CONCLUSIONS:
      Although overall QOL of was better among female heart transplant recipients than
      candidates, both groups of women reported poor QOL. Clinicians need to identify
      potential resources and interventions to improve QOL both before and after heart
      transplant surgery.

PMID- 15019647
TI  - New therapeutic option for cardiac ischemia in transplant vasculopathy: spinal
      cord stimulation.

PMID- 15019648
TI  - Gastric pacing for severe gastroparesis in a heart-lung transplant recipient.
AB  - Gastroparesis is a serious complication of lung and heart-lung transplantation
      that can lead to malnutrition, gastroesophageal reflux, aspiration pneumonia and
      deteriorating lung function. Some patients with severe gastroparesis have
      symptoms that are refractory to dietary modifications and gastric promotility
      agents and require surgery. We describe the successful use of gastric pacing for
      the management of intractable gastroparesis, malnutrition and recurrent
      aspiration in a heart-lung allograft recipient. Lung transplant recipients with
      severe gastroparesis may benefit from gastric pacing.

PMID- 15019649
TI  - Right pneumonectomy for adenocarcinoma stage IIIA-N2 in a heart transplant
      patient after induction chemotherapy.
AB  - Lung tumors are the most frequent solid tumor in the heart transplant population.
      Unfortunately, most of these patients are in an advanced stage of disease at the
      time of presentation, which carries a poor prognosis. We present a heart
      transplant patient with histologically proven. Stage IIIA-N2 bronchogenic
      adenocarcinoma who had complete lymph-node downstaging after induction
      chemotherapy and underwent a complete tumor resection by right pneumonectomy.

PMID- 15019650
TI  - Further evidence of cardiomyocyte apoptosis in humoral (microvascular) rejection
      of human cardiac allografts.

PMID- 15019651
TI  - An examination of the incidence of intubation and mechanical ventilation beyond
      the peri-operative period in pediatric heart transplant recipients.

PMID- 15019652
TI  - Surgical research revisited: clinical trials in the cardiothoracic surgical
      literature.
AB  - OBJECTIVE: Surgeons have been criticised for not undertaking high-quality
      research. This study examines the quality of randomised controlled trials (RCTs)
      in the cardiothoracic surgical literature with a view to revisiting the role of
      RCTs in surgical research. METHODS: All RCTs published in 1998 and 1999 in three
      major international cardiothoracic journals were analysed for basic components of
      trial design and presentation. RESULTS: We found 119 papers presented as RCTs.
      The median size of treatment arms per RCT was 20 (interquartile range 14-40). Of
      20 dimensions of trial quality examined, 12 or more were deficient (not described
      or performed inadequately) in half of the studies. Key information was frequently
      missing. Additionally, most trials relied on 'soft' endpoints, using surrogate
      (72, 61%) rather than clinical, and numerical (102, 86%) rather than categorical
      outcomes suggesting lack of power to detect clinically relevant differences.
      Although most trials reported positive results (73, 63%), only in 18 (15%) did
      authors make recommendations for practice change. CONCLUSIONS: Many RCTs in
      surgery by virtue of their design, sample size, and insufficient power are
      incapable of answering the questions researchers seek to address. Surgical trials
      often may not exclude bias because of lack of blinding and variations in surgical
      technique and performance. It is arguable that for most study questions in
      clinical surgery, comparative analysis of large case series and databases will
      provide more robust evidence.

PMID- 15019653
TI  - Myocardial ischemia, stunning, inflammation, and apoptosis during cardiac
      surgery: a review of evidence.
AB  - Cardiac surgery (CS), in particular cardiopulmonary bypass and cardioplegia, have
      been reported to trigger myocardial inflammation and apoptosis. This surgery
      related inflammatory reaction appears to be of extreme complexity with regard to
      its molecular, cellular and tissue mechanisms. Both experimental and clinical
      studies have ascertained the role of several hormonal mediators, mitochondria,
      cardioplegia and extracorporeal circulation temperature, apoptosis and even
      genetic modulators of damage. However, the correlations between these factors in
      vivo and post-surgery outcome and prognosis have not yet been systematically
      investigated. In animal models of myocardial cardioplegia and/or ischemia
      reperfusion, experimental drugs such as antioxidants have been documented to
      provide amelioration of post-intervention cardiac performance and reduction of
      apoptosis suggesting the possibility of new therapeutic strategies. However,
      these findings have been only partially confirmed in humans. Moreover, markers
      for the differential detection of early and late phases of apoptosis are subjects
      of intense investigations. This review will provide an overview of the major
      studies about the link between ischemia, myocardial inflammation and apoptosis
      during and after CS, with particular regard to the markers and methods for
      apoptosis detection.

PMID- 15019654
TI  - On-line variable live-adjusted displays with internal and external risk-adjusted
      mortalities. A valuable method for benchmarking and early detection of
      unfavourable trends in cardiac surgery.
AB  - OBJECTIVE: Benchmarking and early detection of unfavourable trends. METHODS: We
      implemented a dedicated project-orientated data warehouse, which continuously
      supplies data for on-line computing of the variable live-adjusted displays
      (VLADs). To calculate the expected cumulative mortality, we used the multi
      variate logistic regression model of the EuroSCORE model. In addition to the
      external EuroSCORE standard, we calculated a centre-specific risk score for
      internal standards by analysing the data of 9135 patients, which enables both
      internal and external comparisons. The VLADs are embedded into the multi-purpose
      web-based information portal, so that the physicians can investigate several
      types of VLADs interactively: performance of different types of surgery and
      individual surgeons for different time intervals. We investigated clinically
      important events such as modification of operative techniques and personnel
      changes of the team by the VLADs. RESULTS: We found transient declines in the
      performance curves during major changes in patient management, indicating that
      systemic--rather than accidental or patient related factors--were involved in the
      mortality risk. The internal standard line represents these clusters more clearly
      than the external line. We evaluated examples of how periods of increased risk
      could be monitored by the VLAD curves: (1) the introduction of OPCAB surgery; (2)
      training of surgeons; (3) staff changes and staff-related management.
      CONCLUSIONS: On-line VLADs based on a day-to-day updated database, displaying
      both internal and external standards, are a helpful visualisation tool for
      earlier detection of unfavourable trends. They enable the surgeon teams and
      clinical management to take countermeasures at an early stage.

PMID- 15019655
TI  - Impairment of cardiovascular autonomic control in patients early after cardiac
      surgery.
AB  - OBJECTIVE: Impairment of the baroreceptor reflex activity reflects an alteration
      of the autonomous regulation of the cardiovascular system and has proven to
      predict fatal outcome in patients after acute myocardial infarction. The
      following study was performed to analyse the baroreceptor sensitivity, heart rate
      variability and blood pressure variability in patients early after coronary
      surgery. METHODS: Twenty-five male patients undergoing coronary artery bypass
      were examined in a prospective study; normal values were obtained from healthy
      volunteers. Arterial pressure signals were recorded from a radial artery catheter
      for 30 min preoperatively and in short intervals after surgery. Mechanical
      manipulations and pharmacological interventions were avoided during the sampling
      periods. Baroreflex function was calculated according to the dual sequence
      method, heart rate variability and blood pressure variability were calculated
      including nonlinear methods. RESULTS: Initial values of the patients did not
      differ from healthy volunteers. The strength of baroreflex sensitivity (increase
      in blood pressure causing a synchronous decrease of heart rate) is low 2 h
      postoperatively. The number of delayed tachycardic changes of heart rate, which
      are caused by sympathetic activation, is only moderately reduced as compared to
      values obtained from healthy volunteers. Heart rate variability is widely
      unchanged as compared to preoperative values; blood pressure variability showed
      an increase of low-frequency components, again indicating sympathetic
      predominance. Nonlinear analyses revealed reduced system complexity at the
      beginning of the postoperative course. CONCLUSION: Obviously, there is a vagal
      suppression 20 h after surgery, while the sympathetic tonus works in a normal
      range. This unbalanced interaction of the autonomous systems is similar to
      findings in patients after myocardial infarction. The predictive value of these
      markers has to be elucidated in further clinical studies.

PMID- 15019656
TI  - Risk factors and outcomes for 'vasoplegia syndrome' following cardiac
      transplantation.
AB  - OBJECTIVE: Vasoplegia syndrome after orthotopic heart transplantation (OHT) is a
      rare but highly lethal syndrome of unknown etiology, characterized by severe
      refractory hypotension, metabolic acidosis, and decreased systemic vascular
      resistance (SVR). The objective of this retrospective study was to identify the
      risk factors contributing to the development of vasoplegia syndrome after OHT in
      order to provide potential algorithms for its management. METHODS: Between
      October 1992 and July 2001, 187 consecutive patients underwent OHT. Complete pre-
      and post-data were available in 147 patients (78%). Mean age was 49+/-11 years,
      82% (120/147) were male, and donor ischemic time was 117+/-62 min. Twenty-eight
      of 147 (19%) developed vasoplegia syndrome, defined as SVR <800 dyns per cm(5)
      with serum bicarbonate <20 mEq/l. RESULTS: Patients who developed vasoplegia
      syndrome demonstrated greater hospital mortality (25 vs. 9%, P=0.031) compared to
      those who did not. Multivariate logistic regression identified pre-operative use
      of intravenous heparin (OR 2.8, CI 1-7.4, P=0.039) and body surface area >1.9
      m(2) (OR 7, CI 0.98-50, P=0.052) as independent predictors for the development of
      post-operative vasoplegia syndrome. Pre-operative use of inotropic support
      conferred protection against the development of post-operative vasoplegia
      syndrome (OR 0.25, CI 0.08-0.79, P=0.018). Pre-operative use of ACE inhibitors
      was not associated with increased risk (55 vs. 59%, P=0.441). CONCLUSIONS:
      Vasoplegia syndrome following OHT is associated with high early mortality. The
      development of a risk stratification profile may help in patient selection as
      well as the post-operative management of vasoplegia syndrome following OHT.

PMID- 15019658
TI  - Autologous peripheral stem cell transplantation in patients with congestive heart
      failure due to ischemic heart disease.
AB  - OBJECTIVE: Ischemic heart disease accounts for 50% of all cardiovascular deaths
      and is the leading cause of congestive heart failure. Medical therapy, cardiac
      assist devices and surgical procedures including heart transplantation have
      limited efficiency and availability. Stem cell transplantation represents a new
      therapeutic opportunity for such patients. METHOD: Six patients with the
      diagnosis of ischemic cardiomyopathy were included in this study. All of the
      patients had clinical, radiological and echocardiographic signs of heart failure,
      and reduced left ventricular ejection fraction (LVEF< or =25%). They underwent
      coronary angiography and stress tests with dobutamine echocardiography, thallium
      scintigraphy and positron emission tomography to assess myocardial ischemia and
      viability. Peripheral stem cells were mobilized and collected by apheresis. They
      were transplanted into areas of injury with open-heart surgery. To increase blood
      flow to the engrafted areas, coronary artery by-pass surgery was also performed.
      RESULTS: The patients were followed at least for 4 months. Echocardiography,
      thallium scintigraphy and positron emission tomography were repeated after at
      least 6 weeks following surgery. There was a significant increase in life quality
      and NYHA class. Some benefit was documented on echocardiography, thallium
      scintigraphy, and positron emission tomography. CONCLUSION: This approach opens a
      new window in the treatment of 'no hope' patients with congestive heart failure.

PMID- 15019657
TI  - Renal recovery after conversion to a calcineurin inhibitor-free immunosuppression
      in late cardiac transplant recipients.
AB  - OBJECTIVE: Calcineurin inhibitor (CNI)-related renal failure is a common problem
      after cardiac transplantation (HTx). The aim of this prospective study was to
      evaluate the safety and efficacy of a completely CNI-free immunosuppressive
      regimen [mycophenolate mofetil (MMF) and sirolimus (Sir)] in HTx-recipients with
      late post-transplant renal impairment. METHODS: Since 2001, 30 HTx-patients (25
      men, 6 women; 0.2-14.2 years after transplantation) with CNI-based
      immunosuppression and a serum creatinine >1.9 mg/dl were included in the study.
      Creatinine and cystatin levels were monitored to detect renal function.
      Conversion was started with 6 mg Sir or 500 mg MMF according to the pre-existing
      regimen and was continued with the dose adjusted to achieve target trough levels
      between 8 and 14 ng/ml (Sir) or 1.5 and 4 microg/ml (mycophenolate).
      Subsequently, the CNIs were tapered down and stopped. Clinical follow-up included
      endomyocardial biopsies, echocardiography and laboratory studies. Additionally,
      every HTx-patient treated at our centre between 1996 and 2001 due to chronic
      renal failure without immunosuppressive conversion and fulfilling the inclusion
      criteria were retrospectively analysed and acted as control group. RESULTS:
      Patient demographics and 1-year survival [93 (conversion) vs 90% (control)] were
      compared. No acute rejection episode was detected in either group. Renal function
      improved significantly in the conversion group (creatinine: 3.18+/-0.71 vs 2.22+/
      0.79 mg/dl, P=0.001; cystatin pre- vs post-conversion: 2.95+/-1.06 vs 2.02+/-1.1
      mg/l, P=0.01). In three patients haemodialysis therapy was stopped completely
      after conversion. In the control group renal impairment was deteriorating,
      creatinine increased from 2.44+/-0.8 to 3.28+/-1 mg/dl (P=0.01). In 10 out of 33
      patients chronic haemodialysis had to be initiated within 1 year. Although side
      effects of CNI-free immunosuppression were common (76%), no patient had to be
      excluded due to adverse effects. CONCLUSIONS: Conversion from CNI-based
      immunosuppression to MMF and Sir in HTx-patients with chronic renal failure was
      safe, preserved graft function and improved renal function.

PMID- 15019660
TI  - Changes in mitral annular and left ventricular dimensions and left ventricular
      pressure-volume relations after off-pump treatment of mitral regurgitation with
      the Coapsys device.
AB  - OBJECTIVE: The objective of this study was to evaluate the changes in mitral
      annular and left ventricular dimensions and left ventricular pressure-volume
      relations produced by the Myocor Coapsys device that has been developed to treat
      functional mitral regurgitation (MR) off-pump. METHODS: The Coapsys device, which
      consists of anterior and posterior epicardial pads connected by a sub-valvular
      chord, was implanted in seven dogs with functional MR resulting from pacing
      induced cardiomyopathy. The Coapsys device was then sized by drawing the
      posterior leaflet and annulus toward the anterior leaflet. During sizing, MR
      grade was assessed using color flow Doppler echocardiography. Final device size
      was selected when MR was eliminated or minimized. Following implantation, heart
      failure was maintained by continued pacing for a period of 8 weeks. Mitral
      annular and left ventricular dimensions and left ventricular pressure-volume
      relations were evaluated by two-dimensional echocardiography and a conductance
      catheter, respectively, at pre-sizing, post-sizing, and after 8 weeks. RESULTS:
      All implants were performed on beating hearts without cardiopulmonary bypass.
      Mean MR grade was reduced from 2.9+/-0.7 at pre-sizing to 0.7+/-0.8 at post
      sizing (P<0.001), and was maintained at 0.8+/-0.8 after 8 weeks (P<0.01). The
      septal-lateral dimensions were significantly reduced at both mitral annular level
      [2.4+/-0.2 cm at pre-sizing, 1.5+/-0.3 cm at post-sizing (P<0.001) and 1.8+/-0.3
      cm after 8 weeks (P<0.05)] and mid-papillary level [4.1+/-0.4 cm at pre-sizing,
      2.4+/-0.2 cm at post-sizing (P<0.001) and 3.3+/-0.4 cm after 8 weeks (P<0.001)].
      The end-systolic pressure-volume relation shifted leftward at post-sizing with a
      significantly steeper slope (P=0.03). There was a significant (P=0.03) leftward
      shift of the end-diastolic pressure-volume relation at post-sizing. After 8
      weeks, these changes in pressure-volume relations tended to return to pre-sizing
      relations. CONCLUSIONS: The Coapsys device significantly reduced MR by treating
      both the mitral annular dilatation and the papillary muscle displacement. Despite
      these significant dimensional changes, the Coapsys device did not negatively
      affect the left ventricular pressure-volume relations.

PMID- 15019661
TI  - Relation between size of prosthesis and valve gradient: comparison of two aortic
      bioprosthesis.
AB  - OBJECTIVES: The outcome of patients undergoing aortic valve replacement (AVR) may
      be affected by the influence of prosthesis-patient mismatch on left ventricular
      mass regression. However, due to the discrepancies in labeled valve size, size of
      sizer and actual valve dimension, it is difficult to compare different valve
      types. In order to perform an objective comparison, this study was designed to
      compare the hemodynamics of the Edwards Lifescience pericardial (ELP) and the
      Medtronic Mosaic porcine (MM) bioprosthesis between patients receiving the same
      valve size and between patients with the same aortic annulus diameter. METHODS:
      This prospective, randomized study was performed on 81 hospital survivors out of
      86 patients undergoing AVR with either the ELP (n=39) or the MM (n=42)
      bioprosthesis. Intra-operative randomization was performed after the surgeon had
      excised the aortic valve, measured the size of the aortic annulus with three
      different sizers (ELP, MM and a set of metric sizers), and decided which size he
      would implant for either of the valve types. All valves were implanted in supra
      annular position with the same implantation technique. Echocardiographic follow
      up was performed early postoperatively and 6 months thereafter. RESULTS: In 12
      (31%) of the patients receiving the ELP-valve, as compared to 3 (7.1%) of the
      patients receiving the MM-valve, the labeled valve size was smaller than the
      aortic annulus diameter (P<0.05). Early postoperatively, mean (17.4+/-3.1 vs
      20.3+/-3.6 mmHg) and peak gradients (30.1+/-4.8 vs 37.6+/-9.6 mmHg) for the 21 mm
      ELP-valve were lower than for the 21 mm MM-valve (P<0.05). All other hemodynamic
      parameters did not show significant differences at any time point. When the same
      aortic annulus diameter was taken as a reference, there were no significant
      hemodynamic differences between either valve type at any time point, regardless
      of the valve size implanted. CONCLUSIONS: This study demonstrates that the
      hemodynamic performance of the ELP and the MM bioprosthesis are comparable when
      the same aortic annulus diameter is taken as a reference. The significant
      variabilities between different valve types with regard to labeled valve size,
      valve-sizer size and actual valve size have to be taken into account, when
      hemodynamic comparisons are performed.

PMID- 15019662
TI  - Late incidence and determinants of reoperation in patients with prosthetic heart
      valves.
AB  - OBJECTIVES: Reoperation is a relatively common event in patients with prosthetic
      heart valves, but its actual occurrence can vary widely from one patient to
      another. With a focus on bioprosthetic valves, this study examines risk factors
      for reoperation in a large patient cohort. METHODS: Patients (N=3233) who
      underwent a total of 3633 operations for aortic (AVR) or mitral valve replacement
      (MVR) between 1970 and 2002 were prospectively followed (total 21,179 patient
      years; mean 6.6+/-5.0 years; maximum 32.4 years). The incidence of prosthetic
      valve reoperation and the impact of patient- and valve-related variables were
      determined with actual and actuarial methods. RESULTS: Fifteen-year actual
      freedom from all-cause reoperation was 94.1% for aortic mechanical valves, 61.4%
      for aortic bioprosthetic valves, 94.8% for mitral mechanical valves, and 63.3%
      for mitral bioprosthetic valves. In both aortic and mitral positions, current
      bioprosthesis models had significantly better durability than discontinued
      bioprostheses (15-year reoperation odds-ratio 0.11+/-0.04; P<0.01 for aortic, and
      0.42+/-0.14; P=0.009 for mitral). Current bioprostheses were significantly more
      durable in the aortic position than in the mitral position (14.3+/-6.8% more
      freedom from 15-year reoperation; (P=0.018)). Older age was protective, but
      smoking was an independent risk factor for reoperation after bioprosthetic AVR
      and MVR (hazard ratio for smoking 2.58 and 1.78, respectively). In patients with
      aortic bioprostheses, persistent left ventricular hypertrophy at follow-up and
      smaller prosthesis size predicted an increased incidence of reoperation, while
      this was not observed in patients with mitral bioprostheses. CONCLUSIONS: These
      analyses indicate that current bioprostheses have significantly better durability
      than discontinued bioprostheses, reveal a detrimental impact for smoking after
      AVR and MVR, and indicate an increased reoperation risk in patients with a small
      aortic bioprosthesis or with persistent left ventricular hypertrophy after AVR.

PMID- 15019663
TI  - The Silzone effect: how to reconcile contradictory reports?
AB  - OBJECTIVE: To attempt to reconcile reports containing contradictory findings with
      the St. Jude Medical Silzone heart valve. METHODS: Major leak and thromboembolism
      data were extracted from available Silzone valve studies. Linearized rates were
      used to summarize and compare the events rates among the studies. RESULTS: The
      Artificial Valve Endocarditis Reduction Trial (AVERT) study reported significant
      higher rate of major leak and the Cardiff Embolic Risk Factor Study (CERFS)
      reported significant higher rate of thromboembolism with Silzone compared to non
      Silzone valves. But, current updates of these studies show a diminution of these
      differences. Three other comparative studies reported no difference between
      Silzone and non-Silzone valves, and three single arm studies reported acceptable
      results with Silzone valves. CONCLUSION: The contradictory findings could be
      partly due to clinical and technical reasons. No new events have been reported
      since the original AVERT (major leak) and CERFS (mitral thromboembolism)
      publications.

PMID- 15019664
TI  - Systolic ventricular filling.
AB  - The evidence of the ventricular myocardial band (VMB) has revealed unavoidable
      coherence and mutual coupling of form and function in the ventricular myocardium,
      making it possible to understand the principles governing electrical, mechanical
      and energetical events within the human heart. From the earliest Erasistratus'
      observations, principal mechanisms responsible for the ventricular filling have
      still remained obscured. Contemporary experimental and clinical investigations
      unequivocally support the attitude that only powerful suction force, developed by
      the normal ventricles, would be able to produce an efficient filling of the
      ventricular cavities. The true origin and the precise time frame for generating
      such force are still controversial. Elastic recoil and muscular contraction were
      the most commonly mentioned, but yet, still not clearly explained mechanisms
      involved in the ventricular suction. Classical concepts about timing of
      successive mechanical events during the cardiac cycle, also do not offer
      understandable insight into the mechanism of the ventricular filling. The net
      result is the current state of insufficient knowledge of systolic and
      particularly diastolic function of normal and diseased heart. Here we summarize
      experimental evidence and theoretical backgrounds, which could be useful in
      understanding the phenomenon of the ventricular filling. Anatomy of the VMB, and
      recent proofs for its segmental electrical and mechanical activation, undoubtedly
      indicates that ventricular filling is the consequence of an active muscular
      contraction. Contraction of the ascendent segment of the VMB, with simultaneous
      shortening and rectifying of its fibers, produces the paradoxical increase of the
      ventricular volume and lengthening of its long axis. Specific spatial arrangement
      of the ascendent segment fibers, their interaction with adjacent descendent
      segment fibers, elastic elements and intra-cavitary blood volume (hemoskeleton),
      explain the physical principles involved in this action. This contraction occurs
      during the last part of classical systole and the first part of diastole.
      Therefore, the most important part of ventricular diastole (i.e. the rapid
      filling phase), in which it receives >70% of the stroke volume, belongs to the
      active muscular contraction of the ascendent segment. We hope that these facts
      will give rise to new understanding of the principal mechanisms involved in
      normal and abnormal diastolic heart function.

PMID- 15019665
TI  - Paediatric video-assisted thoracoscopic clipping of patent ductus arteriosus:
      experience in more than 700 cases.
AB  - OBJECTIVE: To overcome drawbacks of thoracotomy and percutaneous techniques, we
      have performed video-assisted thoracoscopic surgery (VATS) since 1991 to treat
      patent ductus arteriosus (PDA). This retrospective study aims to analyse
      morbidity and outcome in order to add data in the evaluation of minimally
      invasive operations. METHODS: From September 1991 to March 2003, 703 patients
      underwent PDA clipping by VATS. The indications for operation were clinically
      significant patency or failure to close in older children. Diameter >8 mm,
      previous thoracotomy, calcifications, infection, or aneurysm were
      contraindications to VATS. In right decubitus, only two thoracostomy incisions
      (for 5-mm trocars) and a smaller one (for direct hook insertion) were required.
      In the post-operative stay two echocardiographic controls were scheduled, the
      first before extubation and the second before discharge. Referring cardiologists
      assured follow-up. RESULTS: Mean age was 3.0+/-3.8 years (5 days-33 years), mean
      weight 10.7+/-8.0 kg (1.2-65 kg), and 3.1% of our activity were low birth-weight
      infants (LBWIs) weighting < or =2.5 kg. Operative and 30-day mortality was nil.
      Median operative time was 20 min and median stay 2 days. Unfavourable events
      globally occurred in 6.8% of cases (13.6% of the LBWIs, RR 4.0, CL 95% 1.5-10.4).
      Recurrent laryngeal nerve injury was noted in 3% (13.6% of the LBWI, RR 5.1, CL
      95% 1.6-15), but only 0.4% had long lasting dysfunction. Incidence of chylothorax
      was 0.6%, thoracotomy 1%, transfusion for bleeding 0.1%, pneumothorax 1.3%. LBWIs
      were at increased risk for the latter two events. Residual patency was detected
      immediately in 1.4% (all non-LBWI) and underwent additional surgery. Incidence of
      residual patency at follow-up was 0.6% (0% LBWI, 0.6% in 2.5-25 kg group, 5.0% in
      >25 kg group, P=0.001). CONCLUSIONS: This study records a long experience of PDA
      treatment in a wide range of body size and age. VATS clipping is safe, but LBWIs
      are at augmented risk of complication. It may be carried out with a high degree
      of efficacy in all the ductus diameters <9 mm. VATS clipping requires minimal
      operating time and avoids morbidity related to chest wall trauma, percutaneous
      vascular access, and intravascular foreign bodies.

PMID- 15019666
TI  - Chronic traumatic aneurysms of the descending thoracic aorta: mid-term results of
      endovascular repair using first and second-generation stent-grafts.
AB  - OBJECTIVE: Endovascular stent-graft repair holds promise for treating traumatic
      injuries of the descending thoracic aorta. The durability of this approach,
      however, remains unknown. The objective is to evaluate the mid-term results of
      stent-graft repair of chronic traumatic aneurysms of the descending thoracic
      aorta. METHODS: Between 1993 and 2000, endovascular repair of the descending
      thoracic aorta with first (custom-fabricated) and second-generation (commercial)
      stent-grafts was performed in 15 patients (mean age 54+/-13 years) at an average
      of 18+/-14 years after the injury. Because of comorbidities, 4 patients (27%)
      were judged not to be reasonable surgical candidates for conventional open
      surgical approach. Follow-up was 100% complete and averaged 55+/-29 months.
      RESULTS: Stent-graft deployment was successful in all without need for surgical
      conversion. One patient died early postoperatively. No neurologic complications
      occurred. Two patients had a primary endoleak, one of them was successfully
      treated before discharge. Actuarial survival estimates at 1 and 6 years were 93+/
      6% and 85+/-10%. Actuarial freedom from reintervention on the descending thoracic
      aorta was 93+/-6% and 70+/-15% at 1 and 6 years, respectively. Actuarial freedom
      from treatment failure (a conservative, all-encompassing performance indicator
      including endoleak, device mechanical fault, reintervention, late aortic-related
      death, or sudden, unexplained late death) at 1 and 6 years was 87+/-8% and 51+/
      15%. CONCLUSIONS: Stent-grafting is safe in selected patients with chronic
      traumatic aneurysms and associated with satisfactory-but not optimal-mid-term
      durability. Serial follow-up surveillance imaging is mandatory to detect late
      stent-graft complications. Younger, good risk patients should be offered
      conventional open operation, reserving stent-grafting for those who are at
      prohibitive operative risk or who have limited life expectancy.

PMID- 15019667
TI  - Using jugular bulb oxyhemoglobin saturation to guide onset of deep hypothermic
      circulatory arrest does not affect post-operative neuropsychological function.
AB  - OBJECTIVES: Deep hypothermic circulatory arrest (DHCA) is commonly used during
      thoracic aortic surgery, and is initiated only after a sufficient degree of
      cerebral hypothermia is induced. The criteria for initiating DHCA vary among
      institutions: most centers use temperature criteria, some use
      electroencephalography, and a minority use jugular bulb oxyhemoglobin saturation
      SjO(2) criteria. The purpose of this study was to determine whether the use of
      SjO(2) monitoring to guide the onset of DHCA was associated with better post
      operative neuropsychological outcome. METHODS: Sixty-one thoracic aortic surgical
      patients underwent both pre- and post-operative neuropsychological testing.
      Patients were divided into three groups: (1) those with SjO(2)> or =95% at DHCA
      onset; (2) those with SjO(2)<95% at DHCA onset; and (3) those without SjO(2)
      monitoring. RESULTS: There were no statistically significant differences in the
      incidence of post-operative decline in neuropsychological function among the
      three groups of patients. Patients in whom SjO(2) data were used to guide onset
      of DHCA had lower esophageal and bladder temperatures at that time compared with
      patients without SjO(2) monitoring. CONCLUSIONS: Monitoring of SjO(2) had no
      apparent effect upon post-operative neuropsychological outcome, and there were no
      trends in our small patient cohort suggesting differences that our study was not
      adequately powered to detect. Use of SjO(2) monitoring was associated with more
      profound hypothermia prior to DHCA due to more prolonged cooling in attempts to
      bring the SjO(2) above the 95% threshold. Using our institutional cooling
      protocol, SjO(2) monitoring does not appear to increase neuroprotection in
      patients undergoing DHCA for thoracic aortic repairs.

PMID- 15019669
TI  - S100 protein and its relation to cerebral microemboli in on-pump and off-pump
      coronary artery bypass surgery.
AB  - OBJECTIVES: S100 protein has been used as a marker for cerebral injury. Studies
      have reported lower levels in off-pump coronary artery surgery (CABG) compared to
      on-pump surgery. However, most of these are flawed as S100 from extracerebral
      sources was included (e.g. blood from cardiotomy suckers). Microemboli (high
      intensity transient signals or HITS) during CABG have been implicated as a cause
      of postoperative neurocognitive dysfunction. The aim of this study was to compare
      the number of HITS during on-pump and off-pump CABG, measure S100 accurately by
      excluding extracerebral sources, and assess whether any changes in S100 were
      related to HITS. METHODS: Thirty-five patients admitted for CABG were randomised
      to on-pump (n=20) or off-pump (n=15) surgery. Bilateral transcranial Doppler
      ultrasonography was performed on the middle cerebral artery to detect HITS. S100
      was measured preoperatively, at termination of bypass in on-pump surgery, at
      completion of anastomoses in off-pump surgery, and 48 h postoperatively. A cell
      saver was used instead of cardiotomy suction in the on-pump group in order to
      limit extracerebral contamination of the S100 assay. RESULTS: The number of HITS
      was 2016+/-1897 during on-pump and 16+/-21 during off-pump surgery (P<0.0001). In
      on-pump surgery S100 increased from 0.05+/-0.03 to 0.50+/-0.28 microg/l
      (P<0.0001) at termination of bypass. In off-pump surgery S100 increased from
      0.08+/-0.05 to 0.35+/-0.20 microg/l (P<0.0001) at completion of anastomoses. The
      mean intraoperative S100 in the on-pump group was 1.6 times greater compared to
      that in the off-pump group (95% CI 0.88-2.8; P=0.01). There was no evidence of a
      relationship between S100 and HITS in both groups. By 48 h S100 decreased to
      0.22+/-0.14 microg/l in the on-pump and 0.21+/-0.09 microg/l in the off-pump
      group (P<0.0001, compared to the preoperative value). CONCLUSIONS: We have
      demonstrated a significantly higher number of cerebral microemboli in patients
      undergoing on-pump compared to off-pump CABG. By limiting contamination from
      extracerebral sources, we have shown S100 beta levels during on-pump CABG one and
      a half times greater than that in off-pump, although this did not reach
      statistical significance. In addition, we have shown no correlation between S100
      beta and the total microemboli count, possibly because of the small numbers in
      this study.

PMID- 15019670
TI  - Cardioplegic arrest does not increase the risk of atrial fibrillation after
      coronary artery bypass surgery.
AB  - OBJECTIVE: Atrial fibrillation (AF) is the most common arrhythmia after coronary
      artery bypass grafting (CABG). It is a considerable source of morbidity, prolongs
      hospital stay and increases costs of treatment. Atrial cannulation,
      cardiopulmonary bypass and cardioplegic arrest have been suggested to play a role
      in the development of AF after CABG. The aim of this case-control study was to
      evaluate the role of cardiopulmonary bypass and cardioplegic arrest in the
      development of postoperative AF. METHODS: Data from 114 patients undergoing CABG
      without cardiopulmonary bypass and cardioplegic arrest (off-pump) between
      October, 1998 and December, 2002 were evaluated for the occurrence of
      postoperative AF. Each patient was individually matched by gender, age (+/-3
      years), left ventricle ejection fraction (+/-5%), history of myocardial
      infarction, unstable angina, and beta-blocker medication with patients undergoing
      CABG with cardiopulmonary bypass and cardioplegic arrest (on-pump) during the
      same period. The data from off-pump and on-pump groups were compared. RESULTS:
      Off-pump and on-pump groups had similar preoperative characteristics. The number
      of distal anastomoses was lower in the off-pump (2.3+/-0.9) than in the on-pump
      (3.9+/-1.1, (P<0.001) group. However, the incidence of postoperative AF in the
      off-pump (36.8%) and the on-pump groups (36.0%) did not differ from each other.
      Old age was the only independent predictor of AF after CABG. CONCLUSIONS: Neither
      cardiopulmonary bypass nor cardioplegic arrest increases the risk of
      postoperative AF after CABG.

PMID- 15019671
TI  - Clopidogrel does not increase bleeding and allogenic blood transfusion in
      coronary artery surgery.
AB  - OBJECTIVES: Platelet dysfunction is one of the major reasons of postoperative
      bleeding following coronary artery surgery. The aim of this study was to evaluate
      the effects of clopidogrel; a specific and potent irreversible inhibitor of
      platelet aggregation; on bleeding and use of blood and blood products after
      coronary artery bypass surgery (CABG). METHODS: Preoperative patient
      characteristics and perioperative and postoperative data were collected
      prospectively in 1628 consecutive patients undergoing isolated CABG performed by
      the same surgical and anesthesia team. Of these, 48 were receiving clopidogrel
      preoperatively. Of the 1628 patients, 1456 underwent elective and 172 (10.6%)
      underwent non-elective operation. Thirty-six (2.5%) of the elective patients and
      12 (7%) of the non-elective patients were using clopidogrel, preoperatively.
      Baseline characteristics, chest tube output, and the need for reexploration or
      for blood and blood product transfusion of clopidogrel recipients and non
      recipients were compared. The clopidogrel group had higher prothrombin time level
      (12.6+/-1.6; 11.5+/-1.7 s, (P=0.013), however comparable aPTT level (32.6+/-4.5
      vs. 31.4+/-4.5 s), and platelet count (275,000+/-98,000 vs. 280,000+/-72,000 dl(
      1)). RESULTS: The need for reexploration or for blood and blood product
      transfusion, chest tube output, ICU length of stay (20.1+/-2.9 vs. 21.9+/-13.5 h;
      P=NS), and hospital length of stay (5.5+/-1.7 vs. 5.4+/-2.1 days; P=NS) were
      similar in clopidogrel recipients and non-recipients, respectively. Further
      analysis demonstrated no significant difference in use of homologous blood or
      fresh frozen plasma, amount of postoperative bleeding and reoperation rates for
      bleeding as well as length of intensive care unit and hospital stay between the
      clopidogrel and the control groups both in elective and non-elective patients.
      CONCLUSIONS: The results of this study suggest that preoperative use of
      clopidogrel is not associated with increased bleeding and need for surgical
      exploration as well as risk of blood and blood product transfusion after CABG.

PMID- 15019672
TI  - Effect of target artery location and severity of stenosis on mid-term patency of
      aorta-anastomosed vs. internal thoracic artery-anastomosed radial artery grafts.
AB  - OBJECTIVE: To verify the effect of location and severity of stenosis of the
      target coronary artery (TCA) on mid-term patency of aorta-anastomosed vs.
      internal thoracic artery (ITA)-anastomosed radial artery (RA) graft. METHODS:
      During a 3-year period 228 consecutive patients received an RA graft at our
      institution. In 131 cases the RA was anastomosed to the aorta whereas in 97 the
      proximal anastomosis was performed on a mammary graft. The two groups were
      comparable in terms of preoperative variables and TCA characteristics. At a mean
      follow-up of 6.5 years 128 cases of the aorta-anastomosed and 95 of the mammary
      anastomosed group were submitted to control angiography. RESULTS: Mid-term
      patency and perfect patency rates were 92.1 and 89.8% (118/128 and 115/128) for
      aorta-anastomosed RA vs. 86.3 and 84.2% for mammary-anastomosed grafts (82/95 and
      80/95; P=0.81 and 0.82). The location of TCA did not influence graft patency in
      the two groups. The severity of the TCA stenosis strongly influenced graft
      patency in both groups but the threshold for failure was clearly higher in the
      mammary-anastomosed group. CONCLUSIONS: ITA-anastomosed RA grafts are more
      vulnerable to the detrimental effect of chronic native competitive flow and
      should be used only for target vessel with subocclusive stenosis. The location of
      the distal anastomosis does not influence long-term RA patency.

PMID- 15019673
TI  - Video-assisted thoracoscopic surgery for pulmonary nodules: rationale for
      preoperative computed tomography-guided hookwire localization.
AB  - OBJECTIVES: Video-assisted thoracic surgery (VATS) provides a minimally invasive
      means to resect pulmonary nodules (PN). Deep localization of PN may jeopardize
      VATS lung resection. The aim of this study was to establish the utility of
      preoperative computed tomography (CT)-guided hookwire localization of PN.
      METHODS: Between January 1993 and September 2001, we performed 151 VATS
      resections for PN. Preoperative CT-guided hookwire localization was not performed
      in 98 patients (group I); it was done just before surgery in 53 patients (group
      II) when, at CT scan, the distance of PN from the lung surface was >15 and/or
      when the size was <10 mm. RESULTS: Pneumothorax occurred in four patients (7.5%).
      Hookwire dislodged in four patients, but the hematoma left on the visceral pleura
      made thoracoscopic localization possible in three of these. Seventeen patients
      (17%) in group I and 4 (7.5%) in group II required conversion to thoracotomy (P<
      or =0.05). The most common reason for conversion was impossibility to localize PN
      in group I (nine cases) and deep localization requiring local enucleation in
      group II (two cases). In 31 group II patients (58%) hookwire positioning led to
      successful VATS resection that would otherwise have been impossible because PN
      were neither visible nor palpable. CONCLUSIONS: Preoperative CT-guided hookwire
      localization for pulmonary nodules is an effective technique which allows VATS
      resection of PN <10 mm located >15 mm from the pleural surface. Even when PN are
      subpleural but <10 mm, hookwire localization makes VATS resection faster. Apical
      and diaphragmatic localization of PN are limitations to the procedure.

PMID- 15019674
TI  - Prognostic significance of surgical-pathologic multiple-station N1 disease in non
      small cell carcinoma of the lung.
AB  - OBJECTIVES: The surgical outcome of pathologic N1 disease in resectable non-small
      cell lung carcinoma (NSCLC) is controversial. The prognosis of the patients with
      multiple/bulky N2 disease was invariably dismal. However, the prognostic
      significance of tumor involvement in more than one hilar or intralobar lymph node
      station has not been fully described. METHODS: From 1996 to 2002, 181 patients
      with NSCLC had complete resection. Four levels of N1 nodes and N2 nodes were
      identified using the new regional lymph node classification for lung cancer
      staging. There were 67 patients (37%) with no nodal disease (N0), 43 patients
      (24%) with N1 and 71 patients (39%) with N2 disease. The N1 subgroup cases were
      reviewed. The prognostic significances of single and multiple N1 diseases were
      tested. RESULTS: The cumulative postoperative survival at 3 and 5 years was 57
      and 29%, respectively. The survival associated with single-station N1 disease was
      significantly better than that of multiple-station N1 disease (45 vs 32% at 5
      years; P=0.03). Five-year survival was similar in patients with multiple N1
      disease and patients with single-station N2 involvement (32 vs 31% at 5 years;
      P=0.84). However, no patient survived when tumor was detected in more than one
      mediastinal station (i.e. multiple N2 disease). CONCLUSIONS: It was suggested
      that N1 disease is a compound of two subgroups: one involving in one node and the
      other (multiple N1 disease) in which the postoperative prognosis was not
      statistically different from that of N2 disease.

PMID- 15019675
TI  - Invasion of blood vessels as significant prognostic factor in radically resected
      T1-3N0M0 non-small-cell lung cancer.
AB  - OBJECTIVES: Radical resection is the therapy of choice in non-small-cell lung
      cancer (NSCLC). However, even in early stages (T1N0, T2N0) up to 35% of patients
      will experience recurrence. The aim of this retrospective study was to evaluate
      the prognostic influence of lymph vessel or blood vessel invasion in N0 patients.
      METHODS: A total of 72 patients (male, 49; female, 23; median age 59; range 40
      72) with NSCLC entered the study. The stages were T1-3N0 (T1, 25; T2, 41; T3, 6).
      Thirteen pneumonectomies and 59 lobectomies or bilobectomies with systematic
      lymphadenectomy and R0 resection were performed. Histologically, 24
      adenocarcinomas, 31 squamous cell carcinomas and 14 subtypes of large cell
      carcinoma were found. In 22 cases microscopic invasion of the lymphatic vessels
      and in 11 invasions of blood vessels were found. Six patients showed invasion of
      either structure. RESULTS: The patients were followed up for at least 5 years or
      until death. During the follow-up period 27 patients died (21 because of
      recurrence and 6 because of diagnosis not related to NSCLC). The 5 years overall
      survival amounted to 62.5%. In cases with invasion of the blood vessels the
      survival rate was 23.5%, in cases without invasion 74.5% (P< or = 0.01), whereas
      lymph vessel invasion had no significant impact on survival. Multivariate
      analysis covering T stages, histological subtypes, location of the tumor,
      grading, age, sex, and invasion of the lymphatic or the blood vessels showed
      invasion of the blood vessels as the only factor with significant prognostic
      impact in the study population. CONCLUSIONS: In resectable N0 patients with NSCLC
      the microscopic invasion of blood vessels should be considered as an additional
      prognostic parameter.

PMID- 15019676
TI  - Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor
      (VEGF) levels, as prognostic indicators in NSCLC.
AB  - OBJECTIVES: Non-small cell lung cancer (NSCLC) tissue produces numerous growth
      factors, which are multifunctional and considered predictive of patient survival.
      This study sought to evaluate the relationship between concentrations of basic
      fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF),
      hepatocyte growth factor (HGF) in NSCLC tissue and clinicopathological factors,
      and determine whether these factors correlate with long-term survival. METHODS:
      We retrospectively investigated 71 patients with histologically confirmed
      adenocarcinoma or squamous cell carcinoma of the lung, for whom the primary
      curative approach was surgery, and who received no chemotherapy or radiotherapy
      prior to surgery. bFGF, VEGF, HGF were measured in extracts prepared from these
      71 frozen tissue samples by ELISA. Five- and 10-year survival was obtained to
      determine the most important predictors of long-term survival. RESULTS: Among
      clinicopathological parameters, the mean concentration of bFGF was significantly
      higher in tissue extracts from cases involving metastatic nodal involvement
      (87.5+/-69.3 ng/100 mg protein) than in those without nodal involvement (57.6+/
      42.5 ng; P<0.05). Levels of VEGF in adenocarcinoma (26.8+/-34.0 ng) were higher
      than for squamous cell carcinoma (12.2+/-13.8 ng; P<0.05). HGF levels also
      demonstrated histological differences (14.7+/-7.7 vs. 10.6+/-9.7 ng, P<0.05).
      bFGF protein levels were basically the same, but showed no statistically
      significant differences with respect to histological type (72.5+/-55.2 vs. 63.6+/
      51.5 ng). Patients with high levels of bFGF or VEGF showed significantly worse
      survival rates than patients with low levels (P=0.0059; P=0.0134). In particular,
      high concentrations of both bFGF and VEGF correlated with markedly poor prognosis
      (P<0.0001). Multivariate analysis indicated that lymph node involvement and
      levels of bFGF and VEGF were independent prognostic factors in cases of NSCLC
      (adenocarcinoma or squamous cell carcinoma) involving patients who had undergone
      curative resection. CONCLUSIONS: Adenocarcinoma associated with lung cancer is
      regarded to have biological characteristics that distinguish it from squamous
      cell carcinoma. Node invasion may be associated with bFGF. bFGF and VEGF augment
      each other and are associated with leading to poor prognosis. The results of this
      study suggests that effective therapy to block angiogenesis may need to address
      at least both of these factors in cases of NSCLC.

PMID- 15019677
TI  - Completion pneumonectomy in cancer patients: experience with 55 cases.
AB  - OBJECTIVE: Analysis of a single institution experience with completion
      pneumonectomy. METHODS: From 1989 to 2002, 55 consecutive cancer patients
      received completion pneumonectomy (mean age 62 years; 25-79). Indications were
      bronchogenic carcinoma in 38 patients (4 first cancers, 8 recurrent cancers, 26
      second cancers), lung metastases in three (one each from breast cancer,
      colorectal neoplasm and lung cancer), lung sarcoma in one, and miscellaneous non
      malignant conditions in 13 patients having been surgically treated for a non
      small cell lung cancer previously (bronchopleural fistula in 4, radionecrosis in
      3, aspergilloma in 2, pachypleura in 1, massive hemoptysis in 1 and pneumonia in
      2). Before completion pneumonectomy, 50 patients had had a lobectomy, three a
      bilobectomy, and two lesser resections. The mean interval between the two
      procedures was 51 months for the whole group (1-469), 60 months for lung cancer
      (12-469), 43 months for pulmonary metastases (21-59) and 29 months for non
      malignant disorders (1-126). RESULTS: There were 35 right (64%) and 20 left (36%)
      resections. The surgical approaches were a posterolateral thoracotomy in 50 cases
      (91%) and a lateral thoracotomy in five cases (9%). Intrapericardial route was
      used in 49 patients (89%). Five patients had an extended resection (2 chest wall,
      1 diaphragm, 1 subclavian artery and 1 superior vena cava). Operative mortality
      was 16.4% (n=9): 11.9% for malignant disease (n=5) and 30.8% for benign disease
      (n=4) Operative mortality was 20% for right completion pneumonectomies (n=7) and
      10% for left-sided procedures (n=2) Twenty-three patients (42%) experienced non
      fatal major complications. Actuarial 3- and 5-year survival rates from the time
      of completion pneumonectomy were 48.4 and 35.2% for the entire group. Three- and
      five-year survival for patients with bronchogenic carcinoma were 56.9 and 43.4%,
      respectively. CONCLUSIONS: These results suggest that completion pneumonectomy in
      the setting of lung malignancies can be done with an operative risk similar to
      the one reported for standard pneumonectomy. In contrast, in cancer patients,
      completion pneumonectomy for inflammatory disorders is a very high-risk
      procedure.

PMID- 15019679
TI  - Gastrobronchial fistula after esophagectomy.

PMID- 15019678
TI  - Lung resection for bronchogenic carcinoma after pneumonectomy: a safe and
      worthwhile procedure.
AB  - OBJECTIVES: Patients treated surgically for lung cancer can develop either a
      metachronous cancer or a recurrence. The appearance of a new cancer on the
      remaining lung after a pneumonectomy poses unique treatment problems, and surgery
      is often considered contraindicated. We report on the outcome of resections for
      lung cancer after pneumonectomy performed for lung cancer. METHODS: We reviewed
      the records of patients who underwent a resection of bronchogenic carcinoma on
      the remaining lung from 1990 to 2002. RESULTS: There were 14 patients (13 males
      and 1 female) with a median age of 64 years (range 51-74). Median preoperative
      Fev1 was 1.45 (range 1.35-2.23), corresponding to 59% of predicted Fev1 (range 46
      80%). Resection was performed between 11 and 264 months after pneumonectomy
      (median 35.5). The resections performed were: one wedge resection in 11 patients,
      two wedge resections in two patients and two segmentectomies in two other
      patients; one patient underwent a third resection. Diagnosis was metachronous
      cancer in 12 patients and metastasis in two patients. Complications occurred in
      three patients (21%), while operative mortality was nil. Mean hospital stay was
      10.5 days (6-25). Two patients received chemotherapy (one after local recurrence,
      one after the third resection). Overall 1, 3 and 5 year survivals were 57, 46 and
      30%, respectively (median 21 months). For patients with a metachronous cancer
      they were 69, 55 and 37% (median 57 months), respectively, while neither patient
      with a metastatic tumor survived 1 year (P=0.03). CONCLUSIONS: Limited lung
      resection on a single lung is a safe procedure associated with acceptable
      morbidity and mortality rates. In patients with a metachronous lung cancer, long
      term survival with a good quality of life can be obtained with limited resection
      on the residual lung.

PMID- 15019680
TI  - Bilateral pulmonary arteriovenous malformations in patient with Rendu-Osler-Weber
      disease.

PMID- 15019681
TI  - Non-fatal penetrating neck trauma.

PMID- 15019682
TI  - Spontaneous haematoma of the oesophagus.
AB  - Haematoma of the oesophagus is a rare occurrence and is usually in response to
      trauma, retching or vomiting. We report a case of spontaneous haematoma of the
      oesophagus that presented with only bruising over the chest. It resolved
      completely with conservative management. We review the literature, common causes,
      the differential diagnosis and the management of oesophageal haematoma.

PMID- 15019683
TI  - True and pseudo aneurysms of coronary arteries in a patient with Behcet's
      disease.
AB  - A 33-year-old man with a 9-year history of Behcet's disease was hospitalized with
      a giant pseudo aneurysm of left anterior descending and true aneurysm of right
      coronary artery. This unusual vascular complication of Behcet's disease treated
      successfully is presented.

PMID- 15019685
TI  - Visceral pleura invasion and lung cancer: further clarifications.

PMID- 15019684
TI  - Successful CABG in a patient with paroxysmal nocturnal hemoglobinuria.
AB  - Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon acquired disorder of
      blood cells characterized by intravascular hemolysis due to an inordinate
      sensitivity to complement-mediated membrane damage. This report documents
      coronary artery revascularization in a patient with PNH, which has not been
      described in the literature so far. We used the on-pump procedure in the present
      patient and successfully performed revascularization by taking prophylactic
      measures against hemolysis.

PMID- 15019686
TI  - Obesity and breast cancer: a review of the literature.
AB  - A woman's build, the risk of breast cancer and its subsequent prognosis seem to
      be related. In most but not all case-control and prospective cohort studies, an
      inverse relationship has been found between weight and breast cancer among
      premenopausal women. However, most large epidemiological studies have found that
      overweight or obese women are at increased risk of developing postmenopausal
      breast cancer. It is suggested that higher body mass index is associated with a
      more advanced stage of breast cancer at diagnosis in terms of tumour size but
      data on lymph node status is not so consistent. All treatment modalities for
      breast cancer such as surgery, radiotherapy, chemotherapy and hormonal treatment
      may be adversely affected by the presence of obesity. The overall and disease
      free survival is worse in most but not all studies of prognosis of obese pre- and
      postmenopausal women with breast cancer.

PMID- 15019687
TI  - Does obesity compromise survival in women with breast cancer?
AB  - Obesity, measured by high body mass index (BMI >30 kg/m2) is associated with an
      increased risk of postmenopausal breast cancer but the effect of obesity on
      prognosis is not clear. A prospectively accrued and regularly validated database
      of 1579 patients with breast cancer treated in a district general hospital
      between 1963 and 1999 was analysed for clinical and pathological tumour
      characteristics including the family history, grade, tumour type, treatment and
      outcome. The risk factors and outcome of obese and non-obese patients were
      compared. Breast cancer in obese women was associated with significantly larger
      tumour size and worse Nottingham prognostic index. There was no statistically
      significant difference in overall and disease-free survival between obese and non
      obese group. Hazard ratios (95% Cl) were 0.81 (0.62-1.06) and 0.80 (0.63-1.01),
      respectively. In the present study, obesity is not an indicator of worst
      prognosis of breast cancer.

PMID- 15019689
TI  - A new system for localization of nonpalpable breast lesions with adhesive marker
      plate.
AB  - The objective of this article is to present a new method of preoperative
      localization of nonpalpable breast lesions by means of an adhesive marker plate
      that makes an anteroposterior approach to the thoracic wall possible. Between
      January 2000 and September 2002, 41 consecutive mammographic localizations were
      performed with the adhesive marker plate. In most cases (n = 34) the lesions were
      microcalcifications. The mean age of the patients was 54.7 years. The device used
      consists of a square plate made of highly flexible plastic with an adhesive film
      on the back for firm attachment to the area of the breast surface corresponding
      to the approximate location of the lesion. This plate contains a network of holes
      and a system of radiopaque coordinates. The technique for its use is described
      step by step. All 41 lesions were localized: to within 5 mm or by transfixation
      of the lesion in 95.1% of cases (39/41) and to within 1 cm in the remaining 2
      cases. Surgical excision of the breast lesions was carried out successfully in
      all cases, and in 56% (23/41) it was possible to use a periareolar incision.
      Histological findings revealed 24 benign and 17 malignant lesions. This new
      technique permits the localization of nonpalpable breast lesions accurately,
      simply, and with very little discomfort to the patient. The anteroposterior
      approach simplifies the surgeon's task in the management of these lesions.

PMID- 15019688
TI  - High incidence of HER-2 positivity in inflammatory breast cancer.
AB  - HER-2 is over-expressed in around 25% of human breast cancers, and is associated
      with poor outcome. We examined the incidence of HER-2 status in inflammatory
      breast cancer (IBC). Forty-nine newly diagnosed IBCs were studied. Formalin-fixed
      paraffin-embedded pre-treatment tissue biopsies were examined
      immunohistochemically for the over-expression of the HER-2 protein and gene using
      the HercepTest and FISH assay. Clinical outcome was compared between the HER-2
      positive (HercepTest score 3 + and FISH positive) and negative groups. Fifty-two
      per cent of the IBCs examined were HER-2 positive. The HER-2 positive group were
      demographically comparable to the HER-2 negative group. Ninety-six per cent of
      the HER-2 positive patients responded to primary chemotherapy compared to 76% of
      the HER-2 negative (P = 0.09). No significant differences in outcome emerged
      between the two groups. In conclusion, this study found the incidence of HER-2
      protein over-expression in IBC is higher than previously reported in non-IBC.
      Early HER-2 directed therapy (such as the monoclonal antibody trastuzumab) as a
      part of multimodal treatment may improve outcome in this poor prognosis cancer.

PMID- 15019690
TI  - Combined image guidance excision of non-palpable breast lesions.
AB  - When mammogramography detects a non-palpable lesion the surgeons may be called
      upon to establish a diagnosis. Various techniques are currently employed. We
      describe a technique, which can be used both for diagnostic and for therapeutic
      procedures. The technique essentially involves localising the tip of a guide
      wire, placed under mammographic guidance, with ultrasound scanning. This
      minimises many of the problems encountered with wire guided excision. We
      conducted a prospective non-randomised study using our combined image guidance
      technique (CIG) for patients undergoing diagnostic (n = 24) and therapeutic
      biopsy (n = 13). We found that significantly smaller diagnostic biopsy weights
      were achievable using CIG, compared to non-CIG techniques. Reduced biopsy weights
      are recommended by current guidelines.

PMID- 15019691
TI  - Differentiation of benign and malignant sub-1 cm breast lesions using dynamic
      contrast enhanced MRI.
AB  - The purpose of this work is to assess the additional benefit of MRI-based
      morphology and quantification of contrast enhancement in the differential
      diagnosis of sub-1cm breast lesions. Forty-three women with suspected breast
      cancer were examined using X-ray mammography, ultrasound mammography, and MRI.
      Dynamic contrast imaging was performed and relative enhancement at various time
      points was calculated. The dynamic data was also processed using a two
      compartment pharmacokinetic model. Radiological interpretation of high-resolution
      post-contrast images revealed a similar accuracy (69%) compared to X-ray
      mammography (69%) and ultrasound mammography (67%). The best individual parameter
      calculated from the dynamic images was found to be the exchange rate constant
      which revealed a diagnostic accuracy of 0.74 +/- 0.08. When information from the
      post-contrast images and dynamic data was combined in a logistic regression model
      a diagnostic accuracy of 0.92 +/- 0.03 was achieved. In conclusion, MR imaging of
      small breast lesions is feasible and the incorporation of quantitative MR derived
      parameters is beneficial.

PMID- 15019692
TI  - Analysis of local complications following explantation of silicone breast
      implants.
AB  - A study was undertaken to analyse local complications in patients with breast
      implants and the total number of implant-related interventions when silicone
      breast implants were explanted. We studied 53 patients who had received breast
      implants for cosmetic augmentation or breast reconstruction following surgery for
      breast cancer at the time of explantation. The clinical records of all these
      patients were analysed, and clinical information on reason for implantation,
      implant properties, number and kind of implant-related interventions and reason
      for explantation was elicited. A complication was defined as a surgical procedure
      performed for any of the following reasons: capsular contracture, loss of implant
      integrity, haematoma or seroma, infection of the implant site, extrusion or wound
      dehiscence, and dissatisfaction with the result. The mean numbers of implant
      related operations were 3.1 in patients who had undergone breast reconstruction
      and 2.3 in patients who had cosmetic augmentation (P < 0.03). We found a total of
      35 complications in 28 patients, 21 patients (75%) each had one complication,
      five patients (18%) had two and two patients (7%) had three complications. A
      significantly higher incidence of early complications in patients who had
      undergone breast reconstruction (P < 0.03) marks the difference from
      complications in the cosmetic group, most of which arose after a longer time (P <
      0.02). A complication analysis is presented. At the time of explantation, 78% of
      the patients decided to have a new implant, while 12% requested permanent removal
      of the implant without replacement. In the present study we saw no patients with
      connective tissue or other autoimmune disorders. When breast reconstruction or
      augmentation with silicone devices is considered, patients must be informed of
      the possible complications and of the potential choices in later implant-related
      revision surgery.

PMID- 15019693
TI  - Local anaesthetic and steroid combined injection therapy in the management of non
      cyclical mastalgia.
AB  - AIMS: We aimed to assess the effectiveness of a local anaesthetic and steroid
      combination injection therapy in the management of non-cyclical mastalgia.
      METHODS: Patients with non-cyclical mastalgia were assessed for rib tenderness
      (lateral chest wall tenderness-LCWT). The tenderest spot was injected with a
      combined preparation of 1 ml 2% lignocaine and 1 ml 40 mg depomedrone. Those who
      declined injection therapy were advised on topical or oral NSAIDs or reassurance.
      All patients were reassessed 6 weeks later. A successful outcome was taken as
      either a complete response (CR) or partial response (PR), i.e. pain although
      present is tolerated. RESULTS: One hundred and thirty eight women were diagnosed
      with LCWT. One hundred and four women were injected. Thirty-four women declined
      and were managed appropriately. At assessment 83 injected cases were successful
      (83%; CR n = 61, PR n = 22) compared to 13 non-injected cases (44.8%; CR n = 5,
      PR n = 8, P < 0.0001). No side effects were recorded. Sixteen cases recurred and
      were successfully re-injected. CONCLUSIONS: A steroid and local anaesthetic
      injection is an effective and safe treatment for LCWT.

PMID- 15019694
TI  - Axillary lymph node clearance: overcoming the technical difficulties.
AB  - BACKGROUND: Complete axillary clearance is recommended as part of the treatment
      in selected patients with invasive breast cancer. There are a number of potential
      technical difficulties in performing level III axillary clearance including: the
      deep and high position of level II and III nodes, their close proximity to the
      axillary vein, the difficulty in adjusting the operating light to illuminate the
      different levels of the axilla and the need for at least one assistant to perform
      the procedure. AIM OF THE STUDY: To evaluate a new axillary clearance retractor,
      which is designed to overcome the technical difficulties in axillary clearance.
      PATIENTS AND METHODS: The retractor was used for level III axillary clearance in
      30 patients with invasive breast cancer either as part of total mastectomy (16
      patients) or breast conservation surgery (14 patients). The retractor is table
      based and provides simultaneous illumination to all levels of the axilla via
      light bundles. It has a long L-shaped component to retract the pectoral muscles
      and a self-retaining component to retract the skin edges. Assistants were not
      required in all patients. The details of the retractor and technique is described
      and literature reviewed. RESULTS: The mean age of patients was 54 years (range 46
      83) and the mean tumour size was 24.9 mm (range 11-70). The mean number of total
      lymph nodes removed was 19.4 nodes (range 11-50). The mean number of lymph nodes
      identified in level III dissection was 2.4 nodes (range 0-8). Six patients
      developed axillary seroma, which was treated by aspiration. CONCLUSION: The
      axillary clearance retractor can be used with ease and without complications. It
      helps to overcome the technical difficulties in this operation.

PMID- 15019695
TI  - The outcome of treatment of breast cancer in a developing country--Oman.
AB  - The aim of the present study was to evaluate the outcome of treatment of breast
      cancer in Oman with an analysis of clinico-pathological features, treatment
      modalities utilized, and prognostic factors. One hundred fifty-two breast cancer
      patients diagnosed between January 1996 and June 2002 were evaluated
      retrospectively. Their mean age was 48.5 (S.D. +/- 10.8) years, and 48% of the
      female patients were premenopausal. The mean tumor size according to pathology
      was 4.6 (S.D. 3.29)cm, and 34.9% and 15.8% of patients had stage III or IV
      disease, respectively. Only 26.3% of the patients had breast-conserving surgery,
      and neoadjuvant chemotherapy was underutilized. The overall 5-year relapse-free
      survival (RFS) and overall (OS) survival rates were 62% and 64%, respectively. On
      multivariate analysis, axillary lymph node involvement and tumor differentiation
      were predictive of RFS and OS, respectively. Thus, breast cancer patients in Oman
      present with advanced stages of the disease at younger ages than their
      counterparts in the West and have lower survival rates. Increasing awareness and
      the introduction of screening programs and of a multidisciplinary approach are
      essential in Oman and other developing countries to improve the outcome of
      treatment.

PMID- 15019696
TI  - Bilateral multiple piloleiomyomas on the breast.
AB  - Piloleiomyomas are benign smooth muscle tumors arising from the erector pilorum
      muscles in the skin. They vary in size and number, and are often spontaneously
      painful or sensitive to touch and cold. In this paper, we present two young
      female patients who have multiple breast piloleiomyoma and discuss the related
      findings.

PMID- 15019697
TI  - Primary carcinoma of breast with small-cell differentiation.
AB  - We present a case of primary carcinoma of breast with neuro-endocrine small-cell
      features in a 58-year-old female. To the best of our knowledge this is the first
      reported case of this kind in the UK. The patient had regional nodal metastasis.
      She underwent breast conserving surgery and adjuvant chemotherapy.
      Immunocytochemistry was positive for neuro-endocrine origin of the tumour. We
      review the literature.

PMID- 15019698
TI  - Primary non-Hodgkin's malignant lymphoma of the breast: long-term follow-up.
AB  - A 56-year-old woman patient was treated for non-Hodgkin's lymphoma in the left
      breast and subsequently for four recurrences over the next 109 months. This case
      illustrates the importance of close and long-term follow-up after the initial
      treatment of this rare disease.

PMID- 15019701
TI  - The diagnosis of mitochondrial muscle disease.
AB  - Mitochondrial respiratory chain abnormalities are an important cause of
      neuromuscular disease and may be due to defects of either the mitochondrial or
      nuclear genome. On account of the clinical and genetic heterogeneity exhibited by
      the mitochondrial myopathies, their investigation and diagnosis remains a
      challenge, requiring a combination of techniques including muscle histochemistry,
      biochemical assessment of respiratory chain function and molecular genetic
      studies. Here, we describe a step-by-step approach to the clinical and laboratory
      diagnosis of mitochondrial muscle disease, highlighting the many potential
      problems that can hinder reaching the correct diagnosis.

PMID- 15019699
TI  - Breast metastases from colorectal carcinoma.
AB  - A case history is presented of a 53-year-old woman with an incidental finding of
      a breast lump, identified after having had chemotherapy for lung metastases from
      a rectal carcinoma. Clinical examination, ultrasound, mammography, fine needle
      aspiration and core biopsies could not prove definitively whether the breast lump
      represented a metastasis from colorectal carcinoma. Following local excision, the
      final diagnosis of metastatic colorectal carcinoma to the breast was based on the
      absence of any site of origin within the breast (i.e. no surrounding DCIS) and on
      the expression of cytokeratin CK7 and CK20 on immunohistochemistry. Postoperative
      chemotherapy was initiated. Four months later, although without local recurrence
      in the breast, the patient developed cutaneous metastatic deposits and active
      treatment was stopped. A review of other cases of breast metastases from
      extramammary sources is presented. Possible mechanisms for this rare and unusual
      phenomenon are discussed.

PMID- 15019702
TI  - Childhood macrophagic myofasciitis-consanguinity and clinicopathological
      features.
AB  - Macrophagic myofasciitis has been almost exclusively detected in adults only. We
      describe six children of Arab Moslem origin with this disorder. Three presented
      with hypotonia, developmental delay and seizures and were evaluated for a
      mitochondrial disorder. The other three children had hypotonia and predominantly
      motor delay. Five of the six families were consanguineous. A massive collection
      of macrophages was present in the fascia and adjacent epimysium in all biopsies.
      The macrophages were periodic-acid-Schiff positive and immunoreactive for CD68.
      One biopsy which was evaluated by electron microscopy and energy-dispersive X-ray
      microanalysis showed crystalline structures containing aluminum in macrophages.
      Two children with motor delay and hypotonia were treated with oral prednisone for
      3 months with no clinical improvement. Genetic predisposition probably accounts
      for the variability in the prevalence of macrophagic myofasciitis in different
      populations. At least in childhood, there seems to be no connection between
      macrophagic myofasciitis as a pathological entity and the clinical symptoms and
      signs.

PMID- 15019704
TI  - Vocal cord and diaphragm paralysis, as clinical features of a French family with
      autosomal recessive Charcot-Marie-Tooth disease, associated with a new mutation
      in the GDAP1 gene.
AB  - Axonal forms of Charot-Marie-Tooth disease, either dominantly or recessively
      inherited, are clinically and genetically heterogeneous. We describe the clinical
      and electrophysiological characteristics of an axonal autosomal recessive form of
      Charot-Marie-Tooth disease in a French family, associated with a new mutation of
      the ganglioside-induced differentiation-associated protein-1 gene (GDAP1). Two
      sisters, born to non-consanguineous parents, presented severe proximal and distal
      sensorimotor deficit, areflexia, pes cavus, scoliosis and vocal cord and
      diaphragm paralysis. They lost ambulation in the third decade and since then they
      have been wheelchair bound. Nerve conduction studies were consistent with an
      axonal neuropathy. Clinical and electrophysiological examination of their parents
      and their brother was normal. Genetic analysis revealed a homozygous thymidine
      deletion at nucleotide position 558 resulting in a frameshift at codon 186 and a
      stop codon at position 205. This axonal form of Charot-Marie-Tooth disease
      associated with a new GDAP1 mutation is recessively inherited and is
      characterized by a severe phenotype, since patients become wheelchair bound in
      the third decade, and present vocal cord and diaphram paralysis, which may be
      missed as they had no respiratory symptoms until the third decade.

PMID- 15019703
TI  - Fatal infantile neuromuscular presentation of glycogen storage disease type IV.
AB  - Glycogen storage disease type IV or Andersen disease is an autosomal recessive
      disorder due to deficiency of glycogen branching enzyme. Typically, glycogen
      storage disease type IV presents with rapidly progressive liver cirrhosis and
      death in childhood. Variants include a cardiopathic form of childhood, a
      relatively benign myopathic form of young adults, and a late-onset
      neurodegenerative disorder (adult polyglucosan body disease). A severe
      neuromuscular variant resembling Werdnig-Hoffmann disease has also been described
      in two patients. The objective was to describe two additional infants with the
      neuromuscular variant and novel mutations in the GBE1 gene. Branching enzyme
      assay, Western blot, RT-PCR and sequencing were performed in muscle biopsies from
      both patients. The cDNA of patient 1 was subcloned and sequenced to define the
      mutations. Muscle biopsies showed accumulation of periodic acid Schiff-positive,
      diastase-resistant storage material in both patients and increased lysosomal
      enzyme activity in patient 1. Branching enzyme activity in muscle was negligible
      in both patients, and Western blot showed decreased branching enzyme protein.
      Patient 1 had two single base pair deletions, one in exon 10 (1238delT) and the
      other in exon 12 (1467delC), and each parent was heterozygous for one of the
      deletions. Patient 2 had a large homozygous deletion that spanned 627 bp and
      included exons 8-12. Patient 1, who died at 41 days, had neurophysiological and
      neuropathological features of Spinal Muscular Atrophy. Patient 2, who died at
      5(1/2) weeks, had a predominantly myopathic process. The infantile neuromuscular
      form of glycogen storage disease type IV is considered extremely rare, but our
      encountering two patients in close succession suggests that the disease may be
      underdiagnosed.

PMID- 15019705
TI  - Localization of the alpha-chemokine SDF-1 and its receptor CXCR4 in idiopathic
      inflammatory myopathies.
AB  - We studied the distribution of stromal cell-derived factor 1 isoforms alpha and
      beta, and their receptor CXCR4, in polymyositis, sporadic inclusion body myositis
      and dermatomyositis using in situ hybridization, immunohistochemistry,
      immunofluorescence and Western blotting. In control muscle, polymyositis and
      sporadic inclusion body myositis, stromal cell-derived factor-1alpha expression
      was noted in muscle fibers, while stromal cell-derived factor-1beta and CXCR4
      were predominantly localized to capillaries and arterioles. In dermatomyositis,
      stromal cell-derived factor-1beta immunoreactivity of blood vessels was focally
      increased. The vast majority of inflammatory cells in idiopathic inflammatory
      myopathies were CXCR4 positive. A subset of helper T-cells and macrophages
      expressed stromal cell-derived factor-1alpha, while only rare inflammatory cells
      expressed stromal cell-derived factor-1beta. A significant increase of stromal
      cell-derived factor-1alpha and CXCR4 was observed in protein extracts of
      idiopathic inflammatory myopathies in comparison with normal controls. The
      abundance of both CXCR4 and its ligand stromal cell-derived factor-1 implicates
      their interaction in the pathogenesis of idiopathic inflammatory myopathies and
      identifies these proteins as possible targets for selective immune therapy.

PMID- 15019707
TI  - Interaction of top-down and bottom-up processing in the fast visual analysis of
      natural scenes.
AB  - The influence of task requirements on the fast visual processing of natural
      scenes was studied in 14 human subjects performing in alternation an "animal"
      categorization task and a single-photograph recognition task. Target photographs
      were randomly mixed with non-target images and flashed for only 20 ms. Subjects
      had to respond to targets within 1 s. Processing time for image-recognition was
      30-40 ms shorter than for the categorization task, both for the fastest
      behavioral responses and for the latency at which event related potentials evoked
      by target and non-target stimuli started to diverge. The faster processing in
      image-recognition is shown to be due to the use of low-level cues, but source
      analysis produced evidence that, regardless of the task, the dipoles accounting
      for the differential activity had the same localization and orientation in the
      occipito-temporal cortex. We suggest that both tasks involve the same visual
      pathway and the same decisional brain area but because of the total
      predictability of the target in the image recognition task, the first wave of
      bottom-up feed-forward information is speeded up by top-down influences that
      might originate in the prefrontal cortex and preset lower levels of the visual
      pathway to the known target features.

PMID- 15019706
TI  - New methods for molecular diagnosis and demonstration of the (CCTG)n mutation in
      myotonic dystrophy type 2 (DM2).
AB  - Myotonic dystrophy types 1 and 2 are autosomal dominant, multisystemic disorders
      with many similarities in their clinical manifestations. Myotonic dystrophy type
      1 is caused by a (CTG)n expansion in the 3' untranslated region of the DMPK gene
      in 19q13.3 and myotonic dystrophy type 2 by a (CCTG)n expansion in intron 1 of
      ZNF9 in 3q21.3. However, the clinical diagnosis of myotonic dystrophy type 2 is
      more complex than that of myotonic dystrophy type 1, and conventional molecular
      genetic methods used for diagnosing myotonic dystrophy type 1 are insufficient
      for myotonic dystrophy type 2. Herein we describe two in situ hybridization
      protocols for the myotonic dystrophy type 2 mutation detection. Chromogenic in
      situ hybridization was used to detect both the genomic expansion and the mutant
      transcripts in muscle biopsy sections. Chromogenic in situ hybridization can be
      used in routine myotonic dystrophy type 2 diagnostics. Fluorescence in situ
      hybridization on extended DNA fibers was used to directly visualize the myotonic
      dystrophy type 2 mutation and to estimate the repeat expansion sizes.

PMID- 15019708
TI  - Where am I? The neurological correlates of self and other.
AB  - Although still controversial, there is growing evidence that information about
      the self is processed in the right hemisphere, specifically the right frontal
      lobe. It has also been hypothesized that self-awareness and mental state
      attribution (inferences about the mental experience of others) are part of a
      similar neurocognitive process [Am. J. Primatol. 2 (1982) 237]. Here we measured
      blood oxygen level-dependent (BOLD) activity when viewing self-faces and when
      thinking about the mental states of others. We found significant activation in
      right superior, middle, and inferior frontal gyri when activation associated with
      self-face processing was compared with activation associated with familiar famous
      face processing. Mental state attribution, as measured by a computerized version
      of the Mind in the Eyes--Revised Test, was associated with activation in the
      right superior and middle frontal gyri, medial superior frontal gyrus, and left
      middle frontal gyrus and superior temporal gyrus/temporal pole. Self-face
      recognition and mental state attribution were colocalized to the middle and
      superior frontal gyri in the right hemisphere. These data support a model
      developed over two decades ago by Gallup [Am. J. Primatol. 2 (1982) 237] that
      posits that self-awareness and mental state attribution are part of a shared
      neurocognitive suite of processing and that neural architecture implicated in
      processing knowledge about the self is called upon when inferring knowledge in
      others.

PMID- 15019709
TI  - Performance of the marmoset monkey on computerized tasks of attention and working
      memory.
AB  - The CAmbridge Neuropsychological Test Automated Battery (CANTAB) is a
      computerised battery of neuropsychological tests presented as stimuli on a touch
      sensitive computer screen that has been used to assess a wide range of cognitive
      functions in neuropsychiatric patients, healthy volunteers, and species of non
      human primate, primarily the rhesus macaque. The common marmoset is a small
      bodied, tractable simian primate that breeds well under laboratory conditions.
      This primate has been quite extensively studied in terms of its abilities and
      limitations with respect to appetitive cognitive conditioning. However, the
      CANTAB versions of sustained/divided attention and working memory tasks have to
      date not been studied in the marmoset. Here we describe adult marmoset
      performance on the CANTAB five-choice serial reaction time task, a delayed match
      to-position task, and a task derived from the CANTAB visuo-spatial paired
      associates learning task that constituted two, concurrent delayed match-to
      position tasks. The acquisition and stable longitudinal performance of these
      tasks provide strong evidence that the marmoset, in addition to the macaque, can
      be the species of choice for CANTAB-based drug and lesion studies of cognitive
      function, using tasks similar to those deployed in the study of human cognition
      and diagnosis of neuropsychiatric disorders.

PMID- 15019710
TI  - Is the human primary motor cortex involved in motor imagery?
AB  - Participation of the primary motor cortex (M1) in motor imagery was addressed
      using functional magnetic resonance imaging at 2.0 T and 2 x 2 x 4 mm3 resolution
      in six right-handed subjects. Paradigms comprised visually cued execution and
      imagination of a sequential finger-to-thumb opposition task (12 s) contrasted
      with motor rest and visual imagery (18 s), respectively. Motor execution
      activated M1 as well as other parts of the motor system including supplementary
      motor area (SMA) and premotor areas (PM). In contrast, motor imagery did not lead
      to activations in M1 except for 1/6 subjects but involved SMA and PM bilaterally
      as well as the anterior intraparietal cortex. Moreover, a region-of-interest
      analysis revealed a weak initial MRI signal increase in M1 in 4/6 subjects. This
      novel finding of a transient response reflecting the onset of imagination which
      does not lead to sustained M1 activation may explain previous contradictory
      reports.

PMID- 15019711
TI  - Constraints on grip selection in hemiparetic cerebral palsy: effects of lesional
      side, end-point accuracy, and context.
AB  - This study was concerned with selection criteria used for grip planning in
      adolescents with left or right hemiparetic cerebral palsy. In the first
      experiment, we asked participants to pick up a pencil and place the tip in a pre
      defined target region. We varied the size of the target to test the hypothesis
      that increased end-point precision demands would favour the use of a grip that
      affords end-state comfort. In the second experiment, we studied grip planning in
      three task contexts that were chosen to let us test the hypothesis that a more
      functional task context would likewise promote the end-state comfort effect. When
      movements were performed with the impaired hand, we found that participants with
      right hemiparesis (i.e., left brain damage) aimed for postural comfort at the
      start rather than at the end of the object-manipulation phase in both
      experiments. By contrast, participants with left hemiparesis (i.e., right brain
      damage) did not favour a particular selection criterion with the impaired hand in
      the first experiment, but aimed for postural comfort at the start in the second
      experiment. When movements were performed with the unimpaired hand, grip
      selection criteria again differed for right and left hemiparetic participants.
      Participants with right hemiparesis did not favour a particular selection
      criterion with the unimpaired hand in the first experiment and only showed the
      end-state comfort effect in the most functional tasks of the second experiment.
      By contrast, participants with left hemiparesis showed the end-state comfort
      effect in all conditions of both experiments. These data suggest that the left
      hemisphere plays a special role in action planning, as has been recognized
      before, and that one of the deficits accompanying left brain damage is a deficit
      in forward movement planning, which has not been recognized before. Our findings
      have both theoretical and clinical implications.

PMID- 15019712
TI  - An electrophysiological study of errorless learning.
AB  - Errorless learning, i.e. learning under conditions that prevent the generation of
      false memory candidates, has been shown to lead to enhanced memory performance
      during retrieval compared to errorful, trial-and-error, learning. These two
      learning methods were implemented in a word-stem completion format and contrasted
      in young healthy subjects with stimulus-locked and response-locked event-related
      brain potentials (ERPs) being recorded during memory retrieval. Retrieval
      accuracy was enhanced for items studied under errorless conditions. Stimulus
      locked ERPs showed a modulation of a right frontal effect that differed in
      amplitude and topography for items learned under errorful and errorless
      conditions. This effect is interpreted as reflecting post-retrieval processes. In
      the response-locked ERPs, a typical error-related negativity (ERN) was observed
      that was most prominent for false alarm trials in the errorless condition, of
      medium amplitude for hits and false alarms in the errorful condition, smaller for
      hits in the errorless condition and virtually absent for items correctly or
      incorrectly classified as new. We propose that the amplitude modulation of the
      ERN is related to the activity of an internal monitoring device checking the
      veridicality of a retrieved memory trace.

PMID- 15019713
TI  - Activation in SI and SII: the influence of vibrotactile amplitude during passive
      and task-relevant stimulation.
AB  - Using functional magnetic resonance imaging (fMRI), responses in human
      somatosensory cortex were quantified in response to changes in the amplitude of
      peripheral stimulation during (1) passive vibration and (2) an attention
      demanding tactile tracking task whereby changes in vibration amplitude were used
      to guide motor behaviour. Functional MRI was conducted using a scanner operating
      at 1.5 T, and vibration was delivered to the volar surface of the right index
      finger with a custom-built magnetomechanical device. Results showed that primary
      somatosensory cortex (SI) reliably reflects changes in vibration amplitude
      applied to the finger during passive vibration and also in the presence of a task
      that modulates the activity in SI. Secondary somatosensory cortex did not reveal
      any clear relationship with vibration amplitude but was more often activated
      during the attention demanding tracking task compared with passive vibration. The
      present study supports an increasing stimulus-response relationship between
      vibrotactile stimuli and activity in SI that persists during attentive, active
      states.

PMID- 15019714
TI  - No direction-specific bimodal facilitation for audiovisual motion detection.
AB  - After several decades of unimodal perceptual research, interest is turning
      increasingly to cross-modal interactions. At a physiological level, the existence
      of bimodal cells is well documented and it is known that correlated audiovisual
      input enhances localisation and orienting behaviours. Audiovisual perceptual
      interactions have also been demonstrated (e.g., the well-known McGurk effect).
      The present study explores motion perception and asks whether correlated
      audiovisual motion signals would be better detected than unimodal motions or
      bimodal motions in opposing directions. Using a dynamic random-dot field with
      variable motion coherence as a visual stimulus, together with an auditory motion
      defined by a stereo noise source smoothly translating along a horizontal
      trajectory, we find that correlated bimodal motion yields only a slight
      improvement (approximately a square root of two advantage) in detection threshold
      relative to unimodal detection. The size of this benefit is consistent with a
      statistical advantage rather than a bimodal facilitation account. Moreover,
      anticorrelated bimodal motion showed the same modest improvement, again speaking
      against linear summation but consistent with statistical combination of visual
      and auditory signals. These findings were replicated in peripheral as well as in
      central vision, and with translating visual objects as well as with spatially
      distributed visual motion. The superadditivity observed neurally (especially in
      deep-layer superior collicular cells), when weak unimodal signals are combined in
      bimodal cells does not apply to the detection of linear translational motion.

PMID- 15019715
TI  - Mu rhythm modulation during observation of an object-directed grasp.
AB  - Recent electrophysiological studies have shown that the human
      electroencephalographic mu rhythm is suppressed during the observation of actions
      performed by other persons, an effect that may be functionally related to the
      behaviour of so-called "mirror neurons" observed in area F5 of nonhuman primates.
      Because mirror neuron activity has been reported to be functionally specific to
      object-oriented actions, the present study was designed to determine if the human
      mu rhythm also exhibits this property. EEG measurements were obtained from 12
      normal subjects while they observed either a precision grip of a manipulandum or
      an empty grip using the same hand position. Our results showed that the magnitude
      of the mu rhythm was significantly lower for the object grip condition than for
      the empty grip condition. These data support the notion that the human mu rhythm
      indexes a brain system that is functionally comparable to the monkey mirror
      neuron system. We propose that nonobject-directed actions may result in
      representational schemas that are either different or less salient than
      motorically equivalent actions that are directed toward objects.

PMID- 15019716
TI  - Preserved auditory cognitive ERPs in severe akinetic mutism: a case report.
AB  - kinetic mustism is a dramatic deficit in spontaneous initiation of voluntary
      motor and speech acts, usually secondary to bilateral lesions of the anterior
      cingulate cortices and supplementary motor areas [Principles of Neurology, McGraw
      Hill, New York, 1989]. Given the obvious limitations of traditional
      neuropsychological testing in this clinical context, the use of
      neurophysiological tools such as bedside auditory cognitive event-related
      potentials (ERPs), recently proven to be relevant to evaluate comatose and
      vegetative patients [Clin. Neurophysiol. 110 (9) (1999) 1601; News Physiol. Sci.
      17 (2002) 38], may constitute an interesting alternative. Here, we present the
      ERPs of a 38-year-old right-handed woman with severe akinetic mutism recorded in
      a passive auditory odd-ball paradigm. In spite of this severe clinical state, we
      could observe the presence of a "Mismatch Negativity", and of a larger P300 in
      rare trials than in frequent ones. By revealing a high level of cognitive
      integration of environmental auditory information, our study emphasizes the
      potential clinical relevance of MMN and P300 recordings in akinetic mutism to
      assess patient cognitive functioning.

PMID- 15019717
TI  - Integration of competing saccade programs.
AB  - Reflexive responses are often in direct competition with voluntary control. We
      test two opposing explanations for how this competition is resolved with respect
      to eye movements. One states that the quickest activation wins. The other states
      that the strongest activation wins. We show that an eye movement is executed
      according to the strongest activation, with the competition being staged at a
      common subcortical site.

PMID- 15019718
TI  - NTP-CERHR Expert Panel report on the reproductive and developmental toxicity of 1
      bromopropane.

PMID- 15019719
TI  - NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of 2
      bromopropane.

PMID- 15019720
TI  - Review of the potential effects of three commonly used antineoplastic and
      immunosuppressive drugs (cyclophosphamide, azathioprine, doxorubicin on the
      embryo and placenta).

PMID- 15019721
TI  - Improvement of an in vitro stem cell assay for developmental toxicity: the use of
      molecular endpoints in the embryonic stem cell test.
AB  - The embryonic stem cell test (EST) takes advantage of the potential of murine
      embryonic stem (ES) cells to differentiate in culture to test embryotoxicity in
      vitro. The EST represents a reliable, scientifically validated in vitro system
      for the classification of compounds according to their teratogenic potential
      based on the morphological analysis of beating cardiomyocytes in embryoid body
      (EB) outgrowths compared to cytotoxic effects on undifferentiated murine ES cells
      and differentiated 3T3 fibroblasts. In order to identify more objective endpoints
      of differentiation other than the microscopic evaluation of "beating areas" and
      to adapt the EST to applications in high-throughput screening systems we improved
      and expanded the EST protocol by establishing molecular endpoints of
      differentiation. The quantitative expression of sarcomeric myosin heavy chain
      (MHC) and alpha-actinin genes under the influence of test compounds was studied
      employing intracellular flow cytometry. Strong embryotoxicants exerted a dose
      dependent effect on both the expression levels of MHC and alpha-actinin and the
      differentiation into beating cardiomyocytes. Furthermore, quantitative FACS
      (fluorescence-activating cell sorting) analysis showed the same sensitivity for
      the classification of substances as the conventional endpoint but allowed a
      significant reduction of the test period. Within 7 days, maximal expression of
      sarcomeric marker proteins was observed. Our findings indicate that structural
      proteins of the sarcomere apparatus, alpha-actinin and myosin heavy chain (MHC),
      seem to be promising candidates to predict developmental toxicity in vivo from in
      vitro data. Thus, the improved EST holds promise as a new predictive screen for
      risk assessment with respect to developmental toxicity using stem cell technology
      and technological advances in the field of gene expression analysis.

PMID- 15019722
TI  - Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats.
AB  - Butyl benzyl phthalate (BBP) was administered in the diet at 0, 750, 3750, and
      11,250 ppm ad libitum to 30 rats per sex per dose for two offspring generations,
      one litter/breeding pair/generation, through weaning of F2 litters. Adult F0
      systemic toxicity and adult F1 systemic and reproductive toxicity were present at
      11,250 ppm (750 mg/kg per day). At 11,250 ppm, there were reduced F1 and F2 male
      anogenital distance (AGD) and body weights/litter during lactation, delayed
      acquisition of puberty in F1 males and females, retention of nipples and areolae
      in F1 and F2 males, and male reproductive system malformations. At 3750 ppm (250
      mg/kg per day), only reduced F1 and F2 offspring male AGD was present. There were
      no effects on parents or offspring at 750 ppm (50 mg/kg per day). The F1 parental
      systemic and reproductive toxicity no observable adverse effect level (NOAEL) was
      3750 ppm. The offspring toxicity NOAEL was 3750 ppm. The offspring toxicity no
      observable effect level (NOEL) was 750 ppm, based on the presence of reduced AGD
      in F1 and F2 males at birth at 3750 ppm, but no effects on reproductive
      development, structures, or functions.

PMID- 15019723
TI  - Exposure of neonatal male rats to estrogen induces abnormal morphology of the
      penis and loss of fertility.
AB  - The research objectives are to determine whether estrogen-induced infertility is
      associated with abnormal morphology of the penis and if morphological alterations
      can be reversed by testosterone (T). Male pups received diethylstilbestrol (DES)
      on alternate days from postnatal days 2 to 12. They received T or empty implants
      at 180 days, were tested for fertility at 188 days, and terminated at 200 days.
      While 5/7 control males sired pups, only 1/6 did in the DES group, and 0/8 in the
      DES plus T group. In addition to reductions in penile length and weight, the
      novel structural change induced by DES, and not reversed by T, was a replacement
      of cavernous spaces by fat cells in the penis body. Hence, T substitution for 8
      days at adulthood did not reverse infertility in rats treated neonatally with DES
      and provided evidence that infertility probably resulted from absence of
      cavernous spaces and/or accumulation of fat cells in the penis body.

PMID- 15019724
TI  - Ontogenic expression of estrogen receptor coactivators in the reproductive tract
      of female mice neonatally exposed to diethylstilbestrol.
AB  - Ontogenic expression of p300, steroid receptor coactivator-1 (SRC-1), GR
      interacting protein-1 (GRIP1) and p300/CBP cointegrator associate protein (p/CIP)
      was examined using an immunohistochemical method in the genital tract of female
      mice neonatally exposed to diethylstilbestrol (DES). Mice were injected with 4
      microg of DES for 5 days and killed on days 10, 15 and 21; some mice were killed
      on day 4 after three injections. The p300 immunoreactive protein in the
      epithelial cells of the oviducts, uteri, and vaginae was almost constant during
      development independent of neonatal DES exposure, while the stromal cells
      exhibited a weaker reaction than that of the vehicle-treated controls on days 4
      and 10. Neonatal DES exposure caused no significant changes in the SRC-1 and
      p/CIP expression patterns but decreased the GRIP1 expression with development in
      the reproductive tract. The constitutive expression of coactivators in both
      epithelial and stromal cells may play a role in the estrogen imprints through ER
      alpha systems during the period of DES treatment.

PMID- 15019725
TI  - Telemetric uterine contraction model in preterm cynomolgus monkeys.
AB  - A telemetric-based model is presented for evaluation of uterine contractions and
      preterm labor (PTL) in pregnant cynomolgus monkeys. The model allows continuous
      monitoring of electromyography (EMG) and intrauterine pressure (IUP) as
      indicators of uterine activity. A pressure sensor was implanted into the amnion
      of pregnant monkeys on gestational day (GD) 120 +/- 3 and biopotential sensors
      were attached to the uterus. A telemetry transmitter was placed in a subcuticular
      pocket located in the flank. Venous catheters were tethered to the next room for
      dosing and blood sampling without disturbing the conscious animals. EMG and/or
      IUP were monitored continuously post-operatively. IUP is a reliable parameter for
      monitoring intrauterine activity, as demonstrated by a close relationship between
      bursts of activity in the EMG and increases in IUP. Animals close to term showed
      a basal level of uterine activity during the daytime, with irregular contractions
      of <10 mmHg. In the night, spontaneous contractions (10-40 mmHg; maximum between
      18:00 and 01:00 h) appeared every 3-6 min. Artificial contractions of 15-40 mmHg
      that mimicked preterm labor were induced at any time of the day by infusion of 5
      60 mU oxytocin (OT) per kilogram per hour. These contractions showed a dose
      dependent response to OT, and were stable for up to 14 h of constant infusion of
      OT. Following withdrawal of oxytocin, contractions returned to baseline within
      1h. No desensitization of oxytocin-induced contractions was observed when
      oxytocin was administered daily for up to several weeks. This telemetric model
      characterizes uterine contractions in non-human primates and provides an
      excellent method to evaluate pharmacological characteristics of drug candidates
      intended to treat PTL.

PMID- 15019727
TI  - Prolonged inadvertent pravastatin use in pregnancy.

PMID- 15019726
TI  - Testicular effects of sub-chronic administration of Hibiscus sabdariffa calyx
      aqueous extract in rats.
AB  - The sub-chronic effect of Hibiscus sabdariffa (HS) calyx aqueous extract on the
      rat testes was investigated with a view to evaluate the pharmacological basis for
      the use of HS calyx extract as an aphrodisiac. Three test groups received
      different doses of 1.15, 2.30, and 4.60 g/kg based on the LD(50). The extracts
      were dissolved in the drinking water. The control group was given equivalent
      volume of water only. The animals were allowed free access to drinking solution
      during the 12-week period of exposure. At the expiration of the treatment period,
      animals were sacrificed, testes excised and weighed, and epididymal sperm number
      recorded. The testes were processed for histological examination. Results did not
      show any significant (P>0.05) change in the absolute and relative testicular
      weights. There was, however, a significant (P<0.05) decrease in the epididymal
      sperm counts in the 4.6 g/kg group, compared to the control. The 1.15 g/kg dose
      group showed distortion of tubules and a disruption of normal epithelial
      organization, while the 2.3 g/kg dose showed hyperplasia of testis with
      thickening of the basement membrane. The 4.6 g/kg dose group, on the other hand,
      showed disintegration of sperm cells. The results indicate that aqueous HS calyx
      extract induces testicular toxicity in rats.

PMID- 15019728
TI  - TbtABM, a multidrug efflux pump associated with tributyltin resistance in
      Pseudomonas stutzeri.
AB  - Tributyltin (TBT) is a toxic agent used in marine antifouling paints. Among the
      bacterial flora of a polluted harbor, TBT-resistant strains of Pseudomonas
      stutzeri have been isolated. In the strain 5MP1 (TBT minimum inhibitory
      concentration (MIC) > or =1000 mg l(-1)), TBT resistance was found to be
      associated with the presence of the operon tbtABM, homologous to the resistance
      nodulation-cell division (RND) efflux pump family, as demonstrated by cloning in
      Escherichia coli. TbtABM exhibited the greatest homology (60.9-84.9%) with the
      TtgDEF and SrpABC systems, both involved in aromatic compound tolerance in P.
      putida. TbtABM conferred multidrug resistance (MDR) including to n-hexane,
      nalidixic acid, chloramphenicol, and sulfamethoxazole (antibiotic MICsx4 for the
      E. coli host strain carrying the operon). By polymerase chain reaction
      amplification and hybridization experiments, the presence of tbtABM was detected
      in the TBT-sensitive P. stutzeri 3MP1 (TBT MIC 25 mg l(-1)). However, the latter
      strain did not seem to express TbtABM. This is the first description of a MDR
      efflux pump in P. stutzeri, and of a new kind of substrate, TBT, for the RND
      family of transporters.

PMID- 15019729
TI  - Differences in mesentericin secretion systems from two Leuconostoc strains.
AB  - Leuconostoc mesenteroides Y105 and L. mesenteroides FR52 produce both
      mesentericin Y105 and B105, in equal amounts. The mesentericin operons of L.
      mesenteroides FR52 and Y105 which are involved in mesentericin Y105 and B105
      production, were both sequenced and compared. Differences were limited to the two
      genes, mesD and mesE, which encode the dedicated transport system of mesentericin
      Y105. Analysis of mesentericin non-producing mutants and complementation
      experiments demonstrated that the major role of the membrane fusion protein,
      MesE, was in bacteriocin secretion for both strains. Moreover, the secretion
      machinery MesDE was demonstrated to be capable of transportation and maturation
      of the two pre-bacteriocins, mesentericin Y105 and B105. We also demonstrate that
      although MesDEs from strains Y105 and FR52 have significant sequence differences,
      both transporters were capable of assuring secretion of either bacteriocin.

PMID- 15019730
TI  - Molecular characterisation of rough strains of Vibrio cholerae isolated from
      diarrhoeal cases in India and their comparison to smooth strains.
AB  - Sixteen of the 18 Vibrio cholerae rough strains isolated from hospitalised
      diarrhoea patients were found to contain O1 serotype-specific (wbe) genes and all
      currently known virulence genes. Expression of the regulatory element ToxR was
      evident in these strains. Cholera toxin production ability of the rough strains
      was found to be higher (c. three- to five-fold) as compared to the smooth
      counterparts and this was transcriptionally regulated. Strains exhibiting the
      rough phenotype were more amenable to the uptake of CTXphi, which led us to
      consider that the rough phenotype could play a role in the generation of genetic
      diversity among V. cholerae strains.

PMID- 15019731
TI  - Quantitative detection of Porphyromonas gingivalis fimA genotypes in dental
      plaque.
AB  - We developed quantitative fimA genotype assays and applied them in a pilot study
      investigating the fimbrial genotype distribution of Porphyromonas gingivalis in
      European subjects with or without chronic periodontitis. P. gingivalis was found
      in 71% and 9% of the samples from patients and healthy subjects, respectively.
      Enumeration of total P. gingivalis cell numbers by polymerase chain reaction and
      immunofluorescence showed excellent correspondence (r = 0.964). 73% of positive
      samples contained multiple fimA genotypes, but generally one genotype
      predominated by one to three orders of magnitude. Genotype II predominated in 60%
      of the samples. Genotype IV occurred with similar prevalence (73%) as genotype II
      but predominated in only 20% of the samples. Genotypes I, III and V were of much
      lower prevalence and cell densities of the latter two remained sparse. Our
      results suggest marked differences among the fimA genotypes' ability to colonize
      host sites with high cell numbers.

PMID- 15019732
TI  - Streptococcus mutans fructosyltransferase interactions with glucans.
AB  - Streptococcus mutans utilizes sucrose to synthesize glucans by
      glucosyltransferase and fructans by fructosyltransferase (FTF). Antibodies raised
      against a recombinant FTF were used to study S. mutans FTF secretion. Low amounts
      of cell-free FTF were found in culture of S. mutans grown with sucrose, while an
      increase in bacteria displaying cell surface FTF was detected. FTF added to S.
      mutans cultures was adsorbed to bacteria grown with sucrose but not to bacteria
      grown with glucose or fructose or to a gtf inactivated mutant grown with sucrose.
      Recombinant FTF was found to have high affinity for glucans suggesting that
      fructans and glucans are an integral part of the polysaccharide matrix of oral
      biofilms.

PMID- 15019733
TI  - Quantification of plasmid loss in Escherichia coli cells by use of flow
      cytometry.
AB  - A method was developed to study plasmid stability in Escherichia coli cells,
      which utilised the high speed analysis properties of flow cytometry. To
      discriminate between plasmid-harbouring cells and plasmid-free cells a plasmid
      encoded Lac repressor protein was used to regulate the expression of a
      chromosomally inserted green fluorescent protein gene in the host cells. Flow
      cytometric analysis enabled detection and quantification of plasmid-free cells
      due to their green fluorescent phenotype. The reported system offers real-time
      analysis in combination with a very low detection level of plasmid loss in
      bacterial populations. This could be useful in future investigations of plasmid
      stability and population selection in bacterial communities.

PMID- 15019734
TI  - Identification of the new T-cell-stimulating antigens from Mycobacterium
      tuberculosis culture filtrate.
AB  - The proteins secreted by Mycobacterium tuberculosis are an important target for
      vaccine development. To identify the antigens from M. tuberculosis culture
      filtrate (CF) that strongly stimulate T-cells, the CF was fractionated by ion
      exchange chromatography and then non-reducing sodium dodecyl sulfate
      polyacrylamide gel electrophoresis with mini-whole gel elution. Each fraction was
      screened for its ability to induce interferon-gamma (IFN-gamma) production in
      peripheral blood mononuclear cells isolated from healthy tuberculin reactors. The
      protein bands that strongly induced IFN-gamma production were subjected to N
      terminal sequencing. Two new proteins, a 17-kDa protein (Rv0164, MTSP17) and an
      11-kDa (Rv3204, MTSP11) protein, were identified. The recombinant MTSP17
      (rMTSP17) and rMTSP11 induced significant production of IFN-gamma and interleukin
      (IL)-12p40 in peripheral blood mononuclear cells from healthy tuberculin
      reactors. Interestingly, IL-12p40 production in response to rMTSP11 was
      significantly higher than that in response to rMTSP17 or the three components of
      the antigen 85 complex. These results suggest that MTSP11 antigen should be
      further evaluated as a component of a subunit vaccine.

PMID- 15019735
TI  - Biochemical characterization and site-directed mutational analysis of the double
      chitin-binding domain from chitinase 92 of Aeromonas hydrophila JP101.
AB  - Chitinase 92 from Aeromonas hydrophila JP101 contains C-terminal repeated chitin
      binding domains (ChBDs) which were named ChBD(CI) and ChBD(CII) and classified
      into family 5 carbohydrate-binding modules on the basis of sequence. In this
      work, we constructed single and double ChBD by use of the pET system, which
      expressed as isolated ChBD(CII) or ChBD(CICII). Polysaccharide-binding studies
      revealed that ChBD(CICII) not only bound to chitin, but also to other insoluble
      polysaccharides such as cellulose (Avicel) and xylan. In comparison with
      ChBD(CII), the binding affinities of ChBD(CICII) are about 10- and 12-fold
      greater toward colloidal and powdered chitin, indicating that a cooperative
      interaction exists between ChBD(CI) and ChBD(CII). In order to investigate the
      roles of the highly conserved aromatic amino acids in the interaction of
      ChBD(CICII) and chitin, we have performed site-directed mutagenesis. The data
      showed that W773A, W792A, Y796A and W797A mutant proteins exhibited a much weaker
      affinity for chitin than wild-type protein, suggesting that these residues play
      important roles in chitin binding.

PMID- 15019736
TI  - Development of specific PCR primers for the detection of Rhizoctonia solani AG 2
      2 LP from the leaf sheaths exhibiting large-patch symptom on zoysia grass.
AB  - Detection of Rhizoctonia solani AG 2-2 LP isolates causing large-patch disease on
      zoysia grass was done using polymerase chain reaction (PCR). Specific primers
      were designed based on an amplified region using random amplified polymorphic DNA
      (RAPD)-PCR. Fifteen primers and three cultural types of R. solani AG 2-2 (types
      IIIB, IV and LP) were used for RAPD-PCR. The banding patterns by RAPD-PCR showed
      that the three cultural types were clearly distinguishable. A dendrogram
      constructed from the results of RAPD-PCR showed that the three cultural types of
      AG 2-2 clustered separately. The sequence of one PCR-amplified region which
      appeared only in LP isolates using primer A09 was selected for designing specific
      primers. Primer pair A091-F/R gave a single product from pure fungal DNA of LP
      isolates but not from those of the other two types (IIIB and IV), R. solani AG 1,
      2-1, 2-3, 2-tulip, 3-10 and BI isolates and other turfgrass fungal pathogens.
      Primer pair A091-F/R also gave a single product from diseased leaf sheaths and
      this product was in accordance with those of pure fungal DNA of LP isolates.
      Primer pair A091-F/R did not yield PCR product from healthy leaf sheaths. The
      frequencies of detection of LP isolates from leaf sheaths of zoysia grass using
      PCR with primer pair A091-F/R were higher than those of the conventional
      isolation technique. These results showed that the PCR-based technique using
      specific primers A091-F/R is useful for the rapid detection of LP isolates from
      leaf sheaths of zoysia grass exhibiting large-patch symptoms.

PMID- 15019737
TI  - Identification of Mycobacterium marinum virulence genes using signature-tagged
      mutagenesis and the goldfish model of mycobacterial pathogenesis.
AB  - Mycobacterium marinum, a causative agent of fish tuberculosis, is one of the most
      closely related Mycobacterium species (outside the M. tuberculosis complex) to M.
      tuberculosis, the etiologic agent of human tuberculosis. Signature-tagged
      mutagenesis was used to identify genes of M. marinum required for in vivo
      survival in a goldfish model of mycobacterial pathogenesis. Screening the first
      1008 M. marinum mutants led to the identification of 40 putative virulence
      mutants. DNA sequence analysis of these 40 mutants identified transposon
      insertions in 35 unique loci. Twenty-eight out of 33 (85%) loci encoding putative
      virulence genes have homologous genes in M. tuberculosis.

PMID- 15019738
TI  - Antigenic secreted proteins from Haemophilus paragallinarum. A 110-kDa putative
      RTX protein.
AB  - Haemophilus paragallinarum is the causal agent of infectious coryza, an
      economically important disease for the poultry industry. This bacterium secreted
      proteins of 25-110 kDa during its growth in brain heart infusion, tryptic soy
      broth, or Luria-Bertani glucose phosphate media, all lacking serum. Some of these
      proteins were recognized by sera from chickens experimentally infected with H.
      paragallinarum. A 110-kDa protein was recognized by a serum pool from
      convalescent-phase pigs naturally infected with Actinobacillus pleuropneumoniae,
      and also by a rabbit polyclonal serum against Apx I as well as a rabbit serum
      against Mannheimia haemolytica leukotoxin, suggesting the presence of an RTX-like
      protein in H. paragallinarum. H. paragallinarum secreted proteins could be
      important immunogens in the control of infectious coryza.

PMID- 15019739
TI  - A high molecular mass cranberry constituent reduces mutans streptococci level in
      saliva and inhibits in vitro adhesion to hydroxyapatite.
AB  - Previous investigations showed that a high molecular mass, non-dialyzable
      material (NDM) from cranberries inhibits the adhesion of a number of bacterial
      species and prevents the co-aggregation of many oral bacterial pairs. In the
      present study we determined the effect of mouthwash supplemented with NDM on oral
      hygiene. Following 6 weeks of daily usage of cranberry-containing mouthwash by an
      experimental group (n = 29), we found that salivary mutans streptococci count as
      well as the total bacterial count were reduced significantly (ANOVA, P < 0.01)
      compared with those of the control (n = 30) using placebo mouthwash. No change in
      the plaque and gingival indices was observed. In vitro, the cranberry constituent
      inhibited the adhesion of Streptococcus sobrinus to saliva-coated hydroxyapatite.
      The data suggest that the ability to reduce mutans streptococci counts in vivo is
      due to the anti-adhesion activity of the cranberry constituent.

PMID- 15019740
TI  - Altered gene expression in the transition phase by disruption of a Na+/H+
      antiporter gene (shaA) in Bacillus subtilis.
AB  - The shaA gene (sodium-hydrogen antiporter gene A, identical to mrpA) is largely
      responsible for Na+ extrusion in Bacillus subtilis. The disruption of shaA
      combined with a low concentration of NaCl completely abolishes sporulation but
      allows normal growth. To investigate the role of shaA and shaA-mediated sodium
      ion homeostasis in sporulation, we performed a comprehensive study of expression
      profiles of eight alternative sigma factors, sigmaB and the seven
      extracytoplasmic function sigma factors (sigmaM, sigmaV, sigmaW, sigmaX, sigmaY,
      sigmaZ, and sigmaYlaC) in an attempt to determine the global change of gene
      expression that results from a disturbance of Na+ homeostasis caused by shaA
      disruption. Induction of sigmaB activity in the transition phase was impaired in
      the shaA mutant, and this effect was enhanced in the presence of 30 mM NaCl. Salt
      stress activation of sigmaB occurred normally in the shaA mutant. sigmaM-, sigmaW
      , sigmaX-dependent transcription and sigZ transcription was also induced in the
      transition phase of the wild-type, which was modulated by shaA disruption. The
      induction of sigmaM-dependent transcription was enhanced in the shaA mutant,
      while that of sigmaX-dependent transcription and sigZ transcription was
      decreased. sigmaW-dependent transcription was increased throughout the growth
      phase of the shaA mutant, which was consistent with the result of proteome
      analysis. We conclude that shaA disruption resulted in the modulated induction of
      alternative sigma factor activities, which would be problematic for the cell upon
      entering the sporulation stage.

PMID- 15019741
TI  - Cloning, expression, and characterization of Mycobacterium tuberculosis
      dihydrofolate reductase.
AB  - The gene for dihydrofolate reductase of Mycobacterium tuberculosis was amplified
      by polymerase chain reaction (PCR) from M. tuberculosis H37Rv strain genomic DNA.
      The protein was expressed in inclusion bodies in high yield in Escherichia coli
      under the control of the T7 promoter. Active enzyme was obtained by refolding
      from guanidine HCl and after a single chromatography step the sample was > 99%
      homogeneous with a specific activity of approximately 15.5 micromol min(-1) mg(
      1). Mass spectrometry analysis confirmed the expected mass of 17.6 kDa. Gel
      filtration of the enzyme indicated that it was a monomer. Steady-state kinetic
      parameters were determined and the effect of pH and KCl on the enzyme examined.
      Methotrexate and trimethoprim inhibited the enzyme.

PMID- 15019742
TI  - Essential residues in the chromate transporter ChrA of Pseudomonas aeruginosa.
AB  - The chrA gene of Pseudomonas aeruginosa plasmid pUM505 encodes the hydrophobic
      protein ChrA, which confers resistance to chromate by the energy-dependent efflux
      of chromate ions. Chromate-sensitive mutants were isolated by in vivo random
      mutagenesis. Transport experiments with cell suspensions of selected mutants
      showed that 51CrO4(2-) extrusion was drastically lowered as compared to
      suspensions of the strain with the wild-type plasmid, confirming that the
      mutations affected a chromate efflux system. DNA sequence analysis showed that
      most point mutations affected amino acids clustered in the N-terminal half of
      ChrA, altering either cytoplasmic regions or transmembrane segments, and replaced
      residues moderately to highly conserved in ChrA homologs. PhoA and LacZ
      translational fusions were used to confirm the membrane topology at the N
      terminal half of the ChrA protein.

PMID- 15019743
TI  - Molecular cloning and functional characterization of avaB, a gene encoding
      Vam6p/Vps39p-like protein in Aspergillus nidulans.
AB  - It has been demonstrated that Saccharomyces cerevisiae Vam6p/Vps39p plays a
      critical role in the tethering steps of vacuolar membrane fusion by facilitating
      guanine nucleotide exchange on small guanosine triphosphatase (GTPase)
      Vam4p/Ypt7p. We report here the identification and characterization of a novel
      protein in Aspergillus nidulans, AvaB, that exhibits similarity to Vam6p/Vps39p
      and plays a critical role in vacuolar morphogenesis in A. nidulans. AvaB is
      comprised of 1058 amino acids with amino-terminal citron homology (CNH) and
      central clathrin homology (CLH) domains, as observed for other Vam6p/Vps39p
      family proteins. Disruption of avaB in A. nidulans resulted in the fragmentation
      of vacuoles and reduced growth rate under various growth conditions, implying its
      importance in maintaining vacuolar morphology and function. Yeast two-hybrid
      analysis demonstrated the interaction of AvaB with AvaA, a Vam4p/Ypt7p homolog in
      A. nidulans, as well as the homooligomer formation of AvaB, suggesting that AvaB
      performs its function through hetero- or homophilic protein-protein interactions.

PMID- 15019744
TI  - Breaking the skin barrier.

PMID- 15019745
TI  - Transdermal drug delivery: past progress, current status, and future prospects.

PMID- 15019746
TI  - Transdermal drug delivery with a pressure wave.
AB  - Pressure waves, which are generated by intense laser radiation, can permeabilize
      the stratum corneum (SC) as well as the cell membrane. These pressure waves are
      compression waves and thus exclude biological effects induced by cavitation.
      Their amplitude is in the hundreds of atmospheres (bar) while the duration is in
      the range of nanoseconds to a few microseconds. The pressure waves interact with
      cells and tissue in ways that are probably different from those of ultrasound.
      Furthermore, the interactions of the pressure waves with tissue are specific and
      depend on their characteristics, such as peak pressure, rise time and duration. A
      single pressure wave is sufficient to permeabilize the SC and allow the transport
      of macromolecules into the epidermis and dermis. In addition, drugs delivered
      into the epidermis can enter the vasculature and produce a systemic effect. For
      example, insulin delivered by pressure waves resulted in reducing the blood
      glucose level over many hours. The application of pressure waves does not cause
      any pain or discomfort and the barrier function of the SC always recovers.

PMID- 15019747
TI  - Microneedles for transdermal drug delivery.
AB  - The success of transdermal drug delivery has been severely limited by the
      inability of most drugs to enter the skin at therapeutically useful rates.
      Recently, the use of micron-scale needles in increasing skin permeability has
      been proposed and shown to dramatically increase transdermal delivery, especially
      for macromolecules. Using the tools of the microelectronics industry,
      microneedles have been fabricated with a range of sizes, shapes and materials.
      Most drug delivery studies have emphasized solid microneedles, which have been
      shown to increase skin permeability to a broad range of molecules and
      nanoparticles in vitro. In vivo studies have demonstrated delivery of
      oligonucleotides, reduction of blood glucose level by insulin, and induction of
      immune responses from protein and DNA vaccines. For these studies, needle arrays
      have been used to pierce holes into skin to increase transport by diffusion or
      iontophoresis or as drug carriers that release drug into the skin from a
      microneedle surface coating. Hollow microneedles have also been developed and
      shown to microinject insulin to diabetic rats. To address practical applications
      of microneedles, the ratio of microneedle fracture force to skin insertion force
      (i.e. margin of safety) was found to be optimal for needles with small tip radius
      and large wall thickness. Microneedles inserted into the skin of human subjects
      were reported as painless. Together, these results suggest that microneedles
      represent a promising technology to deliver therapeutic compounds into the skin
      for a range of possible applications.

PMID- 15019748
TI  - Low-frequency sonophoresis: a review.
AB  - Application of ultrasound enhances skin permeability to a variety of molecules
      (sonophoresis). The enhancement induced by ultrasound is particularly significant
      at low-frequencies (f<100 kHz, low-frequency sonophoresis). This review
      summarizes mechanisms and applications of low-frequency sonophoresis. In vitro,
      in vivo, as well as clinical studies demonstrating the effect of low-frequency
      ultrasound on transdermal drug delivery and glucose extraction are summarized.
      Mechanistic insights gained through a number of investigations are also reviewed.
      Finally, reports on the synergistic effect of low-frequency ultrasound with other
      enhancers including chemicals and iontophoresis are summarized.

PMID- 15019749
TI  - Penetration enhancers.
AB  - One long-standing approach for improving transdermal drug delivery uses
      penetration enhancers (also called sorption promoters or accelerants) which
      penetrate into skin to reversibly decrease the barrier resistance. Numerous
      compounds have been evaluated for penetration enhancing activity, including
      sulphoxides (such as dimethylsulphoxide, DMSO), Azones (e.g. laurocapram),
      pyrrolidones (for example 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or
      decanol), glycols (for example propylene glycol, PG, a common excipient in
      topically applied dosage forms), surfactants (also common in dosage forms) and
      terpenes. Many potential sites and modes of action have been identified for skin
      penetration enhancers; the intercellular lipid matrix in which the accelerants
      may disrupt the packing motif, the intracellular keratin domains or through
      increasing drug partitioning into the tissue by acting as a solvent for the
      permeant within the membrane. Further potential mechanisms of action, for example
      with the enhancers acting on desmosomal connections between corneocytes or
      altering metabolic activity within the skin, or exerting an influence on the
      thermodynamic activity/solubility of the drug in its vehicle are also feasible,
      and are also considered in this review.

PMID- 15019750
TI  - Iontophoretic drug delivery.
AB  - The composition and architecture of the stratum corneum render it a formidable
      barrier to the topical and transdermal administration of therapeutic agents. The
      physicochemical constraints severely limit the number of molecules that can be
      considered as realistic candidates for transdermal delivery. Iontophoresis
      provides a mechanism to enhance the penetration of hydrophilic and charged
      molecules across the skin. The principal distinguishing feature is the control
      afforded by iontophoresis and the ability to individualize therapies. This may
      become significant as the impact of interindividual variations in protein
      expression and the effect on drug metabolism and drug efficacy is better
      understood. In this review we describe the underlying mechanisms that drive
      iontophoresis and we discuss the impact of key experimental parameters-namely,
      drug concentration, applied current and pH-on iontophoretic delivery efficiency.
      We present a comprehensive and critical review of the different therapeutic
      classes and molecules that have been investigated as potential candidates for
      iontophoretic delivery. The iontophoretic delivery of peptides and proteins is
      also discussed. In the final section, we describe the development of the first
      pre-filled, pre-programmed iontophoretic device, which is scheduled to be
      commercialized during the course of 2004.

PMID- 15019751
TI  - Skin electroporation for transdermal and topical delivery.
AB  - Electroporation is the transitory structural perturbation of lipid bilayer
      membranes due to the application of high voltage pulses. Its application to the
      skin has been shown to increase transdermal drug delivery by several orders of
      magnitude. Moreover, electroporation, used alone or in combination with other
      enhancement methods, expands the range of drugs (small to macromolecules,
      lipophilic or hydrophilic, charged or neutral molecules) which can be delivered
      transdermally. Molecular transport through transiently permeabilized skin by
      electroporation results mainly from enhanced diffusion and electrophoresis. The
      efficacy of transport depends on the electrical parameters and the
      physicochemical properties of drugs. The in vivo application of high voltage
      pulses is well tolerated but muscle contractions are usually induced. The
      electrode and patch design is an important issue to reduce the discomfort of the
      electrical treatment in humans.

PMID- 15019752
TI  - Lipid vesicles and other colloids as drug carriers on the skin.
AB  - Colloids from an aqueous suspension can cross the skin barrier only through
      hydrophilic pathways. Various colloids have a different ability to do this by
      penetrating narrow pores of fixed size in the skin, or the relevant nano-pores in
      barriers modelling the skin. Such ability is governed by colloid adaptability,
      which must be high enough to allow penetrant deformation to the size of a pore in
      such barrier: for a 100 nm colloid trespassing the skin this means at least 5
      fold deformation/elongation. (Lipid) Bilayer vesicles are normally more adaptable
      than the comparably large (lipid coated) fluid droplets. One of the reasons for
      this, and an essential condition for achieving a high bilayer adaptability and
      pore penetration, is a high bilayer membrane elasticity. The other reason is the
      relaxation of changing colloid's volume-to-surface constraint during pore
      penetration; it stands to reason that such relaxation requires a concurrent, but
      only transient and local, bilayer permeabilisation. Both these phenomena are
      reflected in bilayer composition sensitivity, which implies non-linear pressure
      dependency of the apparent barrier penetrability, for example. Amphipats that
      acceptably weaken a membrane (surfactants, (co)solvents, such as certain
      alcohols, etc.) consequently facilitate controlled, local bilayer destabilisation
      and increase lipid bilayer flexibility. When used in the right quantity, such
      additives thus lower the energetic expense for elastic bilayer deformation,
      associated with pore penetration. Another prerequisite for aggregate transport
      through the skin is the colloid-induced opening of the originally very narrow (
      approximately 0.4 nm) gaps between cells in the barrier to pores with diameter
      above 30 nm. Colloids incapable of enforcing such widening-and simultaneously of
      self-adapting to the size of 20-30 nm without destruction-are confined to the
      skin surface. All relatively compact colloids seem to fall in this latter
      category. This includes mixed lipid micelles, solid (nano)particles, nano
      droplets, biphasic vesicles, etc. Such colloids, therefore, merely enter the skin
      through the rare wide gaps between groups of skin cells near the organ surface.
      Transdermal drug delivery systems based on corresponding drug formulations,
      therefore, rely on simple drug diffusion through the skin; the colloid then, at
      best, can modulate drug transport through the barrier. In contrast, the
      adaptability-and stability-optimised mixed lipid vesicles (Transfersomes, a
      trademark of IDEA AG) can trespass much narrower pathways between most cells in
      the skin; such highly adaptable colloids thus mediate drug transport through the
      skin. Sufficiently stable ultra-adaptable carriers, therefore, can ensure
      targeted drug delivery deep below the application site. This has already been
      shown in numerous preclinical tests and several phase I and phase II clinical
      studies. Drug delivery by means of highly adaptable drug carriers, moreover,
      allows highly efficient and well-tolerated drug targeting into the skin proper.
      Sustained drug release through the skin into systemic blood circulation is
      another field of ultradeformable drug carrier application.

PMID- 15019753
TI  - A longitudinal study of the effects of age and time to death on hospital costs.
AB  - Recent studies indicate that approaching death, rather than age, may be the main
      demographic driver of health care costs. Using a 29-year longitudinal English
      dataset, this paper uses more robust methods to examine the effects of age and
      proximity to death on hospital costs. A random effects panel data two-part model
      shows that approaching death affects costs up to 15 years prior to death. The
      large tenfold increase in costs from 5 years prior to death to the last year of
      life overshadows the 30% increase in costs from age 65 to 85. Hence, expenditure
      projections must consider remaining life expectancy in the populations.

PMID- 15019754
TI  - Valuing health care using willingness to pay: a comparison of the payment card
      and dichotomous choice methods.
AB  - This paper compares willingness to pay (WTP) estimates generated from the
      dichotomous choice (DC) and payment card (PC) approaches. In a split-sample WTP
      experiment concerned with allocating scarce health care resources across three
      health care interventions, the DC approach is shown consistently to generate
      larger welfare estimates than the PC. Observed difference between PC and DC
      experiments cannot be explained by the inclusion of non-demanders or methods of
      statistical analysis but may be partly explained by "yea-saying". No evidence of
      range bias or mid-point bias was found with PC responses. Data were also
      collected on respondents' ordinal rankings of the three interventions and person
      trade-offs (PTOs). Neither of these approaches converged with WTP. Future work
      must address the decision heuristics individuals employ when responding to
      valuation experiments.

PMID- 15019755
TI  - Parental bargaining, health inputs and child mortality in India.
AB  - The primary objective of this paper is to examine the relationship between the
      status of women in the household, the use of health care (demand for prenatal
      care and hospital delivery) and child mortality in India. Parents care about the
      health of their children but cannot directly affect child health by their
      actions. Instead they can, through their actions, control the use of health
      inputs. I jointly estimate the decision to use prenatal care, the decision to
      deliver the baby in hospital and child mortality. The estimation methodology
      allows us to account for unobserved heterogeneity and self-selection in the use
      of health inputs. The estimation results show that: (1) a woman's education has a
      stronger effect on health care usage relative to that of her husband; (2) a
      woman's control over household resources (ability to keep money aside) has a
      significant effect on health care usage; (3) both prenatal care and hospital
      delivery significantly reduces the hazard of child mortality; and (4) not
      accounting for unobserved heterogeneity and self-selection in the use of health
      inputs results in under-estimation of the effect of health inputs on child
      mortality.

PMID- 15019756
TI  - Lighting up and slimming down: the effects of body weight and cigarette prices on
      adolescent smoking initiation.
AB  - This paper examines the influence of body weight, body image, and cigarette
      prices in determining adolescent smoking initiation. Adolescents who desire to
      lose weight may initiate smoking as a method of appetite control. Such behavior
      may undermine the goals of tobacco control policies that seek to prevent smoking
      initiation. Using a nationally representative panel of adolescents, we show that
      smoking initiation is more likely among females who are overweight, who report
      trying to lose weight, or who describe themselves as overweight. In contrast,
      neither objective nor subjective measures of weight predict smoking initiation by
      males. Higher cigarette prices decrease the probability of smoking initiation
      among males but have no impact on female smoking initiation. These gender
      specific differences may help explain the mixed and inconclusive evidence of the
      impact of price on smoking initiation found in previous literature.

PMID- 15019757
TI  - Exploring social welfare functions and violation of monotonicity: an example from
      inequalities in health.
AB  - The social welfare function (SWF) has been used within the economics literature,
      to study trade-offs between equality and efficiency. These SWFs are characterised
      by properties determined by traditional welfare economics. One of these
      properties, the monotonicity principle is explored in this paper. In the context
      of health there may be occasions when the monotonicity principle is violated as
      there may be circumstances where distributional issues dominate efficiency
      concerns. When this is the case, conventional SWFs are not flexible enough to
      represent such social preferences. Therefore, we propose a SWF with an
      alternative specification, which is general enough to accommodate preferences
      that are not necessarily monotonic. A survey of the Spanish general public was
      undertaken to estimate preferences regarding equality in health, relative to
      efficiency in health. The results (with 973 usable responses) give strong support
      to the existence of public preferences which violate the monotonicity principle,
      and thus to the usefulness of the alternative specification proposed here.

PMID- 15019760
TI  - Adjusting to changes in health: implications for cost-effectiveness analysis.
AB  - This article introduces a model in which individuals incur adjustment costs
      associated with adaptations made following changes in their health. With
      adjustment costs, patients' preferences for health states depend on their initial
      health in such a way that improvements have lower values than corresponding
      deteriorations. Improvement and deterioration must therefore be treated
      asymmetrically in CEA. The inclusion of adjustment costs also has other
      consequences. It produces a more stringent CEA criterion, and may affect the
      relative rankings of interventions. In addition, when health is multi
      dimensional, and adjustment costs are incorporated, we show that a consensus on
      even ordinal rankings of health states becomes impossible.

PMID- 15019761
TI  - A new and more robust test of QALYs.
AB  - Previous empirical tests of quality-adjusted life-years (QALYs), the most widely
      used outcome measure in economic evaluations of health care, generally yielded
      negative results. These tests were, however, for the most part based on expected
      utility, which is now widely acknowledged to be descriptively inaccurate. The
      observed violations might, therefore, have been caused by violations of expected
      utility. We performed a new test of QALYs, which is valid under expected utility
      and under the two most influential non-expected utility theories, rank-dependent
      utility and prospect theory, and found considerable support for the QALY model.
      Our findings suggest that QALYs may be valid if nonexpected utility formulas are
      used to compute health state utilities.

PMID- 15019762
TI  - Medicare upcoding and hospital ownership.
AB  - Many hospitals in the 1990s many hospitals were accused of "upcoding" patient
      diagnostic related groups (DRGs) to increase Medicare reimbursements. We find
      that between 1989 and 1996, the percentage point share of the most generous DRG
      for pneumonia and respiratory infections rose by 10 points among not-for-profit
      hospitals, 23 points among for-profit hospitals, and 37 points in hospitals
      converting to for-profit status. Not-for-profit upcoding was also higher in
      markets with a larger for-profit hospital share. Upcoding appears to reflect both
      risk-taking by administrators and a closer alignment between the goals of the
      administration and the behavior of the clinical staff.

PMID- 15019764
TI  - Unmasking forensic diagnosis.

PMID- 15019763
TI  - A flexible approach for estimating the effects of covariates on health
      expenditures.
AB  - Our estimation strategy uses sequences of conditional probability functions,
      similar to those used in discrete time hazard rate analyses, to construct a
      discrete approximation to the density function of an outcome of interest
      conditional on exogenous explanatory variables. Once the conditional density
      function has been constructed, we can examine expectations of arbitrary functions
      of the outcome of interest and evaluate how these expectations vary with observed
      exogenous covariates. We demonstrate the features and precision of the
      conditional density estimation method (and compare it to other commonly used
      methods) through Monte Carlo experiments and an application to health
      expenditures using the RAND Health Insurance Experiment data. Overall, we find
      that the approximate conditional density estimator provides accurate and precise
      estimates of derivatives of expected outcomes for a wide range of types of
      explanatory variables.

PMID- 15019765
TI  - Prosecution of violent psychiatric inpatients: theoretical and practical issues.

PMID- 15019766
TI  - Mentally disordered offenders: from forensic state hospital to conditional
      release in California.

PMID- 15019767
TI  - Psychopathy-related personality traits in male juvenile delinquents: An
      application of a person-oriented approach.

PMID- 15019768
TI  - Managed mental health care's effects on arrest and forensic commitment.

PMID- 15019769
TI  - Behavioral changes during forensic psychiatric (TBS) treatment in the
      Netherlands.

PMID- 15019770
TI  - Ambivalence of PES patients toward hospitalization and factors in their
      disposition.

PMID- 15019771
TI  - Informing patients about tardive dyskinesia: A survey of clinicians' attitudes in
      three countries.

PMID- 15019772
TI  - The Membrane-associated form of the DNA repair protein Ku is involved in cell
      adhesion to fibronectin.
AB  - The Ku heterodimer (Ku70/Ku80) plays a central role in DNA double-strand breaks
      recognition and repair. However, Ku is expressed also on the surface of different
      types of cells along with its intracellular pool within the nucleus and the
      cytoplasm. Participation of membrane-associated Ku in cell-cell interaction has
      been reported recently. Here, we describe a novel function of cell-surface Ku as
      an adhesion receptor for fibronectin (Fn). The role of Ku in cell adhesion was
      investigated by comparing the Ku80 deficient Chinese hamster ovary (CHO) cell
      line, xrs-6, with clones transfected stably with either the hamster or human Ku80
      cDNA. Ku expression in transfectant cells resulted in a significant increased
      adhesion on Fn and type IV collagen as compared to control cells. The observed
      increase in cell adhesion relied on Ku cell-surface expression, since antibodies
      directed against Ku70 or Ku80 subunit inhibited adhesion on Fn of Ku80, but not
      control vector, transfected xrs-6 cells. In addition, both Ku70 and Ku80 present
      a structural relationship with integrin I (or A) domains and the A1 and A3
      domains of von Willebrand factor, domains known to be involved in Fn binding.
      Both Ku70 and Ku80 exhibit a complete set of residues compatible in their
      position and chemical nature with the formation of a metal ion-dependent adhesion
      (MIDAS) site implicated in ligand binding and integrin activation. Taken
      together, these functional and structural approaches support a new role for Ku as
      an adhesion receptor for Fn.

PMID- 15019773
TI  - De novo folding of membrane proteins: an exploration of the structure and NMR
      properties of the fd coat protein.
AB  - De novo folding simulations of the major pVIII coat protein from filamentous fd
      bacteriophage, using a newly developed implicit membrane generalized Born model
      and replica-exchange molecular dynamics, are presented and discussed. The quality
      of the predicted structures, judged by comparison of the root-mean-square
      deviations of a room temperature ensemble of conformations from the replica
      exchange simulations and experimental structures from both solid-state NMR in
      lipid bilayers and solution-phase NMR on the protein in micelles, was quite good,
      reinforcing the general quality of the folding simulations. The transmembrane
      helical segment of the protein was well defined in comparison with experiment and
      the amphipathic helical fragment remained at the membrane/aqueous phase boundary
      while undergoing significant conformational flexibility due to the loop
      connecting the two helical segments of the protein. Additional comparisons of
      computed solid-state NMR properties, the 15N chemical shift and 15N-1H dipolar
      coupling constants, showed semi-quantitative agreement with the corresponding
      measurements. These findings suggest an emerging potential for the de novo
      investigation of integral membrane peptides and proteins and a mechanism to
      assist experimental approaches to the characterization and structure
      determination of these important systems.

PMID- 15019774
TI  - Solution structure of the KIX domain of CBP bound to the transactivation domain
      of c-Myb.
AB  - The hematopoietic transcription factor c-Myb activates transcription of target
      genes through direct interactions with the KIX domain of the co-activator CBP.
      The solution structure of the KIX domain in complex with the activation domain of
      c-Myb reveals a helical structure very similar to that adopted by KIX in complex
      with the phosphorylated kinase inducible domain (pKID) of CREB. While pKID
      contains two helices, alphaA and alphaB, which interact with KIX, the structure
      of bound c-Myb reveals a single bent amphipathic helix that binds in the same
      hydrophobic groove as the alphaB helix of pKID. The affinity of c-Myb for KIX is
      lower than that of pKID, and relies more heavily on optimal interactions of the
      single helix of c-Myb with residues in the hydrophobic groove. In particular, a
      deep hydrophobic pocket in KIX accounts for more than half the interactions with
      c-Myb observed by NMR. A bend in the alpha-helix of c-Myb enables a critical
      leucine side-chain to penetrate into this pocket more deeply than the equivalent
      leucine residue of pKID. The components that mediate the higher affinity of pKID
      for KIX, i.e. the phosphate group and the alphaA helix, are absent from c-Myb.
      Results from isothermal titration calorimetry, together with the structural data,
      point to a key difference between the two complexes in optimal pH for binding, as
      a result of differential pH-dependent interactions with histidine residues of
      KIX. These results explain the structural and thermodynamic basis for the
      observed constitutive versus inducible activation properties of c-Myb and CREB.

PMID- 15019775
TI  - A pathogenesis-associated mutation in human mitochondrial tRNALeu(UUR) leads to
      reduced 3'-end processing and CCA addition.
AB  - Point mutations in mitochondrial tRNAs can cause severe multisystemic disorders
      such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like
      episodes (MELAS) and myoclonus epilepsy with ragged-red fibers (MERRF). Some of
      these mutations impair one or more steps of tRNA maturation and protein
      biosynthesis including 5'-end-processing, post-transcriptional base modification,
      structural stability, aminoacylation, and formation of tRNA-ribosomal complexes.
      tRNALeu(UUR), an etiologic hot spot for such diseases, harbors 20 of more than 90
      disease-associated mutations described to date. Here, the pathogenesis-associated
      base substitutions A3243G, T3250C, T3271C, A3302G and C3303T within this tRNA
      were tested for their effects on endonucleolytic 3'-end processing and CCA
      addition at the tRNA 3'-terminus. Whereas mutations A3243G, A3302G and C3303T
      reduced the efficiency of 3'-end cleavage, only the C3303T substitution was a
      less efficient substrate for CCA addition. These results support the view that
      pathogenesis may be elicited through cumulative effects of tRNA mutations: a
      mutation can impede several pre-tRNA processing steps, with each such reduction
      contributing to the overall impairment of tRNA function.

PMID- 15019776
TI  - Nuclear control of cloverleaf structure of human mitochondrial tRNA(Lys).
AB  - The evolutionary loss in eukaryotic cells of mitochondrial (mt) tRNA genes and of
      tRNA structural information in the surviving genes has led to the appearance of
      mt-tRNAs with highly unusual structural features. One such mt-tRNA is the human
      mt-tRNALys, which relies on post-transcriptional base modification to achieve
      correct three-dimensional structure. It has been shown that the in vitro
      transcript of human mt-tRNALys adopts a particular, non-cloverleaf structure when
      devoid of modified bases, while the native, fully modified tRNA shows the
      expected cloverleaf structure. Furthermore, a methyl group at position A9-N1,
      introduced chemically in an otherwise unmodified mt-tRNALys transcript, was found
      to induce a stable cloverleaf conformation, raising the question of how the
      specific methyltransferase recognizes the unmodified transcript. In order to shed
      light on this unusual case of tRNA maturation, the tRNA modification enzymes
      contained in protein extracts from either highly purified HeLa cell mitochondria
      or HeLa cell cytosol were first identified and compared, and then used to analyze
      the mt-tRNALys. An initial screening for modification activities, using as
      substrates unmodified in vitro transcripts of tRNA genes with well characterized
      structures, namely yeast cytosolic tRNAPhe, human cytosolic tRNA3Lys, and human
      mt-tRNAIle, revealed the presence of nine and 11 modification activities in the
      mitochondrial and cytosolic protein extracts, respectively, the mitochondrial
      extract including a tRNA (adenine-9,N1)-methyltransferase activity. The
      comparison of the level and kinetics of A9-N1 methylation and other secondary
      modifications in the unmodified, misfolded mt-tRNALys and in a cloverleaf-shaped
      structural mutant, engineered to adopt the tRNALys cloverleaf structure without
      post-transcriptional modifications, suggested strongly that the methylation of A9
      N1 in tRNALys proceeds via a cloverleaf-shaped intermediate. Therefore, it is
      proposed that this intermediate is present in the in vitro transcript as part of
      a dynamic equilibrium, and that the mitochondrial protein extract contains an
      activity that stabilizes, by secondary modification, such a transient cloverleaf
      shaped intermediate. Thus, countering the evolutionary loss of structural
      information in mt-tRNA genes, the mt-tRNA structure is maintained by a
      modification enzyme encoded in nuclear DNA.

PMID- 15019777
TI  - Histone-like protein HU from Deinococcus radiodurans binds preferentially to four
      way DNA junctions.
AB  - The histone-like protein HU from Escherichia coli is involved in DNA compaction
      and in processes such as DNA repair and recombination. Its participation in these
      events is reflected in its ability to bend DNA and in its preferred binding to
      DNA junctions and DNA with single-strand breaks. Deinococcus radiodurans is
      unique in its ability to reconstitute its genome from double strand breaks
      incurred after exposure to ionizing radiation. Using electrophoretic mobility
      shift assays (EMSA), we show that D.radiodurans HU (DrHU) binds preferentially
      only to DNA junctions, with half-maximal saturation of 18 nM. In distinct
      contrast to E.coli HU, DrHU does not exhibit a marked preference for DNA with
      nicks or gaps compared to perfect duplex DNA, nor is it able to mediate
      circularization of linear duplex DNA. These unexpected properties identify DrHU
      as the first member of the HU protein family not to serve an architectural role
      and point to its potential participation in DNA recombination events. Our data
      also point to a mechanism whereby differential target site selection by HU
      proteins is achieved and suggest that the substrate specificity of HU proteins
      should be expected to vary as a consequence of their individual capacity for
      inducing the required DNA bend.

PMID- 15019778
TI  - Engineering strand-specific DNA nicking enzymes from the type IIS restriction
      endonucleases BsaI, BsmBI, and BsmAI.
AB  - More than 80 type IIA/IIS restriction endonucleases with different recognition
      specificities are now known. In contrast, only a limited number of strand
      specific nicking endonucleases are currently available. To overcome this
      limitation, a novel genetic screening method was devised to convert type IIS
      restriction endonucleases into strand-specific nicking endonucleases. The genetic
      screen consisted of four steps: (1) random mutagenesis to create a plasmid
      library, each bearing an inactivated endonuclease gene; (2) restriction digestion
      of plasmids containing the wild-type and the mutagenized endonuclease gene; (3)
      back-crosses with the wild-type gene by ligation to the wild-type N-terminal or C
      terminal fragment; (4) transformation of the ligated DNA into a pre-modified host
      and screening for nicking endonuclease activity in total cell culture or cell
      extracts of the transformants. Nt.BsaI and Nb.BsaI nicking endonucleases were
      isolated from BsaI using this genetic screen. In addition, site-directed
      mutagenesis was carried out to isolate BsaI nicking variants with minimal double
      stranded DNA cleavage activity. The equivalent amino acid substitutions were
      introduced into BsmBI and BsmAI restriction endonucleases with similar
      recognition sequence and significant amino acid sequence identity and their
      nicking variants were successfully isolated. This work provides strong evidence
      that some type IIS restriction endonucleases carry two separate active sites.
      When one of the active sites is inactivated, the type IIS restriction
      endonuclease may nick only one strand.

PMID- 15019779
TI  - Comparison of the differential context-dependence of DNA deamination by APOBEC
      enzymes: correlation with mutation spectra in vivo.
AB  - To investigate the extent to which in vivo mutation spectra might reflect the
      intrinsic specificities of active mutators, genetic and biochemical assays were
      used to analyse the DNA target specificities of cytidine deaminases of the APOBEC
      family. The results reveal the critical importance of nucleotides immediately 5'
      of the targeted C for the specificity of all three enzymes studied (AID, APOBEC1
      and APOBEC3G). At position -1, APOBEC1 showed a marked preference for dT, AID for
      dA/dG and APOBEC3G a strong preference for dC. Furthermore, AID and APOBEC3G
      showed distinct dependence on the nucleotide at position -2 with dA/dT being
      favoured by AID and dC by APOBEC3G. Most if not all activity of the recombinant
      deaminases on free dC could be attributed to low-level contamination by host
      enzymes. The target preference of APOBEC3G supports it being a major but possibly
      not sole contributor to HIV hypermutation without making it a dominant
      contribution to general HIV sequence variation. The specificity of AID as deduced
      from the genetic assay (which relies on inactivation of sacB of Bacillus
      subtilis) agrees well with that deduced by Pham et al. using an in vitro assay
      although we postulate that major intrinsic mutational hotspots in immunoglobulin
      V genes in vivo might reflect favoured sites of AID action being generated by
      proximal DNA targets located on opposite DNA strands. The target specificity of
      AID also accords with the spectrum of mutations observed in B lymphoma-associated
      oncogenes. The possibility of deaminase involvement in non-lymphoid human tumours
      is hinted at by tissue-specific differences in the spectra of dC transitions in
      tumour-suppressor genes. Thus, the patterns of hypermutation in antibodies and
      retroviruses owe much to the intrinsic sequence preferences of the AID/APOBEC
      family of DNA deaminases: analogous biases might also contribute to the spectra
      of cancer-associated mutation.

PMID- 15019780
TI  - Nucleotide binding to DNA gyrase causes loss of DNA wrap.
AB  - DNA gyrase negatively supercoils DNA in a reaction coupled to the binding and
      hydrolysis of ATP. Limited supercoiling can be achieved in the presence of the
      non-hydrolysable ATP analogue, 5'-adenylyl beta,gamma-imidodiphosphate (ADPNP).
      In order to negatively supercoil DNA, gyrase must wrap a length of DNA around
      itself in a positive sense. In previous work, the effect of ADPNP on the gyrase
      DNA interaction has been assessed but has produced conflicting results; the aim
      of this work was to resolve this conflict. We have probed the wrapping of DNA
      around gyrase in the presence and in the absence of ADPNP using direct
      observation by atomic force microscopy (AFM). We confirm that gyrase indeed
      generates a significant curvature in DNA in the absence of nucleotide and we show
      that the addition of ADPNP leads to a complete loss of wrap. These results have
      been corroborated using a DNA relaxation assay involving topoisomerase I. We have
      re-analysed previous hydroxyl-radical footprinting and crystallography data, and
      highlight the fact that the gyrase-DNA complex is surprisingly asymmetric in the
      absence of nucleotide but is symmetric in the presence of ADPNP. We suggest a
      revised model for the conformation of DNA bound to the enzyme that is fully
      consistent with these AFM data, in which a closed loop of DNA is stabilised by
      the enzyme in the absence of ADPNP and is lost in the presence of nucleotide.

PMID- 15019781
TI  - Mechanics of DNA flexibility visualized by selective 2'-amine acylation at
      nucleotide bulges.
AB  - We used selective acylation of 2'-amine-substituted nucleotides to visualize
      local backbone conformations that occur preferentially at bulged sites in DNA
      duplexes. 2'-Amine acylation reports local nucleotide flexibility because
      unconstrained 2'-amino nucleotides more readily reach a reactive conformation in
      which the amide-forming transition state is stabilized by interactions between
      the amine nucleophile and the adjacent 3'-phosphodiester group. Bulged 2'-amine
      substituted cytidine nucleotides react approximately 20-fold more rapidly than
      nucleotides constrained by base-pairing at 35 degrees C. In contrast, base-paired
      2'-amine-substituted nucleotides flanked by a 5' or 3' bulge react two- or six
      fold more rapidly, respectively, than the perfectly paired duplex. The relative
      lack of 2'-amine reactivity for nucleotides adjacent to a DNA bulge emphasizes,
      first, that structural perturbations do not extend significantly into the
      flanking duplex structure. Second, the exquisite sensitivity towards very local
      perturbations in nucleic acid structure suggests that 2'-amine acylation can be
      used to chemically interrogate deletion mutations in DNA. Finally, these data
      support the mechanical interpretation that the reactive ribose conformation for
      2'-amine acylation requires that the base lies out of the helix and in the major
      groove, a mechanistic insight useful for designing 2'-amine-based sensors.

PMID- 15019782
TI  - Recognition of the pro-mutagenic base uracil by family B DNA polymerases from
      archaea.
AB  - Archaeal family B DNA polymerases contain a specialised pocket that binds tightly
      to template-strand uracil, causing the stalling of DNA replication. The mechanism
      of this unique "template-strand proof-reading" has been studied using equilibrium
      binding measurements, DNA footprinting, van't Hoff analysis and calorimetry.
      Binding assays have shown that the polymerase preferentially binds to uracil in
      single as opposed to double-stranded DNA. Tightest binding is observed using
      primer-templates that contain uracil four bases in front of the primer-template
      junction, corresponding to the observed stalling position. Ethylation
      interference analysis of primer-templates shows that the two phosphates,
      immediately flanking the uracil (NpUpN), are important for binding; contacts are
      also made to phosphates in the primer-strand. Microcalorimetry and van't Hoff
      analysis have given a fuller understanding of the thermodynamic parameters
      involved in uracil recognition. All the results are consistent with a "read
      ahead" mechanism, in which the replicating polymerase scans the template, ahead
      of the replication fork, for the presence of uracil and halts polymerisation on
      detecting this base. Post-stalling events, serving to eliminate uracil, await
      full elucidation.

PMID- 15019783
TI  - Prediction and functional analysis of native disorder in proteins from the three
      kingdoms of life.
AB  - An automatic method for recognizing natively disordered regions from amino acid
      sequence is described and benchmarked against predictors that were assessed at
      the latest critical assessment of techniques for protein structure prediction
      (CASP) experiment. The method attains a Wilcoxon score of 90.0, which represents
      a statistically significant improvement on the methods evaluated on the same
      targets at CASP. The classifier, DISOPRED2, was used to estimate the frequency of
      native disorder in several representative genomes from the three kingdoms of
      life. Putative, long (>30 residue) disordered segments are found to occur in 2.0%
      of archaean, 4.2% of eubacterial and 33.0% of eukaryotic proteins. The function
      of proteins with long predicted regions of disorder was investigated using the
      gene ontology annotations supplied with the Saccharomyces genome database. The
      analysis of the yeast proteome suggests that proteins containing disorder are
      often located in the cell nucleus and are involved in the regulation of
      transcription and cell signalling. The results also indicate that native disorder
      is associated with the molecular functions of kinase activity and nucleic acid
      binding.

PMID- 15019784
TI  - Identifying target genes regulated downstream of Cdx2 by microarray analysis.
AB  - The caudal-related homeobox transcription factor (Cdx2) plays an important role
      in intestinal development, differentiation, and homeostasis. However, only a
      limited number of Cdx2-regulated target genes have been elucidated. To delineate
      the molecular mechanism regulated downstream of Cdx2, we aimed to define Cdx2
      regulated genes. We engineered a rat intestinal epithelial cell line, IEC-6, with
      minimal endogenous Cdx2 expression to express exogenous Cdx2. The gene expression
      patterns for Cdx2-inducing cells and control cells were examined using
      oligonucleotide arrays. In the present study, differential expression of 23 genes
      was confirmed by a semi-quantitative reverse transcription-polymerase chain
      reaction (RT-PCR) analysis using gene-specific primers. Increased expression of
      genes was involved in the Notch signaling pathway, xenobiotic metabolism, enzymes
      associated with tumor suppression, RNA binding protein, receptors, signal
      transduction, and transcription factors. The wide-ranging collection of such
      inducing genes suggests to the functions of Cdx2 in cell fate decision and
      maintenance of intestinal epithelia.

PMID- 15019785
TI  - Structural and catalytic diversity in the two family 11 aldo-keto reductases.
AB  - Aldo-keto reductases (AKRs) are a large superfamily of NAD(P)H-dependent enzymes
      that function in a wide range of biological processes. The structures of two
      enzymes from the previously uncharacterized family 11 (AKR11A and AKR11B), the
      products of the iolS and yhdN genes of Bacillus subtilis have been determined.
      AKR11B appears to be a relatively conventional member of the superfamily with
      respect to structural and biochemical properties. It is an efficient enzyme,
      specific for NADPH and possesses a catalytic triad typical for AKRs. AKR11A
      exhibits catalytic divergence from the other members of the superfamily and,
      surprisingly, AKR11B, the most closely related aldo-keto reductase in sequence.
      Although both have conserved catalytic residues consisting of an acidic tyrosine,
      a lysine and an aspartate, a water molecule interrupts this triad in cofactor
      bound AKR11A by inserting between the lysine and tyrosine side-chains. This
      results in a unique architecture for an AKR active site with scant catalytic
      power. In addition, the absence of a bulky tryptophan side-chain in AKR11A allows
      an unconventional conformation of the bound NADP+ cosubstrate, raising the
      possibility that it donates the 4-pro-S hydride rather than the 4-pro-R hydride
      seen in most other AKRs. Based upon the architecture of the active site and the
      resulting reaction velocities, it therefore appears that functioning as an
      efficient oxido-reductase is probably not the primary role of AKR11A. A
      comparison of the apo and holo forms of AKR11A demonstrates that the cosubstrate
      does not play the dramatic role in active site assembly seen in other superfamily
      members.

PMID- 15019786
TI  - Substrate and metal complexes of 3-deoxy-D-arabino-heptulosonate-7-phosphate
      synthase from Saccharomyces cerevisiae provide new insights into the catalytic
      mechanism.
AB  - 3-Deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthases are metal-dependent
      enzymes that catalyse the first committed step in the biosynthesis of aromatic
      amino acids in microorganisms and plants, the condensation of 2
      phophoenolpyruvate (PEP) and d-erythrose 4-phosphate (E4P) to DAHP. The DAHP
      synthases are possible targets for fungicides and represent a model system for
      feedback regulation in metabolic pathways. To gain further insight into the role
      of the metal ion and the catalytic mechanism in general, the crystal structures
      of several complexes between the tyrosine-regulated form of DAHP synthase from
      Saccharomyces cerevisiae and different metal ions and ligands have been
      determined. The crystal structures provide evidence that the simultaneous
      presence of a metal ion and PEP result in an ordering of the protein into a
      conformation that is prepared for binding the second substrate E4P. The site and
      binding mode of E4P was derived from the 1.5A resolution crystal structure of
      DAHP synthase in complex with PEP, Co2+, and the E4P analogue glyceraldehyde 3
      phosphate. Our data suggest that the oxygen atom of the reactive carbonyl group
      of E4P replaces a water molecule coordinated to the metal ion, strongly favouring
      a reaction mechanism where the initial step is a nucleophilic attack of the
      double bond of PEP on the metal-activated carbonyl group of E4P. Mutagenesis
      experiments substituting specific amino acids coordinating PEP, the divalent
      metal ion or the second substrate E4P, result in stable but inactive Aro4p
      derivatives and show the importance of these residues for the catalytic
      mechanism.

PMID- 15019787
TI  - Anchoring a cationic ligand: the structure of the Fab fragment of the anti
      morphine antibody 9B1 and its complex with morphine.
AB  - The crystal structures of an anti-morphine antibody 9B1 (to 1.6A resolution) and
      its complex with morphine (to 2.0 A resolution) are reported. The morphine
      binding site is described as a shallow depression on the protein surface, an
      unusual topology for a high-affinity ( Ka approximately 10(9) M(-1)) antibody
      against a small antigen. The polar part of the ligand is exposed to solvent, and
      the cationic nitrogen atom of the morphine molecule is anchored at the bottom of
      the binding site by a salt-bridge to a glutamate side-chain. Additional affinity
      is provided by a double cation-pi interaction with two tryptophan residues.
      Comparison of the morphine complex with the structure of the free Fab shows that
      a domain closure occurs upon binding of the ligand.

PMID- 15019788
TI  - Increasing stability reduces conformational heterogeneity in a protein folding
      intermediate ensemble.
AB  - A multi-site, time-resolved fluorescence resonance energy transfer methodology
      has been used to study structural heterogeneity in a late folding intermediate
      ensemble, IL, of the small protein barstar. Four different intra-molecular
      distances have been measured within the structural components of IL. The IL
      ensemble is shown to consist of different sub-populations of molecules, in each
      of which one or more of the four distances are native-like and the remaining
      distances are unfolded-like. In very stable conditions that favor formation of
      IL, all four distances are native-like in most molecules. In less stable
      conditions, one or more distances are unfolded-like. As stability is decreased,
      the proportion of molecules with unfolded-like distances increases. Thus, the
      results show that protein folding intermediates are ensembles of different
      structural forms, and they demonstrate that conformational entropy increases as
      structures become less stable. These observations provide direct experimental
      evidence in support of a basic tenet of energy landscape theory for protein
      folding, that available conformational space, as represented by structural
      heterogeneity in IL, becomes restricted as the stability is increased. The
      results also vindicate an important prediction of energy landscape theory, that
      different folding pathways may become dominant under different folding
      conditions. In more stable folding conditions, uniformly native-like compactness
      is achieved during folding to IL, whereas in less stable conditions, uniformly
      native-like compactness is achieved only later during the folding of IL to N.

PMID- 15019789
TI  - Helix packing moments reveal diversity and conservation in membrane protein
      structure.
AB  - Helical membrane proteins are more tightly packed and the packing interactions
      are more diverse than those found in helical soluble proteins. Based on a linear
      correlation between amino acid packing values and interhelical propensity, we
      propose the concept of a helix packing moment to predict the orientation of
      helices in helical membrane proteins and membrane protein complexes. We show that
      the helix packing moment correlates with the helix interfaces of helix dimers of
      single pass membrane proteins of known structure. Helix packing moments are also
      shown to help identify the packing interfaces in membrane proteins with multiple
      transmembrane helices, where a single helix can have multiple contact surfaces.
      Analyses are described on class A G protein-coupled receptors (GPCRs) with seven
      transmembrane helices. We show that the helix packing moments are conserved
      across the class A family of GPCRs and correspond to key structural contacts in
      rhodopsin. These contacts are distinct from the highly conserved signature motifs
      of GPCRs and have not previously been recognized. The specific amino acid types
      involved in these contacts, however, are not necessarily conserved between
      subfamilies of GPCRs, indicating that the same protein architecture can be
      supported by a diverse set of interactions. In GPCRs, as well as membrane
      channels and transporters, amino acid residues with small side-chains (Gly, Ala,
      Ser, Cys) allow tight helix packing by mediating strong van der Waals
      interactions between helices. Closely packed helices, in turn, facilitate
      interhelical hydrogen bonding of both weakly polar (Ser, Thr, Cys) and strongly
      polar (Asn, Gln, Glu, Asp, His, Arg, Lys) amino acid residues. We propose the use
      of the helix packing moment as a complementary tool to the helical hydrophobic
      moment in the analysis of transmembrane sequences.

PMID- 15019790
TI  - Structure and substrate binding properties of cobB, a Sir2 homolog protein
      deacetylase from Escherichia coli.
AB  - Sirtuins are NAD+-dependent protein deacetylase enzymes that are broadly
      conserved from bacteria to human, and have been implicated to play important
      roles in gene regulation, metabolism and longevity. cobB is a bacterial sirtuin
      that deacetylates acetyl-CoA synthetase (Acs) at an active site lysine to
      stimulate its enzymatic activity. Here, we report the structure of cobB bound to
      an acetyl-lysine containing non-cognate histone H4 substrate. A comparison with
      the previously reported archaeal and eukaryotic sirtuin structures reveals the
      greatest variability in a small zinc-binding domain implicated to play a
      particularly important role in substrate-specific binding by the sirtuin
      proteins. Comparison of the cobB/histone H4 complex with other sirtuin proteins
      in complex with acetyl-lysine containing substrates, further suggests that
      contacts to the acetyl-lysine side-chain and beta-sheet interactions with
      residues directly C-terminal to the acetyl-lysine represent conserved features of
      sirtuin-substrate recognition. Isothermal titration calorimetry studies were used
      to compare the affinity of cobB for a variety of cognate and non-cognate acetyl
      lysine-bearing peptides revealing an exothermic reaction with relatively little
      discrimination between substrates. In contrast, similar studies employing intact
      acetylated Acs protein as a substrate reveal a binding reaction that is
      endothermic, suggesting that cobB recognition of substrate involves a burial of
      hydrophobic surface and/or structural rearrangement involving substrate regions
      distal to the acetyl-lysine-binding site. Together, these studies suggest that
      substrate-specific binding by sirtuin proteins involves contributions from the
      zinc-binding domain of the enzyme and substrate regions distal to the acetyl
      lysine-binding site.

PMID- 15019791
TI  - Highly discriminating protein-protein interaction specificities in the context of
      a conserved binding energy hotspot.
AB  - We explore the thermodynamic basis for high affinity binding and specificity in
      conserved protein complexes using colicin endonuclease-immunity protein complexes
      as our model system. We investigated the ability of each colicin-specific
      immunity protein (Im2, Im7, Im8 and Im9) to bind the endonuclease (DNase) domains
      of colicins E2, E7 and E8 in vitro and compared these to the previously studied
      colicin E9. We find that high affinity binding (Kd < or = 10(-14) M) is a common
      feature of cognate colicin DNase-Im protein complexes as are non-cognate protein
      protein associations, which are generally 10(6)-10(8)-fold weaker. Comparative
      alanine scanning of Im2 and Im9 residues involved in binding the E2 DNase
      revealed similar behaviour to that of the two proteins binding the E9 DNase;
      helix III forms a conserved binding energy hotspot with specificity residues from
      helix II only contributing favourably in a cognate interaction, a combination we
      have termed as "dual recognition". Significant differences are seen, however, in
      the number and side-chain chemistries of specificity sites that contribute to
      cognate binding. In Im2, Asp33 from helix II dominates colicin E2 specificity,
      whereas in Im9 several hydrophobic residues, including position 33 (leucine),
      help define its colicin specificity. A similar distribution of specificity sites
      was seen using phage display where, with Im2 as the template, a library of
      randomised sequences was generated in helix II and the library panned against
      either the E2 or E9 DNase. Position 33 was the dominant specificity site
      recovered in all E2 DNase-selected clones, whereas a number of Im9 specificity
      sites were recovered in E9 DNase-selected clones, including position 33. In order
      to probe the relationship between biological specificity and in vitro binding
      affinity we compared the degree of protection afforded to bacteria against
      colicin E9 toxicity by a set of immunity proteins whose affinities for the E9
      DNase differed by up to ten orders of magnitude. This analysis indicated that the
      Kd required for complete biological protection is <10(-10)M and that the
      "affinity window" over which the selection of novel immunity protein
      specificities likely evolves is 10(-6)-10(-10)M. This comprehensive survey of
      colicin DNase-immunity protein complexes illustrates how high affinity protein
      protein interactions can be very discriminating even though binding is dominated
      by a conserved hotspot, with single or multiple specificity sites modulating the
      overall binding free energy. We discuss these results in the context of other
      conserved protein complexes and suggest that they point to a generic specificity
      mechanism in divergently evolved protein-protein interactions.

PMID- 15019792
TI  - Crystal structure of the GTP-binding protein Obg from Thermus thermophilus HB8.
AB  - Obg comprises a unique family of high-molecular mass GTPases conserved from
      bacteria to eukaryotes. Bacterial Obg is essential for cellular growth,
      sporulation, and differentiation. Here, we report the crystal structure of the
      full-length form of Obg from Thermus thermophilus HB8 at 2.07 A resolution, in
      the nucleotide-free state. It reveals a three-domain arrangement, composed of the
      N-terminal domain, the guanine nucleotide-binding domain (G domain), and the C
      terminal domain. The N-terminal and G domains have the Obg fold and the Ras-like
      fold, respectively. These global folds are similar to those of the recently
      published structure of the C-terminal domain-truncated form of Obg from Bacillus
      subtilis. On the other hand, the C-terminal domain of Obg was found to have a
      novel fold (the OCT fold). A comparison of the T.thermophilus and B.subtilis
      nucleotide-free Obg structures revealed significant conformational changes in the
      switch-I and switch-II regions of the G domain. Notably, the N-terminal domain is
      rotated drastically, by almost 180 degrees, around the G domain axis. In the
      T.thermophilus Obg crystal, the nucleotide-binding site of the G domain interacts
      with the C-terminal domain of the adjacent molecule. These data suggest a
      possible domain rearrangement of Obg, and a potential role of the C-terminal
      domain in the regulation of the nucleotide-binding state.

PMID- 15019793
TI  - Induction of pseudopregnancy using artificial VCS: importance of lordosis
      intensity and prestimulus estrous cycle length.
AB  - In cycling female rats, vaginocervical stimulation (VCS) received naturally
      during mating or by artificial mechanical stimulation induces neuroendocrine and
      behavioral responses that are critical for reproduction, including bi-circadian
      prolactin surges which result in pregnancy or an 8-14-day diestrous period called
      pseudopregnancy (PSP). Following mating, the incidence of PSP is higher when
      females receive high (10) as opposed to low (3-5) numbers of intromissions.
      Therefore, a threshold level of VCS must be exceeded before hypothalamic changes
      required for PSP can occur. This study characterized the threshold curve for PSP
      induction for artificial VCS (VCS-a). Proestrous females were given 1, 2, 3, 4,
      or 8 VCS-a applied with a glass rod using 200 g of force for 2 s, with an 8-min
      interval between stimulations. The lordosis response (LR) to the stimulus was
      measured on a scale of increasing intensity from 0 to 3, and the occurrence of
      PSP was measured by daily vaginal lavage. In contrast to previous findings, VCS-a
      induced robust lordosis responses without concurrent flank and perineal
      stimulation. The frequency of PSP induction did not increase in females as a
      function of amounts of VCS-a. However, the occurrence of PSP was strongly tied to
      the maximum lordosis response (LR(max)) observed. PSP was observed only among
      multiply stimulated females that showed the highest LR(max) (3.0) to at least one
      of the stimulations. Multiply stimulated females that showed a LR(max) < 3.0 or
      females that received only one VCS-a never became PSP. PSP and a stronger LR(max)
      were more likely to occur in females that had 5-day compared to 4-day prestimulus
      estrous cycle lengths. We conclude that central mechanisms important for VCS
      induced PSP and lordosis may be potentiated by estradiol's actions in estrogen
      concentrating forebrain areas.

PMID- 15019794
TI  - Responsiveness of expectant male cotton-top tamarins, Saguinus oedipus, to mate's
      pregnancy.
AB  - In the cotton-top tamarin, a primate where paternal care is critical to the
      survival of the offspring, we found that expectant fathers experienced multiple
      hormonal changes during their mate's pregnancy. Fathers that had experienced
      several previous births showed significant changes in urinary estrogens,
      androgens, prolactin and cortisol in the last 2 months before birth, whereas less
      experienced fathers (LEF) did not. The female's midpregnancy rise in
      glucocorticoids was followed within 1-2 weeks by a peak of cortisol and
      corticosterone in her paired male in 70% of all males and 100% of all experienced
      males. Examination of behavioral interactions between the pairs did not reveal
      changes in rates of interactions between the experienced pairs over pregnancy.
      However, the less-experienced pairs had significantly higher levels of
      affiliative and sexual interactions. Therefore, behavioral communication between
      the pair did not appear to account for the hormonal changes occurring within the
      experienced fathers (EF). The midpregnancy rise of glucocorticoids in females may
      stimulate a glucocorticoid response in male tamarins and thereby activate other
      hormonal changes in males to prepare them for their parenting role.

PMID- 15019795
TI  - Diurnal rhythms of free estradiol and cortisol during the normal menstrual cycle
      in women with major depression.
AB  - To investigate whether depression is accompanied by changes in diurnal rhythms of
      free estradiol and cortisol in different phases of the menstrual cycle, we
      measured these two hormone levels in saliva samples collected every 2 h for 24 h
      from 15 healthy normally cycling women and 12 age-matched normally cycling women
      suffering from major depression taking antidepressants. The assessments were
      repeated four times over one menstrual cycle: during menstruation and in the late
      follicular/peri-ovulating, early to mid-luteal and late luteal phases,
      respectively. Quantification with a nonlinear periodic regression model revealed
      distinct diurnal rhythms in free estradiol and free cortisol in all subjects. For
      the diurnal cortisol rhythm, significant differences were found in the peak-width
      and ultradian amplitude among different menstrual phases, both in controls and
      depressed patients, while no significant differences were found between the two
      groups. The diurnal estradiol rhythm, on the other hand, was quite consistent
      among different menstrual phases within both groups, while the depressed patients
      had overall larger amplitudes than controls, which is negatively correlated with
      disease duration. Significant positive correlations between the two hormone
      rhythms were found for 24-h mean level (mesor), peak, and trough in late luteal
      phase, and for ultradian harmonics in early to mid-luteal phase in controls, but
      only for ultradian harmonics in late follicular/peri-ovulating phase and for
      acrophase in the menstruation phase in depressed patients. A sub-analysis was
      also performed in patients who received Fluoxetine (n = 7). The findings
      implicate a close correlation between the hypothalamic-pituitary-adrenal axis and
      the hypothalamic-pituitary-gonadal axis, both of which may be involved in
      depression.

PMID- 15019796
TI  - Effects of repeated aggressive encounters on approach to a female and plasma
      testosterone in male mice.
AB  - Effects of repeated experience of aggression accompanied by social victories or
      social defeat in 10 daily agonistic confrontations on testosterone levels in and
      the behavioral response of CBA/Lac male mice exposed to a receptive female from
      behind a perforated transparent partition have been examined. Testosterone levels
      were not changed significantly in the mice that had consistently been victorious
      over 10 days (winners) or in the mice that had consistently been defeated over 10
      days (losers). Losers and controls (mice that had been caged individually for 5
      days) responded with increased levels of behavioral activity near the partition
      and elevated testosterone. Winners showed a significantly poorer behavioral and
      hormonal response. It is concluded that the repeated display of aggression by
      male mice led to a reduction in both their behavioral and neuroendocrine
      responses to an estrous female.

PMID- 15019797
TI  - An endocrine disrupter increases growth and risky behavior in threespined
      stickleback (Gasterosteus aculeatus).
AB  - There is considerable concern that endocrine disrupting chemicals (EDCs) can
      affect wildlife and humans. While several studies have reported that acute
      exposure to EDCs can cause changes in reproductive traits, we are in the early
      stages of discerning whether such changes have significant deleterious fitness
      consequences. In this study, chronic exposure of threespined stickleback
      (Gasterosteus aculeatus) to an environmentally relevant level of an EDC used in
      the birth control pill and post-menopausal hormone replacement therapy produced
      changes in growth and behavior that were related to fitness. Exposure to 100 ng/l
      ethinyl estradiol accelerated growth rate and increased levels of behavior that
      makes individuals more susceptible to predation (activity and foraging under
      predation risk). Moreover, the costs of exposure to ethinyl estradiol took their
      ultimate toll via mortality later in life, and were particularly high for females
      and for one population. The ecological approach taken in this work revealed
      heretofore unexamined effects of EDCs and has direct implications for the way we
      evaluate the impact of EDCs in the environment.

PMID- 15019798
TI  - Opposing hormonal mechanisms of aggression revealed through short-lived
      testosterone manipulations and multiple winning experiences.
AB  - Territorial aggression is influenced by many social and environmental factors.
      Since aggression is a costly behavior, individuals should account for multiple
      factors such as population density or reproductive status before engaging in
      aggression. Previous work has shown that male California mice (Peromyscus
      californicus) respond to winning aggressive encounters by initiating aggression
      more quickly in future encounters, and we investigated the physiological basis
      for this effect. We found that injections that produced a transient increase in
      testosterone (T) following an aggressive encounter caused males to behave more
      aggressively in an encounter the following day. Experience alone was not enough
      to change aggression, as males treated with saline injections showed no change in
      aggression. The effect of T injections on aggression was androgen-based, as the
      inhibition of aromatase did not block the T injections from increasing
      aggression. Aromatase inhibition did, however, increase aggression in the initial
      aggression tests (before application of T or saline injections), and aromatase
      activity in the bed nucleus of the stria terminalis (BNST) was negatively
      correlated with aggression. A previous study suggested that aromatase activity in
      the BNST decreases after males become fathers. Thus, distinct neuroendocrine
      mechanisms allow male California mice to adjust aggressive behavior in response
      to changes in social and reproductive status.

PMID- 15019799
TI  - Modulatory role of testosterone in alarm pheromone release by male rats.
AB  - An alarm pheromone released from stressed conspecifics evokes behavioral and
      autonomic responses in rats. We have previously reported that male Wistar rats
      show behavioral changes including increased sniffing, walking and rearing, and
      decreased resting as well as exaggerated response of body temperature to a novel
      environment [known as stress-induced hyperthermia (SIH)] when they are exposed to
      an alarm pheromone released from other male rats receiving foot shocks. The
      purpose of the present study was to examine the role of testosterone in the
      production and release of the alarm pheromone using these behavioral and
      autonomic responses in recipient rats. Three groups of alarm pheromone donors
      were presented, namely, intact males, castrated males, and testosterone-implanted
      castrated males. The effects of the alarm pheromone on the autonomic responses
      did not differ among the three groups, regardless of the donor's steroidal
      milieu, whereas behavioral responses were altered by castrating the donor males
      and the effects were restored by testosterone implantation. These results suggest
      that the alarm pheromone released from stressed male rats can be classified into
      at least two categories according to the androgen dependency of their production
      and/or release.

PMID- 15019800
TI  - Spatial memory retention is enhanced by acute and continuous estradiol
      replacement.
AB  - Estradiol replacement to ovariectomized female rats causes dramatic changes in
      hippocampal structure and function as well as in performance on hippocampally
      dependent tasks. Using a delayed matching-to-place version of the water maze, the
      present study examines the time course of estradiol-induced enhancements in
      memory retention as well as the effectiveness of acute and continuous patterns of
      replacement. One 10-microg injection of estradiol administered on each of two
      successive days resulted in significant improvements in memory retention that
      persisted for approximately 4 days following the second injection. When estradiol
      administration continued for 10 consecutive days, these improvements in memory
      retention persisted. These findings indicate that estradiol replacement can
      improve memory retention and that these improvements can be maintained by
      continuous replacement for at least 10 days.

PMID- 15019801
TI  - Effects of central vasotocin and mesotocin manipulations on social behavior in
      male and female zebra finches.
AB  - Male and female zebra finches (Taeniopygia guttata; total n = 40) were fitted
      with chronic guide cannulae directed at the lateral ventricle and were tested for
      aggression, affiliation, and partner preference following infusions of mesotocin
      (MT), vasotocin (VT), their antagonists, and vehicle control. Aggressive behavior
      was tested in a mate competition paradigm and tests of intersexual affiliation
      and partner preference were conducted following 1 day of cohabitation with an
      opposite-sex individual. These tests also provided data on male courtship
      singing. The results demonstrate a modest dose-dependent facilitation of
      aggression by VT, but not MT, in both male and female finches. However, only
      males were sensitive to infusions of a vasopressin antagonist, suggesting that
      endogenous VT is more important for behavioral modulation in males. Peptide
      effects were specific to aggression, as no treatments influenced intersexual
      affiliation, partner preference, or male courtship singing. Thus, in contrast to
      rodents, partner preference is not readily induced by VT or MT in this species.
      However, the potential necessity of endogenous VT and MT for natural pair-bond
      formation remains to be tested.

PMID- 15019803
TI  - Cryopreservation of isolated ovine primordial follicles with propylene glycol and
      glycerol.
AB  - OBJECTIVE: To verify the viability of isolated primordial follicles to different
      propylene glycol (PROH) and glycerol (GLY) concentrations before and after
      cryopreservation. DESIGN: Isolated primordial follicles were stained with trypan
      blue to evaluate the effect of different PROH and GLY concentrations before and
      after cryopreservation. SETTING: Laboratorio Renzo Giuliani, University of
      Florence, Italy. PATIENT(S): Thirty- to forty-day-old lambs. INTERVENTION(S): :
      Isolation of primordial follicles with subsequent exposure to cryoprotectant and
      freezing. MAIN OUTCOME MEASURE(S): Histologic structure and follicular mortality.
      RESULT(S): After the isolation procedure (control), the mean number of live
      primordial follicles/mL was 2,688 and 4,452 in the GLY and PROH groups,
      respectively. When GLY was used, the number of live follicles before
      cryopreservation was 820, 756, 640, 524, 564, and 460 follicles/mL with
      concentrations of 0, 0.5, 1.0, 1.5, 2.0, and 2.5 mol/L, respectively. After
      cryopreservation, this number decreased to 0, 12, 36, 100, 84, and 68
      follicles/mL, respectively, with the same concentrations. When PROH was used, the
      number of live follicles before cryopreservation was 4,216, 3,880, 3,560, 1,812,
      704, and 568 follicles/mL with concentrations of 0, 0.5, 1.0, 1.5, 2.0, and 2.5
      mol/L, respectively. After cryopreservation, this number decreased to 0, 116,
      336, 472, 360, and 244 follicles/mL, respectively, with the same concentrations.
      CONCLUSION(S): Both cryoprotectants were shown to preserve isolated primordial
      follicles after cryopreservation.

PMID- 15019802
TI  - Evidence that androgenic and estrogenic metabolites contribute to the effects of
      dehydroepiandrosterone on cognition in postmenopausal women.
AB  - Prior studies of the effects of dehydroepiandrosterone (DHEA) on cognition have
      produced complex and inconsistent results. We hypothesize that these results may
      arise, in part, because of DHEA's metabolism into estrogens and androgens that
      produce opposing effects on cognition. Our study administered 50 mg of oral DHEA
      daily for 4 weeks in a placebo-controlled crossover design to six postmenopausal
      women. We measured blood levels of androgens (total testosterone, free
      testosterone, DHEA, DHEAS), estrogens (estradiol, estrone), and cognitive
      performance on recognition memory, perceptual identification, digit span memory,
      and visual attentional vigilance under both drug and placebo conditions. Multiple
      regression models incorporating the factors of age and body mass index (BMI) were
      used to ascertain the relation between sex steroids and cognitive performance.
      Our results demonstrated that estrogens produced a positive effect on recognition
      memory, while androgens produced a negative effect. This pattern reversed in
      perceptual identification with estrogens producing a negative effect and
      androgens producing a positive effect. In addition, BMI produced a negative
      effect on digit span memory, age produced a negative effect on perceptual
      identification, and androgens produced a negative effect on visual attentional
      vigilance. These results help, in part, to explain DHEA's complex effects on
      cognition. The diverse effects of sex steroids across tasks underscore the
      importance of identifying the specific cognitive mechanisms influenced by sex
      steroids and emphasizes that one should not expect sex steroids to produce
      homogeneous effects across cognitive tasks.

PMID- 15019804
TI  - Osteopontin is up-regulated in human decidual stromal cells.
AB  - OBJECTIVE: To analyze expression and regulation of osteopontin in human stromal
      endometrial and decidual cells. DESIGN: Study by immunohistochemistry, RNase
      protection assay, and in vitro study. SETTING: Academic research unit.
      PATIENT(S): Twenty-five fertile women. INTERVENTION(S): Expression of osteopontin
      mRNA and protein was analyzed by RNase protection assay (RPA) and
      immunohistochemistry in secretory endometrium and decidua. Regulation of
      osteopontin expression in endometrial epithelial cell and stromal cells was
      analyzed by incubation with 17beta-estrogen, progesterone, IL-1beta, IL-6, and
      LIF and by incubation with cell culture supernatants of decidual natural killer
      cells. Furthermore, osteopontin expression was studied in stromal cells,
      decidualized in vitro. MAIN OUTCOME MEASURE(S): mRNA and protein expression and
      regulation of endometrial stromal osteopontin. RESULT(S): Osteopontin mRNA and
      protein are expressed at increasing concentrations in human secretory endometrium
      and in decidua. High concentrations in total decidua were due to high osteopontin
      concentrations in decidualized stromal cells. Osteopontin mRNA and protein
      expression was not regulated by incubation of endometrial epithelial and stromal
      cells with steroids, cytokines, and natural killer cell supernatant for 6 and 24
      hours. In contrast, decidualization of stromal cells for 7, 14, and 21 days
      resulted in significant up-regulation of osteopontin mRNA and protein.
      CONCLUSION(S): Osteopontin is expressed at high concentrations in secretory
      endometrium in epithelial cells and in decidua in stromal cells. Decidual stromal
      expression of osteopontin is up-regulated by decidualization.

PMID- 15019805
TI  - Estradiol regulation of oviductin/oviduct-specific glycoprotein messenger
      ribonucleic acid expression in human oviduct mucosal cells in vitro.
AB  - OBJECTIVE: To determine whether oviduct mucosal cell culture with exogenous
      17beta E(2) supports the continued production of oviductin, a putative
      embryotrophic protein. DESIGN: Semiquantitative reverse-transcriptase polymerase
      chain reaction analysis of oviductin mRNA expression after oviduct mucosal cell
      culture in the presence of 17beta E(2). Three different culture systems were
      studied to investigate the response to E(2). SETTING: University-based obstetrics
      and gynecology department. SUBJECTS: Oviduct tissue was obtained from 18 women
      undergoing laparoscopy for benign gynecologic conditions. INTERVENTION(S): The
      mucosal layer was isolated from the oviduct tissue and exposed to three different
      culture systems, which contained various concentrations of 17beta E(2), or
      vehicle-only control. MAIN OUTCOME MEASURE(S): The relationship between exposure
      to 17beta E(2) and expression of oviductin messenger (m)RNA by cultured oviduct
      mucosal cells. RESULT(S): There was a significant increase in oviductin mRNA
      expression after the addition of 17beta E(2) to the culture system in which the
      in vivo cell-to-cell and cell-to-basement-membrane contacts of the oviduct had
      been maintained. CONCLUSION(S): Estradiol failed to alter oviductin mRNA
      expression in oviduct mucosal cells cultured under conditions in which the
      ciliated mucosal cell phenotype plus the cell-to-cell and cell-to-basement
      membrane contacts of the oviduct were lost. However, with a culture system that
      maintained the cell architecture, E(2) initiated and significantly increased
      oviductin mRNA expression.

PMID- 15019806
TI  - Conjugated equine estrogens reverse the effects of aging on central and
      peripheral allopregnanolone and beta-endorphin levels in female rats.
AB  - OBJECTIVE: To compare beta-endorphin and allopregnanolone levels and their
      response to a 2-week oral estrogen treatment with conjugated equine estrogens
      (CEE) in young ovariectomized (ovx) and in healthy aged female rats. DESIGN:
      Prospective study. SETTING: Animal laboratory in an academic environment.
      ANIMAL(S): Twenty-four young ovx and 24 healthy aged female Wistar rats were
      treated with CEE. Three 8-rat control groups (cycling, ovx, and aged rats) were
      also included. INTERVENTION(S): Treated rats underwent 14-day oral treatment with
      three doses of CEE: 0.1 mg/kg/day, 0.5 mg/kg/day, and 2 mg/kg/day. MAIN OUTCOME
      MEASURE(S): Cerebral and peripheral beta-endorphin and allopregnanolone levels.
      RESULT(S): Beta-endorphin levels were lower in aged vs. cycling and ovx control
      rats. In brain and serum allopregnanolone levels were lower in aged vs. cycling
      control rats, whereas in the adrenals they were higher in aged vs. cycling
      animals. In the hypothalamus and anterior pituitary allopregnanolone levels were
      lower in ovx vs. aged animals. In both ovx and aged animals, CEE treatment
      reverted the effects of ovariectomy and aging, in a dose-dependent manner.
      CONCLUSION(S): Aging is associated with a decrease in cerebral and peripheral
      beta-endorphin and allopregnanolone. In hypoestrogenic rats, CEE treatment
      restores allopregnanolone and beta-endorphin content; this indicates a role for
      these compounds as neuroendocrine mediators of the effects of estrogens.

PMID- 15019807
TI  - Incidence of Fas positivity and deoxyribonucleic acid double-stranded breaks in
      human ejaculated sperm.
AB  - OBJECTIVE: To determine the incidence of Fas positivity and DNA double-strand
      breaks (DSB) as indicators of early- and late-stage apoptosis in ejaculated
      sperm. DESIGN: Fas positivity was assessed by flow cytometry and DSB by the
      neutral Comet assay. SETTING: Andrology Laboratory, Royal Maternity Hospital,
      Belfast, Northern Ireland, United Kingdom. PATIENT(S) AND INTERVENTION(S): Forty
      five infertile men undergoing infertility investigations and 10 fertile men
      undergoing vasectomies. MAIN OUTCOME MEASURE(S): Percentage Fas-positive cells,
      percentage DNA fragmentation, olive tail moment. RESULT(S): The apoptotic marker
      Fas was detected in ejaculated sperm, with a higher incidence of Fas positivity
      in teratozoospermic and asthenozoospermic than in normozospermic semen. No Fas
      positivity was observed in fertile men's sperm. Deoxyribonucleic acid
      fragmentation (DSB) was greater in infertile than in fertile men's sperm and also
      greater in sperm in semen than in sperm prepared for assisted conception. There
      was an inverse relationship between DSB and both sperm concentration and
      motility. There was no relationship between Fas positivity and DNA damage.
      CONCLUSION(S): Fas was expressed in sperm of infertile men. In contrast, DNA
      fragmentation was observed in all sperm of fertile and infertile men and
      correlated with inadequate concentration and motility, which suggests that sperm
      DSB are ubiquitous and are not solely associated with apoptosis.

PMID- 15019808
TI  - Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous
      endometriosis in baboons.
AB  - OBJECTIVE: To determine the efficacy of anti-tumor necrosis factor therapy
      (etanercept) for treating endometriosis in baboons. DESIGN: A randomized, placebo
      controlled, blinded study using the baboon endometriosis model. SETTING:
      Southwest National Primate Research Center. ANIMAL(S): Twelve female baboons with
      spontaneous peritoneal endometriosis. INTERVENTION(S): Etanercept (n = 8) or
      sterile water (n = 4) was administered subcutaneously three times per week. MAIN
      OUTCOME MEASURE(S): After 8 weeks, the number, color, and surface area of
      peritoneal lesions was evaluated. Revised American Society for Reproductive
      Medicine staging was used. RESULT(S): A statistically significant decrease in red
      lesion surface area in the treatment group was observed. A trend toward a
      decrease in the absolute number of red lesions was noted in the treatment group.
      White and black lesion number and total surface area slightly increased in both
      groups but failed to achieve statistical significance. Endometriosis was
      diagnosed in 60% of captive-born baboons with primary infertility. CONCLUSION(S):
      These results indicate that etanercept effectively reduces the amount of
      spontaneously occurring active endometriosis in the baboon.

PMID- 15019809
TI  - Differences in the implantation rates of rat embryos developed in vivo and in
      vitro: possible role for plasminogen activators.
AB  - OBJECTIVE: To assess the participation of urokinase-type (uPA) and tissue-type
      (tPA) plasminogen activators in embryo development and implantation. DESIGN: The
      study was set to compare the activities of PAs in embryos developed in vivo and
      in vitro and their implantation rates. Endometrial PA activity was studied as
      well. SETTING: University laboratories. PATIENT(S): None. INTERVENTION(S): None.
      MAIN OUTCOME MEASURE(S): Plasminogen activator activity in embryos. RESULT(S):
      Whereas tPA activity in in vivo-developed embryos decreased from the zygote to
      the blastocyst stages, it did not change in embryos developed in vitro. The
      activity of uPA was lowest in two-cell-stage embryos, both in vivo and in vitro,
      and increased as embryos developed into blastocysts. The activity of uPA in the
      in vitro-developed embroys was lower in all developmental stages as compared with
      those developed in vivo. Whereas endometrial tPA activity did not change during
      the preimplantation period, uPA activity increased gradually toward the time of
      implantation. The implantation rate of the in vitro-developed embryos was much
      lower than that of those developed in vivo. CONCLUSION(S): Taken together, these
      data indicate that in vitro embryo development leads to lower PA activities as
      compared with in vivo development. The increased activity of uPA toward the
      blastocyst stage supports uPA's role in the implantation process. Moreover, the
      rise in endometrial uPA might also indicate its importance in this process.

PMID- 15019810
TI  - Detection of granulocyte colony-stimulating factor and its receptor in human
      follicular luteinized granulosa cells.
AB  - OBJECTIVE: To evaluate concentration of granulocyte colony-stimulating factor (G
      CSF) in serum and follicular fluid (FF) at the time of oocyte retrieval and to
      detect expression of G-CSF and its receptor by luteinized granulosa cells (GCs).
      DESIGN: Collection of serum and FF at the time of oocyte retrieval. SETTING: A
      university IVF-ICSI program. PATIENT(S): Serum and FF were obtained from 82 women
      undergoing oocyte retrieval. INTERVENTION(S): Serum and FF were obtained from 82
      women. Granulosa cells were pooled from 15 patients (three experiments with five
      patients each; 3-14 oocytes each). MAIN OUTCOME MEASURE(S): Granulocyte colony
      stimulating factor concentration was determined by ELISA, the expression of G
      CSF, and its receptor by the immunocytochemical technique and reverse
      transcriptase polymerase chain reaction analysis. Additionally, G-CSF expression
      was investigated by cell culture time course studies. RESULT(S): The median G-CSF
      level in FF (117.98 pg/mL) was significantly higher than that in serum (67.5
      pg/mL). Granulocyte colony-stimulating factor and its receptor were expressed by
      GCs. CONCLUSION(S): The significantly higher level of G-CSF in FF than in serum
      and the expression of G-CSF and its receptor in FF by GCs suggest an important
      role for this growth factor in ovarian function.

PMID- 15019811
TI  - Oxidative stress indices in seminal plasma, as measured by the
      thermochemiluminescence assay, correlate with sperm parameters.
AB  - OBJECTIVE: To examine the effect of oxidation of proteins and lipids, as measured
      by a novel thermochemiluminescence (TCL) analyzer, and to evaluate the
      correlation between TCL indices in seminal plasma and sperm parameters. DESIGN:
      Experimental and prospective clinical studies. SETTING: An infertility unit.
      PATIENT(S): One hundred forty-eight men undergoing semen analysis.
      INTERVENTION(S): Bovine serum albumin (BSA) and linolenic acid were oxidized and
      tested by TCL, protein carbonyls, and conjugated dienes assays. All participants
      underwent semen analysis. Seminal plasma was tested by TCL and conjugated dienes.
      MAIN OUTCOME MEASURE(S): Thermochemiluminescence indices before and after
      oxidation of BSA and linolenic acid, compared with protein carbonyl and
      conjugated dienes indices. Correlation between semen parameters and TCL and
      conjugated dienes indices in seminal plasma. RESULT(S): Oxidation of BSA and
      linolenic acid was marked by characteristic changes in their TCL curve pattern
      and an increase in the levels of protein carbonyls and conjugated dienes. Among
      125 sperm-containing semen samples, the TCL curve exhibited two patterns: a
      positive relative ratio curve (group A, 87 patients) and a negative relative
      ratio curve (group B, 38 patients). Sperm concentration was lower and total
      motile sperm and rapid motile sperm were fewer in group B. A significant
      correlation was found between TCL indices, conjugated dienes, and sperm quality
      in group B. CONCLUSION(S): Oxidation affects TCL curve pattern of proteins and
      lipids in a characteristic manner. Thermochemiluminescence indices in seminal
      plasma closely correlate with sperm characteristics among patients with sperm
      disturbances, and it might serve as a tool in the evaluation, treatment, and
      monitoring of subfertile men.

PMID- 15019812
TI  - Detection of erythropoietin in human seminal plasma.
AB  - OBJECTIVE: To examine the presence of erythropoietin (EPO) in ejaculates and the
      association between EPO levels in seminal plasma and semen parameters. DESIGN:
      Retrospective analysis. SETTING: University hospital in Japan. PATIENT(S): Eighty
      three infertile males and 16 volunteers with proven fertility. INTERVENTION(S):
      Semen was obtained by masturbation after 5 days of abstinence. Blood sample and
      split ejaculates of 16 volunteers with proven fertility were collected. MAIN
      OUTCOME MEASURE(S): Western blot analysis and enzyme-linked immunoassay in the
      seminal plasma and sperm parameters. RESULT(S): Western blot analysis showed that
      EPO protein was present in the seminal plasma. The EPO titers in the seminal
      plasma ranged from 1.5 mIU/mL to 45.0 mIU/mL by enzyme-linked immunoassay. There
      was no significant association between EPO levels and semen parameters. The first
      fraction of samples obtained by split ejaculation contained almost the same
      amount of EPO as the second fraction. CONCLUSION(S): Erythropoietin protein was
      constitutively present in seminal plasma. The seminal EPO originated from the
      prostate and seminal vesicle. No association between EPO levels in seminal plasma
      and sperm parameters was found in the present study.

PMID- 15019813
TI  - Activation pattern of caspases in human spermatozoa.
AB  - OBJECTIVE: We investigated the activation of caspases 8, 9, 1, and 3 in human
      ejaculated spermatozoa to study main pathways of apoptosis. Potential functional
      impact of this phenomenon and possible activation mechanisms were examined by [1]
      subjecting cells to freezing and thawing, and [2] testing the dependence of
      caspase activity on membrane integrity. DESIGN: Experimental study. SETTING:
      Andrology Center Leipzig (European Academy of Andrology). PATIENT(S): Ten healthy
      volunteers, 40 semen samples. INTERVENTION(S): Sperm populations were separated
      by annexin V magnetic activated cell sorting (MACS) according to externalized
      phosphatidylserine. MAIN OUTCOME MEASURE(S): Active caspases 8, 9, 1, and 3 were
      examined in human ejaculated spermatozoa before and after cryopreservation.
      RESULT(S): The active caspases were localized in the postacrosomal region
      (caspases 8, 1, and 3) or in the midpiece (caspase 9). Cryopreservation led to a
      significant increase in the number of cells showing activation of all caspases.
      The MACS separation resulted in a significant depletion of sperm positive for
      activated caspases within the externalized phosphatidylserine-negative fraction.
      CONCLUSION(S): Caspases 8, 9, 1, and 3, representing the main pathways of
      apoptosis, are present in human spermatozoa and can become activated,
      particularly after freezing and thawing, and are associated with changes in the
      outer cell membrane. Spermatozoa showing these changes and caspase activation can
      be efficiently removed from semen samples by the annexin V MACS technique.

PMID- 15019814
TI  - Hepatocyte growth factor may be involved in cellular changes to the peritoneal
      mesothelium adjacent to pelvic endometriosis.
AB  - OBJECTIVE: To investigate the possible involvement of hepatocyte growth factor
      (HGF) in the cellular changes of pelvic mesothelium and the association of these
      changes with macrophage (Mphi) infiltration and the different stages of pelvic
      endometriosis. DESIGN: Controlled clinical study using intact tissue. SETTING:
      Nagasaki University School of Medicine, Nagasaki, Japan. PATIENT(S): Biopsy
      specimens from 25 red lesions, 20 black lesions of pelvic endometriosis and their
      adjacent peritoneum were excised either en bloc or separately during laparoscopy.
      INTERVENTION(S): Hepatocyte growth factor and activated macrophage-marker CD68
      were immunolocalized using respective antibodies, and were quantitated by a
      computer analyzed quantitative-histogram (Q-H) score and light microscopy,
      respectively. MAIN OUTCOME MEASURE(S): The possible immunoreaction of HGF near
      the endometriotic lesions and their adjacent peritoneal mesothelium was examined.
      The association between immunostaining of HGF and macrophage infiltration around
      these cells was also investigated. RESULT(S): A fraction of biopsy specimens of
      pelvic peritoneum revealed histologically proven change from normal flat to
      cuboidal or columnar cell types. In cuboidal cells or flat cells of mesothelium
      adjacent to red lesions, the immunoreaction of HGF, as expressed by the Q-H
      scores, was found to be significantly higher than in corresponding cells adjacent
      to black lesions. The flat or cuboidal cells of pelvic mesothelium surrounding
      the red lesions also demonstrated greater macrophage infiltration than the cells
      surrounding black lesions. The Q-H scores of HGF in the cuboidal or columnar
      cells surrounding the red lesions showed a statistically significant correlation
      with the accumulation of macrophage in the cells; no similar correlation was
      demonstrated for black lesions. CONCLUSION(S): Adjacent peritoneum of pelvic
      endometriotic lesions may manifest an inflammatory response. Hepatocyte growth
      factor might be involved in the cellular changes found in the peritoneal
      mesothelium of women with pelvic endometriosis.

PMID- 15019815
TI  - Light and electron microscopic evaluation of antileukotriene therapy for
      experimental rat endometriosis.
AB  - OBJECTIVE: To evaluate the effect of antileukotriene therapy, we examined the
      morphologic alteration in experimental rat endometriosis both with and without
      leukotriene receptor antagonist treatment. DESIGN: Light and electron microscopic
      analysis. SETTING: Tochigi Institute of Clinical Pathology, Japan. ANIMAL(S):
      Female Sprague-Dawley rats maintained on a schedule of 12 hours of light and 12
      hours of dark for 2 weeks. INTERVENTION(S): Uterine transplants were attached to
      rat peritoneum via the surgical autotransplantation technique. After
      autotransplantation, the rats were given daily administration of leukotriene
      receptor antagonist, and the lesions were examined at 4 and 7 days after
      autotransplantation. MAIN OUTCOME MEASURE(S): The morphologic comparison of rat
      endometriosis with and without antileukotriene therapy. RESULT(S): In the rats
      treated with leukotriene receptor antagonist, a significant decrease in stromal
      proliferation was observed when compared with nontreated rats. The treated rats
      showed not only the suppression of infiltration and activation of mast cells but
      also widespread apoptosis of proliferative fibroblasts in the lesions.
      CONCLUSION(S): Our results reveal that a leukotriene receptor antagonist has
      significant therapeutic value for the treatment of rat endometriosis. It is
      likely that antileukotriene therapy would be efficacious in the treatment and
      prevention of human endometriosis.

PMID- 15019816
TI  - In vitro growth and maturation as well as fertilization of mouse preantral
      oocytes from vitrified ovaries.
AB  - OBJECTIVE: To examine the capacity for fertilization and development of preantral
      oocytes in oocyte-granulosa cell complexes (OGC) originating from vitrified
      ovaries. DESIGN: Experimental animal study. SETTING: University-based research
      laboratory. ANIMAL(S): Normal (C57BL/6xDBA2) F1 mice in a laboratory environment.
      INTERVENTION(S): Vitrification of mouse ovaries using polyester sheets as a
      storage device; collection of OGC by enzymatic treatment; in vitro growth (IVG),
      in vitro maturation (IVM), and in vitro fertilization (IVF). MAIN OUTCOME
      MEASURE(S): We performed histologic analysis of vitrified and warmed ovaries, and
      measured the successful rate in IVG, IVM, and IVF of oocytes in the OGC collected
      from the ovaries. RESULT(S): The cortical region of ovaries maintained good
      morphologic structure after vitrification and warming. Upon IVG and IVM, 75.9% of
      oocytes in OGC matured to the metaphase II (MII) stage. The fertilization rate of
      these oocytes was 57.5% as compared with 69.5% for fresh ovaries. CONCLUSION(S):
      The vitrification method used was effective for storage of ovaries. The oocytes
      enclosed in preantral follicles from the ovaries preserved capacity for
      fertilization and development to preimplantation embryos.

PMID- 15019817
TI  - Stampidine is a potential nonspermicidal broad-spectrum anti-human
      immunodeficiency virus microbicide.
AB  - OBJECTIVE: Stampidine (2,'3'-didehydro-3'-deoxythymidine-5'-(p-bromophenyl
      methoxy alaninyl phosphate) is a novel aryl phosphate derivative of stavudine/d4T
      with broad-spectrum anti-HIV activity in vitro and in vivo. This study
      investigated the potential utility of stampidine as a nonspermicidal microbicide.
      DESIGN: Prospective, controlled study. SETTING: Center for Advanced Preclinical
      Sciences and Reproductive Biology Department. PATIENT(S): Seven sperm donors.
      ANIMAL(S): Fifty-two sexually mature, female and twenty-four male New Zealand
      white rabbits. INTERVENTION(S): Human semen and genital tract epithelial cells
      were exposed to stampidine (up to 1 mM). Ovulated does in subgroups of 12 were
      artificially inseminated with rabbit semen pretreated with stampidine (1 mM) or
      vehicle. Does in subgroups of four and three, respectively, were exposed
      intravaginally to a gel or a thermoreversible ovule formulation with and without
      0.5%, 1.0%, or 2.0% stampidine (9 to 36 mM) for 14 days. MAIN OUTCOME MEASURE(S):
      Effect of stampidine on human sperm motility, kinematics, penetration through
      cervical mucus, and epithelial cell viability. Reproductive parameters on
      gestation day 8. Vaginal tissues were histologically scored 24 hours after
      dosing. RESULT(S): Exposure of human sperm to stampidine even at a concentration
      10(6)-times higher than its in vitro anti-HIV-1 activity (50% inhibitory
      concentration = 1 nM) had no adverse effect on sperm motility, kinematics,
      cervical mucus penetrability, or the viability of vaginal and endocervical
      epithelial cells. Reproductive indices of pregnancy rate, embryo implantation,
      and preimplantation losses were not affected by pretreatment of rabbit semen with
      stampidine. Gel formulations of 0.5% to 2.0% stampidine (9 to 36 mM) lacked
      mucosal toxicity. CONCLUSION(S): The broad-spectrum anti-HIV agent stampidine had
      no adverse effect on sperm functions, was not cytotoxic, and did not induce
      mucosal toxicity. Stampidine has clinical potential as a prophylactic microbicide
      without contraceptive activity.

PMID- 15019818
TI  - Gonadotropin-releasing hormone agonist administration reduced vascular
      endothelial growth factor (VEGF), VEGF receptors, and vascular permeability of
      the ovaries of hyperstimulated rats.
AB  - OBJECTIVE: Using hyperstimulated rats, to elucidate the mechanisms of
      gonadotropin-releasing hormone agonist (GnRH-a) treatment to prevent early
      ovarian hyperstimulation syndrome (OHSS). DESIGN: Descriptive study of
      hyperstimulated rats as an early OHSS model with Western blot analysis, Northern
      blot hybridization, and vascular permeability assay. SETTING: Experimental
      laboratory research. ANIMAL(S): Sprague-Dawley female rats were used for
      collecting ovarian samples. INTERVENTION(S): Hyperstimulated rats received
      consecutive GnRH-a treatment from the start of pregnant mare serum gonadotropin
      (PMSG) treatment through 2 days after hCG administration. MAIN OUTCOME
      MEASURE(S): Expressions of vascular endothelial growth factor (VEGF), VEGF
      receptor-1 (VEGFR-1: Flt-1), VEGF receptor-2 (VEGFR-2: KDR/Flk-1), and vascular
      permeability by Evans blue leakage. RESULT(S): GnRH-a treatment significantly
      reduced expressions of VEGF, VEGFR-1, and VEGFR-2 both in mRNA and protein levels
      in the ovaries of hyperstimulated rats. GnRH-a treatment also reduced vascular
      permeability in the ovaries of hyperstimulated rats. CONCLUSION(S): It is
      speculated that GnRH-a treatment may prevent early OHSS by reducing vascular
      permeability through the decrease in VEGF and its receptors.

PMID- 15019819
TI  - Noninvasive polarized light microscopy quantitatively distinguishes the
      multilaminar structure of the zona pellucida of living human eggs and embryos.
AB  - OBJECTIVE: To characterize the architecture of the zona pellucida in living human
      eggs and embryos, noninvasively with the PolScope, a digital polarizing light
      microscope. DESIGN: The PolScope was used to examine zonae pellucida of living
      human eggs and embryos. SETTING: Academic IVF clinic. PATIENT(S): Patients
      undergoing fresh, nondonor infertility treatment who underwent egg aspiration,
      fertilization by intracytoplasmic sperm injection or traditional IVF, and
      cleavage-stage embryo transfer (day 3). INTERVENTION(S): The PolScope imaged the
      zona of eggs before intracytoplasmic sperm injection and in cleavage-stage
      embryos before transfer. MAIN OUTCOME MEASURE(S): Thickness and retardance of
      three zona layers were measured from eight quadrants. Mean and variance in
      thickness and retardance were calculated for individual eggs and embryos, between
      eggs and embryos of a cohort, and across the sample patient population.
      RESULT(S): Cleavage-stage (day 3) embryos have thinner zonae (15.2 +/- 2.9
      microm) than both immature (20.4 +/- 2.4 microm) and mature (19.5 +/- 2.2 microm)
      eggs. The zona of embryos is thinner, primarily owing to thinning of the outer
      layer. The thicker the zona layer, the greater its retardance. Considerable
      variation exists in the thickness and retardance of zona layers around individual
      eggs and embryos and between members of a cohort. The zona of eggs and embryos
      from different patients differ in thickness, retardance, and variation.
      CONCLUSION(S): Thickness and organization of zonae pellucida of human eggs and
      embryos varies considerably and can be quantitatively imaged with the PolScope.

PMID- 15019820
TI  - Immunolocalization of angiopoietin 1 in human peritoneal endometriotic lesions.
AB  - OBJECTIVE: To analyze the expression of angiopoietin 1 (ANGPT1) in pigmented and
      nonpigmented endometriosis implants and specify its role in the interaction of
      angiogenic factors. DESIGN: Experimental retrospective study. SETTING: University
      hospital. PATIENT(S): Eighty-two sections from 201 laparoscopic tissue samples of
      43 female patients. INTERVENTION(S): Biopsies of peritoneal endometriotic lesions
      of macroscopically different forms. MAIN OUTCOME MEASURE(S): Angiopoietin 1
      expression and location pattern in endothelial cells, periendothelial cells,
      glandular epithelium, and stromal structures. RESULT(S): Angiopoietin 1 is
      immunohistochemically detectable in endothelial cells, periendothelial cells, in
      the glandular epithelium, and in the stroma. Differences in the expression of
      pigmented and nonpigmented lesions are not statistically significant.
      CONCLUSION(S): Pigmented and nonpigmented endometriotic lesions differ according
      to their clinical activity and angiogenic potential. Angiopoietin 1 is an
      important representative of the angiogenic factors and is involved in the
      angiogenic processes of these lesions. There were no significant differences in
      the expression and location within different lesion types for ANGPT1. Thus, it is
      not a direct activity marker of a lesion.

PMID- 15019821
TI  - Differential expression of KIR/NKAT2 and CD94 molecules on decidual and
      peripheral blood CD56bright and CD56dim natural killer cell subsets.
AB  - OBJECTIVE: To investigate killer inhibitory receptor (KIR) expression by natural
      killer (NK) cells in early pregnancy. DESIGN: Case-control study of immunologic
      markers. SETTING: University hospital. PATIENT(S): Thirty pregnant women and 22
      nonpregnant women. INTERVENTION(S): Peripheral venous blood sampling and decidual
      tissue collection after elective abortion. MAIN OUTCOME MEASURE(S): Flow
      cytometry was used to assess expression of KIR by NK cells in the cell samples.
      RESULT(S): In contrast to CD56(bright) peripheral blood NK cells, CD56(dim) cells
      express killer cell Ig-like receptor KIR/NKAT2. However, KIR/NKAT2 and lectin
      like CD94 are present on both subsets of decidual NK cells. We found no
      differences between peripheral blood NK cell subsets from pregnant and
      nonpregnant women. CONCLUSION(S): Our findings demonstrate that NK cell subsets,
      distributed in accordance with CD56 molecule density on cell surface, express
      killer inhibitory receptors CD94 and KIR/NKAT2 in a different way. Our data
      support the view that CD56(bright)KIR/NKAT2+CD94+ decidual NK cells are
      specialized NK cells that have an important role to play in early pregnancy.

PMID- 15019823
TI  - Expression of macrophage inflammatory protein-3beta in human endometrium
      throughout the menstrual cycle.
AB  - OBJECTIVE: To determine the expression of macrophage inhibitory protein-3beta
      (MIP-3beta), a potential chemoattractant for endometrial natural killer (NK)
      cells, in the human endometrium. DESIGN: An experimental study. SETTING:
      University department of obstetrics and gynecology. PATIENT(S): Thirty-seven
      fertile women with regular menstrual cycles and nonpathological endometrium,
      undergoing hysterectomy. INTERVENTION(S): Endometrium was obtained from operative
      samples. MAIN OUTCOME MEASURE(S): Paraffin-embedded endometrium was immunostained
      to determine the localization of MIP-3beta. The number of NK cells was counted in
      10 nonoverlapping stromal areas. The MIP-3beta concentration in the homogenized
      endometrium was determined by ELISA. RESULT(S): Immunoreactivity for MIP-3beta
      was observed in the surface epithelia, glandular epithelia, and stroma with some
      menstrual cycle-dependent fluctuation. The MIP-3beta concentration was
      significantly higher in the late secretory phase than in the other phases. It
      showed a trend toward correlation with the number of endometrial NK cells.
      CONCLUSION(S): MIP-3beta was expressed in the human endometrium, but our results
      could not strongly support the hypothesis that MIP-3beta is a potential
      chemoattractant for endometrial NK cells.

PMID- 15019822
TI  - Expression of angiopoietin 1 and 2 in ectopic endometrium on the chicken
      chorioallantoic membrane.
AB  - OBJECTIVE: To investigate the role of angiopoietin 1 and 2 (ANGPT1/ANGPT2) in
      angiogenesis of the ectopic endometrium as a crucial step in the development of
      an endometriotic lesion, we analyzed their expression patterns in an experimental
      model of endometriosis. DESIGN: Experimental prospective study. SETTING:
      University hospital. PATIENT(S): Endometrium samples obtained from healthy,
      ovulating women undergoing hysterectomy for benign gynecologic conditions.
      INTERVENTION(S): Endometrial fragments were transplanted to the chicken
      chorioallantoic membrane (CAM) and cultivated for 0, 24, 48, and 72 hours. MAIN
      OUTCOME MEASURE(S): Expression of ANGPT1 and ANGPT2 mRNA was quantified by
      competitive reverse transcriptase polymerase chain reaction (RT-PCR) and
      normalized to expression of the housekeeping gene human glyceraldehyde 3
      phosphate dehydrogenase (GAPDH) mRNA. The expression of ANGPT1 and ANGPT2 protein
      was analyzed by immunohistochemical staining. RESULT(S): All grafts expressed
      ANGPT1 and ANGPT2 mRNA. The mRNA concentration of both factors decreased after
      cultivation, but the ANGPT2/ANGPT1 ratio increased considerably during the first
      24 hours of cultivation. The immunohistochemical investigation for ANGPT1 and
      ANGPT2 revealed presence of both proteins at all the times but no obvious
      correlation with the duration of cultivation. CONCLUSION(S): The ratio of
      ANGPT2/ANGPT1 mRNA in endometrial grafts increased after 24 hours of cultivation
      on the chicken chorioallantoic membrane and shows a shift toward a more dominant
      role of ANGPT2. This agrees with the current model of angiopoietin action in
      angiogenesis and might indicate angiogenic activity in the endometrial graft. The
      angiopoietins are likely to play an important role in the pathogenesis of
      endometriosis.

PMID- 15019824
TI  - Histologic and molecular changes in the ipsilateral and contralateral
      epididymides of the rat in response to unilateral testicular torsion followed by
      detorsion.
AB  - OBJECTIVE: To investigate the histologic and molecular changes in the ipsilateral
      and contralateral epididymides in response to unilateral testicular torsion
      followed by detorsion. DESIGN: Controlled experimental study using rats. SETTING:
      Seoul National University College of Medicine, Seoul, Korea. ANIMAL(S): Thirty
      five, 8-week-old Sprague-Dawley male rats: six experimental groups and a sham
      operated control group. INTERVENTION(S): Testes of male rats were subjected to
      torsion for 10 minutes. At 0, 1, 4, 8, 24 hours and 1 week after detorsion,
      ipsilateral and contralateral epididymides were harvested. Microscopic
      examination and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick
      end labeling (TUNEL) staining was performed. The percentage of apoptotic ducts in
      the epididymis was determined by counting 100 duct cross-sections of the head and
      the tail of the epididymis of each specimen. MAIN OUTCOME MEASURE(S): Morphologic
      change, including in situ apoptosis, of the ductal epithelium was evaluated.
      RESULT(S): There was no evidence of morphologic or apoptotic changes in the 0- or
      1-hour detorsion groups. However, enlargement of the interstitial fibrous tissue
      was found 8 and 24 hours after detorsion and marked degeneration of ductal
      epithelium was observed at 1 week in both the ipsilateral and contralateral
      epididymides. Apoptosis was first observed at 4 hours after detorsion, and the
      percentage of apoptotic ducts was significantly increased at 8 hours, peaked at
      24 hours, and slightly decreased at 1 week in both the ipsilateral and
      contralateral epididymides. CONCLUSION(S): Both morphologic changes and
      intracellular molecular alterations occur not only in the ipsilateral but also in
      the contralateral epididymis following unilateral testicular torsion/detorsion.

PMID- 15019825
TI  - Effect of site of transplantation on follicular development of human ovarian
      tissue transplanted into intact or castrated immunodeficient mice.
AB  - OBJECTIVE: To study the response of human ovarian xenografts to transplantation
      into different sites and in different host conditions. DESIGN: Controlled
      experiment. SETTING: Academic research laboratory. PATIENT(S): Donated ovarian
      tissue from two young women. INTERVENTION(S): Human ovarian cortical pieces were
      transplanted either under the kidney capsule or to the subcutaneous space of
      intact or castrated male nonobese diabetic (NOD) severe combined immune-deficient
      (SCID) mice. Grafts were recovered after euthanasia. MAIN OUTCOME MEASURE(S):
      Microscopic examination of histologic sections to determine proportions of
      growing follicles, and serum estradiol concentration measurements. RESULT(S): Six
      months after transplantation, ovarian grafts transplanted under the kidney
      capsule of intact male mice had significantly higher proportions of growing
      follicles compared with those recovered from the castrated/kidney capsule and
      intact/subcutaneous groups. However, no difference was detected between the
      intact/kidney capsule and the castrated/subcutaneous groups. Mean estradiol
      concentrations in serum were nonsignificantly increased in mice with ovarian
      grafts compared with those in mice without a graft. CONCLUSION(S): Follicular
      development in xenotransplanted human ovarian tissue is influenced by the site of
      transplantation and the condition of the host.

PMID- 15019827
TI  - Role of activin A as a mediator of in vitro endometrial stromal cell
      decidualization via the cyclic adenosine monophosphate pathway.
AB  - OBJECTIVE: To elucidate the regulation and role of activin A in endometrial
      stromal decidualization. DESIGN: In vitro model of human stromal cell
      decidualization with cyclic adenosine monophosphate (cAMP) used to evaluate
      expression of activin A and to evaluate the effect of the addition of
      follistatin, a known activin inhibitor, on expression of the decidualized
      phenotype (as measured by levels of insulin-like growth factor binding protein-1
      [IGFBP-1]). SETTING: Academic research environment. PATIENT(S): Four
      premenopausal, normally cycling subjects (age range: 32-40 years).
      INTERVENTION(S): Endometrial samples were obtained from the subjects after
      informed consent was obtained. Endometrial stromal cells were treated with cAMP
      (decidualizing stimulus) and 50 ng/mL, 100 ng/mL, and 200 ng/mL of follistatin
      for 48 hours. MAIN OUTCOME MEASURE(S): Levels of IGFBP-1 secreted from cells
      decidualized in the absence and presence of three different concentrations of
      follistatin. RESULT(S): Addition of follistatin, a known binding protein
      inhibitor of activin A, resulted in a dose-dependent inhibition of IGFBP-1
      secreted into conditioned medium, with the greatest decrease observed at 4 days
      of decidualization. Cells treated with cAMP and 50 ng/mL, 100 ng/mL, and 200
      ng/mL of follistatin demonstrated 67.3%, 58.6%, and 35.5%, respectively, of the
      IGFBP-1 levels observed with cAMP but without follistatin. CONCLUSION(S): These
      data suggest that activin A is a necessary component of the cAMP pathway leading
      to endometrial stromal decidualization. The role of activin A in regulating
      endometrial stromal decidualization and its known promotion of the invasive
      phenotype of the trophoblast suggest unique autocrine and paracrine interactions
      at the maternal/fetal interface during implantation, which might have important
      clinical implications for the understanding and treatment of fertility and
      pregnancy disorders.

PMID- 15019826
TI  - Nasal delivery of levonorgestrel for contraception: an experimental study in
      rats.
AB  - OBJECTIVE: To ascertain the nasal bioavailability of Levonorgestrel and change
      formulation components to provide long-term effective concentrations of the drug
      in blood. An experimental study was conducted on rats to reduce dose and/or
      frequency of drug administration to reduce expected side effects reported in
      humans. DESIGN: In vivo study in rats. SETTING: Centre of Relevance & Excellence
      in new drug delivery systems, Pharmacy Dept., G.H. Patel Budg., Faculty of
      Technology and Engineering, M.S. University of Baruda, Fatehgunj, Vadodara,
      Gujarat, India. ANIMAL(S): Rats of proven fertility. INTERVENTION(S):
      Formulations containing 10-microg of levonorgestrel were administered in rats via
      the nasal route. Similarly, a 10-microg drug suspension was administered orally.
      The influence of the mucoadhesive agents chitosan and carbopol 934p on nasal
      absorption of the drug was also evaluated. MAIN OUTCOME MEASURE(S): Plasma drug
      concentration and pharmacokinetics. RESULT(S): Relative bioavailabilities of
      29.93%, 32.14%, and 25.97% were observed after nasal administration of plain
      drug, physical mixture, and liposomal formulations, respectively. Mucoadhesive
      agents in nasal formulations were found to produce a threefold increase in drug
      bioavailability. Bioavailability was improved from 29.93% to 101.70% and 99.42%,
      respectively, for chitosan (0.5%) and carbopol 934p (0.5%) formulations, with a
      significantly improved plasma half life from 7.0 hours to 55.7 hours and 52.9
      hours, respectively. Pharmacodynamic studies indicate that the dosing interval
      can be changed from daily oral administration to nasal administration once every
      2 days without changing the dose. CONCLUSION(S): Levonorgestrel with mucoadhesive
      agents administered nasally in rats is superior for maintaining effective drug
      concentrations over an extended period of time when compared with the presently
      available orally administered form.

PMID- 15019829
TI  - Decreased expression of mitochondrial genes in human unfertilized oocytes and
      arrested embryos.
AB  - OBJECTIVE: To evaluate the relationship between mitochondrial gene expression of
      oocytes/embryos and their fertilizability in unfertilized oocytes, arrested
      embryos, and tripronucleate zygotes, because both nuclear and cytoplasmic factors
      contribute to oocyte activation, fertilization, and subsequent development.
      DESIGN: Prospective laboratory research. SETTING: In vitro fertilization (IVF)
      laboratory in a university hospital. PATIENT(S): Seventy-five unfertilized
      oocytes, 45 arrested embryos, and 24 tripronucleate (3PN) embryos from 45 female
      patients undergoing IVF. INTERVENTION(S): Analysis of mitochondrial gene
      expression by semiquantitative reverse transcription polymerase chain reaction
      (RT-PCR). MAIN OUTCOME MEASURE(S): Comparison of the expression levels of
      mitochondrial genes including ND2, CO I, CO II, ATPase 6, CO III, ND3, ND6, and
      Cyt b in three groups. RESULT(S): Significantly decreased transcription levels
      were expressed in unfertilized oocytes and arrested embryos. The average
      expression levels of the eight determined genes compared with the control (GAPDH)
      was 4.4 +/- 0.7, 6.4 +/- 1.1, and 13.2 +/- 1.1 in unfertilized oocytes, arrested
      embryos, and 3PN embryos, respectively. Significantly decreased expressions of
      the ATPase 6, CO III, and ND3 genes were detected from samples with 4977-bp
      common deletion in the mitochondrial DNA (mtDNA) compared with the non-deletion
      group. CONCLUSION(S): The present study is the first report to present globally
      decreased mitochondrial gene expression levels in human compromised oocytes and
      embryos. These data support the notion that the down-regulation of mitochondrial
      RNA by defective oxidative phosphorylation genes possibly affects oocyte quality
      including fertilization and further embryo development.

PMID- 15019828
TI  - Regulation of endometrial stromal cell matrix metalloproteinase activity and
      invasiveness by interleukin-8.
AB  - OBJECTIVE: To evaluate the effect of interleukin-8 (IL-8) on endometrial stromal
      cell metalloproteinase (MMP) activity and invasiveness. DESIGN: Experimental
      laboratory study. SETTING: University medical center. PATIENT(S): Reproductive
      age women without endometriosis. INTERVENTION(S): Endometrial stromal cells were
      grown in culture and treated with recombinant IL-8 (0.0001-10 ng/mL) for 24 to 48
      hours. Supernatants were collected for soluble assay of collagenase activity and
      gelatin zymography. Endometrial stromal cells were plated on 8-microm pore
      membranes coated with Matrigel or human simple matrix and treated with IL-8 for
      48 hours. MAIN OUTCOME MEASURE(S): Collagenase activity and MMP2 and 9 activity
      of control vs. IL-8 treated endometrial cells, and number of endometrial cells
      that invade through Matrigel or human simple matrix. RESULT(S): Collagenase
      activity in cells treated with IL-8 (1-10 ng/mL) was higher than in control
      cells. On gelatin zymograms, MMP2 and MMP9 activity of endometrial stromal cells
      was stimulated by IL-8 treatment (1-10 ng/mL). The number of cells that invaded
      the Matrigel or human simple matrix was 1.7-fold higher in the group treated with
      10 ng/mL of IL-8 compared with the control group. CONCLUSION(S): IL-8 increases
      MMP activity and invasive capability of endometrial stromal cells in culture; IL
      8 may be involved in the pathogenesis of endometriosis and menstrual physiology.

PMID- 15019830
TI  - Influence of thyroid hormone on mouse preantral follicle development in vitro.
AB  - OBJECTIVE: To evaluate the role of 3,3',5-triiodothyronine (T(3)) on ovarian
      follicle development in vitro. DESIGN: Experimental study. SETTING: University
      reproductive biology unit. ANIMAL(S): CD1 mice (female). INTERVENTION(S): In
      vitro culture. MAIN OUTCOME MEASURE(S): Assessment of follicle and oocyte
      development following a 6-day culture with FSH (100 mU/mL), (Bu)(2)cAMP (0.5 mM),
      and T(3) (1-100 nM), alone or in combination. RESULT(S): A high percentage of in
      vitro grown (IVG) FSH-stimulated follicles formed an antral cavity (AC), while
      the addition of T(3) (100 nM) significantly reduced this response in a
      statistically significant manner. A statistically significant recovery of AC
      formation was obtained by limiting exposure to 4 days of culture. Formation of AC
      was induced by (Bu)(2)cAMP, which prevented T(3)-mediated suppression of AC
      formation. Under different conditions, high proportions of germinal vesicle
      arrested IVG oocytes displayed condensed chromatin configuration. The capacity to
      undergo germinal vesicle breakdown (GVBD) was similar in all groups, and a
      statistically significant reduction in the percentage of oocytes with PB1 was
      recorded when T(3) was added to FSH or (Bu)(2)cAMP. This ability was partially
      recovered by removing T(3) on day 4 of culture. CONCLUSION(S): Exposure to high
      T(3) concentrations can impair preantral follicle development, but this effect
      can be partly reverted by restoring a physiological hormonal milieu before
      follicle commitment to antral development.

PMID- 15019831
TI  - Characterization of a fasciclin I-like protein with cell attachment activity from
      sea urchin (Strongylocentrotus intermedius) ovaries.
AB  - Fasciclin I, a neuronal cell adhesion molecule, was first identified in the
      grasshopper. To date, various fasciclin I-like proteins have been identified but
      their biological functions have not been well characterized. Here, we have
      purified a fasciclin I-like protein with a molecular weight of 33kDa from sea
      urchin (Strongylocentrotus intermedius) ovaries using hydrophobic chromatography
      and gel filtration. The protein was not N-glycosylated. Partial amino acid
      sequences of cyanogen bromide (CNBr)-cleaved fragments were highly conserved to
      other sea urchin fasciclin I-like proteins identified previously. The circular
      dichroism (CD) spectrum analysis demonstrated that the 33kDa protein contained
      high content of alpha-helical structure. These results suggest that the 33kDa
      protein is a fasciclin I-like family. Additionally, the fasciclin I-like protein
      promoted HT1080 human fibrosarcoma cell attachment. Further, a synthetic peptide
      (P1: GLREAANIAEQVDLRQVLRDVDL) of the protein corresponding to a highly conserved
      region of the fasciclin I-like family promoted heparin-dependent HT1080 cell
      attachment. Moreover, the peptide inhibited HT1080 cell attachment to the
      fasciclin I-like protein. These results suggest that the 33kDa protein from sea
      urchin ovaries isolated here is a member of the fasciclin I family and that the N
      terminal region of the protein is important for cell attachment activity. The
      protein has a potential to be involved in biological functions in sea urchin as a
      cell adhesive molecule.

PMID- 15019832
TI  - N-Acetylated alpha-linked acidic dipeptidase expressed in rat adipocytes is
      localized in the insulin-responsive glucose transporter (GLUT4) intracellular
      compartments and involved in the insulin-stimulated GLUT4 recruitment.
AB  - The GLUT4-containing vesicles purified from rat adipocyte contain many protein
      species of unknown identity, some of which are likely to play a critical role in
      the trafficking of GLUT4. Presently, we describe an 85-kDa protein in GLUT4
      vesicles of rat adipocytes as a potential GLUT4 traffic regulatory protein. MALDI
      TOF MS, RT-PCR, gene cloning, protein sequence analysis, and immunoreactivity
      assay have identified this protein as N-acetylated alpha-linked acidic
      dipeptidase (NAALADase) expressed in rat adipocytes. NAALADase in rat adipocytes
      was mostly membrane-associated and colocalized in discrete GLUT4-compartments
      with enrichment in putative GLUT4-sorting endosomes (G4G(L)). Total cell lysates
      of adipocytes exhibited NAALADase activity. Next, we treated rat adipocytes with
      2-[phosphonomethy]pentanedionic acid (2-PMPA), a potent NAALADase inhibitor, and
      studied its effect on the distribution of GLUT4 and 3-O-methyl glucose (3OMG)
      flux. In 2-PMPA-treated adipocytes, there was a significant reduction (by 40%) in
      the insulin-stimulated GLUT4 translocation to the plasma membrane. The 3OMG flux
      in insulin-stimulated adipocytes was also delayed (51% of control) by 2-PMPA
      treatment, indicating that 2-PMPA impairs insulin-stimulated GLUT4 recruitment
      and the uptake of glucose. It is suggested that NAALADase may function as a
      regulator required for the insulin-stimulated GLUT4 vesicle movement and/or its
      exocytosis, thus may regulate insulin-induced GLUT4 recruitment in rat
      adipocytes.

PMID- 15019833
TI  - Acetylcholine-induced calcium signalling in adrenaline- and noradrenaline
      containing adrenal chromaffin cells.
AB  - Adrenal chromaffin cells secrete catecholamines in response to cholinergic
      receptor activation by acetylcholine (ACh). Characteristics of Ca(2+) transients
      induced by activation of nicotinic (nAChRs) and muscarinic (mAChRs) receptors
      were analyzed using Fura-2 fluorescent measurements on rat chromaffin cells. We
      first found two populations of chromaffin cells, which differently responded on
      AChR stimulation. In the first group (n-cells), consecutive ACh applications
      evoked persistent Ca(2+) transients, whereas desensitizing transients were
      observed in the other group (m-cells). The AChR agonists and antagonists
      precisely imitated or abolished the ACh action on n- and m-type cells,
      respectively. Cytochemical staining showed that n-cells contained adrenaline,
      whereas m-cells-noradrenaline. Thus, for the first time we found that nAChRs and
      mAChRs are differentially expressed in adrenergic and noradrenergic chromaffin
      cells, respectively. Our data suppose that chromaffin cells can be differentially
      regulated by incoming ACh signals and in such way release different substances
      adrenaline and noradrenaline.

PMID- 15019834
TI  - The effect of reciprocal active site mutations in human cytochromes P450 1A1 and
      1A2 on alkoxyresorufin metabolism.
AB  - Five reciprocal active site mutants of P450 1A1 and 1A2 and an additional mutant,
      Val/Leu-382 --> Ala, were constructed, expressed in Escherichia coli, and
      purified by Ni-NTA affinity chromatography. In nearly every case, the residue
      replacement led to loss of 7-methoxy- and 7-ethoxyresorufin O-dealkylase activity
      compared to the wild-type enzymes, except for the P450 1A1 S122T mutation which
      increased both activities. Mutations at position 382 in both P450 1A1 and 1A2
      shifted substrate specificity from one enzyme to another, confirming the
      importance of this residue. Changes in activity of P450 1A enzymes upon amino
      acid replacement were, in general, consistent with molecular dynamics analyses of
      substrate motion in the active site of homology models.

PMID- 15019835
TI  - Quantitative evaluation of the effects of mitochondrial permeability transition
      pore modifiers on accumulation of calcium phosphate: comparison of rat liver and
      brain mitochondria.
AB  - Mitochondria play a critical role in some forms of apoptosis, and the Ca(2+)
      dependent permeability transition (PT) is a key initiator of this process. We
      quantitatively examined major control mechanisms of PT in rat brain (RBM) and
      liver (RLM) mitochondria. Compared with RLM, RBM were less sensitive to
      cyclosporin A (CsA), but the combined action of CsA+ADP was much more pronounced
      in RBM. Carboxyatractyloside abrogated the effects of all mPTP inhibitors in RBM
      but not in RLM, where the effects of CsA were not reduced. Estimated H(+)/Ca(2+)
      ratios were 0.81+/-0.01 for RLM and 0.84-0.93 for RBM, suggesting that Ca(2+) and
      Pi were sequestered in the matrix as CaHPO(4) and Ca(3)(PO(4))(2) salts, and that
      RBM sequester more CaPi as the least soluble salt. We conclude that: (1) RBM and
      RLM differ in their baseline behavior of the PT and in their responses to PT
      modifiers, and (2) PT modifiers can be functionally divided into those which
      directly affect the mitochondrial PT pore and are not energy-dependent (CsA, free
      Ca(2+), ADP(ex), and Mg(2+)), and those which affect the energy-dependent calcium
      phosphate sequestration process (ADP(mt), CATR, local anesthetics). We also
      conclude that ANT affects PT by changing mitochondrial capacity for energization.

PMID- 15019836
TI  - Purpureotin: a novel di-dimeric C-type lectin-like protein from Trimeresurus
      purpureomaculatus venom is stabilized by noncovalent interactions.
AB  - Purpureotin, a novel di-dimeric C-type lectin-like protein (CLP) from
      Trimeresurus purpureomaculatus, was purified and sequenced. While its native
      molecular mass was determined to be 63kDa, purpureotin showed a single band of
      30kDa on nonreducing SDS-PAGE and two polypeptide chains (16.0 and 14.5kDa) under
      reducing condition. These results were subsequently confirmed by mass
      spectrometric analyses. Based on these results, we postulate that purpureotin is
      a dimer of the alpha,beta-heterodimer which is held together by noncovalent
      interactions. Molecular modeling studies indicate that a dimer of alpha,beta
      heterodimers can be formed where the alpha chains are held together by
      electrostatic charges and beta chains via hydrophobic interactions. Functionally,
      purpureotin induced platelet aggregation without any cofactor in a dose-dependent
      manner. However, the platelet aggregation effect was blocked by echicetin.
      Therefore, purpureotin is assumed to be a GPIb-binding protein which binds to the
      same or a closely related GPIb site on platelets as echicetin.

PMID- 15019837
TI  - Transcriptional regulation of angiogenesis-related puromycin-insensitive leucyl
      specific aminopeptidase in endothelial cells.
AB  - Puromycin-insensitive leucyl-specific aminopeptidase (PILSAP) was expressed in
      endothelial cells (ECs) and played an important role in angiogenesis. Here, we
      characterized its transcriptional regulation. Mouse PILSAP gene contained 19
      exons and located in the chromosome 13C1-C2. We identified two transcripts; one
      transcribed from exon 1 and the other from exon 2. Mouse ECs expressed dominantly
      the one from exon 1. The promoter analysis using 5' upstream region of exon 1
      revealed that -1868 to -1812 was critical for its transcription in mouse ECs. We
      identified a motif of the transcription factor PEBP2 in this region, and the
      deletion or mutation of this motif decreased promoter activity. Protein extracted
      from mouse ECs bound specifically to this motif. AML1/Runx1/PEBP2alphaB increased
      PILSAP mRNA in mouse ECs, whereas dominant interfering chimerical PEBP2beta-MYH11
      decreased it. These results indicate that the expression of PILSAP in mouse ECs
      is regulated, at least in part, by PEBP2.

PMID- 15019838
TI  - Characterization of a class alpha glutathione-S-transferase with glutathione
      peroxidase activity in human liver microsomes.
AB  - A 25.5kDa class alpha glutathione S-transferase (GST) designated as microsomal Ya
      GST or M-GSTA has been purified to electrophoretic homogeneity from human liver
      microsomes. Limited proteolysis, gel filtration chromatography followed by EDTA,
      and alkaline Na(2)CO(3) treatments of microsomes indicate that the M-GSTA is
      intrinsic to the microsomes. Western immunoblot analysis revealed that human
      liver M-GSTA and the previously reported 17-kDa microsomal GST (FEBS Lett. 315
      (1993) 77) did not have immunological cross reactivity. The enzyme showed
      conjugation activity towards substrates like 1-chloro-2,4-nitrobenzene (CDNB) and
      7-chloro-4-nitrobenzo-2-oxa-1,3-diazole, and 4-hydroxy-2-nonenal (4-HNE), a
      genotoxic alpha,beta-unsaturated aldehyde product of lipid peroxidation. In
      addition, the M-GSTA exhibited significant glutathione peroxidase activity
      towards physiologically relevant fatty acid hydroperoxides as well as
      phosphatidylcholine hydroperoxide, but not with H(2)O(2). C-terminal amino acid
      sequence analysis revealed a high homology with the human liver cytosolic GST-A1
      and A3 isozymes. Western immunoblot analyses of the microsomes prepared from
      human hepatoblastoma (HepG2) showed that the expression of this M-GSTA was
      induced upon treatment with such prooxidants as H(2)O(2), suggesting that it may
      play an important role in the protection of cellular membranes from peroxidative
      damage.

PMID- 15019839
TI  - Reaction of superoxide with trityl radical: implications for the determination of
      superoxide by spectrophotometry.
AB  - Superoxide radicals can be measured by redox methods which utilize the
      oxidation/reduction reactions of specific compounds. The redox methods, however,
      suffer from various interferences, which limit their use in the assay of
      superoxide. Electron paramagnetic resonance (EPR) spectroscopy using spin traps
      has been widely used as an alternative and direct technique to measure superoxide
      radicals. In our recent study, we have demonstrated the detection of superoxide
      in cellular system by EPR spectroscopy with triarylmethyl (trityl) free radical,
      TAM Ox063. TAM is highly water-soluble and stable in the presence of many
      biological oxidizing and reducing agents such as hydrogen peroxide, ascorbate,
      and glutathione. TAM reacts with superoxide with an apparent second order rate
      constant of 3.1x10(3)M(-1)s(-1). In the present work, we investigated the
      feasibility of a spectrophotometric assay of superoxide by taking advantage of
      the newly formed distinct absorption peak corresponding to the product formed
      from the reaction between TAM and superoxide. The effects of different fluxes of
      superoxide and concentrations of TAM on the efficiency and sensitivity of
      quantification of superoxide were investigated and compared with the widely used
      cytochrome c method of superoxide determination. The results demonstrated that
      the TAM method is comparable to the cytochrome c method for the assay of
      superoxide and further revealed that the assay is not affected by the presence of
      hydrogen peroxide. In summary, the TAM spectrophotometric assay of superoxide
      provides a suitable alternative method to the cytochrome c assay to measure
      superoxide and further complements our earlier reported TAM-EPR assay of
      superoxide.

PMID- 15019840
TI  - L-Glutamate in the extracellular space regulates endogenous D-aspartate
      homeostasis in rat pheochromocytoma MPT1 cells.
AB  - In previous studies [FEBS Lett. 434 (1998) 231, Arch. Biochem. Biophys. 404
      (2002) 92], we demonstrated for the first time that D-aspartate (D-Asp) is
      synthesized in cultured mammalian cell lines, such as pheochromocytoma 12 (PC12)
      and its subclone, MPT1. Our current focus is analysis of the dynamics of D-Asp
      homeostasis in these cells. In this communication, we show that L-glutamate (Glu)
      and L-Glu transporter substrates in the extracellular space regulate the
      homeostasis of endogenous D-Asp in MPT1 cells. D-Asp is apparently in dynamic
      homeostasis, whereby endogenous D-Asp is constantly released into the
      extracellular space by an undefined mechanism, and continuously and intensively
      taken up into cells by an L-Glu transporter. Under these conditions, L-Glu and
      its transporter substrates in the medium may competitively inhibit the uptake of
      D-Asp via the transporter, resulting in accumulation of the amino acid in the
      extracellular space. We additionally demonstrate that DL-TBOA, a well-established
      L-Glu transporter inhibitor, is taken up by the transporter during long time
      intervals, but not on a short time-scale.

PMID- 15019841
TI  - Identification and characterization of the pseudopterosin diterpene cyclase,
      elisabethatriene synthase, from the marine gorgonian, Pseudopterogorgia
      elisabethae.
AB  - The pseudopterosins are diterpene glycosides isolated from the marine gorgonian,
      Pseudopterogorgia elisabethae, which exhibit anti-inflammatory and analgesic
      activity greater than the industry standard, indomethacin. Previously, we
      isolated the pseudopterosin diterpene cyclase product, elisabethatriene, using a
      radioactivity-guided isolation. Identification of this metabolite, and the
      conversion of labeled geranylgeranyl diphosphate to elisabethatriene, provided us
      with an assay to guide the isolation of the enzyme responsible for this
      cyclization. The soluble protein preparation from P. elisabethae has been
      partially purified (approximately 15,000-fold) using a combination of low
      resolution anion-exchange, low-resolution hydrophobic interaction, high
      resolution hydroxyapatite, and high-resolution anion-exchange chromatography. The
      diterpene cyclase was identified by comparing the molecular weight from gel
      permeation chromatography (approximately 47,000Da) with those of protein bands
      from purified fractions using SDS-PAGE gel electrophoresis. Kinetic analysis and
      evaluation of amino acid inhibition studies indicated that the enzyme displays
      similar characteristics to other terpenoid cyclases isolated from terrestrial
      sources. This report represents the first purification and characterization of a
      terpene biosynthetic enzyme from a marine invertebrate.

PMID- 15019843
TI  - MAPK signaling pathways modulate IL-1beta expression in human keratinocytes.
AB  - The signaling pathways that modulate IL-1beta expression in human keratinocytes
      have not been well defined. We have previously shown that TCDD-stimulated AhR
      dependent IL-1beta expression in human keratinocytes is due to
      posttranscriptional regulation involving mRNA stabilization. Since TCDD activates
      a variety of cellular signaling pathways such as PKC, JNK, and ERK, we
      investigated these pathways to determine their roles in TCDD-stimulated IL-1beta
      expression in the human keratinocyte cell line SCC-12F. In this study, we used
      specific signaling inhibitors to show that ERK and JNK, but not transglutaminase,
      PKC, or p38, signaling modulate IL-1beta expression. In addition, we show that
      ERK is constitutively active and unaffected by TCDD treatment and
      differentiation, while the JNK signaling pathway is modulated by TCDD in an AhR
      dependent manner. Thus, both the ERK and JNK MAPK pathways are necessary for IL
      1beta expression in TCDD-stimulated human keratinocytes, however, they act at
      different levels to modulate IL-1beta expression.

PMID- 15019842
TI  - Competition between ammonia derived from internal glutamine hydrolysis and
      hydroxylamine present in the solution for incorporation into UTP as catalysed by
      Lactococcus lactis CTP synthase.
AB  - CTP synthase catalyses the reaction: glutamine+UTP+ATP -->
      glutamate+CTP+ADP+P(i). The reaction is greatly stimulated by the allosteric
      binding of GTP. In addition to glutamine that is hydrolysed by the enzyme to
      ammonia and glutamate, CTP synthase will also utilise external sources of amino
      donors such as NH(4)Cl. This reaction is no longer dependent on allosteric
      activation by GTP. Hydroxylamine is also a substrate for Lactococcus lactis CTP
      synthase and results in the formation of N4-OH CTP. This product has the feature
      that it absorbs at 300nm where CTP absorption was shown to be greatly reduced and
      enabled the determination of N4-OH CTP formation in the presence of CTP synthesis
      derived from glutamine hydrolysis. Differences in initial rates determined for
      the hydroxylamine dependent reaction at 291nm in the presence and absence of
      glutamine and GTP were ascribed to simultaneous CTP and N4-OH CTP synthesis in
      the presence of these compounds. A characterisation of the apparent inhibition by
      GTP and glutamine of N4-OH CTP synthesis determined at 300nm showed that
      glutamine dependent CTP synthesis occurs at a rate of about 60% of that in the
      absence of hydroxylamine. GTP dependent inhibition of the ammonium chloride
      dependent reaction of L. lactis CTP synthase by the glutamine analog glutamate
      gamma-semialdehyde showed a partial inhibition with a maximum inhibition of about
      60%. These results are interpreted in terms of a "half of the sites" mechanism
      for glutamine hydrolysis on CTP synthase.

PMID- 15019844
TI  - [Two years].

PMID- 15019845
TI  - [Laparoscopic pancreatectomy: a series of 22 patients].
AB  - INTRODUCTION: Laparoscopic pancreatic surgery underwent many changes in the last
      few years. Current indications include staging laparoscopy for pancreatic
      neoplasms, palliative treatment of non-resectable tumors, and pseudocysts
      drainage. Pancreatic tail resection or pancreatic enucleation have also been
      reported, but are currently under investigation. We report our experience in this
      domain. MATERIAL AND METHODS: Retrospective study of patients who had a
      pancreatic tail resection or pancreatic enucleation, in a single institution.
      RESULTS: From November 1993 to June 2002, a laparoscopic pancreatic resection was
      attempted in 22 patients. Nineteen patients were operated by laparoscopy (86%),
      two patients had conversion to laparotomy (9%), and one had conversion to a "hand
      assisted" technique (4%). There was 17 left pancreatectomies and five
      enucleations. Median operating time was 4.1 hours (range 1.6 to 6.6 hours). There
      were no deaths in the first 30 post-operative days. Global morbidity rate was
      31.8% (N =7), including four pancreatic fistulas (18%), one superficial
      phlebitis, one prolonged ileus, and one peri-pancreatic fluid collection. Median
      hospital stay was six days (1 to 26 days). CONCLUSION. - Pancreatic tail
      resections and enucleations are feasible by laparoscopy, with a mortality and
      morbidity rate similar to open surgery. The potential advantages of laparoscopy
      (reduced post-operative pain, hospital stay and recovery time) should be balanced
      with a potential increase in pancreatic fistula rate. That risk should be
      addressed before laparoscopy is generalized for pancreatic resections.

PMID- 15019848
TI  - [Could we trust clinical statistics from data banks of the National Health
      Service (NHS)?].
AB  - Can we accept the statistics provided by the Ministry of Health, which uses large
      computerized databases? Through MEDECHO, the Ministry provides to hospital
      managers, reports cards on different interventions. These reports compare
      different hospitals performances. Surgeons involved in the process hesitate to
      accept this information. Using the results of the performance of cholecystectomy
      provided by this system (Gr: A), we compared the same cohort (1 April-31 December
      1996 = 346 cholecystectomies) but using specific criteria determined as relevant
      to our surgeons (Gr: B). The rate of complication gives a crude aftermath and no
      attempt was used to adjust for severity. The MEDECHO data are adjusted for
      severity. The global rate of complications is similar Gr: A 11%, Gr: B 12%. Major
      complication rate for pulmonary embolism, hemorrhage and biliary duct trauma are
      identical. The rate of surgical site infection is higher in Gr: B (5% vs. 2%).
      The patients are seen in the outpatient clinic and these observations are not
      included by the analytical system unless the patient has been readmitted. For our
      hospital, the MEDECHO data are valid and reliable even though they underestimated
      the wound infection rate. These results could be explained by an appropriate
      interpretation of the code system by the archivist and by the surgeons' precision
      to complete the summary sheet of hospitalization. We can conclude that these data
      can be used as a means to evaluate the quality of outcome of a surgical service.

PMID- 15019850
TI  - [Fecal incontinence following anal sphincter rupture: influence of the aetiology
      on the repair results].
AB  - Short-term functional results are usually good after sphincter repair but they
      could deteriorate with time if the disruption is due to obstetric damage. The aim
      of this study was to compare short and long-term results after sphincter repair
      according to the etiology of the damage. METHODS: Fifty-five women have been
      operated on for a sphincter disruption due to obstetrical damage (Ob) (28) or to
      postoperative damage (Op) (27) and were retrospectively studied. Surgical
      procedure was similar for every patients but the puborectalis muscle was also
      approximated in case of obstetric damage. Functional results were recorded by
      clinical examinations two months after the operation and during the year 2001.
      RESULTS: The two groups were similar, except for the rate of defunctionning stoma
      undergone and for the duration of symptoms before the operation. Mortality and
      morbidity were similar between the two groups. Short-term functional results were
      better in the postoperative group (96 vs 78%) (P =0.05). At the end of the follow
      up the results remained significantly better in group Op (85 vs 65%; P <0.05).
      The cumulative rates of functional good results also decreased more rapidly in
      group Ob but the difference was not significant. CONCLUSION: Short and long-time
      functional results after sphincter repair seem to be better in case of
      postoperative disruption. Pudendal nerve damages frequently observed after
      traumatic delivery could explain this difference.

PMID- 15019849
TI  - [Management of thymic cysts].
AB  - OBJECTIVE: The thymic cysts are rare tumors of the neck and anterior mediastinum.
      The management of these patients in our institution is reported. Minimally
      invasive procedures are discussed. PATIENTS AND METHODS: Six patients operated in
      our institution within ten years, with a follow-up of 7.1 +/-3.7 years are
      studied retrospectively. RESULTS: There were four women and two men with an
      average of 39.8 +/-16.5 years. The tumor was found on chest radiograph in four
      asymptomatic patients, one took medical advice for laryngeal discomfort and
      another for dysphagia and dyspnea. The tumor was localized in the anterior
      mediastinum in three cases, in the cervicomediastinal site in two cases and in
      the cervical site in one case. CT scan was practiced in three patients with a
      mediastinal tumor and MR imaging in one of them. In patients with cervical or
      cervicomediastinal tumor, a cervical echography was practiced. All patients were
      operated on: three by cervicotomy, one by sternotomy, one by partial upper mini
      sternotomy and one by right lateral video-assisted mini-thoracotomy. Histology
      confirmed benign epithelial thymic cyst. CONCLUSION: There is no specific marker
      of thymic cysts. Only the surgical management, leads to precise the diagnosis and
      to treat these tumors. No mortality, no complications or recurrences are
      reported. The minimally invasive surgery takes an interesting place for thoracic
      location, to explore and treat these benign mediastinal lesions.

PMID- 15019852
TI  - [Barrett's oesophagus with high grade dysplasia: which treatment?].

PMID- 15019851
TI  - [Iatrogenic perforation of the gallbladder during laparoscopic cholecystectomy
      does not influence the prognosis. Prospective study].
AB  - BACKGROUND: Perforation of the gallbladder and spillage of gallstones frequently
      occur in laparoscopic cholecystectomy. As stones may be lost and as spilled bile
      is known to be contaminated, influence on morbidity may be expected. AIMS: To
      evaluate the immediate and late consequences on morbidity of peroperative
      gallbladder perforation during laparoscopic cholecystectomy (LC) in an
      universitary hospital center. PATIENTS AND METHODS: One hundred and twenty one LC
      were prospectively evaluated with a mean follow-up of 30 months. Elective
      operations on 30 men and 91 women with a mean age of 56.4 years (18-85) were
      carried out for symptomatic cholecystolithiasis in 97 cases (80%), and in 24
      cases for complicated cholecystolithiasis. The "french technique" was used for
      all LC, with systematic intra-operative cholangiography and ultra Sonography.
      Thirty-seven (30.5%) LC were performed by surgical trainees, 84 LC by confirmed
      surgeons. The consequences of ultra-operative gallbladder perforation were
      evaluated in the immediate postoperative period, especially for septic
      complications, and thereafter, patients were followed up 1, 6, 12 and 24 months
      postoperatively. RESULTS: Ultra-operative gallbladder perforation occurred in 24
      cases (20%), in 83.3% during gallbladder dissection. Gallstone spillage occurred
      six times, and all spilled stones were removed. Gallbladder perforation was more
      frequent (but non significant) in acute cholecystitis (25 vs 19%, ns). A clear
      correlation to the skill and experience of the surgeon is shown (32.4 vs 14.2%, P
      =0.01). Gallbladder perforation is accompanied by an elevated (nonsignificant)
      postoperative morbidity (16.6 vs 7.2%, P =0.62) which is, in fact related to
      older patient and more acute cholecystitis in this group. No reoperations were
      necessary. One and two years follow-up revealed no long-term complications
      specially due to lost gallstones. CONCLUSION: Peroperative gallbladder
      perforation during LC carries no morbidity, provided a total and complete
      recuperation of gallstones spilled and local treatment of bile contamination with
      local irrigation and antibiotics. This complication is correlated to the
      surgeon's skill and experience.

PMID- 15019853
TI  - [Necrotizing enterocolitis during pregnancy in a woman operated on at six months
      of Hirschsprung's disease].
AB  - Necrotizing enterocolitis is a rare and severe complication of Hischsprung's
      disease. Aggravation of unknown or undertreated Hischsprung's disease may be seen
      during pregnancy. To our knowledge, the following case is the first combining
      those two elements: necrotizing enterocolitis in a 20 years old women operated on
      of Hischsprung's disease when she was six months. The final diagnosis was made 24
      hours later. Definitive treatment was a three-stage ileal pouch-anal anastomosis.

PMID- 15019854
TI  - [Recurrent pancreatitis after pancreaticoduodenectomy: reoperation for stenosis
      of the pancreaticojejunostomy].
AB  - Stenosis of the pancreaticojejunostomy is a late and rarely symptomatic
      complication of pancreaticoduodenectomy, observed in approximately 30% of cases.
      Treatment of symptomatic strictures is difficult. We report a case of reoperation
      for stenosis of the pancreaticojejunostomy responsible for recurrent
      pancreatitis. The treatment strategy is discussed.

PMID- 15019855
TI  - [Haemobilia after blunt hepatic trauma: a sometimes delayed complication].
AB  - Haemobilia is a rare but serious complication of hepatic blunt trauma. Its
      diagnosis can be difficult because the delay between initial trauma and
      haemobilia ranges from few days to several months. Once the diagnosis is
      considered, a diagnostic and therapeutic arteriography must be performed as soon
      as possible. We reported the case of a patient who developed hemobilia 2 months
      after hepatic blunt trauma, due to pseudoaneurism of the anterior branch of the
      right hepatic artery; haemostasis was successfully obtained by arteriographic
      embolisation.

PMID- 15019856
TI  - [Surgical exposure of visceral arteries].
AB  - Surgery of visceral arteries is mainly indicated for ostial and juxtaostial
      atherosclerosis of the celiac axis and superior mesenteric arteries. Their
      surgical exposures are often difficult because of their deepness.

PMID- 15019857
TI  - Optimal care for the patient with diabetes across the cardiovascular disease
      spectrum. Proceedings of a symposium. January 25-26, 2003. Chicago, Illinois,
      USA.

PMID- 15019858
TI  - The diabetes epidemic: a national and global crisis.
AB  - Diabetes mellitus is a serious problem that will soon reach epidemic proportions
      in the United States and throughout the world. The incidence of this condition
      will skyrocket in the next quarter century as demographic changes increase the
      size of highly susceptible populations (e.g., the elderly and Hispanic
      communities) and sociocultural developments create a more sedentary populace as
      well as expose people in developing nations to new risk factors for this disease.
      Along with substantial direct morbidity and mortality, diabetes is independently
      associated with the incidence and severity of a variety of cardiovascular
      illnesses. Individuals with diabetes are substantially more likely than their
      nondiabetic counterparts to suffer stroke, myocardial infarction, or heart
      failure, with a worse prognosis following any of these conditions. Many factors
      may be relevant to this association, but recent studies have elucidated a major
      role for the metabolic syndrome, which has been shown to be predictive of both
      diabetes and cardiovascular disease. Consequently, early intervention to control
      blood glucose levels and other risk factors may mitigate the severity of these
      conditions, possibly even before the disease begins.

PMID- 15019860
TI  - Type 2 diabetes mellitus: what is the optimal treatment regimen?
AB  - Treatment options for type 2 diabetes mellitus currently consist of insulin
      sensitizers, alpha-glucosidase inhibitors, secretagogues, and insulin. However,
      the emphasis on initial therapy has been shifting from secretagogues and alpha
      glucosidase inhibitors to insulin sensitizers such as metformin and the
      thiazolidinediones (TZDs). This article outlines the benefits of treatment with
      sensitizers vis a vis alpha-glucosidase inhibitors and secretagogues as part of a
      comprehensive treatment algorithm for type 2 diabetes. Secretagogues and alpha
      glucosidase inhibitors effectively lower plasma glucose levels only, whereas
      insulin sensitizers reduce several important cardiac risk factors in addition to
      reducing plasma glucose levels. TZDs, in particular, are also beneficial for
      their ability to preserve or even rejuvenate pancreatic beta-cell function. The
      treatment algorithm has a layered approach, beginning with a combination of
      insulin-sensitizer therapy and incrementally progressing to triple oral therapy
      with the addition of secretagogues and, if necessary, the addition of
      subcutaneous insulin to maintain glycemic control.

PMID- 15019859
TI  - Correlation between cardiovascular disease and diabetes mellitus: current
      concepts.
AB  - Individuals exhibiting precursor symptoms of diabetes mellitus or reaching
      diagnostic thresholds for diabetes are at increased risk of death due to
      cardiovascular disease (CVD). Moreover, patients with diabetes alone, as well as
      those who have diabetes paired with established CVD, remain undertreated for
      cardiovascular risk factors. The clear correlation between these disease
      processes has led many to speculate that they share common pathogenetic
      processes. Recent research has made it increasingly evident that the core
      metabolic defects that mark diabetes, including impaired glucose tolerance,
      insulin resistance, and proinflammatory and prothrombotic states, lead to
      endothelial dysfunction and accelerate atherogenesis. Moreover, increases in
      sympathetic tone with diabetes are associated with changes in cardiac and
      vascular function that lead to hypertension, left ventricular dysfunction, and
      cardiac autonomic neuropathy; such changes set the stage for arrhythmia, silent
      infarction, and sudden death. Furthermore, diabetes-related changes in metabolic
      and autonomic functioning, as well as increases in inflammatory and thrombotic
      signaling, compromise the ability of myocardial and vascular tissue to remodel
      after injury and to recover and sustain functionality. Because potentiation of
      atherogenesis and cardiac dysfunction occurs in the presence of early diabetic
      symptoms as well as in the established disease, early implementation of
      strategies to reduce cardiovascular risk factors and to slow diabetes progression
      may help to improve long-term outcomes for at-risk individuals. Such
      interventions may include well-established treatments for hypertension and
      dyslipidemia, diet improvements, weight loss, and exercise as well as novel
      pharmacologic interventions aimed at newly identified therapeutic targets.

PMID- 15019861
TI  - The importance of blood pressure control in the patient with diabetes.
AB  - In individuals with diabetes mellitus, higher risk for renal and cardiovascular
      disease is seen with blood pressure levels >130/80 mm Hg. Findings of several
      studies, as well as new guidelines, indicate that individuals with diabetes will
      benefit from more aggressive treatment of hypertension. Angiotensin-converting
      enzyme inhibitors, angiotensin-receptor blockers, diuretics, beta-adrenoceptor
      blockers, and calcium-channel blockers are effective antihypertensive agents in
      type 2 diabetes. Moreover, combinations of these agents are frequently required
      to reach the target blood pressure of <130/80 mm Hg and reduce risk for renal and
      cardiovascular events. All of these agents have demonstrated benefits in treating
      patients. Clinical evidence also indicates that the new vasodilating beta
      blockers offer advantages beyond blood pressure control, including cardiovascular
      risk reduction without exacerbating metabolic parameters. With increased
      awareness of the need for aggressive treatment of hypertension, clinicians can
      provide significant benefit to their patients with diabetes. The new beta
      blockers may play an important role in achieving blood pressure goals.

PMID- 15019862
TI  - Preventing cardiovascular events in patients with diabetes mellitus.
AB  - Diabetes mellitus and obesity are becoming increasingly prevalent in the United
      States. Patients with diabetes are 2 to 3 times more likely to develop
      cardiovascular disease (CVD) than are individuals without diabetes, but proper
      diabetes management and metabolic control can reduce this risk. Nonpharmacologic
      interventions, such as diet and exercise, can help to reduce weight and control
      insulin resistance, blood glucose levels, and lipid abnormalities, thereby
      lowering the risk of adverse cardiovascular outcomes. However, diet and exercise
      can provide particular challenges for the patient with diabetes. Antiobesity
      drugs, such as sibutramine and orlistat, can help individuals with diabetes lose
      weight and can have some effect on metabolic control. Alcohol use and hormone
      replacement therapy are still controversial topics with regard to reducing the
      risk of CVD. Smoking is known to be particularly dangerous for those with
      diabetes, and it is important for health care providers to help their patients
      stop smoking. Early and aggressive intervention in treating risk factors can
      reduce the risk of developing diabetes and prevent CVD in the patient with
      diabetes.

PMID- 15019863
TI  - Management of the patient with diabetes mellitus and myocardial infarction:
      clinical trials update.
AB  - The increasing prevalence of diabetes mellitus and its association with
      cardiovascular disease have become serious public health issues. Although
      diabetes and coronary artery disease (CAD) may have different clinical
      manifestations, their atherosclerotic burden and prognosis are quite similar.
      However, patients with diabetes who have underlying CAD have a different, more
      complex pathophysiology and a worse prognosis. Optimal management of these
      patients requires a comprehensive multifactorial approach to prevent
      microvascular and macrovascular events. In the setting of an acute myocardial
      infarction (MI), immediate management should focus on limiting infarct size. This
      can be achieved by using fibrinolytic agents, primary percutaneous intervention
      (in ST-segment elevation MI), or glycoprotein IIb/IIIa inhibitors followed by
      coronary angiography within 24 to 48 hours and, when appropriate, by coronary
      intervention (in non-ST-segment elevation MI). Drug-eluting stents may have an
      important role in patients with diabetes, who have a higher rate of
      postintervention coronary restenosis than do nondiabetic individuals. In
      addition, all patients with an acute MI (ST- and non-ST-segment elevation) should
      be given aspirin, nitrates, beta-blockers, and angiotensin-converting enzyme
      (ACE) inhibitors. The long-term pharmacologic management after MI is similar in
      all patients, regardless of the initial presentation. Antiplatelet agents
      (aspirin and/or clopidogrel), ACE inhibitors, beta-blockers, lipid-lowering
      agents, and glycemic control have all been shown to be effective in decreasing
      long-term mortality. Despite advances in the management of MI, the mortality
      rates of patients with diabetes remain 1.5- to 2-fold greater than those of
      persons without diabetes. Maximizing the use of lifesaving therapies proved
      effective in large randomized clinical trials and tight metabolic control can
      further decrease mortality rates. However, many of these lifesaving therapies are
      underused in patients with diabetes because of the misconception that potential
      adverse effects may outweigh their benefits. New programs aimed at improving
      postinfarction quality of care in patients with diabetes, based on guidelines and
      expert recommendations, have shown promise. However, more effort must be devoted
      to the improvement of outcomes related to these public health problems.

PMID- 15019865
TI  - Managing the patient with diabetes mellitus and heart failure: issues and
      considerations.
AB  - Heart failure affects nearly 5 million Americans and is associated with high
      morbidity and mortality rates. It is now recognized that activation of multiple
      neurohormonal systems is intrinsic in the pathophysiology of heart failure.
      Patients with diabetes mellitus are at high risk for heart failure, and some of
      the complications of diabetes (e.g., insulin resistance) contribute to the
      development and progression of heart failure, partly because of their effects on
      neurohormonal systems. Pharmacologic intervention directed toward these systems
      (i.e., angiotensin-converting enzyme [ACE] inhibition, use of aldosterone
      antagonists, and beta-adrenergic blockade) has been shown to decrease the
      morbidity and mortality associated with heart failure. Despite this knowledge,
      ACE inhibitors, aldosterone antagonists, and beta-blockers are grossly underused,
      and deaths and hospitalizations due to heart failure have steadily increased.
      Guidelines for the management of heart failure recommend the use of ACE
      inhibitors and beta-blockers in patients with mild, moderate, or severe disease.
      Aldosterone antagonists are recommended in severe heart failure, and recent data
      also support their use in mild to moderate heart failure. Concerns about the
      increased incidence of hypoglycemia, worsening dyslipidemia, and decreased
      insulin sensitivity with beta-blocker use may be preventing physicians from
      prescribing these agents for patients with diabetes with heart failure. Although
      evidence from earlier clinical trials justifies some of these concerns, newer
      vasodilating beta-blockers (e.g., carvedilol) have been shown to have a neutral
      or positive effect on dyslipidemia and insulin resistance. beta-Blockade in
      conjunction with ACE inhibition should be standard therapy for all patients with
      diabetes who have heart failure. Furthermore, early in-hospital initiation of
      neurohormonal intervention can provide earlier benefit to these patients.

PMID- 15019864
TI  - New insights into diastolic heart failure: role of diabetes mellitus.
AB  - Heart failure affects nearly 5 million people in the United States and is a major
      contributor to mortality, hospitalization, and medical costs. Approximately 40%
      of patients with heart failure have preserved left ventricular systolic function,
      thus exhibiting diastolic heart failure. More common in women and the elderly,
      this condition is associated with hypertension, coronary artery disease, and/or
      atrial fibrillation. With the exception of the Digitalis Investigation Group
      (DIG) and the Candesartin in Heart Failure: Assessment of Reduction in Mortality
      and Morbidity (CHARM)-Preserved trials, no completed large randomized clinical
      trial has addressed the management of such patients. Symptomatic treatment
      involves administration of diuretics and nitrates, but long-term management with
      angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers,
      aldosterone antagonists, beta-blockers, and calcium channel blockers targets the
      underlying disorders. Recent studies found that diabetes mellitus produces
      functional, biochemical, and morphologic myocardial abnormalities independent of
      coronary atherosclerosis and hypertension. These abnormalities may result in
      impaired left ventricular diastolic function, contributing importantly to heart
      failure with normal systolic function. Although tight glycemic control decreases
      the risk of heart failure in patients with diabetes, the effects of different
      diabetic treatment regimens on heart failure with normal systolic function are
      unknown and remain subject to future investigation.

PMID- 15019866
TI  - Closing statement.

PMID- 15019867
TI  - Predictors of angina pectoris versus myocardial infarction from the Women's
      Health Initiative Observational Study.
AB  - Although risk factors for acute coronary syndromes have been extensively studied,
      characteristics distinguishing women who will develop unstable angina rather than
      acute myocardial infarction (MI) are less well understood. This analysis
      evaluates baseline demographic, physical, and medical characteristics as
      predictors of angina versus MI in the Women's Health Initiative Observational
      Study. During a prospective 4.5-year follow-up of 92,152 postmenopausal women,
      1,527 hospitalizations for angina and 797 for MI were confirmed by centrally
      trained physician adjudicators. In a multivariate analysis of women with incident
      angina or MI, high cholesterol (odds ratio [OR] 0.62, 95% confidence interval
      [CI] 0.47 to 0.80; p = 0.0004) and prior coronary disease (OR 0.70, 95% CI 0.55
      to 0.89; p = 0.004) independently predicted angina (referent), whereas current
      cigarette smoking (OR 1.60, 95% CI 1.13 to 2.26; p = 0.007) and diabetes mellitus
      (1.44, 95% CI 1.10 to 1.87; p = 0.007) predicted MI. Older age and hypertension
      were independently, but less strongly, predictive of MI. Aspirin or statin use,
      physical activity, body mass index, and educational levels were not independently
      associated with one or the other type of acute coronary syndrome. Thus, specific
      risk factors strongly and independently predicted whether women with an acute
      coronary syndrome would present with angina or with MI.

PMID- 15019868
TI  - Effect of clopidogrel pretreatment on inflammatory marker expression in patients
      undergoing percutaneous coronary intervention.
AB  - Platelets play an important role in the inflammatory response. In a nonrandomized
      comparison, we examined the effect of clopidogrel pretreatment on platelet
      inflammatory marker expression in patients undergoing percutaneous coronary
      intervention (PCI). Platelet expression of the inflammatory markers CD40 ligand
      (L) and CD62 P-selectin (P) and serum levels of interleukin-6 and CD40L were
      compared in patients pretreated (>24 hours before PCI) or not pretreated with
      clopidogrel. Blood samples were obtained before and after the procedure, and from
      18 to 24 hours later. Marker expression in resting and adenosine diphosphate
      (ADP) (50 micromol/L) and thrombin receptor activating peptide (TRAP) (10
      micromol/L) activated samples was quantified by flow cytometry. Serum CD40L and
      interleukin (IL)-6 levels were determined by enzyme-linked immunosorbent assay.
      Seventy-nine patients were recruited into the study. Forty-two percent were
      pretreated with clopidogrel for a median of 5 days (range 1 to 1,325).
      Clopidogrel pretreatment was associated with lower ADP-activated platelet CD40L
      expression in baseline and postprocedural samples. Similarly, platelet CD62P
      expression at all time points in ADP-activated and in baseline and postprocedural
      TRAP-activated samples was lower in patients pretreated with clopidogrel. These
      differences remained after multivariate adjustment between the groups. Serum
      CD40L levels increased from 2.13 +/- 2.37 ng/ml at baseline to 4.77 +/- 3.86
      ng/ml at 18 to 24 hours after the procedure (p <0.0001). Similarly, serum IL-6
      levels increased at 18 to 24 hours after the procedure (14.8 +/- 42.0 pg/ml
      before vs 25.5 +/- 36.0 pg/ml at 18 to 24 hours after the procedure, p <0.0001).
      Clopidogrel pretreatment did not affect serum IL-6 or CD40L levels. Thus,
      clopidogrel pretreatment reduces platelet inflammatory marker expression in
      patients undergoing PCI.

PMID- 15019869
TI  - Latent abnormal fatty acid metabolism in apparently normal perfusion during
      stress in patients with restenosis after coronary angioplasty: assessment by
      exercise stress thallium-201 and iodine-123-labeled 15-(p-iodophenyl)-3-R,S
      methylpentadecanoic acid-dual myocardial single-photon emission computed
      tomography.
AB  - Restenosis is a major problem in patients undergoing coronary angioplasty.
      Reduced uptake of iodine-123-labeled 15-(p-iodophenyl)-3-R,S-methylpentadecanoic
      acid (I-BMIPP-123) relatively to thallium-201 (Tl-201) has been attributed to the
      metabolic damage in the myocardium in patients with coronary artery disease.
      Therefore, we performed exercise stress Tl-201 and I-BMIPP-123 dual myocardial
      single-photon emission computed tomography (SPECT) to detect coronary restenosis
      in 48 patients (35 men and 13 women, mean age 66 +/- 8 years), followed by
      coronary angiography at follow-up. Patients were divided into 2 groups: those
      with (n = 24) and without (n = 24) restenosis. Redistribution of Tl-201 was seen
      more frequently in the restenosis group than in no-restenosis group (58% [14 of
      24] vs 8% [2 of 24], p <0.05). Five of 10 patients (50%) with restenosis but
      without Tl-201 redistribution had Tl-201/I-BMIPP-123 discrepancy during stress.
      In patients without restenosis, only 1 patient had this discrepancy during
      stress. Incorporation of Tl-201/I-BMIPP-123 uptake discrepancy during stress
      significantly improved the sensitivity (58% [14 of 24] to 79% [19 of 24]) with
      preserved specificity (92% [22 of 24] to 88% [21 of 24]). Exercise stress Tl-201
      and I-BMIPP-123 dual myocardial SPECT revealed that latent abnormal fatty acid
      metabolism may exist in apparently normal perfusion during stress in patients
      with restenosis after coronary angioplasty. Use of I-BMIPP-123 together with Tl
      201 during stress SPECT substantially improved the diagnostic accuracy of
      restenosis based on Tl-201 redistribution (from 75% to 83%).

PMID- 15019870
TI  - Treatment program for erectile dysfunction in patients with cardiovascular
      diseases.
AB  - The present study assesses the effectiveness of our progressive treatment program
      for erectile dysfunction in patients with cardiovascular diseases. The study
      sample included 453 patients aged 36 to 91 years. Therapy in all patients was
      begun with sildenafil citrate 25 to 100 mg. Those with contraindications, drug
      adverse effects, or a negative response (erection insufficient for vaginal
      penetration) were given intracavernous injections of a cocktail of vasoactive
      drugs (dimix, trimix, or quadmix), followed by the addition of sildenafil citrate
      to the trimix in case of failure, and then a penile prosthesis. Patients were
      followed for 2 years; in cases of treatment ineffectiveness during follow-up,
      drug dosages were increased or a penile prosthesis was suggested. Sildenafil
      citrate was offered to 417 patients of whom 205 (49.2%) responded positively. The
      remaining 248 patients received intracavernous injections: 135 (54.4%) had a
      positive response to the dimix, 85 (75.2%) to the trimix, and 16 (57.1%) to the
      quadmix. Four of the other 12 patients (0.9%) responded to sildanefil citrate +
      trimix, and 2 (0.4%) agreed to a penile prosthesis. At the 2-year follow-up of
      447 patients, 131 (29.3%) were successfully treated with sildanefil citrate, 92
      (20.6%) with dimix, 122 (27.3%) with trimix, 12 (2.7%) with quadmix, and 2 (0.4%)
      with sildanefil citrate + trimix; 5 patients (1.1%) had a penile implant. Forty
      eight patients (10.7%) achieved spontaneous erection, of whom 46 were taking
      aspirin. Twenty-six patients (5.8%) stopped treatment because of health and
      family reasons and 9 (2%) had a negative response. Our progressive treatment
      program for erectile dysfunction has a high success rate in patients with
      cardiovascular disease: Overall, 98.7% achieved an erection sufficient for
      vaginal penetration immediately after the trial and 92.2% on follow-up; 10.7%
      achieved spontaneous erections.

PMID- 15019872
TI  - Usefulness of plasma brain natriuretic peptide levels in predicting dobutamine
      induced myocardial ischemia.
AB  - Plasma brain natriuretic peptide (BNP) levels have been associated with left
      ventricular dysfunction and acute myocardial infarction. Although natriuretic
      peptide responses have been linked to exercise-induced myocardial ischemia, it is
      not known whether BNP levels predict dobutamine-induced myocardial ischemia. The
      aim of this study was to determine whether elevations in BNP levels immediately
      before or after dobutamine-induced stress are associated with echocardiographic
      myocardial ischemia. Plasma BNP was measured before and after stress during
      dobutamine-stress echocardiography in 317 patients (aged 68 +/- 11 years; 46%
      women) who had creatinine <1.5 mg/dl and did not have valvular disease. Ischemia,
      as assessed by blinded echocardiographic interpretation, was noted in 31 patients
      (10%). In univariable analyses, prestress BNP was predictive of echocardiographic
      ischemia (rates of ischemia according to tertiles of BNP 4%, 9%, and 16%, chi
      square for trend = 8, p = 0.0059). The change in BNP levels with dobutamine
      stress was not associated with ischemia. In multivariable analyses, after
      adjusting for age, gender, and left ventricular ejection fraction, BNP before and
      after stress remained predictive of ischemia (1 SD increase in the log of resting
      BNP adjusted odds ratio 2.0, 95% confidence interval 1.3 to 3.0, p = 0.002). In
      this pilot study, resting BNP was predictive of dobutamine-induced ischemia.
      Future work is needed to confirm these findings.

PMID- 15019871
TI  - Excimer laser angioplasty in acute myocardial infarction (the CARMEL multicenter
      trial).
AB  - Patients with acute myocardial infarction (AMI) with thrombus-laden lesions
      constitute a revascularization challenge. Thrombus and atherosclerotic plaque
      absorb laser energy; thus, we studied the safety and efficacy of excimer laser in
      AMI. In a multicenter trial, 151 patients with AMI underwent excimer laser
      angioplasty. Baseline left ventricular ejection fraction was 44 +/- 13%, and 13%
      of patients were in cardiogenic shock. A saphenous vein graft was the target
      vessel in 21%. Quantitative coronary angiography and statistical analysis were
      performed by independent core laboratories. A 95% device success, 97%
      angiographic success, and 91% overall procedural success rate were recorded.
      Maximal laser gain was achieved in lesions with extensive thrombus burden (p
      <0.03 vs small burden). Thrombolysis In Myocardial Infarction (TIMI) trial flow
      increased significantly by laser: 1.2 +/- 1.1 to 2.8 +/- 0.5 (p <0.001), reaching
      a final 3.0 +/- 0.2 (p <0.001 vs baseline). Minimal luminal diameter increased by
      laser from 0.5 +/- 0.5 to 1.6 +/- 0.5 mm (mean +/- SD, p <0.001), followed by 2.7
      +/- 0.6 mm after stenting (p <0.001 vs baseline and vs after laser). Laser
      decreased target stenosis from 83 +/- 17% to 52 +/- 15% (mean +/- SD, p <0.001 vs
      baseline), followed by 20 +/- 16% after stenting (p <0.001 vs baseline and vs
      after laser). Six patients (4%) died, each presented with cardiogenic shock.
      Complications included perforation (0.6%), dissection (5% major, 3% minor), acute
      closure (0.6%), distal embolization (2%), and bleeding (3%). In a multivariant
      regression model, absence of cardiogenic shock was a significant factor affecting
      procedural success. Thus, in the setting of AMI, gaining maximal thrombus
      dissolution in lesions with extensive thrombus burden, combined with a
      considerable increase in minimal luminal diameter and restoration of anterograde
      TIMI flow, support successful debulking by excimer laser. The presence of
      thrombus does not adversely affect procedural success; however, cardiogenic shock
      remains a predictor of major adverse events during hospitalization.

PMID- 15019873
TI  - Heart rate variability in atrial fibrillation related to left atrial size.
AB  - The purpose of this investigation was to determine whether heart rate variability
      (HRV) in atrial fibrillation (AF) can be related to any echocardiographic-derived
      measurements of cardiac dimensions or function. AF is characterized by marked
      HRV. Although HRV in normal sinus rhythm has been studied and shown to have
      important clinical implications, there have been relatively few published reports
      dealing with the phenomenon in AF. This study examines HRV in AF taking into
      account the influence of heart rate. HRV measurements were obtained in 38
      patients with persistent AF who had undergone 24-hour ambulatory
      electrocardiographic monitoring. Taking into account a strong heart rate
      dependence of the HRV measurements, regressions were calculated. The relations
      were then re-examined using the differences (diff) in HRV from the expected for
      the average RR intervals. No significant correlations were found between
      unadjusted HRV measurements and any clinical features or echocardiographic
      variables. However, taking into account heart rate relations, with negative
      HRVdiff signifying less HRV than expected, reduced HRV correlated with increasing
      left atrial and left ventricular dimensions. On multivariate regression analysis,
      left atrial dimension emerged as an independent determinant of HRV. Also, HRV was
      greater in patients with lone AF than in those with cardiac disorders. HRV in AF
      is highly rate dependent. Unless this influence is taken into account, important
      relations may be obscured. When HRVdiff are related to echocardiographic
      measurements, increasing left atrial dimensions correlate with less HRV.

PMID- 15019874
TI  - Long-term alcohol consumption and the risk of atrial fibrillation in the
      Framingham Study.
AB  - Atrial fibrillation (AF) is a major risk factor for stroke. Although acute
      alcohol intake has been associated with AF, it is not known whether long-term
      alcohol consumption in moderation is associated with an increased risk of AF. We
      used a risk set method to assess the relation of long-term alcohol consumption to
      the risk of AF among participants in the Framingham Study. For each case, up to 5
      controls were selected and matched for age, age at baseline examination, sex,
      cohort, baseline history of hypertension, congestive heart failure, and
      myocardial infarction. Within each risk set, alcohol consumption was averaged
      from baseline until the examination preceding the index case of AF. Of the 1,055
      cases of AF occurring during a follow-up of >50 years, 544 were men and 511 were
      women. In a conditional logistic regression with additional adjustment for
      systolic blood pressure, age at baseline examination, education, and cumulative
      history of myocardial infarction, congestive heart failure, diabetes mellitus,
      left ventricular hypertrophy, and valvular heart disease, the relative risks were
      1.0 (reference), 0.97 (95% confidence interval [CI] 0.78 to 1.22), 1.06 (95% CI
      0.80 to 1.38), 1.12 (95% CI 0.80 to 1.55), and 1.34 (95% CI 1.01 to 1.78) for
      alcohol categories of 0, 0.1 to 12, 12.1 to 24, 24.1 to 36, and >36 g/day,
      respectively. In conclusion, our data indicate little association between long
      term moderate alcohol consumption and the risk of AF, but a significantly
      increased risk of AF among subjects consuming >36 g/day (approximatively >3
      drinks/day).

PMID- 15019875
TI  - Quality of heart failure care in managed Medicare and Medicaid patients in North
      Carolina.
AB  - Use of angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic
      receptor blockers in patients with heart failure (HF) remains low despite the
      results of clinical trials and evidence-based guidelines that support their use.
      The quality of HF care in managed Medicare and Medicaid programs in North
      Carolina participating in a HF quality improvement program was assessed. Managed
      care plans identified adult patients with 1 inpatient or 3 outpatient claims for
      HF during 2000. A stratified random sample of 971 Medicare and 642 Medicaid
      patients' outpatient medical records from 5 plans were reviewed by trained nurse
      abstractors to obtain data regarding type of HF, demographics, comorbidities, and
      therapies. Left ventricular function assessment was performed in 88% of patients.
      Among 494 patients with systolic dysfunction, 86% were appropriately treated with
      respect to ACE inhibitors (73% prescribed, 13% had a documented
      contraindication). In contrast, beta-blocker therapy was appropriate in 61% (49%
      prescribed, 12% contraindication). There were no significant differences in drug
      use by insurance, gender, race, or age. Ventricular function assessment and ACE
      inhibitor prescription rates are higher than beta-blocker prescription rates
      among Medicare and Medicaid managed care patients in North Carolina.
      Opportunities for improvement remain, particularly for beta-blocker use.

PMID- 15019876
TI  - Attenuation of biologic compensatory action of cardiac natriuretic peptide system
      with aging.
AB  - Although plasma B-type natriuretic peptide (BNP) levels increase with age, the
      mechanisms responsible for this increase are unknown. We investigated the
      predictors of elevated BNP in older subjects without cardiac systolic dysfunction
      and overt renal dysfunction. Furthermore, we analyzed the relations between BNP
      and its second messenger, cyclic guanosine monophosphate (cGMP), to aging. In 252
      subjects (mean age 69 +/- 12 years) with left ventricular ejection fraction
      >/=50% and creatinine levels <==1.5 mg/dl, plasma levels of BNP, cGMP, blood urea
      nitrogen, creatinine, and beta2-microglobulin (an endogenous marker of renal
      function), estimated glomerular filtration rate, and echocardiographic data were
      prospectively evaluated. Plasma BNP levels increased with age (r = 0.4, p
      <0.0001). With use of multivariate analysis, predictors of elevated BNP levels
      were age, use of beta blockers, and serum beta2-microglobulin levels. The molar
      ratio of cGMP to BNP significantly decreased with aging (r = 0.55, p <0.0001).
      Elevated BNP in older subjects with normal cardiac systolic function may be due
      in part to renal impairment. With aging, biologic compensation of the cardiac
      natriuretic peptide system may be attenuated.

PMID- 15019877
TI  - Evidence of early impairments in both right and left ventricular inotropic
      reserves in children with Duchenne's muscular dystrophy.
AB  - In Duchenne's muscular dystrophy (DMD), cardiac function deteriorates with time
      and heart failure is one of the major causes of death. The aim of the study was
      to determine if a decrease in the ventricular inotropic reserves could be an
      early sign of cardiac dysfunction in these children. Nineteen children with DMD
      (aged 9 to 18 years, mean age 13.6 +/- 2.4) underwent equilibrium radionuclide
      angiography at rest and during an inotropic stimulation with low-dose dobutamine
      perfusion (7.5 to 15 microg. kg(-1). min(-1)). In all patients, this
      investigation was short (<30 minutes), successful, and uncomplicated. At rest,
      left ventricular (LV) ejection fraction (EF) was normal (>0.50) in 79% of
      patients, and right ventricular (RV) EF was normal (>0.45) in 95%. There was a
      trend toward a decrease with age for rest LVEF (p = 0.051) but not for rest RVEF
      (p = 0.8). By contrast, marked declines with age could be documented for the
      increases (Delta) in LVEF and RVEF during dobutamine perfusion (p = 0.002 for
      DeltaLVEF and p = 0.015 for DeltaRVEF). Thus, by multivariate analysis, the sole
      best indicator of decline in cardiac function with age was LVEF determined with
      dobutamine. In children with DMD, low-dose dobutamine radionuclide angiography
      gives evidence of an early decline with age of the inotropic reserves of both
      ventricles.

PMID- 15019878
TI  - Angiographic right and left ventricular function in arrhythmogenic right
      ventricular dysplasia.
AB  - We prospectively documented right ventricular (RV) and left ventricular (LV)
      volumes and ejection fractions in a large series of patients with arrhythmogenic
      RV dysplasia/cardiomyopathy (ARVD/C). Eighty-five patients with ARVD/C and 11
      controls underwent 2 successive orthogonal right and left monoplane x-ray
      digitized cineangiographies. Volumes were calculated using the hemielliptical RV
      and ellipsoidal LV models. All controls and 58 of 85 patients (ARVD/C-I) had a RV
      ejection fraction > or =35% and 27 patients had a RV ejection fraction <35%
      (ARVD/C-II). Tricuspid annulus plane systolic excursion (TAPSE) was lower in
      ARVD/C-II than in ARVD/C-I patients (6 +/- 3 vs 14 +/- 3 mm) and controls (16 +/-
      2 mm) (each p <0.001). In patients with ARVD/C, TAPSE was positively related to
      RV ejection fraction (r = 0.79) and to crista supraventricularis shortening (r =
      0.81) (each p <0.001). Sensitivity and specificity of TAPSE <12 mm in identifying
      patients with RV ejection fraction <35% were 96% and 78%, respectively. LV
      ejection fraction was > or =50% in 68 patients, 40% to 49% in 10, and <40% in 7.
      Diffuse RV outflow tract aneurysm was observed in 9 patients, all belonging to
      ARVD/C-II, and this sign identified patients with LV ejection fraction <40% with
      86% sensitivity and 96% specificity. In conclusion, 68% of ARVD/C patients had
      normal RV ejection fraction and RV volumes, and 80% of ARVD/C patients had normal
      LV ejection fraction. Decreased TAPSE <12 mm and a diffuse RV outflow tract
      aneurysm were sensitive and specific indicators of RV ejection fraction <35% and
      LV ejection fraction <40%, respectively.

PMID- 15019879
TI  - Role of angiotensin-converting enzyme inhibitors in the prevention of atrial
      fibrillation.

PMID- 15019880
TI  - Subclinical atherosclerosis as a target of therapy: potential role of statins.

PMID- 15019881
TI  - Comparison of outcomes up to six months of Heparin-Coated with noncoated stents
      after percutaneous coronary intervention for acute myocardial infarction.
AB  - We prospectively followed 238 patients who underwent percutaneous coronary
      intervention for acute ST-elevation myocardial infarction and compared the
      outcomes of patients who received heparin-coated stents (n = 124) with those of
      patients who received noncoated stents (n = 114). The clinical characteristics
      and adjunctive medications of the 2 groups were similar. The use of heparin
      coated stents was associated with improved 30-day outcome but had no significant
      effect on 180-day outcome.

PMID- 15019883
TI  - Predictors of troponin elevation after percutaneous coronary intervention.
AB  - The predictors of troponin release after percutaneous coronary intervention were
      prospectively assessed in 405 consecutive patients. Troponin release occurred
      frequently (27%) and was associated with complications during the procedure,
      including sapheneous vein graft interventions, multistent use, glycoprotein
      IIb/IIIa use, and a history of hypercholesterolemia.

PMID- 15019882
TI  - Evaluation of routine functional testing after percutaneous coronary
      intervention.
AB  - Following percutaneous coronary intervention, 348 patients were randomized to
      either routine or selective functional testing strategies. For the primary end
      point of maximal exercise endurance on a treadmill at 9 months, achievement was
      similar in the routine and selective groups. For the secondary end points
      measuring functional status and quality of life, scores were also similar. There
      was little difference in the rates of invasive cardiac procedures for the 2
      groups at 9 months.

PMID- 15019884
TI  - Incidence, predictors, and clinical significance of troponin-I elevation without
      creatine kinase elevation following percutaneous coronary interventions.
AB  - The objectives of this study were to investigate the incidence, predictors, and
      clinical significance of isolated postprocedural troponin-I elevations in a
      consecutive series of patients who underwent percutaneous coronary intervention.
      We observed, in a series of 1,128 patients, that isolated troponin-I elevations
      without concomitant creatine kinase elevations occurred in 17% of patients after
      percutaneous coronary intervention, and that even troponin-I elevations 5 times
      above the upper limit of normal did not predict events after hospital discharge.

PMID- 15019885
TI  - Prevalence of troponin-T elevation during out-of-hospital cardiac arrest.
AB  - To determine the prevalence of myocardial ischemia before out-of-hospital cardiac
      arrest (OOHCA), we determined the prevalence of elevated cardiac troponin-T
      levels in subjects at the time of OOHCA. Plasma was collected from 63 subjects
      during resuscitation. Troponin levels were elevated (> or =0.03 ng/ml) in 25
      subjects (39.7%; 95% confidence intervals [CI] 29% to 52%). Increasing age was
      associated with elevated troponin (OR 1.10; 95% CI 1.04 to 1.17). Elevated
      troponin levels did not reliably predict short-term outcome. Because troponin
      increases hours after the onset of ischemia, these data reveal that about 40% of
      OOHCA cases can undergo intervention before collapse.

PMID- 15019886
TI  - Relation of depression to heart rate nonlinear dynamics in patients > or =60
      years of age with recent unstable angina pectoris or acute myocardial infarction.
AB  - Depression is common among older patients and it has been related to a worsened
      coronary prognosis. The basis for this association is controversial. The aim of
      this study was to ascertain whether patients with a recent acute coronary event
      show depression-related changes of heart rate variability (HRV) nonlinear
      dynamics. Alterations of the HRV have been recently shown to predict mortality in
      patients recovering from an acute myocardial infarction. In 52 patients > or =60
      years (52% women) with recent (within 24 to 72 hours) unstable angina pectoris or
      myocardial infarction, we obtained conventional time- and frequency-domain HRV
      measurements, along with nonlinear HRV measurements, including SD of the
      instantaneous beat-to-beat variability (SD1), scaling exponent alpha1 (alpha1),
      and approximate entropy (ApEn) from 10-minute RR-interval recordings. We also
      evaluated the presence of clinical depression and measured its severity by means
      of a 21-item Hamilton Depression Scale. On admission to the coronary care unit,
      19 patients (37%) were depressed; alpha1 was higher (1.23 +/- 0.21 vs 1.03 +/-
      0.30, p <0.05), whereas SD1 (10.4 +/- 3.7 vs 14.4 +/- 7.3, p <0.05) and ApEn
      (0.98 +/- 0.22 vs 1.16 +/- 0.15, p <0.001) were lower in depressed patients.
      Also, alpha1 increased (r = 0.31, p <0.05) and both SD1 (r = -0.46, p <0.01) and
      ApEn (r = -0.28, p <0.05) decreased with worsening depressive symptoms. In our
      sample, depression was associated with increased correlation and decreased
      complexity of the interbeat interval time series in older adults who had recently
      developed an acute coronary syndrome.

PMID- 15019887
TI  - Treatment of In-Stent restenosis using a stent with non-polymer-based paclitaxel
      elution.
AB  - Treatment of in-stent restenosis remains a therapeutic challenge. Twenty-seven
      lesions with in-stent restenosis were treated with non-polymer-based paclitaxel
      eluting stents. At 6-month follow-up, in-stent late loss was 0.44 +/- 0.54 mm and
      the restenosis rate was 20%, indicating effective treatment for reduction of
      recurrent restenosis.

PMID- 15019889
TI  - Examination of gender bias in the evaluation and treatment of angina pectoris by
      cardiologists.
AB  - One hundred fifty-eight patients (76 men and 82 women) presenting to an
      outpatient cardiology clinic with a new complaint of angina were prospectively
      followed to determine if there was a gender bias in the management of suspected
      coronary artery disease when physicians trained in cardiology managed their care.
      Overall, there were no differences in the percentage of women who underwent
      noninvasive evaluation, invasive evaluation, and treatment of suspected coronary
      artery disease compared with men.

PMID- 15019888
TI  - The effects of off-normal hours, age, and gender for coronary angioplasty on
      hospital mortality in patients undergoing coronary angioplasty for acute
      myocardial infarction.
AB  - Percutaneous transluminal coronary angioplasty (PTCA) was performed in all 1,050
      patients hospitalized within 24 hours of symptoms of documented acute myocardial
      infarction (AMI) from 1998 to 2002. Hospital mortality was similar in women and
      men who underwent PTCA for AMI but was higher in patients aged 75 to 95 years
      (10%) than in patients aged 21 to 50 (2.1%, p <0.001), 51 to 64 (2.3%, p <0.001),
      and 65 to 74 years (4%, p <0.02). Hospital mortality was higher in patients who
      had PTCA for AMI during off-normal (5.8%) than normal hours (3.2%, p <0.05).

PMID- 15019890
TI  - Impact of age on hospital course and cost of coronary artery bypass grafting.
AB  - In-hospital outcomes and cost were examined among 2,272 elderly patients (> or
      =75 years) and 9,745 younger patients (<75 years) who underwent coronary artery
      bypass graft surgery at 5 United States and 4 Canadian hospitals. Hospital course
      and cost data were obtained from a resource and cost accounting system used by
      each of the 9 hospitals. Compared with younger patients, elderly patients had
      longer hospital stays, increased in-hospital mortality, and increased costs.
      After controlling for clinical differences, age > or =75 years was associated
      with an increase in cost of 11%. Given the aging North American population, these
      results have important implications for health care planning for the next several
      decades.

PMID- 15019891
TI  - Heart rate dependent modification of the QTc cut-off values can improve accurate
      evaluation of QT prolongation.
AB  - Significant amounts of over- and underestimation to detect QT prolongation were
      observed using Bazett's formula or Fridericia's formula for heart rate correction
      with any fixed QTc cut-off value. Heart rate dependent modification of the QTc
      cut-off values can improve accurate evaluation of QT prolongation.

PMID- 15019892
TI  - Superior short-term cholesterol control and achievement of the adult treatment
      panel III low-density lipoprotein goals with initiation of statin therapy by the
      time of hospital discharge following acute myocardial infarction.
AB  - In a community-based population, we compared serum cholesterol concentrations
      following hospital discharge after acute myocardial infarction based on statin
      therapy at the time of hospital discharge. At the time of follow-up cholesterol
      measurement, patients discharged from the hospital on a statin had lower mean low
      density lipoprotein (LDL) (106.4 vs 116.7 mg/dl, p <0.01) and total cholesterol
      (182.2 vs 193.6 mg/dl, p <0.01) concentrations, larger absolute reductions in LDL
      (-24.7 vs -4.7 mg/dl, p <0.01) and total cholesterol (-24.2 vs -0.1 mg/dl, p
      <0.01) from pre-myocardial infarction levels, and superior attainment of the
      Adult Treatment Panel III LDL goal of <100 mg/dl at the time of follow-up
      compared with patients who were discharged without a statin (49% vs 33%; adjusted
      odds ratio 2.56; p <0.01).

PMID- 15019893
TI  - Initial low-density lipoprotein response to statin therapy predicts subsequent
      low-density lipoprotein response to the addition of ezetimibe.
AB  - This small retrospective study confirms the hypothesis that patients who are
      hyporesponders to statin therapy are hyper-responders to ezetimibe therapy and
      may help identify a patient population in whom ezetimibe would be particularly
      effective in lowering low-density lipoprotein cholesterol.

PMID- 15019894
TI  - Analysis of pravastatin to prevent recurrence of atrial fibrillation after
      electrical cardioversion.
AB  - To test the hypothesis that a statin could reduce the recurrence rate of atrial
      fibrillation after electrical cardioversion (EC), we performed an open,
      controlled multicenter study. Patients (n = 114) who had atrial fibrillation >48
      hours and who were scheduled for EC were randomized to receive 40 mg of
      pravastatin once daily for 3 weeks before and 6 weeks after EC or no drug in
      addition to standard therapy. Pravastatin did not reduce the recurrence rate of
      atrial fibrillation after EC.

PMID- 15019895
TI  - Effect of angiotensin-converting enzyme inhibitors, beta blockers, statins, and
      aspirin on C-reactive protein levels in outpatients with heart failure.
AB  - C-reactive protein (CRP) levels were measured in a cohort of 96 outpatients with
      heart failure. Baseline angiotensin-converting enzyme inhibitor plus beta-blocker
      use were associated with lower levels of CRP; no relation was found between CRP
      levels and aspirin or statin use.

PMID- 15019896
TI  - Relation between pulse pressure and survival in patients with decompensated heart
      failure.
AB  - Elevated pulse pressure (PP), an indicator of increased arterial stiffness, has
      been shown to predict adverse outcome in patients with stable heart failure.
      However, the dependence of PP on hemodynamic factors, such as stroke volume and
      peak aortic blood flow, suggests that the relation between PP and outcome may
      depend on the clinical setting. We evaluated the relation between PP and all
      cause mortality in 489 patients with decompensated heart failure. We found that
      the association of PP with outcome in this setting is reversed, with low PP being
      an independent predictor of mortality.

PMID- 15019897
TI  - Prenatal molecular genetic diagnosis of congenital long QT syndrome by strategic
      genotyping.
AB  - We demonstrate how genetic testing enabled a molecular prenatal diagnosis of
      congenital long QT syndrome in a 20-week fetus presenting with fetal bradycardia
      in the setting of maternal beta-blocker therapy. Before prenatal testing,
      strategic genotyping, based on a family history of a near drowning, was performed
      on a 3-generation family with clinically diagnosed long QT syndrome in which the
      affected mother was pregnant.

PMID- 15019898
TI  - Skeletal muscle hemodynamics and endothelial function in patients after Fontan
      operation.
AB  - To elucidate the relation between exercise capacity and peripheral hemodynamics
      in patients after the Fontan operation, near-infrared spectroscopy was performed
      on the vastus lateralis muscle, and flow-mediated vasodilation of the brachial
      and posterior tibial arteries was done with high-resolution ultrasonography. In
      Fontan patients, diminished exercise capacity was related to a reduced blood flow
      supply and an attenuated post-exercise oxygen resaturation of the working
      skeletal muscle, which also was related to impaired endothelium-dependent
      vasodilation.

PMID- 15019899
TI  - Normal right and left ventricular mass development during early infancy.
AB  - The average newborn's right ventricular mass, indexed to body surface area, is
      approximately 20% above the adult level, consistent with in utero physiologic
      hypertrophy. In contrast, the left ventricular mass index is underdeveloped by
      about 30% at birth, resulting in a ratio of right to left ventricular mass that
      is nearly 75% higher than at maturity. Left ventricular mass index increases
      rapidly during the first 2 weeks of life and then more slowly thereafter, whereas
      the right ventricular mass index decreases steadily during the first 4 months of
      life.

PMID- 15019900
TI  - Effectiveness of cardiac surgery in trisomies 13 and 18 (from the Pediatric
      Cardiac Care Consortium).
AB  - Because of severely reduced lifespan in children with trisomies 13 and 18,
      surgical repair of congenital heart lesions has rarely been offered. With data
      from a multicenter registry, we report 35 cases of cardiac surgery in infants and
      children with trisomy 13 or 18 with a 91% hospital survival rate. Those patients
      without an extended preoperative ventilatory requirement did not require
      prolonged mechanical ventilation after surgery.

PMID- 15019901
TI  - Risk of recoarctation should not be a deciding factor in the timing of
      coarctation repair.
AB  - To determine whether early coarctation repair is a significant risk for
      recoarctation in the modern era, 120 patients, including 87 infants, who
      underwent isolated coarctation repair at a single institution, were reviewed. At
      a mean follow-up of 44.4 months, there have were no late reoperations, and 2
      patients required balloon aortoplasty. The overall incidence of late
      reintervention was 1.7%, with only 2.4% (2 of 83) in those <1 year old.

PMID- 15019902
TI  - Risk for subsequent coronary artery disease after preeclampsia.
AB  - We studied the history of hypertensive pregnancies and conventional risk factors
      in 141 relatively young (<66 years) parous women with angiographically documented
      coronary artery disease and in age-matched controls. Our study showed that
      hypertension, diabetes, hypercholesterolemia, advanced age, smoking, and
      preeclampsia are independent risk factors for subsequent coronary artery disease.

PMID- 15019903
TI  - Two more drugs for dyslipidemia.

PMID- 15019904
TI  - Questionable origins of left bundle branch block.

PMID- 15019906
TI  - Therapy by design: evaluating the UK hospital building program.
AB  - A renewed interest in hospital design in the UK, prompted by the Private Finance
      Initiative, provides an opportunity to consider hospitals as 'therapeutic
      environments'. Noting that the therapeutic value of hospitals is related to their
      physical, social and symbolic design, this paper argues that 'expert' knowledges
      have encouraged the development of hospitals that all-too-rarely provide benign
      settings for promoting patient recovery and healing. The recent programme of
      hospital building in the UK, however, has been accompanied by a vigorous debate
      over what constitutes good hospital design, with four significant ideas emerging:
      hospitals should be clinically efficient, be integrated within the community, be
      accessible to consumers and the public, and encourage patient and staff well
      being. Suggesting that all four goals demand careful consideration of the real
      and imagined spatiality of hospital environments, the paper concludes by
      suggesting ways that health geographers can contribute to debates surrounding PFI
      hospital design.

PMID- 15019907
TI  - Investigating relationships between health need, primary care and social care
      using routine statistics.
AB  - Closer integration of primary and social care is central to the agenda of Primary
      Care Groups and Trusts (PCG/Ts) in England. Relationships between the need for
      care and primary and social care provision at local levels are investigated using
      routinely available statistics. Primary care provision is negatively associated
      with need resulting from material deprivation, but positively associated with
      older age-related need. Conversely, provision of social care is positively
      related to need resulting from deprivation but is unrelated to the size of local
      elderly populations. The 'inverse care law' does not capture the complexity of
      the relationships between need and provision. A lack of boundary coterminosity
      represents a serious impediment to the goal of establishing integrated health and
      social care systems for local populations.

PMID- 15019909
TI  - Health attitudes and behaviors: comparison of Japanese and Americans of Japanese
      and European Ancestry.
AB  - Adults living in Japan (N = 357) and the US (N = 223) completed semi-structured
      interviews assessing health-related attitudes and practices. The US respondents
      were of Japanese (N = 106) and European (N = 117) ancestry. Results indicated
      considerable similarity between the two US groups and significant differences
      between the Japanese and American respondents. The Japanese respondents placed
      less priority on health, had less belief in the efficacy of health screening
      tests, lower levels of internal health locus of control (HLOC), and higher levels
      of chance and powerful-others HLOC. While Japanese and Americans had similar
      overall levels of healthy behaviors, the Japanese were less likely to have
      obtained health screening tests (especially gynecologic exams). The findings have
      implications for adapting health promotion programs in the context of Japanese
      and American cultures.

PMID- 15019908
TI  - Relationships between pediatric asthma and socioeconomic/urban variables in
      Baltimore, Maryland.
AB  - Spatial relationships between clinical data for pediatric asthmatics (hospital
      and emergency department utilization rates), and socioeconomic and urban
      characteristics in Baltimore City were analyzed with the aim of identifying
      factors that contribute to increased asthma rates. Socioeconomic variables and
      urban characteristics derived from satellite data explained 95% of the spatial
      variation in hospital rates. The proportion of families headed by a single female
      was the most important variable accounting for 89% of the spatial variation.
      Evidence suggests that the high rates of hospital admissions and emergency
      department (ED) visits may partially be due to the difficulty of single parents
      with limited resources managing their child's asthma condition properly. This
      knowledge can be used for education towards mitigating ED and hospital events in
      Baltimore City.

PMID- 15019910
TI  - Monitoring mental health reform in a Canadian inner city.
AB  - This ecological study investigated whether the relationship between social
      disadvantage and hospitalization for psychoses changed during a time of social
      and economic stressors in an urban setting. Hospital separation rates were
      compared in the census years 1991 and 1996. Rates were 66% higher in the lowest
      income areas compared to the richest areas; but this relationship did not change
      over time. Instead, rates for psychoses increased by about 15% over time. These
      findings may be due to an increase in the need, a change in the level of
      resources or in coding practices. As hospital separation data are collected
      systematically in many countries, they can be used to monitor the progress of
      mental health reform. Variations in an area may signify that resources need to be
      redistributed more equitably and/or at a faster pace.

PMID- 15019911
TI  - Users' perspectives on epidemiological, GIS and point pattern approaches to
      analysing environment and health data.
AB  - Despite examples showing the usefulness of geographical information systems (GIS)
      and spatial point pattern analysis in health research, there remain barriers to
      their widespread use within health service settings. This paper explores
      potential users' views on the relative usefulness of such approaches for
      analysing spatially referenced environmental health data. Our findings indicate
      that researchers and practitioners do not always prefer the approach with which
      they are most familiar. In addition, there is a need for higher levels of
      understanding of, and confidence in, GIS and point pattern analysis techniques
      amongst health service professionals. The greatest need is for multi-disciplinary
      research which uses the most appropriate approach for each investigation, rather
      than that with which researchers are most familiar.

PMID- 15019912
TI  - A tale of two continents: a multilevel comparison of the determinants of child
      nutritional status from selected African and Indian regions.
AB  - This paper compares individual and household predictors of underweight among
      young children in sub-Saharan Africa and India, while also assessing the impact
      of clustering of weight for age z-scores at the household, community and regional
      levels. Multilevel statistical models are employed to compare the strength of the
      correlates of underweight (using weight-for-age z-scores) in six sub-Saharan
      African countries and four Indian states. The multilevel approach controls for
      correlation among children resulting from clustering within families,
      communities, or regions and in addition enables tests for differences in the
      regional, community and household effects for children from families of different
      socio-economic characteristics. Findings demonstrate the importance of individual
      and household level predictors such as age, the size of child at birth, prolonged
      breast-feeding, recent diarrhoea episodes, and maternal education as predictors
      of low weight-for-age z-scores across regions. Strong family effects are observed
      as well as significant community and regional random effects on variation in
      weight for age z-scores. In some regions, socio-economic characteristics of the
      household result in significant differences in the household or community level
      variance in weight for age z-scores, suggesting that the impact of the
      geographical context varies by socio-economic status of the household.

PMID- 15019913
TI  - Neoadjuvant chemoradiotherapy is not associated with a higher complication rate
      vs. surgery alone in patients undergoing esophagectomy.
AB  - Recent studies have claimed a higher rate of perioperative complications related
      to the use of neoadjuvant chemoradiotherapy in the treatment of esophageal
      cancer. We tested the hypothesis that neoadjuvant chemoradiotherapy has no
      significant effect on the perioperative complication rate. Data on 155 patients
      with esophageal carcinoma treated between 1996 and 2001 were collected in a
      prospective database. This included 61 patients (40%) treated with neoadjuvant
      chemoradiotherapy (group I) and 94 patients (60%) who underwent esophagectomy
      alone (group II). Neoadjuvant therapy consisted of two courses of cisplatinum and
      continuous-infusion 5-fluorouracil with radiation followed by esophagectomy. Ivor
      Lewis esophagectomy was performed in 146 (94%) and a transhiatal resection in
      nine (6%). The two groups (I vs. II) were comparable in terms of age (61.3+/-11
      years vs. 64.8+/-11 years), diagnosis (adenocarcinoma: 82% vs. 83%; squamous cell
      carcinoma:11% vs. 16%), and stage (stage 0 to I: 39% vs. 38%; stage II: 25% vs.
      34%; stage III: 30% vs. 24%; and stage IV: 6% vs. 4%). The neoadjuvant group had
      23 complete responses, 11 partial responses, and 27 nonresponses. There were 39
      complications (25.1%) for the cohort, which included three deaths (1.9%) and four
      anastomotic leaks (2.6%) demonstrated by Gastrografin swallow (1 in group I vs. 3
      in group II. Only one leak required reoperation (group II); all others responded
      to conservative treatment. Group I had 14 complications (22.9%) vs. 25 (26.5%) in
      group II (P=NS). Groups were comparable with respect to the rate of pulmonary
      events (4.9% vs. 6.3%), arrhythmias (6.5% vs. 8.5%), and stricture formation
      (6.5% vs. 7.4%). Neoadjuvant chemoradiotherapy in patients with esophageal cancer
      was not associated with increased perioperative morbidity or mortality. Complete
      response to chemoradiotherapy also did not affect the complication rate (26% vs.
      22%).

PMID- 15019914
TI  - Factors affecting quality of life after minimally invasive Heller myotomy for
      achalasia.
AB  - The effect of prior nonoperative treatment, type of fundoplication, and surgical
      approach on quality of life after minimally invasive Heller myotomy (MIHM) for
      achalasia in not known. MIHM for achalasia was performed in 105 patients (primary
      102; redo 3). Sixty-five patients had prior nonoperative treatment (dilations in
      41; botulinum toxin injections in 13; dilations and botulinum toxin injections in
      11). Primary laparoscopic MIHM with fundoplication (Dor in 32; Toupet in 56) was
      performed in 88 patients and thoracoscopic MIHM without fundoplication in 14.
      Achalasia and quality-of-life-related symptoms were evaluated prospectively with
      a visual analogue scoring scale. Median follow-up was 25 months. There was a
      trend toward a higher incidence of intraoperative esophageal perforation and
      recurrent dysphagia in patients with prior nonoperative treatment. Patients with
      prior nonoperative treatment had significant improvement in achalasia-related
      symptoms postoperatively. Patients with prior botulinum toxin injections with or
      without dilations had no improvement in quality of life after MIHM. The operative
      success of MIHM may be compromised if prior nonoperative treatment is used.
      Botulinum toxin injections may blunt the beneficial effect of MIHM on quality of
      life. The outcome of MIHM is good regardless of the type of fundoplication or
      surgical approach.

PMID- 15019915
TI  - Clinicopathologic characteristics of gastric cancer in a young patient
      population.
AB  - The aim of this study was to analyze the clinicopathologic characteristics of
      young patients with gastric cancer with special attention to hereditary gastric
      cancer in a tertiary referral university hospital. Charts from all patients 40
      years of age or younger at the time of diagnosis, during the period from January
      1, 1987 to December 31, 2001, were retrospectively reviewed. Demographic
      variables, family history of gastric cancer, clinicopathologic characteristics,
      and treatment-related variables were analyzed. Overall survival was the main
      outcome variable. Survival curves were constructed by means of the Kaplan-Meier
      method, univariate analysis was performed with the log-rank test, and
      multivariate analysis with Cox regression. Significance was considered at P<0.05.
      During the study period, 558 cases of gastric cancer were seen at our
      institution, 83 (14.8%) were in patients 40 years of age or younger. Mean patient
      age was 33.2 years. Forty-five patients (54.2%) were male. Fourteen patients
      (16.9%) had a family history of gastric cancer. Five patients (6%) fulfilled the
      criteria of hereditary gastric cancer. Surgery was performed in 88% of patients,
      but only 35% of the operations had a curative intent. Operative mortality was
      2.4%. On univariate analysis, advanced tumor stage, hypoalbuminemia, low
      performance status, diffuse type, pangastric tumor location, noncurative surgery,
      and lack of adjuvant chemotherapy had a significant negative impact on survival.
      On multivariate analysis, advanced tumor stage, pangastric tumor location, and
      absence of adjuvant chemotherapy were significantly associated with poor
      prognosis. Family history of gastric cancer or hereditary gastric cancer did not
      have any impact on prognosis. There is a high frequency of gastric cancer in
      young patients at our institution. Most patients present in advanced stages,
      which favors a poor overall survival. Family history of gastric cancer or
      hereditary gastric cancer did not have a significant impact on survival. Complete
      resection and adjuvant chemotherapy appeared to confer the only chance of
      prolonged survival.

PMID- 15019917
TI  - 2003 SSAT-AGA-ASGE Workshop on "Palliative Therapy of Rectal Cancer". Summary
      statement.

PMID- 15019916
TI  - Choledochal cysts in western adults: complexities compared to children.
AB  - Choledochal cysts occur most frequently in East Asian children and rarely in
      Western adults. Over the past two decades, pediatric treatment has been
      standardized, but relatively little information is available on the management of
      Western adults with choledochal cysts. Therefore the aims of this analysis were
      to compare the presentation, management, and late results of Western adults and
      children with choledochal cysts. Records were reviewed of patients with
      choledochal cysts at three academic institutions in Wisconsin. Fifty-seven
      patients were identified, and 51 of these patients (89%) were managed surgically.
      Thirty-one patients (54%) were adults, and the adults were more likely to be male
      (29% vs. 4%, P<0.02). Pain (81% vs. 42%, P<0.01) and cholangitis (35% vs. 15%)
      were more common in adults. Forty-one patients (71%) had type I cysts, but type
      IVa or V cysts with dilated intrahepatic ducts were more common in adults (39%
      vs. 15%, P=0.05). Seventeen adults had undergone biliary surgery prior to
      referral compared to only four children (59% vs. 15%, P<0.01). Preoperative
      endoscopic or percutaneous stents were employed more commonly in adults (42% vs.
      15%, P<0.01). Hospital mortality was 0%, and morbidity was low in both adults and
      children (25% vs. 8%). An associated biliary malignancy correlated with age
      (P<0.05): 0 to 30 years (0%), 31 to 50 years (19%), and 51 to 70 years (50%). In
      addition, adults were more likely to have late problems with cholangitis (19% vs.
      4%, P<0.07) and secondary biliary cirrhosis (13% vs. 4%). This analysis suggests
      that compared to children, Western adults with choledochal cysts are more likely
      to have (1) type IVA or V cysts, (2) undergone prior surgery, (3) preoperative
      biliary stents, (4) an associated biliary malignancy, and (5) late hepatobiliary
      problems. We conclude that surgery in Western adults with choledochal cysts is
      frequently complicated and should be performed by specialists in complex biliary
      surgery.

PMID- 15019918
TI  - Palliative therapy of rectal cancer. Overview: epidemiology, indications, goals,
      extent, and nature of work-up.
AB  - Each year in the United States, it is estimated that there will be 42,000 new
      cases of rectal cancer and 8,500 deaths.(1,2) Some patients present with an
      incurable rectal cancer but more often death follows development of recurrent
      rectal cancer after failed curative-intent therapy. Knowledge of the natural
      history of rectal cancer and limitations of treatment options coupled with sound
      clinical judgment and compassion are essential prerequisites for the clinician
      providing palliative care.

PMID- 15019919
TI  - Indications and surgical alternatives for palliation of rectal cancer.
AB  - The goals of palliation of rectal cancer are relief of disabling symptoms and
      maximizing quality of life. Surgical intervention is appropriate in specific
      situations, where the selected procedure is chosen based on likelihood of
      achieving these goals, balanced against morbidity and recognition of the
      patient's limited life expectancy. Locally unresectable rectal cancer may be
      treated by transanal procedures where obstruction is the major feature;
      techniques used include local resection, self-expanding metal stents, and laser
      debulking of tumor where the rectal lumen is compromised. As well, colostomy may
      be used with or without external beam radiation therapy but is preferred when
      transanal techniques are unsuitable. Resective techniques such as anterior
      proctosigmoidectomy and anastomosis, Hartmann's resection, or abdominoperineal
      rectal excision are preferred in fit patients where local clearance is possible
      and longevity expectations are deemed reasonable--e.g., six months or more.
      Decisions for performing restorative procedures are based on risk assessment for
      anastomotic leak and quality of anal function. In rare cases, palliative
      exenteration is an option, although controversial. Recognition of
      contraindications to resection will minimize the risk of disabling or lethal
      complications of these procedures.

PMID- 15019921
TI  - Endoscopic methods (other than stents) for palliation of rectal carcinoma.
AB  - Patients with unresectable or metastatic rectal cancer may have symptoms of
      obstruction, bleeding, pain, or tenesmus. Insertion of a self-expandable metal
      stent is the most durable nonsurgical method for relieving obstruction and has
      been reviewed in the previous article. Other endoscopic methods of palliating
      obstruction have been largely replaced by expandable metal stent placement.
      However, laser ablation is still a useful therapy for some patients, particularly
      when the predominant symptom is rectal bleeding. The indications and results of
      endoscopic laser therapy along with other endoscopic treatments for the
      palliation of rectal cancer will be reviewed here.

PMID- 15019920
TI  - Indications and results of endoscopic rectal stenting.
AB  - Self expandable metal stents (SEMS) are a useful option to diverting colostomy
      for the palliation of malignant rectal obstruction. SEMS can be successfully
      placed in approximately 90% of cases with acceptable complication rates. Covered
      SEMS allow closure of malignant rectovaginal and rectovesical fistulae associated
      with rectal obstruction. The main drawback to these devices is the inability to
      palliate bleeding.

PMID- 15019922
TI  - Palliative management of rectal cancer: the roles of chemotherapy and radiation
      therapy.
AB  - One of the first maxims of oncologic care is that we must never miss an
      opportunity to cure a patient. Perhaps an equally important corollary is that to
      provide the best possible care for each individual, it is necessary to accurately
      recognize when a curative option does not exist and to adjust our treatment
      recommendations accordingly. A discussion of palliative care in a patient with
      rectal cancer must therefore be based on the assumption that the patient does not
      have a realistic chance of undergoing a curative intervention.

PMID- 15019923
TI  - Palliative treatment of rectal cancer: is radiotherapy alone a good option?

PMID- 15019925
TI  - Does "clonal progression" relate to the development of intraductal papillary
      mucinous tumors of the pancreas?
AB  - Intraductal papillary mucinous tumors of the pancreas show a unique histologic
      feature in that the wide spectrum of intraductal epithelium is observed in the
      same pancreas. The aim of this study was to clarify whether or not the "clonal
      progression" relates to the development of this tumor. A total of 210 intraductal
      epithelium samples were microdissected from 23 resected specimens of intraductal
      papillary mucinous tumors of the pancreas, including nine carcinomas, five
      borderline tumors, and nine adenomas. After histologic grading (grades 1 to 4) of
      the individual epithelium, the K-ras point mutation and loss of heterozygosity in
      9p21(p16) and 17p13(p53) were investigated. From the distribution of the K-ras
      point mutation of 210 microdissected specimens, an identical sequence of K-ras
      was demonstrated in the precursor lesions in most cases. K-ras mutation showed a
      single pattern, and the multiple or heterogeneous mutation pattern was not seen
      in this study. In the same ways, the distribution of loss of heterozygosity in
      9p21(p16) and 17p13(p53) of 210 microdissected specimens was shown to be mostly
      clonal, without the presence of the genetic alterations. Such distributions of
      the identical genetic statuses in the precursor lesions are consistent with the
      presence of clonal progression during the development of this tumor.

PMID- 15019927
TI  - Hilar cholangiocarcinoma.
AB  - Cancer of the biliary tree, including those occurring at the major biliary
      bifurcation (Klatskin's tumor), is an uncommon malignancy. Meaningful experience
      with these tumors has been limited to a few centers. Recent reports with
      increasing numbers of patients have allowed the construction of rational
      approaches to these patients. It is clear from these reports that complete
      resection with negative histologic margins is the only treatment that offers the
      possibility of long-term survival. Complete resection of hilar
      cholangiocarcinomas remains a technically demanding procedure requiring expertise
      in biliary and hepatic surgery. Patients with unresectable disease constitute a
      distinct majority and have traditionally been very difficult to successfully
      palliate and impossible to cure. A panel of hepatobiliary surgeons experienced in
      the management of hilar cholangiocarcinoma presented a symposium on issues
      relating to these patients at the recent joint American Hepato-Pancreato-Biliary
      Association/American Association for the Study of Liver Diseases (AHPBA-AASLD)
      forum in Boston, MA. The report below offers a summarization of the main points
      and comments raised by this panel. These summarizations are not meant as an
      exhaustive review and primarily reflect the opinions of the speakers based upon
      their experiences and interpretation of the existing literature.

PMID- 15019924
TI  - Predicting resectability of periampullary cancer with three-dimensional computed
      tomography.
AB  - The radiographic assessment of extent of tumor burden and local vascular invasion
      appears to be enhanced with three-dimensional computed tomography (3D-CT). The
      purpose of this study was to evaluate the impact of preoperative 3D-CT in
      determining the resectability of patients with periampullary tumors.
      Intraoperative findings from exploratory laparotomy were gathered prospectively
      from 140 patients who were thought to have periampullary tumors and were deemed
      resectable after undergoing preoperative 3D-CT imaging. CT findings were compared
      to intraoperative findings, and the accuracy of 3D-CT in predicting tumor
      resectability and, ultimately, the likelihood of obtaining a margin-negative
      resection were assessed. Of the 140 patients who were thought to have resectable
      periampullary tumors after preoperative 3D-CT, 115 (82%) were subsequently
      determined to have periampullary cancer. The remaining 25 patients had benign
      disease. Among the patients with periampullary cancer, the extent of local tumor
      burden involving the pancreas and peripancreatic tissues was accurately depicted
      by 3D-CT in 93% of the patients. 3D-CT was 95% accurate in determining cancer
      invasion of the superior mesenteric vessels. Preoperative 3D-CT accurately
      predicted periampullary cancer resectability and a margin-negative resection in
      98% and 86% of patients, respectively. For patients with pancreatic
      adenocarcinoma (n=85), preoperative 3D-CT resulted in a resectability rate and a
      margin-negative resection rate of 79% and 73%, respectively. The ability of 3D-CT
      to predict a margin-negative resection for periampullary cancer, including
      pancreatic adenocarcinoma, relies on its enhanced assessment of the extent of
      local tumor burden and involvement of the mesenteric vascular anatomy.

PMID- 15019928
TI  - Adult-adult living donor liver transplantation.
AB  - After the first report from Denver in 1998 of a successful liver transplant in an
      adult using the right lobe from a living donor, the procedure was rapidly adopted
      by many transplant centers as a potential solution to the critical shortage of
      donor livers. By the end of 2000, when the National Institutes of Health held a
      Consensus Conference on Adult-Adult Living Donor Transplantation (AALDT), a
      substantial body of literature had already developed and many of the associated
      technical and medical pitfalls had been defined. The exponential expansion of the
      procedure came to a dramatic halt in January 2002 when the death of a donor
      occurred at Mount Sinai Hospital--the busiest AALDT center in the United States.
      This led to a widespread reassessment of the risks inherent in right lobe
      donation. Yet, the problem that drove the development of this controversial
      technique--the dire shortage of organs for transplantation--still persists. After
      a 50% drop in the number of AALDT procedures performed in the United States in
      2002 compared with 2001, centers are regrouping and approaching AALDT with
      renewed interest, albeit with heightened awareness of the attendant risks. On
      November 2, 2002, a state-of-the-art symposium on AALDT was held in Boston, MA,
      under the combined auspices of the American Hepatico-Pancreato-Biliary
      Association and the American Association for the Study of Liver Diseases. This
      article comprises the presentations at the symposium on three subjects of
      critical importance concerning AALDT. These include advances in surgical
      technique, candidate selection, and hepatic regeneration; each subject is
      acknowledged by an expert in the field.

PMID- 15019930
TI  - Preoperative lower esophageal sphincter pressure affects outcome of laparoscopic
      esophageal myotomy for achalasia.
AB  - The primary aim of this study was to identify factors that influence outcome of
      the surgical treatment of achalasia. A secondary aim was to compare outcomes
      after laparoscopic Heller myotomy and partial fundoplication using either a Dor
      or Toupet hemifundoplication. Between 1994 and 2002, a total of 78 patients
      underwent laparoscopic Heller myotomy and partial fundoplication. Preoperative
      investigations included esophageal manometry, a videoesophogram, and upper
      gastrointestinal endoscopy with biopsy. In 64 patients (35 males and 29 females),
      telephone contact was possible at a median 24 months (IQR 14-34). A Dor
      fundoplication was performed in 41 patients and a Toupet fundoplication in 23.
      Symptoms were assessed prior to surgery and at follow-up by an independent
      physician using standardized definitions to grade the severity of dysphagia,
      regurgitation, and chest pain. To assess outcome, dysphagia was categorized as
      persistent or resolved. Persistent was defined as dysphagia that occurred on a
      weekly or daily basis. Resolved was defined as dysphagia that occurred
      occasionally or not at all. At follow-up, patients were asked to make a personal
      evaluation of their outcome as to whether (1) their swallowing was improved by
      the procedure, (2) they were satisfied with the outcome, and (3) they would
      undergo surgery again under the same circumstances. There was a significant
      improvement in dysphagia and regurgitation scores after surgery (P<0.05). The
      scores for chest pain/heartburn remained unchanged. By physician assessment,
      dysphagia was resolved in 49 patients (77%) and persisted in 15 (33%). By patient
      assessment, 62 patients (97%) reported an improvement in the symptom of
      dysphagia, and 60 (94%) stated that they were satisfied with their improvement
      and would undergo surgery if they had to make the choice again. On univariate
      analysis, patients who had resolution of their dysphagia had a significantly
      higher resting lower esophageal sphincter (LES) pressure prior to myotomy
      (P=0.01) and on multivariate analysis only a high resting LES pressure prior to
      surgery was a predictor of resolution of dysphagia (P=0.015). Outcome comparison
      of patients with Dor and Toupet fundoplications showed no significant differences
      in physician assessment of postoperative symptom scores and resolution of
      dysphagia, patient assessment of outcome, or postoperative use of proton pump
      inhibitors. Ninety-four percent of patients are satisfied with their surgical
      myotomy for achalasia. By physician assessment dysphagia was resolved in 77% of
      patients. A high LES resting pressure before surgery predicted resolution of
      dysphagia.

PMID- 15019931
TI  - Effects of manometrically discovered nonspecific motility disorders of the
      esophagus on the outcomes of antireflux surgery.
AB  - Nonspecific motility disorders (NMDs) of the esophagus are common manometric
      findings in patients evaluated for gastroesophageal reflux disease (GERD).
      However, it is unclear how these disorders affect the outcomes of antireflux
      surgery. The purpose of this study was to assess symptomatic outcomes of patients
      with and without NMDs undergoing surgical treatment for GERD. A prospectively
      gathered database of all patients undergoing antireflux surgery was
      retrospectively reviewed for preoperative symptoms, symptom severity using the
      GERD-HRQL (best score 0, worst score 50), esophageal manometry measurements,
      presence of NMD, type of operation, any transient or permanent postoperative
      dysphagia, severity of postoperative dysphagia (best score 0, worst score 5), and
      postoperative symptom severity. A total of 239 patients were studied; 24% had a
      NMD identified by preoperative esophageal manometry, and 17% of this +NMD group
      had preoperative dysphagia or atypical chest/epigastric pain compared to 28% of
      those without a NMD (-NMD group) (P=NS). Preoperative symptom scores were +NMD 33
      vs. -NMD 27 (P=0.01). Postoperative symptom scores were +NMD 5 vs. -NMD 3 (P=NS).
      There were no differences in preoperative or postoperative dysphagia scores.
      Transient postoperative dysphagia was 15.8% in the +NMD group vs. 16.4% in the 
      NMD group (P=NS). Postoperative dilation was 0% in the +NMD group vs. 2% in the 
      NMD group (P=NS). Manometrically discovered NMDs do not appear to affect
      preoperative symptoms or symptomatic outcomes of patients surgically treated for
      GERD. These findings my reflect the severity of GERD and may improve with
      antireflux surgery.

PMID- 15019929
TI  - Protection of the liver during hepatic surgery.
AB  - Very few areas in medicine have seen as many controversies as the evaluation and
      treatment of patients with liver diseases. Many novel therapies, often marketed
      before conclusive demonstration of their efficacy, have been developed to enable
      selective destruction of liver tumors to minimize the risk of liver failure
      associated with major surgery. Whether these techniques are effective and result
      in lesser complications often remains speculative. Persisting challenges in
      selecting the optimal therapy are the evaluation of the risk of surgery in
      patients with normal or diseased liver and the preparation for surgery. A panel
      of hepato-biliary surgeons experienced in the management of complex cases
      convened at the annual meeting of the American Hepato-Pancreato-Biliary
      Association in Boston, MA, to address the rapidly evolving field of protective
      strategies for hepatic surgery.

PMID- 15019932
TI  - Lymphoepithelial cysts of the pancreas: case report and review of the literature.
AB  - The aim of this report was to describe the clinical and pathologic features of
      lymphoepithelial cysts of the pancreas, establish the differential diagnosis of
      other pancreatic cysts, and review the literature. A 53-year-old man was
      incidentally diagnosed with a pancreatic lesion after an abdominal CT scan. This
      study showed a solid mass in the tail of the pancreas not enhanced by helical CT.
      Endoscopic ultrasound examination revealed a low-density tissue mass on the
      surface of the pancreas, less echogenic than the surrounding parenchyma. Distal
      pancreatectomy and splenectomy were performed with a suspected diagnosis of
      mucinous cystic tumor. The patient has had an uneventful postoperative period,
      and the pathologic finding was a lymphoepithelial cyst of the pancreas.
      Lymphoepithelial cyst of the pancreas is an unusual and benign entity that must
      be taken into consideration when evaluating a cystic lesion of the pancreas
      because a different therapeutic approach may be required.

PMID- 15019933
TI  - The role and interactions of nitric oxide (NO), carbon monoxide (CO), and
      prostanoids in the pathogenesis of postoperative ileus in rats.
AB  - The effects of heme oxygenase (HO) inhibitors, zinc-protoporphyrin-IX (ZnPP-IX),
      and tin protoporphyrin-IX (SnPP-IX) and their interactions with L-arginine/nitric
      oxide synthase (NOS) and cyclooxygenase (COX) pathways were investigated in
      postoperative ileus in rats. Intestinal transit was measured as Evans blue
      migration after skin incision, laparotomy or laparotomy plus gut evisceration and
      handling. Laparotomy and small intestinal manipulations increased blood plasma
      nitrites/nitrates level 1.88-fold. N(omega)-nitro-L-arginine methyl ester,
      indomethacin, a selective COX-1 blocker (resveratrol) and COX-2 antagonists
      (nimesulide, DuP-697, NS-398) reversed the additional inhibitory effects of gut
      manipulation subsequent to laparotomy. In contrast, N-(3
      (aminomethyl)benzyl)acetamidine or S-methylisothiourea, highly selective
      inducible NOS blockers, remained ineffective. ZnPP-IX and SnPP-IX overturned the
      effects of laparotomy on dye propulsion, but were only partially effective after
      laparotomy and gut handling attenuating the additional inhibitory influences of
      gut manipulation, the intestinal transit reaching 89.21%, 92.87%, 53.46%, and
      48.56% of respective controls transit. Salutary effects of L-NAME, ZnPP-IX, and
      SnPP-IX were dose-dependent, L-arginine or hemin (HO substrate) sensitive.
      Administration of indomethacin and resveratrol subsequent to SnPP-IX reversed the
      inhibitory effects of laparotomy and manipulation, amounting to 93.91% and 87.43%
      of controls. On the other hand, L-NAME injected after SnPP-IX abolished the
      salutary effects of the latter, study dye migration reached 25.18% of control
      rat. Therefore we demonstrated that nitric oxide, carbon monoxide, and
      prostanoids play a role in the pathogenesis of postoperative ileus albeit in
      different mechanisms. Laparotomy stimulated HO activity, whereas gut manipulation
      led to an excessive constitutive NOS stimulation accompanied by augmented
      prostanoid synthesis by COX-1. Unaffected synthesis of either NO or CO enables a
      return of gastrointestinal transit during postoperative period, whereas a
      pharmacological blockade of two complementary metabolic pathways provides a most
      effective measure against postoperative ileus development.

PMID- 15019934
TI  - Successful perioperative management of factor X deficiency associated with
      primary amyloidosis.
AB  - Acquired bleeding abnormalities are common in patients with primary amyloid light
      chain amyloidosis. Factor X deficiency is the most common coagulopathy associated
      with life-threatening hemorrhagic complications when surgery is indicated. Fresh
      frozen plasma (FFP) or prothrombin complex concentrates (PCCs) are the most
      frequently used blood products in this disease; however, FFP is often ineffective
      in controlling bleeding and PCCs have a significant risk of thrombosis when used
      intraoperatively. This report describes a patient with primary amyloidosis and
      factor X deficiency who underwent hemicolectomy with preoperative and
      intraoperative administration of recombinant human factor VIIa and postoperative
      administration of Bebulin (a PCC that contains the highest concentration of
      factor X). The management was successful with no signs of bleeding
      postoperatively. To our knowledge, few reports of successful perioperative
      management of factor X deficiency have been published to date. This is the first
      case report using recombinant human factor VIIa and Bebulin in the perioperative
      management of factor X deficiency associated with primary amyloidosis.
      Recombinant human factor VIIa and Bebulin may allow for successful perioperative
      management of bleeding disorders in patients with primary amyloidosis.

PMID- 15019935
TI  - DiO-labeled CC531s colon carcinoma cells traverse the hepatic sinusoidal
      endothelium via the Fas/FasL pathway.

PMID- 15019937
TI  - Agrin-induced AChR aggregate formation requires cGMP and aggregate maturation
      requires activation of cGMP-dependent protein kinase.
AB  - Previously, it was demonstrated that agrin acting through the gaseous, signaling
      molecule, nitric oxide (NO), induces the formation of AChR aggregates on myotubes
      in culture. Soluble guanylyl cyclase (sGC), which is present at the neuromuscular
      junction, is a common target of NO. Therefore, we hypothesized that sGC and cGMP
      are involved in the agrin signaling cascade. Inhibition of sGC hindered AChR
      aggregation in both agrin- and NO donor-treated cultured myotubes; whereas, a
      cGMP analogue was able to induce the formation of AChR aggregates on naive muscle
      cells. Due to the presence of cyclic GMP-dependent protein kinase (PKG) at the
      neuromuscular junction, we tested the ability of a PKG inhibitor to alter the
      agrin signaling cascade. PKG inhibition did not prevent nascent AChR aggregate
      formation; however, these aggregates were diffuse and composed of numerous
      microaggregates consistent with incomplete maturation. Thus, we conclude that
      cGMP is important for the initiation of AChR aggregation, while PKG is involved
      in the maturation of AChR aggregates.

PMID- 15019938
TI  - Identification of two NOGO/RTN4 genes and analysis of Nogo-A expression in
      Xenopus laevis.
AB  - Myelin-associated axon growth inhibitors such as Nogo-A/RTN4-A impair axon
      regeneration in the adult mammalian central nervous system (CNS). Here, we
      describe the cloning and expression of two independent Xenopus laevis rtn4
      orthologs. As in mammals, alternative transcripts are generated both through
      differential splicing and promoter usage, giving rise to Xenopus nogo-A, -B, -C
      and to a new isoform, nogo-N/rtn4-N. Xenopus is therefore the 'lowest' vertebrate
      where Nogo-A was identified. Xenopus Nogo-A/RTN4-A is predominantly expressed in
      the nervous system, whereas the other isoforms mainly occur in nonneuronal
      tissues. Nogo-A/RTN4-A specific antisera detect the protein in myelinated fiber
      tracts of the spinal cord, hindbrain, optic nerve, tectum opticum and in isolated
      oligodendrocytes. In addition, subpopulations of CNS neurons are Nogo-A/RTN4-A
      positive. This expression pattern is consistent with that observed for rat Nogo-A
      and suggests similar functions. Nogo-A in Xenopus myelin might therefore
      contribute to the failure of spinal cord regeneration in frogs-a feature that may
      have evolved during the transition from fish to land vertebrates.

PMID- 15019939
TI  - Developmental regulation of notochord-derived repulsion for dorsal root ganglion
      axons.
AB  - During the initial stages of development, the notochord provides repulsive
      signals for dorsal root ganglion (DRG) axons via semaphorin 3A/neuropilin-1,
      axonin-1/SC2, and other unknown repulsive molecules. The notochord is known to
      produce aggrecan, one of the chondroitin sulfate proteoglycans (CSPGs). We report
      here that adding aggrecan to the culture medium cannot only induce DRG growth
      cone collapse, but also inhibit DRG axonal growth. Using cocultures composed of
      tissues derived from chick embryos or neuropilin-1-deficient mice treated with
      chondroitinase ABC, we show the direct evidence that CSPGs are involved in
      notochord-derived repulsion for DRG axons. At later developmental stages, CSPGs
      are involved in perinotochordal sheath-derived axon repulsion, but not in
      notochord core-derived repulsion. We further demonstrate that TAG-1/axonin-1/SC2
      is not involved in mediating repulsive activities by CSPGs, but is required for
      notochord core-derived axon repulsion. Thus, notochord-derived multiple axon
      repulsions act in a spatiotemporal-specific manner to shape the initial
      trajectories of DRG axons.

PMID- 15019940
TI  - Dual phases of migration of cerebellar granule cells guided by axonal and
      dendritic leading processes.
AB  - During lamination of the cerebellar cortex, granule cells initially migrate
      tangentially along the external granule layer, and then make a vertical turn and
      migrate radially to the internal granule layer. We comparatively analyzed the
      properties of biphasic migration of granule cells in a microexplant culture in
      which quantitation of morphology and subcellular localization of molecules were
      readily accomplished. Tangential migration was guided by a leading process that
      later formed a parallel fiber axon. Translocation of the soma within the axonal
      process occurred independently of the rapid displacement of the large growth
      cone. On the other hand, radial migration was guided by a leading process that
      differentiated into a dendrite after completion of migration. Displacement of the
      soma and the tiny growth cone were linked so that the radial leading process
      adopted locomotion and kept a constant length. We propose that the dual phases of
      granule cell migration are achieved by distinct cellular mechanisms guided by the
      leading processes forming an axon and a dendrite, respectively.

PMID- 15019942
TI  - Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in
      adult CNS and their response following CNS demyelination.
AB  - To design therapies for demyelinating diseases such as multiple sclerosis, it
      will be important to understand the mechanisms that control oligodendrocyte
      progenitor cell (OPC) numbers in the adult central nervous system (CNS). During
      development, OPC numbers are limited by the supply of platelet-derived growth
      factor-A (PDGF-A). Here, we examine the role of PDGF-A in regulating OPC numbers
      in normal and demyelinated adult CNS using transgenic mice that overexpress PDGF
      A in astrocytes under the control of the glial fibrillary acidic protein (GFAP)
      gene promoter (GFAP-PDGF-A mice). In adult GFAP-PDGF-A mice, there was a marked
      increase in OPC density, particularly in white matter tracts, indicating that the
      PDGF-A supply controls OPC numbers in the adult CNS as well as during
      development. To discover whether increasing PDGF expression increases the number
      of OPCs following demyelination and whether this enhances the efficiency of
      remyelination, we induced demyelination in GFAP-PDGF-A transgenic mice by
      intraspinal injection of lysolecithin or dietary administration of cuprizone. In
      both demyelinating models, OPC density within lesions was significantly increased
      compared to wild-type mice. However, morphological analysis of lysolecithin
      lesions did not reveal any difference in the time course or extent of
      remyelination between GFAP-PDGF-A and wild-type mice. We conclude that the
      availability of OPCs is not rate limiting for remyelination of focal demyelinated
      lesions in the mouse. Nevertheless, our experiments show that it is possible to
      increase OPC population density in demyelinated areas by artificially increasing
      the supply of PDGF.

PMID- 15019941
TI  - Schwann cells and astrocytes induce synapse formation by spinal motor neurons in
      culture.
AB  - Glia constitute 90% of cells in the human nervous system, but relatively little
      is known about their functions. We have been focusing on the potential synaptic
      roles of glia in the CNS. We recently found that astrocytes increase the number
      of mature, functional synapses on retinal ganglion cells (RGCs) by sevenfold and
      are required for synaptic maintenance in vitro. These observations raised the
      question of whether glia similarly enhance synapse formation by other neuron
      types. Here we have investigated whether highly purified motor neurons isolated
      from developing rat spinal cords are able to form synapses in the absence of glia
      or whether glia similarly enhance synapse number. We show that spinal motor
      neurons (SMNs) form few synapses unless Schwann cells or astrocytes are present.
      Schwann cells increase the number of functional synapses by ninefold as measured
      by immunostaining, and increase spontaneous synaptic activity by several
      hundredfold. Surprisingly, the synapses formed between spinal motor neurons were
      primarily glutamatergic, as they could be blocked by CNQX. This synapse-promoting
      activity is not mediated by direct glial-neuronal cell contact but rather is
      mediated by secreted molecule(s) from the Schwann cells, as we previously found
      for astrocytes. Interestingly, the synapse-promoting activity from astrocytes and
      Schwann cells was functionally similar: Schwann cells also promoted synapse
      formation between retinal ganglion cells, and astrocytes promoted synapse
      formation between spinal motor neurons. These studies show that both astrocytes
      and Schwann cells strongly promote synapse formation between spinal motor neurons
      and demonstrate that glial regulation of synaptogenesis extends to other neuron
      types.

PMID- 15019943
TI  - Identification and characterization of two novel brain-derived immunoglobulin
      superfamily members with a unique structural organization.
AB  - We recently used a differential display PCR screen to identify secreted and
      transmembrane proteins that are highly expressed in the developing rat basilar
      pons, a prominent ventral hindbrain nucleus used as a model for studies of
      neuronal migration, axon outgrowth, and axon-target recognition. Here we describe
      cloning and characterization of one of these molecules, now called MDGA1, and a
      closely related homologue, MDGA2. Analyses of the full-length coding region of
      MDGA1 and MDGA2 indicate that they encode proteins that comprise a novel subgroup
      of the Ig superfamily and have a unique structural organization consisting of six
      immunoglobulin (Ig)-like domains followed by a single MAM domain. Biochemical
      characterization demonstrates that MDGA1 and MDGA2 proteins are highly
      glycosylated, and that MDGA1 is tethered to the cell membrane by a GPI anchor.
      The MDGAs are differentially expressed by subpopulations of neurons in both the
      central and peripheral nervous systems, including neurons of the basilar pons,
      inferior olive, cerebellum, cerebral cortex, olfactory bulb, spinal cord, and
      dorsal root and trigeminal ganglia. Little or no MDGA expression is detected
      outside of the nervous system of developing rats. The similarity of MDGAs to
      other Ig-containing molecules and their temporal-spatial patterns of expression
      within restricted neuronal populations, for example migrating pontine neurons and
      D1 spinal interneurons, suggest a role for these novel proteins in regulating
      neuronal migration, as well as other aspects of neural development, including
      axon guidance.

PMID- 15019944
TI  - Metabotropic glutamate receptor signalling in perirhinal cortical neurons.
AB  - Long-term depression (LTD) induction relies upon receptor cross-talk between
      group I and group II metabotropic glutamate receptors (mGluRs) in perirhinal
      cortex. The molecular mechanism of this mGluR interplay is not clear. Here, we
      show that the mGluR subtypes postulated to be involved in this mechanism are
      developmentally regulated and mGluR2 has a preferential role over mGluR3 in the
      synergistic interaction with mGluR5. We have identified a >70% reduction in basal
      cAMP levels following mGluR2 stimulation, which could lead to increased mGluR5
      function via reduced PKA mediated phosphorylation and decreased desensitisation
      of mGluR5. To further investigate the roles of mGluRs in downstream intracellular
      signalling, we have examined the effects of mGluRs on the phosphorylation state
      of cAMP response element-binding protein (CREB). Both group I and group II
      agonists increased the phosphorylation of CREB, which indicates a cAMP- and PKA
      independent signalling mechanism. These results suggest a convergence of
      signalling mechanisms from surface mGluRs to CREB-mediated transcription.

PMID- 15019945
TI  - Neurturin signalling via GFRalpha2 is essential for innervation of glandular but
      not muscle targets of sacral parasympathetic ganglion neurons.
AB  - Neurturin, a member of the glial cell-derived neurotrophic factor familys of
      ligands, is important for development of many cranial parasympathetic ganglion
      neurons. We have investigated the sacral component of the parasympathetic nervous
      system in mice with gene deletions for neurturin or its preferred receptor,
      GFRalpha2. Disruption of neurturin signalling decreased cholinergic VIP
      innervation to the mucosa of the reproductive organs, but not to the smooth
      muscle layers of these organs or to the urinary bladder. Thus, neurturin and its
      receptor are involved in parasympathetic innervation of a select group of pelvic
      visceral tissues. In contrast, noradrenergic innervation was not affected by the
      gene ablations. The epithelium of reproductive organs from knockout animals was
      atrophied, indicating that cholinergic innervation may be important for the
      maintenance of normal structure. Cholinergic neurons express GFRalpha2 on their
      terminals and somata, indicating they can respond to neurotrophic support, and
      their somata are smaller when neurturin signalling is disrupted. Colocalisation
      studies showed that many peripheral glia express GFRalpha2 although its role in
      these cells is yet to be determined. Our results indicate that neurturin, acting
      through GFRalpha2, is essential for parasympathetic innervation of the mucosae of
      reproductive organs, as well as for maintenance of a broader group of sacral
      parasympathetic neurons.

PMID- 15019946
TI  - Prevention of neuron and oligodendrocyte degeneration by interleukin-6 (IL-6) and
      IL-6 receptor/IL-6 fusion protein in organotypic hippocampal slices.
AB  - We investigated the effects of IL-6 and a chimeric derivative of IL-6 and soluble
      IL-6 receptor (IL6RIL6 chimera) on excitotoxic injury in rat organotypic
      hippocampal slices. Brief application of N-methyl-d-aspartate (NMDA) induced
      astrocyte reactivity, neuron cell death, and oligodendrocyte degeneration, the
      latter caused by secondary activation of AMPA/kainate receptors. Both these
      cytokines rescued neurons and oligodendrocytes, albeit the chimeric compound was
      much more potent and efficient than IL-6. No change was produced on reactive
      astrocytosis. The cytokines preserved myelin basic protein (MBP) production in
      slices exposed to excitotoxic insult, and when applied singularly for a week,
      they also enhanced both MBP and proteolipid protein expression. These effects
      occurred through activating the signal transducer gp130 and were associated with
      stimulation of transcription factors STAT1 and STAT3. Our results suggest that IL
      6 and IL6RIL6 may prove to be valuable in treating neurodegenerative and
      demyelinating diseases.

PMID- 15019947
TI  - Microglia express GABA(B) receptors to modulate interleukin release.
AB  - gamma-Aminobutyric acid (GABA) can act as a neuroprotective agent besides its
      well-established role as the main inhibitory neurotransmitter in the CNS. Here we
      report that microglial cells express GABA(B) receptors indicating that these
      prominent immunocompetent cells in the brain are a target for GABA. Agonists of
      GABA(B) receptors triggered the induction of K(+) conductance in microglial cells
      from acute brain slices and in culture. Both subunits of GABA(B) receptors were
      identified in cultured microglia by Western blot analysis and
      immunocytochemistry, and were detected on a subpopulation of microglia in situ by
      immunohistochemistry. In response to facial nerve axotomy, we observed an
      increase in GABA(B) receptor expressing microglial cells in the facial nucleus.
      We activated microglial cells in culture with lipopolysaccharide (LPS) to induce
      the release of interleukin-6 and interleukin-12p40. This release activity was
      attenuated by simultaneous activation of the GABA(B) receptors indicating that
      GABA can modulate the microglial immune response.

PMID- 15019949
TI  - Ca(2+)-independent spine dynamics in cultured hippocampal neurons.
AB  - Developing spines are highly dynamic processes that undergo rapid morphologic
      changes. We have investigated whether basal developmentally regulated spine
      motility is triggered by spontaneous changes in intracellular Ca(2+)
      ([Ca(2+)](i)). To address the link between Ca(2+) transients and motility, we
      have used the cell-permeable chelator BAPTA-AM. Consistent with others, we found
      that young cultured hippocampal neurons [7-13 days in vitro (DIV)] display
      significantly more spine motility than older neurons (14-21 days in vitro).
      Control experiments indicate that BAPTA-AM can lower basal [Ca(2+)](i) as well as
      block synaptically mediated Ca(2+) transients. However, globally buffering
      [Ca(2+)](i) by BAPTA-AM treatment failed to significantly alter the basal
      motility of developing spines measured at either relatively slow (5 min) or
      faster sampling times (every 20 s). We conclude that the basal spine motility of
      cultured hippocampal neurons may represent an intrinsic feature of developing
      neurons and is not necessarily choreographed by ongoing changes in [Ca(2+)](i)
      levels.

PMID- 15019948
TI  - Hedgehog interacting protein in the mature brain: membrane-associated and soluble
      forms.
AB  - Hedgehog interacting protein (Hip) is considered as a membrane protein implicated
      in sequestering the hedgehog (hh) morphogens during embryonic development. Here,
      we demonstrate that Hip transcription also occurs in cells scattered in discrete
      brain areas of adult rodents and we identify the presence of membrane-associated
      and soluble forms of Hip in the mature brain. Moreover, we show that soluble
      forms of Hip, present in the conditioned medium of HEK293 cells overexpressing
      Hip, inhibit Sonic hedgehog (Shh)-induced differentiation of C3H10T1/2 cells, a
      well-characterised response associated with Shh signalling. After transfection in
      HEK293 cells, Hip partitions with the raft component ganglioside GM1 during
      density gradient centrifugation. Analysis of tagged Hip constructs reveals that
      the putative transmembrane domain of Hip is not cleaved suggesting that other
      mechanisms are implicated in the release of its soluble forms. Taken together,
      these data are consistent with the involvement of both membrane-associated and
      soluble Hip in the regulation of Shh signalling in adult neural tissues.

PMID- 15019950
TI  - Blocked MAP kinase activity selectively enhances neurotrophic growth responses.
AB  - Bone morphogenetic proteins (BMPs) 4 and 6 as well as MEK inhibitors PD98059 and
      U0126 potentiate neurotrophin 3 (NT3)- and neurturin (NTN)-induced neurite
      outgrowth and survival of peripheral neurons from the E9 chicken embryo.
      Preexposure to BMP4 or PD98059 was sufficient to prime the potentiation of
      subsequently added NT3. Phosphorylation of Erk2, induced by NT3, was reduced by
      MEK inhibition but unaffected by BMP signaling. Real-time PCR showed that neither
      BMP stimulation nor MEK inhibition increased Trk receptor expression and that the
      BMP-induced genes Smad6 and Id1 were not upregulated by PD98059. In contrast,
      both MEK inhibition and BMP signaling suppressed transcription of the serum
      response element (SRE)-driven Egr1 gene. A reporter assay using NGF-stimulated
      PC12 cells demonstrated that MEK/Erk/Elk-driven transcriptional activity was
      inhibited by Smad1/5 and by PD98059. Thus, suppression of SRE-controlled
      transcription represents a likely convergence point for pathways regulating
      neurotrophic responses.

PMID- 15019951
TI  - Prenatal stress, moderate fetal alcohol, and dopamine system function in rhesus
      monkeys.
AB  - This study examined the striatal dopamine system integrity and associated
      behavior in 5- to 7-year-old rhesus monkeys born from mothers that experienced
      stress and/or consumed moderate levels of alcohol during pregnancy. Thirty-one
      young adult rhesus monkeys were derived from females randomly assigned to one of
      four groups: (1) control group that consumed isocaloric sucrose solution
      throughout gestation; (2) stress group that experienced prenatal stress (10-min
      removal from home cage and exposure to three random loud noise bursts,
      gestational days 90 through 145); (3) alcohol group that consumed alcohol (0.6
      g/kg/day) throughout gestation; or (4) combined alcohol plus stress group that
      received both treatments. The subjects were assessed for striatal dopamine system
      function using positron emission tomography (PET), in which the dopamine (DA)
      rich striatum was evaluated in separate scans for the trapping of [(18)F]
      Fallypride (FAL) and 6-[(18)F]fluoro-m-tyrosine (FMT) to assess dopamine D2
      receptor binding potential (BP) and DA synthesis via dopa decarboxylase activity,
      respectively. Subjects were previously assessed for non-matching-to-sample (NMS)
      task acquisition, with ratings of behavioral inhibition, stereotypies, and
      activity made after each NMS testing session. Subjects from prenatal stress
      conditions (Groups 2 and 4) showed an increase in the ratio of striatal dopamine
      D2 receptor BP and DA synthesis compared to controls (Group 1). An increase in
      the radiotracer distribution volume ratios (DVRs), which is used to evaluate the
      balance between striatal DA synthesis and receptor availability, respectively,
      was significantly correlated with less behavioral inhibition. The latter supports
      a hypothesis linking striatal function to behavioral inhibitory control.

PMID- 15019952
TI  - Gestational exposure to methylmercury retards choice in transition in aging rats.
AB  - Developmental exposure to methylmercury has behavioral effects that extend into
      adulthood and aging. In this study, methylmercury's prolonged effects on the
      acquisition of choice and sensitivity to changes in reinforcement rates were
      studied. Pregnant female rats were exposed to drinking water containing 0, 0.5,
      or 6.4 ppm Hg as methylmercury, resulting in about 40 and 500 microg/kg/day of
      mercury intake. Maternal exposure began at least 4 weeks before mating, and
      continued to postnatal day 16. Then all mercury exposure ended. The behavior of
      1.7- and 2.3-year-old offspring was maintained under various concurrent schedules
      of reinforcement. Thus, one reinforcement schedule maintained left-lever
      responding and a separate one maintained right-lever responding. The animal could
      switch ("changeover") between the two levers at any time. For the first 30 min of
      a 3-h session, the left and right levers each produced reinforcement at the same
      rate and left:right response ratios were about 1:1. After 30 min, either the left
      lever became richer than the right; the right lever became richer than the left,
      or there was no change. Terminal reinforcer ratios (left:right) used were 9:1,
      4:1, 3:1, 1:1, 1:3, 1:4, and 1:9. Response rates on the two levers were tracked
      continuously through a session. This novel procedure for examining choice, and
      its acquisition, in a single session, was validated through many comparisons with
      the extant literature. Both response rates and changeover rates were influenced
      by the reinforcer ratios for the 1.7-year-olds. Changeover rates were not
      influenced by reinforcement rate for their 2.3-year-old littermates. For the 1.7
      year-olds, there was no effect of methylmercury on changeover or response rates
      and there was no interaction between exposure and reinforcer ratio. In controls
      and most methylmercury-exposed rats, response ratios (the measure of choice)
      approximately matched reinforcer ratios by the end of the single session. This is
      commonly interpreted as reflecting sensitivity to reinforcement rates.
      Methylmercury exposure did not affect this measure systematically. The single
      session transition from baseline (response ratios about 1:1) to terminal
      performance was retarded in many methylmercury-exposed rats relative to controls,
      especially in the older rats. The 2.3-year-old control rats required about 20 to
      25 reinforcers to complete one half of the 9:1 and 4:1 transitions, respectively,
      and exposed rats required about twice as many. Thus, prenatal methylmercury
      exposure specifically retarded the acquisition of choice in older rats.
      Methylmercury did not interfere with the final expression of choice. Moreover,
      two rate measures, lever-press rates and changeover rates, were not
      systematically affected by methylmercury. The acquisition of choice appears to be
      very sensitive to subtle consequences of developmental methylmercury exposure.
      The specific tactics greatly reduced the time required to study behavior in
      transition from a month in previous reports to a single session here.

PMID- 15019953
TI  - Toluene alters appetite, NPY, and galanin immunostaining in the rat hypothalamus.
AB  - Toluene is a neurotoxic organic solvent widely used in industry and extensively
      inhaled by solvent abusers. Toluene, diluted 1:1 in olive oil, was administered
      intraperitoneally at a dose of 1.3 ml/kg/day for 4 days. Controls received the
      vehicle in the same dose and duration. Food intake and body weight were measured
      daily. A regional hypothalamic NPY and galanin immunocytochemical study was also
      performed. Acute toluene administration in rats generated a reduction in food
      intake and body weight gain. A significant decrease in NPY immunostaining in the
      paraventricular nucleus and an increase in arcuate nucleus without changes in
      other hypothalamic regions were observed. Also, acute toluene administration
      increased galanin immunostaining in paraventricular and arcuate nuclei. These
      results suggest that the hypothalamic NPY arcuate-paraventricular projection is
      involved in the anorectic effect of acute high-dose toluene administration.
      Changes in regional hypothalamic galanin expression could represent a
      compensatory mechanism against toluene-induced anorexia.

PMID- 15019954
TI  - Chronic maternal methanol inhalation in nonhuman primates (Macaca fascicularis):
      exposure and toxicokinetics prior to and during pregnancy.
AB  - Toxicokinetic studies were conducted following daily inhalation exposure to
      methanol vapor prior to and throughout pregnancy in adult female Macaca
      fascicularis monkeys. They were part of a larger study to investigate the effects
      of chronic methanol exposure on maternal reproductive performance and early
      offspring effects. In a two-cohort study design, 48 females (24/cohort) were
      assigned to parallel exposure groups at 0 (control), 200, 600, or 1800 ppm
      methanol vapor for approximately 2.5 h/day, 7 days/week throughout breeding and
      pregnancy. Blood methanol at 30 min postexposure was monitored biweekly. The time
      course for the clearance of blood MeOH concentrations following exposure was
      characterized on four occasions: twice during the prebreeding period and during
      mid- and late pregnancy. Average blood methanol concentrations at 30 min
      postexposure were 5, 11, and 35 microg/ml across all four toxicokinetic studies
      in the 200, 600 and 1800 ppm groups, respectively. Blood concentrations in the
      200 ppm group were barely above basal (preexposure) blood methanol concentrations
      or those observed in the control group (approximately 3 microg/ml). Nonlinear
      elimination kinetics were observed in most of the 1800 ppm group females. There
      was a decrease in elimination half-life (7-20%) and an increase in clearance
      (30%) after 3-months of daily MeOH exposure compared to the initial exposure.
      There were no statistically significant changes in the first-order blood methanol
      half-life or clearance during pregnancy, but the mean distribution volume per
      kilogram body weight decreased by 22% and 17% in the 600 and 1800 ppm groups.
      Plasma formate levels did not differ between the methanol and control exposure
      groups. Plasma formate and serum folate concentrations increased slightly over
      the course of this study in both the exposed and control groups but these
      increases were not related to methanol exposure.

PMID- 15019955
TI  - Perinatal choline supplementation does not mitigate motor coordination deficits
      associated with neonatal alcohol exposure in rats.
AB  - Prenatal alcohol exposure can disrupt brain development, leading to a variety of
      behavioral alterations including learning deficits, hyperactivity, and motor
      dysfunction. We have been investigating the possibility that perinatal choline
      supplementation may effectively reduce the severity of alcohol's adverse effects
      on behavioral development. We previously reported that perinatal choline
      supplementation can ameliorate alcohol-induced learning deficits and
      hyperactivity in rats exposed to alcohol during development. The present study
      examined whether perinatal choline supplementation could also reduce the severity
      of motor deficits induced by alcohol exposure during the third trimester
      equivalent brain growth spurt. Male neonatal rats were assigned to one of three
      treatment groups. One group was exposed to alcohol (6.6 g/kg/day) from postnatal
      days (PD) 4 to 9 via an artificial rearing procedure. Artificially and normally
      reared control groups were included. One half of subjects from each treatment
      received daily subcutaneous injections of a choline chloride solution from PD 4
      to 30, whereas the other half received saline vehicle injections. On PD 35-37,
      subjects were tested on a parallel bar motor task, which requires both balance
      and fine motor coordination. Ethanol-exposed subjects exhibited significant motor
      impairments compared to both control groups whose performance did not differ
      significantly from one another. Perinatal choline treatment did not affect motor
      performance in either ethanol or control subjects. These data indicate that the
      beneficial effects of perinatal choline supplementation in ethanol-treated
      subjects are task specific and suggest that choline is more effective in
      mitigating cognitive deficits compared to motor deficits associated with
      developmental alcohol exposure.

PMID- 15019956
TI  - Validation of an auditory startle response system using chemicals or parametric
      modulation as positive controls.
AB  - Neurotoxicity regulatory guidelines mandate that automated test systems be
      validated using chemicals. However, in some cases, chemicals may not necessarily
      be needed to prove test system validity. To examine this issue, two independent
      experiments were conducted to validate an automated auditory startle response
      (ASR) system. In Experiment 1, we used adult (PND 63) and weanling (PND 22)
      Sprague-Dawley rats (10/sex/dose) to determine the effect of either d-amphetamine
      (4.0 or 8.0 mg/kg) or clonidine (0.4 or 0.8 mg/kg) on the ASR peak amplitude (ASR
      PA). The startle response of each rat to a short burst of white noise (120 dB
      SPL) was recorded over 50 consecutive trials. The ASR PA was significantly
      decreased (by clonidine) and increased (by d-amphetamine) compared to controls in
      PND 63 rats. In PND 22 rats, the response to clonidine was similar to adults, but
      d-amphetamine effects were not significant. Neither drug affected the rate of the
      decrease in ASR PA over time (habituation). In Experiment 2, PND 31 Sprague
      Dawley rats (8/sex) were presented with 150 trials consisting of either white
      noise bursts of variable intensity (70-120 dB SPL in 10 dB increments, presented
      in random order) or null (0 dB SPL) trials. Statistically significant sex- and
      intensity-dependent differences were detected in the ASR PA. These results
      suggest that in some cases, parametric modulation may be an alternative to using
      chemicals for test system validation.

PMID- 15019957
TI  - A search for residual behavioral effects of trichloroethylene (TCE) in rats
      exposed as young adults.
AB  - Trichloroethylene (TCE) is an organic solvent with robust acute effects on the
      nervous system, but poorly documented long-term effects. This study employed a
      signal detection task (SDT) to assess the persistence of effects of repeated
      daily inhalation of TCE on sustained attention in rats. Adult male Long-Evans
      rats inhaled TCE at 0, 1600, or 2400 ppm, 6 h/day for 20 days (n=8/group) and
      began learning the SDT 3 weeks later. Rats earned food by pressing one
      retractable response lever in a signal trial and a second lever in a blank (no
      signal) trial. TCE did not affect acquisition of the response rule or performance
      of the SDT after the intertrial interval (ITI) was changed from a constant value
      to a variable one. Increasing the trial presentation rate reduced accuracy
      equivalently in all groups. Injections of ethanol (0, 0.5, 1.0, 1.5 g/kg ip) and
      d-amphetamine (0, 0.1, 0.3, 1.0 mg/kg sc) systematically impaired performance as
      functions of drug dose. d-Amphetamine (1.0 mg/kg) reduced P(hit) more in the 2400
      ppm TCE group than in the other groups. All rats required remedial training to
      learn a reversal of the response contingencies, which TCE did not interfere with.
      Thus, a history of exposure to TCE did not significantly alter learning or
      sustained attention in the absence of drugs. Although ethanol did not
      differentially affect the TCE groups, the effect of d-amphetamine is consistent
      with solvent-induced changes in dopaminergic functions in the CNS. Calculations
      indicated power values of 0.5 to 0.8 to detect main effects of TCE for the three
      primary endpoints.

PMID- 15019958
TI  - Lead (Pb2+) modulation of potassium currents of guinea pig outer hair cells.
AB  - Outer hair cells (OHC) are mechanosensitive sensory cells of the inner ear
      cochlea and are involved in modulating the activity of inner hair cells in the
      transduction of an acoustic stimulus. Potassium (K(+)) currents play an important
      role in the sensory transduction process. K(+) currents were recorded from
      acutely dissociated OHC obtained from the guinea pig organ of Corti. The whole
      cell patch clamp technique was employed. We identified a channel that exhibited
      outward current of the delayed rectifier type (Kv). Kv channels mediating inward
      currents carried by potassium ions were also identified and took on the
      appearance of a previously described inwardly rectifying current. Lead (Pb(2+))
      acetate at concentrations of 0.1, 1.0, 10, and 100 microM was bath applied. Time
      to activation for outward-going current was not affected by Pb(2+). The time
      course of Pb(2+) effects was seen as a dose-dependent reduction of K(+) current
      over time, with very little or no recovery after washout. Pb(2+) inhibited the
      outward Kv relative current with values of 0.10, 0.14, 0.18, and 0.30 at 0.1,
      1.0, 10, and 100 microM, respectively. Pb(2+) did not modulate time to
      activation, peak current, or inactivation of inward I(K). The effects of Pb(2+)
      on the potassium currents of OHC are not remarkable and therefore OHC are
      probably not a major cause of purported peripheral hearing loss observed in
      Pb(2+)-exposed animals and humans.

PMID- 15019959
TI  - Low-dose perinatal diethylstilbestrol exposure affected behaviors and
      hypothalamic estrogen receptor-alpha-positive cells in the mouse.
AB  - To estimate the potential risk of perinatal exposure to estrogenic endocrine
      disrupters, pregnant female mice received daily oral administration of
      diethylstilbestrol (DES; either 0.3 or 3 microg/kg body weight) dissolved in corn
      oil from gestation days 11 to 17 and from postnatal days 2 to 6. Multiple
      behaviors that are sexually dimorphic were examined, and the numbers of estrogen
      receptor-alpha and tyrosine hydroxylase-immunoreactive (ER-IR and TH-IR) cells in
      some brain loci related to these behaviors were investigated. Perinatal exposure
      to DES caused significantly enhanced open-field activity in both males and
      females and significantly poorer passive avoidance performance in males. In
      addition, a significant increase in the number of ER-IR cells in the ventromedial
      hypothalamic nucleus (VMH) was demonstrated for the first time. The DES-induced
      increases in the sexual and aggressive behaviors, although statistically
      nonsignificant, and the increase in the number of ER-IR cells did not agree with
      those obtained in previous studies using high-dose DES, which suggests that DES
      may have a different effect on these endpoints depending on the dose used. The
      relationship between the increase in ER-IR cells and behavioral changes should be
      further examined.

PMID- 15019960
TI  - Visual contrast sensitivity testing: a comparison of two F.A.C.T. test types.
AB  - Measures of visual contrast sensitivity (VCS), rather than traditional measures
      of visual acuity using high-contrast stimuli, have been presented as better
      appraisals of visual dysfunction resulting from chemical exposures. The present
      study sought to determine if differences exist between two available measures of
      contrast sensitivity that use similar stimuli, specifically, a hand-held chart
      and an Optec 1000 vision tester. Monocular contrast sensitivity measures using
      both tests were obtained from 45 individuals as part of a NIOSH neurobehavioral
      test-battery appraisal. Test-retest reliability was found to be high for both the
      hand-held system and the Optec 1000 test (r=.750 and.773, respectively). In
      comparison to the automated test, the hand-held version produced statistically
      significant higher contrast sensitivity scores for lower spatial frequencies (1.5
      and 3.0 cycles per degree) and lower scores for a relatively higher spatial
      frequency (18.0 cycles per degree [cpd]). Consequently, this study documents a
      difference in spatial frequency scores obtained with the hand-held form and Optec
      1000 form of contrast sensitivity test, and attributes these differences to
      design characteristics affecting viewing. It is concluded that caution should be
      taken when making absolute comparisons of contrast sensitivity test scores
      between neurobehavioral studies that have used different forms of VCS testing.

PMID- 15019961
TI  - P-VECP can reveal visual toxicity in pigmented rats of repeated doses of
      ethambutol.
AB  - We determined if pattern visually evoked cortical potentials (P-VECPs) in
      pigmented rats would reveal visual toxicity induced by a drug even when in cases
      of repeated doses. We obtained appropriate conditions of P-VECPs measurement; the
      spatial frequency, 0.16 cycle/degree; the mean stimulation luminance, 25 cd/m(2);
      and the stimulation frequency, 2 Hz. Twelve adult male pigmented rats (Iar: Long
      Evans), weighing 210-301 g, were grouped into two (six per group): the control
      and the ethambutol (EB) 500 mg/kg administered groups. In the EB 500 mg/kg group,
      the rats were administered EB subcutaneously once daily for 6 weeks. Rats in the
      control group were given the vehicle subcutaneously once daily for 6 weeks. P
      VECPs were carried out prior to initiation of drug administration and at the
      first, second, third, fourth, and sixth week of the administration. Prolongation
      of P1 latency in the P-VECPs was evident in the EB 500 mg/kg at fourth and sixth
      weeks, and there were no marked changes in the control group and no marked
      changes in P1N1 amplitude in either group. These findings suggest that P-VECPs in
      pigmented rats can detect chemically induced visual toxicity even in cases of
      repeated dosing of a drug. This approach is useful for evaluating the visual
      toxicity of drugs given repeatedly.

PMID- 15019962
TI  - Low birth weight in relation to parental occupations-a population-based registry
      in Singapore (1994-1998).
AB  - OBJECTIVES: To study the association between parental occupation and low birth
      weight (LBW) in infants born in Singapore between 1994 and 1998. Other factors
      that may be related to LBW were also investigated. METHODS: A retrospective
      study. Information was obtained from the Singapore National Registry of Births
      and Deaths on parental occupations for live births between 1 January 1994 to 31
      December 1998. Parental date of birth, ethnic group, and highest educational
      qualification were also obtained. The associations between these factors and the
      occurrence of LBW was assessed using descriptive statistics and logistic
      regression analysis. RESULTS: A total 208,360 live births were studied. Analyses
      were restricted to singleton births > or =37th week gestation (total of 189,064).
      No significant differences in LBW risk were found for the different maternal
      occupational groups, compared with a referent group ("legislators, senior
      officers, and managers"). However, fathers who were "not working" (OR=2.04; 1.57
      2.65), "not classifiable by occupation" (OR=1.34; 1.09-1.65), and "cleaners,
      laborers, and related workers" (OR=1.32; 1.12-1.55) had the highest risk of LBW
      infants when compared with "legislators, senior officers, and managers," after
      adjustment for maternal occupation, ethnic group, educational level and age,
      paternal educational level, infant gestational age, sex, and birth order.
      CONCLUSION: Certain paternal occupational groups appear to be associated with a
      higher risk of having LBW infants. This may be linked to socioeconomic status and
      possible work-related factors. Future studies of pregnancy outcomes should not
      ignore the potential contributions of fathers.

PMID- 15019963
TI  - Amphetamine and stress responses in developmentally lead-exposed rats.
AB  - In this study, pregnant Wistar dams were exposed to 220 ppm of lead (Pb) in
      drinking water during gestation and lactation. The response to the locomotor
      stimulating effects of 0.5 mg/kg of amphetamine (AMPH) was evaluated in 35-day
      old male offspring. The results demonstrated that developmental Pb exposure
      induced no differences in the response to the drug, although an increase in
      locomotor activity induced by a single saline (SAL) injection was observed
      selectively in the Pb-exposed group. Considering evidence that suggests a
      relationship between increased locomotor activity and stress response, a time
      course analysis of corticosterone (CS) secretion and locomotor performance was
      carried out. Higher basal levels of CS and elevated stress-induced secretion of
      this hormone in response to the injection were observed in Pb-exposed rats
      compared to controls, a pattern that showed a time-related increase in locomotor
      activity. Habituation to SAL injections prior to testing restored both CS
      secretion and locomotor response to SAL to levels comparable to controls and did
      not modify AMPH locomotor response measured in these new experimental conditions.
      Additionally, we demonstrated that these behavioral/hormonal disruptions were no
      longer detectable later in adulthood. Collectively, these data suggest that the
      stimulant-locomotor effect of AMPH in Pb-exposed rats is independent of the
      arousal of the animal at the time of its administration. They also support a
      unique profile of integrated behavioral and hormonal hyperresponsiveness in 35
      day-old low-level Pb-exposed rats evidenced as hyperlocomotion and altered
      secretion of CS in response to an environmental manipulation, an effect that was
      no longer present later in life.

PMID- 15019964
TI  - Long-term functional neurotoxicity of paraoxon and chlorpyrifos: behavioural and
      pharmacological evidence.
AB  - Organophosphate (OP) compounds are chemicals widely used in agriculture, industry
      and households and even as chemical weapons. The major mechanism of acute toxic
      action is the inhibition of acetylcholinesterase (AChE), which is responsible for
      the degradation of the neurotransmitter acetylcholine. A chronic OP-induced
      neuropsychiatric disorder (COPIND), which could result from both long-term
      exposure to subclinical doses of OP and after acute intoxication, has been
      proposed. These reports claim to develop animal models that could parallel
      behavioural and cognitive effects and that could later help to elucidate the
      mechanisms involved in this long-term affectation of the central nervous system.
      The present study uses a series of behavioural tests to discern the short- and
      long-term effects of acute intoxications with paraoxon (Px) or chlorpyrifos
      (CPF). Our results suggest that months after acute exposure to these OPs
      functional central nervous system alterations can be detected using a repeated
      acquisition spatial task in the water maze, for CPF, and in amphetamine-induced
      place preference paradigm, for both Px and CPF.

PMID- 15019965
TI  - Prenatal cocaine exposure does not alter working memory in adult rats.
AB  - The present study was designed to assess working memory in adult rats exposed to
      intravenous cocaine in utero, as part of an examination of various cognitive and
      affective functions. The study included four groups: a saline control and three
      groups exposed to ascending doses of cocaine from gestational days 8 to 21 (0.5,
      1.0, or 3.0 mg/kg). This exposure regimen (route of administration and dose) has
      been shown to accurately reproduce the pharmacokinetic profile and physiological
      effects of human recreational cocaine use. This report describes the results of a
      series of automated alternation tasks, in which the animals were rewarded for
      alternating their responses between two response ports on successive trials. In
      the final task, the delay between trials varied randomly between 0, 20, 40, and
      80 s, thereby varying the retention interval. Although performance declined
      dramatically as the retention interval increased, the rate of this decline did
      not differ across treatment groups. These results suggest that prenatal cocaine
      exposure, at doses that model recreational use, does not produce lasting changes
      in explicit memory or working memory. However, subtle, sex-specific effects of
      prenatal cocaine exposure were seen on measures that indicate impairments in
      sustained attention and "readiness", as well as altered reactivity to task
      related stressors such as waiting for long and unpredictable delays.

PMID- 15019966
TI  - Electroencephalographic, behavioral, and c-fos responses to acute domoic acid
      exposure.
AB  - Domoic acid, a potent excitotoxic analogue of glutamate and kainate, may cause
      seizures, amnesia, and sometimes death in humans consuming contaminated
      shellfish. Continuous behavioral observations and recordings of the
      electrocorticogram (ECoG, via bipolar, epidural electrodes) were obtained from
      nonanesthetized rats for 2 h after intraperitoneal injection with either saline,
      2.2, or 4.4 mg/kg of domoic acid. Rats were then sacrificed for c-fos
      immunohistochemistry. Fast Fourier transformation (FFT) of the ECoG data to
      obtain the voltage as a function of frequency indicated that the lower frequency
      bands (theta, 4.75-6.75 Hz and delta, 1.25-4.50 Hz) were the first to respond,
      with a significant elevation by 30 min after the high dose of domoic acid. The
      lower dose of domoic acid also caused a significant elevation of ECoG voltage,
      but not until later in the session. Sixty minutes after dosing, the behavioral
      biomarkers of "ear scratching" and "rearing, praying" (RP) seizures became
      significantly elevated in the high-dose rats. The low-dose rats showed no
      significant alterations in behavior at any time during the session. In postmortem
      brains obtained immediately after the sessions, c-fos was activated in the
      anterior olfactory nucleus by both the low and high doses of domoic acid.
      However, only the high dose increased c-fos immunoreactivity in the hippocampus,
      affecting both the granule and pyramidal neurons. These data indicate that
      electroencephalographic and c-fos responses can be obtained at a dose of domoic
      acid that fails to activate the behavioral response most commonly used as a
      bioassay for this marine toxin: ear scratching with the ipsilateral foot.

PMID- 15019967
TI  - Flavonoids and isoflavones: absorption, metabolism, and bioactivity.

PMID- 15019968
TI  - Absorption and metabolism of flavonoids.
AB  - The benefits of flavonoids as chemopreventive dietary or dietary supplemental
      agents are still only "potential." Much has been learned about possible
      mechanisms of action of these agents, but whether they can reach their multiple
      intended sites of action, particularly in humans, is largely unknown. The
      biological fate of the flavonoids, including their dietary glycoside forms, is
      highly complex, dependent on a large number of processes. This review is intended
      to bring some order into this complex area and deals with the fate of the
      naturally occurring glycosides, their enzymatic hydrolysis, as well as the
      resulting aglycones. The impact of membrane transporters as well as metabolic
      enzymes on the cellular availability of these phytochemicals is examined. A
      reevaluation of the concept of oral bioavailability applied to the dietary
      flavonoids is presented.

PMID- 15019969
TI  - Flavonoids: antioxidants or signalling molecules?
AB  - Many studies are accumulating that report the neuroprotective, cardioprotective,
      and chemopreventive actions of dietary flavonoids. While there has been a major
      focus on the antioxidant properties, there is an emerging view that flavonoids,
      and their in vivo metabolites, do not act as conventional hydrogen-donating
      antioxidants but may exert modulatory actions in cells through actions at protein
      kinase and lipid kinase signalling pathways. Flavonoids, and more recently their
      metabolites, have been reported to act at phosphoinositide 3-kinase (PI 3
      kinase), Akt/protein kinase B (Akt/PKB), tyrosine kinases, protein kinase C
      (PKC), and mitogen activated protein kinase (MAP kinase) signalling cascades.
      Inhibitory or stimulatory actions at these pathways are likely to affect cellular
      function profoundly by altering the phosphorylation state of target molecules and
      by modulating gene expression. A clear understanding of the mechanisms of action
      of flavonoids, either as antioxidants or modulators of cell signalling, and the
      influence of their metabolism on these properties are key to the evaluation of
      these potent biomolecules as anticancer agents, cardioprotectants, and inhibitors
      of neurodegeneration

PMID- 15019970
TI  - The iron cycle and oxidative stress in the lung.
AB  - Iron is critical for many aspects of cellular function, but it can also generate
      reactive oxygen species that can damage biological macromolecules. To limit
      oxidative stress, iron acquisition and its distribution must be tightly
      regulated. In the lungs, which are continuously exposed to the atmosphere, the
      risk of oxidative damage is particularly high because of the high oxygen
      concentration and the presence of significant amounts of catalytically active
      iron in atmospheric particulates. An effective system of metal detoxification
      must exist to minimize the associated generation of oxidative stress in the
      lungs. Here we summarize the evidence that a number of specific proteins that
      control iron uptake in the gastrointestinal tract are also employed in the lung
      to transport iron into epithelial cells and sequester it in a catalytically
      inactive form in ferritin. Furthermore, these and other proteins facilitate
      ferritin release from lung cells to the epithelial and bronchial lining fluids
      for clearance by the mucociliary system or to the reticuloendothelial system for
      long-term storage of iron. These pathways seem to be the primary mechanism for
      control of oxidative stress presented by iron in the respiratory tract.

PMID- 15019971
TI  - Overexpression of heme oxygenase (HO)-1 renders Jurkat T cells resistant to fas
      mediated apoptosis: involvement of iron released by HO-1.
AB  - We recently demonstrated that heme oxygenase (HO)-1 is constitutively expressed
      in human CD4+CD25+ regulatory T cells and induced by anti-CD28 or anti-CD28/anti
      CD3 stimulation, even in CD4+CD25- responder T cells. To study the effects of HO
      1 expression on lymphocyte survival, we transfected the HO-1 gene or induced the
      gene to express HO-1 protein with cobalt protoporphyrin (CoPP) in Jurkat T cells.
      Consistently, anti-Fas antibody triggered apoptotic cell death in wild-type
      Jurkat T cells. Surprisingly, however, HO-1-overexpressing Jurkat T cells showed
      strong resistance to Fas-mediated apoptosis. In contrast, abrogation of HO-1
      expression by antisense oligomer against HO-1 gene from CoPP-treated cells or
      depletion of iron by desferrioxamine from HO-1-transfected cells abolished the
      resistance. In addition, exogenously added iron rendered wild-type Jurkat T cells
      resistant. The resistance involved IkappaB kinase (IKK) activation via iron
      induced reactive oxygen species formation, NF-kappaB activation by activated IKK,
      and c-FLIP expression by activated NF-kappaB. Primary CD4+ T cells induced by
      CoPP to express HO-1 also showed more resistance to Fas-mediated apoptosis than
      untreated cells. Our findings suggest that HO-1 plays a critical and nonredundant
      role in Fas-mediated activation-induced cell death of T lymphocytes.

PMID- 15019972
TI  - Inclusion complexes of carotenoids with cyclodextrins: 1H NMR, EPR, and optical
      studies.
AB  - Direct evidence of carotenoid/cyclodextrin inclusion complex formation was
      obtained for the water-soluble sodium salt of beta-caroten-8'-oic acid (IV) by
      using 1H NMR and UV-Vis absorption spectroscopy. It was shown that this
      carotenoid forms a stable 1:1 inclusion complex with beta-cyclodextrin (stability
      constant K11 approximately 1500 M(-1)). All other carotenoids under study in the
      presence of cyclodextrins (CDs) form large aggregates in aqueous solution as
      demonstrated by very broad absorption spectra and considerable change in color.
      By using the EPR spin trapping technique, the scavenging ability of IV toward OOH
      radicals was compared in DMSO and in the aqueous CD solution. A considerable
      decrease in PBN/OOH spin adduct yield was detected in the presence of uncomplexed
      IV because of a competing reaction of the carotenoid with OOH radical. No such
      decrease occurred in the presence of the IV/CD complex. Moreover, a small
      increase in spin adduct yield (pro-oxidant effect) is most likely due to the
      reaction of the carotenoid with Fe3+ to regenerate Fe2+, which in turn
      regenerates the OOH radical. Our data show that CD protects the carotenoid from
      reactive oxygen species. On the other hand, complexation with CD results in
      considerable decrease in antioxidant ability of the carotenoid.

PMID- 15019973
TI  - The transcriptosomal response of human A549 lung cells to a hydrogen peroxide
      generating system: relationship to DNA damage, cell cycle arrest, and caspase
      activation.
AB  - Intracellular oxidative stress is a dynamic situation characterized by the
      accumulation of reactive oxygen metabolites, such as hydrogen peroxide. This is
      traditionally associated with both macromolecular damage and adaptive changes in
      gene expression, aimed at preventing cellular demise. However, the overall extent
      of such genetic changes is not well characterized. Here we present a
      comprehensive analysis of altered mRNA profiles in human A549 type II lung
      epithelial cells in response to hydrogen peroxide, at concentrations failing to
      induce necrotic toxicity. The results of an Affymetrix-based screen of the steady
      state levels of mRNAs for several thousand genes revealed a complex pattern of
      transcriptional and/or posttranscriptional response to oxidative stress, which
      can be functionally related to both the oxidation and repair of damaged DNA, the
      induction and permanency of cell cycle arrest, and caspase-3 activation. Many of
      the genetic events can be related to activation of the p53/p21 pathway, but many
      other novel inductions and suppressions were detected, revealing the intricacy of
      the response. The data also disclosed a potential interaction between hydrogen
      peroxide treatment and increased sensitivity to cell killing by TRAIL, which
      could be functionally confirmed at the level of induction of caspase-3 activity.

PMID- 15019974
TI  - Hydroxylation at C4' or C6 is essential for apoptosis-inducing activity of
      flavanone through activation of the caspase-3 cascade and production of reactive
      oxygen species.
AB  - Previous studies demonstrated that hydroxyl groups play important roles in the
      antioxidative activities of flavonoids; however, the importance of structurally
      related hydroxylation in their apoptosis-inducing activities is still undefined.
      In the present study, flavanone with hydroxylation at C4' and C6 had a
      significant cytotoxic effect in human leukemia HL-60 cells accompanied by the
      occurrence of DNA ladders, apoptotic bodies, and hypodiploid cells,
      characteristics of apoptosis. The replacement of a hydroxyl group (OH) by a
      methoxyl (OCH3) group at C4' or C6 attenuated the apoptotic effect in cells, and
      there was no significant cytotocity of flavanone or flavanone with OH or OCH3 in
      C7-treated HL-60 cells. Induction of enzyme activity of caspase-3 and -9, but not
      caspase-1 and -8, accompanied by release of cytocrome C from mitochondria to
      cytosol and the appearance of cleaved of PARP (85 kDa), D4-GDI (23 kDa), and
      caspase-3 (p17/p15) fragments, was identified in 4'-OH- or 6-OH- flavanone
      treated HL-60 cells. Caspase-3 and -9 inhibitors Ac-DEVD-FMK and Ac-LEHD-FMK, but
      not caspase-1 and -8 inhibitors Ac-YVAD-FMK and Ac-LETD-FMK, attenuated 4'-OH- or
      6-OH-flavanone-induced cell death. And, inhibition of capsase-9 activity by Ac
      LEHD-FMK suppresses caspase-3 protein procession induced by 4'-OH- and 6-OH
      flavanone, indicative of caspase-9 activation locating upstream of caspase-3. A
      decrease in the antiapoptotic protein Mcl-1 and increases in the pro-apoptotic
      proteins Bax and Bad were found in 4'-OH- or 6-OH-flavanone-treated HL-60 cells.
      Induction of endogenous ROS production was detected in 4'-OH- or 6-OH-flavanone
      treated HL-60 cells by the DCHF-DA assay. Antioxidants such as N-acetylcysteine
      (NAC), catalase (CAT), superoxide dismutase (SOD), and allopurinol (ALL), but not
      pyrrolidine dithiocarbamate (PDTC) or diphenylene iodonium (DPI), significantly
      inhibited 4'-OH- or 6-OH-flavanone-induced ROS production, with blocking of the
      apoptosis induced by 4'-OH- or 6-OH-flavanone. The apoptosis-inducing activity of
      4'-OH- or 6-OH-flavanone was also observed in another leukemia cell line
      (Jurkat), but was not found in mature monocytic cells (THP-1) and normal human
      polymorphonuclear neutrophils (PMNs). This suggests that hydroxylation at C4' or
      C6 is important to the apoptosis-inducing activities of flavanone through ROS
      production, and that activation of the caspase-3 cascade, downstream of caspase-9
      activation, is involved.

PMID- 15019975
TI  - Aggregation of ALS mutant superoxide dismutase expressed in Escherichia coli.
AB  - Although large amounts of wild-type human Cu,Zn superoxide dismutase (SOD) are
      easily expressed in Escherichia coli, the amyotrophic lateral sclerosis
      associated mutants have a strong propensity to aggregate into inclusion bodies.
      The alanine to valine mutation at the fourth codon (A4V) is responsible for a
      rapidly progressive disease course and is particularly prone to aggregation when
      expressed in E. coli. We found that A4V SOD remained soluble when expressed at 18
      degrees C, but >95% A4V SOD aggregated in inclusion bodies when expressed at 23
      degrees C or above. The SOD aggregates dissolved with 4 M urea, suggesting that
      intermolecular hydrophobic interactions were predominantly responsible for making
      SOD insoluble. Many of the urea-solubilized subunits were cross-linked via
      disulfide bridges. Fully active mutant SOD could be produced by dialyzing urea
      away in the presence of beta-mercaptoethanol and subsequently adding copper plus
      zinc, providing a fast procedure for purifying hundreds of milligrams of protein.
      Extensive rinsing removed most contaminating E. coli proteins from A4V SOD
      inclusion bodies except for a 37 kDa protein identified as outer membrane protein
      F using MALDI ToF/ToF mass spectrometry. Our results indicate that metal
      deficient ALS-mutant SOD folds into stable apo conformation able to rebind
      metals. At high protein concentrations, SOD forms aggregates through hydrophobic
      interactions between subunits that seem to act as a kinetic snare to entrap
      additional proteins.

PMID- 15019976
TI  - Effects of curcumin and curcumin derivatives on mitochondrial permeability
      transition pore.
AB  - Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a
      natural compound with antiproliferative properties. Recent studies suggest that
      these properties might be due to the ability of curcumin to induce apoptosis in
      tumor cells by increasing the permeability of the mitochondrial membrane. In the
      present study, we confirm these observations and provide a molecular mechanism
      for the action of curcumin in rat liver mitochondria. Curcumin induced
      mitochondrial swelling, the collapse of Deltapsi, and the release of cytochrome
      C, events associated with the opening of the permeability transition pore (PTP).
      Experiments were performed with chemically substituted curcumin derivatives. Some
      derivatives were obtained by modification of groups on the terminal aromatic
      rings, and others were obtained by substitution of the diketone function with the
      cyclohexanone function. They demonstrated that phenol and methoxy groups were
      essential to promote PTP opening. Curcumin and curcumin derivatives that open the
      PTP were able to oxidize thiol groups. In addition, PTP opening was abolished in
      medium devoid of O2 and decreased in the presence of catalase, ferrozine, o
      phenanthroline, mannitol, or N-ethylmaleimide. These data suggest that the
      mechanism by which curcumin promotes PTP opening involves the reduction of Fe3+
      to Fe2+, inducing hydroxyl radical (HO*) production and oxidation of thiol groups
      in the membrane, leading to pore opening.

PMID- 15019977
TI  - Absorption and metabolism of delphinidin 3-O-beta-D-glucopyranoside in rats.
AB  - The absorption and metabolism of delphinidin 3-O-beta-d-glucopyranoside (Dp3G),
      which is the most potent antioxidant among the blueberry anthocyanins, were
      studied in rats. Dp3G rapidly appeared in the blood plasma within 15 min of oral
      administration (100 mg/kg body wt). The plasma level of absorbed Dp3G showed two
      peaks at 15 and 60 min after ingestion and then decreased time-dependently.
      However, the plasma level was maintained at approximately 30 nmol/l even after 4
      h. Besides the Dp3G peak, a single major metabolite peak was detected by HPLC in
      the blood plasma obtained at 15 min. MS and NMR spectroscopy clarified that the
      chemical structure of the metabolite was 4'-O-methyl delphinidin 3-O-beta-d
      glucopyranoside (methylation of the 4'-OH on the delphinidin B-ring). The present
      finding of this unique metabolite in anthocyanin metabolism strongly suggests
      that methylation of the 4'-OH on the flavonoid B-ring is a common metabolic
      pathway for flavonoids that carry the pyrogallol structure on the B-ring, as the
      same type of metabolite has been reported for other flavonoids such as
      epigallocatechin, but not for flavonoids carrying the catechol structure.

PMID- 15019979
TI  - Nuclear retinoid receptors and the transcription of retinoid-target genes.
AB  - The pleiotropic effects of retinoids are mediated by nuclear retinoid receptors
      (RARs and RXRs) which are ligand-activated transcription factors. In response to
      retinoid binding, RAR/RXR heterodimers undergo major conformational changes and
      orchestrate the transcription of specific gene networks, through binding to
      specific DNA response elements and recruiting cofactor complexes that act to
      modify local chromatin structure and/or engage the basal transcription machinery.
      Then the degradation of RARs and RXRs by the ubiquitin-proteasome controls the
      magnitude and the duration of the retinoid response. RARs and RXRs also integrate
      a variety of signaling pathways through phosphorylation events which cooperate
      with the ligand for the control of retinoid-target genes transcription. These
      different modes of regulation reveal unexpected levels of complexity in the
      dynamics of retinoid-dependent transcription.

PMID- 15019978
TI  - Treatment with a catalytic antioxidant corrects the neurobehavioral defect in
      ataxia-telangiectasia mice.
AB  - Ataxia-telangiectasia is caused by mutations in the ATM gene, the protein product
      of which is essential for effective response to double-stranded DNA breaks. Loss
      of ATM function explains most aspects of the disease, but not the cerebellar
      neurodegeneration characteristic of the disease. Mice lacking ATM provide an
      excellent model of the human disorder. In addition to deficient response to DNA
      damage, these mice exhibit oxidative stress, which we hypothesized is the cause
      of cerebellar dysfunction. We show that treatment with a catalytic antioxidant
      corrects the neurobehavioral deficit in these mice.

PMID- 15019980
TI  - Simple repeat replacements support similar functions of distinct repeats in inter
      species mRNA homologs.
AB  - Simple repeats are ubiquitous in metazoan genomes, but function has been elusive.
      We reported that distinct, short tandem repeats (STRs) were coupled with rigorous
      polarity and register, suggesting order in simple repeat usage. Several STRs that
      lacked internal, canonical base pairs were associated with mRNAs encoding
      membrane functions and transcription factors. We hypothesized that diverse,
      simple repeats, such as (AC)n, (GU)n, (AG)n, (CU)n and (CUUU)n, had similar
      functions. The hypothesis predicts that closely related mRNAs would sometimes
      exhibit STR replacements. Comparing aquaporin 3 mRNAs, in rodents and humans,
      (GU)20 replaced (AG)29. Comparing biglycan mRNAs, (GU)25 replaced (CA)12.
      Comparing immunoglobulin superfamily member 9 mRNAs, the STR-couple, (CU)17(GU)9
      replaced the STR-couple, (GU)19(GC)4. Comparing tumor necrosis factor receptor-21
      mRNAs, (GU)24 replaced (CUUU)16. In a collection of 52 rodent-H. sapiens
      homologous mRNAs that had STRs, six (11.5%) STR-STR replacements occurred,
      significantly more than expected based on an STR frequency of 0.13% in all
      reported UTRs (p<0.001). Database studies and the observation of STR replacements
      among transcript homologs independently support the hypothesis that diverse
      repeat sequences, such as (AG)n, (AC)n, (GU)n, (CU)n and (CUUU)n, have similar
      usage that is consistent with analogous functions.

PMID- 15019981
TI  - Molecular cloning of zebrafish and medaka vitellogenin genes and comparison of
      their expression in response to 17beta-estradiol.
AB  - In the present study, both zebrafish and medaka vitellogenin genes have been
      isolated and used as a biomarker to compare the two small aquarium fish in
      response to estrogen treatment and thus to evaluate the two fish models in
      development of a biomonitoring system for environmental estrogens. The isolated
      zebrafish vitellogenin gene, zvtg1, is the most abundantly expressed vitellogenin
      gene in zebrafish and its complete protein sequence of 1360 amino acids was
      deduced from a genomic and a cDNA clone. The isolated medaka vitellogenin (mvtg1)
      genomic clone covers 1053 amino acids in the N-terminal. Both zebrafish zvtg1 and
      medaka mvtg1 are specifically expressed in female liver and their expression can
      be induced by 17beta-estradiol (E2) in male fish both by intramuscular injection
      and immersion treatment. A real-time reverse transcriptase polymerase chain
      reaction (RT-PCR) assay was developed for quantification of vitellogenin mRNA
      level in both control fish and E2-treated fish. The lowest-observed-effect
      concentrations of E2 for the induction of vitellogenin mRNAs were observed at 1
      microg/l for zebrafish and 0.1 microg/l for medaka in a 2-day exposure
      experiment. Further kinetics studies of the two fish models indicated that medaka
      was able to respond much faster to E2 treatment than zebrafish, while the
      zebrafish can attain a much higher level of vitellogenin mRNAs than medaka after
      a long-term E2 treatment. The implication of these observations may be that the
      medaka system is better in monitoring acute treatment while the zebrafish system
      is better in monitoring chronic exposure.

PMID- 15019982
TI  - Profiling Cu,Zn-superoxide dismutase expression in Drosophila melanogaster--a
      critical regulatory role for intron/exon sequence within the coding domain.
AB  - Cu,Zn-superoxide dismutase (SOD1) represents along with catalase the first
      coordinated line of defense against ROS and is found in all aerobic organisms.
      The dissection of the regulatory controls that drive the expression of SOD1 may
      provide further insight into the functional significance of this enzyme. The aim
      of this study was to elucidate temporal and spatial patterns of SOD1 expression,
      as well as to identify gene domains that govern its expression. Immunostaining
      analysis was used to delineate marked tissue and stage-specific expression
      patterns during the course of development and aging. By and large, there were no
      significant alterations in SOD1 mRNA and protein levels in response to the stress
      that accompanies aging, nor in response to different environmental insults, such
      as heat and hyperoxia. Expression of SOD1 seems to be largely determined by
      intrinsic factors. By histochemical analysis of transgenics carrying various sod1
      reporter gene fusions, it was also possible to identify sequence domains,
      governing SOD1 expression. In particular a 1140 base pair region, composed of the
      single sod1 intron along with exon 2, was found to be essential for permitting
      spatial and temporal expression patterns that approximate normal endogenous
      expression.

PMID- 15019983
TI  - Another face of the Treacher Collins syndrome (TCOF1) gene: identification of
      additional exons.
AB  - Treacher Collins syndrome (TCS) is characterized by an abnormality in
      craniofacial development during early embryogenesis. TCS is caused by mutations
      in the gene TCOF1, which encodes the nucleolar phosphoprotein treacle. Genetic
      and proteomic characterizations of TCS/treacle are based on the previously
      reported 26 exons of TCOF1. Here, we report the identification of 231-nucleotide
      (nt) exon 6A (between exons 6 and 7) and 108-nt exon 16A (between exons 16 and
      17). Isoforms with exon 6A are up to 3.7-fold more abundant than alternatively
      spliced variants without exon 6A, but only minor isoforms contain exon 16A. Exon
      6A encodes a peptide sequence containing basic and acidic domains similar to 10
      other exons of TCOF1. Unlike the other exons, exon 6A encodes a nuclear
      localization signal (NLS) which does not, however, alter the nucleolar
      localization of full-length treacle. The discovery of exons 6A and 16A is
      relevant to mutational analysis of the TCOF1 gene in TCS patients, and to
      functional analysis of its gene product.

PMID- 15019984
TI  - Cloning and expression analysis of two novel PCTAIRE 3 transcripts from human
      brain.
AB  - PCTAIRE 3 is a member of the PCTAIRE subfamily of cdc2-related serine/threonine
      protein kinases. In the present study, cDNAs encoding two isoforms of PCTAIRE 3
      have been cloned and the genomic organization of the human PCTAIRE 3 gene is
      reported. The gene spans 28.15 kb on chromosome 1q31-32 and contains 16 exons.
      The major transcript of PCTAIRE 3, designated PCTAIRE 3a, has an open reading
      frame that is 474 amino acids in length. Transcripts for PCTAIRE 3a were evident
      throughout the brain and in the majority of tissues analyzed. A second transcript
      containing an insert that adds 90 nucleotides to the third exon of the gene was
      also identified. This transcript, designated PCTAIRE 3b, encodes a polypeptide of
      504 amino acids. Expression of PCTAIRE 3b was limited to several subcortical
      nuclei of the basal gangli and the spinal cord and substantial levels of this
      transcript were not evident outside of the central nervous system. Primary
      sequence comparisons between different cdc2-related serine/threonine protein
      kinases reveal that these proteins are most heterogeneous in their N-terminal
      domains and the PCTAIRE subfamily is further diversified by the presence of
      isoforms within this region.

PMID- 15019985
TI  - Expression analysis of the gene encoding for the U-box-type ubiquitin ligase
      UBE4A in human tissues.
AB  - The Ubiquitination Factor E4A gene (UBE4A) encodes for a U-box-type ubiquitin
      ligase, originally described as an E4 ubiquitination factor. UBE4A is a mammalian
      homolog of Saccharomyces cerevisiae Ufd2. The UBE4A gene has been mapped on the
      human chromosome region 11q23.3, a critical region involved in some specific
      cancers such as neuroblastoma. Northern blots analysis on foetal and adult human
      tissues revealed a single band of approximately 7.5 kb transcript most abundant
      in the heart, skeletal muscle and kidney. We generated a polyclonal antibody to
      UBE4A and performed immunoblot and immunohistochemical analysis. The UBE4A
      protein appeared as a single band of approximately 125 kDa. UBE4A was present in
      the skeletal muscle, kidney and liver; a faint band was visible in peripheral
      blood leukocytes and spleen. We did not reveal expression of UBE4A in whole
      brain, colon, lung and heart. At the cellular level, UBE4A results predominantly
      expressed in the nucleus and the cytoplasm of cortical neurons and liver and in
      the nucleus of tubular kidney cells. In the liver, the nucleus of similar cells
      appeared to be unstained or stained at different levels suggesting that UBE4A may
      have a cell cycle dependent expression or a role of in cell cycle control. In
      conclusion, our results show that UBE4A is expressed in different tissues in a
      pattern that seems to be dependent from cell type and cell cycle and that UBE4A
      might have a specific role in different biochemical processes other than
      ubiquitination, including growth or differentiation.

PMID- 15019986
TI  - Cloning and characterization of the full-length mouse Ptk7 cDNA encoding a
      defective receptor protein tyrosine kinase.
AB  - The 3.8-kb full-length mouse Ptk7 cDNA encoding a defective receptor protein
      tyrosine kinase was cloned by reverse transcription-PCR of mouse liver mRNA. The
      mouse PTK7 polypeptide showed 92.6% identity to human PTK7. The mouse Ptk7 gene
      consists of 20 exons and has exactly the same exon structure as the human PTK7
      gene. Mouse PTK7 was shown to be phosphorylated neither by itself nor by other
      protein tyrosine kinases. In addition, its expression did not affect the phospho
      tyrosine level of cellular proteins in COS-1 cells. The mouse Ptk7 mRNA was
      expressed at high levels in lung and un-pregnant uterus among adult tissues, and
      in the tail, limbs, somites, gut, and craniofacial regions among embryonic
      tissues. These data suggest that mouse PTK7, an orthologue of human PTK7, plays
      multiple roles in embryonic development.

PMID- 15019987
TI  - Comparative analysis of the complete cag pathogenicity island sequence in four
      Helicobacter pylori isolates.
AB  - The cytotoxin-associated gene (cag) pathogenicity island (PAI) is important for
      the virulence of Helicobacter pylori. In this study, we have compared the
      complete nucleotide sequence of the cag PAI in four clinical isolates. These
      isolates were selected from patients matched for age and sex from the same
      geographical region. The patients suffered from either gastric cancer (Ca52 and
      Ca73) or duodenal ulcer (Du23:2 and Du52:2). All four strains induced an
      interleukin (IL)-8 response in AGS cells and translocated CagA into host cells
      where the protein was tyrosine phosphorylated, and thus harboured a functional
      type IV secretion system encoded by the cag PAI. The cagA gene contains a
      variable region close to its 3' end. Different compositions of this region has
      been proposed to exert various degrees of morphological changes in cultured
      gastric epithelial cells, and there are indications that the structure of the
      repetitive region is connected to the severity of disease. One of the studied
      strains (Du23:2) possessed five Western-type repeat regions while the other three
      strains harboured one Western-type repeat. Strain Du23:2 also contained a major
      rearrangement or large insertion/duplication in the intergenic region between
      HP0546 and HP0547 (cagA). Sequence similar to that of genes HP0510 and HP0509 was
      found in the 5' end of this region. The 3' end was similar to the corresponding
      region of strain ATCC 43504, including a mini IS605 element and a duplication of
      the 3' end of the cag PAI. Finally, a novel gene was identified in the cag PAI in
      three of the sequenced strains at the position of HP0521. This gene, HP0521B, is
      present in approximately half of Swedish H. pylori isolates.

PMID- 15019988
TI  - AtPARN is an essential poly(A) ribonuclease in Arabidopsis.
AB  - Deadenylation is the first and rate-limiting step in the degradation of many
      mRNAs in a wide-range of organisms from yeast to higher eukaryotes. It can also
      play a regulatory role in early development. In this study, we examined the
      Arabidopsis homolog of poly(A) ribonuclease (PARN), a deadenylase first
      identified in mammals and absent from yeast. Consistent with the conservation of
      domains and residues important for catalytic activity, Arabidopsis PARN (AtPARN)
      expressed in Escherichia coli has poly(A) degradation activity in vitro. Protein
      localization experiments in plant cells indicate that AtPARN resides in both the
      nucleus and cytoplasm. To address the importance of the enzyme in vivo, we
      identified three independent T-DNA insertion mutants of AtPARN which interrupt
      the gene at different positions between the ATG and the stop codon. All three
      alleles cause lethality prior to seed germination, indicating that AtPARN is an
      essential gene first required during early development. Although homologous genes
      have yet to be inactivated in any other organism, our observations argue for the
      critical importance of PARN and suggest that it may be essential in many other
      multicellular eukaryotes.

PMID- 15019989
TI  - VAAMANA--a BEL1-like homeodomain protein, interacts with KNOX proteins BP and STM
      and regulates inflorescence stem growth in Arabidopsis.
AB  - Plant shoot growth depends on the activity of the shoot apical meristem (SAM),
      where organ primordia are initiated. In turn, the function of the SAM depends on
      the activities of homeodomain (HD) proteins of the knotted1-like homeobox (KNOX)
      class [Long et al., Nature 379 (1996) 66; Vollbrecht et al., Development 127
      (2000) 3161]. In plants, KNOX proteins have been shown to interact specifically
      with the BEL1-like (BELL) class of homeodomain proteins [Bellaoui et al., Plant
      Cell 13 (2001) 2455; Muller et al., Plant 27 (2001) 13; Smith et al., Proc. Natl.
      Acad. Sci. USA 99 (2002) 9579], through a domain conserved between plants and
      animals. We have isolated a mutation in a BELL homeobox gene VAAMANA (VAN) that
      causes a dwarf phenotype. In addition, van inflorescence stems have clusters of
      cauline leaves; typically three are produced at each node. VAN interacts
      specifically with the class I KNOX proteins SHOOTMERISTEMLESS (STM),
      BREVIPEDICELLUS (BP), and KNAT6 (K6), and nuclear localisation of a VAN-GFP
      fusion depends on co-expression of STM or BP in tobacco leaves. This suggests
      that localisation of VAN, like that of the animal PBC homeodomain protein
      [Rieckhof et al., Cell 91 (1997) 171; Berthelsen et al., Genes Dev. 13 (1999)
      946], is also regulated by interaction with a partner homeodomain protein.

PMID- 15019990
TI  - Cloning, expression pattern and essentiality of the high-affinity copper
      transporter 1 (ctr1) gene in zebrafish.
AB  - The high-affinity copper transporter 1 (Ctr1) is a highly conserved transmembrane
      protein that mediates the internalization of copper ions from the extracellular
      medium. In this study, we have isolated the zebrafish ctr1 gene. The zebrafish
      ctr1 cDNA encodes a protein with 69% identity to the human orthologue and shows
      conservation of specific amino acid residues involved in copper transport. We
      find only a single ctr1 gene in the zebrafish genome which maps to linkage group
      5. The genomic structure of the zebrafish gene shows that it consists of five
      exons and that exon-intron boundaries are absolutely conserved with the mammalian
      ctr1 genes. Expression in embryos was analyzed by reverse transcription
      polymerase chain reaction (RT-PCR) and by in situ hybridization. Zebrafish ctr1
      is maternally loaded, and transcripts can be detected throughout development and
      in adult fish. Distribution of ctr1 message appears ubiquitous during early
      stages becoming restricted to the brain and ventral tissues by 24 h post
      fertilization (hpf). Beginning at 3 days post fertilization (dpf), expression is
      found mainly in the developing intestine. Specific knockdown of ctr1 by antisense
      morpholino oligonucleotides (MOs) causes early larval lethality. Defects include
      cell death in tissues where ctr1 is most heavily expressed, a finding similar to
      that described for a mouse knockout of mCtr1. Despite the existence of at least
      one other copper transport mechanism in the fish, our studies show that zebrafish
      ctr1 is an essential gene for development.

PMID- 15019991
TI  - Cloning and expression pattern of connexin39, a new member of the gap junction
      gene family isolated from the neural tube of chicken embryos.
AB  - In this study, a new gap junction (GJ) connexin (Cx) gene was isolated from the
      neural tube of chicken (c) embryos (HH21) and cloned by degenerate reverse
      transcription-polymerase chain reaction (RT-PCR). The open reading frame of the
      gene encodes for a protein of 343 amino acid residues with strong similarity to
      highly conserved connexin sequences. On the basis of the predicted molecular mass
      of 39144 kDa, we denominated it as cCx39. Sequence analysis allocated the cCx39
      to the alpha-group of connexin gene family. The mRNA expression of cCx39 was
      detected by RT-PCR and Northern blot in several tissues of chicken, including
      different parts of central nervous system, heart, liver, kidney, aorta and ovary.
      In situ hybridisation analysis of chicken brain showed strong expression in
      neurons of granular layers of cerebellum, optic tectum and ectostriatum. The in
      situ hybridisation of extracererebral tissues revealed strong expression of cCx39
      in the atrium of the heart, the external layer of the aorta and endothelium of
      biliary vessels; moderate expression was found in the endothelium of the aorta.

PMID- 15019992
TI  - Negative selection on neutralization epitopes of poliovirus surface proteins:
      implications for prediction of candidate epitopes for immunization.
AB  - For development of effective vaccines against viruses, it is of importance to
      choose appropriate epitopes as the target for immunization. These epitopes should
      eventually be determined experimentally, but it would be helpful if we could
      predict candidate epitopes computationally because it accelerates the entire
      process. To predict candidate epitopes for immunization, it is of great interest
      to characterize the target epitopes of poliovirus vaccine, which has empirically
      proven to be the most effective among all vaccines available. Here I show that
      almost all amino acid sites of poliovirus surface proteins VP1, VP2, and VP3
      including neutralization epitopes are negatively selected and no site is under
      positive selection. These results, together with those obtained in previous
      studies, indicate that vaccines directed against epitopes, which consist of
      negatively selected sites protect vaccinees more effectively than those directed
      against epitopes which contain positively selected sites. These observations
      suggest that candidate epitopes for immunization are predicted by the molecular
      evolutionary analysis of viral protein (and its coding nucleotide) sequences, as
      the epitopes which consist exclusively of negatively selected amino acid sites.

PMID- 15019993
TI  - Nek8, a NIMA family kinase member, is overexpressed in primary human breast
      tumors.
AB  - The family of human Nek (NIMA Related Kinase) kinases currently contains 11
      members. We have identified Nek8 as a new member of the Nek kinase family. For
      many of the Nek family members, primary tumor expression data and function have
      been limited. However, all of the Nek family proteins share considerable homology
      with the Never In Mitosis, gene A (NIMA) kinase from the filamentous fungus
      Aspergillus nidulans. NIMA, as well as its most closely related human ortholog,
      Nek2, are required for G(2)/M progression and promote centrosome maturation
      during mitosis. We isolated Nek8 from a primary human colon cDNA library, and
      found it to be highly homologous to murine Nek8. Recently, a previously named
      Nek8 sequence was renamed Nek9/Nercc1 in Genbank due to its lack of homology to
      murine Nek8 and its high homology to murine Nek9. Interestingly, in our study,
      phylogenetic analysis suggests that human Nek8 and Nek9 form a subfamily within
      the Nek family. Nek8 has high homology to the Nek family kinase domain as well as
      to a regulator of chromosome condensation domain (RCC1), which is also present in
      Nek9. The open reading frame of human Nek8 encodes a 692 amino-acid protein with
      a calculated molecular weight of 75 kDa. Nek8 is differently expressed between
      normal human breast tissue and breast tumors. Overexpression of a mutated kinase
      domain Nek8 in U2-0S cells led to a decrease in actin protein, and a small
      increase in the level of cdk1/cyclinB1. Our data demonstrate for the first time
      that Nek8 is a novel tumor associated gene, and shares considerable sequence
      homology with the Nek family of protein kinases and may be involved in G(2)/M
      progression.

PMID- 15019994
TI  - Transcription factor accessibility and histone acetylation of the progesterone
      receptor gene differs between parental MCF-7 cells and a subline that has lost
      progesterone receptor expression.
AB  - The human progesterone receptor (PgR) gene has a complex promoter that produces
      alternate mRNAs encoding the PgRA (94 kDa) and PgRB (120 kDa) protein isoforms.
      Expression of PgR is induced by estradiol (E(2)) in the breast, reproductive
      tract and many cell lines despite the lack of a classical estrogen responsive
      element (ERE) in the promoter regions. We employed chromatin immunoprecipitation
      (ChIP) to analyze the sites of estrogen receptor alpha (ERalpha) and Sp1
      occupancy of the PgR promoters in vivo. We also assessed the functional relevance
      of histone acetylation levels on the accessibility of transcription factors to
      the promoter and subsequent hormone-induced transcription. We utilized MCF-7
      human breast cancer cells that express PgR in response to E(2) and the MCF-7
      derived C4 cell strain that has lost PgR expression as a model system. We found
      that promoter-wide levels of histone acetylation were not decreased in C4 cells,
      but that access was partially blocked for Sp1 and completely blocked for ERalpha.
      The basal level of histone acetylation at six localized regions of the promoter
      did show some differences between cell lines, but it did not correlate with
      transcription factor binding. Furthermore, we found only a modest and highly
      localized change in histone acetylation levels in response to E(2) at only one of
      three sites of ERalpha binding in MCF-7 cells. This was at the B1 site at the
      distal 5' end of the promoter. This site also showed a significant decrease in
      basal histone acetylation in C4 compared to MCF-7 cells. We speculate that the
      histone acetylation level at this site may be a marker for chromatin structure
      that affects the access of transcription factors to the whole promoter.

PMID- 15019996
TI  - Genomic organization and promoter analysis of the gene encoding the mouse
      chemoattractant-like receptor, CMKLR1.
AB  - Chemoattractant-like receptor 1 (CMKLR1) is a functionally unknown ("orphan") G
      protein coupled receptor. It has been implicated in osseous and cartilage
      development, and it also has a pathophysiological role as one of the minor
      coreceptors involved in human immunodeficiency virus type I (HIV-1)/simian
      immunodeficiency virus (SIV) infection of CD4(+) immune cells. Here we report the
      cloning of the mouse cmklr1 gene, the characterization of its genomic structure
      for comparison with the human gene, and the mapping and functional analysis of
      its 5' flanking sequence. The gene was found to contain three exons intercepted
      by one larger and one smaller intron. The overall structure resembles the human
      orthologue. The promoter lacks classical TATA and CCAAT boxes but contains
      several GC-rich regions as well as AP-4 elements, C/EBP motifs, and GATA-1 and
      GATA-2 binding sites. Promoter function was analyzed in mouse neuroblastoma (NB4
      1A3) cells, endogenously expressing CMKLR1, as well as in mouse embryonic
      fibroblastic (3T3 clone A31) cells not expressing CMKLR1. 5' Deletion analysis
      and luciferase reporter gene assays of the promoter indicated that a 280-bp
      sequence adjacent to the transcription start site (established through 5'-RACE)
      is essential for initiating transcription. Within this region it was possible to
      identify four potential Sp1-binding sites that may be active in the transcription
      of the gene. Thus, we show that the mcmklr1 gene has several conserved features
      in common with its human counterpart, which suggests that they are regulated in a
      similar manner. The promoter does not seem to be tissue specific but other
      elements or enhancers may be missing. The results provide a necessary basis for
      further studies of the gene regulation and function of this chemoattractant-like
      receptor and will be useful when manipulating the gene in the development of
      transgenic animal models.

PMID- 15019995
TI  - Cloning and functional characterization of the murine mastermind-like 1 (Maml1)
      gene.
AB  - The Notch signaling pathway controls cell fate decisions and plays a critical
      role in normal development and diseases. The human mastermind-like (MAML) family
      members (MAML1, 2 and 3) encode critical transcriptional co-activators for Notch
      receptors. In this study, we cloned a murine cDNA that is highly homologous to
      the human MAML1 gene, Maml1. Mouse Maml1 encodes a nuclear protein, binds to the
      ankyrin repeat domain of Notch receptors, forms a ternary complex with the
      intracellular domain of Notch (ICN) and the DNA binding protein CSL, and enhances
      Notch-induced transcription of the target gene, HES-1. Therefore, Maml1 is the
      murine homologue for human MAML1 and functions as a transcriptional co-activator
      for Notch signaling. We also characterized the organization of the mouse Maml1
      gene: It spans at least 35 kilobases (kb) on chromosome 11 and contains five
      exons and four introns. Analysis of the 5' flanking region revealed that the
      promoter is TATA-less, and contains consensus binding sites for transcription
      factors such as Sp1, glucocorticoid receptor (GR), activating transcription
      factor (ATF) and cAMP response element-binding protein (CREB). Moreover, we
      examined Maml1 expression during early mouse development and found that Maml1
      gene is expressed widely but selectively in several tissues. There seems to be
      close correlation of the spatial and temporal expression among Maml1, Notch1 and
      Hes1 in the central nervous system (CNS) during early development, implicating a
      role for the Maml1 gene in neurogenesis.

PMID- 15019997
TI  - Origin and diversity of the SOX transcription factor gene family: genome-wide
      analysis in Fugu rubripes.
AB  - The SOX family of transcription factors are found throughout the animal kingdom
      and are important in a variety of developmental contexts. Genome analysis has
      identified 20 Sox genes in human and mouse, which can be subdivided into 8
      groups, based on sequence comparison and intron-exon structure. Most of the SOX
      groups identified in mammals are represented by a single SOX sequence in
      invertebrate model organisms, suggesting a duplication and divergence mechanism
      has operated during vertebrate evolution. We have now analysed the Sox gene
      complement in the pufferfish, Fugu rubripes, in order to shed further light on
      the diversity and origins of the Sox gene family. Major differences were found
      between the Sox family in Fugu and those in humans and mice. In particular, Fugu
      does not have orthologues of Sry, Sox15 and Sox30, which appear to be specific to
      mammals, while Sox19, found in Fugu and zebrafish but absent in mammals, seems to
      be specific to fishes. Six mammalian Sox genes are represented by two copies each
      in Fugu, indicating a large-scale gene duplication in the fish lineage. These
      findings point to recent Sox gene loss, duplication and divergence occurring
      during the evolution of tetrapod and teleost lineages, and provide further
      evidence for large-scale segmental or a whole-genome duplication occurring early
      in the radiation of teleosts.

PMID- 15019998
TI  - SCC-112, a novel cell cycle-regulated molecule, exhibits reduced expression in
      human renal carcinomas.
AB  - We report here the identification and an initial characterization of a novel cell
      cycle-regulated molecule, SCC-112. SCC-112 cDNA (6744 bp) encodes a longest open
      reading frame (ORF) comprised of 1297 amino acids, representing a approximately
      150-kDa nuclear protein. SCC-112 mRNA and protein levels were relatively high
      during the G2/M phase of the cell cycle in MDA-MB 435 breast cancer cells.
      Transient expression of SCC-112 cDNA in COS-1 cells led to an increase in the
      number of cells in sub-G1 phase and enhanced activity of caspase-3, a downstream
      effector of apoptosis. Stable transfection of SCC-112 cDNA in MDA-MB 231 breast
      cancer cells also led to an increase in the number of cells in sub-G1 phase (
      approximately 2-3-fold), indicative of apoptosis. The examination of the paired
      sets of human normal and tumor tissues revealed that the SCC-112 mRNA level was
      significantly high in normal breast and kidney tissues as compared to the
      corresponding primary tumor tissues (P<0.0001; breast, n=50, and kidney, n=20).
      Consistent with these observations, SCC-112 protein expression (150 kDa) was high
      in a majority of the normal renal tissues examined as compared to the matched
      renal tumor tissues (67%, 1.2-fold to>10-fold, n=18). Taken together, these
      findings suggest that the SCC-112 gene expression is likely to be associated with
      normal cell growth and proliferation.

PMID- 15019999
TI  - The motivation and behaviour of hospital Trusts.
AB  - This paper explores the motivation and behaviour of hospitals, using data from UK
      hospital Trusts. Managers and consultants (hospital specialists) are identified
      as the main alternative sources of power within Trusts. It is hypothesised that
      consultants are interested in production or service (volume and quality) while
      managers are interested primarily in financial break-even, and that in the long
      run consultants will dominate. A survey of 1500 consultants and managers and a
      statistical analysis of the behaviour of 100 Trusts over 3 years yielded the
      empirical results that were largely but not entirely consistent with these
      hypotheses. Consultants did indeed consider production goals to be more important
      than financial breakeven, but within those goals, considered quality to be more
      important than service volume. While the break-even target was found to be the
      primary goal of managers on average, they proved to be a heterogeneous group with
      quality ranking as the main priority among those managers who are closest to
      service delivery. This is at odds with the apparent objective of Trusts, which
      both groups perceive as being the single-minded pursuit of financial targets,
      consistent with the formal, government-set requirements. We find that this strong
      and unequivocal financial driver is not owned or acted upon by either consultants
      or managers and it is inferred that, in accordance with the dominant motivation
      of consultants, the Trust's primary objective is to maintain service quality.

PMID- 15020000
TI  - Effects of early health-insurance programs on European mortality and fertility
      trends.
AB  - In this study, we examined the mortality and fertility effects of the early
      health-insurance programs sponsored by several European governments in the course
      of the demographic transition. Three sets of effects were hypothesized, and
      tested with data for five countries, covering the 1875-1913 period. First,
      although initially small, the growing health-insurance coverage of national
      populations accelerated longer-term downtrends in mortality. It not only expanded
      access to health care, but also helped in disseminating health information and
      awareness. Second, widening coverage also had an opposite effect on fertility; by
      lowering the costs of bearing and rearing children, it acted to slow the ongoing
      downtrend in marital fertility. Third, there was a diverse set of interactions
      between the mortality and fertility effects. Improved prospects for the survival
      of infants and children weakened parents' motivation to produce "extra" offspring
      to offset losses to mortality and to insure against future losses. Child survival
      was further enhanced by longer intervals between births and fewer children per
      family. However, the reduced cost of children tended to dilute these antenatal
      effects. Our regression results supported the expected pattern of partial
      effects, but simulations were needed to gauge the total impacts of health
      insurance. Two sets of simulations were conducted: first, historical simulations,
      which closely tracked the actual experience of each sample country; second,
      counterfactuals, in which health-insurance coverage was set at zero for the
      entire time period. Comparisons of the historical and counterfactual simulations
      clearly indicated that health-insurance accelerated the downtrend in mortality,
      but slightly retarded the secular decline in marital fertility. These effects
      varied in magnitude, but not in direction, among the sample countries.

PMID- 15020001
TI  - Disability in society-medical and non-medical determinants for disability pension
      in a Norwegian total county population study.
AB  - The objective of this study was to describe sociomedical determinants and
      developments for the medically based disability pension in Norway by linking
      individual based data from a county health survey to data on disability from the
      National Insurance Administration. Two cross-sectional total population health
      surveys with an approximate 10-year interval were conducted in Nord-Trondelag
      county, HUNT I (1984-86) and HUNT II (1995-97), which allows for analyses of
      changes over time, supplied with official incidence data on disability pension.
      The large-scale variations and overall increasing incidence rates of disability
      pension in Norway during the last 20 years also applied to the county of Nord
      Trondelag. The prevalence of disability pension generally increased in the
      population from the mid-1980s to the mid-1990s. A striking finding was a
      consistent pattern of increasing prevalence of disability pension with decreasing
      socio-economic status and education. A geographic pattern for disability pension
      prevalence on a municipality level suggested that structural and cultural factors
      were important in determining the level of disability in society. Medical
      determinants alone cannot explain either the dramatic variations or the overall
      increased incidence rates of disability pension in the last two decades in
      Norway. The results demonstrate the importance of social, non-medical and
      contextual determinants for disability pension, how these determinants result in
      important prevalence differences by socio-economic status, and their impact on
      the level of disability in society.

PMID- 15020002
TI  - Portfolio evaluation of health programs: a reply to Sendi et al.
AB  - Sendi et al. (Soc. Sci. Med. 57 (2003) 2207) extend previous research on cost
      effectiveness analysis to the evaluation of a portfolio of interventions with
      risky outcomes using a "second best" approach that can identify improvements in
      efficiency in the allocation of resources. This method, however, cannot be used
      to directly identify the optimal solution to the resource allocation problem.
      Theoretically, a stricter adherence to the foundations of portfolio theory would
      permit direct optimization in portfolio selection, however, when we include
      uncertainty in our analysis in addition to the traditional concept of risk (which
      is often mislabelled uncertainty) complexities are introduced that create
      significant hurdles in the development of practical applications of portfolio
      theory for health care policy decision making.

PMID- 15020003
TI  - Portfolio theory and the alternative decision rule of cost-effectiveness
      analysis: theoretical and practical considerations.
AB  - Bridges and Terris (Soc. Sci. Med. (2004)) critique our paper on the alternative
      decision rule of economic evaluation in the presence of uncertainty and
      constrained resources within the context of a portfolio of health care programs
      (Sendi et al. Soc. Sci. Med. 57 (2003) 2207). They argue that by not adopting a
      formal portfolio theory approach we overlook the optimal solution. We show that
      these arguments stem from a fundamental misunderstanding of the alternative
      decision rule of economic evaluation. In particular, the portfolio theory
      approach advocated by Bridges and Terris is based on the same theoretical
      assumptions that the alternative decision rule set out to relax. Moreover,
      Bridges and Terris acknowledge that the proposed portfolio theory approach may
      not identify the optimal solution to resource allocation problems. Hence, it
      provides neither theoretical nor practical improvements to the proposed
      alternative decision rule.

PMID- 15020004
TI  - Adjustment latitude and attendance requirements as determinants of sickness
      absence or attendance. Empirical tests of the illness flexibility model.
AB  - This study investigates whether the two dimensions of illness flexibility at
      work, adjustment latitude and attendance requirements are associated to sickness
      absence and sickness attendance. Adjustment latitude describes the opportunities
      people have to reduce or in other ways change their work-effort when ill. Such
      opportunities can be to choose among work tasks or work at a slower pace.
      Attendance requirements describe negative consequences of being away from work
      that can affect either the subject, work mates or a third party. In a cross
      sectional design data based on self-reports from a questionnaire from 4924
      inhabitants in the county of Stockholm were analysed. The results showed that low
      adjustment latitude, as predicted, increased women's sickness absence. However,
      it did not show any relation to men's sickness absence and men's and women's
      sickness attendance. Attendance requirements were strongly associated to both
      men's and women's sickness absence and sickness attendance in the predicted way.
      Those more often required to attend were less likely to be absent and more likely
      to attend work at illness. As this is the first study of how illness flexibility
      at work affects behaviour at illness, it was concluded that more studies are
      needed.

PMID- 15020005
TI  - Social class and self-reported health status among men and women: what is the
      role of work organisation, household material standards and household labour?
AB  - Social class understood as social relations of ownership and control over
      productive assets taps into parts of the social variation in health that are not
      captured by conventional measures of social stratification. The objectives of
      this study are to analyse the association between self-reported health status and
      social class and to examine the role of work organisation, material standards and
      household labour as potential mediating factors in explaining this association.
      We used the Barcelona Health Interview Survey, a cross-sectional survey of 10,000
      residents of the city's non-institutionalised population in 2000. This was a
      stratified sample, strata being the 10 districts of the city. The present study
      was conducted on the working population, aged 16-64 years (2345 men and 1874
      women). Social class position was measured with Erik Olin Wright's indicators
      according to ownership and control over productive assets. The dependent variable
      was self-reported health status. The independent variables were social class,
      age, psychosocial and physical working conditions, job insecurity, type of labour
      contract, number of hours worked per week, possession of appliances at home, as
      well as household labour (number of hours per week, doing the housework alone and
      having children, elderly or disabled at home). Several hierarchical logistic
      regression models were performed by adding different blocks of independent
      variables. Among men the prevalence of poor reported health was higher among
      small employers and petit bourgeois, supervisors, semi-skilled (adjusted odds
      ratio-aOR: 4.92; 95% CI: 1.88-12.88) and unskilled workers (aOR: 7.69; 95%CI:
      3.01-19.64). Work organisation and household material standards were associated
      with poor health status with the exception of number of hours worked per week.
      Work organisation variables were the main explanatory variables of social class
      inequalities in health, although material standards also contributed. Among
      women, only unskilled workers had poorer health status than the referent category
      of manager and skilled supervisors (aOR: 3.25; 95%CI: 1.37-7.74). All indicators
      of work organisation and household material standards reached statistical
      significance, excepting the number of hours worked per week. In contrast to men,
      among women the number of hours per week of household labour was associated with
      poor health status (aOR: 1.02; 95% CI: 1.01-1.03). Showing a different pattern
      from men in the full model, household material deprivation and hours of household
      labour per week were associated with poor health status among women. Our findings
      suggest that among men, part of the association between social class positions
      and poor health can be accounted for psychosocial and physical working conditions
      and job insecurity. Among women, the association between the worker (non-owner,
      non-managerial, and un-credentiated) class positions and health is substantially
      explained by working conditions, material well being at home and amount of
      household labour.

PMID- 15020007
TI  - Maintenance of subjective health during a merger: the role of experienced change
      and pre-merger social support at work in white- and blue-collar workers.
AB  - Prospective research on psychosocial effects on employees' health associated with
      organizational mergers has been scarce. The first aim of this study was to
      explore the subjective health effects (exhaustion and functional incapacity) of
      an organizational merger among employees who had experienced a change in their
      own job position differently (improved, unaltered, and declined). Secondly, the
      effects of pre-merger social support (organizational, supervisor, and coworkers)
      at work on the experienced change in job position and on subjective health were
      examined. The merger took place in 1999 between two multinational firms of equal
      size. The study is based on two surveys (n=2,225) carried out in 1996 and in 2000
      in the Finnish part of the company. The data on age, sex, pre-merger sickness
      absence (1996-98) and subjective health status (1996) were used as covariates.
      The results indicate that all sources of social support had a significant effect
      on the experience of change in one's job position. A decline in job position
      strongly increased the risk of poor subjective health after the merger. Weak
      organizational support was associated with impaired subjective health, especially
      in blue-collar workers, while weak supervisor support impaired functional
      capacity in white-collar workers. In turn, strong co-workers' support increased
      the risk of poor subjective health among blue-collar workers when their job
      position declined. We conclude that negative changes experienced in one's job
      position and lack of upper-level social support at work create a potential risk
      for health impairment in different employee groups in merging enterprises.

PMID- 15020006
TI  - Tinker, tailor, soldier, patient: work attributes and depression disparities
      among young adults.
AB  - Prior studies have consistently found the occurrence of depression to be higher
      among persons with lower socio-economic status (SES), but causal mechanisms for
      this relationship are often not well understood. For example, while depression
      has been shown to increase during spells of unemployment, little work has been
      done on job attributes that may be related to depression among employed people
      early in their careers. This study links the 1992 wave of the National
      Longitudinal Survey of Youth 1979 cohort-which included Depression symptom scores
      on the Center for Epidemiologic Studies Depression (CES-D) instrument-to the US
      Department of Labor's new occupational characteristics O*Net dataset. The
      resulting dataset includes information regarding depression, SES, and specific
      attributes of jobs held by the young adult respondents. Job attributes included
      measures of social status, interpersonal stressors, and physical conditions.
      Multivariate analysis revealed that for young men, higher job status is
      associated with lower CES-D scores. Higher scores on the opposition scale, which
      measures the extent to which employees are obliged to take a position opposed to
      others, is associated with higher CES-D scores. For young women, physically
      uncomfortable or dangerous jobs are associated with more depressive symptoms.
      Results are stratified by race/ethnicity. For Black men, unlike for White men or
      Latinos, job security is associated with fewer depressive symptoms; and for
      Latino men, but not for Black or White men, physically uncomfortable or dangerous
      jobs are associated with more depressive symptoms. For Black women, job status is
      associated with fewer depressive symptoms. We conclude that part of the SES
      depression relationship may arise from the psychosocial aspects of jobs, which we
      have found to be significantly and meaningfully associated with depressive
      symptoms among employed young adults.

PMID- 15020008
TI  - Child well-being and neighbourhood quality: evidence from the Canadian National
      Longitudinal Survey of Children and Youth.
AB  - In this paper, we use the Canadian National Longitudinal Survey of Children and
      Youth data to examine the links between child well-being and neighbourhood
      'quality.' This study adds to the literature by (i) investigating the
      relationship between neighbourhood quality and child health, (ii) by utilizing
      subjective assessments by individuals familiar with the neighbourhood (i.e., the
      survey respondent and interviewer), and (iii) by utilizing multiple assessments
      of neighbourhood quality, and (iv) by investigating several measures of health.
      Other work has found that controlling for family level characteristics reduces or
      eliminates the apparent association between neighbourhood quality and health. We
      find, measuring both child well-being and neighbourhood quality multi
      dimensionally, that even after controlling for family level characteristics
      neighbourhood quality has strong associations with child well-being.

PMID- 15020009
TI  - The (mis)estimation of neighborhood effects: causal inference for a practicable
      social epidemiology.
AB  - The resurgence of interest in the effect of neighborhood contexts on health
      outcomes, motivated by advances in social epidemiology, multilevel theories and
      sophisticated statistical models, too often fails to confront the enormous
      methodological problems associated with causal inference. This paper employs the
      counterfactual causal framework to illuminate fundamental obstacles in the
      identification, explanation, and usefulness of multilevel neighborhood effect
      studies. We show that identifying useful independent neighborhood effect
      parameters, as currently conceptualized with observational data, to be
      impossible. Along with the development of a dependency-based methodology and
      theories of social interaction, randomized community trials are advocated as a
      superior research strategy, one that may help social epidemiology answer the
      causal questions necessary for remediating disparities and otherwise improving
      the public's health.

PMID- 15020010
TI  - Estimating neighborhood health effects: the challenges of causal inference in a
      complex world.

PMID- 15020011
TI  - The relevance of multilevel statistical methods for identifying causal
      neighborhood effects.

PMID- 15020012
TI  - Causal inference and the relevance of social epidemiology.

PMID- 15020013
TI  - Patients or partners? Case studies of user involvement in the planning and
      delivery of adult mental health services in London.
AB  - User or patient involvement (UI) in the planning and delivery of health services
      is an aspiration of many industrialized economies, and has been promoted by
      United Kingdom (UK) governments for over two decades. This paper reports the
      findings of qualitative case studies of UI in two mental health provider Trusts
      in London. Semi-structured interviews were conducted with a variety of
      stakeholders, including Trust staff at all levels and user group members, to
      compare the expectations of diverse stakeholders and the extent to which these
      were achieved. We found that UI remained in the gift of provider managers:
      providers retained control over decision making, and expected users to address
      Trust agendas and conform to Trust management practices. Users wanted to achieve
      concrete changes to policies and services, but had broader aspirations to improve
      the status and condition of people with mental health problems. Suggestions are
      made about the direction of future strategies to improve UI.

PMID- 15020014
TI  - Cumulative biological risk and socio-economic differences in mortality: MacArthur
      studies of successful aging.
AB  - Previous research has suggested that socio-economic status (SES) differences in
      mortality are only partially explained by differences in life-style,
      psychological and social factors. Seven year mortality data (1988-1995) from the
      MacArthur Study of Successful Aging, a longitudinal study of adults, aged 70-79,
      from New Haven, CT; East Boston, MA; and Durham, NC; were used to test the
      hypothesis that a cumulative measure of biological dysregulation ("allostatic
      load"), reflecting multiple regulatory systems, would serve as a further mediator
      of SES differences in mortality. Logistic regression analyses revealed that a
      cumulative index of biological risk explained 35.4% of the difference in
      mortality risk between those with higher versus lower SES (as measured by less
      than high school education versus high school or greater educational attainment).
      Importantly, the cumulative index provided independent explanatory power, over
      and above a measure of doctor-diagnosed disease, though the latter also
      contributed to education-related variation in mortality risks. The summary
      measure of biological risk also accounted for more variance than individual
      biological parameters, suggesting the potential value of a multi-systems view of
      biological pathways through which SES ultimately affects morbidity and mortality.

PMID- 15020015
TI  - Modernized education of traditional medicine in Korea: is it contributing to the
      same type of professionalization seen in Western medicine?
AB  - In Korea, the teaching of traditional medicine (TM) has been institutionalized
      for more than five decades, and accordingly the formulated educational system has
      a structure similar to that of Western medicine (WM). The authors therefore
      assumed that TM and WM students would share similar attitudes and values
      regarding professionalism. To test this hypothesis, we administered a
      questionnaire to TM students nationwide, and compared the results with those of
      WM students. We found that, despite the large differences in philosophy,
      concepts, and clinical content between the medical disciplines, the professional
      socializations of TM and WM students were progressing in a similar way.

PMID- 15020016
TI  - Parental role in medical decision-making: fact or fiction? A comparative study of
      ethical dilemmas in French and American neonatal intensive care units.
AB  - Neonatal intensive care has been studied from an epidemiological, ethical,
      medical and even sociological perspective, but little is known about the impact
      of parental involvement in decision-making, especially in critical cases. We rely
      here on a comparative, case-based approach to study the parental role in decision
      making within two technologically identical but culturally and institutionally
      different contexts: France and the United States. These contexts rely on two
      opposed models of decision-making: parental autonomy in the United States and
      medical paternalism in France. This paternalism model excludes parents from the
      decision-making process. We investigate whether parental involvement leads to
      different outcomes from exclusively medically determined decisions or whether
      "technological imperatives" outplay all other factors to shape a unique,
      'medically optimal' outcome. Using empirical data generated from extensive
      ethnographic fieldwork, in-depth interviews with 60 clinicians and 71 parents and
      chart review over a year in two neonatal intensive care units (one in France and
      one in the US), we analyze the factors that can explain the observed differences
      in decision-making in medically identical cases. Parental involvement and the
      legal context play a less role than physicians' differential use of certainty
      versus uncertainty in prognosis, a conclusion that corroborates the fact that
      medical control over ethical dilemmas remains even in the context of autonomy.
      French physicians do not ask parents permission to withdraw care (as expected in
      a paternalistic context); but symmetrically, American neonatologists (despite the
      prevailing autonomy model) tend not to ask permission to continue. The study
      provides an analysis of the making of "ethics", with an emphasis on how decisions
      are conceptualized as ethical dilemmas. The final conclusion is that the ongoing
      medical authority on ethics remains the key issue.

PMID- 15020017
TI  - Educational differences in starting excessive alcohol consumption: explanations
      from the longitudinal GLOBE study.
AB  - This paper describes educational differences in starting excessive alcohol
      consumption during 6 1/2 years of follow-up among 1648 initially alcohol
      consuming Dutch adults. The longitudinal GLOBE study provides the unique
      possibility to study explanations for educational differences due to the
      collection of extensive baseline information on educational level, alcohol
      consumption, stressors (tension reduction theory) and vulnerability indicators
      (differential vulnerability theory) in 1991. Alcohol consumption was again
      assessed in 1997. We report that lower educated people were almost three times
      more likely to start excessive alcohol consumption during follow-up compared to
      the highest educated persons. Both educational differences in exposure to
      stressors (financial problems) and vulnerability (low social support) contributed
      to the educational differences in starting excessive alcohol consumption and
      explained 23% of the educational variation in starting excessive alcohol
      consumption. Remaining educational differences were however still statistically
      significant. These results are discussed with regard to implications for
      interventions and possible additional explanatory mechanisms.

PMID- 15020018
TI  - Prediction of survival: a comparison between two subjective health measures in an
      elderly population.
AB  - A large amount of evidence shows that the subjective evaluation of health is a
      predictor of survival in many different populations. Subjective health (SH) is
      measured using different types of measures such as a general evaluation of health
      or a comparative evaluation of health. The aim of this study was to compare the
      prediction of survival by two measures of SH (a general measure and an age
      related measure) and evaluate the association with other variables in an elderly
      population. The baseline survey was conducted during 1994, covering 1138 men and
      women aged over 70. The survival status was ascertained 7 years later. After
      adjustment for age, sex, education, marital status, perceived socioeconomic
      status and presence of diseases the two SH measures were found to be predictors
      of mortality, but only in men. In men, there was no significant difference
      between the two types of SH measures in their prediction of mortality. Also in
      men, when there was only one or no disease, being married had a protective effect
      compared with not being married when both types of SH measures were used. In
      elderly women, the association between the two types of SH and survival
      diminished after adjusting for the various variables. However, the general SH
      measure may be the preferable measure to use when needed. Education in women was
      associated with mortality only via the age-related SH measure.

PMID- 15020019
TI  - Changing geographic access to and locational efficiency of health services in two
      Indian districts between 1981 and 1996.
AB  - In developing countries, including India, the role of the private sector in the
      provision of basic healthcare services is gradually expanding, since the public
      sector provides limited services and covers only limited areas. Using location
      allocation models (LAM), this paper (1) examines the changing geographic access
      to and locational efficiency of basic public healthcare vis-a-vis private
      healthcare services in two districts located in northwestern part of India, and
      (2) interrogates the factors that govern their geographic accessibility and
      locational-efficiency. Although this research confirms regional inequalities in
      geographic accessibility and locational efficiency of both public and private
      healthcare services in the selected districts, the locational efficiency of
      private health services is significantly lower than that of public health
      services. This paper further demonstrates the use of LAM for new site
      identification (keeping the existing healthcare sites intact) that will, in the
      future, improve locational efficiency of these services. This paper not only
      recommends improved geographic access to both public and private health services
      and their enhanced complementary role, but also stresses the need to evaluate
      geographic access from the service-users' perspective and the use of more
      realistic data on demand and supply in future research. The findings of this
      paper can be extended to areas with similar geographic settings, and socio
      economic and demographic conditions.

PMID- 15020020
TI  - Social networks and self-rated health in two French-speaking Canadian community
      dwelling populations over 65.
AB  - The objective was to evaluate the associations between older persons' health
      status and their social integration and social networks (family, children,
      friends and community), in two French-speaking, Canadian community dwelling
      populations aged 65 years and over, using the conceptual framework proposed by
      Berkman and Thomas. Data were taken from two 1995 surveys conducted in the city
      of Moncton (n = 1518) and the Montreal neighbourhood of Hochelaga-Maisonneuve (n
      = 1500). Social engagement (a cumulative index of social activities), networks
      consisting of friends, family and children and social support were measured using
      validated scales. Multiple logistic regressions based on structured inclusion of
      potentially mediating variables were fitted to estimate the associations between
      health status and social networks. Self-rated health was better for those with a
      high level of social integration and a strong network of friends in both
      locations. In addition, in Hochelaga-Maisonneuve family and children networks
      were positively associated with good health, though the effect of friend networks
      was attenuated in the presence of disability, good social support from children
      was associated with good health. Age, sex and education were included as
      antecedent variables; smoking, alcohol consumption, exercise, locus of control
      and depressive symptoms were considered intermediary variables between social
      networks and health. In conclusion, social networks, integration and support
      demonstrated unique positive associations with health. The nature of these
      associations may vary between populations and cultures.

PMID- 15020021
TI  - Effects of drug treatment for heroin sniffers: a protective factor against moving
      to injection?
AB  - We explore the relationship between contact with treatment and transition to
      injection for heroin sniffers. Our primary research question is, does contact
      with treatment delay onset of injection for heroin sniffers? A stratified network
      based sample was recruited from multiple communities in South Florida which were
      known for high drug use. Three categories of respondents were recruited based on
      injection outcome: long-term injectors, short-term injectors, and sniffers (n =
      900). We answer our research question in two steps. First, we investigate the
      prevalence of drug treatment for heroin sniffers and injectors using case-control
      methods. The preliminary findings indicate a positive relationship between
      contact with treatment and injection status outcome. Second, we further examine
      the relationship by attempting to identify the causal factors that delay initial
      injection for a subgroup of current injectors using survival regression
      procedures. Delaying or preventing transition to injection could significantly
      decrease risk of HIV transmission by reducing or eliminating risky injecting
      behaviors. We conclude with a discussion of policy implications and suggestions
      for future research.

PMID- 15020022
TI  - Midwives under threat again.

PMID- 15020023
TI  - Partnership in midwifery care in New Zealand.
AB  - OBJECTIVE: to examine whether equal power is essential to the perceptions of
      partnership in midwifery practice and to propose an alternative model of how
      power might best be shared. DESIGN: a cross-sectional design was employed using
      the predominant methods of interview, questionnaires and thinking aloud tape
      recordings as triangulation of data. SETTING: two large metropolitan hospitals in
      Auckland, New Zealand and home birth settings. SAMPLE: Forty one independent and
      hospital-based midwives and 37 nulliparous women at low obstetric risk for whom
      labour care was provided. FINDINGS: the majority of the midwives and the women in
      the two studies presented believed they had achieved a midwifery partnership with
      little emphasis placed on the need for equality in decision making. KEY
      CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: the model proposed provides a
      framework that identifies how power can be shared without the need for equality.
      The integration of this model into practice may assist midwives and women to
      recognise and utilise differences in their experience and knowledge to achieve
      their aims of achieving a partnership and a successful birth.

PMID- 15020024
TI  - An intrapartum intervention scoring system for the comparison of maternity units'
      intrapartum care of nulliparous women suitable for midwifery-led care.
AB  - OBJECTIVE: To develop an intrapartum intervention scoring tool which could be
      used to define maternity units as either 'lower intrapartum intervention' or
      'higher intrapartum intervention' units. This scoring tool was designed to form
      the basis of a comparison of the perception of risk by midwives working in either
      'lower intrapartum intervention' or 'higher intrapartum intervention' units.
      DESIGN: Three aspects were included: (1) the systematic data reduction of the St.
      Mary's Maternity Information System database used by 11 maternity units to
      include Caucasian nulliparous women suitable for midwifery-led care; (2) the
      calculation and the ranking of frequency distributions for the following
      interventions/management: (a) the management of breech presentation and of one
      previous caesarean section, the choice of home birth; and (b) augmentation of
      labour, use of electronic fetal monitoring, use of epidural, method of delivery;
      (3) the sum of the individual intrapartum ranking marks made up the final
      intrapartum score for each unit. RESULTS: Intrapartum interventions varied
      considerably between units. The scoring system enabled units to be described as
      either 'Lower intrapartum intervention' or 'Higher intrapartum intervention'
      units. CONCLUSIONS: Routinely collected computerised data can be used to identify
      the outcomes of intrapartum care. This study suggests that the analysis of
      computerised data could provide a suitable basis for the audit and the comparison
      of intrapartum interventions for the care of women suitable for midwifery-led
      care.

PMID- 15020025
TI  - The trials and tribulations of intrapartum studies.
AB  - OBJECTIVE: To review the reporting of randomised controlled trials for
      intrapartum interventions. METHODS: This was a literature search addressing the
      period from the publication of the CONSORT statement i.e. 1996-2002. Databases
      searched: Medline and CINAHL. Search terms: pregnancy, low-risk, normal,
      intrapartum, labour and labor. INCLUSION CRITERIA: randomised controlled trials
      reported in English which involved women experiencing: normal or 'low risk'
      pregnancy; intrapartum interventions; women who had a spontaneous onset of
      labour. DATA EXTRACTION: timing of consent and randomisation, proportion of
      eligible women recruited, 'losses' to the study. Included Studies fourteen
      published and one unpublished study that fitted the inclusion criteria were
      identified. Three studies were subsequently excluded because of a lack of
      information about the method and a further study was excluded due to its small
      sample size. FINDINGS: Three strategies for recruitment and randomisation for
      intrapartum studies were reported in the literature: antenatal recruitment and
      randomisation; consent and randomisation conducted on admission in labour or at
      the time of the intervention; staged recruitment and randomisation, which may be
      two- or three-staged. Different study designs have done much to improve the
      appearance of intrapartum studies and reduce post-randomisation losses. However,
      the problem of bias in RCTs is not limited to attrition alone and these designs
      may simply be moving the problem to an earlier stage in the study resulting in
      selection bias and limiting generalisability. CONCLUSIONS: The importance of
      accurate documentation of numbers at all stages in the research process is
      highlighted, in particular the number of eligible people not recruited, to allow
      the reader to assess the generalisability of the study.

PMID- 15020026
TI  - Can support and education for smoking cessation and reduction be provided
      effectively by midwives within primary maternity care?
AB  - OBJECTIVE: To test the hypothesis that appropriate interventions delivered by
      midwives within usual primary maternity care, can assist women to stop or reduce
      the amount they smoke and facilitate longer duration of breast feeding. DESIGN,
      SETTING AND PARTICIPANTS: In a cluster randomised trial of smoking education and
      breast-feeding interventions in the lower North Island, New Zealand, midwives
      were stratified by locality and randomly allocated into a control group and three
      intervention groups. The control group provided usual care. Midwives in the
      intervention groups delivered either a programme of education and support for
      smoking cessation or reduction, a programme of education and support for breast
      feeding or both programmes. Sixty-one midwives recruited a total of 297 women.
      INTERVENTIONS: Structured programmes provided by midwives. FINDINGS: Women
      receiving only the smoking cessation or reduction programme were significantly
      more likely to have reduced, stopped smoking or maintained smoking changes than
      women in the control group, at 28 weeks and 36 weeks gestation. Women receiving
      both the smoking cessation and breast-feeding education and support programmes
      were significantly more likely than women in the control group to have changed
      their smoking behaviour at 36 weeks gestation. There was no difference in rates
      of cessation or reduction between the groups in the postnatal period. There was
      no difference in rates of full breast feeding between the control and
      intervention groups for women who planned to breast feed. KEY CONCLUSIONS:
      Education and support by midwives, as part of primary midwifery, can facilitate
      smoking cessation and reduction during pregnancy.

PMID- 15020027
TI  - What can a meta-analysis tell us about traditional birth attendant training and
      pregnancy outcomes?
AB  - OBJECTIVE: to summarise the available published and unpublished studies on
      traditional birth attendant (TBA) training effectiveness. DESIGN: a meta
      analysis. STUDY SAMPLE: sixty studies (n=60) spanning 1971-1999 from 24 countries
      and three regions. MEASUREMENTS: the effect size index, Cohen's h for each
      outcome; the variance-weighted mean effect size and 95% confidence interval for
      sub-group of outcomes; homogeneity tests on the distribution of the weighted mean
      effect sizes; and sensitivity analysis to detect the presence of publication
      bias. FINDINGS: TBA training was associated with significant increases in
      attributes such as TBA 'knowledge' (90%), 'attitude' (74%), 'behaviour' (63%) and
      'advice' (90%) over the untrained TBA baseline. Results for 'behaviour' and
      'advice' in specific content areas related to peri-neonatal health outcome,
      however, reveal sources of variability and underscore the conflicting evidence on
      TBA training. TBA training was also associated with small but significant
      decreases in peri-neonatal mortality (8%) and birth asphyxia mortality (11%).
      Incomplete reporting limited the assessment of neonatal mortality due to tetanus
      and acute respiratory infection, maternal mortality, as well as assessment of the
      relationship between intervention characteristics and outcomes. The quality of
      studies included in the meta-analysis lack sufficient rigour to address the
      question of causality. Thus, while the data suggest that TBA training is
      effective in terms of the outcomes measured, we are unable to demonstrate that it
      is a cost-effective intervention. IMPLICATIONS: skilled attendance at birth is a
      distant reality in many developing countries and effective community-based
      strategies are needed to help reduce high levels of mortality. Given the
      magnitude of peri-neonatal mortality, the associations observed between TBA
      training peri-neonatal and birth asphyxia mortality, and TBA attributes in
      content relevant to peri-neonatal survival, we suggest that these strategies may
      usefully include TBA training in appropriate settings. If TBAs are to be trained,
      however, it is imperative that their training be adequately evaluated in order to
      develop the strong evidence base that is lacking to-date and that is necessary
      for sound policy and programming.

PMID- 15020028
TI  - The influence of maternity units' intrapartum intervention rates and midwives'
      risk perception for women suitable for midwifery-led care.
AB  - OBJECTIVE: to test the hypothesis that midwives working in higher intervention
      units would have a higher perception of risk for the intrapartum care of women
      suitable for midwifery-led care than midwives working in lower intervention
      units. METHODS: an initial retrospective analysis of the computerised records of
      9887 healthy Caucasian women in spontaneous labour enabled the categorisation of
      11 units as either 'lower intrapartum intervention' or 'higher intrapartum
      intervention' units. A survey of the midwives involved in intrapartum care in
      these 11 units, using standardised scenario questionnaires, was used to
      investigate midwives' options for intrapartum interventions, their perceptions of
      intrapartum risk and the accuracy of these perceptions in the light of actual
      maternity outcomes. FINDINGS: midwives working in maternity units that had a
      higher level of intervention generally perceived intrapartum risks to be higher
      than midwives working in lower intervention units. However, midwives generally
      underestimated the ability of women to progress normally and overestimated the
      advantages of technological interventions, in particular epidural analgesia.
      CONCLUSIONS: variations in intrapartum care cannot be solely explained by the
      characteristics of the women. The influence of the workplace culture plays a
      significant role in shaping midwives' perceptions of risk, but it seems even more
      likely that the medicalisation of childbirth has had an influence on midwives'
      appreciation of intrapartum risks. Intervention rates for low-risk births are
      often higher than recommended by research. The level of interventions varies
      across hospitals and higher rates are associated with higher perception of risk
      by midwives. Attention needs to be given to the influence the workplace plays in
      shaping midwives' perception of risk; and to the effect of organisational culture
      on intervention rates.

PMID- 15020029
TI  - A midwifery practice dichotomy on oral intake in labour.
AB  - OBJECTIVE: to assess the views and practices of midwives regarding oral intake in
      labour for women with low-risk pregnancies. DESIGN: an exploratory survey design
      including open- and closed-ended questions. SETTING: four hospitals in Sydney,
      Australia. PARTICIPANTS: 89 practising midwives who provided care for labouring
      women. FINDINGS: midwives were divided on the issue of what and when labouring
      women should, or should not, be allowed to eat and drink. The views and practices
      of these midwives were influenced by the accepted practice in the hospital in
      which they were employed and the types of midwifery models in which they have
      practised. KEY CONCLUSIONS: there is insufficient conclusive research evidence to
      support any stance on oral intake for labouring women. Most information purported
      by supporters of oral intake is based on anecdotal evidence and assumptions based
      on the physiology of the body. 'Nil by mouth' policies have never been researched
      while clear fluid policies are based on research performed with non-obstetric
      patients. IMPLICATIONS FOR PRACTICE: without reliable research evidence for the
      management of oral intake for labouring women no hospital practice or policy is
      valid. This leaves midwives with the responsibility of deciding what they believe
      is the best management for the oral intake of labouring women in their care.

PMID- 15020031
TI  - An interview study of the impact of domestic violence training on midwives.
AB  - OBJECTIVES: to evaluate the impact on midwives of a training programme designed
      to increase their awareness and understanding of violence against women from men
      they know. DESIGN: a cross-sectional survey using semi-structured interviews.
      PARTICIPANTS: a stratified sample of 55 midwives who attended training between
      April 1999 and June 2000 were asked to participate, 26 agreed. SETTING: midwifery
      services of the Leeds Teaching Hospital NHS Trust. RESULTS: participants reported
      greater awareness and understanding of domestic violence, and an increased
      likelihood of identifying and supporting women, partly through improved knowledge
      of other helping agencies. However, there was considerable uncertainty over
      issues of confidentiality and documentation. Practical difficulties were raised
      in implementing training within the midwifery role; these included time and
      privacy. CONCLUSION: this research adds to the scarce evidence base related to
      the effectiveness of health-care professionals' training in domestic violence.
      Further research should also explore the impact of training on women's
      experiences of healthcare.

PMID- 15020030
TI  - Presenting and discussing nuchal translucency screening for fetal abnormality in
      the UK.
AB  - OBJECTIVE: to investigate the relationship between information giving by midwives
      and decision-making by women offered nuchal translucency (NT) screening. To
      establish how risk figures are discussed in practice, with the intention of
      relating this to the existing, and often critical, literature on women's accounts
      of antenatal screening. DESIGN: a qualitative study following women through the
      process of being offered and deciding to undergo NT screening. Tape recording of
      consultations, analysed in their entirety, was combined with post-screening
      interviews. SETTING: a large teaching hospital in the UK. PARTICIPANTS: fourteen
      pregnant women eligible for NT screening at the time of recruitment. DATA
      COLLECTION: (i) tape recordings of consultations between community midwives and
      pregnant women where nuchal translucency screening was offered; (ii) tape
      recordings of consultations between hospital midwives and pregnant women
      immediately post-screening; (iii) individual face-to-face interviews with
      pregnant women between two and six weeks after the screening, carried out by the
      first author. FINDINGS: NT screening was in general well received, particularly
      by those women who had undergone serum screening with previous pregnancies.
      However, communicating the nature of a risk figure is an interactionally complex
      process. A large amount of interactional work is required by midwives both before
      and after screening to ensure that women comprehend this information. Despite the
      emphasis placed in these consultations on understanding the purpose of NT
      screening and the status of the results, women often framed their decision to
      undergo NT screening in terms of it being a formality, or of presuming that all
      was well. This sometimes created practical and personal difficulties in terms of
      decision-making. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: previous
      sociological and psychological research has tended to be critical of midwives in
      terms of ensuring informed choice in screening, but this research is often based
      on post hoc accounts. Examining actual consultations with these accounts helps to
      illustrate the other factors that affect women's perceptions of testing, and the
      way in which risk, choice and decision-making are introduced and discussed in
      practice. Encouraging women to consider what action they might take on the basis
      of a personally unfavourable NT result in advance of undergoing the scan may help
      them to decide whether the information gained will be useful to them. Recognising
      the complex interactional work required in making sure that women understand the
      nature of the results that will be obtained is an important issue for the
      education and training of midwives.

PMID- 15020032
TI  - Women's satisfaction with decision-making related to augmentation of labour.
AB  - OBJECTIVE: to describe women's experiences of participating in decision-making
      related to augmentation of labour. DESIGN: a qualitative approach using modified
      grounded theory technique. Open-ended interviews were conducted 1-3 days after
      childbirth. SETTING: the interviews were performed in the postnatal wards in five
      hospitals (tertiary level) in Stockholm, Sweden. PARTICIPANTS: 20 newly delivered
      women who had received oxytocin infusion for augmentation of labour during
      childbirth. FINDINGS AND KEY CONCLUSIONS: support and guidance from midwives in
      combination with knowledge and expectations about the intervention seemed to be
      important for women's satisfaction with decision-making concerning augmentation
      of labour. Four patterns of decision-making were found. One group of women
      participated in the decision-making regarding augmentation of labour while a
      second group was invited, but refrained from participation. These women were
      satisfied with the decisions made. A third group of women did not participate,
      but wanted to and they were dissatisfied with the decisions made. The fourth
      group did not participate in the decision-making-and did not want to. These women
      accepted the decisions made. The desire for information exceeded the desire for
      involvement in decision-making and the majority of women had confidence in the
      midwives' assessment.

PMID- 15020033
TI  - Assessment of blinding in clinical trials.
AB  - Success of blinding is a fundamental issue in many clinical trials. The validity
      of a trial may be questioned if this important assumption is violated. Although
      thousands of ostensibly double-blind trials are conducted annually and
      investigators acknowledge the importance of blinding, attempts to measure the
      effectiveness of blinding are rarely discussed. Several published papers proposed
      ways to evaluate the success of blinding, but none of the methods are commonly
      used or regarded as standard. This paper investigates a new approach to assess
      the success of blinding in clinical trials. The blinding index proposed is scaled
      to an interval of -1 to 1, 1 being complete lack of blinding, 0 being consistent
      with perfect blinding and -1 indicating opposite guessing which may be related to
      unblinding. It has the ability to detect a relatively low degree of blinding,
      response bias and different behaviors in two arms. The proposed method is applied
      to a clinical trial of cholesterol-lowering medication in a group of elderly
      people.

PMID- 15020034
TI  - Bayesian sample size calculations in phase II clinical trials using informative
      conjugate priors.
AB  - A number of researchers have discussed phase II clinical trials from a Bayesian
      perspective. A recent article by Tan and Machin focuses on sample size
      calculations, which they determine by specifying a diffuse prior distribution and
      then calculating a posterior probability that the true response will exceed a
      prespecified target. In this article, we extend these sample size calculations to
      include informative prior distributions using various strategies that allow
      researchers with both optimistic and pessimistic priors direct involvement in the
      sample size decision making. We select the informative priors via multiple
      methods determined by the mean, median or mode of the conjugate prior. These
      cases can result in varying sample sizes.

PMID- 15020035
TI  - Comparing the power of the discontinuation design to that of the classic
      randomized design on time-to-event endpoints.
AB  - The discontinuation design has been proposed as an alternative to the classic
      randomized design for evaluating the effect of an experimental agent on time-to
      disease progression and survival duration. With this design, all enrolled
      patients are treated with an experimental agent for a fixed course of therapy.
      Those patients with progressive disease at or before the end of this fixed period
      are removed from trial while those with stable disease or better are randomized
      to continued treatment with the experimental agent or standard of care.
      Simulations presented in this paper demonstrate that for realistic situations,
      the loss in information on patients enrolled but not randomized in the
      discontinuation design is of sufficient magnitude that it is underpowered as
      compared to the classic design of randomizing all enrolled subjects.

PMID- 15020037
TI  - Implementation of the Prostate Cancer Prevention Trial (PCPT).
AB  - The Prostate Cancer Prevention Trial is a randomized double blind chemoprevention
      trial of 18,882 men. It is designed to test the difference in the histologically
      proven prostate cancer prevalence between a group of participants given
      finasteride and another given placebo for 7 years. We present an overview of the
      study design, details of the administrative structure of the study and a
      description of the successful implementation of the accrual phase.

PMID- 15020038
TI  - Preventing chronic ectopic bone-related pain and disability after hip replacement
      surgery with perioperative ibuprofen. A multicenter, randomized, double-blind,
      placebo-controlled trial (HIPAID).
AB  - Postoperative ectopic bone formation affects about 40% of people undergoing
      elective hip replacement surgery. Despite clear evidence that a short course of
      perioperative nonsteroidal anti-inflammatory drugs (NSAIDs) can substantially
      reduce the occurrence of ectopic bone, the use of NSAID-based prophylactic
      therapy is uncommon in Australia or New Zealand. In part, this reflects surgeons'
      uncertainty about the importance of ectopic bone as a cause of impaired long-term
      outcome, and in part, concerns about possible increased risk for gastrointestinal
      complications and excess wound bleeding in patients undergoing orthopedic
      surgery. To address this uncertainty, a multicenter randomized controlled
      clinical trial is being conducted amongst 1000 patients undergoing elective total
      hip replacement (or revision) surgery. Patients are randomly allocated to 14 days
      of treatment with either 1200 mg ibuprofen (a commonly used NSAID) or matching
      placebo commencing within 24 h of surgery. Treatment outcomes will be assessed 6
      12 months later. The primary outcome will be self-reported pain and physical
      function. Secondary outcomes include quality of life and physical performance
      measures. Patient recruitment has commenced in more than 20 orthopedic centers
      throughout Australia and New Zealand and will be complete by the end of October
      2003. The prevention of chronic ectopic bone-related pain and disability after
      hip replacement surgery with anti-inflammatory drugs study (HIPAID) has been
      designed to provide precise and reliable information about the overall balance of
      risks and benefits associated with a short 14-day perioperative course of
      ibuprofen among individuals undergoing elective total hip replacement surgery.

PMID- 15020036
TI  - The UCSD Statin Study: a randomized controlled trial assessing the impact of
      statins on selected noncardiac outcomes.
AB  - There has been persistent controversy regarding possible favorable or adverse
      effects of statins or of cholesterol reduction on cognition, mood and behavior
      (including aggressive or violent behavior), muscle function, and quality of life.
      The UCSD Statin Study seeks to ascertain the beneficial or adverse effects of
      statin cholesterol-lowering drugs on a set of noncardiac endpoints, including
      cognition, behavior, and serotonin biochemistry. The study will enroll 1000
      subjects (minimum 20% female) of mixed ethnicity from San Diego. Subjects must be
      age 20 and older, postmenopausal if female, without known cardiovascular disease
      or diabetes, and with LDL-cholesterol between 115 and 190 mg/dl. Subjects will be
      randomized to a double-blind, placebo-controlled trial with assignment 1/3, 1/3,
      1/3 to placebo, simvastatin 20 mg, or pravastatin 40 mg (equipotent LDL
      cholesterol-lowering doses for drug arms with simvastatin and pravastatin chosen
      to represent the extremes of the lipophilicity spectrum) for 6 months of
      treatment followed by 2 months postcessation follow-up. Primary outcomes are
      cognition (cognitive battery), irritability/aggression (behavior measure), and
      serotonin (gauged by whole blood serotonin), assessed as the difference between
      baseline and 6 months, judging combined statin groups vs. placebo. Secondary
      outcomes include mood (CES-D and Wakefield depression inventory), quality of life
      (SF-12V), sleep (Leeds sleep scale, modified), and secondary aggression measures
      (Conflict Tactics Scale; Overt Aggression Scale, Modified). Cardiovascular
      reactivity will be examined in a 10% subset. As additional secondary endpoints,
      primary and selected secondary outcomes will be assessed by statin assignment
      (lipophilic simvastatin vs. hydrophilic pravastatin). "Reversibility" of changes,
      if any, at 2 months postcessation will be determined. If effects (favorable or
      unfavorable) are identified, we will seek to ascertain whether there are baseline
      variables that predict who will be most susceptible to these favorable or adverse
      noncardiac effects (i.e., effect modification).

PMID- 15020041
TI  - To the 30-nm chromatin fiber and beyond.
AB  - Chromatin fibers are intrinsically dynamic macromolecular complexes whose
      biological functions are intimately linked with their structure and interactions
      with chromatin-associated proteins (CAPs). Three-dimensional architectural
      transitions between or within the two co-existing chromatin types referred to as
      euchromatin and heterochromatin have been associated with activation or
      repression of nuclear functions. The presence of specific subsets of chromosomal
      proteins co-existing with the different chromatin conformations suggests a
      functional significance for their co-localization. The major points of emphasis
      of this review will assess the structure, function and recently documented
      exchanges amongst various members of the CAP family.

PMID- 15020042
TI  - Anatomy of a hypersensitive site.
AB  - The 600-bp accessible region at the activated PHO5 promoter in S. cerevisiae has
      become a paradigm for hypersensitive sites. In this review, we summarize the
      various experimental strategies used to characterize chromatin at the active
      promoter and point out their virtues and their limitations. We describe the
      properties of chromatin at the active PHO5 promoter and what we currently know
      about the transition from the inactive to the active state. The implications for
      generating a hypersensitive region in chromatin are discussed.

PMID- 15020040
TI  - Histone chaperones, a supporting role in the limelight.
AB  - In eukaryotic cells, highly basic histone proteins are associated with the DNA to
      form the nucleosome, the fundamental unit of chromatin. Histones are closely
      escorted by histone chaperones from their point of synthesis up to their delivery
      site. We will present an overview of the histone chaperones identified to date
      with their various roles, in an attempt to highlight their importance in cellular
      metabolism. Nucleoplasmin will illustrate a role in histone storage and Nap-1, a
      histone translocator. CAF-1 and Hira will provide examples of distinct histone
      deposition factors coupled to and uncoupled from DNA synthesis, respectively,
      while Asf1 could act as a histone donor. We then will illustrate with two
      examples how histone chaperones can be associated with chromatin remodeling
      activities. Finally, we will discuss how the RbAp46/48 proteins, as escort
      factors, are part of multiple complexes with various functions. Based on these
      examples, we will propose a scheme in which the diverse roles of histone
      chaperones are integrated within an assembly line for chromatin formation and
      regulation. Finally, we discuss how these chaperones may have more than a
      supporting role in a histone metabolic pathway.

PMID- 15020043
TI  - Modifying chromatin to permit steroid hormone receptor-dependent transcription.
AB  - Lipophilic hormones, including steroids, exert their physiological effects
      through binding to high-affinity superfamily of steroid hormone receptor (SR)
      proteins that function as ligand-dependent DNA binding transcription factors. To
      date, SR proteins are among a few transcription factors shown to directly
      interact with higher order chromatin structures to regulate gene expression. To
      perturb chromatin, SRs employ enzymatic multicomplexes that can either remodel or
      modify chromatin. Here we examine the current state of knowledge concerning
      multicomplex chromatin remodeling/modification machines and SR-dependent
      transcription. We will focus on the role of these protein-protein and chromatin
      protein interactions in vivo with the MMTV promoter as a primary model. In
      addition, we discuss emerging evidence implicating chaperone proteins and
      proteasome degradation machinery in SR-mediated gene regulation within chromatin.

PMID- 15020044
TI  - Dynamics of nuclear receptor movement and transcription.
AB  - Following a hormone signal, steroid/nuclear receptors bind regulatory elements in
      chromatin and initiate the recruitment of a variety of multi-protein complexes to
      promoter sequences. These complexes ultimately lead to the recruitment of general
      transcription factors and the initiation of transcription. Traditional models
      suggest that these factors remain statically bound to each other and to chromatin
      until other signals are received to reduce transcription. Recent findings
      demonstrate that the processes and actions involved are much more complex than
      traditional models convey, and that the movement of receptors and coactivators is
      remarkably dynamic. Transcription factors are highly mobile in the nuclear
      environment, and interact only briefly with target sites in the nucleus. As a
      result of these transient interactions, promoters move through many states during
      activation and repression. Two general concepts emerge from current data: (1)
      Various transcription factors appear to follow "ordered recruitment" to promoters
      on a time scale of minutes to hours in response to a stimulus. During this
      response, the proteins that interact with chromatin may cycle on and off the
      promoter multiple times. (2) During these ordered recruitment cycles, the
      individual molecules that form functional complexes often exchange rapidly on a
      time scale of seconds. This rapid exchange of molecules within a formed complex
      occurs independently of long-term cycling on chromatin. Several processes are
      implicated in rapid nuclear dynamics, including potential roles for molecular
      chaperones, the proteasome degradation machinery and chromatin remodeling
      complexes.

PMID- 15020045
TI  - Mi-2/NuRD: multiple complexes for many purposes.
AB  - The vertebrate Mi-2/NuRD complex is a multi-subunit protein complex containing
      both histone deacetylase and nucleosome-dependent ATPase subunits. Current models
      predict that this complex functions primarily in transcriptional repression.
      Surprisingly, every subunit of this complex presents heterogeneity at the protein
      and gene level. This raises the intriguing possibility of functional
      specialization resulting from incorporation of unique gene products into the
      complex. The MTA (metastasis-associated) proteins represent one class of
      alternative subunits of the human Mi-2/NuRD complex. The members of this family
      in human cells are differentially expressed depending on cell type and on
      physiologic parameters. We summarize evidence supporting the view that the
      alternative subunits of the complex that have arisen during vertebrate evolution
      endow unique functional properties.

PMID- 15020046
TI  - Nucleosome remodeling: one mechanism, many phenomena?
AB  - The term 'nucleosome remodeling' subsumes a large number of energy-dependent
      alterations of canonical nucleosome structure, catalyzed by dedicated ATPases in
      large multiprotein complexes. The importance of these factors for gene regulation
      and other processes with chromatin substrate have emerged from genetic studies.
      Mechanistic analyses of nucleosome remodeling by different enzymes provided a
      diverse, almost confusing phenomenology of ATP-dependent derangement of
      nucleosomes in vitro, suggesting that different remodeling machines follow
      different strategies to disrupt histone-DNA interactions. This review explores
      the alternative possibility that the rich phenomenology of nucleosome remodeling
      may be brought about by variations of one basic remodeling reaction.

PMID- 15020047
TI  - The RNA polymerase II transcription cycle: cycling through chromatin.
AB  - The cycle of events that characterizes RNA polymerase II transcription has been
      the focus of intense study over the past two decades. Our knowledge of the
      molecular processes leading to transcriptional initiation is greatly improved,
      and the focus of many recent studies has shifted towards the less well
      characterized events taking place after assembly of the pre-initiation complex,
      such as promoter clearance, elongation, and termination. This review gives a
      brief overview of the transcription cycle as a whole, focusing especially on
      selected mechanisms that may drive or restrict the cycle, and on how the presence
      of chromatin may influence these mechanisms.

PMID- 15020048
TI  - H2B ubiquitylation: the end is in sight.
AB  - Historically, the first eukaryotic protein found to be modified by ubiquitin was
      H2A, originally isolated from HeLa cells in 1975 by Harrison Busch and coworkers
      as a histone-like, nonhistone chromosomal protein called A24. Ubiquitylated
      histones have subsequently been found in many eukaryotic species, and to date,
      the core histones H2A, H2B, H3, the linker histone H1, and the histone variant
      H2A.Z are known to carry this modification. Although first on the scene, it was
      only recently that studies on histone ubiquitylation have enjoyed a renaissance.
      Part of the reason for the relatively slow pace of research on this fascinating
      histone modification was the absence of a good genetic system with which to study
      its cellular roles. This changed in 2000, when histone H2B was found to be
      ubiquitylated in the budding yeast S. cerevisiae, an organism with a low histone
      gene copy number and highly tractable genetics. Another factor was the almost
      exclusive focus of research on the role of polyubiquitylation in protein
      turnover. Because histones are generally monoubiquitylated, a form of the
      modification that is not associated with protein degradation, the significance of
      this minimalist ubiquitin conjugation was not heavily pursued. But perhaps the
      key reason for the renewed interest in histone ubiquitylation was the unexpected
      discovery of the past year that ubiquitylated H2B plays an important role in the
      trans-histone methylation of histone H3, a modification with close ties to the
      regulation of gene expression. This review will highlight some of the recent
      findings on the regulation and cellular roles of H2B ubiquitylation in yeast.

PMID- 15020049
TI  - Transcriptional elongation control by RNA polymerase II: a new frontier.
AB  - The transcription elongation complex, once thought to be composed of merely the
      DNA template, RNA polymerase II and the nascent RNA transcript, is now burgeoning
      as a unit as multifaceted and complicated as the transcription initiation
      complex. Studies concentrated in defining the elongation stage of transcription
      during the past recent years have resulted in the discovery of a diverse
      collection of transcription elongation factors that are either directly involved
      in the regulation of the rate of the elongating RNA polymerase II or can modulate
      messenger RNA (mRNA) processing and transport. Such studies have demonstrated
      that the elongation stage of transcription is highly regulated and has opened a
      new era of studies defining the molecular role of such transcription elongation
      factors in cellular development, differentiation and disease progression. Recent
      studies on the role of RNA polymerase II elongation factors in regulating of the
      overall rate of transcription both in vitro and in vivo, histone modification by
      methylation and organismal development will be reviewed here.

PMID- 15020050
TI  - Transcription through chromatin: understanding a complex FACT.
AB  - In eukaryotic cells, genomic DNA is assembled with chromosomal proteins, mainly
      histones, in a highly compact structure termed chromatin. In this form, DNA is
      not readily accessible to the cellular machineries, which require DNA as a
      template. Dynamic changes in chromatin organization play a critical role in
      regulation of DNA-dependent processes such as transcription, DNA replication,
      recombination and repair. Chromatin structure is altered in transcriptionally
      active loci: the basic chromatin unit, the nucleosome, appears to be depleted for
      one histone H2A/H2B dimer. Previously, reconstitution of RNA polymerase II
      (PolII)-driven transcription on chromatin templates in a highly purified in vitro
      system led to identification of FACT (for facilitates chromatin transcription),
      which was required for productive transcript elongation through nucleosomes. FACT
      was proposed to promote PolII transcription through nucleosomes by removing
      either one or both H2A/H2B dimers. Here we present an overview of the earlier
      studies, which resulted in the initial identification and characterization of
      FACT, as well as the recent findings that refine the model for the mechanism of
      FACT function in transcription.

PMID- 15020051
TI  - ISWI complexes in Saccharomyces cerevisiae.
AB  - The imitation switch (ISWI) class of chromatin remodeling ATPase is ubiquitous in
      eukaryotes. It is becoming clear that these enzymes exist as part of larger
      complexes and the nature of the associated proteins dictate the function
      associated with a complex both in biochemical assays and in the cell. Much
      progress has been made in understanding these relationships in the budding yeast
      Saccharomyces cerevisiae, containing two ATPases, Isw1p and Isw2p. This has been
      aided by the ease of genetic manipulation, by a number of systematic screens
      designed to specifically detect ISWI function and by the plethora of data
      generated from a number of global screens for function. At present, many
      functions for yeast Isw1p and Isw2p are related to effects on RNA levels and are
      associated with the controlled repression of gene expression that crudely fall
      into three types: displacement of the basal transcription machinery to repress or
      silence transcription of genes (Isw2 complex and Isw1/Ioc3 complex); control of
      the activation of expression leading to coordination of transcription elongation;
      and efficient termination of transcription (Isw1/Ioc4/Ioc2 complex). The latter
      two functions are regulated by specific phosphorylation of residues within the
      carboxy terminal domain (CTD) of the largest subunit of RNA polymerase II
      (RNAPII). Other functions may relate to the ability of ISWI complex to displace
      transcription factors or enzymes from the template. Other ISWI-containing
      complexes that have yet to be characterized indicate that much remains to be
      learnt about yeast ISWI itself and importantly, how the various forms cooperate
      with different classes of chromatin remodeling ATPase, complexes containing
      histone acetylases, deacetylases, methylases and both DNA and RNA polymerases.

PMID- 15020052
TI  - Multiple roles for ISWI in transcription, chromosome organization and DNA
      replication.
AB  - ISWI functions as the ATPase subunit of multiple chromatin-remodeling complexes.
      These complexes use the energy of ATP hydrolysis to slide nucleosomes and
      increase chromatin fluidity, thereby modulating the access of transcription
      factors and other regulatory proteins to DNA. Here we discuss recent progress
      toward understanding the biological functions of ISWI, with an emphasis on its
      roles in transcription, chromosome organization and DNA replication.

PMID- 15020053
TI  - Multiple pathways for telomere tethering: functional implications of subnuclear
      position for heterochromatin formation.
AB  - Technical advances in the imaging of GFP derivatives in living cells have
      improved our ability to determine the position and dynamics of specific chromatin
      loci. This approach, combined with genetics and functional assays, has shed new
      light on how nuclear compartments facilitate gene repression in yeast.

PMID- 15020054
TI  - Genetic analysis of RNA-mediated transcriptional gene silencing.
AB  - The 'nuclear side' of RNA interference (RNAi) is increasingly recognized as an
      integral part of RNA-mediated gene silencing networks. Current data are
      consistent with the idea that epigenetic changes, such as DNA (cytosine-5)
      methylation and histone modifications, can be targeted to identical DNA sequences
      by short RNAs derived via Dicer cleavage of double-stranded RNA (dsRNA). To
      determine the relationships among RNA signals, DNA methylation and chromatin
      structure, we are carrying out a genetic analysis of RNA-mediated transcriptional
      gene silencing (TGS) in Arabidopsis. Results obtained so far indicate that in
      response to RNA signals, different site-specific DNA methyltransferases (DMTases)
      cooperate with each other and eventually with histone-modifying enzymes to
      establish and maintain a transcriptionally inactive state at a homologous target
      promoter. Processing of dsRNA in Arabidopsis occurs in the nucleus and in the
      cytoplasm, where distinct Dicer-like (DCL) activities are thought to generate
      functionally distinct classes of short RNAs. RNA silencing pathways thus operate
      throughout the cell to defend against invasive nucleic acids and to regulate
      genome structure and function.

PMID- 15020055
TI  - The activities of eukaryotic replication origins in chromatin.
AB  - DNA replication initiates at chromosomal positions called replication origins.
      This review will focus on the activity, regulation and roles of replication
      origins in Saccharomyces cerevisiae. All eukaryotic cells, including S.
      cerevisiae, depend on the initiation (activity) of hundreds of replication
      origins during a single cell cycle for the duplication of their genomes. However,
      not all origins are identical. For example, there is a temporal order to origin
      activation with some origins firing early during the S-phase and some origins
      firing later. Recent studies provide evidence that posttranslational chromatin
      modifications, heterochromatin-binding proteins and nucleosome positioning can
      control the efficiency and/or timing of chromosomal origin activity in yeast.
      Many more origins exist than are necessary for efficient replication. The
      availability of excess replication origins leaves individual origins free to
      evolve distinct forms of regulation and/or roles in chromosomes beyond their
      fundamental role in DNA synthesis. We propose that some origins have acquired
      roles in controlling chromatin structure and/or gene expression. These roles are
      not linked obligatorily to replication origin activity per se, but instead
      exploit multi-subunit replication proteins with the potential to form context
      dependent protein-protein interactions.

PMID- 15020056
TI  - Chromatin remodeling and the maintenance of genome integrity.
AB  - DNA damage of any type is threatening for a cell. If lesions are left unrepaired,
      genomic instability can arise, faithful transmission of genetic information is
      greatly compromised eventually leading the cell to undergo apoptosis or
      carcinogenesis. In order to access/detect and repair these damages, repair
      factors must circumvent the natural repressive barrier of chromatin. This review
      will present recent progress showing the intricate link between chromatin, its
      remodeling and the DNA repair process. Several studies demonstrated that one of
      the first events following specific types of DNA damage is the phosphorylation of
      histone H2A. This mark or the damage itself are responsible for the association
      of chromatin-modifying complexes near damaged DNA. These complexes are able to
      change the chromatin structure around the wounded DNA in order to allow the
      repair machinery to gain access and repair the lesion. Chromatin modifiers
      include ATP-dependent remodelers such as SWI/SNF and Rad54 as well as histone
      acetyltransferases (HATs) like SAGA/NuA4-related complexes and p300/CBP, which
      have been shown to facilitate DNA accessibility and repair in different pathways
      leading to the maintenance of genome integrity.

PMID- 15020057
TI  - Homologous pairing and chromosome dynamics in meiosis and mitosis.
AB  - Pairing of homologous chromosomes is an essential feature of meiosis, acting to
      promote high levels of recombination and to ensure segregation of homologs.
      However, homologous pairing also occurs in somatic cells, most regularly in
      Dipterans such as Drosophila, but also to a lesser extent in other organisms, and
      it is not known how mitotic and meiotic pairing relate to each other. In this
      article, I summarize results of recent molecular studies of pairing in both
      mitosis and meiosis, focusing especially on studies using fluorescent in situ
      hybridization (FISH) and GFP-tagging of single loci, which have allowed
      investigators to assay the pairing status of chromosomes directly. These
      approaches have permitted the demonstration that pairing occurs throughout the
      cell cycle in mitotic cells in Drosophila, and that the transition from mitotic
      to meiotic pairing in spermatogenesis is accompanied by a dramatic increase in
      pairing frequency. Similar approaches in mammals, plants and fungi have
      established that with few exceptions, chromosomes enter meiosis unpaired and that
      chromosome movements involving the telomeric, and sometimes centromeric, regions
      often precede the onset of meiotic pairing. The possible roles of proteins
      involved in homologous recombination, synapsis and sister chromatid cohesion in
      homolog pairing are discussed with an emphasis on those for which mutant
      phenotypes have permitted an assessment of effects on homolog pairing. Finally, I
      consider the question of the distribution and identity of chromosomal pairing
      sites, using recent data to evaluate possible relationships between pairing sites
      and other chromosomal sites, such as centromeres, telomeres, promoters and
      heterochromatin. I cite evidence that may point to a relationship between matrix
      attachment sites and homologous pairing sites.

PMID- 15020058
TI  - Chromatin and cell death.
AB  - HMGB1, a very mobile chromatin protein, leaks out from necrotic cells and signals
      to neighbouring cells that tissue damage has occurred. At least one receptor for
      extracellular HMGB1 exists, and signals to different cells to divide, migrate,
      activate inflammation or start an immune response. Remarkably, apoptotic
      chromatin binds HMGB1 irreversibly, thereby ensuring that it will not diffuse
      away to activate responses from neighbouring cells. Thus, dying cells use their
      own chromatin to signal how they have died. We argue that the nuclear events in
      apoptosis serve to control the molecular signals that dying cells send out.

PMID- 15020059
TI  - Differential expression of chemokines and chemokine receptors during microglial
      activation and inhibition.
AB  - Intrauterine infection produces an inflammatory response in the fetus
      characterized by increased inflammatory cytokines in the fetal brain and
      activation of brain microglial cells. Intrauterine infection can release
      bacterial cell wall products into the fetal circulation. Lipopolysaccharides
      (LPS) are derived from the cell walls of gram negative organisms. The degree of
      microglial cell activation may influence the extent of brain injury following an
      inflammatory stimulus. Chemokines, which are released by activated microglia,
      regulate the influx of inflammatory cells to the brain. Accordingly, therapeutic
      strategies that reduce the extent of chemokine expression in microglial cells may
      prove neuroprotective. Minocycline (MN), a semisynthetic tetracycline derivative,
      protects brain against global and focal ischemia in rodents and inhibits
      microglial cell activation. To determine if minocycline can reduce the production
      of chemokines and chemokine receptors in response to LPS, microglial-like BV-2
      and HAPI cells were cultured in the presence or absence of 100 ng/ml of LPS.
      Enzyme-linked immunosorbent assay (ELISA) and semi-quantitative RT-PCR were used
      to examine changes in inflammatory chemokines (macrophage inflammatory protein-1
      (MIP-1alpha), regulated upon activation, normal T cell expressed and secreted
      (RANTES), and inducible protein-10 (IP-10)) and chemokine receptor (C-C chemokine
      receptor 5 (CCR5) and C-X-C chemokine receptor 3 (CXCR3)) production,
      respectively. We found that in both cell lines chemokine release after 4-, 8-,
      and 16-h exposure to LPS was significantly higher compared to non-exposed cells
      for all the chemokines measured, P<0.001. Minocycline inhibited chemokine release
      of LPS-stimulated BV-2 cells. There was even greater inhibition (up to 50%) of
      mRNA expression after exposure to LPS (P<0.001). We conclude that endotoxin
      enhanced the expression of chemokines and chemokine receptors in microglial-like
      cell lines. Modulation of this expression was achieved with minocycline.
      Recognition of the mechanisms whereby minocycline exerts its anti-inflammatory
      effect on microglia may uncover specific targets for pharmacologic intervention.

PMID- 15020060
TI  - A novel protective model against experimental allergic encephalomyelitis in mice
      expressing a transgenic TCR-specific for myelin oligodendrocyte glycoprotein.
AB  - Myelin oligodendrocyte glycoprotein (MOG) is an important autoantigen in multiple
      sclerosis and in experimental autoimmune encephalomyelitis (EAE). We generated a
      T cell receptor (TCR) transgenic (Tg) mouse expressing a TCR derived from an
      encephalitogenic T cell clone specific for MOG(35-55). This mouse failed to
      develop EAE spontaneously and developed mild EAE at late onset when immunized
      with MOG(35-55). The Tg T cells produced large amounts of IL-4 when stimulated
      with MOG(35-55) and underwent FAS/FAS-L-mediated activation-induced cell death
      when stimulated with MOG(35-55) and IL-12. The unique phenotype of these
      autoantigen-specific T cells may represent an important mechanism of protection
      against autoimmune disease.

PMID- 15020061
TI  - Influence of the course of brain inflammation on the endogenous IL-1beta/IL-1Ra
      balance in the model of brain delayed-type hypersensitivity response to bacillus
      Calmette-Guerin in Lewis rats.
AB  - Interleukin-1beta (IL-1beta) is a key player in the pathogenesis of acute and
      chronic inflammatory diseases at the periphery and in the brain. Its action is
      regulated by interleukin-1 receptor antagonist (IL-1Ra), the specific endogenous
      antagonist of IL-1 receptors. The ratio between local concentrations of IL-1Ra
      and IL-1beta is known to influence the initiation and progression of many
      inflammatory and autoimmune diseases at the periphery. In order to determine
      whether this is also the case in the brain, brain and plasma concentrations of IL
      1beta and IL-1Ra were measured by ELISA in a model of chronic brain inflammation
      in Lewis rats, the hippocampal delayed-type hypersensitivity (DTH) response to
      bacillus Calmette-Guerin (BCG). Brain IL-1beta increased rapidly after
      intracerebral (i.c.) injection of BCG and came back to baseline concentrations 1
      week later, whereas IL-1Ra increased gradually over time and remained elevated
      during the last 2 weeks post-BCG intracerebral injection. Following peripheral
      BCG challenge, brain IL-1beta increased at the site of the brain BCG and peaked
      12 days later before decreasing on day 16 post-challenge. Brain IL-1Ra remained
      elevated during the first days post-challenge and then decreased from the 12th
      day post-challenge. The same temporal variations were observed in the plasma
      concentrations of IL-1beta and IL-1Ra. The increase in the IL-1beta/IL-1Ra ratio
      that was apparent from day 3 to day 12 post-challenge might be correlated with
      the invasion of peripheral inflammatory cells at the site of intracerebral
      injection. Besides showing that the course of inflammation alters the brain IL
      1beta/IL-1Ra ratio, these findings point to the importance of monitoring plasma
      IL-1beta/IL-1Ra ratio to predict the course of brain inflammation.

PMID- 15020063
TI  - Inflammatory cell expression of cyclooxygenase-2 in the multiple sclerosis
      lesion.
AB  - Multiple sclerosis (MS) is a progressive immune-mediated disease characterized by
      the loss of the oligodendrocytes that constitute the myelin sheath. Recent
      reports show that glutamate-mediated excitotoxic death of oligodendrocytes
      contributes to pathogenesis in demyelinating disease. A link between the immune
      mediated inflammatory response and glutamate-mediated excitotoxicity of
      oligodendrocytes could involve the interaction of inducible isoforms of nitric
      oxide synthase (iNOS) and cyclooxygenase (COX-2). Both enzymes are tightly
      coupled to neuronal excitotoxic death. We examined tissue from two controls and
      seven MS patients with chronic active lesions to determine the extent of COX-2
      and iNOS expression. In contrast to the lack of expression in controls, there was
      a marked induction of COX-2 in all these MS lesions. COX-2 was frequently
      expressed in association with iNOS. COX-2 was found in areas that contained
      catabolites of myelin basic protein, indicating recent demyelination. COX-2
      expression was found near damaged oligodendrocytes in cells that expressed the
      macrophage/microglia marker CD64, indicating that a substantial portion of the
      COX-2 in the lesions was expressed in immune-derived cells. We discuss these
      findings in the context of how COX-2 could be coupled with iNOS to contribute to
      excitotoxic death and damage of oligodendrocytes.

PMID- 15020062
TI  - Effects of photoperiod history on immune responses to intermediate day lengths in
      Siberian hamsters (Phodopus sungorus).
AB  - Seasonal changes in day length enhance or suppress immune function in individuals
      of several mammalian species. Siberian hamsters (Phodopus sungorus) are long-day
      breeders that adjust reproductive physiology and behavior, body mass, and immune
      function following exposure to short photoperiods. Photoperiods of intermediate
      duration, encountered in nature by juvenile hamsters born in early-spring and by
      those born in mid-summer, trigger gonadal development in the former cohort and
      inhibit the onset of puberty in the latter. Divergent reproductive responses to
      the same intermediate photoperiod depend on a photoperiod history, communicated
      during gestation. These experiments assessed whether photoperiod history during
      gestation likewise impacts immunological responses to intermediate photoperiods.
      Male hamsters were gestated in long photoperiods and remained in long
      photoperiods postnatally, or were transferred to an intermediate-duration or a
      short-duration photoperiod; other males were gestated in short days and
      transferred to an intermediate-duration photoperiod at birth. Long days
      stimulated, and short days inhibited, somatic and reproductive development;
      intermediate day lengths either accelerated or inhibited somatic and reproductive
      development, depending on whether hamsters were gestated in short days or long
      days, respectively. By contrast, photoperiod during gestation did not affect most
      immune endpoints. The data suggest that photoperiodic mechanisms that enhance and
      suppress several aspects of immunity in young-adult hamsters are not responsive
      to prenatally communicated photoperiod history information.

PMID- 15020064
TI  - Peripheral macrophage depletion reduces central nervous system parasitism and
      damage in Trypanosoma cruzi-infected suckling rats.
AB  - We aim at investigating the role of blood born macrophages on the brain reaction
      to Trypanosoma cruzi infection in suckling rats. This infection provoked the
      appearance of numerous ED1(+) cells in the neural parenchyma and increased the
      amount of meningeal and perivascular ED2(+) macrophages. CD8(+) and NKR(+) cells
      also occurred. Parenchymal blood vessels showed strong ICAM-1 and decreased
      occludin immunoreactivities. Selective depletion of peripheral macrophages by
      clodronate liposomes decreased tissue parasitism, nodular lesions, ICAM-1
      upregulation and leukocyte infiltration. Occludin immunoreactivity remained as in
      uninfected animals. Our results indicate a role for blood-born macrophages in
      both parasite invasion and brain reaction. Microglia activation cannot be
      discarded.

PMID- 15020065
TI  - Production of neuroprotective NGF in astrocyte-T helper cell cocultures is
      upregulated following antigen recognition.
AB  - Astrocytic production of nerve growth factor (NGF) is increased during
      inflammation of the central nervous system (CNS). Here we show that cell-cell
      interaction between primary murine astrocytes and myelin basic protein (MBP)
      specific T cell receptor (TCR) transgenic Th1 and Th2 cells significantly
      increased production of NGF. This upregulation was found to be dependent on
      antigen recognition. Neutralization of cytokines produced in cocultures did not
      affect NGF production. This novel finding suggests a neuroprotective role of
      astrocytes during T cell-mediated inflammation in the CNS.

PMID- 15020066
TI  - Protective DNA vaccination against experimental autoimmune encephalomyelitis is
      associated with induction of IFNbeta.
AB  - DNA vaccines encoding encephalitogenic peptides protect against subsequent
      development of rat experimental autoimmune encephalomyelitis (EAE) through
      unknown mechanisms. We investigated immune cell phenotypes at different time
      points after DNA vaccination with vaccine encoding myelin oligodendrocyte
      glycoprotein peptide 91-108 and subsequent induction of EAE. In protected rats,
      we observed (i) no alterations in antigen-specific Th2 or Th3 responses, (ii)
      reduced MHC II expression on splenocytes early after EAE induction, (iii) antigen
      specific upregulation of IFNbeta upon recall stimulation and (iv) reduced IL
      12Rbeta2 on lymphocytes. We suggest that the underlying mechanism of DNA
      vaccination is associated with immunomodulation exerted by induced IFNbeta.

PMID- 15020067
TI  - The extent of cytokine induction in peripheral nerve lesions depends on the mode
      of injury and NMDA receptor signaling.
AB  - We compared cytokine and chemokine induction in mice after sciatic nerve crush
      and chronic constriction injury (CCI) by quantitative reverse transcriptase
      polymerase chain reaction. In both nerve lesion paradigms, transcripts for tumor
      necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-10, and monocyte
      chemoattractant protein-1 (MCP-1) were significantly increased in degenerating
      nerve stumps already at day 1, with a greater magnitude and longer duration in
      CCI. NMDA receptor blockade significantly reduced cytokine expression after CCI
      on the mRNA and protein level. In dorsal root ganglia, only IL-10 mRNA levels
      were modified after nerve injury. Our study indicates that the mode of nerve
      injury influences the extent of cytokine expression, and identifies NMDA-mediated
      signaling as one mechanism of cytokine induction in peripheral nerves.

PMID- 15020068
TI  - Estriol treatment ameliorates disease in males with experimental autoimmune
      encephalomyelitis: implications for multiple sclerosis.
AB  - Estrogen treatment has been found to be protective in experimental autoimmune
      encephalomyelitis (EAE) and possibly multiple sclerosis (MS). We investigated
      whether the effect of estrogen treatment is gender-specific. Estrogen receptor
      (ER) expressions, ERalpha and ERbeta, were found to be equivalent in both
      genders. EAE disease severity in both females and males was decreased with
      estriol treatment as compared to placebo. Finally, proinflammatory cytokine
      production during autoantigen-specific immune responses was decreased with
      estriol treatment in both females and males. These data support a potential role
      for estriol treatment for men in addition to women with MS.

PMID- 15020070
TI  - alpha-Tocopherol reduces lipopolysaccharide-induced peroxide radical formation
      and interleukin-6 secretion in primary murine microglia and in brain.
AB  - The purpose of this study was to determine if alpha-tocopherol-a reactive oxygen
      species (ROS) scavenging agent-inhibits LPS-induced oxidative stress and
      interleukin-6 (IL-6) production in murine microglia and brain. LPS increased
      intracellular peroxides and IL-6 in a dose-dependent fashion in primary
      microglia. The LPS-induced increase in ROS and IL-6 was reduced by pretreatment
      of alpha-tocopherol. Intraperitoneal injection (i.p.) of LPS induced lipid
      peroxidation and IL-6 in brain. Importantly, three daily injections (20 mg) of
      alpha-tocopherol increased brain alpha-tocopherol and decreased LPS-induced lipid
      peroxidation and IL-6 in brain. Taken together, these data indicate that alpha
      tocopherol can mitigate inflammatory cytokine production in the brain.

PMID- 15020069
TI  - Chronic morphine accelerates the progression of lipopolysaccharide-induced sepsis
      to septic shock.
AB  - Opiate addicts have been shown to have a high susceptibility to bacterial
      infection. We investigated how treatment with morphine alters lipopolysaccharide
      (LPS)-induced inflammatory responses in the rat. Chronic morphine alone elevated
      serum endotoxin levels. Animals treated with morphine and LPS (250 microg/kg)
      developed hypothermia, decreased mean arterial pressure (MAP), increased plasma
      thrombin anti-thrombin III (TAT) complex, and approximately 67% of animals
      exhibited progressive intramicrovascular coagulation. Morphine also enhanced LPS
      induced leukocyte-endothelial adhesion (LEA), suppressed leukocyte flux, and
      corticosterone production, and elevated interleukin-1beta, tumor necrosis factor
      alpha, and interleukin-6 serum levels. Our study presents both the molecular and
      cellular mechanisms underlying the potentiated LPS-induced inflammation and
      accelerated progression to septic shock seen with chronic morphine exposure.

PMID- 15020071
TI  - Nociceptin/orphanin FQ modulates human T cell function in vitro.
AB  - Although nociceptin/orphanin FQ (N/OFQ) and its receptor (ORL-1) are widely
      distributed throughout the immune system, its role has yet to be elucidated. This
      study shows that N/OFQ (10(-14)-10(-12) M) modulates T cell activation by up
      regulating activation marker expression, e.g. CD28, leading to enhanced
      proliferation and modulation of TNFalpha secretion. However, on re-stimulated T
      cells N/OFQ causes inhibition of proliferation, which could be linked with N/OFQ
      up-regulating CTLA-4 expression. We have also shown that some of these effects
      are partly prostaglandin-dependent and that N/OFQ induces prostaglandin
      synthesis. This report suggests that N/OFQ could exert a key modulatory role in
      human T cell functions.

PMID- 15020072
TI  - The scope and activation mechanisms of chemokine gene expression in primary
      astrocytes following infection with Theiler's virus.
AB  - Intracerebral infection with Theiler's virus induces a demyelinating disease that
      resembles human MS. In order to delineate the early events in virus-induced
      inflammatory disease, we have analyzed chemokine gene activation following
      Theiler's murine encephalomyelitis virus (TMEV) infection. Infection of primary
      astrocyte cultures results in activation of various chemokine genes (GRO-1, MCP
      1, MCP-5, MIP-1alpha, MIP-1beta, MIP-2, RANTES, IP-10 and MCP-3) that are
      important in the initiation of an inflammatory response. As early as 1-3 h after
      TMEV infection, chemokine gene expression is strongly activated. In addition,
      proinflammatory cytokines do not interfere with TMEV-induced chemokine gene
      expression and some cytokines may function synergistically for virus-induced
      upregulation of chemokine gene expression. Chemokine gene activation by TMEV
      appears to be largely independent of the IFNalphabeta pathway and partly
      dependent on dsRNA-dependent protein kinase (PKR) and MAP kinase pathways.
      However, TMEV-induced chemokine gene expression is completely dependent on the
      NFkappaB pathway. These results strongly suggest that the expression of select
      chemokine genes upon TMEV infection is activated via the NFkappaB pathway,
      similar to that of proinflammatory cytokine genes, and these cellular gene
      products appear to synergistically promote inflammatory responses in the CNS.

PMID- 15020073
TI  - Production of hydroxyeicosatetraenoic acids and prostaglandins by a novel rat
      microglial cell line.
AB  - We have established a clonal cell line derived from rat microglia that
      proliferates in response to macrophage-colony stimulating factor (CSF-1). Like
      primary neonatal microglia, these cells (named RTMGL1) exhibit a ramified
      morphology, bind isolectin B4, express CD68 and are weakly positive for CD11b and
      MHC class II. CSF-1-dependent proliferation requires intact signal transduction
      through several pathways. RTMGL1 synthesize multiple cyclooxygenase (COX)
      products including 11- and 15-hydroxyeicosatetraenoic acid (HETE) and express COX
      2. RTMGL1 synthesize 5-HETE from arachidonic acid (AA) likely via a 5
      lipoxygenase (LO). Thus, RTMGL1 have morphological and histological
      characteristics of primary microglia and metabolize AA via both COX and LO
      pathways.

PMID- 15020074
TI  - In vivo monitoring of macrophage infiltration in experimental autoimmune neuritis
      by magnetic resonance imaging.
AB  - We report on the in vivo assessment of macrophage infiltration in adoptive
      transfer experimental autoimmune neuritis (AT-EAN), a prototypic Th-1-mediated
      autoimmune disorder of the peripheral nervous system (PNS). Lewis rats received
      systemic injections of superparamagnetic iron oxide (SPIO) particles at days 2,
      3, 4, 5, or 9 after adoptive transfer of P2-specific T-cells and were scanned by
      standard 1.5 T magnetic resonance imaging (MRI) always 24 h later. MRI revealed
      focal signal loss of the cauda equina indicating iron accumulation in spinal
      nerves already at the preclinical stage (day 3). Signal loss peaked at day 4,
      when first clinical signs developed. At the maximum of clinical disease, signal
      loss already declined and disappeared on days 6 and 10. In spinal nerve sections,
      Perl's iron stain showed focal cellular accumulation of SPIO at days 3, 4, and 5
      in ED1-positive macrophages. Spinal nerves at days 6 and 10 exhibited massive
      macrophage infiltrates, but no more iron deposition. In conclusion, SPIO-enhanced
      MRI provides a novel in vivo tool to assess the timing of macrophage entry into
      target tissues during an immunopathologic attack and holds promise to monitor
      immunotherapeutic interventions.

PMID- 15020076
TI  - Haemophilus influenzae as a possible cause of Guillain-Barre syndrome.
AB  - Recent reports have contained conflicting results on the relationship between
      antecedent Haemophilus influenzae infection and Guillain-Barre syndrome (GBS). To
      investigate the prevalence of H. influenzae infection in GBS patients in a
      British population, we carried out a retrospective study with 62 consecutive GBS
      patients and 63 normal controls of similar age and sex. Whole bacteria of both
      encapsulated and nonencapsulated strains of H. influenzae were employed as
      antigens in an enzyme-linked immunosorbent assay (ELISA) for anti-H. influenzae
      IgG, IgM and IgA antibodies. Elevated antibodies of two or three classes were
      found in one GBS patient and none in the normal controls. Six GBS patients had
      IgG antibodies against nonencapsulated H. influenzae compared with only one in
      the normal control group (p=0.06). Western blot for IgG antibody showed that all
      the sera with IgG antibodies recognized the lipopolysaccharide (LPS) of both
      strains of H. influenzae. Antiganglioside GM1 antibody was not associated with
      anti-H. influenzae antibody in our study. Absorption with encapsulated or
      nonencapsulated H. influenzae, Campylobacter jejuni and Escherichia coli before
      testing on Western blot showed that only nonencapsulated H. influenzae absorbed
      the anti-LPS antibodies. In conclusion, there is a possible but rare association
      of GBS with nonencapsulated H. influenzae in the UK.

PMID- 15020075
TI  - Different patterns of nicotinic acetylcholine receptor subunit transcription in
      human thymus.
AB  - Clinical observations suggest that the thymus is strongly implicated in the
      pathogenesis of myasthenia gravis (MG), but questions such as the level and
      location of nicotinic acetylcholine receptor (AChR) subunit expression that are
      fundamental to postulate any pathogenic mechanism, remain controversial. We have
      re-examined this question by combining calibrated RT-PCR and real-time PCR to
      study nicotinic AChR subunit mRNA expression in a panel of normal and myasthenic
      thymi. The results suggest that the expression of the different AChR subunits
      follows three distinct patterns: constitutive for, neonatal for gamma and
      individually variable for alpha1, beta1 and delta. Experiments using confocal
      laser microdissection suggest that AChR is mainly expressed in the medullary
      compartment of the thymus but there is not a clear compartmentalization of
      subunit expression. The different patterns of subunit expression may influence
      decisively the level of central tolerance to the subunits and explain the
      focusing of the T cell response to the alpha and gamma subunits.

PMID- 15020078
TI  - CSF chemokine levels in relapsing neuromyelitis optica and multiple sclerosis.
AB  - The pathogenesis of relapsing neuromyelitis optica (RNMO) remains unknown. We,
      for the first time, studied the levels of four chemokines in the cerebrospinal
      fluid in RNMO with ELISA and compared the data with those in multiple sclerosis
      (MS) and control. CXCL10/IP-10 and CCL17/TARC were significantly elevated in both
      RNMO and MS. Conversely, CCL2/MCP-1 was significantly lower in MS, but not in
      RNMO, than in control. CCL11/Eotaxin was not different between groups. None of
      the four chemokines studied was significantly different between RNMO and MS.

PMID- 15020079
TI  - Immunolocalization of protectin (CD59) and macrophages in polymyositis and
      dermatomyositis.
AB  - Immunohistochemical stainings for protectin (CD59) and for the
      macrophage/monocyte antigen were performed in muscle specimens of polymyositis
      (PM) and dermatomyositis (DM) patients. In control muscles, a granular
      immunostaining of CD59 at the surface of 10-15% from among muscle fibers and an
      intense reaction in endothelia of blood vessels were noted. Strong immunostaining
      appeared inside vacuoles of vacuolar degeneration changes of muscle fibers, and
      in regenerating muscle fibers in PM and DM. No macrophages were found next to the
      CD59 positive muscle regions. The results seem to strongly support a role of the
      complement (C) system and of the factors protecting cells from the C-induced
      damage in the mechanism of muscle injury in PM and DM. The findings can have
      treatment implications.

PMID- 15020077
TI  - The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate
      cyclase activating polypeptide (PACAP) modulate several biochemical pathways in
      human leukemic myeloid cells.
AB  - The neuropeptides Vasoactive-intestinal peptide (VIP) and Pituitary adenylate
      cyclase activating protein (PACAP) increased cAMP levels in three out of five
      human myeloid leukemic cell lines tested while an increased in calcium
      intracytoplasmic levels was seen only in one cell line (HEL). This increase was
      phospholipase C, Pertussis toxin dependent and associated with an increase in c
      fos and c-jun protein expression together with the formation of functional AP-1
      transcriptional factor complex. Cell exposure to VIP or PACAP resulted in a
      decrease in HEL cell proliferation associated with a down-regulation of the
      erythroid marker, Glycophorin A. Both peptides were found to increase intra
      cytoplasmic calcium levels in blasts isolated from patients with myeloid
      leukemia. Thus VIP and PACAP are involved in the physiology and pathophysiology
      of human myeloid cells.

PMID- 15020081
TI  - CD4 T cell activation and disease activity at onset of multiple sclerosis.
AB  - We studied CD4 T cell activation in patients with clinically isolated syndromes
      (CIS) suggesting an initial attack of multiple sclerosis. The percentage of blood
      CD26+ CD4 T cells was increased in these patients, and correlated with magnetic
      resonance imaging disease activity and clinical disease severity. In contrast,
      the percentage of CD25+ CD4 T cells in cerebrospinal fluid correlated negatively
      with the cerebrospinal fluid concentration of myelin basic protein and the
      presence of IgG oligoclonal bands. These results suggest that distinct systemic
      and intrathecal T cell activation states correlate with disease activity and risk
      of subsequently developing MS in CIS patients.

PMID- 15020080
TI  - Identification and functional characterization of a highly polymorphic region in
      the human TRAIL promoter in multiple sclerosis.
AB  - TNF-related apoptosis-inducing ligand (TRAIL) is not only involved in cell death
      but also in other immunoregulatory mechanisms. So far, the regulation of the
      TRAIL pathway in physiologic and pathologic conditions remains unclear. Due to
      the implication in brain damage and the elevated expression in peripheral immune
      cells of patients with multiple sclerosis (MS), an autoimmune disease of the
      central nervous system, TRAIL might play a central role in the pathology of this
      disease. Here, we have identified a highly polymorphic region in the TRAIL
      promoter. Using single-strand conformation polymorphism analysis, we found four
      single nucleotide polymorphisms (SNPs) within 111 base pairs. One of these SNPs
      is located in a binding site for the transcription factor AP-1. However, the RNA
      and protein expression of TRAIL revealed no obvious differences in relation to
      the genotypes. Furthermore, investigating samples from both MS patients and
      healthy controls we could not detect any association of these newly described
      polymorphisms to the clinical disease pattern. Thus, the TRAIL promoter contains
      a highly polymorphic area which has, however, no impact on molecule expression,
      and is neither directly related to increased risk of developing MS nor associated
      with a certain course of this heterogeneous disease in our population.

PMID- 15020082
TI  - Regulation of human peripheral blood lymphocytes IL-10 BY SMS 201-995.
AB  - The somatostatin analog SMS 201-995 inhibits human peripheral blood lymphocytes
      (PBL) proliferation and here we demonstrate that it induces a significant
      increase in T cells IL-10 release as is evidenced in double fluorescence
      experiments. Seizing IL-10 by monoclonal antibody, SMS does not affect lymphocyte
      proliferation, suggesting that this cytokine is involved in the antiproliferative
      effect of these analog. We previously demonstrated that SMS inhibits T cells
      acting on the CD28 rather than the CD3-mediated signal in exactly the same way as
      does IL-10. Thus SMS inhibits human PBL activation by inducing IL-10 release and
      the consequent inhibition of the CD28 co-stimulatory pathway providing new
      perspectives on developing immunosuppressive strategies.

PMID- 15020083
TI  - A new cytochemical method for ultrastructural localization of Co2+ in rat
      hippocampal CA1 pyramidal neurons in vitro.
AB  - This paper describes new cytochemical method for the ultrastructural localization
      of Co(2+) following blockade of synaptic transmission. In the CA1 region of rat
      hippocampal slices, electrical stimulation of the Schaffer collaterals elicited
      field excitatory postsynaptic potentials (fEPSPs). The fEPSPs were completely
      blocked within 2 min after the addition of Co(2+) (2 mM). The slice was then
      fixed and precipitated Co(2+) was examined by means of a solution containing 2.5%
      glutaraldehyde and 10 mM K(3)[Fe(3+)(CN)(6)] in 90 mM NaCl. Electron
      spectroscopic imaging confirmed Co in the precipitate. The precipitates were
      found as clusters on the membranes of the fine apical dendrites and their spine
      heads of CA1 pyramidal neurons. No clustered precipitate was found when slices
      were treated: (1) without Co(2+); (2) after recovery from the Co(2+)-induced
      blockade of fEPSPs; (3) without electrical stimulation of the Schaffer
      collaterals; and (4) with dl-2-amino-5-phosphonopentanoate and 6-cyano-7
      nitroquinoxaline-2,3-dione. After administrating glutamate (5 mM) in the presence
      of tetrodotoxin (1 microM) and Co(2+), precipitates were found on dendritic
      membranes and spine heads. These results indicate that the Schaffer collaterals
      stimulation induces the binding of Co(2+) on CA1 pyramidal neuron membrane.

PMID- 15020084
TI  - Simultaneous birefringence and scattered light measurements reveal anatomical
      features in isolated crustacean nerve.
AB  - Simultaneous fast birefringence and scattered light changes associated with
      crustacean nerve activation have different time courses and are produced by
      separate biophysical mechanisms. Technological advances in illumination,
      photodiodes and amplification circuitry achieved better signal-to-noise than
      earlier studies revealing optical signals in axonal nerve bundles as small as
      crayfish ventral cord and claw. The birefringence measurements yielded signals
      that could be observed in single trials, with temporally separated peaks
      associated with axonal populations of different diameters. A slit aperture placed
      perpendicular to the nerve reduced the spatial-temporal integration and enhanced
      the temporal structure of the separate peaks in the birefringence signal. Moving
      the slit aperture farther from the stimulation point delayed the signal in time,
      and also enhanced the separation between peaks. Different propagation velocities
      of the separate peaks provided evidence for at least three neuronal populations
      in the bundle. These studies underscore the advantages of birefringence over
      scattering measurements. Application of birefringence methods can optimize non
      invasive imaging techniques being developed to detect fast optical responses
      associated with electrical neural activity in humans.

PMID- 15020085
TI  - Unbiased analysis of bulk axonal segregation patterns.
AB  - The projection of retinal ganglion cell axons to the dorsal lateral geniculate
      nucleus of the thalamus (dLGN) is organized into eye-specific layers, which are
      macroscopic structures that reflect the bulk organization of thousands of axons.
      The processes that underlie the formation of these layers is the focus of
      research in several laboratories. The recent advent of fluorescently tagged
      tracers allows for the simultaneous visualization of axons from both eyes in the
      same dLGN section and therefore the analysis of axonal segregation patterns.
      However, the techniques traditionally used to quantify eye-specific segregation
      are far from standardized. Here we present an analysis method that objectively
      quantifies the extent of segregation. We apply this analyses to dLGN images from
      mice with normal retinogeniculate projection patterns and genetically altered
      mice with dramatically altered projection patterns. In addition, we compare dLGN
      images acquired at different optical resolutions to measure the spatial scale
      over which we can determine segregation unambiguously.

PMID- 15020086
TI  - Unbiased characterization of high-density oligonucleotide microarrays using probe
      level statistics.
AB  - Affymetrix GeneChips are being used increasingly for quantitative monitoring of
      gene expression in a variety of biological systems. Depending on the experiment,
      the analysis of Affymetrix results can have several different goals ranging from
      calculation of signal strength for a variety of inter-gene comparisons to the
      determination of which genes show significant differential expression between
      sample conditions. There have been several proposed methods for precise
      quantification of expression signal with promising results; however the question
      of what constitutes a significant change between replicate groups still remains.
      We have designed a method which performs statistical analysis on the differential
      expression of genes in the Affymetrix GeneChip system at the probe level in order
      to bypass the assumptions made in other analysis techniques. Validation using
      both spike-in data and real experimental data proves the method is effective at
      isolating differentially expressed genes statistically, thereby eliminating the
      need for arbitrary restrictions such as fold change. Application to an existing
      neural stem cell data set demonstrates the method's applicability to highly
      complex systems and its ability to detect very low expression differences (<1.2
      fold change), providing resolution which may be of significant interest in neural
      systems such as this.

PMID- 15020087
TI  - Telemetric recordings of single neuron activity and visual scenes in monkeys
      walking in an open field.
AB  - This paper describes a portable recording system and methods for obtaining
      chronic recordings of single units and tracking rhesus monkey behavior in an open
      field. The integrated system consists of four major components: (1)
      microelectrode assembly; (2) head-stage; (3) recording station; and (4) data
      storage station, the first three of which are carried by the monkey and weigh 800
      g. Our system provides synchronized video and electrophysiological signals, which
      are transmitted by a wireless system to a distance of 50 m. Its major advantages
      are that neuronal recordings are made in freely moving monkeys, and well
      separated action potentials with amplitude five times higher than the background
      noise are usually recorded and readily kept for many hours. Using this system, we
      were able to study "place cells" in non-human primate brains. The described
      methods provide a new way to examine correlations between single neuron activity
      and primate behaviors, and can also be used to study the cellular basis of social
      behaviors in non-human primates.

PMID- 15020088
TI  - A posture optimization algorithm for model-based motion capture of movement
      sequences.
AB  - We have developed and evaluated a new optical motion capture approach that is
      suitable for a wide range of studies in neuroethology and motor control. Based on
      the stochastic search algorithm of Simulated Annealing (SA), it utilizes a
      kinematic body model that includes joint angle constraints to reconstruct posture
      from an arbitrary number of views. Rather than tracking marker trajectories in
      time, the algorithm minimizes an error function that compares predicted model
      projections to the recorded views. Thus, each video-frame is analyzed
      independently from other frames, enabling the system to recover from incorrectly
      analyzed postures. The system works with standard computer and video equipment.
      Its accuracy is evaluated using videos of animated locust leg movements, recorded
      by two orthogonal views. The resulting joint angle RMS errors range between 0.7
      degrees and 4.9 degrees, limited by the pixel resolution of the digital video. 3D
      movement reconstruction is possible even from a single view. In a real
      experimental application, stick insect walking sequences are analyzed with leg
      joint angle deviations between 0.5 degrees and 3.0 degrees. This robust and
      accurate performance is reached in spite of marker fusions and occlusions, simply
      by exploiting the natural constraints imposed by a kinematic chain and a known
      experimental setup.

PMID- 15020089
TI  - Spike sorting based on automatic template reconstruction with a partial solution
      to the overlapping problem.
AB  - A new method for spike sorting is proposed which partly solves the overlapping
      problem. Principal component analysis and subtractive clustering techniques are
      used to estimate the number of neurons contributing to multi-unit recording.
      Spike templates (i.e. waveforms) are reconstructed according to the clustering
      results. A template-matching procedure is then performed. Firstly all temporally
      displaced templates are compared with the spike event to find the best-fitting
      template that yields the minimum residue variance. If the residue passes the
      chi(2)-test, the matching procedure stops and the spike event is classified as
      the best-fitting template. Otherwise the spike event may be an overlapping
      waveform. The procedure is then repeated with all possible combinations of two
      templates, three templates, etc. Once one combination is found, which yields the
      minimum residue variance among the combinations of the same number of component
      templates and makes the residue pass the chi(2)-test, the matching procedure
      stops. It is unnecessary to check the remaining combinations of more templates.
      Consequently, the computational effort is reduced and the over-fitting problem
      can be partly avoided. A simulated spike train was used to assess the performance
      of the proposed method, which was also applied to a real recording of chicken
      retina ganglion cells.

PMID- 15020090
TI  - Dual enhancement of triple immunofluorescence using two antibodies from the same
      species.
AB  - Triple immunofluorescence method with two mouse monoclonal antibodies and another
      rabbit polyclonal antibody was established with catalyzed reporter deposition
      (CARD) amplification on thick floating sections from the rat cerebellum. One of
      the monoclonal antibodies (anti-calbindin), diluted maximally, probed with anti
      mouse IgG-horseradish peroxidase (HRP) and amplified with Cy5-conjugated
      tyramide, immunolabeled cerebellar Purkinje cells and their arborization.
      Subsequently, a rabbit polyclonal IgG (anti-glial fibrillary acidic protein (anti
      GFAP)), probed with anti-rabbit IgG-HRP, amplified with biotin-tyramide and
      visualized with fluorescein-isothiocyanate (FITC)-streptavidin, immunolabeled
      Bergmann's glia. Another mouse monoclonal IgG (anti-SNAP25), probed with anti
      mouse IgG-rhodamine without CARD amplification, selectively visualized synaptic
      sites, because the maximal dilution of the other monoclonal antibody (anti
      calbindin) was below the detection threshold of this anti-mouse IgG-rhodamine.
      Separation of the two signals (calbindin and SNAP25), each detected through mouse
      monoclonal antibody, was then based on the difference of sensitivity either with
      or without CARD amplification. Triple immunofluorescence is possible when just
      one of the three primary antibodies is from different species. Intensification of
      two of the three signals provides further advantages to examine
      immunolocalization of multiple epitopes on histological sections.

PMID- 15020092
TI  - Separation of individual neurons using dielectrophoretic alternative current
      fields.
AB  - Experimental investigations into the dynamics of neuronal networks are a
      fundamental step towards understanding how the nervous system works. Memory
      formation and development are associated with changes in the electrical activity
      of the neurons. To understand the changes in the electrical activity, it is
      essential to conduct in vitro studies on individual neurons. Hence, there is an
      enormous need to develop novel ways for isolating and localizing individual
      neurons. To this end, we designed and fabricated a 4x4 multiple microelectrode
      array system to spatially arrange neurons by generating dielectrophoretic traps
      using gradient alternating current (AC) fields. We characterized the electric
      field distribution inside our test platform by using three-dimensional finite
      element modeling (FEM) and estimated the location of neurons over the electrode
      array. As the first stage in forming a neuronal network, dielectrophoretic AC
      fields were employed to separate the neurons from the glial cells and to position
      individual neurons over single electrodes. The extracellular electrical activity
      from a single neuron was recorded. The frequency spectrum of the electrical
      activity was generated using fast Fourier transformation analysis (FFT) to
      determine the characteristic burst rates of individual neurons.

PMID- 15020091
TI  - A two-dimensional imaging biosensor to monitor enhanced brain glutamate release
      stimulated by nicotine.
AB  - In this study, we have imaged and monitored real-time release of neurotransmitter
      glutamate from mouse brain slices stimulated by nicotine and physiological salts
      using a newly developed two-dimensional (2D) imaging biosensor. Nicotine, the
      addictive substance contained in cigarettes and other tobacco baring products,
      affects human body through interactions with both central and peripheral nervous
      system receptors and exists in various concentrations in body organs including
      the brain. The 2D imaging biosensor, designed for sensitive glutamate monitoring,
      is prepared through the use of a flat silica plate that is covalently attached
      with an enzyme, glutamate dehydrogenase (GDH). The 2D imaging biosensor can
      spatially resolve glutamate release and has a detection limit of 40 nM in
      detecting glutamate release from glutaminergic neurons in the brain slices. Using
      this biosensor, we have shown that the administration of nicotine (50 nM) on the
      brain slice stimulates repetitive glutamate release. To the best of our
      knowledge, this is the first time that a biosensor was used to define the vital
      role of nicotine in glutamate release. Physiological salts such as KCl and
      CaCl(2) have also been used to characterize the biosensor in measuring glutamate
      release. It is found in this study that nicotine stimulation is much more potent
      than physiological salts. The real-time detection of newly released glutamate
      from mouse brain slices clearly demonstrates the feasibility of the two
      dimensional glutamate biosensor for real-time monitoring of dynamic glutamate
      release from living specimen.

PMID- 15020093
TI  - Equations for nickel-chromium wire heaters of column transfer lines in gas
      chromatographic-electroantennographic detection (GC-EAD).
AB  - Heating of chromatographic columns, transfer lines, and other devices is often
      required in neuroscience research. For example, volatile compounds passing
      through a capillary column of a gas chromatograph (GC) can be split, with half
      exiting the instrument through a heated transfer line to an insect antenna or
      olfactory sensillum for electroantennographic detector (GC-EAD) recordings. The
      heated transfer line is used to prevent condensation of various chemicals in the
      capillary that would otherwise occur at room temperature. Construction of such a
      transfer line heater is described using (80/20%) nickel-chromium heating wire
      wrapped in a helical coil and powered by a 120/220 V ac rheostat. Algorithms were
      developed in a computer program to estimate the voltage at which a rheostat
      should be set to obtain the desired heater temperature for a specific coil. The
      coil attributes (radius, width, number of loops, or length of each loop) are
      input by the user, as well as AWG size of heating wire and desired heater
      temperature. The program calculates total length of wire in the helix, resistance
      of the wire, amperage used, and the voltage to set the rheostat. A discussion of
      semiochemical isolation methods using the GC-EAD and bioassays is presented.

PMID- 15020094
TI  - Tracking neurons recorded from tetrodes across time.
AB  - Tetrodes allow isolation of multiple neurons at a single recording site by
      clustering spikes. Due to electrode drift and perhaps due to time-varying
      neuronal properties, positions and shapes of clusters change in time. As data is
      typically collected in sequential files, to track neurons across files one has to
      decide which clusters from different files belong to the same neuron. We report
      on a semi-automated neuron tracking procedure that uses computed similarities
      between the mean spike waveforms of the clusters. The clusters with the most
      similar waveforms are assigned to the same neuron, provided their similarity
      exceeds a threshold. To set this threshold, we calculate two distributions: of
      within-file similarities, and of best matches in the across adjacent file
      similarities. The threshold is set to the value that optimally separates the two
      distributions. We compare different measures of similarity (metrics) by their
      ability to separate these distributions. We find that these metrics do not differ
      drastically in their performance, but that taking into account the cross-channel
      noise correlation significantly improves performance of all metrics. We also
      demonstrate the method on an independent dataset and show that neurons, as
      assigned by the procedure, have consistent physiological properties across files.

PMID- 15020095
TI  - PSTH-based classification of sensory stimuli using ensembles of single neurons.
AB  - The problem of understanding how ensembles of neurons code for somatosensory
      information has been defined as a classification problem: given the response of a
      population of neurons to a set of stimuli, which stimulus generated the response
      on a single-trial basis? Multivariate statistical techniques such as linear
      discriminant analysis (LDA) and artificial neural networks (ANNs), and different
      types of preprocessing stages, such as principal and independent component
      analysis, have been used to solve this classification problem, with surprisingly
      small performance differences. Therefore, the goal of this project was to design
      a new method to maximize computational efficiency rather than classification
      performance. We developed a peri-stimulus time histogram (PSTH)-based method,
      which consists of creating a set of templates based on the average neural
      responses to stimuli and classifying each single trial by assigning it to the
      stimulus with the 'closest' template in the Euclidean distance sense. The PSTH
      based method is computationally more efficient than methods as simple as linear
      discriminant analysis, performs significantly better than discriminant analyses
      (linear, quadratic or Mahalanobis) when small binsizes are used (1 ms) and as
      well as LDA with any other binsize, is optimal among other minimum-distance
      classifiers and can be optimally applied on raw neural data without a previous
      stage of dimension reduction. We conclude that the PSTH-based method is an
      efficient alternative to more sophisticated methods such as LDA and ANNs to study
      how ensemble of neurons code for discrete sensory stimuli, especially when
      datasets with many variables are used and when the time resolution of the neural
      code is one of the factors of interest.

PMID- 15020096
TI  - New lumbar method for monitoring cerebrospinal fluid pressure in rats.
AB  - OBJECTIVE: Monitoring cerebrospinal fluid pressure or intracranial pressure (ICP)
      is crucial in the study of neurosurgical disorders. In the present study, we
      report a new lumbar method for monitoring ICP in rats. METHODS: A PE10 catheter
      connected to a pressure transducer was placed into the subarachnoid space of L5
      through the duramater after laminectomy to record lumbar cerebrospinal fluid
      pressure (lumbar-ICP). ICP at the cisterna magna (cisterna-ICP) was recorded
      simultaneously via a catheter in the subarachnoid space at the cisterna magna.
      Eighteen anesthetized adult male S-D rats were subjected to baseline recording
      followed by either experimental subarachnoid hemorrhage (SAH) induced by
      intravascular puncture method or experimental intracerebral hemorrhage (ICH)
      induced by blood injection with a stereotaxic system. RESULTS: Baseline lumbar
      ICP and cisterna-ICP varied between 6 and 8 mmHg, and respiratory variation could
      be detected. A similar acute response to SAH was recorded in both the lumbar-ICP
      and cisterna-ICP in all rats. In rats subjected to SAH, the lumbar catheter
      continuously and accurately monitored lumbar-ICP, and reliable pressure tracings
      were obtained for up to 24 h after SAH. However, continued cisterna-ICP
      monitoring was abandoned in two rats in the cisterna magna method due to
      obstruction of the catheter by blood clots (hematoma). CONCLUSION: This new
      lumbar-ICP method is simple, safe, easy, and reliable in rats. Continued lumbar
      ICP measurements provided monitoring for up to 24 h after experimental
      manipulation.

PMID- 15020097
TI  - A non-invasive gating device for continuous drug delivery that allows control
      over the timing and duration of spontaneous opiate withdrawal.
AB  - Opiate dependence in laboratory animals is commonly induced by two methods: (1)
      subcutaneous (s.c.) insertion of morphine pellets, and (2) daily injections of
      increasing doses of opiates. While both of these methods reliably induce opiate
      dependence, they do not allow one to discontinue, and subsequently reestablish
      steady state opiate plasma levels with minimal invasive procedures. We developed
      an "ON-OFF" gating device for repeatedly and non-invasively turning ON or OFF
      opiate delivery by standard osmotic minipumps. The reliability of this "device"
      was tested utilizing naloxone (NAL)-precipitated somatic signs of withdrawal, and
      body mass index (BMI) as measures of withdrawal. Rats were implanted with osmotic
      minipumps equipped with the gating device, containing heroin (2.66 mg per day).
      Three days after surgery, somatic signs of withdrawal were precipitated every 48
      h by NAL (0.3mg/kg), with minipumps gated ON or OFF. For BMI, spontaneous
      withdrawal was repeatedly (three times) induced by turning OFF and ON the gating
      devices every 48 h. Body weights were measured every 4h from 06:00 to 22:00 h
      daily. Results show that NAL precipitated intense somatic signs of withdrawal
      when gating devices were ON. This effect was almost abolished when gating devices
      were OFF. BMI rapidly decreased after the gating devices were turned OFF with
      maximum weight loss occuring 12 h post-OFF position, and gradually returning to
      baseline values after gating devices were turned back ON. These results
      demonstrate the validity of the "ON-OFF" gating device for non-invasively and
      repeatedly inducing physical dependence to opiates over a prolonged time.

PMID- 15020098
TI  - A post-processing/region of interest (ROI) method for discriminating patterns of
      activity in statistical maps of fMRI data.
AB  - To combine functional neuroimaging studies across subjects, anatomical and
      functional data are typically either transformed to a common space or averaged
      across regions of interest (ROIs). However, if there are (1) anatomical
      variations within the subject pool (as in clinical or aging populations), (2) non
      Gaussian distributions of task-related activity within a typical ROI or, (3) more
      ROIs than subjects, neither spatial transformation of the data to a common space
      nor averaging across all subjects' ROIs is suitable for standard discriminant
      analysis. To solve these problems, we describe a post-processing method that uses
      voxel-based statistics representing task-related activity (pooled within ROIs) to
      establish combinations of ROIs that maximally differentiate tasks across all
      subjects. The method involves randomized resampling from multiple ROIs within
      each subject, multivariate linear discriminant analysis across all subjects and
      validation with bootstrapping techniques. When applied to experimental data from
      healthy subjects performing two motor tasks, the method detected some brain
      regions, including the supplementary motor area (SMA), that participated in a
      distributed network differentially active between tasks. However there was not a
      significant difference in SMA activity when this region was examined in
      isolation. We suggest this method is a practical means to combine voxel-based
      statistics within anatomically defined ROIs across subjects.

PMID- 15020099
TI  - Context-dependent stimulus presentation to freely moving animals in 3D.
AB  - The presentation of controllable, dynamic sensory stimuli provides a powerful
      experimental paradigm, which has been extensively applied to explore sensory
      processing in walking and tethered flying insects. Recent advances in computer
      hardware and software technology provide the opportunity to track the 3D flight
      path of free-flying insects and process these data in real-time, opening up the
      possibility to present dynamic stimuli to free-flying animals. To accommodate for
      the increased complexity relating to 3D space, we partitioned experimental
      design, real-time data acquisition and stimulus control into multiple self
      contained modules. 3D experimental scenarios were created in a stand-alone
      application by forging multiple 3D space-stimulus relationships. The use of
      dynamic cues is illustrated by an experiment, in which dynamic acoustic cues were
      presented to a free-flying parasitoid fly in a large 3D environment. The
      combination of loosely coupled modules provides robust and flexible solutions,
      allowing new paradigms to be readily implemented based on existing technologies.
      We demonstrate this with a test system that displayed a complex visual stimulus,
      controlled in real-time by the 2D position and orientation of a test object. The
      presented methods are applicable in a variety of novel experimental paradigms,
      including learning paradigms, for various sensory modalities in walking, swimming
      and flying animals.

PMID- 15020100
TI  - Focused microwave irradiation of the brain preserves in vivo protein
      phosphorylation: comparison with other methods of sacrifice and analysis of
      multiple phosphoproteins.
AB  - At any point in time, net protein phosphorylation represents the contribution of
      protein kinase and protein phosphatase activities affecting a specific site on a
      given substrate. Preservation of phosphorylated proteins in neural tissues has
      traditionally included flash-freezing or fresh tissue processing following tissue
      isolation. Rapid heat inactivation of protein kinases and phosphatases by focused
      microwave irradiation sacrifice represents another method to preserve, in vivo,
      brain protein phosphorylation state. In this study, we compared preservation of
      the phosphorylation state of a variety of phosphoproteins in the brain following
      sacrifice of mice by decapitation, decapitation into liquid nitrogen and focused
      microwave irradiation. We found that microwave irradiation generally provided the
      highest and most consistent levels of protein phosphorylation, regardless of the
      substrates examined in striatum and hippocampus. In general, flash-freezing
      resulted in the least preservation of phospho-state with ERK1/2 and CREB showing
      almost complete dephosphorylation. When regions of freshly decapitated brains
      were homogenized and incubated on ice for 30 min, ERK1/2 phosphorylation was
      completely lost, whereas it was well preserved in microwaved samples left at room
      temperature for 2 h. Loss of ERK1/2 phosphorylation in the fresh samples could
      not be attributed to substrate proteolysis. Our results indicate that focused
      microwave irradiation sacrifice may be required to achieve biologically relevant
      data for the in vivo protein phosphorylation state of many phosphoproteins.

PMID- 15020101
TI  - A pre-embedding immunogold approach for detection of synaptic endocytic proteins
      in situ.
AB  - During the past decade, many molecular components of clathrin-mediated
      endocytosis have been identified and proposed to play various hypothetical roles
      in the process [Nat. Rev. Neurosci. 1 (2000) 161; Nature 422 (2003) 37]. One
      limitation to the evaluation of these hypotheses is the efficiency and resolution
      of immunolocalization protocols currently in use. In order to facilitate the
      evaluation of these hypotheses and to understand more fully the molecular
      mechanisms of clathrin-mediated endocytosis, we have developed a protocol
      allowing enhanced and reliable subcellular immunolocalization of proteins in
      synaptic endocytic zones in situ. Synapses established by giant reticulospinal
      axons in lamprey are used as a model system for these experiments. These axons
      are unbranched and reach up to 80-100 microm in diameter. Synaptic active zones
      and surrounding endocytic zones are established on the surface of the axonal
      cylinder. To provide access for antibodies to the sites of synaptic vesicle
      recycling, axons are lightly fixed and cut along their longitudinal axis. To
      preserve the ultrastructure of the synaptic endocytic zone, antibodies are
      applied without the addition of detergents. Opened axons are incubated with
      primary antibodies, which are detected with secondary antibodies conjugated to
      gold particles. Specimens are then post-fixed and processed for electron
      microscopy. This approach allows preservation of the ultrastructure of the
      endocytic sites during immunolabeling procedures, while simultaneously achieving
      reliable immunogold detection of proteins on endocytic intermediates. To explore
      the utility of this approach, we have investigated the localization of a GTPase,
      dynamin, on clathrin-coated intermediates in the endocytic zone of the lamprey
      giant synapse. Using the present immunogold protocol, we confirm the presence of
      dynamin on late stage coated pits [Nature 422 (2003) 37] and also demonstrate
      that dynamin is recruited to the coat of endocytic intermediates from the very
      early stages of the clathrin coat formation. Thus, our experiments show that the
      current pre-embedding immunogold method is a useful experimental tool to study
      the molecular mechanisms of synaptic vesicle recycling.

PMID- 15020102
TI  - A computer model of field potential responses for the study of short-term
      plasticity in hippocampus.
AB  - Activity-dependent synaptic plasticity has important implications for network
      function. The previously developed model of the hippocampal CA1 area, which
      contained pyramidal cells (PC) and two types of interneurons involved in feed
      forward and recurrent inhibition, respectively, and received synaptic inputs from
      CA3 neurons via the Schaffer collaterals, was enhanced by incorporating dynamic
      synaptic connections capable of changing their weights depending on presynaptic
      activation history. The model output was presented as field potentials, which
      were compared with those derived experimentally. The parameters of Schaffer
      collateral-PC excitatory model synapse were determined, with which the model
      successfully reproduced the complicated dynamics of train-stimulation sequential
      potentiation/depression observed in experimentally recorded field responses. It
      was found that the model better reproduces the time course of experimental field
      potentials if the inhibitory synapses on PC are also made dynamic, with expressed
      properties of frequency-dependent depression. This finding supports experimental
      evidence that these synapses are subject to activity-dependent depression. The
      model field potentials in response to various randomly generated and real
      (derived from recorded CA3 unit activity) long stimulating trains were
      calculated, illustrating that short-term plasticity with the observed
      characteristics could play specific roles in frequency processing in hippocampus
      and thus providing a new tool for the theoretical study of activity-dependent
      synaptic plasticity.

PMID- 15020103
TI  - Improved ballistocardiac artifact removal from the electroencephalogram recorded
      in fMRI.
AB  - The simultaneous recording of electroencephalogram (EEG) and functional magnetic
      resonance image (fMRI) is a promising tool that is capable of providing high
      spatiotemporal brain mapping, with each modality supplying complementary
      information. One of the major barriers to obtain high-quality simultaneous
      EEG/fMRI data is that pulsatile activity due to the heartbeat induces significant
      artifacts in the EEG. The purpose of this study was to develop a novel algorithm
      for removing heartbeat artifact, thus overcoming problems associated with
      previous methods. Our method consists of a mean artifact wave form subtraction,
      the selective removal of wavelet coefficients, and a recursive least-square
      adaptive filtering. The recursive least-square adaptive filtering operates
      without dedicated sensor for the reference signal, and only when the mean
      subtraction and wavelet-based noise removal is not satisfactory. The performance
      of our system has been assessed using simulated data based on experimental data
      of various spectral characteristics, and actual experimental data of alpha-wave
      dominant normal EEG and epileptic EEG.

PMID- 15020105
TI  - Quantitation of mRNA levels of steroid 5alpha-reductase isozymes in the rat brain
      by "one-step" RT-PCR and capillary electrophoresis.
AB  - The enzyme 5alpha-reductase (5alpha-R) is present in many mammalian tissues,
      including the brain. The physiological importance of 5alpha-R in the brain
      derives from its capability to convert testosterone (T) to a more potent
      androgen, dihydrotestosterone (DHT), and to convert progesterone to its 5alpha
      reduced derivative, precursors of allopregnanolone, potent allosteric modulator
      of the gamma-aminobutyric acid receptor (GABA(A)-R). 5alpha-R occurs as two
      isoforms, 5alpha-R type 1 (5alpha-R1) and 5alpha-R type 2 (5alpha-R2). We present
      an accurate, rapid, and modestly labor-intensive method to precisely quantitate
      5alpha-R mRNA species in the cerebral cortex of the rat. This approach combines
      the high specificity of "one-step" reverse transcription-polymerase chain
      reaction (RT-PCR) with the sensitivity of laser-induced fluorescence capillary
      electrophoresis (LIF-CE). Both cDNA synthesis and PCR amplification are performed
      with the same enzyme and site-specific primers, improving the efficiency of cDNA
      synthesis. The specific target mRNA and a mimic DNA fragment, used as a
      competitive internal standard, were co-amplified in a single reaction in which
      the same primers are used. The method presented in this paper enables a more
      efficient quantitative determination of 5alpha-R mRNA isozymes, and may lead to a
      better understanding of the role of 5alpha-R isozymes in the physiology of the
      central nervous system.

PMID- 15020104
TI  - An inexpensive device for non-invasive electroretinography in small aquatic
      vertebrates.
AB  - Electroretinographic (ERG) method records a sum field potential of the retina in
      response to light. It mainly arises in the outer retina and is used as a non
      invasive measure in both animal experiments and the clinic. Since it is a
      comprehensive method to assess outer retinal function, it is becoming
      increasingly useful in genetic studies of vision. Here we present a simple in
      house built setup to measure ERGs of aquatic vertebrates. We have used this setup
      to efficiently and reliably measure intact larvae of zebrafish (Danio rerio),
      Medaka fish (Oryzias latipes), and Xenopus laevis tadpoles. By slight
      modification of the setup, we were also able to measure adult zebrafish and
      Medaka, demonstrating the general versatility of the setup. We picked these
      organisms since they are increasingly used to study visual function with genetic
      means. This setup is easily built and will be particularly useful for
      laboratories setting up ERG measurements as a complement to their genetic
      studies.

PMID- 15020106
TI  - Biomimetic apatite coatings on micro-arc oxidized titania.
AB  - Biomimetic apatite coatings on micro-arc oxidized titania films were investigated
      and their apatite-inducing ability was evaluated in a simulated body fluid (1.0
      SBF) as well as in a 1.5 times concentrated SBF (1.5 SBF). Titania-based films on
      titanium were prepared by micro-arc oxidation at various applied voltages (250
      500 V) in an electrolytic solution containing beta-glycerophosphate disodium salt
      pentahydrate (beta-GP) and calcium acetate monohydrate (CA). Macro-porous, Ca-
      and P-containing titania-based films were formed on the titanium substrates. The
      phase, Ca and P content, morphology, and thickness of the films were strongly
      dependent on the applied voltage. In particular, Ca- and P-containing compounds
      such as CaTiO3, beta-Ca2P2O7 and alpha-Ca3(PO4)2 were produced at higher voltages
      (>450 V). When immersed in 1.0 SBF, a carbonated hydroxyapatite was induced on
      the surfaces of the films oxidized at higher voltages (>450 V) after 28 days,
      which is closely related to the Ca- and P-containing phases. The use of 1.5 SBF
      shortened the apatite induction time and apatite formation was confirmed even on
      the surface of the films oxidized at 350 V, which suggests that the incorporated
      Ca and P in the titania films play a similar role to the Ca- and P-containing
      compounds in the SBF.

PMID- 15020107
TI  - Fluor-hydroxyapatite sol-gel coating on titanium substrate for hard tissue
      implants.
AB  - Hydroxyapatite (HA) and fluor-hydroxyapatite (FHA) films were deposited on a
      titanium substrate using a sol-gel technique. Different concentrations of F- were
      incorporated into the apatite structure during the sol preparation. Typical
      apatite structures were obtained for all coatings after dipping and subsequent
      heat treatment at 500 degrees C. The films obtained were uniform and dense, with
      a thickness of approximately 5 microm. The dissolution rate of the coating layer
      decreased with increasing F- incorporation within the apatite structure, which
      demonstrates the possibility of tailoring the solubility by a functional gradient
      coating of HA and FHA. The cell proliferation rate on the coating layer decreased
      slightly with increasing F- incorporation. The alkaline phosphatase (ALP)
      activity of the cells on all the HA and FHA coated samples showed much higher
      expression levels compared to pure Ti. This confirmed the improved activity of
      cell functions on the substrates with the sol-gel coating treatment.

PMID- 15020109
TI  - Fatigue characteristics of bioactive glass-ceramic-coated Ti-29Nb-13Ta-4.6Zr for
      biomedical application.
AB  - A new surface-coating method by which CaP invert glass is used to improve the
      bioactivity of titanium alloys has been developed recently. In this method, the
      powder of CaP invert glass (CaO-P2O5-TiO2-Na2O) is coated on the surface of
      titanium alloy samples and heated between 1073 and 1123 K. With this treatment, a
      calcium phosphate layer mainly containing beta-Ca3(PO4)2 phase can be coated
      easily on titanium alloy samples. In the present study, the effect of this
      coating process on the fatigue properties of Ti-29Nb-13Ta-4.6Zr, a new metastable
      beta alloy for biomedical applications, has been investigated. The fatigue
      endurance limit of the coated alloy was found to be about 15% higher than that of
      uncoated alloy, as a result of the formation of a hard (alpha + beta) layer and a
      small amount of the omega phase during the coating process. The coating exhibits
      excellent adhesion to the substrate during the tensile and fatigue tests.
      Subsequent ageing at 673 K for 259.2 ks greatly improves the fatigue resistance
      of the coated alloy due to isothermal omega phase precipitation, and does not
      have obvious detrimental effect on the coating properties.

PMID- 15020108
TI  - Effects of periodate and chondroitin 4-sulfate on proteoglycan stabilization of
      ostrich pericardium. Inhibition of calcification in subcutaneous implants in
      rats.
AB  - Chemical modification of biological materials used in the manufacture of cardiac
      valves tends to reduce the relatively high degree of biodegradation and
      calcification of the implanted bioprostheses. The most widely used treatment to
      reduce biodegradability of the valves is glutaraldehyde fixation. However, this
      treatment is potentially toxic and induces tissue calcification. In order to
      minimize these undesirable effects, we have analyzed the effect of a pre-fixation
      of endogenous proteoglycans and exogenous glycosaminoglycans, as well as the
      borohydride reduction influence on the different modified ostrich pericardium
      implants after subcutaneous implantation in rats. The presence of calcific
      deposits was detected in all implanted GA-fixed samples; however, calcification
      was highly reduced in both groups of periodate-prefixed materials, which showed
      also a very low Ca/P molar ratio. Borohydride post-treatment of these
      biomaterials resulted in a significant increase in calcium phosphate
      precipitation, with the appearance of calcium deposits mainly in an amorphous
      form even though X-ray diffraction allowed the detection of brushite- and apatite
      like crystals. Regarding tissue stability, no significant differences were found
      among the borohydride-untreated implants but higher levels of matrix
      metalloproteinases were observed by gelatin zymography in the periodate pre-fixed
      materials. This increase was partially reduced by pre-fixation of exogenous
      chondroitin 4-sulfate. On the other hand, borohydride post-treatment not only
      increased calcification, but also reduced tissue stability and increased the
      presence of matrix-degrading activities.

PMID- 15020110
TI  - On the microstructure of biocomposites sintered from Ti, HA and bioactive glass.
AB  - Sintering reactions and fine structures of the biocomposites prepared from powder
      mixtures of titanium ( alpha -Ti), hydroxyapatite (HA) and bioactive glass (BG)
      (SiO2-CaO-P2O5-B2O3-MgO-TiO2-CaF2) were investigated by X-ray diffraction and
      transmission electron microscopy. The results showed that complex reactions among
      the starting materials mainly depended on the initial Ti/HA ratios as well as the
      sintering temperatures. And the reaction could be expressed by the following
      illustrative equation: Ti+Ca10(PO4)6(OH)2-
      >CaTiO3+CaO+TixPy+(Ti2O)+(Ca4P2O9)+H2O.

PMID- 15020111
TI  - A study of the nanostructure and tensile properties of ultra-high molecular
      weight polyethylene.
AB  - Ultra-high molecular weight polyethylene (UHMWPE) has gained worldwide acceptance
      as a bearing material used in orthopaedic implants. Despite its widespread use,
      inherent properties of the polymer continue to limit the wear resistance and the
      clinical lifespan of implanted knee and hip prosthetics containing UHMWPE
      components. The degree of crystallinity of UHMWPE is known to strongly influence
      several of its tensile mechanical properties such as Young's modulus, yield
      stress, strain-hardening rates, work of fracture and ultimate tensile properties.
      In this study, medical grade UHMWPE was subjected to four different
      crystallization conditions resulting in UHMWPE with a range of crystalline
      morphologies. Thereafter, the crystalline nanostructure was quantitatively
      characterized using a combination of ultra-small angle X-ray scattering and
      differential scanning calorimetry. Low-voltage scanning electron microscopy was
      employed as a supplementary technique to compare the crystalline morphology
      resulting from each crystallization condition. In addition, uniaxial tensile
      tests were performed to assess the effects of crystallization conditions on the
      mechanical properties of UHMWPE. This study showed that while crystallization
      conditions strongly influenced the morphology of UHMWPE, in most cases the
      mechanical properties of the material were not significantly affected.

PMID- 15020112
TI  - Glass ionomer cement: evidence pointing to fluorine release in the form of
      monofluorophosphate in addition to fluoride ion.
AB  - The fluoride ion released from glass ionomer cements into water is reportedly, in
      part, complexed with other elements present in the cement. When measured using
      ion selective electrode potentiometry (ISE) a decomplexant TISAB IV (T) is used
      to convert all fluoride to F- ion which the ISE can detect. In this study, an
      additional decomplexing procedure (H) designed to hydrolyse fluorine covalently
      bonded to phosphorus in the monofluorophosphate (MFP) ion into F- was also used.
      The soluble products from three glass ionomers were analysed by both techniques
      (H & T). Five 1 x 10 mm discs were each immersed in 10 ml of de-ionised water.
      This was changed and 4 ml analysed by T and 4 ml by H at 1, 2, 3, 6, 10, 13, 17,
      21, 24, 28, and 31 days. H was greater than T for 161 of the 165 pairs (
      chi2=74.7, p=<0.001 ). The total cumulative F release H (in micromol/g cement) at
      31 days for AH2 was 122.3, s.d. 30.8; LG26 44.0, s.d. 1.55; LG30 10.0, s.d. 3.15
      as compared T results of 100.1, s.d. 31.1; 30.3, s.d. 1.92; 3.7, s.d. 1.36,
      respectively. In all three cases the H was significantly greater than T (matched
      pair 't' test with p=0.01 or less). H-T was show to have a very strong
      associative relationship with t1/2 (R2=0.98 or greater p<0.001 ). Evaluating the
      ratio of P:F in the cements in comparison with the ratio of additional F measured
      by H to that measured by T produced a relationship log[(H-T)/T]=0.28 x log[P/F]
      0.45 with R2=0.999. It is concluded that glass ionomers release more fluorine
      than is detected by ISE using TISAB IV. If this F is in the form of MFP this may
      be released more completely into saliva than F as F-, release of which is
      substantially reduced by Ca2+, since calcium monofluorophosphate is more soluble
      than CaF2.

PMID- 15020113
TI  - Cellular biocompatibility and stimulatory effects of calcium metaphosphate on
      osteoblastic differentiation of human bone marrow-derived stromal cells.
AB  - In the present study, the in vitro biocompatibility of calcium metaphosphate
      (CMP) with human bone marrow stromal cells (HBMSCs) and its effect on
      osteoblastic differentiation have been investigated. Powder and disk forms of CMP
      do not exert a cytotoxic effect on the HBMSCs undergoing osteoblastic
      differentiation. In addition, the HBMSCs adhere to the surface of the CMP disk as
      successfully as to the culture plate or hydroxyapatite (HA) disk. The HBMSCs
      adhered to either the HA or CMP disk display an undistinguishable actin
      arrangement and cellular phenotypes, indicating that the CMP does not disrupt
      normal cellular responses. An analysis of the differentiation of the HBMSCs
      cultured on culture plate, the HA and the CMP disk shows that three matrices are
      capable of supporting osteoblastic differentiation of the HBMSCs as accessed by
      alkaline phosphatase (ALP) staining. Further molecular analysis of osteoblastic
      differentiation of HBMSCs reveals that the CMP disk has a better ability than the
      HA disk to induce an expression of osteoblast-related genes, including ALP,
      osteoprotegerin (OPG), a decoy receptor for RANK ligand, and osteopontin (OPN), a
      non-collagenous bone matrix protein. The results demonstrate that, in addition to
      favorable biocompatibility, the CMP can stimulate osteoblastic differentiation of
      the HBMSCs in vitro.

PMID- 15020114
TI  - Strengthening mechanisms in Ti-Nb-Zr-Ta and Ti-Mo-Zr-Fe orthopaedic alloys.
AB  - The microstructural evolution and attendant strengthening mechanisms in two novel
      orthopaedic alloy systems, Ti-Nb-Zr-Ta and Ti-Mo-Zr-Fe, have been compared and
      contrasted in this paper. Specifically, the alloy compositions considered are Ti
      34Nb-9Zr-8Ta and Ti-13Mo-7Zr-3Fe. In the homogenized condition, both alloys
      exhibited a microstructure consisting primarily of a beta matrix with grain
      boundary alpha precipitates and a low-volume fraction of intra-granular alpha
      precipitates. On ageing the homogenized alloys at 600 degrees C for 4 hr, both
      alloys exhibited the precipitation of refined scale secondary alpha precipitates
      homogeneously in the beta matrix. However, while the hardness of the Ti-Mo-Zr-Fe
      alloy marginally increased, that of the Ti-Nb-Zr-Ta alloy decreased substantially
      as a result of the ageing treatment. In order to understand this difference in
      the mechanical properties after ageing, TEM studies have been carried out on both
      alloys prior to and post the ageing treatment. The results indicate the existence
      of a metastable B2 ordering in the Ti-Nb-Zr-Ta alloy in the homogenized condition
      which is destroyed by the ageing treatment, consequently leading to a decrease in
      the hardness.

PMID- 15020115
TI  - Characterization of titanium surfaces with calcium and phosphate and osteoblast
      adhesion.
AB  - The titanium surfaces containing calcium, phosphate ions and the carbonate
      apatite were characterized. The effect of surface chemistry on the initial rabbit
      osteoblast response on these surfaces was investigated. The cell count and
      alkaline phosphatase (ALP) specific activity assay were used for biochemical
      analyses. Scanning electron microscopy was used for morphology observation and in
      particular X-ray photoelectron spectroscopy (XPS) for surface chemistry
      characterization. The number of cells adhering to the apatite coating surface was
      the maximum, the number of cells on the surface containing calcium without
      phosphate ions was higher than that containing phosphate without calcium, and the
      number on the unmodified titanium surface was the least. The osteoblasts cultured
      on the apatite surface exhibited the highest ALP specific activity, next were the
      ones on the surface containing solely calcium, the lowest were on the unmodified
      titanium surface. On the substrate surfaces removed of adhered cells, the order
      of nitrogen amounts detected by XPS was consistent with ones of ALP specific
      activity and cell number, except for the unmodified titanium surface. For the
      substrate surfaces removed of adhered osteoblasts, XPS analysis showed that
      calcium and phosphorous amounts decreased during cell adhesion. After cell
      culture the Ca2p binding energy (BE) values for apatite coating and the surface
      containing solely calcium were similar to those of the two surfaces adsorbed
      bovine serum albumin (BSA). The P2p BE values for the surfaces containing
      phosphate ions, including the apatite coating and the surface containing solely
      phosphate ions, showed the same change. But after cell culture the decrease of
      the P2p BE value for the coating surface was larger than the one for the surface
      containing solely phosphate ions. Considering the bovine serum albumin adsorption
      on the same samples, these results indicated that calcium ions on titanium
      surfaces play a more important role than phosphate ions in initial interactions
      among culture medium, osteoblasts and titanium surfaces. On the apatite coating
      surface, calcium ions are active sites for osteoblast adhesion, while calcium and
      phosphate ions co-exist on titanium surfaces, the former promotes the osteoblast
      adhesion onto the phosphate sites on titanium surfaces. The cell adhesion was a
      complicated biological and chemical process relating to surface several elements
      similar to protein adsorption.

PMID- 15020117
TI  - Surface-adsorbed alpha1-microglobulin modulation of human fibroblasts spreading
      and matrix metalloproteinases release.
AB  - The lipocalin alpha1-microglobulin (alpha1-m), an immunoregulatory protein
      produced by human hepatocytes and distributed in various organs and fluids, is
      physiologically adsorbed onto polymer surfaces from both serum and urine, and its
      adsorption correlated to the degree of surface hydrophobicity. Starting from the
      hypothesis that alpha1-m holds a modulatory role at the biomaterials-tissue
      interface, we have observed a dose-dependent reduction in adhesion of human
      fibroblasts (cell line MRC-5) seeded onto polystyrene (PS) in a serum-free medium
      in the presence of adsorbed alpha(1)-m (2.1+/-0.2 x 10(4) cells/cm2 at 200 ng/ml
      alpha1-m ) compared to cells seeded onto cell grade PS (2.9+/-0.05 x 10(4)
      cells/cm2) after 72 h. Moreover, in the presence of alpha1-m, adherent MRC-5
      cells exhibit an altered shape due to inhibition of cell spreading, and release
      of matrix metalloproteinase -2 (gelatinase A, MMP-2) by fibroblasts was also
      increased by 1.6-1.9-fold after 72 h of incubation. These data extend the known
      spectrum of alpha1-m activities, suggesting a possible role of this protein in
      the complex series of events occurring at the tissue-biomaterial interface.

PMID- 15020116
TI  - Biological evaluation of carbon-fibre-reinforced polybutyleneterephthalate
      (CFRPBT) employed in a novel acetabular cup.
AB  - Polymer composites are potentially useful materials for orthopaedic applications
      as they can be tailored to closely match the various moduli of bone. The
      Cambridge epiphyseal cup has been designed using one such material, carbon-fibre
      reinforced polybutyleneterephthalate (CFRPBT), so that more of the load can be
      transferred to bone in order to reduce bone loss around the implant. We have
      evaluated the suitability of CFRPBT for this application using several standard
      and custom biological tests, both in vitro and in vivo, and have also started the
      initial clinical evaluation of the prosthesis. CFRPBT showed no toxicity in bulk
      form and only minimal toxicity as a particulate. It was non-haemolytic, non
      immunogenic and showed no genotoxicity. No adverse responses were seen after in
      vivo implantation, and the results obtained following 9 months of clinical
      evaluation have been very encouraging with a good clinical outcome and good bone
      bonding to the hydroxyapatite-coated CFRPBT.

PMID- 15020118
TI  - The immobilization of hepatocytes on 24 nm-sized gold colloid for enhanced
      hepatocytes proliferation.
AB  - Bioartificial liver and hepatocyte transplantation is anticipated to supply a
      temporary metabolic support for candidates of liver transplantation or for
      patients with fulminant liver failure. An essential restriction of this form is
      the inability to acquire an enough amount of hepatocytes. Enhancement of the
      proliferation and differentiated function of hepatocytes is becoming a pursued
      target. Here, porcine hepatocytes were successfully immobilized on nano-sized
      gold colloid particles to construct a "hepatocyte/gold colloid" interface at
      which hepatocytes can be quickly proliferated. The properties of this resulting
      interface were characterized and confirmed by scanning electron microscopy and
      atomic force microscopy. The proliferative mechanism of hepatocytes was also
      discussed. The proliferated hepatocytes could be applied to the clinic based on
      their excellent functions for the synthesis of protein, glucose and urea as well
      as lower lactate dehydrogenase release.

PMID- 15020119
TI  - Effect of the particle size on the micro and nanostructural features of a calcium
      phosphate cement: a kinetic analysis.
AB  - The aim of this work is to investigate the possibility of controlling the final
      micro and nanostructural features of a calcium phosphate cement by modifying the
      particle size of the starting powder, and to study the effect of this parameter
      on the kinetics of the setting reaction. The development of calcium phosphate
      materials with tailored structures at the micro and nanoscale levels could allow
      the modulation of some specific responses in biologic phenomena such as protein
      adsorption and cell adhesion, which strongly depend on the nano-sized roughness
      of the interface. It is shown that the higher specific surface, produced by the
      reduction of the particle size of the powder, strongly accelerates the hydrolysis
      of the alpha-TCP into calcium-deficient hydroxyapatite. The higher degree of
      supersaturation attained in the solution favours the nucleation of smaller
      crystals. Thus, by increasing the specific surface of the starting powder in a
      factor of 5, the size of the precipitated crystals is strongly reduced, and the
      specific surface of the set cement increases by a factor of 2. The reduction of
      the particle size produces a substantial decrease of the setting time and
      accelerates the hardening of the cement without significantly affecting the final
      strength attained. The mechanical strength achieved by the cement cannot be
      univocally related to the degree of reaction, without considering the
      microstructural features.

PMID- 15020120
TI  - Thermal sprayed hydroxyapatite splats: nanostructures, pore formation mechanisms
      and TEM characterization.
AB  - Microstructure of thermal sprayed hydroxyapatite (HA) splats was characterized
      using transmission electron microscopy (TEM), and the formation mechanisms of
      micropores within the splats were investigated with the aid of simulated body
      fluids (SBF). High-velocity oxy-fuel and direct current (DC) plasma spray
      techniques were both utilized for the splats' deposition. The microstructure
      features of individual HA splats were revealed through TEM observation of as
      sprayed, and ion-milled splats. Amorphous calcium phosphate and tricalcium
      phosphate phases were observed at the splats' fringes, which indicated that
      extensive decomposition of HA had occurred at these locations. The fringes of the
      HA splats are essentially nanostructured ( approximately 20-50 nm grains), while
      calcium phosphate grains up to 5 microm, depending on flattening state, are
      present at the center of the splats. Morphological observation classified the
      pores within the HA splats into three main categories according to distinctive
      features in their microstructure: open pores, sealed pores and through-thickness
      pores. It was found that particle velocity with which the particle impinged on
      the substrate surface, particle melt state, and structure of starting particle
      (mainly porosity) are the key variables in determining the formation and
      morphology of the micropores within the flattened splats. Influence of subsequent
      splats on the pores of prior deposited splat was also studied using an in vitro
      incubation test in SBF. Obvious pore-sealing action on the open pores was
      revealed, which was achieved through liquid filling of subsequent droplets. It
      was postulated that the overall porosity of a bulk coating could be attributed
      primarily to the sealed pores and flaws among the splats, and, it could be
      adequately governed through appropriate particle melt state and optimized
      velocity of the particles during coating formation.

PMID- 15020122
TI  - Platelet adhesion on titanium oxide gels: effect of surface oxidation.
AB  - The correlations between titanium oxide layers on oxidized titanium (Ti)
      substrates and platelet adhesion were examined. Ti substrates were prepared by
      three different oxidation methods: the first one was treated with hydrogen
      peroxide (H2O2) solution, the second one was heated in air at moderate
      temperatures, and the third one was processed with both H2O2 and heating. The
      titanium oxide layers formed on the Ti substrates were characterized by
      wettability, chemical composition, thickness, and crystal phase. The platelet
      adhesion on these oxide layers was examined and correlated to the
      characterizations of the surface layers. The number of adhesive platelets
      seemingly correlated with the contact angle towards distilled water, because the
      number increased close to 70-80 degrees of the contact angle. The effect of
      surface oxidation on platelet adhesion was examined in detail and it was found
      that the composition and thickness of the oxide layer influenced platelet
      adhesion rather than wettability. Thick titanium oxide layers formed on Ti
      substrates by heating displayed less platelet adhesion than thin oxide layers on
      untreated Ti substrates. The largest number of adhesive platelets was found on
      H2O2-oxidized substrates; the substrates found on amorphous titanium oxide
      contained the Ti-peroxide radical species. The number of platelets, on the other
      hand, could hardly be observed on Ti substrates treated with H2O2 and
      subsequently heated above 300 degrees C. The titanium oxide layer on the
      substrate was thick and we found it to consist of only a few radical species.
      That is, the effect of heat treatment accelerates the growth of the oxide layer,
      and decomposes or decreases the number of radical species. Ti substrates with
      H2O2 and heat treatment above 300 degrees C held the least number of platelets,
      and were concluded to be the most inhibitory for platelet adhesion.

PMID- 15020121
TI  - Hemocompatibilty of new ionic polyurethanes: influence of carboxylic group
      insertion modes.
AB  - New segmented polyurethane (PU) anionomers based on hydroxytelechelic
      polybutadiene (HTPB) were synthesized via two environment-friendly chemical
      routes. The effects of carboxylic content and ion incorporation mode on the
      surface properties were investigated by mean of water absorption analysis and
      static contact angle measurements using water, diiodomethane, formamide and
      ethylene glycol. Blood compatibility of the PUs was evaluated by in vitro
      adhesion assay using 111In-radiolabeled platelet rich plasma and 125I-fibrinogen.
      The morphology of platelet adhesion was also observed by scanning electron
      microscopy (SEM). Results were compared with a biomedical-grade PU, Pellethane.
      Insertion of the carboxylic groups on the soft segments (S-alpha series), using
      thioglycolic acid (TGA), increases surface hydrophilicity, limits water uptake
      (5%, for an ion content of 3.6 wt%), and reduces platelet adhesion and fibrinogen
      adsorption on the PUs' surfaces. In contrast, the classical insertion onto the
      hard segment (H-alpha series), using dimethylolpropionate (DMPA) as chain
      extender, leads to high water uptake (18%, for an ion content of 3.6 wt%) and
      promotes platelet and fibrinogen adhesion. SEM analyses of the non-ionic PUs
      exhibited surfaces with adhered platelets which underwent morphological
      modification. Similarly, the H-alpha ionic PUs show adherent and activated
      platelets. On the contrary, no platelet morphology changes were observed on the S
      alpha ionic surfaces. In conclusion, insertion of carboxyl groups on the soft
      segments of PUs reduces their thrombogenicity.

PMID- 15020123
TI  - In vitro blood compatibility of polymeric biomaterials through covalent
      immobilization of an amidine derivative.
AB  - We present a surface coating with anticoagulant characteristics showing
      significantly reduced coagulation activation. The synthesis of a monomeric
      conjugate containing a benzamidine moiety was carried out and its inhibitory
      activity against human thrombin, the key enzyme of the blood coagulation cascade,
      was determined using a chromogenic assay. Based on that, low-thrombogenic
      interfaces were prepared by covalent attachment of this low-molecular weight
      thrombin inhibitor on poly(octadecene-alt-maleic anhydride) copolymer thin films
      and characterized using ellipsometry, XPS and dynamic contact angle measurements.
      The in vitro hemocompatibility tests using freshly drawn human whole blood
      showed, in agreement with the SEM images, that a PO-MA film modified with a
      benzamidine moiety using a PEG spacer decreased the activation of coagulation,
      platelets and the complement system. The decreased protein adsorption, in
      addition to the specific inhibition of thrombin, effectively enhanced the short
      term hemocompatibility characteristics.

PMID- 15020124
TI  - Patterning protein molecules on poly(ethylene glycol) coated Si(111).
AB  - We demonstrate spatially localized immobilization of protein molecules on high
      density poly(ethylene glycol) (PEG) coated Si(111). Patterns of HO- and CH3O
      terminated PEG regions are formed on silicon surfaces based on soft lithography
      techniques and an efficient reaction between alcohol functional groups and
      chlorine-terminated silicon. Activation of the HO-terminated PEG brush is
      achieved via either partial oxidation to form aldehyde groups or via attachment
      of efficient leaving groups. Protein molecules are covalently immobilized to
      these activated regions on the PEG/Si surface.

PMID- 15020125
TI  - The influence of molecular weight, crosslinking and counterface roughness on TNF
      alpha production by macrophages in response to ultra high molecular weight
      polyethylene particles.
AB  - The response of murine macrophages to clinically relevant polyethylene wear
      particles generated from different polyethylenes at various time points and
      volumetric doses in vitro was evaluated. Clinically relevant ultra high molecular
      weight polyethylene (UHMWPE) wear debris was generated in vitro in a lubricant of
      RPMI 1640 supplemented with 25% (v/v) foetal calf serum using a multi-directional
      pin-on-plate wear rig under sterile conditions. Wear debris was cultured with C3H
      murine peritoneal macrophages at various particle volume (microm(3)): cell number
      ratios. The secretion of TNF-alpha was determined by ELISA. Initially the effect
      of molecular weight of UHMWPE was considered. Higher molecular weight GUR415HP
      was shown to have a lower wear rate than the lower molecular weight GUR1120,
      however a greater volume of the wear debris produced by the high molecular weight
      GUR415HP was in the 0.1-1.0 microm size range. Wear debris from GUR415HP produced
      significant levels of TNF-alpha at a concentration of 1 microm(3)/cell while at
      least 10 microm(3)/cell of GUR1120 wear debris per cell was needed to produce
      significant levels of TNF-alpha. Secondly the effects of crosslinking GUR1050 was
      examined when worn against a scratched counterface. The wear rate of the material
      was shown to decrease as the level of crosslinking increased. However the
      materials crosslinked with 5 and 10 Mrad of gamma irradiation produced higher
      percentages of 0.1-1.0 microm size wear particles than the non-crosslinked
      material. While the crosslinked material was able to stimulate cells to produce
      significantly elevated TNF-alpha levels at a particle concentration of just 0.1
      microm(3)/cell only concentrations of 10 microm(3)/cell and above of the non
      crosslinked wear debris were stimulatory. When the counterface was changed from
      scratched to smooth the wear rate for all three GUR1050 materials was further
      reduced. For the first time nanometre size wear particles were observed from
      polyethylene which reduced the percentage mass of debris in the 0.1-1.0 microm
      size range. For all three materials on the smooth counterface only concentrations
      of 50 microm(3)/cell and above were stimulatory. This study has demonstrated that
      molecular weight, crosslinking and counterface roughness are important factors in
      determining the biological activity of polyethylene.

PMID- 15020126
TI  - Influence of the concentrations of hyaluronic acid on the properties and
      biocompatibility of Cs-Gel-HA membranes.
AB  - The object of this study was to investigate the relationship between the
      concentrations of HA solutions and the physicochemical properties and the
      biocompatibility of Cs-Gel-HA membranes. The addition of different concentrations
      of HA not only improved the wettability significantly and extended the
      degradation time of Cs-Gel-HA membranes, but also changed their mechanical
      properties. The concentration of HA had a significant influence on the
      biocompatibility of Cs-Gel-HA membranes. Results demonstrated that it was only
      the concentrations of HA in a certain range (0.01-0.1%), that could promote the
      cell adhesion, migration and proliferation, while the concentration of HA was
      above 0.1% it would either reduce or even inhibit these behaviors.

PMID- 15020127
TI  - Photo-crosslinkable microcapsules formed by polyelectrolyte copolymer and
      modified collagen for rat hepatocyte encapsulation.
AB  - New anionic polyelectrolyte tetra-copolymers with photo-crosslinkable 4-(4
      methoxycinnamoyl)phenyl methacrylate monomer in addition to a HEMA-MMA-MAA ter
      copolymer system were synthesized. The tetra-copolymers were used to form photo
      crosslinkable microcapsules with modified collagen by complex coacervation for
      rat hepatocytes encapsulation. The hepatocytes were encapsulated within a two
      layered membrane comprising of modified collagen as the inner core and an outer
      photo-crosslinkable copolymer shell. Upon photo-crosslinking of the microcapsules
      with UV-Vis light irradiation, the mechanical strength and chemical stability of
      the microcapsules, and the cellular functions of the encapsulated hepatocytes
      were enhanced. Particularly, the mechanical stability of the microcapsules was
      dramatically strengthened. The new photo-crosslinkable tetra-copolymer
      formulation described in this article has opened a way to the development of
      hepatocyte microencapsulation technology for bioartifical liver assist device.

PMID- 15020128
TI  - Effects of crosslinking degree of an acellular biological tissue on its tissue
      regeneration pattern.
AB  - It was reported that acellular biological tissues can provide a natural
      microenvironment for host cell migration and may be used as a scaffold for tissue
      regeneration. To reduce antigenicity, biological tissues have to be fixed with a
      crosslinking agent before implantation. As a tissue-engineering scaffold, it is
      speculated that the crosslinking degree of an acellular tissue may affect its
      tissue regeneration pattern. In the study, a cell extraction process was employed
      to remove the cellular components from bovine pericardia. The acellular tissues
      then were fixed with genipin at various known concentrations to obtain varying
      degrees of crosslinking. It was shown in the in vitro degradation study that
      after fixing with genipin, the resistance against enzymatic degradation of the
      acellular tissue increased significantly with increasing its crosslinking degree.
      In the in vivo subcutaneous study, it was found that cells (inflammatory cells,
      fibroblasts, endothelial cells, and red blood cells) were able to infiltrate into
      acellular tissues. Generally, the depth of cell infiltration into the acellular
      tissue decreased with increasing its crosslinking degree. Infiltration of
      inflammatory cells was accompanied by degradation of the acellular tissue. Due to
      early degradation, no tissue regeneration was observed within fresh (without
      crosslinking) and the 30%-degree-crosslinking acellular tissues. This is because
      the scaffolds provided by these two samples were already completely degraded
      before the infiltrated cells began to secrete their own extracellular matrix. In
      contrast, tissue regeneration (fibroblasts, neo-collagen fibrils, and neo
      capillaries) was observed for the 60%- and 95%-degree-crosslinking acellular
      tissues by the histological examination, immunohistological staining,
      transmission electron microscopy, and denaturation temperature measurement. The
      95%-degree-crosslinking acellular tissue was more resistant against enzymatic
      degradation than its 60%-degree-crosslinking counterpart. Consequently, tissue
      regeneration was limited in the outer layer of the 95%-degree-crosslinking
      acellular tissue throughout the entire course of the study (1-year
      postoperatively), while tissue regeneration was observed within the entire sample
      for the 60%-degree-crosslinking acellular tissue. In conclusion, the crosslinking
      degree determines the degradation rate of the acellular tissue and its tissue
      regeneration pattern.

PMID- 15020129
TI  - Synthesis of a novel structural triblock copolymer of poly(gamma -benzyl-l
      glutamic acid)-b-poly(ethylene oxide)-b-poly(epsilon-caprolactone).
AB  - A novel structural triblock copolymer of poly(gamma-benzyl-l-glutamic acid)-b
      poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PBLG-PEO-PCL) was synthesized
      by a new approach in the following three steps: (1) sequential anionic ring
      opening polymerization (ROP) of ethylene oxide and epsilon-caprolactone with an
      acetonitrile/potassium naphthalene initiator system to obtain a diblock copolymer
      CN-PEO-PCL with a cyano end-group; (2) conversion of the CN end-group into NH2
      end-group by hydrogenation to obtain NH2-PEO-PCL; (3) ROP of gamma-benzyl-l
      glutamate-N-carboxyanhydrides (Bz-l-GluNCA) with NH2-PEO-PCL as macroinitiator to
      obtain the target triblock copolymer. The structures from CN-PEO precursor to the
      triblock copolymers were confirmed by FT-IR and 1H NMR spectroscopy, and their
      molecular weights were measured by gel permeation chromatography. The monomer of
      Bz-l-GluNCA can react almost quantitatively with the amino end-groups of NH2-PEO
      PCL macroinitiator by ROP.

PMID- 15020130
TI  - Porous methacrylate scaffolds: supercritical fluid fabrication and in vitro
      chondrocyte responses.
AB  - This paper describes a method of foaming a polymer system comprising poly(ethyl
      methacrylate)/tetrahydrofurfuryl methacrylate (PEMA/THFMA), characterisation of
      the resulting porosity and use of the foam for chondrocyte culture. The potential
      for this polymer system to support cartilage repair has been investigated
      previously, both in vivo and in vitro. PEMA/THFMA foamed created using
      supercritical carbon dioxide were characterised using scanning electron
      microscopy, mercury intrusion porosimetry and helium pycnometry. Foams were found
      to be 82% porous with open porosities of 57%. The mean pore diameter was found to
      be 99+60 microm. Bovine chondrocytes seeded directly onto the surface of the
      foamed and unfoamed PEMA/THFMA demonstrated lower proliferation on the foamed
      material, greater retention of the rounded cell morphology and increased
      glycosaminoglycan synthesis. In conclusion, this study has shown that a porous
      PEMA/THFMA system can further enhance the ability of the material to support
      chondrocytes in vitro. However, further modifications in processing are necessary
      to determine optimum conditions for cartilage tissue formation.

PMID- 15020131
TI  - Theoretical model to determine the effects of geometrical factors on the
      resorption of calcium phosphate bone substitutes.
AB  - A theoretical approach was used to determine the effect of geometrical factors on
      the resorption rate of calcium phosphate bone substitutes that are either dense,
      microporous, and/or contain spherical macropores. Two cases were considered: (a)
      macroporous blocks that can be invaded by resorbing cells either directly because
      the structure is fully open-porous, or indirectly after some resorption of the
      macropores walls and/or interconnections. (b) Microporous or dense
      blocks/granules that cannot be invaded by resorbing cells, i.e. can only be
      resorbed from the outside to the inside, layer by layer. The theoretical approach
      was based on five assumptions: (i) the pores are spherical; (ii) the pores are
      ordered according to a face-centered cubic packing; (iii) the resorption is
      surface-controlled; (iv) the resorption is only possible if the surface can be
      accessed by blood vessels of 50 microm in diameter; and (v) the resorption time
      of a given amount of calcium phosphate is proportional to the net amount of
      material. Based on these assumptions, the calculations showed that the resorption
      time of a macroporous block could be minimized at a specific pore radius. This
      pore radius depended (i) on the size of the bone substitute and (ii) on the
      interpore distance. Typical radii were in the range of 100-400 microm. These
      values are similar to the numerous pore size optima mentioned in the scientific
      literature. For microporous or dense blocks/granules, the model suggested that a
      relatively small radius should be preferred. Such a radius leads to an optimum
      combination of a high surface area favorizing resorption and the presence of
      large intergranular gaps favorizing blood vessel ingrowth. In that case, the
      optimum of granule radius is around 100-200 microm. Finally, a very good
      agreement was found between the predictions of the model and experimental data,
      i.e. the model explained in all but two cases the results with an accuracy
      superior to 80%. In conclusion, the model appears to be a useful tool to better
      understand in vivo results, and possibly better define the geometry and
      distribution of the pores as well as the size of a bone substitute.

PMID- 15020132
TI  - Layer-by-layer deposition of hyaluronic acid and poly-L-lysine for patterned cell
      co-cultures.
AB  - A novel method for patterning cellular co-cultures that uses the layer-by-layer
      deposition of ionic biopolymers is described. Non-biofouling hyaluronic acid (HA)
      micropatterns were used to immobilize cells and proteins to glass substrates.
      Subsequent ionic adsorption of poly-L-lysine (PLL) to HA patterns was used to
      switch the HA surfaces from cell repulsive to adherent thereby facilitating the
      adhesion of a second cell type. The utility of this approach to pattern co
      cultures of hepatocytes or embryonic stem cells with fibroblasts was
      demonstrated. In addition, the versatility of this approach to generate patterned
      co-cultures irrespective of the primary cell seeding and relative adhesion of the
      seeded cells was demonstrated. Thus, the proposed method may be a useful tool for
      fabricating controlled cellular co-cultures for cell-cell interaction studies and
      tissue engineering applications.

PMID- 15020133
TI  - Biomaterials with hierarchically defined micro- and nanoscale structure.
AB  - Biomaterials and tissue engineering are becoming increasingly important in
      biomedical practice, particularly as the population ages. It is clear that
      cellular responses to materials depend on structural properties of the material
      at both the micrometer- and nanometer scale, but general methods for controlling
      material properties on both of these scales are lacking. Using a hierarchical
      approach that mimics natural material formation processes, we developed a method
      to produce materials with controlled physical structures at both the micrometer-
      and nanometer scale. Our method is based upon a pre-organized micropatterned
      template and conformal transformation of the architecture with nanostructured
      minerals, namely hydroxyapatite. The newly developed materials were biocompatible
      with bone cells, induced a range of desirable cellular responses, and may
      therefore have direct application in bone tissue engineering. In addition, the
      design principles employed in this study can be extrapolated to the other classes
      of biomedical materials, including polymers, metals, ceramics or hybrid
      combinations.

PMID- 15020134
TI  - The effect of galectin 1 on 3T3 cell proliferation on chitosan membranes.
AB  - Galectin-1 (GAL1), a beta-galactoside-binding protein, functions in cell
      adhesion, development, and growth regulation. A number of studies suggest that
      GAL1 play an important role in enhancing cell adhesion to extracellular matrix
      and inducing cell proliferation. Chitosan is a derivative of chitin extracted
      from lobsters, crabs and shrimps' exoskeletons. In clinical medicine, chitosan
      membrane had been used as a semi-permeable biological dressing. Although chitosan
      membranes show no cytotoxicity, some cell types (e.g. 3T3 cells) fail to attach
      and proliferate on their surface. In these studies, we show that over-expression
      of GAL1 does not enhance 3T3 cell proliferation on chitosan membranes. However,
      coating the chitosan membrane with recombinant GAL1 proteins significantly
      expedites 3T3 cells proliferation. The enhanced cell growth was inhibited by
      thiodigalactoside (TDG, a potent inhibitor of beta-galactoside binding) and GAL1
      monoclonal antibodies, suggesting GAL1's specific effect on the proliferation of
      3T3 cells upon chitosan membranes. Moreover, immunoblotting detected a markedly
      suppressed tyrosine phosphorylation in several proteins on 3T3 cell growths upon
      GAL1-coated chitosan membrane. Pretreating the cells with sodium fluoride (NaF, a
      phosphatase inhibitor) inhibits the attachment and proliferation of 3T3 cells.
      These findings support a proposed role for altered levels of protein
      phosphorylation in GAL1-mediated cell attachment and proliferation on chitosan
      membranes.

PMID- 15020135
TI  - Guided tissue regeneration: porcine matrix does not transmit PERV.
AB  - OBJECTIVE: For cardiovascular tissue engineering, acellularized scaffolds of
      porcine matrices have been successfully used. However, the possibility of porcine
      endogenous retrovirus (PERV) transmission remains debatable. In this study, we
      investigated whether acellularized porcine vascular scaffolds cause cross-species
      transmission of PERV in a xenogenic model. METHODS: Porcine pulmonary arteries
      were acellularized and implanted into sheep in orthotopic position (n=6).
      Cardiopulmonary bypass support was used for all operations. Blood samples were
      collected regularly up to 6 months after the operation, and cellular components
      were tested for PERV infection by PCR and RT-PCR. Grafts were explanted 6 and 12
      months after implantation. Tissue samples were characterized by histology and
      electron microscopy and tested for PERV sequences. RESULTS: All animals survived
      the procedure and follow up until explantation of the grafts. PERV DNA was
      detectable in acellularized scaffolds of porcine matrices. Acellular porcine
      pulmonary arteries scaffolds were repopulated in vivo by autologous cells of the
      host, leading to a vessel consisting of all cellular components of the vessel
      wall. No PERV sequences were detectable neither in all tested peripheral blood
      samples nor in tissue samples of in vivo recellularized grafts up to 6 months
      after implantation. Electron microscopy revealed no signs of graft infection by
      retrovirus. CONCLUSIONS: Guided tissue regeneration of acellularized vascular
      porcine matrix scaffolds leads to structured vessels up to one year without risk
      of PERV transmisson.

PMID- 15020137
TI  - Contact guidance induced organization of extracellular matrix.
AB  - The scarring response following injury to the central nervous system disrupts the
      anatomical organization of nervous tissue posing a barrier to the regeneration of
      axons. In the present study, using materials with nanometer level surface
      features we examined whether matrix organization could be controlled by
      engineering meningeal cell asymmetry. Following 5 days in culture, the
      organization of meningeal cells along with their cytoskeletal elements and
      extracellular matrix proteins was evaluated. Meningeal cell morphology was
      markedly affected by nanometer level substrate topography. Cell alignment
      increased with increasing surface roughness. In addition, linear arrays of
      extracellular matrix were expressed that appeared related to cellular
      orientation. When cultured on substrates with topographical features of less than
      10 nm neither cells nor their extracellular matrix showed organizational
      asymmetry. However, as oriented surface roughness increased, cellular and matrix
      asymmetrical organization became more pronounced reaching a threshold at 345 nm.
      These results suggest that biomaterial surface topography or other methods of
      altering the orientation of cells may be used to engineer orientation into the
      secreted extracellular matrix and as such may be a potential strategy for
      developing organized cell-derived matrix as a bridging material for nerve repair
      or other regenerative applications.

PMID- 15020136
TI  - New modified polyetheretherketone membrane for liver cell culture in biohybrid
      systems: adhesion and specific functions of isolated hepatocytes.
AB  - There has been growing interest in innovative materials with physico-chemical
      properties that provide improved blood/cell compatibility. We propose new
      polymeric membranes made of modified polyetheretherketone (PEEK-WC) as materials
      with potential for use in biohybrid devices. PEEK-WC exhibits high chemical,
      thermal stability and mechanical resistance. Owing to its lack of crystallinity
      this polymer can be used for preparing membranes with cheap and flexible methods.
      We compared the properties of PEEK-WC membranes to polyurethane membranes
      prepared using the same phase inverse technique and commercial membranes. The
      physico-chemical properties of the membranes were characterised by contact angle
      measurements. The different parameters acid (gamma+), base (gamma-) and Lifshitz
      van der Waals (gammaLW) of the surface free energy were calculated according to
      Good-van Oss's model. We evaluated the cytocompatibility of PEEK-WC membranes by
      culturing hepatocytes isolated from rat liver. Cell adhesion and metabolic
      behaviour in terms of ammonia elimination, urea synthesis and protein synthesis
      were evaluated during the first days of culture. Liver cells adhered and formed
      three-dimensional aggregates on the most tested membranes. PEEK-WC membranes
      promoted hepatocyte adhesion most effectively. Urea synthesis, ammonia
      elimination and protein synthesis improved significantly when cells adhered to
      PEEK-WC membrane. The considerable metabolic activities of cells cultured on this
      membrane confirmed the good structural and physico-chemical properties of the
      PEEK-WC membrane that could be a promising biomaterial for cell culture in
      biohybrid devices.

PMID- 15020138
TI  - IGF-I and TGF-beta 1 incorporated in a poly(D,L-lactide) implant coating maintain
      their activity over long-term storage-cell culture studies on primary human
      osteoblast-like cells.
AB  - Biodegradable coating of osteosynthetic materials with poly(D,L-lactide) (PDLLA)
      and incorporated growth factors has been used successfully as drug carrier to
      stimulate fracture healing in several rat and porcine models. A cold coating
      technique was used to incorporate growth factors without loss of activity during
      the coating process. The aim of this study was to investigate the activity of
      incorporated insulin like growth factor-I and transforming growth factor-beta 1
      (TGF-beta1) after long-time storage (5 and 14 months at -20 degrees C). Primary
      human osteoblast-like cells (HOB) were cultured in a non-contact manner with
      titanium wires coated with PDLLA and IGF-I (33 microg) and TGF-beta1 (6 microg)
      for 0, 5, 10 and 15 days. Osteoblast culture without wires, with titanium wires
      or wires with the PDLLA coating served as control ( n=3 each time point and
      group). Cell vitality, cell proliferation and the production of procollagen 1
      were measured. No differences in cell count and vitality were accessed in the two
      growth factor treated groups compared to the control groups at the same time
      point. Independently from the storage duration, the incorporated growth factors
      significantly stimulated the production of osteoblast specific type I collagen
      (CICP) compared to the controls. The results indicate, that the growth factors
      stimulated osteoblast to an enhanced collagen 1 production and that the coating
      method meets a major requirement for clinical use of growth factor-coated
      implants: biological activity of the incorporated growth factors for at least 14
      months.

PMID- 15020139
TI  - Development of hybrid materials based on hydroxyethylmethacrylate as supports for
      improving cell adhesion and proliferation.
AB  - A novel hydrogel based on 2-hydroxyethylmethacrylate and fumed silica
      nanoparticles is presented. The filler was mixed at increasing amount (3-40% w/w)
      to the organic monomer, before accomplish thermal polymerization. The hybrid
      composite materials obtained were characterized as far as concern the physical
      chemical stability and sorption behaviour in water and water solutions. The novel
      hybrid hydrogels were compared to poly(hydroxyethylmethacrylate) (pHEMA) on
      cytocompatibility and ability to elicit cell adhesion and proliferation. These in
      vitro assays showed that the first ones were supporting cell growth better then
      pHEMA, moreover experiments on murine fibroblasts showed improved adhesion and
      proliferation with the increase of the nanomeric filler content. For a more
      physiological response, the in vitro tests should match biomaterials with cell
      populations typical of the implant site. Therefore, in view of future
      applications of these composites as scaffolds for bone engineering, in a
      successive step of our research we selected primary cultures of human osteoblasts
      (OB) as the most appropriate models to study the in vitro performance of these
      materials. The preliminary results obtained confirmed the remarkable improvement
      of OB adhesion properties of the new hybrids with respect to pure pHEMA.

PMID- 15020140
TI  - Encapsulated cells: an atomic force microscopy study.
AB  - Two types of cells--human platelets and spore cells--were encapsulated in polymer
      shells by adsorbing polyanions and polycations in a stepwise fashion. The
      encapsulated cells were attached to gold and silicon surfaces and their
      morphological and adhesion properties were studied in air using tapping mode
      atomic force microscopy (AFM). The roughness of the encapsulated cells increased
      upon the addition of a new polymer layer. The increase in roughness can be
      attributed to the formation of a shell around the cells, which is stabilized by
      electrostatic interactions, as well as to the drying effects associated with the
      immobilization and dehydration of the cells. Trigger mode was used to perform the
      force imaging and map out the adhesion characteristics of the cells. Systematic
      "maps" of the adhesion properties of the encapsulated cells to clean and amine
      terminated AFM tips were collected. The adhesion force data for the different
      tips and encapsulated cells showed dependence not only on the number and
      thickness of the polymer layers, but also on the interactions between these
      layers. The encapsulated cells' morphology and roughness characteristics remained
      intact over a substantial storage period. This stability and adhesion properties
      make them suitable building blocks for the design and construction of biomimetic
      templates where AFM is used as the primary tool to do the fabrication.

PMID- 15020141
TI  - Immune reactions of lymphocytes and macrophages against PEG-grafted pancreatic
      islets.
AB  - Graft rejection is the major limiting factor in islet transplantation and is
      closely related with the recruitment and activation of T cells and macrophages
      against the graft. To reduce the immunogenicity of islets, we have grafted
      biocompatible polyethylene glycol (PEG) onto the collagen capsule of islets
      without changing the morphology and function of islets. In this study, we
      evaluated whether the grafted PEG molecules on the collagen capsule of islet
      could prevent the activation of immune cells, and investigated factors that are
      mainly related to the immune reaction in vitro. During the co-culture with
      lymphocytes, the morphology and viability of PEG-grafted islets were not damaged,
      and the amounts of IL-2 and TNF-alpha secreted from lymphocytes co-cultured with
      PEG-grafted islets were significantly lower than that of free islets. However,
      when both kinds of islets were cultured with macrophages, there were no
      significant differences in morphology, viability and the secreted amounts of
      cytokines and nitric oxide. In conclusion, the grafted PEG could inhibit
      activation of lymphocytes, which are essential in initiating the graft rejection
      process. However, the grafted PEG molecules could not completely prevent the
      infiltration of cytotoxic molecules into the islets.

PMID- 15020142
TI  - Fabrication of low temperature macroporous hydroxyapatite scaffolds by foaming
      and hydrolysis of an alpha-TCP paste.
AB  - The development of the new technologies of bone tissue engineering requires the
      production of bioresorbable macroporous scaffolds. Calcium phosphate cements are
      good candidate materials for the development of these scaffolds, as an
      alternative to the traditional porous sintered ceramics. In this work a novel two
      step method, based in the foaming of an alpha-tricalcium phosphate (alpha-TCP)
      cement paste and its subsequent hydrolysis to a calcium deficient hydroxyapatite
      (CDHA) is presented. The foaming agent was a hydrogen peroxide (H2O2) solution,
      which decomposes in water and oxygen gas. CDHA foams, which combined an
      interconnected macroporosity with a high microporosity were obtained. The
      apatitic phase obtained by the hydrolysis reaction was more similar to the
      biologic one, in terms of chemical composition, crystallinity and specific
      surface than the hydroxyapatites obtained by sintering. The percentage of
      porosity in the foams reached a 66%. It was shown that it was possible to control
      the porosity, and pore size and shape by different processing parameters such as
      the liquid-to-powder ratio, the concentration of the H2O2 solution and the
      particle size of the powder.

PMID- 15020143
TI  - Tissue engineering of biphasic cartilage constructs using various biodegradable
      scaffolds: an in vitro study.
AB  - Biological restoration of osteochondral defects requires suitable subchondral
      support material that also allows the induction of hyaline cartilage tissue.
      Biphasic implants consisting of pre-fabricated neocartilage and an underlying
      biodegradable osteoconductive base may meet these requirements. Here we explore
      various candidate biodegradable support materials onto which neo-cartilage was
      produced in vitro. Porcine chondrocytes were seeded in a closed and static
      bioreactor with a base of biomaterial consisting of either poly-L-lactide
      [P(L)LA], poly-d,l-lactide [P(D,L)LA] or Collagen-hydroxyapatite [Col-HA] and
      were cultured for 15 weeks. Viable neo-cartilage was produced on each biomaterial
      with differing amounts of cellular colonisation. P(D,L)LA breakdown was more
      rapid and uneven among the three biomaterials, leading to constructs of irregular
      shape. Little or no breakdown or chondrocyte colonisation was evident in P(L)LA.
      Col-HA constructs were superior in terms of viability, implant morphology and
      integration between neo-cartilage and biomaterial. These results indicate that
      our reported system has potential for producing biphasic implants that may be
      adequate for the repair of osteochondral defects.

PMID- 15020144
TI  - Evaluation of antibiotic-loaded collagen-hyaluronic acid matrix as a skin
      substitute.
AB  - The 1-ethyl-(3-3-dimethylaminopropyl) carbodiimide hydrochloride-crosslinked
      collagen-hyaluronic acid (HA) matrices containing tobramycin or ciprofloxacin as
      an antibiotic agent were fabricated for the control of wound contamination and
      characterized with respect to morphology, mechanical strength, in vitro release,
      antibacterial activity and cytotoxicity. For the tobramycin loaded matrix, the
      antibacterial capacity increased with the drug loading. Tobramycin and
      ciprofloxacin loaded matrices maintained their antibacterial effects for over 96
      and 48 h, respectively. However, cell viability testing revealed that 0.4 mg/ml
      of ciprofloxacin has a cytotoxic effect on fetal human dermal fibroblasts. The
      effects of the bilayered collagen-HA matrices containing tobramycin and growth
      factors were also evaluated using an in vivo full thickness dermal defect model.
      Though the tobramycin incorporated collagen-HA matrix had no significant effect
      on wound healing compared with the control, the tobramycin incorporated matrix
      containing basic fibroblast growth factor or platelet-derived growth factor
      significantly enhanced wound healing. This study demonstrates the potential
      efficacy of crosslinked collagen-HA matrix containing antibiotics and growth
      factors for defective skin tissue replacement and infection prevention.

PMID- 15020145
TI  - Properties of engineered vascular constructs made from collagen, fibrin, and
      collagen-fibrin mixtures.
AB  - Vascular constructs were formed by embedding rat aortic smooth muscle cells in
      three-dimensional matrices of Type I collagen, fibrin, or a mixture of collagen
      and fibrin in a 1:1 ratio, at total matrix protein concentrations of 2 and 4
      mg/ml. Morphological and mechanical properties were evaluated after 6 days in
      culture, and the effect of cyclic mechanical strain on collagen-fibrin mixture
      constructs was also studied. Constructs made with the lower protein concentration
      compacted to the greatest degree, and fibrin was found to enhance gel compaction.
      Each matrix type exhibited a characteristic stress-strain profile. Pure collagen
      had the highest linear modulus and pure fibrin had the lowest. The ultimate
      tensile stress was strongly dependent on the degree of gel compaction, and
      collagen-fibrin mixtures at 2mg/ml total protein content exhibited the highest
      values. Application of cyclic mechanical strain to collagen-fibrin mixture
      constructs caused a significant increase in gel compaction and a decrease in cell
      proliferation. The linear modulus, ultimate tensile stress and toughness of the
      constructs were all augmented by mechanical strain. These results demonstrate
      that the properties of engineered vascular tissues can be modulated by the
      combination of selected extracellular matrix components, and the application of
      mechanical stimulation.

PMID- 15020146
TI  - Inkjet printing for high-throughput cell patterning.
AB  - The adaptation of inkjet printing technology to the complex fields of tissue
      engineering and biomaterial development presents the potential to increase
      progress in these emerging technologies through the implementation of this high
      throughput capability via automated processes to enable precise control and
      repeatability. In this paper, a method of applying high-throughput inkjet
      printing to control cellular attachment and proliferation by precise, automated
      deposition of collagen is presented. The results indicate that commercial inkjet
      printing technology can be used to create viable cellular patterns with a
      resolution of 350 microm through the deposition of biologically active proteins.
      This method demonstrates a combination of off-the-shelf inkjet printing and
      biomaterials and has potential to be adapted to tissue engineering and colony
      patterning applications. Adapting this method into the three-dimensional
      construction of cellular structures for eventual high-throughput tissue
      engineering using a bottom-up approach is possible.

PMID- 15020148
TI  - Synthesis and pH sensitivity of carboxymethyl chitosan-based polyampholyte
      hydrogels for protein carrier matrices.
AB  - Novel polyampholyte hydrogels based on carboxymethyl chitosans (CMC) of various
      degree of deacetylation (DD) and substitution (DS) were prepared by crosslinking
      with glutaraldehyde. The hydrogel showed typical amphoteric character responding
      to pH of the external medium. At the isoelectric point (IEP), the hydrogel shrunk
      most, when the pH deviated from IEP, the swelling degree (Ds) increased. With
      increasing DD or DS value, the hydrogel changed from polyampholyte into
      polycations or polyanions, respectively. Osmotic forces and intermolecular
      interactions among CMC chains regulate the swelling behavior of CMC gel. The
      carboxymethyl chitin hydrogels were loaded with bovine blood proteins (BSA), and
      their release studies were performed in both the simulated gastric and intestinal
      pH conditions. The release was much quicker in pH 7.4 buffer than pH 1.2
      solution; the release followed Fickian diffusion in the first 4h and then
      steadily increased with the dissolution of the hydrogels.

PMID- 15020147
TI  - Contractile cardiac grafts using a novel nanofibrous mesh.
AB  - Cardiomyoctes are terminally differentiated cells and therefore unable to
      regenerate after infarction. The use of autologous bioengineered cardiac grafts
      has been suggested to replace infarcted myocardium and enhance cardiac function.
      Here we report the development of an in vitro system for engineered myocardium.
      Cardiac nanofibrous meshes (CNM) were developed by culturing cardiomyocytes from
      neonatal Lewis rats on electrospun, nanofibrous polycaprolactone (PCL) meshes.
      The mesh had an ECM-like topography and was suspended across a wire ring that
      acted as a passive load to contracting cardiomyocytes. The cardiomyocytes started
      beating after 3 days and were cultured in vitro for 14 days. The cardiomyocytes
      attached well on the PCL meshes and expressed cardiac-specific proteins such as
      alpha-myosin heavy chain, connexin43 and cardiac troponin I. The results
      demonstrate the formation of contractile cardiac grafts in vitro. Using this
      technique, cardiac grafts can be matured in vitro to obtain sufficient function
      prior to implantation. It is conjectured that cardiac grafts with clinically
      relevant dimensions can be obtained by stacking CNMs and inducing vascularization
      with angiogenic factors.

PMID- 15020149
TI  - Poly(D,L-lactide-ran-epsilon-caprolactone)-poly(ethylene glycol)-poly(D,L-lactide
      ran-epsilon-caprolactone) as parenteral drug-delivery systems.
AB  - P(DLAX-ran-CLY)n-b-PEG-b-P(DLAX-ran-CLY)ns (P(DLAX-ran-CLY)m: Poly(d,l-lactide
      ran-epsilon-caprolactone), PEG: Poly(ethylene glycol), X: d,l-lactyl unit ratio,
      Y: epsilon-caproyl unit ratio, m : molecular weight of P(DLAX-ran-CLY)), were
      investigated as the novel parenteral drug-delivery system. The thermal behavior
      in the DSC characterization and variable viscosity with temperature suggest their
      potential usuage as a injectable drug-delivery system. The variation of tri-block
      structure affects the drug release behavior by changing the morphology and also
      by changing the interaction between the polymer matrix and the hydrophilic drug.

PMID- 15020151
TI  - Immobilization of L-asparaginase on the microparticles of the natural silk
      sericin protein and its characters.
AB  - The natural silk sericin recovered from Bombyx mori silk waste by the degumming
      processing in the high-temperature and high-pressure is a macromolecular protein.
      Amino acid composition and molecular weight range of the sericin protein as a
      vector for enzyme immobilization were investigated. The silk sericin protein with
      different molecular mass from 50 to 200 kDa was poorly soluble microparticles
      with an average size of about 10 microm. Anti-leukemic enzyme L-asparaginase (L
      ASNase) was covalently conjugated on the microparticles of the sericin protein.
      The immobilized L-ASNase on the natural support by cross-linking with
      glutaraldehyde maintained 62.5% of the original activity of the enzyme. The Km of
      sericin-conjugates was 8 times lower than that of native L-ASNase. The
      bioconjugation of L-ASNase widened the optimum reactive temperature range of the
      enzyme. The immobilized L-ASNase showed significantly higher stability when the
      temperature raised to 40-50 degrees C, it also showed preferable resistance to
      trypsin digestion as compared with native enzyme. The results are discussed
      regarding the possible explanations of sericin-induced enzyme stability, as well
      as the possible applications of immobilized L-ASNase research.

PMID- 15020150
TI  - A novel polymeric chlorhexidine delivery device for the treatment of periodontal
      disease.
AB  - An implantable, anti-microbial delivery device for the treatment of periodontal
      disease has been developed. In this polymer-based delivery system, the
      encapsulation efficiency, release characteristics, and bioactivity of anti
      microbial agent were controlled by the complexation of the drug with
      cyclodextrins of differing lipophilicity. Microparticles of poly(dl-lactic-co
      glycolic acid) (PLGA) containing chlorhexidine (Chx) free base, chlorhexidine
      digluconate (Chx-Dg) and their association or inclusion complex with methylated
      beta-cyclodextrin (MBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) were
      prepared by single emulsion, solvent evaporation technique. It was observed that
      encapsulation efficiency and release of the chlorhexidine derivatives from the
      microparticles was a function of the lipophilicity of the cyclodextrin.
      Complexation of the poorly water soluble Chx with the more hydrophilic HPBCD
      resulted in 62% higher encapsulation efficiency and longer duration of sustained
      release over a 2-week period than complexation with the more lipophilic MBCD. In
      contrast, the complexation of the more water-soluble derivative of chlorhexidine,
      Chx-Dg, with the more lipophilic MBCD improved encapsulation efficiency by 12%
      and prolonged its release in comparison to both the free Chx-Dg and its complex
      with HPBCD. Furthermore, it was observed that the initial burst effect could be
      diminished by complexation with CD. Preliminary studies have shown that the
      chlorhexidine released from PLGA chips is biologically active against bacterial
      population that is relevant in periodontitis (P. gingivalis and B. forsythus) and
      a healthy inhibition zone is maintained in agar plate assay over a period of at
      least a 1-week. The PLGA/CD delivery system described in this paper may prove
      useful for the localized delivery of chlorhexidine salts and other anti-microbial
      agents in the treatment of periodontal disease where prolonged-controlled
      delivery is desired.

PMID- 15020152
TI  - Denatured collagen as support for a FGF-2 delivery system: physicochemical
      characterizations and in vitro release kinetics and bioactivity.
AB  - Collagen-based materials have scaffold properties to support bioactive molecules
      such as growth factor (GF). Gelatin, a denatured collagen, may have also some
      potential to interact with GF. An alternative process to denature collagen using
      trifluoroacetic acid (TFA) was investigated. Physicochemical characterization
      (XPS, DSC, isoelectric point, water uptake) of TFA-denatured collagen was
      comparable to regular gelatin, except a significant hydrophilicity and a pH
      sensitivity. FGF-2 was mixed with either regular gelatin or TFA-denatured
      collagen, then incorporated to a collagen sponge. Autoradiography revealed a
      relatively homogenous distribution of radiolabeled FGF-2 within the sponge. In
      vitro release kinetic of radiolabeled FGF-2 was investigated as well as the
      bioactivity of FGF-2 towards endothelial cell growth. The mixture was also sorbed
      to hydrogels made of ethylene vinyl acetate co-polymer and poly(2-hydroxyethyl
      methacrylate), and to cell culture insert membranes as control. Release of FGF-2
      from collagen was progressive in the presence of TFA-denatured collagen, and cell
      growth was stimulated (significant peak at 8 and 10 days) by TFA-denatured
      collagen and FGF-2 eluted particularly from collagen sponges. Whereas control
      hydrogels, and those with regular gelatin showed a early stimulation of cell
      growth (1-5 days). Thus, the combination of both FGF-2 and an acid-denatured
      collagen in collagen sponges allows to sustain in vitro endothelial cell
      activity.

PMID- 15020153
TI  - Poly(vinyl alcohol) and poly(vinyl pyrrolidone) blended films for local nitric
      oxide release.
AB  - The nitric oxide (NO) donor S-nitrosoglutathione (GSNO) was incorporated in solid
      polymeric films of poly(vinyl alcohol) (PVA), poly(vinyl pyrrolidone) (PVP) and
      blended PVA/PVP. These matrices were found to provide a great stabilization
      effect on the thermal decomposition of GSNO, leading to 8-16-fold reduction in
      the first-order rate constants of NO release, compared to aqueous GSNO solutions.
      PVA/PVP-GSNO released 90% of the NO supply, over a time period of 24h at 37
      degrees C. Differential scanning calorimetry has confirmed the miscibility
      between the two polymeric components. Stress-strain analysis has shown an
      improvement of the mechanical property of PVA films in the PVA/PVP blend, which
      leads to an increase of 25% in the stress at break. Scanning electron microscopy
      has shown that the PVA/PVP-GSNO blend leads to a smooth coating of metallic
      surfaces. These properties, allied to the already known good biocompatibility of
      PVA and PVP, makes GSNO-containing PVA and PVA/PVP blend films good candidates
      for the local and controlled release of NO in target areas.

PMID- 15020154
TI  - Galactosylated chitosan/DNA nanoparticles prepared using water-soluble chitosan
      as a gene carrier.
AB  - Water-soluble chitosan (WSC) was used to increase the stability of chitosan in
      water and decrease the cytotoxicity induced by acetic acid. Lactobionic acid (LA)
      bearing galactose group was coupled with WSC for hepatocytes specificity. The
      composition of galactose in galactosylated chitosan (GC) was determined by NMR
      spectroscopy. The GC was complexed with plasmid DNA in various GC/DNA (N/P)
      charge ratios and the resulting complex was characterized by dynamic light
      scattering, gel retardation, and turbidity to determine the particle sizes,
      complex formation, and complex stability, respectively. Cytotoxicity and
      transfection efficiency of GC were also studied in cultured HepG2 human
      hepatoblastoma cell line and HeLa human cervix epithelial carcinoma cells. The
      complete GC/DNA complex was formed at the charge ratio of 5 and the GC/DNA
      complex to DNase I resistance was obtained. Particle sizes decreased with
      increasing charge ratio of GC to DNA and had a minimum value around 120 nm at the
      charge ratio of 5. And no significant difference in particle sizes from the
      charge ratio of 5-20 was found. The suspension of GC/DNA complexes exhibited no
      significant change in turbidity at the charge ratios of 10, indicating the
      complete shielding of DNA charge. Cytotoxicity study showed that GC prepared by
      the water-soluble chitosan had no cytotoxic effects on cells. And transfection
      efficiency into HepG2, which has asialoglycoprotein receptors (ASGP-R), was
      higher than that into HeLa without ASGP-R.

PMID- 15020155
TI  - Synthesis, characterization and controlled drug release of thermosensitive IPN
      PNIPAAm hydrogels.
AB  - A method was developed to prepare thermosensitive poly(N-isopropylacrylamide)
      (PNIPAAm) hydrogels with an interpenetrating polymer network (IPN) structure for
      the purpose of improving its mechanical properties, response rate to temperature
      and sustained release of drugs. Although the differential scanning calorimetry
      data exhibited similarly lower critical solution temperature (LCST) between IPN-
      and non-IPN-PNIPAAm hydrogels, an increase in the glass transition temperature
      (Tg) of the IPNs relative to the normal PNIPAAm hydrogel was observed. In
      addition, the mechanical properties of the IPNs were greatly improved when
      compared with the normal PNIPAAm hydrogel. The interior morphology of the IPN
      PNIPAAm hydrogels was revealed by scanning electron microscopy (SEM); the IPN
      hydrogels showed a fibrillar-like porous network structure that normal PNIPAAm
      did not have. Furthermore, by measuring the temperature dependence of the
      swelling ratio and deswelling kinetics, these IPN hydrogels also exhibited
      improved intelligent characteristics (e.g., controllable faster response rate)
      that depended on the composition ratio of the two network components. From the
      applications viewpoint, the effects of a shrinking-reswelling cycle around the
      LCST on the properties of the IPN hydrogels were examined to determine if these
      properties would be stable for potential applications. Bovine serum albumin was
      chosen as the model protein for examining its release from the IPNs at different
      temperatures. The release data suggested that an improved controlled release
      could be achieved by the IPN-PNIPAAm hydrogels without losing their intelligent
      properties.

PMID- 15020156
TI  - Hydroxyapatite particles as a controlled release carrier of protein.
AB  - This study examines the possibility of using hydroxyapatite (HAp) particles as a
      controlled release carrier of protein. In order to achieve effective protein
      release from HAp particles, it is necessary to regulate the conjugated amount of
      protein on HAp and the resorption of HAp. HAp particles were synthesized at
      different temperatures (40 degrees C, 60 degrees C, 80 degrees C) in wet
      condition and the physico-chemical properties of synthesized HAp particles were
      examined. HAp particles synthesized at low temperatures showed low crystallinity,
      high solubility and large specific surface area. The useful growth factors for
      bone regeneration, such as BMP, bFGF and TGF-beta, are basic proteins, so
      cytochrome c (pI=10.2) was used as a model protein and the adsorptive property of
      protein on HAp particles was investigated. The protein adsorption on HAp
      particles changed depending on its specific surface area and the chart of protein
      adsorption on HAp particles showed a typical Langmuir curve. These findings
      suggest that the adsorbed amount of protein on HAp particles could be regulated
      by HAp synthesizing temperature and the concentrations of protein solution. The
      release kinetics of protein from the HAp particles that adsorbed the protein (HAp
      pro) was also evaluated in different pH solutions (pH 4.0 and 7.0). The released
      protein gradually increased time dependently when HAp-pro were immersed in pH 4.0
      solution, but the released protein was significantly smaller when HAp-pro were
      immersed in pH 7.0 solution. Moreover, the release rate of protein from HAp-pro
      differed in each HAp that was synthesized at different temperatures, suggesting
      that the release of protein from HAp-pro depended on HAp resorption. These
      results suggest that HAp particles synthesized at different temperature are
      useful as a controlled release carrier of protein.

PMID- 15020157
TI  - A study of intra-cochlear electrodes and tissue interface by electrochemical
      impedance methods in vivo.
AB  - This paper presents methods, results and analysis for measurements of the
      electrochemical impedance of platinum electrodes (approximately 0.43 mm2) over a
      6-month implantation in the cat cochlea. The study aimed to improve our
      understanding of the effects of tissue response on impedance behaviour. An
      increase in impedance in the post-operative period was evident with a rise of the
      distorted arc at high frequencies in the complex plane, correlating to anomalous
      charge transport at the electrode-tissue interface. The impedance at low
      frequencies generally showed a capacitive dispersion modelled as a constant phase
      element, indicating a blocking characteristic of the electrodes. The study
      suggests that a reduction and changes in composition of perilymph or
      extracellular fluid adjacent to the electrodes, as a consequence of tissue
      response, causes the elevated "contact impedance". This affects the efficiency
      and quality of neural stimulating electrodes and neural recording electrodes. The
      finding of the crucial role of perilymph or extracellular fluid thin layer
      provides a new strategy for surface materials of neural electrodes, which is
      discussed in the paper. The interface characteristics must be considered during
      interpretation of studies undertaken in vitro or in acute experiments in vivo,
      where physiological fluid is abundant.

PMID- 15020158
TI  - Bioresorbable composite bone paste using polysaccharide based nano
      hydroxyapatite.
AB  - Aim of this study concerns to the development of bioresorbable composite
      materials for bone repair and regeneration. Despite nano hydroxyapatite (HA) has
      wide range of medical applications, particles mobilization and slow resorbable
      nature limits its use in certain applications particularly, periodontal and
      alveolar ridge augmentation. To enhance its usage, we have prepared HA composite
      bone paste with a natural polysaccharide, chitosan, using wet chemical method at
      low temperature. The prepared composites were analyzed by various physicochemical
      methods and suggesting that the nano HA crystallites are well intact with the
      chitosan macromolecules. FT-IR results are indicating the existence of hydroxyl
      and amide groups in addition to the characteristic peaks of nano HA in the
      composite paste. The physical nature of paste form implies that it would be
      highly beneficial for the particle immobilization upon implantation. In vitro
      physiological stability and solubility of the composite was performed in
      phosphate buffered saline under physiological condition and found that the rate
      of resorbability of composite was quite higher than nano HA. These findings
      suggest that the HA/chitosan composites may have a great impact on human health
      care systems as bioresorbable bone substitute.

PMID- 15020159
TI  - Accumulation of aluminium in lamellar bone after implantation of titanium plates,
      Ti-6Al-4V screws, hydroxyapatite granules.
AB  - Titanium plates, Ti6Al4V screws and surrounding tissues, and biopsies of
      hydroxyapatite (Osprovit) grafts of maxillary sinus lifting were investigated to
      evaluate the release and accumulation of ions. Optical microscopy, SEM and X-ray
      microanalysis were carried out to evaluate the plates and screws removed from
      patients presenting inflammation and biopsies. Ions release from metallic
      appliances or leaching from granules towards soft tissues was observed. An
      accumulation of aluminium but not titanium was found in soft tissues. A peculiar
      accumulation of aluminium in the dense lamella of newly formed bone was recorded.
      The results seem to indicate that biological perturbations may be related to
      aluminium release from the tested biomaterials. The aluminium content of these
      biomaterials, its diffusion and accumulation are discussed. Further studies on
      ion release from biomaterials and aluminium fate in skeletal tissues are
      suggested.

PMID- 15020160
TI  - ProNectin F-grafted-ethylene vinyl alcohol copolymer (EVAL) as a liquid type
      material for treating cerebral aneurysm--an in vivo and in vitro study.
AB  - The authors aimed to develop a liquid material for embolization of aneurysms. In
      vitro and in vivo performances of the new embolic material were examined by cell
      culture and using an aneurysm model made in common carotid arteries (CCAs) of
      adult rats. Engineered protein ProNectin F (PnF), which contains 13 sites of an
      arginine-glycine-aspartic acid (RGD), was grafted onto ethylene vinyl alcohol
      copolymer (EVAL-g-PnF). The liquid material, EVAL-g-PnF dissolved in DMSO, was
      infused into an aneurysm model. The blood segments were harvested 2, 5, and 14
      days and examined histologically. A number of bovine coronary artery endothelial
      cells became able to attach to and form cobblestone-like islands on the EVAL by
      incorporating PnF. The aneurysm model infused with the EVAL-g-PnF solution
      revealed that the aneurysm lumen was filled with proliferated fibroblasts and
      macrophages. On the other hand, the aneurysm model treated with unmodified EVAL
      showed that the cavity was almost filled with EVAL mass and that fibroblasts and
      macrophages filled a narrow space between the EVAL mass and the cavity wall. The
      results indicate that EVAL-g-PnF could be more suitable for reorganizing the
      cavity of an aneurysm than native EVAL.

PMID- 15020161
TI  - Immune reactions associated with silicone-based ventriculo-peritoneal shunt
      malfunctions in children.
AB  - The implantation of ventriculo-peritoneal (VP) shunting systems is the most
      commonly performed neurological procedure in children with hydrocephalus.
      Although the overall complication risk is low, the cumulative risk of shunt
      failure is high and unfortunately results in a high prevalence of revision
      surgeries. In this study, we explored the concept that some pediatric patients
      may develop an immune response to either the proteins attached to the silicone
      implant surface or to the biomaterial itself, and that this reaction may
      contribute to VP shunt failure in some individuals. The data displays that the
      sterile shunt malfunction group had a higher rate of protein deposition and
      increased levels of autoantibodies to the extracted surface proteins as compared
      to individuals with functioning shunting systems. The precise nature of the shunt
      bound proteins that serve as antigens in this experiment have not yet been
      determined. The data also indicated that some individuals develop antibodies to
      polymeric substances that cross-react with partially polymerized acrylamide. The
      detection of significant amounts of shunt-bound protein, antibody responses to
      these proteins and to polymeric substances suggest that an immunological response
      to these proteins may play a role in the mechanism behind sterile shunt
      malfunctions.

PMID- 15020162
TI  - In vivo calcium deposition on polyvinyl alcohol matrix used in hollow fiber cell
      macroencapsulation devices.
AB  - The encapsulation of genetically modified cells represents a promising approach
      for the delivery of therapeutic proteins. The functionality of the device is
      dependent on the characteristics of the biomaterials, the procedures used in its
      confection and the adaptability of the encapsulated cells in the host. We report
      conditions leading to the development of calcifications on the polyvinyl alcohol
      (PVA) matrix introduced in hollow fiber devices for the encapsulation of primary
      human fibroblasts implanted in mice. The manufacturing procedures, batches of PVA
      matrix and cell lineages were assessed for their respective role in the
      development of the phenomenon. The results showed that the calcification is
      totally prevented by substituting phosphate-buffer saline with ultra-pure sterile
      water in the rinsing procedure of the matrix. Moreover, a positive correlation
      was found, when comparing two fibroblast cell lineages, between the level of
      lactate dehydrogenase (LDH) activity measured in the cells and the degree of
      calcium deposition. Higher LDH activity may decrease calcium depositions because
      it generates in the device a more acidic microenvironment inhibiting calcium
      precipitation. The present study defines optimized conditions for the
      encapsulation of primary human fibroblasts in order to avoid potentially
      detrimental calcifications and to allow long-term survival of encapsulated cells.

PMID- 15020163
TI  - Age hardening by dendrite growth in a low-gold dental casting alloy.
AB  - Commercial low-gold dental casting alloy composed of Ag-Pd-In-Au-Zn was studied
      to clarify the age-hardening mechanism and related microstructural changes. The
      hardness of solution-treated specimen began to increase and reached the maximum
      value with ageing time, and then the maximum hardness value decreased by further
      ageing. The changes of X-ray diffraction (XRD) pattern during isothermal ageing
      revealed that the age hardening was not caused by phase transformation. By
      comparing the age-hardening curve with the changes in full-width at half-maximum
      of the XRD peaks at each ageing time, it was revealed that the coherency strains
      were formed in the Ag-rich matrix, which contributed to the hardness increase
      during ageing. From scanning electron microscopic observation and electron probe
      microanalysis, it was clarified that fine particle-like structures composed of
      InPd containing small amount of Zn gathered by diffusion in the Ag-rich matrix,
      and the coherency strains which formed during that time caused the hardness
      increase in the early stage of age-hardening process. The coherency strains were
      released by the progress of coarsening of Zn-containing InPd dendrite during
      further ageing, which caused the overaging in the later stage of age-hardening
      process.

PMID- 15020164
TI  - Feasibility of knitted carbon/PEEK composites for orthopedic bone plates.
AB  - This paper focuses on fabrication and characterization of knitted carbon/PEEK
      fabric composites for orthopedic bone plate application. Bending performance of
      the knitted carbon/PEEK composite bone plates was investigated with respect to
      two principal knitting directions (wale- and course-directions). As a result, the
      wale-direction knitted composite bone plates had much scattering in bending
      stiffness and maximum bending moment although they exhibited the same bending
      behavior as that of the course-direction specimens. In comparison with our
      previously developed braided composite bone plates, the knitted composite bone
      plates had 55-59% bending stiffness, 40-63% yield bending moment, and 54-77%
      maximum bending moment. However, the knitted composite bone plates showed higher
      deformability. Based on the results of the braided composite bone plates, it is
      considered that the knitted composite plate with 3.2mm thickness can be suitable
      for forearm or humerus treatment especially when damaged bones need higher
      deformation to encourage bone ossification.

PMID- 15020165
TI  - Enhancement of initial stability of press-fit femoral stems using injectable
      calcium phosphate cement: an in vitro study in dog bones.
AB  - In this in vitro study we evaluated the initial stability of cementless femoral
      stems using an injectable calcium phosphate (Ca-P) cement. The cement was not
      used to form a cement mantle as is routinely done in PMMA cemented prostheses but
      functioned as an additive to fill the small gaps that exist between a press-fit
      placed titanium plasma sprayed implant and the bone bed. Six pair of Beagle
      femora were used in this study. In a random fashion, one femur of each pair was
      used for placement of a prosthesis without Ca-P cement, the contralateral was
      used for press-fit placement after injection of the calcium phosphate cement into
      the intramedullary canal. The reconstructions were placed in a MTS testing
      machine, tilted 15 degrees in varsus and 15 degrees of endorotation to obtain a
      physiological load on the femoral head. The load was applied stepwise from zero
      to a maximum of 100, 250 and 400 N, respectively. At each loading step the load
      was applied dynamically at a frequency of 1 Hz for 30 min. Between the loading
      steps, the load was removed for 10 min to allow elastic recovery. The stability
      of the stems was determined at each loading step with roentgen
      stereophotogrammetric analysis. Results showed that with the prostheses without
      Ca-P cement the most important displacements were movement into varus (max. 818
      microm under 400 N) and subsidence (max. 587 microm under 400 N). The
      displacements showed large variation. After unloading some elastic recovery
      occurred. In the specimens with Ca-P cement, displacements were negligible. As
      determined by an F-test the variations found were significantly smaller for the
      press-fit+Ca-P cement relative to the press-fit prosthesis at all loading steps
      (p<0.05). A paired t-test revealed significant differences in the mentioned
      displacements between the press-fit- and press-fit+Ca-P cement prosthesis at a
      loading with 400 N (P<0.05). On the basis of these results we conclude that the
      use of Ca-P cement increases the initial stability of press-fit inserted plasma
      sprayed femoral prostheses and corrects for the high variability in displacements
      found with press-fit insertion of these femoral hip prostheses.

PMID- 15020166
TI  - Radionuclides-hyaluronan-conjugate thromboresistant coatings to prevent in-stent
      restenosis.
AB  - Catheter-based brachytherapy is one of the most effective modalities to inhibit
      hyperplasia following revascularization procedures. Radioactive stents have
      failed, however, to prevent clinical hyperplasia due to excessive late lumen loss
      on the edge of the devices. Numerous strategies have been proposed to circumvent
      the drawbacks of irradiation therapies, such as the use of more appropriate
      radionuclides or the "hot-end" stents approach. This paper describes versatile
      radioactive devices obtained by coating plasma functionalized surfaces-stents or
      catheters-with a hyaluronan (HA)-diethylenetriamine pentaacetic acid (DTPA)
      conjugate (HA-DTPA) complexed with a gamma or beta radionuclide. Yttrium and
      indium were used as radionuclide models, due to their suitability for
      endovascular radiotherapy. X-ray photoelectron microscopy and time-of-flight
      secondary ions mass spectrometry analyses confirmed the successful immobilization
      of the HA-DTPA conjugate on both the metallic (NiTi) and polymeric (Teflon)
      plasma functionalized surfaces. HA-DTPA-coated surfaces were significantly more
      hydrophilic than bare surfaces (39.5 degrees vs. 67 degrees on NiTi substrate and
      29 degrees vs. 128 degrees on Teflon substrate). Therapeutic doses of yttrium and
      indium were easily loaded onto the surfaces and remained stable over 2 weeks with
      a radionuclide loss of about 6%. The HA-DTPA-coated Teflon surfaces presented
      significantly less fibrinogen adsorption than uncoated materials in an in vitro
      flow model. This approach, which combines the hemocompatibility of HA-coated
      surfaces and the anti-proliferative effects of an appropriate radiotherapy,
      constitutes a promising methodology to alleviate the restenosis induced by
      existing devices.

PMID- 15020167
TI  - Characterisation of commercial ionomer glasses using magic angle nuclear magnetic
      resonance (MAS-NMR).
AB  - Five commercial ionomer glasses (Fuji IX, Ketac Molar, G338, G2, and G2SR) used
      to produce glass (ionomer) polyalkenoate dental cements were studied. 29Si, 27Al,
      31P and 19F magic angle spinning nuclear magnetic resonance (MAS-NMR)
      Spectroscopy was used to characterise the glasses and the resulting spectra
      compared with previous studies of model glasses. The 29Si NMR spectra were
      consistent with Q4(3Al) and Q4(4Al) units being present and agreed with the low
      non-bridging oxygen contents calculated from the elemental composition. The 27Al
      NMR spectra typically exhibited three distinct sites at 45-60, 20 and 0 ppm which
      have been attributed to Al(IV), Al(V) and Al(VI) coordinate aluminium. The
      presence of Al(V) and Al(VI) are consistent with previous studies of model
      ionomer glasses. The 31P spectra all exhibited a chemical shift between -8 and 
      23 ppm with the exception of the Ketac Molar glass, which exhibited a peak at 2-3
      ppm consistent with orthophosphate. The chemical shift of 31P in the range -8 to 
      23 ppm indicates a PO(4) tetrahedra surrounded by 1-4 Al moieties. The (19)F NMR
      spectra indicated the presence of Al-F-Ca(n) in the G2 and G338 glasses, Al-F
      Sr(n) in the G2SR and Fuji IX glasses and crystalline CaF2, LaF3, Al-F-Ca(n) in
      the Ketac Molar glass. The G338 glass with a high non-bridging oxygen content
      showed the presence of a F-Ca(n) species. There was also present in all the
      glasses a peak corresponding to Al-F-Na(n). The intensity of this peak was
      approximately proportional to the sodium content.

PMID- 15020168
TI  - The effect of surface charge on hydroxyapatite nucleation.
AB  - Both the charged surfaces and condition of supersaturated solutions are thought
      to be the important factors that greatly affect the nucleation of hydroxyapatite
      (HAp) onto the substrates. In the present study self-assembled monolayers (SAM)
      terminated with amino (NH2-SAM) and hydroxyl (OH-SAM) headgroups were employed to
      generate the positively and negatively charged surfaces, respectively. The
      soaking experiments for HAp nucleation were carried out in the supersaturated
      solutions (1.5 SBF) with Ca2+ and PO4(3-) ions concentrations 1.5 times higher
      than in simulated body fluid (SBF). The stability of solutions deeply depends on
      pH values if other factors (temperature, ionic series and their concentration,
      etc.) are fixed. Consequently, the opposite micropatterns of HAp films were
      observed on the UV-patterned SAM with NH2 and OH terminals in a stable solution
      (1.5 SBF, pH=7.2) where no particles formed and in an unstable solution (1.5 SBF,
      pH=7.6) where homogeneous nucleation occurred. The preferential nucleation of HAp
      was found on negative surface (OH-SAM) in a stable supersaturated solution, while
      selective deposition of HAp was formed on positive surface (NH2-SAM) in the
      unstable solution. Considering the latter results, it is conceivable that the
      electrostatic adhesion of microparticles formed in the solution dominated the
      formation of HAp in the unstable solution.

PMID- 15020169
TI  - Control over the crystal phase, shape, size and aggregation of calcium carbonate
      via a L-aspartic acid inducing process.
AB  - The acidic amino acid, such as aspartic acid (l-Asp), and glutamic acid are the
      primary active molecules of the glycoprotein on the organic/inorganic interface
      of biomineralized tissue. In this study, aspartic acid was used as the organic
      template in inducing the nucleation and growth of calcium carbonate. With the
      analysis of X-ray diffraction we investigated the relationship between the l-Asp
      concentration and the precipitation phase crystal structure of calcium carbonate.
      SEM and TEM were employed in the analysis of the morphological characteristic of
      the precipitation and the aggregation of the nanoscale porous phase. In order to
      get the direct evidence of the interaction between Ca2+ and l-Asp, the technique
      of QCM was used in the investigation of the coordinate interaction of Ca2+/l-Asp.
      As the results have shown, l-Asp alone is adequate to switch the transformation
      between calcite and vaterite, and neither soluble organic additions nor metal
      ions are needed. Meanwhile, the morphology, size and aggregative way of the
      deposition are also mediated with change of l-Asp concentration. To interpret the
      cause of the hierarchic structure range from nanoscale to micron-scale and the
      formation of the porous spheres of vaterite, an assumption of limited-fusion was
      proposed from the view of the small biomolecules polarity that can control over
      the growth of the crystals and the aggregation of the micro crystals. The
      conclusion also provide a new material synthesize strategy.

PMID- 15020170
TI  - Impact of a physician-oriented intervention on follow-up in colorectal cancer
      screening.
AB  - BACKGROUND: Complete diagnostic evaluation or CDE (i.e., colonoscopy or combined
      flexible sigmoidoscopy plus barium enema X-ray) is often not performed for
      persons with an abnormal screening fecal occult blood test (FOBT+) result.
      METHOD: This study evaluated the impact of a reminder-feedback and educational
      outreach intervention on primary care practice CDE recommendation and performance
      rates. Four hundred seventy primary care physicians (PCPs) in 318 practices
      participated in the study. Patients were mailed an FOBT kit annually as part of a
      screening program. Practices were randomly assigned to a Control Group (N = 198)
      or an Intervention Group (N = 120). During an 18-month pre-randomization period
      and a 9-month post-randomization period, 2992 screening FOBT+ patients were
      identified. Intervention practices received the screening program and the
      intervention. Control practices received only the screening program. Study
      outcomes were baseline-adjusted CDE recommendation and performance rates.
      RESULTS: At baseline, about two-thirds of FOBT+ patients received a CDE
      recommendation, and about half had a CDE performed. At endpoint, CDE
      recommendation and performance rates were both significantly higher for the
      Intervention as compared to the Control practices (OR = 2.28; 95% CI: 1.37, 3.78,
      and OR = 1.63; 95% CI: 1.06, 2.50, respectively). CONCLUSIONS: The reminder
      feedback plus educational outreach intervention significantly increased CDE
      recommendation and performance.

PMID- 15020171
TI  - Monitoring of nevus density in children as a method to detect shifts in melanoma
      risk in the population.
AB  - BACKGROUND: Nevus density in children, a well-known risk factor for malignant
      melanoma, depends both on constitutional factors and on previous ultraviolet (UV)
      exposure. Secular trends of childhood UV exposure could thus be indirectly
      monitored by repeated standardized surveys assessing nevus density in children,
      such as the "childhood monitoring of nevus density (CMONDE-Study)". METHODS: Two
      complete surveys comprising all children at the time of school enrolment were
      performed in the city and county of Gottingen, Germany, during the years 1999 and
      2000. A total of 4252 children with a median age of 6.25 years were examined as
      part of the mandatory school enrolment health assessment, and complete data were
      available for 3881 children. RESULTS: Median nevus density was 5.8/m(2) in the
      entire study group. The subgroup-specific median increased from "Fitzpatrick skin
      type" IV to II, but the density was not increased for the type I subgroup.
      Similarly, nevus density rose with increasing lightness of hair color, but was
      very low in red-haired individuals. While the number of freckles was also
      strongly associated with nevus density, the association between iris color and
      skin reflectance, respectively, was weak. The duration of the additional
      examination for CMONDE was on average 3-5 min per child. CONCLUSION: We regard
      CMONDE as a highly feasible surveillance instrument, which should be implemented
      as an important addition to regular regional or national health reporting.

PMID- 15020172
TI  - Predictors of perceived breast cancer risk and the relation between perceived
      risk and breast cancer screening: a meta-analytic review.
AB  - BACKGROUND: Perceived risk is a principal variable in theoretical models that
      attempt to predict the adoption of health-protective behaviors. METHODS: This
      meta-analysis synthesizes findings from 42 studies, identified in PubMed and
      PsycInfo from 1985 onward. Studies examined demographic and psychological
      variables as predictors of perceived breast cancer risk and the relationship
      between perceived risk and breast cancer screening. Statistical relationships,
      weighted for sample size, were transformed to effect sizes and 95% CIs. RESULTS:
      Women do not have accurate perceptions of their breast cancer risk (N = 5561, g =
      1.10). Overall, they have an optimistic bias about their personal risk (g =
      0.99). However, having a positive family history (N = 70660, g = 0.88),
      recruitment site, and measurement error confounded these results. Perceived risk
      is weakly influenced by age (N = 38000, g = 0.13) and education (N = 1979, g =
      0.16), and is moderately affected by race/culture (N = 2192, g = 0.38) and worry
      (N = 6090, g = 0.49). There is an association between perceived risk and
      mammography screening (N = 52766, g = 0.19). It is not clear whether perceived
      risk influences adherence to breast self-examination. Women who perceived a
      higher breast cancer risk were more likely to pursue genetic testing or undergo
      prophylactic mastectomy. CONCLUSION: Perceived breast cancer risk depends on
      psychological and cognitive variables and influences adherence to mammography
      screening guidelines.

PMID- 15020173
TI  - Cost-effectiveness of a tailored intervention to increase screening in HMO women
      overdue for Pap test and mammography services.
AB  - BACKGROUND: Research has established the societal cost-effectiveness of providing
      breast and cervical cancer screening to women. Less is known about the cost of
      motivating women significantly overdue for services to receive screening.
      METHODS: In this intent-to-treat study, a total of 254 women, aged 52-69, who
      were overdue for both Pap test and mammography, were randomized to two groups, a
      tailored, motivational outreach or usual care. For effectiveness, we calculated
      the percent of women who received both services within 14 months of
      randomization. We used a comprehensive cost model to estimate total cost, per
      participant cost, and the incremental cost-effectiveness of delivering the
      outreach intervention from the health plan perspective. We also conducted
      sensitivity analyses around two key parameters, target population size and level
      of effectiveness. RESULTS: Compared with usual care, outreach (P = 0.006)
      screened significantly more women. The intervention cost US dollars 167.62 (2000
      U.S. dollars) for each woman randomized to outreach, and incremental cost
      effectiveness of outreach over usual care was US dollars 818 per additional woman
      screened. Sensitivity analyses estimated incremental cost-effectiveness between
      Us dollars 19 and US dollars 90 per additional woman screened. CONCLUSIONS:
      Larger health plans can likely increase Pap test and mammography services in this
      population for a relatively low cost using this outreach intervention.

PMID- 15020174
TI  - Integrating smoking cessation treatment into primary care: an effectiveness
      study.
AB  - BACKGROUND: Lack of interest has been cited as a reason not to offer cessation
      assistance to smokers, but research suggests that smokers accept treatments
      offered proactively. This study assessed acceptability, utilization, and
      effectiveness of free smoking cessation treatment among diverse primary care
      patients. METHOD: Medical assistants invited 4174 adult smokers to participate.
      Enrollees (1869) self-selected or were assigned to receive free nicotine patch
      therapy alone or in combination with the Committed Quitters(R) program, and for
      some, individual counseling. RESULTS: In nearly 68% of cases, patients accepted a
      treatment invitation; 77% of eligible smokers enrolled; 85% of these picked up
      free patches. Given a choice of treatments, 75% of participants elected a
      psychosocial treatment in addition to patch therapy. Thirteen percent of
      treatment initiators achieved biochemically confirmed 7-day point-prevalence
      abstinence at 1 year, with no significant treatment effects. Minority patients
      showed greater initial interest but less utilization did than White patients.
      CONCLUSIONS: Free, readily accessible smoking cessation treatment offered in
      primary care settings was accepted and used by the majority of unselected smokers
      of diverse racial/ethnic origins. Psychosocial treatment components did not
      significantly increase abstinence rates. Barriers, rather than lack of interest,
      may keep minority smokers from using cessation treatments.

PMID- 15020175
TI  - Focus groups of Y-K Delta Alaska Natives: attitudes toward tobacco use and
      tobacco dependence interventions.
AB  - BACKGROUND: Tobacco dependence interventions developed for Alaska Natives are
      virtually nonexistent. Alaska Natives residing on the Yukon-Kuskokwim (Y--K)
      Delta in southwestern Alaska use a unique form of smokeless tobacco (ST) known as
      Iqmik. This study employed focus group methodology to explore attitudes toward
      tobacco use and tobacco dependence interventions among Alaska Natives residing on
      the Y-K Delta. METHODS: Twelve focus groups of former and current tobacco users
      were conducted in four villages in the Y-K Delta. Participants were 35 adults
      (83% female) and 22 adolescents (27% female). Participants completed a brief
      demographic and tobacco use history form. Statements from the focus groups were
      transcribed for content coding and analysis of the major themes. RESULTS: Use of
      Iqmik in the villages is thought to be ubiquitous. Y-K Delta Alaska Natives are
      introduced to Iqmik at a very young age. Iqmik is mostly used and prepared by
      young Alaska Natives and adult women. There are few perceived adverse health
      effects of Iqmik or other tobacco use. Although there is interest in stopping,
      there is a perceived lack of availability of tobacco dependence interventions.
      The major barriers to preventing the initiation of and stopping tobacco use are
      the social acceptance and widespread use and availability of tobacco. CONCLUSION:
      The attitudes toward tobacco and identified barriers to stopping will be useful
      in developing tobacco dependence interventions for Alaska Natives.

PMID- 15020176
TI  - Rationale and design of the Rockford CHIP, a community-based coronary risk
      reduction program: results of a pilot phase.
AB  - PURPOSE: While residential lifestyle intervention programs have demonstrated
      coronary risk reduction through education, diet, and exercise, this pilot study
      was designed to assess the feasibility of a community-based lifestyle
      intervention program that is both affordable and effective in facilitating better
      lifestyle choices and health habits and thus effecting indicators of better
      clinical outcomes. MATERIALS AND METHODS: A 40-h educational curriculum,
      delivered over a 30-day period with clinical and nutritional assessments before
      and after, was offered through the SwedishAmerican Center for Complementary
      Medicine to the general public. The participants were instructed to exercise 30
      min/day and to embrace a more optimal diet (ad libitum) of largely unrefined
      plant foods high in complex carbohydrates and fiber, yet quite low in fat (<15%),
      animal protein, sugar, and salt, and virtually free of cholesterol. RESULTS: Of
      the 250 enrollees, 242 "graduated" (78 men and 164 women; almost all Caucasian;
      mean age 54 +/- 12 years). They had coronary artery disease (CAD) (12%), diabetes
      (16%), hypertension (55%), most were overweight (88%), and the majority (79%) had
      low-density lipoprotein (LDL) levels >or=100 mg%. At 4 weeks, stratified analyses
      of total cholesterol (TC), LDL, triglycerides (TG), blood glucose, blood
      pressure, and weight showed that those at highest risk also had the greatest
      improvements. Depending on baseline levels, TC means dropped 10-23% in men and 6
      13% in women. At the same time, LDL means declined 5-30% in men and 6-14% in
      women. In TG, the biggest drop (48%) was found in men who at baseline were in the
      highest risk category (in women, the biggest TG drop was 32%). CONCLUSION:
      Community-based intervention strategies can be successfully and affordably
      utilized to lower coronary risk factor levels in a self-selected, free-living
      population. The true test, however, will be to what extent social infrastructures
      can be modified and alumni activities sustained to facilitate long-term adherence
      and sustained benefits.

PMID- 15020177
TI  - Behavioral variables and education are predictors of dietary change in the
      Women's Health Trial: Feasibility Study in Minority Populations.
AB  - BACKGROUND: Reducing the intakes of fats and increasing consumption of fruits and
      vegetables are an important goal for improving population health. Analyzing the
      effects of nutrition education programs on subjects' dietary intakes
      incorporating factors such as habit persistence in diets, unhealthy eating
      habits, perceptions of health risks, participation motivation, and expectancies
      can yield useful insights. METHODS: A Food Frequency Questionnaire (FFQ) was used
      to measure intakes at baseline, 6 and 12 months, by 318 and 548 postmenopausal
      women in, respectively, the Control and Intervention groups of the Women's Health
      Trial: Feasibility Study in Minority Populations (WHTFSMP). Information on
      background, behavioral, and anthropometric variables was collected. The
      Intervention group met in classes led by nutritionists. Dynamic random effects
      models were estimated for the two groups using the data at baseline, 6 and 12
      months on the intakes of carbohydrate, saturated, monounsaturated, and
      polyunsaturated fats, fiber, beta-carotene, ascorbic acid, and calcium. RESULTS:
      The nutrition education program lowered the intakes of fats while increasing
      fiber, beta-carotene, and ascorbic acid intakes especially in subjects scoring
      high on indices reflecting concerns about health, desirability of change, and
      participation motivation. In addition, subjects' education was a predictor of
      dietary intakes in the Intervention group. CONCLUSIONS: Nutrition education can
      be an effective tool for improving diets, but behavioral characteristics deserve
      greater attention in helping to design the most effective approaches for various
      target groups.

PMID- 15020178
TI  - The associations between blood lipids and the Food Guide Pyramid: findings from
      the Third National Health and Nutrition Examination Survey.
AB  - BACKGROUND: Dietary recommendations are based on nutrients, foods, and food
      groups, but the relationship between the Food Guide Pyramid (FGP) food groups and
      serum lipids has not been studied. METHODS: NHANES III data were obtained for US
      adults who met the following criteria: aged 20-59 years, reliable participant,
      and typical 24-h recall. We examined whether serum lipids (serum total
      cholesterol (STC), high-density lipoprotein cholesterol (HDL-C), low-density
      lipoprotein cholesterol (LDL-C), and triacylglycerol) were related to FGP food
      group intake (dairy, fruit, grain, meat, and vegetable). RESULTS: A sample of
      9111 participants qualified for this analysis. Fruit intakes were inversely
      related to STC, HDL-C, and LDL-C (P = 0.012, P = 0.001, and P = 0.014,
      respectively) and directly related to triacylglycerol levels (P = 0.003). Grain
      intake was inversely associated with both STC and HDL-C (P = 0.020 and P =
      0.000). Dairy and meat intakes were directly related to LDL-C (P = 0.026 and P =
      0.020). CONCLUSIONS: Food groups are related to serum lipids. Universal
      definitions for food groups are needed in research and nutrition education.
      Studying the relationships between food groups and serum lipids is important for
      future dietary recommendations related to serum lipids.

PMID- 15020179
TI  - The cardiovascular health of residents in selected metropolitan cities in China.
AB  - BACKGROUND: To better understand the cardiovascular health and leisure-time
      physical activity of residents in major metropolitan cities in China, 2196
      subjects (39.0 +/- 10.7 years) who lived in Beijing, Shanghai and Hong Kong were
      investigated. METHODS: During the months of January to June 2001, residents of
      the three cities who went through annual medical examinations at participating
      hospitals and exercise physiology laboratories were recruited as subjects, with a
      target of 800-900 subjects per city. Data on their behavior and health-related
      cardiovascular heart disease (CHD) risk factors were assessed. RESULTS AND
      CONCLUSIONS: It was found that over 80% of the subjects were sedentary
      (participating less than 90 min/week in leisure physical activity). The
      percentages of subjects having three or more cardiovascular heart disease risk
      factors were highest in Beijing (72.2%), followed by Shanghai (53.5%) and then
      Hong Kong (29.3%), suggesting that the cardiovascular health of Hong Kong
      residents was the best. It was noted that while all cities have similar health
      problems, there were significant differences in CHD risk factor due to
      geographical differences: Beijing residents smoked, drank, had high serum
      cholesterol and did not exercise; Shanghai residents had high blood pressure and
      drank; and Hong Kong residents were overweight and had lower HDL level. It was
      found that as subjects grew older, their cardiovascular health became worse.
      Gender differences were also observed-female subjects have generally fewer CHD
      risk factors and thus better health than male subjects. A model to examine the
      effects of age and behavior-related factors on health was developed for each
      city. Implications on planning strategies and primary prevention programs of CHD
      were discussed, in light of intervening identified risk factors.

PMID- 15020180
TI  - Influence of selected lifestyle factors on risk of acute myocardial infarction in
      subjects with familial predisposition for the disease.
AB  - BACKGROUND: The joint effect of family history of acute myocardial infarction
      (AMI) and selected adult life risk factors on the risk of the disease is not
      clear. METHODS: We used the combined data set from three Italian case-control
      studies including 1737 cases of incident, nonfatal AMI and 2317 hospital
      controls, aged less than 75 years. An adult lifestyle risk score (ALRS) was
      computed, including tobacco, body mass index, physical activity, and consumption
      of coffee, alcohol, fish, and vegetables. RESULTS: Compared to the reference
      category (subjects with no family history of AMI and low ALRS), the risk of AMI
      was 4.97 (95% confidence intervals, CI: 4.00-6.18) in subjects without family
      history and high ALRS, 2.19 (95% CI: 1.65-2.90) in subjects with family history
      and low ALRS, and 11.90 (95% CI: 8.94-15.84) in subjects with family history and
      high ALRS. CONCLUSIONS: The risk of AMI in subjects with a familial
      predisposition to ischaemic heart disease might be substantially reduced by
      intervention on selected lifestyle risk factors for AMI. In absolute terms, any
      such intervention would be more effective than a comparable one on subjects
      without a familial predisposition.

PMID- 15020181
TI  - Differences in brief interventions on excessive drinking and smoking by primary
      care physicians: qualitative study.
AB  - BACKGROUND: Brief interventions by primary care physicians have been shown to be
      effective in reducing both smoking and excessive drinking. However, physicians
      seem to target smoking more often than drinking. We aimed to explore this
      difference in health promotion practises for finding ways to improve alcohol
      interventions in primary health centres. METHODS: Qualitative semistructured
      interviews of 35 physicians in four health centres in Finland, and triangulation
      by audit of notes made by these doctors concerning alcohol drinking and smoking
      in medical records (n = 1200) of randomly selected 20-60 years old patients, who
      had visited their physician at least once in a 12-month study period. RESULTS: On
      the basis of the interviews, there were five main differences in preventive work
      between issues of alcohol use and smoking: recognition, perceived importance as a
      health risk factor, intervention tools available, stigmatising label, and
      expectations about the effectiveness of counselling. In 106 (8.8%) of medical
      records, there was a mention of smoking, and in 82 (6.8%) of alcohol use (P <
      0,0001). Quantity of alcohol consumption was described obscurely. When one of the
      visits was made for hypertension, diabetes, dyspepsia, general health check or
      heart arrhythmias, smoking was recorded more often than alcohol consumption.
      CONCLUSIONS: Tobacco use was mentioned more often in medical records than alcohol
      drinking. Physicians were more comfortable in undertaking a preventive approach
      for smoking than for alcohol use. The factors contributing to this difference
      must be considered in any attempts to improve implementation of secondary
      prevention of alcohol misuse.

PMID- 15020182
TI  - Gender and smoking status-based analysis of views regarding waterpipe and
      cigarette smoking in Aleppo, Syria.
AB  - BACKGROUND: Narghile (waterpipe) smoking is increasing across the Eastern
      Mediterranean region (EMR), though little is known about the social attitudes and
      perceptions related to this method of tobacco use, and how those attitudes and
      perceptions are influenced by gender. METHODS: Data from two cross-sectional
      surveys conducted in 2003 in Aleppo, Syria, were used to examine these issues.
      Overall, 855 participants were included (439 men, 416 women; mean age, 24.4+/-7.1
      years; response rate, 97%). The current analysis focuses on responses to four
      similar nine-item questions tapping perceptions related to narghile smoking by
      women or men, and cigarette smoking by women or men. Scores on the nine items
      were summed to yield a total score to gauge participants' perceptions about
      narghile and cigarette. RESULTS: Generally, participants were less positive about
      women smoking relative to men smoking, and cigarette smoking relative to narghile
      smoking. Cigarette smoking by women was the behavior least associated with
      positive perceptions. Individuals who resided in the city, were economically
      better-off, and were Christian, had higher perception scores (i.e., more positive
      attitudes) toward all forms of smoking, whereas older and married participants
      had higher perception scores for narghile only. Smoking status of participants,
      especially narghile smoking, was also associated with more positive perceptions
      toward smoking in general. CONCLUSIONS: We conclude that preliminary analysis
      shows that views on different forms of smoking in Syria differ by gender and
      smoking status.

PMID- 15020183
TI  - Does adolescent perception of difficulty in getting cigarettes deter
      experimentation?
AB  - BACKGROUND: Considerable controversy surrounds tobacco control emphasis on youth
      access-to-tobacco laws, as there is limited evidence that such enforcement
      reduces youth smoking. In California, access-law enforcement increased
      substantially in 1996 compared to earlier in the decade. METHODS: Two
      longitudinal cohorts of adolescent never smokers from the large, population-based
      California Tobacco Surveys of 1993 and 1996 were followed-up 3 years later (1993
      1996 [n = 1764] and 1996-1999 [n = 2119]). We examined transition to any smoking
      by follow-up with adolescent perception that cigarettes are easy or hard to get,
      during periods with less and more access law enforcement. RESULTS: Transition to
      any smoking by follow-up among 12- to 15-year-old never smokers was identical in
      the 1993-1996 cohort, regardless of whether they perceived cigarettes as hard or
      easy to get (about 38%), but was lower in the 1996-1999 cohort for those who
      perceived that cigarettes were hard (25.9%) vs. easy (36.1%) to get. This
      differential effect was confirmed in multivariate analyses that adjusted for
      demographics, cohort, and other known predictors of adolescent smoking.
      CONCLUSIONS: Increased enforcement of access laws may help protect young
      adolescents from experimenting with cigarettes by strengthening societal anti
      tobacco norms. Such enforcement appears warranted as part of a comprehensive
      tobacco control program.

PMID- 15020184
TI  - Accuracy of self-reported smoking status among participants in a chemoprevention
      trial.
AB  - BACKGROUND: Exposure to tobacco products is readily assessed through self- or
      interview-administered questionnaires. Degree of misreporting among participants
      in chemoprevention trials is unknown. We assessed the level of discrepancy
      between self-reported smoking exposure and plasma cotinine among participants in
      a chemoprevention trial. METHODS: Analyses were conducted among 824 men and women
      who participated in a dietary trial of adenoma recurrence. Smoking exposure was
      ascertained through self-administered questionnaires at three time-points. Plasma
      cotinine was measured by gas chromatography among 283 never, 446 former and 95
      current self-reported smokers. Sensitivity and specificity were assessed using
      various plasma cotinine cut-points. RESULTS: Degree of misclassification for self
      reported current smokers was minor (0-3%), regardless of cotinine cut-point used.
      Using a cut-point of 20 ng/ml, which takes into account exposure to environmental
      tobacco smoke among nonsmokers, sensitivity and specificity were 98.9% and 80.2%,
      respectively. CONCLUSIONS: These data indicate that degree of misreport for
      current smokers is extremely low; however, approximately 20% of self-reported
      never smokers misreport their exposure, suggesting that validation of self-report
      is needed for these individuals.

PMID- 15020185
TI  - Predictors of smoking cessation among African-Americans enrolled in a randomized
      controlled trial of bupropion.
AB  - OBJECTIVES: Identification of individual characteristics that predict successful
      smoking cessation treatment has been limited to studies with mostly white
      participants. This study identifies factors that predict successful quitting
      among African-Americans participating in a smoking cessation trial. METHODS:
      Twenty-one baseline variables were analyzed as potential predictors from a double
      blind placebo-controlled, randomized trial that used bupropion SR for smoking
      cessation among 600 African-American smokers. Chi-square tests, two sample t
      tests, and multiple logistic regression procedures were employed to identify
      predictors of 7-day abstinence among the 535 participants who completed the 7
      week medication phase. RESULTS: Univariate predictors of cessation were receiving
      bupropion (P < 0.0001), not smoking menthol cigarettes (P = 0.0062), smoking
      after 30 min of waking (P < 0.0001), older age (P = 0.0085), smoking fewer
      cigarettes per day (P = 0.0038), and lower cotinine levels (P = 0.0002). Logistic
      regression identified three significant independent predictors. Participants who
      received bupropion treatment were more than twice as likely to quit smoking at
      the end of treatment compared to participants who received placebo (OR = 2.62;
      95% CI = 1.77-3.88, P < 0.0001), while smoking within 30 min of waking (OR =
      0.40; 95% CI = 0.25-0.62, P < 0.0001) and higher salivary cotinine levels at
      baseline (OR = 0.799; 95% CI = 0.629-0.922, P < 0.0001) reduced the likelihood of
      quitting. CONCLUSIONS: This is the first report identifying predictors of smoking
      cessation among African-Americans participating in a clinical trial. Results
      indicate that, aside from bupropion treatment, various indicators of addiction
      were the strongest predictors. While this is similar to findings among white
      smokers, thresholds of addiction may need to be adjusted for African-American
      smoking patterns. Additional studies focused on diverse populations are needed to
      improve treatment approaches and to identify population-specific factors that are
      important for treatment-matching approaches.

PMID- 15020186
TI  - The role of mobile phones in improving vaccination rates in travelers.
AB  - RATIONALE: Noncompliance with vaccination schedules undermines the potential
      benefits of immunization. The purpose of this study was to evaluate whether a
      reminder of the next vaccine dose sent by the Short Messaging Service (SMS) to
      the vaccinee's mobile phone increases compliance with hepatitis A + B and
      hepatitis A vaccination schedule. SUBJECTS AND METHODS: In this experimental,
      controlled study, the study group comprised travelers who went to the
      Internacional-Clinic Vaccination Centre between the 1st June and 30th September
      of 2001 for the standard immunization schedule against hepatitis A + B and
      against hepatitis A. Trained health-care workers entered the data into a computer
      to generate text messages reminding vaccinees of their scheduled doses. Two
      control groups, one from the same period of the same year including travelers
      from the third office (Control 2001) and the second, all travelers seen in the
      same period of the previous year (Control 2000), were used. RESULTS: For the
      second hepatitis A + B dose, compliance in the study group (Message Groups) was
      88.4% (83.3-92.2); in the Control 2001, 80.7% (76.3-84.4, relative risk [RR] 1.10
      [1.02-1.17]); and in the Control 2000, 77.2% (73.3-80.5, RR 1.15 [1.07-1.22]).
      For the third hepatitis A + B vaccine dose, results were 47.1% (40.5-53.8); 26.9%
      (22.8-31.7, RR 1.75 [1.41-2.17]); and 23.6% (20.1-27.4, RR 2.00 [1.63-2.45]),
      respectively. As for the hepatitis A vaccine, compliance rates for the second
      dose were 27.7% (23.9-31.9); 16.4% (14.4-18.6, RR 1.69 [1.40-2.04]); and 13.2%
      (11.6-14.9, RR 2.10 [1.75-2.54]); respectively. CONCLUSIONS: SMS seems to be an
      effective tool for increasing compliance with vaccination schedules.

PMID- 15020189
TI  - Molecular pathways in dermatotoxicology.

PMID- 15020190
TI  - Epidermal CYP2 family cytochromes P450.
AB  - Skin is the largest and most accessible drug-metabolizing organ. In mammals, it
      is the competent barrier that protects against exposure to harmful stimuli in the
      environment and in the systemic circulation. Skin expresses many cytochromes P450
      that have critical roles in exogenous and endogenous substrate metabolism. Here,
      we review evidence for epidermal expression of genes from the large CYP2 gene
      family, many of which are expressed preferentially in extrahepatic tissues or
      specifically in epithelia at the environmental interface. At least 13 CYP2 genes
      (CYP2A6, 2A7, 2B6, 2C9, 2C18, 2C19, 2D6, 2E1, 2J2, 2R1, 2S1, 2U1, and 2W1) are
      expressed in skin from at least some human individuals, and the majority of these
      genes are expressed in epidermis or cultured keratinocytes. Where epidermal
      expression has been localized in situ by hybridization or immunocytochemistry,
      CYP2 transcripts and proteins are most often expressed in differentiated
      keratinocytes comprising the outer (suprabasal) cell layers of the epidermis and
      skin appendages. The tissue-specific transcriptional regulation of CYP2 genes in
      the epidermis, and in other epithelia that interface with the environment,
      suggests important roles for at least some CYP2 gene products in the production
      and disposition of molecules affecting competency of the epidermal barrier.

PMID- 15020192
TI  - Toxic effects of ultraviolet radiation on the skin.
AB  - Ultraviolet (UV) irradiation present in sunlight is an environmental human
      carcinogen. The toxic effects of UV from natural sunlight and therapeutic
      artificial lamps are a major concern for human health. The major acute effects of
      UV irradiation on normal human skin comprise sunburn inflammation (erythema),
      tanning, and local or systemic immunosuppression. At the molecular level, UV
      irradiation causes DNA damage such as cyclobutane pyrimidine dimers and (6-4)
      photoproducts, which are usually repaired by nucleotide excision repair (NER).
      Chronic exposure to UV irradiation leads to photoaging, immunosuppression, and
      ultimately photocarcinogenesis. Photocarcinogenesis involves the accumulation of
      genetic changes, as well as immune system modulation, and ultimately leads to the
      development of skin cancers. In the clinic, artificial lamps emitting UVB (280
      320 nm) and UVA (320-400 nm) radiation in combination with chemical drugs are
      used in the therapy of many skin diseases including psoriasis and vitiligo.
      Although such therapy is beneficial, it is accompanied with undesirable side
      effects. Thus, UV radiation is like two sides of the same coin--on one side, it
      has detrimental effects, and on the other side, it has beneficial effects.

PMID- 15020191
TI  - Solar ultraviolet radiation as a trigger of cell signal transduction.
AB  - Ultraviolet light radiation in sunlight is known to cause major alterations in
      growth and differentiation patterns of exposed human tissues. The specific
      effects depend on the wavelengths and doses of the light, and the nature of the
      exposed tissue. Both growth inhibition and proliferation are observed, as well as
      inflammation and immune suppression. Whereas in the clinical setting, these
      responses may be beneficial, for example, in the treatment of psoriasis and
      atopic dermatitis, as an environmental toxicant, ultraviolet light can induce
      significant tissue damage. Thus, in the eye, ultraviolet light causes cataracts,
      while in the skin, it induces premature aging and the development of cancer.
      Although ultraviolet light can damage many tissue components including membrane
      phospholipids, proteins, and nucleic acids, it is now recognized that many of its
      cellular effects are due to alterations in growth factor- and cytokine-mediated
      signal transduction pathways leading to aberrant gene expression. It is generally
      thought that reactive oxygen intermediates are mediators of some of the damage
      induced by ultraviolet light. Generated when ultraviolet light is absorbed by
      endogenous photosensitizers in the presence of molecular oxygen, reactive oxygen
      intermediates and their metabolites induce damage by reacting with cellular
      electrophiles, some of which can directly initiate cell signaling processes. In
      an additional layer of complexity, ultraviolet light-damaged nucleic acids
      initiate signaling during the activation of repair processes. Thus, mechanisms by
      which solar ultraviolet radiation triggers cell signal transduction are
      multifactorial. The present review summarizes some of the mechanisms by which
      ultraviolet light alters signaling pathways as well as the genes important in the
      beneficial and toxic effects of ultraviolet light.

PMID- 15020193
TI  - Fate of chemicals in skin after dermal application: does the in vitro skin
      reservoir affect the estimate of systemic absorption?
AB  - Recent international guidelines for the conduct of in vitro skin absorption
      studies put forward different approaches for addressing the status of chemicals
      remaining in the stratum corneum and epidermis/dermis at the end of a study. The
      present study investigated the fate of three chemicals [dihydroxyacetone (DHA), 7
      (2H-naphtho[1,2-d]triazol-2-yl)-3-phenylcoumarin (7NTPC), and disperse blue 1
      (DB1)] in an in vitro absorption study. In these studies, human and fuzzy rat
      skin penetration and absorption were determined over 24 or 72 h in flow-through
      diffusion cells. Skin penetration of these chemicals resulted in relatively low
      receptor fluid levels but high skin levels. For DHA, penetration studies found
      approximately 22% of the applied dose remaining in the skin (in both the stratum
      corneum and viable tissue) as a reservoir after 24 h. Little of the DHA that
      penetrates into skin is actually available to become systemically absorbed. 7NTPC
      remaining in the skin after 24 h was approximately 14.7% of the applied dose
      absorbed. Confocal laser cytometry studies with 7NTPC showed that it is present
      across skin in mainly the epidermis and dermis with intense fluorescence around
      hair. For DB1, penetration studies found approximately 10% (ethanol vehicle) and
      3% (formulation vehicle) of the applied dose localized in mainly the stratum
      corneum after 24 h. An extended absorption study (72 h) revealed that little
      additional DB1 was absorbed into the receptor fluid. Skin levels should not be
      considered as absorbed material for DHA or DB1, while 7NTPC requires further
      investigation. These studies illustrate the importance of determining the fate of
      chemicals remaining in skin, which could significantly affect the estimates of
      systemically available material to be used in exposure estimates. We recommend
      that a more conclusive means to determine the fate of skin levels is to perform
      an extended study as conducted for DB1.

PMID- 15020194
TI  - In vitro evaluation of matrix metalloproteinases as predictive testing for
      nickel, a model sensitizing agent.
AB  - The identification of potential damage due to chemical exposure in the workplace
      is a major health and regulatory concern. Traditional tests that measure both
      sensitization and elicitation responses require the use of animals. An
      alternative to this widespread use of experimental animals could have a crucial
      impact on risk assessment, especially for the preliminary screening of new
      molecules. We developed an in vitro model for the screening of potential toxic
      compounds. Human keratinocytes (HaCat) were used as target cells while matrix
      metalloproteinases (MMP) were selected as responders because they are key enzymes
      involved in extracellular matrix (ECM) degradation in physiological and
      pathological conditions. Chemical exposure was performed using nickel sulphate as
      a positive tester. Nickel contact induced upregulation of MMP-2 and IL-8 mRNA
      production. Molecular activation occurred even at very low nickel concentrations
      even though no phenotypic changes were observed. MMP-9 accumulation was found in
      the medium of treated cells with respect to controls. These observations led to
      the hypothesis that even minimal exposure can accumulate transcriptional activity
      resulting in long-term clinical signs after contact. Our simple in vitro model
      can be applied as a useful preliminary complement to the animal studies to screen
      the effects of new potential toxic compounds.

PMID- 15020196
TI  - Skin toxicity of jet fuels: ultrastructural studies and the effects of substance
      P.
AB  - Topical exposure to jet fuel is a significant occupational hazard. Recent studies
      have focused on dermal absorption of fuel and its components, or alternatively,
      on the biochemical or immunotoxicological sequelae to exposure. Surprisingly,
      morphological and ultrastructural analyses have not been systematically
      conducted. Similarly, few studies have compared responses in skin to that of the
      primary target organ, the lung. The focus of the present investigation was 2
      fold: first, to characterize the ultrastructural changes seen after topical
      exposure to moderate doses (335 or 67 microl/cm2) of jet fuels [Jet A, Jet
      Propellant (JP)-8, JP-8+100] for up to 4 days in pigs, and secondly, to determine
      if co-administration of substance P (SP) with JP-8 jet fuel in human epidermal
      keratinocyte cell cultures modulates toxicity as it does to pulmonary toxicity in
      laboratory animal studies. The primary change seen after exposure to all fuels
      was low-level inflammation accompanied by formation of lipid droplets in various
      skin layers, mitochondrial and nucleolar changes, cleft formation in the
      intercellular lipid lamellar bilayers, as well as disorganization in the stratum
      granulosum-stratum corneum interface. An increased number of Langerhans cells
      were also noted in jet fuel-treated skin. These changes suggest that the primary
      effect of jet fuel exposure is damage to the stratum corneum barrier. SP
      administration decreased the release of interleukin (IL)-8 normally seen in
      keratinocytes after JP-8 exposure, a response similar to that reported for SP's
      effect on JP-8 pulmonary toxicity. These studies provide a base upon which
      biochemical and immunological data collected in other model systems can be
      compared.

PMID- 15020195
TI  - Platelet activating factor receptor binding plays a critical role in jet fuel
      induced immune suppression.
AB  - Applying military jet fuel (JP-8) or commercial jet fuel (Jet-A) to the skin of
      mice suppresses the immune response in a dose-dependent manner. The release of
      biological response modifiers, particularly prostaglandin E2 (PGE2), is a
      critical step in activating immune suppression. Previous studies have shown that
      injecting selective cyclooxygenase-2 inhibitors into jet fuel-treated mice blocks
      immune suppression. Because the inflammatory phospholipid mediator, platelet
      activating factor (PAF), up-regulates cyclooxygenase-2 production and PGE2
      synthesis by keratinocytes, we tested the hypothesis that PAF-receptor binding
      plays a role in jet fuel-induced immune suppression. Treating keratinocyte
      cultures with PAF and/or jet fuel (JP-8 and Jet-A) stimulates PGE2 secretion. Jet
      fuel-induced PGE2 production was suppressed by treating the keratinocytes with
      specific PAF-receptor antagonists. Injecting mice with PAF, or treating the skin
      of the mice with JP-8, or Jet-A, induced immune suppression. Jet fuel-induced
      immune suppression was blocked when the jet fuel-treated mice were injected with
      PAF-receptor antagonists before treatment. Jet fuel treatment has been reported
      to activate oxidative stress and treating the mice with anti-oxidants (Vitamins
      C, or E or beta-hydroxy toluene), before jet fuel application, interfered with
      immune suppression. These findings confirm previous studies showing that PAF
      receptor binding can modulate immune function. Furthermore, they suggest that PAF
      receptor binding may be an early event in the induction of immune suppression by
      immunotoxic environmental agents that target the skin.

PMID- 15020197
TI  - Active ingredients in sunscreens act as topical penetration enhancers for the
      herbicide 2,4-dichlorophenoxyacetic acid.
AB  - Agricultural workers are encouraged to use sunscreen to decrease the risk of UV
      related skin cancer. Our previous studies have shown certain commercial
      sunscreens to be penetration enhancers. The focus of this project is to determine
      whether active ingredients in sunscreen formulations (i.e., the UV absorbing
      components and insect repellants for the sunscreen/bug repellant combinations)
      also act as dermal penetration enhancers for herbicides in vitro. The total
      percentages of 2,4-dichlorophenoxyacetic acid (2,4-D) penetrating through
      hairless mouse skin in 24 h ranged from 54.9 +/- 4.7 for the no sunscreen control
      to 86.9 +/- 2.5 for padimate-o. Of the active ingredients tested (7.5% octyl
      methoxycinnamate, 7% octocrylene, 0.6% oxybenzone, 5% homosalate, 5% octyl
      salicylate, 8% padimate-o, 10% sulisobenzone, and 9.5% and 19% N,N-diethyl-m
      toluamide [DEET]), all but octocrylene led to a significant increase in total 2,4
      D penetration as compared to the control (P < 0.05), and only octocrylene and
      oxybenzone did not significantly decrease the corresponding lag time. Octyl
      salicylate (P < 0.01) and octyl methoxycinnimate (P < 0.05) significantly
      increased the 3H2O penetration across mouse skin, indicating physical damage to
      the stratum corneum. Additional studies demonstrated that the penetration
      enhancement seen across hairless mouse skin also occurred with human skin. Thus,
      the active ingredients of sunscreen formulations enhance dermal penetration of
      the moderately lipophilic herbicide 2,4-D.

PMID- 15020198
TI  - Topical application of dimethylbenz[a]anthracene results in the generation of
      multiple melanocytic nevi in C3H/HeN mice.
AB  - Melanocytic nevi are a common dermatological problem for which there are few in
      vivo models. It has been postulated that environmental factors contribute to
      their development. Experiments were therefore conducted to determine whether
      application of dimethylbenz[a]anthracene (DMBA) to the skin of mice would result
      in the development of melanocytic nevi. One hundred microliters of a 0.1%, 0.5%,
      or 1.0% solution of DMBA was applied to the dorsal skin of C3H/HeN mice. The mice
      were then observed for the appearance of pigmented lesions. Histological
      examination revealed perifollicular accumulations of nevus cells, which were S
      100-protein and HMB-45-positive, confirming their melanocytic origin. Pigmented
      lesions did not occur in animals treated with vehicle alone. Dose response
      studies revealed both greater numbers of nevi and lesions with larger diameters
      as the dose of DMBA was increased from 0.1% to 0.5%. In no instance was an
      invasive melanoma observed even after 40 weeks. The fact that melanocytic nevi
      can be produced by topical application of DMBA suggests that xenobiotics may play
      a previously unrecognized role in the development of this common benign neoplasm.
      Because this is one of the only animal models for melanocytic nevi, further
      examination of this model may facilitate identification of the molecular and
      biochemical mechanisms that lead to the development of pigmented nevi and the
      factors that promote their evolution into invasive melanomas.

PMID- 15020199
TI  - Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion
      markers in CD-1 mouse skin by oleandrin.
AB  - Oleandrin, derived from the leaves of Nerium oleander, has been shown to possess
      anti-inflammatory and tumor cell growth-inhibitory effects. Here, we provide
      evidence that oleandrin could possess anti-tumor promoting effects. We determined
      the effect of topical application of oleandrin to CD-1 mice against l2-O
      tetradecanoylphorbol-13-acetate (TPA), a widely studied skin tumor promoter, 
      induced conventional and novel markers of skin tumor promotion. Topical
      application of oleandrin (2 mg per mouse) 30 min before TPA (3.2 nmol per mouse)
      application onto the skin afforded significant inhibition, in a time-dependent
      manner, against TPA-mediated increase in cutaneous edema and hyperplasia,
      epidermal ornithine decarboxylase (ODC) activity and ODC and cyclooxgenase-2 (COX
      2) protein expression. In search for novel markers of skin tumor promotion, we
      found that TPA application to mouse skin resulted, as an early event, in an
      increased expression of phosphatidyinositol 3-kinase (PI3K), phosphorylation of
      Akt at threonine308 and activation of nuclear factor kappa B (NF-kappaB). Topical
      application of oleandrin before TPA application to mouse skin resulted in
      significant reduction in TPA-induced expression of PI3K and phosphorylation of
      Akt, and inhibition of NF-kappaB activation. NF-kappaB is a eukaryotic
      transcription factor that is critically involved in regulating the expression of
      specific genes that participate in inflammation, apoptosis and cell
      proliferation. Employing Western blot analysis, we found that oleandrin
      application to mouse skin resulted in inhibition of TPA-induced activation of NF
      kappaB, IKKalpha and phosphorylation and degradation of IkappaBalpha. Our data
      suggest that oleandrin could be a useful anti-tumor promoting agent because it
      inhibits several biomarkers of TPA-induced tumor promotion in an in vivo animal
      model. One might envision the use of chemopreventive agents such as oleandrin in
      an emollient or patch for chemoprevention or treatment of skin cancer.

PMID- 15020200
TI  - Photoprotective effects of sulindac against ultraviolet B-induced phototoxicity
      in the skin of SKH-1 hairless mice.
AB  - Sulindac is a nonsteroidal anti-inflammatory drug with demonstrated potency as a
      chemopreventive agent in animal models of carcinogenesis and in patients with
      familial adenomatous polyposis. Because tumor promotion is generally associated
      with exposure to pro-inflammatory stimuli, it is likely that anti-inflammatory
      agents may have potent antitumor effects. In human skin, sulindac reduces
      bradykinin-induced edema. In this study, we tested the hypothesis that the
      cyclooxygenase inhibitor sulindac can protect against ultraviolet (UVB)-induced
      injury that is crucial for the induction of cancer. Exposure of SKH-1 hairless
      mice to two consecutive doses of UVB (230 mJ/cm2) induces various inflammatory
      responses including erythema, edema, epidermal hyperplasia, infiltration of
      polymorphonuclear leukocytes, etc. Topical application of sulindac (1.25-5.0
      mg/0.2 ml acetone) to the dorsal skin of SKH-1 hairless mice either 1 h before or
      immediately after UVB exposure substantially inhibited these inflammatory
      responses in a dose-dependent manner. Oral administration of sulindac in drinking
      water (160 ppm) for 15 days before and during UVB irradiation similarly reduced
      these inflammatory responses. These potent anti-inflammatory effects of sulindac
      suggested the possibility that the drug could inhibit signaling processes that
      relate to carcinogenic insult by UVB. Accordingly, studies were conducted to
      assess the efficacy of sulindac in attenuating the expression of UVB-induced
      early surrogate molecular markers of photodamage and carcinogenesis. UVB exposure
      enhanced the expression of p53, c-fos, cyclins D1 and A, and PCNA 24 h after
      irradiation. Treatment of animals with either topical or oral administration of
      sulindac largely abrogated the expression of these UVB-induced surrogate markers.
      These results indicate that the cyclooxygenase inhibitor sulindac is effective in
      reducing UVB-induced events relevant to carcinogenesis and that this category of
      topically applied or orally administered drugs may prove to be effective
      chemopreventive agents for reducing the risk of photocarcinogenesis in human
      populations.

PMID- 15020201
TI  - Quantification of anti-angiogenesis using the capillaries of the chick
      chorioallantoic membrane demonstrates that the effect of human angiostatin is age
      dependent.
AB  - We present a method whereby en face estimation of the chorionic capillary plexus
      can be generated in the living chick chorioallantoic membrane (CAM) and confirmed
      by post-fixation cross section analysis. This value does not alter significantly
      with age and provides a reliable and simple method to evaluate anti-angiogenesis.
      Anti-angiogenesis may be induced by an intervention, such as a pharmacological
      agent, applied to the surface of the CAM. We describe the use of silastic rings
      that are associated with minimal inflammatory reaction, in this process. By
      estimating changes in the chorionic capillary plexus to quantify anti
      angiogenesis, together with silastic rings, we examined the anti-angiogenic
      effect of human angiostatin and demonstrated that although there is a significant
      loss of capillaries en face after exposure from days 7 to 9 of incubation, in
      contrast there is no significant inhibition after exposure to a similar dose of
      angiostatin from days 11 to 13 of incubation. This not only demonstrates the
      important effects on neo-angiogenesis compared to mature vessels, but also
      illustrates the potential of the CAM to readily provide a means for such a
      comparison.

PMID- 15020203
TI  - Blood transit time heterogeneity is associated to oxygen extraction in exercising
      human skeletal muscle.
AB  - Capillary transit time and its heterogeneity have a marked impact on oxygen
      extraction in different tissues. Animal studies have shown that exercise shortens
      capillary transit time but the effects on capillary transit time heterogeneity
      have been controversial. We investigated whether exercise changes muscle blood
      transit time heterogeneity in humans in vivo and whether this heterogeneity
      correlates to muscle oxygen extraction. Muscle blood flow, blood volume, and
      oxygen uptake were measured during rest and low-intensity exercise in 12 healthy
      men using positron emission tomography (PET). Blood transit time was calculated
      from parametric PET images voxel by voxel by dividing blood volume with blood
      flow. Oxygen extraction was calculated by nonlinear fitting from dynamic 15O-O2
      data. Relative dispersion (=SD/mean) was calculated as an index of heterogeneity
      of blood volume and blood transit time. As expected, exercise significantly
      shortened blood transit time and increased oxygen extraction. Furthermore,
      exercise decreased transit time heterogeneity (from 47 +/- 9% to 39 +/- 10%,
      P=0.07). Transit time heterogeneity correlated inversely to oxygen extraction in
      the exercising (r=-0.76, P=0.004) but not in the resting muscle (r=0.04, P=0.89).
      These results show that even low-intensity exercise shortens blood transit time
      markedly and decreases its heterogeneity in human skeletal muscle in vivo.
      Findings in correlation analyses suggest that less heterogeneous blood transit
      time associates to better muscle oxygen extraction during exercise. This may have
      effects on muscle oxygenation during exercise.

PMID- 15020202
TI  - A new image analysis method based on topological and fractal parameters to
      evaluate the angiostatic activity of docetaxel by using the Matrigel assay in
      vitro.
AB  - Angiogenesis is regulated both by positive and negative factors that modulate the
      migration, proliferation, proteolytic activity, and differentiation of
      endothelial cells. Various in vivo and in vitro models have been developed to
      test the effect of angiogenic agonists or antagonists. Until very recently,
      morphometric methods to evaluate the effects of angiogenic inducers and
      inhibitors were mostly descriptive. Here, we have described a new, automatic,
      image analysis method to evaluate the angiostatic activity of docetaxel by using
      the in vitro Matrigel assay. This method allows to establish several parameters,
      such as dimensional (area % covered by endothelial cells and the total length of
      the cellular network per field), topological (the number of meshes and the number
      of branching points per field), and fractal (fractal dimension, lacunarity) of
      the capillary-like network. Following docetaxel treatment, a reduction of about
      25% in the size parameters of cell network, of about 45% in branching points per
      field, and more 50% in mesh number were observed. The resulting fractal analysis
      was consistent with these findings and fractal dimension significantly correlated
      with both the number of branching points and the number of meshes. These results
      indicate that both topological and fractal parameters allowed a characterization
      of the spatial texture generated by endothelial cells during in vitro
      angiogenesis, the former being easier to implement in a computer program and
      faster to calculate. Finally, topological parameters seem to exhibit a wider
      dynamic range than the fractal ones.

PMID- 15020204
TI  - Rheological properties of erythrocytes from male hypercholesterolemia.
AB  - Diet and general health status has close relation to the flow behavior of blood,
      which influences the circulation of the blood in the body. In this study, we have
      compared the rheological properties of erythrocyte, plasma and whole blood from
      high-cholesterol male subjects with healthy male subjects. Intravenous blood was
      taken from healthy males (n=10) and males with high cholesterol (n=14). Basic
      health profile, BMI, hematological count and lipid profile (total cholesterol,
      LDL, HDL and triglyceride) of the blood were determined. Viscosity and shear rate
      dependent flow behavior of the subjects blood were measured by cone and plate
      rheometer, and permeability of erythrocytes by pulsed field gradient NMR. Using
      the microchannel flow analyzer (MC-FAN), the microcirculation of erythrocyte and
      plasma were investigated. Our data showed a difference in viscosity and
      consistency index of the whole blood, and permeability (P<0.05) of erythrocytes
      between the two groups. Also, the time taken for the flow of erythrocyte and
      plasma through the MC-FAN was slower for the high-cholesterol group. Correlation
      study showed that consistency index of the blood is closely related to the level
      of LDL (P<0.05), and total cholesterol, HDL and LDL (P<0.01) highly correlated
      with the microcirculation of erythrocyte and plasma. A negative correlation
      (P<0.05) was found between total cholesterol, HDL and LDL, and permeability of
      erythrocytes. It is concluded that high level of cholesterol, LDL and HDL in vivo
      alter the morphology and flow behavior of blood cells that can subsequently
      increase the risk of impairing physical function and microcirculation.

PMID- 15020206
TI  - Evaluation of peripheral arterial occlusive disease and postsurgical viability
      using reflectance spectroscopy of skin.
AB  - HYPOTHESIS: Stress-induced changes in skin microcirculation allow staging of
      peripheral arterial vascular pathology using diffuse reflectance spectroscopy
      (DRS) of the skin. DESIGN AND METHODS: The changes in relative concentration of
      oxyhemoglobin and deoxyhemoglobin in the cutaneous microvasculature were assessed
      at rest, during limb elevation, dependency, and cuff-mediated reactive hyperemia
      for the forearm of 25 normal subjects and 105 feet of patients with peripheral
      arterial occlusive disease (PAOD) (normal=28, claudication=34, limb threatening
      ischemia=44). Thirty-four patients who had revascularization procedures were
      again evaluated within the first week postoperatively. RESULTS: Two measurements
      correlated with clinical staging: (1) the relative absorbance of oxyhemoglobin
      after 225 s of limb dependency and (2) the time to reach 50% of peak reactive
      hyperemia response (Spearman's rank: rs=0.625, P<0.001). Using these criteria
      alone, ischemic limbs were identified to a sensitivity of 69% and specificity of
      95%. Significant post-revascularization improvement was identified in 14 of 34
      patients' legs which had previously been classified as limb-threatening ischemia
      (n=14, W=105, P<0.001). CONCLUSIONS: These simple bedside evaluations of the
      superficial skin microvasculature allow staging of large vessel vascular
      insufficiency and may suggest and differentiate focal areas of tissue at risk for
      ulceration or necrosis.

PMID- 15020205
TI  - Structural and functional characteristics of lung macro- and microvascular
      endothelial cell phenotypes.
AB  - Lung macro- and microvascular endothelial cells exhibit unique functional
      attributes, including signal transduction and barrier properties. We therefore
      sought to identify structural and functional features of endothelial cells that
      discriminate their phenotypes in the fully differentiated lung. Rat lung macro-
      (PAEC) and microvascular (PMVEC) endothelial cells each exhibited expression of
      typical markers. Screening for reactivity with nine different lectins revealed
      that Glycine max and Griffonia (Bandeiraea) simplicifolia preferentially bound
      microvascular endothelia whereas Helix pomatia preferentially bound macrovascular
      endothelia. Apposition between the apical plasmalemma and endoplasmic reticulum
      was closer in PAECs (8 nm) than in PMVECs (87 nm), implicating this coupling
      distance in the larger store operated calcium entry responses observed in
      macrovascular cells. PMVECs exhibited a faster growth rate than did PAECs and,
      once a growth program was initiated by serum, PMVECs sustained growth in the
      absence of serum. Thus, PAECs and PMVECs differ in their structure and function,
      even under similar environmental conditions.

PMID- 15020207
TI  - Enhanced production and action of cyclic ADP-ribose during oxidative stress in
      small bovine coronary arterial smooth muscle.
AB  - Recent studies in our lab and by others have indicated that cyclic ADP-ribose
      (cADPR) as a novel second messenger is importantly involved in vasomotor response
      in various vascular beds. However, the mechanism regulating cADPR production and
      actions remains poorly understood. The present study determined whether changes
      in redox status influence the production and action of cADPR in coronary arterial
      smooth muscle cells (CASMCs) and thereby alters vascular tone in these arteries.
      HPLC analyses demonstrated that xanthine (X, 40 microM)/xanthine oxidase (XO, 0.1
      U/ml), a superoxide-generating system, increased the ADP-ribosyl cyclase activity
      by 59% in freshly isolated bovine CASMCs. However, hydrogen peroxide (H2O2, 1-100
      microM) had no significant effect on ADP-ribosyl cyclase activity. In these
      CASMCs, X/XO produced a rapid increase in [Ca2+]i (Delta[Ca2+]i=201 nM), which
      was significantly attenuated by a cADPR antagonist, 8-Br-cADPR. Both inhibition
      of cADPR production by nicotinamide (Nicot) and blockade of Ca2+-induced Ca2+
      release (CICR) by tetracaine (TC) and ryanodine (Rya) significantly reduced X/XO
      induced rapid Ca2+ responses. In isolated, perfused, and pressurized small bovine
      coronary arteries, X at 2.5-80 microM with a fixed XO level produced a
      concentration-dependent vasoconstriction with a maximal decrease in arterial
      diameter of 45%. This X/XO-induced vasoconstriction was significantly attenuated
      by 8-Br-cADPR, Nicot, TC, or Rya. We conclude that superoxide activates cADPR
      production, and thereby mobilizes intracellular Ca2+ from the SR and produces
      vasoconstriction in coronary arteries.

PMID- 15020208
TI  - Functional modulation of smooth muscle cells by the inflammatory mediator CAP37.
AB  - CAP37, a neutrophil-derived protein, originally identified for its antimicrobial
      activity is now known to have strong immunoregulatory effects on host cells.
      Recently, we described its expression and localization within the vascular
      endothelium associated with atherosclerotic plaques. Since CAP37 is a potent
      activator of endothelial cells and monocytes, two of the key cellular components
      of the atherosclerotic plaque, this study was undertaken to determine whether
      CAP37 had functional effects on smooth muscle cells another important cellular
      participant in atherosclerosis. Sections from atherosclerotic lesions were
      stained for the presence of CAP37 and smooth muscle cell alpha actin. The effect
      of CAP37 on aorta smooth muscle cell migration and proliferation was investigated
      and the upregulation of adhesion molecules was determined. Immunocytochemistry
      indicated that CAP37 was present in a subset of smooth muscle cells within
      atherosclerotic lesions, but was absent in normal vessels. Flow cytometry using
      double labeling for the proliferation marker Ki-67 and CAP37 demonstrates that
      CAP37 is mainly expressed in proliferating smooth muscle cells. We show that
      CAP37 supports migration and proliferation of smooth muscle cells in vitro.
      Furthermore, CAP37-treated smooth muscle cells expressed higher levels of the
      cell adhesion molecule ICAM-1 when compared with untreated cells. We suggest that
      due to its localization to atherosclerotic plaques and its ability to modulate
      smooth muscle cells, CAP37 may play a role in the progression of this disease.

PMID- 15020209
TI  - C1-inhibitor reduces hepatic leukocyte-endothelial interaction and the expression
      of VCAM-1 in LPS-induced sepsis in the rat.
AB  - INTRODUCTION: Increased leukocyte-endothelial interaction (LEI) leading to
      hepatic microperfusion disorders is proposed as major contributor for hepatic
      failure during sepsis. Recently it has been demonstrated that complement
      inhibition by C1-inhibitor (C1-INH) is an effective treatment against
      microcirculatory disturbances in various diseases. The purpose of this study was
      to investigate the influence of C1-INH on microcirculation and LEI in the liver
      in a rat model of sepsis. MATERIALS AND METHODS: Rats received
      lipopolysaccharides (LPS) from Escherichia coli intravenously. Controls received
      Ringer solution only. Ninety minutes after LPS infusion some animals were treated
      with C1-INH intravenously (LPS + C1-INH). Others (LPS + SC) and controls (Ringer
      + SC) received sodium chloride (SC). Hepatic LEI and mean erythrocyte velocity
      (MEV) were quantified by intravital microscopy (IVM) 90 min after LPS or Ringer
      infusion (0) and 30, 60, 90 and 120 min following treatment. VCAM-1 m-RNA in
      hepatic tissue, C3a, TNF-alpha and hepatic enzyme liberation in blood was
      analysed. RESULTS: Leukocyte sticking to the endothelial wall in postsinusoidal
      venules was significantly reduced in the LPS + C1-INH vs. the LPS + SC group 30,
      60, 90 and 120 min after treatment. VCAM-1 m-RNA expression in the hepatic tissue
      was markedly and C3a levels in plasma were significantly reduced in the LPS + C1
      INH vs. the LPS + SC group. No differences in TNF-alpha levels were detected
      between these two groups. MEV was improved in the LPS + C1-INH vs. the LPS + SC
      group. CONCLUSIONS: Our results indicate that even upon delayed treatment hepatic
      adhesion molecule expression and LEI can be reduced by C1-INH. The
      multifunctional regulator may reduce hepatic microcirculatory disturbances during
      sepsis under clinical conditions.

PMID- 15020210
TI  - Role of histamine release in nonspecific vasodilatation during anodal and
      cathodal iontophoresis.
AB  - Nonspecific vasodilatation during iontophoresis is an important confounding
      factor in experimental pharmacology. In this investigation, we studied the
      involvement of sensory nerves and histamine-related reactions in causing
      nonspecific vasodilatation in a model of anodal and cathodal iontophoresis of
      sodium chloride. Firstly, we applied a mixture of local anesthetic (EMLA) cream
      to confirm its suppressive effect on nonspecific vasodilatation and to measure
      its efficacy in three different dosages (duration: 1, 2, and 3 h). We then
      investigated the role of histamine in nonspecific vasodilatation by giving an
      oral antihistamine drug (cetirizine) to subjects who had and had not been given
      EMLA. We found substantial suppression of the nonspecific vasodilatation in all
      EMLA-treated groups (all dosages) compared with untreated controls (with
      suppression rates of 60-65%). Dosage had no significant effect. A further
      suppression of nonspecific vasodilatation was seen after oral cetirizine during
      anodal and cathodal iontophoresis in both EMLA-treated and untreated groups. The
      antihistamine effect was most pronounced during anodal iontophoresis. These
      results suggest a histaminergic increase in perfusion that may be independent of
      neurogenic mechanisms and depend on polarity (anode or cathode). Local nerve
      blocks (EMLA) together with cetirizine may therefore be used to reduce
      nonspecific vasodilatation in both anodal and cathodal iontophoresis.

PMID- 15020211
TI  - A protocol for iontophoresis of acetylcholine and sodium nitroprusside that
      minimises nonspecific vasodilatory effects.
AB  - Iontophoresis of vasoactive substances is a promising tool for studying
      pharmacological aspects of the (patho)physiology of the microvasculature.
      However, nonspecific microvascular responses are a common problem in most
      protocols used. We studied the effect of current density (mA/cm2), charge density
      (mC/cm2), drug concentration (mass %) and vehicle concentration (M) on the
      nonspecific vasodilatation during iontophoresis of sodium chloride, acetylcholine
      (ACh) and sodium nitroprusside (SNP). We found that nonspecific vasodilatation
      depended on current density and charge density in both anodal and cathodal
      iontophoresis. The responses to ACh and SNP were dependent on current density,
      charge density and drug concentration. We found that by limiting current density
      (<0.01 mA/cm2) and charge density (<7.8 mC/cm2) and with adjusted concentrations
      for drugs and vehicles, it is possible to prevent nonspecific effects during
      iontophoresis of ACh and SNP, while maximum drug effects (plateaus in the dose
      response curves) are still obtained. These new findings are important for future
      iontophoresis studies in which vasoactive drugs are used to assess microvascular
      function because the presented approach has advantages compared to older
      techniques, which mainly have attempted to suppress or compensate for the
      nonspecific responses during iontophoresis by the use of local anaesthetics or
      the measurement of drug-minus-vehicle responses, both of which present well-known
      experimental shortcomings.

PMID- 15020213
TI  - Memory retrieval given two independent cues: cue selection or parallel access?
AB  - A basic but unresolved issue in the study of memory retrieval is whether multiple
      independent cues can be used concurrently (i.e., in parallel) to recall a single,
      common response. A number of empirical results, as well as potentially applicable
      theories, suggest that retrieval can proceed in parallel, though set forth a
      model that denies that possibility. In this paper, five quantitative models are
      developed to test broad candidate principles. In multiple experiments, subjects
      were trained to retrieve a vocal digit response for each member of a set of
      letter or color cues. In subsequent test and transfer phases, single cue trials
      were randomly mixed with dual cue trials on which the two cues always required
      the same response. For the first few repetitions of each new set of dual cue
      items, there was no evidence of parallel retrieval over any part of the RT
      distribution. After more repetitions, dual cue trials were performed faster than
      single cue trials, but only under conditions that were favorable to development
      of a "chunked" dual cue representation. These results indicate that associative
      independence is an important modulating variable that must be heeded in any
      general model of attention and memory retrieval. Further, the results are most
      consistent with a model that places the performance bottleneck prior to the
      retrieval stage of processing.

PMID- 15020212
TI  - Low skin temperature impairs the cutaneous vasodilator response to local
      progressive pressure strain.
AB  - A pressure-induced vasodilation (PIV) was recently reported as a putative
      protective response in human skin. Therefore, we examined the influence of skin
      temperatures on cutaneous blood flow responses to local progressive pressure
      strain. Ten healthy volunteers were studied at different ambient temperatures
      leading to low (29.0 +/- 0.3 degrees C), intermediate (32.6 +/- 0.1 degrees C),
      high (33.9 +/- 0.1 degrees C) and very high (36.0 +/- 0.1 degrees C) skin
      temperatures. We measured cutaneous blood flow using laser Doppler flowmetry on
      the foot in response to a local progressive pressure increase of 5.0 mm Hg min(
      1). Progressive pressure strain led to an almost linear cutaneous laser Doppler
      flow decrease at both low and intermediate skin temperatures (-40.1 +/- 6.6% and 
      31.2 +/- 6.5% from baseline at 30 +/- 1.25 mm Hg), whereas at both high and very
      high skin temperatures, subjects responded with a transient cutaneous
      vasodilation (+33.6 +/- 10.6% and +50.6 +/- 15.4% from baseline at 30 +/- 1.25 mm
      Hg). These findings suggest that high skin temperatures are required for the PIV
      to develop.

PMID- 15020214
TI  - Heuristics as beliefs and as behaviors: the adaptiveness of the "hot hand".
AB  - and analyzed reasoning by asking: what are the reasoner's goals? This emphasizes
      the adaptiveness of behavior rather than whether a belief is normative. Belief in
      the "hot hand" in basketball suggests that players experiencing streaks should be
      given more shots, but this has been seen as a fallacy due to failure to find
      dependencies between players' shots. Based on their findings, I demonstrate by
      Markov modeling and simulation that streaks are valid allocation cues for
      deciding who to give shots to, because this behavior achieves the team goal of
      scoring more. Empirically I show that this adaptive heuristic is supported by the
      fallacious belief in dependency, more so as skill level increases. I extend the
      theoretical analysis to identify general conditions under which following streaks
      should be beneficial. Overall, this approach illustrates the advantages of
      analyzing reasoning in terms of adaptiveness.

PMID- 15020215
TI  - A model for evidence accumulation in the lexical decision task.
AB  - We present a new model for lexical decision, REM-LD, that is based on REM theory
      (e.g., ). REM-LD uses a principled (i.e., Bayes' rule) decision process that
      simultaneously considers the diagnosticity of the evidence for the 'WORD'
      response and the 'NONWORD' response. The model calculates the odds ratio that the
      presented stimulus is a word or a nonword by averaging likelihood ratios for
      lexical entries from a small neighborhood of similar words. We report two
      experiments that used a signal-to-respond paradigm to obtain information about
      the time course of lexical processing. Experiment 1 verified the prediction of
      the model that the frequency of the word stimuli affects performance for nonword
      stimuli. Experiment 2 was done to study the effects of nonword lexicality, word
      frequency, and repetition priming and to demonstrate how REM-LD can account for
      the observed results. We discuss how REM-LD could be extended to account for
      effects of phonology such as the pseudohomophone effect, and how REM-LD can
      predict response times in the traditional 'respond-when-ready' paradigm.

PMID- 15020216
TI  - Temperature-dependent subunit exchange and chaperone-like activities of Hsp16.3,
      a small heat shock protein from Mycobacterium tuberculosis.
AB  - Small heat shock proteins (sHsps) usually exist as oligomers that undergo dynamic
      oligomeric dissociation/re-association, with the dissociated oligomers as active
      forms to bind substrate proteins under heat shock conditions. In this study,
      however, we found that Hsp16.3, one sHsp from Mycobacterium tuberculosis, is able
      to sensitively modulate its chaperone-like activity in a range of physiological
      temperatures (from 25 to 37.5 degrees C) while its native oligomeric size is
      still maintained. Further analysis demonstrated that Hsp16.3 exposes higher
      hydrophobic surfaces upon temperatures increasing and that a large soluble
      complex between Hsp16.3 and substrate is formed only in the condition of heating
      temperature up to 35 and 37.5 degrees C. Structural analysis by fluorescence
      anisotropy showed that Hsp16.3 nonameric structure becomes more dynamic and
      variable at elevated temperatures. Moreover, subunit exchange between Hsp16.3
      oligomers was found to occur faster upon temperatures increasing as revealed by
      fluorescence energy resonance transfer. These observations indicate that Hsp16.3
      is able to modulate its chaperone activity by adjusting the dynamics of
      oligomeric dissociation/re-association process while maintaining its static
      oligomeric size unchangeable. A kinetic model is therefore proposed to explain
      the mechanism of sHsps-binding substrate proteins through oligomeric
      dissociation. The present study also implied that Hsp16.3 is at least capable of
      binding non-native proteins in vivo while expressing in the host organism that
      survives at 37 degrees C.

PMID- 15020218
TI  - Dexras1 inhibits adenylyl cyclase.
AB  - Dexras1 is a steroid hormone-induced Ras family G protein that acts as a receptor
      independent activator of signaling by Gi/o family heterotrimeric G proteins. We
      examined the effects of Dexras1 on the activity of adenylyl cylase, a target of
      inhibitory regulation by Gialpha x GTP. Constitutively active Gsalpha (Q227L)
      increased cAMP levels 43-fold above baseline, and Dexras1 expression inhibited
      cAMP levels by 61% (P < 0.01). Dexras1 mediated inhibition of adenylyl cyclase
      was blocked by treatment pertussis toxin or by co-expression of RGS4, but was not
      inhibited by with dominant-interfering (G203T or G204A) mutants of Gi alpha2.
      Dexras1 decreased forskolin-stimulated CREB activation (P < 0.01) and this
      activity was also inhibited by co-expression of RGS4. These findings indicate
      that Dexras1 expression leads to ligand-independent activation of both Gialpha-
      and G(beta)gamma-dependent arms of the Gi signaling cascade, and suggest that
      Dexras1 may exert physiologically relevant inhibitory effects on the cAMP-PKA
      CREB.

PMID- 15020217
TI  - Identification of a sodium-dependent organic anion transporter from rat adrenal
      gland.
AB  - In this study, a novel sodium-dependent organic anion transporter (Soat) was
      identified. Soat is expressed in rat brain, heart, kidney, lung, muscle, spleen,
      testis, adrenal gland, small intestine, and colon. The Soat protein consists of
      370 amino acids and shows 42% and 31% overall amino acid sequence identity to the
      ileal sodium-dependent bile acid transporter (Isbt) and the Na(+)/taurocholate
      cotransporting polypeptide (Ntcp), respectively. Soat is predicted to have nine
      transmembrane domains, with an N-terminus outside the cell and an intracellular C
      terminus. The Soat gene is localized on chromosome 14 and is coded by six exons
      mapped in region 14p22. When expressed in Xenopus laevis oocytes, Soat shows
      transport function for estrone-3-sulfate (Km = 31 microM, Vmax = 5557
      fmol/oocyte/30 min) and dehydroepiandrosterone sulfate (Km = 30 microM, Vmax =
      5682 fmol/oocyte/30 min). Soat does not transport taurocholate, estradiol-17beta
      glucuronide, nor ouabain.

PMID- 15020219
TI  - Direct measurements of the compressive properties of single proteoglycan
      aggregates.
AB  - Proteoglycan aggregate is a major component of the extracellular matrix in
      articular cartilage and is considered to be responsible for the resistance to
      compression of this tissue. The reduced stiffness of articular cartilage due to
      the loss of proteoglycan aggregate has been reported in osteoarthritis. In order
      to understand the mechanical properties of extracellular matrix in articular
      cartilage at molecular level, the compressive properties of 36 single molecules
      of proteoglycan aggregate were directly measured using a laser
      tweezers/interferometer system. The proteoglycan aggregates showed resistance
      when compressed to approximately 30% of their contour length. The stiffness of
      proteoglycan aggregates increased non-linearly from 2.6+/-3.8 pN/microm
      (compressed to 30-35% of their contour length) to 115.5+/-30.9 pN/microm
      (compressed to 2.5-5% of their contour length).

PMID- 15020220
TI  - Intermediate filament steady-state mRNA levels in amyotrophic lateral sclerosis.
AB  - We have examined the steady-state levels of intermediate filament mRNA in
      amyotrophic lateral sclerosis using the RNAse protection assay (NFL, NFM, NFH;
      corrected against GAPDH) or by PCR (peripherin, alpha-internexin, nestin, and
      vimentin; corrected against beta-actin). Significant elevations of NFL and
      peripherin mRNA levels were observed within the ALS cervical and lumbar spinal
      cord, with all other IF mRNA levels being comparable between control and ALS
      cases. These findings suggest that disturbances in both NFL and peripherin
      expression, independently known to contribute to the generation of motor neuron
      dysfunction in transgenic mice, are evident in ALS.

PMID- 15020221
TI  - Lysophospholipase A activity of Pseudomonas aeruginosa type III secretory toxin
      ExoU.
AB  - Acute lung injury in Pseudomonas aeruginosa pneumonia depends primarily on ExoU
      that is delivered directly into the eukaryotic cell via the type III secretion
      system. Recent studies demonstrated that ExoU has lipase activity, and that the
      cytotoxicity of ExoU is dependent on its patatin-like phospholipase domain. We
      investigated the phospholipase A (PLA) activity of ExoU. ExoU, but not non
      catalytic ExoU-S142A, preincubated with the BEAS-2B cell lysate showed a weak
      increase of Ca(2+)-independent PLA(2) activity. When activated ExoU was mixed
      with secretory type PLA(2), more phospholipase activity was observed, suggesting
      that ExoU has lysophospholipase A (lysoPLA) activity. A significant increase in
      lysoPLA activity was also observed. Glycerol enhanced this activity and
      inhibitors of iPLA(2) suppressed ExoU's lysoPLA activity. Our results suggest
      that ExoU has a potent lysoPLA activity that requires the presence of the
      catalytically active site Ser(142) with an unknown eukaryotic cell factor(s) for
      its activation.

PMID- 15020222
TI  - Stimulation of beta-amyloid precursor protein alpha-processing by phorbol ester
      involves calcium and calpain activation.
AB  - Normal processing of Alzheimer's beta-amyloid precursor protein (APP) is markedly
      stimulated by phorbol esters, but the underlying mechanisms have yet to be fully
      understood. In this study, we observed that: (a) Phorbol 12,13-dibutyrate (PDBu)
      stimulated APP secretion in cultured SH-SY5Y neuroblastoma and fibroblast cells
      was blocked by EGTA and calpain inhibitors in a concentration-dependent manner,
      but not by other protease inhibitors. (b) Secretion of fibronectin, another
      secretory protein tested for comparison, was enhanced by PDBu, but insensitive to
      calpain inhibitors. (c) PDBu stimulated intracellular calpain activity as
      measured by the hydrolysis of a fluorogenic calpain substrate. (d) PDBu also
      induced rapid proteolysis of two endogenous substrates of calpains, i.e., tau and
      microtubule-associated protein-2 (MAP-2) and the proteolysis was blocked by EGTA
      and calpain inhibitors. Taken together, these results suggest that stimulation of
      APP alpha-processing by PDBu is through a mechanism that involves the activation
      of Ca(2+) and, most notably, calpain. The implications of the findings are
      discussed in relation to the regulatory mechanism of APP alpha-processing.

PMID- 15020223
TI  - In vivo two-photon laser-scanning microscopy of Ca2+ dynamics in visual motion
      sensitive neurons.
AB  - We applied two-photon laser-scanning microscopy (TPLSM) to motion-sensitive
      visual interneurons of the fly to study Ca(2+) dynamics in vivo at a higher
      spatial and temporal resolution than possible with conventional fluorescence
      microscopy. Based on a custom-built two-photon microscope, we performed line
      scans to measure changes in presynaptic Ca(2+) concentrations elicited by visual
      stimulation. We used a fast avalanche photodiode (APD) with a high quantum
      efficiency to detect even low levels of emitted fluorescence. Our experiments
      show that our in vivo preparation is amenable to TPLSM: with excitation
      intensities low enough not to cause photodamage, activity-dependent fluorescence
      changes of Ca(2+)-sensitive dyes can be detected in small neuronal branches. The
      performance of two-photon and conventional Ca(2+) imaging carried out
      consecutively at the same neuron is compared and it is demonstrated that two
      photon imaging allows us to detect differences in Ca(2+) dynamics between
      individual neurites.

PMID- 15020224
TI  - Compound K induces expression of hyaluronan synthase 2 gene in transformed human
      keratinocytes and increases hyaluronan in hairless mouse skin.
AB  - Ginsenosides, the major active ingredients of ginseng, have a variety of
      biomedical efficacies such as anti-aging, anti-oxidation, and anti-inflammatory
      activities. To understand the effects of compound K (20-O-beta-D-glucopyranosyl
      20(S)-protopanaxadiol), one of the major metabolites of ginsenosides, on the
      skin, we assessed the expression levels of about 100 transcripts in compound K
      treated HaCaT cells using cDNA microarray analysis. One gene up-regulated by
      compound K was hyaluronan synthase2 (HAS2). Semi-quantitative RT-PCR showed that
      compound K increased HAS2 mRNA in time- and dose-dependent manners. ELISA and
      immunocytochemistry using hyaluronan (HA)-binding protein showed that compound K
      effectively increased HA production in HaCaT cells. Finally, treatment of
      compound K on hairless mouse skin increased the amount of HA in the epidermis and
      papillary dermis. Our study suggests that topical application of compound K might
      prevent or improve the deteriorations, such as xerosis and wrinkles, partly
      ascribed to the age-dependent decrease of the HA content in human skin.

PMID- 15020225
TI  - Resistance to viral infection by intraepithelial lymphocytes in HIV-1 P18-I10
      specific T-cell receptor transgenic mice.
AB  - For the analysis of mucosal immunity to HIV-1, we have recently established a
      line of transgenic (Tg) mice expressing the TCRalpha and TCRbeta genes of the
      murine CTL clone RT1 specific for P18-I10 (RGPGRAFVTI), an immunodominant gp160
      envelope-derived epitope of IIIB isolate, restricted by the H-2D(d) MHC-I
      molecule. Here we examine those cells bearing specific TCR among the
      intraepithelial lymphocytes (IELs), with flow cytometric analysis using H
      2D(d)/P18-I10 tetramers. We observed three distinct CD3(+), tetramer positive
      populations among the IELs: extra-thymic CD8alphabeta(+), alphabetaTCR T-cells;
      CD8 alphaalpha+, gammadeltaTCR T-cells; and thymus-derived CD8alphabeta+,
      alphabetaTCR T-cells. Challenge of these Tg mice with P18-I10 encoded by a
      vaccinia virus vector, either intrarectally (i.r.) or intraperitoneally (i.p.),
      revealed that the intraepithelial compartment seems to be a major site for
      prevention of the spread of viral infection. Such immunity appears due to the
      thymus-derived, CD8alphabeta+ antigen-specific CTLs together with CD8alphaalpha+
      gammadelta cells, which regulate virus spread. This model system for studying CTL
      based immunity at mucosal sites should prove helpful in developing rational
      approaches for HIV control.

PMID- 15020226
TI  - MUC1 can interact with adenomatous polyposis coli in breast cancer.
AB  - The MUC1 tumor antigen is overexpressed on most breast tumors and metastases. It
      interacts with signaling proteins such as the ErbB kinases and beta-catenin, and
      is involved in mammary gland oncogenesis and tumor progression. Herein, we report
      a novel interaction between MUC1 and adenomatous polyposis coli (APC), a tumor
      suppressor involved in downregulating beta-catenin signaling. Initially
      identified in colorectal cancer, APC is also downregulated in breast tumors and
      presumably involved in mammary carcinogenesis. MUC1 and APC co-immunoprecipitate
      from the ZR-75-1 human breast carcinoma cell line and co-localize in mouse
      mammary glands and tumors. These studies also indicate that the association of
      MUC1 and APC may be increased by epidermal growth factor stimulation.
      Intriguingly, the co-immunoprecipitation of MUC1 and APC increases in human
      breast tumors and metastases as compared to adjacent normal tissues, indicating
      that this association may play a role in the formation and progression of breast
      tumors.

PMID- 15020227
TI  - Hg2+ and small-sized polyethylene glycols have inverse effects on membrane
      permeability, while both impair neutrophil cell motility.
AB  - Toxic effects after exposure to mercury are well documented in human. Little is,
      however, known about how Hg(2+) affect host defense in general and neutrophil
      functions in particular. We show here that exposure of human neutrophils to
      HgCl(2) dose-dependently impairs chemoattractant-stimulated motility. Long-term
      exposure (5-10 min) to Hg(2+) yields a rapid influx of extracellular Ca(2+)
      followed by leakage of cytosolic fluorophores, as assessed using fura-2 and ratio
      imaging microscopy. The inhibition on motility was partly reversible, since pre
      treated neutrophils placed in an Hg(2+)-free environment displayed higher
      migration rates. The Hg(2+)-induced fluxes were prevented by addition of small
      sized polyethylene glycols (PEG 200-400), which also dose-dependently inhibited
      neutrophil transmigration. Localized, minute micropipette additions of Hg(2+) or
      PEG caused retraction of the leading edge and redirection of cell migration.
      Since Hg(2+) increases and PEGs decrease membrane permeability in a partially
      competitive manner, we suggest that the known aquaporin-inhibitor Hg(2+) alters
      membrane permeability by affecting the bidirectional flux through the leukocyte
      aquaporin-9 (AQP9) while small-sized PEGs yield decreased membrane permeability
      by becoming trapped in the promiscuous channel. The local additions of Hg(2+) or
      PEG probably force other cell regions to take over from those with blocked AQPs.
      Hence, the cells turn direction of motility away from the micromanipulator
      needle.

PMID- 15020228
TI  - Characterization of the calcium-binding sites of Listeria monocytogenes InlB.
AB  - The Listeria monocytogenes protein InlB promotes invasion of mammalian cells
      through activation of the receptor tyrosine kinase Met. The InlB N-cap, a
      approximately 40 residue part of the domain that binds Met, was previously
      observed to bind two calcium ions in a novel and unusually exposed manner.
      Because subsequent work raised questions about the existence of these calcium
      binding sites, we assayed calcium binding in solution to the InlB N-cap. We show
      that calcium ions are bound with dissociation constants in the low micromolar
      range at the two identified sites, and that the sites interact with one another.
      We demonstrate that the calcium ions are not required for structure, and also
      find that they have no appreciable effect on Met activation or intracellular
      invasion. Therefore, our results indicate that the sites are fortuitous in InlB,
      but also suggest that the simple architecture of the sites may be adaptable for
      protein engineering purposes.

PMID- 15020229
TI  - Retinoic acid-induced differentiation into astrocytes and glutamatergic neurons
      is associated with expression of functional and activable phospholipase D.
AB  - Phospholipase D (PLD) activity in mammalian cells has been associated with cell
      proliferation and differentiation. Here, we investigated the expression of PLD
      during differentiation of pluripotent embryonal carcinoma cells (P19) into
      astrocytes and neurons. Retinoic acid (RA)-induced differentiation increased PLD1
      and PLD2 mRNA levels and PLD activity that was responsive to phorbol myristate
      acetate. Various agonists of membrane receptors activated PLD in RA
      differentiated cells. Glutamate was a potent activator of PLD in neurons but not
      in astrocytes, whereas noradrenaline and carbachol increased PLD activity only in
      astrocytes. P19 neurons but not astrocytes released glutamate in response to a
      depolarizing stimulus, confirming the glutamatergic phenotype of these neurons.
      These results indicate upregulation of PLD gene expression associated with RA
      induced neural differentiation.

PMID- 15020230
TI  - Observation of multi-step conformation switching in beta-amyloid peptide
      aggregation by fluorescence resonance energy transfer.
AB  - We have observed the conformation switching of Abeta(11-25) in the course of
      amyloid aggregation by employing time-resolved fluorescence resonance energy
      transfer (FRET). The amyloid peptides undergo multi-step conformational changes
      during self-assembling such as random coil (monomers), collapsed coil
      (multimers), micellar structure, and extended beta-sheet in fibrils. We first
      identified the critical micelle concentration of Abeta(11-25) that occurs at ca.
      3 microM for pH 5.0 and ca. 70 microM for pH 7.4. Our experimental results show
      clearly that the end-to-end distance of micellar Abeta(11-25) becomes much
      shorter than that of the collapsed coil or fibril structure.

PMID- 15020231
TI  - Induction of cyclooxygenase-2 in macrophages by catalase: role of NF-kappaB and
      PI3K signaling pathways.
AB  - Induction of COX-2 by catalase in smooth muscle cells, endothelial cells, and
      neuronal cells has been previously reported. However, the mechanism by which
      catalase up-regulates COX-2 remains poorly understood. In this study, we
      investigated the effect of catalase on induction of COX-2 in macrophages. The
      addition of catalase into Raw 264.7 macrophages induced COX-2 expression that was
      correlated with increased COX-2 transcription and mRNA stability. Catalase also
      induced activation of NF-kappaB, PI3K, ERKs, p38s, or JNKs. Catalase-induced COX
      2 expression was abrogated by treatment of MG-132 (a NF-kappaB inhibitor) or
      LY294002 (a PI3K inhibitor), but not by treatment of PD98059 (an ERK inhibitor),
      SB203580 (a p38 inhibitor), or SP600125 (a JNK inhibitor). Moreover, inhibition
      of PI3K by LY294002 caused partial decrease of catalase-induced COX-2
      transcription and steady-state COX-2 transcript levels, but not COX-2 mRNA
      stability. Together, these results suggest that catalase induces the expression
      of COX-2 in Raw 264.7 macrophages, and the induction is related with activation
      of NF-kappaB transcription factor and PI3K signaling pathway.

PMID- 15020232
TI  - Mitosis increases levels of secretory leukocyte protease inhibitor in
      keratinocytes.
AB  - Chronic wounds are a major health care burden. Multiple factors produced by
      healing wounds play important roles in efficient and orderly wound healing.
      Secretory leukocyte protease inhibitor (SLPI) is constitutively expressed in
      epithelial cells, and its expression is increased by inflammation. SLPI has
      antimicrobial activities and improves wound healing. We hypothesized that SLPI
      expression correlates with keratinocyte growth rate and is increased by epidermal
      growth factor (EGF). Keratinocytes were isolated from neonatal foreskin.
      Subconfluent and confluent culture conditions were used. SLPI-specific primers
      were designed for use in quantitative-competitive reverse-transcription
      polymerase chain reaction assays to detect and quantify SLPI mRNA expression
      levels. SLPI levels were increased 2-fold in subconfluent cultures and 1.6-fold
      in confluent cultures to which EGF had been added. Confluent cultures also
      demonstrated 7-fold (growth factor depleted) and 6-fold (EGF) increase in SLPI
      RNA copy number, compared to subconfluent cultures. The results indicate that EGF
      increases SLPI expression.

PMID- 15020233
TI  - Glycogen synthase kinase-3beta is tyrosine-phosphorylated by MEK1 in human skin
      fibroblasts.
AB  - Glycogen synthase kinase-3beta (GSK-3beta) can be associated with several
      proteins in cell. We analyzed the immunoprecipitates by an anti-GSK-3beta
      antibody from cell lysate of human fibroblasts and found that this protein was co
      precipitated with mitogen-activated protein kinase kinase (MEK1/2). U0126, a
      MEK1/2 inhibitor, inhibited tyrosine phosphorylation of GSK-3beta, suggesting
      that MEK1/2 was involved in the phosphorylation of Tyr(216) in GSK-3beta. In
      vitro kinase assay was carried out using a recombinant human active MEK1 and we
      found that GSK-3beta was phosphorylated on Tyr(216) by this kinase in a dose- and
      time-dependent manner. Further, the pretreatment of fibroblasts with U0126
      inhibited serum-induced nuclear translocation of GSK-3beta. These results
      suggested that MEK1/2 induces tyrosine phosphorylation of GSK-3beta and this
      cellular event might induce nuclear translocation of GSK-3beta. This is the first
      report to suggest that MEK1/2 phosphorylates not only ERK1/2 but also GSK-3beta.

PMID- 15020234
TI  - Genetic variant Arg57His in human H+/peptide cotransporter 2 causes a complete
      loss of transport function.
AB  - We evaluated the functional consequences of genetic variations in human
      H(+)/peptide cotransporter 2 (hPEPT2, SLC15A2) resulting in the amino acid
      changes Arg57His (R57H) and Pro409Ser (P409S). The transport activity of variant
      R57H was completely abolished, whereas that of variant P409S was comparable with
      that of wild-type hPEPT2 at pH 5.0-8.0. R57H variant protein was detected in the
      crude membranes of transiently expressed HEK293 cells by Western blot analysis.
      The expression of the R57H variant at the plasma membrane was confirmed by
      indirect immunofluorescence in Xenopus oocytes, suggesting that the loss of
      transport function of hPEPT2 R57H was not due to a change in membrane protein
      expression. This is the first demonstration of a functional impairment of the
      SLC15A family induced by a single nucleotide polymorphism.

PMID- 15020236
TI  - Streptomyces lividans potassium channel KcsA is regulated by the potassium
      electrochemical gradient.
AB  - It is currently held that the Streptomyces lividans potassium channel, KcsA,
      requires an intracellular pH<5 to exhibit activity in planar lipid bilayers.
      Here, we show that KcsA functions well at normal physiological pH in the presence
      of a potassium electrochemical gradient. Single-channel conductance and open
      probability increased directly as the extracellular potassium concentration was
      decreased. Channel activity was sensitive to both the membrane potential and the
      size of the gradient, thus indicating that gating of the channel depends on both
      components of the electrochemical potential. When [K(+)(in)]/[K(+)(ex)] was 200
      mM/10 mM, chord conductance was 24pS with subconductance 15pS; open probability
      was 0.9. The permeability series was K(+) > Rb(+) >>> Cs(+); K(+) selectivity
      over Rb(+) was 1.2-fold and selectivity over Na(+) was 12-fold. The channels were
      disrupted by intracellular Na(+) and blocked by intracellular Ba(2+). A
      hypothetical supramolecular model for the channel is presented.

PMID- 15020235
TI  - Growth inhibition of breast epithelial cells by celecoxib is associated with
      upregulation of insulin-like growth factor binding protein-3 expression.
AB  - Several experimental and epidemiological studies have suggested a role for the
      use of cyclooxygenase (COX)-2 inhibitors in the prevention of breast cancer. The
      relative lack of toxicity associated with these compounds favors their use as
      chemopreventive agents, but the underlying mechanism of their chemopreventive
      effect remains unclear. We have observed that the COX-2 inhibitor celecoxib
      inhibits growth and induces apoptosis in the immortalized breast epithelial cell
      line 184htert. Microarray gene expression analysis of 184htert cells treated with
      50 microM celecoxib for 6h revealed the modulation of several genes of interest,
      including a significant induction of expression of the mRNA encoding insulin-like
      growth factor binding protein-3 (IGFBP-3). IGFBP-3 is a potent pro-apoptotic
      protein and growth inhibitor of breast cancer cells, which acts mainly by
      inhibiting the access of the mitogens IGF-I and IGF-II to their cell surface
      receptor, but also via IGF-independent effects. Quantitative real-time RT PCR
      demonstrated that 50 microM celecoxib induced a approximately 3-fold increase in
      expression of IGFBP-3 mRNA after 6h. Furthermore, ligand blot analysis revealed
      that celecoxib treatment was associated with the upregulation of IGFBP-3 at the
      protein level. IGFBP-3 (500 ng/ml) treatment of 184htert cells inhibited IGF-I
      and serum-induced proliferation, but had no effect on cell growth under serum
      free conditions, indicating that IGF-independent effects of IGFBP-3 are not
      observed in this system. Our results suggest that celecoxib may decrease IGF-I
      associated breast cancer risk by a mechanism involving induction of expression of
      IGFBP-3 and subsequent reduced proliferation of at-risk breast epithelial cells.

PMID- 15020237
TI  - Distinct genomic sequence of the CNR/Pcdhalpha genes in chicken.
AB  - CNR/Pcdhalpha family proteins have been first identified as a receptor family
      that corporate with Fyn, a family of the Src family of tyrosine kinase, and known
      as synaptic cadherins. Here we report the complete genomic sequence and
      organization of the chicken (Gallus gallus) CNR/Pcdhalpha The total length of
      chicken CNR/Pcdhalpha is 177kb. The chicken CNR/Pcdhalpha cluster encodes 12
      variable and 3 constant exons. The genomic organizations of the chicken, rat,
      mouse, and human CNR/Pcdhalpha are basically orthologous. The constant-region
      exons (CP1, CP2, and CP3) are highly conserved between chicken and mammals, with
      percent identities of 90.9%, 90.7%, and 91.8% at the amino-acid level for chicken
      versus rat, mouse, and human, respectively. In contrast, the percent identities
      of the variable-region exons between chicken and mammals were lower: 51.8%,
      51.3%, and 52.7%, on average, for chicken versus rat, mouse, and human,
      respectively, at the amino-acid level. Moreover, the chicken variable-region
      exons (from v1 to v12) are highly conserved paralogously (91.4%: nucleic acid,
      92.4%: amino acid) in comparison with those of mammals. The CG content of each
      variable exon in the chicken (v1 to v12) is 74% on average and the CpG
      dinucleotide frequency in each variable-region exon is twice that of mammals. Due
      to the high CG content, chicken variable exons (from v1 to v12) encode 3 to 4
      frame-shifted open reading frames, which span 1.5-3.0kb, in both the sense and
      anti-sense orientations.

PMID- 15020238
TI  - Sea urchin neural alpha2 tubulin gene: isolation and promoter analysis.
AB  - Expression of Talpha2 gene, during sea urchin Paracentrotus lividus development,
      is spatially and temporally regulated. In order to characterize this gene, we
      isolated the relevant genomic sequences and scanned the isolated 5'-flanking
      region in searching for cis-regulatory elements required for proper expression.
      Gel mobility shift and footprinting assays, as well as reporter gene (CAT and
      beta-gal) expression assays, were used to address cis-regulatory elements
      involved in regulation. Here we report that an upstream 5'-flanking fragment of
      PlTalpha2 gene drives temporal expression of reporter genes congruent with that
      of endogenous Talpha2 gene. The fragment contains cis-elements able to bind
      nuclear proteins from the gastrula stage (at which the Talpha2 gene is expressed)
      whose sequences could be consistent with the consensus sequences for
      transcription factors present in data bank.

PMID- 15020239
TI  - Characterization and immunolocalization of an NTP diphosphohydrolase of
      Trypanosoma cruzi.
AB  - An ecto-NTP diphosphohydrolase (NTPDase) activity, insensitive to inhibitors of
      ATPases and phosphatases, was characterized on the surface of live Trypanosoma
      cruzi intact parasites. The enzyme exhibits broad substrate specificity, typical
      of NTPDases, and a high hydrolysis rate for GTP. A 2282 bp message encoding a
      full-length NTPDase was cloned by RT-PCR using epimastigote mRNA. A single
      protein was immunoprecipitated from [(35)S]methionine-labeled parasites using
      antibodies against Toxoplasma gondii NTPase I. This antibody localized an NTPDase
      on the external surface of all forms of T. cruzi, as seen by confocal immuno
      fluorescence microscopy. The NTPDase could be part of the parasite's purine
      salvage pathway. Additionally, trypomastigotes (infective form) presented a 2:1
      ATP/ADP hydrolysis ratio, while epimastigotes (non-infective form) presented a
      1:1 ratio, suggesting a possible role for the NTPDase in the parasite's virulence
      mechanisms.

PMID- 15020240
TI  - Autoregulation of bone sialoprotein gene in pre-osteoblastic and non-osteoblastic
      cells.
AB  - Regulation of the bone sialoprotein (BSP) gene is important in the
      differentiation of osteoblasts, in bone matrix mineralization, and in tumor
      metastasis. We investigated BSP gene transcription by performing functional
      analysis of the 9256bp of the 5' flanking region of the murine BSP gene
      containing its promoter. We found that the forced expression of BSP stimulated
      mouse BSP promoter activity in a dose-dependent manner in both MC3T3-E1
      preosteoblast and HEK-293 cell lines, which was transcriptional factor Cbfa1
      independent. Co-culture of cells separately expressing BSP promoter reporter and
      BSP failed to mediate the BSP autoregulation, suggesting that the event might
      happen intracellularly. Deletion analysis of the BSP promoter indicated that the
      proximal promoter (110bp) was sufficient to confer this autoregulation. We
      conclude that the BSP gene is autoregulated in part by a positive feedback on its
      own promoter.

PMID- 15020241
TI  - A perforin-like protein from a marine mollusk.
AB  - Abalone (gastropod mollusks) express a protein, abMpeg1, which is a homolog of
      two mammalian proteins that share homology with mammalian perforin, a cytolytic
      and immune-regulatory protein of lymphocytes. One of the mammalian proteins,
      Mpeg1, is expressed in mature macrophage and prion-infected mouse brains, while
      the other, Epcs50, is expressed in ectoplacental cone cells of the invading
      placenta. Although the functions of these three proteins remain unknown, their
      structural similarity to mammalian perforin suggests that they may be involved in
      cell killing, the inflammatory response or tissue invasion. Consistent with these
      proposed functions, the Mpeg1 gene family shows the signature of positive
      Darwinian selection (adaptive evolution). The perforin-homology domain of abMpeg1
      contains the cytolytic "helix-turn-helix" domain of perforin, supporting the idea
      that abMpeg1 is a cytolytic protein of the abalone innate immune system. The
      alpha-helices of abMpeg1 are amphipathic as are those of perforin. The
      conservation among abMpeg1, mammalian Mpeg1, and Epcs50 shows that Mpeg1 proteins
      represent a novel, ancient protein family of probable immunological function.

PMID- 15020242
TI  - Analysis of multimerization of the SARS coronavirus nucleocapsid protein.
AB  - Severe Acute Respiratory Syndrome (SARS), an emerging disease characterized by
      atypical pneumonia, has recently been attributed to a novel coronavirus. The
      genome of SARS Coronavirus (SARS-CoV) has recently been sequenced, and a number
      of genes identified, including that of the nucleocapsid protein (N). It is noted,
      however, that the N protein of SARS-CoV (SARS-CoV N) shares little homology with
      nucleocapsid proteins of other members of the coronavirus family [Science 300
      (2003) 1399; Science 300 (2003) 1394]. N proteins of other coronavirus have been
      reported to be involved in forming the viral core and also in the packaging and
      transcription of the viral RNA. As data generated from some viral systems other
      than coronaviruses suggested that viral N-N self-interactions may be necessary
      for subsequent formation of the nucleocapsid and assembly of the viral particles,
      we decided to investigate SARS-CoV N-N interaction. By using mammalian two-hybrid
      system and sucrose gradient fractionations, a homotypic interaction of N, but not
      M, was detected by the two-hybrid analysis. The mammalian two-hybrid assay
      revealed an approximately 50-fold increase in SEAP activity (measurement of
      protein-protein interaction) in N-N interaction compared to that observed in
      either M-M or mock transfection. Furthermore, mutational analyses characterized
      that a serine/arginine-rich motif (SSRSSSRSRGNSR) between amino acids 184 and 196
      is crucial for N protein oligomerization, since deletion of this region
      completely abolished the N protein self-multimerization. Finally, the full-length
      nucleocapsid protein expressed and purified from baculovirus system was found to
      form different levels of higher order structures as detected by Western blot
      analysis of the fractionated proteins. Collectively, these results may aid us in
      elucidating the mechanism pertaining to formation of viral nucleocapsid core, and
      designing molecular approaches to intervene SARS-CoV replication.

PMID- 15020243
TI  - Taurine prevents the ischemia-induced apoptosis in cultured neonatal rat
      cardiomyocytes through Akt/caspase-9 pathway.
AB  - Activated Akt kinase has been proposed as a central role in suppressing apoptosis
      by modulating the activities of Bcl-2 family proteins and/or caspase-9. To study
      the mechanism underlying the anti-apoptotic effect of taurine, the interaction
      between taurine and Akt/caspase-9 pathway was examined using a simulated ischemia
      model with cultured rat neonatal cardiomyocytes sealed in closed flasks. Taurine
      (20mM) treatment attenuated simulated ischemia-induced decline in the activity of
      Akt. Although taurine treatment had no effect on the expression of Bcl-2 in
      mitochondria and the level of cytosolic cytochrome c, it inhibited ischemia
      induced cleavage of caspases 9 and 3. Moreover, adenovirus transfer of the
      dominant negative form of Akt objected taurine-mediated anti-apoptotic effects,
      cancelling the suppression of caspase-9 and caspase-3 activities by taurine.
      These findings provide the first evidence that taurine inhibits ischemia-induced
      apoptosis in cardiac myocytes with the increase in Akt activities, by
      inactivating caspase-9.

PMID- 15020244
TI  - USAG-1: a bone morphogenetic protein antagonist abundantly expressed in the
      kidney.
AB  - Bone morphogenetic proteins (BMPs) play critical roles in cellular proliferation,
      differentiation, and programmed cell death in multiple tissues. An increasing
      body of recent evidence has suggested that classes of molecules collectively
      termed BMP antagonists play important roles for the local regulation of BMP
      actions by binding BMPs and neutralizing their activities. Uterine sensitization
      associated gene-1 (USAG-1) was previously reported as a gene of unknown function,
      preferentially expressed in sensitized endometrium of the rat uterus. Here, we
      show that USAG-1 is abundantly expressed in the kidney and functions as a BMP
      antagonist. Recombinant USAG-1 binds directly to BMPs and antagonizes the BMP
      mediated induction of alkaline phosphatase in C2C12 cells. USAG-1 also induces
      formation of secondary axis and/or hyperdorsalization when its mRNA is injected
      to Xenopus embryos. In the early stage of mouse embryogenesis, USAG-1 is
      expressed in the first and second branchial arches and in metanephros, while in
      later stages the expression is confined to renal tubules and ameloblasts of
      teeth. Postnatally, the expression is further restricted to distal tubules of
      kidney, in a pattern similar to the localization of BMP-7, which has been shown
      to be important in the development of kidney and preservation of adult renal
      functions under pathological stresses. Collectively, we suggest that USAG-1 is a
      BMP antagonist that interacts with BMP-7 in the developing and adult kidney.

PMID- 15020245
TI  - Temporal dynamics of NMDA receptor-induced changes in spine morphology and AMPA
      receptor recruitment to spines.
AB  - Recent studies have shown that the activation of NMDA receptors can induce rapid
      changes in dendritic morphology and synaptic recruitment of AMPA receptors in
      dendritic spines. Here, we analyze the time course of NMDA receptor-induced
      changes in dendrite morphology and recruitment of AMPA receptors to synapses in
      cultured neurons. Activation of NMDA receptors causes a rapid transient increase
      in the size of preexisting spines and then the gradual formation of new dendritic
      protrusions and spines. NMDA receptor activation also induced GFP-tagged AMPA
      receptors to cluster in dendrites and to be inserted into the surface of
      dendritic spines. These results indicate that NMDA receptor activation induces
      several phases of dendritic plasticity, initial expansion of dendritic spines,
      followed by the de novo formation of spines and AMPA receptor dendritic
      clustering and surface expression on spines. Each of these forms of plasticity
      may have significant effects on the efficacy of synaptic transmission.

PMID- 15020246
TI  - SKIP modifies gene expression by affecting both transcription and splicing.
AB  - SKIP has been described as a transcriptional coregulator as well as a spliceosome
      component, but the relationship between these functions is not clear. We found
      that SKIP activated reporter gene expression from the basal promoters of viral
      origin. SKIP exhibited more prominent effect on the promoters with stronger
      activities, in an experiment employing a series of reporter constructs carrying
      different numbers of GC boxes. We also found that SKIP suppressed aberrant
      splicing at a cryptic splice donor site in the luciferase reporter gene. In
      addition, SKIP suppressed splicing of an extra intron created by a beta
      thalassemia mutation in the human beta-globin gene. In the transfection
      experiment, an intronless reporter exhibited a higher level of expression, but
      was less significantly activated by SKIP, than the intron-containing reporter.
      These results indicate that SKIP affects gene expression by both transcriptional
      activation and regulation of pre-mRNA splicing.

PMID- 15020247
TI  - 2-Chloro-2'-deoxyadenosine synergistically enhances azidothymidine cytotoxicity
      in azidothymidine resistant T-lymphoid cells.
AB  - This report presents quantitative analysis of the synergistic interaction of
      azidothymidine (AZT) and cladribine (CdA) in human H9-lymphoid cell lines
      sensitive and resistant to AZT (H9-araC cells). H9-araC cells obtained by
      cultivation of H9 cells in the presence of 0.5 microM arabinosyl-cytosine (araC)
      had lower deoxycytidine kinase and thymidine kinase (TK) activities and expressed
      cross-resistance to araC and AZT. The IC(50) values of AZT and CdA were
      calculated by using median-effect analysis and CalcuSyn software. The IC(50)
      values were 0.44 and 0.82 microM for CdA and 67.8 and 30,310 microM for AZT in H9
      and H9-araC cells, respectively. However, when the drugs were used in combination
      the IC(50) values of CdA and AZT were reduced to 0.12 and 15.5 microM in H9 cells
      and to 0.19 and 24.9 microM in H9-araC cells, respectively. Calculation of dose
      reduction index (DRI) indicated that at 50-90% growth inhibition level, the
      combination of the drugs caused 3.6-5.8- and 4.1-11.5-fold reduction in the dose
      of CdA and 4.4-37.6- and > 1000-fold reduction in the dose of AZT in H9 and H9
      araC cells, respectively. The combination index (CI) values simulated from these
      data suggested synergistic to very strong synergistic lymphocytotoxic effects of
      AZT combined with CdA. These findings suggest the potential usefulness of a
      double-targeted approach for designing efficacious therapeutics for the kinase
      deficient drug resistant tumors.

PMID- 15020248
TI  - EST-based identification of genes expressed in the hypothalamus of adult tilapia,
      Oreochromis mossambicus.
AB  - The hypothalamus is involved in many physiological functions in teleosts. To
      accelerate the molecular analysis of hypothalamic functions, a list of
      transcripts expressed in the hypothalamus of adult tilapia, Oreochromis
      mossambicus, was compiled using the expressed sequence tag (EST) strategy. Of 161
      clones, 130 clones were unique genes and 31 clones were found to be redundant. Of
      130 unique genes, 32.3% (42/130 ESTs) were identified as known genes and 67.7%
      (88/130 ESTs) as unknown genes. The functional categorization of the known genes
      was analyzed. Bioinformatic analysis revealed that 62 of 88 unknown genes (62/130
      ESTs, 47.7%) showed a significant homology to neither nucleotide nor translated
      peptide sequences in the public database. These genes might be particularly
      expressed in the tilapia hypothalamus.

PMID- 15020249
TI  - TNFalpha induces rapid activation and nuclear translocation of telomerase in
      human lymphocytes.
AB  - Maintenance of telomeres regulates chromosomal stability and cellular mitosis
      through a checkpoint mechanism. Continuous cell proliferation requires telomerase
      to maintain chromosomal stability and to counteract the cellular mitotic clock.
      Importantly, nuclear expression of telomerase activity is required for elongation
      of telomere sequences. In this study, we show that tumor necrosis factor alpha
      (TNFalpha) induces telomerase activity in the cytoplasm of peripheral blood
      lymphocytes (PBL) at 60 min, followed by translocation of activated telomerase to
      the nucleus at 120 min. Conversely, the phosphoinositol 3-kinase (PI3K) inhibitor
      wortmannin blocks TNFalpha-induced activation of telomerase, whereas the specific
      NF-kappaB translocation inhibitor SN-50 blocks TNFalpha-induced nuclear
      translocation of activated telomerase. These studies suggest that activation and
      nuclear translocation of telomerase are regulated by PI3K/Akt/NF-kappaB signaling
      pathways in PBL.

PMID- 15020250
TI  - Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation.
AB  - Insulin signaling can be negatively regulated by phosphorylation of serine 307 of
      the insulin receptor substrate (IRS)-1. Rapamycin, an inhibitor of the kinase
      mTOR, can prevent serine 307 phosphorylation and the development of insulin
      resistance. We further investigated the role of mTOR in regulating serine 307
      phosphorylation, demonstrating that serine 307 phosphorylation in response to
      insulin, anisomycin, or tumor necrosis factor was quantitatively and temporally
      associated with activation of mTOR and could be inhibited by rapamycin. Amino
      acid stimulation activated mTOR and resulted in IRS-1 serine 307 phosphorylation
      without activating PKB or JNK. Okadaic acid, an inhibitor of the phosphatase
      PP2A, activated mTOR and stimulated the phosphorylation of serine 307 in a
      rapamycin-sensitive manner, indicating serine 307 phosphorylation requires mTOR
      activity but not PP2A, suggesting that mTOR itself may be responsible for
      phosphorylating serine 307. Finally, we demonstrated that serine 307
      phosphorylated IRS-1 is detected primarily in the cytosolic fraction.

PMID- 15020251
TI  - Synechocystis Fe superoxide dismutase gene confers oxidative stress tolerance to
      Escherichia coli.
AB  - The superoxide dismutase (SOD) gene (slr 1516) from the cyanobacterium
      Synechocystis sp. PCC 6803 was cloned and overexpressed in Escherichia coli BL 21
      (DE3) using the pET-20b(+) expression vector. E. coli cells transformed with pET
      SOD overexpressed the protein in cytosol, upon induction by isopropyl beta-D
      thiogalactopyranoside (IPTG). The recombinant protein was purified to near
      homogeneity by gel filtration and ion-exchange chromatography. The SOD activity
      of the recombinant protein was sensitive to hydrogen peroxide and sodium azide,
      confirming it to be FeSOD. The pET-FeSOD transformed E. coli showed significantly
      higher SOD activity and tolerance to paraquat-mediated growth inhibition compared
      to the empty vector transformed cells. Based on these results it is suggested
      that overexpression of FeSOD gene from a heterologous source like Synechocystis
      sp. PCC 6803 may provide protection to E. coli against superoxide radical
      mediated oxidative stress mediated by paraquat.

PMID- 15020252
TI  - AP-1-independent sensitization to oxidative stress-induced apoptosis by
      proteasome inhibitors.
AB  - Hydrogen peroxide (H(2)O(2)) induces apoptosis of mesangial cells via c-Jun N
      terminal kinase (JNK)-activator protein-1 (AP-1) and extracellular signal
      regulated kinase (ERK)-AP-1 pathways. We recently found that subtoxic doses of
      proteasome inhibitors, MG132 and lactacystin, dramatically enhanced H(2)O(2)
      induced apoptosis in mesangial cells. In this report, we examined molecular
      mechanisms involved in this phenomenon, especially focusing on AP-1 pathways.
      Reporter assays showed that MG132 induced activation of AP-1. However,
      pharmacological inhibitors of AP-1, retinoic acid, and curcumin, did not suppress
      the proapoptotic effect of MG132. Suppression of JNK-AP-1 by transfection with
      either a dominant-negative mutant of JNK or a dominant-negative mutant of c-Jun
      did not attenuate the apoptosis enhancement by MG132. Similarly, suppression of
      ERK-AP-1 by PD98059 or dominant-negative mutants of ERK did not affect the
      apoptosis-promoting effect of MG132. Interestingly, pretreatment with MG132 did
      not enhance activation of AP-1 by H(2)O(2). These data suggested a novel, AP-1
      independent promotion of apoptosis by proteasome inhibitors.

PMID- 15020253
TI  - Enhancement of the releases of GABA and glycine during ischemia in rat spinal
      dorsal horn.
AB  - The present study examined a change in spontaneous inhibitory postsynaptic
      currents (sIPSCs) following ischemia in substantia gelatinosa (SG) neurons of
      adult rat spinal cord slices by using the whole-cell patch-clamp technique. At
      about 10 min after superfusion of an oxygen- and glucose-free medium, sIPSCs were
      remarkably increased in amplitude and frequency when compared with those in the
      control. In a phase of the increase in sIPSC activities, GABAergic and
      glycinergic sIPSCs, which were observed in the presence of strychnine and
      bicuculline, respectively, with TTX, were increased greatly in frequency with a
      minimal change in their amplitudes. It is concluded that the in vitro ischemia
      increases the spontaneous quantal releases of GABA and glycine to SG neurons from
      nerve terminals; a part of this enhancement is possibly due to an increase in
      spontaneous activities of inhibitory interneurons. GABA released thus might serve
      to inhibit the release of l-glutamate from nerve terminals.

PMID- 15020254
TI  - The osmoprotectants glycine and its methyl derivatives prevent the thermal
      inactivation of protective antigen of Bacillus anthracis.
AB  - Protective antigen (PA) is the main immunogenic constituent of all vaccines
      against anthrax. It is known to lose its biological activity even at 37 degrees
      C. Its thermolabile nature has, thus, remained a cause of concern as even
      transient exposure of the vaccine to higher temperature could compromise its
      efficacy. Various types of cosolvent excipients have been used to stabilize a
      number of proteins with variable success. However, no comprehensive and
      systematic study to stabilize anthrax PA molecule using this approach has ever
      been undertaken. We have carried out a systematic study on the effect of
      osmoprotectants like glycine and its methyl derivatives, sarcosine,
      dimethylglycine, and betaine, on the thermostability of PA. The thermal stability
      of PA was found to be highly sensitive to pH with maxima at pH 7.9. All the
      cosolvent additives used were able to enhance the thermal stability of PA as
      inferred from an increase in T(1/2) values, the temperature at which 50% activity
      was retained during short-term incubation. Glycine was found to be the best
      stabilizer, while the ability of its methyl derivatives to stabilize PA decreased
      with an increase in the number of substituted methyl groups suggesting
      perturbation of hydrophobic interactions. On extended incubation at 40 degrees C
      the half-life of PA thermal inactivation increased more than four times in the
      presence of glycine. Thus, glycine could be used as an effective stabilizer to
      enhance the shelf life of recombinant vaccine against anthrax.

PMID- 15020255
TI  - Cloning of hypoxia-inducible factor 1alpha cDNA from a high hypoxia tolerant
      mammal-plateau pika (Ochotona curzoniae).
AB  - Hypoxia-inducible factor 1 is a transcription factor composed of HIF-1alpha and
      HIF-1beta. It plays an important role in the signal transduction of cell response
      to hypoxia. Plateau pika (Ochotona curzoniae) is a high hypoxia-tolerant and cold
      adaptation species living only at 3000-5000 m above sea level on the Qinghai
      Tibet Plateau. In this study, HIF-1alpha cDNA of plateau pika was cloned and its
      expression in various tissues was studied. The results indicated that plateau
      pika HIF-1alpha cDNA was highly identical to those of the human (82%), bovine
      (89%), mouse (82%), and Norway rat (77%). The deduced amino acid sequence (822bp)
      showed 90%, 92%, 86%, and 86% identities with those of the human, bovine, house
      mouse, and Norway rat, respectively. Northern blot analyses detected two isoforms
      named pLHIF-1alpha and pSHIF-1alpha. The HIF-1alpha mRNA was highly expressed in
      the brain and kidney, and much less in the heart, lung, liver, muscle, and
      spleen, which was quite different from the expression pattern of mouse mRNA.
      Meanwhile, a new variant of plateau pika HIF-1alpha mRNA was identified by RT-PCR
      and characterized. The deduced protein, composed of 536 amino acids, lacks a part
      of the oxygen-dependent degradation domain (ODD), both transactivation domains
      (TADs), and the nuclear localization signal motif (NLS). Our results suggest that
      HIF-1alpha may play an important role in the pika's adaptation to hypoxia,
      especially in brain and kidney, and pika HIF-1alpha function pattern may be
      different from that of mouse HIF-1alpha. Furthermore, for the high ratio of HIF
      1alpha homology among the animals, the HIF-1alpha gene may be a good phylogenetic
      performer in recovering the true phylogenetic relationships among taxa.

PMID- 15020256
TI  - Osteoblasts and osteoclasts express PEDF, VEGF-A isoforms, and VEGF receptors:
      possible mediators of angiogenesis and matrix remodeling in the bone.
AB  - Pigment epithelial derived factor (PEDF) is one of the most effective inhibitors
      of angiogenesis described so far, especially in controlling the growth of blood
      vessels in the eye. We now describe the localization of PEDF in regions of active
      bone formation in the mid-gestation mouse embryo and its specific and high levels
      of secretion by osteoblasts. PEDF is detected to a lesser extent in osteoclasts
      as well. The proangiogenic factors, VEGF and its receptors VEGF-R1 and VEGF-R2,
      are also expressed by both osteoblasts and osteoclasts. These findings suggest
      that bone angiogenesis and matrix remodeling may be mediated both by PEDF and by
      VEGF.

PMID- 15020257
TI  - Novel testis- and embryo-specific isoforms of the phosphofructokinase-1 muscle
      type gene.
AB  - We have identified novel transcriptional isoforms of the human and mouse genes
      encoding muscle type phosphofructokinase-1 (PFK-M). These isoforms are expressed
      specifically in the testis and in the mid-gestation embryo, and have been termed
      TE-PFK-M (testis- and embryo-specific PFK-M). The 5'UTR of TE-PFK-M is composed
      of three newly identified exons that lie much farther upstream of the PFK-M
      coding region than the previously characterized 5'UTR. In addition, this upstream
      region encodes a series of small polyadenylated transcripts, some of which share
      the same exons found in the 5'UTR of TE-PFK-M, and which may play some role in
      regulating TE-PFK-M expression. These findings indicate an even more complex
      level of control of PFK-M expression than previously thought.

PMID- 15020258
TI  - Actin filaments play an essential role for transport of nascent HIV-1 proteins in
      host cells.
AB  - To investigate the role of actin filaments (F-actin) for human immunodeficiency
      virus type 1 (HIV-1) production in host cells, the effect of mycalolide B that is
      a novel actin-depolymerizing marine toxin was examined. Mycalolide B blocked the
      production of HIV-1 from primary infected T-lymphoblastoid and clonically
      infected monocytoid cells in a concentration-dependent manner. In the presence of
      10 microM of mycalolide B, F-actins were disorganized and mostly disappeared in
      the host cells, and viral envelope- and capsid-proteins did not reach the plasma
      membrane, but were distributed in the cytoplasm forming aggregates. In electron
      micrographs, no HIV-1 virions were detected on the cell surface, but many
      lysosome-like vesicles containing electron dense granules were observed in the
      cytoplasm, implying that mycalolide B did not disturb the synthesis of viral
      proteins, but rather inhibited their transport processes of HIV-1 in the host
      cells.

PMID- 15020259
TI  - Elderly acute myeloid leukemia: patients are not all the same.

PMID- 15020260
TI  - Familial lymphoid neoplasms in patients with mantle cell lymphoma.

PMID- 15020261
TI  - Expansion of cord blood hematopoietic stem cells for clinical application.

PMID- 15020262
TI  - International Committee of Medical Journal Editors (ICMJE): Uniform Requirements
      for Manuscripts Submitted to Biomedical Journals: writing and editing for
      biomedical publication.

PMID- 15020263
TI  - Short-term ex vivo expansion sustains the homing-related properties of umbilical
      cord blood hematopoietic stem and progenitor cells.
AB  - BACKGROUND AND OBJECTIVES: The homing of stem cells to the bone marrow
      microenvironment following transplantation is a specific movement eventually
      leading to the stem cells lodging in specialized niches of hematopoiesis. The
      present study was designed to develop an ex vivo expansion system capable of
      preserving the homing potential of hematopoietic stem/progenitor cells (HSPC).
      DESIGN AND METHODS: Umbilical cord blood (UCB) CD34+ cells were expanded in QBSF
      60 serum-free medium with a simple early-acting combination of cytokines and were
      re-selected from the expanded products at different time points. The homing
      related characteristics and expansion rate of CD34+ cells were simultaneously
      examined. RESULTS: It was observed that the number of HSPC increased
      significantly under our expansion protocol. The expression of CD49d, CD44, CD11a
      and CD49e on expanded CD34+ cells increased or remained at the same levels as
      those on freshly isolated CD34+ UCB cells, while the expression of CD54 on
      expanded CD34+ cells was lower during the second week of culture than at the
      start. The spontaneous and SDF-1-induced adhesion of CD34+ cells was increased
      during the first 10 days of culture, with the adhesion rates reaching peak levels
      (62.8 12.8% and 90.5 11.7% for spontaneous and induced adhesion, respectively) on
      day 10. Neither spontaneous nor SDF-1-induced migration had changed significantly
      by day 7. INTERPRETATION AND CONCLUSIONS: These data demonstrate that, although
      ex vivo expansion may alter cell properties, our one-week expansion protocol can
      preserve most of the homing-related characteristics and activities of UCB HSPC.

PMID- 15020264
TI  - Effects of hydroxyurea on the membrane of erythrocytes and platelets in sickle
      cell anemia.
AB  - BACKGROUND AND OBJECTIVES: Adhesion molecules on the surface of erythrocytes,
      leukocytes and platelets are involved in vascular occlusion in sickle cell
      anemia. Hydroxyurea treatment of sickle cell anemia patients leads to clinical
      improvement and reduces the incidence of vaso-occlusive episodes. It has been
      previously demonstrated that hydroxyurea treatment also reduces the expression of
      adhesion molecules on the surface of erythrocytes. Phosphatidylserine (PS)
      exposure on the surface of erythrocytes has been considered to be the main
      determinant of altered erythrocyte adhesion in sickle cell anemia. In this study
      we examine the expression of PS on the surface of erythrocytes and platelets of
      sickle cell anemia patients before and during treatment with hydroxyurea. DESIGN
      AND METHODS: Blood samples from 15 sickle cell anemia patients were analyzed
      before and during treatment with hydroxyurea. The profile of PS expression was
      examined by flow cytometry. RESULTS: Hydroxyurea was effective, as determined by
      the patients  clinical improvement and increased hemoglobin (8.3 vs 9.1 g/dL, p<
      0.005), F cells (15.9% vs 37.1%, p< 0.005) and mean corpuscular volume ( 82 fL vs
      101 fL, p< 0.005). PS expression on the surface of erythrocytes and platelets
      decreased from 6.27% to 2.96% (p< 0.005) and from 13.5% to 4.7% (p< 0.005),
      respectively. INTERPRETATION AND CONCLUSIONS: Hydroxyurea treatment reduces PS
      expression on the surface of erythrocytes and platelets, thus contributing to the
      favorable effects of this therapy.

PMID- 15020265
TI  - Submicroscopic deletions in 5q- associated malignancies.
AB  - BACKGROUND AND OBJECTIVES: The deletion of the long arm of chromosome 5 is common
      in myelodysplastic syndromes (MDS) but is not limited to the 5q- syndrome as it
      is also seen in acute myeloid leukemia (AML), where it is often associated with
      other karyotypic aberrations. The aim of this study was to investigate whether
      deletions of known suppressor sequences occur in myeloid malignancies associated
      with 5q-. DESIGN AND METHODS: Thirty patients with MDS or AML were selected for
      the presence of a 5q karyotypic deletion, either isolated (19 cases) or
      associated with other chromosome changes (11 cases). Multiple fluorescent in situ
      hybridization (FISH) in interphase nuclei was applied in all cases using a panel
      of eleven probes for known suppressor genes or loci deleted in MDS/AML. Metaphase
      FISH was also performed to clarify discrepancies between conventional and
      molecular cytogenetics. RESULTS: No additional deletions were found in nineteen
      cases with an isolated 5q-. Mono-allelic deletions where found in 9/11 cases, 3
      of which were related to monosomies by conventional cytogenetics. Interphase-FISH
      showed p53, AML1, D13S25, NF1, or Ikaros in six out of nine (66%) patients with
      5q- and additional karyotypic changes. Metaphase FISH was helpful in assigning
      some of these cryptic events to non-proliferating cells. INTERPRETATION AND
      CONCLUSIONS: Our study emphasizes that isolated 5q- is the marker of a highly
      stable clone in both MDS and AML. AML with isolated 5q- are molecularly closer to
      5q- syndrome than to AML with complex changes. Interphase-FISH data strongly
      support a mutator phenotype underlying complex karyotypes with a 5q deletion.

PMID- 15020266
TI  - Promyelocytic leukemia retinoid signaling targets regulate apoptosis,tissue
      factor and thrombomodulin expression.
AB  - BACKGROUND AND OBJECTIVES: Retinoids are involved in cell differentiation,
      morphogenesis, proliferation and antineoplasic processes. Thus, the retonoic acid
      receptor (RARalpha) agonist, AM80, regulates tissue factor (TF), thrombomodulin
      (TM) expression and granulocytic differentiation in promyelocytic cells, while
      the RARgamma-selective retinoid, CD437, inhibits in vitro cell proliferation and
      induces apoptosis. The mitogen-activated protein kinase (MAPK) and the
      phosphatidylinositol-3-kinase (PI3K) pathways constitute key integration points
      along the signal transduction cascades that link diverse extracellular stimuli to
      proliferation, differentiation and survival. DESIGN AND METHODS: PI3K and MEK/ERK
      kinase-dependent pathways were examined as potential targets of retinoid
      signaling. Likewise, by using specific inhibitors, the role of those kinases in
      retinoid-induced granulocytic differentiation, apoptosis, and TF and TM
      expression n NB4 cells were analyzed. RESULTS: AM80-treated NB4 cells had
      increased PI3K activity and phosphoinositide turnover. High steady-state pERK-1/
      2 activity levels were not significantly changed by AM80. Yet, PI3K inhibitor
      LY294002 significantly reduced AM80-elicted ERK-1/-2 activity. Thus, the PI3K
      pathway might contribute to elevated ERK-1/-2 activity in NB4 cells. Inhibition
      of the PI3K and MEK/ERK pathways reversed AM80-induced granulocytic
      differentiation, TF down-regulation and TM induction. Besides, CD437
      significantly reduced ERK-1/-2 activity of NB4 cells. Further ERK-1/-2 activity
      inhibition with the MEK inhibitor, PD98059, increased the retinoid pro-apoptotic
      effect with an additive effect. INTERPRETATION AND CONCLUSIONS: Regardless the
      different regulation of PI3K and MAPK pathways promoted by AM80 and CD437, there
      is a varying degree of cross-talk between these pathways in the control of the
      overall response of promyelocytic cells to retinoids. Thus, disruption of
      targeted pathways, together with specific retinoids, might be an effective
      therapeutic treatment for acute promyelocytic leukemia.

PMID- 15020267
TI  - Survival of elderly patients with acute myeloid leukemia.
AB  - BACKGROUND AND OBJECTIVES: The prognosis of elderly patients with acute
      myelogenous leukemia (AML) is usually dismal, while the true survival of older
      patients not included in clinical trials is not known. We retrospectively
      evaluated the impact on survival of an aggressive versus a non-aggressive
      approach in 1005 patients aged >60 years registered in the database of the GIMEMA
      cooperative group. DESIGN AND METHODS: Group A patients (n=621) received
      aggressive treatment, while group B patients (n=384) underwent non-aggressive
      therapy. The groups were different for risk factor distribution: the patients in
      group B had a higher median age, worse performance status (PS) and a higher
      proportion of previous myelodysplastic disease. RESULTS: The overall median
      survival was 7 and 5 months in groups A and B, respectively (p min of 0.0001). At
      multivariate analysis the following factors were associated with a significantly
      shorter survival: age >71 years (RR=1.27; 95% CI=1.07-1.50), PS=2-4 (RR=1.44; 95%
      CI=1.24-1.68), white cell count > 10,000 mL (RR=1.37; 95% CI=1.06-1.75), and
      heart dysfunction requiring treatment (RR=1.26; 95% CI=1.05-1.50). No difference
      in survival was associated with aggressive or non-aggressive treatment (RR=1.1;
      95% CI=0.94-1.32). Patients aged min of 70 years, with no heart disease, but a
      white cell count > 10,000/mL showed a significantly better survival when treated
      aggressively (median survival 7 vs 3 months, p = 0.011). INTERPRETATION AND
      CONCLUSIONS: Despite an obvious selection of patients with a worse prognosis in
      group B, the difference in survival between the two groups was marginal.
      Multivariate analysis failed to demonstrate a significant survival benefit in
      aggressively treated patients. All these considerations indicate that elderly
      patients with AML are overall unlikely to benefit from aggressive treatment, so
      that this should be offered only to selected patients.

PMID- 15020268
TI  - The diagnostic value of CD123 in B-cell disorders with hairy or villous
      lymphocytes.
AB  - BACKGROUND AND OBJECTIVES: CD123 is an antibody that identifies the a chain of
      the human interleukin-3 receptor and is expressed in a variety of normal
      hematopoietic cells, acute leukemia and hairy cell leukemia (HCL). The aim of the
      study was to investigate the diagnostic value of CD123 expression in B-cell
      disorders with circulating hairy and villous lymphocytes. DESIGN AND METHODS: We
      investigated the diagnostic value of CD123 expression in neoplastic cells from 59
      patients with B-cell disorders with circulating hairy or villous lymphocytes: HCL
      (n=24), the variant form of HCL (n=11) and splenic lymphoma with villous
      lymphocytes (SLVL) (n=24). Cells from 12 patients with chronic lymphocytic
      leukemia were used as controls. Immunophenotypic analysis was performed by flow
      cytometry on 77 samples from peripheral blood (n=48), bone marrow (n=25) and
      spleen cell suspensions (n=4). RESULTS: Our findings show that cells from 95% of
      typical HCL express CD123 with strong to moderate intensity while this molecule
      is absent in circulating cells from most cases of HCL-variant (91%) and SLVL
      (97%). INTERPRETATION AND CONCLUSIONS: We conclude that CD123 is a useful new
      marker for distinguishing B-cell disorders with circulating villous lymphocytes
      as its expression is characteristic of typical HCL with high sensitivity and
      specificity. However CD123 does not allow the distinction between HCL-variant and
      SLVL, as both are CD123 negative.

PMID- 15020269
TI  - Long-term follow-up of front-line treatment of hairy cell leukemia with 2
      chlorodeoxyadenosine.
AB  - BACKGROUND AND OBJECTIVES: Although remission of hairy cell leukemia (HCL) after
      treatment with 2-chlorodeoxyadenosine (2-CdA) appears to be long lasting, few
      reports currently provide results from follow-up exceeding 5 years. DESIGN AND
      METHODS: We reviewed our HCL patients treated with front-line 2-CdA (by 2-hour
      infusion) either for 5 consecutive days at 0.14 mg/kg/day (daily subset, n=21) or
      once a week at 0.14 mg/kg for 5 cycles (weekly subset, n=16). RESULTS: Of the 37
      eligible patients, 30 (81%) achieved complete response (CR) and 7 (19%) partial
      response (PR) (overall response rate, 100%); identical response rates were
      recorded in the daily and weekly subsets. After a median follow-up of 122 months
      (range, 54-156), the overall relapse rate was 27% (8/30): 24% (4/17) had relapsed
      in the subset treated daily whereas 30% (4/13) had done so in the subset treated
      weekly (p=ns). The projected 13-year overall and the relapse-free survivals are
      96% and 52%, respectively. In terms of hematologic toxicity, the weekly 2-CdA
      schedule was associated with significantly fewer cases of grade 3-4 neutropenia.
      INTERPRETATION AND CONCLUSIONS: In HCL patients, a single dose of 2-CdA induces a
      long-term CR. Over 90% of patients are alive 13 years later and over 50% of
      patients appear to be clinically cured by this treatment. The weekly schedule
      seems to be a safer option for neutropenic HCL patients, while apparently
      providing equivalent results in terms of response rates and long-term outcome.

PMID- 15020271
TI  - Splenectomy in relapsing and plasma-refractory acquired thrombotic
      thrombocytopenic purpura.
AB  - BACKGROUND AND OBJECTIVES: Acquired thrombotic thrombocytopenic purpura (TTP) is
      often due to autoantibodies inhibiting ADAMTS-13 activity resulting in impaired
      processing of very large von Willebrand factor multimers. TTP usually presents
      with an acute onset and a fulminant, sometimes fatal course. With appropriate
      treatment including plasma exchange, and fresh frozen plasma replacement, often
      supplemented by immuno-suppressive therapy, the acute episode generally resolves
      within days to weeks. DESIGN AND METHODS: We describe the clinical course of 3
      patients with acquired TTP. One was refractory to PE, the other 2 relapsed after
      this treatment. All three were treated with splenectomy. ADAMTS-13 activity and
      inhibitor levels were monitored. RESULTS: ADAMTS-13 activity was initially < 5%
      in all 3 patients. After splenectomy the inhibitor against ADAMTS-13 disappeared
      rapidly in 2 patients and there was full recovery of ADAMTS-13 activity in all 3
      patients. INTERPRETATION AND CONCLUSIONS: Splenectomy, by eliminating a source of
      pathogenic autoantibody production, can be a successful treatment for patients
      with relapsing or plasma-refractory acquired TTP due to autoantibody-mediated
      ADAMTS-13 deficiency.

PMID- 15020270
TI  - Familial lymphoid neoplasms in patients with mantle cell lymphoma.
AB  - BACKGROUND AND OBJECTIVES: Familial aggregation has been recognized in patients
      with several lymphoid neoplasms, but the genetic basis for this familial
      clustering is not known. Germ-line mutations in the ataxia-telangiectasia mutated
      (ATM) and CHK2 genes have been detected in patients with mantle cell lymphoma
      (MCL), suggesting a potential role of these genes in genetic predisposition to
      these tumors. However, no familial association has been previously recognized in
      MCL. DESIGN AND METHODS: To determine the possible existence of familial lymphoid
      neoplasms in MCL, we searched clinical records of MCL patients and identified
      three families in which a MCL, an acute B-cell lymphoblastic leukemia, and a
      lymphoplasmacytic lymphoma occurred in a first-degree relative of a MCL patient.
      RESULTS: The neoplasms in two daughters appeared at an earlier age and were more
      aggressive than that in the respective parent, suggesting that the phenomenon of
      anticipation may characterize familial lymphomas associated with MCL. No
      mutations were detected in the ATM, CHK2, CHK1, and p53 genes. INTERPRETATION AND
      CONCLUSIONS: Our findings suggest that inactivation of the investigated DNA
      damage response genes do not account for familial disease aggregation in MCL
      patients, although such aggregation may occur and seems to be associated with the
      phenomenon of anticipation.

PMID- 15020272
TI  - Mutation analysis of HPS1, the gene mutated in Hermansky-Pudlak syndrome, in
      patients with isolated platelet dense-granule deficiency.
AB  - BACKGROUND AND OBJECTIVES: Isolated platelet dense granule (PDG) deficiency is a
      heterogeneous disorder frequently found among patients with mild to moderate
      bleeding diatheses. However, the molecular basis of this disorder is unknown.
      Genes involved in other rare bleeding disorders with associated reduction in the
      numbers of platelet dense-granules may play a role in isolated PDG deficiency.
      Among such genes, HPS1 is known to play a key role in the genesis of PDG and as
      many as 18 different HPS1 mutations have been identified in patients with
      Hermansky-Pudlak syndrome. Recently, we have identified subjects with one HPS1
      heterozygous mutation displaying significant reductions in PDG without the
      clinical phenotype of Hermansky-Pudlak syndrome. This suggested that HPS1
      mutations could be involved in isolated PDG deficiency. DESIGN AND METHODS: We
      sequenced all coding exons, and flanking intron regions of HPS1 in 16 patients
      with mild to severe PDG deficiency, most of whom had mild bleeding episodes. Nine
      patients reported a familial history of bleeding diathesis with PDG deficiency.
      We also evaluated the prevalence of HPS1 variations in 215 controls. Transmission
      electron microscopy was used to evaluate the number and morphology of PDG from
      patients and selected controls. RESULTS: No patient with PDG deficiency carried
      severe mutations of the HPS1 gene. We identified 6 previously described and 5 new
      polymorphisms in the HPS1 gene. Platelet electron microscopy in controls carrying
      these polymorphisms revealed that they did not significantly modify the number or
      morphology of PDG. INTERPRETATION AND CONCLUSIONS: Mutations affecting the HPS1
      gene play a minor role in isolated PDG deficiency. These results support a
      molecular heterogeneity responsible for the number and morphology of PDG.

PMID- 15020273
TI  - Ultrastructural analysis of granulocyte inclusions in genetically confirmed MYH9
      related disorders.
AB  - BACKGROUND AND OBJECTIVES: MYH9-related disorders are autosomal dominant
      hereditary macrothrombocytopenias caused by mutations in the MYH9 gene. This gene
      encodes the non-muscular myosin heavy chain type II A (MHCIIA). Among these
      disorders, May-Hegglin anomaly (MHA), Sebastian syndrome (SS), and Fechtner
      syndrome (FS) are associated with different types of ribosome inclusions in
      granulocytes. FS also exhibits Alport-like manifestations: nephropathy,
      neurosensory deafness, and cataracts. The aim of our study was to assess the
      granulocyte inclusion ultrastructure in genetically confirmed MYH9-related
      disorders. DESIGN AND METHODS: Ten individuals were studied. All fulfilled the
      clinical and laboratory findings to be diagnosed as having an MYH9-related
      disorder. The ultrastructure of 50 granulocyte sections for each patient was
      examined, and the percentages of the different types of inclusion were
      established. Mutations of the MYH9 gene were also analyzed. RESULTS: The patients
      were classified as having MHA if the inclusions contained parallel longitudinal
      filaments. If not, they were classified as having SS or FS. FS patients also
      showed Alport-like manifestations. In all syndromes we observed a wide
      variability of the inclusion ultrastructure. Moreover, a small number of
      inclusions typical of other syndromes was observed. A new cross-striated
      inclusion variant was identified in SS. A significant number of pure ribosome
      aggregates were identified in all syndromes. INTERPRETATION AND CONCLUSIONS: Like
      other MYH9-related traits, the variation and partial overlap in the inclusion
      ultrastructure could be attributed to specific changes in the polymerization,
      assembly, or stability of the MHCIIA. These changes might be associated with MYH9
      gene mutations as well as with its heterogeneous expression.

PMID- 15020274
TI  - Characterization of interleukin-15 gene-modified human natural killer cells:
      implications for adoptive cellular immunotherapy.
AB  - BACKGROUND AND OBJECTIVES: Natural killer (NK)-92 cells are effective against a
      broad range of malignant targets both in vitro and in vivo. Interleukin-15 (IL
      15) is an important cytokine for NK cell development and differentiation. IL-15
      gene-modified NK-92 cells need to be characterized and their clinical
      implications investigated. DESIGN AND METHODS: IL-15 cDNA was inserted into a
      pcDNA3 eukaryotic expression vector and the recombinant vector (pcDNA3-IL15) was
      tranfected into NK-92 cells. The IL-15 gene-modified NK-92 cells (NK92-IL15) were
      cloned and characterized with regard to their cytokine production, proliferation,
      cytotoxicity and surface phenotype. RESULTS: NK92-IL15 cells continuously
      produced a high level of IL-15 in culture supernatant, which made the cells
      proliferate significantly more rapidly in response to stimulation with low doses
      of IL-2 or IL-15; the cumulative number of cells in long-term culture was also
      significantly higher. NK92-IL15 cells became adherent to plastic and their
      expression of CD54 increased, which may explain their improved proliferating
      potential, like adherent NK cells. NK92-IL15 cells were more strongly cytotox
      against a broad range of target tumor cells than the parent NK-92 cells, and this
      increased cytotoxicity was correlated to the increased expression of cytotoxic
      effector molecules, such as perforin, Fas ligand and IFNgamma, and up- or down
      regulated expression of activating or inhibitory NK cell receptors (NKG2D or
      NKG2A/CD94). INTERPRETATION AND CONCLUSIONS: These results demonstrate that NK92
      IL15 cells are promising for adoptive cellular immunotherapy.

PMID- 15020275
TI  - Established and experimental treatments for sickle cell disease.
AB  - Sickle cell disease (SCD) is characterized by the presence of sickle hemoglobin
      (HbS), which has the unique property of polymerizing when deoxygenated. The
      sickling process is markedly accelerated when intracellular concentration of HbS
      is increased. Due to the unique dependence of HbS polymerization on its cell
      concentration, a slight reduction in HbS concentration is likely to have a
      beneficial effect on the kinetic of polymerization and on the generation of
      dense, dehydrated red cells. The pathophysiology of acute and chronic clinical
      manifestations of SCD is strictly related to the hemoglobin cyclic
      polymerization, to the generation of dense, dehydrated red cells and to the
      interaction between sickle red cells and abnormal activated vascular endothelial
      cells. In the present paper we have reviewed the principal therapeutic strategies
      and we have explored the future treatment options for sickle cell disease.
      Therapy of sickle cell disease is based on two major goals. The first one is the
      decrease in intracellular HbS concentration obtained with agents activating fetal
      hemoglobin synthesis, such as hydroxyurea (HU) or with erythrocyte-active agents
      blocking different red cell membrane ion pathways and preventing sickle cell
      dehydration. The second one is based on therapeutic strategies, which may reduce
      sickle cell-endothelial adhesive events.

PMID- 15020277
TI  - Homozygosity for transferrin receptor-2 Y250X mutation induces early iron
      overload.
AB  - Two Italian subjects, aged three and sixteen years, presented with early iron
      overload as shown by increased serum iron indices and hepatic iron concentration.
      They both carried the Y250X mutation of the TFR2 gene in the homozygous state. We
      suggest that transferrin receptor-2 is important in maintaining iron balance in
      the first decades of life.

PMID- 15020278
TI  - Circulating endothelin-3 levels in patients with sickle cell disease during
      hydroxyurea treatment.
AB  - Abnormal adhesion of red blood cells to the endothelium and the production of
      cytokines and vasoactive substances, such as endothelin-1 contribute to the
      pathogenesis of microvascular occlusion in sickle cell disease (SCD), even during
      the steady state. Endothelin-3 (ET-3) is a vasoconstrictive agent, which has not
      yet been studied in SCD.

PMID- 15020276
TI  - Iron status and anemia in a population-based study of women with and without
      disability living in the community: the Women's Health and Aging Studies.
AB  - Iron status and associated risk factors were assessed in a population-based study
      of 684 community-dwelling women, 70-79 years old. Iron deficiency, iron
      deficiency anemia, and elevated iron stores were found in 5.8%, 3.8%, and 9.0% of
      women, respectively. The prevalence of both anemia and iron deficiency anemia
      increased significantly with increasing disability.

PMID- 15020279
TI  - High incidence of neutropenia in patients treated with rituximab after autologous
      stem cell transplantation.
AB  - We report a high incidence of neutropenia in patients treated with rituximab
      prior to and following autologous stem cell transplantation (ASCT). Fourteen
      patients with follicular or mantle-cell lymphoma were treated with high dose (HD)
      therapy followed by an in vivo-purged autologous graft.

PMID- 15020280
TI  - Differences in the expression pattern of apoptosis-related molecules between
      childhood and adult de novo acute myeloid leukemia.
AB  - Distinct expression patterns of pro- and anti-apoptotic proteins may contribute
      to different prognoses and therapy outcomes in adult versus childhood acute
      myeloid leukemia (AML). Therefore, we investigated whether expression levels of
      apoptosis-related proteins CD95, Bcl-2, Bax, Bcl-xL, procaspase-3, XIAP, cIAP-1,
      and survivin differ between children and adults with de novo AML.

PMID- 15020281
TI  - A randomized trial of dexamethasone before remission induction, in de novo
      childhood acute lymphoblastic leukemia.
AB  - We evaluated the impact of adding dexamethasone before chemotherapy in 95
      children with de novo standard-risk acute lymphoblastic leukemia (ALL). The
      children were randomly divided into 2 groups: one group was given dexamethasone,
      the other was not. The initial characteristics and mean follow-up of both groups
      were similar. Day +14 blast percentage was significantly lower in the
      dexamethasone group. Disease-free survival at 40-months follow-up was better
      (almost significantly so) in the dexamethasone group.

PMID- 15020282
TI  - Quantification of Epstein-Barr viral load and determination of a cut-off value to
      predict the risk of post-transplant lymphoproliferative disease in a renal
      transplant cohort.
AB  - Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening Epstein
      Barr virus (EBV)-driven B-cell malignancy occurring in 1 to 3% of renal
      transplant patients. Recently, EBV DNA quantification has become a useful tool
      for identifying patients at risk of developing PTLD. However, studies on EBV load
      differ in design, methodology and type of patients.

PMID- 15020284
TI  - Soluble syndecan-1 levels in different plasma cell dyscrasias and in different
      stages of multiple myeloma.
AB  - We measured serum levels of syndecan-1 in patients with multiple myeloma (MM),
      solitary plasmocytoma and monoclonal gammopathy of undetermined significance
      (MGUS). We then studied serum syndecan-1 levels in MM patients stratified by the
      Durie-Salmon staging system and the correlation of syndecan-1 levels with well
      known independent prognostic factors of MM.

PMID- 15020285
TI  - Oral idarubicin, dexamethasone and vincristine in the treatment of multiple
      myeloma: final analysis of a phase II trial.
AB  - This prospective phase II study evaluated a regimen with vincristine, oral
      idarubicin and dexamethasone (VID) in 74 patients with multiple myeloma. A
      partial response was achieved in 57% (16/28) of patients with previously
      untreated disease and in 35% (16/46) with refractory diseases. VID chemotherapy
      is an effective and tolerable oral alternative in an outpatient setting for these
      patients.

PMID- 15020283
TI  - High incidences of malignant lymphoma in patients infected with hepatitis B or
      hepatitis C virus.
AB  - It is still not clear whether there is an association between malignant lymphomas
      and hepatitis B or hepatitis C virus infections. Most studies from Italy and
      Japan support this association, but studies from other countries generally do
      not. We conducted a hospital-based case-control study to evaluate this
      association and show a significant association between the development of
      malignant lymphoma and infections by these viruses.

PMID- 15020286
TI  - Allogeneic bone marrow transplantation with non-T-cell-depleted marrow from two
      HLA-antigen-mismatched related donors.
AB  - Allogeneic BMT from 2 antigen-mismatched donors has been difficult to perform
      without T-cell depletion. Seven patients with advanced-stage hematologic
      malignancies underwent BMT with intensified graft-versus-host disease prophylaxis
      consisting of tacrolimus, methotrexate, and methylprednisolone. No rejection or
      acute GVHD >or= grade III was observed. This preliminary result is very
      promising.

PMID- 15020287
TI  - Reduced-intensity allogeneic stem cell transplantation for renal cell carcinoma:
      in vivo evidence of a graft-versus-tumor effect.
AB  - We report the cases of 3 patients with advanced renal cell carcinoma who
      underwent reduced-intensity allogeneic stem cell transplantation. In 2 partial
      responders, histologic analyses of metastases revealed prominent accumulation of
      CD8+ T cells and degenerative changes of clear cell carcinoma, suggestive of
      induction of tumor-specific cytotoxic T lymphocytes.

PMID- 15020288
TI  - Enhanced long-term survival, but no increase in replicative capacity, following
      retroviral transduction of human cord blood CD34+ cells with human telomerase
      reverse transcriptase.
AB  - Overexpression of telomerase reverse transcriptase (hTERT) can immortalize some
      primary human mesenchymal cells. We investigated whether retrovirally-mediated
      expression of hTERT in CD34+ umbilical cord blood (UCB) cells can extend the
      replicative lifespan of human hematopoietic progenitor cells. Overexpression of
      hTERT did not immortalize these cells but did lead to enhanced survival of mature
      hematopoietic cells.

PMID- 15020289
TI  - Clinical significance of breakthrough fungemia caused by azole-resistant Candida
      tropicalis in patients with hematologic malignancies.
AB  - A 5-year retrospective analysis of fungemia in patients with hematologic
      malignancies revealed that four patients, who received fluconazole and
      itraconazole during neutropenia, developed breakthrough candidemia due to azole
      resistant Candida tropicalis isolates. This observation suggests that causative
      organisms of candidemia in neutropenic patients receiving azoles should be
      suspected of being azole-resistant.

PMID- 15020290
TI  - Association of the interleukin-1 receptor antagonist gene with asthma.
AB  - The interleukin-1 cluster on human chromosome 2q12-2q14 harbors various promising
      candidate genes for asthma and other inflammatory diseases. We conducted a
      systematic association study with single-nucleotide polymorphisms (SNPs) located
      in candidate genes situated in this cluster. Single-marker, two-locus and three
      locus haplotype analysis of SNPs yielded several significant results (p < 0.05
      0.0021) for the human IL1RN gene encoding the IL-1 receptor antagonist protein,
      an antiinflammatory cytokine that plays an important role in maintaining the
      balance between inflammatory and antiinflammatory cytokines. These findings were
      replicated and confirmed in an independent Italian family sample in which
      significant, although weaker, association with asthma was detected. A sequencing
      approach to the coding region of the human IL1RN gene revealed additional DNA
      variants, from which a selection was also associated with the disease in German
      and Italian samples. Calculation of the linkage disequilibrium for the human
      IL1RN gene showed strong linkage disequilibrium for nearly all analyzed SNPs.
      Further haplotype analysis indicated that six SNPs are sufficient for tagging all
      haplotypes with a prevalence of more than 1%. The most frequent haplotype
      constructed from these SNPs was 1.4-fold overtransmitted in the German family
      sample.

PMID- 15020291
TI  - Hypoxia suppresses symptom perception in asthma.
AB  - Any factor that inhibits the ability of an individual with asthma to recognize
      their symptoms appropriately may contribute to treatment delay, "near miss"
      events, and death during acute severe asthma. The purpose of this study was to
      investigate the effects of two common features of acute severe asthma--hypoxia
      and hypercapnia--on respiratory sensation. Sixteen individuals with stable asthma
      were exposed to three gas conditions (34 minutes each): isocapnic hypoxia
      (arterial blood O2 saturation of approximately 80%), hypercapnia (increase in end
      tidal CO2 of approximately 5-10 Torr), or isocapnic normoxia on 3 separate days.
      The perceived magnitude of externally applied resistive loads, measured during
      each gas condition, was reduced throughout hypoxia compared with normoxia, and
      there was a trend for a progressive decline during hypercapnia. Within the 15
      minutes postgas inhalation period, methacholine-induced symptoms of difficult
      breathing, chest tightness, and breathlessness, measured using modified Borg
      scales, were 25-30% lower after hypoxia compared with normoxia but were not
      reduced after hypercapnia. We conclude that 30 minutes of sustained hypoxia and
      possibly hypercapnia impair sensations of respiratory load and that the effects
      of hypoxia persist for at least 10 minutes after returning to normoxia.

PMID- 15020292
TI  - Protective effects of sphingosine 1-phosphate in murine endotoxin-induced
      inflammatory lung injury.
AB  - Our prior in vitro studies indicate that sphingosine 1-phosphate (S1P), a
      phospholipid angiogenic factor, produces endothelial cell barrier enhancement
      through ligation of endothelial differentiation gene family receptors. We
      hypothesized that S1P may reduce the vascular leak associated with acute lung
      injury and found that S1P infusion produced a rapid and significant reduction in
      lung weight gain (more than 50%) in the isolated perfused murine lung. The effect
      of S1P was next assessed in a murine model of LPS-mediated microvascular
      permeability and inflammation with marked increases in parameters of lung injury
      at both 6 and 24 hours after intratracheal LPS. Each parameter assessed was
      significantly reduced by intravenous S1P (1 microM final) and in selected
      experiments by the S1P analogue FTY720 (0.1 mg/kg, intraperitoneally) delivered 1
      hour after LPS. S1P produced an approximately 40-50% reduction in LPS-mediated
      extravasation of Evans blue dye albumin, bronchoalveolar lavage protein content,
      and lung tissue myeloperoxidase activity (reflecting phagocyte infiltration).
      Consistent with systemic barrier enhancement, S1P significantly decreased Evans
      blue dye albumin extravasation and myeloperoxidase content in renal tissues of
      LPS-treated mice. These studies indicate that S1P significantly decreases
      pulmonary/renal vascular leakage and inflammation in a murine model of LPS
      mediated acute lung injury and may represent a novel therapeutic strategy for
      vascular barrier dysfunction.

PMID- 15020293
TI  - The role of Toll-like receptor 4 in environmental airway injury in mice.
AB  - Inhalation of toxins commonly found in air pollution contributes to the
      development and progression of asthma and environmental airway injury. In this
      study, we investigated the requirement of toll-like receptor 4 (TLR4) in mice for
      pulmonary responses to three environmental toxins: aerosolized
      lipopolysaccharide, particulate matter (residual oil fly ash), and ozone. The
      physiologic and biologic responses to these toxins were evaluated by the extent
      of airway responsiveness, neutrophil recruitment to the lower respiratory tract,
      changes in inflammatory cytokines, and the concentration of protein in the lavage
      fluid. Genetically engineered, TLR4-deficient mice (C57BL/6(TLR4-/-)) were
      unresponsive to inhaled lipopolysaccharide, except for minimal increases in some
      inflammatory cytokines. In contrast, C57BL/6(TLR4-/-) mice did not differ from
      wild-type mice in their airway response to instilled residual oil fly ash or
      acute ozone exposure; however, we found that, despite a robust inflammatory
      response, C57BL/6(TLR4-/-) mice are protected against the development of airway
      hyperresponsiveness after subchronic ozone exposure. These data demonstrate in
      the mouse that the requirement of TLR4 for pulmonary inflammation depends on the
      nature of the toxin and appears specific to toxin and exposure conditions.

PMID- 15020294
TI  - Extracellular superoxide enhances 5-HT-induced murine pulmonary artery
      vasoconstriction.
AB  - Accumulating evidence suggests that changes in both 5-hydroxytryptamine (5-HT)
      receptor activity and in the levels of reactive oxygen species (ROS) play an
      important role in regulating pulmonary artery (PA) vascular responsiveness,
      particularly in the setting of pulmonary hypertension. Therefore, we hypothesized
      that increased levels of superoxide enhance 5-HT-induced PA constriction. With
      the use of a small-vessel bioassay, 5-HT (0.01-10 microM) induced a concentration
      dependent vasoconstriction in isolated wild-type murine intrapulmonary arteries
      (100-150 microm diameter) that was enhanced by both removal of the endothelium
      and by treatment with either N(G)-nitro-L-arginine methyl ester (30 microM) or
      xanthine (10 microM) + xanthine oxidase (0.005 U/ml). PA isolated from
      extracellular superoxide dismutase (EC-SOD) knockout mice also showed enhanced
      constriction. On the other hand, PA constriction to 5-HT was attenuated by either
      the addition of GR-127935 (0.1 microM, a selective inhibitor of 5-HT(1B/1D)
      receptor) or copper/zinc-containing superoxide dismutase (Cu/Zn SOD, 150 U/ml)
      and in PA isolated from transgenic mice overexpressing human EC-SOD. With the use
      of both oxidative fluorescent confocal microscopy and lucigenin-enhanced
      chemiluminescence, superoxide levels were increased significantly after 5-HT
      induced PA vasoconstriction. This increase in superoxide levels could be blocked
      by the exogenous addition of Cu/Zn SOD (150 U/ml) or by apocynin (30 microM, an
      inhibitor of NADPH oxidase) but was not affected by gp91(phox) knockout mice.
      Overall, our results are consistent with 5-HT increasing vascular smooth muscle
      superoxide production via an NADPH oxidase pathway that is independent of
      gp91(phox), which leads to increases in extracellular superoxide levels, which in
      turn enhances 5-HT-induced murine pulmonary vasoconstriction.

PMID- 15020295
TI  - Myeloperoxidase deficiency enhances inflammation after allogeneic marrow
      transplantation.
AB  - Myeloperoxidase (MPO)-derived oxidants participate in the respiratory
      antimicrobial defense system but are also implicated in oxidant-mediated acute
      lung injury. We hypothesized that MPO contributes to lung injury commonly
      observed after bone marrow transplantation (BMT). MPO-sufficient (MPO+/+) and 
      deficient (MPO-/-) mice were given cyclophosphamide and lethally irradiated
      followed by infusion of inflammation-inducing donor spleen T cells at time of
      BMT. Despite suppressed generation of nitrative stress, MPO-/- recipient mice
      unexpectedly exhibited accelerated weight loss and increased markers of lung
      dysfunction compared with MPO+/+ mice. The increased lung injury during MPO
      deficiency was a result of donor T cell-dependent inflammatory responses because
      bronchoalveolar lavage fluids (BALF) from MPO-/- mice contained increased numbers
      of inflammatory cells and higher levels of the proinflammatory cytokine TNF-alpha
      and the monocyte chemoattractant protein-1 compared with wild-type mice. Enhanced
      inflammation in MPO-/- mice was associated with suppressed apoptosis of BALF
      inflammatory cells. The inflammatory process in MPO-/- recipients was also
      associated with enhanced necrosis of freshly isolated alveolar type II cells,
      critical for preventing capillary leak. We conclude that suppressed MPO-derived
      oxidative/nitrative stress is associated with enhanced lung inflammation and
      persistent alveolar epithelial injury.

PMID- 15020296
TI  - Pseudomonas aeruginosa pyocyanin directly oxidizes glutathione and decreases its
      levels in airway epithelial cells.
AB  - Production of pyocyanin enhances Pseudomonas aeruginosa virulence. Many of
      pyocyanin's in vitro and in vivo cytotoxic effects on human cells appear to
      result from its ability to redox cycle. Pyocyanin directly accepts electrons from
      NADH or NADPH with subsequent electron transfer to oxygen, generating reactive
      oxygen species. Reduced glutathione (GSH) is an important cellular antioxidant,
      and it contributes to the regulation of redox-sensitive signaling systems. Using
      the human bronchial epithelial (HBE) and the A549 human type II alveolar
      epithelial cell lines, we tested the hypothesis that pyocyanin can deplete airway
      epithelial cells of GSH. Incubation of both cell types with pyocyanin led to a
      concentration-dependent loss of cellular GSH (up to 50%) and an increase in
      oxidized GSH (GSSG) in the HBE, but not A549 cells, at 24 h. An increase in total
      GSH, mostly as GSSG, was detected in the culture media, suggesting export of GSH
      or GSSG from the pyocyanin-exposed cells. Loss of GSH could be due to pyocyanin
      induced H(2)O(2) formation. However, overexpression of catalase only partially
      prevented the pyocyanin-mediated decline in cellular GSH. Cell-free electron
      paramagnetic resonance studies revealed that pyocyanin directly oxidizes GSH,
      forming pyocyanin free radical and O(2)(-). Pyocyanin oxidized other thiol
      containing compounds, cysteine and N-acetyl-cysteine, but not methionine. Thus
      GSH may enhance pyocyanin-induced cytotoxicity by functioning as an alternative
      source of reducing equivalents for pyocyanin redox cycling. Pyocyanin-mediated
      alterations in cellular GSH may alter epithelial cell functions by modulating
      redox sensitive signaling events.

PMID- 15020297
TI  - Effects of matrix metalloproteinase inhibitor on LPS-induced goblet cell
      metaplasia.
AB  - Bacterial infections of the lung are known to induce inflammatory responses,
      which lead to mucus hypersecretion. Moreover, mucin synthesis in the airways has
      been reported to be regulated by neutrophilic inflammation-induced epidermal
      growth factor receptor (EGFR) expression and its activation. Furthermore, matrix
      metalloproteinases (MMPs), especially MMP-9, have been reported to promote the
      transmigration of activated neutrophils. In this study, we investigated the
      associations between lipopolysaccharide (LPS)-induced goblet cell (GC) metaplasia
      and EGFR expression and the effects of MMP inhibitor (MMPI). Various
      concentrations of LPS were instilled into the tracheas of pathogen-free Sprague
      Dawley rats, and airways were examined at different times after LPS instillation.
      To examine the role of MMP-9, we treated rats 3 days before LPS instillation and
      daily thereafter with MMPI. Neutrophilic infiltration, Alcian blue/periodic acid
      Schiff (AB/PAS) staining, and immunohistochemical staining for MUC5AC, EGFR, and
      MMP-9 were performed. The instillation of LPS increased AB/PAS and MUC5AC
      staining in time- and dose-dependent manners, and treatment with MMPI
      significantly prevented GC metaplasia. The instillation of LPS into the trachea
      also induced neutrophilic infiltration and EGFR and MMP-9 expression in the
      airway epithelium, and MMPI was found to significantly prevent neutrophil
      recruitment, GC metaplasia, and EGFR and MMP-9 expression. This study
      demonstrates that the MMP-9 and EGFR cascades are associated with LPS-induced
      mucus hypersecretion.

PMID- 15020298
TI  - Contribution of caveolin-1 alpha and Akt to TNF-alpha-induced cell death.
AB  - We used retrovirus insertion-mediated random mutagenesis to generate tumor
      necrosis factor-alpha (TNF-alpha)-resistant lines from L929 cells. Using this
      approach, we discovered that caveolin-1 alpha is required for TNF-alpha-induced
      cell death in L929 cells. The need for caveolin-1 alpha in TNF-alpha-induced cell
      death was confirmed by the restoration of sensitivity to TNF-alpha after ectopic
      reconstitution of caveolin-1 alpha/beta expression. This caveolin-1 alpha-mutated
      line was also resistant to H(2)O(2) and staurosporine, but not to lonidamine.
      HepG2 cells are known to lack endogenous caveolins. HepG2 cells stably
      transfected with caveolin-1 alpha/beta were found to be much more sensitive to
      TNF-alpha than either parental cells transfected with caveolin-1 beta or parental
      cells transfected with an empty vector. In contrast to its extensively documented
      antiapoptotic effect, the elevated activity of Akt appears to be important in
      sensitizing caveolin-1-expressing cells to TNF-alpha, since pretreatment of cells
      with the phosphatidylinositide 3-kinase (PI3K) inhibitor LY-294002 or wortmannin
      completely blocked PI3K activation and markedly improved the survival of TNF
      alpha-treated L929 cells. The survival rates of caveolin-1 alpha-normal and
      caveolin-1 alpha-deficient L929 cells were comparable after treatment with PI3K
      inhibitor and TNF-alpha. Similar results were obtained with HepG2 cells that
      stably expressed caveolin-1 alpha/beta or -beta and parental cells transfected
      with an empty vector. In summary, our results indicate that caveolin-1 alpha
      preferentially sensitizes L929 cells to TNF-alpha through the activation of a
      PI3K/Akt signaling pathway.

PMID- 15020299
TI  - Differentiation-dependent responsiveness of bronchial epithelial cells to IL-4/13
      stimulation.
AB  - The Th2 cytokines interleukin (IL)-4 and IL-13 are thought to play critical roles
      in the airway inflammation and hyperresponsiveness that characterize asthma.
      Recent evidence indicates that IL-13 can mediate these effects by acting directly
      on airway epithelial cells. Here we evaluated early [signal transducer and
      activator of transcription (STAT)6 phosphorylation] and delayed
      [granulocyte/macrophage colony-stimulating factor (GM-CSF) and transforming
      growth factor-beta(2) (TGF-beta(2)) secretion] responses of airway epithelial
      cells to IL-4 and IL-13 stimulation and the dependence of these responses on the
      culture technique employed. As expected, normal human bronchial epithelial cells
      grown on microporous inserts at an air-liquid interface (ALI) expressed a well
      differentiated mucociliary phenotype; in contrast, cells grown on plastic in
      submerged cultures were poorly differentiated. When stimulated with IL-4 or IL
      13, the magnitude and duration of STAT6 phosphorylation under the differing
      culture conditions were statistically indistinguishable. In contrast, cytokine
      secretion responses to IL-4 and IL-13 were highly dependent on the culture
      technique; cells cultured on plastic exhibited significant concentration
      dependent increases in GM-CSF and TGF-beta(2) secretion, whereas cells grown at
      ALI showed no statistically significant response. These results demonstrate that
      the coupling between early signal transduction responses to IL-4 and IL-13 and
      downstream functions such as cytokine secretion may be critically dependent on
      the cell culture technique employed and the resulting differentiation status of
      bronchial epithelial cells.

PMID- 15020300
TI  - Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile
      function.
AB  - Endothelin-1 (ET-1) has acute positive inotropic effects, but consequences of
      chronically increased ET-1 on contractile function of cardiac myocytes are
      largely unknown. In the present study, effects of long-term treatment with ET-1
      (10 nM) for 5 days on both force development [force of contraction (FOC)] and
      kinetics of contraction were determined in heart tissue reconstituted from rat
      cardiac cells. Isometric force was measured in response to cumulative
      concentrations of Ca(2+) and isoprenaline. ET-1 augmented basal FOC by 64 +/- 11%
      (P < 0.05), which was associated with a significantly blunted contractile
      response to Ca(2+) and isoprenaline. Moreover, ET-1 significantly prolonged
      relaxation (62 +/- 3 vs. 53 +/- 2 ms). Selective ET(A) (BQ-123) and ET(B)
      receptor blockade (BQ-788) demonstrated that effects of ET-1 on contractile
      function were mediated through the ET(A) receptor subtype. Effects of ET-1 were
      prevented by cotreatment with either Ro31-8425, a PKC inhibitor, or
      dimethylamiloride, an inhibitor of the Na(+)/H(+) exchanger. In contrast to long
      term ET-1 treatment, no changes in contractile parameters were observed after ET
      1 treatment for 3 h before force measurement. These data suggest that chronic ET
      1 stimulation has dual effects on contractility: improvement of basal force but
      impairment of twitch kinetics and inotropic responsiveness to beta-adrenoceptor
      stimulation. The signaling pathways involved include ET(A) receptors, PKC, and
      the Na(+)/H(+) exchanger. The present in vitro findings raise the possibility
      that ET-1 may exert both adaptive and maladaptive effects in the failing
      myocardium in which local accumulation of ET-1 is present.

PMID- 15020301
TI  - Heart rate reduction by zatebradine reduces infarct size and mortality but
      promotes remodeling in rats with experimental myocardial infarction.
AB  - The importance of heart rate for left ventricular remodeling and prognosis after
      myocardial infarction is not known. We examined the contribution of heart rate
      reduction by zatebradine, a direct sinus node inhibitor without negative
      inotropic effects on left ventricular function and dilatation, on mortality,
      energy metabolism, and neurohormonal changes in rats with experimental myocardial
      infarction (MI). Thirty minutes after left coronary artery ligation or sham
      operation, the rats were randomized to receive either placebo or zatebradine (100
      mg x kg(-1) x day(-1) per gavage) continued for 8 wk. Mortality during 8 wk was
      33.3% in the placebo and 23.0% in the zatebradine group (P < 0.05); MI size was
      36 +/- 2% and 30 +/- 1% (means +/- SE, P < 0.05), respectively. Zatebradine
      improved stroke volume index in all treated rats but increased left ventricular
      volume in rats with small MI (2.43 +/- 0.10 vs. 1.81 +/- 0.10 ml/kg, P < 0.05)
      but not in rats with large MI (2.34 +/- 0.09 vs. 2.35 +/- 0.11 ml/kg, not
      significant). Zatebradine reduced left and right ventricular norepinephrine and
      increased left and right ventricular 3,4-dihydroxyphenyl ethylene glycol-to
      norepinephrine ratio suggesting aggravation of cardiac sympathetic activation by
      zatebradine after MI. Creatine kinase and lactate dehydrogenase isoenzymes in
      rats with MI remained unchanged by zatebradine. Lowering heart rate per se
      reduces mortality and MI size in this model but induces adverse effects on left
      ventricular remodeling in rats with small MI.

PMID- 15020302
TI  - Impairment of endothelial function in women with a history of preeclampsia: an
      indicator of cardiovascular risk.
AB  - Preeclampsia is a disorder of pregnancy diagnosed by gestational hypertension and
      proteinuria. Epidemiological evidence suggests that women who experience
      preeclampsia are at a greater risk of hypertension and heart disease later in
      life compared with women who had normal pregnancies. Our objective was to
      determine whether endothelial function is impaired in postpartum women with a
      history of preeclampsia in their first pregnancy. We measured forearm blood flow
      (FBF) by venous occlusion plethysmography in 50 healthy women: 16 with prior
      preeclampsia, 14 with a prior normotensive pregnancy, and 20 never pregnant
      controls. The postpartum women participated 6-12 mo after delivery. Heart rate
      (HR) and blood pressure (BP) were concurrently monitored on the contralateral
      arm. Hemodynamic variables were assessed at baseline and during a mental stress
      test known to elicit endothelium-dependent vasodilatation. We found that baseline
      FBF, HR, systolic BP, and diastolic BP did not significantly differ among the
      groups, whereas mean arterial pressure in the preeclamptic group was greater than
      that of the normal pregnancy group (P = 0.03). Stress-induced FBF (percent change
      over baseline) was reduced in the preeclamptic group compared with both the
      normal pregnancy and never pregnant groups (P = 0.06) and was significantly
      attenuated compared with women with prior normal pregnancies (91% vs. 147%, P =
      0.006). These data demonstrate that women with a history of preeclampsia exhibit
      impaired endothelial function up to 1 yr postpartum. This observation may explain
      their increased risk for hypertension and cardiovascular disease.

PMID- 15020303
TI  - Rapid exchange of actin-bound nucleotide in perfused rat heart.
AB  - In the rat heart the actin-bound nucleotide contained both ATP and ADP. The ratio
      of bound ATP to bound ADP depended on the functional state of the heart; it was
      higher in hearts stopped reversibly in diastole (low Ca(2+), high Mg(2+), or high
      K(+)), than in stimulated (inotropic agents or pacing) hearts. Immunoblotting and
      gel electrophoresis showed the existence of G-actin (30% of total actin) in the
      cytoplasm of the heart. Pure actin was isolated from rat hearts: in G-actin the
      bound nucleotide readily exchanged with ATP or ADP, and in F-actin the bound
      nucleotide did not exchange with ATP or ADP. The free and bound nucleotides were
      separated in the intact heart by extraction with 75% methanol at -15 degrees C.
      In rat hearts perfused with (32)P-labeled orthophosphate the actin-bound
      nucleotide rapidly exchanged with the cytoplasmic ATP. The full exchange of the
      bound ATP was immediate, whereas the full exchange of the bound ADP was slower.
      The full exchange of the bound ATP was independent of the heartbeat frequency,
      whereas the full exchange of the bound ADP was frequency dependent. The data
      suggest that the transformation of actin monomer-ATP to actin polymer-ADP is a
      part of the normal contraction-relaxation cycle of the rat heart.

PMID- 15020304
TI  - Protein kinase C plays an essential role in sildenafil-induced cardioprotection
      in rabbits.
AB  - Sildenafil citrate (Viagra) is the most widely used pharmacological drug for
      treating erectile dysfunction in men. It has potent cardioprotective effects
      against ischemia-reperfusion injury via nitric oxide and opening of mitochondrial
      ATP-sensitive K(+) channels. We further investigated the role of protein kinase C
      (PKC)-dependent signaling pathway in sildenafil-induced cardioprotection. Rabbits
      were treated (orally) with sildenafil citrate (1.4 mg/kg) 30 min before index
      ischemia for 30 min and reperfusion for 3 h. The PKC inhibitor chelerythrine (5
      mg/kg i.v.) was given 5 min before sildenafil. Infarct size (% of risk area)
      reduced from 33.65 +/- 2.17 in the vehicle (saline) group to 15.07 +/- 0.63 in
      sildenafil-treated groups, a 45% reduction compared with vehicle (mean +/- SE, P
      < 0.05). Chelerythrine abolished sildenafil-induced protection, as demonstrated
      by increase in infarct size to 31.14 +/- 2.4 (P < 0.05). Chelerythrine alone had
      an infarct size of 33.5 +/- 2.5, which was not significantly different compared
      with DMSO-treated group (36.8 +/- 1.7, P > 0.05). Western blot analysis
      demonstrated translocation of PKC-alpha, -, and -delta isoforms from cytosol to
      membrane after treatment with sildenafil. However, no change in the PKC-beta and 
      epsilon isoforms was observed. These data provide direct evidence of an essential
      role of PKC, and potentially PKC-alpha, -, and -delta, in sildenafil-induced
      cardioprotection in the rabbit heart.

PMID- 15020306
TI  - Ascorbic acid does not affect large elastic artery compliance or central blood
      pressure in young and older men.
AB  - Large elastic artery compliance is reduced and arterial blood pressure (BP) is
      increased in the central (cardiothoracic) circulation with aging. Reactive oxygen
      species may tonically modulate central arterial compliance and BP in humans, and
      oxidative stress may contribute to adverse changes with aging. If so, antioxidant
      administration may have beneficial effects. Young (Y; 26 +/- 1 yr, mean +/- SE)
      and older (O; 63 +/- 2 yr, mean +/- SE) healthy men were studied at baseline and
      during acute (intravenous infusion; Y: n = 13, O: n = 12) and chronic (500 mg/day
      for 30 days; Y: n = 10, O: n = 10) administration of ascorbic acid (vitamin C).
      At baseline, peripheral (brachial artery) BP did not differ in the two groups,
      but carotid artery compliance was 43% lower (1.2 +/- 0.1 vs. 2.1 +/- 0.1
      mm(2)/mmHg x 10(-1), P < 0.01) and central (carotid) BP (systolic: 116 +/- 5 vs.
      101 +/- 3 mmHg, P < 0.05, and pulse pressure: 43 +/- 4 vs. 36 +/- 3 mmHg, P =
      0.16), carotid augmentation index (AIx; 27.8 +/- 7.8 vs. -20.0 +/- 6.6%, P <
      0.001), and aortic pulse wave velocity (PWV; 950 +/- 88 vs. 640 +/- 38 cm/s, P <
      0.01) were higher in the older men. Plasma ascorbic acid concentrations did not
      differ at baseline (Y: 71 +/- 5 vs. O: 61 +/- 7 micromol/l, P = 0.23), increased
      (P < 0.001) to supraphysiological levels during infusion (Y: 1240 +/- 57 and O:
      1,056 +/- 83 micromol/l), and were slightly elevated (P < 0.001 vs. baseline)
      with supplementation (Y: 96 +/- 5 micromol/l vs. O: 85 +/- 6). Neither ascorbic
      acid infusion nor supplementation affected peripheral BP, heart rate, carotid
      artery compliance, central BP, carotid AIx, or aortic PWV (all P > 0.26). These
      results indicate that the adverse changes in large elastic artery compliance and
      central BP with aging in healthy men are not 1). mediated by ascorbic acid
      sensitive oxidative stress (infusion experiments) and 2). affected by short-term,
      moderate daily ascorbic acid (vitamin C) supplementation.

PMID- 15020305
TI  - NMDA receptors in nucleus tractus solitarii are linked to soluble guanylate
      cyclase.
AB  - We sought to test the hypothesis that cardiovascular responses to activation of
      ionotropic, but not metabotropic, glutamate receptors in the nucleus tractus
      solitarii (NTS) depend on soluble guanylate cyclase (sGC) and that inhibition of
      sGC would attenuate baroreflex responses to changes in arterial pressure. In
      adult male Sprague-Dawley rats anesthetized with chloralose, the ionotropic
      receptor agonists N-methyl-d-aspartate (NMDA) and dl-alpha-amino-3-hydroxy-5
      methylisoxazole-propionic acid (AMPA) and the metabotropic receptor agonist trans
      dl-amino-1,3-cyclopentane-dicarboxylic acid (ACPD) were microinjected into the
      NTS before and after microinjection of sGC inhibitors at the same site.
      Inhibition of sGC produced significant dose-dependent attenuation of
      cardiovascular responses to NMDA but did not alter responses produced by
      injection of AMPA or ACPD. Bilateral inhibition of sGC did not alter arterial
      pressure, nor did it attenuate baroreflex responses to pharmacologically induced
      changes in arterial pressure. This study links sGC with NMDA, but not AMPA or
      metabotropic, receptors in cardiovascular signal transduction through NTS.

PMID- 15020307
TI  - Interpreting cardiac muscle force-length dynamics using a novel functional model.
AB  - To describe the dynamics of constantly activated cardiac muscle, we propose that
      length affects force via both recruitment and distortion of myosin cross bridges.
      This hypothesis was quantitatively tested for descriptive and explanative
      validity. Skinned cardiac muscle fibers from animals expressing primarily alpha
      myosin heavy chain (MHC) (mouse, rat) or beta-MHC (rabbit, ferret) were activated
      with solutions from pCa 6.1 to 4.3. Activated fibers were subjected to small
      amplitude length perturbations [deltaL(t)] rich in frequency content between 0.1
      and 40 Hz. In descriptive validation tests, the model was fit to the ensuing
      force response [deltaF(t)] in the time domain. In fits to 118 records, the model
      successfully accounted for most of the measured variation in deltaF(t) (R(2)
      range, 0.997-0.736; median, 0.981). When some residual variations in deltaF(t)
      were not accounted for by the model (as at low activation), there was very little
      coherence (<0.5) between these residual force variations and the applied
      deltaL(t) input function, indicating that something other than deltaL(t) was
      causing the measured variation in deltaF(t). With one exception, model parameters
      were estimated with standard errors on the order of 1% or less. Thus parameters
      of the recruitment component of the model could be uniquely separated from
      parameters of the distortion component of the model and parameters estimated from
      any given fiber could be considered unique to that fiber. In explanative
      validation tests, we found that recruitment and distortion parameters were
      positively correlated with independent assessments of the physiological entity
      they were assumed to represent. The recruitment distortion model was judged to be
      valid from both descriptive and explanative perspectives and is, therefore, a
      useful construct for describing and explaining dynamic force-length relationships
      in constantly activated cardiac muscle.

PMID- 15020308
TI  - Aalpha,beta-methylene ATP enhances P2Y4 contraction of rabbit basilar artery.
AB  - Interactions between different selective P2 receptor agonists have been used as
      tools to identify different P2 receptor subtypes. In the present study, we
      examined the P2 receptor subtypes and the mechanisms of potentiation of UTP
      contraction (P2Y contraction) by alpha,beta-methylene ATP [(2-carboxypiperazin-4
      yl)propyl-1-phosphanoic acid (CPP), a P2X agonist] using isometric tension in the
      denuded rabbit basilar artery. We made the following observations: 1). a
      predominant P2X receptor contraction was observed in the rabbit ear artery by the
      rank order of CPP >> 2-methylthioATP > ATP > UTP; 2). functional P2Y receptors
      were observed in the rabbit basilar artery by the rank order of UTP >> ATP = CPP
      = 2-methylthioATP; 3). CPP potentiated UTP-, ATP-, and ATPgammaS-induced
      contractions, possibly by activation of P2Y4 receptors because ATPgammaS does not
      activate P2Y6 receptors; and 4). ectonucleotidase did not play a predominant role
      in the potentiative effect of CPP because Evans blue, Ca(2+)-free medium, or
      divalent cation Ni(2+) did not affect the effect of CPP. Evans blue potentiated
      the contraction by UTP but not by ATP or ATPgammaS. We conclude that CPP enhanced
      P2Y4-mediated contraction in the rabbit basilar artery, and the influence by
      ectonucleotidases on CPP-potentiation remains unclear.

PMID- 15020309
TI  - Blood pressure regulates the activity and function of the Na-K-2Cl cotransporter
      in vascular smooth muscle.
AB  - The Na-K-2Cl cotransporter (NKCC1) is one of several transporters that have been
      linked to hypertension, and its inhibition reduces vascular smooth muscle tone
      and blood pressure. NKCC1 in the rat aorta is stimulated by vasoconstrictors and
      inhibited by nitrovasodilators, and this is linked to the contractile state of
      the smooth muscle. To determine whether blood pressure also regulates NKCC1, we
      examined the acute effect of hypertension on NKCC1 in rats after aortic
      coarctation. In the hypertensive aorta (28-mmHg rise in mean blood pressure), an
      increase in NKCC1 activity (measured as bumetanide-sensitive (86)Rb efflux) was
      apparent by 16 h and reached a plateau of 62% greater than control at 48 h. In
      contrast, there was a slight decrease in NKCC1 activity in the hypotensive aorta
      (21% decrease in mean blood pressure). Measurement of NKCC1 mRNA by real-time PCR
      revealed a fivefold increase in the hypertensive aorta compared with the
      hypotensive aorta or sham aorta. The inhibition by bumetanide of isometric force
      response to phenylephrine was significantly greater in the hypertensive aorta
      than in the control aorta or hypotensive aorta. We conclude that NKCC1 in rat
      aortic smooth muscle is regulated by blood pressure, most likely through changes
      in transporter abundance. This upregulation of NKCC1 is associated with a greater
      contribution to force generation in the hypertensive aorta. This is the first
      demonstration that NKCC1 in vascular smooth muscle is regulated by blood pressure
      and indicates that this transporter is important in the acute response of
      vascular smooth muscle to hypertension.

PMID- 15020310
TI  - Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13
      week, randomised, double blind study versus placebo and celecoxib.
AB  - OBJECTIVES: To compare the efficacy and safety of lumiracoxib with placebo and
      celecoxib for osteoarthritis OA in a 13 week, multicentre, randomised, double
      blind study. METHODS: After a 37 day washout period for nonsteroidal
      antiinflammatory drugs, 1702 patients with knee OA were randomised to lumiracoxib
      200 or 400 mg once daily od, celecoxib 200 mg od, or placebo 2221. A visual
      analogue scale VAS pain intensity > or =40 mm was required. Primary efficacy
      variables were OA pain intensity VAS mm in the target knee, patients global
      assessment of disease activity VAS mm, and WOMAC pain subscale and total scores
      at 13 weeks. OA pain intensity, patients and physicians global assessment of
      disease activity, and WOMAC total and all subscale scores were analysed by visit
      as secondary variables. RESULTS: Lumiracoxib showed significant improvements in
      all primary and secondary variables compared with placebo. Lumiracoxib 200 mg od
      and celecoxib 200 mg od achieved similar improvements in OA pain intensity and
      functional status. Lumiracoxib 400 mg od demonstrated better efficacy for OA pain
      intensity and patients global assessment of disease activity at weeks 2, 4, and 8
      and similar efficacy at week 13 compared with celecoxib 200 mg od. The incidence
      of adverse events AEs, serious AEs, and discontinuations due to AEs was similar
      in each group. CONCLUSION: Lumiracoxib demonstrated significant improvement in OA
      pain intensity, patients global assessment of disease activity, and the WOMAC
      pain subscale and total scores compared with placebo. Lumiracoxib was well
      tolerated in this study, with overall tolerability similar to that of placebo and
      celecoxib.

PMID- 15020311
TI  - Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta
      analysis of randomised controlled trials.
AB  - OBJECTIVE: To assess the best available evidence for efficacy of paracetamol
      (acetaminophen) in the treatment of osteoarthritis (OA). DESIGN: Systematic
      review and meta-analysis of randomised controlled trials (RCTs). DATA SOURCES:
      Medline, Embase, Scientific Citation Index, CINAHL, Cochrane Library, and
      conference abstracts in the past 2 years from the British Society for
      Rheumatology, the European League Against Rheumatism, the American College of
      Rheumatology, and the Osteoarthritis Research Society International. SUBJECTS: 10
      RCTs including 1712 patients with either symptomatic OA of the knee (6 trials) or
      hip/knee (3 trials) or multiple joints (1 trial). MAIN OUTCOME MEASURES: (a).
      effect size (ES) for pain, stiffness, and functional scores from baseline to end
      point; (b). rate ratio (RR) and number needed to treat for clinical response rate
      and patient preference for treatment. RESULTS: Paracetamol was effective in
      relieving pain due to OA (ES = 0.21, 95% confidence interval (CI) 0.02 to 0.41).
      Non-steroidal anti-inflammatory drugs (NSAIDs) were better than paracetamol for
      pain relief (ES = 0.20, 95% CI 0.10 to 0.30). Clinical response rate was higher
      with NSAIDs than with paracetamol (RR = 1.24, 95% CI 1.08 to 1.41), and the
      number of patients who preferred NSAIDs was more than twice the number of those
      preferring paracetamol (RR = 2.46, 95% CI 1.51 to 4.12). NSAIDs were associated
      with more frequent gastrointestinal discomfort than paracetamol (RR = 1.35, 95%
      CI 1.05 to 1.75). CONCLUSION: Paracetamol is an effective agent for pain relief
      due to OA. Although safer, it is less effective than NSAIDs. For safety reasons
      paracetamol should be the first line treatment, with NSAIDs reserved for those
      who do not respond.

PMID- 15020312
TI  - Patient preferences for treatment of rheumatoid arthritis.
AB  - OBJECTIVE: To elicit treatment preferences of patients with rheumatoid arthritis
      (RA) for disease modifying antirheumatic drugs (DMARDs) with varying risk
      profiles. METHODS: Patient values for 16 DMARD characteristics were ascertained
      using published data about side effects, effectiveness, and cost. Patient
      preferences were determined by Adaptive Conjoint Analysis, an interactive
      computer program that predicts preferences by asking patients to make trade-offs
      between specific treatment characteristics. Simulations were run to derive
      preferences for four drugs: methotrexate, gold, leflunomide, and etanercept,
      under different risk-benefit scenarios. Infliximab was not included because it is
      given with methotrexate, and we did not include preferences for combination
      therapy. Based on each patient's expressed preferences, and the characteristics
      of the treatments available at the time of the study, the option that best fitted
      each patient's perspective was identified. RESULTS: 120 patients (mean age 70
      years) were interviewed. For the base case scenario (which assumed the maximum
      benefits reported in the literature, a low probability of adverse effects, and
      low equal monthly "co-pays" (out of pocket costs)), 95% of the respondents
      preferred etanercept over the other treatment options. When all four options were
      described as being equally effective, 88% continued to prefer etanercept owing to
      its safer short term adverse effect profile. Increasing etanercept's co-pay to
      $30.00 decreased the percentage of patients preferring this option to 80%.
      CONCLUSIONS: In this study, older patients with RA, when asked to consider trade
      offs between specific risk and benefits, preferred etanercept over other
      treatment options. Preference for etanercept is explained by older patients' risk
      aversion for drug toxicity.

PMID- 15020321
TI  - Combating the burden of musculoskeletal conditions.

PMID- 15020322
TI  - Unlocking the "PAD" lock on rheumatoid arthritis.

PMID- 15020323
TI  - Sonography and subclinical synovitis.

PMID- 15020324
TI  - Clinimetric evaluation of shoulder disability questionnaires: a systematic review
      of the literature.
AB  - OBJECTIVE: To identify all available shoulder disability questionnaires designed
      to measure physical functioning and to evaluate evidence for the clinimetric
      quality of these instruments. METHODS: Systematic literature searches were
      performed to identify self administered shoulder disability questionnaires. A
      checklist was developed to evaluate and compare the clinimetric quality of the
      instruments. RESULTS: Two reviewers identified and evaluated 16 questionnaires by
      our checklist. Most studies were found for the Disability of the Arm, Shoulder,
      and Hand scale (DASH), the Shoulder Pain and Disability Index (SPADI), and the
      American Shoulder and Elbow Surgeons Standardised Shoulder Assessment Form
      (ASES). None of the questionnaires demonstrated satisfactory results for all
      properties. Most questionnaires claim to measure several domains (for example,
      pain, physical, emotional, and social functioning), yet dimensionality was
      studied in only three instruments. The internal consistency was calculated for
      seven questionnaires and only one received an adequate rating. Twelve
      questionnaires received positive ratings for construct validity, although
      depending on the population studied, four of these questionnaires received poor
      ratings too. Seven questionnaires were shown to have adequate test-retest
      reliability (ICC >0.70), but five questionnaires were tested inadequately. In
      most clinimetric studies only small sample sizes (n<43) were used. Nearly all
      publications lacked information on the interpretation of scores. CONCLUSION: The
      DASH, SPADI, and ASES have been studied most extensively, and yet even published
      validation studies of these instruments have limitations in study design, sample
      sizes, or evidence for dimensionality. Overall, the DASH received the best
      ratings for its clinimetric properties.

PMID- 15020325
TI  - Musculoskeletal pain in Europe: its impact and a comparison of population and
      medical perceptions of treatment in eight European countries.
AB  - OBJECTIVES: To describe the impact of musculoskeletal pain (MP); to compare
      management of MP by the population and by primary care physicians; and to
      identify misconceptions about treatment. METHODS: 5803 people with MP and 1483
      primary care physicians, randomly selected, in eight European countries were
      interviewed by telephone. A structured questionnaire was used to ask about usual
      management of MP and perceived benefits and risks of treatment. Current health
      status (SF-12) was also assessed. RESULTS: From primary care physicians'
      perceptions, MP appears to be well managed. All presenting patients are offered
      some form of treatment, 90% or more doctors are trying to improve patients'
      quality of life, and most are aware and concerned about the risks of treatment
      with NSAIDs. From a population perspective, up to 27% of people with pain do not
      seek medical help and of those who do, several wait months/years before seeing a
      doctor. 55% or fewer patients who have seen a doctor are currently receiving
      prescription treatment for their pain. Communication between doctors and patients
      is poor; few patients are given information about their condition; and many have
      misconceptions about treatment. CONCLUSIONS: Management of MP is similar across
      eight European countries, but there is discordance between physician and patient
      perspectives of care. Some people with pain have never sought medical help
      despite being in constant/daily pain. Those who do seek help receive little
      written information or explanation and many have misperceptions about the
      benefits and risks of treatment that limit their ability to actively participate
      in decisions about their care.

PMID- 15020326
TI  - Liposomal targeting of glucocorticoids to synovial lining cells strongly
      increases therapeutic benefit in collagen type II arthritis.
AB  - OBJECTIVE: To investigate the effect of a single intravenous treatment with
      glucocorticoids (GC) encapsulated in long-circulating PEG-liposomes on both joint
      inflammation and cartilage destruction and to investigate the phenomenon of
      selective homing of these liposomes in the inflamed synovium. METHODS: Mice with
      collagen type II-induced arthritis (CIA) were intravenously treated with
      liposomal and free prednisolone phosphate (PLP) a few days after the first signs
      of the disease. Joint inflammation was scored during 1 week after treatment,
      after which sections of the knee joints were prepared for assessment of cartilage
      damage. In addition, arthritic mice were treated with liposomes containing
      colloidal gold. 24 hours after injection, knee joint sections were prepared in
      which the location of liposomes was visualised. RESULTS: Treatment of CIA with 10
      mg/kg liposomal PLP resulted in a strong and lasting resolution of joint
      inflammation. 10 mg/kg free PLP only became slightly effective after repeated
      daily injections. Although joint inflammation recurred 1 week after treatment
      with liposomal PLP, knee joint sections prepared at this time indicated that the
      cartilage damage was still reduced. Localisation of gold labelled liposomes in
      the inflamed joints was seen in the proximity of blood vessels, in the cellular
      infiltrate, but mainly in the synovial lining. Unaffected joints did not take up
      liposomes. CONCLUSIONS: By using the property of long-circulating liposomes to
      target the synovial lining selectively in inflamed joints, the anti-inflammatory
      activity of GC can be greatly increased, showing also the beneficial effect of
      reduced cartilage destruction.

PMID- 15020327
TI  - Joint erosion in rheumatoid arthritis: interactions between tumour necrosis
      factor alpha, interleukin 1, and receptor activator of nuclear factor kappaB
      ligand (RANKL) regulate osteoclasts.
AB  - BACKGROUND: Osteoclasts, specialised bone resorbing cells regulated by RANKL and
      M-CSF, are implicated in rheumatoid joint erosion. Lymphocyte-monocyte
      interactions activate bone resorption, this being attributed to tumour necrosis
      factor alpha (TNFalpha) and interleukin 1 beta (IL1beta) enhanced osteoblast
      expression of RANKL. In animal studies, TNF potently increases osteoclast
      formation in the presence of RANKL. RANKL-independent osteoclastogenesis also
      occurs, though IL1 is required for resorptive function in most studies. These
      inflammatory cytokines have a pivotal role in rheumatoid arthritis, OBJECTIVE: To
      study the interactions of TNFalpha and IL1beta with RANKL, particularly the time
      course of the interactions and the role of lymphocytes. METHOD: Cultures of
      lymphocytes and monocytes (osteoclast precursors) or of purified CD14(+) cells
      alone (osteoclast precursors) were exposed to various combinations of TNFalpha,
      RANKL, and IL1beta or the inhibitors osteoprotegerin, IL1 receptor antagonist, or
      neutralising antibodies to RANKL or to IL1. Osteoclastogenesis and resorptive
      activity were assessed on microscopy of dentine slices. RESULTS: TNFalpha
      potently increased osteoclast proliferation/differentiation in the presence of
      RANKL. This effect was greatest when RANKL was present before but not after
      exposure of osteoclast precursor cells to TNFalpha. The resorptive activity of
      osteoclasts generated by TNFalpha in the absence of RANKL was critically
      dependent upon IL1, which was expressed by lymphocyte-monocyte interaction.
      CONCLUSION: TNFalpha potently enhances RANKL mediated osteoclast activity.
      Interactions between TNFalpha and IL1 also result in osteoclastic activity
      independently of RANKL. These findings will inform therapeutic approaches to the
      prevention of joint erosion in rheumatoid arthritis.

PMID- 15020328
TI  - Inpatient rehabilitation for hip or knee osteoarthritis: 2 year follow up study.
AB  - OBJECTIVE: To examine the course of pain, physical function, and other health
      dimensions after a comprehensive inpatient rehabilitation intervention in
      patients with osteoarthritis (OA) of the hip or knee. METHODS: An observational,
      prospective cohort study with assessments at baseline (entry into clinic), 1
      (discharge from inpatient rehabilitation), 3, 6, 9, 12, and 24 months after
      baseline. Consecutively referred patients to an inpatient rehabilitation centre
      fulfilling the inclusion criteria were studied. 3-4 week comprehensive
      rehabilitation intervention, including strengthening exercise, flexibility
      training, endurance training, relaxation strategies, and consultations for
      preventive measures, was carried out. Individual home rehabilitation programmes
      were taught. Generic health status was measured using the SF-36, condition
      specific health was measured with the WOMAC questionnaire. Effects were analysed
      with sensitivity statistics (effect size, ES) and non-parametric tests. RESULTS:
      Data from 128 patients with complete follow up data were analysed. Both pain and
      physical function improved moderately (WOMAC pain: ES = 0.56, WOMAC function ES =
      0.44) until discharge. Although the effect in pain reduction remained significant
      by month 24 (WOMAC: ES = 0.26), physical function deteriorated close to baseline
      values after 12 months. CONCLUSIONS: Comprehensive inpatient rehabilitation of
      patients with OA of the hip or knee may improve pain and physical function in the
      mid-term, and pain in the long term.

PMID- 15020329
TI  - Carboxymethylated chitin reduces MMP-1 expression in rabbit ACLT osteoarthritic
      cartilage.
AB  - OBJECTIVE: To examine the in vivo effects of carboxymethylated chitin (CMC),
      intra-articularly administered, on cartilage degradation and the level and
      distribution of cartilage matrix metalloproteinase-1 (MMP-1). METHODS:
      Osteoarthritis (OA) was induced in 20 rabbits by unilateral anterior cruciate
      ligament transection (ACLT). The experimental group, comprising 10 rabbits
      randomly selected, was given an intra-articular injection of 0.3 ml of 2% CMC
      solution at 1, 3, and 5 weeks after ACLT. A further 10 rabbits that received an
      intra-articular injection of 0.3 ml normal saline at the same time served as
      controls. All knees were harvested at 6 weeks after surgery. Cartilage
      degradation of femoral condyles was evaluated at two levels: macroscopic and
      light microscopic. Tissue level and distribution of MMP-1 was documented by
      reverse transcriptase-polymerase chain reaction (RT-PCR) and
      immunohistochemistry. RESULTS: Cartilage degradation in the control group was
      significantly more severe than that in the experimental group both on the
      macroscopic grading scale and on Mankin's grading scale. In RT-PCR the amount of
      MMP-1 was significantly reduced by the treatment of CMC. Immunohistochemical
      study showed that in the experimental group MMP-1 was predominantly expressed in
      the superficial and upper intermediate layers of cartilage, and the amount of MMP
      1 in the experimental group was also lower than that in control group.
      CONCLUSION: CMC significantly reduces the severity of cartilage degradation and
      reduces the expression of MMP-1 in cartilage, both at the mRNA and the protein
      level, and thus may be a potential drug for the treatment of OA.

PMID- 15020331
TI  - Should oligoarthritis be reclassified? Ultrasound reveals a high prevalence of
      subclinical disease.
AB  - OBJECTIVE: To determine the prevalence of subclinical synovitis using ultrasound
      (US) imaging of both painful and asymptomatic joints, in patients with early (<12
      months), untreated oligoarthritis (</=5 joints). METHODS: Eighty patients
      underwent a detailed clinical assessment by two physicians. All painful joints
      were identified, which were immediately scanned by a sonographer. In the last 40
      patients, an additional standard group of joints was scanned to establish the
      prevalence of synovitis in asymptomatic joints. RESULTS: In 80 patients, 644
      painful joints (with and without clinical synovitis) were identified and each
      underwent a US assessment. Of these joints, 185 had clinical synovitis, of which,
      US detected synovitis in only 79% (147/185). In the other 38 joints US
      demonstrated tenosynovitis instead of synovitis in 12 joints and possible, but
      not definite, synovitis in 11 joints. Fifteen joints were, however, normal on US.
      In 459 joints that were not clinically synovitic, US detected synovitis in 33%
      (150/459). In 64% (51/80) of patients, US detected synovitis in more joints than
      clinical examination and in 36% (29/80) of patients, US detected a polyarthritis
      (>6 joints). Of the 826 asymptomatic (non-painful) joints scanned, 13% (107/826)
      had US detected synovitis. CONCLUSION: Sonography detected more synovitis than
      clinical examination in patients with oligoarthritis. In almost two thirds of
      patients there was evidence of subclinical disease while one third could be
      reclassified as polyarticular. These findings suggest that a definition of
      oligoarthritis based purely on clinical findings may be inappropriate, which may
      have important implications for disease management.

PMID- 15020330
TI  - Expression and activity of citrullinating peptidylarginine deiminase enzymes in
      monocytes and macrophages.
AB  - BACKGROUND: Antibodies directed to proteins containing the non-standard amino
      acid citrulline, are extremely specific for rheumatoid arthritis (RA).
      Peptidylcitrulline can be generated by post-translational conversion of arginine
      residues. This process, citrullination, is catalysed by a group of calcium
      dependent peptidylarginine deiminase (PAD) enzymes. OBJECTIVE: To investigate the
      expression and activity of four isotypes of PAD in peripheral blood and synovial
      fluid cells of patients with RA. RESULTS: The data presented here show that
      citrullination of proteins by PAD enzymes is a process regulated at three levels:
      transcription-in peripheral blood PAD2 and PAD4 mRNAs are expressed predominantly
      in monocytes; PAD4 mRNA is not detectable in macrophages, translation-translation
      of PAD2 mRNA is subject to differentiation stage-specific regulation by its 3'
      UTR, and activation-the PAD proteins are only activated when sufficient Ca(2+) is
      available. Such high Ca(2+) concentrations are normally not present in living
      cells. In macrophages, which are abundant in the inflamed RA synovium, vimentin
      is specifically citrullinated after Ca(2+) influx. CONCLUSION: PAD2 and PAD4 are
      the most likely candidate PAD isotypes for the citrullination of synovial
      proteins in RA. Our results indicate that citrullinated vimentin is a candidate
      autoantigen in RA.

PMID- 15020333
TI  - The economic burden associated with osteoarthritis, rheumatoid arthritis, and
      hypertension: a comparative study.
AB  - OBJECTIVE: To compare the economic burden to society incurred by patients with
      RA, OA, or high blood pressure (HBP) in Ontario, Canada. METHODS: Consecutive
      subjects recruited by 52 rheumatologists (RA) and 76 family physicians (OA and
      HBP) were interviewed at baseline and 3 months. Information was collected on
      demographics, health status, and any comorbidities. A detailed, open ended
      resource utilisation questionnaire inquired about the use of medical and non
      medical resources and patient and care giver losses of time and related expenses.
      Annual costs were derived as recommended by national costing guidelines and
      converted to American dollars (year 2000). Statistical comparisons were made
      using ordinary least squares regression on raw and log transformed costs, and
      generalised linear modelling with adjustment for age, sex, educational
      attainment, and presence of comorbidities. RESULTS: Baseline and 3 month
      interviews were completed by 253/292 (86.6%) patients with RA and 473/585 (80.9%)
      patients with OA and/or HBP. Baseline and total annual disease costs for RA (n =
      253), OA and HBP (n = 191), OA (n = 140), and HBP (n = 142), respectively, were
      $9300, $4900, $5700, and US$3900. Indirect costs related to RA were up to five
      times higher than indirect costs incurred by patients with OA or HBP, or both.
      The presence of comorbidities was associated with disease costs for all
      diagnoses, cancelling out potential effects of age or sex. CONCLUSION: The
      economic burden incurred by RA significantly exceeds that related to OA and HBP,
      while differences between patients with a diagnosis of OA without HBP or a
      diagnosis of HBP alone were non-significant, largely owing to the influence of
      comorbidities.

PMID- 15020332
TI  - Anti-dsDNA antibodies and disease classification in antinuclear antibody positive
      patients: the role of analytical diversity.
AB  - BACKGROUND: The presence of "anti-DNA antibodies in abnormal titres" is a well
      established criterion for SLE classification, but there is no agreement on the
      performance of this test. OBJECTIVE: To study the correlation between clinical
      findings and five different solid and solution phase anti-DNA antibody assays.
      METHODS: 158 consecutively collected ANA positive sera were studied in a double
      blind fashion. Anti-DNA antibodies were determined by different solid phase
      assays (ssDNA-, dsDNA- specific ELISA, EliA anti-dsDNA assay, Crithidia luciliae
      assay), and by an experimental solution phase anti-DNA assay using biotinylated
      pUC18 plasmid, human, calf thymus, and E coli DNA. Antibody affinity was
      determined by surface plasmon resonance. Clinical data were obtained
      independently of the laboratory analyses and later related to the anti-dsDNA
      findings. RESULTS: Anti-dsDNA antibodies were most frequently detected by ELISA,
      but were not specific for SLE as they were present in up to 30% of other disease
      groups. Those detected by the Crithidia luciliae assay were predictive for SLE,
      while antibodies binding in solution phase ELISA using the pUC18 correlated
      strongly with the Crithidia luciliae assay. Surface plasmon resonance analysis
      showed that antibody binding to pUC18 was not due to higher relative affinity for
      dsDNA in general, but apparently to specificity for that plasmid DNA. Serum
      samples from three patients with lupus nephritis were positive in both pUC18
      solution phase and Crithidia luciliae assays. CONCLUSIONS: Assay principle
      selection is decisive for the detection of clinically significant anti-DNA
      antibodies. Revision of the anti-DNA antibody criterion in the SLE classification
      may be needed.

PMID- 15020334
TI  - Reduced functional performance in the lower extremity predicted radiographic knee
      osteoarthritis five years later.
AB  - BACKGROUND: Reduced quadriceps strength is an early finding in subjects with knee
      osteoarthritis, but it is not clear whether it is a cause or a consequence of
      knee osteoarthritis. OBJECTIVE: To determine whether reduced functional
      performance in the lower extremity predicts the incidence or progression of
      radiographic knee osteoarthritis. DESIGN: Prospective, epidemiological,
      population based cohort study. PATIENTS: 148 subjects (62 women), aged 35-54
      (mean 44.8), with chronic knee pain from a population based cohort. MEASUREMENTS:
      Predictors analysed were age, sex, body mass index, baseline knee pain, and three
      tests of lower extremity functional performance: maximum number of one-leg rises
      from sitting, time spent walking 300 m, and timed standing on one leg.
      Weightbearing tibiofemoral knee radiographs were obtained at baseline and after 5
      years (median 5.1, range 4.2-6.1), and classified according to Kellgren and
      Lawrence as no osteoarthritis (Kellgren and Lawrence = 0, n = 94) or prevalent
      osteoarthritis (Kellgren and Lawrence >/=1, n = 54). RESULTS: Fewer one-leg rises
      (median 17 v 25) predicted incident radiographic osteoarthritis five years later
      (OR 2.6, 95% CI 1.1 to 6.0). The association remained significant after
      controlling for age, sex, body mass index, and pain. No significant predictor of
      radiographic progression in the group with prevalent osteoarthritis was found.
      CONCLUSION: Reduced functional performance in the lower extremity predicted
      development of radiographic knee osteoarthritis 5 years later among people aged
      35-55 with chronic knee pain and normal radiographs at baseline. These findings
      suggest that a test of one-leg rises may be useful, and interventions aimed at
      improving functional performance may be protective against development of knee
      osteoarthritis.

PMID- 15020335
TI  - Clinical comorbidity in patients with osteoarthritis: a case-control study of
      general practice consulters in England and Wales.
AB  - OBJECTIVES: To determine patterns of clinical comorbidity in general practice
      consulters with OA and compare them with comorbidity in consulters without OA.
      METHODS: A case-control study nested in a one-year prevalence survey of
      consultations in 60 general practices in England and Wales. Cases were 11 375
      subjects aged 50 and over who had consulted with OA during the study year.
      Controls were 11 780 subjects matched for age and sex who had consulted during
      the study year, but not for OA. Morbidity outcomes were based on a standard
      clinical classification system. RESULTS: After adjusting for age, sex, and social
      class, cases were significantly more likely to have high levels of comorbidity
      than controls (2.35; 2.16 to 2.55). Significant OA comorbid associations with
      other musculoskeletal conditions included arthropathies (OR 2.26; 99% CI 1.50 to
      3.41), upper limb sprain (2.04; 1.38 to 3.00), synovial and tendon disorders
      (2.03; 1.54 to 2.68), and other joint disorders (2.00; 1.71 to 2.32). OA non
      musculoskeletal associations were with obesity (2.25; 1.73 to 2.92), gastritis
      (1.98; 1.46 to 2.68), phlebitis (1.80; 1.28 to 2.52), diaphragmatic hernia (1.80;
      1.29 to 2.51), ischaemic heart disease (1.73; 1.13 to 2.66) and intestinal
      diverticula (1.63; 1.20 to 2.23). CONCLUSIONS: Comorbidity for OA was extensive,
      with musculoskeletal as well as non-musculoskeletal conditions. Age, sex, and
      social class did not explain this comorbidity but propensity to consult may be a
      part explanation. An important question remains as to whether comorbidity in
      general practice significantly adds to the disability or further impairs the
      health of patients with OA.

PMID- 15020336
TI  - Evaluation of anti-citrullinated filaggrin antibodies as hallmarks for the
      diagnosis of rheumatic diseases.
AB  - BACKGROUND: Anti-filaggrin antibodies (AFA) are among the most specific
      antibodies for rheumatoid arthritis, so procedures for their detection should be
      included in early biological diagnoses. AFA can be detected by indirect
      immunofluorescence (anti-keratin antibodies, AKA) or by new enzyme immunoassays
      (EIA). Their comparative performance needs to be established. OBJECTIVE: To
      compare these technical procedures to optimise the serological diagnosis of
      rheumatoid arthritis. METHODS: Results obtained using AKA and EIA were compared
      in 271 sera from 140 patients with rheumatoid arthritis at various stages, 98
      patients with other autoimmune diseases, and 33 healthy subjects. EIA were
      successively undertaken with citrullinated linear filaggrin peptide (home made
      EIA) or cyclic citrullinated peptide (CCP2, commercial kits). Rheumatoid factor
      (RF) was assessed by EIA in all patients. RESULTS: Anti-CCP2 kits showed the best
      sensitivity and specificity (65% and 96%, respectively). Among the 140 patients
      with rheumatoid arthritis, those with very recent disease (less than six months'
      duration, n = 21) were studied as a separate group. In this group, the
      sensitivity of anti-CCP2 kits decreased to approximately 50%. Nevertheless this
      assay remained the most accurate when compared with AKA or home made EIA using
      linear filaggrin peptides. The combination of anti-CCP2 and RF only slightly
      increased the sensitivity of the diagnosis of very early rheumatoid arthritis.
      CONCLUSIONS: Kits using citrullinated cyclic peptides (CCP2) were more suitable
      than either AKA or EIA using linear filaggrin peptides for the diagnosis of early
      rheumatoid disease.

PMID- 15020338
TI  - Dose escalation of infliximab in clinical practice: improvements seen may be
      explained by a regression-like effect.
AB  - OBJECTIVE: To determine whether increased infliximab doses result in better
      clinical outcome in rheumatic diseases. METHODS: Subjects were 124 patients with
      rheumatoid arthritis treated with biological agents at a single institute. Index
      cases were 44 patients whose infliximab doses had been increased. Controls were
      patients treated with infliximab without dose increase (n = 44), and patients
      treated with etanercept (n = 36). Disease activity score (DAS28), ACR28 swollen
      joint counts, and numerical ACR responses were compared before and after dose
      increases. For the controls, the point at which the DAS28 value showed any
      increase (despite infliximab/etanercept treatment) was used as the reference time
      point. Comparisons were made between three sets of outcomes: best outcome
      achieved before the dose increase (cases) or before the reference time point
      (controls); outcomes at this point; and best outcomes after this point. RESULTS:
      Following dose increase, disease activity showed modest but statistically
      significant improvements. The improvement achieved after dosage escalation was
      equal to, but not better than, the best values before dose escalation. While this
      finding could be interpreted as "recapturing" the previous response, similar
      improvements were seen in both control groups. Thus the same pattern of worsening
      and subsequent improvement was seen with or without the infliximab dose increase.
      CONCLUSIONS: Clinical improvement with increased infliximab dose, and the
      impression that a previous response can be "recaptured" with higher doses, cannot
      be taken at face value, as similar improvements occurred in two control groups.
      The use of infliximab at doses higher than 3 mg/kg needs to be evaluated further.

PMID- 15020337
TI  - Increased levels of antibodies to cytokeratin 18 in patients with rheumatoid
      arthritis and ischaemic heart disease.
AB  - OBJECTIVE: To determine whether raised levels of antibodies to CK18 in patients
      with RA are associated with ischaemic heart disease (IHD). METHODS: IgA, IgG, and
      IgM antibodies to CK18 were measured by enzyme linked immunosorbent assay (ELISA)
      in patients with RA with (n = 34) or without (n = 28) IHD. The relationship
      between CK18 antibody levels and markers of inflammatory and/or cardiovascular
      disease was examined. RESULTS: Initial analysis showed that IgG antibody levels
      to CK18 were higher in patients with RA with IHD than in those without (50.1 v
      34.5 AU, p = 0.047), although significance was lost after correction for multiple
      comparisons. Further analysis showed a significant difference (p = 0.015) between
      patients with IHD and a positive family history, and patients without IHD and a
      negative family history (53.7 v 29.0 AU, Kruskal-Wallis multiple comparison Z
      value test). There was also a significant trend of increasing 10 year
      cardiovascular risk with increasing CK18 IgG antibody levels (p = 0.01). No
      association was found between CK18 antibody levels and conventional markers of
      inflammation or cardiovascular disease, but an association was found between
      levels of CK18 IgG and IgG antibodies to cytomegalovirus (CMV) (Spearman's r(s) =
      0.379, p(corr) = 0.04). No evidence for cross reactivity of CK18 antibodies with
      CMV antigens was found. CONCLUSION: Levels of IgG antibodies to CK18 are raised
      in patients with RA with IHD, particularly if they also have a positive family
      history. This may reflect damage to CK18 containing cells in the cardiac
      vasculature and/or in atherosclerotic plaques, and may be a useful additional
      marker for the identification of patients with, or likely to develop, IHD.

PMID- 15020339
TI  - Urinary tract infections and lupus erythematosus.
AB  - BACKGROUND: Infections are one of the main causes of morbidity and mortality in
      patients with systemic lupus erythematosus. OBJECTIVE: To analyse urinary tract
      infection (UTI) risk factors in lupus patients; the influence of these factors on
      disease activity, organ damage, and disease development; the type and prevalence
      of UTI; and the micro-organisms involved. METHOD: 86 control subjects and 81
      lupus patients were studied prospectively over a 12 month period and examined on
      five occasions. Epidemiological data and information on urinary symptoms, disease
      activity (SLEDAI), and organ damage (SLICC/ACR) data were collected.
      Autoantibodies, complement levels, urine culture, and antibiogram were
      determined; urological studies were also carried out. SPPS 10.0 and STATA 6.0.
      were used for statistical analysis. RESULTS: The prevalence of UTI in lupus
      patients was 36%. Lupus influences the onset of UTI (p = 0.001), regardless of
      other variables. UTI risk factors in lupus patients were age (p = 0.002),
      previous cases of UTI (p = 0.0001), antinuclear antibodies (ANA) >1/80 IU/ml (p =
      0.022), thrombocytopenia (p = 0.02), and admission to hospital due to UTI (p =
      0.002). Leucopenia (p = 0.09) and the weekly administration of methotrexate (p =
      0.06) had a bearing on the onset of UTI; disease development (p = 0.99), lupus
      activity (p = 0.32), and organ damage (p = 0.36) do not. The uropathogen most
      frequently isolated was E coli (60%). CONCLUSIONS: Lupus patients are likely to
      have UTI, usually manifesting in the lower tract. They are community acquired,
      basically caused by E coli, and favoured by age, previous UTI, admissions to
      hospital due to UTI, thrombopenia, ANA, leucopenia, and methotrexate treatments.

PMID- 15020340
TI  - Non-isotopic RNase cleavage assay for mutation detection in MEFV, the gene
      responsible for familial Mediterranean fever, in a cohort of Greek patients.
AB  - BACKGROUND: The MEFV gene is responsible for familial Mediterranean fever (FMF).
      Several disease associated mutations have been identified. The range of genetic
      variation in MEFV in Greek patients has not been determined. OBJECTIVE: To
      describe a method that facilitates the routine screening of the entire coding
      sequence of MEFV (excluding exon 1). METHODS: The non-isotopic RNase cleavage
      assay (NIRCA) was optimised and used as a first step screening method to screen
      exons 2 to 10 of MEFV. Exons 2 and 10 were analysed separately at DNA level,
      while exons 3 to 9 were analysed together at cDNA level. The sample group
      consisted of 26 FMF patients diagnosed using established clinical criteria, six
      asymptomatic relatives, 12 patients with atypical clinical manifestations, nine
      patients suffering from various inflammatory diseases, and three normal
      individuals. All were analysed by NIRCA for mutations in the MEFV gene and direct
      sequencing was applied subsequently to confirm the results. RESULTS: MEFV
      mutations were identified in 25 of 26 typical FMF patients and in two of 12
      patients with atypical manifestations. NIRCA results were in concordance with
      sequencing findings in all sequences analysed, suggesting that the method is
      highly reliable in this disease. Sixteen alterations of MEFV were identified
      (eight missense mutations and eight single nucleotide polymorphisms).
      CONCLUSIONS: NIRCA can be used for rapid screening of the coding sequence of the
      MEFV gene in patients suspected of suffering from FMF.

PMID- 15020342
TI  - A link between irritable bowel syndrome and fibromyalgia may be related to
      findings on lactulose breath testing.
AB  - BACKGROUND: An association between irritable bowel syndrome (IBS) and small
      intestinal bacterial overgrowth (SIBO) has been found. OBJECTIVE: To compare the
      prevalence and test results for bacterial overgrowth between IBS and
      fibromyalgia. METHODS: Subjects with independent fibromyalgia and IBS were
      compared with controls in a double blind study. Participants completed a
      questionnaire, and a lactulose hydrogen breath test was used to determine the
      presence of SIBO. The prevalence of an abnormal breath test was compared between
      study participants. Hydrogen production on the breath test was compared between
      subjects with IBS and fibromyalgia. The somatic pain visual analogue score of
      subjects with fibromyalgia was compared with their degree of hydrogen production.
      RESULTS: 3/15 (20%) controls had an abnormal breath test compared with 93/111
      (84%) subjects with IBS (p<0.01) and 42/42 (100%) with fibromyalgia (p<0.0001 v
      controls, p<0.05 v IBS). Subjects with fibromyalgia had higher hydrogen profiles
      (p<0.01), peak hydrogen (p<0.0001), and area under the curve (p<0.01) than
      subjects with IBS. This was not dependent on the higher prevalence of an abnormal
      breath test. The degree of somatic pain in fibromyalgia correlated significantly
      with the hydrogen level seen on the breath test (r = 0.42, p<0.01). CONCLUSIONS:
      An abnormal lactulose breath test is more common in fibromyalgia than IBS. In
      contrast with IBS, the degree of abnormality on breath test is greater in
      subjects with fibromyalgia and correlates with somatic pain.

PMID- 15020341
TI  - Tibial cartilage volume change in healthy postmenopausal women: a longitudinal
      study.
AB  - OBJECTIVE: To determine whether the amount of joint cartilage in healthy
      postmenopausal women is stable or changes over time, and whether oestrogen
      replacement therapy (ERT) influences this. DESIGN: A cohort study in healthy
      postmenopausal women without knee pain, initially selected on the basis of having
      either used ERT long term (more than five years) or never having used ERT.
      METHODS: 81 women (42 taking ERT and 39 non-users) had baseline knee radiographs
      and magnetic resonance imaging (MRI) on the dominant knee; 57 of these (70%) were
      followed with repeat MRI approximately 2.5 years later. Knee cartilage volume was
      measured at baseline and at follow up. Risk factors assessed at baseline,
      including ERT use, were tested for their association with change in knee
      cartilage volume over time. RESULTS: 29 subjects who were initially taking ERT
      and 28 non-users at baseline completed the study. Total tibial articular
      cartilage decreased, on average, by (mean (SD)) 2.4 (3.2)% per year (95%
      confidence interval for mean, 1.5% to 3.2%). Average annual reduction in medial
      and lateral tibial cartilage was 2.4 (3.6)% (1.4% to 3.3%) and 2.3 (4.2)% (1.2%
      to 3.4%), respectively. No association between ERT and the rate of reduction in
      cartilage volume was shown. CONCLUSIONS: Mean tibial cartilage volume loss in
      healthy postmenopausal women is between 1.5% and 3.2% a year. Whether this rate
      of change is similar throughout adult life or in men will require further
      investigation.

PMID- 15020343
TI  - Trabecular bone mass and bone formation are preserved after limb immobilisation
      in p53 null mice.
AB  - OBJECTIVES: To determine whether disruption of the p53 gene leads to preservation
      of trabecular bone volume (BV) after limb immobilisation. MATERIALS AND METHODS:
      Tibias of immobilised hind limbs of p53 gene knockout (p53(-/-)) and wild-type
      (p53(+/+)) mice were compared. Right knee joints of 8 week old mice were
      immobilised in full extension for 7 days. Trabecular structure and bone formation
      were similar in the p53(-/-) and p53(+/+) control groups. RESULTS: Immobilisation
      significantly reduced BV to 77% of the control in p53(+/+) mice, but no change
      was noted in p53(-/-) mice. After immobilisation, bone formation rate was
      significantly reduced in p53(+/+) but not in p53(-/-) mice. In bone marrow cell
      cultures the numbers of alkaline phosphatase positive colony forming units
      fibroblastic and mineralised nodules were significantly reduced by immobilisation
      in p53(+/+) but not in p53(-/-) mice. Immobilisation enhanced p53 mRNA expression
      in marrow cells of p53(+/+) mice and increased terminal dUTP nick end labelling
      positive osteocytes and marrow cells in p53(+/+) but not in p53(-/-) mice. Lack
      of p53 in immobilised mice was associated with preservation of trabecular bone
      mass and bone formation and suppression of significant apoptosis of marrow cells.
      CONCLUSION: Disruption of the p53 gene preserves trabecular bone mass and leads
      to bone formation after limb immobilisation.

PMID- 15020344
TI  - Multiple rib infarcts: a rare form of osteonecrosis in antiphospholipid syndrome.

PMID- 15020345
TI  - Symmetrical peripheral gangrene complicating Klebsiella pneumoniae sepsis
      associated with antiphospholipid antibodies.

PMID- 15020346
TI  - An unusual case of ankle arthropathy.

PMID- 15020347
TI  - Does etanercept monotherapy enhance the risk of Listeria monocytogenes
      meningitis?

PMID- 15020348
TI  - Autoantibodies against glucose-6-phosphate isomerase are not a diagnostic marker
      for juvenile idiopathic arthritis.

PMID- 15020350
TI  - Isolated cranial nerve syndromes without proximal carotid involvement in
      aortoarteritis.

PMID- 15020349
TI  - Haemorrhagic myositis associated with prophylactic heparin use in
      dermatomyositis.

PMID- 15020351
TI  - Myeloablative immunosuppressive treatment with autologous haematopoietic stem
      cell transplantation in a patient with psoriatic arthropathy and monoclonal
      gammopathy of undetermined significance.

PMID- 15020352
TI  - Peripheral blood lymphocyte phenotypes in patients with spondyloarthropathy.

PMID- 15020353
TI  - Fenofibrate and losartan.

PMID- 15020354
TI  - Treatment of resistant giant cell arteritis with etanercept.

PMID- 15020357
TI  - Clinical use of intensity-modulated radiotherapy: part II.
AB  - Intensity-modulated radiotherapy (IMRT) is a novel conformal radiotherapy
      technique which is gaining increasingly widespread use. This second clinical
      article aims to summarize the published data pertaining to prostate cancer,
      pelvic irradiation, gynaecological and breast cancer. Prostate cancer patients
      represent the largest group treated to date. The main indication has been
      radiation dose escalation within acceptable normal tissue late toxicity. Phase II
      data are promising, but no randomized clinical trial data are available to
      support its use. Pelvic IMRT aims to deliver radical radiation doses to pelvic
      lymph nodes while sparing the bowel and bladder. Indications for breast IMRT data
      are reviewed, and current data presented. Further data from randomized trials are
      required to confirm the anticipated benefits of IMRT in patients.

PMID- 15020356
TI  - Does it matter what a hospital is "high volume" for? Specificity of hospital
      volume-outcome associations for surgical procedures: analysis of administrative
      data.
AB  - OBJECTIVE: To determine whether the improved outcome of a surgical procedure in
      high volume hospitals is specific to the volume of the same procedure. DESIGN AND
      SETTING: Analysis of secondary data in Ontario, Canada. PARTICIPANTS: Patients
      having an oesophagectomy, colorectal resection for cancer,
      pancreaticoduodenectomy, major lung resection for cancer, or repair of an
      unruptured abdominal aortic aneurysm between 1994 and 1999. MAIN OUTCOME
      MEASURES: Odds ratio for death within 30 days of surgery in relation to the
      hospital volume of the same surgical procedure and the hospital volume of the
      other four procedures. Estimates were adjusted for age, sex, and comorbidity and
      accounted for hospital level clustering. RESULTS: With the exception of
      colorectal resection, 30 day mortality seemed to be inversely related not only to
      the hospital volume of the same procedure but also to the hospital volume of most
      of the other procedures. In some cases the effect of the volume of a different
      procedure was stronger than the effect of the volume of the same procedure. For
      example, the association of mortality from pancreaticoduodenectomy with hospital
      volume of lung resection (odds ratio for death in hospitals with a high volume of
      lung resection compared with low volume 0.36, 95% confidence interval 0.23 to
      0.57) was much stronger than the association of mortality from
      pancreaticoduodenectomy with hospital volume of pancreaticoduodenectomy (0.76,
      0.44 to 1.32). CONCLUSION: The inverse association between high volume of
      procedure and risk of operative death is not specific to the volume of the
      procedure being studied.

PMID- 15020358
TI  - Exclusion of brain lesions: is MR contrast medium required after a negative fluid
      attenuated inversion recovery sequence?
AB  - We hypothesized that in patients with negative fluid-attenuated inversion
      recovery (FLAIR) images T(2) weighted fast spin-echo (FSE) images and T(1)
      weighted spin-echo (SE) images before and after intravenous administration of
      gadolinium-based contrast medium display no pathology either. Thus, we assessed
      the negative predictive value of FLAIR images to rule out MR-detectable brain
      lesions. 1026 consecutive cranial MR examinations were reviewed. Routine MRI of
      the brain included T(1) weighted coronal imaging before and after administration
      of gadopentetate dimeglumine, axial T(2) weighted FSE and fast-FLAIR imaging. The
      FLAIR images were rated by two radiologists into categories of 0 (without
      pathologic changes) and 1 (with pathologic changes). Two other radiologists
      analysed the complete examination. In 284 MR examinations of the brain no
      abnormalities were found (28%). FLAIR-ratings were false-negative in four cases
      and false-positive in 30 cases. Sensitivity and specificity of the FLAIR sequence
      for MR-detectable brain lesions were 99.5% and 89.4%. The unselective application
      of gadolinium avoided one false-negative MR-reading and improved the sensitivity
      of the MR-examination from 99.5% to 99.6%. Positive and negative predictive
      values were 96.1% and 98.4%, respectively. The interobserver reliability was
      kappa=0.93 for the FLAIR-readers and 0.89 for the readers who rated the complete
      examination. In conclusion, negative FLAIR images provide a high negative
      predictive value for MR-detectable brain lesions. Thus, in patients with negative
      FLAIR images the unselective application of gadolinium seems to be unnecessary.

PMID- 15020359
TI  - Are T1 weighted images helpful in MRI of cervical radiculopathy?
AB  - MRI in patients with cervical myelopathy or radiculopathy usually includes T(1)
      weighted (T(1)W) and T(2) weighted (T(2)W) images. We prospectively examined a
      hypothesis that T(2)W alone is sufficient to diagnose the cause of cervical
      myelopathy and radiculopathy and that the T(1)W sagittal images do not provide
      additional useful information. 30 patients presenting with a history of cervical
      radiculopathy with or without myelopathy were prospectively assessed by MRI.
      Those with a history suggestive of intrinsic primary cord disease or who had
      previously had surgery were excluded. Two neuroradiologists, blinded to the
      clinical information, separately viewed the sagittal and axial T(2)W images
      alone, and at a later time, the full set of T(1)W and T(2)W images. Image
      quality, location and severity of disease and confidence of diagnosis at each
      level were scored on 4- or 5-point scales. The T(1) sequences did not demonstrate
      any significant lesions not already seen on the T(2)W images alone. The T(1)W
      sequence may safely be omitted in patients with radiculopathy.

PMID- 15020360
TI  - Hereditary intraosseous vascular malformation of the craniofacial region: imaging
      findings.
AB  - Benign vascular lesions can be classified into two categories depending on
      clinical behaviour and endothelial cell characteristics: neoplasms (haemangiomas)
      and vascular malformations. However, intraosseous vascular anomaly, previously
      called intraosseous haemangioma, is a very rare malformation. In our previous
      study, we described the first hereditary form of intraosseous vascular
      malformation of the craniofacial region, vascular malformation osseous (VMOS).
      Characteristic findings are autosomal recessive inheritance, severe and diffuse
      intraosseous vascular malformation in all craniofacial bones without soft tissue
      involvement and associated mid-line abnormalities such as umbilical hernia and
      supra-umbilical raphe. In this paper, we discuss the imaging findings of this new
      disorder in detail.

PMID- 15020361
TI  - Influence of the characteristic curve on the clinical image quality of lumbar
      spine and chest radiographs.
AB  - The "European Guidelines on Quality Criteria for Diagnostic Radiographic Images"
      do not address the choice of the film characteristic (H&D) curve, which is an
      important parameter for the description of a radiographic screen-film system. The
      image contrast of clinical lumbar spine and chest radiographs was altered by
      digital image processing techniques, simulating images with different H&D curves,
      both steeper and flatter than the original. The manipulated images were printed
      on film for evaluation. Seven experienced radiologists evaluated the clinical
      image quality by analysing the fulfilment of the European Image Criteria (ICS)
      and by visual grading analysis (VGA) of in total 224 lumbar spine and 360 chest
      images. A parallel study of the effect of the H&D curve has also been made using
      a theoretical model. The contrast (DeltaOD) of relevant anatomical details was
      calculated, using a Monte Carlo simulation-model of the complete imaging system
      including a 3D voxel phantom of a patient. Correlations between the calculated
      contrast and the radiologists' assessment by VGA were sought. The results of the
      radiologists' assessment show that the quality in selected regions of lumbar
      spine and chest images can be significantly improved by the use of films with a
      steeper H&D curve compared with the standard latitude film. Significant (p<0.05)
      correlations were found between the VGA results and the calculations of the
      contrast of transverse processes and trabecular details in the lumbar spine
      vertebrae, and with the contrast of blood vessels in the retrocardiac area of the
      chest.

PMID- 15020362
TI  - Anticipation and planning for anaesthesia provision within MR units in the UK.
AB  - We surveyed 33 UK MR units that have been developed by New Opportunity Funding
      (NOF) with reference to planning for and provision of anaesthetic services. The
      likely clinical and resource implications were documented. Units were developed
      predominantly in acute general hospitals with paediatric, critically ill and
      neuroscience patients represented. It may be predicted that up to 50% of newly
      built units will require anaesthetic provision and this should be anticipated at
      the planning stage. A senior anaesthetist should be involved in the planning
      process.

PMID- 15020363
TI  - Differences in proximal femur geometry distinguish vertebral from femoral neck
      fractures in osteoporotic women.
AB  - Bone mineral density (BMD) is generally used to predict the risk of fracture in
      osteoporotic subjects. However, femoral neck BMD and spine BMD have been reported
      not to be significantly different among patients with hip or vertebral fractures,
      suggesting that other risk factors are needed to determine the different fracture
      types. Proximal femur geometry (PFG) parameters, such as hip axis length (HAL),
      femoral neck-shaft angle (NSA) and femoral neck diameter (FND) have also been
      shown to predict the risk of hip fracture. These parameters are statistically
      different in spine fractures compared with both types of hip fractures
      (trochanteric and femoral neck) when considered together. We wanted to assess the
      difference in these parameters by comparing spine fractures with a homogeneous
      group of hip fractures, i.e. femoral neck fractures. 807 post-menopausal women
      were divided into three groups; those with vertebral fractures (182), those with
      femoral neck fractures (134) and a control group without fractures (491). Dual X
      ray absorptiometry (DXA) scans of the spine and hip were carried out to measure
      BMD and define the PFG parameters of the hip. Data were statistically analysed.
      In agreement with other authors, we found that women with femoral neck fractures
      had longer HAL, wider FND and larger NSA than controls, whereas there were no
      statistically significant differences in PFG between women with spine fractures
      and controls. Logistic regression showed HAL and NSA could predict the risk of
      femoral neck but not vertebral fracture. These data indicate specificity of some
      PFG parameters for hip fracture risk.

PMID- 15020364
TI  - Evaluation of the use of six diagnostic X-ray spectra computer codes.
AB  - A knowledge of photon energy spectra emitted from X-ray tubes in radiology is
      crucial for many research domains in the medical field. Since spectrometry is
      difficult because of high photon fluence rates, a convenient solution is to use
      computational models. This paper describes the use of six computer codes based on
      semiempirical or empirical models. The use of the codes was assessed, notably by
      comparing theoretical half value layers and air kerma with measurements on five
      different X-ray tubes used in a research hospital. It was found that three out of
      the six computer codes give relative spectra very close to those produced by X
      ray units equipped with constant potential generators: the mean difference
      between measured and modelled half value layer was less than 3% with a standard
      deviation of 3.6% whatever the tube and the applied voltage. Absolute output is
      less accurate: for four computer codes, the mean difference between the measured
      and modelled air kerma was between 18% and 36%, with a standard deviation of 9%
      whatever the tube (except for the single phase generator) and the applied
      voltage. One of the codes gives a good output and beam quality for X-ray units
      equipped with 100% ripple voltage generators. The use of computational codes as
      described in this paper provides a means of modelling relative diagnostic X-ray
      spectra, the usefulness of the tube output data depending on the accuracy
      required by the end user.

PMID- 15020365
TI  - Detection or decision errors? Missed lung cancer from the posteroanterior chest
      radiograph.
AB  - A test bank of verified chest radiographs was compiled for visual search
      experiments to investigate radiology performance in the detection of early lung
      cancer. A measure of the physical characteristics of the lesions was derived to
      determine the conspicuity (chi) of the nodules and to investigate possible causes
      of failed detection. Observer performance was measured by alternate free response
      operating characteristic (AFROC) methodology and was supplemented with visual
      search recording. Correlation of AFROC scores and the chi values was poor but
      inspection of the visual search recordings showed that most nodules were fixated.
      Fixations on missed lesions produced average dwell times greater than three times
      the minimum duration thought to be associated with detection. We conclude that
      the majority of errors were failures of decision rather than detection and
      comment on the implications of this for strategies to improve diagnostic
      effectiveness.

PMID- 15020366
TI  - Two- and three-dimensional ultrasound in the development of a needle-free
      injection system.
AB  - Ultrasound was used to assess a needle-free injection device for both intradermal
      and subcutaneous injections. The aim of this study was, first, to differentiate
      intradermal from subcutaneous injections, both in vivo and in vitro using 2D
      ultrasound, and second, to quantify the amount of injectate that actually arrives
      within the dermis or subcutaneous tissues using volume measurements derived from
      high-resolution 3D ultrasound data sets, using a freehand system (Stradx),
      developed by the Cambridge University Departments of Engineering and Radiology.
      For the in vitro study the devices were filled with dye and injected into a pig
      preparation. The injection site was examined with high-resolution ultrasound and
      subsequently dissected to locate the injected dye with respect to the dermis. For
      the in vivo study, 8 volunteers received needle-free injections of normal saline.
      High-resolution 2D images and 3D data sets were obtained of the injected sites.
      Proprioceptive information for the 3D data sets was produced using an optically
      tracked freehand system. Segmentation of the 3D data sets gave an estimation of
      the volume of injected material (injectate) within the dermis. The results
      demonstrated that 2D ultrasound could identify the location of the injectate in
      the in vitro experiments and successfully distinguished an intradermal from a
      subcutaneous injection. In the in vivo study, 2D ultrasound clearly demonstrated
      the injectate location within the volunteers' dermis but was less able to
      demonstrate the dispersion of injectate within the subcutaneous tissues.

PMID- 15020367
TI  - Hydrocele of the canal of Nuck in a girl: ultrasound and MR appearance.
AB  - Hydrocele of the canal of Nuck is a rare condition in females. A small
      evagination of parietal peritoneum forms the canal of Nuck. Failure of complete
      obliteration of the canal results in either an indirect inguinal hernia or a
      hydrocele of the canal of Nuck. We present a case in a 7-year-old girl. On
      ultrasound, there was a comma-shaped cyst with the tail directed cranially toward
      the inguinal canal. The cyst had no internal echoes and demonstrated increased
      through transmission. Coronal and axial MR showed a thin walled cystic mass.

PMID- 15020368
TI  - Benign complications of expandable metal stents used in the palliation of
      oesophageal carcinoma: two case reports.
AB  - We describe two patients who were treated with self-expanding metal stent (SEMS)
      insertion as palliation of malignant oesophageal strictures. Both patients re
      presented with dysphagia several months after SEMS insertion due to benign
      strictures. Initial treatment with balloon dilation and medical management had
      limited success so both patients had further SEMS inserted across the secondary
      benign strictures. This provided very good symptomatic relief. Chemotherapy and
      chemo-radiation in patients with inoperable oesophageal carcinoma are prolonging
      patient survival. As patients survival lengthens benign complications of SEMS may
      become an increasing clinical problem.

PMID- 15020370
TI  - Ultrasound diagnosis of paratesticular rhabdomyosarcoma.
AB  - Rhabdomyosarcoma is the most common tumour of the lower genitourinary tract in
      children in the first two decades. Paratesticular rhabdomyosarcoma is associated
      with a significantly better outcome than lesions elsewhere in the genitourinary
      tract. Although ultrasound is considered the imaging modality of choice for
      evaluating intrascrotal pathology, the ultrasound appearance of paratesticular
      rhabdomyosarcoma has rarely been reported and may be confused with other disease
      entities such as epididymitis, adenomatoid tumour and leiomyoma. We present the
      ultrasound features of a paratesticular rhabdomyosarcoma, discussing the clinical
      features and differential diagnosis.

PMID- 15020369
TI  - Appearance of a type B duplex appendix on barium enema.
AB  - Anomalies of the appendix are rare and are usually found in the adult population
      as an incidental finding during the course of surgery. We describe the
      appearances of a Type B duplicated appendix demonstrated on a barium enema for
      the first time. A review of the literature is presented with a discussion of
      different forms of duplicated appendices and the clinical significance of this
      finding.

PMID- 15020371
TI  - Castleman's disease of the neck: a description of four cases on contrast-enhanced
      CT.
AB  - Castleman's disease of the neck is an uncommon benign lymphoproliferative disease
      that usually presents as homogeneously enhancing enlarged lymph nodes on contrast
      enhanced CT scan. We described the appearance of four confirmed cases of
      Castleman's disease of the neck on contrast-enhanced CT scan. Three of these
      presented as a solitary enhancing lymph node and the fourth case presented with
      multiple bilateral enhancing lymph nodes. A central non-enhancing area was
      present in two of the three cases that presented as a solitary node. Pathological
      correlation of one of these cases showed that this was due to a central fibrotic
      scar. One of the enhancing nodes in the fourth case with multiple and bilateral
      lymphadenopathy also contained a central non-enhancing area. We would like to
      propose that if a central non-enhancing scar is observed in an enhancing lymph
      node in the neck on CT scan, Castleman's disease should be considered as a
      possible diagnosis.

PMID- 15020372
TI  - False positive fluorine-18 fluorodeoxy-D-glucose positron emission tomography
      finding caused by osteoradionecrosis in a nasopharyngeal carcinoma patient.
AB  - Nasopharyngeal carcinoma (NPC) is treated by radiotherapy with or without
      chemotherapy. It is not uncommon to find the residual/recurrent lesion in the
      skull base area. For patients who had received radiotherapy, it is difficult to
      differentiate the skull base tumour from post-treatment change in the CT or MRI.
      (18)F-2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) provides
      an alternative diagnostic choice in this situation for head and neck cancer
      including NPC especially when there is inconclusive CT/MRI finding. This report
      of an NPC patient who received radiotherapy 18 months previously, describes the
      misdiagnosis of tumour recurrence at the skull base found in both MRI and FDG PET
      scan. Histopathological studies showed osteoradionecrosis of the debrided tissue
      and follow-up PET showed complete regression of the skull base lesion. Therefore,
      a false positive result in FDG PET caused by osteoradionecrosis was confirmed. To
      the best of our knowledge, this is the first case report in the literature.

PMID- 15020373
TI  - Prosthetic mesh used for inguinal and ventral hernia repair: normal appearance
      and complications in ultrasound and CT.
AB  - The use of prosthetic mesh has now become accepted practice in the treatment of
      patients with both inguinal and ventral hernias. This pictorial review
      illustrates the various radiological appearances of these meshes and also
      demonstrates the post-operative complications associated with their implantation.

PMID- 15020374
TI  - Multiple cerebral enhancing lesions in an acutely ill child.

PMID- 15020376
TI  - Primary care research in the postmodern world.

PMID- 15020377
TI  - Why hypertensive patients do not comply with the treatment: results from a
      qualitative study.
AB  - BACKGROUND: Medical non-compliance has been identified as a major public health
      problem in the treatment of hypertension. There is a large research record
      focusing on the understanding of this phenomenon. However, to date, the majority
      of studies in this field have been focused from the medical care perspective, but
      few studies have focused on the patients' point of view. OBJECTIVE: Our aim was
      to identify factors related to non-compliance with the treatment of patients with
      hypertension. METHODS: We use a qualitative study in which data were gathered
      from seven focus group discussions conducted in March-May 2001. Patients were
      identified as non-compliant, using the Morisky-Green test, at two primary health
      care centres of the Spanish National Health Service. RESULTS: A complex web of
      factors was identified that influenced non-compliance. Patients had fears and
      negative images of antihypertensive drugs. The data also revealed a lack of basic
      background knowledge about hypertension. The clinical encounter was viewed as
      unsatisfactory because of its length, few explanations given by the physician and
      low physician-patient interaction. CONCLUSIONS: Most of the factors related to
      poor compliance have implications for patient management. Knowing patients'
      priorities regarding the most important aspects of care that have high potential
      for low compliance may be helpful in improvement of the quality of hypertensive
      patient care.

PMID- 15020378
TI  - Patients in waiting: a qualitative study of type 2 diabetes patients' perceptions
      of diagnosis.
AB  - OBJECTIVE: Our aim was to examine how diagnosis is perceived by a sample of newly
      diagnosed type 2 diabetes patients. METHODS: A qualitative study was carried out
      in the Lothian region of Scotland using in-depth interviews of 40 newly diagnosed
      type 2 diabetes patients recruited from 16 general practices in four Local Health
      Care Co-operatives and three hospital clinics. Purposive selection ensured that
      the sample's demographic characteristics were broadly representative of newly
      diagnosed type 2 diabetes patients in Lothian/Scotland. RESULTS: Clarity, timing
      and authority of the diagnosis delivery were highly salient for patients. Many
      patients perceived their GP as unwilling to deliver/confirm the diagnosis.
      Patients who were not referred to hospital were unclear why a referral had not
      taken place. Those referred perceived confirmation of diagnosis by the consultant
      as a central reason. Waiting for a hospital appointment could be problematic for
      patients. Most wanted the diagnosis confirmed before they felt confident making
      lifestyle changes. Input from health services during the period prior to the
      hospital visit was highly valued. Waiting was taken by some asymptomatic patients
      to indicate that they did not have the condition. Others used a lengthy period of
      waiting to confirm their view that they had a 'milder' or 'less serious' form of
      diabetes than other patients. CONCLUSIONS: Adequate input from practitioners is
      needed to ensure that diagnosis is fully exploited as a crucial period in which
      patients learn to adapt to their condition. Being explicit about the diagnosis at
      first contact may avoid the problem of patients feeling 'in limbo' or uncertain
      whether they have type 2 diabetes. Practitioners should convey to patients that
      post-diagnosis/initial care is a process, stages of this process should be
      clarified to avoid misunderstanding and services should be integrated during this
      interim period to best effect.

PMID- 15020379
TI  - Abusive behaviour experienced by primary care receptionists: a cross-sectional
      survey.
AB  - BACKGROUND: Receptionists act as gatekeepers to GPs, and thus are often placed in
      situations of conflict. However, there is a lack of research in this area.
      OBJECTIVE: The purpose of this study was to identify the incidence and
      associations of verbal and physical abuse against primary care receptionists,
      both pre- and post-'zero tolerance'. METHODS: A postal questionnaire was
      designed, piloted and sent to all reception staff in 50 randomly selected general
      practices in Leeds. The primary purpose was to identify any verbal or physical
      abuse experienced in the 12 months prior to the survey and assess the association
      between abuse experienced and deprivation. RESULTS: Seventy percent of
      receptionists completed and returned the questionnaire. Over two-thirds of
      receptionists had experienced verbal abuse in the last year. During the same time
      period, 60% reported telephone abuse and 55% reported face to face abuse. The
      incidence of abuse was higher in the year prior to the study than in the
      preceding period. Practice deprivation was identified as a significant factor for
      verbal abuse (P = 0.003). CONCLUSION: Verbal abuse against receptionists is
      significantly associated with the level of deprivation of the practice area.
      There is no evidence that 'zero tolerance' led to a reduction in abuse
      experienced by primary care receptionists. All primary care receptionists should
      receive adequate training on managing abuse.

PMID- 15020380
TI  - Alternative forms of consulting: survey of patients and GPs about their
      consultations.

PMID- 15020381
TI  - Teenagers and their family practitioner: matching between their reasons for
      encounter.
AB  - OBJECTIVES: The aim of this study was to analyse the reasons for encounter of
      teenagers in family practice and to compare them with the reasons recorded by
      their family practitioner (FP). METHODS: This cross-sectional study involved 91
      FPs from the Paris area and from the French-speaking part of Belgium. The
      teenagers (12-17 years old) filled in an auto-administered questionnaire in the
      waiting room of their FP during a 1-week period. The doctor independently filled
      in a similar form after the consultation. Both questionnaires were matched
      afterwards to assess the concordance between the reasons for encounter recorded
      by the young patient and by his/her FP. RESULTS: More than 100 reasons for
      encounter were given by 457 teenagers. The majority of the complaints were
      respiratory (26%), general health (18.5%), osteoarticular (15%), digestive (11%)
      and neurological problems (9.5%). Gender did not influence the nature of the
      complaints, but age played a role. The older teenagers had more respiratory
      complaints, general and pregnancy/contraception problems. In 80% of the cases,
      the ailments listed by the teenagers were picked up by the practitioner. In 18%
      of the consultations, the FP recorded problems that had not been noted by the
      patient. CONCLUSION: Many common and a few serious although frequent youth
      problems were found among the reasons for encounter. Most of them were recorded
      by the practitioner. Time and communication skills are important to give the
      opportunity to the teenager to share sensitive topics with his/her FP.

PMID- 15020382
TI  - Patients' use of GPs and community pharmacists in minor illness: a cross
      sectional questionnaire-based study.
AB  - BACKGROUND: Despite pharmacists having increased involvement in managing minor
      illness, many patients continue to attend their GP with problems that could be
      managed by community pharmacists. OBJECTIVE: Our aim was to investigate the
      prevalence of visits to the GP that GPs felt could be managed by a pharmacist,
      and to explore patients' reasons for such visits. METHODS: This cross-sectional
      questionnaire study was conducted at 13 general practices in West Sussex, UK. A
      questionnaire was given to all patients attending appointments with their GP in
      these practices over a 1-week period, asking what the presenting problem was and
      whether the advice of a pharmacist had been sought. If patients had not sought
      the advice of a pharmacist, they were asked why not. The GP was then asked to
      indicate whether, in their opinion, the patient's problem could have been managed
      by a community pharmacist. RESULTS: The response rate was 94% (3984),
      representing 87% of all patients consulting their doctor during the week of the
      study. GPs felt that only 7% (260) of these visits could have been managed by a
      community pharmacist. The proportion of 'unnecessary' visits was significantly
      higher (P < 0.001) amongst young adults, those presenting with new medical
      problems and those consulting about a child's health. Skin and musculoskeletal
      problems were the most common causes of 'unnecessary' visits to the GP. The
      majority of patients making 'unnecessary' visits (59%) disagreed with the GP and
      felt that the pharmacist would not have been appropriate for their problem.
      CONCLUSIONS: GPs and patients were, on the whole, in agreement over which
      conditions were appropriate for GP attention. There is, however, a need for
      education to increase awareness of the roles of pharmacists, aimed particularly
      at young adults and at those with children.

PMID- 15020383
TI  - Engaging the reluctant GP in care of the opiate misuser: Pilot study of change
      orientated reflective listening (CORL).
AB  - BACKGROUND: The GP is central to plans for improved general health care and
      increased availability and delivery of addiction treatment to drug misusers in
      the UK. Attention to the actual quality of overall primary care, rather than just
      the treatment of dependence, has, however, been limited. OBJECTIVES: The purpose
      of this study was to test the feasibility of delivery and potential value of a
      brief motivational enhancement intervention targeting the quality of primary care
      given to opiate misusers by GPs. METHOD: This study had an observational 'before
      and after' design with follow-up assessment after 2-3 months. The target
      population was all GPs in two Primary Care Groups who had neither attended
      training events nor were involved in the treatment of drug dependence (n = 66),
      who were then approached via a telephone-administered change-orientated
      reflective listening intervention, based on principles of motivational
      interviewing, with informational adjunct. Outcome measures for the study sample
      (n = 29) were overall therapeutic commitment and motivation to follow up and
      actual clinical activity and willingness to deliver specified general health care
      interventions for drug misusers. RESULTS: Across the study sample, therapeutic
      commitment improved over time, whilst motivation did not. Change among individual
      practitioners in receipt of the intervention was observed in both positive and
      negative directions, and in four of the positive changers, this was judged
      attributable to the intervention. Positive changes were more than twice as
      frequent as negative changes. CONCLUSIONS: The direction and extent of change
      detected were encouraging. Further initiatives are needed to influence
      practitioner motivation, based on improved understanding of GPs' views on the
      delivery of primary care for drug misusers.

PMID- 15020384
TI  - GPs' and physicians' interpretation of risks, benefits and diagnostic test
      results.
AB  - BACKGROUND: Understanding pre-test probability and baseline risks helps to
      interpret the results of diagnostic tests and the benefits of treatment, but how
      good is the understanding of these concepts? OBJECTIVES: Our aim was to assess
      the ability of GPs and consultant physicians to make accurate estimates and
      understand the application of pre-test probability and baseline risk for two
      common clinical conditions. METHODS: A two-stage questionnaire survey based on
      case scenarios of patients with angina and congestive heart failure was carried
      out of 202 physicians, randomly selected from the members of the Royal College of
      Physicians in the NW of England, 205 GPs randomly chosen from the practice list
      of the NW Health Authorities and 128 MRCGP examiners attending an examiners
      meeting. A total of 115, 106 and 81 members of these groups, respectively,
      responded to the first stage, and 44, 46 and 64 to the second. The main outcome
      measures were the stated likelihood of true ischaemic heart disease (IHD) being
      present and the predicted 1-year mortality; the impact of changing prevalence and
      baseline risk on these results; and interpretation of different methods of risk
      presentation. RESULTS: Estimates of pre-test probability of IHD being present
      ranged from 5 to 100% and of baseline risk of 1-year mortality from 0 to 86%.
      More GP examiners and consultant physicians understood the impact of increasing
      age on the test result than did the random sample of GPs. A majority of each
      group correctly said that increasing age would reduce the number needed to treat
      (NNT). Presentation of benefit as relative risk reduction was a greater stimulus
      to starting treatment than the NNT or measures of population impact. CONCLUSION:
      Clinicians should collect data to allow a better knowledge of the likelihood of
      disease and of baseline risk in their patient populations. Methods to increase
      the understanding of the influence of pre-test probability on diagnostic test
      results and of how to quantify and demonstrate the impact of the benefit of
      interventions should be explored.

PMID- 15020385
TI  - Quality indicators and variation in primary care: modelling GP referral patterns.
AB  - BACKGROUND: Health agencies frequently seek to develop indicators of the quality
      and performance of work done by clinicians. The validity of such indicators is a
      subject of debate among clinicians and health managers. OBJECTIVES: Our aim was
      to quantify the effects of chance and small caseload on an indicator of referral
      behaviour for GPs. METHODS: The study used random simulation of GP referral to
      physiotherapy and variance components analysis of routinely collected accident
      insurance data. It analysed 129 079 episodes of accident-related back pain in New
      Zealand which were managed by 2679 GPs. The main outcome measure was the
      percentage of back pain cases referred for physiotherapy and for specialist
      assessment and by each GP. RESULTS: The observed number of GPs who refer to
      physiotherapy at high levels is satisfactorily accounted for by chance. The
      variability of practice among GPs within any one area is not related to the
      absolute level of referral. CONCLUSION: The primary care setting, in which a low
      caseload for any one condition is the norm, presents challenges for measuring
      clinical performance. An emphasis upon changing the behaviour of GPs with
      extremely high levels on a performance indicator cannot necessarily be expected
      to have an impact upon the level of the indicator across a geographic area.
      Indicators for quality improvement should be used across whole populations of
      practitioners, rather than used to focus upon extremely high referring
      individuals.

PMID- 15020386
TI  - Choosing to attend an asthma doctor: a qualitative study in adults attending
      emergency departments.
AB  - BACKGROUND: Asthma treatment guidelines currently recommend a 'therapeutic
      partnership' to achieve best care. It is frequently assumed that individuals
      presenting to emergency departments with asthma do not have a good doctor-patient
      relationship. We asked what is the nature of patients' relationships with their
      doctors in those presenting to hospital emergency departments for asthma care.
      METHODS: A qualitative study of all consenting individuals aged 18-70 years who
      presented to a hospital emergency department over 2 months was carried out. Sixty
      two participants (19 male) engaged in in-depth interviews which were taped,
      transcribed and underwent thematic analysis. Questionnaire data were also
      collected and asthma severity determined. RESULTS: Nearly all patients (61/62)
      had a doctor whom they saw for their asthma. Patients made thoughtful choices on
      where they sought care according to their needs. Our findings identified that
      perceptions of doctors' competence, listening to patients and time constraints
      were important influences on doctor-patient relationships. Participants had
      strong expectations that their personal disease experience would be acknowledged
      by their doctors. CONCLUSION: This group of patients had doctors who cared for
      their asthma. The acceptability of medical care was determined as much by patient
      choice as by the quality of the doctor-patient relationship.

PMID- 15020388
TI  - The impact of a general practice co-operative on accident and emergency services,
      patient satisfaction and GP satisfaction.
AB  - BACKGROUND: The advent of general practice co-operatives represented a
      fundamental change in the delivery and organization of out-of-hours services.
      Concerns have been voiced that co-operatives might impact adversely on workload
      in accident and emergency (A&E) departments. OBJECTIVE: The purpose of this study
      was to assess the impact of establishing a general practice co-operative on use
      of A&E services, patient satisfaction and GP satisfaction. METHODS: A controlled
      before and after study of a GP co-operative in Sheffield, UK was carried out. A
      postal questionnaire was sent to 26 911 people, 13 442 before and 13 469 after
      the opening of the co-operative, to determine service use, in particular A&E
      attendance, in the previous 4 weeks. Patient satisfaction was assessed through
      structured interviews with 653 patients. GP satisfaction was assessed using a
      postal survey of all 98 Sheffield practices 2 years after the opening of the co
      operative. RESULTS: There was no change in the use of A&E services, odds ratio =
      1.08 (95% confidence interval 0.60-1.94). There was no change in patient
      satisfaction overall, mean difference 0.02 (-0.32 to 0.36). Sixty-seven per cent
      of doctors in member practices were much more satisfied with out-of-hours duty
      compared with 10% in non-member practices (P < 0.001). CONCLUSIONS: General
      practice co-operatives have been successful in achieving their policy objectives,
      improving GP morale without jeopardizing patient satisfaction or impacting
      adversely on A&E services.

PMID- 15020387
TI  - Six month outcomes after emergency admission of elderly patients to a community
      or a district general hospital.
AB  - BACKGROUND: Emergency admissions account for 40% of National Health Service bed
      usage. Recent policy is to increase the role of intermediate care, which includes
      the use of community hospitals (CHs). However, the proposed expansion presumes
      that CH care is as effective as acute hospital care. No direct comparison of
      outcomes between CHs and district general hospitals (DGHs) has been undertaken.
      OBJECTIVES: The aim of this study was to compare patient-based outcomes at 6
      months following emergency admission to a DGH or CH. METHODS: We designed a
      prospective cohort study, with strict eligibility criteria. The study was set in
      one DGH and five CHs in Devon, UK. Study participants were people aged >70 years
      with an acute illness requiring hospital admission, but whose condition could
      have been treated in either hospital setting. A cohort of people admitted to each
      setting was identified and followed-up for 6 months. The primary outcome measure
      was change in quality of life 6 months after admission, as measured by SF-36 and
      EuroQol. Secondary outcome measures were death, readmission and place of
      residence at 6 months. The use of drugs and investigations during the hospital
      stay were also measured. RESULTS: A total of 376 patients were recruited and
      completed baseline measures, 254 of whom were followed-up at the 6-month stage
      (136 CH, 118 DGH). There were no differences in outcome between settings, with a
      small increase in quality of life scores at 6 months in both cohorts: the mean
      change in EuroQol 5D in CH was 6.6 points (95% confidence interval, 2.8-10.4) and
      in DGH was 6.5 (2.4-10.7); P = 0.97. Mortality and place of residence at 6 months
      were similar in the two groups. The numbers of investigations (median CH four
      investigations, DGH 22; P < 0.001) and of prescribed medications during the
      hospital stay (median CH eight drugs, DGH 11; P < 0.001) were significantly
      higher in the DGH. CONCLUSIONS: The quality of life and mortality in the CH
      cohort was similar to those in the DGH cohort. CH care can be used as an
      alternative to DGH care for a wide range of conditions requiring emergency
      admission.

PMID- 15020389
TI  - Learning with computerized guidelines in general practice?: A randomized
      controlled trial.
AB  - BACKGROUND: Evidence-based guidelines are seen as an important instrument to
      transfer scientifically generated knowledge into daily clinical practice and to
      ensure high standards of clinical care. Despite wide promulgation, clinical
      guidelines so far have a limited impact on individual professional learning and
      on changing daily medical practice. OBJECTIVES: Our aims were (i) to study a
      potential knowledge increase among German GPs after implementation of web- and
      evidence-based guidelines and (ii) to identify and analyse potential barriers to
      individual professional learning with computerized guidelines. METHODS: A
      prospective, randomized controlled trial was conducted including 72 GPs (21%
      female, 79% male). The intervention group (n = 38) had access to clinical
      guidelines via the Internet or CD-ROM, the control group had not (n = 34). Both
      groups received a standardized two-part questionnaire. An increase of knowledge
      was measured with 25 multiple choice questions related to four different medical
      topics. In addition, reasons for using or not using computerized guidelines were
      analysed after access to guidelines was open to all participating physicians.
      RESULTS: There was no significant knowledge increase in the intervention group (P
      = 0.69). Twenty-two (58%) GPs of the intervention group had used the guidelines.
      Unspecified curiosity (76%) and a specific medical question (38%) were
      predominant motives for usage among physicians who had used the guidelines. Among
      'non-users', 78% stated 'lack of time' as the main reason for not using
      guidelines. CONCLUSION: An efficient knowledge transfer through computerized
      guidelines was not achieved. Usage, individual learning and potential
      implementation depend on adequate incentives and pragmatic aspects of clinical
      practice: easy and quick access.

PMID- 15020390
TI  - Health and the Internet--changing boundaries in primary care.
AB  - BACKGROUND: Little is known about the frequency with which information from the
      Internet is presented by patients within primary care consultations or the
      subsequent impact that it may have on those consultations. OBJECTIVES: The aims
      of this study were to describe the frequency with which Internet information was
      presented within primary care consultations in one inner-city health authority
      and to describe the characteristics of the subsequent consultation from the
      perspective of the health professionals involved. METHODS: A postal survey was
      used to estimate the frequency of Internet information presentation and eight in
      depth interviews were used to obtain health professionals' perceptions of the
      consultations that followed. RESULTS: Presentation of information from the
      Internet was relatively infrequent within primary care at the time of the survey
      (November 2000 to March 2001), but frequencies of presentation were higher for
      GPs than for any other health professional group. Health professionals have
      stereotypical views of Internet users and fear for their own professional status
      in relation to the Internet-informed patient or client. CONCLUSIONS: Although
      presentation of information from the Internet to date remains relatively
      infrequent, health professionals appear to feel threatened by it and adopt
      strategies that minimize its impact on the subsequent consultation.

PMID- 15020391
TI  - Doctors' prediction of certified sickness absence.
AB  - BACKGROUND: Doctors' ability to predict the duration of their patients' certified
      sickness absence is important for follow-up efforts aimed at patients with
      increased probability of long-term absence. OBJECTIVES: The aim of this study was
      to examine the accuracy of doctors' predictions of their patients' sickness
      absence status 4 weeks ahead, and which factors were associated with it. METHODS:
      A questionnaire survey was carried out in primary health care concerning 796
      patients certified sick within 140 days after the start of absence. The episodes
      of absence were labelled short-standing (up to 2 weeks) and long-standing (from 3
      to 20 weeks), at the time of consultation. The doctors' prediction of the
      patients' absence status 4 weeks ahead, diagnoses, work ability, clinical
      information sources used and the presence of non-medical factors that could have
      influenced the doctors' work ability assessments were collected. The predictions
      were compared with the patients' absence status 4 weeks later by positive
      predictive values (PPVs) for the statements 'returned to work' and 'still
      certified sick'. Factors associated with the accuracy of the predictions were
      analysed by multiple logistic regression analyses. RESULTS: The doctors
      accurately predicted return to work in 84% [95% confidence interval (CI) 79-87]
      of the cases in short-standing episodes, and in 53% (43-62) in long-standing
      episodes. The corresponding PPVs for still certified sick were 72% (62-80) and
      91% (85-94). In short-standing episodes, the doctors' probability of making
      accurate predictions was higher for respiratory disorders [odds ratio (OR) 2.84;
      95% CI 1.36-5.90], than for the reference category 'all other disorders', and
      lower for mental disorders (0.46; 0.24-0.89). In long-standing episodes, the
      probability was lower for musculoskeletal disorders (0.33; 0.12-0.86) and
      injuries (0.12; 0.03-0.48). Neither the age nor gender of patients or doctors,
      nor the degree of work ability reduction, nor other factors were associated with
      the accuracy of the predictions. CONCLUSIONS: The doctors' predictions were
      highly accurate for return to work in short-standing episodes, and for still
      certified sick in long-standing episodes. Diagnoses were associated with the
      accuracy; other factors, including the doctors' work ability assessments, were
      not.

PMID- 15020392
TI  - Medically unexplained symptoms: perceptions of physicians in primary health care.
AB  - BACKGROUND: Patients presenting with multiple symptoms represent a substantial
      part of a GP's total work load. At the same time, these patients account for the
      majority of the people on long-term sick-leave in Sweden today. OBJECTIVE: The
      aim of this study was to explore GPs' perceptions and ways of managing patients
      with medically unexplained symptoms (MUS). METHODS: Five focus group discussions
      were conducted with a total of 27 GPs. In the collection and analysis of data, a
      phenomenographic approach was used. RESULTS: The GPs described how they used four
      different approaches to manage patients with MUS: a biomedical, a psychological,
      an educational and a psychosocial approach. Different approaches were used,
      depending on the patient and the situation, and the GPs even switched approach
      when working with the same patient. CONCLUSIONS: In their work with patients with
      MUS, GPs need support and further training to improve the way the biomedical
      frame of reference is integrated with the humanistic perspective.

PMID- 15020393
TI  - Patients' experiences of medication for anxiety and depression: effects on
      working life.
AB  - BACKGROUND: and objectives. The prevalence of depression and anxiety has
      increased in recent years, leading to extensive use of medication. This study
      used a qualitative, in-depth approach to investigate patients' experiences of
      taking medication prescribed for these conditions. Sampling from a range of
      occupational sectors, the research explored the impact of medication on working
      life. METHODS: The research involved nine focus groups with sufferers of anxiety
      and depression to investigate the personal experiences of mental ill-health and
      the impact of psychotropic drugs. A further three focus groups were conducted
      with staff in human resources, personnel, occupational health, and health and
      safety departments, to explore the organizational perspectives on psychotropic
      medication in the workplace. Focus groups were held at Loughborough University
      and at workplace settings throughout the UK. Results were presented to an expert
      panel (comprising practitioners and researchers in health care and occupational
      health) to consider implications for practice. RESULTS: Physical symptoms
      associated with anxiety and depression included: nausea, headaches, dizziness,
      trembling, insomnia and lack of energy. Psychological symptoms involved: poor
      concentration, emotional distress and lack of motivation. Non-compliance was
      widespread due to side effects, lack of improvement in symptoms or because
      medication made patients feel worse. Patients did not feel well informed about
      their medication. People took less than the prescribed amount or stopped taking
      the medication. Concerns about dependency caused patients to cease medication
      prematurely. CONCLUSION: Patients felt ill informed about their medication and
      would have welcomed more information. Drawing on the results, the authors outline
      areas for improvement in the care of patients with anxiety and depression.

PMID- 15020394
TI  - An alternative trial design to overcome validity and recruitment problems in
      primary care research.
AB  - BACKGROUND: Although the randomized controlled trial is widely accepted as the
      best design to investigate new interventions, conducting a trial in primary care
      may present researchers with many methodological problems. OBJECTIVE: Our aim was
      to present an alternative trial design to overcome internal validity and
      recruitment problems. METHODS: In a randomized controlled trial, fatigued
      employees absent from work were selected among the population of an occupational
      health service in the South of The Netherlands. Patients randomly assigned to the
      experimental condition received cognitive behavioural therapy by a research GP
      near their home address, whereas patients in the control group received no
      intervention. We describe our considerations for building an alternative design.
      Research GPs and patients were recruited separately for the study. The pre
      randomization design was applied. RESULTS: Nine research GPs performed all the
      interventions. Seventy-six experimental patients and 75 control patients were
      selected for study participation. Of these, only six patients in the experimental
      group and seven patients in the control group withdrew from the study at some
      point during follow-up. CONCLUSION: Results suggest that recruitment and
      randomization procedures in the alternative design served their purpose well. The
      alternative design proposed here might have several advantages compared with
      conventional trial procedures. However, our design is not widely applicable and
      there are ethical aspects involved that should be considered. Researchers should
      address their creativity when trying to minimize the problems they may encounter
      in designing a study.

PMID- 15020395
TI  - Consent rates for video-recording general practice consultations: effect of
      ethnicity and other factors.
AB  - We sought consent for video-recording general practice consultations from 260
      consecutive attenders in nine surgeries. Intensive fieldwork including language
      support, from both the researcher and professional interpreters, was undertaken.
      The overall consent rate was 77.3%. No significant differences in consent rates
      were found between white and south Asian patients, even after controlling for
      age, gender and self-reported understanding of English. No differences in consent
      rates were found with respect to age, gender and self-reported understanding of
      English.

PMID- 15020396
TI  - Managing acute cystitis in women.

PMID- 15020397
TI  - Diagnosis of acute otitis media in primary care.

PMID- 15020398
TI  - Screening for alcohol misuse.

PMID- 15020399
TI  - Feasibility of recruiting in a student bar for a trial of chlamydia screening in
      young women.

PMID- 15020400
TI  - A centennial: George W. Beadle, 1903-1989.

PMID- 15020401
TI  - Introducing student inquiry in large introductory genetics classes.
AB  - An appreciation of genetic principles depends upon understanding the individual
      curiosity that sparked particular investigations, the creativity involved in
      imagining alternative outcomes and designing experiments to eliminate these
      outcomes, and the clarity of thought necessary to convince one's scientific peers
      of the validity of the conclusions. At large research universities, students
      usually begin their study of genetics in large lecture classes. It is widely
      assumed that the lecture format, coupled with the pressures to be certain that
      students become familiar with the principal conclusions of genetics
      investigations, constrains most if not all departures from the formats textbooks
      used to explain these conclusions. Here I present several examples of mechanisms
      to introduce meaningful student inquiry in an introductory genetics course and to
      evaluate student creative effort. Most of the examples involve altered student
      preparation prior to class and additional in-class activities, while a few depend
      upon a smaller recitation section, which accompanies the course from which the
      examples have been drawn. I conclude that large introductory classes are suitable
      venues to teach students how to identify scientific claims, determine the
      evidence that is essential to eliminate alternative conclusions, and convince
      their peers of the validity of their arguments.

PMID- 15020402
TI  - Drift increases the advantage of sex in RNA bacteriophage Phi6.
AB  - The pervasiveness of sex and recombination remains one of the most enigmatic
      problems in evolutionary biology. According to many theoretical models,
      recombination can increase the rate of adaptation by restoring genetic variation.
      However, the potential for genetic drift to generate conditions that produce this
      outcome has yet to be studied experimentally. We have designed and performed an
      experiment that reveals the effects of drift on existing genetic variation by
      minimizing the influence of variation on beneficial mutation rate. Our experiment
      was conducted in populations of RNA bacteriophage Phi6 initiated from a common
      source population at varying bottleneck sizes. The segmented genome of this virus
      results in genetic exchange between viruses that co-infect the same host cell. In
      response to selection for growth in a high-temperature environment, sexual lines
      outperformed their asexual counterparts on average. The advantage of sex
      attenuated with increasing effective population size, implying that the rate of
      adaptation was limited by clonal interference among segments caused by drift.
      This is the first empirical evidence that the advantage of sex during adaptation
      increases with the intensity of drift.

PMID- 15020403
TI  - Strong positive selection and recombination drive the antigenic variation of the
      PilE protein of the human pathogen Neisseria meningitidis.
AB  - The PilE protein is the major component of the Neisseria meningitidis pilus,
      which is encoded by the pilE/pilS locus that includes an expressed gene and eight
      homologous silent fragments. The silent gene fragments have been shown to
      recombine through gene conversion with the expressed gene and thereby provide a
      means by which novel antigenic variants of the PilE protein can be generated. We
      have analyzed the evolutionary rate of the pilE gene using the nucleotide
      sequence of two complete pilE/pilS loci. The very high rate of evolution
      displayed by the PilE protein appears driven by both recombination and positive
      selection. Within the semivariable region of the pilE and pilS genes,
      recombination appears to occur within multiple small sequence blocks that lie
      between conserved sequence elements. Within the hypervariable region, positive
      selection was identified from comparison of the silent and expressed genes. The
      unusual gene conversion mechanism that operates at the pilE/pilS locus is a
      strategy employed by N. meningitidis to enhance mutation of certain regions of
      the PilE protein. The silent copies of the gene effectively allow "parallelized"
      evolution of pilE, thus enabling the encoded protein to rapidly explore a large
      area of sequence space in an effort to find novel antigenic variants.

PMID- 15020404
TI  - Chl1p, a DNA helicase-like protein in budding yeast, functions in sister
      chromatid cohesion.
AB  - From the time of DNA replication until anaphase onset, sister chromatids remain
      tightly paired along their length. Ctf7p/Eco1p is essential to establish sister
      chromatid pairing during S-phase and associates with DNA replication components.
      DNA helicases precede the DNA replication fork and thus will first encounter
      chromatin sites destined for cohesion. In this study, I provide the first
      evidence that a DNA helicase is required for proper sister-chromatid cohesion.
      Characterizations of chl1 mutant cells reveal that CHL1 interacts genetically
      with both CTF7/ECO1 and CTF18/CHL12, two genes that function in sister-chromatid
      cohesion. Consistent with genetic interactions, Chl1p physically associates with
      Ctf7p/Eco1p both in vivo and in vitro. Finally, a functional assay reveals that
      Chl1p is critical for sister-chromatid cohesion. Within the budding yeast genome,
      Chl1p exhibits the highest degree of sequence similarity to human CHL1 isoforms
      and BACH1. Previous studies revealed that human CHLR1 exhibits DNA helicase-like
      activities and that BACH1 is a helicase-like protein that associates with the
      tumor suppressor BRCA1 to maintain genome integrity. Our findings document a
      novel role for Chl1p in sister-chromatid cohesion and provide new insights into
      the possible mechanisms through which DNA helicases may contribute to cancer
      progression when mutated.

PMID- 15020405
TI  - Population genetics of the wild yeast Saccharomyces paradoxus.
AB  - Saccharomyces paradoxus is the closest known relative of the well-known S.
      cerevisiae and an attractive model organism for population genetic and genomic
      studies. Here we characterize a set of 28 wild isolates from a 10-km(2) sampling
      area in southern England. All 28 isolates are homothallic (capable of mating-type
      switching) and wild type with respect to nutrient requirements. Nine wild
      isolates and two lab strains of S. paradoxus were surveyed for sequence variation
      at six loci totaling 7 kb, and all 28 wild isolates were then genotyped at seven
      polymorphic loci. These data were used to calculate nucleotide diversity and
      number of segregating sites in S. paradoxus and to investigate geographic
      differentiation, population structure, and linkage disequilibrium. Synonymous
      site diversity is approximately 0.3%. Extensive incompatibilities between gene
      genealogies indicate frequent recombination between unlinked loci, but there is
      no evidence of recombination within genes. Some localized clonal growth is
      apparent. The frequency of outcrossing relative to inbreeding is estimated at
      1.1% on the basis of heterozygosity. Thus, all three modes of reproduction known
      in the lab (clonal replication, inbreeding, and outcrossing) have been important
      in molding genetic variation in this species.

PMID- 15020406
TI  - The yeast splicing factor Prp40p contains functional leucine-rich nuclear export
      signals that are essential for splicing.
AB  - To investigate the function of the essential U1 snRNP protein Prp40p, we
      performed a synthetic lethal screen in Saccharomyces cerevisiae. Using an allele
      of PRP40 that deletes 47 internal residues and causes only a slight growth
      defect, we identified aphenotypic mutations in three distinct complementation
      groups that conferred synthetic lethality. The synthetic phenotypes caused by
      these mutations were suppressed by wild-type copies of CRM1 (XPO1), YNL187w, and
      SME1, respectively. The strains whose synthetic phenotypes were suppressed by
      CRM1 contained no mutations in the CRM1 coding sequence or promoter. This
      indicates that overexpression of CRM1 confers dosage suppression of the synthetic
      lethality. Interestingly, PRP40 and YNL187w encode proteins with putative leucine
      rich nuclear export signal (NES) sequences that fit the consensus sequence
      recognized by Crm1p. One of Prp40p's two NESs lies within the internal deletion.
      We demonstrate here that the NES sequences of Prp40p are functional for nuclear
      export in a leptomycin B-sensitive manner. Furthermore, mutation of these NES
      sequences confers temperature-sensitive growth and a pre-mRNA splicing defect.
      Although we do not expect that yeast snRNPs undergo compartmentalized biogenesis
      like their metazoan counterparts, our results suggest that Prp40p and Ynl187wp
      contain redundant NESs that aid in an important, Crm1p-mediated nuclear export
      event.

PMID- 15020407
TI  - Fus1p interacts with components of the Hog1p mitogen-activated protein kinase and
      Cdc42p morphogenesis signaling pathways to control cell fusion during yeast
      mating.
AB  - Cell fusion in the budding yeast Saccharomyces cerevisiae is a temporally and
      spatially regulated process that involves degradation of the septum, which is
      composed of cell wall material, and occurs between conjugating cells within a
      prezygote, followed by plasma membrane fusion. The plasma membrane protein Fus1p
      is known to be required for septum degradation during cell fusion, yet its role
      at the molecular level is not understood. We identified Sho1p, an osmosensor for
      the HOG MAPK pathway, as a binding partner for Fus1 in a two-hybrid screen. The
      Sho1p-Fus1p interaction occurs directly and is mediated through the Sho1p-SH3
      domain and a proline-rich peptide ligand on the Fus1p COOH-terminal cytoplasmic
      region. The cell fusion defect associated with fus1Delta mutants is suppressed by
      a sho1Delta deletion allele, suggesting that Fus1p negatively regulates Sho1p
      signaling to ensure efficient cell fusion. A two-hybrid matrix containing fusion
      proteins and pheromone response pathway signaling molecules reveals that Fus1p
      may participate in a complex network of interactions. In particular, the Fus1p
      cytoplasmic domain interacts with Chs5p, a protein required for secretion of
      specialized Chs3p-containing vesicles during bud development, and chs5Delta
      mutants were defective in cell surface localization of Fus1p. The Fus1p
      cytoplasmic domain also interacts with the activated GTP-bound form of Cdc42p and
      the Fus1p-SH3 domain interacts with Bni1p, a yeast formin that participates in
      cell fusion and controls the assembly of actin cables to polarize secretion in
      response to Cdc42p signaling. Taken together, our results suggest that Fus1p acts
      as a scaffold for the assembly of a cell surface complex involved in polarized
      secretion of septum-degrading enzymes and inhibition of HOG pathway signaling to
      promote cell fusion.

PMID- 15020408
TI  - REP3-mediated silencing in Saccharomyces cerevisiae.
AB  - In yeast the Sir proteins and Rap1p are key regulators of transcriptional
      silencing at telomeres and the silent mating-type loci. Rap1 and Sir4 also
      possess anchoring activity; the rotation of plasmids bound by Sir4 or Rap1 is
      constrained in vivo, and Rap1 or Sir4 binding can also correct the segregation
      bias of plasmids lacking centromeres. To investigate the mechanistic link between
      DNA anchoring and regulation of transcription, we examined the ability of a third
      defined anchor in yeast, the 2micro circle REP3 segregation element, to mediate
      transcriptional silencing. We find that placement of the REP3 sequence adjacent
      to the HML locus in a strain deleted for natural silencer sequences confers
      transcriptional repression on HML. This repression requires the Sir proteins and
      is decreased in strains lacking the REP3-binding factors Rep1 and Rep2. The yeast
      cohesin complex associates with REP3; we show that REP3 silencing is also
      decreased in strains bearing a mutated allele of the MCD1/SCC1 cohesin gene.
      Conventional silencing is increased in some strains lacking the 2micro circle and
      decreased in strains overexpressing the Rep1 and Rep2 proteins, suggesting that
      the Rep proteins antagonize conventional silencing.

PMID- 15020409
TI  - Genetic evidence of a role for membrane lipid composition in the regulation of
      soluble NEM-sensitive factor receptor function in Saccharomyces cerevisiae.
AB  - SEC9 and SPO20 encode SNARE proteins related to the mammalian SNAP-25 family.
      Sec9p associates with the SNAREs Sso1/2p and Snc1/2p to promote the fusion of
      vesicles with the plasma membrane. Spo20p functions with the same two partner
      SNAREs to mediate the fusion of vesicles with the prospore membrane during
      sporogenesis. A chimeric molecule, in which the helices of Sec9p that bind to
      Sso1/2p and Snc1/2p are replaced with the homologous regions of Spo20p, will not
      support vesicle fusion in vegetative cells. The phosphatidylinositol-4-phosphate
      5-kinase MSS4 was isolated as a high-copy suppressor that permits this chimera to
      rescue the temperature-sensitive growth of a sec9-4 mutant. Suppression by MSS4
      is specific to molecules that contain the Spo20p helical domains. This
      suppression requires an intact copy of SPO14, encoding phospholipase D.
      Overexpression of MSS4 leads to a recruitment of the Spo14 protein to the plasma
      membrane and this may be the basis for MSS4 action. Consistent with this,
      deletion of KES1, a gene that behaves as a negative regulator of SPO14, also
      promotes the function of SPO20 in vegetative cells. These results indicate that
      elevated levels of phosphatidic acid in the membrane may be required specifically
      for the function of SNARE complexes containing Spo20p.

PMID- 15020410
TI  - Marker-based cloning of the region containing the UhAvr1 avirulence gene from the
      basidiomycete barley pathogen Ustilago hordei.
AB  - Race-cultivar specialization during the interaction of the basidiomycete smut
      pathogen Ustilago hordei with its barley host was described in the 1940s.
      Subsequent genetic analyses revealed the presence of dominant avirulence genes in
      the pathogen that conform to the gene-for-gene theory. This pathosystem therefore
      presents an opportunity for the molecular genetic characterization of fungal
      genes controlling avirulence. We performed a cross between U. hordei strains to
      obtain 54 progeny segregating for three dominant avirulence genes on three
      differential barley cultivars. Bulked segregant analysis was used to identify
      RAPD and AFLP markers tightly linked to the avirulence gene UhAvr1. The UhAvr1
      gene is located in an area containing repetitive DNA and this region is
      undetectable in cosmid libraries prepared from the avirulent parental strain. PCR
      and hybridization probes developed from the linked markers were therefore used to
      identify cosmid clones from the virulent (Uhavr1) parent. By walking on Uhavr1
      linked cosmid clones, a nonrepetitive, nearby probe was found that recognized
      five overlapping BAC clones spanning 170 kb from the UhAvr1 parent. A contig of
      the clones in the UhAvr1 region was constructed and selected probes were used for
      RFLP analysis of the segregating population. This approach genetically defined an
      approximately 80-kb region that carries the UhAvr1 gene and provided cloned
      sequences for subsequent genetic analysis. UhAvr1 represents the first avirulence
      gene cloned from a basidiomycete plant pathogen.

PMID- 15020411
TI  - REN1 is required for development of microconidia and macroconidia, but not of
      chlamydospores, in the plant pathogenic fungus Fusarium oxysporum.
AB  - The filamentous fungus Fusarium oxysporum is a soil-borne facultative parasite
      that causes economically important losses in a wide variety of crops. F.
      oxysporum exhibits filamentous growth on agar media and undergoes asexual
      development producing three kinds of spores: microconidia, macroconidia, and
      chlamydospores. Ellipsoidal microconidia and falcate macroconidia are formed from
      phialides by basipetal division; globose chlamydospores with thick walls are
      formed acrogenously from hyphae or by the modification of hyphal cells. Here we
      describe rensa, a conidiation mutant of F. oxysporum, obtained by restriction
      enzyme-mediated integration mutagenesis. Molecular analysis of rensa identified
      the affected gene, REN1, which encodes a protein with similarity to MedA of
      Aspergillus nidulans and Acr1 of Magnaporthe grisea. MedA and Acr1 are presumed
      transcription regulators involved in conidiogenesis in these fungi. The rensa
      mutant and REN1-targeted strains lack normal conidiophores and phialides and form
      rod-shaped, conidium-like cells directly from hyphae by acropetal division. These
      mutants, however, exhibit normal vegetative growth and chlamydospore formation.
      Nuclear localization of Ren1 was verified using strains expressing the Ren1-green
      fluorescent protein fusions. These data strongly suggest that REN1 encodes a
      transcription regulator required for the correct differentiation of
      conidiogenesis cells for development of microconidia and macroconidia in F.
      oxysporum.

PMID- 15020412
TI  - Incomplete penetrance and variable expressivity of a growth defect as a
      consequence of knocking out two K(+) transporters in the euascomycete fungus
      Podospora anserina.
AB  - We describe an example of incomplete penetrance and variable expressivity in the
      filamentous fungus Podospora anserina, two genetic properties classically
      associated with mutations in more complex organisms, such as green plants and
      animals. We show that the knockouts of two TRK-related K(+) transporters of this
      ascomycete present variability in their phenotype that cannot be attributed to
      fluctuations of the genetic background or the environment. Thalli of the knockout
      strains derived from independent monokaryotic ascospores or from a single
      monokaryotic ascospore and cultivated under standard growth conditions may or may
      not present impaired growth. When impaired, thalli exhibit a range of phenotypes.
      Environmental conditions control expressivity to a large extent and penetrance to
      a low extent. Restoration of functional potassium transport by heterologous
      expression of K(+) transporters from Neurospora crassa abolishes or strongly
      diminishes the growth impairment. These data show that incomplete penetrance and
      variable expressivity can be an intrinsic property of a single Mendelian loss-of
      function mutation. They also show that such variability in the expression of a
      mutant phenotype can be promoted by a phenomenon not obviously related to the
      well-known chromatin structure modifications, i.e., potassium transport. They
      provide a framework to understand human channelopathies with similar properties.

PMID- 15020413
TI  - The Podospora rmp1 gene implicated in nucleus-mitochondria cross-talk encodes an
      essential protein whose subcellular location is developmentally regulated.
AB  - It has been previously reported that, at the time of death, the Podospora
      anserina AS1-4 mutant strains accumulate specific deleted forms of the
      mitochondrial genome and that their life spans depend on two natural alleles
      (variants) of the rmp1 gene: AS1-4 rmp1-2 strains exhibit life spans strikingly
      longer than those of AS1-4 rmp1-1. Here, we show that rmp1 is an essential gene.
      In silico analyses of eight rmp1 natural alleles present in Podospora isolates
      and of the putative homologs of this orphan gene in other filamentous fungi
      suggest that rmp1 evolves rapidly. The RMP1 protein is localized in the
      mitochondrial and/or the cytosolic compartment, depending on cell type and
      developmental stage. Strains producing RMP1 without its mitochondrial targeting
      peptide are viable but exhibit vegetative and sexual defects.

PMID- 15020414
TI  - sel-7, a positive regulator of lin-12 activity, encodes a novel nuclear protein
      in Caenorhabditis elegans.
AB  - Suppressor genetics in C. elegans has identified key components of the LIN
      12/Notch signaling pathway. Here, we describe a genetic and molecular
      characterization of the suppressor gene sel-7. We show that reducing or
      eliminating sel-7 activity suppresses the effects of constitutive lin-12
      activity, enhances the effects of partially reduced lin-12 activity, and causes a
      synthetic Lin-12(0) phenotype when combined with a null mutation in the sel-12
      presenilin gene. These observations suggest that sel-7 is a positive regulator of
      lin-12 activity. We also show that SEL-7 encodes a novel nuclear protein. Through
      yeast two-hybrid screening, we identified an apparent interaction partner,
      K08E3.8, that also interacts with SEL-8, a known component of the nuclear complex
      that forms upon LIN-12 activation. Our data suggest potential roles for SEL-7 in
      the assembly or function of this nuclear complex.

PMID- 15020415
TI  - eat-2 and eat-18 are required for nicotinic neurotransmission in the
      Caenorhabditis elegans pharynx.
AB  - Mutations in eat-2 and eat-18 cause the same defect in C. elegans feeding
      behavior: the pharynx is unable to pump rapidly in the presence of food. EAT-2 is
      a nicotinic acetylcholine receptor subunit that functions in the pharyngeal
      muscle. It is localized to the synapse between pharyngeal muscle and the main
      pharyngeal excitatory motor neuron MC, and it is required for MC stimulation of
      pharyngeal muscle. eat-18 encodes a small protein that has no homology to
      previously characterized proteins. It has a single transmembrane domain and a
      short extracellular region. Allele-specific genetic interactions between eat-2
      and eat-18 suggest that EAT-18 interacts physically with the EAT-2 receptor.
      While eat-2 appears to be required specifically for MC neurotransmission, eat-18
      also appears to be required for the function of other nicotinic receptors in the
      pharynx. In eat-18 mutants, the gross localization of EAT-2 at the MC synapse is
      normal, suggesting that it is not required for trafficking. These data indicate
      that eat-18 could be a novel component of the pharyngeal nicotinic receptor.

PMID- 15020416
TI  - The sys-1 and sys-3 genes cooperate with Wnt signaling to establish the proximal
      distal axis of the Caenorhabditis elegans gonad.
AB  - To form the proximal-distal axis of the C. elegans gonad, two somatic gonadal
      precursor cells, Z1 and Z4, divide asymmetrically to generate one daughter with a
      proximal fate and one with a distal fate. Genes governing this process include
      the lin-17 frizzled receptor, wrm-1/beta-catenin, the pop-1/TCF transcription
      factor, lit-1/nemo-like kinase, and the sys-1 gene. Normally, all of these
      regulators promote the distal fate. Here we show that nuclear levels of a pop-1
      GFP fusion protein are less abundant in the distal than in the proximal Z1/Z4
      daughters. This POP-1 asymmetry is lost in mutants disrupting Wnt/MAPK
      regulation, but retained in sys-1 mutants. We find that sys-1 is haplo
      insufficient for gonadogenesis defects and that sys-1 and pop-1 mutants display a
      strong genetic interaction in double heterozygotes. Therefore, sys-1 is a dose
      sensitive locus and may function together with pop-1 to control Z1/Z4 asymmetry.
      To identify other regulatory genes in this process, we screened for mutants
      resembling sys-1. Four such genes were identified (gon-14, -15, -16, and sys-3)
      and shown to interact genetically with sys-1. However, only sys-3 promotes the
      distal fate at the expense of the proximal fate. We suggest that sys-3 is a new
      key gene in this pathway and that gon-14, gon-15, and gon-16 may cooperate with
      POP-1 and SYS-1 at multiple stages of gonad development.

PMID- 15020417
TI  - A mosaic genetic screen reveals distinct roles for trithorax and polycomb group
      genes in Drosophila eye development.
AB  - The wave of differentiation that traverses the Drosophila eye disc requires rapid
      transitions in gene expression that are controlled by a number of signaling
      molecules also required in other developmental processes. We have used a mosaic
      genetic screen to systematically identify autosomal genes required for the normal
      pattern of photoreceptor differentiation, independent of their requirements for
      viability. In addition to genes known to be important for eye development and to
      known and novel components of the Hedgehog, Decapentaplegic, Wingless, Epidermal
      growth factor receptor, and Notch signaling pathways, we identified several
      members of the Polycomb and trithorax classes of genes encoding general
      transcriptional regulators. Mutations in these genes disrupt the transitions
      between zones along the anterior-posterior axis of the eye disc that express
      different combinations of transcription factors. Different trithorax group genes
      have very different mutant phenotypes, indicating that target genes differ in
      their requirements for chromatin remodeling, histone modification, and
      coactivation factors.

PMID- 15020418
TI  - Knockouts of Kekkon1 define sequence elements essential for Drosophila epidermal
      growth factor receptor inhibition.
AB  - Throughout development, cells utilize feedback inhibition of receptor tyrosine
      kinase (RTK) signaling as an important means to direct cellular fates. In
      Drosophila, epidermal growth factor receptor (EGFR) activity is tightly regulated
      by a complex array of autoregulatory loops, involving an assortment of inhibitory
      proteins. One inhibitor, the transmembrane protein Kekkon1 (Kek1) functions
      during oogenesis in a negative feedback loop to directly attenuate EGFR activity.
      Kek1 contains both leucine-rich repeats (LRRs) and an immunoglobulin (Ig) domain,
      two of the most prevalent motifs found within metazoan genomes. Here we
      demonstrate that Kek1 inhibits EGFR activity during eye development and use this
      role to identify kek1 loss-of-function mutations that implicate the LRRs in
      directing receptor inhibition. Using a GMR-GAL4, UAS kek1-GFP misexpression
      phenotype we isolated missense mutations in the kek1 transgene affecting its
      ability to inhibit EGFR signaling. Genetic, molecular, and biochemical
      characterization of these alleles indicated that they represent two functionally
      distinct classes. Class I alleles directly diminish Kek1's affinity for EGFR,
      while class II alleles disrupt Kek1's subcellular localization, thereby
      indirectly affecting its ability to associate with and inhibit the receptor. All
      class I alleles map to the first and second LRRs of Kek1, suggesting a primary
      role for these two repeats in specifying association with and inhibition of EGFR.
      Last, our analysis implicates glycine 160 of the second LRR in regulating EGFR
      binding.

PMID- 15020419
TI  - Conservation of an inhibitor of the epidermal growth factor receptor, Kekkon1, in
      dipterans.
AB  - Regulation of epidermal growth factor receptor (EGFR) signaling requires the
      concerted action of both positive and negative factors. While the existence of
      numerous molecules that stimulate EGFR activity has been well documented, direct
      biological inhibitors appear to be more limited in number and phylogenetic
      distribution. Kekkon1 (Kek1) represents one such inhibitor. Kek1 was initially
      identified in Drosophila melanogaster and appears to be absent from vertebrates
      and the invertebrate Caenorhabditis. To further investigate Kek1's function and
      evolution, we identified kek1 orthologs within dipterans. In D. melanogaster,
      kek1 is a transcriptional target of EGFR signaling during oogenesis, where it
      acts to attenuate receptor activity through an inhibitory feedback loop. The
      extracellular and transmembrane portion of Kek1 is sufficient for its inhibitory
      activity in D. melanogaster. Consistent with conservation of its role in EGFR
      signaling, interspecies comparisons indicate a high degree of identity throughout
      these regions. During formation of the dorsal-ventral axis Kek1 is expressed in
      dorsal follicle cells in a pattern that reflects the profile of receptor
      activation. D. virilis Kek1 (DvKek1) is also expressed dynamically in the dorsal
      follicle cells, supporting a conserved role in EGFR signaling. Confirming this,
      biochemical and transgenic assays indicate that DvKek1 is functionally
      interchangeable with DmKek1. Strikingly, we find that the cytoplasmic domain
      contains a region with the highest degree of conservation, which we have
      implicated in EGFR inhibition and dubbed the Kek tail (KT) box.

PMID- 15020420
TI  - Genetic dissection of itpr gene function reveals a vital requirement in aminergic
      cells of Drosophila larvae.
AB  - Signaling by the second messenger inositol 1,4,5-trisphosphate is thought to
      affect several developmental and physiological processes. Mutants in the inositol
      1,4,5-trisphosphate receptor (itpr) gene of Drosophila exhibit delays in molting
      while stronger alleles are also larval lethal. In a freshly generated set of EMS
      alleles for the itpr locus we have sequenced and identified single point
      mutations in seven mutant chromosomes. The predicted allelic strength of these
      mutants matches the observed levels of lethality. They range from weak hypomorphs
      to complete nulls. Interestingly, lethality in three heteroallelic combinations
      has a component of cold sensitivity. The temporal focus of cold sensitivity lies
      in the larval stages, predominantly at second instar. Coupled with our earlier
      observation that an itpr homozygous null allele dies at the second instar stage,
      it appears that there is a critical period for itpr gene function in second
      instar larvae. Here we show that the focus of this critical function lies in
      aminergic cells by rescue with UAS-itpr and DdCGAL4. However, this function does
      not require synaptic activity, suggesting that InsP(3)-mediated Ca(2+) release
      regulates the neurohormonal action of serotonin.

PMID- 15020421
TI  - Pleiotropic effect of disrupting a conserved sequence involved in a long-range
      compensatory interaction in the Drosophila Adh gene.
AB  - Recent advances in experimental analyses of the evolution of RNA secondary
      structures suggest a more complex scenario than that typically considered by
      Kimura's classical model of compensatory evolution. In this study, we examine one
      such case in more detail. Previous experimental analysis of long-range
      compensatory interactions between the two ends of Drosophila Adh mRNA failed to
      fit the classical model of compensatory evolution. To further investigate and
      verify long-range pairing in Drosophila Adh with respect to models of
      compensatory evolution and its potential functional role, we introduced site
      directed mutations in the Drosophila melanogaster Adh gene. We explore two
      alternative hypotheses for why previous analysis of long-range compensatory
      interactions failed to fit the classical model. Specifically, we investigate
      whether the disruption of a conserved short-range pairing within Adh exon 2 has
      an effect on Adh expression or if there is a dual functional role of a conserved
      sequence in the 3'-UTR in both long-range pairing and the negative regulation of
      Adh expression. We find that a classical result was not observed due to the
      pleiotropic effect of changing a nucleotide involved in both long-range base
      pairing and the negative regulation of gene expression.

PMID- 15020422
TI  - The P cytotype in Drosophila melanogaster: a maternally transmitted regulatory
      state of the germ line associated with telomeric P elements.
AB  - The incomplete P elements TP5 and TP6 are inserted in the TAS repeats near the
      left telomere of the Drosophila melanogaster X chromosome. These telomeric P
      elements repress P-induced gonadal dysgenesis and germ-line hypermutability in
      both sexes. However, their capacity to repress hypermutability is lost when they
      are transmitted patroclinously in a cross. TP5 and TP6 do not repress P-element
      activity in somatic cells, nor do they alter the somatic or germ-line phenotypes
      of P-insertion alleles. In the germ line, these elements suppress the phenotype
      of a P-insertion allele of the singed gene that is evoked by other P elements,
      presumably because these other elements encode repressor polypeptides. This
      suppression is more effective when the telomeric P elements are inherited
      maternally. Regulation by telomeric P elements parallels that of the P cytotype,
      a state that represses P-element activity in some strains of Drosophila. This
      state exists only in the germ line and is maternally transmitted along with the P
      elements themselves. Regulation by known repressor P polypeptides is not
      restricted to the germ line and does not require maternal transmission of the
      relevant P elements. Regulation by telomeric P elements appears to be epistatic
      to regulation by repressor P polypeptides.

PMID- 15020423
TI  - Establishment and maintenance of the P cytotype associated with telomeric P
      elements in Drosophila melanogaster.
AB  - P elements inserted near the left telomere of the X chromosome are associated
      with the P cytotype, a maternally transmitted condition that strongly regulates
      the activity of the P transposon family in some strains of Drosophila. The
      regulatory abilities of two such elements, TP5 and TP6, are stable in homozygous
      stocks over many generations. However, these regulatory abilities are attenuated
      when the telomeric P elements are transmitted through heterozygous females, and
      they are utterly lost when the elements are transmitted through males. Paternally
      transmitted telomeric P elements reacquire regulatory ability when they pass
      through a female germ line. This reacquisition is enhanced if the females in
      which it occurs came from mothers who carried a telomeric P element. The
      enhancement has two components: (1). a strictly maternal effect that is
      transmitted to the females independently of the mother's telomeric P element
      ("presetting" or the "pre-P cytotype") and (2). a zygotic effect associated with
      inheritance of the mother's telomeric P element. One telomeric P element can
      enhance the reacquisition of another's regulatory ability. When X chromosomes
      that carry telomeric P elements are extracted through males and made homozygous
      by using a balancer chromosome, most of the resulting stocks develop strong
      regulatory abilities in a few generations. However, some of the stocks do not
      attain the regulatory ability of the original population.

PMID- 15020424
TI  - Evolution of autosomal suppression of the sex-ratio trait in Drosophila.
AB  - The sex-ratio trait is the production of female-biased progenies due to X-linked
      meiotic drive in males of several Drosophila species. The driving X chromosome
      (called SR) is not fixed due to at least two stabilizing factors: natural
      selection (favoring ST, the nondriving standard X) and drive suppression by
      either Y-linked or autosomal genes. The evolution of autosomal suppression is
      explained by Fisher's principle, a mechanism of natural selection that leads to
      equal proportion of males and females in a sexually reproducing population. In
      fact, sex-ratio expression is partially suppressed by autosomal genes in at least
      three Drosophila species. The population genetics of this system is not
      completely understood. In this article we develop a mathematical model for the
      evolution of autosomal suppressors of SR (sup alleles) and show that: (i). an
      autosomal suppressor cannot invade when SR is very deleterious in males (c <
      (1)/(3), where c is the fitness of SR/Y males); (ii). "SR/ST, sup/+"
      polymorphisms occur when SR is partially deleterious ( approximately 0.3 < c <
      1); while (iii). SR neutrality (c = 1) results in sup fixation and thus in total
      abolishment of drive. So, surprisingly, as long as there is any selection against
      SR/Y males, neutral autosomal suppressors will not be fixed. In that case, when a
      polymorphic equilibrium exists, the average female proportion in SR/Y males'
      progeny is given approximately by ac + 1 - a + a (2) c + 1 (2) + 1 - 4ac /4ac,
      where a is the fitness of SR/ST females.

PMID- 15020425
TI  - The Drosophila GAGA factor is required for dosage compensation in males and for
      the formation of the male-specific-lethal complex chromatin entry site at 12DE.
AB  - Drosophila melanogaster males have one X chromosome, while females have two. To
      compensate for the resulting disparity in X-linked gene expression between the
      two sexes, most genes from the male X chromosome are hyperactivated by a special
      dosage compensation system. Dosage compensation is achieved by a complex of at
      least six proteins and two noncoding RNAs that specifically associate with the
      male X. A central question is how the X chromosome is recognized. According to a
      current model, complexes initially assemble at approximately 35 chromatin entry
      sites on the X and then spread bidirectionally along the chromosome where they
      occupy hundreds of sites. Here, we report that mutations in Trithorax-like (Trl)
      lead to the loss of a single chromatin entry site on the X, male lethality, and
      mislocalization of dosage compensation complexes.

PMID- 15020426
TI  - No evidence for an association between common nonsynonymous polymorphisms in
      delta and bristle number variation in natural and laboratory populations of
      Drosophila melanogaster.
AB  - We test the hypothesis that naturally occurring nonsynonymous variants in the
      Delta ligand of the Notch signaling pathway contribute to standing variation in
      sternopleural and/or abdominal bristle number in Drosophila melanogaster, for
      both a large cohort of wild-caught flies and previously described laboratory
      lines. We sequenced the transcribed region of Delta for 16 naturally occurring
      chromosomes and 65 SNPs, including 7 nonsynonymous SNPs (nsSNPs), were observed.
      Identified nsSNPs and 6 additional common SNPs, all located in exon 6 and the 3'
      UTR, were genotyped in 2060 wild-caught flies using an OLA-based methodology and
      genotyped in 38 additional natural chromosomes via DNA sequencing. None of the
      genotyped nsSNPs were significantly associated with natural variation in bristle
      number as assessed by a permutation test. A 95% upper bound on the additive
      genetic variance attributable to each genotyped SNP in the large natural cohort
      is <2% of the total phenotypic variation. Results suggest that two previously
      detected genotype/phenotype associations between bristle number and variants in
      the introns of Delta cannot be explained by linkage disequilibrium between these
      variants and nearby nonsynonymous variants. Unidentified regulatory variants more
      parsimoniously explain previous observations.

PMID- 15020428
TI  - Velvet, a dominant Egfr mutation that causes wavy hair and defective eyelid
      development in mice.
AB  - In the course of a large-scale program of ENU mutagenesis, we isolated a dominant
      mutation, called Velvet. The mutation was found to be uniformly lethal to
      homozygotes, which do not survive E13.5. Mice heterozygous for the Velvet
      mutation are born with eyelids open and demonstrate a wavy coat and curly
      vibrissae. The mutation was mapped to the proximal end of chromosome 11 by genome
      wide linkage analysis. On 249 meioses, the locus was confined to a 2.7-Mb region,
      which included the epidermal growth factor receptor gene (Egfr). An A --> G
      transition in the Egfr coding region of Velvet mice was identified, causing the
      amino acid substitution D833G. This substitution alters an essential triad of
      amino acids (DFG --> GFG) that is normally required for coordination of the ATP
      substrate. As such, kinase activity is at least mostly abolished, but quaternary
      structure of the receptor is presumably maintained, accounting for the dominant
      effect. Velvet is the first known dominant representative of the Egfr allelic
      series that is fully viable, a fact that makes it particularly useful for
      developmental studies.

PMID- 15020427
TI  - First-generation linkage map of the gray, short-tailed opossum, Monodelphis
      domestica, reveals genome-wide reduction in female recombination rates.
AB  - The gray, short-tailed opossum, Monodelphis domestica, is the most extensively
      used, laboratory-bred marsupial resource for basic biologic and biomedical
      research worldwide. To enhance the research utility of this species, we are
      building a linkage map, using both anonymous markers and functional gene loci,
      that will enable the localization of quantitative trait loci (QTL) and provide
      comparative information regarding the evolution of mammalian and other vertebrate
      genomes. The current map is composed of 83 loci distributed among eight autosomal
      linkage groups and the X chromosome. The autosomal linkage groups appear to
      encompass a very large portion of the genome, yet span a sex-average distance of
      only 633.0 cM, making this the most compact linkage map known among vertebrates.
      Most surprising, the male map is much larger than the female map (884.6 cM vs.
      443.1 cM), a pattern contrary to that in eutherian mammals and other vertebrates.
      The finding of genome-wide reduction in female recombination in M. domestica,
      coupled with recombination data from two other, distantly related marsupial
      species, suggests that reduced female recombination might be a widespread
      metatherian attribute. We discuss possible explanations for reduced female
      recombination in marsupials as a consequence of the metatherian characteristic of
      determinate paternal X chromosome inactivation.

PMID- 15020429
TI  - Optimal designs for linkage disequilibrium mapping and candidate gene association
      tests in livestock populations.
AB  - Simulation was used to evaluate the performance of different selective genotyping
      strategies when using linkage disequilibrium across large half-sib families to
      position a QTL within a previously defined genomic region. Strategies examined
      included standard selective genotyping and different approaches of discordant and
      concordant sib selection applied to arbitrary or selected families. Strategies
      were compared as a function of effect and frequency of QTL alleles, heritability,
      and phenotypic expression of the trait. Large half-sib families were simulated
      for 100 generations and 2% of the population was genotyped in the final
      generation. Simple ANOVA was applied and the marker with the greatest F-value was
      considered the most likely QTL position. For traits with continuous phenotypes,
      genotyping the most divergent pairs of half-sibs from all families was the best
      strategy in general, but standard selective genotyping was somewhat more precise
      when heritability was low. When the phenotype was distributed in ordered
      categories, discordant sib selection was the optimal approach for positioning QTL
      for traits with high heritability and concordant sib selection was the best
      approach when genetic effects were small. Genotyping of a few selected sibs from
      many families was generally more efficient than genotyping many individuals from
      a few highly selected sires.

PMID- 15020430
TI  - The allele frequency spectrum in genome-wide human variation data reveals signals
      of differential demographic history in three large world populations.
AB  - We have studied a genome-wide set of single-nucleotide polymorphism (SNP) allele
      frequency measures for African-American, East Asian, and European-American
      samples. For this analysis we derived a simple, closed mathematical formulation
      for the spectrum of expected allele frequencies when the sampled populations have
      experienced nonstationary demographic histories. The direct calculation generates
      the spectrum orders of magnitude faster than coalescent simulations do and allows
      us to generate spectra for a large number of alternative histories on a
      multidimensional parameter grid. Model-fitting experiments using this grid reveal
      significant population-specific differences among the demographic histories that
      best describe the observed allele frequency spectra. European and Asian spectra
      show a bottleneck-shaped history: a reduction of effective population size in the
      past followed by a recent phase of size recovery. In contrast, the African
      American spectrum shows a history of moderate but uninterrupted population
      expansion. These differences are expected to have profound consequences for the
      design of medical association studies. The analytical methods developed for this
      study, i.e., a closed mathematical formulation for the allele frequency spectrum,
      correcting the ascertainment bias introduced by shallow SNP sampling, and dealing
      with variable sample sizes provide a general framework for the analysis of public
      variation data.

PMID- 15020431
TI  - Multilocus analysis of variation and speciation in the closely related species
      Arabidopsis halleri and A. lyrata.
AB  - Nucleotide variation in eight effectively unlinked genes was surveyed in species
      wide samples of the closely related outbreeding species Arabidopsis halleri and
      A. lyrata ssp. petraea and in three of these genes in A. lyrata ssp. lyrata and
      A. thaliana. Significant genetic differentiation was observed more frequently in
      A. l. petraea than in A. halleri. Average estimates of nucleotide variation were
      highest in A. l. petraea and lowest in A. l. lyrata, reflecting differences among
      species in effective population size. The low level of variation in A. l. lyrata
      is concordant with a bottleneck effect associated with its origin. The A.
      halleri/A. l. petraea speciation process was studied, considering the orthologous
      sequences of an outgroup species (A. thaliana). The high number of ancestral
      mutations relative to exclusive polymorphisms detected in A. halleri and A. l.
      petraea, the significant results of the multilocus Fay and Wu H tests, and
      haplotype sharing between the species indicate introgression subsequent to
      speciation. Average among-population variation in A. halleri and A. l. petraea
      was approximately 1.5- and 3-fold higher than that in the inbreeder A. thaliana.
      The detected reduction of variation in A. thaliana is less than that expected
      from differences in mating system alone, and therefore from selective processes
      related to differences in the effective recombination rate, but could be
      explained by differences in population structure.

PMID- 15020432
TI  - A 3347-locus genetic recombination map of sequence-tagged sites reveals features
      of genome organization, transmission and evolution of cotton (Gossypium).
AB  - We report genetic maps for diploid (D) and tetraploid (AtDt) Gossypium genomes
      composed of sequence-tagged sites (STS) that foster structural, functional, and
      evolutionary genomic studies. The maps include, respectively, 2584 loci at 1.72
      cM ( approximately 600 kb) intervals based on 2007 probes (AtDt) and 763 loci at
      1.96-cM ( approximately 500 kb) intervals detected by 662 probes (D). Both
      diploid and tetraploid cottons exhibit negative crossover interference; i.e.,
      double recombinants are unexpectedly abundant. We found no major structural
      changes between Dt and D chromosomes, but confirmed two reciprocal translocations
      between At chromosomes and several inversions. Concentrations of probes in
      corresponding regions of the various genomes may represent centromeres, while
      genome-specific concentrations may represent heterochromatin. Locus duplication
      patterns reveal all 13 expected homeologous chromosome sets and lend new support
      to the possibility that a more ancient polyploidization event may have predated
      the A-D divergence of 6-11 million years ago. Identification of SSRs within 312
      RFLP sequences plus direct mapping of 124 SSRs and exploration for CAPS and SNPs
      illustrate the "portability" of these STS loci across populations and detection
      systems useful for marker-assisted improvement of the world's leading fiber crop.
      These data provide new insights into polyploid evolution and represent a
      foundation for assembly of a finished sequence of the cotton genome.

PMID- 15020433
TI  - High-density linkage mapping revealed suppression of recombination at the sex
      determination locus in papaya.
AB  - A high-density genetic map of papaya (Carica papaya L.) was constructed using 54
      F(2) plants derived from cultivars Kapoho and SunUp with 1501 markers, including
      1498 amplified fragment length polymorphism (AFLP) markers, the papaya ringspot
      virus coat protein marker, morphological sex type, and fruit flesh color. These
      markers were mapped into 12 linkage groups at a LOD score of 5.0 and
      recombination frequency of 0.25. The 12 major linkage groups covered a total
      length of 3294.2 cM, with an average distance of 2.2 cM between adjacent markers.
      This map revealed severe suppression of recombination around the sex
      determination locus with a total of 225 markers cosegregating with sex types. The
      cytosine bases were highly methylated in this region on the basis of the
      distribution of methylation-sensitive and -insensitive markers. This high-density
      genetic map is essential for cloning of specific genes of interest such as the
      sex determination gene and for the integration of genetic and physical maps of
      papaya.

PMID- 15020435
TI  - The dominance of the herbicide resistance cost in several Arabidopsis thaliana
      mutant lines.
AB  - Resistance evolution depends upon the balance between advantage and disadvantage
      (cost) conferred in treated and untreated areas. By analyzing morphological
      characters and simple fitness components, the cost associated with each of eight
      herbicide resistance alleles (acetolactate synthase, cellulose synthase, and
      auxin-induced target genes) was studied in the model plant Arabidopsis thaliana.
      The use of allele-specific PCR to discriminate between heterozygous and
      homozygous plants was used to provide insights into the dominance of the
      resistance cost, a parameter rarely described. Morphological characters appear
      more sensitive than fitness (seed production) because 6 vs. 4 differences between
      resistant and sensitive homozygous plants were detected, respectively. Dominance
      levels for the fitness cost ranged from recessivity (csr1-1, ixr1-2, and axr1-3)
      to dominance (axr2-1) to underdominance (aux1-7). Furthermore, the dominance
      level of the herbicide resistance trait did not predict the dominance level of
      the cost of resistance. The relationship of our results to theoretical
      predictions of dominance and the consequences of fitness cost and its dominance
      in resistance management are discussed.

PMID- 15020434
TI  - An internal rearrangement in an Arabidopsis inverted repeat locus impairs DNA
      methylation triggered by the locus.
AB  - In plants, transcribed inverted repeats trigger RNA interference (RNAi) and DNA
      methylation of identical sequences. RNAi is caused by processing of the double
      stranded RNA (dsRNA) transcript into small RNAs that promote degradation of
      complementary RNA sequences. However, the signals for DNA methylation remain to
      be fully elucidated. The Arabidopsis tryptophan biosynthetic PAI genes provide an
      endogenous inverted repeat that triggers DNA methylation of PAI-identical
      sequences. In the Wassilewskija strain, two PAI genes are arranged as a tail-to
      tail inverted repeat and transcribed from an unmethylated upstream promoter. This
      locus directs its own methylation, as well as methylation of two unlinked singlet
      PAI genes. Previously, we showed that the locus is likely to make an RNA signal
      for methylation because suppressed transcription of the inverted repeat leads to
      reduced PAI methylation. Here we characterize a central rearrangement in the
      inverted repeat that also confers reduced PAI methylation. The rearrangement
      creates a premature polyadenylation signal and suppresses readthrough
      transcription into palindromic PAI sequences. Thus, a likely explanation for the
      methylation defect of the mutant locus is a failure to produce readthrough dsRNA
      methylation triggers.

PMID- 15020436
TI  - Identification of wheat chromosomal regions containing expressed resistance
      genes.
AB  - The objectives of this study were to isolate and physically localize expressed
      resistance (R) genes on wheat chromosomes. Irrespective of the host or pest type,
      most of the 46 cloned R genes from 12 plant species share a strong sequence
      similarity, especially for protein domains and motifs. By utilizing this
      structural similarity to perform modified RNA fingerprinting and data mining, we
      identified 184 putative expressed R genes of wheat. These include 87 NB/LRR
      types, 16 receptor-like kinases, and 13 Pto-like kinases. The remaining were
      seven Hm1 and two Hs1(pro-1) homologs, 17 pathogenicity related, and 42 unique
      NB/kinases. About 76% of the expressed R-gene candidates were rare transcripts,
      including 42 novel sequences. Physical mapping of 121 candidate R-gene sequences
      using 339 deletion lines localized 310 loci to 26 chromosomal regions
      encompassing approximately 16% of the wheat genome. Five major R-gene clusters
      that spanned only approximately 3% of the wheat genome but contained
      approximately 47% of the candidate R genes were observed. Comparative mapping
      localized 91% (82 of 90) of the phenotypically characterized R genes to 18
      regions where 118 of the R-gene sequences mapped.

PMID- 15020437
TI  - Formation of unreduced megaspores (diplospory) in apomictic dandelions (Taraxacum
      officinale, s.l.) is controlled by a sex-specific dominant locus.
AB  - In apomictic dandelions, Taraxacum officinale, unreduced megaspores are formed
      via a modified meiotic division (diplospory). The genetic basis of diplospory was
      investigated in a triploid (3x = 24) mapping population of 61 individuals that
      segregated approximately 1:1 for diplospory and meiotic reduction. This
      population was created by crossing a sexual diploid (2x = 16) with a tetraploid
      diplosporous pollen donor (4x = 32) that was derived from a triploid apomict. Six
      different inheritance models for diplospory were tested. The segregation ratio
      and the tight association with specific alleles at the microsatellite loci MSTA53
      and MSTA78 strongly suggest that diplospory is controlled by a dominant allele D
      on a locus, which we have named DIPLOSPOROUS (DIP). Diplosporous plants have a
      simplex genotype, Ddd or Dddd. MSTA53 and MSTA78 were weakly linked to the 18S
      25S rDNA locus. The D-linked allele of MSTA78 was absent in a hypotriploid (2n =
      3x - 1) that also lacked one of the satellite chromosomes. Together these results
      suggest that DIP is located on the satellite chromosome. DIP is female specific,
      as unreduced gametes are not formed during male meiosis. Furthermore, DIP does
      not affect parthenogenesis, implying that several independently segregating genes
      control apomixis in dandelions.

PMID- 15020439
TI  - Linkage disequilibrium testing when linkage phase is unknown.
AB  - Linkage disequilibrium, the nonrandom association of alleles from different loci,
      can provide valuable information on the structure of haplotypes in the human
      genome and is often the basis for evaluating the association of genomic variation
      with human traits among unrelated subjects. But, linkage phase of genetic markers
      measured on unrelated subjects is typically unknown, and so measurement of
      linkage disequilibrium, and testing whether it differs significantly from the
      null value of zero, requires statistical methods that can account for the
      ambiguity of unobserved haplotypes. A common method to test whether linkage
      disequilibrium differs significantly from zero is the likelihood-ratio statistic,
      which assumes Hardy-Weinberg equilibrium of the marker phenotype proportions. We
      show, by simulations, that this approach can be grossly biased, with either
      extremely conservative or liberal type I error rates. In contrast, we use
      simulations to show that a composite statistic, proposed by Weir and Cockerham,
      maintains the correct type I error rates, and, when comparisons are appropriate,
      has similar power as the likelihood-ratio statistic. We extend the composite
      statistic to allow for more than two alleles per locus, providing a global
      composite statistic, which is a strong competitor to the usual likelihood-ratio
      statistic.

PMID- 15020440
TI  - Developmental associations between traits: covariance and beyond.
AB  - Statistical associations between phenotypic traits often result from shared
      developmental processes and include both covariation between the trait values and
      more complex associations between higher moments of the joint distribution of
      traits. In this article, an analytical technique for calculating the covariance
      between traits is presented on the basis of (1). the distribution of underlying
      genetic and environmental variation that jointly influences the traits and (2).
      the mechanics of how these underlying factors influence the development of each
      trait. It is shown that epistasis can produce patterns of covariation between
      traits that are not seen in additive models. Applying this approach to a trait in
      parents and the same trait in their offspring allows us to study the consequences
      of epistasis for the evolution of additive genetic variance and heritability.
      This analysis is then extended to the study of more complicated associations
      between traits. It is shown that even traits that are not correlated may exhibit
      developmental associations that influence their joint evolution.

PMID- 15020438
TI  - Recombination within a nucleotide-binding-site/leucine-rich-repeat gene cluster
      produces new variants conditioning resistance to soybean mosaic virus in
      soybeans.
AB  - The soybean Rsv1 gene for resistance to soybean mosaic virus (SMV; Potyvirus) has
      previously been described as a single-locus multi-allelic gene mapping to
      molecular linkage group (MLG) F. Various Rsv1 alleles condition different
      responses to the seven (G1-G7) described strains of SMV, including extreme
      resistance, localized and systemic necrosis, and mosaic symptoms. We describe the
      cloning of a cluster of NBS-LRR resistance gene candidates from MLG F of the
      virus-resistant soybean line PI96983 and demonstrate that multiple genes within
      this cluster interact to condition unique responses to SMV strains. In addition
      to cloning 3gG2, a strong candidate for the major Rsv1 resistance gene from
      PI96983, we describe various unique resistant and necrotic reactions coincident
      with the presence or absence of other members of this gene cluster. Responses of
      recombinant lines from a high-resolution mapping population of PI96983
      (resistant) x Lee 68 (susceptible) demonstrate that more than one gene in this
      region of the PI96983 chromosome conditions resistance and/or necrosis to SMV. In
      addition, the soybean cultivars Marshall and Ogden, which carry other previously
      described Rsv1 alleles, are shown to possess the 3gG2 gene in a NBS-LRR gene
      cluster background distinct from PI96983. These observations suggest that two or
      more related non-TIR-NBS-LRR gene products are likely involved in the allelic
      response of several Rsv1-containing lines to SMV.

PMID- 15020441
TI  - Impact of nonrandom mating on genetic variance and gene flow in populations with
      mass selection.
AB  - The mechanisms by which nonrandom mating affects selected populations are not
      completely understood and remain a subject of scientific debate in the
      development of tractable predictors of population characteristics. The main
      objective of this study was to provide a predictive model for the genetic
      variance and covariance among mates for traits subjected to directional selection
      in populations with nonrandom mating based on the pedigree. Stochastic
      simulations were used to check the validity of this model. Our predictions
      indicate that the positive covariance among mates that is expected to result with
      preferential mating of relatives can be severely overpredicted from neutral
      expectations. The covariance expected from neutral theory is offset by an
      opposing covariance between the genetic mean of an individual's family and the
      Mendelian sampling term of its mate. This mechanism was able to predict the
      reduction in covariance among mates that we observed in the simulated populations
      and, in consequence, the equilibrium genetic variance and expected long-term
      genetic contributions. Additionally, this study provided confirmatory evidence on
      the postulated relationships of long-term genetic contributions with both the
      rate of genetic gain and the rate of inbreeding (deltaF) with nonrandom mating.
      The coefficient of variation of the expected gene flow among individuals and
      deltaF was sensitive to nonrandom mating when heritability was low, but less so
      as heritability increased, and the theory developed in the study was sufficient
      to explain this phenomenon.

PMID- 15020442
TI  - Inference on recombination and block structure using unphased data.
AB  - In this study compatibility with a tree for unphased genotype data is discussed.
      If the data are compatible with a tree, the data are consistent with an
      assumption of no recombination in its evolutionary history. Further, it is said
      that there is a solution to the perfect phylogeny problem; i.e., for each
      individual a pair of haplotypes can be defined and the set of all haplotypes can
      be explained without invoking recombination. A new algorithm to decide whether or
      not a sample is compatible with a tree is derived. The new algorithm relies on an
      equivalence relation between sites that mutually determine the phase of each
      other. (The previous algorithm was based on advanced graph theoretical tools.)
      The equivalence relation is used to derive the number of solutions to the perfect
      phylogeny problem. Further, a series of statistics, R ( j ) ( M ), j >or= 2, are
      defined. These can be used to detect recombination events in the sample's history
      and to divide the sample into regions that are compatible with a tree. The new
      statistics are applied to real data from human genes. The results from this
      application are discussed with reference to recent suggestions that recombination
      in the human genome is highly heterogeneous.

PMID- 15020443
TI  - In silico study of transcriptome genetic variation in outbred populations.
AB  - Dissecting the genetic architecture of regulatory elements on a genome-wide basis
      is now technically feasible. The potential medical and genetical implications of
      this kind of experiment being very large, it is paramount to assess the
      reliability and repeatability of the results. This is especially relevant in
      outbred populations, such as humans, where the genetic architecture is
      necessarily more complex than in crosses between inbred lines. Here we simulated
      a chromosome-wide SNP association study using real human microarray data. Our
      model predicted, as observed, a highly significant clustering of quantitative
      trait loci (QTL) for gene expression. Importantly, the estimates of QTL positions
      were often unstable, and a decrease in the number of individuals of 16% resulted
      in a loss of power of approximately 30% and a large shift in the position
      estimate in approximately 30-40% of the remaining significant QTL. We also found
      that the analysis of two repeated measures of the same mRNA can also result in
      two QTL that are located far apart. The intrinsic difficulties of analyzing
      outbred populations should not be underestimated. We anticipate that (many)
      conflicting results may be collected in the future if whole-genome association
      studies for mRNA levels are carried out in outbred populations.

PMID- 15020444
TI  - Estimating effective population size or mutation rate with microsatellites.
AB  - Microsatellites are short tandem repeats that are widely dispersed among
      eukaryotic genomes. Many of them are highly polymorphic; they have been used
      widely in genetic studies. Statistical properties of all measures of genetic
      variation at microsatellites critically depend upon the composite parameter theta
      = 4Nmicro, where N is the effective population size and micro is mutation rate
      per locus per generation. Since mutation leads to expansion or contraction of a
      repeat number in a stepwise fashion, the stepwise mutation model has been widely
      used to study the dynamics of these loci. We developed an estimator of theta,
      theta; (F), on the basis of sample homozygosity under the single-step stepwise
      mutation model. The estimator is unbiased and is much more efficient than the
      variance-based estimator under the single-step stepwise mutation model. It also
      has smaller bias and mean square error (MSE) than the variance-based estimator
      when the mutation follows the multistep generalized stepwise mutation model.
      Compared with the maximum-likelihood estimator theta; (L) by, theta; (F) has less
      bias and smaller MSE in general. theta; (L) has a slight advantage when theta is
      small, but in such a situation the bias in theta; (L) may be more of a concern.

PMID- 15020446
TI  - A bivalent polyploid model for mapping quantitative trait loci in outcrossing
      tetraploids.
AB  - Two major aspects have made the genetic and genomic study of polyploids extremely
      difficult. First, increased allelic or nonallelic combinations due to multiple
      alleles result in complex gene actions and interactions for quantitative trait
      loci (QTL) in polyploids. Second, meiotic configurations in polyploids undergo a
      complex biological process including either bivalent or multivalent formation, or
      both. For bivalent polyploids, different degrees of preferential chromosome
      pairings may occur during meiosis. In this article, we develop a maximum
      likelihood-based model for mapping QTL in tetraploids by considering the
      quantitative inheritance and meiotic mechanism of bivalent polyploids. This
      bivalent polyploid model is implemented with the EM algorithm to simultaneously
      estimate QTL position, QTL effects, and QTL-marker linkage phases by
      incorporating the impact of a cytological parameter determining bivalent
      chromosome pairings (the preferential pairing factor). Simulation studies are
      performed to investigate the performance and robustness of our statistical method
      for parameter estimation. The implication and extension of the bivalent polyploid
      model are discussed.

PMID- 15020445
TI  - The effect of genetic conflict on genomic imprinting and modification of
      expression at a sex-linked locus.
AB  - We examine how genomic imprinting may have evolved at an X-linked locus, using
      six diallelic models of selection in which one allele is imprintable and the
      other is not. Selection pressures are generated by genetic conflict between
      mothers and their offspring. The various models describe cases of maternal and
      paternal inactivation, in which females may be monogamous or bigamous. When
      inactivation is maternal, we examine the situations in which only female
      offspring exhibit imprinting as well as when both sexes do. We compare our
      results to those previously obtained for an autosomal locus and to four models in
      which a dominant modifier of biallelic expression is subjected to the same
      selection pressures. We find that, in accord with verbal predictions, maternal
      inactivation of growth enhancers and paternal inactivation of growth inhibitors
      are more likely than imprinting in the respective opposite directions, although
      these latter outcomes are possible for certain parameter combinations. The
      expected outcomes are easier to evolve than the same outcomes for autosomal loci,
      contradicting the available evidence concerning the direction of imprinting on
      mammalian sex chromosomes. In most of our models stable polymorphism of
      imprinting status is possible, a behavior not predicted by verbal accounts.

PMID- 15020447
TI  - Influence of dominance, leptokurtosis and pleiotropy of deleterious mutations on
      quantitative genetic variation at mutation-selection balance.
AB  - In models of maintenance of genetic variance (V (G)) it has often been assumed
      that mutant alleles act additively. However, experimental data show that the
      dominance coefficient varies among mutant alleles and those of large effect tend
      to be recessive. On the basis of empirical knowledge of mutations, a joint-effect
      model of pleiotropic and real stabilizing selection that includes dominance is
      constructed and analyzed. It is shown that dominance can dramatically alter the
      prediction of equilibrium V (G). Analysis indicates that for the situations where
      mutations are more recessive for fitness than for a quantitative trait, as
      supported by the available data, the joint-effect model predicts a significantly
      higher V (G) than does an additive model. Importantly, for what seem to be
      realistic distributions of mutational effects (i.e., many mutants may not affect
      the quantitative trait substantially but are likely to affect fitness), the
      observed high levels of genetic variation in the quantitative trait under strong
      apparent stabilizing selection can be generated. This investigation supports the
      hypothesis that most V (G) comes from the alleles nearly neutral for fitness in
      heterozygotes while apparent stabilizing selection is contributed mainly by the
      alleles of large effect on the quantitative trait. Thus considerations of
      dominance coefficients of mutations lend further support to our previous
      conclusion that mutation-selection balance is a plausible mechanism of the
      maintenance of the genetic variance in natural populations.

PMID- 15020448
TI  - Controlling the proportion of false positives in multiple dependent tests.
AB  - Genome scan mapping experiments involve multiple tests of significance. Thus,
      controlling the error rate in such experiments is important. Simple extension of
      classical concepts results in attempts to control the genomewise error rate
      (GWER), i.e., the probability of even a single false positive among all tests.
      This results in very stringent comparisonwise error rates (CWER) and,
      consequently, low experimental power. We here present an approach based on
      controlling the proportion of false positives (PFP) among all positive test
      results. The CWER needed to attain a desired PFP level does not depend on the
      correlation among the tests or on the number of tests as in other approaches. To
      estimate the PFP it is necessary to estimate the proportion of true null
      hypotheses. Here we show how this can be estimated directly from experimental
      results. The PFP approach is similar to the false discovery rate (FDR) and
      positive false discovery rate (pFDR) approaches. For a fixed CWER, we have
      estimated PFP, FDR, pFDR, and GWER through simulation under a variety of models
      to illustrate practical and philosophical similarities and differences among the
      methods.

PMID- 15020449
TI  - Bayesian estimation of genomic distance.
AB  - We present a Bayesian approach to the problem of inferring the number of
      inversions and translocations separating two species. The main reason for
      developing this method is that it will allow us to test hypotheses about the
      underlying mechanisms, such as the distribution of inversion track lengths or
      rate constancy among lineages. Here, we apply these methods to comparative maps
      of eggplant and tomato, human and cat, and human and cattle with 170, 269, and
      422 markers, respectively. In the first case the most likely number of events is
      larger than the parsimony value. In the last two cases the parsimony solutions
      have very small probability.

PMID- 15020450
TI  - One-hybrid screens at the Saccharomyces cerevisiae HMR locus identify novel
      transcriptional silencing factors.
AB  - In Saccharomyces cerevisiae, genes located at the telomeres and the HM loci are
      subject to transcriptional silencing. Here, we report results of screening a Gal4
      DNA-binding domain hybrid library for proteins that cause silencing when targeted
      to a silencer-defective HMR locus.

PMID- 15020451
TI  - Compensatory evolution in the human malaria parasite Plasmodium ovale.
AB  - The fixation of neutral compensatory mutations in a population depends on the
      effective population size of the species, which can fluctuate dramatically within
      a few generations, the mutation rate, and the selection intensity associated with
      the individual mutations. We observe compensatory mutations and intermediate
      states in populations of the malaria parasite Plasmodium ovale. The appearance of
      compensatory mutations and intermediate states in P. ovale raises interesting
      questions about population structure that could have considerable impact on the
      control of the associated disease.

PMID- 15020453
TI  - The 2004 Thomas Hunt Morgan Medal.

PMID- 15020452
TI  - On the Metropolis-Hastings acceptance probability to add or drop a quantitative
      trait locus in Markov chain Monte Carlo-based Bayesian analyses.
AB  - The Metropolis-Hastings algorithm used in analyses that estimate the number of
      QTL segregating in a mapping population requires the calculation of an acceptance
      probability to add or drop a QTL from the model. Expressions for this acceptance
      probability need to recognize that sets of QTL are unordered such that the number
      of equivalent sets increases with the factorial of the QTL number. Here, we show
      how accounting for this fact affects the acceptance probability and review
      expressions found in the literature.

PMID- 15020454
TI  - The 2004 Genetics Society of America Medal.

PMID- 15020455
TI  - The 2004 George W. Beadle Medal.

PMID- 15020456
TI  - Ira Herskowitz: 1946-2003.

PMID- 15020457
TI  - Developing a genetic system in Deinococcus radiodurans for analyzing mutations.
AB  - We have applied a genetic system for analyzing mutations in Escherichia coli to
      Deinococcus radiodurans, an extremeophile with an astonishingly high resistance
      to UV- and ionizing-radiation-induced mutagenesis. Taking advantage of the
      conservation of the beta-subunit of RNA polymerase among most prokaryotes, we
      derived again in D. radiodurans the rpoB/Rif(r) system that we developed in E.
      coli to monitor base substitutions, defining 33 base change substitutions at 22
      different base pairs. We sequenced >250 mutations leading to Rif(r) in D.
      radiodurans derived spontaneously in wild-type and uvrD (mismatch-repair
      deficient) backgrounds and after treatment with N-methyl-N'-nitro-N
      nitrosoguanidine (NTG) and 5-azacytidine (5AZ). The specificities of NTG and 5AZ
      in D. radiodurans are the same as those found for E. coli and other organisms.
      There are prominent base substitution hotspots in rpoB in both D. radiodurans and
      E. coli. In several cases these are at different points in each organism, even
      though the DNA sequences surrounding the hotspots and their corresponding sites
      are very similar in both D. radiodurans and E. coli. In one case the hotspots
      occur at the same site in both organisms.

PMID- 15020458
TI  - General stress response regulator RpoS in adaptive mutation and amplification in
      Escherichia coli.
AB  - Microbial cells under growth-limiting stress can generate mutations by mechanisms
      distinct from those in rapidly growing cells. These mechanisms might be specific
      stress responses that increase mutation rates, potentially altering rates of
      evolution, or might reflect non-stress-specific processes in rare growing cells.
      In an Escherichia coli model system, both frameshift reversion mutations and gene
      amplifications occur as apparent starvation-induced mutations. Whereas frameshift
      reversion ("point mutation") requires recombination proteins, the SOS response,
      and error-prone DNA polymerase IV (DinB), amplification requires neither SOS nor
      pol IV. We report that both point mutation and amplification require the
      stationary-phase and general stress response transcription factor RpoS (sigmaS).
      Growth-dependent mutation does not. Alternative interpretations are excluded. The
      results imply, first, that point mutation and amplification are stress responses
      that occur in differentiated stationary-phase (not rare growing) cells and,
      second, that transient genetic instability, producing both point mutation and
      genome rearrangement, may be a previously unrecognized component of the RpoS
      dependent general stress response.

PMID- 15020459
TI  - Distinct signatures for mutator sensitivity of lacZ reversions and for the
      spectrum of lacI/lacO forward mutations on the chromosome of nondividing
      Escherichia coli.
AB  - A conditional lethal galE(Ts)-based strategy was employed in Escherichia coli,
      first to eliminate all growth-associated chromosomal reversions in lacZ or
      forward mutations in lacI/lacO by incubation at the restrictive temperature and
      subsequently to recover (as papillae) spontaneous mutations that had arisen in
      the population of nondividing cells after shift to the permissive temperature.
      Data from lacZ reversion studies in mutator strains indicated that the products
      of all genes for mismatch repair (mutHLS, dam, uvrD), of some for oxidative
      damage repair (mutMT), and of that for polymerase proofreading (dnaQ) are
      required in dividing cells; some others for oxidative damage repair (mutY, nth
      nei) are required in both dividing and nondividing cells; and those for
      alkylation damage repair (ada ogt) are required in nondividing cells. The
      spectrum of lacI/lacO mutations in nondividing cells was distinguished both by
      lower frequencies of deletions and IS1 insertions and by the unique occurrence of
      GC-to-AT transitions at lacO +5. In the second approach to study mutations that
      had occurred in nondividing cells, lacI/lacO mutants were selected as late
      arising papillae from the lawn of a galE+ strain; once again, transitions at lacO
      +5 were detected among the mutants that had been obtained from populations
      initially grown on poor carbon sources such as acetate, palmitate, or succinate.
      Our results indicate that the lacO +5 site is mutable only in nondividing cells,
      one possible mechanism for which might be that random endogenous alkylation (or
      oxidative) damage to DNA in these cells is efficiently corrected by the Ada Ogt
      (or Nth Nei) repair enzymes at most sites but not at lacO +5. Furthermore, the
      late-arising papillae from the second approach were composed almost exclusively
      of dominant lacI/lacO mutants. This finding lends support to "instantaneous
      gratification" models in which a spontaneous lesion, occurring at a random site
      in DNA of a nondividing cell, is most likely to be fixed as a mutation if it
      allows the cell to immediately exit the nondividing state.

PMID- 15020460
TI  - Effector genes of Xanthomonas axonopodis pv. vesicatoria promote transmission and
      enhance other fitness traits in the field.
AB  - Establishing durable disease resistance in agricultural crops, where much of the
      plant defense is provided through effector-R gene interactions, is complicated by
      the ability of pathogens to overcome R gene resistance by losing the
      corresponding effector gene. Many proposed methods to maintain disease resistance
      in the field depend on the idea that effector gene loss results in a fitness cost
      to the pathogen. In this article we test for fitness costs of effector gene
      function loss. We created directed knockouts of up to four effector genes from
      the bacterial plant pathogen Xanthomonas axonopodis pv. vesicatoria (Xav) and
      examined the effect of the loss of a functional gene product on several important
      fitness parameters in the field. These traits included transmission, lesion
      development, and epiphytic survival. We found that the products of all four
      effector genes had significant and often additive effects on fitness traits.
      Additional greenhouse tests revealed costs of effector gene loss on in planta
      growth and further showed that the effects on lesion development were separable
      from the effects on growth. Observable fitness effects of the three plasmid-borne
      effector genes were dependent upon the loss of functional avrBs2, indicating that
      complex functional interactions exist among effector genes with Xav.

PMID- 15020461
TI  - A synthetic lethal screen identifies a role for the cortical actin
      patch/endocytosis complex in the response to nutrient deprivation in
      Saccharomyces cerevisiae.
AB  - Saccharomyces cerevisiae whi2Delta cells are unable to halt cell division in
      response to nutrient limitation and are sensitive to a wide variety of stresses.
      A synthetic lethal screen resulted in the isolation of siw mutants that had a
      phenotype similar to that of whi2Delta. Among these were mutations affecting
      SIW14, FEN2, SLT2, and THR4. Fluid-phase endocytosis is severely reduced or
      abolished in whi2Delta, siw14Delta, fen2Delta, and thr4Delta mutants.
      Furthermore, whi2Delta and siw14Delta mutants produce large actin clumps in
      stationary phase similar to those seen in prk1Delta ark1Delta mutants defective
      in protein kinases that regulate the actin cytoskeleton. Overexpression of SIW14
      in a prk1Delta strain resulted in a loss of cortical actin patches and cables and
      was lethal. Overexpression of SIW14 also rescued the caffeine sensitivity of the
      slt2 mutant isolated in the screen, but this was not due to alteration of the
      phosphorylation state of Slt2. These observations suggest that endocytosis and
      the organization of the actin cytoskeleton are required for the proper response
      to nutrient limitation. This hypothesis is supported by the observation that
      rvs161Delta, sla1Delta, sla2Delta, vrp1Delta, ypt51Delta, ypt52Delta, and
      end3Delta mutations, which disrupt the organization of the actin cytoskeleton
      and/or reduce endocytosis, have a phenotype similar to that of whi2Delta mutants.

PMID- 15020462
TI  - Homology modeling and mutational analysis of Ho endonuclease of yeast.
AB  - Ho endonuclease is a LAGLIDADG homing endonuclease that initiates mating-type
      interconversion in yeast. Ho is encoded by a free-standing gene but shows 50%
      primary sequence similarity to the intein (protein-intron encoded) PI-SceI. Ho is
      unique among LAGLIDADG endonucleases in having a 120-residue C-terminal putative
      zinc finger domain. The crystal structure of PI-SceI revealed a bipartite enzyme
      with a protein-splicing domain (Hint) and intervening endonuclease domain. We
      made a homology model for Ho on the basis of the PI-SceI structure and performed
      mutational analysis of putative critical residues, using a mating-type switch as
      a bioassay for activity and GFP-fusion proteins to detect nuclear localization.
      We found that residues of the N-terminal sequence of the Hint domain are
      important for Ho activity, in particular the DNA recognition region. C-terminal
      residues of the Hint domain are dispensable for Ho activity; however, the C
      terminal putative zinc finger domain is essential. Mutational analysis indicated
      that residues in Ho that are conserved relative to catalytic, active-site
      residues in PI-SceI and other related homing endonucleases are essential for Ho
      activity. Our results indicate that in addition to the conserved catalytic
      residues, Hint domain residues and the zinc finger domain have evolved a critical
      role in Ho activity.

PMID- 15020463
TI  - Identification of Edc3p as an enhancer of mRNA decapping in Saccharomyces
      cerevisiae.
AB  - The major pathway of mRNA decay in yeast initiates with deadenylation, followed
      by mRNA decapping and 5'-3' exonuclease digestion. An in silico approach was used
      to identify new proteins involved in the mRNA decay pathway. One such protein,
      Edc3p, was identified as a conserved protein of unknown function having extensive
      two-hybrid interactions with several proteins involved in mRNA decapping and 5'
      3' degradation including Dcp1p, Dcp2p, Dhh1p, Lsm1p, and the 5'-3' exonuclease,
      Xrn1p. We show that Edc3p can stimulate mRNA decapping of both unstable and
      stable mRNAs in yeast when the decapping enzyme is compromised by temperature
      sensitive alleles of either the DCP1 or the DCP2 genes. In these cases, deletion
      of EDC3 caused a synergistic mRNA-decapping defect at the permissive
      temperatures. The edc3Delta had no effect when combined with the lsm1Delta,
      dhh1Delta, or pat1Delta mutations, which appear to affect an early step in the
      decapping pathway. This suggests that Edc3p specifically affects the function of
      the decapping enzyme per se. Consistent with a functional role in decapping, GFP
      tagged Edc3p localizes to cytoplasmic foci involved in mRNA decapping referred to
      as P-bodies. These results identify Edc3p as a new protein involved in the
      decapping reaction.

PMID- 15020464
TI  - Reciprocal translocations in Saccharomyces cerevisiae formed by nonhomologous end
      joining.
AB  - Reciprocal translocations are common in cancer cells, but their creation is
      poorly understood. We have developed an assay system in Saccharomyces cerevisiae
      to study reciprocal translocation formation in the absence of homology. We induce
      two specific double-strand breaks (DSBs) simultaneously on separate chromosomes
      with HO endonuclease and analyze the subsequent chromosomal rearrangements among
      surviving cells. Under these conditions, reciprocal translocations via
      nonhomologous end joining (NHEJ) occur at frequencies of approximately 2-7 x 10(
      5)/cell exposed to the DSBs. Yku80p is a component of the cell's NHEJ machinery.
      In its absence, reciprocal translocations still occur, but the junctions are
      associated with deletions and extended overlapping sequences. After induction of
      a single DSB, translocations and inversions are recovered in wild-type and rad52
      strains. In these rearrangements, a nonrandom assortment of sites have fused to
      the DSB, and their junctions show typical signs of NHEJ. The sites tend to be
      between open reading frames or within Ty1 LTRs. In some cases the translocation
      partner is formed by a break at a cryptic HO recognition site. Our results
      demonstrate that NHEJ-mediated reciprocal translocations can form in S.
      cerevisiae as a consequence of DSB repair.

PMID- 15020465
TI  - Mec1 and Rad53 inhibit formation of single-stranded DNA at telomeres of
      Saccharomyces cerevisiae cdc13-1 mutants.
AB  - Here we examine the roles of budding-yeast checkpoint proteins in regulating
      degradation of dsDNA to ssDNA at unprotected telomeres (in Cdc13 telomere-binding
      protein defective strains). We find that Rad17, Mec3, as well as Rad24, members
      of the putative checkpoint clamp loader (Rad24) and sliding clamp (Rad17, Mec3)
      complexes, are important for promoting degradation of dsDNA in and near telomere
      repeats. We find that Mec1, Rad53, as well as Rad9, have the opposite role: they
      inhibit degradation. Downstream checkpoint kinases Chk1 and Dun1 play no
      detectable role in either promoting degradation or inhibiting it. These data
      suggest, first, that the checkpoint sliding clamp regulates and/or recruits some
      nucleases for degradation, and, second, that Mec1 activates Rad9 to activate
      Rad53 to inhibit degradation. Further analysis shows that Rad9 inhibits ssDNA
      generation by both Mec1/Rad53-dependent and -independent pathways. Exo1 appears
      to be targeted by the Mec1/Rad53-dependent pathway. Finally, analysis of double
      mutants suggests a minor role for Mec1 in promoting Rad24-dependent degradation
      of dsDNA. Thus, checkpoint proteins orchestrate carefully ssDNA production at
      unprotected telomeres.

PMID- 15020466
TI  - Rtg2 protein links metabolism and genome stability in yeast longevity.
AB  - Mitochondrial dysfunction induces a signaling pathway, which culminates in
      changes in the expression of many nuclear genes. This retrograde response, as it
      is called, extends yeast replicative life span. It also results in a marked
      increase in the cellular content of extrachromosomal ribosomal DNA circles
      (ERCs), which can cause the demise of the cell. We have resolved the conundrum of
      how these two molecular mechanisms of yeast longevity operate in tandem. About
      50% of the life-span extension elicited by the retrograde response involves
      processes other than those that counteract the deleterious effects of ERCs.
      Deletion of RTG2, a gene that plays a central role in relaying the retrograde
      response signal to the nucleus, enhances the generation of ERCs in cells with
      (grande) or in cells without (petite) fully functional mitochondria, and it
      curtails the life span of each. In contrast, overexpression of RTG2 diminishes
      ERC formation in both grandes and petites. The excess Rtg2p did not augment the
      retrograde response, indicating that it was not engaged in retrograde signaling.
      FOB1, which is known to be required for ERC formation, and RTG2 were found to be
      in converging pathways for ERC production. RTG2 did not affect silencing of
      ribosomal DNA in either grandes or petites, which were similar to each other in
      the extent of silencing at this locus. Silencing of ribosomal DNA increased with
      replicative age in either the presence or the absence of Rtg2p, distinguishing
      silencing and ERC accumulation. Our results indicate that the suppression of ERC
      production by Rtg2p requires that it not be in the process of transducing the
      retrograde signal from the mitochondrion. Thus, RTG2 lies at the nexus of
      cellular metabolism and genome stability, coordinating two pathways that have
      opposite effects on yeast longevity.

PMID- 15020467
TI  - Effect of breeding structure on population genetic parameters in Drosophila.
AB  - The breeding structure of populations has been neglected in studies of
      Drosophila, even though Wright and Dobzhansky's pioneering work on the genetics
      of natural populations was an attempt to tackle what they regarded as an
      essential factor in evolution. We compared the breeding structure of sympatric
      populations of D. melanogaster and D. simulans, two sibling species that are
      widely used in evolutionary studies. We recorded changes in population density
      and microsatellite variation patterns for 3 years in a temperate environment of
      southwestern France. Results were distinctively different in the two species.
      Maximum population levels in summer and in autumn were similar and fluctuated
      greatly over years, each species being in turn the most abundant. However,
      genetic data showed that D. melanogaster made up a continuous breeding population
      in time and space of practically infinite effective size. D. simulans was
      fragmented into isolates with a local effective size of between 50 and 350
      individuals. A consequence of this was that, while a local sample provided a
      reliable estimate of regional genetic variability in D. melanogaster, a sample
      from the same area provided an underestimate of this parameter in D. simulans. In
      practical terms, this means that variations in breeding structure should be
      accounted for in sampling schemes and in designing evolutionary genetic models.
      More generally, this suggests the existence of differential reactions to local
      environments that might contribute to several genomic differences observed
      between these species.

PMID- 15020468
TI  - Genetic complexity underlying hybrid male sterility in Drosophila.
AB  - Recent genetic analyses of closely related species of Drosophila have indicated
      that hybrid male sterility is the consequence of highly complex synergistic
      effects among multiple genes, both conspecific and heterospecific. On the
      contrary, much evidence suggests the presence of major genes causing hybrid
      female sterility and inviability in the less-related species, D. melanogaster and
      D. simulans. Does this contrast reflect the genetic distance between species? Or,
      generally, is the genetic basis of hybrid male sterility more complex than that
      of hybrid female sterility and inviability? To clarify this point, the D.
      simulans introgression of the cytological region 34D-36A to the D. melanogaster
      genome, which causes recessive male sterility, was dissected by recombination,
      deficiency, and complementation mapping. The 450-kb region between two genes,
      Suppressor of Hairless and snail, exhibited a strong effect on the sterility.
      Males are (semi-)sterile if this region of the introgression is made homozygous
      or hemizygous. But no genes in the region singly cause the sterility; this region
      has at least two genes, which in combination result in male sterility. Further,
      the males are less fertile when heterozygous with a larger introgression, which
      suggests that dominant modifiers enhance the effects of recessive genes of male
      sterility. Such an epistatic view, even in the less-related species, suggests
      that the genetic complexity is special to hybrid male sterility.

PMID- 15020469
TI  - On the rate and linearity of viability declines in Drosophila mutation
      accumulation experiments: genomic mutation rates and synergistic epistasis
      revisited.
AB  - High rates of deleterious mutations could severely reduce the fitness of
      populations, even endangering their persistence; these effects would be mitigated
      if mutations synergize each others' effects. An experiment by Mukai in the 1960s
      gave evidence that in Drosophila melanogaster, viability-depressing mutations
      occur at the surprisingly high rate of around one per zygote and that the
      mutations interact synergistically. A later experiment by Ohnishi seemed to
      support the high mutation rate, but gave no evidence for synergistic epistasis.
      Both of these studies, however, were flawed by the lack of suitable controls for
      assessing viability declines of the mutation-accumulation (MA) lines. By
      comparing homozygous viability of the MA lines to simultaneously estimated
      heterozygous viability and using estimates of the dominance of mutations in the
      experiments, I estimate the viability declines relative to an appropriate
      control. This approach yields two unexpected conclusions. First, in Ohnishi's
      experiment as well as in Mukai's, MA lines showed faster-than-linear declines in
      viability, indicative of synergistic epistasis. Second, while Mukai's estimate of
      the genomic mutation rate is supported, that from Ohnishi's experiment is an
      order of magnitude lower. The different results of the experiments most likely
      resulted from differences in the starting genotypes; even within Mukai's
      experiment, a subset of MA lines, which I argue probably resulted from a
      contamination event, showed much slower viability declines than did the majority
      of lines. Because different genotypes may show very different mutational
      behavior, only studies using many founding genotypes can determine the average
      rate and distribution of effects of mutations relevant to natural populations.

PMID- 15020470
TI  - Genetic and bioinformatic analysis of 41C and the 2R heterochromatin of
      Drosophila melanogaster: a window on the heterochromatin-euchromatin junction.
AB  - Genomic sequences provide powerful new tools in genetic analysis, making it
      possible to combine classical genetics with genomics to characterize the genes in
      a particular chromosome region. These approaches have been applied successfully
      to the euchromatin, but analysis of the heterochromatin has lagged somewhat
      behind. We describe a combined genetic and bioinformatics approach to the base of
      the right arm of the Drosophila melanogaster second chromosome, at the boundary
      between pericentric heterochromatin and euchromatin. We used resources provided
      by the genome project to derive a physical map of the region, examine gene
      density, and estimate the number of potential genes. We also carried out a large
      scale genetic screen for lethal mutations in the region. We identified new
      alleles of the known essential genes and also identified mutations in 21 novel
      loci. Fourteen complementation groups map proximal to the assembled sequence. We
      used PCR to map the endpoints of several deficiencies and used the same set of
      deficiencies to order the essential genes, correlating the genetic and physical
      map. This allowed us to assign two of the complementation groups to particular
      "computed/curated genes" (CGs), one of which is Nipped-A, which our evidence
      suggests encodes Drosophila Tra1/TRRAP.

PMID- 15020471
TI  - A bacterial genetic screen identifies functional coding sequences of the insect
      mariner transposable element Famar1 amplified from the genome of the earwig,
      Forficula auricularia.
AB  - Transposons of the mariner family are widespread in animal genomes and have
      apparently infected them by horizontal transfer. Most species carry only old
      defective copies of particular mariner transposons that have diverged greatly
      from their active horizontally transferred ancestor, while a few contain young,
      very similar, and active copies. We report here the use of a whole-genome screen
      in bacteria to isolate somewhat diverged Famar1 copies from the European earwig,
      Forficula auricularia, that encode functional transposases. Functional and
      nonfunctional coding sequences of Famar1 and nonfunctional copies of Ammar1 from
      the European honey bee, Apis mellifera, were sequenced to examine their molecular
      evolution. No selection for sequence conservation was detected in any clade of a
      tree derived from these sequences, not even on branches leading to functional
      copies. This agrees with the current model for mariner transposon evolution that
      expects neutral evolution within particular hosts, with selection for function
      occurring only upon horizontal transfer to a new host. Our results further
      suggest that mariners are not finely tuned genetic entities and that a greater
      amount of sequence diversification than had previously been appreciated can occur
      in functional copies in a single host lineage. Finally, this method of isolating
      active copies can be used to isolate other novel active transposons without
      resorting to reconstruction of ancestral sequences.

PMID- 15020473
TI  - Differential segregation patterns of sperm mitochondria in embryos of the blue
      mussel (Mytilus edulis).
AB  - In Mytilus, females carry predominantly maternal mitochondrial DNA (mtDNA) but
      males carry maternal mtDNA in their somatic tissues and paternal mtDNA in their
      gonads. This phenomenon, known as doubly uniparental inheritance (DUI) of mtDNA,
      presents a major departure from the uniparental transmission of organelle
      genomes. Eggs of Mytilus edulis from females that produce exclusively daughters
      and from females that produce mostly sons were fertilized with sperm stained with
      MitoTracker Green FM, allowing observation of sperm mitochondria in the embryo by
      epifluorescent and confocal microscopy. In embryos from females that produce only
      daughters, sperm mitochondria are randomly dispersed among blastomeres. In
      embryos from females that produce mostly sons, sperm mitochondria tend to
      aggregate and end up in one blastomere in the two- and four-cell stages. We
      postulate that the aggregate eventually ends up in the first germ cells, thus
      accounting for the presence of paternal mtDNA in the male gonad. This is the
      first evidence for different behaviors of sperm mitochondria in developing
      embryos that may explain the tight linkage between gender and inheritance of
      paternal mitochondrial DNA in species with DUI.

PMID- 15020474
TI  - Transposition of the Tol2 element, an Ac-like element from the Japanese medaka
      fish Oryzias latipes, in mouse embryonic stem cells.
AB  - The Tol2 transposable element of the Japanese medaka fish belongs to the hAT
      family of transposons including hobo of Drosophila, Ac of maize, and Tam3 of
      snapdragon. To date, Tol2 is the only natural transposon in vertebrates that has
      ever been shown to encode a fully functional transposase. It has not been known,
      however, whether Tol2 can transpose in vertebrates other than fish. We report
      here transposition of Tol2 in mouse embryonic stem (ES) cells. We constructed a
      transposon donor plasmid containing a nonautonomous Tol2 element with the
      neomycin resistance gene and a helper plasmid capable of expressing the
      transposase and introduced the donor plasmid with various amounts of the helper
      plasmid by electroporation into mouse ES cells. The number of G418-resistant ES
      colonies increased as the amount of helper plasmid was increased, in a dose
      dependent manner, indicating that the transposase activity elevated the
      integration efficiency. These G418-resistant ES colonies were cloned and the
      structure of the junction of the integrated Tol2 element and the genomic DNA was
      analyzed by inverse PCR. In those clones, Tol2 was surrounded by mouse genomic
      sequences and an 8-bp direct repeat was created adjacent to both ends of Tol2,
      indicating that Tol2 was integrated in the genome through transposition. The Tol2
      transposon system is thus active in mouse as well as in fish. We propose that it
      should be used as a genetic tool to develop novel gene transfer, transgenesis,
      and mutagenesis methods in mammals.

PMID- 15020475
TI  - A new deletion of the mouse Y chromosome long arm associated with the loss of
      Ssty expression, abnormal sperm development and sterility.
AB  - The mouse Y chromosome carries 10 distinct genes or gene families that have open
      reading frames suggestive of retained functionality; it has been assumed that
      many of these function in spermatogenesis. However, we have recently shown that
      only two Y genes, the testis determinant Sry and the translation initiation
      factor Eif2s3y, are essential for spermatogenesis to proceed to the round
      spermatid stage. Thus, any further substantive mouse Y-gene functions in
      spermatogenesis are likely to be during sperm differentiation. The complex Ssty
      gene family present on the mouse Y long arm (Yq) has been implicated in sperm
      development, with partial Yq deletions that reduce Ssty expression resulting in
      impaired fertilization efficiency. Here we report the identification of a more
      extensive Yq deletion that abolishes Ssty expression and results in severe sperm
      defects and sterility. This result establishes that genetic information (Ssty?)
      essential for normal sperm differentiation and function is present on mouse Yq.

PMID- 15020476
TI  - Hybrid breakdown caused by substitution of the X chromosome between two mouse
      subspecies.
AB  - Hybrid breakdown is a type of reproductive failure that appears after the F2
      generation of crosses between different species or subspecies. It is caused by
      incompatibility between interacting genes. Genetic analysis of hybrid breakdown,
      particularly in higher animals, has been hampered by its complex nature (i.e., it
      involves more than two genes, and the phenotype is recessive). We studied hybrid
      breakdown using a new consomic strain, C57BL/6J-X(MSM), in which the X chromosome
      of C57BL/6J (derived mostly from Mus musculus domesticus) is substituted by the X
      chromosome of the MSM/Ms strain (M. m. molossinus). Males of this consomic strain
      are sterile, whereas F1 hybrids between C57BL/6J and MSM/Ms are completely
      fertile. The C57BL/6J-X(MSM) males showed reduced testis weight with variable
      defects in spermatogenesis and abnormal sperm head morphology. We conducted
      quantitative trait locus (QTL) analysis for these traits to map the X-linked
      genetic factors responsible for the sterility. This analysis successfully
      detected at least three distinct loci for the sperm head morphology and one for
      the testis weight. This study revealed that incompatibility of interactions of X
      linked gene(s) with autosomal and/or Y-linked gene(s) causes the hybrid breakdown
      between the genetically distant C57BL/6J and MSM/Ms strains.

PMID- 15020472
TI  - Molecular and comparative genetics of mental retardation.
AB  - Affecting 1-3% of the population, mental retardation (MR) poses significant
      challenges for clinicians and scientists. Understanding the biology of MR is
      complicated by the extraordinary heterogeneity of genetic MR disorders. Detailed
      analyses of >1000 Online Mendelian Inheritance in Man (OMIM) database entries and
      literature searches through September 2003 revealed 282 molecularly identified MR
      genes. We estimate that hundreds more MR genes remain to be identified. A novel
      test, in which we distributed unmapped MR disorders proportionately across the
      autosomes, failed to eliminate the well-known X-chromosome overrepresentation of
      MR genes and candidate genes. This evidence argues against ascertainment bias as
      the main cause of the skewed distribution. On the basis of a synthesis of
      clinical and laboratory data, we developed a biological functions classification
      scheme for MR genes. Metabolic pathways, signaling pathways, and transcription
      are the most common functions, but numerous other aspects of neuronal and glial
      biology are controlled by MR genes as well. Using protein sequence and domain
      organization comparisons, we found a striking conservation of MR genes and
      genetic pathways across the approximately 700 million years that separate Homo
      sapiens and Drosophila melanogaster. Eighty-seven percent have one or more fruit
      fly homologs and 76% have at least one candidate functional ortholog. We propose
      that D. melanogaster can be used in a systematic manner to study MR and possibly
      to develop bioassays for therapeutic drug discovery. We selected 42 Drosophila
      orthologs as most likely to reveal molecular and cellular mechanisms of nervous
      system development or plasticity relevant to MR.

PMID- 15020477
TI  - Enhancers and suppressors of testicular cancer susceptibility in single- and
      double-mutant mice.
AB  - Susceptibility to spontaneous testicular germ cell tumors (TGCTs), a common
      cancer affecting young men, shows unusual genetic complexity. Despite remarkable
      progress in the genetics analysis of susceptibility to many cancers, TGCT
      susceptibility genes have not yet been identified. Various mutations that are
      inherited as Mendelian traits in laboratory mice affect susceptibility to
      spontaneous TGCTs on the 129/Sv inbred genetic background. We compared the
      frequency of spontaneous TGCTs in single- and double-mutant mice to identify
      combinations that show evidence of enhancer or suppressor effects. The lower-than
      expected TGCT frequencies in mice with partial deficiencies of TRP53 and MGF-SLJ
      and in 129.MOLF-Chr19 (M19) consomic mice that were heterozygous for the A(y)
      mutation suggest that either these genes complement each other to restore normal
      functionality in TGCT stem cells or together these genes activate mechanisms that
      suppress incipient TGCTs. By contrast, the higher-than-expected TGCT frequencies
      in Mgf(Sl-J)-M19 compound heterozygous mice suggest that these mutations
      exacerbate each other's effects. Together, these results provide clues to the
      genetic and molecular basis for susceptibility to TGCTs in mice and perhaps in
      humans.

PMID- 15020478
TI  - Genomic duplication, fractionation and the origin of regulatory novelty.
AB  - Having diverged 50 MYA, rice remained diploid while the maize lineage became
      tetraploid and then fractionated by losing genes from one or the other duplicate
      region. We sequenced and annotated 13 maize genes (counting the duplicate gene as
      one gene) on one or the other of the pair of homeologous maize regions; 12 genes
      were present in one cluster in rice. Excellent maize-rice synteny was evident,
      but only after the fractionated maize regions were condensed onto a finished rice
      map. Excluding the gene we used to define homeologs, we found zero retention.
      Once retained, fractionation (loss of functioning DNA sequence) could occur
      within cis-acting gene space. We chose a retained duplicate basic leucine zipper
      transcription factor gene because it was well marked with big, exact phylogenetic
      footprints (CNSs). Detailed alignments of lg2 and retained duplicate lrs1 to
      their rice ortholog found that fractionation of conserved noncoding sequences
      (CNSs) was rare, as expected. Of 30 CNSs, 27 were conserved. The 3 unexpected,
      missing CNSs and a large insertion support subfunctionalization as a reflection
      of fractionation of cis-acting gene space and the recent evolution of lg2's novel
      maize leaf and shoot developmental functions. In general, the principles of
      fractionation and consolidation work well in making sense of maize gene and
      genomic sequence data.

PMID- 15020480
TI  - Molecular-genetic characterization of CMS-S restorer-of-fertility alleles
      identified in Mexican maize and teosinte.
AB  - Restorer-of-fertility (Rf) alleles for S-type cytoplasmic male sterility (CMS-S)
      are prevalent in Mexican races of maize and teosinte. Forty-five Rf alleles from
      26 races of maize and 6 Rf alleles from different accessions of teosinte were
      found to be homozygous viable, consistent with the hypothesis that they are
      naturally occurring Rf alleles. Mapping and allelism studies were performed to
      assess the number of genes represented by these 51 alleles. Forty-two of the Rf
      alleles mapped to the long arm of chromosome 2 (2L), and 5 of these were further
      mapped to the whp1-rf3 region. The Rf3 restoring allele, found in some U.S. maize
      inbred lines, cosegregates with internal processing of CMS-S mitochondrial
      transcripts. Three of the 5 mapped Rf alleles were associated with a similar RNA
      processing event. Allelism or tight linkage was confirmed between Rf3 and 2
      teosinte alleles (Rf K-69-6 and Rf 9477) and between Rf3 and the Conico Norteno
      allele Rf C-N (GTO 22). The rf3 region of 2L potentially encodes a complex of
      linked rf genes. The prevalence of restoring alleles in this chromosomal region,
      among normal-cytoplasm accessions of Mexican maize and teosinte, supports the
      conclusion that these alleles have functions in normal mitochondrial gene
      expression that by chance allow them to restore male fertility in S cytoplasm.

PMID- 15020479
TI  - Meiotic recombination between paralogous RBCSB genes on sister chromatids of
      Arabidopsis thaliana.
AB  - Paralogous genes organized as a gene cluster can rapidly evolve by recombination
      between misaligned paralogs during meiosis, leading to duplications, deletions,
      and novel chimeric genes. To model unequal recombination within a specific gene
      cluster, we utilized a synthetic RBCSB gene cluster to isolate recombinant
      chimeric genes resulting from meiotic recombination between paralogous genes on
      sister chromatids. Several F1 populations hemizygous for the synthRBCSB1 gene
      cluster gave rise to Luc+ F2 plants at frequencies ranging from 1 to 3 x 10(-6).
      A nonuniform distribution of recombination resolution sites resulted in the
      biased formation of recombinant RBCS3B/1B::LUC genes with nonchimeric exons. The
      positioning of approximately half of the mapped resolution sites was effectively
      modeled by the fractional length of identical DNA sequences. In contrast, the
      other mapped resolution sites fit an alternative model in which recombination
      resolution was stimulated by an abrupt transition from a region of relatively
      high sequence similarity to a region of low sequence similarity. Thus, unequal
      recombination between paralogous RBCSB genes on sister chromatids created an
      allelic series of novel chimeric genes that effectively resulted in the
      diversification rather than the homogenization of the synthRBCSB1 gene cluster.

PMID- 15020481
TI  - PIF- and Pong-like transposable elements: distribution, evolution and
      relationship with Tourist-like miniature inverted-repeat transposable elements.
AB  - Miniature inverted-repeat transposable elements (MITEs) are short, nonautonomous
      DNA elements that are widespread and abundant in plant genomes. Most of the
      hundreds of thousands of MITEs identified to date have been divided into two
      major groups on the basis of shared structural and sequence characteristics:
      Tourist-like and Stowaway-like. Since MITEs have no coding capacity, they must
      rely on transposases encoded by other elements. Two active transposons, the maize
      P Instability Factor (PIF) and the rice Pong element, have recently been
      implicated as sources of transposase for Tourist-like MITEs. Here we report that
      PIF- and Pong-like elements are widespread, diverse, and abundant in eukaryotes
      with hundreds of element-associated transposases found in a variety of plant,
      animal, and fungal genomes. The availability of virtually the entire rice genome
      sequence facilitated the identification of all the PIF/Pong-like elements in this
      organism and permitted a comprehensive analysis of their relationship with
      Tourist-like MITEs. Taken together, our results indicate that PIF and Pong are
      founding members of a large eukaryotic transposon superfamily and that members of
      this superfamily are responsible for the origin and amplification of Tourist-like
      MITEs.

PMID- 15020482
TI  - Multiple origins and nrDNA internal transcribed spacer homeologue evolution in
      the Glycine tomentella (Leguminosae) allopolyploid complex.
AB  - Despite the importance of polyploidy in the evolution of plants, patterns of
      molecular evolution and genomic interactions following polyploidy are not well
      understood. Nuclear ribosomal DNA is particularly complex with respect to these
      genomic interactions. The composition of nrDNA tandem arrays is influenced by
      intra- and interlocus concerted evolution and their expression is characterized
      by patterns such as nucleolar dominance. To understand these complex interactions
      it is important to study them in diverse natural polyploid systems. In this study
      we use direct sequencing to isolate and characterize nrDNA internal transcribed
      spacer (ITS) homeologues from multiple accessions of six different races in the
      Glycine tomentella allopolyploid complex. The results indicate that in most
      allopolyploid accessions both homeologous nrDNA repeats are present, but that
      there are significant biases in copy number toward one homeologue, possibly
      resulting from interlocus concerted evolution. The predominant homeologue often
      differs between races and between accessions within a race. A phylogenetic
      analysis of ITS sequences provides evidence for multiple origins in several of
      the polyploid races. This evidence for diverse patterns of nrDNA molecular
      evolution and multiple origins of polyploid races will provide a useful system
      for future studies of natural variation in patterns of nrDNA expression.

PMID- 15020483
TI  - Chromosome instabilities and programmed cell death in tapetal cells of maize with
      B chromosomes and effects on pollen viability.
AB  - B chromosomes (B's), knobbed chromosomes, and chromosome 6 (NOR) of maize undergo
      nondisjunction and micronucleus formation in binucleate tapetal cells. These
      chromosome instabilities are regular events in the program of tapetal cell death,
      but the B's strongly increase A chromosome instability. We studied 1B and 0B
      plants belonging to selected lines for high or low B transmission rate and their
      F1 hybrids. These lines are characterized by meiotic conservation or loss of B
      chromosomes, respectively. The female B transmission (fBtl) allele(s) for low B
      transmission is dominant, inducing micronucleus formation and B nondisjunction.
      We hypothesize that the fBtl allele(s) induces knob instability. This instability
      would be sufficient to produce B loss in both meiocytes and binucleate tapetal
      cells. B instability could, in turn, produce instabilities in all chromosomes of
      maize complement. To establish whether the chromosomal instabilities are related
      to the tapetal programmed cell death (PCD) process, we applied the TUNEL
      technique. PCD, estimated as the frequency of binucleate tapetal cells with TUNEL
      label, was significantly correlated with the formation of micronuclei and the
      frequency of pollen abortion. It can be concluded that the observed chromosome
      instabilities are important to the PCD process and to the development of
      microspores to form viable pollen grains.

PMID- 15020485
TI  - Derivation of a Bayes factor to distinguish between linked or pleiotropic
      quantitative trait loci.
AB  - A simple procedure to calculate the Bayes factor between linked and pleiotropic
      QTL models is presented. The Bayes factor is calculated from the marginal prior
      and posterior densities of the locations of the QTL under a linkage and a
      pleiotropy model. The procedure is computed with a Gibbs sampler, and it can be
      easily applied to any model including the location of the QTL as a variable. The
      procedure was compared with a multivariate least-squares method. The proposed
      procedure showed better results in terms of power of detection of linkage when
      low information is available. As information increases, the performance of both
      procedures becomes similar. An example using data provided by an Iberian by
      Landrace pig intercross is presented. The results showed that three different QTL
      segregate in SSC6: a pleiotropic QTL affects myristic, palmitic, and
      eicosadienoic fatty acids; another pleiotropic QTL affects palmitoleic, stearic,
      and vaccenic fatty acids; and a third QTL affects the percentage of linoleic
      acid. In the example, the Bayes factor approach was more powerful than the
      multivariate least-squares approach.

PMID- 15020484
TI  - Patterns of gene duplication and functional evolution during the diversification
      of the AGAMOUS subfamily of MADS box genes in angiosperms.
AB  - Members of the AGAMOUS (AG) subfamily of MIKC-type MADS-box genes appear to
      control the development of reproductive organs in both gymnosperms and
      angiosperms. To understand the evolution of this subfamily in the flowering
      plants, we have identified 26 new AG-like genes from 15 diverse angiosperm
      species. Phylogenetic analyses of these genes within a large data set of AG-like
      sequences show that ancient gene duplications were critical in shaping the
      evolution of the subfamily. Before the radiation of extant angiosperms, one event
      produced the ovule-specific D lineage and the well-characterized C lineage, whose
      members typically promote stamen and carpel identity as well as floral meristem
      determinacy. Subsequent duplications in the C lineage resulted in independent
      instances of paralog subfunctionalization and maintained functional redundancy.
      Most notably, the functional homologs AG from Arabidopsis and PLENA (PLE) from
      Antirrhinum are shown to be representatives of separate paralogous lineages
      rather than simple genetic orthologs. The multiple subfunctionalization events
      that have occurred in this subfamily highlight the potential for gene duplication
      to lead to dissociation among genetic modules, thereby allowing an increase in
      morphological diversity.

PMID- 15020486
TI  - Identification of genetic networks.
AB  - In this report, we propose the use of structural equations as a tool for
      identifying and modeling genetic networks and genetic algorithms for searching
      the most likely genetic networks that best fit the data. After genetic networks
      are identified, it is fundamental to identify those networks influencing cell
      phenotypes. To accomplish this task we extend the concept of differential
      expression of the genes, widely used in gene expression data analysis, to genetic
      networks. We propose a definition for the differential expression of a genetic
      network and use the generalized T2 statistic to measure the ability of genetic
      networks to distinguish different phenotypes. However, describing the
      differential expression of genetic networks is not enough for understanding
      biological systems because differences in the expression of genetic networks do
      not directly reflect regulatory strength between gene activities. Therefore, in
      this report we also introduce the concept of differentially regulated genetic
      networks, which has the potential to assess changes of gene regulation in
      response to perturbation in the environment and may provide new insights into the
      mechanism of diseases and biological processes. We propose five novel statistics
      to measure the differences in regulation of genetic networks. To illustrate the
      concepts and methods for reconstruction of genetic networks and identification of
      association of genetic networks with function, we applied the proposed models and
      algorithms to three data sets.

PMID- 15020487
TI  - Polygenic variation maintained by balancing selection: pleiotropy, sex-dependent
      allelic effects and G x E interactions.
AB  - We investigate three alternative selection-based scenarios proposed to maintain
      polygenic variation: pleiotropic balancing selection, G x E interactions (with
      spatial or temporal variation in allelic effects), and sex-dependent allelic
      effects. Each analysis assumes an additive polygenic trait with n diallelic loci
      under stabilizing selection. We allow loci to have different effects and consider
      equilibria at which the population mean departs from the stabilizing-selection
      optimum. Under weak selection, each model produces essentially identical,
      approximate allele-frequency dynamics. Variation is maintained under pleiotropic
      balancing selection only at loci for which the strength of balancing selection
      exceeds the effective strength of stabilizing selection. In addition, for all
      models, polymorphism requires that the population mean be close enough to the
      optimum that directional selection does not overwhelm balancing selection. This
      balance allows many simultaneously stable equilibria, and we explore their
      properties numerically. Both spatial and temporal G x E can maintain variation at
      loci for which the coefficient of variation (across environments) of the effect
      of a substitution exceeds a critical value greater than one. The critical value
      depends on the correlation between substitution effects at different loci. For
      large positive correlations (e.g., rho(ij)2>3/4), even extreme fluctuations in
      allelic effects cannot maintain variation. Surprisingly, this constraint on
      correlations implies that sex-dependent allelic effects cannot maintain polygenic
      variation. We present numerical results that support our analytical
      approximations and discuss our results in connection to relevant data and
      alternative variance-maintaining mechanisms.

PMID- 15020488
TI  - Influence of spatial and temporal heterogeneities on the estimation of
      demographic parameters in a continuous population using individual microsatellite
      data.
AB  - Drift and migration disequilibrium are very common in animal and plant
      populations. Yet their impact on methods of estimation of demographic parameters
      was rarely evaluated especially in complex realistic population models. The
      effect of such disequilibria on the estimation of demographic parameters depends
      on the population model, the statistics, and the genetic markers used. Here we
      considered the estimation of the product Dsigma2 from individual microsatellite
      data, where D is the density of adults and sigma2 the average squared axial
      parent-offspring distance in a continuous population evolving under isolation by
      distance. A coalescence-based simulation algorithm was used to study the effect
      on Dsigma2 estimation of temporal and spatial fluctuations of demographic
      parameters. Estimation of present-time Dsigma2 values was found to be robust to
      temporal changes in dispersal, to density reduction, and to spatial expansions
      with constant density, even for relatively recent changes (i.e., a few tens of
      generations ago). By contrast, density increase in the recent past gave Dsigma2
      estimations biased largely toward past demographic parameters values. The method
      was also robust to spatial heterogeneity in density and estimated local
      demographic parameters when the density is homogenous around the sampling area
      (e.g., on a surface that equals four times the sampling area). Hence, in the
      limit of the situations studied in this article, and with the exception of the
      case of density increase, temporal and spatial fluctuations of demographic
      parameters appear to have a limited influence on the estimation of local and
      present-time demographic parameters with the method studied.

PMID- 15020489
TI  - Modes of reproduction and the accumulation of deleterious mutations with
      multiplicative fitness effects.
AB  - Mutational load depends not only on the number and nature of mutations but also
      on the reproductive mode. Traditionally, only a few specific reproductive modes
      are considered in the search of explanations for the maintenance of sex. There
      are, however, many alternatives. Including these may give radically different
      conclusions. The theory on deterministic deleterious mutations states that in
      large populations segregation and recombination may lead to a lower load of
      deleterious mutations, provided that there are synergistic interactions.
      Empirical research suggests that effects of deleterious mutations are often
      multiplicative. Such situations have largely been ignored in the literature,
      since recombination and segregation have no effect on mutation load in the
      absence of epistasis. However, this is true only when clonal reproduction and
      sexual reproduction with equal male and female ploidy are considered. We consider
      several alternative reproductive modes that are all known to occur in insects:
      arrhenotoky, paternal genome elimination, apomictic thelytoky, and automictic
      thelytoky with different cytological mechanisms to restore diploidy. We give a
      method that is based on probability-generating functions, which provides
      analytical and numerical results on the distributions of deleterious mutations.
      Using this, we show that segregation and recombination do make a difference.
      Furthermore, we prove that a modified form of Haldane's principle holds more
      generally for thelytokous reproduction. We discuss the implications of our
      results for evolutionary transitions between different reproductive modes in
      insects. Since the strength of Muller's ratchet is reduced considerably for
      several forms of automictic thelytoky, many of our results are expected to be
      also valid for initially small populations.

PMID- 15020490
TI  - Selection, subdivision and extinction and recolonization.
AB  - In a subdivided population, the interaction between natural selection and
      stochastic change in allele frequency is affected by the occurrence of local
      extinction and subsequent recolonization. The relative importance of selection
      can be diminished by this additional source of stochastic change in allele
      frequency. Results are presented for subdivided populations with extinction and
      recolonization where there is more than one founding allele after extinction,
      where these may tend to come from the same source deme, where the number of
      founding alleles is variable or the founders make unequal contributions, and
      where there is dominance for fitness or local frequency dependence. The behavior
      of a selected allele in a subdivided population is in all these situations
      approximately the same as that of an allele with different selection parameters
      in an unstructured population with a different size. The magnitude of the
      quantity N(e)s(e), which determines fixation probability in the case of genic
      selection, is always decreased by extinction and recolonization, so that
      deleterious alleles are more likely to fix and advantageous alleles less likely
      to do so. The importance of dominance or frequency dependence is also altered by
      extinction and recolonization. Computer simulations confirm that the theoretical
      predictions of both fixation probabilities and mean times to fixation are good
      approximations.

PMID- 15020491
TI  - The effect of selection on genealogies.
AB  - The coalescent process can describe the effects of selection at linked loci only
      if selection is so strong that genotype frequencies evolve deterministically.
      Here, we develop methods proposed by Kaplan, Darden, and Hudson to find the
      effects of weak selection. We show that the overall effect is given by an
      extension to Price's equation: the change in properties such as moments of
      coalescence times is equal to the covariance between those properties and the
      fitness of the sample of genes. The distribution of coalescence times differs
      substantially between allelic classes, even in the absence of selection. However,
      the average coalescence time between randomly chosen genes is insensitive to the
      current allele frequency and is affected significantly by purifying selection
      only if deleterious mutations are common and selection is strong (i.e., the
      product of population size and selection coefficient, Ns>3). Balancing selection
      increases mean coalescence times, but the effect becomes large only when mutation
      rates between allelic classes are low and when selection is extremely strong. Our
      analysis supports previous simulations that show that selection has surprisingly
      little effect on genealogies. Moreover, small fluctuations in allele frequency
      due to random drift can greatly reduce any such effects. This will make it
      difficult to detect the action of selection from neutral variation alone.

PMID- 15020492
TI  - Is alcohol anti-inflammatory in the context of coronary heart disease?
AB  - Although the cardioprotective effect of alcohol has been primarily explained by
      its effect on blood lipids and platelets, could an anti-inflammatory mechanism be
      involved?

PMID- 15020493
TI  - Isolated commissural detachment of the aortic valve after minor trauma.

PMID- 15020494
TI  - Ischaemic preconditioning and myocardial adaptation to serial intracoronary
      balloon inflation: cut from the same cloth?
AB  - Elective percutaneous coronary intervention fulfils many of the criteria needed
      of a clinical model of ischaemic preconditioning. But is this really a reflection
      of the laboratory phenomenon of ischaemic preconditioning?

PMID- 15020495
TI  - Coronary thrombus in unstable angina: a moving target.

PMID- 15020496
TI  - Rheumatic heart disease in rural Pakistan.
AB  - In the developing countries of the world, rheumatic fever and rheumatic heart
      disease remain significant medical and public health problems

PMID- 15020497
TI  - Patency of the left subclavian artery following implantation of stent graft to
      rectify a stenosis, as demonstrated by multislice computed tomography.

PMID- 15020498
TI  - Acute coronary syndromes: should women receive less antithrombotic medication
      than men?
AB  - A recent meta-analysis of all randomised trials assessing the efficacy and safety
      of glycoprotein IIb/IIIa agents with acute coronary syndromes showed that there
      was a significant interaction with sex. Explaining this difference requires an
      analysis of whether it has any pathophysiological basis, whether antithrombotic
      medications are indeed less efficacious in women in different clinical
      situations, and whether there are any specific reasons that may have led to the
      provocative results of the meta-analysis.

PMID- 15020499
TI  - Sinus of Valsalva to right atrial fistula.

PMID- 15020500
TI  - Double right aortic sinus inlet of the right coronary artery.

PMID- 15020502
TI  - Diagnosis of aortic intramural haematoma.

PMID- 15020504
TI  - Aortic intramural haematoma: natural history and predictive factors for
      complications.

PMID- 15020506
TI  - Aortic intramural haematoma: current therapeutic strategy.

PMID- 15020508
TI  - Aortic intramural haematoma: remarks and conclusions.

PMID- 15020509
TI  - Hypertrophic cardiomyopathy with persistent ST segment elevation simulating acute
      myocardial infarction.

PMID- 15020510
TI  - Temperature at birth, coronary heart disease, and insulin resistance: cross
      sectional analyses of the British women's heart and health study.
AB  - OBJECTIVE: To assess the association of mean outdoor temperature around the time
      of birth with insulin resistance and coronary heart disease in later life.
      DESIGN: Cross sectional study. SETTING: 23 British towns. PARTICIPANTS: 4286
      women aged 60-79 years. MAIN OUTCOME MEASURES: Coronary heart disease and insulin
      resistance. RESULTS: Coronary heart disease prevalence was greatest among women
      born during the coldest months: the age adjusted odds ratio comparing women born
      in the coldest quarter of monthly outdoor birth temperatures with the remaining
      three quarters was 1.24 (95% confidence interval (CI) 1.03 to 1.50). Cold outdoor
      temperature at birth was also associated with increased insulin resistance,
      increased triglyceride concentrations, and poorer lung function. The link between
      cold outdoor temperature at birth and coronary heart disease was only partly
      explained by known coronary disease risk factors: fully adjusted (for all
      measured potential explanatory and confounding factors) odds ratio 1.19 (95% CI
      0.95 to 1.48). The association between cold temperature at birth and coronary
      heart disease was most pronounced among those whose fathers were either
      unemployed or in manual social classes when the participants were children, and
      was non-existent in those from non-manual social classes in childhood.
      CONCLUSIONS: Cold outdoor temperature at birth is associated with increased
      coronary heart disease, insulin resistance, dyslipidaemia, and poor lung
      function. Further research is needed to determine whether this finding reflects
      events occurring late in the third trimester of intrauterine growth or early in
      the postnatal period.

PMID- 15020511
TI  - Caseous calcification of the mitral annulus: an underappreciated variant.

PMID- 15020512
TI  - Reduction of daily life ischaemia by aspirin in patients with angina: underlying
      link between thromboxane A2 and macrophage colony stimulating factor.
AB  - OBJECTIVES: To evaluate whether aspirin reduces the incidence and frequency of
      daily life myocardial ischaemia in a cohort of patients with chronic stable
      coronary artery disease. SETTING: Tertiary referral centre. METHODS: 60 patients
      with chronic stable coronary artery disease underwent 48 hour Holter monitoring
      to assess the incidence and frequency of daily life myocardial ischaemia. Those
      with myocardial ischaemia (40/60) entered a double blind, crossover trial of
      aspirin (300 mg/day for three weeks) versus placebo. After each treatment arm, 48
      hour Holter monitoring was repeated and urinary thromboxane (Tx) B2, 11-dehydro
      TxB2, plasma prothrombin fragment F1+2, macrophage colony stimulating factor
      (MCSF), and interleukin (IL)-6 were measured. RESULTS: Aspirin reduced the total
      number and duration of ischaemic episodes from 339 to 251 and from 1765 to 1365
      minutes, respectively (p < 0.01 for both). TxB2 was also reduced from 0.2 to 0.1
      ng/mg creatinine, 11-dehydro-TxB2 from 3.3 to 1.3 ng/mg creatinine, F1+2 from 1.5
      to 1.2 nmol/l, MCSF from 991 to 843 pg/ml, and IL-6 from 3.5 to 2.9 pg/ml (p <
      0.05 for all). 11-dehydro-TxB2 excretion with and without aspirin was related to
      MCSF concentrations (p < 0.01), and the percentage reduction of MCSF by aspirin
      was related to the reduction of 11-dehydro-TxB2 (p < 0.05) and the reduction of
      the ischaemic burden compared with placebo (p < 0.05). CONCLUSIONS: In patients
      with daily life ischaemia, aspirin reduces the incidence and frequency of
      ischaemic episodes as well as the systemic concentrations of
      haemostatic/inflammatory markers. Aspirin may prevent transient coronary flow
      reductions through platelet, thrombin, and cytokine inhibition.

PMID- 15020513
TI  - Status of rheumatic heart disease in rural Pakistan.
AB  - OBJECTIVES: To determine the community based prevalence of rheumatic heart
      disease (RHD) in the rural population of the district of Rahim Yaar Khan in
      Pakistan. SUBJECTS AND METHODS: A representative sample of the rural population
      of Rahim Yaar Khan district was selected. RHD was screened for by physical
      examination and the diagnosis was confirmed with echocardiographic Doppler
      studies. Sociodemographic data on each screened person were collected. RESULTS:
      54 cases of RHD were found among the 9430 people screened (prevalence of 5.7 in
      1000, 95% confidence interval 4.2 to 7.2). Females were significantly more likely
      to be affected. There was no significant relation with other factors studied
      (education, crowding, and socioeconomic status). Less than 20% of those found to
      have RHD were aware of their diagnosis before participation in this study and
      only three affected people (8%) were taking rheumatic prophylaxis. CONCLUSIONS:
      There is a high prevalence of RHD among the rural population of Pakistan. The
      prevalence has not declined over the past three decades. Nearly all people with
      RHD, including most of those who know their diagnosis, do not receive the benefit
      of potentially life saving secondary prevention measures.

PMID- 15020514
TI  - Subaortic stenosis caused by flail discrete membrane in an older patient.

PMID- 15020515
TI  - Fibrosis in left atrial tissue of patients with atrial fibrillation with and
      without underlying mitral valve disease.
AB  - OBJECTIVE: To examine the hypothesis that major extracellular matrix (ECM)
      proteins are expressed differently in the left atrial tissue of patients in sinus
      rhythm (SR), lone atrial fibrillation (AF), and AF with underlying mitral valve
      disease (MVD). DESIGN: Case-control study. PATIENTS: 118 patients with lone AF,
      MVD+AF, and SR. MAIN OUTCOME MEASURES: Collagen I, collagen III, and fibronectin
      protein expression measured by quantitative western blotting techniques and
      immunohistochemical methods. RESULTS: Protein concentrations increased in
      patients with AF (all forms) compared with those in SR (all forms): collagen I
      (1.15 (0.11) v 0.45 (0.28), respectively; p = 0.002), collagen III (0.74 (0.05) v
      0.46 (0.11); p = 0.002, and fibronectin (0.88 (0.06) v 0.62 (0.13); p = 0.08).
      Especially, collagen I was similarly enhanced in both lone AF (1.49 (0.15) and
      MVD+AF (1.53 (0.16) compared with SR (0.56 (0.28); both p = 0.01). Collagen III
      was not significantly increased in lone AF but was significantly increased in AF
      combined with MVD (0.84 (0.07) both compared with SR (0.46 (0.11); p = 0.01). The
      concentration of fibronectin was not significantly increased in lone AF and
      MVD+AF (both compared with SR). Furthermore, there was a similar degree of
      enhanced collagen expression in paroxysmal AF and chronic AF. CONCLUSIONS: AF is
      associated with fibrosis. Forms of AF differ from each other in collagen III
      expression. However, there was no systematic difference in ECM expression between
      paroxysmal AF and chronic AF. Enhanced concentrations of ECM proteins may have a
      role in structural remodelling and the pathogenesis of AF as a result of
      separation of the cells by fibrotic depositions.

PMID- 15020516
TI  - Pulsed tissue Doppler imaging detects early myocardial dysfunction in
      asymptomatic patients with severe mitral regurgitation.
AB  - OBJECTIVE: To assess whether tissue Doppler myocardial imaging (TDI) indices can
      predict postoperative left ventricular function in patients with mitral
      regurgitation (MR) after surgical correction. METHODS: 84 patients (mean (SD) age
      54.3 (10.8) years) with asymptomatic severe MR, an end systolic diameter < 45 mm,
      and an ejection fraction (EF) > 60% were subdivided in two groups: 43 patients
      with a postoperative EF reduction < 10% (group 1) and 41 patients with a
      postoperative EF reduction > or = 10% (group 2).TDI systolic indices of the
      lateral annulus were analysed preoperatively to assess myocardial systolic wave
      (Sm) velocity, myocardial precontraction time (PCTm), myocardial contraction time
      (CTm), and the PCTm:CTm ratio. RESULTS: Postoperative EF decreased significantly
      (from 67 (5)% to 60 (5.5)%, p = 0.0001). Group 2 had a higher PCTm, CTm, and
      PCTm:CTm ratio and a lower Sm velocity than group 1 (PCTm 100.4 (19) ms v 82
      (21.8) ms, p = 0.004; CTm 222 (3.1) ms v 215 (2.3) ms, p = 0.01; PCTm:CTm 0.45
      (0.08) v 0.38 (0.09), p = 0.001; Sm velocity 10.4 (1.1) cm/s v 13 (1.3) cm/s, p =
      0.0001). Multivariate regression analysis showed that the combination of PCTm:CTm
      ratio > or = 40 ms and Sm velocity < or = 10.5 cm/s was the main independent
      predictor of postoperative EF reduction > or = 10% (sensitivity 78%, specificity
      95%). CONCLUSIONS: TDI systolic indices can predict postoperative left
      ventricular function in patients with asymptomatic MR undergoing surgical
      correction.

PMID- 15020517
TI  - Acute haemodynamic benefits of biatrial atrioventricular sequential pacing:
      comparison with single atrial atrioventricular sequential pacing.
AB  - OBJECTIVE: To evaluate the acute effects on haemodynamic variables of biatrial
      pacing in comparison with high right atrial (HRA) pacing and left lateral atrial
      pacing. PATIENTS AND DESIGN: 23 patients were paced from the HRA site, the
      lateral site of the coronary sinus (CS), and both sites on two fixed
      atrioventricular delays (100 and 150 ms) during atrioventricular sequential
      pacing at 80 and 100 beats/min in random order. MAIN OUTCOME MEASURES: After five
      minute pacing, the maximum P wave duration on a 12 lead ECG, cardiac output,
      pulmonary capillary wedge pressure, and the transmitral flow pattern by
      transthoracic echocardiography were measured. RESULTS: Biatrial pacing delivered
      the shortest P wave duration (133 (25) ms, 133 (27) ms, and 96 (15) ms during
      HRA, CS, and biatrial pacing, respectively; p < 0.001), and the most improvement
      in cardiac output and pulmonary capillary wedge pressure (3.71 (0.93) l/min and
      15 (7) mm Hg, 3.79 (0.97) l/min, and 14 (6) mm Hg, and 4.09 (1.01) l/min and
      13(6) mm Hg during HRA, CS, and biatrial pacing, respectively; p < 0.01).
      Biatrial pacing most significantly decreased the intervals between the atrial
      pacing spike and the peak and end of the atrial filling wave (186 (16) ms and 250
      (22) ms, 172 (19) ms and 242 (24) ms, and 153 (15) ms and 227 (23) ms during HRA,
      CS, and biatrial pacing, respectively; p < 0.001). It also significantly
      increased the mitral flow time velocity integral and peak atrial filling wave
      velocity (7.5 (3.4) cm and 63.8 (17.6) cm/s, 7.8 (3.0) cm and 62.4 (16.6) cm/s,
      and 8.3 (3.4) cm and 67.8 (19.3) cm/s during HRA, CS, and biatrial pacing,
      respectively; p < 0.05). The improvements in haemodynamic variables were
      especially remarkable in patients who had a longer interatrial conduction delay.
      CONCLUSIONS: Biatrial pacing yielded the most significant improvements in
      haemodynamic variables. These haemodynamic benefits may play a part in reducing
      intra-atrial pressure and preventing atrial fibrillation.

PMID- 15020518
TI  - C Reactive protein, moderate alcohol consumption, and long term prognosis after
      successful coronary stenting: four year results from the GENERATION study.
AB  - OBJECTIVES: To determine the impact of moderate alcohol consumption on long term
      prognosis after successful coronary stenting, and whether it could be related to
      preprocedural plasma C reactive protein (CRP). DESIGN: Part of the prospectively
      designed GENERATION study which investigated the impact of several biochemical
      factors, including plasma CRP, on long term prognosis after coronary stenting.
      SETTING: Tertiary referral centre. PATIENTS: 483 consecutive patients with stable
      or unstable coronary artery disease who underwent successful coronary stenting
      and were followed for up to four years. Information about alcohol consumption was
      collected prospectively. INTERVENTIONS: Successful coronary stenting. MAIN
      OUTCOME MEASURES: The incidence of the composite end point of readmission to
      hospital for unstable angina, non-fatal myocardial infarction, or cardiac death,
      whichever occurred first. RESULTS: By the end of follow up the incidence of the
      composite end point was 22.8%. Patients with a baseline plasma CRP concentration
      of < 0.68 mg/dl (defined by ROC analysis) did not show any difference in the
      composite end point (p = 0.9) or its components, regardless of the amount of
      alcohol consumed during follow up. However, among patients with plasma CRP
      concentration of > or = 0.68 mg/dl, those who drank moderately had a lower
      incidence of the composite end point (p < 0.001) or its components. CONCLUSIONS:
      Moderate alcohol consumption may have a beneficial impact on the long term
      prognosis following successful coronary stenting. The extent of this effect is
      positively related to preprocedural inflammatory status. An anti-inflammatory
      action of moderate alcohol consumption cannot be excluded.

PMID- 15020519
TI  - Magnetic resonance angiography in an adult with aortic coarctation associated
      with subclavian stenosis.

PMID- 15020523
TI  - Parents' understanding of their child's congenital heart disease.
AB  - OBJECTIVES: To assess parents' understanding of their child's congenital heart
      disease in various knowledge domains and to identify significant determinants of
      parental knowledge. DESIGN: Cross sectional questionnaire survey SETTING:
      Tertiary paediatric cardiac centre. PATIENTS: 156 parents of children with
      relatively simple congenital heart defects were recruited from the outpatient
      clinic of a tertiary cardiac centre over a three month period. The questionnaire
      comprised 10 items of knowledge under three domains: nature of heart disease and
      its treatment; impact of heart disease on exercise capacity; and infective
      endocarditis and its prevention. The frequency distribution of the parents'
      knowledge in the different domains was determined. Univariate analyses and
      logistic regression were performed to identify significant determinants of
      knowledge in selected items. RESULTS: While 59% of parents correctly named their
      child's congenital heart disease, only 28.8% correctly indicated the heart
      lesion(s) diagrammatically. However, more than 80% of parents were aware of the
      indications and aims of previous surgical and transcatheter interventions. About
      half of the parents were aware of possible aetiologies and of the hereditary
      nature and symptoms attributable to underlying heart disease. Disappointingly, of
      the 56 parents whose children were taking cardiac medications, only 25 (44.6%)
      and 4 (7.1%) knew correctly the functions and important side effects of the
      medications, respectively. With regard to exercise capacity, 59% of parents
      indicated its level appropriate for the heart lesion. While 26.9% of parents had
      heard of the term "infective endocarditis", slightly more than half of the
      parents were aware of the need for antibiotics before dental procedures.
      Significant determinants of knowledge in the nature of heart disease were cardiac
      diagnosis, occupation of parents, and their educational level. Logistic
      regression failed to identify any significant determinants of parental knowledge
      in the other two domains. CONCLUSIONS: Parents of children with congenital heart
      disease have important knowledge gaps. Our findings suggest that the current
      educational programme is inadequate and needs to be refined to promote better
      parental understanding of their child's heart disease, with the ultimate aim of
      enabling parents to impart such knowledge accurately to their children.

PMID- 15020522
TI  - Association between early and three month cognitive outcome after off-pump and on
      pump coronary bypass surgery.
AB  - OBJECTIVE: To describe the association between cognitive outcome in the first
      postoperative week and that at three months after both off-pump and on-pump
      coronary bypass surgery, and to make a direct comparison of early cognitive
      outcome after off-pump versus on-pump surgery. DESIGN: Randomised trial with an
      additional prediction study within the two randomised groups. SETTING: Three
      centres for heart surgery in the Netherlands. PATIENTS: 281 patients, mean age 61
      years. INTERVENTIONS: Participants were randomly assigned to off-pump or on-pump
      coronary bypass surgery. MAIN OUTCOME MEASURES: Cognitive outcome, assessed by
      psychologists who administered neuropsychological tests one day before and four
      days and three months after surgery. A logistic regression model was used to
      study the predictive association between early cognitive outcome, together with
      eight clinical variables, and cognitive outcome after three months. RESULTS:
      Cognitive outcome in the first week after surgery was determined for 219 patients
      and was a predictor of cognitive decline after three months. This association was
      stronger in on-pump patients (odds ratio (OR) 5.24, p < 0.01) than in off-pump
      patients (OR 1.80, p = 0.23). Early decline was present in 54 patients (49%)
      after off-pump surgery and 61 patients (57%) after on-pump surgery (OR 0.73, p =
      0.25). CONCLUSIONS: In patients undergoing first time coronary bypass surgery,
      early cognitive decline predicts cognitive outcome after three months. Early
      cognitive decline is not significantly influenced by the use of cardiopulmonary
      bypass.

PMID- 15020520
TI  - Pharmacological modulation of the ATP sensitive potassium channels during
      repeated coronary occlusions: no effect on myocardial ischaemia or function.
AB  - BACKGROUND: Repeated episodes of myocardial ischaemia may lead to ischaemic
      preconditioning. This is believed to be mediated by the ATP sensitive potassium
      channels. OBJECTIVE: To examine the effect of pharmacological modulation of the
      ATP sensitive potassium channels during repeated coronary occlusions. DESIGN:
      Double blind, double dummy study. METHODS: 38 patients with a proximal stenosis
      of the left anterior descending coronary artery and no visible coronary
      collateral vessels underwent three identical 90 second balloon occlusions, each
      followed by five minutes of reperfusion. The patients were randomised to
      pinacidil 25 mg, glibenclamide 10.5 mg, or matching placebo 90 minutes before the
      start of the procedure. Myocardial ischaemia was measured by continuous
      monitoring of ECG ST segment changes. Changes in left ventricular function were
      recorded with a miniature radionuclide detector, and angina was scored on the
      Borg scale. RESULTS: In all patients the first balloon occlusion led to
      significant ST segment elevation, a clear decrease in left ventricular ejection
      fraction, and angina pectoris. This response was not attenuated at the second or
      third balloon occlusion, either in the placebo group or in the patients
      pretreated with pinacidil or glibenclamide. CONCLUSIONS: Under the given
      experimental conditions, this randomised and double blind study did not support
      the view that the human myocardium has an intrinsic protective mechanism that is
      activated by short lasting episodes of ischaemia.

PMID- 15020524
TI  - 5-flurouracil induced coronary artery vasospasm.

PMID- 15020525
TI  - Cyclo-oxygenase-2 (COX-2) expression at the site of recent myocardial infarction:
      friend or foe?
AB  - BACKGROUND: Cyclo-oxygenase-2 (COX-2) is induced in cardiomyocytes only in
      response to stress, such as ischaemia. OBJECTIVE: To assess COX-2 expression at
      the site of recent myocardial infarction. METHODS: COX-2 expression was evaluated
      by specific immunostaining in cardiomyocytes from 23 subjects who died 10-60 days
      after acute myocardial infarction. The relation between COX-2 myocardial
      expression and apoptotic rate was investigated. Cardiomyocyte apoptotic rate was
      defined as the number of cells co-expressing in situ end labelling of DNA
      fragmentation (TUNEL) and immunostaining for activated caspase-3. RESULTS: COX-2
      expression was found in cardiomyocytes at the site of infarction in nine of 23
      cases (39%). It was associated with fivefold higher apoptotic rates (median 17.9%
      (interquartile range 11.0-25.4%) v 3.7% (0.6-12.8%); p = 0.016), and apoptotic
      rate increased progressively from mild to intense COX-2 staining (p for trend
      0.009). COX-2 expression co-localised with TUNEL nuclear staining in myocytes,
      and there was a high concordance between COX-2 and hypoxia induced factor 1-alpha
      staining (78%, p = 0.021) and between COX-2 and bax (83%, p = 0.014). Subjects
      showing myocardial COX-2 expression were more likely to have enlarged hearts (p =
      0.050), and intense COX-2 staining was strictly associated with symptomatic heart
      failure (p = 0.035). CONCLUSIONS: COX-2 is expressed in cardiomyocytes in nearly
      40% of cases at the site of recent acute myocardial infarction, even late after
      the index event. Its expression was associated with extremely high apoptotic
      rates. These findings suggest a potential cause-effect link between COX-2
      expression and enhanced myocardial apoptosis in ischaemic cardiomyopathy.

PMID- 15020526
TI  - Positive correlation between coronary arterial remodelling and prodromal angina
      in acute myocardial infarction.

PMID- 15020527
TI  - Testosterone treatment for men with chronic heart failure.

PMID- 15020529
TI  - Effect of statin treatment on coronary collateral flow in patients with coronary
      artery disease.

PMID- 15020530
TI  - Pregnancy in heart disease.

PMID- 15020531
TI  - Angina pectoris and normal coronary arteries: cardiac syndrome X.

PMID- 15020532
TI  - Inflammatory mediators in chronic heart failure: an overview.

PMID- 15020534
TI  - Right ventricular aneurysm following right ventricular infarction.

PMID- 15020535
TI  - Acute myocardial infarction as a cause of death in palliated hypoplastic left
      heart syndrome.
AB  - A 20 month old child with hypoplastic left heart syndrome died suddenly from a
      massive myocardial infarction 15 months after a hemi-Fontan operation. This was
      confirmed at postmortem examination and histological examinations. The sites of
      surgical reconstruction were all in good condition, there were no gross
      anatomical coronary abnormalities, and the coronary ostia were unobstructed. On
      microscopy the internal coronary arteries had notable intimal and medial
      thickening with narrowing of the lumen, although no thrombotic occlusion was
      seen. To the authors' knowledge, this is the first published report of
      arteriosclerosis of the coronary arteries in hypoplastic left heart syndrome. It
      raises the question as to whether there may be a primary histological abnormality
      in some children with this condition or whether some mechanism of accelerated
      arteriosclerosis is at work.

PMID- 15020537
TI  - Malignant vasovagal syndrome in two patients with Wolff-Parkinson-White syndrome.
AB  - The presence of Wolff-Parkinson-White (WPW) syndrome in patients presenting with
      syncope suggests that tachyarrhythmia may be the cause. However, the symptoms
      require careful evaluation. Two young patients presented with syncope and were
      found to have WPW syndrome on their ECG. In both patients symptoms were
      suggestive of vasovagal syncope. During tilt testing, both the patients developed
      their typical symptoms with a fall in blood pressure and heart rate confirming
      the diagnosis of malignant vasovagal syndrome.

PMID- 15020536
TI  - Paraprosthetic leak unmasked by thrombolysis for thrombosed mitral valve.
AB  - Prosthetic valve thrombosis (PVT) is classically a cardiothoracic surgical
      emergency. Case series, however, report thrombolysis as first line management for
      PVT. A case of mitral PVT treated successfully with thrombolysis is described.
      Immediately after thrombolysis a trivial paraprosthetic leak noted on
      pretreatment transoesophageal echocardiography had increased significantly in
      severity. The paraprosthetic leak subsequently required repeat mitral valve
      replacement. It is speculated that the thrombolytic treatment interfered with the
      usual healing process by disrupting the fibrin deposited at the valve ring
      margin. This suggests that fibrin is important in the formation of the annular
      seal of the prosthetic valve and that patients receiving thrombolysis should be
      monitored for this complication.

PMID- 15020538
TI  - Situs inversus and acute coronary syndrome.
AB  - Dextrocardia is a rare clinical phenomenon with a reported incidence of one in 10
      000. Consequently, acute coronary syndromes in such patients are rare. When chest
      pain occurs in this setting, it is important to be aware of the unique problems
      that may occur if coronary intervention is contemplated. Previous case reports
      have shown successful attempts at reperfusing one coronary artery percutaneously.
      In this case, coronary stents were successfully deployed in two vessels of a man
      with situs inversus, which has not been reported before. Additionally, the
      angiographic results that followed from successful intervention did not produce
      the expected haemodynamic and electrocardiographic changes.

PMID- 15020539
TI  - Left main coronary artery and right pulmonary vein compression by a large
      pulmonary artery aneurysm.
AB  - Pulmonary artery aneurysms are uncommon and may be associated with significant
      morbidity and mortality. The unique combination of left main coronary artery and
      upper right pulmonary vein compression by a large pulmonary artery aneurysm is
      reported. Furthermore, the aetiology, clinical manifestations, complications,
      diagnostic approach, and possible therapeutic interventions are briefly
      discussed.

PMID- 15020540
TI  - Haemopericardium causing cardiac tamponade: a late complication of pectus
      excavatum repair.
AB  - A 24 year old man presented to the emergency department with clinical signs of
      cardiac tamponade requiring emergency surgery. The cause was a sternal wire from
      a pectus excavatum repair two years previously that had fractured and migrated
      through the pericardium causing an epicardial injury and a haemopericardium.

PMID- 15020541
TI  - Does theory inform practice in health promotion in Australia?
AB  - In recent years, there have been numerous papers discussing the importance of
      improving the link between health promotion researchers and practitioners.
      Several reviews have been undertaken to determine the extent to which health
      promotion research is disseminated to, and utilized by, practitioners in the
      development and implementation of health promotion programs. These studies have
      generally been limited to reviews of literature rather than directly gathering
      data from practitioners. This paper reports on a survey of Australian health
      promotion practitioners undertaken to investigate the extent to which they are
      aware of, understand and utilize the major health promotion theories and models
      derived from research in the areas of psychology and communication. We found that
      none of the theories or models included in this study-the 'standard' theories and
      models taught in health promotion courses, and included in the leading textbooks
      were used by more than 50% of practitioners in their work. The only models being
      used by more than one-third of the practitioners were PRECEDE-PROCEED and the
      Transtheoretical (Stages of Change) Model. The paper concludes with possible
      explanations for the low level of utilization of theories and models, and
      suggestions for increasing their usage based on information sources accessed by
      these practitioners.

PMID- 15020542
TI  - What determines future smoking intentions of 12- to 13-year-old UK African
      Caribbean, Indian, Pakistani and white young people?
AB  - It is important to know when designing adolescent smoking interventions how
      ethnicity and gender influence intention. This paper reports an investigation
      into how ethnicity influences the smoking intentions of disadvantaged UK African
      Caribbean (n = 275), Indian (n = 397), Pakistani (n = 687) and white (n = 1792)
      12-13 year olds. The Attitudes-Social influences-Efficacy (ASE) model underpinned
      the study. It states that ASE determinants (advantages, disadvantages, social
      acceptance, social norms, modelling, perceived pressure and self-efficacy)
      directly influence behavioural intention. External factors (country, ethnicity
      and gender) indirectly influence intention by influencing ASE determinants. ASE
      determinant scores and future smoking intentions were measured. Linear regression
      analyses showed that smoking intention varied by ethnicity and gender.
      Differences in ASE scores largely explained these variations. Ethnicity and
      gender did not modify the predictive effects of equivalent ASE determinant scores
      on intention. Being a white boy had a small independent direct influence on
      intention, which was ascribed to affective beliefs underpinning fitness and
      sporting prowess. Otherwise, ethnicity had no independent direct effects on
      intention. Culturally appropriate interventions that aim to change cognitions
      underpinning ASE determinants and, thus, ASE scores would, consequently, be
      expected to be equally effective amongst disadvantaged UK African-Caribbean,
      Indian, Pakistani and white adolescents.

PMID- 15020543
TI  - Women's perceptions of support from partners, family members and close friends
      for smoking cessation during pregnancy--combining quantitative and qualitative
      findings.
AB  - This article reports on data collected as part of a four-phase study initiated to
      strengthen practice in the field of smoking cessation during pregnancy. It
      focuses on the perceived support pregnant smokers would receive for quitting
      smoking and how this support could be effectively used by incorporating the
      education of partners/family in smoking cessation intervention strategies. Both
      quantitative and qualitative methods were employed, and data were collected from
      pregnant smokers through semistructured interviews and self-completed
      questionnaires. From the questionnaire data, the women reported that they would
      receive considerable support from their partners if they decided to stop smoking.
      The interviews, however, revealed that this support was 'potential' rather than
      'real' and that the partners mostly made 'token gestures' such as smoking
      outside. None of the interviewed respondents reported receiving help in educating
      their partner/family about the risks of active and passive smoking, thus reducing
      the potential positive role they could play in smoking cessation. Whilst health
      professionals are aware of the important role the partner/family may play in
      successful smoking cessation interventions, these significant others are
      generally not involved. This study highlights the need for consideration to be
      given to providing opportunities for couples to be fully involved in smoking
      cessation interventions outside the antenatal environment.

PMID- 15020544
TI  - Butt in, butt out: pupils' views on the extent to which staff could and should
      enforce smoking restrictions.
AB  - Schools which enforce a no-smoking policy may experience lower rates of pupil
      smoking. Little is known, however, about how young people view such restrictions
      and it has been argued that smoking bans might actually encourage adolescent
      smoking. This paper presents pupils' views on the extent to which staff could,
      and should, enforce smoking restrictions. Twenty-five single-sex discussion
      groups were held with 13-year-old pupils who had been purposively selected from
      two Scottish secondary schools. Both schools served relatively deprived
      communities and ostensibly had no-smoking policies, but varied in their pupil
      smoking rates. The pupils' accounts suggested that staff enforcement could
      interrupt pupil smoking and discourage smoking on school premises, but did not
      affect whether or not they actually smoked. Pupils viewed staff efforts as
      ineffective and felt staff did not always have the authority or status needed to
      enforce a ban. Differences were found between the schools, but these did not
      explain the variation in their smoking profiles.

PMID- 15020545
TI  - Effects of in-school and tailored out-of-school smoking prevention among Dutch
      vocational school students.
AB  - This paper evaluates a smoking prevention intervention aimed at vocational school
      students, consisting of an existing Dutch in-school program (three lessons each
      lasting 50 min) and a computer-based tailored out-of-school program (three
      tailored letters with smoking prevention messages mailed to students' homes).
      Nineteen schools that already participated in the in-school program were randomly
      assigned to the in-school or to the combined in-school and out-of-school
      condition. The remaining 17 schools were randomly assigned to the out-of-school
      condition or to the control group. Effect outcomes were assessed at 6, 12 and 18
      months after a pre-test, and were based on initiation among never-smokers and
      continuation among ever-smokers. Twelve months after the pre-test (post-test 2),
      the in-school intervention was successful in preventing vocational school
      students from continuing to smoke, compared with students in the control
      condition [odds ratio (OR) = 0.49; 95% confidence interval (CI) = 0.29-0.84].
      Eighteen months after the pre-test (post-test 3), the tailored out-of-school
      intervention was successful in preventing smoking initiation, compared with
      students in the control condition (OR = 0.42; 95% CI = 0.18-0.96). The effect of
      the combined approach was not larger than the sum of the effects of the in-school
      and the out-of-school effects.

PMID- 15020546
TI  - The misperceived social norm of drunkenness among early adolescents in Finland.
AB  - Adolescents tend to overestimate peer drinking; the resulting misperception of
      the social norm predicts the child's own future drinking. This study examined the
      misperception's relatedness to a person's drinking pattern in order to facilitate
      the segmentation of the audience for health education interventions. Adolescent
      Health and Lifestyle Survey (Finland) data on 14 year olds' drinking patterns and
      perceptions of peer drinking were gathered using self-administered mailed
      questionnaires in 1989 (N = 3105, response rate 77%), 1995 (N = 8382, 79%) and
      2001 (N = 7292, 70%). The perceptions of peer drinking were significantly related
      to respondents' drinking patterns. Non-drinkers and those drinking recurrently
      until drunkenness held reasonably correct views of their peers' drinking.
      However, the segment between these two extremes comprising around half of the
      cohort incorrectly thought that their peers drank more; they misperceived the
      normative drinking pattern to be drunkenness. From health education perspective,
      three different target audiences can be identified: non-drinkers, moderate
      drinkers and heavy drinkers. The intermediate group, drinkers not normally
      getting drunk, holds the view most influenced by the social norm misperception
      and are likely to feel pressured to increase their drinking. The social norms
      marketing approach to health education should find this group the most viable
      target.

PMID- 15020547
TI  - Preventing alcohol-related harm in college students: Alcohol-related Harm
      Prevention program effects on hypothesized mediating variables.
AB  - The Alcohol-related Harm Prevention (AHP) program is a normative education and
      skill-acquisition program designed to reduce serious, long-term alcohol-related
      harm in college students. Without admonishing students not to drink, which is
      likely to fail in many student populations, the AHP program attempts to give
      students the necessary perceptions, motivation and skills to intervene within
      their peer group, and to make proactive harm-avoidance plans with friends prior
      to social occasions that involve using alcohol. The AHP program is a two-session,
      in-class intervention that corrects misperceived norms regarding levels of
      alcohol use, caring about friends, acceptability of risky behaviors and
      willingness to intervene. The program also makes use of interactive discussions
      with students and a graded, peer interview assignment to identify and promote
      harm-prevention strategies. The AHP program was implemented during fall 1999 at a
      large northeastern university. The program was received very well by students and
      showed significant effects on the proximal outcomes hypothesized to mediate more
      distal health-relevant outcomes.

PMID- 15020548
TI  - Health rights in secondary schools: student and staff perspectives.
AB  - This paper examines the perspectives of secondary school students and staff about
      the extent to which young people's health rights are catered for at school. The
      United Nations Convention on the Rights of the Child and the concept of Health
      Promoting Schools encourage the provision of healthy school environments. A
      postal survey of secondary schools in New Zealand elicited responses from 821
      Year 11 (15-16 year olds) students and 438 staff in 107 schools. Most students
      and staff reported that sources of health advice were available at their schools,
      but only a minority of students saw these sources as accessible or trustworthy.
      In every area of health promotion, students saw information and advice as less
      accessible than staff did. Most staff and students identified mental health
      problems such as depression as a source of concern in schools, but only a quarter
      of students (compared to half of staff) thought that this topic was covered
      during classtime. Students in lower-income schools reported the school
      environment as slightly less healthy than did students in high-income schools.
      The paper concludes that schools and policy makers should seek the voices and
      opinions of young people in order to improve effectiveness in catering for health
      rights.

PMID- 15020549
TI  - Creating SunSmart schools.
AB  - Kidskin was a sun-protection intervention study involving 1776 children attending
      33 primary schools in Perth, Western Australia. There were three study groups: a
      control group, a moderate intervention group and a high intervention group. In
      addition to receiving a specially designed curricular intervention (1995-1998),
      the moderate and high intervention groups received an environmental intervention
      aimed at creating SunSmart schools (1996-1998). The environmental intervention
      focused on encouraging implementation of 'No hat, no play' policies and reducing
      sun exposure at lunchtime. In 1995 and 1998, observational methods were used to
      measure children's lunchtime sun exposure (i.e. polysulfone film badges) and hat
      wearing (i.e. video-taping of children). The proportion of children wearing broad
      brimmed hats or legionnaire caps increased in seven of the eight high
      intervention schools between 1995 and 1998. In three schools, however, the impact
      was very positive with almost all children wearing these hats in 1998. There was
      no improvement in wearing these types of hats in either the moderate intervention
      group or the control group. In terms of sun exposure, there were only small non
      significant differences among the three groups in terms of lunchtime sun
      exposure. The Kidskin program had a positive effect on hat wearing in the
      playground, but did not change children's use of shade at lunchtime. In this
      study, disseminating policy guidelines to schools using a mail-only strategy was
      ineffective, even when combined with an awards program. More information on
      'champions' who bring about change in schools is required.

PMID- 15020553
TI  - New editor for a quality journal.

PMID- 15020550
TI  - Comparison of knowledge on diarrheal disease management between two types of
      community-based distributors in Oyo State, Nigeria.
AB  - Community-based distributors (CBDs) have been trained and utilized to promote a
      variety of health commodities. In addition, a variety of different types of
      community residents have been trained ranging from traditional birth attendants
      (TBAs) to patent medicine vendors. A training programme for CBD agents in the
      Akinyele Local Government Area of Oyo State, Nigeria, provided the opportunity to
      compare the knowledge of two different types of CBD agents, TBAs and volunteer
      village health workers (VHWs). Although VHWs were younger and better educated
      than the TBAs, the two groups had similar levels of knowledge about diarrhea
      recognition, cause and prevention. It was common for the respondents to confuse
      diarrhea and dehydration in their answers about signs (recognition) and
      prevention, showing that at least they had some perception that the two
      conditions were connected. Overall knowledge results showed some gaps that may
      likely be a natural result of knowledge decay. The major lesson learned is that
      the type of CBD agent may not be as important as the fact that they receive
      follow-up after they have been trained.

PMID- 15020554
TI  - Meeting the patient partnership agenda: the challenge for health care workers.

PMID- 15020555
TI  - Should health plans be accountable for clinical performance measures?

PMID- 15020556
TI  - Rating the strength of scientific evidence: relevance for quality improvement
      programs.
AB  - OBJECTIVE: To summarize an extensive review of systems for grading the quality of
      research articles and rating the strength of bodies of evidence, and to highlight
      for health professionals and decision-makers concerned with quality measurement
      and improvement the available "best practices" tools by which these steps can be
      accomplished. DESIGN: Drawing on an extensive review of checklists,
      questionnaires, and other tools in the field of evidence-based practice, this
      paper discusses clinical, management, and policy rationales for rating strength
      of evidence in a quality improvement context, and documents best practices
      methods for these tasks. RESULTS: After review of 121 systems for grading the
      quality of articles, 19 systems, mostly STUDY DESIGN: specific, met a priori
      scientific standards for grading systematic reviews, randomized controlled
      trials, observational studies, and diagnostic tests; eight systems (of 40
      reviewed) met similar standards for rating the overall strength of evidence. All
      can be used as is or adapted for particular types of evidence reports or
      systematic reviews. CONCLUSIONS: Formally grading study quality and rating
      overall strength of evidence, using sound instruments and procedures, can produce
      reasonable levels of confidence about the science base for parts of quality
      improvement programs. With such information, health care professionals and
      administrators concerned with quality improvement can understand better the level
      of science (versus only clinical consensus or opinion) that supports practice
      guidelines, review criteria, and assessments that feed into quality assurance and
      improvement programs. New systems are appearing and research is needed to confirm
      the conceptual and practical underpinnings of these grading and rating systems,
      but the need for those developing systematic reviews, practice guidelines, and
      quality or audit criteria to understand and undertake these steps is becoming
      increasingly clear.

PMID- 15020557
TI  - Do health plans influence quality of care?
AB  - OBJECTIVE: To investigate the relative impact of physician groups and health
      plans on quality of care measures. DESIGN: Secondary data analysis of receipt of
      preventive care services included in the Health Plan Employer Data and
      Information Set (HEDIS) among 10 758 patients representing 21 health maintenance
      organizations and 22 large provider groups in the San Francisco and Los Angeles,
      California, areas in 1997. Each patient was eligible for (at least) one of six
      HEDIS-measured services. Data identify whether or not the service was provided,
      the patient's health plan, and the provider group responsible for the care. We
      used logistic regression to examine variations across plans in HEDIS rates, and
      whether variations persist after controls for provider groups are included.
      SETTING: Patients from 21 health maintenance organizations serving San Francisco
      and Los Angeles, California, in 1997. MAIN OUTCOME MEASURES: Breast cancer
      screening, childhood immunizations, cervical cancer screening, diabetic retinal
      exam, prenatal care in the first trimester, and check-ups after delivery among
      patients for whom these services are appropriate. RESULTS: There are
      statistically significant differences across health plans in utilization rates
      for the six services examined. These differences are not substantially affected
      when we control for the provider group that cared for the patient. That is,
      controlling for provider group does not explain variations across plans,
      consistent with the view that health plans have an impact on HEDIS quality
      measures independent of the providers that they contract with. CONCLUSIONS: There
      are activities that plans can undertake which influence their HEDIS scores. On
      the face of it, these results suggest that plans can independently improve
      quality, in contrast to hypotheses that plans would be "too far" from patients to
      have an influence. Continued attention to collecting plan-level data is
      warranted. Further work should address other possible sources of variations in
      HEDIS scores, such as variability in the quality of plan administrative
      databases.

PMID- 15020558
TI  - Improving the hospital management of malnourished children by participatory
      research.
AB  - OBJECTIVE: To improve the clinical management of severely malnourished children
      in rural hospitals in South Africa. STUDY DESIGN: A pre- and post-intervention
      descriptive study in three stages: assessment of the clinical management of
      severely malnourished children, planning and implementing an action plan to
      improve quality of care, and monitoring and evaluating targeted activities. A
      participatory approach was used to involve district and hospital nutrition teams
      in all stages of the research. SETTING: Two rural first-referral level hospitals
      (Mary Theresa and Sipetu) in Mount Frere District, Eastern Cape Province. MAIN
      MEASURE: A retrospective record review of all admissions for severe malnutrition
      to obtain patient characteristics and case fatality rates, a detailed review of
      randomly selected cases to illustrate general case management, structured
      observations in the paediatric wards to assess adequacy of resources for care of
      malnourished children, and in-depth interviews and focus group discussions with
      nursing and medical staff to identify barriers to improved quality of care.
      RESULTS: Before the study, case fatality rates were 50% and 28% in Mary Theresa
      and Sipetu hospitals, respectively. Information from case studies, observations,
      interviews, and focus group discussions revealed many inadequacies in knowledge,
      resources, and practices. The hospital nutrition team developed and implemented
      an action plan to improve the quality of care and developed tools for monitoring
      its implementation and evaluating its impact. In the 12-month period immediately
      after implementation, case fatality rates fell by approximately 25% in both
      hospitals. CONCLUSION: Participatory research led to the formation of a hospital
      nutrition team, which identified shortcomings in the clinical management of
      severely malnourished children and took action to improve quality of care. These
      actions were associated with a reduction in case fatality rates.

PMID- 15020559
TI  - Symptom-based framework for assessing quality of HIV care.
AB  - OBJECTIVE: To evaluate HIV quality of care using a symptom-based, patient
      centered framework. METHODS: An expert panel developed 13 quality indicators for
      three common symptoms: cough with fever and/or shortness of breath; severe or
      persistent diarrhea; and significant weight loss. A nationally representative
      probability sample of HIV-infected adults was interviewed between 1996 and 1997.
      PARTICIPANTS: were asked about the presence and severity of HIV symptoms during
      the preceding 6 months, and care received. Variation in adherence to the
      indicators was assessed by symptom type and patient characteristics. RESULTS: In
      all, 2864 (71%) patients completed interviews and 920 reported being at least
      moderately bothered with one of the three symptoms. Of these, 41, 74, and 65% of
      patients with a symptom of cough, weight loss, or diarrhea, respectively,
      reported receiving all indicated care. Performance was better for patients with
      more severe HIV, measured as a CD4 cell count <50 cells/microliter, compared with
      those with less severe HIV, measured as CD4 cell count >500 cells/microliter (43%
      versus 60%; P = 0.02). Uninsured patients had worse performance than Medicare
      patients (45% versus 62%; P = 0.04), but care did not differ by patient's age,
      gender, ethnicity, HIV risk factor, providers' HIV patient load, or region. Only
      CD4 count remained significantly associated with performance in the multivariate
      analyses. CONCLUSIONS: Symptom-based quality indicators may provide a useful
      supplement to conventional measures. Patients with HIV reported substantial
      underuse of services for common, burdensome symptoms. Although adherence to
      quality indicators was better for patients with more advanced HIV disease, many
      still received suboptimal care. Vulnerable patient groups generally did not
      receive worse quality of care, suggesting that symptom-based measures of quality
      may measure domains that are distinct from those captured by conventional
      indicators.

PMID- 15020560
TI  - Exploring the impact of complications on length of stay in major surgery
      diagnosis-related groups.
AB  - STUDY OBJECTIVE: To analyze, in terms of the length of stay (LOS), the use of
      resources by patients classified under surgical diagnosis-related groups (DRGs)
      with complication and/or comorbidity (DRGCCs), divided into subgroups where
      complications were and were not detected, and to explore the repercussions on
      hospital reimbursement. DESIGN: The Complication Screening Program(Copyright )
      (CSP) was used to divide the patients in 14 DRGCCs into subgroups with and
      without complications, and to compare the LOS between the subgroups and with the
      equivalent DRG without CC. The ratios between the LOS and the relative weight of
      the DRGs for reimbursement were also compared. SETTING: The population
      hospitalized for major surgery between 1995 and 1999 in the Hospital of Mataro,
      Catalonia, Spain. PARTICIPANTS: Patients (4227) hospitalized for major surgery.
      MAIN RESULT: The percentage of complications identified by the CSP ranged from
      17.5% to 52.4%. The LOS of the DRGCCs was almost twice as long as in the DRGs
      without CC; 2.48 times greater if the DRGCC was flagged by the CSP and 70%
      greater if it was not. On average, the DRGCCs selected were reimbursed at a rate
      93% higher than their counterpart DRGs without CC. In 11 of the 14 DRG pairs with
      or without CC, the reimbursement ratio was lower than the LOS ratio. CONCLUSIONS:
      DRGCCs can be classified into clearly differentiated groups based on the presence
      or absence of CSP-flagged complications. CSP-flagged complications produce an
      increase in LOS greater than the increase in the relative weights for
      reimbursement.

PMID- 15020561
TI  - Improving assessment and treatment of pain in the critically ill.
AB  - OBJECTIVE: Efforts to improve pain assessment and treatment in critically ill
      patients are poorly studied and represent an opportunity to improve quality of
      care. We sought to improve pain assessment and treatment in patients in a
      surgical intensive care unit at an academic medical center. DESIGN: We performed
      a prospective study of pain assessment and treatment in two surgical intensive
      care units in 2001. We measured pain assessment as the percentage of 4-h
      intervals where the patient's pain was measured using a visual analog scale. We
      measured pain treatment as the percentage of 4-h intervals where the patient's
      pain score on the scale was < or =3. We then implemented four separate "plan-do
      study-act" cycles to improve pain assessment and treatment. MAIN OUTCOME
      MEASURES: We evaluated the percentage of 4-h patient-nursing intervals that were
      scored numerically pre- and post-intervention. We evaluated the percentage of 4-h
      patient-nursing intervals where the patients had a pain score of < or =3 pre- and
      post-intervention. In addition, we monitored naloxone use as a measure of adverse
      events related to pain treatment. RESULTS: Our baseline assessment of pain was
      42% and the baseline treatment was 59%. After 5 weeks, pain assessment improved
      to 71% and pain management improved to 97%. CONCLUSION: Our interventions were
      associated with significant improvements in pain assessment and treatment without
      an increase in adverse events related to pain therapy. Our interventions were
      relatively simple and may be implemented broadly. Our interventions provide
      insights into the application of complexity theory in improvement efforts.

PMID- 15020562
TI  - Which data source in clinical performance assessment? A pilot study comparing
      self-recording with patient records and observation.
AB  - OBJECTIVE: A pilot study aimed to determine the extent to which each of three
      data sources could provide complete and reliable data for valid assessment of
      clinical performance. DESIGN: Clinical decisions taken in 168 consultations by
      seven family physicians were reviewed against guidelines for 15 clinical
      conditions. In total, 206 criteria were reviewed using three sources: medical
      records, observation in surgery, and structured self-recording by the physicians.
      SETTING AND PARTICIPANTS: Seven family practices in the Netherlands. MAIN
      MEASURE: Scores (%) of data recorded/total were obtained for each method. Kappa
      scores for the agreement between the three data sources were also obtained.
      RESULTS: Medical record examination provided 40%, observation 72%, and physician
      self-recording 95% of the data required for the review against guidelines. Nine
      per cent of the clinical decisions could be reviewed when using medical records,
      46% when using observation data, and 69% when using data from prospective self
      recording. In particular, decisions in the area of patient education and
      diagnostic examinations could not be reviewed validly using medical records only.
      Kappa agreements between the data available from the three sources as well as
      between the review results appeared to be 0.79. CONCLUSIONS: Medical records
      alone only supply sufficient information for the review of a very limited set of
      clinical decisions. Physician self-recording has significantly more potential for
      valid review of a broad range of clinical decisions. Furthermore, self-recording
      seems a reliable data collection method that deserves further research.

PMID- 15020563
TI  - Quality of rheumatoid arthritis care: the patient's perspective.
AB  - OBJECTIVE: To identify health care aspects of inadequate quality in rheumatoid
      arthritis (RA) care from the perspective of patients, and to study to what extent
      patients' perspectives on quality of care are associated with patient
      characteristics. DESIGN: Cross-sectional questionnaire survey performed in 1999.
      SETTING: Secondary and tertiary rheumatology outpatient clinics. STUDY
      PARTICIPANTS: A random sample (n = 683) of patients diagnosed with rheumatoid
      arthritis according to the 1987 revised American College of Rheumatology
      criteria. Patients varied widely with respect to age (mean 61.5 years) and
      disease duration (mean 10.7 years). MAIN OUTCOME MEASURES: Using the method of
      the QUOTE-questionnaire, patients' were asked to rate the importance to them of
      29 aspects of care, and to rate the performance of five different health care
      providers [i.e. rheumatologist, general practitioner (GP), physiotherapist, home
      nurse, and formal home help] relating to these aspects. To identify aspects of
      inadequate quality, patients' performance ratings were weighted by importance
      ratings within each health care service. Inadequate performance on an extremely
      important aspect was found to be a more serious quality problem than an
      inadequate performance on an aspect that was less important to patients. Using
      regression analyses, the association between patients' quality ratings and
      patient characteristics was assessed. RESULTS: Several aspects of inadequate
      quality were identified, namely in the field of knowledge of rheumatism and
      particularly for GPs, physiotherapists, home nurses, and formal home help, and in
      the field of information on medication and treatment for rheumatologists and GPs.
      Furthermore, for the majority of the importance and performance ratings, we found
      no association with patient-related characteristics. CONCLUSIONS: Our study
      demonstrated that the quality of care could be improved further from the
      perspective of patients. These findings may be used for making health care more
      responsive to patients' needs.

PMID- 15020564
TI  - Meeting patient's expectations in primary care consultations in Lithuania.
AB  - OBJECTIVE: Patient satisfaction with health care services is considered an
      important factor of health care. Although research on patient satisfaction has
      become standard in Western Europe, in countries such as Lithuania the concept of
      patient satisfaction is still a relatively new one. This study aimed to
      investigate how the meeting of patients' expectations is related to increased
      satisfaction with medical consultation. STUDY DESIGN: The methodology used by
      Williams et al. in the UK was applied to the Lithuanian health care setting.
      Forty physicians from 22 primary health care centres attending courses on general
      practice at Vilnius University were recruited for the study. Every third adult
      patient coming to a practice during a 5-day period was invited to participate in
      the study. In all, 609 patients coming to meet their physician regarding health
      problems were included in the study sample. The patients were asked to complete
      three standardized questionnaires: the Patient Intentions Questionnaire prior to
      the consultation, and the Expectations Met Questionnaire and Medical Interview
      Satisfaction Scale after the consultation. Cronbach's alpha statistic was used
      for the validation of the questionnaires and principal components analysis was
      used to determine the factors of patient expectations. RESULTS: The response rate
      was 78%. ANALYSIS: of 460 sets of questionnaires revealed that satisfaction with
      medical consultation is higher among patients who have a greater number of
      expectations met. Physicians' success in meeting different types of patient
      expectations also had different influences on patient satisfaction. The most
      important expectations to be met were "understanding and explanation", followed
      by expectations of "emotional support", while "getting information" was less
      important. CONCLUSIONS: The most frequently reported expectations on the Patient
      Intentions Questionnaire were for "getting information" and "understanding and
      explanation" of the patients' health problem items, and the least mentioned were
      for emotional support items. Patients with more expectations met were found to
      have significantly higher scores on the satisfaction index. Satisfaction with the
      consultation is best predicted by meeting the patient's expectations for
      understanding and explanation, and for emotional support. Providing desired
      information to the patient as well as meeting the patient's expectations for
      diagnostic procedures and treatment is less associated with patient satisfaction.

PMID- 15020565
TI  - The use of maximum likelihood methods to estimate the risk of tuberculous
      infection and disease in a Canadian First Nations population.
AB  - BACKGROUND: Tuberculosis (TB) notification rates among First Nations people in
      British Columbia, Canada, are higher than those among non-First Nations people,
      although rates are declining more rapidly in the First Nations population. The
      epidemiology of tuberculous infection and disease during the period 1926-2000 in
      this population was investigated. METHODS: The trend in the annual risk of
      infection (ARI) since 1926 was estimated using tuberculous meningitis mortality
      statistics and skin testing data. Risks of progression from infection to disease
      were estimated by fitting model predictions of disease incidence to TB
      notifications, using maximum likelihood methods. Infectious TB notifications were
      matched with ARI estimates to obtain the number of transmissions per infectious
      case over time. RESULTS: We estimate that the ARI decreased from more than 10%
      during the prechemotherapy era to less than 0.1% by 2000. The risks of primary,
      reactivation, and exogenous re-infection disease among adults aged 25-44 years
      were 22%, 0.1%, and 6%, respectively. The number of transmissions per infectious
      case decreased from 16 to 2 from the early 1970s to the late 1990s. CONCLUSIONS:
      This study shows that the risk of infection among British Columbia First Nations
      people is decreasing, while the relative contribution of reactivation to disease
      incidence is increasing. Once infected, First Nations people may have a higher
      risk of developing disease than other populations.

PMID- 15020567
TI  - Trends in reported incidences of gastric cancer by tumour location, from 1975 to
      1989 in Japan.
AB  - BACKGROUND: This study was performed to estimate the incidence of gastric cancer
      by tumour location and to clarify whether the relative and absolute rates of
      gastric cancer in Japan changed between 1975 and 1989. METHODS: The stomach was
      anatomically divided into the upper, middle, and lower thirds. Age- and sex
      specific incidences by tumour location were estimated by multiplying the age- and
      sex-specific national incidences of gastric cancer by the corresponding
      proportions of tumour location. We studied 171 721 cases of gastric cancer from
      the Gastric Cancer Registry of Japan. RESULTS: Over 15 years, the proportion of
      tumours in the upper third of the stomach increased in men but did not change
      much in women. The proportion of tumours in the middle third of the stomach
      increased among both men and women while the proportion of tumours in the lower
      third of the stomach decreased among both men and women. The incidence of tumours
      in the upper third of the stomach showed an increasing trend among elderly men
      and women but not among young ones. The incidence of tumours in the lower third
      of the stomach decreased significantly among men and women of most age groups.
      CONCLUSIONS: The present study added evidence of disparate trends in the
      incidence of gastric cancer by tumour location. The separate epidemiological
      features may indicate different aetiologies as well as changes in the degree of
      influence of these aetiologies.

PMID- 15020566
TI  - Antibiotic sales and the prevalence of symptoms of asthma, rhinitis, and eczema:
      The International Study of Asthma and Allergies in Childhood (ISAAC).
AB  - BACKGROUND: It has been hypothesized that antibiotic use early in life may
      increase the subsequent risk of asthma. We have conducted an ecologic analysis of
      the relationship between antibiotics sales and the prevalence of symptoms of
      asthma, allergic rhinoconjunctivitis, and atopic eczema in 99 centres from 28
      countries. METHODS: Data for antibiotics sales for 28 countries were obtained
      from the Institute for Medical Statistics (IMS), Health Global Services, UK and
      converted to defined daily doses (DDD). Data on the prevalence of symptoms of
      asthma, rhinitis, and eczema in 13-14 year olds were based on the responses to
      the written and video questionnaires from the International Study of Asthma and
      Allergies in Childhood (ISAAC). The analysis was adjusted for gross national
      product (GNP) as an estimate of the level of affluence. RESULTS: In general,
      there was a positive association between per capita antibiotics sales and the
      prevalence of symptoms for asthma, rhinitis, and eczema, but the associations
      generally became negative once the analyses had been adjusted for GNP. In
      particular, there were non-significant negative associations between total
      antibiotics sales and the prevalence of wheeze ever, wheeze in the last 12
      months, nose problems with itchy-watery eyes, itchy rash in the last 12 months,
      and eczema ever. On the other hand there were weak non-significant positive
      associations for asthma ever, nose problems ever, nose problems in the last 12
      months, and itchy rash ever. There was a statistically significant positive
      association with wheeze at rest as measured by the asthma video questionnaire;
      however, even this association was weak and would not account for more than a 1%
      difference in asthma prevalence between countries. CONCLUSIONS: These findings
      are generally not consistent with the hypothesis that antibiotic use increases
      the risk of asthma, rhinitis, or eczema. If there is a causal association of
      antibiotic use with asthma risk, it does not appear to explain the international
      differences in asthma prevalence.

PMID- 15020568
TI  - Within-person variation in serum lipids: implications for clinical trials.
AB  - BACKGROUND: Little is known about the degree to which behavioural, biological,
      and genetic traits contribute to within-person variation in serum cholesterol.
      Materials and Methods The authors studied within-person variation in serum total
      and high density lipoprotein (HDL) cholesterol in 458 participants of 27 dietary
      intervention studies in Wageningen, The Netherlands, from 1976 to 1995. RESULTS:
      For a median of 4 days between blood draws, the geometric mean of the within
      person standard deviation was 0.13 mmol/l ( approximately 5 mg/dl, coefficient of
      variation = 3.0%) for total cholesterol and 0.04 mmol/l ( approximately 1.5
      mg/dl, coefficient of variation = 3.0%) for HDL cholesterol. In mixed-model
      linear regressions using within-person variance as the dependent variable and
      including lipid concentration and covariates listed below, within-person variance
      of both total cholesterol and HDL cholesterol was higher for greater number of
      days between blood draws and for self-selected diet rather than investigator
      controlled diet. Within-person variance of total cholesterol only was higher for
      non-standardized versus standardized phlebotomy protocol and for female sex. The
      authors found evidence that the APOA4 -347 (12/22 genotype) and MTP -493 (11
      genotype) polymorphisms may increase the within-person variation in total
      cholesterol. CONCLUSION: Under certain study design (self-selected diet, use of
      non-standardized phlebotomy protocol) or participant characteristics (female,
      certain polymorphisms) within-person lipid variance is increased and required
      sample size will be greater. These findings may have important implications for
      the time and cost of such interventions.

PMID- 15020569
TI  - Comparison of two cluster sampling methods for health surveys in developing
      countries.
AB  - BACKGROUND: The Expanded Program for Immunization (EPI) random walk method has
      been widely used by the World Health Organization and others for rapid cluster
      sample surveys where an up-to-date household sampling frame is not available.
      However, it is not a probability sample, does not allow for population movement
      since the last census, and does not ensure objectivity in household selection or
      permit call-backs for non-response. Compact segment sampling avoids these
      problems and has been proposed as a slower but cleaner alternative. METHODS: We
      conducted two surveys, one using the EPI scheme and one using compact segment
      sampling, to estimate vaccination coverage in Western Region of The Gambia within
      3 months of each other in 2000-2001. RESULTS: Point estimates for vaccination
      coverage from the two surveys rarely differed by more than 2%. Any differences
      were more likely to be due to household selection than to population movement. A
      simple mathematical model showed that even in extreme situations, ignoring
      population movement since the last census is unlikely to have any appreciable
      effect. Rates of homogeneity did not differ systematically between the surveys.
      CONCLUSIONS: In situations where quality of fieldwork can be guaranteed, the EPI
      random walk method can give accurate and precise results. However, compact
      segment sampling is generally to be preferred as it ensures objectivity in
      household selection and permits the estimation of population totals (such as
      those unvaccinated), which are helpful for planning service provision.

PMID- 15020570
TI  - TGFbeta1 polymorphism (L10P) and risk of colorectal adenomatous and hyperplastic
      polyps.
AB  - BACKGROUND: Transforming growth factor-beta1 (TGFbeta1) is a multifunctional
      signalling molecule with a wide array of roles. Animal experiments suggest that
      TGFbeta1 plays a biphasic role in carcinogenesis by protecting against the early
      formation of benign epithelial growths, but promoting malignant transformation of
      those growths that do develop. A polymorphism in the signal peptide sequence of
      the TGFbeta1 gene (L10P) has been associated with increased levels of plasma
      TGFbeta1 in individuals with the P allele. METHODS: We investigated whether this
      polymorphism was associated with the risk of colorectal adenomatous or
      hyperplastic polyps in a case-control study of individuals from Minnesota. Risk
      of colorectal polyps was evaluated separately for individuals with adenomatous
      polyps (n = 513) and hyperplastic polyps (n = 191) relative to polyp-free
      controls (n = 606) using logistic regression analysis. RESULTS: No overall
      association was seen between the L10P polymorphism and risk of colorectal
      adenomatous polyps. The age- and sex-adjusted odds ratios (OR) of developing
      colorectal hyperplastic polyps were 1.0 (95% CI: 0.7, 1.4) and 0.7 (95% CI: 0.4,
      1.1) for individuals with the LP and PP genotypes, respectively, compared with
      individuals with the LL genotype. When stratified by smoking, evidence for a
      decreased risk of hyperplastic polyps associated with the P allele was seen only
      among ever smokers (P for trend = 0.05). CONCLUSIONS: Whereas adenoma risk did
      not vary by TGFbeta1 L10P genotype, these results suggest that the L10P variant
      allele may have a protective role in the development of colorectal hyperplastic
      polyps, possibly consistent with its role as an inhibitor of epithelial growths.

PMID- 15020571
TI  - Smoking among high school adolescents in Karachi, Pakistan.

PMID- 15020572
TI  - Commentary: use of antibiotics and risk of asthma.

PMID- 15020573
TI  - Influences of head positions and bite opening on collapsibility of the passive
      pharynx.
AB  - A collapsible tube surrounded by soft material within a rigid box was proposed as
      a two-dimensional mechanical model for the pharyngeal airway. This model predicts
      that changes in the box size (pharyngeal bony enclosure size anatomically defined
      as cross-sectional area bounded by the inside edge of bony structures such as the
      mandible, maxilla, and spine, and being perpendicular to the airway) influence
      patency of the tube. We examined whether changes in the bony enclosure size
      either with head positioning or bite opening influence collapsibility of the
      pharyngeal airway. Static mechanical properties of the passive pharynx were
      evaluated in anesthetized, paralyzed patients with sleep-disordered breathing
      before and during neck extension with bite closure (n = 11), neck flexion with
      bite closure (n = 9), and neutral neck position with bite opening (n = 11). Neck
      extension significantly increased maximum oropharyngeal airway size and decreased
      closing pressures of the velopharynx and oropharynx. Notably, neck extension
      significantly decreased compliance of the oropharyngeal airway wall. Neck flexion
      and bite opening decreased maximum oropharyngeal airway size and increased
      closing pressure of the velopharynx and oropharynx. Our results indicate the
      importance of neck and mandibular position for determining patency and
      collapsibility of the passive pharynx.

PMID- 15020574
TI  - Regulation of gastric motility at simulated high altitude in conscious rats.
AB  - The aim of the present study was to examine the effects of acute exposure to
      hypobaric hypoxia on gastric and colonic motilities. Wistar rats, which were
      instrumented chronically with strain gauge force transducer to measure gastric
      and colonic motilities, were exposed acutely to hypobaric hypoxia [0.5 atmosphere
      absolute (ATA, 380 Torr)] over 1 h. In a separate group, the gastric branches of
      the vagal nerves were cut and underwent the same experimental protocol. Each
      contraction wave of the stomach and colon was analyzed into frequency and area
      under the curves, which were then averaged every 10 min. Acute exposure to 0.5
      ATA resulted in significant (P < 0.05) decreases in frequency and area of gastric
      contraction wave by 0.5 +/- 0.1 cycles/min and 64.6 +/- 4.0%, respectively.
      Gastric vagotomy abolished completely the suppression in the area observed in the
      intact rats during the 0.5-ATA exposures. Colonic motility increased
      significantly only at the start and end of exposure to 0.5 ATA and sham exposure
      [1 ATA (760 Torr), time control] in both intact and vagotomized rats. These data
      suggest that the acute suppression of the area of the gastric contraction wave
      that occurred during 0.5-ATA exposure is likely to be mediated by the vagal
      nerve.

PMID- 15020575
TI  - Depression of diaphragm motor cortex excitability during mechanical ventilation.
AB  - The effect of mechanical ventilation on the diaphragm motor cortex remains
      unknown. We assessed the effect of mechanical ventilation on diaphragm motor
      cortex excitability by measuring the costal and crural diaphragm motor-evoked
      potential (MEP) elicited by single and paired transcranial magnetic stimulation.
      In six healthy subjects, MEP recruitment curves of the costal and crural
      diaphragms were assessed at relaxed end expiration during spontaneous breathing
      [baseline tidal volume (Vt(baseline))] and isocapnic volume cycled ventilation
      delivered noninvasively (NIV) at three different levels of tidal volume
      (Vt(baseline), Vt(baseline) + 5 ml/kg liters, and Vt(baseline) + 10 ml/kg
      liters). The costal and crural diaphragm response to peripheral stimulation of
      the right phrenic nerve was not reduced by NIV. NIV reduced the costal and crural
      MEP amplitude during NIV (P < 0.0001) with the maximal reduction at Vt(baseline)
      + 5 ml/kg. Response to paired TMS showed that NIV (Vt(baseline) + 5 ml/kg)
      significantly increased the sensitivity of the cortical motoneurons to
      facilitatory (>9 ms) interstimulus intervals (P = 0.002), suggesting that the
      diaphragm MEP amplitude depression during NIV is related to neuromechanical
      inhibition at the level of motor cortex. Our results demonstrate that mechanical
      ventilation directly inhibits central projections to the diaphragm.

PMID- 15020576
TI  - Dependence of lung injury on inflation rate during low-volume ventilation in
      normal open-chest rabbits.
AB  - Lung mechanics and morphometry were assessed in two groups of nine normal open
      chest rabbits mechanically ventilated (MV) for 3-4 h at zero end-expiratory
      pressure (ZEEP) with physiological tidal volumes (Vt; 11 ml/kg) and high (group
      A) or low (group B) inflation flow (44 and 6.1 ml x kg(-1) x s(-1),
      respectively). Relative to initial MV on positive end-expiratory pressure (PEEP;
      2.3 cmH(2)O), MV on ZEEP increased quasi-static elastance and airway and
      viscoelastic resistance more in group A (+251, +393, and +225%, respectively)
      than in group B (+180, +247, and +183%, respectively), with no change in
      viscoelastic time constant. After restoration of PEEP, quasi-static elastance and
      viscoelastic resistance returned to control, whereas airway resistance, still
      relative to initial values, remained elevated more in group A (+86%) than in
      group B (+33%). In contrast, prolonged high-flow MV on PEEP had no effect on lung
      mechanics of seven open-chest rabbits (group C). Gas exchange on PEEP was equally
      preserved in all groups, and the lung wet-to-dry ratios were normal. Relative to
      group C, both groups A and B had an increased percentage of abnormal alveolar
      bronchiolar attachments and number of polymorphonuclear leukocytes in alveolar
      septa, the latter being significantly larger in group A than in group B. Thus
      prolonged MV on ZEEP with cyclic opening-closing of peripheral airways causes
      alveolar-bronchiolar uncoupling and parenchymal inflammation with concurrent,
      persistent increase in airway resistance, which are worsened by high-inflation
      flow.

PMID- 15020577
TI  - Role of nitric oxide in exercise sympatholysis.
AB  - The production of nitric oxide is the putative mechanism for the attenuation of
      sympathetic vasoconstriction (sympatholysis) in working muscles during exercise.
      We hypothesized that nitric oxide synthase blockade would eliminate the reduction
      in alpha-adrenergic-receptor responsiveness in exercising skeletal muscle. Ten
      mongrel dogs were instrumented chronically with flow probes on the external iliac
      arteries of both hindlimbs and a catheter in one femoral artery. The selective
      alpha(1)-adrenergic agonist (phenylephrine) or the selective alpha(2)-adrenergic
      agonist (clonidine) was infused as a bolus into the femoral artery catheter at
      rest and during mild and heavy exercise. Before nitric oxide synthase inhibition
      with N(G)-nitro-l-arginine methyl ester (l-NAME), intra-arterial infusions of
      phenylephrine elicited reductions in vascular conductance of -91 +/- 3, -80 +/-
      5, and -75 +/- 6% (means +/- SE) at rest, 3 miles/h, and 6 miles/h and 10% grade,
      respectively. Intra-arterial clonidine reduced vascular conductance by -65 +/- 6,
      -39 +/- 4, and -30 +/- 3%. After l-NAME, intra-arterial infusions of
      phenylephrine elicited reductions in vascular conductance of -85 +/- 5, -85 +/-
      5, and -84 +/- 5%, whereas clonidine reduced vascular conductance by -67 +/- 5, 
      45 +/- 3, and -35 +/- 3%, at rest, 3 miles/h, and 6 miles/h and 10% grade.
      alpha(1)-Adrenergic-receptor responsiveness was attenuated during heavy exercise.
      In contrast, alpha(2)-adrenergic-receptor responsiveness was attenuated even at a
      mild exercise intensity. Whereas the inhibition of nitric oxide production
      eliminated the exercise-induced attenuation of alpha(1)-adrenergic-receptor
      responsiveness, the attenuation of alpha(2)-adrenergic-receptor responsiveness
      was unaffected. These results suggest that the mechanism of exercise
      sympatholysis is not entirely mediated by the production of nitric oxide.

PMID- 15020579
TI  - Reducing the time period of steady state does not affect the accuracy of energy
      expenditure measurements by indirect calorimetry.
AB  - Achievement of steady state during indirect calorimetry measurements of resting
      energy expenditure (REE) is necessary to reduce error and ensure accuracy in the
      measurement. Steady state is often defined as 5 consecutive min (5-min SS) during
      which oxygen consumption and carbon dioxide production vary by +/-10%. These
      criteria, however, are stringent and often difficult to satisfy. This study aimed
      to assess whether reducing the time period for steady state (4-min SS or 3-min
      SS) produced measurements of REE that were significantly different from 5-min SS.
      REE was measured with the use of open-circuit indirect calorimetry in 39
      subjects, of whom only 21 (54%) met the 5-min SS criteria. In these 21 subjects,
      median biases in REE between 5-min SS and 4-min SS and between 5-min SS and 3-min
      SS were 0.1 and 0.01%, respectively. For individuals, 4-min SS measured REE
      within a clinically acceptable range of +/-2% of 5-min SS, whereas 3-min SS
      measured REE within a range of -2-3% of 5-min SS. Harris-Benedict prediction
      equations estimated REE for individuals within +/-20-30% of 5-min SS. Reducing
      the time period of steady state to 4 min produced measurements of REE for
      individuals that were within clinically acceptable, predetermined limits. The
      limits of agreement for 3-min SS fell outside the predefined limits of +/-2%;
      however, both 4-min SS and 3-min SS criteria greatly increased the proportion of
      subjects who satisfied steady state within smaller limits than would be achieved
      if relying on prediction equations.

PMID- 15020578
TI  - Exercise delays allogeneic tumor growth and reduces intratumoral inflammation and
      vascularization.
AB  - This investigation determined whether daily strenuous exercise would alter the
      progression and regression of an allogeneic lymphoid tumor in mice. We also
      determined whether exercise would alter the cellular composition and vascularity
      of the tumor. Female BALB/c mice (age 6-8 wk) were randomly assigned to sedentary
      control (Con) or daily exercised groups (EXH). EXH mice ran on a treadmill at
      incremental speeds (20-40 m/min) for 3 h or until fatigue. Each mouse was
      subcutaneously injected with 20 x 10(6) EL-4 lymphoma cells immediately after the
      first exercise bout (day 1) and run daily. Tumor volume was measured daily with
      calipers. In some experiments, mice were euthanized on days 5-10, 12, and 14.
      Tumors were excised and stained with hematoxylin and eosin or for Factor VIII
      associated antigen using immunohistochemistry and analyzed in a blinded fashion
      under a light microscope. There was no significant treatment main effect found
      for tumor volumes. Interestingly, a significant treatment x time interaction was
      found, such that there was a 2-day delay in peak tumor volume and a more rapid
      tumor regression in EXH. Tumors isolated from Con exhibited significantly higher
      numbers of apoptotic bodies, blood vessels, macrophages, and neutrophils when
      compared with EXH. Intratumoral lymphocytes were higher in Con early in tumor
      growth but higher in EXH at peak tumor size. These data indicate that daily
      strenuous exercise may influence tumor growth by affecting the microenvironment
      of the tumor, resulting in a delay in tumor growth and a more rapid regression.

PMID- 15020580
TI  - Tissue heterogeneity in the mouse lung: effects of elastase treatment.
AB  - We developed a network model in an attempt to characterize heterogeneity of
      tissue elasticity of the lung. The model includes a parallel set of pathways,
      each consisting of an airway resistance, an airway inertance, and a tissue
      element connected in series. The airway resistance, airway inertance, and the
      hysteresivity of the tissue elements were the same in each pathway, whereas the
      tissue elastance (H) followed a hyperbolic distribution between a minimum and
      maximum. To test the model, we measured the input impedance of the respiratory
      system of ventilated normal and emphysematous C57BL/6 mice in closed chest
      condition at four levels of positive end-expiratory pressures. Mild emphysema was
      developed by nebulized porcine pancreatic elastase (PPE) (30 IU/day x 6 days).
      Respiratory mechanics were studied 3 wk following the initial treatment. The
      model significantly improved the fitting error compared with a single-compartment
      model. The PPE treatment was associated with an increase in mean alveolar
      diameter and a decrease in minimum, maximum, and mean H. The coefficient of
      variation of H was significantly larger in emphysema (40%) than that in control
      (32%). These results indicate that PPE treatment resulted in increased time
      constant inequalities associated with a wider distribution of H. The
      heterogeneity of alveolar size (diameters and area) was also larger in emphysema,
      suggesting that the model-based tissue elastance heterogeneity may reflect the
      underlying heterogeneity of the alveolar structure.

PMID- 15020582
TI  - A new fluorescence resonance energy transfer approach demonstrates that the
      histone variant H2AZ stabilizes the histone octamer within the nucleosome.
AB  - Nucleosomes are highly dynamic macromolecular complexes that are assembled and
      disassembled in a modular fashion. One important way in which this dynamic
      process can be modulated is by the replacement of major histones with their
      variants, thereby affecting nucleosome structure and function. Here we use
      fluorescence resonance energy transfer between fluorophores attached to various
      defined locations within the nucleosome to dissect and compare the structural
      transitions of a H2A.Z containing and a canonical nucleosome in response to
      increasing ionic strength. We show that the peripheral regions of the DNA
      dissociate from the surface of the histone octamer at relatively low ionic
      strength, under conditions where the dimer-tetramer interaction remains
      unaffected. At around 550 mm NaCl, the (H2A-H2B) dimer dissociates from the (H3
      H4)(2) tetramer-DNA complex. Significantly, this latter transition is stabilized
      in nucleosomes that have been reconstituted with the essential histone variant
      H2A.Z. Our studies firmly establish fluorescence resonance energy transfer as a
      valid method to study nucleosome stability, and shed new light on the biological
      function of H2A.Z.

PMID- 15020581
TI  - Expression of nitric oxide synthase-2 in the lungs decreases airway resistance
      and responsiveness.
AB  - Individuals with asthma have increased levels of nitric oxide in their exhaled
      air. To explore its role, we have developed a regulatable transgenic mouse
      capable of overexpressing inducible nitric oxide synthase in a lung-specific
      fashion. The CC10-rtTA-NOS-2 mouse contains two transgenes, a reverse
      tetracycline transactivator under the control of the Clara cell protein promoter
      and the mouse nitric oxide synthase-2 (NOS-2) coding region under control of a
      tetracycline operator. Addition of doxycycline to the drinking water of CC10-rtTA
      NOS-2 mice causes an increase in nitric oxide synthase-2 that is largely confined
      to the airway epithelium. The fraction of expired nitric oxide increases over the
      first 24 h from approximately 10 parts per billion to a plateau of approximately
      20 parts per billion. There were no obvious differences between CC10-rtTA-NOS-2
      mice, with or without doxycycline, and wild-type mice in lung histology,
      bronchoalveolar protein, total cell count, or count differentials. However,
      airway resistance was lower in CC10-rtTA-NOS-2 mice with doxycycline than in CC10
      rtTA-NOS-2 mice without doxycycline or wild-type mice with doxycycline. Moreover,
      doxycycline-treated CC10-rtTA-NOS-2 mice were hyporesponsive to methacholine
      compared with other groups. These data suggest that increased nitric oxide in the
      airways has no proinflammatory effects per se and may have beneficial effects on
      pulmonary function.

PMID- 15020583
TI  - Regulation of Nrf2 transactivation domain activity. The differential effects of
      mitogen-activated protein kinase cascades and synergistic stimulatory effect of
      Raf and CREB-binding protein.
AB  - Transcription factor NF-E2-related factor 2 (Nrf2) regulates the induction of
      Phase II detoxifying enzymes as well as anti-oxidative enzymes. In this study, we
      investigated the transactivation potential of different Nrf2 transactivation
      domain regions by using the Gal4-Nrf2 chimeras and Gal4-Luc reporter co
      transfection assay system in HepG2 cells. The results indicated that chimera Gal4
      Nrf2-(1-370), which contains the full transactivation domain showed very potent
      transactivation activity. The high transactivation activity of Gal4-Nrf2-(113
      251) and the diminished transactivation activities of chimera Gal4-Nrf2-(1-126)
      and Gal4-Nrf2-(230-370) suggested that the Nrf2 N-terminal 113-251 amino acids
      region is critical in maintaining its transactivation activity. Overexpression of
      upstream MAPKs such as Raf, MEKK1, TAK1-DeltaN, and ASK1 up-regulated the
      transactivation activities of Gal4-Nrf2-(1-370) and Gal4-Nrf2-(113-251) in a dose
      dependent manner. Further investigation on the effects of the three MAPK pathways
      on Nrf2 transactivation domain activity demonstrated that both ERK and JNK
      signaling pathways stimulated the Gal4-Nrf2-(1-370) transactivation activity
      while the p38 pathway played a negative role. Site-directed mutagenesis studies
      on potential MAPK phosphorylation sites of Gal4-Nrf2-(113-251) showed no
      significant effect on its basal transactivation activity or the fold of induction
      by Raf. Interestingly, the nuclear transcription coactivator CREB-binding protein
      (CBP), which can bind to Nrf2 transactivation domain and can be activated by ERK
      cascade, showed synergistic stimulation with Raf on the transactivation
      activities of both the chimera Gal4-Nrf2-(1-370) and the full-length Nrf2. Taken
      together, this study clearly demonstrated that different segments of Nrf2
      transactivation domain have different transactivation potential and different
      MAPKs have differential effects on Nrf2 transcriptional activity. It also
      suggested that the up-regulation of Nrf2 transactivation domain activity by
      upstream MAPKs such as Raf may not be mediated by direct phosphorylation of the
      Nrf2 transactivation domain, but rather by regulation of the transcriptional
      activity of coactivator CBP.

PMID- 15020584
TI  - Glycogen synthase kinase-3beta regulates growth, calcium homeostasis, and
      diastolic function in the heart.
AB  - Glycogen synthase kinase (GSK) 3beta is a negative regulator of stress-induced
      cardiomyocyte hypertrophy. It is not clear, however, if GSK-3beta plays any role
      in regulating normal cardiac growth and cardiac function. Herein we report that a
      transgenic mouse expressing wild type GSK-3beta in the heart has a dramatic
      impairment of normal post-natal cardiomyocyte growth as well as markedly abnormal
      cardiac contractile function. The most striking phenotype, however, is grossly
      impaired diastolic relaxation, which leads to increased filling pressures of the
      left ventricle and massive atrial enlargement. This is due to profoundly abnormal
      calcium handling, leading to an inability to normalize cytosolic [Ca2+] in
      diastole. The alterations in calcium handling are due at least in part to direct
      down-regulation of the sarcoplasmic reticulum calcium ATPase (SERCA2a) by GSK
      3beta, acting at the level of the SERCA2 promoter. These studies identify GSK
      3beta as a regulator of normal growth of the heart and are the first of which we
      are aware, to demonstrate regulation of expression of SERCA2a, a critical
      determinant of diastolic function, by a cytosolic signaling pathway, the activity
      of which is dynamically modulated. De-regulation of GSK-3beta leads to severe
      systolic and diastolic dysfunction and progressive heart failure. Because down
      regulation of SERCA2a plays a central role in the diastolic and systolic
      dysfunction of patients with heart failure, these findings have potential
      implications for the therapy of this disorder.

PMID- 15020585
TI  - Stabilizing and destabilizing clusters in the hydrophobic core of long two
      stranded alpha-helical coiled-coils.
AB  - Detailed sequence analyses of the hydrophobic core residues of two long two
      stranded alpha-helical coiled-coils that differ dramatically in sequence,
      function, and length were performed (tropomyosin of 284 residues and the coiled
      coil domain of the myosin rod of 1086 residues). Three types of regions were
      present in the hydrophobic core of both proteins: stabilizing clusters and
      destabilizing clusters, defined as three or more consecutive core residues of
      either stabilizing (Leu, Ile, Val, Met, Phe, and Tyr) or destabilizing (Gly, Ala,
      Cys, Ser, Thr, Asn, Gln, Asp, Glu, His, Arg, Lys, and Trp) residues, and
      intervening regions that consist of both stabilizing and destabilizing residues
      in the hydrophobic core but no clusters. Subsequently, we designed a series of
      two-stranded coiled-coils to determine what defines a destabilizing cluster and
      varied the length of the destabilizing cluster from 3 to 7 residues to determine
      the length effect of the destabilizing cluster on protein stability. The results
      showed a dramatic destabilization, caused by a single Leu to Ala substitution, on
      formation of a 3-residue destabilizing cluster (DeltaT(m) of 17-21 degrees C)
      regardless of the stability of the coiled-coil. Any further substitution of Leu
      to Ala that increased the size of the destabilizing cluster to 5 or 7 hydrophobic
      core residues in length had little effect on stability (DeltaT(m) of 1.4-2.8
      degrees C). These results suggested that the contribution of Leu to protein
      stability is context-dependent on whether the hydrophobe is in a stabilizing
      cluster or its proximity to neighboring destabilizing and stabilizing clusters.

PMID- 15020587
TI  - A novel Tctex2-related light chain is required for stability of inner dynein arm
      I1 and motor function in the Chlamydomonas flagellum.
AB  - Tctex1 and Tctex2 were originally described in mice as putative
      distorters/sterility factors involved in the non-Mendelian transmission of t
      haplotypes. Subsequently, these proteins were found to be light chains of both
      cytoplasmic and axonemal dyneins. We have now identified a novel Tctex2-related
      protein (Tctex2b) within the Chlamydomonas flagellum. Tctex2b copurifies with
      inner arm I1 after both sucrose gradient centrifugation and anion exchange
      chromatography. Unlike the Tctex2 homologue within the outer dynein arm, analysis
      of a Tctex2b-null strain indicates that this protein is not essential for
      assembly of inner arm I1. However, a lack of Tctex2b results in an unstable
      dynein particle that disassembles after high salt extraction from the axoneme.
      Cells lacking Tctex2b swim more slowly than wild type and exhibit a reduced
      flagellar beat frequency. Furthermore, using a microtubule sliding assay we
      observed that dynein motor function is reduced in vitro. These data indicate that
      Tctex2b is required for the stability of inner dynein arm I1 and wild-type
      axonemal dynein function.

PMID- 15020586
TI  - Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a
      potential role for cardiac fibroblasts.
AB  - Erythropoietin has recently been shown to have effects beyond hematopoiesis such
      as prevention of neuronal and cardiac apoptosis secondary to ischemia. In this
      study, we evaluated the in vivo protective potential of erythropoietin in the
      reperfused rabbit heart following ventricular ischemia. We show that
      "preconditioning" with erythropoietin activates cell survival pathways in
      myocardial tissue in vivo and adult rabbit cardiac fibroblasts in vitro. These
      pathways, activated by erythropoietin in both whole hearts and cardiac
      fibroblasts, are also activated acutely by ischemia/reperfusion injury. Moreover,
      in vivo studies indicate that erythropoietin treatment either prior to or during
      ischemia significantly enhances cardiac function and recovery, including left
      ventricular contractility, following myocardial ischemia/reperfusion. Our data
      indicate that a contributing in vivo cellular mechanism of this protection is
      mitigation of myocardial cell apoptosis. This results in decreased infarct size
      as evidenced by area at risk studies following in vivo ischemia/reperfusion
      injury, translating into more viable myocardium and less ventricular dysfunction.
      Therefore, erythropoietin treatment may offer novel protection against ischemic
      heart disease and may act, at least in part, by direct action on cardiac
      fibroblasts and myocytes to alter survival and ventricular remodeling.

PMID- 15020588
TI  - Regulation of the cystic fibrosis transmembrane conductance regulator channel by
      beta-adrenergic agonists and vasoactive intestinal peptide in rat smooth muscle
      cells and its role in vasorelaxation.
AB  - The signaling events that regulate vascular tone include voltage-dependent Ca(2+)
      influx and the activities of various ionic channels; which molecular entities are
      involved and their role are still a matter of debate. Here we show expression of
      the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel in
      rat aortic smooth muscle cells. Immunoprecipitation and in vitro protein kinase A
      phosphorylation show the appearance of mature band C of CFTR. An
      immunohistochemistry study shows CFTR proteins in smooth muscles of aortic rings
      but not in skeletal muscles. Using the iodide efflux method, a combination of
      agonists and pharmacological agents was used to dissect the function of CFTR.
      Agonists of the cAMP pathway, the beta-adrenergic agonist isoproterenol, and the
      neuropeptide vasoactive intestinal peptide activate CFTR-dependent transport from
      cells maintained in a high but not low extracellular potassium-rich saline,
      suggesting that depolarization of smooth muscle is critical to CFTR activation.
      Smooth muscle CFTR possesses all of the pharmacological attributes of its
      epithelial homologues: stimulation by the CFTR pharmacological activators MPB-07
      (EC(50) = 158 microm) and MPB-91 (EC(50) = 20 microm) and inhibition by
      glibenclamide and diphenylamine-2-carboxylic acid but not by 5,11,17,23
      tetrasulfonato-25,26,27,28-tetramethoxy-calix[4]arene. Contraction measurements
      on isolated aortic rings were performed to study the contribution of CFTR to
      vascular tone. With aortic rings (without endothelium) preconstricted by high
      K(+) saline or by the alpha-adrenergic agonist norepinephrine, CFTR activators
      produced a concentration-dependent relaxation. These results identify for the
      first time the expression and function of CFTR in smooth muscle where it plays an
      unexpected but fundamental role in the autonomic and hormonal regulation of the
      vascular tone.

PMID- 15020589
TI  - The myosin cardiac loop participates functionally in the actomyosin interaction.
AB  - The motor protein myosin in association with actin transduces chemical free
      energy in ATP into work in the form of actin translation against an opposing
      force. Mediating the actomyosin interaction in myosin is an actin binding site
      distributed among several peptides on the myosin surface including surface loops
      contributing to affinity and actin regulation of myosin ATPase. A structured
      surface loop on beta-cardiac myosin, the cardiac or C-loop, was recently
      demonstrated to affect myosin ATPase and was indirectly implicated in the
      actomyosin interaction. The C-loop is a conserved feature of all myosin isoforms
      with crystal structures, suggesting that it is an essential part of the core
      energy transduction machinery. It is shown here that proteolytic digestion of the
      C-loop in beta-cardiac myosin eliminates actin-activated myosin ATPase and
      reduces actomyosin affinity in rigor more than 100-fold. Studies of C-loop
      function in smooth muscle myosin were also undertaken using site-directed
      mutagenesis. Mutagenesis of a single charged residue in the C-loop of smooth
      muscle myosin alters actomyosin affinity and doubles myosin in vitro motility and
      actin-activated ATPase velocities, thereby involving a charged region of the loop
      in the actomyosin interaction. It appears likely that the C-loop is an essential
      electrostatic binding site for actin involved in modulation of actomyosin
      affinity and regulation of actomyosin ATPase velocity.

PMID- 15020590
TI  - A single mutation in cytochrome P450 BM3 induces the conformational rearrangement
      seen upon substrate binding in the wild-type enzyme.
AB  - The multidomain fatty-acid hydroxylase flavocytochrome P450 BM3 has been studied
      as a paradigm model for eukaryotic microsomal P450 enzymes because of its
      homology to eukaryotic family 4 P450 enzymes and its use of a eukaryotic-like
      diflavin reductase redox partner. High-resolution crystal structures have led to
      the proposal that substrate-induced conformational changes lead to removal of
      water as the sixth ligand to the heme iron. Concomitant changes in the heme iron
      spin state and heme iron reduction potential help to trigger electron transfer
      from the reductase and to initiate catalysis. Surprisingly, the crystal structure
      of the substrate-free A264E heme domain mutant reveals the enzyme to be in the
      conformation observed for substrate-bound wild-type P450, but with the iron in
      the low-spin state. This provides strong evidence that the spin-state shift
      observed upon substrate binding in wild-type P450 BM3 not only is caused
      indirectly by structural changes in the protein, but is a direct consequence of
      the presence of the substrate itself, similar to what has been observed for
      P450cam. The crystal structure of the palmitoleate-bound A264E mutant reveals
      that substrate binding promotes heme ligation by Glu(264), with little other
      difference from the palmitoleate-bound wild-type structure observable. Despite
      having a protein-derived sixth heme ligand in the substrate-bound form, the A264E
      mutant is catalytically active, providing further indication for structural
      rearrangement of the active site upon reduction of the heme iron, including
      displacement of the glutamate ligand to allow binding of dioxygen.

PMID- 15020592
TI  - Engineering dimer-stabilizing mutations in the TATA-binding protein.
AB  - The TATA-binding protein (TBP) plays a central role in assembling eukaryotic
      transcription complexes and is subjected to extensive regulation including auto
      inhibition of its DNA binding activity through dimerization. Previously, we have
      shown that mutations that disrupt TBP dimers in vitro have three detectable
      phenotypes in vivo, including decreased steady-state levels of the mutants,
      transcriptional derepression, and toxicity toward cell growth. In an effort to
      more precisely define the multimeric structure of TBP in vivo, the
      crystallographic dimer structure was used to design mutations that might enhance
      dimer stability. These mutations were found to enhance dimer stability in vitro
      and significantly suppress in vivo phenotypes arising from a dimer-destabilizing
      mutation. Although it is conceivable that phenotypes associated with dimer
      destabilizing mutants could arise through defective interactions with other
      cellular factors, intragenic suppression of these phenotypes by mutations
      designed to stabilize dimers provides compelling evidence for a crystallographic
      dimer configuration in vivo.

PMID- 15020591
TI  - Flavocytochrome P450 BM3 mutant A264E undergoes substrate-dependent formation of
      a novel heme iron ligand set.
AB  - A conserved glutamate covalently attaches the heme to the protein backbone of
      eukaryotic CYP4 P450 enzymes. In the related Bacillus megaterium P450 BM3, the
      corresponding residue is Ala264. The A264E mutant was generated and characterized
      by kinetic and spectroscopic methods. A264E has an altered absorption spectrum
      compared with the wild-type enzyme (Soret maximum at approximately 420.5 nm).
      Fatty acid substrates produced an inhibitor-like spectral change, with the Soret
      band shifting to 426 nm. Optical titrations with long-chain fatty acids indicated
      higher affinity for A264E over the wild-type enzyme. The heme iron midpoint
      reduction potential in substrate-free A264E is more positive than that in wild
      type P450 BM3 and was not changed upon substrate binding. EPR, resonance Raman,
      and magnetic CD spectroscopies indicated that A264E remains in the low-spin state
      upon substrate binding, unlike wild-type P450 BM3. EPR spectroscopy showed two
      major species in substrate-free A264E. The first has normal Cys-aqua iron
      ligation. The second resembles formate-ligated P450cam. Saturation with fatty
      acid increased the population of the latter species, suggesting that substrate
      forces on the glutamate to promote a Cys-Glu ligand set, present in lower amounts
      in the substrate-free enzyme. A novel charge-transfer transition in the near
      infrared magnetic CD spectrum provides a spectroscopic signature characteristic
      of the new A264E heme iron ligation state. A264E retains oxygenase activity,
      despite glutamate coordination of the iron, indicating that structural
      rearrangements occur following heme iron reduction to allow dioxygen binding.
      Glutamate coordination of the heme iron is confirmed by structural studies of the
      A264E mutant (Joyce, M. G., Girvan, H. M., Munro, A. W., and Leys, D. (2004) J.
      Biol. Chem. 279, 23287-23293).

PMID- 15020593
TI  - Crystal structure of yeast allantoicase reveals a repeated jelly roll motif.
AB  - Allantoicase (EC 3.5.3.4) catalyzes the conversion of allantoate into
      ureidoglycolate and urea, one of the final steps in the degradation of purines to
      urea. The mechanism of most enzymes involved in this pathway, which has been
      known for a long time, is unknown. In this paper we describe the three
      dimensional crystal structure of the yeast allantoicase determined at a
      resolution of 2.6 A by single anomalous diffraction. This constitutes the first
      structure for an enzyme of this pathway. The structure reveals a repeated jelly
      roll beta-sheet motif, also present in proteins of unrelated biochemical
      function. Allantoicase has a hexameric arrangement in the crystal (dimer of
      trimers). Analysis of the protein sequence against the structural data reveals
      the presence of two totally conserved surface patches, one on each jelly roll
      motif. The hexameric packing concentrates these patches into conserved pockets
      that probably constitute the active site.

PMID- 15020594
TI  - Spontaneous DNA damage in Saccharomyces cerevisiae elicits phenotypic properties
      similar to cancer cells.
AB  - To determine the spectrum of effects elicited by specific levels of spontaneous
      DNA damage, a series of isogenic Saccharomyces cerevisiae strains defective in
      base excision repair (BER) and nucleotide excision repair (NER) were analyzed. In
      log phase of growth, when compared with wild type (WT) or NER-defective cells,
      BER-defective cells and BER/NER-defective cells possess elevated levels of
      unrepaired, spontaneous oxidative DNA damage. This system allowed establishment
      of a range of approximately 400 to 1400 Ntg1p-recognized DNA lesions per genome
      necessary to provoke profound biological changes similar in many respects to the
      phenotypic properties of cancer cells. The BER/NER-defective cells are
      genetically unstable, exhibiting mutator and hyper-recombinogenic phenotypes.
      They also exhibit aberrations in morphology, DNA content, and growth
      characteristics compared with WT, BER-defective, and NER-defective cells. The
      BER/NER-defective cells also possess increased levels of intracellular reactive
      oxygen species, activate the yeast checkpoint response pathway via Rad53p
      phosphorylation in stationary phase, and show profound changes in transcription
      patterns, a subset of which can be ascribed to responses resulting from
      unrepaired DNA damage. By establishing a relationship between specific levels of
      spontaneous DNA damage and the ensuing deleterious biological consequences, these
      yeast DNA excision repair-defective strains are an informative model for gauging
      the progressive biological consequences of spontaneous DNA damage accumulation
      and may have relevancy for delineating underlying mechanisms in tumorigenesis.

PMID- 15020595
TI  - Semiquantitative proteomic analysis of rat forebrain postsynaptic density
      fractions by mass spectrometry.
AB  - The postsynaptic density (PSD) of central excitatory synapses plays a key role in
      postsynaptic signal transduction and contains a high concentration of glutamate
      receptors and associated scaffold and signaling proteins. We report here a
      comprehensive analysis of purified PSD fractions by liquid chromatography coupled
      with tandem mass spectrometry (LC-MS/MS). We identified 374 different proteins
      that copurified with the PSD structure and discovered thirteen phosphorylated
      sites from eight proteins. These proteins were classified into numerous
      functional groups, implying that the signaling pathways in the PSD are complex
      and diverse. Furthermore, using quantitative mass spectrometry, we measured the
      molar concentration and relative stoichiometries of a number of glutamate
      receptor subunits and scaffold proteins in the postsynaptic density. Thus this
      proteomic study reveals crucial information about molecular abundance as well as
      molecular diversity in the PSD, and provides a basis for further studies on the
      molecular mechanisms of synaptic function and plasticity.

PMID- 15020597
TI  - Reactivity studies of the Fe(III) and Fe(II)NO forms of human neuroglobin reveal
      a potential role against oxidative stress.
AB  - Neuroglobin, recently discovered in the brain and in the retina of vertebrates,
      belongs to the class of hexacoordinate globins, in which the distal histidine
      coordinates the iron center in both the Fe(II) and Fe(III) forms. As for most
      other hexacoordinate globins, the physiological function of neuroglobin is still
      unclear, but seems to be related to neuronal survival following acute hypoxia. In
      this study, we have addressed the question whether human neuroglobin could act as
      a scavenger of toxic species, such as nitrogen monoxide, peroxynitrite, and
      hydrogen peroxide, which are generated at high levels in the brain during
      hypoxia; we have also investigated the kinetics of the reactions of its Fe(III)
      (metNGB) and Fe(II)NO forms with several reagents. Binding of cyanide or NO* to
      metNGB follows bi-exponential kinetics, showing the existence of two different
      protein conformations. In the presence of excess NO*, metNGB is converted into
      NGBFe(II)NO by reductive nitrosylation, in analogy to the reactions of NO* with
      metmyoglobin and methemoglobin. The Fe(II)NO form of neuroglobin is oxidized to
      metNGB by peroxynitrite and dioxygen, two reactions that also take place in
      hemoglobin, albeit at lower rates. In contrast to myoglobin and hemoglobin,
      metNGB unexpectedly does not generate the cytotoxic ferryl form of the protein
      upon addition of either peroxynitrite or hydrogen peroxide. Taken together, our
      data indicate that human neuroglobin may be an efficient scavenger of reactive
      oxidizing species and thus may play a role in the cellular defense against
      oxidative stress.

PMID- 15020596
TI  - Resveratrol is a peroxidase-mediated inactivator of COX-1 but not COX-2: a
      mechanistic approach to the design of COX-1 selective agents.
AB  - Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a phytoalexin found in grapes
      that has anti-inflammatory, cardiovascular protective, and cancer chemopreventive
      properties. It has been shown to target prostaglandin H(2) synthase (COX)-1 and
      COX-2, which catalyze the first committed step in the synthesis of prostaglandins
      via sequential cyclooxygenase and peroxidase reactions. Resveratrol discriminates
      between both COX isoforms. It is a potent inhibitor of both catalytic activities
      of COX-1, the desired drug target for the prevention of cardiovascular disease,
      but only a weak inhibitor of the peroxidase activity of COX-2, the isoform target
      for nonsteroidal anti-inflammatory drugs. We have investigated the unique
      inhibitory properties of resveratrol. We find that it is a potent peroxidase
      mediated mechanism-based inactivator of COX-1 only (k(inact) = 0.069 +/- 0.004 s(
      1), K(i(inact)) = 1.52 +/- 0.15 microm), with a calculated partition ratio of 22.
      Inactivation of COX-1 was time- and concentration-dependent, it had an absolute
      requirement for a peroxide substrate, and it was accompanied by a concomitant
      oxidation of resveratrol. Resveratrol-inactivated COX-1 was devoid of both the
      cyclooxygenase and peroxidase activities, neither of which could be restored upon
      gel-filtration chromatography. Inactivation of COX-1 by [(3)H]resveratrol was not
      accompanied by stable covalent modification as evident by both SDS-PAGE and
      reverse phase-high performance liquid chromatography analysis. Structure activity
      relationships on methoxy-resveratrol analogs showed that the m-hydroquinone
      moiety was essential for irreversible inactivation of COX-1. We propose that
      resveratrol inactivates COX-1 by a "hit-and-run" mechanism, and offers a basis
      for the design of selective COX-1 inactivators that work through a mechanism
      based event at the peroxidase active site.

PMID- 15020598
TI  - Selective cytoplasmic translocation of HuR and site-specific binding to the
      interleukin-2 mRNA are not sufficient for CD28-mediated stabilization of the
      mRNA.
AB  - The interleukin-2 mRNA is a labile transcript containing AU-rich elements that is
      transiently stabilized by CD28 receptor signaling. For a number of proto
      oncogenes and cytokines, the HuR protein has been shown to avidly bind the AU
      rich elements that confer instability upon their mRNAs. HuR was originally
      thought to participate in mRNA degradation but subsequent studies indicated that
      it actually functions to stabilize mRNA. Binding of HuR to the mouse interleukin
      2 mRNA has not been studied. We tested if HuR binds the interleukin-2 mRNA and
      whether such binding is related to CD28-mediated stabilization of the mRNA.
      First, we confirm that T cell receptor signaling, which is sufficient to induce
      interleukin-2 transcription, also triggers translocation of HuR from the nucleus
      to the cytoplasm. Interestingly, T cell receptor-triggered translocation is
      selective as heterogeneous nuclear ribonucleoprotein A1 does not shuttle under
      the same conditions. Engagement of both the T cell and CD28 receptors, which
      enhance interleukin-2 transcription and induce stabilization of the mRNA, did not
      further increase the level of cytoplasmic HuR. Using an in vitro binding assay,
      we demonstrate that HuR binds the interleukin-2 mRNA and localize binding to a
      sequence downstream of the single nonameric AU-rich element that is present in
      its 3'-untranslated region. However, we conclude that HuR binding to the
      interleukin-2 mRNA, both in vitro and in vivo, is not associated with alterations
      in mRNA stability.

PMID- 15020599
TI  - De novo ceramide accumulation due to inhibition of its conversion to complex
      sphingolipids in apoptotic photosensitized cells.
AB  - The oxidative stress induced by photodynamic therapy (PDT) with the
      photosensitizer phthalocyanine 4 is accompanied by increases in ceramide mass. To
      assess the regulation of de novo sphingolipid metabolism during PDT-induced
      apoptosis, Jurkat human T lymphoma and Chinese hamster ovary cells were labeled
      with [14C]serine, a substrate of serine palmitoyltransferase (SPT), the enzyme
      catalyzing the initial step in the sphingolipid biosynthesis. A substantial
      elevation in [14C]ceramide with a concomitant decrease in [14C]sphingomyelin was
      detected. The labeling of [14C]ceramide was completely abrogated by the SPT
      inhibitor ISP-1. In addition, ISP-1 partly suppressed PDT-induced apoptosis.
      Pulse-chase experiments showed that the contribution of sphingomyelin degradation
      to PDT-initiated increase in de novo ceramide was absent or minor. PDT had no
      effect on either mRNA amounts of the SPT subunits LCB1 and LCB2, LCB1 protein
      expression, or SPT activity in Jurkat cells. Moreover in Chinese hamster ovary
      cells LCB1 protein underwent substantial photodestruction, and SPT activity was
      profoundly inhibited after treatment. We next examined whether PDT affects
      conversion of ceramide to complex sphingolipids. Sphingomyelin synthase, as well
      as glucosylceramide synthase, was inactivated by PDT in both cell lines in a dose
      dependent manner. These results are the first to show that in the absence of SPT
      up-regulation PDT induces accumulation of de novo ceramide by inhibiting its
      conversion to complex sphingolipids.

PMID- 15020600
TI  - Alpha-helix formation is required for high affinity binding of human
      apolipoprotein A-I to lipids.
AB  - Apolipoprotein (apo) A-I is thought to undergo a conformational change during
      lipid association that results in the transition of random coil to alpha-helix.
      Using a series of deletion mutants lacking different regions along the molecule,
      we examined the contribution of alpha-helix formation in apoA-I to the binding to
      egg phosphatidylcholine (PC) small unilamellar vesicles (SUV). Binding isotherms
      determined by gel filtration showed that apoA-I binds to SUV with high affinity
      and deletions in the C-terminal region markedly decrease the affinity. Circular
      dichroism measurements demonstrated that binding to SUV led to an increase in
      alpha-helix content, but the helix content was somewhat less than in
      reconstituted discoidal PC.apoA-I complexes for all apoA-I variants, suggesting
      that the helical structure of apoA-I on SUV is different from that in discs.
      Isothermal titration calorimetry showed that the binding of apoA-I to SUV is
      accompanied by a large exothermic heat and deletions in the C-terminal regions
      greatly decrease the heat. Analysis of the rate of release of heat on binding, as
      well as the kinetics of quenching of tryptophan fluorescence by brominated PC,
      indicated that the opening of the N-terminal helix bundle is a rate-limiting step
      in apoA-I binding to the SUV surface. Significantly, the correlation of
      thermodynamic parameters of binding with the increase in the number of helical
      residues revealed that the contribution of alpha-helix formation upon lipid
      binding to the enthalpy and the free energy of the binding of apoA-I is -1.1 and 
      0.04 kcal/mol per residue, respectively. These results indicate that alpha-helix
      formation, especially in the C-terminal regions, provides the energetic source
      for high affinity binding of apoA-I to lipids.

PMID- 15020601
TI  - Cryopyrin-induced interleukin 1beta secretion in monocytic cells: enhanced
      activity of disease-associated mutants and requirement for ASC.
AB  - Several autoinflammatory disorders are associated with missense mutations within
      the nucleotide-binding oligomerization domain of cryopyrin. The mechanism by
      which cryopyrin mutations cause inflammatory disease remains elusive. To
      understand the molecular bases of these diseases, we generated constructs to
      express three common cryopyrin disease-associated mutations, R260W, D303N, and
      E637G, and compared their activity with that of the wild-type protein. All
      cryopyrin mutant proteins tested were found to induce potent NF-kappaB activity
      when compared with the wild-type protein. This activation was dependent on the
      expression of ASC, an adaptor protein previously suggested to mediate cryopyrin
      signaling. When the disease-associated mutants were expressed in monocytic THP-1
      cells (which express endogenous ASC), each induced spontaneous IL-1beta
      secretion, whereas wild-type protein did not. In the absence of stimuli, wild
      type cryopyrin was unable to bind to ASC, whereas the three mutants
      coimmunoprecipitated with ASC, suggesting a mechanism involved in the
      constitutive activation of mutant proteins. The induction of cryopyrin activity
      by enforced oligomerization in THP-1 cells resulted in ASC binding and the
      secretion of IL-1beta, an effect that was abolished by the inhibition of ASC
      expression with small interfering RNAs. Thus, cryopyrin-mediated IL-1beta
      secretion requires ASC in monocytic cells. Further, these results indicate that
      cryopyrin disease-associated mutants are constitutively active and able to induce
      NF-kappaB activation and IL-1beta secretion at least in part by an increased
      ability to interact with ASC.

PMID- 15020602
TI  - A cellular UDP-glucose deficiency causes overexpression of glucose/oxygen
      regulated proteins independent of the endoplasmic reticulum stress elements.
AB  - A low level of UDP-Glc occurs in cells exposed to hypoxia or glucose starvation.
      This work reveals that a 65% reduction in the cellular UDP-Glc level causes up
      regulation of the mitochondrial chaperone GRP75 and the endoplasmic reticulum
      (ER) resident chaperones GRP58, ERp72, GRP78, GRP94, GRP170, and calreticulin.
      Conditions that cause misfolding of proteins within the ER activate the
      transcription factors ATF6alpha/beta and induce translation of the transcription
      factors XBP-1/TREB5 and ATF4/CREB2. These transcription factors induce the
      overexpression of ER chaperones and CHOP/GADD153. However, the 65% decrease in
      the cellular UDP-Glc level does not cause activation of ATF6alpha, splicing of
      XBP-1/TREB5, induction of ATF4/CREB2, or expression of CHOP/GADD153. The activity
      of the promoters of the ER chaperones is increased in UDP-Glc-deficient cells,
      but the activity of the CHOP/GADD153 promoter is not affected, in comparison with
      their respective activities in cells having compensated for the UDP-Glc
      deficiency. The results demonstrate that the unfolded protein response remains
      functionally intact in cells with a 65% decrease in the cellular UDP-Glc level
      and provide evidence that this decrease is a stress signal in mammalian cells,
      which triggers the coordinate overexpression of mitochondrial and ER chaperones,
      independently of the ER stress elements.

PMID- 15020603
TI  - Psychological outcomes in long-term survivors of childhood brain cancer: a report
      from the childhood cancer survivor study.
AB  - PURPOSE: To evaluate and compare psychological outcomes in long-term survivors of
      pediatric brain cancer and siblings of childhood cancer survivors, and to
      identify significant correlates of psychological distress. METHODS: One thousand
      one hundred one adult survivors of childhood brain cancer and 2,817 siblings
      completed a long-term follow-up questionnaire allowing assessment of symptoms
      associated with depression, somatization, and anxiety, as well as demographic,
      health, and medical information. RESULTS: A large majority of siblings and
      survivors report few, if any, symptoms of psychological distress. The prevalence
      of distress approximating clinically significant levels for both survivors (11%)
      and siblings (5%) reflects rates found in the general population. Yet when
      accounting for significant sociodemographic, socioeconomic, and health-status
      variables, survivors of childhood brain cancer, in the aggregate, appear to
      report significantly higher global distress and depression scores than do
      siblings. As in the general population, higher levels of distress among survivors
      and siblings were associated with female sex, low household income, lower
      educational attainment, being unmarried, not being employed in the past 12
      months, and poor physical health status. No diagnostic or treatment-related
      variables were directly and significantly associated with increases in distress
      symptoms for survivors of childhood brain cancer. CONCLUSION: Cancer treatment
      does not appear to contribute directly to increased psychological distress.
      Instead, distress appears to be associated with diminished social functioning
      that may be related to cancer type or treatment. Implementation and evaluation of
      supportive interventions that enhance survivors' social and vocational skills
      should be considered.

PMID- 15020604
TI  - Antiandrogen withdrawal alone or in combination with ketoconazole in androgen
      independent prostate cancer patients: a phase III trial (CALGB 9583).
AB  - PURPOSE: Antiandrogen withdrawal (AAWD) results in a prostate-specific antigen
      (PSA) response (decline in PSA level of > or =50%) in 15% to 30% of androgen
      independent prostate cancer (AiPCa) patients. Thereafter, adrenal androgen
      ablation with agents such as ketoconazole (K) is commonly utilized. The
      therapeutic effect of AAWD alone was compared with simultaneous AAWD and K
      therapy. PATIENTS AND METHODS: AiPCa patients were randomized to undergo AAWD
      alone (n=132), or together with K (400 mg orally [p.o.] tid) and hydrocortisone
      (30 mg p.o. each morning, 10 mg p.o. each evening; n=128). Patients who developed
      progressive disease after AAWD alone were eligible for deferred treatment with K.
      RESULTS: Eleven percent of patients undergoing AAWD alone had a PSA response,
      compared to 27% of patients who underwent AAWD and simultaneous K (P=.0002).
      Objective responses were observed in 2% of patients treated with AAWD alone
      compared to 20% in patients treated with AAWD/K (P=.02). There was no difference
      in survival. PSA and objective responses were observed in 32% and 7%,
      respectively, of patients receiving deferred K, and were more common in patients
      with prior AAWD response. Treatment with K was well tolerated, and resulted in a
      decline in adrenal androgen levels, which rose at the time of disease
      progression. CONCLUSION: K has modest activity in AiPCa patients, while AAWD
      alone has minimal activity. Adrenal androgen levels fall with treatment with K
      and then climb at the time of progression, suggesting that progressive disease
      while on K may be due to tachyphylaxis to the adrenolytic properties of K.

PMID- 15020605
TI  - 2-18fluoro-deoxy-D-glucose positron emission tomography is a reliable predictor
      for viable tumor in postchemotherapy seminoma: an update of the prospective
      multicentric SEMPET trial.
AB  - PURPOSE: To define the clinical value of 2-18fluoro-deoxy-D-glucose positron
      emission tomography (FDG PET) as a predictor for viable residual tumor in
      postchemotherapy seminoma residuals in a prospective multicentric trial. PATIENTS
      AND METHODS: FDG PET studies in patients with metastatic pure seminoma who had
      radiographically defined postchemotherapy residual masses were correlated with
      either the histology of the resected lesion or the clinical outcome documented by
      computer tomography (CT), tumor markers, and/or physical examination during
      follow-up. The size of the residual lesions on CT, either >3 cm or < or =3 cm,
      was correlated with the presence or absence of viable residual tumor. RESULTS:
      Fifty-six FDG PET scans of 51 patients were assessable. All 19 cases with
      residual lesions >3 cm and 35 (95%) of 37 with residual lesions < or =3 cm were
      correctly predicted by FDG PET. The specificity, sensitivity, positive predictive
      value, and negative predictive value of FDG PET were 100% (95% CI, 92% to 100%),
      80% (95% CI, 44% to 95%), 100%, and 96%, respectively, versus 74% (95% CI, 58% to
      85%), 70% (95% CI, 34% to 90%), 37%, and 92%, respectively, for CT discrimination
      of the residual tumor by size (>3 cm/< or =3 cm). CONCLUSION: This investigation
      confirms that FDG PET is the best predictor of viable residual tumor in
      postchemotherapy seminoma residuals and should be used as a standard tool for
      clinical decision making in this patient group.

PMID- 15020606
TI  - Mucinous epithelial ovarian cancer: a separate entity requiring specific
      treatment.
AB  - PURPOSE: Invasive mucinous carcinoma of the ovary (mucinous epithelial ovarian
      cancer [mEOC]) is a histologic subgroup of epithelial ovarian cancer (EOC).
      Chemotherapy for mEOC is chosen according to guidelines established for EOC. The
      purpose of this study is to determine whether this is appropriate. PATIENTS AND
      METHODS: Women with advanced mEOC (International Federation of Gynecology and
      Obstetrics stage III or IV) who underwent first-line platinum-based chemotherapy
      were compared with women with other histologic subtypes of EOC in a case
      controlled study. RESULTS: Eighty-one patients (27 cases, 54 controls) treated
      with platinum-based regimens were analyzed. The response rates for cases and
      controls were 26.3% (95% CI, 9.2% to 51.2%) and 64.9% (95% CI, 47.5% to 79.8%),
      respectively (P=.01). The odds ratio for complete or partial response to
      chemotherapy for mEOC was 0.19 (95% CI, 0.06 to 0.66; P=.009) compared with other
      histologic subtypes of EOC. Median progression-free survival was 5.7 months (95%
      CI, 1.9 to 9.6 months) versus 14.1 months (95% CI, 12.0 to 16.2 months; P<.001)
      and overall survival was 12.0 months (95% CI, 8.0 to 15.6 months) versus 36.7
      months (95% CI, 25.2 to 48.2 months; P<.001) for cases and controls,
      respectively. The hazard ratio for progression and death was 2.94 (95% CI, 1.71
      to 5.07; P<.001) and 3.08 (95% CI, 1.69 to 5.6; P<.001), respectively, for mEOC
      patients as compared with controls. CONCLUSION: Patients with advanced mEOC have
      a poorer response to platinum-based first-line chemotherapy compared with
      patients with other histologic subtypes of EOC, and their survival is worse.
      Specific alternative therapeutic approaches should be sought for this group of
      patients, perhaps involving fluorouracil-based chemotherapy.

PMID- 15020607
TI  - Safety of treatment of metastatic breast cancer with trastuzumab beyond disease
      progression.
AB  - PURPOSE: In a pivotal phase III trial, the addition of trastuzumab to
      chemotherapy significantly improved response rate, time to disease progression,
      and overall survival in women with HER2 overexpressing metastatic breast cancer.
      We conducted an extension study to this trial to obtain additional safety
      information and to provide trastuzumab following disease progression. PATIENTS
      AND METHODS: A total of 247 patients with documented disease progression received
      weekly intravenous trastuzumab in the extension study. Concurrent therapies were
      administered at the discretion of the treating physician. Patient groups were
      based on initial study treatment: chemotherapy alone (group 1, n=154) or
      chemotherapy plus trastuzumab (group 2, n=93). RESULTS: Sixty-eight percent of
      group 1 and 76% of group 2 received chemotherapy plus trastuzumab in the
      extension trial; the remainder received trastuzumab alone or combined with
      palliative radiotherapy or hormonal therapy. Seventy-six percent of group 1 and
      55% of group 2 experienced at least one adverse event, similar to effects
      observed in the pivotal trial. Symptomatic or asymptomatic cardiac dysfunction
      occurred in 9% of group 1 and 2% of group 2 patients. Overall objective response
      rates were 14% in group 1 and 11% in group 2; median durations of response
      exceeded 6 months in both groups. CONCLUSION: Our results suggest that prolonged
      use of trastuzumab therapy is safe and well tolerated. Longer durations of
      therapy did not appear to increase the risk of cardiac dysfunction. Patients
      progressing on trastuzumab-containing therapy demonstrate some response to a
      second trastuzumab-containing regimen. The independent contribution of
      trastuzumab in this setting merits further study.

PMID- 15020608
TI  - Docetaxel combined with trastuzumab is an active regimen in HER-2 3+
      overexpressing and fluorescent in situ hybridization-positive metastatic breast
      cancer: a multi-institutional phase II trial.
AB  - PURPOSE: To determine the efficacy and safety of weekly docetaxel and trastuzumab
      as first- or second-line therapy in women with HER-2-overexpressing metastatic
      breast cancer and to correlate the efficacy of trastuzumab with HER-2 status as
      determined by immunohistochemistry assay and fluorescent in situ hybridization
      (FISH). PATIENTS AND METHODS: Twenty-six women with HER-2-positive (HercepTest
      [Dako Corp, Carpenteria, CA]2 to 3+) metastatic breast cancer were enrolled onto
      this study of trastuzumab (4 mg/kg load; 2 mg/kg/wk administered intravenously)
      and docetaxel (35 mg/m2/wk for 6 weeks). RESULTS: Using an intent-to-treat
      analysis, the overall response rate was 50% (13 of 26 patients). Eight patients
      (31%) had a period of stable disease posttherapy. Among HER-2 3+ patients, the
      overall response rate was 63% (12 of 19 patients) compared with a 14% response
      rate (one of seven patients) for HER-2 2+ patients (P=.07). Patients with FISH
      positive tumors experienced an overall response rate of 64%. Median time to
      progression was 12.4 months for the entire cohort (HER-2 3+ tumors, 12.3 months;
      HER-2 2+ lesions, 9.5 months) and median survival was 22.1 months. All HER-2 3+
      patients were FISH-positive; the only HER-2 2+ patient responding to treatment
      was also FISH-positive. Grade 4 toxicities occurred in four patients; most
      toxicities were mild. CONCLUSION: Trastuzumab plus docetaxel is an active and
      well-tolerated regimen in women with HER-2 3+ overexpressing or FISH-positive
      metastatic breast cancer.

PMID- 15020610
TI  - Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid
      leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): results from CALGB 8461.
AB  - PURPOSE: To study the impact of repetitive (three to four courses) versus a
      single course of high-dose cytarabine (HDAC) consolidation therapy on outcome of
      patients with acute myeloid leukemia (AML) and inv(16)(p13q22) or
      t(16;16)(p13;q22). PATIENTS AND METHODS: We examined the cumulative incidence of
      relapse (CIR), relapse-free survival (RFS), and overall survival (OS) for 48
      adults younger than 60 years with inv(16)/t(16;16) who had attained a complete
      remission on one of four consecutive clinical trials and were assigned to receive
      HDAC consolidation therapy. Twenty-eight patients were assigned to either three
      or four courses of HDAC, and 20 patients were assigned to one course of HDAC
      followed by alternative intensive consolidation therapy. RESULTS: Pretreatment
      features were similar for the two groups. The CIR was significantly decreased in
      patients assigned to receive three to four cycles of HDAC compared with patients
      assigned to one course (P=.03; 5-year CIR, 43% v 70%, respectively). The
      difference in RFS also approached statistical significance (P=.06). In a
      multivariable analysis that adjusted for potential confounding covariates, only
      treatment assignment (three to four cycles of HDAC) predicted for superior RFS
      (P=.02). The OS of both groups was similar (P=.93; 5-year OS, 75% for the three
      to four cycles of HDAC group v 70% for the one cycle of HDAC group), reflecting a
      high success rate with stem-cell transplantation salvage treatment administered
      among patients in both treatment groups. CONCLUSION: We conclude that, in AML
      patients with inv(16)/t(16;16), repetitive HDAC therapy decreases the likelihood
      of relapse compared with consolidation regimens including less HDAC.

PMID- 15020609
TI  - Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients
      with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic
      syndrome: a phase III trial (E2995).
AB  - PURPOSE: To determine whether adding the multidrug resistance gene-1 (MDR-1)
      modulator valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) to
      chemotherapy provided clinical benefit to patients with poor-risk acute myeloid
      leukemia (AML) and high-risk myelodysplastic syndrome (MDS). PATIENTS AND
      METHODS: A phase III randomized study was performed using valspodar plus
      mitoxantrone, etoposide, and cytarabine (PSC-MEC; n=66) versus MEC (n=63) to
      treat patients with relapsed or refractory AML and high-risk MDS. RESULTS: For
      the PSC-MEC versus MEC arms, complete response (CR) was achieved in 17% versus
      25% of patients, respectively (P=not significant). For patients who had not
      received prior intensive chemotherapy (ie, with secondary AML or high-risk MDS),
      the CR rate was increased--35% versus 15% for the remaining patients (P=.018); CR
      rates did not differ between treatment arms. The median disease-free survival in
      those achieving CR was similar in the two arms (10 versus 9.3 months) as was the
      patients' overall survival (4.6 versus 5.4 months). The CR rates in MDR+ (69% of
      patients) versus MDR- patients were similar for those receiving either
      chemotherapy regimen (16% versus 24%). The CR rate for unfavorable cytogenetic
      patients (45% of patients) was 13% compared to the remainder, 28% (P=.09).
      Population pharmacokinetic analysis demonstrated that the clearances of
      mitoxantrone and etoposide were decreased by 59% and 50%, respectively,
      supporting the empiric dose reductions in the PSC-MEC arm designed in
      anticipation of drug interactions between valspodar and the chemotherapeutic
      agents. CONCLUSION: CR rates and overall survival were not improved by using PSC
      MEC compared to MEC chemotherapy alone in patients with poor-risk AML or high
      risk MDS.

PMID- 15020611
TI  - Rapid mobilization of CD34+ cells following administration of the CXCR4
      antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma.
AB  - PURPOSE: Interactions between the chemokine receptor CXCR4 and its ligand stromal
      derived factor-1 regulate hematopoietic stem-cell trafficking. AMD3100 is a CXCR4
      antagonist that induces rapid mobilization of CD34+ cells in healthy volunteers.
      We performed a phase I study assessing the safety and clinical effects of AMD3100
      in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). PATIENTS
      AND METHODS: Thirteen patients (MM, n=7; NHL, n=6) received AMD3100 at a dose of
      either 160 microg/kg (n=6) or 240 microg/kg (n=7). WBC and peripheral blood (PB)
      CD34+ cell counts were analyzed at 4 and 6 hours following injection. RESULTS:
      AMD3100 caused a rapid and statistically significant increase in the total WBC
      and PB CD34+ counts at both 4 and 6 hours following a single injection. The
      absolute CD34+ cell count increased from a baseline of 2.6 +/- 0.7/microL (mean
      +/- SE) to 15.6 +/- 3.9/microL and 16.2 +/- 4.3/microL at 4 hours (P=.002) and 6
      hours after injection (P =.003), respectively. The absolute CD34+ cell counts
      observed at 4 and 6 hours following AMD3100 were higher in the 240 microg/kg
      group (19.3 +/- 6.9/microL and 20.4 +/- 7.6/microL, respectively) compared with
      the 160 microg/kg group (11.3 +/- 2.7/microL and 11.3 +/- 2.5/microL,
      respectively). The drug was well tolerated and only grade 1 toxicities were
      encountered. CONCLUSION: AMD3100 appears to be a safe and effective agent for the
      rapid mobilization of CD34+ cells in patients who have received prior
      chemotherapy. Further studies in combination with granulocyte colony-stimulating
      factor in patients with lymphoid malignancies are warranted.

PMID- 15020612
TI  - Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to
      gefitinib in advanced non-small-cell lung cancer.
AB  - PURPOSE: Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine
      kinase, induces radiographic regressions and symptomatic improvement in patients
      with non-small-cell lung cancer (NSCLC). Phase II trials suggested female sex and
      adenocarcinoma were associated with response. We undertook this analysis to
      identify additional clinical and pathologic features associated with sensitivity
      to gefitinib. PATIENTS AND METHODS: We reviewed medical records, pathologic
      material, and imaging studies of all 139 NSCLC patients treated on one of three
      consecutive studies of gefitinib monotherapy performed at our institution. We
      identified patients experiencing a major objective response and compared their
      clinical and pathologic features with the others. Univariate and multivariable
      analyses were performed on potential predictive features associated with
      sensitivity to gefitinib. RESULTS: Of 139 patients, 21 (15%; 95% CI, 9% to 21%),
      experienced a partial radiographic response. Variables identified as significant
      in univariate analysis included adenocarcinoma versus other NSCLC (19% v 0%;
      P=.004), adenocarcinoma with bronchioloalveolar features versus other
      adenocarcinomas (38% v 14%; P<.001), never smoker status versus former/current
      (36% v 8%; P<.001), and Karnofsky performance status > or =80% versus < or =70%
      (22% v 8%; P=.03). Multivariable analysis revealed the presence of adenocarcinoma
      with any bronchioloalveolar features (P=.004) and being a never smoker (P=.006)
      were independent predictors of response. CONCLUSION: Our data suggest that
      individuals in whom gefitinib is efficacious are more likely to have
      adenocarcinomas of the bronchioloalveolar subtype and to be never smokers. These
      observations may provide clues to mechanisms determining sensitivity to this
      agent and suggest that NSCLC has a different biology in patients who never smoked
      and those with bronchioloalveolar carcinoma.

PMID- 15020613
TI  - Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with
      carboplatin and etoposide in patients with small-cell lung cancer.
AB  - PURPOSE: Bcl-2 is expressed in the majority of cases of small cell lung cancer
      (SCLC) and may contribute to chemotherapeutic resistance. Bcl-2 suppression by
      G3139 (oblimersen sodium), a phosphorothioate oligonucleotide complementary to
      the bcl-2 mRNA, has the potential to enhance the antitumor efficacy of standard
      cytotoxic chemotherapy. A dose-finding study was performed evaluating the
      combination of G3139, carboplatin, and etoposide in patients with previously
      untreated extensive stage SCLC. PATIENTS AND METHODS: Sixteen patients were
      treated in three consecutive cohorts. Cohort 1 (n=5) received G3139 5 mg/kg/d on
      days 1 to 8 of a 21 day cycle, with carboplatin area under the curve (AUC)=6 on
      day 6, and etoposide 80 mg/m2/d on days 6 to 8. In cohort 2 (n=4), carboplatin
      dose was reduced to AUC=5. In cohort 3 (n=7), G3139 dose was escalated to 7
      mg/kg/d. G3139 plasma concentrations and Bcl-2 protein levels in peripheral blood
      mononuclear cells were evaluated. RESULTS: Two of three assessable patients in
      cohort 1 experienced cycle 1 dose-limiting toxicity (grade 4 neutropenia). No
      cycle 1 dose-limited toxicity was observed in cohorts 2 or 3. Of 14 patients
      assessable for response, partial response was documented in 12 patients (86%),
      and stable disease in two. Median time to progression was 5.9 months. Carboplatin
      and etoposide administration did not appear to alter G3139 pharmacokinetics. No
      evidence of Bcl-2 suppression in peripheral blood mononuclear cells was observed.
      CONCLUSION: The combination of G3139, carboplatin, and etoposide is well
      tolerated and results in an encouraging response rate and time to progression in
      patients with extensive stage SCLC.

PMID- 15020614
TI  - Fotemustine compared with dacarbazine in patients with disseminated malignant
      melanoma: a phase III study.
AB  - PURPOSE: To compare fotemustine and dacarbazine (DTIC) in terms of overall
      response rate (ORR) as primary end-point and overall survival, duration of
      responses, time to progression, time to occurrence of brain metastases (BM), and
      to assess safety and quality of life in patients with disseminated cutaneous
      melanoma. PATIENTS AND METHODS: Patients received either intravenous fotemustine
      100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4
      weeks (two cycles). Nonprogressive patients received a maintenance treatment
      every 4 weeks (fotemustine 100 mg/m2 or DTIC 250 mg/m2 for 5 days). RESULTS: Two
      hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms.
      The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent
      to-treat population (n=229; 15.2% v 6.8%; P=.043) and in full analysis set
      (n=221) (15.5% v 7.2%; P=.053). Similar median durations of responses (5.8 months
      with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9
      months, respectively) were observed. In patients without BM at inclusion, the
      median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC
      (P=.059). Median survival was 7.3 months with fotemustine versus 5.6 months with
      DTIC (P=.067). The main toxicity was grade 3 to 4 neutropenia (51% with
      fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No
      significant difference was noted for quality of life between arms. CONCLUSION:
      ORR was higher in the fotemustine arm compared to the DTIC arm in first-line
      treatment of disseminated melanoma. A trend in favor of fotemustine in terms of
      overall survival and time to BM was evidenced.

PMID- 15020615
TI  - Evaluation of diagnostic assessment units in oncology: a systematic review.
AB  - PURPOSE: This systematic review was undertaken to identify clinical and economic
      evaluations of diagnostic assessment units for cancer; summarize measures used to
      evaluate such programs; and discuss the strengths and weaknesses of these
      evaluations. METHODS: The review was conducted to identify randomized controlled
      trials, case control studies, and prospective or retrospective cohort studies
      examining the outcomes of diagnostic centers for patients with a presumptive
      diagnosis of breast, colorectal, lung, head and neck, or prostate cancer. Data on
      methodology and study results were tabulated. RESULTS: Twenty articles were
      eligible for review. Eleven studies examined outcomes associated with breast
      cancer assessment units: six with head and neck assessment units and three with
      colorectal assessment units. No studies were found that examined one-stop
      diagnostic assessment centers for lung cancer or prostate cancer. Seventeen
      studies were case series, one was a case-control study, and two were randomized
      controlled trials. No thorough economic analyses have been undertaken. There were
      no studies that based their assessment on measures suggested by a conceptual
      framework or validated model of diagnostic care. Few studies explicitly based
      their investigations on established quality indicators or clinical practice
      guideline recommendations. Diagnostic assessment centers appear to decrease the
      time to arrive at a diagnosis, which in turn appears to decrease patient anxiety
      and increase patient satisfaction. CONCLUSION: A comprehensive understanding of
      the benefit of diagnostic assessment centers can only be determined if such
      services are developed for a variety of disease sites and more rigorous
      evaluations are carried out to assess their benefit.

PMID- 15020616
TI  - Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking
      tolerance.
AB  - The development of malignant disease might be seen as a failure of immune
      surveillance. However, not all tumors are naturally immunogenic, and even among
      those that are immunogenic, the uncontrolled rapid growth of a tumor may
      sometimes out-run a robust immune response. Nevertheless, recent evidence
      suggests that mechanisms of tolerance that normally exist to prevent autoimmune
      disease may also preclude the development of an adequate antitumor response and
      that tumors themselves have the ability to thwart the development of effective
      immune responses against their antigens. A major challenge has been to develop
      approaches to breaking this tolerance in tumor-bearing hosts, and recent advances
      in our understanding of antigen presentation and tolerance have led to some
      promising strategies. An alternative approach is to use T cells from nontumor
      bearing, allogeneic hosts in the form of lymphocyte infusions, with or without
      hematopoietic cell transplantation. Immunotherapy may occur in this setting via
      the response of nontolerant, tumor antigen-specific T cells from nontumor-bearing
      hosts or via the powerful destructive effect of an alloresponse directed against
      antigens shared by malignant cells in the recipient. Approaches to exploiting
      this beneficial effect without the deleterious consequence of graft-versus-host
      disease in allogeneic hematopoietic cell recipients are discussed.

PMID- 15020617
TI  - Case 1. Right ventricular outflow obstruction caused by metastatic hepatocellular
      carcinoma.

PMID- 15020618
TI  - Case 2. Intracardiac metastasis from a Merkel cell carcinoma.

PMID- 15020619
TI  - Case 3. Grey-Turner's sign as the first indication of a ruptured hepatocellular
      carcinoma.

PMID- 15020620
TI  - Ototoxicity in patients with dose-intensive therapy for cisplatin-resistant germ
      cell tumors.

PMID- 15020622
TI  - High-risk lesions in high-risk women: a high-risk formalin-based biology!

PMID- 15020624
TI  - Doomed trials for promising adenoviruses: a rationale for success.

PMID- 15020626
TI  - Hormonal treatment duration in elderly patients: an open question.

PMID- 15020628
TI  - Is withdrawal of consolidation radiotherapy an evidence-based strategy in primary
      central nervous system lymphomas?

PMID- 15020631
TI  - Molecular cloning of low-temperature-inducible ribosomal proteins from soybean.
AB  - Three ribosomal protein genes induced by low-temperature treatment were isolated
      from soybean. GmRPS13 (742 bp) encodes a 17.1 kDa protein which has 95% identity
      with the 40S ribosomal protein S13 of Panax ginseng (AB043974). GmRPS6 (925 bp)
      encodes a 28.1 kDa protein which has 94% identity with the 40S ribosomal protein
      S6 of Asparagus officinalis (AJ277533). GmRPL37 (494 bp) encodes a 10.7 kDa
      protein which has 85% identity with the 60S ribosomal protein L37 of Arabidopsis
      thaliana (AF370216). The expression of these ribosomal protein genes started to
      increase 3 d after low-temperature treatment, whereas the cold-stress protein
      src1 was highly induced from the first day. Such late response of these ribosomal
      protein genes may be due to secondary signals during cold adaptation. The
      induction of ribosomal protein genes might enhance the translation process or
      help proper ribosome functioning under low-temperature conditions.

PMID- 15020632
TI  - Ethanol synthesis and aerobic respiration in the laboratory by leader segments of
      Douglas-fir seedlings from winter and spring.
AB  - Stem segments from terminal leaders of Douglas-fir, Pseudotsuga menziesii (Mirb.)
      Franco, seedlings were sampled in mid-December when cambial cells were dormant.
      The residual, debudded leaders were resampled again in early May when the cambium
      was metabolically active. May stems had higher constitutive ethanol
      concentrations than December stems. This was not the result of cambial hypoxia
      generated by rapid spring respiration rates, because when aerobic respiration was
      stimulated by incubating the stems in air at 30 degrees C ethanol production was
      induced in December, but not in May. Rapid respiration rates at 30 degrees C may
      have depleted O(2) supplies and induced ethanol production in December stems
      because dormant, thick-walled cambial cells may be less permeable to CO(2) and
      O(2), compared with metabolically active, thin-walled cambial cells in May.
      December stem segments incubated in a N(2) atmosphere at 30 degrees C synthesized
      1.8 times more ethanol than segments from May, most likely because spring growth
      had reduced the soluble sugars available for fermentation. CO(2) efflux from May
      stems (after 5.5 h of incubation at 30 degrees C) was equal to December stems per
      unit volume, but greater than December stems per unit surface area. N(2)-induced
      ethanol concentrations were positively related with CO(2) efflux per unit volume,
      indicating that rapidly respiring leaders can maintain rapid fermentation rates,
      provided soluble sugars are readily available. N(2)-induced ethanol and CO(2)
      efflux per unit volume declined with increasing leader diameter in both seasons,
      whereas there were no relationships between CO(2) efflux per unit surface area
      and diameter. Cambium physiology and phenology influence the induction of
      fermentation and concentrations of ethanol produced in terminal leaders of
      Douglas-fir, and probably other conifers as well. This needs to be considered
      when comparing fermentation among species, or comparing individuals from
      different seasons, or disparate ages within a species.

PMID- 15020633
TI  - Cloning of a cDNA encoding an ETR2-like protein (Os-ERL1) from deep water rice
      (Oryza sativa L.) and increase in its mRNA level by submergence, ethylene, and
      gibberellin treatments.
AB  - A cDNA from deep water rice treated with ethylene, encoding an ethylene receptor
      homologous to Arabidopsis thaliana ETR2 and EIN4, was isolated using differential
      display and RACE techniques. The cDNA (2880 bp), corresponding to the Os-ERL1
      gene (Oryza sativa ETHYLENE RESPONSE 2 like 1; GenBank accession number
      AB107219), contained an open reading frame of 2289 bp coding for 763 amino acids.
      The protein Os-ERL1 has 50% and 52% similarity to Arabidopsis ETR2 and EIN4,
      respectively. The Os-ERL1 gene was up-regulated by flooding, and by treatment
      with ethylene and gibberellin. These results suggest that deep water rice
      responds to flooding by increasing the number of its ethylene receptors.

PMID- 15020634
TI  - Surface growth at the reproductive shoot apex of Arabidopsis thaliana pin-formed
      1 and wild type.
AB  - With the aid of a non-destructive replica method and computational protocol,
      surface geometry and expansion at the reproductive shoot apex are analysed for
      pin-formed 1 (pin1) Arabidopsis thaliana and compared with the wild type. The
      observed complexity of geometry and expansion at the pin1 apex indicates that
      both components of shoot apex growth, i.e. the meristem self-perpetuation and
      initiation of lateral organs, are realized by the pin1 apex. The realization of
      the latter component, however, is only occasionally completed. The pin1 apex is
      generally dome-shaped, but its curvature is not uniform, especially later during
      apex ontogeny, when bulges and saddle-shaped regions appear on its periphery. The
      only saddle-shaped regions at the wild-type shoot apex are creases separating
      flower primordia from the meristem. Surface expansion at the pin1 apex is faster
      than at the wild type. In both pin1 and wild type the apex surface is
      differentiated into regions of various areal strain rates. In the pin1 apex, but
      not in the wild type, these regions correspond to the geometrically distinguished
      central and peripheral zones. Expansion of the central zone of the pin1 apex is
      nearly isotropic and slower than in the peripheral zone. The peripheral zone is
      differentiated into ring-shaped portions of different expansion anisotropy. The
      distal portion of this zone expands anisotropically, similar to regions of the
      wild-type apex periphery, which contact older flower primordia. The proximal
      portion expands nearly isotropically, like sites of flower initiation in the wild
      type. The peripheral zone in pin1 is surrounded by a 'basal zone', a sui generis
      zone, where areal strain rates are low and expansion is anisotropic. The possible
      relationships between the observed regions of different expansion and the various
      gene expression patterns in the pin1 apex known from the literature are
      discussed.

PMID- 15020635
TI  - FRAP analysis of photosynthetic membranes.
AB  - Fluorescence Recovery after Photobleaching (FRAP) is a technique widely used in
      cell biology to observe the dynamics of biological systems, including the
      diffusion of membrane components. More information is needed on the dynamics of
      photosynthetic membranes in order to help to understand processes such as
      photosynthetic electron transport, regulation of light-harvesting, and biogenesis
      and turnover of the photosynthetic apparatus. FRAP has the potential to provide
      this information, although applying the technique to photosynthetic membranes is
      not always straightforward. This review explains the potential and the problems,
      and gives a brief guide to performing FRAP measurements and analysing the data.

PMID- 15020636
TI  - Chloroplast proteomics: potentials and challenges.
AB  - With the available Arabidopsis genome and near-completion of the rice genome
      sequencing project, large-scale analysis of plant proteins with mass spectrometry
      has now become possible. Determining the proteome of a cell is a challenging
      task, which is complicated by proteome dynamics and complexity. The biochemical
      heterogeneity of proteins constrains the use of standardized analytical
      procedures and requires demanding techniques for proteome analysis. Several
      proteome studies of plant cell organelles have been reported, including
      chloroplasts and mitochondria. Chloroplasts are of particular interest for plant
      biologists because of their complex biochemical pathways for essential metabolic
      functions. Information from the chloroplast proteome will therefore provide new
      insights into pathway compartmentalization and protein sorting. Some approaches
      for the analysis of the chloroplast proteome and future prospects of plastid
      proteome research are discussed here.

PMID- 15020637
TI  - Characterization of promoter expression patterns derived from the Pht1 phosphate
      transporter genes of barley (Hordeum vulgare L.).
AB  - By comparison with dicot plant species, relatively little work has been reported
      on the phosphate transporter (Pht1) gene family from monocot species. Initial
      studies have shown that barley contains at least eight homologous genes. The
      promoters of six of these genes were analysed for the presence of regulatory
      elements potentially associated with expression specificity. In particular, the
      P1BS-like elements (implicated in phosphorus-regulated expression of genes in
      plants) was identified in all HvPht1 promoters examined. For two members of the
      family (HvPht1;1 and HvPht1;2), promoter fusions to beta-glucuronidase and green
      fluorescent protein reporter genes were constructed, transformed into rice, and
      the expression profiles observed. The inclusion of an intron derived from Adh1
      enhanced gene expression approximately 20-fold, but did not appear to affect the
      specificity of expression. The HvPht1;1 and HvPht1;2 promoters showed minor
      differences in expression patterns but, in general, expression was observed at
      high levels in trichoblast cells (root hairs) and stele of the nodal root,
      throughout secondary roots, and at a relatively low level in leaf tissues. Under
      phosphorus deficiency, expression was induced by up to 5-fold. These observations
      are consistent with a primary role for the encoded genes in the uptake of
      phosphate by root hairs from soil solution and further current understanding of
      the mechanisms involved. The promoters also have application for providing a new
      resource for cereal transformation, ideally suited for driving the expression of
      foreign genes associated with nutrient uptake.

PMID- 15020638
TI  - Pectin esterase gene family in strawberry fruit: study of FaPE1, a ripening
      specific isoform.
AB  - Pectin esterases (PE, EC 3.1.1.11) catalyse the demethylation of pectin. As a
      result of its activity, structural interactions among cell wall components during
      cell wall turnover and loosening are affected. In plants, PEs are typically
      encoded by a gene family. This family has been studied in strawberry (Fragaria x
      ananassa Duch.) in order to investigate the role of distinct PE genes during
      fruit ripening and senescence. By a combination of a PCR-based library screening
      and RT-PCR four different strawberry PE cDNAs, termed FaPE1 to FaPE4, have been
      isolated. Differential expression of each FaPE gene in various organs and during
      fruit development was revealed by northern blot. FaPE1 is specifically expressed
      in fruit, showing an increasing expression during the ripening process up to a
      maximum in the turning stage. Concerning hormone regulation, auxin treatment
      increased FaPE1 mRNA levels in green fruit, whereas exogenous ethylene decreased
      FaPE1 mRNA levels in ripe and senescing fruits. It is proposed that this
      repression of FaPE1 expression could be involved in textural changes occurring
      during fruit senescence.

PMID- 15020639
TI  - Novel expression patterns of phosphatidylinositol 3-hydroxy kinase in nodulated
      Medicago spp. plants.
AB  - A cDNA clone encoding a phosphatidylinositol 3-kinase (PtdIns 3-kinase) has been
      characterized from Medicago truncatula, Mtpi3k, that is highly homologous to
      their counterparts from soybean (over 84%). The results suggest the presence of
      at least two genes coding PtdIns 3-kinases in M. truncatula. Mtpi3k transcript
      levels increased in nodules, compared with non-infected roots. Strikingly, Mtpi3k
      mRNA accumulated in young elongating stems at higher levels than that observed in
      other organs. Enhanced transcription of genes coding PtdIns 3-kinases might occur
      in tissues experiencing a high degree of vesicle trafficking and cell elongation.

PMID- 15020640
TI  - Soybean cultivars 'Williams 82' and 'Maple Arrow' produce both urea and ammonia
      during ureide degradation.
AB  - The ability of two soybean (Glycine max L. [Merrill]) cultivars, 'Williams 82'
      and 'Maple Arrow', which were reported to use different ureide degradation
      pathways, to degrade the ureides allantoin and allantoate was investigated.
      Protein fractions and total leaf homogenates from the fourth trifoliate leaves of
      both cultivars were examined for the ability to evolve either (14)CO(2) or
      [(14)C]urea from (14)C-labelled ureides in the presence of various inhibitors.
      (14)CO(2) evolution from [2,7-(14)C]allantoate was catalysed by 25-50% saturated
      ammonium sulphate fractions of both cultivars. This activity was inhibited by
      acetohydroxamate (AHA), which has been used to inhibit plant ureases, but not by
      phenylphosphorodiamidate (PPD), a more specific urease inhibitor. Thus, in both
      cultivars, allantoate may be metabolized by allantoate amidohydrolase. This
      activity was sensitive to EDTA, consistent with previous reports demonstrating
      that allantoate amidohydrolase requires manganese for full activity. Total leaf
      homogenates of both cultivars evolved both (14)CO(2) and [(14)C]urea from [2,7
      (14)C] (ureido carbon labelled) allantoin, not previously reported in either
      'Williams 82' or in 'Maple Arrow'. In situ leaf degradation of (14)C-labelled
      allantoin confirmed that both urea and CO(2)/NH(3) are direct products of ureide
      degradation. Growth of plants in the presence of PPD under fixing and non-fixing
      conditions caused urea accumulation in both cultivars, but did not have a
      significant impact on total seed nitrogen. Urea levels were higher in N-fixing
      plants of both cultivars. Contrary to previous reports, no significant
      biochemical difference was found in the ability of these two cultivars to degrade
      ureides under the conditions used.

PMID- 15020642
TI  - Caspase-like activity in the seedlings of Pisum sativum eliminates weaker shoots
      during early vegetative development by induction of cell death.
AB  - Activation of aspartate-specific cysteine proteases (caspases) plays a crucial
      role in programmed cell death (PCD) in animals. Although to date caspases have
      not been identified in plants, caspase-like activity was described in tobacco
      during a hypersensitive response to pathogens and in Arabidopsis and tomato cell
      cultures during chemical-induced PCD. Caspase-like activity was also detected in
      the course of plant development during petal senescence and endosperm PCD. It is
      shown here that caspase-like proteases play a crucial role in the developmental
      cell death of secondary shoots of pea seedlings that emerge after removal of the
      epicotyl. Caspase-like activity was induced in senescing secondary shoots, but
      not in dominant growing shoots, in contrast to the papain-like cysteine protease
      activity that was stronger in the dominant shoot. Revitalization of the senescing
      shoot by cutting of the dominant shoot reduced the caspase-like activity.
      Injection of caspase or cysteine protease inhibitors into the remaining epicotyl
      tissue suppressed the death of the secondary shoots, producing seedlings with two
      equal shoots. These results suggest that shoot selection in pea seedlings is
      controlled by PCD, through the activation of caspase-like proteases.

PMID- 15020641
TI  - Dormancy release during hydrated storage in Lolium rigidum seeds is dependent on
      temperature, light quality, and hydration status.
AB  - The influence of temperature, light environment, and seed hydration on the rate
      of dormancy release in Lolium rigidum (annual ryegrass) seeds during hydrated
      storage (stratification) was investigated. In a series of experiments, seeds were
      subjected to a range of temperatures (nine between 5 degrees C and 37 degrees C),
      light (white, red, far-red, and dark), and hydration (4-70 g H(2)O 100 g(-1) FW)
      during stratification for up to 80 d. Samples were germinated periodically at
      25/15 degrees C or constant 15, 20, or 25 degrees C with a 12 h photoperiod to
      determine dormancy status. Dark-stratification was an alternative, but not
      equivalent dormancy release mechanism to dry after-ripening in annual ryegrass
      seeds. Dormancy release during dark-stratification caused a gradual increase in
      sensitivity to light, but germination in darkness remained negligible.
      Germination, but not dormancy release, was greater under fluctuating diurnal
      temperatures than the respective mean temperatures delivered constantly. Dormancy
      release rate was a positive linear function of dark-stratification temperature
      above a base temperature for dormancy release of 6.9 degrees C. Dormancy release
      at temperatures up to 30 degrees C could be described in terms of thermal dark
      stratification time, but the rate of dormancy release was slower at < or =15
      degrees C (244 degrees Cd/probit increase in germination) than > or =20 degrees C
      (208 degrees Cd/probit). Stratification in red or white, but not far-red light,
      inhibited dormancy release, as did insufficient (<40 g H(2)O 100 g(-1) FW) seed
      hydration. The influence of dark-stratification on dormancy status in annual
      ryegrass seeds is discussed in terms of a hypothetical increase in available
      membrane-bound phytochrome receptors.

PMID- 15020643
TI  - Regulation of sulphate assimilation by glutathione in poplars (Populus tremula x
      P. alba) of wild type and overexpressing gamma-glutamylcysteine synthetase in the
      cytosol.
AB  - Glutathione (GSH) is the major low molecular weight thiol in plants with
      different functions in stress defence and the transport and storage of sulphur.
      Its synthesis is dependent on the supply of its constituent amino acids cysteine,
      glutamate, and glycine. GSH is a feedback inhibitor of the sulphate assimilation
      pathway, the primary source of cysteine synthesis. Sulphate assimilation has been
      analysed in transgenic poplars (Populus tremula x P. alba) overexpressing gamma
      glutamylcysteine synthetase, the key enzyme of GSH synthesis, and the results
      compared with the effects of exogenously added GSH. Although foliar GSH levels
      were 3-4-fold increased in the transgenic plants, the activities of enzymes of
      sulphate assimilation, namely ATP sulphurylase, adenosine 5'-phosphosulphate
      reductase (APR), sulphite reductase, serine acetyltransferase, and O-acetylserine
      (thiol)lyase were not affected in three transgenic lines compared with the wild
      type. Also the mRNA levels of these enzymes were not altered by the increased GSH
      levels. By contrast, an increase in GSH content due to exogenously supplied GSH
      resulted in a strong reduction in APR activity and mRNA accumulation. This
      feedback regulation was reverted by simultaneous addition of O-acetylserine
      (OAS). However, OAS measurements revealed that OAS cannot be the only signal
      responsible for the lack of feedback regulation of APR by GSH in the transgenic
      poplars.

PMID- 15020644
TI  - Effect of low molecular size humic substances on nitrate uptake and expression of
      genes involved in nitrate transport in maize (Zea mays L.).
AB  - In this study, a detailed characterization of earthworm low molecular size humic
      substances (LMS) was performed and these substances were used to study their
      effect on the nitrate influx in roots, tissue nitrate content, and expression of
      maize genes putatively involved in nitrate uptake in maize (Zea mays L.). The
      results show that the humic fraction with low molecular size used in this study
      is endowed with the characteristic structural network described for most humic
      substances so far isolated and confirm the presence of IAA in this fraction. The
      results also show that the LMS fraction of humic substances stimulates the uptake
      of nitrate by roots and the accumulation of the anion at the leaf level.
      Moreover, the analysis of the expression of genes encoding two putative maize
      nitrate transporters (ZmNrt2.1 and ZmNrt1.1) and of two maize H(+)-ATPase
      isoforms (Mha1 and Mha2) show that these substances may exert direct effects on
      gene transcription in roots, as shown for the Mha2 gene, and long-distance
      effects in shoots, as observed for the ZmNrt2.1 gene.

PMID- 15020645
TI  - Alkali grass resists salt stress through high [K+] and an endodermis barrier to
      Na+.
AB  - In order to understand the salt-tolerance mechanism of alkali grass (Puccinellia
      tenuiflora) compared with wheat (Triticum aestivum L.), [K(+)] and [Na(+)] in
      roots and shoots in response to salt treatments were examined with ion element
      analysis and X-ray microanalysis. Both the rapid K(+) and Na(+) influx in
      response to different NaCl and KCl treatments, and the accumulation of K(+) and
      Na(+) as the plants acclimated to long-term stress were studied in culture-
      solution experiments. A higher K(+) uptake under normal and saline conditions was
      evident in alkali grass compared with that in wheat, and electrophysiological
      analyses indicated that the different uptake probably resulted from the higher
      K(+)/Na(+) selectivity of the plasma membrane. When external [K(+)] was high,
      K(+) uptake and transport from roots to shoots were inhibited by exogenous Cs(+),
      while TEA (tetraethylammonium) only inhibited K(+) transport from the root to the
      shoot. K(+) uptake was not influenced by Cs(+) when plants were K(+) starved. It
      was shown by X-ray microanalysis that high [K(+)] and low [Na(+)] existed in the
      endodermal cells of alkali grass roots, suggesting this to be the tissue where
      Cs(+) inhibition occurs. These results suggest that the K(+)/Na(+) selectivity of
      potassium channels and the existence of an apoplastic barrier, the Casparian
      bands of the endodermis, lead to the lateral gradient of K(+) and Na(+) across
      root tissue, resulting not only in high levels of [K(+)] in the shoot but also a
      large [Na(+)] gradient between the root and the shoot.

PMID- 15020647
TI  - CD38 low IgG-secreting cells are precursors of various CD38 high-expressing
      plasma cell populations.
AB  - Despite the important role immunoglobulin G (IgG)-secreting plasma cells play in
      memory immune responses, the differentiation and homeostasis of these cells are
      not completely understood. Here, we studied the differentiation of human IgG
      secreting cells ex vivo and in vitro, identifying these cells by the cellular
      affinity matrix technology. Several subpopulations of IgG-secreting cells were
      identified among the cells isolated from tonsils and bone marrow, particularly
      differing in the expression levels of CD9, CD19, and CD38. CD38 low IgG-secreting
      cells were present exclusively in the tonsils. A major fraction of these cells
      appeared to be early plasma cell precursors, as upon activation of B cells in
      vitro, IgG secretion preceded up-regulation of CD38, and on tonsillar sections,
      IgG-containing, CD38 low cells with a plasmacytoid phenotype were found in
      follicles, where plasma cell differentiation starts. A unitary phenotype of
      migratory peripheral blood IgG-secreting cells suggests that all bone marrow
      plasma cell populations share a common precursor cell. These data are compatible
      with a multistep model for plasma cell differentiation and imply that a common
      CD38 low IgG-secreting precursor gives rise to a diverse plasma cell compartment.

PMID- 15020646
TI  - Advanced glycation end-products increase monocyte adhesion to retinal endothelial
      cells through vascular endothelial growth factor-induced ICAM-1 expression:
      inhibitory effect of antioxidants.
AB  - Accumulating evidence indicates a role for advanced glycation end-products (AGEs)
      in the development of diabetic retinopathy. In the present study, we examined the
      in vitro effect of AGEs on human monocyte adhesion to bovine retinal endothelial
      cells (BRECs) and the molecular mechanisms involved in this effect. Treatment of
      cultured BRECs with AGEs led to a significant increase in monocyte adhesion and
      intercellular cell adhesion molecule-1 (ICAM-1) expression. These effects were
      inhibited by antioxidants including gliclazide and vitamins C and E. On the basis
      of the stimulatory effect of AGEs on vascular endothelial growth factor (VEGF)
      secretion by retinal endothelial cells, the role of this growth factor as
      mediator of AGE-induced monocyte adhesion to BRECs was next investigated.
      Incubation of BRECs with VEGF increased monocyte adhesion to these cells and
      enhanced ICAM-1 expression. Treatment of BRECs with an anti-VEGF antibody
      abrogated AGE-induced monocyte adhesion and ICAM-1 expression. Finally,
      incubation of BRECs with protein kinase C (PKC) and nuclear factor (NF)-kappaB
      inhibitors suppressed monocyte adhesion and ICAM-1 expression elicited by AGEs
      and VEGF. Taken together, these data indicate that AGEs increase monocyte
      adhesion to BRECs and that this effect is mediated through VEGF-induced ICAM-1
      expression. They also demonstrate that this effect is oxidative stress-sensitive
      and involves PKC and NF-kappaB-dependent signaling pathways.

PMID- 15020648
TI  - Eosinophil degranulation in the allergic lung of mice primarily occurs in the
      airway lumen.
AB  - Eosinophil degranulation is thought to play a pivotal role in the pathogenesis of
      allergic disorders. Although mouse models of allergic disorders have been used
      extensively to identify the contribution of eosinophils to disease,
      ultrastructural evidence of active granule disassembly has not been reported. In
      this investigation, we characterized the degree of eosinophil activation in the
      bone marrow, blood, lung tissue, and airways lumen [bronchoalveolar lavage fluid
      (BALF)] of ovalbumin-sensitized and aero-challenged wild-type and interleukin-5
      transgenic mice. Degranulation was most prominent in and primarily
      compartmentalized to the airways lumen. Eosinophils released granule proteins by
      the process of piecemeal degranulation (PMD). Accordingly, recruitment and
      activation of eosinophils in the lung correlated with the detection of cell-free
      eosinophil peroxidase in BALF and with the induction of airways hyper-reactivity.
      As in previous studies with human eosinophils, degranulation of isolated mouse
      cells did not occur until after adherence to extracellular matrix. However,
      higher concentrations of exogenous stimuli appear to be required to trigger
      adherence and degranulation (piecemeal) of mouse eosinophils when compared with
      values reported for studies of human eosinophils. Thus, mouse eosinophils undergo
      PMD during allergic inflammation, and in turn, this process may contribute to
      pathogenesis. However, the degranulation process in the allergic lung of mice is
      primarily compartmentalized to the airway lumen. Understanding the mechanism of
      eosinophil degranulation in the airway lumen may provide important insights into
      how this process occurs in human respiratory diseases.

PMID- 15020649
TI  - Expression of CD45RB functionally distinguishes intestinal T lymphocytes in
      inflammatory bowel disease.
AB  - The importance of CD45RB expression on T cells was already shown in mice where
      CD45RB(high) expression determines pathogenic potential. In this study, we
      analyzed the expression of CD45RA, CD45RB, and CD45RO on CD4(+) T lymphocytes in
      the intestinal mucosa and in the circulation of patients with inflammatory bowel
      disease (IBD). In addition, we studied the cytokine profile of these cells. In
      the circulation, virtually all CD4(+)CD45RB(high) T cells expressed the naive
      marker CD45RA, and circulating CD4(+)CD45RB(low) cells expressed the memory
      marker CD45RO in IBD patients and a control patient population. In contrast, the
      intestinal CD4(+) CD45RB(high) T cells are in normal controls for 90% CD45RO(+).
      However, in IBD, 27.7% [Crohn's disease (CD)] and 49% [ulcerative colitis (UC)]
      of the intestinal CD4(+) CD45RB(high) T cells are CD45RA(+). This special
      CD4CD45RA(+) T cell in IBD can be found in the lamina propria as well as in
      lymphoid follicles (confocal laser-scanning microscopy). The CD4(+)CD45RB(high) T
      lymphocytes produce significantly less interleukin (IL)-10 and IL-4 and produce
      more tumor necrosis factor alpha than CD45RB(low) T lymphocytes in control
      patients. CD4(+)CD45RB(low) T cells from IBD patients produced less IL-10 than
      CD4(+)CD45RB(low) T lymphocytes of controls, and interferon-gamma production by
      both T lymphocyte subsets was decreased in IBD. These data indicate that CD and
      UC are characterized by an influx of CD4(+)CD45RB(high) T lymphocytes. These
      CD4(+)CD45RB(high) T lymphocytes seem to be important in the pathogenesis of IBD,
      as they produce more proinflammatory cytokines and less anti-inflammatory
      cytokines compared with CD4(+)CD45RB(low) T lymphocytes.

PMID- 15020650
TI  - MCP-1-dependent signaling in CCR2(-/-) aortic smooth muscle cells.
AB  - Monocyte chemoattractant protein-1 (MCP-1, CCL2) is a mediator of inflammation
      that has been implicated in the pathogenesis of a wide variety of human diseases.
      CCR2, a heterotrimeric G-coupled receptor, is the only known receptor that
      functions at physiologic concentrations of MCP-1. Despite the importance of CCR2
      in mediating MCP-1 responses, several recent studies have suggested that there
      may be another functional MCP-1 receptor. Using arterial smooth muscle cells
      (SMC) from CCR2(-/-) mice, we demonstrate that MCP-1 induces tissue-factor
      activity at physiologic concentrations. The induction of tissue factor by MCP-1
      is blocked by pertussis toxin and 1,2-bis(O-aminophenyl-ethane-ethan)-N,N,N',N'
      tetraacetic acid-acetoxymethyl ester, suggesting that signal transduction through
      the alternative receptor is G(alphai)-coupled and dependent on mobilization of
      intracellular Ca(2+). MCP-1 induces a time- and concentration-dependent
      phosphorylation of the mitogen-activated protein kinases p42/44. The induction of
      tissue factor activity by MCP-1 is blocked by PD98059, an inhibitor of p42/44
      activation, but not by SB203580, a selective p38 inhibitor. These data establish
      that SMC possess an alternative MCP-1 receptor that signals at concentrations of
      MCP-1 that are similar to those that activate CCR2. This alternative receptor may
      be important in mediating some of the effects of MCP-1 in atherosclerotic
      arteries and in other inflammatory processes.

PMID- 15020651
TI  - Molecular mechanisms governing thymocyte migration: combined role of chemokines
      and extracellular matrix.
AB  - Cell migration is crucial for thymocyte differentiation, and the cellular
      interactions involved now begin to be unraveled, with chemokines, extracellular
      matrix (ECM) proteins, and their corresponding receptors being relevant in such
      oriented movement of thymocytes. This notion derives from in vitro, ex vivo, and
      in vivo experimental data, including those obtained in genetically engineered and
      spontaneous mutant mice. Thymic microenvironmental cells produce both groups of
      molecules, whereas developing thymocytes express chemokine and ECM receptors. It
      is important that although chemokines and ECM proteins can drive thymocyte
      migration per se, a combined role of these molecules likely concurs for the
      resulting migration patterns of thymocytes in their various differentiation
      stages. In this respect, among ECM moieties, there are proteins with opposing
      functions, such as laminin or fibronectin versus galectin-3, which promote,
      respectively, adhesion and de-adhesion of thymocytes to the thymic
      microenvironment. How chemokines and ECM are produced and degraded remains to be
      more clearly defined. Nevertheless, matrix metalloproteinases (MMPs) likely play
      a role in the intrathymic ECM breakdown. It is interesting that these molecules
      also degrade chemokines. Thus, the physiological migration of thymocytes should
      be conceived as a resulting vector of multiple, simultaneous, or sequential
      stimuli, involving chemokines, adhesive, and de-adhesive ECM proteins. Moreover,
      these interactions may be physiologically regulated in situ by matrix MMPs and
      are influenced by hormones. Accordingly, one can predict that pathological
      changes in any of these loops may result in abnormal thymocyte migration. This
      actually occurs in the murine infection by the protozoan Trypanosoma cruzi, the
      causative agent of Chagas disease. In this model, the abnormal release of
      immature thymocytes to peripheral lymphoid organs is correlated with the higher
      migratory response to ECM and chemokines. Lastly, the fine dissection of the
      mechanisms governing thymocyte migration will provide new clues for designing
      therapeutic strategies targeting developing T cells. The most important function
      of the thymus is to generate T lymphocytes, which once leaving the organ, are
      able to colonize specific regions of peripheral lymphoid organs, the T cell
      zones, where they can mount and regulate cell-mediated, immune responses. This
      intrathymic T cell differentiation is a complex sequence of biological events,
      comprising cell proliferation, differential membrane protein expression, gene
      rearrangements, massive programmed cell death, and cell migration. In this
      review, we will focus on the mechanisms involved in controlling the migration of
      thymocytes, from the entrance of cell precursors into the organ to the exit of
      mature T cells toward peripheral lymphoid organs. Nevertheless, to better
      comprehend this issue, it appeared worthwhile to briefly comment on some key
      aspects of thymocyte differentiation and the tissue context in which it takes
      place, the thymic microenvironment.

PMID- 15020652
TI  - Estrogen receptor-alpha deficiency promotes increased TNF-alpha secretion and
      bacterial killing by murine macrophages in response to microbial stimuli in
      vitro.
AB  - In this series of studies, we determined the potential role of intracellular
      estrogen receptors (ER), ERalpha and ERbeta, on macrophage function in response
      to bacterial stimuli. The sex hormone 17beta-estradiol (E(2)) and ER have been
      shown to modulate inflammatory responses as well as T helper cell type 1
      (TH1)/TH2 responses. The mechanisms E(2) and its receptors use to alter these
      immune functions remain largely unknown. ERalpha and ERbeta possess complex
      actions in tissues where they are expressed. We have characterized the receptor
      repertoire of murine dendritic cells and thioglycollate-elicited peritoneal
      macrophages (PM). Both cell types express mRNA for ERalpha. Neither cell type
      expressed detectable amounts of ERbeta mRNA, as determined by reverse
      transcriptase-polymerase chain reaction using exon-specific primers spanning each
      of the seven intron/exon junctions. Primary macrophages from ERalpha- and ERbeta
      deficient severe combined immunodeficiency mice [ERalpha knockout (KO) and
      ERssKO, respectively] were used to delineate the effects and potential mechanisms
      via which steroid receptors modulate macrophage function. ERalpha-deficient PM
      exposed ex vivo to lipopolysaccharide or Mycobacterium avium exhibited
      significant increases in tumor necrosis factor alpha (TNF-alpha) secretion as
      well as reduction in bacterial load when compared with wild-type (WT) PM. In
      contrast, ERbeta-deficient PM possessed no significant difference in TNF-alpha
      secretion or in bacterial load when compared with WT littermates. These studies
      suggest that ERalpha, but not ERbeta, modulates murine PM function.

PMID- 15020653
TI  - Antagonism of the alpha4 integrin subunit attenuates the acute inflammatory
      response to stent implantation yet is insufficient to prevent late intimal
      formation.
AB  - Mononuclear leukocytes infiltrate the artery wall via integrin-mediated
      mechanisms and play an integral role in intimal formation after stenting. We
      sought to determine if acute antagonism of the alpha4 subunit of very late
      antigen-4 is sufficient for the late attenuation of stent intimal area (IA).
      Twenty-four hypercholesterolemic rabbits underwent iliac artery balloon injury,
      followed 2 weeks later by stent implantation, and the animals were randomized to
      receive an anti-alpha4 antibody (HP1/2) or a nonspecific isotypic control
      immunoglobulin (1E6) intravenously 1 h before stenting. Compared with controls,
      HP1/2-treated rabbits showed 50%, 51%, and 44% reductions in the percentage on
      intimal cells that were macrophages on days 3, 7, and 28 after stenting and a 59%
      reduction in intimal proliferation on day 3. Although stent IA was reduced by 63%
      and 48% in the antibody-treated group compared with the control group on days 3
      and 7, this difference was not present on day 28. These data highlight the need
      for sustained, anti-inflammatory therapies for the prevention of stent intimal
      formation.

PMID- 15020654
TI  - VIP/PACAP oppositely affects immature and mature dendritic cell expression of
      CD80/CD86 and the stimulatory activity for CD4(+) T cells.
AB  - The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate
      cyclase-activating polypeptide (PACAP) released within lymphoid organs from nerve
      terminals and/or immune cells play a significant, anti-inflammatory role by
      inhibiting macrophage-induced inflammatory reactions and promoting T helper cell
      type 2 (Th2) responses. However, dendritic cells (DC) and not macrophages often
      are the major antigen-presenting cells and link between innate and adaptive
      immunity. The role of VIP/PACAP in DC development and function is mostly unknown.
      Here, we report that bone marrow-derived DC express VIP/PACAP receptors and that
      VIP and PACAP exert a differential effect on immature DC (iDC) and
      lipopolysaccharide (LPS)-treated DC. In iDC, VIP/PACAP up-regulates CD86
      expression and enables them to stimulate T cell proliferation and differentiation
      into Th2 effectors in vivo and in vitro. In contrast, VIP/PACAP down-regulates
      CD80/CD86 expression in LPS-stimulated DC and strongly reduces their capacity to
      stimulate T cell proliferation and secretion of Th1 and Th2 cytokines. The
      VIP/PACAP effects on iDC and LPS-stimulated DC are mediated primarily through the
      VIP receptor 1. These results indicate that neuropeptides such as VIP and PACAP
      can differentially affect the function of iDC and mature DC. In the absence of an
      ongoing immune response, VIP/PACAP contributes to the initiation of Th2-type
      immunity, whereas in the presence of a full-blown, inflammatory reaction,
      VIP/PACAP act as anti-inflammatory agents.

PMID- 15020655
TI  - Heparin-disaccharide affects T cells: inhibition of NF-kappaB activation, cell
      migration, and modulation of intracellular signaling.
AB  - We previously reported that disaccharides (DS), generated by enzymatic
      degradation of heparin or heparan sulfate, inhibit T cell-mediated immune
      reactions in rodents and regulate cytokine [tumor necrosis factor alpha (TNF
      alpha), interleukin (IL)-8, and IL-1beta] secretion by T cells, macrophages, or
      intestinal epithelial cells. Here, we investigated the effects of a trisulfated
      heparin DS (3S-DS) on two aspects of T cell function: secretion of
      proinflammatory cytokines and migration to an inflamed site. 3S-DS down-regulated
      nuclear factor-kappaB activity and reduced the secretion of TNF-alpha and
      interferon-gamma (IFN-gamma) by anti-CD3-activated T cells. In addition, 3S-DS
      inhibited CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor-1alpha)
      dependent migration in vitro and in vivo and decreased CXCL12-induced T cell
      adhesion to the extracellular matrix glycoprotein, fibronectin (FN). This
      inhibition was accompanied by attenuation of CXCL12-induced Pyk2 phosphorylation
      but did not involve internalization of the CXCL12 receptor, CXCR4, or
      phosphorylation of extracellular-regulated kinase. Despite inhibiting CXCL12
      induced adhesion, 3S-DS, on its own, induced T cell adhesion to FN, which was
      accompanied by phosphorylation of Pyk2. A monosulfated DS showed no effect. Taken
      together, these data provide evidence that 3S-DS can regulate inflammation by
      inducing and modulating T cell-signaling events, desensitizing CXCR4, and
      modulating T cell receptor-induced responses.

PMID- 15020656
TI  - Clinicopathologic features of asymptomatic gastric adenocarcinoma patients in
      Korea.
AB  - OBJECTIVE: The aim of this study was to analyze the characteristics of patients
      diagnosed with gastric adenocarcinoma without the presence of symptoms and to
      evaluate the usefulness of screening programs for gastric cancer in Korea.
      METHODS: We retrospectively analyzed the characteristics of 1277 gastric
      adenocarcinoma patients at Seoul National University Hospital (SNUH) (665 in
      1996; 612 in 2001) by dividing them into two groups according to the presence or
      absence of symptoms (symptomatic group vs asymptomatic group). RESULTS: The
      proportion of asymptomatic patients increased from 1996 (4.7%) to 2001 (17.2%) (P
      < 0.001). Gastroscopy was the most commonly used screening tool (77.4% in 1996,
      95.2% in 2001). The proportion of early gastric cancer (EGC) in the asymptomatic
      group was higher than in the symptomatic group (74.2% vs 25.9% in 1996, 78.1% vs
      35.7% in 2001) (P < 0.001). The curative operation rate was significantly higher
      in the asymptomatic group. The asymptomatic group had a higher 5-year survival
      rate (87.7%) than the symptomatic group (51.6%) (P < 0.01). Complementary data
      from a screening program at the SNUH showed that 19 gastric cancer cases (0.76%)
      were detected out of 2501 endoscopic examinations; of these, 78.9% (15/19) were
      early gastric cancer cases, which is in agreement with our results. CONCLUSION:
      Patients with asymptomatic gastric adenocarcinoma had fewer advanced lesions, a
      greater chance for curative operation and a higher survival rate than symptomatic
      patients. An increase in the number of asymptomatic patients contributed to the
      increase in overall EGC from 1996 to 2001. These results seemed to support the
      usefulness of gastroscopy as a screening test for gastric cancer in Korea, where
      the incidence of gastric cancer is high.

PMID- 15020657
TI  - Weekly irinotecan in patients with metastatic gastric cancer failing cisplatin
      based chemotherapy.
AB  - BACKGROUND: The goal of this study is to determine the efficacy and toxicity of
      weekly irinotecan as second-line chemotherapy in advanced gastric cancer after
      failure of cisplatin-based regimen. METHODS: Gastric cancer patients failing
      cisplatin-based chemotherapy received 125 mg/m(2) of irinotecan weekly for 4
      weeks followed by 2-week rest, until disease progression. RESULTS: Thirty-seven
      patients were enrolled into this study. The objective response was documented in
      seven of 35 patients with measurable lesion (response rate 20%, 95% CI: 6.1
      33.9). Eight patients (22.9%) had stable disease and overall tumor control rate
      was 42.9%. The disease remained stable in both of two patients without measurable
      disease. At a median follow-up duration of 15.8 months, median time to
      progression and overall survival were 2.6 months (95% CI: 2.4-2.8) and 5.2 months
      (95% CI: 3.6-6.7), respectively. Neutropenia and diarrhea were the main
      toxicities. Among 37 patients treated, grade 3/4 (G3/4) neutropenia occurred in
      43.2/24.3% of patients, respectively, and was accompanied with fever in three
      patients. Non-hematologic toxicities consisted mainly of delayed diarrhea (G3/4,
      18.9/0%) and nausea/vomiting (G3/4, 18.9/0%). These toxicities were manageable
      and there was no treatment-related death. CONCLUSIONS: This weekly schedule of
      irinotecan was modestly active against cisplatin-refractory gastric cancer and
      relatively well-tolerated with appropriate dose modification.

PMID- 15020658
TI  - Radical cystectomy for invasive bladder cancer: results of multi-institutional
      pooled analysis.
AB  - BACKGROUND: We report the outcome of radical cystectomy for patients with
      invasive bladder cancer, who did not have regional lymph node or distant
      metastases, at 21 hospitals. METHODS: Retrospective, non-randomized, multi
      institutional pooled data were analyzed to evaluate outcomes of patients who
      received radical cystectomy. Between 1991 and 1995, 518 patients with invasive
      bladder cancer were treated with radical cystectomy at 21 hospitals. Of these,
      250 patients (48.3%) received some type of neoadjuvant and/or adjuvant therapy
      depending on the treatment policy of each hospital. RESULTS: The median follow-up
      period was 4.4 years, ranging from 0.1 to 11.4 years. The 5-year overall survival
      rate was 58% for all 518 patients. The 5-year overall survival rates for patients
      with clinical T2N0M0, T3N0M0 and T4N0M0 were 67%, 52% and 38%, respectively. The
      patients with pT1 or lower stage, pT2, pT3 and pT4 disease without lymph node
      metastasis had 5-year overall survivals of 81%, 74%, 47% and 38%, respectively.
      The patients who were node positive had the worst prognosis, with a 30% overall
      survival rate at 5 years. Neoadjuvant or adjuvant chemotherapy did not provide a
      significant survival advantage, although adjuvant chemotherapy improved the 5
      year overall survival in patients with pathologically proven lymph node
      metastasis. CONCLUSIONS: The current retrospective study showed that radical
      cystectomy provided an overall survival equivalent to studies reported
      previously, but surgery alone had no more potential to prolong survival of
      patients with invasive cancer. Therefore, a large-scale randomized study on
      adjuvant treatment as well as development of new strategies will be needed to
      improve the outcome for patients with invasive bladder cancer.

PMID- 15020659
TI  - Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a
      luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist
      monotherapy as first-line treatment for advanced prostate cancer: interim results
      of a randomized study in Japanese patients.
AB  - OBJECTIVES: To evaluate bicalutamide (Casodex) 80 mg as a component of maximum
      androgen blockade (MAB) in Japanese patients with previously untreated advanced
      prostate cancer. METHODS: 205 patients with previously untreated stage C/D
      prostate cancer were randomized (1:1) to receive once-daily bicalutamide 80 mg or
      placebo, each combined with a luteinizing hormone-releasing hormone (LHRH)
      agonist. Primary study variables were the 12 week prostate-specific antigen (PSA)
      normalization (i.e. PSA level <or=4 ng/ml) rate, the 12 week overall tumor
      response rate (proportion with a partial response or better) and the proportion
      of withdrawals due to adverse drug reactions (ADRs) at follow-up. This interim
      analysis was undertaken after a minimum of 6 months' follow-up (median 15
      months). RESULTS: The 12 week PSA normalization rate was 79.4% for MAB and 38.6%
      for LHRH agonist monotherapy (P < 0.001). The 12 week overall tumor response rate
      was 77.5 and 65.3%, respectively (P = 0.063). The withdrawal rate due to ADRs was
      8.8% and 10.9%, respectively. There were differences in favor of MAB over
      monotherapy with respect to time to treatment failure (TTTF) (P = 0.038) and time
      to progression (TTP) (P = 0.016). There have been too few deaths (n = 10) to
      analyze survival. The profiles of adverse events and ADRs were broadly similar in
      the two treatment groups. CONCLUSION: In Japanese patients with advanced prostate
      cancer, first-line treatment with bicalutamide 80 mg in combination with an LHRH
      agonist is superior to LHRH agonist monotherapy in terms of the antitumor
      response at 12 weeks, and also time to treatment failure and progression, and
      does not compromise treatment safety. The study is ongoing.

PMID- 15020660
TI  - Radical external beam radiotherapy for prostate cancer in Japan: preliminary
      results of the 1999-2001 patterns of care process survey.
AB  - BACKGROUND: A Patterns of Care Study (PCS) has been conducted to evaluate the
      standards of practice for prostate cancer patients treated with radiotherapy in
      Japan. This study examines the influence of institutional stratification on the
      process of care for patients receiving radical external beam radiotherapy for
      prostate cancer in the 1999-2001 PCS in Japan. These PCS results were compared
      with those of the 1999 PCS in the USA. METHODS: A national survey of 36
      institutions was conducted using two-stage cluster sampling and detailed
      information was accumulated on 305 clinically localized prostate cancer patients
      who received radiotherapy between 1999 and 2001. Of these, 181 patients treated
      with radical external beam radiotherapy were selected and the preliminary results
      were analyzed. Institutions were classified as A1 (academic institutions treating
      >or=430 patients a year) or B1 (non-academic institutions treating >or=130
      patients a year). RESULTS: In both A1 and B1 institutions, more than 80% of the
      patients had intermediate or unfavorable risk diseases. There were no significant
      differences in the patients' disease characteristics between A1 and B1
      institutions, while the institutional stratification significantly affected the
      patterns of radiotherapy; such as the beam energy (>or=10 MV, A1 89.9%, B1 72.2%;
      P = 0.0022), the use of a CT simulator (A1 91.0%, B1 80.0%; P = 0.0340) and the
      administration of conformal therapy (A1 85.0%, B1 20.5%; P < 0.0001). The median
      number of full-time equivalent (FTE) radiation oncologists was 2.7 in A1
      institutions and only 0.7 in B1 institutions. Median radiation doses of 66.00 Gy
      (A1 institutions) and 69.00 Gy (B1 institutions) were delivered and hormonal
      therapy was commonly used before, during and after radiotherapy, with a mean
      duration of 1.3 years (88.0% in A1 institutions; 90.0% in B1 institutions). In
      comparing the results of PCS in Japan (1999-2001) with those in the USA (1999),
      patients in Japan were found to have more advanced primary diseases with higher
      PSA levels than those in the USA. The median prescribed dose to the primary tumor
      was not significantly different between the two countries (69.00 Gy in Japan and
      70.45 Gy in the USA). Conversely, almost half of the patients in the USA were
      treated with higher prescription dose levels (>or=72 Gy), whereas only 9.4% of
      the Japanese patients received these dose levels. Hormonal therapy was used more
      frequently in Japan (88.1% of the patients) than in the USA (50% of the
      patients). Most of the Japanese patients with a favorable prognosis (72.0%) were
      treated with hormonal therapy, compared with 30% in the USA. On the other hand,
      most of the patients in the unfavorable risk group were treated with radiotherapy
      in conjunction with hormonal therapy both in Japan (91.1%) and the USA (81%).
      CONCLUSIONS: During the period 1999-2001, the majority of the prostate cancer
      patients treated in Japan with radical external beam radiotherapy had advanced
      diseases and institutional stratification significantly affected the patterns of
      radiotherapy. In both academic and non-academic institutions, radiotherapy in
      conjunction with long-term hormonal therapy was commonly used. In comparison with
      the 1999 PCS in the USA, Japanese patients had more advanced diseases, but the
      higher prescribed doses (>or=72 Gy) were less common in Japan. Administration
      rates of hormonal therapy for favorable risk patients were different between
      Japan and the USA. On the other hand, for unfavorable risk patients, radiotherapy
      in conjunction with hormonal therapy appeared to be an accepted approach both in
      Japan and in the USA.

PMID- 15020661
TI  - Adequacy of cancer pain management in a Japanese Cancer Hospital.
AB  - BACKGROUND: Pain is one of the most frequent and deleterious symptoms in cancer
      patients. This study was carried out to investigate the adequacy of pain
      management at the National Cancer Center Hospital East, Japan. METHODS: The
      available data were obtained from 138 ambulatory cancer patients with pain. The
      data included pain severity, which patients reported using the Japanese version
      of the M. D. Anderson Symptom Inventory, along with such medical information as
      cancer and treatment information and currently prescribed analgesics. Adequacy of
      pain management was assessed using the Pain Management Index, which revealed
      whether prescribed analgesic drugs were congruent with pain severity. RESULTS:
      Physicians undertreated pain in 70% of patients. Patients with non-advanced
      cancer (local cancer or no evidence of any recurrent cancer) were more likely to
      receive inadequate treatment than those with advanced cancer [P = 0.009, odds
      ratio = 0.18, Exp (95% CI) lower = 0.05, higher = 0.64] in the exploratory
      logistic regression analysis. Additionally, we found significant differences
      among physicians in ability to manage cancer pain, unrelated to a physician's
      years of experience as an oncologist. CONCLUSIONS: This study suggests that
      cancer pain management is insufficient at the investigated institute. Remedial
      action should be taken, including increasing awareness of symptom management in
      medical staff and incorporating existing knowledge into routine clinical
      practice.

PMID- 15020662
TI  - Feasibility study of neoadjuvant chemotherapy followed by interval cytoreductive
      surgery for stage III/IV ovarian, tubal and peritoneal cancers: Japan Clinical
      Oncology Group Study JCOG0206.
AB  - A feasibility study was started in January 2003 on neoadjuvant chemotherapy (NAC)
      followed by interval cytoreductive surgery (ICS) and postoperative chemotherapy
      for stage III/IV mullerian carcinomas such as ovarian, tubal and peritoneal
      carcinomas. The purpose is to assess the safety and efficacy of the treatment
      starting with NAC and also to know whether we can accurately diagnose these
      advanced carcinomas by imaging studies, cytologic findings and tumor markers
      without staging laparotomy or laparoscopy. Fifty-six patients with advanced
      mullerian carcinomas will be recruited to the study. After confirmation of
      diagnosis by laparoscopic inspection and biopsies, patients undergo four cycles
      of chemotherapy as NAC, followed by ICS and an additional four cycles of post
      surgical chemotherapy. The primary endpoint is proportion of clinical complete
      remission after accomplishment of the protocol treatment, while the major
      secondary endpoint is positive predictive value of diagnosis before laparoscopy
      regarding tumor origin, histology and stage. Based on the results of this study,
      we will conduct a phase III study to compare the treatment starting with NAC and
      primary cytoreductive surgery followed by post-surgical chemotherapy.

PMID- 15020663
TI  - Late pulmonary metastasis of renal cell carcinoma resected 25 years after
      nephrectomy.
AB  - A 50-year-old male underwent a left nephrectomy for clear cell type renal cell
      carcinoma (RCC) in February 1978. A right pulmonary metastasis was resected in
      February 1994. At that time, chest computed tomography revealed the presence of
      three small nodules in the left lung, but these were followed up as inflammatory
      lesions. In January 2002, a right pleural metastasis, which showed rapid growth,
      was detected and it was resected in June of the same year. A gradual growth was
      observed in the left lung nodules, and the patient underwent wedge resection of
      the left lung in March 2003, 25 years after nephrectomy. These nodules were
      diagnosed as metastatic RCC. Currently, the patient is doing well with no signs
      of recurrence, 8 months after the third metastasectomy.

PMID- 15020664
TI  - Survival rates of childhood cancer patients in Osaka, Japan.
AB  - BACKGROUND: Survival of childhood cancer patients is often described in
      specialized hospitals and/or institutions, but not in the general population.
      METHODS: The trends and patterns of childhood cancer survival during 20 years
      were investigated using the Osaka Cancer Registry's data. The study subjects were
      3443 reported cases diagnosed as having the first primary cancer between 1975 and
      1994 at the ages of 0-14 years and who lived in Osaka Prefecture, excluding Osaka
      City. All childhood cancers were classified into 12 diagnostic groups according
      to the International Classification of Childhood Cancer based on the histology of
      the cancer. The 5 year relative survival was calculated by the Ederer II method.
      RESULTS: The 5-year relative survival was 58% for all cancers. The survivals of
      retinoblastoma and kidney tumor patients were as high as 89 and 72%,
      respectively, whereas those of leukemia and liver tumor patients were as low as
      45 and 47%, respectively. When divided into the first and second half-periods,
      the survival for all cancers was markedly improved from 48 to 68%. The survivals,
      especially for patients with leukemia, lymphoma, neuroblastoma, hepatoma and
      gonadal or embryonal tumors, were enhanced by >20% between the first and second
      half-periods. When these results were compared with those reported in England and
      Wales and the USA, however, the survivals for many diagnostic groups in Osaka
      were lower, except that for neuroblastoma. CONCLUSIONS: The survivals of
      childhood cancer patients have been markedly improved in Japan, but this finding
      suggested that the introduction and practice of chemotherapy was insufficient.

PMID- 15020666
TI  - The JAK/STAT signaling pathway.

PMID- 15020665
TI  - Disposition mechanisms of raloxifene in the human intestinal Caco-2 model.
AB  - The purpose of this study was to determine the mechanisms responsible for
      transport of raloxifene and its hydrophilic conjugates. Human intestinal Caco-2
      cell culture model and Caco-2 cell lysate were used for the studies. The results
      indicated that absorptive permeability (PAB) of raloxifene was lower than its
      secretory permeability (PAB). As the concentration increased, the efflux ratio
      (PBA/PAB) decreased, but PBA increased. PAB was also increased in the presence of
      verapamil and cyclosporine A, two P-glycoprotein inhibitors. Raloxifene was
      extensively metabolized into sulfated and glucuronidated conjugates. The extent
      of metabolism or clearance was decreased as the concentration increased from 3.4
      (96%) to 30 (22%) microM. Multidrug resistance-related protein inhibitors MK-571
      (C26H26ClN2O3S2) and leukotriene C4 significantly decreased (maximal 80%) apical
      efflux of both conjugates. They also significantly decreased (maximal 85%)
      basolateral efflux of glucuronides but not sulfates. On the other hand, organic
      anion transporter (OAT) inhibitor estrone sulfate and estrone glucuronide
      significantly decreased (maximal 50%) the efflux of sulfate from both sides but
      had variable effects on glucuronide efflux. Inhibition of conjugate efflux with
      the OAT inhibitor estrone sulfate was concentration dependent, which resulted in
      increased transport of intact raloxifene (maximal 90%). This increase in
      raloxifene transport was also observed in the presence of another OAT inhibitor
      estrone glucuronide (70%). In conclusion, this is the first report that
      inhibition of an efflux transporter responsible for the transport of metabolites
      can result in increase in the transport of the intact compound. It also provides
      additional explanation why raloxifene has low bioavailability but a long half
      life.

PMID- 15020667
TI  - Mary Osborn. Interview by Fiona Watt.

PMID- 15020668
TI  - Watch thy neighbor: cancer is a communal affair.
AB  - Malignant transformation of an epithelium occurs within the context of a
      dynamically evolving tissue stroma that is composed of multiple cell types
      surrounded by an extracellular matrix. Because stromal-epithelial interactions
      regulate tissue homeostasis and can profoundly influence tumorigenesis it has
      been proposed that the stromal microenvironment is an epigenetic tumor modifier
      that can either positively or negatively regulate the malignant behavior of
      genetically aberrant cells. New work reported in this issue of Journal of Cell
      Science now provides compelling evidence that alterations in the stroma are
      necessary and also sufficient for induction of malignant behavior by genetically
      normal cells.

PMID- 15020669
TI  - Cdc42--the centre of polarity.
AB  - All cell types polarize, at least transiently, during division or to generate
      specialized shapes and functions. This capacity extends from yeast to mammals,
      and it is now clear that many features of the molecular mechanisms controlling
      polarization are conserved in all eukaryotic cells. At the centre of the action
      is Cdc42, a small GTPase of the Rho family. Its activity is precisely controlled
      both temporally and spatially, and this can be achieved by a wide variety of
      extracellular cues in multicellular organisms. Moreover, although the functional
      characteristics of cell polarity are extremely variable (depending on the cell
      type and the biological context), Cdc42 has an amazing capacity to co-ordinate
      the control of multiple signal transduction pathways.

PMID- 15020670
TI  - Rho-family GTPases: it's not only Rac and Rho (and I like it).
AB  - The Rho-family proteins make up a major branch of the Ras superfamily of small
      GTPases. To date, 22 human genes encoding at least 25 proteins have been
      described. The best known 'classical' members are RhoA, Rac1 and Cdc42. Highly
      related isoforms of these three proteins have not been studied as intensively, in
      part because it has been assumed that they are functionally identical to their
      better-studied counterparts. This now appears not to be the case. Variations in C
      terminal-signaled modifications and subcellular targeting cause otherwise highly
      biochemically related isoforms (e.g. RhoA, RhoB and RhoC) to exhibit surprisingly
      divergent biological activities. Whereas the classical Rho GTPases are regulated
      by GDP/GTP cycling, other Rho GTPases are also regulated by other mechanisms,
      particularly by transcriptional regulation. Newer members of the family possess
      additional sequence elements beyond the GTPase domain, which suggests they
      exhibit yet other mechanisms of regulation.

PMID- 15020671
TI  - Designing biosensors for Rho family proteins--deciphering the dynamics of Rho
      family GTPase activation in living cells.
AB  - Rho family GTPases are molecular switches that couple changes in the
      extracellular environment to intracellular signal transduction pathways. Their
      ability to regulate behaviors such as cell motility suggests very tight kinetic
      and spatial control of their activity, which is missed in most biochemical
      assays. Fluorescent probes that non-invasively report the changing subcellular
      location of Rho GTPase activity in single living cells are now allowing us to
      examine spatio-temporal regulation of the activity of these proteins, and are
      providing new biological insights. Several strategies can be used to construct
      such probes, and there are advantages and disadvantages associated with the
      diverse probe designs.

PMID- 15020672
TI  - Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion
      inhibitor of primary human trophoblasts.
AB  - Trophoblast invasion of the uterine extracellular matrix, a critical process of
      human implantation and essential for fetal development, is a striking example of
      controlled invasiveness. To identify molecules that regulate trophoblast
      invasion, mRNA signatures of trophoblast cells isolated from first trimester
      (high invasiveness) and term placentae (no/low invasiveness) were compared using
      U95A GeneChip microarrays yielding 220 invasion/migration-related genes. In this
      'invasion cluster', KiSS-1 and its G-protein-coupled receptor KiSS-1R were
      expressed at higher levels in first trimester trophoblasts than at term of
      gestation. Receptor and ligand mRNA and protein were localized to the trophoblast
      compartment. In contrast to KiSS-1, which is only expressed in the villous
      trophoblast, KiSS-1R was also found in the extravillous trophoblast, suggesting
      endocrine/paracrine activation mechanisms. The primary translation product of
      KiSS-1 is a 145 amino acid polypeptide (Kp-145), but shorter kisspeptins (Kp)
      with 10, 13, 14 or 54 amino acid residues may be produced. We identified Kp-10, a
      dekapeptide derived from the primary translation product, in conditioned medium
      of first trimester human trophoblast. Kp-10, but not other kisspeptins, increased
      intracellular Ca(2+) levels in isolated first trimester trophoblasts. Kp-10
      inhibited trophoblast migration in an explant as well as transwell assay without
      affecting proliferation. Suppressed motility was paralleled with suppressed
      gelatinolytic activity of isolated trophoblasts. These results identified Kp-10
      as a novel paracrine/endocrine regulator in fine-tuning trophoblast invasion
      generated by the trophoblast itself.

PMID- 15020673
TI  - Dynamics of novel feet of Dictyostelium cells during migration.
AB  - We observed the dynamics of actin foci in live Dictyostelium cells expressing GFP
      actin. Actin foci were dynamic structures, but they were fixed on the substratum
      during cell migration. Interference reflection microscopy revealed that the
      ventral cell membrane was closer to the substratum at sites of actin foci.
      Furthermore, some actin foci were incorporated into the retraction fibers, ripped
      off from the cells and eventually shed on the substratum after the cells moved
      away. The velocity of the cells was inversely proportional to the number of actin
      foci. Measurement of traction force using a silicone substratum demonstrated that
      the traction force was transmitted to the substratum through actin foci. Taken
      together, several lines of evidence strongly suggest that actin foci function as
      the active 'feet' of Dictyostelium cells. We also found evidence suggesting that
      changing step is regulated in a coordinated manner during cell migration.
      Possible mechanisms by which these cells migrate across substrata are discussed
      in this context.

PMID- 15020674
TI  - MyoD enhances BMP7-induced osteogenic differentiation of myogenic cell cultures.
AB  - The muscle-specific, basic helix-loop-helix transcription factor MyoD can induce
      cells from other mesenchymal lineages to express a skeletal muscle phenotype.
      Interestingly, MyoD is initially upregulated in myogenic cells incubated with
      bone morphogenetic proteins (BMPs), a treatment that induces osteogenic
      differentiation, suggesting that MyoD has a role in BMP-induced osteogenesis of
      myogenic cells. This possibility is supported by our observations that muscle
      satellite cells derived from adult MyoD(-/-) mice show severely impaired
      osteogenic induction by BMP-7 (osteogenic protein 1; OP-1) as indicated by the
      decreased gene expression of the bone markers alkaline phosphatase, osteocalcin,
      Runx2/Cbfa1, and Osterix. Ectopic expression of MyoD increased alkaline
      phosphatase activity and Osterix mRNA expression in response to BMP treatment.
      Similarly, ectopic expression of MyoD in the pluripotent mesenchymal cell line
      C3H10T1/2 increased alkaline phosphatase activity induced by BMP-7. Transcription
      assays showed that transfection with a MyoD-expression vector, but not other
      myogenic basic helix-loop-helix transcription factors (Myf5, myogenin) increased
      Runx2/Cbfa1 transactivation of a reporter gene construct containing either six
      OSE sequences in tandem or a single OSE site. This effect was enhanced by BMP
      treatment. These studies, therefore, demonstrate that the muscle transcription
      factor MyoD is required for efficient BMP-induced osteogenesis of myogenic cells
      and indicate that MyoD might exert its effects through co-operative interactions
      with Runx2/Cbfa1.

PMID- 15020675
TI  - Developmental-stage-specific triacylglycerol biosynthesis, degradation and
      trafficking as lipid bodies in Plasmodium falciparum-infected erythrocytes.
AB  - Triacylglycerol (TAG) serves as a major energy storage molecule in eukaryotes. In
      Plasmodium, however, this established function of TAG appears unlikely, despite
      detecting previously considerable amount of TAG associated with intraerythrocytic
      parasites, because plasmodial cells have very little capacity to oxidize fatty
      acids. Thus, it is plausible that TAG and its biosynthesis in Plasmodium have
      other functions. As a first step in understanding the biological significance of
      TAG and its biosynthesis to the intraerythrocytic proliferation of Plasmodium
      falciparum, we performed detailed characterization of TAG metabolism and
      trafficking in parasitized erythrocyte. Metabolic labeling using radiolabeled
      oleic and palmitic acids in association with serum albumin, which have been shown
      to be among the serum essential factors for intraerythrocytic proliferation of P.
      falciparum, revealed that accumulation of TAG was strikingly pronounced from
      trophozoite to schizont, whereas TAG degradation became active from schizont to
      segmented schizont; the consequent products, free fatty acids, were released into
      the medium during schizont rupture and/or merozoite release. These results were
      further supported by visualization of lipid bodies through immunofluorescence and
      electron microscopy. At the schizont stages, there is some evidence that the
      lipid bodies are partly localized in the parasitophorous vacuole. Interestingly,
      the discrete formation and/or trafficking of lipid bodies are inhibited by
      brefeldin A and trifluoperazine. Inhibition by trifluoperazine hints at least
      that a de novo TAG biosynthetic pathway via phosphatidic acid contributes to
      lipid body formation. Indeed, biochemical analysis reveals a higher activity of
      acyl-CoA:diacylglycerol acyltransferase, the principal enzyme in the sn-glycerol
      3-phosphate pathway for TAG synthesis, at trophozoite and schizont stages.
      Together, these results establish that TAG metabolism and trafficking in P.
      falciparum-infected erythrocyte occurs in a stage-specific manner during the
      intraerythrocytic cycle and we propose that these unique and dynamic cellular
      events participate during schizont rupture and/or merozoite release.

PMID- 15020676
TI  - The N-terminus of the long MLCK induces a disruption in normal spindle morphology
      and metaphase arrest.
AB  - We have shown previously that only the long myosin light chain kinase (MLCK),
      which is the predominant MLCK isoform expressed in nonmuscle cells, localizes to
      the cleavage furrow. To further examine the in vivo localization of the long MLCK
      in HeLa cells and the mechanisms responsible for kinase targeting during the cell
      cycle, we examined the distribution of the endogenous kinase and constructed
      green fluorescent protein (GFP) fusions of long HeLa MLCK truncations. A GFP
      fusion containing the N-terminal IgG domain and the five DXR motifs localized to
      stress fibers during interphase and the cleavage furrow during mitosis. Although
      individual fusions of the five DXRs and IgG domain both independently localized
      to stress fibers, only the five DXRs demonstrated a cortical localization in
      mitotic cells. Thus, robust targeting of the long MLCK to the cleavage furrow
      required the five DXRs and additional sequences from the IgG domain. Expression
      of the IgG domain alone or with five DXRs increased the number of multinucleate
      cells tenfold, whereas expression of the five DXRs or GFP had no effect.
      Furthermore, expression of the IgG domain alone or with five DXRs disrupted
      normal spindle morphology during mitosis. Extended astral microtubules and
      increased bundling of kinetochore microtubules, and spindle pole fragmentation
      were detected in mitotic cells. These microtubule defects were associated with
      abnormalities in metaphase chromosome alignment and a subsequent metaphase arrest
      caused by activation of the spindle assembly checkpoint at the kinetochores of
      mono-oriented chromosomes. Together, these results suggest that MLCK has an
      unexpected regulatory function during mitosis.

PMID- 15020677
TI  - Contractile filament architecture and force transmission in swine airway smooth
      muscle.
AB  - It is well known that the cyclic interaction of myosin cross bridges with actin
      filaments is responsible for force and shortening generation in smooth muscle.
      The intracellular organization of contractile filaments, however, is still poorly
      understood. Here, we show electron microscopic and functional evidence that
      contractile filaments in airway smooth muscle lie parallel to the longitudinal
      axis of the cell bundle, in contrast to the obliquely arranged filaments depicted
      in conventional models. The parallel arrangement of contractile filaments is
      maintained despite the fact that individual cells are spindle-shaped. This is
      accomplished through filament attachment to membrane-associated dense plaques
      that are in turn connected to similar structures on neighboring cells.
      Intracellularly, the parallel arrangement is maintained despite the centrally
      located nucleus. This is accomplished by attachment of actin filaments to the
      nuclear envelope and making the nucleus a force transmitting structure. The
      results suggest that smooth muscle cells in tissue form a mechanical syncytium
      and are able to function properly only as a group.

PMID- 15020678
TI  - Deregulation of Flk-1/vascular endothelial growth factor receptor-2 in fibroblast
      growth factor receptor-1-deficient vascular stem cell development.
AB  - We have employed embryoid bodies derived from murine embryonal stem cells to
      study effects on vascular development induced by fibroblast growth factor (FGF)-2
      and FGF receptor-1, in comparison to the established angiogenic factor vascular
      endothelial growth factor (VEGF)-A and its receptor VEGF receptor-2. Exogenous
      FGF-2 promoted formation of morphologically distinct, long slender vessels in the
      embryoid bodies, whereas VEGF-A-treated bodies displayed a compact plexus of
      capillaries. FGF-2 stimulation of embryonal stem cells under conditions where
      VEGF-A/VEGFR-2 function was blocked, led to formation of endothelial cell
      clusters, which failed to develop into vessels. FGFR-1(-/-) embryoid bodies
      responded to VEGF-A by establishment of the characteristic vascular plexus, but
      FGF-2 had no effect on vascular development in the absence of FGFR-1. The FGFR-1(
      /-) embryoid bodies displayed considerably increased basal level of vessel
      formation, detected by immunohistochemical staining for platelet-endothelial cell
      adhesion molecule (PECAM)/CD31. This basal vascularization was blocked by
      neutralizing antibodies against VEGFR-2 or VEGF-A and biochemical analyses
      indicated changes in regulation of VEGFR-2 in the absence of FGFR-1 expression.
      We conclude that VEGF-A/VEGFR-2-dependent vessel formation occurs in the absence
      of FGF-2/FGFR-1, which, however, serve to modulate vascular development.

PMID- 15020679
TI  - An alternative form of paraptosis-like cell death, triggered by TAJ/TROY and
      enhanced by PDCD5 overexpression.
AB  - Accumulating reports demonstrate that apoptosis does not explain all the forms of
      programmed cell death (PCD), particularly in individual development and
      neurodegenerative disease. Recently, a novel type of PCD, designated
      'paraptosis', was described. Here, we show that overexpression of TAJ/TROY, a
      member of the tumor necrosis factor receptor superfamily, induces non-apoptotic
      cell death with paraptosis-like morphology in 293T cells. Transmission electron
      microscopy studies reveal extensive cytoplasmic vacuolation and mitochondrial
      swelling in some dying cells and no condensation or fragmentation of the nuclei.
      Characteristically, cell death triggered by TAJ/TROY was accompanied by
      phosphatidylserine externalization, loss of the mitochondrial transmembrane
      potential and independent of caspase activation. In addition, TAJ/TROY suppressed
      clonogenic growth of HEK293 and HeLa cells. Interestingly, overexpression of
      Programmed cell death 5 (PDCD5), an apoptosis-promoting protein, enhanced
      TAJ/TROY-induced paraptotic cell death. Moreover, cellular endogenous PDCD5
      protein was significantly upregulated in response to TAJ/TROY overexpression.
      These results provide novel evidence that TAJ/TROY activates a death pathway
      distinct from apoptosis and that PDCD5 is an important regulator in both
      apoptotic and non-apoptotic PCD.

PMID- 15020680
TI  - Roles of microtubules, cell polarity and adhesion in electric-field-mediated
      motility of 3T3 fibroblasts.
AB  - Direct-current electric fields mediate motility (galvanotaxis) of many cell
      types. In 3T3 fibroblasts, electric fields increased the proportion, speed and
      cathodal directionality of motile cells. Analogous to fibroblasts' spontaneous
      migration, we initially hypothesized that reorientation of microtubule components
      modulates galvanotaxis. However, cells with intact microtubules did not reorient
      them in the field and cells without microtubules still migrated, albeit slowly,
      thus disproving the hypothesis. We next proposed that, in monolayers wounded and
      placed in an electric field, reorientation of microtubule organizing centers and
      stable, detyrosinated microtubules towards the wound edge is necessary and/or
      sufficient for migration. This hypothesis was negated because field exposure
      mediated migration of unoriented, cathode-facing cells and curtailed migration of
      oriented, anode-facing cells. This led us to propose that ablating microtubule
      detyrosination would not affect galvanotaxis. Surprisingly, preventing
      microtubule detyrosination increased motility speed, suggesting that
      detyrosination inhibits galvanotaxis. Microtubules might enhance adhesion/de
      adhesion remodeling during galvanotaxis; thus, electric fields might more
      effectively mediate motility of cells poorly or dynamically attached to
      substrata. Consistent with this hypothesis, incompletely spread cells migrated
      more rapidly than fully spread cells. Also, overexpression of PAK4, a Cdc42
      activated kinase that decreases adhesion, enhanced galvanotaxis speed, whereas
      its lack decreased speed. Thus, electric fields mediate fibroblast migration via
      participation of microtubules and adhesive components, but their participation
      differs from that during spontaneous motility.

PMID- 15020681
TI  - The EBP50-moesin interaction involves a binding site regulated by direct masking
      on the FERM domain.
AB  - Members of the ezrin-radixin-moesin (ERM) protein family serve as regulated
      microfilament-membrane crosslinking proteins that, upon activation, bind the
      scaffolding protein ERM-phosphoprotein of 50 kDa (EBP50). Here we report a 3.5 A
      resolution diffraction analysis of a complex between the active moesin N-terminal
      FERM domain and a 38 residue peptide from the C terminus of EBP50. This
      crystallographic result, combined with sequence and structural comparisons,
      suggests that the C-terminal 11 residues of EBP50 binds as an alpha-helix at the
      same site occupied in the dormant monomer by the last 11 residues of the
      inhibitory moesin C-terminal tail. Biochemical support for this interpretation
      derives from in vitro studies showing that appropriate mutations in both the
      EBP50 tail peptide and the FERM domain reduce binding, and that a peptide
      representing just the C-terminal 14 residues of EBP50 also binds to moesin.
      Combined with the recent identification of the I-CAM-2 binding site on the ERM
      FERM domain (Hamada, K., Shimizu, T., Yonemura, S., Tsukita, S., and Hakoshima,
      T. (2003) EMBO J. 22, 502-514), this study reveals that the FERM domain contains
      two distinct binding sites for membrane-associated proteins. The contribution of
      each ligand to ERM function can now be dissected by making structure-based
      mutations that specifically affect the binding of each ligand.

PMID- 15020682
TI  - CRM1 and Ran are present but a NES-CRM1-RanGTP complex is not required in
      Balbiani ring mRNP particles from the gene to the cytoplasm.
AB  - Messenger RNA is formed from precursors known as pre-mRNA. These precursors
      associate with proteins to form pre-mRNA-protein (pre-mRNP) complexes. Processing
      machines cap, splice and polyadenylate the pre-mRNP and in this way build the
      mRNP. These processing machines also affect the export of the mRNP complexes from
      the nucleus to the cytoplasm. Export to the cytoplasm takes place through a
      structure in the nuclear membrane called the nuclear pore complex (NPC). Export
      involves adapter proteins in the mRNP and receptor proteins that bind to the
      adapter proteins and to components of the NPC. We show that the export receptor
      chromosomal region maintenance protein 1 (CRM1), belonging to a family of
      proteins known as importin-beta-like proteins, binds to gene-specific Balbiani
      ring (BR) pre-mRNP while transcription takes place. We also show that the GTPase
      known as Ran binds to BR pre-mRNP, and that it binds mainly in the
      interchromatin. However, we also show using leptomycin B treatment that a NES
      CRM1-RanGTP complex is not essential for export, even though both CRM1 and Ran
      accompany the BR mRNP through the NPC. Our results therefore suggest that several
      export receptors associate with BR mRNP and that these receptors have redundant
      functions in the nuclear export of BR mRNP.

PMID- 15020683
TI  - Trophic signals acting via phosphatidylinositol-3 kinase are required for normal
      pre-implantation mouse embryo development.
AB  - The growth and survival of the preimplantation mammalian embryo may be regulated
      by several autocrine trophic factors that have redundant or overlapping actions.
      One of the earliest trophic factors to be produced is embryo-derived platelet
      activating factor (1-O-alky-2-acetyl-sn-glyceryl-3-phosphocholine). The addition
      of platelet-activating factor to embryo culture media exerted a trophic effect,
      but structurally related lipids (3-O-alky-2-acetyl-sn-glyceryl-1-phosphocholine,
      1-O-alky-sn-glyceryl-3-phosphocholine, octadecyl-phosphocholine) had no effect.
      Platelet-activating factor induced a pertussis toxin-sensitive [Ca(2+)](i)
      transient in two-cell embryos that did not occur in platelet-activating factor
      receptor null (Pafr-/-) genotype embryos. Fewer Pafr-/- mouse zygotes developed
      to the blastocyst stage in vitro compared with Pafr+/+ zygotes (P<0.02), those
      that developed to blastocysts had fewer cells (P<0.001) and more cells with
      fragmented nuclei (P<0.001). The inhibition of 1-O-phosphatidylinositol 3-kinase
      (LY294002 (3 microM and 15 microM) and wortmannin (10 nM and 50 nM)) caused a
      dose-dependent inhibition of platelet-activating factor-induced [Ca(2+)](i)
      transients (P<0.001). The two-cell embryo expressed 1-O-phosphatidylinositol 3
      kinase catalytic subunits p110 alpha, beta, gamma and delta, and regulatory
      subunits p85 alpha and beta. LY294002 and wortmannin each caused a significant
      reduction in the proportion of embryos developing to the morula and blastocyst
      stages in vitro, reduced the number of cells within each blastocyst, and
      significantly increased the proportion of cells in blastocysts with fragmented
      nuclei. The results indicate that embryo-derived platelet-activating factor (and
      other embryotrophic factors) act through its membrane receptor to enhance embryo
      survival through a 1-O-phosphatidylinositol 3-kinase-dependent survival pathway.

PMID- 15020684
TI  - Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2,
      and chromosome congression.
AB  - During mitosis, the recruitment of spindle-checkpoint-associated proteins to the
      kinetochore occurs in a defined order. The protein kinase Bub1 localizes to the
      kinetochore very early during mitosis, followed by Cenp-F, BubR1, Cenp-E and
      finally Mad2. Using RNA interference, we have investigated whether this order of
      binding reflects a level of dependency in human somatic cells. Specifically, we
      show that Bub1 plays a key role in the assembly of checkpoint proteins at the
      kinetochore, being required for the subsequent localization of Cenp-F, BubR1,
      Cenp-E and Mad2. In contrast to studies in Xenopus, we also show that BubR1 is
      not required for kinetochore localization of Bub1. Repression of Bub1 increases
      the number of cells with lagging chromosomes at metaphase, suggesting that Bub1
      plays a role in chromosome congression. However, repression of Bub1 does not
      appear to compromise spindle checkpoint function either during normal mitosis or
      in response to spindle damage. This raises the possibility that, in the absence
      of Bub1, other mechanisms contribute to spindle checkpoint function.

PMID- 15020685
TI  - Microtubules continuously dictate distribution of actin filaments and positioning
      of cell cleavage in grasshopper spermatocytes.
AB  - We systematically examined the impact of microtubules on distribution of actin
      filaments and positioning of cell cleavage using micromanipulation to
      progressively alter the symmetric distribution of spindle microtubules in
      grasshopper spermatocytes. The initial microtubule asymmetry was induced by
      placing a single chromosome at one spindle pole using a microneedle, which
      facilitates regional assembly of spindle microtubules. We augmented chromosome
      induced microtubule asymmetry by further removing the aster from the achromosomal
      pole, producing unichromosome-bearing monopolar spindles. We created the highest
      spindle asymmetry by cutting early anaphase cells in two, each containing a full
      set of segregating chromosomes in a half-spindle. We demonstrate that the
      location of the spindle midzone, distribution of actin filaments, and position of
      cell cleavage depend on the amount of microtubule asymmetry generated, shifting
      up to 48.6+/-3.8% away from the spindle equator in cut cells. The positional
      shift is dynamic, changing incessantly as spindle microtubules reorganize during
      cytokinesis. These results suggest that microtubules continuously dictate the
      distribution of actin filaments and positioning of cell cleavage in grasshopper
      spermatocytes.

PMID- 15020686
TI  - p130Cas interacts with estrogen receptor alpha and modulates non-genomic estrogen
      signaling in breast cancer cells.
AB  - Steroid hormones bind to their receptors and trans-activate target genes. Rapid
      non-genomic action of steroid hormones has been proposed in addition to the one
      at the genomic level. Estrogen has been described to activate c-Src kinase and
      this activation has been shown to be responsible for estrogen-dependent
      mitogenicity. A major substrate of c-Src kinase activity is the cytoskeletal
      protein p130Cas, originally identified in v-Src-transformed cells. We show that
      in the human breast carcinoma T47D cells, upon estrogen treatment, p130Cas
      rapidly and transiently associates with the estrogen receptor alpha in a multi
      molecular complex containing the c-Src kinase and the p85 subunit of PI 3-kinase.
      Association of p130Cas with the estrogen receptor alpha occurs within 3 minutes
      of estrogen treatment and is dependent on c-Src kinase activation. Transient
      overexpression of p130Cas in T47D cells increases estrogen-dependent Src kinase
      and Erk1/2 MAPKs activities and accelerates their kinetics of stimulation. A
      similar effect was detected on estrogen-dependent cyclin D1 expression,
      suggesting a role for p130Cas in regulating estrogen-dependent cell cycle
      progression. Double-stranded small RNA interference (siRNA) by silencing
      endogenous p130Cas protein, was sufficient to inhibit estrogen-dependent Erk1/2
      MAPKs activity and cyclin D1 induction, demonstrating the requirement of p130Cas
      in such events. Therefore, our data show that the adaptor protein p130Cas
      associates with the estrogen receptor transducing complex, regulating estrogen
      dependent activation of c-Src kinase and downstream signaling pathways.

PMID- 15020687
TI  - Physiological mechanisms of lysophosphatidylcholine-induced de-ramification of
      murine microglia.
AB  - Activation of microglial cells, the resident macrophages of the brain, occurs
      rapidly following brain injury. De-ramification, i.e. transformation from
      ramified into amoeboid morphology is one of the earliest manifestations of
      microglial activation. In the present study, we identified the physiological
      mechanisms underlying microglial de-ramification induced by
      lysophosphatidylcholine (LPC). Patch-clamp experiments revealed activation of non
      selective cation currents and Ca(2+)-dependent K(+) currents by extracellular
      LPC. LPC-activated non-selective cation channels were permeable for monovalent
      and divalent cations. They were inhibited by Gd(3+), La(3+), Zn(2+) and
      Grammostola spatulata venom, but were unaffected by diltiazem, LOE908MS,
      amiloride and DIDS. Ca(2+) influx through non-selective cation channels caused
      sustained increases in intracellular Ca(2+) concentration. These Ca(2+) increases
      were sufficient to elicit charybdotoxin-sensitive Ca(2+)-dependent K(+) currents.
      However, increased [Ca(2+)](i) was not required for LPC-induced morphological
      changes. In LPC-stimulated microglial cells, non-selective cation currents caused
      transient membrane depolarization, which was followed by sustained membrane
      hyperpolarization induced by Ca(2+)-dependent K(+) currents. Furthermore, LPC
      elicited K(+) efflux by stimulating electroneutral K(+)-Cl(-) cotransporters,
      which were inhibited by furosemide and DIOA. LPC-induced microglial de
      ramification was prevented by simultaneous inhibition of non-selective cation
      channels and K(+)-Cl(-) cotransporters, suggesting their functional importance
      for microglial activation.

PMID- 15020688
TI  - Lumbar sympathetic nerve activity and hindquarter blood flow during REM sleep in
      rats.
AB  - The present study aimed to investigate the response of lumbar sympathetic nerve
      activity (LSNA) to the onset of rapid eye movement (REM) sleep and its
      contribution to the regulation of muscle blood flow during REM sleep in rats.
      Electrodes for the measurements of LSNA, electroencephalogram, electromyogram and
      electrocardiogram and a Doppler flow cuff for the measurements of blood flow in
      the common iliac and mesenteric arteries, also catheters for the measurements of
      systemic arterial and central venous pressures were implanted chronically. REM
      sleep resulted in a step increase in LSNA, by 22 +/- 9% (mean +/-S.E.M., P <
      0.05), a reduction of iliac vascular conductance, by -16 +/- 3% (P < 0.05) and a
      gradual increase in systemic arterial pressure, reaching a maximum value of 8.1
      +/- 2.0 mmHg (P < 0.05) at 89 s after onset of REM sleep, while mesenteric
      vascular conductance increased simultaneously by 5 +/- 2% (P < 0.05). There was a
      significant (Pearson's correlation coefficient = 0.94, P < 0.05) inverse linear
      relationship between LSNA and the iliac blood flow. Unilateral lumbar
      sympathectomy blunted the reduction of iliac blood flow induced by the onset of
      REM sleep. The present observations suggest that the onset of REM sleep appears
      to be associated with a vasodilation in viscera and a vasoconstriction in
      skeletal muscle, such that systemic arterial pressure increases during REM sleep
      in rats.

PMID- 15020689
TI  - CLC-3 knockout hints at swelling-activated chloride channel complexity.

PMID- 15020690
TI  - Fluid exchange in the microcirculation.

PMID- 15020693
TI  - Direct evidence for the contribution of the superior colliculus in the control of
      visually guided reaching movements in the cat.
AB  - The production of visually guided reaching movements relies on a large neural
      network. Based on indirect experimental evidence, it has been suggested that the
      superior colliculus, a subcortical centre known for its key role in controlling
      rapid orienting gaze shifts, also belongs to this network. The aim of the present
      study was to investigate the role of the cat superior colliculus (SC) in the
      control of visually guided reaching movements. To address this issue, we studied
      the effect of SC electrical stimulation on forelimb reaching movements in two
      cats trained to catch a piece of food. Electrical stimulation delivered just
      after the movement onset yielded a consistent perturbation of the movement
      trajectory of the forelimb extremity. This perturbation followed stimulation
      onset by 56 +/- 11 ms on average, and consisted of a deviation of the spatial
      path and a deceleration of the movement. The forelimb perturbation was elicited
      in the absence of concomitant gaze or head displacement in 52% of the stimulation
      trials. Forelimb perturbations were followed by in-flight adjustments so that
      reaching movements reliably ended on the target. The present results constitute
      the first behavioural evidence for a contribution of the cat SC to the control of
      visually guided forelimb movements.

PMID- 15020691
TI  - CaT1 knock-down strategies fail to affect CRAC channels in mucosal-type mast
      cells.
AB  - CaT1, the calcium transport protein 1 encoded by TRPV6, is able to generate a
      Ca(2+) conductance similar but not identical to the classical CRAC current in
      mucosal-type mast cells. Here we show that CaT1-derived Ca(2+) entry into HEK293
      cells is effectively inhibited either by expression of various dominant negative
      N-terminal fragments of CaT1 (N(334)-CaT1, N(198)-CaT1 and N(154)-CaT1) or by
      antisense suppression. By contrast, the endogenous CRAC current of the mast cells
      was unaffected by CaT1 antisense and siRNA knockdown but markedly suppressed by
      two (N(334)-CaT1, N(198)-CaT1) of the dominant negative N-CaT1 fragments.
      Inhibition of CRAC current was not an unspecific, toxic effect, as inward
      rectifier K(+) and MagNuM currents of the mast cells were not significantly
      affected by these N-CaT1 fragments. The shortest N(154)-CaT1 fragment inhibited
      CaT1-derived currents in mast cells, but failed to inhibit CRAC currents. Thus,
      the structural requirements of rCaT N-terminal fragments for inhibition of rCaT1
      and CRAC channels are different. These results together with the lack of CaT1
      antisense and siRNA effects on currents render it unlikely that CaT1 is a
      component of native CRAC channels in mast cells. The data further demonstrate a
      novel strategy for CRAC current inhibition by an N-terminal structure of CaT1.

PMID- 15020692
TI  - Cyclooxygenase-2 contributes to dysmotility and enhanced excitability of
      myenteric AH neurones in the inflamed guinea pig distal colon.
AB  - We have previously demonstrated that trinitrobenzene sulphonic acid (TNBS)
      induced colitis in guinea pig is associated with hyperexcitability of myenteric
      AH neurones, enhanced synaptic activity in the myenteric plexus, increased
      serotonin (5-HT) availability in the mucosa, and decreased propulsive motor
      activity. The current study tested the hypothesis that the activation of
      cyclooxygenase (COX) contributes to these alterations in bowel functions. DFU
      inhibition of COX-2, but not SC-560 inhibition of COX-1, restored to normal
      levels the electrical properties of myenteric AH neurones, the proportion of S
      neurones exhibiting slow EPSPs, and the rate of propulsive motor activity.
      Neither inhibitor was effective in altering the level of inflammation, the
      increased availability of mucosal 5-HT, or the enhanced fast EPSPs in myenteric
      AH and S neurones. COX-2 expression is enhanced in the myenteric plexus and cells
      within the smooth muscle layers during colitis, possibly reflecting the site at
      which COX-2 inhibition acts to allow recovery of motor function. In support of
      this concept, COX-1, but not COX-2, inhibition was effective in restoring normal
      mucosal prostaglandin levels. These results indicate that the various changes
      that occur in the motor neural pathways of the distal colon in TNBS-induced
      colitis do not involve a single neuroimmune mechanism. COX-2 activation is a
      critical step in the enhanced excitability of AH neurones as well as diminished
      propulsive motility in TNBS colitis, whereas other yet to be resolved pathways,
      that do not involve COX-1 or COX-2 activation, lead to altered 5-HT content in
      the mucosa and an augmentation of fast EPSPs.

PMID- 15020694
TI  - SUR2A C-terminal fragments reduce KATP currents and ischaemic tolerance of rat
      cardiac myocytes.
AB  - C-terminal fragments of the sulphonylurea receptor SUR2A can alter the functional
      expression of cloned ATP-sensitive K(+) channels (K(ATP)). To investigate the
      protective role of K(ATP) channels during metabolic stress we transfected SUR2A
      fragments into adult rat cardiac myocytes. A fragment comprising residues 1294
      1358, the A-fragment, reduced sarcolemmal K(ATP) currents by over 85% after 2
      days (pinacidil-activated current densities were: vector alone 7.04 +/- 1.22; and
      A-fragment 0.94 +/- 0.07 pA pF(-1), n= 6,6, P < 0.001). An inactive fragment
      (1358-1545, current density 6.30 +/- 0.85 pA pF(-1), n= 6) was used as a control.
      During metabolic inhibition (CN and iodoacetate) of isolated myocytes stimulated
      at 1 Hz, the A-fragment delayed action potential shortening and contractile
      failure, but accelerated rigor contraction and increased Ca(2+) loading. On
      reperfusion, A-fragment-transfected cells also showed increased intracellular
      Ca(2+) and the proportion of cells recovering contractile function was reduced
      from 40.0 to 9.5% (P < 0.01). The protective effect of pretreatment with 2,4
      dinitrophenol, measured from increased functional recovery and reduced Ca(2+)
      loading, was abolished by the A-fragment. Our data are consistent with a role for
      K(ATP) channels in causing action potential failure and reduced Ca(2+) loading
      during metabolic stress, and with a major role in protection by preconditioning.
      The effects of the A-fragment may arise entirely from reduced expression of the
      sarcolemmal K(ATP) channel, but we also discuss the possibility of mitochondrial
      effects.

PMID- 15020695
TI  - Developmental plasticity of the hypoxic ventilatory response in rats induced by
      neonatal hypoxia.
AB  - Neonatal hypoxia alters the development of the hypoxic ventilatory response in
      rats and other mammals. Here we demonstrate that neonatal hypoxia impairs the
      hypoxic ventilatory response in adult male, but not adult female, rats. Rats were
      raised in 10% O(2) for the first postnatal week, beginning within 12 h after
      birth. Subsequently, ventilatory responses were assessed in 7- to 9-week-old
      unanaesthetized rats via whole-body plethysmography. In response to 12% O(2),
      male rats exposed to neonatal hypoxia increased ventilation less than untreated
      control rats (mean +/-s.e.m. 35.2 +/- 7.7%versus 67.4 +/- 9.1%, respectively; P=
      0.01). In contrast, neonatal hypoxia had no lasting effect on hypoxic ventilatory
      responses in female rats (67.9 +/- 12.6%versus 61.2 +/- 11.7% increase in hypoxia
      treated and control rats, respectively; P > 0.05). Normoxic ventilation was
      unaffected by neonatal hypoxia in either sex at 7-9 weeks of age (P > 0.05).
      Since we hypothesized that neonatal hypoxia alters the hypoxic ventilatory
      response at the level of peripheral chemoreceptors or the central neural
      integration of chemoafferent activity, integrated phrenic responses to isocapnic
      hypoxia were investigated in urethane-anaesthetized, paralysed and ventilated
      rats. Phrenic responses were unaffected by neonatal hypoxia in rats of either sex
      (P > 0.05), suggesting that neonatal hypoxia-induced plasticity occurs between
      the phrenic nerve and the generation of airflow (e.g. neuromuscular junction,
      respiratory muscles or respiratory mechanics) and is not due to persistent
      changes in hypoxic chemosensitivity or central neural integration. The basis of
      sex differences in this developmental plasticity is unknown.

PMID- 15020696
TI  - Characterization of a hyperpolarization-activated time-dependent potassium
      current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left
      atrium.
AB  - Cardiomyocytes from the pulmonary vein sleeves (PVs) are known to play an
      important role in atrial fibrillation. PVs have been shown to exhibit time
      dependent hyperpolarization-induced inward currents of uncertain nature. We
      observed a time-dependent K(+) current upon hyperpolarization of PV and left
      atrial (LA) cardiomyocytes (I(KH)) and characterized its biophysical and
      pharmacological properties. The activation time constant was weakly voltage
      dependent, ranging from 386 +/- 14 to 427 +/- 37 ms between -120 and -90 mV, and
      the half-activation voltage averaged -93 +/- 4 mV. I(KH) was larger in PV than LA
      cells (e.g. at -120 mV: -2.8 +/- 0.3 versus-1.9 +/- 0.2 pA pF(-1), respectively,
      P < 0.01). The reversal potential was approximately -84 mV with 5.4 mm[K(+)](o)
      and changed by 55.7 +/- 2.4 mV per decade [K(+)](o) change. I(KH) was exquisitely
      Ba(2+) sensitive, with a 50% inhibitory concentration (IC(50)) of 2.0 +/- 0.3
      microm (versus 76.0 +/- 17.9 microm for instantaneous inward-rectifier current, P
      < 0.01), and showed similar Cs(+) sensitivity to instantaneous current. I(KH) was
      potently blocked by tertiapin-Q, a selective Kir3-subunit channel blocker (IC(50)
      10.0 +/- 2.1 nm), was unaffected by atropine and was significantly increased by
      isoproterenol (isoprenaline), carbachol and the non-hydrolysable guanosine
      triphosphate analogue GTPgammaS. I(KH) activation by carbachol required GTP in
      the pipette and was prevented by pertussis toxin pretreatment. Tertiapin-Q
      delayed repolarization in atropine-exposed multicellular atrial preparations
      studied with standard microelectrodes (action potential duration pre- versus post
      tertiapin-Q: 190.4 +/- 4.3 versus 234.2 +/- 9.9 ms, PV; 202.6 +/- 2.6 versus
      242.7 +/- 6.2 ms, LA; 2 Hz, P < 0.05 each). Seven-day atrial tachypacing
      significantly increased I(KH) (e.g. at -120 mV in PV: from -2.8 +/- 0.3 to -4.5
      +/- 0.5 pA pF(-1), P < 0.01). We conclude that I(KH) is a time-dependent,
      hyperpolarization-activated K(+) current that likely involves Kir3 subunits and
      appears to play a significant role in atrial physiology.

PMID- 15020697
TI  - Altered properties of volume-sensitive osmolyte and anion channels (VSOACs) and
      membrane protein expression in cardiac and smooth muscle myocytes from Clcn3-/-
      mice.
AB  - ClC-3, a member of the large superfamily of ClC voltage-dependent Cl(-) channels,
      has been proposed as a molecular candidate responsible for volume-sensitive
      osmolyte and anion channels (VSOACs) in some cells, including heart and vascular
      smooth muscle. However, the reported presence of native VSOACs in at least two
      cell types from transgenic ClC-3 disrupted (Clcn3(-/-)) mice casts considerable
      doubt on this proposed role for ClC-3. We compared several properties of native
      VSOACs and examined mRNA transcripts and membrane protein expression profiles in
      cardiac and pulmonary arterial smooth muscle cells from Clcn3(+/+) and Clcn3(-/-)
      mice to: (1) test the hypothesis that native VSOACs are unaltered in cells from
      Clcn3(-/-) mice, and (2) test the possibility that targeted inactivation of the
      Clcn3 gene using a conventional murine global knock-out approach may result in
      compensatory changes in expression of other membrane proteins. Our experiments
      demonstrate that VSOAC currents in myocytes from Clcn3(+/+) and Clcn3(-/-) mice
      are remarkably similar in terms of activation and inactivation kinetics, steady
      state current densities, rectification, anion selectivity (I(-) > Cl(-)>> Asp(-))
      and sensitivity to block by glibenclamide, niflumic acid, DIDS and extracellular
      ATP. However, additional experiments revealed several significant differences in
      other fundamental properties of native VSOACs recorded from atrial and smooth
      muscle cells from Clcn3(-/-) mice, including: differences in regulation by
      endogenous protein kinase C, differential sensitivity to block by anti-ClC-3
      antibodies, and differential sensitivities to [ATP](i) and free [Mg(2+)](i).
      These results suggest that in response to Clcn3 gene deletion, there may be
      compensatory changes in expression of other proteins that alter VSOAC channel
      subunit composition or associated regulatory subunits that give rise to VSOACs
      with different properties. Consistent with this hypothesis, in atria from Clcn3(
      /-) mice compared to Clcn3(+/+) mice, quantitative analysis of ClC mRNA
      expression levels revealed significant increases in transcripts for ClC-1, ClC-2,
      and ClC-3, and protein expression profiles obtained using two-dimensional
      polyacrylamide gel electrophoresis revealed complex changes in at least 35
      different unidentified membrane proteins in cells from Clcn3(-/-) mice. These
      findings emphasize that caution needs to be exercised in simple attempts to
      interpret the phenotypic consequences of conventional global Clcn3 gene
      inactivation.

PMID- 15020698
TI  - A voltage-dependent K+ current contributes to membrane potential of acutely
      isolated canine articular chondrocytes.
AB  - The electrophysiological properties of acutely isolated canine articular
      chondrocytes have been characterized using patch-clamp methods. The 'steady
      state' current-voltage relationship (I-V) of single chondrocytes over the range
      of potentials from -100 to +40 mV was highly non-linear, showing strong outward
      rectification positive to the zero-current potential. Currents activated at
      membrane potentials negative to -50 mV were time independent, and the I-V from 
      100 to -60 mV was linear, corresponding to an apparent input resistance of 9.3 +/
      1.4 G Omega (n= 23). The outwardly rectifying current was sensitive to the K(+)
      channel blocking ion tetraethylammonium (TEA), which had a 50% blocking
      concentration of 0.66 mM (at +50 mV). The 'TEA-sensitive' component of the
      outwardly rectifying current had time- and membrane potential-dependent
      properties, activated near -45 mV and was half-activated at -25 mV. The reversal
      potential of the 'TEA-sensitive' current with external K(+) concentration of 5 mm
      and internal concentration of 145 mM, was -84 mV, indicating that the current was
      primarily carried by K(+) ions. The resting membrane potential of isolated
      chondrocytes (-38.1 +/- 1.4 mV; n= 19) was depolarized by 14.8 +/- 0.9 mV by 25
      mM TEA, which completely blocked the K(+) current of these cells. These data
      suggest that this voltage-sensitive K(+) channel has an important role in
      regulating the membrane potential of canine articular chondrocytes.

PMID- 15020699
TI  - Effects of aerobic training on pyruvate dehydrogenase and pyruvate dehydrogenase
      kinase in human skeletal muscle.
AB  - This study examined the effects of short- and long-term aerobic training on the
      stable up-regulation of pyruvate dehydrogenase (PDH) and PDH kinase (PDK) in
      human skeletal muscle. We hypothesized that 8 weeks, but not 1 week, of aerobic
      training would increase total PDH (PDHt) and PDK activities compared to
      pretraining, and this would be detectable at the level of gene transcription
      (mRNA) and/or gene translation (protein). Resting muscle biopsies were taken
      before and after 1 and 8 weeks of aerobic cycle exercise training. PDHt and PDK
      activities, and their respective protein and mRNA expression, did not differ
      after 1 week of aerobic training. PDHt activity increased 31% after 8 weeks and
      this may be partially due to a 1.3-fold increase in PDH-E(1)alpha protein
      expression. PDK activity approximately doubled after 8 weeks of aerobic training
      and this was attributed to a 1.3-fold increase in PDK2 isoform protein
      expression. Similar to 1 week, no changes were observed at the mRNA level after 8
      weeks of training. These findings suggest that aerobically trained human skeletal
      muscle has an increased maximal capacity to utilize carbohydrates, evident by
      increased PDHt, but increased metabolic control sensitivity to pyruvate through
      increased contribution of PDK2 to total PDK activity.

PMID- 15020700
TI  - Multiple mechanisms govern the dynamics of depression at neocortical synapses of
      young rats.
AB  - Synaptic transmission between pairs of excitatory neurones in layers V (N= 38) or
      IV (N= 6) of somatosensory cortex was examined in a parasagittal slice
      preparation obtained from young Wistar rats (14-18 days old). A combined
      experimental and theoretical approach reveals two characteristics of short-term
      synaptic depression. Firstly, as well as a release-dependent depression, there is
      a release-independent component that is evident in smaller postsynaptic responses
      even following failure to release transmitter. Secondly, recovery from depression
      is activity dependent and is faster at higher input frequencies. Frequency
      dependent recovery is a Ca(2+)-dependent process and does not reflect an
      underlying augmentation. Frequency-dependent recovery and release-independent
      depression are correlated, such that at those connections with a large amount of
      release-independent depression, recovery from depression is faster. In addition,
      both are more pronounced in experiments performed at physiological temperatures.
      Simulations demonstrate that these homeostatic properties allow the transfer of
      rate information at all frequencies, essentially linearizing synaptic responses
      at high input frequencies.

PMID- 15020701
TI  - Effect of high intensity training on capillarization and presence of angiogenic
      factors in human skeletal muscle.
AB  - The effect of intense training on endothelial proliferation, capillary growth and
      distribution of vascular endothelial growth factor (VEGF) and basic fibroblast
      growth factor (bFGF) was examined in human skeletal muscle. Two intermittent knee
      extensor training protocols (at approximately 150% (Study 1) versus approximately
      90% (Study 2) of leg (O(2) max)) were conducted. Muscle biopsies were obtained
      throughout the training periods for immunohistochemical assessment of
      capillarization, cell proliferation (Ki-67-positive cells), VEGF and bFGF. In
      Study 1, microdialysis samples were collected from the trained and untrained leg
      at rest and during exercise and added to endothelial cells to measure the
      proliferative effect. After 4 weeks of training there was a higher (P < 0.05)
      capillary-to-fibre ratio (Study 1: 2.4 +/- 0.1 versus 1.7 +/- 0.1) and number of
      Ki-67-positive cells (Study 1: 0.18 +/- 0.05 versus 0.00 +/- 0.01) than before
      training. Neither the location of proliferating endothelial cells nor
      capillarization was related to muscle fibre type. The endothelial cell
      proliferative effect of the muscle microdialysate increased from rest to exercise
      in both the untrained leg (from 262 +/- 60 to 573 +/- 87% of control perfusate)
      and the trained leg (from 303 +/- 75 to 415 +/- 108% of perfusate). VEGF and bFGF
      were localized in endothelial and skeletal muscle cells and training induced no
      changes in distribution. The results demonstrate that intense intermittent
      endurance training induces capillary growth and a transient proliferation of
      endothelial cells within 4 weeks, with a similar growth occurring around type I
      versus type II muscle fibres.

PMID- 15020702
TI  - Patch clamp study of the UNC-105 degenerin and its interaction with the LET-2
      collagen in Caenorhabditis elegans muscle.
AB  - Degenerins have emerged from genetic studies in Caenorhabditis elegans as
      candidate mechanically gated amiloride-sensitive ion channels for transducing
      mechanical stimuli into cellular responses. In C. elegans muscle, the existence
      of a genetic interaction between the unc-105 degenerin gene and let-2, a gene
      encoding an alpha2(IV) collagen, raised the possibility that UNC-105 may function
      as a mechanically gated channel in a stretch receptor complex. However, to date,
      ion channel activity of UNC-105 has only been recorded in a gain-of-function
      mutant form in heterologous expression systems. In this study we investigated the
      in situ properties of UNC-105 using the whole cell configuration of the patch
      clamp technique on body wall muscle cells from acutely dissected C. elegans.
      Amiloride was found to be without effect on membrane potential of wild-type
      muscle cells, suggesting that the UNC-105 degenerin is electrically silent in
      resting muscle. Hypo-osmotic shocks induced a reversible depolarization of muscle
      cells but which was not affected by amiloride. Deformation of the cells by
      applying tension to the filamentous complex on which muscle cells remained
      attached or by ejecting external solution under pressure failed to induce any
      change of membrane potential. In gain-of-function unc-105(n506) mutant cells, an
      amiloride-sensitive inward Na(+) current was found to be constitutively active,
      leading to maintained muscle depolarization. An associated mutation in the
      alpha2(IV) collagen LET-2 led to the closure of the mutant UNC-105(n506) channel
      while a collagenase treatment of these double mutant cells caused it to re-open,
      giving evidence for a functional interaction between LET-2 collagen and mutant
      UNC-105 channel.

PMID- 15020705
TI  - Identification of 20 microRNAs from Oryza sativa.
AB  - MicroRNAs (miRNAs) are present in both plant and animal kingdoms and represents a
      growing family of non-coding RNAs. These tiny RNAs act as small guides and direct
      negative regulations usually in the process of development through sequence
      complementarity to target mRNAs. Although a large number of miRNAs have been
      identified from various animals, so far plant miRNA studies have focused mainly
      on Arabidopsis. Here we describe the identification of 20 miRNAs from a rice cDNA
      library. All the miRNAs were presumably processed from precursors with stem-loop
      structures and were positively detected in rice cells from at least one tissue,
      some of which showed tissue-specific expression. Twenty-three unique rice genes
      were identified to be feasible targets for seven rice miRNAs, including four
      members of Scarecrow-like transcription factor, the targets of miR-39 that had
      been characterized in Arabidopsis. Lacking long complementarity, the regulatory
      targets of 13 miRNAs remain to be further investigated. A possible mechanism of
      translational repressor for plant miRNAs that lack perfect complementarity to
      target mRNAs is discussed.

PMID- 15020704
TI  - Inhibition of hepatitis C virus IRES-mediated translation by small RNAs analogous
      to stem-loop structures of the 5'-untranslated region.
AB  - Translation of the hepatitis C virus (HCV) RNA is mediated by the interaction of
      ribosomes and cellular proteins with an internal ribosome entry site (IRES)
      located within the 5'-untranslated region (5'-UTR). We have investigated whether
      small RNA molecules corresponding to the different stem-loop (SL) domains of the
      HCV IRES, when introduced in trans, can bind to the cellular proteins and
      antagonize their binding to the viral IRES, thereby inhibiting HCV IRES-mediated
      translation. We have found that a RNA molecule corresponding to SL III could
      efficiently inhibit HCV IRES-mediated translation in a dose-dependent manner
      without affecting cap-dependent translation. The SL III RNA was found to bind to
      most of the cellular proteins which interacted with the HCV 5'-UTR. A smaller RNA
      corresponding to SL e+f of domain III also strongly and selectively inhibited HCV
      IRES-mediated translation. This RNA molecule interacted with the ribosomal S5
      protein and prevented the recruitment of the 40S ribosomal subunit. This study
      reveals valuable insights into the role of the SL structures of the HCV IRES in
      mediating ribosome entry. Finally, these results provide a basis for developing
      anti-HCV therapy using small RNA molecules mimicking the SL structures of the 5'
      UTR to specifically block viral RNA translation.

PMID- 15020706
TI  - Functional interactions between alternatively spliced forms of Pax6 in crystallin
      gene regulation and in haploinsufficiency.
AB  - Pax6 is essential for development of the eye, olfactory system, brain and
      pancreas. Haploinsufficiency of Pax6 causes abnormal eye development. Two forms
      of Pax6 protein, PAX6 and PAX6(5a), differ in a 14 amino acid insertion encoded
      by an alternatively spliced exon 5a in the N-terminal DNA-binding paired domain
      (PD), and they are simultaneously expressed. Here, we show that PAX6 and PAX6(5a)
      together synergistically activate transcription from promoters recognized by Pax6
      PD and PD5a, but not by their homeodomain. This synergism promotes activation of
      transcription by c-Maf and MafA on the alphaB-crystallin promoter, and is
      required for transcriptional co-activation by RARbeta/RXRbeta and PAX6/PAX6(5a)
      on the gammaF-crystallin promoter. To determine the role of this synergism in
      haploinsufficiency, we tested four human missense (G18W, R26G, G64V and R128C)
      and one nonsense (R317X) mutants, with reporters driven by Pax6 PD consensus
      binding sites and the alphaB-crystallin promoter. The simultaneous activity of
      Pax6 proteins [PAX6, mutated PAX6, PAX6(5a) and mutated PAX6(5a)] modeling
      haploinsufficiency yielded results not predicted by properties of individual PAX6
      or PAX6(5a). Taken together, these results indicate that complex ocular
      phenotypes due to Pax6 haploinsufficiency originate, at least partially, from
      functional interactions between alternatively spliced PAX6 and PAX6(5a) variants
      and other factors, e.g. MafA/c-Maf.

PMID- 15020707
TI  - The maize ID1 flowering time regulator is a zinc finger protein with novel DNA
      binding properties.
AB  - The INDETERMINATE protein, ID1, plays a key role in regulating the transition to
      flowering in maize. ID1 is the founding member of a plant-specific zinc finger
      protein family that is defined by a highly conserved amino sequence called the ID
      domain. The ID domain includes a cluster of three different types of zinc fingers
      separated from a fourth C2H2 finger by a long spacer; ID1 is distinct from other
      ID domain proteins by having a much longer spacer. In vitro DNA selection and
      amplification binding assays and DNA binding experiments showed that ID1 binds
      selectively to an 11 bp consensus motif via the ID domain. Unexpectedly, site
      directed mutagenesis of the ID1 protein showed that zinc fingers located at each
      end of the ID domain are not required for binding to the consensus motif despite
      the fact that one of these zinc fingers is a canonical C2H2 DNA binding domain.
      In addition, an ID1 in vitro deletion mutant that lacks the extra spacer between
      zinc fingers binds the same 11 bp motif as normal ID1, suggesting that all ID
      domain-containing proteins recognize the same DNA target sequence. Our results
      demonstrate that maize ID1 and ID domain proteins have novel zinc finger
      configurations with unique DNA binding properties.

PMID- 15020708
TI  - Conservation of RNA structures enables TNV and BYDV 5' and 3' elements to
      cooperate synergistically in cap-independent translation.
AB  - The subgenomic RNA 2 of tobacco necrosis virus A (TNV sgRNA2) encodes the viral
      coat protein, is unpolyadenylated and presumably uncapped. Here, we show that TNV
      sgRNA2 is translated cap independently. This cap-independent translation requires
      the leader and a 140 nt element of the trailer both in wheat germ extract and in
      tobacco protoplasts. Similar to barley yellow dwarf virus (BYDV), the TNV 5' and
      3' elements stimulate translation synergistically. Computer-aided phylogenetic
      analysis of the secondary structure of the TNV trailer revealed that the 3'
      translation element is part of a major conserved stem-loop that contains
      similarities to structures in the BYDV 3' translation element. These data suggest
      that the translation mechanisms of TNV sgRNA2 and BYDV RNA are related. To
      further characterize this relationship, we tested whether cooperativity exists
      between TNV sgRNA2 and BYDV 5' and 3' elements. We found that the TNV sgRNA2 5'
      element stimulates translation synergistically with the BYDV 3' element in vitro.
      This finding is the first evidence for conservation of structures that enable a
      5'-3' interaction stimulating cap-independent translation.

PMID- 15020709
TI  - Bioinformatical assay of human gene morbidity.
AB  - Only a fraction of eukaryotic genes affect the phenotype drastically. We compared
      18 parameters in 1273 human morbid genes, known to cause diseases, and in the
      remaining 16 580 unambiguous human genes. Morbid genes evolve more slowly, have
      wider phylogenetic distributions, are more similar to essential genes of
      Drosophila melanogaster, code for longer proteins containing more alanine and
      glycine and less histidine, lysine and methionine, possess larger numbers of
      longer introns with more accurate splicing signals and have higher and broader
      expressions. These differences make it possible to classify as non-morbid 34% of
      human genes with unknown morbidity, when only 5% of known morbid genes are
      incorrectly classified as non-morbid. This classification can help to identify
      disease-causing genes among multiple candidates.

PMID- 15020710
TI  - Chemical synthesis and translesion replication of a cis-syn cyclobutane thymine
      uracil dimer.
AB  - The cytosine base in DNA undergoes hydrolytic deamination at a considerable rate
      when UV radiation induces formation of a cyclobutane pyrimidine dimer (CPD) with
      an adjacent pyrimidine base. We have synthesized a phosphoramidite building block
      of a cis-syn cyclobutane thymine-uracil dimer (T[]U), which is the deaminated
      form of the CPD at a TC site, and incorporated it into oligodeoxyribonucleotides.
      The previously reported method for synthesis of the thymine dimer (T[]T) was
      applied, using partially protected thymidylyl-(3'-5')-2'-deoxyuridine as the
      starting material, and after triplet- sensitized irradiation, the configuration
      of the base moiety in the major product was determined by NMR spectroscopy.
      Presence of the cis-syn cyclobutane dimer in the obtained oligonucleotides was
      confirmed by UV photoreversal and reaction with T4 endonuclease V. Using a 30mer
      containing T[]U, translesion synthesis by human DNA polymerase eta was analyzed.
      There was no difference in the results between the templates containing T[]T and
      T[]U and pol eta bypassed both lesions with the same efficiency, incorporating
      two adenylates. This enzyme showed fidelity to base pair formation, but this
      replication causes a C-->T transition because the original sequence is TC.

PMID- 15020712
TI  - PtdIns-specific MPR pathway association of a novel WD40 repeat protein, WIPI49.
AB  - WIPI49 is a member of a previously undescribed family of WD40-repeat proteins
      that we demonstrate binds 3-phosphorylated phosphoinositides. Immunofluorescent
      imaging indicates that WIPI49 is localized to both trans-Golgi and endosomal
      membranes, organelles between which it traffics in a microtubule-dependent
      manner. Live cell imaging establishes that WIPI49 traffics through the same set
      of endosomal membranes as that followed by the mannose-6-phosphate receptor
      (MPR), and consistent with this, WIPI49 is enriched in clathrin-coated vesicles.
      Ectopic expression of wild-type WIPI49 disrupts the proper functioning of this
      MPR pathway, whereas expression of a double point mutant (R221,222AWIPI49) unable
      to bind phosphoinositides does not disrupt this pathway. Finally, suppression of
      WIPI49 expression through RNAi, demonstrates that its presence is required for
      normal endosomal organization and distribution of the CI-MPR. We conclude that
      WIPI49 is a novel regulatory component of the endosomal and MPR pathway and that
      this role is dependent upon the PI-binding properties of its WD40 domain.

PMID- 15020711
TI  - Ubiquitin-mediated targeting of a mutant plasma membrane ATPase, Pma1-7, to the
      endosomal/vacuolar system in yeast.
AB  - Pma1-7 is a mutant plasma membrane ATPase that is impaired in targeting to the
      cell surface at 37 degrees C and is delivered instead to the endosomal/vacuolar
      pathway for degradation. We have proposed that Pma1-7 is a substrate for a
      Golgibased quality control mechanism. By contrast with wild-type Pma1, Pma1-7 is
      ubiquitinated. Ubiquitination and endosomal targeting of Pma1-7 is dependent on
      the Rsp5-Bul1-Bul2 ubiquitin ligase protein complex but not the transmembrane
      ubiquitin ligase Tul1. Analysis of Pma1-7 ubiquitination in mutants blocked in
      protein transport at various steps of the secretory pathway suggests that
      ubiquitination occurs after ER exit but before endosomal entry. In the absence of
      ubiquitination in rsp5-1 cells, Pma1-7 is delivered to the cell surface and
      remains stable. Nevertheless, Pma1-7 remains impaired in association with
      detergent-insoluble glycolipid-enriched complexes in rsp5-1 cells, suggesting
      that ubiquitination is not the cause of Pma1-7 exclusion from rafts. In vps1
      cells in which protein transport into the endosomal pathway is blocked, Pma1-7 is
      routed to the cell surface. On arrival at the plasma membrane in vps1 cells, Pma1
      7 remains stable and its ubiquitination disappears, suggesting deubiquitination
      activity at the cell surface. We suggest that Pma1-7 sorting and fate are
      regulated by ubiquitination.

PMID- 15020713
TI  - Rabenosyn-5 and EHD1 interact and sequentially regulate protein recycling to the
      plasma membrane.
AB  - EHD1 has been implicated in the recycling of internalized proteins to the plasma
      membrane. However, the mechanism by which EHD1 mediates recycling and its
      relationship to Rab-family-controlled events has yet to be established. To
      investigate further the mode of EHD1 action, we sought to identify novel
      interacting partners. GST-EHD1 was used as bait to isolate a approximately 120
      kDa species from bovine and murine brain cytosol, which was identified by mass
      spectrometry as the divalent Rab4/Rab5 effector Rabenosyn-5. We mapped the sites
      of interaction to the EH domain of EHD1, and the first two of five NPF motifs of
      Rabenosyn-5. Immunofluorescence microscopy studies revealed that EHD1 and
      Rabenosyn-5 partially colocalize to vesicular and tubular structures in vivo. To
      address the functional roles of EHD1 and Rabenosyn-5, we first demonstrated that
      RNA interference (RNAi) dramatically reduced the level of expression of each
      protein, either individually or in combination. Depletion of either EHD1 or
      Rabenosyn-5 delayed the recycling of transferrin and major histocompatibility
      complex class I to the plasma membrane. However, whereas depletion of EHD1 caused
      the accumulation of internalized cargo in a compact juxtanuclear compartment,
      Rabenosyn-5-RNAi caused its retention within a dispersed peripheral compartment.
      Simultaneous RNAi depletion of both proteins resulted in a similar phenotype to
      that observed with Rabenosyn-5-RNAi alone, suggesting that Rabenosyn-5 acts
      before EHD1 in the regulation of endocytic recycling. Our studies suggest that
      Rabenosyn-5 and EHD1 act sequentially in the transport of proteins from early
      endosomes to the endosomal recycling compartment and back to the plasma membrane.

PMID- 15020714
TI  - Cytoplasmic dynein-dynactin complex is required for spermatid growth but not
      axoneme assembly in Drosophila.
AB  - Spermatids derived from a single gonial cell remain interconnected within a cyst
      and elongate by synchronized growth inside the testis in Drosophila. Cylindrical
      spectrin-rich elongation cones form at their distal ends during the growth. The
      mechanism underlying this process is poorly understood. We found that developing
      sperm tails were abnormally coiled at the growing ends inside the cysts in the
      Drosophila Dynein light chain 1 (ddlc1) hemizygous mutant testis. A quantitative
      assay showed that average number of elongation cones was reduced, they were
      increasingly deformed, and average cyst lengths were shortened in ddlc1
      hemizygous testes. These phenotypes were further enhanced by additional partial
      reduction of Dhc64C and Glued and rescued by Myc-PIN/LC8 expression in the gonial
      cells in ddlc1 backgrounds. Furthermore, DDLC1, DHC, and GLUED were enriched at
      the distal ends of growing spermatids. Finally, ultrastructure analysis of ddlc1
      testes revealed abnormally formed interspermatid membrane, but the 9 + 2
      microtubule organization, the radial spoke structures, and the Dynein arms of the
      axoneme were normal. Together, these findings suggest that axoneme assembly and
      spermatid growth involve independent mechanisms in Drosophila and DDLC1 interacts
      with the Dynein-Dynactin complex at the distal ends of spermatids to maintain the
      spectrin cytoskeleton assembly and cell growth.

PMID- 15020715
TI  - HIV-1 Tat enters T cells using coated pits before translocating from acidified
      endosomes and eliciting biological responses.
AB  - The HIV-1 Tat protein is secreted by infected cells. Extracellular Tat can affect
      bystander uninfected T cells and induce numerous biological responses such as
      apoptosis and cytokine secretion. Tat is likely involved in several immune
      disorders during AIDS. Nevertheless, it is not known whether Tat triggers cell
      responses directly upon binding to signaling receptors at the plasma membrane or
      after delivery to the cytosol. The pathway that enables Tat to reach the cytosol
      is also unclear. Here we visualized Tat within T-cell-coated pits and endosomes.
      Moreover, inhibitors of clathrin/AP-2-mediated uptake such as chlorpromazine,
      activated RhoA, or dominant-negative mutants of Eps15, intersectin, dynamin, or
      rab5 impaired Tat delivery to the cytosol by preventing its endocytosis.
      Molecules neutralizing low endosomal pH or Hsp90 inhibitors abolished Tat entry
      at a later stage by blocking its endosomal translocation, as directly shown using
      a cell-free translocation assay. Finally, endosomal pH neutralization prevented
      Tat from inducing T-cell responses such as NF-kappaB activation, apoptosis, and
      interleukin secretion, indicating that cytosolic delivery is required for Tat
      signaling. Hence, Tat enters T cells essentially like diphtheria toxin, using
      clathrin-mediated endocytosis before low-pH-induced and Hsp90-assisted endosomal
      translocation. Cell responses are then induced from the cytosol.

PMID- 15020716
TI  - Modulation of microtubule dynamics by tau in living cells: implications for
      development and neurodegeneration.
AB  - The neural microtubule-associated protein tau binds to and stabilizes
      microtubules. Because of alternative mRNA splicing, tau is expressed with either
      3 or 4 C-terminal repeats. Two observations indicate that differences between
      these tau isoforms are functionally important. First, the pattern of tau isoform
      expression is tightly regulated during development. Second, mutation-induced
      changes in tau RNA splicing cause neuronal cell death and dementia simply by
      altering the isoform expression ratio. To investigate whether 3- and 4-repeat tau
      differentially regulate microtubule behavior in cells, we microinjected
      physiological levels of these two isoforms into EGFP-tubulin-expressing cultured
      MCF7 cells and measured the effects on the dynamic instability behavior of
      individual microtubules by time-lapse microscopy. Both isoforms suppressed
      microtubule dynamics, though to different extents. Specifically, 4-repeat tau
      reduced the rate and extent of both growing and shortening events. In contrast, 3
      repeat tau stabilized most dynamic parameters about threefold less potently than
      4-repeat tau and had only a minimal ability to suppress shortening events. These
      differences provide a mechanistic rationale for the developmental shift in tau
      isoform expression and are consistent with a loss-of-function model in which
      abnormal tau isoform expression results in the inability to properly regulate
      microtubule dynamics, leading to neuronal cell death and dementia.

PMID- 15020717
TI  - Activation of mammalian unfolded protein response is compatible with the quality
      control system operating in the endoplasmic reticulum.
AB  - Newly synthesized secretory and transmembrane proteins are folded and assembled
      in the endoplasmic reticulum (ER) where an efficient quality control system
      operates so that only correctly folded molecules are allowed to move along the
      secretory pathway. The productive folding process in the ER has been thought to
      be supported by the unfolded protein response (UPR), which is activated by the
      accumulation of unfolded proteins in the ER. However, a dilemma has emerged;
      activation of ATF6, a key regulator of mammalian UPR, requires intracellular
      transport from the ER to the Golgi apparatus. This suggests that unfolded
      proteins might be leaked from the ER together with ATF6 in response to ER stress,
      exhibiting proteotoxicity in the secretory pathway. We show here that ATF6 and
      correctly folded proteins are transported to the Golgi apparatus via the same
      route and by the same mechanism under conditions of ER stress, whereas unfolded
      proteins are retained in the ER. Thus, activation of the UPR is compatible with
      the quality control in the ER and the ER possesses a remarkable ability to select
      proteins to be transported in mammalian cells in marked contrast to yeast cells,
      which actively utilize intracellular traffic to deal with unfolded proteins
      accumulated in the ER.

PMID- 15020718
TI  - Measuring the size of biological nanostructures with spatially modulated
      illumination microscopy.
AB  - Spatially modulated illumination fluorescence microscopy can in theory measure
      the sizes of objects with a diameter ranging between 10 and 200 nm and has
      allowed accurate size measurement of subresolution fluorescent beads (
      approximately 40-100 nm). Biological structures in this size range have so far
      been measured by electron microscopy. Here, we have labeled sites containing the
      active, hyperphosphorylated form of RNA polymerase II in the nucleus of HeLa
      cells by using the antibody H5. The spatially modulated illumination-microscope
      was compared with confocal laser scanning and electron microscopes and found to
      be suitable for measuring the size of cellular nanostructures in a biological
      setting. The hyperphosphorylated form of polymerase II was found in structures
      with a diameter of approximately 70 nm, well below the 200-nm resolution limit of
      standard fluorescence microscopes.

PMID- 15020719
TI  - Large transgenes reveal their secrets. Focus on "differential expression of the
      closely linked KISS1, REN, and FLJ10761 genes in transgenic mice".

PMID- 15020721
TI  - Ensuring ethics.

PMID- 15020722
TI  - Chemical hazards in the workplace: an overview.

PMID- 15020720
TI  - Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in
      aging.
AB  - Previously we demonstrated that aging in coronary arteries is associated with
      proinflammatory phenotypic changes and decreased NO bioavailability, which, we
      hypothesized, promotes vascular disease by enhancing endothelial apoptosis. To
      test this hypothesis we characterized proapoptotic alterations in the phenotype
      of coronary arteries of aged (26 mo old) and young (3 mo old) F344 rats. DNA
      fragmentation analysis and TUNEL assay showed that in aged vessels there was an
      approximately fivefold increase in the number of apoptotic endothelial cells. In
      aged coronary arteries there was an increased expression of TNFalpha, TNFbeta,
      and caspase 9 (microarray, real-time PCR), as well as increased caspase 9 and
      caspase 3 activity, whereas expression of TNFR1, TNFalpha-converting enzyme
      (TACE), Bcl-2, Bcl-X(L), Bid, Bax, caspase 8, and caspase 3 were unchanged. In
      vessel culture (18 h) incubation of aged coronary arteries with a TNF blocking
      antibody or the NO donor S-nitroso-penicillamine (SNAP) decreased apoptotic cell
      death. Incubation of young arteries with exogenous TNFalpha increased caspase 9
      activity and elicited endothelial apoptosis, which was attenuated by SNAP.
      Inhibition of NO synthesis in cultured young coronary arteries also induced
      apoptotic cell death and potentiated the apoptotic effect of TNFalpha. Thus we
      propose that age-related upregulation of TNFalpha and caspase 9 and decreased
      bioavailability of NO promote endothelial apoptosis in coronary arteries that may
      lead to impaired endothelial function and ischemic heart disease in the elderly.

PMID- 15020723
TI  - Organophosphate toxicity and occupational exposure.
AB  - The ubiquitous organophosphates present a continuing health hazard in
      agriculture, public health eradication programmes and as chemical warfare agents.
      Despite significant progress in understanding the potential mechanisms of
      toxicity far beyond the commonly accepted mechanism of cholinesterase inhibition
      in intentional exposures, the precise health effects following occupational
      exposures are yet to be completely defined. A much greater understanding exists
      of the clinical features of organophosphate poisoning. These are characterized by
      a triphasic response involving an initial acute cholinergic phase, an
      intermediate syndrome (both associated with high mortality) and a disabling but
      non-lethal delayed polyneuropathy. The delayed polyneuropathy may occur in the
      absence of the cholinergic or intermediate phases. However, progress is still
      required in order to improve the quantification and assessment of occupational
      exposures and the implementation of appropriate preventive measures. Finally,
      evidence-based guidelines for appropriate or optimal therapeutic interventions
      following poisoning are required urgently and collaborative work with colleagues
      in developing countries, where the occurrence of organophosphate exposures is
      more frequent, may provide the answers.

PMID- 15020724
TI  - Lead toxicity.
AB  - Lead is one of the oldest known and most widely studied occupational and
      environmental toxins. Despite intensive study, there is still vigorous debate
      about the toxic effects of lead, both from low-level exposure in the general
      population owing to environmental pollution and historic use of lead in paint and
      plumbing and from exposure in the occupational setting. The majority of
      industries historically associated with high lead exposure have made dramatic
      advances in their control of occupational exposure. However, cases of
      unacceptably high exposure and even of frank lead poisoning are still seen,
      predominantly in the demolition and tank cleaning industries. Nevertheless, in
      most industries blood lead levels have declined below levels at which signs or
      symptoms are seen and the current focus of attention is on the subclinical
      effects of exposure. The significance of some of these effects for the overt
      health of the workers is often the subject of debate. Inevitably there is
      pressure to reduce lead exposure in the general population and in working
      environments, but any legislation must be based on a genuine scientific
      evaluation of the available evidence.

PMID- 15020725
TI  - The treatment of cyanide poisoning.
AB  - Cyanide has gained historical notoriety as a poison used with intent to cause
      fatality. Its occurrence in industry is confined to a small number of uses in a
      relatively narrow range of industries, including the manufacture of Perspex and
      nylon and in electroplating. With proper controls in these settings, episodes of
      poisoning are extremely rare. However, because of the potential for a fatal
      outcome, procedures for the treatment of acute poisoning are essential. Antidotes
      include methaemoglobin generators, direct binding agents and sulphur donors, but
      there is a lack of international consensus about the treatment of choice. This
      article reviews the mechanisms and treatment of cyanide intoxication and
      emphasizes the importance of having agreed local procedures for the emergency
      treatment of poisoning.

PMID- 15020726
TI  - Injuries to Scottish farmers while tagging and clipping cattle: a cross-sectional
      survey.
AB  - BACKGROUND: Anecdotal reports suggested that farmers were sustaining significant
      injuries while ear tagging newborn calves or clipping cattle prior to slaughter.
      AIMS: This national survey was designed for determining the incidence and nature
      of self-reported injuries to farmers that were sustained while tagging calves and
      clipping cattle. METHODS: A cross-sectional, anonymous, postal questionnaire
      survey was sent to all members of the National Farmers Union of Scotland with
      beef or dairy cattle (n = 4495). RESULTS: In total, 2439 (54%) usable
      questionnaires were received and 1341 injuries were reported by 591 (24%)
      respondents. Tagging-related injuries were reported by 297 (12%) respondents. The
      most commonly described injury was bruising, but lacerations (3%) and fractures
      (3%) also occurred. Fifty-eight (20%) individuals lost time from work, with a
      median of 3 days [interquartile range (IQR) = 2-7 days]. Four hundred and
      eighteen (17%) respondents reported clipping-related injuries. The most common
      injury was bruising, but lacerations (6%) and fractures (7%) also occurred.
      Ninety-five (23%) individuals lost time from work, with a median of 4 days (IQR =
      2-14 days). Tagging injuries more commonly affected lower limbs and the trunk,
      while clipping injuries affected the upper limbs. Tagging injuries were
      associated with working alone, in an open field and with a vehicle nearby, while
      clipping injuries were associated with working alone, with beef cattle and with
      younger age. Both types of injury were associated with injuries from livestock in
      other circumstances. CONCLUSIONS: Tagging calves and clipping cattle prior to
      slaughter are associated with a significant risk of injury, which may be severe,
      necessitating treatment and time lost from work. Policy makers, safety advisers
      and the farming community should reconsider whether these procedures are
      necessary and whether current guidelines should be modified in order to improve
      safety.

PMID- 15020727
TI  - Farmers are at risk for anxiety and depression: the Hordaland Health Study.
AB  - AIMS: To examine whether, and why, farmers and non-farmers differ regarding
      levels of anxiety and depression. METHODS: The study encompassed 17 295 workers
      age 40-49 years, including 917 farmers, from the population-based Hordaland
      Health Study 1997-99 (HUSK). Levels of anxiety and depression were assessed by
      the Hospital Anxiety and Depression Scale (HADS-A and HADS-D, respectively). Self
      reported information on various work-related factors, demographics, lifestyle and
      somatic health problems was included. The main analytical methods were univariate
      analysis of variance (ANOVA)/Kruskal-Wallis test, chi(2)/Fisher's exact test and
      logistic regression. RESULTS: Compared with non-farmers, farmers had higher
      levels and prevalences of depression, particularly the male farmers, who also had
      higher anxiety levels. Among men, farmers reported longer work hours, lower
      income, higher psychological job demands and less decision latitude compared with
      non-farmers. Farmers had physically heavier work and a lower level of education
      than non-farmers. Generally, the differences were largest between full-time
      farmers and non-farmers. Differences in anxiety and depression levels between
      male full-time farmers and non-farmers could be explained by the farmers' longer
      work hours, physically harder work and lower income. CONCLUSIONS: Farming is
      associated with increased levels of anxiety and increased levels and prevalences
      of depression. As regards depression, preventative measures and screening for
      cases in need of treatment should be strongly considered.

PMID- 15020729
TI  - Underreporting of fatal occupational injuries in Catalonia (Spain).
AB  - BACKGROUND: Thoroughness in a given health information system is one of its most
      important quality indicators. In Spain, in approximately 30% of serious
      occupational injuries, there is no information on the final outcome. AIM: To
      assess underreporting of fatal occupational injuries in Catalonia. METHODS: All
      serious occupational injuries (excluding commuting injuries) reported in
      Catalonia (Spain) between 1994 and 1998 (n = 7330) were linked with data from the
      Catalonian Mortality Register, 117 deaths being identified during the year
      following the injury date. In order to assess whether death could or could not
      have been related to the prior occupational injury, two experts examined these
      cases independently. RESULTS: The experts concluded (kappa = 0.98) that 69 (59%)
      of these deaths were probably related to occupational injuries; the vast majority
      (n = 65) occurred within 3 months of the injury. This represents an accumulated
      risk of dying of approximately 1% for the total of serious injuries, not varying
      with economic activity or job category. However, this risk varied depending on
      the form of accident, and the site and nature of the injury. CONCLUSIONS:
      Occupational injury cases, especially serious ones, should be followed up over at
      least 3 months. These results suggest the importance of carrying out active case
      finding and of incorporating the death certificate as one of the documents to be
      systematically reviewed in order to complete the statistics.

PMID- 15020728
TI  - Chemical, biological, radiological and nuclear terrorism: an introduction for
      occupational physicians.
AB  - BACKGROUND: Chemical, biological, radiological and nuclear terrorism poses
      considerable threat throughout the world. AIM: To provide occupational physicians
      with an understanding of this threat and its main forms and what action can be
      taken to counter this threat. METHODS: Presenters at a conference on chemical,
      biological, radiological and nuclear terrorism were asked to contribute their
      evidence-based opinions in order to produce a review article. RESULTS: This paper
      presents a summary of the different forms of chemical, biological, radiological
      and nuclear terrorism and the effective counter-measures and also provides a
      review of current scientific literature. CONCLUSION: The threat of chemical,
      biological, radiological and nuclear terrorism is present throughout the world
      and is one that occupational physicians should be aware of, as well as the action
      that can be taken to counter it.

PMID- 15020730
TI  - Organizational practices, work demands and the well-being of employees: a follow
      up study in the metal industry and retail trade.
AB  - BACKGROUND: Rapid technological change and increased international competition
      have changed working life and work organizations. These changes may not be
      considered when researching employee work ability and well-being. AIM: This study
      investigates the impact of organizational practices, work demands and individual
      factors on work ability, organizational commitment and mental well-being of
      employees in the metal industry and retail trade. METHOD: A follow-up study was
      conducted to examine these connections among 1389 employees (mean age 42 years at
      baseline) in 91 organizations. The first survey was conducted in 1998 and was
      repeated in 2000. RESULTS: Changes in organizational practices and the demands of
      work were strongly associated with changes in employee well-being. Work ability,
      organizational commitment and the mental well-being of employees were increased
      most if the opportunities for development and influence and the promotion of
      employee well-being were increased and if the supervisory support and
      organization of work were improved. Well-being also improved with less
      uncertainty at work and with decreasing mental and physical work demands. In
      addition physical exercise and affluence also had favourable effects.
      CONCLUSIONS: The results confirm that several features of organizational
      practices are strongly associated with employees' well-being. Organizational
      development is an important method of improving employees' work ability,
      commitment and well-being.

PMID- 15020731
TI  - Perfectionism and coping strategies as risk factors for the development of non
      specific work-related upper limb disorders (WRULD).
AB  - BACKGROUND: The incidence of non-specific work-related upper limb disorders
      (WRULD) is rising throughout western society. Literature and our own WRULD file
      (>1200 patients) revealed that both physical and psychosocial work-related
      factors are major causes of non-specific WRULD. It also appeared that non
      specific WRULD was more likely to develop in patients with neurotic-perfectionist
      personalities. AIM: To see if, alongside physical and psychosocial work-related
      factors, personality factors play an important role in developing non-specific
      WRULD. METHOD: This was a case-control study with two control groups, comparing
      45 computer workers with non-specific WRULD with 45 computer workers free from
      upper limb disorder (first control group) and 42 chronic pain patients (second
      control group). Main questionnaires administered were: the Utrecht Coping List
      (UCL), measuring coping-styles; the Multidimensional Perfectionism Scale (MPS),
      measuring neurotic perfectionism; and the Symptom Check List (SCL-90), measuring
      general psychological complaints (psychoneuroticism). The SCL-90 was added
      because of its known high correlation with neurotic perfectionism. RESULTS:
      Logistic regression analysis revealed significant differences in SCL-90 scores
      (chi(2) = 17.2, P < 0.0001), thereby potentially negating the significance of the
      higher neurotic perfectionism in the non-specific WRULD group. A second control
      group of chronic pain patients, with prospective high score on the SCL-90, was
      added. Logistic regression showed that, after controlling for psychoneuroticism,
      non-specific WRULD patients had more neurotic perfectionist traits (chi(2) =
      22.83, P < 0.0001). There were no significant differences in mean UCL scores (P >
      0.05). CONCLUSION: Alongside physical and psychosocial work-related factors,
      psychoneuroticism and neurotic perfectionism appear to be important risk factors
      for developing non-specific WRULD.

PMID- 15020732
TI  - Hand-arm vibration syndrome.

PMID- 15020736
TI  - Stress in police officers.

PMID- 15020737
TI  - Teaching of occupational medicine to undergraduates.

PMID- 15020739
TI  - Risk factors for low back pain.

PMID- 15020741
TI  - A bifunctional 3,5-epimerase/4-keto reductase for nucleotide-rhamnose synthesis
      in Arabidopsis.
AB  - l-Rhamnose is a component of plant cell wall pectic polysaccharides, diverse
      secondary metabolites, and some glycoproteins. The biosynthesis of the activated
      nucleotide-sugar form(s) of rhamnose utilized by the various
      rhamnosyltransferases is still elusive, and no plant enzymes involved in their
      synthesis have been purified. In contrast, two genes (rmlC and rmlD) have been
      identified in bacteria and shown to encode a 3,5-epimerase and a 4-keto reductase
      that together convert dTDP-4-keto-6-deoxy-Glc to dTDP-beta-l-rhamnose. We have
      identified an Arabidopsis cDNA that contains domains that share similarity to
      both reductase and epimerase. The Arabidopsis gene encodes a protein with a
      predicated molecular mass of approximately 33.5 kD that is transcribed in all
      tissue examined. The Arabidopsis protein expressed in, and purified from,
      Escherichia coli converts dTDP-4-keto-6-deoxy-Glc to dTDP-beta-l-rhamnose in the
      presence of NADPH. These results suggest that a single plant enzyme has both the
      3,5-epimerase and 4-keto reductase activities. The enzyme has maximum activity
      between pH 5.5 and 7.5 at 30 degrees C. The apparent K(m) for NADPH is 90 microm
      and 16.9 microm for dTDP-4-keto-6-deoxy-Glc. The Arabidopsis enzyme can also form
      UDP-beta-l-rhamnose. To our knowledge, this is the first example of a
      bifunctional plant enzyme involved in sugar nucleotide synthesis where a single
      polypeptide exhibits the same activities as two separate prokaryotic enzymes.

PMID- 15020743
TI  - Silencing of the mitogen-activated protein kinase MPK6 compromises disease
      resistance in Arabidopsis.
AB  - Here, we use a loss-of-function approach to demonstrate that the Arabidopsis
      (Arabidopsis thaliana) mitogen-activated protein kinase (MAPK) MPK6 plays a role
      in resistance to certain pathogens. MPK6-silenced Arabidopsis showed no apparent
      morphological phenotype or reduced fertility, indicating MPK6 is not required for
      development. However, resistances to an avirulent strain of Peronospora
      parasitica and avirulent and virulent strains of Pseudomonas syringae were
      compromised, suggesting that MPK6 plays a role in both resistance gene-mediated
      and basal resistance. Furthermore, this result demonstrates that MPK6's function
      cannot be fully complemented by other endogenous MAPKs. Although MPK6-silenced
      plants exhibited enhanced disease susceptibility, their ability to develop
      systemic acquired resistance or induced systemic resistance was unaffected.
      Expression of the pathogen-inducible gene VEGETATIVE STORAGE PROTEIN1 (VSP1) in
      MPK6-silenced plants was severalfold lower than in control plants, but the
      expression of other defense genes was comparable to the level observed in control
      plants. Taken together, these results provide direct evidence that a specific
      MAPK positively regulates VSP1 expression and resistance to a primary infection
      by certain pathogens, whereas systemic resistance and expression of several other
      defense genes appears to be mediated either by a functionally redundant MAPK(s)
      or independently from MPK6-dependent resistance.

PMID- 15020746
TI  - The petunia ortholog of Arabidopsis SUPERMAN plays a distinct role in floral
      organ morphogenesis.
AB  - Arabidopsis (Arabidopsis thaliana) SUPERMAN (SUP) plays a role in establishing a
      boundary between whorls 3 and 4 of flowers and in ovule development. We
      characterized a Petunia hybrida (petunia) homolog of SUP, designated PhSUP1, to
      compare with SUP. Genomic DNA of the PhSUP1 partially restored the stamen number
      and ovule development phenotypes of the Arabidopsis sup mutant. Two P. hybrida
      lines of transposon (dTph1) insertion mutants of PhSUP1 exhibited increased
      stamen number at the cost of normal carpel development, and ovule development was
      defective owing to aberrant growth of the integument. Unlike Arabidopsis sup
      mutants, phsup1 mutants also showed extra tissues connecting stamens, a petal
      tube and an ovary, and aberrancies in the development of anther and placenta.
      PhSUP1 transcripts occurred in the basal region of wild-type flowers around
      developing organ primordia in whorls 2 and 3 as well as in the funiculus of the
      ovule, concave regions of the placenta, and interthecal regions of developing
      anthers. Overexpression of PhSUP1 in P. hybrida resulted in size reduction of
      petals, leaves, and inflorescence stems. The shortening of inflorescence stems
      and petal tubes was primarily attributable to suppression of cell elongation,
      whereas a decrease in cell number was mainly responsible for the size reduction
      of petal limbs.

PMID- 15020745
TI  - Purification and characterization of serine proteases that exhibit caspase-like
      activity and are associated with programmed cell death in Avena sativa.
AB  - Victoria blight of Avena sativa (oat) is caused by the fungus Cochliobolus
      victoriae, which is pathogenic because of the production of the toxin victorin.
      The victorin-induced response in sensitive A. sativa has been characterized as a
      form of programmed cell death (PCD) and displays morphological and biochemical
      features similar to apoptosis, including chromatin condensation, DNA laddering,
      cell shrinkage, altered mitochondrial function, and ordered, substrate-specific
      proteolytic events. Victorin-induced proteolysis of ribulose-1,5-bisphosphate
      carboxylase/oxygenase (Rubisco) is shown to be prevented by caspase-specific and
      general protease inhibitors. Evidence is presented for a signaling cascade
      leading to Rubisco proteolysis that involves multiple proteases. Furthermore, two
      proteases that are apparently involved in the Rubisco proteolytic cascade were
      purified and characterized. These proteases exhibit caspase specificity and
      display amino acid sequences homologous to plant subtilisin-like Ser proteases.
      The proteases are constitutively present in an active form and are relocalized to
      the extracellular fluid after induction of PCD by either victorin or heat shock.
      The role of the enzymes as processive proteases involved in a signal cascade
      during the PCD response is discussed.

PMID- 15020744
TI  - Molecular and genetic mechanisms of floral control.

PMID- 15020747
TI  - Genetic interaction of an origin recognition complex subunit and the Polycomb
      group gene MEDEA during seed development.
AB  - The eukaryotic origin recognition complex (ORC) is made up of six subunits and
      functions in nuclear DNA replication, chromatin structure, and gene silencing in
      both fungi and metazoans. We demonstrate that disruption of a plant ORC subunit
      homolog, AtORC2 of Arabidopsis (Arabidopsis thaliana), causes a zygotic lethal
      mutant phenotype (orc2). Seeds of orc2 abort early, typically producing embryos
      with up to eight cells. Nuclear division in the endosperm is arrested at an
      earlier developmental stage: only approximately four nuclei are detected in orc2
      endosperm. The endosperm nuclei in orc2 are dramatically enlarged, a phenotype
      that is most similar to class B titan mutants, which include mutants in
      structural maintenance of chromosomes (SMC) cohesins. The highest levels of ORC2
      gene expression were found in preglobular embryos, coinciding with the stage at
      which homozygous orc2 mutant seeds arrest. The homologs of the other five
      Arabidopsis ORC subunits are also expressed at this developmental stage. The orc2
      mutant phenotype is partly suppressed by a mutation in the Polycomb group gene
      MEDEA. In double mutants between orc2 and medea (mea), orc2 homozygotes arrest
      later with a phenotype intermediate between those of mea and orc2 single mutants.
      Either alterations in chromatin structure or the release of cell cycle
      checkpoints by the mea mutation may allow more cell and nuclear divisions to
      occur in orc2 homozygous seeds.

PMID- 15020750
TI  - Transgenic maize and the evolution of landrace diversity in Mexico. The
      importance of farmers' behavior.

PMID- 15020742
TI  - Anchoring 9,371 maize expressed sequence tagged unigenes to the bacterial
      artificial chromosome contig map by two-dimensional overgo hybridization.
AB  - Our goal is to construct a robust physical map for maize (Zea mays)
      comprehensively integrated with the genetic map. We have used a two-dimensional
      24 x 24 overgo pooling strategy to anchor maize expressed sequence tagged (EST)
      unigenes to 165,888 bacterial artificial chromosomes (BACs) on high-density
      filters. A set of 70,716 public maize ESTs seeded derivation of 10,723 EST
      unigene assemblies. From these assemblies, 10,642 overgo sequences of 40 bp were
      applied as hybridization probes. BAC addresses were obtained for 9,371 overgo
      probes, representing an 88% success rate. More than 96% of the successful overgo
      probes identified two or more BACs, while 5% identified more than 50 BACs. The
      majority of BACs identified (79%) were hybridized with one or two overgos. A
      small number of BACs hybridized with eight or more overgos, suggesting that these
      BACs must be gene rich. Approximately 5,670 overgos identified BACs assembled
      within one contig, indicating that these probes are highly locus specific. A
      total of 1,795 megabases (Mb; 87%) of the total 2,050 Mb in BAC contigs were
      associated with one or more overgos, which are serving as sequence-tagged sites
      for single nucleotide polymorphism development. Overgo density ranged from less
      than one overgo per megabase to greater than 20 overgos per megabase. The
      majority of contigs (52%) hit by overgos contained three to nine overgos per
      megabase. Analysis of approximately 1,022 Mb of genetically anchored BAC contigs
      indicates that 9,003 of the total 13,900 overgo-contig sites are genetically
      anchored. Our results indicate overgos are a powerful approach for generating
      gene-specific hybridization probes that are facilitating the assembly of an
      integrated genetic and physical map for maize.

PMID- 15020751
TI  - Plant genome research outreach portal. A gateway to plant genome research
      "outreach" programs and activities.

PMID- 15020749
TI  - Electron tomographic analysis of somatic cell plate formation in meristematic
      cells of Arabidopsis preserved by high-pressure freezing.
AB  - We have investigated the process of somatic-type cytokinesis in Arabidopsis
      (Arabidopsis thaliana) meristem cells with a three-dimensional resolution of
      approximately 7 nm by electron tomography of high-pressure frozen/freeze
      substituted samples. Our data demonstrate that this process can be divided into
      four phases: phragmoplast initials, solid phragmoplast, transitional
      phragmoplast, and ring-shaped phragmoplast. Phragmoplast initials arise from
      clusters of polar microtubules (MTs) during late anaphase. At their equatorial
      planes, cell plate assembly sites are formed, consisting of a filamentous
      ribosome-excluding cell plate assembly matrix (CPAM) and Golgi-derived vesicles.
      The CPAM, which is found only around growing cell plate regions, is suggested to
      be responsible for regulating cell plate growth. Virtually all phragmoplast MTs
      terminate inside the CPAM. This association directs vesicles to the CPAM and
      thereby to the growing cell plate. Cell plate formation within the CPAM appears
      to be initiated by the tethering of vesicles by exocyst-like complexes. After
      vesicle fusion, hourglass-shaped vesicle intermediates are stretched to dumbbells
      by a mechanism that appears to involve the expansion of dynamin-like springs.
      This stretching process reduces vesicle volume by approximately 50%. At the same
      time, the lateral expansion of the phragmoplast initials and their CPAMs gives
      rise to the solid phragmoplast. Later arriving vesicles begin to fuse to the
      bulbous ends of the dumbbells, giving rise to the tubulo-vesicular membrane
      network (TVN). During the transitional phragmoplast stage, the CPAM and MTs
      disassemble and then reform in a peripheral ring phragmoplast configuration. This
      creates the centrifugally expanding peripheral cell plate growth zone, which
      leads to cell plate fusion with the cell wall. Simultaneously, the central TVN
      begins to mature into a tubular network, and ultimately into a planar fenestrated
      sheet (PFS), through the removal of membrane via clathrin-coated vesicles and by
      callose synthesis. Small secondary CPAMs with attached MTs arise de novo over
      remaining large fenestrae to focus local growth to these regions. When all of the
      fenestrae are closed, the new cell wall is complete. Few endoplasmic reticulum
      (ER) membranes are seen associated with the phragmoplast initials and with the
      TVN cell plate that is formed within the solid phragmoplast. ER progressively
      accumulates thereafter, reaching a maximum during the late PFS stage, when most
      cell plate growth is completed.

PMID- 15020748
TI  - Crystal structures of a poplar xyloglucan endotransglycosylase reveal details of
      transglycosylation acceptor binding.
AB  - Xyloglucan endotransglycosylases (XETs) cleave and religate xyloglucan polymers
      in plant cell walls via a transglycosylation mechanism. Thus, XET is a key enzyme
      in all plant processes that require cell wall remodeling. To provide a basis for
      detailed structure-function studies, the crystal structure of Populus tremula x
      tremuloides XET16A (PttXET16A), heterologously expressed in Pichia pastoris, has
      been determined at 1.8-A resolution. Even though the overall structure of
      PttXET16A is a curved beta-sandwich similar to other enzymes in the glycoside
      hydrolase family GH16, parts of its substrate binding cleft are more reminiscent
      of the distantly related family GH7. In addition, XET has a C-terminal extension
      that packs against the conserved core, providing an additional beta-strand and a
      short alpha-helix. The structure of XET in complex with a xyloglucan
      nonasaccharide, XLLG, reveals a very favorable acceptor binding site, which is a
      necessary but not sufficient prerequisite for transglycosylation. Biochemical
      data imply that the enzyme requires sugar residues in both acceptor and donor
      sites to properly orient the glycosidic bond relative to the catalytic residues.

PMID- 15020752
TI  - Robust-LongSAGE (RL-SAGE): a substantially improved LongSAGE method for gene
      discovery and transcriptome analysis.
AB  - Serial analysis of gene expression (SAGE) is a widely used technique for large
      scale transcriptome analysis in mammalian systems. Recently, a modified version
      called LongSAGE (S. Saha, A.B. Sparks, C. Rago, V. Akmaev, C.J. Wang, B.
      Vogelstein, K.W. Kinzler [2002] Nat Biotechnol 20: 508-512) was reported by
      increasing tag length up to 21 bp. Although the procedures for these two methods
      are similar, a detailed protocol for LongSAGE library construction has not been
      reported yet, and several technical difficulties associated with concatemer
      cloning and purification have not been solved. In this study, we report a
      substantially improved LongSAGE method called Robust-LongSAGE, which has four
      major improvements when compared with the previously reported protocols. First, a
      small amount of mRNA (50 ng) was enough for a library construction. Second,
      enhancement of cDNA adapter and ditag formation was achieved through an extended
      ligation period (overnight). Third, only 20 ditag polymerase chain reactions were
      needed to obtain a complete library (up to 90% reduction compared with the
      original protocols). Fourth, concatemers were partially digested with NlaIII
      before cloning into vector (pZEro-1), greatly improving cloning efficiency. The
      significant contribution of Robust-LongSAGE is that it solved the major technical
      difficulties, such as low cloning efficiency and small insert sizes associated
      with existing SAGE and LongSAGE protocols. Using this protocol, one can generate
      two to three libraries, each containing over 4.5 million tags, within a month. We
      recently have constructed five libraries from rice (Oryza sativa), one from maize
      (Zea mays), and one from the rice blast fungus (Magnaporthe grisea).

PMID- 15020754
TI  - On systems thinking, systems biology, and the in silico plant.
AB  - The recent summary report of a Department of Energy Workshop on Plant Systems
      Biology (P.V. Minorsky [2003] Plant Physiol 132: 404-409) offered a welcomed
      advocacy for systems analysis as essential in understanding plant development,
      growth, and production. The goal of the Workshop was to consider methods for
      relating the results of molecular research to real-world challenges in plant
      production for increased food supplies, alternative energy sources, and
      environmental improvement. The rather surprising feature of this report, however,
      was that the Workshop largely overlooked the rich history of plant systems
      analysis extending over nearly 40 years (Sinclair and Seligman, 1996) that has
      considered exactly those challenges targeted by the Workshop. Past systems
      research has explored and incorporated biochemical and physiological knowledge
      into plant simulation models from a number of perspectives. The research has
      resulted in considerable understanding and insight about how to simulate plant
      systems and the relative contribution of various factors in influencing plant
      production. These past activities have contributed directly to research focused
      on solving the problems of increasing biomass production and crop yields. These
      modeling approaches are also now providing an avenue to enhance integration of
      molecular genetic technologies in plant improvement (Hammer et al., 2002).

PMID- 15020753
TI  - Self-reporting Arabidopsis expressing pH and [Ca2+] indicators unveil ion
      dynamics in the cytoplasm and in the apoplast under abiotic stress.
AB  - For noninvasive in vivo measurements of intra- and extracellular ion
      concentrations, we produced transgenic Arabidopsis expressing pH and calcium
      indicators in the cytoplasm and in the apoplast. Ratiometric pH-sensitive
      derivatives of the green fluorescent protein (At-pHluorins) were used as pH
      indicators. For measurements of calcium ([Ca(2+)]), luminescent aequorin variants
      were expressed in fusion with pHluorins. An Arabidopsis chitinase signal sequence
      was used to deliver the indicator complex to the apoplast. Responses of pH and
      [Ca(2+)] in the apoplast and in the cytoplasm were studied under salt and
      "drought" (mannitol) stress. Results are discussed in the frame of ion flux,
      regulation, and signaling. They suggest that osmotic stress and salt stress are
      differently sensed, compiled, and processed in plant cells.

PMID- 15020755
TI  - UDP-glucose pyrophosphorylase. An old protein with new tricks.

PMID- 15020756
TI  - The SOS3 family of calcium sensors and SOS2 family of protein kinases in
      Arabidopsis.

PMID- 15020758
TI  - Molecular analysis of 10 coding regions from Arabidopsis that are homologous to
      the MUR3 xyloglucan galactosyltransferase.
AB  - Plant cell walls are composed of a large number of complex polysaccharides, which
      contain at least 13 different monosaccharides in a multitude of linkages. This
      structural complexity of cell wall components is paralleled by a large number of
      predicted glycosyltransferases in plant genomes, which can be grouped into
      several distinct families based on conserved sequence motifs (B. Henrissat, G.J.
      Davies [2000] Plant Physiol 124: 1515-1519). Despite the wealth of genomic
      information in Arabidopsis and several crop plants, the biochemical functions of
      these coding regions have only been established in a few cases. To lay the
      foundation for the genetic and biochemical characterization of putative
      glycosyltransferase genes, we conducted a phylogenetic and expression analysis on
      10 predicted coding regions (AtGT11-20) that are closely related to the MUR3
      xyloglucan galactosyltransferase of Arabidopsis. All of these proteins contain
      the conserved sequence motif pfam 03016 that is the hallmark of the beta-d
      glucuronosyltransferase domain of exostosins, a class of animal enzymes involved
      in the biosynthesis of the extracellular polysaccharide heparan sulfate. Reverse
      transcriptase-polymerase chain reaction and promoter:beta-glucuronidase studies
      indicate that all AtGT genes are transcribed. Although six of the 10 AtGT genes
      were expressed in all major plant organs, the remaining four genes showed more
      restricted expression patterns that were either confined to specific organs or to
      highly specialized cell types such as hydathodes or pollen grains. T-DNA
      insertion mutants in AtGT13 and AtGT18 displayed reductions in the Gal content of
      total cell wall material, suggesting that the disrupted genes encode
      galactosyltransferases in plant cell wall synthesis.

PMID- 15020757
TI  - Genome-wide identification of Arabidopsis coiled-coil proteins and establishment
      of the ARABI-COIL database.
AB  - Increasing evidence demonstrates the importance of long coiled-coil proteins for
      the spatial organization of cellular processes. Although several protein classes
      with long coiled-coil domains have been studied in animals and yeast, our
      knowledge about plant long coiled-coil proteins is very limited. The repeat
      nature of the coiled-coil sequence motif often prevents the simple identification
      of homologs of animal coiled-coil proteins by generic sequence similarity
      searches. As a consequence, counterparts of many animal proteins with long coiled
      coil domains, like lamins, golgins, or microtubule organization center
      components, have not been identified yet in plants. Here, all Arabidopsis
      proteins predicted to contain long stretches of coiled-coil domains were
      identified by applying the algorithm MultiCoil to a genome-wide screen. A
      searchable protein database, ARABI-COIL (http://www.coiled-coil.org/arabidopsis),
      was established that integrates information on number, size, and position of
      predicted coiled-coil domains with subcellular localization signals,
      transmembrane domains, and available functional annotations. ARABI-COIL serves as
      a tool to sort and browse Arabidopsis long coiled-coil proteins to facilitate the
      identification and selection of candidate proteins of potential interest for
      specific research areas. Using the database, candidate proteins were identified
      for Arabidopsis membrane-bound, nuclear, and organellar long coiled-coil
      proteins.

PMID- 15020760
TI  - A new resource for cereal genomics: 22K barley GeneChip comes of age.
AB  - In recent years, access to complete genomic sequences, coupled with rapidly
      accumulating data related to RNA and protein expression patterns, has made it
      possible to determine comprehensively how genes contribute to complex phenotypes.
      However, for major crop plants, publicly available, standard platforms for
      parallel expression analysis have been limited. We report the conception and
      design of the new publicly available, 22K Barley1 GeneChip probe array, a model
      for plants without a fully sequenced genome. Array content was derived from
      worldwide contribution of 350,000 high-quality ESTs from 84 cDNA libraries, in
      addition to 1,145 barley (Hordeum vulgare) gene sequences from the National
      Center for Biotechnology Information nonredundant database. Conserved sequences
      expressed in seedlings of wheat (Triticum aestivum), oat (Avena strigosa), rice
      (Oryza sativa), sorghum (Sorghum bicolor), and maize (Zea mays) were identified
      that will be valuable in the design of arrays across grasses. To enhance the
      usability of the data, BarleyBase, a MIAME-compliant, MySQL relational database,
      serves as a public repository for raw and normalized expression data from the
      Barley1 GeneChip probe array. Interconnecting links with PlantGDB and Gramene
      allow BarleyBase users to perform gene predictions using the 21,439 non-redundant
      Barley1 exemplar sequences or cross-species comparison at the genome level,
      respectively. We expect that this first generation array will accelerate
      hypothesis generation and gene discovery in disease defense pathways, responses
      to abiotic stresses, development, and evolutionary diversity in monocot plants.

PMID- 15020759
TI  - Evaluation of monocot and eudicot divergence using the sugarcane transcriptome.
AB  - Over 40,000 sugarcane (Saccharum officinarum) consensus sequences assembled from
      237,954 expressed sequence tags were compared with the protein and DNA sequences
      from other angiosperms, including the genomes of Arabidopsis and rice (Oryza
      sativa). Approximately two-thirds of the sugarcane transcriptome have similar
      sequences in Arabidopsis. These sequences may represent a core set of proteins or
      protein domains that are conserved among monocots and eudicots and probably
      encode for essential angiosperm functions. The remaining sequences represent
      putative monocot-specific genetic material, one-half of which were found only in
      sugarcane. These monocot-specific cDNAs represent either novelties or, in many
      cases, fast-evolving sequences that diverged substantially from their eudicot
      homologs. The wide comparative genome analysis presented here provides
      information on the evolutionary changes that underlie the divergence of monocots
      and eudicots. Our comparative analysis also led to the identification of several
      not yet annotated putative genes and possible gene loss events in Arabidopsis.

PMID- 15020761
TI  - Production of reactive oxygen species, alteration of cytosolic ascorbate
      peroxidase, and impairment of mitochondrial metabolism are early events in heat
      shock-induced programmed cell death in tobacco Bright-Yellow 2 cells.
AB  - To gain some insight into the mechanisms by which plant cells die as a result of
      abiotic stress, we exposed tobacco (Nicotiana tabacum) Bright-Yellow 2 cells to
      heat shock and investigated cell survival as a function of time after heat shock
      induction. Heat treatment at 55 degrees C triggered processes leading to
      programmed cell death (PCD) that was complete after 72 h. In the early phase,
      cells undergoing PCD showed an immediate burst in hydrogen peroxide (H2O2) and
      superoxide (O2*-) anion production. Consistently, death was prevented by the
      antioxidants ascorbate (ASC) and superoxide dismutase (SOD). Actinomycin D and
      cycloheximide, inhibitors of transcription and translation, respectively, also
      prevented cell death, but with a lower efficiency. Induction of PCD resulted in
      gradual oxidation of endogenous ASC; this was accompanied by a decrease in both
      the amount and the specific activity of the cytosolic ASC peroxidase (cAPX). A
      reduction in cAPX gene expression was also found in the late PCD phase. Moreover,
      changes of cAPX kinetic properties were found in PCD cells. Production of ROS in
      PCD cells was accompanied by early inhibition of glucose (Glc) oxidation, with a
      strong impairment of mitochondrial function as shown by an increase in cellular
      NAD(P)H fluorescence, and by failure of mitochondria isolated from cells
      undergoing PCD to generate membrane potential and to oxidize succinate in a
      manner controlled by ADP. Thus, we propose that in the early phase of tobacco
      Bright-Yellow 2 cell PCD, ROS production occurs, perhaps because of damage of the
      cell antioxidant system, with impairment of the mitochondrial oxidative
      phosphorylation.

PMID- 15020762
TI  - Human papillomavirus (HPV) origin-binding protein associates with mitotic
      spindles to enable viral DNA partitioning.
AB  - Human papillomaviruses (HPVs) establish long-term infections in patients. The
      mechanism for extrachromosomal HPV DNA persistence in cycling cells is unknown.
      We show that HPV origin-containing plasmids partition as minichromosomes,
      attributable to an association of the viral origin recognition protein E2 with
      mitotic spindles. alpha-, beta-, and gamma-tubulins were pulled down with a
      tagged E2. The N-terminal transacting and C-terminal protein dimerization/DNA
      binding domains independently associated with the spindles. We suggest that this
      E2 property enables these viruses to establish persistence. Its implication for
      HPV oncogenesis is presented.

PMID- 15020763
TI  - Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac
      disease.
AB  - Celiac disease, also known as celiac sprue, is a gluten-induced autoimmune-like
      disorder of the small intestine, which is strongly associated with HLA-DQ2. The
      structure of DQ2 complexed with an immunogenic epitope from gluten, QLQPFPQPELPY,
      has been determined to 2.2-A resolution by x-ray crystallography. The glutamate
      at P6, which is formed by tissue transglutaminase-catalyzed deamidation, is an
      important anchor residue as it participates in an extensive hydrogen-bonding
      network involving Lys-beta71 of DQ2. The gluten peptide-DQ2 complex retains
      critical hydrogen bonds between the MHC and the peptide backbone despite the
      presence of many proline residues in the peptide that are unable to participate
      in amide-mediated hydrogen bonds. Positioning of proline residues such that they
      do not interfere with backbone hydrogen bonding results in a reduction in the
      number of registers available for gluten peptides to bind to MHC class II
      molecules and presumably impairs the likelihood of establishing favorable side
      chain interactions. The HLA association in celiac disease can be explained by a
      superior ability of DQ2 to bind the biased repertoire of proline-rich gluten
      peptides that have survived gastrointestinal digestion and that have been
      deamidated by tissue transglutaminase. Finally, surface-exposed proline residues
      in the proteolytically resistant ligand were replaced with functionalized
      analogs, thereby providing a starting point for the design of orally active
      agents for blocking gluten-induced toxicity.

PMID- 15020764
TI  - New biphenol-based, fine-tunable monodentate phosphoramidite ligands for
      catalytic asymmetric transformations.
AB  - Monodentate phosphoramidite ligands have been developed based on enantiopure 6,6'
      dimethylbiphenols with axial chirality. These chiral ligands are easy to prepare
      and flexible for modifications. The fine-tuning capability of these ligands plays
      a significant role in achieving high enantioselectivity in the asymmetric
      hydroformylation of allyl cyanide and the conjugate addition of diethylzinc to
      cycloalkenones.

PMID- 15020766
TI  - Mixed-membership models of scientific publications.
AB  - PNAS is one of world's most cited multidisciplinary scientific journals. The PNAS
      official classification structure of subjects is reflected in topic labels
      submitted by the authors of articles, largely related to traditionally
      established disciplines. These include broad field classifications into physical
      sciences, biological sciences, social sciences, and further subtopic
      classifications within the fields. Focusing on biological sciences, we explore an
      internal soft-classification structure of articles based only on semantic
      decompositions of abstracts and bibliographies and compare it with the formal
      discipline classifications. Our model assumes that there is a fixed number of
      internal categories, each characterized by multinomial distributions over words
      (in abstracts) and references (in bibliographies). Soft classification for each
      article is based on proportions of the article's content coming from each
      category. We discuss the appropriateness of the model for the PNAS database as
      well as other features of the data relevant to soft classification.

PMID- 15020767
TI  - Asymmetric catalysis in complex target synthesis.
AB  - This article describes three distinct strategies by which stereochemically
      complex molecules are synthesized and the ways asymmetric catalysis can impact on
      all three. The development of general methods to prepare synthetically useful
      building blocks leads to an expanded "chiral pool" of potential starting
      materials for asymmetric synthesis. The possibility of discovering new reactions
      to access new types of building blocks is particularly attractive and serves to
      help define the frontiers of the field. Asymmetric catalysis can also be applied
      to diastereoselective synthesis such that the stereochemistry of the catalyst,
      and not that of the substrate, determines the relative configuration of the
      product. Finally, in reactions where multiple stereocenters are generated
      simultaneously or in tandem, catalyst and substrate control can operate in a
      complementary manner to achieve one of many possible stereochemical outcomes
      selectively.

PMID- 15020765
TI  - Nitric oxide, oxidants, and protein tyrosine nitration.
AB  - The occurrence of protein tyrosine nitration under disease conditions is now
      firmly established and represents a shift from the signal transducing
      physiological actions of (.)NO to oxidative and potentially pathogenic pathways.
      Tyrosine nitration is mediated by reactive nitrogen species such as peroxynitrite
      anion (ONOO(-)) and nitrogen dioxide ((.)NO2), formed as secondary products of
      (.)NO metabolism in the presence of oxidants including superoxide radicals (O2(.
      )), hydrogen peroxide (H2O2), and transition metal centers. The precise interplay
      between (.)NO and oxidants and the identification of the proximal intermediate(s)
      responsible for nitration in vivo have been under controversy. Despite the
      capacity of peroxynitrite to mediate tyrosine nitration in vitro, its role on
      nitration in vivo has been questioned, and alternative pathways, including the
      nitrite/H2O2/hemeperoxidase and transition metal-dependent mechanisms, have been
      proposed. A balanced analysis of existing evidence indicates that (i) different
      nitration pathways can contribute to tyrosine nitration in vivo, and (ii) most,
      if not all, nitration pathways involve free radical biochemistry with carbonate
      radicals (CO3(.-)) and/or oxo-metal complexes oxidizing tyrosine to tyrosyl
      radical followed by the diffusion-controlled reaction with (.)NO2 to yield 3
      nitrotyrosine. Although protein tyrosine nitration is a low-yield process in
      vivo, 3-nitrotyrosine has been revealed as a relevant biomarker of (.)NO
      dependent oxidative stress; additionally, site-specific nitration focused on
      particular protein tyrosines may result in modification of function and promote a
      biological effect. Tissue distribution and quantitation of protein 3
      nitrotyrosine, recognition of the predominant nitration pathways and individual
      identification of nitrated proteins in disease states open new avenues for the
      understanding and treatment of human pathologies.

PMID- 15020769
TI  - A nascent polypeptide domain that can regulate translation elongation.
AB  - The evolutionarily conserved fungal arginine attenuator peptide (AAP), as a
      nascent peptide, stalls the translating ribosome in response to the presence of a
      high concentration of the amino acid arginine. Here we examine whether the AAP
      maintains regulatory function in fungal, plant, and animal cell-free translation
      systems when placed as a domain near the N terminus or internally within a large
      polypeptide. Pulse-chase analyses of the radiolabeled polypeptides synthesized in
      these systems indicated that wild-type AAP functions at either position to stall
      polypeptide synthesis in response to arginine. Toeprint analyses performed to map
      the positions of stalled ribosomes on transcripts introduced into the fungal
      system revealed that ribosome stalling required translation of the AAP coding
      sequence. The positions of the stalled ribosomes were consistent with the sizes
      of the radiolabeled polypeptide intermediates. These findings demonstrate that an
      internal polypeptide domain in a nascent chain can regulate eukaryotic
      translational elongation in response to a small molecule. Apparently the peptide
      sensing features are conserved in fungal, plant, and animal ribosomes. These data
      provide precedents for translational strategies that would allow domains within
      nascent polypeptide chains to modulate gene expression.

PMID- 15020771
TI  - Waves and aggregation patterns in myxobacteria.
AB  - Under starvation conditions, a population of myxobacteria aggregates to build a
      fruiting body whose shape is species-specific and within which the cells
      sporulate. Early in this process, cells often pass through a "ripple phase"
      characterized by traveling linear, concentric, and spiral waves. These waves are
      different from the waves observed during slime mold aggregation that depend on
      diffusible morphogens, because myxobacteria communicate by direct contact. The
      difference is most dramatic when waves collide: rather than annihilating one
      another, myxobacterial waves appear to pass through one another unchanged. Under
      certain conditions, the spacing and location of the nascent fruiting bodies is
      determined by the wavelength and pattern of the waves. Later in fruiting body
      development, waves are replaced by streams of cells that circulate around small
      initial aggregates enlarging and rounding them. Still later, pairs of motile
      aggregates coalesce to form larger aggregates that develop into fruiting bodies.
      Here we present a mathematical model that quantitatively explains these wave and
      aggregation phenomena.

PMID- 15020770
TI  - The transforming activity of Wnt effectors correlates with their ability to
      induce the accumulation of mammary progenitor cells.
AB  - Ectopic activation of the Wnt signaling pathway is highly oncogenic for many
      human tissues. Here, we show that ectopic Wnt signaling increases the effective
      stem cell activity in mouse mammary glands in vivo. Furthermore, Wnt effectors
      induce the accumulation of mouse mammary epithelial progenitors (assayed by
      Hoechst dye exclusion, a surrogate stem cell marker, side population cells) both
      in vivo and in vitro. The longevity of stem cells makes them good candidate tumor
      precursors, and we propose that Wnt-induced progenitor amplification is likely to
      be key to tumor initiation. In support of this notion, mammary glands from a
      tumor-resistant strain of mice (carrying a null mutation in syndecan-1) contain
      fewer side population cells. When this strain is crossed to mice that overexpress
      effectors of the beta-catenin/T cell factor Wnt pathway, the amplification of
      progenitors is reduced, together with all subsequent events of tumor development.
      We propose that the growth dynamic of the stem cell fraction is a major
      determinant of tumor susceptibility.

PMID- 15020772
TI  - Calcium signaling in chemorepellant Slit2-dependent regulation of neuronal
      migration.
AB  - Migration of neuronal precursor cells in the developing brain is guided by
      extracellular cues, but intracellular signaling processes underlying the guidance
      of neuronal migration are largely unknown. By examining the migration of
      cerebellar granule neurons along the surface of cocultured astroglial cells, we
      found that an extracellular gradient of Slit2, a chemorepellant for neuronal
      migration in vivo, caused a reversal in the direction of migration without
      affecting the migration speed. A Slit2 gradient elevated the intracellular
      concentration of Ca2+, probably due to calcium release from the internal store,
      led to a reversal of the preexisting asymmetric intracellular Ca2+ distribution
      in the soma of migrating neurons, and this reversal was closely related with its
      action of reversing the migrating direction. Asymmetric Ca2+ distribution in the
      soma was both necessary and sufficient for directing neuronal migration. These
      results have demonstrated an important role for Ca2+ in mediating neuronal
      responses to Slit2 and suggest a general mechanism for neuronal guidance.

PMID- 15020773
TI  - Trp zipper folding kinetics by molecular dynamics and temperature-jump
      spectroscopy.
AB  - We studied the microsecond folding dynamics of three beta hairpins (Trp zippers 1
      3, TZ1-TZ3) by using temperature-jump fluorescence and atomistic molecular
      dynamics in implicit solvent. In addition, we studied TZ2 by using time-resolved
      IR spectroscopy. By using distributed computing, we obtained an aggregate
      simulation time of 22 ms. The simulations included 150, 212, and 48 folding
      events at room temperature for TZ1, TZ2, and TZ3, respectively. The all-atom
      optimized potentials for liquid simulations (OPLS(aa)) potential set predicted
      TZ1 and TZ2 properties well; the estimated folding rates agreed with the
      experimentally determined folding rates and native conformations were the global
      potential-energy minimum. The simulations also predicted reasonable unfolding
      activation enthalpies. This work, directly comparing large simulated folding
      ensembles with multiple spectroscopic probes, revealed both the surprising
      predictive ability of current models as well as their shortcomings. Specifically,
      for TZ1-TZ3, OPLS for united atom models had a nonnative free-energy minimum, and
      the folding rate for OPLS(aa) TZ3 was sensitive to the initial conformation.
      Finally, we characterized the transition state; all TZs fold by means of similar,
      native-like transition-state conformations.

PMID- 15020775
TI  - Protein arrays from cDNA expression libraries.
AB  - This chapter describes the production of a cDNA expression library from human
      fetal brain, the construction of a high-density protein array from such a
      library, and two applications to screen the array for binding proteins. After
      producing the library and decollating the expression clones, one can pick
      thousands of expression clones with a laboratory robot and can deposit them into
      microtiter plates in an ordered manner. Such ordered clone libraries are the
      starting material for the construction of a high-density protein array. This
      array is constructed by spotting the expression clones onto a protein-binding
      membrane. Following cell growth and induction of protein expression on the
      membrane, the cell spots are lysed and their recombinant protein immobilized on
      the membrane. The so-constructed array carries thousands of proteins without the
      need to clone, express, and spot individual proteins. Such arrays allow one to
      screen for numerous protein functions in a high-throughput manner.

PMID- 15020776
TI  - Protein expression arrays for proteomics.
AB  - As biology approaches the 50th year of deciphering the DNA code, the next
      frontier toward understanding cell function has protein biochemistry in the form
      of structural and functional proteomics. To accomplish the needs of proteomics,
      novel strategies must be devised to examine the gene products or proteins,
      emerged as en masse. The authors have developed a high-throughput system for the
      expression and purification of eukaryotic proteins to provide the resources for
      structural studies and protein functional analysis. The long-term objective is to
      overexpress and purify thousands of proteins encoded by the human genome. This
      library of proteins--the human proteome--can be arrayed in addressable format in
      quantities and purities suitable for high-throughput studies. Critical technology
      involved in efficiently moving from genome to proteome includes parallel sample
      handling, robust expression, and rapid purification procedures. Automation of
      these processes is essential for the production of thousands of recombinant
      proteins and the reduction of human error.

PMID- 15020777
TI  - Generation of protein in situ arrays by DiscernArray technology.
AB  - A cell-free DiscernArray technology is described for making protein arrays
      directly from polymerase chain reaction deoxyribonucleic acid (PCR DNA)
      fragments. In this method, individual tagged proteins are synthesized in a cell
      free system on a tag-binding surface, such that the tagged proteins are
      immobilized on the surface as they are produced. This technology is particularly
      useful for arraying proteins/domains that cannot be functionally produced by
      heterologous expression or for which the cloned DNA is not available. Protein
      arrays of single-chain antibodies, ligand-binding domains, and enzymes have been
      successfully generated by this method.

PMID- 15020774
TI  - Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates
      adverse remodeling in infarcted murine myocardium.
AB  - After myocardial infarction (MI), adverse remodeling with left ventricular (LV)
      dilatation is a major determinant of poor outcome. Skeletal myoblast (SkM)
      implantation improves cardiac function post-MI, although the mechanism is
      unclear. IL-1 influences post-MI hypertrophy and collagen turnover and is
      implicated in SkM death after grafting. We hypothesized that SkM expressing
      secretory IL-1 receptor antagonist (sIL-1ra) at MI border zones would
      specifically attenuate adverse remodeling and exhibit improved graft cell number.
      Stable murine male SkM lines (5 x 10(5) cells), expressing or nonexpressing
      (cont) for sIL-1ra, were implanted into infarct border zones of female nude mice
      immediately after left coronary artery occlusion. LV ejection fraction (LVEF),
      end-diastolic diameter, and transmitral peak early/late (E/A) flow velocity ratio
      were determined by echocardiography. Cardiac myocyte hypertrophy and fibrosis
      were assessed by morphometry, picrosirius red staining, and hydroxyproline assay.
      At 3 weeks, cont-SkM-engrafted hearts showed reduced hypertrophy, improved LVEF
      (55.7 +/- 1.2% vs. MI-only: 40.3 +/- 2.9%), and preserved E/A ratios. sIL-1ra-SkM
      implantation enhanced these effects (LVEF, 67.0 +/- 2.3%) and significantly
      attenuated LV dilatation (LV end-diastolic diameter, 4.0 +/- 1.1 mm vs. cont-SkM,
      4.5 +/- 1.2 mm vs. MI-only, 4.8 +/- 1.8 mm); this was associated with greater
      graft numbers, as shown by PCR for male-specific smcy gene. Enzyme zymography
      showed attenuated matrix metalloproteinase-2 and -9 up-regulation post-MI by
      either donor SkM type, although infarct-remote zone collagen was reduced only
      with sIL-1ra-SkM. These results suggest that SkM implantation improves cardiac
      function post-MI by modulation of adverse remodeling, and that this effect can be
      significantly enhanced by targeting IL-1 as a key upstream regulator of both
      adverse remodeling and graft cell death.

PMID- 15020778
TI  - Multiplexed protein analysis using spotted antibody microarrays.
AB  - This chapter describes methods for the production and use of antibody
      microarrays. The methods are divided into (a) antibody handling and microarray
      production, (b) sample preparation, and (c) microarray use. Two types of
      detection methods are described: direct labeling and a fluorescence-linked
      immunosorbent assay (FLISA). In the direct labeling method, all proteins in a
      complex mixture are labeled with either a fluorophore or a hapten that allows
      subsequent detection. In FLISA detection, a capture antibody on the microarray
      captures the unlabeled protein target, which is detected by a detection antibody
      and a fluorophore-labeled secondary antibody. Each method has particular optimal
      uses, which are discussed in the text.

PMID- 15020779
TI  - Target-assisted iterative screening of phage surface display cDNA libraries.
AB  - The novel screening format, target-assisted iterative screening (TAIS), comprises
      a simple and rapid two-step procedure for in vitro affinity selection of specific
      binders from enormous molecular diversities to the target molecule of interest.
      This detailed protocol describes the application of TAIS to a T7 phage-displayed
      complementary DNA (cDNA) library with a protein domain as a target. Protocols for
      purification of the target as glutathione-S-transferase (GST) fusion protein and
      modifications of the purified target that are required for the screening
      complement the TAIS protocol. The described application is a method of choice for
      the researchers interested in the identification and characterization of novel
      protein-protein interactions mediated by peptide recognition domains.

PMID- 15020780
TI  - Design, construction, and use of tissue microarrays.
AB  - Tissue microarrays are a platform for high-throughput analysis of tissue
      specimens in research. They are used for target verification of results from
      complementary deoxyribonucleic acid (cDNA) microarrays, expression profiling of
      tumors and tissues, as well as in epidemiology-based investigations. Tissue
      microarrays are a simple reagent that can be constructed from archival paraffin
      embedded tissue for immunohistochemical staining, in situ hybridization, and
      other methodologies. The design and precision in execution of a tissue microarray
      is essential to obtain the desired results. Tissue microarrays are a powerful
      proteomic platform for research.

PMID- 15020781
TI  - A streptavidin-biotin-based microarray platform for immunoassays.
AB  - The authors describe a microarray system for disease diagnosis based on antibody
      antigen interactions. Either biotinylated antibodies or antigens are coupled via
      streptavidin linkers onto a gold surface. This platform has been used to
      establish recombinant antibody-antigen interactions and to detect specific IgM
      antibodies in sera of patients suspected of Lyme borreliosis. Therefore, this
      microarray system can be adapted for further applications.

PMID- 15020783
TI  - Processing of photoaptamer microarrays.
AB  - Photoaptamers are single-stranded nucleic acids selected for their high affinity
      to specific proteins of interest. Photoaptamer microarrays capture and quantify
      proteins from complex samples using a unique protocol that leverages both high
      affinity capture with covalent retention of analytes. The initial capture of
      proteins from solution is similar to the well-known antibody capture, but the
      "secondary binding event" affected by photoaptamers is a covalent crosslink
      between the photoaptamer capture agent and the protein analyte. The nature of
      this specific covalent reaction allows a unique microarray processing that is
      described in detail in this chapter.

PMID- 15020782
TI  - Site-specific immobilization of biotinylated proteins for protein microarray
      analysis.
AB  - The postgenome era has led to a new frontier of proteomics that requires the
      development of protein microarray, which enables us to unravel the biological
      function of proteins in a massively parallel fashion. Several ways of
      immobilizing proteins onto surfaces have been reported, but many of these
      attachments are unspecific, resulting in the unfavorable orientation of the
      immobilized proteins. His6 tag has been used to site-specifically immobilize
      proteins onto nickel-coated slides, which presumably oriented proteins uniformly
      on the surface of the slide. However, the binding between Ni-NTA and His tag
      proteins is not strong, causing the immobilized proteins to dissociate from the
      slide even under simple wash conditions. The authors have developed a novel
      strategy of using an intein-mediated expression system to generate biotinylated
      proteins suitable for immobilization onto avidin-functionalized glass slides.
      Array-scan results not only show successful immobilization of proteins onto
      slides by antibody detection method but also full retention of biological
      activities of the immobilized proteins. The strong and specific interaction
      between biotin and avidin also permits the use of stringent incubation and
      washing conditions on the protein microchip, thus making it a highly robust
      method for array studies.

PMID- 15020785
TI  - Evaluation of antibodies and microarray coatings as a prerequisite for the
      generation of optimized antibody microarrays.
AB  - Antibody microarrays are becoming a major tool for the parallel analysis of
      complex samples. So far, many efforts have been made to increase the complexity
      and sensitivity of antibody microarrays. In contrast to enzyme-linked
      immunosorbent assay (ELISA) experiments, not all antibodies remain functional in
      the microarray format. Sensitivity is very much dependent on the type of coating
      and its application. The method described in this chapter is a quick and reliable
      method that has been very useful in determining the functionality of antibodies
      and the suitability of coatings for antibody microarrays. At the same time, a
      detailed description of how to prepare an inexpensive and highly efficient
      antibody microarray surface is given.

PMID- 15020784
TI  - Use of a small molecule-based affinity system for the preparation of protein
      microarrays.
AB  - This chapter describes a method for preparing protein microarrays, using a small
      molecule, chemical affinity system.

PMID- 15020786
TI  - Printing functional protein microarrays using piezoelectric capillaries.
AB  - The use of piezoelectric dispensers for the fabrication of protein biochips has
      become a popular approach owing to its inherent advantages of noncontact with the
      printing surface and the opportunity for recovery of unused sample. Despite the
      inherent advantages of this printing method, little attention has been devoted to
      the quantitative aspects of dispensing small volumes of dilute protein solutions
      from the borosilicate glass capillaries employed by piezoelectric dispensers.
      Here, a method is detailed that demonstrates the benefits of using a low-ionic
      strength phosphate printing buffer containing the carrier protein bovine serum
      albumin (BSA) to deposit capture antibody microspots. When this buffer is used to
      deposit biotinylated capture antibodies, 3.6- to 44-fold more protein is
      delivered to an avidin-coated surface compared to when the antibodies are
      deposited in standard phosphate-buffered saline (PBS) in the absence of BSA.
      Further, this method results in the deposition of capture antibodies that adopt a
      more uniform spot morphology.

PMID- 15020787
TI  - The use of precision glass syringes and a noncontact microsolenoid dispenser for
      the production of high-throughput low-density arrays.
AB  - The advantages of using nondisposable precision glass syringes in automated high
      throughput microdispensers and a single-channel noncontact microsolenoid
      dispenser in creating highly uniform and reproducible protein, nucleic acid, and
      organic compound array filters, slides, and plates are described. Using a
      HydraPlus-One system, protein solutions of up to 100 mg/mL (in 100 nL) can be
      spotted onto slides and plates at a speed of 0.6 s per spot. Using the Hydra
      microdispenser and Tango liquid handling system, as little as 100 nL of
      polymerase chain reaction (PCR)-amplified human cancer-related genes,
      housekeeping genes, and protein solutions can be spotted onto nylon membranes,
      coated slides, or plates. Using these microdispensers equipped with syringes, up
      to 6144 uniform and reproducible spots per membrane and up to 1000 spots per
      slide, with a precision variation of less than 10%, were printed at a speed of as
      fast as 2.5 min per membrane.

PMID- 15020788
TI  - A protein microarray ELISA for screening biological fluids.
AB  - Protein microarrays permit the simultaneous measurement of many proteins in a
      small sample volume and therefore provide an attractive approach for the
      quantitative measurement of proteins in biological fluids, including serum. This
      chapter describes a microarray enzyme-linked immunosorbent assay (ELISA). Capture
      antibodies are immobilized onto a glass surface; the covalently attached
      antibodies bind a specific antigen from a sample overlaying the array. A second,
      biotinylated antibody that recognizes the same antigen as the first antibody, but
      at a different epitope, is then used for detection. Detection is based on an
      enzymatic signal-enhancement method known as tyramide signal amplification (TSA).
      By coupling a microarray-ELISA format with the signal amplification of tyramide
      deposition, the assay sensitivity is as low as sub-pg/mL.

PMID- 15020789
TI  - Protein-domain microarrays.
AB  - Protein domains are independently folded regions of proteins that are often
      involved in protein-protein interactions. They are good candidates for the
      generation of protein microarrays because of their small size, their globular
      structures, and the fact that they are the protein-interacting workhorses of the
      cell. In addition, arrayed recombinant protein domains retain much of their
      binding specificity. Such microarrays can be probed with other recombinant
      proteins or fluorescently labeled peptides to identify potential binding partners
      and also determine how posttranslational modifications influence specific
      interactions. Thus, protein domains provide us with a system-oriented array that
      is focused on elucidating signal transduction pathway specificity and regulation.

PMID- 15020790
TI  - SH3 domain protein-binding arrays.
AB  - First identified as part of the Rous sarcoma oncogene product Src, SH3 (Src
      Homology 3) domains play an important role in intercellular communication and
      intracellular signal transduction. A high-throughput assay for ligand binding to
      SH3 domains--SH3 domain proteins immobilized on a membrane--allows rapid
      visualization of numerous SH3 domain protein-protein interactions with no
      expensive equipment or radioactivity required. Once the array is constructed or
      obtained commercially, the procedure is straightforward: The protein of interest
      is cloned into a fusion-tagged expression vector and expressed in bacteria, the
      prepared bacterial extract is incubated with the array membrane, and the signal
      is measured using a chemiluminescence detection system.

PMID- 15020791
TI  - Site-specific peptide immobilization strategies for the rapid detection of kinase
      activity on microarrays.
AB  - The massive throughput offered by array-based technologies can only be realized
      with the development of equally powerful strategies that offer reproducible
      consistency. The competence of arrays and efficacy of screening come under
      scrutiny, with most existing immobilization schemes that do not site-specifically
      ligate peptides on the arrays. Thus, it is crucial in array-based experiments to
      orientate peptides in an ordered and uniform fashion. Two new approaches were
      developed for the directed immobilization of peptides on a microarray, by
      exploiting measures involving native chemical ligation reactions as well as
      biotin-streptavidin interactions. This makes it possible to stably immobilize
      peptides in a consistent manner and in a predetermined orientation on the
      microarray. The first scheme employs glass slides that are functionalized with
      avidin for attachment of terminally biotinylated peptides. The second uses slides
      containing thioester moieties to ligate N-terminal cysteine containing peptides.
      The authors successfully immobilized peptides on chip using these strategies,
      and, in extending their method to the study of kinase activity on microarrays,
      they also developed a novel detection scheme that abrogates the dependence on
      traditional radioactivity-based kinase screening assays. This method employs
      fluorescently labeled antiphosphoserine and antiphosphotyrosine antibodies in
      assessing and monitoring kinase activity on arrays. The above methodologies
      provide for a fast and sensitive approach with which to conveniently assess
      kinase activity using peptide microarrays.

PMID- 15020792
TI  - Simultaneous monitoring of multiple kinase activities by SELDI-TOF mass
      spectrometry.
AB  - Cellular response to the external environment is often controlled by one or more
      protein kinases. We report a methodology for simultaneously monitoring multiple
      kinase activities across multiple signal-transduction pathways using ProteinChip
      Array technology. Based on the addition of specific peptide reporters, kinase
      activity is detected by the presence of a mass shift of 80 Da (or multiple
      thereof) corresponding to the addition of one or more phosphate groups. These
      phosphorylated peptide substrates are then enriched using an immobilized metal
      affinity capture (IMAC)-Ga array and detected directly by surface-enhanced laser
      desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). SELDI-TOF
      MS is sensitive, tagless (nonradioactive, nonfluorescent), can be easily
      multiplexed for the analysis of several different kinases in a single reaction
      mixture (limited only by the specificity of the kinase for its substrate
      peptides), and is directly scalable through the use of robotic sample processing.
      By multiplexing kinase assays, one can dramatically increase the amount of
      information obtained from rare or volume-limited samples. More important, results
      reflect closely the complex interrelationships between kinases and show high
      correlation with in vivo assays.

PMID- 15020793
TI  - Cytokine protein arrays.
AB  - Cytokines play important roles in many aspects of cell physiology and pathology.
      The simultaneous determination of multiple cytokine-expression levels is
      receiving much attention in the research community. Multiple cytokine-expression
      levels can be simultaneously determined using enzyme-linked immunosorbent assay
      (ELISA)-based protein array technology. In this approach, target proteins are
      captured by the arrayed capture antibody and then detected in a sandwich ELISA
      format using a cocktail of biotinylated detection antibodies. The signals are
      visualized by either horseradish peroxidase (HRP)-conjugated streptavidin and
      enhanced chemiluminescence, or cy3-conjugated streptavidin and laser scanner.
      Several key factors and steps are described, including selection of solid
      supports, selection of suitable antibodies, determination of specificity and
      sensitivity of cytokine protein arrays, array design, sample preparation, and
      detailed experimental procedures for macroarray and microarray formats. An
      account of the successful development and application of cytokine protein arrays
      is presented.

PMID- 15020794
TI  - Fabrication and application of G protein-coupled receptor microarrays.
AB  - The increased number of drug targets and compounds demands novel high-throughput
      screening technologies that could be used for parallel analysis of many genes and
      proteins. Protein microarrays are evolving promising technologies for the
      parallel analysis of many proteins with respect to their abundance, location,
      modifications, and interactions with other biological and chemical molecules.
      This chapter specifically describes the fabrication of G protein-coupled receptor
      (GPCR) microarrays, a unique subset of protein microarrays, using contact-pin
      printing technology. The bioassays and potential applications of GPCR microarrays
      for the determination of compound affinities and potencies are also included.

PMID- 15020795
TI  - ProteinChip array-based amyloid beta assays.
AB  - Amyloid-beta (A beta) fragments are found in plaques of patients with Alzheimers.
      Three secretases cleave the amyloid precursor protein, producing multiple A beta
      fragments that accumulate in the brain and fluids of patients with Alzheimers. A
      beta peptides are difficult to detect using standard methods because of their
      small size and multiple isoforms. However, multiple peptide fragments can be
      detected using a single ProteinChip Array-Based assay. Specific antibodies
      recognizing various amyloid epitopes are immobilized on a ProteinChip Array.
      Crude samples, such as tissue lysates, serum, cerebral spinal fluid (CSF), or
      cell culture media, are applied to the antibody-coated arrays. A beta peptides
      are specifically retained by the antibody, whereas other sample components are
      removed by washing. The multiple peptide fragments are detected by surface
      enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF
      MS), which can easily resolve the different fragments because of the
      corresponding changes in peptide mass.

PMID- 15020796
TI  - Serum protein-expression profiling using the ProteinChip biomarker system.
AB  - Protein-expression profiling of serum is a common approach to the discovery of
      potential diagnostic and therapeutic markers of disease. Like any other proteome,
      the serum proteome is characterized by protein expression across a large dynamic
      range. This single facet requires the employment of fractionation procedures
      prior to detection of protein. The authors use a combination of conventional
      column chromatography with array-based chromatography to simplify the serum
      proteome into subproteomes, thus providing a greater representation of the serum
      proteome. Robotics is employed to increase the throughput of sample processing.
      These procedures result in large amounts of data that are analyzed through a
      series of preprocessing and postprocessing steps. A well-designed serum profiling
      project can therefore result in the discovery of statistically sound, clinically
      meaningful protein biomarkers.

PMID- 15020797
TI  - Protein arrays for serodiagnosis of disease.
AB  - Protein microarrays offer the possibility to circumvent most of the current
      limitations in the serodiagnosis of allergy, autoimmune, and infectious disease
      by allowing the simultaneous, multiparametric determination of specific
      subclasses of antibodies directed against many pathogenic antigens. Microarray
      immunoassays have been developed with these characteristics. A first-generation
      assay, for the serodiagnosis of infectious disease, allows the determination of
      IgG and IgM antibodies to various viral and bacterial antigens. In addition, a
      second-generation assay, designed for the serodiagnosis of allergic disease,
      permits the determination of IgE antibodies to various allergens implicated in
      allergic disease. Slides printed with antibody dilution curves and antigen are
      first incubated with serum samples and then subsequently with secondary
      antibodies. For detection of human IgG and IgM, fluorescently labeled secondary
      antibodies are employed. However, because of low-level concentrations of
      circulating IgE antibodies, a more sensitive protocol is required for human IgE
      detection. Here, fluorescence is delivered via the coupling of the secondary
      antibody to tyramide signal-amplification reagentry. Human IgG, IgM, or IgE bound
      to the printed antigens can then be revealed by confocal scanning microscopy and
      quantified with internal calibration curves. Generation of analytical and
      clinical data have demonstrated that the microarray test format provides
      equivalent performance to enzyme-linked immunosorbent assay (ELISA) tests and
      offers a significant advantage in convenience and cost when compared to
      traditional test formats.

PMID- 15020798
TI  - Mobile genetic elements as natural tools for genome evolution.
AB  - Transposable elements (TEs) are ubiquitous components of all living organisms,
      and in the course of their coexistence with their respective host genomes, these
      parasitic DNAs have played important roles in the evolution of complex genetic
      networks. The interaction between mobile DNAs and their host genomes are quite
      diverse, ranging from modifications of gene structure and regulation to
      alterations in general genome architecture. Thus over evolutionary time these
      elements can be regarded as natural molecular tools in shaping the organization,
      structure, and function of eukaryotic genes and genomes. Based on their intrinsic
      properties and features, mobile DNAs are widely applied at present as a technical
      "toolbox," essential for studying a diverse spectrum of biological questions. In
      this chapter we aim to review both the evolutionary impact of TEs on genome
      evolution and their valuable and diverse methodological applications as the
      molecular tools presented in this book.

PMID- 15020799
TI  - Detection of transposable elements in Drosophila salivary gland polytene
      chromosomes by in situ hybridization.
AB  - In situ hybridization is particularly appropriate for mapping specific DNA
      sequences on polytene chromosomes of Drosophila and other dipterans. This
      technique is based on the recognition and binding of one labeled sequence (the
      probe) to homologous sequences on chromosomes fixed on a microscope slide. The
      probes are labeled with biotin or other nonradioactive products, and the probe
      signal can be detected as a thin line on the chromosomes, following the shape of
      the classical Giemsa-stained chromosome bands, thus allowing the detection of TE
      insertions within the range of 50 to 200 kb. In our laboratory we work on many
      individuals from natural populations, and as a result we process high numbers of
      slides hybridized with various DNA probes of transposable elements every day.
      Therefore, the in situ hybridization technique we use is a simplification of
      earlier published protocols. This chapter presents our simplified standard in
      situ hybridization protocol for labeling polytene chromosomes of Drosophila with
      biotin and a fluorescence stain (FISH).

PMID- 15020800
TI  - Fluorescent in situ hybridization with transposable element probes to mitotic
      chromosomal heterochromatin of Drosophila.
AB  - The technique of in situ hybridization of DNA probes to Drosophila chromosomes
      has been initially applied to the salivary gland polytene chromosomes and is now
      routinely used for mapping single-copy and repetitive DNA sequences, such as
      transposable elements, to the euchromatic regions of these chromosomes. However,
      most of the heterochromatin normally escapes cytogenetic analyses on polytene
      chromosomes because it is organized in a poorly differentiated cytological
      structure called the chromocenter. This peculiar organization does not allow a
      detailed mapping of DNA clones to heterochromatin. Such a limitation can be
      overcome by the fluorescent in situ hybridization (FISH) technique on mitotic
      chromosomes of D. melanogaster, where heterochromatin has been extensively
      characterized by banding techniques and subdivided into several cytologically
      diverse regions. Digital images of FISH signals and DAPI staining can be
      separately recorded by CCD camera, pseudocolored, and merged using specific
      software for image analysis. The visualization of the signals and DAPI banding
      pattern on a single chromosome enables the mapping of a given sequence to
      specific cytological regions of mitotic heterochromatin. This method has
      initially proven successful in the detection and mapping of transposable element
      clusters in the heterochromatin of D. melanogaster and has been used to study the
      distribution of repeated and even single-copy sequences.

PMID- 15020801
TI  - Southern blot analysis of individual Drosophila flies.
AB  - Detection of novel insertions and the ability to explore heterochromatin are two
      key goals in the study of mobile elements in Drosophila. The Southern blot
      analysis of individual flies can prove useful in both types of investigations,
      alone or in combination with genetic and cytological approaches. This chapter
      describes the protocol for carrying out such an analysis and provides some clues
      for the interpretation of the results.

PMID- 15020802
TI  - Computational analysis of transposable element sequences.
AB  - This chapter provides a simple guide for the computational analysis of
      transposable element (TE) sequences. Web links are provided for a number of
      sequence analysis applications, and their potential use in the analysis of TE
      sequences is briefly described. The level of detail provided is intended to be
      sufficient for a naive user to begin to analyze TE sequences in silico. The
      emphasis is placed on the identification, retrieval and manipulation of TE
      sequences. Information is also provided on the evolutionary study of TE sequences
      including the use phylogenetics programs.

PMID- 15020803
TI  - Biochemical analysis of long terminal repeat retrotransposons.
AB  - A brief survey of the retrotransposition cycle is given with emphasis on
      intermediary steps and their identification by biochemical analysis. References
      include some older key publications that may not be easily accessible via
      electronic databases. Methods for enrichment of viruslike particles from plant
      material and from yeast are described.

PMID- 15020804
TI  - Tn5 as a molecular genetics tool: In vitro transposition and the coupling of in
      vitro technologies with in vivo transposition.
AB  - The development of in vitro transposition technologies have provided many
      powerful tools for the molecular genetics research laboratory. In this chapter we
      describe some of these tools with a focus on the Tn5 transposition system. Tn5
      technologies are particularly useful because the Tn5 transposition system has
      simple requirements, is efficient, random in target recognition, and robust. In
      particular we will describe the use of in vitro Tn5 transposition in transposon
      tagging and in the generation of nested deletions. We will also describe a unique
      in vitro/in vivo technology in which Tn5 inserts can be generated in a wide
      spectrum of bacterial species through the electroporation of preformed tranposase
      transposon DNA complexes.

PMID- 15020805
TI  - Gene targeting in Drosophila.
AB  - DNA double-strand breaks provide a powerful means to modify the genome. This
      chapter describes how to generate and use these breaks to target specific
      sequences, or other modifications to the Drosophila genome. Both P element
      dependent gene conversion, in which the chromosomal DNA is broken, and the Rong
      and Golic gene-targeting technique, in which the targeting vector contains the
      DNA break are explained. The strengths and limitations of both methods are
      presented so that the user can choose the appropriate method for their particular
      situation. The efficiency of both methods depends upon the genomic location being
      modified, although few, if any, genomic locations are refractory to either
      method. It cannot be emphasized strongly enough that the investigator should be
      prepared to invest sufficient time into setting up and running these experiments
      properly.

PMID- 15020806
TI  - TE-based mutagenesis systems in plants: a gene family approach.
AB  - Insertions in specific genes belonging to large and homogeneous gene families
      often do not cause a visible phenotype due to genetic redundancy. Therefore,
      several single-insertion mutants may have to be combined into double or even
      triple mutants in order to obtain a loss-of-function phenotype. It is therefore
      most useful to shift from single-gene insertion selection toward selection at the
      gene family level. Here, we present an alternative screening methodology that is
      highly suited for the functional analysis of gene families. Labeled primers
      designed from conserved regions present in the gene family and a transposon
      derived primer are combined in an optimized polymerase chain reaction (PCR) to
      screen a three-dimensionally pooled insertion library in a single step. PCR
      products are sized by polyacrylamide gel electrophoresis (PAGE), and putative
      insertion fragments are isolated from the gel, reamplified, and sequenced
      directly. Because the identification of insertions is sequence-based, insertions
      into highly homologous genes can easily be distinguished. Taking advantage of the
      presence of conserved domains in gene families, this approach allows simultaneous
      screening for insertion events in different family members, and it has the
      additional advantage of identifying yet unknown family members through their
      corresponding insertion mutant.

PMID- 15020807
TI  - The use of double-stranded RNA to knock down specific gene activity.
AB  - In many eukaryotes, the introduction of double-stranded RNA (dsRNA) into cells
      triggers the degradation of cognate mRNAs through a posttranscriptional gene
      silencing mechanism. This phenomenon has been called RNA interference or RNAi.
      Several methods for delivering dsRNA into the model organism C. elegans are
      described; these methods include (1) microinjecting dsRNA synthesized in vitro
      into the body cavity of the worm, (2) soaking worms in a solution of dsRNA, (3)
      feeding worms dsRNA-expressing bacteria, and (4) engineering transgenic worm
      strains to express dsRNA in vivo. Variations of these methods may be used to
      perform RNAi in other species as well. The choice of which delivery method to
      use, along with other options (region to target, length of dsRNA) are also
      discussed.

PMID- 15020809
TI  - MITE display.
AB  - Genome size differences among crop plants are largely due to unequal accumulation
      of repetitive DNA sequences, mainly transposable elements (TEs). Over the past
      decade, many families of miniature inverted-repeat transposable elements (MITEs)
      have been identified and characterized in a variety of organisms including
      animals and plants. MITEs are characterized by short terminal inverted repeats
      (TIRs) (10-15 bp), small size (approx 100 to 500 bp), high-copy-number (approx
      1000 to 15,000 per haploid genome), and a preference for insertion into 2-bp to 3
      bp targets that are rich in A and T residues. In this chapter, we present a
      modified transposon display procedure based on the maize MITE family Heartbreaker
      (Hbr). This technique is similar to AFLP in which AFLP adaptors are ligated to
      compatible ends of digested genomic DNA. Subsets of Hbr-containing fragments are
      then amplified using one AFLP primer and another primer complementary to an
      internal sequence of the Hbr element. Like AFLP, the Hbr display method permits
      the simultaneous analysis of numerous DNA fragments. Given the plethora of
      available marker systems, the major advantage of Hbr markers, and perhaps most
      MITE-based markers, is a preference for insertion in or near transcriptionally
      active genomic regions. This feature may be especially valuable in the large
      genomes of agriculturally important plants like maize, wheat, and barley where
      gene-rich islands are thought to exist in a sea of retrotransposons. Having a
      class of markers that are enriched in genic regions, coupled with the ease of
      isolating MITE markers, could expedite chromosome walks and map-based cloning
      protocols in these organisms.

PMID- 15020808
TI  - The application of LTR retrotransposons as molecular markers in plants.
AB  - Retrotransposons are major, dispersed components of most eukaryotic genomes. They
      replicate by a cycle of transcription, reverse transcription, and integration of
      new copies, without excising from the genome in the process. Because they
      represent a major share of the genome, cause easily detectable genetic changes
      having known ancestral and derived states, and contain conserved regions for
      which polymerase chain reaction (PCR) primers may be designed, retrotransposon
      insertions can be exploited as powerful molecular marker systems. Here, we
      describe the background and strategies, as well as give detailed laboratory
      protocols, for four key retrotransposon-based methods: SSAP, IRAP, REMAP, and
      RBIP. The SSAP, IRAP, and REMAP methods are multiplex and generate anonymous
      marker bands; RBIP scores individual loci, much as microsatellite-based marker
      systems do. The methods are variously suited to marker detection on agarose and
      polyacrylamide slab gels, slab and capillary sequencing devices, and arrays on
      solid supports. The different strengths and weaknesses of these approaches and
      their performance relative to conventional marker methods are discussed, together
      with their applicability to marker-assisted breeding, phylogenetic analyses,
      biodiversity determinations, and evolutionary studies.

PMID- 15020810
TI  - Retroposon mapping in molecular systematics.
AB  - Advances in genome sciences are demonstrating the dynamic nature of noncoding DNA
      regions, which are comprised largely of repetitive elements with no apparent
      function. Retroposons are one class of mobile genetic elements that amplify and
      move about the genome via a copy-and-paste mechanism that employs an RNA
      intermediate. Short and long interspersed elements (SINEs and LINEs,
      respectively) are types of retroposons of particular interest because of their
      active role in shaping the architecture of genomes and their diagnostic value as
      evolutionary markers for studies of phylogeny and population biology. Although
      the use of SINEs and LINEs for molecular systematic studies is proliferating, a
      comprehensive laboratory protocol that explicitly outlines how to isolate and
      characterize retroposons for systematic studies in a detailed, step-by-step
      fashion has been lacking. The present chapter addresses this gap in the
      literature by focusing on the strategy for isolating new SINEs from a genomic
      library, the screening process, the sequencing and characterization of clones
      into subfamilies, quantification of copy number in host taxa, and the critical
      diagnosis of phylogenetically informative SINE and LINE insertion patterns.
      Practical limits to the method are discussed in relation to sampling design,
      systematic character theory, and the empirical distribution of elements observed
      in eukaryotic lineages. Major steps in the experimental process are illustrated
      with case examples from a diversity of taxonomic groups and by published results
      in the molecular biology and systematics literature.

PMID- 15020811
TI  - Transformation systems in insects.
AB  - Genetic transformation is an important technology that provides unique
      opportunities to find, isolate, and analyze genes, as well as to create organisms
      with unique functional characteristics. Insect biologists have been developing
      genetic transformation technologies that rely extensively on transposable
      elements. A number of class II transposable elements isolated originally from
      insects have been converted into broad host range insect gene vectors. Class II
      transposable elements are particularly amenable to gene vector development,
      although they suffer from some limitations such as low rates of recombination.
      Use of these gene vectors requires the physical introduction of the vectors into
      developing insect embryos by microinjection. Microinjection methods vary to
      accommodate the unique physical and developmental characteristics of the target
      insects. All methods rely on the use of fine glass needles in conjunction with
      micromanipulators and a microscope. A serious constraint on the use of existing
      systems can be the inefficiency of successfully delivering the gene vectors to
      the germ cells of the developing embryo. The general method for vector delivery
      to insect germ cells is described, as well as variations that are useful under
      some conditions.

PMID- 15020813
TI  - BAC library construction.

PMID- 15020812
TI  - Transposable elements for transgenesis and insertional mutagenesis in
      vertebrates: a contemporary review of experimental strategies.
AB  - Functional genomic analyses in vertebrate model systems, including fish, frogs,
      and mice, have greatly contributed to our understanding of embryonic development
      and human disease. However, new molecular tools and strategies are needed to meet
      the increasing demands of linking sequence information to gene function.
      Transposable elements (TEs) are very efficient at integrating into DNA, and are
      therefore useful vectors for transferring new genetic material into genomes. In
      particular, members of the Tc1/mariner superfamily of elements are able to
      transpose in species other than their hosts, and are therefore emerging tools for
      functional genomics in several organisms. This chapter describes strategies of
      using retrovirus vectors and DNA-based TEs for transgenesis and insertional
      mutagenesis in vertebrates, with special emphasis on the Sleeping Beauty (SB)
      element, a reconstructed Tc1/mariner-like transposon from fish. SB jumps
      efficiently in cells of diverse vertebrate species in culture, as well as in
      somatic and germline tissues of the mouse in vivo. Simple structure and easy
      laboratory handling of transposon vectors are coupled with efficient and stable
      transgene integration and persistent, long-term transgene expression by
      transposon-mediated gene transfer. These features all contribute to the
      usefulness of TEs as tools for vertebrate functional genomics, as well as for
      animal biotechnology and human gene therapy.

PMID- 15020814
TI  - Construction of small genome BAC library for functional and genomic applications.

PMID- 15020815
TI  - Preparation of BAC libraries from bacterial genomes by in vitro packaging.

PMID- 15020816
TI  - Exploring transformation-associated recombination cloning for selective isolation
      of genomic regions.

PMID- 15020817
TI  - Purification of BAC DNA.

PMID- 15020818
TI  - Hybridization-based selection of BAC clones.

PMID- 15020820
TI  - BAC mapping using fluorescence in situ hybridization.

PMID- 15020819
TI  - Applications of interspersed repeat sequence polymerase chain reaction.

PMID- 15020821
TI  - High-throughput BAC fingerprinting.

PMID- 15020822
TI  - BAC end sequencing.

PMID- 15020823
TI  - Radiation hybrid mapping with BAC ends.

PMID- 15020824
TI  - Shotgun library construction for DNA sequencing.

PMID- 15020825
TI  - Rolling circle amplification for sequencing templates.

PMID- 15020826
TI  - Transposon-mediated sequencing.

PMID- 15020827
TI  - Pyrosequencing: a tool for DNA sequencing analysis.

PMID- 15020828
TI  - Use of Fimers to eliminate polymerase chain reaction and primer-dimer artifacts
      and to increase yield in BAC-sequencing reactions.

PMID- 15020829
TI  - Retrofitting BACs and PACs with LoxP transposons to generate nested deletions.

PMID- 15020830
TI  - Preparing nested-deletion template DNA for field inversion gel electrophoresis
      analyses and position-specific end sequencing with transposon primers.

PMID- 15020832
TI  - Using the TIGR assembler in shotgun sequencing projects.

PMID- 15020831
TI  - BAC finishing strategies.

PMID- 15020833
TI  - Finishing "working draft" BAC projects by directed sequencing with ThermoFidelase
      and Fimers.

PMID- 15020834
TI  - Optimized multiplex polymerase chain reaction: an effective method for rapid gap
      closure.

PMID- 15020835
TI  - Assembly of DNA sequencing data.

PMID- 15020836
TI  - Sequence finishing.

PMID- 15020837
TI  - Quality assessment of finished BAC sequences.

PMID- 15020838
TI  - The mechanism of the anti-tumor activity of the histone deacetylase inhibitor,
      suberoylanilide hydroxamic acid (SAHA).
AB  - Histone deacetylases (HDAC) are ubiquitously distributed through chromatin.
      Nevertheless HDAC inhibitors (HDACi), such as SAHA, selectively alter the
      transcription of as few as 2-5% of expressed genes in various transformed cells.
      p21(WAF1) is one of the most commonly induced genes in cells cultured with SAHA.
      Understanding the mechanism of the selective effects of the HDACi is a
      challenging problem. Gui et al. have identified effects of SAHA on p21(WAF1)
      promotor associated proteins that explain, at least in part, the selective
      effects of HDAC in altering gene expression.

PMID- 15020839
TI  - When the checkpoints have gone: insights into Cdc25 functional activation.
AB  - DNA-responsive checkpoints operate at the G(2)/M transition to prevent premature
      mitosis in the presence of incompletely replicated or damaged DNA. These pathways
      prevent mitotic entry, at least in part, by suppressing Cdc25, the phosphatase
      that activates Cdc2/Cyclin B. To gain insight into how checkpoint signaling
      controls Cdc25 function, we have carefully examined the individual steps in Cdc25
      activation. We found that removal of the regulatory protein, 14-3-3, that binds
      to phosphorylated Cdc25 during interphase is one of the early steps in mitotic
      activation. Moreover, our studies unexpectedly implicated the phosphatase PP1 and
      the G(1)/S kinase Cdk2 in the process of Cdc25 activation. Here we integrate our
      findings and those of others to propose a model for Cdc25 activation in an effort
      to provide insight into novel loci of DNA-responsive checkpoint control of
      mitotic entry.

PMID- 15020840
TI  - Splitting the apoptosome.
AB  - Assembly of the apoptosome in response to mitochondrial permeabilization, the
      hallmark of the intrinsic apoptotic pathway, involves binding of cytochrome c to
      Apaf1, recruitment and auto-processing of the apical/signaling pro-caspase-9, and
      coupled activation of downstream/executioner caspases like caspase 3. Evidence
      now indicates that certain apoptotic cascades can bypass the apoptosome and
      activate caspase-9 independent of the mitochondria. Recently, we have
      demonstrated that caspase-9 can be activated in Apaf1-mutant primary myoblasts,
      but not fibroblasts, in response to stimuli that are known to act via the
      mitochondria. Thus, apoptosomal activation of caspase-9 seems to represent only
      one of the routes for its activation; other pathways, some of which are yet to be
      discovered, can bypass the requirement for Apaf1 and activate caspase-9 in a
      tissue and context specific manner.

PMID- 15020843
TI  - Could condensin scaffold the mitotic chromosome?
AB  - One of the most remarkable and yet poorly understood events during the cell cycle
      is how dispersed chromatin fragments are transformed into chromosomes every time
      cells undergo mitosis. It has been postulated that mitotic chromosomes might
      contain an axial scaffold that is involved in condensation but its molecules and
      structure have remained elusive. Recent data suggests that the condensin complex
      might indeed be an essential part of the scaffold that provides a platform for
      other proteins to localize and promote different aspects of chromosome
      condensation.

PMID- 15020841
TI  - Estrogen receptor expression and sensitivity to paclitaxel in breast cancer.
AB  - A retrospective analysis of CALGB trial 9344 suggested paclitaxel administration
      following cyclophosphamide and doxorubicin adjuvant chemotherapy is most
      beneficial for patients with ERalpha negative (ERalpha-) breast cancer. Since the
      cytotoxic effects of paclitaxel are cell cycle dependent, we postulated that the
      relationship between ERalpha and the effectiveness of adjuvant paclitaxel
      reflects the observation that ERalpha positive (ERalpha+) breast cancers
      proliferate more slowly than ERalpha- breast cancers. Three in vitro models (MCF
      7, T47D and ZR-75) were examined to compare growth rates and paclitaxel-induced
      apoptosis in ERalpha+ and ERalpha- clones of the same, originally ERalpha+ cell
      line. For the T47D and ZR-75 cell lines, loss of ERalpha was associated with a
      decrease in doubling time and an increase in paclitaxel sensitivity. However,
      when cell culture conditions were altered to achieve equivalent cell
      proliferation rates, no difference in paclitaxel sensitivity was observed.
      Similarly, an ERalpha- clone of MCF-7 cells that did not exhibit an enhanced
      growth rate compared to its ERalpha+ counterpart also did not show increased
      paclitaxel sensitivity. The combined apoptotic effects of tamoxifen and
      paclitaxel on MCF-7 cells were not synergistic or even clearly additive. In these
      in vitro models, the effectiveness of paclitaxel correlated more closely with
      growth rate than ERalpha expression. These data suggest that measurements of
      tumor proliferation may provide more accurate predictive markers for the benefits
      of adjuvant paclitaxel than ERalpha analysis.

PMID- 15020842
TI  - Resisting arrest: recovery from checkpoint arrest through dephosphorylation of
      Chk1 by PP1.
AB  - The G2 DNA damage checkpoint prevents mitotic entry in the presence of damaged
      DNA, and thus is essential for cells to replicate with stable genetic
      inheritance. Whilst significant progress has been made in the past 10 years on
      the mechanism of checkpoint activation, little attention has been paid to how the
      DNA damage checkpoint is switched off to allow cell cycle re-entry. Insight into
      the mechanism of cell cycle re-entry was recently provided by our finding that
      the Schizosaccharomyces pombe type 1 phosphatase (PP1) Dis2 dephosphorylates the
      checkpoint effector kinase Chk1. This occurs on a site phosphorylated by the ATR
      homologue Rad3 in response to DNA damage, and results in Chk1 inactivation and
      checkpoint release. Here we discuss the implications of this finding on DNA
      damage checkpoint signaling, and speculate on models for checkpoint maintenance
      and release.

PMID- 15020844
TI  - Cytoplasmic p53: bax and forward.
AB  - p53, a chief tumor suppressor in multicellular organisms, induces cell cycle
      arrest, DNA repair and apoptosis to promote genomic stability and tissue
      homeostasis. The function of p53 is normally ascribed to its regulation of
      numerous p53-responsive genes through direct interactions with both chromatin and
      regulators of transcription. Nonetheless, evidence exists that p53 has an
      extranuclear role in the cytoplasm to induce apoptosis. Recently, p53 has been
      shown to directly activate the pro-apoptotic Bcl-2 protein Bax allowing for
      mitochondrial membrane permeabilization and apoptosis. In parallel, p53 can
      release pro-apoptotic Bcl-2 proteins sequestered by Bcl-x(L). These data suggest
      that cytoplasmic p53 functions analogously to the BH3-only proteins, a subset of
      pro-apoptotic Bcl-2 proteins.

PMID- 15020845
TI  - Oncogenic K-ras in mouse models of myeloproliferative disease and acute myeloid
      leukemia.
AB  - Oncogenic N-RAS and K-RAS mutations are among the most frequently detected
      genetic alterations in patients with acute myeloid leukemia (AML). Recently, the
      role of oncogenic K-ras in leukemogenesis was investigated in a novel mouse model
      utilizing interferon (IFN)-inducible, Cre-mediated expression of oncogenic K-ras
      from its endogenous promoter. Conditional expression of oncogenic K-ras from its
      endogenous promoter in the hematopoietic system induces a lethal
      myeloproliferative disease in mice, but not AML, indicating that additional
      mutations are required for AML development. These results are consistent with a
      model in which the AML phenotype requires at least two cooperating mutations in
      the hematopoietic progenitor cells: one promoting proliferation and enhanced cell
      survival (such as oncogenic ras or a constitutively activated receptor tyrosine
      kinase) and one associated with impaired differentiation and enhanced
      immortalization (such as loss-of-function mutations in hematopoietic
      transcription factors). The model system with oncogenic K-ras provides a
      versatile platform to test the contribution of cooperating mutations in AML, and
      the efficacy of Ras pathway inhibitors in vivo.

PMID- 15020846
TI  - Ethanol treatment of hepatocellular carcinoma: high potentials of low
      concentrations.
AB  - Primary hepatocellular carcinoma (HCC) is one of the most common malignant tumors
      worldwide, which is associated with a very poor prognosis. A curative treatment
      is difficult to achieve and is only possible in a low number of patients.
      Therefore, many different therapeutic strategies have been developed as
      alternative treatment. Among these, percutaneous injection of high concentrations
      of ethanol (>50 mM) has been proven to be effective for the treatment of small
      HCC (less than 3 cm in diameter). However, the principal problem with using
      ethanol is its toxic effects on non-tumor cells adjacent to the tumor area. The
      objective of this review is to juxtapose the therapeutic potential of high and
      low concentrations of ethanol in the treatment of HCC, based on experimental
      studies obtained with the human hepatocellular tumor cell line (HepG2). They have
      shown that high concentrations of ethanol lead to necrosis, while low
      concentrations induce apoptosis due to activation of Fas-receptors. Triggering of
      apoptosis through Fas-receptors represents a mechanism of action different from
      that observed with high concentrations of ethanol, thus, reducing the
      complications that follow the inflammatory process due to necrosis. Therefore,
      the use of low concentrations of ethanol could be an effective treatment for HCC.

PMID- 15020847
TI  - Coupling the transcriptional regulatory action of Brn-3b to the cell cycle clock.

PMID- 15020848
TI  - The gift of absorption.

PMID- 15020849
TI  - [Bacterial granulomatous hepatitis].
AB  - The liver may react to different infectious and non- infectious agents,
      developing granulomatous lesions which characterize granulomatous hepatitis.
      Granulomas of the liver are circumscribed inflammatory lesions (size from 50 to
      300 mm) composed of epithelioid cells, varied numbers of mononuclear cells and
      eosinophils and multinucleated giant cells. They represent a specialized cell
      mediated immune response to a wide variety of etiological factors. A broad
      spectrum of microorganisms may trigger hepatic granulomas. M. tuberculosis is the
      more frequent agent (~ 44%). Granulomatous hepatitis is characterized by a
      febrile illness with systemic signs and symptoms such as fatigue, sweating,
      shivering, hepatomegaly and/or splenomegaly, abnormalities in serum liver tests
      (aminotransferase, alkaline phosphatase). Liver biopsy provides diagnostic
      information in approximately 15-30% of cases, identifying directly the microbial
      agent with special microbial stains and polymerase chain reaction or finding
      distinctive microscopic features, suggestive of specific microorganisms. In such
      cases appropriate therapy is possible. Unfortunately in one third of cases is
      impossible to reach aetiological diagnosis on histological criteria alone. In
      these cases a therapeutic attempt with steroids, effective in the idiopathic
      granulomatous hepatitis, may be useful.

PMID- 15020850
TI  - [Mediastinal tubercular lymphadenitis and adenobronchial fistulas (TABF) in the
      paediatric age. 1980-2001 case record].
AB  - The aim of this study is to assess the frequency and clinical importance of
      mediastinal tubercular lymphadenitis and adenobronchial fistulas (TABF) and to
      evaluate the role of fiberbronchoscopy and surgical bronchoscopy associated with
      antimicrobical chemotherapy. 136 cases of primary pulmonary TBC, admitted to the
      Unit of Infectious Diseases, Bambino Gesu Children Hospital in Rome, between 1980
      and 2001, were enrolled in the study. We considered 56 patients with clinical and
      radiological evidence of mediastinal tubercular lymphadenitis and 28 patients
      with adenobronchial fistulas (TABF). The incidence of TABF was 20,58% of primary
      pulmonary TBC. All patients were treated by medical therapy combined with local
      endobronchial surgery. TABF emerges as a complication of pediatric primary
      pulmonary TBC. We suggest a clinical and radiological survey to decide the
      utility of a diagnostic and therapeutic surgical bronchoscopy

PMID- 15020851
TI  - [Factors associated with the time to clinical diagnosis of infectious
      endocarditis. Analysis of a multicentre case-record].
AB  - The authors demonstrate that time necessary for diagnosis in 902 patients with
      validated infectious endocarditis was significantly shorter in 249 drug addicts
      confronted with 653 non-addicted patients. With regard to the latter category we
      noticed a significant tendency in diagnostic time reduction in the last five
      years of observation and this is probably due to the improved knowledge on
      infectivologists regarding the clinical presentation of infectious endocarditis
      rather than the application of validating protocols

PMID- 15020852
TI  - [Tuberculosis infection and disease in immigrant children].
AB  - From the second half of the eighties, the cases of tuberculosis (TBC) in Italy
      have been constantly increasing. The increase in TBC cases in developed countries
      is related to different factors, including HIV epidemic and increased number of
      immigrants from countries with high TBC incidence and important socio-economic
      problems. Compared with adults few children with TBC were homeless or coinfected
      with HIV, nonetheless the children lived frequently in low socioeconomic status
      and consequently high risk of being uninsured and with adults at risk for
      tuberculosis (immediate relative, household members, or recently immigrated). An
      epidemiologic study was carried out, in order to evaluate the impact of TBC
      infection in immigrant children. From January 2001 to December 2002, Mantoux test
      (5 IU) was performed in immigrant children hospitalized or followed in two
      children hospitals. They included 228 children: mean age 4 years (range 1 month
      to 15 years). The patients came from: South America (44%) (especially from
      Ecuador), from Africa (20%), from Eastern Europe (19%), (especially from Middle
      East and North Africa), from Far East (17%). In 30 cases (13,2%) Mantoux test was
      positive. Among these latter, 21 presented latent infection, whereas another 9
      had tuberculous disease with pulmonary localization and one of them associated
      with cervical adenopathy. In the study period, among all children (4426) admitted
      the two Units, the prevalence of tuberculous disease was 2,5% in immigrant
      children compared 0.2% in native children. Accurate epidemiologic monitoring,
      further clinical studies aimed at highlighting TBC peculiar aspects in children,
      and adequate therapy can lead to TBC control in the immigrant children.

PMID- 15020853
TI  - Visceral leishmaniasis and HIV co-infection: a rare case of pulmonary and oral
      localization.
AB  - Visceral leishmaniasis (VL) has increased as a complicating infection in subjects
      with human immunodeficiency virus (HIV) in countries bordering the Mediterranean
      sea. The clinical course as well as organ involvement of VL are often atypical in
      HIV positive subjects. In this study a case of VL with pulmonary and oral mucose
      localisation in a patient with acquired immune deficiency syndrome (AIDS), is
      reported. These findings, together with the presence of the parasite in the
      peripheral blood smear, confirm that in HIV positive patients the impaired immune
      system allows the spreading and the atypical localisation of the Leishmania
      amastigotes more easily than in immuno-competent individuals. In endemic areas
      and in HIV positive subjects a systemic and careful parasitological follow-up is
      necessary to ensure that any clinical form of leishmaniasis is not overlooked.

PMID- 15020854
TI  - Mycobacterium flavescens vertebral osteomyelitis in an immunocompetent host.
AB  - The aim of this paper is to describe a rare case of vertebral osteomyelitis
      caused by Mycobacterium flavescens in an immunocompetent patient. Mycobacterium
      flavescens is a rapidly growing, pigmented, non-tuberculous mycobacterium,
      usually described as non-pathogenic for humans but occasionally reported as the
      cause of serious infectious complications recognized in clinical practice. This
      study stressed the importance of recent reports that describe the occurrence of
      vertebral osteomyelitis due to non-tuberculous mycobacteria that have also been
      recognized with an increasing incidence among immunocompetent hosts. A brief
      review of the current literature on human disease caused by Mycobacterium
      flavescens is also reported.

PMID- 15020855
TI  - Acute mediastinitis: a severe complication of transdermal therapy in a patient
      with ischaemic heart disease. A case report.
AB  - Acute mediastinitis is an uncommon and potentially devastating infection.
      Generally, mediastinitis occurs as a postoperative infection following median
      sternotomy. We describe a case of acute mediastinitis in a patient with ischaemic
      heart disease, secondary to the spread of cutaneous infection of the chest wall
      in the application site of transdermal nitroglycerine patches.

PMID- 15020856
TI  - Sternoclavicular joint infection in an adult without predisposing risk factors.
AB  - Septic arthritis of the sternoclavicular joint (SCJ) is an uncommon condition and
      it has been associated with numerous predisposing factors. We describe a rare
      case of SCJ infection due to Staphylococcus aureus in an adult without known
      underlying predisposing conditions and in which recovery was achieved with
      medical therapy alone.

PMID- 15021044
TI  - Deep dermatophytosis: rare infections or common, but unrecognised, complications
      of lymphatic spread?

PMID- 15021045
TI  - Zoonotic poxvirus infections in humans.
AB  - PURPOSE OF REVIEW: The 2003 USA monkeypox epidemic caused by imported African
      rodents, newly emergent poxvirus zoonoses in Brazil and the possible use of
      variola virus for biological warfare has led to renewed interest in poxviruses
      and anti-poxviral therapies. Increasing foreign travel and importation of exotic
      animal species increases the likelihood of poxvirus infections occurring outside
      their usual geographical range and diagnostic delay has important implications.
      The present review provides an overview of these rare zoonoses. RECENT FINDINGS:
      Three genera of Poxviridae are known to cause human zoonoses: orthopoxviruses,
      parapoxviruses and yatapoxvirus. Most cases are occupational, sporadic and have
      few cutaneous lesions with low morbidity. The exception is monkeypox, similar to
      smallpox, with significant morbidity and childhood mortality. Molecular
      characterization using polymerase chain reaction (PCR) amplification and other
      methods provides accurate phylogenetic identification and suggests that a cowpox
      like virus is the probable ancestor of variola and other zoonotic poxviruses. DNA
      genomic sequencing of the Brazilian Cantagalo and Aracatuba viruses shows a close
      relationship to vaccinia virus. Poxviruses have potential in cancer immunotherapy
      and their ability to evade host-cell immune responses may provide a basis for new
      antipoxvirus therapies. Other agents, particularly nucleoside phosphonates such
      as cidofovir, show therapeutic action against poxviruses. SUMMARY: Human zoonotic
      poxvirus infections are rare but increasingly encountered outside their usual
      geographical range. The 2003 USA monkeypox outbreak emphasizes the importance of
      early accurate diagnosis, particularly because increasing numbers of
      immunosuppressed individuals increases the potential for severe or fatal
      infections. PCR methodology enables accurate phylogenetic typing and has
      identified new diseases, but rapid, reliable methods must be made available for
      clinicians. More research into therapeutic agents for the prevention and
      treatment of poxvirus infections is required.

PMID- 15020857
TI  - [Anthrax and carbuncle: two sides of the same coin].
AB  - The disease caused by Bacillus anthracis is one of the most critical concerns to
      the general public and public health authorities due both to the anthrax cases
      caused by the intentional release of the germ in the USA at the close of 2001
      when letters and packages were contaminated with anthrax spores, and the current
      threat of biological warfare. After a brief excursus on the history of the terms
      Anthrax and Carbuncle, we survey the main evidence of anthrax found in the
      ancient literature, and deal with the identification of the pathogenic agent
      responsible for the disease and the subsequent discovery of the first anthrax
      vaccine and its use in order to control the spread of the disease in the cattle.
      Finally, we examine some of the most important episodes of occupational exposure
      to the Bacillus anthracis that occurred in the past two centuries and the
      preventive measures applied both to employees and the workplace.

PMID- 15021046
TI  - Bacteria and wound healing.
AB  - PURPOSE OF REVIEW: Wound healing is a complex process with many potential factors
      that can delay healing. There is increasing interest in the effects of bacteria
      on the processes of wound healing. All chronic wounds are colonized by bacteria,
      with low levels of bacteria being beneficial to the wound healing process. Wound
      infection is detrimental to wound healing, but the diagnosis and management of
      wound infection is controversial, and varies between clinicians. RECENT FINDINGS:
      There is increasing recognition of the concept of critical colonization or local
      infection, when wound healing may be delayed in the absence of the typical
      clinical features of infection. The progression from wound colonization to
      infection depends not only on the bacterial count or the species present, but
      also on the host immune response, the number of different species present, the
      virulence of the organisms and synergistic interactions between the different
      species. There is increasing evidence that bacteria within chronic wounds live
      within biofilm communities, in which the bacteria are protected from host
      defences and develop resistance to antibiotic treatment. SUMMARY: An appreciation
      of the factors affecting the progression from colonization to infection can help
      clinicians with the interpretation of clinical findings and microbiological
      investigations in patients with chronic wounds. An understanding of the
      physiology and interactions within multi-species biofilms may aid the development
      of more effective methods of treating infected and poorly healing wounds. The
      emergence of consensus guidelines has helped to optimize clinical management.

PMID- 15021047
TI  - New treatments for tinea capitis.
AB  - PURPOSE OF REVIEW: Tinea capitis, a dermatophyte infection involving the hair
      shaft on the scalp, is primarily a disease of preadolescent children. The
      predominant pathogen varies according to the geographical location. Trichophyton
      tonsurans and Microsporum canis account for the majority of infections in north
      America and certain parts of Europe. The current standard of care for the
      treatment of tinea capitis in the USA is oral griseofulvin, but evidence is
      accumulating that some of the newer antifungal agents may also be useful. RECENT
      FINDINGS: The newer oral antifungal agents such as terbinafine, itraconazole and
      fluconazole seem to be effective, safe, and have the advantage of a shorter
      treatment duration. Although a significant number of clinical studies and reports
      have documented experience with terbinafine and itraconazole for the treatment of
      tinea capitis, it should be noted that only a few trials have been conducted
      utilizing fluconazole. Both 2% ketoconazole and 1% selenium sulfide shampoos are
      often recommended as adjuvant topical therapy. SUMMARY: Currently, many experts
      consider griseofulvin to be the drug of choice for tinea capitis. Short-term
      terbinafine, itraconazole and fluconazole therapy have been shown to be
      comparable in efficacy and safety with griseofulvin. Regular epidemiological
      surveillance of causative fungal organisms in the community and their antifungal
      susceptibility is an essential component in the management of this condition.

PMID- 15021048
TI  - Shorter course therapy of serious respiratory infections: new data for new
      approaches to management.

PMID- 15021050
TI  - New developments in the pathogenesis of acute exacerbations of chronic
      obstructive pulmonary disease.
AB  - PURPOSE OF REVIEW: Acute exacerbations of chronic obstructive pulmonary disease
      were a poorly defined and understood entity. The application of better study
      designs and new research methodologies has shed considerable light on the
      pathogenesis of this common clinical syndrome. RECENT FINDINGS: Inflammation is
      an important component of the pathogenesis of chronic obstructive pulmonary
      disease, and exacerbations probably represent acute increases in airway
      inflammation brought about by one or more etiological agents. Environmental
      particulate and gaseous pollutants have been linked in epidemiological studies
      with increased respiratory symptoms and mortality in chronic obstructive
      pulmonary disease. Bacterial, viral and atypical pathogens, either alone or in
      concert, induce the majority of acute exacerbations. SUMMARY: A bacterial cause
      of a substantial proportion of exacerbations is now firmly established by the
      results of bronchoscopy, molecular epidemiology, immunology and airway
      inflammation studies. Future research should focus on pathogenic mechanisms and
      host defence against the microbial pathogens associated with acute exacerbations
      of chronic obstructive pulmonary disease, in order to develop better treatment
      and prevention strategies.

PMID- 15021049
TI  - Role of nebulized antibiotics for the treatment of respiratory infections.
AB  - PURPOSE OF REVIEW: The purpose of this review is to summarize modern data
      pertaining to the use of aerosolized antimicrobials for the treatment of and
      prophylaxis against pulmonary infections. RECENT FINDINGS: Few recent
      publications have examined the safety and efficacy of nebulized antibiotics. Two
      well conducted trials have been published that describe the utility of tobramycin
      solution for inhalation among cystic fibrosis patients. A couple of good reviews
      have also been published that have summarized the use of aerosolized antibiotics
      in other patient populations. SUMMARY: Data regarding this topic are scarce. At
      this time, data support the use of aerosolized tobramycin solution for inhalation
      in cystic fibrosis patients infected or colonized by Pseudomonas aeruginosa.
      Apart from this situation, widespread aerosolized administration of other agents
      in cystic fibrosis and non-cystic fibrosis patient populations should not be
      advocated.

PMID- 15021051
TI  - Importance of severity of illness assessment in management of lower respiratory
      infections.
AB  - PURPOSE OF REVIEW: Patients with lower respiratory infections display a wide
      spectrum of disease severity. Management decisions regarding site of care, extent
      of investigations and level of treatment are mainly based on disease severity.
      Several severity assessment tools are still undergoing evaluation. This review
      highlights recent relevant studies. RECENT FINDINGS: Severity prediction rules
      such as the Pneumonia Severity Index cannot be relied upon as the sole means of
      identifying patients with lower respiratory infections who do not need hospital
      admission. Up to 40% of patients assigned to low-risk groups may require
      hospitalization. The most common medical reason for hospitalization in these
      circumstances is the presence of unstable comorbid illness. Social factors are
      equally important in the decision to admit. A new prediction rule based on the
      British Thoracic Society prediction rule has been proposed. This divides patients
      with community acquired pneumonia into three management groups based on risk of
      mortality. A prediction rule for use in patients with HIV-associated community
      acquired pneumonia has also been proposed. An IL-10 polymorphism has been
      identified as a prognostic factor in community acquired pneumonia. Audits
      examining the impact of adherence to severity-based guidelines on the outcome of
      community acquired pneumonia have revealed conflicting results. Differences in
      outcome may only be significant for patients with the most severe illness.
      SUMMARY: Severity of illness assessment is important in guiding management
      options at various stages in the clinical course of lower respiratory infections.
      However, no prediction rule should supercede clinical judgment.

PMID- 15021052
TI  - Pneumonia in the elderly.
AB  - PURPOSE OF REVIEW: This review provides an update on new data about the etiology,
      clinical characteristics, outcomes, and prevention of community-acquired
      pneumonia. The impact of severe acute respiratory syndrome in older persons is
      also addressed. RECENT FINDINGS: Streptococcus pneumoniae remains the most
      important cause of community-acquired pneumonia in the very elderly (80 years and
      over). Pneumococcus is also an important etiologic agent of pneumonia in
      residents of long-term care facilities. Clinical signs and symptoms of community
      acquired pneumonia are less distinct in this group compared with younger
      patients. New data about influenza immunization reveal better mucosal immunity
      with the intranasal vaccine compared with the intramuscular vaccine. A review of
      clinical trial evidence differs from observational studies that demonstrate a
      clear benefit of the polysaccharide pneumococcal vaccine in the elderly. The
      prospect of severe acute respiratory syndrome in older adults is the most
      important new issue to emerge, as older adults are at increased risk from
      complications and death. SUMMARY: There are many challenges in preventing and
      managing community-acquired pneumonia in the elderly. S. pneumoniae remains the
      most important cause. The clinical presentation of pneumonia in the very elderly
      can be nonspecific. Given the safety profile of the vaccine and supportive
      observational evidence, public health policymakers should continue to support use
      of the polysaccharide pneumococcal vaccine. However, research into new vaccine
      strategies, including use of conjugate or common antigen vaccines, is a priority.

PMID- 15021053
TI  - Recent development in melioidosis.
AB  - PURPOSE OF REVIEW: Burkholderia pseudomallei, the causative agent of melioidosis
      and a potential biological weapon, is still unfamiliar in some areas where
      sporadic cases are being reported among travelers. This review highlights
      findings in 2002-2003 and is an extension of a recent review by Dance. RECENT
      FINDINGS: The allele profiles of B. pseudomallei are distinguishable from
      avirulent Burkholderia thailandensis, but Burkholderia mallei is a clone of B.
      pseudomallei. Capsule and a type III protein secretion apparatus enable B.
      pseudomallei to survive intracellular killing and facilitate intercellular
      spread. A strong antibody response to infection is useful for monitoring disease
      activity. A mutant that is auxotrophic in the branched chain amino acid
      biosynthetic pathway has been found to be attenuated and protective. A new
      selective media is useful for isolation from contaminated specimens and the
      environment. Molecular techniques have been developed to distinguish B.
      pseudomallei from B. thailandensis and B. mallei as well as for serological
      diagnosis. Classification of the clinical manifestation is proposed to facilitate
      global communication, and will be useful to compare the efficacies of new
      regimens and adjunctive immunomodulatory therapies, such as granulocyte colony
      stimulating factor and activated protein C for septicemic melioidosis. SUMMARY:
      Study of pathogenesis and intracellular survival of B. pseudomallei is advancing
      and may lead to better methods of therapy and vaccine production. New
      antimicrobial agents and immunomodulators are being studied to shorten the
      duration of treatment in the acute and maintenance phases, reduce the high
      mortality rate in septicemic melioidosis, and prevent relapses.

PMID- 15021054
TI  - Q fever pneumonia.
AB  - PURPOSE OF REVIEW: In this era of emerging infectious diseases and bioterrorism
      it is important to be up to date with the diagnosis and management of Q fever
      pneumonia. RECENT FINDINGS: A considerable amount of new information has emerged
      regarding the pathogenesis of Coxiella burnetii infection. The complete genome of
      this microorganism has now been sequenced and there are several unique features.
      The spectrum of manifestations of infection due to C. burnetii continues to
      expand. Some of the more recently described findings are acalculous
      cholecystitis, rhabdomyolysis, long-term persistence of Coxiella, post Q fever
      fatigue syndrome, and hemolytic uremic syndrome. Pneumonia as a manifestation of
      acute Q fever shows tremendous geographic variation, being common in one area of
      a country such as Spain but not in another area. SUMMARY: Pneumonia continues to
      be an important manifestation of infection with C. burnetii. It responds to
      treatment with doxycycline, quinolones or macrolides.

PMID- 15021055
TI  - Severe acute respiratory syndrome.
AB  - PURPOSE OF REVIEW: Severe acute respiratory syndrome (SARS) is an infectious
      disease first recognized in November 2002 in Guangdong Province, China. It spread
      to many countries all over the world during February to June 2003, with 8098
      cases reported. Twenty-one percent of the affected people were health care
      workers. Because SARS is a new emerging disease, this review describes the
      current understanding about the etiology, clinical pictures, laboratory and
      radiological findings of SARS. RECENT FINDINGS: Severe acute respiratory syndrome
      associated coronavirus (SARS-CoV) was quickly found to be the etiological agent
      of SARS in April 2003. The transmission of SARS-CoV between human beings is
      mainly due to close contact. Using barrier precautions, the transmission of SARS
      CoV can be prevented. The most common clinical presentations of patients with
      SARS include fever, cough, and dyspnea. The common laboratory findings include
      lymphopenia, thrombocytopenia, elevated serum alanine and aspartate
      aminotransferase, lactate dehydrogenase, creatine phosphokinase, and C-reactive
      protein. The most common radiological finding is pneumonic lesion(s) in the chest
      radiogram. Many patients experience exacerbation of clinical symptoms in the
      second week of disease course and some may progress to respiratory failure and
      need mechanical ventilatory support. The overall case fatality rate is 9.6%. The
      current method of treatment of SARS is still controversial. SUMMARY: SARS is an
      infectious disease with high contagiousness and a high mortality rate. Early case
      identification and infection control are two important factors to limit its
      spread.

PMID- 15021056
TI  - Bibliography. Current world literature. Skin and soft tissue infections.

PMID- 15021058
TI  - The use of sputum eosinophils in the evaluation of occupational asthma.
AB  - PURPOSE OF REVIEW: The diagnosis of occupational asthma needs to be made
      objectively using as many criteria as possible. These include laboratory exposure
      tests with occupational agent(s), which are only available in specialized
      centres. Another approach is to monitor peak expiratory flow or methacholine
      airway responsiveness during periods at work and away from work. However, these
      measurements are open to misinterpretation when they are not performed optimally.
      Airway inflammation is one of the main characteristics of occupational asthma,
      but is not often assessed during its investigation. The purpose of this work was
      to review recent studies that have investigated and characterized the changes in
      sputum cell counts occurring in patients with occupational asthma, in order to
      evaluate the role of the analysis of sputum cell counts. RECENT FINDINGS: There
      is evidence that monitoring sputum eosinophils can help in the management of
      asthma. In the majority of cases of occupational asthma, the percentage of sputum
      eosinophils increases after exposure to occupational agents in the laboratory
      compared with baseline, but an increase in sputum neutrophils has also been
      observed. The changes in airway inflammation occurring at the workplace have been
      less investigated, but indicate that there are significant changes in airway
      inflammation and especially sputum eosinophils when workers are exposed to a
      sensitizer at their workplace compared with periods away from the workplace.
      SUMMARY: Induced sputum has successfully been used to manage patients with mild
      to moderate asthma. Its use is promising in occupational asthma, and its role in
      the investigation of occupational asthma needs to be better defined.

PMID- 15021059
TI  - Eosinophilic bronchitis in the workplace.
AB  - PURPOSE OF REVIEW: The purpose of this review is to report that eosinophilic
      bronchitis without asthma may occur as an occupational airway disease. This
      condition is characterized by cough that is responsive to corticosteroids and
      eosinophilia detectable in the sputum, without variable airflow obstruction or
      airway hyperresponsiveness. RECENT FINDINGS: Eosinophilic bronchitis can be
      regarded as an occupational respiratory disorder when it develops as a
      consequence of work exposures. Recently, exposure to certain occupational
      allergens or sensitizers, such as natural rubber latex, mushroom spores,
      acrylates and an epoxy resin hardener, have been reported to cause eosinophilic
      bronchitis without asthma. Several hypotheses have been put forward trying to
      explain why patients with eosinophilic bronchitis do not have airway
      hyperresponsiveness. It is unknown whether eosinophilic bronchitis may progress
      to typical occupational asthma, or if eosinophilic airway inflammation may
      persist when asthma symptoms and airway hyperresponsiveness have waned after the
      cessation of exposure to the occupational agent. SUMMARY: Eosinophilic
      bronchitis, like asthma, may arise from occupational exposures. The examination
      of induced sputum should be added to the objective monitoring of lung function
      during periods at work and away from work, as well as before and after specific
      inhalation challenges with occupational agents.

PMID- 15021060
TI  - Pathogenesis of hypersensitivity pneumonitis.
AB  - PURPOSE OF REVIEW: Hypersensitivity pneumonitis is a group of immunologically
      mediated diseases caused by an abnormal response to a wide variety of inhaled
      antigens. Its pathogenesis is complex and involves many immunological concepts.
      This review discusses recent advances in our understanding of the pathogenesis of
      hypersensitivity pneumonitis. RECENT FINDINGS: Over the last 3 years, several
      studies on the pathogenesis of hypersensitivity pneumonitis have been published.
      New antigens have been identified. We now have a better understanding of the role
      of inflammatory cells and mediators, and promoting and protective factors have
      been suggested. SUMMARY: Most of the mechanisms involved in the pathogenesis of
      hypersensitivity pneumonitis remain incompletely understood. Current and future
      findings will not only help our understanding of the disease and its prevention,
      but also improve its treatment.

PMID- 15021061
TI  - Natural rubber latex allergens: new developments.
AB  - PURPOSE OF REVIEW: New allergenic latex proteins have been identified, whereas
      further information on known latex allergens has emerged in recent years.
      Although prevalence figures for sensitization to the various latex allergens have
      been published in several studies in the past, the data have not been collated to
      facilitate cross-comparison. RECENT FINDINGS: Salient characteristics of the
      three most recently identified latex allergens, Hev b 11, 12 and 13 are
      described, whereas new findings on some of the previously recognized allergens
      are examined. Hev b 2 is viewed from the standpoint of allergenicity and protein
      glycosylation, Hev b 4 in relation to its biochemical identity and molecular
      cloning, Hev b 5 with respect to its recombinant form, and Hev b 6 in connection
      with conformational IgE epitopes. Reports on sensitization or allergic reaction
      to purified latex allergens from recent and past work are summarized. The use of
      latex allergens in latex allergy diagnostics is reviewed and discussed. SUMMARY:
      Thirteen latex allergens have been recognized by the International Union of
      Immunological Societies. Based on the results of published studies, native Hev b
      2, recombinant Hev b 5, native or recombinant Hev b 6, native Hev b 13, and
      possibly native Hev b 4 are the major allergens relevant to latex-sensitized
      adults. Although there is an increasing tendency to identify and characterize
      latex allergens largely on the basis of their recombinant forms, not all such
      recombinant proteins have been fully validated against their native counterparts
      with respect to clinical significance.

PMID- 15021062
TI  - Animal models for diisocyanate asthma: answers for lingering questions.
AB  - PURPOSE OF REVIEW: Diisocyanates are the leading cause of occupational asthma,
      the most commonly reported lung disease associated with the workplace. Clinical
      studies have implicated the immune system in the pathogenesis of occupational
      asthma, but ethical and moral issues prevent mechanistic investigations in
      humans. For this reason, the development and characterization of animal models
      are germane to further understanding of diisocyanate occupational asthma and to
      identify avenues for therapeutic intervention. This review will highlight
      important features of existing experimental animal models with emphasis on new
      developments. RECENT FINDINGS: Experimental animal models of diisocyanate
      occupational asthma have demonstrated an immunological basis for the disease.
      Mice can be sensitized by dermal or respiratory exposure, suggesting that either
      exposure route may be important in the workplace. Recent findings show that
      sensitized mice develop airway hyperreactivity and inflammation, reflective of
      human disease. The transfer of lymphocytes or serum from sensitized mice can
      cause clinical disease in naive mice. Transgenic animals have identified a role
      for specific immunity, including the involvement of T-helper type 1/2 responses
      as well as CD4 and CD8 T cells in diisocyanate occupational asthma. Recent animal
      models have shown that sensitization can occur through subchronic inhalation of
      vapor-phase diisocyanate at levels as low as 20 ppb. SUMMARY: Recent progress
      using animal models has been instrumental in furthering current understanding of
      the involvement of the immune system in disease pathogenesis. The demonstration
      of diisocyanate occupational asthma in a murine model after sub-chronic
      inhalation exposure at relevant exposure levels should provide opportunities for
      more accurate risk assessment data.

PMID- 15021063
TI  - What can we do NOW?

PMID- 15021064
TI  - Hygiene hypothesis and endotoxin: what is the evidence?
AB  - PURPOSE OF REVIEW: The hygiene hypothesis has gained strong support over the past
      few years. Exposure to microbial products in early life could be an underlying
      factor in this hypothesis, but the mechanisms that lead from a less clean and
      more crowded environment to a lower prevalence of asthma and allergies are not
      known. Among the variety of potential microbial molecules that may confer
      protection against the development of asthma and allergies, endotoxin, a
      component of Gram-negative bacteria, has incited lively as well as controversial
      discussions. This review focuses on recent studies on endotoxin and its role in
      the context of the hygiene hypothesis. RECENT FINDINGS: Results from cross
      sectional surveys, prospective cohorts, and experimental studies in vitro and in
      rodents suggest that exposure to house dust endotoxin in early life protects from
      atopic sensitization and IgE-mediated diseases, but is a risk factor for wheezing
      in infancy. SUMMARY: Numerous studies have supported the hygiene hypothesis, but
      whether endotoxin by itself confers the protection or whether it acts as a marker
      for another environmental exposure is still unclear. The challenge for the future
      will be to identify those factors that confer the protection proposed by the
      hygiene hypothesis, and to find strategies to modify the environment without
      causing harm to susceptible individuals.

PMID- 15021065
TI  - Allergen avoidance and prevention of atopy.
AB  - PURPOSE OF REVIEW: Recent increases in the prevalence of atopic disease argue
      strongly that environmental factors operating primarily in early life play a
      significant role. Exposure to food and inhalant allergens early in life may
      constitute a risk factor amenable to manipulation. RECENT FINDINGS: Recent
      observational and interventional studies have produced conflicting data regarding
      the effectiveness of allergen avoidance in primary and secondary prevention of
      atopic diseases. SUMMARY: Exclusive breast feeding for 4-6 months may protect
      against the development of allergic diseases in early childhood and remains good
      advice. Convincing proof for the preventive effects of the delayed introduction
      of solid foods and hydrolyzed formula in formula-fed infants is lacking. There is
      some evidence to support a preventive effect of house dust mite allergen
      avoidance before sensitization occurs. The effect of exposure to animal allergen
      is uncertain, with some studies showing an increase in sensitization while others
      suggest a protective effect. Therefore, no evidence-based advice can be given at
      this stage regarding allergen avoidance measures to be adopted by families with
      infants at high risk of atopy, except perhaps to breast feed exclusively for at
      least 4 months. Data regarding the secondary prevention of allergic disease by
      allergen avoidance were more secure until the publication this year of two
      randomized controlled trials which suggest that mattress impermeable covers, the
      main dust mite allergen avoidance measure, may not work. Allergen avoidance,
      however, should remain an essential part of the management of allergic diseases,
      even if the benefit of mattress covers is in doubt.

PMID- 15021066
TI  - Diet and the development of atopic disease.
AB  - PURPOSE OF REVIEW: The present review addresses the current literature regarding
      the impact of diet and the development of atopic disease. A search of the
      literature was carried out covering the following topics: diet and nutrition
      combined with immediate hypersensitivity, atopy, atopic disease, atopic
      dermatitis, and food allergy. RECENT FINDINGS: The search results identified a
      significant contribution in the form of reviews considering this important topic,
      which ultimately led to the author's recommendation of these reviews to impress
      upon readers the impact of the atopy triad: atopic dermatitis to allergic
      rhinitis and asthma. SUMMARY: A great deal of information exists in the
      pathomechanisms of atopic disease that will affect the classification of allergic
      and non-allergic atopic diseases. Increasing data on the genetic, humoral and
      cellular forms associated with these diseases will provide more clear-cut
      diagnostic criteria, treatment regimens and a more strict definition of the
      disease variants.

PMID- 15021068
TI  - Bibliography. Current world literature. Occupational disease.

PMID- 15021067
TI  - Allergen immunotherapy in the prevention of asthma.
AB  - PURPOSE OF REVIEW: Asthma is a disease causing significant morbidity and
      mortality. In the recent past, there has been an explosion of pharmacotherapeutic
      options attempting to control the disease. Unfortunately, none of the current
      options offers the promise of prevention or a permanent cure. However, there
      appear to be exciting, new data emerging to support the hypothesis that the
      prevention or early treatment of allergic rhinitis, such as with the use of
      allergen immunotherapy, may help mitigate the severity of bronchial symptoms and
      even prevent the development of asthma. In this paper, we review recent research
      published proposing immunotherapy as a means of preventing the development of, or
      at least ameliorating, allergic asthma. RECENT FINDINGS: There is evidence that
      the upper and lower airways may be considered a single unit, with the nasal and
      bronchial mucosa having features in common. Epidemiological, pathophysiological
      and clinical studies have shown that they can be affected by similar inflammatory
      triggers, with interconnected mechanisms amplifying the inflammatory cascade.
      Allergic rhinitis is interrelated to, and is a risk factor for, the development
      of asthma. An evidence-based review validates the successful use of allergen
      immunotherapy in treating allergic rhinitis and asthma. There is promising
      evidence advocating its use in the prevention of clinical asthma. SUMMARY: This
      article explores current research pertaining to the use of immunomodulation, such
      as by using allergen immunotherapy, to ameliorate and prevent the development of
      allergic asthma.

PMID- 15021071
TI  - Assessing dynamic cerebral autoregulation after stroke using a novel technique of
      combining transcranial Doppler ultrasonography and rhythmic handgrip.
AB  - OBJECTIVES: Dynamic cerebral autoregulation (CA) is impaired after stroke.
      Methods employed to assess this phenomenon usually involve deliberate alterations
      in blood pressure (BP) by physical means. We performed a pilot study to assess
      dynamic CA in acute stroke patients using a novel technique of combining
      transcranial Doppler (TCD) ultrasonography with rhythmic handgrip. METHODS: Ten
      patients with ischaemic stroke in the middle cerebral artery (MCA) territory were
      studied. We performed continuous recordings of bilateral MCA velocities and used
      rhythmic handgrip to induce BP oscillations. Changes in autoregulation were
      indicated by changes in phase shift and gain of MCA velocity in relation to BP.
      Patients were examined at <7 days, 6 weeks, and 3 months after stroke. RESULTS:
      There were no significant differences in phase shift or gain between the affected
      and unaffected cerebral hemispheres. Combining the results from both hemispheres,
      there was a trend of increasing phase shift (P=0.04) and decreasing gain (P=0.24)
      over the first three months after stroke, indicating improving CA. Rhythmic
      handgrip produced an average percentage change in BP (peak-to-trough) of 10%
      around the mean, and the frequency of the induced BP oscillations was very
      similar to that of the rhythmic handgrip. CONCLUSIONS: Combining TCD with
      rhythmic handgrip appeared to be a useful technique for assessing dynamic CA and
      it deserves further studies. In this pilot study, there was some evidence that CA
      might improve up to 3 months after ischaemic stroke.

PMID- 15021072
TI  - Venous blood redistribution alters the accuracy of Omron HEM-705CP.
AB  - BACKGROUND: Validation procedures of automated blood pressure measuring devices
      are carried out at rest only. DESIGN: We aimed to determine whether venous blood
      redistribution affects the accuracy of the OMRON HEM-705CP (Osc). Lower body
      negative pressure stimulus (-40 mmHg) (LBNP) was used to simulate changes of body
      position. METHODS: Fifty-four young healthy volunteers had their blood pressure
      (BP) measured simultaneously by Osc and mercury sphygmomanometer (HgS) at rest
      (at 3 and 5 min) and during LBNP (at 7 and 9 min). RESULTS: Differences (delta)
      between HgS and Osc for systolic and diastolic BP (SBP and DBP) were calculated.
      The deltaSBP obtained in minute 9 (deltaSBP-9) was bigger than the one taken in
      minute 5(deltaSBP-5) (-2.89+/- 4.3 versus -1.35+/-5.2 mmHg, P<0.02). The rest of
      the deltaSBP values and all the deltaDBP values were constant at rest and during
      venous blood redistribution caused by LBNP. We calculated the fall in SBP
      separately for HgS and Osc by subtracting SBP-9 from SBP-5 for each patient. The
      fall measured by Osc was bigger than by HgS (-5.87+/-4.0 versus -4.3+/-4.5 mmHg;
      P<0.02). When graded according to British Hypertension Society protocol, Osc
      remained in the class of recommendation (A or B) for every minute of the
      procedure. CONCLUSIONS: Even if an oscillometric device passes various validation
      tests, they do not give sufficient information about its accuracy during venous
      blood redistribution. This knowledge is of particular importance when BP
      regulation abnormalities occurring during changes in body position are diagnosed
      with the oscillometric method.

PMID- 15021074
TI  - Validation of the Pharma-Smart PS-2000 public use blood pressure monitor.
AB  - OBJECTIVE: To test the Pharma-Smart Model PS-2000 public use blood pressure
      monitor for compliance with the Association for the Advancement of Medical
      Instrumentation's Standard (AAMI) and to a modified British Hypertension Society
      (BHS) Protocol. METHODS: Subjects tested ranged in age from 18-74, with the
      average age of 40. Arm circumference ranged from 22-38 cm. Resting systolic blood
      pressure (BP) ranged from 91-252 mmHg, and resting diastolic pressure ranged from
      57-160 mmHg. There were 44 males, and 41 females. For each subject the readings
      obtained by the PS-2000 were compared with auscultatory readings obtained by two
      clinicians, blinded to the results of each other and the device. The manual
      reference measurements were alternated with the readings obtained by the device.
      RESULTS: The average differences between the reference readings (average of the
      two clinicians) using the AAMI analysis and the automated readings were 0.07+/
      7.0 mmHg (Mean+/-SD) for systolic BP, and -0.3+/-6.6 mmHg for diastolic BP.
      CONCLUSIONS: The device met the accuracy requirements of the AAMI standard. In
      addition, when the data were analyzed to assess the compliance with the current
      British Hypertension Society Protocol (BHS), the device earned the highest rating
      of 'A' for both systolic and diastolic pressure. We believe that the Pharma-Smart
      PS-2000 will provide valid readings when placed in non-medical public use sites.

PMID- 15021073
TI  - The Accoson Greenlight 300, the first non-automated mercury-free blood pressure
      measurement device to pass the International Protocol for blood pressure
      measuring devices in adults.
AB  - BACKGROUND: Accurate blood pressure measurement is critical to successful care of
      the hypertensive patient. The mercury manometer is rapidly being removed from
      clinical practice due to concerns about environmental contamination. The Accoson
      Greenlight 300 device is the first non-automated mercury-free device for
      auscultatory blood pressure measurement to pass the International Protocol for
      validation of blood pressure measuring devices in adults. METHODS: Fifty-one
      patients were enrolled to obtain the 33 patients required to fill the three
      systolic blood pressure (SBP) ranges (low 90-129 mmHg, medium 130-160 mmHg, high
      161-180 mmHg) and diastolic blood pressure (DBP) ranges (low 40-79 mmHg, medium
      80-100 mmHg, high 101-130 mmHg). Nine sequential blood pressure measurements by
      two observers with the mercury manometer and the supervisor with the Greenlight
      300 were taken. The first two observer blood pressures were used to classify the
      SBP and DBP range. The readings were then analyzed in two phases to determine
      whether the device passed the International Protocol. RESULTS: The device passed
      Phase 1 using 15 subjects. In Phase 2.1 (n=33) for the 99 readings of SBP, 84 of
      99 were within 5 mmHg, 95 of 99 were within 10 mmHg, and 98 of 99 were within 15
      mmHg. For the 99 readings of DBP, 74 of 99 were within 5 mmHg, 90 of 99 were
      within 10 mmHg, and 96 of 99 were within 15 mmHg. In Phase 2.2 (n=33) for SBP, 33
      of 33 had 2 of 3 SBP within 5 mmHg and none had all three readings >or=5 mmHg.
      For DBP, 27 of 33 had 2 of 3 of their DBP within 5 mmHg and only three had all
      three readings > or =5 mmHg. CONCLUSIONS: The Accoson Greenlight 300 is the first
      electronic non-automated blood pressure measurement device to pass the
      International Protocol.

PMID- 15021075
TI  - Accuracy of the Omron RX-M, an automated blood pressure measuring device,
      measuring blood pressure at the wrist, according to a modified British
      Hypertension Society protocol.
AB  - OBJECTIVE: To determine the accuracy of the Omron RX-M, a device measuring blood
      pressure oscillometrically at the wrist. METHODS: In 89 subjects (mean age 55+/
      14 years) blood pressure measurements at the wrist with the Omron RX-M were
      compared to sequential blood pressure measurements with a mercury
      sphygmomanometer at the (same) upper-arm and to simultaneous measurements with
      the Omron HEM-705 CP at the opposite arm.Measurements with analyzed according to
      the British Hypertension Society (BHS) - protocol 1993, to the protocol of the
      Association for the Advancement of Medical Instrumentation (AAMI) and
      (retrospectively) to the new 'International Protocol'. RESULTS: Mean differences
      (+/-SD) between the measurements with the mercury sphygmomanometer and the Omron
      RX-M were -7.5+/-8.4 mmHg for diastolic blood pressure (DBP) and -2.5+/-12.2 mmHg
      for systolic blood pressure (SBP), thus not fulfilling the AAMI-criteria (< or
      =5+/-8). According to the BHS-criteria a grade D was achieved for both DBP and
      SBP. Compared to the Omron HEM 705 CP results were -6.3+/-7.1 for DBP (grade D)
      and -4.1+/-12.7 for SBP (grade D). The Omron RX-M also failed to pass the new
      'International Protocol' in phase 1. CONCLUSION: Although easy to use, based on
      this study the Omron RX-M can not be recommended to determine blood pressure
      accurately.

PMID- 15021076
TI  - Clinical evaluation of an automated oscillometric blood pressure wrist device.
AB  - OBJECTIVES: Up to one-third of all blood pressure devices sold are for
      measurement at the wrist. Wrist monitors are thought to be subject to errors
      associated with movement and incorrect posture. We used the British Hypertension
      Society protocol to determine the accuracy of the Omron Rx automated wrist blood
      pressure monitor in adults. We also investigated the errors associated with
      miscuffing and posture with measurements at the wrist compared to the upper arm.
      METHODS: The study was conducted at a large teaching hospital in the UK.
      Participants 18 years and over were eligible for inclusion. Exclusion criteria
      were cardiac arrhythmias and inaudible Korotkoff sounds. Eighty-five participants
      were selected for the main validation study. Thirty-four subjects took part in
      the study investigating miscuffing issues and 15 subjects were included in the
      study investigating postural errors. RESULTS: The Omron Rx achieved an overall
      grade B according to the British Hypertension Society Protocol. The mean
      differences (standard deviation) between the observers and the device were 0.3
      (9.0) and 2.5 (8.8) mmHg for systolic and diastolic blood pressure respectively.
      In the medium and high-pressure ranges (> or =130/80 mmHg) the device achieved a
      grade C. When used at home the mean blood pressure reading over 60 measurements
      in 15 subjects was 123/75 mmHg when taken with the Omron Rx and 124/77 mmHg when
      taken with the automated upper arm device with no significant difference in the
      standard deviation of the readings. When compared with mercury sphygmomanometry
      using both a medium and large cuff, the wrist device readings were closest to the
      mercury measurements when the most appropriately sized cuff was used.
      CONCLUSIONS: The Omron Rx wrist monitor is accurate according to the British
      Hypertension Society protocol, but narrowly fails the Association of the
      Advancement of Medical Instrumentation criteria. Measurements at the wrist are
      not associated with miscuffing errors. Use of the wrist device by patients in the
      home setting gives comparable readings to a standard upper arm device.

PMID- 15021077
TI  - Comparison of the automated non-invasive oscillometric blood pressure monitor
      (BpTRU) with the auscultatory mercury sphygmomanometer in a paediatric
      population.
AB  - BACKGROUND: To directly compare the accuracy of the BpTRU (an automated
      oscillometric blood pressure device) with standard auscultatory mercury
      sphygmomanometry in a pediatric population. DESIGN: The BpTRU was connected in
      parallel with a standard mercury sphygmomanometer. Two observers measured the
      blood pressures at the same time as it was being measured by the BpTRU. The
      observers and the BpTRU were all blinded from each other. METHODS: For each of
      the demographic data--subject age, sex and arm sizes--the mean, standard
      deviation (SD) and range was calculated. The difference between the mean BpTRU
      and the standard reference measurements (observer average) was calculated with SD
      and ranges. The percentage of measurements within 5, 10 and 15 mmHg agreement was
      expressed. RESULTS: From the 36 subjects recruited aged 3-18 years, 162 pairs of
      sitting blood pressures were included. The difference between the mean BpTRU
      readings and the reference standard measurements (as determined by the observers)
      was 1.45+/-5.67 mmHg for systolic blood pressures, and -3.24+/-7.39 mmHg for
      diastolic pressure and 0.20+/-2.47 bpm for heart rate. CONCLUSION: The BpTRU is
      of similar accuracy in measuring blood pressure in children as it was in an adult
      population.

PMID- 15021078
TI  - Overall accuracy of the BpTRU--an automated electronic blood pressure device.
AB  - BACKGROUND: The objective of this report is to combine the data from an earlier
      adult study with the data from a paediatric study in order to determine the
      overall accuracy of the BpTRU (BPM-100 model) as compared to the recognized
      standard, auscultatory mercury sphygmomanometer. DESIGN: The individual blood
      pressure points recorded for both adult and paediatric studies were compared
      directly to its corresponding observer reference measurements from data collected
      and stored from the two separate studies. There were 255 sets of readings in the
      adult study and 162 sets from the paediatric study, which were combined to make
      417 pairs of blood pressure readings for this study. METHODS: The overall
      observer standard reference mean for the 417 measurements was calculated and the
      difference between this and the overall mean BPM-100 was calculated with SD and
      ranges. Measurements within 5, 10 and 15 mmHg agreement were expressed as
      percentages. RESULTS: A total of 121 subjects were included for this study (85
      from the adult study and 36 from the paediatric study). From these, 417 paired
      measurements were recorded. The mean difference between the BpTRU and the
      reference standard systolic blood pressure (BP) was 0.47+/-5.40 mmHg with 89.2%
      measurements within 5 mmHg, 96.4% within 10 mmHg and 99.3% within 15 mmHg. The
      mean difference between the BpTRU and reference diastolic BP was -2.12+/-5.93
      mmHg with 81.1% within 5 mmHg, 92.1% within 10 mmHg and 97.6% within 15 mmHg.
      CONCLUSION: The BpTRU has been shown to be an accurate non-invasive blood
      pressure monitoring device in the general population over a wide range of ages (3
      83 years). This combined study meets all requirements of the Association of
      Advancement of Medical Instrumentation and achieved a grade 'A' in the BHS
      protocol.

PMID- 15021079
TI  - Home blood pressure measurement: validation of the Braun BP 2550 (UG) monitor
      according to the ESH International Protocol.
AB  - BACKGROUND: The Sixth Report of the Joint National Committee states that the
      'measurement of blood pressure outside the clinician's office may provide
      valuable information for the initial evaluation of patients with hypertension and
      for monitoring the response to treatment'. Prior to their marketing, however,
      blood pressure measuring devices should be independently validated for safety and
      accuracy using standard guidelines. OBJECTIVE: The main objective of the present
      study was the clinical evaluation of the Braun Precision Sensor 2550 upgrade
      (Braun BP 2550 (UG)) according to the International Protocol of the European
      Society of Hypertension (ESH). METHODS: Measurements of systolic and diastolic
      blood pressure in 33 subjects were obtained using the mercury sphygmomanometer
      (Baumanometer) and the device. The sizes of the cuffs used for different arm
      circumferences were 12 x 23 cm, 15 x 33 cm and 18 x 36 cm for the thin adult,
      adult and overweight adult, respectively. The adult size was mostly used. If the
      cuff of the sphygmomanometer did not fall between the two range lines, a larger
      or smaller cuff was required. The reproducibility of self-blood pressure
      measurement was compared in 33 subjects (99 measurements). Nine sequential same
      arm measurements comparing the test device and the standard mercury
      sphygmomanometer were carried out according to the International Protocol of the
      ESH in three steps (phases 1, 2.1 and 2.2). RESULTS: The device passed phases 1
      and 2.1 as 75 systolic and 78 diastolic readings fell within 5 mmHg, exceeding
      the total of 65 required for approval. It also passed phase 2.2 as 30 subjects
      for systolic and 29 for diastolic had at least two out of three comparisons
      within 5 mmHg, exceeding the 22 subjects required. The difference-against-mean
      plots showed that the device-sphygmomanometer disagreement was -1.58+/-4.84 for
      systolic pressure (the Braun being lower) and +2.23+/-3.84 for diastolic pressure
      (the Braun being higher), respectively. CONCLUSIONS: The equipment passed both
      phases of the International Protocol (subject measurements and subject accuracy).
      The difference of 0-5 mmHg between the sphygmomanometer and the device represents
      'measurements considered to be very accurate and with no error of clinical
      relevance'. It can therefore be used at home as an adjunct to physicians' effort
      to control blood pressure in their hypertensive patients.

PMID- 15021088
TI  - What is causing this scalp lesion? Discoid lupus erythematosus.

PMID- 15021086
TI  - Arginine and wound healing: a case study.

PMID- 15021089
TI  - Obtaining wound specimens: 3 techniques.

PMID- 15021091
TI  - Debridement: controlling the necrotic/cellular burden.
AB  - PURPOSE: To provide physicians and nurses with an overview of the options for
      debriding a chronic wound to improve wound healing. TARGET AUDIENCE: This
      continuing education activity is intended for physicians and nurses with an
      interest in learning about methods for debriding chronic wounds to promote wound
      healing. LEARNING OBJECTIVES: After reading the article and taking the test, the
      participant will be able to: 1. Describe the 4 types of debridement most commonly
      used in clinical practice. 2. Describe when to debride a wound and how to
      determine which method to use.

PMID- 15021093
TI  - Factors associated with pressure ulcers in adults in acute care hospitals.
AB  - OBJECTIVES: To identify and describe the relationship of factors associated with
      pressure ulcers in adults in acute care hospitals. DESIGN: Cross-sectional
      prevalence studies. SETTING: University teaching hospital. PATIENTS: Prevalence
      studies conducted from 1993 to 1995 with a total of 1992 subjects served as the
      derivation sample and a 1996 prevalence study with 581 subjects served as the
      validation sample. MAIN OUTCOME MEASURES: Pressure ulcers and the Braden risk
      assessment subscale scores. DATA ANALYSIS: Logistic regression analysis was used
      to derive a model that fit the data and performed well at identifying factors
      associated with pressure ulcers. Performance of the model, in terms of
      calibration, was statistically evaluated using the Hosmer-Lemeshow goodness-of
      fit test. The effectiveness of the model, in terms of discrimination, was
      assessed by considering the cut-off values using 2 by 2 classification tables to
      measure the overall percentage of subjects correctly classified in the validation
      sample. MAIN RESULTS: Factors associated with pressure ulcers in adults in acute
      care hospitals were identified as age, male gender, sensory perception, moisture,
      mobility, nutrition, and friction/shear. Three interactions were also found to be
      associated with pressure ulcers; 2 interactions (age and sensory perception and
      moisture and sensory perception) were negatively associated and 1 interaction
      (nutrition and gender/male) was positively associated with pressure ulcers. The
      Hosmer-Lemeshow goodness-of-fit test for the derivation sample (.76) and the
      validation sample (.79) indicated that the model was well calibrated and a good
      fit. The overall percentage of subjects correctly classified using the validation
      sample was 88%, indicating that the model performed well. CONCLUSIONS: : This
      study enhances the knowledge of the relationship of factors associated with
      pressure ulcers in adults in acute care populations and enhances the use and
      relative importance of particular Braden Scale sub-scales.

PMID- 15021094
TI  - Will Medicare pay for concurrent hospital-owned outpatient wound department
      visits and procedures?

PMID- 15021095
TI  - MRSA and VRSA in wound care: accept the challenge.

PMID- 15021124
TI  - Case of un-united fracture of Os Brachii, successfully treated. 1927.

PMID- 15021125
TI  - Nonunion: general principles and experimental data.
AB  - Nonunions of long bone fractures can be treated successfully with one operative
      procedure in more than 90% of patients. In fact, 80% of patients can have good to
      excellent final restoration of mechanical axis alignment and proper length.
      Patients with infected nonunions may require more than one procedure to eliminate
      infection and heal the nonunion. Treatment must be tailored to the individual
      patient to address all components of the problem. We reviewed the main
      experimental data regarding the knowledge of nonunions and the basic methods that
      may be applied to the treatment of nonunions.

PMID- 15021126
TI  - Internal fixation of nonunions.
AB  - We review the two major types of internal fixation of nonunions (plating and
      intramedullary nailing), and analyze nonunions in different locations (upper and
      lower extremities). Depending on the type and the location of the nonunion,
      plating or intramedullary nailing may be selected. Both have advantages and
      disadvantages: plating requires opening the nonunion site, which entails some
      damage to the soft tissues, and carries with it a risk of secondary infection.
      With plating, it often is impossible to do a real decortication because the
      periosteum may be thin and poorly adherent to bone, and the quality of bone may
      prove insufficient to achieve good fixation with most of the screws. However,
      plating still is used in metaphyseal nonunions, and angular deformities may be
      corrected by applying a plate under tension on the convex side of the bone.
      Nailing can be done percutaneously in numerous cases; it has a smaller risk of
      infection but, should an infection be present, there is a risk that it may spread
      over the entire length of the medullary cavity. Nailing stimulates bone
      formation, but noninterlocking nails may cause shortening and rotational
      instability of the nonunion site. Plate fixation was popular approximately 20
      years ago, but now has been largely superseded by intramedullary nailing except
      for proximal or distal nonunions. Dynamic locking nails are preferable.
      Successful treatment of nonunions often requires several consecutive surgical
      actions and a global strategy must be established from the beginning, taking care
      not to interfere with the successive steps.

PMID- 15021127
TI  - Treatment of nonunions with electric and electromagnetic fields.
AB  - Electric and electromagnetic fields are, collectively, one form of biophysical
      technique which regulate extracellular matrix (ECM) synthesis and may be useful
      in clinically stimulating repair of fractures and nonunions. Preclinical studies
      have shown that electric and electromagnetic fields regulate proteoglycan (PG)
      and collagen synthesis in models of endochondral ossification, and increase bone
      formation in vivo and in vitro. A substantial number of clinical studies have
      been done that suggest acceleration of bone formation and healing, particularly
      osteotomies and spine fusions, by electric and electromagnetic fields. Many of
      these studies have used randomized, placebo controlled designs. In osteotomy
      trials, greater bone density, trabecular maturation, and radiographic healing
      were observed in actively treated, compared with placebo-treated patients. In
      spine fusions, average union rates of 80% to 90% were observed in actively
      treated patients across numerous studies compared with 65% to 75% in placebo
      treated patients. Uncontrolled, longitudinal cohort studies of delayed and
      nonunions report mean union rates of approximately 75% to 85% in fractures
      previously refractory to healing. The few randomized controlled studies in
      delayed and nonunions suggest improved results with electric and electromagnetic
      fields compared with placebo treatment, and equivalent to bone grafts.

PMID- 15021128
TI  - Stimulation of growth factor synthesis by electric and electromagnetic fields.
AB  - Biophysical input, including electric and electromagnetic fields, regulate the
      expression of genes in connective tissue cells for structural extracellular
      matrix (ECM) proteins resulting in an increase in cartilage and bone production.
      In in vivo models and clinical situations, this can be manifested as enhanced
      repair and a gain in mechanical properties of the repairing tissues. The
      mechanisms by which cell functions are regulated by biophysical input is the
      subject of this review. Biophysical interactions of electric and electromagnetic
      fields at the cell membrane are not well understood and require considerable
      additional study. We review information on transmembrane signaling, channel
      activation and receptor stimulation or blockade. Understanding physical
      interactions and transmembrane signaling will most likely be necessary to
      establish dosing paradigms and improve therapeutic efficacy. Considerable
      information has been generated on an intermediary mechanism of activity - growth
      factor stimulation. Electric and electromagnetic fields increase gene expression
      for, and synthesis of, growth factors and this may function to amplify field
      effects through autocrine and paracrine signaling. Electric and electromagnetic
      fields can produce a sustained upregulation of growth factors, which enhance, but
      do not disorganize endochondral bone formation. Progress in the areas of signal
      transduction and growth factor synthesis is very rapid and future directions are
      suggested.

PMID- 15021130
TI  - Nonunions of the humerus.
AB  - Humerus fractures comprise 5% to 8% of all fractures. Nonunions are uncommon, but
      when they occur, they present a challenge to the orthopaedic surgeon and often
      are debilitating to patients. There are risk factors that may predispose patients
      to nonunion. Many methods of treating these nonunions have been described with
      varying degrees of success. We review the literature concerning the treatment of
      proximal, midshaft, and distal humeral nonunions and describe our treatment
      protocol based on the literature.

PMID- 15021129
TI  - Free vascularized fibular grafts have a high union rate in atrophic nonunions.
AB  - Free vascularized fibular grafting currently is an extremely useful tool in the
      armamentarium of the orthopaedic, reconstructive surgeon. Certain problematic
      nonunions, aseptic or infected, have to be treated by vascularized bone grafts
      when previous operations are not successful. The common characteristics of these
      nonunions are several previous operations and fixations, bone atrophy and damage
      of the surrounding soft tissue, and frequently focal, active infection. After the
      bone and soft tissue debridement, the bony defect is bridged by a vascularized
      fibula strut. Depending on the recipient bone, different methods of internal
      fixation can be used, usually plates and external fixators. Free vascularized
      fibular grafts in recalcitrant, atrophic nonunions provide a high success rate.
      According to the results, this is a safe, reliable method that is indicated when
      a fracture does not heal after several surgeries, when there is an associated
      bone lost, and when infection is present.

PMID- 15021131
TI  - Nonunion of distal radius fractures.
AB  - Nonunion of a distal radius fracture is extremely uncommon. Healing problems in
      the distal radius seem to be related to unstable situations, such as concomitant
      fracture of the distal radius and ulna, and to an inadequate period of
      immobilization. Nonunion should be suspected if there is continuing pain after
      remobilization of the wrist in combination with a progressing deformity. The
      diagnosis may be confirmed by showing movement at the fracture site on lateral
      radiographs of the wrist in flexion and extension. Because of the rarity of
      distal radius fracture nonunion, it is not surprising that there is no consensus
      on the optimum mode of operative treatment. Based on our experience with
      reconstruction surgery in 23 patients, we think that most nonunions of the distal
      radius are amenable to attempts to re-align and heal the fracture even when the
      distal fragment is small. Therefore, surgeons should try to preserve even a small
      amount of wrist motion and reserve wrist fusion as a final resort.

PMID- 15021132
TI  - Femoral neck nonunion treatment.
AB  - Femoral neck fracture nonunion is a challenging complication for the orthopaedic
      surgeon. The etiology of nonunion can be complicated and multifactorial. The
      diagnosis usually is established clearly with clinical and radiographic
      examinations. There are no clear guidelines for treatment, although multiple
      factors must be taken into account. Treatment options include refixation,
      solitary bone grafting, osteotomy (with and without bone grafting), and
      prosthetic arthroplasty. The relative indications, shortcomings,
      contraindications, and results of these different forms of treatment are
      discussed.

PMID- 15021133
TI  - Circular external fixation in tibial nonunions.
AB  - The Ilizarov method based on compression-distraction and subperiostic corticotomy
      was used in 82 lower extremities. There were 45 tibial nonunions without a
      significant bone defect and 37 tibial nonunions with a bone defect that required
      radical removal of the necrotic bone and bone lengthening or bone transport. Bone
      healing was obtained in 39 of the 45 tibial nonunions without bone defect (mean
      bone healing, 5.4 months) and in all patients with bone defect (mean bone
      healing, 15 months for patients treated with bone transport) although secondary
      surgeries (autografting and tibial nails) were frequent (23 patients). Infection
      was eradicated in all patients after necrotic bone removal and bone transport.
      The final mean limb length discrepancy was 0.7 cm for the patients without a bone
      defect and 2.03 cm for the patients with a bone defect. In the patients in the
      bone transport group, residual axial deviation and residual limb shortening were
      common. Circular external fixation is a useful method to solve complex tibial
      nonunions in patients in whom internal devices and autografting have failed.
      Patients must be cooperative, and must understand the length of time the frame
      needs to be worn, and that complications are a probability.

PMID- 15021134
TI  - Nonunion of the spine: a review.
AB  - Originally described for the treatment of tuberculosis of the spine, spinal
      fusion has become a widely done procedure for various spinal disorders. Among
      other indications, spinal fusion is used for treatment of degenerative disc
      disease, congenital and developmental deformities such as scoliosis, and spinal
      instability secondary to trauma. One of the most common complications of spinal
      fusion is nonunion. The incidence of nonunion has been reported as high as 56% in
      the lumbar spine. Recognizing and treating nonunion of the spine may be crucial
      in preventing progressive deformity in identifying instrumentation failure, and
      in relieving persistent pain. The purpose of this article was to review the
      clinical evaluation and significance of failed union.

PMID- 15021135
TI  - Glenoid cementing may generate sufficient heat to endanger the surrounding bone.
AB  - Glenoid loosening is a common complication of shoulder arthroplasty. One possible
      cause is bone necrosis from the exothermic reaction of polymethylmethacrylate.
      The relationship between the amount of cement used in glenoid fixation and the
      risk of thermal injury to bone was examined. Glenoid arthroplasty was done on 17
      fresh cadaver scapulas, recording the amount of cement used. The bone surface
      temperature during cement curing was measured using infrared thermography. Using
      these data and published thresholds for thermal necrosis, the frontal plane area
      of bone that would be at risk for necrosis in vivo was estimated. The average
      weight of cement implanted was 5.35 g (2.65-8.08 g). The maximum temperature
      recorded averaged 64.7 degree C (48.2 degree-76.8 degree C). The area of bone at
      risk correlated with the amount of cement used. This study indicates that
      potentially dangerous amounts of heat may be generated during cementing of
      glenoid components.

PMID- 15021136
TI  - Role of the coracoacromial ligament as restraint after shoulder hemiarthroplasty.
AB  - Patients with an irreparable rotator cuff tear and glenohumeral degeneration
      often are treated with hemiarthroplasty. This procedure has proven effective as
      long as the coracoacromial ligament remained intact. The ligament reportedly acts
      as a restraint against anterosuperior dislocation. The purpose of the current
      study was to test the role of the coracoacromial ligament as an anterosuperior
      restraint after hemiarthroplasty in shoulders from cadavers with simulated
      irreparable rotator cuff tears. Six fresh-frozen shoulders were dissected to
      mimic a massive rotator cuff tear. After a hemiarthroplasty was done, each
      shoulder was mounted in a fixture, which was attached to a materials testing
      device. Using this device, the role of the coracoacromial ligament was evaluated
      by loading the shoulders in various positions and then measuring displacement
      before and after excision of the ligament. The mean difference in anterosuperior
      displacement was 3.44 mm. In all shoulders, subjective observation revealed that
      the humeral head often becomes wedged between the coracoid and the acromion
      during axial loading after excision of the coracoacromial ligament. Therefore,
      the coracoacromial ligament should be preserved to enhance the stability of the
      joint and to preserve the superior fulcrum.

PMID- 15021137
TI  - Metastatic burst fracture risk prediction using biomechanically based equations.
AB  - Clinical guidelines are a useful adjunct to select patients with spinal
      metastases for prophylactic intervention. The objective of this study is to
      determine the ability of biomechanically based models to accurately predict
      metastatic burst fracture risk. Ninety-two vertebrae with osteolytic spinal
      metastases were examined retrospectively. Vertebrae were categorized as burst
      fractured, wedge fractured, or intact and analyzed using three predictive models:
      vertebral bulge (maximum radial displacement under load), vertebral axial
      displacement (maximum axial displacement under load), and a volumetric estimate
      of tumor size. The load-bearing capacity parameter (tumor volume, bone mineral
      density, disc quality, pedicle involvement) was determined from computed
      tomography while the load-bearing requirement parameter (pressure load, loading
      rate) was determined using computed tomography and patient records (retrieved for
      37 patients [52%]). Fracture prediction was optimized using the vertebral bulge
      model considering only load-bearing capacity with a specificity, sensitivity, and
      confidence interval of 1 to yield a clear threshold for burst fracture risk.
      Fracture prediction in the other two models, vertebral axial displacement
      considering only load-bearing capacity and tumor size, also was strong with
      receiver-operator curve values of 0.992 and 0.988, respectively. The predictive
      power of these models can provide useful clinical information for prophylactic
      decision-making.

PMID- 15021138
TI  - Traumatic lumbosacral dislocation: four cases and review of literature.
AB  - Diagnosis, physiopathology, and treatments of four patients with traumatic
      lumbosacral dislocations are described. This is a rare but severe lesion of the
      lumbosacral junction that usually occurs in patients with multiple trauma. It
      often is not thought of and the diagnosis may be missed. Evidence of lumbosacral
      dislocation should be examined and confirmed by computed tomography scans in
      patients with multiple fractures of transverse lumbar processes, asymmetric
      lumbosacral joints on frontal images, or slipping of L5 over S1 on lateral
      images. Treatment consists of reduction of the dislocated and fractured parts,
      lumbosacral arthrodesis, a posterolateral graft, and posterior instrumentation.
      Instrumentation may be short, extending from L5 to S1, or long, from L4 to S1,
      depending on the extension of the lesion. In some cases, reduction can be done
      intraoperatively, when the L4-S1 instrumentation is inserted, provided L5
      transpedicle screws are pulled posteriorly. It usually is preferable to explore
      the vertebral canal to ensure that there is no disc lesion compressing the dura
      before proceeding with reduction. Compression of the dura could be avoided with a
      preoperative magnetic resonance imaging scan on which a lesion of the L5-S1 disc
      is sought. Additional interbody vertebral arthrodesis should be considered when
      the L5-S1 disc is affected severely. This lesion should be looked for
      preoperatively with a magnetic resonance imaging scan and intraoperatively by
      exploring the canal. This can be done at the time of the posterior surgery or
      during a second anterior surgical procedure.

PMID- 15021139
TI  - Total hip arthroplasty using an Omniflex modular system: 5 to 12 years followup.
AB  - We evaluated intermediate-term results of primary cementless Omniflex prostheses.
      Forty-nine patients (57 hips) with a mean age of 44 years were observed for an
      average of 8.6 years. The average Harris hip score was 46 points before surgery
      and 87 points at final followup. Revision was done in five hips (9%) in five
      patients. Two acetabular components (4%) were revised because of breakage of the
      polyethylene insert. Three femoral components (5%) were revised because of
      aseptic loosening. Six femoral components (10%) were radiographically loose.
      Overall, 11 hips (19%) were considered mechanical failures. Osteolysis was
      identified around three acetabular components (5%) and around 20 femoral
      components (35%). Nine hips (16%) had femoral osteolysis around the distal stem
      tip. The average annual polyethylene liner wear was 0.18 mm. These results were
      inferior to those using other recent cementless total hip systems.

PMID- 15021140
TI  - Weber rotation total hip replacement: a prospective 5- to 20-year followup study.
AB  - Between 1974 and 1989, 315 primary total hip replacements (274 patients) were
      done using the cemented Weber Rotation prosthesis and standardized operative
      technique, which was modified for the stem in 1978. After the first postoperative
      year, all patients had routine clinical and radiologic examinations at 2-year
      intervals. Twenty-one patients (22 hips) were lost to followup. At the most
      recent followup, 30 of 293 hips (253 patients) had been revised: 24 hips for
      aseptic loosening, five hips for infection, and one hip for a femoral fracture.
      Survivorship analyses with revision for aseptic loosening as an end point for the
      315 hips showed 93% and 78% survival after 10 and 15 years, respectively.
      Separate survival analyses for the socket showed 99% and 89% survival after 10
      and 15 years, respectively. The stem had a survival of 94% and 81%, respectively,
      during the same time. Survival at 15 years with radiologic evidence of loosening
      as an end point was 85% for the socket and 72% for the stem. The cementing
      technique and the design of the acetabular component significantly influenced the
      rate of loosening. Survivorship analyses with revision for aseptic loosening of
      the socket, using a modified second generation cementing technique and a
      hemispheric socket, showed 100% survival after 10 years and 98% after 13 years.

PMID- 15021141
TI  - Durability of the cemented femoral stem in patients 60 to 80 years old.
AB  - The importance of surface roughness and durability of fixation of the cemented
      femoral stem were examined. Three cohorts of patients approximately 60 to 80
      years old, had cemented total hip replacements: Charnley (1978-1983) with first
      generation cement technique consisting of canal-plugging and digital packing;
      Omnifit (1986-1991), and Ranawat-Burstein (R-B) Interlok (1992-1994) with
      modified third-generation cement technique. Kaplan-Meier survivorships, using
      failure for all causes (best case) were 90% +/- 5.1% at 20 years for the Charnley
      95.1%+/- 3.4% at 15 years for the Omnifit and 99.5% +/- 0.5% at 9 years for the R
      B Interlok prosthesis. Log rank test with paired data showed no significant
      differences between the groups for mechanical failure as an end point.
      Comparisons of survivorship curves for failure from all causes showed significant
      differences between the Charnley compared with the Omnifit and Interlok series
      respectively, with no significant differences between the Omnifit and R-B
      Interlok series. The cemented femoral stem, with a good cement mantle and surface
      roughness ranging from 30 to 150 microinches, did not show any significant
      differences in mechanical failure. Other variables such as stem centralization
      and low polyethylene wear need additional evaluation in survivorship of cemented
      total hip replacements.

PMID- 15021142
TI  - Radiographic evaluation of screw position in revision total hip arthroplasty.
AB  - Injury to intrapelvic structures during removal of screws in revision acetabular
      arthroplasty is an uncommon, yet potentially serious complication. Bicortical
      screws are at greatest risk for causing injury during removal, especially if
      directed toward intrapelvic vessels and nerves. Complications can be minimized
      with thorough evaluation of screw position before revision surgery. A study of
      seven cadaveric pelves was done to determine if plain radiographic views provide
      useful information regarding screw position. In each pelvis, bicortical
      transacetabular screws were fixed in all acetabular quadrants 15 mm longer than
      the measured depth. Afterward, anteroposterior, inlet, Judet, and cross-table
      lateral radiographic views were obtained and intrapelvic dissections were done.
      Radiographs and intrapelvic dissections were compared to determine screw
      position. We found that the obturator and iliac oblique (Judet) views were most
      useful in defining screw position. The iliac oblique view clearly revealed screws
      that violated the quadrilateral surface and therefore were directed toward the
      obturator vessels and nerve. The obturator oblique view revealed screws that
      violated the anterior column and therefore were directed toward the external
      iliac vessels. The lateral view additionally clarified such screws by determining
      general anterior or posterior direction.

PMID- 15021143
TI  - Pseudoseptic reactions to hylan viscosupplementation: diagnosis and treatment.
AB  - Hyaluronans are used widely in the treatment of osteoarthritis of the knee. Three
      commercial hyaluronan preparations currently are available in the United States:
      sodium hyaluronate (Hyalgan), sodium hyaluronate (Supartz), and hylan G-F 20
      (Synvisc). Although the sodium hyaluronates are derived naturally, hylan is
      chemically modified to increase its molecular weight. All three products have
      been shown to be well tolerated in clinical trials, however, there have been
      reports in the literature of pseudoseptic reactions, or severe acute inflammatory
      reactions, after injections with hylan. Our study reviewed the reported incidence
      of pseudosepsis. The pathogenic mechanisms and clinical treatment of this
      reaction are presented.

PMID- 15021144
TI  - In vivo laxity of low contact stress mobile-bearing prostheses.
AB  - A stress arthrometric study was done on 60 knees in 54 patients with total knee
      arthroplasties using a Telos arthrometer, to determine anteroposterior and
      abduction and adduction laxity and to evaluate the relationship between laxity
      and retention of the posterior cruciate ligament using low contact stress mobile
      bearing prostheses. Thirty knees had posterior cruciate ligament-retaining and 30
      had posterior cruciate ligament-sacrificing prostheses. The selected patients had
      successful knee arthroplasty 6 months previously. Anteroposterior displacement
      was measured at 30 degree and 90 degree flexion; there were no statistically
      significant differences between the posterior cruciate ligament-retaining (10.5
      mm at 30 degree, 9.3 mm at 90 degree) and posterior cuciate ligament-sacrificing
      (9.8 mm at 30 degree, 9.7 mm at 90 degree) groups. Abduction and adduction were
      between 0 degree and 20 degree flexion, there were no significant differences
      between the two groups. Because all the patients in this study had good clinical
      results, approximately 10 mm anteroposterior displacement and 4 degree laxity in
      the coronal direction are considered favorable in low contact stress mobile
      bearing prostheses of both designs.

PMID- 15021145
TI  - Surgical reconstruction of severe patellofemoral maltracking.
AB  - Dysfunction of the patellofemoral mechanism presents in many ways. Results from
      different realignment procedures show great variability in patient outcome. A
      surgical technique is presented that attempts to correct all the abnormalities of
      patellofemoral maltracking. The procedure consists of a lateral release, a vastus
      medialis (obliquus) tendon advancement, and a tibial tubercle transfer. Along
      with being moved medially, the tubercle also is moved distally to correct patella
      alta and elevated anteriorly to reduce patellofemoral joint reaction forces. One
      hundred seven knees in 84 patients were reviewed. Fifty-five percent of patients
      had frank dislocation. The remaining patients had anterior knee pain and had
      abnormal patella tracking on examination. The mean followup was 5.6 years.
      Seventy-nine percent of patients had a good to excellent functional outcome and
      84% of patients stated they would have the operation again. Two patients with
      marked generalized ligamentous laxity had recurrent dislocation of the patella.

PMID- 15021146
TI  - Acetabular osteoarticular allograft after Ewing's sarcoma resection.
AB  - Ewing's sarcoma of the pelvis traditionally has been a difficult problem in
      orthopaedic oncology. Multiple studies have had inferior outcomes when compared
      with outcomes of patients with similar stage disease involving only the
      extremities. A major reason for this discrepancy is the difficulty associated
      with resection and reconstruction of pelvic tumors. Often the tumors are deemed
      nonresectable and are treated with chemotherapy and radiation or radiation alone.
      Patients treated in this manner have lower 5-year survival rates, higher local
      recurrence rates, and multiple long-term complications. The case of a 4-year-old
      girl with Ewing's sarcoma of the left hemi-pelvis is reported. Combined with
      adjuvant chemotherapy, this patient was treated with resection followed by
      osteoarticular allograft reconstruction. At 2 years followup, the patient was
      disease-free with an excellent functional outcome.

PMID- 15021147
TI  - Synovial sarcoma: the importance of size and location for survival.
AB  - A retrospective analysis was done on 135 consecutive patients with extremity and
      truncal synovial sarcomas seen at our institutions between 1961 and 1996. Ninety
      nine patients (73%) presented with a newly diagnosed localized primary sarcoma,
      nine patients (7%) presented with a locally recurrent sarcoma previously treated
      at another institution, and 27 patients (20%) presented with metastatic disease.
      The median followup for surviving patients was 78 months (range, 20-420 months).
      The overall survival for patients with localized primary and locally recurrent
      synovial sarcoma was 51% at 10 years. Patients with localized synovial sarcomas
      less than 5 cm in longest diameter had a survival at 10 years of 88% compared
      with a 10-year survival of 38% and 8% for patients with sarcomas 5 to 10 cm and
      greater than 10 cm in longest diameter, respectively. Distal location (hands and
      feet) and histologic grade also were statistically significant predictors of
      patient survival for localized synovial sarcoma on univariate analysis. On
      multivariate analysis size greater than 10 cm and size 5 to 10 cm were associated
      with an 18-fold and a 3.1-fold increased risk of death compared with tumors
      smaller than 5 cm. Grade and location were not found to be independent predictors
      of survival on multivariate analysis. Primary tumor size and initial status at
      presentation were prognostic for survival and patients with synovial sarcomas
      larger than 5 cm or locally recurrent at presentation should be considered for
      more aggressive surgical and adjunctive radiotherapy or chemotherapy.

PMID- 15021148
TI  - Glomangioma arising from the superficial palmar arch in the hand: case report.
AB  - A patient presented with a glomangioma that presented as an aneurysm of the
      superficial palmar arch. Throbbing pain, tenderness over the tumor, and cold
      intolerance were clinical features. Cold intolerance was the major problem. The
      pathologic diagnosis was glomangioma. Excision of the tumor provided a good
      result and there has been no recurrence.

PMID- 15021149
TI  - The concept of curative margin in surgery for bone and soft tissue sarcoma.
AB  - To clarify the safety margin in excision of bone and soft tissue sarcomas, a new
      evaluation method for surgical margins was drafted by the Bone and Soft Tissue
      Committee of the Japanese Orthopaedic Association in 1989. This new evaluation
      system was applied to 1329 patients with bone and soft tissue sarcomas, of whom
      492 were excluded because of insufficient details, leaving 837 patients (901
      surgeries) for the current study. Based on the results derived from analyzing
      these registered surgical margins, predictable safety margins under different
      conditions could be determined. When preoperative treatment is not done or is
      ineffective in high-grade sarcoma, a margin greater than 3 cm wide is necessary.
      When the preoperative modality is effective, a 2-cm wide margin is permissible.
      However, for recurrent sarcoma, whether low-grade or high-grade, a curative
      procedure is necessary. For low-grade sarcoma, obtaining an adequate wide margin
      is essential but partial marginal margins are acceptable at sites where barriers
      exist. When the margin is insufficient, radiotherapy should be used regardless of
      the tumor grade. Making a safety margin definitive through this system, an
      optimum treatment can be obtained and unnecessary adjunctive modalities can be
      avoided.

PMID- 15021150
TI  - Hip fracture incidence in central norway: a followup study.
AB  - Studies in the 1980s, including one from central Norway, in most cases showed
      that the incidence of hip fractures was increasing. In the 1990s, however,
      studies from Sweden and the United States indicated that the increase may have
      stopped. We report the current incidence of hip fractures in subjects in central
      Norway and compare it with that previously reported. The number of cervical and
      trochanteric fractures in a defined region of Central Norway in 1992 to 1993 and
      in 1997 to 1998 was found by a thorough search and collation of the hand written
      surgery reports, the reports from radiology departments, and hospital discharge
      reports. One thousand three hundred twelve hip fractures were sustained during
      1997 to 1998, 10% more than in the preceding period. This was almost entirely
      attributable to aging of the population. In contrast to the highly statistically
      significant increase in the actual incidence of 2% per year previously reported
      between 1972 to 1973 and 1983 to 1984, there was no statistically significant
      increase in incidence between 1983 to 1984 and 1997 to 1998 (0.55% per year). The
      incidence of hip fractures was 18% higher in subjects in urban areas than in
      subjects in rural areas in 1992 to 1993, and 33% higher in 1997 to 1998. Whereas
      the proportion of trochanteric fractures was 32% in 1972 to 1973 and in 1983 to
      1984, it increased to 44% in 1992 to 1993 and to 68% in 1997 to 1998. There has
      been an insignificant increase in hip fracture incidence since 1983 to 1984. The
      lower incidence of hip fractures in subjects in rural areas persists, and there
      has been a dramatic increase in the proportion of trochanteric fractures.

PMID- 15021151
TI  - Antibiotic prophylaxis in hip fracture surgery: a metaanalysis.
AB  - A metaanalysis was done to identify the most effective prophylactic antibiotic
      regimen in hip fracture surgery. Specific comparisons addressed were antibiotics
      at any dose versus placebo, multiple doses (>24 hours coverage) versus one dose
      of antibiotics, and multiple doses versus 24 hours antibiotic coverage. Outcomes
      measured included overall wound infections, deep wound infection, superficial
      wound infection, urinary tract infection, and mortality. A computer search of the
      Medline and EMBASE databases (English language literature from 1966 to 2000 and
      1988 to 2000, respectively) retrieved 15 randomized controlled trials which
      addressed the specific aims. Most studies evaluated antibiotics from the
      cephalosporin group. Antibiotic prophylaxis significantly reduced overall wound
      infections when compared with placebo and was equally effective for deep and
      superficial infections. One dose of intravenous antibiotics seemed no different
      than multiple doses. Antibiotic use also was associated with a significant
      reduction in the incidence of urinary tract infection but had no significant
      effect on mortality.

PMID- 15021152
TI  - Nonunion of fractures of the subtrochanteric region of the femur.
AB  - There are no large clinical series to guide the clinician treating a
      subtrochanteric nonunion. Deformity, bone loss from previous hardware, and the
      high stresses in the subtrochanteric region all pose challenges to achieving
      successful bony union with reoperation. The purpose of this study was to
      retrospectively review a consecutive series of patients treated with reoperation
      using contemporary techniques for subtrochanteric nonunion. Between 1992 and
      2002, 23 patients with a mean age of 55 years (range, 16-88 years) with 23
      subtrochanteric nonunions were treated with additional attempts to achieve union.
      Two patients were lost to followup. The remaining 21 patients were followed up
      for a mean of 12 months (range, 6-39 months). Implants used for revision internal
      fixation were as follows: eight patients were treated with a cephalomedullary
      nail, seven patients were treated with a standard antegrade femoral nail, five
      patients were treated with a 95 degree angled blade plate, one patient was
      treated with a sliding hip screw, one patient was treated with a 95 degree
      dynamic condylar screw, and one patient was treated with dual large fragment
      plates. Eighteen of 23 patients had bone grafting: eight had autograft, six had
      allograft, and both were used in three patients. One patient had free
      vascularized fibular transfer. Twenty of 21 nonunions healed (95%). At last
      followup, all patients with healed fractures had no or minimal pain. All were
      ambulatory. There were no intraoperative complications. There was one
      postoperative complication (4%), an adynamic ileus that was treated medically.
      Revision internal fixation and selected bone grafting for subtrochanteric
      nonunion led to a high rate of fracture union and functional improvement.
      Intramedullary devices with fixation into the femoral head and neck and fixed
      angled devices were effective in achieving stable fixation of the proximal bony
      fragment.

PMID- 15021153
TI  - Myofibroblast numbers are elevated in human elbow capsules after trauma.
AB  - Elbow contractures, a frequent problem after injury, can be treated by excision
      of the joint capsule. However, the underlying changes in the joint capsule are
      poorly understood. Based on skin healing work, we examined the hypotheses that
      myofibroblast numbers and expression of a myofibroblast marker alpha-smooth
      muscle actin, are elevated in patients with posttraumatic joint contractures.
      Anterior capsules were obtained from six patients who had operative release of
      posttraumatic contractures greater than 5 months after injury and six elbows of
      organ donors free of contractures. Immunohistochemical studies revealed that
      myofibroblast numbers and percentage of total cells that were myofibroblasts were
      significantly elevated in the joint capsules from patients with contractures (326
      +/- 61 cells per field, 36% +/- 4% total cells) when compared with similar
      tissues of the organ donors (69 +/- 41 cells per field, 9% +/- 4% total cells).
      Western blot analysis showed that protein levels of alpha-smooth muscle actin
      were significantly elevated in patients with posttraumatic joint contractures.
      However, analysis with reverse transcription-polymerase chain reaction determined
      that messenger ribonucleic acid levels for smooth muscle actin normalized to the
      housekeeping gene glyceraldehyde-3-phosphate dehydrogenase were not significantly
      different between the two groups. An association between increased numbers of
      myofibroblasts and posttraumatic joint contractures has been established in the
      human elbow capsule. Additional work is required to determine whether
      myofibroblast regulators may be targets for adjuvant therapies of posttraumatic
      contractures.

PMID- 15021154
TI  - Slipped capital femoral epiphysis in a child with sickle cell disease.
AB  - Slipped capital femoral epiphysis in a child with sickle cell disease has not
      been reported previously. The diagnostic challenges, role of imaging techniques,
      and the medical treatment of this patient are discussed. The presentation of
      acute hip or leg pain in a child with sickle cell disease should alert the
      treating physician to the possibility of a vaso-occlusive crisis as the likely
      source of the child's pain. The goal of the current case report is to emphasize
      the need to maintain a high index of suspicion for other potential causes of hip,
      thigh, or knee pain such as slipped capital femoral epiphysis in an adolescent.
      Preoperative and postoperative care for a child with sickle cell disease needs to
      be modified to minimize the risks of vaso-occlusive complications.

PMID- 15021155
TI  - Magnetic resonance evaluation of remodeling process in patellar tendon graft.
AB  - Several studies have shown the accuracy of magnetic resonance imaging in
      evaluating the reconstructed anterior cruciate ligament. The purpose of the
      current study was to clarify the clinical usefulness of magnetic resonance
      imaging for evaluating the reconstructed anterior cruciate ligament in comparison
      with using arthroscopy. Sixty-nine patients who had an anterior cruciate ligament
      reconstruction using a bone-tendon-bone autograft were examined by magnetic
      resonance imaging and arthroscopy an average of 12 months after surgery. There
      were 41 males and 28 females with an average age of 25.9 years (range, 15-66
      years). The interval from surgery to the magnetic resonance imaging or
      arthroscopic evaluation was a mean of 12 months (range, 4-32 months). The
      magnetic resonance imaging findings of the reconstructed anterior cruciate
      ligament were classified as either high, intermediate, or low intensity. The
      arthroscopic findings also were classified as either graft impingement at the
      intercondylar notch or no impingement. In the 47 anterior cruciate ligament
      grafts that were not impinged, the signal intensity remained low and did not
      increase during second-look arthroscopy. In contrast, 22 anterior cruciate
      ligament grafts that were impinged showed an increased signal intensity in the
      distal area of the graft at the time of the second-look arthroscopy. Furthermore,
      no significant correlation was observed between the presence of a high signal
      intensity and postoperative instability. The high signal intensity of the
      anterior cruciate ligament graft on magnetic resonance imaging was found to be
      caused by graft impingement. These findings therefore show a clear association
      between graft impingement and the subsequent appearance of the graft on magnetic
      resonance imaging.

PMID- 15021156
TI  - Reduction of initial tension in the in situ frozen anterior cruciate ligament.
AB  - The purposes of this study were to develop a new method to measure in situ
      tension in the anterior cruciate ligament, and to show degradation changes in the
      tension applied to the in situ frozen-thawed anterior cruciate ligament during a
      12-week period postoperatively. Eighteen mature Beagles were used in the current
      study. Each dog had the in situ freeze and thaw treatment to its anterior
      cruciate ligament, and an initial tension of 20 N was applied to the anterior
      cruciate ligament. The in situ tension in the anterior cruciate ligament was
      measured immediately after surgery (n = 4) and at 6 and 12 weeks (n = 5,
      respectively) with a method developed specifically for this study. A commercially
      available force transducer, the utility and the validity of which were
      established in previous studies, was inserted into the anterior cruciate
      ligament, and the transducer was calibrated in situ using a tensile tester after
      sacrifice. The four remaining animals were used for histologic examinations. The
      average tension in the anterior cruciate ligament decreased from 19.1 N
      immediately after surgery to 14.2 N and 4.7 N at 6 and 12 weeks, respectively.
      There were significant differences among the times. At 12 weeks, histologically,
      degenerative changes were seen with asteroid-shaped cells and vacuoles in the
      anterior cruciate ligament. The current study showed that the high initial
      tension applied to the in situ frozen anterior cruciate ligament gradually
      decreased with time until 12 weeks.

PMID- 15021157
TI  - Leiomyosarcoma of the distal femur after anterior cruciate ligament
      reconstruction.
AB  - We report a case of leiomyosarcoma of the distal femur arising at the site of a
      previous anterior cruciate ligament reconstruction using a metallic interference
      screw. This, to our knowledge, is the first reported case of a malignancy
      occurring at the site of a prior anterior cruciate ligament reconstruction. We
      discuss lesions occurring after anterior cruciate ligament reconstruction.

PMID- 15021158
TI  - Shoulder capsule shrinkage and consequences on shoulder movements.
AB  - A study was designed to find landmarks to avoid restriction of range of motion or
      insufficient shortening of the ligaments after thermal shoulder capsule
      shrinkage. In 15 nonembalmed shoulders from cadavers, shrinkage was done in three
      steps: (1). the middle glenohumeral ligament, (2). the anterior part of the
      inferior glenohumeral ligament, and (3). the posterior part of the glenohumeral
      ligament. Before and after each step passive range of motion of the glenohumeral
      joint was studied. Results indicated that flexion and the external rotation were
      not affected. External rotation in the scapular plane with 45 degree elevation
      diminished after shrinkage of the middle glenohumeral ligament. External rotation
      in full abduction diminished after shrinkage of the anterior part of the inferior
      glenohumeral ligament. Abduction diminished after shrinkage of the anterior and
      posterior parts of the inferior glenohumeral ligament. Internal rotation in full
      abduction was restricted after shrinkage of the posterior part of the inferior
      glenohumeral ligament. These results show a constant relation between the
      reduction of a given movement and the shrunken area, by providing useful
      landmarks to reduce the passive hyperabduction that is constant in anterior
      shoulder instability and to control the immediate effects on the other ranges of
      motion. To control the immediate consequences of shrinkage may help avoid
      excessive restriction of motion or insufficient reduction of capsular redundancy.

PMID- 15021159
TI  - Periosteal augmentation of a tendon graft improves tendon healing in the bone
      tunnel.
AB  - Secure fixation of tendon or ligament to bone has been a challenging problem. The
      periosteum is an osteogenic organ that regulates bone growth and remodeling at
      the outer surface of cortical bone and also is known to play an important role in
      forming a tendon insertion site to bone. Therefore, we hypothesized that a
      freshly harvested periosteum can be used as a stimulative scaffold to
      biologically reinforce the attachment of tendon graft to bone. Using a rabbit
      hallucis longus tendon and calcaneus process model, we found that a periosteal
      augmentation of a tendon graft could enhance the structural integrity of the
      tendon-bone interface, when the periosteum is placed between the tendon and bone
      interface with the cambium layer facing toward the bone. Clinically, the use of
      an autogenous periosteum patch would be an optimal choice for biologic
      augmentation of the tendon graft in the bone tunnel, because the tissue is
      readily available for harvest from the patient's body.

PMID- 15021160
TI  - Biomechanical study of pins in cementing of contained proximal tibia defect.
AB  - Defects from curettage for giant cell tumors of bone frequently have been
      reconstructed with bone cement with or without reinforcement pins. The
      biomechanical basis for the addition of reinforcement pins was examined using a
      model of a contained defect in the proximal tibia. Fifty-four cadaveric proximal
      tibia in matched pairs were divided into five test groups: intact tibia, medial
      metaphyseal contained defect, defect reconstructed with cement alone, defect
      reconstructed with cement and pins inserted within the medullary canal, and
      defect reconstructed with cement and pins inserted through the cortex. Specimens
      were tested to failure during one cycle of compressive loading. Defect specimens
      were significantly weaker and less stiff than intact specimens, establishing the
      validity of the model-contained defects. For the reconstructions, there was no
      statistically significant difference in load to failure, stiffness, energy to
      failure, or displacement for the polymethylmethacrylate treatment alone when
      compared with matched specimen receiving polymethylmethacrylate and pins
      treatment. Similarly, there was no statistical difference in biomechanical
      properties in comparing matched specimens treated with polymethylmethacrylate
      alone or polymethylmethacrylate/pins (cortex). For contained defects of the
      proximal tibia that are typical after curettage for giant cell tumor, there
      appears to be no biomechanical advantage to use of reinforcement pins in the
      cement.

PMID- 15021161
TI  - Human intervertebral disc cell culture for disc disorders.
AB  - Repair of degenerated intervertebral discs by engineered tissue is a clinical
      challenge in spinal surgery. Prerequisites are cultivation of intervertebral disc
      cells and determination of their biologic properties. The influence of disc
      damage in different spinal disorders on the outcome of disc cell cultures has not
      been discussed previously. This study showed the feasibility of cultivation of
      cells from damaged human intervertebral discs and the dependence of cellular
      culture properties on the underlying disc disorder. Human intervertebral disc
      cells were isolated from disc tissue obtained during surgical procedures for
      scoliosis, osteochondrosis, and disc herniation. After proliferation in monolayer
      culture, cells were embedded in a mixed matrix composed of fibrin and hyaluronic
      acid. Deoxyribonucleic acid content, hydroxyproline content, and proteoglycan
      synthesis were determined on Days 7, 14, and 21. In a three-dimensional
      environment only cells obtained from scoliotic and osteochondrotic discs showed
      significant deoxyribonucleic acid and proteoglycan synthesis. However,
      hydroxyproline content increased only in cells from scoliotic discs. The results
      of this study show that the formation of extracellular matrix components under
      three-dimensional culture conditions is dependent on the nature of intervertebral
      disc damage of the tissue processed.

PMID- 15021162
TI  - Effects of fracture fixation stability on ossification in healing fractures.
AB  - Temporal distribution of intramembranous and endochondral bone formation was
      studied in experimental fracture defects in rats under different stability of
      fracture fixation and fracture environments. Animals were surgically treated with
      a specially developed external fixation construct: Group 1 had 42 rats with a 0
      mm fracture gap with bone ends touching corresponding to an axial stiffness of
      265.00 +/- 34.00 N/mm and Group 2 had 42 rats with a 2-mm fracture gap
      corresponding to an axial stiffness of 30.38+/- 2.07 N/mm. From each group, six
      animals were sacrificed at 4 days and 1, 2, 3, 4, 6, and 12 weeks. Qualitative
      histologic and morphometric analyses revealed that less fixation rigidity and
      increased fracture gap induces a later response of bone formation and greater
      endochondral bone formation leading to prolonged time for full ossification.
      Furthermore, in the early phase of fracture healing temporal distribution and
      histologic characteristics of periosteal and intramedullary bone formation are
      similar and not influenced by rigidity and fracture environment. Results also
      showed that if tissues associated with the intramedullary region are preserved,
      intramedullary bone formation is substantial. Finally, histologic data indicate
      that woven bone might be a prerequisite for the differentiation process of
      endochondral bone formation.

PMID- 15021163
TI  - Effect of weightbearing on bone formation during distraction osteogenesis.
AB  - The effect of weightbearing on the bone formation during distraction osteogenesis
      was studied with 24 goats after standardized osteotomy and distraction. Twelve
      goats were allowed to bear weight immediately and 12 were not allowed to bear
      weight. With the pattern of weightbearing documented, the formation of bone was
      monitored with serial radiographs and the bone forming activity was studied with
      histologic examination and immunohistochemical study of transforming growth
      factor-beta 1 expression. The results of the study showed that the bone formation
      as depicted by radiologic assessment of callus width and mineralized tissue was
      significantly better in the weightbearing group. Histologic study showed more
      bone formation qualitatively and quantitatively in the weightbearing group. This
      study confirmed the beneficial effect of weightbearing activity during
      distraction osteogenesis. Distraction provides pulsed form stimulation by tension
      stress across the osteotomy site and initiates osteogenesis while the compression
      stress exerted by the weightbearing is continuous in daily activities and
      enhances new bone formation. The clinical practice of early weightbearing during
      distraction osteogenesis should be reinforced.

PMID- 15021164
TI  - Pasteurized autologous bone graft in surgery for bone and soft tissue sarcoma.
AB  - For skeletal reconstruction in surgery for bone tumors, pasteurization of bone
      has been used with favorable results over autoclaving or boiling. Twenty-three
      patients with primary malignant bone tumors and two patients with soft tissue
      sarcoma invading bone reconstruction surgery with pasteurized autologous bone
      graft comprised the study group. There were 16 females and nine males, between 7
      and 77 years of age who were followed up for at least 3 years (mean, 52 months).
      The International Society of Limb Salvage graft evaluation method was used for
      evaluation of the radiographs. Fifteen patients (60%) had complete incorporation
      of the graft and eight patients (32%) had partial incorporation. Viability of the
      grafts was evaluated by bone scintigraphy. Of 22 patients evaluated, uptake was
      detected in 17 patients from approximately 6 months postoperatively after which
      it increased gradually. The functional results were assessed by the system of the
      Musculoskeletal Tumor Society, and the mean functional rating was 86%. Eighteen
      patients have been disease-free and seven have died of disease. Fracture (12%)
      and infection (20%) were the main complications. No local recurrence was
      detected. These results indicate that pasteurization of bone may be a useful
      option for reconstruction after resection of malignant bone tumors. The
      advantages of extracorporeal pasteurization include convenience of use, avoidance
      of intraspecies infection and allogenic reactions, and satisfactory bone
      remodeling.

PMID- 15021165
TI  - Implications of muscle design on surgical reconstruction of upper extremities.
AB  - The basic anatomic and physiologic properties of human upper extremity muscles
      have been elucidated using a novel intraoperative sarcomere length measuring
      device in conjunction with quantitative anatomic and biomechanic models of these
      same muscles. We reviewed the genesis of these studies which began with
      development of the optical tools, validation using animal models, and application
      to human upper extremity surgery. Human muscles have a remarkable degree of
      specialization, even among synergists. Mechanical properties of human tendons
      provide another source of specialization such that the muscle-tendon unit does
      not simply retain the properties of a muscle plus a tendon. The operating range
      of different muscles is also a method whereby the balance of the joint can be
      maintained in the face of altered moment arms and muscle forces. The derivation
      of these principles is explained along with their importance in surgical tendon
      transfers where one muscle substitutes function for another.

PMID- 15021167
TI  - How we prevent prevention of musculoskeletal disorders in the workplace.
AB  - American businesses face huge costs for work-related musculoskeletal pain. Work
      related musculoskeletal pain is not new or unique to the population of the United
      States. Many historic manifestations of workplace pain have been related to
      innovation and technology changes. Incidence rates and severity of symptoms have
      had an interesting relationship to the public concern and governmental decisions.
      In 1999, a National Academy of Sciences study found total costs to be more than
      US dollar 1 trillion per year and concluded that effective prevention of
      workplace pain through active intervention is not only possible, but results in a
      significant cost savings for the employer while reducing the disability
      experienced by the employee. Employers have been reluctant to embrace the
      benefits of workplace prevention for work-related musculoskeletal pain. The
      purpose of this review is to examine (1). what is know about prevention of work
      related musculoskeletal pain and workplace musculoskeletal disorders, (2). a
      brief description of several prevention preventing behaviors, (3). an analysis of
      how these preventing behaviors are maintained, and (4). suggestions on how to
      reverse these prevention preventing behaviors.

PMID- 15021166
TI  - Differential diagnosis of hip disease versus spine disease.
AB  - Many clinicians find it difficult to differentiate between symptoms caused by a
      spine disorder or a hip disorder. If surgery is indicated, the order in which
      these operations take place is an important factor in the patient's long-term
      outcome. A prospective evaluation and retrospective chart review of patients with
      lower extremity pain was performed at the principal investigator's clinic to
      determine which signs and symptoms best predict the primary source of pain in
      patients with hip and spine disorders. Medical histories, physical examinations,
      and diagnostic tests were done on 97 patients with lower extremity pain to
      determine which signs and symptoms were the best predictors of a primary source
      of the pain (a hip or a spine disorder). The presence of a limp, groin pain, or
      limited internal rotation of the hip significantly predicted the diagnosis of a
      disorder as originating primarily from the hip, as opposed to originating from
      the spine. Patients with a limp were seven times more likely to have a hip
      disorder only or a hip and spine disorder than a spine only disorder. Similarly,
      patients with groin pain or limited internal rotation of the hips were seven and
      14 times, respectively, more likely to have a hip disorder only or a hip and
      spine disorder than a spine only disorder. These variables are of primary
      importance to the clinician when making a differential diagnosis between hip
      disease and spine disease.

PMID- 15021168
TI  - Dissection of complex genetic disease: implications for orthopaedics.
AB  - The sequencing of the human genome is a landmark achievement in the history of
      mankind and, in conjunction with new developments in genetic technology, is
      paving the way to a new era in biomedical research. The complete anatomy of the
      human genome is almost available. Detailed dissection to identify genes
      contributing to clinical disorders is underway and these will shape our
      understanding and treatment of common clinical conditions. This already is
      beginning to make an impact in medicine in terms of understanding disease
      etiology, clinical heterogeneity, and differential diagnosis. Furthermore it is
      advancing risk prediction for susceptibility, severity and outcome, the
      identification of new targets for drug discovery, and pharmacogenetic profiling
      of patients to predict their response to individual therapies. Major advances in
      genetics are occurring and it is important for clinicians in all areas of
      medicine to be aware of genomic approaches to understanding human disease. This
      is particularly important regarding orthopaedic conditions where the underlying
      genetic components are being established. This article does not presume a
      detailed knowledge in genetics by the reader and is intended to provide an
      introduction and concise overview of the potential future applications of
      genetics with reference to some orthopaedic conditions.

PMID- 15021169
TI  - Proximal femur fractures: the pioneer era of 1818 to 1925.
AB  - The foundations of the modern era of the treatment of proximal femur fractures
      were laid by Cooper who in 1819 published the first therapeutically oriented
      classification of these fractures. During the following 100 years the clinical
      diagnostics were further developed; five classifications of proximal femur
      fractures were formulated including the terminology used until now
      (peritrochanteric, intertrochanteric), and surgical treatment was started. The
      first attempt at internal fixation of the proximal femur in the 1850s was by
      Langenbeck. His patient died of sepsis. The first successful internal fixation of
      proximal femur fractures was done in 1875 by Konig. At the beginning of the
      twentieth century the method of surgical treatment for proximal femur fractures
      was improved by Lambotte, Delbet, and Putti. However, the time was not ready yet
      for this method of treatment. Only technologic progress (stainless steel, new
      technology), the additional development of anesthesia and asepsis, improvement of
      xray apparatus, and introduction of the traction table created the prerequisites
      for successful gradation of Smith-Petersen's method from 1925 to 1931, and which
      a few years later was used worldwide.

PMID- 15021170
TI  - Hip pain in a 6-year-old girl.

PMID- 15021171
TI  - Relationship between motion velocity and rhythm [corrected].

PMID- 15021173
TI  - Gender differences in patellofemoral joint biomechanics.

PMID- 15021175
TI  - C-reactive protein in patients who had operative fracture treatment.

PMID- 15021178
TI  - Chronic obstructive pulmonary disease in women: exploring gender differences.
AB  - PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a major cause
      of morbidity and mortality throughout the world. This major public health threat
      is ranked twelfth as a worldwide burden of disease and is projected to rank fifth
      by the year 2020 as a cause of lost quantity and quality of life. The impact of
      this disease in women is significantly understudied but the evidence that does
      exist reveals potentially substantial gender differences in the susceptibility
      to, severity of, and response to management of COPD. RECENT FINDINGS: The best
      known risk factor for the development of COPD is tobacco smoking. While smoking
      rates in women have largely stabilized in developed countries, the rates are
      continuing to climb in developing countries. While it is not clear whether women
      are more susceptible to the toxic effects of cigarette smoke than men, it is
      known that the incidence and prevalence of COPD will continue to climb as more
      women smoke. Other known risk factors for the development of COPD include air
      pollution, infections, occupational exposures, and genetic factors. Air
      pollution, particularly fine particulate indoor air pollution from biomass fuels
      disproportionately affects women. Infections such as human immunodeficiency virus
      (HIV) and tuberculosis (TB) disproportionately affect vulnerable populations such
      as poor women and occupational exposures to various dusts and toxins are often
      gender specific. Genetic factors are still being explored but there seems a
      preponderance of women who are affected by early-onset and non-smoking related
      COPD. Women with COPD also seem to be underdiagnosed by physicians and may have
      different responses to medical treatment, smoking cessation interventions, and
      pulmonary rehabilitation programs. SUMMARY: Chronic obstructive pulmonary disease
      in women is an understudied subject but is gaining attention as a significant
      public health threat. In developed countries, efforts at preventing the
      initiation of tobacco smoking and targeting smoking cessation programs in women
      are needed. In developing countries, efforts to promote cleaner fuels, improved
      stoves, better home ventilation, reduce toxic dust and fume exposures, combat
      infectious diseases such as TB and HIV, and improve nutrition are all ways in
      which the lung health of women can be improved.

PMID- 15021179
TI  - Sleep and chronic obstructive pulmonary disease.
AB  - PURPOSE OF REVIEW: Sleep disorders are pervasive in patients with chronic
      obstructive pulmonary disease (COPD). The patient with COPD is especially
      vulnerable to sleep-induced gas exchange aberrations. Most sleep disturbances
      affect the quality of life and some potentially affect survival in these
      patients. These issues impact treatment of these patients. RECENT FINDINGS:
      Insomnia is very common in COPD but might respond to inhaled anticholinergic
      agents. The use of hypnotics in the hypercapnic patient with severe COPD might be
      dangerous. The incidence of sleep apnea in COPD patients is allegedly very high,
      but recent studies suggest this association to be artifactual. Nocturnal oxygen
      desaturation, which is common in these patients, occurs even in mild COPD. This
      clinical complication might reflect sleep-disordered breathing or REM sleep
      related hypoventilation. We need cost-effective and reliable methods to help
      distinguish between these causes without routinely resorting to formal
      polysomnography. SUMMARY: Development of sound clinical algorithms to address
      this clinical dilemma is indeed a focus for future research. Some of these
      patients might require continuous positive pressure therapy, whereas others might
      need long-term oxygen therapy. Although oxygen therapy in COPD patients with only
      mild hypoxemia and nocturnal desaturation has not uniformly been shown to be
      beneficial, it is perhaps too soon to abandon this important clinical
      intervention in these patients.

PMID- 15021180
TI  - Inhaled corticosteroids in chronic obstructive pulmonary disease: is there a long
      term benefit?
AB  - PURPOSE OF REVIEW: The use of inhaled corticosteroids is one of the most
      controversial issues in COPD pharmacotherapy. Experts disagree about the benefits
      and harms of ICS for patients with COPD, yet a majority of patients with COPD are
      being treated with inhaled corticosteroids. This is a review of the most recent
      literature on this subject. RECENT FINDINGS: Evidence suggests that ICS, with or
      without a long-acting beta2-agonist, are cost-effective in reducing exacerbation
      rates and retarding the decline in health status of COPD patients, although they
      do not significantly modify the rate of decline in FEV1 or change mortality. This
      discrepancy is likely related to the differences in pathology of COPD when
      compared with asthma. Evidence also suggests that ICS may be safe regarding the
      effects on adrenals and bone mineral density. We have yet to identify reliable
      criteria for predicting a response to ICS in COPD, but it has become clear that
      in mild disease, no beneficial effect has been demonstrated. SUMMARY: In contrast
      to asthma, inhaled corticosteroids should not be used as a first-line medication
      in patients with COPD. Identification of patients with COPD who might benefit
      from long-term treatment with ICS remains paramount.

PMID- 15021181
TI  - Improving health-related quality of life in chronic obstructive pulmonary
      disease.
AB  - PURPOSE OF REVIEW: Most current treatments for chronic obstructive pulmonary
      disease (COPD) have been unable to improve survival or arrest decline in lung
      function. This reality highlights the importance of patient-focused outcomes that
      address symptom relief, functional status, and overall health-related quality ov
      life (HRQOL). Measures of HRQOL can complement established physiologic outcomes
      that have been traditionally used. RECENT FINDINGS: There are several generic and
      disease-specific instruments that can be used to measure HRQOL, each
      incorporating various aspects of physical, psychological, and social function.
      Basic concepts regarding these instruments are presented. Recent studies suggest
      that HRQOL is an important measure of prognosis and healthcare resource
      utilization in COPD patients. SUMMARY: An increasing number of studies now
      incorporate HRQOL as an outcome measure. Interventions that have shown a positive
      effect on some or all components of HRQOL, including inhaled corticosteroids,
      inhaled bronchodilators, opioids, oxygen therapy, pulmonary rehabilitation,
      implementation of a disease-specific self-management program, and lung volume
      reduction surgery are discussed in this review.

PMID- 15021182
TI  - Lung-volume reduction surgery for severe emphysema: appraisal of its current
      status.
AB  - PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is the fourth
      leading cause of death in the United States, as well as a major cause of
      disability. In its end stages, its inexorable progression results in profound
      suffering for those afflicted. Medical therapy has proven largely ineffective in
      improving dyspnea and functional status, and does not alter pulmonary function.
      Over the past decade, lung-volume reduction surgery (LVRS) has been proposed as a
      palliative treatment for certain subgroups of COPD patients with emphysema, but
      initial enthusiasm over its application had been confounded by uncertainty about
      the potential cost and morbidities associated with LVRS, as well as durability of
      its beneficial effects. Longer-term follow-up data of initial uncontrolled trials
      along with several landmark controlled trials have recently been published,
      offering insight as to the "proper" place of LVRS in the treatment of these
      unfortunate patients. This review will summarize and offer perspective on these
      recent findings, as well as offer thoughts on recent refinements in preoperative
      imaging assessment, and pioneering efforts in less invasive bronchoscopic lung
      volume reduction that should further aid the clinician in defining who should
      benefit from this treatment approach. RECENT FINDINGS: Lung-volume reduction
      surgery can result in demonstrable benefit in selected subgroups of COPD patients
      with upper-lobe disease and poor exercise capacity before surgery with
      improvements in six-minute walk distances, forced expiratory volume in the first
      second (FEV1), dyspnea scores and quality-of-life scores, and decreases in
      residual volume (RV) as well as the need for supplemental oxygen. Patients with
      FEV1 less than 20% of predicted and either homogeneous emphysema or diffusing
      capacities (DLCO) less than 20% of predicted do not benefit from LVRS and have
      unacceptable peri-operative mortalities. Costs to society are high, with a cost
      of $98,000 per quality-adjusted-life year gained over a 2-year period if only
      those with upper-lobe disease are offered the procedure. SUMMARY: Lung-volume
      reduction surgery can improve both objective and subjective measures of lung
      performance in properly selected COPD patients. Durable effects of up to 5 years
      have now been demonstrated. As costs (both fiscal and emotional) of such an
      approach are high, refinement in patient selection remains a current goal in the
      surgical approach to COPD.

PMID- 15021183
TI  - Bronchiolitis obliterans: an update.
AB  - PURPOSE OF REVIEW: Bronchiolitis obliterans (BO) occurs in both post-lung
      transplant and nontransplant-related individuals, and is characterized by mainly
      irreversible airflow obstruction that is often ultimately progressive. RECENT
      FINDINGS: While post-lung transplant BO is a major cause of lung allograft
      dysfunction, and hence is better characterized than nontransplant-related BO, it
      is likely that many similarities in pathogenesis and treatment apply to both
      categories. SUMMARY: Optimal management for BO remains to be established, and the
      role of retransplantation in this disease requires further consensus.
      Minimization of risk factors for BO and earlier detection in the form of
      methacholine challenge testing and HRCT scans of the chest amongst other forms of
      detection, may help in the stabilization and possible resolution of early BO.

PMID- 15021186
TI  - Bibliography. Current world literature. Obstructive,occupational, and
      environmental diseases.

PMID- 15021184
TI  - Advances in methods used in evaluation of occupational asthma.
AB  - PURPOSE OF REVIEW: Diagnosing occupational asthma (OA) is a complex undertaking,
      the primary goal of which is to demonstrate a causal relation between exposure to
      a specific agent encountered at work and asthmatic responses. Recent development
      or refinement of diagnostic tools may improve the diagnostic accuracy, which may
      have important economic and social consequences for both employers and workers.
      RECENT FINDINGS: Although specific inhalation challenge (SIC) testing is the gold
      standard for diagnosis of OA, these tests are not widely available in many
      countries. Thus, new less invasive techniques used in the measurement of airway
      inflammation, such as exhaled nitric oxide and induced sputum are highlighted as
      are recent developments in both in vivo and in vitro immunologic testing.
      SUMMARY: Although new perspectives are being evaluated, the diagnosis of
      occupational asthma still relies mostly on specific inhalation challenge. Further
      studies are required to confirm the utility of these new techniques in the
      diagnosis of OA.

PMID- 15021185
TI  - Occupational asthma in greenhouse workers.
AB  - PURPOSE OF REVIEW: A prevalence of asthma over 5% has been reported in flower
      farmers,and work inside greenhouses has emerged as an additional risk factor.
      Workplace determinants behind this high prevalence has been examined, and a
      prevalence of sensitization to workplace allergens over 30% has been reported
      being pollens, moulds, and Tetranychus urticae allergens the main sensitizers.
      Bronchial challenge tests in the workplace have demonstrated occupational asthma
      in more than 20% of the sensitized greenhouse growers. RECENT FINDINGS: Air
      contamination inside greenhouses is mainly related to moulds, and is facilitated
      by the high indoor temperature and humidity. Cladosporium, Penicillium,
      Aspergillus, and Alternaria and a wide range of flower pollens are able to
      sensitize the greenhouse worker and cause occupational asthma. Tetranychus
      urticae have allergens shared with other mites, but the low prevalence of cross
      sensitization between them confirm that Tetranychus urticae contains species
      specific allergens that may cause respiratory symptoms. Additionally, working
      inside greenhouses has been related to an increase in the prevalence of chronic
      bronchitis in nonsmokers. SUMMARY: The cultivation of greenhouse crops may cause
      occupational asthma through sensitization to workplace pollens, moulds, and
      Tetranychus urticae allergens. In greenhouse flower growers, skin testing
      identifies sensitization to these allergens in one third of the growers, and more
      than one fifth of the sensitized workers will develop occupational asthma.
      Greenhouse work has also been related to chronic bronchitis in nonsmokers,
      suggesting a causal effect of greenhouse air contaminants on this disease as
      well.

PMID- 15021189
TI  - Regulation of energy balance.

PMID- 15021191
TI  - Continuous positive airway pressure: current controversies.
AB  - PURPOSE OF REVIEW: Continuous positive airway pressure is increasingly being used
      in the care of premature infants. The purpose of this review is to highlight the
      current controversies in the use of neonatal continuous positive airway pressure.
      RECENT FINDINGS: This review explores information about the devices available for
      delivering continuous positive airway pressure and the pressures that can be
      used. It also investigates the controversial issues of using continuous positive
      airway pressure during resuscitation of premature infants and whether infants who
      are going to be managed on continuous positive airway pressure should be
      intubated and given surfactant before continuous positive airway pressure is
      started. It reviews the use of continuous positive airway pressure and the
      prevention of chronic lung disease and the use of nasal intermittent positive
      pressure ventilation and the difficult area of weaning from continuous positive
      airway pressure. SUMMARY: Existing evidence suggests that short binasal prongs
      are most effective, nasal intermittent positive pressure ventilation is a useful
      way of augmenting neonatal continuous positive airway pressure and that very
      premature infants can be managed with neonatal continuous positive airway
      pressure in the delivery room as part of the resuscitation. Further research is
      required to determine whether important outcomes are improved with the use of
      nasal continuous positive airway pressure rather than endotracheal intubation
      and, if so, whether surfactant should be given to infants so managed. Definition
      of optimal levels of continuous positive airway pressure for infants at varying
      stages of their disease also requires further research.

PMID- 15021192
TI  - Patency of the ductus arteriosus in the premature infant: is it pathologic?
      Should it be treated?
AB  - PURPOSE OF REVIEW: The ductus arteriosus is a vessel that connects the pulmonary
      artery to the aorta and provides a pulmonary-to-systemic diversion during fetal
      life. In the vast majority of infants, the ductus arteriosus closes by 3 days of
      life. In some infants, especially preterm infants with lung disease, there is
      delayed closure of the ductus arteriosus. There has been controversy as to
      whether or when the ductus arteriosus should be closed by either pharmacologic or
      surgical methods. RECENT FINDINGS: There have been several epidemiologic studies
      describing an association between a patent ductus arteriosus and the development
      of morbidities, such as chronic lung disease. These associations have suggested
      to some that a causal relationship exists between patency of the ductus
      arteriosus and chronic lung disease and other morbidities. However, recent
      metaanalyses of randomized, controlled trials of the use of indomethacin for the
      prevention and treatment of the patent ductus arteriosus have not documented a
      decrease in the incidence of these morbidities after treatment, despite success
      in closure of the patent ductus arteriosus. SUMMARY: In preterm infants, patency
      of the ductus arteriosus may represent a normal physiologic adaptation to allow
      shunting from either systemic-to-pulmonary circulation (eg, in the first day of
      life) or from pulmonary-to-systemic circulation (eg, in the presence of severe
      lung disease). Therapies designed to close the ductus arteriosus are
      contraindicated in some settings and should not be considered a standard of care
      at any time until these therapies are proven to decrease long-term clinical
      morbidities in randomized, placebo-controlled trials.

PMID- 15021193
TI  - Fluid and electrolyte therapy and chronic lung disease.
AB  - PURPOSE OF REVIEW: To evaluate the role of fluid and electrolyte therapy in the
      pathogenesis of chronic lung disease. RECENT FINDINGS: There have been no new
      studies since 2000, and there are minimal data addressing this issue specifically
      in infants at highest risk of chronic lung disease (ie, extremely low birth
      weight infants). Most observational studies demonstrate a significant association
      between increased fluid intake or differences in measures of changes in total
      body water balance in the first week of life and chronic lung disease. However, a
      metaanalysis of three randomized, controlled clinical trials did not reveal a
      significant increase in the risk of chronic lung disease with higher fluid
      intakes. The results of two randomized, controlled trials of different sodium
      intakes were conflicting regarding whether increased intake led to an increased
      prevalence of chronic lung disease. SUMMARY: The evidence is insufficient to
      conclude that fluid and electrolyte therapy plays a role in the pathogenesis of
      chronic lung disease. Even if fluid and electrolyte therapy does play a small
      role, the data are insufficient to help with decisions about what fluid and
      electrolyte intake in an individual infant in a specific clinical setting might
      reduce the risk of chronic lung disease. However, net negative water and sodium
      balances and the resultant contraction of the extracellular space are probably
      physiologic in preterm infants in the first week of life and evidence suggests
      that a positive water and sodium balance and expansion of the extracellular space
      during this period increase morbidity. It is not clear what degree of contraction
      is appropriate or whether varying degrees of contraction of the extracellular
      space alter morbidity.

PMID- 15021194
TI  - Neonatal resuscitation: raising the bar.
AB  - PURPOSE OF REVIEW: To provide an overview of neonatal resuscitation practices
      with an emphasis on interventions that are not currently accepted or adapted into
      existing resuscitation guidelines. RECENT FINDINGS: Current resuscitation
      guidelines do not contain specific guidelines for the approach to the extremely
      low birth weight infant. The differences in environment and management between
      the neonatal ICU and delivery room are striking and are magnified in the
      resuscitation of extremely low birth weight infants for whom maintenance of a
      neutral thermal environment is essential. The use of a polyethylene wrap applied
      at delivery has been shown to reduce the occurrence of hypothermia and decrease
      mortality. There is substantial evidence that term and near-term newborn infants
      can be effectively resuscitated with room air, and recent follow-up studies have
      demonstrated that this approach is not associated with increased significant
      differences in neurologic handicap, somatic growth, or developmental milestones
      when compared with the use of 100% oxygen. The safety and potential benefits of
      this approach require prospective evaluation in the premature and especially
      extremely low birth weight infant. There is preexisting evidence that
      demonstrates that the use of prolonged inflations and t-piece resuscitators may
      be advantageous during resuscitation, but not all guidelines support these
      interventions. Although regulated continuous positive airway pressure, pulse
      oximeters, and blenders are routinely used once an infant is admitted to the
      neonatal ICU, none of these interventions is recommended in the delivery area.
      Although prospective studies have demonstrated that the use of colorimetric CO2
      detectors significantly decreases the time to recognize misplaced endotracheal
      tubes placed during resuscitation, their use is not required by current
      guidelines. The duration of an intubation attempt during resuscitation had never
      been prospectively evaluated, and our recent findings suggest that a limit of 30
      seconds is well tolerated and provides adequate time for a successful attempt.
      SUMMARY: There is significant potential for improvement in current resuscitation
      environments and interventions that will only be realized through further
      prospective research.

PMID- 15021196
TI  - Recent advances in congenital nephrotic syndrome.
AB  - PURPOSE OF REVIEW: This review provides a concise update of the most recent
      literature related to the diagnosis and care of patients with congenital
      nephrotic syndrome. This topic is of particular interest in light of the rapidly
      growing body of literature regarding mutations of proteins such as nephrin and
      podocin that are expressed at or near the podocyte slit diaphragm. RECENT
      FINDINGS: The phenotypic variance of patients with congenital nephrotic syndrome
      with nephrin and podocin mutations resulting from triallelic mutations represents
      an important advance in our understanding of the effect of multiple genetic
      mutations on clinical disease expression. Clinically, the management of patients
      with unilateral nephrectomy, rather than the classic bilateral nephrectomy,
      represents an efficacious alternative management strategy and may impart better
      chances of graft survival by allowing later transplantation. Identification of a
      subset of patients with congenital nephrotic syndrome at increased risk of
      recurrence who also have antinephrin antibodies may enhance our understanding of
      recurrent disease in congenital nephrotic syndrome after transplantation.
      SUMMARY: Exciting recent findings in the genotypic/phenotypic correlations of
      patients with congenital nephrotic syndrome may not only modify our understanding
      of this disease but may also help to revolutionize our understanding of human
      genetics. Promising outcomes with unilateral nephrectomy in patients with
      congenital nephrotic syndrome have permitted transplantation to be delayed and
      may potentially decrease the risk of complications. New findings regarding
      recurrence of nephrotic syndrome in patients with congenital nephrotic syndrome
      after transplantation may lead to improved survival in future renal
      transplantations.

PMID- 15021197
TI  - Polycystic kidney disease: the cilium as a common pathway in cystogenesis.
AB  - PURPOSE OF REVIEW: Polycystic kidney disease (PKD) is characterized by the
      formation and progressive expansion of cysts in the kidney, frequently leading to
      renal failure. The purpose of this review is to summarize recent studies that
      have provided insight into the mechanisms of cytogenesis. RECENT FINDINGS:
      Mutations in cilia-associated proteins have been identified in a number of
      diseases associated with cyst formation, including autosomal dominant and
      recessive PKD, and nephronophthisis. The primary cilia are finger-like
      projections on the surface of all kidney cells, except acid-base transporting
      intercalated cells in the collecting duct. Cilia have been proposed to serve as
      mechano- or chemosensors, responding to and interacting with the
      microenvironment. Abnormal cilia structure or function or both may lead to
      abnormalities in cell proliferation and tubular differentiation, ultimately
      leading to cyst formation. In addition to ciliary dysfunction, other potential
      mechanisms of cystogenesis need to be explored. SUMMARY: Our understanding of the
      importance of the primary cilium in renal cyst formation may guide potential
      therapy for cystic kidney diseases by targeting the structural and functional
      integrity of the cilia.

PMID- 15021198
TI  - Familial hematuria due to type IV collagen mutations: Alport syndrome and thin
      basement membrane nephropathy.
AB  - PURPOSE OF REVIEW: Recent molecular genetic studies have shown that mutations in
      type IV collagen account for a significant proportion of patients with persistent
      glomerular hematuria. This review will discuss the implications of these findings
      for the diagnosis and management of persistent glomerular hematuria. RECENT
      FINDINGS: Type IV collagen mutations are associated with a continuum of disease
      severity. Heterozygous mutations typically cause isolated, nonprogressive
      hematuria. Mutations in both alleles of the autosomal type IV collagen genes, or
      hemizygous mutations in the X-linked gene encoding the alpha 5 chain of type IV
      collagen, result in progressive renal disease that is often associated with
      sensorineural deafness (Alport syndrome). Animal models of Alport syndrome have
      begun to provide insights into the pathogenesis of end-stage renal disease in
      Alport syndrome, with potentially important implications for therapy. SUMMARY:
      Recognition that glomerular hematuria frequently has a genetic basis is important
      for accurate genetic counseling, early identification of individuals at risk for
      end-stage renal disease development, and institution of therapies to delay the
      onset of ESRD.

PMID- 15021199
TI  - Inherited Na transport disorders: the taming of the syndromes.
AB  - PURPOSE OF REVIEW: The study of inherited renal sodium (Na) transport disorders
      has greatly benefited from the use of new molecular biology research tools. This
      review discusses the recent findings that have expanded our knowledge and may
      impact clinical decision-making. RECENT FINDINGS: The genetic and molecular
      biology diagnostic tools have to a large extent validated conclusions drawn from
      physiologic studies that documented suppressed or enhanced Na transport in
      specific distal nephron segments in various disorders. However, many surprises
      were also encountered. In several conditions, no mutation in the Na transporter
      itself was found despite apparent dysfunction of the transporter. Further search
      has led to discovery of additional mechanisms. Some involve mutations in other
      transporters, especially potassium (K) and chloride (Cl) channels, which
      secondarily affect function of the Na transporter by altering electrochemical
      gradients across the cell membrane. Examples include certain types of Bartter
      syndrome. In other patients, search for mechanism has led to discovery of novel
      physiologic regulatory pathways that, if abnormal, will lead to up- or
      downregulation of an Na transporter. Examples include some types of Bartter
      syndrome and Gordon syndrome. Genetic diagnosis has also revealed hitherto
      unexplained phenotypic heterogeneity between patients carrying the same mutation,
      implying a contributory role for other factors. SUMMARY: Genetic and molecular
      diagnosis will have an expanding role in the understanding and management of the
      Na transport disorders. Predicting prognosis and inheritance pattern, as well as
      treatment plans will in the future be based on genetic diagnosis.

PMID- 15021200
TI  - The molecular basis of kidney stones.
AB  - PURPOSE OF REVIEW: To emphasize an exploration of mechanisms of kidney stone
      disease based on a molecular understanding of excess urinary excretions of
      calcium, oxalate, cystine, and uric acid. RECENT FINDINGS: Hypercalciuria is
      discussed relative to mutations in the renal chloride genes CLCN5 and CLCNKB, WNK
      kinases, ATPB61, and NPT2. Hyperoxaluria is discussed relative to mutations in
      AGXT and GRHPR. Cystinuria is discussed relative to mutations in SLC3A1 and
      SLC7A9. Hyperuricosuria is discussed with novel gene findings, and
      hyperxanthinuria with new findings in XDH. SUMMARY: An enhanced understanding of
      the diagnosis, course, and prognosis for genetic causes of kidney stone diseases
      has been made available to the clinician caring for patients with kidney stones
      and to the scientist interested in their cause, as a result of molecular
      breakthroughs in the kidney handling of normal urinary constituents. We look
      forward to a new era of the therapeutics of kidney stones based on such advances.

PMID- 15021201
TI  - Distal renal tubular acidosis.
AB  - PURPOSE OF REVIEW: Research in the past several years has led to the
      understanding of numerous genetic mutations that lead to inheritable forms of
      distal renal tubular acidosis (dRTA). Most of these mutations affect the
      physiology of the A-intercalated cells of the renal cortical collecting duct.
      These include mutations of genes encoding carbonic anhydrase II, kidney anion
      exchanger 1, and different subunits of the H+-ATPase proton pump. Genetic defects
      in any one of these components may impair renal acidification and thereby result
      in persistent acidosis, failure to thrive, and nephrocalcinosis. RECENT FINDINGS:
      The present review provides a summary of the most recently identified genetic
      mutations resulting in a dRTA phenotype and, when possible, describes a
      mechanism. Most causes of dRTA are due to loss of function or inappropriate
      targeting of transporters. SUMMARY: The collaboration of clinicians, geneticists,
      and renal physiologists has enabled us to better understand at the cellular level
      the different mechanisms leading to dRTA. Such information should lead to earlier
      diagnosis and treatment, thereby minimizing the irreversible complications
      affecting patients with this or similar diseases.

PMID- 15021202
TI  - Therapeutics and toxicology issues associated with the agitated, violent, or
      psychotic pediatric patient.

PMID- 15021203
TI  - Chemical restraints for the agitated, violent, or psychotic pediatric patient in
      the emergency department: controversies and recommendations.
AB  - PURPOSE OF REVIEW: Chemical restraint in the pediatric patient is an evolving
      clinical practice. Although a rare occurrence, chemically restraining a child may
      be necessary for the child's safety, healthcare worker's safety, and to expedite
      the medical evaluation. The purpose of this manuscript to review the definition
      and indications for chemical restraints, specific classes of drugs used for
      chemical restraints, and the legal implications associated with chemical
      restraints. RECENT FINDINGS: Three classes of drugs will be reviewed:
      benzodiazepines, neuroleptics, and atypical antipsychotics, including side
      effects, dosages, and routes of administration. There are controversies
      surrounding some of these drugs. Very few recent studies have focused this topic
      on the pediatric patient. A recently published practice parameter will be
      reviewed that addresses the prevention and management of aggressive behavior in
      children and adolescents. In addition, specific studies looking at different
      drugs, particularly the newer atypical antipsychotics, will be reviewed.
      Literature discussing the controversies regarding droperidol usage in the
      emergency department will also be highlighted. SUMMARY: The differential
      diagnosis for the agitated, violent, or psychotic patient is extensive and must
      be taken into consideration when deciding to use chemical restraints. When the
      decision is made to use chemical restraints, healthcare workers should be aware
      of the pharmacologic options as well as the complications associated with the
      agents.

PMID- 15021204
TI  - Drug-induced rhabdomyolysis.
AB  - PURPOSE OF REVIEW: Drug-induced rhabdomyolysis is a common syndrome that is
      complex and potentially life threatening. This article reviews the
      pathophysiology, clinical presentations, and common compounds that cause drug
      induced rhabdomyolysis. RECENT FINDINGS: The list of drugs and inciting agents
      that cause rhabdomyolysis is quite extensive. Rhabdomyolysis is defined as
      skeletal muscle injury that leads to the lysis of muscle cells and the leakage of
      myocyte contents into the extracellular compartments. The presenting clinical
      features are myalgias, myoglobinuria, and an elevated serum creatine kinase.
      There have been several case reports in the literature involving some common
      pediatric drugs that are associated with rhabdomyolysis. Diphenhydramine,
      Ecstasy, and baclofen have recently been implicated as the etiology of drug
      induced rhabdomyolysis in several pediatric patients. Alkalinization of the urine
      is a controversial treatment of drug-induced rhabdomyolysis and has proven to be
      beneficial in some patients. SUMMARY: A high index of suspicion, early
      recognition, and adequate treatment will result in an excellent prognosis of drug
      induced rhabdomyolysis.

PMID- 15021205
TI  - Management of drug-induced hyperthermia.
AB  - PURPOSE OF REVIEW: To review the current literature describing drug-induced
      hyperthermia and its treatment. Specifically, five syndromes will be discussed:
      malignant hyperthermia, neuroleptic malignant syndrome, anticholinergic
      poisoning, sympathomimetic poisoning, and serotonin syndrome. RECENT FINDINGS:
      The most recent findings in the literature are the recognition of previously
      undescribed drugs or drug combinations that have lead to hyperthermia. Recent
      literature also attests to the potential morbidity and mortality of drug-induced
      hyperthermia. SUMMARY: Although the recognition of causative agents is
      increasing, the treatment of drug-induced hyperthermia remains unchanged and
      continues to be primarily supportive.

PMID- 15021207
TI  - Update on attention-deficit/hyperactivity disorder.
AB  - PURPOSE OF REVIEW: Attention-deficit/hyperactivity disorder (ADHD) is present in
      3% to 10% of children in the United States. Children with ADHD can have academic
      impairments, social dysfunction, and poor self-esteem. There is also a higher
      risk of both cigarette smoking and substance abuse. Given this, the importance of
      treatment for ADHD needs to be underscored. This article will briefly review the
      diagnosis, etiology, and treatment of ADHD, with particular focus on nonstimulant
      medication and alternative treatment modalities. RECENT FINDINGS: Recent evidence
      suggests that the overall rate of medication treatment for ADHD has been
      increasing, with over 2 million children being treated with stimulants in 1997.
      With this increase, controversy has arisen over the possible association of
      stimulants with growth suppression. In addition, estimates indicate that as many
      as 30% of children with ADHD either do not respond to stimulant treatment or
      cannot tolerate the treatment secondary to side effects. This has lead to the
      consideration of treatment with both nonstimulant medications as well as
      alternative therapies, including diet, iron supplementation, herbal medications,
      and neurofeedback. Considering the various treatment options now available for
      ADHD, along with the complexity of the condition, clinical practice guidelines
      are emerging for the treatment of ADHD and will be discussed. SUMMARY: ADHD
      continues to be a serious health problem. Adequate treatment is needed to avoid
      academic impairments, social dysfunction, and poor self-esteem. This treatment
      includes consideration of stimulant medication, nonstimulant medication, as well
      as alternative therapies. The child with ADHD is likely better served with a
      mutimodal treatment plan, including medication, parent/school counseling, and
      behavioral therapy. Implementing an evidenced based algorithm for the treatment
      of ADHD may prove to be most effective.

PMID- 15021209
TI  - Update on sudden infant death syndrome.
AB  - PURPOSE OF REVIEW: With the introduction of the Back to Sleep campaign by the
      American Academy of Pediatrics in 1992, the incidence of Sudden infant death
      syndrome has decreased by almost 50%. Despite this success, SIDS continues to be
      the most common cause of unexplained infant death in Western countries. This
      article will briefly review the definition, etiology, and risk factors of SIDS.
      Attention will then focus on ways to target specific associated risk factors and
      at risk populations to promote a continued downward trend in the number of SIDS
      deaths. RECENT FINDINGS: Recent literature in SIDS research has focused on
      identifying infants at continued risk for SIDS. Children attending child care
      centers have an increased risk for SIDS, which is of particular concern as the
      number of infants in child care continues to rise. The reasons for this, along
      with strategies to decrease this risk, will be reviewed. In addition, the SIDS
      rate among black infants continues to be more than twice that of white infants. A
      review of the reasons for this disparity and ways to intervene through targeted
      campaigns will be discussed. Recent data has also suggested that the prevention
      of SIDS should not be an indication for use of home cardiorespiratory monitoring.
      The use of home monitoring may be warranted for some infants and will be
      reviewed. SUMMARY: Our jobs as pediatricians should be to ensure that the
      incidence of SIDS continues to decline. This can be done through parent education
      at each and every well child visit, lobbying to enforce state law to implement
      SIDS education campaigns for child care centers and within African-American
      communities, and continued review of the most current literature in SIDS research
      to keep ourselves current and well informed.

PMID- 15021211
TI  - Current world literature. Neonatology and perinatology.

PMID- 15021210
TI  - An update on child abuse and neglect.
AB  - PURPOSE OF REVIEW: Nonaccidental trauma and neglect continue to be major problems
      for children, families, and the providers who care for them. Whereas prevention
      is the key to ending child abuse and neglect, diagnosis and treatment continue to
      be the mainstays of practice. This article will briefly review the epidemiology,
      diagnosis, sequelae, and prevention of abuse and neglect in today's world. RECENT
      FINDINGS: The latest statistics estimate that more than 900000 children are
      victims of child maltreatment. Abuse occurs at all ages but is most common in
      younger children. Child abuse may manifest as skin injuries, skeletal trauma,
      head injury, or many other forms. Information on abusive head trauma has been
      published in large amounts in the past year and is reviewed in further depth. The
      long-term consequences, the keys to prevention, and the role for pediatric
      providers are also reviewed. SUMMARY: Whereas great strides have been made in
      diagnosing and treating child abuse, our work has been cut out for us in
      preventing child abuse. Pediatric clinicians must continue to screen patients and
      families, recognize signs and symptoms of abuse and neglect, and find time to
      advocate for home visits, early intervention programs, and education on this very
      important topic.

PMID- 15021214
TI  - The dawn of genetic testing for glaucoma.
AB  - PURPOSE OF REVIEW: To review recent trends in genetic testing in medicine as they
      apply to newly evolving tests for patients with glaucoma. RECENT FINDINGS: The
      utilization of powerful molecular methods for genetic testing is now entering its
      early stages in the practice of medicine in general, and with testing, many
      issues, both medical and societal, have been raised. Only recently has testing
      for a disease risk factor in primary open angle glaucoma (POAG) become available.
      It is known that some mutations in the gene myocilin are associated with POAG.
      MYOC.mt1 is a relatively common promoter region variant in the myocilin gene for
      which there is a commercially available test. Some investigators have found that
      MYOC.mt1 may increase disease severity in patients with POAG, whereas others have
      not found this association. There is a need for further testing for the role of
      the MYOC.mt1 variant in the pathogenesis of POAG. SUMMARY: Genetic testing for
      glaucoma holds great promise. Currently available tests for disease-related tests
      in patients with glaucoma or at risk for this disease remain controversial.

PMID- 15021215
TI  - The immune system and glaucoma.
AB  - PURPOSE OF REVIEW: Compelling evidence obtained from studies over the last decade
      strongly suggests the involvement of immune system regulation in cell fate
      decisions in glia and retinal ganglion cells that lead to glaucomatous optic
      nerve degeneration. RECENT FINDINGS: Recent studies reveal seemingly conflicting
      roles of the immune system in glaucomatous optic nerve degeneration. T cells
      directed against specific antigens may have a beneficial effect to protect
      neurons from the consequences of axonal injury. However, the immune response in
      glaucoma also has the capacity to cause neuronal injury. The balance between the
      benefit of protective immunity and the risk of inducing an autoimmune
      neurodegenerative disease is critical. The immunoregulatory function of glial
      cells and the presence of tissue stress seem to be important factors that
      determine the balance between diverse roles of the immune system in glaucomatous
      optic nerve degeneration. Thus, the net effect of immunoregulation may be either
      neuroprotective or neurodestructive. SUMMARY: Despite the neuroprotective
      features of the immune system, an autoimmune component, resulting from a failure
      to properly control aberrant, stress-induced immune response, likely accompanies
      the progression of neurodegeneration in glaucoma in some patients. A better
      understanding of the diverse roles of the immune system in all forms of
      glaucomatous optic nerve degeneration will facilitate the development of
      effective neuroprotective strategies in glaucoma. The basis of a sustainable
      neuroprotective strategy is to harness immunoregulation of glial and retinal
      ganglion cell fate to maximize beneficial effects, while minimizing negative
      sequelae, for therapeutic gain.

PMID- 15021216
TI  - Corneal thickness in glaucoma screening, diagnosis, and management.
AB  - PURPOSE OF REVIEW: Variability in central corneal thickness (CCT) is a potent
      confounder of most tonometry techniques, especially Goldmann applanation
      tonometry. The Ocular Hypertension Treatment Study (OHTS) provided important
      information regarding predictive factors for the eventual development of glaucoma
      in patients at risk of the disease. Among the most striking of the OHTS' findings
      was that CCT was a powerful predictor of glaucoma risk. In this review, studies
      subsequent to the OHTS report will be reviewed and placed in the context of what
      is known about CCT and its relation with tonometry and glaucoma risk. RECENT
      FINDINGS: Several well-designed studies have since expanded on this hypothesis,
      confirming that CCT bears an inverse relation with the risk of developing
      glaucoma damage. Other investigators have confirmed the presence of racial
      differences in CCT and pilot studies suggest that CCT may vary systematically in
      different forms of glaucoma. SUMMARY: The absence of a widely-accepted algorithm
      for the correction of IOP measurements should not prevent the widespread adoption
      of pachymetry as part of the comprehensive eye exam, as knowledge of an
      individual's CCT provides valuable information about their glaucoma risk.

PMID- 15021217
TI  - The role of diurnal pressure measurements in the management of open angle
      glaucoma.
AB  - PURPOSE OF REVIEW: The measurement of intraocular pressure (IOP) is essential in
      the diagnosis and management of open-angle glaucoma, but a single measurement in
      the ophthalmologist's office may or may not reflect what the IOP is at other
      times of the day or night. It is well documented that the range of the daily
      fluctuations in IOP is greater in patients with glaucoma than in normal
      individuals, and a report by Asrani et al. suggested that the range of the
      diurnal fluctuation may be an independent risk factor for the progression of
      visual field loss. There have been reports of nocturnal increases in IOP,
      particularly in patients with normal tension glaucoma, and some ophthalmologists
      believe these may account for progression of visual field loss in some patients
      with glaucoma. This review will analyze recent articles that report the impact of
      various glaucoma therapies on the diurnal IOP curve and the use of diurnal curves
      in glaucoma diagnosis. RECENT FINDINGS: A number of recent publications document
      that antiglaucoma medications with a long duration of action reduce the range of
      diurnal fluctuation more than the shorter duration medications. Laser
      trabeculoplasty and trabeculectomy also narrow the range of diurnal fluctuation,
      and at least one recent study finds that trabeculectomy reduces the diurnal range
      more than medical therapy does. Several recent studies of diurnal IOP in patients
      with glaucoma have failed to document such diurnal IOP spikes, so the published
      data available have not supported this hypothesis. SUMMARY: One recent report has
      reconfirmed that a single IOP measurement in the office may not accurately
      indicate what is happening to the IOP of a patient with glaucoma throughout the
      day. Other reports have confirmed that treatment that lowers IOP narrows the
      range of diurnal IOP fluctuation, and one of these reports suggests that surgical
      reduction of IOL may narrow the fluctuation more than medical reduction of IOP.
      The reports of IOP during the night have not provided clear answers about what
      happens to IOP during sleep.

PMID- 15021218
TI  - Detection of glaucoma: the role of new functional and structural tests.
AB  - PURPOSE OF REVIEW: It is thought that our current techniques for investigating
      open-angle glaucoma may not be the most sensitive ones for the earliest detection
      of the disease. Newly developed psychophysical and imaging techniques may have an
      important role in clinical practice. This review outlines some of the issues
      involved in adopting these techniques. RECENT FINDINGS: To date there are many
      cross-sectional studies that report on the sensitivity and specificity
      characteristics of these techniques based on our current definitions of open
      angle glaucoma. There are a limited number of studies available that show the
      efficacy of the new techniques for the early detection of open-angle glaucoma.
      SUMMARY: More longitudinal studies are now needed to demonstrate that the new
      techniques that are being adopted in clinical practice can detect glaucoma
      earlier. More importantly, studies are required to prove that early treatment in
      individuals detected with these new techniques makes a meaningful impact on the
      patients' prognosis.

PMID- 15021219
TI  - Relationship between structure of optic nerve/nerve fiber layer and functional
      measurements in glaucoma.
AB  - PURPOSE OF REVIEW: Glaucoma is a progressive optic neuropathy characterized by
      structural changes of the optic nerve and retina that are associated with the
      development of visual functional defects. The temporal relation between
      structural signs of the disease with psychophysical measures such as visual field
      tests is important to clarify to determine the best methods to detect glaucoma
      and progressive glaucomatous damage in the clinical setting. This paper reviews
      recent advancement in the perception of this structure-function relation. RECENT
      FINDINGS: Quantitative measurement of optic disc and nerve fiber layer integrity
      have shown initial promise in early longitudinal studies in detecting progressive
      glaucoma before the development of progression using standard perimetry.
      Additionally, selective measures of visual function may be able to detect
      glaucoma before conventional methods as well; however, the relation between these
      newer specialized functional tests and optic disc analyzers in detecting
      progression awaits further study. SUMMARY: Defining the clinical relation between
      structure and function cannot be done outside of the context of the
      instrumentation used to assess these parameters. Unfortunately, longitudinal
      studies that compare newer clinical instruments that measure the structural and
      functional characteristics of the optic nerve to current conventional testing are
      lacking, but are required to validate these emerging technologies.

PMID- 15021221
TI  - Risk and risk factors for blindness from glaucoma.
AB  - PURPOSE OF REVIEW: Estimates of blindness from glaucoma and risk factors for
      blindness remain of interest for all ophthalmologists. RECENT FINDINGS: Long-term
      retrospective studies of patients with open-angle glaucoma in developed countries
      have noted that progression to bilateral blindness among treated patients is
      relatively uncommon. Risk factors for development of blindness include advanced
      visual field loss at presentation and noncompliance with the treatment regimen.
      Age is a risk factor in some studies. Many of those with blindness are blind at
      presentation. Untreated rates of blindness are higher. Population-based studies
      of glaucoma in developing countries have highlighted the obstacles to prevention
      of blindness in such settings, with astonishingly high rates of blindness noted.
      SUMMARY: The risk of blindness from glaucoma is very high among patients in
      developing countries, the vast majority of whom do not know they are afflicted.
      When considering all glaucoma worldwide, the greatest risk factor for blindness
      is almost certainly being an average citizen of a developing country. Among those
      with open-angle glaucoma in developed countries, more advanced visual field loss
      at presentation and noncompliance are risk factors for development of blindness,
      as well as advanced age. Effective public education about glaucoma and targeted
      screening of those most likely to have glaucoma are necessary if the number of
      blind from glaucoma is to be reduced worldwide. Better treatment options for
      those in developing countries must also be developed.

PMID- 15021220
TI  - Factors for progression and glaucoma treatment: the Early Manifest Glaucoma
      Trial.
AB  - PURPOSE OF REVIEW: This review summarizes factors for progression in the Early
      Manifest Glaucoma Trial (EMGT), including the effect of treatment. EMGT
      randomized patients with early glaucoma either to argon laser trabeculoplasty
      plus betaxolol (n = 129) or to no immediate treatment (n = 126) and followed them
      every 3 months. RECENT FINDINGS: Treated patients had delayed progression, as
      compared with controls. In Cox regression, EMGT treatment halved the risk of
      progression (hazard ratio = 0.50; 95% confidence interval: 0.35, 0.71). Risk
      decreased about 10% with each millimeter mercury of intraocular pressure (IOP)
      reduction from baseline; the higher (or lower) the IOP at follow-up, the higher
      (or lower) the risk. Baseline factors increasing progression were higher IOP,
      exfoliation, bilateral disease, worse perimetric mean deviation and older age;
      frequent disc hemorrhages at follow-up also increased risk. SUMMARY: EMGT
      treatment reduced progression risk in half, demonstrating the value of IOP
      lowering in early glaucoma. Age and indicators of disease severity also predicted
      progression.

PMID- 15021222
TI  - Refractive surgery in glaucoma.
AB  - PURPOSE OF REVIEW: The purpose of this review is to discuss the topics relevant
      to the topic of LASIK in glaucoma patients or suspects. The safety of LASIK and
      the implications of LASIK on glaucoma diagnostic testing are reviewed. RECENT
      FINDINGS: Most studies have found no change in the nerve fiber layer thickness or
      optic disc after LASIK. Several reports of steroid-induced glaucoma after LASIK
      have been published. Important new syndromes such as the interlamellar stromal
      cyst have been described. Most investigators, but not all, have found intraocular
      pressure to be lower after LASIK, most likely an artifact of measurement as a
      result of reduced central corneal thickness. SUMMARY: The safety of LASIK in
      patients with glaucoma has not been proved. However, based on the published
      literature, LASIK may be a viable option for some glaucoma patients. Although not
      an absolute contraindication, glaucoma is a relative contraindication, and
      careful patient education and life-long follow-up is mandatory. The clinician
      must be ever mindful of the important effects that LASIK may have on diagnostic
      testing.

PMID- 15021223
TI  - Current management of glaucoma.
AB  - PURPOSE OF REVIEW: This study reviews current concepts in the goals of glaucoma
      therapy, interventional sequence, and options for the management of glaucoma in
      light of recent clinical trials. RECENT FINDINGS: Recent randomized prospective
      trials of ocular hypertension and glaucoma have provided evidence for more
      specific treatment goals in glaucoma therapy. In addition, the advent of the
      prostaglandin analogs, advances in laser technology, and innovative techniques
      for filtering surgery have expanded the armamentarium that ophthalmologists use
      in the treatment of glaucoma. SUMMARY: Despite continued advances in laser and
      incisional surgery, medical therapy still appears to be the primary means by
      which intraocular pressure is controlled. Initial medical therapy has changed
      with the introduction of prostaglandin analogs, which are replacing beta
      antagonists as the drug of first choice. Laser trabeculoplasty, using either
      photocoagulative (argon and diode) or photodisruptive (frequency doubled Nd:YAG)
      lasers, is still reserved for patients who do not improve with medical therapy,
      although there is good evidence that initial laser trabeculoplasty is just as
      effective as initial medical therapy. Trabeculectomy with antifibrotic agents (5
      fluorouracil or mitomycin C) is still the next step in intraocular pressure
      control, and glaucoma drainage implants are reserved for refractory cases.
      Cyclophotocoagulation is a last resort procedure because of poor visual outcomes
      and is reserved for patients with intractable pain and vision thought not to be
      useful.

PMID- 15021224
TI  - Glaucoma management in developing countries: medical, laser, and surgical options
      for glaucoma management in countries with limited resources.
AB  - PURPOSE OF REVIEW: Most people affected by glaucoma live in developing countries.
      Recent trials and reports provide sound evidence for management of glaucoma. This
      review extrapolates relevant articles to the developing world. RECENT FINDINGS:
      The predictive value of gonioscopy for progression of primary angle closure
      suspects (PACS) to primary angle closure (PAC) is only 22% (95% CI: 9.80-34.2).
      PACS are not uncommon; laser peripheral iridotomy (LPI) is neither indicated nor
      feasible for all. Twenty-eight and a half percent of PAC progress to primary
      angle closure glaucoma; the number needed to treat (NNT) for LPI to prevent
      progression is only 4. Laser peripheral iridoplasty controls acute angle closure
      glaucoma (AACG) faster than medical therapy alone. Primary lens extraction has
      also been suggested as treatment for AACG after control of the acute attack. A 5
      year NNT for ocular hypertension (OH) of 20 is too high to allow treatment of all
      OH. High-risk OH and primary open angle glaucoma (POAG) have an NNT of 5 to 6 and
      merit treatment. Latanoprost and brimonidine are effective in lowering IOP in
      Asian eyes with POAG, but primary surgical therapy may be a more viable option.
      For cataract and coexistent glaucoma requiring filtration, trabeculectomy
      combined with the Blumenthal technique of cataract surgery may be as effective as
      trabeculectomy combined with phacoemulsification. SUMMARY: The principles of
      glaucoma management should be the same the world over. Considering the paucity of
      resources and competing opportunity costs, countries with limited resources have
      to extrapolate available information in a sensible and cost-effective manner.

PMID- 15021225
TI  - Fixed combinations of topical glaucoma medications.
AB  - PURPOSE OF REVIEW: Topical medical therapy remains the first line of treatment in
      the management of glaucoma. Utilization studies and clinical trials have
      demonstrated that many patients with glaucoma require multiple medications to
      achieve adequate control of intraocular pressure. Fixed combinations of commonly
      used drugs have been developed, tested, and in some (but not all) cases, approved
      for use in the United States and abroad. In this review the authors discuss the
      principles of fixed combination therapy and examine the existing fixed
      combinations. RECENT FINDINGS: The first modern combination product was the
      dorzolamide-timolol fixed combination. It works better than either constituent
      and at least as well as concomitant therapy with both constituents. In comparison
      with newer agents, the dorzolamide-timolol fixed combination was equal in
      efficacy to latanoprost monotherapy, timolol and unoprostone concomitant therapy,
      and timolol and brimonidine concomitant therapy. Concomitant latanoprost and
      brimonidine demonstrated better efficacy than the dorzolamide-timolol fixed
      combination. The latanoprost-timolol fixed combination is available in many
      countries but not the United States. This combination has demonstrated modest
      additional efficacy over latanoprost monotherapy. The latanoprost-timolol fixed
      combination provided greater efficacy than concomitant timolol and brimonidine.
      SUMMARY: Fixed combinations offer benefits of convenience, cost, and safety, but
      limit individualization of dosing. Understanding the advantages and disadvantages
      of prescribing fixed combinations facilitates success in using these products in
      clinical practice.

PMID- 15021226
TI  - Management of inflammatory glaucomas.
AB  - PURPOSE OF REVIEW: To review the epidemiology, pathogenesis and management of
      uveitic glaucoma in the light of significant studies published during the review
      period (October 2002-2003). RECENT FINDINGS: The visual prognosis of glaucoma
      secondary to certain types of uveitis, for example Juvenile Idopathic Arthritis,
      remains poor because of late presentation and a high rate of corticosteroid
      responsiveness. Production of Myocilin is intimately linked with outflow
      resistance and corticosteroid responsiveness. Although Myocilin gene expression
      is widespread in the eye, corticosteroid-induction is specific for trabecular
      meshwork. The hypotensive effect of some glaucoma medications such as Latanoprost
      and Brimonidine may be partially blocked by concurrent administration of NSAIDs,
      though the risk of redcrudescence of uveitis with Latanoprost appears to be much
      lower than initially feared. Use of Mitomycin C in uveitic trabeculectomy has not
      clearly translated into better long-term IOP control, though this may be due to
      an absence of prospective studies. Glaucoma drainage devices appear to be more
      successful in uveitic glaucoma than in other recalcitrant types. SUMMARY: The
      management of uveitic glaucoma requires a careful balance between adequate anti
      inflammatory therapy and appropriate intraocular pressure (IOP)-lowering to
      prevent long-term visual loss. In the foreseeable future, successful elucidation
      of the function of Myocilin is most likely to lead to improvements in the
      management of corticosteroid-induced and hence uveitic glaucoma.

PMID- 15021227
TI  - Update on antifibrotic use in glaucoma surgery, including use in trabeculectomy
      and glaucoma drainage implants and combined cataract and glaucoma surgery.
AB  - PURPOSE OF REVIEW: This paper summarizes the use of antifibrotic agents
      adjunctive to glaucoma surgery, reviews recently published studies that address
      current use of these antifibrotics, and reviews new methods of wound modulation.
      RECENT FINDINGS: The use of antifibrotic agents, namely, 5-fluorouracil and
      mitomycin C, in conjunction with glaucoma surgery has resulted in lower
      postoperative intraocular pressures after trabeculectomy or combined cataract and
      glaucoma surgery. Mixed results have been seen when these agents are used with
      glaucoma drainage device surgery. The use of antifibrotic agents has also created
      and increased complications. Therefore, methods of antifibrotic use have become
      more refined and modified for specific circumstances. Promising new wound
      modulation agents, such as CAT-152, are currently under study. SUMMARY:
      Antifibrotics are potent adjuncts to glaucoma surgery, but along with their
      beneficial use are risks that need to be considered. While we continue to look
      for more efficacious agents and methods to treat glaucoma, we must continue to
      modify techniques with the individual patient's best interest in mind.

PMID- 15021228
TI  - Avoiding and managing complications of glaucoma drainage implants.
AB  - PURPOSE OF REVIEW: The incentive for continued interest in aqueous devices in
      selected cases is mainly the result of the 5% incidence of late "blebitis" and
      endophthalmitis. The purpose of this review is to cover the most common
      complications that may arise and to offer strategies and techniques to avoid or
      rectify the complication. RECENT FINDINGS: Complications of aqueous drainage
      devices are categorized in three stages: intraoperative, early postoperative (<1
      month), and late postoperative (>1 month). Intraoperative complications consist
      of anterior chamber entry, tube misdirection, and scleral perforation. Early
      postoperative complication includes hypotony and flat anterior chamber, choroidal
      effusions, and suprachoroidal hemorrhage. Late postoperative complication
      comprise tube migration, tube or plate extrusion, motility disturbance, and
      infection. SUMMARY: Most complications seen in glaucoma drainage implants are
      self-resolving and rarely threaten visual outcome.

PMID- 15021231
TI  - Bibliography. Current world literature. Glaucoma.

PMID- 15021229
TI  - Management of late-onset bleb leaks.
AB  - PURPOSE OF REVIEW: This paper reviews various methods of both medical and
      surgical management of late bleb leaks. RECENT FINDINGS: The hood procedure
      without bleb removal may be preferred for small leaking blebs and autologous
      conjunctival bleb resurfacing for large leaking blebs. If hypotony is present
      preleak, revision of the underlying scleral flap may also be required. SUMMARY:
      Blebs with late leaks are a major problem after glaucoma filtration surgery and
      can result in hypotony or endophthalmitis. Conservative treatment and laser
      therapy both have limited success in sealing the leaks and are not as effective
      as surgical management. Many surgical techniques are used, but none is
      universally successful.

PMID- 15021232
TI  - Static encephalopathies become dynamic.

PMID- 15021233
TI  - Down syndrome and beta-amyloid deposition.
AB  - PURPOSE OF REVIEW: Exciting new therapeutic approaches to the treatment or
      prevention of Alzheimer's disease involve preventing, slowing or reversing beta
      amyloid accumulation. These interventions may also apply to the treatment of
      Alzheimer's disease in Down syndrome. The purpose of the current review is
      therefore to summarize developments and advances in our understanding of beta
      amyloid pathogenesis in Down syndrome over the past year. RECENT FINDINGS: A
      shift in research to a focus on early events in beta-amyloid pathogenesis in Down
      syndrome has led to several novel observations. Several authors have reported the
      accumulation of both soluble and intracellular beta-amyloid before extracellular
      beta-amyloid (senile plaques) in Down syndrome. Increases in beta-amyloid levels
      in Down syndrome may reflect the increased expression and protein levels of beta
      site amyloid precursor protein cleavage enzyme 2 on chromosome 21. The impact of
      the accumulation of beta-amyloid may have differential effects on development and
      aging in Down syndrome. SUMMARY: The past year has seen significant advances in
      our understanding of beta-amyloid pathogenesis and the functional consequences of
      beta-amyloid accumulation in Down syndrome. However, there are still large gaps
      in our knowledge of the pathways involved in beta-amyloid degradation and
      clearance. It will be critical to conduct clinical trials to test therapeutic
      strategies that may reduce beta-amyloid in Down syndrome directly to determine
      the optimal age and dose for specific interventions. Given the differences in the
      mechanism of beta-amyloid accumulation in Down syndrome, careful consideration
      needs to be given to potential clinical trials to treat this disorder.

PMID- 15021234
TI  - Recent advances in neurofibromatosis type 1.
AB  - PURPOSE OF REVIEW: The past decade, since the identification of the
      neurofibromatosis type 1 (NF1) gene, has witnessed great advances in our
      understanding of the role of the NF1 gene in the molecular pathogenesis of NF1
      associated clinical abnormalities. The purpose of this review is to highlight
      recent advances in defining the molecular etiology of nervous system tumors and
      learning disabilities. RECENT FINDINGS: Neurofibromas and optic pathway gliomas
      result from NF1 inactivation in Schwann cells and astrocytes, respectively, but
      other cellular factors contribute to tumorigenesis. In addition, malignant
      progression of plexiform neurofibromas to malignant peripheral nerve sheath
      tumors requires additional genetic changes, including increased expression of
      growth factor receptors, molecules that are involved in tumor invasion and
      metastasis, and inactivation of critical cell cycle regulators. In addition,
      specific types of NF1 gene mutation may be associated with an increased risk for
      malignancy in individuals with NF1. SUMMARY: Research over the past few years has
      resulted in a detailed understanding of the molecular genetics of benign and
      malignant tumors affecting individuals with NF1 as well as the development of
      refined small animal models for these tumors. In addition, clinical studies have
      begun to define specific subpopulations of patients at risk for cancer and have
      identified targeted therapies for NF1-associated tumors, based on basic science
      research advances.

PMID- 15021236
TI  - White matter imaging in holoprosencephaly in children.
AB  - PURPOSE OF REVIEW: Holoprosencephaly is a disorder of forebrain development
      characterized by a failure of the brain to separate into two hemispheres during
      early development. It is now clear that many cases of holoprosencephaly are
      caused by alterations in the genetic programmes that pattern the nervous system.
      Less is known about how a holoprosencephalic brain either forms or fails to form
      connections between various brain structures. RECENT FINDINGS: Abnormalities in
      the corpus callosum, corticospinal tract, medial lemniscus and cerebellar
      peduncles can be seen in holoprosencephaly. Diffusion tensor imaging has been and
      will continue to be an important tool for imaging white matter in the brain, and
      will be reviewed here. Furthermore, recent evidence suggests that
      holoprosencephaly can be associated with delays or abnormalities in myelination.
      The functional implications of white matter abnormalities in children with
      holoprosencephaly is only beginning to be understood. SUMMARY: Modern
      neuroimaging has led to a better appreciation of the variability seen in
      holoprosencephaly, an anomaly known to have multiple etiologies. Recent reviews
      of the biology of holoprosencephaly identify the condition as a defect in
      dorsoventral patterning. More detailed white and grey matter structure-function
      studies are likely to shed light on how a brain with drastically altered
      composition and connectivity does or does not organize itself to accomplish
      increasingly complex developmental functions.

PMID- 15021235
TI  - Clinical aspects of the disorders of GABA metabolism in children.
AB  - PURPOSE OF REVIEW: There has been increased recognition of the pediatric
      neurotransmitter disorders. This review focuses on the clinical disorders of GABA
      metabolism. RECENT FINDINGS: The known clinical disorders of GABA metabolism are
      pyridoxine dependent epilepsy, GABA-transaminase deficiency, SSADH deficiency,
      and homocarnosinosis. Pyridoxine dependent epilepsy is diagnosed clinically but
      potentially more common presentations, with later and atypical features, widen
      the spectrum. No gene locus has been confirmed; the pathophysiology may involve
      alterations in PLP transport, binding to GAD, or other PLP-dependent pathways.
      SSADH deficiency is associated with developmental delay, prominent language
      deficits, hypotonia, ataxia, hyporeflexia, and seizures. Increased detection is
      reported when specific ion monitoring is used for GHB on urine organic acids. The
      most consistent MRI abnormality is increased signal in the globus pallidus. MR
      spectroscopy has demonstrated the first example of increased endogenous GABA in
      human brain parenchyma in this disorder. GABA-transaminase deficiency and
      homocarnosinosis appear to be very rare but require CSF for detection, thus
      allowing for the possibility that these entities, as in the other pediatric
      neurotransmitter disorders, are underrecognized. SUMMARY: The disorders of GABA
      metabolism require an increased index of clinical suspicion. Pyridoxine dependent
      epilepsy is a treatable condition with a potentially widening clinical spectrum,
      but with a prognosis dependent on early intervention. SSADH deficiency has a
      heterogeneous spectrum and requires careful urine organic acid testing for
      screening, followed by enzymatic confirmation allowing appropriate prognostic and
      genetic counseling.

PMID- 15021237
TI  - Rodent models for treatment of spinal cord injury: research trends and progress
      toward useful repair.
AB  - PURPOSE OF REVIEW: In this review, we have documented some current research
      trends in rodent models of spinal cord injury. We have also catalogued the
      treatments used in studies published between October 2002 and November 2003, with
      special attention given to studies in which treatments were delayed for at least
      4 days after injury. RECENT FINDINGS: Most spinal cord injury studies are
      performed with one of three general injury models: transection, compression, or
      contusion. Although most treatments are begun immediately after injury, a growing
      number of studies have used delayed interventions. Mice and the genetic tools
      they offer are gaining in popularity. Some researchers are setting their sights
      beyond locomotion, to issues more pressing for people with spinal cord injury
      (especially bladder function and pain). SUMMARY: Delayed treatment protocols may
      extend the window of opportunity for treatment of spinal cord injury, whereas
      continued progress in the prevention of secondary cell death will reduce the
      severity of new cases. The use of mice will hopefully accelerate progress towards
      useful regeneration in humans. Researchers must improve cross-study comparability
      to allow balanced decisions about potentially useful treatments.

PMID- 15021238
TI  - Recent advances in newborn screening for neurometabolic disorders.
AB  - PURPOSE OF REVIEW: Newborn screening for neurometabolic disorders offers a unique
      and promising opportunity to practice preventive medicine in children with
      diverse inborn errors of metabolism. The benefits of the early identification and
      presymptomatic treatment of these disorders are now recognized. RECENT FINDINGS:
      The rapid pace of developments in the field of expanded newborn screening has
      been made possible by technological advances in the ability to detect multiple
      compounds diagnostic of diverse inborn errors of metabolism in neonatal dried
      blood specimens. Launched by the success of newborn screening for
      phenylketonuria, experts in this area are optimistic that further public health
      benefits will follow the same pathway. This review highlights the population
      model and public health issues inherent in advances in newborn screening for
      selected neurometabolic disorders. Current and future diagnostic and therapeutic,
      as well as social and ethical, dilemmas are discussed. SUMMARY: Newborn screening
      represents one of the major child health advances of this past century. As
      developments in the field of expanded newborn screening for neurometabolic
      disease progress forward, the long-term success of this important project will
      pose future challenges and opportunities.

PMID- 15021239
TI  - From epilepsy genes to epileptogenic networks: the missing links.

PMID- 15021240
TI  - Mortality in patients with epilepsy.
AB  - PURPOSE OF REVIEW: Prospective and retrospective incidence cohort studies have
      been consistent in identifying an increased mortality in patients with epilepsy,
      although risk ratios vary considerably. Standardized mortality ratios in these
      populations range from 1.6 to 5.3, but they tend to be higher in studies in
      selected populations. RECENT FINDINGS: A few studies have addressed the mortality
      rate in patients after epilepsy surgery. Mortality seemed to be lower for surgery
      than for non-surgery patients. The main factors contributing to the late
      mortality rate in this population are the persistence of seizures after surgery,
      the long duration of epilepsy before surgery, and the side of the resection.
      Despite recent improvements in diagnosis and therapeutic management, status
      epilepticus is still associated with significant mortality, with a case fatality
      reaching 39%. Early patient management could influence the outcome of status
      epilepticus. Reports on suicide in epilepsy are based on small samples from
      different populations, highly selected groups of patients, using different
      methods of analysis. The rates vary from zero to 25%, and seem to be related more
      to a psychiatric co-morbidity than the severity of epilepsy. Sudden unexplained
      death is considered to be the most frequent epilepsy-related death. Clinical and
      experimental evidence supports the theory that sudden unexplained death is a
      recent seizure-mediated event with ictal stimulation of the autonomic system.
      SUMMARY: In some situations, the increased risk of death could be prevented by a
      better definition of populations at increased risk, better therapeutic
      management, and adequate neurological follow-up.

PMID- 15021241
TI  - Genetics of the epilepsies.
AB  - PURPOSE OF REVIEW: This article reviews the most significant advances in the
      field of genetics of the epilepsies during the past year, with emphasis on newly
      identified genes and functional studies leading to new insights into the
      pathophysiology of epilepsy. RECENT FINDINGS: Mutations in the chloride channel
      gene CLCN2 have been associated with the most common forms of idiopathic
      generalized epilepsies. A mutation in the ATP1A2 sodium potassium ATPase pump
      gene has been described in a family in which familial hemiplegic migraine and
      benign familial infantile convulsions partly co-segregate. The leucine-rich,
      glioma-inactivated 1 gene (LGI1) (also known as epitempin) was found to be
      responsible for autosomal-dominant lateral temporal lobe epilepsy in additional
      families. The serine-threonine kinase 9 gene (STK9) was identified as the second
      gene associated with X-linked infantile spasms. Mutations in the Aristaless
      related homeobox gene (ARX) have been recognized as a cause of X-linked infantile
      spasms and sporadic cryptogenic infantile spasms. A second gene underlying
      progressive myoclonus epilepsy of Lafora, NHLRC1, was shown to code for a
      putative E3 ubiquitin ligase. SUMMARY: Genes associated with idiopathic
      generalized epilepsies remain within the ion channel family. Mutations in non-ion
      channel genes are responsible for autosomal-dominant lateral temporal lobe
      epilepsy, a form of idiopathic focal epilepsy, malformations of cortical
      development, and syndromes that combine X-linked mental retardation and epilepsy.
      Most genetic epilepsies have a complex mode of inheritance, and genes identified
      so far account only for a minority of families and sporadic cases. Functional
      studies are leading to a better understanding of the mechanisms underlying
      hyperexcitability and seizures.

PMID- 15021242
TI  - Basic mechanisms of partial epilepsies.
AB  - PURPOSE OF REVIEW: Partial epilepsies are characterized by cell loss with
      consequences for neuronal organization, excitability, mnestic and cognitive
      functions and present with pharmaco-resistance and difficulties in clinical
      management. While mesial temporal lobe epilepsies present frequently with cell
      loss and neuronal reorganization, neocortical epilepsies frequently involve
      developmental alterations. RECENT FINDINGS: There is increasing evidence that
      nerve cells in epileptic tissue become more vulnerable to excitotoxic cell death
      due to impairment of mitochondrial functions and that free radical formation is
      critically involved in these processes. Whether and to what extent such
      alterations contribute to pharmaco-resistance is unclear. However, at least three
      mechanisms may contribute to pharmaco-resistance: changes in target molecules for
      antiepileptic drugs, upregulation of drug transporters, and potentially
      reorganization processes in inhibitory networks. Upregulation of drug
      transporters also seems to be involved in pharmaco-resistance of developmental
      alterations underlying focal epilepsies. Recent data from the literature suggest
      that transgenic models for disturbances of cortical development may be useful
      models for the study of these variable forms of partial epilepsies. SUMMARY: The
      data suggest that improvement of therapy could result from free radical
      scavenging and from manipulation of drug transport into the affected tissue. New
      models of developmental epilepsies may help us to understand mechanisms
      underlying increased vulnerability to seizures as well as improving strategies
      for treatment.

PMID- 15021243
TI  - Febrile seizures and mesial temporal sclerosis.
AB  - PURPOSE OF REVIEW: The sequence of febrile seizures followed by intractable
      temporal lobe epilepsy is rarely seen from a population perspective. However,
      several studies have shown a significant relationship between a history of
      prolonged febrile seizures in early childhood and mesial temporal sclerosis. The
      interpretation of these observations remains quite controversial. One possibility
      is that the early febrile seizure damages the hippocampus and is therefore a
      cause of mesial temporal sclerosis. Another possibility is that the child has a
      prolonged febrile seizure because the hippocampus was previously damaged by a
      prenatal or perinatal insult or by genetic predisposition. RECENT FINDINGS:
      Imaging studies have shown that prolonged and focal febrile seizures can produce
      acute hippocampal injury that evolves to hippocampal atrophy, and that complex
      febrile seizures can originate in the temporal lobes in some children. Several
      lines of evidence now indicate that genetic predisposition is an important causal
      factor of febrile seizures and mesial temporal sclerosis. From recent clinical
      and molecular genetic studies, it appears that the relationship between febrile
      seizures and later epilepsy is frequently genetic, and there are several syndrome
      specific genes for febrile seizures. SUMMARY: Mesial temporal sclerosis probably
      has different causes. A number of retrospective studies showed that complex
      febrile seizures are a causative factor for the later development of mesial
      temporal sclerosis and temporal lobe epilepsy. However, contradictory results
      have come from several prospective and retrospective studies. The association
      between febrile seizures and temporal lobe epilepsy probably results from complex
      interactions between several genetic and environmental factors.

PMID- 15021244
TI  - Multimodality imaging in partial epilepsies.
AB  - PURPOSE OF REVIEW: The rapid expansion of novel applications and the development
      of new techniques in structural and functional imaging modalities present a
      troubling challenge to keep up with and harness potential valuable information
      created in this critical field of epilepsy localization and non-invasive in-vivo
      research. RECENT FINDINGS: Recent advances in epilepsy imaging have centered on:
      (1) improving the localization of epileptogenic tissue beyond that of state-of
      the-art structural magnetic resonance imaging; (2) monitoring the development and
      progression of epileptogenic pathology, particularly mesial temporal sclerosis;
      and (3) an investigation of the in-vivo structural and functional disturbances
      underlying and revealing mechanisms of partial epilepsy pathophysiology. SUMMARY:
      The main impact of the progress in epilepsy localization with multimodality
      imaging is to allow more effective presurgical evaluation and the selection of
      patients with intractable seizures. By combining serial imaging findings and
      genetic studies, the major questions surrounding the development and progression
      of mesial temporal sclerosis with regard to the cause and consequence of epilepsy
      will soon be answered. Long-standing questions concerning in-vivo metabolic and
      neurotransmitter disturbances associated with partial epilepsy, detected and
      depicted (but not understood) with magnetic resonance spectroscopy and positron
      emission tomography, are finally being addressed.

PMID- 15021245
TI  - Clinical outcome of epilepsy surgery.
AB  - PURPOSE OF REVIEW: The outcome from current surgical methods of treating drug
      resistant epilepsy will be considered, looking at changes in classical resective
      surgery and new methodology being introduced in the functional treatment of these
      patients. RECENT FINDINGS: There is now class I evidence that temporal lobe
      surgery is effective. Sophisticated and appropriate magnetic resonance imaging
      sequences, together with an assessment of the electroclinical syndrome, allow
      patients to be assessed for resective surgery. The concept of 'surgically
      remediable syndromes' determines the type of procedure that is effective for
      particular patients. Technical advances such as neuronavigation techniques and
      intra-operative magnetic resonance imaging have improved the effectiveness of
      these procedures. Other techniques of disconnection, such as multiple subpial
      transection, and stimulation both indirectly using the vagus nerve and directly
      using various intracranial targets, are currently effective and have potential
      for future development. SUMMARY: This review will demonstrate that current
      surgical techniques are safe and effective in relieving drug-resistant epilepsy.

PMID- 15021246
TI  - Complex I assembly: a puzzling problem.
AB  - PURPOSE OF REVIEW: Disturbances in the mitochondrial oxidative phosphorylation
      pathway most often lead to devastating disorders with a fatal outcome. Of these,
      complex I deficiency is the most frequently encountered. Recent characterization
      of the mitochondrial and nuclear DNA-encoded complex I subunits has allowed
      mutational analysis and reliable prenatal diagnosis. Nevertheless, complex-I
      deficient patients without a mutation in any of the known subunits remain. It is
      assumed that these patients harbour defects in proteins involved in the assembly
      of this largest member of the oxidative phosphorylation complexes. This review
      describes current understanding of complex I assembly, new developments and
      future perspectives. RECENT FINDINGS: The first model of human complex I assembly
      has been proposed recently. New insights into supercomplex assembly and stability
      may help to explain combined deficiencies. Recent functional characterization of
      some of the 32 accessory subunits of the complex may link these subunits to
      complex I biogenesis and activity regulation. SUMMARY: Research on complex I
      assembly is increasing rapidly. However, comparison between theoretical and
      experimental models of complex I assembly is still problematic. The growing
      understanding of complex I assembly at the subunit and supercomplex level will
      clarify the picture in the future. The elucidation of complex I assembly, by
      combining patient data with new experimental methods, will facilitate the
      diagnosis of (and possibly therapy for) many uncharacterized mitochondrial
      disorders.

PMID- 15021247
TI  - The latest on leukodystrophies.
AB  - PURPOSE OF REVIEW: Important advances in our understanding of genetic disorders
      of the white matter have been made and are discussed here. RECENT FINDINGS: It
      has recently been discovered that mutations in the genes encoding the five
      subunits of eukaryocytic initiation factor 2B (eIF2B) are the cause of vanishing
      white-matter disease/childhood ataxia with central hypomyelination syndrome. The
      extension of the clinical features of the eIF2B-related disorders to encompass
      both infant- and adult-onset disorders is discussed. New clinico-imaging
      syndromes such as hypomyelination with atrophy of the basal ganglia and
      cerebellum and leukoencephalopathy with brain-stem and spinal cord involvement
      and elevated white-matter lactate are described. Recent findings include evidence
      that mitochondrial fat-oxidation abnormalities may be important in the
      pathogenesis of adrenoleukodystrophy, and that a mutant myelin protein can cause
      maldistribution of other myelin proteins, causing dysmyelination, axonal damage,
      or both. SUMMARY: This review focuses on advances in the understanding of the
      role of eIF2B as a cause of a common leukodystrophy syndrome. eIF2B-related
      disorders have a clinical spectrum ranging from a severe, rapidly progressive
      congenital or early infantile encephalopathy to a slowly progressive cognitive
      and motor deterioration often associated with premature ovarian failure. Two
      newly recognized leukodystrophy syndromes are described: hypomyelination with
      atrophy of the basal ganglia and cerebellum, and leukoencephalopathy with brain
      stem and spinal cord involvement and elevated white-matter lactate. An update is
      also given for adrenoleukodystrophy and myelin-protein-related disorders. This
      update demonstrates that an increasing number of genetic defects are being
      identified that may cause primary white-matter disorders.

PMID- 15021248
TI  - Impaired glucose transport into the brain: the expanding spectrum of glucose
      transporter type 1 deficiency syndrome.
AB  - PURPOSE OF REVIEW: Glucose transporter type 1 deficiency syndrome (OMIM 606777)
      is a treatable epileptic encephalopathy resulting from impaired glucose transport
      into the brain. In recent years, the increasing number of patients has generated
      substantial insights into the manifestations and mechanisms of this disease.
      Current understanding of this novel disorder is reviewed, and recent advances in
      diagnosis and treatment are highlighted. RECENT FINDINGS: The syndrome is now
      understood to be a complex neurological disorder. The clinical spectrum has
      recently been extended by infants with 'benign' transient hypoglycorrhachia,
      glucose transporter type 1 deficiency syndrome without seizures, and by adult
      cases. Other key findings in the last couple of years include (1) the description
      of electroencephalogram abnormalities, (2) a characteristic cerebral metabolic
      footprint in positron emission tomography imaging, and (3) the definition of
      molecular mechanisms and functional domains within the glucose transporter type 1
      protein by in-vitro mutagenesis. The disease has also shed a new light on the
      mechanisms and the effectiveness of the ketogenic diet for seizure control.
      SUMMARY: The syndrome is now well characterized in children and should be
      considered in any patient with intractable epilepsy. An effective therapy is
      available. The clinical spectrum and the molecular basis of the disease are
      increasingly heterogeneous and indicate complex pathogenic mechanisms that will
      ultimately lead to a classification on clinical, biochemical, and molecular
      grounds.

PMID- 15021249
TI  - Serine-deficiency syndromes.
AB  - PURPOSE OF REVIEW: Serine-deficiency disorders comprise a new group of
      neurometabolic diseases and are caused by defects in the biosynthesis of the
      amino acid L-serine. In contrast to most neurometabolic disorders, serine
      deficiency disorders are potentially treatable. Furthermore, the severe
      neurological symptoms observed in patients underscore the important roles of the
      serine biosynthetic pathway in brain tissue. An overview of the patients with
      serine-deficiency disorders reported to date, the biochemical findings and the
      results of treatment with amino acids is presented. RECENT FINDINGS: L-Serine
      biosynthesis plays an important role in multiple cellular reactions, particularly
      in the brain, as L-serine is a precursor of important metabolites such as
      nucleotides, phospholipids and the neurotransmitters glycine and D-serine.
      Disturbances of serine-glycine metabolism in relation to N-methyl-D-aspartate
      receptor activation are supposed to play a role in psychiatric disease as well.
      Recent findings concerning these roles of L-serine-derived phospholipids and
      neurotransmitters are presented. SUMMARY: Congenital microcephaly, seizures and
      severe psychomotor retardation are symptoms of serine deficiency and can be
      treated with supplementation of L-serine, sometimes combined with glycine. The
      symptoms observed in serine deficiency confirm that L-serine and L-serine-derived
      metabolites play important roles in the central nervous system.

PMID- 15021251
TI  - Bibliography. Current world literature. Developmental disorders.

PMID- 15021250
TI  - Defective glycosylation in congenital muscular dystrophies.
AB  - PURPOSE OF REVIEW: The recent identification of mutations in five genes coding
      for proteins with putative or demonstrated glycosyltransferase activity has shed
      light on a novel mechanism responsible for muscular dystrophy. Abnormal
      glycosylation of alpha-dystroglycan appears to be a common finding in all these
      conditions. Surprisingly, the disease severity due to mutations in several of
      these genes is extremely variable. This article provides an overview of the
      clinical, biochemical and genetic advances that have been made over the last year
      in this field. RECENT FINDINGS: Mutations in the human LARGE gene, a putative
      glycosyltransferase mutated in the myodystrophy mouse, have now been identified
      in a form of human muscular dystrophy. In addition, the clinical variability of
      patients with mutations in the genes encoding fukutin, protein O-linked mannose
      beta1,2-N-acetylglucosaminyltransferase 1 and the fukutin-related protein has
      been significantly expanded. Disease severity in patients with mutations in the
      gene encoding the fukutin-related protein varies from a severe prenatal form of
      congenital muscular dystrophy with cobblestone lissencephaly and structural eye
      defects to a mild form of limb-girdle muscular dystrophy with onset in adult life
      and neither brain nor eye involvement. SUMMARY: Glycosylation disorders represent
      a rapidly growing and common group of muscular dystrophies. Accurate genetic
      diagnosis can now be made for five forms, and it is anticipated that several
      other variants will eventually fall into these categories.

PMID- 15021278
TI  - Cool it on cooling--at least during aneurysm surgery.

PMID- 15021279
TI  - Buprenorphine-soaked absorbable gelatin sponge: an alternative method for
      postlaminectomy pain relief.
AB  - There have been several reports of instillation of buprenorphine in the intact
      epidural space in an attempt to control postoperative pain, but none in which an
      absorbable gelatin sponge soaked with buprenorphine is placed directly in the
      epidural space. In the present study, carried out on 30 patients (study group)
      undergoing noncervical laminectomies, 0.3 mg buprenorphine diluted to 5 mL with
      normal saline soaked into an absorbable gelatin sponge was placed in the epidural
      space under direct vision. In 30 other patients (control group) undergoing
      laminectomies, absorbable gelatin sponge soaked with 5 mL normal saline was
      placed in the epidural space. Pulse rate, mean arterial pressure, respiratory
      rate, pain score by visual analog scale, duration of analgesia, and adverse
      effects, if any, were noted preoperatively and postoperatively at 1, 2, 3, 4, 5,
      6, 12, 18, and 24 hours. The presence of any neurologic symptoms was also
      assessed at these time intervals as well as on the seventh postoperative day. The
      authors observed that changes in pulse rate, mean arterial pressure, and
      respiratory rate were not statistically significant between the control and the
      study groups. The pain relief score, duration of pain relief (14.8 +/- 0.77 hours
      in the study group vs. 0.66 +/- 0.15 hours in the control group), and sedation
      were significantly better in the study group. No patient demonstrated any
      respiratory depression (respiratory rate <12/min), bradycardia, pruritus, or
      neurologic pressure symptoms, although the incidence of nausea was higher in the
      study group.

PMID- 15021280
TI  - Effect of single-dose dexamethasone on blood glucose concentration in patients
      undergoing craniotomy.
AB  - Dexamethasone, a corticosteroid used to treat cerebral edema, is known to produce
      elevations in the blood glucose concentration, but the effect of a single
      intraoperative dose of dexamethasone on the blood glucose concentration is
      unknown. Glucose concentrations in response to either a 10-mg intravenous bolus
      of dexamethasone or a saline placebo were evaluated in nondiabetic patients
      undergoing elective craniotomy. Both arterial and venous blood glucose
      concentrations were obtained immediately before and after treatment and hourly
      for 4 hours intraoperatively. The arterial blood glucose concentration in those
      who received 10 mg dexamethasone (n = 10) increased from 97 +/-15 mg/dL (mean +/-
      SD) to 149 +/- 23 mg/dL over the course of the study, compared with a change from
      88 +/- 11 mg/dL to 103+/-12 mg/dL in those who received placebo (n = 10) (P <
      0.05 for 4-hour sample vs. baseline for both groups; P < 0.05 between groups at 4
      hours). Further, venous blood glucose concentrations were highly predictive of
      arterial glucose values (R = 0.98; P < 0.001). Since elevations in the blood
      glucose concentration should be avoided in the setting of central nervous system
      ischemia, findings from this investigation suggest that contemplated
      corticosteroid use should be reviewed for appropriateness of treatment. If
      dexamethasone is used, even as a single dose during craniotomy, intraoperative
      blood glucose concentrations should be carefully monitored and hyperglycemia
      treated, particularly in patients at risk for glucose-mediated exacerbation of
      brain injury.

PMID- 15021281
TI  - Dexmedetomidine for awake carotid endarterectomy: efficacy, hemodynamic profile,
      and side effects.
AB  - : A randomized, double-masked, placebo-controlled study was designed to compare
      dexmedetomidine as a primary sedative agent with a commonly used drug combination
      in patients undergoing awake carotid endarterectomy (CEA). Sixty-six patients
      undergoing CEA (ASA II-IV) were randomly assigned to receive either
      dexmedetomidine (total dose of 97.5 +/- 54.7 mcg) or normal saline (control).
      Supplemental doses of midazolam, fentanyl, and/or propofol were administered as
      deemed necessary by the anesthesiologist. An observer blinded to the study drug
      assessed sedation level (Observer's Assessment of Alertness-Sedation [OAA/S]
      scale). The primary outcomes were defined as the number of patients with an OAA/S
      score of 4 intraoperatively and an OAA/S score of 5 postoperatively. The authors
      also compared cardiorespiratory parameters, intra- and postoperative side
      effects, and complications. Chi-square tests were used to analyze the primary
      endpoints. All secondary parameters were analyzed using the Wilcoxon rank sum
      test. Three patients in the dexmedetomidine group (10%) had an OAA/S score of 4
      at all four time points assessed intraoperatively, while no patient in the
      control group had a score of 4 at all the time points considered. Thirteen
      patients in the dexmedetomidine group had a score of 4 at three or more time
      points (42%) compared with six patients (19%) in the control group. Four patients
      in the control group (13%) and one patient in the dexmedetomidine group (3%) did
      not achieve a score of 4 at any of the four critical intraoperative time points
      (chi for association = 9.9, P < 0.05; chi for a trend = 8.6, P < 0.004, with the
      trend favoring dexmedetomidine). More patients in the control group required
      treatment with metoprolol (26% vs. 6%, P = 0.04) and labetalol (48% vs/ 6%, P <
      0.01). Plasma levels of norepinephrine were significantly lower in the
      dexmedetomidine group during and after surgery compared with the control group.
      Six patients (19%) in the dexmedetomidine group required intra-arterial shunts,
      while only two patients (6%) required shunts in the control group (P = 0.16).
      These data show that the use of dexmedetomidine in patients undergoing awake CEA
      resulted in fewer fluctuations from the desired sedation level. Patients
      receiving dexmedetomidine required less antihypertensive therapy compared with
      the midazolam/fentanyl/propofol combination. The effect of dexmedetomidine on
      cerebrovascular circulation in the study population needs further investigation.

PMID- 15021283
TI  - Use of cuffed oropharyngeal airway (COPA) for awake intracranial surgery.
AB  - A comprehensive anesthetic plan for managing patients undergoing "awake:
      intracranial surgery (AICS) must include a means of rescuing the patient if the
      airway becomes obstructed. Since access to the patient's airway is limited, mask
      ventilation can be challenging and laryngoscopy and tracheal intubation,
      impossible. The need exists for an alternative airway device that is easy to
      insert, would allow controlled ventilation, and would facilitate a smooth
      emergence with minimal coughing. The cuffed oropharyngeal airway (COPA) was
      introduced as a supraglottic airway device in spontaneously breathing patients.
      The authors report their preliminary experience of its use in AICS. The COPA was
      inserted in 20 patients on 31 occasions. Insertion of the COPA was accomplished
      easily at the first attempt in all cases irrespective of patient position. Airway
      maneuvers were required when patients were supine but not lateral. The COPA is a
      useful device to instrument the airway in patients undergoing AICS using the
      asleep-awake-asleep technique in the lateral position.

PMID- 15021282
TI  - Desflurane increases intracranial pressure more and sevoflurane less than
      isoflurane in pigs subjected to intracranial hypertension.
AB  - Desflurane and sevoflurane may have advantages over isoflurane in
      neuroanesthesia, but this is still under debate. A porcine model with
      experimental intracranial hypertension was used for paired comparison of
      desflurane, sevoflurane, and isoflurane with respect to the effects on cerebral
      blood flow (CBF), cerebrovascular resistance (CVR), and intracranial pressure
      (ICP). The agents, given in sequence to each of six pigs, were compared at 0.5
      and 1.0 minimal alveolar concentrations (MAC) and three mean arterial blood
      pressure (MAP) levels (50, 70, and 90 mm Hg) at normocapnia and one MAP level (70
      mm Hg) at hypocapnia. MAC for each agent had been previously determined in a
      standardized manner for comparison reliability. CBF was measured with Xe. MAP was
      lowered by inflation of a balloon catheter in the inferior caval vein and raised
      by inflation of a balloon catheter in the descending aorta. ICP was measured
      intraparenchymally. Two Fogarty catheters positioned extradurally were inflated
      to a baseline ICP of 20 to 22 mm Hg at 0.2 MAC of each agent. CBF and ICP with
      the three agents at normocapnia and MAP 70 and 90 mm Hg at both 0.5 and 1.0 MAC
      were as follows (P < 0.05): desflurane > isoflurane > sevoflurane. None of the
      agents abolished CO2 reactivity. High-dose desflurane resulted in a higher CBF at
      hypocapnia than corresponding doses of sevoflurane or isoflurane, but there were
      no significant differences between the agents in ICP at hypocapnia. The present
      study showed that desflurane increased ICP more and sevoflurane less than
      isoflurane during normoventilation, but the differences disappeared with
      hyperventilation.

PMID- 15021284
TI  - Plasma ropivacaine levels following scalp block for awake craniotomy.
AB  - The plasma levels of ropivacaine HCl with 5 mcg/mL epinephrine were measured in
      10 patients following scalp blockade for awake craniotomy. A mean dose of 260 mg
      (3.6 mg/kg) resulted in peak plasma concentrations of 1.5 +/- 0.6 mcg/mL, with a
      median time to peak plasma concentration of 15 minutes. The pattern of rise of
      plasma level was similar in all patients and rapid compared with other regional
      blocks (epidural, intercostal, and axillary brachial plexus block). Despite this
      rapid rise of plasma level, no signs of cardiovascular or central nervous system
      toxicity were observed. In this group of patients undergoing awake craniotomy for
      excision of lesions in the eloquent areas of the cerebral cortex, ropivacaine HCl
      with epinephrine appeared to be a safe and effective local anesthetic agent in
      the dosages used.

PMID- 15021285
TI  - High intraoperative blood loss may be a risk factor for postoperative hematoma.
AB  - The authors studied the incidence of postoperative intracranial hematoma to
      improve care after intracranial surgery. Five years (1995-1999) of surgical
      records were analyzed retrospectively. Patients were included if evacuation of an
      intracranial postoperative hematoma was reported. A control group was randomly
      selected. Forty-nine patients (0.8%) had postoperative hematomas requiring
      evacuation. The amount of intraoperative blood loss was significantly larger in
      the hematoma group (762 +/-735 mL [median 500 mL]) than in the control group (415
      +/-403 mL; median 300 mL) (P = 0.004). Clinical deterioration occurred within the
      first 24 hours in 80%, within 6 hours in 51%, and within 1 hour in 12% of the
      patients. Those who deteriorated within 24 hours had a faster and more life
      threatening deterioration than those who had a hematoma after 24 hours. A
      decreased level of consciousness was found in 61% and increased focal neurologic
      signs were found in 33% of the patients. An elevated intracranial pressure was
      seen significantly more often in the hematoma group (9/10 patients, 90%) than in
      the control group (1/8 patients, 12.5%) (P = 0.001). In this study, a large
      amount of intraoperative blood loss and elevated intracranial pressure were
      warning signs of postoperative hematoma and should alert the clinician to the
      increased risk. Most hematomas occurred within 24 hours after surgery, and in
      this time period the deterioration was more severe compared with the hematomas
      that occurred later.

PMID- 15021286
TI  - Jet injection of local anesthetic decreases pain of arterial cannulation in awake
      neurosurgical patients.
AB  - Arterial cannulation through the standard skin wheal of local anesthetic raised
      with a needle may be painful. The authors compared the efficacy of local
      anesthetic injected via a 25G needle versus a Bioject jet injector for arterial
      cannulation in awake neurosurgical patients. After institutional review board
      approval, 40 patients were randomized to receive 0.3 mL 1% lidocaine adjusted to
      pH 7.0 with NaHCO3 by Bioject with a 2-cm spacer between the syringe and skin or
      by 25G needle injection. Two pain assessments were used at the time of local
      anesthetic injection and at arterial cannulation. Patients rated their pain on a
      visual analog scale (VAS) (0 = no pain, 100 = worst pain). Observers scored
      patient response as 0 (no response), 1 (flinch), or 2 (withdrawal). The VAS at
      injection was 23 +/- 19 for the needle group and 3 +/- 6 for the Bioject group (P
      < 0.001). The VAS at arterial cannulation was 39 +/- 25 for the needle group and
      15 +/- 22 for the Bioject group (P < 0.001). Median observer scores at injection
      and cannulation were 1 (range 0-2) for the needle group and 0 (range 0-2) for the
      Bioject group (P < 0.001). Patients in the Bioject group experienced
      significantly less pain during lidocaine administration and at the time of
      arterial cannulation by their own and by an observer's assessment than the needle
      injection group. Jet injection of local anesthetic should be considered prior to
      arterial cannulation in awake patients.

PMID- 15021287
TI  - Bradycardia and sinus arrest following saline irrigation of the brain during
      epilepsy surgery.
AB  - Adverse cardiac events during the intraoperative period are life-threatening. The
      authors report three episodes of severe bradycardia and sinus arrest that
      occurred in a patient undergoing anterior temporal lobectomy and amygdalo
      hippocampectomy for the treatment of epilepsy. The first episode occurred during
      resection of the amygdala; the other two episodes were observed during subsequent
      irrigation of the exposed brain structures, most likely the brain stem
      structures, because of a rent that the surgeon had deliberately made into the
      basilar cistern for better anatomic appreciation of the structures to be excised.
      The patient responded well to treatment with no adverse outcomes. The probable
      mechanisms leading to this event are discussed; the authors excluded insular
      cortex stimulation, the effects of the anesthetic drugs used, and venous air
      embolism as a cause of bradycardia and sinus arrest. The amygdala resection was
      the most likely cause of the first episode of bradycardia; the second episode of
      bradycardia and sinus arrest occurred because of inadvertent stimulation of brain
      structures by the high temperature (42 degree C) of the saline used for
      irrigation. To counter its effects, saline irrigation at room temperature (20
      degree C) was started, and this caused the third episode of bradycardia, most
      likely because of "temperature shock" of the exposed brain. Prompt communication
      with the surgical team and vigilance are crucial for the appropriate management
      of such an incident, which may pose a threat to life. Avoiding irrigation of the
      exposed brain with high-temperature saline may prevent such an incident.

PMID- 15021288
TI  - Global cerebral edema and subarachnoid hemorrhage in a patient with systemic
      lupus erythematosus.
AB  - Systemic lupus erythematosus is a multifactorial autoimmune disease of complex
      etiology, which may be associated with cognitive dysfunction, seizures, and
      headache. The authors present an unusual presentation of systemic lupus
      erythematosus complicated by global cerebral edema and subarachnoid hemorrhage
      secondary to rupture of a cerebral aneurysm. The complicated patient management
      issues are discussed.

PMID- 15021289
TI  - Strategies for managing decreased motor evoked potential signals while
      distracting the spine during correction of scoliosis.
AB  - Surgical correction of kyphoscoliosis may result in spinal cord injury and
      neurologic deficits. Monitoring somatosensory evoked potentials (SSEPs) and
      transcranial motor evoked potentials (MEPs) intraoperatively may allow for early
      detection and reversal of spinal cord injury. Controlled hypotension and
      isovolemic hemodilution are often used during these cases to reduce blood loss
      and transfusion. However, these physiologic parameters may affect the quality of
      SSEP and MEP signals. Acute reduction or loss of MEP or SSEP signals during
      spinal distraction presents a crisis for the operative team: should distraction
      be immediately relieved? The authors describe three patients who showed a
      decrease in evoked potential signals under hypotensive, hemodiluted conditions at
      the stage of spinal distraction. Each case illustrates a different strategy for
      successful management of these patients.

PMID- 15021290
TI  - Management of phlegmasia alba dolens using hirudin in a neurosurgical patient
      with heparin-induced thrombocytopenia.

PMID- 15021299
TI  - Society for neurosurgical anesthesia and critical care: 31st annual meeting
      report.

PMID- 15021300
TI  - Spinal abscess after epidural anesthesia: need for more vigilance and better
      patient advice.

PMID- 15021308
TI  - The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a
      review of two overlapping epidemics.
AB  - Increasing evidence demonstrates a substantial link between the epidemics of
      sexually transmitted HIV-1 and herpes simplex virus (HSV)-2 infection. More than
      30 epidemiologic studies have demonstrated that prevalent HSV-2 is associated
      with a 2- to 4-fold increased risk of HIV-1 acquisition. Per-sexual contact
      transmission rates among couples from Rakai, Uganda indicate that at all levels
      of plasma HIV-1 RNA in the source partner, HSV-2-seropositive HIV-1-susceptible
      persons have a 5-fold greater risk of acquiring HIV-1 compared with HSV-2
      negative persons. In vitro and in vivo studies suggest that mucosal HIV-1
      shedding is more frequent and in greater amounts during mucocutaneous HSV-2
      replication, including subclinical mucosal reactivations. Most HIV-1-infected
      persons are coinfected with HSV-2, and most experience frequent subclinical and
      clinical reactivations of HSV-2. Subclinical HSV reactivation elevates serum HIV
      1 RNA levels, and daily therapy with acyclovir appears to reduce plasma HIV-1
      RNA. These data show that greater attention to the diagnosis and treatment of HSV
      2 among HIV-1-infected persons is warranted, especially those who continue to be
      sexually active, those not on antiretroviral therapy, or those whose disease is
      not well suppressed by antiretrovirals.

PMID- 15021309
TI  - Cytokine and chemokine gene polymorphisms among ethnically diverse North
      Americans with HIV-1 infection.
AB  - Twenty-four common single nucleotide polymorphisms (SNPs) in 10 cytokine and
      chemokine genes were defined in 579 North Americans at high risk of HIV-1
      infection due to sexual behavior and injection drug use. Among the 3 major ethnic
      (African-American, Hispanic/Latino, and other) groups involved, HIV-1
      seropositive individuals differed significantly from ethnically matched HIV-1
      seronegative individuals (odds ratios = 2.13-4.82; P = 0.003-0.05) for several
      SNPs and haplotypes defined at the IL4, IL4R, IL6, IL10, CCL5 (RANTES), and
      CXCL12 (SDF1) loci. In addition, the homozygous IL4-590T/T genotype was
      associated with higher (+87-131 cells/microL) CD4 T-cell counts in HIV-1-infected
      and AIDS-free adolescents not receiving antiretroviral therapy (adjusted P =
      0.004). No SNPs at IFNG, IL2, IL12B, TNF, or CCL2 (MCP1) showed any association
      with HIV-related outcomes. Additional typing for IL1A, IL1B, IL1R1, IL1RN, and
      TGFB1 SNPs also failed to demonstrate any influence on HIV-1 infection or
      virologic/immunologic control in more selected patient groups. Coupled with
      previous findings, our data suggest that heritable IL4 and IL10 variations may
      contribute to the acquisition or progression of HIV infection and that the
      effects of other targeted loci in the cytokine and chemokine system cannot be
      established unequivocally in the study populations.

PMID- 15021310
TI  - Human alpha defensin in HIV-exposed but uninfected individuals.
AB  - Human alpha defensins 1, 2, and 3 are produced by CD8 T cells of HIV-infected
      long-term nonprogressors and have an antiviral activity. alpha Defensins were
      examined in peripheral blood mononuclear cells (PBMCs), cervical-vaginal
      mononuclear cells (CVMCs), and cervical biopsies of 9 HIV-1-exposed but
      uninfected women (ESNs), 10 HIV-infected patients (HIV), and 13 low-risk healthy
      controls (HCs). Results showed that, whereas alpha defensin production and alpha
      defensin-expressing CD8 lymphocytes were comparable in ESNs and HIV patients,
      constitutive alpha defensin production by peripheral CD8 and CVMCs was augmented
      in ESNs compared with HCs (P = 0.001 and P = 0.058, respectively); alpha defensin
      mRNA was increased in PBMCs of ESNs; unstimulated, alpha defensin-expressing
      peripheral and mucosal CD8 lymphocytes were 10-fold higher in ESNs compared with
      HCs (P = 0.003 and P = 0.01, respectively); and alpha defensin mRNA and alpha
      defensin-expressing cells were augmented in cervical biopsies of ESN compared
      with HCs (mRNA:P = 0.03). The differences were reduced upon in vitro mitogen
      stimulation. A robust constitutive production of alpha defensin is seen in HIV
      exposed uninfected individuals; these peptides could have a role in the
      potentially protective immune response that characterizes ESNs.

PMID- 15021311
TI  - Daily versus thrice-weekly interferon alfa-2b plus ribavirin for the treatment of
      chronic hepatitis C in HIV-infected persons: a multicenter randomized controlled
      trial.
AB  - Among HIV-infected persons, chronic hepatitis C virus (HCV) infection causes
      substantial morbidity and mortality. However, few studies have evaluated the
      safety and efficacy of interferon alfa (IFN) and ribavirin (RBV) therapy in co
      infected persons. Accordingly, a randomized, controlled, open-label, multicenter
      trial was conducted to establish the safety, tolerability, and efficacy of IFN
      alfa-2b 3 mIU daily plus RBV 800 mg/d compared with IFN alfa-2b 3 mIU thrice
      weekly (TIW) plus RBV 800 mg/d in HCV treatment-naive, HIV-infected subjects with
      compensated liver disease and stable HIV disease. The primary endpoint was
      sustained virologic response (SVR), defined as an undetectable HCV RNA level 24
      weeks after discontinuation of HCV therapy. At study entry, subjects in both
      groups were similar with respect to age, gender, HCV genotype, and HIV disease
      status. Of 180 randomized subjects, 162 received at least 1 dose of study
      medication, constituting the modified intention-to-treat population. After 12
      weeks of therapy, 122 (75%) had serum HCV RNA levels assessed; of these subjects,
      early virologic response (undetectable HCV RNA or >2 log10 decrease from
      baseline) was observed in 33 (42%) and 13 (16%) of subjects taking daily and TIW
      IFN, respectively (P < 0.001). SVR was observed in 15 (19.0%) and 7 (8.4%) of
      subjects taking daily and TIW IFN, respectively (P = 0.05). Adverse events were
      similar in both groups. However, while no deaths or opportunistic infections were
      observed, nearly 30% of subjects stopped treatment due to adverse events and 7
      subjects experienced a serious adverse event. In conclusion, SVR was achieved in
      19% of HIV/HCV coinfected subjects treated with daily IFN plus RBV, but the
      effectiveness of therapy was substantially diminished by relatively high rates of
      treatment-related toxicity.

PMID- 15021314
TI  - Efavirenz versus nevirapine in current clinical practice: a prospective, open
      label observational study.
AB  - An open-label, observational, prospective 18-month survey was conducted to
      compare the efficacy and tolerability of the 2 available nonnucleoside reverse
      transcriptase inhibitors (NNRTIs) in all possible indications of current clinical
      practice. A broad range of clinical and laboratory variables accounting for drug
      efficacy and tolerability (with special emphasis on metabolic and hepatic
      toxicity) were measured in 287 evaluable patients treated with efavirenz,
      compared with 258 subjects taking nevirapine for 18 months. A separate efficacy
      analysis was performed in 154 antiretroviral-naive subjects, 298 patients
      experienced with 2-7 prior anti-HIV lines who abandoned protease inhibitors
      (PIs), and 103 subjects entering a salvage regimen containing at least 4 drugs,
      including PIs. Antiretroviral-naive patients experienced greater efavirenz
      activity at 3-12 months (maximum HIV RNA drop =-2.4 log(10) copies/mL),
      associated with a significantly higher rate of complete viral suppression, while
      immunologic results proved significant only after 6-9 months. When assessing
      experienced patients and those on rescue regimens, a similar and progressively
      blunted laboratory response was achieved, on the ground of a worse baseline
      virologic and immunologic profile, and duration of prior anti-HIV therapy. Both
      first-month (4.2 and 4.3% for efavirenz and nevirapine, respectively) and overall
      discontinuation rates (11.5 and 12%, respectively) proved similar, but a profound
      difference emerged as to the different spectrum of untoward events: central
      nervous system (CNS) disturbances, persisting metabolic abnormalities, and
      possibly gynecomastia and laboratory pancreatic abnormalities for efavirenz vs.
      immediate allergy and increased hepatotoxicity (regardless of chronic infection
      with hepatitis B or C virus and methadone use) for nevirapine. A limited
      virologic and immunologic advantage of efavirenz was observed in the first 12
      month assessment of antiretroviral-naive patients, whereas all other examined
      situations did not disclose relevant efficacy differences between efavirenz and
      nevirapine throughout the 18-month comparison. Although the short- and long-term
      toxicity and withdrawal rates of the 2 drugs were comparable, the different
      pathways prompting allergic, metabolic, liver, and CNS disturbances observed with
      NNRTIs deserve careful investigation, to prevent toxicity of these relevant
      antiretroviral compounds.

PMID- 15021313
TI  - Abnormal vaginal cytology in HIV-infected and at-risk women after hysterectomy.
AB  - OBJECTIVE: To determine the frequency of and risk factors for abnormal vaginal
      Papanicolaou smears in HIV-infected women after hysterectomy. METHODS: Data were
      from the HIV Epidemiology Research (HER) study, a prospective multisite study of
      HIV-infected and uninfected women. Semiannual vaginal Papanicolaou smears and
      colposcopy data were obtained from 102 HIV-infected and 46 at-risk women who had
      hysterectomy either before or during the study. Analytic models used include Cox
      proportional hazards (women with hysterectomy during the study) and multiple
      logistic regressions, which corrected for repeated measures (all women). RESULTS:
      Among the HIV-infected women, evidence of cervical intraepithelial neoplasia
      before or at hysterectomy was associated with abnormal cytology during follow-up;
      63% had squamous intraepithelial lesions (SIL) on vaginal Papanicolaou smears
      following hysterectomy. CD4 counts of <200 cells/microL at hysterectomy and HIV
      viral load of >10,000 copies/mL at hysterectomy were predictive of SIL vaginal
      cytology. Prevalent SIL vaginal cytology was associated with low CD4 count and
      human papillomavirus risk type. Of the 102 HIV-infected women, 16 (16%) had
      vaginal intraepithelial neoplasia on biopsy. CONCLUSIONS: The high rate of SIL on
      vaginal Papanicolaou smears and the presence of high-grade vaginal
      intraepithelial neoplasia among HIV-infected women after hysterectomy demonstrate
      the need for continued follow-up for lower genital tract lesions.

PMID- 15021312
TI  - Drug-resistant variants that evolve during nonsuppressive therapy persist in HIV
      1-infected peripheral blood mononuclear cells after long-term highly active
      antiretroviral therapy.
AB  - The aim of this study was to determine whether drug-resistant virus persists in
      peripheral blood mononuclear cells (PBMCs) after long-term suppression of virus
      replication. Proviral DNA was extracted from the PBMCs of 11 patients on long
      term highly active antiretroviral therapy (HAART). Genotyping of the reverse
      transcriptase (RT) and protease gene of several proviral variants was performed
      using limiting dilution polymerase chain reaction and single-copy sequencing. All
      patients were on successful HAART for a mean period of 59 months but had a
      history of suboptimal therapy and genotypic drug resistance before. Comparison of
      the amino acid sequence of the RT and protease gene in the different proviral
      variants, with that of the plasma virus isolated before HAART treatment, revealed
      that the different drug-resistant viral variants that evolved during the process
      of gradually building up resistance were still detectable in the PBMCs in 10 of
      the 11 patients tested. The proportion of resistant variants was found to
      correlate with the time that the resistant variants had been able to replicate.
      These data clearly show that virus variants that are able to replicate for a
      certain period enter the latent reservoir and remain archived in the PBMCs for a
      very long period.

PMID- 15021315
TI  - High-risk behavior and potential transmission of drug-resistant HIV among
      injection drug users.
AB  - Evidence of increasing prevalence of drug resistance among recent HIV
      seroconverters indicates a growing public health concern and warrants an
      examination of the problem from a prevention perspective. Among 638 HIV-infected
      injection drug users (IDUs) completing 2731 visits between December 1996 and
      February 2000 in an ongoing cohort study in Baltimore, Maryland, factors
      associated with unprotected sex and needle sharing were determined. Participants
      were classified as being at higher or lower risk of HIV and of drug-resistant HIV
      transmission based on viral load, antiretroviral therapy use, and reported high
      risk behavior. Stored plasma of those at higher risk of drug-resistant HIV
      transmission was tested for resistance by VirtualPhenotype (Vircolab, Rockville,
      MD). Women were nearly twice as likely as men to engage in unprotected sex, and
      IDUs were more likely to have unprotected sex if their sexual partners were also
      HIV infected. IDUs were at higher risk of HIV and drug-resistant HIV transmission
      at 19% and 6% of all visits, respectively. Participants were infected with drug
      resistant HIV at 14% of visits when they were at higher risk of HIV transmission.
      Intensive risk reduction counseling is needed and must be integrated into routine
      HIV clinical care.

PMID- 15021316
TI  - Failure to return for HIV test results among persons at high risk for HIV
      infection: results from a multistate interview project.
AB  - BACKGROUND: Voluntary counseling and testing is an important strategy for HIV
      prevention. For optimal impact, however, clients must return for HIV test results
      and counseling. The goal of this study was to document the frequency of self
      reported failure to return for HIV test results (FTR) and associated reasons
      among persons at high risk for HIV infection. METHODS: Respondents were recruited
      at gay bars (men who have sex with men [MSM]), by street intercept (injection
      drug users [IDUs]), or at sexually transmitted disease clinics (high-risk
      heterosexuals [HRHs]) in 7 US states in 2000. Self-reported history of and
      reasons for FTR were evaluated. RESULTS: FTR was commonly reported among 2241
      respondents: 10% of MSM, 20% of HRHs, and 27% of IDUs reported FTR at least once.
      FTR was significantly (P < 0.05) more common among those with higher perceived
      risk of HIV infection and significantly less common among HRHs who had completed
      more than high school (vs. high school or General Education Development
      certificate) or were employed part time (vs. unemployed). About one fourth of
      respondents cited fear of getting test results as an important reason for FTR.
      CONCLUSION: Self-reported occurrences of FTR in our venue-recruited sample were
      similar to proportions of FTR previously reported from publicly funded venues.
      Increased pretest counseling on fear of learning HIV status and on the
      availability of rapid testing may help to reduce FTR.

PMID- 15021317
TI  - Behavioral impact, acceptability, and HIV incidence among homosexual men with
      access to postexposure chemoprophylaxis for HIV.
AB  - BACKGROUND: Little is known about the behavioral impact, acceptability, and
      incidence of HIV infection in persons with easy access to post-sexual exposure
      prophylaxis (PEP) to prevent HIV. METHODS: Participants were recruited from a
      well-characterized, high-risk HIV seronegative homosexual male cohort in Rio de
      Janeiro, Brazil, given a 4-day supply of zidovudine and lamivudine, and
      instructed to begin PEP immediately after an eligible exposure. For eligible
      exposures, an additional 24-day supply was provided. Reported behavior, PEP
      utilization, adverse events, and incident HIV infection were the main study
      outcomes. The observed and expected incidences of HIV infection were compared.
      RESULTS: Two hundred subjects were enrolled and followed for a median of 24.2
      months. The median age was 28 years. PEP was initiated 109 times by 68
      participants (34.0%). In comparison to reported behavior at baseline, reported
      high-risk sexual activities on average declined over time for both PEP and non
      PEP users. There were no serious drug-related adverse events. There were 11 HIV
      seroconversions, 10 among non-PEP users and 1 that was a PEP failure. The overall
      seroincidence was 2.9 per 100 person-years (95% CI = 1.4, 5.1). The expected
      number of new HIV infections and corresponding expected seroincidence based on
      the risk profile were 11.8 and 3.1, respectively (P > 0.97). The most commonly
      reported reasons for not initiating PEP among seroconverters were sex with a
      steady partner and not considering the exposure to be of sufficiently high risk
      to warrant PEP. CONCLUSION: PEP was safe and did not appear to be associated with
      increases in reported high-risk behavior in our cohort. Ready access to PEP did
      not appear to substantially affect HIV transmission, suggesting a limited public
      health impact of this intervention.

PMID- 15021318
TI  - Associations of race/ethnicity with HIV prevalence and HIV-related behaviors
      among young men who have sex with men in 7 urban centers in the United States.
AB  - Using data from a multisite venue-based survey of male subjects aged 15 to 22
      years, we examined racial/ethnic differences in demographics, partner type,
      partner type-specific condom use, drug use, and HIV prevalence in 3316 US black,
      multiethnic black, Latino, and white men who have sex with men (MSM). We further
      estimated associations of these factors with HIV infection and their influence on
      racial/ethnic disparities in HIV prevalence. HIV prevalences were 16% for both
      black and multiethnic black participants, 6.9% for Latinos, and 3.3% for whites.
      Paradoxically, potentially risky sex and drug-using behaviors were generally
      reported most frequently by whites and least frequently by blacks. In a multiple
      logistic regression analysis, positive associations with HIV included older age,
      being out of school or work, sex while on crack cocaine, and anal sex with
      another male regardless of reported condom use level. Differences in these
      factors did not explain the racial/ethnic disparities in HIV prevalence, with
      both groups of blacks experiencing more than 9 times and Latinos experiencing
      approximately twice the fully adjusted odds of infection compared with whites.
      Understanding racial/ethnic disparities in HIV risk requires information beyond
      the traditional risk behavior and partnership type distinctions. Prevention
      programs should address risks in steady partnerships, target young men before
      sexual initiation with male partners, and tailor interventions to men of color
      and of lower socioeconomic status.

PMID- 15021319
TI  - Comparison of generic zidovudine + lamivudine (Cipla, Duovir) and the
      GlaxoSmithKline brand (Combivir) tablets.

PMID- 15021320
TI  - Can HIV-infected patients fast during the month of Ramadan?

PMID- 15021321
TI  - Hepatotoxicity associated with nevirapine use.

PMID- 15021322
TI  - Detection of acute atrial thrombus in a porcine model with atrial fibrillation
      with tc 99m-apcitide.
AB  - RATIONALE AND OBJECTIVES: Technetium-99m apcitide (AcuTect) is a peptide with
      high affinity and specificity for glycoprotein IIb/IIIa receptors on platelets
      and is currently approved for the diagnosis of deep venous thrombosis. This study
      evaluates the use of Tc-99m apcitide for detecting intracardiac thrombus in an
      animal model with atrial fibrillation. METHODS: Thrombogenic material (0.23+/-
      0.03 g) was implanted within the left atrium of 5 swine with induced atrial
      fibrillation. Scintigraphy was performed with a small field of view gamma camera
      (minimum of 400000 counts) 1 hour after implantation at 10, 60, and 120 minutes
      after the injection of the Tc-99m apcitide. Animals were then euthanized and a
      postmortem examination performed to confirm thrombus formation. RESULTS: : In all
      animals, thrombi and microthrombi were confirmed within the left atrial
      appendage. The average wet weight of the thrombus was 1.4 +/- 0.2 g. Tc-99m
      apcitide detected left atrial thrombus in all animals. CONCLUSIONS: This study
      suggests that AcuTect may prove useful for detecting intracardiac thrombus in
      future clinical studies in man.

PMID- 15021324
TI  - Xenon-inhalation computed tomography for noninvasive quantitative measurement of
      tissue blood flow in hepatocellular carcinoma.
AB  - OBJECTIVE: The purpose of this study was to separately measure the arterial and
      portal venous tissue blood flow (TBF) of hepatocellular carcinoma (HCC) with a
      noninvasive method using xenon inhalation CT (xenon-CT) and to differentiate
      between well-differentiated HCCs and moderately and poorly differentiated HCCs.
      MATERIALS AND METHODS: Total, arterial and portal venous TBFs of 38 surgically
      proven HCC nodules from 38 patients were measured by means of xenon-CT. Serial
      abdominal CT scans were obtained before and after inhalation of nonradioactive
      xenon gas. TBF was computed using the Fick principle, after which the correlation
      between TBF and pathologic features of the tumors was determined. RESULTS: Total,
      arterial, and portal venous TBFs of HCC were 125.7 +/- 59.9 mL/min/100g, 102.5 +/
      37.3, and 22.2 +/- 11.4, respectively, and the corresponding findings for
      hepatic parenchyma were 67.3 +/- 13.1, 25.2 +/-9.6, and 42.4 +/- 11.0. Total and
      arterial TBFs of HCC were significantly higher than those of the hepatic
      parenchyma (P < 0.01), whereas portal venous TBF of HCC was significantly lower
      than that of hepatic parenchyma (P < 0.01). Arterial TBF of moderately or poorly
      differentiated HCC (120.4 +/- 38.2) was significantly higher than that of well
      differentiated HCC (60.4 +/- 43.5) (P < 0.01). CONCLUSIONS: Arterial and portal
      venous TBFs of HCC could be measured separately, noninvasively, and safely with
      xenon-CT. Correlation between TBF and pathologic features of tumors indicate that
      xenon-CT can be used to differentiate between well-differentiated HCCs and
      moderately and poorly differentiated HCCs.

PMID- 15021323
TI  - Evaluation of chest motion and volumetry during the breathing cycle by dynamic
      MRI in healthy subjects: comparison with pulmonary function tests.
AB  - RATIONALE AND OBJECTIVES: To investigate diaphragm and chest wall motion during
      the whole breathing cycle using magnetic resonance imaging (MRI) and a volumetric
      model in correlation with spirometry. MATERIALS AND METHODS: Breathing cycles of
      15 healthy volunteers were examined using a trueFISP sequence (5 slices in 3
      planes, 3 images per second). Time-distance curves were calculated and correlated
      to spirometry. A model for vital capacity (VC), continuous time-dependent vital
      capacity (tVC), and investigating the influence of horizontal and vertical
      parameters on tVC was introduced. RESULTS: Time-distance curves of the breathing
      cycle using MRI correlated highly significant with spirometry (P < 0.0001). VC
      calculated by the model was similar to VC measured in spirometry (5.00 L vs. 5.15
      L). tVC correlated highly significantly with spirometry (P < 0.0001). Vertical
      parameters had a more profound influence on tVC change than horizontal
      parameters. CONCLUSIONS: Dynamic MRI is a simple noninvasive method to evaluate
      local chest wall motion and respiratory mechanics. It widens the repertoire of
      tools for lung examination with a high temporal resolution.

PMID- 15021325
TI  - Low mechanical index contrast-enhanced ultrasound better reflects high arterial
      perfusion of liver metastases than arterial phase computed tomography.
AB  - RATIONALE AND OBJECTIVES: We investigated whether observing the arterial
      vascularization of liver metastases by contrast-enhanced ultrasound with low
      mechanical index (low-MI) imaging offers additional diagnostic information for
      the characterization of the liver lesions. METHODS: Twenty nine patients with
      untreated liver metastases of different primaries were examined. Measurements
      were performed using a low frame rate, low-MI pulse inversion technique after
      injection of 2.4 mL SonoVue. The relative maximum signal intensity of the liver
      lesions related to the normal liver tissue was quantified. Ultrasound findings
      were compared with contrast-enhanced, dual-phase computed tomography (CT) using a
      pattern-based classification scheme. RESULTS: Compared with contrast-enhanced CT,
      this modality better detects arterial perfusion. Metastases, even those usually
      considered hypovascularized, often showed homogeneous enhancement (66%) and
      higher arterial vascularization than normal liver tissue. CT did not show a
      comparable vascularization pattern (P < 0.001) or any similarly early signal
      intensity (P < 0.001). CONCLUSIONS: Contrast-enhanced CT may not be able to
      visualize short-lasting but large differences of the arterial perfusion of liver
      metastases, as does contrast-enhanced low-MI ultrasound. This offers new methods
      for their characterization and for monitoring of therapeutic effects.

PMID- 15021326
TI  - Multisegment and halfscan reconstruction of 16-slice computed tomography for
      detection of coronary artery stenoses.
AB  - RATIONALE AND OBJECTIVES: To compare the diagnostic accuracy and image quality of
      2 reconstruction algorithms (multisegment and halfscan) for computed tomography
      (CT) coronary angiography in patients without beta-blocker medication. MATERIALS
      AND METHODS: Thirty-four patients with 42 significant coronary stenoses in 136
      main coronary branches were examined using a 16-slice CT scanner (Aquilion,
      Toshiba, Otawara, Japan). Twenty-seven patients (79%) had heart rates above 65
      beats/min. RESULTS: Without exclusion of branches the sensitivity, specificity,
      accuracy, and rate of nonassessable segments with multisegment versus halfscan
      reconstruction were 88 versus 74%, 91 versus 71%, 90 versus 72%, and 2 versus 21%
      (P < 0.01), respectively. Multisegment reconstruction improved the average vessel
      length free of motion artifacts by 56% compared with halfscan reconstruction (P <
      0.01). Image quality in terms of vessel continuity and visibility of side
      branches (P < 0.005) was significantly better using multisegment reconstruction.
      CONCLUSIONS: Multisegment reconstruction has superior diagnostic accuracy and
      image quality compared with halfscan reconstruction in patients with normal heart
      rates.

PMID- 15021327
TI  - Quantification of aortic valve calcification with electron beam tomography: a
      histomorphometric validation study.
AB  - RATIONALE AND OBJECTIVES: The exact quantification of the amount of calcification
      in aortic valves may be useful for the identification of risk factors for the
      progression of aortic valve calcification and to evaluate new therapeutic
      approaches for aortic valve disease. Electron beam tomography (EBT) allows the in
      vivo detection of calcifications in coronary vessels and in the aortic valve. The
      aim of this study was to validate the quantification of aortic valve
      calcification by EBT with in vivo and in vitro investigations. METHODS: In 15
      patients (aortic stenosis in 13, aortic regurgitation in 2 cases), EBT was
      performed before aortic valve replacement (40 cross sections, 3-mm slice
      thickness, matrix 512 x 512, field of view 28 cm, ECG trigger at 40% of the
      cardiac cycle). EBT was repeated on the explanted aortic valve using the same
      protocol. In both data sets, the amount of aortic valve calcification was
      determined using a volumetric score. In serial cuts of the explanted valve
      (distance 1 mm), the calcified volume was determined by an independent
      investigator using histomorphometric analysis. RESULTS: The mean calcified volume
      of the aortic valves as quantified by EBT was 1650.0 +/- 1401.0 mml in vivo
      (EBT1) and 1544.4 +/- 1266.5 mml in vitro (EBT2). Histomorphometric analysis
      showed a mean calcified volume of 1555.7 +/- 1272.5 mml. The mean difference
      between EBT1 and EBT2 was 4.2 +/- 14.7%, between EBT1 and histomorphometry 3.6 +/
      12.1%, and between EBT2 and histomorphometry -0.5 +/- 5.9%. CONCLUSION: EBT
      allows accurate in vivo quantification of aortic valve calcifications.

PMID- 15021328
TI  - Ln(III)-DOTAMGly complexes: a versatile series to assess the determinants of the
      efficacy of paramagnetic chemical exchange saturation transfer agents for
      magnetic resonance imaging applications.
AB  - RATIONALE AND OBJECTIVES: Paramagnetic Ln-DOTAMGly complexes (Ln not equal La,
      Lu, and Gd) are the prototypes of a novel class of contrast agents for magnetic
      resonance imaging based on chemical exchange saturation transfer (CEST). Their
      ability to reduce the water signal intensity depends on the interplay of several
      physico-chemical properties of the agent and instrumental parameters. This study
      aims to identify possible routes for their optimization METHODS: Saturation
      transfer (ST) has been measured in vitro at 7.05 T as a function of pH,
      temperature, and concentration of the agent. RESULTS: Large saturation transfer
      effects have been observed upon irradiating the coordinated water protons (for Ln
      = Pr, Nd, Eu, and Tb). The comparison of the results obtained by irradiating
      water versus amide protons allows the set-up of ratiometric methods through which
      the ST response can be made independent on the concentration of the agent.
      CONCLUSIONS: The modulation of the magnetic properties along the lanthanide
      series allows an in-depth understanding of the determinants of ST effect and
      provides useful insights for the design of more efficient agents.

PMID- 15021329
TI  - Noninvasive extracorporeal thrombolysis using electrical discharge-induced shock
      waves: in vitro experiments.
AB  - RATIONALE AND OBJECTIVES: Many thrombectomy approaches have been developed for
      the treatment of venous thrombosis; however, no reference standard exists at this
      time. The aim of this study was to evaluate the efficacy of the transcutaneous
      application of electrical discharge-induced shock waves for thrombolysis in an in
      vitro model. METHODS: Shock waves were applied on a thrombus positioned in a
      plasma-containing silicon tube using 2 different energy flux densities (0.53 and
      2.26 mJ/mm). Depending upon the specific experiment, the thrombus was slightly
      moved to mimic pulsatory motions or/and additional Actilyse was added. Plasma
      samples were taken to determine the d-dimers before and after the application of
      shock waves. RESULTS: Energy of 0.53 mJ/mm was insufficient for thrombolysis
      whereas the energy of 2.26 mJ/mm yielded a removal rate of up to 76.4% when the
      thrombus was slightly moved during the procedure. The amount of d-dimers
      correlated well with the addition of Actilyse. However, this did not affect the
      removal rate significantly. CONCLUSION: The results demonstrate the potential of
      electrical discharge-induced shock waves for thrombolysis.

PMID- 15021440
TI  - If it feels good, do it: use of glucosamine sulfate to prevent the progression of
      osteoarthritis in postmenopausal women.

PMID- 15021441
TI  - Libido and the perimenopausal women.

PMID- 15021442
TI  - Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women
      with knee osteoarthritis: evidence from two 3-year studies.
AB  - OBJECTIVE: To investigate the effect of glucosamine sulfate on long-term symptoms
      and structure progression in postmenopausal women with knee osteoarthritis (OA).
      DESIGN: This study consisted of a preplanned combination of two three-year,
      randomized, placebo-controlled, prospective, independent studies evaluating the
      effect of glucosamine sulfate on symptoms and structure modification in OA and
      post-hoc analysis of the results obtained in postmenopausal women with knee OA.
      Minimal joint space width was assessed at baseline and after 3 years from
      standing anteroposterior knee radiographs. Symptoms were scored by the algo
      functional WOMAC index at baseline and after 3 years. All primary statistical
      analyses were performed in intention-to-treat, comparing joint space width and
      WOMAC changes between groups by ANOVA. RESULTS: Of 414 participants randomized in
      the two studies, 319 were postmenopausal women. At baseline, glucosamine sulfate
      and placebo groups were comparable for demographic and disease characteristics,
      both in the general population and in the postmenopausal women subset. After 3
      years, postmenopausal participants in the glucosamine sulfate group showed no
      joint space narrowing [joint space change of +0.003 mm (95% CI, -0.09 to 0.11)],
      whereas participants in the placebo group experienced a narrowing of -0.33 mm
      (95% CI, -0.44 to -0.22; P < 0.0001 between the two groups). Percent changes
      after 3 years in the WOMAC index showed an improvement in the glucosamine sulfate
      group [-14.1% (95%, -22.2 to -5.9)] and a trend for worsening in the placebo
      group (5.4% (95% CI, -4.9 to 15.7) (P = 0.003 between the two groups).
      CONCLUSION: This analysis, focusing on a large cohort of postmenopausal women,
      demonstrated for the first time that a pharmacological intervention for OA has a
      disease-modifying effect in this particular population, the most frequently
      affected by knee OA.

PMID- 15021444
TI  - Voice impairment and menopause.
AB  - OBJECTIVE: Menopause rating scales still do not regard voice impairment as a
      genuine climacteric symptom, although voice changes are frequently reported. The
      purpose of this study was both to register and differentiate voice alterations
      and disorders in menopausal women. DESIGN: A total of 107 women between 37 and 71
      years of age who were rated as postmenopausal according to their hormonal status
      answered a questionnaire on voice changes and vocal discomfort. RESULTS: Of this
      group, 49 women mentioned voices changes, and 35 of those women associated these
      changes with subjective discomfort, whereas 58 women mentioned neither voice
      changes nor discomfort. Sixteen of the women who mentioned voice changes and
      eight who did not participated in a comprehensive investigation, which included
      completion of the Klimax questionnaire, a head and neck examination,
      videostroboscopy, perceptual evaluation of voice sound, voice range profile
      measurements, and voice dysfunction index determination. CONCLUSIONS: Voice
      changes during menopause might be a common problem seen in clinical practice.
      Therefore, an additional systematic registration of voice impairment in future
      menopause rating scales should be considered if further studies confirm our
      findings of a high prevalence of voice complaints associated with menopause.
      Severe menopausal voice impairments, even without other climacteric symptoms,
      should be regarded as an indication for phoniatric examination.

PMID- 15021443
TI  - Predictors of decreased libido in women during the late reproductive years.
AB  - OBJECTIVE: To identify risk factors for decreased libido among women in the late
      reproductive years. DESIGN: Prospective cohort. Women aged 35 to 47 years
      identified through random digit dialing were prospectively followed for 4 years
      with serial hormone assays and standardized questionnaires. Mean hormone values,
      hormone trends over 4 years, and fluctuation in hormone levels were compared
      among women with and without a decrease in libido at the last assessment period.
      Total testosterone, dihydroepiandrosterone sulfate, estradiol, follicle
      stimulating hormone, luteinizing hormone, body mass index, psychosocial, and
      socioeconomic variables were evaluated using multivariable logistic regression.
      RESULTS: Of 326 women, 87 (27%) reported a decreased libido, whereas 239 (73%)
      did not. Participant-specific means for all hormone levels over the study period
      were similar among both groups. However, total testosterone fluctuation over the
      study was significantly different between groups. Women whose testosterone levels
      fluctuated from 3.8 to 21.5 ng/dL around a mean value of 9 ng/dL were four times
      more likely to report decreased libido compared with women with little
      fluctuation in testosterone [odds ratio (OR) 4.0; 95% CI, 1.6-10.0]. Depression
      (OR 3.4; 95%CI, 1.9-6.1), vaginal dryness (OR 3.5; 95%CI, 1.8-6.6), and children
      living at home (OR 1.4; 95%CI, 1.1-1.7) were also independently associated with
      decreased libido. CONCLUSIONS: Decreased libido in the late reproductive years is
      associated with a pronounced fluctuation in total testosterone over time. Other
      independent risk factors for decreased libido include vaginal dryness,
      depression, and living with children. Sexual dysfunction is a complex disorder,
      related to physiological and psychosocial factors, requiring further
      investigation.

PMID- 15021445
TI  - Androgens, insulin-like growth factor-I (IGF-I), and carrier proteins (SHBG,
      IGFBP-3) in postmenopause.
AB  - OBJECTIVE: To determinate the profile of androstenedione (A), total (T), and free
      testosterone (FT), dehydroepiandrosterone (DHEA), DHEA-sulphate (DHEAS), sex
      hormone-binding globulin (SHBG), insulin-like growth factor-I (IGF-I) and IGF
      binding protein-3 (IGFBP-3) in non-smoking, postmenopausal women of normal weight
      and to search for correlations between hormones and carrier proteins and
      chronological age, number of years of postmenopause and age of onset of
      menopause. DESIGN: A group of 149 postmenopausal women aged 49 to 74 years were
      divided into three groups based on the number of years of postmenopause: 2-4
      years (group A), 9-12 years (group B), and 19 years or more (group C). Seventy
      two women aged 21 to 35 years were the controls. Hormones and carriers were
      assessed in all groups. RESULTS: A, DHEA, DHEAS, and IGF-I were significantly
      lower than controls in all groups, whereas T, FT, SHBG, and IGBFP-3 were lower
      only in groups B and C. All hormones and carriers were negatively correlated with
      the number of years of postmenopause; DHEA and T also showed a positive
      correlation with the age of onset of menopause. CONCLUSIONS: Androgens, SHBG, and
      IGF-I/IGFBP-3 show a diversified decline in postmenopause that is involved in the
      physiological aging process. Thus, a modification, in excess or deficiency, could
      favor the development of central symptoms or pathologies.

PMID- 15021446
TI  - Transition from estrogen therapy to raloxifene in postmenopausal women: effects
      on treatment satisfaction and the endometrium-a pilot study.
AB  - OBJECTIVE: To compare the effects of transferring from low-dose, transdermal
      estrogen to raloxifene with a phase of alternate-day raloxifene therapy with or
      without low-dose transdermal estrogen on patient satisfaction, endometrial
      changes, and overall safety in healthy, postmenopausal women previously
      administered hormone therapy. DESIGN: Healthy postmenopausal women were
      randomized to one of two treatment groups: raloxifene + low-dose, transdermal
      estrogen (RLX+E) and raloxifene + placebo (RLX+P). The study consisted of four
      equal phases of 8 weeks each: Phase I (low-dose, transdermal estrogen, 25
      microg/day), phase II (double-blind, alternate-day raloxifene 60 mg + low-dose,
      transdermal estrogen or placebo patch), phase III (alternate-day RLX 60 mg +
      placebo patch), and phase IV (raloxifene 60 mg/day + placebo patch). Primary
      endpoints included patient satisfaction, endometrial changes, overall safety, and
      quality of life. RESULTS: Sixty women were randomized in this study. Baseline
      characteristics were similar between the two treatment groups. For the primary
      analysis (phase II to phase IV, inclusive), there were no significant differences
      between the therapy sequences for patient satisfaction, endometrial thickness, or
      quality of life. In the therapy comparison phase (phase II), mean change in
      patient satisfaction score was 3.2 mm (SD = 16.2) for RLX+E and -17.1 mm (SD =
      38.7) for RLX+P (P = 0.003), whereas mean change in endometrial thickness was 0.8
      mm (SD = 2.7) for RLX+E and -0.9 mm (SD = 1.5) for RLX+P (P = 0.021). The RLX+P
      group showed a significantly greater increase in vasomotor events, with a mean
      score change of 1.7 (SD = 1.9) compared with a mean score change of 0.2 (SD =
      1.8) in the RLX+E group (P = 0.005). There were no statistically significant
      differences between the two therapy groups in the reporting of treatment-emergent
      adverse events. CONCLUSION: Gradual conversion to raloxifene from low-dose
      estrogen, with a progression from 60 mg every alternate day to 60 mg/day, is a
      viable option in potentially symptomatic, postmenopausal women.

PMID- 15021447
TI  - A one-year follow-up on the effects of raloxifene on thyroid function in
      postmenopausal women.
AB  - OBJECTIVE: Estrogens increase serum thyroxine-binding globulin (TBG) and total
      thyroxine (TT4) concentrations. Serum free thyroxine (FT4) concentrations,
      however, remain normal. Raloxifene (RAL) is a selective estrogen receptor
      modulator used to treat postmenopausal osteoporosis. Data on the long-term
      effects of RAL on thyroid physiology are scanty. We evaluated the effects of RAL
      administration for 1 year on thyroid function in osteopenic, postmenopausal
      women. DESIGN: Fifty osteopenic, postmenopausal women were randomly assigned to
      receive either RAL (60 mg/day, n = 25) or placebo (PL, n = 25) for 1 year, in a
      double-blind study. Measurements of serum TBG, TT4, FT4, thyroid-stimulating
      hormone (TSH), thyroid hormone-binding ratio (THBR), FT4 index (FT4-I) and
      TT4/TBG ratio were carried out at baseline and after 4 and 12 months of therapy.
      RESULTS: Baseline values were similar in both treatment groups. Serum TBG
      concentrations were increased during RAL treatment from baseline values of 29.60
      +/- 0.9 microg/mL to 31.45 +/- 1.33 and 32.34 +/- 1.37 microg/mL at 4 months and
      1 year, respectively (P < 0.05, baseline v 1-year values) but were unchanged
      during PL treatment. A small, insignificant increase in TT4 and TSH
      concentrations occurred in the RAL group and no changes in the PL group. All
      other values were unchanged during either treatment. CONCLUSIONS: These results
      demonstrate that RAL significantly increased serum TBG levels, but the changes
      were small and not accompanied by changes in FT4-I, FT4, or TSH concentrations,
      suggesting that long-term RAL treatment is unlikely to clinically affect the
      thyroid status in euthyroid, postmenopausal women.

PMID- 15021448
TI  - Ovarian volume, age, and menopausal status.
AB  - OBJECTIVE: The purposes of this study were to verify whether ovarian volume
      differs according to chronological age and menopausal status in healthy women and
      to evaluate the sensitivity and specificity of ovarian volume alone and ovarian
      volume associated with age in predicting menopausal status. DESIGN: The
      participants in this study were premenopausal (n = 121) and postmenopausal (n =
      71) women between 40 and 55 years of age who were interviewed about social,
      demographic, and medical conditions. These women underwent transvaginal
      ultrasound to determine ovarian volume. Analysis of variance (ANOVA) was applied
      to evaluate the correlation between ovarian volume, age, and menopausal status.
      Receiver operating characteristic (ROC) curves were elaborated to evaluate the
      sensitivity and specificity of ovarian volume and age related to menopausal
      status. RESULTS: The difference in ovarian volume was significant and uniform as
      age increased in both groups (P = 0.03). Premenopausal women presented larger
      ovaries than did postmenopausal women. Menopausal status and age were correlated
      with ovarian volume. Menopausal status seemed more important than age in
      determining ovarian volume decrease (R = 0.36) because age contributed little
      when added to a model already containing menopausal status. ROC curves indicated
      that ovarian volume and age were effective in determining menopausal status. The
      best cutoff points in terms of sensitivity and specificity were ovarian volume
      less than 4 cm and age 48 years or older. The areas under the ROC curves of
      ovarian volume and ovarian volume plus age were similar. CONCLUSION: Ovarian
      volume differs according to age in premenopausal and postmenopausal women.
      Menopausal status is more important than age in determining ovarian volume. The
      data suggest that ovarian volume and age are quite accurate in predicting
      menopausal status.

PMID- 15021449
TI  - Staging reproductive aging: a comparison of proposed bleeding criteria for the
      menopausal transition.
AB  - OBJECTIVE: A staging system for female reproductive aging has recently been
      proposed. Bleeding criteria are an important component of a staging system, as
      bleeding patterns are readily observable. Several different bleeding criteria
      have been proposed, but their concordance and validity have not been evaluated.
      Five proposed bleeding criteria or markers for the onset of early menopausal
      transition and four criteria for the onset of the late transition were evaluated
      using data from the Menstruation and Reproductive History Study, or Tremin Trust.
      DESIGN: Correlations between time from age 35 to each marker event were assessed
      using Kendall's tau correlation coefficients. Kaplan-Meier survival analysis was
      used to examine associations between the marker events and age at final menstrual
      period (FMP). RESULTS: The first occurrence of marker events for the late
      menopausal transition demonstrated low to high correlation (r = 0.23 to 0.77),
      whereas the first occurrence of marker events for the early transition stage
      demonstrated no correlation to moderate correlation (r = 0.0 to 0.65). After age
      40, the occurrence of the marker events distinguished a subgroup of women who
      were more proximate to their FMP. Differences in years to FMP between women with
      and without the marker events were greatest in the early to mid-40s and declined
      with age. CONCLUSIONS: A 60-day cycle may be a desirable marker for entry into
      the late transition stage because of its reliability, proximity to the FMP, and
      ease of calculation. More work is needed to conceptually define the onset of the
      early menopausal transition before appropriate bleeding criteria can be
      established.

PMID- 15021450
TI  - Self-reported sleep in postmenopausal women.
AB  - OBJECTIVE: We aimed to find how self-reported sleep (measured by the St. Mary's
      Hospital Sleep Questionnaire) in postmenopausal women having hot flash activity
      was related to objective sleep (actigraphy), psychological and somatic symptoms
      [Women's Health Questionnaire (WHQ)], and cognitive test performance
      (computerized tests). A secondary aim was to find if self-reported sleep showed
      expected correlations with hyperarousal (Hyperarousal Scale). DESIGN: Drug trial
      baseline data from 88 healthy, postmenopausal women were retrospectively
      analyzed. Multivariate regression was used to adjust for confounder variables and
      test whether differences in self-reported sleep measures were systematically
      associated with differences in objective sleep, WHQ symptom measures, or
      cognitive test performance scores. RESULTS: Increased self-report scores for low
      sleep quality were associated with an increased risk of WHQ symptoms and reduced
      cognitive test performance. Self-reported sleep measures showed little
      correlation with their analogous objective measures. Self-reported low sleep
      quality proved most closely associated with the WHQ symptoms of tiredness,
      clumsiness, and difficulty concentrating. Women whose self-reported sleep-onset
      latency times were longer than the median overestimated their objective sleep
      onset time by 30 min, whereas the other women underestimated theirs by 15 min (P
      < 0.0001). Women whose self-reported total sleep was longer or shorter than the
      median, respectively, underestimated objective sleep times by 9 and 71 min (P <
      0.0001). High hyperarousal scores were associated with underestimations of
      objective sleep. CONCLUSION: Self-reports of lower sleep quality were associated
      with increased WHQ psychological and somatic symptom measures and decreased
      cognitive test performance more than with differences in objective sleep. Self
      reported trouble sleeping may signal problems independent from objectively low
      sleep quality, such as subjective distress or diminished cognitive function.

PMID- 15021451
TI  - Childhood abuse and neglect histories in low-income women: prevalence in a
      menopausal population.
AB  - OBJECTIVES: To examine the prevalence of self-reported childhood abuse and
      neglect in a primary care population of menopausal women. DESIGN: A cross
      sectional questionnaire-based study. RESULTS: Three of four women (119/160, 74%)
      reported histories of childhood abuse and neglect. The prevalence of emotional
      abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect were
      43%, 35%, 33%, 49%, and 44%, respectively. Eleven percent of the sample reported
      maltreatment in all five categories of trauma. Fifteen percent of women studied
      met criteria for severe-extreme levels of maltreatment, usually in more than one
      category. CONCLUSIONS: A high prevalence of self-reported childhood trauma was
      detected in our low-income population of menopausal women attending primary care
      clinics. Because of the potential impact of childhood trauma on physical and
      mental health, clinicians need to inquire about childhood maltreatment in women
      of menopausal age and appropriately refer women to mental health intervention and
      treatment.

PMID- 15021452
TI  - Postmenopausal estrogen and progestogen therapy and the risk of uterine
      leiomyomas.
AB  - OBJECTIVE: Leiomyomas are common benign neoplasms. Although hormone therapy is
      the most common and effective treatment for menopausal symptoms, little is known
      about its effect on leiomyomas. We examined the risk of a first diagnosis of
      leiomyomas in peri- and postmenopausal women associated with prior use of
      estrogen and progestogen therapy (EPT). DESIGN: A case-control study was
      conducted among enrollees from a nonprofit health plan. Cases had a first
      diagnosis of leiomyomas confirmed by surgery or ultrasound. Controls were women
      of the same age range without a diagnosis of leiomyomas selected at random from
      membership and outpatient files. Participants were interviewed regarding prior
      use of exogenous hormones, medical history, and reproductive history. This
      analysis was restricted to cases (n = 256) and controls (n = 276) who were peri-
      or postmenopausal and more than 40 years of age. Adjusted odds ratios (OR) and
      95% CIs were estimated using logistic regression models. RESULTS: EPT use for
      more than 5 years was associated with a 1.7-fold increased risk of leiomyomas
      (95% CI, 0.9-3.3). Associations with EPT use were only present among women with a
      body mass index less than 24 kg/m; OR (ever-use), 2.3 (95% CI, 1.2-4.3); and OR
      (>or= 5 years use), 4.0 (95% CI, 1.6-10.3). CONCLUSION: Among peri- and
      postmenopausal women, prior EPT use was associated with an increased risk of a
      subsequent leiomyomas. This association seemed limited to the subset of women
      with low body mass index. Exogenous sources of estrogen and progestin in the
      setting of low adiposity may contribute to the development of leiomyomas.

PMID- 15021453
TI  - Age and symptom experience at menopause in the Selska Valley, Slovenia.
AB  - OBJECTIVE: To assess age and symptom experience at menopause in a high-altitude
      population in the Selska Valley of Slovenia. DESIGN: In four mountain villages,
      all houses were approached and 80% of eligible residents were interviewed.
      Additional women were interviewed for comparison in the valley below. Age at
      interview ranged from 32.7 to 85.5 years, with a mean of 58.2 years. The majority
      of women (62%) were aged 40 to 65 years. RESULTS: Of the 58 women interviewed, 7
      had undergone menopause by hysterectomy (12%). Recalled age at natural menopause
      ranged from 42 to 54, with a mean of 50.3 (SD 2.9). By probit analysis, median
      age at natural menopause was 52.03. Fifty-five percent of participants reported
      ever having experienced a hot flash, although only 24% reported hot flashes
      during the 2 weeks before being interviewed. When the sample was limited to women
      aged 40 to 65, frequency of hot flashes in the 2 weeks before the interview was
      39%. For all participants, the most frequent complaint was lack of energy (66%),
      followed by backaches (59%), and joint stiffness (53%). CONCLUSIONS: In contrast
      to expectations, age at menopause was not earlier and hot flash frequency was not
      significantly lower at higher elevations.

PMID- 15021454
TI  - Rise and fall of hormone therapy in postmenopausal women with cardiovascular
      disease.
AB  - Whereas observational data for postmenopausal women using hormone therapy (HT)
      have shown a protective effect against cardiovascular disease, prospective,
      randomized trials have demonstrated a harmful effect on the vascular system. This
      study describes the effects of HT on lipids, hemostatic parameters, inflammation,
      and the vascular wall. Reasons for the different results of observational and
      experimental studies of HT are postulated. The timing of hormonal supplementation
      seems crucial. Used chronically, HT has no harmful effects; however, first-time
      use of HT after a recent cardiovascular event results in an early increase in
      adverse cardiovascular events. In most observational studies, women started HT
      for postmenopausal symptoms, whereas in experimental studies, women started HT 10
      to 20 years or longer after menopause. Cumulative evidence supports the
      hypothesis that HT has more effect in maintaining vascular health than in
      alleviating endothelial dysfunction. HT has not proven beneficial in the long
      term in women at risk of a cardiovascular event. The interval between menopause
      and the start of HT plays a crucial role in the effectiveness of HT in the
      vascular system.

PMID- 15021455
TI  - Women's health initiative.

PMID- 15021497
TI  - More information on national salaries.

PMID- 15021498
TI  - Conquer chronic wounds with wound bed preparation.

PMID- 15021500
TI  - Prescriptive authority and barriers to NP practice.

PMID- 15021501
TI  - CHF: effects of cardiac rehabilitation and brain natriuretic peptide.

PMID- 15021502
TI  - Epilepsy drug gets expanded indication.

PMID- 15021504
TI  - When patients refuse treatment.

PMID- 15021505
TI  - Detect ovulation with one-step test.

PMID- 15021506
TI  - Promoting breast cancer screening to women of color.

PMID- 15021507
TI  - Patient advocacy groups act as NP's ally.

PMID- 15021515
TI  - Taking charge of hospital-acquired pneumonia.

PMID- 15021764
TI  - Point prevalence of barotitis and its prevention and treatment with nasal balloon
      inflation: a prospective, controlled study.
AB  - INTRODUCTION: The most common cause of barotitis is pressure changes induced
      during descent in aviation. The incidence after air flight has been reported to
      vary from 8% to 17%. OBJECTIVES: We conducted this study to estimate the
      incidence of barotitis after flight, to evaluate whether the incidence of
      barotitis can be reduced by nasal balloon inflation during descent, and, finally,
      to estimate the effect of nasal balloon inflation in case of negative middle ear
      pressure after landing. STUDY DESIGN: Aircraft passengers were examined by
      otoscopy and tympanometry before and after flying and filled in a questionnaire
      inquiring about ear problems. On half of the flights, the passengers were asked
      to inflate a nasal balloon during descent, whereas the other half were control
      flights. RESULTS: A total of 188 passengers filled in the questionnaire. Of
      these, 134 were examined before and after the flight. Otoscopic signs of
      barotitis were found in 15% of the ears in the control group compared with 6% in
      the balloon inflation group. In ears with a negative pressure after flying, the
      pressure could be equalized by Valsalva's maneuver in 46%. Passengers who were
      unable to equalize the pressure in this way inflated a nasal balloon, and in 69%,
      this maneuver cleared the middle ear pressure. CONCLUSION: The incidence of
      barotitis in this study of aircraft passengers was 14%. This figure could be
      reduced to 6% in passengers who performed nasal balloon inflation during descent.
      We recommend nasal balloon autoinflation in aircraft passengers who have
      difficulty clearing their ears during and after flying.

PMID- 15021765
TI  - Mastoid osteomas: report of two cases.
AB  - OBJECTIVE: To discuss the differential diagnosis of two cases with mastoid mass.
      STUDY DESIGN: Case report and review of the literature. SETTING: The study was
      carried out in Gulhane Military Medical Academy, Haydarpasa Training Hospital,
      Istanbul, Turkey. PATIENT, INTERVENTION, AND RESULTS: Both cases were 23-year-old
      males. They admitted to our clinic with masses behind their left ears that had
      been progressively enlarging for 5 years. In both cases, coronal and axial
      computerized tomography scans revealed a wide-based lesion involving temporal
      bone cortex. The cases were operated on for diagnosis and for correction of the
      cosmetic deformity. Histopathological examinations were consistent with mixed and
      spongiotic osteoma. CONCLUSIONS: Mastoid osteoma is a rare, benign tumor of bone.
      It may cause cosmetic deformity such as external mass or an auricular protrusion.
      Other neoplasms of the mastoid region, such as osteosarcoma and osteoblastic
      metastasis, should be considered for the differential diagnosis.

PMID- 15021766
TI  - Ossicular reconstruction using bone cement.
AB  - OBJECTIVE: The objective of this study was to describe our results of ossicular
      reconstruction using bone cement. STUDY DESIGN: We conducted a retrospective
      review of 264 patients with chronic suppurative otitis media operated on since
      1999. SETTING: Academic tertiary referral center. PATIENTS: : Two hundred sixty
      four patients with chronic suppurative otitis media underwent mastoidectomy with
      tympanoplasty. Eighty patients had incudostapedial disarticulation secondary to
      infection and or cholesteatoma and were reconstructed using an incus
      interposition graft (n = 31), a partial ossicular prosthesis (POP; n = 31), or
      more recently, bone source (n = 18). This study evaluates the results of the
      ossiculoplasties using bone source. INTERVENTION: Ossicular discontinuity was
      repaired using bone cement. MAIN OUTCOME MEASURE: Audiometric studies pre- and
      postintervention were compared. One to 3 years of follow up are provided.
      RESULTS: Preoperative air-bone gaps ranged from 18 dB to 60 dB and averaged 33
      dB. Postoperative air-bone gaps ranged from 1 to 24 dB and averaged 10 dB. No
      patients have experienced any increase in their persistent conductive hearing
      loss. The pre-/postoperative hearing loss comparisons showed statistically
      significant hearing improvement. There were no complications. CONCLUSION: The use
      of POPs and incus interposition grafts is fraught with the possibility of
      migration and resultant recurrent conductive hearing loss. Using bone cement to
      reconstruct the ossicular chain restores the integrity of the ossicular chain in
      the most natural of ways. This reconstruction technique provides an excellent
      alternative to currently accepted methods and should be considered for incus
      stapes disarticulation. There has been no dissolution of the bone source and the
      results have persisted thus far.

PMID- 15021767
TI  - Gold and titanium in the oval window: a comparison of two metal stapes
      prostheses.
AB  - OBJECTIVE: The objective of this study was to evaluate the hearing results of
      stapes surgery with 2 different full metal stapes prostheses. STUDY DESIGN:
      Retrospective analyses were carried out on the pre- and postoperative hearing
      results obtained after primary stapedotomy with 2 different prostheses. PATIENTS:
      We studied 106 patients with otosclerosis treated by stapes surgery.
      INTERVENTION: Fifty-three patients had a stapedotomy with a gold piston and 53
      patients received a titanium piston after stapedotomy. MAIN OUTCOME MEASURES: The
      results were compared according to mean audiometric parameters. Furthermore, the
      individual audiologic results were demonstrated with the Amsterdam Hearing
      Evaluations Plot (AHEP). This method is a visual presentation of the hearing
      result for each operated ear. RESULTS: These AHEPs showed that the heavier gold
      piston (shaft O 0.4 mm and weight 10192.0 microg) gives more overclosure gain
      (28.3%) than the lightweight (shaft O 0.4 mm and weight 2541.0 microg) titanium
      piston (9.4% cases of overclosure). CONCLUSIONS: Because of the different
      properties of the 2 pistons (gold very malleable, titanium rather stiff), a
      choice can be made for different anatomic or pathologic situations in the
      operated middle ear. The "overclosure effect" of the gold piston is higher
      compared with the titanium piston.

PMID- 15021768
TI  - Hearing outcome of laser stapedotomy minus prosthesis (STAMP) versus conventional
      laser stapedotomy.
AB  - OBJECTIVE: The objective of this study was to compare short-and long-term hearing
      outcomes for patients undergoing primary laser stapedotomy minus prosthesis
      (STAMP) versus conventional laser stapedotomy. STUDY DESIGN: We conducted a
      retrospective case review of 167 consecutive patients from 1993 to 2002. SETTING:
      Otology/neurotology tertiary referral center. PATIENTS: We studied those with
      clinical otosclerosis without previous otologic surgery. INTERVENTIONS: Patients
      with otosclerosis confined to the fissula ante fenestram underwent STAMP.
      Patients with more extensive otosclerosis or anatomic contraindications to STAMP
      underwent standard laser stapedotomy. MAIN OUTCOME MEASURES: Pure-tone audiometry
      was performed before surgery, postoperatively, and on routine follow-up
      examination. RESULTS: Of the 183 ears in 167 patients, 128 (67.1%) underwent
      laser stapedotomy and 55 (32.98%) underwent STAMP. The STAMP mean air-bone gap
      (ABG) closed from a preoperative value of 22 dB (standard deviation [SD], 10 dB)
      to 6 dB (SD, 7 dB) on average follow up of 778 days. In 128 laser stapedotomy
      patients with an average follow up of 747 days, the preoperative mean ABG closed
      from 27 dB (SD, 10 dB) to 8 dB (SD, 7 dB). There was a trend toward improvement
      in high-frequency air conduction thresholds after STAMP versus worsening of high
      frequency thresholds in the conventional stapedotomy group. There was a
      statistically significant improvement in most recent postoperative high-frequency
      (6000-8000 Hz) air conduction thresholds in the STAMP patients compared with
      patients who underwent conventional laser stapedotomy. CONCLUSION: Laser STAMP,
      when used for isolated anterior footplate otosclerosis, provides excellent high
      frequency hearing, yields lasting results similar to conventional laser
      stapedotomy, and has a low incidence of refixation necessitating revision
      surgery.

PMID- 15021769
TI  - Pediatric cochlear implant patient performance as a function of age at
      implantation.
AB  - OBJECTIVE: The objective of this study was to examine the effect that age at
      implantation has on performance of children who received multichannel cochlear
      implants. STUDY DESIGN: This is a retrospective study of 295 children who were
      broken down into 5 age groups based on age at implantation: 1-3 years, 3-5 years,
      5-7 years, 7-9 years, and 9-11 years. Speech perception test scores obtained 12,
      24, and 36 months postactivation were compared for the 5 groups using repeated
      measures analysis of variance. SETTING: This study was carried out at a tertiary
      academic medical center. PATIENTS: Subjects consisted of 295 children who ranged
      in age from 12 months to 10 years 11 months at the time they obtained their
      cochlear implant. INTERVENTION: All patients received their cochlear implant at a
      single implant facility. MAIN OUTCOME MEASURES: Performance on several speech
      perception tests was compared 12, 24, and 36 months postactivation. Performance
      was evaluated as a function of age at implantation. RESULTS: Patients in all 5
      groups demonstrated improved scores when compared with scores obtained
      preoperatively with hearing aids. Repeated-measures analysis of variance (ANOVA)
      revealed a significant group by time interaction for 3 of the 5 measures. For all
      three of these measures, children implanted at younger ages demonstrated greater
      gains in speech perception over time than children implanted at older ages.
      CONCLUSIONS: These results are in agreement with those of previous studies
      indicating that early implantation facilitates improved development of speech
      perception skills in profoundly deaf children.

PMID- 15021770
TI  - Superior semicircular canal dehiscence presenting as conductive hearing loss
      without vertigo.
AB  - OBJECTIVE: The objective of this study was to describe superior semicircular
      canal dehiscence (SSCD) presenting as otherwise unexplained conductive hearing
      loss without vestibular symptoms. STUDY DESIGN: Retrospective. SETTING: Tertiary
      referral center. PATIENTS: The study comprised 8 patients (10 ears), 5 males and
      5 females aged 27 to 59 years. All 10 ears had SSCD on high-resolution computed
      tomography scan of the temporal bone. DIAGNOSTIC TESTS AND RESULTS: All 10 ears
      had significant conductive hearing loss. The air-bone gaps were largest in the
      lower frequencies at 250, 500, and 1000 Hz; the mean gaps for these 3 frequencies
      for the 10 ears were 49, 37, and 35 dB, respectively. Bone-conduction thresholds
      below 2000 Hz were negative (-5 dB to -15 dB) at one or more frequencies in 8 of
      the 10 ears. There were no middle ear abnormalities to explain the air-bone gaps
      in these 10 ears. Computed tomography scan and laboratory testing indicated lack
      of middle ear pathology; acoustic reflexes were present, vestibular evoked
      myogenic potentials (VEMPs) were present with abnormally low thresholds, and umbo
      velocity measured by laser Doppler vibrometry was above mean normal. Middle ear
      exploration was negative in six ears; of these six, stapedectomy had been
      performed in three ears and ossiculoplasty in two ears, but the air-bone gap was
      unchanged postoperatively. The data are consistent with the hypothesis that the
      SSCD introduced a third mobile window into the inner ear, which in turn produced
      the conductive hearing loss by 1) shunting air-conducted sound away from the
      cochlea, thus elevating air-conduction thresholds; and 2) increasing the
      difference in impedance between the oval and round windows, thus improving
      thresholds for bone-conducted sound. CONCLUSION: SSCD can present with a
      conductive hearing loss that mimics otosclerosis and could explain some cases of
      persistent conductive hearing loss after uneventful stapedectomy. Audiometric
      testing with attention to absolute bone-conduction thresholds, acoustic reflex
      testing, VEMP testing, laser vibrometry of the umbo, and computed tomograph
      scanning can help to identify patients with SSCD presenting with conductive
      hearing loss without vertigo.

PMID- 15021771
TI  - Side-lying as an alternative to the Dix-Hallpike test of the posterior canal.
AB  - OBJECTIVE: Limitations in passive or active range of motion preclude testing some
      patients suspected of benign paroxysmal positional vertigo of the posterior
      semicircular canal (BPPV) with the Dix-Hallpike maneuver. The goal of this study
      was to determine if an alternative test, brisk side-lying with the nose turned 45
      degrees away from the tested side, yields the same results as the Dix-Hallpike
      maneuver. STUDY DESIGN: Prospective, within-groups. SETTING: Diagnostic
      laboratory at a tertiary care center. PATIENTS: The 61 patients, seen before
      their physicians had determined their diagnoses, were all referred by their
      physicians for objective diagnostic tests. All subjects complained of vertigo
      elicited by up or down rotations of the head or turning over in bed, often
      provocative positions for BPPV. METHODS: Results from the Dix-Hallpike maneuver
      and side-lying maneuver were compared. Group 1 was tested with the Dix-Hallpike
      maneuver followed up by side-lying; Group 2 was tested in reverse order. MAIN
      OUTCOME MEASURES: Slow-phase eye velocity of nystagmus. RESULTS: With the groups
      collapsed to eliminate possible order effects, no significant differences were
      found between the tests. Significantly more subjects had no response to testing
      than minimal or stronger responses. CONCLUSIONS: Side-lying is a valid
      alternative test to the Dix-Hallpike maneuver, which could be useful when range
      of-motion limitations or other problems preclude use of the Dix-Hallpike
      maneuver.

PMID- 15021772
TI  - Characterizing and treating dizziness after mild head trauma.
AB  - OBJECTIVE: The objectives of this study were to characterize patterns of
      dizziness seen after mild head trauma and to examine the diagnosis and treatment
      of this disorder. STUDY DESIGN: Prospective patient registry. SETTING: Tertiary
      referral center. PATIENTS: Fifty-eight cases of active duty and retired military
      personnel who sustained mild head trauma and had resultant dizziness.
      INTERVENTIONS: Vestibular evaluation, characterization by group, and treatment.
      MAIN OUTCOME MEASURES: Outcome measures include characterization of diagnosis
      types, patient distribution by diagnosis type, and patient outcome. RESULTS:
      Individuals suffering from dizziness after mild head injury were divided into
      three diagnostic groups. Forty-one percent of the individuals suffered from
      posttraumatic vestibular migraines, 28% of the individuals had posttraumatic
      positional vertigo, and 19% of the individuals were classified as posttraumatic
      spatial disorientation. The remaining 12% of the patients could not be
      characterized. The positional group had objective physical examination findings,
      which cleared with treatment in all cases. The migraine group of patients and the
      disorientation group of patients had distinct abnormalities of the vestibulo
      ocular reflex (VOR) and the vestibulo-spinal reflex (VSR). Eighty-four percent of
      the migraine group demonstrated an improvement of these test results as compared
      with 27% of the disorientation group. Mean time to return to work was less than 1
      week for the positional group, 3.8 weeks for the migraine group, and greater than
      3 months for the disorientation group. CONCLUSIONS: Using our patient registry of
      individuals suffering from dizziness after mild head trauma, we were able to
      characterize the majority of these cases into one of three more specific
      diagnostic groups. We present diagnostic criteria, suggested treatment
      guidelines, and our prognostic data.

PMID- 15021773
TI  - Is perception of handicap related to functional performance in persons with
      vestibular dysfunction?
AB  - OBJECTIVE: The purpose of this study was to determine if scores between 0 and 30
      (mild), 31 and 60 (moderate), and 61 and 100 (severe) on the Dizziness Handicap
      Inventory (DHI) differentiated a person's functional abilities. STUDY DESIGN:
      Retrospective case series. SETTING: Tertiary balance outpatient center. PATIENTS:
      Patients (n = 85; mean age, 61 years) with a variety of vestibular diagnoses
      participated. INTERVENTIONS: Patients completed the DHI, the Dynamic Gait Index
      (DGI), the 5 times sit to stand test (FTSST), the Activities-specific Balance
      Confidence (ABC) scale, gait speed, and the Timed "Up & Go" (TUG) during the same
      session. Reported numbers of falls within the last 4 weeks were recorded. MAIN
      OUTCOME MEASURES: The DGI, FTSST, ABC, gait speed, TUG, and gait speed were
      compared among DHI groups. RESULTS: Significant differences were identified using
      an analysis of variance between DHI groups on the DGI, the FTSST, ABC, and number
      of falls (p < 0.05). A significant difference was found between DHI groups (mild
      vs. severe and moderate vs. severe) on the DGI (p < 0.05) with greater DHI scores
      exhibiting more impaired walking. The FTSST was different between DHI groups mild
      and severe and DHI groups moderate and severe (p < 0.05), with slower FTSST
      scores with higher DHI scores. Reported falls were higher among the severe DHI
      group and the other 2 DHI groups (p < 0.05). All 3 DHI groupings were different
      from each other on the ABC (p < 0.001). CONCLUSION: Patients who perceive a
      greater handicap as a result of dizziness demonstrate greater functional
      impairment than patients who perceive less handicap from dizziness.

PMID- 15021774
TI  - Clinical usefulness of extratympanic electrocochleography in the diagnosis of
      Meniere's disease.
AB  - OBJECTIVE: Electrocochleography has been introduced to aid the diagnosis of
      endolymphatic hydrops. The aim of this study was to evaluate the clinical
      effectiveness of extratympanic electrocochleography in the diagnosis of Meniere's
      disease. STUDY DESIGN: The medical records of patients diagnosed as having
      Meniere's disease at the department of otolaryngology were reviewed
      retrospectively. Thirty-seven healthy ears were included to calculate the upper
      level of the 95th percentile range of the extratympanic electrocochleography
      variables. SETTING: Tertiary referral university hospital. PATIENTS: One hundred
      fifty-eight patients (97 women and 61 men) diagnosed as having Meniere's disease
      without previous treatments were included. A retrospective analysis of their
      medical records, electrocochleographic results, audiograms, and follow-up records
      was performed. The mean age was 48.6 years. MAIN OUTCOME MEASURES: The upper
      level of the 95th percentile range of the extratympanic electrocochleography
      variables of normal subjects were calculated. Electrocochleography recording
      results were compared with the diagnostic scale and stage, presence of
      fluctuating hearing loss, and duration of symptoms. RESULTS: The 95% upper limit
      for baseline summating potential and action potential ratio was 0.34. Sensitivity
      and specificity of electrocochleography in the diagnosis of Meniere's disease
      were 71% and 96%, respectively. The results statistically correlated with the
      Meniere's current diagnostic criteria and did not correlate with the stage of
      disease, presence of fluctuating hearing loss, or duration of symptoms.
      CONCLUSION: Extratympanic electrocochleography may play an important role,
      especially in patients with less definite symptoms, but the diagnosis should also
      be anchored in the patient's clinical history, symptoms, and audiogram.

PMID- 15021775
TI  - Hearing changes after diagnosis in neurofibromatosis type 2.
AB  - OBJECTIVE: Describe the changes in hearing ability and progression of disease
      over time in subjects with neurofibromatosis Type 2 enrolled in a multicenter
      natural history study of vestibular schwannomas in neurofibromatosis Type 2.
      STUDY DESIGN: Retrospective clinical study. SETTING: International
      neurofibromatosis Type 2 tertiary care centers. PATIENTS: Study participants had
      a clinical diagnosis of neurofibromatosis Type 2, at least one untreated
      vestibular schwannoma, and were at least 5 years old. Sixty-three subjects (108
      ears) with audiology data at either short-term follow-up (7 mo-2 yr) or long-term
      follow-up (3-5 yr) after diagnosis were examined in this study. MAIN OUTCOME
      MEASURES: Changes in four-frequency pure-tone average and speech discrimination
      score before any treatment intervention for both follow-up intervals. RESULTS:
      Within 2 years of the diagnosis of neurofibromatosis Type 2, 27% of the ears
      experienced a significant loss in pure-tone average relative to diagnosis, and
      73% of the ears experienced no significant change in hearing. CONCLUSION: Newly
      diagnosed neurofibromatosis Type 2 patients who do not require immediate
      treatment of both vestibular schwannomas are likely to have stable hearing in the
      unoperated ear(s) for approximately 1 to 2 years.

PMID- 15021776
TI  - Expression of neuregulin and activation of erbB receptors in vestibular
      schwannomas: possible autocrine loop stimulation.
AB  - HYPOTHESIS: We sought to determine whether vestibular schwannomas are capable of
      producing and responding to the glial growth factor neuregulin. BACKGROUND:
      Neuregulin is a neuronally derived trophic factor that interacts with erbB2 and
      erbB3 receptors on Schwann cells and is required for normal Schwann cell
      proliferation, survival, and development. Vestibular schwannomas grow several
      millimeters or even centimeters away from adjacent axons, suggesting that
      vestibular schwannomas do not depend critically on axons for their proliferation
      or survival. This raises the possibility that vestibular schwannomas themselves
      produce and respond to trophic factors in an autocrine fashion. METHODS:
      Pathologic specimens from eight patients undergoing microsurgical removal of
      vestibular schwannomas and one patient undergoing vestibular nerve section were
      immunostained with anti-neuregulin, anti-erbB2, anti-erbB3, and anti
      phosphorylated-erbB2 antibodies. Three patients had received previous gamma knife
      radiation therapy and two patients had neurofibromatosis Type 2. RESULTS: The
      Scarpa ganglion neurons express neuregulin, and normal vestibular Schwann cells
      express erbB2 and erbB3. Vestibular schwannomas from all eight patients
      demonstrated neuregulin, erbB2, and erbB3 immunoreactivity. In addition, all
      vestibular schwannomas demonstrated immunoreactivity to anti-phosphorylated-erbB2
      antibody that only recognizes erbB2 when it is phosphorylated, or activated.
      CONCLUSION: These results demonstrate that vestibular schwannomas express
      neuregulin and its receptors, erbB2 and erbB3. Because erbB2 exists in an
      activated state, as evidenced by phosphorylated-erbB2 immunoreactivity, it likely
      responds to the locally produced neuregulin. This suggests the possibility that
      vestibular schwannomas produce and respond to neuregulin in an autocrine fashion.

PMID- 15021777
TI  - Intralabyrinthine schwannomas: diagnosis, management, and a new classification
      system.
AB  - OBJECTIVE: To outline the diagnosis and management of intralabyrinthine
      schwannomas and to propose a new classification system to further define them.
      STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center at a
      university hospital. PATIENTS: Twenty-eight patients seen at the institution with
      intralabyrinthine schwannomas between 1996 and 2002 were included in the study.
      INTERVENTIONS: Diagnosis was made with magnetic resonance imaging in all but one
      case. Our ability to detect these tumors has been greatly enhanced by the
      introduction of high-resolution T2-weighted magnetic resonance imaging. Treatment
      options were observation with serial magnetic resonance imaging versus complete
      surgical removal via a translabyrinthine or transotic approach. Surgery was
      indicated for dizziness caused by the tumor or extralabyrinthine growth. MAIN
      OUTCOME MEASURES: Clinical features, audiology, radiology, and management
      outcomes were evaluated. RESULTS: Eight patients have undergone successful
      surgery with removal of their tumors and resolution of symptoms. One patient
      chose to have stereotactic radiotherapy. Of the 20 patients who were managed with
      observation and serial magnetic resonance imaging, only 1 has shown significant
      growth requiring surgical removal. CONCLUSION: Intralabyrinthine schwannomas are
      uncommon tumors that mimic the clinical features of many other neurotologic
      conditions. A high index of suspicion and precise imaging are often required to
      detect these tumors. Surgical treatment is indicated for specific indications and
      will be needed in the minority of patients with this disorder. The classification
      system that we propose is helpful in both the diagnosis and the management of
      these tumors.

PMID- 15021778
TI  - A long-term study on hearing status in patients with nasopharyngeal carcinoma
      after radiotherapy.
AB  - OBJECTIVE: To study the long-term sensorineural hearing status after radiotherapy
      in patients suffering from nasopharyngeal carcinoma. STUDY DESIGN: A prospective
      study of 220 patients (395 ears) with a median follow-up of 36 months. SETTING: A
      university hospital. PATIENTS: Four criteria were needed. The patient had to have
      had at least 12 months of audiologic follow-up, no concurrent chronic ear
      disease, no direct tumor invasion of ear, and no significant sensorineural
      hearing loss before radiotherapy. INTERVENTION: Pure-tone audiography and
      impedance audiometry-which were performed before and at the third month after
      completion of radiotherapy and at a yearly interval thereafter-formed the basis
      of the study. MAIN OUTCOME MEASURES: The significance level in this study was
      defined as a bone conduction threshold increase of more than 10 dB between the
      initial audiogram and those obtained after the completion of radiotherapy. An
      increase of more than 30 dB was defined as severe loss. RESULTS: Paired t test
      indicated that the mean bone conduction threshold before and after radiotherapy
      were significantly different (paired t test, p < 0.05). Logistic regression
      showed that patient age was related to the significant loss at speech frequency
      but not to the loss at 4 kHz. The presence of postradiation otitis media with
      effusion, preirradiation hearing status, and addition of chemotherapy were found
      to be not influential on hearing change. CONCLUSION: Hearing deterioration may
      begin as early as 3 months after the completion of radiotherapy. Early change may
      be transient, but the effect of radiation on hearing tended to be chronic and
      progressive.

PMID- 15021779
TI  - Vertigo and hearing disturbance as the first sign of a glioblastoma (World Health
      Organization grade IV).
AB  - OBJECTIVE: To describe vertigo and hearing disturbance as a first sign of
      glioblastoma. STUDY DESIGN: Case report. SETTING: Ear, Nose, and Throat
      Department of the University of Regensberg, Germany. Primary Care Center.
      PATIENTS: A patient with a left temporal glioblastoma. RESULTS: A 67-year-old man
      presented with a 2-month history of vertigo and hearing disturbance. Radiological
      imaging revealed a left temporal tumor with dural inflation and erosion of the
      petrous bone and superior semicircular duct. The surgery involved total resection
      of the tumor and resurfacing of the gap in the superior canal. The
      histopathological examination revealed World Health Trade Organization IV
      glioblastoma. Postoperatively, the debilitating symptoms were relieved and the
      patient received radiation therapy. Tumor progression indicated a recraniotomy
      and a mastoidectomy. The tumor was only partially resected, and required
      chemotherapy. It subsequently developed otoliquorrhea and required a
      remastoidectomy. Histopathology of a pathological fracture of the X thoracic
      vertebra revealed a metastasis of the known glioblastoma. The patient died from
      respiratory distress syndrome. CONCLUSION: To the best of our knowledge, we are
      presenting the first case with transdural infiltration of bony structures by a
      glioblastoma at the moment of diagnosis. The transdural spread could be via the
      sinus petrosus and along the nervous petrosus major in the petrosal bone.
      Superior canal dehiscence syndrome should be considered in the differential
      diagnosis of vertigo and hearing disturbance. Two different processes for the
      etiology of the superior canal dehiscence syndrome are discussed previously in
      the literature; however, we present a new entity with a tumor-cause dehiscence of
      the bone overlying the superior canal.

PMID- 15021780
TI  - Sensorineural hearing loss and word deafness caused by a mesencephalic lesion:
      clinicoelectrophysiologic correlations.
AB  - OBJECTIVE: To assess the role of inferior colliculi as a generator of Wave V of
      brainstem auditory evoked potentials and in modulating the olivocochlear efferent
      auditory system. STUDY DESIGN: Case review. SETTING: University and tertiary
      referral centers. PATIENTS: Case report of a patient with word deafness caused by
      mesencephalic hemorrhage according to audiologic and electrophysiologic findings.
      RESULTS: The patient is a 48-year-old woman who suffered word deafness caused by
      hemorrhage localized at the quadrigeminal plate (including the inferior
      colliculi). At a follow-up visit, her pure-tone audiogram revealed symmetric
      severe sensorineural hearing loss that had partially resolved, whereas speech
      audiometry showed persistent word deafness. Acoustic reflexes were elicited, with
      normal thresholds bilaterally. Transient evoked otoacoustic emissions were
      recorded from both ears, with normal response and signal-to-noise ratio, but
      there was a failure for their amplitude to be suppressed with contralateral sound
      stimulation. Brainstem auditory evoked potentials were of normal amplitude and
      latencies bilaterally. CONCLUSION: The finding of normal brainstem auditory
      evoked potentials supports the view that the neural generator of Wave V lies
      caudally to the inferior colliculi. Moreover, the abnormal suppression of
      transient evoked otoacoustic emissions indicates that descending collicular input
      is capable of modulating levels of excitability within the olivary nucleus and
      the cochlea.

PMID- 15021781
TI  - Management of cystic facial neuromas: an alternative approach.
AB  - OBJECTIVE: To describe the treatment of cystic facial neuroma with drainage and
      marsupialization as an alternative to tumor removal and facial nerve grafting.
      STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral hospital.
      PATIENTS: Two cases of cystic facial neuroma. MAIN OUTCOME MEASURES: Maintenance
      of facial nerve function at or better than preoperative function. RESULTS: Both
      cases were managed with cyst drainage. Case 1 retained House-Brackmann Grade I
      facial nerve function. Case 2 retained Grade II function. CONCLUSION: Cyst
      drainage provides a useful alternative to tumor removal and nerve sacrifice in
      patients with predominantly cystic facial neuromas and serviceable facial
      function.

PMID- 15021782
TI  - Attenuation of cerebral oxygen toxicity by sound conditioning.
AB  - HYPOTHESIS: Sound conditioning might reduce cerebral oxygen toxicity. BACKGROUND:
      Cerebral oxygen toxicity is related to high levels of reactive oxygen species.
      Noise-induced hearing loss has been shown to result from ischemia-reperfusion, in
      which reactive oxygen species play a major role. Repeated exposure to loud noise
      at levels below that which produces permanent threshold shift prevented noise
      induced hearing loss and was associated with significant elevation of the
      antioxidant enzymes measured in the inner ear. We tested the hypothesis that
      sound conditioning might reduce cerebral oxygen toxicity. METHODS: Forty-five
      guinea pigs were prepared for electroencephalography and auditory brainstem
      recording. The auditory brainstem recording detection threshold was determined to
      confirm baseline normal hearing. The animals were divided into three equal groups
      and subjected to the following procedures: Group 1, electroencephalography
      electrode implantation and auditory brainstem recording only; Group 2, exposure
      to oxygen at 608 kPa (the latency to the first electrical discharge in the
      electroencephalogram preceding the appearance of seizures was measured); and
      Group 3, sound conditioning followed by oxygen exposure. The animals were killed,
      and the brains were excised and homogenized. Brain levels of superoxide
      dismutase, catalase, glutathione peroxidase, glutathione transferase, glutathione
      reductase, glucose-6-phosphate dehydrogenase, and thiobarbituric acid reactive
      substances were compared among the groups. RESULTS: Latency to the first
      electrical discharge was compared between Groups 2 and 3, and was found to be
      significantly longer in Group 3 (27.9 +/- 11 versus 20.4 +/- 7.6 min, p < 0.03).
      No significant changes were found in brain levels of superoxide dismutase,
      catalase, glutathione peroxidase, glutathione transferase, glutathione reductase,
      glucose-6-phosphate dehydrogenase, or thiobarbituric acid reactive substances.
      CONCLUSION: Our data show that sound conditioning prolongs the latency to oxygen
      induced convulsions. This effect was not accompanied by significant changes in
      whole-brain antioxidant enzyme activity or the magnitude of lipid peroxidation.

PMID- 15021783
TI  - Superficial siderosis of the central nervous system.

PMID- 15021784
TI  - Temporal bone fracture.

PMID- 15021791
TI  - Let's target and achieve standards of excellence.
AB  - Clearly communicate standards to your staff for optimal performance.

PMID- 15021792
TI  - Successfully meet pain assessment standards.
AB  - Learn how to best meet updated pain assessment standards.

PMID- 15021793
TI  - Immigration considerations: what to know when recruiting a foreign nurse.
AB  - Address several important issues before deciding to recruit a foreign registered
      nurse.

PMID- 15021794
TI  - Patients first when budgeting.

PMID- 15021795
TI  - What works... and what doesn't?

PMID- 15021797
TI  - Turn on the staying power.
AB  - As a nurse leader, you're in a pivotal position to influence recruitment and
      retention initiatives. Here, review best practices.

PMID- 15021799
TI  - Shoulder work intensity with Six Sigma.
AB  - Follow one hospital system's efforts to reduce nurses' work intensity using the
      "Six Sigma" problem-solving approach.

PMID- 15021800
TI  - Bringing end-of-life care out of the shadows.
AB  - Understand what resources are available to help you incorporate palliative and
      end-of-life care into your nursing practice.

PMID- 15021801
TI  - Case study: using ultrafiltration to manage CHF.
AB  - Identify and properly treat CHF through a thorough understanding of the disease's
      progression.

PMID- 15021802
TI  - Optimal patient safety a computer chip away?
AB  - Discover the latest technologic initiatives used to increase patient safety.

PMID- 15021804
TI  - Bringing talk to the table.
AB  - Unit-based interdisciplinary focus teams chaired by physician employee advocates
      strengthen nurse-physician communication.

PMID- 15021822
TI  - The organ center of the United Network for Organ Sharing and twenty years of
      organ sharing in the United States.
AB  - The increasing size of the transplant waiting list and the increasing use of
      expanded criteria donors places a premium on efficient use of recovered organs.
      Maximal organ utilization often necessitates organ sharing between transplant
      organizations. Optimal organ sharing requires rapid, integrated communication of
      donor information combined with expedited organ transportation. For more than 20
      years, the United Network for Organ Sharing's Organ Center has fulfilled this
      task for the United States transplant community. This overview details a brief
      history of United States organ sharing and the role played by the Organ Center.
      The current scope and modes of Organ Center operations are detailed.

PMID- 15021824
TI  - Platelet-derived growth factor regulates cytomegalovirus infection-enhanced
      obliterative bronchiolitis in rat tracheal allografts.
AB  - BACKGROUND: Cytomegalovirus (CMV) infection is a risk factor for the development
      of obliterative bronchiolitis (OB) after lung transplantation. METHODS: In the
      rat tracheal allograft model, rat CMV (RCMV) infection is associated with
      accelerated OB through enhanced alloimmune activation and increased smooth muscle
      cell (SMC) proliferation. Using this model, we investigated the role of platelet
      derived growth factor (PDGF) in RCMV infection-enhanced OB. RESULTS:
      Immunohistochemistry and in situ hybridization revealed that RCMV infection
      significantly up-regulates PDGF ligand and receptor expression in inflammatory
      and SMC-like cells in tracheal allografts. Selective inhibition of PDGF receptor
      tyrosine kinase activity by CGP 53716 prevents the development of OB in RCMV
      infected allograft recipients. CONCLUSION: The results of this study emphasize
      the key regulatory role of PDGF in the pathogenesis of RCMV infection-enhanced
      OB, suggesting a novel strategy for the prevention of this fibroproliferative
      disorder.

PMID- 15021823
TI  - Targeted bone marrow radioablation with 153Samarium-lexidronam promotes
      allogeneic hematopoietic chimerism and donor-specific immunologic
      hyporesponsiveness.
AB  - BACKGROUND: Transplantation tolerance, defined as acceptance of a graft by an
      otherwise fully immunocompetent host, has been an elusive goal. Although robust
      tolerance has been achieved by the induction of stable hematopoietic chimerism
      after bone marrow transplantation, lethal or sublethal radiation conditioning
      used to induce long-term chimerism precludes its clinical use. We studied whether
      targeted delivery of radiation to bone marrow could allow for bone marrow cell
      (BMC) engraftment, chimerism, and donor-specific tolerance in the absence of the
      side effects associated with external irradiation. METHODS: We administered a
      radioactive bone-seeking compound (Samarium-Lexidronam, Quadramet, Berlex
      Laboratories, Wayne, NJ) together with transient T-cell costimulatory blockade to
      recipient mice. Allogeneic BMCs were given 7 or 14 days after preconditioning.
      Costimulatory blockade was obtained by the use of an anti-CD154 antibody for 4
      weeks. Chimerism was assessed by flow cytometry. Mice then received donor
      specific and third-party skin grafts. Graft survival was analyzed with mechanisms
      of donor-specific hyporesponsiveness. RESULTS: High levels of stable chimerism
      across an allogeneic barrier were achieved in mice by a single administration of
      Samarium-Lexidronam, transient T-cell costimulatory blockade, and BMC
      transplantation. A large percentage of chimeric animals retained donor-derived
      skin grafts for more than 120 days without requiring additional
      immunosuppression, suggesting that harsh cytotoxic preconditioning is not
      necessary to achieve stable chimerism and donor specific hyporesponsiveness.
      Analysis of the T-cell repertoire in chimeras indicates T-cell deletional
      mechanisms. CONCLUSIONS: These data broaden the potential use of BMC
      transplantation for tolerance induction and argue for its potential in treating
      autoimmune diseases.

PMID- 15021825
TI  - Stage-dependent effect of pancreatic transplantation on diabetic ocular
      complications in the Spontaneously Diabetic Torii rat.
AB  - BACKGROUND: In terms of the temporal relationship between pancreas
      transplantation (PTx) and reversal of diabetic ocular complications, it has been
      difficult but important to determine a "point of no return." Thus, it is of great
      clinical interest to evaluate the efficacy of PTx on diabetic ocular
      complications. METHODS: A spontaneous type 2 diabetic model of Spontaneously
      Diabetic Torii (SDT; RT1) rats was used in the present study, and syngeneic PTx
      was performed. RESULTS: In the control SDT rats that received no treatment,
      hyperglycemia (>250 mg/dL) was developed from 25.2+/-3.9 weeks of age. Lens
      opacity was observed in all rats at 15 weeks after the onset of diabetes.
      Fluorescein angiography and immunohistochemistry detected the nonperfusion area
      and neovascularization in the retina at 5 weeks of diabetes. Daily insulin
      treatment could not prevent or reverse the ocular changes in our experiment.
      Fluorescein filling defect of the retinal vessels was observed at 10 weeks of
      diabetes. However, in the PTx rats, normoglycemia was achieved at all
      experimental time points. Diabetic cataract and retinopathy could have been
      prevented and improved if PTx had been performed at 5 weeks, but not at 10 weeks
      after the onset of diabetes. With PTx treatment, an inhibition of angiogenesis in
      the retina at 5 weeks after the onset of diabetes was demonstrated by
      immunohistochemistry. CONCLUSIONS: Our results indicate that the potential use of
      the SDT rat for diabetes study and the positive effect of PTx performed before
      the "point of no return" could prevent and cure diabetic ocular complications.

PMID- 15021826
TI  - Pirfenidone inhibits obliterative airway disease in a murine heterotopic tracheal
      transplant model.
AB  - BACKGROUND: Chronic lung allograft rejection in the form of bronchiolitis
      obliterans syndrome and its histopathologic correlate, obliterative bronchiolitis
      (OB), are a major source of morbidity and mortality after lung transplantation.
      Murine heterotopic tracheal transplants into fully allogeneic mismatched
      recipients develop obliterative airway disease (OAD), which is a suitable model
      of OB. Using this murine heterotopic tracheal allograft model, we evaluated the
      effect of pirfenidone, a novel antifibrotic agent, on the development of OAD.
      METHODS: Mice transplanted with complete MHC-mismatched tracheal allografts
      received pirfenidone (0.5%) in pulverized food according to different schedules:
      daily for the first 14 days after transplantation or daily for the duration of
      the study beginning on posttransplantation days 0, 5, or 10. RESULTS: Mice on a
      continuous daily regimen of pirfenidone failed to develop evidence of chronic
      allograft rejection at the termination of the study (60 days). Mice receiving
      pirfenidone limited to the early posttransplantation period had delayed onset of
      OAD to 60 days. Forty percent (2/5) of mice receiving a continuous regimen of
      pirfenidone beginning on day 5 after transplantation had no evidence of OAD at 28
      days. However, when the drug was started on day 10, all mice developed OAD by 28
      days. CONCLUSIONS: Our results demonstrate a delay of onset or abrogation of OAD
      when pirfenidone is administered in the early posttransplantation period. These
      findings suggest that pirfenidone is a candidate drug to be evaluated for
      prevention of the fibrotic changes seen in OB in human recipients of lung
      transplants.

PMID- 15021827
TI  - Reduction of circulating redox-active iron by apotransferrin protects against
      renal ischemia-reperfusion injury.
AB  - BACKGROUND: Warm ischemia-reperfusion (I/R) injury plays an important role in
      posttransplant organ failure. In particular, organs from marginal donors suffer
      I/R injury. Although iron has been implicated in the pathophysiology of renal I/R
      injury, the mechanism of iron-mediated injury remains to be established. The
      authors therefore investigated the role of circulating redox-active iron in an
      experimental model for renal I/R injury. METHODS: Male Swiss mice were subjected
      to unilateral renal ischemia for 45 min, followed by contralateral nephrectomy
      and reperfusion. To investigate the role of circulating iron, mice were treated
      with apotransferrin, an endogenous iron-binding protein, or iron-saturated
      apotransferrin (holotransferrin). RESULTS: Renal ischemia induced a significant
      increase in circulating redox-active iron levels during reperfusion.
      Apotransferrin, in contrast to holotransferrin, reduced the amount of circulating
      redox-active iron and abrogated renal superoxide formation. Apotransferrin
      treatment did not affect I/R-induced renal apoptosis, whereas holotransferrin
      aggravated apoptotic cell death. Apotransferrin, in contrast to holotransferrin,
      inhibited the influx of neutrophils. Both apo- and holotransferrin reduced I/R
      induced complement deposition, indicating that the effects of transferrin are
      differentially mediated by its iron and protein moiety. Finally, apotransferrin,
      in contrast to holotransferrin, dose-dependently inhibited the loss of renal
      function induced by ischemia. CONCLUSIONS: Redox-active iron is released into the
      circulation in the course of renal I/R. Reducing the amount of circulating redox
      active iron by treatment with apotransferrin protects against renal I/R injury,
      inhibiting oxidative stress, inflammation, and loss of function. Apotransferrin
      could be used in the treatment of acute renal failure, as seen after
      transplantation of ischemically damaged organs.

PMID- 15021828
TI  - Role of natural killer cells in the rejection process of corneal allografts in
      rats.
AB  - BACKGROUND: The exact mechanism of human corneal allograft rejection, which is
      the major cause of corneal transplant failure, remains unclear. We investigated
      the role of natural killer (NK) cells in rat corneal allograft rejection by
      examining the aqueous humor (AH) cell infiltrate on different postoperative days.
      METHODS: Flow cytometric analysis was performed on the AH and submandibular
      draining lymph node (DLN) cells before transplantation and at different time
      points thereafter. In addition, we performed functional cytotoxicity assays with
      cells present in the AH during corneal rejection. RESULTS: We demonstrated a
      gradual increase in the absolute cell number of different hematopoietic
      subpopulations in the AH after allogeneic cornea transplantation. CD3CD4 cells,
      mainly monocytes and macrophages, were the predominant subpopulation 2 days after
      transplantation, followed by a successive relative increase of CD4 T cells, CD8 T
      cells, CD161 T cells, and NK cells. NK and CD161 T cells were present at a 10- to
      15-fold higher percentage than in the DLN, suggestive of local expansion of these
      cells. A higher percentage of NK cells were CD8-negative compared with DLN NK
      cells. AH cells specifically lysed allogeneic cells, and this cytotoxicity was
      mainly attributable to NK cells but not to CD4 or CD8 T lymphocytes. CONCLUSION:
      These results confirm the crucial role of CD4 cells in the allogeneic corneal
      graft rejection process and implicate NK cells as possible mediators of the
      rejection.

PMID- 15021829
TI  - Combination therapy with sirolimus and mycophenolate mofetil: effects on the
      kidney and on transforming growth factor-beta1.
AB  - Sirolimus (SRL) is not nephrotoxic, but it has been shown to increase
      transforming growth factor (TGF)-beta. We investigated the effect of combining
      mycophenolate mofetil (MMF) with SRL on renal structure and function and on TGF
      beta1. Rats treated with vehicle (VH), MMF 10 mg/kg/d, SRL 0.3 mg/kg/d, or
      SRL+MMF were killed at 28 days. The physiologic and histologic changes and
      expression of TGF-beta1, plasminogen activator inhibitor-1, and extracellular
      matrix proteins were studied. Although SRL alone did not alter renal function and
      structure, it increased TGF-beta1 mRNA by 44% and protein by 48% (P <0.05 vs.
      VH). Treatment with MMF did not affect TGF-beta1. When combined with SRL, MMF
      decreased TGF-beta1 expression to VH levels. A similar trend was observed with
      plasminogen activator inhibitor-1 and extracellular matrix proteins. The long
      term consequence of increased TGF-beta in SRL-treated kidneys remains unknown.
      However, because MMF can reverse this trend, SRL and MMF combination therapy may
      be protective.

PMID- 15021830
TI  - Cyclosporine A sensitizes the kidney to tubulointerstitial fibrosis induced by
      renal warm ischemia.
AB  - BACKGROUND: Renal warm ischemic injury and immunosuppression with cyclosporin A
      (CsA) may contribute to chronic allograft nephropathy after cadaveric
      transplantation. This study establishes whether CsA can sensitize the kidney to
      injury and fibrosis induced by renal warm ischemia (RWI). METHODS: The left
      kidney of Sprague-Dawley rats was subjected to 30 min of warm ischemia and/or
      intraperitoneal CsA (15 mg/kg/d) for 30 days (n=6 per group). Renal injury and
      fibrosis were assessed histologically together with immunohistochemistry for
      collagen III, transforming growth factor (TGF)-beta1, ED1 (macrophage marker),
      and alpha-smooth muscle actin. Renal mRNAs for collagen III, TGF-beta 1, matrix
      metalloproteinase (MMP)-2, and tissue inhibitor of metalloproteinase-1 together
      with MMP enzyme activity were also determined. RESULTS: RWI or CsA alone produced
      only minor effects on renal injury and fibrosis. However, in CsA-treated rats,
      RWI produced a marked increase in tubulointerstitial fibrosis, as shown by the
      potentiation of collagen III and TGF-beta1 determined by immunochemistry and mRNA
      analysis. The up-regulation of tissue inhibitor of metalloproteinase-1 mRNA was
      associated with a decrease in MMP enzyme activity. In CsA-treated rats, RWI was
      also associated with an increase in inflammatory infiltrates, elevated
      immunostain for ED1 (indicating extensive macrophage influx), and elevated
      immunostain for alpha-smooth muscle actin (indicating myofibroblast activation).
      CONCLUSIONS: In the rat, CsA can sensitize the kidney to fibrosis induced by
      renal warm ischemia. In renal transplantation, when cadaveric donor kidneys have
      been subjected to a period of warm ischemia, CsA may be an inappropriate choice
      for immunosuppressive therapy.

PMID- 15021831
TI  - Pulmonary embolism on postmortem examination: an under-recognized complication in
      lung-transplant recipients?
AB  - INTRODUCTION: Postmortem reports highlight the importance of factors that
      individually or collectively limit survival. The prevalence of pulmonary embolism
      (PE) at autopsy in lung-transplant recipients has not been characterized
      previously. OBJECTIVE: We aimed to describe the prevalence of PE, infection, and
      acute and chronic rejection at autopsy and their respective contributions to
      death in lung-transplant recipients according to survival posttransplantation.
      METHODS: We retrospectively reviewed 126 autopsy reports performed in lung-and
      heart-lung-transplant recipients between June 1990 and September 2002. RESULTS:
      PE was identified at autopsy in 34 (27.0%) of 126 lung- and heart-lung-transplant
      recipients. The prevalence of autopsy-established PE was highest, at 36.4%, in
      the early group (1-30 days) compared with 20.0% and 23.8% in the intermediate (31
      365 days) and late (>365 days) groups, respectively. Although fungal and viral
      pneumonia were noted most frequently in the early and intermediate groups,
      bacterial pneumonia was noted in 32% to 45% of autopsies over the posttransplant
      period. Acute cellular rejection and bronchiolitis obliterans were present in
      29.5% and 2.3%, 40.0% and 17.5%, and 35.7% and 42.9% of patients in the early,
      intermediate, and late groups, respectively. The most frequent cause of death was
      bacterial infection. CONCLUSIONS: The prevalence of PE was highest in
      mechanically ventilated lung-transplant recipients in the early postoperative
      period. Heart-lung recipients were at lower risk for PE compared with double- and
      single-lung recipients. PE may be an under-appreciated complication contributing
      to respiratory failure in the early postoperative period.

PMID- 15021832
TI  - Solitary renal allografts from pediatric cadaver donors less than 2 years of age
      transplanted into adult recipients.
AB  - BACKGROUND: Transplantation of solitary pediatric renal allografts from donors 2
      years of age or younger into adult recipients is controversial. METHODS: Between
      1998 and 2001, 15 solitary renal allografts from pediatric donors 2 years of age
      or younger were transplanted into adult recipients. Thirty-three en bloc renal
      allografts transplanted between 1994 and 2001 were used for comparison. En bloc
      kidneys were considered for separation if they measured greater than or equal to
      6 cm in length. Renal function (creatinine clearance [CrCl]) was estimated using
      the Cockroft-Gault formula. RESULTS: Two-year graft survival for the solitary and
      en bloc groups were 93% and 77%, respectively (P =0.405). Five grafts were lost
      because of arterial thrombosis (four en bloc and one solitary). Ureteral
      complications occurred in three grafts in the en bloc group. One-year
      postoperative CrCl of the surviving solitary (n=14) and en bloc (n=26) grafts
      were 51.4+/-26.2 mL/min and 55.1+/-27.5 mL/min (P >0.05), respectively. Donor
      weight and kidney length were greater in the solitary group (14.3+/-3.5 kg and
      6.3+/-0.4 cm, respectively) compared with the en bloc group (10.8+/-2.6 kg and
      5.9+/-0.3 cm, respectively) (P =0.001 and P <0.001). CONCLUSIONS: Separation of
      en bloc pairs into solitary allografts can be considered when the graft measures
      greater than or equal to 6 cm in length and donor weight is greater than or equal
      to 14 kg. The transplantation of solitary pediatric kidneys into adult recipients
      is successful, and the majority of pediatric en bloc allografts can be separated
      before transplantation.

PMID- 15021833
TI  - Hepatitis C virus is independently associated with increased insulin resistance
      after liver transplantation.
AB  - BACKGROUND AND AIMS: There is a strong epidemiologic association between diabetes
      mellitus (DM) and hepatitis C virus (HCV) infection. However, the pathogenetic
      basis for this association has not been established. We sought to evaluate the
      association between insulin resistance (IR), beta-cell dysfunction, and HCV among
      orthotopic liver transplant (OLT) recipients. METHODS: We performed a cross
      sectional analysis comparing 39 HCV(+) with 60 HCV(-) OLT recipients. IR and beta
      cell function were calculated using validated measures and were correlated with
      clinical variables. RESULTS: By multivariate analysis of the entire cohort, HCV
      infection and body mass index (BMI) were independent predictors of IR (P =0.04
      and 0.0006, respectively). HCV infection was associated with 35% increase in IR.
      Because the model used to calculate IR was derived from nondiabetic subjects, we
      performed additional analysis of patients who did not meet criteria for diabetes
      at the time of their study evaluation. In this analysis, HCV(+) subjects had
      greater fasting insulin and homeostasis model assessment (HOMA) IR (15.3 mu U/mL
      and 3.8) compared with HCV(-) patients (10.7 mu U/mL and 2.5) (P =0.03, 0.03).
      There was no difference in beta-cell function or hepatic insulin extraction
      between the HCV (+) and (-) groups. HCV (P =0.0005), BMI (P <0.0001), and high
      high-density lipoprotein (P =0.039) were the only independent predictors of IR.
      The presence of HCV infection and a 10-fold increase in HCV RNA were associated
      with a 62% and 8% increase in IR, respectively. CONCLUSIONS: HCV is independently
      associated with increased IR after OLT. These findings provide a possible
      pathogenetic basis for the association of DM with HCV.

PMID- 15021834
TI  - Reduced hemoglobin after heart transplantation is no independent risk factor for
      survival but is associated closely with impaired renal function.
AB  - BACKGROUND: Reduced hemoglobin (Hb) levels after heart transplantation (HTX) are
      common; however, there are only limited data on the association of posttransplant
      anemia with survival. METHODS: In the present study, the effect of Hb levels
      determined 7 to 12 months after HTX on survival was investigated in 156 heart
      transplant recipients (129 men and 27 women; age at transplantation, 51.3+/-10.45
      years; follow-up, 6.77+/-3.6 years) by univariate and multivariate analyses
      including a broad range of clinical and demographic patient characteristics.
      RESULTS: Anemia by standard definition was found in 141 of 156 (91.6%) patients.
      According to Hb levels above or below the gender-specific median (men, 12.07
      g/dL; women, 11.69 g/dL), patients were separated into a high- or low-Hb group,
      respectively. Kaplan-Meier analysis demonstrated significantly worse survival in
      the low-Hb group (P =0.033). Those patients showed significantly lower body
      weight, higher serum creatinine levels, and lower calculated creatinine
      clearance; the association of creatinine clearance and Hb levels was highly
      significant (P <0.0001). No differences were demonstrated between groups for age,
      preoperative cardiac diagnosis, diabetes, azathioprine, steroid or angiotensin
      converting enzyme inhibitor medication, leukocyte and thrombocyte levels,
      rejection index, or cytomegalovirus (CMV) infection or serostatus. Multivariate
      Cox stepwise regression analysis demonstrated that CMV infection, diabetes, and
      female donor gender were significant risk factors for post-HTX survival. An Hb
      level below the median was, however, completely lost as a risk factor (P =0.44);
      instead, a strong trend for reduced creatinine clearance could be demonstrated (P
      =0.09). Subsequently, a significant association was demonstrated between low
      calculated creatinine clearance and impaired survival by separate Kaplan-Meier
      analysis (P =0.02). CONCLUSIONS: Low Hb levels after HTX do not represent an
      independent risk factor for reduced survival, but the demonstrated correlation
      appears to be primarily caused by concomitant functional renal impairment.
      Further studies will be required to investigate the role of post-HTX anemia as a
      sensitive indicator of functional renal impairment and the effects of anemia
      treatment on long-term survival.

PMID- 15021836
TI  - Safety of duct-to-duct biliary reconstruction in right-lobe live-donor liver
      transplantation without biliary drainage.
AB  - BACKGROUND: Duct-to-duct biliary reconstruction is frequently used in right-lobe
      live-donor liver transplantation (RLDLT), and routine biliary drainage has been
      recommended. The aim of the present study was to evaluate the safety and
      operative outcomes of duct-to-duct biliary reconstruction after RLDLT without
      biliary drainage. METHODS: The study comprised 41 RLDLT recipients who had duct
      to-duct biliary reconstruction. During donor and recipient operations,
      precautions were taken to preserve blood supply to the bile duct. Biliary
      anastomosis was performed with fine Prolene sutures without stents or drainage
      tubes. The operative outcomes were prospectively evaluated. RESULTS: The median
      postoperative intensive care unit and hospital stay were 3 days (range, 1-47
      days) and 19 days (range, 8-114 days), respectively. There was no hospital
      mortality. At a median follow-up of 13.3 months (range, 4.0-26.8 months), the
      graft and patient survival rates were 95% and 98%, respectively. Three (7%)
      patients had biliary leakage. These three patients and the other seven patients
      developed late biliary stricture. The overall biliary complication rate was 24%.
      On multivariate analysis, preoperative Model for End-Stage Liver Disease (MELD)
      score of greater than or equal to 35 was the risk factor associated with biliary
      complication (P =0.032; risk ratio, 4.58). CONCLUSIONS: Duct-to-duct anastomosis
      without biliary drainage is safe in RLDLT. Patients with a high preoperative MELD
      score were associated with an increased incidence of biliary complications.
      Further studies are required to investigate the hemodynamic changes and
      modulation of blood flow of liver grafts in patients with chronic liver disease,
      which may significantly affect the incidence of biliary complications.

PMID- 15021837
TI  - Presentation of donor major histocompatibility complex class II antigens by dna
      vaccination prolongs heart allograft survival.
AB  - BACKGROUND: Donor major histocompatibility complex (MHC) antigens play an
      important role in both allograft rejection and tolerance. With the use of several
      animal models, it has been shown that presentation of donor antigens before
      transplantation can lead to allograft tolerance. Vaccination of animals with a
      DNA plasmid encoding an antigen enables highly efficient expression of the
      protein in vivo. METHODS: In this study, we used DNA vaccination delivered
      through intramuscular, intraperitoneal, or intravenous routes to indirectly
      present donor antigens and to determine the effect in the modulation of the
      allograft response. LEW.1A recipients of a LEW.1W heart allograft were treated
      before grafting by vaccination with a plasmid encoding the donor RT1.D MHC class
      II or RT1.A class I molecules. RESULTS: Only anti-MHC II vaccination
      significantly prolonged allograft survival compared with untreated rats. We
      observed a significant prolongation of heart allograft survival with the
      intramuscular route of injection, but surprisingly we found the intravenous and
      intraperitoneal routes to be the best. CONCLUSION: After transplantation the anti
      donor cellular response was significantly decreased in vaccinated rats. This was
      accompanied by a significant reduction in interferon-gamma mRNA expression in the
      grafted hearts and T helper 1-type alloantibody production, indicating that the
      vaccination modifies the alloresponse against the grafts.

PMID- 15021835
TI  - Efficacy and safety of ABI793, a novel human anti-human CD154 monoclonal
      antibody, in cynomolgus monkey renal allotransplantation.
AB  - BACKGROUND: Anti-CD154 monoclonal antibodies (mAbs) cause long-term graft
      survival in preclinical allotransplantation experiments. This is the first report
      on the efficacy and safety of ABI793, a novel human anti-human CD154 mAb, in
      Cynomolgus renal transplant recipients. METHODS: ABI793 (human immunoglobulin
      G1:kappa) was derived from a hybridoma generated after immunization of human
      immunoglobulin transgenic mice (HuMAb-Mouse, Medarex Inc., Annandale, NJ).
      Cynomolgus monkey recipients of major histocompatibility complex-mismatched, life
      supporting renal allografts were treated repeatedly with intravenous ABI793 for a
      3-month period posttransplantation. Graft function was monitored by serum
      creatinine, and rejection was confirmed histologically. RESULTS: ABI793 binds to
      human, Cynomolgus and Rhesus monkey CD154; it inhibits dose dependently in vitro
      CD154:CD40 binding and human mixed lymphocyte reaction. ABI793 is comparable to
      the mouse anti-human CD154 mAbs 5c8 and 24-31 with respect to affinity,
      inhibitory capacity, and species specificity; however, ABI793 binds to a
      different CD154 epitope. With 20 mg/kg of ABI793, five of nine recipients showed
      substantially prolonged graft survival after cessation of treatment, whereas four
      of nine recipients were killed because of high serum creatinine while still
      receiving treatment. ABI793 treatment was associated with episodes of severe
      acute tubular necrosis (which was unrelated to rejection and responded to fluid
      and diuretic treatment) and a decrease in platelet numbers. Chronic and acute
      thromboembolic vascular lesions with hemorrhages were observed in the lung and
      brain of two allograft recipients. None of these side effects were observed in
      animals that underwent autotransplantation, thus excluding direct toxicity of
      ABI793. CONCLUSIONS: ABI793 treatment effectively prevents graft rejection in
      Cynomolgus monkeys. Evidence for rare thromboembolic events, as also previously
      observed with different anti-human CD154 mAbs, suggests that thromboembolic
      complications may be a class effect of anti-CD154 mAbs, unrelated to their
      epitope specificity.

PMID- 15021838
TI  - Low molecular weight dextran sulfate prevents the instant blood-mediated
      inflammatory reaction induced by adult porcine islets.
AB  - BACKGROUND: One of the main obstacles to clinical islet xenotransplantation is
      the injurious instant blood-mediated inflammatory reaction (IBMIR) that causes
      rapid binding of platelets to the islet surface, activation of the coagulation
      and complement systems, and leukocyte infiltration of the islets when the islets
      are exposed to blood. METHODS: This study assesses the effect of low molecular
      weight dextran sulfate (LMW-DS) on IBMIR induced by porcine islets in an in vitro
      tubing loop assay using human blood and in an in vivo model using diabetic
      athymic mice. RESULTS: In vitro experiments demonstrated that platelet
      consumption, coagulation, and complement activation were already reduced in the
      presence of LMW-DS at 0.01 mg/mL, and that at 0.1 mg/mL, LMW-DS prevented IBMIR.
      Immunohistochemical investigation showed that the leukocyte infiltration was
      abrogated at the highest dose. In vivo experiments showed that the transplanted
      pig islets survived for a significantly longer period in recipients treated with
      LMW-DS, and morphologic examination of transplanted islets showed a reduction in
      IBMIR analogous to that demonstrated by in vitro studies. CONCLUSIONS: Given that
      LMW-DS has been used in clinical studies without serious adverse reactions, it
      has potential as a drug candidate that can control the strong innate immune
      response induced by pig islets when transplanted through the portal vein.

PMID- 15021839
TI  - Hemodynamic effects of amlodipine, bisoprolol, and lisinopril in hypertensive
      patients after liver transplantation.
AB  - BACKGROUND: Hypertension is common after liver transplantation. There are few
      published data on optimum treatment. Augmentation index (AIx) is a measure of
      arterial wave reflection determined by pulse wave analysis. METHODS: Amlodipine
      was administered to 24 hypertensive liver transplant recipients. Thirteen
      patients intolerant of or unresponsive to amlodipine were randomized to a
      crossover study comparing bisoprolol with lisinopril. RESULTS: With amlodipine,
      systolic blood pressure (SBP) fell from 154+/-2 mm Hg to 130+/-2 mm Hg, and AIx
      also fell. With bisoprolol, SBP fell from 154+/-2 mm Hg to 142+/-4 mm Hg, but AIx
      increased. With lisinopril, SBP fell from 154+/-2 mm Hg to 130+/-5 mm Hg, and AIx
      also fell (P <0.001 throughout). CONCLUSIONS: Amlodipine is an effective
      treatment for hypertension. The increased AIx with bisoprolol indicates increased
      wave reflection such that central aortic pressure is reduced less than peripheral
      SBP. Lisinopril reduces AIx and reduces SBP more than bisoprolol and is the
      preferred drug.

PMID- 15021840
TI  - Allogeneic sensitization is more effective than xenogeneic sensitization in
      eliciting Gal-mediated skin graft rejection.
AB  - The generation of Gal knockout (KO) pigs is likely to be an important advance in
      xenotransplantation. However, recent reports suggesting that expression of Gal
      may not be completely eliminated raise the possibility of a continuing anti-Gal
      immune response. The authors used a Gal-mismatched skin graft model to study cell
      mediated anti-Gal rejection. Gal KO mice on a BALB/c or C57BL/6 background were
      sensitized with allogeneic or xenogeneic (rat) Gal-positive skin grafts and
      underwent transplantation with a secondary skin graft solely mismatched for Gal
      21 days later. Most allograft-sensitized recipients rejected the secondary graft
      (n=26 [96%]) compared with less than half of xenograft-sensitized recipients
      (n=25 [44%]). An immunoglobulin (Ig) M response was detected in some xenograft
      sensitized but not allograft-sensitized recipients. No recipients developed
      detectable anti-Gal IgG. The authors' findings contrast with previous reports
      that xenografts are more potent than allografts in eliciting an anti-Gal response
      and suggest that a predominantly cell-mediated response can mediate rejection.

PMID- 15021841
TI  - Functional heterogeneity of mitochondria after cardiac cold ischemia and
      reperfusion revealed by confocal imaging.
AB  - BACKGROUND: Mitochondria play a critical role in ischemia-reperfusion injury of
      the heart. The purpose of the present study was to analyze the intracellular
      region-specific functional state of mitochondria after cold ischemia-reperfusion
      in a rat heart transplant model. METHODS: Imaging of the mitochondrial functional
      state in situ in nonfixed myocardial fibers was performed by confocal microscopy
      of mitochondrial flavoprotein autofluorescence as redox state indicator;
      fluorescence of Rhod-2, a specific probe for mitochondrial calcium; and of
      tetramethylrhodamine ethyl ester fluorescence to monitor the mitochondrial
      membrane potential. RESULTS: This imaging demonstrated that, in contrast to
      control fibers, 10-hr heart cold storage, heterotopic cardiac transplantation,
      and 24-hr reperfusion result in a highly heterogeneous mitochondrial functional
      state (mitochondrial calcium content, redox state, and inner membrane potential),
      thus suggesting local permeability transitions and heterogeneous mitochondrial
      damage. CONCLUSIONS: Imaging of in situ mitochondria allows topologic assessment
      of mitochondrial defects and heterogeneity, consequently providing new insights
      into the mechanisms of cardiac ischemia-reperfusion injury.

PMID- 15021842
TI  - Selective cell dissemination into the heart by retrograde intracoronary infusion
      in the rat.
AB  - Cell transplantation through the intracoronary route has theoretical advantages
      over direct intramuscular injection in global cell dissemination into the
      myocardium with less injury. The authors have established a novel experimental
      model of retrograde intracoronary infusion in the rat by which the feasibility of
      this infusion for cell transplantation and the dynamics of myoblasts grafted by
      this route were investigated. After retrograde intracoronary implantation of beta
      galactosidase-expressing myoblasts, myoblasts were observed to disseminate to all
      layers of only the left ventricular free wall, with little myocardial damage, and
      to differentiate into multinuclear myotubes by day 28. Beta-galactosidase enzyme
      activity estimated that 31.4% of initially grafted myoblasts existed within the
      heart at 10 min after implantation. The number slightly increased by day 3,
      increased to 117.3% at day 7, and reached a plateau of 132.1% at day 14. These
      data suggest the utility of retrograde intracoronary infusion for selective cell
      dissemination into the myocardium.

PMID- 15021843
TI  - Conversion to sirolimus: a successful treatment for posttransplantation Kaposi's
      sarcoma.
AB  - The increased incidence of Kaposi's sarcoma (KS) in organ transplantation has
      been related to the KS herpesvirus and the permissive effect of immunosuppressive
      therapy. Calcineurin inhibitors are the cornerstone of immunosuppression in organ
      transplantation, although they could promote tumor progression. In contrast,
      sirolimus, a new immunosuppressive agent, exhibits potent antitumor activity. We
      postulated that conversion from cyclosporine to sirolimus in patients with KS
      could favor regression of KS lesions without increasing the risk of graft
      rejection. Two renal transplant recipients with KS underwent conversion from
      cyclosporine to sirolimus. Both patients showed complete regression of KS lesions
      and excellent clinical and functional results. Sirolimus offers a new and
      promising approach to the management of posttransplantation KS and probably to
      other types of malignancies in organ transplant recipients.

PMID- 15021846
TI  - Frequency and impact of nonadherence to immunosuppressants after renal
      transplantation: a systematic review.
AB  - Nonadherence to immunosuppressants is recognized to occur after renal
      transplantation, but the size of its impact on transplant survival is not known.
      A systematic literature search identified 325 studies (in 324 articles) published
      from 1980 to 2001 reporting the frequency and impact of nonadherence in adult
      renal transplant recipients. Thirty-six studies meeting the inclusion criteria
      for further review were grouped into cross-sectional and cohort studies and case
      series. Meta-analysis was used to estimate the size of the impact of nonadherence
      on graft failure. Only two studies measured adherence using electronic
      monitoring, which is currently thought to be the most accurate measure. Cross
      sectional studies (n=15) tended to rely on self-report questionnaires, but these
      were poorly described; a median (interquartile range) of 22% (18%-26%) of
      recipients were nonadherent. Cohort studies (n=10) indicated that nonadherence
      contributes substantially to graft loss; a median (interquartile range) of 36%
      (14%-65%) of graft losses were associated with prior nonadherence. Meta-analysis
      of these studies showed that the odds of graft failure increased sevenfold (95%
      confidence interval, 4%-12%) in nonadherent subjects compared with adherent
      subjects. Standardized methods of assessing adherence in clinical populations
      need to be developed, and future studies should attempt to identify the level of
      adherence that increases the risk of graft failure. However, this review shows
      nonadherence to be common and to have a large impact on transplant survival.
      Therefore, significant improvements in graft survival could be expected from
      effective interventions to improve adherence.

PMID- 15021844
TI  - Regulatory CD4+CD25+ T cells in the peripheral blood of lung transplant
      recipients: correlation with transplant outcome.
AB  - BACKGROUND: The subset of CD4+CD25+ regulatory T cells, recently identified in
      humans, may play a central role in the regulation of immune tolerance to graft
      survival. METHODS: This study assesses the frequency and functional profile of
      CD4+CD25+CD69- cells in the peripheral blood of lung transplant recipients (>3
      years from transplantation), 10 of whom were in a stable clinical condition and
      11 of whom demonstrated chronic rejection (bronchiolitis obliterans syndrome). We
      also studied a group of seven healthy subjects. RESULTS: The frequency of CD4+ T
      cells expressing CD25 (CD4+CD25+) and the highest levels (CD25) were lower in
      patients with bronchiolitis obliterans syndrome compared with healthy subjects
      and subjects in a stable clinical condition (P < or = 0.01). Purified CD4+CD25+
      cells exhibited a regulatory functional profile in vitro: they were
      hyporesponsive, suppressed the proliferation of CD4+CD25- cells, and produced
      interleukin-10. CONCLUSION: These results provide in vivo evidence that
      peripheral CD4+CD25+ T cells may represent an important regulatory subset in lung
      transplantation.

PMID- 15021847
TI  - Medication noncompliance: another iceberg's tip.
AB  - After renal transplantation, immunosuppressive medications must be taken long
      term to avoid acute rejection and the cascade of events leading to "chronic
      allograft dysfunction" and loss. In the past, when posttransplant
      immunosuppression was limited to azathioprine and prednisone, acute rejection
      episodes were common, and it was difficult to identify the impact of medication
      noncompliance. However, with more potent and effective drugs, acute rejection is
      uncommon, and medication noncompliance emerges as an increasingly important
      factor in the outcome of solid-organ transplantation. Recent studies have clearly
      demonstrated that medication noncompliance leads to an increased incidence of
      acute rejection, chronic rejection, and graft loss. Today, although a number of
      questions remain unanswered, new methodologies, such as electronic monitors,
      provide opportunities to study medication noncompliance and its risk factors, and
      the potential for earlier intervention to improve clinical outcomes.

PMID- 15021848
TI  - Noncompliance with immunosuppressive medications in pediatric and adolescent
      patients receiving solid-organ transplants.
AB  - Advances in knowledge in transplantation have improved 1-year renal allograft
      survival in all age groups of pediatric patients. However, the results from many
      studies have shown that the long-term allograft survival is least successful in
      adolescent recipients. The major cause of late graft failure in adolescents can
      be contributed in large measure to medication noncompliance. Medication
      noncompliance in teenagers has been shown to be more than four times greater in
      adolescents than in adults. The teenage years are a time of transition from
      childhood to adulthood. Important tasks during this transition include the
      development of an autonomous identity that progresses to full independence.
      However, the cognitive skills and intellectual maturation of adolescents are
      still limited, and this is particularly true in adolescents with chronic
      diseases. They have difficulty with abstract thinking, particularly the
      conceptualization of future consequences of present actions. This leads to
      characteristic risk-taking behaviors, including noncompliance with medical
      treatments. This transition is more intricate for adolescents with chronic
      illness because of their physical limitations. There are a number of strategies
      that are helpful in mitigating noncompliance. Adolescents must be dealt with
      directly. Previous noncompliant behaviors need to be acknowledged and dealt with,
      because studies show that noncompliance is a "stable" personality attribute that
      persists over time. Efforts should be made to choose medications that have the
      least side effects. Psychological and psychiatric conditions such as
      posttraumatic stress disorder require early recognition, diagnosis, and
      treatment. It is necessary to build rapport with teenagers, and this should start
      before transplantation. A multidisciplinary approach with physicians, social
      workers, nurses, and transplant coordinators is an effective mean of enhancing
      compliance. These and other strategies outlined in this discussion will enable
      the adolescent to achieve good compliance rates and prevent graft loss.

PMID- 15021849
TI  - Compliance: the patient, the doctor, and the medication?
AB  - Noncompliance can be defined as covert nonadherence to prescribed medication used
      for the prophylaxis of allograft rejection and threatening impaired kidney
      histology or function. It is an increasingly significant long-term problem in
      transplantation as the failure rates from other causes have diminished. Formal
      approaches to diagnosis, prophylaxis, and treatment, together with a greater
      understanding of what should be regarded as a syndrome, are thus increasingly
      important components of reducing the chronic attrition of graft function and
      survival. It is possible to classify noncompliant behavior using four facets of
      the syndrome: timing, frequency, origin, and diagnostic certainty. There are a
      number of different ways of approaching diagnosis, such as observation of
      behavior through pill counting or electronic measurements of pill container
      opening; blood level measurement of relevant drugs; physical examination; and
      observation of the consequences. However, the only certainty of diagnosis comes
      from direct patient admission of nonadherence to the prescribed
      immunosuppression. It is possible to define the highest risk patients through
      assessment of a number of patient-, drug-, and physician-associated variables,
      and then to influence the outcome through education, compliance monitoring, and
      simplified regimens targeted to the highest risk patients. It is important for
      all transplant units to address the issues raised by noncompliance if the chronic
      loss of allografts is to be reduced.

PMID- 15021850
TI  - Measuring compliance with drug regimens after renal transplantation: comparison
      of self-report and clinician rating with electronic monitoring.
AB  - Nonadherence to immunosuppressants in renal transplant recipients is a major
      factor affecting graft survival, but it is difficult to detect accurately in
      clinical practice. Adherence was measured in 153 adult renal transplant
      recipients using self-report questionnaires and interview, clinician rating, and
      cyclosporine levels. The sensitivity and specificity of these measures were
      determined by comparison with electronic monitoring in a randomly selected
      subsample of 58 subjects. Measures of adherence in current clinical use do not
      perform well when tested against electronic monitoring. Self-report at a
      confidential interview was the best measure of adherence for the detection of
      both missed doses and erratic timing of medication. However, the use of a
      confidential interview is not directly applicable to a clinical setting. Further
      research on how best to facilitate disclosure in clinical settings may be the
      best way to develop adherence measures for use in routine practice.

PMID- 15021851
TI  - Treatment of Bowen's disease with imiquimod 5% cream in transplant recipients.

PMID- 15021852
TI  - Lupus anticoagulant in a 5-year-old liver transplant patient.

PMID- 15021853
TI  - Successful arterial revascularization in liver transplantation using a
      cryopreserved arterial allograft.

PMID- 15021854
TI  - Presumed consent: the case of the John Doe donor.

PMID- 15021857
TI  - William James and the religious experience.

PMID- 15021860
TI  - Divalproex and epilepsy.
AB  - Valproic acid, a branched chain carboxylic acid, has a broad spectrum of action
      as an antiepilepsy drug. While effective in myoclonus syndromes and absence
      epilepsy, the drug has efficacy for patients with generalized convulsive and
      partial seizures as well. Mechanisms of action are similar to other drugs used to
      treat epilepsy, in that valproate limits sustained repetitive firing by actions
      on the voltage sensitive sodium channel. However, the drug facilitates the
      removal of glutamate from synaptic regions by up regulating glial glutamate
      transporters while prolonging the action of GABA by limiting production of
      inhibitory transmitter transporter proteins. Adverse effects include
      hepatotoxicity that requires informing patients and establishing clinical
      monitoring plans. Teratogenicity occurs with valproate and requires informing
      patients and careful monitoring in women during pregnancy.

PMID- 15021861
TI  - The efficacy of divalproex for partial epilepsies.
AB  - Valproic acid has clear efficacy in the treatment of partial epilepsies. Its
      multiple mechanisms predicted its broad spectrum of efficacy and preclinical
      experimental data prompted its clinical use. Valproic acid's efficacy has been
      repeatedly demonstrated in clinical trials over the past 25 years. Its efficacy
      in the treatment of partial epilepsies is similar or better than both the
      traditional and new antiepileptic drugs. Its side effect profile is well known
      and manageable, especially with extended-release formulations.

PMID- 15021862
TI  - Divalproex in the treatment of bipolar disorder.
AB  - Valproate is commonly used as a first-line agent for the treatment of acute
      bipolar I mania. Its efficacy in the treatment of acute mania has been
      established in randomized, controlled trials versus placebo, lithium,
      haloperidol, and olanzapine. Only preliminary data regarding the efficacy of
      valproate in acute bipolar depression are currently available. The efficacy of
      valproate in the maintenance treatment of bipolar disorder has not been
      definitively established but most evidence from randomized, controlled trials
      suggests that it may have comparable efficacy to lithium and olanzapine. The
      results of randomized, controlled trials of valproate in the treatment of bipolar
      disorder are reviewed along with their implications for clinical practice.

PMID- 15021863
TI  - Schizophrenia and valproate.
AB  - Valproate (the active moiety of both valproic acid and divalproex sodium) is
      commonly used as an adjunctive agent for the treatment of schizophrenia. Among
      the anticonvulsants, valproate is the most extensively studied in patients with
      schizophrenia. Theoretical underpinnings for valproate in schizophrenia include
      its effect on voltage-gated ion channels and on the g-aminobutyric acid (GABA)
      system, thus modulating mesolimbic dopaminergic activity. Case reports,
      retrospective studies, and randomized clinical trials support the use of
      valproate combined with antipsychotics in managing schizophrenia. A recently
      completed 28-day, double-blind, randomized clinical trial of 249 patients with
      schizophrenia demonstrated faster improvement in psychopathology with a
      combination therapy of divalproex and risperidone or olanzapine, compared to
      monotherapy with risperidone or olanzapine. Additional research is needed to
      assess the utility of valproate in specialized populations such as those with
      treatment-refractory schizophrenia or agitation in schizophrenia. Regarding the
      latter, positive double-blind, randomized clinical trials have already been
      conducted in patients with borderline personality disorder, dementia, and with
      disruptive adolescents. It is anticipated that future research will focus on the
      new extended-release formulation of divalproex that can be administered on a once
      daily basis.

PMID- 15021864
TI  - The use of divalproex in the treatment of addictive disorders.
AB  - To date, few medications have shown efficacy in the treatment of addictive
      disorders. The lack of effective treatments has led to the evaluation of a
      variety of pharmacotherapies to reduce alcohol or illicit drug use. The
      anticonvulsant agents are a class of medications that may represent novel
      treatments for addictive disorders. One of the most studied anticonvulsant agents
      in the treatment of addictive disorders has been valproate. This article will
      review the literature regarding the use of valproate in treating alcohol
      withdrawal symptoms and in reducing the use of alcohol and cocaine.

PMID- 15021865
TI  - Divalproex in the treatment of migraine.
AB  - Valproic acid has been used in the treatment of migraine headache for nearly 20
      years. During this period of use several additional delivery modes have been
      developed to either improve tolerability or patient compliance with the
      divalproex sodium formulation and the extended-release formulation of divalproex
      sodium. Additionally, an intravenous formulation has become available which
      permits rapid achievement of therapeutic levels of the drug. There have been a
      number of reports on the use of valproic acid in migraine and other headache
      disorders, suggesting it to be an efficacious treatment. This paper reviews the
      results of the published reports of valproic acid in migraine and other headache
      disorders, including open-label studies, comparator trials, and double-blind,
      placebo-controlled trials. These studies have been conducted with the various
      formulations of valproic acid that have been on the market. The papers utilized
      in this study were obtained though Medline searches on valproic acid and
      divalproex sodium coupled with the various headache disorders. Additionally, the
      CD-ROM of past issues of Headache and Cephalalgia was reviewed for similar
      keywords. Lastly, the indices of the journal Headache Quarterly were reviewed for
      additional articles on valproic acid and divalproex sodium. Valproic acid in its
      various formulations has been demonstrated to be an efficacious and well
      tolerated agent for the preventive treatment of migraine, chronic daily headache,
      and cluster headache. Additionally, it has been demonstrated to be efficacious
      and well tolerated in treating acute migraine attacks when given as an
      intravenous solution.

PMID- 15021866
TI  - Valproate use in neuropsychiatric disorders in the elderly.
AB  - The literature regarding the use of valproate in the elderly derives primarily
      from studies in patients with dementia who experience agitation. At this
      juncture, there are 5 case reports or case series in patients with mixed
      neuropsychiatric disorders and 18 in patients with dementia, while there are 3
      placebo-controlled studies in patients with dementia. In the aggregate, the
      published reports point toward probable improvement in agitation in a substantial
      proportion of patients. The level of evidence is not sufficient to define
      clinical practice, however, which is also a limitation with some other commonly
      used therapies, nor is the behavioral target of persistent agitation recognized
      by the Food and Drug Administration. Basic and preclinical studies of mechanism
      of action suggest a possible effect of valproate on cellular survival which, in
      theory, could be beneficial in patients with Alzheimer's disease. This hypothesis
      will be addressed in a multicenter trial beginning in 2003.

PMID- 15021867
TI  - [Acoustic histology of dental tissues].
AB  - New data on tooth enamel and dentin microstructure, obtained by acoustic
      microscopy methods, which are based on evaluation of distribution of the local
      elastic and mechanical properties, are presented. The results demonstrate that
      the acoustic microscopy methods are more sensitive to changes in mechanical
      properties of dental tissues in caries in comparison with optic microscopy.

PMID- 15021868
TI  - [Study of age-specific changes in labeled citrate metabolism in health and
      disease].
AB  - A new coefficient - mineralized tissues/biological fluids (MT/BF) - is suggested
      for evaluating the distribution of compounds adsorbed by MT and dissolved in BF.
      The relative radioactivity (RRA) was estimated for the periods of 10 min to 96 h
      after intraperitoneal injection of [3-(14)C]citrate to rats aged 1 and 3 months
      and over 1 year by dividing the percent of incorporation in MT by the percent of
      incorporation in BF. Changes in RRA for molar root/blood serum (R/BS) and RRA for
      dentin/blood serum (D/BS) are similar: low values at the beginning of experiment,
      an increase 1 h postinjection, a decrease 2-3 h postinjection, and another
      increase (65-80 times) by 96 h postinjection. A biphasic reaction with a rapid
      elevation and decrease after 1-2 h and a second elevation before the end of the
      experiment due to citrate adsorption on hydroxyapatite and influence of D and R
      proteins on stable hemosorption of citrate by MT was observed. The time course of
      RRA enamel/oral fluid was different: a decrease 1 h postinjection and an increase
      2-3 h postinjection. Two weeks after crossing the inferior alveolar nerve, the
      R/BS RRA decreased to a lesser degree in 1-month-old rats in comparison with 3
      month-old animals, which can be explained by higher efficiency of the adaptive
      compensatory mechanisms in growing rats.

PMID- 15021869
TI  - [Status of the buccal mucosa in subjects occupationally exposed to
      chlorophenoxyherbicides].
AB  - Examinations of workers engaged in the production of chlorophenoxyherbicides
      showed high prevalence of diseases of the buccal and labial mucosa with a trend
      to development of hyperkeratosis (exfoliative cheilitis, hyperkeratosis of the
      tongue, lips, buccal mucosa (BM), flat form of the BM and red lip leukoplakia).
      Cytogenetic effects of toxins on BM result in an increase of keratinization
      level, higher incidence of nuclear abnormalities, and appearance of the
      micronuclei in BM epithelium. A direct relationship between the severity of these
      symptoms, duration of exposure, and intensity of workers' contact with
      chlorophenoxyherbicides was revealed. The complex of noninvasive and atraumatic
      methods used in our study helped evaluate the BM status and can be used not only
      for visual examination, but also for the diagnosis of transformation of the
      defense reaction of the epithelium into pathological process and for preclinical
      detection of precancer changes in BM.

PMID- 15021870
TI  - [Results of treatment of chronic generalized periodontitis with a dispersed
      biomaterial Alloplant].
AB  - There is a method of treatment of generalized chronic periodontitis with using
      dispersing biomaterial Alloplant and immunological, histomorphological criteria
      of this estimation.

PMID- 15021871
TI  - [Combined method for preventing alveolar process deformation after tooth
      extraction].
AB  - This paper presents a combined method for prevention of deformation of the
      alveolar process of the jaws after tooth extraction. This method was used in 26
      patients of different age. Use of colapol in the KP-3l modification and laser
      coagulation method in combination with immediate orthodontic treatment led to
      reduction of the incidence of inflammatory complications. The method is
      recommended for practical use.

PMID- 15021872
TI  - [Study of free-radical processes and antioxidant defense parameters during
      hirudotherapy of patients with diseases of salivary glands].
AB  - Hirudotherapy was used in the treatment of 39 patients (10 male and 29 female)
      aged 28-58 years with chronic sialadenitis and sialadenosis. Control group
      consisted of 15 normal subjects without diseases of salivary glands. Lipid
      peroxidation (LPO) and antioxidant defense (AOD) parameters were under study.
      Hirudotherapy led to improvement of the clinical status in the majority of
      patients with sialadenosis; the content of superoxide dismutase (SOD) normalized
      and ceruloplasmin (CP) level increased. The status of patients with sialadenitis
      also improved; catalase and glutathione peroxidase levels normalized and SOD and
      CP levels increased. The best therapeutic effect was attained in patients with
      sialadenitis. No appreciable improvement was observed in patients with chronic
      parenchymatous parotitis in the presence of Sjogren's syndrome.

PMID- 15021873
TI  - [Use of local UHF hyperthermia and CO(2) laser in treatment of cancer of the lip,
      lingual mucosa, and bottom of the oral cavity].
AB  - A total of 424 patients with cancer of the lips, lingual mucosa, and bottom of
      the oral cavity were treated using local hyperthermia and CO(2) laser. The best
      results were attained in patients with the disease stage T1N0M0-T2N0M0: 5-year
      survival without local relapses and metastases was 43.3-58.5% in this group.

PMID- 15021875
TI  - [Fundamentals of medical rehabilitation of patients with asymmetrical deformation
      of the maxilla complicated by cross occlusion].
AB  - The problem of medical rehabilitation of patients with asymmetrical deformation
      of the facial skull, complicated by cross occlusion, is discussed. The authors
      suggest osteotomy of the maxillary complex with translocation of the osteotomied
      fragment in the sagittal, transverse, and vertical planes with osteotomy to a
      distance needed for elimination of deep cross occlusion. This method in
      combination with orthodontic treatment repairs the anatomic and functional
      abnormalities and brings about good esthetic results.

PMID- 15021874
TI  - [Role of total systems' connective tissue disease in the development of
      posttraumatic changes in the temporomandibular joint].
AB  - The aim of our work was to ascertain the relationship between temporomandibular
      joint (TMJ) complications of jaw fractures and displasia of connective tissue
      (DCT). The results of this investigation suggest, that DCT is an important factor
      of risk for joint disturbance such as arthritis and osteoarthrosis of TMJ.

PMID- 15021876
TI  - [Remote effects of the Chernobyl accident: evaluation of the maxillodental status
      of the children].
AB  - Examinations of children exposed to the Chernobyl factor showed deterioration of
      the maxillodental status, presenting as a decrease in the incidence of normal-for
      age status in comparison with children from the control group. The incidence of
      dental abnormalities in children whose parents participated in the Chernobyl
      accident aftermath is increased by 240,09%. The determination of remote effects
      of the Chernobyl accident for the health status of Russian children requires a
      differentiated approach and deserves a special study.

PMID- 15021877
TI  - [An example of "leveling extraction" for repair of the 21st tooth supraposition].
AB  - A supercomplect retained tooth, situated under the 21st tooth, was removed in
      order to eliminate the supraposition (vestibular position) of the 21st tooth
      under conditions of lack of place in the dental arch. The 14th tooth on the
      contralateral side of the jaw was removed in order to maintain the symmetry and
      order of the anterior part of the maxillary dental arch and for creating place
      for the 21st tooth. Further transposition of the 13th tooth to the place
      previously occupied by 14th tooth, 11th tooth instead of 12th tooth, and
      establishment of the 21st tooth into correct position in the dental arch were
      carried out using orthodontic devices.

PMID- 15021878
TI  - Locomotion of monocytes on endothelium is a critical step during extravasation.
AB  - Monocytes, like all leukocytes, undergo a series of sequential steps during
      extravasation from blood into tissues: tethering, rolling, adhesion and
      diapedesis. We have discovered an essential step, which we call locomotion, in
      which the monocyte moves from a site of firm adhesion to the nearest junction to
      begin diapedesis. Blocking CD11a-CD18 and CD11b-CD18 on human monocytes or
      adhesion molecules ICAM-1 and ICAM-2 on endothelial cells prevented the monocytes
      from reaching junctions. The blocked monocytes spun in circles as if they were
      unable to direct their movement despite being able to adhere and polarize
      normally. This step fills a gap in the paradigm of extravasation as a multistep
      process.

PMID- 15021879
TI  - The STAT3 isoforms alpha and beta have unique and specific functions.
AB  - Signal transducer and activator of transcription 3 (STAT3) is the main mediator
      of interleukin 6 (IL-6)-type cytokine signaling. It exists in two isoforms: the
      full-length STAT3 alpha and the truncated STAT3 beta, generally thought to act as
      a dominant negative factor. To assess their relative functions, we ablated the
      expression of either isoform by gene targeting. We show here that in vivo STAT3
      beta is not a dominant negative factor. Its expression can rescue the embryonic
      lethality of a STAT3-null mutation and it can by itself induce the expression of
      specific STAT3 target genes. Nevertheless, STAT3 alpha has nonredundant roles
      such as modulation of cellular responses to IL-6 and mediation of IL-10 function
      in macrophages.

PMID- 15021880
TI  - A cis element in the recombination activating gene locus regulates gene
      expression by counteracting a distant silencer.
AB  - We have identified a silencer and an antisilencing element that interact at a
      distance of 85 kilobases to regulate expression of the recombination activating
      genes Rag1 and Rag2 in thymocytes. Transgenic experiments showed that Rag
      promoter-proximal cis elements directed tissue-specific expression and that a
      Runx-dependent intergenic silencer suppressed expression in developing T cells.
      Deletion of the antisilencing element from the genomic Rag locus unmasked the
      intergenic silencer and abrogated Rag expression in developing CD4(+)CD8(+) T
      cells. We speculate that the Rag antisilencing element belongs to a class of cis
      elements that might be useful for genome diversification by activating genes
      encoded by otherwise silent transposable elements.

PMID- 15021884
TI  - Ubiquitin-like protein activation.
AB  - Post-translational covalent attachment of ubiquitin and ubiquitin-like proteins
      (ubls) has emerged as a predominant cellular regulatory mechanism, with important
      roles in controlling cell division, signal transduction, embryonic development,
      endocytic trafficking and the immune response. Ubls function by remodeling the
      surface of their target proteins, changing their target's half-life, enzymatic
      activity, protein-protein interactions, subcellular localization or other
      properties. At least 10 different ubiquitin-like modifications exist in mammals,
      and attachment of different ubls to a target leads to different biological
      consequences. Ubl-conjugation cascades are initiated by activating enzymes, which
      also coordinate the ubls with their downstream pathways. A number of biochemical
      and structural studies have provided insights into the mechanism of ubl
      activating enzymes and their roles in ubl conjugation cascades.

PMID- 15021885
TI  - The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common
      modular architecture.
AB  - Neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4) is the
      prototypical protein in a family of E3 ubiquitin ligases that have a common
      domain architecture. They are comprised of a catalytic C-terminal HECT domain and
      N-terminal C2 domain and WW domains responsible for cellular localization and
      substrate recognition. These proteins are found throughout eukaryotes and
      regulate diverse biological processes through the targeted degradation of
      proteins that generally have a PPxY motif for WW domain recognition, and are
      found in the nucleus and at the plasma membrane. Whereas the yeast Saccharomyces
      cerevisiae uses a single protein, Rsp5p, to carry out these functions, evolution
      has provided higher eukaryotes with several related Nedd4 proteins that appear to
      have specialized roles. In this review we discuss how knowledge of individual
      domain function has provided insight into the physiological roles of the Nedd4
      proteins and describe recent results that suggest discrete functions for
      individual family members.

PMID- 15021886
TI  - Nedd8 on cullin: building an expressway to protein destruction.
AB  - This review summarizes recent advances concerning the Nedd8 regulatory pathway in
      four areas. One, substantial progress has been made in delineating the role of
      cullin family proteins, the only known substrates of the Nedd8 modification
      system. Cullins are molecular scaffolds responsible for assembling the ROC1/Rbx1
      RING-based E3 ubiquitin ligases, of which several play a direct role in
      tumorigenesis. Two, a large body of work has helped elucidate the molecular
      details underlying the Nedd8 modification reaction, which results in covalent
      conjugation of a Nedd8 moiety onto a conserved cullin lysine residue. Three,
      studies using a variety of genetic model systems have established an essential
      role for Nedd8 in cell cycle control and in embryogenesis by upregulating the
      activities of cullin-based E3 ligases. In vitro experiments have revealed a
      direct role for Nedd8 in activating ubiquitination. Construction of a model of
      the ROC1/Rbx1-CUL1-Nedd8 structure suggests a mechanism by which the cullin
      linked Nedd8 may assist the neighboring ROC1/Rbx1 in landing and positioning the
      E2 conjugating enzyme for the ubiquitin transfer reaction. Finally, increasing
      evidence indicates that removal of Nedd8 from its cullin targets, by the action
      of COP9 Signalosome and possibly other proteases, plays a significant role in the
      regulation of cullin-mediated proteolysis.

PMID- 15021887
TI  - SUMO: a regulator of gene expression and genome integrity.
AB  - Post-translational modification with the ubiquitin-like SUMO protein is involved
      in the regulation of many cellular key processes. The SUMO system modulates
      signal transduction pathways, including cytokine, Wnt, growth factor and steroid
      hormone signalling. SUMO frequently restrains the activity of downstream
      transcription factors in these pathways presumably by facilitating the
      recruitment of corepressors or mediating the assembly of repressor complexes.
      Additionally, evidence is accumulating that SUMO controls pathways important for
      the surveillance of genome integrity. SUMO regulates the PML/p53 tumour
      suppressor network, a key determinant in the cellular response to DNA damage.
      Moreover, proteins that maintain genomic stability by functioning at the
      interface between DNA replication, recombination and repair processes undergo
      SUMOylation. We will discuss some key findings that exemplify the role of SUMO in
      transcriptional regulation and genome surveillance.

PMID- 15021888
TI  - Regulation of apoptosis proteins in cancer cells by ubiquitin.
AB  - Ubiquitin inhibitors act at many levels to enhance apoptosis signaling. For TNF
      related apoptosis-inducing ligand (TRAIL)-mediated apoptosis signaling, there are
      at least five mechanisms by which apoptosis are regulated by the ubiquitin
      proteasome pathway. First, proteasome inhibitors can decrease Fas-like inhibitor
      protein (FLIP) protein levels in tumors, resulting in increased apoptosis
      signaling due to increased caspase-8 activation. This appears to involve the
      ubiquitin ligase TNF receptor activation factor-2 (TRAF2) and acts indirectly by
      causing cell-cycle arrest at a stage where there is high degradation of the FLIP
      TRAF2 complex. Second, the regulation of the proapoptotic Bcl-2 family member BAX
      occurs indirectly. Apoptosis signaling and caspase activation results in a
      confirmation change in the normally monomeric BAX, which exposes the BH3 domain
      of BAX, leading to dimerization and resistance to ubiquitin degradation. BAX then
      translocates into the mitochondria, resulting in the release of proapoptotic
      mitochondrial factors such as cytochrome c and second mitochondria-derived
      activator of caspase (SMAC). This results in the activation of caspase-9 and
      formation of the apoptosome and efficient apoptosis signaling. A third mechanism
      of the regulation of TRAIL signaling in the ubiquitin-proteasome pathway is
      mediated by the inhibitor of apoptosis proteins (IAP) E3 ligases. These IAPs can
      directly bind to caspases but also can act as ubiquitin ligases for caspases,
      resulting in the degradation of these caspases. IAP binding to caspases can be
      inhibited by SMAC, which exhibits a caspase-9 homology domain. The fourth
      mechanism for apoptosis activation by proteasome inhibitors is through the
      stabilization of the inhibitor of the kappaB (IkappaB)/NF-kappaB complex and
      prevention of nuclear translocation of the antiapoptosis transcription factor NF
      kappaB. During TRAIL-DR4, DR5 signaling, this pathway is activated by
      interactions of activated Fas-associated death domain with activated receptor
      interacting protein (RIP), which in turn activates NF-kappaB-inducing kinase and
      phosphorylates IkappaB. Therefore, the inhibition of IkappaB degradation blocks
      this RIP-mediated antiapoptosis signaling event. Last, p53 protein levels, and
      susceptibility to apoptosis, can be deregulated by the human homolog Hdm2 (Mdm2)
      E3 ligase. This process is inhibited by p53 phosphorylation and by sequestration
      of Mdm2 by ARF. Better mechanisms to inhibit the ubiquitin-proteasome pathway
      targeted at the ubiquitin-proteasome degradation process itself, or more
      specifically at the E3 ligases known to modulate and downregulate proapoptosis
      pathways will lead to the enhancement of TRAIL apoptosis signaling and better
      cancer therapeutic outcomes act through this pathway.

PMID- 15021889
TI  - The spindle checkpoint, aneuploidy, and cancer.
AB  - Cancer cells contain abnormal number of chromosomes (aneuploidy), which is a
      prevalent form of genetic instability in human cancers. Defects in a cell cycle
      surveillance mechanism called the spindle checkpoint contribute to chromosome
      instability and aneuploidy. In response to straying chromosomes in mitosis, the
      spindle checkpoint inhibits the ubiquitin ligase activity of the anaphase
      promoting complex or cyclosome (APC/C), thus preventing precocious chromosome
      segregation and ensuring the accurate partition of the genetic material. We
      review recent progress toward the understanding of the molecular mechanism of the
      spindle checkpoint and its role in guarding genome integrity at the chromosome
      level.

PMID- 15021890
TI  - The many faces of beta-TrCP E3 ubiquitin ligases: reflections in the magic mirror
      of cancer.
AB  - Beta-transducin repeats-containing proteins (beta-TrCP) serve as the substrate
      recognition subunits for the SCFbeta-TrCP E3 ubiquitin ligases. These ligases
      ubiquitinate specifically phosphorylated substrates and play a pivotal role in
      the regulation of cell division and various signal transduction pathways, which,
      in turn, are essential for many aspects of tumorigenesis. We review the functions
      of the SCFbeta-TrCP ligases in the light of their relevance to cell growth,
      survival and transformation. Mechanisms underlying beta-TrCP regulation and their
      aberration in human and animal cancer as well as prospective of targeting beta
      TrCP as a means of anticancer therapy are also discussed.

PMID- 15021891
TI  - Oncogenic aberrations of cullin-dependent ubiquitin ligases.
AB  - Accumulating evidence points to a key role of the ubiquitin-proteasome pathway in
      oncogenesis. Aberrant proteolysis of substrates involved in cellular processes
      such as the cell division cycle, gene transcription, the DNA damage response and
      apoptosis has been reported to contribute significantly to neoplastic
      transformation. Cullin-dependent ubiquitin ligases (CDLs) form a class of
      structurally related multisubunit enzymes central to the ubiquitin-mediated
      proteolysis of many important biological substrates. In this review, we describe
      the role of CDLs in the ubiquitinylation of cancer-related substrates and discuss
      how altered ubiquitinylation by CDLs may contribute to tumor development.

PMID- 15021892
TI  - Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and
      proteolysis.
AB  - In eukaryotic cells, control mechanisms of cell-cycle progression have evolved to
      accurately monitor the integrity of genetic information to be transferred to the
      progeny. Cdc25A phosphatase is an essential activator of cell-cycle progression
      and is targeted by checkpoint signals. Ubiquitylation regulates Cdc25A activity
      through fine tuning of its protein levels. Two different ubiquitin ligases (APC/C
      and SCF complex) are involved in Cdc25A turnover. While APC/C is involved in
      regulating Cdc25A at the exit of mitosis, SCF regulates the abundance of Cdc25A
      in S phase and G2. In response to DNA damage or to stalled replication, the
      activation of the ATM and ATR protein kinases leads to Chk1 and Chk2 activation
      and to Cdc25A hyperphosphorylation. These events stimulate SCF-mediated
      ubiquitylation of Cdc25A and its proteolysis. This contributes to delaying cell
      cycle progression, thereby preventing genomic instability. Based on recent
      findings, we discuss the role of Cdc25A ubiquitylation and degradation in cell
      cycle progression and in response to DNA damage. Moreover, we discuss the role of
      phosphorylation at multiple sites in triggering ubiquitylation signals.

PMID- 15021893
TI  - Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine
      kinases.
AB  - Growth factors and their transmembrane receptor tyrosine kinases play pivotal
      roles in morphogenesis, cell fate determination and pathogenesis, including
      multiple stages of cancer. The amplitude and kinetics of signaling by growth
      factor receptors are determined by an endocytic process, which sorts activated,
      autophosphorylated receptors to degradation in lysosomes. Recent studies
      uncovered the role of protein ubiquitylation in vesicular trafficking of growth
      factor receptors. Decoration of ligand-activated receptors by multiple monomeric
      ubiquitins distinguishes this degradative route from the proteasome-mediated
      pathway, which involves polymeric chains of ubiquitin. Although receptor
      ubiquitylation occurs at the cell surface, its major role is to sort internalized
      receptors to the lumen of the multivesicular body, en route to the lysosome. The
      ubiquitin ligases that control this late sorting event belong to the Cbl family
      of RING finger adaptors, which bind specific phosphotyrosine residues in the
      receptors upon activation by ligand. Another group of E3 ubiquitin ligases, the
      Nedd4 family, regulates the initial sorting event, which targets receptors to
      clathrin-coated regions of the plasma membrane. This step entails ubiquitin
      dependent assembly of a clathrin-binding complex of adaptors such as epsins,
      which share ubiquitin-interacting motifs. The concerted action of both ubiquitin
      binding adaptors of membrane coats and E3 ligases, as well as their regulation by
      protein phosphorylation and ubiquitylation, ensure robust endocytosis of growth
      factor receptors. Genetic defects and virus-mediated manipulations of the
      endocytic pathway divert receptors to a default recycling pathway, thereby
      enabling unrestrained signaling characteristic to transformed cells.

PMID- 15021895
TI  - Ubiquitin and breast cancer.
AB  - The regulation of protein stability by the ubiquitin-proteasome pathway is a
      critical issue central to the comprehension of the molecular basis of
      carcinogenesis. However, ubiquitin modification of target substrates signals many
      cellular processes other than proteolysis that are also important for the
      development of cancer. It is noteworthy that many proteins studied by clinical
      breast cancer researchers are involved in these ubiquitin pathways. This review
      summarizes recent works on such proteins including cyclins, CDK inhibitors, and
      the SCF in cell cycle control; the breast and ovarian cancer suppressor BRCA1
      BARD1; ErbB2/HER2/Neu and its ubiquitin ligase c-Cbl or CHIP; and the estrogen
      receptor and its downstream target Efp. Understanding these pathways may provide
      some hints toward developing diagnostic tools and treatments for breast cancer
      patients.

PMID- 15021894
TI  - Regulation of the TGFbeta signalling pathway by ubiquitin-mediated degradation.
AB  - The transforming growth factor-beta (TGFbeta) superfamily controls a plethora of
      biological responses, and alterations in its signalling pathway are associated
      with a range of human diseases, including cancer. TGFbeta superfamily ligands
      signal through a heteromeric complex of Ser/Thr kinase receptors that propagate
      the signal to the Smad family of intracellular proteins. The ubiquitin-mediated
      proteasomal degradation pathway is an evolutionary conserved cascade that tightly
      regulates TGFbeta superfamily signalling. Both the size of the Smad pool in
      unstimulated cells and Smad protein levels subsequent to the activation of the
      pathway are controlled by ubiquitination. E3 ligases are components of the
      ubiquitin-degradation complex that specifically recognize targeted proteins and
      the E3 ligases, Smad ubiquitination-related factor 1 (Smurf1), Smurf2 and
      SCF/Roc1 have been implicated in Smad degradation. The Smurfs are of particular
      importance to TGFbeta signalling, as Smads also function as adapters that recruit
      the Smurfs to various pathway components including the TGFbeta receptor complex
      and the transcriptional repressor, SnoN, and thereby regulate the degradation of
      these Smad-associating proteins. Thus, by controlling the level of Smads as well
      as positive and negative regulators of the pathway, Smurfs provide for complex
      and fine control of signalling output. Finally, growing evidence demonstrates
      that ubiquitination and proteasomal degradation is also implicated in the
      turnover of tumor-derived Smad mutants and may thus contribute to disease
      progression.

PMID- 15021896
TI  - A central role for the ring finger protein RNF11 in ubiquitin-mediated
      proteolysis via interactions with E2s and E3s.
AB  - The identification of novel tumor-associated genes represents an important area
      of cancer research. To that end, we have discovered a number of genes whose
      expression is altered in breast tumors. One of these genes has been identified as
      the ring finger protein 11 (RNF11) and its expression is elevated in breast and
      prostate cancer. The RNF11 gene encodes a 154 amino-acid protein that contains a
      ring finger and a PY motif. RNF11 is capable of binding numerous proteins, which
      encompass a wide variety of cellular pathways and mechanisms. This gives RNF11 a
      corresponding breadth of functions, including involvement in TGF-beta and
      epidermal growth factor receptor (EGFR) signaling. In addition, RNF11 has the
      potential to mediate the ubiquitination and subsequent proteolysis of many
      cellular proteins. Thus, it may represent an important target of novel cancer
      therapies.

PMID- 15021897
TI  - Regulating the p53 system through ubiquitination.
AB  - The tumor suppressor p53 is tightly controlled at low levels in cells by constant
      ubiquitination and proteasomal degradation. In response to stresses,
      ubiquitination of p53 is inhibited through diverse pathways, depending on the
      nature of the stimulus and cell type. This leads to the accumulation and
      activation of p53, which induces cell cycle arrest and/or apoptosis to prevent
      cells from transformation. Many studies have indicated that defects of the p53
      system are present in most, if not all, human tumor cells. Meanwhile, significant
      progress has been made in understanding the molecular mechanisms of p53
      ubiquitination and the regulation of the p53 system. Therefore, it is possible
      now to consider targeting ubiquitination as a means to regulate and reactivate
      p53 in tumors. Emerging evidence suggests that inhibiting the E3 activity of
      Mdm2, blocking the interaction of p53 and Mdm2, and restoring the function of
      mutated p53 are potential effective strategies to kill certain tumor cells
      selectively. It is conceivable that new chemotherapeutic agents based on these
      studies will be generated in the not-so-distant future.

PMID- 15021898
TI  - Epstein-Barr virus oncogenesis and the ubiquitin-proteasome system.
AB  - Epstein-Barr virus (EBV), a human herpesvirus associated with lymphoid and
      epithelial cell tumors, encodes several proteins that exploit the ubiquitin
      proteasome system to regulate latency and allow the persistence of infected cells
      in immunocompetent hosts. Further modifications of ubiquitin-dependent
      proteolysis by activated cellular oncogenes contribute to malignant
      transformation. A detailed understanding of these processes may lead to the
      development of new therapeutic strategies for EBV-associated cancers.

PMID- 15021899
TI  - A link between p73 transcriptional activity and p73 degradation.
AB  - The p53 family of proteins includes three members, p53, p63, and p73. The levels
      and stability of p53 are controlled in large part by MDM2, which can bind the p53
      N-terminus and promote its degradation. Because the MDM2 gene is
      transcriptionally activated by p53, it forms part of an autoregulatory feedback
      loop that directly links the transcriptional activity of p53 with its
      degradation. In contrast, little is known about the mechanisms that control p63
      or p73 stability. In the current study, p73 deletion or point mutants that lacked
      transactivation activity were stable compared to wild-type p73. A naturally
      occurring p73 variant (DeltaNp73) was also stable compared to wild-type p73.
      Finally, fusion of the VP16-transactivation domain to an inactive, stable p73
      mutant restored transactivation function and rendered the mutant protein
      unstable. These results demonstrate that p73 transactivation activity is
      necessary for rapid p73 turnover, and suggest that one or more transcriptional
      targets of p73 may promote its degradation.

PMID- 15021900
TI  - LMW-PTP is a positive regulator of tumor onset and growth.
AB  - Low molecular weight protein tyrosine phosphatases (LMW-PTPs) are an enzyme
      family that plays a key role in cell proliferation control by
      dephosphorylating/inactivating both tyrosine kinase receptors (such as PDGF,
      insulin, and ephrin receptors) and docking proteins (such, as beta-catenin)
      endowed with both adhesion and transcriptional activity. Besides being a frequent
      event in human tumors, overexpression of LMW-PTP has been recently demonstrated
      to be sufficient to induce neoplastic transformation. We recently demonstrated
      that overexpression of LMW-PTP strongly potentiates the stability of cell-cell
      contacts at the adherens junction level, which powerfully suggests that LMW-PTP
      may also contribute to cancer invasivity. Focusing on mechanisms by which LMW-PTP
      is involved in cancer onset and progression, the emerging picture is that LMW-PTP
      strongly increases fibronectin-mediated cell adhesion and mobility but,
      paradoxically, decreases cell proliferation. Nevertheless, LMW-PTP-transfected
      NIH3T3 fibroblasts engrafted in nude mice induce the onset of larger
      fibrosarcomas, which are endowed with higher proliferation activity as compared
      to mock-transfected controls. Quite opposite effects have been obtained with
      engrafted fibroblasts transfected with a dominant-negative form of LMW-PTP.
      Notably, in sarcoma extracts, LMW-PTP overexpression greatly influences the
      ephrin A2 (EphA2) but not PDGF receptor or beta-catenin tyrosine phosphorylation.
      The high association of dephosphorylated EphA2 overexpression with most human
      cancers and our observation that cell growth stimulation by LMW-PTP
      overexpression is restricted to the in vivo model, strongly suggest that LMW-PTP
      oncogenic potential is mediated by its EphA2 tyrosine dephosphorylating activity.

PMID- 15021901
TI  - Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor
      suppressor gene.
AB  - Germline mutations of the LKB1 gene are responsible for Peutz-Jeghers syndrome
      (PJS), an autosomal dominant inherited disorder bestowing an increased risk of
      cancer. We have recently demonstrated that LKB1 inactivating mutations are not
      confined to PJS, but also appear in lung adenocarcinomas of sporadic origin,
      including primary tumors and lung cancer cell lines. To accurately determine the
      frequency of inactivating LKB1 gene mutations in lung tumors we have sequenced
      the complete coding region of LKB1 in 21 additional lung cancer cell lines. Here
      we describe the mutational status of LKB1 gene in 30 lung cancer cell lines from
      different histopathological types, including 11 lung adenocarcinomas (LADs) and
      11 small cell lung cancers (SCLCs). LKB1 gene alterations were present in six
      (54%) of the LAD cell lines tested but in none of the other histological types.
      Similar to our previous observations in primary tumors, all point mutations were
      of the nonsense or frameshift type, leading to an abnormal, truncated protein.
      Moreover, 2 cell lines (A427 and H2126) harbored large gene deletions that
      spanned several exons. Hence, we have identified additional lung cancer cell
      lines carrying inactivating mutations of the LKB1 tumor suppressor gene, further
      attesting to the significance of this gene in the development of LADs and
      providing new natural LKB1 knockouts for studies of the biological function of
      the LKB1 protein.

PMID- 15021902
TI  - A critical role of PI-3K/Akt/JNKs pathway in benzo[a]pyrene diol-epoxide
      (B[a]PDE)-induced AP-1 transactivation in mouse epidermal Cl41 cells.
AB  - Mouse skin tumorigenicity studies indicate that benzo[a]pyrene-7,8-diol-9,10
      epoxide (B[a]PDE) contributes to carcinogenesis as both a tumor initiator and
      promoter. However, the mechanisms that mediate B[a]PDE tumor promotion effects
      remain unclear. Our results demonstrated that in mouse epidermal Cl41 cells,
      B[a]PDE treatment resulted in marked activation of AP-1 and its upstream MAPKs,
      including ERKs, JNKs and p38K. B[a]PDE exposure also led to activation of
      phosphotidylinositol 3-kinase (PI-3K), Akt and p70 S6 kinase (p70S6k). B[a]PDE
      induced AP-1 transactivation was inhibited by pretreatment of cells with PI-3K
      inhibitors, wortmannin or Ly294002. In contrast, inhibition of p70S6k with
      rapamycin did not show any inhibitory effects. An overexpression of dominant
      negative mutant of PI-3K, Deltap85, impaired B[a]PDE-induced activation of PI-3K,
      Akt and AP-1 transactivation. Furthermore, an overexpression of dominant-negative
      Akt mutant, Akt-T308A/S473A, blocked B[a]PDE-induced activation of Akt, AP-1 and
      JNKs, while it did not affect the activation of p70S6k, ERKs and p38 kinase.
      These results demonstrated that B[a]PDE was able to induce AP-1 transactivation
      and this AP-1 induction was specific through PI-3K/Akt/JNKs-dependent and p70S6k
      independent pathways. This study also indicated that Akt-T308A/S473A blocks
      B[a]PDE-induced AP-1 activation specific through impairing JNK pathway. These
      findings will help us to understand the signal transduction pathways involved in
      the carcinogenic effects of B[a]PDE.

PMID- 15021903
TI  - The effects of Brn-3a on neuronal differentiation and apoptosis are
      differentially modulated by EWS and its oncogenic derivative EWS/Fli-1.
AB  - The Brn-3 family of POU (Pit-Oct-Unc) homeodomain transcription factors regulate
      differentiation of neuronal cell types. The transcriptional activator Brn-3a is
      expressed in Ewing's sarcomas, which also express characteristic chimaeric
      proteins as a consequence of fusion of the TET family gene EWS to one of several
      ETS genes. We have previously demonstrated a physical interaction between Brn-3a
      and EWS proteins, and show here that the C-terminal POU domain but not N-terminal
      activation domain of Brn-3a can interact in vitro with the RNA-binding domain of
      EWS. Likely due to POU domain homology, the related factor Brn-3b can also
      interact with EWS, but to a lesser extent than Brn-3a. Importantly, Brn-3a but
      not Brn-3b interacts in vitro with chimaeric EWS/Fli-1, EWS/ATF-1 and EWS/ERG
      proteins. Furthermore, overexpression of EWS/Fli-1 but not EWS or Fli-1 inhibits
      Brn-3a-associated growth arrest and neurite outgrowth in neuronal cells, and
      specifically inhibits Brn-3a-dependent activation of p21 and SNAP-25
      transcription. In contrast, upregulation of Bcl-2 expression and inhibition of
      apoptosis by Brn-3a is antagonized more by EWS than by EWS/Fli-1. These data
      demonstrate that oncogenic rearrangement of EWS to produce EWS/Fli-1 may enhance
      the antiapoptotic effect of Brn-3a and inhibit its ability to promote neuronal
      differentiation.

PMID- 15021904
TI  - Cancer chemopreventive activity of a mixture of Chinese herbs (antitumor B) in
      mouse lung tumor models.
AB  - Antitumor B (ATB), also known as Zeng Sheng Ping, is a Chinese herbal mixture
      composed of six plants. Previously, clinical studies have shown a significant
      chemopreventive efficacy of ATB against human esophageal and lung cancers. In the
      present study, A/J mice harboring a dominant-negative p53 and/or heterozygous
      deletion of Ink4a/Arf and treated with benzo[a]pyrene were used to investigate
      the chemopreventive effects of ATB on chemically induced lung tumorigenesis. Mice
      with various genotypes treated with ATB displayed a significant reduction in lung
      tumor multiplicity and tumor load. Treatment with ATB resulted in an
      approximately 40% decrease in tumor multiplicity and a 70% decrease in tumor load
      in both wild-type mice and in mice with a loss of the Ink4a/Arf tumor suppressor
      genes. Interestingly, ATB decreased tumor multiplicity and volume by 50 and 90%,
      respectively, in mice with a dominant-negative p53 and in mice with both a p53
      mutation and deletion of Ink4a/Arf. Kras2 mutation analysis of the lung tumors
      revealed that tumors harbored mutations in the 12th codon of Kras2. There were no
      differences in either the incidence or types of mutations between tumors treated
      with or without ATB. Oligonucleotide array analysis revealed 284 genes that were
      differentially expressed in mouse lung tumors as compared to the normal lung, and
      it was found that 114 out of these 284 genes changed their expression toward the
      normal levels in tumors treated with ATB. Most of the genes modulated by ATB
      belong to several cellular signaling pathways, including Notch (Notch homolog 2,
      manic fringe homolog), growth factor (FGF intracellular-binding protein,
      PDGFalpha), G protein-Ras-MAPK (MAPK3, MAP3K4, rab3A, Rap1, RSG5, PKCtheta),
      ubiquitin-proteasome (CDC34, Cullin1, 26S proteasome), and apoptosis (BAD
      promoter, caspase 3). These results suggest that ATB is an effective
      chemopreventive against mouse lung tumorigenesis. Furthermore, ATB exhibited an
      enhanced inhibitory effect in animals harboring genetic alterations (Kras2, p53,
      and Ink4a/Arf), which are often seen in human lung adenocarcinomas.

PMID- 15021905
TI  - Direct binding of the human homologue of the Drosophila disc large tumor
      suppressor gene to seven-pass transmembrane proteins, tumor endothelial marker 5
      (TEM5), and a novel TEM5-like protein.
AB  - The human homologue of the Drosophila discs large tumor suppressor gene (hDlg) is
      a member of the membrane-associated guanylate kinase family with three PSD
      95/Dlg/ZO-1 (PDZ) domains. hDlg has been shown to bind tumor suppressor proteins,
      adenomatous polyposis coli (APC) and protein tyrosine phosphatase and tensin
      homologue (PTEN), and several viral oncoproteins, and has been implicated in the
      negative regulation of cell proliferation. hDlg has furthermore been shown to
      localize at the plasma membrane of synapses and to scaffold cell surface
      receptors and channels. In epithelial cells, hDlg localizes at the basolateral
      plasma membrane, but its localization mechanism is unknown. We searched here for
      a transmembrane protein that directly bound to hDlg. hDlg bound tumor endothelial
      marker 5 (TEM5), a seven-pass transmembrane protein that is homologous to the
      family B of G-protein-coupled receptors (GPCRs). TEM5 has previously been
      reported to display elevated expression during tumor angiogenesis and
      neoangiogenesis. The PDZ domains of hDlg bound the C-terminal PDZ-binding motif
      of TEM5. The expression of TEM5 was detected in endothelial cells of embryonic
      liver, where hDlg colocalized with TEM5. hDlg furthermore bound a novel seven
      pass transmembrane protein, which was homologous to TEM5, and was named here a
      TEM5-like protein (TEM5-like). These results suggest that hDlg localizes at the
      plasma membrane through TEM5 and TEM5-like and furthermore scaffolds these GPCRs
      in endothelial cells during tumor angiogenesis and neoangiogenesis.

PMID- 15021907
TI  - Ablation of PARP-1 does not interfere with the repair of DNA double-strand
      breaks, but compromises the reactivation of stalled replication forks.
AB  - Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant DNA end-sensing and binding
      molecule. Inactivation of PARP-1 by chemicals and genetic mutations slows cell
      proliferation, increases sister chromatid exchange (SCE), micronuclei formation
      and chromosome instability, and shortens telomeres. Given its affinity to DNA
      breaks and temporal occupation on DNA strand break sites, PARP-1 is proposed to
      prevent inappropriate DNA recombination. We investigated the potential role of
      PARP-1 in repair of DNA double-strand breaks (DSBs) and stalled replication
      forks. PARP-1-/- embryonic stem cells and embryonic fibroblast cells exhibited
      normal repair of DNA DSBs by either homologous recombination (HR) or
      nonhomologous end-joining (NHEJ) pathways. Inactivation of PARP-1 did not
      interfere with gene-targeting efficiency in ES cells. However, PARP-1-/- cells
      were hypersensitive to the replication damage agent hydroxyurea (HU)-induced cell
      death and exhibited enhanced SCE formation. Ablation of PARP-1 delayed
      reactivation of stalled replication forks imposed by HU and re-entry into the G2
      M phase after HU release. These data indicate that PARP-1 is dispensable in HR
      induced by DSBs, but is involved in the repair and reactivation of stalled
      replication forks.

PMID- 15021906
TI  - Multiple cell-type-specific elements regulate Myc protein stability.
AB  - Myc is a highly unstable transcription factor that is destroyed by ubiquitin (Ub)
      mediated proteolysis. We have previously identified an amino-terminal 'degron'
      within Myc that signals its destruction; this degron spans the transcriptional
      activation domain of Myc, and includes two highly conserved regions called Myc
      boxes I and II. We now report the identification of a second element--the D
      element--which is also required for Myc proteolysis. The centrally located D
      element is distinct from the PEST domain in Myc, but includes Myc box III, a
      third highly conserved region with no previously known function. We show that
      deletion of the D-element stabilizes the Myc protein without affecting its
      ubiquitylation, and report that the D-element and the degron act in a cell-type
      specific manner to direct Myc proteolysis. These data thus demonstrate that Myc
      stability is regulated at both the ubiquitylation and postubiquitylation levels,
      and reveal that substrates of the Ub-proteasome system can be targeted for
      destruction differently in different cell types.

PMID- 15021908
TI  - Carcinogen-induced colon tumors in mice are chromosomally stable and are
      characterized by low-level microsatellite instability.
AB  - The azoxymethane (AOM)-induced mouse colon tumor model recapitulates many of the
      histopathological features associated with the multistage progression of human
      sporadic colorectal cancers (CRCs). To better define the genetic events
      associated with tumorigenesis in this murine model, we analysed tumors from A/J
      mice for chromosomal (CIN) and microsatellite (MSI) instabilities, two
      fundamental pathways of genomic instability that play a critical role in the
      pathogenesis of human CRCs. Male A/J mice, 6-week old, were injected with either
      AOM (n=5) (10 mg/kg b.w., i.p.) or vehicle (n=5) (0.9% NaCl solution) once a week
      for 6 weeks. At 32 weeks after the last dose, comparative genomic hybridization
      (CGH) was performed on 16 tumors harvested from five animals. Although 25% of the
      tumors displayed either a gain of chromosome 2 or loss of Y, the majority (75%)
      showed no genomic imbalances. Further analysis of chromosomal aberrations, using
      CGH and spectral karyotyping (SKY) was performed in our recently established A/J
      colon tumor-derived cell line, AJ02-NM0. Results showed a pseudotetraploid
      karyotype with loss of only the Y chromosome in these cultured cells, thereby
      providing additional evidence for the minimal role of CIN in the primary AOM
      induced tumors. Interestingly, the majority (81%) of A/J tumors displayed low
      level microsatellite instability (MSI-L) when analysed using mono- and
      dinucleotide repeat markers, and showed a significant expansion to high-level
      instability (MSI-H) in the AJ02-NM0 cells. This finding in cultured cells
      additionally provides evidence that a mild mutator pathway may contribute to the
      development of behaviorally benign carcinomas in situ in A/J mice. To better
      understand the tumorigenic process in the A/J colons, we screened for mutational
      alterations in key regions of the K-ras and Apc genes. Results showed a very low
      frequency (6%) of K-ras activating mutations, together with the absence of Apc
      truncation mutations in primary tumors and AJ02-NM0 cells. However, these tumors
      displayed intense nuclear accumulation of beta-catenin protein, indicating
      activation of the Wnt signaling pathway. Based on our molecular and cytogenetic
      findings, we propose that carcinogen-induced tumors may develop via mechanisms
      independent of the 'classical' CIN or MSI pathways.

PMID- 15021909
TI  - c-Myc represses the proximal promoters of GADD45a and GADD153 by a post-RNA
      polymerase II recruitment mechanism.
AB  - The c-Myc cellular oncogene has diverse activities, including transformation,
      proliferation, and apoptosis. These activities are dependent on the ability of c
      Myc to regulate gene transcription. c-Myc downregulates the GADD45a and GADD153
      (DDTI3) genes that are induced in response to genotoxic stresses and that encode
      protein products with antiproliferative activities. We show that c-Myc represses
      the expression of GADD45a and GADD153 in response to thapsigargin, a nongenotoxic
      stress, as well as other endoplasmic reticulum (ER) stress agents. c-Myc
      represses both the basal expression and the magnitude of ER stress induction of
      GADD gene transcription. This repression requires the minimal promoter region of
      GADD45a and GADD153 and is not dependent on the ER stress element or p53-binding
      sites in the regulatory regions of these genes. Further analysis by chromatin
      immunoprecipitation shows that c-Myc binds to the minimal promoter region of
      GADD45a and GADD153 in vivo. c-Myc-associated protein X (Max) is also bound to
      both GADD gene promoters, whereas c-Myc interacting zinc-finger protein 1 (Miz-1)
      is bound to the GADD153, but not GADD45a, promoter. RNA polymerase II (RNAPII) is
      recruited to the GADD gene promoters in the presence and absence of c-Myc, which
      suggests that c-Myc represses these genes through a post-RNAPII recruitment
      mechanism.

PMID- 15021910
TI  - Upregulation of IKKalpha/IKKbeta by integrin-linked kinase is required for
      HER2/neu-induced NF-kappaB antiapoptotic pathway.
AB  - Constitutively active HER2/neu activates nuclear factor kappa-B (NF-kappaB) in
      cells and induces their resistance to apoptotic stimuli such as tumor necrosis
      factor-alpha (TNF-alpha). Here, we show that integrin-linked kinase (ILK), the
      crucial signal transducer in the integrin pathway, is involved in HER2/neu
      mediated activation of NF-kappaB. Expression of HER2/neu increases ILK activity.
      Blocking ILK activity with a kinase-deficient mutant ILK (ILK-KD) inhibits NF
      kappaB activation and sensitizes HER2/neu-transformed cells to TNF-alpha-induced
      apoptosis. Stable expression of ILK-KD in HER2/neu-transformed cells suppressed
      Akt phosphorylation and the expression of IkappaB kinase alpha and beta (IKKalpha
      and beta) at both the protein and mRNA levels, preventing IkappaB-alpha
      degradation and NF-kappaB activation. Furthermore, HER2/neu stimulated the
      transcriptional activity of the putative IKKbeta promoter through ILK and Akt.
      Our results demonstrate that upregulation of IKKalpha and IKKbeta by the ILK/Akt
      pathway is required for the HER2/neu-mediated NF-kappaB antiapoptotic pathway.

PMID- 15021911
TI  - The RNA binding protein Sam68 is acetylated in tumor cell lines, and its
      acetylation correlates with enhanced RNA binding activity.
AB  - Sam68 (Src-associated in mitosis; 68 kDa) is a member of the STAR (signal
      transduction and activation of RNA) family of KH domain-containing RNA binding
      proteins. Accumulating evidence suggests that it plays an important role in cell
      cycle control. Tyrosine phosphorylation by Src family kinases and breast tumor
      kinase can negatively regulate its RNA binding activity. To date, there are no
      reports of a factor, such as a phosphatase, which can positively regulate Sam68
      association with RNA. Acetylation is a reversible post-translational modification
      known to influence the activity of DNA binding proteins. However, acetylation of
      a cellular RNA binding protein as a mechanism for regulating its activity has not
      yet been reported. Here we demonstrate Sam68 to be acetylated in vivo. A screen
      of several human mammary epithelial cell lines revealed variations in Sam68
      acetylation. Interestingly, the highest level of acetylation was found in
      tumorigenic breast cancer cell lines. The screen also showed a positive
      correlation between Sam68 acetylation and its ability to bind RNA. The
      acetyltransferase CBP was shown to acetylate Sam68 and enhance its binding to
      poly(U) RNA. These results suggest that Sam68 association with RNA substrates may
      be positively regulated by acetylation, and that enhanced acetylation and RNA
      binding activity of Sam68 may play a role in tumor cell proliferation.

PMID- 15021912
TI  - MEK1-induced Golgi dynamics during cell cycle progression is partly mediated by
      Polo-like kinase-3.
AB  - MEK1, a gene product that regulates cell growth and differentiation, also plays
      an important role in Golgi breakdown during the cell cycle. We have recently
      shown that polo-like kinase (Plk3) is Golgi localized and involved in Golgi
      dynamics during the cell cycle. To study the mode of action of Plk3 in the Golgi
      fragmentation cascade, we examined functional as well as physical interactions
      between Plk3 and MEK1/ERKs. In HeLa cells, although a significant amount of Plk3
      signals dispersed in a manner similar to those of Golgi during mitosis
      concentrated Plk3 was detected at spindle poles, which colocalized with phospho
      MEKs and phospho-ERKs. Pull-down assays showed that Plk3 physically interacted
      with MEK1 and ERK2. Nocodazole activated Plk3 and its activation was blocked by
      MEK-specific inhibitors (PD98059 or U0126). Moreover, transfection of activated
      MEK1 resulted in an enhanced kinase activity of Plk3; Plk3-induced fragmentation
      of Golgi stacks was significantly reduced after treatment with MEK inhibitors.
      Consistently, ectopic expression of activated MEK1, but not kinase-dead
      MEK1(K97R), stimulated Plk3 to induce Golgi breakdown and the stimulation was not
      observed in cells expressing Plk3(K52R). Furthermore, PLK3(-/-) murine embryonic
      fibroblast cells exhibited a significantly less fragmentation of the Golgi
      complex than that in wild-type cells after exposed to nocodazole. Thus, our
      studies strongly suggest that Plk3 may be a key protein kinase mediating MEK1
      function in the Golgi fragmentation pathway during cell division.

PMID- 15021913
TI  - SMAGP, a new small trans-membrane glycoprotein altered in cancer.
AB  - Using the Affymetrix array technology, we previously identified an EST strongly
      expressed in several metastatic cell lines. In the present study, we cloned the
      corresponding cDNA that encodes a new glycoprotein composed of 97 amino acids and
      containing a trans-membrane domain. Therefore, we named it SMAGP for Small trans
      Membrane And Glycosylated Protein. SMAGP is strongly conserved during evolution.
      It is expressed by normal epithelia of various organs, the protein being notably
      localized to the lateral face of the plasma membrane of cohesive well-polarized
      epithelial cells. In addition, SMAGP contains binding domains for the protein 4.1
      and the PDZ domain of MAGUK proteins. Similar protein features are observed in
      several cell-surface proteins involved via ternary complexes in intercellular
      processes leading to cytoskeleton assembly as well as intracellular signalling.
      Thus, SMAGP might similarly be involved in a scaffolding protein complex, and
      therefore participate in the epithelium organization or in subsequent functions.
      Immunohistochemical data obtained using human breast, colon and lung cancer
      samples sustain this hypothesis since they showed that, in both primary tumours
      and metastases, reduced expression and/or cytoplasmic redistribution of SMAGP is
      superimposable with low histological tumour differentiation features, namely a
      lack of epithelial cell polarity and disorganized tissue phenotype.

PMID- 15021914
TI  - Interleukin-6 activates phosphoinositol-3' kinase in multiple myeloma tumor cells
      by signaling through RAS-dependent and, separately, through p85-dependent
      pathways.
AB  - The IL-6-induced activation of the phosphatidylinositol-3' kinase (PI3-K)/AKT
      cascade in multiple myeloma (MM) cells is critical for tumor cell proliferation
      and viability. Since the IL-6 receptor does not contain binding sites for the p85
      regulatory portion of PI3-K, intermediate molecules must play a role.
      Coimmunoprecipitation studies in MM cell lines demonstrated the IL-6-induced
      formation of two independent PI3-K-containing complexes: one containing p21 RAS
      but not STAT-3 and a second containing STAT-3 but not RAS. Both complexes
      demonstrated IL-6-induced lipid kinase activity. IL-6 also generated kinase
      activity in a mutant p110 molecule that could not bind p85. Use of dominant
      negative (DN) constructs confirmed the presence of two independent pathways of
      activation: a DN RAS prevented the IL-6-induced generation of lipid kinase
      activity in the mutant p110 molecule but had no effect on activity generated in
      the STAT-3-containing complex. In contrast, a DN p85 prevented the generation of
      kinase activity in the STAT-3-containing complex but had no effect on activity
      generated in the p110 molecule. Both DN constructs significantly prevented the IL
      6-induced activation of AKT. MM cells expressing activating RAS mutations
      demonstrated enhanced IL-6-independent growth and constitutive PI3-K activity.
      These data indicate two potential independent pathways of PI3-K/AKT activation in
      MM cells: one mediated via signaling through RAS which is independent of p85 and
      a second mediated via p85 and due to a STAT-3-containing complex.

PMID- 15021915
TI  - A dynamic switch in Rb+/- mediated neuroendocrine tumorigenesis.
AB  - Rb+/- mice develop a complex spectrum of neuroendocrine tumors on a mixed genetic
      (129Sv x C57BL/6) background. To understand how the 129Sv and C57BL/6
      contributions affect Rb+/- tumorigenesis, we serially backcrossed Rb+/- animals
      to the 129Sv or C57BL/6 strain, and analysed their pathological profiles.
      Strikingly, the length of survival and the penetrance, severity and multiplicity
      of neuroendocrine tumors switch dramatically between Rb+/- animals from the two
      genetic backgrounds. In fact, the 129Sv background significantly enhances both
      the initiation and progression of tumorigenesis in the intermediate lobe of the
      pituitary (ILP) in Rb+/- animals. This is due to the surprising fact that ILPs
      from wild-type 129Sv animals are inherently abnormal, and thus greatly
      predisposed to neoplasia. This is likely to explain the high incidence of ILP
      tumors, an otherwise rare tumor type in wild-type mice, in numerous knockout
      studies performed on the 129Sv strain, and raises the intriguing possibility that
      the classic Rb+/- neuroendocrine tumors may fade away in another as of yet
      unidentified inbred strain. Finally, we have increased the utility of the Rb+/-
      tumor model, since Rb+/- animals on the C57BL/6 background develop high
      penetrance tumors of the anterior lobe of the pituitary, a class of tumors
      estimated to occur in 20-25% of humans.

PMID- 15021917
TI  - A novel apoptotic pathway induced by the drs tumor suppressor gene.
AB  - The drs gene was originally isolated as a suppressor against v-src
      transformation. Expression of drs mRNA was markedly downregulated in a variety of
      human cancer cell lines and tissues, suggesting that the drs gene acts as a tumor
      suppressor. In this study, we found that ectopic expression of the Drs protein
      induced apoptosis in human cancer cell lines. Analyses using deletion mutants of
      drs revealed that both the C-terminal region and the three consensus repeats in
      the N-terminal region are essential for the induction of apoptosis. Caspase-12, 
      9, and -3 were sequentially activated by drs, and specific inhibitors of caspase
      3 and -9 suppressed drs-induced apoptosis. The release of cytochrome c from the
      mitochondria into the cytoplasm was not observed in apoptosis by drs, suggesting
      that the mitochondrial pathway does not mediate drs-induced apoptosis.
      Furthermore, we found that the Drs protein can interact with ASY/Nogo-B/RTN-x(S),
      an apoptosis-inducing protein localized in the endoplasmic reticulum, and that
      coexpression of these genes increased the efficiency of apoptosis. These results
      indicated that Drs induces apoptosis by a novel pathway mediated by ASY/Nogo
      B/RTN-x(S), caspase-12, -9, and -3.

PMID- 15021916
TI  - SOCS1 [corrected] inhibits HPV-E7-mediated transformation by inducing degradation
      of E7 protein.
AB  - Human papilloma viruses (HPVs) are small double-stranded DNA viruses that infect
      mucosal and cutaneous epithelium and induce cervical cancer. It has been shown
      that interferon (IFN)gamma suppresses proliferation of HPV-infected cells by
      suppressing expression of HPV E7. Here, we found that IFNgamma induces not only
      suppression of E7 transcription but also proteasome-dependent degradation.
      Suppressor of cytokine signaling-1 (SOCS1)/JAB, a suppressor of cytokine
      signaling, is known to be induced by IFNgamma, and functions as an antioncogene
      against various hematopoietic oncogenic proteins. SOCS1 contains the SOCS-box,
      which is shown to recruit ubiquitin transferase to the molecules that interact
      with SOCS1. We found that SOCS1 interacted with HPV E7 protein and induced
      ubiquitination and degradation of E7 in a SOCS-box-dependent manner. SOCS1
      overexpression also increased Rb protein levels and suppressed proliferation of
      cervical cancer cell lines infected with HPV. Moreover, E7 protein levels were
      higher and Rb protein levels were lower in SOCS1-deficient fibroblasts infected
      with retrovirus vector carrying E7 gene than in wild-type fibroblasts. E7 induced
      anchorage-independent growth in SOCS1-deficient fibroblasts, but not in wild-type
      cells. These data suggested that SOCS1 plays an important role in regulating the
      levels of E7 protein and their transforming potential, and could be a new
      therapeutic tool for HPV-mediated tumors.

PMID- 15021918
TI  - Anlaysis of complementary expression profiles following WT1 induction versus
      repression reveals the cholesterol/fatty acid synthetic pathways as a possible
      major target of WT1.
AB  - The Wilms' tumour suppressor gene, WT1, encodes a zinc-finger protein that is
      mutated in Wilms' tumours and other malignancies. WT1 is one of the earliest
      genes expressed during kidney development. WT1 proteins can activate and repress
      putative target genes in vitro, although the in vivo relevance of such target
      genes often remains unverified. To better understand the role of WT1 in
      tumorigenesis and kidney development, we need to identify downstream target
      genes. In this study, we have expression profiled human embryonic kidney 293
      cells stably transfected to allow inducible WT1 expression and mouse mesonephric
      M15 cells transfected with a WT1 antisense construct to abolish endogenous
      expression of all WT1 isoforms to identify WT1-responsive genes. The
      complementary overlap between the two cell lines revealed a pronounced repression
      of genes involved in cholesterol biosynthesis by WT1. This pathway is
      transcriptionally regulated by the sterol responsive element-binding proteins
      (SREBPs). Here, we provide evidence that the C-terminal end of the WT1 protein
      can directly interact with SREBP, suggesting that WT1 may modify the
      transcriptional function of SREBPs via a direct protein-protein interaction.
      Therefore, the tumour suppressor activities of WT1 may be achieved by repressing
      the mevalonate pathway, thereby controlling cellular proliferation and promoting
      terminal differentiation.

PMID- 15021921
TI  - [Endophenotype--a new concept for biological characterization of psychiatric
      disorders].
AB  - In the field of psychiatric genetics, the concept of endophenotypes is presently
      receiving high popularity. Current difficulties in the search for susceptibility
      genes of complex diseases have been attributed to the etiological heterogeneity
      of the clinical, psychopathologically defined phenotype of the disease.
      Neurobiological correlates of the disease which are genetically influenced and
      stable over time are considered to be more promising targets of phenotypes. They
      are more directly influenced by gene effects and presumably defined by a genetic
      determination which is less complex than the phenotype of the disorder. The
      endophenotype strategy has already been successful in complex disorders of other
      areas in medicine, including alcoholism and late-onset Alzheimer's disease. For
      schizophrenia, a series of endophenotypes for molecular/genetic investigation has
      been suggested, but the concept "endophenotype" also provides a basis for
      biological classification of mental disorders.

PMID- 15021923
TI  - [Value of diagnostic imaging in evaluation of electroconvulsive therapy].
AB  - Magnetic resonance imaging (MRI), positron emission tomography (PET), and single
      photon emission computed tomography (SPECT) may be able to investigate the
      clinical efficacy and underlying neuronal processes of electroconvulsive therapy
      (ECT). The following review focuses on neuroimaging in ECT. Neuroimaging findings
      support that ECT does not result in significant macroscopic structural changes.
      However, in patients with subtle structural changes such as subcortical lesions
      and dilatation of lateral ventricles before ECT, the possibilities of poor
      therapeutic outcome, increased incidence of delirium, and longer-lasting
      cognitive deficits should be considered. Functional studies show reduced blood
      flow and glucose metabolism during the first days after ECT. Afterwards, their
      normalization can be observed, which seems to correlate to clinical improvement.
      The importance of this suppression effect needs to be further elucidated. Future
      studies of receptor systems and longitudinal studies will open new perspectives
      in future imaging research.

PMID- 15021924
TI  - [Short-term effects of acute inpatient treatment of alcoholics. A prospective,
      multicenter evaluation study].
AB  - BACKGROUND: In spite of a high prevalence of patients with alcohol addiction
      being treated in mental hospitals, the acute treatment of alcoholism has seldom
      been evaluated. METHODS: This follow-up study was conducted in five mental
      hospitals in northwestern Germany. Enrolled were 479 consecutively admitted
      patients, of whom 411 (86%) could be interviewed 3 months after discharge.
      RESULTS: 3 months after discharge, 60.5% of the intention-to-treat sample and 54%
      of the follow-up sample had relapsed. Twenty-eight percent had taken part in
      inpatient rehabilitation programmes, and 26.5% had had at least one further
      inpatient withdrawal treatment. There were highly significant reductions in
      quantity of consumed alcohol, numbers of drinking days, and numbers of
      intoxication days. Multivariate analyses revealed that biographical, social, and
      treatment-related items were predictors of unfavourable outcome (excessive
      alcohol consumption and/or readmission to inpatient treatment). A short length of
      stay was identified as a predictor of unfavourable health status after 3 months.
      CONCLUSIONS: For many patients, inpatient acute treatment is an effective
      intervention which promotes abstinence, reduces alcohol consumption, and enhances
      integration into the addiction treatment system. For chronically addicted and
      repeat patients, this treatment as a repetitive crisis intervention helps in the
      short term but does not result in lasting changes in the course of illness.

PMID- 15021922
TI  - [Cytokine network in patients with schizophrenia and its significance for the
      pathophysiology of the illness].
AB  - Experimental findings from psychoimmunologic research in humans and
      epidemiological data suggest that alterations in cytokine networks may induce
      acute psychopathologic symptoms and may be involved in the pathogenesis and
      pathophysiology of schizophrenia by influencing brain development. However, there
      is insufficient evidence from genetic, post-mortem, and cerebrospinal fluid
      studies to demonstrate this in the CNS of schizophrenic patients. In contrast,
      there are quite robust findings from peripheral blood that interleukin (IL)-2, IL
      6, tumor necrosis factor-alpha, and interferon cytokine systems in patients are
      regulated differently than in controls. However, these findings are not specific
      to schizophrenia, they are confounded by numerous intervening variables such as
      stress, smoking, and medication, and their pathophysiologic relevance for
      processes in the CNS is undetermined. Therefore, future research on the
      involvement of cytokines in the pathogenetics, pathophysiology, and treatment of
      schizophrenia is needed.

PMID- 15021925
TI  - [High dose L-thyroxine in therapy refractory depression. Case analysis and
      catamnesis as quality control].
AB  - In a depression unit in a state hospital, 28 patients who had failed in six
      antidepressant strategies were treated with L-thyroxine at an average dose of 350
      micro g/die. Outcomes were moderate in 39.3% and very good in 21.5%,
      corresponding to 21-item HAMD scores of < or =16 and < or =8 and clinical
      judgement. Of all patients, 39.3% had to stop treatment due to nonresponse or
      side effects. Follow-up of all responders to treatment was conducted 45.2 weeks
      after discharge. Those 28.6% patients who had stopped treatment had significantly
      more readmissions, i.e., 62.5%, vs none in those who continued, whereas
      subjective clinical ratings did not differ between the two groups. In contrast to
      the literature not finding serious side effects in 70 mainly bipolar patients, we
      found cardial arrhythmia in 10.7% of inpatients and 7.1% of follow-up patients
      that was serious enough to discontinue treatment. In conclusion, systematic
      investigation of high-dose L-thyroxine treatment in treatment-resistant
      depression seems promising and necessary.

PMID- 15021928
TI  - [Heart disease in schizophrenia].
AB  - A 63-year-old male patient diagnosed with chronic schizophrenia and characterized
      by formal disorders of thought with neologism and paranoid ideation, especially
      grandiose delusions and feelings of being influenced by radiation, is presented.
      At admission to psychiatric hospital, the patient reported attacks of weakness
      and dizziness, which he attributed to his feelings of alien influence. The
      diagnosis of cardiac disease with severe bradycardia could already be established
      by basic physical examination. Further diagnostic procedures (e.g., ECG) revealed
      symptomatic atrioventricular conduction defects (atrioventricular block III).
      After implantation of a cardiac pacemaker, the somatic symptoms vanished and the
      patient recovered completely in terms of physical condition.

PMID- 15021926
TI  - [Drug therapy of acute manias. A retrospective data analysis of inpatients from
      1997 to 1999].
AB  - The aim of the present retrospective chart analysis was to compare published
      treatment algorithms with the treatment patterns of 90 consecutive inpatients
      suffering from acute mania or hypomania at the Department of General Psychiatry,
      University of Vienna, from 1997 to 1999. Treatment strategies during the first 14
      days and on discharge as well as sociodemographic and illness related data were
      evaluated. The results of our study reflect that international guidelines were
      not included in daily practice from 1997 to 1999 with regard to the usage pattern
      of atypical antipsychotics versus typical neuroleptics. Also, recommendations
      have not been taken into account about monotherapy with a mood stabilizer as
      first-line treatment for acute mania (polypharmacia was the predominant treatment
      scheme) and the advice to taper off benzodiazepines (at discharge).

PMID- 15021927
TI  - [Neuropsychiatric aspects of Huntington chorea. Presentation of 2 cases and
      review of the literature].
AB  - Huntington's disease (HD) is an autosomal, dominant, inherited disorder of the
      central nervous system with characteristic neurodegenerative alterations in the
      basal ganglia and cortex. Dependent on the individual CAG expansion load, disease
      onset occurs between the third or fourth decade of life, entailing an invariably
      lethal progression within 10 to 20 years. Although the clinical picture is
      characterized equally by cognitive and psychiatric disturbances, the apparent
      neurodegenerative alterations and presentation as a choreatic movement disorder
      account for the traditional link of Huntington's disease to the field of
      neurology. In contrast to the traditionally emphasized core features of chorea
      and dementia, recent empirical evidence points to the frequent emergence of
      nonchoreatic motor signs and subtle cognitive and psychiatric complaints,
      especially in asymptomatic gene carriers and early disease stages. The case
      studies presented here emphasize the spectrum of neuropsychiatric phenomena
      associated with HD and illustrate the resulting difficulties of differential
      diagnosis in clinical settings. Furthermore, current scientific knowledge of HD
      pleiotrophy is reviewed and the diagnostic power of specific neuropsychological
      approaches is explained.

PMID- 15021930
TI  - [Creation of the first university chair in psychiatry: Johann Christian August
      Heinroth in Leipzig].
AB  - Much research has been done on the work of the alleged "psychicist" Johann
      Christian August Heinroth (1773-1843). However, his academic career has not yet
      been investigated in depth. For the first time, original archive material and
      other sources are quoted to illuminate his history and that of the first European
      chair of psychiatry at Leipzig University in Germany. Heinroth was first
      appointed associate professor (without a specific subject), and on 21 October
      1811 he became the first associate professor of "psychic therapy". Despite his
      efforts, this chair was not transformed into a fellow professorship in 1815. In
      1819, Heinroth succeeded in being appointed fellow professor, but for medicine in
      general and not psychiatry in particular. Thus his position was upgraded but his
      subject was not. After Heinroth's death in 1843, Justus Radius (1797-1884) took
      over psychiatry as a third, "part-time" chair. After several shifts in
      responsibilities, he ceased being explicitly referred to as professor of
      psychiatry.

PMID- 15021929
TI  - [New developments in pharmacotherapy of depression].
AB  - In spite of recent progress in the pharmacotherapy of depression, major issues
      are still unresolved. These include the nonresponse rate of approximately 30% to
      conventional antidepressant pharmacotherapy, side effects of available
      antidepressants, and the latency period of several weeks until clinical
      improvement. Current treatment strategies aim to enhance serotonergic and/or
      noradrenergic neurotransmission. However, in the meantime, several new
      pharmacological principles are under investigation with regard to their
      antidepressant potency. Placebo-controlled, double-blind studies have been
      performed with 5-HT(1A) receptor agonists and tachykinin receptor antagonists
      which point towards antidepressant efficacy. While there is some evidence for
      putative antidepressant properties of various interventions within the
      hypothalamic-pituitary-adrenal system such as CRH(1) receptor antagonists,
      steroid synthesis inhibitors, and glucocorticoid receptor antagonists in animal
      studies, case series, open studies, and small placebo-controlled studies, no
      definite proof for their antidepressant efficacy has been furnished.
      Nevertheless, follow-up of new pharmacological strategies is of major importance
      to provide even better strategies for the clinical management of depression,
      which also has great socioeconomic impact.

PMID- 15021931
TI  - [Treatment for viral respiratory infections: Principles of action, strategies,
      and future prospects].
AB  - Pulmonary viral infections are associated with substantial morbidity and
      socioeconomic costs. Rhinovirus, influenza A and B, adenovirus, parainfluenza,
      respiratory syncytial virus (RSV), and coronavirus are etiologies most often
      associated with infections of the upper and lower respiratory tract. Therapy of
      viral infections in nonimmunocompromised hosts has only developed slowly during
      recent years, despite the enormous socioeconomic impact. This is in part due to
      the complex virus/host interactions and numerous and varying mechanisms of
      infection. Neuraminidase inhibitors have produced notable progress in the
      therapeutic approaches to influenza-associated pulmonary infections and are at
      least able to shorten the duration of symptoms in selected patients. However,
      neuraminidase inhibitors can only be applied in specific infections and the
      spectrum of agents with antiviral activity is broad. This article summarizes
      major principles of antiviral efficacy and reviews recent clinical trials.

PMID- 15021932
TI  - [Livedoid vasculopathy with heterozygous factor V Leiden mutation and sticky
      platelet syndrome].
AB  - A 64-year-old male patient presented with painful ulcerations and livedo racemosa
      of both lower limbs. He had a history of cerebral and myocardial infarctions.
      Dermatohistologic findings and laboratory tests of the patient's coagulation
      system revealed the diagnosis of livedoid vasculopathy with heterozygous factor V
      Leiden mutation and sticky platelet syndrome type II. Systemic treatment with
      acetylsalicylic acid and heparin as well as topical therapy with disinfectant and
      granulation-inducing agents resulted in improvement of the skin lesions.

PMID- 15021934
TI  - [Polypoid basal cell carcinoma].
AB  - Basal cell carcinoma, the most common malignant neoplasm of the skin, has many
      clinical and histologic variants. We report about a 58-year-old patient with a
      rarely described, polypoid variant of this tumor. Polypoid basal cell carcinoma
      differs clinically from other variants by being exophytic and pedunculated and,
      histologically, the tumor aggregations are restricted only to the polypoid part.

PMID- 15021933
TI  - [Photodynamic therapy of cutaneous leishmaniasis. A promising new therapeutic
      modality].
AB  - We report about a 19-year-old Turkish patient who presented with cutaneous
      leishmaniasis after a holiday in Turkey. Cutaneous leishmaniasis often heals
      spontaneously leading to life-long immunity, but it can persist and lead to
      extensive scarring. In the literature, many therapeutic modalities have been
      reported; however, they can be accompanied by severe side effects. In our
      patient, photodynamic therapy resulted in healing of the lesion with only slight
      hypopigmentation.

PMID- 15021935
TI  - [Verrucous squamous cell carcinoma developing in hypertrophic lichen planus].
AB  - We report about a 64-year-old patient who developed a verrucous squamous cell
      carcinoma in a long-standing hypertrophic lichen planus of the right lower leg.
      Neoplastic transformation of hypertrophic lichen planus has rarely been described
      in the literature.

PMID- 15021936
TI  - [IgA pemphigus. Successful treatment with mycophenolate mofetil].
AB  - IgA pemphigus is a rare intraepidermal autoimmune disease characterized by the
      presence of intercellular IgA deposits, intraepidermal acantholysis with
      infiltration of neutrophils, and circulating IgA autoantibodies against
      keratinocyte cell surface components. We report for the first time about a
      patient with IgA pemphigus who was successfully treated with mycophenolate
      mofetil.

PMID- 15021937
TI  - [Topical immunomodulators: a therapeutic option for oral cicatricial pemphigoid].
AB  - Oral cicatricial pemphigoid is a chronic autoimmune blistering disease which
      affects predominantly the gingiva and the buccal mucosa. The pathogenesis of this
      disease is still incompletely understood; however, there is compelling evidence
      that cicatricial pemphigoid might be mediated by T lymphocytes. Therefore, we
      performed immunomodulatory therapy with topical tacrolimus in patients with long
      standing, therapy-resistant oral cicatricial pemphigoid. Following 3 months of
      treatment, complete healing and ongoing remission could be achieved.

PMID- 15021938
TI  - [Bullous systemic lupus erythematosus].
AB  - Bullous systemic lupus erythematosus is a rare disease associated with
      subepidermal blistering and, in most cases, severe systemic manifestations. We
      describe a 19-year-old man with systemic lupus erythematosus who developed a
      bullous eruption along with a flare-up of systemic manifestations during the
      course of his disease and discuss the different forms of bullous lesions in
      patients with lupus erythematosus.

PMID- 15021939
TI  - [Large B-cell lymphoma of the lower leg].
AB  - Primary cutaneous B cell lymphomas are rare malignant lymphoproliferative
      disorders of the skin. The prognosis is dependent on the clinical and histologic
      subtype; generally, these disorders show an indolent clinical course. We describe
      a 80-year-old woman with a large cutaneous B cell lymphoma of the lower leg. In
      contrast to other variants of cutaneous B cell lymphomas, this entity is
      characterized by an aggressive clinical course with an unfavorable prognosis. The
      mean survival rate is approximately 50%. This should be taken into account in the
      choice of treatment.

PMID- 15021940
TI  - [Does imbalance lead to allergic symptoms? Regulatory T-cells and atopy].

PMID- 15021943
TI  - [Outpatient arthroscopic surgery].
AB  - Arthroscopic surgery is being used more and more frequently worldwide for a
      growing number of indications and for almost all joints. In Germany, there is,
      however, no consensus on correct methods of arthroscopic surgery on an outpatient
      basis. Structural, personnel, and anesthesiologic factors and appropriate follow
      up care play important roles in this type of operation. This study examines some
      basic requirements and presents an overview of the individual indications for
      such operations performed in an outpatient setting.

PMID- 15021944
TI  - [Primary varicosis. Differentiated surgical therapy on an outpatient or short
      term hospitalisation basis].
AB  - Differentiated surgical therapy prior to the occurrence of serious complications
      makes good medical sense and is becoming an economic necessity. It includes
      verification and interruption of points of insufficiency, permanent elimination
      of varicosis, minimisation of complications, and the best cosmetic results. New
      operating techniques have emerged during the breathtaking development of
      minimally invasive surgery and now been added to the repertoire. In the hands of
      experienced surgeons, these methods, either alone or in conjunction with vein
      stripping, are more precise. Due to the low surgical trauma, they also achieve
      less wound infection and good cosmesis in conjunction with reduced relapse rates.
      Given the pressure to reduce health care costs, a further increase in outpatient
      surgery for varicosis can be expected in the future. It must meet the same
      standards of quality demanded in treatment methods involving hospitalisation.
      There will nevertheless remain a significant number of patients with varicosis
      requiring surgical treatment and hospitalisation due to risk factors, extent of
      the varicosis, or stage of the disease.

PMID- 15021946
TI  - [Outpatient hand surgery--possibilities and limitations].
AB  - On January 1st 2004, a new contract between the government, health insurance
      services, and hospitals was inaugurated in Germany. The aim of the contract is to
      decrease costs for surgical therapies by abolishing or at least minimizing
      hospitalization of patients. Hand surgery is widely affected by the new contract,
      since a very large part of surgical therapies for the hand was declared to be
      compulsory outdoor and another major part to be preferable outdoor. The surgeon
      may decide whether a patient needs inpatient or outpatient treatment but has to
      justify his decision. Hospitals and surgical clinics are both allowed to offer
      outpatient hand surgery and get the same payment under the same regulations. For
      most hospitals, structural changes will be necessary to offer outpatient surgery
      without financial loss. In our experience a personal and regular contact between
      patient and surgeon is most necessary for the best surgical result. Many of the
      compulsory outpatient operations in hand surgery can be done sufficiently and at
      high standard. This may not be the case for the second group to be handled not
      compulsory outdoor. The new contract allows hospitals to offer postoperative care
      for only 14 days, whereas many specific hand surgical procedures will need the
      surgeon's control and care for a much longer time. On the other hand, clinics and
      general practitioners have strict limitations for the prescription of hand
      therapies. We believe that the quality of hand surgery is highly dependent on
      sufficient postoperative treatment. If the postoperative care is neglected or
      restricted, secondary costs such as sick leave will increase.

PMID- 15021945
TI  - [Laparoscopy: potential and limitations in outpatient and short-term inpatient
      surgery].
AB  - Many laparoscopic operations can usually be performed on an outpatient or at
      least short-term inpatient basis. Since the postoperative risk is easily
      estimated and can be determined on the 1st or 2nd postoperative day, it quickly
      becomes clear whether the healing process will be undisturbed or complications
      will occur. Prerequisites are comprehensive information to the patient as well as
      his cooperation and that of his social setting. From a medical standpoint,
      suitable administrative and infrastructural conditions must be arranged that
      enable safe, efficient preop preparation and guarantee reliable postoperative
      care of the patient. The newly begun shift in the German health care delivery
      system toward outpatient and short-term inpatient treatment must be introduced
      carefully and step by step, since the resultant reduction in postoperative
      inpatient care goes hand in hand with reduced patient comfort and without
      question places a greater burden on the patient's social setting.Clearly, optimal
      collaboration with local doctors is necessary to accompany this nationwide
      reduction in hospital stay, and the distribution of responsibility among the
      various physicians must be clarified. However, independently these elements, the
      success of outpatient and short-term inpatient laparoscopy still can be
      guaranteed only by surgeons' high experience and minimal complications.

PMID- 15021947
TI  - [AMBU-KISS: quality control in outpatient surgery].
AB  - INTRODUCTION: Surgical site infections are associated with considerable morbidity
      and additional health care costs arising from lengthy hospitalization. According
      to the German Infection Protection Act implemented on 1 January 2001, hospitals
      and outpatient surgery institutions are required to assess and document
      nosocomial infections. The data are to be made available to the German Ministry
      of Health on demand. METHOD: We report on a new surveillance module (AMBU-KISS)
      designed to assess and document surgical site infections in outpatient surgery.
      The objective is to create a reference database for these institutions. RESULTS:
      Preliminary results obtained for two indicator procedures show no significant
      differences in surgical site infection rates between outpatient surgery
      institutions and the hospital setting (OP-KISS). The arithmetic mean values of
      surgical site infection rates in arthroscopic surgery of the knee are 0.09% in
      AMBU-KISS and 0.11% in OP-KISS. For inguinal hernias, the respective rates are
      0.65% and 0.78%. A significant difference was observed only for vein stripping
      procedures, with surgical site infection rates of 0.38% in AMBU-KISS and 0.64%in
      OP-KISS CONCLUSIONS: The results indicate that AMBU-KISS is a reliable tool for
      assessing surgical site infections in outpatient surgery.

PMID- 15021948
TI  - [Treatment of MRSA infection in orthopedic surgery].
AB  - INTRODUCTION: Infection with methicillin-resistant Staphylococcus aureus (MRSA)
      remains a major challenge both therapeutically and hygienically. METHODS: Between
      January 2000 and January 2002, 27 patients with MRSA infections were treated and
      evaluated in a prospective clinical study. For effective wound management,
      operative revisions were performed every 3rd day. Following debridement, the
      wounds were vacuum sealed and specific i.v. antibiotics were administered. Wound
      closure was performed if three consecutive wound samples submitted for bacterial
      culture remained negative. RESULTS: All patients with MRSA infections were
      treated successfully until signs of infection disappeared and bacterial cultures
      were negative. An average of 7.3 operations per patient was required to eradicate
      MRSA infection. Follow-up of patients revealed recurrence of infection in four
      patients. CONCLUSION: Prevention of further spreading and successful treatment of
      MRSA infections in reconstructive orthopedic surgery is possible with appropriate
      surgical and hygienic concepts. In almost every second patient complex revision
      procedures were required.

PMID- 15021949
TI  - [Identification of pelvic autonomic nerves during partial and total mesorectal
      excision--influence parameters and significance for neurogenic bladder].
AB  - INTRODUCTION: The objective of the present prospective study was to determine the
      frequency of pelvic autonomic nerve preservation (PANP) during total mesorectal
      excision (TME) for rectal carcinoma, and to identify a possible link between PANP
      and postoperative micturition disturbances. METHODS: Between March 1997 and
      February 2003, 229 patients with adenocarcinoma of the rectum were operated on
      with sphincter preservation in 178 (78%) cases. In 101 (48%) patients, the tumor
      did not invade the muscularis propria. To determine influence parameters on the
      achievement of complete PANP, a multivariate analysis was performed. The number
      of complete-partial-or nonidentification of the nerves (superior hypogastric
      plexus up to the neurovascular bundles) was documented and correlated with
      micturition disturbances. RESULTS: The pelvic autonomic nerves were identified
      completely in 169 (74%), partially in 25 (11%), and could not be demonstrated in
      35 (15%) patients. Multivariate analysis showed multivisceral resection (
      p<0.001), gender ( p<0.001), surgeon (<25 operations >, p<0.001), and tumor site
      (middle/upper third vs lower third of rectum, p= 0.011) to exert an independent
      influence on the achievement of complete PANP. Twenty (8.8%) patients needed a
      long-term urinary catheter. Preservation of the parasympathetic nerves was
      associated with low bladder dysfunction rates (4.1 vs 22.4%, p<0.001).
      CONCLUSIONS: To minimize the risk of postoperative micturition disturbances due
      to neurogenic bladder, pelvic autonomic nerves should be identified during TME.
      Neurogenic bladder after TME is a useful parameter to assess the quality of
      surgical treatment for rectal carcinoma.

PMID- 15021951
TI  - [Demonstration of increased natural spontaneous activity of cranioesophageal and
      laryngeal muscles by PET-CT].
AB  - The muscles of the cranioesophageal sphincter system feature continuous natural
      spontaneous resting activity. Thus, they resemble the anorectal sphincter system.
      We studied metabolic activity and morphology of the proximal sphincter system at
      rest in 23 individuals (14 females, nine males) using PET-CT scanning. We found
      that metabolic activity was significantly higher than in other muscle groups of
      the body at rest (P=0.001). In contrast to the horizontally oriented anal
      sphincters, the proximal sphincter system is developed as a vertical assembly of
      long, interlocking muscular tubes. These are innervated by five cranial nerves
      and three sensory organ nerves and form a functional unit that extends from the
      orbicularis oris muscle via the pharynx and larynx to the lower esophageal
      sphincter. The larynx shows only one active muscle, i.e., the posterior
      cricoarytaenoid muscle, that maintains airway patency. The lower esophageal
      sphincter can be visualized by PET-CT as a vertically oriented stretching
      sphincter. It features a spiral-shaped design made up of muscle maxima and minima
      which correlates well with its asymmetric muscle activity. This complex proximal
      sphincter system shows great developmental variability among different animal
      species. However, the general functional principle is similar in all.

PMID- 15021950
TI  - [Angiogenesis investigations in tissue engineering. The cylinder model on the
      chorioallantois membrane].
AB  - INTRODUCTION: Tissue engineering (TE) applications include the isolation,
      culture, and seeding of cells into a suitable matrix or scaffold prior to in vivo
      transplantation. After transplantation, vascularization of the scaffold is a
      principal factor limiting cell viability for the first 6-8 days post
      transplantation. A model has been developed for systematic analysis of this
      process. METHODS: Fertilized white Leghorn eggs were incubated and opened at day
      3 of incubation. Preadipocyte-seeded fibrin constructs were implanted in a
      specially designed plastic cylinder and placed through the opening onto the
      surface of the chorioallantoic membrane (CAM) at day 8 of incubation.
      Vascularization of the constructs by chorioallantoic blood vessels was assessed
      for up to 8 days post transplantation. RESULTS: The survival rate for embryos
      receiving constructs was about 90%. Histology confirmed transplant cell viability
      at day 4 post transplantation, and vascularization of the constructs by avian
      endothelial cells progressively increased thereafter. CONCLUSION: A new in vivo
      model to study the effect of angiogenesis in TE constructs including assessments
      of viability, proliferation, and differentiation of transplanted cells and
      biomaterial properties is presented. Advantages include easy access to the CAM
      vascular network, lack of immunocompetence, low cost, and avoidance of animal
      experiments.

PMID- 15021952
TI  - [Interdisciplinary consensus on sentinel node biopsy in breast cancer].

PMID- 15021954
TI  - [Vomiting after gynecologic laparoscopy and under general anesthesia is
      associated with changes in excretion of serotonin metabolites].
AB  - INTRODUCTION: The efficacy of 5-HT(3)-receptor antagonists suggests a role of
      serotonin in the pathogenesis of postoperative nausea and vomiting (PONV).
      However, studies investigating the relationship between the turnover of serotonin
      and PONV were contradictory. Therefore we carried out a pilot study in order to
      find out whether results can be obtained that would justify further studies on a
      larger scale. METHODS: A total of 22 patients scheduled for elective
      gynaecological laparoscopy were enrolled. A balanced anaesthesia using
      sufentanil, etomidate, cisatracurium, isoflurane and nitrous oxide was
      administered and 5-hydroxyindoleaceticacid (5-HIAA) concentrations in the urine
      were measured within the 24 h after surgery. RESULTS: Only the patients that
      vomited postoperatively had a significant change in the concentrations of 5-HIAA
      over the time course investigated. However, comparison of urinary 5-HIAA
      concentrations of the group comprising patients that vomited with those that had
      no PONV did not reveal a significant difference. CONCLUSIONS: Results of this
      study support further investigation of the relationship between serotonin and
      PONV and suggest that there may in fact be an association between PONV and
      increased serotonin turnover.

PMID- 15021955
TI  - [Desflurane in acute intermittent porphyria].
AB  - Despite the low incidence of the acute porphyrias, a profound knowledge of the
      disease is essential for anaesthesiologists, as a variety of perioperatively
      administered drugs are potential triggers of an acute attack. There is an ongoing
      discussion about the use of volatile anaesthetics in porphyrias, but halothane
      and isoflurane seem to be safe. There is no clinical data or case report about
      the use of desflurane in this specific patient group, but its fast and relatively
      unchanged elimination and the minimal induction of the cytochrome P 450 system
      seem to be favorable in this setting. We report the use of desflurane in a
      patient with acute intermittent porphyria, scheduled for hemihepatectomy. To
      minimize perioperative distress by pain or the need for postoperative mechanical
      ventilation, we chose a balanced anaesthesia technique with desflurane,
      sufentanil and atracurium in combination with a continuous epidural analgesia
      (bupivacain and fentanyl) for the postoperative period. Preoperatively the
      porphyrin precursors were analyzed in serum and urine and postoperatively the 24
      h-urine was screened every 2 days until postoperative day 6 to monitor the
      porphyria activity. The preoperative data showed high concentrations of porphyrin
      precursor excretion, confirming the diagnosis of AIP. The postoperative data in
      the 24 h-urine were significantly lower than preoperative levels and reached
      normal levels at postoperative day 5. There were no clinical symptoms of a
      porphyric attack during the postoperative hospitalization. The patient was
      discharged on postoperative day 21 in excellent condition. We conclude that our
      perioperative management prevented an acute porphyric attack in this case.
      Desflurane might be a valuable alternative to other hypnotics in patients with
      AIP.

PMID- 15021956
TI  - [Acute respiratory failure and mediastinal mass syndrome].
AB  - A 46-year-old female with a history of a chronic obstructive lung disease was
      intubated by the emergency physician for acute respiratory failure. However,
      after intubation she developed circulatory failure and required cardio-pulmonary
      resuscitation. The reason for the circulatory failure following muscle relaxation
      and intubation was identified as a mediastinal mass syndrome. Chest X-ray and
      computed tomography revealed an apical right-sided large tumor of 8 x 8 cm, which
      displaced the V. cava superior and caused obstruction of the inferior trachea and
      right main stem bronchus. She underwent surgery in our institution on the
      following day and the tumor could be removed completely. Patho-histologic
      examination verified the diagnosis of a Schwann cell tumor. After stepwise
      reduction in airway pressures, the patient was successfully weaned from the
      ventilator without neurologic deficit. About 24 h later she was transferred to
      the normal surgical ward. A mediastinal tumor with airway and central venous
      obstruction may be a rare cause of acute respiratory and circulatory failure.

PMID- 15021953
TI  - [Gene polymorphism in intensive care patients. Is the course of disease
      predetermined?].
AB  - Molecular biology has revolutionized medicine by increasing our understanding of
      the pathophysiological mechanisms of disease and the ability to assess genetic
      risk. Individual differences in disease manifestation and course in intensive
      care medicine often cannot be explained by known phenotypic risk factors alone.
      Recent data suggest an association between specific genotypes and the risk of
      adverse clinical outcomes. This includes inflammatory responses (i.e. TNF-alpha,
      Il-10), infectious diseases such as pneumonia or meningitis, sepsis, ARDS, as
      well as the mortality of critically injured patients (polytrauma, severe brain
      trauma). Continued identification of such allotypes and haplotypes may not only
      provide insight as to why the response to treatment varies amongst individuals in
      the intensive care unit, but also may potentially decrease morbidity and
      mortality through improved risk assessment and the administration of prophylactic
      therapy.

PMID- 15021959
TI  - [Responsibilities of the medical practitioner in the postoperative and post
      anesthesia phases].

PMID- 15021957
TI  - [Evidence-based intensive care medicine. Practice, use and significance].
AB  - The process of evidence-based medicine incorporates structured clinical problem
      solving aimed at providing an optimal, patient-centred therapeutic approach.
      Evidence-based medicine is supported by justified therapeutic principles rather
      than physicians' intuition only. Few of the published articles allow firm
      conclusions for a rational patient approach. The methodological quality of at
      least some of these articles is insufficient to guide rational therapy. Thus,
      critical appraisal of the literature seems mandatory. The following article
      highlights the process of evidence-based medicine and its implementation in daily
      clinical practice. Besides the careful analysis of source data, evidence-based
      medicine warrants the final evaluation of outcomes for process improvement. This
      can be obtained utilising surrogate parameters, such as organ failure, resource
      allocation, or quality of life, or crude mortality of the patients. The
      integration of personal know-how together with sufficient knowledge and critical
      appraisal of the current literature may finally lead to improved outcomes.

PMID- 15021960
TI  - [Effective literature searching. Focusing the question and using PubMed queries].
AB  - Apart from clinical and social expertise, the availability of contemporary
      knowledge is a key component in organisations within the health system that aim
      for excellence and competitiveness. Efficient literature searching is within this
      context a core business of evidence-based medicine. In addition to the need for
      valid data, the retrieval of information based on published literature has so far
      constituted a critical hurdle. Based on these requirements, two core issues for
      success with respect to literature searching are described: First, the generation
      of a structured question to form the basis of the most promising search terms.
      Second, a new feature of the web service of the national library of medicine,
      called "clinical queries", that allows the application of predefined filters to
      allocate clinically relevant data in terms of published clinical trials and
      systematic reviews.

PMID- 15021958
TI  - [Non-opioid analgesics for perioperative pain therapy. Risks and rational basis
      for use].
AB  - Non-opioid analgesics play a central role in the management of postoperative
      pain. In this review, the pharmacology, the analgesic efficacy and the side
      effects of non-opioid analgesics are summarized. First, the pharmacology of
      diclofenac, acetyl salicylic acid, dipyrone, acetaminophen and the COX-2
      inhibitors is described. Second, the analgesic efficacy of non-opioid analgesics
      is analyzed for moderate pain (e.g. ambulatory surgery) and for moderate to
      severe pain (e.g. abdominal surgery-in combination with opioids). There is
      limited evidence for an additive analgesic effect of two non-opioid analgesics.
      Third, the major side-effects of non-opioid analgesics are discussed in relation
      to the pathophysiology, the frequency and the clinical relevance of these
      effects. In particular, side-effects on the gastrointestinal tract (ulcus
      formation), on coagulation (bleeding and thrombosis), on the renal (renal
      insufficiency), the pulmonary (bronchospasm) and the hematopoetic systems
      (agranulocytosis) are described. Recommendations for the clinical use of non
      opioid analgesics for perioperative pain therapy are given.

PMID- 15021963
TI  - Endotoxin-induced liver damage in rats is minimized by beta 2-adrenoceptor
      stimulation.
AB  - OBJECTIVE AND DESIGN: To investigate the effects of beta(2)-adrenoceptor (beta(2)
      AR) stimulation on endotoxin-induced liver damage and systemic cytokine levels in
      rats. SUBJECTS: Standard male Wistar rats. TREATMENT: A disease-model of
      lipopolysaccharide (LPS)-induced acute systemic inflammation was used. The
      beta(2)-selective AR agonist clenbuterol was administered before, during, and
      after LPS-challenge to investigate its effects on the acute inflammatory response
      and associated liver-failure. METHODS: The following parameters have been
      measured in plasma: TNF alpha, IL-1 beta, IL-6, IL-10, AST, ALT, and Bilirubin.
      Liver histological examination was performed to look for changes in tissue
      morphology. RESULTS: Administration of clenbuterol (p.o.) one hour before, or
      intravenous at the same time as LPS-challenge resulted in a marked reduction of
      plasma levels of TNF alpha, IL-1 beta, and IL-6. A change both in plasma-level
      and in time-concentration profile of the anti-inflammatory cytokine IL-10 was
      found. Clenbuterol minimized LPS-induced liver damage, as represented by
      significantly lowered concentrations of several parameters for liver-failure
      (AST, ALT, Bilirubin), and improved hepatic tissue morphology. Clenbuterol
      administration after LPS challenge failed to inhibit TNF alpha-release but
      reduced liver-damage. Simultaneous use of the beta(2)-AR antagonist propranolol
      augmented LPS-induced liver failure, suggesting a role of endogenous adrenoceptor
      agonists in prevention of organ-failure during systemic inflammation.
      CONCLUSIONS: The results indicate that a selective beta(2)-AR agonist might be
      used as an additional therapeutic agent in the clinic for the treatment of
      (acute) systemic inflammatory disorders in order to reduce or prevent subsequent
      liver failure.

PMID- 15021962
TI  - Regulation of Con A-dependent cytokine production from CD4+ and CD8+ T
      lymphocytes by autosecretion of histamine.
AB  - OBJECTIVES: Previously we have shown that both CD4+ T cells and CD8+ T cells
      produce histamine when activated with Con A. The aim of this study was to examine
      whether cytokine production by these cells is regulated by autosecretion of
      histamine. MATERIALS: CD4+ and CD8+ T cells were separated from spleen cells of
      C57BL/6 mice and mice lacking the H1 receptor (H1R) or H2R, using anti-CD4+- and
      anti-CD8+-coupled magnetic beads, respectively. RESULTS: Depletion of the H1R
      resulted in decreases in the release of IL-2 and IL-10 from both CD4+ and CD8+
      cells and increases in the release of IL-4 from CD4+ T cells and IFN-gamma from
      CD8+ cells. Mice lacking the H2R showed up-regulation of IFN-gamma secretion from
      CD8+ cells and of IL-4 from CD4+ and CD8+ T cells. Release of IL-2 and IL-10 from
      CD4+ as well as CD8+ cells was down-regulated in these mice. Both CD4+ and CD8+ T
      cell fractions synthesized histamine, which was enhanced in the H1R-deficient
      CD8+ T cells. Treatment of the cells with alpha-fluoromethyl-histidine, a
      specific inhibitor of HDC, or histaminase increased IFN-gamma from CD8+ cells,
      whereas it had no appreciable effect on IL-4 secretion from CD4+ cells.
      CONCLUSION: These results suggest that cytokine production by CD4+ and CD8+ T
      lymphocytes is regulated by autosecretion of histamine.

PMID- 15021964
TI  - Induction of intracellular cytokine production in human monocytes/macrophages
      stimulated with ligands of pattern recognition receptors.
AB  - OBJECTIVE: This study addressed the role of the pattern recognition receptors
      (PRR), which recognize different molecular structures present on microorganisms,
      apoptotic, senescent and tumor cells, in the stimulation of human monocyte and
      monocyte-derived macrophages (MDM) for the production of intracellular cytokines.
      MATERIALS AND METHODS: Monocytes and MDM were stimulated with different ligands
      of scavenger receptors (SR) and mannose receptor (MR). Production of
      intracellular cytokines: tumor necrosis factor alpha (TNF alpha), interleukin 10
      and 12 (IL-10, IL-12) was determined by flow cytometry following staining with
      anti-cytokine monoclonal antibodies (mAbs). RESULTS: The ligands of SR type A:
      fucoidan, polyguanylic acid (polyG), chemically modified low density lipoproteins
      (LDL), ligands of SR-B: native and chemically modified LDL, and ligand of mannose
      receptor (MR)-mannan induced strong expression of intracellular TNF alpha and
      weaker IL-10 in monocytes, while phosphatidylserine (PdS) was without effect. IL
      12 was stimulated only by fucoidan and polyG. The induction of cytokine m-RNA
      generally followed the pattern and the magnitude of intracellular cytokine
      production. In MDM, intracellular TNF alpha and IL-12 expression was induced by
      mannan, native and modified LDL, but not other ligands. Expression of IL-10 was
      less pronounced and occurred following stimulation with fucoidan, polyG and
      modified, but not native, LDL. CONCLUSIONS: These results suggest that some PRR
      ligands may be involved in activation of monocytes/MDM for the production of
      mainly proinflammatory cytokines (TNF alpha, IL-12) implicating their role in the
      response to microbial and tumor invasion.

PMID- 15021965
TI  - Mast cell density during initiation and progression of the local Shwartzman
      reaction.
AB  - OBJECTIVE AND DESIGN: To quantify the number of mast cells in the skin of rabbits
      during initiation and progression of the local Shwartzman reaction. MATERIALS:
      Thirty New Zealand rabbits were divided in two groups (n = 15/group). One group
      was subjected to the Shwartzman reaction and the other group served as control.
      Subsequently, animals were further subdivided in six groups of five animals each
      according to time of euthanasia. TREATMENTS: The local Shwartzman reaction was
      induced by two inoculations of Salmonella typhimurium lipopolysaccharide.
      Preparatory inoculation was given intradermally and, 24 h later, the provocative
      injection was administered intravenously. Controls were subjected to the same
      procedure but received saline. After provocative injection animals were killed at
      1, 8, and 15 days. METHODS: Skin samples were fixed in Carnoy's solution and mast
      cells were identified employing a low pH toluidine blue stain. Numbers of mast
      cells were determined per square millimetre and, subsequently, those cells
      degranulated were identified and quantified to obtain absolute values. A
      Student's t test was initially used to compare Shwartzman versus controls at each
      time point. Subsequently, an ANOVA test employing a factorial experiment was used
      to assess a possible interaction between time of euthanasia and treatments.
      RESULTS: The values were transformed (natural logarithms) for appropriate
      statistical comparisons. Independent comparisons at each time point showed that
      Shwartzman groups had higher numbers of mast cells than controls at 1 and 8 days,
      but not at 15 days (5.71 +/- 1.00 Vs. 2.40 +/- 0.58, P < 0.005; 3.77 +/- 0.90 Vs.
      2.33 +/- 0.56, P < 0. 025, and 2.61 +/- 0.25 Vs. 2.39 +/- 0.39, P > 0.05,
      respectively). Degranulated cells were numerous in Shwartzman groups,
      particularly at day 1 (3.48 +/- 0.78) and less obvious at day 8 (0.72 +/- 0.50),
      but were scarce by day 15 (-0.67 +/- 0.99) as well as controls (-0.68 +/- 0.91).
      The factorial experiment demonstrated that the Shwartzman reaction and time of
      euthanasia were independently significant (P < 0.005) but their interaction at
      day 1 was the major contributor (P < 0.005). Tukey's w pairwise comparisons of
      means confirmed that the Shwartzman group killed at day 1 was significantly
      different from the others (P < 0.05). CONCLUSIONS: Mast cells significantly
      increase in the early stages of the local Shwartzman reaction. Thus, mast cells
      are a highly dynamic cell population, which have a prominent role during the
      acute phase of this lipopolysaccharide-induced inflammatory reaction but not
      during healing.

PMID- 15021966
TI  - Chronic rhinosinusitis--need for further classification?
AB  - OBJECTIVE AND DESIGN: The etiology and classification of chronic rhinosinusitis
      with and without nasal polyps still remain unclear. Based on investigations of
      inflammation type in biopsies from patients with nasal polyposis and chronic non
      polypous rhinosinusitis, we tried to determine whether there is a need for
      further classification of chronic rhinosinusitis into two disease entities.
      SUBJECTS: Biopsies of diffuse nasal polyposis (n= 37) and chronic rhinosinusitis
      without nasal polyps (n= 41) were examined for eosinophil and neutrophil tissue
      infiltration, degree of inflammation, and involved cytokines in inflammation
      mechanisms. METHODS: Neutrophil elastase positive neutrophils and CD38-positive
      lymphocytes were characterized in nasal polyposis and chronic non-polypous
      rhinosinusitis by immunohistochemistry. Using a monoclonal antibody against
      eosinophilic cationic protein (ECP) activated eosinophils were identified. In
      tissue homogenates, albumin was quantified as a marker for inflammation vascular
      permeability. In addition, interleukin (IL)-8 and IL-5 were determined by means
      of quantitative ELISA measurements in homogenates. RESULTS: Significantly
      increased numbers of eosinophils and neutrophils were detected in nasal
      polyposis. In chronic rhinosinusitis without nasal polyps, tissue infiltration
      was dominated by lymphocytes and neutrophils. The concentration of albumin and IL
      5 was significantly higher in nasal polyps than in chronic rhinosinusitis without
      nasal polyps. IL-8 protein levels did not differ significantly between the two
      tissue types. In addition, patients' durations of illness did not differ
      significantly. CONCLUSIONS: Different types and quantities of inflammatory cells
      as well as different levels of inflammation support our hypothesis that there is
      need for further subdivision of chronic rhinosinusitis into two disease entities.

PMID- 15021967
TI  - Controlled dermal cell damage as human in vivo model for localised pain and
      inflammation.
AB  - OBJECTIVE AND DESIGN: An unspecific human in vivo model of dermal pain and
      inflammation was developed by means of limited, localised and controlled cell
      damage. SUBJECTS: Twelve participants were recruited. TREATMENT: Dermal
      microdialysis was used to deliver randomised and single blinded aqueous sodium
      dodecyl sulphate (SDS) at concentrations of 0.01%, 0.1% and 0.5% w/v to the volar
      forearm. METHODS: Nociceptive responses were recorded on a numerical scale,
      vasodilatation was assessed by laser Doppler scanning and sampled tissue fluid
      was analysed for PGE2 by ELISA. RESULTS: Saline control and 0.01% SDS did not
      differ in their ability to cause vasodilatation, flare reaction or pain. In
      contrast, SDS (0.1 and 0.5%) evoked a significant increase of blood flow
      (p<0.005), a widespread reddening (p<0.01), and stinging-burning pain (p<0.005).
      PGE2 concentration in the dialysate did not change during 0.01% SDS perfusion
      (p>0.9), but increased significantly following the stimulation with 0.1% and 0.5%
      SDS (20 to 30-fold). No significant differences of released PGE2 levels were
      determined between 0.1% and 0.5% SDS stimulation (p>0.05). CONCLUSIONS: We
      demonstrated that localised intradermal administration of SDS induces a limited
      pain and inflammatory response in humans. Excitation of nociceptors was
      accompanied by a massive PGE2 release. Employing this experimental model, the
      relative contribution of endogenous mediators to induce, maintain or facilitate
      pain and vasodilatation can be investigated.

PMID- 15021968
TI  - Effects of bisphosphonates on joint damage and bone loss in rat adjuvant-induced
      arthritis.
AB  - OBJECTIVE AND DESIGN: Examination of the effects of bisphosphonates on joint
      damage and generalized bone loss. MATERIALS: Adjuvant-arthritis was induced by
      injection of Mycobacterium butyricum into the footpad of the right hind paw of
      Lewis rats (8 animals/group) on day 0. TREATMENT: Arthritic rats were treated
      with the vehicle (saline), etidronate or alendronate (subcutaneously, daily 5
      times a week for 3 weeks from day 1 to day 21). Experiment-1: Etidronate (0.1,
      0.5, 2.5, 12.5 mg/kg) or alendronate (0.02, 0.1, 0.5, 2.5 mg/kg), Experiment-2:
      Etidronate (2.5, 5, 10mg/ kg) or alendronate (0.001, 0.01, 0.1 mg/kg). METHODS:
      In the adjuvant-injected side of the hind limbs, paw swelling was evaluated at 1
      week intervals, and bone mineral density (BMD) in the proximal tibia,
      histopathology and radiographical findings in the tibio-tarsal region were
      evaluated at the time of sacrifice (on day 21). RESULTS: In all treatment
      schedules, both bisphosphonates significantly prevented paw swelling and bone
      loss. Alendronate reduced paw swelling at higher doses (over 0.1 mg/ kg) compared
      with its effect on BMD decrease (over 0.001 mg/kg). In contrast, etidronate
      reduced paw swelling and joint damage at doses similar to those (over 2.5 mg/kg)
      prevented BMD decrease. CONCLUSIONS: Both etidronate and alendronate are
      effective in reducing arthritic damage, but their effective dose ranges for
      inflammatory responses and BMD decrease clearly differ; i.e., the etidronate dose
      ranges for anti-inflammatory and anti-resorptive effects are similar, whereas the
      dose range for anti-inflammatory effects of alendronate is 100-fold higher than
      that for its anti-resorptive effects.

PMID- 15021969
TI  - Functional interactions between mucosal IL-1, IL-ra and TGF-beta 1 in ulcerative
      colitis.
AB  - OBJECTIVE: Studies aiming to define key cytokines in inflammatory bowel disease
      have been restricted to gene expression or protein quantitation but lack
      functional information on cytokine interactions. Some of the major cytokines that
      govern the extent and duration of the inflammatory process in ulcerative colitis
      (UC), appear to be interleukin 1 (IL-1), its natural inhibitor IL-1 receptor
      antagonist (IL-1ra) and transforming growth factor beta1 (TGF-beta 1). Indeed, as
      a predictor of inflammation, the mucosal status of IL-1, depicted as a ratio of
      IL-1ra/IL-1, has often been used. METHODS: Using an IL-1 bioassay and specific
      anti-cytokine antibodies we have identified the functional role of these
      cytokines and their interactions in mucosal biopsy samples taken from patients
      with UC. RESULTS: Compared with control specimens, the secreted and tissue levels
      of IL-1 were consistently raised in UC samples. Levels of IL-1, rather than IL
      1ra or the ratio of IL-1ra/IL-1, most closely mirrored the severity of
      inflammation. Using specific antibodies we showed that IL-1ra and TGF-beta 1
      appear to modulate the degree of inflammation at different stages of the
      inflammatory process. Only in severely inflamed tissue, when IL-1 levels were
      high did IL-1ra inhibit IL-1-induced activity. In contrast, the levels of TGF
      beta 1, and its effect in controlling inflammation, was most marked in mild but
      not severe UC. CONCLUSIONS: The functional roles of these cytokines in the
      inflammatory process can now be more carefully elucidated using a bioassay and
      specific neutralising antibodies.

PMID- 15021970
TI  - Competition between IL-1, IL-1ra and TGF-beta 1 modulates the response of the
      ELA4.NOB-1/CTLL bioassay: implications for clinical investigations.
AB  - OBJECTIVE: The use of ELISA techniques to measure cytokine levels in clinical
      samples has chiefly replaced more labour intensive bioassays. ELISA measurements,
      however, do not reflect the functional activity of a cytokine within a sample;
      interleukin-1 (IL-1), for example, has two agonist isoforms (IL-1 alpha and IL-1
      beta) and a competitive receptor antagonist (IL-1ra), and can be regulated by
      transforming growth factor beta1 (TGF-beta 1). The net effect of these cytokines,
      rather than IL-1 levels, are frequently suggested to regulate tissue
      inflammation, but confirming this has been difficult. METHODS: We used the
      ELA4.NOB-1/CTLL co-culture IL-1 bioassay to investigate whether IL-1 activity was
      inhibited by IL-1ra and TGF-beta 1 in a predictable manner. RESULTS: Thymidine
      incorporation into CTLL cells, induced by IL-1, was reduced dose dependently by
      IL-1ra and TGF-beta 1. With optimal levels of IL-1 CTLL responsiveness was
      reduced by 90% by 1 ng/ml TGF-beta 1 and completely abolished by 100 ng/ml IL
      1ra. As expected, TGF-beta 1 and IL-1ra had independent mechanisms of action on
      the bioassay cell lines, and, in combination, they caused an additive, but not
      synergistic, effect. Importantly, the effect of these cytokines could be
      completely abolished in the presence of neutralising antibodies. CONCLUSIONS:
      Bioassay should provide specific functional information on the net IL-1 activity
      of clinical samples, while the use of specific antibodies could ascertain the
      contribution of individual cytokines within such samples.

PMID- 15021971
TI  - Leukotrienes mediate 5-hydroxytryptamine-induced plasma extravasation in the rat
      knee joint via CysLT-type receptors.
AB  - OBJECTIVE AND DESIGN: The aim of this study was to investigate whether
      leukotrienes synthesized by 5-lipoxygenase (5-LO) and acting via leukotriene (LT)
      receptors contribute to 5-hydroxytryptamine (5-HT)-induced knee joint plasma
      extravasation (PE). MATERIALS AND METHODS: Knee joints of rats under anesthesia
      were perfused with 5-HT and synovial vascular Evans Blue dye leakage was measured
      spectrophotometrically. A series of 5-LO inhibitors and LT receptor antagonists
      were investigated for their ability to inhibit 5-HT-induced synovial PE. RESULTS:
      Inhibitors of 5-LO (NDGA and REV 5901) significantly attenuated 5-HT-induced
      plasma extravasation. MK 571, LY 171883, BAY u9773 (CysLT receptor antagonists)
      and REV 5901 (a CysLT receptor antagonist and a 5-LO inhibitor) were equally
      effective in inhibiting 5-HT-induced PE, indicating that leukotrienes mediate 5
      HT-induced PE via CysLT receptors. In contrast, antagonists selective for LTB(4)
      receptors (BLT(1) and BLT(2) receptors) failed to reduce 5-HT-induced PE.
      CONCLUSIONS: These results demonstrate that leukotrienes, specifically cysteinyl
      leukotrienes contribute to synovial plasma extravasation and suggest that
      leukotrienes act downstream of 5-HT in the inflammatory cascade.

PMID- 15021972
TI  - Histopathological features of murine systemic vasculitis caused by Candida
      albicans extract--an animal model of Kawasaki disease.
AB  - OBJECTIVE AND DESIGN: We examined the histopathological features of systemic
      vasculitis caused in mice by injection of a Candida albicans ( C. albicans)
      extract and investigated the principal genetic roles in the development of
      vasculitis. MATERIALS AND METHODS: C. albicans extract was injected
      intraperitoneally for five consecutive days in the 1st and 5th weeks to CD-1,
      C57BL/6N, C3H/HeN, BALB/cAnN, DBA/2N and CBA/JN mice. At week 8, mice were
      killed, and histological examination was performed by light microscopy. RESULTS:
      Arteritis had developed in 66% of CD-1 mice. The extramural coronary arteries and
      aortic root close to the orifice of coronary arteries were most frequently
      involved. Histologically, the characteristic feature of the arteritis was
      proliferative and granulomatous inflammation accompanied by numerous macrophages,
      lymphocytes, plasma cells and neutrophils. Fibrocellular intimal thickening with
      destruction of the internal elastic lamina and media was also observed. Five
      mouse strains after injection of C. albicans extract were clearly classified into
      a resistant group (CBA/JN, DBA/2N and BALB/cAnN mice) and a sensitive group
      (C3H/HeN and C57BL/6N mice). The inbred mouse strains which showed the same
      histocompatibility-2 (H-2) haplotype exhibited a different susceptibility to
      development of vasculitis. CONCLUSION: This arteritis murine model shows unique
      histological features that have not been observed in other animal vasculitis
      models and it most closely resembles Kawasaki disease in humans. The genetic
      control of susceptibility to induction of vasculitis by the C. albicans extract
      is dependent to the mouse strains, but is not linked to the H-2 loci.

PMID- 15021973
TI  - Modulation of allergic and immune complex-induced lung inflammation by bradykinin
      receptor antagonists.
AB  - OBJECTIVE: The effect of bradykinin (B(1) or B(2)) receptor antagonists was
      studied in allergic and immune-complex-induced lung inflammation. METHODS: Lungs
      of BALB/c mice were examined 24 h after induction of lung inflammation, either
      allergic (ovalbumin-sensitized submitted to two aerosol of antigen, one week
      apart) or immune-complex induced (intratracheal instillation of IgG antibodies
      followed by intravenous antigen). The bradykinin B(2) receptor antagonist, HOE
      140 or bradykinin B(1) receptor antagonist, R-954 were given intraperitoneally
      (100 microg/kg), 30 min before induction. RESULTS: In allergic inflammation, pre
      treatment with R-954 reduced eosinophil infiltration into the lungs, mucus
      secretion and the airway hyperreactivity to methacholine. Pre-treatment with HOE
      140 increased eosinophil infiltration but did not affect the other parameters. In
      immune-complex inflammation, HOE-140 increased neutrophil infiltration but not
      their activation nor the hemorrhagic lesions. R-594 pre-treatment did not change
      the parameters examined. CONCLUSION: These results show important modulatory
      effects of bradykinin B(1) and B(2) receptor antagonists in both models of lung
      inflammation.

PMID- 15021974
TI  - Heparin protects against skin flap necrosis: relationship to neutrophil
      recruitment and anti-coagulant activity.
AB  - OBJECTIVE AND DESIGN: Heparin has been shown to improve survival of surgical skin
      flaps. However, it is not known whether the protective effect of heparin is
      related to its anticoagulative or anti-inflammatory effects. METHODS: Surgical
      flaps were raised in the dorsal skin of Sprague-Dawley rats. Neutrophil
      recruitment was determined by measuring the tissue content of myeloperoxidase
      (MPO) and clotting time was estimated by assessment of activated partial
      thromboplastin time (APTT) in plasma. RESULTS: Administration of heparin (150
      U/kg) significantly increased skin flap survival from 44% in vehicle-treated
      controls to 91%. This heparin treatment increased APTT by 4.5 fold. However,
      administration of 150 U/kg of heparin had no effect on skin flap neutrophil
      recruitment. In contrast, we found that the polysaccharide fucoidan reduced MPO
      and also improved skin flap survival. CONCLUSIONS: In conclusion, we demonstrate
      that protective effect of clinically relevant doses of heparin correlates with
      its ability to prolong clotting time and not to inhibition of neutrophil
      accumulation in the healing of skin flaps.

PMID- 15021975
TI  - Upregulation of bronchioloalveolar carcinoma-derived C-X-C chemokines by tumor
      infiltrating inflammatory cells.
AB  - OBJECTIVE AND DESIGN: The presence of increased numbers of tumor-infiltrating
      neutrophils is associated with poorer outcome in patients with adenocarcinoma of
      the bronchioloalveolar (BAC) subtype. We evaluated the role of inflammatory
      environment on C-X-C chemokine tumor production. MATERIALS: Bronchoalveolar
      lavage from 31 consecutive patients with adenocarcinoma of the BAC subtype as
      well as tumor and normal pulmonary tissue samples. A549 BAC cell line. Peripheral
      blood mononuclear cells (PBMC), polymorphonuclear neutrophils (PMN) and alveolar
      macrophages (AM). METHODS: Elisa measurements and immunohistochemical studies of
      ENA-78, IL-8, IL-1beta and TNF-alpha. RNA isolation, reverse transcription, and
      PCR amplification of ENA-78 and IL-8. RESULTS: C-X-C peptides were expressed by
      tumor cells of all the tumor specimens tested. ENA-78 and IL-8 were also
      expressed by AM. To better understand the regulation of the C-X-C production, BAC
      cell line was cultured alone or with inflammatory cells. PBMC upregulated both
      tumor ENA-78 and IL-8 mRNA expression and protein release whereas AM only
      upregulated ENA-78 mRNA expression and protein release; PMN had no effect. Anti
      human IL-1beta antibodies (ab) inhibited the A549 ENA-78 and IL-8 production
      stimulated by PBMC-CM. Anti-human TNF-alpha ab inhibited A549 ENA-78 production
      stimulated by AM-CM. IL-1beta and TNF-alpha were expressed in vivo by
      inflammatory cells, although TNF-alpha was also expressed by tumor cells.
      CONCLUSIONS: This work emphasizes the role of the host inflammatory response in
      promoting tumor growth in vivo.

PMID- 15021976
TI  - GM-CSF counteracts hemorrhage-induced suppression of cytokine-producing capacity.
AB  - OBJECTIVE AND DESIGN: To study whether a treatment with the hematopoietic growth
      factor GM-CSF restores the attenuated ex-vivo cytokine-producing capacity of
      macrophages after sublethal hemorrhagic shock. SUBJECTS: Male Sprague-Dawley
      rats. TREATMENT: 20 microg/animal of recombinant murine GM-CSF after shock via
      arterial line. METHODS: Hemorrhagic shock was established by pressure-controlled
      bleeding to a mean arterial pressure of 50 mm Hg for 35-40 min and consecutive
      resuscitation. 24 h after hemorrhage, lipopolysaccharide (LPS)-induced cytokine
      production of isolated macrophages derived from different compartments was
      measured. RESULTS: A significant reduction of LPS-induced TNFalpha production was
      found in whole blood cultures (1.0 +/- 0.7 ng/ml after sham vs. 0.23 +/- 0.08
      ng/ml after shock operation), macrophages derived from spleen (0.88 +/- 0.23
      ng/ml after sham vs. 0.03 +/- 0.1 ng/ml after shock operation), peritoneum (2.2
      +/- 0.7 ng/ml after sham vs. 0.29 +/- 0.4 ng/ml after shock operation) and
      bronchoalveolar fluid (0.65 +/- 0.13 ng/ml after sham vs. 0.003 +/- 0.027 ng/ml
      after shock operation, mean +/- S.D.). In cells from animals treated with GM-CSF
      a significantly enhanced LPS-induced TNFalpha production in splenic, alveolar and
      peritoneal macrophages was found after shock compared to the cells derived from
      untreated animals (peritoneum: 289 +/- 366 ng/ml TNFalpha after shock vs. 2066 +/
      94 ng/ml TNFalpha after shock and GM-CSF; lung: 9 +/- 12 ng/ml TNFalpha after
      shock vs. 64 +/- 17 ng/ml TNFalpha after shock and GM-CSF; spleen: 58 +/- 96
      ng/ml TNFalpha after shock vs. 548 +/- 47 ng/ml TNFalpha after shock and GM-CSF).
      Blood cultures collected from rats after hemorrhagic shock did not show a
      significant increase of TNFalpha-production after GM-CSF treatment. CONCLUSION:
      Hemorrhagic shock caused a depression of the TNFalphaa response to LPS which was
      partly counteracted by treatment with GM-CSF. Therefore, GM-CSF represents a
      promising approach to normalise trauma- and shock-induced immune dysfunction.

PMID- 15021977
TI  - Spatial distribution and temporal onset of NF-kB activation and inducible nitric
      oxide synthase within pancreatic islets in the pre-diabetic stage of genetic,
      diabetic-prone BB rats: attenuation by drug intervention decreases inflammatory
      cell infiltration and incidence of diabetes.
AB  - OBJECTIVE AND DESIGN: To document in vivo immunolocalization and activation of
      nuclear factor-kappaB (NF-kappaB) and inducible nitric oxide synthase (iNOS)
      expression in prediabetic stages of diabetes mellitus. MATERIAL OR SUBJECTS:
      Genetic, diabetic-prone or diabetic-resistant BB rats (total = 189). TREATMENT:
      Various doses of an oral dithiocarbamate derivative, NOX-700, or cyclosporine
      (2.5 mg/kg) starting at 30 or 60 days of age. METHODS: Immunohistochemistry,
      electrophoretic mobility shift assays, plasma glucose. RESULTS: NF-kappaB and
      iNOS was increased in pancreas of hyperglycemic, diabetic-prone rats but not
      normoglycemic, diabetic-resistant rats. Immunostaining for NF-kappaB and iNOS was
      largely confined to islets and occurred in diabetic-prone rats prior to overt
      hyperglycemia. NOX-700 decreased cell infiltration, delayed the onset of disease
      and decreased the incidence of hyperglycemia to levels achieved by
      immunosuppressant therapy. NOX-700 also decreased the intensity of immunoreactive
      NF-kappaB and iNOS within pancreatic islets. CONCLUSIONS: These studies support a
      role of NF-kB and iNOS in diabetogenesis in vivo.

PMID- 15021979
TI  - Different patterns of the L-histidine decarboxylase (HDC) gene expression in mice
      resistant and susceptible to experimental cutaneous leishmaniasis.
AB  - OBJECTIVE AND DESIGN: In the present study the experimental murine Leishmania
      major ( L. major) infection model was used to investigate the role of histamine
      biosynthesis in cutaneous leishmaniasis. SUBJECTS, TREATMENT AND METHODS: A novel
      RNase Protection Assay (RPA) was developed and applied for the assessment of L
      histidine decarboxylase (HDC) gene expression in organs of resistant C57BL/6 and
      susceptible BALB/c mice after infection with L. major. RESULTS: In the acute
      phase of infection a rapid but transient induction of HDC expression was observed
      in the infected lymph nodes of both strains correlating both temporally and
      spatially with parasite spread. The signal was present in the draining popliteal
      lymph nodes of both hosts, however, only susceptible mice known to be unable to
      control parasite dissemination showed induction of HDC in their distant
      periaortic lymph nodes as well. During the chronic phase of infection only the
      heavily parasitized organs of BALB/c mice showed high HDC gene expression.
      CONCLUSIONS: These data suggest that expression of the histamine-producing enzyme
      HDC in the decisive acute phase of leishmaniasis is not coupled with development
      of either appropriate Th1 or inadequate Th2 responses to L. major. We
      hypothesize, however, that during the chronic phase of infection elevated HDC
      levels, possibly of mast cell origin, are associated with Th2-dominated responses
      and serious disease development.

PMID- 15021978
TI  - KF19514, a phosphodiesterase 4 and 1 inhibitor, inhibits TNF-alpha-induced GM-CSF
      production by a human bronchial epithelial cell line via inhibition of PDE4.
AB  - OBJECTIVE AND DESIGN: Bronchial epithelium plays an important role in the
      regulation of inflammatory reactions in the airways. We investigated the effect
      of KF19514, a phosphodiesterase (PDE) 4 and 1 inhibitor, on granulocyte
      macrophage colony-stimulating factor (GM-CSF) production by a human bronchial
      epithelial cell line, BEAS-2B. METHODS: BEAS-2B cells were stimulated with the
      tumor necrosis factor-alpha (TNF-alpha) and various concentrations of test agents
      for 48 h. Supernatants were assayed for GM-CSF by using an enzyme-linked
      immunosorbent assay (ELISA). In addition, intracellular cyclic AMP (cAMP) levels
      were measured in the presence of various agents. RESULTS: KF19514 significantly
      inhibited the release of GM-CSF by BEAS-2B cells in a concentration-dependent
      manner. The other PDE4 inhibitors and cAMP-elevating agents also inhibited the GM
      CSF production. In the BEAS-2B cells, KF19514 and PDE4 inhibitors concentration
      dependently increased intracellular cAMP levels. The inhibitory effect of KF19514
      on the GM-CSF production was significantly reduced by a cAMP-dependent protein
      kinase A (PKA) inhibitor, H89. On the other hand, other PDE isozyme inhibitors
      did not inhibit the GM-CSF production by BEAS-2B cells, and did not elevate the
      intracellular cAMP levels. CONCLUSIONS: These results indicate that KF19514 and
      PDE4 inhibitors reduce TNF-alpha-induced GM-CSF production of BEAS-2B cells via a
      cAMP-dependent pathway. PDE4 may be a possible target for the regulation of
      cytokine production in epithelial cells.

PMID- 15021980
TI  - Growth and reproduction of fungal feeding Collembola as affected by fungal
      species, melanin and mixed diets.
AB  - Fungal feeding soil invertebrates feed on a wide spectrum of fungal species
      suggesting that mixed diets increase fitness. We investigated relationships
      between food preferences for seven saprophytic fungal species/forms and fitness
      parameters (mortality, growth, time to reproduction, reproduction, egg size) in
      two Collembola species, Folsomia candida and Protaphorura armata. The fungal
      species/forms studied included the wild type and a melanin-deficient form of
      Aspergillus fumigatus to investigate the role of melanin in collembolan
      nutrition. Also, three mixed diets consisting of a preferred fungal species
      (Cladosporium cladosporioides) and species of intermediate or low food quality
      were investigated. Both Collembola species preferred similar fungal species/forms
      as food. Food preference generally matched fitness parameters, i.e. growth and
      reproduction of Collembola was at a maximum when feeding on preferred fungi. This
      was not the case for A. fumigatus. The wild type and the melanin-deficient form
      ranked among the least preferred fungi. Growth and reproduction of Collembola
      were low when feeding on the wild type but high when feeding on the melanin
      deficient form indicating that the Collembola misjudged the food quality of the
      latter in the preference tests. The results show for the first time that genes
      driving melanin syntheses (pksP) strongly affect the food quality of fungi for
      fungal feeding invertebrates. Feeding on mixed diets generally increased growth
      and reproduction of Collembola except when the diets included toxic species
      (Penicillium sp.). The results support the nutrient balance hypothesis and also
      show that the detection of toxic species in the diet is important. They indicate
      that the widespread generalist feeding mode of Collembola maximizes fitness if
      toxic fungal species are avoided. The fitness parameters growth, reproduction and
      time until onset of reproduction were correlated closely but egg volume, which
      also varied with fungal diet, correlated poorly with the other fitness
      parameters. Variation in egg size with fungal diet shows that the diet of
      Collembola may have transgenerational effects.

PMID- 15021981
TI  - Climate change affects the outcome of competitive interactions-an application of
      principal response curves.
AB  - It has been hypothesised that climate change may affect vegetation by changing
      the outcome of competitive interactions. We use a space-for-time approach to
      evaluate this hypothesis in the context of alpine time-of-snowmelt gradients.
      Principal response curves, a multivariate repeated-measurement analysis
      technique, are used to analyse for compositional differences in local ridge-to
      snowbed gradients among 100 m altitudinal bands from 1,140 to 1,550 m a.s.l.,
      corresponding to a temperature gradient of 2.5 degrees C (local lapse rate is 0.6
      degrees C). The interaction between time-of-snowmelt and altitude is strongly
      significant statistically, indicating that the altitudinal gradient cannot be
      explained simply by the physiological responses of the species, but that there
      are also changes in the outcome of competitive interactions. At higher altitudes,
      there is a decrease in the time-of-snowmelt ranges of species which have
      intermediate times-of-snowmelt optima, whereas snowbed (chinophilous) species
      have wider time-of-snowmelt ranges. As snowbed species can survive, grow and
      reproduce at very early snow-free sites at high altitudes, the most likely
      explanation for their absence from all but the latest time-of-snowmelt habitats
      at lower altitudes is competitive exclusion by more vigorous lee-side species.
      This suggests that with future climate change snowbed species will experience, in
      addition to habitat fragmentation and reduced size of habitats due to increased
      temperature and snowmelt, an indirect effect due to competitive exclusion from
      late-snowmelt sites by species that have their optima outside snowbeds.

PMID- 15021983
TI  - Supplementary fed Ural owls increase their reproductive output with a one year
      time lag.
AB  - Life-history components may be food-limited. We supplemented food to 18 Ural owl,
      Strix uralensis, nests during the nestling period. Food supplementation led to a
      higher somatic condition in the female parent, but effects in males were
      moderate. Parents delivered less food to fed nests than to control nests.
      Offspring survival and fledging condition did not differ between control and fed
      nests. In the season following food supplementation, fed pairs bred 1 week
      earlier than control pairs and, coupled to this advance in laying date, fed pairs
      produced 0.6 eggs more than control pairs. This is the first evidence that food
      limitation in the current season may constrain next season's reproduction. Such
      carry-over effects of food-limitation may have important consequences for
      population dynamics.

PMID- 15021982
TI  - Characterization of an urban-rural CO2/temperature gradient and associated
      changes in initial plant productivity during secondary succession.
AB  - To examine the impact of climate change on vegetative productivity, we exposed
      fallow agricultural soil to an in situ temperature and CO2 gradient between
      urban, suburban and rural areas in 2002. Along the gradient, average daytime CO2
      concentration increased by 21% and maximum (daytime) and minimum (nighttime)
      daily temperatures increased by 1.6 and 3.3 degrees C, respectively in an urban
      relative to a rural location. Consistent location differences in soil temperature
      were also ascertained. No other consistent differences in meteorological
      variables (e.g. wind speed, humidity, PAR, tropospheric ozone) as a function of
      urbanization were documented. The urban-induced environmental changes that were
      observed were consistent with most short-term (approximately 50 year) global
      change scenarios regarding CO2 concentration and air temperature. Productivity,
      determined as final above-ground biomass, and maximum plant height were
      positively affected by daytime and soil temperatures as well as enhanced [CO2],
      increasing 60 and 115% for the suburban and urban sites, respectively, relative
      to the rural site. While long-term data are needed, these initial results suggest
      that urban environments may act as a reasonable surrogate for investigating
      future climatic change in vegetative communities.

PMID- 15021984
TI  - Temporal and sexual variation of leaf-produced pollinator-attracting odours in
      the dwarf palm.
AB  - Information on intra-specific variation in pollinator-attracting floral traits
      provides clues to selective pressures imposed by pollinators. However, these
      traits also reflect constraints related to floral phenology or morphology. The
      specific weevil pollinator Derelomus chamaeropsis of the dioecious Mediterranean
      dwarf palm Chamaerops humilis is attracted by volatile compounds that leaves, and
      not flowers, release during anthesis. Production of these olfactory cues is thus
      probably not constrained by any other floral function. This provides the
      opportunity to study variation of a "floral" trait that is not produced by a
      floral organ. We studied volatile compounds emitted by leaves of 12 individual C.
      humilis over the whole flowering season. The quantity of volatile compounds
      emitted by leaves reached a maximum when plants required pollinator visits. The
      relationship between odour emission and floral phenology was slightly different
      between male and female plants, probably reflecting differences in the exact time
      at which females and males benefit from pollinator visitation. Male plants
      produced higher quantities of volatile compounds than females. Odour composition
      was highly variable among individuals but did not differ between male and female
      plants. In this system, female C. humilis are pollinated by deceit and
      pollinators should be selected to avoid visiting them. The absence of sexual
      difference in blend composition may thus prevent pollinators from discriminating
      between male and female plants.

PMID- 15021985
TI  - A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L)
      maps to chromosome 12q24.
AB  - Charcot-Marie-Tooth disease (CMT) is one of the most common inherited
      neurological disorders with a prevalence estimated at 1/2500. The axonal form of
      this disorder is referred to as Charcot-Marie-Tooth type 2 disease (CMT2).
      Recently, a large Chinese family with CMT2 was found in the Hunan and Hubei
      provinces of China. The known loci for CMT1A, CMT2D, CMT1B (the same locus is
      also responsible for CMT2I and CMT2J), CMT2A, CMT2E, and CMT2F were excluded in
      this family by linkage analysis. A genome-wide screening was then carried out,
      and the results revealed linkage of CMT2 to a locus at chromosome 12q24.
      Haplotype construction and analyses localized this novel locus to a 6.8-cM
      interval between microsatellite markers D12S366 and D12S1611. The maximal two
      point LOD score of 6.35 and multipoint LOD score of 8.08 for marker D12S76 at a
      recombination fraction (theta) of 0 strongly supported linkage to this locus.
      Thus, CMT2 neuropathy in this family represents a novel genetic entity that we
      have designated as CMT2L.

PMID- 15021986
TI  - Diagnostic telepathology: long-term experience of a single institution.
AB  - OBJECTIVES: The paper reviews the development of the application of telepathology
      in a department of surgical pathology between 1991 and 2003. The goal of the
      efforts during this time was to give up the concept of programming a single
      application, available only between two fixed workstations with sophisticated
      devices and special software, and to find the virtual "largest common
      denominator" for implementing as many different applications as possible with the
      same basic system. METHODS: A new telepathology system was designed as a client
      server system with a relational database at its centre. The clients interact
      together by transferring the questions (texts and images) to a record (case) in
      the database on the server and by transferring the answers to the same record on
      the database. RESULTS: The new "open" telepathology system iPath
      (http://telepath.patho.unibas.ch) has been very well accepted by many groups
      around the world. The main application fields are: consultations between
      pathologists and medical institutions without a pathologist (e.g. for frozen
      section diagnoses or for surgical diagnoses in hospitals in South Asia or
      Africa), tumour boards, field studies and distance education
      (http://teleteach.patho.unibas.ch). CONCLUSIONS: Having observed that with iPath
      we have succeeded in satisfying all our telepathology needs, we are inclined to
      put the emphasis on the nature of the tasks being performed, as opposed to the
      methods or technical means for performing a given task. The three organisation
      models proposed by Weinstein et al. (2001) can be reduced to only two models: the
      model of discussion groups and the model of expert groups (virtual institutes).

PMID- 15021987
TI  - Possible involvement of nitric oxide and peroxynitrite in the pathogenesis of
      human vocal polyps and nodules.
AB  - Nitric oxide (NO) is a molecule involved in multiple functions including
      vasodilatation, neural transmission, immune response and inflammation. However,
      the role of NO in the pathophysiology of vocal cord diseases is not clear. The
      present study investigated the possible involvement of NO and its toxic
      metabolite, peroxynitrite, in the pathogenesis of vocal polyps and nodules. Vocal
      polyps and nodules were obtained from patients receiving surgery for their
      conditions. Immunohistochemistry was applied to evaluate the expression of the
      inducible form of nitric oxide synthase (iNOS) as well as the production of
      peroxynitrite represented by the formation of its biological footprint, 3
      nitrotyrosine (3-NT). Each section was given a score of 0 to 4 according to the
      labeling intensity seen, with the highest number representing the highest
      labeling intensity. The results showed that vocal polyp had an average iNOS
      labeling score of 3.2, which was significantly higher than the value of 1.9 in
      vocal nodules. The average labeling score of 3-NT was 2.8 in vocal polyps, which
      was also significantly higher than the value of 1.8 in vocal nodules. There was
      also a positive correlation between the level of iNOS expression and the extent
      of 3-NT formation. These results suggest that increased peroxynitrite production,
      resulting from increased iNOS expression and NO formation, may have an important
      pathogenic role in these vocal diseases.

PMID- 15021988
TI  - Kimura's disease presenting as bilateral parotid masses.
AB  - Kimura's disease, a unique angiolymphoid proliferative disorder with unknown
      cause, is apparently more prevalent in a young Oriental males, but also occurs
      rarely in Western people. It has occasionally been misdiagnosed as malignant
      tumor or other serious diseases, leading to unnecessary radical surgery. Hence,
      clinicians should be made aware of this disease. The most common presentation is
      a unilateral soft-tissue mass in the head and neck region. Kimura's disease of
      bilateral parotid involvement has been reported rarely. We encountered a rare
      case of Kimura's disease presenting as bilateral parotid region masses and
      treated it successfully with surgery.

PMID- 15021989
TI  - [The global risk for cardiovascular disease. Who is a candidate for
      pharmacological prevention?].
AB  - Despite the epidemiological importance of coronary artery disease, cardiovascular
      events are rare from the individual viewpoint. There is considerable uncertainty
      when to start medical treatment. A given risk factor modification results in a
      relative risk reduction independent of the global risk. Therefore the global risk
      determines the absolute benefit of a preventive measure. The global risk can be
      estimated using different scoring systems. Using the global risk and the expected
      relative risk reduction, the Number Needed to Treat (NNT) to avoid one event or
      cardiac death can be calculated. The NNT is a measure for the usefulness of a
      preventive intervention. A NNT of < 200 appears acceptable for primary
      prevention. This can be achieved with pharmacological preventive strategies if
      the global risk of 10 years is > or = 20%. As age is one of the most important
      risk predictors the need for treatment at comparable risk factor constellations
      is age dependent. Risk stratification with estimation of the NNT is therefore
      important for the decision to treat or not to treat.

PMID- 15021990
TI  - [Primary prevention: physical activity].
AB  - Traditional risk factors such as smoking, hypertension and being overweight have
      received considerable attention in recent years, whereas physical activity as a
      preventive strategy does not enjoy the same public attention. In recent years the
      level of physical activity has decreased dramatically in children and adolescents
      in favor of time spent on the internet and in front of the TV. If this trend is
      allowed to develop along the same direction, a sharp increase in cardiovascular
      disease can be anticipated. The protective action of physical activity on the
      cardiovascular system has been well documented in large numbers of patients, and
      the basic physiological mechanisms have been elucidated. Metabolic changes
      comprise loss of weight, reduction in triglyceride and LDL levels, as well as an
      increase in HDL. Insulin sensitivity is enhanced in all tissues postponing the
      manifestation of diabetes mellitus. Shear forces created by physical activity
      induce ecNOS within the endothelial lining of the arteries. This enzyme is
      responsible for controlling vasomotion through the elaboration of NO which causes
      vasodilation in the smooth muscle within the vessel wall. Utilization of
      preformed collateral vessels has been postulated repeatedly; so far, however, it
      only could be documented in animals, not in humans. Nearly all studies concerned
      with primary prevention have shown a significant negative correlation between
      energy expenditure during exercise and cardiovascular mortality, even light and
      moderate exercise will result in a lower incidence. In order to eliminate a
      sedentary life style in children and adolescents, adequate programs should be
      initiated in all schools; they should aim for 60 min of physical activity on a
      daily basis.

PMID- 15021991
TI  - [Cholesterol: blood levels or total risk as a guide to preventive treatment?].
AB  - The results of a cholesterol lowering therapy with statins do belong to the best
      documented steps in medical treatment. The newer studies like HPS and LIPID have
      shown a therapeutic benefit across all serum-cholesterol levels, nearly obviating
      the need for a prior determination of the cholesterol values. Why not using the
      serum-cholesterol level as the only guide to therapy? Since there is no threshold
      indicating the need for treatment, there is the danger of an unlimited inflation
      of the indications for therapy, possibly leading to a collapse of the health care
      system. At the upper extreme, therapy would have to start at a very young age,
      and no one can predict the side effects of a statin therapy over many decades.
      Improving the target for therapy can only be achieved via determination of the
      total risk of cardiovascular disease. Several algorithms like PROCAM ( www.chd
      taskforce.de), the risk chart of the European Society of Cardiology or the
      Framingham risk-scores will come to similar results. In this manner, one can
      differentiate further, and persons with a low risk of cardiovascular disease like
      women and young adults do not have to be treated unnecessarily. However, it must
      not be overlooked that the sensitivity of these risk-scores is rather low. The
      majority of myocardial infarctions occur in the average risk population, because
      of sheer numbers. Independent indicators of cardiovascular risk, such as the CRP,
      the intima-media thickness of the carotid artery and in particular the
      determination of the coronary calcium score via EBT or ultrafast scan can lead to
      more clarity. To improve the estimation of the individual risk, we will need a
      combination of risk-factors and -indicators.

PMID- 15021992
TI  - [Prevention of coronary disease and sudden death by nutrition].
AB  - Nutrition influences sudden cardiac death (SCD) not only by determining the
      development of atherosclerotic coronary disease but possibly also by more
      specific rhythm stabilizing abilities of some nutrients. QUANTITATIVE ASPECTS: A
      body mass index >30 is associated with a 2.6-fold risk of SCD, probably via the
      risk factors diabetes and hypertension. QUALITATIVE ASPECTS: alpha-linolenic acid
      (ALA) is a substrate for the production of the N-3-fatty acids eicosapentaenoic
      acid (EPA) und docosahexaenoic acid (DHA). The consumption of ALA correlates with
      decreased MI risk. Fish consumption is (in case control studies) associated with
      reduced MI-risk and (in prospective controlled studies) with decreased risk of
      SCD. Two or more fish meals/week and the estimated N-3-fatty acids (n-3-FA)
      ingestion of > 1.2 g/week correlate with a reduced SCD-risk. The blood level of
      the N-3-FA EPA and DHA correlate highly with a reduced risk for SCD. It is likely
      that the marine production of N-3-FA will not suffice to supply the amount needed
      for large scale prevention. Industrial farming of algae and genetic modification
      of mammal muscle cells resulting in improved ability to transform N-6-FA to
      corresponding N-3-FA could contribute to better availability of N-3-FA for
      prevention. Nutrition influences sudden cardiac death (SCD) not only by
      determining the development of atherosclerotic coronary disease but possibly also
      by more specific rhythm stabilizing abilities of some nutrients.

PMID- 15021993
TI  - [Cardiovascular risk stratification in general practice].
AB  - CONCLUSION: The ESC risk charts are helpful to identify high risk patients in
      general practice who are candidates for preventive treatment. The use of the ESC
      charts is one important step to initiate "evidence based medicine" in the daily
      practice of preventive cardiology.Cardiovascular diseases are the most important
      causes of premature disability and death in Germany. High risk patients however
      are frequently not recognized. A systematic risk stratification in general
      practice could identify high risk persons and allow a cost effective treatment
      approach. The goal of the CAD-scoring week was to identify high risk persons with
      the use of the ESC risk charts and to evaluate the treatment resulting from risk
      stratification. In addition the feasibility of the risk charts in daily office
      routine was to be evaluated. A total of 1122 of 20 000 (5.6%) contacted general
      physicians agreed to participate in the screening procedure. More than 27 000
      patients (> 50 yrs) were evaluated using the ESC risk charts. 21.6% of women (n =
      15 018) vs 22.2%* of men (n = 12 361) had markedly elevated blood pressure (> 150
      mmHg), 29 vs. 24%* had a total cholesterol > 250 mg/dl (6.5 mmol/l), 25.5 vs
      29.9%* smoked and 28.4 vs. 31.9%* had diabetes (*female vs male: p < 0.0003).
      Altogether 19.4% of women vs. 53% of men were newly identified as high risk
      patients (risk > 20% in 10 years). More than 40% of these high risk patients
      received drug treatment for prevention (ASA, lipid lowering drugs or ACE
      inhibitors). More than 70% of the participating physicians judged the risk charts
      to be helpful in patient management.

PMID- 15021994
TI  - [Primary prevention of coronary heart disease with aspirin].
AB  - According to the meta-analysis and the results of the two studies with the
      highest power, aspirin is effective in primary prevention of coronary heart
      disease. These beneficial effects, however, are at least partially outweighed by
      unwanted effects-such as intense gastrointestinal bleeding and hemorrhagic
      stroke. These side effects remain constant with increasing risk of coronary heart
      disease, whereas the protective effects increase. If an annual risk of coronary
      heart disease of < or = 0.6% exists, aspirin is normally not indicated; for a
      risk of 0.7-1.4% the facts should be discussed with the patient. If a risk of >
      or = 1.5% exists, aspirin should be given.

PMID- 15021995
TI  - [Primary prevention of non-communicable diseases. Experiences from population
      based intervention in Finland for the global work of WHO].
AB  - Globally most people die from noncommunicable diseases. Especially in developing
      countries noncommunicable diseases are on the rise, effecting especially poorer
      societal segments. The noncommunicable diseases contribute greatly to societal
      and economic losses and inequities in health status. The North Karelia Project
      was started in Finland to prevent noncommunicable diseases and with the main aim
      to curb the high mortality from cardiovascular diseases. In collaboration with
      the community, the health sector, the food industry and mass media, initiatives
      were started to promote a healthy diet, physical activity and reduce smoking.
      Over the last 25 years, the age adjusted mortality rate among men of 25-64 years
      of age from cardiovascular diseases fell by 73%, from lung cancer by 71% and
      total mortality fell 49%. Each country should plan and implement its own
      prevention programs, but lessons can be learned from the North Karelia Project.
      The paper discusses some key lessons and recommendation from the project for
      countries and for global work. In the last few years WHO has started to up-grade
      its work to fight noncommunicable diseases. Some initiatives are presented and
      discussed.

PMID- 15021996
TI  - [Position paper on primary prevention of cardiovascular diseases. Current edition
      of 25 March 2003 by the governing body of the German Society of Cardiology-Heart-
      and Cardiovascular Research, revised by request of the governing body via the
      Prevention Project Group].

PMID- 15021997
TI  - [Pharmacological aspects of secondary prevention post-MI].
AB  - The pharmacological evaluation of medications used in secondary prevention of
      myocardial infarction offers interesting insights that facilitate the
      individualization of therapy. One example is the strong evidence of a reduced
      patient benefit with comedication of ACE inhibitors and acetylsalicylic acid
      after myocardial infarction. Over the past years, the effects of n-3
      polyunsaturated-fatty acids after myocardial infarction have been investigated
      intensely. They act via several physiological mechanisms that are of potential
      benefit in reducing cardiovascular mortality. While epidemiological and study
      data suggest antiarrhythmic properties as the main reason for reduced mortality,
      recent papers also point to a intensification of plaque stability.

PMID- 15021998
TI  - [Sudden cardiac death (SCD) and guidelines for SCD].
AB  - Sudden cardiac death is mainly caused by arrhythmic events, triggered by
      ischemia. About half of the affected persons had no previous diagnosis of
      coronary heart disease, thus rendering them practically unreachable for specific
      preventive measures. This fact makes it necessary to optimize reanimation
      conditions. The establishment of international reanimation standards (ILCOR) has
      stimulated an intensified scientific evaluation of therapeutic options. While the
      use of vasopressin, adrenaline and reanimation by bystanders is being evaluated
      at the moment, amiodarone has not fulfilled the expectation of reducing
      mortality. Secondary prevention of sudden cardiac death after cardiac events is
      based on betablockers, ACE inhibitors and antilipemic therapy. Guidelines on
      prevention of sudden cardiac death also recommend aldosterone blockade and n-3
      fatty acids. Persons at highest risk gain most from the use of ICDs, yet it has
      not been shown that their use immediately after myocardial infarction reduces
      mortality.

PMID- 15021999
TI  - [Treatment of acute myocardial infarction-state of the art].
AB  - Clinical data in acute STEMI clearly show the superiority of intracoronary
      intervention vs thrombolysis. Short- and long-term events with the exception of
      major bleeding are significantly reduced by PTCA. Recent clinical data show that
      even transfer to interventional centers does not reduce the overall benefits
      significantly. If transfer is necessary, onset of symptoms within less than 3
      hours might indicate equality in mortality outcome for both treatments. To ensure
      optimal outcome of PTCA, intracoronary interventions have to be performed on a
      regular basis. A very low frequency of interventions levels the benefit of PTCA
      vs lysis.

PMID- 15022000
TI  - [Risk-adjusted prevention post-MI].
AB  - A recent clinical registry with 96 participating hospitals specialized in
      cardiological rehabilitation provided data from 47,324 patients. Registry data
      showed a significant reduction of risk factors over time. The incidence of
      systolic hypertension, for example, was reduced from 44.6 to 16.9%. In addition,
      clinical rehabilitation raised awareness of AMI survivors for individual risk
      factors, thus providing the basis for a lifestyle change that allows an improved
      long-term outcome.

PMID- 15022001
TI  - [Diabetic patients after myocardial infarction].
AB  - Diabetes mellitus is not just another risk factor for cardiovascular events; it
      per se defines maximal risk for target organ damage including the cardiovascular
      system. Diabetes is one of the main drivers in the race towards a higher
      incidence in cardiovascular disease worldwide. In addition, it is also one of the
      often unrecognized predecessors of myocardial infarction and sudden cardiac
      death. About three quarters of patients post-MI show impaired glucose tolerance
      or full blown diabetes. The MONICA/KORA data have shown that the higher risk for
      mortality and morbidity in diabetics is maintained past the first event. However,
      the STENO-2 trial has shown that consequently managing diabetes and concomitant
      cardiovascular risk factors can significantly reduce the risk for cardiovascular
      events in this high-risk group.

PMID- 15022003
TI  - [Statins-a panacea?].
AB  - Statins have proven their therapeutical value for a wide range of patients with
      coronary heart disease. The average reduction of the relative risk for
      cardiovascular events is 23%. This remains true even in the light of ALLHAT,
      which had failed to show a significant reduction in mortality in the statin
      subgroup, yet its significance suffered from an insufficient difference in the
      reduction of plasma lipids in the intervention group as compared to usual care.
      On the other hand, ASCOT and PROSPER have demonstrated the efficacy of statins in
      normolipemic hypertensives and elderly patients. The safety of statin therapy can
      be considered as good; for example the Prospective Pravastatin Pooling Project
      with 19,592 patients found a rate of unexpected events equal to placebo.

PMID- 15022002
TI  - [Prehospital delay-not just a question of patient knowledge].
AB  - Patients with acute myocardial infarction reaching the hospital within the first
      hour after symptom onset preserve their chances for an optimal treatment. But
      only about one fifth of them actually reach the hospital within this "golden
      hour". Information of the public to reduce time from symptom onset to medical
      service call have shown success only during the time the continuous publicity was
      maintained. Soon after the end of such activities the prehospital delay again
      reached the initial duration. Because of restricted resources, prehospital
      thrombolysis as another means of reducing time to treatment is as yet only used
      for a very small proportion of patients. Reduction of door-to-balloon and 
      treatment time seems to have reached its limit in recent years. In patients with
      delayed hospital admission, the use of PTCA interventions seems to result in
      better outcome data compared to thrombolysis.

PMID- 15022004
TI  - [Recommendations for secondary prevention after myocardial infarction].
AB  - The new ESC guidelines for secondary prevention after STEMI recommend
      acetylsalicylic acid, betablockers, ACE inhibitors, statins and as a new
      therapeutic option 1 g n-3-fatty acids. They also advocate strict control of
      elevated blood pressure and plasma glucose level. To stop smoking remains
      obligatory, supplemented by the advice to adhere to a mediterranean diet. The
      clinical value of using 1 g n-3-fatty acids was shown in the GISSI-P trial and
      seem to reduce especially arrhythmic events. Considering the number needed to
      treat for the different pharmacologic therapies, betablockers and ACE inhibitors
      are essentials if not contraindicated, n-3-fatty acids and statins show each
      comparable efficacy while acetylsalicylic acid still provides a good cost/benefit
      relation due to its low price.

PMID- 15022006
TI  - Surgical results of posterior fossa decompression for patients with Chiari I
      malformation.
AB  - INTRODUCTION: An increasing number of children with Chiari I malformations are
      coming to the attention of neurosurgeons today, although a consensus on the
      surgical approach to these lesions has yet to be found. METHODS: We present a
      retrospective analysis of posterior fossa decompression (PFD) performed at our
      institution on 96 patients from 1989 to 2001. Statistical analyses based on
      clinical and radiographic presentation and the types of surgical procedures used
      formed the basis for our review. RESULTS: Most of the patients with hydromyelia
      underwent duraplasty procedures with or without tonsillar manipulation. In
      contrast, most patients without hydromyelia underwent bony decompression with
      dural scoring and intraoperative ultrasound. PFD with bony decompression and
      dural scoring showed a 72% success rate, compared with 68% for duraplasty. Dural
      opening was not more likely to improve or arrest hydromyelia. The group subjected
      to duraplasty, however, had a significantly higher complication rate. Patients
      under the age of 8 fared better than their older counterparts. CONCLUSIONS:
      Overall, we favor a tailored posterior fossa craniectomy with dural scoring as
      the initial surgical procedure in children with Chiari I malformation with or
      without a syrinx. This less invasive approach minimizes complications associated
      with dural opening and offers comparable success rates.

PMID- 15022007
TI  - The persistence of an open anterior fontanel in a 4-year-old girl.
AB  - CASE REPORT: A 3-year-old girl was transferred to our hospital with a history of
      persistent open anterior fontanel. The patient was conscious and had no
      neurological deficits. Upon arrival, the patient appeared normal for her age and
      had no defects or anomalies other than the aforementioned lesion. The initial
      skull X-ray and CT were significant for a 20-mm open anterior fontanel. All other
      findings were normal. OUTCOME: After a follow-up period of 1.5 years, the
      anterior fontanel was still open, with a slight decrease in size to 15 mm.
      Delayed closure of the anterior fontanel without intracranial hypertension is
      associated with various disorders. The pathogenesis of the current patient's
      condition is unclear. Due to the patient's normal appearance and stable
      neurological status, we will follow her conservatively for any changes in
      condition.

PMID- 15022009
TI  - [Cause and repair of a corneoscleral fistula in two patients].
AB  - BACKGROUND: A slowly progressing bulbar hypotension with maculopathy in a male
      patient as well as an endophthalmitis in a female patient both required surgical
      repair of posttraumatic leaks. PATIENTS AND METHODS: In a 32-year-old male
      patient, a filtration bleb leak occurred 4 months after a penetrating stab wound
      in the corneoscleral region. Persistent bulbar hypotension demanded microsurgical
      revision, revealing a 1 x 1 mm scleral defect. The leakage area was close to the
      limbus. In a 75-year-old female patient, signs of endophthalmitis occurred 4
      years after extracapsular cataract extraction with posterior intraocular lens
      implantation. The place of entry of the inflammation was a 1 x 3 mm
      subconjunctival fistula in the corneoscleral scar. In both cases the leakage
      areas were repaired by an autologous 4 x 4 mm scleral graft obtained from the
      pars plana region in the same eye. RESULTS: The postoperative course was without
      complications, the intraocular pressure was back to normal within a few days in
      both cases. Two weeks after surgical repair in the first patient, normal ocular
      fundus and normal visual acuity were observed. In both cases complete and
      permanent leakage closure was achieved. CONCLUSIONS: There are various surgical
      possibilities for the repair of scleral defects. Patching the defects with
      autologous scleral grafts has several advantages. Dissection of the graft in the
      pars plana region is relatively simple. The graft comprising 30% of the scleral
      thickness is sufficiently firm and supple and there is no danger of infection
      transmission or of rejection.

PMID- 15022011
TI  - Diffusion-weighted MR imaging in acute spinal cord ischemia.
AB  - We report diffusion-weighted (DW) MR findings for acute spinal cord ischemia in a
      56-year-old patient. MR imaging obtained approximately 3 h after symptom onset
      demonstrated an area of hyperintensity on DW images, but no conspicuous signal
      abnormality on T2-weighted images in the conus medullaris. DW imaging of the
      spinal cord can contribute to the early detection of spinal cord vascular
      compromise.

PMID- 15022012
TI  - The anterior glenohumeral joint capsule: macroscopic and MRI anatomy of the
      fasciculus obliquus or so-called ligamentum glenohumerale spirale.
AB  - The purpose of this study was to demonstrate the macroscopic and MRI anatomy of
      the fasciculus obliquus, otherwise known as the ligamentum glenohumerale spirale
      or spiral GHL of the anterior shoulder joint capsule. Conventional and MR
      arthrography (1.5-T device Somatom Symphony, Siemens with shoulder coil) images
      in standard planes were compared with gross anatomic dissection findings in six
      fresh shoulder specimens from three cadavers. The MR imaging protocol included
      T1, PD and DESS 3D WI sequences. The macroscopically recognisable band-the spiral
      GHL-was identified by anatomic dissection and MRI in all the specimens. It was
      best visualised by MR arthrography on axial and oblique sagittal planes (T1; PD
      WI) and appeared as a low signal intensity stripe within the superficial layer of
      the anterior joint capsule. The absence of the variable middle glenohumeral
      ligament did not influence the anatomic properties and the MR imaging of the
      spiral GHL. Diagnostic visualisation of the normal anatomic structures is a
      prerequisite to distinguish between normal and pathologic conditions. Anatomy of
      the spiral GHL can be used by radiologists for more detailed interpretation of
      the anterior shoulder joint capsule ligaments on MR images.

PMID- 15022013
TI  - Dispersal and size fractionation of embryogenic callus increases the frequency of
      embryo maturation and conversion in hybrid tea roses.
AB  - Plant regeneration from embryogenic cells of two Rosa hybrida cultivars, Kardinal
      and Classy, was increased by dispersing embryogenic callus in liquid medium for 3
      h followed by size-fractionation to isolate proembryogenic masses that were
      smaller than 530 microm. Dispersed callus of three cultivars, Kardinal, Classy,
      and Tineke, produced 61-135 cotyledonary-stage embryos/100 mg fresh weight (FW)
      as compared to intact callus that had not been dispersed, which produced only
      zero to three cotyledonary-stage embryos/100 mg FW. Over 500 cotyledonary-stage
      embryos/100 mg FW callus developed from proembryogenic masses of Kardinal,
      Classy, and Tineke following 2 months of culture on solidified Murashige and
      Skoog's basal salts medium supplemented with 0.25% activated charcoal.
      Cotyledonary-stage embryos of Classy that developed from both dispersed callus
      and fractionated cells of various sizes showed a significantly higher conversion
      frequency to plants (28%) than cotyledonary-stage embryos isolated from intact
      callus (9%). The highest conversion frequencies for Kardinal (50-58%) occurred
      from cotyledonary-stage embryos that developed from dispersed callus and from the
      fraction of cells smaller than 850 microm.

PMID- 15022014
TI  - High-frequency plant regeneration through callus initiation from mature embryos
      of maize ( Zea Mays L.).
AB  - An efficient maize regeneration system was developed using mature embryos.
      Embryos were removed from surface-sterilized mature seeds and sliced into halves.
      They were used as explants to initiate callus on induction medium supplemented
      with 4.0 mg l(-1) 2,4-dichlorophenoxyacetic acid (2,4-D). The induction frequency
      of primary calli was over 90% for all inbred lines tested. The primary calli were
      then transferred onto subculture medium supplemented with 2.0 mg l(-1) 2,4-D.
      Following two biweekly subcultures, embryogenic calli were formed. Inclusion of a
      low concentration (0.2 mg l(-1)) of 6-benzylaminopurine (BA) in the subculture
      medium significantly promoted the formation of embryogenic callus. The addition
      of silver nitrate (10 mg l(-1)) also supported an increased frequency of
      embryogenesis. The embryogenic callus readily formed plantlets on regeneration
      medium supplemented with 0.5 mg l(-1) BA. The regenerated plantlets were
      transferred to half-strength Murashige and Skoog medium supplemented with 0.6 mg
      l(-1) indole-3-butyric acid to develop healthy roots. The regenerated plantlets
      were successful on transfer to soil and set seed. Using this system, plantlets
      were regenerated from seven elite maize inbred lines. The frequency of forming
      green shoots ranged from 19.8% to 32.4%. This efficient regeneration system
      provides a solid basis for genetic transformation of maize.

PMID- 15022015
TI  - Factors affecting somatic embryogenesis in Prunus incisa cv. February Pink.
AB  - Factors affecting somatic embryogenesis from root explants of Prunus incisa
      Thunb. cv. February Pink were investigated. Using a medium containing Murashige
      and Skoog salts and vitamins supplemented with 10 microM 2,4
      dichlorophenoxyacetic (2,4-D), we evaluated the effects of light, growth
      regulators, amino acids, carbohydrate source, and root induction medium. Explants
      cultured under light or dark conditions both resulted in the formation of
      embryos. Embryogenesis was inhibited by the addition of 6-benzyladenine,
      thidiazuron, or gibberellic acid to the medium. Amino acids were not effective in
      promoting embryogenesis, with high levels of amino acids actually inhibiting it.
      Sucrose and glucose effectively induced embryogenesis, while sorbitol and
      mannitol completely inhibited it. Sucrose and glucose also promoted secondary
      embryogenesis. Embryos that formed in medium containing 4% or 5% sucrose were
      abnormally shaped and did not fully develop, while those that formed in medium
      with sucrose concentrations of 2% or 3% were much more vigorous. Root explants
      that were induced on medium containing 1.0 micro M indole-3-butyric acid (IBA)
      produced more somatic embryos than explants induced on medium without IBA.
      Approximately 50% of the roots induced on medium containing 1.0 microM IBA
      produced somatic embryos on medium containing 10 microM 2,4-D and 3% sucrose.

PMID- 15022017
TI  - Vaccination.

PMID- 15022016
TI  - A new enrichment approach identifies genes that alter cell cycle progression in
      Saccharomyces cerevisiae.
AB  - Mechanisms that coordinate cell growth with division are thought to determine the
      timing of initiation of cell division and to limit overall cell proliferation. To
      identify genes involved in this process in Saccharomyces cerevisiae, we describe
      a method that does not rely on cell size alterations or resistance to pheromone.
      Instead, our approach was based on the cell surface deposition of the Flo1p
      protein in cells having passed START. We found that over-expression of HXT11
      (which encodes a plasma membrane transporter), PPE1 (coding for a protein methyl
      esterase), or SIK1 (which encodes a protein involved in rRNA processing)
      shortened the duration of the G1 phase of the cell cycle, prior to the initiation
      of DNA replication. In addition, we found that, although SIK1 was not part of a
      mitotic checkpoint, SIK1 over-expression caused spindle orientation defects and
      sensitized G2/M checkpoint mutant cells. Thus, unlike HXT11 and PPE1, SIK1 over
      expression is also associated with mitotic functions. Overall, we used a novel
      enrichment approach and identified genes that were not previously associated with
      cell cycle progression. This approach can be extended to other organisms.

PMID- 15022018
TI  - Inguinal hernia in the new millennium.
AB  - Since 1884, when Edoardo Bassini started the modern era of surgical correction of
      inguinal hernia (today the most common procedure performed by the general
      surgeon), many techniques have been introduced, some short-lived, others with
      proven long-term results. At the start of the new millennium, the surgeon has
      three clear alternatives: tension repairs, tension-free repairs, and laparoscopic
      procedures. This paper analyzes these three options and offers an update
      regarding the pros and cons of the most commonly performed operations in surgical
      centers around the world.

PMID- 15022019
TI  - High-energy laser therapy of Barrett's esophagus: preliminary results.
AB  - We present the preliminary results obtained by our research group utilizing
      Nd:YAG and diode lasers to treat Barrett's esophagus (BE). A total of 15 patients
      with BE (mean age 58 years) underwent endoscopic laser therapy: 11 with
      intestinal metaplasia, 2 with low-grade dysplasia, and 2 with high-grade
      dysplasia. The mean length of BE was 4 cm (range 1-12 cm). Six of these patients
      also underwent antireflux surgery, and nine were prescribed acid-suppressive
      medication. Endoscopic Nd:YAG laser treatment was carried out from 1997 to 1999;
      thereafter, diode laser was employed. The mean follow-up of these patients after
      the first laser session was 28 months. Patients underwent a mean of 6.5 laser
      sessions (range 3-17 sessions), with no apparent complications. The mean energy
      per session was 1705 JJ. Only six of these patients (40%) showed complete
      endoscopic and histologic remission, but a mean of 77% (SD 23.8%) of the total
      metaplastic tissue in all these patients was ablated. The percentage of healed
      mucosa was higher in patients with short-segment BE (92%) ( p < 0.05) and in
      subjects treated by two or more laser sessions per centimeter of BE length (89%)
      ( p < 0.05). All four patients with dysplasia showed histologic regression to
      nondysplastic BE or to squamous epithelium, without recurrence during a mean
      follow-up of 30 months. The patients who underwent antireflux surgery and those
      prescribed pharmacologic treatment had similar results. Nd:YAG and diode laser
      treatment of BE is a safe, effective procedure; it required two sessions per
      centimeter of metaplasia; and it achieved complete regression of the dysplasia.
      Further studies are necessary to quantify its effect on cancer incidence.

PMID- 15022020
TI  - Fishing line suture: cost-saving alternative for atraumatic intracutaneous skin
      closure--randomized clinical trial in Rwanda.
AB  - Experience with the use of nylon fishing line for surgical sutures has been
      reported from several African countries. A recent publication suggested that
      fishing line and an injection needle may provide an atraumatic suture that is
      especially suitable for intracutaneous skin closures. This article provides
      further empirical support for such alternative technology. We describe a
      randomized, blinded clinical trial conducted in Butare (Rwanda) with 220
      cutaneous wounds closed by intracutaneous sutures, with either the homemade
      suture or a commercial nylon thread (Ethilon). We compared the clinical outcomes
      as well as the costs of those two materials. There are no significant differences
      between the two sutures in terms of clinical findings or in the reported ease of
      use by the surgeons. The cost of a homemade atraumatic suture is US $0.07, which
      is less than one-thirtieth the cost of the commercial thread. The advantage of
      the commercial thread is the assurance of quality. We consider whether this
      quality assurance justifies the large price difference, and if the homemade
      suture should be recommended to surgeons in countries where the costs of surgical
      material often remain an obstacle for life-saving operations.

PMID- 15022021
TI  - Micrometastases of solitary hepatocellular carcinoma and appropriate resection
      margin.
AB  - We studied the pattern of intrahepatic micrometastases using large pathologic
      sections on liver resection specimens with ample resection margins from 113
      patients with a solitary hepatocellular carcinoma (HCC). The liver tissues around
      the HCC were divided into proximal and distal areas according to the direction of
      the portal vein flow. These areas were further divided into zones based on fixed
      criteria. Altogether, 273 micrometastases were identified, including 254 (93.0%)
      intravascular micrometastases and 19 (7.0%) tumor satellite micronodules. The
      distance of spread of these micrometastases ranged from 0.05 to 6.10 cm. The
      number of micrometastases was less in the proximal area than in the distal area.
      In addition, the farther the distance away from the primary tumor, the fewer
      micrometastases there were. Micrometastases extended beyond the 2 cm margin in
      only nine (8.0%) patients. In conclusion, micrometastases could spread via
      invasion of portal vein branches at an early stage even when the tumor was
      solitary and small. Anatomic segment resection is preferred for patients with a
      solitary HCC. Nonanatomic resection may be used as an alternative in patients
      with impaired liver function, but adequate resection margins should be achieved.
      For HCCs < or = 3 cm, a proximal resection margin and a distal margin of 1.0 cm
      are recommended. For HCCs > 3 cm, a 1.0 proximal resection margin and a 2.0 cm
      distal margin are recommended.

PMID- 15022022
TI  - "On table" positioning for optimal access for cancer excision in the lower
      rectum.
AB  - Poor visualization and restricted access often make tumor lesions in the lower
      rectum difficult to excise, particularly in a narrow male pelvis. The aim of this
      study was therefore to study whether (and if so to what extent) different
      positions of the patient on the operating table might improve accessibility.
      Twenty consecutive patients (men and women) undergoing laparotomy with surgery of
      the lower rectum were studied. The geometric configuration of the pelvis was
      studied and compared on lateral radiographs obtained at the operating table in
      each of four positions. Compared with the conventional lithotomy position, "the
      thighs-flat" position caused significant extension movement of the lumbosacral
      joint. Augmentation of the lumbar lordosis widened the pelvic view and enabled a
      more vertical view of the lower rectum (27.5 degrees in lithotomy position, 13.0
      degrees in the thighs-flat position). Insertion of a "lumbar pad" contributed
      further to the augmentation (7 degrees). When compared on radiographic studies,
      the thighs-flat position is preferable to the conventional lithotomy position in
      terms of facilitating low rectal surgery by improving both visibility and
      accessibility to the pelvic cavity.

PMID- 15022024
TI  - Ballistic study of the SAPL GC27 gun: is it really "nonlethal"?
AB  - To evaluate the potential dangers of the "nonlethal" 12-gauge single-shot handgun
      SAPL GC27 with Fun-Tir (FT) and mini-Gomm-Cogne (mGC) ammunition, a ballistic
      study was performed with both types of ammunition. Nine unembalmed human corpses
      covered with a cloth sheet were shot through the right and left pectoral regions.
      With the mGC ammunition, rib fractures were observed when the firing range was
      less than 2 meters, skin perforation when the range was less than 1.5 meters,
      with lung injuries at less than 0.2 meter; the heart and the aorta were lacerated
      at contact range (0 meter). No skin perforation was observed with the FT
      ammunition, but rib fractures were observed when it was fired at up to 2 meters.
      Our study shows that the mGC ammunition, shot by the CG27 firearm, can be lethal
      at contact range and that pellets penetrate the skin at ranges of less than 1
      meter. These results led us to conclude that this weapon is too dangerous to be
      marketed as a "nonlethal" weapon. The term "reduced wounding power weapon" is
      preferable.

PMID- 15022023
TI  - Sternocleidomastoid muscle flap preventing Frey syndrome following parotidectomy.
AB  - Frey syndrome is one of the potential sequelae of parotidectomy. Various medical
      and surgical treatments have been used in an attempt to avoid this embarrassing
      condition. Recently, interposing barriers between the overlying skin flap and the
      parotid bed, such as the sternocleidomastoid muscle (SCM) flap, have been used to
      prevent this condition. The purpose of this study was to evaluate the impact of
      using this flap on Frey syndrome. A series of 138 patients who underwent subtotal
      or total parotidectomy from January 1995 to December 2001 were divided into two
      groups. One group had an SCM flap reconstruction (n = 24), and the other group
      did not (n = 19). A subjective clinical questionnaire and the objective Minor's
      starch iodine test were used to evaluate the incidence of this syndrome. The
      postoperative period varied from 12 to 90 months. The frequency exact test of
      Fisher and the nonparametric test of Mann-Whitney were applied. The association
      with the absence of sweating and the presence of the SCM flap was significant (p
      = 0.0002). There was no association with flushing or pain and the flap. There was
      a significant association with the starch iodine test and the presence of the
      flap (p = 0.0016). The only significant association of the epidemiologic and
      clinical characterization of the patients with a negative or positive Minor's
      test was between sweating and a positive Minor's test (p = 0.0001). The only
      significant aspect in the diagnosis of Frey syndrome is gustatory sweating. There
      is a significant association with a negative Minor's test and the presence of the
      SCM flap and with sweating and a positive Minor's test. The SCM flap is an
      efficient method for preventing Frey syndrome following parotidectomy.

PMID- 15022026
TI  - Lower limb ischemia reperfusion injury as a cause of systemic inflammatory
      response. (DOI: 10.1007/s00268-003-7093-6).

PMID- 15022025
TI  - Palliation of metastatic gastric cancer: impact of preoperative symptoms and the
      type of operation on survival and quality of life.
AB  - Patients with advanced, incurable gastric cancer may present with mild symptoms
      or require immediate therapeutic intervention. The influence of the intensity of
      preoperative symptoms on postoperative survival and quality of life (QoL) was
      evaluated in a palliative setting. In a historical cohort analysis of 492
      patients with gastric cancer treated between 1992 and 2001, a total of 169
      (34.4%) patients had incurable disease (i.e., pTxNxM1). Patients were classified
      as having major symptoms if they presented with upper gastrointestinal bleeding
      (i.e., hematemesis or bloody stools), gastric inlet or outlet obstruction (i.e.,
      symptomatic and endoscopically proven stenosis), or perforation caused by the
      tumor. All other patients were defined as having minor symptoms. QoL was assessed
      prospectively using the EORTC questionnaire. The questionnaire was given to the
      patients before operation, before discharge, and 3 months after operation; and it
      was analyzed by the Mann-Whitney U-test. Survival, demographic data, and
      histopathologic characteristics were assessed and analyzed by the log-rank test
      and the chi(2) test, respectively. Of the 169 patients, 75 (44.3%) presented with
      major symptoms and 94 (55.7%) with minor symptoms. The distribution of patients
      undergoing resection or exploration was comparable for the two groups [major: 61
      (81.5%)/14 (18.5%); minor: 77 (81.9%)/17 (18.1%)]. Despite comparable demographic
      and histopathologic characteristics with equal hospital mortality and morbidity
      (14.6% vs. 8.5%/49.3% vs. 40.4%), the median survival rates in two groups were 4
      and 6 months, respectively ( p < 0.05). This was not influenced by the type of
      operation. QoL was not different in patients with major or minor symptoms before
      operation or 3 months thereafter. However, preoperative symptoms such as
      nausea/vomiting and melena were rated significantly higher in patients with major
      symptoms. In patients with incurable gastric cancer the preoperative intensity of
      symptoms has a significant impact on survival and QoL, which is not influenced by
      the operation. The necessity of surgery in patients with minor symptoms requires
      careful consideration.

PMID- 15022028
TI  - Enzyme reactions and genes in aflatoxin biosynthesis.
AB  - Aflatoxins are highly toxic and carcinogenic substances mainly produced by
      Aspergillus flavus and Aspergillus parasiticus. Sterigmatocystin is a penultimate
      precursor of aflatoxins and also a toxic and carcinogenic substance produced by
      many species, including Aspergillus nidulans. Recently, the majority of the
      enzyme reactions involved in aflatoxin/sterigmatocystin biosynthesis have been
      clarified, and the genes encoding the enzymes have been isolated. Most of the
      genes constitute a large gene cluster in the fungal genome, and their expression
      is mostly regulated by a product of the regulatory gene aflR. This review will
      summarize the enzymatic steps and the genes in aflatoxin/sterigmatocystin
      biosynthesis.

PMID- 15022029
TI  - Meckel's diverticulum with segmental dilatation of the ileum: radiographic
      diagnosis in a neonate.
AB  - We report a neonate with segmental dilatation of the ileum and a Meckel's
      diverticulum that was diagnosed preoperatively on the plain abdominal radiograph.

PMID- 15022031
TI  - P-glycoprotein function in the elderly.
AB  - OBJECTIVE: The MDR1-encoded P-glycoprotein (Pgp) represents the best-studied
      membraneous efflux pump defending the body against xenobiotics. Various
      polymorphisms (single nucleotide polymorphisms; SNPs) in the MDR1 gene have been
      identified, and a silent mutation in exon 26 (C3435T) has been correlated with
      duodenal expression of Pgp, which might affect the disposition of certain drugs.
      The C3435T SNP has been shown to be linked to another SNP (G2677T/A) in exon 21
      which leads to an amino acid exchange. So far, the influence of age on Pgp
      function has been neglected. As the function of Pgp might be altered in advanced
      age, we investigated in groups of fit and frail elderly subjects whether the
      efflux of the Pgp-probe rhodamine 123 from CD56(+) natural killer cells was age
      dependent and whether it was affected by the two SNPs. METHODS: Leukocytes were
      isolated from blood of 18 healthy elderly subjects (mean age 69 years) and 20
      geriatric frail patients (mean age 78 years) and data compared with 21 previously
      studied young healthy Caucasian individuals (mean age 33 years). Subjects were
      homozygous for either CC- or TT-genotype (SNP C3435T) and additionally
      differentiated according to genotype GG or TT of the SNP G2677T. Using flow
      cytometry, rhodamine fluorescence was monitored in CD56(+) cells. RESULTS: In
      contrast to the young controls, in both elderly populations no significant
      difference between the CC and TT genotypes (exon 26) could be observed in
      rhodamine fluorescence. Furthermore, only for the TT genotype (exon 26) did frail
      elderly demonstrate some reduced Pgp function ( P=0.03) if compared with the
      young healthy subjects. If the three groups were compared independent of the
      genotype, no age effects were observed. For all assessed genotypes, there was no
      significant difference between fit and frail elderly subjects. CONCLUSION: Aging
      and frailty have apparently only a minor impact on this validated cellular Pgp
      model and it could be assumed that function of Pgp is quite well preserved in
      patients of advanced age.

PMID- 15022030
TI  - Phenotype and genotype for thiopurine methyltransferase activity in the French
      Caucasian population: impact of age.
AB  - OBJECTIVE: Thiopurine drugs are commonly used in pediatric patients for the
      treatment of acute leukemia, organ transplantation and inflammatory diseases.
      They are catabolized by the cytosolic thiopurine methyltransferase (TPMT), which
      is subject to a genetic polymorphism. In children, enzyme activities are immature
      at birth and developmental patterns vary widely from one enzyme to another. The
      present study was undertaken to evaluate erythrocyte TPMT activity and the
      correlation between genotype and phenotype in different age groups from birth to
      adolescence and adulthood. METHODS: The study included 304 healthy adult blood
      donors, 147 children and 18 neonates (cord bloods). TPMT activity was measured by
      liquid chromatography, and genotype was determined using a polymerase chain
      reaction reverse dot-blot analysis identifying the predominant TPMT mutant
      alleles (TPMT*3A, TPMT*3B, TPMT*3C, TPMT*2). RESULTS: There was no significant
      difference in TPMT activity between cord bloods ( n=18) and children ( n=147)
      (17.48+/-4.04 versus 18.62+/-4.14 respectively, P=0.424). However, TPMT was
      significantly lower in children than in adults (19.34+/-4.09) ( P=0.033). In the
      whole population, there were 91.9% homozygous wild type, 7.9% heterozygous
      mutants and 0.2% homozygous mutants. The frequency of mutant alleles was 3.0% for
      TPMT*3A, 0.7% for TPMT*2 and 0.4% for TPMT*3C. CONCLUSION: No impact of child
      development on TPMT activity could be evidenced, suggesting that TPMT activity is
      already mature at birth. The difference between children and adults was low with
      reduced clinical impact expected. When individual TPMT activity was compared with
      genotype, there was an overlapping region where subjects (4.5%, 12 adults, 9
      children) were either homozygous wild type or heterozygous, with a TPMT activity
      below the antimode value. This result highlighted the importance of measuring
      TPMT activity to detect all patients at risk of thiopurine toxicity.

PMID- 15022032
TI  - Salivary caffeine metabolic ratio in alcohol-dependent subjects.
AB  - OBJECTIVES: To determine whether caffeine (CA) clearance and salivary
      paraxanthine (PX)/CA ratio were altered in alcohol-dependent subjects and also
      whether salivary PX/CA ratio was affected by arylamine-N-acetylation 2 ( NAT-2)
      genotypes. METHODS: Of 30 male individuals recruited in assessing PX/CA ratio and
      CA clearance by ingestion of CA, 13 were healthy control, 10 were alcohol
      dependent subjects with abnormal liver function tests and 7 were alcohol
      dependent subjects with normal liver function. CA and PX levels were analysed by
      means of high-performance liquid chromatography. CA clearance was calculated from
      concentrations of CA in saliva at various time intervals. In another study, PX/CA
      ratios were assessed in 46 healthy male subjects. Their NAT2 status was genotyped
      using polymerase chain reaction with restriction fragment length polymorphism
      assay. RESULTS: Salivary CA clearance was well correlated with plasma and
      salivary PX/CA ratios in a wide range of the clearance. Correlation between
      salivary PX/CA ratio and CA clearance was considered high from the first hour
      after CA ingestion and continued so for at least 9 h (r=0.94-0.96, P<0.001).
      PX/CA ratio in saliva was also well correlated with plasma PX/CA ratio (r=0.98,
      P<0.001). Salivary CA clearance in the control group was significantly higher
      than that of patients with abnormal liver function tests, i.e. (mean+/-SEM; 95%
      confidence limits; l/h/kg) 0.094+/-0.013 (0.064-0.124) and 0.044+/-0.019 (0.002
      0.091), respectively, and not different from that of patients with normal liver
      function tests [0.107+/-0.017 (0.066-0.149)]. Similarly, the same is true for
      PX/CA ratio. NAT2 genotype status did not apparently affect PX/CA ratio.
      CONCLUSION: Saliva-based PX/CA ratio was a convenient and robust method for
      assessment of CYP1A2 activity and liver function and it was shown to be altered
      in alcohol-dependent patients with mild abnormal liver function test.

PMID- 15022034
TI  - European analytical column No. 32 (January 2004).

PMID- 15022033
TI  - Drug utilisation in outpatient children. A comparison among Tenerife, Valencia,
      and Barcelona (Spain), Toulouse (France), Sofia (Bulgaria), Bratislava (Slovakia)
      and Smolensk (Russia).
AB  - INTRODUCTION: Scarce information about comparative diagnostic and therapeutic
      patterns in paediatric outpatients of different countries is found in the
      literature. OBJECTIVE: To describe the similarities and differences observed in
      diagnosis and therapeutic patterns of paediatric patients of seven locations in
      different countries. DESIGN: Cross-sectional, prospective, international
      comparative, descriptive study. PATIENTS AND METHODS: A randomly selected sample
      of 12,264 paediatric outpatients seen in consultation rooms of urban and rural
      areas and attended by paediatricians or general practitioners of the
      participating locations. Data on patient demographic information, diagnosis and
      pharmacological treatment were collected using pre-designed forms. Diagnoses were
      coded using the ICD-9 and drugs according to the ATC classification. RESULTS:
      Among the ten most common diagnoses, upper respiratory tract infections are in
      the first position in all locations; asthma prevalence is highest in Tenerife
      (8.4%). Tonsillitis, otitis, bronchitis and dermatological affections are the
      most common diagnoses in all locations. Pneumonia is only reported in Sofia
      (3.8%) and Smolensk (2.3%). The average number of drugs prescribed per child
      varied from 1.3 in Barcelona to 2.9 in Smolensk. There are no great differences
      in the profile of pharmacological groups prescribed, but a considerable range of
      variations in antibiotic therapy is observed: prescription of cephalosporins is
      low in Smolensk (0.7%) and higher in the other locations, from 16.5% (Bratislava)
      to 28% (Tenerife). Macrolides prescriptions range from 12.6% (Toulouse) to 24.7%
      (Smolensk), except in Sofia where they drop to 5.6%. Trimethoprim and its
      combinations are used in Smolensk (23.3%), Sofia (11.8%) and Bratislava (8.7%).
      Check-up consultations are not recorded in Smolensk and Bratislava, whereas in
      Toulouse these visits account for 16.2% of all consultations and in the other
      locations the percentage varies from 6.1% (Tenerife) to 1.9% (Sofia). Homeopathic
      treatments are registered only in Toulouse. CONCLUSION: Except in asthma
      prevalence, there are no great differences in diagnostic maps among locations.
      Significant variations in the number of drugs prescribed per child and antibiotic
      therapies are observed. Areas for improvement have been identified.

PMID- 15022036
TI  - Incidence and function of sigma factors in Ralstonia metallidurans and other
      bacteria.
AB  - Bacterial sigma factors are essential for directing the bacterial RNA polymerase
      to promoter regions during transcription initiation. Genomic sequencing of the
      highly heavy-metal-resistant beta-proteobacterium Ralstonia metallidurans strain
      CH34 revealed 17 candidate genes for sigma factors. This review compares the
      sigma factor machinery of R. metallidurans to that of other bacteria. The sigma
      factors of 105 bacterial genomes were assigned to sigma factor clusters and
      families formed around the factors from Escherichia coli, Bacillus subtilis, and
      R. metallidurans. Genes for between 1 and 65 sigma-factor-related proteins were
      found in these genomes. Although prediction of sigma factor function from
      sequence comparisons can be misleading, organization of the R. metallidurans
      sigma factors into clusters and protein families, together with a discussion of
      the physiological function of members of these clusters, might yield insight into
      the cellular roles of bacterial sigma factors and the genes that depend on them
      for their expression.

PMID- 15022035
TI  - Kinetics of orally administered di(2-ethylhexyl) phthalate and its metabolite,
      mono(2-ethylhexyl) phthalate, in male pigs.
AB  - Di(2-ethylhexyl) phthalate (DEHP) is used as a plastic softener in the polymer
      industry and is widespread in medical devices. DEHP has been incriminated as an
      endocrine-disrupting chemical, and the effects of DEHP in various species have
      included disturbances in the reproductive system. The effects of the chemical
      have varied, depending upon exposure routes and species. This study was performed
      in order to characterise the kinetics of DEHP and its metabolite mono(2
      ethylhexyl) phthalate (MEHP) in the young male pig, an omnivore model-species for
      research in reproductive toxicology. Eight pigs were given 1000 mg DEHP/kg
      bodyweight by oral gavage. The concentrations of DEHP and MEHP were then measured
      in the plasma and tissues of the pigs at different time points after
      administration. There was no consistent rise above contamination levels of
      concentrations of DEHP in the plasma of the pigs. However, the metabolite MEHP
      reached the systemic blood circulation. The half-life of MEHP in the systemic
      blood circulation was calculated to be 6.3 h. Absorption from the intestine was
      biphasic in six of the eight pigs and the mono-exponential elimination-phase
      started 16 h after the after the administration of DEHP. To conclude, MEHP
      consistently reaches the systemic circulation in the pig when DEHP is
      administered orally. The kinetic pattern of the parent substance on the other
      hand is more difficult to characterise.

PMID- 15022038
TI  - Ultrasonography and articular cartilage defects in the knee: an in vitro
      evaluation of the accuracy of cartilage thickness and defect size assessment.
AB  - The purpose of this cadaver study was to test the accuracy of ultrasonography in
      measuring cartilage thickness, and the extent and depth of induced cartilage
      defects on the medial and lateral femoral condyles of the knee in a clinically
      relevant setting. With the knees maximally flexed, cartilage thickness was
      measured at 24 marked sites in four knees with a 10 MHz probe. The areas of
      measurement were then excised and the thickness measured with a calliper gauge.
      In another seven cadaver knees, 21 cartilage defects were produced. The defect
      diameter varied from 4 to 8 mm. The depths of the defects were either a partial
      cartilage defect (grade 2), a defect to intact subchondral bone (grade 3), or a
      defect involving subchondral bone (grade 4) (classification by ICRS). The limits
      of agreement between ultrasonography and calliper gauge measurement for cartilage
      thickness were chi(diff)+/-2SD(diff)=0.0+/-0.4 mm. For cartilage defect diameter,
      the limits of agreement between ultrasonography and the slide ruler measurement
      were chi(diff)+/-2SD(diff)=-0.2+/-1.0 mm. For the depths of the lesions there was
      a 100% agreement between radiologist and actual lesion depth for the
      classification into International Cartilage Repair Society (ICRS) grades 2, 3,
      and 4. Our conclusion is that ultrasonography is capable of measuring accurately
      both cartilage thickness and the extent and depth of induced cartilage defects in
      a cadaver model.

PMID- 15022037
TI  - In vivo application of 3D-line skeleton graph analysis (LSGA) technique with high
      resolution magnetic resonance imaging of trabecular bone structure.
AB  - Over the last several years magnetic resonance (MR) imaging has emerged as a
      means of measuring in vivo 3D trabecular bone structure. In particular, MR based
      diagnosis could be used to complement standard bone mineral density (BMD) methods
      for assessing osteoporosis and evaluating longitudinal changes. The aim of this
      study was to demonstrate the feasibility of using the 3D-LSGA technique for the
      evaluation of trabecular bone structure of high-resolution MR images,
      particularly for assessing longitudinal changes, in vivo. First, the
      reproducibility of topological 3D-LSGA based measurements was evaluated in a set
      of seven volunteers, and coefficients of variations ranged from 3.5% to 6%.
      Second, high-resolution MR images of the radius in 30 postmenopausal women from a
      placebo controlled drug study (Idoxifene), divided into placebo ( n=9) and
      treated ( n=21) groups, were obtained at baseline (BL) and after 1 year of
      treatment (follow-up, FU). In addition, dual X-ray absorptiometry (DXA) measures
      of BMD were obtained in the distal radius. Standard morphological measurements
      based on the mean intercept length (MIL) technique as well as 3D-LSGA based
      measurements were applied to the 3D MR images. Significant changes from BL to FU
      were detected, in the treated group, using the topological 3D-LSGA based
      measurements, morphological measures of volume of connected trabeculae and App
      Tb.N from MIL analysis. The duration of the study was short, and the number of
      patients remaining in the study was small, hence these results cannot be
      interpreted with regard to a true therapeutic response. Furthermore, the site
      (wrist) and the drug (idoxifene) are not optimal for follow-up study. However,
      this paper demonstrated the feasibility of using 3D-LSGA based evaluation coupled
      with in vivo high-resolution MR imaging as a complementary approach for the
      monitoring of trabecular bone changes in individual subjects.

PMID- 15022039
TI  - Sufentanil in the ICU setting.

PMID- 15022040
TI  - Developing methods for assessing quality of life in different cultural settings.
      The history of the WHOQOL instruments.
AB  - BACKGROUND: This review traces the 12-year history of an international
      collaboration of researchers-the WHOQOL Group-who were brought together by the
      World Health Organisation to develop and produce a cross-cultural measure of
      quality of life for use in health and health care. DISCUSSION: The theoretical
      and philosophical basis of the WHOQOL instrument is outlined as it evolved
      throughout the design and adjustment of a reflexive methodology that places an
      assessment of the users' views at the centre of health care. The stages of
      research are further expanded and explained in recounting the scientific
      experience of this unique collaboration. The WHOQOL is available in 40 countries
      and most majority languages. Adaptations exist for assessing particular
      conditions, e. g. spirituality, religion and personal beliefs.

PMID- 15022042
TI  - Rural-urban differences in the prevalence of major depression and associated
      impairment.
AB  - BACKGROUND: The possibility of a rural and urban difference in the prevalence of
      major depression has been of interest to researchers and mental health service
      providers. The objectives of this analysis were to determine the rural and urban
      difference in the 12-month prevalence of major depressive episode(s) (MDE) in
      Canada and whether participants in rural and urban areas differed in the
      impairment levels due to depressive symptoms and in mental health service
      utilization. METHODS: Data from the 1998-1999 Canadian National Population Health
      Survey (NPHS) were used in this study. In the NPHS, MDE was measured by the
      Composite International Diagnostic Interview-Short Form for Major Depression. Two
      week disability and daily life interference due to depressive symptoms were used
      as indicators of impairment in this analysis. The prevalence of MDE in rural and
      urban areas, at national and regional levels, was calculated. The association
      between urbanicity and MDE was evaluated by Odds Ratios, controlling for
      potential confounders. Impairment levels and mental health service utilization
      were also compared between the rural and urban groups. RESULTS: NPHS participants
      in rural areas had a lower prevalence of MDE than those in urban areas,
      controlling for the effects of race, immigration status, working status and
      marital status. Non-immigrants and those who are white in rural areas had a lower
      prevalence of MDE than did those in urban areas, and such differences depended on
      age and geographic regions. Rural and urban participants did not differ in 2-week
      disability and daily life interference due to depressive symptoms. However, rural
      participants were less likely to have contacted health professionals for mental
      health problems. CONCLUSIONS: The reasons for the rural and urban differences in
      the prevalence of MDE are complex. This may depend on individuals' age,
      immigration status, race, working status, marital status and the provinces where
      they live. These differences should be considered in future mental health service
      planning, particularly at provincial levels. There may be gaps between rural and
      urban areas in terms of availability of mental health services. This should be
      addressed in future studies and in mental health service planning.

PMID- 15022043
TI  - The difference between single and married mothers in the 12-month prevalence of
      major depressive syndrome, associated factors and mental health service
      utilization.
AB  - BACKGROUND: Previous studies suggest that single mothers are at a higher risk of
      major depression and more likely to use mental health services than are married
      mothers. The objectives of this analysis were to provide estimates of the
      prevalence of major depressive syndrome among single and married mothers, to
      investigate the factors which may affect the difference in the prevalence of
      major depressive syndrome among single and married mothers and to estimate the
      health care service utilization by single and married mothers. METHODS: This was
      a cross-sectional study using the data from the 1996-97 Canadian National
      Population Health Survey (NPHS). Major depressive syndrome was evaluated using
      the Composite International Diagnostic Interview-Short Form for major depression.
      The prevalence of major depressive syndrome was calculated among 3030 single and
      10195 married mothers. The effects of demographic, socioeconomic and biological
      variables on the association between single-mother status and major depressive
      syndrome were evaluated by stratified analyses. RESULTS: In the NPHS, the
      difference between single and married mothers in the prevalence of major
      depressive syndrome was found among women who were between the ages of 25 and 50.
      The association in this age group depended on race and on whether they had one or
      more jobs. Education,problem drinking, daily smoking, having one or more long
      term medical illnesses, financial hardship and social support did not affect the
      association between single-mother status and major depressive syndrome. Single
      mothers were more likely to visit health professionals for mental problems than
      were married mothers. CONCLUSION: The difference between single and married
      mothers in the prevalence of major depression is age-specific. Single mothers who
      reported having had one or more jobs and who are non-white had an increased risk
      of having major depressive syndrome, compared to married mothers. Future studies
      need to replicate the findings of this analysis and investigate why single
      mothers with ethnic minority backgrounds and those who are working are at high
      risk of having depressive disorders.

PMID- 15022041
TI  - The epidemiology of depersonalisation and derealisation. A systematic review.
AB  - BACKGROUND: Symptoms of depersonalisation (DP) and derealisation (DR) are
      increasingly recognised in both clinical and non-clinical settings, but their
      importance and underlying pathophysiology is only now being addressed. METHODS:
      This paper is a systematic review of the current state of knowledge about the
      prevalence of depersonalisation and derealisation using computerised databases
      and citation searches. All potential studies were examined and numerical data
      included. Three categories of study are reviewed: questionnaire and interview
      surveys of selected student and non-clinical samples; population-based community
      surveys using standardised diagnostic interviews; and clinical surveys of
      depersonalisation/derealisation symptoms occurring within inpatients with
      psychiatric disorders. In addition, we present newly analysed data of the
      prevalence of depersonalisation/derealisation from five large population-based
      studies. RESULTS: Epidemiological surveys demonstrate that transient symptoms of
      depersonalisation/derealisation in the general population are common, with a
      lifetime prevalence rate of between 26 and 74% and between 31 and 66% at the time
      of a traumatic event. Community surveys employing standardised diagnostic
      interviews reveal rates of between 1.2 and 1.7 % for one month prevalence in a UK
      sample and a 2.4% current prevalence rate in a Canadian sample. Current
      prevalence rates in samples of consecutive inpatient admissions are reported
      between 1 and 16%, although screening measures employed may have resulted in
      these being an underestimate. Prevalence rates in clinical samples of specific
      psychiatric disorders vary between 30% of war veterans with PTSD and 60% of those
      with unipolar depression. There is a high prevalence within panic disorder with
      rates varying from 7.8 to 82.6%. DISCUSSION: DP and DR symptoms are common in
      normal and psychiatric populations, but prevalence estimates are hampered by
      inconsistent definitions and the use of variable time-frames. Population-based
      surveys using diagnostic interviews yield prevalence rates of clinically
      significant DP/DR in the region of 1-2%. Surveys of clinical populations in which
      common screening and assessment instruments were used also yield consistently
      high prevalence rates. The use of reliable diagnostic assessments and rating
      scales is needed. The relationship between DP/DR and certain other psychiatric
      disorders (e. g. panic) suggests possible common pathophysiological or
      aetiological factors.

PMID- 15022044
TI  - Decline in Common Mental Disorder prevalence in men during the sixth decade of
      life. Evidence from the National Psychiatric Morbidity Survey.
AB  - BACKGROUND: The impact of social transitions that might improve mental health,
      such as retirement, has attracted limited attention. Adverse occupational
      conditions and involuntary exit from work are linked to high rates of common
      mental disorders, but voluntary retirement is associated with improved mental
      health. AIMS: We aimed to estimate the prevalence of common mental disorders
      around the conventional retirement age and to identify the associated factors
      that might explain differences in rates. METHODS: Data were from the Psychiatric
      Morbidity Survey of Great Britain (2000), covering a sample of 8,580 respondents
      aged 16-74 years. Current common mental (neurotic) disorder presence was based on
      the revised Clinical Interview Schedule. RESULTS: Prevalence rates for having any
      common mental disorder in men aged 65-69 years (5%; 95% CI: 2.7-7.3) were
      dramatically lower than in the agegroup 60-64 years (14.5%; 95 % CI: 10.6-18.5).
      This pattern applied to individual disorders and to the prevalence of very high
      symptoms counts. Prevalence rates in women peaked at age 50 and declined
      thereafter, but no large changes in prevalence are evident around age 60 or 65
      years. In men leaving work early (aged 50-64 years), prevalence of common mental
      disorders remains high until the conventional retirement age. There is little
      change in exposure to other studied risk factors capable of explaining prevalence
      reduction, with the exception of decreased economic hardship in the older group.
      CONCLUSION: In the general population aged 50-74 years,there is a dramatic
      improvement in mental health in men after the conventional retirement age, but
      not in women. In men who leave work earlier, prevalence remains relatively high
      until after age 65.

PMID- 15022045
TI  - Social environment and psychiatric illnessA follow-up study of 9,170 women and
      men in Sweden.
AB  - OBJECTIVE: The aim of this follow-up study is to examine whether the individual's
      social and physical environment predicts incidence rates of psychiatric illness,
      after adjusting for demographic and socio-economic characteristics. METHODS: A
      random sample of the Swedish population (9,170 women and men, aged 25-74) were
      interviewed between 1990 and 1991 and followed through December 1998 for
      incidence rates of psychiatric illness. A social participation index and a
      physical environment index were constructed, based on the interview data. Cox's
      regression was used to estimate relative risks expressed as hazard ratios (HR).
      We also stratified for self-reported long-term psychiatric illness at the time of
      the interview. RESULTS: Respondents with low scores in the social participation
      index exhibited an increased age- and sex-adjusted risk of psychiatric illness
      with an HR = 2.00 (95 % CI 1.32-3.03) compared with individuals with high scores
      in the social participation index. After inclusion of education, housing tenure
      and the physical environment index, the HR of psychiatric illness decreased only
      slightly to 1.69 (95% CI 1.07-2.66) for respondents with low scores in the social
      participation index. There was no relationship between the physical environment
      index and psychiatric illness. CONCLUSIONS: In order to prevent and treat
      psychiatric illness, it is of importance also to consider the individual's social
      environment.

PMID- 15022046
TI  - Suicide risk in small areas in England and Wales, 1991-1993.
AB  - BACKGROUND: There is growing evidence that areas characterised by high levels of
      social fragmentation have higher suicide rates. Previous ecological studies have
      focused on relatively large geographic areas and/or examined associations in all
      age groups combined. METHODS: Negative binominal regression was used to assess
      age- and sex-specific suicide rate ratios for a range of census-derived
      indicators of the social, health and economic characteristics of small areas
      (mean population aged > or = 15: 4500) in England and Wales. RESULTS: Indicators
      of social fragmentation (e. g. proportion of people living alone or population
      mobility) were most consistently associated with suicide risk. For example,
      across quartiles of wards ranked according to increasing proportions of single
      person households, age- and sex-adjusted suicide rate ratios were: 1.00, 1.05
      (1.00, 1.11), 1.14 (1.08, 1.19) and 1.42 (1.36, 1.49). Associations were
      strongest in 15 to 44 and 45 to 64 year-olds. Associations with social
      fragmentation persisted after controlling for the effect of other area
      characteristics. CONCLUSIONS: Targeted mental health promotion and social policy
      initiatives to reduce area-health inequalities in suicide might usefully focus on
      areas with high levels of social fragmentation.

PMID- 15022047
TI  - Increase in involuntary psychiatric admissions of minors. A register study.
AB  - OBJECTIVE: The aim of this study was to assess the frequency and trend over time
      of involuntary psychiatric admissions of minors, and to examine the psychiatric
      diagnoses in involuntary admissions of minors as compared to those admitted on a
      voluntary basis. METHOD: A retrospective register study was made during the
      period 1996-2000 of a nationally representative hospital discharge register in
      Finland. RESULTS: Involuntary admissions of children (aged < 12) and adolescents
      (aged 12-17) increased vastly over the study period, both in absolute figures and
      in proportion to all admissions in the age groups. Although some disorders were
      more likely to be linked to compulsory admission than others, a variety of
      individual diagnoses were represented under compulsory admission. CONCLUSION:
      More comprehensive guidance for clinicians is needed regarding the involuntary
      admission of minors. More theoretical and empirical research is needed on minors'
      competence to consent to or refuse treatment.

PMID- 15022048
TI  - Demographic, clinical, social and service variables associated with higher needs
      for care in community psychiatric service patients. The South Verona Outcome
      Project 8.
AB  - BACKGROUND: Mental health services should be provided on the basis of need. This
      study investigated a representative sample of patients attending a community
      based psychiatric service. The aim was to identify the profile of patients with
      higher needs for care, by considering a full range of potential demographic,
      clinical, social and service correlates. METHODS: A total of 268 patients using
      mental health services in South Verona, Italy, had cross-sectional assessments of
      their needs (using the Camberwell Assessment of Need), symptomatology,
      disability, functioning, quality of life, service use and satisfaction with care
      analysed using linear regression. RESULTS: A model comprising being male, being
      unemployed, having high symptomatology and disability, having low functioning and
      self-reported quality of life, and a high number of outpatient and community
      contacts accounted for 67% of the variance in total level of need. CONCLUSIONS:
      Patients who meet any of these criteria may be more likely to have higher needs,
      which has implications for clinical practice and audit. Assessment of needs for
      care by using the CAN provides a good overall measure of the number and the
      severity of a patient's problems in several key areas of everyday life.

PMID- 15022050
TI  - Perception of stigma among patients with schizophrenia.
AB  - BACKGROUND: Many individuals with schizophrenia are stigmatized by society. It is
      necessary to understand the factors contributing to stigma. This study
      investigated the relation of symptoms and other patient characteristics with
      perceived stigmatization in patients with schizophrenia. METHOD: Sixty patients
      with schizophrenia were included in the study. Symptomatology was assessed with
      the Positive and Negative Syndrome Scale. Perceived stigmatization was measured
      by several questions which were included in the World Health Organization
      Disability Assessment Schedule-II (WHODAS-II). Patients were grouped as positive
      or negative for perceived stigmatization. Characteristics of patients and
      severity of symptoms were compared between the two groups. RESULTS: The results
      showed that patients who reported to perceive stigmatization had more severe
      symptoms than the patients who did not perceive stigmatization. Positive symptoms
      and general psychopathology scores were significantly higher in the group
      perceiving stigmatization. Patients reporting stigmatization were significantly
      more disabled than the group negative for perceived stigmatization. Demographic
      variables were not different between the two groups. Stepwise regression analysis
      showed that depression and active social avoidance were the items which could
      predict the perception of stigmatization. CONCLUSION: The relation between
      perception of stigmatization and symptoms is a vicious circle in which the
      elements reinforce each other. Interruption of this circle will increase the
      adaptive abilities and decrease the disability of these patients.

PMID- 15022049
TI  - Substance misuse at presentation to an early psychosis program.
AB  - BACKGROUND: Substance misuse is a significant problem in schizophrenia. The
      purpose of this study was to examine the prevalence and correlates of substance
      misuse in individuals with a first episode of psychosis at the time they first
      present for treatment. METHOD: The first 357 consecutive admissions to a
      comprehensive early psychosis program were included. Assessment measures were the
      Positive and Negative Syndrome Scale, the Calgary Depression Scale for
      Schizophrenia, the Quality of Life Scale, the Case Manager Rating Scale and the
      Premorbid Adjustment Scale. RESULTS: Forty-four percent of the sample, the
      majority of whom used alcohol or cannabis, met diagnostic criteria for substance
      abuse/dependence. The prevalence was significantly higher than in the general
      population. Substance misuse was significantly associated with male gender, young
      age and age of onset. CONCLUSIONS: This study confirms the high rates of
      substance misuse, in particular cannabis, in first-episode psychosis.
      Implications for treatment are addressed.

PMID- 15022051
TI  - Attitudes and roles of general practitioners in the treatment of schizophrenia
      compared with community mental health staff and patients.
AB  - BACKGROUND: Most general practitioners (GPs) are currently treating a small
      number of patients with schizophrenia; however, little is known about GPs'
      experiences in this area. This paper examines the attitudes and roles of
      Australian GPs in the treatment of schizophrenia and their relationships with
      specialist services. METHODS: A total of 192 GPs' ratings of possible sources and
      forms of help for patients with schizophrenia were compared with the ratings of
      50 mental health services (MHS) staff and 129 patients. Comparisons within the
      health professionals were also made in relation to diagnostic and treatment
      confidence, perceived roles, and typical problems encountered. RESULTS: Perceived
      helpfulness ratings were reasonably consistent across groups. However, patients
      tended to rank close family members as more helpful. GPs and MHS staff reported
      complementary roles, with a shared responsibility for early detection and relapse
      prevention. Treatment compliance, and communication and accessibility to
      specialist agencies were identified as major problems. CONCLUSIONS: GPs fulfil a
      valuable role in the treatment of schizophrenia, which could be enhanced through
      improved training. Mental health services need to work more effectively with GPs
      in treating schizophrenia and acknowledge their complementary roles.

PMID- 15022054
TI  - Do squirrel monkeys (Saimiri sciureus) and capuchin monkeys (Cebus apella)
      predict that looking leads to touching?
AB  - Squirrel monkeys (Saimiri sciureus) and capuchin monkeys (Cebus apella) were
      tested using an expectancy violation procedure to assess whether they use an
      actor's gaze direction, signaled by congruent head and eye orientation, to
      predict subsequent behavior. The monkeys visually habituated to a repeated
      sequence in which the actor (a familiar human or a puppet) looked at an object
      and then picked it up, but they did not react strongly when the actor looked at
      an object but then picked up another object. Capuchin monkeys' responses in the
      puppet condition were slightly more suggestive of expectancy. There was no
      differential responding to congruent versus incongruent look-touch sequences when
      familiarization trials were omitted. The weak findings contrast with a strongly
      positive result previously reported for tamarin monkeys. Additional evidence is
      required before concluding that behavior prediction based on gaze cues typifies
      primates; other approaches for studying how they process attention cues are
      indicated.

PMID- 15022053
TI  - Comparison of breath-hold 2D phase-contrast with non breath-hold cine phase
      contrast MRA in the assessment of azygos venous blood flow in portal
      hypertension.
AB  - Azygos venous blood flow as an index of blood flow through the gastroesophageal
      collaterals and varices is of value in the prediction of gastrointestinal
      bleeding. Measurement of azygos venous blood flow has been achieved by non breath
      hold (NBH) cine phase-contrast magnetic resonance imaging. The objective of this
      study was to compare the faster breath-hold (BH) phase-contrast technique with
      the standard (NBH) cine phase-contrast technique in the measurement of azygos
      blood flow. Thirty-two cirrhotic patients with esophageal varices were examined
      by magnetic resonance imaging using a BH technique and a NBH cine phase-contrast
      technique to measure the flow velocity, flow volume and calibre of the azygos
      vein at the mid-right atrial level. The flow values were obtained on the velocity
      image of the phase-contrast study. Values obtained from the two methods were
      evaluated statistically for the strength and significance of correlation by the
      Pearson test. Measurement by the BH method performed at full-inspiration as well
      as end-expiration was also obtained in 15 healthy volunteers. The breath-hold
      phase-contrast method has significant but weak correlation with non BH cine phase
      contrast method in the measurement of azygos venous blood flow volume (r = 0.55,
      p < 0.01) and flow velocity (r = 0.43, p = 0.01). However, the calibre of the
      azygos vein gave a strong correlation in these two methods (0.82). In the
      subgroup of patients whose azygos blood flow velocity was greater than 7.4 cm/s,
      the correlation of azygos blood flow volume is strong (r = 0.80, p < 0.01). The
      azygos vein calibre remains highly correlated between the BH and NBH method, in
      both high flow velocity (r = 0.73) and low flow velocity (r = 0.83) groups.
      Breath-hold sequence leads to higher values for flow velocity and flow volume in
      the cirrhotic patients and also the control group. In patients with portal
      hypertension, BH 2D phase-contrast (PC) magnetic resonance angiography (MRA)
      could give a comparable estimation of the calibre of the azygos vein as the NBH
      2D cine PC MRA but not for azygos flow volume. In patients with high azygos flow
      velocity, the strong correlation in flow volume between the BH and NBH method
      suggests that the BH method may be a time-saving alternative to the NBH method.

PMID- 15022055
TI  - Transport of tools to food sites in tufted capuchin monkeys (Cebus apella).
AB  - Tool use and transport represent cognitively important aspects of early hominid
      evolution, and nonhuman primates are often used as models to examine the
      cognitive, ecological, morphological and social correlates of these behaviors in
      order to gain insights into the behavior of our early human ancestors. In 2001,
      Jalles-Filho et al. found that free-ranging capuchin monkeys failed to transport
      tools (stones) to food sites (nuts), but transported the foods to the tool sites.
      This result cast doubt on the usefulness of Cebus to model early human tool-using
      behavior. In this study, we examined the performance of six captive tufted
      capuchin monkeys (Cebus apella) in a tool transport task. Subjects were provided
      with the opportunity to transport two different tools to fixed food reward sites
      when the food reward was visible from the tool site and when the food reward was
      not visible from the tool site. We found that the subjects quickly and readily
      transported probing tools to an apparatus baited with syrup, but rarely
      transported stones to a nut-cracking apparatus. We suggest that the performance
      of the capuchins here reflects an efficient foraging strategy, in terms of energy
      return, among wild Cebus monkeys.

PMID- 15022057
TI  - Subglottic ductal cysts associated with complete tracheal ring deformity:
      coexistence of two rare airway abnormalities with fatal outcome.
AB  - Subglottic cysts are rare and may cause airway obstruction. Most cases are
      acquired secondary to endotracheal intubation, even short-term, particularly in
      the premature neonate. Complete tracheal rings are rare anomalies associated with
      tracheal stenosis. To our knowledge, the two have not been reported coexisting. A
      16-month-old ex-premature boy was found unresponsive, with his tracheostomy tube
      dislodged. Tracheomalacia, subglottic stenosis, and a laryngeal cyst had been
      diagnosed shortly after birth, and the cyst was surgically treated at that time.
      At autopsy, a complete tracheal ring was noted in the subglottic region, above
      the tracheostomy site, and the tracheal diameter was markedly decreased in this
      area. In addition, multiloculated cysts were present at that level, arising from
      both anterolateral tracheal walls. These completely occluded the airway. To our
      knowledge, this is the first case of a combination of tracheal ring anomaly and
      subglottic cysts. Pediatric pathologists must be aware of iatrogenic lesions
      associated with care of the premature neonate, particularly as the age of
      viability continues to decrease.

PMID- 15022058
TI  - Congenital fibrosarcoma with metastasis in a fetus.
AB  - It is well known that congenital or infantile fibrosarcoma has a much less
      aggressive behavior than fibrosarcoma in adults, and it rarely metastasizes. We
      report a case of congenital fibrosarcoma in a 26-wk-old fetus, the diagnosis of
      which was made by an in utero needle core biopsy. Metastatic tumors were
      identified at autopsy when the pregnancy was terminated 3 wk later. English
      literature of metastatic congenital fibrosarcoma was also reviewed.

PMID- 15022059
TI  - Case of large placental chorioangioma associated with diffuse neonatal
      hemangiomatosis.
AB  - Chorioangioma is the most frequent nontrophoblastic tumor of the placenta with a
      incidence ranging from 0.01 to 1.3%. Vascular anomalies of the placenta
      coincidental with infantile hemangioendothelioma (IH) of the liver are rarely
      described. Here we report a case of a large chorioangioma of the placenta
      associated with cutaneous hemangiomatosis and IH of the liver. The relationship
      between hemangiomas and placental chorioangioma is discussed.

PMID- 15022060
TI  - Cytogenetic distinction among benign fibro-osseous lesions of bone in children
      and adolescents: value of karyotypic findings in differential diagnosis.
AB  - Benign fibro-osseous lesions of bone (BFOL) comprise a group of clinically
      distinct entities with significant histologic overlap and often occur in children
      and adolescents. Because of prior studies indicating that these lesions possess
      distinct karyotypic abnormalities, we conducted a retrospective review of
      cytogenetic analyses performed in a series of 16 BFOL in children and adolescents
      diagnosed at two institutions. These comprised five cases with the diagnosis of
      ossifying fibroma, four with osteofibrous dysplasia, and seven with fibrous
      dysplasia arising in the skeleton of 16 children and adolescents. All cases were
      analyzed using standard G-banding techniques on fresh tumors explanted in tissue
      culture media. Spectral karyotyping (SKY) and fluorescence in situ hybridization
      (FISH) were used to analyze selected metaphases of a talar lesion with the
      histologic features of ossifying fibroma. All four confirmed ossifying fibromas,
      including the talar lesion, contained clonal aberrations fusing breakpoints on
      Xq26 and 2q33, and one case with dissimilar histology did not. Three of four
      osteofibrous dysplasias contained multiple copies of chromosomes 8, 12, and/or
      21. All but two fibrous dysplasia cases exhibited either a completely normal
      karyotype or single cell aberrations. One fibrous dysplasia had subtle
      chromosomal abnormalities not seen in other cases in the series, and another had
      complex abnormalities involving multiple chromosomes. Our current and published
      results indicate that cytogenetics might be of ancillary use in the diagnosis of
      BFOL and that a characteristic chromosomal arrangement is associated with
      ossifying fibroma.

PMID- 15022062
TI  - Epstein-Barr virus-associated smooth muscle tumor of the basal ganglia in an HIV+
      child: case report and review of the literature.
AB  - We describe the clinicopathologic features of an Epstein-Barr virus (EBV)
      associated smooth muscle tumor arising in the basal ganglia of a 10-year-old
      human immunodeficiency virus (HIV)-positive child. Only a few cases of
      intracranial smooth muscle tumors are reported in the literature and virtually
      all of these have been extra-axial, involving the dura or sinuses in HIV+ adults.
      Our case underscores the need to include an EBV-associated smooth muscle tumor in
      the differential diagnosis when evaluating intracranial mass lesions in
      immunodeficient children.

PMID- 15022063
TI  - Maternal vascular underperfusion: nosology and reproducibility of placental
      reaction patterns.
AB  - Placental examination can be a useful tool for specifying the etiology,
      prognosis, and recurrence risk of pregnancy disorders. The purpose of this study
      was to test the reliability of a predetermined set of placental reaction patterns
      seen with maternal vascular underperfusion in the hope that this might provide a
      useful diagnostic framework for practicing pathologists. Study cases (14 with
      clinical and pathologic evidence of maternal underperfusion plus 6 controls) were
      evaluated for the presence or absence of 11 lesions by eight perinatal
      pathologists. After analysis of initial results, diagnostic criteria were refined
      and a second, overlapping set of cases was reviewed. The collective sensitivity,
      specificity, and efficiency of individual assessments for the 11 lesions relative
      to the group consensus ranged from 74-93% (22/33 > 90%). Reproducibility was
      measured by unweighted kappa-values and interpreted as follows: < 0.2 poor, 0.2
      0.6 fair/moderate, > 0.6 substantial. Kappa values for lesions affecting villi
      and the intervillous space were increased syncytial knots (any -0.42, severe 
      0.50), villous agglutination (0.42), increased intervillous fibrin (0.25), and
      distal villous hypoplasia (0.57). Individual estimates of percent involvement for
      syncytial knots, intervillous fibrin, and distal villous hypoplasia were
      correlated with placental and fetal weight for gestational age. Extent of
      increased intervillous fibrin showed the strongest correlation with both
      placental weight ( R = -0.64) and fetal weight ( R = -0.45). Kappa values for
      lesions affecting maternal vessels and the implantation site were acute atherosis
      (0.50), mural hypertrophy of membrane arterioles (0.43), muscularized basal plate
      arteries (0.48), increased placental site giant cells (0.54), and immature
      intermediate trophoblast (0.36). Correlation of maternal vessel and implantation
      site lesions with the clinical diagnosis of preeclampsia showed that excessive
      placental site giant cells and immature intermediate trophoblast were more
      sensitive and efficient predictors, whereas atherosis and muscularized basal
      plate arteries were more specific. Kappa value for a thin umbilical cord, a
      possible indicator of fetal volume depletion, was 0.61. Reproducibility for a
      global impression of maternal vascular underperfusion, taking into account all of
      the above lesions, was moderate (kappa 0.54) and improved after inclusion of
      additional pathologic and clinical data (kappa 0.68). Adoption of this clearly
      defined, clinically relevant, and pathologically reproducible terminology could
      enhance clinicopathologic correlation and provide a more objective framework for
      future clinical research.

PMID- 15022064
TI  - Optimal diagnostic testing for urinary tract infection in young children.
AB  - Urinary tract infection (UTI) is a major concern in young febrile children.
      Current recommendations favor use of urine obtained by bladder catheterization or
      aspiration, but opinion varies as to the best ancillary tests to predict a
      positive culture and guide initial management. The utility of dipstick leukocyte
      esterase, blood, and nitrite; unspun urine leukocyte count; gram stain of
      cytocentrifuged urine; and standard spun sediment examination was evaluated in
      142 febrile, < 5-year-old children seen in the Emergency Department, 25 of whom
      had culture-proven UTI. Using sensitivity and negative predictive values as
      criteria for performance, unspun urine leukocyte count and gram stain of
      cytocentrifuged urine used in parallel was the best approach but still failed to
      detect some UTI. Analysis of the nature of the specimens evaluated provided
      explanation of differences from previous observations. Adoption of this modified
      approach to prediction of urinary tract infection appears to improve prediction
      but has operational implications and creates potential problems for the
      laboratory.

PMID- 15022065
TI  - HBL-3 cell line, derived from precursor B-cell lymphoblastic leukemia, lacks
      somatic hypermutation of immunoglobulin heavy chain variable region genes.
AB  - Somatic mutation (SM) analysis provides a useful tool for understanding the
      stages at which neoplastic differentiate from normal B-cells. B-cell precursor
      neoplasms are considered to be somatically premutational. However, the variable
      frequency of SM of the variable region (VH) genes has been described in cases of
      precursor B-cell acute lymphoblastic leukemia (PB-ALL). To better characterize PB
      ALL based on the differentiation stage, we investigated the SM of the VH genes
      expressed by tumor cells of the surface immunoglobulin (sIg)(-) HBL-3 cell line
      derived from childhood PB-ALL. In the HBL-3 cell line, the rearranged Ig heavy
      chain VH gene sequence showed no SM in the complementarity-determining regions of
      1, 2, and 3, or in the framework regions of 1, 2, and 3 relative to the putative
      germline VH gene sequences. In addition, the VH segment of HBL-3 cells showed no
      intraclonal sequence heterogeneity, indicating ongoing SM. Our data demonstrated
      that HBL-3 cells express unmutated and developmentally regulated rearrangement of
      VH genes at the stage of B-cell precursor cells. HBL-3 cells, which are derived
      only from the sIg(-) PB-ALL, showed that SM cannot be recognized in VH genes of
      tumor cells before the expression of sIg.

PMID- 15022066
TI  - Placental findings after laser ablation of communicating vessels in twin-to-twin
      transfusion syndrome.
AB  - As laser ablation of placental vascular communications gains acceptance as
      treatment option for severe twin-to-twin transfusion syndrome (TTTS),
      pathologists are increasingly confronted with the interpretation of laser-treated
      placentas. We present our preliminary institutional experience with the gross and
      microscopic analysis of these specimens. Patients underwent selective ablation
      for severe TTTS (Quintero stages II to V) between 16 and 25 wk gestation and the
      placentas were examined between < 24 h and 19 wk postoperatively. The placental
      vasculature was injected with gelatin-dye mixtures. The type and number of
      vascular anastomoses were recorded, followed by routine histopathological
      analysis of the placenta. Foci of laser impact were identified in all placentas
      examined within 1 month after laser coagulation. Located along the recipient side
      of the dividing membrane, the laser-treated vessels appeared hemorrhagic and
      showed a characteristic abrupt interruption of dye filling after vascular
      injection. In placentas examined more than 1 month after intervention, the most
      frequent gross finding was the absence or relative paucity of intertwin
      anastomoses, associated with subchorionic fibrin deposition. Microscopically,
      laser-treated vessels showed varying degrees of necrosis, associated with focal
      hemorrhage, avascular villi, and fibrin deposition in the underlying parenchyma.
      In some cases of intrauterine fetal demise or placental disruption, no definite
      laser scars were identified. As expected, the number of residual anastomoses (all
      types) was significantly smaller in laser-treated placentas than in control
      monochorionic placentas (2.4 +/- 2.2 [ n = 10] vs. 6.2 +/- 3.2 [ n = 70], P <
      0.01). Velamentous cord insertion was noted in 50% of cases; markedly uneven
      placental sharing in 60%. Detailed analysis of laser-treated placentas and
      clinicopathological correlation may lead to a better understanding of the
      pathophysiology of TTTS and continued refinement of therapeutic approaches for
      this often lethal condition.

PMID- 15022067
TI  - Liver involvement in the histiocytic disorders of childhood.
AB  - The liver can be involved directly, by infiltration, and indirectly--by remote
      effects--in the histiocytoses of childhood. Langerhans cell disease, the most
      well recognized of these, infiltrates the liver directly but has a remarkable
      selectivity for the bile ducts. Early involvement is by Langerhans cell
      histiocytosis (LCH) infiltration leading to a sclerosing cholangitis and,
      eventually, biliary cirrhosis. Gamma glutamyl transpeptidase is a sensitive
      indicator of liver infiltration in a child with LCH. The indirect effects on the
      liver of LCH elsewhere in the body are mediated through an accompanying
      macrophage activation syndrome that is most likely responsible for hepatomegaly
      and hypoalbuminemia but without direct infiltration. These indirect effects are
      completely reversible. Juvenile xanthogranuloma/xanthoma disseminatum, a related
      dendritic cell disorder that can have systemic manifestations, has a strikingly
      different pattern, with a predominantly portal infiltrate spilling over into the
      adjacent lobule but sparing the biliary tree. The biology of the liver lesions is
      not clear but regression has been documented. Myeloproliferative disorders and
      myeloid leukemias can express CD1a and/or S100 protein, mimicking LCH but
      distinguished by their sinusoidal pattern. The primary macrophage histiocytoses
      such as the familial hemophagocytic syndromes can lead to severe liver damage.
      Although a portal lymphohistiocytic infiltrate is most characteristic, it is
      probably cytokine-mediated hepatocellular damage that can cause substantial
      functional impairment or even hepatic failure as a presenting feature. Liver
      involvement in other, more unusual histiocytic disorders, is also illustrated.

PMID- 15022069
TI  - Malignant peripheral nerve sheath tumor arising from an adrenal ganglioneuroma in
      a 6-year-old boy.
AB  - This report describes the youngest patient to develop a malignant peripheral
      nerve sheath tumor arising from a ganglioneuroma (MPNST ex Ganglioneuroma). The
      patient, a 6-year-old boy, was never irradiated and had no history or stigmata of
      neurofibromatosis. The report also includes a review of the previously published
      related cases, and an analysis of the immunohistochemistry and electron
      microscopy data available to date on the subject.

PMID- 15022071
TI  - Collapsing glomerulopathy in a 16-year-old girl with pulmonary tuberculosis: the
      role of systemic inflammatory mediators.
AB  - Idiopathic collapsing glomerulopathy is an aggressive variant of focal segmental
      glomerulosclerosis (FSGS) seen primarily in adults. Its etiology is unknown.
      Nearly identical pathology is seen in association with nephrotic syndrome in
      human immunodeficiency virus type 1 (HIV-1)-infected patients, raising the
      possibility that viral infection plays a role in pathogenesis. This is supported
      by the recent discovery of parvovirus B19 DNA in some cases of idiopathic
      collapsing glomerulopathy. We report a case of collapsing glomerulopathy in a 16
      year-old girl who presented with steroid-resistant nephrotic syndrome and
      pulmonary tuberculosis. In the absence of the usual associations (adult age
      group, African-American race, or history of intravenous drug abuse), infection is
      the sole known risk factor in this case. This lends support to the hypothesis
      that immune dysregulation due to infection per se, rather than infection by
      specific viral agents, may lead to collapsing glomerulopathy in susceptible
      individuals.

PMID- 15022073
TI  - Pediatric forensic pathology in crisis.

PMID- 15022074
TI  - Congenital cystic adenomatoid malformation type 4 and aneurysm of the vein of
      Galen: a rare coincidence or possibly related association.
AB  - As far as the prognosis is concerned, it is important to diagnose the exact type
      of congenital cystic adenomatoid malformation (CCAM) in order to exclude
      associated anomalies, as well as the risk of development of malignancies in later
      life. The frequency of associated malformations of CCAM type 4 is unknown. We
      report a 4-month-old boy with CCAM type 4 and aneurysmal malformation of the vein
      of Galen (AVG). Although AVG is the most frequent arteriovenous malformation
      during childhood, this is the first case report, to our knowledge, of CCAM type 4
      in association with an anomaly. In addition, we speculate that the relation
      between CCAM type 4 and AVG appears to be more likely a possibly related
      association rather than a rare coincidence, as both malformations develop at the
      same stages of embryonic life, and pathogenetically, apoptosis play a significant
      role in both entities. However, further studies are needed to validate this
      speculation placing emphasis on the association of the two anomalies, otherwise a
      rare coincidence cannot be excluded.

PMID- 15022077
TI  - Preliminary study on the cytoarchitecture of the human parabrachial/Kolliker-fuse
      complex, with reference to sudden infant death syndrome and sudden intrauterine
      unexplained death.
AB  - The parabrachial/Kolliker-Fuse complex has been defined, in different animal
      species, to lie in the dorsolateral part of the pontine tegmentum and to be
      subdivided into three well-defined regions: the medial parabrachial nucleus, the
      lateral parabrachial nucleus, and the Kolliker-Fuse nucleus. Experimental studies
      have shown that the parabrachial/Kolliker-Fuse complex is involved in a variety
      of functional activities and above all plays an important role in respiratory
      modulation. In human brainstem, the cytoarchitecture and physiology of this
      complex have not yet been fully characterized. The aim of the present study was
      to examine fetal and infant human brainstems in order to define the precise
      morphology of the three nuclei of the parabrachial/Kolliker-Fuse complex, and to
      determine whether this nervous center shows morphologic alterations in sudden
      infant death syndrome (SIDS) and in sudden intrauterine unexplained death (SIUD).
      In serial sections of 31 brainstems of subjects aged from 32 gestational wk to 10
      months of life, we studied, by morphologic and morphometric analyses, the
      cytoarchitecture and the extension of the three nuclei of the
      parabrachial/Kolliker-Fuse complex. All the morphometric parameters were very
      similar in SIUD and SIDS cases to those of the respective control group, as shown
      by the absence of significant statistical differences between the two fetus and
      infant groups. We observed that the features of both the lateral and the medial
      parabrachial nuclei are largely consistent with those reported in experimental
      studies. In contrast, the Kolliker-Fuse nucleus appears to be more developed in
      human beings than in other animal species, showing a greater extension and a more
      complex structure, as well as subdivision into two subnuclei (compactus and
      dissipatus).

PMID- 15022078
TI  - Expression of cytokeratins 7 and 20 in Helicobacter pylori-associated chronic
      gastritis in children.
AB  - Helicobacter pylori gastric infection induces structural changes in the gastric
      epithelium. Among them, variations in the expression of cytokeratins have been
      reported in adult patients. In the present study, we describe the expression of
      CK7 and CK20 in gastric samples taken from the antrum in three groups of
      pediatric patients: (A) Helicobacter pylori-associated chronic gastritis (mean
      age: 11.4 years); (B) previous H. pylori chronic gastritis patients (mean age:
      9.4 years); and (C) controls (mean age: 8.8 years). In all, the presence of
      sulfomucins was assessed with Alcian blue-periodic acid-Schiff pH 1.0.
      Immunoreactivity was graded as absent (0), weak (1+), moderate (2+), or intense
      (3+), in accordance with the intensity of the staining, and its distribution as
      focal or diffuse. CK7 reactivity was 2+ either focal or diffuse in all group A
      biopsies. The reactivity was more evident in the cells at the neck of the glands,
      in the areas with more inflammatory infiltrates, decorating long vertical
      segments of epithelium. In groups B and C, CK7 reactivity was also focal and 1+
      at the cells of the necks of the glands. However, group B presented longer
      vertical segments of positive cells as compared to group C, and shorter than
      those of group A. The deeper glandular structures were focally 1+ in both groups.
      CK20 expression was comparable in all three groups, depicting a 2+ diffuse
      reactivity at the surface epithelium and interposed pits with absence or focal
      reactivity at the neck and coiled gland areas. Ki-67 immunostaining paralleled
      that of the CK7. Staining for sulfated mucosubstances was positive in two of five
      cases of groups A and B, and in none of the cases of group C. We conclude that:
      (1) the long segments of CK7-positive glandular necks in H. pylori cases most
      probably indicate intense regenerative activity during active inflammation; (2)
      eradication of H. pylori does not warrant ad integrum restitution since long
      segments of Ki-67+, CK7+ cells at the germinative compartment of the glands (as
      well as cells with sulfomucins) were still recognizable in ex- H. pylori
      patients; (3) finally, differing from what happens in adults, children somehow
      manage to maintain fully differentiated CK20+ superficial epithelium while the H.
      pylori is in action.

PMID- 15022104
TI  - 3D QSAR studies on peroxisome proliferator-activated receptor gamma agonists
      using CoMFA and CoMSIA.
AB  - The peroxisome proliferator-activated receptors (PPARs) have increasingly become
      attractive targets for developing novel anti-type 2 diabetic drugs. We employed
      comparative molecular field analysis (CoMFA) and comparative molecular similarity
      indices analysis (CoMSIA) to study three-dimensional quantitative structure
      activity relationship (3D QSAR) based on existing agonists of PPARgamma
      (including five thiazolidinediones and 74 tyrosine-based compounds). Predictive
      3D QSAR models with conventional r2 and cross-validated coefficient (q2) values
      up to 0.974 and 0.642 for CoMFA and 0.979 and 0.686 for COMSIA were established
      using the SYBYL package. These models were validated by a test set containing 18
      compounds. The CoMFA and CoMSIA field distributions are in general agreement with
      the structural characteristics of the binding pockets of PPARgamma, which
      demonstrates that the 3D QSAR models built here are very useful in predicting
      activities of novel compounds for activating PPARgamma.

PMID- 15022105
TI  - A new subtilisin family: nucleotide and deduced amino acid sequences of new high
      molecular-mass alkaline proteases from Bacillus spp.
AB  - Six genes encoding high-molecular-mass subtilisins (HMSs) of alkaliphilic
      Bacillus spp. were cloned and sequenced. Their open reading frames of 2,394-2,424
      bp encoded prosubtilisins of 798-808 amino acids (aa) consisting of the
      prepropeptides of 151-158 aa and the mature enzymes of 640-656 aa. The deduced aa
      sequences of the mature enzymes exhibited 60-95% identity to those of FT protease
      of Bacillus sp. strain KSM-KP43, a subtilisin-like serine protease, and a minor
      serine protease, Vpr, of Bacillus strains. Three of the six recombinant enzymes
      were susceptible to proteolysis, but the others were autodigestion resistant. All
      enzymes had optimal pH values of 10.5-11.0, optimal temperatures of 40-45 degrees
      C for hydrolysis of a synthetic substrate, and were heat labile. These alkaline
      proteases seem to form a new subtilisin family, as judged by their aa sequences
      and phylogenetic analysis.

PMID- 15022106
TI  - Clinicopathological study of the WHO classification in childhood lupus nephritis.
AB  - Over the past 10 years, at our center, 25 children diagnosed with systemic lupus
      erythematosus (SLE) have undergone an early renal biopsy; 15 underwent a second
      biopsy. The objective of this study was to determine whether clinical and
      laboratory parameters used to evaluate lupus disease activity and nephritis
      correlated with the WHO class on biopsy. At diagnosis, the presence of
      proteinuria, hematuria, a lower serum albumin, and the need for blood pressure
      medication were all associated with a worse class of lupus nephritis ( P<0.05).
      On follow-up biopsy, however, none of these parameters correlated with the WHO
      class. Thus, it appears that while the WHO classification is useful for
      categorizing disease at presentation, it may be less useful for the evaluation of
      disease progression. Other biopsy indices need to be evaluated in serial renal
      biopsies to better understand the progression of lupus nephritis once treatment
      has been initiated.

PMID- 15022107
TI  - Usefulness of an automated urinary flow cytometer in mass screening for
      nephritis.
AB  - We aimed to assess the utility of a newly developed automated urinary flow
      cytometer (UFCM) in differentiating the origin of hematuria in the mass screening
      system for renal diseases in school children. In total, 4,620 children aged 6-14
      years with abnormal urinary findings by the screening program in Tokyo were
      enrolled. Tentative diagnoses were made based on the criteria for this screening
      program: nephritis in 11, suspected nephritis in 104, hematuria in 771, minimal
      hematuria in 1,506, proteinuria in 477, urinary tract infection in 83, and
      healthy in 1,668. Glomerular hematuria, assessed by UFCM, was found in 81.8% of
      nephritis, 58.7% of suspected nephritis, 59.7% of hematuria, 57.4% of minimal
      hematuria, 13.4% of proteinuria, and 21.5% of the healthy group. The presence of
      glomerular hematuria assessed by UFCM had a sensitivity of 61.0%, specificity of
      78.5%, positive predictive value of 16.3%, and negative predictive value of 96.7%
      for the diagnosis of nephritis and suspected nephritis. Thus, our results imply
      that the absence of glomerular hematuria as assessed by UFCM is highly predictive
      of the absence of nephritis. If "healthy" children with non-glomerular hematuria
      by UFCM could be excluded, the total annual cost saving would be approximately
      147.4 million JPY, which is equivalent to 5.2% of the current system. In
      conclusion, a simple, automated and rapid test for glomerular hematuria using
      UFCM is useful for mass screening. It can precisely predict children with only
      transient hematuria who do not have any serious illness, and therefore can
      exclude further unnecessary examinations, resulting in the improvement of cost
      effectiveness of the current program.

PMID- 15022108
TI  - The effect of heparin on graft thrombosis in pediatric renal allografts.
AB  - Graft thrombosis is an important cause of early (<4 weeks) renal graft loss.
      Reports show that heparin reduces the incidence of early renal allograft
      thrombosis. Routine peri-operative administration of unfractionated heparin was
      introduced in our unit in 1994. We conducted a retrospective study of 254
      transplants, undertaken in children, between 1987 and 2000. There were 126
      children who did not receive heparin (group 1) and 128 who did (group 2).
      Recipient characteristics and immunosuppression were similar in both groups. The
      incidence of graft loss secondary to thrombosis was compared between the groups.
      Variables previously identified with increased risk of graft loss, including
      donor age, recipient age, cold ischaemia time (CIT), multiple donor vessels,
      surgical complications, and side of graft donation, were examined using logistic
      regression. Thrombosis occurred in 14 grafts in group 1 and 11 grafts in group 2
      (odds ratio 0.7, 95% confidence interval 0.3-1.6, P=not significant). The mean
      time to graft loss was similar in groups 1 and 2 (6.6, SD 3.9, range 2-12 days
      and 7.9, SD 4.4, range 1-14 days, respectively) ( P=0.445). Young recipient age (
      P=0.006), young donor age ( P=0.009), increasing CIT ( P=0.007), and surgical
      complications ( P=0.002) increased the risk of graft thrombosis. A reduction in
      the incidence of early renal allograft thrombosis upon introduction of heparin
      was not demonstrated.

PMID- 15022109
TI  - [Gastroenterological oncology].

PMID- 15022110
TI  - [Buried bumper - a new method of non-surgical removal].
AB  - Buried bumper syndrome is a rare complication among patients with PEG for long
      term feeding. Tight fixation of the external bumper causes pressure necrosis
      beneath the internal bumper. This leads to the internal bumper's penetration of
      the deeper gastric wall, where it is completely overgrown by gastric mucosa. A
      method is shown how the buried bumper can be removed without an operation. This
      method was used successfully in seven patients. The buried bumper syndrome can be
      avoided with careful precautions.

PMID- 15022112
TI  - Perforation of a pancreatic pseudocyst induced by abdominal sonography.
AB  - A fifty-year-old man complained of abdominal pain, nausea, loss of appetite,
      postprandial vomiting and loss of weight. Abdominal sonography revealed a chronic
      calcifying pancreatitis with a tubular stenosis of the common bile duct,
      dilatation of the pancreatic duct and multiple pancreatic duct stones. Distal of
      the pylorus there was an intramural pseudocyst, which had led to the obstruction
      of the duodenal lumen. Shortly after the ultrasound examination abdominal pain
      increased. In addition, an elevation of serum lipase levels was noted, but
      reclined rapidly the next day and was normalized a few days later. The patient
      was well the next morning, the symptoms of gastric retention disappeared and he
      had a good appetite. A CT of the abdomen two days later showed the chronic
      pancreatitis but could not confirm the pseudocyst and a subsequent repeat
      sonography revealed only a remnant of the pseudocyst. In conclusion it can be
      assumed that the intramural pseudocyst ruptured when pressure was applied with
      the ultrasound transducer to displace interfering colonic gas. Although it cannot
      be advised as a treatment measure for a pseudocyst, regression of a pseudocyst
      due to emptying into the gastrointestinal tract has to be expected.

PMID- 15022111
TI  - [Gastrointestinal stromal tumors: a broad clinical spectrum from incidental 
      discovery to acute gastrointestinal bleeding].
AB  - Three cases of gastrointestinal stromal tumors (GIST) are reported as typical
      examples of the broad clinical spectrum in which these rare tumors can be
      detected. The first case describes an 82-year-old patient with a hemorrhagic
      shock due to upper gastrointestinal bleeding from a GIST of the stomach. GIST
      most frequently present with either gastrointestinal bleeding, abdominal pain or
      a detectable mass on physical examination or by ultrasound imaging. Clinically
      asymptomatic tumor growth also occurs as demonstrated by the second case of a 44
      year-old -woman with an incidental finding of GIST during surgery of the
      esophagus. The cases are used to discuss the consequences for therapy and
      prognosis resulting from the heterogeneity of this tumor entity; the relevant
      immunohistochemical markers used to distinguish between various tumor subtypes of
      gastrointestinal mesenchymal tumors (GIMT) are listed. Since gastrointestinal
      stromal tumors (GIST) represent the most common subgroup of GIMT, we focus on the
      clinicopathological prognostic factors of GIST. The third case of a 40-year-old
      patient with a malignant GIST recurrence after surgery and exhibiting secondary
      resistance after one year of successful therapy with the receptor tyrosine kinase
      inhibitor imatinib (Gleevec), antagonizing pathogenetically relevant constitutive
      c-KIT activation, illustrates the potential and limitations of the only effective
      drug treatment for advanced GIST.

PMID- 15022113
TI  - [Position paper on capsule endoscopy for the diagnosis of small bowel disorders].

PMID- 15022114
TI  - [Pancreatic carcinoma].
AB  - Despite considerable progress in the areas of epidemiology and molecular
      genetics, pancreatic cancer is still characterized by a dismal prognosis. The
      current overview attempts a critical analysis of the published data resulting in
      recommendations for diagnostic and therapeutic algorithms. The diagnostic work-up
      of suspected pancreatic cancer patients includes an initial abdominal ultrasound
      which in case of ambiguous results or the absence of distant metastases is
      followed by "one-stop-MRI" and explorative laparotomy. Locally confined tumour
      disease should proceed to resective surgery which however results in cure only in
      a minority of resected patients even in specialized centers. Adjuvant
      chemotherapy might be of some benefit in terms of survival. Locally advanced but
      irresectable disease can be considered for combined radiochemotherapy. Systemic
      chemotherapy with Gemcitabine -results in marginal benefit of overall survival
      and may offer clinical benefit to a subgroup of patients. Best supportive care
      still remains the mainstay of irresectable disease. This summary highlights the
      urgent need for the development of innovative diagnostic and therapeutic
      strategies.

PMID- 15022115
TI  - [(13)C-breath tests for the assessment of liver function].
AB  - Routine work-up of hepatic diseases is performed by regular laboratory tests
      which indicate changes in the metabolic capacity of various hepatic cellular
      systems. A (13)C-based breath test may offer further selective characterisation
      of hepatic enzymes by means of a non-invasive technique. We present an overview
      on current test systems and their potential relevance in the assessment of
      hepatic diseases.

PMID- 15022118
TI  - [Peak torque and proprioception at the ankle of dancers in professional
      training].
AB  - The ankle is a frequent site of injury for dancers. The aim of the controlled
      study was to examine the proprioceptive and sensorimotor control of the ankle in
      a group of dancers in professional training and to compare it with persons unused
      to physical training. The purpose was to investigate whether dance training
      influences the torque ratio of plantar flexion to dorsiflexion (PF/DF) and the
      proprioceptive performance compared to controls. 42 dancers (31 f, 11 m) in
      professional training and 40 sex- and age-matched controls performed a isokinetic
      peak torque test, a passive angle-reproduction test (Biodex System 3), and a
      single-limb-standing test. The female dancers showed a significantly higher peak
      torque ratio PF/DF at 30 degrees/s. The difference between male dancers and the
      controls did not reach a significant level. The dancers did not demonstrate lower
      absolute errors in passive angle-reproduction (5 degrees and 25 degrees PF) than
      controls. In the single-limb-standing test, the dancers achieved significantly
      better results than controls. Dancers could profit from special training of the
      dorsiflexors. In view of the balance deficits, coordinative exercises should be
      integrated into school and recreational sports more frequently.

PMID- 15022119
TI  - [Fractures of the lower leg in professional skiers].
AB  - Fractures of the lower leg due to skiing accidents remain an important concern.
      Few studies have focussed on the special demands of professional athletes who
      sustain these injuries. We present our experience with three cases of lower leg
      fractures in competitive professional downhill skiers and discuss management and
      treatment concepts. We performed limited reamed compression nailing in all the
      patients presented because it offers the advantages of high mechanical stability
      and optimized fragment apposition. Plate osteosynthesis of the fibula is not
      required in most typical fractures. All patients resumed ski training. Two of
      them returned to World Cup. Only one achieved her pre-injury World Cup level of
      performance and success. In conclusion, a successful return for professional
      skiers with lower leg fractures is feasible using an optimized treatment
      strategy.

PMID- 15022121
TI  - [Traumatic anterior dislocation of the sportsman's hip].
AB  - We report on a 46-year-old male patient without any prior deformities who got a
      luxation of the right hip when he played soccer. After the immediate reposition
      during general anaesthesia the patient is symptom-free up to now. Luxations after
      hip replacement are indeed well-known and common, but this traumatic luxation in
      an adult patient is an unusual sports injury.

PMID- 15022120
TI  - [Treatment of the avulsion of the distal biceps tendon by anatomic reinsertion
      with suture anchors by using a limited anterior approach--follow-up of 24
      patients].
AB  - Avulsion of the distal biceps tendon is a clear indication of operative therapy.
      Different techniques have been described. From 10/97 till 4/02 we have treated 25
      patients with avulsion of the distal biceps tendon by anatomic reinsertion at the
      radial tuberosity with suture anchors by using a limited anterior approach. 24
      patients underwent a clinical follow-up of at least 3 months, the average follow
      up was 15.8 months. All patients were men with a mean age of 46 years (32-64
      years). Surgery was performed within 9 days (1-28 days) after trauma. No wound
      healing complication was observed. 2-3 suture anchors have been used in each
      patient. After 3 months, most patients reached a free range of motion and full
      strength with unlimited recreational and professional activity. In three cases
      (12.5 %) a heterotopic ossification occurred, two of them (8.3 %) underwent
      surgical revision. In one case (4.2 %) we observed a rerupture after 6 weeks. 6
      patients (12.5 %) described an intermittent disturbance of sensitivity in their
      radial forearm, in two cases (8.3 %) the lack of sensitivity persisted. Each
      patient would choose the same procedure in case of injury.

PMID- 15022122
TI  - [Competitive karate and the risk of HIV infection--review, risk analysis and risk
      minimizing strategies].
AB  - Bleeding facial injuries are not uncommon in competitive karate. Nevertheless,
      the risk of an infection with HIV is extremely low. Guidelines about the
      prevention of HIV infections are presented. Especially in contact sports and
      martial arts the athletes, judges and staff have to recognize and employ these
      recommendations. Bleeding wounds of the hands due to contact with the opponents
      teeth can be minimized by fist padding.

PMID- 15022124
TI  - Molecular imaging for pediatric lung diseases.
AB  - Molecular imaging is a rapidly developing multidisciplinary field that combines
      advances in contrast agent development, instrumentation, and molecular/cell
      biology to follow cellular and sub-cellular events in intact organisms. Platforms
      for molecular imaging include radionuclide-based methods, optical methods, and
      magnetic resonance. To date, molecular imaging studies of the lungs have been
      used to monitor the effectiveness of gene transfer, neutrophilic inflammation,
      and cell trafficking. Eventually, the goal will be to translate these new
      techniques to clinical settings such as cystic fibrosis.

PMID- 15022125
TI  - Early radiographic and clinical features associated with bronchiectasis in
      children.
AB  - Bronchiectasis among children living in developing regions is associated with
      respiratory infections during early childhood, but specific risk factors that
      precede childhood bronchiectasis are not fully characterized. We hypothesized
      that severe respiratory syncytial viral (RSV) infection in infancy would increase
      the risk of bronchiectasis among Alaska Native children in rural Alaska. This was
      a follow-up cohort study of a 1993-1996 case-control study of RSV-hospitalized
      case patients and their controls. For each 5-8-year-old former case-patient and
      control subject, we reviewed medical records, interviewed parents, performed
      physical examinations and spirometry, collected sera, and analyzed all historical
      chest radiographs. Ten (11%) RSV cases and 10 (9%) controls had radiographic
      evidence of bronchiectasis. The mean age at radiographic diagnosis of
      bronchiectasis was 3.3 years (range, 1.2-6.1 years). Children were more likely to
      develop bronchiectasis if their chest radiographs, when they were < 2 years of
      age, showed lung parenchymal densities (RR = 3.9, P < 0.013), persistent
      parenchymal densities > 6 months' duration (RR = 3.0, P = 0.02), or infiltrates
      on multiple episodes (test for trend, P = 0.003). Radiographic features of
      hyperinflation and atelectasis among children < 2 years old were not associated
      with eventual bronchiectasis. A single severe infection with RSV alone did not
      predispose Alaska Native infants to bronchiectasis. Childhood bronchiectasis was
      associated with lung and hence airway injury, manifested on radiographs by
      parenchymal densities or "pneumonia" rather than by hyperinflation or
      atelectasis.

PMID- 15022127
TI  - Drug delivery and adherence in young children.
AB  - The aim of this pilot study was to compare a the HaloLite Paediatric Nebulizer
      (HPN) with a pressurized metered dose inhaler and valved holding chamber (pMDI
      VHC, Aerochamber) in terms of drug delivery, adherence to treatment, compliance
      with device, true adherence, and acceptability. Fourteen children aged 11-36
      months with asthma on regular treatment with inhaled corticosteroids were
      enrolled into an open, randomized, crossover trial. They received budesonide for
      2 weeks with each delivery system. Both devices incorporated a datalogger which
      recorded information on how the device was used. The HPN was preprogrammed to
      deliver 25 microg of budesonide to the patient. A single actuation of budesonide
      200 microg was used with the pMDI VHC. The median delivered dose of budesonide
      was 36 microg (range, 31-45 microg; CV, 15%) for the HPN and 53 microg (range, 17
      85 microg; CV, 47%) for the pMDI VHC. The median adherence was 68% (range, 11
      96%) with the HPN and 71% (range, 11-100%) with the pMDI VHC. The median device
      compliance was 30% and 51% and the median true adherence was 23% and 36%,
      respectively. The shape, size, and weight of the HaloLite Paediatric Nebulizer
      were generally less acceptable than the shape, size, and weight of the pMDI VHC
      with datalogger. These results indicate that reproducible quantities of drug can
      be delivered to very young children using AAD technology such as that
      incorporated into the HPN. Drug delivery with the pMDI VHC was more variable, but
      parents preferred this device.

PMID- 15022126
TI  - Predicting response to rhDNase and hypertonic saline in children with cystic
      fibrosis.
AB  - Daily recombinant human deoxyribonuclease (rhDNase) is an established but
      expensive treatment in cystic fibrosis (CF). Alternate-day rhDNase and hypertonic
      saline (HS) represent potential cheaper alternative therapies. However, not all
      patients improve on treatment. To assess response, many CF centers have developed
      formal n-of-1 trials of treatment to find out who benefits. Response to daily
      rhDNase at 3 months has been shown to be a good predictor of response at 1 year.
      There are no data correlating individual response at a shorter time period with 3
      month response. We assessed whether individual responses to daily rhDNase,
      alternate-day rhDNase, and HS could be predicted from lung function response at 6
      weeks, thus shortening the n-of-1 trial, or from baseline patient
      characteristics, therefore avoiding the need for an n-of-1 trial. In a randomized
      crossover trial, 48 CF children were allocated consecutively to 12 weeks of once
      daily 2.5-mg rhDNase, alternate-day 2.5-mg rhDNase, and twice-daily 5 ml of 7%
      HS. Forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) were
      measured at baseline and then at 6 and 12 weeks into each treatment period. Lung
      function response to the drugs at 6 weeks was highly predictive of response at 3
      months. There was some evidence that response to HS was worse in patients with
      lower baseline lung function. However, there was no association between response
      to alternate-day or daily rhDNase and baseline characteristics. In conclusion,
      response to rhDNase and HS at 6 weeks was highly predictive of response at 3
      months. For daily and alternate-day rhDNase, at least, the drug needs to be
      administered for at most 6 weeks initially to assess long-term response to
      treatment. Response to treatment could not be reliably predicted from baseline
      characteristics.

PMID- 15022128
TI  - Maximal expiratory flow at FRC (V'maxFRC): Methods of selection and differences
      in reported values.
AB  - We compared three methods of reporting maximal expiratory flow (V'maxFRC)
      measured in partial expiratory flow-volume curves (PEFVCs) at the point of
      functional residual capacity (FRC). PEFVCs were obtained with the rapid
      thoracoabdominal compression technique (RTC) on a total of 446 occasions in 281
      HIV-negative, asymptomatic infants (4.8-28.1 months old). Three different
      expressions of V'maxFRC were recorded: 1) the highest measured flow (maxV'FRC),
      2) the mean of the three highest flows (mean3V'FRC), and 3) the flow at FRC in a
      composite curve (compV'FRC) consisting of PEFVCs, obtained at different jacket
      pressures and superimposed at their distal limb. The numerical value of maxV'FRC
      was 7.4% (+/-5.6%) higher than the mean3V'FRC, and 11.9% (+/-17.7%) higher than
      the compV'FRC; the mean3V'FRC was 5% (+/-18.3%) higher than the compV'FRC. Bland
      Altman analysis was used to evaluate the agreement between the three indices. The
      mean difference and 95% limits of agreement were: maxV'FRC -mean3V'FRC, 14 +/- 18
      ml/sec; maxV'FRC - compV'(FRC), 23 +/- 58 ml/sec; and mean3V'(FRC) - compV'(FRC),
      10 +/- 52 ml/sec. The differences between the slopes of the three indices
      (regressed against height) were statistically significant, although clinically
      unimportant. We conclude that despite their high correlation, the mean3V'FRC and
      maxV'FRC should not be used interchangeably, and that the composite analysis,
      although useful, does not improve the reproducibility of V'maxFRC, and thus it
      cannot be recommended for routine use in its current form.

PMID- 15022129
TI  - Factors affecting clinical outcome in gastrostomy-fed children with cystic
      fibrosis.
AB  - In order to assess the effects of gastrostomy feeding on nutritional status,
      respiratory function, and survival in children with cystic fibrosis (CF), we
      studied all patients undergoing gastrostomy between 1989-1997 at the Royal
      Children's Hospital, Melbourne. Clinical information was collected from medical
      records, including serial measurements of weight-for-age standard deviation
      scores (WAZ) and forced expired volume in 1 sec (FEV1) (percent predicted).
      Measurements were compared for 2 years before and 2 years after gastrostomy
      placement. Data on gastroesophageal reflux (GER), adherence to the gastrostomy
      feeding program, and sputum culture were also assessed. Of 37 children (22 male;
      mean age, 11.6 +/- 4.8 years; range, 3-20), 11 died during the study period (7
      female, 4 male). Female patients were more likely to die within 2 years of
      gastrostomy placement (OR = 3.9; 95% CI, 0.72-23.2; P = 0.07). Mortality was
      significantly associated with a WAZ score < -2 (OR = 10.7; 95% CI, 1.07-466.6; P
      = 0.02) and predicted FEV1 < 50% (OR = 10.8; 95% CI, 1.07-512.9; P = 0.02) at
      time of gastrostomy. Patients with clinical evidence of GER (n = 11) had
      significantly lower weight gain after gastrostomy (delta WAZ, -0.32 +/- 0.26 vs.
      0.03 +/- 0.39; P = 0.03). In conclusion, the presence of advanced lung disease,
      GER, and female gender were factors associated with a poor clinical outcome after
      gastrostomy placement.

PMID- 15022130
TI  - Reduced neurocognition in children who snore.
AB  - Obstructive sleep apnea syndrome (OSAS) has been associated with reduced
      neurocognitive performance in children, but the underlying etiology is unclear.
      The aim of this study was to evaluate the relationship between hypoxemia,
      respiratory arousals, and neurocognitive performance in snoring children referred
      for adenotonsillectomy. Thirteen snoring children who were referred for
      evaluation regarding the need for adenotonsillectomy to a children's hospital
      otolaryngology/respiratory department underwent detailed neurocognitive and
      polysomnographic (PSG) evaluation. PSGs were evaluated for respiratory
      abnormalities and compared with 13 nonsnoring control children of similar age who
      were studied in the same manner. The snoring children had an obstructive
      respiratory disturbance index within normal range (mean obstructive
      apnea/hypopnea index, 0.6/hr). Despite this, several domains of neurocognitive
      function were reduced in the snoring group. These included mean verbal IQ scores
      (snorers 92.6 vs. nonsnorers 110.2, P < 0.001), mean global IQ scores (snorers
      96.7 vs. nonsnorers 110.2, P < 0.005), mean selective attention scores (snorers
      46.4 vs. nonsnorers 11.8, P < 0.001), mean sustained attention scores (snorers
      8.0 vs. nonsnorers 2.2, P = 0.001), and mean memory index (snorers 95.2 vs.
      nonsnorers 112.1, P = 0.001). There was a direct relationship between number of
      mild oxygen desaturations of > or = 3%, obstructive hypopneas with > or = 3%
      oxygen desaturations, and respiratory arousals and severity of neurocognitive
      deficits, with the greatest effect being on memory scores. The disruption of
      sleep in snoring children produced by relatively mild changes in oxygen
      saturation or by increases in respiratory arousals may have a greater effect on
      neurocognitive function than hitherto appreciated. A possible explanation for
      these neurocognitive deficits may be the combination of the chronicity of sleep
      disruption secondary to snoring which is occurring at a time of rapid
      neurological development in the first decade of life. Future studies need to
      confirm the reversal of these relatively mild neurocognitive decrements post
      adenotonsillectomy.

PMID- 15022131
TI  - NO pathway in CF and non-CF children.
AB  - Controversy exists concerning abnormalities of the nitric oxide (NO) pathway in
      cystic fibrosis (CF) lung disease. Although some studies suggested that NO
      activity is impaired in CF, changes in NO production in young children have not
      been studied. We hypothesized that nitric oxide synthase (NOS II) expression is
      decreased in young children with CF, leading to decreased production of lower
      airway NO, and that decreased NOS II expression is related to airway
      inflammation. Accordingly, we measured lower airway exhaled NO, nitrate, and NOS
      II expression in airway epithelium and macrophages by bronchoscopy,
      bronchoalveolar lavage (BAL), and bronchial brushing in 13 children with CF, 4
      adolescent patients with CF, and 14 disease control children. Lower airway NO and
      nitrate were not different between CF and disease controls. Immunostaining
      studies of NOS II expression in airway epithelial cells and macrophages were
      similar in CF and control patients. Within the CF group, however, expression of
      NOS II was inversely related to BAL neutrophil counts and IL-8, two markers of
      airway inflammation. We conclude that lower airway NO, nitrate levels, and NOS II
      expression are not different in young children with CF and disease control
      patients, but that NOS II expression decreases in CF as airway inflammation
      increases.

PMID- 15022132
TI  - Exercise testing and training in German CF centers.
AB  - Physical exercise is increasingly recognized as a valuable diagnostic and
      therapeutic modality for patients with cystic fibrosis (CF). We sought to
      characterize the use of exercise testing and training as well as the attitude
      toward both issues through a national survey. A questionnaire was sent to 107
      specialized CF centers (caring for a total of 5,231 patients) and 7 inpatient
      rehabilitation institutions. Answers were available from 62 specialized centers
      caring for 3,580 patients and from 4 rehabilitation centers with 520 treatment
      episodes per year. Sixty percent of specialized centers performed some sort of
      exercise testing at an average frequency of 1 in 2.3 years for patients aged 8
      and above. However, protocols and indication criteria were often unstandardized
      or not specified at all. Equipment availability was no major problem, and the
      majority of tests were conducted by a physician alone. Nineteen centers had
      adopted exercise testing as part of their diagnostic routine. Two thirds of
      caregivers advised their patients to engage in physical activity, but failed to
      discuss specific modalities and potential hazards. Nevertheless, physical
      exercise was viewed as "extremely important" or "very important" by 87%. In a
      rehabilitation setting, an exercise test was conducted 1.1 times per patient
      stay, and a training program offered in 100% of cases. In conclusion,
      standardized exercise testing and training programs appear to be underused in
      German CF centers, despite a high degree of interest in the topic. Supplementary
      material for this article can be found on the Pediatric Pulmonology website
      (http//www.interscience.wiley.com/jpages/8755-6863/suppmat).

PMID- 15022133
TI  - Airway inflammation in children with tracheostomy.
AB  - We hypothesised that long-term tracheostomy in infants and children may
      perpetuate chronic airway inflammation and airway remodeling due to easier access
      to the lungs for microorganisms. Pulmonary surfactant represents an important
      part of the initial host defense, and in particular, the surfactant proteins (SP)
      A and D may directly interact with invading microorganisms and also modulate the
      activity of local immune cells. The goals of this study were to determine the
      presence and intensity of a peripheral airway inflammation and of potential
      deficiency states of surfactant proteins in nonsymptomatic children with
      tracheostomy. Bronchoalveolar lavage (BAL) cell pattern, bacteria and viruses
      recovered, and concentrations of SP-A, SP-B, SP-C, and SP-D were assessed in 46
      children (4.3 years (1.6-6)) median (range) carrying a tracheostomy for 2.4 years
      (1.3-4.9), and were compared to 16 children with no lung disease. Children with
      tracheostomy had an increased total number of cells, increased neutrophils, and
      more frequently bacteria, but no viruses were recovered. SP-D concentration was
      reduced by 50% on average (P = 0.0002). SP-A, SP-B, and SP-C were not different
      between the two groups. SP-D was inversely correlated to neutrophils, and high
      numbers of bacteria were associated with lower SP-D concentrations. We suggest
      that bacteria and low SP-D support neutrophilic inflammation in the lower
      respiratory tract of nonsymptomatic with children with tracheostomy.

PMID- 15022134
TI  - Survey of breast-feeding practices and outcomes in the cystic fibrosis
      population.
AB  - The aim of this study was to survey cystic fibrosis (CF) patients to determine
      the frequency of breast-feeding and its association with onset and severity of CF
      symptoms. Three thousand, two hundred questionnaires were sent to 30 accredited
      CF centers for anonymous completion. Eight hundred and sixty-three questionnaires
      were returned and scanned into a database. All results were adjusted for age at
      time of filling out the questionnaire. Age at onset of symptoms, percent forced
      expired volume in 1 sec (FEV1%) predicted, and intravenous (IV) antibiotic use
      were analyzed based on breast-feeding history. Approximately 49% of respondents
      received human breast milk at some time, but only 18% were exclusively breast
      fed. Breast-feeding exclusively for greater than 6 months was associated with a
      decrease in disease severity based on recent intravenous antibiotic use compared
      to no breast-feeding (P = 0.03). There was no statistically significant change in
      onset of symptoms in the setting of breast-feeding; however, a trend toward
      delayed onset was seen in those receiving human milk. Fifty-three percent of
      those who breast-fed exclusively > or = 6 months had FEV1% values > 90%, compared
      to 47% of those not breast-fed. This is a suggestive but not statistically
      significant difference. In conclusion, breast-feeding for > or = 6 months is
      associated with decreased use of intravenous antibiotics in the 2 years prior to
      administering the questionnaire. This survey indicates that breast-feeding is not
      harmful to children with CF, and may be beneficial.

PMID- 15022135
TI  - Leiomyosarcoma of the main bronchus in a girl: a long-time survivor with multiple
      lung metastases.
AB  - Primary leiomyosarcoma of the respiratory tract is a very rare malignancy,
      especially in childhood, with only 15 cases in patients under 16 years old having
      been reported. In the present case, the survival period from the onset of
      symptoms has been over 7 years, despite incomplete resection. Based on the 15
      published cases, the prognosis is poorer when the tumor is unresected or
      incompletely resected, but under favorable circumstances, prolonged survival is
      possible.

PMID- 15022136
TI  - Cleft sternum: case report and literature review.
AB  - The isolated sternal cleft is a rare congenital anomaly that presents from birth
      to adulthood. We describe the late presentation and management in a child with
      this condition. The modern investigative and operative options are reviewed.

PMID- 15022138
TI  - The cystic fibrosis effort in Canada: advancing on many fronts.

PMID- 15022141
TI  - Developments in treatment of anxiety disorders: psychotherapy, pharmacotherapy,
      and psychosurgery.
AB  - A selection of articles that focus on psychosocial treatments, pharmacotherapy,
      and psychosurgery of anxiety disorders are reviewed. While some medications look
      clearly beneficial or potentially effective in the treatment of anxiety
      disorders, other compounds seem less promising or not effective. A combination of
      proven pharmacotherapies and psychotherapies may be the most clinically prudent
      approach to the treatment of anxiety disorders. Thermocapsulotomy may be an
      "extreme" option in selected cases of severe nonobsessive anxiety but may carry a
      significant risk of adverse effects indicative of frontal lobe functioning
      impairment. In spite of all the research and progress in studying relatively well
      defined therapies, many patients suffering from anxiety and depression still use
      complementary and alternative therapies. The use of alternative and complementary
      is likely to increase as insurance coverage expands.

PMID- 15022142
TI  - Risk factors and outcome in ambulatory assault victims presenting to the acute
      emergency department setting: implications for secondary prevention studies in
      PTSD.
AB  - Prevention of post-traumatic stress disorder (PTSD) in trauma victims is an
      important public health goal. Planning for the studies required to validate
      prevention strategies requires identification of subjects at high risk and
      recruitment of unbiased samples that represent the larger high-risk population
      (difficult because of the avoidance of many trauma victims). This study recruited
      high-risk victims of interpersonal violence (sexual or physical assault)
      presenting to an urban emergency department for prospective 1- and 3-month follow
      up. Of 546 victims who were approached about participating, only 56 agreed to be
      contacted and only 46 participated in either the 1- or 3-month interviews. Of the
      46, 43 had been previously victimized with a mean of over six traumas in the
      group; 21% had prior PTSD, 85% had prior psychiatric illness, and 37% had prior
      substance abuse. Sixty-seven percent had positive urine for alcohol or drugs on
      presentation. Fifty-six percent developed PTSD at 1 or 3 months with the rate
      declining between 1 and 3 months. There was high use of medical and psychiatric
      services. These findings document both the difficulty of recruiting large samples
      of high-risk assault victims to participate in research, and the high rate of
      prior traumatization, PTSD, substance use, and psychiatric morbidity in these
      subjects which, if still active at the time of victimization, may complicate
      efforts to document preventive treatment effects.

PMID- 15022143
TI  - Linear and nonlinear measures of blood pressure variability: increased chaos of
      blood pressure time series in patients with panic disorder.
AB  - Arterial blood pressure (BP) variability increases progressively with the
      development of hypertension and an increase in BP variability is associated with
      end organ damage and cardiovascular morbidity. On the other hand, a decrease in
      heart rate (HR) variability is associated with significant cardiovascular
      mortality. There is a strong association between cardiovascular mortality and
      anxiety. Several previous studies have shown decreased HR variability in patients
      with anxiety. In this study, we investigated beat-to-beat variability of systolic
      and diastolic BP (SBP and DBP) in normal controls and patients with panic
      disorder during normal breathing and controlled breathing at 12, and 20 breaths
      per minute using linear as well as nonlinear techniques. Finger BP signal was
      obtained noninvasively using Finapres. Standing SBPvi and DBP BPvi (log value of
      BP variance corrected for mean BP divided by HR variance corrected for mean HR)
      were significantly higher in patients compared to controls. Largest Lyapunov
      exponent (LLE) of SBP and DBP, a measure of chaos, was significantly higher in
      patients in supine as well as standing postures. The ratios of LLE (SBP/HR) and
      LLE (DBP/HR) were also significantly higher (P<.001) in patients compared to
      controls. These findings further suggest dissociation between HR and BP
      variability and a possible relative increase in sympathetic function in anxiety.
      This increase in BP variability may partly explain the increase in cardiovascular
      mortality in this group of patients.

PMID- 15022144
TI  - Posttraumatic stress disorder in callers to the Anxiety Disorders Association of
      America.
AB  - We surveyed callers to the Anxiety Disorders Association of America (ADAA) with
      posttraumatic stress disorder (PTSD) and subthreshold PTSD (SPTSD). Most subjects
      heard about ADAA through media referrals and were satisfied with the service
      given by the association. The most frequent requests were for written
      information, learning how to cope with anxiety, and access to a local support
      group. Among callers, rates of PTSD (n=80) and SPTSD (n=111) were 8.0% and 11.1%,
      respectively. PTSD or SPTSD subjects were more likely to be younger, female, and
      with lower income than their no-Axis I psychiatric disorder controls (NAC) who
      had been exposed to trauma. In addition, they presented with more history of
      trauma, especially violent trauma, psychiatric comorbidity, recent psychotropic
      use, and side effects. More medical comorbidity, increased health service use,
      and reduced work productivity were also found among the PTSD and SPTSD subjects.
      SPTSD subjects were comparable to PTSD subjects on most of the measures with a
      few exceptions (more likely to be married, to have less psychiatric comorbidity,
      less medication use for mood and social fear, and fewer sedation and sexual side
      effects, and to have less health service use and work impairment). In conclusion,
      callers to ADAA with PTSD were particularly impaired and used the health care
      system extensively. Although the SPTSD subjects were not as impaired as those
      with PTSD, they were disadvantaged in many ways.

PMID- 15022145
TI  - Cross-sectional 7-year follow-up of anxiety in primary care patients.
AB  - We describe the longitudinal patterns of anxiety symptoms and mental health
      treatment among patients recruited from a primary care clinic, and provide a
      naturalistic view of anxiety symptoms, disorders, and treatment at two time
      periods 7 years apart. Study participants were originally identified in a primary
      care setting in 1992 as positive but untreated for the presence of anxiety and/or
      depressive symptoms and disorders. Data were collected through telephone
      interviews assessing current psychological status for anxiety and depression
      symptoms, disorders, and general functioning and well being. There were no
      planned interventions. Participants were re-interviewed after 7 years. Two
      hundred seventy-one of the identified 1992 population of 784 patients were
      followed up by interview in 1999. Comparisons of the scores demonstrated that
      respondents were less symptomatic in 1999 than in 1992, with 45% of respondents
      reporting no symptoms whatsoever at follow-up. Severity of symptom status in 1992
      was indicative of follow-up symptom severity. Most respondents (68%) had not
      received mental health treatment over the 7 years, largely because they wanted to
      handle problems on their own. This study demonstrates the tendency of anxiety to
      remain or reappear years after originally identified, with 55% of patients
      reporting symptoms after 7 years. Initially untreated and underdiagnosed anxiety
      is associated with continued impairment in functional status and quality of life
      and continued underrecognition and undertreatment.

PMID- 15022146
TI  - Medical and productivity costs of anxiety disorders: case control study.
AB  - This retrospective case-control study examines the medical and productivity costs
      associated with a diagnosis of anxiety. The study used a data set from a large
      employer database that collected medical, pharmaceutical, absenteeism, short-term
      disability, and worker compensation records during 2000 from 6 major employers.
      Patients diagnosed with anxiety disorders (n= 1917) were matched at a 1:1 ratio
      to patients not diagnosed with anxiety disorders (n= 1917) based on age, sex,
      metropolitan statistical area, and type of insurance coverage. Paired-difference
      t tests, McNemer's test, and analyses of covariance were used to compare the
      anxiety population with the control group. Employees diagnosed with anxiety
      disorders were significantly more likely to have additional diagnoses, use more
      services, require hospitalization, or visit the emergency room compared with the
      control group. Furthermore, after controlling for differences in comorbidities,
      employees diagnosed with anxiety disorders had significantly higher medical costs
      [$1555; 95% confidence interval (CI) $1066-2043], productivity costs ($1366; 95%
      CI $708-2023), and total costs ($2920; 95% CI $2035-3805) compared with the
      control group. Results indicate that anxiety disorders are associated with
      significant medical and productivity costs.

PMID- 15022147
TI  - Preliminary experience with adjunctive quetiapine in patients receiving selective
      serotonin reuptake inhibitors.
AB  - Treatment of depression and anxiety disorders with selective serotonin reuptake
      inhibitors (SSRIs) has been shown by numerous studies to be generally effective.
      Less well understood is how clinically to address the residual anxiety symptoms a
      significant minority of such patients treated with SSRIs continue to experience.
      We assessed quetiapine as adjunctive therapy to SSRIs for patients with anxiety
      symptoms complicating a depressive or anxiety disorder. Patients receiving a
      stable dosage of an SSRI for at least 6 weeks who also had persistent anxiety
      symptoms (Hamilton Anxiety scale [HAM-A] > or =16), were enrolled in a 9-week,
      open-label, variable dose study. Changes in clinical status were assessed with
      the Hamilton Depression Rating Scale (HAM-D), HAM-A, and State Anxiety Inventory
      (SAI). Statistically and clinically significant reductions of > or =50% in the
      HAM-D and HAM-A occurred by the second week of treatment in 10 of the 11
      patients. These improvements continued throughout the study along with a
      significant improvement on the SAI scale. The most frequent side effects reported
      were mild dry mouth, constipation, and transient drowsiness with dose escalation.
      The results provide evidence that quetiapine may be an effective adjunctive
      treatment for recalcitrant anxiety symptoms in individuals treated with SSRIs for
      either anxiety or depressive disorders. Given the open-label design of the trial,
      more rigorous studies are clearly indicated.

PMID- 15022148
TI  - Pooled analysis of venlafaxine XR efficacy on somatic and psychic symptoms of
      anxiety in patients with generalized anxiety disorder.
AB  - We evaluated the relative efficacy of venlafaxine XR on the psychic versus
      somatic symptoms of anxiety in patients with generalized anxiety disorder as
      determined by the Diagnostic and Statistical Manual of Mental Disorders, 4th
      Edition. Data were pooled and analyzed from 1,841 patients with generalized
      anxiety disorder who participated in five short-term (8-week) double-blind,
      multicenter, placebo-controlled studies, two of which had long-term (6-month)
      extensions. Somatic and psychic anxieties were studied using the Hamilton rating
      scale for anxiety (HAM-A) factor scores. We examined response rates (> or =50%
      improvement over baseline severity score) in the overall population and in
      patients with mainly somatic symptomatology at baseline (somatizers). Venlafaxine
      XR significantly reduced factor scores for both psychic and somatic HAM-A factors
      compared with placebo, from the first and second weeks of treatment,
      respectively. Patients treated with venlafaxine XR had significantly higher rates
      of response than patients receiving placebo on the psychic (58% vs. 38%, P<.001
      at week 8; 66% vs. 35% at week 24, P<.001) and somatic (56% vs. 43%, P<.001 at
      week 8; 67% vs. 47% at week 24, P<.001) factors of the HAM-A. There was a
      TreatmentxFactor interaction (P<.027) in response rates: Patients treated with
      venlafaxine showed similar somatic and psychic anxiety response rates, whereas
      placebo-treated patients showed higher somatic compared with psychic response
      rates. Somatizers showed similar rates of response to the total population for
      the somatic factor of the HAM-A in either treatment group. Patients with
      generalized anxiety disorder treated with venlafaxine XR showed similar absolute
      rates of response on somatic and psychic symptoms, but relative to patients
      treated with placebo, more improvement in psychic than somatic symptoms.

PMID- 15022149
TI  - Prevalence of anxiety symptoms among a sample of outpatients in an internal
      medicine clinic: a pilot study.
AB  - Previous studies in primary care settings indicate that Axis I anxiety disorders
      range in prevalence from 2.1% to 14.8%. However, the prevalence of anxiety
      symptoms, rather than Axis I diagnoses, has undergone limited study. In a pilot
      study, we surveyed 88 outpatients in an internal medicine clinic and explored the
      prevalence of various anxiety symptoms based on four measures of anxiety and
      worry. Thirty percent of participants endorsed mixed anxiety features, 33%
      reported generalized anxiety symptoms, nearly half acknowledged obsessive
      compulsive personality symptoms, and nearly a quarter identified meaningful
      levels of worry. Seventeen percent of participants were positive on all four
      study measures. These data suggest that anxiety symptoms are probably more
      prevalent in primary care settings than recognized.

PMID- 15022150
TI  - Then and now: quality of life of young breast cancer survivors.
AB  - BACKGROUND: Women under age 50, a quarter of all cases of breast cancer, are
      especially vulnerable to physical and psychosocial late effects of their
      treatment due to having more aggressive treatment and their relative youth.
      METHODS: In person interviews were conducted with the population-based sample:
      185 women who were under 50 at diagnosis and were cancer-free 5 years later.
      Quality of life in the physical, psychological, social, and spiritual domains was
      assessed and compared with results obtained a few months after diagnosis.
      RESULTS: Five years after diagnosis, 92% rated their health as good or excellent,
      and only 10% said their health had been getting worse. Between baseline and 5
      years, there were significant improvements in surgical symptoms, body image,
      worry about the future, patient-physician communication, intrusiveness of
      treatment, and all of the SF-36 measures except for general health. There were
      significant decreases in emotional support and the size of one's social network.
      More women were now menopausal (75% due to treatment) and there were fewer
      children at home. There were no significant changes in employment status,
      marital/partner status, sexual activity, sexual problems, self-esteem, and
      attendance at religious services or frequency of prayer. In multivariate models,
      a greater increase in physical quality of life was associated with reporting
      fewer chronic conditions, being employed, having been treated by chemotherapy and
      fewer had no children under age 18 living at home. A greater increase in mental
      quality of life was associated with fewer chronic conditions and a smaller
      decrease in emotional support. CONCLUSIONS: Five years after diagnosis, young
      breast cancer survivors who remained cancer-free enjoyed good health and improved
      quality of life. Nonetheless, physical, social, and psychological concerns must
      be addressed so that young breast cancer survivors will continue to be resilient
      as they age.

PMID- 15022151
TI  - The quality of life for cancer children (QOLCC) in Taiwan (part I): reliability
      and construct validity by confirmatory factor analysis.
AB  - Part 1, the current paper describes the development and testing of a quality-of
      life (QOL) assessment specifically designed for Taiwanese pediatric cancer
      patients (7-18 years) and their parents/caregivers. The assessment instrument was
      established based on a qualitative study, then refined using recognized item
      analysis methods and pilot tested on a group of 25 patients. The final assessment
      instrument included three versions of the same instrument, a patient self-report
      (QOLCC-7-12, for children aged 7-12 years; QOLCC-ADO for adolescent aged 13-18
      years) and a parent proxy-report (QOLCC-PAR). The final seven-subscale tool has a
      total of 34 items and was tested among 106 young cancer patients and 106 their
      parents. Psychometric properties of the measure were tested using item analysis,
      Cronbach's alpha, and a confirmatory factor analysis. Results suggest acceptable
      reliability and goodness of fit of this seven-scale measure. In order to test the
      factor validity of QOLCC, an independent group of 42 children with cancer
      participated. The results of confirmatory factor analysis shows the goodness of
      fit in QOLCC.

PMID- 15022152
TI  - The quality of life for cancer children (QOLCC) for Taiwanese children with
      cancer (part II): feasibility, cross-informants variance and clinical validity.
AB  - The quality of life in childhood cancer (QOLCC) is a research instrument that has
      been developed to assess the quality of life for children and adolescents who
      suffer from cancer in Taiwan. The current paper is the second of a two-part
      series of research reports. Part I is reported in this journal (Yeh et al.,
      2003). Part II describes the range of measurement, concordance of cross
      informants reports, and clinical validity of Taiwanese pediatric cancer children
      (7-12 years) and adolescents (13-18 years) and their parents/caregivers. Due to
      the cognitive ability of children and adolescents, data were analyzed for
      children and adolescent separately. The validity of cross-referenced information
      between parent and child forms was subsequently examined using Pearson product
      correlation. The feasibility (percentage of missing values per item) and range of
      measurement [percentage of minimum (floor effect) and maximum (ceiling effect)
      possible scores] was calculated for the five QOLCC and the total scale score. The
      findings of medium to high correlation of the patient/parent responses strongly
      imply that relevant information might be obtainable through parents when children
      are unable or unwilling to complete the assessment instrument. Feasibility for
      the QOLCC was very good.

PMID- 15022154
TI  - The skull beneath the skin: cancer survival and awareness of death.
AB  - Terror management theory predicts that people made aware of their own mortality
      (mortality salience) will seek to boost their self-esteem in order to buffer the
      anxiety they feel. One common resource to achieve this is strengthening social
      bonds with an admired in-group. It would also seem to predict that cancer
      survivors and those close to them would be driven to a greater closeness. A
      similar closeness might be predicted between those with terminal illness and
      their families and other supporters. Some empirical observations suggest that
      there are other forms of death-related salience which do not conform to the
      predictions of terror management theory. We suggest that some of those who have
      recovered from cancer may be made death salient, while those close to them remain
      mortality salient. Death salience seems to turn people inward to the resources
      and challenges of their deep (subconscious and unconscious) minds, and confronts
      them with the realities of their deep identities. A third form of salience, dying
      salience, affects those who have terminal illness. Distinguishing between death
      salience and mortality salience provides one explanation for the frequency with
      which close relationships break down after recovery from cancer. The distinctive
      nature of dying salience raises important questions about the inappropriateness
      of survivors as providers of support for the dying.

PMID- 15022153
TI  - The psychosocial needs of breast cancer survivors; a qualitative study of the
      shared and unique needs of younger versus older survivors.
AB  - Due to improvements in medical treatment and survival following breast cancer,
      researchers have turned their attention to investigating the needs of breast
      cancer survivors. There is disagreement about the extent to which survivors
      continue to experience psychological morbidity after treatment ends. Whilst the
      majority of women adjust well to breast cancer, some may have continued
      psychosocial needs. Available research suggests that younger pre-menopausal women
      are at increased risk of psychological morbidity following breast cancer. The
      present study aimed to gather preliminary qualitative data on the psychosocial
      needs of breast cancer survivors and to identify the shared and unique needs of
      younger versus older survivors. A qualitative methodology was chosen as this was
      a relatively unexplored area of enquiry. Patients treated for early-stage breast
      cancer who had completed their hospital-based treatment 6-24 months prior to
      participation were recruited. Sampling was discontinued when informational
      redundancy was achieved. Eighteen telephone interviews were conducted. A wide
      variety of on-going psychosocial and information needs were reported by breast
      cancer survivors including support needs, psychological needs, practical needs,
      physical needs and information needs. Younger women reported more needs than
      their older counterparts. Several needs reported by younger women were directly
      related to being of younger age or pre-menopausal at the time of diagnosis.
      Clinical implications are discussed.

PMID- 15022155
TI  - Immune function and adjustment style: do they predict survival in breast cancer?
AB  - The aim of this study was to investigate the role of immune status and
      psychosocial factors in survival from early breast cancer (N=61). Baseline
      assessments included lymphocyte number and function, natural killer cell activity
      (NKA), plasma cortisol and prolactin level. Psychosocial measures included
      anxiety, depression and mental adjustment to cancer and social support. Length of
      follow-up was 6.1-7.9 years with 14 (23%) breast cancer deaths. In Cox
      proportional hazards models adjusting for lymph node status two parameters
      predicted longer survival, low NKA (HR 29 per LLU, p=0.003) and minimizing the
      illness adjustment (HR 0.64 per scale point, p=0.012). These data provide little
      evidence for a psychoneuroimmunological mechanism in the survival from breast
      cancer. While this study is limited due to small sample size, and therefore the
      possibility of inflated estimates, longer survival in those minimizing the
      illness is a finding consistent with recent studies; however, the counter
      intuitive finding that high NKA predicts shorter survival may be a marker for
      current disease or response to treatments.

PMID- 15022156
TI  - Depressive symptoms after breast cancer surgery: relationships with global,
      cancer-related, and life event stress.
AB  - For women with breast cancer, rates of depression are the third highest of any
      cancer diagnostic group. Stress, defined as life events or perceptions of stress,
      is associated with depressive symptoms. However, little is known about the
      relationships between different types of stress and these symptoms in women with
      breast cancer. This relationship was tested in 210 women assessed after initial
      surgical treatment for regional breast cancer. Using Hierarchical Multiple
      Regression, three types of stress were examined: the occurrence of five stressful
      life events in the year prior to cancer diagnosis, perceptions of global stress,
      and perceptions of cancer-related traumatic stress. Other potentially relevant
      correlates of depressive symptoms were also examined, including the personality
      trait neuroticism, sociodemographics, and disease/treatment characteristics.
      Fifty-three percent of the variance in depressive symptoms was accounted for by
      three stress variables (perceptions of global and cancer-related traumatic stress
      and the life event-major financial difficulty) and two control variables
      (neuroticism and racial group). Specifically, global stress perceptions coupled
      with cancer-related intrusive thoughts and financial concerns along with the
      tendency towards negativity (neuroticism) may conspire to heighten a women's risk
      for depressive symptoms. Assessing multiple sources of stress would improve our
      ability to identify women 'at risk' for depressive symptoms and provide
      appropriate intervention.

PMID- 15022157
TI  - Effect of antiparkinson drug HP-200 (Mucuna pruriens) on the central
      monoaminergic neurotransmitters.
AB  - HP-200, which contains Mucuna pruriens endocarp, has been shown to be effective
      in the treatment of Parkinson's disease. Mucuna pruriens endocarp has also been
      shown to be more effective compared to synthetic levodopa in an animal model of
      Parkinson's disease. The present study was designed to elucidate the long-term
      effect of Mucuna pruriens endocarp in HP-200 on monoaminergic neurotransmitters
      and its metabolite in various regions of the rat brain. HP-200 at a dose of 2.5,
      5.0 or 10.0 g/kg/day was mixed with rat chow and fed daily ad lib to Sprague
      Dawley rats (n = 6 for each group) for 52 weeks. Controls (n = 6) received no
      drug. Random assignment was made for doses and control. The rats were sacrificed
      at the end of 52 weeks and the neurotransmitters were analyzed in the cortex,
      hippocampus, substantia nigra and striatum. Oral administration of Mucuna
      pruriens endocarp in the form of HP-200 had a significant effect on dopamine
      content in the cortex with no significant effect on levodopa, norepinephrine or
      dopamine, serotonin, and their metabolites- HVA, DOPAC and 5-HIAA in the
      nigrostriatal tract. The failure of Mucuna pruriens endocarp to significantly
      affect dopamine metabolism in the striatonigral tract along with its ability to
      improve Parkinsonian symptoms in the 6-hydorxydopamine animal model and humans
      may suggest that its antiparkinson effect may be due to components other than
      levodopa or that it has an levodopa enhancing effect.

PMID- 15022158
TI  - Antispasmodic activity of extracts and compounds of Acalypha phleoides Cav.
AB  - The aerial parts of Acalypha phleoides are usually prescribed in the Mexican
      traditional medicine for a variety of gastrointestinal complaints. The MeOH
      CHCl(3) (1:1) extract of the aerial part of A. phleoides showed an inhibitory
      effect on the gastrointestinal propulsion of a charcoal meal in mice. In isolated
      guinea-pig ileum, this extract produced a concentration dependent inhibition of
      the contractions induced by 5-hydroxytryptamine, but it was unable to inhibit the
      contractions elicited by acetylcholine, histamine, KCl and BaCl(2). This extract
      produced also a concentration dependent inhibition of the spontaneous pendular
      movement of the isolated rabbit jejunum. This inhibitory activity was partially
      blocked by propranolol. The essential oil, obtained from the aerial part of this
      plant, was more potent than the MeOH-CHCl(3) (1:1) extract in inhibiting the
      spontaneous pendular movement of the rabbit jejunum. Thymol, camphor and gamma
      terpinene were identified from the essential oil by GC-MS. These monoterpenes
      showed antispasmodic activity in the rabbit jejunum preparation, thymol was the
      most active compound, followed by camphor and gamma-terpinene. Thymol and camphor
      in high concentrations also showed tracheal relaxant properties, but gamma
      terpinene did not. These in vivo and in vitro results tend to support the
      traditional use of A. phleoides as an antispasmodic agent.

PMID- 15022159
TI  - Chemoprotective effect of plant phenolics against anthracycline-induced toxicity
      on rat cardiomyocytes. Part I. Silymarin and its flavonolignans.
AB  - Silymarin, an extract of fl avonolignans from the dried fruits of milk thistle
      (Silybum marianum L. Gaertneri) and its constituents silibinin, dehydrosilibinin,
      silychristin and silydianin were tested for protective effects on rat
      cardiomyocytes exposed to doxorubicin. Silymarin and individual fl avonolignans
      did not exert cytotoxicity in the range 25-100 micro m (incubation 9 h).
      Dehydrosilibinin was tested only at 25 micro m concentration due to its low
      solubility. All substances increased the cell ATP level. Silymarin and fl
      avonolignans displayed a dose-dependent cytoprotection against doxorubicin (100
      micro m, incubation 8 h). The protective effects of silymarin, silibinin,
      dehydrosilibinin and silychristin were comparable to that of dexrasoxane, while
      silydianin exerted the best protective effect. The ability of silymarin complex
      and its components to protect cardiomyocytes against doxorubicin-induced
      oxidative stress is due mainly to their cell membrane stabilization effect,
      radical scavenging and iron chelating potency.

PMID- 15022160
TI  - Analgesic studies on total alkaloids and alcohol extracts of Eclipta alba (Linn.)
      Hassk.
AB  - A variety of analgesics are used for the treatment of acute and chronic pain in
      different disease states. A narcotic or a non-narcotic analgesic that does not
      cause respiratory depression and addiction is needed. In Ayurveda a large number
      of indigenous drugs have been mentioned possessing analgesic properties (e.g.
      Guggul, Erand, Rasna, Bhringaraj, Methika, Palandu and Prasikayavani). The
      present experimental research work was undertaken to determine the analgesic
      activity of the total ethanol extract of Eclipta alba, and also the isolated
      alkaloids of Eclipta alba in albino mice by using standard experimental models
      such as the tail clip method, the tail flick method and the acetic acid induced
      writhing response. The results from this study show that both the ethanol extract
      as well as the total alkaloids produce good analgesic activity in all the
      different models of analgesia used. The total alkaloidal fraction was the most
      efficacious in all models tested.

PMID- 15022161
TI  - Phytotoxic and antimicrobial constituents of Bacopa monnieri and Holmskioldia
      sanguinea.
AB  - The phytochemicals betulinic acid (1), wogonin (2) and oroxindin (3) isolated
      from the aerial parts of Bacopa monnieri and Holmskioldia sanguinea showed
      significant antifungal activity against the two fungi Alternaria alternata and
      Fusarium fusiformis. Inhibition of root growth germination of wheat seeds was
      observed for all three compounds which showed 100% inhibition at 10 micro g/mL.
      Compounds (1) and (2) showed potent inhibition of Alternaria alternata compared
      with oroxindin at a concentration of 4 micro g/mL, whereas compound (2) was an
      effective inhibitor of both fungi. The structures of the compounds were
      established by spectral and chemical studies.

PMID- 15022162
TI  - Effect of Withania somnifera on B16F-10 melanoma induced metastasis in mice.
AB  - Withania somnifera, a plant with known immunopotentiating activity and its
      bioactive fraction-Withanolide D were studied for their anti-metastatic activity
      using B16F-10 melanoma cells in C57BL/6 mice. Simultaneous administration of
      Withania extract (122 +/- 10 tumour nodules) and Withanolide (126 +/- 9 lung
      tumour nodules) could significantly (p < 0.001) inhibit the metastatic colony
      formation of the melanoma in lungs. 72.58% by extract and 69.84% by Withanolide
      treated, as compared to the untreated control animals also increased the survival
      days. Lung collagen hydroxyproline content was highly elevated in the control
      animals (23.5 +/- 0.9 micro g/mg protein), which was reduced by the simultaneous
      administration of both the extract (16.3 +/- 2.0 micro g/mg protein) and
      Withanolide (15.3 +/- 1.8 micro g/mg protein). The level of lung hexosamines
      (4.85 +/- 0.20 mg/100 mg tissue) and uronic acids (330.1 +/- 23.7 micro g/100 mg
      tissue) content was also elevated in the control animals. The elevated level of
      hexosamine was significantly reduced by the treatment with extract (1.92 +/-
      0.05) and Withanolide (1.85 +/- 0.05). Similarly, the uronic acid content was
      also been reduced by the simultaneous administration of both Withania extract
      (194.2 +/- 17.4) and Withanolide (183.2 +/- 8.8). The control animals had 35.3 +/
      3.8 U/L gamma-glutamyl transpeptidase (gamma-GT), which was reduced by 50% by
      the treatment of extract and Withanolide to 17.5 +/- 4.0 U/L and 16.3 +/- 4.4 U/L
      respectively. There was a significant reduction in the levels of sialic acid in
      the serum of Withania extract (60.7 +/- 7.7) and Withanolide (67.16 +/- 5.8)
      treated animals compared to the higher level (102.2 +/- 8.7) in the control
      animals. Histopathological analysis of the lung tissues also correlated with
      these findings. Prophylactic administrations of both extract as well as
      Withanolide were ineffective in inhibiting the metastasis of B16F-10 melanoma
      cells.

PMID- 15022163
TI  - Quercetin allievates oxidative stress in streptozotocin-induced diabetic rats.
AB  - Diabetes mellitus is found in almost all populations and is emerging as a growing
      problem in developing countries. A large number of studies are in progress to fi
      nd natural sources, which are effective in reducing the intensity of diabetes.
      Quercetin, a constituent present in fruits and vegetables, was studied in two
      different doses (50 and 80 mg/kg body weight) for 45 days to assess its effect on
      streptozotocin induced diabetes. The blood glucose level was elevated in diabetic
      rats. Circulatory lipid peroxidation, vitamin C, vitamin E and enzymic
      antioxidants such as superoxide dismutase and catalase were analyzed. Alterations
      in the antioxidant defense were observed in diabetic animals compared to normal.
      Oral administration of quercetin to diabetic rats resulted in a decrease in the
      levels of blood glucose, plasma thiobarbituric acid reactive substances and
      hydroperoxides. Quercetin also resulted in the activities of superoxide
      dismutase, catalase coming to near normal, along with the levels of vitamin C and
      vitamin E. Quercetin at lower doses was found to be more effective. These result
      indicate that quercetin ameliorated the diabetes-induced changes in oxidative
      stress.

PMID- 15022164
TI  - Antiplasmodial constituents of Cajanus cajan.
AB  - Bioactivity-guided fractionation of extracts of roots and leaves of Cajanus cajan
      afforded 8 compounds: betulinic acid, biochanin A, cajanol, genistein and 2'
      hydroxygenistein, longistylin A and C, and pinostrobin. The two stilbenes,
      longistylin A and C, and betulinic acid showed a moderately high in vitro
      activity against the chloroquine-sensitive Plasmodium falciparum strain 3D7.

PMID- 15022165
TI  - Arjunetin from Terminalia arjuna as an insect feeding-deterrent and growth
      inhibitor.
AB  - Crude ethanolic extract of the stem bark of Terminalia arjuna (Combretaceae) and
      its three compounds namely arjunic acid, arjungenin and arjunetin were evaluated
      for antifeedant, growth inhibitory and oviposition-deterrent activities against a
      lepidopterous insect Spilarctia obliqua. The compound arjunetin showed highest
      growth inhibitory and feeding-deterrent properties with a growth inhibition
      (GI(50)) and feeding-inhibition (FD(50)) of 188.5 and 287.1 micro g/g diet
      respectively. Oviposition bioassays indicated no oviposition-deterrence in any of
      the compounds tested. The structure-activity relationship study indicated the
      importance of a glycosidation linkage in arjunetin.

PMID- 15022166
TI  - Ternatin, a flavonoid, prevents cyclophosphamide and ifosfamide-induced
      hemorrhagic cystitis in rats.
AB  - To compare the classical uroprotective efficacy of mesna (2
      mercaptoethanesulfonic acid) with ternatin (flavonoid isolated from Egletes
      viscosa Less.) in cyclophosphamide (CYP) and ifosfamide (IFS) induced hemorrhagic
      cystitis (HC). Male Wistar rats received an intraperitoneal injection of saline,
      CYP or IFS and were treated with saline or mesna, 5 min before, 4 and 8 h after
      CYP or IFS administration. In other animals, 1, 2 or 3 doses of mesna were
      replaced with ternatin or 3 doses of mesna were replaced with dimethylsulphoxide
      (DMSO), ternatin diluent. In an additional group, the last 2 doses of mesna were
      replaced with saline. HC was evaluated 24 h after CYP or IFS administration. CYP
      or IFS treatment induced marked changes in macroscopic and microscopic evaluation
      and in bladder wet weight (BWW), and these alterations were significantly
      inhibited by treatment with 3 doses of mesna, as well as by the replacement of 1
      or 2 doses of mesna with ternatin. The replacement of 2 doses of mesna with
      saline or all doses of mesna with ternatin or DMSO did not prevent HC. In
      conclusion, the replacement of 1 or 2 doses of mesna with ternatin efficiently
      blocked CYP- or IFS-induced HC, however mesna is necessary for initial
      uroprotection.

PMID- 15022167
TI  - Protective effects of alpinae oxyphyllae fructus (Alpinia oxyphylla MIQ) water
      extracts on neurons from ischemic damage and neuronal cell toxicity.
AB  - Alpinae Oxyphyllae Fructus (Alpinia oxyphylla MIQ) (Korean name Ik-Jj-In) is a
      medicinal plant used in Korea for the treatment of various symptoms accompanying
      hypertension and cerebrovascular disorders. The present study was performed to
      investigate the effects of Alpinae Oxyphyllae Fructus water-extracts (AOF) on a
      cultured primary neuron cell system, cell cytotoxicity and lipid peroxidation in
      Abeta treatment conditions. Cell killing was significantly enhanced by addition
      of increasing concentrations of Abeta. Pretreatment of AOF attenuated in cell
      killing enhanced by increasing concentrations of Abeta. Abeta-induced cell death
      was protected by the application of water extract of AOF in a dose-dependent
      manner, and concentrations of 50 to 100 micro g/ml had a significant effect
      compared to exposure of Abeta only. AOF has been shown to protect primary
      cultured neurons from N-methyl-D-aspartate (NMDA) receptor-mediated glutamate
      toxicity. The evidence indicated that AOF protects neurons against ischemia
      induced cell death. Oral administration of AOF into mice prevented ischemia
      induced learning disability and rescued hippocampal CA1 neurons from lethal
      ischemic damage. The neuroprotective action of exogenous AOF was also confirmed
      by counting synapses in the hippocampal CA1 region. The presence of AOF in neuron
      cultures did not repress a NMDA receptor-mediated increase in intracellular
      Ca(2+), but rescued the neurons from NO-induced death. AOF may exert its
      neuroprotective effect by reducing the NO-mediated formation of free radicals or
      antagonizing their toxicity.

PMID- 15022169
TI  - Estimation of naphthaquinones from Arnebia hispidissima (Lehm.) DC. In vivo and
      in vitro. I. Anti-inflammatory screening.
AB  - The hexane extract of Arnebia hispidissima yielded a mixture of naphthaquinones:
      arnebin-1, arnebin-7, tiglic acid (ester of dihydroxy alkannin), alkannin,
      arnebinol and cycloarnebin-7. To evaluate the anti-inflammatory activities of
      hexane extract and isolated naphthaquinones, models with carrageenan-induced
      acute arthritis and complete Freund's adjuvant (CFA)-induced chronic arthritis in
      rats were conducted. The observed results indicated that pretreatment with
      cycloarnebin-7 significantly inhibited the carrageenan-induced acute arthritis.
      Moreover, arnebin-1, significantly suppressed the development of chronic
      arthritis induced by CFA. The present study deals with the quantification of
      naphthaquinones from in vivo and in vitro cell cultures of plant species and
      isolated compounds from intact plant tested for their swelling inhibitory
      potency. It has been reported that arnebin-1 was the major naphthaquinone both in
      vivo (0.62%) and in vitro (0.27%) cell cultures.

PMID- 15022168
TI  - Comparing an in vitro electrochemical measurement of superoxide scavenging
      activity with an in vivo assessment of antioxidant potential in Chinese tonifying
      herbs.
AB  - The in vitro superoxide scavenging activity (as determined by electrochemical
      measurement) and the in vivo antioxidant potential (as determined by a mouse
      model of carbon tetrachloride (CCl(4)) hepatotoxicity) of methanolic extracts
      prepared from 10 Chinese tonifying herbs were compared. Electrochemical
      measurement using a cytochrome c (Cyt. c) sensor showed that all of the tested
      herbal extracts exhibited a medium superoxide scavenging activity of different
      potency, as indicated by their IC(50) values. The in vivo measurement
      demonstrated that 80% of the herbal extracts displayed in vivo antioxidant
      potential, as assessed by the percentage of protection of the activity of plasma
      alanine aminotransferases and the hepatic glutathione regeneration capacity under
      CCl(4)-intoxicated condition. Although the in vitro antioxidant activity did not
      correlate quantitatively with the in vivo antioxidant potential, for 8 out of 10
      samples a similar tendency was found. The rapid amperometric assessment of
      antioxidant potential by Cyt. c sensor may offer a convenient and direct method
      for screening as well as the quality control of herbal products.

PMID- 15022170
TI  - Effect of Acanthopanax senticosus on lipoprotein lipase in 3T3-L1 adipocytes.
AB  - The effect of Acanthopanax senticosus (AS) leaves on lipoprotein lipase (LPL) was
      investigated in 3T3-L1 adipocytes. A water extract of AS leaves increased the LPL
      activity in culture medium of adipocytes in a dose- and time-dependent manner.
      The AS extract contained heparin-like LPL releasing components, however, the
      increase of medium LPL activity was continued up until 12 h, in contrast to the
      rapid decline after heparin treatment. The increase of LPL mRNA was also observed
      after AS extract treatment, suggesting that LPL induction occurs at the
      transcriptional level. The AS extract could partially reverse the LPL suppression
      by tumour necrosis factor-alpha in 3T3-L1 adipocytes. These results of an AS
      extract-induced increase of LPL activity in vitro suggest the possible action of
      AS as a facilitator of plasma triglyceride clearance.

PMID- 15022171
TI  - A hot water extract of Chlorella pyrenoidosa reduces body weight and serum lipids
      in ovariectomized rats.
AB  - The effects of a hot water extract of Chlorella pyrenoidosa, which contains
      chlorella growth factor (CGF), on the body weight, serum lipids, and the bone
      mass were evaluated using an ovariectomized rat as a model for postmenopausal
      bone loss. Rats were divided into four groups: sham-operated (Sham), Sham given
      the CGF solution, ovariectomized (OVX), and OVX given the CGF solution,
      respectively. Administration of the extract to OVX rats suppressed the body
      weight gain. After 7 weeks, the administration of the extract to the OVX group
      reduced increases in both serum total cholesterols and high-density lipoprotein
      (HDL) cholesterols. It also normalized the decrease of triglyceride level in the
      OVX group. The ovariectomy decreased the tibial bone mineral density (BMD) by
      19%, and the administration of the extract to OVX rats did not inhibit this
      decrease. These results suggest that a dietary supplement of CGF may be useful to
      control the body weight and improve lipid metabolism of menopausal women.

PMID- 15022172
TI  - Studies on psychopharmacological effects of Cleome viscosa Linn. extract in rats
      and mice.
AB  - Methanol extract of the entire plant Cleome viscosa Linn. (CVME) was evaluated
      for different psychopharmacological actions such as general behaviour,
      exploratory behaviour, muscle relaxant activity and phenobarbitone induced
      sleeping time and effects on normal body temperature in rats and mice. The
      extract was found to cause reduction in spontaneous activity, decrease in
      exploratory behavioural pattern by the head dip and Y-maze test, reduction in the
      muscle relaxant by rotarod, 30 degrees inclined screen and traction tests and
      caused significant lowering of body temperature. In addition, CVME significantly
      potentiated the phenobarbitone-induced sleeping time. Preliminary tests indicate
      that the methanol extract of Cleome viscosa Linn. in doses of 200-400 mg/kg has
      significant psychopharmacological activity.

PMID- 15022173
TI  - An antidepressant effect of Sho-ju-sen, a Japanese herbal medicine, assessed by
      learned helplessness model in mice.
AB  - The antidepressant effect of Sho-ju-sen, a Japanese herbal medicine composed of
      extracts of three herbs; kumazasa leaf (Sasa Kurinensis Makino et Sibata),
      Japanese red pine leaf (Pinus densiflora Sieb. et Zucc) and ginseng radix (Panax
      ginseng C.A. Meyer), was assessed using a learned helplessness model in mice. The
      learned helplessness was produced by presenting 120 unavoidable/inescapable
      shocks for 3 days to the mouse in a shuttle box, and the avoidance training was
      carried out on day 4. Compared with the control group given tap water, free
      consumption of Sho-ju-sen (1%, 3% and 10%) for 21 days resulted in a significant
      amelioration of the response rate at 1% and 3%, and both the response rate and %
      avoidance at 10%. Although Sho-ju-sen (10%) caused no significant effect
      following the 7-day intake, it ameliorated the response rate following the 14-day
      intake. The extract of Japanese red pine leaf, but not kumazasa leaf or ginseng
      radix, mildly improved the response rate. Learned helplessness was significantly
      and dose-dependently reduced by imipramine (10 and 30 mg/kg i.p.), while only
      mildly by diazepam (1 mg/kg p.o.). These results suggest that a long-term
      consumption of Sho-ju-sen is effective for the amelioration of depression, and
      the effectiveness is derived mainly from the extract of Japanese red pine leaf.

PMID- 15022174
TI  - Effect of green tea polyphenols on the genes with atherosclerotic potential.
AB  - The genomics of atherosclerosis can arise as a result of cross-talk between the
      genes coding for the LDL-receptor (LDL-R), LXR-alpha, PPARs (alpha, gamma), CD36
      and C-myc because these genes control lipid metabolism, cytokine production and
      cellular activity within the arterial wall. The effect of green tea polyphenols
      (GTPs) upon such genomics revealed their ability to down-regulate genes coding
      for PPAR-gamma, CD36, LXR-alpha, C-myc coupled with up-regulation of genes coding
      for LDL-R and PPAR-alpha at the transcriptional level. Based upon these results,
      it is proposed that GTPs have the inherent capacity to inhibit the development of
      atherosclerotic lesions.

PMID- 15022175
TI  - Antibacterial activity of ent-kaurene diterpenoids from Rabdosia rosthornii.
AB  - Biological activities of ent-kaurene diterpenoids, rosthornins A-D, isolated from
      the ether extract of the dried leaves of Rabdosia rosthornii (Diels) Hara
      (Labiatae) were tested. They exhibited antibacterial activity specifically
      against Gram-positive bacteria, among which Propionibacterium acnes was noted to
      be the most susceptible.

PMID- 15022176
TI  - Pseudoguaianolide sesquiterpene lactones with high activities against the human
      malaria parasite Plasmodium falciparum.
AB  - Four sesquiterpene lactones of the pseudo-guaianolide type (helenalin,
      dihydrohelenalin and their acetates), have shown activities against asexual blood
      forms of Plasmodium falciparum in vitro. Their IC(50) values were situated in the
      range of 0.23 to 7.41 micro M. The activity found for helenalin was high, even
      compared to the activity found for artemisinin.

PMID- 15022177
TI  - Effectiveness of Harpagophytum extracts and clinical efficacy.
AB  - Various preparations from Harpagophytum procumbens are used for the treatment of
      pain in the joints and lower back. Studies published in peer reviewed journals
      were examined for their clinical evidence. The studies offering preparations with
      50-60 mg harpagoside in the daily dosage are of better quality and provide more
      reliable evidence on efficacy than a proprietary ethanol extract with half the
      amount of harpagoside per day. However, confirmatory studies are required for all
      extracts before they can gain a place in treatment guidelines.

PMID- 15022178
TI  - Progressive supranuclear palsy: new disease or variant of postencephalitic
      parkinsonism?
AB  - We review the etiological importance of the epidemic encephalitis for progressive
      supranuclear palsy (PSP) and addresses the question of whether the explosion of
      PSP literature in the mid-20th century reflects the appearance of a new disease.
      We examined 2,000 studies on Parkinson's disease from 1861 to 1963 and found PSP
      like cases in the past, before the epidemic encephalitis era. It can be assumed
      that PSP is neither a new disease nor a variant of postencephalitic parkinsonism.

PMID- 15022179
TI  - Identification of psychogenic, dystonic, and other organic tremors by a coherence
      entrainment test.
AB  - The differentiation of psychogenic from organic tremors, particularly those of a
      dystonic nature, can be difficult on clinical grounds. Entrainment of tremulous
      movements of different body parts into a single rhythm has been used clinically
      as a means of distinguishing these tremor forms, based on the inability of a
      patient with hysterical tremor to generate voluntary tapping oscillations
      independent of their ongoing tremor oscillation. The coherence entrainment test
      is a quantified electrophysiological entrainment test performed on accelerometer
      or surface EMG tremor signals. This test was carried out on 25 patients referred
      with suspected psychogenic tremor or dystonic tremor and on 10 normal subjects
      attempting to tap two independent voluntary oscillations. Using established and
      new clinical diagnostic criteria, patients were assigned the following final
      clinical diagnoses: 6 cases of clinically definite dystonic tremor, 5 cases of
      probable dystonic tremor, 2 cases of classic essential tremor, 5 cases of
      clinically definite psychogenic tremor, 3 cases of probable psychogenic tremor
      and 4 uncertain cases. On comparing these clinical diagnoses with those reached
      by a coherence entrainment test subsequently carried out on each patient, there
      was 100% concordance in both clinically definite and clinically probable
      patients. In uncertain cases, when later clinical information came to light, this
      also corroborated with the coherence entrainment diagnosis. No normal subjects
      were able to "mimic" organic tremor. The coherence entrainment test appears to be
      a sensitive and specific means of distinguishing psychogenic tremor from dystonic
      and other organic tremors.

PMID- 15022180
TI  - Factor structure of parkinsonian signs in the community-dwelling elderly.
AB  - Parkinsonian signs are present in 40% of older people. Factor analysis of the
      motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) in patients
      with Parkinson's disease (PD) has identified several principal domains, including
      rigidity, axial function, and rest tremor. We hypothesized that if Parkinsonian
      signs in the elderly were due to basal ganglia dysfunction that this same
      constellation of factors (rigidity, axial function, rest tremor) would emerge in
      a factor analysis. We carried out factor analysis, using the principal component
      method with orthogonal (varimax) rotation, on motor UPDRS scores in community
      dwelling elderly without PD. A modified (10-item) version of the motor portion of
      the UPDRS was administered to 1,339 older adults living in the Washington Heights
      Inwood community and it was found that Parkinsonian signs were present in 537
      (40.1%). Three factors (rigidity, axial function. and rest tremor) were obtained
      from the factor analysis and, together, explained 67.4% of the variance. A second
      factor analysis was carried out excluding the 26 participants with rest tremor,
      and two factors (rigidity, axial function) emerged. These data support the view
      that Parkinsonian signs in older adults might be due to basal ganglia
      dysfunction, a possibility that requires further exploration.

PMID- 15022181
TI  - Corticospinal excitability accompanying ballistic wrist movements in primary
      dystonia.
AB  - Current models of basal ganglia dysfunction in primary dystonia propose that the
      excessive muscle activity results from an increase in the excitability of the
      primary motor cortex. Neurophysiological and neuroimaging studies, however, have
      shown consistently reduced movement-related sensorimotor cortical activity. To
      explore this paradox, we used transcranial magnetic stimulation (TMS) to examine
      changes in corticospinal excitability preceding and during ballistic movements of
      the wrist in 9 patients with primary dystonia affecting the arm and 9 matched
      control subjects. The onset time, rate of rise, and duration of changes in the
      excitability of corticospinal projections to the agonist muscle were normal in
      the patients with dystonia. Increases in excitability were selective to the
      initial agonist muscle, suggesting that the spatial recruitment of corticospinal
      neurons was normal. Nonetheless, movements were slower in the patients by an
      average of 26%. The onset of the first agonist muscle burst was normal in
      magnitude and timing but the activity in this muscle subsequently became
      attenuated as movement progressed. Muscle activity in antagonist and proximal
      muscles of the upper arm was reduced significantly in the dystonia patients.
      These findings support the view that movement preparation and initiation at the
      level of the primary motor cortex is normal in patients with dystonia.
      Bradykinesia could not be attributed to co-contraction or overflow of activity
      and was associated with reduced rather than excessive muscle activity.

PMID- 15022182
TI  - Objective assessment of motor slowness in Huntington's disease: clinical
      correlates and 2-year follow-up.
AB  - Functional disability of patients with Huntington's disease (HD) is determined by
      impairment of voluntary motor function rather than the presence of chorea.
      However, only few attempts have been made to quantify this motor impairment. By
      using a simple reaction time paradigm, we measured the time needed for movement
      initiation (akinesia) and execution (bradykinesia) in 76 HD patients and 127
      controls. Akinesia and bradykinesia were already evident in early stages and
      increased linearly with increasing disease stage. Quantified motor slowness
      correlated with clinical impairment of voluntary movements but also with
      cognitive impairment and medication use. In patients without severe cognitive
      impairment, quantified motor slowness reflected clinical motor impairment more
      purely. During 1.9 years follow-up (range, 0.8-3.8 years), quantified akinesia
      and bradykinesia progressed concomitantly with progression of clinical impairment
      of voluntary movements, cognition, and functional capacity. However, rate of
      change in motor slowness did not discriminate between patients whose disease
      stage remained stable and those whose disease stage progressed. We conclude that
      the reaction time paradigm may be used to quantify akinesia and bradykinesia in
      HD, at least in patients without severe cognitive impairment. Although reaction
      and movement times increased in time, these measures failed to detect
      functionally important changes during our follow-up period.

PMID- 15022184
TI  - Long-term follow-up of cervical dystonia patients treated with botulinum toxin A.
AB  - We followed the course in 100 consecutive patients with cervical dystonia (CD)
      after they were initially treated with botulinum toxin (BTX) in the form of
      Dysport 10 to 12 years ago. A total of 4 patients had died, and 6 were lost to
      follow-up. Of the remaining 90 patients, 57 (63%) were still treated with BTX. In
      the patients treated at one centre over the whole period with Dysport, mean dose
      used during each treatment session was 833 (SD +/- 339) units Dysport with a
      cumulative dose of 20,943 (SD +/- 9462) units Dysport over a mean of 26.8 (SD +/-
      8.6) treatment cycles. Secondary nonresponse was detected in 3 of the 90
      patients. During follow-up, 12 patients developed blepharospasm, 13 oromandibular
      dystonia, and 17 patients writer's cramp. We conclude that BTX remains effective
      and safe for approximately 60% of CD patients for more than 10 years.

PMID- 15022183
TI  - Cardiovascular effects of methamphetamine in Parkinson's disease patients.
AB  - Cardiovascular responses after intravenous methamphetamine were assessed in 11
      Parkinson's disease (PD) patients. Systolic blood pressure (SBP), diastolic blood
      pressure (DBP), heart rate (HR), and electrocardiogram (ECG) were monitored for
      103 minutes. After methamphetamine administration, SBP and DBP increased
      significantly in both PD and normal controls whereas placebo had no effect. In PD
      patients, however, the duration of SBP and DBP responses to methamphetamine and
      the maximum increase from baseline was attenuated compared with the controls. A
      significant correlation was found between individual BP responsiveness and the
      Unified Parkinson's Disease Rating Scale (UPDRS) motor score. These findings
      suggest that in PD there is impairment of catecholamine release from peripheral
      sympathetic presynaptic terminals, which correlates with motor impairment.

PMID- 15022185
TI  - Assessing quality of life in Parkinson's disease: can a short-form questionnaire
      be useful?
AB  - Various instruments with good psychometric properties have been developed for the
      assessment of health-related quality of life (HRQoL) in Parkinson's disease,
      (PD); however, in everyday practice a brief questionnaire is needed for quick
      screening of patients. We present the process of development and validation of
      the Greek version of PD questionnaire-8 (PDQ-8(GrV)), which is an 8-item scale
      derived from a well-known measure for the evaluation of HRQoL in PD, the PD
      questionnaire (PDQ-39). PDQ-8 (GrV) was applied to 228 nondemented Greek PD
      patients. Data from PDQ-39 were also collected from these patients for
      comparisons between the total scores of the two scales. Detailed statistical
      analysis showed that PD-8(GrV) has psychometric properties analogous to its
      parent questionnaire.

PMID- 15022186
TI  - Health-related quality of life evaluation by proxy in Parkinson's disease:
      approach using PDQ-8 and EuroQoL-5D.
AB  - Patient- and caregiver-based scores were compared and agreement levels
      ascertained to determine the reliability of proxy evaluation of Parkinson's
      Disease (PD) patients' health-related quality of life (HRQoL) using the EuroQoL
      and PD questionnaire (PDQ)-8. Of 72 patient-caregiver pairs, 64 (88.88%) returned
      the questionnaires. The degree of agreement varied for individual dimensions.
      Proxy evaluation of PD patients' HRQoL showed limitations mainly with assessments
      using the EuroQoL and especially in patients with severe disease and depression.

PMID- 15022187
TI  - Parkinson's prevalence estimated by a state registry.
AB  - A solid understanding of the descriptive epidemiology of a disease is essential
      in etiologic investigations; this includes prevalence and incidence, as well as
      groups within the larger community who may have noticeably lower or higher rates.
      We ascertained the usefulness of a non-traditional registry in describing
      Parkinson's disease (PD) patterns in a community. A passive surveillance PD
      registry in Nebraska began data collection on 1 January 1997. All physicians were
      required to report PD diagnosis, pharmacists reported new prescriptions of anti
      PD drugs (PD cases were confirmed later with the prescribing physician), and
      there was a patient self-report mechanism. The overlap of reporting by the
      sources allowed estimation of the number not reported by any source, using the
      statistical technique "capture-recapture." As of January 2000, the Nebraska PD
      Registry had reports of 5,062 PD patients. The number not reported by any
      Registry reporting source was calculated to be 117, leading to an estimated total
      of 5,179 cases and a prevalence of 329.3 per 100,000 population. Tabulations of
      age- and gender-specific prevalence rates, as well as county-level estimates,
      allow examination of areas of elevated or lowered prevalence. The combination of
      a passive surveillance system and capture-recapture technique presents a useful
      method for epidemiologic description, and more traditional survey methods could
      benefit by including capture-recapture capability.

PMID- 15022189
TI  - Gestes antagonistes in psychogenic dystonia.
AB  - We report on a patient with psychogenic craniocervical dystonia who had complete
      amelioration of her dystonia using typical gestes antagonistes. This exceptional
      case underlines the lack of specificity of these maneuvers for organic dystonia
      when confronted with more obvious clinical clues.

PMID- 15022188
TI  - Autosomal recessive juvenile parkinsonism Cys212Tyr mutation in parkin renders
      lymphocytes susceptible to dopamine- and iron-mediated apoptosis.
AB  - Mutations in parkin are implicated in the pathogenesis of autosomal recessive
      juvenile parkinsonism (AR-JP) disease. We show that homozygote Cys212Tyr parkin
      mutation in AR-JP patients renders lymphocytes sensitive to dopamine, iron and
      hydrogen peroxide stimuli. Indeed, dopamine-induced apoptosis by four alternative
      mechanisms converging on caspase-3 activation and apoptotic morphology: (1) NF
      kappaB-dependent pathway; mitochondrial dysfunction either by (2) H(2)O(2) or (3)
      hydroxyl exposure and (4) increase of unfolded-protein stress. We also
      demonstrate that 17beta-estradiol and testosterone prevent homozygote lymphocytes
      from oxidative stressors-evoked apoptosis. These results may contribute to
      understanding the relationship between genetic and environmental factors and iron
      in AR-JP.

PMID- 15022190
TI  - Psychogenic palatal tremor.
AB  - Recent criteria for the classification of palatal tremor use clinical, imaging,
      and electrophysiological features to differentiate essential and symptomatic
      forms. A case of probable psychogenic palatal tremor (PPT) is described within
      the context of these criteria, which lack clear guidelines for diagnosing PPT.
      The heterogenous nature of essential palatal tremor and its relationship with
      PPT, voluntary palatal movements, and tics is discussed.

PMID- 15022191
TI  - Reversal of hypertonic co-contraction after bilateral pallidal stimulation in
      generalised dystonia: a clinical and electromyogram case study.
AB  - In a patient of generalised dystonia treated with bilateral pallidal stimulation,
      serial surface EMGs recorded from the neck muscles during alternating head
      movements revealed progressive reduction in hypertonic activity and reversal of
      co-contraction to reciprocal contraction, which preceded clinical improvement.

PMID- 15022192
TI  - Gliomatosis cerebri may present as an atypical parkinsonian syndrome.
AB  - An 85-year-old man presented with 3 years of a progressive akinetic rigid
      syndrome with ataxia, falls, levodopa unresponsiveness, and autonomic
      dysfunction. Early in the course of illness, cranial magnetic resonance imaging
      (MRI) was thought to show pontine enlargement but later was reinterpreted by
      experts as normal. Two subsequent cranial MRIs were believed to show only mild
      atrophy. An initial clinical diagnosis of multiple system atrophy was made. The
      patient died 4 years after the onset of symptoms. Pathological examination
      revealed diffuse infiltration of multiple brain regions with cells of astrocytic
      and microglial origin consistent with a diagnosis of gliomatosis cerebri.

PMID- 15022193
TI  - Myoclonus and generalized digestive dysmotility in triple A syndrome with AAAS
      gene mutation.
AB  - We report on the case of a 25-year-old woman with triple A syndrome and gene
      mutation, who, during the long follow-up period of 23 years, developed myoclonus
      of the face and the upper limbs (with normal brain magnetic resonance
      spectroscopy) and widespread digestive dysmotility, involving small bowels and
      gall bladder. These features, not previously described, illustrate an extension
      of the cerebral and digestive neurological involvement in this syndrome.

PMID- 15022194
TI  - Gaze-evoked brainstem myoclonus.
AB  - The clinical and electrophysiological aspects of a case where brainstem reticular
      reflex myoclonus was related to an enlarging pontine lesion are described. It had
      the unusual characteristic of being evoked by sustained up gaze and left gaze.

PMID- 15022195
TI  - Chorea and contraceptives: case report with pet study and review of the
      literature.
AB  - Chorea is a well-recognized but rare complication of oral contraceptive use. A 27
      year-old woman developed right hemichorea while taking an oral contraceptive
      (OC). No other causes of chorea were found. A positron emission tomography (PET)
      study with (18)F-fluorodeoxyglucose demonstrated a dense focus of increased
      glucose metabolism involving the body of the left caudate nucleus. To our
      knowledge, this is the first report of a PET study in a patient with OC-induced
      chorea in the absence of systemic lupus erythematosus or antiphospholipid
      antibodies.

PMID- 15022196
TI  - Asymmetrical awake bruxism associated with multiple system atrophy.
AB  - We describe a 51-year-old man who developed awake bruxism during the course of
      multiple system atrophy. Electromyographic studies revealed side-to-side
      amplitude asymmetry of the bursts of motor activity. The bruxism responded
      favourably to low-dose levodopa-carbidopa therapy. Possible mechanisms of this
      rare association are discussed.

PMID- 15022197
TI  - Phosphorylated amino acids: model compounds for solid-state 31P NMR spectroscopic
      studies of proteins.
AB  - Solid-state 31P NMR spectroscopy was applied to measure the isotropic chemical
      shifts, chemical shift anisotropies and asymmetry parameters of three
      phosphorylated amino acids, O-phospho-L-serine, O-phospho-L-threonine and O
      phospho-L-tyrosine. The cross-polarization buildup rates and longitudinal
      relaxation times of 31P and 1H were-determined and compared with the values
      measured for a triphosphate (GppCH2p) bound to a crystalline protein (Ras). It is
      shown that the phosphorylated amino acids are well-suited model compounds, e.g.
      for the optimization of experiments on crystalline proteins. Two-dimensional
      exchange experiments on O-phospho-L-tyrosine indicate the existence of an
      exchange between the two different conformations of the molecule.

PMID- 15022198
TI  - Structural elucidation by 1D and 2D NMR of three isomers of a carotenoid
      lysophosphocholine and its synthetic precursors.
AB  - A carotenoic acid was used to obtain a long-chain unsaturated lysophosphocholine.
      The carotenoid lysophosphocholine was synthesized by two methods. The first
      method resulted in mixtures of regioisomers for each step in the synthetic route.
      Homo- and heteronuclear 1D and 2D NMR methods were employed to elucidate the
      structures of the individual isomers and their intermediates. The pure
      regioisomer [1-(beta-apo-8'-carotenoyl)-2-lyso-glycero-3-phosphocholine] was
      obtained by a second method, but in low yield. The 1D 1H NMR subtraction spectrum
      of the mixture and the pure regioisomer was used to interpret the 1H shifts of
      the unsaturated acyl moieties. The 1H and 13C signals of the acyl chain show
      characteristic shifts depending on the positions of the choline and the acyl
      group attached to the glycerol backbone. Therefore, the unsaturated acyl chain
      signals have diagnostic values for the identification of isomers of unsaturated
      (lyso)phosphocholines. Chemical shifts and indirect coupling constants are
      reported for each of the major components of the mixtures. The methods used were
      1D (1H, 13C and 31P) and 2D (H,H-COSY, HMBC, HSQC and HETCOR) NMR.

PMID- 15022199
TI  - Evidence of a phase transition of RbHCO3 from high-resolution solid-state 13C and
      87Rb NMR by comparison with KHCO3.
AB  - A variable-temperature high-resolution 13C and 87Rb solid-state NMR study of
      powder rubidium hydrogencarbonate, RbHCO3, is presented for the first time. At
      ambient temperature, RbHCO3 is formed by centrosymmetric dimers linked by
      hydrogen bonds, but almost no information is available on this compound
      concerning proton disorder and the low-temperature phase. However, potassium
      hydrogencarbonate, KHCO3, which has an isomorphic structure for the high
      temperature phase, was well studied: it undergoes a non-ferroic, non
      ferroelectric phase transition at Tc = 318 K between two monoclinic structures.
      The protons are disordered in an asymmetric double-well potential in the low
      temperature phase, and the double-well potential becomes symmetric in the high
      temperature phase. By comparison with recent solid-state NMR experimental results
      on KHCO3, we show that RbHCO3 undergoes a phase transition at Tc approximately
      245 K, and give evidence that the proton dynamic disorder in both compounds is
      very similar.

PMID- 15022200
TI  - Chiral discrimination studies of (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid
      by high-performance liquid chromatography and NMR spectroscopy.
AB  - Chiral discrimination studies using (+)-(18-crown-6)-2,3,11,12-tetracarboxylic
      acid (18-C-6-TA) as a chiral selector were performed by high-performance liquid
      chromatography (HPLC) and NMR spectroscopy. The enantiomers of alanine (Ala) or
      alanine methyl ester (Ala-ME) were well separated on the chiral stationary phases
      (CSPs) derived from (+)-18-C-6-TA by HPLC. The chiral selector, (+)-18-C-6-TA,
      used in the CSP was also applied for the chiral discrimination of the Ala and Ala
      ME enantiomers, and it discriminated these enantiomers successfully by NMR
      spectroscopy. The chemical shift differences (Delta Delta delta) of the alpha
      proton of these enantiomers in the presence of an equimolecular solution of 18-C
      6-TA were observed to be 0.10 ppm for Ala in methanol-d4 containing 10 mM H2SO4
      and 0.11 ppm for Ala-ME in methanol-d4. The observed NMR results agreed with the
      chromatographic data on the (+)-18-C-6-TA-derived CSP by HPLC in terms of both
      the elution order and solvents effects.

PMID- 15022201
TI  - Is high-resolution magic angle spinning NMR a practical speciation tool for
      cheese samples? Parmigiano Reggiano as a case study.
AB  - High-resolution magic angle spinning (HRMAS) NMR is probably the most apt NMR
      method to analyze complex materials involving a solid phase, e.g. foodstuffs. We
      present here an HRMAS analysis of grated cheese (Parmigiano Reggiano). A full NMR
      characterization of this cheese allows the identification of the presence of
      fatty acids (saturated and unsaturated), amino acids and other small organic
      molecules. Since the presence and relative concentration of these molecules have
      previously been shown to correlate with organoleptic, origin and age
      characterization, HRMAS NMR of cheese is likely to provide a good complimentary
      tool for the analysis of this food material.

PMID- 15022202
TI  - Structure elucidation of 11-amino-8-hydroxypentacyclo[5.4.0.0(2, 6).0(3, 10).0(5,
      9)]undecane-8,11-lactam through selective acetylation and complete 1H and 13C NMR
      spectral assignment of the mono-, di- and triacetates.
AB  - NMR techniques cannot unambiguously distinguish between 11-amino-8
      hydroxypentacyclo[5.4.0.0(2, 6).0(3, 10).0(5, 9)]undecane-8,11-lactam and 8-amino
      11-hydroxypentacyclo[5.4.0.0(2, 6).0(3, 10).0(5, 9)]undecane-8,11-lactam, both of
      which are possible products during the reaction of pentacyclo[5.4.0.0(2, 6).0(3,
      10).0(5, 9)]undecane-8,11-dione with Strecker reagents. Treatment of 11-amino-8
      hydroxy-pentacyclo[5.4.0.0(2, 6).0(3, 10).0(5, 9)]undecane-8,11-lactam with
      acetic anhydride at room temperature produced a monoacetate. With acetic
      anhydride containing sodium acetate, a triacetate was obtained at reflux
      temperature. Treatment with acetyl chloride and N,N-dimethylaniline produced a
      diacetate. High-field 1H and 13C NMR techniques were used in the structure
      elucidation and assignment of the different NMR resonances of these three
      acetylated compounds.

PMID- 15022203
TI  - Assignment of 13C resonances of a nematic liquid crystal using off-magic angle
      spinning.
AB  - A novel method for assigning the resonances in the 13C NMR spectrum of a static
      liquid crystalline sample in its nematic phase is proposed. The method is based
      on the fact that the carbon chemical shifts in the isotropic phase and in the
      oriented phase under static and off-magic angle spinning (OMAS) conditions are
      uniquely related by the tensorial property of the CSA tensor, requiring just one
      OMAS spectrum and the assignment in the isotropic phase. A computational
      procedure is proposed to take into account deviations arising out of non-ideal
      experimental conditions and the assignments are made by identifying the minimum
      in the differences in the frequencies between calculated and experimental line
      positions. Practical implementation of the method has also been demonstrated in
      the case of the liquid crystal N-(4-ethoxybenzylidene)-4-n-butylaniline.

PMID- 15022204
TI  - 47, 49Ti NMR spectra of half-sandwich titanium(IV) complexes.
AB  - The 47, 49Ti chemical shifts, resonance line half-widths (Deltanu1/2) and
      energies of the first electronic charge-transfer transitions (lambdamax1.CT) of
      Cp'TiX3, where Cp' = eta5-C5H5 (Cp), eta5-C5H4Me (MeCp), eta5-C5HMe4 (Me4Cp),
      eta5-C5Me5 (Me5Cp), eta5-C5H4SiMe3 (SiCp), eta5-C5H4SnMe3 (SnCp) and eta5
      C5H4SiMe2Cl (Si'Cp) and X = Cl, Br, I and OBut, half-sandwich complexes are
      reported. For the compounds studied, a direct linear relationship between
      delta(49Ti) and lambdamax1.CT was found.

PMID- 15022205
TI  - Case/pseudocontrol analysis in genetic association studies: A unified framework
      for detection of genotype and haplotype associations, gene-gene and gene
      environment interactions, and parent-of-origin effects.
AB  - Estimation and testing of genetic effects (genotype relative risks) are often
      performed conditionally on parental genotypes, using data from case-parent trios.
      This strategy avoids having to estimate nuisance parameters such as parental
      mating type frequencies, and also avoids generating spurious results due to
      confounding causes of association such as population stratification. For effects
      at a single locus, the resulting analysis is equivalent to matched case/control
      analysis via conditional logistic regression, using the case and three
      "pseudocontrols" derived from the untransmitted parental alleles. We previously
      showed that a similar approach can be used for analyzing genotype and haplotype
      effects at a set of closely linked loci, but with a required adjustment to the
      conditioning argument that results in varying numbers of pseudocontrols,
      depending on the disease model that is to be fitted. Here we extend this method
      to include the analysis of epistatic effects (gene-gene interactions) at unlinked
      loci, to include parent-of-origin effects at one or more loci, and to allow
      additional incorporation of gene-environment interactions. The conditional
      logistic approach provides a natural and flexible framework for incorporating
      these additional effects. By relaxing the conditioning on parental genotypes to
      allow exchangeability of parental genotypes, we show how the power of this
      approach can be increased when studying parent-of-origin effects. Simulations
      suggest that there is limited power to distinguish between parent-of-origin
      effects and effects due to interaction between genotypes of mother and child.

PMID- 15022206
TI  - Properties of case/pseudocontrol analysis for genetic association studies:
      Effects of recombination, ascertainment, and multiple affected offspring.
AB  - The case/pseudocontrol approach is a general framework for family-based
      association analysis, incorporating several previously proposed methods such as
      the transmission/disequilibrium test and log-linear modelling of parent-of-origin
      effects. In this report, I examine the properties of methods based on a
      case/pseudocontrol approach when applied to a linked marker rather than (or in
      addition to) the true disease locus or loci, and when applied to sibships that
      have been ascertained on, or that may simply contain, multiple affected sibs.
      Through simulations and analytical calculations, I show that the expected values
      of the observed relative risk parameters (estimating quantities such as effects
      due to a child's own genotype, maternal genotype, and parent-of-origin) depend
      crucially on the ascertainment scheme used, as well as on whether there is non
      negligible recombination between the true disease locus and the locus under
      study. In the presence of either recombination or ascertainment on multiple
      affected offspring, methods based on conditioning on parental genotypes are shown
      to give unbiased genotype relative risk estimates at the true disease locus (or
      loci) but biased estimates of population genotype relative risks at a linked
      marker, suggesting that the resulting estimates may be misleading when used to
      predict the power of future studies. Methods that allow for exchangeability of
      parental genotypes are shown (in the presence of either recombination or
      ascertainment on multiple affected offspring) to produce false-positive evidence
      of maternal genotype effects when there are true parent-of-origin or mother-child
      interaction effects, even when analyzing the true locus. These results suggest
      that care should be taken in both the interpretation and application of parameter
      estimates obtained from family-based genetic association studies.

PMID- 15022207
TI  - Evaluations of maximization procedures for estimating linkage parameters under
      heterogeneity.
AB  - Locus heterogeneity is a major problem plaguing the mapping of disease genes
      responsible for complex genetic traits via linkage analysis. A common feature of
      several available methods to account for heterogeneity is that they involve
      maximizing a multidimensional likelihood to obtain maximum likelihood estimates.
      The high dimensionality of the likelihood surface may be due to multiple
      heterogeneity (mixing) parameters, linkage parameters, and/or regression
      coefficients corresponding to multiple covariates. Here, we focus on this
      nontrivial computational aspect of incorporating heterogeneity by considering
      several likelihood maximization procedures, including the expectation
      maximization (EM) algorithm and the stochastic expectation maximization (SEM)
      algorithm. The wide applicability of these procedures is demonstrated first
      through a general formulation of accounting for heterogeneity, and then by
      applying them to two specific formulations. Furthermore, our simulation studies
      as well as an application to the Genetic Analysis Workshop 12 asthma datasets
      show that, among other observations, SEM performs better than EM. As an aside, we
      illustrate a limitation of the popular admixture approach for incorporating
      heterogeneity, proved elsewhere. We also show how to obtain standard errors (SEs)
      for EM and SEM estimates, using methods available in the literature. These SEs
      can then be combined with the corresponding estimates to provide confidence
      intervals of the parameters.

PMID- 15022208
TI  - Multipoint linkage analysis of quantitative traits on sex-chromosomes.
AB  - Variance component models form a powerful and flexible tool for multipoint
      linkage analysis of quantitative traits. Estimates of genetic similarity are
      needed for the variance component model to detect linkage and to locate genes,
      and two methods are commonly used to calculate multipoint identity-by-descent
      (IBD) estimates for autosomes. Fulker et al. ([1995] Am. J. Hum. Genet. 56: 1229
      1233) and Almasy and Blangero ([1998] Am. J. Hum. Genet. 62: 119-121) used
      multiple regression to estimate the IBD sharing along a chromosome, while the
      approach of Kruglyak and Lander ([1995] Am. J. Hum. Genet. 57: 439-454) is based
      on a hidden Markov model. In this paper, we modify the variance component model
      to accommodate sex-chromosomes, and we extend both multipoint IBD estimation
      methods to accommodate sex-linked loci. Simulation studies demonstrate the power
      and precision of the variance component model to detect QTLs located on the sex
      chromosome. The two multipoint IBD estimation methods have the same accuracy to
      identify QTL position, but the hidden Markov model yields a larger average
      maximum LOD score to detect linkage than the regression model. The extension of
      the multipoint IBD estimation methods and the variance component model to the X
      chromosome shows that the variance component model is a powerful and flexible
      tool for linkage analysis of quantitative traits on both autosomes and sex
      chromosomes.

PMID- 15022209
TI  - Latent class and genetic analysis does not support migraine with aura and
      migraine without aura as separate entities.
AB  - Latent class and genetic analyses were used to identify subgroups of migraine
      sufferers in a community sample of 6,265 Australian twins (55% female) aged 25-36
      who had completed an interview based on International Headache Society (IHS)
      criteria. Consistent with prevalence rates from other population-based studies,
      703 (20%) female and 250 (9%) male twins satisfied the IHS criteria for migraine
      without aura (MO), and of these, 432 (13%) female and 166 (6%) male twins
      satisfied the criteria for migraine with aura (MA) as indicated by visual
      symptoms. Latent class analysis (LCA) of IHS symptoms identified three major
      symptomatic classes, representing 1) a mild form of recurrent nonmigrainous
      headache, 2) a moderately severe form of migraine, typically without visual aura
      symptoms (although 40% of individuals in this class were positive for aura), and
      3) a severe form of migraine typically with visual aura symptoms (although 24% of
      individuals were negative for aura). Using the LCA classification, many more
      individuals were considered affected to some degree than when using IHS criteria
      (35% vs. 13%). Furthermore, genetic model fitting indicated a greater genetic
      contribution to migraine using the LCA classification (heritability, h(2)=0.40;
      95% CI, 0.29-0.46) compared with the IHS classification (h(2)=0.36; 95% CI, 0.22
      0.42). Exploratory latent class modeling, fitting up to 10 classes, did not
      identify classes corresponding to either the IHS MO or MA classification. Our
      data indicate the existence of a continuum of severity, with MA more severe but
      not etiologically distinct from MO. In searching for predisposing genes, we
      should therefore expect to find some genes that may underlie all major recurrent
      headache subtypes, with modifying genetic or environmental factors that may lead
      to differential expression of the liability for migraine.

PMID- 15022213
TI  - Amine-catalyzed epoxidation of alkenes: a new mechanism for the activation of
      oxone.

PMID- 15022210
TI  - Power of non-parametric linkage analysis in mapping genes contributing to human
      longevity in long-lived sib-pairs.
AB  - This report investigates the power issue in applying the non-parametric linkage
      analysis of affected sib-pairs (ASP) [Kruglyak and Lander, 1995: Am J Hum Genet
      57:439-454] to localize genes that contribute to human longevity using long-lived
      sib-pairs. Data were simulated by introducing a recently developed statistical
      model for measuring marker-longevity associations [Yashin et al., 1999: Am J Hum
      Genet 65:1178-1193], enabling direct power comparison between linkage and
      association approaches. The non-parametric linkage (NPL) scores estimated in the
      region harboring the causal allele are evaluated to assess the statistical power
      for different genetic (allele frequency and risk) and heterogeneity parameters
      under various sampling schemes (age-cut and sample size). Based on the genotype
      specific survival function, we derived a heritability calculation as an overall
      measurement for the effect of causal genes with different parameter settings so
      that the power can be compared for different modes (dominant, recessive) of
      inheritance. Our results show that the ASP approach is a powerful tool in mapping
      very strong effect genes, both dominant and recessive. To map a rare dominant
      genetic variation that reduces hazard of death by half, a large sample (above 600
      pairs) with at least one extremely long-lived (over age 99) sib in each pair is
      needed. Again, with large sample size and high age cut-off, the method is able to
      localize recessive genes with relatively small effects, but the power is very
      limited in case of a dominant effect. Although the power issue may depend heavily
      on the true genetic nature in maintaining survival, our study suggests that
      results from small-scale sib-pair investigations should be referred with caution,
      given the complexity of human longevity.

PMID- 15022214
TI  - A new arene synthesis--or: how inert is the cyclopentadienyl ligand?

PMID- 15022215
TI  - Metal carboxylates with open architectures.
AB  - The field of inorganic open-framework materials is dominated by aluminosilicates
      and phosphates. The metal carboxylates have emerged as an important family in the
      last few years. This family includes not only mono- and dicarboxylates of
      transition, rare-earth, and main-group metals, but also a variety of hybrid
      structures. Some of the carboxylates possess novel adsorption and magnetic
      properties. Dicarboxylates and related species provide an effective means of
      designing novel hybrid structures with porous and other properties. In some of
      these structures, the dicarboxylate acts as a linker between two inorganic units.
      Hybrid nanocomposites are also of particular note, for example, cadmium oxalate
      host lattices that can accommodate extended alkali-metal halide structures. This
      Review discusses the synthesis, structure, and properties of various types of
      open-framework metal carboxylates.

PMID- 15022216
TI  - A red, green, and blue (RGB) polymeric electrochromic device (PECD): the dawning
      of the PECD era.

PMID- 15022217
TI  - Three-dimensional frameworks of gallium selenide supertetrahedral clusters.

PMID- 15022218
TI  - Preparation of mesoporous silica monoliths with ordered arrays of macrochannels
      templated from electric-field-oriented hydrogels.

PMID- 15022219
TI  - A 3D hybrid network containing large spherical cavities formed through a
      combination of metal coordination and hydrogen bonding.

PMID- 15022220
TI  - Ordered self-assembly and electronic behavior of C60-anthrylphenylacetylene
      hybrid.

PMID- 15022222
TI  - Combinatorial catalysis with bimetallic complexes: robust and efficient catalysts
      for atom-transfer radical additions.

PMID- 15022221
TI  - Site-specific introduction of sialic acid into insulin.

PMID- 15022223
TI  - Thermal and photochemical properties of 4',7-dihydroxyflavylium in water-ionic
      liquid biphasic systems: a write-read-erase molecular switch.

PMID- 15022224
TI  - Ionic perylenetetracarboxdiimides: highly fluorescent and water-soluble dyes for
      biolabeling.

PMID- 15022226
TI  - Shape effect in nanoparticle self-assembly.

PMID- 15022225
TI  - Minimal functional model of hemostasis in a biomimetic microfluidic system.

PMID- 15022227
TI  - Pt hollow nanospheres: facile synthesis and enhanced electrocatalysts.

PMID- 15022228
TI  - The X-ray structure of a vinyl cation.

PMID- 15022229
TI  - A three-dimensional mesoporous titanosilicate support for gold nanoparticles:
      vapor-phase epoxidation of propene with high conversion.

PMID- 15022230
TI  - Renewable alkanes by aqueous-phase reforming of biomass-derived oxygenates.

PMID- 15022231
TI  - Side-wall opening of single-walled carbon nanotubes (SWCNTs) by chemical
      modification: a critical theoretical study.

PMID- 15022232
TI  - Self-assembled aggregates of IgGs as templates for the growth of clusters of gold
      nanoparticles.

PMID- 15022233
TI  - Enantioselective total synthesis of batzelladine A.

PMID- 15022235
TI  - Enantioselective Mannich-type reaction catalyzed by a chiral Bronsted acid.

PMID- 15022234
TI  - Dimeric aminoglycosides as antibiotics.

PMID- 15022236
TI  - Chemical synthesis of a skeleton structure of sperm CD52-A GPI-anchored
      glycopeptide.

PMID- 15022237
TI  - Theoretical search for very short metal-actinide bonds: NUIr and isoelectronic
      systems.

PMID- 15022238
TI  - Efficient hydration of nitriles to amides in water, catalyzed by ruthenium
      hydroxide supported on alumina.

PMID- 15022239
TI  - Modular synthesis of ruthenium-labeled diaryl ether peptoids.

PMID- 15022240
TI  - Directed reduction of six-membered nitrogen heterocycles--selective formation of
      polynuclear titanium complexes.

PMID- 15022241
TI  - Efficient, copper-catalyzed, aerobic oxidation of primary alcohols.

PMID- 15022242
TI  - Aminoglycoside microarrays to study antibiotic resistance.

PMID- 15022243
TI  - Mixed helices--a general folding pattern in homologous peptides?

PMID- 15022245
TI  - Non-ablative technologies.

PMID- 15022247
TI  - Influence of pulse duration and pulse number in selective RPE laser treatment.
AB  - BACKGROUND AND OBJECTIVES: The therapeutic effect of laser treatment for macular
      diseases is related to the damage to the retinal pigment epithelium (RPE) and the
      subsequent restoration of the defect due to RPE proliferation. In contrast to
      conventional laser treatment, it is possible to damage the RPE selectively and to
      spare the photoreceptors by using repetitive microsecond laser pulses. It was the
      aim of the study to investigate the influence of pulse duration and number of
      pulses on angiographically and ophthalmoscopically visible retinal damage
      thresholds in order to optimize treatment modalities. STUDY DESIGN/MATERIALS AND
      METHODS: In total, 625 laser lesions with various parameters were applied to the
      retina in 11 eyes of 6 Chinchilla breed rabbits using an experimental laser
      system (Nd:YLF at 527 nm). Pulse duration (1.7 microseconds and 200 nanoseconds)
      and number of pulses (100, 10, and 1 pulses) were varied at a constant repetition
      rate of 100 Hz. Damage thresholds were determined in terms of ophthalmoscopic and
      fluorescein angiographic visibility, and the therapeutic window (TW; angiographic
      ED(50) vs. ophthalmoscopic ED(50)) as well as the safety range (SR; angiographic
      ED(84) vs. ophthalmoscopic ED(16)) between both thresholds were calculated.
      Selected laser lesions were evaluated by histology. RESULTS: Generally, the
      ED(50) radiant exposure for angiographic visibility decreases for shorter laser
      pulses and with an increase in the number of pulses. The TW for both pulse
      durations (1.7 microseconds and 200 nanoseconds) was wider with 100 pulses than
      with single pulses. The widest TW was found for 100 pulses at 200 nanoseconds
      pulse duration (5.9-fold above the angiographic threshold), and the smallest TW
      with a factor of 1.6 was found for 1.7 microseconds single pulses. In terms of
      SR, only irradiation with 100 pulses at 200 nanoseconds pulse duration was
      associated with a ratio >2. Independently of pulse duration, histological
      examination of laser sites 1 hour after irradiation revealed widely intact
      photoreceptors, while the underlying RPE was damaged. CONCLUSIONS: Pulse duration
      and number of pulses have a significant influence on RPE damage thresholds and
      consecutively on TW and SR. Because fundus pigmentation in humans may vary intra-
      and interindividually by a factor of 2, a large TW and ideally also a large SR
      should be ensured in a clinical treatment context. In rabbits, the safety range
      with 200 nanoseconds pulses is higher than with the pulse duration of 1.7
      microseconds currently in clinical use. These findings suggest the need for
      clinical pilot studies to prove whether these results can be transposed to the
      situation in humans.

PMID- 15022246
TI  - Treatment of erosive oral lichen planus by the 308 nm excimer laser.

PMID- 15022248
TI  - Comparative study of the phototoxicity of two chrolin type photosensitizers, ATX
      S10(Na) and verteporfin, on vascular endothelial and retinal pigment epithelial
      cells.
AB  - BACKGROUND AND OBJECTIVES: To compare the phototoxicity in photodynamic therapy
      (PDT) of ATX-S10(Na) and Verteporfin on human microvascular endothelial cells
      (HMVEC), vascular endothelial cells of monkey choroid and retina (CRVEC), and
      human retinal pigment epithelial cells (HRPE). STUDY DESIGN/MATERIALS AND
      METHODS: PDT was performed in two different ways. In short dye-exposure PDT,
      HMVEC and CRVEC were exposed to each photosensitizer for 5 minutes followed by
      laser irradiation of 670 nm wavelength for ATX-S10(Na) or 689 nm for Verteporfin
      without washing out the photosensitizer in the medium. In long dye-exposure PDT,
      the cells were exposed to photosensitizers for times ranging from 5 minutes to 2
      hours, washed out the photosensitizers, followed by laser irradiation in a fresh
      medium. PDT was performed on HRPE with PDT doses that resulted in damaging 90% of
      the HMVEC (ED(90)). Phototoxicity was determined by MTS Assay 1 day after PDT.
      RESULTS: The degree of phototoxicity depended on the dye concentration, laser
      dose, and dye exposure time. In short dye-exposure PDT on HMVEC with a laser dose
      of 50 J/cm(2), the ED(90) was 6.3 microg/ml of ATX-S10(Na) and 0.04 microg/ml of
      Verteporfin, while in long dye-exposure PDT the ED(90) was 50.0 microg/ml of ATX
      S10(Na) and 0.04 microg/ml of Verteporfin when the medium was supplemented with
      5% fetal calf serum. The phototoxic rate on HMVEC was higher when the medium
      contained 5% as contrasted with 10% of serum. In short dye-exposure PDT, the
      ED(90) of CRVEC was 100 microg/ml of ATX-S10(Na) and an irradiance of 100
      J/cm(2), and 0.08 microg/ml of Verteporfin and an irradiance of 100 J/cm(2) when
      the medium was supplemented with 10% serum. With some doses of short dye-exposure
      PDT, the ATX-S10(Na) achieved higher phototoxic rates on HMVEC and CRVEC than on
      the HRPE. However, long dye-exposure PDT with ATX-S10(Na) and short and long dye
      exposure PDT with Vereteporfin failed to obtain higher phototoxic rates on HMVEC
      and CRVEC than on HRPE. CONCLUSIONS: Verteporfin had a higher phototoxicity than
      ATX-S10(Na) on HMVEC and CRVEC. The CRVEC resisted more than HMVEC following PDT
      with both photosensitizers. In short dye-exposure PDT, ATX-S10(Na) had a more
      selective phototoxicity on HMVEC and CRVEC than on HRPE.

PMID- 15022249
TI  - Experimental application of pulsed Ho:YAG laser-induced liquid jet as a novel
      rigid neuroendoscopic dissection device.
AB  - BACKGROUND AND OBJECTIVES: Although water jet technology has been considered as a
      feasible neuroendoscopic dissection methodology because of its ability to perform
      selective tissue dissection without thermal damage, problems associated with
      continuous use of water and the ensuing fountain-effect-with catapulting of the
      tissue-could make water jets unsuitable for endoscopic use, in terms of safety
      and ease of handling. Therefore, the authors experimented with minimization of
      water usage during the application of a pulsed holmium:yttrium-aluminum-garnet
      (Ho:YAG) laser-induced liquid jet (LILJ), while assuring the dissection quality
      and the controllability of a conventional water jet dissection device. We have
      developed the LILJ generator for use as a rigid neuroendoscope, discerned its
      mechanical behavior, and evaluated its dissection ability using the cadaveric
      rabbit ventricular wall. STUDY DESIGN/MATERIALS AND METHODS: The LILJ generator
      is incorporated into the tip of a stainless steel tube (length: 22 cm; internal
      diameter: 1.0 mm; external diameter: 1.4 mm), so that the device can be inserted
      into a commercial, rigid neuroendoscope. Briefly, the LILJ is generated by
      irradiating an internally supplied water column within the stainless steel tube
      using the pulsed Ho:YAG laser (wave length: 2.1 microm, pulse duration time: 350
      microseconds) and is then ejected through the metal nozzle (internal diameter:
      100 microm). The Ho:YAG laser pulse energy is conveyed through optical quartz
      fiber (core diameter: 400 microm), while cold water (5 degrees C) is internally
      supplied at a rate of 40 ml/hour. The relationship between laser energy (range:
      40-433 mJ/pulse), standoff distance (defined as the distance between the tip of
      the optical fiber and the nozzle end; range: 10-30 mm), and the velocity, shape,
      pressure, and average volume of the ejected jet were analyzed by means of high
      speed camera, PVDF needle hydrophone, and digital scale. The quality of the
      dissection plane, the preservation of blood vessels, and the penetration depth
      were evaluated using five fresh cadaveric rabbit ventricular walls, under
      neuroendoscopic vision. RESULTS: Jet velocity (7.0-19.6 m/second) and pressure
      (0.07-0.28 MPa) could be controlled by varying the laser energy, which determined
      the penetration depth in the cadaveric rabbit ventricular wall (0.07-1.30
      mm/shot). The latter could be cut into desirable shapes-without thermal effects
      under clear neuroendoscopic vision. The average volume of a single ejected jet
      could be confined to 0.42-1.52 microl/shot, and there was no accompanying
      generation of shock waves. Histological specimens revealed a sharp dissection
      plane and demonstrated that blood vessels of diameter over 100 microm could be
      preserved, without thermal damage. CONCLUSIONS: The present pulsed LILJ system
      holds promise as a safe and reliable dissection device for deployment in a rigid
      neuroendoscope.

PMID- 15022250
TI  - A first trial in the clinical application of photodynamic therapy for the
      prevention of restenosis after coronary-stent placement.
AB  - BACKGROUND AND OBJECTIVES: The aim of this clinical study was to evaluate the
      safety of local delivery of a photosensitizer followed by photodynamic therapy
      (PDT), to determine its effectiveness in reducing in-stent restenosis. STUDY
      DESIGN/PATIENTS AND METHODS: Porfimer sodium was administered via a local
      delivery catheter to five coronary-stent implanted lesions followed by
      irradiation with a pulse laser. Coronary angiography (CAG) was performed at the
      baseline, after the procedure and at a 6-month follow-up. RESULTS: By the 18
      month clinical follow-up, no adverse events such as photodermatosis, or
      myocardial ischemia had occurred. At the follow-up, no coronary embolization,
      dissection, or aneurysmal dilatation was observed in the CAG. In-stent diameter
      stenosis, late loss, and loss index were 19.16+/-8.20%, 0.37+/-0.18 mm, and
      0.19+/-0.12, respectively. No in-stent restenosis was observed. CONCLUSIONS: This
      study suggests that PDT, with local delivery of Porfimer sodium, is safe and may
      be a feasible technique in preventing in-stent restenosis.

PMID- 15022251
TI  - In vivo targeted gene transfer in skin by the use of laser-induced stress waves.
AB  - BACKGROUND AND OBJECTIVES: Much interest has been shown in the use of lasers for
      nonviral targeted gene transfer, since the spatial characteristics of laser light
      are quite well defined. The aim of this study was to demonstrate in vivo gene
      transfer by the use of laser-induced stress waves (LISWs). STUDY DESIGN/MATERIALS
      AND METHODS: After reporter genes had been intradermally injected to rat skin in
      vivo, a laser target was placed on the gene-injected skin. LISWs were generated
      by the irradiation of an elastic laser target with 532-nm nanosecond laser pulses
      of a Q-switched Nd:YAG laser. RESULTS: Levels of luciferase activities for the
      skin exposed to LISWs were two orders of magnitude higher than those for the skin
      injected with naked DNA. Expressions of enhanced green fluorescent protein (EGFP)
      and beta-galactosidase were observed only in the area that was exposed to LISWs,
      and in addition, epidermal cells were selectively transfected. No major side
      effects were observed, and luciferase activity levels as high as 10(5) RLU per mg
      of protein were sustained even 5 days after gene transfer. CONCLUSION: Highly
      efficient and site-specific gene transfer can be achieved by applying a few
      pulses of nanosecond pulsed LISWs to rat skin in vivo.

PMID- 15022252
TI  - Early differentiation between caries and tooth demineralization using laser
      induced autofluorescence spectroscopy.
AB  - BACKGROUND AND OBJECTIVES: The intrinsic fluorescence of carious human teeth, of
      different stages of teeth demineralization, and the correspondence of such
      fluorescence to the mineral and organic distribution within the lesions were
      investigated. STUDY DESIGN/MATERIALS AND METHODS: Fluorescence spectra of teeth
      excited with 337 nm nitrogen laser were recorded. Spectra were obtained from
      healthy enamel, dentine, demineralized areas, and different carious stages of the
      teeth investigated. RESULTS: Spectra obtained from sound enamel consisted of one
      intensive peak at 480-500 nm and one secondary peak at 430-450 nm. In dentine,
      this secondary component had much higher intensity. Fluorescence spectra of
      normal teeth were similar to those of enamel layer. A significant decrease of the
      intensity of the fluorescence signal was observed in both cases-in demineralized
      teeth and in carious lesion. The appearance of a fluorescence peak in the red
      spectral region was observed in the spectra of the initial carious lesions. In
      the teeth demineralization process, we observed an increase of the relative
      fluorescence peak intensity at 430-450 nm related to thinned out of enamel.
      CONCLUSIONS: A differentiation between initial tooth demineralization and early
      stages of caries could be made by the laser-induced fluorescence spectroscopy
      method.

PMID- 15022253
TI  - Bond strength to dentin of primary teeth irradiated with varying Er:YAG laser
      energies and SEM examination of the surface morphology.
AB  - BACKGROUND AND OBJECTIVES: This study aimed to assess in vitro the influence of
      Er:YAG laser energy on the shear bond strength of a total-etch adhesive to lased
      dentin of primary teeth, and observe under SEM the morphological appearance of
      laser-ablated dentin surfaces. STUDY DESIGN/MATERIALS AND METHODS: For SBS,
      specimens were irradiated with the energies 60 mJ/2 Hz (G2), 80 mJ/2 Hz (G3), 100
      mJ/2 Hz (G4). Control (G1) was not irradiated. Dentin surfaces were acid-etched,
      Single Bond adhesive (3 M) was applied, and resin cylinders were fabricated from
      Z250 resin (3 M). Bond strength was tested in shear (0.5 mm/min). For
      morphological analysis, specimens were irradiated using the same energies, either
      or not acid-etched, and observed by SEM. RESULTS AND CONCLUSIONS: SBS means, in
      MPa, were: G1-17.89(+/-4.75); G2-12.34(+/-4.85); G3-10.30(+/-3.67); G4-10.41(+/
      4.20). Overall, Er:YAG laser irradiation of primary teeth dentin, prior to the
      adhesive protocol, adversely affected bond strength. Furthermore, it was noticed
      that even though there was no significant difference among the Er:YAG laser
      treated groups, the increase of laser energy resulted in increasingly cratered
      surfaces, regardless of acid-etching association.

PMID- 15022254
TI  - Effect of low-power laser irradiation on protein synthesis and ultrastructure of
      human gingival fibroblasts.
AB  - BACKGROUND AND OBJECTIVES: Low-power lasers improve wound healing. Cell
      proliferation and protein secretion are important steps of this process. The aim
      of this study was to analyze both protein synthesis and ultrastructural
      morphology of human gingival fibroblasts irradiated by a low-power laser. STUDY
      DESIGN/MATERIALS AND METHODS: The cell line FMM1 was grown in nutritional
      deficit. Laser irradiation was carried out with a gallium-aluminum-arsenate (Ga
      Al-As) diode laser (904 nm, 120 mW, energy density of 3 J/cm(2)). The protein
      synthesis analysis and ultrastructural morphology of control (non-irradiated) and
      irradiated cultures were obtained. RESULTS: There were changes in the structure
      of cytoplasm organelles of treated cells. The procollagen was not altered by the
      laser irradiation; however, there were a significant reduction of the amount of
      protein in the DMEM conditioned by irradiated cells. CONCLUSIONS: Low-power laser
      irradiation causes ultrastructural changes in cultured fibroblasts. We suggest
      that these alterations may lead to disturbances in the collagen metabolism.

PMID- 15022255
TI  - Flashlamp pulsed dye laser (FPDL) did not cure papulopustular rosacea.
AB  - BACKGROUND AND OBJECTIVES: Pharmacological treatment has a fairly good effect on
      the papulopustular lesions in rosacea, but not as good an effect on the erythema
      and telangiectases. The aim was to treat rosacea patients with both
      erythematotelangiectatic and papulopustular lesions with flashlamp pulsed dye
      laser (FPDL) until telangiectases/erythema disappeared, and to evaluate whether
      the treatment might also be effective on papulopustular lesions. STUDY
      DESIGN/MATERIALS AND METHODS: Ten patients were treated on one side of the face
      with FPDL. The final examination was blinded and performed on the average 10
      months after the last treatment. RESULTS: Two of the patients had more lesions
      after treatment, three were unchanged, three had only slightly less, and two had
      markedly less papulopustular lesions. CONCLUSION: Our conclusion from this small
      sample of patients is that FPDL probably has limited value on papulopustular
      lesions in rosacea. This indicates that the origin of rosacea may not be only
      vascular.

PMID- 15022256
TI  - Anesthesia technique for outpatient facial laser resurfacing.
AB  - BACKGROUND AND OBJECTIVES: Multiple anesthetic approaches exist for full-face
      laser resurfacing. The purpose of this study was to describe an anesthesia
      technique based on combination of eutectic mixture local anesthetics (EMLA) and
      remifentanil sedation, that can be utilized by anesthesiologists in the
      ambulatory environment. STUDY DESIGN/MATERIALS AND METHODS: Fifty patients
      elected for facial laser resurfacing. All patients received topical anesthesia in
      full face with EMLA cream at 60 minutes (min) before laser procedure. On arrival
      at the operating room, intravenous (IV) sedation was administered with
      remifentanil (0.20 mcg/kg/minute), midazolam (1.5- 2 mg bolus IV), and propofol
      infusion (0.5-1 mg/kg/hour). The subsequent infusion rate of remifentanil was
      varied to maintain an adequate level of sedation and analgesia. Five minutes
      before the operation conclusion, the sedation infusion was discontinued. Patients
      were discharged after achieving a minimum criteria for recovery. RESULTS: Almost
      all the patients were successfully anesthetized by this combination technique,
      only four patients needed complementary anesthesia with regional nerve blockade.
      The mean level of sedation scored 2-3 on the Ramsay scale. The mean discharge
      time was 55 minutes. No complications were observed. CONCLUSIONS: The use of a
      combination of topical EMLA anesthesia and IV conscious sedation based on
      remifentanil provided an adequate depth of anesthesia for outpatient facial laser
      resurfacing without complications.

PMID- 15022258
TI  - Effect of low power 655 nm diode laser irradiation on the neuromuscular junctions
      of the mouse diaphragm.
AB  - BACKGROUND AND OBJECTIVES: Low level laser therapy (LLLT) in specific wavelengths
      and fluence maintains the electrophysiological activity of injured peripheral
      nerve in rats, preventing scar formation (at injury site) as well as degenerative
      changes in the corresponding motor neurons of the spinal cord, thus accelerating
      regeneration of the injured nerve. We studied the effect of LLLT on the
      neurotransmitter release in neuromuscular junctions of the mouse diaphragm. STUDY
      DESIGN/MATERIALS AND METHODS: Thirty-nine diaphragm muscles were studied. LLLT
      with GaAlAs 655 nm (1-12 J/cm(2)) was used. Neurotransmitter release was studied
      by conventional intracellular recording techniques on curarised or high magnesium
      media. Quantal content, amplitude, latency and rise time were analysed for end
      plate potentials (EPPs). Frequency and amplitude were evaluated for the miniature
      end-plate potentials (MEPPs). Short-term plasticity of the neurotransmitter
      release (fast facilitation) was also evaluated by paired pulse stimulation.
      RESULTS AND CONCLUSIONS: This study showed that LLLT (655 nm) in these doses has
      no detectable physiological effect on the motor end-plate neurotransmitter
      release in mice.

PMID- 15022257
TI  - Comparison and sequential study of long pulsed Nd:YAG 1,064 nm laser and
      sclerotherapy in leg telangiectasias treatment.
AB  - BACKGROUND AND OBJECTIVES: Millisecond pulsed 1,064 nm Nd:YAG lasers have been
      developed for the treatment of leg telangiectasias. To date there have been very
      few side by side comparison studies of laser versus the gold standard
      sclerotherapy in treating small leg veins. This study aims to compare a long
      pulsed Nd:YAG laser with contact cooling to sclerotherapy for treating small
      diameter leg telangiectasias by evaluating objective and subjective clinical
      effects. STUDY DESIGN/PATIENTS AND METHODS: Fourteen patients were selected with
      leg telangiectasias ranging from 0.5 to 2 mm at four comparable sites. One site
      was treated with long pulsed Nd:YAG alone, the second received sclerotherapy
      alone, the third laser then sclerotherapy, and the last one sclerotherapy then
      laser. The patients were followed up at 3 months after the last treatment.
      Photographs were taken pre-operatively and at 3 months after the last session.
      They were used for objective and comparative analysis. Statistical analysis was
      performed using Friedman's test controlling for subject. RESULTS: Improvement was
      tabulated from the photographic assessment on an improvement scale from 0 (no
      change) to 4 (greater than 75% clearing). There were clinical improvements in the
      laser group than sclerotherapy without statistical significance. Side effects
      were minimal and included hyperpigmentation. CONCLUSIONS: This pilot study
      demonstrates that the Smartepil LS long pulse Nd:YAG 1,064 nm laser can yield
      results similar to sclerotherapy in the treatment of small leg telangiectasias.
      Combination of both methods could increase response to treatment.

PMID- 15022259
TI  - Comparison of single and multiple applications of GaAlAs laser on rat medial
      collateral ligament repair.
AB  - BACKGROUND AND OBJECTIVES: To examine single versus multiple applications of the
      gallium aluminum arsenide (GaAlAs) laser on the healing of surgically injured
      medial collateral ligaments (MCLs) in rats. STUDY DESIGN/MATERIALS AND METHODS:
      Sixteen rats were studied, with 12 receiving surgical transection to their right
      MCL and 4 receiving a sham injury. Group 1 (n = 4) received a single dose of
      GaAlAs laser therapy (wavelength 660 nm, average power 8.8 mW, pulse 10 kHz,
      dosage 31.6 J/cm(2)) directly to their MCL during surgery. Group 2 (n = 4)
      received 9 doses of GaAlAs laser therapy applied transcutaneously on alternate
      days (wavelength 660 nm, average power 8.8 mW, pulse 10 kHz, dosage 3.5 J/cm(2)).
      The controls (Group 3, n = 4) received one session of placebo laser at the time
      of surgery, with the laser equipment shut down, while the sham injured Group 4 (n
      = 4) received no treatment. Biomechanical tests for structural stiffness,
      ultimate tensile strength (UTS), and load-relaxation were done at 3 weeks after
      injury. The stiffness and UTS data were normalized by expressing as a percentage
      of the left side of each animal before statistical analysis. RESULTS: The load
      relaxation data did not show any differences between the groups (P = 0.18). The
      normalized stiffness levels of Groups 2 (81.08+/-11.28%) and 4 (92.66+/-13.19%)
      were significantly higher (P = 0.025) than that of the control Group 3 (58.99+/
      15.91%). The normalized UTS of Groups 2 (81.38+/-5.68%) and 4 (90.18+/-8.82%)
      were also significantly higher (P = 0.012) than that of the control (64.49+/
      9.26%). Although, Group 1 had higher mean stiffness and UTS values than the
      control, no statistically significant difference was found between these two
      groups. CONCLUSIONS: Multiple laser therapy improves the normalized strength and
      stiffness of repairing rat MCLs at 3 weeks after injury. The multiple treatments
      seem to be superior to a single treatment when the cumulative dosages are
      comparable between the two modes of application.

PMID- 15022260
TI  - Aging of the nigrostriatal system in the squirrel monkey.
AB  - Increasing incidence of Parkinson's disease with advancing age suggests that age
      related processes predispose the nigrostriatal dopaminergic system to
      neurodegeneration. Several hypotheses concerning the effects of aging on
      nigrostriatal neurons were assessed in this study using a non-human primate
      model. First, we examined the possibility that the total number of dopaminergic
      neurons decline in the substantia nigra as a function of age. Stereological
      counting based on both tyrosine hydroxylase immunoreactivity (TH-ir) and
      neuromelanin (NM) content revealed no difference in cell number between young,
      middle-aged and old squirrel monkeys. We then determined whether advancing age
      changed the relative proportion of neurons characterized by 1) TH-ir in the
      absence of NM, 2) the presence of both TH-ir and NM, or 3) NM without TH-ir.
      Indeed, a progressive age-related depletion of TH only cells was paralleled by an
      increase in NM only neurons. The possibility that these changes could underlie a
      functional impairment of the nigrostriatal system was supported by striatal
      dopamine measurements showing a decrease in older monkeys. Finally, we tested the
      hypotheses that aging may enhance cell vulnerability to injury and that different
      dopaminergic subpopulations display varying degrees of susceptibility. When
      monkeys were exposed to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine, cell loss was markedly more pronounced in older animals, and
      the ranking of vulnerability was TH only < TH/NM < NM only cells. The data
      indicate that, even in the absence of an overall neuronal loss, changes in the
      characteristics of dopaminergic cells reflect functional deficits and increased
      vulnerability to injury with age. NM content appears to be an important marker of
      these age-related effects.

PMID- 15022262
TI  - Lateral cervical nucleus projections to periaqueductal gray matter in cat.
AB  - The midbrain periaqueductal gray matter (PAG) integrates the basic responses
      necessary for survival of individuals and species. Examples are defense behaviors
      such as fight, flight, and freezing, but also sexual behavior, vocalization, and
      micturition. To control these behaviors the PAG depends on strong input from more
      rostrally located limbic structures, as well as from afferent input from the
      lower brainstem and spinal cord. Mouton and Holstege (2000, J Comp Neurol 428:389
      410) showed that there exist at least five different groups of spino-PAG neurons,
      each of which is thought to subserve a specific function. The lateral cervical
      nucleus (LCN) in the upper cervical cord is not among these five groups. The LCN
      relays information from hair receptors and noxious information and projects
      strongly to the contralateral ventroposterior and posterior regions of thalamus
      and to intermediate and deep tectal layers. The question is whether the LCN also
      projects to the PAG. The present study in cat, using retrograde and anterograde
      tracing techniques, showed that neurons located in the lateral two-thirds of the
      LCN send fibers to the lateral part of the PAG, predominantly at rostrocaudal
      levels A0.6-P0.2. This part of the PAG is known to be involved in flight
      behavior. A concept is put forward according to which the LCN-PAG pathway alerts
      the animal about the presence of cutaneous stimuli that might represent danger,
      necessitating flight. J. Comp. Neurol. 471:434-445, 2004.

PMID- 15022261
TI  - Projections from bed nuclei of the stria terminalis, posterior division:
      implications for cerebral hemisphere regulation of defensive and reproductive
      behaviors.
AB  - The posterior division of the bed nuclei of the stria terminalis has three major
      nuclei: principal, interfascicular, and transverse, which receive topographically
      ordered inputs from the medial amygdalar nucleus. The overall pattern of axonal
      projections from each nucleus was determined in male rats with the Phaseolus
      vulgaris-leucoagglutinin method. Together, these nuclei project topographically
      back to the medial amygdalar nucleus, to the adjacent lateral septal nucleus, to
      the nucleus accumbens and substantia innominata, to hypothalamic parts of the
      behavior control column, and to the hypothalamic periventricular region, which
      controls patterned neuroendocrine and autonomic responses. The principal nucleus
      preferentially innervates septal and hypothalamic regions that control
      reproductive behavior and visceromotor responses, confirming a similar analysis
      by Gu et al. (J Comp Neurol [2003] 460:542-562). In contrast, the interfascicular
      and transverse nuclei differentially innervate septal and hypothalamic regions
      that control defensive as well as reproductive behaviors. In addition, the
      transverse nucleus projects significantly to midbrain parts of the behavior
      control column concerned with foraging/exploratory behavior. All three posterior
      division nuclei also project to thalamocortical feedback loops (by means of the
      nucleus reuniens and paraventricular nucleus). These structural data may be
      interpreted to suggest that the bed nuclei posterior division forms part
      (pallidal) of a corticostriatopallidal system involved in controlling two major
      classes of social (defensive and reproductive) behavior.

PMID- 15022263
TI  - Human cardiovascular and gustatory brainstem sites observed by functional
      magnetic resonance imaging.
AB  - The reflex control and relay to higher brain sites of visceral sensory
      information within the central nervous system is mediated via discrete sites in
      the brainstem. Anatomical characterization of these sites in humans has been
      limited due to the invasive nature of such research. The present study employed 4
      Tesla functional magnetic resonance imaging (fMRI) to characterize brainstem
      sites involved in autonomic control in the human. Eight subjects performed tasks
      that activate the general visceral (the isometric hand-grip, maximal inspiration,
      Valsalva maneuver) or special visceral sensory systems (sucrose administration to
      the tongue). Activation of the nucleus of the solitary tract and parabrachial
      nucleus was consistently observed with all general visceral tasks. Periaqueductal
      gray area activation was observed during the maximal inspiration and Valsalva
      maneuver conditions and raphe activation was present in response to isometric
      hand-grip and maximal inspiration tasks. The activation in the nucleus of the
      solitary tract was consistently more rostral in the medulla during sucrose
      administration than during performance of the other experimental tasks. This
      finding is consistent with what has been previously demonstrated in animals. This
      is the first study to image the human brainstem with respect to visceral control
      and demonstrates the feasibility of using high-resolution fMRI to study the
      functional organization of the human brainstem.

PMID- 15022264
TI  - Dual viral transneuronal tracing of central autonomic circuits involved in the
      innervation of the two kidneys in rat.
AB  - The neural control of renal function is exerted by the central nervous system via
      sympathetic innervation of the kidneys. To determine the extent to which the
      control of the two kidneys is provided by the same brain neurons, the central
      circuitry involved in the innervation of both kidneys was characterized in
      individual rats by dual viral transneuronal tracing using isogenic recombinant
      strains (PRV-152 and BaBlu) of pseudorabies virus. Prior to dual tracing, the
      neuroinvasive properties of PRV-152 and BaBlu were characterized by conducting
      parametric studies, using the two kidneys as an anatomical model, and comparing
      the pattern of infection with that obtained following injection of the parental
      strain, PRV-Bartha, into the left kidney. Once the optimal concentrations of
      virus required to obtain equivalent infection were established, PRV-152 and BaBlu
      were injected into the left and right kidney, respectively, in the same rats.
      Immunocytochemical localization of viral reporter proteins at different
      postinoculation times allowed us to determine the sequence of infection in the
      brain, as well as to quantify dual- and single-labeled neurons in each infected
      area. Neurons that influence autonomic outflow to one or both kidneys coexist in
      all brain areas involved in the control of the sympathetic outflow to the kidneys
      at every hierarchical level of the circuit. The proportions of dual-infected
      neurons with respect to the number of total infected neurons varied across
      regions, but they were maintained at different survival times. The pattern of
      infection suggests that the activity of each kidney is controlled independently
      by organ-specific neurons, whereas the functional coordination of the two kidneys
      results from neurons that collaterize to modulate the sympathetic outflow to both
      organs. The advantages of using an anatomical symmetrical system, such as the two
      kidneys, as an experimental approach to characterize PRV recombinants in general
      are also discussed.

PMID- 15022266
TI  - Special issue on the cognitive revolution in clinical psychology: Beyond the
      behavioral approach-Introductory remarks.
AB  - Recently, the impact of the cognitive revolution on the clinical field has been
      challenged by behavioral professionals at both theoretical and practical levels.
      This article is a brief introduction to a special issue of the Journal of
      Clinical Psychology and presents the objectives and the structure of this special
      issue.

PMID- 15022265
TI  - Regionally specific expression of L1 and sialylated NCAM in the retinofugal
      pathway of mouse embryos.
AB  - We have examined expression of L1 and the polysialic acid-associated form of the
      neural cell adhesion molecule (PSA-NCAM) in mouse embryos during the major period
      of axon growth in the retinofugal pathway to determine whether they are expressed
      in patterns that relate to the changes in axon organization in the pathway.
      Immunostaining for L1 and PSA-NCAM was found on all axons in the retina and the
      optic stalk. In the chiasm, while L1 immunoreactivity remained high on the axons,
      PSA-NCAM staining was obviously reduced. At the threshold of the optic tract, L1
      immunoreactivity was maintained only in a subpopulation of axons, whereas PSA
      NCAM staining was dramatically elevated in axons at the caudal part of the tract.
      Further investigations of the tract showed that both L1 and PSA-NCAM were
      preferentially expressed on the dorsal but not ventral optic axons, indicating a
      regionally specific change of both adhesion molecules on the axons at the chiasm
      tract junction. Moreover, intense PSA-NCAM expression was also observed in the
      tract of postoptic commissure (TPOC), which lies immediately caudal to the optic
      tract. Immunohistochemical and retrograde tracing studies showed that these PSA
      NCAM-positive axons arose from a population of cells rostral to the CD44-positive
      chiasmatic neurons. These findings indicate that, in addition to the chiasmatic
      neurons, these PSA-NCAM-positive diencephalic cells also contribute axons to the
      TPOC. These early generated commissural axons together with the regionally
      specific pattern of cell adhesion molecule expression on the optic axons may
      control formation of the partial retinotopic axon order in the optic tract
      through homophilic or heterophilic interactions that involve PSA-NCAM.

PMID- 15022267
TI  - The information-processing approach to the human mind: Basics and beyond.
AB  - Cognitive psychology attempts to understand the nature of the human mind by using
      the information-processing approach. In this article, the fundamentals of the
      cognitive approach will be presented. It will be argued that the human mind can
      be described at three levels-computational, algorithmic-representational, and
      implementational-and that the cognitive approach has both important theoretical
      and practical/clinical implications. Finally, it will be suggested that the study
      of cognitive psychology can provide a foundation for other fields of social
      science, including the field of clinical psychology.

PMID- 15022268
TI  - The role of cognition in classical and operant conditioning.
AB  - For the past 35 years, learning theorists have been providing models that depend
      on mental representations, even in their most simple, deterministic, and
      mechanistic approaches. Hence, cognitive involvement (typically thought of as
      expectancy) is assumed for most instances of classical and operant conditioning,
      with current theoretical differences concerning the level of cognition that is
      involved (e.g., simple association vs. rule learning), rather than its presence.
      Nevertheless, many psychologists not in the mainstream of learning theory
      continue to think of cognitive and conditioning theories as rival families of
      hypotheses. In this article, the data pertaining to the role of higher-order
      cognition in conditioning is reviewed, and a theoretical synthesis is proposed
      that provides a role for both automatic and cognitively mediated processes.

PMID- 15022269
TI  - Applied cognitive psychology: Implications of cognitive psychology for clinical
      psychology and psychotherapy.
AB  - Cognitive psychology has made numerous contributions to clinical psychology, and
      these contributions are considered especially with reference to the anxiety
      disorders. It is argued that there are four major contributions that can be
      identified. First, the cognitive approach has led to the development of complex
      models showing the main cognitive processes and structures of relevance to an
      understanding of anxiety disorders. Second, controlled laboratory studies permit
      a more detailed investigation of cognitive biases in anxious patients than
      generally is feasible in more naturalistic settings. Third, the cognitive
      approach provides relevant evidence with respect to the issue of whether
      cognitive biases play a role in the development and maintenance of anxiety
      disorders. Fourth, the enhanced understanding of the anxiety disorders that has
      arisen from the cognitive approach has had beneficial effects on therapeutic
      practice in a number of significant ways. In sum, it is claimed that clinical
      psychology has benefited considerably from cognitive theory and research.

PMID- 15022270
TI  - Cognitive factors in health psychology and behavioral medicine.
AB  - Research in health psychology and behavioral medicine has increased exponentially
      over the past three decades. Prevention and control efforts across a variety of
      diseases have recognized that individual difference factors, belief systems,
      attitudes, behaviors, and environments can affect an individual's health. This
      work continues, as there has been no abatement in the rate at which aversive,
      chronic, and life-threatening diseases continue to affect millions of Americans
      each year. The purpose of this review is to discuss the influence of cognitive
      factors on health psychology and behavioral medicine using the cancer literature
      as an example. The main discussion focuses on the impact of cognitive constructs
      on behavioral medicine and health psychology in cancer, which appears to be
      widespread. The article concludes with some implications for future research in
      the area.

PMID- 15022271
TI  - Cognition and the cognitive revolution in psychotherapy: promises and advances.
AB  - This article describes the history and conceptual changes wrought by the gradual
      development from psychodynamic therapy to behavioral therapy to cognitive
      behavioral therapy. The practical impact of the cognitive revolution on
      psychotherapy theory and practice is discussed. The empirical status of
      behavioral therapy and cognitive-behavioral therapy is summarized, and
      suggestions for future changes are made.

PMID- 15022272
TI  - Cognitive and behavioral treatments for anxiety disorders: a review of meta
      analytic findings.
AB  - Behavioral and cognitive psychotherapies are the most widely studied
      psychological interventions for anxiety disorders. In the present article, the
      results of ten years of meta-analytic studies on psychotherapies for the various
      anxiety disorders are reviewed and the relative effectiveness of cognitive and
      behavioral therapeutic methods is examined. Meta-analytic results support the
      effectiveness of combined cognitive and behavioral approaches for anxiety
      disorders. Pure behavioral therapies also are effective and appear to work as
      well as combined treatment for some disorders. Due to the small number of outcome
      studies involving pure cognitive treatments, reliable conclusions about the
      effectiveness of this approach cannot be offered. Additional theoretical and
      practical considerations are discussed.

PMID- 15022273
TI  - Commentary: The evolution of evidence-based psychotherapy.
AB  - What has been identified as a revolution actually represents an evolution,
      stemming directly from the basic behavioral tenets of the early to mid 20th
      century. Cognitive-behavior approaches within behavior therapy are not really
      new. As early as the 1950s a substantial number of behaviorists saw a clear role
      for cognition and relied on hypothetical constructs to explain behavior. There
      are at least two major challenges for cognitive-behavior approaches. The first is
      the assurance of the validity and reliability of the measurement of both outcome
      and the cognitive factors that are presumed to serve as mediators of the observed
      effects. As the cognitive factors being studied become more complex, the
      measurement of the variables of interest becomes more difficult. The second
      challenge is to be open to new paradigms and approaches that may bring into
      question well-established concepts. The preeminence of the cognitive-behavioral
      approach is directly related to the fact that its concepts and methods can be
      subjected to empirical scrutiny.

PMID- 15022274
TI  - Special issue on the cognitive revolution in clinical psychology: beyond the
      behavioral approach-conclusions: toward an evidence-based psychology and
      psychotherapy.
AB  - Integrating the criticisms of the cognitive psychology approach offered by
      behavioral oriented professionals, as well as the information offered in this
      special issue of the Journal of Clinical Psychology, the article presents an
      overview of the theoretical and practical implications of the cognitive
      revolution on the clinical field and discusses the unique contribution of this
      approach beyond the contribution of the behavioral approach.

PMID- 15022275
TI  - The ethics of reporting and disseminating results of clinical research trials.

PMID- 15022276
TI  - Differential gene and protein expression in primary breast malignancies and their
      lymph node metastases as revealed by combined cDNA microarray and tissue
      microarray analysis.
AB  - BACKGROUND: Metastatic disease is a major adverse prognostic factor in breast
      carcinoma. Lymph node metastases often represent the first step in the metastatic
      process. METHODS: To gain insight into the molecular events that underlie breast
      carcinoma metastasis, the authors compared gene expression profiles, obtained by
      cDNA microarray analysis, of nine matched primary tumors and metastases after
      screening for enrichment of tumor cells. Statistical analysis identified genes
      that are expressed at elevated or decreased levels in metastases relative to the
      corresponding primary tumors. Multidimensional scaling analysis indicated that in
      terms of expression levels, primary tumors were tightly clustered, whereas
      metastases exhibited a greater spread; this finding points to the more
      heterogeneous nature of metastases. Among the differentially expressed entities
      were the invasion- and tissue modeling-related genes IGFBP5, fibronectin, and
      MMP2; the cell cycle regulatory gene cyclin D1; other genes, such as enolase 2;
      and an expressed sequence tag similar to angiopoietin 1. To validate and extend
      these initial findings, the authors constructed a tissue microarray consisting of
      100 primary malignancies paired with their lymph node metastases. Antibodies for
      the IGFBP-5, fibronectin, MMP-2, cyclin D1, and MDM-2 proteins were used to stain
      tissue array sections. RESULTS: Consistent with microarray data, statistically
      significant overexpression of IGFBP-5, down-regulation of cyclin D1, and
      unchanged MDM-2 levels were observed in metastatic tumor cells. Nonetheless,
      although fibronectin and MMP2 mRNA expression levels were decreased in many
      metastasis specimens, expression levels of the corresponding proteins in the
      extracellular matrix were elevated in most metastases. Decreased expression of
      fibronectin and MMP2 in lymph node metastases was further confirmed by real-time
      polymerase chain reaction assays performed on five additional specimen pairs.
      CONCLUSIONS: The results of the current study suggest that extracellular matrix
      protein expression and nuclear gene expression are associated via a negative
      feedback regulatory mechanism. Therefore, gene expression profiling and tissue
      array validation should be combined to elucidate molecular events associated with
      the metastatic process.

PMID- 15022277
TI  - Follicular thyroid carcinoma: histology and prognosis.
AB  - BACKGROUND: Follicular thyroid carcinoma (FTC) is the second most common thyroid
      malignancy after papillary thyroid carcinoma. The authors studied the clinical
      course of 132 patients with FTC to determine whether there was a direct relation
      between the histologic degree of invasion, tumor recurrence, and patient
      survival. METHODS: The 132 patients in the study population underwent 182 thyroid
      carcinoma-related operations, and their mean follow-up was 7.5 years (median:,6
      years; range, 0-39 years). The following criteria were used to define malignant
      follicular neoplasms: 1) minimally invasive, tumor invasion through the entire
      thickness of the tumor capsule; 2) moderately invasive, tumor with angioinvasion
      (with or without capsular invasion); and 3) widely invasive, broad area or areas
      of transcapsular invasion of thyroid and extrathyroidal tissue. Forty-five of 119
      patients (37.8%) presented with minimally invasive FTC (capsular invasion only),
      50 patients (42%) presented with moderately invasive FTC (angioinvasion with or
      without capsular invasion), and 24 patients (20%) presented with widely invasive
      FTC. At presentation, 12 patients (9%) had distant metastases, and 8 patients
      (6%) had lymph node metastases. RESULTS: Excluding 12 patients who presented with
      distant metastases, 21 patients (16%) developed recurrent metastases 6 months
      after their initial treatment. Among 45 patients with capsular invasion only, 6
      patients (13%) developed recurrent or persistent disease, and 5 patients (11%)
      died. Of the 50 patients who had angioinvasion with or without capsular invasion,
      10 patients (20%) developed recurrent or persistent disease, and 7 patients (14%)
      died. Patients who had angioinvasion with or without capsular invasion had a less
      favorable prognosis compared with patients who had capsular invasion only (P <
      0.0001). Among patients who had widely invasive FTC, 9 of 24 patients (38%)
      developed recurrent disease, and 8 patients (33%) died; in addition, 7 of the
      other 24 patients (29%) had persistent disease and died. The overall death rate
      for patients with widely invasive FTC was 62%. Patients with persistent disease
      had a poorer prognosis compared with patients who had recurrent disease (P <
      0.0001). Twenty-eight patients (21%) in the entire group died of FTC.
      CONCLUSIONS: In the current retrospective investigation, the authors demonstrate
      that patients with minimally invasive FTC (capsular invasion only) had a slightly
      better survival rate at 5 years (98%) compared with patients who had
      angioinvasion with or without capsular invasion (80%) and had better survival
      compared with patients who had widely invasive FTC (38%). Other (but not all)
      reports in the literature support the findings that FTC with angioinvasion is
      more aggressive than FTC with only capsular invasion yet is less aggressive than
      widely invasive FTC. The authors conclude that FTC no longer should be classified
      as either minimally invasive or widely invasive; rather, they recommend
      classifying FTC as minimally invasive, moderately invasive, or widely invasive,
      because prognosis varies according to these groupings.

PMID- 15022278
TI  - Expression of regenerating gene I in gastric adenocarcinomas: correlation with
      tumor differentiation status and patient survival.
AB  - BACKGROUND: Regenerating gene I (REG) was identified as a growth factor for
      pancreatic islet beta cells. Enhanced REG expression was observed during the
      healing of gastric mucosa. REG expression was observed in various tumors
      including gastric carcinoma, but to the authors' knowledge, the correlation
      between REG expression and clinicopathologic characteristics and patient
      prognosis have not been evaluated. METHODS: The REG messenger RNA level was
      analyzed by Northern blot analysis and localization was performed by in situ
      hybridization and immunohistochemistry in gastric adenocarcinoma specimens. The
      correlations between REG expression and clinicopathologic features and survival
      of the patients were analyzed. RESULTS: Of the 68 patients studied, 24 (35%) were
      positive for REG. There was a significant consistency in the intensity and
      localization of REG transcript and protein expressions. REG expression was
      enhanced in advanced T classification tumors and in tumors that were not well
      differentiated. A significant number of metastatic lymph nodes were present in
      REG-positive tumors. Overall and disease-free survival were found to be poor for
      patients with REG-positive tumors. REG expression was reported to be an
      independent predictor of overall patient survival. CONCLUSIONS: Determination of
      REG expression may help to identify aggressive gastric tumors and to tailor
      appropriate therapy for patients with REG-positive tumors.

PMID- 15022279
TI  - The impact of testicular carcinoma and its treatment on sperm DNA integrity.
AB  - BACKGROUND: In patients with testicular germ cell carcinoma (TGCC),
      spermatogenesis and fertility are impaired. Intracytoplasmic sperm injection has
      improved their possibility of fatherhood, but might also impose a risk of
      transmitting DNA defects to the offspring. The aim of the current study was to
      evaluate the impact of chemotherapy and irradiation on sperm DNA integrity.
      METHODS: The study included 74 patients with TGCC. Semen samples were collected
      before and at specific time points after patients received therapy. Sperm DNA
      integrity was assessed by the sperm chromatin structure assay. Controls comprised
      278 military conscripts. RESULTS: There was no significant difference in the
      fraction of sperm with fragmented DNA (DNA fragmentation index [DFI]) between
      controls and patients with TGCC before postoperative cancer treatment (11% vs.
      13%). Men treated with adjuvant radiotherapy had a transiently (up to 2 years)
      higher DFI than nontreated patients (18% vs. 13%; P = 0.03). Patients who
      received 1-2 cycles of adjuvant chemotherapy had a significantly lower DFI 6
      months after treatment than after 1-2 years (9.1% vs. 13%; P = 0.004). Higher
      doses of chemotherapy among patients resulted in a significantly lower DFI
      compared with controls (7.3% vs. 11%; P = 0.028), which persisted throughout the
      5 years of follow-up. CONCLUSIONS: Postorchiectomy, the DFI in sperm samples from
      patients with testicular carcinoma was at the level of controls. Radiotherapy
      caused a transient increase in the proportion of DFI, whereas this value
      decreased after chemotherapy. The biologic implications of such changes in sperm
      DNA after cancer therapy need to be elucidated.

PMID- 15022280
TI  - Restaging surgery for women with borderline ovarian tumors: results of a French
      multicenter study.
AB  - BACKGROUND: The purpose of the current study was to examine the surgical
      management of women with borderline ovarian tumors and the adequacy of initial
      staging according to the guidelines of the International Federation of Gynecology
      and Obstetrics; to evaluate the impact of restaging operations; and to identify
      risk factors for initial understaging. METHODS: In a retrospective French
      multicenter study, 54 of 360 women with borderline ovarian tumors underwent a
      restaging operation. After excluding women with initial complete staging (n =
      62), epidemiologic, surgical, and histologic parameters and risk of recurrence
      were compared between women who underwent restaging (n = 54) and those who did
      not (n = 244). RESULTS: One hundred fifty (41.6%) of 360 women underwent
      intraoperative histologic examination, which led to the diagnosis of a borderline
      tumor in 97 cases (64.7%). Thirty-seven (38.1%) of these 97 women had undergone
      complete initial staging procedures. A restaging operation was performed for 54
      women. A lower median age and a higher rate of conservative treatment were noted
      in the group that underwent restaging. Eight (14.8%) of the 54 women who
      underwent restaging had their tumors upstaged: 7 of the 41 cases initially
      diagnosed as Stage IA tumors were upstaged to Stage IB (n = 3) or to Stage IIA,
      IIB, IIIA, or IIIC (n = 1 for each); in the eighth case, a Stage IC tumor was
      upstaged to Stage IIIA. Upstaging tended to be more common in women with serous
      borderline tumors (P = 0.06) and in women who underwent cystectomy (P = 0.08).
      There was no difference in recurrence rates according to whether a restaging
      operation was performed. The recurrence rates after conservative and radical
      treatment were 15.6% (25 of 160) and 4.5% (9 of 200), respectively (P < 0.001).
      CONCLUSIONS: Women who initially were diagnosed with Stage IA disease and who had
      serous borderline tumors or underwent cystectomy appeared to derive the most
      benefit from restaging surgery. Nonetheless, the indications for restaging
      surgery remain controversial, as no difference in recurrence rate was observed
      between women who underwent restaging and those who did not.

PMID- 15022281
TI  - Secondary cytoreductive surgery for patients with relapsed epithelial ovarian
      carcinoma: who benefits?
AB  - BACKGROUND: This study was performed to address patient selection criteria and
      the role of secondary cytoreductive surgery (SCR) in patients with epithelial
      ovarian carcinoma (EOC) who had relapsed tumors after a progression-free interval
      > or = 3 months. METHODS: One hundred seventeen patients with relapsed EOC after
      a clinical complete remission duration > or = 3 months who underwent SCR were
      entered on this prospective trial. Survival curves were generated using the
      Kaplan-Meier method, and statistical comparisons were performed using log-rank
      tests, logistic stepwise regression analyses, and a Cox stepwise regression
      model. RESULTS: The median patient age at the time of relapse was 53 years
      (range, 20-78 years). The median survival was 22 months and the estimated 5-year
      survival rate for the entire cohort was 17.2%. Tumor was confined to a solitary
      site in 33 patients and to > or = 2 sites in 84 patients. After they underwent
      SCR, 11 patients were rendered macroscopically disease free, 61 patients had
      residual disease that measured < or = 1 cm in greatest dimension, and 45 patients
      had bulky intraabdominal residual disease. Survival was influenced by the extent
      of relapse disease (solitary site vs. multiple sites; P < 0.0001), the size of
      residual disease after SCR (0 cm vs. < or = 1 cm [P = 0.1211], < or = 1 cm vs. >
      1 cm [P = 0.0002], and 0 cm vs. > 1 cm [P = 0.0011]), Eastern Cooperative
      Oncology Group performance status (0 vs. 1 [P = 0.134], 1 vs. 2 [P = 0.007], and
      0 vs. 2 [P = 0.0012]), and the number of cycles of salvage chemotherapy (1-2
      cycles vs. 3-5 cycles [P = 0.0144]; 1-2 cycles vs. > or = 6 cycles [P < 0.0001];
      and 3-5 cycles vs. > or = 6 cycles [P = 0.0009]). The outcome of SCR was
      influenced by the extent of relapse disease (multiple sites [51.2%] vs. solitary
      sites [87.9%]; relative risk [RR] = 9.1237; P = 0.0002) and by the use of bowel
      resection (yes [60.9%] vs. no [37.5%]; RR = 0.3828; P = 0.0106). CONCLUSIONS: SCR
      was found to be safe for patients with relapsed EOC who achieved a clinical
      complete remission that lasted > or = 3 months, with resectability similar to
      that of primary debulking surgery. Optimal surgical outcomes were achieved easily
      in patients who apparently had solitary tumor sites, with bowel resection making
      it possible to remove bulky tumors that involved the intestine. A survival
      benefit was provided by optimal SCR, particularly when surgery was supported by
      multiple courses of salvage chemotherapy.

PMID- 15022283
TI  - Is concurrent chemoradiation the treatment of choice for all patients with Stage
      III or IV head and neck carcinoma?
AB  - BACKGROUND: Many patients with small primary tumors of the oropharynx have AJCC
      Stage III/IV disease on the basis of lymphadenopathy. In the current
      retrospective study, the authors hypothesized that these patients have high rates
      of locoregional control when treated with radiotherapy, either alone or combined
      with neck surgery, and may not require concurrent chemotherapy. METHODS: Two
      hundred ninety-nine patients met staging and inclusion criteria. Stage
      distribution was as follows: T1, 99 patients (33%); T2, 182 patients (61%); Tx,
      18 patients (6%); N1, 74 patients (25%); N2, 170 patients (57%); N3, 39 patients
      (13%); and Nx, 16 patients (5%). Primary tumor resection or tonsillectomy had
      been performed in 36 patients (12%) and excisional lymph node biopsy or formal
      neck dissection in 192 patients (64%). Thirty-three additional patients (10%)
      received chemotherapy and were analyzed separately. RESULTS: The median follow-up
      was 82 months (range, 8-299 months). The actuarial 5-year rates of locoregional
      failure, distant metastases, and overall survival were 15%, 19%, and 64%,
      respectively. T status was associated with the 5-year rate of locoregional
      control: 95% for patients with T1-/Tx disease, compared with 79% for patients
      with T2 disease (P < 0.01). The 5-year rate of distant metastases for patients
      with N1/2a disease was 11%, compared with 28% for patients with N2b/N2c/N3
      disease (P < 0.001). CONCLUSIONS: Patients with early-T status oropharyngeal
      carcinoma, which is considered advanced due to the presence of lymphadenopathy,
      have high rates of locoregional control when treated with radiotherapy without or
      with neck surgery. Local treatment intensification by the addition of concurrent
      chemotherapy to radiotherapy would not significantly benefit most of these
      patients.

PMID- 15022282
TI  - Comparison of plasma Epstein-Barr virus (EBV) DNA levels and serum EBV
      immunoglobulin A/virus capsid antigen antibody titers in patients with
      nasopharyngeal carcinoma.
AB  - BACKGROUND: Serologic measurement of antibodies to Epstein-Barr virus (EBV)
      immunoglobulin A/viral capsid antigen (IgA/VCA) and early antigen (IgA/EA) has
      been used widely to screen for nasopharyngeal carcinoma (NPC) in China. Recently,
      it was found that plasma EBV DNA concentration is an indicator for the staging
      and prognosis of patients with NPC. To determine whether there is a correlation
      between plasma EBV DNA levels and serum levels of IgA/VCA, the authors measured
      both in patients with NPC and in a control group. METHODS: Real-time polymerase
      chain reaction was used for quantitative analysis of plasma EBV DNA
      concentration, and enzyme-linked immunoadsorbent assay was used to measure EBV
      VCA/IgA in patients with primary NPC (n = 120 patients), locally recurrent NPC (n
      = 8 patients), and distant metastatic NPC (n = 21 patients) among 76 patients
      with NPC after the completion of radiotherapy, in 60 patients with NPC in
      clinical remission, in 38 patients with non-NPC tumors, and in 47 control
      individuals. RESULTS: The median plasma EBV DNA levels were 6200 copies/mL, 9200
      copies/mL, and 2050 copies/mL in patients with primary, locally recurrent, and
      distant metastatic NPC, respectively, but declined to 0 copies/mL in patients
      with clinically remissive NPC, in patients who completed radiotherapy, in
      patients with non-NPC tumors, and in the control group. In contrast, EBV VCA/IgA
      titers and detection rates remained high in all NPC groups. Plasma EBV DNA levels
      were significantly higher in patients who had serum VCA/IgA titers > or = 1:640
      (median, 83,450 copies/mL) compared with the levels in patients who had titers <
      or = 1:320 (median, 17,200 copies/mL). Patients with NPC who had advanced TNM
      stage (Stages III and IV; median, 8530 copies/mL) and T classification (T3 and T4
      tumors; median, 8530 copies/mL) had significantly higher plasma EBV DNA levels
      compared with patients who had early TNM stage (Stages I and II; median, 930
      copies/mL) and T classification (T1 and T2 tumors; median, 3700 copies). Patients
      who had advanced TNM stage NPC had significantly higher mean VCA/IgA titers
      (1:424) compared with patients who had early TNM stage NPC (1:246), but there was
      no correlation between IgA/VCA titer and T or N classification of NPC.
      CONCLUSIONS: The results suggest that plasma EBV DNA detection is a more
      sensitive and specific marker than the serum IgA/VCA titer for the diagnosis and
      monitoring of patients with NPC. These findings provide convincing evidence for
      the use of plasma EBV DNA measurements for the early diagnosis and staging of NPC
      as well as for monitoring recurrence and metastasis of this tumor.

PMID- 15022285
TI  - Thalidomide for patients with recurrent lymphoma.
AB  - BACKGROUND: Thalidomide has significant clinical activity in patients with
      multiple myeloma. However, its activity against other lymphoid tumors is unknown.
      The authors reported their experience with thalidomide in patients with
      recurrent/refractory non-Hodgkin lymphoma and in patients with Hodgkin disease.
      METHODS: Nineteen patients (median age, 62 years) who had undergone a median of 5
      previous treatment regimens were treated with escalating doses of thalidomide
      (200-800 mg per day) until disease progression or prohibitive toxicity was
      observed. The authors measured serum levels of angiogenesis factors before and
      after treatment. RESULTS: One patient (5%) with evidence of recurrent gastric
      mucosa-associated lymphoid tissue lymphoma achieved a complete response, and 3
      patients (16%) achieved stable disease. CONCLUSIONS: The current study suggests
      that thalidomide has limited single-agent activity in heavily pretreated patients
      with recurrent or refractory lymphoma.

PMID- 15022284
TI  - Relation between the duration of remission and hyperglycemia during induction
      chemotherapy for acute lymphocytic leukemia with a hyperfractionated
      cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate
      cytarabine regimen.
AB  - BACKGROUND: Hyperglycemia, which is not uncommon during the treatment of acute
      lymphocytic leukemia (ALL), has been shown to be an independent predictor of
      adverse outcomes among hospitalized patients with undiagnosed diabetes; it also
      may have the potential to affect leukemic cell proliferation through altered
      metabolism. The purpose of the current study was to determine the prevalence of
      hyperglycemia during induction chemotherapy for ALL using a regimen comprised of
      hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone
      (Hyper-CVAD) and to determine its effect on survival, duration of disease
      remission, and treatment-related complications. METHODS: Two hundred seventy
      eight adult patients with previously untreated ALL who achieved a complete
      remission with the hyper-CVAD regimen were evaluated. Hyperglycemia was defined
      as > or = 2 glucose determinations of > or = 200 mg/dL during the first 30 days
      of induction chemotherapy. Induction chemotherapy was comprised of fractionated
      cyclophosphamide at a dose of 300 mg/m2 twice daily on Days 1-3, doxorubicin at a
      dose of 50 mg/m2 on Day 4, vincristine at a dose of 2 mg on Days 4 and 11, and
      dexamethasone at a dose of 40 mg on Days 1-4 and Days 11-14 (hyper-CVAD). Hyper
      CVAD, given in odd-number courses (Courses 1, 3, 5, and 7), was alternated with
      methotrexate and cytarabine (MTX/Ara-C), given in even-number courses (Courses 2,
      4, 6, and 8). MTX/Ara-C was comprised of MTX at a dose of 200 mg/m2 over 2 hours
      followed by 800 mg/m2 over 22 hours on Day 1, Ara-C at a dose of 3 g/m2 every 12
      hours for 4 doses over 2 days (Days 2 and 3), and intravenous methylprednisolone
      given at a dose of 50 mg twice daily on Days 1-3. The complete remission duration
      (CRD), survival, and treatment-related complications were determined for patients
      with and without hyperglycemia; differences between the two groups were assessed
      using standard statistical methods. RESULTS: Hyperglycemia was found to occur in
      103 patients (37%). Patients with hyperglycemia had a shorter median CRD (24
      months vs. 52 months; P = 0.001) and a shorter median survival (29 months vs. 88
      months; P < 0.001); they also were more likely to develop sepsis (16.5% vs. 8.0%;
      P = 0.03) or any complicated infection (sepsis, pneumonia, or fungal) (38.8% vs.
      25.1%; P = 0.016) compared with patients without hyperglycemia. CONCLUSIONS:
      Patients with hyperglycemia during induction chemotherapy for ALL with the hyper
      CVAD regimen were found to have a shorter CRD, experience a significant increase
      in overall mortality, and be at an increased risk for developing complicated
      infections.

PMID- 15022286
TI  - Genetic alterations in early-stage pulmonary large cell neuroendocrine carcinoma.
AB  - BACKGROUND: Small cell lung carcinoma (SCLC) and pulmonary large cell
      neuroendocrine carcinoma (LCNEC) are high-grade malignant neuroendocrine tumors.
      Histologic differentiation between SCLC and LCNEC is difficult in some cases and
      to the authors' knowledge, genetic alterations associated with LCNEC have not
      been identified. Therefore, the authors studied genetic alterations found in
      LCNEC and compared them with those of SCLC and classic large cell carcinoma
      (CLCC). METHODS: Twenty-two patients with UICC TNM Stage I LCNEC, 12 patients
      with Stage I CLCC, and 11 patients with SCLC with limited disease were studied.
      All tumors were resected completely. Loss of heterozygosity (LOH) of the tumor
      cells was detected using fluorescent primers. Methylation status of the p16 gene
      and expression of the p53 protein, retinoblastoma protein, and p16 protein were
      evaluated immunohistochemically. RESULTS: LOH at TP53 and 13q14 was observed in
      most patients. The prevalence of LOH at D3S1295, D3S1234, and D5S407 was
      significantly higher in patients with LCNEC and SCLC than in patients with CLCC.
      The prevalence of LOH at D5S422 was higher in patients with CLCC and in patients
      with SCLC than in patients with LCNEC. Expression of the p16 protein was observed
      more frequently in SCLC than in CLCC or LCNEC. Hypermethylation of the p16 gene
      was observed more frequently in LCNEC than in SCLC. Patients with allelic losses
      at D3S1234 and D10S1686 had poorer prognoses compared with patients without
      allelic losses at these sites. CONCLUSIONS: Genetic alterations of LCNEC were
      akin to those of SCLC. However, allelic losses at 5q and abnormalities in the p16
      gene may differentiate LCNEC from SCLC.

PMID- 15022288
TI  - Frequency and risk factors for meningioma in clinically healthy 75-year-old
      patients: results of the Transdanube Ageing Study (VITA).
AB  - BACKGROUND: The prevalence of clinically silent intracranial tumors in specific
      populations is poorly researched. It is known that, in advanced age groups, the
      number of clinically manifest meningiomas constitute a small proportion of the
      actual number of cases. The goals of the current study were to determine the
      frequency of asymptomatic patients with meningioma in advanced age and to
      identify risk factors for meningiomas in this population. METHODS: Between May
      2000 and November 2002, 532 probands from a specifically defined geographic area
      of Vienna who were age 75 years underwent a magnetic resonance imaging scan of
      the brain and were evaluated for the presence of a space-occupying mass. All
      probands were examined clinically and neurologically as well as by a
      neuropsychiatrist. The patients' medical histories were carefully documented with
      regard to previous diseases, medication, and lifestyle, as were their laboratory
      reports. The collected data were correlated and similarities among subjects with
      meningioma were determined. RESULTS: Nine meningiomas that were unknown until the
      time of investigation were observed among the 318 women included in the trial
      (corresponding to a calculated prevalence of 2800/100,000 clinically silent
      meningiomas in 75-year-old women). No tumors were found among men. Associated
      clinical changes or deficits were not observed in any subject. Apart from
      advanced age and female gender, no other accepted or well known risk factors were
      observed in the tumor patients. CONCLUSIONS: Clinically quiescent meningiomas in
      the elderly female population were more common than was believed to be the case
      to date. Known and influenceable risk factors were found to be less important
      than age and gender. The high frequency of this lesion should be considered when
      deciding on the treatment of patients with incidentally discovered, clinically
      quiescent meningiomas.

PMID- 15022287
TI  - Pegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade
      glioma.
AB  - BACKGROUND: Doxorubicin exhibits high efficacy in malignant glioma cell cultures.
      Nonetheless, as a standard formulation, doxorubicin has not been used clinically,
      due to poor penetration of the blood-brain barrier. Furthermore, doxorubicin is
      known to induce tumor resistance genes. To address both of these issues, the
      authors investigated the use of pegylated liposomal doxorubicin (Caelyx; Essex
      Pharma, Munich, Germany) alone (Trial 1) and in combination with tamoxifen (Trial
      2) in two sequentially performed nonrandomized prospective Phase II trials
      involving patients with recurrent high-grade glioma. METHODS: Twenty patients
      were included in each trial. Progression-free survival at 6 months (PFS-6) and
      toxicity were the primary endpoints. Expression of the tumor resistance proteins
      multidrug resistance protein 1 (MDR-1) and multiple resistance protein (MRP) was
      evaluated by immunohistochemical methods and by sestamibi-single-photon emission
      computed tomography (SPECT). RESULTS: The overall response rate (including cases
      of disease stabilization) was 40% in both Trial 1 and Trial 2. PFS-6 was 15%, and
      the median time to disease progression was 17 weeks. It is noteworthy that 40% of
      patients with Grade III tumors had long-term responses, which lasted for up to 3
      years. There was no significant difference between Trial 1 and Trial 2 in terms
      of efficacy. Both regimens were well tolerated, with the main side effect being
      palmoplantar erythrodysesthesia. The authors found no correlation between
      clinical response and expression of tumor resistance genes or between clinical
      response and SPECT data. CONCLUSIONS: Pegylated liposomal doxorubicin
      administered alone or in combination with tamoxifen is safe and moderately
      effective in patients with recurrent high-grade glioma. None of the putative
      predictors for response that were evaluated proved to be significant in this
      setting.

PMID- 15022289
TI  - Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory
      glioblastoma multiforme.
AB  - BACKGROUND: The primary objective of the current prospective Phase II study of
      cyclophosphamide (CYC) in adult patients with recurrent, temozolomide-refractory
      glioblastoma multiforme was to evaluate 6-month progression-free survival (PFS).
      METHODS: Forty patients (28 men and 12 women) ages 28-67 years (median age, 51.5
      years), with recurrent glioblastoma multiforme were treated. All patients had
      been treated previously with surgery and involved-field radiotherapy (median
      dose, 60 grays [Gy]; range, 59-61 Gy). In addition, all patients were treated
      adjuvantly with either nitrosourea-based chemotherapy (21 patients: procarbazine,
      lomustine, and vincristine in 13 patients; carmustine in 8 patients) or
      temozolomide (19 patients). Twenty-one patients who were treated previously with
      a nitrosourea were treated with temozolomide at the time of first recurrence.
      Twenty-one patients were treated with CYC at the time of second recurrence, and
      19 patients were treated with CYC at the time of first recurrence. CYC was
      administered intravenously on 2 consecutive days (750 mg/m2 per day) every 4
      weeks (operationally defined as a single cycle). Neurologic and neuroradiographic
      evaluations were performed every 8 weeks. RESULTS: All patients were evaluable.
      In total, 170 cycles of CYC (median, 2 cycles; range, 2-12 cycles) were
      administered. CYC-related toxicity included alopecia in all patients (100%),
      anemia in 6 patients (3.5%), thrombocytopenia in 7 patients (4.1%), and
      neutropenia in 9 patients (5.3%). Four patients required transfusions (two
      required red blood cell transfusion, and two required platelet transfusion). One
      patient developed neutropenic fever without bacteriologic confirmation. No
      treatment-related deaths occurred. Seven patients (17.5%; 95% confidence interval
      [95% CI], 8-33%) exhibited a neuroradiographic partial response, 11 patients
      (27.5%; 95% CI, 15-44%) had stable disease, and 22 patients (55%) had progressive
      disease after a single cycle of CYC. The time to tumor progression ranged from 2
      months to 18 months (median, 2 months). Survival ranged from 3 months to 24
      months (median, 4 months). In patients with either a neuroradiographic response
      or stable disease (n = 18 [45%]), the median time to tumor progression was 6
      months (range, 4-18 months; 95% CI, 6-8 months), and the median survival was 10
      months (range, 5-24 months; 95% CI, 8-10 months). The 6-month PFS rate was 20%.
      CONCLUSIONS: CYC exhibited modest efficacy with acceptable toxicity in the
      current cohort of adult patients with recurrent glioblastoma multiforme, all of
      whom had previously experienced treatment failure after temozolomide
      chemotherapy.

PMID- 15022290
TI  - A multicenter study of the prognosis and treatment of adult brain ependymal
      tumors.
AB  - BACKGROUND: The current analysis of outcomes in a large series of adult patients
      with intracranial ependymal tumors contributes to the characterization of the
      primary prognostic factors and to the therapeutic management of this rare
      disease, for which limited information is available in the literature. METHODS:
      The authors analyzed data on patient and tumor characteristics, treatment, and
      survival in a series of 70 patients age > 17 years with pathologic diagnoses of
      brain ependymal tumors from 4 institutions. RESULTS: The 5- and 10-year overall
      survival (OS) rates (+/- standard errors) were 67% +/- 6% and 50% +/- 8%,
      respectively. The 5- and 10-year failure-free survival (FFS) rates were 43% +/-
      7% and 24% +/- 6%, respectively. Younger age and infratentorial tumor location
      were associated with longer survival. Among patients with Grade 2 ependymoma (n =
      51), 21 (41%) received no postsurgical treatment. These 21 patients had a 5-year
      OS rate of 78% +/- 10% and a 10-year OS rate of 68% +/- 13%; the 5- and 10-year
      FFS rates for these patients were 47% +/- 12% and 12% +/- 11%, respectively.
      Twenty-six patients with Grade 2 ependymoma (51%) received postoperative
      radiotherapy (RT). These 26 patients had a 5-year OS rate of 71% +/- 9% and a 10
      year OS rate of 59% +/- 11%; the 5- and 10-year FFS rates for these patients were
      54% +/- 10% and 34% +/- 10%, respectively. Among patients with Grade 2
      ependymoma, neither OS nor FFS differed significantly between those who did not
      receive postoperative RT and those who did; however, these two groups were
      heterogeneous with respect to prognostic factors. On multivariate analysis, RT
      use exhibited a trend toward improved OS and was significantly predictive of
      improved FFS. CONCLUSIONS: The current analysis does not rule out the possibility
      that deferral of RT at the time of recurrence could have a detrimental effect on
      FFS or OS in patients with Grade 2 ependymoma, regardless of the degree of
      ablation. The role of postoperative RT for patients who undergo imaging-based
      macroscopic total resection remains to be addressed.

PMID- 15022291
TI  - The histologic grade is a main prognostic factor for patients with intracranial
      ependymomas treated in the microneurosurgical era: an analysis of 258 patients.
AB  - BACKGROUND: Ependymomas account for 3-5% of all intracranial malignancies and
      occur most often in children and young adults. These neoplasms continue to
      generate considerable controversy with regard to their rational clinical
      management. It has been shown that the histologic classification of ependymoma is
      a significant predictor of clinical outcome in patients with ependymoma. METHODS:
      Ependymomas from 258 patients who underwent microsurgery at a single institution
      were evaluated histologically to elucidate the prognostic utility of a recently
      proposed grading scheme. Pathologic and clinical data then were compared using
      univariate and multivariate analyses. RESULTS: Increasing grade of ependymoma
      malignancy was found to be associated strongly and independently with worse
      clinical outcomes in terms of both event-free survival and overall survival. The
      effect of radiotherapy also was found to be related to histologic grade and was
      more beneficial for patients who had anaplastic ependymomas and had undergone
      complete tumor removal. CONCLUSIONS: The application of a uniform diagnostic
      criteria for grading ependymomas highlighted the key role of tumor histology in
      clinical outcome in a cohort of patients who were treated in the microsurgical
      era. The recently proposed grading scheme is likely to be practically useful,
      reproducible, and clinically applicable.

PMID- 15022292
TI  - Dissemination of information on legislative mandates and consensus-based programs
      addressing payment of the costs of routine care in clinical trials through the
      World Wide Web.
AB  - BACKGROUND: Legislative and consensus-based programs that ensure payment for
      routine care costs in a trial have been enacted by a number of states and
      government-sponsored health benefits programs. To eliminate the potential for
      denial of payment by a health plan that can act as a barrier to participation,
      the public must be aware that these programs exist and what they entail. METHODS:
      World Wide Web sites are utilized by patients and their surrogates as a prime
      source of healthcare-related information. A review of cancer research
      organization and advocate group web sites was performed to document the degree to
      which these sites provided information on clinical trial coverage programs. The
      objective was to determine whether patients were being given sufficient
      information to overcome barriers to participation related to the existence of
      clinical trials, their potential benefits, and health plan payment. RESULTS:
      Fewer than 5% of the 373 sites reviewed provided sufficient information to
      communicate to a patient that 1) the institution participates in sponsored cancer
      clinical research, 2) patients can derive direct benefits by participating in a
      clinical trial, and 3) payment for treatment in a clinical trial is largely
      provided by their health plan. CONCLUSIONS: Sites on the World Wide Web are a key
      source of healthcare-related information for patients and their surrogates.
      Organizations involved in clinical cancer research should examine their web sites
      to ensure that the content it contains is sufficiently detailed, accessible, and
      readable to inform potential participants fully of the clinical trial options.

PMID- 15022293
TI  - Spectroscopic and perfusion magnetic resonance imaging predictors of progression
      in pediatric brain tumors.
AB  - BACKGROUND: In vivo biomarkers to predict progression of brain tumors are of
      great value in clinical practice. Therefore, the authors tested the hypothesis
      that changes in choline ratios by magnetic resonance (MR) spectroscopic imaging
      and/or relative tumor blood volume (rTBV) can differentiate clinically stable
      from progressive pediatric brain tumors. METHODS: MR spectroscopic imaging
      examinations were performed on 27 children with neuroglial brain tumors during
      therapy on a 1.5-Tesla MR system. Normalized rTBV values were measured in 11 of
      27 patients. Each examination was rated as stable or progressive by clinical and
      imaging criteria. RESULTS: The percent change in normalized choline (Cho) was
      significantly greater in patients who had progressive examinations compared with
      patients who had stable examinations (P = 0.03). The percent change in Cho/N
      acetylaspartate (Cho/NAA) was significantly higher in patients who had
      progressive outcomes (n = 18 patients) compared with patients who had stable
      outcomes (n = 32 patients; P < 0.001; sensitivity, 0.89; specificity, 0.88) and
      was identified as the most important prognostic indicator of tumor progression by
      logistic regression (likelihood ratio test, 33.4; P < 0.001). The odds of tumor
      progression were approximately 55 times greater for patients who showed at least
      a 20% change in Cho/NAA. rTBV distinguished between progressing and stable tumors
      (P = 0.03), and Cho/NAA and rTBV values showed interaction to predict the
      probability of a progressing clinical outcome. CONCLUSIONS: The percent change in
      Cho/NAA by proton MR spectroscopic imaging, assisted by rTBV, was useful in
      predicting tumor progression in children with brain tumors.

PMID- 15022294
TI  - Gemcitabine and docetaxel as front-line chemotherapy in patients with carcinoma
      of an unknown primary site.
AB  - BACKGROUND: The current study was performed to evaluate the efficacy and toxicity
      of a noncisplatin-based chemotherapy regimen combining gemcitabine and docetaxel
      as front-line chemotherapy for patients with carcinoma of an unknown primary
      site. METHODS: Patients were to receive intravenous gemcitabine at a dose of 1000
      mg/m2 over 30 minutes on Days 1 and 8 and docetaxel at a dose of 75 mg/m2 over 1
      hour on Day 8 in an outpatient setting. The schedule was repeated every 3 weeks
      for a maximum of 6 cycles. RESULTS: Thirty-five patients were assessable for
      response and survival. One complete and 13 partial responses were observed. The
      overall response rate was 40% (95% confidence interval, 28-52%). The median time
      to disease progression was 2 months (range, 1-4 months). The median overall
      survival time was 10 months (range, 0-32 months). Toxicity was reported to be
      manageable. CONCLUSIONS: The combination of gemcitabine and docetaxel was found
      to be active in patients with carcinomas of an unknown primary site. However, the
      overall outcome of these patients remains poor and novel treatment approaches are
      required.

PMID- 15022295
TI  - Quality of colon carcinoma pathology reporting: a process of care study.
AB  - BACKGROUND: In 1996, the Association of Directors of Anatomic and Surgical
      Pathology (ADASP) published recommendations for colon carcinoma reporting. Since
      this publication, no study has evaluated physician practice in relation to these
      recommendations. The objectives of the current study were to describe pathology
      reporting for colon carcinoma, evaluate potential variations in reporting, and
      identify areas for improvement. METHODS: Data were obtained from a population
      based study of incident colon carcinoma in 33 counties in North Carolina between
      1997 and 2000. All subjects with surgically resected colon carcinoma of tumor
      stage T2-T4 with available surgical pathology reports were eligible for inclusion
      in the current analysis. The authors reviewed pathology reports for adherence to
      recommendations of the ADASP. RESULTS: Four hundred thirty-eight pathology
      reports were included for analysis. Adherence to ADASP recommendations was < 90%
      for descriptions of how specimen was received (68%), how specimen was identified
      (71%), macroscopic depth of penetration (82%), appearance of serosa adjacent to
      tumor (50%), and status of residual bowel (73%). All other criteria were reported
      in > 90% of patients. Teaching hospital and contract pathology laboratories had
      greater adherence to recommendations, compared with community hospital
      laboratories. Hospitals with the highest colon carcinoma case volume demonstrated
      greater adherence to recommendations, compared with low-volume hospitals.
      CONCLUSIONS: Pathology reports were effective in communicating most pertinent
      findings from surgically resected colon carcinoma specimens. Omissions of some
      critical characteristics did occur, however, and significant variability in
      reporting existed based on laboratory affiliation and hospital case volume.

PMID- 15022296
TI  - Fractionated low-dose radiotherapy after myeloablative stem cell transplantation
      for local control in patients with high-risk neuroblastoma.
AB  - BACKGROUND: The optimal administration of radiotherapy for patients with high
      risk neuroblastoma (NB) currently is undefined in the context of modern therapy
      using myeloablative chemotherapy with autologous stem cell rescue (hematopoietic
      stem cell transplantation [HSCT]). METHODS: The authors conducted a retrospective
      review of the records of 21 consecutive patients with high-risk NB to assess
      local control and toxicity of external beam radiotherapy (XRT). Therapy included
      multiagent induction chemotherapy and delayed surgical resection, consolidation
      of HSCT and local XRT, and 13-cis-retinoic acid maintenance therapy. XRT was
      delivered to the primary site, using postchemotherapy volumes, and to initial
      metastatic sites with 1-2 cm margins to 2100 centigrays (cGy) using 14 fractions
      administered once daily. RESULTS: Four of 21 patients did not receive XRT due to
      toxic death (n = 2), disease progression before XRT (n = 1), or parental refusal
      (n = 1). The median time to XRT post-HSCT was 54 days. Thirteen patients received
      a second peripheral blood stem cell infusion after completing XRT. Twelve of the
      14 patients who received XRT post-HSCT and for whom toxicity data were available
      had Grade 3-4 acute toxicities, including gastrointestinal toxicity (n = 8),
      hematologic toxicity (n = 9), and infection (n = 1). Nonrecurrent long-term
      toxicities included prolonged nutritional deficiency (n = 9) and leg-length
      discrepancy (n = 1). Tumors recurred in 7 of 21 patients (5 of 17 patients who
      received radiotherapy), either within a radiation field (n = 1) or at distant
      nonirradiated sites (n = 6). The estimated local failure rate was 7% (95%
      confidence interval [95% CI], 0-14%), with a 2-year event-free survival rate of
      48% (95% CI, 26-70%). CONCLUSIONS: Post-HSCT, fractionated XRT to 2100 cGy was a
      tolerable and effective treatment for patients with high-risk NB, and minimal
      recurrences were observed at designated XRT sites.

PMID- 15022297
TI  - Optimism and survival in lung carcinoma patients.
AB  - BACKGROUND: It is popular belief that the psychologic response to a diagnosis of
      cancer influences survival in patients with cancer; however, research has
      produced contradictory results. In this prospective study, the authors
      investigated the relation between pretreatment levels of optimism and survival in
      patients with nonsmall cell lung carcinoma (NSCLC). METHODS: Two hundred four
      patients who were participating in a randomized trial that compared accelerated
      and conventional radiotherapy with and without carboplatin chemotherapy were
      asked to complete two questionnaires assessing optimism. The first assessment was
      just prior to commencing treatment and the second assessment took place after
      completing treatment. Survival was measured from the date of randomization to the
      date of death. Surviving patients were followed until February 8, 2001. RESULTS:
      The pretreatment questionnaire was completed by 179 patients, and 148 of those
      patients completed the posttreatment questionnaire. There was a small but
      significant reduction in optimism scores after treatment (P = 0.005). There was
      no association noted between pretreatment optimism and progression-free survival
      (P = 0.52, unadjusted; P = 0.22, adjusted for Eastern Cooperative Oncology Group
      performance status and patient age), nor was there an association noted between
      pretreatment optimism and overall survival (P = 0.36, unadjusted; P = 0.19,
      adjusted for disease stage). CONCLUSIONS: There was no evidence that a high level
      of optimism prior to treatment enhanced survival in patients with NSCLC.
      Encouraging patients to "be positive" only may add to the burden of having cancer
      while providing little benefit, at least in patients with NSCLC.

PMID- 15022298
TI  - Recurrence-free survival rates after external-beam radiotherapy for patients with
      clinical T1-T3 prostate carcinoma in the prostate-specific antigen era: what
      should we expect?
AB  - BACKGROUND: The objective of the current study was to report biochemical
      recurrence-free survival (bRFS) rates among men with T1-T3 prostate carcinoma who
      were treated with external-beam radiotherapy (RT) at the Cleveland Clinic
      Foundation (Cleveland, OH). METHODS: In total, 1352 patients were identified
      between 1987 and 2000 with a minimum follow-up of 1 year (median follow-up, 55
      months; range, 12-189 months). The median radiation dose was 74.0 grays (Gy)
      (range, 63.0-83.0 Gy). The median radiation doses for patients who received <
      68.0 Gy (n = 201), 68.0-72.0 Gy (n = 373), and > or = 72.0 Gy (n = 778) were 66.6
      Gy, 70.0 Gy, and 78.0 Gy, respectively. The RT techniques used were standard RT
      in 41% of patients, 3-dimensional conformal RT in 34% of patients, and intensity
      modulated RT in 25% of patients. Androgen-deprivation (AD) therapy lasting < or =
      6 months was administered to 34% of patients. RESULTS: The 5-year and 7-year bRFS
      rates were 63% and 59%, respectively. On multivariate analysis, T classification
      (P < 0.001), pretreatment prostate-specific antigen level (P < 0.001), biopsy
      Gleason score (P = 0.001), radiation dose (P < 0.001), and year of therapy (P <
      0.001) were independent predictors of biochemical failure. Age, race, AD therapy,
      and RT technique did not predict for biochemical failure. For patients with low
      risk tumors, the 5-year bRFS rates for those who received RT doses of < or = 68.0
      Gy, 68.0-72.0 Gy, and > or = 72.0 Gy were 52%, 82%, and 93%, respectively (P <
      0.001); for patients with intermediate-risk tumors, the respective 5-year bRFS
      rates were 27%, 51%, and 83% (P < 0.001); and for patients with high-risk tumors,
      the respective 5-year bRFS rates were 21%, 29%, and 71%, respectively (P <
      0.001). CONCLUSIONS: The most significant therapeutic factor affecting bRFS rates
      after RT was radiation dose, rather than AD therapy use or radiation technique.

PMID- 15022299
TI  - Estimation of an optimal radiotherapy utilization rate for melanoma: a review of
      the evidence.
AB  - BACKGROUND: Radiotherapy is not used commonly in the treatment of patients with
      malignant melanoma. The benchmark optimal radiotherapy utilization rates for
      melanoma are largely unknown, despite the fact that melanoma is a very common
      cancer. METHODS: To develop an evidence-based benchmark for the optimal
      proportion of patients with melanoma who should receive radiotherapy, the authors
      reviewed major treatment guidelines for melanoma. A radiotherapy decision tree
      was constructed showing the clinical features of melanoma patients for whom
      radiotherapy was indicated based on evidence. The proportions of melanoma
      patients with indications for radiotherapy were obtained from epidemiologic data
      and were used to calculate the optimal proportion of melanoma patients who should
      receive radiotherapy. RESULTS: The proportion of patients with melanoma for whom
      radiotherapy is indicated at some point in their illness, according to the best
      available evidence, was calculated at 23% of all melanoma patients. The
      utilization rates of radiotherapy for melanoma recorded in actual practice were
      13% in New South Wales, 6% in data from the American College of Surgeons, and 1%
      according to Surveillance, Epidemiology, and End Results data. CONCLUSIONS:
      Strategies for implementing the evidence-based guidelines are recommended to
      overcome the shortfall in the use of radiotherapy in the treatment of patients
      with melanoma.

PMID- 15022300
TI  - A randomized clinical trial of energy conservation for patients with cancer
      related fatigue.
AB  - BACKGROUND: The efficacy of energy conservation and activity management (ECAM)
      for fatigue reduction and maintenance of functional performance has never been
      evaluated in adults with cancer who are undergoing treatment. METHODS: A
      randomized clinical trial compared an ECAM intervention with a control
      intervention focused on nutrition. Individuals initiating chemotherapy,
      radiotherapy, or concurrent therapy for cancer were randomized to receive either
      the semistructured ECAM intervention (n = 200) or the control intervention (n =
      196). Participants in each group participated in 3 telephone sessions with an
      oncology nurse during the first 5 weeks of treatment. Data on fatigue and
      limitation of functioning were obtained before cancer treatment and at two follow
      up points that coincided with times of high fatigue for each type of treatment.
      The outcomes of interest included perception of fatigue and functional
      performance. RESULTS: A repeated-measures analysis of covariance using the type
      of cancer treatment as a covariate revealed a significant study group-by-time
      interaction indicating that the ECAM group experienced a greater decrease in
      fatigue over time compared with the control group (F(2,544) = 4.5; P = 0.01). The
      intervention was not associated with changes in overall functional performance.
      CONCLUSIONS: Individuals who received the ECAM intervention derived a modest but
      significant benefit from it. To achieve a more robust clinical benefit from the
      intervention, it may be necessary to manage other key symptoms in addition to
      fatigue. Research is needed to examine symptom clusters or combinations
      associated with negative outcomes as well as combination strategies for symptom
      management.

PMID- 15022302
TI  - The burdens of cancer therapy: clinical and economic outcomes of chemotherapy
      induced mucositis.

PMID- 15022304
TI  - Systemic lupus erythematosus and Sjogren's syndrome: historical perspective and
      ongoing concerns.

PMID- 15022301
TI  - Intestinal expression of mutant and wild-type progastrin significantly increases
      colon carcinogenesis in response to azoxymethane in transgenic mice.
AB  - BACKGROUND: The authors recently reported that transgenic mice (hGAS) expressing
      pharmacologic levels of progastrin (PG) (> 10 nM to 100 nM) exhibited increased
      susceptibility to colon carcinogenesis in response to azoxymethane (AOM). It is
      not known whether PG functions as a cocarcinogen at the concentrations observed
      in patients with hypergastrinemia (approximately 1.0 nM). METHODS: The authors
      generated transgenic mice that overexpressed either wild-type (wtPG) or mutant
      (mtPG) human PG in the intestinal mucosa using the murine fatty acid binding
      protein (Fabp) promoter. Fabp-PG mice and their wild-type littermates were
      treated with AOM, and their colons were examined for preneoplastic (aberrant
      crypt foci [ACF]) and neoplastic (adenomas [Ads] and adenocarcinomas [AdCas])
      lesions after 2 weeks and 6 months of treatment. RESULTS: ACF and tumors were
      significantly more common (by a factor of approximately 2) in colon specimens
      from both Fabp-wtPG mice and Fabp-mtPG mice relative to wild-type mice. It is
      noteworthy that the multiplicity of ACF and the total number of small and large
      Ads and AdCas were significantly greater in colon specimens from Fabp-PG mice
      compared with colon specimens from wild-type mice, irrespective of gender.
      CONCLUSIONS: The results of the current study suggest that at concentrations
      (approximately 1.0 nM) far lower than the ones observed in hGAS mice, PG
      functions as an equally potent cocarcinogen and significantly increases the risk
      of colon carcinogenesis in response to AOM. Thus, PG may represent a clinically
      relevant target molecule in patients with hypergastrinemia or colon carcinoma.

PMID- 15022305
TI  - Autoimmunity to the nuclear autoantigen DFS70 (LEDGF): what exactly are the
      autoantibodies trying to tell us?

PMID- 15022306
TI  - Natural killer cell dysfunction: A common pathway in systemic-onset juvenile
      rheumatoid arthritis, macrophage activation syndrome, and hemophagocytic
      lymphohistiocytosis?

PMID- 15022307
TI  - Radiographic progression depicted by probability plots: presenting data with
      optimal use of individual values.

PMID- 15022309
TI  - Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid
      arthritis in patients with undifferentiated arthritis: a prospective cohort
      study.
AB  - OBJECTIVE: Rheumatoid arthritis (RA) is a common, severe, chronic inflammatory
      joint disease. Since the disease may initially be indistinguishable from other
      forms of arthritis, early diagnosis can be difficult. Autoantibodies seen in RA
      can be detected years before clinical symptoms develop. In an inception cohort of
      patients with recent-onset arthritis, we undertook this study to assess the
      predictive value of RA-specific autoantibodies to cyclic citrullinated peptides
      (CCPs) in patients with undifferentiated arthritis (UA). METHODS: Anti-CCP2
      antibody tests were performed at baseline in 936 consecutive, newly referred
      patients with recent-onset arthritis. Patients who could not be properly
      classified 2 weeks after inclusion were categorized as having UA. Patients with
      UA were followed up for 3 years and evaluated for progression of their disease to
      RA as defined by the American College of Rheumatology (ACR) 1987 revised
      criteria. RESULTS: Three hundred eighteen of 936 patients with recent-onset
      arthritis were classified as having UA and were available for analysis. After 3
      years of followup, 127 of 318 UA patients (40%) had been classified as having RA.
      RA had developed in 63 of 249 patients (25%) with a negative anti-CCP test and in
      64 of 69 patients (93%) with a positive anti-CCP test (odds ratio 37.8 [95%
      confidence interval 13.8-111.9]). Multivariate analysis of the presence of anti
      CCP antibodies and parameters from the ACR criteria identified polyarthritis,
      symmetric arthritis, erosions on radiographs, and anti-CCP antibodies as
      significant predictors of RA. CONCLUSION: Testing for anti-CCP antibodies in UA
      allows accurate prediction of a substantial number of patients who will fulfill
      the ACR criteria for RA.

PMID- 15022310
TI  - Use of multispectral magnetic resonance imaging analysis to quantify erosive
      changes in the hands of patients with rheumatoid arthritis: short-term and long
      term longitudinal studies.
AB  - OBJECTIVE: Magnetic resonance imaging (MRI) has been shown to be more sensitive
      than radiography for detecting bone erosions in rheumatoid arthritis (RA).
      Semiquantitative scoring based on visual image assessment has been introduced.
      However, there is considerable interest in true quantitative measures,
      particularly in the context of clinical trials designed to show differences
      between treatment groups. This study was undertaken to investigate the use of a
      new quantitative approach, multispectral (MS) image analysis, for assessing
      erosive change. METHODS: T1-weighted spin-echo (SE) and fat-suppressed gradient
      echo (GE) sequences of metacarpophalangeal joints of the dominant hand were
      acquired at various time points throughout a 2-year period. MS analysis was
      applied to all images, resulting in segmentation into a generalized bone and a
      soft tissue class. Voxel changes from one to the other class identified apparent
      bone lesion volume change (Delta BLV). MR images were also visually scored for
      erosions (E score). All analyses were performed separately, on a per-joint basis,
      for short-term and long-term data sets. RESULTS: Analysis of variance with
      adjustment for individual effect revealed similar results in the short-term and
      the long-term studies, using either GE or SE images for visual assessment.
      Patients with an increase in E score on visual assessment had a significantly
      higher Delta BLV than those without. CONCLUSION: Temporal MS analysis of MRIs can
      be used to detect and quantify erosive changes in RA. This semiautomated method
      may be useful for demonstrating differences between treatment groups in clinical
      trials.

PMID- 15022311
TI  - Lack of response to anakinra in rheumatoid arthritis following failure of tumor
      necrosis factor alpha blockade.
AB  - OBJECTIVE: In patients with rheumatoid arthritis (RA) treated with tumor necrosis
      factor alpha (TNF alpha)- blocking therapy, there is heterogeneity of response.
      This raises the possibility that in certain circumstances, cytokines such as
      interleukin-1 (IL-1) may dominate the drive toward joint inflammation. This study
      was undertaken to investigate whether blocking the action of IL-1 with an IL-1
      receptor antagonist (IL-1Ra) is efficacious in patients with disease that did not
      respond to TNF alpha blockade. METHODS: We identified 26 RA patients whose
      disease had failed to respond to TNF alpha-blocking therapy, defined as failure
      to achieve or sustain a 20% improvement in disease activity according to the
      criteria of the American College of Rheumatology (ACR20 response). These patients
      were then treated with anakinra (100 mg/day subcutaneously) for 12 weeks, and
      their levels of response were assessed. RESULTS: After 3 months of anakinra
      therapy, only 2 of 26 patients (8%) achieved an ACR20 response; none achieved an
      ACR50 or ACR70 response. A rise in the mean C-reactive protein level and an
      increase in the mean swollen joint count were noted during the study period.
      CONCLUSION: This study demonstrates that patients with disease that fails to
      respond to TNF alpha blockade also do not respond to IL-1Ra. These data do not
      provide evidence of a dominant role for IL-1 in patients who do not respond to
      TNF alpha blockade, but they do not exclude a role for other proinflammatory
      mediators.

PMID- 15022313
TI  - Clustering of disease features within 512 multicase rheumatoid arthritis
      families.
AB  - OBJECTIVE: To determine whether specific rheumatoid arthritis (RA) disease
      features demonstrate the presence of significant familial clustering. METHODS: We
      studied 1,097 individuals with RA from 512 multicase families enrolled in the
      North American Rheumatoid Arthritis Consortium. All patients were interviewed and
      examined to collect standardized information about demographic and clinical
      characteristics. Affected individuals also underwent radiography of the hands and
      wrists and were genotyped for the HLA-DRB1 shared epitope. Familial clustering of
      disease features was assessed using contingency table analysis and Pearson
      correlation coefficients. Multivariate logistic and linear regression analyses
      were used to account for other characteristics that might influence familial
      clustering, such as disease duration, sex, and age at diagnosis. RESULTS: Several
      disease characteristics exhibited significant familial clustering, including
      seropositivity (multivariate odds ratio [OR] 4.3, P < 0.0001), nodules (OR 2.3, P
      < 0.0001), and age at RA diagnosis (multivariate regression coefficient [beta]
      0.44, P < 0.0001). Other characteristics demonstrated statistically significant
      but modest degrees of familial clustering (Joint Alignment and Motion score,
      Health Assessment Questionnaire score, and year of RA diagnosis) or modest but
      nonsignificant familial clustering (other extraarticular manifestations, other
      autoimmune diseases). CONCLUSION: The clustering of certain disease
      characteristics implicates specific genetic or nongenetic causes. These results
      highlight the importance of considering disease phenotype in future genetic and
      epidemiologic studies of RA.

PMID- 15022312
TI  - Investigation of susceptibility loci identified in the UK rheumatoid arthritis
      whole-genome scan in a further series of 217 UK affected sibling pairs.
AB  - OBJECTIVE: A previous whole-genome scan (WGS) of 182 UK rheumatoid arthritis (RA)
      affected sibling pair (ASP) families suggested linkage to HLA and 11 other
      chromosome regions. Replication of such findings in an independent cohort can
      help to distinguish true linkages from false-positive linkages. Since RA is a
      heterogeneous disease, some loci may be linked only in subsets of patients. Thus,
      the aim of this study was to investigate in an additional set of RA ASP families
      linkage to regions showing deviation in expected allele-sharing ratios in the UK
      WGS and to perform subset analysis on the combined cohort. METHODS: Twenty loci
      were investigated for linkage in 217 Caucasian UK RA ASPs. Stratification
      analysis was performed on the combined cohort of 377 RA ASP families to account
      for sex, RA severity, and the shared epitope (SE). RESULTS: None of the regions
      of linkage identified in the initial WGS achieved statistical significance in the
      second cohort. In contrast, after stratification analysis, 14 regions showed
      nominal evidence of linkage (logarithm of odds score >0.8) in one or more
      subgroups. In particular, the strength of evidence for linkage to chromosome 16p
      was increased in subsets of ASPs with younger age at disease onset (LOD score
      2.38) and for linkage to chromosome 6q in female-female ASPs (LOD score 2.31) and
      in ASPs in which both siblings had 2 copies of the SE (LOD score 3.03).
      CONCLUSION: These results support the evidence for heterogeneity of RA. This
      information will inform the future design of association-based investigations as
      the search for disease genes in the linked regions begins.

PMID- 15022314
TI  - Tumor necrosis factor receptor II gene polymorphism and severity of rheumatoid
      arthritis.
AB  - OBJECTIVE: The gene encoding tumor necrosis factor receptor type II (TNFRII) is a
      strong candidate in the pathogenesis of rheumatoid arthritis (RA). An association
      between a single-nucleotide polymorphism (196M/R) in exon 6 of the TNFRII gene
      and familial RA was recently reported. The present study was undertaken to test
      the hypothesis that there is an association between this polymorphism and the
      severity of RA. METHODS: One hundred two white patients with early RA were
      included in this prospective study. The French version of the Health Assessment
      Questionnaire (F-HAQ) and a radiographic damage score (modified Sharp/van der
      Heijde method) were used to quantify the functional and structural severity of RA
      at baseline and after 4 years of followup. TNFRII 196M/R polymorphism genotyping
      was performed by polymerase chain reaction-restriction fragment length
      polymorphism analysis. RESULTS: Among the 102 patients with RA, 63 (61.8%) were
      homozygous for the 196M allele, 36 (35.3%) were heterozygous for alleles 196M and
      196R, and 3 (2.9%) were homozygous for the 196R allele. At baseline, the median
      radiographic and F-HAQ scores did not differ between RA patients who carried the
      196R allele and those who did not. After 4 years of followup, the F-HAQ score was
      higher in RA patients carrying the 196R allele (median 1 [interquartile range
      (IQR) 0.125, 1.375]) than in noncarriers (0.375 [IQR 0, 1]) (P = 0.02), while the
      median radiographic score did not differ between RA patients who carried the 196R
      allele and those who did not. CONCLUSION: The results of the present study
      support the hypothesis that there is an association between the TNFRII 196 M/R
      gene polymorphism and the functional severity of early RA.

PMID- 15022315
TI  - Haplotype analysis in simplex families and novel analytic approaches in a case
      control cohort reveal no evidence of association of the CTLA-4 gene with
      rheumatoid arthritis.
AB  - OBJECTIVE: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a negative
      regulator of T cells and is, therefore, a strong candidate susceptibility gene
      for T cell-mediated autoimmune diseases. The association of CTLA-4 single
      nucleotide polymorphisms (SNPs) with rheumatoid arthritis (RA) has been
      investigated previously, with inconsistent results. Recently, SNPs mapping to the
      gene (and not previously investigated in RA) have been associated with both type
      1 diabetes mellitus and Graves' disease. The aim of this study was to investigate
      the association of the CTLA-4 polymorphism with RA. METHODS: Primer extension
      methods were used to genotype 5 haplotype-tagging SNPs (htSNPs) (-1722 T/C, -1661
      A/G, -658 C/T, -319 C/T, and +49 A/G), and the TaqMan 5' allelic discrimination
      assay was used to genotype an additional 2 SNPs (CT60 and rs1863800) mapping to
      the CTLA-4 gene. Association to the 5 htSNPs was investigated using the
      transmission disequilibrium test in RA simplex families (n = 122). Allele
      frequencies for the htSNPs were also investigated in affected sibling pairs (n =
      96) and unrelated controls (n = 173). For the SNPs CT60 and rs1863800, unrelated
      patients with RA (n = 759) were compared with controls (n = 755). RESULTS: No
      evidence for association to single markers or haplotypes of the 5 htSNPs was
      detected in either RA simplex families or the affected sibling-control cohort.
      Neither of the 2 SNPs recently associated with Graves' disease showed evidence
      for association in the unrelated patient-control cohort. CONCLUSION: No evidence
      for association of CTLA-4 with RA was detected using family or case-control
      methods.

PMID- 15022316
TI  - Lack of association of the HLA-DRB1 shared epitope with rheumatoid nodules: an
      individual patient data meta-analysis of 3,272 Caucasian patients with rheumatoid
      arthritis.
AB  - OBJECTIVE: The objective of this individual patient data (IPD) meta-analysis was
      to examine the relationship of rheumatoid nodules to the HLA-DRB1 shared epitope
      (SE) and to individual SE genotypes. METHODS: English-language studies that
      enrolled adult non-Hispanic Caucasian patients with rheumatoid arthritis (RA)
      were identified by searches of Medline and Embase, and by manual searches of
      medical journals. All authors were contacted for IPD. Meta-analysis was performed
      to assess the association of SE presence, dose, and genotype with rheumatoid
      nodules. Meta-analyses adjusted for disease duration and cumulative meta-analyses
      were also performed to assess the influence of RA duration and year of study
      publication on the results. RESULTS: A total of 24 studies and 3,272 patients
      were available for analysis. IPD were obtained for 22 of the studies. There was a
      nonsignificant association between the presence of the SE (i.e., 1 or 2 alleles
      versus 0 alleles) and rheumatoid nodules (summary odds ratio [OR] 1.3, 95%
      confidence interval [95% CI] 0.97-1.6). Analysis by SE genotype, however,
      demonstrated a weak relationship with inheritance of a single DRB1*0401 SE allele
      (OR 1.4, 95% CI 1.1-1.8). No other genotypes achieved statistical significance in
      the adjusted or unadjusted analyses. CONCLUSION: The presence of the HLA-DRB1 SE
      does not appear to significantly increase the risk of rheumatoid nodules among
      Caucasian patients with RA. Analysis by DRB1 SE genotype was uninformative,
      suggesting only a potential (and at most modest) role of the DRB1*0401 SE allele.
      Results from this IPD meta-analysis implicate other genetic, stochastic, and/or
      environmental factors in the susceptibility to rheumatoid nodules.

PMID- 15022317
TI  - Additional genetic susceptibility for rheumatoid arthritis telomeric of the DRB1
      locus.
AB  - OBJECTIVE: Rheumatoid arthritis (RA) has an estimated genetic contribution of 30
      50%, approximately one-third of which arises from the major histocompatibility
      complex on 6p21.3. Many studies have implicated alleles of DRB1 that encode a
      shared epitope. However, several recent studies have suggested that additional
      telomeric genetic influences may exist. In this study, we sought to investigate
      whether a separate non-DRB1 effect could be detected and to determine its likely
      location. METHODS: We typed 13 single-nucleotide polymorphisms, located mainly in
      the telomeric class III region of the major histocompatibility complex, in 164
      British Caucasian families with RA that had at least 1 affected offspring and
      used unconditioned and DRB1-conditioned transmission disequilibrium tests (TDTs).
      RESULTS: Unconditioned TDTs revealed overtransmission of shared epitope alleles
      (P = 2.12 x 10(-5)) and an allele of the HLA-B-associated transcript 1 (BAT1)
      gene in the telomeric class III region (P = 0.009). Using a DRB1-conditioned TDT
      to assess whether an independent effect existed, we detected unequal transmission
      of alleles of lymphocyte-specific transcript 1 (P = 0.004), BAT1 (P = 0.003), and
      PG8 (P = 0.003). CONCLUSION: At least 1 additional non-DRB1 susceptibility locus
      for RA exists in an interval that encompasses the junction of the class III and I
      regions. This is a genomic segment of high linkage disequilibrium containing a
      large number of poorly characterized immunomodulatory genes.

PMID- 15022318
TI  - Association of a programmed death 1 gene polymorphism with the development of
      rheumatoid arthritis, but not systemic lupus erythematosus.
AB  - OBJECTIVE: The expression of autoimmunity in mice deficient in programmed death 1
      (PD-1) suggests that PD-1 is a candidate gene involved in the development of
      human autoimmune diseases such as systemic lupus erythematosus (SLE) and
      rheumatoid arthritis (RA). We therefore tested the potential association between
      PD-1 and the development of SLE and RA by conducting case-control genetic
      association studies. METHODS: Ninety-eight SLE patients, 84 RA patients, and sex
      matched control subjects for each disease group were recruited and genotyped for
      a single-nucleotide polymorphism, C+872T, in the human PD-1 gene. The
      significance of the association of the PD-1 gene with SLE or with RA was analyzed
      by statistical tests for the difference in genotype distribution between disease
      and control groups. RESULTS: The human PD-1 gene was found to be significantly
      associated with disease development in RA patients, but not SLE patients. The
      risk of RA development appeared to be significantly increased by carriage of the
      T allele (odds ratio 3.32, P < 0.0001) or the C/T genotype (odds ratio 3.52, P <
      0.00005). CONCLUSION: The PD-1 gene is significantly associated with RA
      susceptibility, suggesting the possibility that PD-1 may contribute to the
      pathogenesis of RA.

PMID- 15022319
TI  - Effector function of type II collagen-stimulated T cells from rheumatoid
      arthritis patients: cross-talk between T cells and synovial fibroblasts.
AB  - OBJECTIVE: To investigate the effector function exerted by type II collagen (CII)
      stimulated T cells on rheumatoid arthritis (RA) fibroblast-like synoviocytes
      (FLS), and to determine their contribution to RA pathogenesis. METHODS: We used
      enzyme-linked immunosorbent assays to measure the levels of interleukin-15 (IL
      15), tumor necrosis factor alpha (TNFalpha), and IL-18 production by FLS that
      were cocultured with antigen-activated T cells. Likewise, we analyzed the levels
      of interferon-gamma (IFN gamma) and IL-17 production by RA T cells coincubated
      with FLS. To investigate the cross-talk between CII-stimulated T cells and RA
      FLS, we examined the effect of using a transwell membrane to separate T cells and
      FLS in a culture chamber, as well as the effect of adding an antibody to block
      CD40 ligation. RESULTS: The levels of IL-15, TNF alpha, IFN gamma, and IL-17 were
      all significantly increased in the serum of RA patients compared with normal
      control serum. Among the patients, the group with a stronger T cell proliferation
      response to CII showed higher levels of these inflammatory mediators. When
      coincubated with RA FLS, these T cells induced the production of IL-15, TNF
      alpha, and IL-18 by FLS with an intensity that increased in proportion to the
      duration of CII stimulation. T cells, in turn, responded to FLS stimulation by
      secreting higher amounts of IL-17 and IFN gamma in coculture. Interestingly, T
      cells that were activated by CII for longer periods of time showed stronger
      induction of these cytokines. The cross-talk between T cells and FLS appeared to
      require direct cell-cell contact as well as CD40 ligation, at least in part.
      CONCLUSION: Through repeated stimulation by CII, RA synovial T cells became
      trained effector cells that induced the production of proinflammatory mediators
      by FLS, while in the process the T cells becoming more sensitized to the
      activation signal from FLS.

PMID- 15022320
TI  - MEK/ERK and signal transducer and activator of transcription signaling pathways
      modulate oncostatin M-stimulated CCL2 expression in human osteoblasts through a
      common transcription factor.
AB  - OBJECTIVE: To analyze the effects of oncostatin M (OSM), a gp130-type cytokine,
      on CCL2 expression in MG-63 cells, a human osteosarcoma cell line with a
      characteristic osteoblastic phenotype, and to investigate the signaling pathway
      involved. METHODS: The expression of messenger RNA (mRNA) for CCL2 and c-Fos was
      analyzed by Northern blotting. Amounts of CCL2 released into the supernatant were
      measured by enzyme-linked immunosorbent assay. Western blotting was used to
      examine the activation of MAPK signaling pathways. Interactions between activator
      protein 1 (AP-1) and DNA were evaluated by electrophoretic mobility shift assay.
      RESULTS: OSM stimulated CCL2 expression at both the mRNA and the protein levels.
      Cyclooxygenase 2 (COX-2) was also induced by OSM. However, the up-regulation of
      CCL2 mRNA was COX-2-independent but required tyrosine kinase and protein kinase C
      (PKC). OSM stimulated the phosphorylation of MEK-1/2 and ERK-1/2 but not p38 and
      JNK. A transient elevation of c-Fos mRNA was induced by OSM, but PD 98059 (MEK
      inhibitor), fludarabine (signal transducer and activator of transcription 1 [STAT
      1] inhibitor), and piceatannol (STAT-3 and STAT-5 inhibitor) abolished this
      effect. Electrophoretic mobility shift assay revealed that OSM stimulated AP-1
      DNA binding, which was also abolished by PD 98059, fludarabine, and piceatannol.
      Supershift study further confirmed the role of c-Fos in the above interaction. PD
      98059, fludarabine, piceatannol, and curcumin (AP-1 inhibitor) inhibited the OSM
      induced expression of CCL2. CONCLUSION: OSM induces CCL-2 expression in
      osteoblasts. Activation of the MEK/ERK and STAT pathways, which leads to c-Fos
      expression and AP-1-DNA binding, is involved in the process. The signaling
      requires tyrosine kinase and PKC but not COX-2.

PMID- 15022321
TI  - The antirheumatic drug leflunomide inhibits osteoclastogenesis by interfering
      with receptor activator of NF-kappa B ligand-stimulated induction of nuclear
      factor of activated T cells c1.
AB  - OBJECTIVE: Suppression of bone destruction is required as part of an effective
      therapeutic strategy for autoimmune arthritis. Although numerous antirheumatic
      drugs are in clinical use, little is known about whether they inhibit bone
      destruction by acting on activated T cells or other cell types, such as bone
      resorbing osteoclasts. This study was undertaken to determine whether leflunomide
      has a direct action on the osteoclast lineage and to gain insights into the
      molecular basis for the bone-protective effect of leflunomide. METHODS: The
      direct effect of leflunomide on osteoclast differentiation was investigated using
      an in vitro culture system of bone marrow monocyte/macrophages stimulated with
      receptor activator of NF-kappa B ligand (RANKL) and macrophage colony-stimulating
      factor. The molecular mechanism of the inhibition was analyzed by genome-wide
      screening. The T cell-independent effect of leflunomide was examined in rag-2(-/
      ) mice. RESULTS: Leflunomide blocked de novo pyrimidine synthesis and RANKL
      induced calcium signaling in osteoclast precursor cells in vitro; hence, the
      induction of nuclear factor of activated T cells c1 (NF-ATc1) was strongly
      inhibited. The inhibition of this pathway is central to the action of
      leflunomide, since the inhibition was overcome by ectopic expression of NF-ATc1
      in the precursor cells. Leflunomide suppressed endotoxin-induced inflammatory
      bone destruction even in rag-2(-/-) mice. CONCLUSION: Leflunomide has a direct
      inhibitory effect on RANKL-mediated osteoclast differentiation by inhibiting the
      induction of NF-ATc1, the master switch regulator for osteoclast differentiation.
      Our study suggests that the direct inhibitory action of leflunomide on osteoclast
      differentiation constitutes an important aspect in the amelioration of bone
      destruction, and that the RANKL-dependent NF-ATc1 induction pathway is a
      promising target for pharmacologic intervention in arthritic bone destruction.

PMID- 15022322
TI  - The genetic contribution to muscle strength, knee pain, cartilage volume, bone
      size, and radiographic osteoarthritis: a sibpair study.
AB  - OBJECTIVE: To estimate the heritability of muscle strength, knee pain, cartilage
      volume, bone size, and radiographic osteoarthritis (ROA), and to assess whether
      heritability of the knee structural components is independent of ROA. METHODS: A
      sibpair design was utilized. Sagittal T1-weighted fat-suppressed magnetic
      resonance imaging (MRI) of the right knee was performed to determine cartilage
      volume and bone size. Standing semiflexed radiographs of the same knee were
      obtained to assess the presence of ROA. Knee pain was assessed by questionnaire
      and muscle strength by dynamometry. Heritability was estimated using the genetic
      analysis program SOLAR. RESULTS: A total of 128 subjects (61 men, 67 women; mean
      age 45 years) from 51 families representing 115 sibpairs were studied. Lower limb
      muscle strength had high heritability (42%; P = 0.02), as did knee pain (44%; P =
      0.07). Heritability estimates for cartilage volume were 65% for medial tibial
      cartilage, 77% for lateral tibial cartilage, and 84% for patellar cartilage, and
      heritability estimates for bone size were 85% for medial tibial bone area, 57%
      for lateral tibial bone area, and 70% for patella bone volume (all P < or =
      0.004). For ROA, heritability was 61% for presence (with a large standard error)
      (P = 0.16) and 61% for severity (P = 0.02). The estimates for tibial bone areas
      were the only ones markedly reduced after adjustment for body size, while all
      estimates with the exception of knee pain were independent of ROA. Cartilage and,
      to a lesser extent, bone sites investigated by MRI were largely under independent
      genetic control, with a lesser shared genetic component. CONCLUSION: With the
      exception of prevalent ROA, all knee modalities assessed had high heritability,
      most likely reflecting a strong genetic component. Cartilage volume, bone size,
      and muscle strength all have the potential to be studied in quantitative trait
      linkage analyses, but their exact relevance with regard to OA remains uncertain
      at this time.

PMID- 15022323
TI  - Quantitative assessment of cartilage status in osteoarthritis by quantitative
      magnetic resonance imaging: technical validation for use in analysis of cartilage
      volume and further morphologic parameters.
AB  - OBJECTIVE: Quantitative diagnostic tools for osteoarthritis (OA) are important
      for evaluating the treatment response to structure-modifying drugs. This study
      was undertaken to test the technical validity (accuracy) of quantitative magnetic
      resonance imaging (qMRI) for reliable determination of the total bone interface
      area, percentage of cartilaginous (denuded) joint surface area, and cartilage
      thickness in OA. METHODS: High-resolution MRIs of femorotibial and patellar
      cartilage were acquired in 21 patients prior to total knee arthroplasty, using a
      T1-weighted gradient-echo sequence with water excitation. After segmentation of
      original bone interface areas (before disease onset) and the actual cartilage
      layer, the percentages of cartilaginous joint surface area, cartilage thickness,
      and cartilage volume were determined using proprietary software. During surgery,
      the patella and the medial and lateral tibia were resected. Results obtained with
      qMRI were compared with those obtained by direct image analysis of surface area,
      cartilage thickness, and cartilage volume of the surgically removed tissue.
      RESULTS: Pairwise differences between results obtained with qMRI and morphologic
      analysis were +/-4.6% for percentage of cartilaginous surface area, +/-8.9% for
      cartilage thickness, and +/-9.1% for cartilage volume. Correlation coefficients
      ranged from 0.92 (thickness) to 0.98 (volume). CONCLUSION: Quantitative MRI
      permits technically accurate and differential assessment of increases in eroded
      joint surface area and reductions in cartilage thickness in OA. The surrogate
      validity of these parameters requires testing in longitudinal studies. These
      parameters may be advantageous over determination of cartilage volume alone when
      diagnosing OA, exploring its progression, or testing responsiveness to new
      therapies.

PMID- 15022324
TI  - Enumeration and phenotypic characterization of synovial fluid multipotential
      mesenchymal progenitor cells in inflammatory and degenerative arthritis.
AB  - OBJECTIVE: To evaluate synovial fluid (SF) for the presence of mesenchymal
      progenitor cells (MPCs), to compare SF MPCs with bone marrow (BM) MPCs, and to
      enumerate these cells in both inflammatory arthritis and osteoarthritis (OA).
      METHODS: SF from 100 patients with arthritis (53 rheumatoid arthritis [RA], 20
      OA, and 27 other arthropathies) was evaluated. To establish multipotentiality,
      polyclonal and single cell-derived cultures of SF fibroblasts were examined by
      standard and quantitative differentiation assays. Their phenotype before and
      after expansion was determined by multiparameter flow cytometry. A colony-forming
      unit-fibroblast assay was used for SF MPC enumeration. RESULTS: Regardless of the
      nature of the arthritis, both polyclonal and single cell-derived cultures of SF
      fibroblasts possessed trilineage mesenchymal differentiation potentials. The
      number of MPCs in a milliliter of SF was higher in OA (median 37) than in RA
      (median 2) (P < 0.00001). No significant differences in MPC numbers were found
      between early and established RA (median 3 and 2 cells/ml, respectively). Culture
      expanded SF and BM MPCs had the same phenotype (negative for CD45 and positive
      for D7-FIB, CD13, CD105, CD55, and CD10). Rare, uncultured SF fibroblasts were
      CD45(low) and expressed low-affinity nerve growth factor receptor, similar to in
      vivo BM MPCs. CONCLUSION: Our findings prove the presence of rare tripotential
      MPCs, at the single-cell level, in the SF of patients with arthritis. SF MPCs are
      clonogenic and multipotential fibroblasts that, despite the pathologic
      environment within a diseased joint, have a phenotype similar to that of
      uncultured BM MPCs. The higher prevalence of MPCs in OA SF suggests their likely
      origin from disrupted joint structures. These findings could determine the role
      of MPCs in the pathogenesis of inflammatory arthritis, together with their role
      in attempted joint regeneration in degenerative arthritis, which has yet to be
      established.

PMID- 15022325
TI  - Suppression of T cell responses by chondromodulin I, a cartilage-derived
      angiogenesis inhibitory factor: therapeutic potential in rheumatoid arthritis.
AB  - OBJECTIVE: Chondromodulin I (ChM-I), a cartilage matrix protein, promotes the
      growth and proteoglycan synthesis of chondrocytes. However, it also inhibits
      angiogenesis. Since ChM-I is expressed not only in cartilage, but also in the
      thymus, we investigated the modulation of T cell function by ChM-I to assess its
      therapeutic potential in rheumatoid arthritis (RA). METHODS: The localization of
      ChM-I expression in mouse thymus tissue was examined by in situ hybridization.
      The proliferative response of peripheral blood T cells and synovial cells
      obtained from patients with RA was evaluated by (3)H-thymidine incorporation
      assay. The effects of ChM-I were examined using recombinant human ChM-I (rHuChM
      I). Modulation of the antigen-specific immune response was evaluated by the
      recall response of splenic T cells and the delayed-type hypersensitivity response
      induced in the ear of mice primed with ovalbumin (OVA). Antigen-induced arthritis
      (AIA) was induced in mice by injecting methylated bovine serum albumin into the
      ankle joints 2 weeks after the priming. RESULTS: ChM-I was expressed in the
      cortex of the thymus. Recombinant human ChM-I suppressed the proliferative
      response of mouse splenic T cells and human peripheral blood T cells stimulated
      with anti-CD3/CD28 antibodies, in a dose-dependent manner. Production of
      interleukin-2 was decreased in rHuChM-I-treated mouse CD4 T cells. Ten micrograms
      of rHuChM-I injected intraperitoneally into OVA-primed mice suppressed the
      induction of the antigen-specific immune response. Finally, rHuChM-I suppressed
      the development of AIA, and also suppressed the proliferation of synovial cells
      prepared from the joints of patients with RA. CONCLUSION: These results suggest
      that ChM-I suppresses T cell responses and synovial cell proliferation, implying
      that this cartilage matrix protein has a therapeutic potential in RA.

PMID- 15022326
TI  - Mechanisms and kinetics of glycosaminoglycan release following in vitro cartilage
      injury.
AB  - OBJECTIVE: Acute joint injury leads to increased risk for osteoarthritis (OA).
      Although the mechanisms underlying this progression are unclear, early
      structural, metabolic, and compositional indicators of OA have been reproduced
      using in vitro models of cartilage injury. This study was undertaken to determine
      whether glycosaminoglycan (GAG) loss following in vitro cartilage injury is
      mediated by cellular biosynthesis, activation of enzymatic activity, or
      mechanical disruption of the cartilage extracellular matrix. METHODS: Immature
      bovine cartilage was cultured for up to 10 days. After 3 days, groups of samples
      were subjected to injurious mechanical compression (single uniaxial unconfined
      compression to 50% thickness, strain rate 100% per second). GAG release to the
      medium was measured, and levels were compared with those in location-matched,
      uninjured controls. The effects of medium supplementation with inhibitors of
      biosynthesis (cycloheximide), of matrix metalloproteinase (MMP) activity (CGS
      27023A or GM 6001), and of aggrecanase activity (SB 703704) on GAG release after
      injury were assessed. RESULTS: GAG release from injured cartilage was highest
      during the first 4 hours after injury, but remained higher than that in controls
      during the first 24 hours postinjury, and was not affected by inhibitors of
      biosynthesis or degradative enzymes. GAG release during the period 24-72 hours
      postinjury was similar to that in uninjured controls, but the MMP inhibitor CGS
      27023A reduced cumulative GAG loss from injured samples between 1 day and 7 days
      postinjury. Other inhibitors of enzymatic degradation or biosynthesis had no
      significant effect on GAG release. CONCLUSION: Injurious compression of articular
      cartilage induces an initially high rate of GAG release from the tissue, which
      could not be inhibited, consistent with mechanical damage. However, the finding
      that MMP inhibition reduced GAG loss in the days following injury suggests a
      potential therapeutic intervention.

PMID- 15022327
TI  - Cigarette smoking and the risk of systemic lupus erythematosus: a meta-analysis.
AB  - OBJECTIVE: Existing studies present conflicting evidence for the role of
      cigarette smoking as a risk factor in the development of systemic lupus
      erythematosus (SLE). We performed an extensive search of the medical literature
      for all studies examining this relationship, and performed a meta-analysis to
      arrive at a more precise estimate of effect. METHODS: We performed a computerized
      literature search for all studies (in all languages), using Medline and EMBASE
      (1966 to present) and the Cochrane Collaboration database, and completed hand
      searches of relevant bibliographies and abstracts of conference proceedings.
      Several investigators systematically extracted data from the relevant studies.
      Unpublished data were obtained from the author of one abstract. Studies were
      examined in aggregate for heterogeneity and publication bias. The relationships
      of current smoking and past smoking (prior to the onset of SLE) to development of
      SLE were analyzed separately. RESULTS: Fifty-two studies were identified and
      chosen for detailed review. Of these, 9 (7 case-control and 2 cohort studies)
      were appropriate for inclusion in our meta-analyses. For current smokers compared
      with nonsmokers, the odds ratio (OR) for development of SLE was significantly
      elevated (OR 1.50, 95% confidence interval [95% CI] 1.09-2.08). Former smokers,
      compared with nonsmokers, did not demonstrate an increased risk of SLE (OR 0.98,
      95% CI 0.75-1.27). Several subgroups were also analyzed. CONCLUSION: Our meta
      analysis of the 7 existing case-control and 2 cohort studies revealed a small but
      statistically significant association between current smoking and development of
      SLE. However, no association between past smoking and development of SLE was
      observed.

PMID- 15022328
TI  - Increased serum matrix metalloproteinase 9 levels in systemic lupus erythematosus
      patients with neuropsychiatric manifestations and brain magnetic resonance
      imaging abnormalities.
AB  - OBJECTIVE: To evaluate whether serum matrix metalloproteinase 9 (MMP-9) levels
      are associated with neuropsychiatric manifestations, particularly cognitive
      dysfunction, as evaluated by neuropsychological testing and brain magnetic
      resonance imaging (MRI) abnormalities in patients with systemic lupus
      erythematosus (SLE). METHODS: MMP-9 determinations were made in 44 patients with
      SLE and 43 healthy controls who underwent a clinical neurologic and
      neuropsychological investigation in order to identify neuropsychiatric
      manifestations. Cerebral MRI scans with volumetric estimation of intracranial
      cerebrospinal fluid spaces, T1-weighted lesions, and T2-weighted lesions were
      performed for all subjects. SLE activity was assessed by the European Consensus
      Lupus Activity Measure (ECLAM) index, and accumulated neuropsychiatric
      abnormality was assessed by the Systemic Lupus International Collaborating
      Clinics (SLICC)/American College of Rheumatology damage index. RESULTS: No
      significant difference was found in serum MMP-9 levels between the overall group
      of SLE patients and controls. However, SLE patients who had at least 1
      neuropsychiatric manifestation (NPSLE patients) had significantly higher serum
      MMP-9 concentrations than did SLE patients without neuropsychiatric syndromes (P
      = 0.009). Among patients with NPSLE, those with cognitive deficits had
      significantly higher concentrations of serum MMP-9 than did those with normal
      cognitive function (P = 0.027). Furthermore, serum MMP-9 levels had a significant
      positive correlation with the volumes of T1-weighted and T2-weighted lesions in
      the brain MRI (P = 0.031 and P = 0.015, respectively). The concentration of serum
      MMP-9 correlated significantly with the SLICC index but not with the ECLAM index.
      CONCLUSION: Elevated levels of serum MMP-9 in patients with SLE may reflect
      neuropsychiatric involvement, particularly cognitive dysfunction. The serum MMP-9
      concentration may be associated with small- vessel cerebral vasculopathy and
      increased risk of cerebral ischemic events in patients with SLE.

PMID- 15022329
TI  - Is alpha-actinin a target for pathogenic anti-DNA antibodies in lupus nephritis?
AB  - OBJECTIVE: Following recent reports that pathogenic murine anti-DNA antibodies
      bind to alpha-actinin, it was obviously of interest to assess the ability of
      human pathogenic anti-double-stranded DNA (anti-dsDNA) antibodies to bind this
      antigen. Both human monoclonal anti-DNA antibodies and antibodies affinity
      purified from the sera of patients with systemic lupus erythematosus (SLE) were
      investigated. METHODS: An enzyme-linked immunosorbent assay was established to
      measure immunoglobulin binding to alpha-actinin. Antibodies binding dsDNA were
      purified from the sera of SLE patients who either had active renal disease or had
      never had renal disease. Serum samples were selected at times when the patients'
      sera exhibited high IgG binding to dsDNA. The binding of supernatants from 3 high
      affinity human anti-dsDNA IgG hybridomas (RH14, B3, and DIL-6) and 7 human IgM
      anti-DNA hybridomas was also investigated. RESULTS: A greater proportion of anti
      dsDNA IgG-binding antibodies purified from patients with renal disease bound to
      alpha-actinin than did those purified from the sera of patients without renal
      disease. The specificity of binding to the 100-kd alpha-actinin molecule was
      confirmed by Western blotting. The pathogenic human antibodies RH14 and B3 bound
      strongly to alpha-actinin, while nonpathogenic DIL-6 bound very weakly. RT84, the
      IgM antibody that binds dsDNA with the highest affinity, exhibited the greatest
      binding to alpha-actinin. CONCLUSION: The results of our study support the
      findings of previous studies using murine anti-DNA monoclonal antibodies, which
      suggest that pathogenic anti-dsDNA antibodies cross-react with alpha-actinin.

PMID- 15022330
TI  - Association of a four-amino acid residue insertion polymorphism of the HS1 gene
      with systemic lupus erythematosus: molecular and functional analysis.
AB  - OBJECTIVE: To investigate whether polymorphism(s) or mutation(s) in the
      hematopoietic cell-specific Lyn substrate 1 (HS1) gene are involved in the
      pathogenesis of systemic lupus erythematosus (SLE). METHODS: The entire coding
      region of the HS1 gene was analyzed by reverse transcriptase-polymerase chain
      reaction/single-strand conformational polymorphism analysis. HS1-transfected WEHI
      231 cells or B lymphocytes from patients with SLE were studied for apoptosis,
      activation, and proliferation by flow cytometric analysis and MTT assay. RESULTS:
      We identified a glutamic acid-proline-glutamic acid-proline insertion between
      codons 366 and 367 (EPEP366-367ins) and 2 amino acid substitutions (A235T and
      E361K). The genotype frequency among individuals homozygous for the EPEP+ allele
      was 0.184 in 201 patients with SLE but only 0.098 in 184 healthy individuals (P =
      0.016). The allele frequency of EPEP366-367ins was 0.408 in patients with SLE;
      this frequency was significantly higher than that in healthy controls (0.312) (P
      = 0.006). WEHI-231 cells transfected with EPEP+ HS1 were 100-fold more sensitive
      to B cell receptor (BCR)-mediated apoptosis than were those transfected with HS1
      without EPEP. B lymphocytes from SLE patients with the EPEP+ allele were
      significantly more apoptotic without BCR stimulation and less activated after BCR
      stimulation than were those from SLE patients without the EPEP allele.
      CONCLUSION: These results suggest that HS1 with the EPEP insertion polymorphism
      transmits accelerated signals from BCR and is involved in the pathogenesis of
      SLE.

PMID- 15022331
TI  - Sjogren's syndrome associated with systemic lupus erythematosus: clinical and
      laboratory profiles and comparison with primary Sjogren's syndrome.
AB  - OBJECTIVE: To address the clinical, serologic, pathologic, and immunogenetic
      features of sicca syndrome that occurs in systemic lupus erythematosus (SLE), as
      well as its similarities to, and differences from, sicca syndrome that occurs in
      primary Sjogren's syndrome (SS). METHODS: A cohort of 283 consecutive unselected
      SLE patients was evaluated for the presence of associated SS using the American
      European classification criteria. Clinical and laboratory parameters in SLE
      patients with SS (SLE-SS) were compared with those in SLE patients without SS
      (SLE-no SS) and with a group of 86 unselected patients with primary SS. RESULTS:
      SS was identified in 26 SLE patients (9.2%); the SS preceded the development of
      lupus in 18 of them (69.2%). Compared with the SLE-no SS group, patients with SLE
      SS were significantly older, had a higher frequency of Raynaud's phenomenon, anti
      Ro/SSA, anti-La/SSB, and rheumatoid factor, but had a significantly lower
      frequency of renal involvement, lymphadenopathy, and thrombocytopenia. Compared
      with the primary SS group, SLE-SS patients displayed a clinically similar sicca
      syndrome, but were significantly younger and had an increased frequency of
      perivascular infiltrates in the salivary glands associated with anticardiolipin
      antibodies in the serum. SLE-SS patients had a high frequency of the DRB1*0301
      allele. This HLA profile distinguished the SLE-SS group from the SLE-no SS group,
      who had an increased frequency of DRB1*1501 and DQB1*0602 alleles, but was
      similar to the HLA profile of the primary SS group, who had an increased
      frequency of DRB1*0301. CONCLUSION: SLE-SS appears to constitute a subgroup of
      patients with distinct clinical, serologic, pathologic, and immunogenetic
      features, in whom SS is expressed as an overlapping entity and is largely similar
      to primary SS.

PMID- 15022332
TI  - Anti-DFS70 antibodies in 597 healthy hospital workers.
AB  - OBJECTIVE: Autoantibodies against DFS70 (dense fine speckles 70) antigen (also
      known as lens epithelium-derived growth factor) have been recently identified
      among the antinuclear antibodies (ANAs) in patients with atopic disorders. We
      undertook this study to examine the frequency of anti-DFS70 antibodies in a large
      number of healthy people. METHODS: Sera of 597 healthy individuals working in a
      hospital (142 men, 455 women) were analyzed for ANAs and for anti-DFS70
      antibodies by indirect immunofluorescence (IIF) with HEp-2 cells as a substrate
      and by immunoblotting using DFS70 recombinant protein and whole HeLa cell
      extract. RESULTS: ANAs were present in 20% of all individuals by IIF. Nine
      percent of subjects were ANA positive at a serum dilution of 1:40, 4.0% at 1:80,
      5.5% at 1:160, 1.0% at 1:320, and 0.3% at 1:640. There were 64 anti-DFS70
      antibody-positive individuals. Surprisingly, this was 11% of the whole population
      and 54% of the ANA-positive population. The percentage of female anti-DFS70
      antibody-positive subjects (86%; 55 of 64 subjects) was higher than the
      percentage of female anti-DFS70 antibody-negative subjects (75%; 398 of 533
      subjects) (P < 0.05). The prevalence of anti-DFS70 antibody-positive sera
      decreased with increasing age (P = 0.0017). CONCLUSION: Considering that anti
      DFS70 antibody positivity is rare in patients with systemic autoimmune diseases,
      introducing the anti-DFS70 antibody examination as a screening test for ANA
      positive persons could be used to rule out systemic autoimmune diseases,
      resulting in considerable cost-saving potential. In addition, this test defines a
      subpopulation of healthy people in whom long-term followup might reveal health
      related implications of this finding, since anti-DFS70 antibodies have been shown
      to be associated with some illnesses.

PMID- 15022333
TI  - Magnetic resonance imaging evaluation of the effects of juvenile rheumatoid
      arthritis on distal femoral weight-bearing cartilage.
AB  - OBJECTIVE: To examine magnetic resonance imaging-derived T2 relaxation times in
      the weight-bearing cartilage of the distal femur in healthy children and in
      children with juvenile rheumatoid arthritis (JRA). METHODS: T2 relaxation time
      maps were created for 39 girls (ages 4.9-10.9 years), 21 of whom were considered
      healthy and 18 of whom had JRA. The spatial distribution of T2 relaxation times
      for the distal femoral weight-bearing cartilage (including epiphyseal and
      articular cartilage) was mapped for each group as a whole. Average data sets for
      each group were then compared using paired t-tests to detect differences between
      the 2 populations. RESULTS: The spatial distribution of T2 relaxation time values
      was nearly identical in the 2 groups, with a concave curve that was highest near
      the subchondral bone and articular surfaces. The average T2 relaxation times were
      significantly higher in the girls with JRA than in the group of healthy girls (P
      < 0.05). CONCLUSION: The finding of an increased average T2 relaxation time in
      the children with JRA suggests that T2 relaxation time maps may reflect cartilage
      microstructure differences that occur in JRA. T2 relaxation time mapping may
      allow for early detection of cartilage changes and provide an objective,
      quantitative method of monitoring disease progression, with the long-term
      potential to guide therapy.

PMID- 15022334
TI  - Quantification of maternal microchimerism by HLA-specific real-time polymerase
      chain reaction: studies of healthy women and women with scleroderma.
AB  - OBJECTIVE: Microchimerism (Mc), originating from bidirectional fetal-maternal
      cell traffic during pregnancy, has recently been identified in healthy adults and
      in patients with scleroderma (systemic sclerosis [SSc]). This study was
      undertaken to investigate the frequency and quantitative levels of maternal Mc
      (MMc) in healthy women and women with SSc. METHODS: HLA-specific primers and
      fluorogenic probes were used in real-time quantitative polymerase chain reaction
      assays to detect and quantify MMc by targeting noninherited, nonshared HLA
      sequences. DNA-based HLA typing was conducted in 67 proband-mother pairs and in
      all children if the proband was parous. Statistical analysis was limited to 50
      proband-mother pairs (including 32 healthy women and 18 women with SSc) in whom
      MMc could be distinguished from potential fetal Mc. RESULTS: MMc in peripheral
      blood mononuclear cells was more frequent among women with SSc (72%) than healthy
      women (22%) (odds ratio 9.3, P = 0.001). However, levels of MMc, expressed as the
      genome equivalent of maternal cells per million (gEq/mil), were not significantly
      different (0-68.6 gEq/mil in SSc patients, 0-54.5 in healthy women). In
      additional studies, positivity for MMc was demonstrated in a bone marrow aspirate
      from an SSc patient in whom peripheral blood had been found to be negative for
      MMc on 4 occasions, and tissue from a subsequent autopsy of this patient had MMc
      levels of 757 and 1,489 gEq/mil in the lung and heart, respectively. CONCLUSION:
      MMc is not uncommon in the peripheral blood of healthy adults, is increased in
      frequency in patients with SSc, and may be present in bone marrow and disease
      affected tissues although absent in the peripheral blood.

PMID- 15022335
TI  - Mutant fibrillin 1 from tight skin mice increases extracellular matrix
      incorporation of microfibril-associated glycoprotein 2 and type I collagen.
AB  - OBJECTIVE: Skin fibrosis in the TSK mouse, a model of skin fibrosis seen in
      systemic sclerosis (SSc), is caused by a large in-frame duplication in the Fbn1
      gene, tsk-Fbn1. We investigated whether tsk-Fbn1 might cause dermal fibrosis by
      affecting Fbn1 and associated extracellular matrices. We also studied whether
      deposition of microfibril-associated glycoprotein 2 (MAGP-2), a protein that is
      associated with fibrillin 1, was altered in the skin of patients with SSc.
      METHODS: An in vitro model of the TSK mouse was created by conditionally
      expressing tsk-Fbn1 in mouse embryonic fibroblasts (MEFs). Cell cultures were
      examined by immunofluorescence and Western and Northern blotting to determine the
      effect of tsk-Fbn1 on the structure, expression, and deposition of fibrillin 1
      (Fbn-1), type I collagen, and MAGP-2. The skin of TSK mice and SSc patients was
      analyzed by immunohistochemistry for MAGP-2 expression. RESULTS: Expression of
      tsk-Fbn1 in cultured MEF cells altered the morphology of Fbn-1 fibers and
      increased the deposition of type I collagen into the extracellular matrix (ECM)
      without concomitantly changing messenger RNA expression, secretion, or processing
      of type I procollagen. Moreover, MEF cells expressing tsk-Fbn1 showed increased
      MAGP-2 matrix. MAGP-2 was increased in the dermis of TSK mice. Fibrotic SSc skin
      also showed higher levels of MAGP-2 in the dermis than nonfibrotic SSc skin and
      normal skin. CONCLUSION: Tsk-Fbn1 altered ECM organization and caused fibrosis by
      affecting the deposition of MAGP-2 or other Fbn-1-associated proteins.
      Alterations in microfibril structure or deposition might contribute to fibrosis
      in SSc.

PMID- 15022336
TI  - Endothelial and platelet microparticles in vasculitis of the young.
AB  - OBJECTIVE: Microparticles are released from endothelial cells in response to a
      variety of injurious stimuli and recently have been shown to be increased in a
      number of diseases associated with endothelial dysfunction. This study examined
      endothelial microparticle (EMP) and platelet microparticle (PMP) profiles in
      children with systemic vasculitis to test the hypothesis that EMPs may provide a
      noninvasive means of examining endothelial activation or injury. METHODS: The
      study cohort comprised 39 children with systemic vasculitis at various stages of
      disease activity, 24 control children with febrile disease, and a control group
      of 43 healthy subjects. Plasma was ultracentrifuged at 17,000g for 60 minutes,
      and the microparticle pellets were examined using flow cytometry. RESULTS: Plasma
      from patients with active systemic vasculitis contained significantly higher
      numbers of E-selectin-positive EMPs compared with that from patients in
      remission, healthy controls, or febrile disease controls (P = 0.000 for each). A
      similar result was obtained for the numbers of EMPs expressing the marker CD105.
      There was also a significant increase in PMPs expressing CD42a in the active
      vasculitis group as compared with the other groups, but this difference was not
      significant for PMPs expressing P-selectin. The EMP counts correlated with the
      Birmingham Vasculitis Activity Score and the acute-phase reactant levels in the
      patients with systemic vasculitis, but there was a poor correlation overall
      between EMP counts and the acute-phase reactant levels in the febrile disease
      controls. CONCLUSION: EMPs may provide a window to the activated endothelium and
      could provide important pathophysiologic insights into the vascular injury
      associated with vasculitis of the young.

PMID- 15022337
TI  - Quality of care indicators for gout management.
AB  - OBJECTIVE: Despite the significant health impact of gout, there is no consensus
      on management standards. To guide physician practice, we sought to develop
      quality of care indicators for gout management. METHODS: A systematic literature
      review of gout therapy was performed using the Medline database. Two abstractors
      independently reviewed each of the articles for relevance and satisfaction of
      minimal inclusion criteria. Based on the review of the literature, 11 preliminary
      quality indicators were developed and then reviewed and refined by an initial
      feasibility panel of community and academic rheumatologists. A twelfth indicator
      was added at the request of the first panel. Using a modification of the
      RAND/University of California at Los Angeles appropriateness method (bridging
      teleconference and white-board Internet technology were added), a second expert
      panel rated each of the proposed indicators for validity using a 9-point scale,
      in which ratings of 1-3, 4-6, and 7-9 were considered "invalid," "indeterminate,"
      and "highly valid," respectively. Indicators were considered valid if the median
      panel rating was > or =7 and there was no evidence of panel disagreement (defined
      to occur when 2 of 6 panelists provided a validity rating of 1-3 and 2 panelists
      provided a validity rating of 7-9). RESULTS: Ten of the 12 draft indicators were
      rated to be valid by our second expert panel. Validated indicators pertained to
      1) the use of urate-lowering medications in chronic gout, 2) the use of
      antiinflammatory drugs, and 3) counseling on lifestyle modifications. CONCLUSION:
      Using a combination of evidence and expert opinion, 10 indicators for quality of
      gout care were developed. These indicators represent an important initial step in
      quality improvement initiatives for gout care.

PMID- 15022338
TI  - Family study of fibromyalgia.
AB  - OBJECTIVE: To assess for familial aggregation of fibromyalgia (FM) and measures
      of tenderness and pain, and for familial coaggregation of FM and major mood
      disorder (major depressive disorder or bipolar disorder). METHODS: Probands
      meeting the American College of Rheumatology criteria for FM and control probands
      with rheumatoid arthritis (RA) and no lifetime diagnosis of FM were recruited
      from consecutive referrals to 2 community-based rheumatology practices. Probands
      were ages 40-55 years and had at least 1 first-degree relative age 18 years or
      older who was available for interview and examination. All probands and
      interviewed relatives underwent a dolorimeter tender point examination and a
      structured clinical interview. Interviewed relatives were asked about first
      degree relatives who were not available for interview, using a structured family
      interview. Logistic and linear regression models, adjusting for the correlation
      of observation within families, were applied to study the aggregation and
      coaggregation effects. RESULTS: Information was collected for 533 relatives of 78
      probands with FM and 272 relatives of 40 probands with RA. FM aggregated strongly
      in families: the odds ratio (OR) measuring the odds of FM in a relative of a
      proband with FM versus the odds of FM in a relative of a proband with RA was 8.5
      (95% confidence interval [95% CI] 2.8-26, P = 0.0002). The number of tender
      points was significantly higher, and the total myalgic score was significantly
      lower in the relatives of probands with FM compared with the relatives of
      probands with RA. FM coaggregated significantly with major mood disorder: the OR
      measuring the odds of major mood disorder in a relative of a proband with FM
      versus the odds of major mood disorder in a relative of a proband with RA was 1.8
      (95% CI 1.1-2.9, P = 0.013). CONCLUSION: FM and reduced pressure pain thresholds
      aggregate in families, and FM coaggregates with major mood disorder in families.
      These findings have important clinical and theoretical implications, including
      the possibility that genetic factors are involved in the etiology of FM and in
      pain sensitivity. In addition, mood disorders and FM may share some of these
      inherited factors.

PMID- 15022340
TI  - In vivo imaging of experimental arthritis with near-infrared fluorescence.
AB  - OBJECTIVE: To visualize early experimental arthritis with near-infrared
      fluorescence (NIRF) imaging in a murine model of antigen-induced arthritis (AIA).
      METHODS: The target of NIRF was the F4/80 antigen present on the surface of
      macrophages infiltrating the inflamed synovial membrane. Imaging was performed
      using anti-F4/80 monoclonal antibodies (mAb) labeled with Cy5.5 fluorochrome. On
      day 7 of AIA, 6 mice received an intravenous (IV) injection of labeled mAb;
      control AIA mice (n = 6) received an IV injection of Cy5.5-labeled isotype
      control antibody. NIRF imaging was performed before injection (baseline) and
      until 72 hours thereafter. Histologic evaluation of arthritis severity and
      immunohistochemical assessment of F4/80 antigen density were also performed on
      day 7. RESULTS: NIRF imaging showed an accumulation of fluorochrome probes in the
      inflamed knee joints and, to a lesser extent, in the contralateral (nonarthritic)
      knee joints. The signal induced by mAb F4/80 was clearly higher than that
      generated by the isotype control. Accumulation of fluorochrome probes in the
      joints was confirmed histologically by confocal laser scanning microscopy.
      CONCLUSION: The use of fluorochromes allows imaging of arthritis in the near
      infrared range. Accumulation in the contralateral, nonarthritic knee joints can
      be explained by the presence of sentinel macrophages in normal synovium or by a
      mild contralateral response due to systemic activation or neurogenic mechanisms.

PMID- 15022339
TI  - Normative values for the Health Assessment Questionnaire disability index:
      benchmarking disability in the general population.
AB  - OBJECTIVE: The Health Assessment Questionnaire (HAQ) disability index (DI) has
      been commonly used in rheumatology to quantify functional disability in patient
      groups, but current general population values of this index are not available.
      This study was undertaken to establish normative values for the HAQ DI in a
      general population and to analyze its correlates. METHODS: The HAQ DI (range of
      scores 0-3) was measured in a random sample of 1,530 adults in the Central
      Finland District. Prevalence rates of disability by strata of age, sex, education
      level, body mass index (BMI), and health behaviors (including smoking and
      exercise habits) were calculated. Pearson's product-moment correlation
      coefficient and ordinary least squares regression were used to analyze the data.
      RESULTS: The estimated population mean HAQ DI was 0.25 (95% confidence interval
      0.22-0.28), and 32% of respondents had at least some disability. Both for men and
      for women, functional disability increased exponentially with age. The HAQ DI was
      correlated with pain (r = 0.58) and global self assessment (r = 0.61). The
      prevalence of disability decreased with increasing number of years of education,
      lower BMI, and increasing frequency of physical exercise. CONCLUSION: Almost one
      third of the general population has some functional disability. Functional
      disability is associated in part with lifestyle choices and increases with age in
      a nonlinear manner. The normative values of the HAQ DI that we have presented
      could be used as a reference benchmark for clinical and epidemiologic studies
      using this measure of disability.

PMID- 15022341
TI  - Plasmid encoding interleukin-4 in the amelioration of murine collagen-induced
      arthritis.
AB  - OBJECTIVE: To evaluate the therapeutic effect of the administration of plasmid
      encoding interleukin-4 (IL-4) via gene-gun delivery and via intradermal injection
      on collagen-induced arthritis (CIA). METHODS: IL-4 plasmid was administered by
      gene-gun delivery and intradermal injection to DBA/1 mice immunized with type II
      collagen (CII). The therapeutic effect on the development of CIA was evaluated
      clinically with a visual scoring method for arthritis and serologically by enzyme
      linked immunosorbent assays and polymerase chain reaction. RESULTS: Treatment
      with IL-4-expressing plasmid significantly reduced the incidence and severity of
      CIA, including a reduction in the anti-CII antibody level. In particular, gene
      gun delivery had a higher immunosuppressive effect on CIA compared with
      intradermal injection. As shown by in vitro stimulation assay, the spleen cells
      from mice immunized with CII and treated with IL-4 plasmid via gene gun exhibited
      higher Th2 cytokine responses compared with cells treated with control plasmid
      after in vitro stimulation with CII. CONCLUSION: The results of this study
      suggest that treatment with IL-4 plasmid may constitute a new clinical use of
      cytokine gene therapy for rheumatoid arthritis.

PMID- 15022342
TI  - Modulation of inflammation and response to dexamethasone by Annexin 1 in antigen
      induced arthritis.
AB  - OBJECTIVE: Annexin 1 (Anx-1) is a putative mediator of the antiinflammatory
      actions of glucocorticoids (GCs). This study investigated the role of Anx-1 in
      experimental arthritis and in GC-mediated inhibition of inflammation, using
      antigen-induced arthritis (AIA) in Anx-1 knockout (Anx-1(-/-)) mice. METHODS:
      Arthritis was induced by intraarticular injection of methylated BSA (mBSA) in
      mice preimmunized with mBSA. Disease was assessed after 7 days by histologic
      examination of the knee joints. Serum levels of anti-mBSA IgG were determined by
      enzyme-linked immunosorbent assay. Cytokine messenger RNA (mRNA) expression was
      detected by real-time polymerase chain reaction. RESULTS: A significant
      exacerbation of arthritis was observed in the Anx-1(-/-) mice compared with wild
      type (WT) mice. This was associated with increased mRNA expression of synovial
      interleukin-1 beta, tumor necrosis factor alpha, interleukin-6, and macrophage
      migration inhibitory factor. Dexamethasone significantly reduced the histologic
      severity of synovitis and bone damage in the WT mice, but exerted no inhibitory
      effects in the Anx-1(-/-) mice, and also significantly reduced the serum levels
      of anti-mBSA IgG and the numbers of peripheral blood neutrophils and lymphocytes
      in WT mice, but had no such effect in Anx-1(-/-) mice. CONCLUSION: Anx-1 exerts
      endogenous antiinflammatory effects on AIA via the regulation of cytokine gene
      expression, and also mediates the antiinflammatory actions of dexamethasone in
      AIA.

PMID- 15022343
TI  - A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with
      antiinflammatory properties in murine collagen-induced arthritis.
AB  - OBJECTIVE: To explore the antiarthritic potential of a novel synthetic
      cannabinoid acid, Hebrew University-320 (HU-320), in the DBA/1 mouse model of
      arthritis, and to investigate in vitro antiinflammatory and immunosuppressive
      effects of HU-320 on macrophages and lymphocytes. METHODS: DBA/1 mice were
      immunized with bovine type II collagen (CII) to induce arthritis and then
      injected intraperitoneally daily with HU-320. The effects of treatment on
      arthritic changes in hind feet were assessed clinically and histologically, and
      draining lymph node responses to CII were assayed. Murine splenic and human blood
      lymphocytes were cultured to study the effect of HU-320 on polyclonal mitogenic
      stimulation. Macrophage cultures were set up to evaluate in vitro effects of HU
      320 on production of tumor necrosis factor alpha (TNF alpha) and reactive oxygen
      intermediates (ROIs). The effect of HU-320 administration on lipopolysaccharide
      induced serum TNF levels was assayed using C57BL/6 mice. Bioactive TNF production
      was measured using BALB/c clone 7 target cells. Evaluation of HU-320
      psychoactivity was performed using established laboratory tests on Sabra mice.
      RESULTS: Systemic daily administration of 1 and 2 mg/kg HU-320 ameliorated
      established CII-induced arthritis. Hind foot joints of treated mice were
      protected from pathologic damage. CII-specific and polyclonal responses of murine
      and human lymphocytes were down-modulated. HU-320 inhibited production of TNF
      from mouse macrophages and of ROIs from RAW 264.7 cells and suppressed the rise
      in serum TNF level following endotoxin challenge. HU-320 administration yielded
      no adverse psychotropic effects in mice. CONCLUSION: Our studies show that the
      novel synthetic cannabinoid acid HU-320 has strong antiinflammatory and
      immunosuppressive properties while demonstrating no psychoactive effects. The
      profound suppressive effects on cellular immune responses and on the production
      of proinflammatory mediators all indicate its usefulness as a novel
      nonpsychoactive, synthetic antiinflammatory product.

PMID- 15022344
TI  - The Toll-like receptor 4 Asp299Gly functional variant is associated with
      decreased rheumatoid arthritis disease susceptibility but does not influence
      disease severity and/or outcome.

PMID- 15022345
TI  - Overexpression of tumor necrosis factor causes bilateral sacroiliitis.

PMID- 15022346
TI  - Intravenous immunoglobulin modulates cutaneous involvement and reduces skin
      fibrosis in systemic sclerosis: an open-label study.

PMID- 15022347
TI  - Ultrasonographic assessment of finger and toe joint inflammation in rheumatoid
      arthritis: comment on the article by Szkudlarek et al.

PMID- 15022349
TI  - The validity and predictive value of magnetic resonance imaging erosions in
      rheumatoid arthritis: comment on the article by Goldbach-Mansky et al.

PMID- 15022350
TI  - Magnetic resonance imaging computerized assessment in rheumatoid arthritis:
      comment on the article by Goldbach-Mansky et al.

PMID- 15022351
TI  - What are the real effects of arthritis self-management education programs on pain
      and disability? Comment on the article by Warsi et al.

PMID- 15022353
TI  - Association of the proinflammatory haplotype (MICA5.1/TNF2/TNFa2/DRB1*03) with
      polymyositis and dermatomyositis.

PMID- 15022354
TI  - Effect of infliximab treatment on T cell cytokine responses in
      spondylarthropathy: comment on the article by Zou et al.

PMID- 15022359
TI  - Musculoskeletal stress markers in Natufian hunter-gatherers and Neolithic farmers
      in the Levant: the upper limb.
AB  - This paper attempts to quantify the changes in activity patterns of early farming
      populations in the Levant through the musculoskeletal stress markers (MSM) of the
      upper limb as seen in skeletal remains. The transition to an agricultural way of
      life resulted in higher loads on the upper limb in Neolithic populations compared
      to the Natufian hunter-gatherer populations that preceded them. The MSM pattern
      for males and females indicates a gender-based division of labor both in the
      Natufian and the Neolithic. It may also suggest that people in the Neolithic
      period were engaged in different (new) activities and occupations compared to the
      Natufian.

PMID- 15022356
TI  - Recurrent pregnancy loss in the context of antiphospholipid antibodies: comment
      on the article by Triolo et al.

PMID- 15022360
TI  - Population history of native groups in pre- and postcontact Spanish Florida:
      aggregation, gene flow, and genetic drift on the Southeastern U.S. Atlantic
      coast.
AB  - Evolutionary trends and population history and structure are discussed for a
      series of late prehistoric and historic-period skeletal samples from the Georgia
      coast and interior (the Guale). Phenotypic dental measurement data were collected
      for nine samples from the late prehistoric (AD 1200-1400) and historic (AD 1608
      1702) periods and subjected to population genetic and statistical analyses. The
      primary trends were for an increase in tooth size through time, and for an
      initial increase in dental variability in the early historic period, followed by
      a subsequent decline in dental variability in the late historic period. Given the
      increasing stress levels, evidenced by previous bioarchaeological analyses
      (Larsen [2001] Bioarchaeology of Spanish Florida, Gainesville: University Press
      of Florida), an environmental explanation for the increase in tooth size is
      unlikely. It is proposed that the early historic period witnessed aggregation and
      gene flow with extraregional populations, possibly African slaves or nonlocal
      Native American population groups. The late historic period may have experienced
      significant loss of phenotypic variability due to genetic drift. In both time
      periods, the evolutionary mechanism increased average tooth size, with
      independent variance effects.Because microevolutionary trends obscure patterns of
      gene flow and population ancestry, the data were detrended following Konigsberg
      ([1990a] Hum. Biol. 62:49-70), and submitted to standard population genetic
      analyses (Relethford et al. [1997] Hum. Biol. 69:443-465). Analysis of the
      precontact samples in isolation (Irene Mound, Irene Mortuary, and an aggregate
      coastal sample) indicated little genetic microdifferentiation (F(ST) = 0.008),
      limited extralocal gene flow, and a small distinction between interior and
      coastal samples. The inclusion of the historic data dramatically increased
      variability levels (F(ST) = 0.019). The analysis of extralocal gene flow
      indicates that the late mission period experienced significantly less external
      gene flow, which is consistent with historic models that suggest the social
      organization of the Guale during this time period may have been significantly
      altered. Genetic distances also indicate a primary division between inland and
      coastal precontact samples and a maintenance of biological populations along the
      coast. In other words, the coastal, early historic, and late historic period
      samples are phenotypically homogeneous, supporting the notion that the mission
      populations were drawn from the local population base. The late mission period
      sample was also, however, more closely related to the interior samples. This may
      suggest that the late mission period population was an aggregate sample composed
      of both remnant interior and coastal population groups.

PMID- 15022361
TI  - Is cribra orbitalia synonymous with anemia? Analysis and interpretation of
      cranial pathology in Sudan.
AB  - Cribra orbitalia is a porotic or sieve-like lesion in the bony orbital roof. Its
      cause has been the object of research and discussion since the end of the 19th
      century. Since about 1960, most scientists have started to agree on the
      hypothesis that the lesion is a result of hypertrophy of the red bone marrow, and
      therefore is proof of anemia. However, recent investigations showed that in some
      cases, the histologic bone structure does not support the diagnosis of anemia.
      The status of cribra orbitalia as an indicator then becomes uncertain. We carried
      out a histologic examination of thin-ground sections in polarized light to
      clarify the possible sources of orbital roof lesions in a Nubian population from
      Missiminia, northern Sudan (n = 333). In at least 56.5% of cribra orbitalia
      cases, there were no histologic features indicating changes due to anemia. Signs
      of other pathological conditions, such as inflammation or osteoporosis, as well
      as pseudopathological cases, were found.

PMID- 15022362
TI  - Petrosal orientation and mandibular ramus breadth: evidence for an integrated
      petroso-mandibular developmental unit.
AB  - The absolute and relative breadths of the mandibular ramus (MRB) display
      substantial variation in modern humans, and are of analytical value in
      paleoanthropology. According to Enlow et al. ([1969] Am. J. Orthod. 56:6-23), the
      ramus is the growth counterpart of the middle cranial fossa (MCF) and the
      pharynx. Such counterpart principles state that variation in ramus breadth is a
      frequent function of the horizontal alignment of the MCF, and both structures
      tend to covary within and between populations. These authors also suggested that
      lateral parts of the basicranium have a particular importance in the positioning
      of facial components. In the present study, this hypothesis is tested, and
      relationships between midline and lateral basicranial elements and ramus breadth
      variation are explored. Two-dimensional landmarks taken from lateral radiographs
      of adult crania representative of three modern human populations (Europeans, West
      Africans, and Japanese) were analyzed by geometric morphometry. Our results are
      consistent with previous counterpart analyses. Furthermore, our findings
      highlight the significance of the orientation of the petrous temporal to modern
      human mandibular ramus variation. Variation in the orientation of the petrosal
      bone appears to alter the spatial position of the mandible and influences MRB.
      Developmental integration of a petroso-mandibular unit may have important
      paleoanthropological implications.

PMID- 15022363
TI  - Genetic analysis and ethnic affinities from two Scytho-Siberian skeletons.
AB  - We extracted DNA from two skeletons belonging to the Sytho-Siberian population,
      which were excavated from the Sebystei site (dating back 2,500 years) in the
      Altai Republic (Central Asia). Ancient DNA was analyzed by autosomal short tandem
      repeats (STRs) and by the sequencing of the hypervariable region 1 (HV1) of the
      mitochondrial DNA (mtDNA) control region. The results showed that these two
      skeletons were not close relatives. Moreover, their haplogroups were
      characteristic of Asian populations. Comparison with the haplogroup of 3,523
      Asian and American individuals linked one skeleton with a putative ancestral
      paleo-Asiatic population and the other with Chinese populations. It appears that
      the genetic study of ancient populations of Central Asia brings important
      elements to the understanding of human population movements in Asia.

PMID- 15022364
TI  - Early population differentiation in extinct aborigines from Tierra del Fuego
      Patagonia: ancient mtDNA sequences and Y-chromosome STR characterization.
AB  - Ancient mtDNA was successfully recovered from 24 skeletal samples of a total of
      60 ancient individuals from Patagonia-Tierra del Fuego, dated to 100-400 years
      BP, for which consistent amplifications and two-strand sequences were obtained. Y
      chromosome STRs (DYS434, DYS437, DYS439, DYS393, DYS391, DYS390, DYS19, DYS389I,
      DYS389II, and DYS388) and the biallelic system DYS199 were also amplified, Y-STR
      alleles could be characterized in nine cases, with an average of 4.1 loci per
      sample correctly typed. In two samples of the same ethnic group (Aonikenk), an
      identical and complete eight-loci haplotype was recovered. The DYS199 biallelic
      system was used as a control of contamination by modern DNA and, along with
      DYS19, as a marker of American origin. The analysis of both mtDNA and Y-STRs
      revealed DNA from Amerindian ancestry. The observed polymorphisms are consistent
      with the hypothesis that the ancient Fuegians are close to populations from south
      central Chile and Argentina, but their high nucleotide diversity and the
      frequency of single lineages strongly support early genetic differentiation of
      the Fuegians through combined processes of population bottleneck, isolation,
      and/or migration, followed by strong genetic drift. This suggests an early
      genetic diversification of the Fuegians right after their arrival at the
      southernmost extreme of South America.

PMID- 15022365
TI  - Illness, injury, and disability among Shiwiar forager-horticulturalists:
      implications of health-risk buffering for the evolution of human life history.
AB  - Human life history is distinguished by long lifespan, delayed reproduction,
      intergenerational asymmetric benefit transfers from adults to juveniles and
      between adults, and a large brain able to engage in unprecedented levels of
      learning, reasoning, and insight. The evolution of these traits depends on
      relatively low human mortality. Understanding why humans have low mortality is
      therefore critical for understanding the evolution of key human traits. One
      explanation is that the evolution of food provisioning during periods of health
      crisis reduced mortality. This hypothesis turns on health risk having posed a
      significant adaptive problem that could be effectively buffered by healthcare
      provisioning. Unfortunately, the frequency, duration, and fitness effects of
      temporary disability are difficult to estimate based on osteological evidence
      alone, and systematic ethno-biological research on these issues among extant
      small-scale societies with little access to Western medical care is lacking. Here
      I present data on 678 injuries and illnesses suffered by 40 Shiwiar forager
      horticulturalists, based on physical evidence and informant reports. A subsample
      of 17 individuals provided data on incidence and duration of disability for 215
      pathological incidents. Results indicate that injury and illness occur frequently
      across the lifespan. Most living individuals have suffered temporarily disabling
      health crises likely to have been lethal without provisioning. The fitness
      effects of surviving these episodes are high, suggesting that the Shiwiar
      population structure and lifeway are dependent on infrequent extended
      provisioning to temporarily disabled individuals, and that provisioning of aid
      during healthcare crises effectively lowers mortality in this small-scale
      society.

PMID- 15022367
TI  - Cancer vaccines 2003: opening address.

PMID- 15022366
TI  - Effects of birthplace and individual genetic admixture on lung volume and
      exercise phenotypes of Peruvian Quechua.
AB  - Forced vital capacity (FVC) and maximal exercise response were measured in two
      populations of Peruvian males (age, 18-35 years) at 4,338 m who differed by the
      environment in which they were born and raised, i.e., high altitude (Cerro de
      Pasco, Peru, BHA, n = 39) and sea level (Lima, Peru, BSL, n = 32). BSL subjects
      were transported from sea level to 4,338 m, and were evaluated within 24 hr of
      exposure to hypobaric hypoxia. Individual admixture level (ADMIX, % Spanish
      ancestry) was estimated for each subject, using 22 ancestry-informative genetic
      markers and also by skin reflectance measurement (MEL). Birthplace accounted for
      the approximately 10% larger FVC (P < 0.001), approximately 15% higher maximal
      oxygen consumption (VO(2)max, ml.min(-1).kg(-1)) (P < 0.001), and approximately
      5% higher arterial oxygen saturation during exercise (SpO(2)) (P < 0.001) of BHA
      subjects. ADMIX was low in both study groups, averaging 9.5 +/- 2.6% and 2.1 +/-
      0.3% in BSL and BHA subjects, respectively. Mean underarm MEL was significantly
      higher in the BSL group (P < 0.001), despite higher ADMIX. ADMIX was not
      associated with any study phenotype, but study power was not sufficient to
      evaluate hypotheses of genetic adaptation via the ADMIX variable. MEL and FVC
      were positively correlated in the BHA (P = 0.035) but not BSL (P = 0.335)
      subjects. However, MEL and ADMIX were not correlated across the entire study
      sample (P = 0.282). In summary, results from this study emphasize the importance
      of developmental adaptation to high altitude. While the MEL-FVC correlation may
      reflect genetic adaptation to high altitude, study results suggest that alternate
      (environmental) explanations be considered.

PMID- 15022368
TI  - Effect of school policy on tobacco use by school personnel in Bihar, India.
AB  - This study examined the relationship between school tobacco policies and tobacco
      use prevalence among school personnel. Two subsets of schools were identified in
      Bihar, India: Federal Schools (with a tobacco policy), and State schools (without
      a tobacco policy). Stratified probability samples of 50 schools each were
      selected. The survey was conducted through an anonymous, self-administered
      questionnaire. School personnel from State Schools (non-policy schools) reported
      significantly higher daily cigarette smoking and daily current smokeless tobacco
      use compared to personnel in Federal schools (policy schools). Teachers in State
      schools did not teach about health consequences of tobacco, and they had not
      received training for such teaching. Extent of teaching about health consequences
      of tobacco varied across topics for teachers in Federal schools. They received
      negligible training, but more than 35% reported access to teaching materials.
      More than one-half the personnel from Federal schools knew about their school's
      policy prohibiting tobacco use among students and school personnel, and about
      policy enforcement. Personnel in State schools did not know about tobacco control
      policy in their schools. All school personnel in both types of schools were near
      unanimous in supporting policy prohibiting tobacco use in schools. The study
      demonstrated an association between enacting a school policy regarding tobacco
      use and school personnel's use of tobacco, curricular teaching, and practical
      training of students. Findings suggest that more extensive introduction of
      comprehensive school policies may help reduce tobacco use among school personnel.

PMID- 15022369
TI  - Does the school nurse-to-student ratio make a difference?
AB  - Public schools must provide an appropriate education for students with complex
      health needs. Chronic illnesses such as asthma and diabetes, social morbidities,
      injuries, and conditions that limit learning such as poor vision commonly affect
      school-aged children. School nurses often assume a leadership role in providing
      services for these children. However, although a national standard for school
      nurse/student ratio has been proposed, little research has examined the
      relationship between different school nurse-to-student ratios, level of health
      services provided in schools, and student outcomes. This study examined data in a
      21-county region in eastern North Carolina served by a regional school nurse
      consultant. The school nurse-to-student ratio in these counties ranged from 1:451
      to 1:7,440 based on full-time equivalencies. Two systems offered no school
      nursing services. Data from school years ending in 2000-2002 were considered in
      the analysis. A significant correlation was found between the increased presence
      of school nurses and services provided to children with diabetes (r = -.52, p =
      .000) and asthma (r = -.43, p = .002). Schools with better ratios provided more
      counseling services to children for social conditions such as depression and
      unintended pregnancy (r = -.38, p = .006), and more follow-up for school-related
      injuries (r = -.43, p = .003), and a higher percentage of children with vision
      problems received follow-up care (r = -.37, p = .007). A case analysis of one
      school district that experienced a significant improvement in nurse/student ratio
      over the study period provides further evidence that school nurses make a
      difference.

PMID- 15022371
TI  - Ethnic variation in drinking, drug use, and sexual behavior among adolescents in
      Hawaii.
AB  - This study examined ethnic differences in substance use and sexual behavior and
      whether drinking and drug use constitute risk factors for unsafe sexual practices
      among Native Hawaiian (NH), Caucasian, and Asian/Pacific Islander (API) high
      school students in Hawaii. A secondary data analysis of the Youth Risk Behavior
      Survey (1997 and 1999) using a representative sample of 2,657 students in 9-12
      grades was performed. Chi-square tests for bivariate associations and
      multivariate regression analyses were conducted to identify predictors. NHs were
      more sexually active, initiated sex earlier, and tended to have multiple
      partners. Alcohol lifetime use was higher in NH, Caucasians, and males. NHs were
      more likely to initiate drinking by age 12 and engage more in episodic drinking.
      Non-episodic or episodic drinkers and students who use drugs were at risk to
      engage in sexual activity, have multiple partners, and use alcohol/drugs during
      sex. Risk was two times higher for substance use during sex if drinking was
      initiated at age 10 or younger compared to 15 years or older. Compared to
      abstainers, the risk doubled for lifetime multiple partners if drinking was
      initiated at ages 13-14. Overall, females were more sexually active. Because
      drinking was associated with sexual initiation and risky behavior, adverse
      effects of alcohol must be addressed in programs targeting underage drinking,
      thus helping youth delay or minimize sexual activity and prevent other associated
      problems. Intervention efforts should enhance life skills that endorse abstinence
      from alcohol and drug use.

PMID- 15022370
TI  - Preliminary testing of a program to prevent type 2 diabetes among high-risk
      youth.
AB  - Type 2 diabetes is increasing among youth, with minority youth at highest risk.
      This preliminary study tested the feasibility of a school-based program to
      prevent type 2 diabetes in youth at risk. Forty-one participants (age 12.6 +/-
      1.1 years; 63% female, 51% African American, 44% Hispanic, and 5% Caucasian) were
      randomly assigned to one of two groups. Both the experimental and control groups
      received nutrition education and exercise training. The experimental group also
      received coping skills training. Data collected included body mass index (BMI),
      insulin resistance, dietary intake (24-Hour Food Recall), self-efficacy (Health
      Behavior Questionnaire), activity (Revised Godin-Shepard Activity Survey), and
      parents' health promoting behaviors (Health Promoting Lifestyle Profile III). At
      baseline BMI ranged from 27 to 53 (M = 36.2 +/- 6.0), and 95% (n = 39)
      demonstrated insulin resistance or pre-diabetes on an oral glucose tolerance
      test. After 12 months, the experimental group showed trends in improved usual
      food choices (p = .1) and increased dietary knowledge (p = .3). They also
      demonstrated lower glucose (p = .07) and insulin levels (p = .2). Experimental
      group parents demonstrated improved health responsibility (p = .03), healthier
      nutrition choices (p = .05), improved stress management skills (p = .05),
      increased activity (p = .2), and increased spirituality (p = .2). Data suggest a
      school-based program tailored to multiethnic youth may prove successful in
      helping these youth increase activity, improve nutrition status, and stabilize
      glucose and insulin metabolism, and also may be effective in changing parent
      health behavior.

PMID- 15022373
TI  - Spirituality and sexuality: compatible components for optimal health.

PMID- 15022372
TI  - Long-term impact of the Gatehouse Project on cannabis use of 16-year-olds in
      Australia.
AB  - This study examined the impact of a school-based preventive intervention on
      cannabis use in adolescence, using a cluster-randomized trial of a multilevel
      intervention aimed at improving social relationships within schools by promoting
      change in school environment. Four waves of data were collected at baseline
      (1997, Year 8: mean age 13 years) and six, 18, and 30 months later (1999, Year
      10: mean age 16 years). Self-reported substance use, school engagement, and
      sociodemographic data were collected using computer-administered questionnaires.
      Some 2.678(74%) Year 8 students participated (wave 1) with minimal attrition (10%
      by wave 4). Adjusting for baseline use, weak evidence existed for an intervention
      effect on the prevalence of any use at Year 10 (OR 0.75, 95% CI 0.54, 1.05) and
      incident weekly use (OR 0.72, 95% CI 0.39, 1.33). These effects were reduced
      after adjusting for confounders. Moderate evidence suggested an interaction
      effect between intervention group and tobacco use (p = 0.04), suggesting the
      intervention was more effective for non-smokers at baseline (Adj. OR 0.50, 95% CI
      0.26, 0.98). This study indicates that a multi-level school-based program may
      provide an innovative direction for sustainable school interventions with the
      potential to reduce substance use.

PMID- 15022374
TI  - Asthma knowledge, awareness, and training among head start and early head start
      staff.

PMID- 15022375
TI  - Expertise to help RNs deliver safe, competent and ethical care.

PMID- 15022376
TI  - Your chance to make a difference.

PMID- 15022377
TI  - Alarm-enhancement systems for ventilators.
AB  - Ventilator alarms can be crucial for safeguarding the health and even the lives
      of patients. Therefore, it's vital that they--like other critical alarms--be
      readily detected in even the busiest, noisiest hospital departments. One way to
      make sure that this happens is to use alarm-enhancement systems, which
      communicate ventilator alarms to locations where they are more likely to be
      detected by caregivers. There are four basic categories of ventilator alarm
      enhancements: (1) interfacing ventilators with networked physiologic monitors,
      (2) incorporating commercially available systems for centralized remote
      monitoring of ventilator alarms, (3) interfacing ventilators with nurse call
      systems, and (4) utilizing remote annunciators for ventilator alarms. These
      options range widely in complexity, cost, and the types of care settings for
      which they're likely to be suitable. In this article, we describe the ventilator
      alarm-enhancement systems that are currently on the market. We highlight their
      pluses and minuses based on information we have gained from product literature,
      through conversations with suppliers, and, where possible, through discussions
      with users. We also provide guidance to facilities on how to choose among the
      various options and products available.

PMID- 15022378
TI  - Triggering of patient-controlled analgesic pumps by clinicians or visitors could
      be lethal.

PMID- 15022379
TI  - Disconnecting wall gas can interrupt ventilation on Drager Evita 2 dura and Evita
      4 ventilators.

PMID- 15022380
TI  - Inspection of medical gas flowmeters.

PMID- 15022381
TI  - [A long road in Europe...].

PMID- 15022382
TI  - Influence of nifedipine on gingiva of Wistar rats.
AB  - Noninflammatory hyperplastic growth of gingiva induced by calcium channel
      blockers, mostly nifedipine, is often seen in everyday dental practice. In order
      to establish an association of nifedipine and gingival hyperplasia, experimental
      model was used. Wistar rats were given water solution of nifedipine in different
      daily doses, using specially designed cannula. At the beginning of the
      experiment, before the application of nifedipine and in the determined time
      periods, gingival volume was measured. The volume of lower incisors interdental
      central papillars, represented multiplied values of vertical height, mesio-distal
      width, and bucco-lingual depth, expressed in millimeters. The results indicated
      that gingival hyperplasia was more excessive in the experimental animals, which
      were given higher doses of the drug for longer time period. Nifedipine is a drug
      which induces gingival fibroblasts to produce higher quantity of collagen that
      causes gingival overgrowth.

PMID- 15022383
TI  - [Osteoid osteoma--ten-years' experience in therapy].
AB  - AIM: To review ten-years experience in diagnostics and operative treatment of
      osteoid osteoma. METHODS: A total of 15 patients were retrospectively analyzed in
      this study. Clinical diagnosis was based on medical check-up, aspirin test, and
      conventional laboratory and radiographic examinations. CAT scan radionuclide bone
      scan, and magnetic resonance were performed in certain cases. All the patients
      were operatively treated by local resection of the tumor-infested bone. The
      resected part of the bone was intraoperatively checked by X-ray. The aim of this
      examination was to verify nidus in the resected bone. Afterwards, the resected
      bone with nidus was histologically analyzed. RESULTS: Osteoid osteoma was
      histologically verified in 86.6% of cases. Other forms of bone tumors were
      verified in 13.3%. In the early postoperative period patients were without
      previous discomforts. Future treatment consisted of regular medical check-up of
      all the patients. In order to verify the final results, in February 2002 another
      medical check-up was performed for 11 patients, upon their consent. All of the
      patients with verified osteoid osteoma were without discomforts. Medical findings
      were regular in each case. Conventional radiography showed a solid bone
      remodelling in place of resected bone. CONCLUSION: Osteoid osteoma is a benign
      bone tumor with typical clinical and radiographic findings. Operative treatment
      represents a method of choice and demands accurate preoperative localization of
      the lesion, with the help of computer-assisted tomography.

PMID- 15022385
TI  - [The role of certain Campylobacter types in the etiology of enterocolitis].
AB  - BACKGROUND: In recent decades, medical community has increasingly been calling
      attention to the importance of Campylobacter as an disease-causing agent in
      humans. Nowadays, Campylobacter jejuni (C. jejuni) is known as the most frequent
      bacterial cause of diarrhea worldwide. Epidemiological differences of the
      infections caused by Campylobacter, present in the developed and the developing
      countries, are attributed to the differences of the types of virulence. Due to
      the specificity, and the demanding features of Campylobacter, as well as poorly
      equipped microbiological laboratories, campylobacteriosis is insufficiently
      studied in our country. This investigation aimed to determine the participation
      of some Campylobacter species in the etiology of diarrheal diseases in our
      population. METHODS: The four-years continuous monitoring of Campylobacter
      presence was performed in the faeces of 12,605 patients with enterocolitis. The
      control group included 5,774 examinees of healthy children and youth. Faeces
      samples were cultivated on Skirrow's selective medium, and further incubated
      according to effective methodology for Campylobacter. Identification of strains
      was based on morphological, cultural and physiologic features of strains (oxidase
      test, catalase test, susceptibility to nalidixic acid, and hypurate hydrolysis).
      As a statistical method, for data processing, chi 2 test and Fisher's exact test
      were used. RESULTS: Campylobacter was proven in 3.86% of enterocolitis patients,
      and in 0.71% of healthy population. Out of 518 Campylobacter isolates, 86.48%
      belonged to enterocolitis outpatients, and 13.51% to inpatients. Predominant
      symptoms of the disease were diarrhea (81.83%), increased temperature (34.71%),
      vomiting (19.77%), and stomach pain (15.17%). The diseased were predominantly
      infants in the first year of life. Out of 300 Campylobacter isolates, 75% were
      identified as Campylobacter jejuni, 23% as Campylobacter coli (C. coli), and 2%
      as Campylobacter lari (C. lari). CONCLUSION: Species of Campylobacter genus
      participate in the etiology of enterocolitis at 3.86%. According to numerous
      parameters the infection in our population coincides with the infection in the
      population of European countries. Frequent findings of C. coli in our region are
      in discrepancy with the results of numerous studies conducted in the developed
      countries.

PMID- 15022384
TI  - [The calcified ascending aorta in aortocoronary bypass].
AB  - Heavily calcified ascending aorta significantly increased morbidity and lethality
      during open-heart surgery. Cannulation and clamping (partial or total) of
      severely atherosclerotic ascending aorta can easily cause damage and rupture of
      aortic wall, with consequential distal (often fatal) embolization with
      atheromatous debris (brain, myocardium). From June 1998. until June 2000, 11 of
      2,136 (0.5%) patients who underwent coronary artery bypass grafting were with the
      severe atheromatous ascending aorta. The site of cannulation was in the aortic
      arch in three patients (aorta was occluded with Foley catheter in one case, and
      single clamp technique was used in the other two cases). The femoral artery was
      the cannulation site in other five cases. Profound hypothermia, ventricular
      fibrillation, and circulatory arrest, with no cross-clamping or cardioplegia,
      were used in three patients. Two patients were operated on with extracorporeal
      circulation, one in normothermia, on the beating heart, the other in moderate
      hypothermia, on fibrillating heart. In three patients myocardial
      revascularization was performed on the beating heart, in normothermia, without
      extracorporeal circulation. Postoperative course was uneventful in all 11
      patients. Neither atheroembolism in the peripheral organs, nor atheroembolism of
      the extremities occurred. The proposed surgical approaches have the potential to
      reduce the prevalence of stroke and systemic embolization associated with
      coronary artery bypass grafting in patients with heavily calcified ascending
      aorta. This result was achieved due to the applied modifications of standard
      cardiosurgical technique.

PMID- 15022386
TI  - [Histopathologic and immunocytochemical changes in the liver in patients with
      chronic hepatitis C].
AB  - BACKGROUND: The presence of lymphocytes within the liver parenchyma is related to
      immunologically mediated liver damage in chronic hepatitis C. The aim of the
      study was to make histological, histochemical, and immunocytochemical assessment
      of liver biopsy specimens in patients with chronic hepatitis C virus (HCV)
      infection. METHODS: Biopsy specimens of 20 patients with chronic HCV disease were
      analyzed, using standard staining procedures to verify histologic liver lesions,
      as well as immunoenzymatic staining with monoclonal antibodies to detect CD4+ T
      lymphocytes, B-lymphocytes, and macrophages. RESULTS: Micromorphologic
      characteristics of chronic active viral hepatitis C were present in all the
      patients, differing, however, by the level of their activity. Dominant changes
      were found within the portal space, consisting of mononuclear lympho-plasmocytic
      infiltration and macrophages. Immunocytochemical investigation of mononuclear and
      macrophageal infiltration showed the correlation between micromorphological
      findings and the degree of the activity. CONCLUSION: The presence of lymphocytic
      and macrophageal infiltration within the hepatic tissue directly correlated with
      the intensity of the liver damage. Analysis of the population of cellular
      infiltrate in the liver together with the monitoring of viremia level and the
      level of hepatocyte necrosis, could be useful tools for elucidation of the
      pathogenesis of chronic hepatitis C.

PMID- 15022387
TI  - [Technetium-99m-tetrofosmin radionuclide mammography in the diagnosis of
      malignant breast tumors].
AB  - BACKGROUND: Technetium-99m (99mTc) tetrofosmin scintigraphy is a new imaging
      method for the diagnosis of various malignancies, such as lung, thyroid, and most
      frequently breast neoplasms. The aim of this study was to evaluate the diagnostic
      reliability of 99mTc-Tetrofosmin breast scintigraphy in the detection of
      malignant breast disease. METHODS: 99mTc-Tetrofosmin scintimammography (SMM) was
      performed in 28 patients with 30 breast lesions suspicious for malignancy.
      Standard mammography (MM) was also done. After surgery, the results of SMM and MM
      were compared to definitive histopathological findings as the "gold standard".
      After intravenous injection of radiotracer, SMM was performed in prone and supine
      views of the thorax, using large field-of-view Gamma camera. RESULTS: The results
      of SMM were interpreted visually and semiquantitatively, and evaluated as
      positive or negative. Sensitivity, specificity and accuracy, positive (PPV) and
      negative predictive value (NPV) were obtained in relation to histopathology.
      After comparing the results of SMM and MM, SMM was proved more sensitive (95% for
      SMM vs. 80% for MM), while the specificity of both methods was similar.
      CONCLUSION: The results of this study indicate that the contribution of SMM as a
      nuclear medicine procedure has its place in the diagnostic protocol for patients
      suspected of malignant breast cancer.

PMID- 15022389
TI  - [Post-traumatic stress disorders].

PMID- 15022388
TI  - [Expression of the Bcl-2 family of proteins in peripheral blood B-lymphocytes in
      patients with chronic lymphocytic leukemia].
AB  - Chronic lymphocytic leukemia (CLL) is a neoplastic disease characterized by the
      accumulation of morphologically mature monoclonal CD 5+ B cells in the early
      phase (G0/G1) of the cell cycle. It is considered that the accumulation of
      neoplastically transformed lymphocytes B (CLL cells) is primarily the consequence
      of the disturbance, i.e., blockade of these cells' apoptosis process. Apoptosis
      is the specific process of programmed cell death regulated by numerous
      extracellular and intracellular mechanisms. The Bcl-2 proteins are well-known
      modulators of this process. Some of these proteins (such as Bcl-2, and Bcl-XI)
      are anti-apoptotic, while others (such as Bad or Bax) are pro-apoptotic. Our
      study included the analysis of 20 peripheral blood specimens from 20 patients
      with CLL, and 20 peripheral blood specimens of healthy persons who represented
      the control group. Using Western blotting analysis, we quantitatively examined
      the protein expression of Bcl-2 family (Bcl-2, Bax, Bad, and Bcl-XI). The level
      of Bcl-2 (p = 3.68 x 10(-10)), Bax (p = 0.019), and Bad (p = 0.073) proteins
      expression was significantly increased in all the analyzed peripheral blood
      samples of patients, while the level of Bcl-XI protein (p = 0.75) did not
      significantly differ in peripheral blood samples of patients, compared to the
      controls. The results of this study showed that the increased level of expression
      of Bcl-2, Bax, and Bad protein represented the most striking feature of CLL
      cells. Moreover, the variations in the expression of only one protein of the Bcl
      2 family could not represent the prognostic parameter in the treatment of this
      disease.

PMID- 15022390
TI  - [The basics of glutamatergic neural transmission].

PMID- 15022391
TI  - [Nutrigenetics--the role of nutrition and heredity in the development and
      prevention of malignant diseases].

PMID- 15022392
TI  - [Diabetic dyslipidemia and atherosclerosis].

PMID- 15022393
TI  - [Fasciocutaneous flaps in the treatment of soft tissue defects of the lower leg
      caused by explosive war injuries].
AB  - The use of fasciocutaneous flaps for the reconstruction of lower leg soft-tissue
      defects inflicted during the bombing of our country is presented in this case
      report. The experience with 9 patients with soft-tissue defects of the lower leg
      is presented with the aim of examining the possibilities of war-wound
      reconstruction. The results of the earlier use of fasciocutaneous flaps in the
      lower leg reconstruction as well as the those obtained during the reconstruction
      of the lower leg soft-tissue defects in war wounds was proven to be safe and
      reliable method of the reconstructions of severe lower leg injuries, particularly
      of its distal segment and the malleolus region.

PMID- 15022394
TI  - [Primary localized cutaneous amyloidosis--lichen amyloidosis].
AB  - This case report presented a female patient with primary-localized-cutaneous
      amyloidosis in the form of lichen amyloidosus. Primary-localized-cutaneous
      amyloidosis is a rare idiopathic dermatosis caused by abnormal deposition of
      amyloid composed primarily of degenerated keratin filaments. In order to
      establish the final diagnosis, detailed clinical and laboratory investigations
      were performed, with a particular emphasis on pathohistological analysis of skin
      specimens, special stains, and electron microscopy.

PMID- 15022395
TI  - [Primary ciliary dyskinesia].
AB  - In patients with chronic respiratory diseases that last since the early
      childhood, primary ciliary dyskinesia (PCD) needs to be considered. Four patients
      reviewed in this paper were with typical disease history and clinical picture, as
      well as clear ciliary axonema damage. Complete examination was performed in all
      the patients, including bronchoscopy with bronchography, and the examination of
      the biopsy samples of respiratory airways' mucous membrane, obtained by
      transmission electron microscope (TEM). In two of the patients spermatozoa were
      also examined by TEM. Large anatomic defects of airways were found in all the
      patients, but pulmonary function was normal (except in one case), representing
      one of PCD's significant characteristics. First two cases fulfilled the criteria
      for Kartagener's syndrome, which was initially sufficient for the diagnosis of
      PCD.

PMID- 15022396
TI  - [Serbian military surgery experience (1876--1918) part III: a quarter century of
      peace].

PMID- 15022397
TI  - [Long-term results of repair surgery of degenerative mitral insufficiency].
AB  - BACKGROUND: Mitral valve repair is probably the procedure of choice for the
      surgical treatment of degenerative mitral insufficiency. AIM: To evaluate the
      late results of mitral valve repair in degenerative mitral insufficiency.
      PATIENTS AND METHOD: The records of 88 patients who underwent mitral valve repair
      for degenerative mitral insufficiency from December 1991 through June 2002 were
      reviewed. Mean age was 59.9 years (range 22 to 82). At least moderate mitral
      insufficiency was present in every patient. Mean left atrial diameter was 55 mm
      and mean end diastolic and end systolic left ventricular diameters were 61 and 37
      mm respectively. RESULTS: The most common underlying lesion was ruptured chordae
      tendineae (66%) and posterior leaflet prolapse (68%). The surgical procedure most
      frequently performed was quadrilateral resection of the posterior leaflet (68%).
      A Carpentier-Edwards ring was placed in 97% of patients. An associated procedure
      was performed in 34%. Operative mortality was 2.3%. A complete follow up was
      obtained in 93% of cases with a mean of 54 +/- 36 months. Overall survival rate
      was 98% at one year, 88% at 5 and 82% at 10 years. Free of cardiac death rates
      were 94% at 5 and 89% at 10 years. Only 2 patients were reoperated during follow
      up, resulting in a 98% reoperation free rate follow up. Functional class improved
      in all patients at the end of follow up. Late echocardiographic evaluation showed
      absent or minimal mitral regurgitation in 83% and mild mitral regurgitation in
      17%. CONCLUSION: Good late results have been obtained with mitral valve repair,
      avoiding the inconveniences of prosthetic replacement. Therefore, mitral valve
      repair should be the procedure of choice to treat degenerative mitral
      insufficiency.

PMID- 15022398
TI  - [Genetic changes in chronic gastritis: study of microsatellite instability and
      loss of heterozygosity].
AB  - BACKGROUND: Multifocal chronic gastritis, associated to intestinal metaplasia, is
      considered a preneoplastic lesion, closely associated to intestinal type gastric
      cancer. AIM: To study the frequency of microsatellite instability (MSI) and loss
      of heterozygosity (LOH) in areas of chronic gastritis and intestinal metaplasia
      in gastric biopsies of patients without cancer. MATERIAL AND METHODS: Gastric
      biopsy samples from 34 patients without cancer (22 with multifocal atrophic
      gastritis and 12 with diffuse antral gastritis), were studied. Glands from areas
      of chronic gastritis and intestinal metaplasia and lymphocytes, were collected
      using laser microdissection of paraffin embedded samples. The analysis of 15 mono
      and dinucleotide microsatellites was used to assess LOH and MSI. RESULTS: LOH and
      MSI were found in some of the markers in 55% (12/22) and 59% (13/22) of cases
      with intestinal metaplasia, respectively. Only one of 12 areas with diffuse
      atrophic gastritis had MSI and a different area had LOH (p < 0.05 or less, when
      compared with areas of multifocal atrophic gastritis). Three areas of normal
      epithelium in patients with multifocal atrophic gastritis, also had alterations.
      Most of these alterations were concordant with adjacent areas with intestinal
      metaplasia. CONCLUSIONS: LOH and MSI was found in areas of intestinal metaplasia
      in more than half of the studied cases and in few areas of atrophic gastritis
      without intestinal metaplasia. These findings suggest that genotypic alterations
      may precede phenotypic modifications and that intestinal metaplasia is a
      preneoplastic lesion.

PMID- 15022400
TI  - [Human papilloma virus (HPV) typing in preneoplastic and neoplastic lesions of
      the uterine cervix in the IX region-Chile].
AB  - BACKGROUND: Uterine cervical cancer (UCC) is an important public health problem
      in Chile. Although HPV infection has been established as the main cause of UCC,
      little is known of its frequency and distribution in our population. AIM: To
      determine the presence and frequency of viral genotypes in uterine cervical
      specimens with preneoplastic and neoplastic lesions. MATERIAL AND METHODS: Two
      nested consensus PCRs followed by identification of amplified product by dot-blot
      hybridization and restriction fragment length polymorphism (RFLP) were used to
      analyze 175 biopsies. RESULTS: Detection of HPV was 40% in cases without
      histological lesion, 88% in low grade lesions, 89% in high grade lesions (HGL)
      and 93.5% in invasive carcinoma. Of all HPV positive cases, 89.5% were classified
      as high risk and only a 4.9% of HPV cases were of low risk type. Six percent of
      cases had multiple infections. Distribution of viral genotypes according to RFLP
      was: HPV33 (25.3%), 16 (18.7%), 52 (13.3%), 31 (12%), 35 (6.6%), 18 (2.7%).
      CONCLUSIONS: Most HPV found in biopsies with HGL and UCC were of high risk
      genotype. The elevated presence of high risk HPV in patients without cervical
      lesions may be a factor that explains the high percentage of UCC cases in our
      region. Most common viral types were: HPV16, 31, 33 and 52. Viral detection and
      typing may provide valuable information for patient selection and follow up and
      for allocation of resources.

PMID- 15022401
TI  - [Iodine nutrition in school children of four areas of Chile during the year
      2001].
AB  - BACKGROUND: In Chile, the recommendation for salt iodination was reduced from 100
      to 40 ppm, after detecting high urinary iodine excretion in school age children.
      AIM: To assess iodine nutrition in school age children after the modification of
      salt iodination. SUBJECTS AND METHODS: Iodine nutrition was studied in 3712
      school age Chilean children of primary level in 4 areas (Calama, Santiago, Temuco
      and Punta Arenas) through palpation of thyroid gland, urinary iodine excretion
      and iodine concentration in salt for human consumption of the surveyed areas.
      RESULTS: A 6.4% goiter prevalence was found (5.9% in boys and 6.8% in girls).
      Grade Ia goiter was more common (5.0%), without detecting differences between
      areas (7.3% in Calama, 5.9% in Santiago, 5.9 in Temuco and 6.7 in Punta Arenas).
      Iodine concentration in salt for human consumption of the areas was adequate
      according to the recent modification of Chilean legislation (25.4 mgI/g salt in
      Calama, 36.2 in Santiago, 27.7 in Temuco and 33.4 in Punta Arenas). Urinary
      iodine excretion was very high according to recommendation in boys and girls
      (2838 and 2852 mgI/g salt in Calama, 700 and 837 in Santiago, 1318 and 1438 in
      Temuco, 407 and 312 in Punta Arenas). CONCLUSIONS: Endemic goiter is not longer a
      problem in Chile. Salt iodination is in agreement with present legislation.
      However, urinary iodine excretion increased in Calama and Temuco, did not change
      in Santiago and decreased only in Punta Arenas in spite of the changes in the
      legislation. It is necessary to investigate the causes of the high urinary iodine
      excretions detected in school age children, and it is very important to have a
      continuous surveillance of iodine nutrition in Chile.

PMID- 15022399
TI  - [Expression of heat shock proteins HSP72 and HSP73 in Colombian patients with
      Hodgkin lymphoma positive and negative for Epstein Barr virus].
AB  - BACKGROUND: The expression of heat shock proteins (HSP70) in tumor cells or virus
      infected cells is important for the induction of specific cellular immune
      response. They are implicated in transport of immunodominants peptides in the
      endoplasmic reticulum, activation of antigen presenting cells and cross priming
      of CD8 T cells. AIM: To analyze the expression of HSP70 protein in its
      constitutive (HSP73) and inducible forms (HSP72) in Hodgkin's lymphoma (HL),
      infected or not by Epstein Barr virus (EBV) and to assess its relationship with
      pathological subtype, clinical stages and treatment response. MATERIAL AND
      METHODS: The analysis of HSP73 and HSP72 was done by immunoperoxidase on
      routinely processed paraffin sections with prior antigen retrieval. RESULTS:
      Sixty seven cases were studied. The expression of HSP73 and HSP72 was detected in
      19.4 and 17.9% of samples respectively. The infiltrating lymphocytes expressed
      HSP72 in 58% of cases. The pathological subtypes with the higher expression in
      lymphocytes were mixed cellularity and nodular sclerosis. No differences in HSP70
      expression were observed, according to clinical stage, treatment response or the
      presence of EBV. CONCLUSIONS: The expression of HSP72 on lymphocytes suggests
      that this protein plays an important role in the induction and amplification of
      antitumor immune response.

PMID- 15022402
TI  - [Frequency of C677T polymorphism of 5, 10-methylenetetrahydrofolate reductase
      (MTHFR) in Chilean mothers of spina bifida cases and controls ].
AB  - BACKGROUND: Several population studies have shown that patients with neural tube
      defects (NTD), have a higher frequency of a genetic mutation related with
      thermolability of the enzyme 5,10-metylentetrahydrofolate reductase (MTHFR).
      There are regional and ethnic variations in the genotypic or allelic frequency of
      this mutation and its possible relationship with NTD and others congenital
      anomalies. AIM: To estimate the frequency of the C677T polymorphism of MTHFR in
      control women and mothers of spina bifida cases. PATIENTS AND METHODS: We
      analyzed 58 blood samples from mothers who had a child diagnosed with spina
      bifida. A group of 184 healthy mothers matched by age and with no NTD offspring
      served as controls. We determined the C677T polymorphism on the MTHFR gene by
      means of PCR and the analysis of the digestion pattern of HinfI restriction
      enzyme. RESULTS: The genotypic frequencies showed concordance with Hardy-Weinberg
      equilibrium, in controls (p = 0.35), and in mothers of the cases (p = 0.95). The
      odds ratio to the TT genotype compared with the CC genotype (reference category)
      was estimated as 1.54 (IC 95%: 0.66-3.61), while the odds ratio for the TC
      genotype compared with CC genotype was 1.06 (IC 95%: 0.48-2.33). CONCLUSION: No
      differences in the C677T polymorphism of the MTHFR were observed between mothers
      who had a child diagnosed with spina bifida and control mothers.

PMID- 15022403
TI  - [Mutations in the Fibroblast Growth Factor Receptor 3 gene (FGFR3) in Chilean
      patients with idiopathic short stature, hypochondroplasia and achondroplasia].
AB  - BACKGROUND: Achondroplasia and hypochondroplasia are skeletal dysplasias of
      autosomal dominant inheritance that represent different degrees of severity of
      the same pathological entity. Both dysplasias are caused by mutations in the
      Fibroblast Growth Factor Receptor 3 (FGFR3) gene. In achondroplasia more than 95%
      of the cases studied to date carry the same mutation (G380R). Hypochondroplasia
      represents a greater clinical and genetic heterogeneity, possibly being confused
      with "idiopathic short stature". The N540K mutation has been detected in 50-70%
      of cases of hypochondroplasia and mutations at the 650 locus in approximately
      2.8%. AIM: To assess the frequency of N540K and G380R mutations, and changes at
      the 650 locus in Chilean patients with idiopathic disproportionate short stature,
      hypochondroplasia and achondroplasia. PATIENTS AND METHODS: We studied 21
      patients referred for idiopathic short stature, 5 with clinically suspected
      hypochondroplasia and 4 with achondroplasia. The G1138A, G1138C (G380R), and
      C1620, C1620A (N540K) mutations and the nucleotide changes at the 650 locus were
      studied using PCR and restriction analysis of genomic DNA. RESULTS: Three out of
      five hypochondroplasia patients were heterozygous for the N540K mutation. All of
      the 4 patients with achondroplasia presented the G1138A mutation. None of these
      mutations were found in patients with idiopathic short stature. CONCLUSION:
      Chilean patients with hypochondroplasia and achondroplasia have the same
      mutations described in other ethnic groups. The identification of mutations in 3
      out of 5 patients with hypochondroplasia shows that this analysis is a useful
      tool for its diagnostic confirmation. In short stature the molecular study should
      only be indicated in those cases presenting other clinical and/or radiological
      features of hypochondroplasia.

PMID- 15022404
TI  - [A diagnostic approach to hepatic abscess].
AB  - BACKGROUND: The non invasive diagnosis of amebic liver abscess allows the use of
      empirical therapy without the requirement of invasive diagnostic procedures. AIM:
      To determine the discriminatory capacity of clinical, laboratory and ultrasound
      studies for the etiological diagnosis of liver abscess. PATIENTS AND METHODS:
      Sixty one patients were initially included in this prospective study, but 12 did
      not comply with the inclusion criteria. Of the rest, 29 (59%) had an amebic liver
      abscess, 16 (33%) had a pyogenic liver abscess and four (8%) had an abscess of
      mixed etiology. Blood cultures were done in 42 patients. Ultrasound guided needle
      aspiration was done in 7 patients with amebic liver abscess and 13 patients with
      non amebic liver abscess. RESULTS: The clinical picture and ultrasound findings
      were similar in all types of amebic abscess. ELISA test for IgG anti-Entamoeba
      histolytica antibodies were positive in 100% of patients with amebic liver
      abscess. Antibodies measured by gel diffusion were positive in 93%. All patients
      with mixed liver abscess had positive antibodies and some of them positive
      culture. Blood cultures were positive for anaerobic bacteria in five patients.
      Cultures of aspirated material were positive in 7 patients (obligate anaerobic
      bacteria in 3 and facultative anaerobic bacteria in the rest). The most common
      complications, whatever the etiology, were right pleural effusion and systemic
      inflammatory response. CONCLUSIONS: A final model of binomial regression analysis
      revealed that age under 40 years, an hematocrit greater than 35% and an elevation
      in prothrombin time of less than 1.5 seconds had enough discriminatory capacity
      for the diagnosis of amoebic liver abscess.

PMID- 15022405
TI  - [Assessment of clinical diagnostic accuracy for skin cancer].
AB  - BACKGROUND: There is an increase in the incidence rates of skin cancer in Chile.
      AIM: To study the clinical diagnostic accuracy (CDA) for skin cancer. MATERIAL
      AND METHODS: CDA was defined as the percentage of agreement between clinical and
      pathological diagnosis. Approximately 600,000 pathological reports from five
      hospitals in Santiago were reviewed. A total of 2,593 skin tumours; 230 Malignant
      Melanoma (MM); 412 Squamous Cell Carcinoma (SCC) and 1,951 Basal Cell Carcinoma
      (BCC) were studied. These tumours were clinically diagnosed and surgically
      treated by dermatologists. The CDA was studied for each tumour, by the anatomical
      localization of the tumour, Breslow Index in MM, by age and sex of the patient.
      RESULTS: The highest CDA was observed for BCC (76.2%); followed by MM (64.3%) and
      SCC (34.7%). By anatomical localization, for MM the highest CDA was observed in
      the soles (p < 0.05); for BCC, the highest CDA was in the face (p < 0.05). No
      significant differences were observed in SCC. By age, for MM, the CDA was higher
      in patients aged less than 50 years. No differences in CDA by age were observed
      in the other two tumours. By sex, no differences were found. A higher CDA was
      found in MM with Breslow indexes III and IV than for MM with Breslow indexes I
      and II. CONCLUSIONS: CDA is affected by the clinical variables analyzed in this
      study. A more accurate clinical diagnosis of skin cancer could be obtained taking
      into account these variables.

PMID- 15022406
TI  - [Orthostatic hypotension: an unusual manifestation of pheochromocytoma].
AB  - Pheochromocytoma, though an uncommon cause of hypertension, can be a lethal
      condition. Because of this it is mandatory to diagnose it or rule it out in
      presence of suggestive symptoms. Typical symptoms are palpitations, sweating,
      severe headaches and hypertension. However, there are other suggestive symptoms
      of this dangerous endocrine entity, one of which is the orthostatic hypotension.
      We report the case of a 65 years old female patient with long standing
      hypertension in whom the pheochromocytoma was suspected after episodes of
      orthostatic hypotension. Although this manifestation was described almost fifty
      years ago, its frequency and pathophysiology has not yet been well established
      and fully elucidated. Moreover, it has meaningful implications in relation to
      preoperatory management and the timing of surgery.

PMID- 15022407
TI  - [Decompressive craniectomy in a patient with herpetic encephalitis associated to
      refractory intracranial hypertension].
AB  - Herpetic encephalitis is the most common cause of viral encephalitis in our
      country. Pathological studies show progressive necrosis and edema in specific
      territories of the brain. The mortality of herpetic encephalitis was reduced from
      70% to 20% with the use of intravenous aciclovir in the first three days of
      illness. However, almost 50% of patients develop a neurological deficit. One of
      the most important causes of death in herpetic encephalitis is the refractory
      intracranial hypertension. There are anecdotal reports of patients with
      refractory intracranial hypertension due to herpetic encephalitis that were
      treated with decompressive craniectomy with good results. We report a 21 years
      old female patient with herpetic encephalitis and refractory intracranial
      hypertension that was successfully treated with a decompressive craniectomy.

PMID- 15022408
TI  - [Acquired aplastic anemia of the adult. Treatment of 2 cases].
AB  - Severe aplastic anemia has an elevated mortality if treatment is unsatisfactory.
      Immunosuppression is the treatment of choice in adults, comparable with
      allogeneic bone marrow transplant in children. We report two adult patients (both
      males, aged 59 and 67 years old) who were treated successfully with
      lymphoglobulin and cyclosporine. The initial response started within 3 months of
      treatment and was almost complete after 2 years, when cyclosporine was stopped.
      After three years, both patients have almost normal blood counts, with minor
      sequels: avascular necrosis of both femoral heads due to the use steroids, that
      recovered spontaneously in 1 patient and reduced vision due to thrombocytopenic
      retinal hemorrhages, in the other.

PMID- 15022409
TI  - [New immunological weapons for medicine in the 21st Century: biological therapy
      based on the use of the latest generation monoclonal antibodies].
AB  - The fusion of a murine B cell and a myeloma cell generates a hybridoma that
      produces monoclonal antibody (mAb). These murine mAb induce the HAMA (human anti
      mouse antibodies) response. Murine mAb have been modified by genetic engineering,
      producing molecules with a higher proportion of human protein. At present,
      chimeric, humanized and fully human mAb are available. mAb block interactions
      between target molecules and their ligands or trigger the lyses of mAb-coated
      tumor cells. Numerous mAb have been developed using the recombinant DNA
      technology and several are available in the market. Trastuzumab, against
      HER2/neu, is useful in breast cancer; rituximab, against CD20 in B lymphocytes is
      useful in lymphoma; alemtuzumah, against CD52 is used in lymphoma and leukemia;
      daclizumab and basiliximab block the IL-2 receptor interaction and reduce acute
      rejection in kidney transplantation; abciximab, an antagonist of GPIIb/IIIa
      platelet receptor, is used in patients undergoing acute coronary syndromes. In
      autoimmunity diseases, blocking tumor necrosis factor by infliximab and
      adalimumab has demonstrated excellent results. Thus, infliximab is useful in the
      treatment of rheumatoid arthritis (RA), Crohn's disease and ulcerative colitis
      while adalimumab is the first fully human mAb available for RA. Infliximab and
      adalimumab reduce signs and symptoms in RA and they also interfere with
      progression of joint damage. Finally, the direct benefits of antagonist treatment
      can occur at the expense of a major adverse effect in some other biological
      function.

PMID- 15022410
TI  - [The impact of domestic violence on children's health].
AB  - BACKGROUND: There is close association between maltreatment during pregnancy and
      child abuse after birth. AIM: To compare anthropometric growth and use of health
      services of children whose mothers suffered maltreatment with children coming
      from families without domestic violence. SUBJECTS AND METHODS: A longitudinal
      study of two cohorts. An index groups formed by 76 children whose mothers
      experienced maltreatment and control group of 46 children coming from families
      without domestic violence. Data was obtained from patient files in private health
      centers. RESULTS: Respiratory diseases were the most prevalent cause of
      consultation and hospital admission. Children in the index group had a 2.8 times
      higher risk of bronchopneumonia in the post natal period and a poor attendance to
      health care controls. In four children, cerebral contusion was registered as the
      cause of hospital admission. CONCLUSIONS: Domestic violence is associated with a
      higher risk of respiratory diseases and hospital admissions in children. New
      strategies are necessary to detect and prevent child abuse and neglect.

PMID- 15022411
TI  - [The physician and the conflict of interest].
AB  - Conflicts of interest are frequent in medical practice. They occur when a
      secondary interest unduly influences professional medical judgment, over and
      above the patients' benefit, his first real interest. Most of these secondary
      interests come from particular businesses of the physicians or their
      relationships with the industry. They may become a threat to the confidence that
      is established in the patient-physician relationship or to the medical profession
      as a whole. These conflicts of interest vary in types and magnitude and are not
      recognized by physicians on most occasions. Solutions are inevitably related to
      the honesty and integrity of each physician. Due to the absence of specific
      national ethical references, it is necessary to discuss the issue and conclude
      recommendations that guide interns, residents, clinicians, researchers, medical
      educators, medical and scientific associations to resolve these types of
      conflicts.

PMID- 15022413
TI  - [Pedophilia. An endocrinologic point of view].

PMID- 15022412
TI  - [On the ownership of medical records].

PMID- 15022414
TI  - [Etymology and phonetics of medical terms].

PMID- 15022415
TI  - Anti-psychotics worsen mental decline.

PMID- 15022417
TI  - Faint praise.

PMID- 15022416
TI  - No more deaths.

PMID- 15022419
TI  - Fighting mad.

PMID- 15022418
TI  - Why not?

PMID- 15022420
TI  - Talking cure.

PMID- 15022421
TI  - Welfare writes.

PMID- 15022422
TI  - Abuse of trust.

PMID- 15022423
TI  - A sense of purpose.

PMID- 15022424
TI  - Medicine for the soul.

PMID- 15022425
TI  - Terms and conditions.

PMID- 15022426
TI  - Where's the evidence?

PMID- 15022427
TI  - Loose nuts.

PMID- 15022428
TI  - [Diagnosis of ocular sarcoidosis].

PMID- 15022429
TI  - [Effect of various anti-glaucoma eyedrops on human corneal epithelial cells].
AB  - PURPOSE: To investigate the effects of antiglaucoma eyedrops and vehicles on the
      proliferation of human corneal epithelial cells. MATERIAL AND METHODS: Seven
      eyedrops[prostaglandin F2 alpha analogs(2), beta blockers(40), topical carbonic
      anhydrase inhibitor(1)], and six of the eyedrop vehicles, excluding that of
      Xalatan, were used. Anti-glaucoma eyedrops and vehicles were serially diluted 2
      fold with culture medium(10-2,560 fold). The mixture was added to human corneal
      epithelial cells and incubated for 48 hrs. Cell proliferation was measured by
      commercial assay kit. Dye-reagents were added to the wells and incubated for 1 h
      at 37 degrees C. Optical density were measured at 490 nm. The dilution rate for
      50% inhibition was calculated as the dilution rate of drugs or vehicles necessary
      to produce 50% inhibition of cell proliferation. RESULT: All drugs completely
      inhibited cell proliferation when the dilution rate was low. At 40-fold dilution,
      Trusopt and Timoptol showed a significant decrease in cell growth inhibition. On
      the other hand, Rescula showed almost 100% inhibition at 160-fold dilution. Above
      640-fold dilution, the inhibition rate of all drugs became 50% or less and there
      was no significant difference between drugs. Vehicles also inhibited cell growth.
      The dilution rates for growth inhibition by vehicles were different from those of
      drugs. The dilution rate at 50% inhibition of anti-glaucoma eyedrops decreased in
      the following order: Rescula > Xalatan > Betoptic > Hypadil > Mikelan > Timoptol
      > Trusopt. The dilution rate for 50% inhibition of vehicles decreased in the
      following order: Rescula vehicle > Hypadil vehicle > Betoptic vehicle > Mikelan
      vehicle > Timoptol vehicle > Trusopt vehicle. CONCLUSION: All anti-glaucoma
      eyedrops inhibited cell proliferation. These effects were stronger in
      prostaglandin F2 alpha analogs and weakest in Trusopt. Furthermore, the
      inhibition of cell proliferation was caused also by the vehicle of eyedrops, and
      the influence of the vehicle varied in each type of eyedrops.

PMID- 15022430
TI  - [Multifocal electroretinograms in patients with retinal vein occlusion].
AB  - PURPOSE: To investigate waveform changes of multifocal electroretinograms(mERG)
      in patients with retinal vein occlusion(RVO). METHODS: Nine eyes of 8 patients
      with RVO and 29 eyes of 29 normal subjects were examined using mERG. An array of
      103 hexagonal elements was displayed on a monitor. mERG latencies(ms) and
      response densities (nV/deg2) were measured for center area(Ct) and for each of
      four quadrant areas. The peak and troughs were named N1, P1 and N2,
      consecutively. RESULTS: In pathological quadrants, although the response
      densities were abnormal in only one eye, latencies of the N2 and P1 were
      prolonged in 7 eyes and in 2 eyes, respectively(over 1 SD-2 SD). The latencies
      were significantly prolonged compared with those of normal eyes(p < or = 0.03, U
      test). On the other hand, in the central area, although the latencies were
      abnormal in 3 eyes, the response densities were reduced in 6 eyes(over 1 SD-2
      SD). The response densities were significantly reduced compared with those of
      normal eyes(p < or = 0.024, U-test). CONCLUSIONS: Both peak latencies in
      pathological quadrants and response densities in the central retinal area can be
      sensitive indicators of retinal dysfunction caused by RVO. The mERG system is
      useful for detecting local retinal dysfunction in patients with RVO.

PMID- 15022431
TI  - [Intravitreal injection of triamcinolone acetonide for cystoid macular edema
      resistant to vitreous surgery].
AB  - PURPOSE: To report the efficacy of intravitreal injection of triamcinolone
      acetonide(TA) for cystoid macular edema remaining after vitreous surgery.
      METHODS: Eight eyes of 7 patients aged from 32 to 84 years old were studied. The
      original diseases that caused macular edema were central retinal vein occlusion
      in 2 eyes, branch retinal vein occlusion in one eye, Irvine-Gass syndrome in 2
      eyes, and diabetic retinopathy in 3 eyes. 4 mg of TA was injected intravitreally
      and visual acuity and foveal thickness measured by optical coherence
      tomography(OCT) were evaluated in before and after the surgery. RESULTS: Macular
      edema resolved rapidly after injection of TA in all cases and cysts were
      extinguished or diminished. The foveal thickness in OCT was reduced significantly
      from preoperative 495 +/- 116 (mean +/- standard deviation) microns to 267 +/-
      117 microns after one week, and 246 +/- 81 microns after one month. The effect
      persisted for three months. Visual improvement of more than two Snellen lines was
      seen in 4 eyes. No side effects were observed except a temporary increase of
      intraocular pressure in one eye. CONCLUSION: Intravitreal injection of TA is
      effective in a short-term for cystoid macular edema remaining after vitrectomy.

PMID- 15022432
TI  - [Diagnosis of ocular sarcoidosis by diagnostic criteria for systemic
      sarcoidosis].
AB  - PURPOSE: To evaluate the diagnostic criteria for systemic sarcoidosis in
      diagnosis of ocular sarcoidosis. SUBJECTS AND METHODS: Subjects were 105 ocular
      sarcoidosis suspects and 37 patients with other uveitis. We diagnosed ocular
      sarcoidosis suspects using the diagnostic criteria for systemic sarcoidosis
      proposed by the Japanese Committee for Diffuse Lung Diseases. The criteria
      included histological and clinical diagnosis, and the clinical diagnosis required
      5 systemic tests: 1) tuberculin skin test, 2) serum gamma-globulin(gamma-gl), 3)
      serum angiotensin converting enzyme(ACE), 4) serum lysozyme, and 5) 67Ga
      scintigraphy. Three positive findings including either 1) or 3) fulfilled the
      clinical diagnosis. RESULTS: Sixty-two patients were histologically and/or
      clinically diagnosed, and 43 patients remained undiagnosed. The histological and
      clinical diagnosis did not produce the same diagnostic yields. The sensitivity of
      ACE and gamma-gl was low. The percentage of patients showing increased
      lymphocytosis and/or CD 4/8 in bronchoalveolar lavage was similarly high in the
      diagnosed and undiagnosed, suggesting the presence of definitive ocular
      sarcoidosis in the undiagnosed. CONCLUSIONS: The diagnostic criteria for systemic
      sarcoidosis yielded false negative results in diagnosing ocular sarcoidosis. The
      selection and combination of systemic tests for clinical diagnosis should be
      further studied.

PMID- 15022433
TI  - [Postoperative results of non-penetrating trabeculectomy for primary open-angle
      glaucoma].
AB  - PURPOSE: To estimate the postoperative results of non-penetrating
      trabeculectomy(NPT), the success rate of postoperative intraocular pressure(IOP)
      and the clinical factors affecting postoperative IOP were evaluated. SUBJECTS AND
      METHODS: 32 eyes of 32 primary open-angle glaucoma(POAG) patients who underwent
      NPT as the first filtering surgery were enrolled in the study. We evaluated
      postoperative IOP using the Kaplan-Meier method, a proportional hazard model, and
      multiple logistic analysis. RESULTS: 53.2% of all patients had an IOP of less
      than 16 mmHg without antiglaucoma medication, and 63.8% had an IOP of less than
      16 mmHg with antiglaucoma medication 36 months postoperatively. The performance
      of Nd:YAG trabeculopuncture(YLT) was indicated as a significant factor affecting
      postoperative IOP by the proportional hazard model(p = 0.037). 72.2% of patients
      who did not undergo YLT had an IOP of less than 16 mmHg without antiglaucoma
      medication, and 36.5% who underwent YLT had a postoperative IOP of less than 16
      mmHg. There was significant difference between the both groups(log rank test, p =
      0.045). Preoperative IOP with antiglaucoma medication was indicated as a
      significant factor affecting performance of YLT by multiple logistic analysis.
      CONCLUSION: These results suggest that NPT may be useful to reduce the use of
      antiglaucoma medication in patients with POAG whose preoperative IOP is
      controllable with antiglaucoma medication.

PMID- 15022434
TI  - [Two cases of orbital myositis with monoclonal gammopathy of undetermined
      significance].
AB  - PURPOSE: We report two cases of idiopathic orbital myositis with monoclonal
      gammopathy. CASE: Case one was a 47-year-old man, who had bilateral swelling of
      the extraocular muscles and impairment of the left optic nerve. Case two was a 27
      year-old woman, who had bilateral proptosis. An immunological test showed that
      both patients had monoclonal gammopathy, and they were diagnosed as having
      monoclonal gammopathy of undetermined significance(MGUS). RESULTS: In case one,
      the patient achieved remission with steroid pulse therapy followed by
      administration of high doses of a steroid. In case two, because of repeated
      recurrence, the patient was treated with steroid pulse therapy and then radiation
      therapy to achieve final remission. CONCLUSION: We need to pay attention in the
      diagnosis of orbital myositis to distinguish MGUS. Such patients have an atypical
      clinical course and are resistant to ordinary steroid therapy.

PMID- 15022436
TI  - [ Urology is a basic specialty].

PMID- 15022435
TI  - [Histopathological study of lattice corneal dystrophy with L 527 R mutation of
      transforming growth factor-beta induced gene].
AB  - PURPOSE: A histopathological study of lattice corneal dystrophy with L 527 R
      mutation of exon 12 on transforming growth factor-beta induced gene(TGFBI).
      PATIENT AND METHODS: The patient was a 66-year-old woman with lattice corneal
      dystrophy. Gene analysis and histopathological study of corneal tissue obtained
      at the corneal transplantation were performed. Mutation analysis was done for
      exon 4, 11, and 12 on the TGFBI gene by direct sequencing. A histological study
      was performed by light microscopy with hematoxylin-eosin staining, dylon
      staining, or congo red staining, and by electron microscopy. RESULTS: Gene
      analysis revealed L 527 R mutation of exon 12 on the TGFBI gene. Light
      microscopic examination showed dylon-positive and Congo red-positive amyloid
      deposit from the superficial to deep layer of the corneal stroma. In transmission
      electron microscopy, the corneal epithelial layer, the basement membrane of the
      epithelium, Descemet's membrane, and the corneal endothelium were normal, but
      irregularity of Bowman's membrane and amyloid fibers in the corneal stroma were
      observed. CONCLUSION: Lattice corneal dystrophy due to L 527 R mutation showed
      histopathological findings similar to those of lattice corneal dystrophy type
      III.

PMID- 15022437
TI  - [Diagnosis and treatment of bladder cancer].
AB  - The authors present a retrospective analysis of the results of transurethral
      conservative and radical operations in 125 patients with invasive cancer of the
      urinary bladder (UB) treated in the Research Institute of Urology throughout 1992
      2002. Transurethral resection (TUR) of the UB was made in 72 patients. Stages
      pT2a, pT2b, T3 and T4 were diagnosed in 23 (31.9%), 18 (25%), 14 (19.5%) and 17
      (23.6%) cases, respectively. 53 patients with advanced invasive UB cancer have
      undergone radical cystectomy varying by the method of urine derivation. Stages
      pT2N0M0, pT3aN0M0, pT3bN0M0, pT4aN0M0 and N1-2 were registered in 4 (7.5%), 13
      (25%), 21 (40%), 7 (12.5%) and 8 (15%) patients, respectively. UB cancer
      recurrences after TUR occurred in 12 (16.7%) patients with stage pT2a, in 8
      (11.1%) patients with stage pT2b. Three-year overall and recurrence-free survival
      after TUR at stage T2 reached 97.5 +/- 3.2 and 47.4 +/- 2.8, respectively, at
      stage T3 and T4--57.1 +/- 4.3 and 26.6 +/- 3.4%, respectively. Postcystectomy
      distant metastases to the lungs, bones and iliac lymph nodes after treatment were
      detected in 3, 2 and 3 patients, respectively. One patient had a local pelvic
      recurrence. For all 53 patients a 2-year corrected survival made up 68 +/- 12.0%.
      Thus, transurethral electrosurgery is an effective treatment of invasive UB
      cancer; the only radical surgical treatment for invasive UB cancer is cystectomy.

PMID- 15022438
TI  - [Vascular endothelial growth factor and insulin-like-growth factors in prostate
      cancer. ].
AB  - To study the levels of vascular endothelium growth factor (VEGF), insulin-like
      growth factor of type I and II (IGF-I and IGF-II), prostate-specific antigen
      (PSA) and their correlations in prostatic cancer (PC) and benign prostatic
      hyperplasia (BPH), we examined 38 PC patients (mean age 66.6 +/- 5.5 years) and
      80 BPH patients (mean age 60.3 +/- 2.5 years). Serum concentrations of VEGF, IGF
      I and IGF-II were measured using kits made by R&D (USA), PSA by Boehringer
      Mannheim (Germany). Sensitivity and specificity of the tests were analysed by
      plotting the curves. The serum VEGF concentration in PC patients was 518.9 +/-
      60.7 pkg/ml, in BPH patients--267.9 +/- 99.9 pkg/ml (p < 0.001). The IGF-I and
      IGF-II it was 178 +/- 19 and 136 +/- 9 ng/ml (p < 0.05), 400 +/- 31 and 351 +/-
      23 ng/ml (p < 0.05), respectively. The ratio of growth factor concentration to
      PSA concentration in the blood serum in BPH patients was higher than in PC
      patients (p < 0.01). Sensitivity and specificity of PSA (4 ng/ml) made up 85.7
      and 57%, VEGF (151.5 pg/ml)--76.2 and 57.6%, IGF-I (157 ng/ml)--57.6 and 50%; IGF
      II (392 ng/ml)--57.5 and 50%, respectively. Sensitivity and specificity VEGF/PSA
      was 85.7 and 70%; IGF-I/PSA--84.2 and 75%; IGF-II/PSA--84.2 and 79.6%,
      respectively. Thus, the ratio of concentrations of IGF-I, IGF-II and VEGF to PSA
      level in blood serum has high sensitivity and specificity for PC detection.
      Clinical implications of serum levels of VEGF, IGF-I and IGF-II for prediction of
      PC course and detection is to be elicited.

PMID- 15022439
TI  - ["I-125 Rapid-Strand" interstitial radiotherapy of localised prostate cancer].
AB  - Nikolai Alekseevich Lopatkin, Academician of the Russian Academy of Medical
      Sciences, has contributed much to development of prostatic cancer (PC) diagnosis
      and treatment in the Russian Federation. N. A. Lopatkin headed specialists from
      the Research Institute of Urology who were the first in Russia to introduce into
      clinical practice the method of interstitial radiotherapy (brachitherapy) of
      local prostatic cancer (PC). A total of 58 PC patients 42 to 76 years of age were
      treated. They had stages T1bN0M0 (n = 5), T2aN0M0 (n = 36), T2bN0M0 (n = 11),
      T3aN0M0 (n = 6). Staging was made by the data of finger rectal examination,
      transrectal ultrasonography, NMR tomography, radionuclide osteoscintigraphy. Mean
      PSA was 2.5-36 ng/ml in the size of the prostatic gland 14.96-52.76 cm3. All the
      patients received neoadjuvant hormone therapy. Four patients one year or more
      before the radiotherapy had TUR of the prostate. Brachytherapy was made under
      peridural anesthesia which allowed implantation of 40-120 sources with activity
      of 0.38-0.35 mCi for 20-45 min. A total dose was 120-160 Gy. Mean hospital stay
      was 4 days. Spontaneous urination recovered within 6 postoperative hours. The
      procedure was well tolerated, complications arose on postimplantation day 2-8. We
      attribute complications to inadequate calculation of the doses at the stage of
      the method introduction. A short follow-up (3 years) is not long enough to allow
      conclusions about the efficacy of the method. Within 3 years biochemical
      recurrence occurred in 4 (6.9%) patients on months 14-26 (stage T2b and 2-T3).
      Four patients were lost for follow-up. Thus, brachytherapy efficacy depended much
      on adequate selection of the patients and planning of the procedure by the
      results of previous volumetry. The procedure is safe and reproducible. The
      studies will be continued.

PMID- 15022440
TI  - [Metastases from renal tumor to adrenals].
AB  - The aim of the study was assessment of diagnosis and surgical treatment of
      adrenal metastases (AM) of renal carcinoma (RC). 10 cases of RC AM have been
      analysed. Bilateral metastases were diagnosed in 2 patients, ipsilateral in 5
      patients, contralateral in 3. Three patients had synchronous metastases, seven
      had metachronous ones. AM were detected 8 months to 14 years after after
      operation on the kidney. Non-invasive dynamic control over the retroperitoneal
      space after nephrectomy for RC using advanced visual methods (ultrasonography, x
      ray and resonance magnetic CT) not only detects AM but also determines metastatic
      genesis of the tumor. Thus, significant verification of RC AM, especially of
      metachronous origin, requires the study of the findings obtained at clinical,
      laboratory, ultrasonic, radiation examinations as well as comparison of
      histological structure of the removed kidney tumor and the adrenal. Early
      diagnosis and removal of a solitary adrenal metastasis of RC provides
      prolongation of the patient's life and survival of patients with RC late stages.

PMID- 15022441
TI  - [Operative treatment of benign prostate hyperplasia: modern aspects].
AB  - A retrospective analysis was made of the treatment results for the last 5 years
      of 879 patients with benign prostatic hyperplasia (BPH), 214 (24.3%) of whom had
      undergone transvesical adenomectomy while 665 (75.7%) had undergone transurethral
      resection (TUR) of the prostate. Adenomectomy had rather high effectiveness but
      was less safe than endoscopic intervention (higher lethality, more frequent
      development of myocardial infarction, pulmonary artery thromboembolism,
      postoperative hemorrhage). Patients operated for BPH are at risk of postoperative
      urethral stricture and sclerosis of urinary bladder cervix. Prebladder and
      postoperative stress urine incontinence appear only after open operations in BPH.

PMID- 15022442
TI  - [Operative treatment of kidney calculi].
AB  - 262 cases of coral nephrolithiasis (CN) treated for the last 5 years (mean age
      51.6 years) have been analysed. Of them, 46 (17.9%) patients have undergone 2 to
      4 operations, 14 (5.4%) patients had bilateral nephrolithiasis. Open surgical
      interventions (section nephrolithotomy, pyelonephrolithotomy) were performed in
      31 and 106 patients, respectively. All of them had a severe form K-3 or K-4.
      Extracorporeal shock-wave lithotrophy (ESWL) was conducted in 72 (27.5%) patients
      with coral concrements K-1, K-2. 'Mean number of the procedures per a stone was
      4.2. Transcutaneous puncture nephrolithotripsy (TPNT) was made in 53 (20.2%)
      patients (K-2, K-3). The results of the treatment were assessed at discharge and
      12 months after it. The efficacy of the treatment was judged by completeness of
      the stone elimination, postoperative complications and interventions to correct
      these complications. Open operations eliminated the stones completely in 71.2%
      patients, in combination with ESWL--in 91.6%, TPNT--in 78%, in combination with
      ESWL--in 94.5%. Efficacy of ESWL as monotherapy + stent reached 68.1%. Open
      operations entailed complications in 41.6% (of them 68.5% in section
      nephrolithotomy), TPNT--in 18.2%, ESWL--in 16.3%. Coral nephrolithiasis should be
      treated by skilled specialists in clinics furnished with modern facilities,
      combination of which minimizes traumatic complications and raises treatment
      efficacy.

PMID- 15022443
TI  - [Use of extracorporeal shockwave lithotripsy for kidney calculi].
AB  - 278 patients with coral nephrolithiasis were examined in 1990-2003.
      Extracorporeal shock-wave lithotripsy was made in 46 (16.5%) patients with 48
      coral stones (mean age 48.2 +/- 18.3 years) as a basic treatment. The length of
      the concrement was 4.9 +/- 1.8 cm, width 3.8 +/- 1.4 cm, a relative area 19.72 +/
      13.01 cm2. All the patients have initially undergone internal drain of the
      kidney by a catheter (n = 13) or stent (n = 33). Each lithotripsy session
      included, on the average, 2882 +/- 318 impulses (17-19 kV). The number of high
      energy impulses per a session comprised 342 +/- 23. A total number of the
      sessions reached 3.4 +/- 1.55. Initial destruction of the concrement requires 1.6
      +/- 0.6 sessions in 10144 +/- 1081.2 impulses per one patient including 1436 +/-
      96.6 high-energy impulses. One procedure comprises 2-3 sessions of lithotripsy
      with a 5-7 day interval. The results were assessed at discharge after the first
      session and 6 months later, the degree of stones elimination from the kidney,
      complications, manipulations to manage the complications. At discharge after 3
      lithotripsy sessions recovery was achieved only in 3 out of 46 (6.52%) patients.
      Six months later the fragments eliminated in 26.1% (12 of 46 patients).
      Monolithotripsy caused complications in 13 patients. Additional manipulations
      made up 65.2%. Inefficacy of explorative treatment necessitated conversion to
      open intervention in 6 (13.1% 0 patients. The use of extracorporeal lithotripsy
      as a monotherapy in coral nephrolithiasis is now limited.

PMID- 15022444
TI  - [Ureterocele and urolithiasis].
AB  - We studied 51 patients with true ureterocele (primarily, orthotopic and
      unilateral--84.3 and 82.3%, respectively) combined with urolithiasis. Mean age of
      the patients was 41.9 +/- 2.0 years, size of ureterocele--20.7 +/- 1.3 mm and
      mean concrement area--1.4 +/- 0.2 cm2. In adult patients with orthotopic or
      heterotopic disease surgery consisted of perforation (n = 5) or dissection of
      ureterocele wall (n = 38). Endoscopic operations were indicated in small and
      middle sized ureterocele (less than 30 mm in size), unaffected contractility of
      terminal ureter, moderate urodynamic disorders of the upper urinary tracts,
      normal function of the kidney and no pyelonephritis exacerbation. Endoscopic
      section of ureterocele wall combined with ureterolithoextraction (n = 26),
      contact ureterolithotripsy using Ho:YAG laser or ultrasound (n = 19). Open
      surgery (ureterocystoneostomy by Politano-Leadbetter was made in orthotopic
      ureterocele over 30 mm in size and in marked urodynamic disturbances of the upper
      urinary tracts (n = 6). At discharge, a complete elimination of the stones in
      ureterocele patients was 81.6%. Effective use of extracorporeal shock-wave
      lithotripsy of nephroliths within 2 months after removal of ureterocele raised
      this percent to 87.7. Thus, choice of surgical policy in ureterocele complicated
      by urolithiasis depends on its size, variant of combination of this defect with
      the concrement, anatomofunctional state of the upper and lower urinary tracts,
      age of the patient and presence of pyelonephritis.

PMID- 15022445
TI  - [Comparative analysis of open and endoscopic operative procedures outcomes for
      posterior urethra obliteration in males].
AB  - Endoscopic recanalization of posterior urethra (PU) obliteration (a novel method)
      was compared to open reconstructive-plastic operations. 242 patients with PU and
      vesicular cervix obliterations entered the study. 93 patients of group 1 have
      undergone open reconstructive-plastic operations, 149 patients of group 2 were
      operated endoscopically (endoscopic recanalization under transrectal ultrasonic
      control). Before surgery the patients were examined using standard tests,
      sonourethrography and intraoperative transurethral ultrasonic investigation were
      added. Recurrence rate in group 1 and 2 was 29.1 and 16.8%, respectively. The
      following complications were observed in group 1: acute pyelonephritis (22.5%),
      enuresis (14%), orchoepididymitis (9.7%), urinary fistulas (5.4%). The patients
      needed long-term postoperative immobilization (10-16 days, mean 14.8 +/- 1.1
      days). After endoscopic recanalization under transrectal ultrasonic control,
      group 2 patients developed acute pyelonephritis (4.8%), orchoepididymitis (4%),
      orthostatic enuresis (4%), short-term urethral fever (85.9%). Bed regime in this
      group was necessary for 1-2 days (1.3 +/- 0.4 days). Mean postoperative hospital
      stay was 2.5-fold less in group 2. The conclusion is made that endoscopic
      recanalization under transrectal ultrasonic control has advantages over open
      reconstructive-plastic surgery: less frequent pyoinflammatory complications,
      enuresis, the absence of such complications as impotence, short penis, formation
      of urinary fistulas.

PMID- 15022446
TI  - [Endoscopic and X-ray endoscopic technologies in urology].
AB  - Present-day urology in the Russian Federation combines achievements of classic
      surgery with innovations of the last two decades which radically changed
      approaches to treatment of many urological diseases. Wide introduction in
      clinical practice of low invasive endoscopic and roentgenoendoscopic
      (endourologic) techniques is a standard for urology progress worldwide. N. A.
      Lopatkin, academician of Russian Academy of Medical Sciences, contributed much to
      advances of domestic urology. He has organized endourological service as a basis
      of further technological progress, introduction of low-invasive methods
      alternative to traumatic open surgical interventions.

PMID- 15022447
TI  - [Modern aspects of child urology].
AB  - Basing on the results of modern investigations applied preoperatively,
      postoperatively and for 20 years of follow-up in more than 36,000 children with
      urogenital diseases, the author believes that further progress of childhood
      urology should advance in the scope of general urology. He proposes basic
      principles underlying decision making on the treatment of urological diseases in
      different age groups. It is shown that many open and endoscopic interventions
      used in the adults are converted into pediatric urological practice disregarding
      pathogenetic and compensatory features in urological diseases in children. Basing
      on specific features of the course of compensatory processes in various age
      groups of children, new terms of corrective operations are proposed.

PMID- 15022448
TI  - [Vesicoureteral reflux in children with hypoplastic kidney].
AB  - Reconstructive plastic operations were conducted in 54 children aged 1 to 14
      years. The children were followed up for 1 to 17 years. In 40 patients reflux
      into the hypoplastic kidney combined with anomaly or another disease of the
      contralateral kidney, in 10 patients--with infravesical obstruction. The
      examination included clinical and laboratory tests, ultrasound diagnosis, x-ray,
      radionuclide investigation, uroflowmetry, on demand cystoscopy. Assessment of
      surgery results was made by function of the hypoplastic kidney and growth of its
      parenchyme, urodynamics, clinical symptoms of pyelonephritis. A good result was
      achieved in 41%, satisfactory--in 39 and unsatisfactory--in 20% patients. Thus,
      timely surgical elimination of vesicoureteral reflux enables effective treatment
      of chronic pyelonephritis, produces a positive action on urodynamics and renal
      parenchyma growth.

PMID- 15022449
TI  - [Treatment of ureteral vast obliteration after kidney transplantation].
AB  - Ureteral ischemia is one of the causes of obliterations arising after kidney
      transplantation. Reureterocystoanastomosis does not solve the problem of
      ischemia. Ureteropyelostomy with the recipient's ureter is the most effective
      open surgical intervention. Choice of operation is made with consideration of
      specific features of blood supply. If the use of own recipient's ureters is
      impossible, pyelocystostomy with Boari flap is indicated for allograft's rescue.

PMID- 15022450
TI  - [Use of ureteral stents in patients with kidney transplantation].
AB  - The aim of the study was to determine indications for application of ureteral
      stents for draining urinary tracts of the renal transplant, after low-invasive
      surgical interventions, for timing drainage, prevention and correction of
      complications. Ureteral stent insertion for management of urological
      complications after transplantation of the kidney was made in 36 patients (25 of
      them have ureteral stricture, 11 had ureteral necrosis). Low-invasive operations
      were made in 28 patients, open reconstructive plastic operations were conducted
      in 12 patients. According to 6-12 follow-up of the stented patients, recurrent
      ureteral stricture was detected only in 4 patients (11.1%). The stricture was
      corrected transcutaneously by antegrade ureteral stenting. It is concluded that
      stenting of the urinary tracts of the transplanted kidney in the treatment of
      urological complications--necrosis and ureteral stricture--in the course of low
      invasive roentgenoendoscopic and open reconstructive-plastic operations raises
      treatment efficacy and prevents recurrent stricture.

PMID- 15022451
TI  - [Alterations in expression of F-actin and DNA of fluid shear stress treated
      mesenchymal stem cells affected by titanium particles loading].
AB  - Particulate wear debris within the bone-prosthesis microenvironment generated by
      normal wear and corrosion of orthopaedic implants is considered to be one of the
      main factors responsible for chronic aseptic inflammation and development of
      osteolysis in the long-term instability and failure of total joint arthroplasty.
      While the decrease in bone volume caused by wear debris-induced osteolysis could
      have been compensated by enough new bone matrix secreted by osteoblasts.
      Actually, the normal osteoblastic population depend on the regular
      differentiation and proliferation of their progenitor cells--bone marrow
      mesenchymal stem cells (MSCs). This study aims to investigate the potential
      mechanism for the rat MSCs cytotoxicity upon exposure to Titanium (Ti) particles.
      Rat mesenchymal stem cells (rMSCs) isolated from 3-month-old male Sprague-Dawley
      rats by Percoll intensity gradient method were cultured in DMEM medium (low
      glucose) supplemented with 10% fetal bovine serum, 100 U/ml penicillin, and 100
      micrograms/ml streptomycin in a humidified incubator with 5% CO2 at 37 degrees C.
      In order to gain the homogenous cell population, rMSCs were passaged to 3-4th
      subpassage which were used in all the experiment groups. Then rMSCs were seeded
      in the 6 well culture plates and exposed to three different circle diameters
      (mean size, TD1: 0.9 micron, TD2: 2.7 microns, TD3: 6.9 microns) with three
      different concentrations (0.1 wt%, 0.05 wt%, 0.01 wt%, W/V) at different
      durations (8 h, 16 h, 24 h,), respectively. Unexposed rMSCs were used as control.
      In the given periods of Ti loading, fluid shear stress (FSS) was applied to each
      group cells. The expression of F-actin and DNA of the rMSCs at the indicated time
      were determined with laser confocal scanning microscopy and image analysis
      software. The results showed that there was up-regulation expression of F-actin
      in the rMSCs without Ti particles loading but in the presence of FSS. Ti
      particles loading can suppress the expression of F-action and DNA of rMSCs, but
      this down-regulation response varied with the three circle diameter,
      concentrations and durations of Ti particles. Among three kinds of diametrically
      different Ti particles, submicron Ti particles (0.9 micron) had the greatest
      suppressive response on rMSCs, together with some apoptosis bodies. Under the
      same diameter condition, the inhibition induced by Ti particles loading was in a
      manner dependent on the particles concentration and exposure duration. The
      reductive effects produced from 0.1 wt% Ti was the greatest and earliest among
      the responses from Ti particles at three different concentrations; and the lower
      the concentration, the weaker the repressive influence. Furthermore, with the
      elongation of exposure to Ti particles, the expression of F-actin and DNA
      decreased gradually, the lowest level was at 32 h. These findings demonstrated
      that Ti particles loading can attenuate rMSCs' viability in a manner dependent on
      the circle diameter, particles concentration, treatment period, suggesting that a
      reduction in the number of viable MSCs together with a compromise of the their
      differentiation into functional osteoblast may exacerbate aseptic loosening of
      total joint implant. Further investigation into particles-mediated suppression of
      MCSs viability may reveal novel mechanism of implant loosening and aid in
      development and application of osteolytic drug therapy and the optimization of
      design and selection of future orthopaedic biomaterials, thereby improving long
      term compatibility and stability for arthroplasty patients.

PMID- 15022452
TI  - [Effects of recombinant bovine basic fibroblast growth factor on osteoblast's
      growth and c-fos expression].
AB  - Rat's osteoblasts cultured in vitro were stimulated by recombinant bovine basic
      fibroblast growth factor(rb-bFGF). After 1-2 days, the osteoblast grew long
      protuberance, the numbers of osteoblasts were greater than the control groups',
      the vitality of osteoblasts was better than that of control groups. After 1 hour,
      the expression of c-fos in osteoblast increased when compared with that in the
      control group. After the osteoblasts having been stimulated for 1-2 days, the
      expression of c-fos increased more conspicuously. These results show that bFGF
      can boost the osteoblast to grow and proliferate and can enhance the expression
      of c-fos gene. The increase of c-fos gene's expression may be an important step
      in the signal transformation process of all kinds of stimulation boosting
      osteoblast to proliferate.

PMID- 15022453
TI  - [Probe into the platelets adhesion to carbonaceous biomaterials].
AB  - In order to clarify the mechanism of blood coagulation for carbonaceous
      biomaterials, the plasma rich in platelet was obtaining through the
      centrifugation of fresh human blood containing anticoagulant. Adhesive tests of
      platelets to surfaces of DLC, diamond film(DF) and graphite was carried out at 37
      degrees C. Then, morphology observation, counting and deformation index
      calculation of the platelets adhering to surfaces of the three kinds of materials
      were analyzed by SEM. It has been shown that there is no any platelet on the
      surface of DLC, but on DF and graphite, a lot of platelets are observed with
      serious deformation of type III-V. The adhesive amounts of platelet on the
      surface of graphite are more than those on DF, but deformation index of platelets
      on the surface of DF is more than that on graphite. Three major conclusions have
      been obtained through comparative analyses with our previous researches and
      related literatures: (1) Adhesion, deformation and collection of platelets
      occurred in succession on material surfaces resulting from protein adsorption are
      the major mechanism of blood coagulation of carbonaceous materials; (2)
      Deformation degree of platelets is more important hemocompatibility index than
      consumption ratio of platelets for carbonaceous materials; (3) The purer the DLC,
      the better is the hemocompatibility. These conclusions possess important
      directive function for improving and designing carbonaceous materials used in
      artificial mechanical heart valves.

PMID- 15022455
TI  - [Studies on synthesis and properties of N-benzoyl-THA targeting for brain].
AB  - It is the intent of these studies to synthesize acylated prodrugs of tacrine
      hydrochloride for improving the penetrating ability across the blood-brain
      barrier (BBB). Prodrugs of tacrine were prepared by benzoylation of the 9 amino
      group of THA. The structures of the synthesized prodrugs were determined by IR,
      1H NMR, MS and UV. Their physical-chemical properties and stability under
      different conditions were investigated. The function of prodrugs targeting for
      brain were evaluated in vitro by biopartition micellar chromatography (BMC). The
      results showed that prodrugs were stable in different environments. Ethyl
      acetate/water partition coefficient indicated that the lipophilicity of prodrugs
      was increased, compared with THA. BMC predicted that prodrugs could improve the
      infiltration ability across BBB of parent-drug. It was suggested that this kind
      of prodrugs be a promising brain-targeting delivery system.

PMID- 15022456
TI  - [Study on a new antarthritic injection--O-carboxymethyl chitosan].
AB  - A type of water-soluble carboxymethyl chitosan (O--CMC), with 76% degree of
      substitution determined by conductivity method, was prepared by using
      chloroacetic acid to react with C6-OH of chitosan. The solubility of O--CMC was
      characterized also. Animal experiment in rabbits showed that O--CMC could
      lubricate arthron, inhibit proliferation of fibroblast cells on rabbits' knee
      joints, benefit the process of repairing pathologic articular cartilage, and
      produce good therapeutic effect on rheumatoid arthritis.

PMID- 15022457
TI  - [Axis registration and image interpolation of rotary scanning echocardiogram].
AB  - The object of this study was to work at accurate axis registration and
      interpolation methods for multi-dimension reconstruction of rotary scanning
      ultrasonic medical images. At first, time-field curves of the images' axes were
      analyzed according to their characteristic points and the axial direction
      registration was realized. Similar matrix was used to find registration pixels
      line near the axes of two images. Auto-correlation function and Fourier spectrum
      were used to evaluate the effects of axes registration. Second, an interpolation
      method was studied for the special space distribution of rotary scanning images.
      Results of experiments indicate that the axes registration and interpolation
      methods were suitable to rotary scanning medical images. The quality of
      reconstruction can be greatly improved by registration-based interpolation
      methods.

PMID- 15022454
TI  - [A pilot study on the culture and differentiation of bone marrow stromal cells
      from SD rats].
AB  - In order to observe the growth, expansion and differentiation of the cultured
      bone marrow stromal cells (BMSC), we isolated the BMSC from adult SD rats and
      cultivated them with LIF and bFGF. Then, we cultured and induced the stem cells
      by using retinoic acid and the culture medium confected in our lab by ourselves.
      We found that the BMSC could expand and generate clones when they were cultured
      in vitro. These cells subcultured grew rapidly and differentiated into neuron
      like cells and astrocyte-like cells. The results showed that BMSC have the
      abilities to self renew and differentiate, thus demonstrating the culture method
      we used is suitable for the culture of BMSC in vitro. The bone marrow stromal
      cell is not difficult to obtain; it is capable of expanding and differentiating
      in culture. If the culture condition is appropriate, it can differentiate into
      neuron and astrocyte. So, it is a kind of perfect seed cells.

PMID- 15022458
TI  - [Time-dependent increase of interleukin-8 production in endothelial cells exposed
      to fluid shear stress].
AB  - Fluid shear stress plays an important role in many physiological and pathological
      processes of the cardiovascular system. Being constantly exposed to mechanical
      shear stress, vascular endothelial cells can sense the changes of blood flow
      forces and regulate vascular structure and function. Previous studies
      demonstrated that IL-8 mRNA expression in endothelial cells was modulated by
      fluid shear stress. To identify the effect of fluid shear stress on IL-8 protein
      production of human umbilical vein endothelial cells (HUVECs), we employed
      quantitative sandwich enzyme-linked immunosorbent assay (ELISA) to measure the IL
      8 protein. It was found that the HUVECs not treated with fluid shear stress
      secreted very little IL-8 in culture media. However, after 1 hour of exposure to
      shear stress, the secretion of IL-8 increased; at 5 hours of exposure, the
      seceretion reached the summit; at 8 hours of exposure, the secretion of IL-8
      decreased and then remained at a constant level till the end (12 hours) of the
      experiment. The increase of IL-8 secretion induced by shear stress was time
      dependent. The biphasic response of IL-8 protein production was found in
      experiments in which the shear stress applied was 2.09 dyne/cm2, 4.61 dyne/cm2,
      and 6.19 dyne/cm2. The IL-8 protein production in response to shear stress was
      very similar to the IL-8 gene expression in response to shear stress, and had the
      obvious delay. The induction of IL-8 protein production by fluid shear stress is
      probably due to the gene expression. This in vitro study demonstrates that the
      production of IL-8 can be regulated by fluid shear stress. Fluid shear stress
      induces a biphasic response of human HUVECs' production of IL-8 protein. These
      observations suggest that the process of the fluid shear stress induced HUVECs'
      production of IL-8 may play an important role in the genesis and development of
      both inflammation and atherosclerosis.

PMID- 15022460
TI  - [Biocompatibility study of the UV surface modified Dacron material].
AB  - The enzyme histochemistry method was used in this experiment to study the
      biocompatibility of the UV surface modified Dacron. The activity of the enzymes
      such as ALP, ACP, NADHD and LDH in the tissue surrounding both the modified and
      unmodified materials after a certain implantation period was semiquantitatively
      measured. The results showed that the biocompatibility of the surface modified
      Dacron was as good as that of the unmodified one.

PMID- 15022459
TI  - [Constructing tandem-repeated sequence of nucleic acid and evaluating its signal
      amplification action].
AB  - Tandem-repeated sequence of nucleic acid was constructed by splicing 4 fragments
      which contain the same sequence in the central part, using overlap extension
      polymerase chain reaction and then repeatedly cloning it in the same vector at
      different site of restriction endonuclease. Its signal amplification action was
      evaluated using electrophoresis of hybridized product and dot hybridization
      assay. 24-repeat sequence was successfully constructed and confirmed by
      restriction endonuclease digestion analysis. The construct was 25-repeat actually
      since the vector itself had the same basic sequence. Hybridized product
      electrophoresis revealed that the 25-repeat sequence could combine with several
      secondary probes. Dot hybridization assay demonstrated that tandem-repeated
      sequence was 16-fold more sensitive than that of non-repeated sequence. Tandem
      repeated sequence had good effect on signal amplification. It could be easily
      cheaply prepared in large amount after cloning. Thus, it might be useful in
      clinical examinations and biological researches.

PMID- 15022461
TI  - [A biomechanic study on the relapse after sagittal split and oblique osteotomy of
      Ramus].
AB  - The relapse after orthognathic surgery was frequently reported in recent years.
      But up to now researches concerning bio-mechanic mechanism of relapse are rare.
      The purpose of this study, by imitating the operation on monkeys, was to examine
      the biomechanical properties and histological characteristics after operation in
      order to investigate the mechanism of the relapse after orthognathic surgery. 20
      rhesus monkeys divided into two groups were subjected to bilateral sagittal split
      and oblique osteotomy, respectively. The broken strength, stress and strain of
      the operated sites were examined with the use of biomechanical methods, and the
      healing scab was observed using histological method and SEM at 3, 6, 12, 24 weeks
      after operation. The results obtained demonstrated that bone healing and
      biomechanical properties reached certain level after 6 to 12 weeks' recovery in
      both operation groups; the biomechanical properties and histological
      characteristics recovered faster in sagittal split group than in oblique
      osteotomy group. Histological examination also demonstrated similar results. From
      the data above it is suggested that the higher relapse rate in sagittal split may
      more closely related to the mechanical effect different from the scab healing,
      although 8 weeks' fixation may meet the requirement of clinical treatment,
      accessory fixation method should be adopted after the removal of inter-maxilla
      fixation.

PMID- 15022462
TI  - [Antigen expression and the endothelization of biologic blood vessel matrix].
AB  - This study sought to explore the change of the major histocompatibility complex
      (MHC) antigen expression and the endothelization of blood vessel in minor pig
      after trypsin treatment, and to provide data for xenotransplantation and pig
      vessel for use in tissue engineering. Western blot assays were conducted for
      detecting the expression of MHC xenoantigens. Scanning electron microscopy was
      used for checking the endothelization of decellularized blood vessel. The results
      showed that MHC antigen is not expressed after trypsin treatment. The
      endothelization is accomplished. The endothelial cells have normal morphological
      distribution. These demonstrate that the antigen of pig aorta is significantly
      decreased and it can be used for constructing new vascular grafts.

PMID- 15022463
TI  - [Study on high strength mica-based machinable glass-ceramic].
AB  - The phase constitution, microstructure and properties of a new type of machinable
      glass-ceramics containing fluorophlogopite-type (FPT) Ca-mica for used in
      restorative dentistry were investigated. According to the results of X-ray
      diffraction (XRD) and energy-dispersive spectrometry(EDS), its main crystalline
      phases were FPT Ca-mica and t-ZrO2, together with few KxCa(1-x)/2Mg2Si4O10F2, m
      ZrO2. The flexible strength was 235 MPa, which was nearly two times larger than
      that of the present mica-based dental materials, and the highest fracture
      toughness was 2.17 MPa.m1/2. The microstructure had a great effect on properties,
      the glass-ceramics contained a large volume, and the fine crystals showed higher
      strength. The material possessed typical microstructure of machinable glass
      ceramics and displayed excellent machinability during drilling test and CAD/CAM.

PMID- 15022464
TI  - [Prospect of the foveola formation in the bovine trabecular bone under fatigue
      process].
AB  - This study aims at the mechanism of foveola formation in bovine trabecular bone
      under fatigue process and its relation with biomechanical pathogenesis of senile
      osteoporosis. The scanning electron microscope equipped with fatigue stage was
      used to observe fatigue micro injury accumulation of cancellous bone. The massive
      foveola formation in the laminal bone of vertical trabeculae was found in the
      tensile fatigue test. There existed the collagen avulsion in the foveola. The
      massive foveola formation was also observed in the lamina bone of the horizontal
      trabeculae in the compressive fatigue test. The bone collagen fibers were
      protracted, debound with hydroxyapatite crystal, and then avulsed under tensile
      and bending stresses. Finally the retraction of the avulsed collagen fibers
      brought on the massive formation of foveolae in lamina bone. The mechanical
      capacity of bone also declined greatly. We infer that the direct mineralization
      of avulsed collagen and foveola in lamina bone would be one of the main processes
      of self repair in vivo, which brings on the increase in fragility and stiffness
      of trabeculae of senile osteoporotic bone along with the agelong accumulation of
      collagen fatigue injury and foveola formation in the lamina bone.

PMID- 15022466
TI  - [The advantages of bovine jugular vein tanned with hydrophilia crosslinking
      agent].
AB  - The bovine jugular veins were divided into two groups and treated with 4% EX-313
      and 0.5% glutaraldehyde respectively, and then they were examined with naked-eye,
      microscope and scanning electron microscope. Biomechnics test and dorsal
      implantation in rats were performed. The aquired data were processed and
      subjected to t-test. The EX-313 fixed material was more pliable than the
      glutaraldehyde treated material, and the former had higher anticalcification than
      the latter. In conclusion, the hydrophilia crosslinking agent EX-313 is superior
      to glutaraldehyde in treating biomaterials, and the bovine jugular vein tanned
      with EX-313 should be a promising material for repairing in cardiovascular
      surgery.

PMID- 15022465
TI  - [Investigation of machinable-infiltrated-ceramic glass infiltrating through the
      aluminous matrix].
AB  - This investigation was amied at the infiltrative capability of the machinable
      infiltrated-ceramic(MIC) glass and the color of the composite after the MIC glass
      infiltrated through the aluminous matrix with different packing densities. By
      heating the components to 1100 degrees C for 2 hours, the MIC glass was made to
      infiltrate through the aluminous matrix with different packing densities. We
      measured the infiltrative depth and the color parameter and observed the rupture
      surface of the composite by means of SEM. There was a linear relation between the
      square of infiltrative depth and the packing density of aluminous matrix. The
      minimal depth was 3.092 mm. No relationship was noted between the composite's
      color coefficient and the packing density of aluminous matrix. In the rupture
      process of the composite, crack deflexion, crystal evulsion, and rupture through
      crystal could be observed. This experiment proved that the infiltrative
      characters of MIC glass meet the clinical requirement, the composite's color is
      steady and the mechanical intensity is stable.

PMID- 15022467
TI  - [An experiment to study the treatment of sarcomas by electroporation].
AB  - In this paper is reported a new approach for the treatment of sarcoma-
      electroporation therapy. Electroporation can accelerate pharmacal molecules into
      cytoplasm by transient electromagnetic pulses. We have utilized the phenomenon of
      electroporation treating the S-180 sarcomas in the hind legs of the Kunming mice
      by intratumoral injection of anti-tumor agent at low dose. From the experiment,
      we learned that this approach can bring about remarkable effect. The technical
      procedure is easy to do and easy to control. Especially, it is useful in curing
      the flat tumor and has little untoward side effect. It deserves to be recommended
      as a new approach to treating the tumor in clinics.

PMID- 15022468
TI  - [Study on viscosity property of gastrointestinal mucus].
AB  - To probe further into the viscosity of gastrointestinal mucus, the samples of
      gastrointestinal mucus were taken from fifty normal people and were tested with
      Low-Shear 30 viscometer, and then the viscosity model was obtained. The results
      indicated that the apparent viscosity of large intestine mucus is greater than
      that of small intestine and stomach. The gastrointestinal mucus is a kind of non
      Newtonian fluid when its apparent viscosity rapidly decreases with the increase
      of shear rate. When the shear rate increase well enough, the apparent viscosity
      of gastrointestinal mucus becomes a constant, and the gastrointestinal mucus
      appears to be a Newtonian fluid.

PMID- 15022469
TI  - [Treatment and mechanism study of electromagnetic stimulation and vibrational
      massage for patients with ejaculatory incompetence].
AB  - Studies on the effective methods and mechanism for the treatment of patients with
      functional ejaculatory incompetence were pursued on the basis of clinical
      practice. 90 patients with functional ejaculatory incompetence were treated by
      giving the electromagnetic stimulation to their pudendal nerve and the
      vibrational massage to their penis. Then the excitation conductive time and
      velocity of their pudendal nerve were simultaneously determined by the electro
      neurophysiology technique. Of the 90 patients with functional ejaculatory
      incompetence, 69(76.7%) obtained cured effects, 19(21.1%) notable effects and
      2(2.2%) improved effects. The total effective rate was 100%. The excitation
      conductive time and velocity of their pudendal nerve were both significantly
      different from those before treatment (P < 0.05). These suggest that it is
      practical to reach the ejaculatory threshold, trigger the ejaculatory reflex and
      complete the process of ejaculation because the nerve with improved excitational
      conductibility may release more acetylcholine from is endings after the
      electromagnetic stimulation to nerve and the vibrational massage to penis.

PMID- 15022471
TI  - [Study of correlation dimension on EEG].
AB  - The study of non-linear EEG is of great significance in clinical practice and
      research work. This paper has gone into the feasibility of calculating the
      correlation dimension and has developed some subjects with the characters of
      correlation dimension and the difference under four conditions: (1) passive eyes
      closed(PEC); (2) mental arithmetic with eyes closed(MAEC); (3) passive eyes
      open(PEO); (4) mental reasoning with eyes open (MRED). The results show it is
      feasible and meaningful to calculate correlation dimension and the correlation
      dimension can reflect the regular patterns of mental activity.

PMID- 15022470
TI  - [Cloning, expression and purification of rabbit metallothionein-I gene in
      Escherichia coli].
AB  - The cDNA encoding the rabbit metallothionein-I was amplified by RT-PCR from the
      rabbit liver induced by cadmium and cloned into prokaryotic fusion expression
      vector pQE40. Then it was transformed into Escherichia coli M15. Positive
      expression clones were detected by colony blotting. Target protein solubility was
      determined by Western blotting analysis. The optimal induction condition of the
      level of protein expression with IPTG induction was established by SDS-PAGE
      electrophoresis and ImageMaster VDS software analysis. The fusion protein can be
      purified from lysates with Ni-NTA agarose. We found that the fusion protein with
      apparent molecular weight 32 KD existed in two ways: soluble and insoluble in
      Escherichia coli. After 1 mM IPTG induction, the level of expression of the
      fusion protein increased with the prolongation of induction time and reached a
      peak in 9 h by ImageMaster VDS software analysis, accounting for 57.4% of all the
      insoluble protein. The purified fusion protein was obtained by Ni-NTA affinity
      chromatography. This fusion protein can be used in further studies on the
      preparation of MT-I protein and development of protein product.

PMID- 15022472
TI  - [Study on the 3D mathematical mode of the muscle groups applied to human mandible
      by a linear programming method].
AB  - Four types of 3D mathematical mode of the muscle groups applied to the human
      mandible have been developed. One is based on electromyography (EMG) and the
      others are based on linear programming with different objective function. Each
      model contains 26 muscle forces and two joint forces, allowing simulation of
      static bite forces and concomitant joint reaction forces for various bite point
      locations and mandibular positions. In this paper, the method of image processing
      to measure the position and direction of muscle forces according to 3D CAD model
      was built with CT data. Matlab optimization toolbox is applied to solve the three
      modes based on linear programming. Results show that the model with an objective
      function requiring a minimum sum of the tensions in the muscles is reasonable and
      agrees very well with the normal physiology activity.

PMID- 15022473
TI  - [An approach based on wavelet transform to removal of noises].
AB  - The electrocardiac signals exhibit obvious unsteadiness and contain many noises
      in the processing of detecting. In this paper, a wavelet transform, which can be
      located in the fields of time and frequency, is introduced to decompose the ECG
      signals on multi-scales. In characteristic scales, the electrocardiac signals can
      be decomposed. After removal of various noises, the electrocardiac signals are
      formed again perfectly. This method provides more accurate ECG data for use in
      medical diagnosis.

PMID- 15022474
TI  - [Experimental study on brain-computer interface based on visual evoked
      potentials].
AB  - Brain-computer interface is a novel EEG-based communication and control system
      between human brain and computer or some other electric device, which has found
      important applications in many fields such as rehabilitation engineering. Study
      has been done in brain-computer interface using visual evoked potentials(VEP).
      Multiple stimulation patterns were produced on the computer screen through
      programming. Several flickering blocks were adopted for representing a number of
      possible selections, and when the subject was fixing his(her) eyes on an object
      on the screen, the very object could be distinguished by the analysis of the
      VEPs. Surface electrodes were placed at Oz of the inion and Cz to collect VEP.
      The wavelet filter and averaging method was used to extract VEP signal. Off-line
      experimental data analysis indicated that the proposed method may be valuable for
      developing real brain-computer interface with relatively high accuracy and speed,
      and the information transfer rates could be higher than 30 bit/min when 12
      selections were on the screen.

PMID- 15022475
TI  - [Power density analysis on millimeter waves irradiated into cell monolayers in
      culture dishes].
AB  - Biological effects of millimeter waves (MMWs) at the cellular level are explored
      in experiments using culture dishes containing cell monolayers with MMW
      irradiated from the underneath. Analysis is carried out for culture dishes with
      diameters much larger than the MMW wavelength to discover the relation between
      the portion of the incident MMW power density (PD) irradiated into the cell
      monolayer and the interfering factors such as the bottom thickness of the culture
      dish, the MMW wavelength, and the electromagnetic parameters of the dish and
      culture solution. With the help of the finite-difference time-domain (FDTD)
      technique, another analysis is performed to display the effect of the dish
      geometries upon the MMW PD irradiated into the cell monolayer in a specific
      culture dish with a diameter similar to the MMW wavelength. The results indicate
      that rigorous analysis, precise measurement and accurate calculation of MMW PD
      are essential accompaniments for these experiments, and large-diameter culture
      dishes are more preferred in experiments to small-caliber ones.

PMID- 15022476
TI  - [The influence of Ce on microstructures and mechanics performances of Ti-Fe-Mo-Mn
      Nb-Zr alloys].
AB  - The influences of Ce on the microstructure and mechanics performances of Ti-Fe-Mo
      Mn-Nb-Zr alloys were studied and presented in this paper. The microstructure of
      no-Ce Ti-Fe-Mo-Mn-Nb-Zr alloy was thick, long and dendritic, and the
      microstructure of alloy was fined by Ce. With the increase in Ce wt%, the
      microstructure became equiaxial gradually. Hardness decreased with the increase
      in Ce wt%. The compression yield strength became greater with the increasing of
      Ce wt%, but after the Ce wt% increased to a certian degree, the compression yield
      strength became smaller with the further increasing of Ce wt%. This phenomenon
      was explained in the light of bond energy and X-ray diffraction experiment. X-ray
      diffraction experiment showed that the alloys were beta-Ti.

PMID- 15022477
TI  - [Research on relationships of gastric cancer with serum trace elements,
      Helicobacter pylori and COX-2 in gastric tissue].
AB  - The relationships of gastric cancer with serum trace elements, helicobacter
      pylori (HP) and COX-2 in gastric tissue were investigated. We took 50 blood
      samples from the gastric cancer patients in Hexi region (the gastric cancer
      group), and 50 blood samples from healthy volunteers (control group) and detected
      the level of trace elements, the rate of HP infection, and the expression of COX
      2 in gastric tissue. The results showed the levels of Cu/Zn, Fe in the serum of
      the gastric cancer group were higher than those of the control group
      respectively(P < 0.05, 0.01), and the levels of Zn, Mn were lower than those of
      the control group respectively (P < 0.05, 0.01). The data on Zn were submitted to
      multi-variate non-conditional logistic analysis. The rate of HP infection and the
      positive expression of COX-2 were 88% and 78% respectively in the gastric cancer
      group, 42.0% and 0 in the control group (P < 0.01). These findings suggest that
      the decrease of Zn in serum may be a precancerous factor of gastric cancer
      development which induces HP infection and the higher expression of COX-2 and
      hence may lead to the development of gastric cancer. Detecting the trace elements
      could conduce to the diagnosis of gastric cancer. Regulating the level of trace
      element in the patient can be an effective chemoprophylaxis for gastric cancer.

PMID- 15022479
TI  - [Surface modification of poly methyl methacrylate intraocular lens by alpha-allyl
      glucoside].
AB  - A method for improving the biocompatibility of the intraocular lens (IOL) and
      reducing the cell attachment was adopted in this study. The alpha-Allyl glucoside
      was used for the surface modification of the poly methyl methacrylate (PMMA) IOL
      by way of plasma-induced in situ polymerization. The surfaces of the control and
      treatment IOLs were characterized by contact angle estimation and ESCA
      techniques. The resolution, diopter and anti-fatigue of loops were determined by
      physical and optical methods. Cell attachment on the surfaces was examined by
      light microscopy. The results indicated that all of the treatment groups had
      excellent physical and optical properties. The modification with the use of alpha
      Allyl glucoside could improve the hydrophilicity of the anterior surface of the
      PMMA IOLs and reduce the cell attachment.

PMID- 15022478
TI  - [Comparison between hemolysis percentage measurement and hemiglobincyanide
      measurement for standardizing the evaluation of hemolytic properties of
      biomaterials].
AB  - In this study, two methods--the supernatant hemoglobin spectrophotometry, i.e.
      hemolysis percentage measurement(according to ISO/TR 7405) and the
      hemiglobincyanide measurement(according to ISO 10993-4)--were used to assay the
      hemolytic properties of hydroxyapatite(bioceramics) and collagen (polymer). The
      results showed that the conclusions drawn from using the two methods were
      basically consistent, and the latter was more sensitive, stable and comparable.
      However, some of the procedures in the hemiglobincyanide method were not defined
      in details. So based on our experiments we have offered some suggestions and
      improvements, which do not deviate from ISO and ASTM standards, for hiher
      practicability of usig it in standardizing the evaluation of the hemolytic
      properties of biomaterials. Hemiglobincyanide measurement is worthy of wider
      application.

PMID- 15022480
TI  - [Application of image identification technology to the analysis system of gene
      chip and image processing by VB].
AB  - Because of the anomalous points distributed in the image, gene chip is hard to be
      distinguished effectively in fact. This article offers some arithmetic of image
      processing by VB such as increasing contrast, self-adapt thresholds, two-values
      and searching for spares and disperse templet which can distinguish all kinds of
      gene chip quickly, well and truly.

PMID- 15022481
TI  - [Studies on crosslinkable coatings for biomedical application].
AB  - A novel crosslinkable coating for biomedical device was prepared by
      copolymerization of the constituent monomers via a free radical method. 1H-NMR
      and IR results indicated it had desirable structure. Surface characterization
      revealed that surface reorganization occurred in aqueous environment and a
      polyethylene oxied (PEO) enrichment surface was developed on coated surface. The
      in-vitro platelet-adhesion test and the plasma recalcification time(PRT)
      determination showed that the coated surface could resist the blood coagulation
      effectively.

PMID- 15022482
TI  - [Study on the distributed integration of the HIS and PACS based on CORBA].
AB  - In medical clinical practice, physicians need to acquire the image and text
      information of the patient. All the information will be of benefit for physicians
      to diagnose disease, improve clinical treatment, and do research work. But the
      information is distributed in different systems, such as medical image
      information in PACS (Picture Archiving and Communication System) and text records
      in HIS (Hospital Information System). Today many hospitals are suffering from
      lack of an integrated system with PACS and HIS. This paper compares PACS with HIS
      and puts forward a distributed integration method of integrating the PACS and HIS
      with the prevailing WWW technology. In such a method, the image and the text
      information are regarded as the common object and the operation whereon as the
      object operation. Thus the method integrates the PACS with HIS effectively and
      implements the information resources sharing with the use of web technology.

PMID- 15022483
TI  - [Research on the feasibility of a magnetic-coupling-driven axial flow blood
      pump].
AB  - A new-designed axial flow blood pump, dived by magnetic coupling and using
      internal hollow brushless DC motor and inlet and outlet in line with impeller,
      was tested in mimic circuit. The results showed good performance of the new pump
      and indicated that its hydrodynamic characteristic can meet the demands of
      clinical extracorporeal circulation and auxiliary circulation.

PMID- 15022484
TI  - [Design a computer program of calculating the normal tissue complication
      probability].
AB  - We have established a computer model of calculating the normal tissue
      complication probability (NTCP) in line with the current primary methods and have
      designed the relevant software. Consequently, the complex calculation becomes
      easy, thus facilitating the clinical use of NTCP and improving the model step by
      step.

PMID- 15022485
TI  - [Application of RNA interference technique in the research of mammalian cells and
      human disease].
AB  - RNA interference provides a new approach for elucidation of gene function. It
      holds the advantages of quickness, convenience, high effect and high specificity.
      In spite of these, the application of RNA interference technique in studying the
      mammalian cells and human disease is still in the beginning. In this paper, a
      review of the development of RNA interference in mammalian cells and human
      disease is presented.

PMID- 15022486
TI  - [Researches in forensic biomechanics].
AB  - Forensic biomechanics is the science of proof, which applies the biomechanical
      theory and technology to resolve problems related to mechanics in the process of
      expert witness. It belongs to the realm of a new subject combining biomechanics
      and forensics. Forensic biomechanics is a new branch of modern biomechanics and
      at the same time a new important branch of forensics, and it is one of the most
      potential research areas in forensics of injury. In this paper, the task of
      forensic biomechanics expert witness, the procedure of expert witness, and the
      forensic biomechanics research methods and cases are reviewed.

PMID- 15022487
TI  - [Bioartificial liver support system: state of the art].
AB  - The temporary function replacement and intensive support play a pivotal role in
      the treatment of patients with acute or chronic end-stage organ failure. The
      hemodialysis and peritoneal dialysis have become routine techniques in the
      management of acute or chronic renal failure. But for the complexity of hepatic
      function, e.g. metabolism, biosynthesis and biotransformation for endogenous or
      exogenous substrates, the simulation or partial replacement of hepatic function
      is a great dream of bionic technologists. With the development of cell biology
      and biomedical material, the combination of biomaterial and the hepatocyte
      cultured ex vivo could provide a range of human liver-specific functions. The
      combination of biomaterial and viable cell was called hybrid or bioartificial
      liver support system (BALSS). It is a chimera of biomaterials and hepatocytes.
      The bionic technologists study the cell and its culture in vitro, which is the
      main component of BASLL. Many types of BALSS were translated into the early
      clinical stage. In this overview, we review the hepatocyte culture and the design
      of different bioreactors. It includes the immune obstacles in xeno-hemoperfusion
      and how to assess pre-clinical and clinical effectiveness.

PMID- 15022488
TI  - [Development of biodegradable and bioabsorbable bone-repaired materials].
AB  - This paper reviews recent work on biodegradable and bioabsorbable materials,
      including macromolecular, inorganic, and compound materials which have been used
      as bone-repaired devices. The properties and uses of poly(lactic acid), chitin
      and tricalcium phosphate are expounded. At the same time, we discuss the trend in
      the development of biodegradable and bioabsorbable bone-repaired materials. In
      our opinion, the development of biodegradable and bioabsorbable bone-repaired
      materials forcuses on the composite of different materials, especially the
      composite of BMP and MSCs; on the improvement of the mechanical properties of
      materials; and on the search for new suitable materials.

PMID- 15022489
TI  - [Progress in the studies on hydrogel burn dressings].
AB  - Synthetic burn dressing remains the central theme for burn dressing development.
      The advantages and disadvantages of current available dressings were reviewed. As
      one of the most successful dressings, the hydrogel burn dressing, its combination
      with other materials and related progress in researches were presented in detail.
      Finally, the trend in development of synthetic burn dressing was presented.

PMID- 15022490
TI  - [Application of atomic force microscopy in cell biology].
AB  - The atomic force microscopy(AFM), an important instrument for the study of cell
      biology, has been used to image the living cells and localize the cell surface
      receptors under physiological conditions by perfect high resolution. It was also
      utilized in the investigations of the cytoskeleton, biological process and
      interactions between cells. The applications of AFM in cell biology have been
      achieved greatly in recent years and many results present a good promise in
      biomedical and clinical medical fields.

PMID- 15022491
TI  - [The relationship between metoclopramide and hypothalamus-pituitary-thyroid axis
      and it's clinical application].
AB  - TSH secretion is controlled by the stimulatory action of hypothalamic TRH and the
      inhibition via central dopaminergic and somatostatinergic mechanisms as well as
      by a hypothalamic inhibitory action of thyroid hormones. Metoclopramide is DA2
      receptor blockade which can accelerate to elevate the concentration of serum TSH
      in hypothyroidism, which is accompanied by a progressive loss of dopaminergic
      tone as demonstrated by a progressive increase in prolaction serum levels,
      especially in patients with differentiated thyroid carcinoma(DTC). So the period
      of L-thyroxine withdrawal is contracted and the symptoms of hypothyroidism is
      released. It's important to monitor and treat DTC patients with radioactive
      iodide.

PMID- 15022492
TI  - Cause for optimism.

PMID- 15022493
TI  - Functional focus.

PMID- 15022495
TI  - The pain fighters.

PMID- 15022494
TI  - More than a chair.

PMID- 15022496
TI  - Gateway to gait.

PMID- 15022497
TI  - Push for power.

PMID- 15022498
TI  - Kid-sized comfort.

PMID- 15022499
TI  - Using what works.

PMID- 15022500
TI  - HIPAA revisited.

PMID- 15022501
TI  - Adding choice to Medicare.

PMID- 15022502
TI  - Treating immunobullous diseases: an update.
AB  - Autoimmune bullous diseases are often associated with significant morbidity and
      some can even cause mortality, if left untreated. Multiple therapies are now
      available to treat these blistering conditions. However, few have been evaluated
      objectively.

PMID- 15022504
TI  - Preventing and treating intertrigo in the large skin folds of adults: a
      literature overview.
AB  - Intertrigo is an inflammatory dermatosis of the skin folds of the body, for which
      a large variety of topical medications may be recommended. A systematic
      literature review was performed to find scientific evidence for preventing and
      treating intertrigo within the nursing domain. Seven electronic databases were
      searched with a simple broad-scope search strategy. The aim was to identify all
      publications that concerned intertrigo itself and other conditions that were
      related to intertriginous regions. This search produced 451 references. A final
      set of 24 studies was retained and analyzed on content and methodologic quality.
      Most studies concerned treatments with antifungals or disinfectants in
      heterogeneous research samples, with only small subsamples of people with
      intertrigo. Six studies were randomized controlled trials. In general, the
      methodologic quality of the studies was poor. The analyzed studies provided no
      scientific evidence for any type of nursing prevention or treatment strategy.
      There is a great need for well-designed clinical studies on intertrigo.

PMID- 15022503
TI  - Total skin electron beam therapy and cutaneous T-cell lymphoma: a clinical guide
      for patients and staff.
AB  - Total skin electron beam therapy (TSEBT) is a technically complicated treatment
      used in the management of mycosis fungoides (MF). A variety of technical and
      clinically oriented issues relating to TSEBT and its effects for patients with MF
      are reviewed.

PMID- 15022505
TI  - Antigens Act I, Scene I.

PMID- 15022506
TI  - What's your assessment? Candidiasis.

PMID- 15022507
TI  - The wound healing process symphony: Part I.

PMID- 15022508
TI  - What's your assessment? Metastatic prostate cancer.

PMID- 15022509
TI  - Atrophic lichen planus.

PMID- 15022511
TI  - Steroid atrophy.

PMID- 15022510
TI  - Topical vitamin D analogs.
AB  - Calcipotriene offers a safe and effective option in the treatment of plaque
      psoriasis. It helps regulate the abnormal growth and production of keratinocytes,
      as well as has a number of effects on inflammation seen with psoriasis. When used
      as monotherapy or in combination with corticosteroids, it may help reduce the
      adverse effects seen with chronic steroid use. Calcipotriene is currently only
      indicated for plaque psoriasis; however, it has shown promise for use in a wide
      range of dermatologic conditions.

PMID- 15022513
TI  - Law and medicine. H.B. 310.

PMID- 15022514
TI  - The social impact of medicine. Chapter 15.

PMID- 15022512
TI  - Little league shoulder: case report and literature review.
AB  - When compared with adults, children have unique injury patterns secondary to
      their anatomical differences. The susceptibility of the growth plate to injury is
      well-documented. "Little Leaguer's shoulder" is the term used for injury to the
      open proximal humeral epiphysis in the Little League pitcher. We present a case
      report and literary review. Discussed are the possible etiologies, patient
      presentation, physical exam, radiographic findings, and treatment
      recommendations.

PMID- 15022515
TI  - In commitment to America's children.

PMID- 15022516
TI  - Unhealthy politics of oral health.

PMID- 15022517
TI  - New findings in preventing HIV-1 infection.

PMID- 15022518
TI  - Use of cholesterol drugs may decrease breast cancer risk.

PMID- 15022519
TI  - Women and depression in the workplace.

PMID- 15022520
TI  - Exercise may reduce risk of breast cancer.

PMID- 15022521
TI  - Disability self-assessment and upper quarter muscle balance between female dental
      hygienists and non-dental hygienists.
AB  - PURPOSE: The purpose of this pilot study was to compare disability self
      assessment and upper quarter muscle balance female dental hygienists and non
      dental hygienist females. The upper quarter was operationally defined as the
      shoulder and neck region. Muscle balance was operationally defined as muscle
      flexibility and muscle performance. METHODS: A convenience sample of 41 working
      dental hygienists and 46 non dental hygienists participated in the study. Muscle
      flexibility of the upper quarter was measured by inclinometry or standard muscle
      length testing. Muscle performance was measured by timing the duration of four
      statically maintained positions. Subjects filled out the Northwick Park Neck Pain
      Questionnaire (NPNPQ), which is a disability self-assessment. Analysis of
      Covariance (ANCOVA) was used during data analysis to adjust for the mean age
      difference between the dental hygienist group (38.0 years) and the non-dental
      hygienist group (29.3 years). RESULTS: The results of this pilot study suggest
      that female dental hygienists are more likely than non dental hygienist females
      to develop tightness in the upper trapezius (p = 0.007) and the levator scapula
      (p = 0.01) of the non dominant upper quarter and lower fibers of the pectoralis
      major of the dominant upper quarter (p = 0.03) Muscle performance trends in the
      dental hygienist group supported muscle balance theory that short muscles remain
      strong while lengthened muscles become weak. The dental hygienist group had
      higher disability scores in all nine parts of the NPNPQ compared to the non
      dental hygienist group, five of which were statistically significant (p < 0.05).
      CONCLUSION: The results of this pilot study suggest that muscle imbalances in the
      upper quarter are more common in female dental hygienists than in female non
      dental hygienists and may contribute to the numerous upper quarter pathologies
      associated with the practice of dental hygiene. Further research is needed to
      determine if upper quarter strengthening and flexibility exercises performed by
      dental hygienists can reduce disability self-assessment.

PMID- 15022522
TI  - Early childhood caries in an urban health department: an exploratory study.
AB  - PURPOSE: The purpose of this investigation was to assess the prevalence of early
      childhood caries (ECC) as a function of various ECC case definitions, in a
      population of children ages one to five, attending a Women, Infants, and Children
      (WIC) or well-child clinic at an urban health department. Additionally, the study
      examines the association of sociodemographic factors, caregiver's oral health
      perceptions, resources, feeding and oral care behaviors, and prenatal and
      perinatal histories as risk factors for early childhood caries. METHOD: A
      convenience sample of 74 children ages one to five years and their parent(s) or
      guardian(s) enrolled in the WIC and Well Child Services Program at the Kansas
      City Health Department participated in this study. Caries experience and
      developmental enamel defects of children were assessed utilizing the deft and
      linear enamel hypoplasia (LEH) indices. Additionally, the children's parents of
      guardians were asked to complete a questionnaire to collect data on predisposing
      risk factors. RESULTS: The proportion of all children with evidence of Type I ECC
      was high (31.5%), with all ethnic minority groups having a large proportion with
      caries. Four of the predisposing risk factor variables were related (p < 0.05) to
      presence of ECC-child's age, gender, age at weaning, and frequency of sweet
      drinks. Child's age and age at weaning were related to a significant increase in
      risk for caries when these effects were adjusted by the effect of other risk
      factor variables. The odds of having caries were increased by 2.3 times (95%, CI
      1.4, 3.9) for each increase in child's age by year, and by 2.8 times (95%, CI
      1.5, 5.2) for each incremental increase in age category for the child at weaning.
      CONCLUSION: This investigation lends further support to the contention that
      quantifying the occurrence of ECC is likely dependent and complicated by diverse
      case definitions. Caregiver's perceptions of their child's oral health were
      generally accurate, thereby supporting proponents for educational and preventive
      strategies aimed at the parent/guardian.

PMID- 15022523
TI  - The impact of Kansas House Bill 2724: perceptions of Kansas dental hygienists and
      dental assistants.
AB  - PURPOSE: Kansas House Bill 2724 (HB 2724), which allows dental assistants to
      perform coronal scaling, was passed by the Kansas legislature in the spring of
      1998. This bill was the legislature's way of addressing access to care and
      manpower issues, in relation to oral health care in Kansas. The intent of this
      study was to collect baseline data related to HB 2724. Specific purposes of this
      study were to, 1) compare overall perceptions of dental hygienists and scaling
      assistants related to HB 2724, 2) compare perceptions of dental hygienists and
      scaling assistants on how HD 2724 has addressed access to care and manpower
      issues, and 3) examine the impact of HB 2724 on the delivery of preventive care
      in underserved areas in Kansas. METHODS: This study employed a nonexperimental
      descriptive survey research design. Two survey instruments were developed
      consisting of Likert scale questions, demographic information, and closed and
      opened-ended questions. All registered Kansas dental hygienists, and dental
      assistants who had completed the training course approved by the Kansas Dental
      Board to perform coronal scaling of teeth, were chosen to participate. RESULTS: A
      total response rate of 38% for dental hygienists, and 42% for scaling assistants
      was achieved. Analyses were conducted to ensure validity and reliability of the
      two survey instruments, including factor analysis and internal reliability
      measures. In relation to overall satisfaction with career choices, both dental
      hygienists and scaling assistants reported being happy in their professions and
      respected by their dentist employers. The majority of dental hygiene respondents
      (79%) did not see HB 2724 addressing either access to care or manpower issues in
      the state, while in contrast a majority (89%) of scaling assistants believed that
      this was the best answer for Kansas in relation to access to care and manpower.
      In examining the impact of HB 2724 on delivery of preventive care in underserved
      areas of Kansas, this study found that the majority of scaling assistants
      reported practicing in metropolitan areas, as opposed to identified oral health
      care shortage areas in the state. CONCLUSIONS: While both dental hygienists and
      scaling assistants are satisfied with their career choices, this legislation does
      not appear to be addressing its main objectives-access to care and increased
      manpower in dentally underserved areas in Kansas.

PMID- 15022524
TI  - Radiographic detection of approximal caries: a comparison between senior dental
      students and senior dental hygiene students.
AB  - PURPOSE: Dental hygienists do not legally (or definitively) diagnose caries, but
      they often are responsible for preliminary interpretation of bitewing (BW)
      radiographs taken during prophylaxis appointments. Given this custom of practice,
      it is important to understand whether there is a difference between the
      capabilities of dental hygienists and dentists in interpreting BWs based on
      education and clinical experience. This study compared proximal carious lesion
      classification from BWs by senior dental students and senior dental hygiene
      students. METHODS AND MATERIALS: Volunteers (40 dental [D] and 54 dental hygiene
      [DH] students) classified proximal carious lesions from BWs of 96 extracted
      teeth, which were mounted in wax to simulate quadrants of the mouth. A soft
      tissue equivalent was placed in front of the mounted teeth before x-ray exposure.
      Films were developed automatically and mounted into six sets point scale. The
      teeth were sectioned vertically and evaluated clinically at 5x magnification with
      an explorer. The "gold standard" of carious lesion classification was then
      compared to the students' classifications. RESULTS: All students detected 54% of
      the carious lesions and correctly identified lack of caries 80.5% of the time.
      There were no differences between the two groups of students in terms of
      sensitivity, but dental students showed higher specificity (p = 0.0006).
      CONCLUSION: Permitting dental hygienists to make preliminary interpretations of
      caries from BWs in the dental office appears to be an acceptable practice.

PMID- 15022525
TI  - Maximizing the dental workforce: implications for a rural state.
AB  - Geographic areas with low socioeconomic status may experience status may
      experience less access to oral health promotion and oral health care.
      Approximately 40% of the licensed dentists in Mississippi practice in two
      metropolitan areas, Jackson and the Gulf Coast. As a result, 38 of the 82
      counties in Mississippi have 4,000 or more persons per dentist. With minimal
      incentives attracting dentists to underserved areas, and with little public
      health intervention providing first-rate care, education, and prevention,
      promotion of case referrals for oral health care should be implemented. Several
      states have loosened restrictions on the level of dental hygienist supervision
      required in order to extend care to populations in need. For the predominantly
      rural state of Mississippi, less restrictive supervision of dental hygienists
      might help address the acute problems of poor oral health and access to care
      issues.

PMID- 15022526
TI  - Patient safety--a recycled buzzword or a new approach?

PMID- 15022527
TI  - The current status of cardiovascular disease in Canada--a call to action.
AB  - The Heart and Stroke Foundation of Canada, in collaboration with the Centre for
      Chronic Disease Prevention and Control as well as the Canadian Cardiovascular
      Society, recently published a report on "The Growing Burden of Heart Disease and
      Stroke in Canada 2003". This article will review some of the information
      contained in this report, as well as the nursing implications. The burden
      associated with cardiovascular disease continues to increase for a number of
      different reasons. Risk-provoking behaviours are increasing, despite growing
      knowledge of the consequences associated with these actions. In fact, the health
      of our future generation is now being threatened with these uncontrolled risk
      behaviours. The cost of providing cardiovascular care remains high. Treating this
      disease entity requires a multifactorial approach. Nurses are in key positions to
      effect change in treating cardiovascular disease by addressing risk-provoking
      behaviours from multiple levels and, therefore, to make a significant change in
      these statistics for future reports.

PMID- 15022528
TI  - Pain in adults post surgical repair of congenital heart defects.
AB  - The purpose of this study was to describe pain in adults post surgical repair for
      congenital heart defects. What is the intensity, sensory, and affective
      dimensions of pain experienced post-operatively? What is the trend in pain
      experienced post-operatively over time? What is the effectiveness of post
      operative pain management strategies? What factors influence the dimensions of
      post-operative pain experienced? A descriptive prospective repeated measures
      design was used with 30 adult congenital heart (ACH) post-operative patients.
      Pain assessments using the McGill Short Form Questionnaire (MSFQ), a visual
      analogue pain scale (VAP), and recordings of other variables (analgesic, anxiety,
      activity level, non-pharmacologic intervention) were performed three times daily
      until hospital discharge. Mean pain intensity scores ranged from 2.44 +/- 1.31
      following extubation to 1.30 +/- 0.66 on post-operative day (POD) five (scale, 0
      5). Mean MSFQ scores ranged from 9.26 +/- 7.21 following extubation to 4.40 +/-
      5.22 on POD five (scale, 0-45). Mean VAP scores ranged from 50.77 +/- 25.79
      following extubation to 18.76 +/- 18.50 on POD five (scale, 0-100). Mean number
      of narcotic doses per day ranged from 4.61 +/- 2.01 to 1.88 +/- 1.98 on PODs one
      and five, respectively. Anxiety predicted VAP and MSFQ scores on PODs one and
      two; anxiety and analgesia doses predicted VAP and MSFQ scores on POD three;
      analgesia doses predicted MSFQ scores, analgesia and anxiety predicted VAP scores
      on POD four; analgesia doses and anxiety predicted VAP and MSFQ scores on POD
      five. No relationships were found among pain and other demographic, treatment, or
      clinical variables. Overall, pain was reported as mild to moderate intensity,
      variable in sensations, decreased over time, and adequately managed.

PMID- 15022529
TI  - [How to influence the practice of physical activity in persons with coronary
      disease?].

PMID- 15022530
TI  - Biventricular pacing and cardiac resynchronization therapy: a fresh approach to
      heart failure and intraventricular conduction delay.
AB  - Approximately 25% of patients diagnosed with symptomatic heart failure have
      evidence of significant intraventricular conduction delay defined by a QRS width
      greater than 120 ms. Heart failure leads to dysynchronous ventricular
      contraction, mechanical inefficiency and further impairment of left ventricular
      function. Patients with severe heart failure are also more likely to be burdened
      by mitral regurgitation. Biventricular pacing is a new therapy for heart failure
      refractory to standard pharmacological therapy. Biventricular pacing has been
      shown to improve the hemodynamics of patients with intraventricular conduction
      delay and low ejection fraction. This is done by simultaneous electrical
      stimulation of both ventricles. This is a review of recent evidence on the
      efficacy of biventricular pacemakers, cardiac resynchronization therapy, and the
      pathophysiology underlying the use of these therapies.

PMID- 15022533
TI  - Application of principles of evidence-based medicine to occlusal treatment for
      temporomandibular disorders: are there lessons to be learned?
AB  - Critical evaluation of treatment methods has become an important part of health
      care and will certainly have a major influence on decisions about acceptable
      treatment methods in the future. Evidence-based medicine (EBM) means the
      systematic, explicit, and judicious implementation of the best evidence in
      patient care. The most reliable sources of evidence are high-quality systematic
      reviews and randomized controlled trials (RCTs). A systematic EBM approach could
      be particularly useful in the treatment of temporomandibular disorders (TMD),
      where controversial and conflicting ideas about management are common. In this
      field, concerns about the lack of evidence are often expressed. This article aims
      to elucidate and discuss the application of EBM to the treatment of TMD, using
      the most controversial treatments (i.e., occlusal treatments) as an example. By
      applying the principles of EBM to TMD treatments, we wish to highlight some of
      the important issues that form the basis for high-quality care in this field. A
      systematic review of occlusal treatments (occlusal splints and occlusal
      adjustment) updated to January 2003 revealed 16 RCTs of occlusal splints and 4 of
      occlusal adjustment. The overall quality of the trials was fairly low. Recently,
      however, some high-quality RCTs of occlusal splints have been published. The most
      obvious methodologic shortcomings in published trials included problems in
      defining the patient population, inadequacies in performing randomization and
      blinding, problems in defining the therapies or appropriate control treatments,
      short follow-ups, and problems in monitoring patient compliance. Occlusal splint
      studies yielded equivocal results. Even in the most studied area, stabilization
      splints for myofascial face pain, the results do not justify definite conclusions
      about the efficacy of splint therapy. Their clinical effectiveness to relieve
      pain also seems modest when compared with pain treatment methods in general. None
      of the occlusal adjustment studies provided evidence supporting the use of this
      treatment method. The clinical implications of the findings and future
      perspectives are discussed.

PMID- 15022531
TI  - Evaluating treatment-seeking for acute myocardial infarction in women.
AB  - A telephone survey of 349 randomly-selected women living in Greater Vancouver was
      conducted to assess their understanding of acute myocardial infarction (AMI). The
      results revealed that women have not yet personalized AMI risk information.
      Participants indicated a need for more information pertaining to symptom
      recognition for AMI; they were largely unaware that females may experience AMI
      differently than do males. Participants were less aware of the risks that
      diabetes, obesity and menopause pose for AMI. Approximately 36% of these women
      intended to delay treatment-seeking in the presence of suspicious AMI symptoms.
      One-third or fewer participants would call for an ambulance for the most serious
      AMI symptoms. Alongside a recent poll result indicating that a large majority of
      Canadians believe immediate emergency care for chest discomfort and chest pain is
      unnecessary, these findings are an alert to health care professionals that much
      work lies ahead in educating the public regarding treatment-seeking for AMI.

PMID- 15022534
TI  - Reduction of clinical temporomandibular joint pain is associated with a reduction
      of the jaw-stretch reflex.
AB  - AIMS: To examine the jaw-stretch reflex after injection of local anesthetic (LA)
      into painful temporomandibular joints (TMJs), since the functional role of jaw
      stretch reflexes in patients with painful temporomandibular disorders is still
      not well understood. METHODS: Thirteen female patients with a clinical diagnosis
      of disc displacement without reduction and TMJ pain participated in this open
      study. Reflex responses were evoked by fast stretches at 15% of the maximal
      voluntary contraction level before and after injection of 1 mL carbocaine into
      the painful TMJ. Electromyographic (EMG) activity was recorded from the left and
      right masseter and temporalis muscles, and the mean level of prestimulus EMG
      activity and peak-to-peak amplitude of the stretch reflex were measured. Visual
      analog scale ratings of TMJ pain and TMJ pressure pain thresholds (PPTs) were
      also obtained. Eleven healthy women were examined with the same protocol (except
      for PPT determinations) before and after injection of LA into the TMJ. RESULTS:
      In patients, injection of LA reduced the TMJ pain during jaw movements and
      maximum clenching (P < .021) and increased the PPTs in the painful TMJ (P < .01).
      The prestimulus EMG activity in the masseter on the painful side (feedback
      muscle) was unaffected by the injection of LA (P > .262). There were no
      significant side-to-side asymmetries of latency or amplitude measures of the
      stretch reflex in the patient group. Both the peak-to-peak amplitude and the
      normalized peak-to-peak amplitude of the stretch reflex were reduced in the
      masseter and temporalis muscles on the painful side and in the masseter on the
      nonpainful side after LA injections (P < .048). There were no effects of LA
      injections into the TMJ in the healthy group on any EMG or stretch parameters.
      CONCLUSION: These results do not support the notion of asymmetries in the jaw
      stretch reflex in patients with TMJ pain, but they do suggest that the reflex
      sensitivity can be influenced by nociceptive activity from the TMJ area.

PMID- 15022535
TI  - Effect of food consistency on temporomandibular joint morphology: an experimental
      study in pigs.
AB  - AIMS: To investigate whether there are any correlations between increased
      masticatory loading, degree of tooth wear, and the size, form, and macroscopic
      surface of the temporomandibular joints (TMJs). METHODS: The degree of tooth wear
      and different TMJ variables were compared in 2 groups of domestic pigs. One group
      of 8 pigs had been raised indoors (ID group), and the other group of 9 pigs had
      been raised outdoors (OD group). The pigs in the ID group were fed a soft diet
      and were not provided any straw in their pens. The OD group was fed a solid diet
      and could also grub in the soil, resulting in an exposure to more abrasive
      components and to greater chewing demands. All pigs were sacrificed at the age of
      22 months. RESULTS: The pigs in the OD group exhibited significantly more tooth
      wear compared to the ID group. No difference in mediolateral size of the condyles
      could be found between the 2 groups. Form and surface changes of the TMJs varied
      substantially between individuals, but not between the 2 groups. No correlation
      could be found between the degree of tooth wear and any of the TMJ variables.
      CONCLUSION: Exposure to a tougher diet containing more abrasive substances has a
      significant impact on the degree of tooth wear but seems to have no consequences
      either for the size of the TMJ condyles or for form or surface changes of the
      TMJs.

PMID- 15022536
TI  - Effect of dexamethasone and dipyrone on lingual and inferior alveolar nerve
      hypersensitivity following third molar extractions: preliminary report.
AB  - AIMS: To study the effect of dexamethazone and dipyrone on sensory changes in the
      innervation territories of the inferior alveolar, infraorbital, and lingual
      nerves caused by third molar extractions. METHODS: Fourteen patients (8 men and 6
      women) were divided randomly into 2 groups. The first group received dipyrone
      preoperatively, while the second group received dipyrone and dexamethazone
      preoperatively. All patients in the study received a prophylactic preoperative
      dose of amoxicillin (500 mg) as well as dipyrone postoperatively. In all
      patients, a single mandibular third molar was removed, while in 2 patients the
      contralateral third molar was removed at a subsequent time. Electrical detection
      thresholds were assessed in the inferior alveolar, lingual, and infraorbital
      nerve regions prior to surgery and 2 and 8 days following surgery. The level of
      perioperative pain, difficulty of extraction, and distance of molar root apices
      from the inferior alveolar nerve canal were also assessed. RESULTS: Patients who
      received only dipyrone had significantly reduced lingual and inferior alveolar
      nerve electrical detection thresholds 2 days after surgery, which returned to
      nearly baseline values by the eighth day postoperatively. In patients who
      received dexamethasone, no significant reduction in the electrical detection
      threshold was found. CONCLUSION: Preoperative treatment with dexamethasone and
      dipyrone but not dipyrone alone prevents sensory hypersensitivity following third
      molar extraction.

PMID- 15022538
TI  - Cardiac wellness program expands with new name and new sponsors. Doctors of Our
      Lady of Lourdes, St. Mary cook heart-healthy foods.
AB  - St. Mary Medical Center, Langhorne, Pa., teams up with Lourdes Medical Center,
      Camden, N.J., in a cardiac awareness campaign focusing on healthful cooking.
      "HeadsUp on Heart Disease" is a newly trademarked name for a program that has
      expanded since its creation in 2003. It features a booklet of recipes, health
      tips and coupons from a number of advertisers. Thanks to sponsorship by healthy
      food product lines and Mastercard, those creating the project expect it to break
      even.

PMID- 15022537
TI  - Pain in Europe. IV. Fourth Congress of the European Federation of IASP Chapters
      (EFIC).

PMID- 15022539
TI  - Georgia hospital wins McGaw Prize for excellence in community service. Phoebe
      Putney Memorial Hospital cited for building coalitions.
AB  - Phoebe Putney Memorial Hospital and Health System, Albany, Ga., has been awarded
      the Foster G. McGaw Prize for excellence in community service. The award is
      sponsored by the American Hospital Association, The Baxter International
      Foundation and the Cardinal Health Foundation. This story contains examples of
      how the $100,000 award will be used for Phoebe's ongoing work in building
      coalitions in its community.

PMID- 15022540
TI  - 'Scrapbooks' provide warm touch to two organizations' annual reports. New York
      Presbyterian Hospital, Meridian Health create beauties.
AB  - As Profiles begins accepting entries for its seventh annual competition for
      Annual Reports, we review examples of two outstanding reports. New York
      Presbyterian Hospital (The University Hospitals of Columbia and Cornell), New
      York; and Meridian Health, Woburn, N.J., both employed the "scrapbook" theme in
      their 2002 annual reports.

PMID- 15022541
TI  - Hospital hooks FISH! Philosophy. Treatment, visits at Silver Cross become more
      pleasant experiences.
AB  - FISH! Philosophy at Silver Cross Hospital, Joliet, Ill., is designed to make the
      hospital experience pleasant, and even fun for patients, visitors and employees.
      Outpatient satisfaction was the first objective in the campaign, which was first
      introduced to hospital staff last year through a two-hour training session. The
      program's four main principles are: Be There; Choose Your Attitude; Play, and
      Make Their Day.

PMID- 15022542
TI  - LifeBridge new publication: Md.MD. Listing of 1,200 physicians a major part of
      consumer-type magazine.
AB  - LifeBridge Health, Baltimore, created a directory of its physicians, which
      developed into a 100-page consumer magazine titled Md.MD A Directory of the
      Region's Finest Physicians. Written and designed in-house, the premier edition
      paid for itself, thanks to publishing partner, Alter Communications. The premier
      edition was mailed to 50,000 Baltimore area homes last September.

PMID- 15022543
TI  - Off to the mall ... to see my doctor? Abington Memorial Hospital promotes
      physicians at Willow Grove.
AB  - Abington Memorial Hospital, Abington, Pa., boosts its physicians with life-sized
      banners throughout the Willow Grove Park Mall. The upscale mall serves exactly
      the same demographic as the hospital, making for a mutually valuable partnership.

PMID- 15022544
TI  - OhioHealth web site wins awards. Draws leadership recognition for outstanding
      redesign.
AB  - OhioHealth, Columbus, Ohio, has redesigned its web site, making it especially
      useful and appealing to women. For the collaborative effort, which included the
      Mayo Clinic and The VIA Group, Portland Maine, it has received numerous awards.

PMID- 15022545
TI  - [Designing and clinical testing of immune-enzyme and immunofluorescence test
      systems for serodiagnosis of ixodes borreliosis].
AB  - The methods of immune enzyme assay (MIEA) and of lanthanide immunofluorescence
      analysis (LIFA) were used to work out the test systems for the detection (in
      blood serum of patients) of specific IgM IgG antibodies to the B. burgdorferi
      spirochete--a causative agent of ixodic borrelioses. The test system was
      clinically tested versus the indirect immunofluorescence reaction (IIFR) and
      commercial immune enzyme test system (CIET). The results of antibodies' detection
      were shown to correlate with the analysis data for the same sera in IIFR and to
      be in line with a real presence or absence of the disease. Test systems based on
      LIFA were proven to be most sensitive and specific.

PMID- 15022546
TI  - [An unusual type of the chromatography profile of blood serum carbohydrates in
      the diagnosis of deep mycosis by gas and liquid chromatography].
AB  - The paper contains a description of a diagnosis method (now under elaboration)
      applicable to human mycosis, which is based on a high-sensitivity gas-liquid
      chromatography. According to the study results, despite its promising nature, the
      method in question is not accurate enough in terms of a precise diagnosis of
      invasive candidosis in oncology patients. The authors point out that the
      chromatography-diagnosis results need now a histological confirmation.

PMID- 15022547
TI  - [Remote monitoring control techniques for biological air disperse systems].
AB  - Described in the paper are the results of designing a combination-luminescence
      lidar for the automated express determination of the concentration and dynamic
      distribution of biological pollutants in the atmosphere. It was established as
      possible to detect simultaneously the signals of aerosols' luminescence and those
      of combined atmospheric nitrogen dispersion to ensure an effective monitoring of
      biological aerosols along the probing route.

PMID- 15022548
TI  - [Chemicals for disinfection and decontamination used and being designed for
      eliminating the aftermaths of biological contamination].
AB  - The efficiency of the key classes of disinfecting and decontaminating chemicals,
      used to eliminate a biological contamination of the human habitat, was analyzed
      in the paper. It is underlined that, should any biological agents with unknown
      properties (biological terror, military threat) be detected, it is advisable to
      choose the ecologically less hazardous disinfectants based on hydrogen peroxide,
      aldehydes and chlorine-containing compounds.

PMID- 15022549
TI  - [Effect of hydrogen peroxide on the virulent properties of anthrax pathogen
      spores].
AB  - The impact exerted by hydrogen peroxide on the virulent properties of anthrax
      pathogen spores was experimentally evaluated. Even a short-term exposure of them
      to a disinfect was shown to cause impairments of the functional nature in the
      spores' vital structures, e.g. suppression of multiplication. At the same time,
      the biological monitoring of disinfection efficiency does not always rule out the
      presence of viable pathogen spores in the disinfected objects.

PMID- 15022550
TI  - [The sporicidal activity of disinfectants based on hydrogen peroxide].
AB  - The authors analyzed the experience of disinfection experts related with the
      designing of new disinfection chemicals and of their composition variations. The
      key regularities were defined, which are important for the designing of effective
      disinfectants with preset properties capable of rapidly and safely inactivating a
      microbe contamination of different objects in the human habitat. A high
      antimicrobial activity and good outlooks are demonstrated for disinfectants made
      on the basis of hydrogen peroxide.

PMID- 15022551
TI  - [Use of new individual protection substances in Mel'tser boxes].
AB  - Described in the paper are the results of research, experiments and designing of
      individual protection means for medical personnel attending the patients with
      extra dangerous infections under the conditions of Meltzer boxes. The authors
      elaborated pressure suits that can protect the medical personnel from being
      infected by microbe aerosols. The testing of the mentioned protection suits in
      infection hospitals of Moscow, Elista, Rostov-on-Don and of other cities was
      positively assessed.

PMID- 15022553
TI  - [The isolation of patients with highly contagious diseases].
AB  - The paper deals with the issue of how to prevent the spread (in the environment)
      of pathogens of extra dangerous infections, whose source could be a patients (not
      isolated in Meltzer box) with a highly contagious disease. Autonomous filtering
      stretchers of a special design are suggested for the transportation of patients;
      the design is sufficient to protect the habitat and medical personnel against
      being contaminated with related microbes and does not affect the physiological
      and-hygienic indices of an isolated patient.

PMID- 15022552
TI  - [Efficiency criteria and basic parameters of powder inhalers].
AB  - A high therapeutic efficiency and ecological safety are typical of powder
      inhalers. However, the designs of devices, serially manufactured in many world
      countries, are different, which affects their technical parameters. There are
      also differences pertaining to the definition "efficiency criterion" of a powder
      inhaler. An attempt is made in the paper to substantiate the efficiency notion of
      the discussed medical equipment and to analyze the methodological approaches to
      define such efficiency in the laboratory setting.

PMID- 15022554
TI  - [Maintenance of cold chain for the delivery of immunobiological drugs by the
      indicators of heating and freezing controls].
AB  - The paper deals with an objective evaluation of a qualitative storage of
      immunobiological drugs including all stages of "cold chain". The results of
      technological research and of designing related with constructing a system of
      indicators for monitoring the temperature regime to maintain the "cold chain"
      functioning are presented. The suggested devices are comparatively described.

PMID- 15022555
TI  - [Growth and development of children and teenagers in Russia].

PMID- 15022556
TI  - [A revised classification of hypoxic conditions].
AB  - The precised classification of circulatory hypoxia described in the paper is
      principally different from those published earlier by that it discriminates
      between hypoxia preconditioned by impaired cardiac-muscle constriction, on the
      one hand, and hypoxia due to malfunctions of smooth muscles (SM), on the other
      hand. The genesis of SM malfunctions is predetermined by impaired interactions of
      serotonin with SM serotonin receptors. The clinical use of serotonin adipinat
      reduces the local organic and total-tissue hypoxia in different pathologies and
      provides for better treatment results. The mentioned precised classification can
      be used to gain more data on the tissue-hypoxia pathogenesis and to schedule the
      clinical-and-experimental research on the purpose-oriented basis.

PMID- 15022557
TI  - [Factors and conditions affecting the process of infecting the fetus during
      different pregnancy stages].
AB  - Etiology, pathogenesis of intrauterine infection of the fetus, factors promoting
      such infection and the status of the local immune system are elucidated in the
      paper. A changed reactivity of the immune homeostasis of a pregnant woman with a
      chronic infection was shown to be potentially an important factor of pathogenesis
      of defects in her baby. The local immunity factors of the reproductive tract,
      i.e. the vagina and neck of uterus, are in the forefront of anti-infectious
      protection, which signal an alert or limit the microorganisms' reproduction;
      besides, they prevent the microorganisms from penetrating into the upper
      genitals. The therapeutic-and-preventive schemes applicable to infected women
      must comprise measures targeted at eliminating an infectious agent and at
      normalizing the pathological changes in the performance of the immune system
      activity.

PMID- 15022558
TI  - [A. I. Arutiunov and Russian neurosurgery (on the occasion of his 100th birthday
      anniversary)].

PMID- 15022559
TI  - Contemporary psychiatry in Bosnia and Herzegovina.

PMID- 15022560
TI  - [Specific psychopathologic reactions in refugee populations and victims of
      torture].
AB  - AIM: Examine differences and specificities of psychological symptoms as a
      response to the trauma of torture and displacement. METHOD: The sample includes
      two groups of 50 subjects. The first group experienced the trauma of
      displacement, and the second group beside the displacement experienced also the
      trauma of torture. RESULTS: The drop in social and economic status is much more
      profound in torture victims compared to refugees. All nine SCL 90-R suscales show
      statistically significant difference in more pronounced psychopathological
      responses in torture victims relative to refugee population. The Mississippi
      questionnaire shows significant differences in PTSD between the two groups and
      higher scores for torture victims. CONCLUSION: Based on the results torture is
      the most intense form of trauma leading to intensive psychopathological responses
      including chronic PTSD. Results show that the psychopathological response is most
      intense and most frequent in the population of torture survivors compared to the
      refugee population.

PMID- 15022561
TI  - [Differences in coping strategies in those who experienced the trauma of war or
      torture and the local population].
AB  - AIM: To define the differences in coping strategies between the victims of
      torture and the local inhabitants with the experience of war. METHOD: The
      subjects were divided in two groups. Each group consisted of 50 subjects. The
      first group included the subjects with the experience of torture, and the second
      group had the subjects who have survived the war but not torture. The Coping
      strategies were registered by the Coping Scale. RESULTS: A significant decrease
      in socioeconomic status of torture victims after the war. On all the subscales of
      the Coping Scale, there is a statistically significant difference between the
      torture victims and the second group to the effect that the prior group has
      higher scores in all subscales as well as the higher overall score of adaptive
      and maladaptive coping strategies. CONCLUSION: Higher mean score in coping
      strategies in significantly more frequent in torture survivors, than in local
      population with the experience of war, that confirms theoretical discussions
      about coping as a dynamical process that is in reciprocal relation between the
      individual and the environment.

PMID- 15022562
TI  - [Analysis of long-term sequelae of the trauma of war on the mental health of
      Bosnian army veterans].
AB  - This paper wants to point out at the serious long-term consequences of the
      psychological trauma of the war on the mental health of a big number of Bosnian
      Army veterans: At the same time, the author is trying to identify crucial
      psychosocial and political reasons that have led to this situation and describe
      this specific psychopathology presented by this group of patients. Although
      nearly eight years has passed since the end of the war, the number of veterans
      who are seeking psychiatric assistance is still not decreasing because they find
      it more and more difficult to cope with their anxiety, irritability, anger and
      fury, inner bitterness, depression, pessimism, insecurity, loneliness and
      isolation, and the permanent feeling of emptiness, helplessness and inability to
      find and give meaning to their very existence. (They seem to be living only by
      default.) A significant number of patients in this group have already been
      diagnosed with serious somatic disorders, most frequently the disorders where
      traumatic stress plays significant role as a causative factor. The author of this
      paper has been actively involved in providing psychiatric assistance to this
      population of patients during the aggression. At that time, this group was
      permanently exposed to nearly all kinds of traumatic events that are known in the
      war. Paradoxically, a very small number of severe breakdowns have been noted at
      that time, and most of them were reversible by nature. The main reason for this
      incredible psychological resilience of our soldiers lies probably in their high
      motivation, because they were involved in defense that had no alternative. The
      end of the war that was unjust (it was ended by an agreement, but the fascism was
      not extinguished), as well as overall societal neglect for the need of this
      heavenly traumatized population in the post-war period, (they live in permanent
      insecurity, deprived of their rights, neglected and often even humiliated),
      present two key reasons that have led to psychological destabilization of a
      significant number of Bosnian Army veterans, and their consecutive impairment of
      social functioning. The psychopathology that is most frequently presented,
      undoubtedly has many elements of chronic PTSD, but in the essence it is much more
      complex and it deserves a great deal more professional attention and analysis
      than it has been given so far.

PMID- 15022563
TI  - [Psychological disorders in women in Bosnia and Herzegovina associated with
      menstruation].
AB  - Premenstrual syndrome consists of different somatic and/or psychological symptoms
      which occur in the second half of the menstrual cycle following ovulation. The
      symptoms usually occur around mid-circle and in majority of cases are most
      intense during the last seven days prior to menstruation. Given the fact that
      this topic has not been adequately addressed in our country the aims of this
      study have been defined as to determine the type and frequency of somatic and
      psychological symptoms related to menstruation. The study was done on the sample
      of 181 women in the age of 15-52 years, of different educational and marital
      status. Four groups were formed: married (78), single (103), and adult (138) and
      adolescent (43). In order to determine the type and frequency of symptoms we used
      a structural interview modified according to DSM-IV criteria. In accordance with
      DSM-IV criteria 52% of subjects have premenstrual dysphoric disorder, among which
      23.4% adolescents, 76.6% adult women. The most frequent somatic symptoms related
      to menstruation are: swelling of the breasts, weight gain, myalgias, arm and leg
      swelling (81.8%), changes in appetite (63.5%), sleep problems (55%), headache
      (47%). The most frequent psychological problems were depressive mood (68%),
      fatigability and lack of energy (53.6%), anger and social withdrawal (49.7),
      anxiety (49%), difficulties of concentrating and difficulties with memory
      (40.7%). There is no statistically significant difference in frequency of
      symptoms between the groups except in the presence of pain which is significantly
      more frequent in adolescents. A defeating fact has been noted in that 64.9% of
      women inadequately define the duration of their menstrual cycle. It is concluded
      that premenstrual syndrome or premenstrual dysphoric disorder is a significant
      problem of women in Bosnia-Herzegovina (present in 52% of women) with a range of
      unpleasant psychological and somatic symptoms. Due to all this as well as the
      fact that a considerable number of women inadequately define the duration of
      their menstrual cycle, it is necessary to devote greater attention to this
      problem by public health professionals, family doctors, gynecologists and
      psychiatrists alike.

PMID- 15022564
TI  - [Characteristics of the dangerous and harmful use of alcohol and psychoactive
      drugs in Bosnia and Herzegovina in the postwar period].
AB  - Problems related to abuse of various psychoactive substances started in Bosnia
      and Herzegovina during the early eighties of the twentieth century. This is
      proven by the data from Counseling for the prevention and treatment of drug
      addiction that was working since 1978 until 1992 at the Psychiatric Clinic of the
      Clinical Center of Sarajevo University. At the end of 1991 this center registered
      1000 drug users among which 50 was heroin addicts on the Methadone maintenance
      treatment. All organized activities on prevention and treatment of drug addiction
      stop during the spring of 1992. During the war 1992-1995, only few cases of drug
      addicts was treated due to overdose, abstinence and toxic psychotic states.
      Catastrophic war devastation had the consequence in social and economic
      disorganization of the whole society in Bosnia and Herzegovina. Large part of the
      population was killed or severely wounded. Majority of civilian population were
      expelled from their homes and spread all over the country and the whole world.
      Violence toward themselves and others, aggressively, tension, and domestic
      violence with large number of stress related mental disorders are still
      characteristics of our society. One of the important features of such a society
      is incensement of drug abuse, starting with alcohol, tobacco and all sorts of
      drugs. Extent of this socio-pathological problem are unknown, but indicators such
      as quantity of confiscated drug, number of legal processes related to drug,
      number of those who are coming to health institutions due to drug related
      problems, number of overdoses, and occasional surveys among youth indicated that
      the problem became more serious than anybody in this society wants to believe.
      All these indicators are showing that the problem of harmful alcohol, tobacco and
      drug use in our society have multiple negative consequences, and that in the
      recent future we cannot expect that these trends will became positive. Obviously,
      without the support from the community in this area we cannot achieve some good
      results. Today it is clear that without a strategy and preventive programs for
      the prevention of alcohol, tobacco and drug use at the state and even regional
      level there cannot be any success in stopping the epidemy of use and abuse of
      legal and illicit psychoactive substances.

PMID- 15022565
TI  - [Characteristics of addictions in Bosnia and Herzegovina a review of prevention
      programs].
AB  - Hazardous and harmful use of alcohol and drugs, accompany human race for
      centuries, and represents transcultural phenomena as well as one of the problems
      that still does not have solution. According to consequences that it's causing to
      individual, family and community it is one of the most severe social problems.
      Although, international community is investing more and more efforts and money to
      prevent illicit drug traffic, reduce consumption of alcohol and improve
      prevention, treatment and rehabilitation of addicts, still some significant
      results are not reached. War in Bosnia and Herzegovina cause severe injuries to
      population and left devastation and misery. War crimes are reflected in 200,000
      deaths, several thousand wounded and over one million traumatized. Transition
      societies, as our, are characterized with big social changes such as migrations,
      urbanization and destruction of traditional social values. Due to this extensive
      drinking and drug use, as a form of escape from the reality and social
      difficulties are characteristic of our society and current civilization. It is
      estimated that currently in B&H exist 10,000 opioid addicts, and 20,000
      alcoholics. Rapid incensement in number of addicts, and problems caused by that
      was the reason why we after the war started with preparations of Preventive
      Programme with focus on primary prevention. Beside programs that was made on the
      local levels, during 2002 Federal Programme of prevention was accepted which
      anticipated activities at all three preventive levels.

PMID- 15022567
TI  - [Relation between benzodiazepine abuse and trauma].
AB  - People have abused drugs from the moment they found out about them. Abuse of
      substances increased during crises (war, displacement, catastrophes, different
      stress-induced circumstances, fear for existence, absence of prospects and hope).
      Benzodiazepines are most frequently abused psychopharmaceuticals due to their
      easy accessibility. The war and aggression on Bosnia and Herzegovina have made
      unforeseeable consequences, they have caused great migration of population,
      deaths, wounding, separation of families, unemployment and social poverty. All
      these factors have had influence on mental health of people. The most frequent
      psychological consequence of war and displacement is PTSP. The survey has shown
      that there is a difference in drugs abuse between the interviewees in collective
      centres and local population. A great percentage of interviewees who are
      accommodated in collective centres are traumatised (63%) and they mostly misused
      benzodiazepines to alleviate fear, nervousness, mood disorder and pain. Due to a
      long-term and uncontrolled use of benzodiazepamines, 50% of interviewees who
      abused benzodiazepamines have become addicted to them.

PMID- 15022566
TI  - [Use of methadone therapy at the Institute for Alcoholism and Drug Addiction in
      the Canton of Sarajevo].
AB  - INTRODUCTION: Number of addicts increased in our country, especially after the
      war, and needed adequate solution of the problem as well as use of the
      experiences from the other countries that faced before us "epidemy" of
      addictions. One of the solutions for harm reduction caused by use of opioid
      substances, primarily heroin, is use of methadone (heptanone), which is a good
      pharmacological replacement. METHODS: In this paper we have presented one-year
      experience in application of methadone for detoxification or substitution among
      the patients in our Institute. This retrospective-prospective study included 104
      patients treated by methadone detoxification therapy and 59 patients included in
      the program of methadone substitution. This study involves analyses of the
      applied therapy compared to age, gender, profession, and duration of addiction,
      employment status and other social and demographic indicators. RESULTS: Methadone
      detoxification therapy. Among all age groups most dominant are addicts age 21-30
      years (71%), and some in the age group 30-35 years (18%). Lack of adequate
      treatment programs, as well as break in continuity of treatment due to the war in
      our country, caused that we have in our sample 10% patients older than 36 years.
      Few patients younger than 20 years of age, we can explain with short working age
      of your department, but even now we can notice the incensement of young addicts
      number. First contact with the drug our addicts usually have between 13 and 18
      years of age (61%), while earliest age of contact was 11. Duration of addiction
      is usually from 1 up to 9 years (65%), although we cannot neglect the number of
      addicts who are using the drug more than 10 years (35%). During our work, up to
      now, we did not have neither one case of HIV infection, which does not means that
      this disease is not present in the addicts population that we have not tested
      yet. Number of Hepatitis B and C positive addicts in our sample is in accordance
      with epidemiological data from other countries. There was 32% Hepatitis B
      positive, 58% Hepatitis C positive, and 23% Hepatitis B and C positive. Methadone
      substitution therapy. Among those included in the MST, male patients are most
      dominant, with average age of 31.4 years. Majority of patients has finished high
      school, they are unemployed, single, and living with their parents. First contact
      with drugs they had in average age of 16.4 years, while the duration of use had
      mean value of 10 years. Initial maintenance doses were between 10 and 50 mg, mean
      36.1 mg, and maintenance doses after the two months had mean value of 61.6 mg.
      Among patients involved in MST, we have noted one HIV positive case, and
      significantly larger number of patients that are positive on Hepatitis: Hepatitis
      C 33%, and Hepatitis B and C (34%). CONCLUSIONS: Our experience during the
      application of both treatment types is positive. This treatment is well accepted
      by the addicts. The MDT and MST methods provides better functioning, easier
      follow up and better participation in the social and psychological therapeutic
      processes, which are conducted at our department. Positive improvement in social
      functioning. Better motivation for the continuation of treatment in the other
      institutions (therapeutic community). We did not have any side effects of the
      treatment in order to stop the therapeutic process. We need continuous education
      and sensibility of the whole society and political community in order to accept,
      finance and maintain methadone programs.

PMID- 15022568
TI  - [Effect of war on alcoholism].
AB  - OBJECT OF WORK: To investigate and analyze the effect of the war upon the
      representation of the hospitalized alcoholics at the Department of Psychiatry at
      the Clinical Hospital of Mostar. RESPONDENTS AND METHODS: In this retrospective
      research was analyzed the representation of alcoholism in all the patients
      hospitalized in the year 1994 and in all the patients hospitalized in the year
      1999, by examining the disease history. All the patients were hospitalized at the
      Department of Psychiatry of the Clinical Hospital of Mostar. The classical
      medical procedure and the biomedical diagnostics parametry were used to make a
      diagnosis. RESULTS AND DISCUSSION: Total number of the hospitalized at the
      Department of Psychiatry in the war period (year 1994) amounted to 329 patients,
      out of who 25.5% due to alcoholism. Five years later the number of the patients
      hospitalized at the Department of Psychiatry amounted to 349, out of whom 28.6%
      owing to alcoholism, which is an increase in the representation of alcoholics
      among the total number of treated patients, but not also a statistically
      significant difference (P > 0.05). The increased number of persons who were
      treated for alcoholism in the post-war year 1999 can be partly explained by the
      occurrence of war related psychic disorders, a combination of severe social and
      material situation and frequent secondary traumatization. CONCLUSION: An increase
      in the number of patients hospitalized owing to alcoholism in the post-war year
      1999 (28.6%) as compared to the war year 1994 (25.5%), is shown.

PMID- 15022569
TI  - [Analysis of the effect of the stress of war on schizophrenic psychosis].
AB  - Several experiments have shown an important relationship between schizophrenia
      and stress. People in Sarajevo and also, schizophrenic patients, who were in
      Sarajevo during the war, were exposed to frightful life experiences for over
      1,300 days. The main goal of this investigation was evaluation of the course of
      schizophrenic psychosis in stress related war. Reason for this epidemiological
      study was a lack of knowledge about influence of war-stress on the course of
      schizophrenic psychosis, as well as, the fact that behavior of schizophrenic
      patients was changed during the war. This study was prospective, retrospective
      and controlled in its design. This influence of war related stress on the length
      and quality of remission of schizophrenic patients, the most common stress
      factors which impacted an schizophrenic patients during the war were identified,
      as wall as, different types and differences in demographic characteristics of
      patients who had different causes of schizophrenic psychosis. With this in mind,
      hypothesis between stress and course of schizophrenic psychosis were set.
      Experiment had covered those following groups: group (E), patients were
      hospitalized from 1.1.1987 to 31.12.1991, control group (K) patients were
      hospitalized from 1.1.1987 to 31.12.1991 but did not live in Sarajevo during the
      war and subsample of control group K (K1) which included schizophrenic patients
      who were hospitalized from 1.1.1987 to 31.12.1991, and were not treated in period
      from 6.4.1992 to 5.04.1995 despite the fact that they lived in Sarajevo during
      that period.

PMID- 15022570
TI  - [Comorbid depression in patients with epilepsy treated with single and multiple
      drug therapy].
AB  - A seizure is a disturbance of movement, feeling or consciousness occasioned by
      sudden, inappropriate and excessive electrical discharges in the grey matter of
      the brain. The most common psychiatric disorder in epilepsy is interictal
      depression, with lifetime prevalence of 40 to 60%. Particular attention should be
      paid to suicidal ideations, due to the fact that most of the patients have easy
      access to potentially lethal when overdosed, antiepileptic drugs. The aim of our
      paper is to determine the presence of depressive symptoms in epileptic patients
      according to their treatment protocols (monotherapy or polytherapy), gender, age,
      social status, age when diagnosed, type and frequency of seizures. Prospective
      evaluation of monotherapy and polytherapy in 60 subjects, (30 subjects in each
      group), who were diagnosed with epilepsy. Assessment of depressive symptoms was
      performed with the use of BDI scale. In both groups there was a similar structure
      according to gender, mean age was 34 (with an s.d. of 11.06). More than 96
      percent of the subjects had low or average socioeconomic status. Average age of
      first attack was 20.43 (with an s.d. of 11.9). In the group treated with
      monotherapy there was the biggest number of generalized convulsive seizures, and
      in the group treated with polyantiepileptic therapy there was the biggest number
      of partial complex seizures. Symptoms of moderate and severe depression were
      registered in 33% patients treated with monotherapy and 60% of patients treated
      with polytherapy (t = 2.198, for p less than 0.05). 16.7 percent of the patients
      had suicidal ideation. On the basis of our research we can conclude that
      significantly more frequent and severe depressive symptoms were found in the
      group of epileptic patients who were treated with polytherapy. In those patients
      the occurrence of partial complex seizures was the biggest, and their frequency
      was weekly or even daily.

PMID- 15022572
TI  - Community mental health care in Europe--an overview.
AB  - Europe shares some historical roots of modern psychiatry. Even before the 19th
      century, there had been institutions for the mentally ill, such as the Bethlem in
      London which was founded more than 750 years ago, and organised forms of care in
      the community for people with mental illness, such as the tradition of family
      care in Geel in Belgium. Modern psychiatry, however, was initiated through the
      spirit of enlightenment and began around 1800. This beginning was marked by the
      symbolic cutting of the chains of mentally ill patients in Paris, the first
      publication of the term 'psychiatry' ("Psychiatric") in Germany in 1803, and the
      establishment of the retreat in York, England. The rise of modern psychiatry as a
      speciality of medicine was closely linked to the development of new institutions
      in both health care and academia. In the 19th century, various universities
      established chairs and academic departments of psychiatry, and large asylums for
      the mentally ill were built across Europe. The asylums were meant to replace the
      family as carriers for the material needs of patients--since many families could
      not fulfill that function in an industrialising society anymore--remove the
      mentally ill from the public scenes of urban life and provide a therapeutic
      environment.

PMID- 15022571
TI  - [Confused states as predictors of epileptic seizures during and after
      cerebrovascular accident].
AB  - The state of mental confusion is described as an dependent risk factor in
      development of early and late epileptic-onset seizures following CVI. The aim of
      this paper is to determine the influence of confused state as possible predictor
      of symptomatic seizures in the course and following CVI. MATERIAL AND METHODS:
      The patients who were treated in The Department of Neurology for early and late
      onset seizures in the course and following CVI in the period between 1.1.1989 and
      31.12.1998. RESULTS: We had total number of 106 patients with symptomatic
      seizures, 56 in the group of late-onset and 50 in the group of early seizures.
      52.8% of the patients have a registered state of mental confusion at the
      admission to hospital (in the stage of acute CVI), 19.2% of patients had a clear
      sensorium. Disorder of consciousness of the type of coma was registered in 27.4%
      of the patients. There was statistically significant increase of the occurrence
      of mental confusion in the group of patients with late-onset seizures, 62.5%
      while there was a statistically significant increase of coma in conditions
      related to type, frequency and outcome of seizures. We can conclude that mental
      confusion has significant influence of the occurrence of late-onset seizures
      while it does not influence the type and frequency of seizures.

PMID- 15022573
TI  - [Bipolar disorders in the light of the latest findings in molecular genetics].
AB  - Bipolar disorders (BP) are characterized by episodes of mania or hippomania and
      depression. Although etiology of these psychiatric disorders is still unknown
      there is a lot of evidence suggesting that genetic component play an important
      role. In many centers all over the world systematic genome screenings were
      performed. As a result of these studies interesting findings on potential
      chromosomal regions harboring genes responsible for liability to BP disorders
      emerged. Significant findings need to be replicated in populations with different
      ethnical and cultural background. Currently independent B&H sample is being
      collected for family based association survey of genes potentially involved in BP
      disorder, type 1.

PMID- 15022574
TI  - Early intervention in psychosis.
AB  - The article describes the development of guidelines for the management of first
      episode psychosis, over the first few years of the illness. Such guidelines
      advocate the use of low dose medication (be this with typical or atypical anti
      psychotics) as well as psychological techniques, and assertive case management.
      The paper will review the development of these guidelines, describe them, and
      suggest outcome measures for the treatment of first and early episodes.

PMID- 15022575
TI  - [Analysis of amoxicillin-clavulanic acid (Xiclav) efficacy and the possibility of
      early switch from parenteral to oral therapy in the treatment of infections].
AB  - Early transition from parenteral to oral antibiotic therapy switch therapy play a
      major role in treatment because of adverse reactions of long parenteral therapy.
      In the prospective, comparative and randomized clinical study the efficacy of two
      treatment regimens were analyzed: XICLAV (amoxicillin + clavulanic acid):
      parenteral regiment with early transition to oral therapy and parenteral regimen
      in patients with bacterial infections without transition to the oral dosage form,
      on the other hand. In our study we've analyzed 240 hospitalized patients in the
      Clinic of infectious Diseases in Tuzla and Sarajevo too, so in the Institution
      for infectious diseases in Zenica. The mean age of our patients was 39.6 years,
      70.8% females. The major (50.5%) patients had urinary or respiratory tract
      infectious (bacterial pneumonia 38.8%) but several patients have had skin
      infections and sepsis. The first 120 patients were initially treated by Xiclav
      administered parenterally i.v. (adults at a dose of 3 x 1.2 gr i.v.; the children
      at a dose of 3 x 30 mg/kg) with early oral switch therapy (adults at a dose of 3
      x 625 mg per os; the children at a dose of 3 x 25-50 mg/kg); whereas the others
      (120 patients) were treated parenterally by the regimen mentioned above. The mean
      length of i.v. therapy and hospitalization in the i.v. group was 4.12/10.21 days
      respectively (p > 0.05). The clinical efficacy switch of both therapeutic
      regimens was comparable. The resolution of all clinical symptoms and laboratory
      signs of infections was noted at 69% patients of both groups, with significant
      improvements at noted at 69% patients of both groups, with significant
      improvements at 21% patients and at 10% patients showed clinical failure. The
      tolerability of Xiclav was very good. The adverse reactions during treatment were
      observed at 5.2% patients. This study noticed satisfied clinical and bacterial
      efficacy so did tolerability of Xiclav in the treatment of bacteriological
      infections. Xiclav apply early transition from parenteral to oral therapy.

PMID- 15022576
TI  - [Correlation of body mass index and aminotransferase activity in healthy
      adolescents].
AB  - The objective of this study to consolidate the correlation between BMI with the
      values of ALT and AST of the healthy adolescents in age of 18, 19 and 20 years.
      To the group of 237 examinees of the healthy adolescents is determined BMI, and
      is measured the activity of ALT and AST. In the sample of the examinees we had
      22% examinees had the increased BMI > or = 25. The examinees who had the
      increased BMI (> or = 25), had the significant increased values ALT, and only
      mildly increased values AST in relation to the upper referent values. On the
      basis of the simple linear regression was confirmed the positive correlation
      between the of body mass indexes and activities ALT i AST.

PMID- 15022577
TI  - [Expected incidence of post-vaccination complications in vaccination programs].
AB  - Incidence rate of the harder adverse immunization reactions in the Program of the
      vaccination children in Federation Bosnia and Herzegovina is similar in the terms
      of kind and frequency as in the countries with high quality programme of the
      vaccination. In the period from 2002-2003 year cases of the adverse reactions
      were not registered, as vaccinal form of polyomyelitis, toxic syndrome or sudden
      acute deaths. The adverse events following immunization were classified in
      relation to 100,000 applicated vaccines, the incidence rate of supurative
      lymphadenitis at BCG vaccination reported are 32@100000, anaphylaxia at MMR
      vaccination 0.8@100000, DTP vaccination encephalopathy 1@100000 and at TT
      vaccination anaphylaxia 2@100000 administered vaccines.

PMID- 15022578
TI  - Alcohol in alcoholic liver disease is a causative factor for development of
      allergic skin manifestations.
AB  - BACKGROUND: We frequently observed allergic skin reactions in patients with
      documented history of alcoholic liver disease (ALD). To assess the potential
      association between alcohol-induced liver damage and urticaria a prospective
      randomized trial investigating immunologic parameters in various stages of
      alcoholic liver disease was designed. Fifty patients were available for analysis.
      METHODS: By means of a multivariate discriminant analysis seven out of a number
      of laboratory and clinical parameters (level of serum proteins, serum globulins,
      gamma globulins, albumin/globulin ratio, and immunoglobulins A, E, and G) have
      been found important for analysis. They were compared with age, general clinical
      status, degree of progression of alcoholic liver disease, and frequency of
      appearance of type I skin reactions. Results were further processed by means of
      logistic general linear models, Chi-square test, and summarized in a structural
      equation model. RESULTS: Alcoholic liver disease does not influence IgA, IgG, and
      A/G Index directly, but it increases levels of IgE. About 13% of variance of IgA,
      IgG, and A/G Index are affected by group membership only in non-alcoholic liver
      disease, and 27% of variance of IgE can be explained by alcoholic liver disease.
      There were striking differences in IgE content between alcoholic liver disease
      and control groups. Degree of liver disease had a negative impact on A/G Index,
      and on IgA, and a positive on IgG. About 16% of variance can be explained by
      degree of liver disease. IgE is not degree related. Alcoholic liver disease as a
      disease was found as the most important predictor of skin reactivity (p =
      0.0046). Of all immunologic parameters investigated IgE followed by A/G Index was
      found as the most significant predictor of allergic skin reactions. The extent of
      alcoholic liver disease plays not a role in allergic skin manifestations.
      Alcoholic nature of liver disease itself is a significant factor causing allergic
      skin reactions (p = 0.0002), but alcoholism itself as an independent factor
      contributes to increased incidence of skin allergies. CONCLUSIONS: Alcoholic
      liver disease plays an important role in development of type I allergic skin
      manifestations. This effect has a direct mechanism through alcohol itself, and an
      indirect through elevation of IgE. Alcohol in liver disease and not liver disease
      causes immunologic abnormalities and accounts significantly for increased
      appearance of allergic skin reactions regardless of the extent of underlying
      liver disease.

PMID- 15022579
TI  - [Color-Doppler ultrasonography in the diagnostic evaluation of erectile
      dysfunction].
AB  - Color-Doppler sonography (CDS) of the cavernosal arteries has received
      considerable attention since its description in 1985 by Lue et al. Color and
      Spectral Doppler analysis, provides a useful noninvasive means of evaluating both
      morphologic and hemodynamic penile abnormalities. CDS is the best method in
      diagnostic evaluation of patients with erectile dysfunction. It assesses the
      integrity of the arterial supply to the penis and provides some useful
      information on the veno-occlusive mechanism. Because the arterial diameter and
      flow rate change during the different phases of erection CDS is performed after
      pharmacostimulation with vasoactive agents. Purpose of this study is diagnostic
      evaluation patients with erectile dysfunction. PATIENTS AND METHOD: We studied 60
      patients suspected for vasculogenic ED, and 30 patients suspected for psyhogenic
      ED, assessing the morphodynamic features of cavernosal arteries by Color-Doppler
      sonography and their response to contravaernosal injection of prostaglandin E1
      (PgE1) and oral dose of Sildenafil citrate. Morphodynamic parameters evaluated by
      color Doppler sonography included: peak systolic velocity, endodiastolic
      velocity, inner arterial diameter, index and acceleration of penile blood flow.
      Patients were divided in the groups: A group (A1--10 patients < 35 years of age,
      A2--20 patients > 35 years of age) underwent pharmacotest with ICI PgE1; B group
      (B1--8 patients < 35 years of age, B2--22 patients 35 years age) were tested with
      oral dose of Sildenafil citrate and C group--30 patients who were also tested
      with the same drug. CONCLUSION: The CDS may be used to evaluate the hemodynamic
      parameters of the erectile dysfunction. Arterial insufficiency is suspected with
      poor blood flow, while veno-occlusive dysfunction is inferred in the face of
      adequate blood flow and poor erectile response.

PMID- 15022580
TI  - [Pharmacoeconomic evaluation of use of ciprofloxacin and norfloxacin with cost
      benefit analysis].
AB  - Pharmacoeconomics is application of economical principles in health and
      pharmaceutical care sector. This is comparative analysis of treatment e.i.
      therapeutic alternatives (drugs), which takes into consideration both their costs
      and their health repercussions. Cost-benefit analysis (CBA) has been used where
      effectiveness of cost was calculated by calculating the sum of costs for urinary
      infections treatment which include the cost of examinations, the costs of therapy
      with ciprofloxacin and norfloksacin, other costs associated with treatment and
      total benefit for both of treatments. CBA of costs are pointing out that it is
      economically justified to prescribe both drugs, ciprofloxacin and norfloksacin,
      due the costs-benefit are the quite equal for both.

PMID- 15022581
TI  - [Stimulation of fetal lung maturation with dexamethasone in unexpected premature
      labor].
AB  - INTRODUCTION: Preterm labour is most common complication of second half of
      pregnancy, incidence is 7 to 10% of all delivers. One of most important causes of
      increased mortality and morbidity of neonates is respiratory distress syndrome.
      Numerous studies prove that corticosteroids given antenatal to mother decrease
      the incidence of preterm delivered neonates. AIM OF THIS STUDY IS: To determined
      influence of dexamethasone given prepartal on maturation of neonatal lungs in
      correlation with gestational age. METHOD: This study include 150 pregnant women
      which delivered before 37 week of gestation. They are divide in three groups: two
      experimental and one control group. Group E1 consists of the pregnant women which
      received dexamethasone for five days in a single dose of 12 mg. Group E2 consists
      of the pregnant women which received dexamethasone less then five days, in a
      single dose of 12 mg. In the control group consists of the pregnant women which
      did not received dexamethasone. In this work we used gestational age in the
      moment of delivery. State of neonate is determined on the base of presence of
      clinical signs of respiratory distress syndrome after birth. Statistical method
      used in this work was test of proportion. RESULTS: In this work we find that
      there is a less number of neonates who has respiratory distress syndrome in group
      consists of the pregnant women which received dexamethasone for five days, 5
      (10%). In group consists of the pregnant women which received dexamethasone less
      then five days, number of neonates with respiratory distress syndrome was 12
      (24%). The number of neonates with respiratory distress syndrome in control group
      was 21 (42%). The value of test of proportion: K/E1 (the pregnant women received
      dexamethasone for five days)-z = 1.95, p < 0.05; K/E2 (pregnant women received
      dexamethasone less than five days)-z = 3.92, p < 0.05. In all three groups
      largest number of neonates with respiratory distress syndrome was between 31-34
      week of gestation. Highest mortality of neonate with respiratory distress
      syndrome was in control group, 7 (14%), than in group consists of the pregnant
      women received dexamethasone lass then five days, 4 (8%). In group consist
      pregnant women received dexamethasone for five days, there were not cases of
      mortality caused by respiratory distress syndrome. The value of test of
      proportion was z = 2.85 (p < 0.05), between control group and group consists of
      the pregnant women received dexamethasone for five days. CONCLUSION:
      Dexamethasone accelerates maturation of fetal lungs, decrease number of neonates
      with respiratory distress syndrome and improves survival in preterm delivered
      neonates. Optimal gestational age for use of dexamethasone therapy is 31 to 34
      weeks of gestation.

PMID- 15022582
TI  - [Effect of topical retinoid therapy on seborrhea using iontophoresis].
AB  - Increased sebum production is one of causes of Acne. This is under androgen
      control. Acne subjects have significantly greater sebum production than subjects
      without Acne and this relates to Acne's severity. Reduction in sebum production
      is associated with improvement in Acne and it can realize with anti-androgen
      therapy and isotretinoin therapy. But these therapies can not keep away from
      systematically influence. Topical retinoids do not affect sebum production and
      approximately 80% of tretinoin applied remains on the skin surface. Iontophoresis
      offer methods for enhancing the percutaneous absorption of drugs and increase of
      drug concentration in skin. The aim of the study was to establish possibility of
      improvement retinoin efficacy by iontophoresis. Our results show that application
      of tretinoin by iontophoresis do not affect on sebum production.

PMID- 15022583
TI  - [Specific psychopathological reactions in the civilian population with and
      without experience of war trauma].
AB  - AIM: The examined differences and specificities of psychological symptoms between
      two groups of subject with experience and without experience under siege and war
      operations. METHODS: The sample includes two groups of 50 subjects. The first
      group experienced the trauma of siege and war operations, and the second group
      were living in the place without siege and war operations. The following measures
      were used: General Questionnaire social and demographic characteristics of the
      subjects before and after the war, SCL-90-R by the author Derogatis, for the
      registration of psychopathological symptoms, Mississippi Questionnaire by the
      Keane, for PTSD. RESULTS: The drop in social and economic status is much more
      profound in subjects who experienced the trauma of siege and war operations
      compared to other group without the trauma of siege and war operations. All nine
      SCL 90-R subscales show statistically significant difference in more pronounced
      psychopathological responses in subjects who experienced the trauma of siege and
      war operations relative to subjects without the trauma of siege and war
      operations. The Mississippi questionnaire shows significant differences in PTSD
      between the two groups and higher scores for the subjects who experienced the
      trauma of siege and war operations. CONCLUSION: Based on the results war is the
      most intense form of trauma leading to intensive psychopathological responses
      including chronic PTSD. Results show that the psychopathological response is most
      intense and most frequent in the population of subjects who experienced the
      trauma of siege and war operations compared to the other group without the trauma
      of siege and war operations.

PMID- 15022584
TI  - [Effect of war trauma on the female population of Bosnia-Herzegovina: demographic
      characteristics].
AB  - The vast majority of research relates to war trauma have been performed on male
      veterans and refugees. There are very few related to female civilians,
      particularly in country of conflict origin. The objective of this paper was to
      present descriptive characteristics of demographic parameters within three BiH
      female cohorts according to their migration characteristics: displaced, domestic
      and refugees. Total of 150 women were analysed. The sample was randomly selected
      within prospective cohort study. For each cohort age, education, religion,
      marital status and number of children were analysed. Our overall distribution
      results were fairly equal to other demographic changes in entire BiH related to
      migration and ethnic cleansing as the war consequence.

PMID- 15022585
TI  - [Primary prevention as the method of choice in the prevention and decrease of
      substance dependence diseases].
AB  - The disease of the dependancy in Bosnia and Herzegovina in the postwar period are
      in the expansion, and the fact is that nobody of the competents can expose the
      correct data about the extension of this occurrence. The reason to this is that
      in the health care institutions are evident only those dependents who attend to
      treatment, and the police evident only the catched breachers of law--the
      producers and the dispersals of the drug. The periodical researches which are
      performed among the different population groups do not give unfortunately, also
      besides the setted endeavour, the right insight into this problematics. Besides
      the fact that the production and distribution of tobacco and alcohol are legal,
      cannot be neglected their lost effect onto the health by the excessive and
      longterm consummation, so to them as the psycoactive substances should dedicate
      the adequative attention. The treatment consequence of the disease dependance is
      longterm and expansive, often with uncertain outcome, especially in narcomen the
      dependence (the percentage of the recovery from 0.5-4.0%), so the basis of the
      struggle against the dependancy disease is the prevention affirmation of the
      healthy styles of living--without tobacco, alcohol and drugs. Many theoretics,
      the authors of the scientific papers from these field prevention share to three
      levels--the primary, secondary and tertial ones, but the public-health care
      approach only the primary three levels the primary prevention considers the right
      prevention which is the dam of the disease occurrence and the damage, the rest
      two levels infact are the diagnostics, treatment and the rehabilitation and not
      the aim is to them the reduce of damage, so much and if is this is possible. Of
      course, should not neglect the great difference in costs in the levels of the
      prevention: the methadone therapy and the commune for the treatment and the
      rehabilitation of the dependents encircle the small number of the dependence and
      cost hundred times more than the primary preventive programmes, which address to
      the unavoidableness of the performance of the strategy of the primary preventions
      against the disease of the dependancy.

PMID- 15022586
TI  - [Public health aspects of family/general medicine in Bosnia and Herzegovina].
AB  - By the Federal programmee of health care protection in B&H was approached by the
      reforms of the primary health care protection, by which the special accent was
      given to the development and implementation of the family medicine. There is the
      series of projects which get realized in this segment by the teens of the various
      state or expert nongovernment association, but unfortunately the official marks
      of the effect of the realization of these projects in the practice in the written
      documents or in the published papers published in the journals. It is evident
      that in the mentioned projects, how much it is to authors from before there are
      the valid experiences about that from the projects which in its time lead the
      Institute for social medicine of the Medical faculty of Sarajevo. It is the fact
      too, that still always there is no unique approach which the model of the family
      medicine adopted as the future concept of the organization of this segment of the
      primary health care protection, and the responsible carries of making decision
      and the projectants and the realizators which have offered the financial
      resources for its concept which momentary get being tested in B&H. The authors
      give their seeing of the future concept of the organization of the family
      medicine, from the aspect of the optimal programme of the health care protection
      by the team of the family medicine, and in accordance with the existing
      nomenclature and standards of the services at the level PHC.

PMID- 15022587
TI  - [Transformation of the system of care of patients with multiple injuries in
      Bosnia and Herzegovina].
AB  - Bosnia and Herzegovina, in the global transition, lives to see also the changes
      in the reconstruction of the health care system and his different segments. One
      from these segments of the healthcare is the urgent medicine. In this segments
      they attempt to find the optimal solutions of the organization of the
      polytraumatized patients in the centers for urgent medicine in the out hospital
      and the hospital institutions. With the programmes of the war and postwar
      conditions. To the programmes of the health involved some of strategies and
      concepts in this field from the developed countries and to us neighboring
      countries with those who we had tried to apply in the war and postwar conditions.
      Those solutions have to be accorded with the general conceptions of the
      development of healthcare in the future period in B&H, and the response, and
      supported on the organizational, functional, technologic and the income--based
      changes of the prehospital and hospital institutions, first of all in the city
      Sarajevo, and then also in other regions of Bosnia and Herzegovina. At the
      example of the transformation of the system of taking care of the polytraumatized
      patients in the Center for urgent medicine the Clinical Center of the University
      of Sarajevo the authors suggest some kind of the unique solution for the rest
      healthcare of the institutions of the similar types in Bosnia and Herzegovina.

PMID- 15022588
TI  - [Stem cells: general characteristics and perspectives of their clinical use].
AB  - Culturing of embryonic and adult stem cells (SC) is characterized. Animal
      experiments on models of human pathology (diabetes mellitus, acute myocardial
      unfarction, cerebral stroke, Parkinson's disease, etc.) have shown that use of SC
      is associated with good effects on the diseases. Pilot results of SC treatment of
      acute myocardial infarction, parkinsonism, hemoblastoses, systemic lupus
      erythematosus, rheumatoid arthritis and others are reviewed.

PMID- 15022589
TI  - [Role of thyroid hormones in regulation of heart function].
AB  - Current data on mechanisms of action of thyroid hormones--T3 and T4--on
      molecular, cellular and organic organs obtained in experimental and clinical
      conditions are reviewed. The results of examination of patients with hypo- and
      hyperthyroidism as well as some clinical syndromes (heart arrhythmia, heart
      failure) have shown physiological and pathophysiological participation of thyroid
      hormones in regulation of cardiac activity at the level of hemodynamics and
      myocardial metabolism.

PMID- 15022590
TI  - [Young's syndrome: morphologic, functional and genetic aspects of the mucociliary
      system].
AB  - The article presents analysis of functional-morphological and genetic aspects and
      condition of reproductive system in Young's syndrome. On the basis of the study
      of the mucociliary system a working conception is proposed of Young's syndrome
      pathogenesis in terms of mucociliary systems of the airways.

PMID- 15022591
TI  - [Diagnosis, pharmacologic therapy and prevention of urolithiasis].
AB  - The article reviews present-day pathogenetic and diagnostic conceptions and
      methods of diagnosis of urolithiasis. Its medication and prevention methods are
      outlined.

PMID- 15022592
TI  - [Hormonal dysregulation of lipid metabolism in pathogenesis of ischemic heart
      disease].
AB  - The aim of the study was to specify postprandial hyperlipidemia (PHL) and the
      level of hormones which regulate metabolism, lipids in particular, in patients
      with ischemic heart disease (IHD) vs those in healthy persons and patients with
      thyrotoxicosis as well as to clarify whether IHD pathogenesis correlates with fat
      metabolism disturbance. Lipid and apoprotein parameters of dyslipoproteinemia,
      concentrations of insulin, hydrocortisone, T3, T4 and thyrotropic hormone were
      tested before and 3, 6 hours after fat loading in IHD patients with
      angiographically documented coronary atherosclerosis, in healthy persons and
      patients with diffuse toxic goiter. In IHD patients postprandial PHL differed
      from that in healthy persons and thyrotoxicosis patients by higher and growing up
      to hour 6 after fat loading hypertriglyceridemia associated with lowering of
      antiatherogenic cholesterol of HDLP. In thyrotoxicosis both fasting and afterload
      lipid and apoprotein indices of the lipoprotein spectrum continued at low level
      except triglycerides the level of which returned to normal level. The hormonal
      spectrum in IHD patients was characterized by higher fasting insulin and its
      noticeable rise after fat loading. As healthy persons and patients with
      thyrotoxicosis had no significant changes in hormones levels after fat loading,
      it is suggested that development of atherogenic postprandial PHL caused primarily
      by hormone dysregulation of fat metabolism with a leading role of
      hyperinsulinemia contributes much to pathogenesis of IHD.

PMID- 15022593
TI  - [Development and course of arterial hypertension based on 24-hour monitoring of
      arterial pressure in a population of the Tyumen region].
AB  - Arterial pressure (AP) was monitored in 46 patients with arterial hypertension
      (AH) aged 18-50 years and in 33 healthy subjects living in Russian North (Tyumen
      Ob area, Nyagan). The comparison group consisted of 55 patients with AH and 33
      healthy subjects living in a moderate climatic zone (Tyumen). The groups were
      comparable by gender, age, duration of AH, office systolic and diastolic AP (SAP
      and DAP). Healthy subjects of Tyumen North compared to those living in the
      moderate climate had more pronounced vegetative imbalance which may transform
      into AH. The North AH is characterized by high meteorability, impaired circadian
      AH profile with reduction of the SAP fall day-night and an increase of the DAP
      fall, greater variability of AP, elevated AP day load, low night DAP. This
      classifies AH in the northerners as isolated systolic. While AH development in
      the North takes place due to marked AP fluctuations, in moderate climate it
      follows a classic variant--due to a DAP rise. The above changes may help
      prognosis of emergence of cardiovascular complications in hypertensive patients
      living in the North.

PMID- 15022594
TI  - [Arterial hypertension as a psychosomatic problem].
AB  - Current conception of stratification of arterial hypertension (AH) risk comprises
      a general strategy of its prevention, treatment and prognosis with consideration
      of personality, medical and social characteristics of the patients. In view of
      this AH is regarded a psychosomatic problem including somatic, psychic and social
      aspects. Of importance is AH study in patients with nonpsychotic mental disorders
      using methods of systemic analysis, multivariate probability models, in
      particular. The most adequate model is logistic regression. Our study included
      1350 patients with borderline conditions. The developed model systems allowed
      isolation of the most significant somatic, psychic and psychosocial factors which
      can be applied as additional predictors of AH risk. Also, the results of the
      analysis may be useful in preventive interventions regarding individual spectrum
      of AH risk under joint efforts of internists, psychiatrist and psychotherapist.

PMID- 15022595
TI  - [Clinical characteristics of respiratory infection in patients with hematologic
      malignancy and neutropenia].
AB  - The aim of the study was a comparative assessment of clinical and laboratory
      findings characterizing the course of pneumonia or bronchitis in patients with
      hematological malignancy (HM) and neutropenia. The course of the respiratory
      infections (RI) was studied in 47 HM patients. RI in HM were found to develop in
      patients with a large tumor, in bone marrow involvement, in patients without a
      complete remission, more frequently pneumonia arises in acute leukemia,
      bronchitis--in patients with lymphoproliferative diseases. Among causative agents
      Gram-negative and Gram-positive microorganisms were detected at the same rate
      (44.2 and 45.9%, respectively), fungi were diagnosed in 9.8% cases.
      Enterobacteriaceae microorganisms were found more often in patients with
      pneumonia. Gram-positive agents occurred more frequently in bronchitis. Such
      clinical markers in neutropenic patients as dyspnea, dullness in the lung,
      weakened respiration, moist rales in the lungs and fever 39 degrees C and higher
      point to pneumonia. If the above markers are absent but there is cough, fever 38
      39 degrees C, tough respiration, dry rales both pneumonia and bronchitis are
      possible.

PMID- 15022596
TI  - [Psychosomatic correlations and autonomic regulation of systemic hemodynamics in
      peptic ulcer in people of the European North of the Russian Federation].
AB  - The examination of 71 patients with ulcer has established correlations between
      psychological status of the patients (personality and reactive anxiety,
      neurotism, type of personality response to the disease) and numerous clinical
      characteristics of the diseases. Features of vegetative regulation of systemic
      hemodynamics in ulcer northerners and correlations between vegetative tonicity
      and psychological status of the patients are characterized.

PMID- 15022597
TI  - [Differential diagnosis of diabetes mellitus in adults: assessment of
      immunogenetic markers of insulin dependence].
AB  - To assess immunogenetic markers of insulin dependence (IMID), 117 patients with
      diabetes mellitus of the adults (DMA) were examined. Of them, 97 patients (77
      females and 20 males, 41 and 10 obese, respectively) were insulin dependent and
      20 (8 males and 12 females) had classic diabetes mellitus (DM) type 2. All the
      analysed immunogenetic markers (genotype SS/SS, alleles 04*, 0301 in HLA-DQ*A2,
      haplotype A1*0301-B1*0302) were associated most often with insulin-dependent DMA.
      The following conclusions were made: both DMA variants can be definitely
      differentiated only by clinico-anamnestic screening; there were no differences in
      distribution of the alleles 0301 in DQ*A1 and 0302 in DQ*B1 in different variants
      of DMA; alleles 04* and 0301 DQ*A1 significantly more frequently occur in DM type
      1 than DM type 2; 0301 allele was more frequent in patients with insulin
      dependent DM type 2 vs DM type 2; an expectant genetic marker of insulin
      dependence (haplotype 0301/0302) occurs significantly more frequently in insulin
      dependent DMA than in healthy subjects and DM type 2.

PMID- 15022598
TI  - [Chronic bronchitis: participation of red cells in the pathologic process].
AB  - To study characteristics of structural-metabolic status and function of
      erythrocytes in patients with chronic bronchitis (CB), the examination was made
      of 53 CB patients (39 male and 14 female). A complex study of morphofunctional
      state of peripheral erythron included investigation of protein and lipid
      composition, microviscosity of the lipid phase of erythrocyte membrane, surface
      architectonics, ultrastructure, reversible aggregation of red cells,
      concentrations of sulfhydric groups, lipoproteins and dry cell mass in
      erythrocytes. CB patients were found to have prominent defects in membrane
      structure and metabolism of mature red cells (reduced dry mass and concentration
      of sulfhydric groups and lipoproteins, abnormal protein composition and lipid
      membrane spectrum, increased viscosity of membrane lipid bilayer), alterations of
      surface architectonics, shape, ultrastructure of erythrocytes. Disorders in
      structural-metabolic status of erythrocytes in CB patients affected their
      functional features, the ability for reversible aggregation, in particular.
      Functional disturbances of erythrocytes in CB patients aggravate the course of
      the disease and need correction with membrane-stabilizing and membrane-repairing
      drugs.

PMID- 15022599
TI  - [Current algorithm of therapy for peptic ulcer].

PMID- 15022600
TI  - [Antibiotic-associated enterocolitis].

PMID- 15022601
TI  - [Trace elements and endemic goiter].
AB  - The effects of xenobiotics on morphological structure and function of the thyroid
      gland (TG) were analysed. Salts of heavy metals (zink, lead, copper, cadmium,
      surma etc.) were measured in TG of 152 citizens of Kama region who had died of
      trauma in the 1960s (n = 73), 1990s (n = 20) and 2000s (n = 52). TG is shown to
      accumulate xenobiotics. As the examinees had no occupational contact with heavy
      metal salts (HMS), their deposits in TG is explained by anthropogenic pollution
      of the environment. HMS in the thyroid tissue was much lower than in later
      decades indicating aggravation of environmental pollution in the Urals. Being
      protoplasmic poisons, HMS bind proteins and provoke immune reaction. All the
      examinees who died after 2000 had histologically proved deposits of
      immunocompetent cells in TG tissue--lymphoid and plasmic TG infiltration. In the
      1960s these TG alterations were absent. Goiter endemia can be stopped by
      improvement of environmental protection in each ecopolluted region and mass
      iodine prophylaxis.

PMID- 15022602
TI  - [Giant cyst of the pancreas as a complication of chronic alcoholic pancreatitis].

PMID- 15022604
TI  - [Cholesterol determination methods (a literature review)].

PMID- 15022603
TI  - [Marked primary hyperparathyroidism not diagnosed before death].
AB  - A case of primary hyperparathyroidism (PHPT) in a patient 47 years of age
      diagnosed only at autopsy is reported. PHPT deposits of calcium into the muscles
      and heart vessels provoked irreversible cardiovascular disorders which caused
      death. Renal lesions were intravitally diagnosed as isolated urolithiasis but not
      as manifestations of PHPT. High blood levels of ionised calcium in this patient
      were thought a laboratory mistake though the above clinical symptoms should have
      excluded such opinion.

PMID- 15022605
TI  - [Biochemical markers of the bone tissue metabolism and bone densitometry in
      primary hyperparathyroidism].

PMID- 15022606
TI  - [Analysis of nitrites and nitrates (Unox) in urine].
AB  - Nitrite (NO2) and nitrate (NO3) concentrations are usually measured as a marker
      of NO metabolism. The aim of this study was to validate and standardize a method
      for the quantification of these two metabolites (nitrite and nitrate) in urine.
      The sample (urine) were deproteinized with NaOH, zinc sulfate and reduced with
      cadmium granules. Analytical recovery of NO3 added to urine samples after
      reduction with cadmium granules was 96-105% (Griess reaction). Calibration curves
      for nitrite and nitrate were linear over the concentration range of 2.1 to 200
      micromole/L in urine. The detection limit of the assay was 0.9 micromole/L and
      the quantification limit was 2.1 micromole/L. Usual values were determined for
      healthy subjects: the mean concentration of NO2/NO3 (Unox) was 51.1 +/- 5.3
      micromole/mmol creatinine (mean +/- SEM) (n = 15). Within-run precision was 6.6%
      and between-day precision was 2.2%.

PMID- 15022607
TI  - [Analysis of the mutagenic activity examplified by interaction of DNA bases with
      nitrous acid].
AB  - Chromatography and spectrophotometry techniques were designed to evaluate both
      qualitatively and quantitatively a degree of DNA-base deamination provoked by
      nitric acid. A possibility is shown of how to apply the above method in studying
      the mutagene activity of deaminating agents.

PMID- 15022608
TI  - [Strategic approach to glycohemoglobin determination].
AB  - The purpose of the case study was to design an approach involving the clinical
      use of glycated hemoglobin (GH) in patients with diabetes mellitus (DM). 139
      patients with DM, types 1 and 2, were examined. GH was quantified by 4 methods,
      i.e. immunochemistry, colorimetry, by oxalic and phosphoric acids and by
      isoelectrofocusing. It was revealed by correlation and regression assays that the
      GH level made a non-linear bond and depended to a great extent on a daily
      glucosuria, daily proteinuria, total serum cholesterol, body weight index and
      disease duration. Whereas no such bond was found for accidental pre- and
      postprandial glycemias. The conclusion is that, with due respect to a comparative
      analysis of different techniques applicable to GH quantification, the discussed
      index still remains a reliable criterion of the profound metabolic conditions,
      and that argumentative methods must be used in its quantification.

PMID- 15022609
TI  - [Comprehensive evaluation of the immune system and various cytokines in patients
      with iron-deficient anemia].
AB  - The functional status of the immune condition was comprehensively evaluated in
      145 patients with posthemorrhagic iron-deficient anemia (IDA) and in 40 virtually
      healthy subjects (controls) by immune-diagnosis tests, degrees 1 to 3. Cytokines
      (negative hemopoiesis regulators), i.e. interleukins 1 and 6 (IL-1 and IL-6),
      tumor necrosis factor alpha (TNF-alpha) and INF-gamma were investigated. A 3
      phase immune-enzyme assay with horse-radish peroxidase as enzyme indicator and
      the "Protein Contour" test-system were made use of. Impairments of the non
      specific, cellular and humoral immunities were found in IDA patients; excessive
      concentrations of IL-1, IL-6 and TNF-alpha were observed in the same group of
      patients, which can explain some of the intercellular interaction mechanisms and
      which can be related with a negative impact exerted by interleukins on
      erythropoiesis in the discussed pathology. Decreasing concentrations of IL-1, IL
      6, TNF-alpha and INF-gamma in IDA patients due to an adequate therapy by iron
      containing drugs is a positive phenomenon in recovering the functional status of
      the immune system; it denotes that the maturation of hemoglobin-containing
      erythron variations and the secondary immune insufficiency are reviving.

PMID- 15022610
TI  - [Laboratory diagnosis of histiocytosis in children (a lecture)].

PMID- 15022611
TI  - [Use of detergents for elimination of non-specific reactions of monoclonal
      antibodies].
AB  - The purpose of the case study was elaboration of methods for removing the false
      positive results in the detection of virus antigens that cause acute respiratory
      lesions both in the plane and dot-membrane variations of immune-enzyme assays of
      monoclonal antibodies. Modeled experiments showed that the non-specific staining
      of biological samples, in which the above viral antigen are looked for, is
      preconditioned by a direct reaction of the substrate with its own oxidizing
      enzymes and by the binding of monoclonal antibodies with biological
      macromolecules free of any viral adherence and sorbated in the solid phase.
      Approaches to solving such issues are described in the paper. They comprise the
      inhibition of the own oxidizing activity of wash-outs by the substrate and the
      application of detergents. Different detergents were comparatively analyzed and
      the optimal compounds were chosen for each variation of immune-enzyme test
      systems. The described techniques ensure more reliable results in the viral
      antigen detection by immune-enzyme assay.

PMID- 15022612
TI  - [Comparative analysis of the functional activity of neutrophil granulocytes from
      blood of patients with renal cell carcinoma before and after the surgical
      treatment].
AB  - Patients with renal cell carcinoma (RCC) were examined by the chemiluminescent
      analysis before and after surgery. The cells of subjects with the discussed
      pathology were found to be in the state of functionally metabolic misbalance,
      i.e. an increased initial level of the synthesis of active oxygen with a
      relatively reduced cell reactivity when additionally stimulated. Such specificity
      of neutrophil granulocytes of peripheral blood is more pronounced in RCC patients
      after surgery. Supposedly, the above phenomenon is preconditioned by a lack of
      metabolic reserves that could provide an adequate functional response to extra
      stimulation and it develops due to a prolonged tumor progression and stress
      brought about by surgical intervention.

PMID- 15022613
TI  - [Cytometric criteria of evaluation of bronchial epithelium dysplasia with various
      types of therapy].
AB  - Examinations of 111 patients with chronic non-specific pulmonary lesion revealed
      the dysplastic changes in the bronchial wall in 90 of them. 47 patients received
      the routine anti-inflammatory therapy course and another 43 patients underwent
      the endoscopic laser therapy. Cytometry, made before and after therapy, provided
      for an objective differentiation of signs in different-severity bronchial
      dysplasia. The application of endoscopic laser irradiation in the correction of
      pretumor changers in the bronchial tree was shown to be effective in 95.3% of
      cases, whereas the routine treatment turned out to be ineffective.

PMID- 15022614
TI  - [Morphological types of the glandular epithelium nuclei from benign and malignant
      mammary gland diseases].
AB  - The morphometric parameters of the nuclear-nucleolar apparatus of benign and
      malignant mammary cells were investigated by computer-aided morphometry of
      cytological specimen stained by a 50% silver nitrate solution. On the basis of a
      static analysis of measurement results a computer soft was created to classify
      the nuclei. The soft, with respect to an analysis of the discriminative functions
      and to a variety of formally logical limitations, subdivides the nuclei into 6
      morphotypes with variations "a" and "b", which correspond to certain clinical and
      morphological variants of breast diseases. From the practical viewpoint, the
      subdivision of nuclei into the 3rd and 4th morphotypes is most interesting
      because it can provide the clinical cytology expert with extra information for
      the differential diagnostics of proliferative and malignant transformations in
      the mammary glands as well as for the definition of dysplasia stages and for the
      determination of tumor-cell malignancy degree.

PMID- 15022615
TI  - [Diagnosis of tropical malaria by express-methods].
AB  - An examination of a thick blood drop and of blood smear for the presence of
      plasmodia is a classic and indisputable diagnostic test for tropic malaria.
      However, express-methods, based on the immune-enzyme analysis, have been
      introduced into the health-care practice primarily in developing and
      underdeveloped countries. The diagnosis of tropic malaria by using the discussed
      methods enables, in the non-laboratory settings, a rapid and reliable detection
      of PI. falciparum in blood. This is important because an untimely diagnosis of
      tropic malaria increases the risk of the lethal outcome.

PMID- 15022616
TI  - [Analysis of virulent and avirulent strains of Vibrio cholerae by the nest
      polymerase chain reaction].
AB  - The detection of cholera enterotoxin in environmental objects and isolation of
      patients are considered to be the most reliable indices of that the cholera agent
      is present. Described in the case study is a method of nested polymerase chain
      reaction (PCR) based on amplifying the ctxA gene fragment coding subunit A of
      enterotoxin. A possibility was shown to use the above method to confirm the
      virulence of strains Vibrio cholerae isolated from different sources. The method
      was tested with 18 virulent and avirulent strains V. cholerae as well as (for the
      sake of verifying the analysis specificity) with DNAs of other human-pathogenic
      microorganisms and with the human genome DNA. The results showed a high
      efficiency of nested PCR in detecting the pathogenicity of cholera-agent strains.

PMID- 15022617
TI  - [Selective culture media for Haemophilus bacteria].
AB  - A selectivity factor was specified to the previously developed nutrient medium
      meant for the cultivation of Haemophilus bacteria--CAE, which is based on the
      acid hydrolysate of casein, enzyme hydrolysate of animal blood (aminopeptide) and
      an extract of nutrient yeast. The above nutrient medium containing additionally
      growth factors V and X, glucose and bacitracin was shown to fit well for the
      primary sowing of Haemophilus bacteria and it can be used in diagnostic
      examinations.

PMID- 15022618
TI  - [Current technologies for enhancing efficiency of laboratory techniques].
AB  - The current approaches to promoting the efficiency of applying the laboratory
      tools were comprehensively analyzed. It was for the first time that the above
      issue was considered from the standpoint of a scientifically substantiated
      management scheme applicable to the laboratory examination volume and within the
      framework of the modern conclusive medicine. The problem can be solved through
      starting, in each clinic, an independent research project and through patient
      management (critical course--technological card) with respect to available
      technological and personnel resources. Finally, the basic principles are outlined
      that are needed for designing the technological cards; the related role of
      experts in clinical laboratory diagnostics is demonstrated.

PMID- 15022619
TI  - [Further thoughts about the loss of appreciation for the medical profession].

PMID- 15022620
TI  - [Biological behavior of polypropylene meshes suitable for intra-abdominal
      implantation in animal model].
AB  - The expected incisional hernia rate is between 11-20% after laparotomy. Using
      mesh repair the results of the hernioplasty have recently improved. However the
      complication of mesh implants--especially in intraperitoneal position--can be
      life threatening. Additionally the appropriate mesh is expensive. We tried to
      create a mesh, which can be used intraperitoneally and generates adhesion in the
      abdominal wall, but keeps the intraabdominal organs adhesion free. Our
      experiments were divided into four groups. In the first we used different
      materials to cover the intraperitoneal side of polypropylene mesh. In the second
      phase three different pore-sized meshes were compared. In the third part the
      biological behavior of three different material-reduced meshes were investigated.
      Based on our previous results in the last session we used only silicone membrane
      protected material-reduced polypropylene meshes to cover the abdominal defects.
      Our experiments have shown that intraperitoneal implant with silicone-covered
      Vypro (Ethicon)/Premilene (B. Braun Medical) mesh significantly decreases the
      formations of adhesion.

PMID- 15022621
TI  - [Neoadjuvant chemotherapy for locally advanced gastric cancer].
AB  - Only surgical resection offers cure in gastric cancer. Curative resection
      unfortunately is possible only in about every second patient diagnosed with
      gastric cancer. Neoadjuvant chemotherapy may help to reach R0 resection in
      patients with locally advanced gastric cancer. AIM: To evaluate the ability of
      ECF neoadjuvant chemotherapy in locally advanced gastric cancer. PATIENTS AND
      METHODS: Between December 1998 and April 2003 twenty-four patients with locally
      advanced gastric cancer were given neoadjuvant chemotherapy according to the ECF
      scheme. Before treatment, staging examinations were carried out: endoscopy,
      barium swallow, chest X-ray, computer-tomography and laparotomy or diagnostic
      laparoscopy. We treated patients with four three-weeks-long courses of
      chemotherapy with bolus injection of epirubicin and cisplatin on day 1, and
      continuous infusion of 5-fluorouracil on day 1 to 21. Twelve weeks long treatment
      was followed by 4 weeks free of treatment, than staging was repeated to determine
      response. RESULTS: 45.83% response rate was achieved. One complete response was
      observed. Ten patients showed partial response, 3 stable diseases and 10
      progressive disease were detected. Twenty-one patients were operated on. Sixteen
      resections were carried out, ten with curative intent. Overall survival and
      disease free survival in the whole group were 12.19 and 8.66 months, while in
      patients with R0 resection 20.66 and 18.33 months. CONCLUSION: Neoadjuvant
      chemotherapy provides a hope for cure for patient with locally advanced gastric
      cancer.

PMID- 15022622
TI  - [The role of glucocorticoid-dependent mechanisms in the progression of
      experimentally induced acute pancreatitis].
AB  - BACKGROUND: The effects of glucocorticoids on acute pancreatitis (AP) have
      remained contradictory. To investigate the time courses of the effects of the
      exogenous glucocorticoid agonists dexamethasone (DEX) and hydrocortisone (HYD)
      and a glucocorticoid antagonist (RU-38486), and to characterize the local and
      systemic responses in experimental AP. METHODS: The glucocorticoid agonists and
      antagonist were administered just before AP induction. Serum amylase activity
      determinations, IL-6 bioassays, pancreatic weight/body weight ratio measurements
      and survival analysis were performed. Liver and lung injuries were assessed via
      neutrophil leukocyte infiltration in myeloperoxidase (MPO) assays, tissue
      adenosine triphosphate (ATP) level determinations and histology. RESULTS: In the
      glucocorticoid agonist groups, the survival rate increased, while the serum
      amylase level, the IL-6 activity and the pancreatic weight/body weight ratio
      decreased significantly as compared with the control and RU-treated groups. AP
      resulted in significant decreases in tissue ATP levels in both the liver and the
      lung. In the DEX- or HYD-treated groups, the liver ATP levels were significantly
      elevated, while both the liver and the lung MPO levels were attenuated as
      compared with the AP and RU-treated groups. CONCLUSIONS: These results suggest
      that glucocorticoids may play important roles in mitigating the progression of
      the inflammatory reaction during the early phases of AP.

PMID- 15022623
TI  - [Results of 300 kidney transplantations].
AB  - Kidney transplantation is a widely used method for the treatment o fend-stage
      renal disease. Between September 3, 1993 and December 2002 a total of 300 kidney
      transplantations were performed at the Department of Surgery at the Medical
      University of Pecs. In 24 patients simultaneous kidney and pancreas
      transplantation was performed. The mean age of the 189 male and 111 female
      patients was 42 years. The HLA B, Dr tissue antigen mismatches was 1.63. The
      average cold ischemic time was 1199 minutes whereas the average anastomotic time
      was 43 minutes. Early surgical complications happened to 16 patients. In spite of
      the immunosuppressive treatment 26 acute steroid resistant rejection have
      occurred, 9 of which were irreversible. In our opinion the meticulous surgical
      technique is as important as the postoperative care is. The early and late
      complications of 300 renal transplants are reviewed by the authors.

PMID- 15022624
TI  - [Surgical treatment of pulmonary embolism].
AB  - The authors describe the pathology and the symptoms of pulmonary embolism with
      possible therapies, including thrombolysis and suction extraction. We performed
      two successful operations and after the examination of the data of the literature
      we think that in most patients the conditions for immediate surgery are not
      present. After the acute period, when the cardio-respiratory status is stabile,
      pulmonary embolectomy can result in complete recovery. Extracorporeal circulation
      and cardiac surgical background are necessary for the intervention. The seven
      Hungarian adult cardiac surgical centers could save the life of many patients.

PMID- 15022625
TI  - [Changes in the operability of colorectal cancers in the past twenty years].
AB  - We lose more than 3000 patients a year in Hungary as a result of colorectal
      cancer. Our aim was to determine how the last 20 years' development of surgical
      techniques and related specialties has affected the outcome in this patient group
      at our Department. This retrospective study shows a significant increase in the
      resectability of colorectal cancer, while there has been a substantial decrease
      in perioperative mortality.

PMID- 15022626
TI  - [Resectable esophageal metastasis of stomach cancer].
AB  - The appearance of distant metastases meant in the past, that gastric cancer was
      incurable. However, experience with colorectal cancer has shown that patients
      with distant metastasis may have a chance for cure, if metastatic disease can be
      completely resected. Considering these experiences in the literature it seems
      that the judgement of gastric cancer has recently changed. It is reasonable to
      excise late and isolated metastasis in some patients to improve the prognosis.
      The authors report a successfully treated case of gastric adenocarcinoma with an
      usual, oesophageal metastasis.

PMID- 15022627
TI  - [Pancreas resection for lung cancer metastasis].
AB  - This case report describes the successful resection of a solitary pancreatic
      metastasis that developed 21 months following lobectomy of an early pulmonary
      adenocarcinoma (pT1N0M0). The metastasis caused no complaints. The resected
      pancreas contained a glucagonoma in addition to the metastasis. In the literature
      we have found no similar case of simultaneous operable metastatic and a secondary
      pancreatic tumor.

PMID- 15022628
TI  - [Evidence for otorhinolaryngology and surgical treatment of head and neck surgery
      -evidence for the management of papillary thyroid cancer].

PMID- 15022629
TI  - [Postoperative hyponatremia in children: pathophysiology, diagnosis and
      treatment].
AB  - OBJECTIVES: To review the current data on pathophysiology, causes and management
      of postoperative hyponatremia in children. DATA SOURCES AND EXTRACTION: The
      Pubmed database was searched for articles, combined with references analysis of
      major articles on the field. DATA SYNTHESIS: The incidence of postoperative
      hyponatremia has been evaluated at 0.34% and its mortality significant.
      Postoperative hyponatremia is triggered by the diminished renal ability to
      excrete free water, due to antidiuretic hormone release. Inappropriate secretion
      of antidiuretic hormone is frequently seen after spine, cardiac and neurosurgery
      but can occur even after minor surgery. In this context, the infusion of
      hypotonic fluids represents a strong risk factor for developing hyponatremia.
      Other causes of hyponatremia are represented by extrarenal fluid losses, cerebral
      salt wasting syndrome, desalination phenomenon, adrenal insufficiency or some
      medications. Preventive treatment is essential and based on prohibition of
      hypotonic fluids infusion and the use of isotonic fluids infusions, maintenance
      of a normal total blood volume, the observance of the good practice
      recommendations for fluid infusion in children, and frequent blood and urine
      sodium concentration determinations in patients at risk for developing
      hyponatremia. Hyponatremic encephalopathy requires an emergent management,
      consisting in respiratory care and hypertonic sodium chloride infusion. Chronic
      hyponatremia is most often asymptomatic and the main neurological risk factor is
      represented by a too rapid correction of plasma sodium, which may lead to
      centropontine myelinolysis.

PMID- 15022630
TI  - [Nosocomial urinary tract infections in adults].

PMID- 15022631
TI  - Consent rule in EU clinical trial directive triggers concern. Experts fear new
      consent guidance could harm patients' rights and leave hospital staff at risk of
      litigation.

PMID- 15022632
TI  - Current awareness on yeast.

PMID- 15022634
TI  - USA won't sign landmine treaty.

PMID- 15022635
TI  - The operons, a criterion to compare the reliability of transcriptome analysis
      tools: ICA is more reliable than ANOVA, PLS and PCA.
AB  - The number of statistical tools used to analyze transcriptome data is
      continuously increasing and no one, definitive method has so far emerged. There
      is a need for comparison and a number of different approaches has been taken to
      evaluate the effectiveness of the different statistical tools available for
      microarray analyses. In this paper, we describe a simple and efficient protocol
      to compare the reliability of different statistical tools available for
      microarray analyses. It exploits the fact that genes within an operon exhibit the
      same expression patterns. In order to compare the tools, the genes are ranked
      according to the most relevant criterion for each tool; for each tool we look at
      the number of different operons represented within the first twenty genes
      detected. We then look at the size of the interval within which we find the most
      significant genes belonging to each operon in question. This allows us to define
      and estimate the sensitivity and accuracy of each statistical tool. We have
      compared four statistical tools using Bacillus subtilis expression data: the
      analysis of variance (ANOVA), the principal component analysis (PCA), the
      independent component analysis (ICA) and the partial least square regression
      (PLS). Our results show ICA to be the most sensitive and accurate of the tools
      tested. In this article, we have used the protocol to compare statistical tools
      applied to the analysis of differential gene expression. However, it can also be
      applied without modification to compare the statistical tools developed for other
      types of transcriptome analyses, like the study of gene co-expression.

PMID- 15022636
TI  - IBM victorious in employee cancer lawsuit.

PMID- 15022637
TI  - UNICEF calls for action to protect indigenous children.

PMID- 15022633
TI  - New ways with old bones. Osteoporosis researchers look for drugs to replace
      hormone replacement therapy.

PMID- 15022638
TI  - Amnesty campaigns to stop gender violence.

PMID- 15022639
TI  - UK Prime Minister launches commission for Africa.

PMID- 15022641
TI  - USA pressured to ease trade demands.

PMID- 15022640
TI  - Proteome-wide classification and identification of mammalian-type GPCRs by binary
      topology pattern.
AB  - G protein-coupled receptors (GPCRs), a large eukaryotic protein family, have
      proved difficult to comprehensively detect and functionally identify by homology
      searches and domain detection, because they are highly divergent and their
      sequences share strikingly little similarity. Transmembrane (TM) topology pattern
      analysis has been used to classify TM proteins, and such patterns are conserved
      within GPCRs of similar function. Here, we developed a stepwise binary topology
      pattern (BTP) method for GPCR classification and identification and used it to
      identify and classify mammalian-type GPCRs in the genomes of 10 different
      eukaryotic species. A binary topology pattern was obtained for each functional
      class or group by assigning binary loop threshold lengths of "0" (short loop) or
      "1" (long loop). The GPCR-classification ability of the BTP method had quite high
      accuracies for classifying GPCR functions at the class level (Classes A, B, C,
      Frizzled/Smoothened, Non-GPCR, based on the GPCRDB classification scheme), with
      many classes being classified with 100% accuracy. Sufficiently high accuracies
      were also maintained at the functional group level, 0.945 over 15 functional
      groups. Proteome-wide mammalian-type GPCR searches in 10 eukaryotic genomes (H.
      sapiens, M. musculus, F. rubripes, C. intestinalis, A. thaliana, D. melanogaster,
      A. gambiae, C. elegans, P. falciparum, S. cerevisiae) using the BTP method showed
      much higher classification/identification in non-mammalian genomes than typical
      BLAST searches, in which a higher number of sequences were classified as Non
      GPCR. This stepwise BTP method should prove useful for the identification and
      functional classification of GPCRs from the genomes of a wide range of species.

PMID- 15022642
TI  - ConPred_elite: a highly reliable approach to transmembrane topology predication.
AB  - The function of transmembrane (TM) proteins is closely correlated to their TM
      topology; large quantities of highly reliable TM topology data are becoming
      increasingly required. We present a new consensus approach for TM topology
      prediction (ConPred_elite) that can predict the whole topology with accuracies of
      0.98 for prokaryotic and 0.95 for eukaryotic proteins on a dataset of
      experimentally-characterized TM topologies. The predicted yield on the dataset is
      30.4% for prokaryotic and 21.5% for eukaryotic proteins. Applying ConPred_elite
      to predicted TM proteins extracted from 29 prokaryotic and 10 eukaryotic
      proteomes, we obtained 3871 and 7271 highly reliable TM topologies (yields, 19.8
      and 13.3%), respectively. The predicted TM topology data may contribute to
      further research into a comprehensive functional classification and
      identification of TM proteins based on information of the topology.

PMID- 15022643
TI  - UK consultants call for reform of national health service. Consultants say that
      European systems, based on compulsory insurance contributions, would be better.

PMID- 15022644
TI  - Prediction of peptide conformation using a scale-transformed entropy sampling
      algorithm.
AB  - An algorithm for predicting the lowest energy structure of a peptide has been
      developed. High-energy barriers on an energy surface can be easily overcome by
      logarithmically transforming the energy space. For efficient optimizations, the
      energy space is searched using a scale-transformed entropy sampling method, and
      conformations specific to a primary structure of the peptide are sampled with
      large weights. The efficiency of the present method is demonstrated by
      calculations on cholecystokinin octapeptide (CCK-8).

PMID- 15022645
TI  - A statement by the editors of The Lancet.

PMID- 15022646
TI  - Reduced bio basis function neural network for identification of protein
      phosphorylation sites: comparison with pattern recognition algorithms.
AB  - Protein phosphorylation is a post-translational modification performed by a group
      of enzymes known as the protein kinases or phosphotransferases (Enzyme Commission
      classification 2.7). It is essential to the correct functioning of both proteins
      and cells, being involved with enzyme control, cell signalling and apoptosis. The
      major problem when attempting prediction of these sites is the broad substrate
      specificity of the enzymes. This study employs back-propagation neural networks
      (BPNNs), the decision tree algorithm C4.5 and the reduced bio-basis function
      neural network (rBBFNN) to predict phosphorylation sites. The aim is to compare
      prediction efficiency of the three algorithms for this problem, and examine
      knowledge extraction capability. All three algorithms are effective for
      phosphorylation site prediction. Results indicate that rBBFNN is the fastest and
      most sensitive of the algorithms. BPNN has the highest area under the ROC curve
      and is therefore the most robust, and C4.5 has the highest prediction accuracy.
      C4.5 also reveals the amino acid 2 residues upstream from the phosporylation site
      is important for serine/threonine phosphorylation, whilst the amino acid 3
      residues upstream is important for tyrosine phosphorylation.

PMID- 15022647
TI  - The iProClass integrated database for protein functional analysis.
AB  - Increasingly, scientists have begun to tackle gene functions and other complex
      regulatory processes by studying organisms at the global scales for various
      levels of biological organization, ranging from genomes to metabolomes and
      physiomes. Meanwhile, new bioinformatics methods have been developed for
      inferring protein function using associative analysis of functional properties to
      complement the traditional sequence homology-based methods. To fully exploit the
      value of the high-throughput system biology data and to facilitate protein
      functional studies requires bioinformatics infrastructures that support both data
      integration and associative analysis. The iProClass database, designed to serve
      as a framework for data integration in a distributed networking environment,
      provides comprehensive descriptions of all proteins, with rich links to over 50
      databases of protein family, function, pathway, interaction, modification,
      structure, genome, ontology, literature, and taxonomy. In particular, the
      database is organized with PIRSF family classification and maps to other family,
      function, and structure classification schemes. Coupled with the underlying
      taxonomic information for complete genomes, the iProClass system
      (http://pir.georgetown.edu/iproclass/) supports associative studies of protein
      family, domain, function, and structure. A case study of the phosphoglycerate
      mutases illustrates a systematic approach for protein family and phylogenetic
      analysis. Such studies may serve as a basis for further analysis of protein
      functional evolution, and its relationship to the co-evolution of metabolic
      pathways, cellular networks, and organisms.

PMID- 15022649
TI  - A statement by Professor John Walker-Smith.

PMID- 15022648
TI  - A statement by Dr Simon Murch. Allegations concerning our 1998 study.

PMID- 15022650
TI  - A statement by Dr Andrew Wakefield.

PMID- 15022651
TI  - A statement by The Royal Free and University College Medical School and The Royal
      Free Hampstead NHS Trust.

PMID- 15022652
TI  - Verbal assault. Advocates hit Triad for courting not-for-profits.

PMID- 15022653
TI  - Valerian does not appear to reduce symptoms for patients with chronic insomnia in
      general practice using a series of randomised n-of-1 trials.
AB  - OBJECTIVE: To investigate the effectiveness of valerian for the management of
      chronic insomnia in general practice. DESIGN: Valerian versus placebo in a series
      of n-of-1 trials, in Queensland, Australia. RESULTS: Of 42 enrolled patients, 24
      (57%) had sufficient data for inclusion into the n-of-1 analysis. Response to
      valerian was fair for 23 (96%) participants evaluating their "energy level in the
      previous day" but poor or modest for all 24 (100%) participants' response to
      "total sleep time" and for 23 (96%) participants' response to "number of night
      awakenings" and "morning refreshment". As a group, the proportion of treatment
      successes ranged from 0.35 (95% CI 0.23, 0.47) to 0.55 (95% CI 0.43, 0.67) for
      the six elicited outcome sleep variables. There was no significant difference in
      the number (P=0.06), distribution (P=1.00) or severity (P=0.46) of side effects
      between valerian and placebo treatments. CONCLUSIONS: Valerian was not shown to
      be appreciably better than placebo in promoting sleep or sleep-related factors
      for any individual patient or for all patients as a group.

PMID- 15022654
TI  - A randomised-controlled trial of the effects of a traditional herbal supplement
      on sleep onset insomnia.
AB  - OBJECTIVES: To study the effectiveness and safety of a traditional herbal
      supplement used for sleep onset insomnia. DESIGN: A double-blind, randomized,
      placebo-controlled, cross-over study. SETTING: A total of 25 healthy volunteers
      (20-65 years of age) suffering from sleep onset insomnia were recruited from the
      general population. INTERVENTION: A traditional Ayurvedic supplement formulated
      to reduce sleep onset insomnia. MAIN OUTCOME MEASURE: Sleep latency. RESULTS: The
      supplement led to a statistically significant decrease in reported sleep latency
      of 16.72 min (S.D.=44.8) as compared to placebo (P=0.003). There were no self
      reported side effects. CONCLUSIONS: The findings suggest that traditional herbal
      supplements may be of significant benefit to patients suffering from sleep onset
      insomnia while avoiding the negative side effects of commonly prescribed
      hypnotics.

PMID- 15022655
TI  - Topical application of natural honey, beeswax and olive oil mixture for atopic
      dermatitis or psoriasis: partially controlled, single-blinded study.
AB  - OBJECTIVES: To investigate the effects of honey, olive oil and beeswax mixture on
      patients with atopic dermatitis (AD) or psoriasis vulgaris (PV). MATERIALS AND
      METHODS: Twenty-one patients with dermatitis and 18 patients with psoriasis were
      entered for patient-blinded, partially controlled study; 11 patients with
      dermatitis used topical betamethasone esters and 10 patients with psoriasis used
      clobetasol propionate. Honey mixture contained honey, beeswax and olive oil
      (1:1:1). Mixtures A, B, and C contained honey mixture with the corticosteroids
      ointment in a ratio of 1:1, 2:1, and 3:1 respectively. Patients with dermatitis
      were subjected to controlled bilateral half-body comparison to evaluate the
      efficacy of honey mixture against Vaseline, or mixture A against Vaseline
      betamethasone esters mixture (1:1) in patients using topical corticosteroid
      treatment. In patients with psoriasis, the effect of honey mixture was compared
      with paraffin in an individual right/left-sites comparison, or mixture A against
      paraffin-clobetasol propionate mixture (1:1) in patients using corticosteroid
      topical therapy. In dermatitis, body lesions on right or left half-body were
      assessed for erythema, scaling, lichenification, excoriation, indurations, oozing
      and itching on a 0-4 points scale. In psoriasis, lesions of selected site were
      assessed for redness, scaling, thickening and itching, on a 0-4 points scale.
      RESULTS: In honey mixture group, 8/10 patients with dermatitis showed significant
      improvement after 2 weeks, and 5/11 patients pretreated with betamethasone esters
      showed no deterioration upon 75% reduction of corticosteroid doses with use of
      mixture C. In psoriasis, 5/8 patients showed a significant response to honey
      mixture. In patients using clobetasol propionate, 5/10 patients showed no
      deterioration upon 75% reduction of corticosteroid doses with use of mixture C.
      CONCLUSION: Honey mixture appears useful in the management of dermatitis and
      psoriasis vulgaris.

PMID- 15022656
TI  - Sham interventions in randomized clinical trials of acupuncture--a review.
AB  - BACKGROUND AND OBJECTIVES: For non-drug interventions such as acupuncture, it is
      difficult to establish placebo or sham controls that are both inert and
      indistinguishable. We reviewed sham-controlled clinical trials of acupuncture to
      investigate (a) which types of sham interventions have been used in the past; (b)
      in what respects true and sham interventions differed; and (c) whether trials
      using different types of sham yielded different results. METHODS: 47 randomized
      controlled trials comparing true and sham acupuncture interventions for pain and
      a variety of other conditions were identified from systematic reviews and through
      a search in PubMed. Details of patients, interventions, sham interventions and
      outcomes were extracted in a standardized manner. RESULTS: In two trials the sham
      intervention consisted of superficial needling of the true acupuncture points,
      four trials used true acupuncture points which were not indicated for the
      condition being treated, in 27 trials needles were inserted outside true
      acupuncture points, five trials used placebo needles and nine trials used pseudo
      interventions such as switched off-laser acupuncture devices. True and sham
      interventions often differed in a variety of other variables, such as
      manipulation of needles, depth of insertion, achievement of an irradiating
      needling sensation (de-chi), etc. There was no clear association between the type
      of sham intervention used and the results of the trials. CONCLUSION: Randomized
      trials investigating the specific effects of acupuncture have used a great
      variety of sham interventions as controls. Summarizing all the different sham
      interventions as "placebo" controls seems misleading and scientifically
      unacceptable.

PMID- 15022658
TI  - An fMRI of sustained attention with endogenous and exogenous engagement.

PMID- 15022657
TI  - NHS patients' perspective on complementary medicine: a survey.
AB  - OBJECTIVES: To examine patients' reasons for seeking complementary and
      alternative medicine (CAM) in the National Health Service, including the nature
      and duration of the patient's main health problem, the impact of CAM on this,
      satisfaction with clinical care, and usage of conventional prescription
      medication. DESIGN: Survey (n=499). SETTING: Out-patient Department, The Royal
      London Homeopathic Hospital, a National Health Service facility dedicated to CAM.
      RESULTS: Five hundred and six questionnaires were returned, 499 were analysed.
      Patients' most frequent reasons for seeking CAM were that other treatment had not
      helped, and concerns about or experience of adverse treatment reactions. Two
      hundred and ninety-seven patients (63%) had had their main problem for more than
      5 years. Musculoskeletal system problems were the most frequent diagnostic group
      (n=151, 32%). Satisfaction with clinical care was high (443/490: 90%). Three
      hundred and eighty patients (81%) indicated their main problem had improved very
      much, moderately or slightly. Of the 262 patients who had been taking
      prescription medicines when they first attended, 76 (29%) had stopped, and 84
      (32%) had reduced their intake. CONCLUSIONS: The results suggest that orthodox
      medicine is not meeting the needs of some patients and that CAM may wholly or
      partly substitute for conventional medicines. Most patients indicated their
      problem had improved with CAM. Implications for future research are discussed.

PMID- 15022659
TI  - Complementary and alternative medicine use by patients with cancer in Wales: a
      cross sectional survey.
AB  - OBJECTIVES: To determine the prevalence and cost of complementary and alternative
      medicine (CAM) use, and examine perceived satisfaction and reasons for using CAM.
      DESIGN AND SETTING: Cross sectional survey of 1697 patients with breast,
      prostate, lung or neurological cancer registered with a single NHS authority in
      Wales. PARTICIPANTS: One thousand and seventy-seven (64%) of patients, aged 18
      years or over with cancer diagnosis of at least 3 months, returned analysable
      questionnaires. Thirty patients were interviewed by telephone. MAIN OUTCOME
      MEASURES: Number and proportion that had used CAM in the past 12 months, the
      types of CAM used, expenditure, satisfaction, demographic characteristics, and
      reasons for using CAM. RESULTS: Five hundred and thirty-four, 49.6% (95% CI 46.6
      52.6) of participants, reported using at least one type of CAM during the past 12
      months: 221, 16.4% (95% CI 14.3-18.8), had consulted a CAM practitioner (average
      cost per person, 28 lbs. per month); 166, 15.4% (95% CI 13.4-17.7), indicated
      using CAM techniques (average cost per person, 16 lbs. per month); 456, 42.3%
      (95% CI 39.4-45.3), reported using over-the-counter diets, remedies or
      supplements (average cost per person, 10 lbs. per month). Dissatisfaction with
      CAM use was low, and most users indicated that they represented value for money.
      CAM users were more likely to be female, younger, better qualified, and to have
      used CAM before their current illness than non-users. Patients used CAM primarily
      for symptom relief and relaxation. CONCLUSIONS: Nearly half the cancer patients
      in this study had used CAM. A co-ordinated approach to quality assurance,
      information and advice, and the assessment of risk/benefit and cost effectiveness
      of CAM use is needed.

PMID- 15022660
TI  - Brain correlates of functional retrograde amnesia in three patients.

PMID- 15022661
TI  - Pay raise. Increased HMO funding excites many.

PMID- 15022662
TI  - A survey of primary care physicians' perceptions of their patients' use of
      complementary medicine.
AB  - PURPOSE: To study the perceptions and attitudes of primary care physicians
      concerning their patients' use of complementary medicine. METHODS: A
      questionnaire was distributed to all 165 primary care physicians attending a
      routine continuing-medicine education program. Items included physicians'
      estimated rates of patient utilization of complementary medicine or herbal
      remedies and of patient reportage of such use; physicians' knowledge about side
      effects and interactions of herbal remedies; and frequency with which physicians
      questioned their patients on the use of complementary medicine and herbal
      remedies. RESULTS: The compliance rate was 90.0% (n=150). Sixty-eight percent of
      physicians estimated that up to 15% of their patients use complementary medicine;
      58% always or often asked their patients about it; 50% estimated that 10% of
      patients report use of complementary medicine, and 60% estimated the same rate
      for herbal remedies; 51% believed that herbal remedies have no or only mild side
      effects; more than 70% claimed that they had little or no knowledge about what
      herbal remedies are; 24% never referred patients for complementary medicine, and
      69% did so occasionally. Twenty-five percent had some training in complementary
      medicine, and 31% practiced some kind of complementary medicine. Most of the
      physicians believed that people turn to alternative methods when they are
      dissatisfied with conventional medicine. CONCLUSIONS: Physicians underestimate
      the rate of complementary medicine use by patients, suggesting that many patients
      do not report such use to their physician. Since alternative treatments are
      potentially harmful and may interact with conventional medications, physicians
      should be encouraged to communicate with patients about complementary medicine in
      general and herbal remedies in particular, and they should regularly include
      questions about their use when taking histories. They should also inform
      themselves about risks of alternative treatments particularly with herbal
      remedies, and have access to appropriate information systems.

PMID- 15022663
TI  - Developing integrated CAM services in Primary Care Organisations.
AB  - OBJECTIVES: To explore policy development and the provision of integrated NHS CAM
      therapy services following the reorganisation of UK primary care services in
      1999. DESIGN: Structured survey interviews with Chairpersons in a stratified
      random sample of 72 Primary Care Organisations (PCOs) in England in 1999 and
      2000; semi-structured telephone interviews with purposive samples of (i)
      providers of primary care CAM services (mostly General Practitioners), and (ii)
      Commissioners of primary care services in two purposive sub-samples of PCOs
      involved in positive policy formation in relation to CAM. RESULTS: By the end of
      2000, it is estimated that 85% of PCOs in England (95% CI 78-91%) had discussed
      CAM at board level, and 37% (95% CI 26-48%) had at least one CAM policy in place.
      The dominant strategy that emerged was a policy of "provide and review",
      particularly in practices that had managed their own budgets under the previous
      fundholding system. We found that a small number of PCOs were developing area
      wide services. Positive influences or "drivers" for CAM policy formation were
      identified as: existing services, local enthusiasm and expertise, patient demand,
      a willingness to consider the wider evidence-base for CAM, and a perception that
      complementary therapies could help the PCOs to meet national NHS targets.
      Negative influences included: the cost of ensuring equitable access to services,
      a perception that CAM lacks the credibility required for public funding, the need
      to prioritize services and the need to direct funding towards meeting national
      and local health objectives. CONCLUSIONS: Opportunities for development of
      integrated NHS services are most likely to occur where CAM provision is seen as a
      potential solution to an NHS problem. Locality-based, integrated CAM services
      that are responsive to NHS priorities may offer a model for the future
      development of CAMs in primary care.

PMID- 15022664
TI  - Neural activity associated with response inhibition following traumatic brain
      injury: an event-related fMRI investigation.

PMID- 15022665
TI  - NCCAM support for the Cochrane Collaboration CAM Field.
AB  - Americans use CAM therapies now more than ever before, yet there is a shortage of
      accessible high-quality evidence from clinical trials to show which CAM therapies
      work best and for which conditions. The need for such evidence is great, not only
      among people with serious, chronic health conditions, but also among healthcare
      providers, who often require clinical trial evidence before recommending a
      medical treatment. For the last few years, the University of Maryland Center for
      Integrative Medicine has been working steadily to meet this need for information
      by identifying published clinical trials of alternative therapies, summarizing
      these into rigorous scientific reviews, and disseminating these reviews to the
      general public and to healthcare providers. In May 2003, the Center was awarded a
      large 4-year research grant from the National Institutes of Health's National
      Center for Complementary and Alternative Medicine (NCCAM) to support and extend
      this important work.

PMID- 15022666
TI  - Becoming a Darwinian: the micro-politics of Sir Francis Galton's scientific
      career 1859-65.
AB  - In 1865 Francis Galton (1822-1911) published 'Hereditary Talent and Character',
      an elaborate attempt to prove the heritability of intelligence on the basis of
      pedigree data. It was the start of Galton's lifelong commitment to investigating
      the statistical patterns and physiological mechanisms of hereditary transmission.
      Most existing attempts to explain Galton's fascination for heredity have argued
      that he was driven by a commitment to conservative political ideologies to seek
      means of naturalizing human inequality. However, this paper shows that another
      factor of at least equal importance has been overlooked by Galton scholars: his
      determination during the 1860s to be accepted among the ranks of the Darwinian
      inner circle. By hitching his career to the fortunes of what looked likely to
      emerge as a new scientific elite, Galton felt that he could bypass the typically
      slow and uncertain route to achieving scientific distinction. For this
      essentially strategic reason, between 1860 and 1865 he drifted away from a set of
      existing scientific concerns that were failing to deliver the approbation that he
      desired. Earnestly seeking to ingratiate himself with the Darwinian lobby, he
      then toyed with a variety of potential research projects relevant to Darwinian
      evolution. Yet Galton consistently failed to stimulate the enthusiasm of the
      Darwinians. Finally, however, after several months of ruminating, in 1864 he
      settled on a study of eminent pedigrees as a subject that was both germane and
      highly useful to the Darwinian enterprise. Galton's willingness to shift the
      direction of his scientific career during the 1860s underscores the importance of
      examining the micro-politics of scientific careers in addition to their broader
      social and political context. This account also emphasizes the limitations of
      class-based explanations even when considering scientists whose work seems so
      manifestly indicative of ideological motivation.

PMID- 15022667
TI  - Characterological psychology and German political economy in the Weimar period
      (1919-1933).
AB  - In the mid-1920s, applied (and theoretical) psychologists in many countries
      turned from studying elementary abilities to studying character or personality.
      This article examines this shift within the offices of the German labor
      administration, which aimed to place all German youths in appropriate jobs.
      Contrary to recent works on the history of psychology, which have emphasized the
      importance of cultural context, this article explains the turn to characterology
      in terms of German industry's evolving production strategies. As German companies
      developed a niche in flexible production, they came to value the highly skilled
      worker, who needed such character qualities as reliability, diligence, and
      conscientiousness. The article thus argues that historical analyses of applied,
      and perhaps even theoretical, psychology should also consider political economy
      as a potentially important context.

PMID- 15022669
TI  - Bush policy on human stem cells faces new challenges.

PMID- 15022668
TI  - "He sees the development of children's concepts upon a background of sociology":
      Jean Piaget's honorary degree at Harvard University in 1936.
AB  - In the recent memory, Jean Piaget has been known as a cognitive developmental
      psychologist. But in 1936 when Harvard gave him his first honorary degree, he was
      recognized mainly as a sociologist. Why did Harvard honor him in 1936? Who knew
      his work well enough to nominate him? This article will address these questions
      by exploring archival documents from different sources. Evidence draws our
      attention to a broad social and intellectual endeavor in philanthropy, other
      social sciences, and especially industrial research that brought Piaget across
      the water. This article also attempts to interpret the circumstances of the
      nomination process inside and outside of Harvard University by using a theory of
      institutional design. It suggests that embodied in Harvard's honor of Piaget in
      1936 was an idealistic act in social designing for a future society.

PMID- 15022670
TI  - On high-tech reproduction, Italy will practice abstinence.

PMID- 15022671
TI  - Companies facing ethical issue as drugs are tested overseas.

PMID- 15022672
TI  - Privately funded research yields new stem-cell lines.

PMID- 15022673
TI  - Database for doctors tracks litigious patients.

PMID- 15022674
TI  - Pesticide testing on humans is ethical, science panel says.

PMID- 15022675
TI  - Between the cup of principle and the lip of practice: ethnic minorities and
      American psychology, 1966-1980.
AB  - By 1980, the previously held dichotomy of Black and White racial identity in
      America had yielded to a mosaic of red, yellow, brown, black, and white. During
      the 1960s and 1970s, identity, and thus psychological knowledge, were articulated
      and differentiated in terms of gender, sexual orientation, and class in
      unprecedented ways. In this article, the author contextualizes efforts to make
      mainstream American psychology more receptive to ethnic minorities between 1966
      and 1980. Advocacy and activism by ethnic minority psychologists forced American
      mainstream psychology to yield a place at the table to non-White, non-European
      individuals. He emphasizes the recruitment and retention of ethnic minority
      graduate students and faculty, and concludes that many individual psychologists
      were important in forcing changes in these areas.

PMID- 15022676
TI  - Mean instantaneous firing frequency is always higher than the firing rate.
AB  - Frequency coding is considered one of the most common coding strategies employed
      by neural systems. This fact leads, in experiments as well as theoretical
      studies, to construction of so-called transfer functions, where the output firing
      frequency is plotted against the input intensity. The term "firing frequency" can
      be understood differently in different contexts. Basically, it means that the
      number of spikes over an interval of preselected length is counted and then
      divided by the length of the interval, but due to the obvious limitations, the
      length of observation cannot be arbitrarily long. Then firing frequency is
      defined as reciprocal to the mean interspike interval. In parallel, an
      instantaneous firing frequency can be defined as reciprocal to the length of
      current interspike interval, and by taking a mean of these, the definition can be
      extended to introduce the mean instantaneous firing frequency. All of these
      definitions of firing frequency are compared in an effort to contribute to a
      better understanding of the input-output properties of a neuron.

PMID- 15022677
TI  - Kalman filter control embedded into the reinforcement learning framework.
AB  - There is a growing interest in using Kalman filter models in brain modeling. The
      question arises whether Kalman filter models can be used on-line not only for
      estimation but for control. The usual method of optimal control of Kalman filter
      makes use of off-line backward recursion, which is not satisfactory for this
      purpose. Here, it is shown that a slight modification of the linear-quadratic
      gaussian Kalman filter model allows the on-line estimation of optimal control by
      using reinforcement learning and overcomes this difficulty. Moreover, the
      emerging learning rule for value estimation exhibits a Hebbian form, which is
      weighted by the error of the value estimation.

PMID- 15022678
TI  - A very private affair.

PMID- 15022680
TI  - Pick of the crop.

PMID- 15022679
TI  - Forcible medication: a new insanity defence.

PMID- 15022681
TI  - A calculated departure: for someone in good health, can suicide ever be a
      rational choice?

PMID- 15022682
TI  - We don't play politics with science.

PMID- 15022683
TI  - The potential of 'brain pacemakers': implanted devices may alter treatment of
      many disorders.

PMID- 15022684
TI  - A 'full range' of bioethical views just got narrower.

PMID- 15022685
TI  - The women behind cloning.

PMID- 15022686
TI  - The ethics of science.

PMID- 15022688
TI  - Bibliography. Current world literature. Rehabilitation medicine in rheumatic
      diseases.

PMID- 15022687
TI  - Data briefing. Winter mortality.

PMID- 15022689
TI  - Are "best dentists" lists legal in Florida?

PMID- 15022690
TI  - Tongue piercing: a restorative perspective?

PMID- 15022691
TI  - INR author speaks out: adolescents and risky sexual behaviour.

PMID- 15022692
TI  - ICN, WHO lead effort to reduce needlesticks.

PMID- 15022693
TI  - Testing your diagnostic skills.

PMID- 15022694
TI  - Sadako Ogata receives Japan's Order of Culture.

PMID- 15022695
TI  - Dentists and technicians must bridge divide.

PMID- 15022696
TI  - Certified technicians are adept team members.

PMID- 15022697
TI  - Diagnostic quiz #50. Case no. 1: Malignant neoplasm. Case no. 2: Addison's
      disease.

PMID- 15022699
TI  - "United by excellence, linked by pride." Recognize dental assistants all year.

PMID- 15022698
TI  - FTC drops advertising case against California Dental Association.

PMID- 15022700
TI  - FDAS returns profit to members, makes service primary goal.

PMID- 15022701
TI  - Diagnostic quiz #48. Case no. 1: traumatic bone cyst. Case no. 2: epithelial
      dysplasia and squamous cell carcinoma.

PMID- 15022702
TI  - It's all about smiles.

PMID- 15022704
TI  - Porcelain veneers--from diagnosis to execution.

PMID- 15022703
TI  - Progress on engineered mandibular condyle holds promise for other joints.

PMID- 15022705
TI  - The esthetic correction of anterior dental mal-alignment conventional vs. instant
      (restorative) orthodontics.
AB  - Creating a flow sheet may assist in the decision whether to use conventional
      orthodontics and what the limitations of treating the patient will be if
      treatment is performed without any orthodontics. The decision process can be
      viewed as a series of questions, and depending upon the answer to the questions,
      the practitioner and patient can decide on whether to involve orthodontics or
      not. Questions can create a framework to help separate the patients who would
      benefit from orthodontic intervention from those we all enjoy treating who can be
      managed with purely restorative care.

PMID- 15022706
TI  - Short tooth syndrome: diagnosis, etiology, and treatment management.
AB  - The periodontal-restorative team is uniquely positioned to provide the esthetic
      procedures that today's sophisticated patient population has come to expect. Not
      only is health and function of great desire but also esthetics is in demand.
      Armed with periodontal-plastic procedures and technically advanced restorative
      materials, the periodontal-restorative team can provide these patient needs. The
      challenge becomes making the correct diagnosis and selecting the appropriate
      treatment regimen.

PMID- 15022707
TI  - Understanding the esthetic evaluation for success.
AB  - With any restorative procedure, a thorough evaluation, diagnosis, and treatment
      plan is essential for a positive outcome. When dealing with esthetic dilemmas,
      the some holds true. Without a sequential esthetic evaluation, diagnosis,
      treatment plan, and execution, an acceptable outcome is difficult to predict. The
      treating clinician should be able to visualize the esthetic problem, visualize
      the proposed changes, and devise a way to achieve the result while still
      maintaining mechanically, functionally, and biologically sound principles.

PMID- 15022708
TI  - Diagnostically generated anterior tooth preparation for adhesively retained
      porcelain restorations: rationale and technique.
AB  - A diagnostically based protocol for anterior tooth preparations for adhesively
      retained porcelain restorations offers dentists and laboratory technicians new
      options to approaching these restorations. Rather than designing a preparation
      and restoration based more on the needs of the products used than on the
      preservation of the remaining tooth structure, practitioners can enhance the
      predictability of these restorations by concentrating simultaneously on three
      distinct zones of the tooth (incisal, middle, and cervical) and four diagnostic
      categories (periodontal, biomechanical, functional, and dentofacial). The result
      of following the technique presented in this article is achieving an
      individualized design that offers a predictable option with minimal risks to the
      remaining tooth structure.

PMID- 15022710
TI  - Say yes to sirtuin; no to lamp shades.

PMID- 15022709
TI  - A simple and predictable direct technique for esthetic provisional veneers.
AB  - There are a number of different techniques for fabricating provisional veneers.
      There are direct and indirect techniques involving acrylic or composite resin
      veneers made with or without a vacuform matrix. This article describes a direct
      technique for fabricating removable provisional veneers using an auto
      polymerizing urethane dimethyacrylate resin and a thermoplastic matrix that may
      later serve as a stent to be worn with the provisional veneers.

PMID- 15022711
TI  - P-glycoprotein-based drug-drug interactions: preclinical methods and relevance to
      clinical observations.
AB  - Multiple drug administration is common in elderly, HIV, and cancer patients. Such
      treatments may result in drug-drug interactions due to interference at the
      metabolic enzyme level, and due to modulation of transporter protein functions.
      Both kinds of interference may result in altered drug distribution and toxicity
      in the human body. In this review, we have dealt with drug-drug interactions
      related to the most studied human transporter, P-glycoprotein. This transporter
      is constitutively expressed in several sites in the human body. Its function can
      be studied in vitro with different cell lines expressing P-glycoprotein in
      experiments using methods and equipment such as flow cytometry, cell
      proliferation, cell-free ATP as activity determination and Transwell culture
      equipment. In vivo experiments can be carried out by mdr1a(-/-) animals and by
      noninvasive methods such as NMR spectrometry. Some examples are also given for
      determination of possible drug-drug interactions using the above-mentioned cell
      lines and methods. Such preclinical studies may influence decisions concerning
      the fate of new drug candidates and their possible dosages. Some examples of
      toxicities obtained in clinics and summarized in this review indicate careful
      consideration in cases of polypharmacy and the requirement of preclinical studies
      in drug development activities.

PMID- 15022713
TI  - Synthesis of 2'-azidoethyl trisaccharide, alpha-D-Gal-(1-->2)-6d-alpha-D-altro
      Hepp-(1-->3)-beta-D-GlcNAc, an O-antigenic repeating unit of C. jejuni O:23 and
      O:36.
AB  - A trisaccharide, the O-antigenic repeating unit of C. jejuni serotype O:23 and
      O:36, was synthesized as a 2'-azidoethyl glycoside by block addition of
      perbenzylated thiogalactoside donors to alpha-altroHepp-(1-->3)-GlcNPhth
      disaccharide acceptor in presence of IDCP promoter. The alpha-linked
      altroheptopyranoside moiety in the glycosyl acceptor was effectively prepared by
      Swern oxidation of alpha-mannohepp-(1-->3)-GlcNPhth disaccharide followed by mild
      reduction with NaCNBH3.

PMID- 15022712
TI  - Diastereoselective synthesis of anti-1,2-aminoalcohol by palladium(II) catalyzed
      aza-Claisen rearrangement.
AB  - In this study, a highly diastereoselective synthesis of anti-1,2-aminoalcohol was
      explored starting from L-amino acids as chiral sources. The higher yield and
      diastereoselectivity was shown when the aza-Claisen rearrangement was performed
      with allylic trichloroacetimidate 6a in the presence of palladium(II) catalyst.

PMID- 15022714
TI  - Synthesis and anticonvulsant evaluations of N-cbz-alpha-amino-N
      alkoxyglutarimides.
AB  - In our previous studies for the development of new anticonvulsant of broad
      spectrum, we found that N-cbz-alpha-aminoglutarimides showed significant
      anticonvulsant activities of broad spectrum enough to be recommended for the new
      anticonvulsants and their anticonvulsant activities were dependent on their imide
      substituent groups. Based on these results, various N-cbz-alpha-amino-N
      alkoxyglutarimides, where the imide N-H was substituted with the hydroxy and
      alkoxy group, were prepared and evaluated for their anticonvulsant activities
      using the Maximal electroshock seizure (MES) and Pentylenetetrazole induced
      seizure (PTZ) tests and also the rotorod test. A series of (R) or (S)-N-cbz-alpha
      amino-N-alkoxyglutarimides could be prepared from the corresponding (R) or (S)-N
      cbz-glutamic acid following the usual synthetic procedure. Among them, (R)-N-cbz
      alpha-amino-N-hydroxyglutarimide (ED50=86.25 mg/kg) was most active in the MES
      test. In the case of the PTZ test, (R)-N-cbz-alpha-amino-N-benzyloxyglutarimide
      (ED50=62.5 mg/kg) was most active. Among the tested compounds, 2a-c, 3a, and 3b
      showed anticonvulsant activities in the MES and PTZ test. All of the tested
      compounds, except 2f and 3f, showed significant anticonvulsant activities in the
      MES or PTZ test. In addition, the neurotoxicities of these compounds were
      comparable to other anticonvulsant drugs.

PMID- 15022715
TI  - Synthesis and antioxidant properties of some novel benzimidazole derivatives on
      lipid peroxidation in the rat liver.
AB  - Some benzimidazole derivatives namely 1-[(substituted thiocarbamoylhydrazine
      carbonyl) methyl]-2-phenyl-1H-benzimidazoles (1a-13a), N-[(2-phenylbenzimidazol-1
      yl methyl)-[1,3,4]-thiadiazole-2-yl]-substituted phenyl amines (1b-13b) and 5-(2
      phenyl benzimidazol-1-yl-methyl)-4-substituted phenyl-4H-1,2,4-triazole-3-thiones
      (1c-13c) were synthesized, and their in vitro effects on the rat liver microsomal
      NADPH-dependent lipid peroxidation (LP) levels were determined. The most active
      compound 10a caused an 84% inhibition of LP at 10(-3) M, which is better than
      that of butylated hydroxytoluene (BHT) (65%).

PMID- 15022716
TI  - Phytochemical constituents of the aerial parts from Solidago virga-aurea var.
      gigantea.
AB  - The chromatographic separation of the MeOH extract of the aerial parts of
      Solidago virga-aurea var. gigantea M(IQ) (Compositae) led to the isolation of six
      terpenoids and four phenolic compounds, trans-phytol (1), ent-germacra
      4(15),5,10(14)-trien-1alpha-ol (2), beta-amyrin acetate (3), ent-germacra
      4(15),5,10(14)-trien-1beta-ol (4), beta-dictyopterol (5), oleanolic acid (6),
      kaempferol (7), kaempferol-3-O-rutinoside (8), methyl 3,5-di-O-caffeoyl quinate
      (9), and 3,5-di-O-caffeoyl quinic acid (10). Their structures were established by
      chemical and spectroscopic methods. Compounds 4, 5, and 10 showed moderate
      cytotoxicity against five cultured human tumor cell lines in vitro with its ED50
      values ranging from 1.52 to approximately 18.57 microg/mL.

PMID- 15022717
TI  - Phenolic compounds obtained from stems of Couepia ulei with the potential to
      induce quinone reductase.
AB  - Activity-guided fractionation of the EtOAc-soluble extract of the stems of
      Couepia ulei, using a bioassay based on the induction of quinone reductase (QR)
      in cultured Hepa 1c1c7 mouse hepatoma cells led to the isolation of two active
      compounds, a new natural product, erythro-2,3-bis(4-hydroxy-3-methoxyphenyl)-3
      ethoxypropan-1-ol (1), and a known compound, evofolin-B (2), along with five
      inactive compounds all of known structure, viz., betulinic acid, oleanolic acid,
      pomolic acid, (+/-)-syringaresinol, and ursolic acid. These isolates were
      identified by analysis of physical and spectral data. Compounds 1 and 2 exhibited
      QR inducing activity, with observed CD (concentration required to double
      induction) values of 16.7 and 16.4 microM, respectively.

PMID- 15022718
TI  - Antioxidative constituents from Lycopus lucidus.
AB  - Three phenolic compounds, rosmarinic acid (1), methyl rosmarinate (2), ethyl
      rosmarinate (3), and two flavonoids, luteolin (4), luteolin-7-O-beta-D
      glucuronide methyl ester (5) were isolated from the aerial part of Lycopus
      lucidus (Labiatae). Their structures were determined by chemical and spectral
      analysis. Compounds 1-5 exhibited potent antioxidative activity on the NBT
      superoxide scavenging assay. The IC50 values for compounds 1-5 were 2.59, 1.42,
      0.78, 2.83, and 3.05 microg/mL respectively. In addition, five compounds were
      isolated from this plant for the first time.

PMID- 15022719
TI  - Antioxidants and inhibitor of matrix metalloproteinase-1 expression from leaves
      of Zostera marina L.
AB  - In order to develop new anti-photoaging agents, we examined the antioxidative
      activity and the inhibition effect of matrix metalloproteinase-1 (MMP-1) on the
      extracts of a marine product, Zostera marina L., which is known for its potent
      activity. Three compounds (compounds 1, 2, and 3) were isolated from an ethyl
      acetate (EtOAc) soluble fraction of the product; they were identified as apigenin
      7-O-beta-D-glucoside (1), chrysoeriol (2), and luteolin (3). These compounds were
      found to scavenge radicals and reactive oxygen species (ROS) and were measured to
      have SC50 values of 0.18 mM, 0.68 mM, and 0.01 mM against the 1,1-diphenyl-2
      picrylhydrazyl (DPPH) radical and 0.04 mM, 0.03 mM, and 0.01 mM against the
      superoxide radical in the xanthine/xanthine oxidase system, respectively.
      Compound 3 suppressed the expression of MMP-1 by up to 44% at 4.0 microM and
      inhibited the production of interleukin 6 (IL-6), which is known as a cytokine
      that induces MMP-1 expression. From these results, compound 3 and the other
      compounds were determined to have antioxidative activity and to inhibit MMP-1
      expression. Thus, the three compounds are expected to be useful for preventing
      the photoaging of skin.

PMID- 15022720
TI  - Antioxidant activities of isoflavones from the rhizomes of Belamcanda chinensis
      on carbon tetrachloride-induced hepatic injury in rats.
AB  - The present study was carried out to clarify whether tectorigenin and tectoridin
      isolated from the rhizomes of Belamcanda chinensis (Iridaceae) inhibit hepatic
      damage induced by carbon tetrachloride (CCl4)-intoxication in rats by the
      experimental methods in vitro and in vivo. Tectorigenin and tectoridin exhibited
      a significant decrease in serum transaminase activities elevated by hepatic
      damage induced by CCl4-intoxication in rats, as well as in a lipid peroxidation
      causing a significant decrease in malondialdehyde (MDA) production by
      thiobarbituric acid (TBA)-reactant assay. Both compounds also showed strong
      increase in the antioxidant enzymes such as hepatic cytosolic superoxide
      dismutase (SOD), catalase and glutathione peroxidase (GSH-px) activities in CCl4
      intoxicated rats. These results suggested that tectorigenin and tectoridin
      isolated from the rhizomes of B. chinensis possess not only the antioxidative,
      but also the hepatoprotective activities in CCl4-intoxicated rats.

PMID- 15022722
TI  - Inhibitory phlorotannins from the edible brown alga Ecklonia stolonifera on total
      reactive oxygen species (ROS) generation.
AB  - Reactive oxygen species (ROS) play an important role in the pathogenesis of many
      human degenerative diseases such as cancer, aging, arteriosclerosis, and
      rheumatism. Much attention has been focused on the development of safe and
      effective antioxidants. To discover sources of antioxidative activity in marine
      algae, extracts from 17 kinds of seaweed were screened for their inhibitory
      effect on total ROS generation in kidney homogenate using 2',7'
      dichlorofluorescein diacetate (DCFH-DA). ROS inhibition was seen in three
      species: Ulva pertusa, Symphyocladia latiuscula, and Ecklonia stolonifera. At a
      final concentration of 25 microg/mL, U. pertusa inhibited 85.65+/-20.28% of total
      ROS generation, S. latiscula caused 50.63+/-0.09% inhibitory, and the Ecklonia
      species was 44.30+/-7.33% inhibition. E. stolonifera Okamura (Laminariaceae),
      which belongs to the brown algae, has been further investigated because it is
      commonly used as a foodstuff in Korea. Five compounds, phloroglucinol (1),
      eckstolonol (2), eckol (3), phlorofucofuroeckol A (4), and dieckol (5), isolated
      from the ethyl acetate soluble fraction of the methanolic extract of E.
      stolonifera inhibited total ROS generation.

PMID- 15022721
TI  - Studies on the anti-inflammatory effects of Clerodendron trichotomum Thunberg
      leaves.
AB  - Clerodendron trichotomum Thunberg Leaves (CTL) have been used for centuries in
      Chinese folk medicine for their anti-inflammatory properties. We have studied the
      anti-inflammatory effects of CTL extracts in rats, mice and in Raw 264.7 cells. 1
      mg/kg solutions of the 30% and 60% methanol extracts of CTL were used and a 1
      mg/kg of indomethacin was used as a positive anti-inflammatory standard; these
      were then administrated to rats. Carrageenan was injected subcutaneously to
      induce hind paw edema in rats. The result of carrageenan-induced rat paw oedema
      showed that a 1 mg/kg of the 30%, and 60% methanol fraction of CTL and 1 mg/kg of
      indomethacin inhibited the hind paw edema by 19.5%, 23.0%, and 20.5%
      respectively. The effect of CTL on inflammation in mice by a capillary
      permeability assay was examined by detecting Evans blue leakage from capillaries
      after the intraperitoneal injection of acetic acid, a potent inflammatory
      stimulus. The 60% methanol fraction of CTL inhibited Evans blue dye leakage by
      47.0%, which was 10% higher than that of the inhibition of 1 mg/kg of
      indomethacin. Also, the 60% methanol fraction of CTL suppressed the prostaglandin
      E2 (PGE2) generation in RAW 264.7 macrophage cells after treatment with
      lipopolysaccharide (LPS) by as much as the inhibition of 1 mg/kg of indomethacin
      and this led to the synthesis of PGE2 by COX-2 induction. The inhibition of the
      carrageenan-induced rat paw oedema, vascular permeability and the PGE2 generation
      demonstrates that the 60% methanol fraction of CTL contains a potent anti
      inflammatory activity.

PMID- 15022723
TI  - Potent inhibition of human cytochrome P450 1 enzymes by dimethoxyphenylvinyl
      thiophene.
AB  - Cytochrome P450 (P450) 1 enzymes such as P450 1A1, 1A2, and 1B1 are known to be
      involved in the oxidative metabolism of various procarcinogens and are regarded
      as important target enzymes for cancer chemoprevention. Previously, several
      hydroxystilbene compounds were reported to inhibit P450 1 enzymes and were rated
      as candidate chemopreventive agents. In this study, we investigated the
      inhibitory effect of 2-[2-(3,5-dimethoxyphenyl)vinyl]-thiophene (DMPVT), produced
      from the chemical modification of oxyresveratrol, on the activities of P450 1
      enzymes. The inhibitory potential by DMPVT on the P450 1 enzyme activity was
      evaluated with the Escherichia coli membranes of the recombinant human cytochrome
      P450 1A1, 1A2, or 1B1 coexpressed with human NADPH-P450 reductase. DMPVT
      significantly inhibited ethoxyresorufin O-deethylation (EROD) activities with
      IC50 values of 61, 11, and 2 nM for 1A1, 1A2, and 1B1, respectively. The EROD
      activity in DMBA-treated rat lung microsomes was also significantly inhibited by
      DMPVT in a dose-dependent manner. The modes of inhibition by DMPVT were non
      competitive for all three P450 enzymes. The inhibition of P450 1B1-mediated EROD
      activity by DMPVT did not show the irreversible mechanism-based effect. The loss
      of EROD activity in P450 1B1 with DMPVT incubation was not blocked by treatment
      with the trapping agents such as glutathione, N-acetylcysteine, or
      dithiothreitol. Taken together, the results suggested DMPVT to be a strong
      noncompetitive inhibitor of human P450 1 enzymes that should be considered as a
      good candidate for a cancer chemopreventive agent in humans.

PMID- 15022724
TI  - Protein carboxylmethylation in porcine spleen is mainly mediated by class I
      protein carboxyl O-methyltransferase.
AB  - The functional role of protein carboxylmethylation (PCM) has not yet been clearly
      elucidated in the tissue level. The biochemical feature of PCM in porcine spleen
      was therefore studied by investigating the methyl accepting capacity (MAC) of
      natural endogenous substrate proteins for protein carboxyl O-methyltransferase
      (PCMT) in various conditions. Strong acidic and alkaline-conditioned (at pH 11.0)
      analyses of the MAC indicated that approximately 65% of total protein methylation
      seemed to be mediated by spleen PCMT. The hydrolytic kinetics of the PCM
      products, such as carboxylmethylesters (CMEs), under mild alkaline conditions
      revealed that there may be three different kinds of CMEs [displaying half-times
      (T1/2) of 1.1 min (82.7% of total CMEs), 13.9 min (4.6%), and 478.0 min (12.7%)],
      assuming that the majority of CME is base-labile and may be catalyzed by class I
      PCMT. In agreement with these results, several natural endogenous substrate
      proteins (14, 31 and 86 kDa) were identified strikingly by acidic-conditioned
      electrophoresis, and their MAC was lost upon alkaline conditions. On the other
      hand, other proteins (23 and 62 kDa) weakly appeared under alkaline conditions,
      indicating that PCM mediated by class II or III PCMT may be a minor reaction. The
      MAC of an isolated endogenous substrate protein (23-kDa) was also detected upon
      acidic-conditioned electrophoresis. Therefore, our data suggest that most spleen
      PCM may be catalyzed by class I PCMT, which participates in repairing aged
      proteins.

PMID- 15022725
TI  - Anti-metastatic activity of glycoprotein fractionated from Acanthopanax
      senticosus, involvement of NK-cell and macrophage activation.
AB  - Previously, we reported that water-extracted Acanthopanax senticosus exhibited
      anti-metastatic activity by stimulating the immune system. In this study, we
      fractionated glycoproteins (EN-SP) from the soluble protein layer (GF-AS) of A.
      senticosus and determined their basic chemical properties. We also investigated
      the anti-tumor and immunostimulating activities of the fractionated glycoprotein,
      EN-SP. We found that intravenous (i.v.) administration of GF-AS dramatically
      inhibited metastasis of colon26-M3.1 carcinoma cells to the lung in a dose
      dependent manner. In vitro analysis showed GF-AS to enhance the proliferation of
      splenocytes. GF-AS also stimulated peritoneal macrophage, which was followed by
      the production of various cytokines such as IL-1beta, TNF-alpha, IL-12 and IFN
      gamma. Furthermore, the production of these cytokines was partially blocked when
      peritoneal macrophage was cultured with the polyclonal antibodies against GF-AS.
      The depletion of NK cells by rabbit anti-asialo GM1 serum partly abolished the
      inhibitory effect of GF-AS on lung metastasis of colon26-M3.1 cells. Using gel
      filtration, EN-SP, an active glycoprotein fraction, is isolated from GF-AS. While
      both GF-AS and EN-SP stimulated the proliferatation of splenocytes of normal
      mice, EN-SP showed higher anti-metastatic activity and more potently stimulated
      the proliferation of splenocytes compared to GF-AS. These results suggest the use
      of EN-SP, the fractionated glycoprotein from A. senticosus, can be used as a
      therapeutical reagent to prevent or inhibit tumor metastasis.

PMID- 15022727
TI  - The beneficial effect of Trolox on sepsis-induced hepatic drug metabolizing
      dysfunction.
AB  - Trolox is a hydrophilic analogue of vitamin E. The aim of this study was to
      investigate its effects on hepatic injury, especially alteration in cytochrome
      P450 (CYP)-dependent drug metabolism during polymicrobial sepsis. Rats were
      subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). The rats
      were treated intravenously with Trolox (2.5 mg/kg) or vehicle, immediately after
      CLP. Serum aminotransferases and lipid peroxidation levels were markedly
      increased 24 h after CLP. This increase was attenuated by Trolox. Total CYP
      content and NADPH-P450 reductase activity decreased significantly 24 h after CLP.
      This decrease in CYP content was attenuated by Trolox. At 24 h after CLP, there
      was a significant decrease in the activity of these CYP isozymes: CYP1A1, 1A2,
      2B1, and 2E1. However, Trolox differentially inhibited the decrease in CYP
      isozyme activity. Trolox had little effect on the decrease in CYP1A1 activity but
      Trolox significantly attenuated decreases in CYP1A2 and 2E1 activities. In fact,
      Trolox restored CYP2B1 activity to the level of activity found in control rats.
      Our findings suggest that Trolox reduces hepatocellular damage as indicated by
      abnormalities in hepatic drug-metabolizing function during sepsis. Our data also
      indicates that this protection is, in part, caused by decreased lipid
      peroxidation.

PMID- 15022726
TI  - Effect of Trolox on altered vasoregulatory gene expression in hepatic
      ischemia/reperfusion.
AB  - This study was designed to investigate the effect of Trolox, a hydrophilic
      analogue of vitamin E, on the alteration of vasoregulatory gene expression during
      hepatic ischemia and reperfusion (I/R). Rats were subjected to 60 min of hepatic
      ischemia in vivo. The rats were treated intravenously with Trolox (2.5 mg/kg) or
      the vehicle as a control 5 min before reperfusion. Liver samples were obtained 5
      h after reperfusion for a RT-PCR analysis on the mRNA for the genes of interest.
      These mRNA peptides are endothelin-1 (ET-1), potent vasoconstrictor peptide, its
      receptor ET(A) and ET(B), vasodilator endothelial nitric oxide synthase (eNOS),
      inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1), tumor necrosis
      factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2). It was seen that serum
      alanine aminotransferase and lipid peroxidation levels were markedly increased
      after I/R and Trolox significantly suppressed this increase. In contrast, the
      glutathione concentration decreased in the I/R group, and this decrease was
      inhibited by Trolox. ET-1 mRNA expression was increased by I/R, an increase which
      was prevented by Trolox. The mRNA levels for ET(A) receptor was significantly
      decreased, whereas ET(B) receptor transcript increased in the I/R group. The
      increase in ET(A) was prevented by Trolox. The mRNA levels for iNOS and HO-1
      significantly increased in the I/R group and Trolox attenuated this increase.
      There were no significant differences in eNOS mRNA expression among any of the
      experimental groups. The mRNA levels for COX-2 and TNF-alpha significantly
      increased in I/R group and Trolox also attenuated this increase. Our findings
      suggest that I/R induces an imbalanced hepatic vasoregulatory gene expression and
      Trolox ameliorates this change through its free radical scavenging activity.

PMID- 15022728
TI  - In vitro metabolism of a new neuroprotective agent, KR-31543 in the human liver
      microsomes: identification of human cytochrome P450.
AB  - KR-31543, (2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5
      ylmethyl)amino]-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-1-benzopyran,
      is a new neuroprotective agent for preventing ischemia-reperfusion damage. This
      study was performed to identify the metabolic pathway of KR-31543 in human liver
      microsomes and to characterize cytochrome P450 (CYP) enzymes that are involved in
      the metabolism of KR-31543. Human liver microsomal incubation of KR-31543 in the
      presence of NADPH resulted in the formation of two metabolites, M1 and M2. M1 was
      identified as N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine on the
      basis of LC/MS/MS analysis with a synthesized authentic standard, and M2 was
      suggested to be hydroxy-KR-31543. Correlation analysis between the known CYP
      enzyme activities and the rates of the formation of M1 and M2 in the 12 human
      liver microsomes have showed significant correlations with testosterone 6beta
      hydroxylase activity (a marker of CYP3A4). Ketoconazole, a selective inhibitor of
      CYP3A4, and anti-CYP3A4 monoclonal antibodies potently inhibited both N
      hydrolysis and hydroxylation of KR-31543 in human liver microsomes. These results
      provide evidence that CYP3A4 is the major isozyme responsible for the metabolism
      of KR-31543 to M1 and M2.

PMID- 15022729
TI  - Prevalence and characterization of vancomycin-resistant enterococci in chicken
      intestines and humans of Korea.
AB  - The prevalence, genotype for antibiotic resistance and antibiotic susceptibility
      of vancomycin resistant enterococci (VRE) were determined. And molecular typings
      of the Enterococcus faecium isolates were analyzed. Prevalence of VRE in
      chickens, healthy children and intensive care unit (ICU) patients was 41.6%,
      7.9%, and 20.4%, respectively. Forty out of 54 isolates from chicken intestines,
      and 9 out of 11 from ICU patients were identified as Enterococcus faecium. Eleven
      out of 13 isolates from non-hospitalized young children were E. gallinarium.
      Twelve strains of E. faecalis were isolated from chicken intestines. The gene for
      the antibiotic resistance in E. faecium, and E. faecalis was vanA, while that in
      E. gallinarium was vanC1. E. faecium isolates were resistant to most of
      antibiotics except ampicillin and gentamicin. Molecular typing of the E. faecium
      strains obtained by pulse field gel electrophoresis and repetitive sequence-based
      PCR suggest that VRE transmit horizontally from poultry to humans, especially
      young children, via the food chains in Korea.

PMID- 15022730
TI  - The influence of cimetidine on the pharmacokinetics of diltiazem and its main
      metabolite in rabbits.
AB  - The purpose of this study was to investigate the pharmacokinetic alteration of
      diltiazem and its main metabolite, deacetyldiltiazem, after oral administration
      of diltiazem in rabbits with or without cimetidine co-administration. The area
      under the plasma concentration-time curve (AUC) of diltiazem was significantly
      elevated in rabbits pretreated with cimetidine, suggesting that the oral
      clearance, an index of intrinsic clearance, may be decreased by the cimetidine
      treatment. Consistent with the increased AUC by the treatment, peak plasma
      concentration (Cmax) for diltiazem was also elevated. Apparent volume of
      distribution normalized by the bioavailability (Vd/F) of diltiazem increased
      significantly in rabbits pretreated with cimetidine increased. Taken together
      with the fact that the first pass metabolism for diltiazem is the primary
      determinant for the oral bioavailability, these observations indicate that
      increases in the oral clearance and Vd/F may be a manifestation of the decreased
      first pass metabolism. Consistent with the hypothesis, the AUC of
      deacetyldiltiazem was significantly decreased in rabbits with cimetidine
      treatment. Ratio of deacetyldiltiazem to total diltiazem in the plasma was
      significantly decreased in rabbits with cimetidine treatment. These observations
      suggested that the metabolism of diltiazem to deacetyldiltiazem was reduced by
      cimetidine treatment and that the dosage of diltiazem should be adjusted when the
      drug is co-administered chronically with cimetidine in a clinical setting.

PMID- 15022731
TI  - Pharmacokinetics of PEG-hemoglobin SB1, a hemoglobin-based oxygen carrier, after
      its intravenous administration in beagle dogs.
AB  - The purpose of the present study was to investigate the pharmacokinetics of PEG
      hemoglobin SB1, a modified bovine hemoglobin with polyethylene glycol, after its
      single and multiple administration in beagle dogs. For this purpose, the
      analytical method of free hemoglobin in the plasma was developed and validated.
      Excellent linearity (r2=0.999) was observed in the calibration curve data, with
      the limit of quantification of 0.005 g/dL. The precision and the deviation of the
      theoretical values for accuracy were always within +/-15% in both the between-
      and the within-day results. The method was tested by measuring the plasma
      concentrations following intravenous administration to beagle dogs and was shown
      to be suitable for pharmacokinetic studies. In a single dose study, the plasma
      half-life (t1/2) increased and the total body clearance (CLt) decreased with the
      dose (i.e., 0.017 to 0.75 gHb/kg as PEG-hemoglobin SB1) in both sexes. The volume
      of distribution at steady-state (Vd(ss)) showed no difference with the dose. In
      contrast, the values of t1/2, CLt and the area under the plasma concentration
      time curve (AUC) after the multiple dose were significantly different from those
      of the single dose administration. The values of t1/2 in the multiple
      administration were about two times higher than that of the single dose. As a
      result, t1/2 of hemoglobin after the administration of PEG-hemoglobin SB1 was
      about 15-30 h, indicating the PEG modification of the hemoglobin lead to a
      prolongation of plasma concentration of the protein. Therefore, these
      observations suggested that the PEG modification of hemoglobin is potentially
      applicable in the hemoglobin-based therapeutics.

PMID- 15022732
TI  - Quality of life of patients with end-stage renal disease at various stages of the
      illness.
AB  - This study aimed to examine the quality of life of patients undergoing different
      types of treatment for End Stage Renal Disease at various points in the course of
      the disease. The theoretical model that guided the study was based on the work of
      Rolland (1987) and Wilson and Clearly (1995). Subjects were 72 patients at the
      largest nephrology center in Israel. Instruments included the SF-36 Health Survey
      (version 1.0) and Parfrey's health questionnaire for End Stage Renal Disease. The
      findings indicate that the negative effects of the disease on quality of life can
      be observed in the pre-dialysis stage, and that the strongest predictor of
      quality of life were patients' symptom reports, independent of objective
      indicators of their health state. Social workers play a key role in aiding
      patients and their families to adjust to the disease and its treatment prior to
      starting dialysis, and in bringing the importance of patients' subjective
      assessments to the attention of the treatment team.

PMID- 15022733
TI  - Transformations: a phenomenological investigation into the life-world of home
      haemodialysis.
AB  - With a growth in home-care, and increased funding for dialysis, there is a need
      for the field of Social Work to understand the life-world of people who
      experience home haemodialysis technology (HDDT). Given little research has
      focussed on the lived-experiences of this population (Nagle, 1995), an
      exploratory qualitative study was employed (Strauss & Corbin, 1998). The study
      investigated the embodied life-world experiences of this population using
      phenomenological methods (Kvale, 1996; van Manen, 1997). The data was collected
      and analyzed in terms of the four basic phenomenological categories of lived
      time, lived-body, lived-spatiality, lived-relations with others and self (van
      Manen, 1997). A purposive sample of four was selected, and interviewed using semi
      structured interviews, with each participant experiencing various lengths of
      HHDT. The findings revealed that their life-world had been transformed by their
      experience of HHDT. In particular, it was documented how participants' adoption
      of medical practice and discourse has impacted the lived-body, suggesting a need
      to adopt a plain language or holistic medical discourse practice approach for
      communication with patients which supports bodily-integrity and sovereignty.
      Additional findings centered on the incorporation of HHDT into the family unit,
      and how HHDT may present a health care access barrier to those without homes.
      Moreover, aspects of the transformation of the home into a hospital were
      highlighted. Finally, it is suggested that social assessment should consider the
      patient and family's experience of the dialysis machine.

PMID- 15022734
TI  - Professional identities and interprofessional relations: evaluation of
      collaborative community schemes.
AB  - Despite the widespread support for integrated community care in the U.K.,
      interdisciplinary working between health and social service staff remains complex
      and tentative. This paper represents the findings of an evaluative research study
      of two collaborative community nursing schemes at differing stages of project
      development within West Yorkshire, England. The studies set out to explore in
      depth the ways social and health care professionals construe their identity and
      relationships within the changing context of collaborative projects. The research
      adopted a constructivist phenomenological approach, conducting focus groups with
      social workers and district nurses; supplemented by in-depth individual
      interviews. Using template analysis enabled the researchers to explore themes and
      issues generated from the groups and individuals. A number of areas associated
      with professional identity and the development of roles in response to changing
      situations were identified as pertinent including; role ambiguity, role erosion
      and extension. In cases where joint working required a reconstructing of
      professional identity, individuals were constrained by their personal meanings,
      organizational arrangements and public perceptions. Implications for research and
      practice are discussed.

PMID- 15022735
TI  - Service needs of male caretakers of HIV-infected and affected children: policy
      and practice implications.
AB  - The number of male caretakers (biological fathers and other men) of HIV-infected
      and affected children is substantial and may increase in the US and elsewhere as
      more women become infected. Little information exists about the needs these men
      have for support services to help them better perform their parenting roles as
      male caretakers (MCs). This paper discusses the service needs of MCs at Ryan
      White CARE Act Title IV programs, the challenges providers at these programs face
      in serving MCs, and the strategies they have found effective in working with MCs.
      Providers report that MCs have specific service needs including the need for
      emotional support. Title IV programs meet these needs in a limited way because
      they are organized primarily around the needs of female rather than male
      caretakers. We discuss how Title IV programs can tailor existing service delivery
      and implement organizational change to facilitate MCs' service access and
      utilization. Further research directly with MCs is necessary to learn more about
      their service needs and the barriers MCs face in accessing services.

PMID- 15022736
TI  - Advance directive group education in a VA outpatient clinic.
AB  - Advance directive education is an important social work role in many medical
      settings. Despite its obvious benefit in terms of time-effectiveness, group
      education around advance directives has received little previous attention in the
      social work research literature. In a retrospective cohort (n = 13,913), we
      compared three education strategies in an attempt to evaluate their effectiveness
      on advance directive completion: (1) participation in a group session, (2) one or
      more individual sessions with a social worker, and (3) no advance directive
      education. Social work education of any kind resulted in an overall completion
      rate of 20% versus 2.1% in the non-intervention group. Group education was twice
      as effective as an individual social work session, and as effective as multiple
      sessions, but less time consuming. Our study confirmed previous findings that
      older patients are more likely to complete advance directives independent of
      education strategy. Participants in the group sessions were also older than the
      rest of the cohort, leading us to hypothesize about the particular appeal of
      group education to older patients. We conclude that group education is an
      effective as well as time- and cost-efficient social work tool for facilitating
      completion of advance medical directives, particularly among older patients.

PMID- 15022737
TI  - Adsorption, transformation, and bioavailability of the fungicides carbendazim and
      iprodione in soil, alone and in combination.
AB  - When studying the effect of mixtures of toxic substances on soil organisms,
      attention must be paid to peculiarities in exposure to mixtures as opposed to
      that of single toxicants. The fungicides carbendazim and iprodione compete in the
      adsorption to soil. The presence of iprodione reduced the adsorption of
      carbendazim by 30%, while carbendazim reduced the adsorption of iprodione by 70%.
      Iprodione had little effect on the transformation rate of carbendazim in soil.
      However, carbendazim retarded the transformation of iprodione in soil by 26%. The
      concentration of the fungicides in pore water was found to be substantially
      higher for mixtures than when a fungicide alone was present in the soil. The
      effect of the additional fungicide on the concentration is especially apparent in
      the period following the first 1 to 2 weeks of the incubation. The inclusion of
      copper in the mixture has little additional effect on the concentration of the
      fungicides in pore water.

PMID- 15022739
TI  - Solvent and surfactant enhanced solubilization, stabilization, and degradation of
      amitraz.
AB  - In an effort to help with the development of effective dip vat management and
      waste disposal strategies this study determined how solution properties such as
      pH, buffer composition, ionic strength, temperature, solubility in organic
      solvents and the addition of commonly used solubilizing agents influenced the
      hydrolysis of amitraz. Amitraz degrade by means of hydrolysis described by a
      pseudo-first order rate process and a type ABCD pH rate profile. Hydrolysis
      increased with temperature and was fastest at low pH, slowest at neutral to
      slightly alkaline pH, and slightly increased above pH 10. However, buffer
      concentration and ionic strength influenced the hydrolysis rate and had to be
      accounted for before constructing a pH rate profile. Hydrolysis seems to depend
      on the dielectric constant of solvent mixtures and was fastest in water, slower
      in propylene glycol and ethanol solutions, and slowest in DMSO mixtures. In
      surfactant solutions, anionic micelles enhanced and cationic micelles retarded
      the hydrolysis rate. The magnitude of micellar effects decreased with increasing
      concentrations of the surfactants. The increased solubility and faster hydrolysis
      of amitraz in the sodium lauryl sulfate solutions showed that anionic surfactants
      potentially could be used for cleaning up amitraz spills, because it both
      solubilized the drug and catalyzed hydrolysis.

PMID- 15022738
TI  - Pyrethrins and piperonyl butoxide adsorption to soil organic matter.
AB  - The adsorption and mobility of pyrethrins (Pys), the major insecticidal
      components obtained from the pyrethrum daisy Tanacetum cinerariifolium, and
      piperonyl butoxide (PBO), a pyrethrum synergist, were determined in soil using
      batch-equilibrium and reverse-phase thin-layer chromatographic techniques. Two
      soil management practices were used, soil mixed with yard waste compost (COM) at
      50 t acre(-1) on dry weight basis and no-mulch (NM) bare soil. Adsorption
      isotherm experiments were carried out using known concentrations of Pys (Py-I and
      Py-II) and PBO mixed with known amounts of COM or NM soil at constant temperature
      and pressure until equilibrium was attained. Pys and PBO in soil extracts were
      purified and concentrated using solid-phase extraction cartridges containing C18
      octadecyl bonded silica. Pys and PBO residues were quantified using a high
      performance liquid chromatograph equipped with a UV detector. Adsorption studies
      showed that compost amended soil adsorbed more Pys and PBO than native (NM) soil.
      Py-I adsorption was greater than Py-II and PBO. Adsorption of Pys and PBO to
      humic and fulvic acids was also studied by reverse-phase thin layer
      chromatography (RPTLC). Results indicated that humic acid, a significant
      component of organic matter, reduced Pys and PBO mobility. Pys and PBO mobility
      decreased as the concentration of humic acid in the mobile phase increased.

PMID- 15022740
TI  - The effect of operational parameters on the photocatalytic degradation of
      pesticide.
AB  - The photocatalytic degradation of Cartap Hydrochloride, a synthetic pesticide.
      has been investigated over coated TiO2 photocatalysts irradiated with a
      ultraviolet (UV) light. The effect of operational parameters, i.e., Cartap
      Hydrochloride concentration, reaction time, light intensity and additive on the
      degradation rate of aqueous solution of Cartap Hydrochloride has been examined.
      Results show that the employment of efficient photocatalysts and the selection of
      optimal operational parameters may lead to degradation of Cartap Hydrochloride
      solutions.

PMID- 15022741
TI  - Photodegradation of pentachlorophenol by sunlight in aquatic surface microlayers.
AB  - Photodegradation of pentachlorophenol (PCP) in aquatic surface microlayer (SM)
      was examined under natural sunlight. SM samples were collected using a glass
      plate, along with corresponding subsurface waters. PCP was added to samples of
      the SM and subsurface water. When all samples were exposed to the same natural
      sunlight conditions, the first order photodegradation rates of PCP in the SM
      water samples were different from those of PCP in corresponding subsurface water
      samples. The difference was correlated with the enrichment of dissolved organic
      carbon (DOC) in SM compared to the corresponding subsurface waters. Enhanced
      photodegradation in SM may be due to increased abundance of photoreactants
      related to the UV-absorbing properties of dissolved organic materials in the SM
      as the result of photo-induced reactions. Effects of environmental factors, pH
      and salinity, on photodegradation process of PCP in SM were also evaluated.

PMID- 15022742
TI  - Mixture of paraquat and linuron formulations examined for genotoxicity in Wistar
      rats by the in vivo micronucleus test--evaluation by different statistical tests.
AB  - The purposes of the present study were the evaluation of the genotoxic effect of
      mixture of paraquat and linuron commercial formulations. the evaluation of the
      possible interaction between the two pesticides and the comparison of different
      statistical tests used for the data analysis. For this purposes the bone marrow
      micronucleus test was used. Dose levels were determined in the base of the LD50
      of each component. According the experimental design, three dose levels of the
      mixture were administered at groups of five Wistar rats from each sex. Sampling
      time was 24 h for all groups plus 48 h for the highest dose and the positive
      control groups. In addition, the formulations were studied separately at two dose
      levels. Cyclophosphamide was used as positive control. For the statistical
      analysis of the results different parametric and nonparametric tests were used.
      The mixture of the two pesticides under the study conditions was not proven to be
      genotoxic. However, cytotoxicity and no signs of interaction were indicated.
      Minor declinations between the statistical tests used for data analysis observed.

PMID- 15022743
TI  - Investigation on the usage of clay modified electrode for the electrochemical
      determination of some pollutants.
AB  - Redox behavior of three pollutants, namely endosulfan (EN), o-chlorophenol (OCP)
      and direct orange 8 (DO8) were investigated electrochemically using sodium
      montmorillonite clay modified glassy carbon electrode. Influence of pH, scan rate
      and concentration were studied on the voltammetric response. Suitable medium for
      the electrochemical studies of EN was pH 1.0 and for other two pollutants pH
      13.0. EN exhibited one well-defined reduction peak accounting for irreversible
      2e(-) transfer and leading to the removal of one chlorine atom. OCP underwent one
      electron oxidation to the formation of phenoxy radical resulting in an oxidation
      peak. DO8 showed two peaks for reductions and two peaks for oxidation as a result
      of the reduction of azo group and oxidation of phenoxide group. These
      electrochemical reactions of the three pollutants reveals the suitability of clay
      modified electrode for the electroanalysis. A differential pulse stripping
      voltammetric procedure for the determination of these pollutants was developed.
      The limits of determination for EN, OCP and DO8 are 5-300, 10-800 and 50-800 ppb,
      respectively.

PMID- 15022744
TI  - Levels of organochlorine pesticide residues in marine-, surface-, ground- and
      drinking waters from the Eastern Cape Province of South Africa.
AB  - Persistent organochlorine pesticides (OCPs) such as DDT and its metabolites (DDDs
      and DDEs). chlordane, hexachlorobenzene (HCB), heptachlor and endosulfan were
      determined in drinking-, ground-, surface- and marine waters from the Eastern
      Cape Province of South Africa. Percentage recoveries of the OCPs from spiked
      river water ranged from 71.03 +/- 8.15% (dieldrin) to 101.25 +/- 2.17% (alpha
      BHC). The levels of OCPs ranged from 5.5 ng/L (2,4-DDD) to 160 ng/L (HCB) in the
      water samples. Some endocrine disrupting OCPs such as DDT, DDE, heptachlor,
      endosulfan and chlordane were detected.

PMID- 15022745
TI  - Toxicity of herbal pharmaceutical wastewater on fish--Lebistes reticulatus
      (Peter).
AB  - Toxic effects of herbal pharmaceutical wastewater on common fish (Lebistes
      reticulatus) under laboratory conditions were studied. LC50 values for raw,
      neutralized, and physico-chemically treated effluent for 24, 48, 72, and 96 h
      ranged between 3.0-9.5%, 5.0-10.5%, and 35-41%, respectively. It was evident from
      the studies that physico-chemical treatment reduces the toxicity by more than
      30%. This article discusses in detail the bioassay evaluation of raw,
      neutralized, and primary treated effluent. Physico-chemically treated effluent
      was further subjected to biological treatment by activated sludge system.
      Effluent from biological treatment revealed no toxic effect even after one month
      of exposure.

PMID- 15022746
TI  - RAPD marker and substrate utilization pattern applied to study microbial
      community diversity in the soil affected by agricultural chemicals.
AB  - Present analyses of random amplified polymorphic DNA (RAPD) and Biolog GN
      substrate utilization pattern are combined to further study the diversity of
      microbial communities in four soils affected by agricultural chemicals. The
      results showed that the four soil microbial communities were apparently
      distinguishable in the diversity at RAPD level in terms of the richness and
      modified richness in the summer, which supports our previous report using the
      same soils in winter. A significant difference for the average well color
      development (AWCD) at 72 h incubation was found among the soils in winter using
      Biolog GN substrate utilization pattern, but this difference was not found among
      the soils in summer. However, Shannon-Weaver indices for microbial communities in
      the summer soils polluted by agricultural chemicals were significantly higher
      than those in winter at metabolic level; in contrast, no significant difference
      existed between the two seasons for microbial communities in the soil without
      chemical pollution. Present results suggest that the combined approach using RAPD
      and substrate utilization pattern could be used to effectively quantify microbial
      community diversity and its changes among the seasons in the soils affected by
      agricultural chemicals, simultaneously at molecular and physiological levels.

PMID- 15022747
TI  - Co-composting of paper mill sludge and hardwood sawdust under two types of in
      vessel processes.
AB  - Recycling of organic residues by composting is becoming an acceptable practice in
      our society. Co-composting dewatered paper mill sludge (PMS) and hardwood
      sawdust, two readily available materials in Canada, was investigated using
      uncontrolled and controlled in-vessel processes. The composted materials were
      characterized for total C and N, water-soluble, acid-hydrolyzable, and non
      hydrolyzable N, extractable lipids, and by Fourier Transform Infrared (FT-IR)
      spectrophotometry. In the controlled scale process, the loss of organic matter
      was approximately 65% higher than in the uncontrolled process. After undergoing
      initial fluctuations in N fractions during the first two days of composting, by
      the end of the process, concentrations of water-soluble N decreased while those
      of acid-hydrolyzable and nonhydrolyzable N increased in the controlled process,
      whereas in the uncontrolled process, water-soluble N increased, but N in the
      other two fractions decreased continuously, indicating that the biochemical
      transformations of organic matter were not completed. Data on extractable lipids
      and FT-IR spectra suggest that the compost produced from the controlled process
      was bio-stable after 14 days, while the uncontrolled process was not stabilized
      after 18 days. In addition, FT-IR data suggest the biological activity during
      composting centered mainly on the degradation of aliphatic structures while
      aromatic structures were preserved. The co-composting of the PMS and hardwood
      sawdust can be successfully achieved if aeration, moisture, and bio available C/N
      ratios are optimized to reduce losses of N.

PMID- 15022748
TI  - Examining farmland applications of composted biosolid wastes depending on
      nutrient balance in soils.
AB  - This study emphasizes nutrient balance of soils in the farmland application of
      composted biosolid wastes. The loading rates of plant nutrients following the
      compost application to farmland in Japan were estimated and compared with the
      nutrient uptake of agricultural plants. Results show that the current compost
      application in Japan can meet the requirements of agricultural plants for plant
      nutrient Ca, except for K, Mg, P, Fe, Mn, Cu, and Zn. The compost application
      could realize the safe disposal of biosolid wastes and the effective recycling of
      plant nutrients in composts to soils without causing heavy metal accumulation.
      The application manner of composts affects the heavy metal accumulation in
      farmlands. Field examination indicates that the excessive compost application has
      led to the heavy metal accumulation in compost-amended farmlands. Measuring the
      nutrient balance in compost-amended farmlands is well suitable for explaining the
      accumulation of heavy metals, such as Cu and Zn.

PMID- 15022749
TI  - Integrated waste management through producers and consumers education: composting
      of vegetable crop residues for reuse in cultivation.
AB  - As part of the design of an integrated waste management scheme through the use of
      the PRECEDE/PROCEED model in the area of Crete, data concerning the applicability
      of composting in various agricultural wastes was considered as necessary.
      Vegetable residues from tomato, cucumber, eggplant, and pepper crops were
      collected, shredded and composted either alone or with the use of olive press
      cake, olive tree leaves, and branches and vine branches as bulking agents. Seven
      random combinations--mixtures of the above materials were composted using
      windrows, where additional four similar windrows were made up by approximately 10
      m3 of the above mentioned vegetable crop residues. All windrows were turned four
      times during the eight weeks thermophylic phase, with the help of a mechanical
      turner. A large number of physiochemical parameters were monitored in the raw
      materials, at the end of the thermophylic phase and at the end of the maturation
      phase. The temperature which was monitored daily, recorded the highest values
      (above 55 degrees C) in the windrows where bulking agents were used. All raw
      vegetable crop residues and their mixtures presented increased electrical
      conductivity values (above 5 mS/cm and up to 9.7 mS/cm) resulting to end products
      with respectively high EC values (above 3 mS/cm and up to 15 mS/cm) probably due
      to the presence of large amounts of soil, rich in fertilisers, attached to the
      roots of the plants. There was no detection of any remains of the 13 pesticides
      for which all 11 composts were tested for. The accuracy of the results was tested
      through a recovery test of the pesticides in mature compost, resulting to
      acceptable recovery values.

PMID- 15022750
TI  - Microbial degradation of livestock-generated ammonia using biofilters at typical
      ambient temperatures.
AB  - The purpose of this research was to neutralize livestock-generated ammonia by
      using biofilters packed with inexpensive inorganic and organic packing material
      combined with multicultural microbial load at typical ambient temperatures. Peat
      and inorganic supporting materials were used as biofiltration matrix packed in a
      perfusion column through which gas was transfused. Results show the ammonia
      removal significantly fell in between 99 and 100% when ammonia concentration of
      200 ppmv was used at different gas flow rates ranged from 0.030 to 0.060 m3 h(-1)
      at a fluctuating room temperature of 27.5 +/- 4.5 C (Mean +/- SD). Under these
      conditions, the emission concentration of ammonia that is liberated after
      biofiltration is less than 1 ppmv (0.707 mg m(-3)) over the period of our study,
      suggesting the usage of low-cost biofiltration systems for long-term function is
      effective at wider ranges of temperature fluctuations. The maximum (100%) ammonia
      removal efficiency was obtained in this biofilter was having an elimination
      capacity of 2.217 g m(-3) h(-1). This biofilter had high nitrification
      efficiencies and hence controlled ammonia levels with the reduced backpressure.
      The response of this biofilter to shut down and start up operation showed that
      the biofilm has a superior stability.

PMID- 15022751
TI  - The combination of zinc compounds and acidic pH limits aerobic growth of a
      Salmonella typhimurium poultry marker strain in rich and minimal media.
AB  - The objective of the present study was to examine the combined effects of zinc
      compounds with different acidic pH levels on the aerobic growth of a S.
      typhimurium poultry isolate in either rich or minimal media. When overall main
      effects of pH levels of medium or concentrations of Zn compounds were compared,
      growth rates of the S. typhimurium poultry isolate were significantly (p < 0.05)
      decreased by stepwise increase of pH levels of medium (pH 4, 5, 6, and 7) or
      concentrations (0.67, 3.35, and 6.03%) of Zn compounds (Zn acetate and Zn
      sulfate). In general growth rates of S. typhimurium poultry isolate appeared to
      be more reduced by Zn acetate than by Zn sulfate and more reduced in minimal
      media compared to rich media.

PMID- 15022752
TI  - Distribution and fractionation of phosphorus, cadmium, nickel, and lead in
      calcareous soils amended with composts.
AB  - Composts improve organic carbon content and nutrients of calcareous soils but the
      accumulation and distribution of phosphorus and heavy metals among various
      fractions in soil may vary under the south Florida conditions. The accumulation
      of P, Cd, Ni, and Pb with depth and the distribution of water soluble,
      exchangeable, carbonate, Fe-Mn oxides, organic and residual forms of each element
      were investigated in soils amended with municipal solid waste (MSW) compost, co
      compost and biosolids compost and inorganic fertilizer (as control). Total
      concentrations of P, Cd, Ni, and Pb were higher in the 0-22 cm soil layers and
      decreased considerably in the rock layers. These elements were in the decreasing
      order of P >> Pb > Ni > Cd. Amounts of water soluble and exchangeable forms of P,
      Cd, Ni and Pb were negligible at 0-22 cm soil depths except for Cd in the 10-22
      cm depth. Amending calcareous soil with either organic or inorganic amendments
      rendered phosphorus, nickle and lead in the residual form followed by Fe-Mn
      oxides form in the 0-10 and 10-22 cm soil layers. Cadmium was predominantly in
      the Fe-Mn oxides fraction followed by the residual and carbonate forms in both
      soil layers. A significant positive correlation was found between various organic
      carbon fractions and organic forms of P, Cd and Pb in the surface soil layer.
      Soil amended with MSW compost had higher concentration of Cd in the organic
      fraction whereas, co-compost and MSW compost amended soil had higher
      concentrations of organic Ni fraction in the 0-10 cm soil layer.

PMID- 15022753
TI  - Phylogenetics of the Thamnocalamus group and its allies (Gramineae:
      Bambusoideae): inference from the sequences of GBSSI gene and ITS spacer.
AB  - Phylogenetics of 33 species (35 species in the ITS analysis) of the Thamnocalamus
      group and its allies inferred from partial sequences of the nuclear GBSSI gene
      and from those of the nuclear ribosomal ITS spacer was discussed in the present
      paper. The analyses of two separate data and combined data sets were performed
      using the parsimony method. Two species from Arundinaria and Acidosasa were used
      as outgroups. All three analyses supported the monophyly of the Thamnocalamus
      group and its allies, which have pachymorph rhizomes and semelauctant
      synflorescences with three stamens. The two sampled species of Chimonocalamus
      were resolved as a strongly supported monophyletic group and as basal in the
      Thamnocalamus group and its allies in the ITS and combined analyses. The
      resolution of the Thamnocalamus group and its allies in the GBSSI-gene-based tree
      was generally poor, while the gene still identified some clades with strongly
      internal supports, i.e., the Chimonocalamus clade, the Ampelocalamus clade, the
      clade of Thamnocalamus spathiflorus and its variety, that of Fargesia porphyrea
      and Yushania bojieana, and the clade of Fargesia edulis and Fargesia fungosa. The
      topology resulting from the GBSSI and ITS combined data analysis had a better
      resolution than those from the two separate data sets. T. spathiflorus and its
      variety comprised another strongly supported basal clade and may be next to the
      Chimonocalamus clade. The positions of the African Thamnocalamus tessellatus and
      Arundinaria (Yushania) alpina, and the monotypic Chinese endemic Gaoligongshania
      were problematic. The Thamnocalamus group per se was resolved as polyphyletic.
      Most species of Fargesia and Yushania formed a group with no bootstrap support.
      This assemblage was heterogeneous according to the morphological characters and
      further investigation is needed. This study implicated that the current
      limitation of three genera of Thamnocalamus, Fargesia (incl. Borinda) and
      Yushania may not reflect the true phylogenetic relationships of the complex. The
      phylogenetic utility of GBSSI gene in closely related woody bamboos was also
      evaluated.

PMID- 15022754
TI  - Potential phylogenetic utility of the nuclear FLORICAULA/LEAFY second intron:
      comparison with three chloroplast DNA regions in Amorphophallus (Araceae).
AB  - FLORICAULA/LEAFY (FLO/LFY) is a single-copy nuclear-encoded homeotic gene
      containing two introns. We have investigated the utility of the second intron of
      FLO/LFY (FLint2) as a tool for phylogeny reconstruction at lower taxonomic
      levels. As an example, the phylogeny of 46 Amorphophallus, two Pseudodracontium,
      and four outgroup species is reconstructed using maximum parsimony and maximum
      likelihood analyses of FLint2 sequences. We designed new primers based on
      conserved sequences of the second and third exon for use in a range of Aroid taxa
      to amplify and sequence the second intron. In Amorphophallus FLint2 proved to be
      rather short (143-222 bp), highly variable and unsaturated. In all but two
      species a single amplification product was found. Results from phylogenetic
      analysis of FLint2 are largely congruent with results using the chloroplast
      regions rbcL, matK, and trnL, and compare favorably in percentage of informative
      characters, overall homoplasy levels, number of well-supported clades in
      consensus trees and resolution of ingroup relationships within Amorphophallus.
      When amplification products are not too large, alignment is relatively
      straightforward, and sequences are used in combination with other fast evolving
      markers, the FLint2 intron may be a valuable new tool for phylogenetic studies at
      lower taxonomic levels.

PMID- 15022755
TI  - Molecular systematics of aphids (Homoptera: Aphididae): new insights from the
      long-wavelength opsin gene.
AB  - Viviparous aphids (Aphididae) constitute a monophyletic group within the
      Homoptera with more than 4000 extant species worldwide but higher diversity in
      temperate regions. Several aspects of their biology account for attention paid to
      this group of insects. Their plant-sap-sucking way of feeding with many species
      transmitting viruses to crop plants has important implications on crop management
      strategies. Cyclical parthenogenesis associated in many groups to host
      alternation and elaborate polyphenisms is of special interests for evolutionists.
      Finally, the ancient association of most aphid species with intracellular
      endosymbiotic bacteria (Buchnera sp.) has also received much attention from
      evolutionists interested in mechanisms involved in the symbiotic process. Knowing
      the phylogenetic relationships among major aphid taxa is of special interest to
      evolutionists interested in the above issues. However, until recently, molecular
      approaches to aphid phylogeny were absent and discussions on the evolution of
      aphid life-cycles and on evolutionary aspects of their symbiotic association with
      Buchnera were framed by morphology-based phylogenies. Recently, two reports using
      molecular approaches attempted to address the yet unresolved phylogeny of
      Aphididae with limited although somehow different conclusions. In the present
      report we study the utility of the long-wave opsin gene in resolving phylogenetic
      relationships among seven subfamilies within the Aphididae. Our results
      corroborate some previously proposed relationships and suggest a revision of some
      others. In particular, our data support grouping the analysed aphid species into
      three main clades, being the subfamily Lachninae one of them, which contradicts
      its generally accepted sistership relationship with the subfamily Aphidinae.
      Moreover, our data also suggest a basal position of Lachninae which has
      implications on current discussions about the ancestrality of conifer-feeding in
      modern aphids.

PMID- 15022756
TI  - Phylogeny of the Mexican coastal leopard frogs of the Rana berlandieri group
      based on mtDNA sequences.
AB  - Phylogenetic relationships among specimens from 25 different locations for the
      six Mexican coastal leopard frog species of the Rana berlandieri species group
      were investigated using 797 bp of the mitochondrial 12S rDNA gene. Relationships
      among the haplotypes obtained were recovered using maximum parsimony and Bayesian
      analyses. Most of the clades recovered by both tree building methods are strongly
      supported, but conflicting clades recovered by each analysis are generally poorly
      supported. Both analyses reject the previously proposed subgroupings of the R.
      berlandieri species group. Based on the strongly supported relationships, genetic
      differentiation, and geographic distribution of the haplotypes examined, nine
      independent lineages appear to comprise the group of study. However, confirmation
      of the new proposed lineages will require further analyses based on other genetic
      markers and additional samples that cover their entire geographic distribution.
      Concordance was noted between Miocene-Pliocene geological and climatic events in
      Mexico and the relationships recovered among the lineages proposed and their
      geographic distribution.

PMID- 15022757
TI  - Molecular phylogeny of naidid worms (Annelida: Clitellata) based on cytochrome
      oxidase I.
AB  - Naidids are tiny, primarily freshwater oligochaete annelids which reproduce
      asexually by fission. We investigated the phylogenetic relationships within this
      group by sequencing 1224 bp of the mitochondrial gene cytochrome oxidase I (COI)
      from 26 species of naidids (representing 13 of the 23 genera currently
      recognized), as well as from four tubificids, their closest allies. Although not
      completely concordant, maximum parsimony and Bayesian inference analyses agreed
      in several important respects, with no well-supported conflicts. Our study, the
      first detailed molecular investigation of naidid relationships, suggests that
      naidids fall into two groups, one comprised of the genus Pristina, and another
      comprised of all other genera sampled. The clear division of naidids into these
      two groups best matches an early, simple classification of the group by Lastockin
      (1924); the more recent classifications proposed by Sperber (1948) and Nemec and
      Brinkhurst (1987) are not as consistent with our results. We note that our study
      suggests the genus Stylaria is comprised of two distinct species, Stylaria
      lacustris and Stylaria fossularis, rather than merely two morphotypes of a single
      species. Based on our phylogenetic results, we suggest that pigmented eyes
      evolved only once among naidids but must have been lost multiple times, and that
      the elongation of the prostomium into a proboscis evolved at least twice
      independently. The simplest form of fission, architomy (fragmentation), occurs in
      two of the most basally branching naidid genera, and may represent the
      plesiomorphic condition for naidids.

PMID- 15022758
TI  - The Pleistocene glaciations and the evolutionary history of the polytypic snail
      species Arianta arbustorum (Gastropoda, Pulmonata, Helicidae).
AB  - The evolutionary history of the snail Arianta arbustorum is controversial. This
      diverse, polytypic species has two distinct forms: one, with a globular shell and
      closed umbilicus, is found from lowland to high altitudes; the other, with a
      depressed shell and open umbilicus, is found at a few scattered, high altitude
      localities. What is the origin of these two forms? Some believe that the
      depressed shell is a recent, local, ecotypic adaptation to alpine environments.
      Others believe that this form is a relic of an ancestral condition that may have
      survived the Pleistocene glaciations on nunatak-like montane refugia, while the
      globular shell is a derived condition and its presence at high altitudes follows
      post-Pleistocene recolonisation. We analysed a portion of the mitochondrial gene
      cytochrome oxidase I for 100 snails of the species A. arbustorum, three
      additional Arianta species, and nine outgroup taxa from five genera, in order to
      understand the phylogeographic history of the species. Despite some confounding
      artefacts that are likely due to introgression among the morphological forms, the
      resulting phylogeny shows that the depressed shell is plesiomorphic, while the
      globular shell is derived. Moreover, their disparate histories suggest that the
      depressed shell variety survived the glaciations in pockets of alpine refugia,
      while the globular shell variety recolonised the alpine environment post
      glacially.

PMID- 15022759
TI  - Calibration of galliform molecular clocks using multiple fossils and genetic
      partitions.
AB  - For more than a century, members of the traditional avian order Galliformes
      (i.e., pheasants, partridges, junglefowl, and relatives) have been among the most
      intensively studied birds, but still a comprehensive timeframe for their
      evolutionary history is lacking. Thanks to a number of recent cladistic
      interpretations for several galliform fossils, candidates now exist that can
      potentially be used as accurate internal calibrations for molecular clocks. Here,
      we describe a molecular timescale for Galliformes based on cytochrome b and ND2
      using nine mostly internal fossil-based anchorpoints. Beyond application of
      calibrations spanning the entire evolutionary history of Galliformes, care was
      taken to investigate the effects of calibration choice, substitution saturation,
      and rate heterogeneity among lineages on divergence time estimation. Results show
      broad consistency in time estimation with five out of the nine total
      calibrations. Our divergence time estimates, based on these anchorpoints,
      indicate that the early history of Galliformes took place in the Cretaceous,
      including the origin of the basal-most megapode and perhaps cracid lineages, but
      that the remaining morphological diversification likely started in the earliest
      Tertiary. The multi-calibration/multi-genetic partition approach used here
      highlights the importance of understanding the genetic saturation, variation, and
      rate constancy spectra for the accurate calculation of divergence times by use of
      molecular clocks.

PMID- 15022760
TI  - Phylogeny and karyotype evolution of the Iberian Leptynia attenuata species
      complex (Insecta Phasmatodea).
AB  - An in-depth analysis of the Leptynia attenuata species complex has been performed
      by cytochrome oxidase subunit 2 (cox2) gene sequencing as well as karyotype and
      allozyme analysis. The whole set of data allows to largely resolve the taxonomy
      of the group and suggests an overall trend of chromosomal repatternings through a
      progressive reduction of the chromosome number. A previously suggested new
      species has been also confirmed on a genetic basis. Data are discussed in order
      to depict a phylogenetic and phylogeographic scenario fitting the observed
      genetic relationships between the different species of the group. Chromosome
      rearrangements are proposed as the major speciation driving force within the
      group and androgenetic reproduction is suggested as a shortcut to overcome the
      problem of fixing chromosomal rearrangements that are strongly underdominant in
      heterozygotes.

PMID- 15022761
TI  - 18S gene trees are positively misleading for monocot/dicot phylogenetics.
AB  - Monocots are consistently paraphyletic in 18S gene trees in all studies to date.
      This anomaly is generally expressed in the phylogenetic associations of two
      lineages, that of Acoraceae, which is excluded from the monocots, and
      Ceratophyllaceae, which sometimes clusters within the monocots. Six explanations
      for these unexpected results are proposed: (1) erroneous published sequences, (2)
      actual paraphyly of monocots with dicots, (3) insufficient taxon density among
      relevant taxa; (4) long-branch attraction between selected taxa, (5) an anomalous
      18S paralogue in the basal species of monocots, and (6) differential lineage
      sorting or other molecular evolutionary events. Tests of each of these hypotheses
      were conducted. For the first five hypotheses, test results refuted the
      hypothesis. Support for the sixth hypothesis, differential lineage sorting, is
      the strongest. Since lineage sorting seems to be restricted to a few species,
      identification and removal of these species prior to performing separate or
      combined phylogenetic analysis of DNA data incorporating sequences from 18S may
      be advisable.

PMID- 15022762
TI  - Molecular systematics of Blepharida beetles (Chrysomelidae: Alticinae) and
      relatives.
AB  - I investigated the phylogenetic relationships within the New World Blepharida and
      among related genera, using sequences of the Internal Transcriber Spacer 2 (ITS2)
      of nuclear ribosomal DNA and sequences of the COI and COII genes of the
      mitochondrial genome. Cladistic analyses were performed using parsimony, maximum
      likelihood, and Bayesian methods. These methods generated almost identical
      topologies using the combined data sets. The analyses suggest that Blepharida
      rhois, the type species, should be separated from the New World Blepharida and
      that the New World Blepharida might be congeneric with closely related Notozona.
      Also, according to this phylogeny, all of the New World Blepharida species that
      feed on Bursera (Burseraceae) form a single monophyletic clade, with the
      Afrotropical species forming its sister clade. The analyses also identified four
      main groups of species within the New World Blepharida.

PMID- 15022763
TI  - Molecular phylogeny of the Cheilodactylidae and Latridae (Perciformes:
      Cirrhitoidea) with notes on taxonomy and biogeography.
AB  - Phylogenetic relationships among cheilodactylid and latrid fishes were estimated
      from cytochrome oxidase I and cytochrome b mitochondrial DNA sequences. Two South
      African cheilodactylids, Cheilodactylus fasciatus and Cheilodactylus pixi, were
      divergent from the remaining members of their genus and family, and the monophyly
      of these groups was rejected based on parametric bootstrap analysis. As C.
      fasciatus is the nominal species for the genus and family, widespread taxonomic
      reassignment is implicated for the remaining 12 and 17 members of these groups,
      respectively. As these 17 cheilodactylids are not genetically or morphologically
      distinct from the latrids, it is proposed that the Latridae should be expanded to
      encompass them. The inferred relationships among those Cheilodactylus requiring
      generic reassignment were largely unresolved, and hence few recommendations can
      be made regarding their placement. Divergence time estimates indicate that chance
      oceanic dispersal subsequent to Gondwanan fragmentation best explains the
      Southern Hemisphere radiation of cheilodactylids.

PMID- 15022764
TI  - Nuclear corroboration of DNA-DNA hybridization in deep phylogenies of
      hummingbirds, swifts, and passerines: the phylogenetic utility of ZENK (ii).
AB  - This paper documents the phylogenetic utility of ZENK at the avian intra-ordinal
      level using hummingbirds, swifts, and passerines as case studies. ZENK sequences
      (1.7 kb) were used to reconstruct separate gene trees containing the major
      lineages of each group, and the three trees were examined for congruence with
      existing DNA-DNA hybridization trees. The results indicate both that ZENK is an
      appropriate nuclear marker for resolving relationships deep in the avian tree,
      and that many relationships within these three particular groups are congruent
      among the different datasets. Specifically, within hummingbirds there was
      topological agreement that the major hummingbird lineages diverged in a graded
      manner from the "hermits," to the "mangoes," to the "coquettes," to the
      "emeralds," and finally to a sister relationship between the "mountain-gems" and
      the "bees." Concerning swifts, the deepest divergences were congruent: treeswifts
      (Hemiprocnidae) were sister to the typical swifts (Apodidae), and the subfamily
      Apodinae was monophyletic relative to Cypseloidinae. Within Apodinae, however,
      were short, unresolved branches among the swiftlets, spinetails, and more typical
      swifts; a finding which coincides with other datasets. Within passerine birds,
      there was congruent support for monophyly of sub-oscines and oscines, and within
      sub-oscines, for monophyly of New World groups relative to the Old World
      lineages. New World sub-oscines split into superfamilies Furnaroidea and
      Tyrannoidea, with the Tyrannoid relationships completely congruent among ZENK and
      DNA-DNA hybridization trees. Within Furnaroidea, however, there was some
      incongruence regarding the positions of Thamnophilidae and Formicariidae.
      Concerning oscine passerines, both datasets showed a split between Corvida and
      Passerida and confirmed the traditional membership of passerid superfamilies
      Muscicapoidea and Passeroidea. Monophyly of Sylvioidea, however, remained
      uncertain, as did the relationships among the superfamiles themselves. These
      results are strikingly similar to other recent findings and indicative of
      continuing uncertainty about the higher level relationships of oscine passerines.

PMID- 15022765
TI  - New nuclear evidence for the oldest divergence among neognath birds: the
      phylogenetic utility of ZENK (i).
AB  - To date, there is little consensus concerning the phylogenetic relationships
      among neognath orders, which include all extant birds except ratites and
      tinamous. Different data sets, both molecular and morphologic, have yielded
      radically different and often unresolved ordinal topologies, especially within
      the neoaves clade. This lack of resolution and ongoing conflict indicates a need
      for additional phylogenetic characters to be applied to the question of higher
      level avian phylogeny. In this study, sequences of a single-copy nuclear gene,
      ZENK, were used to reconstruct an ordinal-level phylogeny of neognath birds.
      Strong support was indicated for the oldest divergence within Neognathae; the
      chicken- and duck-like birds formed a clade that was sister to all other modern
      birds. In addition, many families of traditional taxonomic orders clustered
      together in the ZENK tree, indicating the gene's general phylogenetic
      reliability. However, within the neoaves clade, there was little support for
      relationships among orders, which is a result similar to all other recent
      molecular studies of higher-level avian phylogeny. This similarity among studies
      suggests the possibility of a rapid radiation of the major neoaves lineages.
      Despite the ongoing lack of neoaves resolution, ZENK's sequence divergence and
      base composition patterns indicate its general utility as a new phylogenetic
      marker for higher-level avian systematics.

PMID- 15022766
TI  - Phylogeny and evolution of Digitulati ground beetles (Coleoptera, Carabidae)
      inferred from mitochondrial ND5 gene sequences.
AB  - Genealogical trees have been constructed using mitochondrial ND5 gene sequences
      of 87 specimens consisting of 32 species which have been believed to belong to
      the division Digitulati (one of the lineages of the subtribe Carabina) of the
      world. There have been recognized six lineages, which are well separated from
      each other. Each lineage contains the following genus: (1) the lineage A:
      Ohomopterus from Japan; (2) the lineage B: Isiocarabus from eastern Eurasian
      Continent; (3) the lineage C: Carabus from China which are further subdivided
      into three sublineages; (4) the lineage D: Carabus from USA; (5) the lineage E:
      Carabus from the Eurasian Continent, Japan and North America; and (6) the lineage
      F: Eucarabus from the Eurasian Continent. Additionally, the genus Acrocarabus
      which had been treated as a constituent of the division Archicarabomorphi has
      been recognized to be the 7th lineage of the division Digitulati from the ND5
      genealogical analysis as well as morphology. These lineages are assumed to have
      radiated within a short period and are largely linked to their geographic
      distribution.

PMID- 15022767
TI  - A deep-sea slant on the molecular phylogeny of the Scleractinia.
AB  - Lophelia pertusa and Madrepora oculata are azooxanthellate corals with nearly
      cosmopolitan distributions. They form cold-water reefs in the upper bathyal zone
      on continental margins and offshore banks [A.D. Rogers, Int. Rev. Hydrobiol. 84
      (1999) 315]. Lophelia is classified in the family Caryophylliidae and Madrepora
      in the family Oculinidae, both on the basis of skeletal morphology. Recent
      molecular studies of the scleractinians have given a new insight into the
      evolutionary history of this group. This study was aimed at clarifying the
      phylogenetic relationships of Lophelia and Madrepora, through the analysis of
      partial sequences of the mitochondrial 16S rDNA. Sequences were obtained for
      samples of L. pertusa collected in the northeast Atlantic and off Brazil, M.
      oculata, four other deep-sea and eight tropical coral species from the Reunion
      island in the Indian Ocean. The sequences were aligned with 69 homologous
      sequences of Scleractinia. Maximum parsimony and Bayesian analyses support
      previously published molecular topologies. The two specimens of L. pertusa
      grouped with two caryophylliids, confirming the existing classification of the
      species, but the large genetic distance between the two Lophelia samples suggests
      that these populations are genetically isolated from one another. M. oculata did
      not cluster with oculinids, but formed a monotypic clade lying between the
      families Pocilloporidae and Caryophyliidae. Phylogenetic analysis also suggested
      cryptic speciation within the tropical taxa Pocillopora meandriana and possibly
      Acropora humilis.

PMID- 15022768
TI  - Leech mycetome endosymbionts are a new lineage of alphaproteobacteria related to
      the Rhizobiaceae.
AB  - Mycetomal organs attached to the esophagus of hematophagous leeches which are
      known to harbor endosymbiotic bacteria were removed from three species in the
      leech family Glossiphoniidae. Anatomical observations indicated that placobdellid
      mycetomes are paired and caecate, inserting into the esophagus posterior to the
      proboscis. Light and electron microscopy demonstrated that there is a single
      layer of mycetome epithelial cells harboring gram-negative rods and that these
      epithelial cells are ultrastructurally distinct from neighboring esophageal
      epithelial cells. Fluorescent in situ hybridization with eubacterial and
      alphaproteobacterial probes localized the bacteria solely to the mycetomes both
      in adult and in unfed juvenile leeches whereas a gammaproteobacterial probe did
      not yield a bound fluorescencent signal. DNA was isolated from these tissues and
      subjected to PCR amplification using bacteria-specific primers for 16S and 23S
      rDNA. Results from sequencing the amplification products and phylogenetic
      analysis with other Alphaproteobacteria revealed that the bacteria resident in
      these organs comprise a new genus of Alphaproteobacteria, Reichenowia n. gen.,
      closely related to the nitrogen-fixing, nodule-forming Rhizobiaceae. The three
      bacterial strains, though different from each other were each other's closest
      relatives, suggesting a history of close coevolution with their leech hosts.

PMID- 15022769
TI  - Phylogenetics of barbets (Aves: Piciformes) based on nuclear and mitochondrial
      DNA sequence data.
AB  - A combination of nuclear (beta-fibrinogen intron 7; 938 bp) and mitochondrial
      (cytochrome b; 1045 bp) DNA sequence data analyzed with model-based phylogenetic
      methods yields a hypothesis of barbet and toucan relationships supported by high
      Bayesian posterior probabilities and several synapomorphic indels in the nuclear
      intron data. The basal topology differs from previous morphology and
      mitochondrial DNA sequence based hypotheses, but is consistent with DNA-DNA
      hybridization results. The mitochondrial DNA sequence data provide resolution at
      the tips of the tree, but when analyzed alone, yield a different basal topology
      than the combined data. However, the basal nodes in the mitochondrial-based tree
      have little statistical support. Combined data analysis produced strong
      statistical support at basal nodes and a relatively simple geographic structure.
      Barbets from each of the three tropical regions are monophyletic, but the Old
      World barbets are paraphyletic. The African and New World clades are sister taxa,
      and the Asian clade is basal. This geographic structure indicates that
      similarities in plumage, voice, and behavior between Gymnobucco and Calorhamphus
      are convergent. The data are not conclusive, but suggest paraphyly of the New
      World barbets. Only 4% of the Bayesian posterior distribution unites Semnornis
      with the other New World barbets.

PMID- 15022770
TI  - Protein phylogenies robustly resolve the deep-level relationships within
      Euglenozoa.
AB  - The deepest-level relationships amongst Euglenozoa remain poorly resolved,
      despite a rich history of morphological examination and numerous molecular
      phylogenetic studies of small subunit ribosomal RNA (SSU rRNA) data. We address
      this question using two nuclear-encoded proteins, the cytosolic isoforms of heat
      shock protein 90 (hsp90) and heat shock protein 70 (hsp70). For both proteins we
      examined sequences from the three primary groups within Euglenozoa (euglenids,
      diplonemids, and kinetoplastids), and from their close relatives, Heterolobosea.
      Maximum likelihood (ML) and ML distance analyses of these proteins support a
      close relationship between diplonemids and kinetoplastids to the exclusion of the
      euglenid Euglena gracilis. In hsp90 and combined protein analyses bootstrap
      support is very strong and alternative topologies are generally rejected by
      'approximately unbiased' (AU) tests. This result is consistent with recent
      molecular biological and morphological data, but contradicts early structural
      accounts and many SSU rRNA analyses that favour a closer relationship between
      diplonemids and euglenids. However, a re-examination of an important SSU rRNA
      data set highlights the instability of the inferences from this marker. The
      protein analyses also suggest that bodonids are paraphyletic, with
      trypanosomatids grouping with 'clade 2' and 'clade 3' bodonids to the exclusion
      of 'clade 1' bodonids.

PMID- 15022771
TI  - Arhynchobdellida (Annelida: Oligochaeta: Hirudinida): phylogenetic relationships
      and evolution.
AB  - A remarkable diversity of life history strategies, geographic distributions, and
      morphological characters provide a rich substrate for investigating the
      evolutionary relationships of arhynchobdellid leeches. The phylogenetic
      relationships, using parsimony analysis, of the order Arhynchobdellida were
      investigated using nuclear 18S and 28S rDNA, mitochondrial 12S rDNA, and
      cytochrome c oxidase subunit I sequence data, as well as 24 morphological
      characters. Thirty-nine arhynchobdellid species were selected to represent the
      seven currently recognized families. Sixteen rhynchobdellid leeches from the
      families Glossiphoniidae and Piscicolidae were included as outgroup taxa.
      Analysis of all available data resolved a single most-parsimonious tree. The
      cladogram conflicted with most of the traditional classification schemes of the
      Arhynchobdellida. Monophyly of the Erpobdelliformes and Hirudiniformes was
      supported, whereas the families Haemadipsidae, Haemopidae, and Hirudinidae, as
      well as the genera Hirudo or Aliolimnatis, were found not to be monophyletic. The
      results provide insight on the phylogenetic positions for the taxonomically
      problematic families Americobdellidae and Cylicobdellidae, the genera Semiscolex,
      Patagoniobdella, and Mesobdella, as well as genera traditionally classified under
      Hirudinidae. The evolution of dietary and habitat preferences is examined.

PMID- 15022772
TI  - Evolution of the gall-forming plant parasitic nematodes (Tylenchida: Anguinidae)
      and their relationships with hosts as inferred from Internal Transcribed Spacer
      sequences of nuclear ribosomal DNA.
AB  - Phylogenetic relationships among gall-forming plant parasitic nematodes of the
      subfamily Anguininae are reconstructed by maximum parsimony and maximum
      likelihood analyses. Sequences of the ITS of rDNA from 53 populations and species
      of gall-forming nematodes and five populations of the Ditylenchus dipsaci species
      complex were analysed. The phylogenetic trees strongly support monophyly of the
      genus Anguina and show nonmonophyly for the genera Mesoanguina and Heteroanguina.
      Morphological and biological characters are generally congruent with the anguinid
      groups identified in the rDNA phylogeny. Analyses of evolution of different gall
      types among anguinids reveal that there are apparent evolutionary trends in gall
      evolution: from abnormal swelling and growth of infested plant organs toward
      small localised galls, and from infestation of vegetative toward generative
      organs. Our study demonstrates that the main anguinid groups are generally
      associated with host plants belonging to the same or related systematic groups.
      The comparison of the ITS phylogenies of anguinids parasitising Poaceae and their
      host grasses shows a high level of cospeciation events.

PMID- 15022773
TI  - The advantages of the ITS2 region of the nuclear rDNA cistron for analysis of
      phylogenetic relationships of insects: a Drosophila example.
AB  - We examined the utility for phylogenetic reconstruction of the second internal
      transcribed spacer (ITS2), lying between the nuclear 5.8S gene and the gene for
      large subunit ribosomal RNA, using sequences of Ceratitis, Bactrocera, Musca, and
      Drosophila. We aligned and analyzed 13 sequences from GenBank and 11 new
      sequences from diverse species of Drosophila. Derivation of the secondary
      structure of the ITS2, the RNA transcript folding pattern required for transcript
      processing into functional RNA units, revealed the facets of sequence
      conservation common to all the sequences, that then allowed alignment of all the
      genera. The resultant tree, though including only a sparse representation of the
      enormous Drosophila diversity, conforms generally with the consensus of all prior
      phylogenetic reconstructions, using eight other nuclear and mitochondrial gene
      regions; where species representation is greater, as in the melanogaster subgroup
      of the Sophophora subgenus representatives, it conforms exactly. The paradigm
      ITS2 secondary structure presented can now be used to assess the genus more
      thoroughly, since its base pairing pattern makes alignment of sequences obvious.
      In addition, it shows that these insects share the ITS2 secondary structure
      characteristics of the other major animal groups as well as the green line of
      eukaryote evolution. The relatively short (<400 bp) ITS2 region seems ideal for
      reconstructing evolutionary relationships at the levels of species, genera, and
      perhaps even higher.

PMID- 15022774
TI  - Decreasing the effects of horizontal gene transfer on bacterial phylogeny: the
      Escherichia coli case study.
AB  - Phylogenetic reconstructions of bacterial species from DNA sequences are hampered
      by the existence of horizontal gene transfer. One possible way to overcome the
      confounding influence of such movement of genes is to identify and remove
      sequences which are responsible for significant character incongruence when
      compared to a reference dataset free of horizontal transfer (e.g., multilocus
      enzyme electrophoresis, restriction fragment length polymorphism, or random
      amplified polymorphic DNA) using the incongruence length difference (ILD) test of
      Farris et al. [Cladistics 10 (1995) 315]. As obtaining this "whole genome
      dataset" prior to the reconstruction of a phylogeny is clearly troublesome, we
      have tested alternative approaches allowing the release from such reference
      dataset, designed for a species with modest level of horizontal gene transfer,
      i.e., Escherichia coli. Eleven different genes available or sequenced in this
      work were studied in a set of 30 E. coli reference (ECOR) strains. Either using
      ILD to test incongruence between each gene against the all remaining (in this
      case 10) genes in order to remove sequences responsible for significant
      incongruence, or using just a simultaneous analysis without removals, gave robust
      phylogenies with slight topological differences. The use of the ILD test remains
      a suitable method for estimating the level of horizontal gene transfer in
      bacterial species. Supertrees also had suitable properties to extract the
      phylogeny of strains, because the way they summarize taxonomic congruence clearly
      limits the impact of individual gene transfers on the global topology.
      Furthermore, this work allowed a significant improvement of the accuracy of the
      phylogeny within E. coli.

PMID- 15022775
TI  - Huxley's line demarcates extensive genetic divergence between eastern and western
      forms of the giant freshwater prawn, Macrobrachium rosenbergii.
AB  - Phylogenetic analysis of representatives from 18 wild populations of the giant
      freshwater prawn, Macrobrachium rosenbergii, utilising a fragment of the 16S rRNA
      mitochondrial gene, identified two major reciprocally monophyletic clades either
      side of a well-known biogeographic barrier, Huxley's line. The level of
      divergence between the two clades (maximum 6.2%) far exceeds divergence levels
      within either clade (maximum 0.9%), and does not concord with geographical
      distance among sites. 'Eastern' and 'western' M. rosenbergii clades have probably
      been separated since Miocene times. Within-clade diversity appears to have been
      shaped by dispersal events influenced by eustatic change.

PMID- 15022776
TI  - [Treatment of uncomplicated Plasmodium falciparum malaria in children: comparison
      of halofantrine with mefloquine].
AB  - AIMS: Halofantrine is the first regimen used for the treatment of uncomplicated
      Plasmodium falciparum malaria in children in France according to the
      recommendations of the French Consensus Conference held in 1999 and pending
      additional data in this population. In 1999, a high rate of clinical relapse
      after a single cure of halofantrine led us to switch to mefloquine for first line
      treatment of uncomplicated malaria. The aims of this study were to evaluate this
      change of attitude and to compare the efficacy of halofantrine and mefloquine in
      the treatment of uncomplicated P. falciparum malaria in children. PATIENTS AND
      METHODS: We retrospectively analysed 118 pediatric cases of malaria treated at
      Armand-Trousseau Children hospital in Paris between January 1st, 1999 and
      December 31st, 2000. RESULTS: 93 patients were treated for an uncomplicated case
      of P. falciparum malaria: 48 received a unique cure of halofantrine and 21 were
      treated with mefloquine. Nine patients relapsed, all having previously received
      halofantrine. No patient treated with mefloquine relapsed. CONCLUSION: These
      results and other recent published data suggest to recommend mefloquine instead
      of halofantrine as first line treatment of uncomplicated P. falciparum malaria in
      children with respect to specific contra-indications. A larger evaluation of
      mefloquine is however necessary. The association atovaquone-proguanil (Malarone)
      is promising but needs to be evaluated in large pediatric studies in comparison
      with other treatments. Its indication as a curative treatment of uncomplicated
      malaria is, to date, restricted to adults and children over 12 years in France.

PMID- 15022777
TI  - [Criteria of severity in childhood falciparum malaria].
AB  - Severe falciparum malaria is responsible for 2 million annual deaths, mostly
      among children under five years living in sub-Saharian Africa. In France, about
      1500 paediatric malaria cases are diagnosed each year, among which 1% are severe
      and 1-2 deaths occur. Children are at high risk for severe forms, since malarial
      immunity is not yet acquired and symptoms are rapidly progressive. The definition
      of severe malaria relies upon WHO criteria revised in 2000. In children living in
      endemic areas, the most frequent criteria are impaired consciousness, severe
      anaemia, respiratory distress or acidosis, multiple convulsions and
      hypoglycaemia. Some of them have a high prognostic value, e.g., coma,
      hypoglycaemia or respiratory distress. The pertinence of WHO criteria was not
      assessed in travelling children, since severe cases are rare. Other severity
      criteria found in recent surveys from endemic zones, such as thrombocytopenia or,
      in infants, dehydration or bacteraemia, should also be investigated in childhood
      imported malaria. However, any fever associated with a convulsion, prostration,
      or impaired consciousness, in a child returning from the tropics, should be
      consider severe malaria and indicate an emergency admission to hospital. In
      France, intravenous quinine is recommended for the treatment of severe forms,
      without loading dose in children.

PMID- 15022778
TI  - [Pneumocystis carinii infections in a pediatric intensive care unit: a
      retrospective study 1980-2002].
AB  - OBJECTIVE: The objective of this study was to ascertain the clinical and
      epidemiological characteristics of Pneumocystis carinii pneumonia (PCP) cases
      admitted to the Pediatric Intensive Care Unit (PICU). PATIENTS AND METHODS: A
      retrospective study was carried out for the 10 PCP cases admitted to the PICU
      from 1980 to 2002. The variables studied were: age, sex, PRISM, underlying
      diseases, immunological status, clinical manifestations, radiology, response to
      therapy and clinical follow up. RESULTS: Age of the patients varied between 5
      months and 15 years and 4 months and there were 7 females and 3 males. Underlying
      diseases included: AIDS (3 cases), renal transplant (2 cases), West syndrome (1
      case), cancer (4 cases). All presented an acute respiratory failure and 8/10
      needed mechanical ventilation (mean duration: 14 days). All were treated by
      trimethoprim-sulfamethoxazole and 6/10 received steroids. Only one child died.
      CONCLUSION: PCP is rare and affects mainly immunocompromised children who exhibit
      ARDS. Steroids treatment is now considered as an useful therapeutic adjuvant. A
      preventive treatment should be administered to children at risk.

PMID- 15022779
TI  - [Ivermectin use in tropical medicine].
AB  - Ivermectin is a major breakthrough for the treatment of onchocerciasis,
      strongyloidosis, scabies and cutaneous larva migrans. Combined with albendazole,
      ivermectin is highly efficient for treating lymphatic filariasis and intestinal
      worms. Ivermectin shows very few side-effects but its use in children below 5 and
      during pregnancy is discussed. Ivermectin tolerance could be related to mdr1 gene
      expression. Additional studies are needed to assess its efficiency for
      pediculosis.

PMID- 15022780
TI  - [Visceral leishmaniasis: new drugs].
AB  - The standard treatment of visceral leishmaniasis is pentavalent antimony
      (meglumine antimoniate or sodium stibogluconate), but toxicity is frequent with
      this drug. Moreover, antimony unresponsiveness is increasing, both in
      immunocompetent and in immunosuppressed patients. Amphotericin B is a polyene
      macrolide antibiotic that binds to sterols in cell membranes. It is the most
      active antileishmanial agent in use. Its infusion-related and renal toxicity may
      be reduced by lipid-based delivery. Liposomal amphotericin B (Ambisome) seems to
      be less toxic than other amphotericin B lipid formulations (Amphocil, Amphotec).
      Optimal drug regimens of Ambisome vary from one geographical area to another. In
      the Mediterranean Basin, a total dose of 18 to 24 mg/kg is safe and effective.
      Shortening the duration of treatment without decreasing the total dose (i.e., 10
      mg/kg/day for 2 days) seems promising to reduce the global cost of the therapy.

PMID- 15022781
TI  - [Parasitic diarrhea in children].
AB  - In many areas, Entamoeba histolytica and Entamoeba dispar are found together and
      their microscopic appearance is identical. Biochemical tests which can show cell
      wall differences are often falsely negative and the only possible way is to treat
      with metronidazole when amoebiasis is suspected. In case of clinical failure of
      metronidazole, a bacterial diarrhea is frequently found. Giardia is an other
      protozoa frequently found in stools of children in endemic areas. Diarrheas due
      to Giardia are possible in normal children and frequent in malnourished. They can
      determine severe atrophy of jejunal mucosa and must be treated. Cryptoridiosis is
      frequently asymptomatic but induces diarrhea in malnourished children. Diarrhea
      due to helminths is rare and only Strongyloides stercoralis induces severe
      diarrhea in malnourished child and must be treated in emergency with Ivermectin
      to avoid dissemination. In immune deficiency induced by corticosteroid treatment
      or cancer chemotherapy, a prophylactic treatment with Ivermectin against
      Strongyloides stercoralis must be given in endemic areas or after return, and
      probably also with metronidazole against Giardia.

PMID- 15022782
TI  - [Pulmonary anti-Aspergillus defences].
AB  - The lung, constantly exposed to inhaled infectious particles, uses a very
      efficient immune system to insure sterility of the airways. It has to be tightly
      regulated for the tissues to be kept from its potentially deleterious effects.
      Pulmonary anti-Aspergillus defences are based upon the concurrent action of
      innate immunity, non specific but rapidly mobilisable, and of adaptative
      immunity. The former first consists in natural barriers, namely the respiratory
      epithelium and its antimicrobial peptides (complement, defensins, collectins).
      Then come the phagocytic cells (macrophages and neutrophils), but also the
      dendritic cells, able to stimulate adaptative responses through the presentation
      of antigens they have phagocytised ans processed. The Toll-like receptors are
      among the key ones involved in the recognition of fungal components. Chemokines
      have a crucial role for the recruitment, maturation and activation of
      neutrophils, while anti-inflammatory cytokines tightly influence T lymphocytes
      functional differentiation. These latter, cornerstones of the adaptative
      immunity, differentiate into two mutually exclusive pathways according to the
      type of cytokines which they produce. The Th1 one is largely protective in the
      context of Aspergillus, while the Th2 one is deleterious. However, a good
      cooperation between these 2 pathways is required for an efficient protection.
      Pulmonary anti-Aspergillus defences are multifactorial. Innate immunity is
      crucial but a capacity of the host to generate specific responses is also
      warranted.

PMID- 15022783
TI  - [Candida infections in newborns].
AB  - Candida infections in newborns are classified, as bacterial ones, in early onset
      or maternofoetal infections and late onset diseases, primitive and nosocomial.
      Candida infections are responsible of less than 1% of early onset sepsis. Their
      diagnosis is facilitated by suggestive cutaneous lesions which can be associated
      or not with systemic infection. Candida nosocomial infections are the most
      frequent, 7% in premature infants < 1500 g; they are associated with a central
      venous catheter or with cutaneous infection in extremely low birth weight
      infants. C. albicans is the predominant species in maternofoetal infections,
      contrary to nosocomial ones where C. parapsilosis is predominant, 60%. Both
      species are sensitive to fluconazole. Amphotericin B and its lipidic derivative
      Ambisome is the reference drug. Because of its lower toxicity and simplicity of
      administration, fluconazole is preferable for sensitive species. Its prophylactic
      use in colonized premature infants has been recently proposed.

PMID- 15022784
TI  - [Severe candidosis infections in neutropenic patient in onco-hematologic
      department].
AB  - Incidence of severe candidal infections is rapidly increasing since 15 years and
      is becoming a major concern in onco-hematology practice, especially due to its
      poor prognosis in neutropenic patients. Diagnosis of candidemia is suspected in
      case of persistent fever resistant to a large antibiotherapy and requires to
      search for secondary locations as cutaneous and hepatosplenic candidal infection.
      Improvement of yeasts detection in blood culture bottles with specific medium is
      now helpful but use of specific immunoserodiagnosis or PCR methods is at this
      point unuseful. Fluconazole and Amphotericine B remain the recommended treatments
      for candidemia. Indications for "new antifongal drugs" are still limited
      regarding their high cost and the limited clinical studies.

PMID- 15022785
TI  - [Invasive pulmonary aspergillosis in immunocompromized children: diagnosis and
      classification].
AB  - Invasive aspergillosis is an opportunistic infection, with frequent lung
      involvement. High-risk children are allogenic bone marrow recipients, and those
      with hematological malignancies, aplastic anemia or chronic granulomatous
      disease. Profound and prolonged neutropenia, and corticosteroid therapy are the
      most important predisposing factors. Building and demolition works represent the
      major environmental risk factor. The diagnosis of invasive aspergillosis remains
      difficult to establish. Clinical manifestations are non-specific. Early thoracic
      computed tomographic scan shows halo sign in most cases. Subsequently appears the
      air crescent sign. Galactomannan research by sandwich ELISA can be useful in
      serum and in bronchoalveolar lavage fluid. Aspergillus DNA detection by PCR is
      still not standardized. Culture of the organism allows species identification.
      Aspergillus hyphae can be found at cytological examination, but a biopsy specimen
      is usually required to affirm tissue damage. A new classification of invasive
      fungal infections in immunocompromised patients was recently proposed by experts
      from the European Organization for Research and Treatment of Cancer and from the
      Mycoses Study Group of the National Institute of Allergy and Infectious Diseases.
      On the basis of host linked criteria, microbiological, clinical and radiological
      features, invasive aspergillosis is classified as proven, probable or possible.
      These definitions should not be used to guide clinical practice in therapy, but
      they will improve the quality of epidemiological data, and help the comparison of
      clinical trial results.

PMID- 15022786
TI  - [Aspergillosis in cystic fibrosis patients].
AB  - Allergic bronchopulmonary aspergillosis (ABPA) should be suspected in any CF
      patient whose pulmonary disease deteriorates precipitously, suddenly or
      unexpectedly, and has to be correlated to fungal hypersensitivity biological
      tests. The standard therapeutic approach is based upon systemic corticosteroids.
      Invasive pulmonary aspergillosis (IPA) may occur mainly but not exclusively in
      immunosuppressed patients undergoing lung transplantation. New antifungal
      compounds (Triazoles, Itraconazole, Voriconazole), Echinochandins (Caspofungin)
      are effective, synergistic, well tolerated, should their contraindications and
      side effects be carefully respected and monitored.

PMID- 15022788
TI  - [Poliomyelitis on the way to global eradication: let us remain careful].

PMID- 15022787
TI  - [New antifungal agents: voriconazole and caspofungin].
AB  - Among new available antifungal agents voriconazole is a new triazole with an
      intravenous (i.v.) and oral formulation, and caspofungin is an echinocandin, new
      family with a new mode of action on the cell wall. It is available as an i.v.
      preparation. Both drugs have a broad spectrum targeting most of the usual
      pathogens: Candida and Aspergillus, even with low suceptibility or resistance to
      other antifungals. Voriconazole is also active on Scedosporium and Fusarium. The
      efficacy of these molecules was established in vitro and in experimental
      infections in animals either normal or immunosuppressed. Voriconazole is active
      in oropharyngeal and esophageal candidiasis, in refractory invasive candidiasis
      and as a first line treatment of invasive aspergillosis with better results than
      amphotericine B. It was also effective in scedosporiosis and in fusariosis.
      Caspofungin is active in oropharyngeal and esophageal candidiasis, in invasive
      candidiasis ranking among the best drugs in non neutropenic patients. It was
      shown effective in refractory aspergillosis. As empirical treatment of febrile
      neutropenic patients, these molecules should probably be restricted to the
      highest risk-population. Safety is good, side effects are a rare cause of
      discontinuation of treatment, class specific drug-drug interactions occur with
      voriconazole. These molecules open an important field of investigations with
      combination of antifungal agents.

PMID- 15022789
TI  - Peripheral in-continuity tissue examination: a modification of Mohs' micrographic
      surgery.
AB  - The use of peripheral in-continuity tissue examination, in which the surgeon or
      dermatologist and pathologist combine their talents to remove cutaneous tumors
      with rapid evaluation of all margins, is useful and practical for excision of
      basal cell and squamous cell carcinomas that are recurrent, large, or occur in
      historically difficult areas to treat. This procedure, like Mohs' micrographic
      surgery, can be used as a tissue-sparing measure while still providing the
      physician and patient with confidence of complete tumor removal. Because the
      technique allows for primary closure and immediate reconstruction of larger and
      more complex tumors, patients can be spared the added inconvenience, pain, and
      expense of multiple separate procedures that may be necessary with Mohs'
      micrographic surgery or traditional tumor excision with permanent section margin
      evaluation.

PMID- 15022790
TI  - The role of Mohs' micrographic surgery in the management of skin cancer and a
      perspective on the management of the surgical defect.
AB  - In the past 30 years, MMS has become recognized as the treatment of choice for
      certain uncommon cutaneous neoplasms and for certain variants of BCC, squamous
      cell carcinoma, and melanoma. It offers an extremely high cure rate and maximally
      preserves healthy tissue, which often allows for preservation of function as well
      as an optimal cosmetic outcome. Because it is performed in an office setting
      under local anesthesia, MMS is a very cost-effective procedure and often extends
      operability to patients who are poor candidates for general anesthesia. In the
      past 30 years, MMS has evolved in a number of ways. The fixed tissue technique is
      uncommonly employed today. This makes the procedure less painful and faster and
      allows for immediate reconstruction. In addition, because statistics have
      demonstrated the reliability of MMS, it has become less necessary to delay
      definitive reconstruction or use temporizing measures. With experience and
      training, more Mohs' surgeons have become adept at repairing the surgical defects
      they create; nevertheless, at times, it is necessary for the Mohs' surgeon to
      call on his or her colleagues to reconstruct the Mohs' defect or to assist in
      ridding patients of their cancer. At times, a multidisciplinary approach may
      provide the best care for patients. It also encourages collegiality and this has
      led to increasing respect for MMS by other surgical disciplines in the past 30
      years.

PMID- 15022791
TI  - Role of radiation therapy for facial skin cancers.
AB  - Radiation therapy is one of many modalities that should be considered and
      explained to patients with basal cell carcinomas and squamous cell carcinomas of
      the head and neck (Fig. 2). Control rates for appropriately selected patients
      should exceed 90% and historically are comparable with most surgical resections.
      For locally advanced T4 lesions, a combined modality approach will give the best
      chance at local control. Postoperative radiation therapy is indicated in patients
      with advanced lesions, positive margins, lymph node metastasis, or perineural
      invasion. We advocate the discussion of this treatment modality with every such
      patient, even if the treating physician does not recommend it. Only then can a
      patient provide genuine "informed consent" for treatment.

PMID- 15022792
TI  - Aesthetic and functional considerations in the reconstruction of large skin
      defects with free flaps.
AB  - Free flaps can be used effectively in the primary reconstruction of large defects
      after resection of large tumors. The ultimate goal is radical excision of tumors
      and achievement of primary wound healing with a single procedure and long-term
      local control of disease. Although this can be obtained with the use of free
      tissue transfer, patients often seek more aesthetic results. Therefore,
      refinements of reconstructive techniques with minimal functional donor site
      morbidity are now the gold standard in our practice.

PMID- 15022793
TI  - Cheek and inferior eyelid reconstruction after skin cancer ablation.
AB  - Most patients with actinic lesions and skin cancer are skin type I or II, older
      than 50 years of age, and have a history of extensive sunlight exposure. These
      patients have been treated in our units according to universal principles. A
      multidisciplinary team approach can produce encouraging long-term results. The
      size and depth of the lesion are assessed in planning the ablation. The residual
      defect after the tumor resection is anticipated in the preoperative plan.
      Adequate resection is mandatory, even if the reconstruction must be delayed to
      ensure clear margins. Attention to unit and subunit anatomy facilitates adequate
      reconstruction with acceptable deformity. Placing scars in borders or along the
      lines of minimal skin tension reduces deformity. Planning the flap so that the
      donor site is in tissue areas with maximum laxity guards against donor site
      deformity. Flaps must be planned to avoid excess tension on the lower lid and
      central face. Attempts should be made to reduce scarring in the central face as
      seen in the frontal view. Respecting these principles will allow for
      reconstruction of the largest facial unit in a manner acceptable to the patient.

PMID- 15022795
TI  - Ear reconstruction.
AB  - The ear is one of the most difficult areas to reconstruct. Experience with and
      knowledge of various methods are tantamount to a successful outcome.

PMID- 15022794
TI  - Lip reconstruction after ablation for skin malignancies.
AB  - When performing lip reconstruction following resection of skin cancer, it is
      important to plan the reconstruction to retain sphincter function and to design
      the flaps so that resulting scars fall into borders or MSLTs. These reliable and
      logical approaches to lip reconstruction will help to restore both form and
      function.

PMID- 15022796
TI  - Aesthetic reconstruction of the nose following skin cancer.
AB  - Nasal reconstruction after skin cancer can be very demanding, especially if the
      patient's expectations are high. Careful assessment of the defect and thorough
      preoperative planning are as important to the final result as is the technical
      execution of the procedure. Often, staged procedures will be required to achieve
      the optimal result. A successful reconstruction can provide a lifetime of
      satisfaction for the patient, however, and can be almost equally rewarding for
      the meticulous surgeon.

PMID- 15022797
TI  - Hand and forearm reconstruction after skin cancer ablation.
AB  - Skin cancer is common on the dorsum of the hand and forearm. The reconstructive
      challenges in this area are significant, and the options are myriad. Thus, the
      surgeon who takes on this challenge must know the various options. These options
      include the entire reconstructive ladder from direct closure all the way through
      to composite-free tissue transfer. Nail bed reconstruction should be mastered. In
      addition, the surgeon should be comfortable with all the reliable flaps,
      including the kite flap, the cross-finger flap, the reverse cross-finger flap,
      the rotation-advancement flaps, transposition flaps, and the radial forearm flap.

PMID- 15022798
TI  - Walking pattern in adults with congenital hip dysplasia: 14 women examined by
      inverse dynamics.
AB  - BACKGROUND: Knowledge of the gait dynamics in patients with hip dysplasia may
      help to understand the consequences of the mechanical changes in the hip.
      PATIENTS AND METHODS: We evaluated the walking pattern of 14 women with hip
      dysplasia (median age 39 (24-50) years) before periacetabular osteotomy and
      compared it with a control group of 12 healthy women (median age 35 (24-56)
      years). Data were collected using five video cameras and two force plates. We
      used an inverse dynamics approach to calculate sagittal joint angles, moments and
      power in the stance phase. RESULTS: The patient group showed increased
      dorsiflexion of the ankle and knee flexion in the second half of the stance
      phase. The hip flexor joint moment in the patient group was both delayed and
      reduced in the second half of the stance phase. Moreover, the angular impulse of
      the hip flexors was significantly reduced in the patient group. INTERPRETATION:
      The pathological deformities of hip dysplasia may explain both the kinematic and
      kinetic gait deviations between the patient group and the control group in the
      second half of the stance phase. We suggest that insufficient cover of the
      femoral head leads to a reduced hip flexor moment and an increased flexion in the
      ankle, knee and hip joints.

PMID- 15022799
TI  - Rotational acetabular osteotomy for hip dysplasia: 61 hips followed for 8-15
      years.
AB  - We operated on 54 patients (61 joints) with rotational acetabular osteotomy (RAO)
      due to dysplasia of the hip with pre- or early-stage osteoarthritis/arthrosis.
      The mean follow-up was 11 (8-15) years. The Merle d'Aubigne median score
      increased from 14 to 15. In 2 patients (2 joints), the score decreased from 15 to
      13. Progression of arthrosis was seen in 6 joints on the radiographs at follow
      up. Kaplan-Meier survivorship analysis predicted an 89% (95% confidence interval
      80-99) prevention of worsening of arthrosis at 10 years. Postoperative joint
      congruency was a risk factor for progression of arthrosis.

PMID- 15022800
TI  - Factors predisposing to periprosthetic fracture after hip arthroplasty: a case (n
      = 31)-control study.
AB  - We compared retrospectively 31 patients with a periprosthetic fracture to 31
      patients in a control group. The Finnish Arthroplasty Register was used to count
      all periprosthetic fractures treated by revision arthroplasty in Finland and in
      Tampere University Hospital district during the years 1990-1999. We used the date
      of the previous operation to find the control group patients operated on at the
      same time in the same hospital district. No other selection or matching criteria
      were used. The type of prosthesis, complications, age, BMI, cementation and
      primary diagnosis were compared. We found that patients who had a fracture as the
      primary diagnosis ran a 4.4 (95%CI = 1.4-14) times higher risk of periprosthetic
      fracture than those operated on for other reasons.

PMID- 15022801
TI  - No adverse effects of early weight bearing after uncemented total hip
      arthroplasty: a randomized study of 20 patients.
AB  - BACKGROUND: Few guidelines are available whether early weight-bearing after an
      uncemented total hip arthroplasty (THA) can be recommended or not. Stability and
      ingrowth may be jeopardized by immediate loading of the implant while functional
      recovery may be promoted and periprosthetic demineralization reduced. PATIENTS
      AND METHODS: We did a prospective study of 20 patients who were operated on with
      a hydroxyapatite-coated (HA), uncemented total hip arthroplasty with a tapered
      stem because of unilateral arthrosis, and randomized the patients to the
      immediate (I) or late (L) weight-bearing (after 3 months) group. The shoe on the
      operated side was equipped with an auditory device signaling when the patient
      placed a load on the extremity. The clinical assessment was done with the Harris
      hip score at the time of the operation and after 12 and 24 months. Radiographs
      and dual-energy x-ray absorptiometry (DEXA) were evaluated for migration, femoral
      remodeling and bone mineral density (BMD) after 3, 6, 12 and 24 months. Tc
      scintigraphy was done after 6, 12 and 24 months. RESULTS: Postoperatively, the
      Harris hip score showed no group difference. After 3 months, we noted a large
      reduction in BMD around the stem prosthesis. This was most marked in the proximal
      regions and the bone loss was significantly larger in zone 1, 4 and 5 in the L
      group. Distally, the BMD normalized with time, but the loss of bone persisted in
      the proximal zones after 24 months. An initial increase in the scintigraphic
      uptake ratio in all zones in both groups declined with time, but it was still
      increased on the operated side after 24 months. Several radiographic signs of
      bone remodeling were seen, but the patterns were similar in both groups.
      INTERPRETATION: We found no adverse effect of immediate weight bearing with this
      prosthesis.

PMID- 15022802
TI  - No need for routine closed suction drainage in elective arthroplasty of the hip:
      a prospective randomized trial in 104 operations.
AB  - BACKGROUND: The purpose of this study was to determine the utility of closed
      suction drainage (CSD) in elective total hip arthroplasty (THA). PATIENTS AND
      METHODS: We randomized 104 elective, consecutive THAs to receive drainage (53) or
      no drainage (51). 60 arthroplasties were cemented and 44 hybrid. RESULTS: In the
      drainage group, 2 hematomas and 2 superficial wound infections occurred; there
      were no wound complications in the undrained group (p = 0.04). Patients receiving
      drainage had a greater reduction in hematocrit (10.4 vs 7.4) (p = 0.03), and
      longer hospital stay (5.1 days vs 4.7) (p = 0.01). At the 3-month follow-up, we
      found no deep wound infections in either group. INTERPRETATION: We no longer use
      CSD in elective, primary, routine THA.

PMID- 15022803
TI  - High prevalence of hip arthrosis in former elite javelin throwers and high
      jumpers: 41 athletes examined more than 10 years after retirement from
      competitive sports.
AB  - We studied the occurrence of hip arthrosis in 19 former elite javelin throwers
      and 22 former elite high jumpers 10 years or more after their retirement from
      competitive sports. Any restriction in the activities of daily living was
      assessed with an ADL-questionnaire. We compared the radiographic findings with
      male, age- and body mass index-matched controls (non-athletes). 22 of 38 hips in
      the javelin throwers (7 of 38 hips in the controls) and 15 of 44 hips in the high
      jumpers (6 of 44 hips in the controls) were classified as stage II or worse
      (Kellgren); hip arthrosis was commoner in both groups than in the controls.
      Despite considerable radiographic degenerative changes, the reduction of function
      in activities of daily living (FFbH score 96% in javelin throwers and 99% in high
      jumpers) was slight, as compared to a corresponding normal population. Javelin
      throwing and high jumping as competitive sports entail a high risk of subsequent
      hip arthrosis.

PMID- 15022804
TI  - Comparison of preoperative templating with postoperative assessment in cementless
      total hip arthroplasty.
AB  - We studied how preoperative templating corresponded to the postoperative leg
      length in total hip arthroplasty. On average, the preoperative predictive value
      of the desired corrective change in leg length was +4.9 (+4.0-+6.7) mm, while the
      true postoperative assessed value of the corrective change in leg length was +4.7
      (+4.0-+6.3) mm. On preoperative radiographs, the ratio of the horizontal offset
      of a pathological side to a normal side was 95%, on average, and it increased to
      96%, on average, after an operation. Preoperatively planned sizes of the
      acetabular cup and the femoral stem by templating showed a high rate of
      coincidence with the sizes used intraoperatively. In conclusion, an accurate and
      careful preoperative templating can result in a balanced hip reconstruction by
      correcting the leg length differences and restoring the offsets.

PMID- 15022805
TI  - No difference between two doses of diclofenac in prophylaxis of heterotopic
      ossifications after total hip arthroplasty.
AB  - BACKGROUND: In a monocentric, randomized, placebo-controlled double-blind study,
      we investigated the efficacy of two doses of diclofenac-cholestyramine for the
      prevention of heterotopic ossification (HO). PATIENTS: The study comprised 245
      patients undergoing total hip arthroplasty (THA). RESULTS: With 150 mg
      cholestyramine-bound diclofenac (2 x 1 capsule Voltaren resinate) daily during a
      postoperative period of 14 days, 19% of patients showed slight HO (Brooker grade
      1), and no patient had more severe ossifications (grades 2-4). In the group
      receiving 75 mg daily (1 x 1 capsule), 17% of patients showed grade 1 HO and 4%
      grade 2 HO. No patient had grades 3-4 HO. No differences in clinical results were
      seen between the two groups 6 months after THA. INTERPRETATION: Since the rate of
      adverse gastrointestinal events was lower (23% versus 38%, p = 0.02) in the group
      receiving the lower dose, we recommend it.

PMID- 15022806
TI  - Are patients with a nonunion after a femoral neck fracture more osteoporotic than
      others? BMD measurement before the choice of treatment?: A pilot study of hip BMD
      and biochemical bone markers in patients with femoral neck fractures.
AB  - The incidence of nonunion is high after a femoral neck fracture. If reliable
      predictors were available, fractures that heal well could be subjected to
      internal fixation while fractures that do not could undergo an arthroplasty. In
      this pilot study of 28 patients, those with a low hip BMD on admission had a
      higher risk of developing non-union.

PMID- 15022807
TI  - The incidence and location of corona mortis: a study on 75 cadavers.
AB  - We dissected 150 fresh cadaver halves by ilioinguinal exposure, and counted all
      vessels more than 2 mm in diameter, connecting the obturator system to the
      external iliac system. The distance between the symphysis pubis and the
      anastomotic vessels was measured. We found vascular anastomoses between the
      obturator and external iliac systems in 91 of 150 sides (61%), and anastomotic
      veins in 78 of 150 exposures (52%). Arterial connections were seen in 29 of the
      exposures (19%). The mean distance between the anastomotic arteries and the
      symphysis pubis was 64 (45-90) mm, and 56 (37-80) mm for the communicating veins.
      There seemed to be no significant difference between genders in the incidence of
      corona mortis and the distance between communicating vessels and the symphysis
      pubis.

PMID- 15022808
TI  - Minimal-invasive treatment of distal femoral fractures with the LISS (Less
      Invasive Stabilization System): a prospective study of 30 fractures with a follow
      up of 20 months.
AB  - BACKGROUND: There is no consensus on the best treatment of distal femoral
      fractures. PATIENTS AND METHODS: In a prospective study, we treated 29 patients
      with 30 distal femoral fractures with the Less Invasive Stabilization System
      (LISS) from 1997 to 2000. Almost 1/2 of them had open fractures, 1/3
      extraarticular type A and 2/3 articular fractures type C (AO classification) and
      these had been caused by high-energy trauma with concomitant severe injuries or
      osteoporosis. RESULTS: The follow-up examinations after mean 20 (13-42) months
      consisted of radiographs, and determination of the Lysholm Knee Score and Knee
      Society Score (KSS). The outcome correlated with the severity of the fracture,
      anatomic reduction, exact positioning and fixation of the LISS and concomitant
      injuries. INTERPRETATION: We found the LISS for treatment of distal femoral
      fractures of all types to be a safe procedure with good results after careful
      planning and experience with this surgical technique. There is usually no need
      for primary cancellous bone grafting.

PMID- 15022809
TI  - N-acetylcysteine attenuates lung injury in a rodent model of fracture.
AB  - BACKGROUND: Neutrophil-mediated lung injury is a cause of significant morbidity
      and mortality in patients with multiple injuries. We have shown previously that
      fracture hematoma can activate neutrophils and is thus a putative mediator of the
      systemic inflammatory response syndrome (SIRS), acute respiratory distress
      syndrome (ARDS) and multiple organ failure (MOF) in those patients with severe
      skeletal trauma. Our aim was to establish a rodent model of fracture which caused
      lung injury and subsequently to administer a drug following fracture to attenuate
      the lung injury. The drug we chose was N-acetylcysteine, a potent antioxidant.
      ANIMALS AND METHODS: Adult Sprague-Dawley rats were assigned to 4 groups: (1)
      general anesthetic only, (2) general anesthetic with bilateral femur fractures
      and nailing, (3) general anesthetic and N-acetylcysteine, (4) general anesthetic
      with bilateral femur fractures and nailing and N-acetylcysteine after the injury
      (n = 6 in each group). The dose of N-acetylcysteine was 0.5 mg/kg which was given
      intraperitoneally after injury to the treated groups. The rats were killed 24
      hours after injury and some parameters of lung injury were evaluated--i.e.,
      bronchoalveolar lavage (BAL), lung tissue myeloperoxidase levels (MPO) and
      wet/dry ratios of lung tissue. The results were analyzed, using one-way analysis
      of variance. RESULTS: Bilateral femur fracture produced a significant lung
      injury, measured by increases in MPO (25-43 microg/g tissue) and BAL protein (460
      605 microg/mL). This effect was attenuated by treatment with N-acetylcysteine
      (MPO 43-9 microg/mL, BAL protein 605-198 microg/mL). INTERPRETATION: N-acetyl
      cysteine, if given after skeletal trauma, is of potential therapeutic benefit, in
      preventing SIRS, ARDS and MOF.

PMID- 15022810
TI  - Autologous blood donation in total knee arthroplasties is not necessary.
AB  - BACKGROUND: This study intends to prove the hypothesis that preoperative
      autologous blood donation in total knee arthroplasties (TKA) is dispensable.
      PATIENTS AND METHODS: The study comprises a prospective analysis of 81
      consecutive TKA without preoperative autologous blood donation (AB-donation).
      Guidelines for blood retransfusion were used. Surgery, as well as the pre- and
      postoperative procedures were identical for each patient. In the analysis of the
      data, the consecutive TKAs were divided into patients who were eligible for
      preoperative autologous blood donation (group 1, n = 46) and those with relevant
      risk factors not permitting preoperative autologous blood donation (group 2, n =
      35). RESULTS: None of the patients in group 1 needed a blood transfusion. 14 of
      35 patients in group 2 needed an allogenic blood transfusion. INTERPRETATION:
      Total knee arthroplasty can be managed without preoperative AB-donation if it is
      performed using a tourniquet, if a postoperative collection and direct
      retransfusion system is used for the wound blood, and if the transfusion
      algorithm is defined according to compulsory and practical guidelines.

PMID- 15022811
TI  - No need for outpatient physiotherapy following total knee arthroplasty: a
      randomized trial of 120 patients.
AB  - BACKGROUND: We have not found any reports on the effect of physiotherapy after
      knee replacement. PATIENTS AND METHODS: In a prospective randomized controlled
      trial, we randomized two groups to receive or not receive outpatient
      physiotherapy following total knee arthroplasty. 120 patients were recruited over
      2 years, each followed up for 1 year. Inclusion criteria were age between 55-90
      years, less than 40 degrees of fixed flexion contracture and the ability to walk
      at least 10 meters unaided preoperatively with monoarticular arthrosis. RESULTS:
      We found no statistically significant benefit of outpatient physiotherapy at any
      of the three times measured. After adjusting for baseline differences between the
      two treatment groups, the mean difference in knee flexion 1 year postoperatively
      was only 2.9 degrees. This mean difference is of no clinical significance.
      INTERPRETATION: We concluded that in a preselected group of patients following
      primary total knee arthroplasty, inpatient physiotherapy with good instructions
      and a well-structured home exercise regime can dispense with the need for
      outpatient physiotherapy.

PMID- 15022812
TI  - Low reproducibility of the intra-operative measurement of the transepicondylar
      axis during total knee replacement.
AB  - BACKGROUND: The transepicondylar axis is often used for positioning of the
      femoral component in knee replacement. METHODS: We studied the reproducibility of
      the intra-operative palpation of the transepicondylar axis for rotational
      alignment of the femoral component in 20 total knee replacement (TKR)
      implantations with a non-image-based navigation system. 2 surgeons defined the
      transepicondylar axis 3 times each without changing the reference plane. RESULTS:
      The angle between the reference plane and the transepicondylar axis was measured
      by the navigation system. The mean intra-observer ranges of variation were 5
      degrees and 6 degrees for both surgeons, with a maximum of 15 degrees. The mean
      inter-observer range of variation was 9 degrees, with a maximum of 15 degrees.
      Variations occurred in either internal or external rotation. Intra-observer
      agreement was considered good for one surgeon and poor for the other. There was
      no agreement between the two observers. INTERPRETATION: To define the rotational
      alignment of the femoral component of a TKR according to the intra-operative
      palpation of the transepicondylar axis may not be as reproducible as expected.
      However, the exact effect of this variability on the outcome after TKR should be
      studied.

PMID- 15022813
TI  - Knee joint proprioception in ACL-deficient knees is related to cartilage injury,
      laxity and age: a retrospective study of 54 patients.
AB  - BACKGROUND: ACL-deficient patients have been found to have proprioceptive
      defects, but the cause of these defects has not been identified nor has the
      relationship between proprioception and subjective function, laxity, activity
      level and age been adequately studied. PATIENTS AND METHODS: Therefore, we
      analyzed proprioception, defined as the threshold to detect a slow passive motion
      (TTDPM), in relation to activity level, laxity, meniscal injuries, collateral
      ligament injuries, cartilage injuries, age and subjective function in 54 patients
      with a previous ACL rupture. We used multiple pair-wise correlation analyses,
      followed by a stepwise linear regression model. RESULTS: We found that poorer
      proprioception was related to lateral cartilage lesions, increased laxity and
      older age while a high activity level before injury was related with better
      proprioception after injury. The results also suggest a relation between
      proprioception and subjective knee function. INTERPRETATION: Anatomical injuy
      classification may need to be considered when discussing proprioceptive ability
      in patients with an ACL injury, laxity is related to proprioception and
      proprioception may decrease with age.

PMID- 15022814
TI  - Tendon graft fixation in ACL reconstruction: in vitro evaluation of bioabsorbable
      tenodesis screw.
AB  - BACKGROUND: Conventional ACL reconstruction requires sufficient tibial bone
      quality for secure graft fixation. We evaluated the mechanical characteristics of
      a supplemental tenodesis screw in cadaveric specimens. MATERIAL AND METHODS: One
      group of 7 specimens from 7-paired tibiae was randomly assigned to undergo
      tibialis anterior tendon graft-bone tunnel fixation with a bioabsorbable
      interference screw, using conventional ACL reconstruction techniques. The other
      group of 7 specimens underwent the same procedure supplemented with a
      bioabsorbable tenodesis screw. All specimens were subjected to pullout testing on
      a servo hydraulic device. RESULTS: Specimens in the supplemental fixation group
      had double the load to failure (tenodesis = 467 (SD 184) N, control group = 223
      (SD 66) N, p = 0.02) and were also one-third stiffer (tenodesis = 31 (SD 13)
      N/mm, control group = 21 (SD 6) N/mm, p = 0.03) than the specimens in the
      conventional fixation group. INTERPRETATION: Supplemental bioabsorbable tenodesis
      screw fixation may be advantageous for primary reconstruction in patients with
      low tibial bone mineral density or during revision procedures. By providing
      secure soft tissue graft-tibia fixation during the early phase after ACL
      reconstruction, supplemental tenodesis fixation may enable patients to
      participate safely in more intense, early rehabilitation.

PMID- 15022815
TI  - Long-term outcome of meniscal degeneration in the knee: poor association between
      MRI and symptoms in 45 patients followed more than 4 years.
AB  - Knee joint-related symptoms are frequent and the use of MRI as a diagnostic tool
      is common. About 25% of MRIs show meniscal degeneration (MD). As the natural
      history of MD has not been well described, we studied the long-term outcome of 50
      MDs. 45 patients were initially evaluated by a MRI, and clinical examination and
      later by another MRI. After 5 years, 38 of the MDs were unchanged, 8 had
      progressed and 4 regressed. Progression of MD was associated with age over 40
      years, trauma during the follow-up period and/or other knee lesions, such as
      osteoarthrosis and ligament rupture. The clinical findings were consistent with
      MDs only in 8 cases.

PMID- 15022816
TI  - Platelet concentrate injection improves Achilles tendon repair in rats.
AB  - BACKGROUND: Blood platelets release a cocktail of growth factors when activated,
      some of which are thought to initiate and stimulate repair. EXPERIMENT AND
      FINDINGS: We studied whether a platelet concentrate injection would improve
      Achilles tendon repair in an established rat model. The Achilles tendon was
      transected and a 3 mm segment removed. After 6 h, a platelet concentrate was
      injected percutaneously into the hematoma. This increased tendon callus strength
      and stiffness by about 30% after 1 week, which persisted for as long as 3 weeks
      after the injection. At this time, the mechanical testing indicated an
      improvement in material characteristics--i.e., greater maturation of the tendon
      callus. This was confirmed by blinded histological scoring. INTERPRETATION:
      Platelet concentrate may prove useful for the treatment of Achilles tendon
      ruptures.

PMID- 15022817
TI  - A prospective cost analysis following operative treatment of unstable ankle
      fractures: 30 patients followed for 1 year.
AB  - BACKGROUND: Ankle fractures remain one of the commonest injuries requiring
      operation. Quality of life and the overall costs associated with the treatment of
      such injuries are rarely reported. We did a pilot study to determine the cost of
      treating patients operatively with unstable ankle fractures and to measure the
      patients' quality of life (utility scores) over time. PATIENTS AND METHODS: 30
      patients (17 men) were eligible and included in the study. They were on the
      average 52 (18-81) years old. All patients had type B Weber fractures (OTA 44B).
      RESULTS: The mean utility score from the Health Utilities Index immediately after
      surgery was 0.4. At 12 months follow-up, this score had increased to 0.78. The
      cost was, on average, USD 2,143 per patient. INTERPRETATION: Our findings
      indicate that patients operated on for ankle fractures had significant gains in
      health at an acceptable cost. These results provide data for studies of larger
      sample size.

PMID- 15022818
TI  - The metabolism of the diabetic foot: in vivo investigation with microdialysis.
AB  - BACKGROUND: Many amputations might be delayed or prevented by more effective
      clinical supervision of the diabetic foot ulcer. The aim of this study was to
      measure the local metabolism on the edge of a diabetic ulcer and compare it to
      healthy subcutaneous tissue. PATIENTS AND METHODS: In 5 non-fasting diabetic
      patients, we inserted a microdialysis catheter into the edge of a diabetic ulcer
      and a reference catheter into healthy abdominal subcutaneous tissue, and recorded
      the local concentrations of glucose, lactate and glycerol during rest. RESULTS:
      The concentrations of glucose in the ulcers were 7.8 mM (SEM 1.9) and in the
      reference tissue 10.6 mM (SEM 1.8) (p = 0.4). The concentrations of lactate were
      2.9 mM (SEM 0.7) and 2.1 mM (SEM 0.7) (p = 0.2), while those of glycerol were 290
      microM (SEM 84) vs 98 microM (SEM 7.2) (p = 0.002). INTERPRETATION: This study
      shows that microdialysis can detect differences in dialysate concentrations of
      metabolites in diabetic ulcers and a reference tissue, providing valuable
      information concerning metabolites in the diabetic foot ulcer. Future studies
      should combine the technique with measurements of local blood flow.

PMID- 15022819
TI  - Adhesion of the subacromial bursa may cause subacromial impingement in patients
      with rotator cuff tears: pressure measurements in 18 patients.
AB  - In order to determine whether adhesion of the subacromial bursa leads to
      impingement, we measured the subacromial contact pressures before and after
      release of adhesion of this bursa. 18 shoulders with cuff tears and adhesion of
      the subacromial bursa were evaluated in 8 male and 10 female patients, of mean
      age 62 (53-71) years and who had no particular limitation of shoulder motion. We
      recorded subacromial pressures using a very sensitive film inserted under the
      acromion during surgery. In passive scapular plane elevation (scaption) at 100
      degrees, the mean subacromial contact pressure and area declined from 1.43 (SD
      0.23) MPa before release to 1.14 (SD 0.35) MPa after release (p < 0.001), and
      from 163 (SD 81) mm2 before release to 80 (SD 46) mm2 after release (p < 0.001),
      respectively. We suggest that adhesion of the subacromial bursa increases
      impingement between the acromion and the insertion of rotator cuff tendons.

PMID- 15022820
TI  - Is the constant score reliable in assessing patients with frozen shoulder? 60
      shoulders scored 3 years after manipulation under anaesthesia.
AB  - We assessed the function of 60 primary frozen shoulders at a mean of 33 months
      after manipulation under general anaesthesia. Each patient was scored according
      to the system described by Constant and Murley (1987). We also evaluated a
      modified method of strength assessment with the sling over the mid-humerus
      (modified Constant score), and analyzed the abbreviated Constant score, which
      excludes the strength measurement (Patel et al. 1999). Moreover, the patients
      filled out an Oxford questionnaire (Dawson et al. 1996). We found a better
      correlation between the Oxford score and the Constant-Murley score when muscle
      strength was excluded or measured by the modified method.

PMID- 15022822
TI  - Physical restraint use in health care settings: public attitudes in Israel.

PMID- 15022821
TI  - Evidence-based protocol: prevention of pressure ulcers.
AB  - Those who provide direct care to older individuals who are functionally impaired
      and immobilized must be constantly vigilant for the potential development of
      pressure ulcers. Use of the evidence-based guideline "Prevention of Pressure
      Ulcers" (Folkedahl et al., 2002) can provide a template for identification of
      patients at risk and implementation of interventions to prevent their occurrence.

PMID- 15022823
TI  - Compiling life history resources for older adults in institutions: development of
      a guide.
AB  - Focus groups were conducted for nursing staff, visiting family members, and
      residents of a long-term care facility, with the purpose of developing a guide
      for compiling a life history resource. When compiling the proposed guideline, one
      must consider not only the topics to include, but also the process of collecting
      the information and the format for presentation. A key finding was that members
      of all three groups believed that the process of sharing and collecting life
      history information was an important step in promoting and enhancing the
      relationship between nursing staff and residents, and nursing staff and
      residents' families.

PMID- 15022824
TI  - Improving nursing home food service: uncovering the meaning of food through
      residents' stories.
AB  - The meaning of food to nursing home residents is explored to examine residents'
      perspectives related to nursing home food and food service, and to identify
      strategies for improving food and food service in nursing homes. An interpretive
      phenomenological approach was used to uncover meaning in a series of "tell me a
      story" interviews about food and food service with nine residents from an eastern
      Washington nursing home. Analysis revealed 14 domains of meaning, each containing
      multiple codes with specific descriptions and exemplars of resident expression
      about food service. Themes that cut across these codes were generated and further
      organized into three rubrics. They were: Mimicking Home, Making Choices, and
      Tailoring the System. Specific information found under these three rubrics can be
      used as a blue print for quality improvement interventions implemented by nursing
      home staff and management, thereby improving quality of life for nursing home
      residents.

PMID- 15022825
TI  - Multisensory environments for leisure: promoting well-being in nursing home
      residents with dementia.
AB  - Multisensory environments such as Snoezelen rooms are becoming increasingly
      popular in health care facilities for older individuals. There is limited
      reliable evidence of the benefits of such innovations, and the effect they have
      on residents, caregivers, and visitors in these facilities. This two-stage
      project examined how effective two types of multisensory environments were in
      improving the well-being of older individuals with dementia. The two multisensory
      environments were a Snoezelen room and a landscaped garden. These environments
      were compared to the experience of the normal living environment. The observed
      response of 24 residents with dementia in a nursing home was measured during time
      spent in the Snoezelen room, in the garden, and in the living room. In the second
      part of the project, face-to-face interviews were conducted with six caregivers
      and six visitors to obtain their responses to the multisensory environments.
      These interviews identified the components of the environments most used and
      enjoyed by residents and the ways in which they could be improved to maximize
      well-being.

PMID- 15022826
TI  - Preventive health practices: comparison of family caregivers 50 and older.
AB  - The purpose of this study was to describe adherence to recommended preventive
      health practices among middle-aged and older male and female family caregivers of
      individuals receiving home health services. Perceptions of the burden and benefit
      of caregiving, wellness orientation, social participation, and community resource
      use by the caregiving dyad (caregiver and carereceiver) were also explored using
      the t test and the chi2 test to detect gender differences. A sample of 319
      participants 50 and older was recruited from a home health agency in southwestern
      Pennsylvania to participate in a telephone survey. Results revealed that
      caregivers had performed 86% of age- and gender-appropriate preventive health
      practices, but they currently adhered to guidelines for 63% of such behaviors,
      regardless of gender. Men experienced less burden than women, and were more
      likely to acknowledge that caregiving made them feel useful and appreciated and
      gave more meaning to their lives. The study suggests that family caregivers may
      be as vigilant in their preventive health behavior as the general population,
      despite their responsibilities. Nurses in contact with middle-aged and older
      family caregivers are well positioned to encourage health promotion and disease
      prevention behaviors in this accessible population.

PMID- 15022827
TI  - The oxygen evolving enhancer protein 1 (OEE) of photosystem II in green algae
      exhibits thioredoxin activity.
AB  - A thioredoxin-like chloroplast protein of the fructosebisphosphatase-stimulating
      f-type, but with an unusually high molecular mass of 28 kDa has previously been
      identified and purified to homogeneity in a fractionation scheme for resolution
      of the acid- and heat-stable, regular-size (12kDa) thioredoxins of the
      unicellular green algae, Scenedesmus obliquus. An apparently analogous protein of
      26 kDa was described in a cyanobacterium, Anabaena sp., but no such large
      thioredoxin species f exists in the thioredoxin profiles of higher plants. The
      structure of the 28 kDa protein, which had been envisaged to represent a
      precursor, or fusion product of the two more specialized, common chloroplast
      thioredoxins f and m has now been determined by amino acid sequencing. Although
      it exhibits virtually all the properties and enzyme-modulating activities of a
      thioredoxin proper this algal protein, surprisingly, does not belong to the
      thioredoxin family of small redox proteins but is identical with OEE (oxygen
      evolving enhancer) protein 1, an auxiliary component of the photosystem II
      manganese cluster. Extracts of Chlorella vulgaris and Chlamydomonas reinhardtii
      also contain heat-stable protein fractions of 23-26 kDa capable of specifically
      stimulating chloroplast fructosebisphosphatase in vitro. In contrast, OEE protein
      1 from spinach is not able to modulate FbPase or NADP malate dehydrogenase from
      spinach chloroplasts. A dual function of the OEE protein in algal photosynthesis
      is envisaged.

PMID- 15022828
TI  - Fourier transform infrared spectroscopy as a new tool to determine rosmarinic
      acid in situ.
AB  - A new procedure has been developed for the in situ FT-IR determination of
      rosmarinic acid (RA) in suspension cultures of Lavandula officinalis. The method
      involves sample preparation on ZnSe crystals or microplates from silicon, and
      measuring absorbance spectra between 4000 and 700 cm(-1). First derivative
      spectra were analysed after normalisation using partial least square (PLS)
      algorithm. The correlation between spectral analysis and HPLC measurements of
      cell extracts shows that the FT-IR procedure is suitable for qualitative and
      quantitative analyses of RA in cell suspension cultures.

PMID- 15022829
TI  - Involvement of endogenous gibberellins in potato tuber dormancy and early sprout
      growth: a critical assessment.
AB  - The role of endogenous gibberellins (GAs) in the regulation of potato (Solanum
      tuberosum) tuber dormancy was examined by determining: 1. changes in endogenous
      GA levels during natural dormancy progression, 2. the effects of GA biosynthesis
      inhibitors on tuber dormancy duration and 3. the dormancy status and tuber GA
      levels in a dwarf mutant of potato. The tubers (cv. Russet Burbank) used in these
      studies were still completely dormant after 98 days of storage. Between 98 and
      134 days of storage, dormancy began to end and tubers exhibited limited (< 2 mm)
      sprout growth. Tuber dormancy weakened with further storage and tubers exhibited
      greater rates of sprout growth after 187 days of storage. Tubers stored for 212
      days or longer were completely non-dormant and exhibited vigorous sprout growth.
      Immediately after harvest, the endogenous contents of GA19, GA20, and GA1 were
      relatively high (0.48-0.62 ng g fresh weight(-1)). The content of these GAs
      declined between 33 and 93 days of storage. Internal levels of GA19, GA20, and
      GA, rose slightly between 93 and 135 days of storage reaching levels comparable
      to those found in highly dormant tubers immediately after harvest. Levels of
      GA19, GA20, and GA1 continued to increase as sprout growth became more vigorous.
      Neither GA4 nor GA8 was detected in any tuber sample regardless of dormancy
      status. Dormant tubers exhibited a time-dependent increase in apparent GA
      sensitivity. Freshly harvested tubers were completely insensitive to exogenous
      GAs. As postharvest storage continued, exogenous GAs promoted premature dormancy
      release with GA1 and GA20 eliciting the greatest response. Injection of up to 5
      microg tuber(-1) of kaurene, GA12, GA19 or GA8 had no effect on dormancy release.
      Sprout growth from non-dormant tubers was also promoted by exogenous GA in the
      following sequence of activity: GA1 = GA20 > GA19. Kaurene, GA12, and GA8 were
      inactive. Continuous exposure of developing tubers to inhibitors of GA
      biosynthesis (AMO-1618, ancymidol, or tetcyclasis) did not extend tuber dormancy
      but rather hastened dormancy release. Comparison of tuber dormancy and GA1
      content in tubers of a wild-type and dwarf mutant of S. tuberosum ssp. andigena
      revealed a near-identical pattern of dormancy progression in spite of the absence
      of detectable levels of GA1 in tubers of the dwarf sibling at any time during
      dormancy progression. Collectively, these results do not support a role for
      endogenous GA in potato tuber dormancy release but are consistent with a role for
      GAs in the regulation of subsequent sprout growth.

PMID- 15022830
TI  - Wide Dynamic Range Vegetation Index for remote quantification of biophysical
      characteristics of vegetation.
AB  - The Normalized Difference Vegetation Index (NDVI) is widely used for monitoring,
      analyzing, and mapping temporal and spatial distributions of physiological and
      biophysical characteristics of vegetation. It is well documented that the NDVI
      approaches saturation asymptotically under conditions of moderate-to-high
      aboveground biomass. While reflectance in the red region (rho(red)) exhibits a
      nearly flat response once the leaf area index (LAI) exceeds 2, the near infrared
      (NIR) reflectance (PNIR) continue to respond significantly to changes in moderate
      to-high vegetation density (LAI from 2 to 6) in crops. However, this higher
      sensitivity of the rho(NIR) has little effect on NDVI values once the rho(NIR)
      exceeds 30%. In this paper a simple modification of the NDVI was proposed. The
      Wide Dynamic Range Vegetation Index, WDRVI = (a * rho(NIR-rho(red))/(a * rho(NIR)
      + rho(red)), where the weighting coefficient a has a value of 0.1-0.2, increases
      correlation with vegetation fraction by linearizing the relationship for typical
      wheat, soybean, and maize canopies. The sensitivity of the WDRVI to moderate-to
      high LAI (between 2 and 6) was at least three times greater than that of the
      NDVI. By enhancing the dynamic range while using the same bands as the NDVI, the
      WDRVI enables a more robust characterization of crop physiological and
      phenological characteristics. Although this index needs further evaluation, the
      linear relationship with vegetation fraction and much higher sensitivity to
      change in LAI will be especially valuable for precision agriculture and
      monitoring vegetation status under conditions of moderate-to-high density. It is
      anticipated that the new index will complement the NDVI and other vegetation
      indices that are based on the red and NIR spectral bands.

PMID- 15022831
TI  - Analysis of an Arabidopsis thaliana protein family, structurally related to
      cytochromes b561 and potentially involved in catecholamine biochemistry in
      plants.
AB  - Cytochromes b561 (cyts b561) constitute a family of eukaryotic membrane proteins,
      catalysing ascorbate (Asc)-mediated trans-membrane electron transport, and hence
      likely involved in Asc regeneration. A class of proteins (DoH-CB) has been
      identified in plants and animals, containing the cyt b561 electron-transport
      domain (CB), combined with the catecholamine-binding regulatory domain of
      dopamine-beta-hydroxylase (DoH). A mammalian DoH-CB protein was previously
      reported to function as a cell-derived growth factor receptor (SDR2). We have
      performed an in silico analysis on DoH-CB proteins from Arabidopsis thaliana and
      demonstrate that structural features of both CB and DoH domains are well
      conserved. The combination of both domains may have evolved from a functional
      interaction between a cyt b561 and a DoH-containing protein, illustrating the so
      called "Rosetta Stone" evolutionary principle, and this hypothesis is supported
      by sequence comparisons. DoH-CB proteins form a newly identified group of
      proteins, likely to play a key role in catecholamine action in plants. It is
      suggested that these proteins may function as trans-membrane electron shuttles,
      possibly regulated by catecholamines. The role and action of catecholamines in
      plants is poorly documented, but it is clear that they are involved in many
      aspects of growth and development. Whether the DoH-CB proteins functionally
      interact with Asc, as is the case for cyts b561, remains to be determined.

PMID- 15022832
TI  - Soybean (Glycine max. L.) and bacteroid glyoxylate cycle activities during
      nodular senescence.
AB  - Soybean (Glycine max. L.) nodular senescence results in the dismantling of the
      peribacteroid membrane (PBM) and in an increase of soybean isocitrate lyase (ICL;
      EC 4.1.3.1) and malate synthase (MS; EC 4.1.3.2) mRNA and protein levels. This
      suggests that in senescing soybean nodular cells, the specific glyoxylate cycle
      enzyme activities might be induced to reallocate carbon obtained from the PBM
      degradation. In order to evaluate as well the carbon metabolism of the nitrogen
      fixing Bradyrhizobium japonicum endosymbiotic bacteroids during nodular
      senescence, their glyoxylate cycle activities were also investigated. To this
      end, partial DNA sequences were isolated from their icl and ms genes, but the
      corresponding mRNAs were not detected in the microorganisms. It was also observed
      that the bacteroid ICL and MS activities were negligible during nodular
      senescence. This suggests that glyoxylate cycle activities are not reinitiated in
      the bacteroids under these physiological conditions. In case the microorganisms
      nevertheless feed on the PBM degradation products, this might occur via the
      citric acid cycle exclusively.

PMID- 15022833
TI  - Reactive oxygen and ethylene are involved in the regulation of regurgitant
      induced responses in bean plants.
AB  - Application of regurgitant from Leptinotarsa decemlineata Say on wound surfaces
      of one wounded leaf of intact bean (Phaseolus vulgaris L.) plants resulted in
      activation of ethylene biosynthesis followed by an increase of both peroxidase
      and polyphenol oxidase activity. The aim of the present investigation was to
      study the source of increased oxidative enzyme activities in regurgitant-treated
      bean leaves and to determine if hydrogen peroxide and ethylene biosynthesis is
      responsible for regurgitant-induced amplification of wound responses in bean
      plants. As the regurgitant contained relative high activities of both peroxidase
      and polyphenol oxidase, there is a possibility that increased enzyme activities
      in bean leaves following regurgitant treatment is an artifact of insect-derived
      enzymes. Localisation experiments and electrophoretic analysis revealed that only
      part of the increased enzyme activities could be attributed to regurgitant
      derived enzymes. Both increase of ethylene production and oxidative enzyme
      activities depended on protein synthesis. To demonstrate if the increase of
      oxidative metabolism was ethylene-dependent, seedlings were pretreated with
      aminooxyacetic acid, an inhibitor of ethylene biosynthesis, and 1
      methylcyclopropene (1-MCP), a competitive inhibitor of ethylene action. Increase
      of both peroxidase and polyphenol oxidase activity in wounded and subsequently
      regurgitant-treated leaf was abolished by both aminooxyacetic acid and 1-MCP.
      Inhibitor studies indicated that H2O2 generated through NADPH oxidase and
      superoxide dismutase is necessary for regurgitant-induced increase of ethylene
      production and oxidative enzyme activities.

PMID- 15022834
TI  - Manganese nutrition effects on tomato growth, chlorophyll concentration, and
      superoxide dismutase activity.
AB  - The effects of Mn nutrition of tomato (Lycopersicon esculentum Mill.) seedlings
      on Mn-, Fe- and CuZn-superoxide dismutase (SOD, EC 1.15.1.1) enzymatic
      activities, metal translocation, chlorophyll concentration, and plant growth were
      tested using a bioassay system consisting of chelator-buffered nutrient culture
      with Mn2+ activities set to pMn (-log activity of Mn2+) of 6.6, 7.6, 8.6, and
      9.6. The two middle levels resulted in optimal plant growth, whereas the two
      extreme levels resulted in a gradual decrease in chlorophyll concentration and
      slower plant growth. At the end of the experiment, 26 days after transfer to the
      Mn treatments, significant differences in shoot Mn concentration were manifested,
      from 10.5 mg kg(-1) in plants grown in pMn 9.6 to 207.4 mg kg(-1) in plants grown
      in pMn 6.6. Other element concentrations in the leaf suggest that growth
      inhibition and chlorophyll synthesis were affected primarily by manganese
      deficiency and excess. Twenty days after transfer of plants to the Mn treatments
      Mn-, Fe- and CuZn-SOD activities were assayed in young expanded leaf tissues by
      electrophoresis running gel. Whereas chloroplastic CuZn-SOD activity did not
      differ among Mn treatments, the cytosolic CuZn-SOD and mitochondrial Mn-SOD
      activities increased in both Mn-excess and Mn-deficient plants.

PMID- 15022835
TI  - Photoinhibition and recovery of photosynthesis in leaves of Vitis berlandieri and
      Vitis rupestris.
AB  - Photoinhibition of photosynthesis was studied in Vitis berlandieri and Vitis
      rupestris leaves under controlled conditions (irradiation of detached leaves to
      about 1900 micromol m(-2) s(-1)). The degree of photoinhibition was determined by
      means of the ratio of variable to maximum chlorophyll (Chl) fluorescence (Fv/Fm)
      and electron transport measurements. The potential efficiency of PS2, Fv/Fm
      declined, Fo increased significantly in leaves of V. berlandieri, while Fo
      decreased in V. rupestris. In isolated thylakoids, the rate of whole chain and
      PS2 activity markedly decreased in high light irradiated more in leaves of V.
      berlandieri than in leaves of V. rupestris. A smaller inhibition of PS1 activity
      was also observed in both leaves. In the subsequent dark incubation, fast
      recovery was observed in both leaves and reached maximum PS2 efficiencies similar
      to those observed in non-photoinhibited leaves. The artificial exogenous electron
      donors DPC, NH2OH and Mn2+ failed to restore the high light induced loss of PS2
      activity in V. berlandieri leaves, while DPC and NH2OH significantly restored in
      V. rupestris leaves. It is concluded that high light inactivates on the donor
      side of PS2 and acceptor side of PS2 in V. rupestris and V. berlandieri leaves,
      respectively. Quantification of the PS2 reaction center protein D1 and 33 kDa
      protein of water splitting complex following high light exposure of leaves showed
      pronounced differences between V. berlandieri and V. rupestris leaves. The marked
      loss of PS2 activity in high light irradiated leaves was due to the marked loss
      of D1 protein and 33 kDa protein in V. berlandieri and V. rupestris leaves,
      respectively.

PMID- 15022836
TI  - Cyclic AMP levels in several macroalgae and their relation to light quantity and
      quality.
AB  - Total cAMP levels were measured in the macroalgae Dictyota dichotoma, Gelidium
      sesquipedale and Ulva rigida under different light conditions in order to study
      its regulation either by phytochrome or photosynthesis. Incubation in red or far
      red light did not promote a phytochrome-like response; instead, it showed a
      synergistic effect upon cAMP accumulation. cAMP levels seemed to depend on the
      amount of energy applied. The correlation between photosynthetic oxygen evolution
      and cAMP variations at sub-saturating white light irradiance pointed to
      photosynthetic electron transport as involved in the regulation of cAMP
      accumulation at least in G. sesquipedale and U. rigida. Inhibitors of thylakoidal
      and mitochondrial electron transport chains reduced cAMP levels in 70 to 99%. We
      conclude that cAMP accumulation could be regulated by photosynthetic activity
      rather than phytochrome in the macroalgae studied.

PMID- 15022837
TI  - Cloning and analysis of a cDNA encoding an endo-polygalacturonase expressed
      during the desiccation period of the silique-valves of turnip-tops (Brassica rapa
      L. cv. Rapa).
AB  - During zygotic embryogenesis of turnip-tops (Brassica rapa L. cv. Rapa), the
      polygalacturonase activity (PG; EC 3.2.1.15), measured as a decrease in viscosity
      of polygalacturonic acid, reached a high when the desiccation process in the
      seeded silique was triggered and the valves had lost more than 70-75% of their
      moisture (45-50 DPA). The PG activity was not detected in any phases of
      developing seeds. This work also characterizes a cDNA with an open reading frame
      of 1303 bp and that codes for a putative PG called BrPG1. This falls into the
      category of clade-B, which includes PG related to shattering and abscission
      processes. The deduced BrPG1 sequence predicted a 434-residue-long precursor
      protein (46.7kDa) with a transit peptide sequence 23 amino acids long. A
      molecular mass of 44.3 kDa was calculated for the mature form of BrPG1, which
      showed high sequence similarity to PGA1 (97%) of B. napus (X98373) and ADPG1
      (87%) of Arabidopsis thaliana (AJ002532). All conserved amino acids at the
      catalytic site of PGs belonging to clade-B were preserved on BrPG1. This BrPG1
      gene was specifically expressed in the silique valves of turnip-tops and was
      temporally expressed at the beginning of its desiccation.

PMID- 15022838
TI  - Somatic embryogenesis in pumpkin (Cucurbita pepo L.): control of somatic embryo
      development by nitrogen compounds.
AB  - Embryogenic cultures of pumpkin (Cucurbita pepo L.) were initiated from
      mechanically wounded mature zygotic embryos on 2,4-D-containing MS medium, and on
      hormone-free, semisolid modified MS medium containing NH4Cl as the sole source of
      nitrogen. The habituated line was derived from the embryogenic tissue induced
      with 2,4-D and maintained on medium without growth regulators. Sustained
      subculturing of the three embryogenic lines on a medium with NH4Cl as the sole
      source of nitrogen enabled the establishment of highly uniform cultures in which
      no further development into mature embryo stages occurred. The tissue consisting
      of proembryogenic globules or globular stage embryos was maintained, without
      decline, for over six years. Globular embryos proceeded to maturity when a
      combination of reduced (NH4) and unreduced (NO3) forms of nitrogen was provided
      in the medium. Different nitrogen sources in the medium caused changes of medium
      pH during subculture in the pH range of 4.0-6.5. The tissue growth and embryo
      development were blocked on medium with pH adjusted and stabilized at 4.0 or at
      3.2.

PMID- 15022840
TI  - Starch deposition and amylase accumulation during somatic embryogenesis in bamboo
      (Dendrocalamus hamiltonii).
AB  - In monocots, the zygotic embryo is protected and nourished by an endosperm. In
      the present study starch deposition and amylase accumulation was noticed during
      somatic embryogenesis in stem callus of a bamboo, Dendrocalamus hamiltonii. SEM
      studies revealed that starch grains were clearly visible in the scutellum during
      the maturation stage of the somatic embryo. As the somatic embryo developed
      further, the scutellum got reduced with corresponding increase in amylase. The
      amylase activity was tested periodically at different developmental stages of
      embryos. The role of scutellum in somatic embryos for starch deposition and
      amylase accumulation is discussed.

PMID- 15022839
TI  - Plant regeneration from encapsulated nodal segments of Dalbergia sissoo Roxb., a
      timber-yielding leguminous tree species.
AB  - One of the alternative methods adopted in recent years is to use biotechnological
      approaches for improving the tree species. The synthetic seeds offer several
      advantages, e.g., easy handling, storability, reduced size of propagules, and
      transportability. Germplasm can be effectively stored in the form of synthetic
      seeds. A protocol has been developed for plant regeneration from encapsulated
      nodal segments of Dalbergia sissoo Roxb. Nodal segments collected from basal
      sprouts of mature trees were encapsulated in calcium alginate beads. Inability of
      nodal segments entrapped in calcium alginate beads to form root was a major
      problem. To avoid this problem, an appropriate root induction treatment was given
      to nodal segments for 10 days, prior to encapsulation to allow formation of root
      primordia. For synthetic seeds production and subsequent conversion into
      plantlet, nodal segments with root primordia were encapsulated using sodium
      alginate and calcium chloride as gelling matrix. The best gel complexation was
      achieved using 3% sodium alginate and 75 mmol/L CaCl2 2H2O. Maximum percentage
      response (85%) for conversion of encapsulated nodal segments into plantlets was
      achieved on 1/2-MS medium without plant growth regulators, after 25 days of
      culture. The frequency of conversion of encapsulated nodal segments into
      plantlets affected by the concentration of sodium alginate, and the presence or
      absence of 1/2-MS nutrients in calcium alginate beads. Plantlets with well
      developed roots and shoots were transferred to pots containing autoclaved mixture
      of peat moss and soil (1:1). Plants were also established in pots. The conversion
      of encapsulated nodal segments into plantlets also occurred when calcium alginate
      beads having entrapped nodal segments were directly sown in autoclaved peat moss
      moistened with 1/2-MS0 medium. Out of 60 encapsulated nodal segments, in each
      experiments, stored at 4 degrees C for 30 days, 44 plants developed under in
      vitro conditions, and 27 on peat moss moistened with 1/2-MS0.

PMID- 15022841
TI  - Influences of synaptic location on the synchronization of rhythmic bursting
      neurons.
AB  - We study how the location of synaptic input influences the stablex firing states
      in coupled model neurons bursting rhythmically at the gamma frequencies (20-70
      Hz). The model neuron consists of two compartments and generates one, two, three
      or four spikes in each burst depending on the intensity of input current and the
      maximum conductance of M-type potassium current. If the somata are connected by
      reciprocal excitatory synapses, we find strong correlations between the changes
      in the bursting mode and those in the stable phase-locked states of the coupled
      neurons. The stability of the in-phase phase-locked state (synchronously firing
      state) tends to change when the individual neurons change their bursting
      patterns. If, however, the synaptic connections are terminated on the dendritic
      compartments, no such correlated changes occur. In this case, the coupled
      bursting neurons do not show the in-phase phase-locked state in any bursting
      mode. These results indicate that synchronization behaviour of bursting neurons
      significantly depends on the synaptic location, unlike a coupled system of
      regular spiking neurons.

PMID- 15022842
TI  - Detection of syntonies between multiple spike trains using a coarse-grain
      binarization of spike count distributions.
AB  - At very short timescales neuronal spike trains may be compared to binary streams
      where each neuron gives at most one spike per bin and therefore its state can be
      described by a binary variable. Time-averaged activity like the mean firing rate
      can be generally used on longer timescales to describe the dynamics;
      nevertheless, enlarging the space of the possible states up to the continuum may
      seriously bias the true statistics if the sampling is not accurate. We propose a
      simple transformation on binary variables which allows us to fix the
      dimensionality of the space to sample and to vary the temporal resolution of the
      analysis. For each time length interactions among simultaneously recorded neurons
      are evaluated using log-linear models. We illustrate how to use this method by
      analysing two different sets of data, recorded respectively in the temporal
      cortex of freely moving rats and in the inferotemporal cortex of behaving monkeys
      engaged in a visual fixation task. A detailed study of the interactions is
      provided for both samples. In both datasets we find that some assemblies share
      robust interactions, invariant at different time lengths, while others cooperate
      only at delimited time resolutions, yet the size of the samples is too small to
      allow an unbiased estimate of all possible interactions. We conclude that an
      extensive application of our method to larger samples of data, together with the
      development of techniques to correct the bias in the estimate of the
      coefficients, would provide significant information about the structure of the
      interactions in populations of neurons.

PMID- 15022843
TI  - A simulation study of information transmission by multi-unit microelectrode
      recordings.
AB  - To analyse the information content of multi-unit signals, cases of two and three
      superimposed neural responses to a stimulus were simulated. The multi-unit
      Shannon information rates were compared with those of the constituent single-unit
      spike trains and also with those of corresponding labelled line signals. The
      mutual information in the multi-unit response was found to depend on the degree
      of similarity in the attribute-specific information of the single-unit spike
      trains. As long as the units were encoding similar attribute-specific
      information, the multi-unit signal had greater information than any of the
      individual units. If the units' responses were confounded by different amounts,
      the multi-unit response could not recover the maximal single-unit information.
      Labelled line and pooled responses had similar mutual information when the
      information in the constituent units was similar. However, the normalized gain in
      information of a labelled line response over a pooled response increased from 27%
      to 84%, relative to the maximum single-unit information rate, as the difference
      in constituent single-unit information increased to 100%. Information in single
      unit responses is not completely lost when multiple units are superimposed. There
      are cases in which the union of single-unit spike trains can fully conserve
      single-unit information and even reduce the effect of confounding information
      present in the individual responses. More information is available in pairs of
      responses when the identities of the units are maintained. Summed responses can
      be used at low informational cost in redundantly encoding clusters of neurons.
      Higher information losses are incurred as the encoding becomes more independent.

PMID- 15022844
TI  - Quantal synaptic failures enhance performance in a minimal hippocampal model.
AB  - Despite the fact that animals are not optimal, natural selection is an optimizing
      process that can readily control small bits and pieces of organisms. It is for
      this reason that we need to explain certain parameters as found in Nature (e.g.,
      number of neurons and their average activity) to fully understand the biological
      basis of cognition. In this optimizing sense, the failure of quantal synaptic
      transmission is problematic because this process incurs information loss at each
      synapse which seems like a bad thing for information processing. However, recent
      work based on an information-theoretic analysis of a single neuron suggests that
      such losses can be tolerated and lead to energy savings. Here we study
      computational simulations of a hippocampal model as a function of failure rate.
      We find that the failure process actually enhances some indices of performance
      when the model is required to solve the hippocampally dependent task of
      transverse patterning or when it is required to learn a simple sequence. Adding
      the random process of synaptic failures to the recurrent CA3-to-CA3 excitatory
      connections results in simulations that are more robust to parametric settings.
      Not only is the model more robust when synaptic failures are part of the model
      but there is a notable increase of sequence length memory capacity. Also, the
      failure process combined with additional neurons allows lower activity settings
      while still remaining compatible with learning the transverse patterning task.
      Indeed, as neuron number tended towards the biological numbers (nearly 5 x 10(4)
      in the simulations), it was not only possible to achieve biological failure rates
      (55-85%) at the minimally tolerated activity setting but these appropriately high
      failure rates were required for successful learning. The results are interpreted
      in terms of previous research demonstrating that randomization during training
      can enhance performance by facilitating implicit state-space search for
      interconnected neurons.

PMID- 15022845
TI  - Doctoral education: why now and why you?

PMID- 15022846
TI  - Methods to confirm feeding tube placement: application of research in practice.
AB  - Numerous published studies have demonstrated that conventional methods for
      documenting proper position of orally or nasally placed feeding tubes in adults
      are inaccurate. The few available studies done in children indicate similar
      inadequacies. Auscultation after insufflation of air over the stomach and other
      less common practices used to verify proper tube position have been shown to be
      ineffective in predicting correct tube position. Checking pH of aspirate has be
      recommended as a better method to confirm feeding tube position at the bedside.
      Careful review of the literature and appropriate application of research findings
      can lead to change in time-honored nursing practices. Although change is often
      difficult, a coordinated effort by nurses across organizational lines may
      facilitate the process.

PMID- 15022847
TI  - Pediatric health care providers' knowledge of pulse oximetry.
AB  - Pulse oximetry monitors have become so commonplace in acute health care settings
      over the last decade that blood oxygen is now considered a "fifth" vital sign.
      This study assessed the knowledge base related to pulse oximetry technology and
      clinical interpretation of the data given. A total of 68 participants--nurses,
      respiratory therapists, and resident physicians at a large general pediatric unit
      of a children's hospital--completed a survey of open-ended questions. Preliminary
      analysis revealed that 84% of the clinicians felt they received adequate
      training; 84% correctly identified what a pulse oximeter measured; 40% correctly
      identified how a pulse oximeter worked, but only 15% had a correct understanding
      of the oxyhemoglobin dissociation curve. Clinicians identified a wide range of
      normal arterial oxygen saturation values and made numerous errors in evaluating
      saturation readings in hypothetical clinical situations. Although the majority of
      pediatric staff felt well trained and knowledgeable about pulse oximetry, there
      was a lack of knowledge of basic principles. The results of this study have
      implications for basic professional education programs and the orientation and
      ongoing education of pediatric health care providers.

PMID- 15022848
TI  - Pediatric thoracic organ transplants: challenges in primary care.
AB  - Pediatric nurse practitioners (PNP) confront numerous challenges when delivering
      care to infants, children, and adolescents who receive thoracic organ
      transplants. Today, thoracic organ transplantation is an acceptable and viable
      option for infants, children, and adolescents with end stage cardiac and
      pulmonary disease. Despite the plateau in the actual numbers of thoracic organ
      transplants performed annually in the United States, they are still being
      performed in a significant number. The care of children who receive transplants
      includes long-term use of immunosuppressants, dealing with infectious diseases,
      and utilizing principles of well child and family care. PNPs play a vital role in
      providing holistic care to infants, children, and adolescents who receive a
      thoracic organ transplant.

PMID- 15022849
TI  - Preventing treatment interference: nurses' and parents' intervention strategies.
AB  - Treatment interference in children with acute and critical conditions is the
      conscious or unconscious, threatened or actual disrupting, dislodgment, or
      removal of the technological equipment/devices used for monitoring and/or
      treating such conditions. The purpose of this research was to explore the
      intervention strategies used by critical care nurses and parents as they
      attempted to maintain the technological interface and avoid treatment
      interference. Using an ethological approach, data were collected by observing and
      interviewing 18 children, ages 3 through 6 years, who were hospitalized in the
      pediatric intensive care unit (PICU) of a pediatric hospital located in the mid
      Atlantic region, reviewing systematically their health care records, and
      interviewing their parents/legal guardians. Field notes were analyzed using a
      qualitative content analysis. Parents used psychosocial and physiologic
      strategies, as well as manual restraint, to avoid treatment interference. Nurses
      used psychosocial, physiologic, activities, and environmental strategies, in
      addition to physical restraint, to maintain the technological interface.

PMID- 15022850
TI  - The cold truth.

PMID- 15022851
TI  - War in Iraq influences health care professional.

PMID- 15022852
TI  - Gastroesophageal reflux in infants: a primary care perspective.
AB  - This clinical paper discusses the role of the pediatric nurse in the evaluation
      and management of gastroesophageal reflux (GER) in infants. During an infant's
      first year of life, GER is a common occurrence and concern of families. The
      infant with uncomplicated GER may be managed conservatively with feeding schedule
      modifications, thickened feeds, changes in positioning, or a trial of formula
      change. Gastroesophageal reflux disease (GERD) is a pathological process in
      infants manifested by poor weight gain, signs of esophagitis, persistent
      respiratory symptoms or complications, and changes in neurobehavior. Management
      of the infant with GERD, in addition to non-pharmacological interventions,
      involves further diagnostic evaluation and pharmacologic therapy, depending upon
      the child's history and clinical presentation. While most cases of GER are self
      limiting, complications include esophagitis, bronchospasm, apnea, aspiration
      pneumonia and other otolaryngologic disorders. The pediatric health care provider
      should offer an ongoing, comprehensive clinical approach to the family based on
      considerations of growth and development, and the quality of interactions between
      the caregivers and child.

PMID- 15022853
TI  - Great expectations: a position description for parents as caregivers: Part II.
AB  - Parents caring for a child with a chronic condition must attend to a myriad of
      day-to-day management responsibilities and activities. Part I of this two-part
      series (in the previous issue of Pediatric Nursing) reviewed both the adult and
      pediatric family caregiving literature within the context of four major
      categories of responsibilities: (a) managing the illness, which includes hands-on
      care, monitoring and interpreting signs and symptoms, as well as problem-solving
      and decision-making processes; (b) identifying, accessing, and coordinating
      resources, which involves assessing and negotiating community resources including
      health care providers; (c) maintaining the family unit, including balancing
      illness and family demands while at the same time attempting to meet the health
      and developmental needs of each family member; and (d) maintaining self,
      including physical, emotional, and spiritual health.. Part II presents a
      multifaceted list of parent caregiving management responsibilities and associated
      activities, and discusses nursing implications. The list was developed to
      facilitate "caregiving" dialogue between health care providers and families of
      children with chronic conditions. It is hoped that through such partnerships
      creative ways of educating, preparing, and supporting caregivers will be
      generated.

PMID- 15022854
TI  - Evidence to support parental concerns as an early indicator of autism in
      children.

PMID- 15022855
TI  - Asthmatic toddler with cough.

PMID- 15022856
TI  - A national survey of PNP curricula: preparing pediatric nurse practitioners to
      meet the challenge in behavioral mental health.
AB  - The emergent mental health needs of children and adolescents have been declared a
      national priority by the Surgeon General of the United States (United States
      Department of Health and Human Services [USDHHS], 1999). Pediatric nurse
      practitioners (PNP) are called upon to respond to a new challenge by increasing
      their knowledge and skills in providing mental health care in the primary care
      setting. In turn, educators of PNP programs across the country are called upon to
      evaluate the status of PNP curricula in the field of behavioral/mental health and
      determine the essential competencies needed to meet the challenge. A survey was
      conducted to determine the extent of pediatric mental/behavioral health content
      currently taught in nationally approved PNP programs to discern the level of
      preparation PNP students received both in the classroom and clinically in the
      area of the assessment, diagnosis, and management of mental/behavioral health
      problems in children and adolescents. The final survey included a total of 78
      nationally recognized PNP programs. Pediatric behavioral/mental health content
      was found to vary widely across programs, but it was apparent that all programs
      had begun to expand their curricula to include more content in this area. As the
      role of the PNP continues to expand, the burden of providing a sound education in
      a feasible time frame will be an increasing challenge.

PMID- 15022857
TI  - Attending to weak signals: the leader's challenge.
AB  - Halverson and Isham (2003) quote sources that report the accidental death rate of
      simply being in a hospital is "... four hundred times more likely than your risk
      of death from traveling by train, forty times higher than driving a car, and
      twenty times higher than flying in a commercial aircraft" (p. 13). High
      reliability organizations such as nuclear power plants and aircraft carriers have
      been pioneers in the business of recognizing weak signals. Weike and Sutcliffe
      (2001) note that high-reliability organizations distinguish themselves from
      others because of their mindfulness which enables them to see the significance of
      weak signals and to give strong interventions to weak signals. To act mindfully,
      these organizations have an underlying mental model of continually updating,
      anticipating, and focusing the possibility of failure using the intelligence that
      weak signals provides. Much of what happens is unexpected in health care.
      However, with a culture that is continually looking for weak signals, and
      intervenes and rescues when these signals are detected, the unexpected happens
      less often. This is the epitome of how leaders can build a culture of safety that
      focuses on recognizing the weak signals to manage the unforeseen.

PMID- 15022858
TI  - Disseminating science-based prevention: lessons learned from CSAP's CAPTs.
AB  - A wide variety of prevention approaches that reduce substance use and associated
      problems have been developed and tested. But successes have been limited in
      promoting the use of these scientific advances by the policy makers,
      practitioners, and concerned citizens. The Center for Substance Abuse
      Prevention's six regional Centers for the Application of Prevention Technologies
      (CSAP's CAPTs) are a major mechanism by which CSAP brings research to practice.
      This article synthesizes the issues that the CAPTs have faced, the solutions they
      have developed, and conclusions concerning the work that still needs to be done
      to increase the application of science-based approaches to prevention. These
      discussions highlight the particular importance of addressing issues related to
      the larger systems in which prevention programs and strategies operate.

PMID- 15022859
TI  - Tracking ecstasy trends in the United States with data from three national drug
      surveillance systems.
AB  - Anecdotal reports have suggested that the use of 3,4
      methylenedioxymethamphetamine (MDMA or "ecstasy") is a prodigious problem across
      the United States. Unfortunately, no longitudinal evidence exists to support this
      contention. In the current study, data from the Drug Abuse Warning Network
      (DAWN), Monitoring the Future (MTF), and National Household Survey on Drug Abuse
      (NHSDA) are used to explore ecstasy use trends in the United States during the
      1990s. While the use of ecstasy has increased over time, its prevalence is
      significantly less than other drugs of abuse. These findings suggest that
      anecdotal reports of an ecstasy epidemic is premature and that a less frenzied
      approach to ecstasy control and education may be warranted.

PMID- 15022860
TI  - Heavy episodic drinking and college entrance.
AB  - The college environment appears to encourage heavy drinking. Consequently,
      correlates of student drinking were assessed at college entrance. First-semester
      freshmen (N = 520, 54 percent women) completed self-report measures of social
      affiliation and self/peer drinking for high school and college. Analyses
      indicated that: 1) increased drinking at college entrance mirrored perceived
      increases by peers, 2) perceptions of peer drinking were robustly overestimated
      with women displaying the larger overestimation bias; and 3) social affiliation
      was associated with men's drinking and moderated its relation to perceived peer
      drinking at college entrance. These results advance understanding of the manner
      in which heavy drinking patterns emerge as men and women enter college, and
      campus programs that consider these factors may better promote health and reduce
      the harms associated with heavy drinking among college students.

PMID- 15022861
TI  - Factors impacting the assessment of maternal culpability in cases of alleged
      fetal abuse.
AB  - These studies explored attitudes toward maternal culpability in cases of alleged
      fetal abuse. In experiment one, general culpability for the use of various
      substances during pregnancy was assessed as well as the impact of other
      potentially relevant factors. One hundred and twenty students completed the
      survey. Participants overwhelmingly supported treating drug use by pregnant women
      as a criminal offense. With regard to the assessment of more specific questions,
      the lack of consensus regarding what factors effect culpability is striking.
      Experiment two examined the possible impact of the mothers' race (White or Black)
      and social class (Poor or Middle class) on the assessment of culpability. One
      hundred and sixty-four community members responded to a survey sent to randomly
      selected persons in upstate South Carolina. The results indicate that at least in
      response to a brief, written, case scenario, neither race nor social class make a
      large impact on participants' sanction recommendations.

PMID- 15022862
TI  - Addressing group dynamics in a brief motivational intervention for college
      student drinkers.
AB  - Previous research indicates that brief motivational interventions for college
      student drinkers may be less effective in group settings than individual
      settings. Social psychological theories about counterproductive group dynamics
      may partially explain this finding. The present study examined potential problems
      with group motivational interventions by comparing outcomes from a standard group
      motivational intervention (SGMI; n = 25), an enhanced group motivational
      intervention (EGMI; n = 27) designed to suppress counterproductive processes, and
      a no intervention control (n = 23). SGMI and EGMI participants reported
      disruptive group dynamics as evidenced by low elaboration likelihood, production
      blocking, and social loafing, though the level of disturbance was significantly
      lower for EGMI individuals (p = .001). Despite counteracting group dynamics in
      the EGMI condition, participants in the two interventions were statistically
      similar in post-intervention problem recognition and future drinking intentions.
      The results raise concerns over implementing individually-based interventions in
      group settings without making necessary adjustments.

PMID- 15022863
TI  - Alcohol and other drug abuse counselors' attitudes and resources for integrating
      research and practice.
AB  - The state of Wisconsin recently launched a Research-to-Practice Initiative. One
      aspect of the Wisconsin initiative was to survey Wisconsin-Certified Alcohol and
      other Drug Abuse Counselors (CADCs) to assess their attitudes, reported
      practices, and resources in regard to the integration of research and practice.
      The sample for the present study included 366 CADCs. Of the 366 respondents, 62
      percent (n = 226) were female and 38 percent (n = 140) were male. The respondents
      were primarily Caucasian (90 percent) with the remaining respondents identifying
      as African American (4 percent), Native American (2 percent), Hispanic (1
      percent), and Asian American (0.5 percent). The results from the survey indicated
      that the majority of respondents have access to computers, e-mail, and the
      Internet at their workplace; report being "satisfied" or "very satisfied" with
      their education and training; and tend to approve of the efforts to integrate
      research and practice. Incentives, barriers and strategies to integrate research
      and practice are discussed.

PMID- 15022864
TI  - Teacher training in norm setting approaches to drug education: a pilot study
      comparing standard and video-enhanced methods.
AB  - Norm setting has been shown to be a crucial element of effective drug education.
      The purpose of this study was to examine the degree to which a videotape
      describing concepts and methods for establishing positive norms would enhance
      standard training. Participants included 35 teachers and 64 health education
      students who were randomly assigned to the standard training condition or the
      video-enhanced training. Participants completed pretest and posttest measures of
      beliefs, attitudes, and knowledge concerning prevention methods. Both the
      standard and the video-based instruction produced improved understanding of norms
      and norm setting prevention methods. However, the video-based instruction
      resulted in several notable improvements beyond what was achieved in standard
      instruction. Video training can be an important tool as research-based drug abuse
      prevention achieves wide-scale dissemination. It offers a way of standardizing
      training and has the potential to increase the fidelity with which prevention
      programs are implemented.

PMID- 15022866
TI  - [Quotidian hemodialysis (editorial)].

PMID- 15022865
TI  - Evaluation of what parents know about their children's drug use and how they
      perceive the most common family risk factors.
AB  - Research on family risk factors for addictive behaviors in young people has not
      paid a great deal of attention to parents' knowledge of their children's
      addictive behaviors and of the family risk factors that affect such behaviors.
      The aim of this work is to compare knowledge about these two aspects in two
      groups of parents that differ regarding their children's declared drug use. The
      research was carried out with a sample of 309 schoolchildren and their families,
      divided into two groups: one of 154 families with children defined as non-Drug
      Users and another of 155 families with children defined as Drug Users. The
      results show that parents with children who consume drugs tend to strongly
      underestimate their children's use. Moreover, they overestimate the control they
      exercise over them and appear to be more familiarized with the use of drugs, if
      we compare them with parents of non-Drug Users. It is suggested that these
      results may be relevant for the planning of strategies that increase motivation
      in families with drug-risk children to participate in prevention programs.

PMID- 15022867
TI  - [Daily hemodialysis: a future for home hemodialysis?].

PMID- 15022868
TI  - [Hepatitis C virus infection in renal-transplant patients].
AB  - Chronic hepatitis C virus (HCV) infection is the first cause of liver disease
      after renal transplantation. The prevalence of HCV infection in dialysis and in
      renal-transplant patients remains high. Mortality of HCV-positive renal
      transplant patients is higher than that of HCV-negative ones. Liver disease and
      sepsis seem to be the main causes of death. Graft survival is also lower in HCV
      positive renal-transplant patients. This seems to be due in part to the
      occurrence of de novo glomerulopathy. The effect of HCV infection upon liver
      fibrosis in renal-transplant patients receiving immunosuppressive treatment
      remains controversial. To date, there is no efficient treatment of HCV infection
      after renal transplantation. Consequently, it is mandatory to treat by alpha
      interferon all HCV-positive/RNA-positive dialysis patients waiting for renal
      transplantation.

PMID- 15022869
TI  - [Frequency of thrombosis in hemodialysis arteriovenous fistulas. Contribution of
      2 surveillance methods: Doppler and dilution ultrasound techniques].
AB  - A correct access flow is one of the most important factors for dialysis
      efficiency. Clinical examination does not allow the detection of flow decrease.
      We conducted a prospective study comparing the dilution ultrasound system
      (Transonic) to duplex Doppler sonography (GE logiq 700 expert series) in two
      phases: Comparison of the access flow values obtained with both devices and
      discussion of their discrepancies. Scheduled survey of vascular access, analysis
      of its results regarding the rate of fistula thrombosis, then definition and
      achievement of a strategy of early preventive surgery. After two years, flow data
      were similar with both systems, provided that Transonic values were corrected by
      a constant coefficient. The use of both techniques during the scheduled survey of
      fistulas resulted in a 43% decrease of the rate of acute thrombosis (p < 0.05).

PMID- 15022870
TI  - [Inequalities to the access of renal transplantation for French patients living
      in the overseas French territories].
AB  - This study explored the access to the French national renal transplantation
      waiting list and the waiting time before transplantation for the patients with
      ESRD on dialysis living in the FOT. Overseas health authorities gave data on ESRD
      incidence and prevalence. Data on patients registered between 1997 and 2000 were
      extracted from the French national waiting list (390 patients from the FOT and
      9378 from continental France). Registered prevalence of ESRD in FOT (726 to 1418
      per million population (pmp)) were higher than continental France (580 pmp). The
      yearly incidence of registration on the national French waiting list was 36 pmp.
      The same figure was observed in the FAT (French Guyana and Caribbean's islands:
      36.8 to 43 pmp), very low in New Caledonia and Tahiti (7.7 and 18.1 pmp), and
      very high in the Reunion Island, where a renal transplantation unit is available
      (77.5 pmp). Median waiting times before transplantation varied significantly,
      FAT: 35.4 months, Reunion Island: 9.9 months, Pacific Territories: 8.8 months and
      the Metropolitan territory: 12.2 months. After adjustment on risk factors known
      to be associated with the waiting times before transplantation, we still observed
      a longer waiting time for patients from FAT (RR = 1,4, p < 0.05) and a lower
      waiting time for patients from Reunion Island (RR = 0.6, p < 0.001) compared to
      waiting time observed in patients from continental France. Consequently,
      transplantation teams in FAT must be developed.

PMID- 15022871
TI  - [Thyrotoxic hypokalaemic periodic paralysis in a Caucasian male].
AB  - We report the case of a caucasian patient with a presentation of a periodic
      paralysis associated with hypokalaemia disclosing Graves' disease. Major
      pathophysiologics hypothesis are discused in order to explain relationships
      between hyperthyroidism and paralysis through a disturbance of the excitability
      of the muscle fibres. A genetic predisposition explain the high incidence of this
      affection in asiatic population while it is uncommon in caucasian race. Potassium
      supplementation is not needed in order to correct hypokalaemia except in case of
      cardiac disturbances. Treatment by beta-blockers is advisable with the specific
      treatment of hyperthyroidism.

PMID- 15022872
TI  - Ossifying fibroma of the face and hyperparathyroidism in a chronic hemodialysis
      patient.

PMID- 15022873
TI  - Douching: a risk to women's healthcare?

PMID- 15022874
TI  - Toxoplasmosis-related knowledge and practices among pregnant women in the United
      States.
AB  - BACKGROUND: Infection with Toxoplasma gondii during pregnancy can lead to severe
      illness in the fetus. Many T. gondii infections are preventable by simple
      hygienic measures. METHODS: We surveyed pregnant women in the US to determine
      their knowledge about toxoplasmosis and their practices to prevent infection.
      Volunteer obstetricians selected to be demographically representative of the
      American College of Obstetricians and Gynecologists recruited the participants.
      RESULTS: Of 403 women responding to the survey, 48% indicated that they had heard
      or seen information about toxoplasmosis; however, only 7% were aware of being
      tested for the disease. Forty percent of responding women knew that toxoplasmosis
      is caused by an infection, but 21% thought that a poison causes it. The highest
      level of knowledge was about cats and T. gondii; 61% responded that the organism
      is shed in the feces of infected cats and 60% responded that people could acquire
      toxoplasmosis by changing cat litter. There was a low level of knowledge about
      other risk factors; only 30% of the women were aware that T. gondii may be found
      in raw or undercooked meat. Nevertheless, a high percentage of women indicated
      that they do not eat undercooked meat during pregnancy and that they practice
      good hygienic measures such as washing their hands after handling raw meat,
      gardening or changing cat litter. CONCLUSION: Except for the risk of transmission
      from cats, knowledge among pregnant women about toxoplasmosis is low. However,
      toxoplasmosis-preventive practices are generally good, suggesting that providers
      should continue to offer education about practices that help prevent foodborne
      diseases in general as well as information about preventing toxoplasmosis
      specifically.

PMID- 15022875
TI  - Inhibition of vaginal lactobacilli by a bacteriocin-like inhibitor produced by
      Enterococcus faecium 62-6: potential significance for bacterial vaginosis.
AB  - OBJECTIVE: Bacterial vaginosis (BV) is characterized by a shift in vaginal tract
      ecology, which includes a decrease in the concentration and/or prevalence of
      facultative lactobacilli. Currently, mechanisms which could account for the
      disappearance of lactobacilli are not well understood. The objective of this
      study was to determine whether vaginal streptococci/enterococci can produce
      bacteriocin-like inhibitors antagonistic to vaginal lactobacilli. METHODS:
      Seventy strains of vaginal streptococci or enterococci were tested for
      antagonistic activities against vaginal lactobacilli using the deferred
      antagonism technique. RESULTS: One strain, Enterococcus faecium 62-6, which
      strongly inhibited growth of lactobacilli was selected for further
      characterization. The spectrum of inhibitory activity of strain 62-6 included
      Gram-positive organisms from the vaginal environment, although native
      lactobacilli from the same host were resistant to inhibitor action. Following
      growth in MRS broth the strain 62-6 inhibitor was shown to be heat- (100 degrees
      C, 30 minutes), cold- (4 degrees C, less than 114 days) and pH- (4-7) stable. The
      sensitivity of inhibitor-containing supernatants to pepsin and alpha-chymotrypsin
      suggested an essential proteinaceous component. The inhibitor was sensitive to
      lipase but resistant to lysozyme. Dialysis of inhibitor-containing culture
      supernatants suggested a molecular mass greater than 12,000 Da. All
      physicochemical properties were consistent with its classification as a
      bacteriocin-like inhibitor. Kinetic assays demonstrated a sharp onset of
      inhibitor production coinciding with a concentration of 62-6 of 10(7) cfu/ml,
      suggesting that production may be regulated by quorum sensing. CONCLUSIONS: These
      results may have clinical significance as a novel mechanism to account for the
      decline of vaginal Lactobacillus populations and contribute to both the
      establishment and recurrence of BV.

PMID- 15022876
TI  - Relationship of fungal vaginitis therapy to prior antibiotic exposure.
AB  - OBJECTIVE: To address the putative association of antibiotic use and subsequent
      yeast vaginitis in a population of non-pregnant women. METHODS: Three hundred and
      sixteen women who received medical care in rural family medicine clinics enrolled
      in this study. Participants were pre-menopausal and non-pregnant and were
      followed until they used a course of antifungal therapy for vaginitis, became
      pregnant or moved from the catchment area. At entry subjects were free of
      vaginitis symptoms and had taken no antibiotics for 30 days. Patients were
      followed by repeated review of clinic records, hospital records and telephone or
      personal interviews. Data collection included documentation of episodes of
      antifungal treatment for vulvovaginal candidiasis and confirmed antibiotic
      treatment or credible history of antibiotic use prior to the use of antifungal
      therapy. Physician-reported uses of antibiotic and antifungal as well as patient
      reported uses of these were recorded. RESULTS: There were four reported cases of
      antifungal therapy following within a month of antibiotic use, in contrast to 484
      antibiotic uses not followed by antifungal use. If time of observation was
      extended to 6 months from antibiotic use, there were 13 uses of antifungal
      therapy after antibiotics and 475 uses of antibiotics not followed by antifungal
      therapy. CONCLUSION: Our results cast doubt on the association of antibiotics as
      a putative cause of yeast vulvovaginitis.

PMID- 15022877
TI  - Bacterial colony counts during vaginal surgery.
AB  - OBJECTIVE: To describe the bacterial types and colony counts present before and
      during vaginal surgery. METHODS: A descriptive study was undertaken of patients
      undergoing vaginal hysterectomy with or without reconstructive pelvic surgery.
      Aerobic and anaerobic bacterial cultures were obtained immediately before and
      throughout the surgical cases at preselected time intervals. Standard
      antimicrobial prophylaxis was administered in all cases. Mean total colony counts
      and mean anaerobic colony counts were determined by adding all colonies
      regardless of bacteria type. 'Contamination' was defined as > or = 5000 colony
      forming units/ml. RESULTS: A total of 31 patients aged 26 to 82 years (mean age
      +/- SD, 51 +/- 15) were included. The highest total and anaerobic colony counts
      were found at the first intraoperative time interval. On the first set of
      cultures (30 minutes after the surgical scrub), 52% (16/31) of the surgical
      fields were contaminated, and at 90 minutes, 41% (12/29) were contaminated. A
      negligible number of subsequent cultures were contaminated. CONCLUSIONS: Any
      future interventions designed to minimize bacterial colony counts should focus on
      the first 30 to 90 minutes of surgery.

PMID- 15022878
TI  - Tubo-ovarian abscess occurring 16 years after supracervical hysterectomy.
AB  - BACKGROUND: Supracervical hysterectomy is seldom performed and there are few
      reports of tubo-ovarian abscess (TOA) after supracervical hysterectomy. CASE: The
      case of a 49-year-old woman with a right TOA is reported. This patient had
      received a supracervical hysterectomy 16 years earlier due to rupture of the
      uterus. At this admission, she presented with complaints of, lower abdominal pain
      and fever. Bimanual and transvaginal ultrasound examinations demonstrated a
      tender mass in the right adnexal region. Laparotomy, pathologic examination and
      microbiologic study confirmed the diagnosis of right TOA. CONCLUSION: After
      supracervical hysterectomy, patients may develop endocervicitis, parametritis
      and/or TOA. This series may be a subtype of ascending infections in the female
      genital tract.

PMID- 15022879
TI  - A case of ovarian actinomycosis.
AB  - BACKGROUND: Pelvic actinomycosis is uncommon and often presents as a complication
      of an intrauterine device (IUD). A diagnosis of actinomycosis can be made from
      the finding of sulfur granules within inflammatory exudate on histologic
      examination after surgery. However, it may be possible to diagnose actinomycosis
      before surgery by finding Actinomyces-like organisms on Papanicolaou smears.
      CASE: A 41-year-old woman had been diagnosed as having a pelvic abscess, and
      bilateral salpingo-oophorectomy was performed. She had been an IUD user for 6
      years. Actinomyces-like organisms were detected in her previous Papanicolaou
      cervical smears. If the patient had been treated when the Actinomyces-like
      organisms were detected by Papanicolaou smears, the serious ovarian actinomycosis
      might have been avoided. CONCLUSION: We suggest that routine cervical
      examinations are important for women who are IUD users.

PMID- 15022882
TI  - [Mexican ceramic material for skin healing].
AB  - Sixty female Wistar rats were employed and divided into three experimental groups
      of 20 rats each. Groups were evaluated at 15, 30, and the last at 45 days after
      surgery. Each group was divided into four sets of five rats each. All rats were
      subjected to surgery; an incision of 2 x 2 cm was done on the back of each
      animal, removing tissue until reaching muscular fascia, where the material was
      applied. Nitro-furazone was employed as positive control. Test materials were
      AlPO added with 0.55% wt of Zn; 0.30% wt of Ca(OH)2, and AlPO added with 0.55% wt
      of Zn and 0.66% wt of Ca(OH)2. Finally, as negative control no material was used.
      The object of this work was in the first place obtension of test materials and to
      evaluate the healing skin process in rats using AlPO enriched with Zn and
      Ca(OH)2; as indicated previously. Obtained materials were characterized employing
      XRD. Histologic studies tested showed that best healing process of dermal tissue
      corresponded to rats treated with AlPO added with 0.55% wt of Zn and 0.30% wt of
      Ca(OH)2. Use of AlPO ceramics to repair skin has not been reported previously.

PMID- 15022881
TI  - [Effect of shortened directly observed treatment on compliance and cure rate of
      pulmonary tuberculosis].
AB  - OBJECTIVE: To evaluate shortened directly observed treatment (DOTS) for
      management of pulmonary tuberculosis and to compare its outcomes with self
      administered therapy (SAT). MATERIAL AND METHODS: Evaluation of DOTS, implemented
      since 1998, was compared with a cohort of pulmonary tuberculosis patients under
      SAT from 1992 to 1997. Efficacy and efficiency of treatment were evaluated to
      agree with the National Tuberculosis Control Program. The study was conducted at
      a primary health care center in Hermosillo, Sonora, Mexico. RESULTS: One hundred
      thirty eight patients with smear-positive pulmonary tuberculosis were included,
      45 in DOTS cohort and 93 in SAT. Efficiency was higher in DOTS-managed cases
      compared with SAT cohort (95.5% vs 76.3%), p<0.05. Indeed, efficiency was
      significantly higher in relapsed patients treated under DOTS, p<0.05. The non
      compliance rate declined to 0.0% in the DOTS cohort. Twenty six percent of DOTS
      patients were supervised as outpatients. CONCLUSIONS: Implementation of DOTS was
      a flexible and effective strategy in treatment of pulmonary tuberculosis. DOTS
      allows treatment completion, decline in non-compliance, and increase in care
      rate.

PMID- 15022883
TI  - [Follow-up of a diploma course graduates in the teaching of medicine].
AB  - Certification in Medical Education; Strategy for Educational Formation. Origins
      and Follow-Up. This study is a review of the problem of educational formation in
      terms of an international context, and determinant factors of this need are
      analyzed, barriers or limitations that have prevented such a formation are
      highlighted, and some development proposals for educational training are offered.
      It is also a description of the actions that the Facultad de Medicina (Medical
      School) of the Universidad Nacional Autonoma de Mexico (National Autonomous
      University of Mexico) implemented from 1965 to 1996 to promote educational
      training. In 1997, the Diplomado en Ensenanza de la Medicina began as a new
      possibility for educational training. The first certification course ran in 1997,
      and there have been 18 courses to date, eight the Medical School and 10 at
      external institutions. In 1999, a follow-up questionnaire was answered by
      physicians trained under the certification program. Results showed that training
      received in the certification course had a positive effect on teaching skills of
      physicians who attended it, thus establishing the program as a good option for
      medical teachers.

PMID- 15022880
TI  - Parvovirus B-19 infection during pregnancy.
AB  - The development of an acute parvovirus B-19 infection during pregnancy can cause
      pregnancy complications ranging from early pregnancy loss to nonimmune hydrops.
      There is no treatment, but preventive measures can be used to decrease perinatal
      mortality. The diagnosis is made on the basis of clinical suspicion and serology.
      If the fetus exhibits hydrops in the latter part of pregnancy, the main treatment
      options include either correcting the associated anemia with intrauterine blood
      transfusion or birth with extrauterine management. Although the serious problems
      associated with this virus during pregnancy are uncommon, they can be fatal. In
      view of this, a pregnant woman who is antibody negative should try to avoid
      contact with large groups of young children in order to decrease contact with
      potential vectors.

PMID- 15022885
TI  - [Maxillofacial fractures and associated factors in Campeche Mexico, Instituto
      Mexicano del Seguro Social medical insurance policyholders. Retrospective
      analysis 1994-1999].
AB  - OBJECTIVE: To determine prevalence, distribution, and associated factors of
      maxillofacial fractures (MFs) among third-party insurance plan patients. METHOD:
      A cross-sectional and descriptive study with data of patients from Oral and
      Maxilofacial Surgery Department (January 1994 to December-1999) at the Instituto
      Mexicano del Seguro Social in Campeche, Mexico, was carried out. Daily
      registries, surgical programming lists' and charts of 1,611 patients were used to
      determine presence of MFs, age, sex, and status of the insured. Analysis was made
      in STATA 7 using X2. Odds ratio (OR) with confidence intervals to 95% were
      calculated (1C95%). RESULTS: The prevalence of MFs was 9.4%. The age average was
      31.04+/-15.49 years old. The major percentage of MFs were dentoalveolar fractures
      (26.3%), followed by mandibular angle (20.4%) and mandibular body (13.2%). Being
      a male was strongly associated with presence of MFs (OR=6.1; 1C95% 4.08, 9.12).
      The groups of age with greater association to MFs were those of 41-50 (RM=3.30
      1C95% 1.57, 6.96) and those of 31-40 (RM=2.87 1C95% 1.53, 5.55). The workers
      category displayed a superior association (RM=6.25 1C95% 3.21, 13.56) to the
      other groups of the insured category. CONCLUSIONS: The epidemiologic
      characteristics of MFs were similar to those reported in the specialized
      literature. Appearing mainly in men and intermediate age groups ages. The
      patterns of fractures in the studied patients were different according to the age
      group to which they belonged.

PMID- 15022884
TI  - [First study of teledermatology in Mexico. A new public health tool].
AB  - BACKGROUND: Telemedicine has been used for more than 50 years. Dermatology has
      been one of the specialties where it has reached great development
      (Teledermatology). When the observation is made simultaneously by the outreach
      specialist and by the non-specialist at the workplace, it is called synchronous
      teledermatology, and asynchronous when information is filmed, stored, and
      presented to the specialist at a later time. OBJECTIVE: To evaluate efficacy and
      reliability of asynchronous teledermatology for adequate diagnosis of skin
      diseases. METHODS: Fifty patients with dermatologic disorders were seen in a poor
      tropical rural zone, first by non-dermatologists in conventional consultation and
      then by dermatologists to obtain a diagnosis (gold standard); the latter step
      consisted of evaluation of filmed lesions by another group of dermatologist later
      on. RESULTS: There was a high concordance of diagnosis between the two groups of
      dermatologists when kappa analysis was performed. CONCLUSION: It appears
      important to use these technological advances in developing-countries to improve
      delivery of health care.

PMID- 15022886
TI  - [Mortality risk factors in the child of a toxemic mother].
AB  - OBJECTIVE: To determine risk factors of mortality in the infant of a toxemic
      mother. MATERIAL AND METHODS: A case-controls study, single products only, of 28
      42 weeks of gestation; cases were either stillborn and neonatal deaths. Where
      controls were survivors. RESULTS: There were 57 cases and 114 controls.
      Significant risk factors were: eclampsia (OR = 4.25, 95%CI 1.76-10.39, p =
      0.0002), placental detachment (OR = 8.13, 95%CI 2.29-31.4, p = 0.00007), general
      anesthesia (OR = 5.32, 95%CI 1.74-16.51, p = 0.0005), respiratory distress
      syndrome (OR = 23.68, 95%CI 3.31-478 p = 0.00004), mechanic ventilation (OR =
      334, 95%CI 42.63-7084, p = 0.000000001), peri-intraventricular hemorrhage (OR =
      64.57, 95%CI 8.36-1361, p = 0.0000001), acute renal failure (OR = 26.13, 95%CI
      5.21-177, p = 0.0000002) and pulmonary hemorrhage (OR = 8.40, 95%CI 2.71-27.11, p
      = 0.000006). We observed as protective factors: high maternal educational level
      (OR = 0.110, 95%CI 0.01-0.66, p = 0.02), intrauterine malnutrition (OR = 0.39,
      95%CI 0.18-0.84, p = 0.008) and transient tachypnea of the newborn (OR = 0.021,
      95%CI 0.00-0.15, p = 0.00000001). CONCLUSIONS: We found as maternal risk factors:
      eclampsia; premature placental detachment; general anesthesia, and maternal
      death, in the newborns they were respiratory distress syndrome, mechanical
      ventilation and peri-intraventricular hemorrhage. The finding of protection
      factors is interesting.

PMID- 15022887
TI  - [From tutorial teaching to long-distance learning].

PMID- 15022888
TI  - [Pneumonia due to Pneumocystis carinii in HIV-infected children].
AB  - Introduction of new antiretroviral agents and development of new prophylaxis
      schedules against opportunistic microorganisms have allowed increase in survival
      as well as better quality of life in HIV-infected patients. These new treatment
      schedules have changed the epidemiology of opportunistic infections that previous
      to use of highly active antiretroviral therapy (HAART), formerly occurred with
      high frequency in HIV-infected children. Specifically, pneumonia due to
      Pneumocystis carinii formerly occurred in 12 to 80% of these patients and was
      associated with high mortality. Currently, with use of combined antiretroviral
      therapy (ART) and prophylactic treatments important reduction of PCP has been
      observed. However, despite these benefits ART is not yet available for many
      patients from several developing countries who are at risk for opportunistic
      infections, mainly due to Pneumocystis carinii, which can affect life expectancy.
      Therefore, the purpose of this paper was a review of epidemiologic, clinical, and
      therapeutic characteristics of P. carinii pneumonia in HIV-infected children.

PMID- 15022890
TI  - [Forty four-year-old male with peripheral edema, ascites, and fatigue].

PMID- 15022889
TI  - [Vasopressin use in shock].
AB  - Arginine-vasopressin (VP), also known as the antidiuretic hormone, is essential
      for water homeostasis. Its synthesis and liberation depends on regulation of
      osmotic, hypovolemic, hormonal, and nonosmotic stimuli. It has been demonstrated
      that it is key for maintenance of cardiovascular homeostasis through vasomotor
      regulation, the determinant of systemic vascular resistance and mean arterial
      pressure, a process acting through V1 receptors. Shock state with refractory
      vasodilation seen in sepsis, systemic inflammatory response, hypovolemia, cardiac
      arrest, polytrauma, etc., is characterized by an initial phase of liberation and
      increased levels of VP followed by a second phase characterized by
      inappropriately low levels of this hormone that are associated with
      refractoriness to management with volume, inotropics, and vasopressors. It has
      been demonstrated in clinical and experimental studies that exogenous VP
      treatment under this condition increases systemic vascular resistance, perfusion
      pressure, and oxygen supply to peripheral tissues, which makes it possible to
      decrease and to suspend vasopressors and also to increase survival.

PMID- 15022891
TI  - [Furunculoid myasis due to Dermatobia hominis. A case imported to the Mexican
      capital's Federal District from Costa Rica].
AB  - Furunculoid myiasis is malignant parasitation caused by larvae of the botfly
      Dermatobia hominis. It is endemic to Southern Mexico and Central and South
      America. We report here on the case of a patient living in Mexico's Federal
      District who was infested with Dermatobia hominis, and who had a history of
      travel to Costa Rica. A review of the literature regarding this uncommon ailment
      in the Valley of Mexico is also presented.

PMID- 15022892
TI  - [Spontaneous renal arteriovenous fistula-caused hematuria: case report].
AB  - OBJECTIVE: To present a case of spontaneous renal arteriovenous fistula treated
      at the Hospital Regional General No. 1 "Gabriel Mancera" of the Instituto
      Mexicano del Seguro Social (IMSS). CASE REPORT: A 27-year-old female with no
      pathologic-medical background who presented with total, intermittent, macroscopic
      hematuria with clots as the only symptom causing severe anemia. Ureterorenoscopy
      and diagnostic renal arteriography were carried out. She was treated with
      percutaneous selective arterial embolization with absolute ethanol. The patient
      experienced a favorable and uncomplicated evolution. After 1 year of follow-up,
      she remains asymptomatic and her laboratory parameters are normal. DISCUSSION:
      Spontaneous renal arteriovenous fistula is a rare disease; the majority of the
      cases are related to renal trauma or renal surgery. Treatment by arterial
      embolization is very effective and prognosis is excellent.

PMID- 15022893
TI  - [Professional ethics of physicians].
AB  - Socrates is considered the great classic moralist, although he was not the first
      to take care of man and morality. Aristotle instituted ethics as an autonomous
      science and clearly defined its fields, its methods and its purposes, formulating
      the concept of "happy medium". In the Aristotelian methodology we find traces of
      Hippocrates, who believed that the physician must always consider the peculiar
      aspects and that the individual characteristics' determinations can be reached by
      sensitivity. Once these particularities have been proved, the physician must rely
      on the "happy medium". Only Stoics could discover, and gradually elaborate, the
      concept of natural law. Apparently they were the first to establish the classic
      distinction between the theorical or ideal morality and the practical morality,
      which is accessible to all people. They refused to compare wisdom, entirely
      turned inward, with the medical art, which does not constitute an aim by itself.
      Modern authors assert that, with stoicism, the notion we can denominated wisdom's
      humanism rised. Today it is admitted that "medicine is more than simply learning
      medical data.... Physicians must have a wisdom learned from human finitude. They
      will need this wisdom to tackle the health care policy debates in the next
      decades". This would be a major cultural undertaking.

PMID- 15022895
TI  - [Genomic medicine].

PMID- 15022894
TI  - [Imaging diagnosis of acute septic arthritis of hip].
AB  - Acute septic arthritis is a common diagnosis usually seen by radiologists,
      internists, and family physicians; it is most commonly caused by pyogenic
      pathogens. In the majority of patients, it is possible to identify, the infection
      mechanism: spread of infection can be due to hematogenous dissemination, a
      contiguous source of infection, direct inoculation, or surgical contamination.
      Radiologic findings include increase in articular space and central and marginal
      bone erosions; the first plain radiograph changes are seen 8-10 days after
      symptoms. We present the case of a 9-year-old girl with septic arthritis of right
      hip; in presenting this case we offer a brief summary of clinical features and
      main imaging findings of septic arthritis (plain radiographs, ultrasonography,
      and gammagraphy).

PMID- 15022896
TI  - [Consensus of a group of Mexican experts: efficacy and safety of metamizol
      (Dipirone)].

PMID- 15022898
TI  - [Ethics and genomics].

PMID- 15022899
TI  - Proliferative lesions of the breast: carcinoma in situ.
AB  - Many breast carcinomas probably arise in a multi-step fashion through a series of
      intermediate lesions viz. ductal hyperplasia to atypical ductal hyperplasias to
      ductal carcinoma in situ (DCIS), and thence to invasive ductal cancer, each of
      which has a greater probability of becoming malignant than the one that preceded
      it. These precursor lesions have differing risk implications, hence treatment
      decisions vary with the risk. The heterogeneous lesions that come under the
      heading of hyperplasias and DCIS can cause problems for the histopathologists
      unless there is a conceptual understanding of the disease process. Since the
      surgical pathology report is the final word in cases of DCIS/LCIS, the
      pathologist becomes a vital partner in the decision making team.

PMID- 15022897
TI  - [Globalization and bioethics in health resources].
AB  - Globalization is the term used to explain the exchange of goods and services
      around the globe. Economy, finances, technology, and information are diversified
      and spread all throughout the world at present. However, it is still being
      debated whether the global economic paradigm can be applied under considerations
      of justice and equity for healthcare systems or in the budget for research
      administration. This issue has become decisive, especially in countries where
      adequate development remains a pending public endeavor.

PMID- 15022900
TI  - Neuropathology of schizophrenia--a review.
AB  - Despite clinical evidence of brain dysfunction in schizophrenia, little progress
      was made for most of the last century in determining its organic parameters.
      Neuropathology, over the past few decades, has made a substantial contribution to
      the understanding of cellular and molecular mechanisms of schizophrenia. During
      the last 10-15 years the concept of schizophrenia as a 'functional' psychosis has
      changed to the current paradigm of schizophrenia as a neurodevelopmental
      disorder. Much still has to be unravelled and learnt. This review gives a brief
      account of the relevant neuroanatomy, viral hypotheses of schizophrenia etiology,
      pathologic findings reported, concept of neurodevelopmental model and avenues for
      the future.

PMID- 15022902
TI  - Study of mast cells in non-neoplastic skin lesions.
AB  - Sixty non-neoplastic skin lesions were studied for mast cells by toluidine blue
      stain. The highest numbers of mast cells were seen in the viral infections of the
      skin (50/mm2) and lowest number of mast cells in congenital diseases (17/mm2).
      Out of the cutaneous bacterial infections, highest numbers of mast cells were
      seen in leprosy (44/mm2) while in lupus vulgaris they were much less (37/mm2). In
      leprosy cases it was observed that as the lesions moved from indeterminate to
      both polar tuberculoid and lepromatous, the mast cell count increased. It could
      therefore be summarised that periodic follow-up of indeterminate and borderline
      lesions for mast cell count might help in predicting stability of lesions. In non
      infectious squamous and papular lesions the mean mast cell count was 39/mm2. The
      highest numbers of mast cells in the non-infectious vesicular and bullous lesions
      were in bullous pemhigoid (57/mm2) and lowest in dermatitis (38/mm2).

PMID- 15022901
TI  - AgNOR counts are not altered in alcoholic cirrhosis.
AB  - One hundred and two liver biopsy specimens were stained for Argyrophilic
      nucleolar organizer regions and associated proteins to assess its utility in
      differentiating normal, cirrhotic and neoplastic liver tissue. A statistically
      significant (p < 0.001) difference was observed between mean AgNOR counts of
      normal (1.53 +/- 0.4), post-hepatitic cirrhosis (3.65 +/- 0.53) and
      hepatocellular carcinoma (7.94 +/- 1.18). In contrast the mean AgNOR count of
      biopsies with alcoholic cirrhosis (1.57 +/- 0.06) was significantly less (p <
      0.001) than post-hepatitic cirrhosis and was similar to that of normal liver
      tissue. It is concluded that AgNORs can act as a good adjuvant to histology in
      diagnosing liver diseases especially in differentiating post-hepatitic and
      alcoholic cirrhosis.

PMID- 15022903
TI  - Clinical profile and cervical cytomorphology in symptomatic postmenopausal women.
AB  - The atrophic changes in menopause reflected in cytology is known, but relevance
      of other features in menopausal management is relatively unknown. One hundred
      postmenopausal patients who presented with symptoms related to urogenital atrophy
      were studied (September 1999 - March 2000). Adequacy, density of inflammation
      with numerical scoring, specific pathogens and predominant cell type were
      assessed in each smear and correlated with presenting symptoms and duration of
      menopause. The most common presenting urinary symptom was dysuria followed by
      frequency and UTI. Smears of all patients showed inflammation, varying in
      intensity, irrespective of the presenting symptoms with a high incidence of
      candidiasis (12%). Three patients who had ASCUS on smears had carcinoma on follow
      up. Six patients who opted for HRT were followed up with cytology. Cytology in
      postmenopause can be used other than to assess hormonal status, to screen for
      malignancy, pathogens in inflammation and to monitor hormone replacement therapy.

PMID- 15022904
TI  - Haematological changes in HIV infection.
AB  - HIV infection is associated with a wide range of hematological abnormalities. The
      peripheral blood findings and the morphological abnormalities in the bone marrow
      can simulate myelodysplastic syndrome, myeloproliferative disorders, and T cell
      lymphoma. We studied the peripheral blood smear and bone marrow findings of 42
      patients with HIV infection over a 3-year period with the aim of recognising the
      morphological findings sufficiently characteristic of HV infection. The salient
      peripheral blood smear findilngs were anemia, bicytopenia and pancytopenia. The
      bone marrow revealed trilineage dysplasia, plasma cells and eosinophils,
      increased megakaryocytes, increased iron and reticulin fibrosis. In two cases the
      bone marrow revealed granulomata.

PMID- 15022905
TI  - Role of FNAC and antithyroid antibodies in the diagnosis of thyroid disorders.
AB  - Multiple parameters are needed to diagnose thyroid disorders. 100 cases of
      thyroid swellings were studied by clinical assessment, hormonal assay, fine
      needle aspiration cytology (FNAC), antithyroglobulin (Tg) and antimicrosomal (Tm)
      antibodies and histopathology. The cases were divided into four groups. Cases of
      thyroiditis on FNAC showed predominance of lymphocytes (76%), hurthle cells
      (77%), epithelioid cells and giant cells (31%) and high titres of Tg (66%) and Tm
      (92%). Non toxic goitre was characterized by colloid and foam cells (100%) and
      low positivity for Tg and Tm (25%). Toxic goitre showed colloid (30%). Hurthle
      cells, anisonucleosis of acinar cells (38%), fire flare (62%) and high positivity
      for Tg and Tm (73%). Neoplasia was diagnosed mainly by cell morphology on FNAC
      and a low positivity for Tg and Tm (30%). FNAC in correlation with thyroid
      antibodies is useful in diagnosing autoimmune thyroiditis, goitre, Grave's
      disease and malignancy of thyroid. Antibodies have a specific role in the
      diagnosis of early stage of thyroiditis.

PMID- 15022906
TI  - Paucity of anti-hepatitis C virus antibodies in the serum of Indian patients with
      Sjogren's syndrome and inflammatory myositis.
AB  - Several extrahepatic manifestations have been associated with infection with
      Hepatitis C virus (HCV) infection. It has been associated with Sjogren's syndrome
      (SS) and inflammatory myositis (IM). The objective was to look at the prevalence
      of anti-HCV antibodies in the serum of SS and IM patients of Indian origin.
      Individuals satisfying the European Economic Community criteria for the diagnosis
      of SS and those satisfying the criteria of Bohan and Peter for the diagnosis of
      IM were recruited in the study. Routine evaluation for liver functions was made.
      Anti-HCV antibodies were tested by a third generation ELISA, using microplate
      HCV3.0 ELISA. Of the 23 patients with SS studied, 14 had extraglandular features.
      The commonest were anaemia and arthritis in six each, followed by in lymphopenia
      in two. One patient each had interstitial lung disease, hypothyroidism and
      chronic active hepatitis. Twenty-two patients with IM were studied alongside.
      None of the patients had abnormal liver functions. One patient with primary SS
      tested positive for anti-HCV antibodies. None of the patients with inflammatory
      myositis tested positive for anti-HCV antibodies. The presence of anti-HCV
      antibodies in our cohort of patients with SS and IM is low and more in keeping
      with the generally low prevalence of the infection in the Indian population.

PMID- 15022907
TI  - Childhood malignancies at BS Medical College: a ten year study.
AB  - A retrospective study of malignant diseases of childhood was carried out at B. S.
      Medical College, Bankura, W.B. to know the prevalence. It includes cases detected
      in this institution during 1990-1999 in the age group of 0-14 years. Cases were
      identified from previous records. Histopathology slides, stained by hematoxylin
      and eosin, were recovered and reviewed. Diagnosis were made by morphology.
      Hematological diagnosis were made by morphology and cyto-chemistry. In total 120
      cases were detected. Acute leukemia (39.2%) was the commonest, followed by
      retinoblastoma (19.2%), lymphoma (10.8%), Wilm's tumor (10%) and rhabdomyosarcoma
      (9.1%). Brain tumors were not found due to non-availability of Neurosurgical Unit
      in this institution. Frequency of neuroblastoma was very low, only 2 out of a
      total of 120. In comparison to studies in Southern India and Western countries
      retinoblastoma and soft tissue sarcoma are more prevalent here, while there is a
      much lower prevalence of neuroblastoma.

PMID- 15022908
TI  - Brush cytology in malignant biliary obstruction.
AB  - Tissue diagnosis is essential for the management of patients with malignant
      biliary obstruction. We prospectively studied brush cytology in 30 patients with
      malignant biliary obstruction. Wire guided brush cytology was obtained from the
      stricturous segment during endoscopic retrograde cholangio-pancreatography. The
      study comprised of 30 patients (16 males, 14 females), with a mean age of 55
      years (range 30-75 years). The obstruction was caused by carcinoma gallbladder in
      16 cases, carcinoma head of the pancreas in 10 cases, and cholangiocarcinoma in 4
      cases. Brush cytology was positive for malignancy in 8 cases (26.7%). Another 3
      samples (10.3%), 1 from each group of tumors, were suspicious for malignancy.
      Cytology was positive in 25% of gallbladder cancers, 50% of pancreatic cancers,
      and 50% of cholangiocarcinomas. Brush cytology was positive in 6 of 18 (33.3%)
      proximal and 5 of 12 (41.7%) distal strictures. Brush cytology yielded a
      sensitivity of 36.7% in the diagnosis of malignant biliary strictures. However, a
      larger study is required to confirm these findings.

PMID- 15022909
TI  - AgNOR counts in cervical lesions.
AB  - Present study was undertaken with a view to assess the utility of AgNOR counts in
      differentiating cervical lesions. One hundred cases of cervical lesions including
      normal, chronic cervicitis, CIN (I, II, III) and carcinoma were taken up for
      study during the period December 1995 to November 1996. Three micron thick
      sections of paraffin were subjected to AgNOR staining as described by Crocker and
      Smith with a little modification of 0.01% safranin counterstain. Statistical
      counts of AgNORs were done. The mean AgNOR counts in cervical epithelium showed a
      progressive and statistically significant increase from normal to chronic
      cervicitis to CIN, I, II and III (P<0.001). Scores in carcinoma also exceeded
      that of CIN (P<0.05). This can prove to be a useful adjunct to routine
      histopathology to evaluate cervical lesions.

PMID- 15022910
TI  - Peripheral nerve sheath tumours--a short series with some uncommon variants.
AB  - Peripheral nerve sheath tumours are rarely malignant (0.001%), such malignant
      peripheral nerve sheath tumours (MPNST) are more common in upper extremities than
      in head and neck. Chondroid differentiation in benign peripheral nerve sheath
      tumours and melanotic schwannoma are very uncommon. In a retrospective analysis
      of 25 peripheral nerve sheath tumours over a period of two years, we reported two
      MPNST one of which was in a parapharyngeal location while the other MPNST showed
      melanotic differentiation. Similar melanotic differentiation was also seen in
      another benign melanotic schwannoma. Chondroid differentiation in a schwannoma
      was also observed which is usually documented in MPNST.

PMID- 15022911
TI  - Pneumocystis carinii pneumonia and its association with other opportunistic
      infections in AIDS--an autopsy report of five cases.
AB  - Pneumocystis carinii pneumonia (PCP) has been reported as one of the
      opportunistic pathogens in AIDS. The significance of this pathogen in AIDS is
      well established so that, the diagnosis of PCP in an adult simultaneously
      establishes the diagnosis of AIDS. This point is well emphasised in the CDC case
      definition of AIDS. In western literature, the occurrence of PCP in AIDS is
      widely reported. However, in Indian literature only sporadic case reports have
      been documented. This study reports 5 cases of PCP encountered amongst 34 AIDS
      autopsies studied. PCP alone was present in 2 cases. It is worth noting that it
      was simultaneously associated with cryptococcosis, tuberculosis and CMV in 3
      remaining cases, highlighting the need for extensive investigations even after
      establishing the diagnosis of PCP in a known full blown AIDS patient.

PMID- 15022912
TI  - Leiomyosarcoma of the scrotum.
AB  - A case of leiomyosarcoma of the scrotum is reported for its rarity. The tumor
      measured 6.2 x 4 x 4 cm and presented as a gradually increasing painless mass of
      1 month duration. Light microscopy showed the typical interlacing fascicles of
      neoplastic cells with mitotic count of 1-2 / 10 HPF in different areas.
      Immunoperoxidase stains of vimentin & desmin and electron microscopy confirmed
      its muscle origin.

PMID- 15022913
TI  - Post kala-azar dermal leishmaniasis (PKDL): a first case report from Nepal.
AB  - Post kala-azar dermal leishmaniasis (PKDL) is a non-ulcerative lesion of the skin
      caused by Leishmania donovani, which is usually seen after completion of
      treatment of the kala-azar. The condition is yet to be reported from Nepal. We
      document and report for the first time a case of PKDL in Nepal.

PMID- 15022915
TI  - Combined occurrence of von Willebrand's disease and factor XIII deficiency: a
      case report.
AB  - We report the case of a three year old female child with combined occurrence of
      von Willebrand's disease and factor XIII deficiency, an extremely rare
      combination. The patient presented with prolonged bleeding following cuts and
      wounds. Clot solubility test using 5M urea was positive. Platelet aggregation
      using ristocetin was reduced, which corrected on adding normal plasma.
      Aggregation with other agonists was normal. We discuss the clinico- hematological
      profile of the case. Only one such case has been reported in literature in the
      past to the best of our knowledge.

PMID- 15022914
TI  - Giant cell tumour of talus with osteosarcomatous transformation in a young male:
      a case report.
AB  - A case of osteosarcomatous transformation in a benign giant cell tumour is
      described. Spontaneous malignant transformation is rare in a giant cell tumour
      with only 17 cases reported in the literature till date. In addition, a giant
      cell tumour arising in the bones of the hands and feet is in itself a rarity. In
      this instance the lesion presented in the talus of the left ankle in a 13 year
      old male.

PMID- 15022916
TI  - Massive ovarian edema with contralateral mature cystic teratoma--a case report of
      an uncommon combination.
AB  - A case with massive ovarian edema (MOE) of left ovary--a rare pseudotumour and
      mature cystic teratoma of right ovary is described in a young unmarried girl of
      16 years. The etiopathological concepts, morphological changes and differential
      diagnosis are described. Knowledge about the entity and its existence are
      important for correct treatment. This is the first reported case from Nepal.

PMID- 15022917
TI  - Lipoblastomatosis--a case report.
AB  - Lipoblastoma and lipoblastomatosis are benign fatty tumors of soft tissues that
      are unique to childhood. A male infant aged 5 months presented with a history of
      recurrent lump in the left scapular region. He had been operated upon for the
      same lump 2 months earlier. A review of the histology of the two consecutive
      lumps showed an adipocytic tumor. Microscopically the tumor was composed of
      lobules of immature adipose tissue separated by thick fibrous septae. Plentiful
      lipoblasts were noted in various stages of differentiation and myxoid material
      was also present. A diagnosis of lipoblastomatosis was made. The second excision
      had a higher proportion of mature adipose tissue.

PMID- 15022918
TI  - Calcifying aponeurotic fibroma: a case report and review of literature.
AB  - Calcifying aponeurotic fibroma is a rare soft tissue tumor that primarily occurs
      in children and adolescents and has a strong predilection for the distal portion
      of the extremities, especially the hands and feet. This paper presents a case
      report of calcifying aponeurotic fibroma.

PMID- 15022919
TI  - Mesenchymal hamartoma of the liver--a case report.
AB  - Mesenchymal hamartoma of the liver is a rare benign tumor of infancy and
      childhood. A case of mesenchymal hamartoma of liver seen in a 37 day old child is
      reported and the available literature on the subject is briefly reviewed.

PMID- 15022921
TI  - Giant thymolipoma--a rare mediastinal tumour: a case report.

PMID- 15022920
TI  - RAEB-t in young adults--a rare entity.
AB  - Refractory anemia with excess blasts in transformation (RAEB-t) in young adults
      is a rare entity. RAEB-t presenting with megaloblastic erythropoiesis should be
      differentiated from nutritional B12 and folic acid deficiency and from acute
      erythroleukemia. We report two cases in the present article.

PMID- 15022922
TI  - Multiple myeloma presenting as collapsing glomerulopathy.
AB  - A 54 year old male patient was admitted with advanced renal failure of recent
      onset. Serology was noncontributory. Renal biopsy showed collapsing
      glomerulopathy with interstitial fibrosis. Bone marrow examination confirmed the
      diagnosis of multiple myeloma. With chemotherapy multiple myeloma went into
      remission. However he continued to remain dialysis dependent and a repeat kidney
      biopsy showed progression to endstage renal disease.

PMID- 15022923
TI  - Isolated conjunctival amyloidosis--a case report.
AB  - Isolated conjunctival amyloidosis is extremely rare and usually diagnosed
      histologically instead of clinically. This has been variously reported as an
      unusual cause of ptosis, complication of trachoma, painless nodular aggregates
      and recurrent subconjunctival hemorrhages. Once diagnosed, evaluation for
      systemic disease is advised though results of examination are almost always
      negative and frustrating.

PMID- 15022925
TI  - True aneurysm of popliteal artery due to trauma: a case report.
AB  - Incidence of true aneurysm of popliteal artery due to trauma is extremely rare
      and not yet known. Medlar search failed to reveal any report. This case is
      presented due to its rarity and atypical clinical manifestations. An awareness of
      this can help in preventing unnecessary amputations.

PMID- 15022924
TI  - Spindle cell carcinoma of the glans penis: a case report.
AB  - Spindle cell carcinoma, an uncommon variant of squamous cell carcinoma arising
      from the penis is extremely rare and only five reports are available at present
      in the medical literature.

PMID- 15022926
TI  - Metanephric adenoma of the kidney--a case report.
AB  - Metanephric adenoma is a relatively novel renal epithelial neoplasm. Herein we
      report a case of metanephric adenoma in a 38 year male patient.

PMID- 15022927
TI  - Idiopathic giant cell myocarditis--a case report and review of literature.
AB  - Idiopathic giant cell myocarditis (IGCM) is a rare clinicopathological entity
      which is usually known to cause in more than half the cases sudden death. The
      histological features are characteristic with a central area of myocardial
      necrosis and a rich cellular infiltration of lymphocytes with a few eosinophils,
      plasma cells, macrophages and multinucleated giant cells. We hereby report a case
      of IGCM in a 72 year old male with history of sudden death. This case is being
      presented for its rarity and a review of literature is made.

PMID- 15022928
TI  - Primary squamous cell carcinoma of the endometrium: a case report.
AB  - Squamous cell carcinoma of the endometrium is extremely rare female genital
      malignancy. Only 64 cases have been reported in the literature. A case of primary
      squamous cell carcinoma of endometrium in a 55-year old-woman is reported.
      Examination revealed pyometra and cervical stenosis. A total abdominal
      hysterectomy with bilateral salpingo-oophorectomy was performed. Histopathology
      confirmed the diagnosis.

PMID- 15022929
TI  - Clinically significant autoantibodies--a case report.
AB  - Auto antiA1 and anti H was found in the serum of a patient admitted in this
      hospital for intracardiac repair of Ventricular Septal defect (VSD). Blood was
      grouped as A1 positive with discrepant cell and serum grouping due to auto anti
      A1 and anti H. No blood units were compatible for the patient. 17 A1, 3 A2 and 8
      O group blood units were crossmatched and found incompatible at 37 degrees C and
      A2 and O at 25 degrees C--as the patient required surgery at hypothermia. Surgery
      was postponed. Antibody status was reviewed after 4 months. The thermal amplitude
      of auto anti H had changed by then but there was no change in auto anti A1.
      Surgery was done using A2 group blood.

PMID- 15022930
TI  - Diagnosis of rare malignant tumours of the breast by FNA cytology--a report of 3
      cases.
AB  - This report describes the fine needle aspiration (FNA) cytology findings in 3
      cases with breast tumours. The characteristic cyto architectural pattern helped
      in the diagnosis of two papillary carcinomas. The predominant spindle cell
      pattern with scattered bizarre cells was interpreted as malignant spindle cell
      tumour in one case. On histopathology, this was diagnosed as metaplastic
      carcinoma.

PMID- 15022931
TI  - Amyloidoma of bone: a report of 2 cases.

PMID- 15022932
TI  - SEN virus infection--a new hepatitis virus: a review.
AB  - Approximately 10% of transfusion associated hepatitis and 20% of community
      acquired hepatitis cases do not have a defined etiology, suggesting the existence
      of an additional causative agent. The recent agents which have been detected in
      blood were Hepatitis G virus (HGV) and TT virus (TTV), members of the family
      Circoviridae. These viruses were initially thought to be associated with post
      transfusion hepatitis but later studies negated this causal effect. Recently, a
      novel DNA virus at the moment designated as SEN virus (SEN-V) was discovered and
      is thought to be associated with post-transfusion hepatitis. This virus is
      related to the above two agents and belongs to the same family. Whether, like HGV
      and TTV causal relationship with hepatitis is finally confirmed only time will
      tell, but, at the moment the association appears to present. The present review
      summarizes the present available data on this new agent of hepatitis.

PMID- 15022933
TI  - Vancomycin resistant Enterococcus in nosocomial urinary tract infections.

PMID- 15022934
TI  - Role of cell surface antigens of Vibrio cholerae 01 and non 01 serovars in
      intestinal adhesion.
AB  - Decrease in adherence of Vibrio cholerae to rabbit small intestine was observed
      following treatment with antisera against outer membrane (OM), lipopolysaccharide
      (LPS) and flagella. Anti LPS antibodies were more efficient than the other two
      antibodies in inducing adherence inhibition and promoting in vivo protection.

PMID- 15022935
TI  - Seroreactivity of 31 kDa and 41 kDa mycobacterial secretory proteins isolated
      from culture filtrate in extra pulmonary tuberculosis.
AB  - Despite rapid advances in molecular genetics for detection of mycobacteria, it is
      clear that interest in serodiagnosis remains high, especially for those
      situations in which a specimen may not contain the infecting agent in particular
      in extrapulmonary tuberculosis. Immune response to excretory-secretory (ES)
      proteins of Mycobacterium tuberculosis (M.tb) has been of diagnostic interest in
      tuberculosis. In earlier study from our laboratory, a secretory protein M.tb ES
      31 has been shown to have diagnostic potential in pulmonary tuberculosis.
      Further, another M.tb H37Ra ES protein (ES-41) was isolated and purified by
      trichloroacetic acid solubilization followed by Fast Performance Liquid
      Chromatography (FPLC). These two protein fractions viz ES-31 and ES-41 secreted
      by M.tb H37 Ra bacilli were employed in stick indirect penicillinase ELISA to
      study seroreactivity in extra pulmonary tuberculosis namely tuberculous
      lymphadenopathy, tuberculous meningitis, abdominal tuberculosis and bone & joint
      tuberculosis. While using ES-31 antigen 88% (22/25) of tuberculous
      lymphadenopathy and 90% (9/10) of tuberculous meningitis cases showed positive
      reaction for tuberculous IgG antibody, ES-41 showed 80% positivity in both
      groups. In abdominal and bone & joint tuberculosis cases, ES-41 antigen showed
      better sensitivity of 81.5% (22/27) and 84.6% (22/26) respectively in IgG
      antibody detection compared to 70% (19/27) and 69.2% (18/26) shown by ES-31. This
      study is of interest that different antigen protein fractions of M.tb exhibit
      differential seroreactivity, as ES-31 protein showed good potential in detecting
      tuberculous IgG antibodies in tuberculous lymphadenopathy (TBLN) & tuberculous
      meningitis (TBM), while ES-41 in abdominal and bone & joint tuberculosis cases.

PMID- 15022936
TI  - Non-fermenters in human infections.
AB  - One thousand and one hundred thirty non-fermenting gram negative bacteria were
      isolated from various samples. Of these, Pseudomonas aeruginosa was the commonest
      isolate (72.83%) followed by Acinetobacter anitratus (8.4%), Alcaligenes faecalis
      (7.6%), Acinetobacter lwoffi (4.4%), Pseudomonas flourescens (2.4%), Schwanella
      putrefaciens (1.6%), Stenotrophomonas maltophilia (1.6%), Pseudomonas putida
      (0.4%), Bravundimonas vesicularis (0.4%) and Flavobacterium meningosepticum
      (0.4%). Antibiotic sensitivity pattern showed multiple drug resistance pattern
      with majority of the isolates being resistance to two or more drugs.

PMID- 15022938
TI  - Serum magnesium level in preterm labour.
AB  - Preterm labour, (PTL) defined as labour after 28 weeks but before 37 completed
      week of gestation, is an ill omen for our country as the incidence is 5-10%
      leading to 70-80% of perinatal deaths. Besides varied etiology, it may be due to
      alteration in basic biochemical functions of the body at cellular level stating
      emphasis to trace elements, of which magnesium, being one of them, is subject of
      interest now a days. Serum magnesium was estimated in fifty cases of Preterm
      labour of idiopathic etiology (28-37 wks), 35 normal pregnancy cases of the same
      gestational age and 15 normal non-pregnant ladies. Varied hypomagnesemia was
      observed in Preterm labour cases (1.47 mg/dl +/- 0.22 S.D.), normal value of
      serum magnesium was found in normal non-pregnant ladies and slightly low value
      were observed in pregnant ladies of same gestational age. Age and parity had no
      significant effect on serum magnesium level in our study. As far as socio
      economic study is concerned, it was found to be higher in high socio-economic
      group and low in lower group. Thus from this study it can be concluded that
      estimation of serum magnesium in pregnancy may prove to be a valuable tool in
      predicting preterm onset of labour.

PMID- 15022937
TI  - Outbreak of neonatal meningitis caused by Salmonella enterica serotype
      Worthington.
AB  - We report an outbreak of Salmonella meningitis in a nursery unit due to serotype
      Worthington. The organism was isolated from blood and CSF samples of five babies.
      The isolates were found to be resistant to commonly used antibiotics such as
      ampicillin, cefotaxime, cefiriaxone and amikacin but were sensitive to
      ciprofloxacin. Serotype Worthington appears to be an emerging pathogen in
      neonatal units.

PMID- 15022939
TI  - Rotavirus associated acute diarrhoea in hospitalized children in Dibrugarh, north
      east India.
AB  - Faecal specimens from 202 children below 5 years with acute diarrhoea
      hospitalized in Assam Medical College from April, 1999 to March, 2000 were
      examined in Regional Medical Research Centre (ICMR), Dibrugarh to know the
      prevalence of rotavirus diarrhoea and molecular pattern of viral strains from
      different localities of Dibrugarh using double antibody sandwich ELISA and SDS
      PAGE analysis. Human group A rotaviruses were detected in 47 (23.27%) specimens
      and 33 of 41 (80.49%) positive specimens were electropherotyped where 16 were
      "long" (48.48%) and 17 "short" (51.52%) types. Rotavirus diarrhoea was
      significantly high (p<0.01) in children between 11 to 20 months (37.75%).
      Children from families of upper middle socioeconomic status (61.59%) suffer most
      (p<0.001). Peak incidence of rotavirus diarrhoea was in winter (38.37%) and
      showed inverse relation with temperature, humidity and rainfall. Besides
      diarrhoea, vomiting was a significant clinical manifestation. "Short"
      electropherotype were common during winter months and in tea garden localities.

PMID- 15022940
TI  - Tuberculous nasal polyp.

PMID- 15022941
TI  - Microfilaria in lung--diagnosis by FNAC.

PMID- 15022942
TI  - A simple staining technique for myeloid precursors in paraffin sections.

PMID- 15022943
TI  - Changing trends in shigellosis at a tertiary care centre.

PMID- 15022944
TI  - Metastasis of phylloides tumour to axillary lymphnode.

PMID- 15022945
TI  - Instituting palliative care in developing countries--an urgently needed and
      achievable goal.

PMID- 15022946
TI  - Hospice and palliative care: a universal human imperative-lessons for the world
      from the innovators.

PMID- 15022947
TI  - Freedom from pain--a mirage or a possibility? Experience in attempts to change
      laws and practices in India.
AB  - The incidence of cancer increases exponentially with age and a large number of
      cancer patients are the older members of society. In many developing and some
      developed countries, the disease is usually detected at a stage when it is too
      late for aggressive anticancer therapy to have the desired effect. Most cancer
      patients suffer moderate to severe pain during the terminal phase of the disease.
      This pain is unpredictable and produces fear and anxiety in patients and family
      members. Morphine is the gold standard analgesic to control this pain, but its
      availability is restricted. The fear of diversion of morphine for non-medical
      uses has led to severe control on its availability. Studies have shown that
      diversion of medical morphine is not really an issue. This paper describes
      attempts to increase morphine availability through the courts in India. The
      courts have issued directives to improve the availability of the drug, yet 97% of
      Indian patients have very poor access to the drug. There is a need to improve
      access to pain-free end-of-life care. In the absence of morphine, physicians lack
      experience in its use. They need to be educated to provide for their patients a
      pain-free life. Patients and their families need to be educated that cancer need
      not end in a painful death. It is not adequate to be able to manage cancer alone;
      one needs to free the society from fear of cancer.

PMID- 15022949
TI  - Palliative care in Argentina: perspectives from a country in crisis.
AB  - Argentina is a large South American country with a high prevalence of chronic
      disease-related mortality and a clear need for implementation of palliative care.
      Primary concerns related to palliative care are cultural, socio-economic and
      educational. Increasing poverty, patients and families receiving inadequate
      information about their diagnosis or prognosis, drug availability and costs, and
      insufficient knowledge by health care providers are obstacles to palliative care.
      Palliative care programs are developing throughout the country and methods by
      which they are meeting their needs are described. Several Argentinean palliative
      care initiatives are described and the role of the Pallium Latinomerica training
      program is discussed.

PMID- 15022948
TI  - Symptom control and palliative care in Chile.
AB  - As in other developed and developing countries, the most common chronic disorders
      affecting the Chilean population are cardiovascular disease, cancer, cirrhosis,
      diabetes, chronic obstructive pulmo- nary disease and external injuries.
      Availability of oncology services is not extensive and there are no academic
      programs to adequately train practitioners in either palliative medicine or
      comprehensive palliative care for allied health professionals including nurses,
      psychologists and chaplains. Major efforts have been made to incorporate
      palliative care as an important health care focus in the last decade and in the
      development of effective policies for opioid availability. Chile now meets 84% of
      the 17 criteria outlined by the World Health Organization and the International
      Narcotics Control Board for opioid availability. Postgraduate medical education
      in symptom control, clinical use of opioids and end-of-life care remains
      relatively poor as judged by the results of a questionnaire administered to 158
      resident physicians at the Pontificia Universidad Catolica de Chile. Improvements
      in symptom control and the development of palliative care in Chile will depend on
      the effective assessment of symptom control effectiveness and improved education
      and training of health professionals in clinical pharmacology, symptom control,
      clinical ethics, and end-of-life care.

PMID- 15022950
TI  - Palliative care in Saudi Arabia: a brief history.
AB  - The palliative care service started at the King Faisal Specialist Hospital and
      Research Center in Riyadh, Saudi Arabia over a decade ago by Dr. Isbister is
      slowly expanding. Excellent facilities for investigations and curative treatment
      are available in the hospital, and these are useful when supportive facilities
      are needed. Nevertheless, there are problems. Most of the staff is western, and
      this is a hindrance when psychosocial and spiritual support is needed by Saudi
      patients. Patients have poor facilities for follow-up in between outpatient
      visits every month. The team has overcome the problem of poor availability of
      opioids, but these essential drugs are not available to the patients at the
      national level. Educational and research services have begun.

PMID- 15022951
TI  - Pain relief in Thailand.
AB  - Pain is a complex problem, for both those who are enduring it and those trying to
      relieve it. Most people in the developed world have access to adequate treatment
      and management of pain, the availability of trained and educated doctors and
      nurses, feasible opioid prescribing policies, as well as ready access to
      appropriate medication. Often, this is not the case in developing countries such
      as Thailand. This paper is based on recent experience in the southeast of
      Thailand providing pain relief for persons with HIV and AIDS in Rayong Province
      at the Camillian Social Centre. The severity and frequency of pain endured by
      this group of individuals presented a daily challenge. Problems encountered in
      providing pain relief for these patients and some potential solutions are
      described. There is a lack of literature on pain relief in Thailand.

PMID- 15022952
TI  - Pain relief and palliative care in Hong Kong.
AB  - Palliative care started in Hong Kong in 1982. It gradually established an
      increasingly important role in cancer care. Hong Kong is fortunate because
      analgesic drugs and expertise from various disciplines and specialties in pain
      management are readily available. A holistic approach to pain management has been
      adopted; various dimensions of pain are assessed and managed, and outcomes
      evaluated. Despite efforts in public education, patient-related barriers to pain
      management still exist, and it is important that misconceptions of patients be
      corrected. To promote the quality of palliative care and pain management, efforts
      have been made to provide training of healthcare professionals, and on formation
      of professional societies for palliative care doctors and nurses. In Hong Kong,
      palliative medicine achieved medical specialty status in 1998, with a curriculum
      and a structured training program designed for doctors interested in this field.
      Efforts are underway to further improve palliative care and pain management in
      Hong Kong through the formation of consultative teams in general hospitals,
      enhanced liaison with nursing homes, and possibly by redefining the role of
      traditional Chinese medicine in pain management.

PMID- 15022953
TI  - Palliative care in Malaysia: a decade of progress and going strong.
AB  - Palliative care first began in Malaysia in 1991, and since then there has been a
      growing interest in the field and its development both from the government and
      nongovernmental organizations. It is important to recognize the potential
      advantages and disadvantages of palliative care provided by both government and
      private programs to maximize development for the greater benefit of patients. A
      close relationship between these two bodies must be created so that there is
      smooth continuity of service and no overlapping of roles. This article highlights
      some thoughts on how palliative care has developed over the years from the
      perspective of a clinician who is currently working in the government sector and
      cooperating with nongovernmental organizations to develop a palliative care
      network in the region.

PMID- 15022954
TI  - Pain and palliative care for people living with HIV/AIDS in Asia.
AB  - Millions of people living with HIV/AIDS (PLHA) in Asia need access to palliative
      care as part of a comprehensive response to their support needs. There are many
      causes of pain in HIV/AIDS, and its prevalence is as high if not higher than in
      cancer, but it is frequently undertreated. Access to adequate pain relief and
      palliative care is impeded by the barriers which face PLHA in Asia. These include
      few care and support services, lack of recognition and acknowledgement of pain in
      HIV/AIDS by health care professionals, widespread stigma and discrimination
      especially towards vulnerable groups such as injecting drug users, government
      regulatory mechanisms which make access to opioids even more difficult for the
      care services which have developed and a lack of understanding of or advocacy for
      pain relief and palliative care in the literature on HIV/AIDS care and support.
      During the growth of palliative care in Asia, there is opportunity for advocates
      of palliative care and care for PLHA to collaborate to influence national policy.

PMID- 15022955
TI  - Pain relief in the developing world: the experience of hospice Africa-Uganda.
AB  - The need for high quality end-of-life care in the developing world is
      increasingly becoming recognized. One of the core parts of such a service is
      adequate pain control. Poor health care infrastructures and lack of access to
      opioid analgesics are common problems. This makes establishing appropriate,
      sustainable end-of-life care particularly challenging in resource poor settings.
      Hospice Africa-Uganda has ten years of experience in developing such a service.
      This paper discusses some of the challenges encountered and how these have been
      addressed. These include access to opioids, educating of health care workers and
      influencing policy makers. Factors that have been important in making the service
      a success, such as choosing an appropriate model of care, and future directions
      for the organization are discussed.

PMID- 15022956
TI  - Palliative care in India: successes and limitations.
AB  - Palliative care in India is in a relatively early stage of development and
      consequently faces numerous problems. The extent of problems relating to the lack
      of such care is not well described for cancer or nonmalignant diseases. Opioid
      availability is seriously limited. Many inexpensive drugs are not readily
      available and some very expensive drugs are often prescribed, adding to the
      patients' burden. Enormous psychosocial needs often are neglected in busy
      clinics. The government's palliative care policy has not been implemented. There
      are clear needs for improvement in multiple areas that must be addressed as new
      services develop. A system based on outpatient care has proven cost-effective,
      empowering families to care for patients at home. Whenever possible, inpatient
      facility and home visits should be available for those who need them. Some
      measures of quality assurance should develop concurrent with growth of the
      palliative care movement. Successes and problems in the development of palliative
      care in India are discussed.

PMID- 15022957
TI  - Palliative care behind bars: the New Zealand prison hospice experience.
AB  - The provision of palliative care for convicted criminals ignites debate about
      morality and equality. The New Zealand prison population includes a higher
      proportion of smokers, Maori (native New Zealanders), and intravenous drug users
      than is found in the general community; prisoners as a group are therefore at
      greater risk of developing a terminal illness. The sparse literature mostly
      originates from America, which necessitates consideration of the relevance to
      corrections systems in other societies. This paper examines some of the issues
      surrounding the provision of palliative care for prisoners in the New Zealand
      correction system. These issues may challenge some of the basic principles on
      which modern hospice care has been developed.

PMID- 15022958
TI  - Ethical issues in palliative care: considerations.
AB  - Discussions on ethics in palliative care often concentrate on issues like patient
      autonomy or euthanasia. However, the reality in the developing world begs
      discussion on an entirely different set of problems altogether. One should have a
      good death, no doubt, but one should also have an opportunity for a good life.
      Globalization unfortunately seems to worsen many of the burdens of the developing
      world, like the negative influence of the mighty pharmaceutical industry.
      Continuing medical education offered only by the pharmaceutical industry instills
      bias into the minds of most medical professionals. Prescription practices by many
      professionals are influenced by the industry; so much so, inexpensive drugs or
      formulations are abandoned in favor of expensive ones, adding to the burden of a
      much-suffering individual. Palliative care should have been a major force against
      such evils, but it seems to get more clinical and institutionalized with time,
      with the social issues taking a back seat. Unethical research practices and
      preferential treatment in drug availability are practices that continue to
      marginalize the less privileged. Adoption of the dominant ideology from the West
      in the developing world also raises problems like cultural unsuitability.
      Considering that the bulk of the suffering in the world is in poorer countries,
      these issues need to be addressed.

PMID- 15022959
TI  - Spiritual care in a multi-religious context.
AB  - Spiritual care is an essential component of palliative care because spirituality
      is an important part of suffering and the relief of pain and suffering. It is
      especially important in the developing world where medical and comfort resources
      are limited. Spiritual resources in the context of many religions are described.
      Understanding pain from a spiritual perspective and approaches when spiritual
      resources appear ineffective are discussed. The role of spiritual resources in
      end-of-life care are described in the context of taking a spiritual inventory.
      The importance of all palliative care clinicians understanding these concepts is
      emphasized.

PMID- 15022960
TI  - Palliative care in developing countries: why research is needed.
AB  - Contemporary medical knowledge is sufficient to control the suffering of most of
      the millions of terminally patients in the world if applied appropriately.
      However, palliative care is still unavailable to most patients in developing
      countries. Effective models of palliative care delivery that have been tested in
      developed countries seldom apply to the developing world where poverty, extended
      families, and insufficient health infrastructure require the adaptation of such
      care to local cultures and circumstances. Research from developing countries is
      therefore needed to develop, implement, and monitor the delivery of palliative
      care in ways that are feasible in resource-poor settings and acceptable to local
      populations. Palliative care research shares most of the obstacles common to
      health research in the developing world. Additional obstacles include a lack of
      consideration of palliative care as part of cancer control strategies and the low
      political acceptability of such care because it involves the use of opioid
      analgesics. Coordinated research efforts through active networking and common
      protocols would increase the visibility of the discipline, provide answers
      relevant to the local contexts, and assist in expanding palliative care services
      across the developing world.

PMID- 15022961
TI  - Palliative care in Kenya: report of the International Association of Hospice and
      Palliative Care Traveling Fellowship.
AB  - In August and September 2001, Dr. David Allbrook from Perth, Western Australia,
      traveled to Maua Methodist Hospital, North Meru District, Kenya, on an
      International Association for Hospice and Palliative Care Traveling Fellowship.
      The visit of Professor Allbrook provided a valuable opportunity that enabled Dr.
      Dietmar Ziegler, and the staff at Maua Methodist Hospital to put together a
      workable proposal for a sustainable community-based palliative care program.

PMID- 15022962
TI  - Palliative care in Papua New Guinea: report of the International Association of
      Hospice and Palliative Care Traveling Fellowship.
AB  - In June and July 2001, Dr. Nell Muirden traveled from Melbourne, Australia to
      Port Moresby General Hospital and Angau Memorial Hospital located in Lae, in
      Papua New Guinea. This visit was supported through an International Association
      for Hospice and Palliative Care Traveling Fellowship. Dr. Muirden's visit greatly
      increased awareness about cancer pain and the importance of palliative care and
      pain relief in cancer and other terminally ill patients. She developed a
      discussion paper relating to the drugs needed for palliative care and the changes
      that should be made. The Pharmaceutical Advisory Committee subsequently adopted
      these recommendations, which will lead to a better range of medications to treat
      pain becoming available throughout Papua New Guinea.

PMID- 15022963
TI  - Palliative care: an emerging issue for American Indians and Alaskan Natives.
AB  - Over 4 million American Indians and Alaskan Natives live in communities that
      receive health care primarily from the federal Indian Health Service or tribal
      health programs. Palliative care has only recently been formally addressed for
      these communities. An Indian Health Service program introduced the topic and
      several programs are ongoing. Needs for and barriers to palliative care in native
      peoples' communities are discussed and several successful programs at various
      stages of development and implementation are described.

PMID- 15022964
TI  - Palliative care education in the developing countries.
AB  - Individuals who have experience in palliative care in wealthier countries with
      well-structured health systems see the palliative care needs of developing
      countries as forbiddingly huge. They are aware of an increasing incidence of
      cancer, but health delivery systems are often patchy and deficient, medications
      for pain management are not widely available, and cultural considerations limit
      opportunities to face advanced illness and focus on symptom control in terminal
      illness. An increasing prevalence of HIV infection compounds palliative care
      needs. Medical practice focuses on interventions that promise cure and earn a
      good reward, while nursing standards are variable and often unsatisfactory. There
      is a need for demonstrations of good care and effective symptom control, even if
      these reach only a small fraction of the needy population. On such demonstrations
      can be built education programs that take account of local realities, and promote
      attitudes, knowledge and skills capable of gradually introducing a greater
      professional concern and a better prospect of effective care for the dying.

PMID- 15022965
TI  - Cross-cultural perspectives in palliative care.
AB  - Patients with advanced, irreversible disease need palliative care in both
      developing and developed countries. The philosophy of palliative care is
      universal. Despite differences among individuals and cultural groups, basic
      needs, cares, and wants are common to human-kind. For truly effective palliative
      care, cultural subtleties and nuances must be considered. Challenging assumptions
      based on one's own culture is essential to the development of knowledge and
      insight into others. Keeping open minds about what is new or different within
      different cultures where we provide care can extend and intensify quality of
      care. This paper reflects the author's experience as a New Zealand Nurse and of
      her visit to the Pain and Palliative Care Clinic in Calicut, India. This was a
      journey that crossed cultural boundaries and it illustrates the importance of
      building bridges to care.

PMID- 15022966
TI  - The International Observatory on End of Life Care: a new initiative to support
      palliative care development around the world.
AB  - The development of palliative care is proceeding rapidly in some areas of the
      world, but major problems continue to exist in several countries and regions.
      Comparative research evidence to inform palliative care development is limited
      and can be difficult to obtain, especially for resource poor settings.
      International collaboration is needed to promote and disseminate an evidence base
      to support the growth of palliative care. The aims and plans of the newly created
      International Observatory on End of Life Care are described, together with its
      orientation to global partnership and collaboration. The Observatory will build
      on public health models to provide research-based intelligence about palliative
      care around the world, drawing also on cultural, historical and ethical
      perspectives.

PMID- 15022967
TI  - Where do we go from here?

PMID- 15022968
TI  - Resources in The Cochrane Library: issue number 1, 2003.
AB  - The Cochrane Library of systematic reviews is published quarterly. Issue 1 for
      2003 contains 2796 reviews of which 1598 are completed and in full text. Ten of
      those are directly relevant to pain management and palliative care. Annotated
      bibliographies for those nine reviews are provided.

PMID- 15022969
TI  - Pain specialists embrace balanced approach to opioid therapy.

PMID- 15022970
TI  - Loeser address on the decade of pain control and research.

PMID- 15022971
TI  - Pain control in hospitals using patient-controlled analgesia must be made safer.

PMID- 15022972
TI  - Undertreatment of pain litigation.

PMID- 15022973
TI  - The role of estrogens in BRCA1/2 mutation carriers: reflections on the past,
      issues for the future.
AB  - Persons undergoing genetic testing for an inherited predisposition to cancer
      often raise questions about recommendations for follow-up care. Missing from
      current guidelines is consideration of the role of estrogens for BRCA1/BRCA2
      mutation carriers. Potential implications of hormones for risk of cancer and
      effectiveness of risk-reduction strategies need to be considered in the design of
      comprehensive guidelines for high-risk women. Patients who are mutation carriers
      may ask questions about the use of oral contraceptives, hormone replacement, and
      utility of current screening modalities. Controversy exists, even when
      considering these issues for the general population, but become more imperative
      when considering young, unaffected women who carry an inherited genetic mutation
      making decisions that may have long-term health consequences. Many patients have
      considered estrogen ablation via prophylactic surgeries as risk-reduction
      interventions. This article reviews data regarding these issues, makes
      recommendations based on available information, and offers future perspectives
      for those identified at high risk for cancer because of genetic predisposition.
      Although questions remain regarding the potential implications of hormones for
      risk of cancer and effectiveness of risk-reduction strategies, all information
      should be considered when educating and caring for such patients.

PMID- 15022975
TI  - Efficacy of therapeutic group by telephone for women with breast cancer.
AB  - A pilot study was conducted to test the efficacy of a therapeutic group by
      telephone conference call for women with breast cancer. Sixty-six women with
      stage I or stage II breast cancer consented to participate in the study.
      Participants were randomly assigned to a usual psychosocial care or intervention
      group, using a permuted block method. Only 2 of 68 patients dropped out of the
      study, which included 27% African Americans. Assessments at 3 time periods
      (pretest, immediately after the intervention, and 3 months after the group ended)
      included evaluation of quality of life (QOL), mood, and immune function. ttests
      were performed to determine if differences on important variables existed at
      pretest. The intervention group had worse QOL and mood scores than did the
      control group on the pretests. A mixed-model repeated-measures procedure
      controlling for pretest differences was used to analyze data. A significant Group
      by Time interaction was found for spiritual well-being and mood. These
      differences were not in the expected direction. The intervention group showed
      improvement in QOL and mood during the intervention, but showed decompensation
      following the intervention. Conversely, the control group demonstrated stable or
      declining scores. This intervention is feasible and practical for women with
      breast cancer, especially African American participants. The puzzling results
      suggest several areas for future research, including a better conceptual fit with
      outcome measures, increasing dosage, and exploration of the value of emotional
      expression.

PMID- 15022974
TI  - Quality of life among older survivors of breast cancer.
AB  - This study investigated the relation among perceived social support, uncertainty,
      and quality of life in older survivors with breast cancer. Proposed hypotheses
      predicted a significant positive correlation between perceived social support and
      quality of life, and a significant negative correlation between uncertainty and
      quality of life. It also was hypothesized that perceived social support and
      uncertainty, considered together, could explain more quality-of-life variance
      than either variable considered independently. A sample of 103 breast cancer
      survivors older than 50 years completed the Social Support Questionnaire, the
      Mishel Uncertainty in Illness Scale - Community Form, and the Ferrans and Powers
      Quality-of-Life Index - Cancer Version. Data were analyzed using Pearson product
      moment correlation, t tests, analysis of variance, and stepwise multiple
      regression. All the hypotheses were supported. Additional findings showed
      significant positive correlations between age and uncertainty, and between
      support network size and social support. Significant negative correlations were
      found between age and perceived social support, and between age and size of
      support network. Uncertainty increased in the presence of other diseases, which
      were associated with poorer quality of life. The study results underscore the
      importance of social support in reducing illness uncertainty and improving the
      quality of life for older survivors of breast cancer.

PMID- 15022976
TI  - Telephone support for caregivers of patients with cancer.
AB  - Caregivers have complex needs as they care for a loved one with cancer at the end
      of life. The objective of this pilot study was to determine the feasibility of
      conducting a brief telephone intervention, Tele-Care II, for caregivers of
      hospice patients. Guided by Hogan's Model of Bereavement, nurse interventionists
      implemented Tele-Care II via teleconference calls with caregivers. Although 14
      caregivers were recruited for the study, only 5 were able to complete the
      intervention before the patient's death. Those completing the intervention
      experienced decreased depression, despair, and disorganization although the
      patient's condition became more serious. Late enrollment in hospice continues to
      be problematic for patients, family caregivers, and hospice staff because it
      allows little time for completion of interventions with family caregivers before
      the patient's death.

PMID- 15022977
TI  - Cancer fatalism: the state of the science.
AB  - Cancer fatalism--the belief that death is inevitable when cancer is present--has
      been identified as a barrier to participation in cancer screening, detection, and
      treatment. Yet this literature has not been reviewed in a comprehensive and
      systematic manner. Therefore, this literature review addressed (1) philosophical
      and theoretical underpinnings of cancer fatalism; (2) relationships among
      demographic factors, cancer fatalism, and cancer screening; (3) the role of
      cancer fatalism for patients diagnosed with cancer; and (4) intervention
      strategies. Most of the reviewed studies were descriptive or correlational, did
      not have an explicit theoretical framework, had varied definitions of fatalism,
      and reported screening as "intent to screen" or as "past screening behaviors."
      Review of the studies suggests that cancer fatalism develops over time and is
      most frequently reported among medically underserved persons and those with
      limited knowledge of cancer. Cancer fatalism may be modified through culturally
      relevant interventions that incorporate spirituality. Emphasis must be placed on
      recognizing the role of cancer fatalism when planning health promotion
      activities. Future studies should focus on the consistent measurement of cancer
      fatalism and testing intervention strategies.

PMID- 15022978
TI  - Nurses' repeat measurement of chemotherapy symptoms: feasibility, resulting
      information, patient satisfaction.
AB  - The aim of this study was to investigate the feasibility and acceptability of a
      repeated measurement of 5 major side effects (pain, nausea, vomiting, anxiety,
      and fatigue) experienced by patients during an entire course of chemotherapy.
      Forty-nine inpatients receiving intravenous chemotherapy in the Medical Oncology
      Department of the Institut Paoli-Calmettes (Marseilles, France) were included in
      the study. At the study entry and every 12 hours from beginning of chemotherapy
      course, nurses assessed symptoms using Visual Analogic Scales (except for
      vomiting measured in number of episodes). Patients' pretreatment characteristics
      and their degree of satisfaction with nursing assessment were also recorded. The
      mean number of symptom measures was 2.9 in courses of less than 3 days, 5.4 in
      courses of 3 days, and 7.5 in courses of more than 3 days. Symptom patterns
      varied according to length of course. Furthermore, patients' pretreatment
      characteristics (age, sex, marital status, education level, type of cancer) had
      an impact on symptom scores at baseline and during treatment. About 80% of
      patients judged the nursing assessment as not constraining and 55% considered
      that its impact on their care was positive. This study demonstrates that repeated
      measurement of chemotherapy side effects was feasible and provide useful
      information for symptom management that might increase patient treatment
      satisfaction.

PMID- 15022980
TI  - Symptom distress, catastrophic thinking, and hope in nasopharyngeal carcinoma
      patients.
AB  - The purposes of this study were to explore symptom distress, catastrophic
      thinking (catastrophizing) and hope, and factors predicting hope in Taiwanese
      nasopharyngeal carcinoma (NPC) patients within 3 years of receiving radiation
      therapy (RT). Instruments used were the modified Symptom Distress Scale, disease
      catastrophizing scale (modified from Coping Strategies Questionnaire), and
      Herth's Hope Index. Adult NPC patients (N = 115; 33 undergoing RT, 44 who
      completed RT within 1 year, and 38 who completed RT more than 1 year but less
      than 3 years) were recruited from an outpatient RT center in Northern Taiwan.
      Although participants' overall symptom distress was mild to moderate, they scored
      moderate level for several distressful symptoms: dry mouth, fatigue, hearing
      difficulty, loss of appetite, insomnia, and pain. Patients undergoing RT had
      greater symptom distress than subjects in the other 2 groups. Regression analysis
      revealed that catastrophizing was the only predictor of hope. Patients who
      engaged in catastrophizing reported much lower levels of hope. Particular care
      and attention are recommended to help NPC patients deal with the top distressful
      symptoms listed. Nursing interventions to reduce catastrophic thinking and
      enhance hope are discussed.

PMID- 15022979
TI  - Palliation of oral mucositis symptoms in pediatric patients treated with cancer
      chemotherapy.
AB  - This prospective randomized 2-period crossover study aimed at comparing the
      efficacy of 2 oral care protocols differing in the type of mouthwashes:
      chlorhexidine versus benzydamine in alleviating oral mucositis symptoms for
      children undergoing chemotherapy. Forty subjects were randomly allocated to
      receive either chlorhexidine first then benzydamine protocols or benzydamine
      first then chlorhexidine protocols. Each protocol was started on the first day of
      chemotherapy and continued for 21 days. Subjects were evaluated in intervals of 3
      to 4 days using the World Health Organization (WHO) grading for mucositis and 10
      cm visual analogue scale for oral symptoms evaluations. Among 34 evaluable
      subjects, 26% and 48% of them using chlorhexidine and benzydamine had WHO grade
      II mucositis, respectively (P < .05). The results revealed a significant
      difference in mean area under the curve (AUC) of mouth pain (1.35 +/- 2.26 versus
      3.09 +/- 3.21) (P = .05), and a trend of a lessening of mean AUC of difficulty in
      eating/chewing (2.49 +/- 3.74 versus 2.71 +/- 4.1) (P = .82) and swallowing (1.34
      +/- 3.31 versus 1.91 +/- 4.03) (P = .53) for subjects receiving chlorhexidine
      compared to those receiving benzydamine. In conclusion, chlorhexidine may be
      helpful in palliating mucositis symptoms for children in chemotherapy. The
      beneficial effect, however, is small and needs to be confirmed in a larger trial.

PMID- 15022982
TI  - [Suspected severe acute respiratory syndrome (SARS). Observations on radiology].

PMID- 15022981
TI  - Understanding stereotactic radiosurgery for intracranial tumors, seed implants
      for prostate cancer, and intravascular brachytherapy for cardiac restenosis.
AB  - Our 21st century has moved us into a world of technology never imagined. The aim
      of our article is to move oncology nurses beyond the realm of external beam
      radiation therapy. We chose to present 3 modalities of high precision that are
      infiltrating the everyday world of radiation therapy. Stereotactic radiosurgery
      for intracranial brain tumors and brachytherapy for prostate cancer require an
      expanded knowledge base for nursing to deliver excellent patient care. Cardiac
      patients receiving radiation seeds is new in the world of oncology nursing. These
      patients are unique but they are now a part of our world. Expanding our knowledge
      base to include a radiation procedure in cardiac care does bring us beyond the
      world of external beam radiation. Patients often seek information from nurses.
      Having an understanding of the basic principles and techniques will enable
      oncology nurses to educate patients. The purpose of this article is to explain
      the procedure of stereotactic radiosurgery, brachytherapy for prostate cancer,
      and intravascular brachytherapy for cardiac restenosis. Our discussion will
      include selection criteria, potential sides effects and risks, and nursing care.

PMID- 15022983
TI  - [Radiologic appearance of epiploic appendages and their complications].
AB  - A wide spectrum of pathologic processes can involve epiploic appendages, and
      primary epiploic appendagitis is the most frequent. Pathologic processes are
      today more frequently identified with the increased use of radiological
      assessment (ultrasound and computed tomography) of patients presenting with acute
      abdominal pain. Recognition of specific imaging abnormalities of complications
      enables the radiologist to make the diagnosis, thus allowing appropriate
      treatment.

PMID- 15022984
TI  - [Sonographic diagnosis of ovarian tumors: pre-operative Doppler evaluation].
AB  - Pelvic sonography is the gold standard for diagnosis of ovarian masses. Only 2%
      of adnexal masses or malignant or bordeline tumors. Does Doppler US improve the
      diagnostic accuracy of sonography? The purpose of this article is to review
      current data and identify what areas still require further evaluation with
      regards to Doppler characterization of adnexal masses. It has been shown that
      Doppler evaluation of the ovary and cyst or tumor improves the diagnostic
      accuracy of US to differentiate between benign and malignant lesions. Hemodynamic
      data collected from pulsed Doppler imaging and Doppler energy vascular mapping
      have been shown to improve the characterization of malignant lesions. These data
      improve the accuracy of B-mode US combined with clinical evaluation and CA125
      measurement. Nonetheless, the sensitivity and specificity values are between 85
      90%, with few missed malignancies, but several false positive results. Useful
      Doppler data include the resistive index and the central intratumoral location of
      vascular flow. The use of 3D US with computer post-processing as well as
      sonographic contrast agents could provide additional information, but these
      techniques have not yet been validated. All suspicious adnexal lesions should be
      evaluated by an experienced sonographer and include discriminatory parameters to
      distinguish between benign and malignant lesions.

PMID- 15022985
TI  - [MR Colonography].
AB  - MR Colonography is a new non invasive technique for colonic imaging. The first
      studies in man appeared in 1997-1998. MR Colonography requires an endoluminal
      contrast and combines volumetric acquisition with sophisticated image post
      processing referred as virtual endoscopy. New technical developments such as
      fecal tagging were recently introduced. MR Colonography now enters into a phase
      of clinical evaluation. This article describes the available technique as well as
      pitfalls and artifacts with regard to our own experience.

PMID- 15022986
TI  - [Pulmonary hypertension: CT findings in pulmonary veno-occlusive disease].
AB  - PURPOSE: To describe the CT findings of pulmonary veno-occlusive disease.
      MATERIALS AND METHODS: Pre-therapeutic CT of 15 patients suffering from pulmonary
      veno-occlusive disease were retrospectively reviewed. Pathologic evaluation of
      pulmonary veno-occlusive disease was obtained after post mortem examination or
      pulmonary transplantation. CT protocol always included intravenous helical CT and
      high resolution CT. RESULTS: The most frequent CT-findings in pulmonary veno
      occlusive disease were the following: ground glass opacity with poorly defined
      nodular opacities (73%), septal lines (93%), and adenopathy (80%). Pericardial
      (60%) and pleural effusions (27%) were also noted. Other parenchymal findings
      were unusual. CONCLUSION: HRCT must be systematically included in the initial CT
      evaluation of pulmonary hypertension. Combination of poorly defined nodular
      opacities, septal lines, and adenopathy are indicative of pulmonary veno
      occlusive disease.

PMID- 15022987
TI  - [Value of ultrasound detection of post-Mammotome scar for preoperative
      localization of breast microcalcifications].
AB  - PURPOSE: We attempted to find ultrasound scar subsequent to vacuum assisted
      breast biopsy (Mammotome system) previously performed, and to enhance its value
      for preoperative localization. MATERIALS AND METHODS: Our study included 34
      females requiring needle localization prior to surgery. They previously had
      Mammotome core biopsies for clustered microcalcifications. US examination was
      systematically performed before insertion of the metallic marker, in order to
      detect a scar. Identification of the scar allowed ultrasonographic guided
      localization. The accuracy was correlated with histologic findings. RESULTS:
      Ultrasonography detected a scar in 21 of the 34 patients (63%). Among all these
      cases, a perfect correlation could be established between ultrasound target and
      histologic scar revealed by microscopic examination. CONCLUSION: Ultrasound
      detection of scar allows ultrasonographic guidance and can therefore be the only
      alternative in cases of absence or displacement of the marker clip.

PMID- 15022988
TI  - [Color and pulsed Doppler ultrasonography imaging of tubal ectopic pregnancy:
      study of 100 cases].
AB  - OBJECTIVE: To describe the color-Doppler findings and the spectral forms of
      pulsed Doppler in tubal ectopic pregnancies. MATERIALS AND METHODS: A prospective
      study of one hundred patients with tubal ectopic pregnancies was carried out in
      the emergency ward by two operators from January 1993 to March 1999. Following
      transabdominal and/or endovaginal sonography of the pelvis, color Doppler of the
      adnexa and of any suspected latero-uterine abnormal vascularity were studied with
      pulsed Doppler. The diastolic index (D/S) was measured on 4 consecutive
      complexes. RESULTS: Sixty-six peripheral hypervascularizations, 27 irregular
      hypervascularizations and 7 false negatives were found with color Doppler. The
      pulsed Doppler spectrum revealed a low-impedance flow in 47 cases (D/S index > or
      = 0.35) and a high-impedance flow in 46 cases (D/S index < 0.35). The latter
      spectrum was found in 7 cases of tubal rupture with massive hemorrhage and 39
      cases of barely evolutive ectopic pregnancies. CONCLUSION: Color Doppler
      facilitated the diagnosis of small ectopic pregnancies (gestational sac less than
      1 cm and echogenic lesions less than 2 cm in maximum diameter). Our work with
      pulsed Doppler revealed the frequence of high-impedance flow which, in the
      absence of massive hemoperitoneum, strongly suggests a barely evolutive ectopic
      pregnancy.

PMID- 15022989
TI  - [Subdural hematomas in children: role of cerebral and spinal MRI in the diagnosis
      of child abuse].
AB  - PURPOSE: To determine if the presence of multiple subdural hematomas (SH) of
      varying signal intensities at MRI was suggestive of repeated injuries allowing a
      diagnosis of non accidental head injury (NAHI). MATERIAL AND METHODS: We included
      13 patients (9 boys/4 girls; mean age 15.3 weeks) with suspected NAHI and
      bilateral SH. Six patients had MRI during acute admission (first week) and seven
      patients between 10 and 30 days after head trauma (mean 12.6 days). A total of
      8/13 patients had spinal MRI. We assessed the distribution and signal intensity
      of SH, brain, epidural and spinal cord abnormalities. Our findings were compared
      to medico-legal investigations in 7/13 patients to evaluate the correlation
      between the age of SH on MRI and the date of injuries. RESULT: Lesions detected
      included cerebral edema, ischemia, contusions and cranio-cervical axonal injury
      and 2/8 patient had spinal epidural hematomas. Multiple SH with varying signal
      intensities were seen. The commonest location was the frontoparietal areas (100%)
      and suboccipital region (77%). In 5/6 cases, MRI during the acute admission
      revealed multiple and small SH having the same signal intensity. When MRI was
      performed later multiple SH of varying signal intensity were found in 54% of
      cases. We found a good correlation between the age of the SH and the date of
      suspected injuries in all cases. Nevertheless, in 5 patients, other SH of various
      ages were present suggesting rebleeding. CONCLUSION: Our findings confirm the
      value of MRI in the detection of brain and spinal cord lesions and SH of varying
      signal intensities in non accidental head injury. MRI is not able to predict
      whether different signal intensities correspond to spontaneous repeated bleedings
      or repeated injuries. The presence of these lesions without clinical evidence of
      accidental trauma justifies a medico-legal evaluation to confirm the diagnosis of
      child abuse and to protect these patients.

PMID- 15022990
TI  - [Aberrant right subclavian artery aneurysms: CT assessment].
AB  - We report two cases of aneurysm of an aberrant right subclavian artery. Imaging
      findings, diagnostic criteria and evolution patterns of this rare condition are
      reviewed. CT seems to be the best imaging modality to assess these aneurysms. To
      avoid rupture, growing aneurysms should be surgically removed whenever it is
      technically feasible.

PMID- 15022991
TI  - [Long-standing deep venous thrombosis of the femoral vein caused by
      leiomyosarcoma: a case report].
AB  - A case of leiomyosarcoma of the superficial femoral vein detected in the follow
      up of a non resolving deep venous thrombosis is presented. A short review of the
      literature focused on this unusual entity is presented.

PMID- 15022992
TI  - [Cherubism: the value of imaging and preoperative embolization].
AB  - Cherubism is a benign, hereditary, autosomal dominant disease, with variable
      penetrance and expressivity. It presents as a characteristic indolent deformity
      of the lower half of the face, associated with multicystic bone tumors. The
      definitive diagnosis is established by pathology. Radiology contributes greatly
      to its diagnosis (CT or MRI scan), and preoperative arterial embolization can
      provide valuable help to the surgeon when excision of this hemorrhagic lesion is
      necessary. The present article presents a case showing the advantage of this type
      of devascularization prior to surgery, not previously described in the
      literature.

PMID- 15022993
TI  - [Intra-abdominal desmoplastic small round cell tumors: US and CT features].
AB  - Intra-abdominal desmoplastic small round cell tumor is an extremely rare entity
      with poor prognosis. The authors report a case of intra-abdominal desmoplastic
      small round cell tumor and describe the imaging and pathologic features of the
      tumor.

PMID- 15022995
TI  - [Bone Club].

PMID- 15022994
TI  - [Quid? Arterioportal fistula].

PMID- 15022996
TI  - Traumatic dental injuries in Brazilian preschool children.
AB  - The purpose of this study was to determine the prevalence and distribution of
      traumatic injuries to primary anterior teeth in children from zero to 6 years
      old, all attendees in 28 public nursery schools in Canoas (Brazil). A total of
      1545 boys and girls participated in the study. The children were clinically
      examined for signs of trauma according to Andreasen's classification. Traumatic
      injuries were identified in 35.5% of children. The largest percentage of injuries
      was demonstrated by 3-4-year-old child, with no significant difference between
      boys and girls. The maxillary central incisor was the most vulnerable to injury,
      without differences between the right and the left side. Single tooth injury was
      predominant in all age groups. Crown fractures represented 83% of all traumatic
      injuries. Our findings emphasize the importance of encouraging parents to visit
      the dentist with their child at an early stage. Furthermore, parents and
      educators should be advised about prevention of traumatic injuries and actions to
      be taken in case of an accident.

PMID- 15022997
TI  - Etiological factors related to dental injuries in Norwegians aged 7-18 years.
AB  - Prevention of diseases and injuries is a field of priority for the health
      authorities in Norway. In 1990, an interdepartmental project was established in
      order to reduce the number of accidents, including dental injuries. The purpose
      of the present study was to examine the causes of dental injuries, the place of
      event and the possibilities for prevention. During a 1-year period, all new
      trauma episodes affecting children aged 7-18 years were registered by calibrated
      dentists in the public dental health service in the county of Nord-Trondelag and
      in the capital city of Oslo. A distinction was made between school and leisure
      time accidents. The severity of injuries was classified as mild, moderate or
      severe, and the dentists were asked tojudge whether the severe injuries were
      preventable. Nearly half of the 1275 injured individuals (48%) were injured at
      school. Almost half of the leisure time injuries occurred during children's play.
      Sports and traffic accidents were less common. Sports accidents represented only
      8% of the total number of injuries, the same as the number of individuals injured
      by violence. Statistically significant associations were observed between the
      cause of injury and county (P < 0.001) and the cause of injury and age group (P <
      0.001). In total, 4% of all injuries were classified as severe, of which only one
      third were assumed to be preventable. In summary, because of the complexity of
      etiological factors, it is neither easy to prevent dental injuries nor to make
      guidelines on prevention.

PMID- 15022999
TI  - Comparison of bioactive glass, mineral trioxide aggregate, ferric sulfate, and
      formocresol as pulpotomy agents in rat molar.
AB  - Bioactive glass (BAG) is often used as a filler material for repair of dental
      bone defects. Although there is evidence of osteogenic potential of this
      material, it is not clear yet whether the material exhibits potential for
      dentinogenesis. Hence, the aim of the present study was to evaluate BAG as a
      pulpotomy agent and to compare it with three commercially available pulpotomy
      agents such as formocresol (FC), ferric sulfate (FS), and mineral trioxide
      aggregate (MTA). Pulpotomies were performed in 80 maxillary first molars of
      Sprague Dawley rats, and pulp stumps were covered with BAG, FC, FS, and MTA.
      Histologic analysis was performed at 2 weeks and then at 4 weeks after treatment.
      Experimental samples were compared with contra-lateral normal maxillary first
      molars. At 2 weeks, BAG showed inflammatory changes in the pulp. After 4 weeks,
      some samples showed normal pulp histology, with evidence of vasodilation. At 2
      weeks, MTA samples showed some acute inflammatory cells around the material with
      evidence of macrophages in the radicular pulp. Dentine bridge formation with
      normal pulp histology was a consistent finding at 2 and 4 weeks with MTA. Ferric
      sulfate showed moderate inflammation of pulp with widespread necrosis in coronal
      pulp at 2 and 4 weeks. Formocresol showed zones of atrophy, inflammation, and
      fibrosis. Fibrosis was more extensive at 4 weeks with evidence of calcification
      in certain samples. Among the materials tested, MTA performed ideally as a
      pulpotomy agent causing dentine bridge formation while simultaneously maintaining
      normal pulpal histology. It appeared that BAG induced an inflammatory response at
      2 weeks with resolution of inflammation at 4 weeks.

PMID- 15022998
TI  - Sealing evaluation of the cervical base in intracoronal bleaching.
AB  - Discoloration of non-vital teeth is an esthetic deficiency frequently requiring
      bleaching treatment. The purpose of this study was to evaluate in vitro the
      cervical base efficacy in order to prevent or to minimize the leakage along the
      root canal filling and into the dentinal tubules. Thirty-eight extracted single
      root human teeth were used, which were biomechanically prepared, filled, and
      divided into three experimental groups: G1, a cervical base was applied (3 mm of
      thickness) below the cemento-enamel junction, with resin-modified glass-ionomer
      cement (Vitremer); G2, the base was done with glass-ionomer cement (Vidrion R);
      and G3 (Control), did not receive any material as base. A mixture of sodium
      perborate and hydrogen peroxide 30% was placed inside the pulp chamber for 3
      days, and the access opening was sealed with Cimpat. This procedure was repeated
      thrice. Soon after this, a paste of calcium hydroxide was inserted into the pulp
      chamber for 14 days. All teeth were covered with two layers of sticky wax, except
      the access opening, and immersed in blue India Ink for 5 days. The results did
      not show statistically significant differences between the three groups
      concerning the leakage inside the dentinal tubules. Regarding the apical
      direction, a statistical difference (ANOVA P < 0.05) was observed among the
      experimental group G1 and control group G3. No statistically significant
      difference was observed between G2 and G3 groups. Therefore, the placement of a
      cervical base before internal bleaching procedures is still recommended.

PMID- 15023000
TI  - Intentional replantation with 180 degrees rotation of a crown-root fracture: a
      case report.
AB  - Crown root fractures are frequently difficult to treat and have a bad prognosis.
      To restore the biological space, intentional replantation can be chosen when
      osteotomy/osteoplasty and dental traction are not viable. Intentional
      replantation with tooth rotation consists of extraction, 180 degrees rotation and
      replantation, thus restoring the biological space. After treatment of
      inflammatory resorption with calcium hydroxide, endodontic treatment was
      completed. The patient was followed up with clinical examination (mobility test,
      gingival sulcus depth) and radiographic analysis (to analyze root resorption:
      inflammatory and/or substitution, and the integrity of the alveolar cortex and
      the periodontal space) for 3 years and there were no signs of resorption.

PMID- 15023001
TI  - Review manuscripts submitted for potential publication in the journal.

PMID- 15023002
TI  - Vocal cord dysfunction.

PMID- 15023003
TI  - Management of swimming-induced pulmonary edema.

PMID- 15023006
TI  - Exercise during pregnancy: what do we really know?

PMID- 15023007
TI  - Confidential reproductive care for adolescents.

PMID- 15023008
TI  - Food insecurity in the United States: its effect on our patients.

PMID- 15023009
TI  - An approach to interpreting spirometry.
AB  - Spirometry is a powerful tool that can be used to detect, follow, and manage
      patients with lung disorders. Technology advancements have made spirometry much
      more reliable and relatively simple to incorporate into a routine office visit.
      However, interpreting spirometry results can be challenging because the quality
      of the test is largely dependent on patient effort and cooperation, and the
      interpreter's knowledge of appropriate reference values. A simplified and
      stepwise method is key to interpreting spirometry. The first step is determining
      the validity of the test. Next, the determination of an obstructive or
      restrictive ventilatory patten is made. If a ventilatory pattern is identified,
      its severity is graded. In some patients, additional tests such as static lung
      volumes, diffusing capacity of the lung for carbon monoxide, and bronchodilator
      challenge testing are needed. These tests can further define lung processes but
      require more sophisticated equipment and expertise available only in a pulmonary
      function laboratory.

PMID- 15023010
TI  - Palmoplantar hyperhidrosis: a therapeutic challenge.
AB  - Excessive sweating from the palms and soles, known as palmoplantar hyperhidrosis,
      affects both children and adults. Diagnosis of this potentially embarrassing and
      socially disabling condition is based on the patient's history and visible signs
      of sweating. The condition usually is idiopathic. Treatment remains a challenge:
      options include topical and systemic agents, iontophoresis, and botulinum toxin
      type A injections, with surgical sympathectomy as a last resort. None of the
      treatments is without limitations or associated complications. Topical aluminum
      chloride hexahydrate therapy and iontophoresis are simple, safe, and inexpensive
      therapies; however, continuous application is required because results are often
      short-lived, and they may be insufficient. Systemic agents such as
      anticholinergic drugs are tolerated poorly at the dosages required for efficacy
      and usually are not an option because of their associated toxicity. While
      botulinum toxin can be used in treatment-resistant cases, numerous painful
      injections are required, and effects are limited to a few months. Surgical
      sympathectomy should be reserved for the most severe cases and should be
      performed only after all other treatments have failed. Although the safety and
      reliability of treatments for palmoplantar hyperhidrosis have improved
      dramatically, side effects and compensatory sweating are still common,
      potentially severe problems.

PMID- 15023011
TI  - Information from your family doctor. Sweaty hands and feet.

PMID- 15023012
TI  - Urticaria and angioedema: a practical approach.
AB  - Urticaria (i.e., pruritic, raised wheals) and angioedema (i.e., deep
      mucocutaneous swelling) occur in up to 25 percent of the U.S. population.
      Vasoactive mediators released from mast cells and basophils produce the classic
      wheal and flare reaction. Diagnosis can be challenging, especially if symptoms
      are chronic or minimally responsive to therapy. A thorough medical history,
      physical examination, and methodical investigation are necessary to uncover
      diagnostic clues. Although serious medical illness can occur concurrently with
      chronic urticaria, acute urticaria generally is benign and self-limited. The
      mainstay of therapy for urticaria is avoidance of known triggering agents,
      judicious use of oral corticosteroids, and treatment with long-acting second
      generation antihistamines, H2-receptor antagonists, tricyclic antidepressants,
      and anti-inflammatory leukotriene antagonists. Consultation for investigative
      therapy may be necessary if symptoms continue despite a stepwise approach to
      diagnosis and therapy.

PMID- 15023013
TI  - Gastric cancer: diagnosis and treatment options.
AB  - Although the overall incidence of gastric cancer has steadily declined in the
      United States, it is estimated that more than 12,000 persons died from gastric
      cancer in 2003. The incidence of distal stomach tumors has greatly declined, but
      reported cases of proximal gastric carcinomas, including tumors at the
      gastroesophageal junction, have increased. Early diagnosis of gastric cancer is
      difficult because most patients are asymptomatic in the early stage. Weight loss
      and abdominal pain often are late signs of tumor progression. Chronic atrophic
      gastritis, Helicobacter pylori infection, smoking, heavy alcohol use, and several
      dietary factors have been linked to increased risks for gastric cancer.
      Esophagogastroduodenoscopy is the preferred diagnostic modality for evaluation of
      patients in whom stomach cancer is suspected. Accurate staging of gastric wall
      invasion and lymph node involvement is important for determining prognosis and
      appropriate treatment. Endoscopic ultrasonography, in combination with computed
      tomographic scanning and operative lymph node dissection, may be involved in
      staging the tumor. Treatment with surgery alone offers a high rate of failure.
      Chemotherapy and radiotherapy have not improved survival rates when used as
      single modalities, but combined therapy has shown some promise. Primary
      prevention, by control of modifiable risk factors and increased surveillance of
      persons at increased risk, is important in decreasing morbidity and mortality.

PMID- 15023014
TI  - Information from your family doctor. What should I know about stomach cancer?

PMID- 15023015
TI  - Obstructive sleep apnea in children.
AB  - Obstructive sleep-disordered breathing is common in children. From 3 percent to
      12 percent of children snore, while obstructive sleep apnea syndrome affects 1
      percent to 10 percent of children. The majority of these children have mild
      symptoms, and many outgrow the condition. Consequences of untreated obstructive
      sleep apnea include failure to thrive, enuresis, attention-deficit disorder,
      behavior problems, poor academic performance, and cardiopulmonary disease. The
      most common etiology of obstructive sleep apnea is adenotonsillar hypertrophy.
      Clinical diagnosis of obstructive sleep apnea is reliable; however, the gold
      standard evaluation is overnight polysomnography. Treatment includes the use of
      continuous positive airway pressure and weight loss in obese children. These
      alternatives are tolerated poorly in children and rarely are considered primary
      therapy. Adenotonsillectomy is curative in most patients. Children with
      craniofacial syndromes, neuromuscular diseases, medical comorbidities, or severe
      obstructive sleep apnea, and those younger than three years are at increased risk
      of developing postoperative complications and should be monitored overnight in
      the hospital.

PMID- 15023016
TI  - Information from your family doctor. Sleep apnea in children.

PMID- 15023018
TI  - Practical selection of antiemetics.
AB  - An understanding of the pathophysiology of nausea and the mechanisms of
      antiemetics can help family physicians improve the cost-effectiveness and
      efficacy of therapy. Nausea and vomiting are mediated primarily by visceral
      stimulation through dopamine and serotonin, by vestibular and central nervous
      system causes through histamine and acetylcholine, and by chemoreceptor trigger
      zone stimulation through dopamine and serotonin. Treatment is directed at these
      pathways. Antihistamines and anticholinergic agents are most effective in
      patients with nausea resulting from vestibular and central nervous system causes.
      Dopamine antagonists block dopamine in the intestines and chemoreceptor trigger
      zone; indications for these agents are similar to those for serotonin
      antagonists. Serotonin antagonists block serotonin in the intestines and
      chemoreceptor trigger zone, and are most effective for treating gastrointestinal
      irritation and postoperative nausea and vomiting. Complementary and alternative
      therapies, such as ginger, acupressure, and vitamin B6, have variable
      effectiveness in the treatment of pregnancy-induced nausea.

PMID- 15023019
TI  - Information from your family doctor. Nausea and vomiting.

PMID- 15023017
TI  - Common intestinal parasites.
AB  - Intestinal parasites cause significant morbidity and mortality. Diseases caused
      by Enterobius vermicularis, Giardia lamblia, Ancylostoma duodenale, Necator
      americanus, and Entamoeba histolytica occur in the United States. E.
      vermicularis, or pinworm, causes irritation and sleep disturbances. Diagnosis can
      be made using the "cellophane tape test." Treatment includes mebendazole and
      household sanitation. Giardia causes nausea, vomiting, malabsorption, diarrhea,
      and weight loss. Stool ova and parasite studies are diagnostic. Treatment
      includes metronidazole. Sewage treatment, proper handwashing, and consumption of
      bottled water can be preventive. A. duodenale and N. americanus are hookworms
      that cause blood loss, anemia, pica, and wasting. Finding eggs in the feces is
      diagnostic. Treatments include albendazole, mebendazole, pyrantel pamoate, iron
      supplementation, and blood transfusion. Preventive measures include wearing shoes
      and treating sewage. E. histolytica can cause intestinal ulcerations, bloody
      diarrhea, weight loss, fever, gastrointestinal obstruction, and peritonitis.
      Amebas can cause abscesses in the liver that may rupture into the pleural space,
      peritoneum, or pericardium. Stool and serologic assays, biopsy, barium studies,
      and liver imaging have diagnostic merit. Therapy includes luminal and tissue
      amebicides to attack both life-cycle stages. Metronidazole, chloroquine, and
      aspiration are treatments for liver abscess. Careful sanitation and use of peeled
      foods and bottled water are preventive.

PMID- 15023021
TI  - Screening for gestational diabetes mellitus.

PMID- 15023022
TI  - Tongue bump.

PMID- 15023023
TI  - Information from your family doctor. Chronic pain medicines.

PMID- 15023024
TI  - Information from your family doctor. Pain relievers: understanding your options.

PMID- 15023025
TI  - Information from your family doctor. Exercise for the elderly.

PMID- 15023026
TI  - Information from your family doctor. Osteoporosis.

PMID- 15023027
TI  - Information from your family doctor. Osteoarthritis: how to stay active.

PMID- 15023028
TI  - Information from your family doctor. Deaf or hard-of-hearing: tips to share with
      your doctor.

PMID- 15023029
TI  - Information from your family doctor. Falls: how to lower your risk.

PMID- 15023030
TI  - ACC/AHA and ASNC release guidelines for the clinical use of cardiac radionuclide
      imaging.

PMID- 15023031
TI  - ACOG releases report on dystocia and augmentation of labor.

PMID- 15023032
TI  - Cutting back on high-dosage narcotics.

PMID- 15023033
TI  - Obstacles to reducing cervical cancer in Vietnam.

PMID- 15023034
TI  - Papanicolaou screening in developing countries: an idea whose time has come.
AB  - Cervical cancer is the leading cause of cancer-related death among women in
      developing countries. Although progress is optional in all settings, Papanicolaou
      screening is feasible anywhere that cervical screening is appropriate and should
      be implemented without further delay in high-risk communities with access to
      curative treatment services. Successful prophylactic cervical cancer vaccines,
      prospects for which remain uncertain, will not eliminate requirements for
      cervical screening. The feasibility of human papillomavirus test analysis has not
      been demonstrated in low-resource developing country settings. Because past
      failures of cervical screening in developing countries are attributable to
      failures in programmatic quality rather than to technological limitations of the
      screening test, a shift in paradigmatic focus from technology toward quality is
      mandatory. Because visual screening techniques coupled with immediate ablative
      treatment are rendered obsolete by an embedded quality-control paradox, a
      moratorium should be placed on all such programs. Considerable opportunity costs,
      borne by the underserved, are associated with prioritizing research of novel
      interventions in developing countries when satisfactory interventions already
      exist.

PMID- 15023035
TI  - The canals of hering might represent a target of methotrexate hepatic toxicity.
AB  - Methotrexate treatment for psoriasis is known to cause hepatic fibrosis in some
      patients, which might progress to cirrhosis. The fine, radiating, fibrous septa
      developing in this setting have a distribution that is reminiscent of the
      location of the canals of Hering (coH). To assess the possibility of fibrous
      obliteration of the coH in patients receiving methotrexate, we developed a
      staining technique by combining an immunohistochemical stain for cytokeratin 7
      with a modified Masson trichrome. Sixteen biopsy specimens from 7 patients were
      evaluated. The biopsies had a variety of histologic changes, including steatosis,
      anisonucleosis, multinucleation, chronic inflammation, bile duct damage, and
      ductular reaction. Fibrosis was present in 13 biopsy specimens (81%) and was mild
      in 7, moderate in 3, and severe in 3 specimens. Compared with normal (control)
      liver specimens, biopsy specimensfrom patients receiving methotrexate had
      decreased numbers of coH (1.9 +/- 0.8 vs 5.2 +/- 1.7; P < .025). In specimens
      with moderate or severe fibrosis, fibrous septa sometimes extended along the coH.
      These findings suggest that scarring of the coH might be a consequence of the
      toxic effects of methotrexate.

PMID- 15023036
TI  - Human herpesvirus 8 immunostaining: a sensitive and specific method for
      diagnosing Kaposi sarcoma in paraffin-embedded sections.
AB  - Human herpesvirus 8 (HHV-8) is recognized as a major causal agent of Kaposi
      sarcoma (KS), and it has been detected in all epidemiologic variants of KS. Until
      now, detection of HHV-8 in paraffin-embedded sections was done mostly by using
      reverse transcriptase-polymerase chain reaction. To assess the sensitivity and
      specificity of an anti-HHV-8 antibody and its potential usefulness for separating
      KS from its mimickers, we immunostained 72 KS samples and 108 samples of
      potential mimickers of KS with the monoclonal antibody latent nuclear antigen-1
      (LNA-1; Advanced Biotechnologies, Columbia, MD). Cases of KS included all
      epidemiologic variants of the disease. Non-KS lesions included 34 angiosarcomas,
      4 kaposiform hemangioendotheliomas, and 70 various benign vascular lesions.
      Immunostaining for CD31, CD34, and/or von Willebrand factor (factor VIII) also
      were performed in all cases. All but 1 case of KS (sensitivity, 99%) and none of
      the non-KS lesions (specificity, 100%) stained with the LNA-1 anti-HHV-8
      antibody. The LNA-1 anti-HHV-8 antibody is a reliable marker of all variants of
      KS. Because KS mimickers are consistently negative for this marker, its use for
      diagnostic purposes is recommended.

PMID- 15023037
TI  - Immunostaining for human herpesvirus 8 latent nuclear antigen-1 helps distinguish
      Kaposi sarcoma from its mimickers.
AB  - We assessed the usefulness of a mouse monoclonal antibody (13B10) against human
      herpesvirus 8 (HHV-8) latent nuclear antigen-1 (LNA-1) in diagnosis of Kaposi
      sarcoma (KS) and for distinguishing it from various mimickers by studying 50
      cases of KS and 53 mimickers (angiosarcoma, 15; kaposiform hemangioendothelioma,
      6; spindle cell hemangioma, 3; reactive angioendotheliomatosis, 3; bacillary
      angiomatosis, 4; acroangiomatous dematitis, 2; microvenular hemangioma, 2;
      hobnail hemangioma, 2; pyogenic granuloma, 5; dermatofibroma, 8; arteriovenous
      hemangioma, 1; verrucous hemangioma, 1; nonspecific vascular proliferation, 1)
      from patients with or without acquired HIV infection. Immunohistochemical
      staining was performed on formalin-fixed, paraffin-embedded tissue sections. All
      50 cases of KS were positive for HHV-8 LNA-1, with immunolocalization in the
      nuclei of the spindle cells and cells lining the primitive and thin-walled
      vascular channels, whereas all 53 mimickers (including 4 lesions from HIV
      positive patients) tested negative. The results idicate that positive
      immunostaining for HHV-8 LNA- 1 exhibits high sensitivity and specificity for the
      diagnosis of KS and is, thus, useful for distinguishing it from the mimickers.

PMID- 15023038
TI  - Cytoplasmic immunoreactivity for thyroid transcription factor-1 in hepatocellular
      carcinoma: a comparative immunohistochemical analysis of four commercial
      antibodies using a tissue array technique.
AB  - To evaluate the consistency of cytoplasmic immunoreactivity in hepatocellular
      carcinoma (HCC), we performed immunohistochemical stains for 4 commercial anti
      thyroid transcription factor (TTF)-1 antibodies (DAKO, Zymed, Novocastra, Santa
      Cruz Biotechnology [see text]) on 77 HCCs and 334 nonhepatic epithelial tumors.
      The HCC cases were submitted for hepatocvte antigen immunohistochemical stain.
      Heat-induced epitope retrieval (HIER) methods were used: with DAKO Target
      Retrieval Solution, the positive rates of cytoplasmic TTF-1 in HCC for DAKO,
      Zymed, Santa Cruz, and Novocastra antibodies were 58% (45), 14% (11), 6% (5), and
      0% (0), respectively; with EDTA buffer, the positive rates increased to 70% (54),
      40% (31), 69% (53), and 0% (0), respectively. Immunoreactivity for the DAKO anti
      TTF-1 antibody generally correlated with that for hepatocyte antigen. Among
      nonhepatic tumors, 2 of 6 ovarian mucinous carcinomas and 2 of 11 pancreatic
      adenocarcinomas showed cytoplasmic reactivity for the DAKO antibody; 28 cases
      showed nonspecific cytoplasmic staining for the Santa Cruz antibody with EDTA
      HIER. Zymed and Novocastra antibodies did not produce cytoplasmic staining in
      nonhepatic tumors. Owing to the staining variation, we do not consider TTF-1 a
      reliable marker to distinguish HCC. In general, the Novocastra antibody with EDTA
      HIER is superior for its consistent nuclear positivity and absence of erratic
      cytoplasmic staining.

PMID- 15023039
TI  - Differential expression of cytokeratins 7 and 20 and thyroid transcription factor
      1 in bronchioloalveolar carcinoma: an immunohistochemical study in fine-needle
      aspiration biopsy specimens.
AB  - We studied the staining patterns of bronchioloalveolar carcinoma (BAC) with
      antibodies to cytokeratin (CK) 7, CK20, and thyroid transcription factor-1 (TTF
      1) to determine the diagnostic usefulness of this panel in differentiating BAC
      from metastatic adenocarcinoma in material obtained by fine-needle aspiration
      biopsy (FNAB) of the lung. We identified 16 cases of BAC. Of these, 6 were
      mucinous, 4 were nonmucinous, and 6 were mixed with focal mucinous
      differentiation. Immunohistochemical analysis with antibodies to CK7, CK20, and
      TTF-1 was performed on cell-block sections. Of the 6 mucinous BACs, 4 (67%) were
      CK7+, CK20+, and TTF-1-. All 4 nonmucinous BACs were CK7+ and CK20-, and 2 (50%)
      were TTF-1+. All 6 mixed BACs were diffusely positive for CK7 and focally
      positive for CK20; 5 (83%) were TTF-1+. Nonmucinous BACs display CK7, CK20, and
      TTF-1 immunoreactivity similar to conventional pulmonary adenocarcinoma. Mucinous
      and mixed BACs have an immunohistochemical phenotype that is different from that
      of conventional pulmonary adenocarcinoma. Knowledge of these staining patterns is
      crucial for distinguishing mucinous and mixed BACs from metastatic adenocarcinoma
      involving the lungs.

PMID- 15023040
TI  - Prognostic significance of DNA ploidy and proliferative index (MIB-1 index) in
      childhood rhabdomyosarcoma.
AB  - The prognostic value of DNA ploidy and proliferative index (PI) are well
      established in many cancers, but their significance in childhood rhabdomyosarcoma
      (RMS) is unclear. We studied the DNA content and PI of 45 cases of childhood RMS
      obtained retrospectively. DNA histograms were hyperdiploid in 30 cases (67%),
      diploid in 6 (13%), tetraploid in 5 (11%), polyploid in 3 (7%), and
      nonclassifiable in 1 (2%). The 5-year overall survival rate by ploidy was 60%
      (3/5) in tetraploid, 57% (17/30) in hyperdiploid, and 0% in diploid and polyploid
      cases (P = .000002). The 5-year overall survival by a PI less than or greater
      than 19% was 62% (13/21) and 21% (5/24), respectively (P = .006). In multivariate
      analysis, DNA ploidy (P = .001) was an important independent prognostic factor.
      DNA content in childhood RMS is an important variable in predicting prognosis.
      DNA hyperdiploid and tetraploid rhabdomyosarcomas had a favorable prognosis,
      while DNA diploid and polyploid tumors had a poor prognosis.

PMID- 15023041
TI  - Flow cytometric analysis of CD5+ B cells: a frame of reference for minimal
      residual disease analysis in chronic lymphocytic leukemia.
AB  - Recent reports suggest that CD5+ B cells constitute up to 47% of the total B
      cells in normal peripheral blood (PB), a finding that would restrict the
      sensitivity of the CD5/CD19 flow cytometric assay for minimal residual disease
      (MRD) analysis in chronic lymphocytic leukemia (CLL). We studied 40 normal
      samples (PB, 20; bone marrow [BM], 20) using CD5-fluorescein isothiocyanate
      (FITC)/CD19-phycoerythrin (PE) immunostaining to evaluate the reference range of
      CD5+ B cells. The mean percentage of CD5+ B cells per total number of B cells was
      12.2% (range, 3.6%-23.9%) in PB and 11.7% (range, 4.4%-19.5%) in BM. On serial
      dilution, this assay could detect 1 CLL cell in 1,000 leukocytes (sensitivity, 0.
      1%). A distinct "bright" CD5+ B-cell subpopulation, consistent with a CLL-like
      phenotype, was observed in 3 samples. Our results suggest that the CD5-FITC/CD19
      PE assay has a clinically useful sensitivity for MRD analysis in CLL. The
      usefulness of this assay as a screening tool to identify the earliest stage of
      indolent CLL needs further study.

PMID- 15023042
TI  - Flow cytometric assessment of TCR-Vbeta expression in the evaluation of
      peripheral blood involvement by T-cell lymphoproliferative disorders: a
      comparison with conventional T-cell immunophenotyping and molecular genetic
      techniques.
AB  - Molecular genetic T-cell receptor (TCR) and flow cytometric analysis using
      antibodies to conventional T-cell antigens and TCR beta-chain variable region
      families (TCR-Vbeta) were performed in 65 peripheral blood specimens evaluated
      for potential involvement by a T-cell lymphoproliferative disorder (TCLPD). A
      normal or reactive conventional T-cell immunophenotype was present in 36 cases;
      TCR-Vbeta flow cytometric and molecular TCR analyses were negative for clonality
      in 32 and 27 of these cases, respectively. In the remaining normal and reactive
      cases, one or both methods seemed to detect dominant cell populations in settings
      with limited T-cell diversity. We identified 29 TCLPDs; all studied cases had
      clonal molecular TCR results; 23 TCLPDs had clonal TCR-Vbeta flow cytometric
      results; the remaining were suggestive of (n = 3) or negative (n = 3) for
      clonality. TCR-Vbeta flow cytometric analysis is a powerful clinical laboratory
      tool that can be used to aid in the rapid diagnosis of peripheral blood
      involvement by T-cell malignant neoplasms.

PMID- 15023044
TI  - Changing pattern of AIDS: a bone marrow study.
AB  - We compared bone marrow findings in 2 groups of patients with AIDS during 2
      different periods: group 1, n = 20; male/female ratio, 19/1; and group 2, n =
      120; male/female ratio, 6/1. Bone marrow iron stores were decreased significantly
      in group 2 (P < .01), and the incidence of AIDS-related lymphomas was higher,
      with frequent bone marrow involvement. Two group 1 patients had Kaposi sarcoma,
      and a 21-month-old girl with transfusion-transmitted AIDS had Burkitt-like
      lymphoma. In group 2, 44 patients had a history of malignant neoplasms, including
      Kaposi sarcoma (10 cases), hematologic neoplasms (33 cases), and metastatic
      leiomyosarcoma (1 case). Of the 120 patients, 15 (12.5%) had bone marrow
      involvement by malignant neoplasms. The majority of the non-Hodgkin lymphomas
      were high-grade lymphomas. Patients with AIDS-related malignant neoplasms had
      higher CD4+ cell counts and viral loads than patients without malignant neoplasms
      (P < .01, P < .05, respectively). The finding of decreased iron stores in
      patients with AIDS might aid clinical management of their anemia. The increased
      incidence of malignant neoplasms, especially lymphomas, in recent years might be
      related to prolonged survival but with incomplete reconstitution of immune
      function after antiretroviral therapy.

PMID- 15023043
TI  - Comparative immunohistochemical analysis of pediatric Burkitt lymphoma and
      diffuse large B-cell lymphoma.
AB  - Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) account for
      nearly all pediatric nonlymphoblastic B-cell lymphomas. Because clinical
      behavior, prognosis, and response to therapy might differ, diagnostic accuracy is
      important. Morphologic examination often is sufficient, but occasionally,
      diagnostic ancillary studies are required. In adults, immunophenotyping is
      useful; however, pediatric data are limited. We characterized the
      immunohistochemical expression of 6 proteins (c-myc, CD10, bcl-6, bcl-2, CD138,
      and MIB-1) in pediatric BL (33 cases) and DLBCL (20 cases) with classic
      morphologic features. Significant differences in c-myc (BL, 30/33 [91%] vs DLBCL,
      5/20 [25%]; P < .0001), bcl-2 (BL, 1/25 [4%] vs DLBCL, 7/19 [37%]; P < .02), and
      mean MIB-1 (BL, 99% vs DLBCL, 56%; P < .0001) expression were observed. There
      were no significant differences for CD10 (100% expression in BL and DLBCL), bcl-6
      (BL, 23/33 [70%] vs DLBCL, 15/20 [75%]), or CD138 (no expression). Thus,
      pediatric BL and DLBCL have distinctive immunohistochemical profiles, and
      staining for c-myc, MIB-1, and bcl-2 might be useful in morphologically difficult
      cases.

PMID- 15023045
TI  - Expression of CD2 in acute promyelocytic leukemia correlates with short form of
      PML-RARalpha transcripts and poorer prognosis.
AB  - We studied the immunophenotype of 100 cases of acute promyelocytic leukemia (APL)
      with cytogenetic evidence of t(15;17)(q22;q21), 72 hypergranular (M3) and 28
      microgranular (M3v), and correlated the results with molecular and clinical
      features. Most neoplasms (75/100 [75%]) had a typical immunophenotype:
      CD13+CD33+CD34-HLA-DR-. CD64, CD2, CD34, and HLA-DR were expressed in 27%
      (24/88), 23% (22/94), 21% (21/100), and 9% (9/98), respectively. CD34 expression
      was restricted to M3v; HLA-DR and CD2 were expressed more often in M3v than in M3
      (P < .001). PML-RARalpha fusion transcripts were detected by reverse
      transcriptase-polymerase chain reaction in all 70 patients assessed. The short
      form of PML-RARalpha transcripts was found more frequently in M3v (P < .002) and
      CD2+ APL (P < .0001) than in M3 and CD2- APL, respectively. The median follow-up
      was 128 weeks. CD2+ APL was associated significantly with leukocytosis (P =
      .004), shorter complete remission duration (P = .03), and a trend toward shorter
      overall survival (P = .07) than CD2- APL. Overall survival for M3v vs M3 (P =
      .68) and short vs long transcripts (P = .21) was not significantly different.
      Immunophenotyping is useful for predicting the biologic and clinical behavior of
      APL.

PMID- 15023046
TI  - Clinicopathologic analysis of 22 cases of subcutaneous panniculitis-like CD56- or
      CD56+ lymphoma and review of 44 other reported cases.
AB  - In 22 histologic cases of subcutaneous panniculitis-like lymphoma, we studied the
      clinicopathologic differences between CD56- and CD56+ cases (11 each). CD56-
      cases had skin ulcers (1 [9%]); tumor invasion in the superficial dermis (1
      [9%]); erythrophagocytosis (10 [91%]); and medium-sized (11 [100%]), CD8+ (10
      [91%]), T-cell receptor (TcR)betaF1+ (10 [91%]), and CD95 (Fas)- tumor cells.
      CD56+ cases had skin ulcers (9 [82%]); tumor invasion in the superficial dermis
      (8 [73%]); erythrophagocytosis (1 [9%]); and pleomorphic large (10 [91%]), CD8+
      (2/10 [20%]), TcRbetaF1 + (3/10 [30%]), and CD95 (Fas)+ (7/10 [70%]) tumor cells.
      These 7 factors were significantly different between groups (P < .01). Median
      survival rates were 96 and 12 months for the CD56- and CD56+ groups,
      respectively. Age younger than 40 years, no skin ulcers, no tumor invasion in the
      superficial dermis, and CD8+, TcRbetaF1 +, CD95 (Fas)-, and CD56- tumor cells
      were significantly better prognostic factors (P < .01). The CD56- and CD56+
      groups showed different tumor cell characteristics, clinicopathologic findings,
      and prognosis. In the CD56+ group, 1 was gamma/delta T-cell phenotype, 3 were
      alpha/beta T-cell, and 6 were TcRbetaF1- and gamma/delta- NK/T-cell, and 3 NK/T
      cell cases had nuclear signals of Epstein-Barr virus-encoded RNA. Cases of CD56+
      T- and NK/T-cell lymphoma had similar clinicopathologic findings and prognosis.

PMID- 15023047
TI  - Interference of carbamazepine and carbamazepine 10,11-epoxide in the fluorescence
      polarization immunoassay for tricyclic antidepressants: estimation of the true
      tricyclic antidepressant concentration in the presence of carbamazepine using a
      mathematical model.
AB  - We evaluated effects of carbamazepine and its metabolite, carbamazepine 10,11
      epoxide, on the measurement of tricyclic antidepressant (TCA) concentrations in
      serum using the fluorescence polarization immunoassay (FPIA). We determined
      apparent TCA concentrations in 30 patients who were receiving carbamazepine but
      no TCAs. Carbamazepine concentrations ranged from 1.4 to 20.9 microg/mL (5.9-88.4
      micromol/L); the observed apparent TCA concentrations ranged from 31.8 to 130.1
      ng/mL (113.4-463.9 micromol/L). When aliquots of the drug-free serum pool were
      supplemented with known concentrations of carbamazepine or its metabolite, we
      observed significant apparent TCA concentrations using the FPIA; however,
      interference of carbamazepine was more than 3-fold more than its metabolite. When
      serum pools prepared from patients receiving TCA but no anticonvulsant
      medications were supplemented with known amounts of carbamazepine or its
      metabolite, we observed falsely elevated TCA concentrations. We formulated an
      equation to calculate the apparent TCA concentration from known carbamazepine
      concentrations. If carbamazepine and TCAs are present in a specimen, the true TCA
      concentration can be estimated by subtracting the calculated TCA concentration
      (due to carbamazepine) from the observed TCA concentration as measured by the TCA
      FPIA. This mathematical modeling is feasible because TCAs, even at very high
      concentrations, showed no interference with the carbamazepine FPIA.

PMID- 15023049
TI  - You can be an ASCP advocate.

PMID- 15023048
TI  - Oxidized low-density lipoprotein/beta2-glycoprotein I complexes and
      autoantibodies to oxLig-1/beta2-glycoprotein I in patients with systemic lupus
      erythematosus and antiphospholipid syndrome.
AB  - Oxidized low-density lipoprotein (oxLDL) interacts with beta2-glycoprotein I
      (beta2-GPI) via oxLDL-derived specific ligands (oxLig-1) forming complexes. The
      prevalence and significance of oxLDL/alpha2-GPI complexes and antibodies to oxLig
      1/alpha2-GPI were evaluated in patients with systemic lupus erythematosus (SLE)
      and antiphospholipid syndrome (APS). The oxLDL/beta2-GPI complex was 69% positive
      (above mean + 3 SD of control subjects) in 97 consecutive patients with SLE, 62%
      in 40 patients with SLE with secondary APS, and 60% in 50 control patients with
      SLE without APS. IgG anti-oxLig-1/beta2-GPI antibody was positive in 31 (32%) of
      97 consecutive patients with SLE, in 26 (65%) of 40 patients with SLE with
      secondary APS, and in 6 (19%) of 32 control patients with SLE. Anti-oxLig-1/beta2
      GPI antibodies were 93.7% specific with a positive predictive value of 90.0% for
      APS, better than anticardiolipin antibodies (80.0% specific, 71.4% predictive
      value). These results confirm that oxLDL/beta2-GPI complexes are common in SLE
      and suggest a possible immunogenic role in APS. In contrast, IgG anti-oxLig
      1/beta2-GPI antibodies not only are associated with but also are clinically
      useful risk factors for APS.

PMID- 15023050
TI  - Use of a multiple-enzyme/multiple-reagent assay system to quantify activity
      levels in samples containing mixtures of matrix metalloproteinases.
AB  - Matrix metalloproteinases (MMPs) are a family of enzymes that are up-regulated in
      many diseases, including osteoarthritis (OA) and rheumatoid arthritis (RA). Here
      we report on a novel technique that can be used to simultaneously measure
      activity levels for a panel of enzymes, such as the MMPs. The technique, termed
      the multiple-enzyme/multiple-reagent assay system (MEMRAS), relies on the use of
      reagents such as substrates with varying selectivity profiles against a group of
      enzymes. When reaction rates are measured by following a change in fluorescence
      with time, for mixtures of enzymes, an equation with unknown concentrations for
      each activity is generated for each reagent used. Simultaneously solving the set
      of equations leads to a solution for the unknown concentrations. We have applied
      this mathematical technique to measure activity levels for mixtures of MMPs such
      as collagenase 3 and gelatinase A. In addition, because we were most interested
      in determining collagenase 3 levels as a potential biological marker for OA, we
      developed highly selective substrates for this enzyme by using results found in
      previous bacteriophage substrate-mapping experiments. Some of the best substrates
      tested have specific activities for collagenase 3 that are 37,000-, 17,000-, 90-,
      and 200-fold selective over stromelysin 1, collagenase 1, and gelatinases A and
      B, respectively.

PMID- 15023051
TI  - Mistletoe lectin I is a sialic acid-specific lectin with strict preference to
      gangliosides and glycoproteins with terminal Neu5Ac alpha 2-6Gal beta 1-4GlcNAc
      residues.
AB  - Mistletoe lectin I (ML-I) is a type II ribosome-inactivating protein, which
      inhibits the protein biosynthesis at the ribosomal level. ML-I is composed of a
      catalytically active A-chain with rRNA N-glycosidase activity and a B-chain with
      carbohydrate binding specificities. Using comparative solid-phase binding assays
      along with electrospray ionization tandem mass spectrometry, ML-I was shown to
      preferentially bind to terminally alpha2-6-sialylated neolacto series
      gangliosides from human granulocytes. IV(6)Neu5Ac-nLc4Cer, VI(6)Neu5Ac-nLc6Cer,
      and VIII(6)Neu5Ac-nLc8Cer were identified as ML-I receptors, whereas the isomeric
      alpha2-3-sialylated neolacto series gangliosides were not recognized. Only
      marginal binding of ML-I to terminal galactose residues of neutral
      glycosphingolipids with a Galbeta1-4Glc or Galbeta1-4GlcNAc sequence was
      determined, whereas a distal Galalpha1-4Gal, GalNAcbeta1-3Gal, or GalNAcbeta1
      4Gal disaccharide did not bind at all. Among the glycoproteins investigated in
      Western blot and microwell adsorption assays, only those carrying Neu5Acalpha2
      6Galbeta1-4GlcNAc residues, exclusively, predominantly, or even as less abundant
      constituents in an assembly with Neu5Acalpha2-3Galbeta1-4GlcNAc-terminated
      glycans, displayed high ML-I binding capacity. From our data we conclude that (i)
      ML-I has to be considered as a sialic acid- and not a galactose-specific lectin
      and (ii) neolacto series gangliosides and sialoglycoproteins with type II
      glycans, which share the Neu5Acalpha2-6Galbeta1-4GlcNAc terminus, are true ML-I
      receptors. This strict preference might help to explain the immunostimulatory
      potential of ML-I toward certain leukocyte subpopulations and its therapeutic
      success as a cytotoxic anticancer drug.

PMID- 15023052
TI  - Induced alpha-helix structure in AF1 of the androgen receptor upon binding
      transcription factor TFIIF.
AB  - In recent years, it has become clear that in many proteins, significant regions
      are encoded by amino acid sequences that do not automatically fold into their
      fully condensed, functional structures. Characterization of the conformational
      propensities and function of the nonglobular protein sequences represents a major
      challenge. Striking among proteins with unfolded regions are numbers of
      transcription factors, including steroid receptors. In many cases, the unfolded
      or partially folded regions of such proteins take shape when the protein
      interacts with its proper binding partner(s), that is, the molecules to which it
      must bind to carry out its function. The AF1 domain of the androgen receptor (AR)
      shows little structure, when expressed as a recombinant peptide. It has been
      shown previously that AF1 interacts with transcription factor TFIIF in vitro.
      Using Fourier transform infrared (FTIR), we tested whether this interaction can
      induce structure in the AR AF1. Our results demonstrate that the recombinant AR
      AF1 can acquire significantly higher helical content after interacting with
      RAP74, a subunit of the TFIIF complex. We further show that this induced
      conformation in the AR AF1 is well-suited for its interaction with SRC-1.

PMID- 15023053
TI  - Participation of histidine-51 in catalysis by horse liver alcohol dehydrogenase.
AB  - Histidine-51 in horse liver alcohol dehydrogenase (ADH) is part of a hydrogen
      bonded system that appears to facilitate deprotonation of the hydroxyl group of
      water or alcohol ligated to the catalytic zinc. The contribution of His-51 to
      catalysis was studied by characterizing ADH with His-51 substituted with Gln
      (H51Q). The steady-state kinetic constants for ethanol oxidation and acetaldehyde
      reduction at pH 8 are similar for wild-type and H51Q enzymes. In contrast, the
      H51Q substitution significantly shifts the pH dependencies for steady-state and
      transient reactions and decreases by 11-fold the rate constant for the transient
      oxidation of ethanol at pH 8. Modest substrate deuterium isotope effects indicate
      that hydride transfer only partially limits the transient oxidation and turnover.
      Transient data show that the H51Q substitution significantly decreases the rate
      of isomerization of the enzyme-NAD(+) complex and becomes a limiting step for
      ethanol oxidation. Isomerization of the enzyme-NAD(+) complex is rate limiting
      for acetaldehyde reduction catalyzed by the wild-type enzyme, but release of
      alcohol is limiting for the H51Q enzyme. X-ray crystallography of doubly
      substituted His51Gln:Lys228Arg ADH complexed with NAD(+) and 2,3- or 2,4
      difluorobenzyl alcohol shows that Gln-51 isosterically replaces histidine in
      interactions with the nicotinamide ribose of the coenzyme and that Arg-228
      interacts with the adenosine monophosphate of the coenzyme without affecting the
      protein conformation. The difluorobenzyl alcohols bind in one conformation. His
      51 participates in, but is not essential for, proton transfers in the mechanism.

PMID- 15023054
TI  - Evidence for the proximity of the extreme N-terminus of the neurokinin-2 (NK2)
      tachykinin receptor to Cys167 in the putative fourth transmembrane helix.
AB  - Neurokinin-2 receptor (NK(2)R) binding of [(3)H]-SR48968, a piperidinyl
      antagonist, is inhibited by methanethiosulfonate ethylammonium (MTSEA) in a time-
      and concentration-dependent manner. By the systematic alanine replacement of
      putative loop and transmembrane region cysteine residues (Cys(4), Cys(81),
      Cys(167), Cys(262), Cys(281), Cys(308), and Cys(309)), we have determined that
      MTSEA perturbs [(3)H]-SR48968 binding by modifying Cys(167) in transmembrane
      helix 4. Data were substantiated using glycine, serine, and threonine
      substitutions of Cys(167). MTSEA preferentially modifies cysteine residues that
      are in proximity to a negatively charged environment. Hence, aspartate and
      glutamate residues were systematically substituted with leucine or valine,
      respectively, and the inhibitory effects of MTSEA on [(3)H]-SR48968 binding were
      reevaluated to determine those acidic residues close to the MTSEA binding
      crevice. Most significantly, substitution of Asp(5) in the receptor's extreme N
      terminus abolished the effects of MTSEA on [(3)H]-SR48968 binding. Therefore, our
      data would suggest close association of the extreme N-terminus with the
      extracellular surfaces of helices 4 and 3 in the NK(2)R in forming a binding
      crevice for MTSEA. The inhibition of SR48968 binding appears to result from loss
      of the SR48968 binding conformation of Gln(166) induced by MTSEA when it is
      coupled to Cys(167). Hence, it is proposed that there is mutually exclusive
      hydrogen bonding of SR48968 and MTSEA to Gln(166).

PMID- 15023055
TI  - Functional characterization of nitric oxide and YC-1 activation of soluble
      guanylyl cyclase: structural implication for the YC-1 binding site?
AB  - Soluble guanylyl cyclase (sGC) is a heterodimeric enzyme formed by an alpha
      subunit and a beta subunit, the latter containing the heme where nitric oxide
      (NO) binds. When NO binds, the basal activity of sGC is increased several hundred
      fold. sGC activity is also increased by YC-1, a benzylindazole allosteric
      activator. In the presence of NO, YC-1 synergistically increases the catalytic
      activity of sGC by enhancing the affinity of NO for the heme. The site of
      interaction of YC-1 with sGC is unknown. We conducted a mutational analysis to
      identify the binding site and to determine what residues were involved in the
      propagation of NO and/or YC-1 activation. Because guanylyl cyclases (GCs) and
      adenylyl cyclases (ACs) are homologous, we used the three-dimensional structure
      of AC to guide the mutagenesis. Biochemical analysis of purified mutants revealed
      that YC-1 increases the catalytic activity not only by increasing the NO affinity
      but also by increasing the efficacy of NO. Effects of YC-1 on NO affinity and
      efficacy were dissociated by single-point mutations implying that YC-1 has, at
      least, two types of interaction with sGC. A structural model predicts that YC-1
      may adopt two configurations in one site that is pseudosymmetric with the GTP
      binding site and equivalent to the forskolin site in AC.

PMID- 15023056
TI  - Structural characterization of lacticin 3147, a two-peptide lantibiotic with
      synergistic activity.
AB  - Lantibiotics are antibacterial peptides isolated from bacterial sources that
      exhibit activity toward Gram-positive organisms and are usually several orders of
      magnitude more potent than traditional antibiotics such as penicillin. They
      contain a number of unique structural features including dehydro amino acid and
      lanthionine (thioether) residues. Introduced following ribosomal translation of
      the parent peptide, these moieties render conventional methods of peptide
      analysis ineffective. We report herein a new method using nickel boride (Ni(2)B),
      in the presence of deuterium gas, to reduce dehydro side chains and reductively
      desulfurize lanthionine bridges found in lantibiotics. Using this approach, it is
      possible to identify and distinguish the original locations of dehydro side
      chains and lanthionine bridges by traditional peptide sequencing (Edman
      degradation) followed by mass spectrometry. The strategy was initially verified
      using nisin A, a structurally well characterized lantibiotic, and subsequently
      extended to the novel two-component lantibiotic, lacticin 3147, produced by
      Lactococcus lactis subspecies lactis DPC3147. The primary structures of both
      lacticin 3147 peptides were then fully assigned by use of multidimensional NMR
      spectroscopy, showing that lacticin 3147 A1 has a specific lanthionine bridging
      pattern which resembles the globular type-B lantibiotic mersacidin, whereas the
      A2 peptide is a member of the elongated type-A lantibiotic class. Also obtained
      by NMR were solution conformations of both lacticin 3147 peptides, indicating
      that A1 may adopt a conformation similar to that of mersacidin and that the A2
      peptide adopts alpha-helical structure. These results are the first of their kind
      for a synergistic lantibiotic pair (only four such pairs have been reported to
      date).

PMID- 15023058
TI  - Effects of Zn(II) binding and apoprotein structural stability on the conformation
      change of designed antennafinger proteins.
AB  - Ligand-induced conformation change is a general strategy for controlling protein
      function. In this work, we demonstrate the relationships between ligand binding
      and conformational stability using a previously designed protein, Ant-F, which
      undergoes a conformation change upon Zn(II) binding. To investigate the effect of
      stabilization of the apo structure on the conformation change, we also created a
      novel protein, Ant-F-H1, into which mutations are introduced to increase its
      stability over that of Ant-F. The chemical denaturation experiments clarified
      that apo-Ant-F-H1 is more stable than apo-Ant-F (DeltaDeltaG = -1.28 kcal/mol)
      and that the stability of holo-Ant-F-H1 is almost the same as that of holo-Ant-F.
      The Zn(II) binding assay shows that the affinity of Zn(II) for Ant-F-H1 is weaker
      than that for Ant-F (DeltaDeltaG = 1.40 kcal/mol). A large part of the increased
      value of free energy in stability corresponds to the decreased value of free
      energy in Zn(II) binding, indicating that the stability of the apo structure
      directly affects the conformation change. The denaturation experiments also
      reveal that Zn(II) destabilizes the conformation of both proteins. From the
      thermodynamic linkage, Zn(II) is thought to bind to the unfolded state with high
      affinity. These results suggest that the binding of Zn(II) to the unfolded state
      is an important factor in the conformational change as well as the stability of
      the apo and holo structures.

PMID- 15023057
TI  - Crystal structure at 1.8 A resolution of CDP-D-glucose 4,6-dehydratase from
      Yersinia pseudotuberculosis.
AB  - CDP-D-glucose 4,6-dehydratase catalyzes the conversion of CDP-D-glucose to CDP-4
      keto-6-deoxyglucose in an NAD(+)-dependent manner. The product of this conversion
      is a building block for a variety of primary antigenic determinants in bacteria,
      possibly implicated directly in reactive arthritis. Here, we describe the
      solution of the high-resolution crystal structure of CDP-D-glucose 4,6
      dehydratase from Yersinia pseudotuberculosis in the resting state. This structure
      represents the first CDP nucleotide utilizing dehydratase of the short-chain
      dehydrogenase/reductase (SDR) family to be determined, as well as the first
      tetrameric structure of the subfamily of SDR enzymes in which NAD(+) undergoes a
      full reaction cycle. On the basis of a comparison of this structure with
      structures of homologous enzymes, a chemical mechanism is proposed in which
      Tyr157 acts as the catalytic base, initiating hydride transfer by abstraction of
      the proton from the sugar 4'-hydroxyl. Concomitant with the removal of the proton
      from the 4'-hydroxyl oxygen, the sugar 4'-hydride is transferred to the B face of
      the NAD(+) cofactor, forming the reduced cofactor and a CDP-4-keto-d-glucose
      intermediate. A conserved Lys161 most likely acts to position the NAD(+) cofactor
      so that hydride transfer is favorable and/or to reduce the pK(a) of Tyr157.
      Following substrate oxidation, we propose that Lys134, acting as a base, would
      abstract the 5'-hydrogen of CDP-4-keto-D-glucose, priming the intermediate for
      the spontaneous loss of water. Finally, the resulting Delta(5,6)-glucoseen
      intermediate would be reduced suprafacially by the cofactor, and reprotonation at
      C-5' is likely mediated by Lys134.

PMID- 15023059
TI  - Crystal structure of the alkylsulfatase AtsK: insights into the catalytic
      mechanism of the Fe(II) alpha-ketoglutarate-dependent dioxygenase superfamily.
AB  - The alkylsulfatase AtsK from Pseudomonas putida S-313 belongs to the widespread
      and versatile non-heme iron(II) alpha-ketoglutarate-dependent dioxygenase
      superfamily and catalyzes the oxygenolytic cleavage of a variety of different
      alkyl sulfate esters to the corresponding aldehyde and sulfate. The enzyme is
      only expressed under sulfur starvation conditions, providing a selective
      advantage for bacterial growth in soils and rhizosphere. Here we describe the
      crystal structure of AtsK in the apo form and in three complexes: with the
      cosubstrate alpha-ketoglutarate, with alpha-ketoglutarate and iron, and finally
      with alpha-ketoglutarate, iron, and an alkyl sulfate ester used as substrate in
      catalytic studies. The overall fold of the enzyme is closely related to that of
      the taurine/alpha-ketoglutarate dioxygenase TauD and is similar to the fold
      observed for other members of the enzyme superfamily. From comparison of these
      structures with the crystal structure of AtsK and its complexes, we propose a
      general mechanism for the catalytic cycle of the alpha-ketoglutarate-dependent
      dioxygenase superfamily.

PMID- 15023060
TI  - Structure of Helicobacter pylori catalase, with and without formic acid bound, at
      1.6 A resolution.
AB  - Helicobacter pylori produces one monofunctional catalase, encoded by katA
      (hp0875). The crystal structure of H. pylori catalase (HPC) has been determined
      and refined at 1.6 A with crystallographic agreement factors R and R(free) of
      17.4 and 21.9%, respectively. The crystal exhibits P2(1)2(1)2 space group
      symmetry and contains two protein subunits in the asymmetric unit. The core
      structure of the HPC subunit, including the disposition of a heme b prosthetic
      group, is closely related to those of other catalases, although it appears to be
      the only clade III catalase that has been characterized that does not bind NADPH.
      The heme iron in one subunit of the native enzyme appears to be covalently
      modified, possibly with a perhydroxy or dioxygen group in a compound III-like
      structure. Formic acid is known to bind in the active site of catalases,
      promoting the breakdown of reaction intermediates compound I and compound II. The
      structure of an HPC crystal soaked with sodium formate at pH 5.6 has also been
      determined to 1.6 A (with R and R(free) values of 18.1 and 20.7%, respectively),
      revealing at least 36 separate formate or formic acid residues in the HPC dimer.
      In turn, the number of water molecules refined into the models decreased from
      1016 in the native enzyme to 938 in the formate-treated enzyme. Extra density,
      interpreted as azide, is found in a location of both structures that involves
      interaction with all four subunits in the tetramer. Electron paramagnetic
      resonance spectra confirm that azide does not bind as a ligand of the iron and
      that formate does bind in the heme pocket. The stability of the formate or formic
      acid molecule found inside the heme distal pocket has been investigated by
      calculations based on density functional theory.

PMID- 15023061
TI  - Crystal structure of the covalent intermediate of amylosucrase from Neisseria
      polysaccharea.
AB  - The alpha-retaining amylosucrase from the glycoside hydrolase family 13 performs
      a transfer reaction of a glucosyl moiety from sucrose to an acceptor molecule.
      Amylosucrase has previously been shown to be able to use alpha-D-glucopyranosyl
      fluoride as a substrate, which suggested that it could also be used for trapping
      the reaction intermediate for crystallographic studies. In this paper, the
      crystal structure of the acid/base catalyst mutant, E328Q, with a covalently
      bound glucopyranosyl moiety is presented. Sucrose cocrystallized crystals were
      soaked with alpha-D-glucopyranosyl fluoride, which resulted in the trapping of a
      covalent intermediate in the active site of the enzyme. The structure is refined
      to a resolution of 2.2 A and showed that binding of the covalent intermediate
      resulted in a backbone movement of 1 A around the location of the nucleophile,
      Asp286. This structure reveals the first covalent intermediate of an alpha
      retaining glycoside hydrolase where the glucosyl moiety is identical to the
      expected biologically relevant entity. Comparison to other enzymes with
      anticipated glucosylic covalent intermediates suggests that this structure is a
      representative model for such intermediates. Analysis of the active site shows
      how oligosaccharide binding disrupts the putative nucleophilic water binding site
      found in the hydrolases of the GH family 13. This reveals important parts of the
      structural background for the shift in function from hydrolase to
      transglycosidase seen in amylosucrase.

PMID- 15023062
TI  - Structure of the functional fragment of auxilin required for catalytic uncoating
      of clathrin-coated vesicles.
AB  - The three-dimensional structure of the C-terminal 20 kDa portion of auxilin,
      which consists of the clathrin binding region and the C-terminal J-domain, has
      been determined by NMR. Auxilin is an Hsp40 family protein that catalytically
      supports the uncoating of clathrin-coated vesicles through recruitment of Hsc70
      in an ATP hydrolysis-driven process. This 20 kDa auxilin construct contains the
      minimal sequential region required to uncoat clathrin-coated vesicles
      catalytically. The tertiary structure consists of six helices, where the first
      three are unique to auxilin and believed to be important in the catalytic
      uncoating of clathrin. The last three helices correspond to the canonical J
      domain of Hsp40 proteins. The first helix, helix 1, which contains a conserved
      FEDLL motif believed to be necessary for clathrin binding, is transient and not
      packed against the rest of the structure. Helix 1 is joined to helix 2 by a
      flexible linker. Helix 2 packs loosely against the J-domain surface, whereas
      helix 3 packs tightly and makes critical contributions to the J-domain core. A
      long insert loop, also unique to the auxilin J-domain, is seen between helix 4
      and helix 5. Comparison with a previously reported structure of auxilin
      containing only helices 3-6 shows a significant difference in the invariant HPD
      segment of the J-domain. The region where helix 1 is located corresponds to the
      expected region of the unstructured G/F-rich domain seen in DnaJ, i.e., the
      canonical N-terminal J-domain protein. In contrast, the location of helix 1
      differs from the substrate binding regions of two other Hsp40 proteins,
      Escherichia coli Hsc20 and viral large T antigen. The variety of biological
      functions performed by Hsp40 proteins such as auxilin, as well as the observed
      differences in the structure and function of their substrate binding regions,
      supports the notion that Hsp40 proteins act as target-specific adaptors that
      recruit their more general Hsp70 partners to specific biological roles.

PMID- 15023063
TI  - Fluorescence and kinetic analysis of the SpoIIAB phosphorylation reaction, a key
      regulator of sporulation in Bacillus subtilis.
AB  - Sporulation in Bacillus subtilis provides a valuable model system for studying
      differential gene expression. The anti-sigma factor SpoIIAB is a bifunctional
      protein, responsible for regulating the activity of the first sporulation
      specific sigma factor, sigma(F). SpoIIAB can either bind to (and thus inhibit)
      sigma(F) or phosphorylate the anti-anti-sigma factor SpoIIAA. The phosphorylation
      reaction follows an unusual time course in which a pre-steady-state phase is
      succeeded by a slower steady-state phase. Previous experiments have shown that in
      the steady-state phase SpoIIAB is unable to inhibit sigma(F). A fluorescent
      derivative of SpoIIAB (AB-F97W) was made that was indistinguishable from the wild
      type in its interactions with SpoIIAA and sigma(F). AB-F97W exhibited distinctive
      changes in its fluorescence intensity when bound to ATP, ADP, or SpoIIAA. By
      following changes in the fluorescence properties of AB-F97W during the
      phosphorylation reaction, we confirmed a previous hypothesis that during the
      steady-state phase the predominant species are SpoIIAA.SpoIIAB.ADP complexes. The
      formation of these complexes is responsible for the slowing of the reaction, an
      important feature during sporulation since it reduces the loss of ATP in the
      nutrient-deprived cell. We also show that, to form a complex with SpoIIAA and ADP
      during the reaction, SpoIIAB must undergo a change in state which increases its
      affinity for ADP, and that this change in state is stimulated by its interaction
      with SpoIIAA. We derive a model of the reaction using previously determined
      kinetic and binding constants, and relate these findings to the known structure
      of SpoIIAB.

PMID- 15023064
TI  - Is aromaticity essential for trapping the catalytic histidine 447 in human
      acetylcholinesterase?
AB  - Replacement of both the acyl pocket residue Phe295 as well as residue Phe338,
      adjacent to the catalytic His447 in human acetylcholinesterase (HuAChE), resulted
      in a 680-fold decline in catalytic activity due to conformational destabilization
      of the histidine side chain [Barak et al. (2002) Biochemistry 41, 8245]. A
      possible restriction of this catalytically nonproductive mobility of His447 in a
      series of F295X/F338A HuAChEs was examined in silico followed by site-directed
      mutagenesis. Simulations suggested that of the 12 aliphatic residues substituted
      at position 295, including hydrophobic and polar amino acids, only methionine was
      capable of maintaining the catalytically viable conformation of His447.
      Examination of the reactivities of the actual F295X/F338A HuAChEs showed that
      indeed the F295M/F338A enzyme was only 2-fold less reactive than the F338A mutant
      toward acetylthiocholine, while enzymes substituted by the similarly bulky
      residues leucine and isoleucine were catalytically impaired. Furthermore, only
      the F295M/F338A enzyme exhibited wild-type-like reactivity toward covalent
      modifiers of the catalytic Ser203 including the methylphosphonate soman and
      transition state analogue m-(N,N,N-trimethylammonio)trifluoroacetophenone
      (TMTFA), as well as a facile dealkylation of the F295M/F338A-soman adduct. A
      different behavior was observed for bulkier ligands which introduce a deformation
      in the acyl pocket, and therefore their activity seems only marginally affected
      by the positioning of His447. The findings emphasize the importance of the
      precise positioning of His447 for catalysis and indicate that, in the absence of
      aromatic "trapping", restriction of the histidine mobility in F295X/F338A HuAChEs
      requires a combination of steric interference and a specific polar interaction.
      The results also underscore the role of the acyl pocket subsite of
      cholinesterases in maintaining the catalytically viable conformation of the
      catalytic histidine.

PMID- 15023065
TI  - Motion of spin label side chains in cellular retinol-binding protein: correlation
      with structure and nearest-neighbor interactions in an antiparallel beta-sheet.
AB  - A goal in the development of site-directed spin labeling in proteins is to
      correlate the motion of a nitroxide side chain with local structure,
      interactions, and dynamics. Significant progress toward this goal has been made
      using alpha-helical proteins of known structure, and the present study is the
      first step in a similar exploration of a beta-sheet protein, cellular retinol
      binding protein (CRBP). Nitroxide side chains were introduced along both interior
      and edge strands. At sites in interior strands, the side-chain motion is strongly
      influenced by interactions with side chains of neighboring strands, giving rise
      to a rich variety of dynamic modes (weakly ordered, strongly ordered,
      immobilized) and complex electron paramagnetic resonance spectra that are
      modulated by strand twist. The interactions giving rise to the dynamic modes are
      explored using mutagenesis, and the results demonstrate the particular importance
      of the non-hydrogen-bonded neighbor residue in giving rise to highly ordered
      states. Along edge strands of the beta-sheet, the motion of the side chain is
      simple and weakly ordered, resembling that at solvent-exposed surfaces of an
      alpha-helix. A simple working model is proposed that can account for the wide
      variety of dynamic modes encountered. Collectively, the results suggest that the
      nitroxide side chain is an effective probe of side-chain interactions, and that
      site-directed spin labeling should be a powerful means of monitoring
      conformational changes that involve changes in beta-sheet topology.

PMID- 15023067
TI  - Solution structure of the two-iron rubredoxin of Pseudomonas oleovorans
      determined by NMR spectroscopy and solution X-ray scattering and interactions
      with rubredoxin reductase.
AB  - Here we provide insights into the molecular structure of the two-iron 19-kDa
      rubredoxin (AlkG) of Pseudomonas oleovorans using solution-state nuclear magnetic
      resonance (NMR) and small-angle X-ray scattering studies. Sequence alignment and
      biochemical studies have suggested that AlkG comprises two rubredoxin folds
      connected by a linker region of approximately 70 amino acid residues. The C
      terminal domain (C-Rb) of this unusual rubredoxin, together with approximately 35
      amino acid residues of the predicted linker region, was expressed in Escherichia
      coli, purified in the one-iron form and the structure of the cadmium-substituted
      form determined at high-resolution by NMR spectroscopy. The structure shows that
      the C-Rb domain is similar in fold to the conventional one-iron rubredoxins from
      other organisms, whereas the linker region does not have any discernible
      structure. This tandem "flexible-folded" structure of the polypeptide chain
      derived for the C-Rb protein was confirmed using solution X-ray scattering
      methods. X-ray scattering studies of AlkG indicated that the 70-amino acid
      residue linker forms a structured, yet mobile, polypeptide segment connecting the
      globular N- and C-terminal domains. The X-ray scattering studies also showed that
      the N-terminal domain (N-Rb) has a molecular conformation similar to that of C
      Rb. The restored molecular shape indicates that the folded N-Rb and C-Rb domains
      of AlkG are noticeably separated, suggesting some domain movement on complex
      formation with rubredoxin reductase to allow interdomain electron transfer
      between the metal centers in AlkG. This study demonstrates the advantage of
      combining X-ray scattering and NMR methods in structural studies of dynamic,
      multidomain proteins that are not suited to crystallographic analysis. The study
      forms a structural foundation for functional studies of the interaction and
      electron-transfer reactions of AlkG with rubredoxin reductase, also reported
      herein.

PMID- 15023066
TI  - Evidence that the C-terminus of the D1 polypeptide of photosystem II is ligated
      to the manganese ion that undergoes oxidation during the S1 to S2 transition: an
      isotope-edited FTIR study.
AB  - Isotope-edited FTIR difference spectroscopy was employed to determine if the C
      terminal alpha-COO(-) group of the D1 polypeptide ligates the (Mn)(4) cluster in
      photosystem II (PSII) and, if so, if it ligates the Mn ion that undergoes an
      oxidation during the S(1) --> S(2) transition. Wild-type and mutant cells of the
      cyanobacterium Synechocystis sp. PCC 6803 were propagated photoautotrophically in
      the presence of L-[1-(13)C]alanine or unlabeled ((12)C) L-alanine. In wild-type
      cells, both the C-terminal alpha-COO(-) group of the D1 polypeptide at D1-Ala344
      and all alanine-derived peptide carbonyl groups will be labeled. In D1-A344G and
      D1-A344S mutant cells, the C-terminal alpha-COO(-) group of the D1 polypeptide
      will not be labeled because this group is no longer provided by alanine. The
      resultant S(2)-minus-S(1) FTIR difference spectra of purified wild-type and
      mutant PSII particles showed that one symmetric carboxylate stretching mode that
      is altered during the S(1) --> S(2) transition is sensitive to L-[1-(13)C]alanine
      labeling in wild-type PSII particles but not in D1-A344G and D1-A344S PSII
      particles. Because the only carboxylate group that can be labeled in the wild
      type PSII particles but not in the mutant PSII particles is the C-terminal alpha
      COO(-) group of the D1 polypeptide, we assign the L-[1-(13)C]alanine-sensitive
      symmetric carboxylate stretching mode to the alpha-COO(-) group of D1-Ala344. In
      unlabeled wild-type PSII particles, this mode appears at approximately 1356 cm(
      1) in the S(1) state and at approximately 1339 or approximately 1320 cm(-1) in
      the S(2) state. These frequencies are consistent with unidentate ligation of the
      (Mn)(4) cluster by the alpha-COO(-) group of D1-Ala344 in both the S(1) and S(2)
      states. The apparent 17-36 cm(-1) downshift in frequency in response to the S(1) 
      -> S(2) transition is consistent with the alpha-COO(-) group of D1-Ala344
      ligating a Mn ion whose charge increases during the S(1) --> S(2) transition.
      Accordingly, we propose that the alpha-COO(-) group of D1-Ala344 ligates the Mn
      ion that undergoes an oxidation during the S(1) --> S(2) transition. Control
      experiments were conducted with Mn-depleted wild-type PSII particles. These
      experiments showed that tyrosine Y(D) may be structurally coupled to the carbonyl
      oxygen of an alanine-derived peptide carbonyl group.

PMID- 15023068
TI  - Changes in the kinetics and emission spectrum on mutation of the chromophore
      binding platform in Vibrio harveyi luciferase.
AB  - The recently proposed model for the bacteria luciferase-flavin mononucleotide
      complex identifies a number of critical intermolecular interactions that define a
      binding platform for the isoalloxazine ring of flavin [Lin, L. Y., Sulea, T.,
      Szittner, R., Vassilyev, V., Purisima, E. O., and Meighen, E. A. (2001) Protein
      Sci. 10, 1563-1571]. A key interaction involving van der Waals contact between
      the isopropyl side chain of alphaVal173 and the 7,8-dimethyl benzene plane of the
      isoalloxazine chromophore represents an important target to test the validity of
      the proposed model. Here, structure-function analysis of luciferase variants
      carrying single point mutations at position alpha173 have verified the functional
      layout of the active site architecture and implicated this site directly in
      flavin binding. Moreover, a decrease in the stability of the enzyme-bound C4a
      hydroperoxyflavin intermediate in the mutants could account for changes in
      saturation with the fatty aldehyde substrate. A predicted red-shift on mutation
      of position alpha173 to increase its polarity confirmed that alphaVal173 was an
      integral component of the chromophore-binding microenvironment. Introduction of
      mutations in residues that contact the pyrimidine plane of the isoalloxazine
      chromophore (alphaA75G/C106V) into the alphaV173A, alphaV173C, alphaV173T, and
      alphaV173S mutants led to the retention of high levels of enzyme activity (10-40%
      of wild type) and further red-shifted the emission spectra in the triple mutants.
      The additivity of the mutation-induced red-shifts in the emission wavelength
      spectrum provides the basis toward engineering luciferase variants that emit
      different light colors with the proposed flavin-luciferase model complex as a
      design reference.

PMID- 15023069
TI  - Proton release and uptake of pharaonis phoborhodopsin (sensory rhodopsin II)
      reconstituted into phospholipids.
AB  - pharaonis phoborhodopsin (ppR, also called pharaonis sensory rhodopsin II, psRII)
      is a photo-receptor for negative phototaxis in Natronobacterium pharaonis. During
      the photoreaction cycle (photocycle), ppR exhibits intraprotein proton movements,
      resulting in proton pumping from the cytoplasmic to the extracellular side,
      although it is weak. In this study, light-induced proton uptake and release of
      ppR reconstituted with phospholipid were analyzed using a SnO(2) electrode. The
      reconstituted ppR exhibited properties in proton uptake and release that are
      different from those of dodecyl maltoside solubilized samples. It showed fast
      proton release before the decay of ppR(M) (M-photointermediate) followed by
      proton uptake, which was similar to that of bacteriorhodopsin (BR), a light
      driven proton pump. Mutant analysis assigned Asp193 to one (major) of the members
      of the proton-releasing group (PRG). Fast proton release was observed only when
      the pH was approximately 5-8 in the presence of Cl(-). When Cl(-) was replaced
      with SO(4)(2-), the reconstituted ppR did not exhibit fast proton release at any
      pH, suggesting Cl(-) binding around PRG. PRG in BR consists of Glu204 (Asp193 in
      ppR) and Glu194 (Pro183 in ppR). Replacement of Pro183 by Glu/Asp, a negatively
      charged residue, led to Cl(-)-independent fast proton release. The transducer
      binding affected the properties of PRG in ppR in the ground state and in the
      ppR(M) state, suggesting that interaction with the transducer extends to the
      extracellular surface of ppR. Differences and similarities in the molecular
      mechanism of the proton movement between ppR and BR are discussed.

PMID- 15023070
TI  - X-ray crystal structure of Desulfovibrio vulgaris rubrerythrin with zinc
      substituted into the [Fe(SCys)4] site and alternative diiron site structures.
AB  - The X-ray crystal structure of recombinant Desulfovibrio vulgaris rubrerythrin
      (Rbr) that was subjected to metal constitution first with zinc and then iron,
      yielding ZnS(4)Rbr, is reported. A [Zn(SCys)(4)] site with no iron and a diiron
      site with no appreciable zinc in ZnS(4)Rbr were confirmed by analysis of the
      anomalous scattering data. Partial reduction of the diiron site occurred during
      the synchrotron X-ray irradiation at 95 K, resulting in two different diiron site
      structures in the ZnS(4)Rbr crystal. These two structures can be classified as
      containing mixed-valent Fe1(III)(mu-OH(-))(mu-GluCO(2)(-))(2)Fe2(II) and
      Fe1(II)(mu-GluCO(2)(-))(2)Fe2(III)-OH(-) cores. The data do not show any evidence
      for alternative positions of the protein or solvent ligands. The iron and ligand
      positions of the solvent-bridged site are close to those of the diferric site in
      all-iron Rbr. The diiron site with only the two carboxylato bridges differs by an
      approximately 2 A shift in the position of Fe1, which changes from six- to four
      coordination. The Fe1- - -Fe2 distance (3.6 A) in this latter site is
      significantly longer than that of the site with the additional solvent bridge
      (3.4 A) but significantly shorter than that previously reported for the diferrous
      site (4.0 A) in all-iron Rbr. The apparent redox-induced movement of Fe1 at 95 K
      in the ZnS(4)Rbr crystal implies an extremely low activation barrier, which is
      consistent with the rapid (approximately 30 s(-1)) room temperature turnover of
      the all-iron Rbr during its catalysis of two-electron reduction of hydrogen
      peroxide. ZnS(4)Rbr does not show peroxidase activity, presumably because the
      [Zn(SCys)(4)] site, unlike the [Fe(SCys)(4)] site, cannot mediate electron
      transfer to the diiron site. One or both of the diiron site structures in the
      cryoreduced ZnS(4)Rbr crystal are likely to represent that (those) of transient
      mixed-valent diiron site(s) that must occur upon return of the diferric to the
      diferrous oxidation level during peroxidase turnover.

PMID- 15023071
TI  - In vitro selection of RNA aptamers that bind to colicin E3 and structurally
      resemble the decoding site of 16S ribosomal RNA.
AB  - Colicin E3 is a ribonuclease that specifically cleaves at the site after A1493 of
      16S rRNA in Escherichia coli ribosomes, thus inactivating translation. To analyze
      the interaction between colicin E3 and 16S rRNA, we used in vitro selection to
      isolate RNA ligands (aptamers) that bind to the C-terminal ribonuclease domain of
      colicin E3, from a degenerate RNA pool. Although the aptamers were not digested
      by colicin E3, they specifically bound to the protein (K(d) = 2-14 nM) and
      prevented the 16S rRNA cleavage by the C-terminal ribonuclease domain. Among
      these aptamers, aptamer F2-1 has a sequence similar to that of the region around
      the cleavage site from residue 1484 to 1506, including the decoding site, of E.
      coli 16S rRNA. The secondary structure of aptamer F2-1 was determined by the base
      pair covariation among the variants obtained by a second in vitro selection,
      using a doped RNA pool based on the aptamer F2-1 sequence. The sequence and
      structural similarities between the aptamers and 16S rRNA provide insights into
      the recognition of colicin E3 by this specific 16S rRNA region.

PMID- 15023072
TI  - Mutant cholinesterases possessing enhanced capacity for reactivation of their
      phosphonylated conjugates.
AB  - Selective mutants of mouse acetylcholinesterase (AChE; EC 3.1.1.7) phosphonylated
      with chiral S(P)- and R(P)-cycloheptyl, -3,3-dimethylbutyl, and -isopropyl
      methylphosphonyl thiocholines were subjected to reactivation by the oximes HI-6
      and 2-PAM and their reactivation kinetics compared with wild-type AChE and
      butyrylcholinesterase (EC 3.1.1.8). Mutations in the choline binding site (Y337A,
      Y337A/F338A) or combined with acyl pocket mutations (F295L/Y337A, F297I/Y337A,
      F295L/F297I/Y337A) were employed to enlarge active center gorge dimensions. HI-6
      was more efficient than 2-PAM (up to 29000 times) as a reactivator of S(P)
      phosphonates (k(r) ranged from 50 to 13000 min(-1) M(-1)), while R(P) conjugates
      were reactivated by both oximes at similar, but far slower, rates (k(r) < 10 min(
      1) M(-1)). The Y337A substitution accelerated all reactivation rates over the
      wild-type AChE and enabled reactivation even of R(P)-cycloheptyl and R(P)-3,3
      dimethylbutyl conjugates that when formed in wild-type AChE are resistant to
      reactivation. When combined with the F295L or F297I mutations in the acyl pocket,
      the Y337A mutation showed substantial enhancements of reactivation rates of the
      S(P) conjugates. The greatest enhancement of 120-fold was achieved with HI-6 for
      the F295L/Y337A phosphonylated with the most bulky alkoxy moiety, S(P)
      cycloheptyl methylphosphonate. This significant enhancement is likely a direct
      consequence of simultaneously increasing the dimensions of both the choline
      binding site and the acyl pocket. The increase in dimensions allows for
      optimizing the angle of oxime attack in the spatially impacted gorge as suggested
      from molecular modeling. Rates of reactivation reach values sufficient for
      consideration of mixtures of a mutant enzyme and an oxime as a scavenging
      strategy in protection and treatment of organophosphate exposure.

PMID- 15023073
TI  - Reaction of Pseudomonas fluorescens kynureninase with beta-benzoyl-L-alanine:
      detection of a new reaction intermediate and a change in rate-determining step.
AB  - Beta-benzoyl-DL-alanine was synthesized from alpha-bromoacetophenone and diethyl
      acetamidomalonate. The racemic amino acid was resolved by carboxypeptidase A
      catalyzed hydrolysis of the N-trifluoroacetyl derivative. Beta-benzoyl-L-alanine
      is a good substrate of kynureninase from Pseudomonas fluorescens, with k(cat) and
      k(cat)/K(m) values of 0.7 s(-1) and 8.0 x 10(4) M(-1) s(-1), respectively,
      compared to k(cat) = 16.0 s(-1) and k(cat)/K(m) = 6.0 x 10(5) M(-1) s(-1) for L
      kynurenine. In contrast to the reaction of L-kynurenine, beta-benzoyl-L-alanine
      does not exhibit a significant solvent isotope effect on k(cat) ((H)k/(D)k = 0.96
      +/- 0.06). The pre-steady-state kinetics of the reaction of beta-benzoyl-L
      alanine were investigated by rapid scanning stopped-flow spectrophotometry. The
      spectra show the formation of a quinonoid intermediate, with lambda(max) = 490
      nm, in the dead time of the instrument, which then decays, with k = 210 s(-1), to
      form a transient intermediate with lambda(max) at 348 nm. In the presence of
      benzaldehyde, the 348 nm intermediate decays, with k = 0.7 s(-1), to form a
      quasistable quinonoid species with lambda(max) = 492 nm. Previous studies
      demonstrated that benzaldehyde can trap an enamine intermediate formed after the
      C(beta)-C(gamma) bond cleavage [Phillips, R. S., Sundararaju, B., and Koushik, S.
      V. (1998) Biochemistry 37, 8783-8789]. Thus, the 348 nm intermediate is
      kinetically competent. The position of the absorption maximum and shape of the
      band is consistent with a PMP-ketimine intermediate. The results from chemical
      quenching analysis do not show a burst of benzoate and, thus, also support the
      formation of benzoate as the rate-determining step. These data suggest that, in
      contrast to L-kynurenine, for which the rate-determining step was shown to be
      deprotonation of the pyruvate-ketimine intermediate [Koushik, S. V., Moore, J.
      A., III, Sundararaju, B., and Phillips, R. S. (1998) Biochemistry 37, 1376-1382],
      the rate-determining step in the reaction of beta-benzoyl-L-alanine with
      kynureninase is C(beta)-C(gamma) bond cleavage.

PMID- 15023074
TI  - Role of Arg100 in the active site of adenosylcobalamin-dependent glutamate
      mutase.
AB  - Arginine-100 is involved in recognizing the gamma carboxylate of the substrate in
      glutamate mutase. To investigate its role in substrate binding and catalysis,
      this residue was mutated to lysine, tyrosine, and methionine. The effect of these
      mutations was to reduce k(cat) by 120-320-fold and to increase K(m(apparent)) for
      glutamate by 13-22-fold; K(m(apparent)) for adenosylcobalamin is little changed
      by these mutations. Even at saturating substrate concentrations, no cob(II)alamin
      could be detected in the UV-visible spectra of the Arg100Tyr and Arg100Met
      mutants. However, in the Arg100Lys mutant cob(II)alamin accumulated to
      concentrations similar to wild-type enzyme, which allowed the pre-steady-state
      kinetics of adenosylcobalamin homolysis to be investigated by stopped-flow
      spectroscopy. It was found that homolysis of the coenzyme is slower by an order
      of magnitude, compared with wild-type enzyme. Furthermore, glutamate binding is
      significantly weakened, so much so that the reaction exhibits second-order
      kinetics over the range of substrate concentrations used. The Arg100Lys mutant
      does not exhibit the very large deuterium isotope effects that are observed for
      homolysis of the coenzyme when the wild-type enzyme is reacted with deuterated
      substrates; this suggests that homolysis is slowed relative to hydrogen
      abstraction by this mutation.

PMID- 15023075
TI  - Characterization of the fast-forming intermediate, des [30-75], in the reductive
      unfolding of onconase.
AB  - A fast-forming intermediate in the reductive unfolding of frog onconase (ONC),
      des [30-75], analogous to the des [40-95] intermediate found in the reductive
      unfolding of its structural homologue, bovine pancreatic ribonuclease A (RNase
      A), has been isolated and characterized. The midpoints of the thermal transition
      and chemical denaturing curves (representing global unfolding) indicate that the
      conformation of des [30-75] is considerably less stable than that of the parent
      molecule, suggesting that the (30-75) disulfide bond plays a significant role in
      the conformational stability of ONC. While des [30-75] is formed very quickly by
      a partial reduction of the parent molecule in a local unfolding step, it is not
      as easily susceptible to further reduction, indicating that its three disulfides
      are much more buried compared to the (30-75) disulfide bond in the parent
      protein. The nature of des [30-75] is similar to that of des [40-95] RNase A, in
      that des [30-75] ONC is also a disulfide-secure species. In addition, based on
      the resistance to mild reducing conditions, structured des species appear to form
      in ONC from unstructured three-disulfide-containing ensembles. This step is key
      in the oxidative folding of RNaseA, and is much faster in ONC than the formation
      of the structured des [40-95] species in RNase A.

PMID- 15023076
TI  - Conserved cysteine 126 in triosephosphate isomerase is required not for enzymatic
      activity but for proper folding and stability.
AB  - In triosephosphate isomerase, Cys126 is a conserved residue located close to the
      catalytic glutamate, Glu165. Although it has been mentioned that Cys126 and other
      nearby residues are required to maintain the active site geometry optimal for
      catalysis, no evidence supporting this idea has been reported to date. In this
      work, we studied the catalytic and stability properties of mutants C126A and
      C126S of Saccharomyces cerevisiae TIM (wtTIM). None of these amino acid
      replacements induced significant changes in the folding of wtTIM, as indicated by
      spectroscopic studies. C126S and C126A have K(M) and k(cat) values that are
      concomitantly reduced by only 4-fold and 1.5-fold, respectively, compared to
      those of wtTIM; in either case, however, the catalytic efficiency (k(cat)/K(M))
      of the enzyme is barely affected. The affinity of mutated TIMs for the
      competitive inhibitor 2-phosphoglycolate augmented also slightly. In contrast,
      greater susceptibility to thermal denaturation resulted from mutation of Cys126,
      especially when it was changed to Ser. By using values of the rate constants for
      unfolding and refolding, we estimated that, at 25 degrees C, C126A and C126S are
      less stable than wtTIM by about 5.0 and 9.0 kcal mol(-)(1), respectively.
      Moreover, either of these mutations slows down the folding rate by a factor of 10
      and decreases the recovery of the active enzyme after thermal unfolding. Thus,
      Cys126 is required for proper stability and efficient folding of TIM rather than
      for enzymatic catalysis.

PMID- 15023077
TI  - Peptide models provide evidence for significant structure in the denatured state
      of a rapidly folding protein: the villin headpiece subdomain.
AB  - The villin headpiece subdomain is a cooperatively folded 36-residue, three-alpha
      helix protein. The domain is one of the smallest naturally occurring sequences
      which has been shown to fold. Recent experimental studies have shown that it
      folds on the 10-micros time scale. Its small size, simple topology, and very
      rapid folding have made it an attractive target for computational studies of
      protein folding. We present temperature-dependent NMR studies that provide
      evidence for significant structure in the denatured state of the headpiece
      subdomain. A set of peptide fragments derived from the headpiece were also
      characterized in order to determine if there is a significant tendency to form a
      locally stabilized structure in the denatured state. Peptides corresponding to
      each of the three isolated helices and to the connection between the first and
      second helices were largely unstructured. A longer peptide fragment which
      contains the first and second helices shows considerable structure, as judged by
      NMR and CD. Concentration-dependent CD measurements and analytical
      ultracentrifugation experiments indicate that the structure is not due to self
      association. NMR studies indicate that the structure is stabilized by tertiary
      interactions involving phenylalanines and Val 50. A peptide in which two of the
      three phenylalanines are changed to leucine is considerably less structured,
      confirming the importance of the phenylalanines. This work indicates that there
      is significant structure in the denatured state of this rapidly folding protein.

PMID- 15023078
TI  - Regulatory role of the C-terminus of the epsilon subunit from the chloroplast ATP
      synthase.
AB  - The ATP synthases from chloroplasts and Escherichia coli are regulated by several
      factors, one of which is the epsilon subunit. This small subunit is also required
      for ATP synthesis. Thylakoid membranes reconstituted with CF1 lacking the epsilon
      subunit (CF1-epsilon) exhibit no ATP synthesis and very high ATP hydrolysis.
      Either native or recombinant epsilon restores ATP synthesis and inhibits ATP
      hydrolysis. Previously, we showed that truncated epsilon, lacking the last 45 C
      terminal amino acids, restored ATP synthesis to membranes reconstituted with CF1
      epsilon but was not an efficient inhibitor of ATP hydrolysis. In this paper, we
      show that this truncated epsilon is unable to inhibit ATP hydrolysis when Mg(2+)
      is the divalent cation present, both for the enzyme in solution and on the
      thylakoid membrane. In addition, the rate of reduction of the disulfide bond of
      the gamma subunit by dithiothreitol is not decreased by truncated epsilon,
      although full-length epsilon greatly impedes reduction. Thylakoid membranes can
      synthesize ATP at the expense of proton gradients generated by pH transitions in
      the dark. Our reconstituted membranes are able to produce a limited amount of ATP
      under these "acid-bath" conditions, with approximately equal amounts produced by
      the membranes containing wild-type epsilon and those containing truncated
      epsilon. However, the membranes containing truncated epsilon exhibit much higher
      background ATP hydrolysis under the same acid-bath conditions, leading to the
      conclusion that, without the C-terminus of epsilon, the CF1CFo is unable to check
      unwanted ATP hydrolysis.

PMID- 15023079
TI  - Plasmon-waveguide resonance studies of ligand binding to the human beta 2
      adrenergic receptor.
AB  - Plasmon-waveguide resonance (PWR) spectroscopy is an optical technique that can
      be used to probe the molecular interactions occurring within anisotropic
      proteolipid membranes in real time without requiring molecular labeling. This
      method directly monitors mass density, conformation, and molecular orientation
      changes occurring in such systems and allows determination of protein-ligand
      binding constants and binding kinetics. In the present study, PWR has been used
      to monitor the incorporation of the human beta(2)-adrenergic receptor into a
      solid-supported egg phosphatidylcholine lipid bilayer and to follow the binding
      of full agonists (isoproterenol, epinephrine), a partial agonist (dobutamine), an
      antagonist (alprenolol), and an inverse agonist (ICI-118,551) to the receptor.
      The combination of differences in binding kinetics and the PWR spectral changes
      point to the occurrence of multiple conformations that are characteristic of the
      type of ligand, reflecting differences in the receptor structural states produced
      by the binding process. These results provide new evidence for the conformational
      heterogeneity of the liganded states formed by the beta(2)-adrenergic receptor.

PMID- 15023081
TI  - Communicating original research in chemistry and related sciences.
AB  - The availability of scientific information in electronic form is the convergence
      of traditional journal publishing, electronic communications, and the widespread
      availability of computer technology. This revolution in scientific communication
      has its roots in developments that started in the mid-19th century and culminated
      with the extraordinary progress in telecommunications and computer technology in
      the latter years of the 20th century. Eighty-three percent of scientific journals
      are now available online. The benefits of electronic journals include rapid
      publication, instantaneous linking to external information sources, and the
      capability to deliver new types of information. To date neither electronic-only
      nor preprint servers have been well received by the chemical sciences community.
      Continued advances in telecommunications, computer technology, and acquisition of
      scientific data in structured formats hold promise for even greater advances in
      communication of scientific information.

PMID- 15023080
TI  - Role of protein-water interactions and electrostatics in alpha-synuclein fibril
      formation.
AB  - Deposition of misfolded alpha-synuclein is a critical factor in several
      neurodegenerative disorders. Filamentous alpha-synuclein is the major component
      of Lewy bodies and Lewy neurites, the intracellular inclusions in the
      dopaminergic neurons of the substantia nigra, which are considered the
      pathological hallmark of Parkinson's disease. We show here that anions induce
      partial folding of alpha-synuclein at neutral pH, forming a critical
      amyloidogenic intermediate, which leads to significant acceleration of the rate
      of fibrillation. The magnitude of the accelerating effect generally followed the
      position of the anions in the Hofmeister series, indicating a major role of
      protein-water-anion interactions in the process at salt concentrations above 10
      mM. Below this concentration, electrostatic effects dominated in the mechanism of
      anion-induced fibrillation. The acceleration of fibrillation by anions was also
      dependent on the cation. Moderate concentrations of anions affected both the
      rates of nucleation and the elongation of alpha-synuclein fibrillation, primarily
      via their effect on the interaction of the protein with water.

PMID- 15023082
TI  - Understanding the importance of protein structure to nature's routes for
      divergent evolution in TIM barrel enzymes.
AB  - It is widely agreed that new enzymes evolve from existing ones through the
      duplication of genes encoding existing enzymes followed by sequence divergence.
      While evolution is an inherently random process, studies of divergently related
      enzymes have shown that the evolution of new enzymes follows one of three general
      routes in which the substrate specificity, reaction mechanism, or active site
      architecture of the progenitor enzyme is reused in the new enzyme. Recent
      developments in structural biology relating to divergently related (beta/alpha)8
      enzymes have brought new insight into these processes and have revealed that
      conserved structural elements play an important role in divergent evolution.
      These studies have shown that, although evolution occurs as a series of random
      mutations, stable folds such as the (beta/alpha)8 barrel and structural features
      of the active sites of enzymes are frequently reused in evolution and adapted for
      new catalytic purposes.

PMID- 15023083
TI  - Molybdenum-catalyzed asymmetric allylic alkylations.
AB  - The highly regio- and enantioselective molybdenum-catalyzed allylic alkylation
      reaction has become a powerful synthetic tool during the past few years. This
      Account describes the achievements gained so far in the area, with special
      attention directed to the different chiral ligands that have been used for
      inducing chirality in the products, the range of allylic substrates and
      nucleophiles employed, mechanistic studies, and applications of the reaction in
      asymmetric syntheses.

PMID- 15023084
TI  - Asymmetric synthesis and organometallic chemistry of functionalized phosphines
      containing stereogenic phosphorus centers.
AB  - A series of organometallic reagents containing orthometalated chiral amine
      auxiliaries have been utilized as chiral templates to activate phospholes,
      vinylphosphines, and alkynylphosphines toward asymmetric ligand transformations
      via cycloaddition and hydroamination reactions. By a systemic manipulation of the
      subtle stereoelectronic properties of the auxiliaries and the metal centers, the
      template properties could be modified and the origins of stereoselectivity
      revealed. The chiral templates are able to control the disposition of selected
      functionalities into designated locations on the transformed P-stereogenic mono-
      and diphosphine ligands. This Account provides an overview of our recent work in
      this area.

PMID- 15023085
TI  - Paramagnetic cp/dithiolene complexes as molecular hinges: interplay of
      metal/ligand electronic delocalization and solid-state magnetic behavior.
AB  - Paramagnetic, flexible organometallic dithiolene complexes associating
      cyclopentadienyl (Cp) and dithiolate (dt) ligands, such as CpM(dt), Cp2M(dt), or
      CpM(dt)2, are investigated in the solid state through their structural and
      magnetic properties. The degree of delocalization of the spin density between the
      metal and the dithiolene fragments in a given complex, its varying molecular
      geometry and frontier orbitals, and the structures adopted in the solid state are
      intimately correlated and adapt mutually to each other. A variety of magnetic
      structures follows, from noninteracting spins to dyads, spin chains, spin
      ladders, or antiferromagnetic ground state, the detailed properties of which are
      highly sensitive to "minor" molecular modifications.

PMID- 15023086
TI  - Homolytic cleavage and aggregation processes in cyclopentadienylchromium
      chemistry.
AB  - The reactivity of the cyclopentadienylchromium tricarbonyl dimer [CpCr(CO)3]2 (Cp
      = C5H5, 1) toward several classes of organo-P-, -S- and -N-compounds will be
      described. The organic substrates include the following: (i)
      bis(diphenylthiophosphinyl)disulfane, R2P(S)SSP(S)R2; (ii)
      bis(thiophosphoryl)disulfane, (RO)2P(S)SSP(S)(OR)2; (iii) tetraalkylthiuram
      disulfides, R2NC(S)SSC(S)NR2; (iv) tetraalkyldiphosphine disulfides,
      R2P(S)P(S)R2; (v) dibenzothiazolyl disulfide, (C6H4NSC)2; and (vi) Lawesson's
      reagent, (CH3OC6H4)2P2S4. The primary products, namely, the complexes
      CpCr(CO)2(SPR2), CpCr(CO)2)(S2CNR2), CpCr(CO)2(SCSN(C6H4)), and
      CpCr(CO)2(SPC6H4OCH3), containing the thiophosphinito, dithiocarbamate, 2
      mercaptobenzothiazole, and dithiophosphorane ligands, respectively, arise from
      facile cleavage of the S-S, P-P, and P-S bonds in the organic substrates. Further
      treatment of these complexes with 1 under thermal activation results in cleavage
      of C-X (X = N, S), P-S, and Cr-E (E = C, N, P, S) bonds, accompanied by C-C and P
      P bond formation in some cases, generating a variety of organometallic compounds
      belonging to the phosphido, phosphinidene, thiocarbenoid, dithiooxamide,
      aminocarbyne, aminoalkenylacyl, and cuboidal types.

PMID- 15023087
TI  - Generation and mesolytic dynamics of organoselenane and selenosilane radical
      ions: development of mechanistically interesting and synthetically useful
      chemistry.
AB  - PET oxidation of PhSe-SePh and R-CH2-Se-R' generates an electrophilic selenium
      and carbocationic species, respectively. Similarly, one-electron reductive
      activations of R-CH2-Se-R' and R3-Si-SePh produces alkyl and alkyl silyl
      radicals, respectively. The possible structure of the reactive electrophilic
      selenium species is discussed and the fragmentation of -C-Se]*+ is found to be
      nucleophilic-assisted. These mechanistically interesting studies have been shown
      to be useful in initiating various synthetic reactions.

PMID- 15023088
TI  - Alcohol expectancy multiaxial assessment: a memory network-based approach.
AB  - Despite several decades of activity, alcohol expectancy research has yet to merge
      measurement approaches with developing memory theory. This article offers an
      expectancy assessment approach built on a conceptualization of expectancy as an
      information processing network. The authors began with multidimensional scaling
      models of expectancy space, which served as heuristics to suggest confirmatory
      factor analytic dimensional models for entry into covariance structure predictive
      models. It is argued that this approach permits a relatively thorough assessment
      of the broad range of potential expectancy dimensions in a format that is very
      flexible in terms of instrument length and specificity versus breadth of focus.

PMID- 15023089
TI  - Construct validation of the Dutch version of the impact of event scale.
AB  - The Impact of Event Scale (ES; M. J. Horowitz, N. Wilner, & W. Alvarez, 1979) is
      a worldwide-used self-report measure to assess the frequency of intrusive and
      avoidant phenomena after a variety of traumatic experiences. The purpose of this
      article is to assess the psychometric value of the Dutch version of the IES (D.
      Brom & R. J. Kleber, 1985) in several samples of individuals who had experienced
      various traumatic stressors. The reliability and structure of the IES were
      evaluated in 3 different samples (total N = 1.588). The reliability of the Dutch
      version of the IES was adequate across the various stressors. The construct
      validity was assessed by using confirmatory factor analyses. Outcomes revealed a
      robust structure over the various samples, generally supporting the composition
      of the original IES.

PMID- 15023090
TI  - A multidimensional perspective of relations between self-concept (Self
      Description Questionnaire II) and adolescent mental health (Youth Self-Report).
AB  - Relations between self-concept and mental health are best understood from a
      multidimensional perspective. For responses by 903 adolescents (mean age = 12.6)
      to a new French translation of the Self Description Questionnaire II (SDQII),
      confirmatory factor analysis demonstrated a well-defined multidimensional factor
      structure of reliable, highly differentiated self-concept factors. Correlations
      between 11 SDQII factors and 7 mental health problems (Youth Self-Report; YSR)
      varied substantially (.11 to -.83; mean r = -.35). Single higher-order factors
      could not explain relations among SDQII factors, among YSR factors, or between
      the SDQII and YSR factors. This highly differentiated multivariate pattern of
      relations supports a multidimensional perspective of self-concept, not the
      unidimensional perspective still prevalent in mental health research and
      assessment.

PMID- 15023091
TI  - Assessment of anger and aggression in male offenders with developmental
      disabilities.
AB  - Systematic assessment of anger among people with developmental disabilities has
      been lacking, especially for hospital inpatients. Reliability and validity of
      anger self-report psychometric scales were investigated with 129 male patients,
      mostly forensic. Anger prevalence and its relationship to demographic, cognitive,
      and personality variables and to hospital assaultive behavior were examined. High
      internal and intermeasure consistency, and some concurrent validity with staff
      ratings, were found. Retrospective validity regarding physically assaultive
      behavior in the hospital was obtained. Hierarchical regressions revealed that
      patient-reported anger was a significant predictor of assaults postadmission,
      controlling for age, length of stay, IQ, violence offense history, and
      personality variables.

PMID- 15023092
TI  - Are dietary restraint scales valid measures of acute dietary restriction?
      Unobtrusive observational data suggest not.
AB  - The finding that dietary restraint scales predict onset of bulimic pathology has
      been interpreted as suggesting that dieting causes this eating disturbance,
      despite the dearth of evidence that these scales are valid measures of dietary
      restriction. The authors conducted 4 studies that tested whether dietary
      restraint scales were inversely correlated with unobtrusively measured caloric
      intake. These studies, which varied in foods consumed, settings, and populations,
      indicated that common dietary restraint scales were largely uncorrelated with
      acute caloric intake. Results suggest that these scales are not valid measures of
      short-term dietary restriction and imply that it may be prudent to reinterpret
      findings from studies thai use these scales, including those that suggest dietary
      restraint is a risk factor for bulimic pathology.

PMID- 15023093
TI  - Eating disorder diagnostic scale: additional evidence of reliability and
      validity.
AB  - The authors conducted 4 studies investigating the reliability and validity of the
      Eating Disorder Diagnostic Scale (HDDS; E. Stice, C. F. Telch, & S. L. Rizvi,
      2000), a brief self-report measure for diagnosing anorexia nervosa, bulimia
      nervosa, and binge eating disorder. Study 1 found that the HDDS showed criterion
      validity with interview-based diagnoses, convergent validity with risk factors
      for eating pathology, and internal consistency. Studies 2 and 3 found that the
      EDDS was sufficiently sensitive to detect the effects of eating disorder
      prevention programs. Regarding predictive validity, Studies 3 and 4 found that
      the EDDS predicted response to a prevention program and future onset of eating
      pathology and depression. Results provide additional evidence of the reliability
      and validity of this scale and suggest it may be useful in clinical and research
      applications.

PMID- 15023094
TI  - Behavioral assessment of gambling: an application of the timeline followback
      method.
AB  - The Gambling Timeline Followback (G-TLFB), a measure of gambling behavior that
      uses the timeline followback methodology, was psychometrically evaluated with
      samples of frequent-gambling young adults. Seven dimensions of gambling behavior
      were assessed: type, frequency, duration, intent, risk, win-loss, and consumption
      of alcohol while gambling. The G-TLFB demonstrated adequate to excellent test
      retest reliability with a sample of 57 frequent gamblers (r=.75 to.96) and with a
      group of 34 disordered gamblers (r=.73 to.93). With a separate sample of 58
      frequent-gambling participants, convergent, concurrent, and discriminant validity
      were assessed. The G-TLFB correlated positively with daily self-monitoring
      reports (r=.59 to.87). The dimensions of frequency and duration demonstrated
      concurrent validity with gambling screening instruments, and standard drinks
      consumed while gambling demonstrated concurrent validity with a measure of
      alcohol misuse. The G-TLFB also demonstrated discriminant validity with
      demographic variables and a measure of positive impression management.

PMID- 15023095
TI  - Comparison of Hispanic children with and without limited English proficiency on
      the Naglieri Nonverbal Ability Test.
AB  - Hispanic children with (n=148) and without (n=148) limited English proficiency
      were given the Naglieri Nonverbal Ability Test (NNAT; J. A. Naglieri. 1997a) and
      the Stanford Achievement Test-9th edition (SAT-9: 1995). The groups were selected
      from the NNAT standardization sample (N=22.620) and matched on geographic region,
      gender, socioeconomic status, urbanicity. and ethnicity. There was a very small
      difference (d ratio=0.1) between the NNAT standard scores for the children with
      limited English proficiency (M - 98.0) and those without limited English
      proficiency (M=96.7). The NNAT correlated moderately and similarly with
      achievement for the 2 groups. The sample of children with limited English
      proficiency earned considerably lower scores on SAT-9 Reading and Verbal
      subtests. Results suggest that the NNAT may be useful for the assessment of
      Hispanic children with and without limited English proficiency.

PMID- 15023096
TI  - A confirmatory analysis of the factor structure and cross-age invariance of the
      Wechsler Adult Intelligence Scale-Third Edition.
AB  - In the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III; D. Wechsler,
      1997), the manual reports several confirmatory factor analyses in support of the
      instrument's latent factor structure. In practice, examiners frequently compare
      an examinee's score from a current administration of the WAIS-III with the
      results from a previous test administration. Implicit in test-retest score
      comparisons is evidence that scores retain similar interpretive meaning across
      time. Establishing an instrument's factorial invariance provides the foundation
      for this practice. This study investigated the factorial invariance of the WAIS
      III across the instrument's 13 age groups. The overall results from this study
      generally support both configural and factorial invariance of the WAIS-III when
      the 11 primary tests are administered.

PMID- 15023097
TI  - Confirmatory factor analysis of the psychopathy checklist: screening version in
      offenders with axis I disorders.
AB  - One hundred forty-nine inpatients within a maximum security psychiatric facility
      were assessed with the Psychopathy Checklist: Screening Version (PCL:SV; S. D.
      Hart, D. N. Cox, & R. D. Hare, 1995). Within the total sample, 68% had a
      psychotic disorder and 30% met criteria for psychopathy. Using confirmatory
      factor analysis, the authors tested the 2-factor PCL:SV model of psychopathy and
      recent 3- and 4-factor models. Results indicated good fit for each model, with
      the 4-factor model showing best overall fit. Structural equation modeling was
      used to determine which psychopathy factors predicted 6-month follow-up of
      inpatient aggression. The 2-, 3-, and 4-factor models, respectively, accounted
      for 16%.27%. and 3l% of the variance in aggression.

PMID- 15023098
TI  - Nitrous oxide or remifentanil for the "at risk" brain.

PMID- 15023099
TI  - Ethics again--hoops, loops and principles.

PMID- 15023100
TI  - Peri-operative troponin I concentration as a marker of long-term postoperative
      adverse cardiac outcomes--a study in high-risk surgical patients.
AB  - We have previously demonstrated that the peri-operative measurement of increased
      serum concentrations of the cardiac markers troponins I and T and creatine kinase
      MB can be predictors of major cardiovascular outcomes (including cardiac death)
      at 3 months after surgery. In the present study, we have followed the
      postoperative course of 157 patients undergoing major vascular surgery or major
      joint arthroplasty to 1 year using a patient questionnaire, general practitioner
      follow-up and case-notes review. Increased postoperative marker concentrations
      were defined as values greater than the upper reference limit. Increases in
      troponin I and troponin T concentrations, as well as a single elevated creatine
      kinase-MB and two successively elevated creatine kinase-MB concentrations were
      measured in 12, 13, 33 and 15 patients respectively. Thirty-nine major adverse
      cardiac outcomes were recorded (cardiac death, myocardial ischaemia, congestive
      cardiac failure, unstable angina, cerebrovascular accident and major arrhythmias
      needing active treatment). There was no association between increases in any of
      these cardiac markers and cardiac death to 1 year. However, increases in troponin
      I and both a single elevated creatine kinase-MB and two successively elevated
      creatine kinase-MB concentrations were associated with an increased incidence of
      major cardiac outcomes, including cardiac death, to 1 year (odds ratio [95%
      confidence intervals] = 4.19 [1.16-14.87], 3.97 [1.65-9.44] and 5.19 [1.60
      16.22], respectively).

PMID- 15023102
TI  - Second and subsequent surgical operations within 12 months of a first operation.
AB  - In a retrospective study, all patients having anaesthetic procedures within a 3
      month period were identified and followed up to establish if they had further
      procedures within a calendar year. The procedures undertaken on these patients
      were then identified to establish if a relationship existed between the
      procedures and what that relationship was. 11% of all patients returned for
      further procedures, 80% of which were within the same surgery specialty. In the
      overwhelming majority, the subsequent procedures were related to the first either
      as planned courses of treatment or by complications of the surgery or the disease
      process. The relationship between the procedures and their time intervals is
      discussed.

PMID- 15023101
TI  - Haemodynamic effects of a milrinone infusion without a bolus in patients
      undergoing off-pump coronary artery bypass graft surgery.
AB  - The haemodynamic effects of a continuous infusion of milrinone without an initial
      bolus dose were evaluated in patients undergoing off-pump coronary artery bypass
      graft surgery. After internal mammary artery harvest, milrinone 0.5 microg.min(
      1).kg(-1) (29 patients) or a normal saline infusion (33 patients) was started and
      continued until all graft anastomoses were completed. Haemodynamic variables were
      recorded before application of the tissue stabiliser, at 1, 3, 5 and 10 min after
      the application of the stabiliser, and after its removal. The administration of a
      milrinone infusion was associated with a smaller decrease in cardiac output and
      mixed venous oxygen saturation during all the coronary artery anastomoses, with
      no severe complications and a decreased dose of norepinephrine infused to
      maintain systemic arterial pressure.

PMID- 15023103
TI  - Odour identification as a marker for postoperative cognitive dysfunction: a pilot
      study.
AB  - The onset of postoperative cognitive dysfunction is delayed in some elderly
      surgical patients and the condition may persist. Increasing age is a risk factor
      for both postoperative cognitive dysfunction and dementia. Major surgery may
      unmask an underlying dementia; we report findings of a pilot study designed to
      inform this hypothesis. Impaired odour identification ability is a characteristic
      of the preclinical phase of some neuro-degenerative diseases. This pilot study
      was designed to establish whether odour identification deficit is a marker for
      postoperative cognitive dysfunction, particularly in elderly patients genetically
      predisposed to develop late-onset Alzheimer's disease. We found no association
      between odour identification ability and postoperative cognitive dysfunction in
      53 patients aged 62-86, undergoing major non-cardiac surgery under general
      anaesthesia. Our pilot study showed that a high number of patients genetically
      predisposed to develop Alzheimer's disease is required to test the utility of
      odour identification as a marker for postoperative cognitive dysfunction.

PMID- 15023104
TI  - Cerebral and extracerebral release of protein S100B in cardiac surgical patients.
AB  - Although several clinical studies have shown that increased serum concentrations
      of protein S100B predict ischaemic brain damage after cardiac surgery, S100B may
      also be released from the heart or other injured tissue. We therefore
      investigated the correlation between serum S100B levels and those of the specific
      cardiac marker troponin I in order to assess the cerebral vs. extracerebral
      origin of S100B. In 64 cardiac surgical patients, serial blood samples were drawn
      for the measurement of S100B and troponin I before surgery and for seven days
      after surgery. Neurological function was assessed before with the National
      Institutes of Health Stroke Scale and the Folstein Mini Mental Test. The data
      show that a sustained increase in serum S100B levels is associated with
      neurological dysfunction, as witnessed by a positive correlation between S100B
      values and the results of the neuropsychological tests. In contrast, the early
      postoperative increased levels of protein S100B derive from cardiac tissue, as
      shown by the positive correlation between S100B and cardiac troponin I levels.

PMID- 15023105
TI  - The effect of epidural analgesia in labour on maternal respiratory function.
AB  - Lumbar epidural analgesia during labour has gained widespread acceptance. The
      impact of epidural analgesia based on mixtures of low-dose local anaesthetic
      solutions and lipophilic opioids on most clinically relevant obstetric outcomes
      is minimal. Since the pregnant state per se is associated with important
      alterations in respiration, we assessed whether a subtle degree of motor blockade
      brought about by epidural analgesia might compromise respiratory function as
      assessed by spirometry. Sixty consenting parturients receiving epidural analgesia
      were consecutively included in this prospective study. We performed spirometry
      during the antepartum visit and in labour after effective epidural analgesia was
      established; at both assessments the women were pain-free. Values were within
      normal ranges but increased significantly after effective epidural analgesia;
      median (IQR [range]) increase for vital capacity 7.4 (3.0-13 [-12-27])% (p <
      0.001); forced vital capacity 4.4 (1.7-9.8 [-13-26])% (p < 0.001); forced
      expiratory volume in 1 s 5.5 (1.7-8.6 [-14-28])% (p < 0.001); and peak expiratory
      flow rate 2.3 (-1.6-5.8 [-18-16])% (p = 0.01)). We conclude that epidural
      analgesia for labour significantly improved respiratory function.

PMID- 15023106
TI  - Pre-operative information and patient-controlled analgesia: much ado about
      nothing.
AB  - We examined whether pre-operative information benefited patients receiving
      patient-controlled analgesia (PCA) after major surgery. We investigated whether
      patients felt better informed about PCA and also whether pre-operative
      information altered the use of PCA, the adequacy of pain relief, worries about
      addiction and safety, and knowledge of side-effects. We investigated the
      effectiveness of information provided in two ways, namely by a patient-determined
      leaflet or an interview by a trained nurse from the pain team, compared with
      routine pre-operative information. We studied 225 patients, 75 in each group.
      Patients in the leaflet group were better informed about PCA, became familiar
      with using PCA more quickly and were less confused about PCA than the control
      group. However, there were no effects on pain relief, worries about addiction and
      safety, and knowledge of side effects. The pre-operative interview resulted in no
      benefits. Our findings indicate that the detailed provision of pre-operative
      information failed to improve patients' experiences of PCA.

PMID- 15023107
TI  - The tenth rib line as a new landmark of the lumbar vertebral level during spinal
      block.
AB  - The purpose of this study was to assess whether the tenth rib line (an imaginary
      line that joins the lowest points of the rib cage on the flanks) could be used as
      a marker of the lumbar vertebral level. Simple X-rays (n = 100) were taken with
      radiopaque markers attached on the lowest points of the rib cage and the
      uppermost points of the iliac crests on both flanks. The spinous process or
      interspinous space that the tenth rib or Tuffier's lines crossed was identified
      and recorded, respectively, in the neutral and fully flexed positions. With
      lumbar flexion, the tenth rib line (median (25th to 75th percentiles)) moved
      upward (L(2) (L(1-2) - L(2)) vs. L(1-2) (L(1-2) - L(1-2)); p < 0.01), but
      Tuffier's line moved downward (L(4-5) (L(4) - L(4-5)) vs. L(4-5) (L(4) - L(5)); p
      < 0.01). Because the ease of palpating the tenth rib line and its distribution
      patterns are comparable to those of the Tuffier's line, the tenth rib line may be
      useful as a new landmark of the lumbar vertebral level as well as a safeguard to
      prevent spinal puncture from being mistakenly performed at a dangerously high
      level.

PMID- 15023108
TI  - Dantrolene--a review of its pharmacology, therapeutic use and new developments.
AB  - Human malignant hyperthermia is a life-threatening genetic sensitivity of
      skeletal muscles to volatile anaesthetics and depolarizing neuromuscular blocking
      drugs occurring during or after anaesthesia. The skeletal muscle relaxant
      dantrolene is the only currently available drug for specific and effective
      therapy of this syndrome in man. After its introduction, the mortality of
      malignant hyperthermia decreased from 80% in the 1960s to < 10% today. It was
      soon discovered that dantrolene depresses the intrinsic mechanisms of excitation
      contraction coupling in skeletal muscle. However, its precise mechanism of action
      and its molecular targets are still incompletely known. Recent studies have
      identified the ryanodine receptor as a dantrolene-binding site. A direct or
      indirect inhibition of the ryanodine receptor, the major calcium release channel
      of the skeletal muscle sarcoplasmic reticulum, is thought to be fundamental in
      the molecular action of dantrolene in decreasing intracellular calcium
      concentration. Dantrolene is not only used for the treatment of malignant
      hyperthermia, but also in the management of neuroleptic malignant syndrome,
      spasticity and Ecstasy intoxication. The main disadvantage of dantrolene is its
      poor water solubility, and hence difficulties are experienced in rapidly
      preparing intravenous solutions in emergency situations. Due to economic
      considerations, no other similar drugs have been introduced into routine clinical
      practice.

PMID- 15023109
TI  - Sleep disruption in critically ill patients--pharmacological considerations.
AB  - Sleep disturbances are common in critically ill patients and contribute to
      morbidity. Environmental factors, patient care activities and acute illness are
      all potential causes of disrupted sleep. Additionally, it is important to
      consider drug therapy as a contributing factor to this adverse experience, which
      patients perceive as particularly stressful. Sedative and analgesic combinations
      used to facilitate mechanical ventilation are among the most sleep disruptive
      drugs. Cardiovascular, gastric protection, anti-asthma, anti-infective,
      antidepressant and anticonvulsant drugs have also been reported to cause a
      variety of sleep disorders. Withdrawal reactions to prescribed and occasionally
      recreational drugs should also be considered as possible triggers for sleep
      disruption. Tricyclic antidepressants and benzodiazepines are commonly prescribed
      in the treatment of sleep disorders, but have problems with decreasing slow wave
      and rapid eye movement sleep phases. Newer non-benzodiazepine hypnotics offer
      little practical advantage. Melatonin and atypical antipsychotics require further
      investigation before their routine use can be recommended.

PMID- 15023110
TI  - Evaluation of a new continuous cardiac output monitor in off-pump coronary artery
      surgery.
AB  - We evaluated a new, ultra-fast response continuous cardiac output monitor in 34
      adult patients undergoing off-pump coronary artery bypass graft surgery. Cardiac
      output was measured with the TruCCOMS continuous cardiac output monitor (Aortech
      International plc, Lanarkshire, UK), using triplicate cold bolus thermodilution
      as the criterion standard, at fixed time points during surgery and during
      dobutamine infusion. The two techniques were compared using linear regression and
      Bland-Altman analysis. Overall, the study device displayed a bias of 0.4 l.min(
      1) with limits of agreement of +2.5 l.min(-1) and -1.7 l.min(-1). The study
      device failed to detect the change in cardiac output caused by dobutamine
      accurately (y = 0.18x + 0.45; r(2) = 0.13), with an error linearly related to the
      magnitude of the change measured. We conclude that the device's failure to detect
      changes in cardiac output could be a major limitation in its clinical use in its
      current form.

PMID- 15023111
TI  - Forehead SpO2 monitoring compared to finger SpO2 recording in emergency
      transport.
AB  - Continuous peripheral oxygen saturation monitoring using a finger pulse oximeter
      is standard in prehospital emergency medicine. Forehead peripheral oxygen
      saturation monitoring has been enhanced for better performance during movement
      and in cold ambient temperatures, both of which are common during emergency
      transport. We compared a new forehead monitor with standard finger pulse
      oximeter. The forehead technique had significantly fewer mean (SD) alarms per
      patient (3.0 (2.2)) than the finger pulse oximeter (7.8 (4.0)) and shorter
      durations of malfunction (76 (60) s compared to 333 (170) s) when using the
      finger pulse oximeter. We conclude that measuring peripheral oxygen saturation
      monitoring with a forehead sensor provides better monitoring quality in emergency
      care.

PMID- 15023112
TI  - The short, tragic life of Robert M. Glover.
AB  - Robert Mortimer Glover (1815-1859) was a contemporary of John Snow and James
      Young Simpson. Although he did not reach the standing of those two giants, his
      researches, writings and lectures were important contributions to the early
      development of British anaesthesia. Glover was the first to explore the
      physiological action of chloroform in the laboratory and to discover its
      anaesthetic effect in 1842. He helped Sir John Fife in Hannah Greener's autopsy
      in January 1848 and influenced Fife's conclusions on the cause of the young
      girl's death. His numerous and extensive articles reviewing the history,
      chemistry, pharmacology and clinical applications of various anaesthetics were
      widely read and quoted by his colleagues, including John Snow. While in Edinburgh
      and Newcastle, Glover was recognised as a remarkably astute physician, original
      researcher, prolific writer and enthusiastic lecturer with an enormous knowledge
      of medicine, the physical sciences, mathematics and philosophy. His brilliant
      career deteriorated after his arrival in London and, especially, after his return
      from the Crimea, although he continued to publish until the week before his
      death. The causes of his decline remain obscure. The last year of his life was
      ruined by his addiction to chloroform, to whose development he had contributed so
      much, and which killed him at the early age of 43.

PMID- 15023113
TI  - Disruption of cleft palate repair following the use of the laryngeal mask airway.
AB  - A 55-year-old man was admitted for routine examination of ears with insertion of
      grommets under general anaesthesia. At 2 years of age he had undergone successful
      repair of cleft lip and palate. A reinforced laryngeal mask airway was employed
      to maintain the airway. Postoperatively, it was evident he had suffered complete
      disruption of the soft palate repair, leading to velopharyngeal insufficiency
      with nasal regurgitation of fluids. We discuss the possible aetiology, having
      found no such reported injury pattern documented in the literature.

PMID- 15023114
TI  - On research and originality.

PMID- 15023115
TI  - Cardiac risk scoring.

PMID- 15023116
TI  - Ethics of training in regional anaesthesia.

PMID- 15023117
TI  - Monitoring and redundancy.

PMID- 15023119
TI  - Can patients tell where epidural catheters go?

PMID- 15023118
TI  - Nitrous oxide in neuroanaesthesia.

PMID- 15023120
TI  - Malposition of a left-sided central venous pressure line.

PMID- 15023121
TI  - Use of the laryngeal tube by paramedic staff.

PMID- 15023122
TI  - Less invasive lung volume reduction surgery.

PMID- 15023124
TI  - A new video laryngoscope.

PMID- 15023125
TI  - Hazards of submental tracheal intubation.

PMID- 15023123
TI  - Why 5% risk of type-1 error but 20% risk of type-2 error?

PMID- 15023126
TI  - Acute orbital cellulitis after sub-Tenon's eye block.

PMID- 15023127
TI  - Mentor system for anaesthesia trainees.

PMID- 15023128
TI  - Hand washing.

PMID- 15023129
TI  - Reluctance of anaesthetists to perform awake intubation.

PMID- 15023130
TI  - Dystonic reaction to cyclizine.

PMID- 15023131
TI  - Quick calculations for infusions.

PMID- 15023132
TI  - Malfunctioning transducer cable causes underestimation of arterial blood
      pressure.

PMID- 15023136
TI  - Biomarkers and surrogate endpoints in renal transplantation: present status and
      considerations for clinical trial design.
AB  - Of major importance in clinical trials is the ability to predict individual
      patient outcome or endpoints using biomarkers, also known as variables or
      predictors, in as safe, efficient, and accurate a manner as possible. This review
      addresses the concepts and possible strategies for use of predictor and surrogate
      biomarkers in the design of clinical trials in renal transplantation. The
      statistical concepts apply equally well to other organ grafts.

PMID- 15023137
TI  - Adult living donor liver transplantation.
AB  - Adult living donor liver transplantation (LDLT) begun in response to deceased
      donor organ shortage and waiting list mortality, grew rapidly after its first
      general application in the United States in 1998. There are significant risks to
      the living donor, including the risk of death and substantial morbidity, and two
      highly publicized donor deaths have led to decreased LDLT since 2001. Significant
      improvements in outcomes have been seen over recent years that have not been
      reported in single center studies; however, LDLT still comprises less than 5% of
      adult liver transplants, significantly less than in kidney transplantation where
      living donors now comprise the majority. The ethics, optimal utility and
      application of LDLT remain to be defined. In addition, studies to date have
      focused on post-transplant outcomes and not included the potential impact of LDLT
      on waiting time mortality. Future analyses should include appropriate control or
      comparison groups that capture the effect of LDLT on overall mortality from the
      time of listing. Further growth of LDLT will depend on defining the optimal
      recipient and donor characteristics for this procedure as well as broader
      acceptance and experience in the public and in transplant centers.

PMID- 15023138
TI  - Acute graft versus host disease following liver transplantation: the enemy
      within.
AB  - This article reviews acute graft vs. host disease (GVHD) as a complication of
      orthotopic liver transplantation (OLT). The incidence, presentation, clinical
      course and outcome of GVHD after OLT are summarized and the pathogenesis is
      discussed, drawing parallels with GVHD after allogeneic haematopoietic stem cell
      transplantation. Risk factors for GVHD after OLT are examined and the potential
      role of donor lymphocyte macrochimerism in the recipient peripheral blood as a
      diagnostic aid for GVHD is discussed. Finally, treatment of GVHD after OLT is
      reviewed with particular emphasis on the potential role of some of the newer
      biological agents.

PMID- 15023139
TI  - Ureteral stenosis in HDAF pig-to-primate renal xenotransplantation: a phenomenon
      related to immunological events?
AB  - The aim of this study was to analyze the incidence of ureteral stenosis in a life
      supporting human decay-accelerating factor (hDAF) transgenic pig-to-cynomolgus
      monkey kidney transplantation model and determine the role of possible
      immunological events in its pathogenesis. Thirty consecutive bi-nephrectomized
      cynomolgus monkeys received a kidney from hDAF transgenic pigs with or without a
      ureteral stent. Four monkeys were euthanized prematurely after transplantation.
      In the remaining 26 cases, the mean survival was 24 +/- 19 days. Except in one
      case, there was a close relationship between ureter and kidney in terms of type
      and severity of rejection. There were six ureteral stenoses; five were repaired
      by stent positioning and resurgery extended survival for an additional 16 +/- 10
      days. The stenotic ureters showed diffuse acute humoral xenograft rejection
      (AHXR), while all cases with no or only focal signs of ureteral rejection never
      revealed ureteral obstruction. Use of a ureteral stent extends the survival of a
      xenografted primate, thereby helping to clarify the immunological events
      surrounding the onset of AHXR in kidneys in long-term xenograft recipients.

PMID- 15023141
TI  - Protective roles of polyethylene glycol and trimetazidine against cold ischemia
      and reperfusion injuries of pig kidney graft.
AB  - Ischemia-reperfusion injury (IRI) represents an allo-independent risk factor
      which favors chronic allograft nephropathy (CAN). Here we analyzed the influence
      of preservation solutions on the function of autotransplanted pig kidneys over 1
      16 weeks after surgery. Kidneys were cold-flushed and cold-stored for 24 or 48 h
      either in University of Wisconsin (UW), modified-UW Hopital Edouard Herriot,
      polyethylene glycol 20 kDa (PEG)-supplemented preservation solutions with low K+
      (ECPEG) or high K+ (ICPEG) content. Animals autotransplanted with kidneys cold
      stored for 24 h in ECPEG exhibited the greatest levels of creatinine clearance
      (Ccr: 161 +/- 12 mL/min, n=10) and the lowest levels of proteinuria (0.5 +/- 0.03
      mg/mL) 16 weeks after surgery as compared with pigs autotransplanted with kidneys
      cold-stored in the other solutions tested (Ccr ranging from 80 and 140 mL/min).
      Similar differences, but with lower Ccr levels, were achieved after a prolonged
      period of cold-storage(48 h). ECPEG better preserved the kidneys from
      monocytes/macrophages and CD4+ T cells infiltrations, VCAM-1 and MHC class II
      overexpressions and occurrence of renal interstitial fibrosis (2%) as compared
      with the other preservation solutions (5%-20%). Adding the anti-ischemic drug
      trimetazidine (TMZ) to the preservation solutions, particularly ECPEG, further
      improved the quality of the week-16 post-transplanted kidneys (Ccr: 182 +/- 12
      mL/min, n=10). These findings demonstrated that adding PEG to extracellular-like
      (with low K+ content) preservation solutions in combination with TMZ
      significantly improved the long-term outcome of kidney grafts in this model of
      autotransplanted pig kidney.

PMID- 15023140
TI  - Exogenous IL-6 inhibits acute inflammatory responses and prevents
      ischemia/reperfusion injury after intestinal transplantation.
AB  - Interleukin-6 (IL-6) is a pleiotropic acute reactant cytokine involved in
      inflammatory responses. To explore the role of IL-6 in inflammation, this study
      examined the efficacy of exogenous IL-6 in preventing intestinal
      ischemia/reperfusion (I/R) injury associated with small bowel transplantation
      (SBTx). Syngenic orthotopic SBTx was performed in Lewis rats after 6-h graft
      preservation in University of Wisconsin (UW) at 4 degrees C. IL-6 mutein (IL-6m,
      500 microg/kg), a recombinant molecular variant of human IL-6, was subcutaneously
      given to donors 2 h before harvesting (IL-6mD) or to excised grafts by luminal
      infusion (IL-6mG). Animal survival was 100% and 75% in IL-6mD (p<0.05 vs.
      control) and IL-6mG groups, respectively, compared with 64.3% in untreated
      controls. The severity of I/R injury (e.g. epithelial denudation, villous
      congestion) was reduced with IL-6m, in addition to a striking increase in re
      epithelization. With IL-6m, neutrophil extravasation was markedly reduced in
      intestinal grafts and in remote organs (e.g. lung). IL-6m mediated anti
      inflammatory effects through the inhibition of I/R-induced up-regulation of
      intragraft and circulating IL-1-beta, tumor necrosis factor-alpha (TNF-alpha) and
      IL-6. IL-6m also increased intestinal graft tissue blood flow. These results show
      that IL-6 is effective in protecting the intestine from cold I/R injury by
      maintaining graft blood flow and reducing pro-inflammatory cytokine up-regulation
      and neutrophil infiltration.

PMID- 15023142
TI  - Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents
      rejection of cardiac allografts in mice.
AB  - T cell immune response c-DNA (TIRC7) is up-regulated during the early stages of T
      cell activation in response to alloantigens. In this study, we analyzed the
      effects of newly developed monoclonal antibodies (mAb) against TIRC7 in acute
      cardiac allograft rejection. Fully vascularized heterotopic allogeneic heart
      transplantation was performed in mice across a full-mismatch barrier (C57Bl/10
      into CBA). Recipients received seven injections (day 0-7) of a novel anti-TIRC7
      mAb or remained untreated. Graft survival, histology and ex vivo lymphocyte
      functions were tested. Targeting of TIRC7 with an anti-TIRC7 mAb diminishes
      lymphocyte infiltration into grafts resulting in delay of morphological graft
      damage and prolongation of allograft survival. The lymphocytes from anti-TIRC7
      mAb-treated animals exhibit hypo-responsiveness without evidence of lymphocyte
      depletion against the donor allo-antigens. Proliferation and expression of
      interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) were
      down-regulated while interleukin-4 (IL-4) and IL-10 expression were spared.
      Moreover, anti-TIRC7 mAb enhanced up-regulation of CTLA-4 expression but
      suppressed up-regulation of CD25 on stimulated lymphocytes in vitro and in vivo.
      Ligation of TIRC7 has important effects on the regulation of co-stimulatory
      signaling pathways associated with suppressing of T-cell activation. Targeting of
      TIRC7 may therefore provide a novel therapeutic approach for modulating T cell
      immune responses during organ transplantation.

PMID- 15023143
TI  - Characterization of pig intercellular adhesion molecule-2 and its interaction
      with human LFA-1.
AB  - Understanding molecular interactions between human leukocytes and porcine
      endothelium is important for the future success of pig-to-human
      xenotransplantation. Here we describe the analysis of pig intercellular adhesion
      molecule-2 (ICAM-2). A 1020-basepair ICAM-2 cDNA generated from pig lung RNA
      contained an open reading frame (ORF) encoding a 277-amino-acid protein with six
      potential N-linked glycosylation sites. The mature protein sequence was 55%
      identical to human ICAM-2, with conservation of five out of six residues critical
      for binding of the human protein to its ligand LFA-1. Northern blot analysis
      identified ICAM-2 transcripts of 4.0 and 1.4 kb in cultured pig endothelial cells
      and mRNA was detected in pig lung, spleen, kidney, liver and heart by RT-PCR. The
      gene structure and endothelial expression of pig ICAM-2 were strikingly similar
      to those of its human and mouse counterparts. However, unlike human ICAM-2,
      expression of pig ICAM-2 on cultured endothelial cells was not down-regulated by
      treatment with the inflammatory cytokines TNF-alpha and IL-1beta. Pig ICAM-2
      expressed on stable transfectants supported firm adhesion of cells expressing
      human LFA-1. This conservation of function across the species barrier suggests
      that pig ICAM-2 plays a role in the cellular interactions associated with
      xenograft rejection.

PMID- 15023144
TI  - Multiple combination therapies involving blockade of ICOS/B7RP-1 costimulation
      facilitate long-term islet allograft survival.
AB  - In recent years a series of novel costimulatory molecules have been identified,
      including inducible costimulator (ICOS). In a fully major histocompatibility
      complex (MHC)-mismatched mouse model of islet transplantation, we demonstrate
      that while monotherapy with CTLA4-Ig, CD40 ligand monoclonal antibody (CD40L mAb)
      or rapamycin each improves islet allograft survival, graft rejection eventually
      develops. Immunohistologic analysis of rejected grafts revealed increased ICOS
      expression, suggesting a role for this costimulatory molecule as an alternate
      pathway for T-cell activation. The combination of a blocking anti-ICOS mAb with
      each of the above therapies resulted in significantly improved islet allograft
      survival, confirming the importance of ICOS signaling in islet allograft
      rejection. Mechanistic studies conducted in mice treated with anti-ICOS mAb and
      rapamycin demonstrated a lack of donor-specific immunological tolerance and an
      absence of regulatory T-cell activity. However, a dramatic effect was seen on
      acute anti-donor responses whereby anti-ICOS mAb and rapamycin significantly
      reduced the initial expansion and function of alloreactive T cells. These data
      demonstrate that blockade of the ICOS/B7RP-1 pathway has potential therapeutic
      benefit given its role in enhancing islet allograft survival and regulating acute
      alloresponses in vivo.

PMID- 15023145
TI  - Immune regulation and graft survival in kidney transplant recipients are both
      enhanced by human leukocyte antigen matching.
AB  - We hypothesized that donor/recipient sharing of the human leukocyte antigen (HLA)
      involved in allopeptide presentation to the T regulatory cell increases the
      incidence of immune regulation, thus contributing to long-term graft survival.
      Peripheral blood mononuclear cells (PBMC) were obtained from 40 living related
      donor (LRD) and 31 cadaver renal transplant recipients. The trans vivo delayed
      type hypersensitivity (DTH) assay was used to assign patients to regulator,
      nonregulator, and sensitized categories. In a large cohort (n=1934 patients),
      primary graft survival and rejection episodes were analyzed using a log rank test
      for comparison with the DTH results. The highest incidence of regulated anti
      donor DTH was observed in the LRD HLA-identical group (6/6; 100%) followed by the
      LRD HLA 1 haplotype matched group (18/27; 67%). Within the cadaver population,
      two DR-matched recipients had a higher frequency of regulated anti-donor DTH
      (6/11; 55%) than 1 & 0 DR-matched recipients (3/18; 17%). In a multivariate
      model, matching for HLA-DR alone, or for DR plus DQ was significantly (p=0.045,
      p=0.041) correlated with DTH regulation. The better HLA-matched groups showed the
      highest incidence of DTH regulation and, in a larger retrospective analysis,
      displayed better graft survival and freedom from acute rejection (p<0.0001). HLA
      matching, and HLA-DR matching in particular, correlates with the incidence of
      immune regulation after kidney transplantation.

PMID- 15023146
TI  - Impact of portal venous pancreas graft drainage on kidney graft outcome in
      simultaneous pancreas-kidney recipients reported to UNOS.
AB  - Clinical data on the potential immunologic impact of portal (PD) vs. systemic
      (SD) venous pancreas graft drainage on outcome remains controversial. We reviewed
      the UNOS database to study the effect of PD vs. SD on the incidence of kidney
      graft rejection and survival in first cadaveric simultaneous pancreas-kidney
      (SPK) recipients transplanted 1994-2001. We studied three groups: all SPK
      (n=6629, 13% PD) (group I), SPK on tacrolimus (n=3563, 17% PD) (group II), and
      SPK on tacrolimus performed at centers with significant PD experience (n=948, 46%
      PD) (group III). The cumulative kidney graft rejection incidence for PD vs. SD
      was only significantly different in group I (for PD vs. SD, respectively: at 6
      months, 31% vs. 36% [p=0.015]; at 1 year, 37% vs. 43% [p=0.006]). Kidney graft
      survival was similar in all groups for PD vs. SD. Multivariate analysis of group
      III showed only transplantation during the earlier era (1994-96), but not SD, to
      be an independent risk factor for kidney graft rejection. Portal venous pancreas
      graft drainage does not affect kidney graft rejection and survival in SPK
      recipients on tacrolimus. Our data suggests that the efficacy of current
      immunosuppressive protocols and increasing center experience are clinically much
      more relevant than any potential immunologic advantage of portal venous drainage
      in SPK recipients.

PMID- 15023147
TI  - Tolerance of liver transplant patients to strenuous physical activity in high
      altitude.
AB  - Physical functioning is improved after liver transplantation but studies
      comparing liver transplant recipients with normal healthy people are lacking. How
      liver (and other organ) transplant recipients tolerate strenuous physical
      activities is unknown. There are no data on the tolerance of transplant patients
      at high altitude. Six liver transplant subjects were selected to participate in a
      trek up Mount Kilimanjaro 5895 m, Tanzania. Physical performance and
      susceptibility to acute mountain sickness were prospectively compared with
      fifteen control subjects with similar profiles and matched for age and body mass
      index. The Borg-scale (a rating of perceived exertion) and cardiopulmonary
      parameters at rest were prospectively compared with six control subjects also
      matched for gender and VO2max. Immunosuppression in transplant subjects was based
      on tacrolimus. No difference was seen in physical performance, Borg-scales and
      acute mountain sickness scores between transplant and control subjects. Eight
      three percent of transplant subjects and 84.6% of control subjects reached the
      summit (p=0.7). Oxygen saturation decreased whereas arterial blood pressure and
      heart rate increased with altitude in both groups. The only difference was the
      development of arterial hypertension in transplant subjects at 3950 m (p=0.036).
      Selected and well-prepared liver transplant recipients can perform strenuous
      physical activities and tolerate exposure to high altitude similar to normal
      healthy people.

PMID- 15023149
TI  - Cost-effectiveness of organ donation: evaluating investment into donor action and
      other donor initiatives.
AB  - Initiatives aimed at increasing organ donation can be considered health care
      interventions, and will compete with other health care interventions for limited
      resources. We have developed a model capable of calculating the cost-utility of
      organ donor initiatives and applied it to Donor Action, a successful
      international program designed to optimize donor practices. The perspective of
      the payer in the Canadian health care system was chosen. A Markov model was
      developed to estimate the net present value incremental lifetime direct medical
      costs and quality adjusted life years (QALYs) as a consequence of increased
      kidney transplantation rates. Cost-saving and cost-effectiveness thresholds were
      calculated. The effects of changing the success rate and time frame of the
      intervention was examined as a sensitivity analysis. Transplantation results in a
      gain of 1.99 QALYs and a cost savings of Can$104,000 over the 20-year time frame
      compared with waiting on dialysis. Implementation of an intervention such as
      Donor Action, which produced as few as three extra donors per million population,
      would be cost-effective at a cost of Can$1.0 million per million population. The
      cost-effectiveness of Donor Action and other organ donor initiatives compare
      favorably to other health care interventions. Organ donation may be underfunded
      in North America.

PMID- 15023148
TI  - Successful renal transplantation across simultaneous ABO incompatible and
      positive crossmatch barriers.
AB  - ABO incompatibility and human leukocyte antigen (HLA) sensitization remain the
      two largest barriers to optimal utilization of kidneys from live donors. Here we
      describe the first successful transplantation of patients who were both ABO
      incompatible and crossmatch positive with their only available donor. A
      preconditioning regimen of plasmapheresis (PP) and low-dose CMV hyperimmune
      globulin (CMVIg) was delivered every other day until donor-specific antibody
      (DSA) titers were reduced to a safe level and isoagglutinin titers were < or =16.
      Each patient received quadruple sequential immunosuppression, splenectomy and
      three protocol post-transplant PP/CMVIg treatments. There was no hyperacute
      rejection. Two of the three patients had a persistent positive cytotoxic
      crossmatch on the day of transplant and eliminated their DSA subsequently.
      Antibody-mediated rejection (AMR) in one patient was reversed by reinitiating
      PP/CMVIg and anti-CD20. The patients are more than 9 months post-transplant with
      excellent graft function. Preconditioning with PP/CMVIg results in a durable
      suppression of DSA and permits accommodation of the allograft to a discordant
      blood type. The ability to cross these two barriers simultaneously is clinically
      important as sensitized patients have often exhausted their blood type compatible
      living donors during previous transplants.

PMID- 15023150
TI  - Infected bilomas in liver transplant recipients, incidence, risk factors and
      implications for prevention.
AB  - Bilomas, infected hepatic fluid collections, are a frequent complication of liver
      transplantation. We report a case-control cohort study to determine the incidence
      and microbiologic profile of bilomas and risk factors for biloma formation in 492
      patients undergoing liver transplantation from 1994 to 2001. Fifty-seven patients
      (11.5%) developed one or more bilomas; 95% in the first year post
      transplantation. The most common initial infecting pathogens were enterococci
      (37%), one-half resistant to vancomycin (VRE); coagulase-negative staphylococci
      (26%); and Candida species (26%). Infection by coagulase-negative staphylococci
      was strongly associated with the presence of a T-tube (OR 9.60, p=0.02). In
      stepwise logistic regression multivariable analyses, hepatic artery thrombosis
      (OR 90.9, p<0.0001), hepatic artery stenosis (OR 13.2, p<0.0001) and Roux-en-Y
      choledochojejunostomy (OR 5.8, p=0.03) were independent risk factors for biloma
      formation; ursodeoxycholic acid use was highly protective (OR 0.1, p=0.002).
      Strategies to prevent biloma formation must focus on measures to prevent hepatic
      artery thrombosis and colonization of liver transplant patients by multiresistant
      nosocomial pathogens. T-tube drainage post-transplantation bears reassessment.
      The protective effect of ursodeoxycholic acid found in this study warrants
      confirmation in a prospective multicenter, randomized trial.

PMID- 15023151
TI  - New onset diabetes mellitus in patients receiving calcineurin inhibitors: a
      systematic review and meta-analysis.
AB  - New onset diabetes mellitus (NODM) is a serious complication of transplantation.
      This meta-analysis evaluates the reported incidence of NODM after solid organ
      transplantation in patients receiving CNI treatment. Databases from January 1992
      to April 2002 were searched. Fifty-six publications providing NODM incidence data
      were reviewed. Sixteen prospective, randomized comparative studies providing
      information on incidence of insulin-dependent diabetes mellitus (IDDM) were
      subjected to meta-analysis. New onset diabetes mellitus was reported in 13.4% of
      patients after solid organ transplantation, with a higher incidence in patients
      receiving tacrolimus than cyclosporine (16.6% vs. 9.8%). This trend was observed
      across renal, liver, heart and lung transplant groups. Meta-analysis of 16
      studies included patients receiving either tacrolimus (n=1636) or cyclosporine
      (n=1407). The incidence of IDDM was significantly higher among tacrolimus-treated
      patients (10.4% vs. 4.5%, p<0.00001), an effect observed in renal (9.8% vs. 2.7%
      p<0.00001) and nonrenal (11.1% vs. 6.2%; p<0.003) groups, and among patients
      receiving equal doses of concomitant medication in both treatment arms (12.0% vs.
      3.0%; p<0.00001). The reported incidence of NODM during the past decade was
      significantly higher among patients receiving tacrolimus than cyclosporine. These
      data provide a quantitative foundation for studies designed to reduce the rates
      of NODM following solid organ transplantation.

PMID- 15023152
TI  - De novo internal neoplasms after liver transplantation: increased risk and
      aggressive behavior in recent years?
AB  - The goal of the study was to determine the incidence and variables associated
      with post-liver transplantation (LT) de novo internal neoplasms development,
      excluding skin tumors and hepatocellular carcinoma. Medical records were reviewed
      for recipient/donor demographics, viral serology, cause of liver disease,
      interval from LT to tumor diagnosis, predisposing factors, immunosuppression and
      survival. Forty-one neoplasms (31 solid and 10 hematologic) developed in 772
      recipients (5.3%) transplanted between 1991 and 2001. Time to tumor diagnosis was
      longer in patients transplanted before 1995 than in those transplanted afterwards
      (58 vs. 22 months; p<0.05). Hematologic neoplasms (HN) appeared earlier than
      solid (2 vs. 21 months; p<0.001), were more prevalent in those transplanted after
      1995 than before (32% vs. 12.5%), and had lower survival than solid (2 vs. 21
      months, p<0.001). While HCV was the most frequent indication in HN (70%), alcohol
      was that of solid tumors (71%). Overall, risk factors for de novo neoplasms
      included alcohol and immunosuppression (p<0.01). In patients undergoing LT in
      recent years, there is a higher incidence of HN with de novo internal neoplasms
      developing at earlier time-points than in those transplanted years ago. Risk
      factors for tumor development include alcohol, HCV and possibly strong
      immunosuppression.

PMID- 15023153
TI  - The impact of donor obesity on outcomes after cadaver pancreas transplants.
AB  - We examined the impact of donor obesity on surgical complications and graft
      function after pancreas transplants. From January 1994 through December 2001, we
      performed 711 cadaver pancreas transplants. We analyzed outcomes for three groups
      based on donor body mass index (BMI): <25 kg/m2 (n=434), 25-30 (n=196), and >30
      (n=81). Donor characteristics were similar between the three groups except for
      donor cause of death. Cerebrovascular deaths were more common in the BMI >30
      group (p=0.002), while trauma deaths were more common in the BMI <25 group
      (p=0.02). In the BMI >30 group, surgical complications, most notably surgical
      infections and thrombosis, were significantly more common; in addition, technical
      failure rates were higher and short-term graft survival was inferior. The
      incidence of technical failure was 9.7% in the BMI <25 group, 16.3% in the BMI 25
      30 group, and 21.0% in the BMI >30 group (p=0.04). However, when we looked at
      only technically successful transplants, we found minimal differences in the
      three groups with regard to graft survival at 1 and 3 years posttransplant. Donor
      obesity increased the incidence of surgical complications in our pancreas
      recipients, but did not affect initial graft function posttransplant. Technically
      successful transplants using obese donors results in good graft function at 1 and
      3 years posttransplant.

PMID- 15023154
TI  - Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of
      cytomegalovirus disease in solid organ transplant recipients.
AB  - We compared the efficacy and safety of valganciclovir with those of oral
      ganciclovir in preventing cytomegalovirus (CMV) disease in high-risk seronegative
      solid organ transplant (SOT) recipients of organs from seropositive donors (D+/R
      ). In this randomised, prospective, double-blind, double-dummy study, 364 CMV
      D+/R- patients received valganciclovir 900 mg once daily or oral ganciclovir 1000
      mg three times a day (tid) within 10 days of transplant and continued through 100
      days. CMV disease, plasma viremia, acute graft rejection, graft loss and safety
      were analyzed up to 6 and 12 months post-transplant. Endpoint committee-defined
      CMV disease developed in 12.1% and 15.2% of valganciclovir and ganciclovir
      patients, respectively, by 6 months, though with a difference in the relative
      efficacy of valganciclovir and ganciclovir between organs (i.e. an organ type
      treatment interaction). By 12 months, respective incidences were 17.2% and 18.4%,
      and the incidence of investigator-treated CMV disease events was comparable in
      the valganciclovir (30.5%) and ganciclovir (28.0%) arms. CMV viremia during
      prophylaxis was significantly lower with valganciclovir (2.9% vs. 10.4%;
      p=0.001), but was comparable by 12 months (48.5% valganciclovir vs 48.8%
      ganciclovir). Time-to-onset of CMV disease and to viremia were delayed with
      valganciclovir; rates of acute allograft rejection were generally lower with
      valganciclovir. Except for a higher incidence of neutropenia with valganciclovir
      (8.2%, vs 3.2% ganciclovir) the safety profile was similar for both drugs.
      Overall, once-daily oral valganciclovir was as clinically effective and well
      tolerated as oral ganciclovir tid for CMV prevention in high-risk SOT recipients.

PMID- 15023155
TI  - Pharmacokinetics of tacrolimus in kidney transplant recipients: twice daily
      versus once daily dosing.
AB  - Tacrolimus a macrolide immunosuppressant that is routinely given in two equally
      divided doses every 12 h. However, the time-dependent pharmacokinetics of
      tacrolimus suggest that once daily morning administration of tacrolimus may
      produce appropriate drug exposure. The purpose of this pilot study was to compare
      the pharmacokinetics and safety of twice vs. once daily administration of
      tacrolimus in stable kidney transplant recipients. Steady-state tacrolimus
      pharmacokinetic parameters were estimated on two occasions in an open-label,
      three-arm, two-period sequential study: twice daily dosing (Phase I) and once
      daily dosing (Phase II). In phase II, 18 patients were assigned to one of three
      arms: those taking 67%, 85% and 100% of their total twice daily dose once in the
      morning. In phase I, the mean area under the blood concentration-time curve (AUC)
      was higher after the morning dose, AUC(0-12) 117 +/- 40 vs. AUC(12-24) 97 +/- 30
      ng/h/mL, p=0.012. In the 85% Group, the mean AUC ratio between twice and once
      daily was 1.0 (95% CI, 0.9-1.1) which predicted the best conversion ratio.
      Tacrolimus given once daily in the morning, at 85% of the twice daily dose,
      provides safe and equivalent drug exposure to twice daily dosing. This convenient
      dosing schedule may help to increase compliance and lower costs.

PMID- 15023156
TI  - Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6
      month safety and efficacy results of two randomized studies.
AB  - Two prospective, randomized studies evaluated everolimus 1.5 vs. 3 mg/day with
      steroids and low-exposure cyclosporine (CsA) (C2 monitoring) in de novo renal
      transplant patients. Everolimus dosing was adjusted to maintain a minimum trough
      level of 3 ng/mL. Study 1 (A2306; n=237) had no induction therapy; in Study 2
      (A2307; n=256) basiliximab was administered (Days 0 and 4). The primary endpoint
      was renal function at 6 months. CsA C2 target levels, initially 1200 ng/mL in
      Study 1 and 600 ng/mL in Study 2, were tapered over time post-transplant. Median
      creatinine levels in Study 1 were 133 and 132 micromol/L at 6 months in the 1.5
      and 3 mg/day groups, respectively, and 130 micromol/L in both groups in Study 2.
      Biopsy-proven acute rejection (BPAR) occurred in 25.0% and 15.2% of patients in
      the 1.5 and 3 mg/day groups in Study 1, and 13.7% and 15.1% in Study 2. Incidence
      of BPAR was significantly higher in patients with an everolimus trough <3 ng/mL.
      There were no significant between-group differences in the composite endpoint of
      BPAR, graft loss or death, nor any significant between-group differences in
      adverse events in either study. Concentration-controlled everolimus with low
      exposure CsA provided effective protection against rejection with good renal
      function.

PMID- 15023157
TI  - Risk factors of invasive aspergillosis after heart transplantation: protective
      role of oral itraconazole prophylaxis.
AB  - The study was designed to identify a subset of heart transplant (HT) recipients
      who could benefit from the administration of targeted antifungal prophylaxis and
      to evaluate the efficacy of oral itraconazole as the preventive drug. We have
      analyzed the risk factors for invasive aspergillosis (IA) in our entire
      population of HT recipients (1988-2002) and also the role of oral itraconazole
      prophylaxis that was provided to all patients since 1995 [400 mg q.d. of
      itraconazole oral (PO) for 3-6 months]. There were 24 cases of IA. Our main
      results indicate that the independent risk factors for IA after heart
      transplantation are: re-operation (RR 5.8; 95% CI 1.8-18, p=0.002),
      cytomegalovirus (CMV) disease (RR 5.2; 95% CI 2-13.9, p=0.001), post-transplant
      hemodialysis (RR 4.9; 95% CI 1.2-18, p=0.02), and the existence of an episode of
      IA in the HT program 2 months before or after the transplantation date (RR 4.6;
      95% CI 1.5-14.4, p=0.007). Itraconazole prophylaxis showed an independent
      protective value against developing IA (RR 0.2; 95% CI 0.07-0.9, p=0.03) and also
      determined a significantly prolonged 1-year survival (RR 0.5; 95% CI 0.3-0.8,
      p=0.01). We believe that antifungal prophylaxis in heart transplant patients
      should be offered at least to patients with one or more of these predisposing
      conditions.

PMID- 15023158
TI  - Clinical utility of cytomegalovirus viral load testing for predicting CMV disease
      in D+/R- solid organ transplant recipients.
AB  - Despite prophylaxis, cytomegalovirus (CMV) disease is common in donor
      seropositive (D+)/recipient seronegative (R-) transplant patients after cessation
      of prophylaxis. Early detection of CMV may allow for pre-emptive therapy to
      prevent active disease. The clinical utility of quantitative plasma viral load
      measurements for predicting CMV disease was determined in 364 D+/R- organ
      transplant patients receiving prophylaxis (100 d of valganciclovir or oral
      ganciclovir). Measurements were performed every 2 weeks until day 100 and at
      months 4, 4.5, 5, 6, 8 and 12 post-transplant. CMV disease occurred in 64 (17.6%)
      patients by 12 months. Using a positive cut-off value of >400 copies/mL,
      sensitivity was 38%, specificity 60%, positive predictive value 17%, and negative
      predictive value 82% for prediction of CMV disease. Therefore, routine monitoring
      would have predicted disease in only 24/64 (38%) patients. The test
      characteristics were not improved by changing the viral load cut-off point for
      defining a positive result. Similarly, single time point measures at the end of
      prophylaxis or month 4 had low sensitivity for disease prediction. Overall,
      regular CMV plasma viral load measurements were only of modest value in
      predicting CMV disease.

PMID- 15023159
TI  - Glomerular enlargement assessed by paired donor and early protocol renal
      allograft biopsies.
AB  - The aim of the study was to evaluate the evolution of glomerular volume 4 months
      after transplantation. Mean glomerular volume (Vg) was estimated according to the
      Weibel and Gomez method in a donor and a protocol biopsy done at 139 +/- 58 d in
      41 stable grafts. Biopsies were also evaluated according to the Banff schema. Vg
      increased after transplantation from 4.1 +/- 1.4 to 5.1 +/- 2.4 x 10(6) micro3
      (p=0.02). In patients with chronic allograft nephropathy in the protocol biopsy
      (n=14), the Vg enlargement was -0.3 +/-x 10(6) micro3 while in patients without
      chronic allograft nephropathy (n=27), glomerular enlargement was 1.6 +/- 2.1 x
      10(6) micro3 (p=0.01). There was a negative association between glomerular volume
      in the donor biopsy and glomerular enlargement after transplantation (R=- 0.34,
      p=0.03). Multivariate regression analysis confirmed that Vg in the donor biopsy
      and chronic allograft nephropathy in the protocol biopsy were independent
      predictors of glomerular enlargement after transplantation (R=0.48, p=0.01).
      Moreover, Vg in the protocol biopsy correlated with creatinine clearance at the
      time of biopsy (R=0.38, p=0.01). Glomeruli enlarge after transplantation and
      glomerular volume after 4 months correlates with creatinine clearance, suggesting
      that glomerular enlargement is a necessary condition for renal adaptation to the
      recipient. Glomerular enlargement is impaired in patients with chronic allograft
      nephropathy.

PMID- 15023160
TI  - Withdrawal of cyclosporine or tacrolimus after addition of mycophenolate mofetil
      in patients with chronic allograft nephropathy.
AB  - There has been a need for a prospective, randomized, controlled trial to
      determine whether the addition of mycophenolate mofetil (MMF) to a calcineurin
      inhibitor (CNI)-based regimen or MMF addition followed by CNI withdrawal is an
      effective treatment for chronic allograft nephropathy (CAN). We conducted the
      first randomized, prospective study to compare the introduction of MMF with or
      without CNI withdrawal in long-term transplant recipients with histologically
      proven CAN and deteriorating renal function. The primary endpoint was renal
      function as indicated by the slope of the inverse serum creatinine vs. time at 32
      weeks after randomization. After an interim analysis found a greater-than
      expected difference between groups in the slopes of the inverse serum-creatinine,
      the study was stopped for ethical reasons. There were 20 patients in the MMF/CNI
      continuation and 19 patients in the MMF/CNI withdrawal groups (mean time post
      transplant 7 years). Renal function improved in the dual-therapy compared with
      the triple-therapy group (p=0.002). Blood pressure decreased in the dual-therapy
      group with a significant difference between groups at 35 weeks (p=0.04). No acute
      rejections occurred. Long-term patients with CAN experience a significant
      improvement in renal function and blood pressure when CNIs are replaced by MMF.

PMID- 15023161
TI  - Pediatric en bloc dual kidney-pancreas transplantation into an adult recipient: a
      simplified technique. Benefits of the en bloc kidney-pancreas transplantation
      technique in pediatric donors.
AB  - The lower age limit for pancreas donors is not well defined. Fear of inadequate
      islet beta-cell mass and of technical complications has hampered the use of
      pediatric donors. A surgical technique of 'en bloc' kidney-pancreas is described.
      Both kidneys and pancreas were removed en bloc from a 13-kg, 31-month-old child.
      During bench preparation, one anastomosis was performed between the portal vein
      and the inferior vena cava. The proximal end of the aorta was closed. The bloc
      was transplanted into a 36-year-old type I diabetic patient intraperitoneally in
      the right iliac fossa. The kidneys functioned immediately. Pancreatic graft
      function resumed after POD 15 but insulin therapy was maintained until POD 112.
      Currently, the patient retains excellent kidney and pancreas graft functions.
      Very young donors can be accepted as pancreas donors for adult recipients,
      although slow recovery of pancreatic function can be expected. Use of the en bloc
      technique is well suited for very small children, as it prevents potential
      vascular complications.

PMID- 15023162
TI  - Management of an abdominal aortic aneurysm in a patient with end-stage liver
      disease.
AB  - Concomitant abdominal aortic aneurysms and cirrhosis that need surgical attention
      are rare. Currently there are no guidelines with regards to the appropriate
      timing of the repair of these aneurysms and transplantation. In addition it also
      raises the issue of which procedure takes precedence. With the advent of
      endovascular repairs, this issue was resolved with relative ease, by doing the
      orthotopic liver transplantation (OLT) first and subsequent endovascular stenting
      on post-operative day 7 during the same hospitalization. This is the first case
      report of stenting an abdominal aortic aneurysm (AAA) in a liver transplant
      recipient. The rationale for the OLT and then AAA repair are discussed and formal
      guidelines are offered.

PMID- 15023164
TI  - Meta-analysis: Helicobacter pylori eradication therapy vs. antisecretory non
      eradication therapy for the prevention of recurrent bleeding from peptic ulcer.
AB  - AIM: To perform a meta-analysis comparing the efficacy of Helicobacter pylori
      eradication therapy vs. antisecretory non-eradication therapy for the prevention
      of recurrent bleeding from peptic ulcer. METHODS: A search was made of the
      Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL and several
      congresses for controlled clinical trials comparing the efficacy of H. pylori
      eradication therapy vs. antisecretory non-eradication therapy for the prevention
      of peptic ulcer re-bleeding. Studies with all patients taking non-steroidal anti
      inflammatory drugs were excluded. Extraction and quality assessment of the
      studies were performed by two reviewers. RESULTS: In the first meta-analysis, the
      mean percentage of re-bleeding in the H. pylori eradication therapy group was
      4.5%, compared with 23.7% in the non-eradication therapy group without long-term
      antisecretory therapy [odds ratio, 0.18; 95% confidence interval (CI), 0.09-0.37;
      'number needed to treat' (NNT), 5; 95% CI, 4-8]. In the second meta-analysis, the
      re-bleeding rate in the H. pylori eradication therapy group was 1.6%, compared
      with 5.6% in the non-eradication therapy group with maintenance antisecretory
      therapy (odds ratio, 0.25; 95% CI, 0.08-0.76; NNT, 20; 95% CI, 12-100). When only
      patients with successful H. pylori eradication were included, the re-bleeding
      rate was 1%. CONCLUSIONS: The treatment of H. pylori infection is more effective
      than antisecretory non-eradication therapy (with or without long-term maintenance
      antisecretory treatment) in the prevention of recurrent bleeding from peptic
      ulcer. Consequently, all patients with peptic ulcer bleeding should be tested for
      H. pylori, and eradication therapy should be prescribed to infected patients.

PMID- 15023166
TI  - Systemic review: the prevalence and clinical course of functional dyspepsia.
AB  - AIM: To examine the prevalence of functional dyspepsia in the general population,
      and to evaluate the natural history/clinical course of patients with functional
      dyspepsia. METHODS: Full-length published manuscripts during 1980-2002 were
      included if: (i) participants had uninvestigated or functional dyspepsia; (ii)
      dyspepsia was defined; (iii) for prevalence, population-based samples were
      evaluated; (iv) for prognosis, the total number of the inception cohort and the
      total number of individuals available at the end of follow-up were reported.
      RESULTS: Twenty-two studies (1976-2002) that examined the prevalence of dyspepsia
      fulfilled the inclusion and exclusion criteria; 17 studies examined more than
      1000 participants, but only two studies provided information sufficient to
      calculate the prevalence of functional dyspepsia (11.5-14.7%). The prevalence of
      uninvestigated dyspepsia was in the range 10-40%. When the definition of
      dyspepsia was restricted to participants with upper abdominal pain, irrespective
      of the presence of heartburn or acid regurgitation, the prevalence rate estimate
      was 5-12%. Thirteen studies examined the clinical course of functional dyspepsia
      (seven retrospective and six prospective). Sample sizes were small (n = 35-209).
      A follow-up ascertainment of symptoms amongst individuals in the original cohorts
      was obtained in 92.5-98.2% of prospective studies and in 67.7-82.2% of
      retrospective studies. The follow-up duration was in the range 1.5-10 years for
      prospective studies and 5-27 years for retrospective studies; the median follow
      up duration for all studies was approximately 5 years. A variable prognosis was
      reported. An outcome of symptom improvement or becoming asymptomatic was reported
      in at least one-half of patients in 10 of the 13 studies, and in at least two
      thirds of patients in six of the 13 studies. Prognostic factors were inconsistent
      and, in general, poorly described. CONCLUSIONS: Functional dyspepsia is prevalent
      world-wide, but the prognosis remains poorly defined. There is a need for
      population-based studies to examine the prevalence and clinical course of
      documented functional dyspepsia.

PMID- 15023165
TI  - Systematic review: the methodological quality of trials affects estimates of
      treatment efficacy in functional (non-ulcer) dyspepsia.
AB  - AIM: To evaluate treatment efficacy using objective quality criteria. METHODS: A
      systematic review was performed of randomized controlled trials of endoscopically
      investigated dyspepsia (1979-2003) using the Jadad score and Rome II guidelines.
      The Jadad score differentiated studies as 'high quality' (score 4-5/5) vs. 'poor
      quality' (score 1-3/5). Three key Rome II guidelines on study design (cut-off of
      0/3 or > 0/3) were also compared with the Jadad score. RESULTS: Poor quality
      trials suggested a benefit of prokinetic therapy [relative risk (RR) of remaining
      dyspeptic, 0.47; 95% confidence interval (CI), 0.39-0.56), which was not
      confirmed in high quality trials (RR, 1.0; 95% CI, 0.84-1.19). There was a marked
      benefit of H2-receptor antagonist therapy in poor quality trials (RR, 0.68; 95%
      CI, 0.61-0.76), but a marginal benefit in good quality trials (RR, 0.87; 95% CI,
      0.79-0.97). Trial quality did not affect the small statistically significant
      benefit seen with Helicobacter pylori eradication. Two high quality trials
      suggested a limited benefit with the use of proton pump inhibitors, with no poor
      quality trials to provide a comparison. Separation of the studies by the Rome II
      criteria had a similar impact on the calculated treatment estimates. CONCLUSIONS:
      The magnitude of benefit of prokinetic and H2-receptor antagonist therapies
      reported in previous meta-analyses has been over-estimated. The quality of trials
      has an impact on the efficacy estimates of treatment. The Rome II criteria for
      study methodology may be appropriate for judging study quality.

PMID- 15023168
TI  - Large hiatal hernia in patients with iron deficiency anaemia: a prospective study
      on prevalence and treatment.
AB  - BACKGROUND: Although large hiatal hernia may cause bleeding from Cameron
      erosions, its role in iron deficiency anaemia has been debated, and no data are
      available on the treatment of these patients with proton pump inhibitors. Aims :
      To determine the prevalence of large hiatal hernia in out-patients with iron
      deficiency anaemia and the role of proton pump inhibitors in the prevention of
      recurrence of anaemia. METHODS: Two hundred and twenty-eight out-patients
      underwent upper/lower endoscopy. Those with large hiatal hernia were given an
      oesophagogram, discontinued iron supplementation and received proton pump
      inhibitor treatment with (group 1) or without (group 2) surgery. Anaemia was re
      assessed during 1 year of follow-up. RESULTS: Large hiatal hernia was the likely
      cause of anaemia in 21 patients (9.2%). The median haemoglobin and ferritin
      values at the diagnosis of anaemia were 7.9 g/dL and 6 micro g/L, respectively.
      Cameron erosions were found in 33% of patients. Ten and eleven patients were
      included in groups 1 and 2, respectively. Haemoglobin values were 13.8 g/dL and
      13.4 g/dL at 3 months of follow-up, and 13.4 g/dL and 13.8 g/dL at 1 year of
      follow-up, in groups 1 and 2, respectively. CONCLUSIONS: Large hiatal hernia may
      cause iron deficiency anaemia, even without Cameron erosions. Surgery in
      combination with proton pump inhibitor therapy is no better than proton pump
      inhibitor therapy alone in preventing the recurrence of anaemia.

PMID- 15023167
TI  - Tenatoprazole, a novel proton pump inhibitor with a prolonged plasma half-life:
      effects on intragastric pH and comparison with esomeprazole in healthy
      volunteers.
AB  - BACKGROUND: Proton pump inhibitors control gastric acidity better during the day
      than at night, when nocturnal acid breakthrough can occur. Tenatoprazole is a
      novel proton pump inhibitor with a seven-fold longer plasma half-life. Aim : To
      compare the effects of tenatoprazole 20 mg (T20), tenatoprazole 40 mg (T40) and
      esomeprazole 40 mg (E40) on intragastric acidity in healthy volunteers. METHODS:
      This randomized, three-period, cross-over study enrolled 18 Helicobacter pylori
      negative volunteers, who received E40, T20 and T40 once daily for 7 days with a
      14-day washout between periods. Twenty-four-hour gastric pH monitoring was
      performed on day 7. Serum gastrin was assessed on day 8. RESULTS: T40 induced a
      more potent acid inhibition than T20 (24-h median pH: 4.6 vs. 4.0, P < 0.01;
      daytime: 4.5 vs. 3.9, P < 0.01; night-time: 4.7 vs. 4.1, P < 0.05). T40 was more
      potent than E40 (24-h median pH: 4.6 vs. 4.2, P < 0.05; night-time: 4.7 vs. 3.6,
      P < 0.01); the pH > 4 holding time was higher during the night for T40 than for
      E40: 64.3% vs. 46.8%, P < 0.01; the nocturnal acid breakthrough duration was
      significantly shorter for T40 than for E40. No significant gastrin increase was
      observed and all drugs were well tolerated. CONCLUSION: T40 is significantly more
      potent than T20 and E40 during the night. The therapeutic relevance of this
      pharmacological advantage deserves further study.

PMID- 15023169
TI  - Mucosal cytokine production during remission after resection for Crohn's disease
      and its relationship to future relapse.
AB  - AIM: To examine whether mucosal cytokine production during remission after
      resection for Crohn's disease is a predictor of future relapse. METHODS: Thirty
      six patients who remained in remission after resection for terminal ileal or ileo
      caecal Crohn's disease were included. At enrollment, blood and mucosal (ileal and
      rectal biopsies) samples were collected. All patients were followed up regularly
      for 1 year after enrollment and the disease activity was assessed according to
      the Crohn's disease activity index. RESULTS: Twenty patients remained in
      remission and 16 patients relapsed during the 1-year follow-up. Interleukin-1
      beta, interleukin-6 and tumour necrosis factor-alpha levels in the ileal mucosa
      were significantly higher in relapsed patients than in patients in remission.
      These cytokine levels in the rectal mucosa were not associated with relapse.
      Conventional blood markers and plasma cytokine levels did not correlate with
      relapse. Amongst the clinical parameters, a younger age, short disease duration
      before operation and fistulating disease were risk factors for relapse. In
      multivariate analysis, only the ileal interleukin-6 level was an independent
      significant predictor for relapse. CONCLUSIONS: The interleukin-6 level in the
      ileal mucosa during remission after resection for ileal or ileo-caecal Crohn's
      disease is an independent significant predictor for future relapse.

PMID- 15023170
TI  - The risk of congenital abnormalities in children fathered by men treated with
      azathioprine or mercaptopurine before conception.
AB  - BACKGROUND: Immunosuppressive therapy with azathioprine and mercaptopurine is
      commonly used in patients with various chronic diseases. The few existing data on
      the reproductive safety of these drugs after paternal use before conception are
      inconclusive. AIM: To examine the risk of congenital abnormalities in children
      fathered by men exposed to azathioprine or mercaptopurine before conception.
      METHODS: This was a Danish population-based cohort study, based on data from the
      Prescription Database, the Medical Birth Registry and the Hospital Discharge
      Registry of North Jutland County, Denmark. Fifty-four exposed pregnancies, in
      which the father filed a prescription for azathioprine or mercaptopurine (between
      1 January 1991 and 31 December 2001) before conception, were included. The
      controls comprised 57 195 pregnancies with no paternal azathioprine or
      mercaptopurine use. RESULTS: Four children with congenital abnormalities
      (underlying paternal diseases: glomerulonephritis and severe skin disease) were
      found in 54 exposed pregnancies (7.4%), compared with 2334 (4.1%) in controls.
      The adjusted odds ratio for congenital abnormalities in children fathered by men
      treated with azathioprine or mercaptopurine was 1.8 (95% confidence interval, 0.7
      5.0). CONCLUSIONS: Our data may indicate that paternal use of azathioprine or
      mercaptopurine before conception is associated with an increased risk of
      congenital abnormalities. However, more data are needed to determine whether the
      association is causal.

PMID- 15023171
TI  - Erythromycin for the treatment of chronic intestinal pseudo-obstruction:
      description of six cases with a positive response.
AB  - BACKGROUND: Chronic intestinal pseudo-obstruction, due to intestinal myopathy or
      neuropathy, is characterized by the signs and symptoms of intestinal obstruction
      in the absence of true obstruction. Episodes are resistant to medical therapy.
      AIM: To determine the value of erythromycin treatment in chronic intestinal
      pseudo-obstruction. METHODS: All patients with proven chronic intestinal pseudo
      obstruction treated with erythromycin were reviewed. Patients with symptomatic
      benefit are described in detail. Responders were compared with non-responders to
      identify the factors associated with benefit. RESULTS: Fifteen consecutive
      patients (nine females; median age, 37 years; median follow-up, 41 months) were
      treated with oral erythromycin, 1.5-2.0 g/day. Six patients (three primary
      visceral myopathy, two normal histology on light microscopy, one visceral
      myopathy secondary to scleroderma) responded, with decreased pain and vomiting,
      normalized bowel dysfunction and decreased episodes of ileus. Five of the six
      patients (83%) who responded to erythromycin were male, compared with two of the
      nine non-responders (22%) (P = 0.04). Four of the six responders (67%) had
      histological or immunohistological visceral myopathy, compared with three of the
      nine patients (33%) who failed to respond. Responders were less likely than non
      responders to be taking long-term opiates. CONCLUSIONS: Erythromycin is effective
      for acute episodes of ileus and chronic symptoms in some patients with chronic
      intestinal pseudo-obstruction.

PMID- 15023172
TI  - Botulinum neurotoxin to treat chronic anal fissure: results of a randomized
      "Botox vs. Dysport" controlled trial.
AB  - BACKGROUND: Botulinum neurotoxin induces healing in patients with idiopathic
      fissure. The optimal dosage is not well established. AIM: To compare the efficacy
      and tolerability of two different formulations of type A botulinum neurotoxin,
      and to provide more evidence with regard to the choice of dosage regimens.
      METHODS: Symptomatic adults with chronic anal fissure were enrolled in a
      randomized study. The outcome of each group was evaluated clinically, and by
      comparing the pressure of the anal sphincters before and after treatment.
      RESULTS: Fifty patients received injections of 50 units of Botox formulation
      (group I), and 50 patients received injections of 150 units of Dysport toxin
      (group II). One month after injection, 11 patients in group I and eight in group
      II had mild incontinence of flatus. At the 2-month evaluation point, 46 patients
      in group I and 47 patients in group II had a healing scar. In group I patients,
      the mean resting anal pressure was 41.8% lower, and the maximum voluntary squeeze
      pressure was 20.2% lower, than the baseline value. In group II patients, the
      resting anal pressure and maximum voluntary squeeze pressure were 60.0 +/- 12.0
      mmHg and 71.0 +/- 30.0 mmHg, respectively. There were no relapses during an
      average of about 21 months of follow-up. CONCLUSIONS: Botulinum neurotoxin may be
      considered an effective treatment in patients with chronic anal fissure. The
      efficacy and tolerability of the two different formulations of botulinum
      neurotoxin were indistinguishable.

PMID- 15023173
TI  - Vitamin B12 deficiency as a cause of hyperhomocysteinaemia.

PMID- 15023174
TI  - Vitamin B12 deficiency in Israel.

PMID- 15023175
TI  - Prevalence of irritable bowel syndrome in a multi-ethnic Asian population.

PMID- 15023176
TI  - Occult hepatitis B virus infection: implications in transfusion.
AB  - Hepatitis B virus (HBV) presents a higher residual risk of transmission by
      transfusion than hepatitis C virus (HCV) or human immunodeficiency virus (HIV).
      While most infectious blood units are removed by screening for hepatitis B
      surface antigen (HBsAg), there is clear evidence that transmission by HBsAg
      negative components occurs, in part, during the serologically negative window
      period, but more so during the late stages of infection. Donations negative for
      HBsAg, but positive for HBV DNA, with or without the presence of HBV antibodies,
      correspond to 'occult' HBV infection (OBI). The frequency of OBI depends on the
      relative sensitivity of both HBsAg and HBV DNA assays. It also depends on the
      prevalence of HBV infection in the population. OBI may follow recovery from
      infection, displaying antibody to hepatitis B surface antigen (anti-HBs) and
      persistent low-level viraemia, escape mutants undetected by the HBsAg assays, or
      healthy carriage with antibodies to hepatitis B e antigen (anti-HBe) and to
      hepatitis B core antigen (anti-HBc). Over time, in the latter situation, anti-HBe
      and, later, anti-HBc may become undetectable. The critical question is whether or
      not OBI is infectious by transfusion. All forms have been shown to be infectious
      in immunocompromised individuals, such as organ- or bone marrow-transplant
      recipients. In immunocompetent recipients, there is no evidence that anti-HBs
      containing components (even at low titre) are infectious. Anti-HBc only, with HBV
      DNA, can be associated with infectivity, as can rare cases of HBV DNA without any
      serological HBV marker. If HBV nucleic acid amplification technology (NAT) is
      considered, the OBI viral load would usually be < 500 IU/ml, making testing of
      plasma pools unsuitable unless the sensitivity of NAT significantly increases by
      genome enrichment or test improvement.

PMID- 15023177
TI  - Distribution of a bovine spongiform encephalopathy-derived agent over ion
      exchange chromatography used in the preparation of concentrates of fibrinogen and
      factor VIII.
AB  - BACKGROUND AND OBJECTIVES: The risk of haemophiliacs contracting variant
      Creutzfeldt-Jakob disease (vCJD) via treatment with factor VIII concentrates is
      not known. Therefore, in order to determine the extent to which the vCJD agent
      might be removed during the preparation of factor VIII concentrate, the
      partitioning of a bovine spongiform encephalopathy (BSE)-derived agent was
      measured over the main purification step used to prepare the Scottish National
      Blood Transfusion Service high-purity factor VIII concentrate (Liberate).
      MATERIALS AND METHODS: Murine-passaged BSE (strain 301V), in the form of a
      microsomal fraction prepared from infected brain, was used to 'spike' a solution
      of factor VIII of intermediate purity. The 'spiked' starting material was
      subjected to solvent-detergent treatment and then to anion-exchange
      chromatography with Toyopearl DEAE-650M. All fractions were tested for 301V
      infectivity using a murine bioassay, including the procedures used to clean the
      ion-exchange media after use. RESULTS: BSE 301V infectivity was reduced by 2.9
      log(10) in the fibrinogen fraction and by 2.7 log(10) in the factor VIII
      fraction. Over 99% of the added 301V infectivity remained bound to the ion
      exchange column after elution of factor VIII. A large quantity of infectivity was
      subsequently removed by washing the ion-exchange media with 2 m NaCl. No further
      BSE 301V infectivity was detected in column eluates after treatment with 0.1 m
      NaOH or a second wash with 2 m NaCl. CONCLUSIONS: Results using a BSE-derived
      agent suggest that vCJD infectivity would be substantially removed by the ion
      exchange process used in the preparation of fibrinogen and factor VIII
      concentrate. Although 301V infectivity remained bound to the ion-exchange matrix
      following elution of factor VIII, this appeared to be eliminated by the procedure
      used for cleaning the ion-exchange media after each use.

PMID- 15023178
TI  - In vitro study of a triple-secured von Willebrand factor concentrate.
AB  - BACKGROUND AND OBJECTIVES: Patients suffering from von Willebrand disease who are
      not responsive to desmopressin require substitutive treatment. This study was
      part of the development of a second-generation plasma-derived von Willebrand
      factor (VWF) concentrate, the manufacturing process of which includes two
      complementary viral-inactivation/elimination steps that are effective against non
      enveloped viruses. MATERIALS AND METHODS: VWF was purified from solvent/detergent
      treated cryoprecipitate through a combination of anion-exchange and affinity
      chromatography. The VWF preparation was diluted and filtered through filters with
      pore size of 35 nm. After concentration and formulation, the product was freeze
      dried and further heated at 80 degrees C for 72 h. Tests were performed to
      evaluate the effects of nanofiltration and dry heating on VWF multimeric
      structure and function. RESULTS: Nanofiltration and dry heating of the formulated
      product increased viral safety but did not modify VWF multimeric structure.
      Furthermore, these steps did not alter the ability of VWF to bind to platelet
      glycoprotein Ib, collagen and Factor VIII. CONCLUSIONS: We have perfected a large
      scale manufacturing process to produce a human plasma-derived VWF concentrate
      that boasts high specific activity and is very safe for the treatment of patients
      with von Willebrand disease.

PMID- 15023180
TI  - White-blood-cell-containing allogeneic blood transfusion, postoperative infection
      and mortality: a meta-analysis of observational 'before-and-after' studies.
AB  - BACKGROUND AND OBJECTIVES: An association of white blood cell (WBC) reduction
      with decreased mortality was reported by one observational, before-and-after
      study. A meta-analysis was undertaken to examine whether this finding is
      supported by all the evidence currently available from before-and-after studies,
      and whether these studies support an association of WBC reduction with a
      decreased risk of postoperative infection. MATERIALS AND METHODS: Observational,
      before-and-after studies were retrieved that reported on postoperative infection
      and/or mortality between January 1997 and June 2003. Six studies met the criteria
      for meta-analysis. Unadjusted summary odds ratios (ORs) of postoperative
      infection or mortality in patients transfused after (compared with before) WBC
      reduction were calculated across the studies if the hypothesis of homogeneity was
      not rejected. Adjusted summary ORs were calculated across three studies that had
      reported multivariate analyses. RESULTS: There was an unadjusted association of
      WBC reduction with a decreased risk of postoperative infection [summary OR =
      0.93; 95% confidence interval (95% CI), 0.88-0.99; P < 0.01] that did not persist
      following adjustment for confounding factors (summary OR = 0.94; 95% CI, 0.85
      1.04; P > 0.05). There was neither an unadjusted nor an adjusted association of
      WBC reduction with decreased mortality (summary OR = 0.94; 95% CI, 0.71-1.23; P >
      0.05; and OR = 0.92; 95% CI, 0.80-1.05; P > 0.05, respectively). CONCLUSIONS: An
      association of WBC reduction with decreased mortality was not detected across the
      results available from all before-and-after studies. An unadjusted association of
      WBC reduction with a decreased risk of postoperative infection exists, but this
      was not detected across the three studies that reported multivariate analyses.

PMID- 15023179
TI  - Quality control system for blood irradiation using a teletherapy unit.
AB  - BACKGROUND AND OBJECTIVES: Irradiation of whole blood and blood components before
      transfusion is currently the only accepted methodology to prevent transfusion
      associated graft-vs.-host disease. In the present work, we developed an automated
      system for blood bag storage during irradiation, using a teletherapy unit.
      MATERIALS AND METHODS: A device with two thermal compartments was constructed in
      acrylic and foam, for the storage of blood bags during irradiation. An automatic
      acquisition system, coupled with an amplifier and a thermal-sensitive probe, were
      developed to check blood temperature during irradiation. A polystyrene phantom
      was constructed to simulate the volume of blood routinely irradiated. The dose
      distribution was measured in the phantom using thermoluminescent dosimeters and
      represented in terms of isodose curves. RESULTS: The thermal device kept the
      blood temperature below 6 degrees C for more than 2 h. Our system allowed the
      simultaneous irradiation of two different blood components while maintaining a
      constant temperature. The temperature monitoring system remained invariant (0.2
      degrees C) over the whole irradiation interval. Phantom dosimetric results showed
      a homogeneous dose distribution when the phantom was irradiated, using rotational
      fields with a 2 r.p.m. frequency. CONCLUSIONS: The methodology developed in the
      present work provides appropriate storage conditions during irradiation of both
      red blood cells and platelet blood components using a teletherapy unit.

PMID- 15023181
TI  - 'Last-ditch' use of recombinant factor VIIa in patients with massive haemorrhage
      is ineffective.
AB  - BACKGROUND AND OBJECTIVES: The aim of this retrospective study was to assess the
      effect of activated recombinant factor VII (rFVIIa) on the natural history of
      massive transfusion episodes. MATERIALS AND METHODS: During 2002, outcome
      parameters were assessed in 50 patients transfused with more than 10 units of
      packed red cells. The effect of the addition of rFVIIa in 10 patients, with
      intractable bleeding, was then observed. RESULTS: Overall mortality was 20% at 24
      h and 34% at 7 days. Severe coagulopathy was confirmed as a serious negative
      prognostic factor and occurred in 42% of patients overall, but in 70% of rFVIIa
      treated patients. Transient cessation or reduction of bleeding was noted in 60%
      of patients following rFVIIa infusion. However, 24-h and 7-day mortality rates
      were 40% and 70%, respectively, in this group. CONCLUSIONS: Last-ditch rFVIIa
      therapy in patients resistant to conventional treatment did not rescue these
      patients or significantly alter outcomes.

PMID- 15023183
TI  - Influence of cell-free DNA in plasma on real-time polymerase chain reaction for
      determination of residual leucocytes in platelet concentrates.
AB  - BACKGROUND AND OBJECTIVES: Real-time quantitative (RQ) polymerase chain reaction
      (PCR) can be used to determine the number of residual leucocytes in leucocyte
      reduced platelet concentrates (LR-PCs), which should contain < 3.3 leucocytes/
      micro l. In this study we investigated the extent to which cell-free DNA, known
      to be present in plasma, might interfere with this determination. In this study,
      RQ-PCR was employed to determine the following: the influence of filtration of
      platelet concentrates (PCs) on the amount of cell-free DNA; the variation in
      concentration of cell-free DNA between the buffy coats (BCs) of different donors;
      and the amount of cell-free DNA during storage and processing of whole blood.
      MATERIALS AND METHODS: PCs were sampled before and after filtration (n = 5), BCs
      were sampled (n = 100) and whole blood units were sampled < 2 h and 16-20 h after
      collection, and the BCs were also sampled after processing the whole blood (n =
      10). Samples were centrifuged to obtain cell-free plasma in which the amount of
      cell-free DNA was determined using an RQ-PCR for the albumin gene. RESULTS: The
      amount of cell-free DNA was not influenced by filtration of the PCs [1.7 +/- 0.8
      vs. 1.5 +/- 0.8 leucocyte-equivalents (eq)/ micro l]. However, the amount of cell
      free DNA in plasma of the BCs varied considerably, from 0.1 to 18.2 leucocyte-eq/
      micro l (median = 1.5 leucocyte-eq/ micro l; mean +/- SD: 2.2 +/- 2.4 leucocyte
      eq/ micro l). In 18% of the BCs the amount cell-free DNA was > 3.3 leucocyte-eq/
      micro l. The amount of cell-free DNA increased during storage, from 0.3 +/- 0.3
      leucocyte-eq/ micro l (< 2 h after collection) to 0.9 +/- 0.6 leucocyte-eq/ micro
      l (16-20 h after collection) and, after processing the whole blood, to 2.0 +/-
      2.0 leucocyte-eq/ micro l. CONCLUSIONS: Variable amounts of cell-free DNA in
      plasma will interfere if RQ-PCR is applied to estimate leucocyte numbers in
      leucocyte-reduced PCs.

PMID- 15023182
TI  - Intravenous immunoglobulin products contain neutralizing antibodies to vaccinia.
AB  - BACKGROUND AND OBJECTIVES: Individuals with primary or secondary immune
      deficiency diseases may be at risk for vaccinia infection if widespread smallpox
      immunization programmes are implemented in the United States of America (USA) for
      bioterrorism preparedness. The objective of this study was to determine whether
      commercial immune globulin (intravenous, human) products contain biologically
      active antibodies to vaccinia that have the potential to protect people, with
      immune deficiencies, from complications of vaccinia. MATERIALS AND METHODS: Eight
      currently United States (US)-licensed and two European intravenous immunoglobulin
      (IVIG) products were tested in a vaccinia plaque-reduction neutralization assay.
      The in vivo activity of five of these lots was assessed in severely immune
      deficient mice. RESULTS: All tested products contained neutralizing anti-vaccinia
      activity, in vitro and in vivo. CONCLUSIONS: The use of IVIG by individuals with
      inherited or acquired humoral immune deficiencies may provide some protection if
      they are inadvertently exposed to vaccinia.

PMID- 15023184
TI  - Weakened expression of 'e' owing to concomitant occurrence of Cys16 and Val245
      (VS antigen).
AB  - BACKGROUND AND OBJECTIVES: The 48 G>C transversion in exon 1 of the RHCE gene
      leads to Trp16Cys, usually present in the conventional RHCE Ce, while Trp16 is
      associated with RHCE ce. The presence of Cys16 in RHCE ce is associated with the
      R(0) (Dce) haplotype in Africans, leading to a weak 'e' antigen expression on red
      blood cells (RBCs). VS is a common red cell antigen in individuals of African
      descent and results from a single point mutation in exon 5 of the RHCE (733C>G),
      leading to Leu245Val substitution; VS positivity is also associated with weak
      expression of 'e'. This study investigated the association of Cys16 and/or VS
      with the RHCE ce alleles in a cohort of sickle cell disease (SCD) patients
      phenotyped as R(0)r or R(0)R(0) and rr. MATERIALS AND METHODS: DNA samples from
      58 SCD patients were tested for the 48 G>C transversion, encoding Cys16, by
      allele-specific polymerase chain reaction (PCR). We also amplified exon 5 of the
      RHCE by PCR and subjected the amplified product to restriction fragment length
      polymorphism analysis, using BfaI, in order to determine the VS status. Further
      cDNA analysis was performed on three samples to verify whether the mutations were
      located on the same or on different alleles. RESULTS: Fifty-six of the 58 SCD
      patients studied (97%) were heterozygous for 48G/48C (Cys16). Of these, 18 (32%)
      were also heterozygous for 733C/G (245Val). All of these 18 samples showed weak
      'e' expression on RBCs when tested with at least one monoclonal antibody to e
      antigen. cDNA sequencing of three of 18 patient samples showed that the genes
      encoding Cys16 and Val245 (VS) were on different alleles. CONCLUSIONS: We found a
      high incidence of Cys16 associated with the RHCE ce in our SCD cohort. A high
      percentage of these patients were also found to be heterozygous for VS. cDNA
      analysis showed that, in at least three samples, the two mutations were on
      different alleles, with consequent weakening of expression of the e antigen on
      RBCs.

PMID- 15023185
TI  - Restriction in the repertoire of the immunoglobulin light chain subgroup in
      pathological cold agglutinins with anti-Pr specificity.
AB  - BACKGROUND AND OBJECTIVES: In cold agglutinin disease, monoclonal red blood cell
      autoantibodies, termed cold agglutinins, induce haemolysis in patients exposed to
      the cold. Commonly, these autoantibodies are directed against the developmentally
      regulated I/i blood groups. A second blood group system, the Pr system (located
      on glycophorins), is involved less frequently. Anti-Pr cold agglutinins recognize
      either alpha 2,3- or alpha 2,6-linked N-acetylneuraminic acid as the
      immunodominant group. Cold agglutinins of anti-I/i specificity show a remarkable
      restriction in their genomic repertoire of the immunoglobulin heavy and light
      chain immunoglobulin-variable domain (i.e. exclusive use of VH4-34 in heavy
      chains). For anti-Pr cold agglutinins, preliminary data on the repertoire of the
      light-chain variable domain indicate a preference for the subgroup Vkappa IV. To
      elucidate restrictions in the light-chain variable-domain subgroup repertoire of
      anti-Pr cold agglutinins systematically, and to discuss these results in the
      context of their anti-Pr(1-3) subclassification and immunodominant sialic acid,
      light chains in 13 anti-Pr cold agglutinins were investigated. MATERIALS AND
      METHODS: The anti-Pr light chains were isolated using temperature-dependent
      absorption/elution techniques. Subsequently, they were subjected to N-terminal
      Edman degradation, and the light chain Vkappa subgroup was affiliated using the
      Kabat database. RESULTS: Five of 13 (38%) light chains belonged to Vkappa IV,
      five of 13 (38%) to Vkappa I and three of 13 (23%) to Vkappa III. Anti-Pr with
      Vkappa IV subgroup light chains exclusively recognized alpha 2,3-linked N
      acetylneuraminic acid. CONCLUSIONS: Including data from the literature, the
      repertoire of the light-chain variable domain in pathological anti-Pr cold
      agglutinins exhibits a clear bias towards the use of the single germline gene
      derived subgroup, Vkappa IV (eight of 17 or 47%). The association of Vkappa IV
      subgroup light chain-containing anti-Pr cold agglutinins with binding to alpha
      2,3-, but not alpha 2,6-linked N-acetyneuraminic acid raises speculations about a
      possible role of subgroup-derived determinants in anti-Pr binding.

PMID- 15023186
TI  - Investigation of frequency of active Borna disease virus infection in Scottish
      blood donors.
AB  - BACKGROUND AND OBJECTIVES: Borna disease virus (BDV) can infect a wide range of
      vertebrate species causing neurological disease. In order to ensure the safety of
      blood supplies, it is essential to monitor blood for emerging pathogens.
      MATERIALS AND METHODS: One-hundred individual white cell pellets and pools
      representing 25 000 plasma donations from human blood were screened for BDV by
      reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: BDV RNA was
      not detected in any of the samples. CONCLUSIONS: The results indicate that BDV is
      not widely spread in the UK human population and does not represent a risk as a
      transfusion-transmitted agent.

PMID- 15023187
TI  - Response to intravenous immunoglobulin G in an infant with immunoglobulin A
      associated autoimmune haemolytic anaemia.

PMID- 15023189
TI  - Promoting lifestyle - is there a role for health?

PMID- 15023190
TI  - Process evaluation of two environmental nutrition programmes and an educational
      nutrition programme conducted at supermarkets and worksite cafeterias in the
      Netherlands.
AB  - INTRODUCTION: This article describes the process evaluation of two environmental
      programmes and an educational nutrition programme, implemented at supermarkets
      and worksite cafeterias. Studies conducted earlier, indicated that the programmes
      had no effect on consumers' eating behaviour. Consequently, the more specific
      purpose of the present study was to identify explanations for the ineffectiveness
      of the programmes and to formulate recommendations for future programmes.
      MATERIALS AND METHODS: The environmental programmes included labelling of healthy
      products and increasing the range of healthy foods on offer. The education
      programme consisted of several elements, such as brochures and a self-help guide.
      Semi-structured interviews were conducted with 21 managers of supermarkets and
      worksite cafeterias where the programmes were implemented. RESULTS: Although
      materials were not always entirely compatible with the different supermarkets and
      worksite cafeterias, the degree of implementation was satisfactory. According to
      the managers, the programmes were not striking enough, the labelling would have
      been more effective if it had discriminated between different brands of a
      product, and the number of new products was too small compared with the total
      range of foods on offer. CONCLUSIONS: The findings suggest that programmes should
      be promoted intensively. Furthermore, the relevant manufacturers and wholesalers
      supplying worksite cafeterias should be encouraged to increase their range of
      suitable low-fat products. Finally, the feasibility and possible effects of brand
      specific labelling should be investigated further.

PMID- 15023191
TI  - The long-term effect of dietary advice on the diet of men with angina: the diet
      and angina randomized trial.
AB  - INTRODUCTION: The long-term effects on diet of dietary advice to eat fruit and
      vegetables or fatty fish are not well described. MATERIALS AND METHODS: From 1990
      to 1996 3114 men aged 37-70 with treated angina were recruited from general
      practices in South Wales. A dietitian randomly allocated the eligible men to
      receive advice to eat more fruit and vegetables, or advice to eat more fatty
      fish, or both these types of advice or neither. In 2000, a brief self-completion
      questionnaire was sent to a sample of 1191 of the men known to be alive at the
      end of March 1999. RESULTS: The questionnaire was returned by 944 of the 1036 men
      alive at the time the questionnaire was sent. Those given fish advice were
      consuming more fatty fish but the difference was modest 21.9 g day(-1) vs. 14.0 g
      day(-1) (P < 0.01). The differences in fruit and vegetables intake between those
      given fruit advice and those not given fruit advice were small 373.2 g day(-1)
      vs. 351.7 g day(-1) (P = 0.05). DISCUSSION: Men of this age group may be
      particularly resistant to fruit and vegetables advice; population-based
      interventions or interventions targeted at women might be more effective.

PMID- 15023192
TI  - Dietary macro- and micronutrient intakes of nonsupplemented pre- and
      postmenopausal women with a perspective on menopause-associated diseases.
AB  - OBJECTIVES: To assess the dietary intakes and diet quality of menopausal women
      relative to premenopausal women, and to determine whether their diets are
      compatible with reducing risks of cardiovascular disease (CVD) and osteoporosis.
      DESIGN: Cross-sectional study using 3-day food records and anthropometric
      measurements. Subjects Thirty apparently healthy, nonoestrogen using and
      nonsupplemented women menopausal since 3-5 years and 30 well-matched
      premenopausal women. Outcome measures Nutrient intakes, diet nutrient density,
      body mass index (BMI), waist circumference, waist-to-hip ratio and serum
      oestradiol. RESULTS: Energy intake and body weight of pre- and postmenopausal
      women were comparable. Their BMI, waist circumference and waist-to-hip ratios
      were within healthy ranges. The diet of postmenopausal women was compatible (less
      total lipids and saturated fatty acids; more fibres, antioxidant vitamins and
      potassium) with North American nutritional recommendations linked to
      cardiovascular health. Their dietary iron intakes exceeded their reduced
      physiological need, which may jeopardize their cardiovascular system. Their
      calcium and vitamin D intakes were far below recommendations for healthy bones.
      Five other nutrients were also suboptimal. Phosphorus intake (high in both
      groups) correlated with dietary proteins, sulphur amino acids and calcium.
      CONCLUSIONS: The diet of the postmenopausal women studied were more compatible
      with national nutritional recommendations than that of premenopausal controls.
      However, these postmenopausal women, not taking hormone replacement therapy (HRT)
      and having inadequate dietary calcium and vitamin D intakes, may be at increased
      risk of osteoporotic fracture later in life. More studies on CVD risk inherent to
      body iron accumulation involving a large number of postmenopausal women are
      warranted before planning public health measures regarding dietary iron intake.

PMID- 15023193
TI  - Comparison of nutritional risk screening tools in patients on admission to
      hospital.
AB  - BACKGROUND AND AIMS: Under nutrition has been frequently reported in patients on
      admission to hospital. Because this is not always detected promptly, screening
      for nutritional risk on admission has been widely advocated. Although there is no
      universally accepted 'gold standard' for defining undernutrition, the definition
      used by McWhirter, J.P. & Pennington, C.R. [(1994) Br. Med. J.308, 945] has been
      widely used by clinical nutrition specialists. This study aimed to compare the
      efficacy of two frequently used nutritional risk screening tools in detecting
      undernutrition according to this definition. METHODS: Both the Nutrition Risk
      Index [Veterans Affairs Total Parenteral Nutrition Co-operative Study Group
      (1991) N. Engl. J. Med.325, 525] and the Nutrition Risk Score [Reilly H.M. et al.
      (1995) Clin. Nutr.14, 269] were used to screen for undernutrition in 359
      admissions to two acute teaching hospitals in Dublin. Undernutrition was defined
      as a Body Mass Index below 20 kg m(-2) and a triceps skinfold thickness or mid
      arm muscle circumference below the 15th percentile. Comparison of stratification
      of nutritional risk by the two screening tools was carried out. RESULTS: Both
      screening tools identified over 40% (Nutrition Risk Index, 44%; Nutrition Risk
      Score, 46%) of all patients assessed as at nutritional risk on admission.
      However, one-third of the undernourished patients were classified as at no
      nutrition risk by the Nutrition Risk Index, while almost one-fifth of those
      undernourished were classified as at low risk by the Nutrition Risk Score. The
      degree of nutritional risk differed with the screening tool used, the Nutrition
      Risk Score classifying 29% of all patients as high risk while the Nutrition Risk
      Index classified only 5% as in the high risk category. CONCLUSIONS: Although a
      large proportion of patients on admission were classified as being at nutritional
      risk, the degree of risk was significantly different depending on the screening
      tool used. Both nutritional risk screening tools evaluated in this study failed
      to recognize many cases of undernutrition. Evaluation of the efficacy of
      nutritional screening tools should be promoted as seriously as the development of
      such tools.

PMID- 15023195
TI  - Patient satisfaction is rated higher by radiation oncology outpatients receiving
      nutrition intervention compared with usual care.
AB  - BACKGROUND: Satisfaction with services has been considered vital for the
      provision of quality health care, however, there are few published papers
      utilizing patient satisfaction with nutrition services as a measurable outcome.
      METHOD: A randomized, controlled trial investigating the impact of nutrition
      intervention (NI) vs. usual care (UC) in 54 ambulatory oncology patients
      receiving radiotherapy to the gastrointestinal or head and neck area demonstrated
      beneficial impacts in terms of body weight, nutritional status, quality of life
      and bowel health. This study reports the changes in patient satisfaction that
      were associated with these improved outcomes for patients receiving NI compared
      with UC. The patient satisfaction with clinical nutrition services questionnaire
      was used to measure overall satisfaction and satisfaction with four components of
      nutrition services 12 weeks after patients commenced radiotherapy. RESULTS:
      Patients receiving NI rated satisfaction higher for staff interpersonal skills (P
      < 0.001), perceived health benefits (P = 0.008), staff presentation skills (P =
      0.044) and for overall patient satisfaction with nutrition services (P = 0.002).
      There were no significant differences between those patients receiving NI or UC
      for the nutrition supplements factor (P = 0.191). CONCLUSIONS: These data suggest
      that patients receiving NI perceive nutrition as being beneficial and of higher
      importance to their health than those receiving UC. This may lead to increased
      compliance with the nutrition prescription and help explain the better outcomes
      observed in the NI group compared with the UC group. Patient satisfaction with
      nutrition services should be conducted regularly to act as a quality-control
      measure and target areas for improvement.

PMID- 15023196
TI  - Peripheral parenteral nutrition in a case of chyle leak following neck
      dissection.
AB  - Chylothorax is an uncommon condition which is potentially life-threatening if
      untreated. The following case study of a 75-year-old man with chyle leak
      following surgery shows how prompt dietetic action prevented further compromise
      in immune function and nutritional status. Dietetic recommendation to minimize
      enteral intake rapidly stopped chyle flow and promoted wound closure. Peripheral
      parenteral nutrition (PPN) was administered in order to prevent malnutrition.
      There is limited literature available for evidence of best practice for cases of
      chyle leakage, however, this particular case demonstrates PPN should be
      considered despite the potential risks.

PMID- 15023197
TI  - Increasing the popularity of school meals: a positive experience.

PMID- 15023203
TI  - A personal journey on the hybrid health library road.

PMID- 15023204
TI  - Evaluating digital libraries in the health sector. Part 2: measuring impacts and
      outcomes.
AB  - This is the second part of a two-part paper which explores methods that can be
      used to evaluate digital libraries in the health sector. Part 1 focuses on
      approaches to evaluation that have been proposed for mainstream digital
      information services. This paper investigates evaluative models developed for
      some innovative digital library projects, and some major national and
      international electronic health information projects. The value of ethnographic
      methods to provide qualitative data to explore outcomes, adding to quantitative
      approaches based on inputs and outputs is discussed. The paper concludes that new
      'post-positivist' models of evaluation are needed to cover all the dimensions of
      the digital library in the health sector, and some ways of doing this are
      outlined.

PMID- 15023205
TI  - Should systematic reviews include searches for published errata?
AB  - Our objective was to perform a pilot study to estimate the proportion of
      published errata linked to randomized controlled trials (RCTs) that are
      worthwhile obtaining when doing a systematic review. medline was searched for
      records that had both 'randomized-controlled-trial' in the publication type field
      and 'erratum' in the comments field. One hundred records from four general
      medical journals were examined independently from two different perspectives.
      From the information specialist's perspective, 74% of the errata were considered
      worthwhile obtaining; these were mainly errors in tables or figures. Another 9%
      described less serious errors, but were worth obtaining if easily available. The
      other 17% were minor errors. From the perspective of the experienced
      reviewer/public health consultant, 5% of errata were classified as likely to
      affect a meta-analysis, and 10% as having significant errors that would affect
      the interpretation of the RCT, but no effect on a meta-analysis; 85% were not
      considered important enough to affect either. About 5% of errata to RCTs appeared
      to matter in terms of changing the final conclusions of a systematic review.
      However, the majority of errata were considered to be worthwhile obtaining, on
      the basis that having full and accurate data can reduce confusion and save
      reviewers time.

PMID- 15023206
TI  - How does your searching grow? A survey of search preferences and the use of
      optimal search strategies in the identification of qualitative research.
AB  - The objective was to gain an overview of researchers experiences of searching the
      literature, with particular reference to the use of optimal search strategies
      (OSSs) and searching for qualitative research studies. A 13-item semi-structured
      questionnaire investigating search behaviour was distributed to members of the
      Cochrane Qualitative Methods Network. Follow-up interviews were conducted with a
      subset of respondents to explore issues raised and clarify points of ambiguity.
      Findings were analysed using data reduction, data displays and verification
      techniques. Eighty-six per cent of distributed questionnaires were returned. All
      respondents reported searching electronic databases as part of their literature
      search, with 80% expressing a preference for searching alone or with colleagues.
      Forty-one per cent indicated that they consider a database search to be only one
      aspect of a comprehensive literature search. The rigour and availability of OSSs
      was a concern for 30% of respondents. Twenty-five per cent of respondents had
      searched for qualitative studies, although the difficulty of locating this type
      of literature was considered problematic because of the varied use of the term
      'qualitative'. Whilst the majority of respondents reported using OSSs in some
      capacity, reservations were expressed about their ability to facilitate a
      comprehensive search. Replies indicated a belief that OSSs can reduce the
      sensitivity of a search, and might limit the breadth of coverage required. A
      greater appreciation of the availability and purpose of OSSs-including the
      ability to optimize either sensitivity or recall-is needed if this enhanced
      approach to accurate data retrieval and potential improvement in time management
      is to become widespread.

PMID- 15023207
TI  - Awareness, use and opinions of methodological search filters used for the
      retrieval of evidence-based medical literature-a questionnaire survey.
AB  - The aim of this study was to determine the level of awareness of methodological
      search filters among health and academic librarians in the UK and Ireland, their
      use of filters and views on the perceived benefits, limitations and ways to
      increase usage of search filters. A random proportional sample of health and
      academic librarians were surveyed by telephone and fax. Overall, 88% (196/224)
      completed the telephone survey to establish awareness and use of filters. Eighty
      four per cent (51/61) completed a fax survey focusing in more depth on usability
      issues surrounding filters. Results indicate a high level of awareness of
      methodological filters, but low level of usage. Furthermore, a high level of
      awareness did not necessarily correlate with a high level of knowledge or
      understanding. Examination of responses revealed limitations and recommendations
      beyond those reported in the literature and highlights the relationship between
      understanding and effective use of filters. Improved dissemination and
      publication of filters is required to better inform librarians on the concept of
      filters and how to use them effectively.

PMID- 15023208
TI  - A study of medical and health queries to web search engines.
AB  - This paper reports findings from an analysis of medical or health queries to
      different web search engines. We report results: (i). comparing samples of 10000
      web queries taken randomly from 1.2 million query logs from the AlltheWeb.com and
      Excite.com commercial web search engines in 2001 for medical or health queries,
      (ii). comparing the 2001 findings from Excite and AlltheWeb.com users with
      results from a previous analysis of medical and health related queries from the
      Excite Web search engine for 1997 and 1999, and (iii). medical or health advice
      seeking queries beginning with the word 'should'. Findings suggest: (i). a small
      percentage of web queries are medical or health related, (ii). the top five
      categories of medical or health queries were: general health, weight issues,
      reproductive health and puberty, pregnancy/obstetrics, and human relationships,
      and (iii). over time, the medical and health queries may have declined as a
      proportion of all web queries, as the use of specialized medical/health websites
      and e-commerce-related queries has increased. Findings provide insights into
      medical and health-related web querying and suggests some implications for the
      use of the general web search engines when seeking medical/health information.

PMID- 15023209
TI  - Library service delivery via hand-held computers--the right information at the
      point of care.
AB  - Today's health and medical librarians are well aware of the move towards evidence
      based clinical practice which has emerged during the past decade. Hand-in-hand
      with this trend is the need for health practitioners to have access to the best
      possible evidence to help them in their clinical decision making. Libraries have
      a key role in the provision of information to their clients, and this means
      keeping abreast, not only of the various information sources available, but also
      the means by which those sources may be used. This paper will examine the effects
      that the hand-held computer is having on the work practices of our clients
      library users. It is hoped that the paper will give an insight into the various
      types of library material which are suitable for use with hand-held devices, and
      an understanding of their advantages and limitations.

PMID- 15023210
TI  - A project to improve information technology skills for flexible trainees and
      overseas doctors.

PMID- 15023211
TI  - Mentoring as a tool for staff development.

PMID- 15023212
TI  - Distance learning in post-qualifying nurse education at Northumbria University:
      implications for the role of the library and library staff.

PMID- 15023213
TI  - Using research in practice.

PMID- 15023214
TI  - Learning and teaching.

PMID- 15023218
TI  - Functional integration of health services.

PMID- 15023219
TI  - The use of bupropion for smoking cessation in rural New South Wales.

PMID- 15023220
TI  - Rural doctors' satisfaction in Japan: a nationwide survey.
AB  - OBJECTIVES: The purpose of this paper was to discover to what degree Japanese
      rural doctors are satisfied with various aspects of their jobs and lives, and to
      find out whether they intend to continue their rural careers. DESIGN: Nationwide
      postal survey. SETTING: Public clinics or hospitals in municipalities that are
      authorised as 'rural' by the national government. SUBJECTS: A total of 4896
      doctors working for public clinics or hospitals. INTERVENTIONS: Self-evaluation
      questionnaires were mailed. The rural doctors were asked to evaluate their
      satisfaction with 19 items related to their job conditions and 10 items
      concerning life conditions, using a four-point scale. They also were asked to
      evaluate their intent to stay in rural practice until retirement. RESULTS: The
      response rate was 64%. Overall, rural doctors were satisfied with both their work
      and life conditions. However, only 27% of respondents hoped to continue rural
      practice beyond the usual age of retirement. Among job-related items, continuing
      medical education and interactions with municipal governments were rated as least
      satisfactory. Among lifestyle-related items, duration of holidays and workload
      were unsatisfactory. Subgroup analysis revealed male doctors showed greater
      intent to stay in rural practice. Doctors aged > 50 years were more satisfied
      with most aspects of their job and lifestyle than younger doctors. A strong
      correlation was found between the degree of intent to stay and several items such
      as interactions with municipal government, human interactions salary and job
      fulfillment. CONCLUSIONS: Strategies, based on the results of this survey, should
      be implemented. Particularly in Japan, positive interaction between doctors and
      municipal governments is crucial. WHAT THIS PAPER ADDS: Though rural doctors in
      Japan in general were satisfied with their lifestyle and work conditions, they
      have low intentions to stay in rural areas. Among the various factors that can
      cause this dissociation between satisfaction and intention to stay, doctors'
      interactions with municipal governments play a pivotal role.

PMID- 15023221
TI  - Work of female rural doctors.
AB  - OBJECTIVE: To identify the impact of family life on the ways women practice rural
      medicine and the changes needed to attract women to rural practice. DESIGN:
      Census of women rural doctors in Victoria in 2000, using a self-completed postal
      survey. SETTING: General and specialist practice. SUBJECTS: Two hundred and
      seventy-one female general practitioners and 31 female specialists practising in
      Rural, Remote and Metropolitan Area Classifications 3-7. General practitioners
      are those doctors with a primary medical degree and without additional specialist
      qualifications. MAIN OUTCOME MEASURE: Interaction of hours and type of work with
      family responsibilities. RESULTS: Generalist and specialist women rural doctors
      carry the main responsibility for family care. This is reflected in the number of
      hours they work in clinical and non-clinical professional practice, availability
      for on-call and hospital work, and preference for the responsibilities of
      practice partnership or the flexibility of salaried positions. Most of the
      doctors had established a satisfactory balance between work and family
      responsibilities, although a substantial number were overworked in order to
      provide an income for their families or meet the needs of their communities.
      Thirty-six percent of female rural general practitioners and 56% of female rural
      specialists preferred to work fewer hours. Female general practitioners with
      responsibility for children were more than twice as likely as female general
      practitioners without children to be in a salaried position and less likely to be
      a practice partner. The changes needed to attract and retain women in rural
      practice include a place for everyone in the doctor's family, flexible practice
      structures, mentoring by women doctors and financial and personal recognition.
      WHAT THIS PAPER ADDS: Women make up less than a quarter of the rural general
      practice workforce and an even smaller percentage of the specialist rural medical
      workforce. As a result their experiences are not well articulated in research on
      rural medical practice and their needs are not well represented in policies and
      programs for rural doctors. The incoming cohort of rural general practitioners
      has a majority of women and it is essential that the practice styles and needs of
      women doctors are understood in order to attract and retain women in rural
      medicine. This survey identifies some of the effects of family responsibilities
      on the work practices of female rural doctors and the changes needed to the
      structure of rural practice to include the way women work.

PMID- 15023222
TI  - Psychosocial investigation of individual and community responses to the
      experience of Ovine Johne's Disease in rural Victoria.
AB  - OBJECTIVE: This paper explores the psychosocial outcomes for individuals and
      communities in rural Victoria who experienced the outbreak of Ovine Johne's
      Disease (OJD). DESIGN: The study uses a qualitative methodology to analyse the
      minutes of evidence provided by the inquiry into the control of OJD to identify
      the psychosocial events, experiences and outcomes associated with the control of
      this outbreak. The inquiry was undertaken by the Environment and Natural
      Resources Committee of the Victorian State Government. SETTING: Public hearings
      were undertaken by the committee across several rural Victorian communities and
      the state capital, Melbourne. SUBJECTS: The transcripts detail 136 submissions
      from 98 individuals and 23 organisations. OUTCOME MEASURES: The analysis aimed to
      provide insight into the impact of the disease on individuals and communities and
      also to explore the factors individuals perceived as associated with these
      outcomes. RESULTS: While the paper identifies that aspects of stock loss
      associated with the outbreak caused substantial emotional and economic distress,
      for farmers the most significant finding was the impact of the government control
      program on individuals, families and rural communities. The control program was
      perceived as having very limited scientific credibility and its implementation
      was described as heartless, inflexible and authoritarian. Involvement with the
      program resulted in farmers reporting emotions, such as, trauma, shame, guilt and
      stigma. Families became discordant and the sense of community within rural
      townships fragmented. Psychological outcomes of grief, depression and anxiety
      emerged as prevalent themes within families and communities. CONCLUSIONS: These
      data highlight the need for significant attention to the management of rural
      disasters, such as, the OJD program. WHAT THIS PAPER ADDS: There is an
      acknowledgement in the literature that rural disasters have a significant impact
      on the well-being of individuals, families and communities. The major focus of
      the previous research has, however, been on the impact of economic losses with
      less recognition of the other psychosocial loss experiences that accompany the
      experience of rural disaster. This paper achieves a clear description of the
      experiences for individuals (trauma, stigma, sense of personal failure, loss of
      identity, diminished self esteem and family disruption) and communities
      (destroyed social cohesion, economic disharmony) caught up in the OJD disaster
      and explores the factors that individuals perceive as responsible for these
      outcomes. The mental health outcomes for individuals, such as, loss, grief and
      depression are also explored within this paper. This paper highlights the
      psychosocial complexity of the experience of rural disaster for individuals and
      communities significantly extending the current knowledge base in this area.

PMID- 15023223
TI  - Cancer and cancer risk in South Australia: what evidence for a rural-urban health
      differential?
AB  - OBJECTIVE: To determine the extent of evidence for a rural-urban health
      differential in cancer and cancer risk in South Australia. DESIGN: Secondary
      analysis and synthesis of data available between 1977 and 2000 from the
      publications of the South Australian Cancer Registry and reports of population
      health surveys carried out by the South Australian Department of Human Services.
      RESULTS: The mean annual age-standardised incidence of all forms of cancer
      combined was about 4% lower for rural residents (265.2 per 100,000 cf. 274.9 per
      100,000). Of 31 types of cancer listed, the incidence of three was significantly
      higher among rural residents, the incidence of eight was significantly higher
      among urban residents and for 20 types there was no significant difference. Five
      year case survival for all cancers combined was 52% in both urban and rural
      residents. Significant survival differences were identified for only 10 cancers
      and survival for each was higher among urban residents. Melanomas were diagnosed
      in situ more often in the country, but invasive cases tended to be thicker. There
      was no rural-urban difference in early detection rates for breast cancer or
      bladder cancer. There were no substantial reported differences in major risk
      factors and early detection experiences apart from higher rates of smoking in the
      country. CONCLUSIONS: There is little evidence for substantial or systematic
      differences in risk factors for, and incidence and early detection of cancers
      between urban and rural South Australia. However, the apparent consistently
      poorer survival among rural residents warrants further study. WHAT THIS PAPER
      ADDS: It is widely reported that the health status of rural Australians is worse
      than that of their urban counterparts. There is an apparent increasing gradient
      in mortality from urban to remote areas of Australia. However, this apparent
      gradient is not evident for all diseases. This paper seeks to answer the
      question: is there any difference in the cancer disease experience (incidence,
      survival and early detection) and cancer risk factors between residents of rural
      and urban South Australia. Cancer registry data indicate that overall, the
      incidence of cancer is similar in rural and urban South Australia. The findings
      on survival differentials are of concern. While overall survival rates are very
      similar in country and city, and this is encouraging, analysis of individual
      types of cancer raises some concerns. The registry reports that significant
      differences in survival were only measured for 10 cancers and for all of these
      rural residents experienced higher mortality rates.

PMID- 15023224
TI  - Is rural medicine a separate discipline?
AB  - BACKGROUND: The Australian College of Rural and Remote Medicine was established
      in 1997 to meet what rural doctors perceived as their unmet educational and
      professional needs. However, the issue of just how different rural practice is
      from urban practice remains a topic of debate. METHODS: This paper explores the
      scope of rural medical practice, through the use of clinical scenarios and a
      synthesis of the research literature, to determine if rural medical practice is
      emerging as a distinct discipline in Australia. CONCLUSION: Rural and remote
      medical practice is different, and additional, to urban practice, in the context,
      content and process of care. Three of the four criteria for determining rural
      medical practice as a distinct discipline exist in Australia. The fourth
      criteria: sufficient external recognition of rural medicine as a distinct
      discipline, awaits resolution. WHAT THIS PAPER ADDS: This paper examines a key
      issue that has been a source of conflict between the relevant stakeholders for a
      decade. By placing the differences between rural and urban medical practice
      within a framework, supported by published work, this paper describes what is
      required to justify rural medical practice as a distinct discipline for the first
      time.

PMID- 15023225
TI  - Educational needs of rural and remote Australian non-specialist medical
      practitioners for obstetric ultrasound.
AB  - OBJECTIVE: To determine the educational needs of rural and remote non-specialist
      Australian doctors for obstetric ultrasound. DESIGN: Survey design. SETTING: The
      study surveyed rural and remote doctors practising in a variety of settings
      including general practice, rural hospitals, Aboriginal communities and flying
      doctor organisations throughout Australia. SUBJECTS: Subjects included 314 solo
      and group practice rural general practitioners, rural hospital medical
      superintendents, senior medical officers, Aboriginal community controlled health
      service doctors, flying doctors, rural locums, registrars and two rural
      obstetricians. A total of 55% of the subjects were general practitioners in group
      practice. Respondents included 68 (22%) women and 246 (78%) men. RESULTS: The
      response rate was 32%. The highest priority areas of need for education included
      detecting foetal abnormalities and anomalies (19.1%), basic routine
      ultrasonography (17.17%), placental position (17.17%), dating (17.17%), foetal
      viability (12.88%) and morphology scan (12.26%). The main areas where doctors
      stated they lacked confidence included detecting foetal abnormalities (29.09%),
      basic routine ultrasonography (including machine use), such as, carrying out and
      interpreting obstetric ultrasound scans (27.27%), morphology scans (16.36%) and
      placental position (14.54%). CONCLUSION: The study showed there was a large unmet
      need for education in obstetric ultrasound among rural and remote non-specialist
      doctors. Information from the needs assessment was used to develop the Australian
      College of Rural and Remote Medicine national obstetric ultrasound professional
      development program. WHAT IS ALREADY KNOWN: The authors could not find any
      published work on the educational needs of Australian non-specialist rural and
      remote doctors for obstetric ultrasound. There is research about the outcome of
      obstetric ultrasound education for urban family physicians in the USA, but no
      information about rural doctors' educational needs or education outcomes. The
      study needed to be done so that obstetric ultrasound professional development
      program of the Australian College of Rural and Remote Medicine could be based on
      the real needs of the target group. WHAT THIS PAPER ADDS: As a result of this
      research, there is now information on the educational needs of rural and remote
      Australian non-specialist medical practitioners that can be used by education
      providers to develop quality education programs in obstetric ultrasound.

PMID- 15023226
TI  - Are rural people getting HeartSmart?
AB  - OBJECTIVE: This study evaluates the impact of a cardiac rehabilitation program
      (HeartSmart) in a rural area on the quality of life, dietary behaviour, weight
      loss and physical activity participation of patients with cardiovascular disease
      (CVD) or at high risk of CVD. DESIGN: The evaluation of the program consisted of
      a single group pre and post-test design with follow-up at 3, 6 and 12 months
      after program completion, complemented with a cross-sectional survey of non
      participants as a pseudo comparison group. SETTING: The HeartSmart program is a
      hospital-based cardiac rehabilitation program in Bunbury, a regional centre of
      Western Australia. SUBJECTS: A total of 203 participants and 159 non
      participants. INTERVENTIONS: The program consisted of 7 weeks of education and
      exercise sessions. RESULTS: The program had a high rate of completion (92%).
      Evaluation results suggested that HeartSmart participants demonstrated
      significant improvements in quality of life, compliance with medication, dietary
      behaviour, weight loss and physical activity participation. The largest changes
      were mostly observed between pre and post-program stages, with sustained
      behaviour change at 6 months after the completion of the program. Further
      evidence of the HeartSmart benefits was provided through significantly better
      health-related behaviour, confidence to diet and exercise, dietary fat intake,
      cardiac knowledge and quality of life scores among HeartSmart participants
      compared with non-participants. CONCLUSIONS: While this program has achieved its
      objectives, there are a few issues that need to be considered by similar
      programs: the post-program stage of patient follow-up by general practitioners;
      the geographical disadvantage of those living outside regional centres to access
      the service; enhancing the primary prevention aspect of the program; adapting the
      program to the needs of Aboriginal clients; facilitating evaluations by
      resourcing and training program staff in computer skills. WHAT IS ALREADY KNOWN
      ON THIS SUBJECT: The viability of establishing cardiac rehabilitation programs in
      rural Australia has been questioned and few if any have been formally evaluated,
      particularly using a follow-up design and a control group. WHAT THIS PAPER ADDS:
      This study ascertains the benefits of secondary prevention programs in rural
      areas not only on the quality of life but also shows positive outcomes in
      lifestyle modification for program participants compared to non-participants. The
      lessons learnt can improve the effectiveness of similar prevention programs.

PMID- 15023230
TI  - In vitro cytogenetic testing of an organoselenium compound and its sulfur
      analogue in cultured rat bone marrow cells.
AB  - BACKGROUND: Selenium (Se) is a non-metal element, occurring in varying degrees in
      the environment and it has been found to be a component of several enzymes.
      Different selenium compounds have been associated with carcinogenicity, toxicity,
      modification of metal toxicity and prevention of cancer. Organoselenium compounds
      had substantially greater bioavailability and less toxicity than that of
      inorganic selenium. From a chemical point of view, Se resembles sulfur (S) in
      many of its properties, thus, Se and S may be considered to be isosteric. The
      ability of a synthetic organoselenium compound; cyclopenta-dienyldicarbonyl
      ironselenoterephthalic acid (CSe) and its sulfur analogue (CS) in the range of 10
      8 to 10-5 M, to induce sister-chormatid exchanges (SCE) and alter cell division
      expressed as mitotic index (MI) as well as cell survival has been investigated.
      METHODS: Rat bone marrow cells were cultured in the presence of CSe and CS in the
      range of 10-8 to 10-5 M with a total exposure time of 4, 16 or 28 h at 37 degrees
      C. Fluorescence-plus-Giemsa (FPG) technique was used to visualize chromosomes for
      SCE analysis and MI determination. Trypan blue exclusion technique was used to
      determine cell viability. RESULTS: At the three exposure times, cell survival
      progressively decreased with increasing concentration, but the effect of either
      chemical was not significant (ANOVA; P < 0.05) as compared to the negative
      control. Significant reductions in MI were calculated at the highest
      concentration (10-5 M) when either chemical was applied for 16 or 28 h.
      Furthermore, the mean SCE increased with longer exposure times and, in general,
      CSe had slightly greater effect on cell survival and caused higher frequencies of
      SCE than CS. The exception was the 10-8 M treatment. However, both CSe and CS
      failed to induce 2-fold SCE as that of the negative control and therefore they
      are not considered as mutagens. CONCLUSION: Both CSe and CS in the range of 10-8
      to 10-5 M could not double the SCE rate of the negative control and therefore not
      considered as mutagens at these experimental conditions.

PMID- 15023229
TI  - Toward a theoretical model of quality-of-life appraisal: Implications of findings
      from studies of response shift.
AB  - Mounting evidence for response shifts in quality of life (QOL) appraisal
      indicates the need to include direct measurement of the appraisal process itself
      as a necessary part of QOL assessment. We propose that directly assessing QOL
      appraisal processes will not only improve our ability to interpret QOL scores in
      the traditional sense, but will also yield a deeper understanding of the
      appraisal process in the attribution of and divergence in meaning. The published
      evidence for response shift is reviewed, and an assessment paradigm is proposed
      that includes the explicit measurement of QOL appraisal process parameters: 1)
      induction of a frame of reference; 2) recall and sampling of salient experiences;
      3) standards of comparison used to appraise experiences; and 4) subjective
      algorithm used to prioritize and combine appraisals to arrive at a QOL rating. A
      QOL Appraisal Profile, which measures key appraisal processes, is introduced as
      an adjunct to existing QOL scales. The proposed theoretical model, building on
      the Sprangers and Schwartz (1999) model and highlighting appraisal processes,
      provides a fully testable theoretical treatment of QOL and change in QOL,
      suggesting hypothesized causal relationships and explanatory pathways for both
      cross-sectional and longitudinal QOL research.

PMID- 15023231
TI  - Low-dose, long-term macrolide therapy in asthma: An overview.
AB  - Macrolides, a class of antimicrobials isolated from Streptomycetes more than 50
      years ago, are used extensively to treat sinopulmonary infections in humans. In
      addition, a growing body of experimental and clinical evidence indicates that
      long-term (years), low (sub-antimicrobial)-dose 14- and 15-membered ring
      macrolide antibiotics, such as erythromycin, clarithromycin, roxithromycin and
      azithromycin, express immunomodulatory and tissue reparative effects that are
      distinct from their anti-infective properties. These salutary effects are
      operative in various lung disorders, including diffuse panbronchiolitis, cystic
      fibrosis, persistent chronic rhinosinusitis, nasal polyposis, bronchiectasis,
      asthma and cryptogenic organizing pneumonia.The purpose of this overview is to
      outline the immunomodulatory effects of macrolide antibiotics in patients with
      asthma.

PMID- 15023232
TI  - Distribution of serum lipids and lipoproteins in patients with beta thalassaemia
      major; an epidemiological study in young adults from Greece.
AB  - BACKGROUND: Beta-thalassaemia major (b-TM) has been defined as a combination of
      chronic hemolytic anemia, iron storage disease and myocarditis, and it has been
      associated with premature death especially due to heart failure. To the best of
      our knowledge the status of blood lipids in these patients has rarely been
      investigated. Thus, we assessed the levels of lipids and lipoproteins in a sample
      of cardiovascular disease free adult men and women with b-TM. METHODS: During
      2003 we enrolled 192 consecutive patients with b-TM that visited our Institution
      for routine examinations. The Institution is considered the major reference
      center for b-TM in Greece. Of the 192 patients, 88 were men (25 +/- 6 years old)
      and 104 women (26 +/- 6 years old). Fasting blood lipid levels were measured in
      all participants. RESULTS: Data analysis revealed that 4% of men and 2% of women
      had total serum cholesterol levels > 200 mg/dl, and 11% of men and 17% of women
      had triglyceride levels > 150 mg/dl. In addition, mean HDL cholesterol levels
      were 32 +/- 11 mg/dl in men and 38 +/- 10 mg/dl in women, lipoprotein-a levels
      were 8.3 +/- 9 mg/dl in men and 8.8 +/- 9 mg/dl in women, apolipoprotein-A1
      levels were 111 +/- 17 mg/dl in men and 123 +/- 29 mg/dl in women, and
      apolipoprotein-B levels were 60 +/- 20 mg/dl in men and 59 +/- 14 mg/dl in women.
      Total-to-HDL cholesterol ratios were 3.7 +/- 1.2 and 3.8 +/- 1.5 in men and
      women, respectively. CONCLUSIONS: The majority of the patients had blood lipid
      levels (by the exception of HDL-cholesterol) within the normal range, and
      consequently the prevalence of lipid and lipoprotein abnormalities was much lower
      as compared to the general population of the same age. Interestingly, is that the
      total-to HDL cholesterol ratio was high in our patients, and may underline the
      importance of this index for the prognosis of future cardiac events in these
      patients.

PMID- 15023234
TI  - Inequalities in purchase of mosquito nets and willingness to pay for insecticide
      treated nets in Nigeria: challenges for malaria control interventions.
AB  - OBJECTIVE: To explore the equity implications of insecticide-treated nets (ITN)
      distribution programmes that are based on user charges. METHODS: A questionnaire
      was used to collect information on previous purchase of untreated nets and
      hypothetical willingness to pay (WTP) for ITNs from a random sample of
      householders. A second survey was conducted one month later to collect
      information on actual purchases of ITNs. An economic status index was used for
      characterizing inequity. MAJOR FINDINGS: The lower economic status quintiles were
      less likely to have previously purchased untreated nets and also had a lower
      hypothetical and actual WTP for ITNs. CONCLUSION: ITN distribution programmes
      need to take account of the diversity in WTP for ITNs if they are to ensure
      equity in access to the nets. This could form part of the overall poverty
      reduction strategy.

PMID- 15023233
TI  - Nonlinear analysis of EEG signals at different mental states.
AB  - BACKGROUND: The EEG (Electroencephalogram) is a representative signal containing
      information about the condition of the brain. The shape of the wave may contain
      useful information about the state of the brain. However, the human observer can
      not directly monitor these subtle details. Besides, since bio-signals are highly
      subjective, the symptoms may appear at random in the time scale. Therefore, the
      EEG signal parameters, extracted and analyzed using computers, are highly useful
      in diagnostics. This work discusses the effect on the EEG signal due to music and
      reflexological stimulation. METHODS: In this work, nonlinear parameters like
      Correlation Dimension (CD), Largest Lyapunov Exponent (LLE), Hurst Exponent (H)
      and Approximate Entropy (ApEn) are evaluated from the EEG signals under different
      mental states. RESULTS: The results obtained show that EEG to become less complex
      relative to the normal state with a confidence level of more than 85% due to
      stimulation. CONCLUSIONS: It is found that the measures are significantly lower
      when the subjects are under sound or reflexologic stimulation as compared to the
      normal state. The dimension increases with the degree of the cognitive activity.
      This suggests that when the subjects are under sound or reflexologic stimuli, the
      number of parallel functional processes active in the brain is less and the brain
      goes to a more relaxed state

PMID- 15023236
TI  - Accelerated partial breast irradiation : a legitimate treatment option?

PMID- 15023235
TI  - Cardiovascular adaptations to exercise training in postmenopausal women with type
      2 diabetes mellitus.
AB  - BACKGROUND: Type 2 diabetes mellitus (DM-2) is one of the most prevalent chronic
      diseases of the aged and contributes to a significant amount of cardiovascular
      disease morbidity and mortality. Exercise training may be beneficial in
      attenuating the cardiovascular maladaptations associated with DM-2. The purpose
      of this study was to examine the effects of exercise training on left ventricular
      (LV) and vascular function in a sample of postmenopausal women with DM-2.
      METHODS: Twenty-eight postmenopausal women with DM-2 (age: 59 +/- 7 yrs) were
      assigned to either an exercise training (ET) (n = 17) or control group (CT) (n =
      7). Cardiorespiratory fitness (VO2peak), LV filling dynamics and arterial
      compliance were assessed at baseline in all participants. The ET group performed
      a supervised aerobic and resistance training intervention three days per week for
      a period of 10 weeks, while the CT group continued normal activities of daily
      living. RESULTS: Body mass index, VO2peak, age and duration of diabetes were
      similar between the ET and CT groups at baseline. VO2peak (21.3 +/- 3.3 to 24.5
      +/- 4.2 ml.kg-1.min-1, p < 0.05) and large artery compliance (1.0 +/- 0.4 to 1.2
      +/- 0.4 mL.mmHg-1, p < 0.05), increased significantly in the ET group following
      training despite no change in LV filling dynamics, blood pressure, lipid profile
      or insulin sensitivity. All variables remained unchanged in the CT group.
      CONCLUSIONS: Exercise training improves large artery compliance and
      cardiorespiratory fitness in postmenopausal women with DM-2, without any
      appreciable changes in LV filling dynamics or conventional risk factors for
      cardiovascular disease.

PMID- 15023241
TI  - Adjuvant radiation therapy after breast-conserving surgery in elderly women with
      early-stage breast cancer: controversy or consensus?
AB  - Breast-conservation therapy (BCT), which consists of breast-conserving surgery
      (BCS) and postoperative radiation therapy (RT), provides similar levels of local
      control and survival compared with mastectomy. Although the incidence of breast
      cancer increases with age and the proportion of elderly women in the population
      continues to increase, clinical trials of BCT have included few women aged > or =
      65 years, limiting the ability to establish clear consensus regarding optimal
      therapy in this population. This article examines the literature on BCT in
      elderly women with early-stage breast cancer. A systematic search of the Medline
      and CancerLit databases was conducted to identify articles specifically
      addressing BCT in elderly women. The outcomes evaluated were local control,
      disease-free survival, overall survival, and treatment-related toxicities. The
      lack of consensus in breast-conservation management in elderly patients is
      highlighted by a paucity of prospective data and numerous retrospective series
      reporting diverse treatment approaches with conflicting results. The available
      evidence from BCT trials with and without age subgroup analyses support BCS with
      postoperative RT as the standard approach associated with the most favorable
      local control outcomes. A low-risk subset of patients in whom RT may be omitted
      without compromising local control remains to be defined. Despite these findings,
      the use of standard therapy significantly decreases with advancing patient age.
      Although data specifically addressing BCT in elderly patients are limited, age
      should not preclude consideration of standard treatment strategies to optimize
      local disease control. Modern clinical trials with representative samples of
      elderly patients evaluating cancer recurrence and survival as well as functional
      and quality-of-life outcomes are needed to define optimal breast-conservation
      management for this important patient population.

PMID- 15023240
TI  - Advances in radiation treatments of breast cancer.
AB  - During the past decade, improvements in treatment-planning tools, computer and
      imaging technologies, and new therapeutic modalities have allowed radiation to be
      delivered in a conformal fashion while minimizing treatment toxicity. It is
      important that physicians involved in breast cancer treatment recognize the
      numerous advances that have occurred in the delivery of radiation therapy.
      Changes in 3 specific areas in treatment planning and delivery have
      revolutionized the way we approach breast cancer treatment: the design of
      radiation fields using computed tomography (CT) data sets, the development of 3
      dimensional dose-calculation algorithms, and the development of new methods to
      modulate the delivery of radiation dose. With the advent of CT simulators,
      individual patient anatomy and pathology can be readily visualized and
      reconstructed in axial, coronal, and sagittal views. With an improved anatomic
      delineation between the target volumes and critical organ structures, the
      treatment fields can be designed to be more congruous to the areas at highest
      risk. In the past few years, new 3-dimensional dose-calculation algorithms have
      been generated that more accurately calculate dose distributions throughout the
      treatment-planning volume. Finally, modern linear accelerators allow for
      modulation of the dose intensity of the radiation beam, which may lead to
      improved aesthetics and decreased side effects while ensuring that the volumes at
      high risk receive the prescribed dose. Radiation therapy can be delivered safely
      and effectively to patients with breast cancer.

PMID- 15023242
TI  - Paclitaxel improves the prognosis in estrogen receptor negative inflammatory
      breast cancer: the M. D. Anderson Cancer Center experience.
AB  - The treatment of inflammatory breast cancer includes preoperative anthracycline
      based chemotherapy, surgery, and radiation therapy. In the past few years,
      taxanes, mainly paclitaxel, have been frequently used for preoperative
      chemotherapy, usually in sequence with anthracyclines. The purpose of this
      retrospective analysis was to determine how adding paclitaxel to anthracycline
      based regimens affects prognosis. A total of 240 patients treated in 6
      consecutive trials between 1973 and 2000 were included in the analysis. Group 1
      (N = 178) consisted of patients treated in the first 4 trials (1973-1993) with
      FAC (5-fluorouracil/doxorubicin/cyclophosphamide) based regimens. Group 2 (N =
      62) consisted of patients treated in the last 2 trials (1994-2000) with FAC
      followed by paclitaxel given every 3 weeks or given in a high-dose weekly
      schedule. The 2 groups differed with respect to median follow-up durations, which
      were 148 months (range, 85-283 months) in group 1 and 45 months (range, 21-99
      months) in group 2. Estrogen receptor (ER) status was negative in 58 cases (33%)
      in group 1 and 40 cases (65%) in group 2. There was no difference in median age
      between the groups. The objective response rates (complete and partial) were
      similar (group 1, 74%; group 2, 82%). The median overall survival (OS) and
      progression-free survival (PFS) were better in the patients treated with
      paclitaxel, and these differences reached statistical significance in the
      patients with ER-negative disease (median OS: group 1, 32 months; group 2, 54
      months; P = 0.03; median PFS: group 1, 18 months; group 2, 27 months; P = 0.04).
      It may be concluded that the addition of paclitaxel to anthracycline-based
      therapy resulted in a statistically significant improvement in outcome in
      patients with ER-negative inflammatory breast cancer.

PMID- 15023244
TI  - Prognostic impact of cyclooxygenase-2 in breast cancer.
AB  - Cyclooxygenase (COX)-2, an inducible isoform of cyclooxygenases, regulates the
      rapid production of high levels of prostaglandins during inflammation.
      Cyclooxygenase-2 is overexpressed in a variety of malignant tumors. This review
      discusses epidemiologic and preclinical data on the role of COX-2 in the
      development and progression of breast cancer, and it will focus on recent studies
      that investigate the prognostic role of COX-2 in breast cancer. In rodent tumor
      models it has been shown that treatment with COX-1 or COX-2 inhibitors reduces
      incidence and growth of breast carcinomas. Possible mechanisms include regulation
      of invasion, increased proliferation, and suppression of apoptosis by COX-2.
      Moreover, there may be an indirect effect of prostaglandins, for example in tumor
      host interactions such as induction of stromal aromatase activity or enhancement
      of angiogenesis in tumor tissue. At least 8 different immunohistochemical studies
      have investigated expression of COX-2 in a total of 2392 primary breast
      carcinomas, of which 40% were found to be COX-2 positive. Overexpression of COX-2
      is associated with indicators of poor prognosis, such as lymph node metastasis,
      poor differentiation, and large tumor size. Four studies have found that
      overexpression of COX-2 is linked to poor prognosis in breast cancer. These
      investigations provide the basis for further evaluation of a possible therapeutic
      effect of COX inhibitors in therapy of breast cancer.

PMID- 15023246
TI  - Qualitative analysis of Cu2+, Co2+, and Ni2+ cations using thin-layer
      chromatography.
AB  - The M(DEDTC)2 (M = Cu, Co, or Ni) and M(PyDTC)2 (M = Cu or Co) complexes prepared
      by reactions of sodium diethyldithiocarbamate and ammonium
      pyrollidinedithiocarbamate with metal (II) nitrates are examined for qualitative
      analysis and separation using thin-layer chromatography systems. These complexes
      and their mixtures are spotted to the activated thin layers of silica gel 60GF254
      (Si-60GF254) with a 250-microm thickness. Pure toluene and a toluene-cyclohexane
      mixture (3:1, v/v) are used as mobile phases for running of the complexes. These
      chromatographic systems are successfully used for qualitative analysis of
      corresponding metal cations and separation of components in both M(DEDTC)2 and
      M(PyDTC)2 complex mixtures.

PMID- 15023245
TI  - Simultaneous determination of thiamine and riboflavin in edible marine seaweeds
      by high-performance liquid chromatography.
AB  - This study presents a high-performance liquid chromatography (HPLC) method for
      simultaneous determination of thiamine and riboflavin and the results of its
      application to a number of edible seaweeds that are sampled in dried form
      (Himanthalia elongata, Laminaria ochroleuca, Undaria pinnatifida, Palmaria sp.,
      and Porphyra sp.) or as canned food (H. elongata and Saccorhiza polyschides).
      Samples are prepared by acid and enzymatic hydrolysis. Optimized conditions for
      reversed-phase HPLC with fluorescence detection are as follow: column, Kromasil
      100 C18; column temperature, 35 degrees C; mobile phase, a 72:28 (v/v) mixture of
      0.005 M ammonium acetate (pH 6.7)-methanol; and flow rate, 1.35 mL/min. With
      these conditions, recovery is 95.52% for thiamine and 90.08% for riboflavin, and
      the method precision (relative standard deviation) is 2.66% for thiamine and
      2.21% for riboflavin. On a dry weight basis, thiamine contents range from 0.14
      microg/g in dried H. elongata to 2.02 microg/g in dried Porphyra and riboflavin
      contents from 0.31 microg/g in canned H. elongata to 6.15 microg/g in dried
      Porphyra.

PMID- 15023243
TI  - Phase II study of weekly docetaxel alone or in combination with trastuzumab in
      patients with metastatic breast cancer.
AB  - This study was designed to determine the efficacy and toxicity of weekly
      docetaxel in metastatic breast cancer when given alone (for HER2/neu negative
      disease) or with trastuzumab (for HER2/neu overexpressing disease). Patients with
      metastatic breast carcinoma received docetaxel given on 2 different schedules
      (group 1A, 33 mg/m2 weekly [n = 21]; group 1B, 40 mg/m2 weekly for 3 weeks with 1
      week off [n = 14]). Patients with HER2/neu overexpressing disease also received
      trastuzumab 4 mg/kg on day 1, then 2 mg/kg on days 8 and 15 of each 28-day cycle
      (group 2). Fifty-two patients were treated with docetaxel alone (group 1A/B, n =
      35) or in combination with trastuzumab (group 2, n = 17). Prior taxane therapy
      given every 3 weeks had been used for metastatic disease in 19 of 35 patients
      (54%) in group 1A/B and in 2 of 17 patients (12%) in group 2. The mean delivered
      dose intensity of docetaxel was 29 mg/m2 per week. Partial response occurred in 7
      of 35 patients (21%; 95% exact binomial confidence interval [CI], 9%-38%) treated
      with docetaxel alone, including 3 of 19 taxane-pretreated patients (16%) and 4 of
      16 taxane-naive patients (25%). Partial response occurred in 10 of 17 patients
      (59%; 95% CI, 34%-82%) treated with docetaxel/trastuzumab. The most common grade
      3/4 toxicities, occurring in more than or equal to 10% of patients, included
      neutropenia (21%), pulmonary toxicity (12%), and hyperglycemia (10%). The median
      times to disease progression were 4.5 months (95% CI, 2.5-6.5 months) in the
      docetaxel group and 8.5 months (95% CI, 4.5-12.5 months) in the
      docetaxel/trastuzumab group. Weekly docetaxel/trastuzumab is an effective regimen
      for patients with HER2/neu overexpressing metastatic breast cancer. Weekly
      docetaxel may be effective in as many as 20% of patients who had progressive
      disease after treatment with taxanes given every 3 weeks.

PMID- 15023248
TI  - Separation and identification of cannabis components by different planar
      chromatography techniques (TLC, AMD, OPLC).
AB  - The use of cannabis is illicit in numerous countries, and the increasing
      consumption has led to a multiplication of scientific studies. New methods of
      planar chromatography such as automated multiple development (AMD) and optimum
      performance laminar chromatography (OPLC) techniques can be used as a substitute
      for the traditional thin-layer chromatography for the identification and
      quantitation of the Indian hemp components. Each method offers its own advantage:
      high resolution with neither diffusion nor spot stretching for AMD and speed,
      efficiency, and the possibility of working in the semipreparative mode for OPLC.

PMID- 15023247
TI  - LC-SSI-MS techniques as efficient tools for characterization of nonvolatile
      phenolic compounds of a special Hungarian wine.
AB  - The utility of high-performance liquid chromatography-mass spectrometry using
      electrospray (ESI) and sonic spray (SSI) ionization for the characterization of
      nonvolatile phenolic compounds is tested using the special Hungarian wine Tokaj
      aszu of 1983 vintage. Besides caffeic-, ferrulic-, chlorogenic-, and 3,4
      dimethoxycinnamic acids; 3,4-dimethoxycinnamoyl-, ferruloyl-, and galloyl
      glucose; gentisic acid-beta-D-glucoside; theogallin; and resveratrol-3-O-beta-D
      glucoside, 26 flavonoids can be identified. It is shown that because of its
      higher sensitivity, SSI is a more powerful tool for characterization and
      monitoring of nonvolatile phenolic compounds than ESI.

PMID- 15023250
TI  - Analysis of destruxins produced from Metarhizium anisopliae by capillary
      electrophoresis.
AB  - Destruxins are insecticidal metabolites of a fungus, Metarhizium anisopliae.
      These metabolites are usually secreted into the culture medium during growth. The
      structure of destruxins is classified as being a cyclic hexadepsipeptide. More
      than 35 different destruxins have been characterized with a wide range of
      insecticidal activities. In this report, the destruxins are extracted by
      acetonitrile and crystallization by lyophilization. The final crystal is
      subjected for capillary electrophoresis analysis. Because destruxins are
      relatively hydrophobic compounds, micellar electrokinetic capillary
      chromatography is used in this series of experiments. The borate-based running
      buffer is optimized according to (1) boric acid concentration, (2) sodium dodecyl
      sulfate (SDS) concentration, (3) acetonitrile concentration, and (4) the pH of
      the running buffer. Optimization is based on resolution and running speed. The
      results indicate that 20 mM boric acid with 40 mM SDS plus 10% acetonitrile with
      pH 9.24 is the best set of conditions for both resolution and running speed.

PMID- 15023249
TI  - Selectivity tuning of serially coupled (S,S) Whelk-O 1 and (R,R) Whelk-O 1
      columns in HPLC.
AB  - The selectivity tuning of two columns coupled in series is investigated in chiral
      high-performance liquid chromatography. Two columns with reversal
      enantioselectivities [(R,R) Whelk-O 1 and (S,S) Whelk-O 1] are coupled in series
      via a T connector. Selectivity of such a column series is tuned by varying the
      mobile phase flows in the individual columns. The flow ratio necessary for the
      required selectivity is calculated on the basis of retention factors measured on
      the individual columns. The performance of this method for adjusting the required
      selectivity is studied by the separation of enantiomers of alkoxy substituted
      esters of phenylcarbamic acid. It is demonstrated that the change of the mobile
      phase flows in the individual columns enables change in the elution order of
      enantiomers.

PMID- 15023251
TI  - Analysis of 1,2(2,3)- and 1,3-positional isomers of diacylglycerols from
      vegetable oils by reversed-phase high-performance liquid chromatography.
AB  - Separation of 1,2(2,3)- and 1,3-positional isomers of diacylglycerols (DAG) from
      vegetable oils by reversed-phase high-performance liquid chromatography (RP-HPLC)
      is investigated. The method is based on isocratic elution using 100% acetonitrile
      and UV detection at 205 nm. The following elution order of DAG molecular species
      is identified: 1,3-dilinolein < 1,2-dilinolein < 1,3-dimyristin < 1-oleoyl-3
      linoleoyl-glycerol < 1,2-dimyristoyl-rac-glycerol < 1(2)-oleoyl-2(3)-linoleoyl
      glycerol < 1-linolenoyl-3-stearoyl-glycerol < 1(2)-linolenoyl-2(3)-stearoyl
      glycerol < 1,3-diolein < 1-palmitoyl-3-oleoyl-glycerol < 1,2-dioleoyl-sn-glycerol
      < 1(2)-palmitoyl-2(3)-oleoyl-glycerol < 1-linoleoyl-3-stearoyl-glycerol < 1,3
      dipalmitin < 1(2)-linoleoyl-2(3)-stearoyl-glycerol < 1-oleoyl-3-stearoyl-glycerol
      < 1,2-dipalmitoyl-rac-glycerol < 1-palmitoyl-3-stearoyl-sn-glycerol < 1,3
      distearin < 1,2-distearoyl-rac-glycerol. Linearity is observed over three orders
      of magnitude. Limits of detection and quantitation range 0.2-0.7 microg/mL for
      1,3-dilinolein to 0.6-1.9 microg/mL for 1,2-dioleoyl-sn-glycerol, respectively.
      Precision and accuracy of the method are also demonstrated. The method is
      developed to separate mixtures of DAG molecular species produced from edible
      oils.

PMID- 15023252
TI  - Simultaneous determination of several antalgic drugs based on their interactions
      with beta-cyclodextrin by capillary zone electrophoresis.
AB  - The binding constants of beta-cyclodextrin (beta-CD) with antalgic drugs such as
      naproxen, ketoprofen, ibuprofen, acemetacin, and aspirin are determined by
      affinity capillary electrophoresis. Based on these interactions, a reliable
      method for the separation and simultaneous determinations of these compounds in
      the presence of 5.0 mM beta-CD in phosphate buffer solution is presented by
      capillary zone electrophoresis with UV detection at 214 nm for naproxen and 200
      nm for the others. The linear ranges for naproxen, ketoprofen, ibuprofen,
      acemetacin, aspirin, and caffeine detections are from 2.0 to 800, 2.5 to 1000,
      2.5 to 700, 2.5 to 700, 2.0 to 800, and 1.5 to 800 microg/mL, respectively. Their
      detection limits are 1.0, 0.5, 0.5, 1.5, 1.5, and 1.0 microg/mL at a signal to
      noise ratio of 3, respectively. This method has been successfully applied to the
      detections of these drugs in the pharmaceutical formulations (tablets or
      capsules) and urine samples.

PMID- 15023253
TI  - The retention of some open-chain diamines on a strong cation-exchange resin in
      ion chromatography as a function of their structure.
AB  - This work reports the results of a study of the influence of the structure of
      some open-chain diamines on their retention in high-performance ion
      chromatography (HPIC). We examine a set of eight diamines, in which the N atoms
      are separated by two C atoms and are differently N- and C-alkyl substituted; four
      of these diamines have the same formula weight. In the other two sets, the
      diamines are different from each other, either in terms of the length of the
      alkyl chain between the N atoms or in terms of the length of the substituent(s)
      on the nitrogen atom(s). The mobile phase is a mixture of HClO4 0.100 mol/L,
      0.160 < C(NaClO4) < 1.50 mol/L, and 0 < acetonitrile% < or = 15 (v/v). The amines
      are detected by integrated amperometry. Interpretation of experimental data shows
      that (a) elution occurs for both ionic and hydrophobic interactions and is
      dependent on all the components of the mobile phase, (b) the diamines are eluted
      in any case as dications, and (c) steric hindrance significantly influences
      elution times. Some examples of separation are proposed.

PMID- 15023254
TI  - Gas chromatographic method for analysis of conjugated linoleic acids isomers
      (c9t11, t10c12, and t9t11) in broth media as application in probiotic studies.
AB  - A gas chromatography (GC) procedure is assayed for analysis of conjugated
      linoleic acid (CLA) isomers cis-9, trans-11-octadecadienoic (c9t11); trans-10, 12
      cis-octadecadienoic (t10c12); and trans-9, trans-11-octadecadienoic (t9t11) in
      culture broth by GC using NaOH-BF3 in methanol for methylating and a long
      capillary (100 m) high-polarity column. Repeatability of the method is assessed;
      the coefficient of variation for CLA isomers ranges from 4.62 for c9t11 to 8.19
      for t9t11. Recovery ranges between 88.01 and 89.76, with a mean value of 89.06
      for all CLA isomers studied. This method may be considered advantageous for
      analysis of CLA isomers in probiotics cultures samples.

PMID- 15023255
TI  - Solid-phase microextraction and gas chromatography-electron capture detection
      analysis of trace organochlorine pesticides in water using novel benzo-15-crown-5
      sol-gel coating.
AB  - A novel dihydroxy-terminated benzo-15-crown-5 is synthesized and applied to
      prepare the solid-phase microextraction (SPME) fiber coating with sol-gel
      technology. Headspace SPME, as a simple, solvent-free method, is applied to the
      analysis of 16 organochlorine pesticides (OCPs) present at trace levels in a
      water sample. A homemade crown ether fiber coated with 80- micro m thickness was
      used for extraction. Analyses are performed using gas chromatography
      electroncapture detection. The optimization of the extraction process is studied.
      Compared with commercially available SPME fibers, polydimethylsiloxane, the new
      phases show better selectivity and sensitivity toward OCPs. The linear
      concentrations range from 1 to 1000 ng/L, the detection limits are in the range
      of 0.01-0.5 ng/L, the recoveries are over 85%, and relative standard deviations
      are below 7.2% for these OCPs.

PMID- 15023256
TI  - Effect of temperature on enantiomer separation of oxzepam and lorazepam by high
      performance liquid chromatography on a beta-cyclodextrin derivatized bonded
      chiral stationary phase.
AB  - A reversed-phase high-performance liquid chromatography (HPLC) method with beta
      cyclodextrin (beta-CD) derivatized as chiral stationary phase is used to directly
      separate oxazepam (Oxa) and lorazepam (Lor) enantiomers. The effect of
      temperature on the direct HPLC separation of Oxa and Lor enantiomers is studied
      for the commercially available beta-CD derivatized bonded chiral stationary
      phase. Chromatographic peak coalescence, appearing as a plateau between the
      resolved peaks, is observed at column temperatures of above 13 degrees C. Peak
      coalescence on the beta-CD derivatized bonded column is attributable to
      racemization of the Oxa enantiomer. By reducing the column temperature to 13
      degrees C, the enantiomeric composition of Oxa and Lor could be determined on the
      chiral column. This method is expected to be useful for the resolution of 3
      hydroxybenzodiazepines. At the same time, the separation mechanism is studied by
      calculating the thermodynamic parameters. The results reveal that the separation
      of Oxa and Lor enantiomer is a case of enthalpy-controlled separation, inclusion
      mechanism does not control the separation. The interaction between Oxa and beta
      CD is an additionally strong pi-pi interaction or hydrogen bonding, but that
      between Lor or beta-CD derivatized is a weak pi-pi interaction or hydrogen
      bonding.

PMID- 15023257
TI  - Gel permeation chromatography of fullerene-centered macromolecules.
AB  - Gel permeation chromatography (GPC) behavior of fullerene-centered macromolecules
      is investigated. Because of the globular shape of the macromolecules, their GPC
      results are different from those of linear polystyrene standards. These
      macromolecules may serve as alternative molecular weight standards for polymers
      or dendrimers of similar globular structures. The results also show that the GPC
      analysis is capable of discerning relatively minor structural differences in the
      fullerene-centered macromolecules.

PMID- 15023258
TI  - Simultaneous determination of metformin in combination with rosiglitazone by
      reversed-phase liquid chromatography.
AB  - A simple, rapid, and precise reversed-phase liquid chromatographic method is
      developed for the simultaneous determination of metformin in combination with
      rosiglitazone. This method uses a Zorbax XDB C(18) 15-cm analytical column, a
      mobile phase of acetonitrile and buffer containing 10mM disodium hydrogen
      phsosphate, and 5mM sodium dodecyl sulphate in the ratio of 34:66 (v/v), and pH
      is adjusted to 7.1 with orthophosphoric acid. The instrumental settings are a
      flow rate of 1 mL/min, column temperature at 40 degrees C, and detector
      wavelength of 226 nm. The internal standard method is used for the quantitation
      of metformin and rosiglitazone. Methylparaben is used as an internal standard.
      The method is validated and shown to be linear. The correlation coefficients for
      metformin and rosiglitazone are 0.9996 and 0.9997, respectively. The relative
      standard deviation for six replicate measurements in two sets of each drug in the
      tablets is always less than 2%.

PMID- 15023259
TI  - Experimental design optimization of a capillary zone electrophoresis method for
      the screening of several diuretics and ACE inhibitors.
AB  - Experimental design methodologies are applied to the development of a capillary
      zone electrophoretic method for the separation of the angiotensin-converting
      enzyme inhibitor enalapril and its derivative enalaprilat and the diuretics
      xipamide and hydrochlorothiazide. The effects of pH, buffer concentration,
      proportion of boric acid in the mixed boric acid-potassium dihydrogen phosphate
      background electrolyte, temperature, applied voltage, and percentage of organic
      modifier are studied. Critical factors are identified in a screening design (a
      2(6-2) fractional factorial design), and afterwards, optimal conditions for the
      separation are reached by means of an optimization design (a 2(2) + 2 x 2 + k
      central composite design). The studied response is the resolution between peaks.
      The four studied compounds can be separated in less than 3.5 min using an
      electrolyte of 20mM boric acid-potassium dihydrogen phosphate (75:25, v/v) with
      5% MeOH adjusted to pH 8.0 with KOH, at a potential of 30 kV. The detection
      wavelength and temperature are 206 nm and 35 degrees C, respectively.

PMID- 15023261
TI  - Multiple peak formation of avidin on an iminobiotin affinity support.
AB  - When pure avidin is chromatographed on a homemade iminobiotin column, two
      distinct peaks are observed using a gradient solvent system starting with a pH 9
      buffer. Proteins in both peaks are shown to be identical by nondenatured
      polyacrylamide gel electrophoretic experiment. The weak interaction of the
      protein with the stationary phase at pH 9 could cause this unusual behavior.

PMID- 15023260
TI  - Determination of zinc dialkyldithiocarbamates in latex condoms.
AB  - A simple high-performance liquid chromatographic (HPLC) assay is developed for
      measuring zinc dialkyldithiocarbamate (DTC) levels in latex condoms. After
      extraction of 14 different brands of latex condoms in acetonitrile, aliquots of
      the extracts are subjected to a preliminary screening assay by treatment with
      cobalt chloride and measurement of UV absorption at 320 nm, which results in the
      identification of 6 DTC-containing samples. Prior to analysis by HPLC, zinc
      dimethyldithiocarbamate (ZDMC) or zinc diethyldithiocarbamate (ZDEC) is added to
      the extracts in order to block transmetalation reactions with the analytes of
      interest. A reversed-phase C(18) column, with gradient elution and UV detection
      at 260 nm, is used to measure the zinc DTCs. The limits of detection for ZDEC and
      zinc dibutyldithiocarbamate (ZDBC) are 5 and 10 micro g/mL. Levels of ZDBC and
      ZDEC range from not detectable to 3.31 and 1.79 mg/condom, respectively. Total
      protein and latex allergenic protein levels are determined and range from 98 to
      776 and 0.01 to 14.04 micro g/unit, respectively, but are not related to the
      level of ZDBC or ZDEC. This methodology provides both screening and specific
      tools for the determination of unstable zinc DTC complexes in latex products.

PMID- 15023262
TI  - High-performance liquid chromatographic method for the determination and
      pharmacokinetic study of mangiferin in plasma of rats having taken the
      traditional Chinese medicinal preparation Zi-Shen pill.
AB  - A high-performance liquid chromatographic method for the determination and
      pharmacokinetic study of mangiferin in the plasma of rats that have been orally
      administered the traditional Chinese medicinal preparation Zi-Shen pill is
      established. Plasma samples taken from rats are pretreated by protein
      precipitation with acetonitrile. Separation of the main effective constituent
      mangiferin is accomplished on a C18 stationary phase and a mobile phase of
      methanol&-water (25:75, v/v) with 0.6% glacial acetic acid. The UV detection
      wavelength is set at 320 nm, and the detection limit for mangiferin in plasma is
      0.163 micro g/mL. After validation, the method is used to take a limited view of
      pharmacokinetic profiles of the traditional Chinese medicinal preparation Zi-Shen
      pill.

PMID- 15023263
TI  - Analysis of unknown organic pollutants in sewage by solid-phase extraction
      combined with gas chromatography-mass spectrometry.
AB  - A rapid, simple, and reliable method of solid-phase extraction (SPE) combined
      with gas chromatography (GC)-mass spectrometry (MS) is developed for the analysis
      of a wide range of polarity of unknown organic pollutants in sewage. Wastewater
      samples are extracted by passing them through disposable C(18) cartridges, and
      the extracts are then analyzed by GC-MS. Different SPE parameters for ten organic
      compounds in the list of priority pollutants suggested by the China Environmental
      Protection Agency (EPA) are studied, and their breakthrough volumes are
      determined. Extraction recoveries for the tested compounds are greater than 60%,
      except the recovery of 1,2-dichloroethane is 48%. The relative standard
      deviations are less than 7.8% (n = 3). The developed approach is successfully
      applied for the identification of organic components in a sewage sample. Over 220
      organic pollutants are identified, with 5 of these present in the list of
      priority pollutants suggested by the U.S. EPA and 4 from the list by the China
      EPA.

PMID- 15023264
TI  - The role of pore size and stationary phase composition in preventing aqueous
      induced retention time loss in reversed-phase HPLC.
AB  - The phenomenon of aqueous mobile phase induced retention time loss, which has
      also been referred to as phase-collapse behavior, is investigated using a variety
      of stationary phases with an aqueous mobile phase. The loss of retention of
      several water-soluble B vitamins is measured as a function of silica pore size,
      bonded-phase chemistry, and bonded stationary phase density. It is found that
      these variables influence the magnitude of the retention time loss behavior and
      that controlling/optimizing these variables can result in a stationary phase with
      sufficient retention of the analyte without the column exhibiting the so-called
      phase-collapse behavior.

PMID- 15023265
TI  - A new HPLC method to determine glomerular filtration rate and effective renal
      plasma flow in conscious dogs by single intravenous administration of iohexol and
      p-aminohippuric acid.
AB  - A high-performance liquid chromatography method to determine iohexol (IOX) and p
      aminohippuric acid (PAH) in the plasma of dogs is evaluated according to
      recovery, reproducibility, and linearity utilizing a gradient pump. The mobile
      phase consists of 50mM sodium dihydrogen phosphate with 0.5mM tetrabutylammonium
      chloride, the pH is adjusted to 4.1, methanol is added to the final ratio of
      90:10 (v/v), the flow rate is set at 1 mL/min, and separation is achieved with an
      ODS2 Luna column. The UV detector is set at 254 nm. IOX and PAH are used for
      evaluation of the effective renal plasma flow (ERPF) and glomerular filtration
      rate (GFR). The present method tested in three dogs demonstrates the accuracy in
      the evaluation of ERPF and GFR. Because of its precision and simplicity and low
      cost, it can be considered a good tool for ERPF and GFR in small animal practice.

PMID- 15023269
TI  - Enteroaggregative Escherichia coli: An Emerging Pathogen.

PMID- 15023270
TI  - Effects of Perioperative Human Granulocyte Colony-stimulating Factor on Immune
      Function and Perioperative Infections in Patients Undergoing Abdominal Surgery.

PMID- 15023271
TI  - Current Assessment of Yellow Fever and Yellow Fever Vaccine.
AB  - Yellow fever (YF) is a mosquito-borne viral illness that causes hemorrhagic fever
      in tropical Africa and South America. Although a very safe and efficient vaccine
      (17D) is available, it is underused. An estimated 200,000 people are still
      infected annually, and YF remains a major public health concern. This article
      reviews the recent data on YF epidemiology, virology, and immunity, and analyzes
      the rare postvaccination adverse effects that have been recently reported. YF
      vaccine should be included in the expanded program of immunization for children
      and sustained for people living in or traveling to endemic areas. A surveillance
      of vaccinated people also should be reinforced. New research programs should be
      developed to identify molecular markers of YF virus tropism and attenuation, and
      to understand mechanisms of host responses to virus infection.

PMID- 15023274
TI  - Reducing Genital Herpes Transmission Using Antiviral Therapy.

PMID- 15023273
TI  - Outbreaks of Gastrointestinal Diseases on Cruise Ships: Lessons from Three
      Decades of Progress.
AB  - Dramatic improvements in sanitary engineering and, especially, operational
      procedures aboard cruise ships began in the mid-1970s after several large
      outbreaks of acute gastroenteritis. The US Centers for Disease Control and
      Prevention's Vessel Sanitation Program, working with the cruise industry,
      conducts ship inspections, provides public access to ship sanitation scores, and
      reports outbreak investigations. The significant increase in median ship
      sanitation scores over the past decade has been concomitant with a reduction in
      outbreak frequency to 3.7 per 1000 cruises. Most outbreaks of the past decade
      were linked to noroviruses (Norwalk-like viruses), enterotoxigenic Escherichia
      coli, or the residual "unknown" causes. Although norovirus outbreaks may begin as
      foodborne or waterborne disease, easy person-to-person transmission occurs
      through fecal- or vomitus-splattered surfaces, other items, clothing, and
      especially, hands. Control of person-to-person spread of illness among crew and
      passengers becomes the major objective. Rigorous handwashing, environmental
      disinfection, and other food service job-related restrictions are required to
      prevent multiple outbreaks on the same ship. Vigilance by public health and
      industry officials has prevented many thousands of illnesses and some associated
      deaths. Clinicians providing pretravel health advice and post-travel diagnoses
      and care can benefit from and contribute to epidemiologic investigations and
      thereby enhance the health of cruise passengers individually and collectively.

PMID- 15023272
TI  - Computed Tomography-guided Drainage of Intra-abdominal Infections.
AB  - Image-guided percutaneous abscess drainage has become a standard method of
      treatment of most abdominal abscesses. In most cases, it should be considered the
      treatment of choice, but there are selected areas and circumstances that require
      specific approaches and methods. Typical abscesses within solid parenchyma organs
      or those in the peritoneal spaces can be reliably detected and efficiently
      drained. Abscesses that are multiple or long and circuitous require careful
      placement of catheters. Management of the drainage catheters includes irrigation
      with fluid to minimize accumulations of material that may impair egress of fluid.
      In selected cases, fibrinolytic agents have proved effective in shortening the
      drainage times and shortening hospital stays. Some controversial areas such as
      splenic abscesses, pancreatic abscesses, echinococcal abscesses, and fungal
      abscesses should only be attempted with careful selection and meticulous
      technique. Successful treatment is most likely with candid consultation among the
      various clinical services.

PMID- 15023275
TI  - Gonorrhea Update.
AB  - This article provides a brief summary of recent US epide-miology, antimicrobial
      resistance, and treatment of Neisseria gonorrhoeae infections. Selected research
      regarding infections caused by N. gonorrhoeae is described, with particular
      emphasis on the advances made by new molecular methods.

PMID- 15023276
TI  - Changing Epidemiology of Syphilis and Its Persistent Relationship with HIV.
AB  - Syphilis rates are increasing, particularly among men who have sex with men, many
      of whom are HIV coinfected. Screening based on risk behaviors, in addition to
      early recognition of primary and secondary syphilis and prompt reporting of cases
      to local and state health departments to assist in partner notification and
      treatment services, may curtail further spread of both infections.

PMID- 15023277
TI  - Adolescent Sexually Transmitted Diseases: Recent Developments.
AB  - Adolescents and young adults continue to have the highest rates of sexually
      transmitted diseases. New chlamydia and gonorrhea diagnostic tests are being used
      in innovative ways to increase the number of infections that are detected.
      Nevertheless, challenges such as gonorrhea resistance and partner notification
      and treatment continue to hinder efforts to reduce the prevalence of these two
      bacterial infections. Although recent surveillance data suggest a decreasing
      trend of herpes simplex virus 2 (HSV-2) incidence among adolescents and young
      adults, the incidence of sexually transmitted human papillomavirus (HPV) in
      adolescent and young adult females remains high. Progress has been made toward
      the development of vaccines that may become available in the future to prevent
      infection with and sequelae from HSV-2 and HPV.

PMID- 15023279
TI  - Drug Interactions Among the Antiretrovirals.
AB  - There are 20 antiretroviral agents approved by the US Food and Drug
      Administration (FDA), four of which were approved in 2003. With 20
      antiretrovirals FDA-approved, interactions occur when the medications alter the
      toxicity profile or efficacy of the other medication. In order to maintain
      clinical relevance, only the most significant interactions published within the
      past 12 months are highlighted in this article. Interactions discussed involve
      atazanavir, fosamprenavir, lopinavir/ritonavir, tenofovir, proton pump
      inhibitors, H(2)-blockers, clarithromycin, and vardenafil. Important interaction
      management strategies also are discussed. The field of HIV pharmacology is
      constantly advancing, as are the drug interaction data. To screen, manage, dose
      adjust, and counsel, the physician and other health care professionals are highly
      advised and encouraged to consult with an infectious disease clinical pharmacist
      when managing patients receiving highly active antiretroviral therapy.

PMID- 15023278
TI  - The Clinical Implications of Reduced Viral Fitness.
AB  - Viral fitness, defined as the extent of viral adaptation to the host environment,
      arises from tissue tropism, immune system evasion, drug resistance, and viral
      replication capacity. The fitness of wild-type and drug-resistant HIV-1 varies
      widely, associating with plasma viremia, CD4+ T-cell count, and clinical
      progression. HIV-1 fitness may be measured in competitive culture assays, single
      cycle assays, or single cycle assays based on a subgenomic fragment of HIV-1,
      which has been standardized as the replication capacity assay (pol RC). During
      virologic failure of antiretroviral therapy, CD4 T-cell counts remain elevated
      while pol RC declines and remains durably lower because of drug-selected changes
      in the gag and pol genes. CD4 T-cell sparing also is observed among patients
      without evidence of drug resistance who carry a low pol RC virus. Reduced HIV-1
      replication capacity and virulence may occur because of drug resistance or viral
      escape from host immune responses.

PMID- 15023281
TI  - Acute Myocardial Infarction: Fibrinolytic Therapy.
AB  - Fibrinolytic therapy (also known as thrombolytic therapy) is an established,
      simple, widely available and cost-effective treatment option for acute myocardial
      infarction. Adjunctive use of antiplatelet and antithrombin therapies has been
      shown to reduce reinfarction rates by 30% to 40%. These agents may also improve
      reperfusion rates and facilitate percutaneous coronary intervention (PCI).
      Adjunctive use of platelet glycoprotein IIb/IIIa inhibitors and newer
      antithrombotic agents (eg, low molecular weight heparin, bivalirudin, or
      pentasaccharide) has not been shown to reduce 30-day mortality rates. Bolus
      administration of fibrinolytic agents enhances their acceptability for
      prehospital use, and dose adjustment of antithrombotic therapy may help to reduce
      the risk of bleeding, particularly in lighter-weight patients and the elderly.
      There is a need for trials comparing newer fibrinolytic regimens with primary PCI
      and facilitated PCI. The time from symptom onset to reperfusion is the most
      important factor affecting patient outcome.

PMID- 15023280
TI  - Risk Stratification in Patients with Unstable Angina and Non-ST-elevation
      Myocardial Infarction.
AB  - Risk stratification in acute coronary syndromes is important both for prognosis
      and for treatment. Consistently, using any of a variety of clinical predictors of
      risk, patients at highest risk for poor outcomes derive the greatest benefit from
      aggressive therapy with early coronary angiography, glycoprotein IIb/IIIa
      antagonists, or low molecular weight heparins. By contrast, patients at low risk
      may be managed conservatively without long-term impact on their risk of death or
      myocardial infarction. Several clinical and laboratory parameters have been
      identified as independent, powerful predictors of poor outcome, helping to
      distinguish high-risk from low-risk patients. Although not a substitute for
      astute clinical judgment, risk prediction scores may help clinicians to
      synthesize the relevant clinical data at presentation into an overall assessment
      of risk, allowing for cost-effective utilization of therapies that add
      significant expense and morbidity. With the ever-expanding range of pharmacologic
      and interventional therapies that impact the treatment of patients with unstable
      angina and non-ST-elevation myocardial infarction (NSTEMI), risk stratification
      will become increasingly important in targeting therapies to those who are likely
      to achieve the most benefit. In this review, we first consider the identifiable
      components of risk in patients presenting with unstable angina or NSTEMI and then
      evaluate the emerging information regarding differential response to treatment
      based on the presence of these risk factors.

PMID- 15023283
TI  - Innovative Surgical Strategies: Minimally Invasive CABG and Off-pump CABG.
AB  - Minimally invasive coronary artery bypass grafting (CABG) and off-pump coronary
      artery bypass grafting (OPCAB) have made up a significant facet of the recent
      attempts of surgical myocardial revascularization to evolve. Driven by an effort
      to limit the deleterious effects of cardiopulmonary bypass (CPB), along with a
      response to both the growing interests in performing procedures through smaller
      incisions and the successes of catheter-based therapies, these therapeutic
      options have found themselves moving into the future by resurrecting their past.
      Minimally invasive CABG is the procedure by which coronary grafting is performed
      through a small anterior thoracotomy, without the use of CPB. Although feasible,
      the inability to offer a more thorough degree of revascularization has limited
      the applicability of this procedure and, therefore, accounts for its overall
      minor contribution to the number of coronary revascularizations performed
      annually. Conversely, as the technical feasibility of performing complete
      revascularization without CPB has been achieved with OPCAB, its place as a mode
      of therapy remains uncertain. Several clinical trials have been performed to date
      with only a few being done in a prospective, randomized fashion. From this data
      has come a mix of information regarding either improvements or, at a minimum, no
      change in the rate of complications between CABG with, and without, CPB, while at
      the same time maintaining equivalent short-term graft patencies. The question
      remains, however, to which patient population is this approach to CABG optimal?
      Our practice has largely reserved OPCAB for those patients in whom manipulation
      of the aorta is considered not feasible due to severe calcification or in "high
      risk" patients who are felt to be unable to tolerate the adverse physiologic
      effects of CPB. This makes up approximately 15% of our CABG population, roughly
      equal to the national average, with the remaining patients being revascularized
      with the assistance of CPB.

PMID- 15023282
TI  - Therapeutic Strategies for Cardiogenic Shock.
AB  - Cardiogenic shock is a devastating consequence of acute myocardial infarction; it
      is associated with an extremely high mortality. Treatment strategies should be
      focused on prompt reperfusion, as well as hemodynamic support. The optimal
      approach for therapy is emergent angiography and revascularization using
      percutaneous coronary intervention or coronary artery bypass surgery, with the
      assistance of intra-aortic balloon pump counterpulsation. Several adjunctive
      pharmacologic agents, particularly inotropic drugs and vasopressors, are also
      helpful for hemodynamic support. However, these agents have not been shown to
      provide a survival benefit, and their use is primarily based on clinical
      experience.

PMID- 15023284
TI  - Transmyocardial Laser Revascularization.
AB  - Transmyocardial laser revascularization (TMR) has been performed on over 12,000
      patients worldwide. Since 1990, the treatment has provided significant angina
      relief for symptomatic end-stage coronary disease that is refractory to medical
      therapy. Seventy-five percent of patients treated with TMR have demonstrated a
      decrease of two or more angina classes postoperatively. As a result, TMR has
      provided a significant improvement in quality of life for patients, resulting in
      fewer hospital admissions and decreased dependency on medications. Two different
      wavelengths of light, carbon dioxide (CO(2)) and holmium yttrium-aluminum-garnet
      (Ho:YAG), have been employed. Results obtained using these lasers differ. The
      CO(2) laser has demonstrated a perfusion benefit as well as long-term improvement
      in quality of life and angina relief. The Ho:YAG laser has not demonstrated these
      results. These differences may, in part, explain the failure of percutaneous
      myocardial laser revascularization. This catheter-based approach was not as
      successful as TMR due to its partial thickness treatment of the myocardium as
      well as its use of the Ho:YAG laser. In addition to the patients with end-stage
      coronary disease who undergo TMR as sole therapy, there are an increasing number
      of patients who have been treated with a combination of coronary artery bypass
      grafting and TMR. This provides a more complete revascularization than leaving
      territories ungrafted. Further enhancement of the angiogenic response seen after
      TMR may be seen by the addition of gene therapy to TMR treatment.

PMID- 15023285
TI  - Diastolic Dysfunction.
AB  - Heart failure is a leading cause of hospital admissions in North America.
      Approximately half of patients with symptoms of heart failure have normal or
      minimally impaired systolic function and are therefore diagnosed, by exclusion,
      with diastolic dysfunction. The therapy of diastolic dysfunction to date is
      largely unsatisfactory. There have been few outcome-based clinical trials to
      guide clinicians, and most treatments have been empirically derived from the data
      from systolic heart failure studies. In general, acute management consists of
      central volume reduction with loop diuretics and long-acting nitrates. In some
      cases improvement in left ventricular filling can be achieved by reducing heart
      rate, usually with either beta blockers or calcium channel blockers. The role of
      digoxin is unclear and it should be used with caution. Theoretically, it has the
      capacity to further impair ventricular function, but one of the few trials in
      diastolic heart failure suggested that it improves symptoms and reduces
      hospitalization. Renin-angiotensin system blockade is a very attractive
      therapeutic avenue; angiotensin-converting enzyme inhibitors and angiotensin
      receptor blockers effectively reduce afterload, induce regression of left
      ventricular hypertrophy in excess of their blood pressure-lowering effect, and
      confer survival benefits to patients at high risk for cardiovascular death.
      Although the results of a recent trial using an angiotensin receptor blocker in
      patients with primarily diastolic heart failure were unimpressive, renin
      angiotensin system blockade should still be considered because of its
      aforementioned benefits. The long-term management of these patients includes a
      careful assessment for and treatment of myocardial ischemia, treatment of
      hypertension, and reduction in left ventricular hypertrophy. For the treatment of
      ischemia, long-acting nitrates and calcium channel blockers may be particularly
      useful. The results of new trials in this area are expected soon, and hopefully
      therapy that directly targets the pathophysiologic pathways of this important
      disease is on the horizon.

PMID- 15023287
TI  - Spinal Cord Stimulation for the Treatment of Angina Pectoris.
AB  - Spinal cord stimulation (SCS) has been demonstrated to cause clinical improvement
      in patients with refractory angina pectoris in the number of anginal episodes, in
      nitroglycerin consumption, in maximal exercise time, in exercise time until
      angina, in the number of episodes of myocardial ischemia, in the duration of
      episodes of myocardial ischemia, and in ischemic ST-segment depression at a
      comparable workload. Double-blind, randomized, placebo-controlled studies have
      not been performed with SCS. The clinical improvement from SCS occurred despite
      no improvement in measured regional myocardial blood flow during exercise or in
      myocardial oxygen consumption as assessed by the heart rate times systolic
      pressure product at maximal exercise. The mechanisms of clinical improvement by
      SCS are unclear. SCS must be considered experimental at this time, and it remains
      a potential therapeutic option for the treatment of refractory angina pectoris in
      patients unable to have coronary revascularization or at very high risk for
      coronary revascularization.

PMID- 15023286
TI  - Door-to-Balloon Delays with PCI in Acute Myocardial Infarction.
AB  - In the treatment of acute myocardial infarction (AMI), the length of time from
      symptom onset to revascularization is a crucial determinant of clinical outcomes
      such as mortality and reinfarction. Direct, or primary, percutaneous transluminal
      coronary angioplasty (PTCA) produces higher rates of infarct-related artery
      patency and improved clinical outcomes compared to thrombolytic therapy. However,
      primary PTCA is associated with an increased time interval from hospital arrival
      to revascularization, the so-called door-to-balloon time. Numerous data support
      the theory that increased door-to-balloon time reduces the benefits of primary
      PTCA in the treatment of AMI. Therefore, institutions that offer PTCA must strive
      to decrease door-to-balloon delays through the use of established treatment
      protocols and frequent assessment of performance.

PMID- 15023288
TI  - Efficacy of cholesterol ester transfer protein inhibitors in prevention of
      atherosclerosis.

PMID- 15023290
TI  - Anglo-Scandinavian cardiac outcomes trial--lipid lowering arm.

PMID- 15023289
TI  - Cholesterol lowering with simvastatin in people with diabetes.

PMID- 15023291
TI  - Hypolipidemic therapy and cholesterol absorption.
AB  - The advent of safe and effective hypolipidemic therapy has revolutionized the
      ability of the clinician to optimize abnormalities in the lipid profile. The
      advent of statin therapy has provided a potent option to decrease low-density
      lipoprotein and frequently allows achievement of National Cholesterol Education
      Program target lipid levels with monotherapy. However, lipid goals are frequently
      not achieved due to inadequate response to therapy or side effects. The role of
      combination therapy in the optimization of the lipid profile provides a means by
      which the implementation of pharmacologic agents with synergistic mechanisms of
      action allows further improvement in circulating levels of low-density
      lipoprotein cholesterol. Statins have been combined with bile acid resins, fibric
      acid derivatives, and nicotinic acid. However, bile acid resins, although not
      systemically absorbed, have significant problems with patient compliance and drug
      interactions. The implementation of therapy with fibric acid derivatives or
      nicotinic acid increases the risk of significant side effects such as
      rhabdomyolysis or liver toxicity. Ezetimibe is a prototype of a new class of
      agents that specifically block the absorption of cholesterol from the
      gastrointestinal tract. Ezetimibe has minimal systemic absorption and a metabolic
      pathway involving enterohepatic circulation that allows for once a day
      administration due to a prolonged half-life. Ezetimibe lacks the drug
      interactions that are common with the bile acid resins and it may be utilized as
      either monotherapy or in combination with other pharmacologic agents. Ezetimibe
      has a relatively flat dose-response curve and titration is not required. This
      review centers on the role of pharmacologic agents that act predominantly by the
      reduction of cholesterol absorption, including colesevelam and ezetimibe.

PMID- 15023292
TI  - Is the use of unfractionated heparin in acute coronary syndrome outmoded?
AB  - Because of the key role of thrombin in the pathogenesis of acute coronary
      syndrome (ACS), the appropriate selection of antithrombotic therapy is important.
      Unfractionated heparin (UFH) has been the agent of choice for decades.
      Unfortunately, UFH has a number of limitations related to its pharmacokinetic and
      pharmacodynamic properties. Low molecular weight heparins (LMWHs) are attractive
      alternatives to UFH for several reasons, including predictable anticoagulation
      and ease of administration. Two LMWHs (dalteparin and enoxaparin) have been
      approved as alternatives to UFH in patients presenting with unstable angina and
      non-ST-segment elevation myocardial infarction. Randomized, controlled trials, in
      addition to open-label series, indicate that LMWH can safely be the agent of
      choice with or without glycoprotein IIb/IIIa in the medical and upstream
      management of patients with ACS. Although the data are not definitive, several
      trials suggest that given intravenously, enoxaparin is safe as the sole
      antithrombotic agent in the catheterization laboratory.

PMID- 15023293
TI  - Homocysteine and cardiovascular disease.
AB  - Research over the past decade has shown that elevated levels of homocysteine have
      a strong association with all forms of atherothrombotic disease and venous
      thromboembolism. This association is particularly strong for coronary disease and
      newer data indicate that screening for homocysteine levels may be warranted in
      those with unexplained thrombotic tendencies and in young patients who develop
      coronary events or disease without the usual predisposing factors such as
      hypertension, smoking, hypercholesterolemia, or diabetes. Although the link
      between hyperhomocysteinemia and cardiac disease has not been conclusively shown
      to be causal as yet, data are emerging that lowering homocysteine levels may be
      beneficial in patients at high risk. Such lowering can be done safely and
      inexpensively with increased intake of fruits and vegetables and in those
      patients who are particularly at high risk using supplementation with folic acid
      and the B vitamins. Preliminary studies have shown that lowering homocysteine
      levels in this manner may slow the progression of atherosclerosis in coronary and
      carotid vessels. No mortality data exist yet showing that reducing homocysteine
      reduces cardiac or total mortality, although it is likely that ongoing and
      planned trials that are underway will shed light on these important questions
      soon.

PMID- 15023294
TI  - Coronary calcium screening and coronary risk stratification.
AB  - Current vital statistics clearly indicate a continuing epidemic of cardiovascular
      disease in the Western hemisphere and strongly suggest that the most desirable
      approach to this ailment is prevention rather than delayed treatment. Over 7
      million people in the United States suffer from coronary artery disease and more
      than 500,000 die from its complications annually. In the majority of cases, the
      event announcing the presence of atherosclerosis is either sudden death or a
      disabling myocardial infarction or stroke. Though recent trials indicate a need
      for treatment of very large segments of the population, a review of current
      clinical practices indicates that the preventive attitude of the majority of
      physicians is not sufficiently developed and remains limited in most training
      programs. Additionally, although traditional risk factors are very helpful in
      predicting the development of cardiovascular disease, many individuals suffer
      events in the absence of established risk factors for atherosclerosis. To meet
      the challenge of coronary artery disease, several tools have been developed to
      identify atherosclerotic disease in its preclinical stages, with the hope of
      modifying its natural history. In this article, we review the current literature
      on utilization of electron beam tomography for detection of coronary artery
      calcification as a tool to conduct risk stratification for coronary artery
      disease events in the general population.

PMID- 15023296
TI  - Premature coronary artery disease: clinical risk factors and prognosis.
AB  - Coronary artery disease (CAD) that becomes manifest in young adults can have
      devastating consequences. Additionally, the study of young patients with CAD may
      provide insight into the genetic basis of coronary disease. Over the past few
      years, our understanding of risk factors in this population has been expanded to
      include social, environmental, and emotional factors. The identification of
      genetic markers for disease is just beginning. Also, it has recently been shown
      that CAD in young adults has a poor long-term prognosis, meaning that clinicians
      caring for these patients must be aggressive in risk factor control.

PMID- 15023295
TI  - Matrix metalloproteinases and atherosclerosis.
AB  - Atherosclerosis is a major cause of coronary heart disease, and matrix
      metalloproteinases (MMPs) play an important role in atherosclerosis by degrading
      the extracellular matrix, which results in cardiovascular remodeling. Recent
      studies have identified enhanced expression of MMPs in the atherosclerotic lesion
      and their contribution to weakening of the vascular wall by degrading the
      extracellular matrix. The transcription, enzyme processing, and specific
      inhibition of MMPs by tissue inhibitors of matrix metalloproteinase (TIMPs)
      regulate these effects. These processes are also modified by inflammatory
      cytokines and cell-cell contact signaling. Both animal experiments and clinical
      sample analysis have shown that balance in expression and activation of MMPs and
      inhibition by TIMPs is critical for the development of stenotic and aneurysmal
      change. Polymorphism in the MMP gene promoter contributes to inter-individual
      differences in susceptibility to coronary heart disease. The development of
      therapeutic drugs specifically targeting MMPs may thus be useful for the
      prevention of atherosclerotic lesion progression, plaque rupture, and restenosis.

PMID- 15023297
TI  - Endothelial lipase and cholesterol metabolism.
AB  - Endothelial lipase (EL), a new member of the lipase gene family, was recently
      cloned and has a significant role in plasma high-density lipoprotein levels
      (HDL). EL has a highly similar molecular homology to lipoprotein lipase and
      hepatic lipase. It is synthesized by endothelial cells and functions at the cell
      surface. EL primarily has phospholipase A1 activity. Animals that overexpress EL
      showed decreased HDL cholesterol levels and those that lack EL show elevated
      levels of HDL cholesterol. The expression is highly regulated by cytokines and
      physical forces. These data suggest that EL may play a significant role in
      atherosclerosis.

PMID- 15023298
TI  - Inflammation and atherosclerosis.
AB  - Inflammation plays a pivotal role in all stages of atherogenesis, from foam cell
      to plaque formation to rupture and ultimately to thrombosis. Insight gained from
      recent basic and clinical data linking inflammation to atherosclerosis has
      yielded important diagnostic and prognostic information. Low-grade chronic
      inflammation as measured by high sensitivity C-reactive protein predicts future
      risk of acute coronary syndrome independent of traditional cardiovascular risk
      factors. In addition, individuals with higher "inflammatory burden" gain the
      largest absolute risk reduction with aggressive risk-lowering therapy. The link
      between inflammation and atherosclerosis provides a new venue for future
      pharmacologic agents that may slow the progression of atherosclerosis by
      inhibiting inflammation.

PMID- 15023299
TI  - Low molecular weight heparin and atherosclerosis.
AB  - Low molecular weight heparin (LMWH) has dramatically impacted the treatment of
      venous thromboembolic disease and acute coronary syndromes. Recent studies help
      define the role of these agents for patients undergoing percutaneous coronary
      interventions and for patients treated with thrombolytic agents for ST-segment
      elevation myocardial infarction. Recent studies also suggest potential usefulness
      of LMWH for patients with peripheral vascular disease and its limits of utility
      in stroke. This review summarizes the evidence about the use of LMWH in these
      clinical situations.

PMID- 15023300
TI  - The role of fibrates in managing hyperlipidemia: mechanisms of action and
      clinical efficacy.
AB  - At a time when the lipid management guidelines give more and more emphasis to the
      identification and treatment of high-risk patients with the metabolic syndrome
      and diabetes, there is an obvious need to balance the known effects of low
      density lipoprotein (LDL) lowering with the new evidence of clinical efficacy
      derived from the adjustment of high-density lipoprotein (HDL) and triglyceride
      levels. Whereas the statins remain the drug of choice for patients who need to
      reach the LDL goal, fibrate therapy may represent the best intervention for
      subjects with atherogenic dyslipidemia and an LDL already close to goal. In
      addition, the concomitant use of fibrates may significantly reduce cardiovascular
      risk in patients whose LDL is controlled by statin therapy. In this review, we
      evaluate the pharmacologic properties of the fibrate drugs, with particular
      attention to the effects of peroxisome proliferator activated receptor a
      activation in the control of dyslipidemia as well as in the attenuation of
      arterial inflammation. Clinical trials of fibrates, such as the Helsinki Heart
      Study, Veterans Affairs High-density lipoprotein Intervention Trial, Diabetes
      Atherosclerosis Intervention Study, and Bezafibrate Infarction Prevention trial,
      have conjured up a scenario for the clinical utility of fibrates and their
      possible superiority to statins in the management of obese, insulin-resistant,
      and diabetic patients presenting with near-goal LDL and inappropriate HDL and
      triglyceride levels.

PMID- 15023302
TI  - [Legionella pneumophila: a genuine permanent health issue].

PMID- 15023303
TI  - [Costs study in Alzheimer's disease].
AB  - The Alzheimer disease (AD) it constitutes one of the socio-sanitary and economic
      problems and more important in the systems of health of the developed countries.
      Also, this problem will be increased in next years with the population's
      progressive aging and the biggest incidence of this illness. The family will
      support the biggest load in the care of these patients. The devices like the
      units by day will give a bigger independence to these families. OBJECTIVES: It is
      sought to study the direct sanitary and social costs of a group of patients with
      AD that live in the area of health of Guadalajara. They will be evaluated the
      global cost and I average according to the degree of deterioration, sex, and age.
      The aspects will be determined that more they influence in these costs, as the
      epidemic variables and the associate comorbility. MATERIAL AND METHODS: An
      observational and descriptive study was designed on 337 patients of EA, selected
      according to the registries of the section of neurology of the university and
      General Hospital of Guadalajara, the registrations EAP of the centres of health
      of the area, and the existent ones in two nursing homes of our environment. For
      the obtaining of the data the clinical histories were used. The used computer
      systems were: the EPINFO V.6 & SPSS V, DBASE IV, EXCEL, and the system of
      hospital costs of the University and General Hospital of Guadalajara. For the
      analysis of the data an error typo I p < 0.05 was used, this analysis began with
      the test of Kolmorov-Smirnov to contrast the normality of the curves of
      distribution of data of each variable. RESULTS: 76% was women and the rest males.
      The global stocking of age was of 73 0.63 years, with more age in the women. The
      associate comorbility was bigger in the men. The stocking of the consumption of
      pharmacotherapy was of 3.1. The costs of the consultations carried out for these
      patients were of a stocking of 2.064,75 euros patient/year, and that of the
      complementary explorations of 639 euros for patient/year. The pharmacy cost was
      of 4.560 euros patient/year, with more expense in women and in the degree sick
      persons II of the EA. The hospital half stay was of 10.8 days with a cost for
      each entrance and patient of 2.778 euros. In Primary Attention the cost for
      patient and year was of 8.615 euros. The cost of these patients in the residences
      was of 11.900 euros for patient and year, in those of private administration, and
      of 12.982 euros in those of mixed administration, according to the degree of
      deterioration, the pharmacy expense was of 2.470 euros for those of degree I, of
      141.359 euros for those of degree II and of 31.059,10 euros for those of the
      degree III. CONCLUSIONS: The half cost of the attendance is three times adult
      that the pensions received by these sick persons, for that that the patients
      and/or the families support more than 60% of the direct cost. The families don't
      have this way more remedy than to increase their expenses because neither the
      society neither the sanitary system have still given an appropriate answer to the
      problem of this illness.

PMID- 15023304
TI  - [Legionella pneumophila pneumonia community epidemic outbreak in Barcelona: "The
      Barceloneta outbreak". Effect on the early diagnosis and treatment].
AB  - OBJECTIVE: Clinical and microbiological descriptive analysis of the outbreak of
      community legionnaire's disease recorded in the Barcelona's Barcelonesa
      neighborhood in November 2000. PATIENTS AND METHODS: Retrospective review of the
      epidemiological and clinical manifestations, as well as the evolution of the
      cases of Legionella pneumophila pneumonia associated with the outbreak and cared
      of in the Hospital del Mar. RESULTS: The 48 patients evaluated, all of them with
      confirmed diagnoses, represent 89% of the cases communicated. Seventy-five
      percent of patients showed some underlying disease, 54% had some criterion for
      severity, and mortality was 4%. In 81% of cases the detection of the antigen of
      Legionella pneumophila in urine was the diagnostic method. CONCLUSIONS: The
      detection in urine of the Legionella pneumophila antigen makes possible the early
      diagnosis of legionnaire's disease, particularly in epidemic outbreaks, which
      that facilitates the fast establishment of the adequate treatment and contributes
      to the reduction in mortality even in patients of high risk.

PMID- 15023305
TI  - [Spanish scientific output in medicine in the years 1994-1999].
AB  - OBJECTIVES: A study through bibliometric indicators of the 1994-1999 Spanish
      international medical scientific output is presented. METHOD: The international
      bibliographic databases Science Citation Index and Social Sciences Citation Index
      were used as data source. RESULTS: The Spanish production in Health Sciences rose
      in the period studied to 53,878 documents, distributed between Basic Medicine
      (54%), Clinical Medicine (53%) and Social Medicine (2.7%). Among the Spanish
      communities with greater production Madrid (31%) and Catalonia (29%) pointed out,
      followed by Andalusia (12%) and Valencia (9%). The principal institutional
      sectors involved in research were hospitals (51%) and university (44%). An
      important increase in the publications from foundations and companies was
      observed. The disciplines of Biochemistry/Molecular biology, Internal/General
      medicine and Pharmacology/Pharmacy pointed out by their high production. With
      regard to the centers of greater production its increase during the period
      studied, the clinical or basic character of research and the average impact
      factor of their documents shown to detect centers of excellence. CONCLUSIONS: The
      analysis carried out shows the growth of clinical and social Medicine, makes
      possible to identify the principal actors in Health Sciences, detect centers of
      excellence in the disciplines, and analyze the specialization of Spain in the
      European context. The publications are more abundant in the journals of the first
      quartile of each specialty.

PMID- 15023301
TI  - Vaccination and atherosclerosis.
AB  - Atherosclerosis is an inflammatory disease. Both innate and adaptive immunity are
      involved in lesion formation and development. A number of antigen candidates,
      such as oxidized low-density lipoprotein and heat shock protein, have been
      associated with the inflammation and immune reaction that is part of the
      atherosclerotic process. Because experimental models of some other
      inflammatory/autoimmune diseases can be improved by vaccination, it is of
      interest to investigate if vaccination can also be applied to prevent or retard
      atherosclerosis. Indeed, the modification of immune responses in animal models
      can greatly affect the development and progression of atherosclerosis. This
      review provides an overview of our current understanding of effects and proposed
      mechanisms of immunization on preventing atherosclerosis.

PMID- 15023307
TI  - [Epigastralgia in a diabetic patient].

PMID- 15023306
TI  - [Recent beginning atrial fibrillation].

PMID- 15023309
TI  - [Enteral nutrition; direct costs in a tertiary care hospital].
AB  - INTRODUCTION: The studies in which the direct costs generated by enteral
      nutrition have been analyzed in hospitals of our country are limited. The
      objective of our study has been the analysis of costs incurred by this treatment
      in our center. MATERIAL AND METHODS: A total of 449 consecutive patients who
      received nutritional support and that were hospitalized in the Hospital Rio
      Ortega (Valladolid) since January 1999 to June 2001 has been studied. In this
      study only the direct costs were analyzed. RESULTS: The nutritional support was
      effective in the complete group with an improvement in the serum levels of
      albumin, prealbumin, and transferrin. In the analysis of direct costs generated
      by enteral nutrition the total median cost was of 598.4 +/- 761 euros/total
      treatment/patient, which represents a daily median cost of 36.3 +/- 8.8
      euros/day/patient. In the analysis of costs by paragraphs, the expendable
      equipment constituted 36% of the total, representing the tubes 3%, the lines of
      nutrition 12%, the containers 21% and the nutritional preparations 64%. A cost
      analysis was also carried out in relation to the different groups of pathologies,
      and in this way the patients with hematological tumors and the patients with
      higher aereodigestive tract tumors showed some greater costs, due to their higher
      median hospital stay. The patients who received nutrition through a gastrostomy
      probe showed also higher costs, in addition due to a greater hospital stay.
      CONCLUSIONS: The costs of the nutritional support were superior in the group of
      patients with hematological tumors and with higher aereodigestive tract, due to
      their greatest hospital stay. A greater cost in the patients whose access route
      was the gastrostomy was also observed.

PMID- 15023308
TI  - [61-year-old male with HIV infection, cutaneous lesions, and right hemiparesis].

PMID- 15023310
TI  - [Controversies and facts about the hormonal replacement therapy for prevention of
      osteoporosis in postmenopausal women].

PMID- 15023311
TI  - [Empiric treatment of community-acquired pneumonia].

PMID- 15023312
TI  - [Clinical assessment of the preventive use of antiplatelet drugs].

PMID- 15023313
TI  - [Metabolic treatment of ischemic cardiopathy].

PMID- 15023314
TI  - [Candida albicans acute septic arthritis in a patient with human immunodeficiency
      virus infection].

PMID- 15023315
TI  - [Use of the public health system by health workers].

PMID- 15023316
TI  - [Linezolide and urinary tract infection].

PMID- 15023317
TI  - [Family medicine key to the spanish university system facing the challenge of the
      European space for higher studies].

PMID- 15023318
TI  - [Impact of a program to improve appropriate prescribing of medications in
      residential facilities for older persons. Results after one year].
AB  - OBJECTIVE: To evaluate the impact after one year of a program to improve
      appropriate prescribing of medications, medical care products and supplies at a
      group of residential centers for older persons. DESIGN: Multicenter, controlled,
      quasi-experimental, before-after study of all outpatient prescriptions charged
      from each center to the Catalonian Health Service during the study period
      (reference year 2001, monitoring year 2002). SETTING: A total of 107 residential
      centers in the Barcelones Norte y Maresme (Barcelona) health region.
      PARTICIPANTS: After situation analysis the centers were divided into two groups:
      intervention (n=21) and control (n=86). A total of 4789 older persons were
      residents at participating centers during the study. Interventions. The actions
      carried out in the intervention group were: a). letter describing the program;
      b). face-to-face interview to provide information; c). distribution of printed
      information about the study's aims and the indicators recorded, and d).
      monitoring with several follow-up interviews. MAIN MEASURES: We recorded
      quantitative indicators (general, specific and urinary incontinence products),
      qualitative indicators (use of medications with high intrinsic pharmacological
      value and generic pharmaceutical specialties) and relative drug use. The data
      were analyzed with a program written for Microsoft Access. RESULTS: In the
      intervention group we found that pharmaceutical costs were contained, a result we
      attributed to the greater efficiency achieved with the intervention (interannual
      increase of 0.7% in the reference period to 16.2% in the monitoring period;
      P=.000). The contribution of urinary incontinence supplies to cost reductions was
      noteworthy. Total costs in terms of numbers of packages dispensed for all
      therapeutic subgroups decreased by 4.8% (P=.000). The use of generic
      pharmaceutical specialties increased by from 7.9% to 13.1%, and the results for
      qualitative indictors for antiasthmatics and recommended NSAIDs also revealed
      improvements in prescribing quality. CONCLUSIONS: The preliminary results of the
      program show it to be effective in improving the efficiency of drug prescribing
      at participating nursing homes. The research method was useful in promoting the
      rational use of medications and improving the quality of prescribing practices.

PMID- 15023319
TI  - [Commentary: the importance of drug therapy for elderly people in homes].

PMID- 15023320
TI  - [Management of osteoporosis at a primary care center].
AB  - OBJECTIVES: To find how suitable a semFYC guide is for the indication of bone
      densitometry in menopausal women; and how appropriate their Osteoporosis
      treatment is. DESIGN: Cross-sectional study.Setting. Girona-3 Health District.
      PARTICIPANTS: Women between 50 and 80 allocated to the Girona-3 Health District.
      Suffering a grave psychiatric disorder or a terminal illness were considered
      criteria for exclusion. 409 out of the 420 women envisaged were included, to
      achieve a 5% accuracy and a 0.05% alpha error. MAIN MEASUREMENTS: Whether bone
      densitometry took place or otherwise, other diagnostic tests, risk factors for
      osteoporosis recorded and drug treatment prescribed. RESULTS: Of the 125 women
      with risk factors for osteoporosis, 12 (9.6%) had had a bone densitometry. 20% of
      all bone densitometries done showed pathology. Only in 3 cases (0.7%) of the
      pathological cases was any recommendation on life-style recorded. 19.8% of the
      women took drug treatment. In 8% this was justified. The most common treatment
      prescribed was calcium, on its own or linked to vitamin D. 20% of cases had a
      bone densitometry to monitor them after 2 years. CONCLUSIONS: The indication for
      bone densitometry is low and its use could be improved. In those cases in which
      bone densitometry is requested, a pharmacological intervention is more common
      than a life-style one.

PMID- 15023321
TI  - [How suitable is thromboembolism prophylaxis for patients with chronic auricular
      fibrillation at 3 primary care centers].
AB  - OBJECTIVE: To find just how suitable thromboembolism prophylaxis (TEP) is in a
      group of patients with chronic auricular fibrillation belonging to the primary
      care environment. DESIGN: Cross-sectional and descriptive multi-centre study.
      SETTING: The study was performed at 3 urban primary care centres in Madrid.
      PARTICIPANTS: All the patients recorded up to April 2001 with the diagnosis of
      chronic auricular fibrillation (n=274) were included. Patients with no clinical
      history or who had a valve prosthesis were excluded. MAIN MEASUREMENTS:
      Demographic variables, existence of factors of risk of embolism, presence of
      counter-indications for oral anti-coagulants, and the kind of thromboembolic
      prophylaxis taken were collected. RESULTS: A total of 274 patients were
      evaluated. Average age was 75 (SD, 9) and 52% were women. 82% of patients had at
      least one factor of risk of thromboembolism. The most commonly used kind of TEP
      was oral anti-coagulants. 45% of patients did not receive suitable TEP. 13.5% of
      patients at risk of embolism and who had no kind of TEP were found. CONCLUSIONS:
      There is a high percentage of patients with chronic auricular fibrillation and a
      high risk of embolism, who do not receive adequate TEP, in the absence of counter
      indications to taking oral anticoagulants. There is great scope for improvement,
      which is within professionals' possibilities.

PMID- 15023322
TI  - [Interaction of nurses and women caring informally for dependent persons].
AB  - OBJECTIVE: To find the attitudes that primary care nurses in Albacete have
      towards family carers. DESIGN: Qualitative research using discussion groups.
      SETTING: Primary care in Albacete: 5 health centres, 2 rural and 3 urban.
      PARTICIPANTS: Nurses following a primary care home visit programme, of both
      sexes, differing experience and training, and coming from both rural and urban
      areas took part. Exclusion criterion: nurses in management and administrative
      posts at time of recruitment. They were recruited by primary care nurses in line
      with the profiles of participants required. METHOD: Information was collected
      through discussion in the groups, which was recorded and later transcribed for
      analysis. RESULTS AND CONCLUSIONS: Those taking part in the 2 discussion groups
      had the following characteristics: 3 men and 8 women. 5 of them were from rural
      health centres (HC) and 6 from urban HC; 3 had under 2 years experience in the
      Home Visit Programme (HVP) and 8 had over 5 years experience in it; 5 completed
      their nursing studies before 1990, and 6 afterwards. In the chats it was clear
      that the broad experience of PC nurses made them aware of the health situation
      and quality of life of informal carers, of the loneliness of these and the inter
      personal conflicts that occur in families when a situation of dependency arises.
      Nurses had their educational function towards the carers assumed despite the
      limitations. The view that the responsibility for the care of the dependent
      person is the family's was predominant, and a concern for lack of resources and
      support was appreciated. Nurses had a view of the carer as a resource and barely
      perceived her as a patient.

PMID- 15023323
TI  - [Measles in Spain: its move into the adult population].

PMID- 15023324
TI  - [Should the menopause be treated?].

PMID- 15023325
TI  - [Synthetic drugs: from use to multiple consumption. Some associated risks and a
      proposal for therapeutic intervention].

PMID- 15023326
TI  - [Muscle and tendon problems as a side-effect of levofloxacine: review of a case].

PMID- 15023327
TI  - [The ATDOM programme in Raval Nord: descriptive analysis of 10 years of primary
      care].

PMID- 15023328
TI  - [Epidemiology of HIV infection in the town of Getafe].

PMID- 15023329
TI  - [When the risk exceeds the benefit].

PMID- 15023330
TI  - [Intimacy, confidentiality and computerised clinical records: reflections
      following the case of Dr. Angel Ruiz Tellez].

PMID- 15023331
TI  - [The difficult measurement of inhalation technique].

PMID- 15023333
TI  - Anchoring notch genetics and biochemistry; structural analysis of the ankyrin
      domain sheds light on existing data.
AB  - Notch signaling is important in development and in human disease. Notch receptors
      regulate transcription through direct interactions with several proteins at the
      promoter regions of target genes. To understand the mechanism of Notch signaling,
      numerous deletion and mutagenesis studies have been carried out to identify
      functional domains in Notch, but domain definition and their role during the
      assembly of the transcriptionally active complex remains controversial. Recently
      reported biophysical and structural studies of the Notch ANK domain permit us to
      reevaluate the existing domain assignments and their predicted functional role,
      thereby providing further insight into the mechanism of Notch signaling.

PMID- 15023334
TI  - Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated
      apoptosis.
AB  - Apoptosis is a key tumor suppression mechanism that can be initiated by
      activation of the proapoptotic factor Bax. The Ku70 DNA end-joining protein has
      recently been shown to suppress apoptosis by sequestering Bax from mitochondria.
      The mechanism by which Bax is regulated remains unknown. Here, we identify eight
      lysines in Ku70 that are targets for acetylation in vivo. Five of these, K539,
      K542, K544, K533, and K556, lie in the C-terminal linker domain of Ku70 adjacent
      to the Bax interaction domain. We show that CBP and PCAF efficiently acetylate
      K542 in vitro and associate with Ku70 in vivo. Mimicking acetylation of K539 or
      K542 or treating cells with deacetylase inhibitors abolishes the ability of Ku70
      to suppress Bax-mediated apoptosis. We demonstrate that increased acetylation of
      Ku70 disrupts the Ku70-Bax interaction and coincides with cytoplasmic
      accumulation of CBP. These results shed light on the role of acetyltransferases
      as tumor suppressors.

PMID- 15023335
TI  - Structural basis for the mechanism and regulation of Sir2 enzymes.
AB  - Sir2 proteins form a family of NAD(+)-dependent protein deacetylases required for
      diverse biological processes, including transcriptional silencing, suppression of
      rDNA recombination, control of p53 activity, regulation of acetyl-CoA synthetase,
      and aging. Although structures of Sir2 enzymes in the presence and absence of
      peptide substrate or NAD(+) have been determined, the role of the enzyme in the
      mechanism of deacetylation and NAD(+) cleavage is still unclear. Here, we present
      additional structures of Sir2Af2 in several differently complexed states: in a
      productive complex with NAD(+), in a nonproductive NAD(+) complex with bound ADP
      ribose, and in the unliganded state. We observe a new mode of NAD(+) binding that
      seems to depend on acetyl-lysine binding, in which the nicotinamide ring of
      NAD(+) is buried in the highly conserved "C" pocket of the enzyme. We propose a
      detailed structure-based mechanism for deacetylation and nicotinamide inhibition
      of Sir2 consistent with mutagenesis and enzymatic studies.

PMID- 15023336
TI  - Endostatin's antiangiogenic signaling network.
AB  - It is here demonstrated that the set of gene expressions underlying the
      angiogenic balance in tissues can be molecularly reset en masse by a single
      protein. Using genome-wide expression profiling, coupled with RT-PCR and
      phosphorylation analysis, we show that the endogenous angiogenesis inhibitor
      endostatin downregulates many signaling pathways in human microvascular
      endothelium associated with proangiogenic activity. Simultaneously, endostatin is
      found to upregulate many antiangiogenic genes. The result is a unique alignment
      between the direction of gene regulation and angiogenic status. Profiling further
      reveals the regulation of genes not heretofore associated with angiogenesis. Our
      analysis of coregulated genes shows complex interpathway communications in an
      intricate signaling network that both recapitulates and extends on current
      understanding of the angiogenic process. More generally, insights into the nature
      of genetic networking from the cell biologic and therapeutic perspectives are
      revealed.

PMID- 15023337
TI  - Cdc42 regulates the Par-6 PDZ domain through an allosteric CRIB-PDZ transition.
AB  - Regulation of protein interaction domains is required for cellular signaling
      dynamics. Here, we show that the PDZ protein interaction domain from the cell
      polarity protein Par-6 is regulated by the Rho GTPase Cdc42. Cdc42 binds to a
      CRIB domain adjacent to the PDZ domain, increasing the affinity of the Par-6 PDZ
      for its carboxy-terminal ligand by approximately 13-fold. Par-6 PDZ regulation is
      required for function as mutational disruption of Cdc42-Par-6 PDZ coupling leads
      to inactivation of Par-6 in polarized MDCK epithelial cells. Structural analysis
      reveals that the free PDZ domain has several deviations from the canonical PDZ
      conformation that account for its low ligand affinity. Regulation results from a
      Cdc42-induced conformational transition in the CRIB-PDZ module that causes the
      PDZ to assume a canonical, high-affinity PDZ conformation. The coupled CRIB and
      PDZ architecture of Par-6 reveals how simple binding domains can be combined to
      yield complex regulation.

PMID- 15023339
TI  - Structure and mechanism of action of Sda, an inhibitor of the histidine kinases
      that regulate initiation of sporulation in Bacillus subtilis.
AB  - Histidine kinases are used extensively in prokaryotes to monitor and respond to
      changes in cellular and environmental conditions. In Bacillus subtilis,
      sporulation-specific gene expression is controlled by a histidine kinase
      phosphorelay that culminates in phosphorylation of the Spo0A transcription
      factor. Sda provides a developmental checkpoint by inhibiting this phosphorelay
      in response to DNA damage and replication defects. We show that Sda acts at the
      first step in the relay by inhibiting autophosphorylation of the histidine kinase
      KinA. The structure of Sda, which we determined using NMR, comprises a helical
      hairpin. A cluster of conserved residues on one face of the hairpin mediates an
      interaction between Sda and the KinA dimerization/phosphotransfer domain. This
      interaction stabilizes the KinA dimer, and the two proteins form a stable
      heterotetramer. The data indicate that Sda forms a molecular barricade that
      inhibits productive interaction between the catalytic and phosphotransfer domains
      of KinA.

PMID- 15023338
TI  - Genome-wide analysis of membrane targeting by S. cerevisiae pleckstrin homology
      domains.
AB  - Pleckstrin homology (PH) domains are small protein modules known for their
      ability to bind phosphoinositides and to drive membrane recruitment of their host
      proteins. We investigated phosphoinositide binding (in vitro and in vivo) and
      subcellular localization, and we modeled the electrostatic properties for all 33
      PH domains encoded in the S. cerevisiae genome. Only one PH domain (from Num1p)
      binds phosphoinositides with high affinity and specificity. Six bind
      phosphoinositides with moderate affinity and little specificity and are membrane
      targeted in a phosphoinositide-dependent manner. Although all of the remaining 26
      yeast PH domains bind phosphoinositides very weakly or not at all, three were
      nonetheless efficiently membrane targeted. Our proteome-wide analysis argues that
      membrane targeting is important for only approximately 30% of yeast PH domains
      and is defined by binding to both phosphoinositides and other targets. These
      findings have significant implications for understanding the function of proteins
      that contain this common domain.

PMID- 15023340
TI  - Features of a leader peptide coding region that regulate translation initiation
      for the anti-TRAP protein of B. subtilis.
AB  - The rtpA gene of Bacillus subtilis encodes the Anti-TRAP protein, AT. AT can bind
      and inhibit the TRAP regulatory protein, preventing TRAP from promoting
      transcription termination in the trpEDCFBA operon leader region. AT synthesis is
      upregulated transcriptionally and translationally in response to the accumulation
      of uncharged tRNA(Trp). Here we analyze AT's translational regulation by rtpLP, a
      10 residue leader peptide coding region located immediately preceding the rtpA
      Shine-Dalgarno sequence. Our findings suggest that, whenever the charged
      tRNA(Trp) level is sufficient to allow the ribosome translating rtpLP to reach
      its stop codon, it blocks the adjacent rtpA Shine-Dalgarno sequence, inhibiting
      AT synthesis. However, when there is a charged tRNA(Trp) deficiency, the
      translating ribosome presumably stalls at one of three adjacent rtpLP Trp codons.
      This stalling exposes the rtpA Shine-Dalgarno sequence, permitting AT synthesis.
      RNA-RNA pairing may also influence AT synthesis. Production of AT would
      inactivate TRAP, thereby increasing trp operon expression.

PMID- 15023341
TI  - Lytic KSHV infection inhibits host gene expression by accelerating global mRNA
      turnover.
AB  - The stimulation of host gene expression by lytic gene products of Kaposi's
      sarcoma-associated herpesvirus (KSHV) has been proposed to play a critical role
      in KS development. We show, however, that lytic KSHV infection strongly inhibits
      host gene expression early in infection by accelerating global mRNA turnover.
      This function is mediated by KSHV ORF37, a homolog of a DNA exonuclease widely
      present in other herpesviruses but which in KSHV has uniquely evolved additional
      functions that mediate its participation in RNA degradation. The ability of KSHV
      to inhibit host gene expression has important implications for models of KS
      pathogenesis that invoke activation of host transcription in lytically infected
      cells as a source of angiogenic or oncogenic factors.

PMID- 15023342
TI  - Selective recognition of distinct classes of coactivators by a ligand-inducible
      activation domain.
AB  - How nuclear receptors (NRs) coordinate the sequential, ligand-dependent
      recruitment of multiple coactivator complexes (e.g., SRC complexes and Mediator)
      that share similar receptor binding determinants is unclear. We show that
      although the receptor binding subunits of these complexes (i.e., SRCs and Med220,
      respectively) share overlapping binding sites on estrogen receptor alpha
      (ERalpha), information contained in the receptor-coactivator interface allows the
      receptor to distinguish between them. In support of this conclusion, we have
      identified an ERalpha AF-2 point mutant (L540Q) that selectively binds and
      recruits Med220, but not SRCs, both in vitro and in vivo. In cells expressing
      this mutant, the recruitment of Med220 to the pS2 promoter is delayed, and the
      expression of the vast majority of estrogen target genes is impaired, suggesting
      a nearly global functional interdependence of these coactivators. Collectively,
      our results suggest that "facilitated recruitment," rather than competition,
      drives the sequential recruitment of SRC complexes and Mediator by NRs.

PMID- 15023343
TI  - The RSC nucleosome-remodeling complex is required for Cohesin's association with
      chromosome arms.
AB  - The fidelity of chromosome segregation requires that the cohesin protein complex
      bind together newly replicated sister chromatids both at centromeres and at
      discrete sites along chromosome arms. Segregation of the yeast 2 micro plasmid
      also requires cohesin, which is recruited to the plasmid partitioning locus. Here
      we report that the RSC chromatin-remodeling complex regulates the differential
      association of cohesin with centromeres and chromosome arms. RSC cycles on and
      off chromosomal arm and plasmid cohesin binding sites in a cell cycle-regulated
      manner 15 min preceding Mcd1p, the central cohesin subunit. We show that in rsc
      mutants Mcd1p fails to associate with chromosome arms but still binds to
      centromeres, and that consequently, the arm regions of mitotic sister chromosomes
      separate precociously while cohesion at centromeres is unaffected. Our data
      suggest a role for RSC in facilitating the loading of cohesin specifically onto
      chromosome arms, thereby ensuring sister chromatid cohesion and proper chromosome
      segregation.

PMID- 15023344
TI  - Snapshots of replication through an abasic lesion; structural basis for base
      substitutions and frameshifts.
AB  - Dpo4 from S. Solfataricus, a DinB-like Y family polymerase, efficiently
      replicates DNA past an abasic lesion. We have determined crystal structures of
      Dpo4 complexed with five different abasic site-containing DNA substrates and find
      that translesion synthesis is template directed with the abasic site looped out
      and the incoming nucleotide is opposite the base 5' to the lesion. The ensuing
      DNA synthesis generates a -1 frameshift when the abasic site remains
      extrahelical. Template realignment during primer extension is also observed,
      resulting in base substitutions or even +1 frameshifts. In the case of a +1
      frameshift, the extra nucleotide is accommodated in the solvent-exposed minor
      groove. In addition, the structure of an unproductive Dpo4 ternary complex
      suggests that the flexible little finger domain facilitates DNA orientation and
      translocation during translesion synthesis.

PMID- 15023345
TI  - IPK'2003. Proceedings of the 3rd International Conference Inhibitors of Protein
      Kinases and Workshop Phosphoryl-Transfer Mechanisms. June 22-28, 2003, Warsaw,
      Poland.

PMID- 15023346
TI  - Structure, regulation and function of PKB/AKT--a major therapeutic target.
AB  - Protein phosphorylation and dephosphorylation play a major role in intracellular
      signal transduction activated by extracellular stimuli. Protein kinase B
      (PKB/Akt) is a central player in the signal transduction pathways activated in
      response to growth factors or insulin and is thought to contribute to several
      cellular functions including nutrient metabolism, cell growth and apoptosis.
      Recently, several significant publications have described novel mechanisms used
      to regulate PKB. Since the alteration of PKB activity is associated with several
      human diseases, including cancer and diabetes, understanding PKB regulation is an
      important task if we are to develop successful therapeutics.

PMID- 15023347
TI  - Advances in the structural biology, design and clinical development of VEGF-R
      kinase inhibitors for the treatment of angiogenesis.
AB  - Initial studies with angiogenesis inhibitors showed little clinical benefit.
      However, recently reported clinical studies in colorectal cancer have shown that
      bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody, in
      combination with cytotoxic therapy has positive effects on patient survival.
      Furthermore, the VEGF receptor kinase (VEGF-R) tyrosine kinase inhibitor,
      vatalanib, has also shown encouraging results in colorectal cancer, with
      molecular resonance imaging providing evidence that the anti-tumor efficacy was
      indeed the result of anti-angiogenic activity. Both of these agents are
      progressing in phase III trials. This proof of concept has stimulated the desire
      for second-generation VEGF-R inhibitors having an improved profile. Structural
      biology insight regarding the binding mode of protein kinase inhibitors is
      valuable for the design of molecules possessing superior selectivity, efficacy
      and tolerability. Towards this goal, we have developed a new series of VEGF-R2
      kinase inhibitors, based upon an anthranilic acid amide scaffold. An X-ray
      crystal structure of a representative compound, AAL993 (ZK260253), in complex
      with the catalytic domain of diphosphorylated VEGF-R2 has revealed that this
      molecule binds to an inactive conformation of the protein. This binding mode,
      similar to that observed for the anti-leukemia drug, imatinib in complex with c
      Abl kinase, may be responsible for the high selectivity of AAL993 and provides
      valuable insight for the design of further compounds.

PMID- 15023348
TI  - Design of hypoxia-targeting protein tyrosine kinase inhibitor using an innovative
      pharmacophore 2-methylene-4-cyclopentene-1,3-dione.
AB  - We review in this report our strategy and tactics for the design of 2
      hydroxyarylidene-4-cyclopentene-1,3-diones as protein tyrosine kinase (PTK)
      inhibitors having low mitochondrial toxicities and/or hypoxia-targeting function.
      We based our synthetic design on an innovative pharmacophore, 2-methylene-4
      cyclopentene-1,3-dione. We first showed the effectiveness of this pharmacophore
      in the development of 2-methylene-4-cyclopentene-1,3-dione as PTK inhibitor that
      have lower mitochondrial toxicity than the potent PTK inhibitor tyrphostin AG17.
      Our results show that the cyclopentenedione-derived TX-1123 is a more potent
      antitumor tyrphostin and also shows lower mitochondrial toxicity than the
      malononitrile-derived AG17. The O-methylation product of TX-1123 (TX-1925)
      retained its tyrphostin-like properties, including mitochondrial toxicity and
      antitumor activities. However, the methylation product of AG17 (TX-1927) retained
      its tyrphostin-like antitumor activities, but lost its mitochondrial toxicity.
      Our comprehensive evaluation of these agents with respect to PTK inhibition,
      mitochondrial inhibition, antitumor activity, and hepatotoxicity demonstrates
      that PTK inhibitors TX-1123 and TX-1925 are more promising candidates for
      antitumor agents than tyrphostin AG17. Secondly, as a further investigation of
      the promising power of this 4-cyclopentene-1,3-dione as an innovative
      pharmacophore, we discuss our strategy of development of hypoxia-targeting PTK
      inhibitor TX-1123 analogues, 2-nitroimidazole-aminomethylenecyclopentenediones,
      such as TX-2036, for cancer treatment, especially for pancreatic cancers, which
      have a high level of hypoxia.

PMID- 15023349
TI  - Biosensors of protein kinase action: from in vitro assays to living cells.
AB  - Protein kinases, and the signal transduction pathways in which they participate,
      are now recognized to be medicinally attractive targets of opportunity.
      Inhibitors of the protein kinase family not only hold great promise as
      therapeutic agents, but are also of profound utility in the characterization of
      signaling pathways. The direct visualization of protein kinase activity in living
      cells provides a genuine assessment of the efficacy and selectivity of these
      inhibitors in a physiological setting. In addition, the ability to visualize the
      activity of a protein kinase in real time furnishes a direct measurement of the
      activation of specific signaling pathways in response to extracellular stimuli.
      We have developed two series of fluorescent substrates for protein kinase C (PKC)
      using a strategy that positions the reporter-group directly on the residue
      undergoing phosphorylation. The first series of PKC substrates is based, in part,
      on the Ca(+2) indicators developed by Tsien and his collaborators during the
      1980s. In this case, phosphorylation of the substrate creates a divalent metal
      ion binding site. Upon metal ion coordination, a fluorescence change transpires
      via a mechanism analogous to that described for the Ca(+2) indicators. The second
      series of PKC sensors was identified via the preparation and subsequent screen of
      a library of fluorescently-labeled PKC peptide substrates. The lead derivative
      displays a phosphorylation-induced fluorescence change that allows the
      visualization of real-time PKC activity in both cell lysates and living cells.
      Furthermore, immunodepletion experiments demonstrate that the fluorescently
      tagged peptide is selectively, if not exclusively, phosphorylated by the
      conventional PKCs. Both of the protein kinase biosensor strategies take advantage
      of the ease with which peptides can be modified to create libraries of
      structurally altered analogs. However, the inherent synthetic mutability of
      peptides is not just limited to library construction. For example, it may
      ultimately be possible to simultaneously monitor multiple protein kinases by
      affixing fluorophores with distinct photophysical properties to appropriately
      designed active site-directed peptides.

PMID- 15023350
TI  - Tyrosine kinase inhibitors: a new approach for asthma.
AB  - The pathogenesis of allergic asthma involves the interplay of inflammatory cells
      and airway-resident cells, and of their secreted mediators including cytokines,
      chemokines, growth factors and inflammatory mediators. Receptor tyrosine kinases
      are important for the pathogenesis of airway remodeling. Activation of epidermal
      growth factor (EGF) receptor kinase and platelet-derived growth factor (PDGF)
      receptor kinase leads to hyperplasia of airway smooth muscle cells, epithelial
      cells and goblet cells. Stimulation of non-receptor tyrosine kinases (e.g. Lyn,
      Lck, Syk, ZAP-70, Fyn, Btk, Itk) is the earliest detectable signaling response
      upon antigen-induced immunoreceptor activation in inflammatory cells. Cytokine
      receptor dimerization upon ligand stimulation induces activation of Janus
      tyrosine kinases (JAKs), leading to recruitment and phosphorylation of signal
      transducer and activator of transcription (STAT) for selective gene expression
      regulation. Activation of chemokine receptors can trigger JAK-STAT pathway, Lck,
      Fyn, Lyn, Fgr, and Syk/Zap-70 to induce chemotaxis of inflammatory cells.
      Inhibitors of tyrosine kinases have been shown in vitro to block growth factor
      induced hyperplasia of airway-resident cells; antigen-induced inflammatory cell
      activation and cytokine synthesis; cytokine-mediated pro-inflammatory gene
      expression in inflammatory and airway cells; and chemokine-induced chemotaxis of
      inflammatory cells. Recently, anti-inflammatory effects of tyrosine kinase
      inhibitors (e.g. genistein, tyrphostin AG213, piceatannol, tyrphostin AG490, WHI
      P97, WHI-P131, Syk antisense) in animal models of allergic asthma have been
      reported. Therefore, development of inhibitors of tyrosine kinases can be a very
      attractive strategy for the treatment of asthma.

PMID- 15023351
TI  - Antisense protein kinase A RI alpha-induced tumor reversion: portrait of a
      microarray.
AB  - Antisense oligonucleotides can selectively block disease-causing genes due to the
      specificity of the Watson-Crick base-pairing mechanism of action. A genome-wide
      view of antisense technology is illustrated via protein kinase A RI alpha
      antisense. Complementary DNA microarray analysis of the RI alpha antisense
      induced expression profile shows the up- and down-regulation of clusters of
      coordinately expressed genes that define the molecular portrait of a reverted
      tumor cell phenotype. This global view broadens the horizons of antisense
      technology; it advances the promise of antisense beyond a single target gene to
      the whole cell and the whole organism. Along with recent rapid advances in
      oligonucleotide technologies-including new chemical and biological understanding
      of more sophisticated nucleic acid drugs-oligonucleotide-based gene silencing
      offers not only an exquisitely specific genetic tool for exploring basic science
      but also an exciting possibility for treating and preventing cancer and other
      diseases.

PMID- 15023352
TI  - A kinetic approach towards understanding substrate interactions and the catalytic
      mechanism of the serine/threonine protein kinase ERK2: identifying a potential
      regulatory role for divalent magnesium.
AB  - We are interested in the mechanism and regulation of the extracellular regulated
      protein kinases, ERK1 and ERK2, due to their key roles in cellular signal
      transduction and disease. Both enzymes phosphorylate a large number of
      structurally disparate proteins upon activation by phorbol esters, serum and
      growth factors, and are activated through a protein kinase cascade, termed the
      mitogen activated protein kinase (MAPK) pathway. ERK2 catalyses the transfer of
      the gamma-phosphate of adenosine triphosphate to serine or threonine residues
      found in Ser-Pro or Thr-Pro motifs on proteins. Its catalytic mechanism is
      intriguing, because it appears to predominantly rely on interactions outside of
      the active site cleft to specify a substrate. To study ERK2, we developed a
      recombinant protein called EtsDelta138, which comprises residues 1-138 of the
      transcription factor Ets-1, an excellent substrate of ERK2. Here we review
      several steady-state kinetic experiments that reveal details of the ERK2
      mechanism and a hitherto unknown process of ERK2 activation by free magnesium.
      The physiological relevance of this mechanism is discussed.

PMID- 15023353
TI  - Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic
      potential.
AB  - The c-Jun N-terminal protein kinases (JNKs) form one subfamily of the mitogen
      activated protein kinase (MAPK) group of serine/threonine protein kinases. The
      JNKs were first identified by their activation in response to a variety of
      extracellular stresses and their ability to phosphorylate the N-terminal
      transactivation domain of the transcription factor c-Jun. One approach to study
      the function of the JNKs has included in vivo gene knockouts of each of the three
      JNK genes. Whilst loss of either JNK1 or JNK2 alone appears to have no serious
      consequences, their combined knockout is embryonic lethal. In contrast, the loss
      of JNK3 is not embryonic lethal, but rather protects the adult brain from
      glutamate-induced excitotoxicity. This latter example has generated considerable
      enthusiasm with JNK3, considered an appropriate target for the treatment of
      diseases in which neuronal death should be prevented (e.g. stroke, Alzheimer's
      and Parkinson's diseases). More recently, these gene knockout animals have been
      used to demonstrate that JNK could provide a suitable target for the protection
      against obesity and diabetes and that JNKs may act as tumour suppressors.
      Considerable effort is being directed to the development of chemical inhibitors
      of the activators of JNKs (e.g. CEP-1347, an inhibitor of the MLK family of JNK
      pathway activators) or of the JNKs themselves (e.g. SP600125, a direct inhibitor
      of JNK activity). These most commonly used inhibitors have demonstrated efficacy
      for use in vivo, with the successful intervention to decrease brain damage in
      animal models (CEP-1347) or to ameliorate some of the symptoms of arthritis in
      other animal models (SP600125). Alternative peptide-based inhibitors of JNKs are
      now also in development. The possible identification of allosteric modifiers
      rather than direct ATP competitors could lead to inhibitors of unprecedented
      specificity and efficacy.

PMID- 15023354
TI  - Molecular dissection of egg fertilization signaling with the aid of tyrosine
      kinase-specific inhibitor and activator strategies.
AB  - Fertilization is triggered by sperm-egg interaction and fusion that initiate a
      transient rise(s) in the free intracellular calcium ([Ca(2+)](i)) that is
      responsible for a series of biochemical and cell biological events, so-called
      "egg activation". Calcium-dependent egg activation leads to the initiation of
      developmental program that culminates in the birth of individuals. A growing body
      of knowledge has uncovered the molecular mechanisms underlying sperm-induced
      transient [Ca(2+)](i) increase(s) to some extent; namely, in most animals so far
      studied, a second messenger inositol 1,4,5-trisphosphate (IP(3)) seems to play a
      pivotal role in inducing [Ca(2+)](i) transient(s) at fertilization. However,
      signaling mechanisms used by sperm to initiate IP(3)-[Ca(2+)](i) transient
      pathway have not been elucidated. To approach this problem, we have employed
      African clawed frog, Xenopus laevis, as a model animal and conducted experiments
      designed specifically to determine the role of the Src family protein-tyrosine
      kinases (SFKs or Src family PTKs) in the sperm-induced egg activation. This
      review compiles information about the use of PTK-specific inhibitors and
      activators for analyzing signal transduction events in egg fertilization.
      Specifically, we focus on molecular identification of Xenopus Src and the
      signaling mechanism of the Src-dependent egg activation that has been established
      recently. We also summarize recent advances in understanding the role of the Src
      family kinases in egg fertilization of other model organisms, and discuss future
      directions of the field.

PMID- 15023355
TI  - HPr kinase/phosphorylase, a Walker motif A-containing bifunctional sensor enzyme
      controlling catabolite repression in Gram-positive bacteria.
AB  - Carbon catabolite repression (CCR) in Gram-positive bacteria is regulated by the
      bifunctional enzyme HPr kinase/phosphorylase (HprK/P). This enzyme catalyses the
      ATP- as well as the pyrophosphate-dependent phosphorylation of Ser-46 in HPr, a
      phosphocarrier protein of a sugar transport and phosphorylation system. HprK/P
      also catalyses the pyrophosphate-producing, inorganic phosphate-dependent
      dephosphorylation (phosphorolysis) of seryl-phosphorylated HPr (P-Ser-HPr). P-Ser
      HPr functions as catabolite co-repressor by interacting with the LacI/GalR-type
      repressor, catabolite control protein A (CcpA), and allowing it to bind to
      operator sites preceding catabolite-regulated transcription units. HprK/P thus
      indirectly controls the expression of about 10% of the genes of Gram-positive
      bacteria. The two antagonistic activities of HprK/P are regulated by
      intracellular metabolites, which change their concentration in response to the
      absence or presence of rapidly metabolisable carbon sources (glucose, fructose,
      etc.) in the growth medium. Biochemical and structural studies revealed that
      HprK/P exhibits no similarity to eukaryotic protein kinases and that it contains
      a Walker motif A (or P-loop) as nucleotide binding site. Interestingly, HprK/P
      has a structural fold resembling that in kinases phosphorylating certain low
      molecular weight substrates such as nucleosides, nucleotides or oxaloacetate. The
      structures of the complexes of HprK/P with HPr and P-Ser-HPr have also been
      determined, which allowed proposing a detailed mechanism for the kinase and
      phosphorylase functions of HprK/P.

PMID- 15023356
TI  - Cdk5, a therapeutic target for Alzheimer's disease?
AB  - Alzheimer's disease (AD) represents the leading cause for senile dementia
      affecting more than 4 million people worldwide. AD patients display a triad of
      pathological features including brain atrophy caused by neuronal loss, beta
      amyloid plaque and neurofibrillary tangles. We previously show that Cyclin
      dependent kinase 5 (Cdk5) is deregulated in AD brains and may contribute to the
      pathogenesis of AD. In AD brains, a calpain cleavage product of its physiological
      regulator p35, p25 is elevated. p25 causes prolonged activation of Cdk5 and
      alteration of its substrate specificity. The implications of p25/Cdk5 in
      neurotoxicity, beta-amyloid plaque and neurofibrillary tangle pathology will be
      discussed.

PMID- 15023357
TI  - Neuronal cyclin-dependent kinase 5: role in nervous system function and its
      specific inhibition by the Cdk5 inhibitory peptide.
AB  - Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclin-dependent kinase
      family that is involved in the regulation of the cell cycle. As their name
      suggests, the Cdks require association with activator proteins called cyclins for
      their activity. Cdk5, however, is unique to this family of proline-directed
      serine/threonine kinases on two accounts. Firstly, Cdk5 has not been found to
      function in the cell cycle and, although expressed in a number of tissues, its
      activity is restricted to the nervous system. Secondly, unlike the other members
      of the Cdk family, Cdk5 is not activated by association with a cyclin, although
      it can bind them. Instead, Cdk5 is activated by the activator proteins p35 and
      p39 that are structurally distinct from cyclins and have, for the most part, a
      neuronal-specific expression pattern. In the past decade of research on Cdk5, it
      is now established that Cdk5 activity is critical for the proper formation and
      function of the brain. Moreover, its role as a central kinase, phosphorylating
      its substrates in its 'cross-talk' control of other kinase and signal
      transduction pathways, has also been determined. In addition to the normal
      physiological role of Cdk5, the kinase has been implicated in certain
      neurodegenerative disorders. For example, Cdk5 associates with the proteolytic,
      more active p25 fragment that is derived through the cleavage of p35. In turn,
      the p25/Cdk5 complex aberrantly phosphorylates its substrates tau and
      neurofilaments, which has been implicated in the pathogenesis of these disorders.
      Here, we attempt to review the past decade of research on Cdk5 from our
      laboratory and others, on the roles of Cdk5 in nervous system function.
      Additionally, our research has recently uncovered a possible therapeutic avenue
      of research, focusing on inhibition of aberrant Cdk5 hyperactivity which may well
      be used to treat the symptoms of a number of neurodegenerative diseases. The
      elucidation of a specific inhibitor of p25/Cdk5, termed CIP, also inhibits
      p25/Cdk5-mediated tau phosphorylation. This may well provide us with avenues of
      research focusing on the inhibition of pathologically damaging p25/Cdk5 species.

PMID- 15023358
TI  - Protein kinases as targets for anti-parasitic chemotherapy.
AB  - Parasitic protozoa infecting humans have a staggering impact on public health,
      especially in the developing world. Furthermore, several protozoan species are
      major pathogens of domestic animals and have a considerable impact on food
      production. In many instances, the parasites have developed resistance against
      available chemotherapeutic agents, making the search for alternative drugs a
      priority. In line with the current interest in protein kinases inhibitors as
      potential drugs against a variety of diseases, the possibility that protein
      kinases may represent targets for novel anti-parasitic agents is being explored.
      Research into parasite protein kinases has benefited greatly from genome and EST
      sequencing projects, with the genomes of a few species fully sequenced (notably
      that of the human malaria parasite Plasmodium falciparum) and several more under
      way. The overall picture that emerged from research in this area shows that the
      phylogenetic isolation of parasitic protozoa is reflected by atypical structural
      and functional properties of many of their protein kinase homologues. Likewise,
      evidence is emerging, which suggests that the organisation of some otherwise well
      conserved signal transduction pathways is divergent in some parasitic species.
      The differences between protein kinases of a parasite and their homologues in its
      host cell suggest that specific inhibition of the former can be achieved. The
      development of anti-parasitic drugs based on protein kinase inhibition is being
      pursued following two avenues: one consists of screening chemical libraries on
      recombinant enzymes; several protein kinases from parasitic protozoa are now
      available for this approach. The second approach relies on the identification of
      the molecular targets of kinase inhibitors which display anti-parasitic
      properties. This has led to promising developments in a few instances, in
      particular regarding PKG as a drug target against Eimeria and Toxoplasma, and
      purvalanol B, a purine-based CDK inhibitor which appears to affect unexpected
      targets in several protozoan parasites. The recent resolution of the structure of
      a Plasmodium protein kinase complexed with small inhibitory molecules opens the
      way to a rational approach towards the design of anti-parasitic drugs based on
      kinase inhibition.

PMID- 15023359
TI  - The UL97 protein kinase of human cytomegalovirus and homologues in other
      herpesviruses: impact on virus and host.
AB  - The human herpesviruses, herpes simplex virus 1 (HSV-1), HSV-2, varicella zoster
      virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human
      herpesvirus 6A (HHV-6A), HHV-6B, HHV-7 and HHV-8, establish persistent infections
      with possible recurrence during immunosuppression. HCMV replication is inhibited
      by the nucleoside analogue ganciclovir (GCV), the compound of choice for the
      treatment of HCMV diseases and preemptive treatment of infections. The viral UL97
      protein (pUL97) which shares homologies with protein kinases and bacterial
      phosphotransferases is able to monophosphorylate GCV. Homologues of pUL97 are
      found in HSV (UL13), VZV (ORF47), EBV (BGLF4), HHV-6 (U69), HHV-8 (ORF36) as well
      as in murine CMV (M97) or rat CMV (R97). Several indolocarbazoles have been
      reported to be specific inhibitors of pUL97. The protein is important for
      efficient replication of the virus. Autophosphorylation of pUL97 was observed
      using different experimental systems. Most recently, it has been shown that pUL97
      interacts with the DNA polymerase processivity factor pUL44. Indolocarbazole
      protein kinase inhibitors are promising lead compounds for the development of
      more specific inhibitors of HCMV.

PMID- 15023360
TI  - Plasmodium falciparum glycogen synthase kinase-3: molecular model, expression,
      intracellular localisation and selective inhibitors.
AB  - Worldwide increasing resistance of Plasmodium falciparum to common anti-malaria
      agents calls for the urgent identification of new drugs. Glycogen synthase kinase
      3 (GSK-3) represents a potential screening target for the identification of such
      new compounds. We have cloned PfGSK-3, the P. falciparum gene homologue of GSK-3
      beta. It encodes a 452-amino-acid, 53-kDa protein with an unusual N-terminal
      extension but a well-conserved catalytic domain. A PfGSK-3 tridimensional
      homology model was generated on the basis of the recently crystallised human GSK
      3 beta. It illustrates how the regions involved in the active site, in substrate
      binding (P+4 phosphate binding domain) and in activity regulation are highly
      conserved. Recombinant PfGSK-3 phosphorylates GS-1, a GSK-3-specific peptide
      substrate, glycogen synthase, recombinant axin and the microtubule-binding
      protein tau. Neither native nor recombinant PfGSK-3 binds to axin. Expression and
      intracellular localisation of PfGSK-3 were investigated in the erythrocytic
      stages. Although PfGSK-3 mRNA is present in similar amounts at all stages, the
      PfGSK-3 protein is predominantly expressed at the early trophozoite stage. Once
      synthesized, PfGSK-3 is rapidly transported to the erythrocyte cytoplasm where it
      associates with vesicle-like structures. The physiological functions of PfGSK-3
      for the parasite remain to be elucidated. A series of GSK-3 beta inhibitors were
      tested on both PfGSK-3 and mammalian GSK-3beta. Remarkably these enzymes show a
      partially divergent sensitivity to the compounds, suggesting that PfGSK-3
      selective compounds might be identified.

PMID- 15023361
TI  - Effects of pharmacological cyclin-dependent kinase inhibitors on viral
      transcription and replication.
AB  - Cyclin-dependent kinases (CDKs) are required for replication of adeno-, papilloma
      and other viruses that replicate only in dividing cells. Surprisingly, CDKs are
      also required for replication of HIV-1, HSV-1, and other viruses that can
      replicate in non-dividing cells. Since two low-molecular weight pharmacological
      CDK inhibitors (PCIs), flavopiridol (Flavo) and roscovitine (Rosco), appear to be
      non-toxic in human clinical trials against cancer, these drugs have been proposed
      as potential antiviral drugs. Rosco preferentially inhibits CDKs involved in cell
      cycle regulation (CDK1, 2, and 7) or neuronal functions (CDK5), whereas Flavo
      preferentially inhibits CDKs involved in cell cycle (CDK1, 2, 4, 7) or
      transcription (CDK7, and 9). As potential antivirals, PCIs display several
      advantages: (i) they are active against many different viruses, including drug
      resistant strains of HIV-1 and HSV-1; (ii) PCI-resistant mutants of HIV-1 or HSV
      1 have not been identified; and (iii) the antiviral effects of PCIs and
      conventional antivirals appear to be additive (as expected from drugs that target
      independent pathways). Moreover, PCIs target both the etiological agents (i.e.,
      the virus) and the pathogenic mechanisms (i.e., unrestricted cell division) of
      the many diseases that include both a CDK-requiring virus and unrestricted cell
      division (e.g., Kaposi's sarcoma, cervical carcinoma, HIV-associated nephropathy
      HIVAN). This is nicely illustrated in a recent study which demonstrated the
      efficacy of Flavo in a mouse model of HIVAN. Herein, we will review the
      involvement of CDKs in viral replication and the antiviral properties of the most
      extensively characterized PCIs, with special emphasis on the mechanisms of
      inhibition of viral transcription.

PMID- 15023363
TI  - Viral and cellular kinases are potential antiviral targets and have a central
      role in varicella zoster virus pathogenesis.
AB  - Herpesviruses utilize viral and cellular kinases for replication, and these
      mediate essential functions that are important for viral pathogenesis.
      Elucidating the roles of kinases in herpesvirus infections may highlight virus
      host interactions that are possible targets for kinase inhibitors with antiviral
      activity. Varicella zoster virus (VZV) encodes two kinases that phosphorylate
      viral proteins involved in regulation, assembly, and virulence. VZV infection
      also induces the activity of host cell cyclin-dependent kinases (cdk4 and cdk2)
      in nondividing cells, causing a disregulation of the cell cycle. Roscovitine and
      Purvalanol, kinase inhibitors that target cdks, prevent VZV replication at
      concentrations with few cytotoxic effects. Cdk inhibitors therefore have
      potential as antivirals that may extend to a broad range of viruses and have the
      added advantage that resistance does not arise easily.

PMID- 15023362
TI  - Inhibitors of Civ1 kinase belonging to 6-aminoaromatic-2-cyclohexyldiamino purine
      series as potent anti-fungal compounds.
AB  - There is today a blatant need for new antifungal agents, because of the recent
      increase in life-threatening infections involving an ever-greater number of
      fungal strains. Fungi make extensive use of kinases in the regulation of
      essential processes, in particular the cell cycle. Most fungal kinases, however,
      are shared with higher eukaryotes. Only the kinases which have no human homologs,
      such as the histidine kinases, can be used as targets for antifungal drugs
      design. This review describes efforts directed towards the discovery of drugs
      active against a novel target, the atypical cell cycle kinase, Civ1.

PMID- 15023364
TI  - Inhibition of Hsp90: a new strategy for inhibiting protein kinases.
AB  - The 90-kDa heat shock protein (Hsp90) is a ubiquitous, evolutionarily highly
      conserved, molecular chaperone in the eukaryotic cytosol. Hsp90, together with a
      number of other chaperones, promotes the conformational maturation of a large
      variety of protein kinases. Inhibition of Hsp90 function results in the collapse
      of the metastable conformation of most of these kinases and leads to their
      proteolytic elimination by the proteasome. Numerous natural and synthetic Hsp90
      inhibitors have been developed in recent years. Some of these inhibitors are also
      involved in sensitizing tumor cells to pro-apoptotic insults, hence serve as anti
      cancer drugs. Here we review these novel protein kinase inhibitors and their
      emerging role in various cellular processes, apart from their inhibition of Hsp90
      protein function. We focus not only on Hsp90-tumor progression, but also on
      cytoarchitecture, as the higher levels of cellular organization need constant
      remodeling, where the role of Hsp90 requires investigation. Our last major aspect
      deals with protein oxidation, since several Hsp90 inhibitors exert pro-oxidant
      effects.

PMID- 15023365
TI  - Kinomics-structural biology and chemogenomics of kinase inhibitors and targets.
AB  - Classifying kinases based entirely on small molecule selectivity data is a new
      approach to drug discovery that allows scientists to understand relationships
      between targets. This approach combines the understanding of small molecules and
      targets, and thereby assists the researcher in finding new targets for existing
      molecules or understanding selectivity and polypharmacology of molecules in
      related targets. Currently, structural information is available for relatively
      few of the protein kinases encoded in the human genome (7% of the estimated 518);
      however, even the current knowledge base, when paired with structure-based design
      techniques, can assist in the identification and optimization of novel kinase
      inhibitors across the entire protein class. Chemogenomics attempts to combine
      genomic data, structural biological data, classical dendrograms, and selectivity
      data to explore, define, and classify the medicinally relevant kinase space.
      Exploitation of this information in the discovery of kinase inhibitors defines
      practical kinase chemogenomics (kinomics). In this paper, we review the available
      information on kinase targets and their inhibitors, and present the relationships
      between the various classification schema for kinase space. In particular, we
      present the first dendrogram of kinases based entirely on small molecule
      selectivity data. We find that the selectivity dendrogram differs from sequence
      based clustering mostly in the higher-level groupings of the smaller clusters,
      and remains very comparable for closely homologous targets. Highly homologous
      kinases are, on average, inhibited comparably by small molecules. This
      observation, although intuitive, is very important to the process of target
      selection, as one would expect difficulty in achieving inhibitor selectivity for
      kinases that share high sequence identity.

PMID- 15023366
TI  - PKA: a portrait of protein kinase dynamics.
AB  - Protein kinases play a critical role in the integration of signaling networks in
      eukaryotic cells. cAMP-dependent protein kinase (PKA) serves as a prototype for
      this large and highly diverse enzyme family. The catalytic subunit of PKA
      provides the best example of how a protein kinase recognizes its substrates, as
      well as inhibitors, and also show how the enzyme moves through the steps of
      catalysis. Many of the relevant conformational states associated with the
      catalytic cycle which have been captured in a crystal lattice are summarized
      here. From these structures, we can begin to appreciate the molecular events of
      catalysis as well as the intricate orchestration of critical residues in the
      catalytic subunit that contribute to catalysis. The entire molecule participates.
      To fully understand signaling by PKA, however, requires an understanding of a
      large set of related proteins, not just the catalytic subunit. This includes the
      regulatory subunits that serve as receptors for cAMP and the A kinase anchoring
      proteins (AKAPs) that serve as scaffolds for PKA. The AKAPs localize PKA to
      specific sites in the cell by docking to the N-terminus of the regulatory
      subunits, thus creating microenvironments for PKA signaling. To fully appreciate
      the diversity and integration of these molecules, one needs not only high
      resolution structures but also an appreciation of how these molecules behave in
      solution. Thus, in addition to obtaining high-resolution structures by X-ray
      crystallography and NMR, we have used fluorescent tools and also
      hydrogen/deuterium exchange coupled with mass spectrometry to probe the dynamic
      properties of these proteins and how they interact with one another. The
      molecular features of these molecules are described. Finally, we describe a new
      recombinantly expressed PKA reporter that allows us to monitor PKA activity in
      living cells.

PMID- 15023367
TI  - Structure/function studies of phosphoryl transfer by phosphoenolpyruvate
      carboxykinase.
AB  - Phosphoenolpyruvate carboxykinase (PCK) catalyzes the conversion of oxaloacetate
      (OAA) to PEP and carbon dioxide with the subsequent conversion of nucleoside
      triphosphate to nucleoside diphosphate (NDP). The 1.9 A resolution structure of
      Escherichia coli PCK consisted of a 275-residue N-terminal domain and a 265
      residue C-terminal domain with the active site located in a cleft between these
      domains. Each domain has an alpha/beta topology and the overall structure
      represents a new protein fold. Furthermore, PCK has a unique mononucleotide
      binding fold. The 1.8 A resolution structure of the complex of ATP/Mg(2+)/oxalate
      with PCK revealed a 20 degrees hinge-like rotation of the N- and C-terminal
      domains, which closed the active site cleft. The ATP was found in the unusual syn
      conformation as a result of binding to the enzyme. Along with the side chain of
      Lys254, Mg(2+) neutralizes charges on the P beta and P gamma oxygen atoms of ATP
      and stabilizes an extended, eclipsed conformation of the P beta and P gamma
      phosphoryl groups. The sterically strained high-energy conformation likely lowers
      the free energy of activation for phosphoryl transfer. Additionally, the gamma
      phosphoryl group becomes oriented in-line with the appropriate enolate oxygen
      atom, which strongly supports a direct S(N)2-type displacement of this gamma
      phosphoryl group by the enolate anion. In the 2.0 A resolution structure of the
      complex of PCK/ADP/Mg(2+)/AlF(3), the AlF(3) moiety represents the phosphoryl
      group being transferred during catalysis. There are three positively charged
      groups that interact with the fluorine atoms, which are complementary to the
      three negative charges that would occur for an associative transition state.

PMID- 15023368
TI  - Models for biological phosphoryl transfer.
AB  - Quantifying the rate of phosphate monoester dianion hydrolysis under
      physiological conditions has implications for designing transition state mimics
      and understanding how catalysis is facilitated. Catalysis is energetically most
      efficient if the mechanistic pathway in solution is stabilised. Monoesters are
      believed to have a "dissociative" transition state that has little bonding to the
      nucleophile and leaving group. However, in many instances, it is suggested that
      enzymes catalyse monoester transfer through an associative (diester-like)
      pathway. This is perhaps easier to rationalise in terms of the active site
      residues available. For example, in the catalytic subunit of protein phosphatase
      1 (PP1), these are metal ions and cationic side chains which might be expected to
      stabilise developing negative charge. By using multiple interactions
      simultaneously, cooperativity in catalysis may be achieved. However, this idea is
      difficult to demonstrate unambiguously in large, complex natural systems. This
      contribution examines the background reactivity of phosphate esters, and reports
      data showing that the substrates for serine/threonine phosphatases have slower
      intrinsic rate constants than any other enzyme substrates. Using model complexes,
      the characteristics of alternative (associative) mechanisms that have been
      proposed for the metallophosphatase catalysed reaction are explored. Finally,
      complementary catalytic groups are combined with this core complex to look for
      experimental evidence for possible cooperativity in this context.

PMID- 15023369
TI  - Structure, dynamics and interaction with kinase targets: computer simulations of
      calmodulin.
AB  - Calmodulin (CaM) is a small protein involved in calcium signaling; among the
      targets of CaM are a number of kinases, including myosin light chain kinases
      (MLCK), various CaM-dependent kinases and phosphorylase kinase. We present
      results of molecular dynamics (MD) simulations of 4-ns length for calmodulin in
      its three functional forms: calcium-free, calcium-loaded, and in complex with
      both calcium and a target peptide, a fragment of the smooth muscle MLCK. The
      simulations included explicit water under realistic conditions of constant
      temperature and pressure, the presence of counterions and Ewald summation of
      electrostatic forces. Our simulation results present a more complete description
      of calmodulin structure, dynamics and interactions in solution than previously
      available. The results agree with a wide range of experimental data, including X
      ray, nuclear magnetic resonance (NMR), fluorescence, cross-linking, mutagenesis
      and thermodynamics. Additionally, we are able to draw interesting conclusions
      about microscopic properties related to the protein's biological activity. First,
      in accord with fluorescence data, we find that calcium-free and calcium-loaded
      calmodulin exhibit significant structural flexibility. Our simulations indicate
      that these motions may be described as rigid-body translations and rotations of
      the N- and C-terminal domains occurring on a nanosecond time scale. Our second
      conclusion deals with the standard model of calmodulin action, which is that
      calcium binding leads to solvent exposure of hydrophobic patches in the two
      globular domains, which thus become ready to interact with the target.
      Surprisingly, the simulation results are inconsistent with the activation model
      when the standard definitions of the hydrophobic patches are used, based on
      hydrophobic clefts found in the X-ray structure of calcium-loaded calmodulin. We
      find that both experimental and simulation results are consistent with the
      activation model after a redefinition of the hydrophobic patches as those
      residues which are actually involved in peptide binding in the experimental
      structure of the calmodulin-peptide complex. The third conclusion is that the
      calmodulin-peptide interactions in the complex are very strong and are dominated
      by hydrophobic effects. Using quasi-harmonic entropy calculations, we find that
      these strong interactions induce a significant conformational strain in the
      protein and peptide. This destabilizing entropic contribution leads to a moderate
      overall binding free energy in the complex. Our results provide interesting
      insights into calmodulin binding to its kinase targets. The flexibility of the
      protein may explain the fact that CaM is able to bind many different targets. The
      large loss of conformational entropy upon CaM:peptide binding cancels the entropy
      gain due to hydrophobic interactions. This explains why the observed entropic
      contribution to the binding free energy is small and positive, and not large and
      negative as expected for a complex with such extensive hydrophobic contacts.

PMID- 15023371
TI  - Transcranial magnetic stimulation in children.
AB  - Single and paired pulse transcranial magnetic stimulation (TMS) provide a non
      invasive, painless method of probing the motor system. These techniques are of
      particular interest for studying maturation of the motor system and may provide
      insights into those developmental disabilities strongly associated with specific
      delays of motor development. This article will review studies using single pulse
      and paired pulse TMS in children, with particular reference to insights into
      neurodevelopment in children. It will also briefly touch on the potential of TMS
      as a diagnostic tool in neurological disorders. It will not address the use of
      repetitive TMS in children.

PMID- 15023372
TI  - Effect of positioning on the incidence of abnormalities of muscle tone in low
      risk, preterm infants.
AB  - BACKGROUND. The preterm infant is subject to the force of gravity: when its body
      lies pressed against the mattress on which it is placed. AIMS: The purpose of
      this study was to investigate short-term effects of varied post-natal lying
      positions in order to prevent neuromuscular and postural abnormalities. METHODS:
      60 low risk preterm infants of 31-36 weeks gestational age were enrolled for this
      randomised clinical trial. Initially each child underwent neurological and
      psychomotor assessments which included tonus and reflex protocols as well as
      behavioral, sensory motor and postural examinations. The lying positions of the
      treated group were varied (back, prone, and side) using a specially designed
      moldable mattress that maintained the functional position of the infant's body.
      The control group was placed on their stomachs, (the standard lying position used
      in 1994) with a standard orthopaedic bolster support under their hips. All
      infants underwent a second round of examinations upon discharge to assess any
      changes in neurological and psychomotor outcomes. RESULTS: The sensory-motor
      skills examinations showed significant abnormalities in the control group: (1)
      dominance of the extensor muscles due to muscle shortening, (2) hyper abduction
      and flexion of the arms, and (3) global neuromuscular rigidity. Psychomotor and
      neurological exams of the control and treatment groups showed delayed
      developmental muscular acquisitions for infants in the control group. CONCLUSION:
      Regular changes in posture, while retaining correct functional positions, allowed
      maintenance of normal neuromuscular and osteo-articular function and permitted
      the development of spontaneous and functional motor activity in low-risk perterm
      infants.

PMID- 15023374
TI  - Hereditary porencephaly: clinical and MRI findings in two Dutch families.
AB  - Familial porencephaly is a rare disorder causing motor impairment, hemiplegia,
      mental retardation and epilepsy in variable degrees. Two families with
      porencephaly and apparently dominant inheritance are reported. Brain MRI findings
      are reviewed and described in seven affected individuals. Most patients also show
      white matter abnormalities in the cerebral hemisphere, also contralateral to the
      cystic lesion. In the first family an obligate carrier was identified who did not
      have a cystic lesion but clear abnormalities of the white matter. Although a
      predisposition for thrombophilia has previously been reported, we did not observe
      any genetic, environmental or epigenetic predisposition for the porencephaly. The
      lesions are most compatible with a deep venous thrombosis/ischemic event
      occurring in a late stage of pregnancy, not necessarily aggravated by perinatal
      asphyxia.

PMID- 15023373
TI  - Hypothalamic hamartoma with gelastic seizures in Swedish children and
      adolescents.
AB  - BACKGROUND: Hypothalamic hamartoma with gelastic seizures (HHGS) is an uncommon,
      often unrecognized, epileptic syndrome with onset of symptoms during childhood.
      AIM: In order to study the occurrence, clinical symptoms and different
      investigations of HHGS in Swedish children and adolescents, a nationwide survey
      was undertaken. Methods. Twelve patients, three females, aged 5 to 19 years were
      identified and their hospital records reviewed. MRI examinations were
      reinvestigated. RESULTS: Gelastic seizures were noted before the age of six
      months in seven patients in at least three as early as the neonatal period.
      During the course of disease one or more other seizure types developed in 11
      patients. Behaviour disorder became subsequently obvious in ten patients, and
      mental retardation was diagnosed in seven. Precocious puberty was diagnosed in
      five patients. A total of 46 MRI examinations were performed in 11 patients,
      revealing hypothalamic tumors, eight of which were drooping with a broad base.
      Interictal and ictal EEG examinations were pathological in 10 patients with
      nonspecific results. Nonspecific results were also found on SPECT and PET
      performed in six and two patients, respectively. Available antiepileptic drugs
      had little or no effect on gelastic seizures, but some effect on other seizure
      types. Precocious puberty was treated with a GnRH-agonist. Neurosurgical
      treatment of the hypothalamic hamartoma, performed in three patients, had a
      rather good outcome concerning gelastic seizures and behaviour. Vagal nerve
      stimulation in five patients had no effect. CONCLUSIONS: Review of the literature
      and experience from this group's own cases confirms that early diagnosis of HHGS
      is important. Hypothalamic hamartoma should be considered in any child with
      laughing attacks. MRI investigation is compulsory, and neurosurgery the most
      important treatment.

PMID- 15023375
TI  - Neonatal seizures and limb malformations associated with liver-specific complex
      IV respiratory chain deficiency.
AB  - An eight-week-old infant, the fourth child of consanguineous parents presented
      with intractable neonatal seizures. The mother had two previous miscarriages. The
      infant initially presented on day one with multifocal myoclonus, complex partial
      and generalised tonic-clonic seizures. On examination, there were dysmorphic
      hands and feet, with absent nails and terminal phalanges of the fingers and toes,
      hepatomegaly, marked axial and peripheral hypotonia and severe global
      developmental delay. Ophthalmological assessment showed 'salt and pepper'
      pigmentary retinopathy. The urinary organic acid profile revealed a marked
      increase in tricarboxylic acid metabolites. Urinary phosphate reabsorption was
      reduced at 84%. Type I fibre atrophy was seen on muscle histology, and a
      cytochrome c oxidase deficiency was found only on enzymology of liver tissue.
      Limb malformations associated with respiratory chain defects have rarely been
      reported. To our knowledge, this child has the most severe limb anomaly
      associated with a tissue-specific complex IV respiratory chain defect.

PMID- 15023377
TI  - Recommendations for the use of new methods to assess the efficacy of disease
      modifying drugs in the treatment of osteoarthritis.
AB  - BACKGROUND: Recent innovations in the pharmaceutical drug discovery environment
      have generated new chemical entities with the potential to become disease
      modifying drugs for osteoarthritis (DMOAD's). Regulatory agencies acknowledge
      that such compounds may be granted a DMOAD indication, providing they demonstrate
      that they can slow down disease progression; progression would be calibrated by a
      surrogate for structural change, by measuring joint space narrowing (JSN) on
      plain X-rays with the caveat that this delayed JSN translate into a clinical
      benefit for the patient. Recently, new technology has been developed to detect a
      structural change of the OA joint earlier than conventional X-rays. OBJECTIVE:
      The Group for the Respect of Ethics and Excellence in Science (GREES) organized a
      working party to assess whether these new technologies may be used as surrogates
      to plain x-rays for assessment of DMOADs. METHODS: GREES includes academic
      scientists, members of regulatory authorities and representatives from the
      pharmaceutical industry. After an extensive search of the international
      literature, from 1980 to 2002, two experts meetings were organized to prepare a
      resource document for regulatory authorities. This document includes
      recommendations for a possible update of guidelines for the registration of new
      chemical entities in osteoarthritis. RESULTS: Magnetic resonance imaging (MRI) is
      now used to measure parameters of cartilage morphology and integrity in OA
      patients. While some data are encouraging, correlation between short-term changes
      in cartilage structure observed with MRI and long-term radiographic or clinical
      changes are needed. Hence, the GREES suggests that MRI maybe used as an outcome
      in phase II studies, but that further data is needed before accepting MRI as a
      primary end-point in phase III clinical trials. Biochemical markers of bone and
      cartilage remodelling are being tested to predict OA and measure disease
      progression. Recently published data are promising but validation as surrogate
      end-points for OA disease progression requires additional study. The GREES
      suggests that biochemical markers remain limited to 'proof of concept' studies or
      as secondary end-points in phase II and III clinical trials. However, the GREES
      emphasizes the importance of acquiring additional information on biochemical
      markers in order to help better understand the mode of action of drugs to be used
      in OA. Regulatory agencies consider that evidence of improvement in clinical
      outcomes is critical for approval of DMOAD. Time to total joint replacement
      surgery is probably the most relevant clinical end-point for the evaluation of
      efficacy of a DMOAD. However, at this time, time to surgery can not be used in
      clinical trials because of bias by non disease-related factors like patient
      willingness for surgery or economic factors. At this stage, it appears that DMOAD
      should demonstrate a significant difference compared to placebo. Benefit should
      be measured by 3 co-primary end-points: JSN, pain and function. Secondary end
      points should include the percentage of patients who are 'responder' (or
      'failure'). The definition of a 'failure' patient would be someone with
      progression of JSN>0.5mm over a period of 2-3 years or who has a significant
      worsening in pain and/or function, based on validated cut-off values. The
      definition of the clinically relevant cut-off points for pain and function must
      be based on data evaluating the natural history of the disease (epidemiological
      cohorts or placebo groups from long-term studies). These cut-offs points should
      reflect a high propensity, for an individual patient, to later require joint
      replacement. CONCLUSION: GREES has outlined a set of guidelines for the
      development of a DMOAD for OA. Although these guidelines are subject to change as
      new information becomes available, the information above is based on the present
      knowledge in the field with the addition of expert opinion.

PMID- 15023376
TI  - Compulsive spitting as manifestation of temporal lobe epilepsy.
AB  - Spitting as a seizure manifestation is described in an autistic child with a mild
      expression of epilepsy. Spitting became a predominant automatism of in seizure
      manifestation. In contrast to most cases in the literature, the epileptic
      discharges were localized in the left temporal lobe, an uncommon side to cause
      spitting seizures. By increasing the dose of carbamazepine, spitting behaviour
      disappeared.

PMID- 15023378
TI  - Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a
      one-year, randomized, double-blind, multicenter study versus placebo.
AB  - OBJECTIVE: To investigate the efficacy and tolerability of a 3-month duration,
      twice a-year, intermittent treatment with oral chondroitin sulfate (CS) in knee
      osteoarthritis (OA) patients. DESIGN: A total of 120 patients with symptomatic
      knee OA were randomized into two groups receiving either 800mg CS or placebo
      (PBO) per day for two periods of 3 months during 1 year. Primary efficacy outcome
      was Lequesne's algo-functional index (AFI); secondary outcome parameters included
      VAS, walking time, global judgment, and paracetamol consumption. Radiological
      progression was assessed by automatic measurement of medial femoro-tibial joint
      space width on weight-bearing X-rays of both knees. Clinical and biological
      tolerability was assessed. RESULTS: One hundred and ten of 120 patients were
      included in the ITT analysis. AFI decreased significantly by 36% in the CS group
      after 1 year as compared to 23% in the PBO group. Similar results were found for
      the secondary outcomes parameters. Radiological progression at month 12 showed
      significantly decreased joint space width in the PBO group with no change in the
      CS group. Tolerability was good with only minor adverse events identically
      observed in both groups. CONCLUSION: This study provides evidences that oral CS
      decreased pain and improved knee function. The 3-month intermittent
      administration of 800mg/day of oral CS twice a year does support the prolonged
      effect known with symptom-modifying agents for OA. The inhibitory effect of CS on
      the radiological progression of the medial femoro-tibial joint space narrowing
      could suggest further evidence of its structure-modifying properties in knee OA.

PMID- 15023379
TI  - Hyaluronic acid levels may have predictive value for the progression of knee
      osteoarthritis.
AB  - STUDY OBJECTIVES: To study prognostic value of different biochemical markers for
      morphological progression of early knee osteoarthritis. DESIGN: A total of 89
      patients with knee osteoarthritis (OA) were enroled into the study. The follow-up
      period was 2 years. Radiological OA progression was evaluated by measuring joint
      space width. Pentosidine was detected using the HPLC method described earlier,
      cartilage oligomeric matrix protein (COMP) using the method published by our
      team. MMP-9, tissue inhibitors of metalloproteinases (TIMP), YKL-40 and
      hyaluronic acid were detected using commercially available kits. RESULTS: In the
      group of patients suffering from knee OA, higher serum levels of pentosidine
      (P=0.04), MMP-9 (P=0.02), TIMP (P=0.04) and COMP (P=0.05) were detected compared
      with healthy control subjects. Using a correlation analysis method, it has been
      found that the patients with higher basic serum levels of hyaluronic acid had a
      faster radiological progression (r=0.56, P<0.005), as well as the patients with
      higher basic serum pentosidine levels (r=0.30, P<0.005). Other biochemical
      markers had no statistically significant prognostic value. CONCLUSIONS: In our
      study, serum levels of hyaluronic acid and pentosidine had a predictive value for
      further development of knee OA in that further joint space narrowing was detected
      in the patients with knee OA in the next 2 years.

PMID- 15023380
TI  - Site specific changes in gene expression and cartilage metabolism during early
      experimental osteoarthritis.
AB  - OBJECTIVES: To characterize the molecular events underlying cartilage injury in
      the early phase of mono-iodoacetate-induced osteoarthritis (OA) in rats. METHODS:
      Experimental osteoarthritis was induced by intra-articular injection of 0.03mg
      mono-iodoacetate (MIA) in Wistar rats. Animals were killed 2, 5, 10, 15 and 20
      days post-injection. Synovial tissue and standardized biopsies from different
      areas of knee cartilage were examined. Proteoglycan synthesis ((35)S
      incorporation) and gelatinase activities (zymography), semi-quantitative RT-PCR
      and immunohistochemistry for IL1beta, iNOS, COX2 and PPARgamma, were performed on
      these samples. RESULTS: Changes in proteoglycan synthesis and gelatinase
      activities were time and site-dependent. Proteoglycan synthesis inhibition was
      maximal by day 2 while the highest gelatinase activities were observed at day 5.
      Central part of patella and posterior plateaus and condyles, i.e. the weight
      bearing cartilage areas, were the most affected. IL1beta and iNOS transcripts
      were induced early in cartilage at time of maximal proteoglycan synthesis
      inhibition, especially in weight-bearing areas. COX-2 was slightly up-regulated
      whereas PPARgamma gene expression remained unchanged. Gene expression profile in
      synovium paralleled that of cartilage, except for PPARgamma which was up
      regulated at day 15 and 20. Immunostaining for IL1beta and iNOS showed that
      proteins were located in diseased cartilage areas at early stage of the
      experimental OA (day 2). At later time-points (day 20), IL1beta and iNOS were
      expressed in perilesional areas whereas immunostaining became below control level
      for COX-2 and PPARgamma. CONCLUSIONS: Time-dependent degradation of cartilage
      after injection of low dose of MIA (0.03mg) into rat knee joint can be related to
      early loss of proteoglycan anabolism, increased gelatinase activities and
      expression of IL1beta and downstream inflammatory genes. Increased susceptibility
      to MIA in weight-bearing areas of cartilage further indicate that MIA-induced
      experimental OA is a relevant model to study not only metabolical but also
      biomechanical aspects of human OA.

PMID- 15023382
TI  - Low oxygen tension stimulates the redifferentiation of dedifferentiated adult
      human nasal chondrocytes.
AB  - OBJECTIVE: To determine the effect of dissolved oxygen tension (DO) on the
      redifferentiation of dedifferentiated adult human nasal septum chondrocytes
      cultured as pellets. DESIGN: After isolation, human nasal chondrocytes were
      expanded in monolayer culture, which resulted in their dedifferentiation.
      Dedifferentiated cells were pelleted, transferred to a bioreactor and maintained
      for up to 21 days at 100% DO (21% oxygen), 25% DO (5.25% oxygen) or 5% DO (1%
      oxygen), which was controlled in the liquid phase. Redifferentiation was assessed
      by staining the extracellular matrix with safranin-O and by the
      immunolocalization of collagen types I, II, IX and of a fibroblast membrane
      marker (11-fibrau). In addition, glycosaminoglycans (GAG) and DNA content were
      determined spectrophotometrically. RESULTS: In monolayer culture, cells
      dedifferentiated and multiplied 90- to 100-fold. Cell pellets cultured in a
      bioreactor under conditions of low oxygen tension (25% DO or 5% DO) stained
      intensely for GAGs and for collagen type II, but very weakly for collagen type I.
      After 14 days of culturing, cell pellets maintained at 5% DO stained more
      intensely for collagen IX and more weakly for 11-fibrau than did those incubated
      at 25% DO. After 21 days of culturing the GAG content of cell pellets maintained
      at 5% DO was significantly greater than that of those incubated at 25% DO. Under
      air-saturated conditions (100% DO), the DNA and GAG contents of cell pellets
      decreased with time in culture. After 21 days of culturing, both parameters were
      substantially lower in cell pellets maintained at 100% DO than in those incubated
      at low oxygen tensions. The staining signals for collagen types II and IX were
      much weaker, and those for the markers of dedifferentiation (collagen type I and
      11-fibrau) much stronger under air-saturated conditions than at low oxygen
      tensions. CONCLUSION: These observations demonstrate that using the present set
      up, low oxygen tension stimulates the redifferentiation of dedifferentiated adult
      human nasal chondrocytes in pellet cultures.

PMID- 15023381
TI  - Effects of transforming growth factor-beta on aggrecanase production and
      proteoglycan degradation by human chondrocytes in vitro.
AB  - OBJECTIVE: Aggrecan is degraded by Aggrecanases (ADAMTS-4 and -5) and MMPs, which
      cleave its core protein at different sites. Transforming growth factor (TGF)beta
      is known to stimulate matrix formation in cartilage, and ADAMTS-4 production in
      synoviocytes. The aim of this in-vitro study was to examine the effects of
      TGFbeta on aggrecanase production in human cartilage. DESIGN: Expression of
      ADAMTS-4 and -5 in chondrocyte cultures from normal or osteoarthritic cartilage
      was studied at mRNA level by RT-PCR. Aggrecanase activity was examined by western
      blot of aggrecanase-generated neoepitope NITEGE, and by measure of proteoglycan
      degradation in cartilage explants. RESULTS: TGFbeta strongly increased mRNA
      levels of ADAMTS-4, while ADAMTS-5 was expressed in a constitutive way in
      chondrocytes from normal and osteoathritic cartilage. TGFbeta also increased
      NITEGE levels and proteoglycan degradation. Addition of an aggrecanase inhibitor
      blocked the increase of NITEGE, and partially inhibited proteoglycan degradation.
      CONCLUSIONS: TGFbeta stimulates ADAMTS-4 expression and aggrecan degradation in
      cartilage. This catabolic action seems to be partially mediated by aggrecanases.
      It is, therefore, proposed that the role of TGFbeta in cartilage matrix turnover
      is not limited to anabolic and anti-catabolic actions, but also extends to
      selective degradation of matrix components such as aggrecan.

PMID- 15023383
TI  - A type XI collagen mutation leads to increased degradation of type II collagen in
      articular cartilage.
AB  - OBJECTIVE: To determine in articular cartilage whether degraded type II collagen
      is more abundant in Col11a1 mutant cho/+ than in age-matched +/+ mice and whether
      collagen degradation occurs in a generalized or localized fashion. DESIGN: Knee
      joints from cho/+ and +/+ mice at 6, 9, 12 and 15 months of age were dissected,
      fixed, cryosectioned, and stained with antibody COL2-3/4m against denatured type
      II collagen using a FITC-conjugated secondary antibody. Sections were viewed and
      photographed under a fluorescence microscope and areas of staining were
      quantified. RESULTS: Before 12 months of age, little degraded collagen staining
      was detectable in +/+ or cho/+ mice. By 15 months, however, cho/+ mice showed
      significantly more degraded type II collagen than age-matched controls. Degraded
      collagen staining was localized at the articular surface, not distributed
      generally throughout the articular cartilage. CONCLUSIONS: The results suggest a
      model in which cumulative biomechanical stresses trigger increased collagen
      synthesis and degradation in both +/+ and cho/+ mice at around 12 months of age.
      Cho/+ mice, however, are less able to synthesize and assemble normal replacement
      collagen fibrils because of the Col11a1 mutation. Degradation is further
      activated, resulting in the accumulation of degraded type II collagen in the
      articular cartilage extracellular matrix. Similar mutations that do not overtly
      affect skeletal development may likewise predispose humans to increased collagen
      degradation and resultant osteoarthritis.

PMID- 15023384
TI  - Upregulated ank expression in osteoarthritis can promote both chondrocyte MMP-13
      expression and calcification via chondrocyte extracellular PPi excess.
AB  - OBJECTIVE: In idiopathic chondrocalcinosis and in osteoarthritis (OA), increased
      extracellular PP(i) (ecPP(i)) promotes calcification. In chromosome 5p-associated
      familial chondrocalcinotic degenerative arthropathy, certain mutations in the
      membrane protein ANK may chronically raise ecPP(i) via enhanced PP(i) channeling.
      Therefore, we assessed if dysregulated wild-type ANK expression could contribute
      to pathogenesis of idiopathic degenerative arthropathy through elevated ecPP(i).
      DESIGN: Using cells with genetic alterations in expression of ANK and the PP(i)
      generating nucleotide pyrophosphatase phosphodiestrase (NPP) PC-1, we examined
      how increased ANK expression elevates ecPPI, testing for codependent effects with
      PC-1. We also evaluated the effects of ANK expression on chondrocyte growth,
      matrix synthesis, and MMP-13 expression and we immunohistochemically examined ANK
      expression in situ in human knee OA cartilages. RESULTS: Using cells expressing
      defective ANK, as well as PC-1 knockout cells, we demonstrated that ANK required
      PC-1 (and vice versa) to raise ecPP(i) and that the major ecPP(i) regulator
      TGFbeta required both ANK and PC-1 to elevate ecPP(i). Upregulation of wild-type
      ANK by transfection in normal chondrocytes not only raised ecPP(i) 5-fold to
      approximately 100nM but also directly stimulated matrix calcification and
      inhibited collagen and sulfated proteoglycans synthesis. In addition, upregulated
      ANK induced chondrocyte MMP-13, an effect that also was stimulated within 2h by
      treatment of chondrocytes with 100nM PP(i) alone. Finally, ANK expression was
      upregulated in situ in human knee OA cartilages. CONCLUSION: Elevation of ecPP(i)
      by ANK critically requires the fraction of cellular PP(i) generated by PC-1. The
      upregulation of ANK expression in OA cartilage and the capacity of increased ANK
      expression to induce MMP-13 and to promote matrix loss suggest that increased ANK
      expression and ecPP(i) exert noxious effects in degenerative arthropathies beyond
      stimulation of calcification.

PMID- 15023386
TI  - Comparison of dynamic and step-and-shoot intensity-modulated radiation therapy
      planning and delivery.
AB  - Intensity-modulated radiation therapy (IMRT) is commonly delivered using the
      dynamic or segmental mode of multileaf collimators (DMLC or SMLC). Both methods
      are designed to deliver intensity-modulated beams as determined by inverse
      planning software. In this study, we have used the Helios IMRT planning system to
      generate ideal treatment plans for 10 cases of 2 common treatment sites (prostate
      and head and neck) and have investigated the actual treatment fluence
      distributions generated for each of the MLC leaf motion choices. The 2 dose
      delivery techniques were dosimetrically compared to each other and to the
      treatment plans. For each technique, point doses were measured in a water phantom
      using ionization chambers. Also for each technique, 2-dimensional dose
      distributions at a selected depth in a plastic phantom were obtained, using
      extended range film. The total delivery time and the number of monitor units (MU)
      delivered by each method were also compared. Our results indicate that the 2
      delivery methods produce comparable results dosimetrically. For the cases
      reviewed, the delivery time was an average of 15% longer for SMLC deliveries,
      while the number of MUs (beam-on time) required by SMLC was an average of 15%
      fewer, than that for the DMLC. In the interest of simplicity, lower beam-on time,
      and potentially fewer mechanically-related problems, we think that the SMLC
      delivery technique may be the better choice when Helios is used for planning and
      Varian linear accelerators are used for delivery.

PMID- 15023385
TI  - Hypoxia inducible factor-1 alpha expression in human normal and osteoarthritic
      chondrocytes.
AB  - BACKGROUND: Articular cartilage is a unique tissue in that it is avascular with
      its nutrition and oxygen supply being dependent on the diffusion of solutes
      through the synovial fluid and to and from the subchondral bone. The oxygen
      levels in articular cartilage, therefore, are assumed to be low. Oxygen is an
      important modulator of gene expression and this regulation occurs largely through
      the activation of the transcriptional complex hypoxia-inducible factor-1 (HIF-1).
      However, little is known about how articular cartilage regulates genes in
      response to O(2)tension and whether this regulation occurs through HIF-1. AIM:
      The aim of this study was to investigate the expression profile of HIF-1alpha in
      normal and osteoarthritic (OA) chondrocytes under normoxic and hypoxic
      conditions, and in response to treatment with tumor necrosis factor alpha
      (TNFalpha). METHODS: Articular chondrocytes from human normal and OA knee
      cartilage were isolated and cultured in suspension under normoxic (21% O(2)) or
      hypoxic conditions (1% O(2)). Chondrocytes were also treated with TNF-alpha under
      normoxic conditions. Nuclear extracts and total RNA were prepared and HIF-1alpha
      protein and mRNA levels were assayed by immunoblotting and Northern
      hybridization. Localization of HIF-1alpha by immunofluorescence was performed on
      frozen sections of cartilage tissue by confocal microscopy. RESULTS: HIF-1alpha
      expression was detectable in human normal and OA chondrocytes and cartilage by
      Northern analysis, immunoblotting and immunofluorescence under normoxic
      conditions. Culture of OA or normal chondrocytes under hypoxic conditions for up
      to 16h resulted in a modest stabilization and/or increase of HIF-1alpha
      expression. Treatment of articular chondrocytes with TNFalpha resulted in an
      increase in HIF-1alpha protein steady state levels under normoxic conditions. The
      increase in HIF-1alpha expression induced by TNFalpha was partially blocked by
      pretreatment of the chondrocytes with inhibitors of NFkappaB or p38 MAP kinase.
      We also observed the expression of HIF-2alpha mRNA in human chondrocytes.
      CONCLUSION: HIF-1alpha is expressed in human normal and OA articular chondrocytes
      cultured under normoxic conditions. HIF-1alpha can be further induced or
      stabilized in articular chondrocytes by hypoxia or by treatment with TNFalpha.
      The relatively high constitutive expression of HIF-1alpha by chondrocytes may be
      an important adaptation to survival in the avascular-hypoxic environment of
      cartilage. Modulation of HIF-1alpha levels by TNF-alpha may have important
      implications for chondrocyte metabolism during degenerative joint disease. In
      addition, we detected for the first time the expression of HIF-2alpha mRNA in
      chondrocytes.

PMID- 15023387
TI  - The effect of an extended source-to-skin distance in the treatment of the spinal
      field in children receiving craniospinal irradiation.
AB  - In this study, we compared a single extended source-to-skin difference (SSD)
      spinal field and the alternative 2-field gapped approach at 100 SSD on dose to
      surrounding normal tissues. Five female patients ranging in age from 3 to 20
      years underwent computed tomography (CT) simulation for treatment planning of the
      craniospinal axis, which was treated in its entirety to 36 Gy. For each slice,
      the clinical target volume (thecal sac and contents), mandible, thyroid gland,
      esophagus, heart, lungs, liver, and ovaries were contoured. Technique A employed
      the use of a single posterior spinal field delivered at SSD = 140 cm (140 SSD),
      and Technique B employed the use of 2 gapped spinal fields using a traditional
      SSD of 100 cm (100 SSD). Dose-volume histograms (DVHs) were obtained for each
      organ contoured and for each technique used. In all patients, the average mean
      dose to all surrounding structures was increased with the use of a single
      extended SSD (Technique A) when compared to the 2 spinal fields prescribed at 100
      SSD (Technique B). The average mean doses to the mandible, thyroid gland,
      esophagus, and heart were 78%, 19%, 6%, and 16%, respectively, higher with
      Technique A as compared to Technique B. In addition, the average mean doses to
      the lungs, liver, and ovaries were 53%, 33% and 69%, respectively, higher as
      compared to Technique B. However, the clinical target volume at the spinal
      junction site received a less homogenous dose with Technique B as compared to
      Technique A. We conclude that although the use of a single-field extended SSD
      delivered a more homogenous dose to the spine, a higher dose to the ovaries,
      thyroid gland, mandible, lungs, liver, and heart was seen.

PMID- 15023388
TI  - Quality assurance measurements of a-Si EPID performance.
AB  - The performance stability of a Varian aS500 amorphous silicon (a-Si) electronic
      portal imaging device (EPID) was monitored over an 18-month period using a
      variety of standard quality assurance (QA) tests. The tests were selected to
      provide ongoing information about image quality and dose response from the time
      of EPID acceptance into clinical service. To evaluate imaging performance, we
      made spatial resolution and contrast measurements using both PortalVision and QC
      3V phantoms for 6- and 15-MV photon beams at repetition rates of 100, 300, and
      400 MU/min in standard scanning mode. To assess operational stability for
      dosimetry applications, we measured central axis radiation response and beam
      pulse variability for the same image acquisition modes. Using the QC-3V phantom,
      values for the critical frequency of 0.435 +/- 0.005 lp/mm for 6 MV and 0.382 +/-
      0.003 lp/mm for 15 MV were obtained. The contrast-to-noise ratio was found to be
      approximately 20% higher for the lower photon energy. Beam pulse variability
      remained within the tolerance of 3% set by the manufacturer. The central axis
      pixel response of the EPID remained constant within +/-1% over a 5-month period
      for the 6-MV beam, but fell approximately 4% over the same period for the 15-MV
      beam. The Varian aS500 EPID studied exhibited consistent image quality and a
      stable radiation response. These characteristics render it suitable for
      quantitative applications such as clinical dose measurement.

PMID- 15023390
TI  - Escalated median dose for pituitary macroadenomas using intensity-modulated
      radiation therapy.
AB  - Three-dimensional conformal radiotherapy (3D CRT) has become an established
      treatment for pituitary macroadenomas. This study is an investigation into the
      possible dosimetric advantages of intensity-modulated radiotherapy for such
      critically located tumors. Three consecutive patients with pituitary macroadenoma
      previously treated with 3D CRT were replanned with inverse-planned IMRT using
      Helax-TMS (V.6.0, Helax AB, Uppsala, Sweden. Fusion of computed tomography (CT)
      with postoperative magnetic resonance imaging (MRI) was performed within the
      planning system to define the gross tumor volume (GTV), planning target volume
      (PTV), and normal structures including the optic chiasm. Dose-volume histograms
      (DVHs) for the 3D CRT plans were then compared with those of the corresponding
      prospective IMRT plans. Both techniques maintained critical structure doses below
      tolerance levels while maintaining a minimum dose of 45 Gy to 100% of the PTV.
      While IMRT plans deliver consistently more heterogeneous dose distributions to
      the PTV, the median PTV dose is elevated in the IMRT plans compared with the 3D
      CRT plans. For critically located tumors like these pituitary macroadenomas, IMRT
      allows escalation of the median dose to the tumor without an accompanying loss in
      critical structure sparing or creating unacceptable cold spots within the PTV.

PMID- 15023389
TI  - Simplified intensity-modulated arc therapy for dose escalated prostate cancer
      radiotherapy.
AB  - Simplified intensity-modulated arc therapy (SIMAT) employs forward planned,
      conformal, and avoidance arc combinations with dynamic multileaf collimation
      (MLC) as a simpler alternative to other forms of intensity-modulated radiotherapy
      (IMRT). In this work, we compare SIMAT with 4-field (4F) and 6-field (6F) 3D
      conformal radiation therapy (CRT) for prostate cancer treatment. Prostate,
      seminal vesicle, bladder, and rectum were contoured on the CT images of 10
      patients being planned for radiotherapy. Two planning target volumes (PTV) were
      defined: PTV1 (prostate + seminal vesicles + 1.0-cm margin) and PTV2 (prostate +
      1.0-cm margin). SIMAT, 4F, and 6F plans were generated with a prescription dose
      of 78 Gy to prostate and 54 Gy to the seminal vesicles. Differences in the 3
      techniques in terms of target and rectal coverage were compared. In addition,
      dose distributions of the SIMAT plans were verified with measurements in a
      phantom. Mean dose to PTV2 (4F, 76 Gy; 6F, 78 Gy; SIMAT, 76 Gy) and the dose
      delivered to 95% of the target volume (D(95)) were similar between the 3
      techniques. Target conformity was better with SIMAT. Mean dose and calculated
      NTCP for the rectum were lower for SIMAT than those for 4F and 6F plans (4F 55.6
      Gy vs. 6F 49.0 Gy vs. SIMAT 42.7 Gy). Mean dose to femoral heads was lower for
      the 4F technique vs. 6F and SIMAT techniques (4F 44.5 Gy vs. 6F 48.9 Gy vs. SIMAT
      49.5 Gy). In-phantom measurement demonstrated good agreement between the plans
      and SIMAT treatments delivered in phantom. We concluded that SIMAT demonstrates
      advantages over 4F and 6F in terms of target conformity mean rectal dose and NTCP
      with good reproducibility in phantom. On the basis of this analysis, we have
      commenced a clinical pilot study of SIMAT for prostate cancer radiotherapy.

PMID- 15023391
TI  - A technique to re-establish dose distributions for previously treated brain
      cancer patients in external beam radiotherapy.
AB  - Tumor recurrences or new tumors may develop after irradiation of local lesion(s)
      in the brain, and additional radiotherapy treatments are often needed for
      previously treated patients. It is critical to re-establish the dose
      distributions delivered during the previous treatment in the current patient
      geometry, so that the previous dose distributions can be accurately taken into
      consideration in the design of the current treatment plan. The difficulty in re
      establishing the previous treatment dose distributions in the current patient
      geometry arises from the fact that the patient position at the time of
      reirradiation is different from that at the previous treatment session. Simple re
      entry of the previous isocenter coordinates, gantry, and couch and collimator
      angles into the new treatment plan would result in incorrect beam orientations
      relative to the new patient anatomy, and therefore incorrect display of the
      previous dose distributions on the current patient anatomy. To address this
      issue, a method has been developed so that the previous dose distributions can be
      accurately re-established in the framework of the current brain treatment. The
      method involves 3 matrix transformations: (1) transformation of beams from
      machine coordinate system to patient coordinate system in the previous treatment;
      (2) transformation of beams from patient coordinate system in the previous
      treatment to patient coordinate system in the current treatment; and (3)
      transformation of beams from patient coordinate system in the current treatment
      to machine coordinate system. The transformation matrices used in the second
      transformation are determined by registration using a mutual information-based
      algorithm with which the old and new computed tomography (CT) scan sets are
      registered automatically without human interpretation. A series of transformation
      matrices are derived to calculate the isocenter coordinates, the gantry, couch,
      and collimator angles of the beams for the previous treatment in the current
      patient geometry, and the previous dose distributions are re-established on the
      current CT images. The method has been proven to be successful and robust.

PMID- 15023393
TI  - Dosimetry around metallic ports in tissue expanders in patients receiving
      postmastectomy radiation therapy: an ex vivo evaluation.
AB  - Postmastectomy breast reconstruction can be accomplished utilizing tissue
      expanders and implants. However, in patients who require postoperative
      radiotherapy, the complication rate with tissue expander/implant reconstruction
      can exceed 50%. One potential cause of this high complication rate may be the
      metallic port in the tissue expander producing altered dosimetry in the region of
      the metallic device. The purpose of this study was to quantify the radiation dose
      distribution in the vicinity of the metallic port and determine its potential
      contribution to this extremely high complication rate. The absolute dosimetric
      effect of the tissue expander's metallic port was quantified using film and
      thermoluminescent dosimetry (TLD) studies with a single beam incident on a
      metallic port extracted from an expander. TLD measurements were performed at 11
      reproducible positions on an intact expander irradiated with tangential fields. A
      computed tomography (CT)-based treatment plan without inhomogeneity corrections
      was used to derive expected doses for all TLD positions. Multiple irradiation
      experiments were performed for all TLD data. Confidence intervals for the dose at
      TLD sites with the metallic port in place were compared to the expected dose at
      the site without the metallic port. Film studies did not reveal a significant
      component of scatter around the metallic port. TLD studies of the extracted
      metallic port revealed highest doses within the casing of the metallic port and
      no consistent increased dose at the surface of the expander. No excess dose due
      to the metallic port in the expander was noted with the phantom TLD data. Based
      upon these results, it does not appear that the metallic port in tissue expanders
      significantly contributes to the high complication rate experienced in patients
      undergoing tissue expander breast reconstruction and receiving radiation therapy.
      Strategies designed to reduce the breast reconstruction complication rate in this
      clinical setting will need to focus on factors other than adjusting the dosimetry
      around the tissue expander metallic port.

PMID- 15023392
TI  - Biological effective dose for comparison and combination of external beam and low
      dose rate interstitial brachytherapy prostate cancer treatment plans.
AB  - We report a methodology for comparing and combining dose information from
      external beam radiotherapy (EBRT) and interstitial brachytherapy (IB) components
      of prostate cancer treatment using the biological effective dose (BED). On a
      prototype early-stage prostate cancer patient treated with EBRT and low-dose rate
      I-125 brachytherapy, a 3-dimensional dose distribution was calculated for each of
      the EBRT and IB portions of treatment. For each component of treatment, the BED
      was calculated on a point-by-point basis to produce a BED distribution. These
      individual BED distributions could then be summed for combined therapies. BED
      dose-volume histograms (DVHs) of the prostate, urethra, rectum, and bladder were
      produced and compared for various combinations of EBRT and IB. Transformation to
      BED enabled computation of the relative contribution of each modality to the
      prostate dose, as the relative weighting of EBRT and IB was varied. The BED-DVHs
      of the prostate and urethra demonstrated dramatically increased inhomogeneity
      with the introduction of even a small component of IB. However, increasing the IB
      portion relative to the EBRT component resulted in lower dose to the surrounding
      normal structures, as evidenced by the BED-DVHs of the bladder and rectum.
      Conformal EBRT and low-dose rate IB conventional dose distributions were
      successfully transformed to the common "language" of BED distributions for
      comparison and for merging prostate cancer radiation treatment plans. The results
      of this analysis can assist physicians in quantitatively determining the best
      combination and weighting of radiation treatment modalities for individual
      patients.

PMID- 15023394
TI  - Obesity and post-prandial lipid metabolism. Feast or famine?
AB  - Both in Western countries and in third world countries there is an increasing
      incidence of obesity. Obesity per se or insulin resistance associated with
      obesity may increase cardiovascular risk factors including dyslipidemia,
      hypertension and Type 2 diabetes. Over the past decade the understanding has
      increased of specific mediators in the hypothalamus that are involved in
      regulating food intake and body weight. In obese humans fasting plasma lipids can
      be normal but postprandial lipid metabolism is abnormal with an accumulation of
      triglyceride-rich remnant lipoproteins. In viscerally obese men chylomicron
      remnant catabolism was markedly decreased when compared with lean individuals.
      The decreased clearance of chylomicron remnants in viscerally obese subjects may
      be explained by competition between chylomicron remnants and the increased
      hepatic production of VLDL for clearance by low density lipoprotein receptors.
      Increased food intake in rodent models of obesity was shown to be associated with
      a delay in the catabolism of remnant lipoprotein particles. Prevention of
      hyperphagia was found to correct the impairment in the metabolism of remnant
      lipoproteins. Under fasting and food restricted conditions the improvement of
      remnant metabolism was associated with an increased oxidation of remnant lipids
      as determined by a novel stable isotope breath test. Anti-obesity and lipid
      lowering drugs have been used for the treatment of obesity. Inhibitors of
      cholesterol synthesis inhibitors (statins) have been shown to be effective in
      treating dyslipidemia. Inhibition of cholesterol synthesis with Atorvastatin was
      shown to improve chylomicron metabolism by increasing chylomicron remnant
      catabolism in obese subjects as assessed by the newly developed stable isotope
      breath test.

PMID- 15023395
TI  - Effect of genistein supplementation on tissue genistein and lipid peroxidation of
      serum, liver and low-density lipoprotein in hamsters.
AB  - The aim of this study was to investigate the effects of genistein supplementation
      in a vitamin E-deficient diet on the genistein concentrations and the lipid
      oxidation of serum, liver and low-density lipoprotein (LDL) of hamsters. Thirty
      six male hamsters were randomly divided into three groups and fed a vitamin E
      deficient semisynthetic diet (AIN-76) containing different levels of genistein,
      i.e., G0 (control group, genistein-free diet), G50 (50 mg genistein/kg diet) and
      G200 (200 mg genistein/kg diet) for 5 weeks. The concentrations of genistein in
      serum and liver significantly increased with the increase of genistein
      supplementation. The vitamin E contents in LDL were higher in hamsters fed G50 or
      G200 diets than in hamsters fed genistein-free diet. Genistein supplementation to
      hamsters significantly reduced the propagation rate during conjugated diene
      formation of LDL oxidation, and the lag time of LDL oxidation in hamsters fed
      G200 diets was significantly lower than that of G0 diets. In addition, genistein
      supplementation significantly raised serum total antioxidant capacity and
      decreased the thiobarbituric acid-reactive substances (TBARS) of LDL and liver in
      hamsters. However, no significant differences in TBARS were found in serum,
      irrespective of genistein addition. On the other hand, the relative contents of
      polyunsaturated fatty acids in LDL were decreased after genistein
      supplementation. There was a negative correlation between lag time and P/S ratio,
      and a positive correlation between lag time and vitamin E contents. These data
      demonstrate that genistein supplementation markedly increased its concentrations
      in body tissues and reduced oxidative stress of lipid oxidation of serum, liver
      and LDL.

PMID- 15023396
TI  - Proximal intestinal absorption of calcium is elevated in proportion to growth
      rate but not bone mass is small for gestational age piglets.
AB  - During the first year of life, body calcium content increases faster in relation
      to body size than any other time during growth. Studies have shown postnatal
      growth and bone mineralization differences between appropriate for gestational
      age and small for gestational age infants. The objective of this study was to
      compare duodenal calcium transport using intestinal ligated loop technique in 21
      day-old small for gestational age (birth weight of <1.2 kg) and appropriate for
      gestational age piglets (birth weight of > or =1.4 kg). Piglets were fed liquid
      formula between day 5 and 21 of life and monitored daily for weight gain. At day
      21 calcium absorption was measured followed by measurement of bone mass using
      dual energy x-ray absorptiometry. Small for gestational age piglets had greater
      calcium absorption and growth rate than appropriate for gestational age piglets.
      Birth weight was negatively related to weight gain and calcium absorption. Weight
      gain was positively related to calcium absorption. Appropriate for gestational
      age piglets had significantly higher whole body bone mineral content than small
      for gestational age piglets even after correction for body size. Whole body bone
      mineral content was positively correlated with birth weight and negatively
      correlated with calcium absorption. These observations suggest that small for
      gestational age piglets are capable of absorbing elevated amounts of calcium in
      the proximal intestine in support of compensatory growth. However, at 21 days of
      age small for gestational age piglets are similar in size but have lower bone
      mass compared to appropriate for gestational age piglets.

PMID- 15023397
TI  - Functional and molecular responses of suckling rat pups and human intestinal Caco
      2 cells to copper treatment.
AB  - Ctr1 and Atp7A are copper (Cu) transporters that may play a role in the
      regulation of intestinal Cu absorption; however, intestinal regulation of these
      transporters by Cu in vivo has not been well defined. In this study, we
      hypothesized that Cu supplementation would alter the expression of intestine Ctr1
      and Atp7A in vivo and further documented effects of Cu exposure on Cu transport,
      Ctr1 and Atp7A levels and localization in enterocyte-like Caco-2 cells. Suckling
      rat pups were supplemented with Cu (0 and 25 microg Cu/day) for 10 days and small
      intestine Cu concentration, Ctr1, Atp7A and metallothionein (MT) gene expression
      were measured by Northern blot analysis. Caco-2 cells were treated with basal
      medium, or medium supplemented with 3 and 94 microM CuSO4 and 67Cu transport,
      Ctr1 and Atp7A levels and localization were determined. In rat pups, Cu
      supplementation increased intestinal Cu, Ctr1 and MT gene expression; however,
      Atp7A gene expression was not significantly affected. Caco-2 cells treated with
      94 microM Cu had lower cellular Cu uptake and export compared to untreated cells.
      While Ctr1 and Atp7A gene and protein levels were unaffected, confocal microscopy
      indicated that Ctr1 was endocytosed and co-localized with transferrin in Cu
      treated cells. This study demonstrates the functional response of intestinal
      cells to Cu treatment and suggests that both Ctr1 and Atp7A may regulate Cu
      absorption.

PMID- 15023398
TI  - A comparison of the effectiveness of soy protein isolate and fish oil for
      reducing the severity of retinoid-induced hypertriglyceridemia.
AB  - The effectiveness of soy protein isolate (SPI) to reduce the severity of retinoid
      induced hypertriglyceridemia has been demonstrated in the rat, but not in human
      subjects. Because fish oil has been demonstrated to be effective at lowering
      serum triglyceride concentration in human subjects undergoing retinoid therapy, a
      study was conducted to compare the ability of SPI with that of fish oil to reduce
      the severity of retinoid-induced hypertriglyceridemia in the rat. Male Fischer
      344 rats, n=8/group, were fed one of four isonitrogenous, isoenergetic diets,
      consisting of a control diet containing 24% casein +20% corn oil (C), and three
      13-cis retinoic acid (13cRA)-supplemented diets containing 24% casein +20% corn
      oil (R), 24% SPI +20% corn oil (SR), and 24% casein +15% fish oil and 5% corn oil
      (FR). There was no effect of diet on food intake or final body weight. Serum
      triglyceride concentration for group R was higher (P<0.001) than for groups C,
      SR, and FR (7.20 vs. 2.50, 2.84, and 2.02 mmol/L, respectively); values for
      groups SR and FR did not differ for this parameter. The serum concentration of
      13cRA for group R did not differ from that for groups SR and FR. Thus, SPI was as
      effective as fish oil in reducing the severity of retinoid-induced
      hypertriglyceridemia in an animal model, suggesting that it may be effective for
      this purpose in human subjects.

PMID- 15023399
TI  - Effect of n-3 fatty acids on serum lipid levels and hepatic fatty acid metabolism
      in BALB/c.KOR-Apoeshl mice deficient in apolipoprotein E expression.
AB  - N-3 fatty acids exert a potent serum lipid-lowering effect in rodents mainly by
      affecting hepatic fatty acid oxidation and synthesis. However, it has been
      observed that fish oil and docosahexaenoic acid ethyl ester do not lower serum
      lipid levels in apolipoprotein E (apoE)-knockout (Apoetm1Unc) mice generated by
      gene targeting. To test the hypothesis that apoE expression is required for n-3
      fatty acid-dependent regulation of serum lipid levels and hepatic fatty acid
      metabolism, we examined the effect of fish oil and n-3 fatty acid ethyl esters on
      the activity and gene expression of hepatic enzymes involved in fatty acid
      oxidation and synthesis using an alternative apoE-deficient mouse model with the
      BALB/c genetic background (BALB/c.KOR-Apoeshl). ApoE-deficient mice were fed
      diets containing 9.4% palm oil, fish oil, or 5.4% palm oil and 1% EPA plus 3% DHA
      ethyl esters for 15 days. In contrast to the reported data on apoE-knockout mice,
      fish oil and n-3 fatty acid ethyl esters greatly decreased serum triacylglycerol,
      cholesterol, and phospholipid levels in the Apoeshl mice. The decreases were
      greater with fish oil than with ethyl esters. The alterations by dietary n-3
      fatty acids of serum lipid levels were accompanied by parallel changes in the
      activity and mRNA levels of enzymes involved in hepatic fatty acid oxidation and
      synthesis. The reason for the discrepancy between the results of the current
      study and previous studies is unknown. However, our study at least indicates that
      a lack of apoE expression does not necessarily accompany deficits in the n-3
      fatty acid-dependent regulation of serum lipid levels and hepatic fatty acid
      metabolism.

PMID- 15023400
TI  - Copper may interact with selenite extracellularly in cultured HT-29 cells.
AB  - Previous studies have demonstrated that copper (15.7 micromol/L) can inhibit
      selenite (12.6 micromol/L)-induced cytotoxicity and apoptosis in HT-29 cells.
      However, the exact nature of the interactions between selenium and copper is not
      fully understood. In this study, the effect of copper on the cell cycle arrest
      induced by selenite or selenocystine was examined. Both selenite and
      selenocystine were effective in inhibition of cell growth and cell cycle
      progression. Cell cycle analysis revealed that selenite (3-5 micromol/L) caused a
      decrease in G1 phase cells that corresponded with an increase in S and G2 phase
      cells, and that 0.625 or 1.25 micromol/L copper sufficiently inhibited selenite
      induced cell cycle arrest. In contrast, selenocystine caused an increase in G1
      phase cells that corresponded with a decrease in S and G2 phase cells.
      Interestingly, 0.625 or 1.25 micromol/L copper did not inhibit selenocystine
      induced cell cycle arrest. In addition, cell free gel shift assay demonstrated
      that selenite suppressed the inhibitory effect of copper on SP-1 DNA binding.
      Furthermore, although 5 micromol/L selenite in culture media significantly
      increased the intracellular selenium content, 1.25 micromol/L copper sulfate
      blocked this increase of the intracellular selenium content. Collectively, these
      data demonstrate that selenite and selenocystine cause cell cycle arrest via
      distinct mechanisms, and suggest that copper may interact with selenite
      extracellularly, which represents the basis of antagonism between copper sulfate
      and selenite.

PMID- 15023401
TI  - Proabsorptive effect of gum arabic in isotonic solutions orally administered to
      rats: effect on zinc and other solutes.
AB  - We have previously shown that the addition of gum arabic (GA) to oral rehydration
      solution (ORS) enhances water and electrolyte absorption during jejunal perfusion
      in rats under anesthesia. This study investigates whether GA by oral
      administration could be equally effective in rats. Isotonic solutions containing
      25 g/L GA (AG), or without GA (A0) were administered via oral tube to lightly
      anesthetized adult female rats. Similar experiments were conducted with
      hypertonic solutions containing no GA (B0), or either 10 (B10) or 50 g/L GA
      (B50). Blood concentrations of sodium, glucose, glutamate, zinc, and tritiated
      water were determined at 0, 15, 30, 60, 90, 120, and 180 minutes, and results
      between treatments were compared. Administration of the isotonic, GA-containing
      solution (AG) resulted in a higher blood zinc level than with the isotonic GA
      free solution (A0) from 15 minutes throughout 180 minutes. Blood zinc at 15
      minutes (means +/- SEM) was as follows: for A0: 69.3 +/- 2.0, for AG: 83.4 +/-
      3.5 nmol/L, P=0.002. At 180 minutes, A0: 52.6 +/- 1.8; AG: 68.1 +/- 4.6 nmol/L,
      P=0.004. The corresponding areas under the curve (AUC) were as follows: for A0:
      10,737 +/- 214; for AG: 13,919 +/- 765 nmol x min/L, P<0.001). Glucose,
      glutamate, sodium, and tritiated water body distribution presented no differences
      in blood concentrations. For sodium and tritiated water body distribution, there
      was a significant time effect (P<0.0001). In hypertonic solutions, blood zinc
      levels declined over time, possibly due to their osmotic, counter-absorptive
      action, thus obscuring possible opposite effects of GA. GA appears to be an
      effective enhancer of zinc absorption when orally administered in isotonic
      solutions to laboratory animals. This proabsorptive capacity could be attributed
      to some of the physicochemical and biochemical properties of GA and suggest
      possible applications of GA in liquid formulas and solid food preparations.

PMID- 15023402
TI  - Tumor immunology at the service of cancer immunotherapy.

PMID- 15023403
TI  - Current developments of immunotherapy in the clinic.
AB  - The clinical application of immunotherapy for cancer is rapidly moving forward in
      multiple areas, including the adoptive transfer of anti-tumor-reactive T cells
      and the use of 'therapeutic' vaccines. Recently, both clinical and immunological
      endpoints have shown improvement. Novel strategies designed in the laboratory and
      proven in preclinical animal tumor models are now entering the clinic, with the
      intent of enhancing current therapeutic efficacy. These novel strategies involve
      breaking tolerance to tumor self-antigens by inhibiting regulatory cells,
      boosting T-cell co-stimulation and using combinations of recombinant cytokines
      and other defined molecules with 'immuno-enhancing' activities.

PMID- 15023404
TI  - Identifying multiple tumor-specific epitopes from large-scale screening for
      overexpressed mRNA.
AB  - The rationale of a T-cell epitope-based approach to cancer treatment is primarily
      rooted in the hypothesis that CD8(+) cytotoxic T cells (CTLs) can be manipulated
      to specifically identify and kill cancer cells. A solid understanding of CTL
      specificity and activation is a fundamental requirement for tumor immunotherapy.
      The means to identify tumor-specific CTL epitopes and to monitor corresponding
      CTL responses are important enabling technologies. Recent advances in these
      enabling technologies include their ability to exploit genomic, transcriptomic
      and proteomic information. These advances constitute new opportunities, which
      will enable approaches to tumor immunotherapy that encompass both human diversity
      and tumor heterogeneity, increase the efficacy of tumor immunotherapy and
      potentially provide the opportunity for individualized therapy.

PMID- 15023405
TI  - Animal models of tumor immunity, immunotherapy and cancer vaccines.
AB  - Reliable animal models are critical for evaluating immunotherapies and for
      defining tumor immunology paradigms. Tumor immunologists are moving away from
      traditional transplantation tumor systems because they do not adequately model
      human malignancies. Transgenic mouse models in which tumors arise spontaneously
      have been developed for most cancers. The models use one of three technologies:
      tissue-specific promoters to drive expression of SV40 large T antigen or tissue
      specific oncogenes; deletion of tumor suppressor genes by gene targeting; or,
      conditional deletion of tumor suppressor genes or activation of oncogenes via Cre
      lox technology. Knockin mice expressing human tumor antigens and gene-targeted
      mice with deletions for immunologically relevant molecules have been integral to
      advancing knowledge of the tumor-host relationship. Although animal models are
      becoming more sophisticated, additional improvements are needed so that more
      realistic models can be developed.

PMID- 15023406
TI  - Aging, immunity and cancer.
AB  - Immunosenescence, the progressive decline in immune function that develops with
      age, results from cumulative alterations in critical B- and T-cell
      subpopulations. Decreases in circulating memory B cells and in germinal center
      formation are evident in the elderly, possibly due to diminished follicular
      dendritic-cell function. T-cell dysfunction is associated with reduced thymic
      generation of naive T cells, virus-induced expansion of terminal effectors and
      increased levels of memory cells producing type I and II cytokines. The diversity
      of the T-cell receptor repertoire is diminished by the first two changes, and
      elevated type I cytokines might contribute to the pro-inflammatory cytokine
      milieu present in the elderly.

PMID- 15023407
TI  - Immunoregulatory T cells in tumor immunity.
AB  - One mechanism of cancer immune evasion is the suppression of anti-tumor immunity
      by immunoregulatory T cells. Recent studies of these cells, especially
      CD4(+)CD25(+) T cells and NKT cells, have revealed molecular and cellular
      mechanisms of immunosuppression. Mouse studies have shown that either removing
      immunoregulatory T cells or blocking an immunoregulatory pathway induced by such
      cells unmasks natural tumor immunosurveillance and improves responses to cancer
      vaccines. Studies of the corresponding T-cell populations in human cancer
      patients support a similar role for immunoregulatory T cells in
      immunosuppression, implying that blocking immunoregulatory T-cell activity might
      improve the efficacy of tumor vaccines or the immunotherapy of cancer.

PMID- 15023408
TI  - Signals that regulate lymphocyte development and differentiation.

PMID- 15023410
TI  - Notch signaling in T- and B-cell development.
AB  - The Notch family of evolutionarily conserved proteins regulates a broad spectrum
      of cell-fate decisions and differentiation processes during fetal and post-natal
      development. The best characterized role of Notch signaling during mammalian
      hematopoiesis and lymphopoiesis is the essential function of the Notch1 receptor
      in T-cell lineage commitment. More recent studies have addressed the roles of
      other Notch receptors and ligands, as well as their downstream targets, revealing
      additional novel functions of Notch signaling in intra-thymic T-cell development,
      B-cell development and peripheral T-cell function.

PMID- 15023409
TI  - Lineage choices in the developing thymus: choosing the T and NKT pathways.
AB  - Thymic development proceeds through several defined stages that generate not only
      alpha beta and gamma delta T cells but can produce dendritic cells and B cells.
      The earliest thymocytes exist in the CD4(-)CD8(-) double negative compartment
      within a heterogeneous fraction termed DN1. Recent progress has identified
      several candidate populations that may be the bone fide T-cell progenitor
      population. The potential roles of these populations, which include hematopoietic
      stem cells, early lymphocyte precursors, common lymphoid progenitors, and early T
      lineage progenitors are being elucidated. The alpha beta T-cell lineage consists
      of distinct subsets, one of which is NKT cells. The developmental relationship of
      NKT cells to conventional T cells has been controversial. Recent work has shown
      that these cells are probably derived from CD4(+)CD8(+) thymocytes. The discovery
      and application of CD1d tetramers has made it possible to more fully describe NKT
      cell development.

PMID- 15023411
TI  - Cytokine functions in the formative stages of a lymphocyte's life.
AB  - Five core cytokines that control lymphocyte differentiation and maintenance have
      been identified and studied in depth. IL-7 sits at the apex of this cytokine
      hierarchy in terms of functional significance during lymphocyte development. The
      IL-7-dominant phase of lymphopoiesis is preceded by the actions of c-Kit ligand
      (also called stem cell factor; SCF) and fetal liver kinase 2 ligand (Flk-2L); the
      function of both of these cytokines is essential for the maintenance and
      development of the progenitor compartment of multiple lineages. IL-7 activity is
      complemented by two cytokines whose receptors share components of the IL-7
      receptor: thymic stromal lymphopoietin (TSLP) and IL-15. The influences of these
      core cytokines on precursor lymphocyte subsets overlap during development and are
      often synergistic. Recent studies are beginning to uncover the molecular
      mechanisms of these interrelated core cytokine functions.

PMID- 15023412
TI  - Signalling in T-lymphocyte development: integration of signalling pathways is the
      key.
AB  - alpha beta T-cell development is restricted to the thymus. Interactions between
      developing lymphocytes and the thymic stroma, together with bone-marrow-derived
      monocytes and dendritic cells, are critical for proper development of the T-cell
      lineage. The developmental sequence through which T-cell progenitors pass on
      their way to maturity is well established, and can be followed by the sequential
      acquisition and/or removal of cell surface molecules. Using the combination of
      modern genetic manipulations, such as transgenesis, gene ablation (knockouts) and
      targeted mutagenesis (knock-ins), with the ever-improving conditional and
      inducible manipulation of gene expression, we are beginning to gain an
      understanding of how intercellular interactions can be relayed via intracellular
      signalling cascades to bring about nuclear re-organisation and the differentiated
      mature CD4(+) and CD8(+) subpopulations.

PMID- 15023413
TI  - Good riddance: Thymocyte clonal deletion prevents autoimmunity.
AB  - Clonal deletion is arguably the most important mechanism of eliminating self
      reactive thymocytes from the T-cell repertoire. Recent work has identified new
      players in this process. On the thymocyte side, several molecules have been newly
      implicated in the pathway from initial T-cell receptor signaling through to the
      final result: gene transcription and thymocyte apoptosis. In addition, several
      proapoptotic molecules have been found to be necessary for the death of self
      reactive thymocytes. On the antigen-presenting cell side, the expression of
      peripheral self-antigens, regulated at least in part by the autoimmune regulator
      (AIRE) protein, is crucial for complete elimination of autoreactive thymocytes.
      The importance of thymic peripheral antigen expression and clonal deletion to
      self-tolerance is demonstrated in the autoimmune diseases autoimmune
      polyendocrinopathy-candidiasis-ectodermal dystrophy and type-1 diabetes mellitus.

PMID- 15023414
TI  - Development and function of CD25+CD4+ regulatory T cells.
AB  - The essential role played by CD25(+)CD4(+) regulatory T cells (T(R) cells) in the
      control of physiological as well as pathological immunity is now well
      established, but many aspects of their biology still remain unclear. One of the
      unresolved issues regards their development: where does this occur, what signals
      are required, and how do T(R) cells fit into the larger taxonomy of the T-cell
      family? Recent data has begun to shed light on the development and function of
      these important cells.

PMID- 15023415
TI  - T-cell anergy.
AB  - Self-reactive T cells that escape negative selection in the thymus must be
      inactivated in the periphery. Anergy constitutes one means of imposing peripheral
      tolerance. Anergic T cells are functionally inactivated and unable to initiate a
      productive response even when antigen is encountered in the presence of full co
      stimulation. Recent studies have provided new insights into the mechanisms
      responsible for the induction and maintenance of T-cell anergy. These studies
      have helped clarify the nature of the signals that induce tolerance, the cells
      able to deliver them and the molecular processes that underlie the unresponsive
      state.

PMID- 15023416
TI  - The role of programming in memory T-cell development.
AB  - Recent studies suggest that memory T-cell differentiation continues for weeks or
      months following antigen clearance, although commitment to the memory lineage
      occurs during the effector stage of development. Several variables associated
      with priming, such as the duration of antigenic stimulation, degree of co
      stimulation, cytokine environment, and CD4(+) T-cell help, may program epigenetic
      qualitative differences into the ensuing effector and memory populations.
      Defining what memory qualities best protect the organism from re-infection, as
      well as how commitment to the memory lineage is specified following T-cell
      activation remains an important goal.

PMID- 15023417
TI  - Plasma cell differentiation and multiple myeloma.
AB  - Microarray analyses and gene targeting have recently enhanced the understanding
      of factors involved in normal plasma cells and multiple myeloma. Plasma cells
      develop from marginal zone or germinal center B cells following stimulation by
      antigen, microbial products, TNF family signals and cytokines. Transcription
      factors, B-lymphocyte-induced maturation protein 1 (Blimp-1) and X-box binding
      protein 1 (XBP-1) are required for plasma cell development. They regulate sets of
      genes that induce immunoglobulin secretion, halt proliferation and block
      alternative B-cell fates. In multiple myeloma, transforming events lead to
      proliferation and survival, but programs for plasma cell differentiation and the
      inhibition of B-cell genes appear to be largely intact.

PMID- 15023418
TI  - Mechanisms for feedback inhibition of the immunoglobulin heavy chain locus.
AB  - The production of immunoglobulin heavy chain (IgH) protein in pro-B cells
      provides feedback to terminate further V(H) gene recombination. This phenomenon
      is referred to as allelic exclusion. The chromatin structure of the V(H) genes
      regulates their recombination potential, hence alterations in chromatin are a key
      factor in allelic exclusion. In pro-B cells, IL-7/IL-7R signaling induces histone
      hyperacetylation and nuclease accessibility of the largest family of V(H) genes
      (J558) and potentially activates these genes for recombination. Loss of these
      signals in the later stages of B-cell development reverts the V(H)J558 gene
      segments to a less accessible state, making them recombinationally refractive.
      This provides a molecular mechanism for allelic exclusion of these genes. Similar
      transient signals may be responsible for enforcing allelic exclusion in other
      V(H) gene families. D-proximal V(H) genes, however, appear to be less susceptible
      to feedback inhibition.

PMID- 15023419
TI  - The regulation of somatic hypermutation.
AB  - Somatic hypermutation and class switch recombination cause genetic alterations in
      immunoglobulin (Ig) genes, which underlie the generation of the secondary
      antibody repertoire in B lymphocytes. Both processes require activation-induced
      cytidine deaminase (AID), whose mechanism of action in not yet known in detail,
      but which mediates the accumulation of point mutations in the Ig locus. This
      highly mutagenic process must be tightly controlled, and multiple levels of
      regulation might exist. Recent experiments show that AID deaminates deoxycytidine
      to deoxyuridine in single-stranded DNA. This mutagenic event is targeted to
      actively transcribed sequences, and the specificity of deamination might be
      related to the chromatin structure of the transcription complex.

PMID- 15023420
TI  - Regulation of B-cell development by antibody specificity.
AB  - Although autoantigen-induced negative selection plays an important role in
      shaping the mature B-cell repertoire, studies in recent years have suggested that
      differentiation into any of the three mature B-cell subsets (marginal zone B
      cells, follicular B cells and B-1 B cells) is not a passive product of
      autoreactive B-cell elimination. Instead, evidence suggests that entry into a
      mature subset involves active B-cell receptor signaling and self-antigen-mediated
      positive selection.

PMID- 15023421
TI  - Survival signaling in resting B cells.
AB  - The survival of mature resting B cells in the periphery depends on signaling from
      the B-cell receptor (BCR) and the B-cell activating factor of the TNF family
      receptor (BAFF-R). Engagement of both receptors promotes NF-kappa B activity,
      which contributes to B-cell survival through different pathways. BCR signaling
      leads to activation of the inhibitor of NF-kappa B kinase (IKK) complex via
      Carma1, Bcl10 and MALT1, whereas BAFF-R engagement promotes processing of NF
      kappa B2 protein p100, which is dependent on NF-kappa B-inducing kinase (NIK) and
      IKK alpha. Proximal signaling intermediates are potentially common to both
      pathways. We suggest that BCR and BAFF-R survival signaling are mutually
      dependent. In addition, we propose that BAFF-R signaling enhances the expression
      of survival genes through direct chromatin modifications in NF-kappa B target
      gene promoters.

PMID- 15023422
TI  - The role of antifungal susceptibility testing in the therapy of candidiasis.
AB  - Prior to the introduction of azoles, no real need for antifungal susceptibility
      testing (AFST) existed, as amphotericin B was the only agent available to treat
      systemic candidiasis. Introduction of fluconazole and itraconazole provided
      alternate, less toxic antifungal therapies. Intrinsic resistance of Candida
      krusei, decreased susceptibility of Candida glabrata, and development of
      resistance by Candida albicans (in mucosal disease in AIDS) to azoles led to
      development of our current AFST methodologies. The goal of AFST, like that of
      antibacterial susceptibility testing, is to predict clinical response, or at
      least to forecast failure. Although the ability of AFST to predict clinical
      outcome (clinical correlation) is still being fully elucidated, current
      methodologies do appear to reliably predict clinical resistance to azoles. Ready
      access to AFST is currently limited, affecting its timely use, but even with this
      lack of timeliness, AFST can still play an important role in patient care.
      Important potential roles include: 1) use in the development of local
      antibiograms to aid empiric selection of antifungals; 2) testing of isolates from
      candidemia or deep infection to aid in selection of long-term therapies; and, 3)
      the testing of isolates from recurrent mucosal disease to aid in selection of
      alternative regimens.

PMID- 15023424
TI  - Spread of bla(VIM-1)-producing E. coli in a university hospital in Greece.
      Genetic analysis of the integron carrying the bla(VIM-1) metallo-beta-lactamase
      gene.
AB  - Bla(VIM-1) gene was detected in four Escherichia coli clinical isolates with both
      reduced susceptibility to carbapenems and an ESBL phenotype. The VIM-1
      determinant was located within the variable region of a Class I integron along
      with a 6'-N-aminoglycoside acetyltransferase gene (aac(6')-Ib) and it could be
      transferred by conjugation. In all four clinical isolates the VIM-1 gene cassette
      presented a characteristic duplication of the 3' end coding 153 nucleotides
      followed by the first 14 nucleotides of the 59 base element (59be) that however
      did not seem to affect either the integrity of the coding sequence or the 59be of
      the gene cassette. These clinical isolates not only harbored the same Class I
      integron, but they also shared the same discrete ribotype-pattern, indicative for
      their clonal origin. Spread of carbapenem resistance genes among
      Enterobacteriaceae in hospital is a matter of great concern.

PMID- 15023423
TI  - Central nervous system infections due to Abiotrophia and Granulicatella species:
      an emerging challenge?
AB  - Although Abiotrophia and Granulicatella species, previously referred to as
      nutritionally variant streptococci, were initially identified over 40 years ago,
      isolation of these pathogens from the central nervous system (CNS) was first
      noted only recently. Recognition of CNS involvement with these organisms is of
      great concern given the association of Abiotrophia/Granulicatella infections with
      increased morbidity and mortality as well as greater bacteriologic failure and
      relapse rates. We describe A. defectiva and G. adiacens CNS infections in two
      patients and review the existing literature of CNS involvement with these
      bacteria. The clinical presentation and initial cerebrospinal fluid analysis has
      varied substantially across reported patients. While most infections have been
      characterized primarily by a localized infection (e.g., abscess), evidence of
      meningitis has usually also been present. Furthermore, nearly all cases have
      followed neurosurgical procedures suggesting possible introduction of the
      organism into the CNS at the time of surgery. Given the significant negative
      clinical impact of Abiotrophia/Granulicatella infections, elucidation of the
      emerging epidemiology of CNS infections with these bacteria is warranted.

PMID- 15023425
TI  - What happens when automated blood culture instrument detect growth but there are
      no technologists in the microbiology laboratory?
AB  - We investigated blood cultures that revealed growth at night when no
      technologists were in the microbiology laboratory and at other times when the
      laboratory was staffed. On average, it took 7 h and 26 min and 2 h and 12 min for
      laboratory personnel to report positive blood culture Gram stain results to
      physicians when growth was detected by automated instruments during the former
      and latter time periods, respectively. When positive blood culture results led to
      a change in therapy, it took an average of 8 h and 21 min and 5 h and 26 min in
      the former and latter groups, respectively, from detection to when the order was
      written.

PMID- 15023426
TI  - Molecular characterization of the integrons in Shigella strains isolated from
      patients with traveler's diarrhea.
AB  - The prevalence and characterization of Class 1 integrons has been performed in
      eighty three strains of Shigella spp., isolated between 1995 and 2000 from
      patients with traveler's diarrhea. A low prevalence (13.25%) was recorded. Nine
      different integrons were found among 11 multiresistant strains, with a total of
      10 different gene cassettes encoding for resistance to trimethoprim (dfrA1,
      dfrA5, dfrA7, dfrA12, and dfrA15), aminoglycosides (aadA1a and aadA2), beta
      lactam antibiotics (oxa2) or ORF with unknown function (orfD and orfF). A high
      prevalence of dfr and aad gene cassettes was observed. The low incidence of Class
      1 integrons observed in this study is in contrast with the known facility that
      the Shigella genus has to gain and transfer plasmids.

PMID- 15023427
TI  - Evaluation of an impedance method for subtyping of Pseudomonas aeruginosa.
AB  - Eight isolates (no. 1 to 8) of Pseudomonas aeruginosa isolated from 8 burn
      patients were typed by pulsed-field gel electrophoresis (PFGE), arbitrarily
      primed polymerase chain reaction (PCR) (AP-PCR), biotyping, antimicrobial
      susceptibility testing, and a newly developed technique-impedance method. By both
      PFGE and AP-PCR, isolates 1 and 2 were designated type A, while isolates 3 to 8
      were designated type B. However, isolates 3 to 8 could be further divided into
      three distinct subtypes (B, C, and D) by the impedance method. Four antibiograms
      were obtained by testing the 8 isolates against six antimicrobial agents and
      designation of antibiogram to each of the 8 isolates was in accordance with those
      obtained by the impedance method. The results of biotyping did not agree with any
      of the above typing methods. In conclusion, the impedance technique had a high
      discriminatory ability to differentiate genetically related clones into subtypes.
      The method is simple, reproducible, and has a high typeability.

PMID- 15023428
TI  - Effect of trimethoprim-sulfamethoxazole prophylaxis in AIDS patients on the
      formation of the small colony variant phenotype of Staphylococcus aureus.
AB  - Emergence of Staphylococcus aureus small colony variants (SCVs) has been
      associated with antibiotic use, particularly with trimethoprim-sulfamethoxazole
      (TMP-SMZ). In this study, 634 specimens of 125 patients with AIDS were
      prospectively screened for S. aureus with normal phenotype and for S. aureus
      SCVs. Charts of these patients were reviewed for previous prophylaxis with TMP
      SMZ often used as long-term pneumocystosis prophylaxis. Thirty-seven patients
      (29.6%) harbored S. aureus in their anterior nares, three of these patients
      (8.1%) had S. aureus SCVs. Interestingly, TMP-SMZ does not appear to select for
      S. aureus SCVs in nasal swabs of these patients.

PMID- 15023429
TI  - PCR detection and identification of oral streptococci in saliva samples using gtf
      genes.
AB  - Oral streptococci are major constituents of dental plaque, and their prevalence
      is implicated in various pathologies. Therefore, accurate identification of oral
      streptococci would be valuable for studies of cariogenic plaque and for
      diagnostic use in infective endocarditis. Many oral streptococci possess
      glucosyltransferase enzymes that synthesize glucan, which is an obligate
      component of dental plaque. We established a rapid and precise method to identify
      oral streptococci by PCR using the species-specific region from the
      glucosyltransferase gene. With the species-specific primers, Streptococcus
      mutans, S. sobrinus, S. salivarius, S. sanguinis, S. oralis, and S. gordonii
      could be successfully distinguished. Further, we developed a simple method to
      extract the bacterial DNA from saliva. Using the resultant DNA as a template, the
      proposed PCR detection was performed. Their distribution was in accord with
      results of conventional biochemical tests. These findings indicate that the
      present PCR method is useful for the analysis of oral streptococci and can be
      successfully used in clinical applications to identify pathogenic bacteria
      associated with oral infectious disease and/or endocarditis.

PMID- 15023430
TI  - In vitro activities of voriconazole, posaconazole, and fluconazole against 4,169
      clinical isolates of Candida spp. and Cryptococcus neoformans collected during
      2001 and 2002 in the ARTEMIS global antifungal surveillance program.
AB  - We examined the in vitro activities of voriconazole, posaconazole, and
      fluconazole against 3,932 isolates of Candida spp. and 237 isolates of
      Cryptococcus neoformans obtained from over 100 medical centers worldwide during
      2001 and 2002. The MICs of the antifungal drugs were determined by broth
      microdilution tests performed according to the National Committee for Clinical
      Laboratory Standards (NCCLS) methods using RPMI 1640 as the test medium.
      Voriconazole and posaconazole were very active against Candida spp. (97-98%
      susceptible at MICs < or =1 microg/ml) and C. neoformans (98-100% susceptible at
      MICs < or =1 microg/mL). C. albicans (MIC90, 0.015-0.03 microg/ml) was the most
      susceptible species of Candida to both agents and C. glabrata (MIC90, 1-2
      microg/mL) was the least susceptible. Both voriconazole and posaconazole were
      more active than fluconazole against all Candida spp. and C. neoformans. These
      results provide further evidence for the increased spectrum and potency of the
      new triazoles against a large and geographically diverse collection of
      opportunistic fungal pathogens.

PMID- 15023431
TI  - Susceptibility testing of Singapore strains of Mycoplasma hominis to
      tetracycline, gatifloxacin, moxifloxacin, ciprofloxacin, clindamycin, and
      azithromycin by the Etest method.
AB  - The minimal inhibitory concentrations of tetracycline, gatifloxacin,
      moxifloxacin, ciprofloxacin, clindamycin and azithromycin for 28 Singapore
      clinical Mycoplasma hominis strains were studied using the Etest method.
      Different incubation conditions did not affect susceptibility categories, except
      for tetracycline intermediate-susceptibility strains. Tetracycline-susceptibility
      was only 35.7%. All strains were susceptible to the fluoroquinolones and
      clindamycin but resistant to azithromycin.

PMID- 15023432
TI  - The status of antimicrobial resistance in Taiwan among gram-negative pathogens:
      the Taiwan surveillance of antimicrobial resistance (TSAR) program, 2000.
AB  - In a nationwide surveillance of antimicrobial resistance (Taiwan Surveillance of
      Antimicrobial Resistance, TSAR), isolates were collected from 21 medical centers
      and regional hospitals throughout Taiwan over a three-month period in 2000 (TSAR
      II). This report summarizes susceptibility data of 7 common Gram-negative bacilli
      (Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Proteus mirabilis,
      Enterobacter cloacae, Pseudomonas aeruginosa, and Acinetobacter baumannii) in the
      TSAR II collection and compared selected key forms of resistance by epidemiologic
      factors and with isolates collected in 1998 (TSAR I) as well as with data from
      international surveillance studies. Resistance of the 5 Enterobacteriaceae
      species to most of the commonly prescribed "first-line" antimicrobials in Taiwan,
      such as ampicillin (78% in E. coli, 68% in P. mirabilis), gentamicin (19% in K.
      pneumonia to 66% in S. marcescens), and trimethoprim/sulfamethoxazole (29% in K.
      pneumoniae to 70% in P. mirabilis), was high, several of which are higher than
      other countries. Resistance to certain broad-spectrum antimicrobials is also more
      acute in Taiwan than most Western countries, such as ceftazidime resistant A.
      baumannii (73%) and ciprofloxacin resistant E. coli (12%). Differences in
      geographic regions and specimen types were associated with certain forms of
      resistance in TSAR II; however, the resistance problem is prevalent among both
      inpatients and outpatients of not only medical centers but also regional
      hospitals throughout Taiwan.

PMID- 15023434
TI  - Radiolabeled antibody therapy in non-Hodgkins lymphoma: radiation protection,
      isotope comparisons and quality of life issues.
AB  - Anti-CD20 antibodies radiolabeled with I-131 tositumomab (Bexxar) or Y-90
      Ibritumomab tiuxetan (Zevalin), are similarly efficacious in treating
      chemotherapy-refractory non-Hodgkin's lymphoma. The relative merits of both
      radioimmunoconjugates with respect to practical issues, including radiation
      exposure risk, the advantages and disadvantages of the respective isotopes and
      other parameters that could affect a patient's quality of life are also
      important. I-131-labeled antibody treatment often requires inpatient
      hospitalization due to the inherent risk of exposure from gamma emissions, and
      patients and families should follow detailed instructions to prevent undue
      exposure. Other issues relevant to patients and medical staff include: (1) the
      need for dosimetry to calculate effective therapeutic doses of I-131-labeled anti
      B1 (Bexxar) compared with the lack of correlation of dosimetry with marrow
      toxicity for IDEC-Y2B8 (Zevalin), (2) determining the acute and long-term toxic
      effects of each agent, (3) time commitments for nuclear medicine staff and
      patients along with the relative ease of administration, and (4) cost
      considerations. A more challenging future issue will be to determine the optimal
      use of Bexxar and Zevalin alone and in combination in ways that will
      significantly affect patient outcome without compromising quality of life. The
      recent demonstration of significant response rates in patients having
      chemotherapy-refractory Non-Hodgkin's Lymphoma (NHL) using both on I-131- and Y
      90-labeled anti-CD20 antibodies with minimal toxicity has stimulated comparison
      of I-131 tositumomab (Bexxar) and Ibritumomab tiuxetan (Zevalin) in terms of
      radiation safety requirements, the advantages and disadvantages of both
      radionuclides, and quality-of-life (QOL) issues. Therefore, in this review, we
      attempt to compare the relative merits of (Bexxar and Zevalin) and address
      important practical considerations that may influence patient and physician
      choices regarding treatment using these agents.

PMID- 15023433
TI  - Cervical lymph node metastases of squamous cell carcinoma from an unknown
      primary.
AB  - Cervical lymph node metastases of squamous cell carcinoma from occult primary
      constitute about 2-5% of all patients with carcinoma of unknown primary site
      (CUP). Metastases in the upper and middle neck are generally attributed to head
      and neck cancers, whereas the lower neck (supraclavicular area) involvement is
      often associated with primary malignancies below the clavicles. The diagnostic
      procedures include physical examination with thorough evaluation of the head and
      neck mucosa using fiber-optic endoscopy, biopsies from all suspicious sites or
      blindly from the sites of possible origin of the primary, computer tomography
      and/or magnetic resonance. A systematic tonsillectomy in the absence of
      suspicious lesions is often recommended since up to 25% of primary tumors can be
      detected in this site. The thoracic primary (tracheal, bronchial, lung,
      esophagus) has to be excluded, especially in the case of lower neck involvement.
      Positron emission tomography (PET) with fluoro-2-deoxy-D-glucose allows detection
      of primary tumor in about 25% of cases, but this procedure is still considered
      investigational. Therapeutic approaches include surgery (lymph node excision or
      neck dissection), with or without postoperative radiotherapy, radiotherapy alone
      and radiotherapy followed by surgery. In early stages (N1), neck dissection and
      radiotherapy seem to have similar efficacy, whereas more advanced cases (N2, N3)
      necessitate combined approaches. The extent of radiotherapy (irradiation of
      bilateral neck and mucosa versus ipsilateral neck radiotherapy) remains
      debatable. A potential benefit from extensive radiotherapy should be weighted
      against its acute and late morbidity and difficulties in re-irradiation in the
      case of subsequent primary emergence. The role of other methods, such as
      chemotherapy and hyperthermia, remains to be determined.

PMID- 15023435
TI  - Male fertility preservation and cancer treatment.
AB  - The diagnosis of cancer in men or women leads to prompt evaluation of the extent
      of the cancer, its treatment, and subsequent prognosis. However, relatively
      little emphasis is placed on fertility following the completion of therapy. As
      the effectiveness of cancer treatment has improved, men can enjoy a longer life
      that is free of cancer. However, chemotherapeutic regimens alone or in
      combination with radiation therapy frequently result in azoospermia or
      infertility. This paper reviews available methods to maintain male fertility in
      patients undergoing chemotherapy or radiation therapy. Certain chemotherapeutic
      agents that are less likely to cause azoospermia may be incorporated into
      potentially curative therapies. Hormonal suppression applied early (prior to) and
      during chemotherapy may protect future male fertility. Alternatively,
      cryopreservation of sperm enables men to reproduce in the future with the
      assistance of in vitro fertilization with intracytoplasmic sperm injection.
      Therefore, oncologists need to discuss male fertility preservation before
      initiating cancer treatment in reproductive-aged men. The emphasis for future
      cancer treatment and its research regarding male fertility preservation needs
      further attention.

PMID- 15023436
TI  - Cardiotoxicity of cytotoxic drugs.
AB  - Cardiotoxicity is a well-known side effect of several cytotoxic drugs, especially
      of the anthracyclines and can lead to long term morbidity. The mechanism of
      anthracycline induced cardiotoxicity seems to involve the formation of free
      radicals leading to oxidative stress. This may cause apoptosis of cardiac cells
      or immunologic reactions. However, alternative mechanisms may play a role in
      anthracycline induced cardiotoxicity. Cardiac protection can be achieved by
      limitation of the cumulative dose. Furthermore, addition of the antioxidant and
      iron chelator dexrazoxane to anthracycline therapy has shown to be effective in
      lowering the incidence of anthracycline induced cardiotoxicity. Other cytotoxic
      drugs such as 5-fluorouracil, cyclophosphamide and the taxoids are associated
      with cardiotoxicity as well, although little is known about the possible
      mechanisms. Recently, it appeared that some novel cytotoxic drugs such as
      trastuzumab and cyclopentenyl cytosine also show cardiotoxic side effects.

PMID- 15023437
TI  - PI3K/Akt signalling pathway and cancer.
AB  - Phosphatidylinositol-3 kinases, PI3Ks, constitute a lipid kinase family
      characterized by their ability to phosphorylate inositol ring 3'-OH group in
      inositol phospholipids to generate the second messenger phosphatidylinositol
      3,4,5-trisphosphate (PI-3,4,5-P(3)). RPTK activation results in PI(3,4,5)P(3) and
      PI(3,4)P(2) production by PI3K at the inner side of the plasma membrane. Akt
      interacts with these phospholipids, causing its translocation to the inner
      membrane, where it is phosphorylated and activated by PDK1 and PDK2. Activated
      Akt modulates the function of numerous substrates involved in the regulation of
      cell survival, cell cycle progression and cellular growth. In recent years, it
      has been shown that PI3K/Akt signalling pathway components are frequently altered
      in human cancers. Cancer treatment by chemotherapy and gamma-irradiation kills
      target cells primarily by the induction of apoptosis. However, the development of
      resistance to therapy is an important clinical problem. Failure to activate the
      apoptotic programme represents an important mode of drug resistance in tumor
      cells. Survival signals induced by several receptors are mediated mainly by
      PI3K/Akt, hence this pathway may decisively contribute to the resistant
      phenotype. Many of the signalling pathways involved in cellular transformation
      have been elucidated and efforts are underway to develop treatment strategies
      that target these specific signalling molecules or their downstream effectors.
      The PI3K/Akt pathway is involved in many of the mechanisms targeted by these new
      drugs, thus a better understanding of this crossroad can help to fully exploit
      the potential benefits of these new agents.

PMID- 15023439
TI  - Inadvertent omission of reference and credit to RJ Albin, et al, and the initial
      identification of prostate-specific antigen.

PMID- 15023438
TI  - The role of HPV DNA testing in the follow-up period after treatment for CIN: a
      systematic review of the literature.
AB  - BACKGROUND: There is an emerging interest concerning the role HPV DNA testing in
      the follow-up period after conservative treatment for cervical intraepithelial
      neoplasia. METHODS: A MEDLINE and EMBASE search was done (1985 to March 2002),
      using the keywords HPV/HPV DNA, together with CIN, follow-up, recurrence and
      LLETZ. References of retrieved articles were also screened. Selection criteria
      were original published English-language reports of prospective or retrospective
      studies, including women with an initial diagnosis of cervical intraepithelial
      neoplasia, who received conservative surgical treatment and were followed with
      HPV DNA testing in addition to cytology, colposcopy and/or biopsy); the latter
      methods were used for verification of residual or recurrent disease. RESULTS:
      There is a marked heterogeneity in the design, population, intervention and
      follow-up policy across different studies. The sensitivity of HPV DNA testing in
      detecting treatment failures was quite good in most studies, reaching 100% in
      four of them, whereas the specificity of the test differed across the studies,
      ranging from 44% to 95%. Among women in whom the treatment was considered to be
      successful, 84.2% had a negative postoperative HPV DNA test and 15.8% a positive
      one. The corresponding rates for cases with treatment failures were 17.2% and
      82.8%, respectively. CONCLUSIONS: It seems that a positive HPV test, even in the
      presence of normal cytology, may pick up early and accurately a treatment
      failure. Cytology and colposcopy may still be needed in order to rule out false
      positive and false negative results. MINI-ABSTRACT: A systematic review of
      studies concerning HPV DNA testing in the follow-up period after conservative
      treatment for cervical intraepithelial neoplasia indicates that a positive HPV
      test, even in the presence of normal cytology, may pick up early and accurately a
      treatment failure. Cytology and colposcopy may still be needed in order to rule
      out false positive and false negative results.

PMID- 15023440
TI  - Clinical effectiveness of radiotherapy for Hodgkin's lymphoma: a summary.

PMID- 15023441
TI  - Clinical effectiveness of radiotherapy for non-Hodgkin's lymphoma: a summary.

PMID- 15023442
TI  - Clinical effectiveness of radiotherapy for breast cancer: a summary.

PMID- 15023443
TI  - Evaluation of a model for leaf to fruit transfer of radionuclides in processing
      tomato plants using an independent set of data.
AB  - Because of their varied possibilities of consumption, tomatoes are an important
      component of the human diet. This paper presents results of the evaluation of a
      dynamic model (Ventomod) for the short-term behaviour of radionuclides deposited
      on tomato plants following a direct contamination event. To check its forecasting
      capability in assessing the risk of radionuclide contamination of the human diet,
      it has been tested with an independent dataset on the leaf to fruit transfer of
      134Cs in a typical Hungarian tomato variety, "Dwarf of Kecskemet". Data obtained
      from this pot experiment were used to evaluate model behaviour. Model constants
      were varied according to the differences between the Hungarian dataset and the
      one used to calibrate it. Results show that the model output well reproduces the
      observed activity of fruits for various levels of contamination and at different
      contamination dates. The main part of this report summarises the experimental
      protocol, compares the experimental results with model predictions generated by
      Ventomod and makes recommendations for both updating model parameters and
      undertaking further experimental work.

PMID- 15023444
TI  - Modelling the vertical distribution of radionuclides in soil. Part 1: the
      convection-dispersion equation revisited.
AB  - The convective-dispersive transport and linear sorption model is discussed for
      the vertical migration of radionuclides in soil. An alternative procedure of
      solving the corresponding system of partial differential equations is presented
      as well as the special solution for the pulse-like fallout initial condition.
      Idealizations and simplifications of the model and properties of the solution are
      discussed. The model is fitted to a set of 528 measured radionuclide soil
      profiles and the resulting model parameters, apparent convection velocity v and
      apparent dispersion constant D, are evaluated statistically. Typical orders of
      magnitude of the velocities and the diffusion constants of Chernobyl-134Cs are
      0.3 cm/year and 0.3 cm2/year, respectively. The mobilities of the radionuclides
      are ranked as 137Cs (global fallout) < 134Cs < 106Ru, 125Sb. Significant regional
      differences (related to different soils and geological properties below ground)
      of v and D exist. These analyses also indicate that v and D are not mere fitting
      parameters, but can be given a real physical interpretation. While in most cases,
      the convection-dispersion equation (CDE) model produces good descriptions for
      near-surface soil layers, potentially important limitations are its failure to
      describe "young" profiles shortly after fallout.

PMID- 15023445
TI  - Environmental characterization and radio-ecological impacts of non-nuclear
      industries on the Red Sea coast.
AB  - The Red Sea is a deep semi-enclosed and narrow basin connected to the Indian
      Ocean by a narrow sill in the south and to the Suez Canal in the north. Oil
      industries in the Gulf of Suez, phosphate ore mining activities in Safaga-Quseir
      region and intensified navigation activities are non-nuclear pollution sources
      that could have serious radiological impacts on the marine environment and the
      coastal ecosystems of the Red Sea. It is essential to establish the radiological
      base-line data, which does not exist yet, and to investigate the present radio
      ecological impact of the non-nuclear industries to preserve and protect the
      coastal environment of the Red Sea. Some natural and man-made radionuclides have
      been measured in shore sediment samples collected from the Egyptian coast of the
      Red Sea. The specific activities of 226Ra and 210Pb (238U) series, 232Th series,
      40K and 137Cs (Bq/kg dry weight) were measured using gamma ray spectrometers
      based on hyper-pure germanium detectors. The specific activities of 210Po (210Pb)
      and uranium isotopes (238U, 235U and 234U) (Bq/kg dry weight) were measured using
      alpha spectrometers based on surface barrier (PIPS) detectors after radiochemical
      separation. The absorbed radiation dose rates in air (nGy/h) due to natural
      radionuclides in shore sediment and radium equivalent activity index (Bq/kg) were
      calculated. The specific activity ratios of 228Ra/226Ra, 210Pb/226Ra, 226Ra/238U
      and 234U/238U were calculated for evaluation of the geo-chemical behaviour of
      these radionuclides. The average specific activity of 226Ra (238U) series, 232Th
      series, 40K and 210Pb were 24.7, 31.4, 427.5 and 25.6 Bq/kg, respectively. The
      concentration of 137Cs in the sediment samples was less than the lower limit of
      detection. The Red Sea coast is an arid region with very low rainfall and the
      sediment is mainly composed of sand. The specific activity of 238U, 235U and 234U
      were 25.3, 2.9 and 25.0 Bq/kg. The average specific activity ratios of
      226Ra/228Ra, 210Pb/226Ra and 234U/238U were 1.67, 1.22 and 1.0, respectively. The
      relationship between 226Ra/228Ra activity ratio and sample locations along the
      coastal shoreline indicates the increase of this ratio in the direction of the
      Shuqeir in the north and Safaga in the south where the oil exploration and
      phosphate mining activities are located. These activities may contribute a high
      flux of 226Ra. The concentration and distribution pattern of 226Ra in sediment
      can be used to trace the radiological impact of the non-nuclear industries on the
      Red Sea coast.

PMID- 15023446
TI  - Application of the Weibull extrapolation to 137Cs geochronology in Tokyo Bay and
      Ise Bay, Japan.
AB  - Considerable doubt surrounds the nature of processes by which 137Cs is deposited
      in marine sediments, leading to a situation where 137Cs geochronology cannot be
      always applied suitably. Based on extrapolation with Weibull distribution, the
      maximum concentration of 137Cs derived from asymptotic values for cumulative
      specific inventory was used to re-establish 137Cs geochronology, instead of
      original 137Cs profiles. Corresponding dating results for cores in Tokyo Bay and
      Ise Bay, Japan, by means of this new method, are in much closer agreement with
      those calculated from 210Pb method than the previous method.

PMID- 15023447
TI  - Resolving Chernobyl vs. global fallout contributions in soils from Poland using
      Plutonium atom ratios measured by inductively coupled plasma mass spectrometry.
AB  - Plutonium in Polish forest soils and the Bor za Lasem peat bog is resolved
      between Chernobyl and global fallout contributions via inductively coupled plasma
      mass spectrometric measurements of 240Pu/230Pu and 241Pu/239Pu atom ratios in
      previously prepared NdF3 alpha spectrometric sources. Compared to global fallout,
      Chernobyl Pu exhibits higher abundances of 240Pu and 241Pu. The ratios
      240Pu/230Pu and 241Pu/239Pu co-vary and range from 0.186 to 0.348 and 0.0029 to
      0.0412, respectively, in forest soils (241Pu/239Pu = 0.2407 x [240Pu/239Pu] -
      0.0413; r2 = 0.9924). Two-component mixing models are developed to apportion
      239+240Pu and 241Pu activities; various estimates of the percentage of Chernobyl
      derived 239+240Pu activity in forest soils range from < 10% to > 90% for the
      sample set. The 240Pu/230Pu - 241Pu/239Pu atom ratio mixing line extrapolates to
      estimate 241Pu/239Pu and the 241Pu/239+240Pu activity ratio for the Chernobyl
      source term (0.123 +/- 0.0007; 83 +/- 5; 1 May 1986). Sample 241Pu activities,
      calculated using existing alpha spectrometric 239+240Pu activities, and the
      240Pu/230Pu and 241Pu/239Pu atom ratios, agree relatively well with previous
      liquid scintillation spectrometry measurements. Chernobyl Pu is most evident in
      locations from northeastern Poland. The 241Pu activities and/or the 241Pu/239Pu
      atom ratios are more sensitive than 240Pu/239Pu or 238Pu/239+240Pu activity
      ratios at detecting small Chernobyl 239+240Pu inputs, found in southern Poland.
      The mass spectrometric data show that the 241Pu activity is 40-62% Chernobyl
      derived in southern Poland, and 58-96% Chernobyl in northeastern Poland. The Bor
      za Lasem peat bog (49.42 degrees N, 19.75 degrees E), located in the Orawsko
      Nowotarska valley of southern Poland, consists of global fallout Pu.

PMID- 15023448
TI  - Conclusions on plutonium separation from atmospheric krypton-85 measured at
      various distances from the Karlsruhe reprocessing plant.
AB  - For wide-area atmospheric monitoring, krypton-85 is the best indicator for
      clandestine plutonium separations. The detection and false alarm rates were
      determined from weekly samples at five different distances from the Karlsruhe
      reprocessing plant between 1985 and 1988. The detection rate for the separation
      of 4 kg of plutonium per week was found to be as high as 80-90% at a distance of
      less than 1 km, 70% at 5 km, 40% at 39 km, and 15% at 130 km. At distances up to
      40 km, the false alarm rate is less than 3.5%. On average, the fuel released 28
      TBq krypton-85 per kg plutonium. For weapons-grade plutonium, the krypton signal
      would be lower by a factor of 2. Hence, the given percentages correspond to the
      detection probabilities for the separation of a significant quantity (8 kg) of
      plutonium per weekly sample under the specific meteorological conditions of the
      WAK. The minimum separation rates that could have been detected are 2 gram of
      weapons-grade plutonium per week at a distance of less than 1 km, 40 g/week at 5
      km, 200 g/week at 39 km, and 1000 g/week at 130 km.

PMID- 15023450
TI  - Modulation of combined-release behaviors from a novel "tablets-in-capsule
      system".
AB  - A multifunctional and multiple unit system, which contains versatile mini-tablets
      in a hard gelation capsule, is developed by preparing Rapid-release Mini-Tablets
      (RMTs), Sustained-release Mini-Tablets (SMTs), Pulsatile Mini-Tablets (PMTs), and
      Delayed-onset Sustained-release Mini-Tablets (DSMTs), each with various lag times
      of release. Based on the combinations of mini-tablets, multiplied pulsatile drug
      delivery system (DDS), site-specific DDS, slow/quick DDS, quick/slow DDS, and
      zero-order DDS could be obtained. Velocity-time curve, instead of the cumulative
      percentage drug release profile, is plotted. The nonlinear least square model fit
      program is applied to process the velocity data of dissolution. The test curves
      coincided with the theoretical curves from simple summation of v-t equations of
      individual mini-tablets. Therefore, the programmed DDS can be predicted by adding
      the v-t equations of various mini-tablets to calculate the theoretical equations
      and be implemented.

PMID- 15023449
TI  - Transdermal delivery of zidovudine: effect of terpenes and their mechanism of
      action.
AB  - The effect of various oxygen-containing monoterpenes such as cineole, menthol,
      alpha-terpineol, menthone, pulegone and carvone was investigated on ex vivo
      permeation of zidovudine (AZT) across rat skin. Furthermore, saturation
      solubility of AZT, its stratum corneum (SC)/vehicle partition coefficient and
      activation energy for diffusion across skin with or without terpene(s) in vehicle
      (66.6% ethanol in water) were determined to understand their mechanism of action.
      All the terpenes studied significantly increased transdermal flux of AZT in
      comparison to vehicle (p<0.05) and their enhancement activities are in the
      following decreasing order: cineole>menthol>menthone approximately pulegone
      approximately alpha-terpineol>carvone>vehiclewater. On the other hand, saturation
      solubility and SC/vehicle partition coefficient of AZT were not significantly
      altered (p>0.05) by terpenes. Activation energies of AZT permeation across rat
      skin from water, vehicle and cineole in vehicle were measured to be 20.4, 18.6
      and 10.6 kcal/mol, respectively. Interactions between terpenes and SC lipids were
      studied with molecular modeling and found that terpenes form hydrogen bonds (bond
      lengths<2 A) with lipid head groups. The mechanism of permeation enhancement of
      AZT by terpenes was explained with thermodynamic activity, SC/vehicle partition
      coefficient, activation energy and molecular modeling studies.

PMID- 15023451
TI  - Design of a novel hydrogel-based intelligent system for controlled drug release.
AB  - The present work focused on the design of an assembled drug delivery system (DDS)
      to provide multifunctions, such as drug protection, self-regulated oscillatory
      release, and targeted uni-directional delivery by a bilayered self-folding gate
      and simple surface mucoadhesion. In this device, a pH-sensitive hydrogel together
      with a poly(hydroxyethyl methacrylate) (HEMA) barrier was used as a gate to
      control drug release. In addition, poly(HEMA) coated with poly(ethylene
      oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO-PPO-PEO) surfactant was
      utilized to enhance mucoadhesion on the device surface. The release profiles of
      two model drugs, acid orange 8 (AO8) and bovine serum albumin (BSA) were studied
      in this assembled system, which compared with the conventional drug-entrapped
      carriers and enteric-coating systems. Furthermore, targeted uni-directional
      release was demonstrated in a side-by-side diffusion cell. In conclusion, for
      such an assembled device, the poly(HEMA) layer not only affects the folding
      direction but also serves as a barrier to protect the model drugs. The release
      time can be controlled by the thickness of the bilayered gate and the drug
      reservoir. Due to the reversible swelling behavior of poly(methyacrylic acid-g
      ethylene glycol) (p(MAA-g-EG)) gels, the bilayered gate can sense the
      environmental pH change and achieve an oscillatory release pattern. Moreover, the
      local targeting and uni-directional release have been successfully demonstrated
      in vitro.

PMID- 15023452
TI  - Effect of the physicochemical properties of initially injected liposomes on the
      clearance of subsequently injected PEGylated liposomes in mice.
AB  - Using mice as a model, we recently reported that the long-circulating properties
      of polyethylene glycol (PEG) (M.W. 2000)-modified liposomes (mPEG(2000)
      liposomes) disappeared when they were intravenously injected at certain intervals
      [referred to as the "accelerated blood clearance (ABC) phenomenon"]. Herein, we
      report on a study of issue of whether physicochemical properties of a prior dose
      of liposomes such as degree of PEGylation, PEG chain length, lipid dose, surface
      charge, size, play a role in inducing this phenomenon. The injection of
      conventional liposomes (without a PEG-coating) significantly induced the
      phenomenon. The PEGylation of conventional liposomes attenuated the induction of
      the phenomenon somewhat with increasing molar content of PEG derivative and PEG
      chain length. These findings clearly suggest that the PEGylation of liposomes are
      not the major cause of the ABC phenomenon but, rather, played a role in
      preventing it. In addition, increasing the lipid dose in a prior dose of
      mPEG(2000)-liposomes (0-25 micromol/kg) increased the induction of the phenomenon
      in a sigmoid manner. The surface charge and size of the liposomes were not
      critical for the induction of the phenomenon, although generally these serve as
      determinants in the biodistribution of liposomes. The results reported here
      clearly indicate that the physicochemical properties of a prior dose of liposomes
      strongly affect the pharmacokinetic behavior of a subsequent injection of
      mPEG(2000)-liposomes: The extent of PEGylation and the lipid dose had an effect,
      but the surface charge and size did not. The results reported herein have a
      considerable impact on the design and engineering of liposomal formulations for
      use in multiple drug therapy as well as in therapy that involves the use of
      liposomal drugs.

PMID- 15023453
TI  - Methadone implants for methadone maintenance treatment. In vitro and in vivo
      animal studies.
AB  - Methadone implant formulations elaborated with polylactide-co-glycolide (PLGA)
      and polylactic acid (PLA) for 1 week and 1 month release duration, respectively,
      were evaluated in vitro and in vivo. One-week implants prepared with methadone
      clorhydrate, methadone clorhydrate/methadone base blend or methadone base were
      tested in vitro. Results showed that the methadone release rate decreased as the
      methadone base increased. The best release profile was achieve when the methadone
      base implants, made by compression of a 50:50 PLGA (12 kDa) and methadone base
      mix, were coated with PLA (30 kDa). For 1-month implants, the methadone base load
      was increased to 65% and PLA of 30 kDa was used as a matrix component. In this
      case the implants were coated with the same polymer. Deconvolution methods could
      not be used for in vivo release estimation because an increase in methadone
      clearance was observed with methadone clorhydrate solution multiple-dose
      treatment. Therefore the amount of drug remaining within the implants was
      evaluated and the deconvolution was only used to establish the release profile
      range. The upper limit was estimated applying the absorption-disposition function
      obtained after multiple-dose administrations while the lower curve was estimated
      using the single-dose function. Methadone serum levels were maintained around 200
      ng/ml during 1 week and approximately 5 weeks with the optimised implants. In
      vivo-in vitro correlations were always very good with slopes near 1.

PMID- 15023454
TI  - Targeted prevention of renal accumulation and toxicity of gentamicin by
      aminoglycoside binding receptor antagonists.
AB  - Receptor-mediated endocytosis plays an important role in accumulation of
      aminoglycosides in renal proximal tubule. To prevent aminoglycoside-induced
      nephrotoxicity following concentrated accumulation of gentamicin in the kidney,
      effect of cationic proteins and their peptide fragments, which could inhibit
      gentamicin binding to its binding receptor(s), was investigated. Among several
      substrates for megalin, an endocytic receptor responsible for renal accumulation
      of aminoglycosides, cytochrome c potently inhibited gentamicin accumulation in
      renal cortex. Concentration-dependent inhibition by cytochrome c on gentamicin
      uptake was also observed in OK kidney epithelial cells expressing megalin. In
      addition, gentamicin-induced increase in urinary excretion of N-acetyl-beta-d
      glucosaminidase (NAG), a marker of renal tubular damage, was significantly
      reduced by cytochrome c. We next attempted to find a peptide fragment with lower
      molecular size showing inhibitory effect on gentamicin uptake. Cyto79-88
      inhibited gentamicin uptake in OK cells, but had little effect on renal
      accumulation of gentamicin in mice in vivo. On one hand, a peptide fragment of
      neural Wiskott-Aldrich syndrome protein (N-WASP), which interacts with acidic
      phospholipids like aminoglycosides, inhibited gentamicin accumulation not only in
      OK cells but also in mouse kidney. These results show that substrates and/or
      their peptide fragments for aminoglycoside binding receptor such as megalin might
      be useful for preventing aminoglycoside-induced nephrotoxicity.

PMID- 15023455
TI  - Localised mapping of water movement and hydration inside a developing bioadhesive
      bond.
AB  - Few studies have investigated the internal processes involved in bioadhesive bond
      formation, particularly where mucus and hydrated polymer contribute jointly to
      bond structure. This paper reports the first study to spatially map the internal
      environment within a developing bioadhesive bond, utilising nuclear magnetic
      resonance (NMR) microscopy to measure localised water self-diffusion coefficients
      (SDC) and confocal laser scanning microscopy (CLSM) to estimate mucin
      concentration. In a model bioadhesive bond formed between an alginate matrix and
      mucin gel, characteristic profiles were observed in which fluorescence
      measurements showed a region of increasing mucin concentration in the mucus layer
      region adjacent to the matrix, corresponding closely with a zone of restricted
      water SDC in the diffusion profiles. These regions extended 144 microm (a normal
      human gastric layer thickness [Clin. Sci. 95 (1998) 97]) into the mucin layer
      after just 30 s, increasing to 800 microm after 30 min. The formation of a
      hydrated polymer layer at the matrix surface, confirmed visually, was also
      reflected in corresponding gradient changes. The results suggest a progressive
      dehydration of the mucus gel during bond formation, and the study demonstrates
      how together, these microscopies can provide non-invasive, quantitative, spatial
      and time-resolved evidence of internal hydration behaviour during bioadhesive
      bond formation.

PMID- 15023456
TI  - The use of a dendrimer-propranolol prodrug to bypass efflux transporters and
      enhance oral bioavailability.
AB  - The aim of the study was to determine the effects on the transport of propranolol
      across monolayers of the human colon adenocarcinoma cell line, Caco-2, of forming
      a prodrug by conjugating to generation 3 (G3) and lauroyl-G3 PAMAM dendrimers.
      Propranolol is a poorly soluble drug and known substrate of the P-glycoprotein (P
      gp) efflux transporter. Propranolol-G3 dendrimer conjugates were synthesised by
      surface attachment of two, four or six propranolol molecules. The apical (A) to
      basolateral (B) apparent permeability coefficient, P(app), of propranolol was
      increased and its B-->A P(app) decreased following conjugation to G3 dendrimers.
      Conjugation of propranolol to lauroyl-G3 dendrimers further increased its A-->B
      P(app). Our findings show that the A-->B P(app) of propranolol conjugates was
      reduced in the presence of the endocytosis inhibitor colchicine and was lower at
      4 degrees C than at 37 degrees C, suggesting that the enhancement mechanism
      involves endocytosis-mediated transepithelial transport. The A-->B P(app) of
      conjugated propranolol was not altered in the presence of the P-gp inhibitor
      cyclosporin A suggesting that conjugation of drug to dendrimer allows the
      bypassing of the efflux transporter. The results suggest that dendrimer-drug
      prodrugs may be used to increase drug solubility and bypass drug efflux
      transporters, therefore increasing drug bioavailability.

PMID- 15023457
TI  - Floating pellets containing bacterial antagonist for control sheath blight of
      rice: formulations, viability and bacterial release studies.
AB  - Floating pellets containing spores of bacterial biological control agent,
      Bacillus megaterium were prepared by extrusion-spheronization process. The
      formulations composed of hydrogenated vegetable oil (HVO), lactose,
      microcrystalline cellulose (Avicel(R) PH101), and a disintegrant; cross-linked
      sodium carboxymethylcellulose (Ac-Di-Sol(R)). The finishing pellets contained
      bacteria ranging from 10(7) to 10(8) CFU/g and the viability of bacteria in all
      formulations remained high after 6 months storage. The scanning electron
      microscope (SEM) was used to observe endospores of B. megaterium on both the
      surface and the inside of the pellets. The formulations were tested for their
      physical properties, floating ability and bacterial release. The level of
      disintegrant in the formulations influenced the floating ability and the
      liberation of antagonistic bacteria from pellets. The bacterial pellets showed
      promising result in suppression of the development of sheath blight lesions in
      greenhouse experiment.

PMID- 15023458
TI  - In vitro study of GDNF release from biodegradable PLGA microspheres.
AB  - Glial cell line-derived neurotrophic factor (GDNF) is a protein with potent
      trophic actions on dopaminergic neurons, which is under investigation as a
      therapeutic agent for the treatment of neurodegenerative disorders, including
      Parkinson's disease. The aim of this work was to develop GDNF-loaded
      microspheres, which could be implanted by stereotaxy in the brain and could offer
      an alternative strategy in the treatment of Parkinson's disease. A w/o/w
      extraction-evaporation technique was chosen to prepare protein-loaded
      microspheres. An in vitro release study of the protein was required to assess the
      retention of integrity and the performance of the microsphere formulation with
      regard to sustained release. In order to assess the in vitro release profile of
      the GDNF-loaded microspheres, a preliminary study was performed to select an
      appropriate buffer for GDNF stabilization, using experimental designs. GDNF was
      measured by both enzyme-linked immunosorbant assay (ELISA) and radioactivity
      using (125)I-GDNF. The GDNF-loaded microsphere release profile was assessed in a
      low continuous flow system, and showed a sustained release over 56 days of
      biologically active GDNF at clinically relevant doses.

PMID- 15023459
TI  - Liposome transduction into cells enhanced by haptotactic peptides (Haptides)
      homologous to fibrinogen C-termini.
AB  - Haptides are 19-21mer cell-binding peptides equivalent to sequences on the C
      termini of fibrinogen beta chain (Cbeta), gamma chain (preCgamma) and the
      extended alphaE chain of fibrinogen (CalphaE). In solution, Haptides accumulated
      in cells by non-saturable kinetics [Exp. Cell Res. 287 (2003) 116]. This study
      describes Haptide interactions with liposomes and Haptide-mediated liposome
      uptake by cells. Haptides became incorporated into negatively charged liposomes,
      changing their zeta potential. Atomic force microscopy and particle sizing by
      light scattering showed that the liposomes dissolved Haptide nanoparticles and
      absorbed them from solution. Pre-mixing fluorescent rhodamine-containing
      liposomes or "stealth" doxorubicin (DOX)-containing liposomes (Doxil) with Cbeta,
      preCgamma or to a lesser degree CalphaE, significantly enhanced their uptake by
      fibroblasts and endothelial cells. Confocal microscopy showed Haptide-induced
      liposome uptake saturated above approximately 40 microM Haptide. Cytotoxicity
      tests with lower concentrations of Doxil liposomes indicated that premixing with
      approximately 40 microM Cbeta or preCgamma increased their toxicity by one order
      of magnitude. It was evident that the liposomes complexed with an amphiphilic
      Haptide are transduced through cell membranes, probably by a non-receptor
      mediated process. These results suggest that Cbeta or pre-Cgamma could be
      employed to augment the cellular uptake of drugs in liposomal formulations.

PMID- 15023460
TI  - Rational design of solid aerosols for immunoglobulin delivery by modulation of
      aerodynamic and release characteristics.
AB  - Parenteral administration of immunoglobulins (Ig) for prevention or treatment of
      respiratory diseases achieves only modest concentrations of antibody in the
      pulmonary interstitial tissue and airways. Aerosols, including spray-dried
      particles, must overcome two limiting factors in order to be effective vehicles
      for pulmonary delivery of Ig: (i) Fc receptor (FcR)-mediated scavenging by
      macrophages and (ii) clearance by the mucociliary system. Ig-incorporated spray
      dried lipid microparticles (SDLM), coformulated with or without a biocompatible
      surfactant (1% w:w) to modulate protein release, were designed and tested for
      their capability to deliver Ig to the respiratory tract. To determine efficacy,
      rodents were immunized with SDLM containing antiinfluenza antibody followed by
      virus challenge and clinical parameters measured. Control of the release kinetics
      resulted in enhanced delivery of immunoglobulins to the respiratory tract and
      interstitial tissue with slow translocation into the systemic circulation. As
      much as 60% of the IgG delivered from nonretentive SDLM could be recovered from
      the lung interstitial tissue within 1 h after aerosol administration at a dose of
      1 mg of Ig/kg of body weight. In addition, nonretentive rather than slow-release
      particles loaded with antiinfluenza antibody were effective in curbing virus
      replication with a resulting positive clinical outcome. Thus, controlled release
      of Ig by manipulating aerosol characteristics and composition allows for a
      significant increase in the efficiency of pulmonary delivery of antibodies.

PMID- 15023461
TI  - Nanobiohybrids as delivery vehicles for camptothecin.
AB  - A novel method of delivering non-ionic, poorly water-soluble drugs such as
      campthothecin was developed. Camptothecin was first incorporated into micelles
      derived from negatively charged surfactants. The negatively charged micelles were
      then encapsulated in nanoparticles of magnesium-aluminum layered double
      hydroxides (LDHs) by an ion exchange process. The resulting nanobiohybrids
      released camptothecin rapidly with complete release within 10 min at both pH 4.8
      and 7.2. The LDH complex with carmine released carmine within 30 min at pH 4.8,
      but took over 70 days at pH 7.2. When administered to Glioma cells in vitro, the
      nanobiohybrid containing camptothecin resulted in significantly lower survival
      times compared to untreated cells, or to cells incubated with the surfactant, the
      pristine LDH, or water (delivery medium). The encapsulation method allowed for an
      approximately threefold increase in solubility of camptothecin. In addition, the
      modification of the surface of the LDH provided potential site-directing of the
      nanohybrids. These enhancements to the delivery scheme suggest the potential use
      of these hybrids for a variety of drug therapies.

PMID- 15023462
TI  - Evaluation of novel starch acetate-diltiazem controlled release tablets in
      healthy human volunteers.
AB  - Highly substituted starch acetate can be used to control drug release from
      directly compressed tablets in vitro. The aim of this study was to evaluate
      controlled release properties of starch acetate in vivo in humans. Three starch
      acetate tablet formulations with different in vitro release rates for diltiazem
      (fast, moderate and slow) were developed. An open, single dose, randomised, four
      treatment, four period, four sequence cross-over pharmacokinetic study was
      conducted in eight healthy volunteers. Diltiazem concentrations in plasma were
      determined by HPLC. Concentration-time profiles of the formulations differed:
      mean C(max) and AUC(0- infinity ) values of the fast, moderate and slow
      formulations were 95, 69, 31 ng/ml and 610, 511, 231 ng h/ml, respectively. In
      vitro-in vivo correlation (IVIVC) was analysed according to the cumulative area
      under the curves and in vitro release profiles. Acceptable limits of prediction
      errors were achieved for C(max) and AUC(0-24 h). The moderate formulation and
      commercial reference tablet showed similar in vitro release profiles and
      diltiazem concentrations in plasma. In conclusion, direct compression starch
      acetate formulations control drug release in humans.

PMID- 15023463
TI  - Novel mucoadhesive buccal formulation containing metronidazole for the treatment
      of periodontal disease.
AB  - Mucoadhesive tablets using different mixture of cellulose and polyacrylic
      derivatives were prepared in order to obtain new formulations containing
      metronidazole for periodontal disease treatment. All tablets were characterized
      by swelling studies, ex vivo and in vivo mucoadhesive time, ex vivo mucoadhesion
      force, in vitro and in vivo release. The best mucoadhesive performance and the
      best in vitro drug release profile were achieved by using hydroxyethyl cellulose
      (HEC) and carbomer 940 2:2 ratio. The chosen tablet, containing 20 mg of
      metronidazole, performed 12 h drug sustained release with buccal concentrations
      always higher than its MIC.

PMID- 15023464
TI  - Electrically assisted skin delivery of liposomal estradiol; phospholipid as
      damage retardant.
AB  - This work investigated transdermal penetration of a model lipophilic drug
      (estradiol) through human epidermis from phosphatidylcholine (PC)-based liposomes
      and saturated aqueous estradiol solution (control). Representative examples of
      cholate-containing ultradeformable (Transfersomes), non-rigid (pure PC) and
      membrane-stabilized (cholesterol-containing) vesicles were used. The unilamellar
      vesicles' diameters and zeta potentials were determined. Transdermal penetration
      studies involved occluded passive penetration for 12 h and cathodic iontophoresis
      (0.8 mA/cm(2)) for 8 h for all systems. Combined electroporation (5 pulses, 100
      V, 100 ms, 1 min spacing) and iontophoresis (0.8 mA/cm(2), for 2 h) was also
      employed for ultradeformable vesicles and control. Estradiol penetration
      parameters (flux and skin deposition) from different formulations were compared.
      All vesicles had essentially the same particle size, with ultradeformable
      liposomes showing the highest negative zeta potential (-29 mV). Occluded passive
      penetration improved estradiol skin penetration from liposomes relative to
      control. Iontophoretic studies revealed the superiority of ultradeformable
      vesicles regarding drug skin penetration and deposition compared to traditional
      liposomes. Combination of electroporation and iontophoresis did not markedly
      improve estradiol penetration for ultradeformable vesicles. The combination
      results implied repair of the skin barrier due to the penetration retarding
      effect of PC monomers released from liposomes.

PMID- 15023465
TI  - Oral insulin delivery: the potential of thiolated chitosan-insulin tablets on non
      diabetic rats.
AB  - It was the aim of this study to develop a delivery system providing an improved
      efficacy of orally administered insulin utilizing a thiolated polymer. 2
      Iminothiolane was covalently linked to chitosan. The resulting chitosan-TBA
      (chitosan-4-thiobutylamidine) conjugate exhibited 453.5+/-64.1 micromol thiol
      groups per gram polymer. 3.1% of these thiol groups were oxidised. Additionally,
      the enzyme inhibitors BBI (Bowman-Birk-Inhibitor) and elastatinal were covalently
      linked to chitosan representing 3.5+/-0.1% and 0.5+/-0.03% of the total weight of
      the resulting polymer conjugate, respectively. Chitosan-TBA conjugate (5 mg),
      insulin (2.75 mg), the permeation mediator reduced glutathione (0.75 mg) and the
      two inhibitor conjugates (in each case 0.75 mg) were compressed to so-called
      chitosan-TBA-insulin tablets. Control tablets consisted of unmodified chitosan
      (7.25 mg) and insulin (2.75 mg). Chitosan-TBA-insulin tablets showed a controlled
      release of insulin over 8 h. In vitro mucoadhesion studies showed that the
      mucoadhesive/cohesive properties of chitosan were at least 60-fold improved by
      the immobilisation of thiol groups on the polymer. After oral administration of
      chitosan-TBA-insulin tablets to non-diabetic conscious rats, the blood glucose
      level decreased significantly for 24 h corresponding to a pharmacological
      efficacy of 1.69+/-0.42% (means+/-S.D.; n=6) versus s.c. injection. In contrast,
      neither control tablets nor insulin given in solution showed a comparable effect.
      According to these results the combination of chitosan-TBA, chitosan-enzyme
      inhibitor conjugates and reduced glutathione seems to represent a promising
      strategy for the oral application of insulin.

PMID- 15023466
TI  - Controlled release of the fibronectin central cell binding domain from polymeric
      microspheres.
AB  - Non-ionic surfactants have been employed as alternatives to PVA for the
      emulsification-encapsulation of a conformationally labile protein (FIII9'-10)
      into PLGA microspheres. FIII9'-10 was encapsulated using a w/o/w double
      emulsification-evaporation technique and the microspheres fabricated were
      characterized by SEM and CLSM. The peptide backbone integrity of FIII9'-10 was
      assayed by SDS-PAGE and the degree of unfolding of FIII9'-10 following
      emulsification-encapsulation was assessed using a fibroblast cell-attachment
      assay. The encapsulation efficiency for FIII9'-10 was 25% when using PVA,
      compared to 50-60% when using Igepal CA-630 or Triton-X100, with values below for
      the other surfactants. FIII9'-10 released from microspheres promoted cell
      attachment in a concentration-dependent manner, only Igepal CA-630 and Triton X
      100 maintaining near-maximal cell attachment, indicating that the conformation of
      the relatively unstable FIII9' domain was preserved. All non-ionic surfactants
      reduced microsphere surface porosity, compared to PVA, and an increasing surface
      rugosity (leading to minor 'ridges') could be correlated with decreasing
      surfactant HLB. Low surface porosities did not effect the diffusion of FIII9'-10
      from the microspheres' internal pores in a 'burst release', as may have been
      imagined. In summary, non-ionic surfactants should be considered over PVA for the
      maintenance of biological activity of conformationally labile proteins during
      encapsulation.

PMID- 15023467
TI  - Modified guar gum matrix tablet for controlled release of diltiazem
      hydrochloride.
AB  - Polyacrylamide-grafted-guar gum (pAAm-g-GG) was prepared by taking three
      different ratios of guar gum to acrylamide (1:2, 1:3.5 and 1:5). Amide groups of
      these grafted copolymers were converted into carboxylic functional groups.
      Fourier transform infrared (FTIR) spectroscopy and differential scanning
      calorimetry were used to characterize copolymers. Tablets were prepared by
      incorporating an antihypertensive drug viz., diltiazem hydrochloride. In-vitro
      drug release was carried out in simulated gastric and intestinal conditions.
      Effect of drug loading on release kinetics was evaluated. Release continued up to
      8 and 12 h, respectively, for pAAm-g-GG and hydrolyzed pAAm-g-GG copolymers.
      Nature of drug transport through the polymer matrices was studied by comparing
      with Higuchi, Hixson-Crowell and Kopcha equations. Drug release was found to be
      dissolution-controlled in case of unhydrolyzed copolymer. With hydrolyzed
      copolymers, drug release was swelling-controlled initially (i.e., in 0.1 N HCl),
      but at later stage, it became dissolution-controlled in pH 7.4. Hydrolyzed pAAm-g
      GG matrices are pH sensitive and can be used for intestinal drug delivery.

PMID- 15023468
TI  - Self-assembled nanoparticles based on glycol chitosan bearing 5beta-cholanic acid
      for RGD peptide delivery.
AB  - The synthetic peptide bearing Arg-Gly-Asp (RGD) sequence is considered to
      specifically bind to alpha(v)beta(3) integrin expressed on endothelial cells in
      the angiogenic blood vessels, which provides a potential to inhibit the tumor
      growth. As a carrier for the RGD peptide, hydrophobically modified glycol
      chitosan (HGC) capable of forming nano-sized self-aggregates was prepared by the
      chemical conjugation of 5beta-cholanic acid to the main backbone of glycol
      chitosan. The RGD peptide labeled with fluoresein isothiocyanate (FITC-GRGDS) was
      loaded into self-aggregates in three different conditions: simple mixing,
      sonication, and solvent evaporation methods. Of different methods applied,
      solvent evaporation method showed the most promising results for peptide loading,
      as judged by the yield (>70%) and loading efficiency (>75%). It was found that
      the presence of FITC-labeled peptides makes the self-aggregates to be compact,
      possibly due to the role of both hydrophobic FITC and peptides containing
      carboxylic acids that allow hydrogen bonding and electrostatic interaction with
      the primary amino groups in the main backbone of glycol chitosan. FITC-labeled
      peptides were released from self-aggregates in a physiological solution (pH 7.4)
      for up to 1 day. From the cell adhesion and migration assays, it was demonstrated
      that FITC labeling of peptides does not significantly deteriorate biological
      activity of the parent peptide drug (GRGDS). Overall, the self-aggregates loaded
      with FITC-GRGDS might be useful for monitoring or destroying the angiogenic
      vessels surrounding the tumor tissue.

PMID- 15023469
TI  - Oral insulin delivery using P(MAA-g-EG) hydrogels: effects of network morphology
      on insulin delivery characteristics.
AB  - Hydrogels of poly(methacrylic acid-g-ethylene glycol) were prepared using
      different reaction water contents in order to vary the network mesh size,
      swelling behavior and insulin loading/release kinetics. Gels prepared with
      greater reaction solvent contents swelled to a greater degree and had a larger
      network mesh size. All of the hydrogels were able to incorporate insulin and
      protected it from release in acidic media. At higher pH (7.4), the release rates
      increased with reaction solvent content. Using a closed loop animal model, all of
      the insulin loaded formulations produced significant insulin absorption in the
      upper small intestine combined with hypoglycemic effects. In these studies,
      bioavailabilities ranged from 4.6% to 7.2% and were dependent on reaction solvent
      content.

PMID- 15023470
TI  - In-vitro evaluation of ion-exchange microspheres for the sustained release of
      liposomal-adenoviral conjugates.
AB  - This study looks at the development of a novel combination vector consisting of
      adenovirus conjugated to liposomes (AL complexes) bound to cation-exchanging
      microspheres (MAL complexes). With adenovirus having a net negative charge and
      the liposomes a net positive charge it was possible to modify the net charge of
      the AL complexes by varying the concentrations of adenovirus to liposomes. The
      modification of the net charge resulted in altered binding and release
      characteristics. Of the complexes tested, the 5:1 and 2:1 ratio AL complexes were
      able to be efficiently bound by the microspheres and exhibited sustained release
      over 24 h. The 1:1 and 1:2 AL complexes, however, bound poorly to the
      microspheres and were rapidly released. In addition the MAL complexes also were
      able to reduce the toxicity of the AL complexes, which was seen with the 10:1
      ratio. The AL complexes showed considerably more toxicity alone than in
      combination with microspheres, highlighting a potential benefit of this vector.

PMID- 15023471
TI  - Comparison of cell uptake, biodistribution and tumor retention of folate-coated
      and PEG-coated gadolinium nanoparticles in tumor-bearing mice.
AB  - The purpose of these studies was to compare the cell uptake, biodistribution and
      tumor retention of folate-coated and PEG-coated gadolinium (Gd) nanoparticles. Gd
      is a potential agent for neutron capture therapy (NCT) of tumors. Gd
      nanoparticles were engineered from oil-in-water microemulsion templates. To
      obtain folate-coated nanoparticles, a folate ligand [folic acid chemically linked
      to distearoylphosphatidylethanolamine (DSPE) via a PEG spacer MW 3350] was
      included in nanoparticle preparations. Similarly, control nanoparticles were
      coated with DSPE-PEG-MW 3350 (PEG-coated). Nanoparticles were characterized based
      on size, size distribution, morphology, biocompatibility and tumor cell uptake.
      In vivo studies were carried out in KB (human nasopharyngeal carcinoma) tumor
      bearing athymic mice. Biodistribution and tumor retention studies were carried
      out at pre-determined time intervals after injection of nanoparticles (10 mg/kg).
      Gd nanoparticles did not aggregate platelets or activate neutrophils. The
      retention of nanoparticles in the blood 8, 16 and 24 h post-injection was 60%,
      13% and 11% of the injected dose (ID), respectively. A maximum Gd tumor
      localization of 33+/-7 microg Gd/g was achieved. Both folate-coated and PEG
      coated nanoparticles had comparable tumor accumulation. However, the cell uptake
      and tumor retention of folate-coated nanoparticles was significantly enhanced
      over PEG-coated nanoparticles. Thus, the benefits of folate ligand coating were
      to facilitate tumor cell internalization and retention of Gd-nanoparticles in the
      tumor tissue. The engineered nanoparticles may have potential in tumor-targeted
      delivery of Gd thereby enhancing the therapeutic success of NCT.

PMID- 15023472
TI  - Preparation, characterization and in vitro release kinetics of clozapine solid
      lipid nanoparticles.
AB  - Clozapine, a lipophilic antipsychotic drug, has very poor oral bioavailability
      (<27%) due to first pass effect. Solid lipid nanoparticle (SLN) delivery systems
      of clozapine have been developed using various triglycerides (trimyristin,
      tripalmitin and tristearin), soylecithin 95%, poloxamer 188 and charge modifier
      stearylamine. Hot homogenization of melted lipids and aqueous phase followed by
      ultrasonication at temperature above the melting point of lipid was used to
      prepare SLN dispersions. Particle size and zeta potential were measured by photon
      correlation spectroscopy (PCS) using Malvern Zetasizer. Process and formulation
      variables have been studied and optimized. Differential scanning calorimetry
      (DSC) and powder X-ray diffraction (PXRD) studies were performed to characterize
      state of drug and lipid modification. In vitro release studies were performed in
      0.1 N HCl, double-distilled water and phosphate buffer, pH 7.4, using modified
      Franz diffusion cell. Stable SLN formulations of clozapine having mean size range
      of 60-380 nm and zeta potential range of -23 to +33 mV were developed. More than
      90% clozapine was entrapped in SLN. DSC and PXRD analysis showed that clozapine
      is dispersed in SLN in an amorphous state. The release pattern of drug is
      analyzed and found to follow Weibull and Higuchi equations.

PMID- 15023473
TI  - Compositional regulation of poly(lysine-g-(lactide-b-ethylene glycol))-DNA
      complexation and stability.
AB  - The search for an effective nonviral gene therapy vector has revealed several
      significant hurdles, such as transient expression and cytotoxicity, that impede
      the success of these systems. A terpolymer of poly(lysine-g-(lactide-b-ethylene
      glycol)) [pK-g-p(LL-b-EG)] has been developed, which is capable of stably
      packaging DNA with significantly less polycation than unmodified polylysine (pK)
      systems. A comparison of unmodified pK (DP=14, M(w)=2930) to pK grafted with p(LL
      b-EG) (M(w tot)=7500) showed that the minimum amine/phosphate ratio (N:P(min))
      needed for complete DNA condensation was reduced by 50%. However, when the
      molecular weight of pK was reduced (DP=4, M(w)=838), there was evidence of
      terpolymer interference with DNA condensation. Increasing the number of grafted
      p(LL-b-EG) chains produced a similar result of incomplete DNA condensation. All
      terpolymer formulations produced complexes with DNA that had greater resistance
      to salt-induced dissociation and short-term exchange with excess DNA. Terpolymer
      DNA complexes exhibited approximately zero-order plasmid release profiles over a
      period of 6 weeks. The rate of release was dependent on the complex N:P ratio as
      well as the molecular weights of pLL and pK. The ability to use terpolymer
      composition to control complex stability and controlled release can provide a
      means for system optimization for sustained expression profiles of exogenous DNA.

PMID- 15023474
TI  - Lactose-conjugated polyion complex micelles incorporating plasmid DNA as a
      targetable gene vector system: their preparation and gene transfecting efficiency
      against cultured HepG2 cells.
AB  - alpha-Lactosyl-poly(ethylene glycol)-poly(2-(dimethylamino)ethyl methacrylate)
      block copolymer (lactose-PEG-PAMA) was synthesized to construct a PIC micellar
      type gene vector potentially useful for selective transfection of hepatic cells.
      Lactose-PEG-PAMA spontaneously formed a polyion complex (PIC) micelle with
      plasmid DNA (pDNA) encoding luciferase (pGL3-Luc) in aqueous solution without any
      precipitate formation. The lactosylated PIC micelle thus prepared achieved
      substantially higher transfection efficiency compared to the control PIC micelle
      without lactose moieties against HepG2 cells possessing asialoglycoprotein (ASGP)
      receptors recognizing the beta-d-galactose residue. This pronounced transfection
      efficacy of the lactosylated PIC micelle was inhibited by the addition of excess
      asialofetuin (ASF), a natural ligand against the ASGP receptor, indicating ASGP
      receptor-mediated endocytosis to be a major route of the cellular uptake of the
      lactosylated micelles. Notably, the lactosylated PIC micelle revealed enhanced
      transfection compared to the control PIC micelle at a lower dose of pDNA,
      demonstrating the feasibility of using the ligand-conjugated PIC micellar vector
      for gene delivery to targeted cells.

PMID- 15023475
TI  - Can depression, anxiety and somatization be understood as appeasement displays?
AB  - BACKGROUND: No satisfactory basis in normal function characterizes major
      depression and its co-morbid disorders. Yet these may represent maladaptive
      expression of adaptive communicational states exhibited normally in many species.
      METHODS: We examined the signal value of depressive and anxious mood states,
      fatigue syndrome and somatoform disorders and found them to resemble appeasement
      or submission to conspecifics (members of a same species) as studied in other
      animals. Moreover, applying game theory formulations of conflict resolution and
      the triune brain theory of MacLean supported the hypothesis. LIMITATIONS: Direct
      experimental evidence must still test hypotheses that emanate from the presented
      framework. CONCLUSIONS: Implications for this approach include improved
      understanding and treatment of depression, improved research strategies, and a
      potential future pathogenesis-focused nosology.

PMID- 15023476
TI  - Serotonergic platelet markers of suicidal behavior--do they really exist?
AB  - BACKGROUND: Abnormal changes in platelets used as peripheral markers of central
      serotonergic functions are said to be associated with suicidality and depression,
      but this association has not been supported by consistent findings. AIM: This
      review based on selected, often quoted publications in this area focuses firstly,
      on obviously contradictory findings and, secondly, on potential methodological
      flaws explaining these discrepancies. RESULTS: The platelet 5-HT transporter has
      been found to have an inconsistent association with suicidality; furthermore, the
      specificity of imipramine for the 5-HT transporter is most likely low, since the
      number of platelet impramine binding sites has not been reliably associated with
      platelet serotonin uptake (Vmax). Significant changes of platelet serotonin
      content in suicidal individuals, as described in various studies, are most likely
      due to washout periods that are too short to eliminate the effects of a previous
      drug intake, or, in violent suicide attempters, due to blood loss and dilution.
      Similar methodological shortcomings might account for an often-reported elevated
      number of platelet 5-HT(2) receptor binding sites in suicidal individuals. In
      many studies, the results have not been sufficiently controlled for drug effects
      on platelet 5-HT(2) receptors, and associations of platelet 5-HT(2) binding with
      selective classifications of suicidal behavior are often generalized as further
      evidence for an association of platelet 5-HT(2) receptors with 'suicidality'.
      Finally, changes in platelet MAO-B-activity in suicidal patients have not been
      reproducibly found, and the impact of smoking on MAO-B activity has not been
      controlled in any studies. CONCLUSIONS: Methodological flaws such as small sample
      sizes, insufficient matching criteria for controls, use of inadequate ligands in
      binding experiments, nonconsideration of comorbidity etc. and considerable
      methodological differences between studies limit their validity and
      comparability. It does not seem possible, at present, to integrate published
      findings and concepts into a plausible biological model of suicidality.

PMID- 15023477
TI  - Investigation of completed suicide and genes involved in cholesterol metabolism.
AB  - BACKGROUND: Several lines of evidence support the association between low or
      lowered levels of serum total cholesterol and suicide. Genetic epidemiological
      studies suggest that genes predispose to suicide. Given that genes control many
      aspects of cholesterol biosynthesis and metabolism, one approach through which to
      explore the putative association between low cholesterol and suicide is through
      genetic studies. METHODS: We examined the potential role of five genes encoding
      proteins involved in cholesterol biosynthesis and transport in a total sample of
      305 male Caucasian subjects, consisting of 145 suicide completers and 160
      controls. We investigated variation in the HMG CoA reductase (HMGCR), 7
      dehydrocholesterol reductase (DHCR7), lipoprotein lipase (LPL), low-density
      lipoprotein receptor (LDLR), and apolipoprotein E (APOE) genes. RESULTS: We were
      unable to detect significant differences in allele or genotype frequencies
      between the suicide cases and controls for any of the genes studied. No
      relationship was found between genotype and impulsivity or aggression as measured
      using the BIS and BDHI, respectively. LIMITATIONS: The limitations of this study
      are consistent with the typical limitations inherent in most genetic association
      studies involving complex behavioral traits. CONCLUSION: Although these genes are
      unlikely to play a major role in susceptibility to suicide, further studies in a
      larger sample are necessary to reveal the smaller genetic effects, if present.

PMID- 15023478
TI  - The relationship between interpersonal sensitivity, anxiety disorders and major
      depression.
AB  - BACKGROUND: While interpersonal sensitivity, as rated by the Interpersonal
      Sensitivity Measure (IPSM) has previously been found to be an efficient predictor
      of depression, there has been less interest in the relationship between the IPSM
      and anxiety disorders. This study examines the performance of the IPSM in
      discriminating between cases and non-cases of the various anxiety disorders. The
      contribution of depression and the perception of parental environment, to any
      relationships found, are also examined. METHODS: A cohort of 156 men and women
      has been assessed at 5-yearly intervals since baseline in 1978, in their last
      year of teacher training. In this fourth wave of follow-up, subjects completed a
      series of self-report questionnaires, including the IPSM, and scales measuring
      neuroticism and trait depression. Perceived parental environment, measured at
      baseline, was also included. DSM-III-R major depression and anxiety disorders
      were generated using the Composite International Diagnostic Interview. The IPSM
      subscales were moderately stable over time. 'Timidity' was associated with
      agoraphobia and simple phobia, and 'separation anxiety' with agoraphobia, panic
      disorder and generalised anxiety disorder. 'Separation anxiety' and 'timidity'
      showed differential gender effects for simple phobia. 'Fragile inner self' and
      'separation anxiety' were associated with subjects with a history of repeated
      episodes of major depression, and the former, with perception of poor parental
      care. LIMITATIONS: The IPSM was not available for inclusion prior to the 1988
      wave. CONCLUSIONS: While the IPSM subscales were consistently correlated with
      neuroticism, they displayed differential associations with specific anxiety
      disorders, episodes of major depression and early parental environment. These
      findings offer greater understanding of mechanisms concerning the relationship of
      vulnerability to anxiety disorders and depression.

PMID- 15023479
TI  - Prophylaxis of schizoaffective disorder with lithium or carbamazepine: outcome
      after long-term follow-up.
AB  - OBJECTIVES: This study was conducted (1) to assess the prophylactic efficacy of
      lithium and carbamazepine in the maintenance treatment of schizoaffective
      disorder (SAD) with long-term follow-up, (2) to find predictors of the success or
      failure of prophylaxis, and (3) to search for differences in outcome between
      schizoaffective patients diagnosed according to either ICD-10 or DSM-IV. METHODS:
      Participating patients met the ICD-10 and/or DSM-IV criteria for schizoaffective
      disorder. Outcome was assessed using the Morbidity Index and time elapsed until
      the first recurrence during prophylaxis. Predictor variables were age at onset of
      illness, gender, and family history, as well as the following parameters prior to
      prophylaxis: time between onset of illness and start of prophylactic treatment
      (latency), severity of illness (hospitalization rate), number of hospital
      admissions and polarity of schizoaffective disorder (schizobipolar vs.
      schizounipolar). The time spent in the hospital per year was used to compare the
      course of illness before maintenance therapy to the time during maintenance
      therapy. Co-medication was taken into account. The clinical data during
      prophylaxis were ascertained prospectively. RESULTS: Forty-nine patients met the
      ICD-10 criteria for schizoaffective disorder, 34 of whom also met the DSM-IV
      criteria. All 49 patients underwent prophylactic therapy with either lithium
      (n=41) or carbamazepine (n=8) for an average of 6.8 years. After initiating
      prophylaxis, the number of days spent in the hospital declined dramatically from
      an average of 71 days to 11 days per year. No independent variable proved to be a
      consistent predictor of the course of treatment. In regard to the subgroup of
      patients diagnosed according to DSM-IV, no significant differences were observed
      when this subgroup was compared to the whole sample. LIMITATIONS: As this is a
      naturalistic study it does not allow for exact quantitative measures of
      effectiveness. CONCLUSIONS: This study is the first of its kind to investigate
      the efficacy of maintenance therapy in SAD over such an extended period of time.
      The results of the study show that lithium and carbamazepine appear to be highly
      effective in treating patients with schizoaffective disorder. However, it remains
      unclear how many schizoaffective patients will respond to mood stabilizer
      treatment and whether predictors of clinical relevance exist. In our sample,
      differences in the ICD-10 and DSM-IV diagnostic criteria for schizoaffective
      disorder were not related to significant differences in clinical outcome.

PMID- 15023480
TI  - Bupropion and paroxetine differentially influence cardiovascular and
      neuroendocrine responses to stress in depressed patients.
AB  - BACKGROUND: There exists a need to identify safe and effective treatments for
      depression in patients with coronary heart disease (CHD). METHODS: Using a cross
      sectional design, 17 depressed patients being treated with bupropion (200-450
      mg/day) were compared with 17 depressed patients being treated with paroxetine
      (10-50 mg/day) and with a group of 15 unmedicated, non-depressed controls for
      cardiovascular, neuroendocrine and heart rate variability (HRV) measures at rest
      and in response to mental and physical stressors. RESULTS: Regardless of
      treatment, both treated groups exhibited blunted plasma cortisol, plasma
      epinephrine, systolic blood pressure, cardiac output, and pre-ejection period
      responses to mental stressors relative to controls. Bupropion treated individuals
      exhibited greater total peripheral resistance (TPR) increases than either the
      paroxetine or control groups, and greater plasma norepinephrine (NE) increases to
      mental stressors than the paroxetine group. The bupropion group also displayed
      reduced HRV at rest relative to the controls and during orthostatic challenge
      relative to both the control and paroxetine groups. LIMITATIONS: Despite the fact
      that the treated groups were well matched for depression and other psychiatric
      histories, lack of randomization into treatment arms may be associated with a
      selection bias in the two treated groups. CONCLUSIONS: Although both
      pharmacological treatments were associated with a blunting of some cardiovascular
      and neuroendocrine responses to stress relative to controls, which may be
      reflective of their therapeutic mechanisms of action, the results of our study
      also suggest that bupropion is associated with a more detrimental autonomic
      profile than paroxetine, as reflected in increased TPR and NE, and reduced HRV.
      The results of this study may have implications for the pharmacological treatment
      of depression in CHD patients.

PMID- 15023481
TI  - Clinical and psychosocial factors associated with the outcome of unipolar major
      depression: a one year prospective study.
AB  - BACKGROUND: The role of psychosocial and clinical variables in the prediction of
      major depression is controversial. In a previous paper, we obtained a one-year
      predictive multivariate model of non-remission for major depression, based on the
      presence of a personality disorder, a low self-esteem and a low satisfaction with
      social support. OBJECTIVES: To evaluate more in depth both personality disorders
      and psychosocial variables as predictors of outcome. METHODS: A prospective study
      on 57 consecutive outpatients with major depressive episodes were followed-up
      monthly during one year. Clinical and psychosocial variables were registered,
      including personality (DSM-IV criteria and IPDE structured interview), previous
      quality of life, self-esteem, social support and dyadic adjustment. Remission was
      defined as a HDS score less than 8. Univariate and multivariate (logistic
      regression) analyses were applied. RESULTS: 68% of the patients reached remission
      at 12 months. Personality disorder (diagnosed clinically but not according to
      IPDE), and previous quality of life were the variables more consistently
      associated to remission at 12 months. Among follow-up variables, remission at 3
      months was strongly associated with remission. CONCLUSIONS: Our findings confirm
      the importance of the clinical diagnosis of personality disorder in the major
      depression outcome. However, more studies are needed to clarify the divergence
      between clinical and structured interview guided diagnosis. With the exception of
      quality of life, psychosocial variables had a weak and non consistent
      relationship with outcome.

PMID- 15023482
TI  - Minor depression: risk profiles, functional disability, health care use and risk
      of developing major depression.
AB  - BACKGROUND: minor depression has been found to affect quality of life, result in
      a increased service utilization, and lead to an increased risk of developing a
      major depression. In this study we examine risk profiles, functional disability,
      service utilization and the risk of developing major depression in minor
      depression. METHODS: a random sample of the Dutch population (n=7076) was
      interviewed at baseline and 1 and 3 years later (response rate: 69.7%). Five
      categories of depression status were defined: major depression with seven to nine
      symptoms; with five or six symptoms; minor depression; one key symptom only; no
      depressive symptoms. Independent variables included: functional disability; care
      utilization; sociodemographic characteristics. RESULTS: functional disability was
      more pronounced in more severe categories of depression. Health care use was also
      found to be most intensive for more severe depression. The risk of developing
      major depression in subjects with minor depression was found to be 8.0% after 2
      years. LIMITATIONS: there had already been some attrition from the study when
      minor depression was measured. A definition of minor depression which approached
      the DSM-IV definition. Absence of homeless individuals in the dataset.
      CONCLUSIONS: depressive disorders seem to exist on a continuum, rather than in
      separate categories. Subjects with minor depression make less use of professional
      services than subjects with major depression, but because minor depression is
      more prevalent than major depression, the absolute number of subjects with minor
      depression receiving professional help is considerable.

PMID- 15023483
TI  - Depression and vascular disease: what is the relationship?
AB  - BACKGROUND: the 'vascular depression' hypothesis proposes that vascular disease
      predisposes to, precipitates or perpetuates depression, and this proposal has
      stimulated further research into the relationship of depression to vascular
      disease. METHODS: We investigated the nature of the relationship between
      depression and vascular diseases by reviewing epidemiological, clinical,
      neuroimaging and neuropathology studies which have reported on the relationship
      of depression to coronary artery disease, stroke disease, alterations in blood
      pressure, vascular dementia, diabetes mellitus and cholesterol levels and by
      reviewing potential mechanisms by which depression could be associated with
      vascular diseases. RESULTS: there is abundant and increasing evidence from these
      different lines of research that depression has a bidirectional association with
      vascular diseases and plausible mechanisms exist which explain how depression
      might increase these vascular diseases and vice versa. LIMITATIONS: this was not
      a systematic review and so not every report of relevance has been included.
      CONCLUSIONS: depression has a clear bidirectional relationship with vascular
      diseases. Further study is needed to clarify the mechanisms involved and to
      investigate the benefits of conventional and novel treatments for vascular
      diseases in depressive illness.

PMID- 15023484
TI  - Social adjustment and self-esteem of bipolar patients: a multicentric study.
AB  - The aim of the present study was to investigate impairment in social adjustment
      and self-esteem of bipolar patients (n=144) in remission for at least 3 months.
      Patients were recruited among four different centres: Sofia, Athens, Jerusalem
      and Milan, and were individually matched to control subjects in relation to sex,
      age and geographical origin. Subjects completed the Rosenberg self-esteem scale
      (SES) and the self-report version of the social adjustment scale (SAS). Bipolar
      patients reported to experience more difficulties in social adjustment than
      controls, specifically for leisure and work activities. Further, our results show
      that bipolar patients have significantly lower self-esteem compared to controls,
      even after remission.

PMID- 15023485
TI  - Use of health services for major depressive episode in Finland.
AB  - BACKGROUND: A universal finding in psychiatric epidemiology is that only a
      minority of currently depressed people seek or receive treatment. AIMS: To
      investigate the predictors of use of health care services for depression.
      METHODS: A representative random sample of 5993 non-institutionalised Finnish
      individuals aged 15-75 years was interviewed in 1996. Major depressive episode
      during the last 12 months was assessed using the Short Form of the University of
      Michigan version of the Composite International Diagnostic Interview (the UM-CIDI
      Short Form). Characteristics and health service use of the 557 depressed
      individuals were assessed. RESULTS: The proportion of people classified as having
      a major depressive episode who used any health services for their depression
      during the past 12 months was only 31% for men and 25% for women. Use of services
      was not predicted by sociodemographic factors. Longer duration, and greater
      severity and perceived disability predicted overall health service use for
      depression, but not significantly whether treatment was sought from primary or
      psychiatric care. CONCLUSIONS: The probability of use of health services for
      major depression increases with duration, severity and perceived disability
      related to depression. Only 59% of those suffering from even the most severe
      major depressive episodes use health services for depression. Use appears to be
      unrelated to sociodemographic factors in Finland.

PMID- 15023486
TI  - Prevention of postnatal distress or depression: an evaluation of an intervention
      at preparation for parenthood classes.
AB  - OBJECTIVES: To determine the effectiveness of a psychosocial intervention,
      provided to expectant couples in routine antenatal classes, on the postpartum
      psychosocial adjustment of women and men. DESIGN: A 3*3 between subjects
      randomised control design was utilised. The two factors were condition and self
      esteem. Preparation for Parenthood programs were randomly allocated to one of
      three conditions: usual service ('control'), experimental ('empathy'), or non
      specific control ('baby-play'). The latter condition controlled for the non
      specific effects of the intervention, these being: the provision of an extra
      class; asking couples to consider the early postpartum weeks; and receiving
      booster information after the antenatal class, and again shortly after the birth.
      Women and men were categorised into three levels of self-esteem, as measured
      antenatally: low, medium and high. METHODS: 268 participants were recruited
      antenatally. Interview data and self-report information was collected from 202 of
      these women at 6 weeks postpartum, and 180 women at 6 months postpartum. The
      intervention consisted of a session focusing on psychosocial issues related to
      becoming first-time parents. Participants discussed possible postpartum concerns
      in separate gender groups for part of the session, and then discussed these
      issues with their partners. Hypothetical scenarios depicting stressful situations
      in the early postpartum weeks for women and men were discussed, with solutions
      that parents have found useful given to the participants. In the non-specific
      control condition, the session focused on the importance of play with a baby,
      with videotapes and discussion around how parents can play with infants. RESULTS:
      At 6 weeks postpartum there was a significant interaction effect between
      condition and self-esteem on maternal adjustment. Women with low self-esteem, who
      had received the intervention, were significantly better adjusted on measures of
      mood and sense of competence than low-self-esteem women in either of the two
      control conditions. There were no main or interaction effects by 6 months
      postpartum. The beneficial effect at 6 weeks was related to partners of these
      women being more aware of how the mother was feeling, and with women reporting
      greater satisfaction with the sharing of home and baby tasks. There were no
      significant main or interaction effects for men at either time point, other than
      men with low self-esteem reporting poorer adjustment. CONCLUSIONS: This brief and
      inexpensive intervention was effective in reducing postpartum distress in some
      first-time mothers at 6 weeks postpartum. The effectiveness of this intervention
      was related to an increased level of awareness in the men as to how their
      partners were experiencing the early postpartum weeks. That the effect was only
      evident for women who, antenatally, reported being low in self-esteem, is an
      important advance in our knowledge of the effectiveness of such prevention
      programs. No previous studies have investigated the differential effectiveness of
      such programs depending upon the woman's level of self-esteem, and this finding
      indicates that future work should measure this variable. These findings should be
      understood in the context that the population sampled were those attending
      preparation for parenthood classes, and thus different interventions will be
      needed for couples who do not attend such classes. This brief psychosocial
      intervention can be readily applied to antenatal classes routinely conducted in
      hospitals or the community.

PMID- 15023487
TI  - Major depressive disorder in a population of urban, African-American young
      adults: prevalence, correlates, comorbidity and unmet mental health service need.
AB  - BACKGROUND: The U.S. Surgeon General recently highlighted the relative dearth of
      research on the mental health of minority populations in the U.S. The present
      report describes the prevalence of major depressive disorder (MDD) in an
      epidemiologically-defined population of 1197, predominately poor, African
      American 19-22-year-olds, living in the greater Baltimore, MD metropolitan area.
      METHODS: The prevalence and correlates of MDD, its comorbidity with other mental
      and substance disorders, and unmet mental health service need were assessed via a
      structured clinical interview administered by lay interviewers. RESULTS: Using
      DSM-IV criteria, the overall prevalence of lifetime MDD for the study population
      was 9.4%, whereas the last year and last month prevalences were 6.2 and 2.7%,
      respectively. Females were approximately 1.6 times more likely to report a
      lifetime episode of MDD than males. MDD was highly comorbid with substance
      disorders. Just under 10% of those who had experienced an episode of MDD within
      the last year reported receiving mental health specialty services within the last
      year. LIMITATIONS: A major limitation was the reliance on a single interview
      conducted by a lay interviewer as opposed to a comprehensive psychiatric
      assessment carried out by a highly trained clinician, integrating information on
      symptoms and functioning from multiple sources. CONCLUSIONS: The lifetime
      prevalence of MDD found in the present study suggests that it is a significant
      mental health problem in the African-American young adults studied, particularly
      amongst women. Moreover, most episodes of MDD went untreated.

PMID- 15023489
TI  - Life events, entrapments and arrested anger in depression.
AB  - OBJECTIVES: A recent, evolution derived theory of depression has suggested that
      aroused but arrested defences of fight (arrested anger) and flight (entrapments)
      may be important components of depression. This study therefore set out to
      explore unexpressed anger and entrapment in depression. The focus was on the
      nature of severe life events and difficulties, the time course of arrested
      defences, fantasies of escaping, fantasies of expressing anger, and reasons for
      not acting on emotions/behaviours. METHODS: Fifty diagnosed depressed people,
      being treated for depression, were interviewed using the Life Event and
      Difficulties Schedule (LEDS). They then completed five further questionnaires:
      the escape inhibition questionnaire; the reasons for not escaping questionnaire;
      the anger inhibition questionnaire; the reasons for not expressing anger
      questionnaire, and the Beck Depression Inventory. RESULTS: In regard to arrested
      flight, 88% of the group acknowledged strong desires to escape difficulties in
      their life but many felt unable to. Transcript analysis from the LEDS also
      indicated strong themes of entrapment. 38.7% felt trapped before becoming
      depressed. Fantasies of escaping were common, but making actual plans to get away
      less common. A variety of reasons were given for not escaping: In regard to
      arrested anger, 82% felt they suppressed their anger and 56% felt this problem
      predated their depression. A number of different reasons were given for not
      expressing anger. Despite self-blame often being seen as important to depression,
      we found that for many severe life events and difficulties patients did not blame
      themselves. Rather they blamed external circumstances or other people and saw
      these as the source of their entrapment. CONCLUSIONS: Disturbances in
      fight/flight mechanisms are common in depression. For some these may predate a
      depression and may play a causal role, whilst for others these experiences emerge
      with the depression. Depression is related to chronic stress states and clinical
      attention to disturbances in flight/flight may throw light on these states and
      offer novel approaches to intervention.

PMID- 15023488
TI  - Effectiveness of pindolol plus serotonin uptake inhibitors in depression: a meta
      analysis of early and late outcomes from randomised controlled trials.
AB  - BACKGROUND: Contradictory results on the efficacy of pindolol associated with
      selective serotonin reuptake inhibitors (SSRIs) in depressive illness have been
      published and no former review has produced an overall figure of its efficacy.
      This study aims to review the efficacy and tolerability of pindolol plus SSRIs in
      depressive illness. METHODS: A meta-analysis of randomised controlled trials
      (RCTs) comparing pindolol plus SSRIs with placebo plus SSRIs. RESULTS: Nine RCTs
      met inclusion criteria. Outcome favoured pindolol at 2 weeks time (N=5; OR=2.8;
      95% CI 1.4-5.7), but not at four to 6 weeks (N=7; OR=1.4; 95% CI 0.8-2.7).
      Results for early outcome studies were robust to sensitivity analysis. Nineteen
      more studies, averaging null results, would be needed to change the overall
      probability (P=0.0001) to a non-significant figure. CONCLUSIONS: Pindolol seems
      to hasten the response to SSRIs in depression with a timing window circumscribed
      to the first weeks of treatment.

PMID- 15023490
TI  - Well-being and life satisfaction in generalized anxiety disorder: comparison to
      major depressive disorder in a community sample.
AB  - BACKGROUND: In most settings, generalized anxiety disorder (GAD) is highly
      comorbid with major depressive disorder (MDD). This raises uncertainty about the
      clinical relevance of GAD as a distinct diagnostic entity. The demonstration of
      functional impairment attached to GAD, independent of that attributable to MDD,
      would support the importance of GAD as a separate diagnostic category. METHODS:
      The Ontario Health Survey Mental Health Supplement, a survey of more than 8000
      residents aged 15-64 of the Canadian province of Ontario, used the University of
      Michigan Composite International Interview Schedule (also used in the US National
      Comorbidity Survey) to assign DSM-III-R diagnoses. Several indicators of
      disability and quality of life were included. Our analytic strategy was to
      compare these indices in persons with and without GAD, stratified by MDD
      comorbidity, and adjusting for the effects of relevant sociodemographic factors
      (e.g., social class, age, gender) and dysthymia. Odds ratios (ORs) are reported;
      SUDAAN was used to adjust for the sampling framework. RESULTS: GAD was highly
      comorbid with MDD on both a lifetime and past-year basis. Both past-year and
      lifetime MDD and GAD were associated with an increased likelihood of low overall
      perceived well-being. Both lifetime MDD and GAD were associated with
      dissatisfaction in one's main activity and with family relationships.
      LIMITATIONS: Other comorbid Axis I or II conditions might be confounders with
      impairment; a lower rate of GAD than in some prior surveys bears consideration.
      CONCLUSIONS: These observations confirm that GAD is associated with an increased
      likelihood of poor global well-being and life satisfaction, beyond that
      associated with MDD. Given the chronicity of GAD relative to the more often
      episodic course of MDD, the long-term functional benefits of treating GAD may be
      substantial.

PMID- 15023491
TI  - Early life menstrual characteristics and pregnancy experiences among women with
      and without major depression: the Harvard study of moods and cycles.
AB  - BACKGROUND: Other than premenstrual dysphoria, few studies have examined the
      extent to which basic characteristics of the menstrual cycle and the occurrence
      of other reproductive landmarks impact on the risk of major depression. METHODS:
      From a population-based sample of 4161 premenopausal women 36-45 years of age, we
      identified 332 women who met DSM criteria for past or current major depression
      and a sample of 644 women with no such history. In person interviews included a
      detailed assessment of menstrual cycle characteristics from age at menarche
      through study enrollment as well as other reproductive landmarks. RESULTS: Risk
      of depression increased significantly with decreasing age at menarche (P<0.001).
      The risk of depression was also higher in women with heavier menstrual flow and
      cycle irregularity during the first 5 years of menstruation. Women with a history
      of multiple abortions were 2-3-times more likely to develop major depression (95%
      CI 1.6-4.1). Increasing months of breastfeeding was associated with a decreased
      risk of depression after adjustment for education, marital status, and number of
      livebirths (P-value, test of trend=0.012). This association was largely confined
      to depression during the postpartum period. LIMITATIONS: Menstrual and pregnancy
      history exposures were self-reported and retrospectively assessed. However, women
      with and without a HISTORY of depression were subject to similar recall
      requirements that likely resulted in an underestimate of most risk estimates.
      CONCLUSIONS: Clinicians involved in routine obstetrical and gynecological care of
      women need to recognize that menstrual and pregnancy history events may serve as
      potential markers for subsequent psychiatric sequelae.

PMID- 15023492
TI  - The characteristics of asymptomatic female adolescents at high risk for
      depression: the baseline assessment from a prospective 8-year study.
AB  - OBJECTIVES: This longitudinal 8-year study assesses potential predictors of major
      depressive disorder (MDD) in a cohort of healthy adolescent females at high
      familial risk for MDD. The objective of this study was to ascertain whether risk
      factors for female onset MDD would differentiate youth at high or usual risk for
      MDD, prior to the onset of depressive symptomology. METHODS: Subjects (ages 12-15
      years) were assigned to a high (n=43) or usual (n=40) risk group according to
      maternal history of MDD. Depressive symptomatology (Beck Depression Inventory,
      Hamilton Rating Scale for Depression), pubertal development (Pubertal
      Developmental Staging Questionnaire), social support (Social Support Scale), and
      cognitive vulnerability (Depressive Experiences Questionnaire) were assessed.
      RESULTS: High risk and usual risk group demonstrated no significant differences
      in demographic variables such as age, body mass index, and grade. Significantly
      more youth in the high risk group (n=40, 93%) had started menstruation, compared
      to youth in the usual risk group (n=31, 77.5%). There were no significant
      differences between the groups on measures of dysphoric cognitive style,
      perceived overall number of social supports, or satisfaction with social support.
      CONCLUSIONS: Females at high familial risk for the onset of depression have
      significant differences in pubertal development, but not in demographics,
      depressive symptoms, social supports, or dysphoric cognitive style, when compared
      to females at usual risk for depression. These findings suggest that in
      prevention trials for depression in asymptomatic young women no non-biological
      risk factors for MDD aid in identifying females at higher risk for MDD.

PMID- 15023494
TI  - Dysfunctional assumptions in bipolar disorder.
AB  - BACKGROUND: Despite the initial encouraging outcome in developing CBT for bipolar
      affective disorder [Arch. Gen. Psychiatry 2002 (in press); Psychol. Med. 31
      (2001) 459-467], very little is known about whether there are any differences in
      dysfunctional attitudes between unipolar and bipolar patients. Both the
      behavioural activation system theory [J. Pers. Soc. Psychol. 67 (1994) 488-498;
      Major Theories of Personality Disorder, Guilford Press, New York, 1996; Psychol.
      Bull. 117 (1995) 434-449] and the cognitive model for bipolar affective disorder
      [Cognitive Therapy for Bipolar Disorder: A Therapist's Guide to Concepts, Methods
      and Practise, Wiley, New York, 1999] postulate high goal striving as a risk
      factor for bipolar disorder. However, the existing subscales in the dysfunctional
      attitude scale (DAS) were derived from patients and relatives of patients
      suffering from unipolar depression, patients with a mixed psychiatric diagnosis
      or normal controls. None of the existing subscales reflects high goal striving
      beliefs. Using a sample of bipolar patients may yield different factors. METHODS:
      A total of 143 bipolar 1 patients filled in the short version of DAS 24.
      Principal component analysis was carried out to derive factors. The scores of
      these factors were compared with those of 109 unipolar patients to investigate if
      these factors distinguish bipolar patients from unipolar patients. RESULTS: Three
      factors were derived: factor 1 'Goal-attainment' accounted for 25.0% of the total
      variance. Factor 2 'Dependency' accounted for 11.0% of the total variance. Factor
      3 'Achievement' accounted for 8.2% of the total variance. However, factor 1
      appeared to consist of items that made a coherent theoretical construct. No
      significant differences were found when the validation sample was compared with
      109 patients suffering from unipolar depression in any of the three factors. When
      subjects who were likely to be in a major depressive episode were excluded, the
      scores of bipolar patients (n=49) were significantly higher than euthymic
      unipolar patients (n=25) in factor 1 'Goal attainment'. Goal-attainment also
      correlated with the number of past hospitalisations due to manic episodes and to
      bipolar episodes as a whole. CONCLUSIONS: The Goal-attainment subscale captures
      the risky attitudes described by the behavioural activation system theory and the
      cognitive model for bipolar affective disorder. It is postulated that these
      beliefs may interact with the illness and predispose bipolar patients to have a
      more severe course of the illness.

PMID- 15023493
TI  - The cAMP-dependent protein kinase A and brain-derived neurotrophic factor
      expression in lymphoblast cells of bipolar affective disorder.
AB  - BACKGROUND: Abnormalities in cAMP signaling and altered expression of downstream
      targets such as brain-derived neurotrophic factor (BDNF) have been postulated in
      patients with bipolar disorder (BD). METHODS: The PKA activity and levels of (3)H
      cAMP binding to PKA R regulatory subunits were measured in lymphoblasts from 10
      BD and 10 control subjects. In addition, the possibility that BDNF expression
      could be altered in these cells has been explored. RESULTS: Results indicate that
      PKA activity significantly increased (t-test; P<0.01), whereas the (3)H-cAMP
      binding to PKA R subunits decreased in cells from BD (t-test; P<0.02). The
      presence of 10 microM Sp-cAMP in culture 24 h before cell harvesting induced an
      increase in enzyme activity and a decrease in (3)H-cAMP binding sites (t-test;
      P<0.01), with a significant difference between BD and controls (t-test; P<0.01).
      This presence of Sp-cAMP also results in increased BDNF expression (t-test,
      P<0.01), but neither in resting cells, nor in stimulated cells, was any
      difference observed in BDNF expression between BD and controls (t-test, NS).
      LIMITATIONS: This study was conducted on a peripheral model cell, whose
      importance of BDNF is unknown. CONCLUSIONS: These data suggest that the
      upregulation of cAMP signaling observed in BD patients results in the
      normalization of the BDNF expression. Studies on signal transduction, gene
      expression and pathologies have implications for development of novel treatments.

PMID- 15023495
TI  - Manic patients receiving ECT in a Brazilian sample.
AB  - BACKGROUND: Characterization of manic inpatients receiving electroconvulsive
      therapy (ECT) has not been done. METHODS: The charts of 425 consecutive
      admissions of 269 inpatients treated for manic or mixed episodes, between 1996
      and 2000, in a Brazilian private psychiatric hospital were reviewed. A logistic
      model was built to determine the predictors of use of ECT for mania. Median total
      length of stay (LOS) and LOS deducted from the delay until ECT was started were
      compared between ECT and non-ECT admissions. The risk of readmission was
      estimated using Cox's regression. RESULTS: Significant predictors of ECT
      prescription were: history of previous admission (OR=4.09), psychotic features
      (OR=1.60), female gender (OR=2.04), married (OR=1.79), and treatment by a
      psychiatrist who assisted more than 20 manic inpatients in the index period
      (OR=1.97). Co-morbidity with cardiovascular disease was negatively associated
      with ECT use (OR=0.49). Median LOS after starting ECT was similar to that of non
      ECT admissions (12 vs. 13 days). ECT reduced (HR=0.678) and previous psychiatric
      admissions increased (HR=2.320) the risk of readmission after a manic episode.
      LIMITATIONS: Only one hospital was included in this study. CONCLUSIONS: The
      presence of psychotic features and violent behavior during manic episodes and
      indicators of chronicity of bipolar illness (history of previous admissions,
      duration of disease) were predictors of ECT use for the treatment of mania.
      Suicidality was not associated with the use of ECT for mania. LOS after ECT was
      started was similar to LOS of non-ECT admissions. The use of ECT for mania
      reduced the risk of readmission.

PMID- 15023496
TI  - Lifetime rates of alcoholism in adults with anxiety, depression, or co-morbid
      depression/anxiety: a community survey of Ontario.
AB  - BACKGROUND: Separate lines of research have demonstrated strong associations
      linking alcohol misuse with major depression on the one hand, and anxiety
      disorders on the other. In the current study we examined the possible confounding
      and/or additive effects of co-morbid depression/anxiety in understanding these
      relationships. METHODS: A total of 7195 individuals in Ontario, aged 15-64, were
      interviewed using the CIDI. Based on lifetime diagnoses, we compared rates of
      alcohol abuse/dependence in four groups consisting of normal controls,
      individuals with unipolar major depression but no anxiety disorders, individuals
      with one or more anxiety disorders without depression, and individuals with co
      morbid major depression and anxiety. Age of onset of alcoholism in the four study
      groups was also compared. RESULTS: In both genders, there were significantly
      higher rates of alcoholism in all three psychiatric groups relative to controls.
      In females only, there was also a significantly higher rate of alcoholism in the
      depressed/anxious group than in the pure anxious group. The age of onset of
      alcoholism was the same across all four study groups. LIMITATIONS: Due to
      limitations related to sample size, we combined subjects with various anxiety
      disorders into a single anxiety group and concurrent and sequential co-morbidity
      were not distinguished. CONCLUSIONS: Both gender effects and depression/anxiety
      co-morbidity may be important considerations in the design and interpretation of
      studies on alcohol misuse. This may be particularly relevant when considering the
      strength of the association between alcoholism and anxiety disorders in women.
      Depression and anxiety do not appear to influence the age of onset of alcoholism.
      Furthermore, no single temporal pattern of onset was identified in individuals
      with all three disorders, suggesting no obvious cause-effect relationship among
      them.

PMID- 15023497
TI  - Anxious Thoughts and Tendencies Scale: an investigation of factor structure and
      the psychometric properties on the basis of an Australian sample.
AB  - BACKGROUND: The factor structure and psychometric properties of the revised
      Anxious Thoughts and Tendencies Scale (AT&T) is investigated. METHODS: An
      Australian sample of 215 students and 33 patients diagnosed with an anxiety
      disorder completed a battery of anxiety-related questionnaires. RESULTS: Factor
      analysis indicated one factor, which accounted for 38% of the variance and had
      high internal consistency and reliability. Significant relationships were found
      with measures of anxiety, anxiety sensitivity, catastrophic cognitions, fear and
      depression. The AT&T discriminated between students and patients, and between
      students with high or low levels of anxiety and fear. LIMITATIONS: The size of
      the clinical sample was very small and the study needs to be replicated with a
      large and carefully recruited clinical sample. CONCLUSIONS: These results support
      the AT&T as a valuable and psychometrically sound measure of the cognitive
      aspects of anxiety.

PMID- 15023498
TI  - History of deliberate self-harm and its association with mood fluctuation.
AB  - BACKGROUND: It is known that mental illness is associated with increased suicide
      risk. It has been postulated that suicidality may be an independent clinical
      phenomenon and we investigate whether variability of mood may be a mediator of
      this. METHODS: Fifty-three psychiatric inpatients were assessed on the Montgomery
      Asberg depression rating scale, once weekly, over a 4-week period. The SCID II
      was administered to diagnose co-morbid personality disorder. Hostility was
      measured with the Hostility and Direction of Hostility questionnaire. A
      Fluctuation Index score was calculated to measure variability of mood. RESULTS:
      Unadjusted analyses suggested that patients with a history of deliberate self
      harm showed greater variability in mood as measured by the fluctuation index
      (mean difference=13.4; 95% CI=4.3 to 22.6; P=0.005) though this relationship was
      no longer significant at the 5% level after adjustment (mean difference=13.4; 95%
      CI=-2.0 to 28.8; P=0.09). LIMITATIONS: There was a high initial dropout rate from
      the study and a small sample size. A prospective study would have more power in
      determining the effect of mood fluctuations. CONCLUSIONS: Mood fluctuation may be
      a useful indicator of risk of deliberate self-harm and attempted suicide.

PMID- 15023499
TI  - Remission in major depression with two antidepressant mechanisms: results from a
      naturalistic study.
AB  - BACKGROUND: Since remission should be the goal of the treatment of depression,
      the aims of this study were to evaluate the rate of remission obtained with SSRIs
      in routine clinical practice and to assess alternative treatments with a combined
      mechanism of action. METHODS: The study involved a prospective naturalistic 6
      month follow-up of 44 consecutive unipolar depressed (DSM-IV) outpatients. After
      6 weeks of treatment with a SSRI, patients were classified as remitted (HAM-D-17
      score <==7), partial responders (>/=50% reduction in HAM-D-17 score but still
      higher than 7) and non-responders. In case of non-response, an antidepressant
      with noradrenergic action (NaA) was added to the ongoing SSRI treatment or were
      switched to venlafaxine in monotherapy when NaA was contraindicated. RESULTS: At
      6 weeks, eight patients (18.1%) achieved full remission, nine patients (20.5%)
      were partial responders and 27 (61.4%) non responders. At the end of follow-up
      31.8% (n=14) of the initial sample remained remitted with SSRIs, whereas 96.2%
      (26/27) of previous non-responders experienced remission with the alternative
      treatment. Non-responders to SSRIs in monotherapy were significantly more likely
      to show melancholic features and to have higher HAM-D-17 scores and lower GAF
      scores than remitted patients with SSRIs. LIMITATIONS: the observational and
      naturalistic design of the study determines inherent limitations. CONCLUSIONS:
      this study showed a low remission rate with SSRIs in the long-term treatment of
      more severe and melancholic depression, and the benefit of using treatments with
      a combined mechanism of action.

PMID- 15023500
TI  - Mixed anxiety-depression in a 1 year follow-up study: shift to other diagnoses or
      remission?
AB  - BACKGROUND: In 1992, the ICD-10 introduced the concept of mixed anxiety
      depression disorder (MAD). However, a study examining the stability of this ICD
      10-diagnosis is lacking. Our objective was to examine the 12 month outcome of MAD
      in comparison to the outcome of depression, anxiety, and comorbid depression and
      anxiety. METHODS: 85 MAD patients, 496 patients with major depression, 296
      patients with anxiety disorders, and 306 comorbid patients were reassessed after
      12 months. Rates of depression, anxiety, and MAD were compared using chi(2)
      tests. RESULTS: While depressive disorders and anxiety disorders showed
      relatively high stability, MAD Patients had no higher rates of MAD at follow-up
      than patients with depression, anxiety or both. LIMITATIONS: Detailed information
      regarding treatment and disorders during the follow-up interval was lacking.
      Prevalence rates of MAD in single centres were too small for contrasting centres.
      CONCLUSIONS: MAD cannot be seen as a stable diagnosis: Most of MAD patients
      remit; many of them shift to other diagnoses than depression or anxiety. The ICD
      10 criteria have to be specified more exactly.

PMID- 15023501
TI  - Phenomenological and comorbid features associated in obsessive-compulsive
      disorder: influence of age of onset.
AB  - BACKGROUND: To explore clinical features of symptoms and comorbidity according to
      the age of onset of patients suffering from obsessive-compulsive disorder (OCD).
      METHODS: The survey involved collecting data from both patient members of an OCD
      association, and a sample of 175 OCD patients seen in OCD specialty practice. All
      the patients (n=617) responded to a questionnaire on family and personal
      psychiatric OCD history, phenomenological features of OCD and comorbidity. They
      were classified according to OCD age at onset [group early age of onset (EO):
      under 15, group late age of onset (LO): older than 15]. RESULTS: A higher
      percentage of patients from Group LO complained of OCD triggering by factors such
      as professional difficulties and childbirth (P<0.05); also they more often had
      (P=0.05) a sudden onset of symptoms. On the other hand, clinical features, such
      as superstition and magic thoughts, parasite obsessions and repeating, counting,
      hoarding, tapping/rubbing and collecting compulsions were significantly more
      frequent (P<0.05) in EO; likewise, history of tics was more frequent in this
      group. The existence of comorbid depression (at least one episode) did not show
      any significant difference between groups. However, depression preceding OCD was
      more frequent in LO. There was no significant difference in treatment response
      according to age of onset OCD. CONCLUSIONS: The results showed a clear
      association of EO with obsessions of superstition and parasites, repetitive
      compulsions and motor and vocal tics, whereas a sudden onset, triggering factors
      and a more frequent depression preceding OCD characterized LO.

PMID- 15023502
TI  - Characteristics of rapid cycling bipolar-I patients in a bipolar speciality
      clinic.
AB  - OBJECTIVES: To investigate the characteristics of patients with rapid cycling
      bipolar illness. METHODS: The charts of bipolar patients treated at the
      Massachusetts General Hospital Bipolar Clinic were reviewed for age of the first
      affective episode, demographics and history of rapid cycling. RESULTS: Data from
      223 bipolar-I-II patients, of whom 11.7% were bipolar-II, were obtained, and only
      the data from 197 bipolar-I patients were analyzed. Forty-three percent of them
      had a positive history of rapid cycling. Rapid cycling was more common in women,
      with rapid cycling females having an earlier age of onset than non-rapid cycling
      bipolar-I females. No such association was found in bipolar-I males. In addition,
      with respect to current age, rapid cyclers were younger than non-rapid cyclers in
      bipolar-I females. No association was found for duration of illness. CONCLUSIONS:
      Women with bipolar-I illness have an increased probability of rapid cycling,
      which may still be increased in those with an early onset. Therefore, biological
      factors, such as sex and age onset, appear to be relevant to the physiology of
      rapid cycling. The retrospective design and the selected population of bipolar-I
      patients from an academic tertiary-referral center may limit the generalizability
      of our results.

PMID- 15023503
TI  - Decreasing TSH levels in patients with Seasonal Affective Disorder (SAD)
      responding to 1 week of bright light therapy.
AB  - BACKGROUND: Seasonal Affective Disorder (SAD) is characterised by lowered mood
      and atypical depressive symptoms such as hypersomnia, weight gain and fatigue.
      These symptoms seem associated with hypothyroidism, but the results of
      evaluations of the thyroid function in SAD patients have been conflicting, most
      likely due to the very small number of observations. METHODS: In total, 83
      patients fulfilling the DSM-III-R criteria for SAD were treated with bright light
      for 1 week in an open trial. Thyroid function was evaluated by TSH (thyroid
      stimulating hormone), T(4) (thyroxine) and T(3) (triiodthyronine) levels at
      baseline and after 1 week of bright light treatment. RESULTS: The response rate
      in terms of a 50% reduction of pre-treatment scores on the Hamilton Depressions
      Rating Scale (HAM-D(17)) was 61%. The TSH levels in all 83 patients decreased
      significantly from 1.57 at baseline to 1.30 at endpoint. In the group of
      responders (n=52) the TSH levels decreased significantly from 1.71 to 1.37, while
      in the group of non-responders (n=31) the decrease in TSH levels was not
      statistically significant. CONCLUSIONS: During 1 week of bright light therapy the
      TSH levels in SAD patients were reduced, with the highest reduction in the group
      of patients responding to light therapy.

PMID- 15023504
TI  - Minor physical anomalies in non-familial unipolar recurrent major depression.
AB  - BACKGROUND: The prevalence of minor physical anomalies (MPAs) was evaluated in
      patients with unipolar recurrent major depression to get indirect data on the
      possible role of aberrant neurodevelopment in the aetiology of major depression.
      One published study [Lohr et al., Am. J. Geriatr. Psychiatry 5 (1997) 318] on the
      MPA prevalence in unipolar depression, evaluated by the recently widely
      criticized Waldrop-scale, reports on a significantly higher MPA rate among
      patients. METHODS: A scale developed by Mehes [Prog. Clin. Biol. Res. 163 (1985)
      45] was used to detect the presence or absence of 57 MPAs in 30 patients with
      major depression and in 30 matched controls. RESULTS: The depressive sample did
      not differ significantly from the control group (P=0.200). By comparing each MPA
      individually we could not find any significant differences between the depressive
      and the control sample. LIMITATIONS: Patients and control subjects had a negative
      family history in connection with affective disorders; a high-risk population
      should give significant positive results. CONCLUSIONS: The results do not support
      the role of an 'early neurodevelopmental origin' in unipolar depression.

PMID- 15023505
TI  - "Near-fatal" deliberate self-harm: characteristics, prevention and implications
      for the prevention of suicide.
AB  - BACKGROUND: There have been few studies of the most serious cases of deliberate
      self-harm (DSH). These cases represent an important clinical problem. They may
      also be suitable as a "proxy" for suicide in research studies. METHODS: We
      developed a definition of "near-fatal" deliberate self-harm (NFDSH) and
      identified all cases attending accident and emergency departments in an urban
      area during an 18-month period. We compared them to less severe DSH on social and
      clinical characteristics, and examined their initial clinical management. We
      compared their age and gender profile with that of completed suicides. NFDSH
      cases who agreed to be interviewed were asked about their experiences of seeking
      help and their views on prevention of suicide. RESULTS: 158 cases were
      identified, 8% of all DSH. The most common method of self-harm was self
      poisoning. The most common psychiatric diagnosis was depression. Compared to less
      severe DSH, near-fatal cases had higher rates of several social and clinical risk
      factors for suicide and showed evidence of greater suicidal intent. Forty-one
      percent were allowed home following assessment. Most admissions lasted 2 days or
      less. The age and gender profile was closer to that of suicide than in DSH
      generally. Few subjects agreed to be interviewed; those who did described poor
      previous experiences of services. LIMITATIONS: We did not assess each case of DSH
      individually but applied a workable definition of NFDSH. Firm conclusions cannot
      be drawn from the qualitative part of the study because of the low rate of
      agreement to interview. CONCLUSIONS: NFDSH is an important clinical phenomenon
      associated with indicators of high suicide risk. This high risk is frequently not
      reflected in clinical management. Further studies of NFDSH could contribute to
      what is known about suicide prevention but the reluctance of NFDSH subjects to be
      interviewed may be a difficulty for future research.

PMID- 15023506
TI  - The relationship between anger and depression in a clinical sample of young men:
      the role of insecure attachment.
AB  - BACKGROUND: Even though the relevance of insecure attachment in the etiology of
      dysfunctional anger is indicated by a number of findings, few studies have
      examined the relationship between anger and depression from the perspective of
      attachment theory. METHODS: Self-reported measures of trait anger, depression,
      and adult attachment style were simultaneously administered to 87 young men with
      clinically significant depressive symptoms. RESULTS: Higher levels of trait anger
      were associated with an insecure style of attachment. Such an association
      remained significant after controlling for the severity of depressive symptoms.
      In a multiple regression model, both a measure of anxious attachment and a
      measure of avoidant attachment emerged as independent predictors of trait anger.
      LIMITATIONS: The study was cross-sectional and the sample did not include women.
      CONCLUSIONS: Insecure attachment is a useful predictor of anger experience among
      patients with depressive symptoms.

PMID- 15023508
TI  - Substance use and perceived symptom improvement among patients with bipolar
      disorder and substance dependence.
AB  - BACKGROUND: Bipolar disorder (BPD) is the Axis I disorder with the highest risk
      for coexisting substance use disorder. One explanation for this phenomenon is the
      'self-medication hypothesis', which states that some patients experience
      improvement in psychiatric symptoms as a result of substance use. We thus
      investigated reasons for substance use and perceived substance-induced
      improvement in BPD symptoms among patients with current BPD and substance
      dependence. METHODS: A total of 45 patients received six monthly assessments; 21
      also received integrated group therapy (IGT), focusing simultaneously on BPD and
      substance dependence, while 24 did not receive IGT. Patients reported at intake
      their current reasons for initiating substance use (including BPD symptoms) and
      the effects of substance use on those symptoms. RESULTS: Nearly all patients
      initiated substance use because of at least one BPD symptom, especially
      depression (77.8%) and racing thoughts (57.8%); most (66.7%) reported improvement
      in at least one BPD symptom as a result of substance use. Among patients
      reporting substance-induced improvement in BPD symptoms, those receiving IGT
      reported fewer days of drug use over the 6-month study period than those not
      receiving IGT; this difference was not significant among patients without
      substance-induced improvement in BPD symptoms. LIMITATIONS: The study is limited
      by its small sample size and by the potential inaccuracy of self-reports
      regarding the effects of substance use on mood. CONCLUSIONS: Substance dependent
      patients who report that substance use improves their BPD symptoms may benefit
      from treatment that focuses simultaneously on both disorders.

PMID- 15023509
TI  - Cerebrospinal fluid interleukin (IL)-6 in unipolar major depression.
AB  - BACKGROUND: Previous studies have suggested that regulation of the
      proinflammatory cytokine interleukin (IL)-6 is abnormal in patients with major
      depression. This study was undertaken to determine whether IL-6 concentrations in
      cerebrospinal fluid (CSF) differ between depressed patients and healthy control
      subjects. METHODS: Lumbar puncture with a standardized procedure was performed on
      18 drug-free patients meeting DSM-IV criteria for unipolar major depression and
      26 age- and sex-matched healthy volunteers. CSF was assayed for IL-6 using a
      quantitative 'sandwich' enzyme immunoassay technique. RESULTS: Mean+/-S.D. CSF IL
      6 levels did not differ between depressed (2.2+/-1.0 pg/ml) and healthy control
      (2.4+/-1.9 pg/ml) subjects. LIMITATIONS: This study had adequate power (0.8) to
      detect a large (d=0.88) effect size at alpha = 0.05. Although sample sizes were
      comparable to or larger than those of previous CSF studies, it is possible that a
      less robust difference between depressed and healthy subjects was not detected.
      CONCLUSIONS: These findings fail to support speculation that immune activation
      may be causally involved in the pathogenesis of depression.

PMID- 15023507
TI  - Oxcarbazepine as add-on treatment in patients with bipolar manic, mixed or
      depressive episode.
AB  - OBJECTIVES: The aim of this preliminary open-label trial was to evaluate the
      efficacy and safety of oxcarbazepine (OXC) as adjunctive therapy in 18 patients
      with bipolar disorder who did not respond satisfactorily to lithium. METHODS:
      Eighteen patients with bipolar I (n=16) and bipolar II (n=2) disorder were
      treated openly with OXC for a 8-week period as add-on treatment to the existing
      lithium regimen. After the 8-week trial, all patients continued the treatment
      with OXC, and were followed-up prospectively. Outcome measures included the
      Clinical Global Impression-Bipolar Version Scale, the Bech-Rafaelsen Mania
      Melancholia Scale and the Brief Psychiatric Rating Scale. These scales were
      administered at baseline and at the end of weeks 2, 4 and 8. Patients were
      subsequently assessed every 4 months for a period of time ranging from 4 to 12
      months with the Longitudinal Interval Follow-up Evaluation. RESULTS: The mean
      dose of OXC at the end of week 8 was 919.4 mg/day (SD+/-335.7). Eleven of the 18
      patients were considered responders. The remaining seven patients were rated as
      nonresponders. Of the eleven responders to the 8-week trial, seven patients
      remained mood-stabilized for the entire period of follow-up. CONCLUSIONS: OXC
      appeared to be significantly effective as add-on strategy in 60% of patients
      after 8 weeks of treatment. A substantial proportion (66.3%) of the 8-week trial
      responders maintained a satisfactory mood stabilization during the follow-up.
      Despite several limitations, our study suggests the potential usefulness of OXC
      as adjunctive therapy to lithium both in acute and long-term treatment of bipolar
      disorder.

PMID- 15023511
TI  - Borderline personality disorder in patients with bipolar disorder and response to
      lamotrigine.
AB  - BACKGROUND: Recent reports suggesting lamotrigine as an effective treatment in
      bipolar disorder, and perhaps borderline personality disorder, a common comorbid
      personality disorder in bipolar patients, led us to retrospectively examine
      patients from two bipolar studies to investigate this pattern of comorbidity, and
      to determine whether lamotrigine effected the dimensions of borderline
      personality. METHODS: Fifteen months following entry into either study, we
      retrospectively assessed DSM-IV dimensions of borderline personality disorder pre
      and post-treatment with lamotrigine in 35 bipolar patients. RESULTS: Forty
      percent met criteria for borderline personality disorder; this subgroup had a
      more frequent history of substance abuse and childhood symptoms of attention
      deficit hyperactivity disorder (ADHD). Dimensions of borderline personality
      improved significantly with treatment in both patient groups, and corresponded
      with response of bipolar symptoms. Six (43%) comorbid bipolar patients endorsed
      three or fewer criteria of borderline personality during treatment with
      lamotrigine. There was a trend for comorbid bipolar patients to require a second
      psychoactive medication in addition to lamotrigine during extended treatment.
      LIMITATIONS: Criteria for borderline personality and improvement were assessed
      retrospectively in an open manner. CONCLUSIONS: Dimensions of borderline
      personality disorder may respond to lamotrigine in comorbid bipolar patients;
      controlled studies appear warranted. Bipolar studies should assess and specify
      the number of patients with personality disorders in the trial.

PMID- 15023510
TI  - The prevalence and clinical correlates of anger attacks during depressive
      episodes in bipolar disorder.
AB  - BACKGROUND: Anger attacks, characterized by sudden episodes of intense anger with
      autonomic arousal, have been described in patients with major depressive disorder
      (MDD). This study compared the prevalence and clinical significance of anger
      attacks in unipolar versus bipolar depression. METHODS: Using the questionnaire
      of Fava et al. [Psychopharmacol. Bull. 27(3) (1991) 275-279], we assessed rates
      of anger attacks among outpatients with MDD (n=50) or bipolar disorder (BPD)
      (n=29) who were currently in a pure depressive episode. RESULTS: Anger attacks
      were significantly more common among bipolar (62%) than unipolar (26%) depressed
      individuals. In a multiple logistic regression, the presence of anger attacks
      emerged as a significant predictor of bipolarity. LIMITATIONS: This preliminary
      finding should be confirmed in a larger sample. CONCLUSIONS: These results
      suggest that anger attacks may be a common feature of bipolar depression.

PMID- 15023512
TI  - Correlates of coping with perceived discriminatory experiences among African
      American adolescents.
AB  - This study examined the relation of background and race-related factors to the
      use of approach and avoidance strategies to cope with perceived discriminatory
      experiences among a sample of African American adolescents of relative affluence
      ( n = 71). Results showed that gender, family structure, socioeconomic status
      (SES), perceived control over discriminatory experiences, discrimination
      distress, and racism-related socialization were significant correlates of coping
      with perceived discriminatory experiences. Results concerning gender, perceived
      control, and stress arousal were consistent with findings from the general
      adolescent stress and coping literature. Results concerning family structure,
      SES, and socialization suggest that certain factors may be very important for the
      positive adjustment of African American adolescents in the face of race-related
      adversity.

PMID- 15023513
TI  - Ethnic identity and self-esteem: examining the role of social context.
AB  - This study explored ethnic identity and self-esteem among 1062 Mexican-origin
      adolescents who were attending one of three schools, which varied in their ethnic
      composition (i.e., predominantly Latino, predominantly non-Latino, and balanced
      Latino/non-Latino). Significant relationships emerged between ethnic identity and
      self-esteem among adolescents in all school settings. Furthermore, controlling
      for generation and maternal education, adolescents attending the predominantly
      non-Latino school reported significantly higher levels of ethnic identity than
      adolescents in the other schools. Consistent with ecological theory, these
      findings challenge researchers to design future studies in ways such that
      multiple layers of context and their influence on development can be examined.

PMID- 15023514
TI  - Gender and identity status differences in late adolescents' possible selves.
AB  - The current study examined gender and identity status differences in late
      adolescents' possible selves. The intent of the study was to clarify conflicts
      between theory and research on gender differences in identity by investigating
      the content of participants' possible selves. Participants completed measures of
      identity and possible selves. The results indicated that there was a relationship
      between gender and the mean number of both feared and balanced interpersonally
      themed possible selves. The pattern of results is discussed in terms of prior
      findings regarding gender differences in both identity and possible selves.
      Suggestions for future research are also provided.

PMID- 15023515
TI  - The role of stressful life events in the development of depressive symptoms in
      adolescence--a longitudinal community study.
AB  - Depressive symptoms were measured in a cohort of community-based adolescents (n =
      163) at two time-points, with 1 year intervening. At Time 2, participants also
      answered a scale about past-year stressful life events. Depressive symptoms
      increased from Time 1 to Time 2, the effect being stronger for girls than for
      boys. Depressive symptoms were significantly correlated with concurrent measures
      of recent stressful life events, but this relationship disappeared after
      controlling for previous depressive symptoms. Rather, previous level of
      depressive symptoms predicted stressful life events. This demonstrates that a
      unidirectional model of stressful life events as the cause of depressive symptoms
      in adolescents is too simplistic.

PMID- 15023516
TI  - The causal ordering of mathematics anxiety and mathematics achievement: a
      longitudinal panel analysis.
AB  - Using data from the Longitudinal Study of American Youth (LSAY), we aimed to
      determine the causal ordering between mathematics anxiety and mathematics
      achievement. Results of structural equation modelling showed that, across the
      entire junior and senior high school, prior low mathematics achievement
      significantly related to later high mathematics anxiety, but prior high
      mathematics anxiety hardly related to later low mathematics achievement.
      Mathematics achievement was more reliably stable from year to year than
      mathematics anxiety. There were statistically significant gender differences in
      the causal ordering between mathematics anxiety and mathematics achievement.
      Prior low mathematics achievement significantly related to later high mathematics
      anxiety for boys across the entire junior and senior high school but for girls at
      critical transition points only. Mathematics anxiety was more reliably stable
      from year to year among girls than among boys.

PMID- 15023517
TI  - After school activities, overweight, and obesity among inner city youth.
AB  - We examined the association of adolescent obesity with participation in sports
      among 5489 low-income, inner city public high school students. Among inner city
      youth 28.5% of males and 33.7% of females were overweight and 15.9% of boys and
      16.4% of girls were obese. For both males and females, participation in an
      increasing number of athletic activities was associated with lower (body mass
      index) BMI after controlling for age, grade, and playing football. While youth
      with lower BMI might be more likely to participate in sports, after school sports
      are a potential opportunity for prevention of obesity in adolescents.

PMID- 15023518
TI  - Attachment contexts of adolescent friendship and romance.
AB  - The purpose of this study was to compare memories of attachments to parents,
      friends, and romantic partners in relation to the maintenance of high school
      friendships and romantic relationships. College students recorded the length of
      their friendships and romantic relationships during high school and rated the
      quality of each. They also rated their memories of attachments to parents,
      friends, and partners during that time. Parental attachments were the most
      reliable predictor of friendship outcomes and romantic attachments the most
      reliable predictor of romantic outcomes, but attachments to parents, friends, and
      partners each predicted unique variation in maintenance of romantic
      relationships.

PMID- 15023519
TI  - Brief report: Test-retest reliability of self-reported adolescent risk behaviour.
AB  - There is a paucity of test-retest reliability data for adolescent self-reports of
      a wide range of risk behaviours. Grade 8 and 11 students (N = 358) completed a
      questionnaire on two occasions between 10 and 14 days apart. It included items
      about use of various substances, violent behaviour, suicidality, and sexuality.
      Cohen's kappa was almost perfect for 1 item (kappa = 85.4%); in the substantial
      range (61-80%) for 4 items; and in the moderate range (41-60%) for 3 items. For
      the remaining 7 items, the percentage agreement was higher than 92.0%. The
      questionnaire thus demonstrates adequate test-retest reliability.

PMID- 15023520
TI  - Brief report: Depressive symptoms and quality of life in adolescents with b
      thalassaemia.

PMID- 15023523
TI  - Influence of an altered methylation potential on mRNA methylation and gene
      expression in HepG2 cells.
AB  - S-adenosylhomocysteine (AdoHcy), a by-product and inhibitor of S
      adenosylmethionine (AdoMet)-dependent methylation reactions, is removed by AdoHcy
      hydrolase. The ratio of AdoMet and AdoHcy, also termed methylation potential
      (MP), is a metabolic indicator for cellular methylation status. In the present
      study, we have investigated the influence of hypoxia and inhibition of AdoHcy
      hydrolase on MP in HepG2 cells. Furthermore, we studied the impact of deviations
      in MP on mRNA and DNA methylation and the expression of selected genes:
      erythropoietin, VEGF-A, AdoHcy hydrolase, cyclophilin, and HIF-1alpha. Under
      hypoxic conditions, the MP raised from 53.4 +/- 3.3 to 239.4 +/- 24.8, which is
      the result of increased AdoMet and decreased AdoHcy levels. Inhibition of AdoHcy
      hydrolase by adenosine-2',3'-dialdehyde leads to a 40-fold reduction of the MP
      under both normoxic and hypoxic conditions. Hypoxia increases erythropoietin (2.7
      fold) and VEGF-A (5-fold) mRNA expression. During a reduced MP erythropoietin
      mRNA expression is lowered under normoxia and hypoxia by 70%, whereas VEGF-A mRNA
      expression is only reduced under hypoxic conditions by 60%. The mRNA expression
      of AdoHcy hydrolase, HIF-1alpha, and cyclophilin is insensitive to an altered MP.
      Furthermore, decreased MP leads to a highly significant decrease in overall mRNA
      methylation. Our results show that the mRNA levels of the studied genes respond
      differentially to changes in MP. This implies that genes with a slower
      transcription rate and mRNAs with a slower turnover are insensitive to short-term
      changes in MP.

PMID- 15023522
TI  - Involvement of reactive oxygen species in cardiotrophin-1-induced proliferation
      of cardiomyocytes differentiated from murine embryonic stem cells.
AB  - Cardiotrophin-1 (CT-1) is a cytokine that is involved in the growth and survival
      of cardiac cells. In the present study, we demonstrate that treatment of embryoid
      bodies grown from pluripotent murine embryonic stem (ES) cells with CT-1
      significantly stimulated cardiomyogenesis and increased nuclear expression of the
      proliferation marker Ki-67. The increase in Ki-67 expression was inhibited upon
      pretreatment with the free radical scavenger vitamin E, indicating a role for
      reactive oxygen species (ROS) in the signaling cascade. CT-1 treatment of cardiac
      cells raised intracellular ROS in ES cell-derived cardiomyocytes. ROS were
      presumably generated by an NADPH-oxidase since ROS generation was down-regulated
      upon preincubation with the NADPH-oxidase inhibitor diphenylen iodonium chloride
      (DPI) and LY294002, which inhibits phosphatidylinositol 3 kinase (PI3-kinase). CT
      1 activated nuclear factor-kappaB (NF-kappaB) and induced phosphorylation of the
      Janus kinase signal transducer-2 (Jak-2), the signal transducer and activator of
      transcription-3 (STAT-3) as well as the extracellular signal-regulated kinase 1,2
      (ERK1/2). STAT-3 and ERK1/2 phosphorylation as well as NF-kappaB activation were
      inhibited by pretreatment with the Jak-2 antagonist AG490, the ERK1/2 inhibitor
      PD98059, the free radical scavenger vitamin E, the NADPH-oxidase inhibitor DPI,
      as well as by LY294002. PD98059 failed to inhibit Jak-2 phosphorylation,
      indicating that the ERK and the Jak/STAT signaling cascade interact on a level
      downstream of Jak-2. It is concluded that CT-1 stimulates the proliferation of ES
      cell-derived cardiomyocytes by signaling pathways that involve ROS as signaling
      molecules in the signal transduction cascade.

PMID- 15023524
TI  - DEF6, a novel PH-DH-like domain protein, is an upstream activator of the Rho
      GTPases Rac1, Cdc42, and RhoA.
AB  - In this paper, we describe the characterization of DEF6, a novel PH-DH-like
      protein related to SWAP-70 that functions as an upstream activator of Rho
      GTPases. In NIH 3T3 cells, stimulation of the PI 3-kinase signaling pathway with
      either H2O2 or platelet-derived growth factor (PDGF) resulted in the
      translocation of an overexpressed DEF6-GFP fusion protein to the cell membrane
      and induced the formation of filopodia and lamellipodia. In contrast to full
      length DEF6, expression of the DH-like (DHL) domain as a GFP fusion protein
      potently induced actin polymerization, including stress fiber formation in COS-7
      cells, in the absence of PI 3-kinase signaling, indicating that it was
      constitutively active. The GTP-loading of Cdc42 was strongly enhanced in NIH 3T3
      cells expressing the DH domain while filopodia formation, membrane ruffling, and
      stress fiber formation could be inhibited by the co-expression of the DH domain
      with dominant negative mutants of either N17Rac1, N17Cdc42, or N19RhoA,
      respectively. This indicated that DEF6 acts upstream of the Rho GTPases resulting
      in the activation of the Cdc42, Rac1, and RhoA signaling pathways. In vitro, DEF6
      specifically interacted with Rac1, Rac2, Cdc42, and RhoA, suggesting a direct
      role for DEF6 in the activation of Rho GTPases. The ability of DEF6 to both
      stimulate actin polymerization and bind to filamentous actin suggests a role for
      DEF6 in regulating cell shape, polarity, and movement.

PMID- 15023525
TI  - Ksp-cadherin is a functional cell-cell adhesion molecule related to LI-cadherin.
AB  - Ksp- and LI-cadherin are structurally homologous proteins coexpressed with E
      cadherin in renal and intestinal epithelia, respectively. Whereas LI-cadherin has
      been shown to mediate Ca2+-dependent homotypic cell-cell adhesion independent of
      stable interactions with the cytoskeleton, little is known about the
      physiological role of Ksp-cadherin. To analyze its potential adhesive and
      morphoregulatory functions, we expressed murine Ksp-cadherin in CHO cells. In
      this report, we show that Ksp-cadherin induces homotypic and Ca2+-dependent cell
      cell adhesion that can be specifically blocked with antibodies raised against the
      cadherin repeats EC1 and EC2. Ksp-cadherin mediates about the same quantitative
      adhesive effect (aggregation index) as LI- and E-cadherin. However, the cellular
      phenotype induced by Ksp-cadherin resembles more closely that of LI- than E
      cadherin. This could reflect our observation, that Ksp-cadherin, as well as LI
      cadherin, does not directly interact with beta-catenin. In conclusion, both
      cadherins are thus not only structurally but also functionally related and may
      share other functions within their respective epithelia.

PMID- 15023526
TI  - Modulation of proliferation-specific and differentiation-specific markers in
      human keratinocytes by SMAD7.
AB  - We examined the potential role of SMAD7 in human epidermal keratinocyte
      differentiation. Overexpression of SMAD7 inhibited the activity of the
      proliferation-specific promoters for the keratin 14 and cdc2 genes and reduced
      the expression of the mRNA for the proliferation-specific genes cdc2 and E2F1.
      The ability of SMAD7 to suppress cdc2 promoter activity was lost in transformed
      keratinocyte cell lines and was mediated by a domain(s) located between aa 195
      395 of SMAD7. This domain lies outside the domain required to inhibit TGFbeta1
      signaling, suggesting that this activity is mediated by a novel functional
      domain(s). Examination of AP1, NFkappaB, serum response element, Gli, wnt, and
      E2F responsive reporters indicated that SMAD7 significantly suppressed the E2F
      responsive reporter and modestly increased AP1 activity in proliferating
      keratinocytes. These data suggest that SMAD7 may have a role in TGFbeta
      independent signaling events in proliferating/undifferentiated keratinocytes. The
      effects of SMAD7 in differentiated keratinocytes indicated a more traditional
      role for SMAD7 as an inhibitor of TGFbeta action. SMAD7 was unable to initiate
      the expression of differentiation markers but was able to superinduce/derepress
      differentiation-specific markers and genes in differentiated keratinocytes. This
      latter role is consistent with the ability of SMAD7 to inhibit TGFbeta-mediated
      suppression of keratinocyte differentiation and suggest that the opposing actions
      of SMAD7 and TGFbeta may serve to modulate squamous differentiation.

PMID- 15023527
TI  - Induction of apoptosis in cultured endothelial cells by a cadherin antagonist
      peptide: involvement of fibroblast growth factor receptor-mediated signalling.
AB  - Cadherins are a family of transmembrane glycoproteins mediating calcium
      dependent, homophilic cell-cell adhesion. In addition, these molecules are
      involved in signaling events, regulating such processes as cell motility,
      proliferation, and apoptosis. Members of the cadherin subfamily, called either
      classical or type I cadherins, contain a highly conserved sequence at their
      homophilic binding site consisting of the three amino acids--histidine-alanine
      valine (HAV). Previous studies have shown that peptides containing the HAV motif
      inhibit cadherin-dependent events such as cell aggregation, compaction, and
      neurite outgrowth. We report here that a cyclic peptide, N-Ac-CHAVC-NH2 can
      perturb cadherin-mediated endothelial cell interactions, resulting in a
      progressive apoptotic cell death. This effect depends on cell density, as it is
      only observed when dense cultures are treated with the peptide. Adherens junction
      (AJ)-associated cadherin and catenins are differentially affected by the N-Ac
      CHAVC-NH2 treatment, as judged by double immunofluorescence labeling followed by
      immunofluorescence-ratio imaging. However, cell-cell adhesions are largely
      retained during the first few hours after addition of the peptide. It was also
      observed that following treatment, actin filaments partially lose their plasma
      membrane anchorage at AJs and translocate towards the cell center. Interestingly,
      addition of basic fibroblast growth factor to confluent, peptide-treated,
      endothelial cell cultures, completely blocks apoptosis and the inhibitory peptide
      reduce the phosphorylation of the FGF receptor target protein FRS2, suggesting
      that the peptide exerts its effect by inhibiting cadherin-mediated activation of
      fibroblast growth factor receptor signaling. We propose that cadherin-mediated
      signaling is essential for maintaining viability of confluent endothelial cells,
      and that its perturbation by N-Ac-CHAVC-NH2 drives these cells to apoptosis.

PMID- 15023528
TI  - Differentiating the effects of Cx36 and E-cadherin for proper insulin secretion
      of MIN6 cells.
AB  - Connexins have been implicated in many cell functions, even though in most cases
      it is still unclear whether these functions may actually be mediated by other
      proteins that are secondarily affected by connexin changes. Secretory systems
      provide useful models in which to tackle this central question. Primary
      pancreatic beta-cells and insulin-producing lines are connected by gap junction
      channels made of Cx36. Using stable transfection of an antisense Cx36 cDNA, we
      have previously obtained clones of MIN6 cells that featured a markedly reduced
      expression of Cx36 and impaired insulin secretion. Here, we first show that this
      change also resulted in loss of E-cadherin and occludin expression, thus
      preventing the attribution of the secretory defects to a specific type of
      membrane protein. To investigate this question, we have now restored the
      expression of either Cx36 or E-cadherin in the Cx36 antisense-transfected cells.
      We show that a lentivirus-mediated transduction efficiently restored Cx36
      expression in MIN6 cells and allowed for expression of variable levels of this
      protein. We further document that adequate but not excessive levels of Cx36
      allowed for recover of normal insulin secretion in response to various
      secretagogues. Finally, we demonstrate that restoration of normal E-cadherin
      expression was not able to achieve the same secretory correction. The data
      demonstrate that Cx36, but not E-cadherin, is necessary to control specific steps
      of beta-cell secretion.

PMID- 15023529
TI  - LIM kinase 1, a key regulator of actin dynamics, is widely expressed in embryonic
      and adult tissues.
AB  - The expression of endogenous LIM kinase 1 (LIMK1) protein was investigated in
      embryonic and adult mice using a rat monoclonal antibody (mAb), which recognizes
      specifically the PDZ domain of LIMK1 and not LIMK2. Immunoblotting analysis
      revealed widespread expression of LIMK1 existing as a 70-kDa protein in tissues
      and in cell lines, with a higher mass form (approximately 75 kDa) present in some
      tissues and cell lines. Smaller isoforms of approximately 50 kDa were also
      occasionally evident. Immunofluorescence analysis demonstrated LIMK1 subcellular
      localization at focal adhesions in fibroblasts as revealed by co-staining with
      actin, paxillin and vinculin in addition to perinuclear (Golgi) and occasional
      nuclear localization. Furthermore, an association between LIMK1 and paxillin but
      not vinculin was identified by co-immunoprecipitation analysis. LIMK1 is enriched
      in both axonal and dendritic growth cones of E18 rat hippocampal pyramidal
      neurons where it is found in punctae that extend far out into filopodia, as well
      as in a perinuclear region identified as Golgi. In situ, we identify LIMK1
      protein expression in all embryonic and adult tissues examined, albeit at
      different levels and in different cell populations. The rat monoclonal LIMK1
      antibody recognizes proteins of similar size in cell and tissue extracts from
      numerous species. Thus, LIMK1 is a widely expressed protein that exists as
      several isoforms.

PMID- 15023530
TI  - Immortalization in a normal foreskin fibroblast culture following transduction of
      cyclin A2 or cdk1 genes in retroviral vectors.
AB  - Human diploid fibroblasts (HDF) rarely, if ever, undergo spontaneous
      transformation to an immortalized cell type. Here we report the immortalization
      of an HDF cell line following transduction with cyclin A2 or cdk1 human genes via
      retroviral vectors. Fluorescence in situ hybridization (FISH) studies using the
      retroviral vector as a probe indicate that these cell lines are monoclonal. No
      telomerase activity could be detected in these cell lines, and the telomere
      length in the immortalized cells was observed to be 10-20 kb longer than that in
      low-passage cells from the parental fibroblast line. Cytogenetic studies revealed
      that the immortal lines share common chromosomal aberrations. FISH studies with a
      probe for p53 revealed loss of one copy of this gene which was associated with
      reduced steady-state levels of both p53 and p53-regulated p21(WAF1/Sdi1/CIP1)
      messages in both quiescent and proliferating immortalized cultures relative to
      the parental cells. Additional FISH studies with probes for p16(INK4a) and Rb,
      carried out after the immortalized cells proliferated in excess of 100 population
      doublings, also revealed loss of one copy of these genes in both cell lines.
      These cell lines, together with the well-characterized parental cells, could
      provide useful research material for the study of the mechanisms of
      immortalization and of regulation of proliferative senescence in HDF.

PMID- 15023531
TI  - PTH-related protein enhances MCF-7 breast cancer cell adhesion, migration, and
      invasion via an intracrine pathway.
AB  - Breast cancer is the most common carcinoma that metastasizes to the bone.
      Parathyroid hormone-related protein (PTHrP), a known stimulator of osteoclastic
      bone resorption, is a major mediator of the osteolytic process in breast cancer.
      PTHrP overexpression increases mitogenesis and decreases apoptosis in the human
      breast cancer cell line MCF-7. In this study, MCF-7 cells were used as a model
      system to study the effects of PTHrP on breast cancer cell adhesion, migration,
      and invasion. Clones of MCF-7 cells were established that overexpress wild-type
      PTHrP or PTHrP mutated in the nuclear localization sequence (NLS). Wild-type
      PTHrP-overexpressing cells showed significantly higher laminin adhesion and
      migration, and Matrigel invasion than empty vector-transfectants or cells
      overexpressing NLS-mutated PTHrP. Wild-type PTHrP also increased the cell surface
      expression of the pro-invasive integrins alpha6 and beta4; deletion of the NLS
      negated these effects. Exogenous PTHrP (1-34), (67-86), (107-139), and (140-173)
      had no effect on integrin expression, or on cell adhesion, migration, and
      invasion. These results indicate that PTHrP exerts its effects on cell adhesion,
      migration, invasion, and integrin expression via an intracrine pathway. PTHrP may
      play a role in breast cancer metastasis by upregulating proinvasive integrin
      expression, and controlling PTHrP production in breast cancer may provide
      therapeutic benefit.

PMID- 15023533
TI  - Exchange of serine residues 263 and 266 reduces the function of mouse gap
      junction protein connexin31 and exhibits a dominant-negative effect on the wild
      type protein in HeLa cells.
AB  - To characterize the role of Cx31 phosphorylation, serine residues 263 and 266
      (Cx31Delta263,266) or 266 (Cx31Delta266) alone were exchanged for amino acids
      that cannot be phosphorylated. HeLa cells, which were stably transfected with
      wild type and the two different mutant Cx31-cDNA constructs, were analyzed for
      expression, phosphorylation, localization, formation of functional gap junction
      channels, and degradation of mutant Cx31 protein. Both mutant proteins showed
      similar reduced phosphorylation levels compared to Cx31 wild type, indicating a
      pivotal role of serine residue 266 for Cx31 phosphorylation. None of these
      mutations did interfere with correct intracellular trafficking of gap junction
      proteins. Pulse chase experiments with the different transfectants revealed an
      increased turnover of both mutated Cx31 proteins. They showed decreased
      intercellular communication as shown by dye transfer to neighboring cells and
      measurement of total conductance (mutant Cx31Delta263,266). Mutated Cx31 protein
      (Cx31Delta263,266) diminished the function of the Cx31 wild-type protein
      dependent on the amount of the mutated protein, indicating a dominant-negative
      effect of the mutated protein in HeLa cells.

PMID- 15023532
TI  - The opioid agonist ethylketocyclazocine reverts the rapid, non-genomic effects of
      membrane testosterone receptors in the human prostate LNCaP cell line.
AB  - Neuropeptides influence cancer cell replication and growth. Opioid peptides, and
      opiergic neurons are found in the prostate gland, and they are proposed to exert
      a role in tumor regulation, influencing cancer cell growth, as opioid agonists
      inhibit cell growth in several systems, including the human prostate cancer cell
      line LNCaP. In the same cell line, the existence of membrane testosterone
      receptors was recently reported, which increase, in a non-genomic manner, the
      secretion of PSA, and modify actin cytoskeleton dynamics, through the signaling
      cascade FAK-->PI-3 kinase-->Cdc42/Rac1. In the present work, we present data
      supporting that the general opioid agonist Ethylketocyclazocine (EKC) decreases
      testosterone-BSA (a non-internalizable testosterone analog) induced PSA
      secretion. Furthermore, we report that this opioid affects this non-genomic
      testosterone action, by modifying the distribution of the actin cytoskeleton in
      the cells, disrupting the above signaling cascade. In addition, after long (>24
      h) incubation, opioids decrease the number of membrane testosterone receptors,
      and reverse their effect on the signaling molecules. In conclusion, our results
      provide some new insights of a possible action of opioids in prostate cancer
      control by interfering with the action and the expression of membrane
      testosterone receptors and signaling.

PMID- 15023534
TI  - Conditioned medium from osteocytes stimulates the proliferation of bone marrow
      mesenchymal stem cells and their differentiation into osteoblasts.
AB  - Osteocytes are the most abundant cells in bone and there is increasing evidence
      that they control bone remodeling via direct cell-to-cell contacts and by soluble
      factors. In the present study, we have used the MLO-Y4 cell line to study the
      effect of osteocytes on the proliferation, differentiation and bone-forming
      capacity of bone marrow mesenchymal stem cells (MSC). Conditioned media (CM) from
      osteocytic MLO-Y4 and osteoblastic MC3T3-E1 cell lines were collected and added
      on mouse bone marrow cultures, in which MSC were induced to osteoblasts. There
      was a significant increase in alkaline phosphatase activity and osteocalcin
      expression in the presence of MLO-Y4 CM. No such stimulus could be observed with
      MC3T3-E1 CM. There was almost 4-fold increase in bone formation and up to 2-fold
      increase in the proliferation of MSC with MLO-Y4 CM. The highly proliferating
      bone marrow cells were negative for ALP and OCN, suggesting that they could
      represent early osteoblast precursors. MLO-Y4 CM did not enhance the viability of
      mature osteoblasts nor protected them of apoptosis. This is the first study to
      describe soluble signals between osteocytes and osteoblasts and there most likely
      are several still unidentified or unknown factors in osteocyte CM. We conclude
      that osteocytes have an active stimulatory role in controlling bone formation.

PMID- 15023535
TI  - Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65
      controls transcription at the nuclear level.
AB  - It has been proposed that ligand-dependent Regulated Intramembrane Proteolysis
      (RIP) of ErbB-4 receptors generates 80 kDa Intra-Cellular Domains (E4.ICDs) that
      relocate to the nuclear compartments where they implement the signaling abilities
      of the ErbB-4 receptors. The E4.ICD may directly regulate gene transcription or,
      in an alternative scenario, the tyrosine kinase activity of E4.ICDs may target
      proteins involved in transcriptional regulation upon its relocation into the
      nucleus. We have identified the transcriptional coactivator YAP65, here referred
      as YAP (Yes Associated Protein), as binding partner of ErbB-4 in a two hybrid
      screening in yeast. Interaction between YAP and ErbB-4 occurs via the WW domain
      of YAP and the PPPPY at positions 1297-1301 and the PPPAY at positions 1052-1056
      of the amino acid sequence of the Cyt-1 isoform of ErbB-4. Stechiometry of
      binding is regulated by the ligand-dependent phosphorylation of Tyr 1056 in the
      PPPAYTPM module that function as "biochemical switch" to decrease the association
      of YAP to ErbB-4. In principle, this novel interaction highlights new mechanisms
      of signaling propagation from the ErbB-4 receptors, offering supporting evidences
      that the E4.ICDs forms released following ligand-receptor engagement may recruit
      YAP and relocate to the nucleus to implement or regulate transcription.

PMID- 15023536
TI  - Intracellular trafficking of heat shock factor 2.
AB  - HSF2 is an enigmatic member of the heat shock factor family, identified in the
      homeotherm classes of birds and mammals. We report the characterization of HSF2
      from an evolutionary ancient vertebrate, the fish rainbow trout (rtHSF2). rtHSF2
      appears closely related to its mammalian counterparts at structural and
      functional levels. The conservation of the distinctive features of HSF2 from fish
      to human suggests that it should ensure important biological functions, not
      redundant with those of HSF1. Proteasome inhibition, reported as a potent
      stimulator of HSF2, leads to the stabilization and to a striking nuclear
      trafficking of rtHSF2-GFP fusion protein. Upon treatment with the proteasome
      inhibitor MG132, rtHSF2-GFP accumulates into PML nuclear bodies (NBs)
      independently of its sumoylation and, if expressed at moderate level, moves to
      nucleoli. The translocation of rtHSF2-GFP from NBs to nucleoli is greatly favored
      by overexpression of the heat shock protein Hsp70. The mammalian counterpart
      mouse HSF2 (mHSF2) also exhibited changes in intracellular distribution upon
      MG132 treatment. mHSF2 partitioned between a juxtanuclear area that we
      characterized as an aggresome and the nucleoli. These relocalizations are likely
      to reflect common structural changes of mouse and trout HSF2 upon activation.

PMID- 15023537
TI  - Cadherin-related neuronal receptor 1 (CNR1) has cell adhesion activity with beta1
      integrin mediated through the RGD site of CNR1.
AB  - Cadherin-related neuronal receptor (CNR) proteins are a diverse set of synaptic
      protocadherins, but little is known about its adhesive properties. We found that
      overexpressed CNR1 protein localized on the cell surface of HEK293T cells and
      increased the calcium-dependent cell aggregation potential. However, we could not
      detect the strong homophilic binding activity of CNR1 EC-Fc fusion protein in
      vitro. Parental HEK293T cells adhered to Arg-Gly-Asp (RGD) motif of EC1 domain of
      CNR1-Fc fusion protein. The fusion protein that the Asp73 of EC1 point-mutated to
      Glu (RGE-Fc) lost the adhesive activity. The adhesion activity of HEK293T cells
      to CNR1 EC-Fc fusion protein was completely blocked by inhibitors of integrins,
      including RGDS peptide and anti-beta1 integrin antibodies. The increased cell
      aggregative property of CNR1 transfectants was also blocked by RGDS peptides. At
      cell-cell junctions of the CNR1 transfectants, co-localization between CNR1 and
      HEK293T endogenous beta1 integrin was observed. Furthermore, the spatiotemporal
      expression patterns of CNR and beta1 integrin nearly overlapped in the molecular
      layer of the developing mouse cerebellum in the main stage of synaptogenesis.
      These results indicate that CNR1 has a heterophilic, calcium-dependent cell
      adhesion activity with the beta1 integrin subfamily, and raise the possibility of
      CNR-beta1 integrin association in synaptogenesis.

PMID- 15023538
TI  - Expression of dominant negative rab5 in HeLa cells regulates endocytic
      trafficking distal from the plasma membrane.
AB  - Ligand-mediated endocytosis is an important regulatory mechanism of epidermal
      growth factor (EGF) receptor (EGFR) signal transduction. Coordinated EGFR
      internalization and degradation function to regulate the spatial and temporal
      components of EGFR-effector interactions. In an effort to better understand the
      molecular mechanisms that control these events, we examined the role of rab5 in
      the endocytic trafficking of the EGFR. Rab5 is a 25-kDa guanine nucleotide
      binding protein that has previously been shown to be involved in the early stages
      of endocytic trafficking. Using adenovirally expressed dominant negative and
      constitutively active rab5 [rab5(S34N) and rab5(Q79L)] in cells with endogenous
      EGFRs, we have found that the guanine nucleotide binding state of rab5 has no
      bearing on the rate of EGFR endocytosis. However, expression of dominant negative
      rab5 affects downstream endocytic trafficking by slowing the ligand-induced
      disappearance of total cellular EGFR. Using confocal microscopy to examine
      EGF/EGFR and rab5 localization indicates that the activity of rab5 governs
      whether internalized EGF/EGFR and rab5 co-localize. Transferrin, which
      internalizes via a constitutively internalized cell surface receptor, co
      sediments with rab5(WT), but not rab5(S34N) on sucrose gradients. Taken together,
      these data are consistent with rab5 functioning to regulate intracellular
      endocytic trafficking distal from the plasma membrane.

PMID- 15023539
TI  - Distinct stress and cell destruction pathways are engaged by TNF and ceramide
      during apoptosis of MCF-7 cells.
AB  - Ceramide has been proposed to be an important signaling intermediate in tumor
      necrosis factor (TNF)-induced apoptosis in human MCF-7 breast adenocarcinoma
      cells. We compared cell death and signal transduction pathways induced by TNF and
      ceramide in TNF-sensitive, parental MCF-7 cells to those in TNF-resistant, MCF-7
      cells (3E9). TNF caused proteolysis of the caspase substrate, polyADP-ribose
      polymerase (PARP) in parental cells, but not in 3E9 cells. Both apoptosis and
      PARP cleavage were strongly prevented by co-incubation with caspase inhibitors.
      In contrast, ceramide-induced cell death was neither affected by TNF resistance
      nor was it associated with PARP cleavage, and death could not be prevented by co
      incubation with caspase inhibitors in either cell line. TNF was able to activate
      JNK/SAPK approximately 30-fold and approximately 5-fold in parental MCF-7 and 3E9
      cells, respectively; in contrast, cell-permeable ceramide only weakly stimulated
      JNK/SAPK activity in either cell type. Although JNK was activated by TNF,
      pharmacological blockade of the JNK pathway did not inhibit TNF- or ceramide
      mediated cell death. Using mass spectroscopic analysis for ceramide, no increase,
      rather, a decrease in total ceramide content in TNF-treated parental cells was
      observed. These results suggest that the cell death signaling and execution
      pathways utilized by ceramide are distinct from those activated by TNF in MCF-7
      cells.

PMID- 15023540
TI  - Synergistic control of keratinocyte adhesion through muscarinic and nicotinic
      acetylcholine receptor subtypes.
AB  - The biological mechanisms involved in initiating, coordinating, and ultimately
      terminating cell-cell adhesion in the stratified epithelium are not well
      understood at present. This study was designed to elucidate the roles of the
      muscarinic M3, the nicotinic alpha3, and the mixed muscarinic-nicotinic alpha9
      acetylcholine receptors in physiologic control of keratinocyte adhesion. Both
      muscarinic and nicotinic antagonists caused keratinocyte detachment and
      reversibly increased the permeability of keratinocyte monolayers, indicative of
      the involvement of both muscarinic and nicotinic pathways in the cholinergic
      control of keratinocyte adhesion. Since phosphorylation of adhesion proteins
      plays an important role in rapid assembly and disassembly of intercellular
      junctions, we measured muscarinic and nicotinic effects on phosphorylation of
      keratinocyte adhesion molecules. The phosphorylation levels of E-cadherin, beta
      catenin, and gamma-catenin increased following pharmacological blockage of
      muscarinic receptors. Long-term blocking of alpha3, alpha9, and M3 receptor
      signaling pathways with antisense oligonucleotides resulted in cell-cell
      detachment and changes in the expression levels of E-cadherin, beta-catenin, and
      gamma-catenin in cultured human keratinocytes. Simultaneous inhibition of several
      receptor subtypes with a mixture of antisense oligonucleotides produced
      intensified abnormalities with cell adhesion. Moreover, altered cell-cell
      adhesion was found in the stratified epithelium of alpha3, alpha9, and M3
      receptor knockout mice. Keratinocytes from these mice exhibited abnormal
      expression of adhesion molecules at both the protein and the mRNA levels. Thus,
      our data indicate that the alpha3, alpha9, and M3 acetylcholine receptors play
      key roles in regulating in a synergistic mode keratinocyte adhesion, most
      probably by modulating cadherin and catenin levels and activities. These findings
      may aid in the development of novel methods useful for the treatment of skin
      adhesion diseases and tumor metastasis.

PMID- 15023542
TI  - Long-term molecular and cellular stability of human neural stem cell lines.
AB  - Human Neural Stem Cells (hNSCs) are excellent candidates for in vitro and in vivo
      molecular, cellular, and developmental research, and also for ex-vivo gene
      transfer and cell therapy in the nervous system. However, hNSCs are mortal
      somatic cells, and thus invariably enter an irreversible growth arrest after a
      finite number of cell divisions in culture. It has been proposed that this is due
      to telomere shortening. Here, we show that long-term cultured (up to 4 years) v
      myc perpetuated hNSC lines do preserve short but stable and homogeneous telomeres
      (TRF and Q-FISH determinations). hNSC lines (but not strains) express high levels
      of telomerase activity, which is activated by v-myc, as demonstrated here.
      Telomerase activity is not constitutive, becoming non-detectable after
      differentiation (in parallel to v-myc down-regulation). hNSC lines also maintain
      a stable cell cycle length, mitotic potential, differentiation and neuron
      generation capacity, and do not express senescence-associated beta-galactosidase
      over years, as studied here. These data, collectively, help to explain the
      immortal nature of v-myc-perpetuated hNSC lines, and to establish them as
      excellent research tools for basic and applied neurobiological and translational
      studies.

PMID- 15023541
TI  - Extracellular alpha 6 integrin cleavage by urokinase-type plasminogen activator
      in human prostate cancer.
AB  - During human prostate cancer progression, the integrin alpha6beta1 (laminin
      receptor) is expressed on the cancer cell surface during invasion and in lymph
      node metastases. We previously identified a novel structural variant of the
      alpha6 integrin called alpha6p. This variant was produced on the cell surface and
      was missing the beta-barrel extracellular domain. Using several different
      concentrations of amiloride, aminobenzamidine and PAI-1 and the urokinase-type
      plasminogen activator (uPA) function-blocking antibody (3689), we showed that
      uPA, acting as a protease, is responsible for production of alpha6p. We also
      showed that addition of uPA in the culture media of cells that do not produce
      alpha6p, resulted in a dose-dependent alpha6p production. In contrast, the
      addition of uPA did not result in the cleavage of other integrins. Using alpha2
      antiplasmin and plasmin depleted media, we observed that uPA cleaves the alpha6
      integrin directly. Further, 12-o-tetradecanoyl-phorbol-13-acetate (TPA) induced
      the production of alpha6p, and this induction was abolished by PAI-1 but not
      alpha2-antiplasmin. Finally, the alpha6p integrin variant was detected in
      invasive human prostate carcinoma tissue indicating that this is not a tissue
      culture phenomenon. These data, taken together, suggest that this is a novel
      function of uPA, that is, to remove the beta-barrel ligand-binding domain of the
      integrin while preserving its heterodimer association.

PMID- 15023543
TI  - Integrin alpha4beta1 involvement in stromal cell-derived factor-1alpha-promoted
      myeloma cell transendothelial migration and adhesion: role of cAMP and the actin
      cytoskeleton in adhesion.
AB  - The chemokine stromal cell-derived factor-1alpha (SDF-1alpha) is expressed by
      bone marrow (BM) stromal cells and plays key roles in cell homing to and
      retention into the bone marrow. In multiple myeloma, blood-borne malignant plasma
      cells home to the BM and accumulate in contact with stromal cells, implicating
      myeloma cell migration across endothelium. Myeloma cells express the SDF-1alpha
      receptor CXCR4, as well as the integrin alpha4beta1, which mediates their
      attachment to BM stroma. We show here that SDF-1alpha promotes transendothelial
      migration of purified BM myeloma cells and myeloma-derived NCI-H929 cells,
      involving a transient upregulation of alpha4beta1-dependent cell adhesion to the
      endothelium. Characterization of intracellular signaling pathways involved in the
      modulation by SDF-1alpha of alpha4beta1-mediated myeloma cell adhesion revealed
      that intracellular cAMP amounts associated with the activation of protein kinase
      A play key roles in this modulation. Furthermore, a functional link between cAMP
      actions on the dynamics of actin cytoskeleton, RhoA activation, and alpha4beta1
      dependent cell adhesion in response to SDF-1alpha has been found. The regulation
      of alpha4beta1-mediated myeloma cell adhesion by SDF-1alpha could play key roles
      during myeloma cell homing into and trafficking inside the BM, and
      characterization of the molecular events involved in SDF-1alpha-activated
      modulation of this adhesion will contribute to a better understanding of
      mechanisms participating in cell migration.

PMID- 15023545
TI  - Saccharomyces cerevisiae CSM1 gene encoding a protein influencing chromosome
      segregation in meiosis I interacts with elements of the DNA replication complex.
AB  - We present the characteristics of the Csm1 (Spo86) protein of Saccharomyces
      cerevisiae that are important for meiotic division. The level of Csm1p does not
      change throughout the cell cycle, but this protein is absent in mature spores.
      Deletion of CSM1 causes incorrect spore formation and meiotic chromosome
      missegregation together with increased sensitivity of vegetative cells to benomyl
      and manganese. In a two-hybrid analysis with Csm1p as bait, we detected
      interactions with three members of the Mcm2-7 family of proteins involved in the
      initiation of DNA replication, and with Clf1p also implicated in replication. The
      Csm1p-Mcm3, Mcm5 and Mcm7p interactions were confirmed by co-immunoprecipitation.
      Three other interacting proteins, Mgs1p, Ulp2, and Plp2, participate in
      chromosome assembling and segregation, whereas the function of two others has not
      been established. Genetic experiments showed that the two-hybrid isolates MGS1,
      CLF1, MCM3, 5, 7 (CDC47), and YDL089w, when overexpressed, partially suppress the
      csm1Delta/csm1Delta sporulation defect. We propose that, besides its other
      functions, Csm1p may be involved in premeiotic DNA replication.

PMID- 15023544
TI  - Interaction of apoptosis signal-regulating kinase 1 with isoforms of 14-3-3
      proteins.
AB  - Apoptosis signal-regulating kinase 1 (ASK1) is a critical mediator of apoptotic
      signaling pathways initiated by a variety of death stimuli. Its activity is
      tightly controlled by various mechanisms such as covalent modification and
      protein-protein interaction. One of the proteins that control ASK1 function is 14
      3-3zeta, a member of the 14-3-3 protein family. Here, we report that ASK1 is
      capable of binding to other isoforms of 14-3-3, suggesting that binding ASK1 is a
      general property of the 14-3-3 family. In support of this notion, mutational
      analysis revealed that the ASK1/14-3-3 interaction was mediated by the conserved
      amphipathic groove of 14-3-3 with some residue selectivity. Functionally,
      expression of various isoforms of 14-3-3 suppressed ASK1-induced apoptosis. To
      understand how 14-3-3 controls the ASK1 activity, we examined intracellular
      localization of ASK1 upon 14-3-3 co-expression. We found that 14-3-3 co
      expression is correlated with the translocation of ASK1 from the cytoplasm to a
      perinuclear localization, likely the ER compartment. Consistent with this notion,
      ASK1(S967A), a 14-3-3 binding defective mutant of ASK, showed no change in
      intracellular distribution upon 14-3-3 co-expression. These data support a model
      that 14-3-3 proteins regulate the proapoptotic function of ASK1 in part by
      controlling its subcellular distribution.

PMID- 15023547
TI  - Modifying the first minute of reperfusion: potential for myocardial salvage.

PMID- 15023546
TI  - Does the loss of transverse tubules contribute to dyssynchronous Ca2+ release
      during heart failure?

PMID- 15023548
TI  - Angiotensin AT2 receptor: the younger sibling attracts attention.

PMID- 15023549
TI  - Pharmacology of cardiac potassium channels.
AB  - Cardiac K+ channels are membrane-spanning proteins that allow the passive
      movement of K+ ions across the cell membrane along its electrochemical gradient.
      They regulate the resting membrane potential, the frequency of pacemaker cells
      and the shape and duration of the cardiac action potential. Additionally, they
      have been recognized as potential targets for the actions of neurotransmitters
      and hormones and class III antiarrhythmic drugs that prolong the action potential
      duration (APD) and refractoriness and have been found effective to
      prevent/suppress cardiac arrhythmias. In the human heart, K+ channels include
      voltage-gated channels, such as the rapidly activating and inactivating transient
      outward current (Ito1), the ultrarapid (IKur), rapid (IKr) and slow (IKs)
      components of the delayed rectifier current and the inward rectifier current
      (IK1), the ligand-gated channels, including the adenosine triphosphate-sensitive
      (IKATP) and the acetylcholine-activated (IKAch) currents and the leak channels.
      Changes in the expression of K+ channels explain the regional variations in the
      morphology and duration of the cardiac action potential among different cardiac
      regions and are influenced by heart rate, intracellular signalling pathways,
      drugs and cardiovascular disorders. A progressive number of cardiac and
      noncardiac drugs block cardiac K+ channels and can cause a marked prolongation of
      the action potential duration (i.e. an acquired long QT syndrome, LQTS) and a
      distinct polymorphic ventricular tachycardia termed torsades de pointes. In
      addition, mutations in the genes encoding IKr (KCNH2/KCNE2) and IKs (KCNQ1/KCNE1)
      channels have been identified in some types of the congenital long QT syndrome.
      This review concentrates on the function, molecular determinants, regulation and,
      particularly, on the mechanism of action of drugs modulating the K+ channels
      present in the sarcolemma of human cardiac myocytes that contribute to the
      different phases of the cardiac action potential under physiological and
      pathological conditions.

PMID- 15023550
TI  - Strategies for directing the differentiation of stem cells into the
      cardiomyogenic lineage in vitro.
AB  - Most studies on stem cell transplantation therapy on myocardially infarcted
      animal models and phase-I human clinical trials have focused on the use of
      undifferentiated stem cells. There is a strong possibility that some degree of
      cardiomyogenic differentiation of stem cells in vitro prior to transplantation
      would result in higher engraftment efficiency, as well as enhanced myocardial
      regeneration and recovery of heart function. Additionally, this may also
      alleviate the probability of spontaneous differentiation of stem cells into
      undesired lineages and reduces the risk of teratoma formation, in the case of
      embryonic stem cells. The development of efficient protocols for directing the
      cardiomyogenic differentiation of stem cells in vitro will also provide a useful
      model for molecular studies and genetic manipulation. This review therefore
      critically examines the various techniques that could possibly be used to direct
      and control the cardiomyogenic differentiation of stem cells in vitro.

PMID- 15023551
TI  - S-nitrosylation: a potential new paradigm in signal transduction.
AB  - Much attention has been paid to nitric oxide (NO) research since its discovery as
      a physiological mediator in the cardiovascular system. In recent years, newer
      roles have been attributed to this molecule and its close relatives, termed
      collectively reactive nitrogen species (RNS). These roles relate to different
      mechanisms of protein modification, among which S-nitrosylation of cysteines has
      emerged as a potential new paradigm in signal transduction and regulation of
      protein function. We review here the chemical basis of this modification compared
      with other protein modifications related to nitric oxide, as well as the kind of
      specificity we can expect from it. We also review the current methodologies that
      can be applied to the study of S-nitrosylation and identification of S
      nitrosylated proteins in cells, and detail the relevance of this modification in
      several proteins related to cardiovascular system.

PMID- 15023552
TI  - A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by
      drugs.
AB  - BACKGROUND: The human cardiac SCN5A gene encodes for the alpha subunit of the
      human cardiac voltage-dependent sodium channel hNav1.5 [Neuron 28 (2) (2000) 365]
      and carries inward Na current (INa). Mutations in SCN5A cause arrhythmia
      syndromes including Brugada syndrome (BrS) and congenital long QT syndrome
      subtype 3 (LQT3). Here, we report a trafficking defective BrS-causing SCN5A
      mutation that was drug-rescued. METHODS AND RESULTS: A 14-year-old Caucasian male
      was diagnosed with BrS with typical ECG pattern for BrS and ventricular
      fibrillation was easily induced. He also had significant HV interval delay (
      approximately 65 ms) and high (31 J) defibrillation thresholds (DFTs). Genomic
      analysis revealed the SCN5A mutation (G1743R). We engineered G1743R into the
      cardiac Na channel and transfected HEK-293 cells for functional studies. The
      mutant channel yielded nearly undetectable sodium channel currents. Coexpression
      with the beta1 subunit, or incubation at low temperature did not increase current
      density. However, mexiletine, a sodium channel blocker, increased current density
      93-fold in G1743R, but only twofold in WT. CONCLUSIONS: This study identifies an
      expression-defective BrS mutation in SCN5A with pharmacological rescue. The
      profoundly decreased sodium current associated with the G1743R suggests a
      molecular basis for the delayed His-Purkinje conduction and elevated DFTs
      observed in the proband. Whether the mutant channel may be rescued in vivo by
      mexiletine and normalize the patient's electrophysiologic parameters remains to
      be tested.

PMID- 15023553
TI  - Reduced synchrony of Ca2+ release with loss of T-tubules-a comparison to Ca2+
      release in human failing cardiomyocytes.
AB  - OBJECTIVES: During cardiac excitation-contraction coupling, Ca2+ release from the
      sarcoplasmic reticulum (SR) occurs at the junctional complex with the T-tubules,
      containing the L-type Ca2+ channels. A partial loss of T-tubules has been
      described in myocytes from failing canine and human hearts. We examined how
      graded reduction of T-tubule density would affect the synchrony of Ca2+ release.
      METHODS: Adult pig ventricular myocytes were isolated and cultured for 24 and 72
      h. T-tubules, visualized with di-8-ANEPPS, and [Ca2+]i transients (Fluo-3) were
      recorded during confocal line scan imaging. RESULTS: Cultured cardiomyocytes
      exhibited a progressive reduction in T-tubule density. [Ca2+]i transients showed
      small areas of delayed Ca2+ release which gradually increased in number and size
      with loss of T-tubules. Local [Ca2+]i transients in the delayed regions were
      reduced. Due to these changes, loss of T-tubules resulted in an overall slowing
      of the rise of [Ca2+] along the entire line scan and transient magnitude tended
      to be reduced, but there was no change in SR Ca2+ content. Human myocytes
      isolated from failing hearts had a T-tubule density comparable to that of freshly
      isolated pig myocytes. The size, but not the number, of delayed release areas
      tended to be larger. The overall rate of rise of [Ca2+]i was significantly faster
      than in pig myocytes with low T-tubule density. CONCLUSIONS: Loss of T-tubules
      reduces the synchrony of SR Ca2+ release. This could contribute to reduced
      efficiency of excitation-contraction coupling in heart failure, though
      dyssynchrony in human failing cells appears to be modest.

PMID- 15023554
TI  - Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting
      events in the early minutes of reperfusion.
AB  - OBJECTIVE: We previously showed that brief intermittent ischemia applied during
      the onset of reperfusion (i.e., postconditioning) is cardioprotective in a canine
      model of ischemia-reperfusion. This study tested the hypothesis that the early
      minutes of reperfusion (R) during which postconditioning (Post-con) is applied
      are critical to its cardioprotection. METHODS: In anesthetized open-chest rats,
      the left coronary artery (LCA) was occluded for 30 min and reperfused for 3 h.
      All rats were randomly divided into six groups: Control (n=8): no intervention at
      R; Ischemic preconditioning (IPC) (n=8): the LCA was occluded for 5 min followed
      by 10 min of R before the index occlusion; Post-con 1 (n=8): after LCA occlusion,
      three cycles of 10 s R followed by 10 s LCA re-occlusion were applied during the
      first minute of R; Post-con 2 (n=8): Six cycles of 10 s R and 10 s re-occlusion
      were applied during the first 2 min of R; Delayed Post-con (n=8): the ligature
      was loosened for full reflow for the first minute of R, after which the three
      cycle Post-con algorithm was applied; Sham (n=6): the surgical procedure was
      identical to other groups, but the LCA ligature was not ligated. RESULTS: Infarct
      size (TTC staining) was 23% smaller in Post-con 1 (40+/-2%*) than in Control
      (52+/-3%), confirmed by plasma creatine kinase activity (18+/-2* vs. 46+/-6 IU/g
      protein). There was no further reduction in infarct size with 6 cycles of Post
      con (40+/-2.9%, p>0.05 vs. Post-con 1). Meanwhile, infarct size reduction was
      significantly greater in the IPC group (17+/-3%) than in Post-con1 (p<0.01). The
      plasma lipid peroxidation product malondialdehyde (MDA, microM/ml) was less after
      R in IPC and Post-con 1 (0.8+/-0.07* and 0.8+/-0.06*) vs. Control (1.21+/-0.08),
      consistent with a visual decrease in superoxide anion generation (dihydroethidium
      staining) in the AAR myocardium after 3 h of reperfusion. Neutrophil accumulation
      (myeloperoxidase activity, MPO, U/100 g tissue) in the AAR was less in IPC (1.4+/
      0.3*) and Post-con 1 (2.5+/-0.3*) vs. Control (5.5+/-0.6). The reductions in
      infarct size, creatine kinase, MDA and DHE staining were lost with delayed Post
      con, while MPO activity remained lower than in Control (3.2+/-0.4*). CONCLUSIONS:
      (1) Post-con at onset of R reduces myocardial injury; (2) cardioprotection may be
      mediated, in part, by inhibiting oxidant generation and oxidant mediated injury;
      (3) the first minute of R in the rat model is critical to cardioprotection by
      Post-con; and (4) cardioprotection by Post-con may be independent of neutrophil
      accumulation in AAR. *p<0.05 Post-con vs. Control.

PMID- 15023555
TI  - Interaction of angiotensin II with the angiotensin type 2 receptor inhibits the
      cardiac transient outward potassium current.
AB  - OBJECTIVE: The Ca2+ -independent transient outward K+ current (Ito) plays a
      crucial role in shaping the cardiac action potential. In the present study, we
      examined whether angiotensin II (AngII) regulated the Ito as well as the putative
      intracellular cascade responsible for the effects. METHODS: Ito was recorded in
      rat ventricular myocytes using the nystatin-perforated patch-clamp configuration.
      RESULTS: AngII (0.1 microM) inhibited Ito (21.9+/-4.8% at +40 mV), but not the
      IK1, in a voltage- and time-independent manner. The inhibition decreased at
      concentrations higher than 1 microM resulting in a bell-shaped dose-response
      curve (IC50 = 3.1+/-1.5 microM). The blocking effects were abolished in the
      presence of the type 2 AngII receptor (AT2R) antagonist PD123319, but not in the
      presence of the selective type 1 AngII receptor (AT1R) antagonist candesartan.
      Moreover, the selective AT2R agonist CGP42112A completely reproduced the effects
      of AngII (20.5+/-2.4% of block at +40 mV), indicating that AngII-induced Ito
      block was mediated via stimulation of AT2R. Furthermore, selective stimulation of
      AT2R by CGP42112A significantly prolonged the rat atrial action potentials
      recorded using conventional microelectrode techniques. The AngII-induced
      inhibition of I(to) was not modified by either Npi-nitro-L-arginine-methyl ester
      (L-NAME) or eicosatetrayonic acid (ETYA), indicating that neither the nitric
      oxide (NO)-guanosine 3',5'-cyclic monophosphate (cGMP) system nor the arachidonic
      acid cascade was implicated in the effects of AngII on Ito. However, the AngII
      induced Ito inhibition was completely abolished by the serine/threonine
      phosphatase type 2A (PP2A) inhibitors, okadaic acid and cantharidin, but not by
      the inactive analog of okadaic acid, 1-norokadaone. Intracellular application of
      PP2A decreased Kv4.2 currents recorded in transiently transfected Chinese hamster
      ovary cells (CHO). CONCLUSION: These results indicate that AngII activates PP2A
      through the stimulation of the AT2R, resulting in a decrease of the Ito
      amplitude.

PMID- 15023556
TI  - Swelling-activated chloride current is activated in guinea pig cardiomyocytes
      from endotoxic shock.
AB  - OBJECTIVE: Myocardial swelling occurs during endotoxic shock. The hypothesis that
      swelling-activated Cl- current (ICl,swell) activates during endotoxic shock was
      tested. METHODS: Endotoxic shock was induced by intravenous lipopolysaccharides
      (10 mg/kg) in guinea pigs. The effects of ICl,swell blockers on the cardiac
      action potentials in papillary muscles and on the ICl,swell in single ventricular
      myocytes were tested. RESULTS: Action potential duration (APD) at 90% of
      repolarization (APD90) was significantly shortened after 5-h endotoxic shock in
      guinea pig papillary muscles. I(Cl,swell) blockers, 9-anthracene carboxylic acid
      (9-AC) and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), dose
      dependently prolonged the shortened APD90. Inducible nitric oxide synthase (iNOS)
      inhibitors, L-N6-(1-iminoethyl) lysine (L-NIL) and N-[[3
      (aminomethyl)phenyl]methyl]-ethanimidamide (1400 W), also prolonged the APD90.
      Protein kinase C (PKC) activators, 4beta-phorbol 12-myristate 13-acetate (PMA)
      and phorbol 12,13-didecanoate (PDD), also prolonged the APD. The addition of
      glibenclamide (an ATP-sensitive K+ channel blocker) on top of these ICl,swell
      blockers hastened the recovery of APD90 compared to the use of ICl,swell blockers
      alone. Whole-cell voltage-clamp study in single ventricular myocytes from
      endotoxic shock heart disclosed activation of a DIDS- and 9-AC-sensitive current.
      These currents displayed outward rectification with reversal potentials similar
      to the calculated Nernst potential for Cl-. The reversal potentials tracked the
      ECl closely when the Cl- gradient was changed, suggesting that Cl- was the major
      charged carrier. CONCLUSIONS: We have shown for the first time that ICl,swell
      activates in guinea pig heart in endotoxic shock. The change in this membrane
      current, together with the activation of ATP-sensitive K+ current, contributes to
      the electrophysiological derangement in endotoxic shock.

PMID- 15023557
TI  - The HMG-CoA reductase inhibitor atorvastatin prevents atrial fibrillation by
      inhibiting inflammation in a canine sterile pericarditis model.
AB  - OBJECTIVE: It has been recently reported that AF is associated with tissue
      inflammation. Statins reduce C-reactive protein (CRP) levels. However, the effect
      of statin on atrial fibrillation (AF) is unclear. The purpose of the present
      study was to evaluate the effect of statin on AF in a canine sterile pericarditis
      model. METHODS: Sterile pericarditis was created in 20 dogs randomly assigned to
      two groups: a control group (10 dogs) and an atorvastatin treatment group (10
      dogs). Atorvastatin was administered orally (2 mg/kg/day) beginning 1 week before
      the operation until the end of the study. Before and 2 days after the operation,
      CRP levels, the duration of induced AF, the atrial effective refractory period
      (AERP), and intra-atrial conduction time were determined. RESULTS: Before the
      operation, there were no significant differences in any of the parameters between
      the two groups. On the second postoperative day, the atorvastatin group had a
      lower CRP level (7.6+/-0.5 versus 11.7+/-1.3 mg/dl, P<0.0001), a shorter AF
      duration (177+/-57 versus 534+/-189 s, P<0.0001), a longer AERP (138+/-6 versus
      130+/-6 ms, P<0.01), and a shorter intra-atrial conduction time (46+/-3 versus
      51+/-5 ms, P<0.01) than the control group. CONCLUSIONS: Atorvastatin can prevent
      maintenance of AF by inhibiting inflammation in the canine sterile pericarditis
      model. Atorvastatin may thus be a novel therapeutic agent for AF.

PMID- 15023558
TI  - Localization of cholinergic innervation in guinea pig heart by
      immunohistochemistry for high-affinity choline transporters.
AB  - OBJECTIVE: Previous studies have used acetylcholinesterase (AChE) histochemistry
      to identify cholinergic nerves in the heart, but this enzyme is not a selective
      marker for cholinergic neurons. This study maps cholinergic innervation of guinea
      pig heart using a new antibody to the human high-affinity choline transporter
      (CHT), which is present only in cholinergic nerves. METHODS: Immunohistochemistry
      was used to localize CHTs in frozen and paraffin sections of heart and whole
      mount preparations of atrial ganglionated nerve plexus. AChE-positive nerve
      fibers were identified in sections from separate hearts for comparison. RESULTS:
      Control experiments established that the antibody to human CHT selectively
      labeled cholinergic neurons in the guinea pig. CHT-immunoreactive nerve fibers
      and AChE-positive nerves were very abundant in the sinus and AV nodes, bundle of
      His, and bundle branches. Both markers also delineated a distinct nerve tract in
      the posterior wall of the right atrium. AChE-positive nerve fibers were more
      abundant than CHT-immunoreactive nerves in working atrial and ventricular
      myocardium. CHT-immunoreactive nerves were rarely observed in left ventricular
      free wall. Both markers were associated with numerous parasympathetic ganglia
      that were distributed along the posterior atrial walls and within the interatrial
      septum, including the region of the AV node. CONCLUSIONS: Comparison of labeling
      patterns for CHT and AChE suggests that AChE histochemistry overestimates the
      density of cholinergic innervation in the heart. The distribution of CHT
      immunoreactive nerve fibers and parasympathetic ganglia in the guinea pig heart
      suggests that heart rate, conduction velocity, and automaticity are precisely
      regulated by cholinergic innervation. In contrast, the paucity of CHT
      immunoreactive nerve fibers in left ventricular myocardium implies that vagal
      efferent input has little or no direct influence on ventricular contractile
      function in the guinea pig.

PMID- 15023559
TI  - Transgenic triadin 1 overexpression alters SR Ca2+ handling and leads to a
      blunted contractile response to beta-adrenergic agonists.
AB  - OBJECTIVE: Ca2+ release from the cardiac junctional sarcoplasmic reticulum (SR)
      is regulated by a complex of proteins, including the ryanodine receptor (RyR),
      calsequestrin (CSQ), junctin (JCN), and triadin 1 (TRD). Moreover, triadin 1
      appears to anchor calsequestrin to the ryanodine receptor. METHODS: To determine
      whether triadin 1 overexpression alters excitation-contraction coupling, we
      examined the effects of cardiac-specific overexpression of triadin 1 on SR Ca2+
      handling and contractility in transgenic (TG) compared to wild-type (WT) mice.
      RESULTS: The overexpression of triadin 1 was associated with an enhanced SR Ca2+
      load, reflected by a 22% higher amplitude of caffeine-induced Ca2+ transients.
      The decline of Ca2+ transients during caffeine exposure was prolonged by 57%. The
      detection of resting spontaneous SR Ca2+ release events (Ca2+ sparks) revealed an
      increased amplitude (by 16%), decline (by 47%), and width (by 47%) in TG. This
      was associated with a redistribution of Ca2+ spark amplitudes from one population
      to two populations. Measurement of cardiac function by echocardiography and left
      ventricular (LV) catheterization revealed a decreased cardiac contractility in
      vivo. The impaired response to beta-adrenergic receptor (beta-AR) stimulation in
      TG hearts was associated with an increased protein expression of beta-AR kinase
      1. In addition, the increase of the L-type Ca2+ peak current and the increase of
      phospholamban (PLB) phosphorylation at Thr17 were reduced under beta-AR
      stimulation. CONCLUSION: Taken together, our data suggest that triadin 1
      overexpression results in a complex modulation of SR Ca2+ handling, which may
      contribute, at least in part, to the depressed basal contractility and the
      blunted response to beta-adrenergic agonists in TG mice.

PMID- 15023560
TI  - Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected
      to myocardial ischemia and reperfusion.
AB  - OBJECTIVES: This study examined the effects of diet-induced hypercholesterolemia
      on the extent of postischemic myocyte apoptosis and elucidated the potential
      mechanisms involved. Furthermore, the effects of rosiglitazone (RSG) on
      postischemic myocardial apoptosis in HC rabbits were investigated. METHODS: Male
      New Zealand rabbits were fed normal or high cholesterol diets for 8 weeks. Three
      weeks after being fed a high cholesterol diet, HC rabbits were randomized to
      receive vehicle or RSG during the remaining 5 weeks. Rabbits were then subjected
      to 60 min of coronary occlusion followed by 4 h of reperfusion. RESULTS: Compared
      with rabbits fed with a normal diet, HC rabbits had increased caspase-3 activity,
      apoptotic cell death and retarded contractile function recovery after
      reperfusion. HC increased iNOS expression, total NOx and nitrotyrosine contents,
      indicating that an increased nitrative stress occurred in HC myocardial tissue.
      Activity of a hypertrophic/anti-apoptotic mitogen-activated protein kinase
      (MAPK), ERK1/2, was significantly decreased while activation of a pro-apoptotic
      MAPK, p38, was increased. Treatment with RSG in HC rabbits attenuated
      postischemic myocardial nitrative stress, restored a beneficial balance between
      pro- and anti-apoptotic MAPK signaling, reduced postischemic myocardial
      apoptosis, and improved cardiac functional recovery. CONCLUSIONS: Our results
      demonstrated that HC increased postischemic myocardial apoptosis likely by
      increasing the production of pro-apoptotic molecules, activating pro-apoptotic
      signaling pathways and inhibiting anti-apoptotic signaling. In addition, our
      results suggest that peroxisome proliferator-activated receptor (PPAR) gamma
      agonists may not only attenuate the formation of atherosclerosis associated with
      hypercholesterolemia as previously reported, but may also protect the heart from
      subsequent ischemic/reperfusion-induced myocardial apoptosis.

PMID- 15023561
TI  - Inhibition of the pentose phosphate pathway decreases ischemia-reperfusion
      induced creatine kinase release in the heart.
AB  - OBJECTIVE: The oxidative pentose phosphate pathway (oxPPP) produces NADPH, which
      can be used to maintain glutathione in its reduced state (anti-oxidant;
      beneficial effects) or to produce radicals or nitric oxide (NO) through NADPH
      oxidase/NO synthase (detrimental effects). Changes in cytosolic redox status have
      been implicated in ischemic preconditioning (PC). This study investigates whether
      (1) PC affects mitochondrial redox state, (2) the oxPPP plays a protective or
      detrimental role in ischemia (I)-reperfusion (R) injury in the intact heart and
      (3) PPP is altered with PC. METHODS: Isolated rat hearts were subjected to 40-min
      global I and 30-min R (CO, control). Ischemia was either preceded by three 5-min
      I/R periods (PC) and/or oxPPP inhibition by 6-aminonicotinamide (6AN) or NADPH
      oxidase/NO synthase inhibition by diphenyleneiodonium (DPI). NADH
      videofluorometry was used to determine mitochondrial redox state. PPP
      intermediates were determined in CO and PC hearts using tandem mass spectrometry.
      RESULTS: PC reduced ischemic damage (creatine kinase, CK, release from 337+/-64
      to 147+/-41 U/R/gdw) and contracture (from 59+/-5 to 31+/-3 mm Hg) and increased
      recovery of contractility (from 48+/-10% to 88+/-8%), as compared to CO. PC was
      without effect on NADH fluorometry. Inhibition of the oxPPP reduced injury (CK
      release: 91+/-24 U/R/gdw) to similar levels as PC, without improving
      contractility. Inhibition of NADPH oxidase/NO synthase mimicked the effects of
      oxPPP inhibition on injury (CK release: 140+/-22 U/R/gdw). Although levels of
      ribose-5P and (ribulose-5P+xylulose-5P) rose several fold during ischemia with
      minor changes in sedoheptulose-7P, demonstrating an active PPP in the heart, PC
      did not affect these levels. CONCLUSIONS: (1) PC can attenuate cardiac
      reperfusion injury without alterations in mitochondrial redox state; (2)
      inhibition of the oxPPP protects the heart against I/R-induced CK release; and
      (3) PC does not result in altered activity of the PPP.

PMID- 15023562
TI  - Non-angiogenic FGF-2 protects the ischemic heart from injury, in the presence or
      absence of reperfusion.
AB  - OBJECTIVE: Fibroblast growth factor-2 (FGF-2), given during ischemia or during
      reperfusion of the ischemic heart is cardioprotective, but its mitogenic activity
      may limit possible clinical applications. We have tested the cardioprotective
      potential of a non-mitogenic FGF-2 mutant (S117A) that no longer activates casein
      kinase 2 (CK2) in both acute and long-term studies. METHODS AND RESULTS: To test
      effects during reperfusion, the ex vivo rat heart, subjected to 30 min of global
      ischemia and 60 min of reperfusion was used. S117A FGF-2 administered during
      reperfusion protected against myocardial contractile dysfunction, activated
      protein kinase C and decreased the release of cytochrome C in the cytosol. To
      study effects on ischemic myocytes in the absence of reperfusion, myocardial
      infarction (MI) was induced in the rat model by irreversible left coronary
      ligation. S117A-, wild type (wt)-FGF-2 or saline, were administered by
      intramyocardial injection into the ischemic ventricular wall. One day later,
      infarct size (assessed by tetrazolium staining), and plasma cardiac troponin T
      levels (assessed by Western blotting) were significantly decreased in the S117A
      FGF-2-, compared to the saline-treated group. Systolic pressure, rates of
      contraction and relaxation and developed pressure, assessed in the Langendorff
      mode, were significantly improved in the S117-FGF-2 group. Improved ejection
      fraction and fractional shortening in the S117A-treated group were maintained up
      to, but not beyond, 7 days post-MI. In comparison, improvements were maintained
      in the wt-FGF-2-treated group at least up to 6 weeks post-MI. At 6 weeks post-MI,
      small vessel density (assessed by immunofluorescence-based detection) in the scar
      bordering viable myocardium was similar between S117A-FGF-2- and saline-treated
      hearts, but significantly increased in the wt-FGF-2-treated group. This was
      accompanied by increased coronary flow in the wt-, but not S117A-FGF-2-treated
      hearts, compared to controls. CONCLUSION: The ability of FGF-2, administered
      during ischemia or during reperfusion, to protect the myocardium acutely from
      tissue loss and dysfunction is independent of its potential for CK2 activation
      and angiogenesis. Non-angiogenic S117A-FGF-2 may be considered in therapies
      aiming for acute prevention of reperfusion-associated pathologies, especially in
      cases where use of mitogens is counter-indicated.

PMID- 15023563
TI  - The role of ADAM protease in the tyrosine kinase-mediated trigger mechanism of
      ischemic preconditioning.
AB  - OBJECTIVE: The aim of this study was to determine the role of an a disintegrin
      and metalloprotease (ADAM) in tyrosine kinase-mediated mechanisms of ischemic
      preconditioning (PC). METHODS AND RESULTS: In isolated rabbit hearts, PC was
      performed with two cycles of 5 min ischemia/5 min reperfusion and infarction was
      induced by 30 min global ischemia/2 h reperfusion. Translocation of protein
      kinase C- (PKC-) and tyrosine phosphorylation in the tissue and TNF-alpha in
      coronary effluent were determined by immunoblotting. PC reduced infarct size from
      55.1+/-6.8% of the left ventricle to 24.4+/-5.2%, and this protection was
      mimicked by pretreatment with 100 nM angiotensin II. Both the PC effect and
      angiotensin II-induced protection were abolished by genistein and by 10 microM KB
      R7785 (KBR), an inhibitor of ADAM12/17, but not by a lower ADAM12-selective dose
      (1 microM) of KBR. AG1478, an inhibitor of EGF receptor tyrosine kinase, did not
      inhibit protection afforded by PC. PC provoked release of TNF-alpha into the
      coronary effluent, which was abolished by 10 microM KBR but not by 1 microM of
      KBR or calphostin C, a PKC inhibitor. PKC- translocation by PC was not affected
      by KBR. PC induced tyrosine phosphorylation of 60 and 90 kDa proteins, and this
      phosphorylation was abolished by 10 microM KBR but not by calphostin C.
      Pretreatment with TNF-alpha limited infarct size to 16.7+/-3.7% and induced
      tyrosine phosphorylation of a 60 kDa protein. CONCLUSIONS: The results support
      the hypothesis that an ADAM contributes to the triggering of a tyrosine kinase
      mediated and PKC-independent pathway of PC. The ADAM responsible for this
      tyrosine kinase-mediated pathway is likely to be ADAM17, which sheds TNF-alpha.

PMID- 15023564
TI  - Ex vivo differentiated endothelial and smooth muscle cells from human cord blood
      progenitors home to the angiogenic tumor vasculature.
AB  - OBJECTIVES: Recent studies have provided increasing evidence that postnatal
      neovascularization does not rely exclusively on sprouting of preexisting vessels,
      but also involves bone marrow-derived circulating endothelial precursors (BM
      EPCs). Animal studies revealed that neovascularization of ischemic tissue can be
      enhanced by BM-EPCs transplantation. But a possible limitation to the use of
      vascular precursors for therapeutic angiogenesis is the relatively low number of
      these cells. In this study, we demonstrate that ex vivo expanded differentiated
      endothelial cells (ECs) and smooth muscle cells (SMCs), may home to the tumor
      vasculature allowing targeting of transgene expression to the neoangiogenic site.
      METHODS: Mononuclear cells (MNCs) or CD34+ -enriched cells were purified from
      cord blood. We have defined culture conditions in which we observed two types of
      clones easily differentiated according to their morphology: cobblestone or
      spindle-shaped. Phenotypic characterization was assessed by immunocytochemistry,
      flow cytometry analysis and polymerase reaction with reverse transcription.
      Formation of capillary-like network in vitro was studied in three-dimensional
      collagen culture. And recruitment of these cells to a tumoral neoangiogenic site
      was assessed into tumor-bearing Severe Combined Immunodeficient (SCID) mouse
      model. RESULTS: The cobblestone cells uniformly positive for CD31, VE-cadherin,
      vWF, VEGF R1 and R2, ecNOS and incorporating acetylated LDL were ECs. Spindle
      shaped cells expressed alpha-smooth muscle actin (alpha-SMA), Smooth Muscle Heavy
      Chain (SMHC), SM22 and calponin. They also displayed a carbachol-induced
      contractility in a medium containing IGF1. So we concluded that spindle-shaped
      cells were SMCs. ECs and SMCs interacted with each other to form a capillary like
      network in three-dimensional type I collagen culture. Moreover, these ex vivo
      differentiated cells are able to home to the tumor vasculature. CONCLUSION: We
      provide evidence that progenitors for ECs and SMCs circulate in human cord blood
      and differentiate into functional ECs and SMCs. These differentiated cells could
      provide a biomaterial for vascular cell therapy, because of their homing capacity
      to the neovascularization site.

PMID- 15023566
TI  - Nitric oxide: inhibitory effects on endothelial cell calcium signaling,
      prostaglandin I2 production and nitric oxide synthase expression.
AB  - OBJECTIVE: Nitric oxide (NO) produced in large amounts by inducible nitric oxide
      synthase exerts many harmful effects such as stimulation of inflammation and
      induction of apoptosis. The effects of excessive NO production on functions of
      endothelial cells, the major physiological source of NO, are not completely
      known. The aim of this study was to investigate the role of NO on the regulation
      of endothelial cell Ca2+ signaling and endothelial cell function. METHODS:
      Primary porcine aortic endothelial cells (PAECs) were used for all these studies.
      Intracellular Ca2+ concentrations ([Ca2+]i) were measured using fura-2/AM.
      Production of prostaglandin I2 (PGI2) and cyclic GMP were assessed using enzyme
      immunoassays, and endothelial NO synthase protein expression was evaluated by
      Western blotting. RESULTS: Bradykinin (BK, 10 nM) and thapsigargin (TG, 1 microM)
      provoked large increases in [Ca2+]i. The NO donor NOC12 reduced these responses,
      respectively, by 21% and 31% at 100 microM, 60% and 55% at 300 microM, and 74%
      and 78% at 500 microM. These effects were also observed with other NO donors
      including spermine NONOate and NOC18, and were completely prevented by carboxy
      PTIO (200 microM), an NO scavenger. 8-Bromo-cGMP, however, had no effects on BK-
      and TG-stimulated Ca2+ responses. A 30-fold increase in PGI2 production was
      observed in cells stimulated with BK. NOC12 again reduced this response by 12%,
      54%, 83% and 95% at 10, 100, 300 and 500 microM, respectively. Endothelial NO
      synthase protein level was reduced by 2%, 15%, 36 and 47% after 2, 6, 12 and 24
      h, respectively, of incubation with NOC18, a NO donor with long half-life.
      CONCLUSIONS: NO, when produced in large amounts, can inhibit agonist-induced Ca2+
      responses independently of cyclic GMP, reduce the production of endothelium
      derived relaxing factors (EDRFs) and interfere with endothelial NO synthase
      protein expression.

PMID- 15023565
TI  - Native LDL induces interleukin-8 expression via H2O2, p38 Kinase, and activator
      protein-1 in human aortic smooth muscle cells.
AB  - BACKGROUND AND OBJECTIVES: Endothelial and monocytic cells appear to play a key
      role in the initiation and progression of atherosclerosis and restenosis via the
      upregulation of inflammatory cytokines and the formation of oxidized low-density
      lipoprotein (ox-LDL). However, the role of smooth muscle cells (SMCs) has been
      underestimated and is not well understood. It was investigated for the first time
      that native LDL stimulates human SMCs to secrete IL-8. The aim of this study was
      to investigate the signaling pathway involved in the upregulation of IL-8,
      induced by LDL in human aortic SMCs. METHODS AND RESULTS: LDL-induced IL-8
      expression (mRNA and protein) is specific to SMCs and likely to be regulated at
      the transcription level in dose- and time-dependent manners, as judged by
      experiments with actinomycin D and ELISA. Although both p38 and ERK 1/2 MAPKs
      were activated by LDL, only p38 MAPK is responsible for the LDL effects, as
      evidenced by a complete blockade of IL-8 upregulation by SB203580. Pretreatment
      with catalase significantly decreased the extent of IL-8 upregulation, indicating
      that H2O2 is necessary for the LDL response. Activation of activator protein (AP)
      1, but not nuclear factor (NF)-kappaB, by p38 or H2O2 appears to be necessary
      along with the concomitant upregulation of c-fos and c-JUN, as judged by
      electrophoretic mobility shift and luciferase reporter assays. CONCLUSIONS: These
      data demonstrated that LDL stimulates SMCs to induce IL-8 production in dose- and
      time-dependent manners at the transcription level and that the LDL signaling in
      hAoSMCs is conveyed via the generation of H2O2, the phosphorylation of p38 MAPK,
      the activation of AP-1, and the participation of NF-kappaB.

PMID- 15023567
TI  - Measurements of nitric oxide concentration and hyporeactivity in rat superior
      mesenteric artery exposed to endotoxin.
AB  - OBJECTIVE: The present study was designed to relate nitric oxide (NO)
      concentration to changes in vascular reactivity in rat superior mesenteric
      arteries treated with lipopolysaccharide (LPS, 10 microg ml-1, 1-8 h). METHODS:
      In rat mesenteric arteries, isometric tension was recorded in wire myographs,
      protein expression was evaluated by Western blot and/or immunohistochemistry and
      NO concentration was measured by application of a NO specific electrode. RESULTS:
      Incubation with LPS (5 h) resulted in inducible NO synthase (iNOS) expression and
      enhanced superoxide dismutase (Cu/Zn-SOD and Mn-SOD) expression, but it did not
      modify endothelial NO synthase (eNOS) expression. Noradrenaline (0.5 microM)
      evoked increases in NO concentration and tension by, respectively, 5.0+/-2.0 nM
      and 4.4+/-0.1 N m-1 (n=6). While NO concentration was unaltered, incubation with
      LPS reduced noradrenaline contraction to 3.5+/-0.2 N m-1 (n=39, P<0.05). In
      contrast to indomethacin, 1400 W (10 microM) restored noradrenaline contraction,
      while the combination of noradrenaline and oxyhaemoglobin (10 microM) evoked less
      contraction in LPS compared to control segments. Polyethylene glycol (PEG)
      catalase in combination with oxyhaemoglobin reversed noradrenaline hyporeactivity
      in LPS-treated segments. LPS did not increase, but reduced basal NO
      concentration, an effect which was reversed by 1400 W and tempol (100 microM). In
      LPS-treated segments contracted with noradrenaline, the NO synthase substrate, l
      arginine (100 microM), relaxed and increased NO concentration with, respectively,
      73+/-9% and 19.5+/-6.5 nM (n=5). 1400 W and oxyhaemoglobin reversed l-arginine
      relaxation and increases in NO concentration. In contrast to tempol and PEG
      catalase, N-acetylcysteine (0.1-1 mM), which is able to release NO from
      intracellular stores, relaxed LPS-treated tissue, an effect that was abolished by
      long-term, but not by short-term, incubation with 1400 W. CONCLUSIONS: The
      present study provides direct evidence that exposure to LPS results in induction
      of iNOS and SOD associated with noradrenaline hyporeactivity, while increased NO
      is only measured when l-arginine is present. A catalase-sensitive mechanism and
      release of NO from N-acetylcysteine-sensitive stores could also contribute to the
      vascular hyporeactivity.

PMID- 15023568
TI  - Downregulation of N-cadherin in the neointima stimulates migration of smooth
      muscle cells by RhoA deactivation.
AB  - OBJECTIVE: The aim of the study was to analyze whether cadherin- and Rho-family
      GTPases-mediated dynamic rearrangement of cell-cell adhesion play an important
      role during human arterial smooth muscle cell (haSMC) migration. METHODS:
      Expression patterns of N-cadherin and beta-catenin were analyzed in a domestic
      pig restenosis model after 14, 28, and 90 days as well as in quiescent and
      migratory haSMCs in vitro. N-cadherin expression was upregulated by transient
      sense; downregulation was induced by antisense transfection. For functional
      inhibition, antibody GC-4 was used. Cell migration was quantified using Boyden
      chamber assays. Regulation of RhoA GTPase was tested by assessment of RhoA
      activity. RESULTS: In vivo analysis of N-cadherin expression in a porcine
      restenosis model revealed downregulation in the neointima after 14 days. After 28
      days, N-cadherin expression was slightly restored, while after 90 days, no
      difference between medial and neointimal expression was detectable. beta-Catenin
      levels remained unchanged during the whole period. According to the in vivo
      situation, N-cadherin was significantly downregulated in migratory haSMCs
      compared to quiescent cells in vitro. After N-cadherin overexpression, haSMC
      migration was reduced by 87% (P<0.001). By contrast, inhibition of N-cadherin in
      quiescent haSMCs by GC-4 increased the migratory potential by 87% (P<0.01). In
      haSMCs overexpressing N-cadherin, a significant upregulation of RhoA activity was
      demonstrated, while RhoA activity was blocked by GC-4. CONCLUSIONS: These results
      indicate that the regulation of haSMC attachment by N-cadherins is essential for
      haSMC migration. Modification of N-cadherin expression and activity induces RhoA
      signaling with relevance for the reorganization of the actin cytoskeleton.

PMID- 15023569
TI  - Decreased 5-HT1A receptor binding in amygdala of schizophrenia.
AB  - BACKGROUND: On the basis of postmortem data and the pharmacological action of
      atypical antipsychotics, serotonin-1A receptors are of interest in the study of
      the pathophysiology of schizophrenia. To investigate serotonin-1A receptors in
      schizophrenia and their relation to symptoms, we measured the availability of
      serotonin-1A receptors in patients with schizophrenia using positron emission
      tomography with [carbonyl-(11)C]WAY-100635. METHODS: Serotonin-1A receptor
      binding of 11 patients with schizophrenia (8 drug-naive and 3 drug-free) was
      compared with that of 22 age-matched and gender-matched healthy control subjects.
      Symptoms were assessed using the Positive and Negative Syndrome Scale. Serotonin
      1A receptor binding in selected regions of interest was quantified by binding
      potential obtained by the reference tissue method. RESULTS: The regional binding
      potential value was lower in the amygdala by about 19% in patients with
      schizophrenia than in normal controls. A significant negative correlation was
      observed between binding potential in the amygdala and the negative and
      depression/anxiety symptom scores on the five-symptom subscale of the Positive
      and Negative Syndrome Scale. CONCLUSIONS: Decreased serotonin-1A receptor binding
      in the amygdala may underlie the affective components included in the symptoms of
      negative and depression/anxiety in schizophrenia.

PMID- 15023570
TI  - Effectiveness of the selective D4 antagonist sonepiprazole in schizophrenia: a
      placebo-controlled trial.
AB  - BACKGROUND: Selective localization of dopamine D(4) receptors in the prefrontal
      cortex and preferential affinity of clozapine for the dopamine D(4) receptor over
      the D(2) receptor led to the hypothesis that the superior efficacy of clozapine
      may be mediated via blockade of the D(4) receptor. This hypothesis was tested by
      evaluating sonepiprazole, a selective D(4) dopamine antagonist, in schizophrenia
      patients. METHODS: We treated 467 hospitalized schizophrenia patients with scores
      of > or = 60 on the Positive and Negative Syndrome Scale (PANSS) with
      sonepiprazole, olanzapine, or placebo once daily for 6 weeks. The primary
      efficacy end point was the mean change from baseline in the PANSS total score at
      6 weeks. Secondary efficacy end points were the mean change from baseline in the
      PANSS factor scores, the Brief Psychiatric Rating Scale score, the Clinical
      Global Impressions Severity of Illness score, and the Calgary Depression Scale
      score. RESULTS: No statistically significant differences were observed between
      placebo and any sonepiprazole dose on the primary or any secondary end point
      after 6 weeks of treatment. Statistically significant differences, favoring
      olanzapine over placebo, were observed on all efficacy end points but the Calgary
      Depression Scale. CONCLUSIONS: Sonepiprazole was ineffective for the treatment of
      patients with schizophrenia.

PMID- 15023571
TI  - Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to
      antipsychotics for the treatment of schizophrenia.
AB  - BACKGROUND: Hypofunction of N-methyl-D-aspartate glutamate receptor had been
      implicated in the pathophysiology of schizophrenia. Treatment with D-serine or
      glycine, endogenous full agonists of the glycine site of N-methyl-D-aspartate
      receptor, or D-cycloserine, a partial agonist, improve the symptoms of
      schizophrenia. N-methylglycine (sarcosine) is an endogenous antagonist of glycine
      transporter-1, which potentiates glycine's action on N-methyl-D-aspartate glycine
      site and can have beneficial effects on schizophrenia. METHODS: Thirty-eight
      schizophrenic patients were enrolled in a 6-week double-blind, placebo-controlled
      trial of sarcosine (2 g/d), which was added to their stable antipsychotic
      regimens. Twenty of them received risperidone. Measures of clinical efficacy and
      side effects were determined every other week. RESULTS: Patient who received
      sarcosine treatment revealed significant improvements in their positive,
      negative, cognitive, and general psychiatric symptoms. Similar therapeutic
      effects were observed when only risperidone-treated patients were analyzed.
      Sarcosine was well-tolerated, and no significant side effect was noted.
      CONCLUSIONS: Sarcosine treatment can benefit schizophrenic patients treated by
      antipsychotics including risperidone. The significant improvement with the
      sarcosine further supports the hypothesis of N-methyl-D-aspartate receptor
      hypofunction in schizophrenia. Glycine transporter-1 is a novel target for the
      pharmacotherapy to enhance N-methyl-D-aspartate function.

PMID- 15023573
TI  - Electroconvulsive seizures induce proliferation of NG2-expressing glial cells in
      adult rat amygdala.
AB  - BACKGROUND: Volumetric changes and glial pathology have been reported in the
      amygdala in patients with major depressive disorder. Here we report an analysis
      of glial cell proliferation in response to electroconvulsive seizures (ECS),
      clinically used for the treatment of severe depression. METHODS: Male Wistar rats
      were subjected to five ECS-treatments and then injected with bromodeoxyuridine
      (BrdU) to detect cell proliferation in the amygdala. The animals were
      transcardially perfused either 12 hours or 3 weeks after the last BrdU injection.
      Tissue sections were double-stained for BrdU and the cell-type markers NG2, OX
      42, RIP, S-100beta, Doublecortin, or NeuN. RESULTS: Electroconvulsive seizures
      dramatically increased the proliferation of amygdala cells expressing the
      oligodendrocyte progenitor marker NG2. Bromodeoxyuridine-labeled NG2-expressing
      cells were still present after 3 weeks of survival, and a small proportion of the
      proliferating cells had differentiated into mature oligodendrocytes. CONCLUSIONS:
      Major depression has been associated with a reduction of glial cells. Our results
      show that ECS, an antidepressant treatment, significantly increases the number of
      NG2+ glial cells and mature oligodendrocytes in the adult rat amygdala.

PMID- 15023572
TI  - Chronic treatment with atypical neuroleptics induces striosomal FosB/DeltaFosB
      expression in rats.
AB  - BACKGROUND: Studies have shown that neuroleptics regulate expression of the
      transcription factor FosB/DeltaFosB in the striatum, including the accumbens and
      caudate-putamen; however, the striatum is also divided into another structural
      dimension, the striosome and matrix compartments. The precise distribution of
      FosB/DeltaFosB induced by chronic neuroleptics in these striatal compartments is
      poorly understood. METHODS: Rats received either single acute injections or
      chronic injections of clozapine (0 or 20 mg/kg, intraperitoneally [IP]),
      olanzapine (0 or 5 mg/kg, IP), or haloperidol (0 or 1.5 mg/kg, IP) for 25 days.
      The levels and compartmental distribution of FosB/DeltaFosB were examined.
      RESULTS: Chronic clozapine induced clustered FosB/DeltaFosB expression within
      striosomes of the caudate-putamen. This pattern was due to increased levels of
      FosB/DeltaFosB in striosomes within the ventrolateral caudate-putamen and reduced
      levels of basal FosB/DeltaFosB in the matrix in the entire caudate-putamen. In
      contrast, chronic haloperidol increased FosB/DeltaFosB equally within the matrix
      and striosomes throughout the entire caudate-putamen. Chronic olanzapine induced
      an intermediate pattern. CONCLUSIONS: The relative absence of FosB/DeltaFosB
      expression in the matrix correlates with the lack of parkinsonism of atypical
      neuroleptics. Expression of FosB/DeltaFosB in the matrix may contribute to
      parkinsonism of typical neuroleptics.

PMID- 15023574
TI  - Repeated electroconvulsive stimulation impairs long-term depression in the
      neostriatum.
AB  - BACKGROUND: Increasing and consistent findings of structural and functional
      abnormalities in patients with mood disorders demonstrate a clear involvement of
      the neostriatum. Therefore, the beneficial effect of electroconvulsive
      stimulation (ECS) treatment of acute state of mood disorder may relate to changes
      in striatal synaptic plasticity. METHODS: We studied the effect of ECS treatment
      on the reported long-term depression (LTD) of synaptic excitatory afferents to
      striatal medium spiny neurons. Stimulation of the white matter between the cortex
      and the striatum elicited excitatory postsynaptic potentials (EPSPs) in medium
      spiny neurons in rat corticostriatal slices while recording using the whole-cell
      patch-clamp technique. RESULTS: The EPSPs evoked in striatal neurons undergo LTD
      with repeated stimulation trains, and LTD of this pathway is impaired in rats
      after ECS treatment for 1 week, similar to what is reported in chronic lithium
      treatment. Electroconvulsive stimulation did not affect intrinsic membrane
      properties or the occurrence of spontaneous EPSCs. Dose-dependent inhibition of
      the EPSPs by a nonselective agonist of metabotropic glutamate receptor did not
      change in rats after ECS treatment. CONCLUSIONS: Our data suggest that the
      effectiveness of electroconvulsive therapy in mood disorders may be a consequence
      of LTD impairment of excitatory cortical afferents to striatal projecting
      neurons.

PMID- 15023575
TI  - Inhibition of stress-induced dopamine output in the rat prefrontal cortex by
      chronic treatment with olanzapine.
AB  - BACKGROUND: Chronic exposure to stressful events precipitates or exacerbates many
      neuropsychiatric disorders, including depression and schizophrenia. Evidence
      suggests that treatment with the atypical antipsychotic drugs olanzapine or
      clozapine results in a superior amelioration of the anxious and depressive
      symptoms that accompany schizophrenia relative to therapy with classical
      antipsychotics such as haloperidol. Moreover, olanzapine and clozapine, but not
      haloperidol, increase the brain content of neuroactive steroids. The effects of
      olanzapine and clozapine on the stress-induced increase in dopamine output in the
      rat cerebral cortex have now been compared with that of haloperidol. METHODS:
      Rats chronically treated (3 weeks, once a day) with each drug were exposed to
      foot-shock stress or injected with a single dose of the anxiogenic benzodiazepine
      receptor ligand FG7142, and dopamine release was then measured in the prefrontal
      cortex by vertical microdialysis. RESULTS: Long-term administration of olanzapine
      or clozapine prevented or markedly inhibited, respectively, the increase in the
      extracellular dopamine concentration induced by foot shock; haloperidol had no
      such effect. Chronic olanzapine treatment also blocked the effect of FG7142 on
      dopamine output. CONCLUSIONS: The reduction in the sensitivity of cortical
      dopaminergic neurons to stress shown to be elicited by treatment with olanzapine
      or clozapine may contribute to the anxiolytic actions of these drugs.

PMID- 15023576
TI  - Endogenous dopamine release induced by repetitive transcranial magnetic
      stimulation over the primary motor cortex: an [11C]raclopride positron emission
      tomography study in anesthetized macaque monkeys.
AB  - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been used as
      a treatment for neuropsychiatric disorders such as depression and Parkinson's
      disease (PD). Despite the growing interest in therapeutic application of rTMS,
      precise mechanisms of its action remain unknown. With respect to PD, activation
      of the mesostriatal dopaminergic pathway is likely to be a candidate mechanism
      underlying the therapeutic effects; however, modulating effects of rTMS over the
      primary motor cortex (M1) on the dopaminergic system have not been studied.
      METHODS: We used [11C]raclopride positron emission tomography to measure changes
      of extracellular dopamine concentration after 5Hz rTMS over the M1 in eight
      anesthetized monkeys. RESULTS: rTMS over the right M1 induced a reduction of
      [11C]raclopride binding potential (BP) in the bilateral ventral striatum,
      including the nucleus accumbens, and a significant increase of BP in the right
      putamen; no significant BP reduction was found in the dorsal striatum. These data
      indicate that rTMS over the motor cortex induces a release of endogenous dopamine
      in the ventral striatum. CONCLUSIONS: Our results suggest that therapeutic
      mechanisms of rTMS may be explained in part by an activation of the mesolimbic
      dopaminergic pathway, which plays critical roles in rewards, reinforcement, and
      incentive motivation.

PMID- 15023577
TI  - Functional magnetic resonance imaging during auditory verbal working memory in
      nonpsychotic relatives of persons with schizophrenia: a pilot study.
AB  - BACKGROUND: First-degree relatives of persons with schizophrenia carry elevated
      genetic risk for the illness and show deficits on high-load information
      processing tasks. We used functional magnetic resonance imaging (fMRI) to test
      whether nonpsychotic relatives show altered functional activation in the
      prefrontal cortex (PFC), thalamus, hippocampus, and anterior cingulate during a
      working memory task requiring interference resolution. METHODS: Twelve
      nonpsychotic relatives of persons with schizophrenia and 12 healthy control
      subjects were administered an auditory, verbal working memory version of the
      Continuous Performance Test during fMRI. An asymmetric, spin-echo, T2*-weighted
      sequence (15 contiguous, 7-mm axial slices) was acquired on a full-body MR
      scanner. Data were analyzed by Statistical Parametric Mapping (SPM). RESULTS:
      Compared with control subjects, relatives showed greater task-elicited activation
      in the PFC and the anterior and dorsomedial thalamus. When task performance was
      controlled, relatives showed significantly greater activation in the anterior
      cingulate. When effects of other potentially confounding variables were
      controlled, relatives generally showed significantly greater activation in the
      dorsomedial thalamus and anterior cingulate. CONCLUSIONS: This pilot study
      suggests that relatives of persons with schizophrenia have subtle differences in
      brain function in the absence of psychosis. These differences add to the growing
      literature identifying neurobiological vulnerabilities to schizophrenia.

PMID- 15023578
TI  - Multichannel near-infrared spectroscopy in depression and schizophrenia:
      cognitive brain activation study.
AB  - BACKGROUND: Recent developments in near-infrared spectroscopy (NIRS) have enabled
      the noninvasive clarification of brain functions in psychiatric disorders with
      measurement of hemoglobin concentrations as cerebral blood volume. METHODS: Ten
      patients with depression, 13 patients with schizophrenia, and 16 age- and gender
      matched healthy control subjects participated in the study after giving consent.
      The relative concentrations of oxyhemoglobin [oxyHb] were measured with frontal
      and temporal probes every.1 sec during word fluency and unilateral finger tapping
      tasks, with two 24-channel NIRS machines. RESULTS: The [oxyHb] increase patterns
      during the word fluency task varied among the three groups, although their task
      performances were similar: the depression group was characterized by a smaller
      [oxyHb] increase during the first half of the task period and the schizophrenic
      group by a small trough of [oxyHb] at the start of the task period and [oxyHb] re
      increase in the posttask period. [OxyHb] increases during the finger-tapping task
      were rather larger in the patient groups than in the control group. CONCLUSIONS:
      The characteristic time courses of [oxyHb] changes in the frontal lobe were
      elucidated for depression and schizophrenia. Near-infrared spectroscopy, with its
      noninvasiveness and high time resolution, can be a useful tool for research and
      clinical purposes in psychiatry.

PMID- 15023579
TI  - A sexually dimorphic ratio of orbitofrontal to amygdala volume is altered in
      schizophrenia.
AB  - BACKGROUND: Neuroanatomic sexual dimorphisms have been correlated with behavioral
      differences between healthy men and women. We have reported higher orbitofrontal
      cortex to amygdala ratio (OAR) in women than men. Although gender differences in
      schizophrenia are evident clinically and correlate with neuroanatomic measures,
      their relationship to OAR has not been examined. METHODS: Magnetic resonance
      imaging was performed in 31 neuroleptic-naive schizophrenic patients (16 men) and
      80 healthy volunteers (34 men), aged less than 50 years. An automated tissue
      segmentation procedure was combined with expert-guided parcellation of
      orbitofrontal and amygdala volumes. RESULTS: Men with schizophrenia had increased
      OAR relative to healthy men, whereas women had decreased OAR. Increased OAR in
      men with schizophrenia reflected abnormally low amygdala volumes, whereas
      decreased OAR in women reflected abnormally low orbitofrontal volumes. Less
      severe negative symptoms were associated with increased OAR in men but with
      decreased OAR in women. In men, increased amygdala volume was associated with
      greater symptom severity, whereas in women higher volumes of both amygdala and
      orbitofrontal regions were associated with lesser severity of negative symptoms.
      CONCLUSIONS: These opposite OAR abnormalities, whereby men show feminization and
      women masculinization, suggest gender-mediated effects of the underlying
      neuropathologic processes. The correlations with symptom severity suggest that
      neuroanatomic abnormalities in OAR reflect compensatory brain changes.

PMID- 15023580
TI  - Prepulse facilitation and prepulse inhibition in schizophrenia patients and their
      unaffected siblings.
AB  - BACKGROUND: Deficits in schizophrenia patients and their first-degree relatives
      have been reported in prepulse inhibition (PPI), a phenomenon that measures an
      early stage of information processing (sensorimotor gating). It is less clear
      whether these information processing deficits extend to prepulse facilitation
      (PPF), which measures a later stage of generalized alerting or orienting.
      METHODS: This study examined three separate issues: first, whether schizophrenia
      patients have deficits in PPI and PPF; second, whether the siblings of patients
      show deficits in these processes; and third, whether prepulse duration influences
      the degree of the deficits. These issues were examined in 76 schizophrenia
      patients, 36 of their siblings, and 41 normal control subjects. RESULTS: Patients
      and siblings did not differ from control subjects in PPI, perhaps due to the use
      of different procedural parameters compared with other laboratories that have
      consistently found PPI deficits in schizophrenia patients. Patients and their
      siblings produced significantly less PPF than control subjects. For both PPI and
      PPF, prepulse duration was not a significant factor. CONCLUSIONS: These results
      imply that PPF deficits reveal a generalized alerting or orienting deficit that
      is present in both schizophrenia patients and their siblings, suggesting that
      this deficit may be tapping an endophenotypic vulnerability factor.

PMID- 15023581
TI  - Amyloid beta peptides in cerebrospinal fluid as profiled with surface enhanced
      laser desorption/ionization time-of-flight mass spectrometry: evidence of novel
      biomarkers in Alzheimer's disease.
AB  - BACKGROUND: The advent of new therapeutic avenues for Alzheimer's disease (AD)
      calls for an improved early and differential diagnosis. METHODS: With surface
      enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF
      MS), cerebrospinal fluid from patients with AD (n = 10) and nondemented control
      subjects (n = 9) was studied. RESULTS: Molecular mass signals were observed
      corresponding to three novel amyloid beta (Abeta) peptides that have not
      previously been described, in addition to those previously known, with molecular
      masses of 4525.1 d, 4846.8 d, and 7755.8 d. The signal-to-noise ratios (S/NR) of
      Abeta(4525.1) and Abeta(7758.8+2H) were significantly decreased in AD
      [Abeta(4525.1): median 2.2 and 4.3 in AD and control subjects, respectively, p
      <.01; Abeta(7758.8+2H): median 1.0 and 14.0 in AD and control subjects,
      respectively, p <.01], whereas the S/NR of Abeta(4846.8) was significantly
      increased in AD (median 3.6 and 2.5 in AD and control subjects, respectively, p
      <.05). The S/NR of two known AD biomarkers, Abeta1-42 and Abeta1-40, expectedly
      turned out to be significantly decreased (p <.01) and unaltered in AD,
      respectively. A moderate and highly significant correlation was observed between
      S/NR of Abeta1-42 and Abeta42 concentration as measured with enzyme-linked
      immunosorbent assay (R =.67, p <.01). CONCLUSIONS: We report evidence of three
      novel amyloid beta peptides that might play an important role in the diagnosis
      and pathophysiology of Alzheimer's disease.

PMID- 15023582
TI  - Opiate addicts lack error-dependent activation of rostral anterior cingulate.
AB  - BACKGROUND: Healthy individuals performing response suppression tasks activate
      anterior cingulate cortex with occurrence of false alarm error responses to
      nontargets. Fundamental questions include whether this error-related activation
      provides a signal contributing to behavioral control and, given generally poorer
      performance on such tasks by addicts, whether this signal is disrupted in
      addiction. METHODS: We used rapid, event-related functional magnetic resonance
      imaging to study 13 individuals with opiate dependence and 26 healthy control
      individuals performing a Go/NoGo task. RESULTS: Compared with controls, opiate
      addicts exhibited an attenuated anterior cingulate cortex error signal and
      significantly poorer task performance. In controls, the individual level of event
      related anterior cingulate cortex activation accompanying false alarm error
      positively predicted task performance, particularly sensitivity in discriminating
      targets from nontargets. CONCLUSIONS: The attenuation of this error signal in
      anterior cingulate cortex may play a role in loss of control in addiction and
      other forms of impulsive behavior.

PMID- 15023583
TI  - Hippocampal volume, spectroscopy, cognition, and mood in patients receiving
      corticosteroid therapy.
AB  - BACKGROUND: Hippocampal volume reduction, declarative memory deficits, and
      cortisol elevations are reported in persons with major depressive disorder;
      however, data linking cortisol elevations with hippocampal atrophy are lacking.
      Prescription corticosteroid-treated patients offer an opportunity to examine
      corticosteroid effects on hippocampal volume and biochemistry and memory in
      humans. METHODS: Seventeen patients on long-term prescription corticosteroid
      therapy and 15 controls of similar age, gender, ethnicity, education, height, and
      medical history were assessed with magnetic resonance imaging and proton magnetic
      resonance spectroscopy, the Rey Auditory Verbal Learning Test, Stroop Color Word
      Test and other neurocognitive measures, the Hamilton Rating Scale for Depression,
      Young Mania Rating Scale, and Brief Psychiatric Rating Scale. RESULTS: Compared
      with controls, corticosteroid-treated patients had smaller hippocampal volumes
      and lower N-acetyl aspartate ratios, lower scores on the Rey Auditory Verbal
      Learning Test and Stroop Color Word Test, and higher Hamilton Rating Scale for
      Depression and Brief Psychiatric Rating Scale scores. CONCLUSIONS: Patients
      receiving chronic corticosteroid therapy have smaller hippocampal volumes, lower
      N-acetyl aspartate ratios, and declarative memory deficits compared with
      controls. These findings support the idea that corticosteroid exposure appears to
      be associated with changes in hippocampal volume and functioning in humans.

PMID- 15023584
TI  - Testosterone, antisocial behavior, and social dominance in boys: pubertal
      development and biosocial interaction.
AB  - BACKGROUND: Studies linking testosterone and antisocial behavior in humans have
      produced mixed results. Adolescence offers a promising period to study this
      relationship; circulating testosterone increases dramatically in boys during
      puberty, and antisocial behavior increases during the same period. METHODS: Our
      analyses were based on boys aged 9-15 years who were interviewed during the first
      three waves of the Great Smoky Mountains Study. Measures included interview
      assessment of DSM-IV conduct disorder (CD) symptoms and diagnosis, blood spot
      measurement of testosterone, Tanner staging of pubertal development, and
      assessment of leadership behaviors and peer deviance. RESULTS: The adolescent
      rise in CD was primarily attributable to an increase in nonphysically aggressive
      behaviors. Increasing levels of circulating testosterone and association with
      deviant peers contributed to these age trends. There was no evidence that
      physical aggression was related to high testosterone. Evidence of biosocial
      interactions was identified; testosterone was related to nonaggressive CD
      symptoms in boys with deviant peers and to leadership in boys with nondeviant
      peers. CONCLUSIONS: The results are consistent with the hypothesis that
      testosterone relates to social dominance, with the assumption that behaviors
      associated with dominance differ according to social context.

PMID- 15023585
TI  - A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine
      refractory obsessive-compulsive disorder.
AB  - BACKGROUND: One of the few combination approaches to the treatment of obsessive
      compulsive disorder (OCD) with encouraging support is the addition of an
      antipsychotic to a serotonin reuptake inhibitor. METHODS: The study consisted of
      a 6-week, placebo-controlled addition of olanzapine 5-10 mg (6.1 +/- 2.1 mg, mean
      +/- SD) to fluoxetine in OCD subjects who were partial or nonresponders to an 8
      week, open-label fluoxetine trial (40 mg in 43 subjects, 20 mg in 1 subject).
      RESULTS: Both the fluoxetine-plus-olanzapine (n = 22) and fluoxetine-plus-placebo
      (n = 22) groups improved significantly over 6 weeks [F(3,113) = 11.64, p <.0001]
      according to Yale-Brown Obsessive Compulsive Scale scores with repeated-measures
      analysis of variance; however, the treatment x time interaction was not
      significant for olanzapine versus placebo addition to fluoxetine. CONCLUSIONS:
      These findings indicate no additional advantage of adding olanzapine for 6 weeks
      in OCD patients who have not had a satisfactory response to fluoxetine for 8
      weeks, compared with extending the monotherapy trial.

PMID- 15023701
TI  - Plant intelligence: an alternative point of view.
AB  - The concept of plant intelligence has been advanced by Trewavas as a potentially
      useful framework to guide those seeking to understand plant growth and
      development. In this short critique, the validity of this concept is critically
      assessed. Central to this critique is the proposition that the concept of the
      individual, to which intelligence and behaviour are intimately linked, cannot
      usefully be applied to plants. It is argued that the adaptive responses of plants
      are best appreciated if the importance of the autonomy of the individual organs
      is acknowledged. Although Trewavas does acknowledge the autonomy of organs by
      describing an individual plant as being 'a democratic confederation', that
      terminology implies a complexity to the interaction between organs which would
      demand a cogitative ability beyond that actually demonstrated in plants. It may
      be more appropriate to consider a plant as operating normally as a simple
      economic federation of many specialized economies (organs and cells).
      Occasionally, there can be a dramatic, and sometimes complex, reshaping of the
      economic balances, with the result that the fate of some or many of the
      individual cells will change. However, such major changes in growth and
      development are driven by a few simple events in an individual organ and cells.
      These driving events are more akin to small local revolutions in individual
      states than they are to democratic decisions in a sophisticated confederation.

PMID- 15023702
TI  - Aspects of plant intelligence: an answer to Firn.
AB  - In a recent 'Invited Review', I stated the case for plant intelligence, provided
      definitions and outlined some of the consequences, illustrating them with
      examples. A short critique of this concept by Firn is given in the preceding
      'Viewpoint' and rebuttals of the criticisms it contains are presented in the
      present article. The importance of plant intelligence as an emergent property
      resulting from interactions and communication of the component tissues is re
      stated. The contentions made by Firn that plants are collectives of physically
      joined organs but acting in relative isolation of each other is subject to
      critical analysis and found to be contradicted by much established literature.
      Viewing plants as expressing intelligent behaviour should lead to better
      understanding of their ecological success and indicate experiments to test the
      basic concept.

PMID- 15023703
TI  - Spatially quantitative control of the number of cotyledons in a clonal population
      of somatic embryos of hybrid larch Larix x leptoeuropaea.
AB  - BACKGROUND AND AIMS: Many conifer embryos, both in natural seeds and in clonal
      populations of somatic embryos, display variability in the number of cotyledons.
      In hybrid larch, Larix x leptoeuropaea (synonymous with L. x marschlinsii Coaz),
      such variability has previously been reported in somatic embryos, together with a
      decrease in the average cotyledon number when benzyladenine (BA) is applied
      exogenously. Described here is a spatially quantitative study with the aim of
      throwing some light on the way cotyledon number is determined, and hence the
      mechanism of cotyledon formation. METHODS: Stock cultures of embryogenic tissue
      were maintained and later made embryogenically active by standard methods.
      Development through cotyledon formation was followed by optical microscopy with
      quantitative measurement of embryo diameter and number of cotyledons. SEMs of
      representative stages and cotyledon numbers were done for purposes of
      illustration in this account. Existing mathematics of waveforms on a disc were
      cast into a form suitable to compare with the quantitative data. RESULTS: The
      number of cotyledons is linearly related to the diameter of the apical surface of
      the embryo (which approximates a circular disc) at the time of first appearance
      of the cotyledon primordia. This linearity is a constant-spacing phenomenon
      between adjacent primordia. Addition of BA to the medium restricts the range of
      apical diameters without changing inter-cotyledon spacing. Slope/intercept ratio
      of the linear plot matches expectation for initiation of cotyledon pattern as a
      harmonic waveform on a circular disc. CONCLUSIONS: The entire pattern of
      cotyledon primordia arises as a single entity coordinated by a mechanism with
      wave-forming properties. This is explicable by diverse mechanisms, especially
      either mechanical buckling ('biophysical') or reaction-diffusion kinetics
      ('physicochemical').

PMID- 15023704
TI  - Modelling the mechanical properties of single suspension-cultured tomato cells.
AB  - BACKGROUND AND AIMS: The relationship between composition and structure of plant
      primary cell walls, and cell mechanical properties is not fully understood,
      partly because intrinsic properties of walls such as Young's modulus cannot be
      obtained readily. The aim of this work is to show that Young's modulus of walls
      of single suspension-cultured tomato cells can be determined by modelling force
      deformation data. METHODS: The model simulates the compression of a cell between
      two flat surfaces, with the cell treated as a liquid-filled sphere with thin
      compressible walls. The cell wall and membrane were taken to be permeable, but
      the compression was so fast that water loss could be neglected in the
      simulations. Force-deformation data were obtained by compressing the cells in
      micromanipulation experiments. RESULTS: Good fits were obtained between the model
      and low-strain experimental data, using the modulus and initial inflation of the
      cell as adjustable parameters. The mean Young's modulus for 2-week-old cells was
      found to be 2.3 +/- 0.2 GPa at pH 5. This corresponds to an instantaneous bulk
      modulus of elasticity of approx. 7 MPa, similar to a value found by the pressure
      probe method. However, Young's modulus is a better parameter, as it should depend
      only on the composition and structure of the cell wall, not on bulk cell
      behaviour. This new method has been used to show that Young's modulus of cultured
      tomato cell walls is at its lowest at pH 4.5, the pH optimum for expansin
      activity. CONCLUSIONS: The linear elastic model is very suitable for estimating
      wall Young's modulus from micromanipulation experiments on single tomato cells.
      This is a powerful method for determining cell wall material properties.

PMID- 15023705
TI  - Metaxenia in the vine cacti Hylocereus polyrhizus and Selenicereus spp.
AB  - BACKGROUND AND AIMS: Flowers of the vine cacti of the genera Hylocereus and
      Selenicereus grown in Israel must be hand pollinated due to self-incompatibility
      and lack of efficient pollinators. In controlled pollination experiments, it was
      found that the time elapsed between pollination and ripening depends on the
      source of the pollen. Therefore a study was made of some effects of the pollen
      source on fruit development. METHODS: Flowers of Hylocereus polyrhizus were
      pollinated on the same day with different pollen sources and the stigmas were
      covered. Fruits were collected 4 d after reaching full colour. RESULTS:
      Pollinating flowers of Hylocereus polyrhizus with Selenicereus grandiflorus and
      S. megalanthus pollen delayed ripening by 1 and 3 weeks, respectively, as
      compared with ripening of fruits pollinated with Hylocereus undatus pollen. Other
      fruit characteristics affected by the pollen source were fruit size, pulp dry
      weight and number of seeds per fruit, all being significantly reduced, while peel
      dry weight was significantly increased by S. megalanthus pollen. Total soluble
      sugar content was reduced in H. polyrhizus fruits pollinated with S. grandiflorus
      pollen. No other major traits were affected. CONCLUSIONS: The results are
      evidence for the existence of metaxenia, i.e. an effect of pollen on maternal
      tissues, in cacti fruits. This pollen effect on the fruit-ripening time may be
      used for extending the marketing period of H. polyrhizus fruits.

PMID- 15023706
TI  - Health plan members' views about disclosure of medical errors.
AB  - BACKGROUND: Various authorities and national organizations encourage disclosing
      medical errors, but there is little information on how patients respond to
      disclosure. OBJECTIVE: To examine how the type of error, severity of adverse
      clinical outcome, and level of disclosure affect patients' responses to error and
      disclosure. DESIGN: Mail questionnaire survey (8 versions were developed) varying
      3 factors in a completely crossed, randomized, factorial design. Each
      questionnaire included a vignette describing 1) a medical error (failure to check
      for penicillin allergy or inadequate monitoring of antiepileptic medication); 2)
      an associated clinical outcome (life-threatening or less serious); and 3) a
      physician-patient dialogue, with either full disclosure (acceptance of
      responsibility and an apology) or nondisclosure (expression of regret without
      acceptance of responsibility or an apology). SETTING: New England-based health
      plan. PARTICIPANTS: Random sample of 1500 adult members received the
      questionnaire, with a 66% response rate. MEASUREMENTS: Likelihood of changing
      physicians, likelihood of seeking legal advice, ratings of patient satisfaction,
      trust and emotional reaction in response to a vignette and dialogue, and views on
      medical error and disclosure. RESULTS: Full disclosure reduced the reported
      likelihood of changing physicians and increased patient satisfaction, trust, and
      positive emotional response. Full disclosure reduced the reported likelihood of
      seeking legal advice in only 1 error-and-outcome vignette. In the other
      vignettes, the percentage of patients indicating that they would seek legal
      advice was relatively high even with full disclosure. Almost all respondents
      (98.8%) wanted to be told of errors, most (83%) favored financial compensation if
      harm occurred, and few (12.7%) favored compensation if no harm occurred.
      LIMITATIONS: Since the study was done in the context of a managed care plan in
      one geographic area, it could not assess whether the results are generalizable to
      other populations. In addition, it could not determine whether responses to the
      simulated situations used predict responses to real situations. CONCLUSIONS:
      Patients will probably respond more favorably to physicians who fully disclose
      medical errors than to physicians who are less forthright, but the specifics of
      the case and the severity of the clinical outcome also affect patients'
      responses. In some circumstances, the desire to seek legal advice may not
      diminish despite full disclosure.

PMID- 15023707
TI  - Mupirocin prophylaxis against nosocomial Staphylococcus aureus infections in
      nonsurgical patients: a randomized study.
AB  - BACKGROUND: Staphylococcus aureus nasal carriage is a major risk factor for
      nosocomial S. aureus infection. Studies show that intranasal mupirocin can
      prevent nosocomial surgical site infections. No data are available on the
      efficacy of mupirocin in nonsurgical patients. OBJECTIVE: To assess the efficacy
      of mupirocin prophylaxis in preventing nosocomial S. aureus infections in
      nonsurgical patients. DESIGN: Randomized, double-blind, placebo-controlled trial.
      SETTING: 3 tertiary care academic hospitals and 1 nonacademic hospital. PATIENTS:
      1602 culture-proven S. aureus carriers hospitalized in nonsurgical departments.
      INTERVENTION: Therapy with mupirocin 2% nasal ointment (n = 793) or placebo
      ointment (n = 809), twice daily for 5 days, started 1 to 3 days after admission.
      MEASUREMENTS: Nosocomial S. aureus infections according to defined criteria, in
      hospital mortality, duration of hospitalization, and time to nosocomial S. aureus
      infection. Staphylococcus aureus isolates were genotyped to assess whether
      infection was caused by endogenous strains. RESULTS: The mupirocin and placebo
      groups did not statistically differ in the rates of nosocomial S. aureus
      infections (mupirocin, 2.6%; placebo, 2.8%; risk difference, 0.2 percentage point
      [95% CI, -1.5 to 1.9 percentage points]), mortality (mupirocin, 3.0%; placebo,
      2.8%; risk difference, -0.2 percentage point [CI, -1.9 to 1.5 percentage
      points]), or duration of hospitalization (median for both, 8 days). However, time
      to nosocomial S. aureus infection was decreased in the mupirocin group from 12 to
      25 days (P > 0.2). A total of 77% of S. aureus nosocomial infections were
      endogenous. LIMITATIONS: A few infections in both groups may have been missed
      because investigators assessed a patient for infection only if microbiology
      culture results were positive for S. aureus. CONCLUSION: Routine culture for S.
      aureus nasal carriage at admission and subsequent mupirocin application does not
      provide effective prophylaxis against nosocomial S. aureus infections in
      nonsurgical patients.

PMID- 15023708
TI  - Individualizing nicotine replacement therapy for the treatment of tobacco
      dependence: a randomized trial.
AB  - BACKGROUND: Despite the well-documented efficacy and different pharmacokinetic
      and pharmacodynamic properties of different forms of nicotine replacement
      therapy, empirical data are insufficient to guide practitioners in selecting a
      particular form of treatment for individual patients with tobacco dependence.
      OBJECTIVE: To evaluate the comparative efficacy of transdermal nicotine and
      nicotine nasal spray and identify predictors of treatment outcome. DESIGN:
      Randomized, open-label clinical trial with a 6-month follow-up period. SETTING: 2
      university-based smoking cessation research programs. PARTICIPANTS: 299 treatment
      seeking smokers who were followed for 6 months after the target quit date.
      INTERVENTION: Behavioral group counseling and 8 weeks of therapy with nicotine
      nasal spray or transdermal nicotine. MEASUREMENTS: Demographic characteristics,
      smoking history, depression symptoms, and body mass index were measured at
      baseline. Smoking practices were biochemically verified at the end of treatment
      and at 6 months after the target quit date. RESULTS: Abstinence rates for the
      transdermal nicotine and nicotine nasal spray groups were not significantly
      different at 6-month follow-up (15.0% vs. 12.2%, respectively; P > 0.2).
      Interactions in abstinence rates for subgroups of smokers were statistically
      significant (P < 0.05). Smokers who had low to moderate dependence levels, were
      not obese, and were white achieved higher abstinence rates with transdermal
      nicotine, whereas smokers who were highly dependent, obese, or members of
      minority groups achieved higher abstinence rates with nasal spray. LIMITATIONS:
      The subgroup findings need confirmation in additional large studies before they
      are routinely applied. CONCLUSIONS: Ethnicity, weight, and level of nicotine
      dependence may help identify smokers who have greater or lesser abstinence rates
      with either transdermal or nasal spray nicotine.

PMID- 15023709
TI  - Accuracy of offspring reports of parental cardiovascular disease history: the
      Framingham Offspring Study.
AB  - BACKGROUND: Family history is used to infer the risk for heart disease; however,
      little is known about the accuracy of family history reports. OBJECTIVE: To
      examine the accuracy of offspring reports of parental cardiovascular disease.
      DESIGN: Validation study. SETTING: Framingham Heart Study. PARTICIPANTS:
      Offspring participants of the multigenerational Framingham Heart Study with both
      parents in the original cohort. MEASUREMENTS: 791 men and 837 women (mean age, 57
      years) completed a family history questionnaire from 1995 to 1998. Offspring
      reports were compared with confirmed medical evidence of parental status, and
      positive and negative predictive values and likelihood ratios were calculated.
      RESULTS: Positive reports of high blood pressure, diabetes, and high cholesterol
      levels in fathers were accurate: Positive predictive values were 83% (95% CI, 80%
      to 86%), 76% (CI, 70% to 82%), and 78% (CI, 73% to 83%), respectively.
      Corresponding positive predictive values for reports in mothers were 91% (CI, 89%
      to 93%), 79% (CI, 73% to 85%), and 88% (CI, 84% to 92%), respectively. Positive
      predictive values for reports of paternal heart attack occurring before 55 years
      of age and for stroke occurring before 65 years of age were 28% (CI, 22% to 34%)
      and 43% (CI, 33% to 53%), respectively, whereas the positive likelihood ratios
      were 8.6 (CI, 6.8 to 10.9) and 11.2 (CI, 9.2 to 13.6), respectively. Negative
      predictive values for parental history reports were greater than 90%, except for
      high blood pressure and high cholesterol level (negative predictive values, 33%
      to 55%, and negative likelihood ratios, 0.47 to 0.88). LIMITATIONS: This study
      does not determine whether more accurate measures of family history would
      meaningfully improve estimation of cardiovascular risk. CONCLUSIONS: Negative
      parental history reports were reliable, except for hypertension and high
      cholesterol levels. Although reports of parental premature heart attack and
      stroke had high likelihood ratios, their predictive values were low because the
      prevalence of these conditions was low in parents. If patients were more aware of
      their parents' medical illnesses, they might be able to estimate their risk for
      disease more accurately and perhaps motivate themselves to follow a healthy
      lifestyle.

PMID- 15023710
TI  - Pain: moving from symptom control toward mechanism-specific pharmacologic
      management.

PMID- 15023711
TI  - Update in perioperative medicine.

PMID- 15023712
TI  - Screening for hepatitis C virus infection in adults: recommendation statement.

PMID- 15023713
TI  - Screening for hepatitis C virus infection: a review of the evidence for the U.S.
      Preventive Services Task Force.
AB  - BACKGROUND: Hepatitis C virus (HCV) is the most common bloodborne pathogen in the
      United States and is an important cause of patient morbidity and mortality, but
      it is unclear whether screening to identify asymptomatic infected persons is
      appropriate. PURPOSE: To synthesize the evidence on risks and benefits of
      screening for HCV infection. DATA SOURCES: MEDLINE (through February 2003),
      Cochrane Clinical Trials Registry (2002, Issue 2), reference lists, and experts.
      STUDY SELECTION: Controlled studies of screening and antiviral therapy and
      observational studies on other interventions, risk factors, accuracy of antibody
      testing, work-up, harms of biopsy, and long-term outcomes. DATA EXTRACTION: Using
      preset criteria, the authors assessed the quality of included studies and
      abstracted information about settings, patients, interventions, and outcomes.
      DATA SYNTHESIS: There are no published trials of screening for HCV infection.
      Approximately 2% of U.S. adults have HCV antibodies, with the majority having
      chronic infection. Risk factor assessment could identify adults at substantially
      higher risk. Antiviral treatment can result in a sustained virologic response
      rate of 54% to 56%, but no trials have been done specifically in asymptomatic
      patients likely to be identified by screening. Data are insufficient to determine
      whether treatment improves long-term outcomes. There are no data to estimate the
      benefit from counseling or immunizations. Although risks of biopsy and treatment
      appear minimal or self-limited, data on other adverse effects of screening, such
      as labeling or anxiety, are sparse. CONCLUSIONS: Antiviral treatment can
      successfully eradicate HCV, but data on long-term outcomes in populations likely
      to be identified by screening are lacking. Although the yield from targeted
      screening, particularly in intravenous drug users, would be substantially higher
      than in the general population, data are inadequate to accurately weigh the
      overall benefits and risks of screening in otherwise healthy asymptomatic adults.

PMID- 15023716
TI  - Mupirocin prophylaxis misses by a nose.

PMID- 15023715
TI  - Words that heal.

PMID- 15023717
TI  - Prevention of ventilator-associated pneumonia.

PMID- 15023718
TI  - Blood pressure control in type 2 diabetes mellitus.

PMID- 15023719
TI  - Randomized trial of warfarin nomograms.

PMID- 15023720
TI  - Randomized trial of warfarin nomograms.

PMID- 15023721
TI  - Randomized trial of warfarin nomograms.

PMID- 15023722
TI  - Randomized trial of warfarin nomograms.

PMID- 15023724
TI  - Randomized trial of warfarin nomograms.

PMID- 15023723
TI  - Randomized trial of warfarin nomograms.

PMID- 15023726
TI  - Randomized trial of warfarin nomograms.

PMID- 15023725
TI  - Randomized trial of warfarin nomograms.

PMID- 15023727
TI  - Angiotensin-converting enzyme inhibitors for secondary erythrocytosis.

PMID- 15023728
TI  - Occupational exposure to bloodborne pathogens.

PMID- 15023729
TI  - Successful treatment of diffuse alveolar hemorrhage with activated factor VII.

PMID- 15023731
TI  - Risks from microbes on the rise: reasons why and ways to prevent future
      epidemics.

PMID- 15023730
TI  - Capecitabine induces severe angina-like chest pain.

PMID- 15023732
TI  - Summaries for patients. The effects of telling patients about medical errors.

PMID- 15023733
TI  - Summaries for patients. Effects of antibiotic nose ointment for hospitalized
      patients with Staphylococcus aureus.

PMID- 15023734
TI  - Summaries for patients. Matching nicotine replacement treatment to particular
      smokers.

PMID- 15023735
TI  - Summaries for patients. The accuracy of adult patients' reports of their parents'
      medical histories.

PMID- 15023736
TI  - Summaries for patients. Screening for hepatitis C virus infection:
      recommendations from the U.S. Preventive Services Task Force.

PMID- 15023737
TI  - Pharmacologic management of migraine.

PMID- 15023738
TI  - Adrenal insufficiency from inhaled corticosteroids.

PMID- 15023739
TI  - Unilateral pseudogynecomastia: a novel work-related disease.

PMID- 15023740
TI  - Sentinel node mapping and an International Sentinel Node Society: current issues
      and future directions.

PMID- 15023741
TI  - Universal applications of sentinel node technology.
AB  - The sentinel node (SN) concept was originally proposed by several pioneers in the
      middle of the last century. After Donald Morton and his colleagues demonstrated
      the clinical significance of the SN concept in melanoma, it attracted vast
      attention in surgical oncology. At recent international conferences, a number of
      new approaches in this field for various solid tumors have been reported. Now,
      there are several possible applications with different technological aspects,
      such as individualized surgical management of solid tumors, multidisciplinary
      treatments, and novel therapeutic approaches. This article provides an overview
      of the future potential of SN technology.

PMID- 15023742
TI  - Sentinel node biopsy for melanoma: Where have we been and where are we going?
AB  - The sentinel node (SN) concept is not new, but its potential surgical application
      was not fully appreciated until the landmark report by Morton and Cochran et al.
      in 1992. It has since been confirmed that SN status in melanoma patients
      accurately reflects the status of the entire regional node field, and is a
      critically important prognostic indicator. However, randomized trials have yet to
      determine whether the SN biopsy technique is of any therapeutic value. With
      extended follow-up times, false-negative SN rates of up to 15% are being reported
      and presumably represent failures of nuclear medicine and/or surgery and/or
      histopathology. Innovative methods of increasing the accuracy of SN
      identification and of checking this retrospectively are being assessed. The next
      great challenge is to develop methods of SN assessment that are noninvasive yet
      are even more accurate than present methods. Techniques such as in vivo proton
      magnetic resonance spectroscopy hold great promise and suggest that this goal
      might be achievable.

PMID- 15023743
TI  - Clinicopathological utility of molecular staging for melanoma patients undergoing
      sentinel lymphadenectomy.
AB  - Lymphatic mapping and sentinel lymph node (SLN) biopsy have been validated in
      malignant melanoma. We hypothesized that histopathologically negative SLNs may
      contain occult metastases that can be identified by sensitive molecular
      approaches such as quantitative reverse transcriptase-polymerase chain reaction
      (RT-PCR) assay. We previously demonstrated that RT-PCR-based detection of occult
      metastasis in frozen SLNs upstaged early-stage cutaneous melanomas and that a
      multiple specific mRNA marker (MM) RT-PCR assay was an independent predictor of
      disease outcome. We recently developed an MM RT-PCR using
      electrochemiluminescence (ECL) and quantitative real-time detection assays. These
      assays can detect occult metastatic melanoma cells in paraffin-embedded (PE) SLNs
      and are of clinical utility for retrospective analysis of specimens with long
      term follow-up. The molecular detection of occult metastasis in PE SLNs has
      significant clinicopathologic and logistic advantages over molecular analysis of
      frozen SLNs.

PMID- 15023745
TI  - Sentinel lymphonodectomy and s-classification: a successful strategy for better
      prediction and improvement of outcome of melanoma.
AB  - The most successful strategies in the management of melanoma have always been
      based on early diagnosis and timely surgical removal. Sentinel lymphonodectomy
      (SLNE) is the most reliable technique for the detection of melanoma
      micrometastases in regional lymph nodes. The micromorphometric S-classification,
      a routinely determinable surrogate of tumor burden in the sentinel lymph node
      (SLN), has high prognostic relevance. SIII metastases, defined by a depth of
      invasion (d) greater than 1 mm below the capsular level, imply a risk of more
      than 50% for the presence of nonsentinel lymph node metastases in the same basin
      and for the emergence of distant metastases within 5 years of follow-up.
      Corresponding risks with SI metastases (d </= 0.3 mm) and SII metastases (0.3 mm
      < d </= 1 mm) do not exceed 15%. The survival curve for patients with SIII
      metastases approaches that of patients in the pre-SLNE era who underwent delayed
      lymph node dissection for subsequently detected nodal macrometastases. The
      survival of patients with initially removed SI and SII metastases is much better,
      similar to that of patients with S0 metastases. This explains the significant
      survival benefit of SLN-guided surgery in the entire population of patients with
      melanomas thicker than 0.75 mm, although the outcome of the subgroup without
      nodal metastases is not influenced by SLNE.

PMID- 15023744
TI  - Optimized assessment of sentinel lymph nodes for metastatic melanoma:
      implications for regional surgery and overall treatment planning.
AB  - Correct identification of the sentinel node (SN) and accurate evaluation of this
      node's tumor status constitute the most precise technique for staging clinically
      localized cutaneous melanoma. However, even if tumor is present in the SN (as in
      approximately 20% of patients), the remaining nodes in the basin are often tumor
      free. We have found that the Breslow thickness of the primary, the relative area
      of tumor in the SN (with respect to the area of the SN), and the density of
      dendritic leukocytes in the SN paracortex not only can predict the likelihood of
      nonsentinel node metastases but also are correlated with likelihood of tumor
      recurrence and melanoma-specific survival. The most robust of these predictors is
      relative tumor area, and this may be used as the basis of practical predictive
      algorithms.

PMID- 15023746
TI  - What is a sentinel node and what is a false-negative sentinel node?
AB  - Morton's original definition of a sentinel node as the first lymph node to
      receive afferent lymphatic drainage from a primary tumor reflects the concept of
      stepwise spread of cancer through the lymphatic system. Several new definitions
      have been developed, based on surgical anatomy and on the technique that is used
      to find the node. The various definitions of a sentinel node are critically
      analyzed. Breast cancer surgeons use three different definitions of a false
      negative sentinel node biopsy. The best definition appears to be based on the
      assumption that the procedure is truly positive if either the sentinel node or a
      suspicious node that is not radioactive or blue contains metastatic disease.

PMID- 15023747
TI  - Failure to remove true sentinel nodes can cause failure of the sentinel node
      biopsy technique: evidence from antimony concentrations in false-negative
      sentinel nodes from melanoma patients.
AB  - We have recently found that antimony (originating from the technetium 99m
      antimony trisulfide colloid, used for preoperative lymphoscintigraphy) can be
      measured in tissue sections from archival paraffin blocks of sentinel nodes (SNs)
      by means of inductively coupled plasma mass spectrometry (ICP-MS) to confirm that
      removed nodes are true SNs. We performed a retrospective analysis of antimony
      concentrations in all our false-negative (FN) SNs to determine whether errors in
      lymphadenectomy (i.e., failure to remove true SNs) may be a cause of FN SN
      biopsies (SNBs). Among 27 patients with an FN SNB, metastases were found on
      histopathologic review of the original slides or additional sections in 7 of 23
      patients for which they were available; however, antimony concentrations were low
      in 5 of 20 presumptive SNs. Our results suggest that an FN SNB can occur because
      of failure to remove the true SN as well as histopathologic misdiagnosis.

PMID- 15023748
TI  - Lymphatic drainage of the skin.
AB  - A successful sentinel lymph node biopsy (SLNB) in melanoma patients requires an
      accurate map of the pattern of lymphatic drainage from the primary site.
      Lymphoscintigraphy (LS) can provide such a map. LS needs an understanding of
      lymphatic physiology, an appropriate small-particle radiocolloid, high-resolution
      collimators, and imaging protocols that detect all sentinel nodes (SNs). Patterns
      of lymphatic drainage from the skin are not clinically predictable. Unexpected
      drainage has been found from the skin of the back to SNs in the triangular
      intermuscular space (TIS) and the paraaortic, paravertebral, and retroperitoneal
      areas. It can also occur from the base of the neck up to nodes in the occipital
      or upper cervical areas or from the scalp down to nodes at the neck base,
      bypassing many node groups. Upper limb drainage can be to SNs above the axilla.
      Interval nodes not uncommonly can be SNs, especially on the trunk. Lymphatic
      drainage may involve SNs in multiple nodal fields, and drainage across the
      midline of the body is quite common. Because micrometastatic disease can be
      present in any SN regardless of its location, all true SNs must be biopsied. LS
      is an important first step to ensure this goal is achieved.

PMID- 15023749
TI  - The staging of malignant melanoma and the Florida Melanoma Trial.
AB  - Lymphatic mapping and sentinel lymph node (SLN) biopsy have changed the standard
      of care for patients with malignant melanoma, by providing a less morbid
      procedure to obtain the nodal staging information that is critical for
      therapeutic decisions. Detailed examination of the SLN identifies patients who
      have an increased risk for recurrence and death. Patients whose melanoma is
      upstaged with very sensitive assays based on reverse transcriptase polymerase
      chain reaction technology are better targeted for clinical trials or surgical or
      adjuvant therapies. In the future, melanoma may be "ultrastaged" by examining the
      SLNs, peripheral blood, and bone marrow. This may improve identification of
      patients who are surgically cured of their disease and therefore can be spared
      the side effects of more radical surgery or the toxicities of adjuvant therapy.
      The lymphatic mapping procedure is the most accurate way to determine the tumor
      status of the regional lymph nodes.

PMID- 15023750
TI  - Paradigm of metastasis for melanoma and breast cancer based on the sentinel lymph
      node experience.
AB  - Lymph node status is the most reliable prognostic indicator for patients with
      melanoma and breast cancer. Because it is the first node draining the primary
      cancer, the sentinel lymph node (SLN) is most likely to harbor metastatic cancer
      cells. The Breslow thickness of the primary melanoma and the size of primary
      breast cancer are highly correlated with SLN metastasis. If the SLN is negative,
      its negative predictive value for the remaining nodal basin exceeds 95%; thus,
      survival rates for melanoma and breast cancer increase when the SLN is negative.
      The rate of SLN identification is more than 95%, and the false-negative rate is
      about 5%. SLN data from melanoma and breast cancer are so convincing that they
      have been incorporated into the new American Joint Committee on Cancer
      classification of these cancers. The therapeutic value of additional lymph node
      dissection after a positive SLN for melanoma or breast cancer is still
      controversial. In melanoma, a 3-year follow-up may confirm better survival when
      the SLN is negative. However, about 25% of histologically negative SLNs may be
      upstaged by molecular techniques, and patients whose SLNs are positive by
      polymerase chain reaction (PCR) assay may develop recurrence. In most cases,
      melanoma and breast cancer follow an orderly progression of metastasis to the
      SLN; however, a small subgroup may develop systemic dissemination without SLN
      involvement. Current SLN experience has confirmed that the earlier the cancer,
      the less its potential for metastasis. Since treatments for metastatic cancer are
      still limited, early detection and resection are imperative. Better understanding
      of the molecular and genetic mechanisms of metastasis will be critical to select
      high-risk patients for adjuvant therapy.

PMID- 15023751
TI  - Sentinel lymph node biopsy does not change melanoma-specific survival among
      patients with Breslow thickness greater than four millimeters.
AB  - Management of patients with cutaneous melanoma in the absence of lymph node
      metastases is still controversial. The experience at the National Cancer
      Institute in Naples was analyzed to evaluate 3-year disease-free survival and
      overall survival for all patients who underwent sentinel lymph node biopsy (SLB)
      with Breslow thickness greater than 4 mm. Data from 359 sentinel biopsies
      performed in the past 5 years were reviewed to determine the effect of the
      treatment on disease-free survival and overall survival after stratifying
      patients for node status, tumor ulceration, and Breslow thickness. Statistical
      analysis showed a better 3-year survival for sentinel node-negative patients than
      for sentinel node-positive cases (88.4% and 72.9%, respectively; P <.05). Tumor
      ulceration retained its prognostic significance despite lymph node status,
      indicating a higher risk for development of distant metastases. Survival curves
      associated with thicker melanomas did not show significant differences between
      negative- and positive-SLB patients. SLB provides accurate staging of nodal
      status in melanoma patients who have no clinical evidence of metastases. Longer
      follow-up and final results from ongoing trials are necessary to definitively
      clarify the role of this procedure.

PMID- 15023752
TI  - Sentinel lymph node dissection and lymphatic mapping for local subcutaneous
      recurrence in melanoma treatment: longer-term follow-up results.
AB  - Lymphatic mapping and sentinel lymph node dissection (LM/SLND) for surgical
      staging of cutaneous primary melanoma is currently being evaluated, but the role
      of these techniques in recurrent (secondary) melanoma is largely unexplored. Our
      experience with 12 patients indicates the potential usefulness of LM/SLND in the
      management of locally recurrent melanoma at subcutaneous sites. We have even used
      mapping to localize the sentinel node draining a subcutaneous local recurrence
      after previous LM/SLND for primary melanoma. The application of LM/SLND may
      therefore be extended beyond primary melanoma management as we understand more
      about the technical issues and appropriate selection of patients.

PMID- 15023753
TI  - NSABP-32: Phase III, randomized trial comparing axillary resection with sentinal
      lymph node dissection: a description of the trial.
AB  - The NSABP-32 trial is a randomized, phase III clinical trial to compare sentinel
      node (SN) resection to conventional axillary dissection in clinically node
      negative breast cancer patients. The primary aims of the trial are to determine
      if removal of only SNs provides survival and regional control equivalent to those
      of axillary dissection, while diminishing the magnitude of surgically related
      side effects. In order to ensure consistency of the outcomes for this trial, a
      standardized method of SN surgery has been utilized for all cases. A secondary
      aim of the B32 trial is to evaluate whether patients with "occult" metastases in
      the SNs have worse survival. Accrual is taking place at 73 institutions in North
      America, and 217 surgeons are enrolling patients.

PMID- 15023754
TI  - The learning curve in sentinel node biopsy: the ALMANAC experience.
AB  - Sentinel node biopsy (SNB) is a minimally invasive procedure to stage the axilla
      in patients with breast cancer. Like any new surgical procedure, it is associated
      with a learning curve. This article describes the learning curve as part of the
      ALMANAC trial. The first phase of this trial is a validation phase in which
      surgeons perform SNB followed by an immediate axillary dissection in a
      consecutive series of 40 patients with invasive breast cancer. Each surgeon
      completes a mandatory program of proctored training during this phase. Surgeons
      who achieve a localization rate of 90% or more and a false-negative rate of 5% or
      less are eligible to proceed to the randomized phase. All 13 surgeons who
      completed 40 procedures as part of the validation phase of the ALMANAC trial
      achieved the set target. This study shows that a standardized training program
      allows surgeons to achieve a satisfactory localization rate and an acceptable
      false-negative rate after 40 SNBs.

PMID- 15023755
TI  - Sentinel lymph node biopsy versus axillary clearance in operable breast cancer:
      The RACS SNAC trial, a multicenter randomized trial of the Royal Australian
      College of Surgeons (RACS) Section of Breast Surgery, in collaboration with the
      National Health and Medical Research Council Clinical Trials Center.
AB  - The aim of the SNAC trial is to determine if sentinel node biopsy (SNB) produces
      less morbidity and equivalent cancer-related outcomes in comparison with
      immediate axillary clearance (AC) in women with early breast cancer. The
      intervention is SNB followed by immediate AC, or SNB followed by AC only if the
      SNB specimen is positive. This is a multicenter, centrally randomized phase III
      trial of 1000 women stratified according to age, tumor palpability, lymphatic
      mapping technique, and center. Accrual rate is 26 women per month; 789 women have
      been randomized to date. Analysis of the first 150 women indicates good
      compliance with study treatment and acceptable surgical technique.

PMID- 15023757
TI  - Redefining prognosis in node-negative breast cancer: can sentinel lymph node
      biopsy raise the threshold for systemic adjuvant therapy?
AB  - Sentinel lymph node (SLN) biopsy is a new standard of care for axillary node
      staging in breast cancer, which for the first time allows enhanced pathologic
      analysis on a routine basis. Although a number of retrospective studies,
      including our own series with 20-year follow-up, suggest that axillary nodal
      micrometastases found in this manner are prognostically significant, prospective
      trials now under way promise a definitive answer to this controversial subject.
      Enhanced pathology using serial sections and immunohistochemical staining
      identifies a high-risk minority of conventionally node-negative patients who are
      converted to node-positive and thereby become candidates for systemic adjuvant
      chemotherapy. The developmental phase of SLN biopsy, now drawing to a close, has
      focused on the identification of this node-positive group. Enhanced pathology
      also identifies a majority of patients who are truly node-negative and whose
      expectation of long-term survival exceeds that of historic norms for node
      negative breast cancer. The next era of SLN biopsy should focus on the
      characterization of this group. SLN biopsy in breast cancer has already extended
      the historic trend toward surgical conservatism. By defining more precisely a low
      risk cohort of patients, SLN biopsy has the potential to initiate a trend toward
      medical conservatism as well.

PMID- 15023756
TI  - Novel techniques in sentinel lymph node mapping and localization of nonpalpable
      breast lesions: the Moffitt experience.
AB  - The concept of lymphatic mapping has helped to redefine the clinical significance
      of lymph nodes with respect to breast cancer. The combination technique using
      both blue dye and radiocolloid is the most effective method of lymphatic mapping.
      The data in the literature support the concept that all patients undergoing
      lumpectomy or especially mastectomy should undergo lymphatic mapping if a
      diagnosis of invasive cancer is remotely possible. The low morbidity, high
      sensitivity, and specificity of mapping indicate its use for increasing numbers
      of patients thought initially not to be candidates for the procedure.

PMID- 15023758
TI  - Sentinel node biopsy in breast cancer patients: triple technique as a routine
      procedure.
AB  - Since its introduction in the early 1990s, the sentinel node (SN) concept in
      breast cancer has been validated by many studies. Because SN biopsy in breast
      cancer enables the identification of node-negative axillae, the potential
      morbidity of an axillary lymph node dissection (ALND) can be avoided. The SN
      procedure is still surrounded by many variables and uncertainties, such as the
      clinical relevance of micrometastases. However, the main goal is to avoid
      unnecessary ALND in node-negative breast cancer patients. Sufficient clinical
      data are available to achieve this goal by incorporating the SN procedure into
      routine clinical practice. The ultimate safety of the applied technique will be
      determined by the number of axillary recurrences during long-term follow-up.
      Preoperative lymphoscintigraphy and intraoperative use of both blue dye and a
      hand-held gamma probe-the triple technique-has been applied at our institute
      since early 1994.

PMID- 15023759
TI  - Minimal residual disease assessment in sentinel nodes of breast and
      gastrointestinal cancer: a plea for standardization.
AB  - Lymph node dissection plays an important role in staging and treatment of solid
      cancers. Sentinel node biopsy (SNB) has been introduced to minimize the extent of
      surgery and to enable assessment of minimal residual disease (MRD) without
      compromising accurate staging or survival. This review addresses the variation in
      technical aspects and outcome of SNB and MRD assessment in patients with breast
      and gastrointestinal cancer. Quality control leading to standardization of SNB
      and pathological examination will enable reliable comparison of studies, which is
      necessary for consensus of diagnostic and therapeutic strategies.

PMID- 15023760
TI  - Current status and future prospects of sentinel node navigational surgery for
      gastrointestinal cancers.
AB  - Until the late 1990s, the application of the sentinel node (SN) concept to
      gastrointestinal (GI) malignancies was not recognized because of the
      multidirectional and complicated lymphatic flow from the GI tract. However,
      several studies supporting the validity of the SN concept for GI cancers have
      been reported in the past 5 years. Because of its anatomical location, gastric
      cancer is one of the most suitable targets for minimally invasive surgery based
      on SN status. Laparoscopic local resection is theoretically feasible for curative
      treatment of SN-negative early gastric cancer. Although SNs in esophageal cancer
      are multiple and are distributed widely from the cervical to the abdominal area,
      selective and modified lymphadenectomy for clinically N0-stage esophageal cancer
      is likely to become feasible and clinically viable. Total mesorectal excision
      (TME) is accepted as a standard surgical procedure for rectal cancer. However,
      there is a risk of aberrant distribution of SNs beyond the extent of TME; for
      example, SNs may be lateral to the lower rectum. SN mapping with scintigraphy is
      useful for effective sampling of SNs in unexpected areas and accurate staging
      without extensive lymph node dissection. There are several practical issues to be
      overcome. The techniques and feasibility of laparoscopic SN sampling are still
      under investigation. Large-scale multicenter prospective validation studies for
      SN mapping in GI cancer are essential. If these remaining issues can be solved,
      SN mapping for GI cancer will have great clinical impact.

PMID- 15023761
TI  - Historical review of lymphatic mapping in gastrointestinal malignancies.
AB  - The advent of sentinel lymph node mapping (SLNM) has had a profound impact on the
      surgical management of breast cancer and melanoma over the past decade. However,
      SLNM in gastrointestinal malignancies is still in its infancy. The role of SLNM
      in gastrointestinal malignancies is to increase staging accuracy and to reduce
      the understaging associated with standard surgical and pathological techniques.
      Numerous authors have described the successful use of SLNM in colon, rectal,
      gastric, esophageal, and anal canal malignancies, with a high degree of accuracy
      and upstaging by detailed pathological analysis of the sentinel nodes. Over the
      past 2 years, research and publications related to gastrointestinal lymphatic
      mapping have dramatically increased worldwide.

PMID- 15023762
TI  - Significance of metastasis detected by molecular techniques in sentinel nodes of
      patients with gastrointestinal cancer.
AB  - The clinical significance of micrometastasis in sentinel nodes (SNs) may differ
      in various organs. In particular, the prognostic value of SN micrometastases
      detected by reverse transcriptase-polymerase chain reaction (RT-PCR) is still
      controversial. We investigated the diagnostic and therapeutic significance of
      nodal molecular metastasis detected by nested RT-PCR for cytokeratin (CK) 19 mRNA
      in gastrointestinal cancer. In 51 cases with GI tract cancer treated by standard
      curative resection, SNs were identified by a radio-guided method. In 10 of 51
      patients, 25 SNs and 3 non-SNs were histologically negative and RT-PCR positive.
      Three non-SNs with positive CK19 mRNA were randomly sampled from the same basin
      where histologically positive SNs were identified. Immunohistochemical analysis
      of six additional step sections obtained at 30- micro m intervals with use of an
      anticytokeratin antibody showed clearly recognizable histological metastases in 4
      of 25 histologically negative/RT-PCR-positive SNs (16%). In one case of
      esophageal squamous cell carcinoma with nodal micrometastasis identified by CK19
      RT-PCR, extranodal local recurrence in the SN basin (left supraclavicular basin)
      was observed 6 months postoperatively. These findings suggest that nodal
      micrometastasis detected by nested RT-PCR has some clinical significance in GI
      cancer. Molecular assessment of the SN may be a valuable tool to complement
      routine histological examination for GI cancers.

PMID- 15023763
TI  - Sentinel node detection in Barrett's and cardia cancer.
AB  - Because of surveillance strategies in patients with known Barrett's esophagus,
      more patients with high-grade dysplasia or early cancer in the distal esophagus
      and at the esophagogastric junction are identified. The need for and extent of
      lymphadenectomy in such patients are controversial. The technique of sentinel
      lymph node dissection (SLND) to diagnose early lymphatic spread is applied
      increasingly in tumors of the gastrointestinal tract. The poorly defined
      lymphatic drainage of the esophagogastric junction has so far prevented many
      investigators from performing SLND in tumors of this anatomic region. We report
      the first results of SLND in Barrett's and cardia cancer. The preliminary
      experience indicates that the method is, even in this anatomical area, feasible
      and yields good results in early tumors. In advanced tumors, the method lacks
      sensitivity. Mapping should be done with blue dye and a radiocolloid. The concept
      of sentinel lymph node mapping and detection thus may open the door to
      individualized therapy for patients with high-grade dysplasia in a Barrett's
      esophagus or with early Barrett's and cardia cancer.

PMID- 15023764
TI  - Refined staging by sentinel lymph node biopsy to individualize therapy in anal
      cancer.
AB  - We evaluated the feasibility of the sentinel lymph node technique to refine
      staging and potentially individualize therapy for anal cancer. Seventeen patients
      with cancer of the anal canal underwent peritumoral injection of 99mTc-colloid,
      followed 17 hours later by lymphoscintigraphy. A selective lymph node biopsy
      (SLNB) was attempted in 12 of 13 cases with scintigraphically detected SLNs.
      Lymph node metastases were present in 5 of 12 cases (42%); in 2 of these 5 cases,
      micrometastases were detected only by immunohistochemical staining. Hence, SLNB
      refines the diagnostic workup for anal cancer and provides an accurate basis for
      individualized therapy.

PMID- 15023765
TI  - Therapeutic implications of sentinel lymph node biopsy in the staging of oral
      cancer.
AB  - The most powerful prognostic factor in patients with oral cancer is the presence
      of lymph node metastases. The management of the neck at diagnosis in the absence
      of adenopathy is still controversial, but sentinel lymph node biopsy (SLB) may
      help resolve this issue. At the National Cancer Institute in Naples, we performed
      SLB in 41 patients with T1 to T2 oral cancer. All patients underwent
      lymphoscintigraphy. Intraoperative blue dye and gamma probe examination
      identified a sentinel node (SN) in 39 patients. Four patients (10%) had double
      drainage, and 7 (18%) had drainage beyond the expected anatomical site. Complete
      concordance between the pathology of the SN and nodes obtained from radical
      dissection confirmed SLB as a reliable staging procedure. Since January 2001,
      seven patients with T1 to T2 oral cancers have been staged with SLB only;
      modified radical neck dissection was carried out only in cases with a positive
      SN. The rate of SN identification was 100%, and all five cases with negative SNs
      were free of disease after a median follow-up of 10 months. Lymphoscintigraphy
      plus SLB seems to be a good staging system for guiding neck management in
      patients with oral cancer. A larger number of patients and a longer follow-up in
      a randomized trial will confirm the potential staging value of this procedure and
      determine which patients might benefit from a conservative approach that avoids
      radical neck dissection.

PMID- 15023766
TI  - Value of sentinel lymphadenectomy in head and neck cancer.
AB  - The increasing interest in the so-called sentinel node concept, which has
      recently been adapted to squamous cell carcinomas of the upper aerodigestive
      tract, can be explained by encouraging results in other tumor entities. Although
      the publications on this topic do not yet allow a final judgment on the
      significance of sentinel lymphadenectomy in head and neck squamous cell
      carcinoma, early results emphasize the importance of this new diagnostic and
      therapeutic concept. The basic prerequisite is a detailed knowledge of the
      existing method-specific limitations in this anatomic region. Critical and
      careful evaluation of the sentinel node concept is mandatory prior to its
      application to other tumor entities. Sentinel lymphadenectomy for head and neck
      cancer may prove helpful if the indications for its use are clearly defined.

PMID- 15023767
TI  - Sentinel node mapping in lung cancer.
AB  - Lymph node metastases are the most significant prognostic factor in localized non
      small-cell lung cancer (NSCLC). Nodal micrometastases may not be detected with
      current standard histologic methods. We review our experience with intraoperative
      injection of radioisotope, the current state of the technique, and the experience
      of other groups with alternate methods and tracers.

PMID- 15023768
TI  - Lymphodynamic properties governing sentinel lymph nodes.
AB  - Biological properties of lymph microvessels include characteristics of
      spontaneous contractions of lymph vessels, nitric oxide (NO)-mediated modulation
      of active lymph pump activity, flow-induced production and release of NO from
      lymphatic endothelial cells, and localization of NO synthase in cultured
      lymphatic endothelial cells. B16-BL6 melanoma cells release factors that inhibit
      active pump activity in isolated lymph microvessels. We have found that basic
      fibroblast growth factor (bFGF) induces significant proliferation and migration
      of canine cultured lymphatic endothelial cells. This growth factor facilitates
      the formation of capillary-like tubes by the cultured endothelial cells.

PMID- 15023769
TI  - Histologic heterogeneity and intranodal shunt flow in lymph nodes from elderly
      subjects: a cadaveric study.
AB  - Gaps of the superficial cortex of the lymph node provide intranodal shunts that
      are more often the cause of skip metastasis than are collateral vessels.
      Examination of lymph nodes from cadavers of elderly subjects often revealed
      cortical gaps, especially in specific three-dimensional assembled cords; these
      cortical gaps were readily seen in para-aortic and pelvic nodes. This
      architecture seemed to be more appropriate for a systemic immune response than a
      local defense. Evidence of poorly developed cortices, anthracosis, and
      hyalinization also suggested impaired nodal function. We suspect that this
      histologic heterogeneity, perhaps a result of aging, affects the nodal trapping
      of colorimetric/isotopic tracers and metastatic cancer cells. This may have
      implications for lymphatic mapping of the sentinel lymph node in elderly patients
      with early-stage cancer.

PMID- 15023771
TI  - Teaching psychocutaneous medicine: time for a reappraisal.

PMID- 15023770
TI  - Thalidomide as a potential treatment for scleromyxedema.

PMID- 15023772
TI  - An optimal method for experimental provocation of polymorphic light eruption.
AB  - BACKGROUND: There is controversy about the best method to induce polymorphic
      light eruption (PLE) experimentally. Objectives To review articles on PLE
      induction and design a UV radiation protocol that improves success rates with
      clinically relevant doses of environmentally relevant solar-simulated radiation
      (SSR). DESIGN AND SETTING: All articles on the experimental provocation of PLE
      published since 1980 were reviewed. Photoprovocation of lesions was studied in 25
      PLE patients. The 24-hour minimal erythemal dose (MED) of SSR was determined.
      Thereafter, six 4 x 4-cm adjacent sites on previously affected and previously
      unaffected skin were exposed to 0.25, 0.5, 0.75, 1.0, 1.25, 1.5 MED of SSR for 3
      to 4 consecutive days. The study periodwas autumn to spring in London, England
      (51 degrees north latitude). MAIN OUTCOME MEASURES: Relationship between PLE
      induction and biological and physical exposure parameters. CONCLUSIONS: The
      review shows that fractionated erythemally effective UV-A exposures were more
      successful than single-sunburning UV-B doses. Photoprovocation of PLE was
      successful in 68% of patients after 2 to 3 SSR exposures that were not
      necessarily erythemal. There was no difference in success rate between previously
      affected and previously unaffected skin. Our data indicate that PLE is more
      likely to be induced when the natural causes of the disease are simulated.

PMID- 15023773
TI  - Differential expression of cytokines in UV-B-exposed skin of patients with
      polymorphous light eruption: correlation with Langerhans cell migration and
      immunosuppression.
AB  - BACKGROUND: Disturbances in UV-induced Langerhans cell migration and T helper
      (T(H)) 2 cell responses could be early steps in the pathogenesis of PLE.
      OBJECTIVE: To establish whether UV-B exposure induces aberrant cytokine
      expression in the uninvolved skin of patients with polymorphous light eruption
      (PLE). DESIGN: Immunohistochemical staining and comparison of microscopic
      sections of skin irradiated with 6 times the minimal dose of UV-B causing
      erythema and the unirradiated skin of patients with PLE and of healthy
      individuals. SETTING: University Medical Center (Dutch National Center for
      Photodermatoses). Patients Patients with PLE (n = 6) with clinically proven
      pathological responses to UV-B exposure and normal erythemal sensitivity. Healthy
      volunteers (n = 5) were recruited among students and hospital staff. MAIN OUTCOME
      MEASURES: Expression of cytokines related to Langerhans cell migration
      (interleukin [IL] 1, IL-18,and tumor necrosis factor [TNF] alpha); T(H)2
      responses (IL-4 and IL-10); and T(H)1 responses (IL-6, IL-12, and interferon
      gamma). Double staining was performed for elastase (neutrophils), tryptase (mast
      cells), and CD36 (macrophages). RESULTS: The number of cells expressing IL-1beta
      and TNF-alpha was reduced in the UV-B-exposed skin of patients with PLE compared
      with the skin of healthy individuals (P<.05 for TNF-alpha). No differences were
      observed in the expression of T(H)1-related cytokines but fewer cells expressing
      IL-4 infiltrated the epidermis of patients with PLE 24 hours after irradiation (P
      =.03). After UV exposure TNF-alpha, IL-4, and, to a lesser extent, IL-10 were
      predominantly expressed by neutrophils. CONCLUSIONS: The reduced expression of
      TNF-alpha, IL-4, and IL-10 in the UV-B-irradiated skin of patients with PLE
      appears largely attributable to a lack of neutrophils, and is indicative of
      reduced Langerhans cell migration and reduced T(H)2 skewing. An impairment of
      these mechanisms underlying UV-B-induced immunosuppression may be important in
      the pathogenesis of PLE.

PMID- 15023774
TI  - Lymphomatoid papulosis in children: a retrospective cohort study of 35 cases.
AB  - BACKGROUND: Lymphomatoid papulosis (LyP) is a rare entity, considered to be part
      of the spectrum of the CD30(+) cutaneous lymphoproliferative disorders. About 10%
      to 20% of the adult LyP patients will develop an associated lymphoid malignancy.
      Only a few cases of LyP have been described in children, and the risk of
      associated lymphoid malignancies in these patients is not known. OBJECTIVES: To
      study the association between childhood onset of LyP and other malignancies and
      to determine the clinical characteristics in this subgroup of patients. DESIGN:
      Retrospective cohort study. SETTING: Referral center at a university hospital.
      Retrospective registry for patients with LyP of childhood onset (< or =18 years).
      Patients Thirty-five patients with childhood-onset LyP (19 boys and 16 girls)
      were interviewed by telephone using a standardized questionnaire. The median
      duration of follow-up was 9.0 years. All included patients were confirmed by
      histologic examination. RESULTS: The age distribution was significantly
      different, with boys having an earlier onset of LyP (P =.03). Of the 35 LyP
      patients, 3 (9%) developed a malignant lymphoma; all were diagnosed as having non
      Hodgkin lymphoma. Compared with the general population, patients with childhood
      onset LyP have a significantly increased risk of developing non-Hodgkin lymphoma
      (relative risk, 226.2; 95% confidence interval, 73.4-697.0). More than two thirds
      of the patients reported being atopic, which is significantly more than the
      expected prevalence of atopy (relative risk, 3.1; 95% confidence interval, 2.2
      4.3). CONCLUSIONS: Lymphomatoid papulosis presents similarly in children and
      adults, including the risk of lymphoid malignancies. Therefore, all LyP patients
      should be closely monitored throughout their lives.

PMID- 15023775
TI  - Increased prevalence of human papillomavirus in hairs plucked from patients with
      psoriasis treated with psoralen-UV-A.
AB  - BACKGROUND: Patients with psoriasis treated with psoralen-UV-A (PUVA) are at
      increased risk of skin cancer; however, the exact causes of this increased
      incidence are not well understood. It has been suggested that PUVA may increase
      expression of the tumorigenic agent human papillomavirus (HPV) in skin by
      directly stimulating virus replication, immune suppression, or both, thereby
      leading to skin cancer formation. OBJECTIVE: To determine whether HPV DNA
      prevalence in the skin is increased after long-term PUVA treatment. DESIGN:
      Screening for the presence of HPV sequences in DNA isolated from plucked body
      hairs of patients with psoriasis with a history of PUVA exposure and a history of
      skin cancer (group A), PUVA exposure and no history of skin cancer (group B), and
      no PUVA exposure and no history of skin cancer (group C). SETTING: University
      hospital. PATIENTS AND METHODS: Hair samples were obtained from 81 patients with
      psoriasis (56 men and 25 women; mean age, 52 years), including 16 in group A
      (mean number of PUVA exposures, 702), 35 in group B (mean number of PUVA
      exposures, 282), and 30 in group C. DNA was isolated from the hair samples and
      analyzed by polymerase chain reaction with the use of 2 nested primer systems
      specific for epidermodysplasia verruciformis-associated or related and genital or
      mucosal virus types, respectively. RESULTS: The rate of HPV DNA positivity was
      significantly higher in groups A (73% [11/15]) and B (69% [24/35]) than in group
      C (36% [10/28]) (A + B vs C, P =.009; chi(2) test; age adjusted). Conclusion The
      prevalence of HPV in the skin (hair follicles) is increased in patients with
      psoriasis who have a history of PUVA exposure.

PMID- 15023776
TI  - Pemphigus vulgaris acantholysis ameliorated by cholinergic agonists.
AB  - BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune, IgG autoantibody-mediated
      disease of skin and mucosa leading to progressive blistering and nonhealing
      erosions. Patients develop autoantibodies to adhesion molecules mediating
      intercellular adhesion and to keratinocyte cholinergic receptors regulating cell
      adhesion. OBSERVATIONS: To determine whether a cholinergic agonist can abolish PV
      IgG-induced acantholysis, litter mates of neonatal athymic nude mice were
      injected with PV IgG together with carbachol (0.04 micro g/g body weight). None
      of these mice developed skin lesions. Through in vitro experiments, we measured
      the expression of adhesion molecules in monolayers of normal human keratinocytes
      incubated overnight in the presence of 0.25mM carbachol using semiquantitative
      Western blot and immunofluorescence. Carbachol caused an elevation of the
      relative amount of E-cadherin in keratinocytes (P<.05) without changing that of
      plakoglobin (P>.05). The phosphorylation level of E-cadherin and plakoglobin was
      increased by PV IgG, whereas this effect of PV IgG was attenuated in the presence
      of 0.5mM carbachol. Pyridostigmine bromide, an acetylcholinesterase inhibitor,
      produced effects similar to those of carbachol, which helps explain its clinical
      efficacy in a patient with active PV that was resistant to treatment with
      systemic glucocorticosteroids. Treatment with pyridostigmine bromide (360 mg/d)
      in a patient with PV allowed to keep his disease under control at a lower dose of
      prednisone than that used before starting pyridostigmine bromide treatment.
      Conclusion Elucidation of the cholinergic control of keratinocyte adhesion merits
      further consideration because of a potential for the development of novel
      antiacantholytic therapies using cholinergic drugs.

PMID- 15023777
TI  - The course of chronic plaque-type psoriasis in placebo groups of randomized
      controlled studies.
AB  - OBJECTIVE: To determine the outcome in placebo-treated patients with plaque-type
      psoriasis. DATA SOURCES: Online search of MEDLINE and EMBASE until January 2001
      and the Cochrane Library (2001, issue 1), supplemented by references, reviews,
      guidelines, and textbooks. STUDY SELECTION: Randomized controlled induction of
      remission trials of patients with chronic plaque-type psoriasis with systemic
      treatments with a placebo group not treated with antipsoriatic medication.
      Identified studies were examined by 2 independent reviewers. Through MEDLINE, 290
      studies could be identified. Twenty-seven placebo-controlled studies were
      included (488 patients). DATA EXTRACTION: Two independent reviewers extracted
      data on first author, year of publication, design, comparison, placebo treatment,
      number of patients, treatment duration, type of psoriasis and baseline severity
      in the placebo group, mean relative change in outcome measures, and/or percentage
      of patients with worsening of psoriasis; no change; minimal, moderate, or good
      improvement; or complete clearance. DATA SYNTHESIS: Owing to substantial
      heterogeneity and differences in the way outcomes were reported, no summary
      estimates could be obtained. The outcome of placebo treatment was poor in most
      studies. Some reported a mean relative change of 11% to 47%. The highest
      percentages of patients ended up in the worsening, no change, or minimal
      improvement categories. Also, complete clearance was possible. No explanation for
      the differences in outcome between placebo groups could be found. Description of
      placebo groups was often insufficient. CONCLUSIONS: The effect of treatment in
      placebo groups varied across studies in an unpredictable way. To evaluate the
      variability, improvement of the standardization of study designs, entry criteria,
      and outcome measures is necessary in psoriasis trials.

PMID- 15023779
TI  - Polymorphic light eruption reassessed.

PMID- 15023778
TI  - A randomized controlled trial of methotrexate and cyclosporine in the treatment
      of psoriasis.

PMID- 15023780
TI  - Localized facial macules and vesicles.

PMID- 15023781
TI  - Erythematous plaques on the trunk of a man.

PMID- 15023782
TI  - Multiple asymptomatic nodules in an African American boy.

PMID- 15023783
TI  - Diffuse verrucous, vascular nodules on the extremities and trunk.

PMID- 15023784
TI  - Skin color is not the same thing as race.

PMID- 15023786
TI  - Smoking overlooked as an important risk factor for squamous cell carcinoma.

PMID- 15023787
TI  - A note on meta-analysis of diagnostic test studies.

PMID- 15023785
TI  - Visual inspection of age-specific incidence rates: don't forget the scaling!

PMID- 15023788
TI  - Calcinosis cutis complicating adult-onset dermatomyositis.

PMID- 15023789
TI  - Successful treatment of psoriasis and psoriatic arthritis with etanercept and
      methotrexate in a patient newly unresponsive to infliximab.

PMID- 15023792
TI  - Dermoscopy of keratinocytic neoplasms: subpatterns of seborrheic keratoses.

PMID- 15023790
TI  - Inflammation of actinic keratoses during capecitabine therapy.

PMID- 15023793
TI  - The average African American male face: an anthropometric analysis.
AB  - OBJECTIVES: To determine the average facial proportions of the African American
      man and compare results with the neoclassical canons of facial proportions and
      the standard for the North American white man. DESIGN: Cross-sectional survey.
      METHODS: Photographs and anthropometric measurements of the face were taken of
      109 men of African American descent aged between 18 and 30 years, and results
      were compared with the neoclassical canons of the facial proportion and the
      averages of the anthropometric measurements for the North American white man.
      Proportional relationships were calculated based on the averages. Statistical
      analysis was performed. RESULTS: The neoclassical canons of facial proportion
      were not found to be applicable to most of the African American men who
      participated in the study. Of the 24 anthropometric measurements obtained, 21
      were significantly different from the measurements of the North American white
      man (P<.05). We present proportional relationships in our subjects. CONCLUSIONS:
      The face of the average African American man differs from the neoclassical canons
      of facial proportion and the averages of anthropometric measurements for the
      North American white man. The proportional relationships found in our subjects
      might serve as a template for facial analysis in this patient population.

PMID- 15023794
TI  - Facial nerve recovery in bcl2 overexpression mice after crush injury.
AB  - OBJECTIVES: To develop a mouse model for measuring facial nerve injury and
      recovery and to test the hypothesis that overexpression of the antiapoptotic
      gene, bcl2, enhances recovery of facial nerve function after peripheral crush
      injury. DESIGN: Prospective analysis of recovery of function after facial nerve
      crush injury in mice at juvenile (postnatal day 7) and adult (postnatal day 30)
      ages with blind comparison of wild-type and transgenic bcl2 overexpression
      littermates at both ages and immunohistologic confirmation of overexpression of
      bcl2 in facial motoneurons in transgenic animals. RESULTS: Adult wild-type mice
      demonstrated full recovery of facial nerve function (measured as eye blink and
      whisker movement) within 3 weeks of injury. Juvenile wild-type mice demonstrated
      diminished recovery of function. Juvenile transgenic bcl2 overexpression mice
      demonstrated more rapid and complete recovery of eye blink but not whisker
      movement in comparison with wild-type littermates. CONCLUSIONS: Measurement of
      facial nerve function in mice after injury is feasible. Enhanced recovery of
      facial nerve function in adult mice and mice overexpressing bcl2 indicates that
      preservation of central motoneurons after injury may improve function after
      peripheral nerve injury.

PMID- 15023795
TI  - The effect of silicone gel on basic fibroblast growth factor levels in fibroblast
      cell culture.
AB  - BACKGROUND: Topical silicone gel has shown promise in the treatment of
      hypertrophic and keloid scars. However, its mechanism of action remains
      undetermined. OBJECTIVE: To investigate whether the presence of silicone alters
      the secretion of basic fibroblast growth factor (bFGF), a key cytokine involved
      in the scar formation process. DESIGN: Serum-free fibroblast cell cultures were
      established from normal, keloid, and fetal skin, which heals without scarring,
      and exposed to silicone gel. Serial cell counts were performed, and supernatants
      were collected for bFGF quantification by enzyme-linked immunosorbent assay at 4,
      24, 72, and 120 hours. RESULTS: Growth curves were similar and no statistically
      significant differences in population doubling times were observed between
      treated and untreated specimens. Statistically significant differences in bFGF
      levels between treated and untreated normal fibroblasts were observed at 24, 72,
      and 120 hours after cell culture initiation. Differences in bFGF levels between
      treated and untreated fetal fibroblasts that approached statistical significance
      were observed at 72 and 120 hours. CONCLUSIONS: These results suggest that
      silicone gel is responsible for increased bFGF levels in normal and fetal dermal
      fibroblasts. We postulate that silicone gel treats and prevents hypertrophic scar
      tissue, which contains histologically normal fibroblasts, by modulating
      expression of growth factors such as bFGF. Our data support the hypothesis that
      substances that favorably influence wound healing do so by correcting a
      deficiency or overabundance of the growth factors that orchestrate the tissue
      repair process.

PMID- 15023796
TI  - Autologous cartilage grafts enhanced by a novel transplant medium using fibrin
      sealant and fibroblast growth factor.
AB  - OBJECTIVE: To introduce and assess a system for the delivery of fibroblast growth
      factor to autologous cartilage grafts using fibrin sealant and analyze whether
      this "enhancement" results in reduced rates of cartilage resorption and greater
      preservation of normal architectural features compared with "unenhanced"
      cartilage grafts. METHODS: Auricular cartilage segments measuring 1 cm(2) were
      harvested from 12 New Zealand white rabbits, morselized, and implanted into the
      subcutaneous dorsum of the upper back for 3 months. The conditions included (1)
      cartilage alone; (2) cartilage + fibrin sealant; (3/4) cartilage + acidic or
      basic fibroblast growth factor (aFGF or bFGF); and (5/6) cartilage + fibrin
      sealant + aFGF or bFGF. Subsequent to graft harvest, gross and microscopic
      assessments were performed to assess size, structural integrity, and
      architectural features, with comparisons performed between each of the
      conditions. RESULTS: The mean areas of the harvested cartilage grafts treated
      with fibrin sealant + aFGF or bFGF were 1.23 cm(2) and 1.19 cm(2), respectively,
      while the corresponding value for the untreated (ie, cartilage alone) specimens
      was 1.03 cm(2). The percentage of decrease in size was 45% for the untreated
      specimens and 0% for the specimens treated with fibrin sealant + aFGF or fibrin
      sealant + bFGF. Cartilage treated with fibrin sealant + bFGF had the greatest
      quantity of elastin fibers of the 6 conditions. Cartilage grafts treated with
      fibrin sealant alone demonstrated the most intense ground substance staining on a
      computerized measure of pixel intensity. CONCLUSIONS: Our findings demonstrated
      significant improvements in graft quality using fibroblast growth factor and
      fibrin sealant or even fibrin sealant alone. These findings may justify changes
      in how cartilage grafts are prepared and delivered for facial augmentation
      procedures to reduce graft resorption and maintain the structural integrity of
      the cartilage. Further trials will be performed to elucidate the optimal growth
      factor concentrations for maximum structural and architectural benefits.

PMID- 15023797
TI  - Safety of blepharoplasty in patients with preoperative dry eyes.
AB  - OBJECTIVES: To assess the safety of blepharoplasty in patients with preoperative
      dry eyes and to report our surgical technique. SETTING: Private practice with
      academic affiliation. DESIGN: Retrospective medical chart review of 67 patients
      with preoperative dry eyes who underwent blepharoplasty. The technique was
      modified by preserving the orbicularis oculi muscle and its innervation during
      upper blepharoplasty. MAIN OUTCOME MEASURES: The severity of preoperative and
      postoperative eye dryness by patient survey. RESULTS: Of the 67 patients, 5 had
      worsening, 5 had improvement, and 50 had no change in the severity of their dry
      eyes. Seven patients could not be located for the follow-up survey. Preserving
      the orbicularis did not affect the cosmetic results. CONCLUSIONS: By preserving
      the orbicularis muscle and its innervation, the dynamics of eyelid closure, tear
      pumping, and tear distribution are not affected. Blepharoplasty can be a safe
      operation in patients with dry eyes.

PMID- 15023798
TI  - Modification of the Skoog dorsal reduction for preservation of the middle nasal
      vault.
AB  - Preservation of the middle nasal vault has increasingly become a topic of
      interest and concern in rhinoplasty. Modification of the nasal dorsum with
      traditional techniques may create unfavorable cosmetic results and adverse
      functional sequelae due to collapse of the middle nasal vault. Nasal dorsal
      reduction invariably involves separating the upper lateral cartilage (ULC)
      attachments from the dorsal septum. A number of procedures are used to
      reestablish the width of the middle nasal vault and competence of the internal
      nasal valve. Spreader grafts are the most frequently used technique. Although
      these grafts reliably preserve the middle vault, dorsal irregularities may
      result. Alternative techniques, such as suture suspension of the ULCs to dorsal
      onlay grafts or direct suturing of the ULCs to the septum, may pose similar
      problems. We have found that a modification of the Skoog technique for dorsal
      hump reduction preserves both a favorable aesthetic contour of the middle nasal
      vault and proper function of the internal valve. This procedure involves removal
      of the osseocartilaginous dorsum en bloc. The nasal dorsum is further reduced;
      the removed portion of nasal dorsum is sculpted and then replaced anatomically.
      Once a favorable position is found for the native dorsal graft, the upper lateral
      cartilages are resuspended to the graft with suture fixation. The dorsal segment
      thus acts as a dorsal onlay spreader graft, reestablishing a natural dorsal
      contour and preserving the middle nasal vault. We can avoid osteotomies in
      patients with an appropriate preoperative width of their bony base while
      correcting the open roof with the replaced dorsal segment.

PMID- 15023799
TI  - Evaluation and treatment of vertical microgenia.
AB  - OBJECTIVE: To evaluate treatment of vertical microgenia in patients with chin
      deformities. METHODS: Twenty-one patients were included in this retrospective
      review. The 3 authors performed a lengthening genioplasty with or without
      interpositional grafting on each patient in either an academic or a private
      practice setting. RESULTS: Subjective analysis suggests a substantial improvement
      of lower face aesthetics in all patients. The degree of subjective change
      depended on the type of deformity, whether there was vertical microgenia alone or
      in combination with a sagittal (horizontal) deficiency, and the morphologic
      characteristics of the labiomental sulcus. There were no significant
      complications. CONCLUSION: Vertical lengthening of the chin should be considered
      in patients with the combination of a vertically short lower facial height,
      deepened labiomental fold, recessive chin, and recessive and/or procumbent lower
      lip.

PMID- 15023800
TI  - Combined silicone and cartilage implants: augmentation rhinoplasty in Asian
      patients.
AB  - Various alloplastic materials are used for nasal augmentation in Asian patients.
      Of these, silicone is the most prevalent because it is durable and facilitates
      sculpting. However, silicone grafts have been associated with complications,
      including tip extrusion, infection, and graft shifting. Often the nasal tip is
      involved, with skin discoloration and possible implant extrusion due to increased
      mechanical pressure. Autogenous material provides a safer alternative for nasal
      augmentation, but the supply of septal or auricular cartilage in Asian patients
      is limited. To augment optimally and reduce extrusion risk, we use auricular
      cartilage grafts at the nasal tip and silicone implants for the nasal dorsum in
      Asian patients. We report the results of this technique in 100 Asian patients
      with up to 5 years of follow-up. Patients were extremely satisfied, and no
      implant extrusions resulted. Other complications included further surgical
      revision due to misalignment of the silicone dorsal implant (5 patients), tip
      graft shifting (2 patients), and recurrent dorsal edema over the implant
      requiring removal (1 patient).

PMID- 15023801
TI  - Rhinoplasty and the nasal SMAS augmentation graft: advantages and indications.
AB  - We evaluated the nasal superficial musculoaponeurotic system (SMAS) as an
      autologous augmentation graft material in the thick-skinned patient undergoing
      cosmetic rhinoplasty using a retrospective review. Representative case reports
      demonstrated preliminary long-term results after augmentation with the nasal SMAS
      graft in an academic rhinoplasty practice. En bloc excision of the nasal SMAS in
      thick-skinned patients produced uniformly favorable improvements in nasal tip
      definition without adverse sequelae. Moreover, in 10 patients, the harvested
      material was also used for volume augmentation at various adjacent nasal sites,
      including the radix, nasal sidewall, and nasal dorsum. Long-term follow-up
      ranging from 1 to 3 years suggests stable volume augmentation in this initial
      patient series. No donor morbidity was observed in properly selected patients,
      and enhancements in nasal tip definition were uniformly favorable. Additional
      studies are needed to more accurately characterize long-term nasal SMAS graft
      survival in all patients.

PMID- 15023802
TI  - Midfacial degloving approach for repair of naso-orbital-ethmoid and midfacial
      fractures.
AB  - OBJECTIVE: To demonstrate that the midfacial degloving (MFD) approach can provide
      the proper exposure to successfully reduce naso-orbital-ethmoid (NOE) and
      midfacial fractures while eliminating the need for external skin incisions.
      DESIGN: A retrospective review of patients with NOE and concomitant midfacial
      fractures that were repaired via the MFD approach for exposure. SETTING: Tertiary
      care academic medical center. METHODS: The MFD approach was used to access NOE
      and concomitant midfacial fractures for repair in 9 patients with facial trauma.
      Physical examination and imaging studies were used for preoperative evaluation.
      Functional and cosmetic results were assessed during follow-up with serial
      physical examinations and postreduction films. RESULTS: No significant technical
      problems were encountered in the treatment of NOE and concomitant fractures,
      which included 5 Le Fort I, 1 Le Fort II, 1 Le Fort III, 6 orbital rim (1
      superior, 4 inferior, and 1 lateral), and 4 zygomatic complex fractures. Physical
      examination and imaging studies showed adequate reduction in all patients, and
      all patients were satisfied with their short- and long-term functional and
      cosmetic results. CONCLUSION: The MFD approach can provide the necessary exposure
      to properly reduce NOE and midfacial fractures without the need for external skin
      incisions.

PMID- 15023803
TI  - Craniofacial approaches to midfacial fractures.

PMID- 15023804
TI  - Julien Bourguet: father of cervical rhytidectomy.

PMID- 15023806
TI  - A frontotemporal family bridge.

PMID- 15023807
TI  - Paroxysmal autonomic instability with dystonia after brain injury.
AB  - A complication of severe brain injury is a syndrome of intermittent agitation,
      diaphoresis, hyperthermia, hypertension, tachycardia, tachypnea, and extensor
      posturing. To capture the main features of this syndrome, derived through
      literature review and our own case series, we propose the term paroxysmal
      autonomic instability with dystonia. We reviewed reports of autonomic
      dysregulation after brain injury and extracted essential features. From the
      clinical features, consistent themes emerge regarding signs and symptoms,
      differential diagnosis, and pharmacological therapies. We used these findings to
      make recommendations regarding diagnosis and treatment. Paroxysmal autonomic
      instability with dystonia appears to be a distinctive syndrome after brain injury
      that can mimic other life-threatening conditions. Early recognition may lead to
      fewer diagnostic tests and a rational approach to management. Prospective trials
      of specific drugs are needed to determine optimal efficacy.

PMID- 15023808
TI  - Plasma levels of beta-amyloid(1-40), beta-amyloid(1-42), and total beta-amyloid
      remain unaffected in adult patients with hypercholesterolemia after treatment
      with statins.
AB  - BACKGROUND: Epidemiological studies suggest that statins reduce the risk of
      developing Alzheimer disease. Cell and animal experiments have revealed a
      connection between cholesterol metabolism and the processing of amyloid precursor
      protein. To our knowledge, the mechanism for statins in risk reduction of
      Alzheimer disease is unknown. OBJECTIVE: To test the effect of statin treatment
      on beta-amyloid (A beta) metabolism in humans. DESIGN: A prospective, randomized,
      dose-finding 36-week treatment trial with statins. Plasma samples were taken at
      baseline (week 0) and at weeks 6, 12, and 36. SETTING: Outpatient clinical study
      at a university hospital. PATIENTS: Thirty-nine patients who met the criteria for
      hypercholesterolemia. INTERVENTIONS: Patients were randomized to oral treatment
      with either simvastatin or atorvastatin calcium according to the following
      regimen: simvastatin, 40 mg/d, or atorvastatin, 20 mg/d, for 6 weeks; followed by
      simvastatin, 80 mg/d, or atorvastatin, 40 mg/d, for 6 weeks; and finally,
      simvastatin, 80 mg/d, or atorvastatin, 80 mg/d, for 24 weeks. MAIN OUTCOME
      MEASURES: Plasma levels of A beta(1-40) and A beta(1-42) were measured using 2
      enzyme-linked immunosorbent assays, and total A beta was quantified by Western
      blotting. RESULTS: Treatment with both statins reduced total plasma cholesterol
      levels by 56% (P =.00). The plasma levels of A beta(1-40), A beta(1-42), and
      total A beta were stable in individual patients during the treatment period. No
      significant change in the level of A beta(1-40), A beta(1-42), or total A beta
      was found. CONCLUSION: This study questions the effect of statins on the
      processing of amyloid precursor protein in humans.

PMID- 15023809
TI  - Increased risk for Alzheimer disease with the interaction of MPO and A2M
      polymorphisms.
AB  - BACKGROUND: The genes encoding myeloperoxidase (MPO) and alpha(2)-macroglobulin
      (A2M) are involved in molecular pathways leading to beta-amyloid deposition. Two
      polymorphic sites in these genes (MPO-G/A and A2M-Ile/Val) have been associated
      with Alzheimer disease (AD), but conflicting findings have been reported in
      populations with different ethnic backgrounds. OBJECTIVES: To study the
      association of MPO-G/A and A2M-Ile/Val polymorphisms with sporadic AD and to
      investigate the interactions among the MPO, A2M, and apolipoprotein E (APOE) gene
      polymorphisms in determining the risk of the development of AD. DESIGN: Case
      control study. SETTING: Referral center for AD in Calabria, southern Italy.
      PARTICIPANTS: One hundred forty-eight patients with sporadic AD and 158 healthy
      control subjects. RESULTS: The MPO-G and A2M-Val alleles were found more
      frequently in cases than in controls, as were the MPO-G/G and A2M-Val/Val
      genotypes. The odds ratio (OR) for the MPO-G/G genotype was 1.78 (95% confidence
      interval [CI], 1.13-2.80); for the A2M-Val/Val genotype, 3.81 (95% CI, 1.66
      8.75). The presence of MPO-G/G and A2M-Val/Val genotypes synergistically
      increased the risk of AD (OR, 25.5; 95% CI, 4.65-139.75). Stratification of cases
      by sex, age at onset of AD, and APOE-epsilon 4 status did not show significant
      differences in the distribution of MPO or A2M polymorphisms. CONCLUSIONS: The MPO
      and A2M polymorphisms are associated with sporadic AD in southern Italy.
      Moreover, a genomic interaction between these polymorphisms increases the risk of
      the development of AD.

PMID- 15023810
TI  - Utilization of intravenous tissue plasminogen activator for acute ischemic
      stroke.
AB  - BACKGROUND: Intravenous tissue plasminogen activator (tPA) is the only approved
      therapy for acute ischemic stroke, although only 2% of patients with stroke
      receive intravenous tPA nationally. OBJECTIVE: To determine the rate of tPA use
      for stroke in the Cleveland, Ohio, community and the reasons why patients were
      excluded from thrombolysis treatment. DESIGN: Retrospective cohort study.
      SETTING: Community. Subjects Patients admitted because of stroke to the 9
      Cleveland Clinic Health System hospitals from June 15, 1999, to June 15, 2000.
      MAIN OUTCOME MEASURES: Utilization of intravenous tPA and reasons for
      ineligibility. RESULTS: There were 1923 admissions for ischemic stroke in the 1
      year period. Of these, 288 (15.0%) arrived within the 3-hour time window, and
      approximately 6.9% were considered eligible for tPA. The most common reasons for
      exclusion among patients arriving within 3 hours were mild neurologic impairment
      and rapidly improving symptoms. The overall rate of tPA use among patients
      presenting within 3 hours was 19.4%, and the rate of use among eligible patients
      was 43.4% (n = 56). The use of tPA did not differ significantly according to race
      or sex. CONCLUSIONS: Only 15% of patients arrived within the 3-hour time window
      for intravenous tPA, making delay in presentation the most common reason patients
      were ineligible for i.v. thrombolysis. Neurologic criteria were the second most
      common group of exclusions. Overall tPA use was low, but it was used in nearly
      half of all patients with no documented contraindications. Intravenous tPA use in
      a community setting can compare favorably with the rate of use seen in academic
      medical settings.

PMID- 15023811
TI  - The combined effect of paraoxonase promoter and coding region polymorphisms on
      the risk of arterial ischemic stroke among young adults.
AB  - BACKGROUND: Serum paraoxonase (PON1) is a high-density lipoprotein-associated
      esterase with antioxidant and antiatherogenic properties that has recently been
      implicated in the pathogenesis of cardiovascular disease. Interindividual
      variability in PON1 levels is determined by the Q192R and L55M coding region
      polymorphisms and by 2 recently described polymorphisms in the promoter of the
      PON1 gene, C(-107)T and G(-824)A. OBJECTIVE: To determine the association of the
      PON1 promoter polymorphisms with arterial ischemic stroke (AIS) in the young.
      DESIGN. SETTING, AND PATIENTS: We studied 118 young patients (age, <45 years)
      with a first nonfatal AIS of undetermined etiology and 118 control subjects,
      matched simultaneously for age and sex. The PON1 C(-107)T polymorphism was
      determined by single-stranded conformational polymorphism analysis and the G(
      824)A substitution by polymerase chain reaction and restriction enzyme digestion.
      RESULTS: The presence of the low-expressor -107T allele was associated with an
      independent increase in overall risk of AIS (odds ratio [OR], 2.69; 95%
      confidence interval [CI], 1.06-6.78; P =.04) by conditional multiple logistic
      regression analysis. Among individuals with the 192RR genotype, the presence of
      the -107T allele led to a higher but nonsignificant risk, yielding an OR of 4.15
      (95% CI, 0.35-48.76; P =.15) when compared with noncarriers of the T allele and
      17.01 (95% CI, 1.74-166.35; P =.02) when compared with noncarriers of either
      variant. No significant difference between groups was found regarding the G(
      824)A polymorphism. CONCLUSION: These findings suggest that the PON1 -107T allele
      is independently associated with the risk of AIS, in addition to interacting with
      and potentiating the risk conferred by the Q192R polymorphism.

PMID- 15023812
TI  - Nonconvulsive status epilepticus in patients with cancer: imaging abnormalities.
AB  - BACKGROUND: Convulsive status epilepticus may cause reversible neuroimaging
      abnormalities. These cortical changes have been reported rarely in association
      with nonconvulsive status epilepticus. OBJECTIVE: To describe patients with
      cancer who had reversible magnetic resonance (MR) imaging abnormalities from
      nonconvulsive status epilepticus and whose altered mental status and MR imaging
      findings were initially considered to result from a structural lesion related to
      their underlying tumor. DESIGN: Retrospective study. SETTING: Department of
      Neurology at Memorial Sloan-Kettering Cancer Center, New York, NY. PATIENTS:
      Eight patients with a diagnosis of nonconvulsive status epilepticus who underwent
      MR imaging. RESULTS: Enhancing cortical abnormalities were observed on MR images
      in 4 (50%) of 8 patients with cancer who had impaired mental status and an
      electroencephalogram demonstrating seizure activity. Follow-up MR images showed
      neuroimaging improvement or resolution in all patients. CONCLUSIONS: Cortical
      enhancement on MR images in patients with cancer who have altered mental status
      may be due to nonconvulsive status epilepticus and not recurrent or metastatic
      tumor. If electroencephalography is not immediately available at initial
      evaluation, a trial of anticonvulsant therapy deserves consideration.

PMID- 15023813
TI  - A preliminary diffusion tensor and magnetization transfer magnetic resonance
      imaging study of early-onset multiple sclerosis.
AB  - BACKGROUND: Early-onset multiple sclerosis (MS) typically has a more favorable
      course than adult-onset disease. OBJECTIVE: To assess the extent of microscopic
      tissue damage in the brain and cervical cord of patients with early-onset MS.
      DESIGN: During a single magnetic resonance imaging session, images of the brain
      and spinal cord were obtained using diffusion tensor and magnetization transfer
      magnetic resonance imaging. PATIENTS: We studied 13 patients with early-onset MS
      and 10 healthy volunteers. RESULTS: Compared with control subjects, patients with
      early-onset MS showed only a slight increase of the average mean diffusivity of
      the normal-appearing brain tissue. CONCLUSION: The relatively modest central
      nervous system damage detected in these patients might explain why early-onset MS
      typically has a more favorable clinical course than adult-onset MS.

PMID- 15023815
TI  - Neurofibrillary tangles mediate the association of amyloid load with clinical
      Alzheimer disease and level of cognitive function.
AB  - OBJECTIVE: To test the hypothesis that the association of amyloid load with
      clinical Alzheimer disease (AD) and cognitive impairment is mediated through
      neurofibrillary tangles. DESIGN: Longitudinal clinicopathologic cohort study.
      PARTICIPANTS AND SETTING: Forty-four individuals with clinically diagnosed AD and
      53 without dementia who participated in the Religious Orders Study underwent a
      uniform structured clinical evaluation for AD and cognitive testing about 8
      months prior to death, and brain autopsy at death. METHODS: The percent area
      occupied by amyloid-beta and the density of neurofibrillary tangles were
      quantified from 6 brain regions and averaged to yield summary measures of amyloid
      load and neurofibrillary tangles. Multivariate regression analyses were used to
      simultaneously examine the effects of amyloid load and neurofibrillary tangles on
      clinically diagnosed AD and level of cognition. MAIN OUTCOME MEASURES: Clinically
      diagnosed AD and level of global cognitive function proximate to death. RESULTS:
      In separate logistic regression analyses, each 1% increase in amyloid load was
      associated with about a 50% increase in the odds of clinical AD (P =.002), and
      each neurofibrillary tangle was associated with a greater than 20% increase in
      the odds of clinical AD (P<.001). When a term for tangles was added to the
      regression model with amyloid, the association of amyloid load with clinical
      disease was reduced by more than 60% and was no longer significant, whereas the
      association of tangles with clinical disease was essentially unchanged. Similar
      results were found in analyses of global cognitive function. CONCLUSION: These
      findings are consistent with a sequence of pathologic events whereby the effect
      of amyloid deposition on clinical disease is mediated by neurofibrillary tangles.

PMID- 15023816
TI  - Reduced body mass index in patients with essential tremor: a population-based
      study in the province of Mersin, Turkey.
AB  - BACKGROUND: Body mass index (BMI) is an important health indicator. Individuals
      with a low BMI are more prone to various health problems and have an increased
      risk of mortality. A reduced BMI in essential tremor (ET) patients who were
      referred to a tertiary referral center was previously demonstrated. To our
      knowledge, this has not been confirmed in other groups of ET patients with
      different demographic characteristics or in a group of unselected ET patients
      living in the population. OBJECTIVE: To compare BMI in ET case and control
      subjects in a population-based study in the province of Mersin. INTERVENTIONS:
      The epidemiological survey used door-to-door examinations to evaluate 2253
      residents in Mersin. There were 89 ET cases (mean age, 57.3 years) who were
      matched to 89 controls based on sex, ward (area of residence), and age. The BMI
      was calculated as weight in kilograms divided by the square of height in meters.
      RESULTS: The mean +/- SD BMI in ET cases was 26.0 +/- 4.3 vs 27.5 +/- 5.0 in
      controls (P =.04), representing, on average, a 5.5% reduction in cases. In a
      linear regression analysis that adjusted for age, sex, years of education,
      socioeconomic status, urban vs rural dwelling, cognitive screen score, and
      Cumulative Illness Rating Scale score, the BMI was lower in cases than in
      controls (P =.02). CONCLUSIONS: A reduction in BMI is a common accompaniment of
      neurodegenerative diseases; a mild reduction also seems to be a feature of ET. It
      is important for physicians to be aware of the potential for a low BMI in their
      ET patients so that nutrition can be addressed as part of the treatment plan.

PMID- 15023814
TI  - Correlation of in vivo neuroimaging abnormalities with postmortem human
      immunodeficiency virus encephalitis and dendritic loss.
AB  - BACKGROUND: In the absence of significant opportunistic infection, the most
      common alterations on neuroimaging in the brains of patients with AIDS include
      enlarged cerebrospinal fluid spaces, white-matter loss, volume loss in striatal
      structures, and white-matter signal abnormalities. Although previous studies have
      linked brain viral levels to these alterations, other neuropathological
      mechanisms might also contribute to them. OBJECTIVE: To examine the relationship
      between findings on premortem magnetic resonance images and postmortem
      neuropathologic evidence of human immunodeficiency virus (HIV) encephalitis and
      neurodegeneration. DESIGN: Morphometric analysis of magnetic resonance imaging in
      seropositive cases with matched seronegative controls, and the correlation of
      these volumes to neuropathological measures in autopsied seropositive cases.
      SETTING: University of California, San Diego, HIV Neurobehavioral Research
      Center. SUBJECTS: Twenty-one seropositive subjects studied at autopsy and 19
      seronegative cases. MAIN OUTCOME MEASURES: In vivo structural magnetic resonance
      imaging data analyzed by quantitative methods, with comparison of volumes from
      magnetic resonance imaging and neuropathological data from autopsies. RESULTS:
      The HIV-seropositive subjects demonstrated cerebrospinal fluid increases relative
      to seronegative controls. These increases were associated with a significant
      decrease in the volumes of cerebral and cerebellar white matter, caudate nucleus,
      hippocampus, and, to a lesser extent, cerebral cortex. The volume of cerebral
      white-matter tissue with elevated signal was also increased. This signal
      elevation in white matter predicted the autopsy diagnosis of HIV encephalitis, as
      well as the extent of dendritic loss as assessed by analysis of microtubule
      associated protein 2 immunoreactivity. CONCLUSIONS: White-matter and cortical
      damage resulting from HIV disease are closely related. In vivo magnetic resonance
      imaging may be a valuable adjunct in the assessment of patients at risk for
      developing HIV encephalitis.

PMID- 15023817
TI  - Subthalamic stimulation in Parkinson disease: with or without anesthesia?
AB  - OBJECTIVE: To study the effects of general anesthesia on the postoperative
      outcome of patients with Parkinson disease (PD) who underwent surgery using
      bilateral placement of stimulating electrodes within the subthalamic nucleus
      (STN). DESIGN: Retrospective analysis. SETTING: Hopital de la Salpetriere, Paris,
      France. PATIENTS: Fifteen PD patients who underwent bilateral implantation of
      electrodes within the STN received general anesthesia because of severe anxiety,
      poorly tolerated off-period dystonia, or respiratory difficulties. These patients
      were compared with 15 patients matched for age, disease duration, and
      parkinsonian motor disability who underwent the same neurosurgical procedure
      under local anesthesia. MAIN OUTCOME MEASURE: Motor disability scores. RESULTS:
      After surgery, the severity of parkinsonian motor disability was markedly
      improved in both groups of patients. Compared with patients who were under local
      anesthesia during the operation, the residual parkinsonian motor score under
      stimulation (with ["on"] or without ["off"] levodopa) and the intensity of
      stimulation were higher in patients who were under general anesthesia during the
      operation. CONCLUSIONS: Although the improvement of parkinsonian motor disability
      is greater in PD patients who receive local anesthesia during surgery, general
      anesthesia can be performed in patients unable to tolerate prolonged states
      without levodopa.

PMID- 15023818
TI  - 17q-linked frontotemporal dementia-amyotrophic lateral sclerosis without tau
      mutations with tau and alpha-synuclein inclusions.
AB  - BACKGROUND: Frontotemporal dementia (FTD) is a clinically heterogeneous condition
      that can be associated with clinical manifestations of an extrapyramidal disorder
      or motor neuron disease. A range of histologic patterns has been described in
      patients with FTD. The most common familial form of this condition is caused by
      mutations in the microtubule-associated protein tau gene (MAP tau) and is
      associated with neuronal or glial tau inclusions. OBJECTIVES: To determine the
      clinical, anatomic, and pathological features of San Francisco family A and to
      map the mutation responsible for disease in this family. DESIGN: A systematic
      clinical, neuropsychologic, neuroimaging, and chromosome segregation analysis of
      San Francisco family A was performed. A pathological and biochemical assessment
      of a family member was made. SETTING: Family study. PATIENTS: San Francisco
      family A, with FTD, variable extrapyramidal symptoms, and prominent motor neuron
      disease. Afflicted family members do not have a MAP tau coding or splice
      regulatory sequence mutation, and the MAP tau is genetically excluded. MAIN
      OUTCOME MEASURES: Comparison of clinical, neuropsychologic, neuroimaging, and
      linkage findings of San Francisco family A with other familial forms of FTD and
      amyotrophic lateral sclerosis (ALS). RESULTS: The most probable location for the
      mutation responsible for this condition is on chromosome arm 17q, distal to the
      MAP tau. All previously identified susceptibility loci for FTD and ALS are
      excluded. Autopsy findings from an afflicted family member show distinctive tau
      and alpha-synuclein inclusions. Another unique feature is that the insoluble tau
      protein consists predominantly of the 4R/0N isoform. CONCLUSION: The condition
      affecting members of San Francisco family A is clinically, pathologically, and
      genetically distinct from previous familial forms of FTD and ALS.

PMID- 15023819
TI  - Postpartum angiopathy with reversible posterior leukoencephalopathy.
AB  - BACKGROUND: Postpartum angiopathy (PPA) is a cerebral vasoconstriction syndrome
      of uncertain cause that affects large and medium-sized cerebral arteries.
      Postpartum angiopathy is frequently complicated by ischemic stroke. The
      reversible posterior leukoencephalopathy syndrome (RPLS) is a distinct clinical
      radiological entity characterized by transient vasogenic edema on brain imaging.
      The pathophysiological features of RPLS are related to small-vessel dysfunction
      and breakdown of the blood-brain barrier. OBJECTIVES: To report the coexistence
      of PPA and RPLS in 4 patients and to discuss possible interrelationships between
      these 2 entities. DESIGN: Four case reports and a review of the literature.
      RESULTS: Four women developed a clinical-radiological syndrome overlapping PPA
      and eclampsia shortly after an uncomplicated pregnancy. All had acute severe
      ("thunderclap") headaches and hypertension. Three developed seizures. All
      patients had reversible angiographic narrowing of large and medium-sized cerebral
      arteries. Serial magnetic resonance imaging showed transient nonischemic brain
      lesions, resembling the lesions described in patients with RPLS. The results of
      extensive tests for cerebral vasculitis were negative. CONCLUSION: These cases,
      and the literature, suggest an interrelationship between RPLS and cerebral
      vasoconstriction syndromes such as PPA.

PMID- 15023820
TI  - Specificity of "peering at the tip of the nose" for a diagnosis of thalamic
      hemorrhage.
AB  - BACKGROUND: Tonic inward and downward deviation of the eyes ("peering at the tip
      of the nose") is regarded as a unique feature of thalamic hemorrhage, but the
      mechanisms of this ocular finding remain obscure. OBJECTIVES: To describe 4
      patients who showed tonic inward and downward deviation of the eyes from
      brainstem or thalamic lesions and to discuss the possible mechanisms involved.
      DESIGN: Case report. SETTING: Secondary and tertiary referral hospitals. RESULTS:
      One patient developed alternating esotropia with downward ocular deviation from
      thalamic hemorrhage compressing the midbrain. Two patients showed multiple
      infarctions in the territory of the posterior circulation with or without the
      involvement of the thalamus. Another patient had lateral pontine hemorrhage
      extending up to the midbrain tegmentum. Ocular bobbing preceded or accompanied
      tonic ocular deviation in 3 patients. CONCLUSIONS: Tonic inward and downward
      deviation of the eyes may develop in thalamic or brainstem lesions. Irritation or
      destruction of the neural structures involved in the vergence and vertical gaze
      may cause this ocular sign in mesodiencephalic lesions. Skew deviation and
      esotropia from abduction deficit may be involved in some patients. Ocular bobbing
      and tonic downward deviation may share a common pathogenesis.

PMID- 15023821
TI  - Absence of lower-limb deficits despite severe spinal cord atrophy.

PMID- 15023822
TI  - Posttraumatic bilateral internuclear ophthalmoplegia with exotropia.

PMID- 15023824
TI  - Juvenile Parkinson disease and the C212Y mutation of parkin.

PMID- 15023823
TI  - Vascular dementia.

PMID- 15023825
TI  - Reversal of acute neurological deterioration from spontaneous intracranial
      hypotension by lumbar subarachnoidal infusion with normal saline.

PMID- 15023826
TI  - Mimicry of variant Creutzfeldt-Jakob disease by sporadic Creutzfeldt-Jakob
      disease: importance of the pulvinar sign.

PMID- 15023827
TI  - The pulvinar sign in variant Creutzfeldt-Jakob disease.

PMID- 15023828
TI  - Acupuncture for chronic headache in primary care: large, pragmatic, randomised
      trial.
AB  - OBJECTIVE: To determine the effects of a policy of "use acupuncture" on headache,
      health status, days off sick, and use of resources in patients with chronic
      headache compared with a policy of "avoid acupuncture." DESIGN: Randomised,
      controlled trial. SETTING: General practices in England and Wales. PARTICIPANTS:
      401 patients with chronic headache, predominantly migraine. Interventions
      Patients were randomly allocated to receive up to 12 acupuncture treatments over
      three months or to a control intervention offering usual care. MAIN OUTCOME
      MEASURES: Headache score, SF-36 health status, and use of medication were
      assessed at baseline, three, and 12 months. Use of resources was assessed every
      three months. RESULTS: Headache score at 12 months, the primary end point, was
      lower in the acupuncture group (16.2, SD 13.7, n = 161, 34% reduction from
      baseline) than in controls (22.3, SD 17.0, n = 140, 16% reduction from baseline).
      The adjusted difference between means is 4.6 (95% confidence interval 2.2 to 7.0;
      P = 0.0002). This result is robust to sensitivity analysis incorporating
      imputation for missing data. Patients in the acupuncture group experienced the
      equivalent of 22 fewer days of headache per year (8 to 38). SF-36 data favoured
      acupuncture, although differences reached significance only for physical role
      functioning, energy, and change in health. Compared with controls, patients
      randomised to acupuncture used 15% less medication (P = 0.02), made 25% fewer
      visits to general practitioners (P = 0.10), and took 15% fewer days off sick (P =
      0.2). CONCLUSIONS: Acupuncture leads to persisting, clinically relevant benefits
      for primary care patients with chronic headache, particularly migraine. Expansion
      of NHS acupuncture services should be considered.

PMID- 15023829
TI  - National cross sectional survey to determine whether the decision to delivery
      interval is critical in emergency caesarean section.
AB  - OBJECTIVE: To examine the association between decision to delivery interval and
      maternal and baby outcomes. DESIGN: National cross sectional survey. SETTING:
      Maternity units in England and Wales. SUBJECTS REVIEWED: 17 780 singleton births
      (99% of all births) delivered by emergency caesarean section in England and Wales
      between 1 May 2000 and 31 July 2000. MAIN OUTCOME MEASURES: Association between
      decision to delivery interval and baby outcomes (Apgar scores of < 7 and < 4 at
      five minutes and stillbirth) and maternal outcomes (requirement for special care
      additional to routine care after caesarean section and where care was provided).
      RESULTS: Compared with babies delivered within 15 minutes, there was no
      difference in maternal or baby outcome for decision to delivery interval between
      16 and 75 minutes. After 75 minutes, however, there was a significantly higher
      odds of a five minute Apgar score of < 7 (odds ratio 1.7, 95% confidence interval
      1.2 to 2.4), and 50% increase in odds of special care additional to routine care
      for mothers. CONCLUSION: A decision to delivery interval of 30 minutes is not an
      absolute threshold for influencing baby outcome. Decision to delivery intervals
      of more than 75 minutes are associated with poorer maternal and baby outcomes and
      should be avoided.

PMID- 15023830
TI  - Cost effectiveness analysis of a randomised trial of acupuncture for chronic
      headache in primary care.
AB  - OBJECTIVE: To evaluate the cost effectiveness of acupuncture in the management of
      chronic headache. DESIGN: Cost effectiveness analysis of a randomised controlled
      trial. SETTING: General practices in England and Wales. PARTICIPANTS: 401
      patients with chronic headache, predominantly migraine. Interventions Patients
      were randomly allocated to receive up to 12 acupuncture treatments over three
      months from appropriately trained physiotherapists, or to usual care alone. MAIN
      OUTCOME MEASURE: Incremental cost per quality adjusted life year (QALY) gained.
      RESULTS: Total costs during the one year period of the study were on average
      higher for the acupuncture group (403 pounds sterling; 768 dollars; 598 euros)
      than for controls (217 pounds sterling) because of the acupuncture practitioners'
      costs. The mean health gain from acupuncture during the one year of the trial was
      0.021 quality adjusted life years (QALYs), leading to a base case estimate of
      9180 pounds sterling per QALY gained. This result was robust to sensitivity
      analysis. Cost per QALY dropped substantially when the analysis incorporated
      likely QALY differences for the years after the trial. CONCLUSIONS: Acupuncture
      for chronic headache improves health related quality of life at a small
      additional cost; it is relatively cost effective compared with a number of other
      interventions provided by the NHS.

PMID- 15023831
TI  - Research subject privacy protection in otolaryngology.
AB  - BACKGROUND: Health Insurance Portability and Accountability Act regulations,
      which took effect on April 14, 2003, placed new constraints on the use of
      protected health information for research purposes. OBJECTIVE: To review
      practices of research subject privacy protection in otolaryngology in order to
      determine steps necessary to achieve compliance with Health Insurance Portability
      and Accountability Act regulations. STUDY DESIGN: Literature review. METHODS:
      Articles appearing in 2001 in 3 widely circulated otolaryngology journals were
      classified according to study design. The "Methods" section of each article was
      reviewed to determine whether the informed consent and institutional review board
      processes were clearly documented. RESULTS: Descriptive studies involving case
      reports and case series were more common than observational studies that include
      a control group (66% vs 11%). Few case series documented the consent process
      (18%) and institutional review board process (19%). Observational designs
      demonstrated better documentation of the consent process (P<.001) and the
      institutional review board exemption and approval process (P<.001). CONCLUSIONS:
      Methods used to protect subject privacy are not commonly documented in case
      series in otolaryngology. More attention needs to be given to research subject
      privacy concerns in the otolaryngology literature in order to comply with Health
      Insurance Portability and Accountability Act regulations.

PMID- 15023833
TI  - A Dutch family with hearing loss linked to the DFNA20/26 locus: longitudinal
      analysis of hearing impairment.
AB  - OBJECTIVES: To perform linkage analysis and to outline hearing loss
      characteristics in a family exhibiting a nonsyndromic, autosomal dominant type of
      progressive sensorineural hearing loss. DESIGN: Genetic analysis was performed
      using microsatellite markers. Audiometric data were collected and analyzed
      longitudinally. Sigmoidal dose-response curves enabled us to perform nonlinear
      regression analysis per frequency and on phoneme recognition scores. Speech
      recognition scores were compared with those of DFNA2, DFNA5, DFNA9, and
      presbyacusis subjects. SUBJECTS: Affected family members of a Dutch family (W99
      060). RESULTS: We revealed linkage of hearing loss to the DFNA20/26 locus
      (maximum logarithm of odds score, 3.1 at theta=0.04) and reduced the critical
      region from 12 to 9.5 centimorgans. Patients younger than 15 years already showed
      gently downsloping audiograms. At ages 15 to 20 and 25 to 40 years, hearing loss
      was profound at 8 kHz and 1 to 4 kHz, respectively. The 0.25- to 0.5-kHz
      thresholds showed more gradual progression by about 1.5 to 2 dB/y. From about age
      40 years onward, hearing was residual. Hearing impairment took a more severe
      course than in a known DFNA20 family. Score recognition in DFNA20/26 subjects was
      better than in DFNA9 subjects at any pure-tone average (1-4 kHz) threshold.
      Compared with subjects having DFNA2 and DFNA5, speech recognition in those with
      DFNA20/26 scored better at threshold levels below 85 dB hearing level, but worse
      at levels above 90 dB. Compared with presbyacusis subjects, those with DFNA20/26
      scored better in speech recognition at levels below 100 dB and worse at levels
      above 100 dB. CONCLUSIONS: Autosomal dominant hearing loss is linked to the
      DFNA20/26 locus in this Dutch family. The critical region is reduced from 12 to
      9.5 centimorgans. Phenotypically, patients are more severely affected than those
      of a known DFNA20 family.

PMID- 15023832
TI  - The genetic component of middle ear disease in the first 5 years of life.
AB  - OBJECTIVE: To determine the genetic component of time with middle ear effusion
      (MEE) and episodes of MEE and acute otitis media. DESIGN: Prospective
      twin/triplet cohort. SETTING: Research center at a tertiary pediatric hospital.
      PARTICIPANTS: A total of 168 healthy same-sex twin and 7 same-sex triplet sets
      were recruited by age 2 months. INTERVENTIONS: Longitudinal assessment of middle
      ear status by pneumatic otoscopy and tympanometry at monthly evaluations, and at
      examinations during upper respiratory tract infections or symptoms of middle ear
      disease. OUTCOME MEASURES: Proportion of time with MEE and episodes of acute
      otitis media and MEE. RESULTS: Of the 140 sets for which zygosity was obtained,
      114 were followed up to age 3 years and 83 sets to age 5 years. The heritability
      estimate for proportion of time with MEE in the first 5 years of life was 0.72
      (P<.001). The correlation of proportion of time with MEE between children within
      a set was significantly higher in monozygotic sets (0.65-0.77) than in dizygotic
      sets (0.31-0.39) for each year to age 3 years. In the fourth and fifth years of
      life, the correlations decreased in both monozygotic and dizygotic twin sets.
      CONCLUSIONS: Findings for the first 2 years of follow-up have been previously
      published and indicate a strong genetic component to the proportion of time with
      MEE. In the present report, which details the entire 5-year follow-up, the effect
      of this component appears to attenuate after the third year but its cumulative
      effect remains significant after 5 years.

PMID- 15023834
TI  - Complications of otitis media before placement of tympanostomy tubes in children.
AB  - OBJECTIVES: To report the incidence of short-term complications from otitis media
      in children before placement of tympanostomy tubes (TTs) and to compare children
      treated according to the Agency for Health Care Policy and Research guidelines
      with those who were treated earlier or later than recommended. DESIGN:
      Retrospective outcomes review. PATIENTS: Subjects were children aged 10 or
      younger who had TTs inserted at a tertiary care county hospital from January 1,
      1999, to December 31, 2000. Exclusion criteria included prior TT placement, any
      concurrent head and neck procedure, and craniofacial defects. INTERVENTION:
      Tympanostomy tube placement. MAIN OUTCOME MEASURES: Any occurrences of otorrhea,
      tympanic membrane perforation, tinnitus, antibiotic reactions, speech or language
      delay, febrile seizures, or meningitis before placement of TTs documented in the
      county hospital records were recorded as complications. Hearing loss was
      considered separately. RESULTS: Of 147 children who met our criteria, 81 (55.1%)
      had 1 or more complications from otitis media before placement of TTs. Fifty-five
      (37.4%) had 2 to 6 complications documented. Adverse reactions to antibiotics
      were the most common complication, reported in 34 (23.1%). CONCLUSIONS: Most
      children in this county hospital experienced short-term complications of otitis
      media before receiving TTs. Even the children treated "on time" according to the
      guidelines from the Agency for Health Care Policy and Research experienced
      complications; however, adherence to the guidelines had no significant effect on
      complications.

PMID- 15023835
TI  - Molecular profiling and the identification of genes associated with metastatic
      oral cavity/pharynx squamous cell carcinoma.
AB  - OBJECTIVE: To investigate differences in gene expression profiles between oral
      cavity/oropharynx squamous cell carcinoma (OC/OP SCC) primary tumors that have
      metastasized to cervical lymph nodes and nonmetastatic OC/OP SCC tumors. DESIGN:
      Oligonucleotide microarray analysis of primary tumors was used to produce gene
      expression profiles. Profile comparisons between metastatic and nonmetastatic
      tumors were performed using principal component analysis, t test, and fold change
      differences. A similar comparison between metastatic tumors and noncancer oral
      mucosa samples was performed to ensure tumor origin. SUBJECTS: A prospective
      cohort of 20 patients with previously untreated OC/OP SCC who underwent
      pathologic staging following surgical resection and lymphadenectomy. RESULTS: Of
      the approximately 9600 genes profiled, 101 demonstrated significant expression
      differences between the metastatic and nonmetastatic tumors (fold change > or
      =1.5; P<.01). Among this subset, 57 genes also exhibited significant differences
      between metastatic tumors and normal mucosa samples (fold change > or =1.5;
      P<.05). This profile included genes related to the extracellular matrix,
      adhesion, motility, inflammation, and protease inhibition. Collagen type 11 alpha
      1 (COL11A1) demonstrated the greatest differential expression between metastatic
      and nonmetastatic OC/OP SCC tumors (fold change=7.61; P=.002). Tissue inhibitor
      of metalloproteinase 1 (TIMP-1) also demonstrated increased expression in
      metastatic tumors (fold change=3.3; P=.003). CONCLUSIONS: Metastatic OC/OP SCC
      has a distinct gene expression profile compared with nonmetastatic OC/OP SCC and
      normal oral mucosa. This metastatic profile includes genes related to the
      extracellular matrix, adhesion, motility, and protease inhibition. Knowledge
      gained through tumor gene expression profiling may facilitate early detection of
      aggressive tumors and targeted therapeutic interventions.

PMID- 15023836
TI  - Association between p53 gene mutations and tobacco and alcohol exposure in
      laryngeal squamous cell carcinoma.
AB  - OBJECTIVES: To analyze the relationship between p53 gene mutations, tobacco
      smoke, and alcohol consumption in patients with laryngeal squamous cell
      carcinoma. DESIGN: We analyzed p53 gene mutations in exons 5 through 8 by
      polymerase chain reaction-single-strand conformation polymorphism analysis in a
      cohort of 84 patients with laryngeal squamous cell carcinoma. SETTING: University
      hospital. RESULTS: p53 gene mutations were detected in 24 (28.6%) cases (95%
      confidence interval, 19.3%-39.5%), and the GC to TA transversion (33%) was the
      most common type of mutation (95% confidence interval, 15.6%-55.3%). Most
      mutations mapped to the p53 DNA-binding domain, which is necessary for the
      physiological activity of p53 as a tumor suppressor. A statistically significant
      association was found between p53 mutations and exposure to tobacco smoke
      (P=.001), which was the only variable significantly associated with p53 mutations
      in a multivariate model. The association with alcohol consumption was only at a
      borderline level of significance (P=.065). CONCLUSION: Our data document that a
      smoking habit is the only independent variable associated with an increased risk
      of p53 mutations in the laryngeal mucosa.

PMID- 15023837
TI  - Study on ceramide expression and DNA content in patients with healthy mucosa,
      leukoplakia, and carcinoma of the larynx.
AB  - OBJECTIVE: To investigate the expression of ceramide produced by sphingomyelin
      and DNA content in patients with healthy laryngeal mucosa, leukoplakia, and
      laryngeal carcinoma. DESIGN: A retrospective review of the clinical and surgical
      records of 178 patients with leukoplakia of the larynx; 23 of them developed
      laryngeal carcinoma. SETTING: University medical center. PATIENTS: One hundred
      seventy-eight consecutive patients with leukoplakia of the larynx were identified
      from the archived pathology files of the Eye Ear Nose and Throat Hospital of
      Fudan University from January 1, 1990, to December 30, 2001. Among them, 23
      developed laryngeal carcinoma. Flow cytometry and immunohistochemistry were
      performed to test DNA content and ceramide expression in healthy tissue, tissue
      with leukoplakia, and tissue with laryngeal carcinoma from the same patient.
      RESULTS: Among 23 patients with leukoplakia, 20 had aneuploidy and 3 had
      diploidy. The healthy tissues were all diploids, and the tissues with laryngeal
      carcinoma were all aneuploids. The expression of ceramide decreased gradually
      from healthy tissue to tissue with leukoplakia to tissue with laryngeal carcinoma
      (0, no staining; 1+, weak staining; 2+, mild staining; 3+, moderate staining; 4+,
      strong staining; and 5+, the highest staining intensity). The expression of
      ceramide in DNA diploid cells is stronger than in aneuploid cells. CONCLUSIONS:
      Ceramide, the second messenger in apoptosis, may associate with the progress of
      leukoplakia to carcinoma of the larynx. The reduction of ceramide may contribute
      to laryngeal carcinogenesis.

PMID- 15023838
TI  - Identification of tyrosine kinases overexpressed in head and neck cancer.
AB  - OBJECTIVE: To identify protein-tyrosine kinases (PTKs) that may be involved in
      the development and progression of head and neck squamous cell carcinoma (HNSCC).
      DESIGN: Messenger RNA from 7 HNSCC specimens was reverse transcribed to
      complementary DNA, and selective amplification of PTK complementary DNA was
      achieved using polymerase chain reaction (PCR) with degenerate PTK primers. The
      resulting PTK PCR products from these 7 HNSCC specimens were then cloned and
      randomly selected for sequencing. The PTKs that were represented multiple times
      in these randomly selected clones were selected as candidate PTKs that may be
      overexpressed in HNSCC. Antibodies against these candidate PTKs were then used
      for immunohistochemical studies on 8 other HNSCC specimens not used in the
      original selection of the candidate PTKs. RESULTS: Three known (EphA1, Brk, and
      Ron) and 2 novel (KIAA0728 and KIAA0279) PTKs were found to be highly expressed
      in the 7 HNSCC samples studied, based on the technique of reverse transcriptase
      PCR with degenerate primers. Immunohistochemical studies with antibodies against
      the 3 known PTKs in 8 other HNSCC specimens not used in the previous reverse
      transcriptase-PCR reaction demonstrated overexpression of EphA1, Brk, and Ron in
      12.5%, 37.5%, and 75% of these specimens. CONCLUSIONS: In this study, we
      identified 5 PTKs that were overexpressed in HNSCC using a reverse transcriptase
      PCR technique and confirmed the overexpression of 3 known PTKs in some of the 8
      archival HNSCC specimens studied. Our finding suggests that the signaling
      pathways mediated through EphA1, Brk, and Ron may be involved in the development
      and progression of HNSCC.

PMID- 15023839
TI  - Hazardous events associated with impaired olfactory function.
AB  - OBJECTIVE: To evaluate the risk of olfactory-related hazardous events in patients
      with impaired olfactory function. DESIGN: Retrospective cohort study. SETTING: A
      university-based clinic for smell and taste disorders. PATIENTS: A total of 445
      patients who underwent olfactory testing between 1983 and 2001. INTERVENTIONS:
      Patient interview, olfactory testing. MAIN OUTCOME MEASURES: (1) Frequency of
      olfactory-related hazardous events including cooking incidents (ie, burning pots
      or pans), undetected fires, undetected gas leaks, and ingestion of spoiled foods
      or toxic substances; (2) level of olfactory function (anosmia; severe, moderate,
      or mild hyposmia; or normosmia) as determined by olfactory testing. RESULTS:
      Olfactory testing revealed that 76% of patients had some degree of impairment;
      30% had complete anosmia. Thirty-seven percent of patients with olfactory
      impairment but only 19% of patients without impairment experienced at least 1
      olfactory-related hazardous event. Of the hazardous events reported by impaired
      patients, cooking-related incidents were most common, representing 45%, with
      ingestion of spoiled food (25%), inability to detect a gas leak (23%), and
      inability to smell a fire (7%) reported less frequently. There was a significant
      correlation between frequency of hazardous events and degree of olfactory
      impairment (Cochran-Armitage trend test, P<.001): at least 1 hazardous event was
      reported by 45.2% of patients with anosmia, 34.1% with severe hyposmia, 32.8%
      with moderate hyposmia, 24.2% with mild hyposmia, and 19.0% of patients with with
      normal olfaction by testing. CONCLUSION: Patients with impaired olfactory
      function are more likely to experience olfactory-related hazardous events than
      those with normal olfactory function.

PMID- 15023840
TI  - Prevalence of the chronic sinusitis diagnosis in Olmsted County, Minnesota.
AB  - BACKGROUND: Commonly cited estimates from the National Health Interview Survey
      rank chronic sinusitis as one of the most prevalent chronic diseases in the
      United States. These data rely on patient self-reporting of the disease. However,
      chronic sinusitis is difficult to diagnose because its symptoms overlap those of
      many other disease processes. As such, these prevalence data may be unreliable.
      OBJECTIVE: To provide an estimate of the prevalence of chronic sinusitis based on
      assigned International Classification of Diseases, Ninth Revision (ICD-9) codes
      for the year 2000 in a population-based sample. This study establishes the
      individual patient as the unit of measure vs previous ICD-9-based estimates that
      measured physician encounters. DESIGN: Using existing databases, we identified
      all residents of Olmsted County, Minnesota, who were assigned an ICD-9 diagnosis
      code for chronic sinusitis (473.x) in the year 2000. SETTING: Primary care and
      referral center serving the general community. PARTICIPANTS: All residents of
      Olmsted County who provided research authorization were eligible. MAIN OUTCOME
      MEASURE: Age- and sex-specific prevalence of chronic sinusitis based on assigned
      ICD-9 diagnosis codes. RESULTS: In the year 2000, 2405 residents of Olmsted
      County were given an ICD-9 diagnosis code for chronic sinusitis. Among these,
      1627 (67.7%) were female and 778 (32.3%) were male. The overall age- and sex
      adjusted prevalence per 100,000 was 1955 (1.96%). The mean (SD) age at the time
      of diagnosis was 39.4 (17.6) years (age range, 4.2 months to 94 years). Eighty
      seven percent were diagnosed at Mayo Clinic, and the balance were from the
      Olmsted Medical Center. At Mayo, family practitioners and internists diagnosed
      most of the cases (70%); only 8% were diagnosed by the Department of
      Otolaryngology. The diagnosis code 473.9 for unspecified chronic sinusitis made
      up 95% of cases. CONCLUSIONS: Current prevalence estimates of chronic sinusitis
      may be exaggerated. Chronic sinusitis has been reported to affect 14% to 16% of
      the US population according to a National Health Interview Survey. In Olmsted
      County, we found a much lower prevalence (1.96%) of chronic sinusitis using ICD-9
      codes as an identifier.

PMID- 15023841
TI  - Time course in the relief of nasal blockage after septal and turbinate surgery: a
      prospective study.
AB  - OBJECTIVE: To evaluate prospectively the time course of the change in efficacy of
      septal and turbinate surgery in relieving nasal obstruction. DESIGN:
      Interventional study, before-after trial. SETTING: Referral center, institutional
      practice, hospitalized care. PATIENTS: Thirty-four consecutive patients
      undergoing septal and turbinate surgery were recruited. Seven patients were
      unwilling to complete the follow-up after surgery. No patient withdrawal was
      because of adverse effects. Twenty-five normal subjects with no nasal obstruction
      were included as control subjects. INTERVENTION: Functional nasal septal and
      turbinate surgery was performed to relieve nasal obstruction. MAIN OUTCOME
      MEASURE: Patient assessment of severity of nasal blockage on a 0-mm (no blockage)
      to 100-mm (maximum blockage) visual analog scale before surgery and at fixed
      intervals after surgery. RESULTS: The mean nasal blockage scores significantly
      decreased from the preoperative values at all intervals of follow-up. For the
      whole group, the nasal blockage score was on average 52% of the preoperative
      value at the last follow-up. The probability of having at least a 50% reduction
      in blockage decreased from 73%, to 60%, to 41%, and then to 27% at 3 months, 6
      months, 1 year, and 2(1/2) years, respectively. CONCLUSIONS: Improvement in nasal
      blockage was found in patients after functional septal and turbinate surgery.
      However, the probability of substantial relief gradually decreased with time.
      Patients should be followed up after septal and turbinate surgery for possible
      recurring symptoms.

PMID- 15023842
TI  - Symptom outcomes after endoscopic sinus surgery for chronic rhinosinusitis.
AB  - OBJECTIVE: To determine the effectiveness of endoscopic sinus surgery (ESS) for
      individual symptoms, medication use, and related factors in patients with chronic
      rhinosinusitis (CRS). DESIGN: Nonrandomized, prospective, clinical trial.
      INTERVENTIONS: Adult patients with medically refractory CRS were examined before
      ESS with the Rhinosinusitis Symptom Inventory to catalog major and minor
      symptoms, medication use, physician visits, and missed workdays due to CRS. After
      a minimum 6-month follow-up after ESS, patients were examined to determine
      response to therapy. After computation of Rhinosinusitis Symptom Inventory
      domains, comparisons were conducted and effect sizes were computed for the change
      in symptoms after surgery. RESULTS: One hundred adults completed the examination,
      with a mean follow-up of 19.0 months. Before surgery, the mean major symptom
      scores ranged from 2.5 to 3.5 (Likert scale, from 0 [symptom absent] to 5
      [maximum severity]) and the minor symptom scores ranged from 0.8 to 2.8. After
      surgery, statistically significant decreases in major and minor symptoms were
      noted (P<.001 for all). The largest effect sizes were noted for the decreases in
      facial pressure, congestion, nasal obstruction, rhinorrhea, and headache
      (absolute value of effect size >0.85 for all). Similarly, large effect sizes were
      noted for decreases in symptoms in the nasal (-1.30), facial (-1.13), and total (
      1.25) symptom domains of the Rhinosinusitis Symptom Inventory. Medication use
      actually increased for topical nasal corticosteroids, but decreased for
      prescription antihistamines. A mean reduction of 1.1 antibiotic courses (mean
      decrease of 2.3 weeks taking antibiotics) was noted after ESS. CONCLUSIONS:
      Endoscopic sinus surgery provides significant symptom relief for the nasal and
      facial symptoms associated with CRS. Patients will often still require topical
      nasal corticosteroids for the management of their CRS, but can expect decreases
      in antibiotic requirements after ESS.

PMID- 15023844
TI  - Bacterial biofilm presence in pediatric tracheotomy tubes.
AB  - OBJECTIVE: To determine whether bacterial biofilms are present on pediatric
      tracheotomy tubes. DESIGN: Prospective observational series. INTERVENTIONS:
      Eleven tracheotomy tubes removed during routine tracheotomy tube changes were
      analyzed for biofilm and live bacteria presence using confocal microscopy and
      vital stains. The external and internal surfaces of the tracheotomy tubes were
      studied in 3 locations: distal tip, midtracheotomy tube, and proximal opening.
      These data were correlated with tracheotomy site cultures and the reason for
      tracheotomy dependence. MAIN OUTCOME MEASURES: Microscopic images were analyzed
      for the presence of a biofilm (its morphological features and the presence of
      live and dead bacteria within the biofilm). RESULTS: Of 11 tracheotomy tubes, 10
      had biofilm present on the internal surface of the distal tip. Externally, at the
      same location, 4 tubes had biofilms. On the internal surface of the
      midtracheotomy site, 8 had biofilm present, whereas only 1 had a biofilm on the
      internal surface of the proximal tracheotomy tube site. In the distal internal
      tracheotomy tube site, the biofilm was confluent in 5 tubes and patchy with
      evidence of microcolony formation in the remaining 5 tubes. Live bacteria were
      present in all biofilms. Control tracheotomy tubes did not have biofilms. All
      tracheotomy site cultures and disease states (chronic aspiration and
      bronchopulmonary dysplasia) were associated with tracheotomy tube biofilms.
      CONCLUSION: Bacterial biofilms containing live bacteria were demonstrated in most
      pediatric tracheotomy tubes, being most frequent and extensive on the internal
      surface of the distal tracheotomy tip.

PMID- 15023843
TI  - Three-step reconstruction of complex saddle nose deformities.
AB  - OBJECTIVE: To evaluate a reproducible surgical technique for augmentation
      rhinoplasty of complex saddle nose deformities, which are characterized by
      substantial loss of nasal structural support and result in multiple nasal
      abnormalities. DESIGN: Case series and surgical outcome study. SETTING: Tertiary
      referral center. PATIENTS: A total of 43 patients (32 female and 11 male; mean +/
      SD age, 36 +/- 12 years) with complex saddle nose deformities and extensive loss
      of nasal volume, shape, and support who underwent reconstructive surgery between
      1997 and 1999. INTERVENTION: A standardized 3-step surgical procedure using
      autogenous costal cartilage. MAIN OUTCOME MEASURES: Assessment of additional
      nasal abnormalities, graft recipient site conditions, postoperative
      complications, postoperative analgesic consumption, and subjective outcome
      assessed with a standardized telephone interview 2 years following surgery.
      RESULTS: Besides nasal abnormalities characteristic of complex saddle nose
      deformities, several additional nasal abnormalities were frequently encountered.
      Forty of the 43 patients had undergone previous septorhinoplasty, 26 of whom
      through multiple procedures. One transplant extrusion was recorded, which
      required revision surgery. In 8 patients, minor surgical corrections were
      performed. Nasal airflow was judged satisfactory or good by 30 of the 37 patients
      who were contacted by telephone and aesthetic appearance was considered good by
      17, satisfactory by 10, and unsatisfactory by 10. CONCLUSIONS: Three-step nasal
      reconstruction with costal cartilage is indicated in severe saddle nose
      deformities. It is a comparatively reliable surgical procedure yielding
      satisfying results even in patients with severe deformities and unfavorable
      recipient site conditions.

PMID- 15023845
TI  - Mandibular distraction for micrognathia and severe upper airway obstruction.
AB  - OBJECTIVE: To determine whether the use of mandibular distraction osteogenesis
      (DOG) can help to avoid tracheotomy or achieve decannulation in patients with
      mandibular hypoplasia and severe upper airway obstruction. DESIGN: Retrospective
      medical record review (spanning a 27-month period). SETTING: Tertiary care
      children's hospital. SUBJECTS: Group A (n=8) was composed of infants with Pierre
      Robin sequence and no tracheotomy (mean age, 2.5 months); group B (n=6), older
      nontracheotomized micrognathic children with obstructive sleep apnea (OSA) (mean
      age, 69 months); and group C (n=12), tracheotomized children with complex
      congenital syndromes (mean age, 33 months). INTERVENTION: Bilateral mandibular
      DOG with endoscopic (n=24) and/or radiographic (n=17) airway evaluation (mean
      follow-up, 16 months [range, 2-42 months]). OUTCOME MEASURES: Group A,
      tracheotomy avoidance; group B, resolution of OSA (clinically or on
      polysomnography); and group C, decannulation. RESULTS: Group A, 7 patients (88%)
      successfully avoided tracheotomy; group B, 5 patients (83%) had resolution of
      OSA; and group C, 2 patients (17%) underwent decannulation. CONCLUSIONS:
      Mandibular DOG (1) allows tracheotomy avoidance in infants with isolated Pierre
      Robin sequence and (2) relieves OSA in older micrognathic children without
      tracheotomy. However, mandibular DOG does not frequently lead to decannulation in
      tracheotomized patients with complex congenital syndromes.

PMID- 15023846
TI  - Variability of electroglottographic glottal closed quotients: necessity of
      standardization to obtain normative values.
AB  - OBJECTIVE: To demonstrate the variability of electroglottographic measurements of
      the glottal closed quotient (GCQ) in normal subjects by the calculation method
      used, fundamental frequency, and intensity. DESIGN: Prospective study. SETTING:
      Tertiary university-based referral center. SUBJECTS: Twenty healthy male
      volunteers without laryngeal disorder. Three successive sustained productions of
      the vowel /a/ were performed by each subject. Electroglottographic recordings of
      GCQ were obtained using the criterion level method, which defines an approximate
      duration of glottal closure and opening. Glottal closed quotient values were
      calculated based on criterion levels ranging from 10% to 40%. MAIN OUTCOME
      MEASURES: The extent of correlation between GCQ variation and the mean
      fundamental frequency and intensity. RESULTS: As the criterion level increased, a
      decrease in the mean GCQ was recorded, which was significant with a 10% criterion
      level increase, up to a critical level of 25%. A significant positive correlation
      was found between GCQ and the variables of fundamental frequency and intensity.
      CONCLUSIONS: This study demonstrated significant effects of the criterion level
      used, fundamental frequency, and intensity in the determination of normative
      values of GCQ. Normative values can only be assessed through the standardization
      of one criterion level reached by consensus.

PMID- 15023847
TI  - The impact of osteoporosis on patients with maxillofacial trauma.
AB  - BACKGROUND: Although maxillofacial injuries in the elderly population frequently
      result from falls and motor vehicle crashes, the association between osteoporosis
      and fractures of the maxillofacial region remains poorly defined. OBJECTIVE: To
      evaluate the relationship between osteoporosis and maxillofacial trauma in the
      elderly. DESIGN, SETTING, AND MAIN OUTCOME MEASURES: A retrospective review of 59
      patients 60 years or older treated for maxillofacial fractures at a trauma center
      between 1989 and 2000 was performed. The severity of osteoporosis was graded by
      evaluating the radiographic appearance of the vertebral bodies of each trauma
      patient using the Saville index. The number of maxillofacial fractures and the
      severity of osteoporosis in each patient was assessed to determine whether an
      association between osteoporosis and maxillofacial trauma exists. RESULTS: Of the
      59 patients evaluated, 51% were injured by falls and 46% were involved in motor
      vehicle crashes. Seventy-three percent of the patients had multiple facial
      fractures. As the severity of osteoporosis worsened, patients were more likely to
      sustain a greater number of maxillofacial fractures (P=.01). The mechanism of
      injury had no impact on the relationship between osteoporosis and the number of
      fractures. CONCLUSIONS: Osteoporosis is an independent risk factor for the
      development of maxillofacial fractures. Since more than half of these patients
      are injured by falls, safety measures must be instituted to prevent fall-related
      maxillofacial injuries in the home and the community.

PMID- 15023848
TI  - Sclerosing polycystic sialadenopathy: a rare cause of recurrent tumor of the
      parotid gland.
AB  - We present a case report of a woman with a recurrent parotid mass that was
      histologically confirmed to be sclerosing polycystic sialadenopathy, a rarely
      reported cause of salivary gland tumor. This tumor measured 11.8 x 6 cm, the
      largest such lesion yet reported. Histologic analysis revealed foci of atypical
      intraductal acinic cell proliferation and necrosis severe enough to amount to
      intraductal carcinoma in situ. Despite its large size, it was successfully
      excised, leaving the patient with only moderate facial nerve dysfunction
      postoperatively.

PMID- 15023849
TI  - Wegener granulomatosis presenting as an infiltrative retropharyngeal mass with
      syncope and hypoglossal paresis.
AB  - We describe a woman who presented with syncopal episodes and unilateral
      hypoglossal paresis in association with a highly infiltrative retropharyngeal
      mass. After an extensive malignancy workup, the patient was found to have Wegener
      granulomatosis (WG), an autoimmune necrotizing vasculitis that presents with
      inflammatory lesions anywhere in the respiratory tract and variable renal
      involvement. The archetypal presentation in the head and neck is erosive
      sinonasal crusting, though otologic, pharyngeal, and laryngeal findings are
      common. Highly uncharacteristic lesions are occasionally encountered and may
      contribute to significant diagnostic dilemmas. Neurologic involvement is not
      uncommon, but few reports of hypoglossal paresis and no reports of syncope as a
      result of WG are found in a review of the literature. Given the variability of
      presentation of WG in the head and neck, the otolaryngologist must maintain a
      high degree of suspicion for this disease in the evaluation of airway lesions.

PMID- 15023850
TI  - Pathology quiz case 1. Multiple myeloma with an extramedullary plasmacytoma
      involving the subglottis.

PMID- 15023851
TI  - Pathology quiz case 2. Laryngeal chondrosarcoma.

PMID- 15023852
TI  - Radiology quiz case 1. Childhood cavernous sinus thrombophlebitis.

PMID- 15023853
TI  - Radiology quiz case 2. Heterotopic gastrointestinal cyst of the oral cavity.

PMID- 15023854
TI  - Interaction of a novel dihydropyridine K+ channel opener, A-312110, with
      recombinant sulphonylurea receptors and KATP channels: comparison with the
      cyanoguanidine P1075.
AB  - 1. ATP-sensitive K(+) channels (K(ATP) channels) are composed of pore-forming
      subunits (Kir6.x) and of regulatory subunits, the sulphonylurea receptors (SURx).
      Synthetic openers of K(ATP) channels form a chemically heterogeneous class of
      compounds that are of interest in several therapeutic areas. We have investigated
      the interaction of a novel dihydropyridine opener, A-312110 ((9R)-9-(4-fluoro-3
      iodophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno [2,3-e]pyridin-8(7H)-one
      1,1-dioxide), with SURs and Kir6/SUR channels in comparison to the cyanoguanidine
      opener P1075. 2. In the presence of 1 mM MgATP, A-312110 bound to SUR2A (the SUR
      in cardiac and skeletal muscle) and to SUR2B (smooth muscle) with K(i) values of
      14 and 18 nM; the corresponding values for P1075 were 16 and 9 nM, respectively.
      Decreasing the MgATP concentration reduced the affinity of A312110 binding to
      SUR2A significantly more than that to SUR2B; for P1075, the converse was true. At
      SUR1 (pancreatic beta-cell), both openers showed little binding up to 100 microM.
      3. In the presence of MgATP, both openers inhibited [(3)H]glibenclamide binding
      to the SUR2 subtypes in a biphasic manner. In the absence of MgATP, the high
      affinity component of the inhibition curves was absent. 4. In inside-out patches,
      the two openers activated the Kir6.2/SUR2A and Kir6.2/SUR2B channels with similar
      potency (approximately 50 nm). Both were almost 2 x more efficacious in opening
      the Kir6.2/SUR2B than the Kir6.2/SUR2A channel. 5. The results show that the
      novel dihydropyridine A-312110 is a potent K(ATP) channel opener with binding and
      channel-opening properties similar to those of P1075.

PMID- 15023855
TI  - Differential regulation of prostaglandin E biosynthesis by interferon-gamma in
      colonic epithelial cells.
AB  - 1. Cyclooxygenase (COX)-2 expression and activity in response to pro-inflammatory
      cytokines TNF alpha and IFN gamma was evaluated in the colonic epithelial cell
      line HT29 and the airway epithelial cell line A549. 2. TNF alpha induced
      concentration- and time-dependent upregulation of COX-2 mRNA, protein and
      prostaglandin (PG)E(2) synthesis. 3. Co-stimulation of TNF alpha with IFN gamma
      resulted in reduced COX-2 mRNA and protein expression. 4. IFN gamma had no effect
      on the stability of TNF alpha-induced COX-2 mRNA. 5. TNF alpha-induced PGE(2)
      biosynthesis was significantly enhanced by the simultaneous addition of IFN gamma
      and was COX-2 dependent. 6. The combination of IFN gamma and TNF alpha induced
      the microsomal prostaglandin E synthase (mPGES), comensurate with the enhanced
      PGE(2) synthesis. 7. These results suggest that, in terms of PGE(2) biosynthesis,
      IFN gamma plays a negative regulatory role at the level of COX-2 expression and a
      positive regulatory role at the level of mPGES expression. This may have
      important implications for the clinical use of IFN gamma in inflammatory
      diseases.

PMID- 15023856
TI  - Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor
      elacridar (GF1210918) in mice.
AB  - 1. Mefloquine is a chiral neurotoxic antimalarial agent showing stereoselective
      brain uptake in humans and rats. It is a substrate and an inhibitor of the efflux
      protein P-glycoprotein. 2. We investigated the stereoselective uptake and efflux
      of mefloquine in mice, and the consequences of the combination with an efflux
      protein inhibitor, elacridar (GF120918) on its brain transport. 3. Racemic
      mefloquine (25 mg kg(-1)) was administered intraperitoneally with or without
      elacridar (10 mg kg(-1)). Six to seven mice were killed at each of 11 time-points
      between 30 min and 168 h after administration. Blood and brain concentrations of
      mefloquine enantiomers were determined using liquid chromatography. 4. A three
      compartment model with zero-order absorption from the injection site was found to
      best represent the pharmacokinetics of both enantiomers in blood and brain. (
      )Mefloquine had a lower blood and brain apparent volume of distribution and a
      lower efflux clearance from the brain, resulting in a larger brain/blood ratio
      compared to (+)mefloquine. Elacridar did not modify blood concentrations or the
      elimination rate from blood for either enantiomers. However, cerebral AUC(inf) of
      both enantiomers were increased, with a stronger effect on (+)mefloquine. The
      efflux clearance from the brain decreased for both enantiomers, with a larger
      decrease for (+)mefloquine. 5. After administration of racemic mefloquine in
      mice, blood and brain pharmacokinetics are stereoselective, (+)mefloquine being
      excreted from brain more rapidly than its antipode, showing that mefloquine is a
      substrate of efflux proteins and that mefloquine enantiomers undergo efflux in a
      stereoselective manner. Moreover, pretreatment with elacridar reduced the brain
      efflux clearances with a more pronounced effect on (+)mefloquine.

PMID- 15023858
TI  - Absence of PAF actions increases angiogenesis.

PMID- 15023857
TI  - Multiple actions of anandamide on neonatal rat cultured sensory neurones.
AB  - 1. We have investigated the effects of the endocannabinoid anandamide (AEA) on
      neuronal excitability and vanilloid TRPV1 receptors in neonatal rat cultured
      dorsal root ganglion neurones. 2. Using whole-cell patch-clamp electrophysiology,
      we found that AEA inhibits high-voltage-activated Ca(2+) currents by 33+/-9%
      (five out of eight neurones) in the absence of the CB(1) receptor antagonist
      SR141716A (100 nM) and by 32+/-6% (seven out of 10 neurones) in the presence of
      SR141716A. 3. Fura-2 fluorescence Ca(2+) imaging revealed that AEA produced
      distinct effects on Ca(2+) transients produced by depolarisation evoked by 30 mM
      KCl. In a population of neurones of larger somal area (372+/-20 microM(2)), it
      significantly enhanced Ca(2+) transients (80.26+/-13.12% at 1 microM), an effect
      that persists after pertussis toxin pretreatment. In a population of neurones of
      smaller somal area (279+/-18 microM(2)), AEA significantly inhibits Ca(2+)
      transients (30.75+/-3.54% at 1 microM), an effect that is abolished by PTX
      pretreatment. 4. Extracellular application of 100 nM AEA failed to evoke TRPV1
      receptor inward currents in seven out of eight neurones that responded to
      capsaicin (1 microM), with a mean inward current of -0.94+/-0.21 nA. In contrast,
      intracellular application of 100 nM AEA elicited robust inward currents in
      approximately 62% of neurones, the mean population response was -0.85+/-0.21 nA.
      When AEA was applied to the intracellular environment with capsazepine (1
      microM), the mean population inward current was -0.01+/-0.01 nA. Under control
      conditions, mean population current fluctuations of -0.09+/-0.05 nA were
      observed.

PMID- 15023859
TI  - Raloxifene acutely suppresses ventricular myocyte contractility through
      inhibition of the L-type calcium current.
AB  - 1. The selective oestrogen (ER) receptor modulator, raloxifene, is widely used in
      the treatment of postmenopausal osteoporosis, but may also possess
      cardioprotective properties. We investigated whether it directly suppresses
      myocyte contractility through Ca(2+) channel antagonism in a similar way to
      17beta-oestradiol. 2. Cell shortening and Ca(2+) transients were measured in
      single guinea-pig ventricular myocytes field-stimulated (1 Hz, 37 degrees C) in a
      superfusion chamber. Electrophysiological recordings were performed using single
      electrode voltage-clamp. 3. Raloxifene decreased cell shortening (EC(50) 2.4
      microm) and the Ca(2+) transient amplitude (EC(50) 6.4 microm) in a concentration
      dependent manner. At a concentration of 1 microm, raloxifene produced a 33+/-2%
      (mean+/-s.e.m) and 24+/-2% reduction, respectively (P<0.001, n=14 for both
      parameters). 4. These inhibitory actions were not observed in myocytes that had
      been incubated with the specific antagonist, ICI 182,780 (10 microm) (n=11). 5.
      Raloxifene (1 microm) shortened action potential durations at 50 and 90%
      repolarisation (P<0.05 and <0.001, respectively; n=27) and decreased peak L-type
      Ca(2+) current by 45%, from -5.1+/-0.5 pA/pF to -2.8+/-0.3 pA/pF (P<0.001, n=18).
      6. Raloxifene did not significantly alter sarcoplasmic reticulum Ca(2+) content,
      as assessed by integrating the Na(+)/Ca(2+) exchanger currents following rapid
      caffeine application. 7. The present study provides evidence for direct
      inhibitory actions of raloxifene on ventricular myocyte contractility, mediated
      through Ca(2+) channel antagonism.

PMID- 15023860
TI  - Peripheral PACAP inhibits gastric acid secretion through somatostatin release in
      mice.
AB  - 1. Studies in rats suggest that PACAP modulates gastric acid secretion through
      the release of both histamine and somatostatin. 2. We characterized the effects
      of exogenous PACAP on gastric acid secretion in urethane-anesthetized mice
      implanted with a gastric cannula and in conscious 2-h pylorus ligated mice, and
      determined the involvement of somatostatin and somatostatin receptor type 2
      (SSTR2) by using somatostatin immunoneutralization, the SSTR2 antagonist, PRL
      2903, and SSTR2 knockout mice. 3. Urethane-anesthetized wild-type mice had low
      basal acid secretion (0.10+/-0.01 micromol (10 min)(-1)) compared with SSTR2
      knockout mice (0.93+/-0.07 micromol (10 min)(-1)). Somatostatin antibody and PRL
      2903 increased basal secretion in wild-type mice but not in SSTR2 knockout
      animals. 4. In wild-type urethane-anesthetized mice, PACAP-38 (3-270 microg kg(
      1) h(-1)) did not affect the low basal acid secretion, but inhibited the acid
      response to pentagastrin, histamine, and bethanechol. 5. In wild-type urethane
      anesthetized mice pretreated with somatostatin antibody or PRL-2903 and in SSTR2
      knockout mice, peripheral infusion of PACAP-38 or somatostatin-14 did not inhibit
      the increased basal gastric acid secretion. 6. In conscious wild-type mice, but
      not in SSTR2 knockout mice, PACAP-38 inhibited gastric acid secretion induced by
      2-h pylorus ligation. The antisecretory effect of PACAP-38 was prevented by
      immunoneutralization of somatostatin. 7. These results indicate that, in mice,
      peripheral PACAP inhibits gastric acid secretion through the release of
      somatostatin and the activation of SSTR2 receptors. There is no evidence for
      stimulatory effects of PACAP on acid secretion in mice.

PMID- 15023861
TI  - Membrane-association and the sensitivity of guanylyl cyclase-coupled receptors to
      nitric oxide.
AB  - Nitric oxide (NO) signal transduction occurs through guanylyl cyclase-coupled
      receptors, which exist in both cytosolic and membranous locations. It has
      recently been reported from experiments using heart tissue that the membrane
      associated receptor has enhanced sensitivity to NO. Owing to its potential
      importance, we tested this finding using a method of applying NO in known,
      constant concentrations. The results showed that the concentration-response
      curves for receptor activation in cytosolic and membrane preparations of two
      different tissues (cerebellum and platelets) were indistinguishable. In all
      cases, half-maximal activation required about 1 nM NO and the curves had Hill
      coefficients of close to 1. The differential sensitivity reported for the heart
      is attributed to NO being scavenged by myoglobin in the cytosol, but not in the
      membrane fraction.

PMID- 15023862
TI  - P2X7 receptors stimulate AKT phosphorylation in astrocytes.
AB  - 1. Emerging evidence indicates that nucleotide receptors are widely expressed in
      the nervous system. Here, we present evidence that P2Y and P2X receptors,
      particularly the P2X(7) subtype, are coupled to the phosphoinositide 3-kinase
      (PI3K)/Akt pathway in astrocytes. 2. P2Y and P2X receptor agonists ATP, uridine
      5'-triphosphate (UTP) and 2',3'-O-(4-benzoyl)-benzoyl ATP (BzATP) stimulated Akt
      phosphorylation in primary cultures of rat cortical astrocytes. BzATP induced Akt
      phosphorylation in a concentration- and time-dependent manner, similar to the
      effect of BzATP on Akt phosphorylation in 1321N1 astrocytoma cells stably
      transfected with the rat P2X(7) receptor. Activation was maximal at 5 - 10 min
      and was sustained for 60 min; the EC(50) for BzATP was approximately 50 microM.
      In rat cortical astrocytes, the positive effect of BzATP on Akt phosphorylation
      was independent of glutamate release. 3. The effect of BzATP on Akt
      phosphorylation in rat cortical astrocytes was significantly reduced by the
      P2X(7) receptor antagonist Brilliant Blue G and the P2X receptor antagonist iso
      pyridoxal-5'-phosphate-6-azophenyl-2',4'-disulfonic acid, but was unaffected by
      trinitrophenyl-ATP, oxidized ATP, suramin and reactive blue 2. 4. Results with
      specific inhibitors of signal transduction pathways suggest that extracellular
      and intracellular calcium, PI3K and a Src family kinase are involved in the BzATP
      induced Akt phosphorylation pathway. 5. In conclusion, our data indicate that
      stimulation of astrocytic P2X(7) receptors, as well as other P2 receptors, leads
      to Akt activation. Thus, signaling by nucleotide receptors in astrocytes may be
      important in several cellular downstream effects related to the Akt pathway, such
      as cell cycle and apoptosis regulation, protein synthesis, differentiation and
      glucose metabolism.

PMID- 15023864
TI  - Role of the epithelium and acetylcholine in mediating the contraction to 5
      hydroxytryptamine in the mouse isolated trachea.
AB  - 1. The 5-HT receptor subtype that mediates bronchocontraction and the involvement
      of neuronal and non-neuronal acetylcholine was assessed in murine isolated
      tracheae. 2. Atropine (1-10 nM) caused a rightward shift of the methacholine
      concentration-effect curves (pA(2)=9.0) but reduced the maximum response to 5-HT,
      suggesting that 5-HT acts as an indirect agonist. The potency of 5-HT receptor
      agonists (alpha-methyl-5-HT approximately 5-HT>5-carboxamidotryptamine), together
      with the competitive antagonism of 5-HT by ketanserin (pA(2)=9.4), suggests the
      involvement of the 5-HT(2A) receptor. 3. While cholinergic twitch responses to
      electrical field stimulation were abolished by the fast sodium channel inhibitor
      tetrodotoxin (300 nM), as well as by combined blockade of N-, P- and Q-type
      voltage-operated calcium channels by omega-conotoxin GVIA (30 nM) and agatoxin
      IVA (100 nM), responses to 5-HT were unaffected. Similarly, botulinum toxin A (50
      nM) inhibited EFS twitch responses, but not contractions to 5-HT. 4. Choline
      acetyltransferase immunoreactivity was localised to ganglia and nerve fibres as
      well as approximately half the epithelial cells in the preparation. Removal of
      the epithelial layer markedly attenuated the contractile response to 5-HT, but
      had no effect on contractions to either methacholine or EFS. 5. These findings
      suggest that 5-HT, acting at 5-HT(2A) receptors on mouse tracheal epithelial
      cells, stimulates these cells to release acetylcholine, which then causes
      contraction of airway smooth muscle. This phenomenon should be borne in mind in
      when interpreting studies of murine models of airway disease.

PMID- 15023863
TI  - Identification in human airways smooth muscle cells of the prostanoid receptor
      and signalling pathway through which PGE2 inhibits the release of GM-CSF.
AB  - 1. The prostanoid receptor(s) on human airways smooth muscle (HASM) cells that
      mediates the inhibitory effect of PGE(2) on interleukin (IL)-1 beta-induced
      granulocyte/macrophage colony-stimulating factor (GM-CSF) release has been
      classified. 2. IL-1 beta evoked the release of GM-CSF from HASM cells, which was
      suppressed by PGE(2), 16,16-dimethyl PGE(2) (nonselective), misoprostol
      (EP(2)/EP(3)-selective), ONO-AE1-259 and butaprost (both EP(2)-selective) with
      pIC(50) values of 8.61, 7.13, 5.64, 8.79 and 5.43, respectively. EP-receptor
      agonists that have selectivity for the EP(1)-(17-phenyl-omega-trinor PGE(2)) and
      EP(3)-receptor (sulprostone) subtypes as well as cicaprost (IP-selective),
      PGD(2), PGF(2 alpha) and U-46619 (TP-selective) were poorly active or inactive at
      concentrations up to 10 microM. 3. AH 6809, a drug that can be used to
      selectively block EP(2)-receptors in HASM cells, antagonised the inhibitory
      effect of PGE(2), 16,16-dimethyl PGE(2) and ONO-AE1-259 with apparent pA(2)
      values of 5.85, 6.09 and 6.1 respectively. In contrast, the EP(4)-receptor
      antagonists, AH 23848B and L-161,982, failed to displace to the right the
      concentration-response curves that described the inhibition of GM-CSF release
      evoked by PGE(2) and ONO-AE1-259. 4. Inhibition of GM-CSF release by PGE(2) and 8
      Br-cAMP was abolished in cells infected with an adenovirus vector encoding an
      inhibitor protein of cAMP-dependent protein kinase (PKA) but not by H-89, a
      purported small molecule inhibitor of PKA. 5. We conclude that prostanoid
      receptors of the EP(2)-subtype mediate the inhibitory effect of PGE(2) on GM-CSF
      release from HASM cells by recruiting a PKA-dependent pathway. In addition, the
      data illustrate that caution should be exercised when using H-89 in studies
      designed to assess the role of PKA in biological processes.

PMID- 15023865
TI  - Sponge-induced angiogenesis and inflammation in PAF receptor-deficient mice (PAFR
      KO).
AB  - 1. To determine biological functions of platelet-activating factor (PAF) in
      chronic inflammation, we have investigated the kinetics of angiogenesis,
      inflammatory cells recruitment and cytokine production in sponge-induced
      granuloma in wild type and PAF receptor-deficient mice (PAFR-KO). 2. Angiogenesis
      as determined by morphometric analysis and hemoglobin content was significantly
      higher in the implants of PAFR-KO mice at all time points. Treatment with PAF
      receptor antagonist UK74505 (30 mg kg(-1)) also increased angiogenesis in sponge
      implants. 3. Neutrophils and macrophages accumulation, as determined by
      myeloperoxidase and N-acetylglucosaminidase activities in the supernatant of
      implanted sponges were markedly decreased in PAFR-KO mice. Surprisingly, the
      levels of the proinflammatory chemokines, keratinocyte-derived chemokine and
      chemokine monocyte chemoattractant protein 1 were higher in the implants of the
      transgenic animals. 4. We have shown that angiogenesis was stimulated in PAFR-KO
      mice whereas inflammation was decreased, indicating that PAF is an endogenous
      regulator of new blood vessels formation in the inflammatory microenvironment
      induced by the sponge implant.

PMID- 15023867
TI  - Relation between pulmonary vein firing and extent of left atrial-pulmonary vein
      connection in patients with atrial fibrillation.
AB  - BACKGROUND: The purpose of this study was to measure the extent of left atrial
      pulmonary vein (LA-PV) connections and determine the relation to PV firing in
      patients with atrial fibrillation (AF). METHODS AND RESULTS: Ten close-bipolar (1
      mm-spacing) Lasso electrograms were recorded circumferentially around 210 PVs
      (excluding 2 right middle PVs and 4 left common trunks) in 62 patients with AF.
      PV firing was provoked by isoproterenol (4 microg/min) and cardioversion of
      pacing-induced AF. The width of each LA-PV connection was measured in tenths of
      PV circumference, based on number of continuous close-bipolar Lasso electrode
      sites required for ablation (10% for each close-bipolar electrode site). One, 2,
      or 3 to 4 discrete LA-PV connections (discrete connection defined by ablation
      along 10% to 30% of PV circumference) were present in 18 (9%), 31 (14%), and 32
      (15%) of 210 PVs, respectively: 1 broad connection (ablation along continuous 40%
      to 80% circumference) in 46 (22%) PVs; 1 broad plus other broad or discrete
      connections in 54 (26%) PVs; and a circumferential connection (ablation along 90%
      to 100%) in 29 (14%) PVs. Circumferential LA-PV connections were more common in
      superior than in inferior PVs (20% versus 7%, P<0.01). There was no major
      difference in distribution of the other types of LA-PV connections between the
      four PVs. PV firing occurred in 27%, 47%, and 72% of PVs with discrete only,
      broad and circumferential connections, respectively (P<0.01). Dissociated PV
      potentials after isolation were more common in arrhythmogenic (firing) PVs (32%
      versus 8%, P<0.01). CONCLUSIONS: The extent of LA-PV connections corresponds with
      arrhythmognesis. The incidence of PV firing increases with progressively wider LA
      PV connections (discrete versus broad versus circumferential).

PMID- 15023866
TI  - Neurokinin NK1 and NK3 receptors as targets for drugs to treat gastrointestinal
      motility disorders and pain.
AB  - NK1 and NK3 receptors do not appear to play significant roles in normal GI
      functions, but both may be involved in defensive or pathological processes. NK1
      receptor antagonists are antiemetic, operating via vagal sensory and motor
      systems, so there is a need to study their effects on other gastro-vagal
      functions thought to play roles in functional bowel disorders. Interactions
      between NK1 receptors and enteric nonadrenergic, noncholinergic motorneurones
      suggest a need to explore the role of this receptor in disrupted colonic
      motility. NK1 receptor antagonism does not exert consistent analgesic activity in
      humans, but similar studies have not been carried out against pain of GI origin,
      where NK1 receptors may have additional influences on mucosal inflammatory or
      "irritant" processes. NK3 receptors mediate certain disruptions of intestinal
      motility. The activity may be driven by tachykinins released from intrinsic
      primary afferent neurones (IPANs), which induce slow EPSP activity in connecting
      IPANs and hence, a degree of hypersensitivity within the enteric nervous system.
      The same process is also proposed to increase C-fibre sensitivity, either
      indirectly or directly. Thus, NK3 receptor antagonists inhibit intestinal
      nociception via a "peripheral" mechanism that may be intestine-specific. Studies
      with talnetant and other selective NK3 receptor antagonists are, therefore,
      revealing an exciting and novel pathway by which pathological changes in
      intestinal motility and nociception can be induced, suggesting a role for NK3
      receptor antagonism in irritable bowel syndrome.

PMID- 15023868
TI  - Improved survival with radial artery versus vein conduits in coronary bypass
      surgery with left internal thoracic artery to left anterior descending artery
      grafting.
AB  - BACKGROUND: Given its proven survival benefit, left internal thoracic artery to
      left anterior descending (LITA-LAD) grafting has become a fundamental part of
      CABG. This grafting also led to increased use of other arterial conduits, of
      which the radial artery is most popular. Whether radial grafting improves
      survival beyond that achieved by LITA-LAD alone is not known. METHODS AND
      RESULTS: We compared 6-year outcomes in propensity-matched CABG-LITA-LAD patients
      (925 each) divided into those with > or =1 radial grafts and those with vein-only
      grafting. Matched patients had essentially identical demographics, comorbidities,
      coronary disease, and operative data. Perioperative outcomes, including death
      (radial, 11 [1.2%]; vein, 10 [1.1%]), were similar for the 2 groups. Cumulative 0
      to 6-year survival was better for radial patients (risk ratio, 0.675),
      particularly after 3 years (P<0.03). Six-year survival in vein (86.8%) and radial
      (92.1%) patients indicated 67% greater overall vein mortality. Incidence rates of
      radial and vein repeated catheterization (190 of 925 [20.5%] versus 199 of 925
      [21.5%]) and revascularization (8.8% versus 8.5%) were similar. Angiography data
      in restudied symptomatic patients showed a trend for greater radial patency. Vein
      failure (66 of 161 [41%]) was significantly worse than radial failure (46 of 157
      [29.3%]) in patients receiving both types of grafts (P=0.039). CONCLUSIONS: Using
      radial as a second arterial conduit in CABG-LITA-LAD as opposed to vein grafting
      improves long-term outcomes as a result of decreased late deaths, especially
      after the third postoperative year.

PMID- 15023869
TI  - Fatty acid translocase/CD36 deficiency does not energetically or functionally
      compromise hearts before or after ischemia.
AB  - BACKGROUND: Evidence from humans suggests that fatty acid translocase (FAT)/CD36
      deficiency can lead to functionally and/or energetically compromised hearts, but
      the data are equivocal, and the subject remains controversial. In this report we
      assessed the contribution of FAT/CD36 to overall fatty acid oxidation rates in
      the intact heart and determined the effect of FAT/CD36 on energy metabolism
      during reperfusion of ischemic hearts. METHODS AND RESULTS: Isolated working
      hearts from wild-type and FAT/CD36-knockout (KO) mice were perfused with Krebs
      Henseleit solution containing 0.4 or 1.2 mmol/L [U-3H]palmitate, 5 mmol/L [U
      14C]glucose, 2.5 mmol/L calcium, and 100 microU/mL insulin at a preload pressure
      of 11.5 mm Hg and afterload pressure of 50 mm Hg. Hearts were aerobically
      perfused for 30 minutes or aerobically perfused for 30 minutes, followed by 18
      minutes of global no-flow ischemia and 40 minutes of aerobic reperfusion. Rates
      of fatty acid oxidation in FAT/CD36-KO hearts were significantly lower than in
      wild-type hearts at both concentrations of palmitate (0.4 or 1.2 mmol/L). In
      addition, hearts from FAT/CD36-KO mice displayed a compensatory increase in
      glucose oxidation rates. On aerobic reperfusion after ischemia, cardiac work of
      FAT/CD36-KO hearts recovered to the same extent as wild-type hearts. CONCLUSIONS:
      FAT/CD36-deficient hearts are not energetically or functionally compromised and
      are not more sensitive to ischemic injury because glucose oxidation can
      compensate for the loss of fatty acid-derived ATP.

PMID- 15023870
TI  - Cyclooxygenase-2 inhibitor treatment improves left ventricular function and
      mortality in a murine model of doxorubicin-induced heart failure.
AB  - BACKGROUND: Progression of heart failure after initial myocardial injury is
      mediated in part by various redundant inflammatory mediators, including the
      widely expressed cyclooxygenase-2 (COX-2). Because COX-2 inhibitors are useful in
      treating many inflammation-mediated diseases, we asked whether COX-2 inhibition
      can attenuate heart failure progression. METHODS AND RESULTS: Heart failure was
      experimentally induced in 100 mice by administration of doxorubicin (4 mg. kg(
      1). wk(-1) for 6 weeks). Beginning at day 42, mice were fed daily with either COX
      2 inhibitor-containing mice chow (n=50) or plain mice chow (controls; n=50). Left
      ventricular ejection fraction was evaluated as a measure of heart failure by a
      novel method of transthoracic echocardiography (with intravascular ultrasound
      catheters) at baseline and on days 42, 56, and 70. From baseline to study
      termination, left ventricular ejection fraction in COX-2 inhibitor-treated mice
      decreased significantly less than in control mice (9% versus 29%, P<0.01).
      Mortality was significantly lower for COX-2 inhibitor-treated mice than for
      control mice (18% versus 38%, P<0.01). These results were confirmed in a
      revalidation study in COX-2 inhibitor-treated mice (n=25) and controls (n=25).
      That study revealed that the hearts from control mice weighed roughly the same as
      hearts from COX-2 inhibitor-treated mice but showed more extensive signs of
      cardiomyopathy (as determined by pathological analysis by an independent, blinded
      observer) and higher levels of COX-2 proteins (as determined by immunoblotting
      [6442+/-1635 versus 4300+/-2408 arbitrary units, P<0.022]). CONCLUSIONS: COX-2
      inhibitors can attenuate the progression of heart failure in a murine model of
      doxorubicin-induced heart failure.

PMID- 15023871
TI  - C-reactive protein modulates risk prediction based on the Framingham Score:
      implications for future risk assessment: results from a large cohort study in
      southern Germany.
AB  - BACKGROUND: The Framingham Coronary Heart Disease (CHD) prediction score is
      recommended for global risk assessment in subjects prone to CHD. Recently, C
      reactive protein (CRP) has emerged as an independent predictor of CHD. We sought
      to assess the potential of CRP measurements to enhance risk prediction based on
      the Framingham Risk Score (FRS) in a large cohort of middle-aged men from the
      general population. METHODS AND RESULTS: We measured CRP and traditional
      cardiovascular risk factors at baseline in 3435 white men of German nationality,
      45 to 74 years of age. All men were drawn from 3 random samples of the general
      population in the Augsburg area located in Southern Germany in 1984 to 1985, 1989
      to 1990, and 1994 to 1995 (response rate, 80%), and the FRS was calculated in all
      of them. Outcome was defined as nonfatal and fatal coronary events, including
      sudden cardiac death. During an average follow-up of 6.6 years, a total of 191
      coronary events occurred. Cox regression showed a significant contribution of CRP
      to coronary event risk prediction independent of the FRS (P=0.0002). In
      stratified analysis for 5 categories of FRS, CRP significantly added prognostic
      information to the FRS in subjects in 2 intermediate risk categories (P=0.03 and
      P=0.02). CONCLUSIONS: Our results suggest that CRP enhances global coronary risk
      as assessed by the FRS, especially in intermediate risk groups. This might have
      implications for future risk assessment.

PMID- 15023872
TI  - Endothelial cell markers and the risk of coronary heart disease: the Prospective
      Epidemiological Study of Myocardial Infarction (PRIME) study.
AB  - BACKGROUND: Tissue factor pathway inhibitor (TFPI), von Willebrand factor (vWF),
      and thrombomodulin (TM) are 3 major hemostatic regulatory molecules synthesized
      by endothelium. Data from epidemiological studies aiming to evaluate the relation
      between plasma levels of these molecules and the development of coronary heart
      disease (CHD) are sparse or contradictory. METHODS AND RESULTS: We examined the
      association between these endothelial-cell markers and the incidence of fatal or
      nonfatal myocardial infarction (hard CHD) and stable or unstable angina (angina
      pectoris) in a prospective cohort (the PRIME Study) of nearly 10 000 healthy men
      recruited in France and Northern Ireland. We measured baseline plasma
      concentration of the free form of TFPI (f-TFPI), vWF, and the soluble form of TM
      (sTM) among 296 participants who subsequently developed CHD over the 5-year
      follow-up (158 with hard CHD and 142 with angina pectoris) and in 563 control
      subjects by use of a nested case-control design. Individuals with plasma vWF
      levels in the highest quartile showed a 3.04-fold increase in the risk of hard
      CHD compared with those in the lowest quartile (95% CI, 1.59 to 5.80).
      Individuals with f-TFPI levels below the 10th percentile had a 2.13-fold
      increased risk of hard CHD compared with those with levels above it (95% CI, 1.08
      to 4.18). The risk for both molecules persisted after control for inflammatory
      parameters. Individuals with vWF levels in the highest quartile and f-TFPI levels
      below the 10th percentile presented a 6.9-fold increased risk of hard CHD
      compared with those with vWF levels in the lowest quartile and f-TFPI levels
      above the 10th percentile (95% CI, 1.3 to 37.8). CONCLUSIONS: vWF and f-TFPI
      plasma levels were independent risk factors for hard CHD events.

PMID- 15023873
TI  - Shed membrane particles from T lymphocytes impair endothelial function and
      regulate endothelial protein expression.
AB  - BACKGROUND: Microparticles (MPs) are membrane vesicles with procoagulant and
      proinflammatory properties released during cell activation. The present study was
      designed to dissect the effects evoked by T lymphocyte-derived MPs on vascular
      function. METHODS AND RESULTS: MPs were produced by treatment of the human
      lymphoid CEM T cell line with actinomycin D or phytohemagglutinin. Incubation of
      mouse aortic rings with 30 nmol/L MPs resulted in a time-dependent impairment of
      acetylcholine-induced relaxation of precontracted vessels, with a maximal
      reduction after 24 hours. MPs also impaired shear stress-induced dilatation of
      mouse small mesenteric arteries by affecting the nitric oxide (NO) and
      prostacyclin but not the endothelium-derived hyperpolarizing factor components of
      the response. However, neither alteration of calcium signaling in response to
      agonists nor reduction of cyclooxygenase-1 expression accounted for the
      impairment of the NO and prostacyclin components of the endothelial response. The
      effect of MPs was rather because of a decrease in expression of endothelial NO
      synthase and an overexpression of caveolin-1. Furthermore, lymphocyte-derived MPs
      from diabetic patients or in vivo circulating MPs from either diabetic or HIV
      infected patients reduced endothelial NO synthase expression. Finally, the
      effects of MPs on endothelial cells were not driven through CD11a/CD18 adhesion
      molecules or the Fas/FasL pathway. CONCLUSIONS: MPs from T cells induce
      endothelial dysfunction in both conductance and resistance arteries by alteration
      of NO and prostacyclin pathways. MPs regulate protein expression for endothelial
      NO synthase and caveolin-1. These data contribute to a better understanding of
      the deleterious effects of enhanced circulating MPs observed in disorders with
      cardiovascular or immune complications.

PMID- 15023874
TI  - Red blood cell nitric oxide as an endocrine vasoregulator: a potential role in
      congestive heart failure.
AB  - BACKGROUND: A respiratory cycle for nitric oxide (NO) would involve the formation
      of vasoactive metabolites between NO and hemoglobin during pulmonary oxygenation.
      We investigated the role of these metabolites in hypoxic tissue in vitro and in
      vivo in healthy subjects and patients with congestive heart failure (CHF).
      METHODS AND RESULTS: We investigated the capacity for red blood cells (RBCs) to
      dilate preconstricted aortic rings under various O2 tensions. RBCs induced cyclic
      guanylyl monophosphate-dependent vasorelaxation during hypoxia (35+/-4% at 1% O2,
      4.7+/-1.6% at 95% O2; P<0.05). RBC-induced relaxations during hypoxia correlated
      with S-nitrosohemoglobin (SNO-Hb) (R2=0.88) but not iron nitrosylhemoglobin
      (HbFeNO) content. Relaxation responses for RBCs were compared with S
      nitrosoglutathione across a range of O2 tensions. The fold increases in
      relaxation evoked by RBCs were significantly greater at 1% and 2% O2 compared
      with relaxations induced at 95% (P<0.05), consistent with an allosteric mechanism
      of hypoxic vasodilation. We also measured transpulmonary gradients of NO
      metabolites in healthy control subjects and in patients with CHF. In CHF patients
      but not control subjects, levels of SNO-Hb increase from 0.00293+/-0.00089 to
      0.00585+/-0.00137 mol NO/mol hemoglobin tetramer (P=0.005), whereas HbFeNO
      decreases from 0.00361+/-0.00109 to 0.00081+/-0.00040 mol NO/mol hemoglobin
      tetramer (P=0.03) as hemoglobin is oxygenated in the pulmonary circulation. These
      metabolite gradients correlated with the hemoglobin O2 saturation gradient
      (P<0.05) and inversely with cardiac index (P<0.05) for both CHF patients and
      control subjects. CONCLUSIONS: We confirm that RBC-bound NO mediates hypoxic
      vasodilation in vitro. Transpulmonary gradients of hemoglobin-bound NO are
      evident in CHF patients and are inversely dependent on cardiac index. Hemoglobin
      may transport and release NO bioactivity to areas of tissue hypoxia or during
      increased peripheral oxygen extraction via an allosteric mechanism.

PMID- 15023875
TI  - Endothelial dysfunction and increased arterial intima-media thickness in children
      with type 1 diabetes.
AB  - BACKGROUND: Endothelial dysfunction may play a pathophysiological role in the
      development of atherosclerosis in subjects with type 1 diabetes. We examined
      whether alterations in vascular endothelial function exist in children with type
      1 diabetes and tested the hypothesis that endothelial dysfunction is associated
      with early structural atherosclerotic vascular changes in these children. METHODS
      AND RESULTS: Noninvasive ultrasound was used to measure brachial artery flow
      mediated dilation (FMD) responses and carotid artery intima-media thickness (IMT)
      in 75 children (mean age 11+/-2 years), 45 with type 1 diabetes (diabetes
      duration 4.4+/-2.9 years) and 30 healthy control children. Children with diabetes
      had lower peak FMD response (4.4+/-3.4% versus 8.7+/-3.6%, P<0.001) and increased
      IMT (P<0.001) compared with controls. Sixteen children with diabetes (36%) had
      endothelial dysfunction defined as total FMD response in the lowest decile for
      normal children. These children had increased carotid IMT (0.58+/-0.05 versus
      0.54+/-0.04 mm, P=0.01) and higher LDL cholesterol concentration (2.63+/-0.76
      versus 2.16+/-0.60 mmol/L, P=0.03) compared with diabetic children without
      endothelial dysfunction. Multivariate correlates of increased IMT included
      diabetes group (P=0.03), low FMD (P=0.03), and high LDL cholesterol (P=0.08).
      CONCLUSIONS: Impaired FMD response is a common manifestation in children with
      type 1 diabetes and is associated with increased carotid artery IMT. These data
      suggest that endothelial dysfunction in children with type 1 diabetes may
      predispose them to the development of early atherosclerosis.

PMID- 15023876
TI  - Initial experience with remote catheter ablation using a novel magnetic
      navigation system: magnetic remote catheter ablation.
AB  - BACKGROUND: Catheters are typically stiff and incorporate a pull-wire mechanism
      to allow tip deflection. While standing at the patient's side, the operator
      manually navigates the catheter in the heart using fluoroscopic guidance. METHODS
      AND RESULTS: A total of 42 patients (32 female; mean age, 55+/-15 years)
      underwent ablation of common-type (slow/fast) or uncommon-type (slow/slow)
      atrioventricular nodal reentrant tachycardia (AVNRT) with the use of the magnetic
      navigation system Niobe (Stereotaxis, Inc). It consists of 2 computer-controlled
      permanent magnets located on opposite sides of the patient, which create a
      steerable external magnetic field (0.08 T). A small magnet embedded in the
      catheter tip causes the catheter to align and to be steered by the external
      magnetic field. A motor drive advances or retracts the catheter, enabling
      complete remote navigation. Radiofrequency current was applied with the use of a
      remote-controlled 4-mm, solid-tip, magnetic navigation-enabled catheter (55
      degrees C, maximum 40 W, 60 seconds) in all patients. The investigators, who were
      situated in the control room, performed the ablation using a mean of 7.2+/-4.7
      radiofrequency current applications (mean fluoroscopy time, 8.9+/-6.2 minutes;
      procedure duration, 145+/-43 minutes). Slow pathway ablation was achieved in 15
      patients, whereas slow pathway modulation was the end point in the remaining
      patients. There were no complications. CONCLUSIONS: The Niobe magnetic navigation
      system is a new platform technology allowing remote-controlled navigation of an
      ablation catheter. In conjunction with a motor drive unit, this system was used
      successfully to perform completely remote-controlled mapping and ablation in
      patients with AVNRT.

PMID- 15023877
TI  - Progression of atherosclerosis as assessed by carotid intima-media thickness in
      patients with HIV infection.
AB  - BACKGROUND: HIV-infected patients may be at increased risk for coronary events.
      The purpose of this study was to identify predictors of carotid intima-media
      thickness (IMT) in HIV patients at baseline and to measure IMT progression over 1
      year. METHODS AND RESULTS: We measured blood lipids, inflammatory markers, and
      IMT in 148 HIV-infected adults (mean age, 45+/-8 years) and in 63 age- and sex
      matched HIV-uninfected control subjects. The mean duration of HIV infection was
      11 years, and the median duration of protease inhibitor treatment was 3.3 years.
      Mean baseline IMT was 0.91+/-0.33 mm in HIV patients and 0.74+/-0.17 mm in
      control subjects (P=0.0001). Multivariable predictors of baseline IMT in HIV
      patients were age (P<0.001), LDL cholesterol (P<0.001), cigarette pack-years
      (P=0.005), Latino race (P=0.062), and hypertension (P=0.074). When the control
      group was added to the analysis, HIV infection was an independent predictor of
      IMT (P=0.001). The rate of progression among the 121 HIV patients with a repeated
      IMT measurement at 1 year was 0.074+/-0.13 mm, compared with -0.006+/-0.05 mm in
      27 control subjects (P=0.002). Age (P<0.001), Latino race (P=0.02), and nadir CD4
      count < or =200 (P=0.082) were multivariable predictors of IMT progression.
      CONCLUSIONS: Carotid IMT is higher in HIV patients than in age-matched control
      subjects and progresses much more rapidly than previously reported rates in non
      HIV cohorts. In HIV patients, carotid IMT is associated with classic coronary
      risk factors and with nadir CD4 count < or =200, suggesting that immunodeficiency
      and traditional coronary risk factors may contribute to atherosclerosis.

PMID- 15023878
TI  - Targeted anticytokine therapy in patients with chronic heart failure: results of
      the Randomized Etanercept Worldwide Evaluation (RENEWAL).
AB  - BACKGROUND: Studies in experimental models and preliminary clinical experience
      suggested a possible therapeutic role for the soluble tumor necrosis factor
      antagonist etanercept in heart failure. METHODS AND RESULTS: Patients with New
      York Heart Association class II to IV chronic heart failure and a left
      ventricular ejection fraction < or =0.30 were enrolled in 2 clinical trials that
      differed only in the doses of etanercept used. In RECOVER, patients received
      placebo (n=373) or subcutaneous etanercept in doses of 25 mg every week (n=375)
      or 25 mg twice per week (n=375). In RENAISSANCE, patients received placebo
      (n=309), etanercept 25 mg twice per week (n=308), or etanercept 25 mg 3 times per
      week (n=308). The primary end point of each individual trial was clinical status
      at 24 weeks. Analysis of the effect of the 2 higher doses of etanercept on the
      combined outcome of death or hospitalization due to chronic heart failure from
      the 2 studies was also planned (RENEWAL). On the basis of prespecified stopping
      rules, both trials were terminated prematurely owing to lack of benefit.
      Etanercept had no effect on clinical status in RENAISSANCE (P=0.17) or RECOVER
      (P=0.34) and had no effect on the death or chronic heart failure hospitalization
      end point in RENEWAL (etanercept to placebo relative risk=1.1, 95% CI 0.91 to
      1.33, P=0.33). CONCLUSIONS: The results of RENEWAL rule out a clinically relevant
      benefit of etanercept on the rate of death or hospitalization due to chronic
      heart failure.

PMID- 15023879
TI  - Pregnancy-associated plasma protein A and its endogenous inhibitor, the proform
      of eosinophil major basic protein (proMBP), are related to complex stenosis
      morphology in patients with stable angina pectoris.
AB  - BACKGROUND: The metalloproteinase pregnancy-associated plasma protein-A (PAPP-A)
      has been implicated in coronary plaque disruption. Its endogenous inhibitor, the
      proform of eosinophil major basic protein (proMBP), may also play a role in this
      process. Atheromatous plaque disruption often presents as complex angiographic
      lesions. We sought to assess whether PAPP-A, proMBP, and PAPP-A/ProMBP ratio are
      markers of angiographic plaque complexity in patients with chronic stable angina.
      METHODS AND RESULTS: We studied 396 stable angina patients (age 63+/-10 years,
      230 men) of whom 289 had angiographically documented coronary artery disease (>
      or =75% stenosis). All coronary stenoses > or =30% diameter reduction (n =531 in
      322 patients) were assessed and classified as complex (n =228) or smooth (n =303)
      by previously validated criteria. PAPP-A, proMBP, and C-reactive protein (hs-CRP)
      serum levels were measured by ELISA. Patients with complex coronary stenoses had
      a significantly (P<0.001) higher PAPP-A/proMBP ratio (3.1+/-1.2 versus 2.7+/
      0.8x10(-3)) and PAPP-A levels (5.9+/-1.6 versus 5.1+/-1.4 mIU/L) than those
      without. On univariate analysis, male gender (P<0.001), age (P<0.001), previous
      history of myocardial infarction (P=0.013), reduced ejection fraction (P<0.001),
      severe coronary artery disease (P<0.001), aspirin treatment (P<0.001), PAPP-A
      levels (P<0.001), and PAPP-A/proMBP ratio (P<0.001) were correlated with the
      number of complex stenoses. Multiple regression analysis showed that male gender,
      age, severe coronary artery disease, and PAPP-A/proMBP ratio were independent
      predictors of the number of angiographically complex stenoses. CONCLUSIONS: In
      patients with stable angina, PAPP-A and PAPP-A/proMBP ratio are associated with
      angiographic plaque complexity.

PMID- 15023880
TI  - Characterization of left ventricular diastolic function by tissue Doppler imaging
      and clinical status in children with hypertrophic cardiomyopathy.
AB  - BACKGROUND: Conventional transmitral Doppler indices are unreliable in assessing
      clinical status in patients with hypertrophic cardiomyopathy (HCM) because they
      are affected by loading conditions. This study sought to determine whether tissue
      Doppler velocities are predictive of adverse clinical outcomes including death,
      cardiac arrest, ventricular tachycardia (VT), significant cardiac symptoms, and
      exercise capacity in children with HCM. METHODS AND RESULTS: We studied 80
      consecutive children (median age 12 years, median follow-up 26 months) evaluated
      at 1 hospital from January 1999 to August 2003 compared with 80 age- and gender
      matched controls. Patients underwent echocardiography, ambulatory Holter
      monitoring, and upright exercise testing. Children with HCM had significantly
      decreased early diastolic tissue Doppler velocities at the lateral mitral (13.2
      versus 19.3 cm/s), tricuspid (13.3 versus 16.3 cm/s), and septal (9.4 versus 13.5
      cm/s) annuli compared with controls (P<0.001 for each comparison). By forward
      stepwise regression analysis, early transmitral left ventricular filling velocity
      (E)/septal Ea ratio predicted death, cardiac arrest, or VT (r=0.610, R2=0.37,
      P<0.001). Peak oxygen consumption (VO2) was most predictive of children who
      developed symptoms (r=0.427, R2=0.182, P<0.001). Peak VO2 correlated inversely
      with E/Ea septal ratio (r=-0.740, P<0.01). CONCLUSIONS: Transmitral E/septal Ea
      ratio predicts children with HCM who are at risk of adverse clinical outcomes
      including death, cardiac arrest, VT, and significant cardiac symptoms. Peak VO2
      correlated with peak exercise capacity in HCM patients.

PMID- 15023881
TI  - Public access defibrillation in out-of-hospital cardiac arrest: a community-based
      study.
AB  - BACKGROUND: The dissemination and use of automated external defibrillators (AEDs)
      beyond traditional emergency medical services (EMS) into the community has not
      been fully evaluated. We evaluated the frequency and outcome of non-EMS AED use
      in a community experience. METHODS AND RESULTS: The investigation was a cohort
      study of out-of-hospital cardiac arrest cases due to underlying heart disease
      treated by public access defibrillation (PAD) between January 1, 1999, and
      December 31, 2002, in Seattle and surrounding King County, Washington. Public
      access defibrillation was defined as out-of-hospital cardiac arrest treated with
      AED application by persons outside traditional emergency medical services. The
      EMS of Seattle and King County developed a voluntary Community Responder AED
      Program and registry of PAD AEDs. During the 4 years, 475 AEDs were placed in a
      variety of settings, and more than 4000 persons were trained in cardiopulmonary
      resuscitation and AED operation. A total of 50 cases of out-of-hospital cardiac
      arrest were treated by PAD before EMS arrival, which represented 1.33% (50/3754)
      of all EMS-treated cardiac arrests. The proportion treated by PAD AED increased
      each year, from 0.82% in 1999 to 1.12% in 2000, 1.41% in 2001, and 2.05% in 2002
      (P=0.019, test for trend). Half of the 50 persons treated with PAD survived to
      hospital discharge, with similar survival for nonmedical settings (45% [14/31])
      and out-of-hospital medical settings (58% [11/19]). CONCLUSIONS: PAD was involved
      in only a small but increasing proportion of out-of-hospital cardiac arrests.

PMID- 15023882
TI  - Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is
      administered concomitantly for 5 weeks in patients with acute coronary syndromes.
AB  - BACKGROUND: The antiplatelet effect of clopidogrel may be attenuated by short
      term coadministration of lipophilic statins. We investigated whether the
      coadministration of atorvastatin for 5 weeks in patients with acute coronary
      syndromes (ACS) could affect the antiplatelet potency of clopidogrel. METHODS AND
      RESULTS: Forty-five hypercholesterolemic patients with the first episode of an
      ACS were included in the study. Patients were randomized to receive daily either
      10 mg of atorvastatin (n=21) or 40 mg of pravastatin (n=24). Thirty patients who
      underwent percutaneous coronary intervention (PCI) received a loading dose of 375
      mg of clopidogrel, followed by 75 mg/d for at least 3 months. In the remaining 15
      patients who refused to undergo PCI, clopidogrel therapy was not administered.
      Eight normolipidemic patients with the first episode of an ACS were also included
      and received only clopidogrel. The serum levels of soluble CD40L and the
      adenosine 5'-diphosphate- or thrombin receptor activating peptide-14-induced
      platelet aggregation, as well as P-selectin and CD40L surface expression, were
      studied at baseline (within 30 minutes after admission) and 5 weeks later.
      Neither atorvastatin nor pravastatin significantly influenced the clopidogrel
      induced inhibition of platelet activation, nor did clopidogrel influence the
      therapeutic efficacy of atorvastatin. CONCLUSIONS: Atorvastatin does not affect
      the antiplatelet potency of clopidogrel when coadministered for 5 weeks in ACS
      patients.

PMID- 15023883
TI  - Blood pressure and risk of secondary cardiovascular events in women: the Women's
      Antioxidant Cardiovascular Study (WACS).
AB  - BACKGROUND: In apparently healthy people, the relation between blood pressure and
      risk of subsequent cardiovascular disease (CVD) is linear. In persons with CVD,
      the relation is uncertain. METHODS AND RESULTS: We conducted a prospective study
      of 5218 older women with CVD who reported their blood pressure at baseline in the
      Women's Antioxidant Cardiovascular Study (WACS), an ongoing double-blind, placebo
      controlled secondary prevention trial of the benefits and risks of antioxidant
      vitamins, folic acid, vitamin B6, and vitamin B12 among women with CVD or > or =3
      coronary risk factors. A total of 661 confirmed CVD events (nonfatal myocardial
      infarction, nonfatal stroke, coronary artery bypass graft procedure, percutaneous
      coronary angioplasty, or CVD death) occurred during a median follow-up of 6.5
      years. After controlling for age, randomized treatment assignment,
      antihypertensive medication use, and coronary risk factors, we found that
      systolic blood pressure (SBP) was a strong predictor of CVD events and that the
      relation between SBP and CVD risk was positive, continuous, and linear (P for
      linear trend=0.001). For each 10-mm Hg increment in SBP, there was a 9% (95% CI
      4% to 15%) increase in risk of secondary CVD events. Diastolic blood pressure,
      mean arterial pressure, and pulse pressure were weaker predictors of CVD risk in
      this cohort, and joint consideration of SBP and diastolic blood pressure found
      that only SBP significantly predicted risk. Use of antihypertensive medication
      did not modify the relationship of SBP with CVD events. CONCLUSIONS: In this
      population of women with CVD, we observed a strong, continuous, and linear
      association between SBP and risk of secondary CVD events. SBP was the blood
      pressure measure most strongly related to CVD risk.

PMID- 15023884
TI  - Renin-angiotensin system gene polymorphisms and atrial fibrillation.
AB  - BACKGROUND: The activated local atrial renin-angiotensin system (RAS) has been
      reported to play an important role in the pathogenesis of atrial fibrillation
      (AF). We hypothesized that RAS genes might be among the susceptibility genes of
      nonfamilial structural AF and conducted a genetic case-control study to
      demonstrate this. METHODS AND RESULTS: A total of 250 patients with documented
      nonfamilial structural AF and 250 controls were selected. The controls were
      matched to cases on a 1-to-1 basis with regard to age, gender, presence of left
      ventricular dysfunction, and presence of significant valvular heart disease. The
      ACE gene insertion/deletion polymorphism, the T174M, M235T, G-6A, A-20C, G-152A,
      and G-217A polymorphisms of the angiotensinogen gene, and the A1166C polymorphism
      of the angiotensin II type I receptor gene were genotyped. In multilocus
      haplotype analysis, the angiotensinogen gene haplotype profile was significantly
      different between cases and controls (chi2=62.5, P=0.0002). In single-locus
      analysis, M235T, G-6A, and G-217A were significantly associated with AF.
      Frequencies of the M235, G-6, and G-217 alleles were significantly higher in
      cases than in controls (P=0.000, 0.005, and 0.002, respectively). The odds ratios
      for AF were 2.5 (95% CI 1.7 to 3.3) with M235/M235 plus M235/T235 genotype, 3.3
      (95% CI 1.3 to 10.0) with G-6/G-6 genotype, and 2.0 (95% CI 1.3 to 2.5) with G
      217/G-217 genotype. Furthermore, significant gene-gene interactions were detected
      by the multifactor-dimensionality reduction method and multilocus linkage
      disequilibrium tests. CONCLUSIONS: This study demonstrates the association of RAS
      gene polymorphisms with nonfamilial structural AF and may provide the rationale
      for clinical trials to investigate the use of ACE inhibitor or angiotensin II
      antagonist in the treatment of structural AF.

PMID- 15023885
TI  - Midterm benefits of left univentricular pacing in patients with congestive heart
      failure.
AB  - BACKGROUND: Resynchronization therapy by simultaneous pacing of the right and
      left ventricles has gained wide acceptance as a useful treatment for patients
      with severe congestive heart failure. Several short-term hemodynamic studies in
      humans and animals failed to demonstrate any benefit of biventricular pacing over
      left univentricular pacing, but long-term studies on this pacing mode are
      lacking. The objective of this study was to assess the outcome over a 1-year
      period of patients paced exclusively in the left ventricle. METHODS AND RESULTS:
      Clinical, angiographic, echocardiographic, and ergometric data were collected at
      baseline and after 12 months in 22 patients (age, 69.3+/-6.5 years) with NYHA
      class III or IV (10 patients), sinus rhythm, left bundle-branch block, and no
      bradycardia indication for pacing. After 12 months, compared with baseline
      values, NYHA class improved significantly by 40% (P<0.0001), 6-minute walk
      distance by 30% (P=0.01), peak VO2 by 26% (P=0.01), left ventricular end
      diastolic diameter by 5% (P=0.02), ejection fraction by 22% (P=0.07), mitral
      regurgitation area by 40% (P=0.01), and norepinephrine level by 37% (P=0.04).
      CONCLUSIONS: In patients with severe congestive heart failure, sinus rhythm, and
      left bundle-branch block despite optimal pharmacological treatment, left
      univentricular pacing is feasible and results in significant midterm benefit in
      exercise tolerance and left ventricular function.

PMID- 15023886
TI  - Catheter-based cryoablation permanently cures patients with common atrial
      flutter.
AB  - BACKGROUND: Cryoablation (cryo) has a high success rate in the short-term
      treatment of atrial flutter (AFL), but evidence of long-term efficacy is lacking.
      The present study reports the long-term effect of cryo of the cavotricuspid
      isthmus (CTI) in patients with common AFL. METHODS AND RESULTS: Thirty-five
      consecutive patients (28 men; mean age, 53 years) underwent cryo of the CTI. In
      34 patients, the AFL had a counterclockwise rotation (cycle length, 242+/-43 ms).
      Eleven patients had structural heart disease. Cryo was performed with a 10F
      catheter with a 6-mm-tip electrode (CryoCor). Applications (3 to 5 minutes each)
      were delivered by use of a point-by-point technique to create the ablation line.
      The acute end point of the procedure was creation of bidirectional isthmus
      conduction block and noninducibility of AFL. A median of 14 applications (range,
      4 to 30) at 10 sites (range, 4 to 19) was given along the CTI with a mean
      temperature of -80.0+/-5.0 degrees C. Mean fluoroscopy and procedure times were
      40+/-26 minutes and 3.2+/-1.3 hours, respectively. Of the 35 patients, 34 were
      acutely successfully ablated (97%). After a mean follow-up of 17.6+/-6.2 months
      (range, 9.6 to 26.1 months), 31 patients (89%) did not have recurrence of AFL.
      Three of the 4 patients with recurrence had a second successful procedure. One
      patient had transient ST elevation in the inferior leads during cryoapplication.
      CONCLUSIONS: Cryo produces permanent bidirectional isthmus conduction block of
      the CTI. Short- and long-term success rates are comparable to those for
      radiofrequency ablation.

PMID- 15023887
TI  - Human mesenchymal stem cells form Purkinje fibers in fetal sheep heart.
AB  - BACKGROUND: We have investigated the usefulness of a model of cardiac development
      in a large mammal, sheep, for studies of engraftment of human stem cells in the
      heart. METHODS AND RESULTS: Adult and fetal human mesenchymal stem cells were
      injected intraperitoneally into sheep fetuses in utero. Hearts at late fetal
      development were analyzed for engraftment of human cells. The majority of the
      engrafted cells of human origin formed segments of Purkinje fibers containing
      exclusively human cells. There were no differences in engraftment of human
      mesenchymal stem cells from adult bone marrow, fetal brain, and fetal liver. On
      average, 43.2% of the total Purkinje fibers in random areas (n=11) of both
      ventricles were of human origin. In contrast, approximately 0.01% of
      cardiomyocytes were of human origin. CONCLUSIONS: Human mesenchymal stem cells
      preferentially engraft at high levels in the ventricular conduction system during
      fetal development in sheep. These findings raise the possibility that stem cells
      contribute to normal development of the fetal heart.

PMID- 15023888
TI  - PR39 inhibits apoptosis in hypoxic endothelial cells: role of inhibitor apoptosis
      protein-2.
AB  - BACKGROUND: PR39 is a proline- and arginine-rich peptide implicated in wound
      healing and myocardial ischemia protection. To determine the potential mechanisms
      of PR39 in ischemia, we examined the role of PR39 in hypoxia-induced apoptosis in
      vascular endothelial cells. METHODS AND RESULTS: Hypoxia results in an increase
      of apoptosis in bovine aortic endothelial cells (BAECs), as determined by
      terminal deoxynucleotidyl transferase-mediated dUTP biotin nick-end labeling
      (TUNEL) analysis and caspase-3 activity. Hypoxia induced 66.2+/-2.7% TUNEL
      positive cells, whereas in the presence of synthesized PR39 peptide, TUNEL
      positive cells were reduced to 29.6+/-1.9% (P<0.05). After 24 hours of hypoxia,
      the addition of PR39 reduced caspase-3 activity to 3.17+/-0.47 pMol/min from
      10.52+/-0.55 pMol/min in hypoxic BAECs. Moreover, PR39 increased inhibitor of
      apoptosis protein-2 (IAP-2) gene and protein expression by 3-fold in a time- and
      dose-dependent manner. The induction of IAP-2 by PR39 conferred an increase in
      IAP-2 gene transcription and IAP-2 mRNA stability. Furthermore, inhibiting IAP-2
      with second mitochondria-derived activator of caspase (Smac) and with small
      interfering RNA targeting IAP-2 abrogated the ability of PR39 to reduce caspase-3
      activity. CONCLUSIONS: We provide the first direct evidence for PR39 as an
      antiapoptotic factor in endothelial cells during hypoxia. These data suggest that
      PR39 inhibits hypoxia-induced apoptosis and decreases caspase-3 activity in
      endothelial cells through an increase of IAP-2 expression.

PMID- 15023889
TI  - CD44 regulates arteriogenesis in mice and is differentially expressed in patients
      with poor and good collateralization.
AB  - BACKGROUND: Arteriogenesis refers to the development of collateral conductance
      arteries and is orchestrated by circulating monocytes, which invade growing
      collateral arteries and act as suppliers of cytokines and growth factors. CD44
      glycoproteins are involved in leukocyte extravasation but also in the regulation
      of growth factor activation, stability, and signaling. Here, we explored the role
      of CD44 during arteriogenesis. METHODS AND RESULTS: CD44 expression increases
      strongly during collateral artery growth in a murine hind-limb model of
      arteriogenesis. This CD44 expression is of great functional importance, because
      arteriogenesis is severely impaired in CD44-/- mice (wild-type, 54.5+/-14.9%
      versus CD44-/-, 24.1+/-9.2%, P<0.001). The defective arteriogenesis is
      accompanied by reduced leukocyte trafficking to sites of collateral artery growth
      (wild-type, 29+/-12% versus CD44-/-, 18+/-7% CD11b-positive cells/square, P<0.01)
      and reduced expression of fibroblast growth factor-2 and platelet-derived growth
      factor-B protein. Finally, in patients with single-vessel coronary artery
      disease, the maximal expression of CD44 on activated monocytes is reduced in case
      of impaired collateral artery formation (poor collateralization, 1764+/-572
      versus good collateralization, 2817+/-1029 AU, P<0.05). CONCLUSIONS: For the
      first time, the pivotal role of CD44 during arteriogenesis is shown. The
      expression of CD44 increases during arteriogenesis, and the deficiency of CD44
      severely impedes arteriogenesis. Maximal CD44 expression on isolated monocytes is
      decreased in patients with a poor collateralization compared with patients with a
      good collateralization.

PMID- 15023890
TI  - Brain natriuretic peptide enhances renal actions of furosemide and suppresses
      furosemide-induced aldosterone activation in experimental heart failure.
AB  - BACKGROUND: The renal actions of brain natriuretic peptide (BNP) in congestive
      heart failure (CHF) are associated with increased diuresis and natriuresis,
      preserved glomerular filtration rate (GFR), and lack of activation of the renin
      angiotensin-aldosterone system (RAAS). In contrast, diuretic-induced natriuresis
      may be associated with reduced GFR and RAAS activation. The objective of this
      study was to test the hypothesis that exogenous BNP enhances the renal diuretic
      and natriuretic actions of furosemide (Fs) and retards the activation of
      aldosterone in a model of CHF. METHODS AND RESULTS: CHF was produced in 2 groups
      of dogs by ventricular pacing. One group received continuous (90-minute)
      intravenous Fs (1 mg x kg(-1) x h(-1)). A second group (Fs+BNP) received 45
      minute intravenous coinfusion of Fs (1 mg x kg(-1) x h(-1)) and low-dose (2 pmol
      x kg(-1) x min(-1)) BNP followed by 45-minute coinfusion of Fs (1 mg x kg(-1) x
      h(-1)) and high-dose (10 pmol x kg(-1) x min(-1)) BNP. Fs increased urinary flow,
      but the effect of Fs+BNP was greater. Similarly, urinary sodium excretion was
      higher in the Fs+BNP group. Although GFR tended to decrease in the Fs group, it
      increased in the Fs+BNP group (35+/-3 to 56+/-4*) (* indicates P<0.05 versus
      baseline) (P<0.0001 between groups). Plasma aldosterone increased with Fs (41+/
      10 to 100+/-11* ng/dL) but was attenuated in the Fs+BNP group (44+/-11 to 54+/-9
      ng/dL low-dose and to 47+/-7 ng/dL high-dose) (P=0.0007 between groups).
      CONCLUSIONS: Fs+BNP has more profound diuretic and natriuretic responses than Fs
      alone and also increases GFR without activation of aldosterone. Coadministration
      of BNP and loop diuretic is effective in maximizing natriuresis and diuresis
      while preserving renal function and inhibiting activation of aldosterone.

PMID- 15023891
TI  - Local delivery of marrow-derived stromal cells augments collateral perfusion
      through paracrine mechanisms.
AB  - BACKGROUND: Bone marrow cell therapy is reported to contribute to collateral
      formation through cell incorporation into new or remodeling vessels. However, the
      possible role of a paracrine contribution to this effect is less well
      characterized. METHODS AND RESULTS: Murine marrow-derived stromal cells (MSCs)
      were purified by magnetic bead separation of cultured bone marrow. The release of
      vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF),
      placental growth factor (PlGF), and monocyte chemoattractant protein-1 (MCP-1)
      was demonstrated by analysis of MSC conditioned media (MSC-CM). MSC-CM enhanced
      proliferation of endothelial cells and smooth muscle cells in a dose-dependent
      manner; anti-VEGF and anti-FGF antibodies only partly attenuated these effects.
      Balb/C mice (n=10) underwent distal femoral artery ligation, followed by adductor
      muscle injection of 1x10(6) MSCs 24 hours later. Compared with controls injected
      with media (n=10) or mature endothelial cells (n=8), distal limb perfusion
      improved, and mid-thigh conductance vessels increased in number and total cross
      sectional area. MSC injection improved limb function and appearance, reduced the
      incidence of auto-amputation, and attenuated muscle atrophy and fibrosis. After
      injection, labeled MSCs were seen dispersed between muscle fibers but were not
      seen incorporated into mature collaterals. Injection of MSCs increased adductor
      muscle levels of bFGF and VEGF protein compared with controls. Finally,
      colocalization of VEGF and transplanted MSCs within adductor tissue was
      demonstrated. CONCLUSIONS: MSCs secrete a wide array of arteriogenic cytokines.
      MSCs can contribute to collateral remodeling through paracrine mechanisms.

PMID- 15023893
TI  - Repetitive 4-week periods of atrial electrical remodeling promote stability of
      atrial fibrillation: time course of a second factor involved in the self
      perpetuation of atrial fibrillation.
AB  - BACKGROUND: Episodes of atrial fibrillation (AF) are known to cause both a rapid
      reduction in atrial refractoriness (atrial electrical remodeling) and a more
      delayed increase in AF stability thought to be due to a so-called "second
      factor." The aim of this study was to quantify the effects and time course of
      such a factor on AF stability in the chronic goat model. METHODS AND RESULTS: AF
      was maintained in 6 goats by burst atrial pacing for 3 consecutive 4-week periods
      separated a mean of 6+/-2.1 days of sinus rhythm. Six days of sinus rhythm was
      just sufficient for refractoriness changes to reverse fully in all goats. Atrial
      effective refractory period, AF inducibility, and duration of individual episodes
      of AF were assessed at regular intervals. There was a progressive reduction from
      month 1 to 2 to 3 in the mean duration of burst pacing required to induce
      individual episodes of AF of 60 seconds (178+/-251, 110+/-102, and 21+/-30
      hours), 1 hour (229+/-224, 136+/-104, and 68+/-51 hours), and 24 hours (277+/
      218, 192+/-190, and 102+/-75 hours; P<0.03). The frequency with which AF was
      induced during extrastimulus pacing increased progressively from 16.7% in month 1
      to 31.7% in month 2 and 46.9% in month 3 (P<0.001). CONCLUSIONS: Sequential 4
      week periods of atrial fibrillation result in a progressive increase in AF
      stability independent of baseline atrial refractory period. This finding suggests
      the presence of a second factor in the self-perpetuation of AF with a time course
      comparable to that of AF-induced ultrastructural changes in the atria.

PMID- 15023892
TI  - Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis.
AB  - BACKGROUND: It remains controversial whether specific blockade of the renin
      angiotensin system confers superior antiatherosclerotic effects over other
      antihypertensive agents in diabetes. Therefore, the aim of this study was to
      compare equihypotensive doses of the angiotensin II subtype 1 (AT1) receptor
      blocker irbesartan with the calcium antagonist amlodipine on diabetes-induced
      plaque formation in the apolipoprotein E (apoE)-null mouse and to explore
      molecular and cellular mechanisms linked to vascular protection. METHODS AND
      RESULTS: Diabetes was induced by injection of streptozotocin in 6-week-old apoE
      null mice. Diabetic animals were randomized to no treatment, irbesartan, or
      amlodipine for 20 weeks. Diabetes was associated with an increase in plaque area
      and complexity in the aorta in association with a significant increase in aortic
      AT1 receptor expression, cellular proliferation, collagen content, macrophage-
      and alpha-smooth muscle actin-positive cell infiltration, as well as an increased
      expression of platelet-derived growth factor-B (PDGF-B), monocyte chemoattractant
      protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1). Irbesartan but
      not amlodipine treatment attenuated the development of atherosclerosis, collagen
      content, cellular proliferation, and macrophage infiltration as well as diabetes
      induced AT1 receptor, PDGF-B, MCP-1, and VCAM-1 overexpression in the aorta
      despite similar blood pressure reductions by both treatments. CONCLUSIONS:
      Diabetes-associated atherosclerosis is ameliorated by AT1 receptor blockade but
      not by calcium channel antagonism, providing further evidence for the vascular
      renin-angiotensin system playing a pivotal role in the development and
      acceleration of atherosclerosis in diabetes.

PMID- 15023895
TI  - Off-pump coronary artery bypass surgery: fundamentals for the clinical
      cardiologist.

PMID- 15023894
TI  - Inhibitors of protein kinase signaling pathways: emerging therapies for
      cardiovascular disease.
AB  - Protein kinases are enzymes that covalently modify proteins by attaching
      phosphate groups (from ATP) to serine, threonine, and/or tyrosine residues. In so
      doing, the functional properties of the protein kinase's substrates are modified.
      Protein kinases transduce signals from the cell membrane into the interior of the
      cell. Such signals include not only those arising from ligand-receptor
      interactions but also environmental perturbations such as when the membrane
      undergoes mechanical deformation (ie, cell stretch or shear stress). Ultimately,
      the activation of signaling pathways that use protein kinases often culminates in
      the reprogramming of gene expression through the direct regulation of
      transcription factors or through the regulation of mRNA stability or protein
      translation. Protein kinases regulate most aspects of normal cellular function.
      The pathophysiological dysfunction of protein kinase signaling pathways underlies
      the molecular basis of many cancers and of several manifestations of
      cardiovascular disease, such as hypertrophy and other types of left ventricular
      remodeling, ischemia/reperfusion injury, angiogenesis, and atherogenesis. Given
      their roles in such a wide variety of disease states, protein kinases are rapidly
      becoming extremely attractive targets for drug discovery, probably second only to
      heterotrimeric G protein-coupled receptors (eg, angiotensin II). Here, we will
      review the reasons for this explosion in interest in inhibitors of protein
      kinases and will describe the process of identifying novel drugs directed against
      kinases. We will specifically focus on disease states for which drug development
      has proceeded to the point of clinical or advanced preclinical studies.

PMID- 15023896
TI  - Cardiology patient page. Heart disease prevention in women. American Heart
      Association.

PMID- 15023897
TI  - Images in cardiovascular medicine. Percutaneous aortic valve replacement in
      animals.

PMID- 15023898
TI  - Breast-feeding may reduce later blood pressure.

PMID- 15023899
TI  - What's wrong with CME?

PMID- 15023902
TI  - Small medical journals and the 10/90 problem: Educatione ad excellentiam.

PMID- 15023903
TI  - Mild SARS in elderly patients.

PMID- 15023904
TI  - Grading evidence.

PMID- 15023906
TI  - Rehabilitation in developing countries.

PMID- 15023907
TI  - SARS and the removal of personal protective equipment.

PMID- 15023909
TI  - New free trade agreement could make generic drugs less accessible in the
      Americas.

PMID- 15023910
TI  - FTAA could interfere with proposed Canadian patent legislation allowing generic
      exports.

PMID- 15023911
TI  - Spanish journal wins lawsuit over COX-2 drug editorial.

PMID- 15023912
TI  - Pandemic plan: is the vaccine supply secure?

PMID- 15023913
TI  - Natural health products: new labels, new credibility?

PMID- 15023915
TI  - Internet pharmacy: prices on the up-and-up.

PMID- 15023916
TI  - Internet pharmacy: the tug-of-war intensifies.

PMID- 15023917
TI  - Ten time-management tips for family physicians.

PMID- 15023918
TI  - Uranium in drinking water, naturally.

PMID- 15023920
TI  - Is regression of coronary atherosclerosis possible by infusing recombinant
      apolipoprotein A-I?

PMID- 15023921
TI  - Lead poisoning from "lead-free" paint.

PMID- 15023922
TI  - Elapsed time from breast cancer detection to first adjuvant therapy in a Canadian
      province, 1999-2000.
AB  - BACKGROUND: A number of studies have examined time intervals between care steps
      in breast cancer diagnosis and treatment. The objective of this study was to
      document the elapsed time from first clinical or mammographic detection of breast
      abnormality to initiation of first adjuvant therapy in women with invasive breast
      cancer in Nova Scotia and to examine the effect of age, disease stage and place
      of residence on these intervals. METHODS: All dates were abstracted from patient
      charts and the Oncology Patient Information System. Eligible women were those
      with invasive breast cancer detected by Sept. 1, 1999, who were referred to 1 of
      2 provincial cancer treatment centres by Sept. 1, 2000. All time intervals were
      calculated in days, and only patients experiencing both care events defining an
      interval were included in the analysis of time to event for that interval. We
      used proportional hazards regression analysis to evaluate the influence of
      patient age, disease stage and place of residence on times between care events.
      RESULTS: A total of 776 new diagnoses of breast cancer were reported to the Nova
      Scotia Cancer Registry over the study period. Of the 776, 467 met the inclusion
      criteria, and 364 patients were eligible for analysis. The overall median time
      from clinical or mammographic detection of breast cancer to initiation of first
      adjuvant therapy was 91 days (interquartile range 72-123 days). Disease stage was
      the strongest predictor of elapsed time: the median interval from disease
      detection to initiation of first adjuvant therapy for patients with stage I
      disease was 118 days, as compared with 85 days for those with stage II disease
      and 75 days for those with stage III disease (adjusted hazard ratio [HR] 2.1, 95%
      confidence interval [CI] 1.6-2.8). Patients aged 70 years or more at diagnosis
      experienced longer elapsed times (median interval 98 days) than did younger
      patients (93 days for those aged 50-69 years and 82 days for those aged 49 years
      or less) (adjusted HR 1.6, 95% CI 1.1-2.4). INTERPRETATION: Women aged 70 or more
      and those with stage I breast cancer experienced longer elapsed times from
      disease detection to initiation of first adjuvant therapy than did younger women
      and those with more advanced disease. These findings may have implications for
      the design of interventions to minimize intervals between steps in breast cancer
      care and should be validated within the Canadian context. Future investigation
      exploring the full spectrum of breast cancer care may lead to a more complete
      understanding of processes and gaps in the current system.

PMID- 15023923
TI  - Fellowship training, workload, fatigue and physical stress: a prospective
      observational study.
AB  - BACKGROUND: Fatigue in physician trainees may compromise patient safety and the
      well-being of the trainees and limit the educational opportunities provided by
      training programs. Anecdotal evidence suggests that the on-call workload and
      physical demands experienced by trainees are significant despite duty-hour
      regulation and support from nursing staff, other trainees and staff physicians.
      METHODS: We measured the workload and the level of fatigue and physical stress of
      11 senior fellows during 35 shifts in the critical care unit at the Hospital for
      Sick Children in Toronto. We determined number of rostered hours, number of
      admissions and discharges, number and type of procedures, nurse:patient ratios
      and related measures of workload. Fellows self-reported the number of pages they
      received and the amount of time they slept. We estimated physical stress by using
      a commercially available pedometer to measure the distance walked, by using
      ambulatory electrocardiographic monitoring to determine arrhythmias and by
      determining urine specific gravity and ketone levels to estimate hydration.
      RESULTS: The number of rostered hours were within current Ontario guidelines. The
      mean shift duration was 25.5 hours (range 24-27 hours). The fellows worked on
      average 69 hours (range 55-106) per week. On average during a shift, the fellows
      received 41 pages, were on non-sleeping breaks for 1.2 hours, slept 1.9 hours and
      walked 6.3 km. Ketonuria was found in participants in 7 (21%) of the 33 shifts
      during which it was measured. Arrhythmia (1 atrial, 1 ventricular) or heart rate
      abnormalities occurred in all 6 participants. These fellows were the most senior
      in-house physician for a mean of 9.4 hours per shift and were responsible for
      performing invasive procedures in two-thirds of their shifts. INTERPRETATION:
      Established Canadian and proposed American guidelines expose trainees to
      significant on-call workload, physical stress and sleep deprivation.

PMID- 15023924
TI  - Trainee fatigue: are new limits on work hours enough?

PMID- 15023925
TI  - Interventions to promote breast-feeding: applying the evidence in clinical
      practice.

PMID- 15023929
TI  - Branching morphogenesis and kidney disease.
AB  - Branching morphogenesis in the kidney is a tightly regulated, complex process and
      its disruption potentially can lead to a broad spectrum of diseases, ranging from
      rare hereditary syndromes to common conditions such as hypertension and chronic
      kidney failure. This review synthesizes data on branching during kidney
      development derived from in vitro and in vivo rodent studies and to apply them to
      human diseases. It discusses how the broad organization of molecular interactions
      during kidney development might provide a mechanistic framework for understanding
      disorders related to aberrant branching.

PMID- 15023930
TI  - Two zebrafish Notch-dependent hairy/Enhancer-of-split-related genes, her6 and
      her4, are required to maintain the coordination of cyclic gene expression in the
      presomitic mesoderm.
AB  - Alterations of the Delta/Notch signalling pathway cause multiple morphogenetic
      abnormalities in somitogenesis, including defects in intersomitic boundary
      formation and failure in maintenance of somite regularity. Notch signalling has
      been implicated in establishing the anteroposterior polarity within maturing
      somites and in regulating the activity of a molecular segmentation clock
      operating in the presomitic mesoderm. The pleiotropy of Notch signalling obscures
      the roles of this pathway in different steps of somitogenesis. One possibility is
      that distinct Notch effectors mediate different aspects of Notch signalling. In
      this study, we focus on two zebrafish Notch-dependent hairy/Enhancer-of-split
      related transcription factors, Her6 and Her4, which are expressed at the
      transition zone between presomitic mesoderm and the segmented somites. The
      results of overexpression/gain-of-function and of morpholino-mediated loss-of
      function experiments show that Her6 and Her4 are Notch signalling effectors that
      feedback on the clock and take part in the maintenance of cyclic gene expression
      coordination among adjacent cells in the presomitic mesoderm.

PMID- 15023926
TI  - Clinical practice guidelines for the care and treatment of breast cancer: 15.
      Treatment for women with stage III or locally advanced breast cancer.
AB  - OBJECTIVE: To define the optimal treatment for women with stage III or locally
      advanced breast cancer (LABC). EVIDENCE: Systematic review of English-language
      literature retrieved from MEDLINE (1984 to June 2002) and CANCERLIT (1983 to June
      2002). A nonsystematic review of the literature was continued through December
      2003. RECOMMENDATIONS: The management of LABC requires a combined modality
      treatment approach involving surgery, radiotherapy and systemic therapy. Systemic
      therapy: chemotherapy. Operable tumours. Patients with operable stage IIIA
      disease should be offered chemotherapy. They should receive adjuvant chemotherapy
      following surgery, or primary chemotherapy followed by locoregional management.
      Chemotherapy should contain an anthracycline. Acceptable regimens are 6 cycles of
      FAC, CAF, CEF or FEC. Taxanes are under intense investigation. Inoperable
      tumours. Patients with stage IIIB or IIIC disease, including those with
      inflammatory breast cancer and those with isolated ipsilateral internal mammary
      or supraclavicular lymph-node involvement, should be treated with primary
      anthracycline-based chemotherapy. Acceptable chemotherapy regimens are FAC, CAF,
      CEF or FEC. Taxanes are under intense investigation. Patients with stage IIIB or
      IIIC disease who respond to primary chemotherapy should be treated until the
      response plateaus or to a maximum of 6 cycles (minimum 4 cycles). Patients with
      stage IIIB disease should then undergo definitive surgery and irradiation. The
      locoregional management of patients with stage IIIC disease who respond to
      chemotherapy should be individualized. In patients with stage IIIB or IIIC
      disease who achieve maximum response with fewer than 6 cycles, further adjuvant
      chemotherapy can be given following surgery and irradiation. Patients whose
      tumours do not respond to primary chemotherapy can be treated with taxane
      chemotherapy or can proceed directly to irradiation followed by modified radical
      mastectomy, if feasible. Systemic therapy: hormonal therapy. Operable and
      inoperable tumours. Tamoxifen for 5 years should be recommended to pre- and
      postmenopausal women whose tumours are hormone responsive. Locoregional
      management. Operable tumours. Patients with stage IIIA disease should receive
      both modified radical mastectomy (MRM) and locoregional radiotherapy if feasible.
      They may be managed with MRM followed by chemotherapy and locoregional
      radiotherapy, or chemotherapy first followed by MRM and locoregional
      radiotherapy. Breast-conserving surgery is currently not a standard approach.
      Locoregional radiotherapy should be delivered to the chest wall and to the
      supraclavicular and axillary nodes. The role of internal mammary irradiation is
      unclear. Inoperable tumours. Patients with stage IIIB disease who respond to
      chemotherapy should receive surgery plus locoregional radiotherapy. The
      locoregional management of patients with stage IIIC disease who respond to
      chemotherapy is unclear and should be individualized. Patients whose disease
      remains inoperable following chemotherapy should receive locoregional
      radiotherapy with subsequent surgery, if feasible. VALIDATION: The authors'
      original text was revised by members of the Steering Committee on Clinical
      Practice Guidelines for the Care and Treatment of Breast Cancer. Subsequently,
      feedback was provided by 9 oncologists from across Canada. The final document was
      approved by the steering committee. SPONSOR: The Steering Committee on Clinical
      Practice Guidelines for the Care and Treatment of Breast Cancer was convened by
      Health Canada. Completion date: December 2003.

PMID- 15023931
TI  - Simvastatin prevents load-induced protein tyrosine nitration in overloaded
      hearts.
AB  - Hydroxymethylglutaryl-coenzyme A reductase inhibitors prevent load-induced left
      ventricular hypertrophy (LVH). Whether this effect is related to antioxidant
      properties of this class of drugs is poorly understood. The aim of the present
      report was to evaluate the regulation of nitrotyrosine production during the
      development of load-induced LVH and the effect of simvastatin treatment in this
      process. Rats were subjected to aortic constriction up to 15 days. LVH was
      evaluated by left/right ventricle mass ratio. Myocardial content of
      nitrotyrosine, nitric oxide synthase (NOS) isoforms, and phagocyte-type NAD(P)H
      oxidase subunits (p67-phox and p22-phox) were analyzed by immunoblotting and
      immunohistochemistry assays. Another group of rats received treatment with either
      simvastatin or placebo for 15 days after the onset of pressure overload, and
      their hearts were also studied. Myocardial nitrotyrosine content was increased
      from 3 to 15 days of pressure overload in regions of cardiac myocytes in close
      apposition to myocardial stroma during LVH. Neuronal NOS (nNOS), inducible NOS
      (iNOS), and endothelial NOS (eNOS) isoforms had their expression increased in
      coronary vessels (nNOS and iNOS) and in myocardial stroma (eNOS) from day 3 to
      day 7 of aortic constriction. However, p67-phox and p22-phox expression was
      increased in cells of myocardial stroma in parallel to augmented myocardial
      nitrotyrosine content. Simvastatin treatment inhibited the increases in
      myocardial nitrotyrosine content and in p67-phox and p22-phox expression, and
      significantly reduced LVH. In conclusion, antioxidant properties of simvastatin
      might play a role in myocardial remodeling induced by pressure overload.

PMID- 15023932
TI  - Insulin resistance and alterations in angiogenesis: additive insults that may
      lead to preeclampsia.
AB  - Altered angiogenesis and insulin resistance, which are intimately related at a
      molecular level, characterize preeclampsia. To test if an epidemiological
      interaction exists between these two alterations, we performed a nested case
      control study of 28 women who developed preeclampsia and 57 contemporaneous
      controls. Serum samples at 12 weeks of gestation were measured for sex hormone
      binding globulin (SHBG; low levels correlate with insulin resistance) and
      placental growth factor (PlGF; a proangiogenic molecule). Compared with controls,
      women who developed preeclampsia had lower serum levels of SHBG (208+/-116 versus
      256+/-101 nmol/L, P=0.05) and PlGF (16+/-14 versus 67+/-150 pg/mL, P<0.001), and
      in multivariable analysis, women with serum levels of PlGF < or =20 pg/mL had an
      increased risk of developing preeclampsia (odds ratio [OR] 7.6, 95% CI 1.4 to
      38.4). Stratified by levels of serum SHBG (< or =175 versus >175 mg/dL), women
      with low levels of SHBG and PlGF had a 25.5-fold increased risk of developing
      preeclampsia (P=0.10), compared with 1.8 (P=0.38) among women with high levels of
      SHBG and low levels of PlGF. Formal testing for interaction (PlGFxSHBG) was
      significant (P=0.02). In a model with 3 (n-1) interaction terms (high PlGF and
      high SHBG, reference), the risk for developing preeclampsia was as follows: low
      PlGF and low SHBG, OR 15.1, 95% CI 1.7 to 134.9; high PlGF and low SHBG, OR 4.1,
      95% CI 0.45 to 38.2; low PlGF and high SHBG, OR 8.7, 95% CI 1.2 to 60.3. Altered
      angiogenesis and insulin resistance are additive insults that lead to
      preeclampsia.

PMID- 15023933
TI  - Novel mechanisms responsible for postmenopausal hypertension.
AB  - Blood pressure increases in many women after menopause. Hypertension is one of
      the major risk factors for cardiovascular disease. However, the mechanisms
      responsible for the postmenopausal increase in blood pressure are yet to be
      elucidated. Various humoral systems have been proposed to play a role in
      postmenopausal hypertension, such as changes in estrogen/androgen ratios,
      increases in endothelin and oxidative stress, and activation of the renin
      angiotensin system (RAS). In addition, obesity, type II diabetes, and activation
      of the sympathetic nervous system are common in postmenopausal women and may also
      play important roles. However, progress in elucidating the mechanisms responsible
      for postmenopausal hypertension has been hampered by the lack of a suitable
      animal model. The aging female spontaneously hypertensive rat (SHR) exhibits many
      of the characteristics found in postmenopausal women. In this review, some of the
      possible mechanisms that could play a role in postmenopausal hypertension are
      discussed, as well as the characteristics of the aged female SHR as a model to
      study.

PMID- 15023934
TI  - Reduction of cardiac fibrosis decreases systolic performance without affecting
      diastolic function in hypertensive rats.
AB  - Pressure-overload left ventricular hypertrophy (LVH) is characterized by an
      increase in myocyte size and fibrosis. However, it is not clear how each of these
      components affects hypertensive heart disease (HHD). We have shown in 2 different
      rat models of hypertension that cardiac fibrosis can be reduced with N-acetyl
      seryl-aspartyl-lysyl-proline (Ac-SDKP), an antifibrotic peptide normally present
      in mammals. To assess how inhibition of fibrosis affects HHD, spontaneously
      hypertensive rats (SHR) and normotensive controls (WKY) were treated with Ac-SDKP
      or vehicle. Cardiac systolic and diastolic function were assessed using in vivo
      pressure-volume (PV) analysis. Left ventricle passive compliance was also
      determined ex vivo. We found that in SHR, Ac-SDKP normalized left ventricle total
      collagen content and interstitial collagen fraction without changing myocyte
      diameter or left ventricle mass. In WKY, collagen did not change significantly
      after treatment. Ac-SDKP did not affect left ventricle diastolic function,
      determined in vivo and ex vivo in SHR and WKY, whereas systolic function was
      significantly decreased in SHR treated with Ac-SDKP and unchanged in treated WKY.
      We concluded that in adult SHR, reducing left ventricle collagen deposition with
      Ac-SDKP does not improve diastolic function, whereas it decreases systolic
      performance. These findings suggest that total left ventricle collagen reduction
      per se does not necessarily benefit cardiac function. In HHD, other factors
      besides collagen quantity, such as myocyte hypertrophy and/or collagen type or
      cross-link, might be targeted to improve cardiac function.

PMID- 15023937
TI  - Validation of publication of new names and new combinations previously
      effectively published outside the IJSEM.
AB  - The purpose of this announcement is to effect the valid publication of the
      following new names and new combinations under the procedure described in the
      Bacteriological Code (1990 Revision). Authors and other individuals wishing to
      have new names and/or combinations included in future lists should send three
      copies of the pertinent reprint or photocopies thereof to the IJSEM Editorial
      Office for confirmation that all of the other requirements for valid publication
      have been met. It is also a requirement of IJSEM and the ICSP that authors of new
      species, new subspecies and new combinations provide evidence that types are
      deposited in two recognized culture collections in two different countries (i.e.
      documents certifying deposition and availability of type strains). It should be
      noted that the date of valid publication of these new names and combinations is
      the date of publication of this list, not the date of the original publication of
      the names and combinations. The authors of the new names and combinations are as
      given below, and these authors' names will be included in the author index of the
      present issue and in the volume author index. Inclusion of a name on these lists
      validates the publication of the name and thereby makes it available in
      bacteriological nomenclature. The inclusion of a name on this list is not to be
      construed as taxonomic acceptance of the taxon to which the name is applied.
      Indeed, some of these names may, in time, be shown to be synonyms, or the
      organisms may be transferred to another genus, thus necessitating the creation of
      a new combination.

PMID- 15023935
TI  - Diagnosis and localization of pheochromocytoma.
AB  - This Hypertension Grand Rounds shows how applying new clinical laboratory
      techniques helped to diagnose pheochromocytoma in a difficult case. In the
      setting of long-standing, sustained hypertension, the patient had a hypertensive
      paroxysm during anesthesia induction for surgery, leading to suspicion of a
      pheochromocytoma. Conventional testing, including CT scanning and fractionated
      urinary metanephrine test, was not diagnostic. The patient had another
      hypertensive paroxysm during subsequent anesthesia induction, requiring intensive
      care. Consistently elevated plasma levels of free normetanephrine provided the
      first and only biochemical evidence for a pheochromocytoma in this case. 6
      [18F]Fluorodopamine positron emission tomography and 123I-metaiodobenzylguanidine
      scintigraphy subsequently agreed on the existence of a small left adrenal mass,
      which when removed surgically proved to be a pheochromocytoma. Postoperatively,
      plasma levels of normetanephrine normalized, and there were no further
      hypertensive paroxysms, although the patient remained hypertensive. This case
      illustrates the superiority of plasma levels of free (unconjugated)
      metanephrines, compared with other biochemical tests, to detect pheochromocytoma.
      It also confirms that functional imaging by 6-[18F]fluorodopamine or 123I
      metaiodobenzylguanidine scanning can localize pheochromocytoma in difficult cases
      in which other imaging tests are not diagnostic.

PMID- 15023936
TI  - Integrating drug pharmacokinetics for phenotyping individual renin response to
      angiotensin II blockade in humans.
AB  - Renin release into plasma has been used to investigate the drug dose-dependence
      of renin-angiotensin system inhibition because it is proportional to the
      interruption of the permanent negative feedback loop of angiotensin II on renin
      secretion. We investigated the 24-hour between-subject differences in renin
      profiles by analyzing the time-dependence of individual renin responses in 16
      mildly sodium-depleted normotensive subjects exposed in a 4-period crossover
      study to single oral doses of 8- and 16-mg (C8 and C16) candesartan cilexetil and
      80- and 160-mg (V80 and V160) valsartan. C8 had a similar effect to V160 in terms
      of the increase in active renin concentration and decrease in blood pressure. C16
      had the strongest effect and V80 the weakest effect on renin release. Within- and
      between-subject variability was more marked for valsartan pharmacokinetics than
      for candesartan pharmacokinetics and influenced variability in renin response. To
      eliminate some of the variability caused by the pharmacokinetics of each drug, we
      corrected the area under time curve of plasma renin levels by that of plasma drug
      levels to obtain an individual normalized index of renin release or
      "renin/pharmacokinetic index". In these experimental conditions, this index was
      found to be a reproducible individual characteristic affecting renin response, in
      addition to the pharmacokinetics and pharmacological properties of angiotensin II
      type-1 receptor antagonists. The pharmacokinetic-pharmacodynamic model of renin
      release described here could be of value for the identification and investigation
      of renin release abnormalities in patients with hypertension and for the
      comparison of renin-angiotensin system blockers.

PMID- 15023938
TI  - Asaia krungthepensis sp. nov., an acetic acid bacterium in the alpha
      Proteobacteria.
AB  - Three bacterial strains were isolated from flowers collected in Bangkok,
      Thailand, by an enrichment-culture approach for acetic acid bacteria.
      Phylogenetic analysis based on 16S rRNA gene sequences showed that the isolates
      were located in the lineage of the genus Asaia but constituted a cluster separate
      from the type strains of Asaia bogorensis and Asaia siamensis. The DNA base
      composition of the isolates was 60.2-60.5 mol% G+C, with a range of 0.3 mol%. The
      isolates constituted a taxon separate from Asaia bogorensis and Asaia siamensis
      on the basis of DNA-DNA relatedness. The isolates had morphological,
      physiological, biochemical and chemotaxonomic characteristics similar to those of
      the type strains of Asaia bogorensis and Asaia siamensis, but the isolates grew
      on maltose. The major ubiquinone was Q(10). On the basis of the results obtained,
      the name Asaia krungthepensis sp. nov. is proposed for the isolates. The type
      strain is isolate AA08(T) (=BCC 12978(T)=TISTR 1524(T)=NBRC 100057(T)=NRIC
      0535(T)), which had a DNA G+C content of 60.3 mol% and was isolated from a
      heliconia flower ('paksaasawan' in Thai; Heliconia sp.) collected in Bangkok,
      Thailand.

PMID- 15023939
TI  - Wautersia gen. nov., a novel genus accommodating the phylogenetic lineage
      including Ralstonia eutropha and related species, and proposal of Ralstonia
      [Pseudomonas] syzygii (Roberts et al. 1990) comb. nov.
AB  - Comparative 16S rDNA sequence analysis indicates that two distinct sublineages,
      with a sequence dissimilarity of >4 % (bootstrap value, 100 %), exist within the
      genus RALSTONIA: the Ralstonia eutropha lineage, which comprises Ralstonia
      basilensis, Ralstonia campinensis, R. eutropha, Ralstonia gilardii, Ralstonia
      metallidurans, Ralstonia oxalatica, Ralstonia paucula, Ralstonia respiraculi and
      Ralstonia taiwanensis; and the Ralstonia pickettii lineage, which comprises
      Ralstonia insidiosa, Ralstonia mannitolilytica, R. pickettii, Ralstonia
      solanacearum and Ralstonia syzygii comb. nov. (previously Pseudomonas syzygii).
      This phylogenetic discrimination is supported by phenotypic differences. Members
      of the R. eutropha lineage have peritrichous flagella, do not produce acids from
      glucose and are susceptible to colistin, in contrast to members of the R.
      pickettii lineage, which have one or more polar flagella, produce acid from
      several carbohydrates and are colistin-resistant. Members of the R. pickettii
      lineage are viable for up to 6 days on tryptic soy agar at 25 degrees C, whereas
      members of the R. eutropha lineage are viable for longer than 9 days. It is
      proposed that species of the R. eutropha lineage should be classified in a novel
      genus, Wautersia gen. nov. Finally, based on the literature and new DNA-DNA
      hybridization data, it is proposed that Pseudomonas syzygii should be renamed
      Ralstonia syzygii comb. nov.

PMID- 15023940
TI  - Aeropyrum camini sp. nov., a strictly aerobic, hyperthermophilic archaeon from a
      deep-sea hydrothermal vent chimney.
AB  - A novel hyperthermophilic archaeon, designated strain SY1(T), was isolated from a
      deep-sea hydrothermal vent chimney sample collected from the Suiyo Seamount in
      the Izu-Bonin Arc, Japan, at a depth of 1385 m. The cells were irregular cocci
      (1.2 to 2.1 micro m in diameter), occurring singly or in pairs, and stained Gram
      negative. Growth was observed between 70 and 97 degrees C (optimum, 85 degrees C;
      220 min doubling time), pH 6.5 and 8.8 (optimum, pH 8.0), and salinity of 2.2 and
      5.3 % (optimum, 3.5 %). It was a strictly aerobic heterotroph capable of growing
      on complex proteinaceous substrates such as yeast extract and tryptone. The G+C
      content of the genomic DNA was 54.4 mol%. Phylogenetic analysis based on the 16S
      rDNA sequence of the isolate indicated that the isolate was closely related to
      Aeropyrum pernix strain K1(T). However, no significant genetic relatedness was
      observed between them by DNA-DNA hybridization. On the basis of the molecular and
      physiological traits of the new isolate, the name Aeropyrum camini sp. nov. is
      proposed, with the type strain SY1(T) (=JCM 12091(T)=ATCC BAA-758(T)).

PMID- 15023941
TI  - Classification of phytoplasma strains in the elm yellows group (16SrV) and
      proposal of 'Candidatus Phytoplasma ulmi' for the phytoplasma associated with elm
      yellows.
AB  - Elm yellows group (16SrV) phytoplasmas, which are associated with devastating
      diseases in elm, grapevine, blackberry, cherry, peach and several other plant
      species in America, Europe and Asia, represent one of the most diverse
      phytoplasma clusters. On the basis of phylogenetic analysis of 16S rDNA
      sequences, elm yellows group phytoplasmas form a discrete subclade within the
      phytoplasma clade. Three phylogenetic parameters, namely 16S rRNA, ribosomal
      protein and secY genes, have been evaluated for their usefulness in
      differentiating elm yellows group phytoplasmas. RFLP analysis of 16S rRNA
      sequences differentiated the elm yellows group phytoplasmas into five subgroups.
      Twelve RFLP subgroups were differentiated on the basis of ribosomal protein and
      13 were differentiated using secY gene sequences. Phylogenetic analysis of the
      ribosomal protein genes and secY gene alone or in combination indicated that the
      subgroups constitute 12 genetically distinct lineages, each of which appears to
      have evolved under different ecological constraints such as specific vector or
      plant hosts. On the basis of unique DNA and biological properties, it is proposed
      that the elm yellows phytoplasma EY1(T) represents a novel taxon, 'Candidatus
      Phytoplasma ulmi'.

PMID- 15023942
TI  - Polyphyly of true branching cyanobacteria (Stigonematales).
AB  - Cyanobacteria with true branching are classified in Subsection V (formerly order
      Stigonematales) in the phylum CYANOBACTERIA: They exhibit a high degree of
      morphological complexity and are known from particular biotopes. Only a few
      stigonematalean morphotypes have been cultured, and therefore the high
      variability of morphotypes found in nature is under-represented in culture.
      Axenic cultures of Chlorogloeopsis and Fischerella sensu Rippka et al. were, to
      date, the only representatives of this Subsection in phylogenetic studies. The
      16S rDNA sequence analysis data in this report confirm that heterocyst-forming
      cyanobacteria are a monophyletic group. However, unlike previous studies have
      suggested, these 16S rDNA data on new Stigonematales strains show that the true
      branching cyanobacteria are polyphyletic and can be separated into at least two
      major groups defined by their branching type, the first group being characterized
      by T-branching and the second group by Y-branching. Cyanobacteria with
      intercalary heterocysts and either no branching or false-branching also formed
      separate clusters. In consequence, our phylogenetic data do not correlate with
      the bacteriological and traditional classifications, which distinguish
      filamentous heterocystous cyanobacteria with or without true branching
      (Nostocales/Stigonematales).

PMID- 15023944
TI  - Mycoplasma ovis comb. nov. (formerly Eperythrozoon ovis), an epierythrocytic
      agent of haemolytic anaemia in sheep and goats.
AB  - Eperythrozoon ovis, an erythrocytic agent that causes haemolytic anaemia in sheep
      and goats, occurs worldwide and is currently thought to be a rickettsia. To
      determine the relationship between this agent and other haemotrophic bacterial
      parasites, the 16S rRNA gene of this organism was sequenced. Phylogenetic
      analysis revealed that this wall-less bacterium is not a rickettsia, but a
      mycoplasma. This mycoplasma is related closely to several other uncultivated,
      epierythrocytic mycoplasmas that comprise a recently identified group, the
      haemotrophic mycoplasmas (haemoplasmas). The haemoplasma group is composed of
      former Eperythrozoon and Haemobartonella species, as well as newly identified
      epierythrocytic mycoplasmas. Haemoplasmas parasitize the surface of erythrocytes
      of a wide variety of vertebrate animal hosts and are transmitted mainly by blood
      feeding arthropod vectors. Recognition that E. ovis is a mycoplasma provides a
      new approach to dealing with this bacterium. It is proposed that E. ovis should
      be reclassified as Mycoplasma ovis comb. nov.

PMID- 15023943
TI  - Amycolatopsis palatopharyngis sp. nov., a potentially pathogenic actinomycete
      isolated from a human clinical source.
AB  - The taxonomic position of an actinomycete, strain 1BDZ(T), isolated from a
      clinical human source was determined using a polyphasic approach. Phylogenetic
      analysis based on almost complete 16S rDNA sequences showed that this organism
      consistently formed a distinct line with the Amycolatopsis methanolica subclade
      within the genus Amycolatopsis, and shared moderately low 16S rDNA similarity
      (<96.5 %) with other species. The organism was also found to have chemical and
      morphological properties typical of members of the genus Amycolatopsis. A range
      of phenotypic characteristics readily distinguished this strain from
      representatives of all species of Amycolatopsis with validly published names. On
      the basis of these data, a novel species, Amycolatopsis palatopharyngis sp. nov.,
      is proposed to accommodate strain 1BDZ(T) (=AS 4.1729(T)=PCM 2600(T)).

PMID- 15023945
TI  - Bacillus shackletonii sp. nov., from volcanic soil on Candlemas Island, South
      Sandwich archipelago.
AB  - A sample of mossy soil taken from the eastern lava flow of northern Candlemas
      Island, South Sandwich archipelago, yielded six isolates of aerobic, endospore
      forming bacteria. Miniaturized routine phenotypic tests and other observations,
      amplified rDNA restriction analysis and SDS-PAGE analysis suggested that the
      strains represent a novel taxon. 16S rDNA sequence comparisons support the
      proposal of a novel species, Bacillus shackletonii sp. nov., the type strain of
      which is LMG 18435(T) (=CIP 107762(T)).

PMID- 15023946
TI  - Thalassomonas ganghwensis sp. nov., isolated from tidal flat sediment.
AB  - A Gram-negative, aerobic, halophilic bacterium, designated strain JC2041(T), was
      isolated from a sediment sample of getbol, the Korean tidal flat. Results of 16S
      rDNA sequence analyses indicated a moderate relationship to Thalassomonas
      viridans within the gamma-Proteobacteria (94.9 % similarity). Depending on the
      tree-making algorithm used, the isolate either formed a monophyletic clade with
      T. viridans or was recovered as a sister group of a class containing the genera
      Thalassomonas and Colwellia. Phenotypic features of the getbol isolate were
      similar to those of T. viridans, but several physiological and chemotaxonomic
      properties, including nitrate reduction, amylase, lecithinase, Tweenase and
      utilization of 13 carbon sources, distinguished strain JC2041(T) from T.
      viridans. The polyphasic data presented in this study indicate that the isolate
      should be classified as a novel species in the genus Thalassomonas. The name
      Thalassomonas ganghwensis sp. nov. is therefore proposed for the getbol isolate;
      the type strain is JC2041(T) (=IMSNU 14005(T)=KCTC 12041(T)=DSM 15355(T)).

PMID- 15023947
TI  - Nocardia tenerifensis sp. nov.
AB  - A Gram-positive, non-spore-forming bacterium (GW39-1573(T)) was isolated from
      soil of the Spanish island of Tenerife. 16S rRNA gene sequence similarity studies
      showed that strain GW39-1573(T) belonged to the genus Nocardia and was most
      closely related to Nocardia brasiliensis (98.0 %), Nocardia beijingensis (97.3
      %), Nocardia transvalensis (97.5 %), Nocardia asteroides (97.2 %) and Nocardia
      farcinica (97.0 %). Strain GW39-1573(T) could be distinguished from all other
      validly described Nocardia species by sequence similarity values of less than 97
      %. Chemotaxonomic data [major menaquinone: MK-8(H(4, omega-cycl)); major polar
      lipids: diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine,
      phosphatidylinositol, phosphatidylinositol mannoside and an unknown glycolipid
      and an unknown phospholipid; major fatty acids: C(16 : 0), C(18 : 1)omega9c and
      10 methyl C(16 : 0)] and the presence of mycolic acids supported the affiliation
      of strain GW39-1573(T) to the genus NOCARDIA: The results of DNA-DNA
      hybridizations and physiological and biochemical tests allowed genotypic and
      phenotypic differentiation of strain GW39-1573(T) from those related species that
      showed 16S rRNA gene sequence similarity values of greater than 97 %. Strain GW39
      1573(T) merits species status, and the name Nocardia tenerifensis is proposed
      with the type strain GW39-1573(T) (=DSM 44704(T)=CIP 107929(T)).

PMID- 15023949
TI  - Taxonomic study of Halorubrum distributum and proposal of Halorubrum terrestre
      sp. nov.
AB  - Halorubrum distributum (basonym, Halobacterium distributum) is an extremely
      halophilic, aerobic archaeon isolated from saline soils, which was described on
      the basis of phenotypic features of several strains. The designated type strain
      of the species (1m(T)=VKM B-1733(T)=JCM 9100(T)) was shown recently to differ
      from the other strains. In this study, Halorubrum distributum isolates have been
      characterized with regard to phenotypic features, polar lipid content, comparison
      of 16S rRNA gene sequences and DNA-DNA hybridization. On the basis of these data,
      a novel species that includes the other isolates is proposed, with the name
      Halorubrum terrestre sp. nov. The type strain of this novel species is 4p(T)
      (=VKM B-1739(T)=JCM 10247(T)). The DNA G+C content of this novel species is 64.2
      64.9 mol% (64.4 mol% for the type strain).

PMID- 15023948
TI  - Ancylobacter rudongensis sp. nov., isolated from roots of Spartina anglica.
AB  - A curved, ring-like bacterium, strain AS 1.1761(T), isolated from the roots of
      Spartina anglica, was studied by a polyphasic approach. According to phylogenetic
      analysis, strain AS 1.1761(T) belongs to the genus Ancylobacter, with 99.21 % 16S
      rDNA sequence similarity to Ancylobacter aquaticus, the only species described so
      far in this genus. However, strain AS 1.1761(T) had no significant DNA-DNA
      binding with the type strain of A. aquaticus. In addition, strain AS 1.1761(T)
      differed from A. aquaticus in many phenotypic features. Based on molecular and
      phenotypic data, a novel species, Ancylobacter rudongensis sp. nov., is proposed.
      The type strain is AS 1.1761(T) (=JCM 11671(T)).

PMID- 15023950
TI  - Characterization of the marine propionate-degrading, sulfate-reducing bacterium
      Desulfofaba fastidiosa sp. nov. and reclassification of Desulfomusa hansenii as
      Desulfofaba hansenii comb. nov.
AB  - A rod-shaped, slightly curved sulfate reducer, designated strain P2(T), was
      isolated from the sulfate-methane transition zone of a marine sediment. Cells
      were motile by means of a single polar flagellum. The strain reduced sulfate,
      thiosulfate and sulfite to sulfide and used propionate, lactate and 1-propanol as
      electron donors. Strain P2(T) also grew by fermentation of lactate. Propionate
      was oxidized incompletely to acetate and CO(2). The DNA G+C content was 48.8
      mol%. Sequence analysis of the small-subunit rDNA and the dissimilatory sulfite
      reductase gene revealed that strain P2(T) was related to the genera Desulfonema,
      Desulfococcus, Desulfosarcina, 'Desulfobotulus', Desulfofaba, Desulfomusa and
      Desulfofrigus. These genera include incomplete as well as complete oxidizers of
      substrates. Strain P2(T) shared important morphological and physiological traits
      with Desulfofaba gelida and Desulfomusa hansenii, including the ability to
      oxidize propionate incompletely to acetate. The 16S rRNA gene similarities of
      P2(T) to Desulfofaba gelida and Desulfomusa hansenii were respectively 92.9 and
      91.5 %. Combining phenotypic and genotypic traits, we propose strain P2(T) to be
      a member of the genus Desulfofaba. The name Desulfofaba fastidiosa sp. nov. (type
      strain P2(T)=DSM 15249(T)=ATCC BAA-815(T)) is proposed, reflecting the limited
      number of substrates consumed by the strain. In addition, the reclassification of
      Desulfomusa hansenii as a member of the genus Desulfofaba, Desulfofaba hansenii
      comb. nov., is proposed. A common line of descent and a number of shared
      phenotypic traits support this reclassification.

PMID- 15023951
TI  - Bifidobacterium psychraerophilum sp. nov. and Aeriscardovia aeriphila gen. nov.,
      sp. nov., isolated from a porcine caecum.
AB  - In a previous study that was based primarily on 16S rDNA sequencing, two groups
      of bifidobacteria that had been recovered from a pig caecum were proposed to
      belong to two novel species, termed 'Bifidobacterium pyschroaerophilum' and
      'Bifidobacterium aerophilum'. In this study, based on DNA G+C content and partial
      heat-shock protein 60 (HSP60) gene sequences, the assignment of 'B.
      pyschroaerophilum', corrected to Bifidobacterium pyschraerophilum, to the genus
      Bifidobacterium was confirmed. The DNA G+C content of 'B. aerophilum' was
      relatively low, which was consistent with its segregation into subcluster II of
      the 16S rDNA phylogenetic tree. Based on partial 16S rDNA and HSP60 gene
      sequences, the species was transferred to a novel genus and reclassified as
      Aeriscardovia aeriphila gen. nov., sp. nov. Biochemical profiles and growth
      parameters were established for both novel species. Interestingly, each had a
      high tolerance to oxygen and grew on agar media under aerobic conditions, a trait
      that may relate to their caecal habitat. Under aerobic growth conditions, the
      short-rod morphology of A. aeriphila lengthened considerably. This appeared to
      arise from incomplete cell division. In addition, B. pyschraerophilum was unusual
      in that it grew at temperatures as low as 4 degrees C. On the basis of genetic,
      phylogenetic and phenotypic data, the identities of Bifidobacterium
      pyschraerophilum sp. nov. (type strain, T16(T)=LMG 21775(T)=NCIMB 13940(T)) and
      Aeriscardovia aeriphila gen. nov., sp. nov. (type strain, T6(T)=LMG
      21773(T)=NCIMB 13939(T)) are confirmed.

PMID- 15023952
TI  - Rhodococcus gordoniae sp. nov., an actinomycete isolated from clinical material
      and phenol-contaminated soil.
AB  - The taxonomic relationships of two actinomycetes provisionally assigned to the
      genus Rhodococcus were determined using a polyphasic taxonomic approach. The
      generic assignment was confirmed by 16S rRNA gene similarity data, as the
      organisms, strains MTCC 1534 and W 4937(T), were shown to belong to the
      Rhodococcus rhodochrous subclade. These organisms had phenotypic properties
      typical of rhodococci; they were aerobic, Gram-positive, weakly acid-fast
      actinomycetes that showed an elementary branching-rod-coccus growth cycle and
      contained meso-diaminopimelic acid, arabinose and galactose in whole-organism
      hydrolysates, N-glycolated muramic acid residues, dehydrogenated menaquinones
      with eight isoprene units as the predominant isoprenologue and mycolic acids that
      co-migrated with those extracted from the type strain of R. rhodochrous. The
      strains had identical phenotypic profiles and belong to the same genomic species,
      albeit one distinguished from Rhodococcus pyridinivorans, with which they formed
      a distinct phyletic line. They were also distinguished from representatives of
      all of the species classified in the R. rhodochrous 16S rRNA gene tree using a
      set of phenotypic features. The genotypic and phenotypic data show that the
      strains merit recognition as a novel species of Rhodococcus. The name proposed is
      Rhodococcus gordoniae sp. nov., with the type strain W 4937(T) (=DSM
      44689(T)=NCTC 13296(T)).

PMID- 15023953
TI  - Anaerotruncus colihominis gen. nov., sp. nov., from human faeces.
AB  - Phenotypic and phylogenetic studies were performed on two isolates of an
      unidentified Gram-positive, anaerobic, non-spore-forming, rod-shaped bacterium
      that was isolated from human faeces. The organisms were catalase-negative,
      produced acetic and butyric acids as end products of metabolism and possessed a
      DNA G+C content of approximately 54 mol%. Comparative 16S rRNA gene sequencing
      demonstrated that the two isolates were related closely to each other and formed
      a hitherto unknown sublineage within the Clostridium leptum rRNA cluster of
      organisms. Based on phylogenetic and phenotypic evidence, it is proposed that the
      unknown bacterium should be classified in a novel genus as Anaerotruncus
      colihominis gen. nov., sp. nov. The type strain of Anaerotruncus colihominis is
      WAL 14565(T)=CCUG 45055(T)=CIP 107754(T).

PMID- 15023954
TI  - Reclassification of Brevibacillus brevis strains NCIMB 13288 and DSM 6472 (=NRRL
      NRS-887) as Aneurinibacillus danicus sp. nov. and Brevibacillus limnophilus sp.
      nov.
AB  - Comparison of the hypervariable region (269-279 bases in length) at the 5' end of
      the 16S rDNA sequences of 29 bacterial strains that were identified previously as
      Brevibacillus brevis showed that 13 strains clustered with Aneurinibacillus
      species, eight strains clustered with Bacillus species and eight strains
      clustered with Brevibacillus species. Based on DNA-DNA hybridization results, 27
      strains, not including [Brevibacillus brevis] NCIMB 13288 and [Brevibacillus
      brevis] DSM 6472, were reidentified as Aneurinibacillus migulanus,
      Aneurinibacillus thermoaerophilus, Bacillus methanolicus, Bacillus oleronius,
      Brevibacillus agri, Brevibacillus brevis and Brevibacillus parabrevis.
      [Brevibacillus brevis] NCIMB 13288, which was located in the Aneurinibacillus
      cluster, showed low DNA-DNA relatedness (<14 %) and low 16S rDNA sequence
      similarity (96.8-97.9 %) to other Aneurinibacillus species. [Brevibacillus
      brevis] DSM 6472, which was located in the Brevibacillus cluster, also showed low
      DNA-DNA relatedness (<12 %) and low 16S rDNA sequence similarity (95.4-98.8 %) to
      other Brevibacillus species. These genotypic and phylogenetic data, plus
      phenotypic and chemotaxonomic characteristics, suggest that [Brevibacillus
      brevis] NCIMB 13288 (=IAM 15048) and [Brevibacillus brevis] DSM 6472 (=NRRL NRS
      887) represent novel species of the genera Aneurinibacillus and Brevibacillus,
      respectively, for which the names Aneurinibacillus danicus sp. nov. and
      Brevibacillus limnophilus sp. nov. are proposed.

PMID- 15023955
TI  - The leucine-responsive regulatory protein (lrp) gene for characterization of the
      relationship among Xanthomonas species.
AB  - Characterization of strains of Xanthomonas axonopodis pv. citri by using DNA
      fingerprints that were generated from primers for enterobacterial repetitive
      intergenic consensus (ERIC) elements led to the discovery of differential
      sequences for a leucine-responsive regulatory protein (lrp) gene in two subgroups
      of strains with different host ranges on Citrus spp. DNA hybridization and PCR
      based assays that used different sets of primers were designed to detect the core
      sequence, as well as to obtain the entire sequence of the lrp gene for several
      Xanthomonas species and pathovars. Higher variability was observed at the
      nucleotide level than at the amino acid level among the different species and
      pathovars, revealing selection pressure on the lrp gene, which is presumably due
      to an essential role of the gene in bacterial metabolism. Moderate variability in
      the 3' and 5' domains was used to study relationships among different species
      within the genus XANTHOMONAS: Species of this genus that were isolated from
      citrus, as well as other pathovars of X. axonopodis, showed highly similar lrp
      gene sequences, whereas other Xanthomonas species, especially Xanthomonas
      campestris, had sequences that were more dissimilar to that of X. axonopodis.
      Thus, the lrp gene sequence is useful to distinguish X. axonopodis pv. citri
      groups and promising for polyphasic taxonomic analysis of the genus XANTHOMONAS:
      Data from analysis of lrp gene sequences support the current concepts for
      classification of xanthomonads, which are based on other approaches.

PMID- 15023956
TI  - Tepidibacter formicigenes sp. nov., a novel spore-forming bacterium isolated from
      a Mid-Atlantic Ridge hydrothermal vent.
AB  - A novel anaerobic, Gram-positive, sporulating and strictly
      chemoorganoheterotrophic bacterium, designated strain DV1184(T), was isolated
      from a deep-sea hydrothermal vent sample from the Mid-Atlantic Ridge. The cells
      were short, straight rods (4 micro m long and 0.8 micro m wide) and were motile
      with peritrichous flagella. They grew between 35 and 55 degrees C (optimum, 45
      degrees C), between pH 5.0 and 8.0 (optimum, 6.0) and at 20-60 g sea salts l(-1)
      (optimum sea salts concentration, 30 g l(-1)). Strain DV1184(T) was able to
      ferment yeast extract, tryptone, peptone, glucose, sucrose, maltose and pyruvate.
      The main fermentation products from glucose were (in decreasing order) formate,
      acetate and ethanol. The genomic DNA G+C content was 29 mol%. Phylogenetic
      analysis of the 16S rRNA gene located the strain within cluster XI of the lineage
      that encompasses the genus Clostridium and related genera in the bacterial
      domain. On the basis of 16S rDNA sequence comparison and physiological and
      biochemical characteristics, it is proposed that the isolate should be described
      as a novel species, Tepidibacter formicigenes sp. nov. The type strain is
      DV1184(T) (=CIP 107893(T)=DSM 15518(T)).

PMID- 15023957
TI  - Gillisia limnaea gen. nov., sp. nov., a new member of the family
      Flavobacteriaceae isolated from a microbial mat in Lake Fryxell, Antarctica.
AB  - A taxonomic study was performed on three strains isolated from microbial mats in
      Lake Fryxell, McMurdo Dry Valleys, Antarctica. Phylogenetic analysis based on 16S
      rRNA gene sequences indicated that these strains belong to the family
      Flavobacteriaceae, in which they form a distinct lineage. The isolates are Gram
      negative, chemoheterotrophic, aerobic, rod-shaped cells. They are psychrophilic
      and yellow-pigmented, with DNA G+C contents in the range 37.8-38.9 mol%. Whole
      cell fatty acid profiles revealed mainly branched fatty acids and 17 : 0 2-OH. On
      the basis of genotypic, phenotypic, chemotaxonomic and phylogenetic results, it
      is proposed that the isolates represent a novel species in a new genus, Gillisia
      limnaea gen. nov., sp. nov. The type strain is LMG 21470(T) (=DSM 15749(T)).

PMID- 15023958
TI  - Streptococcus minor sp. nov., from faecal samples and tonsils of domestic
      animals.
AB  - Nine isolates, which were obtained from tonsils, anal swabs and faeces of dogs
      and from tonsils of a cat and a calf, constituted a homogeneous but unidentified
      taxon after screening with tRNA intergenic length polymorphism analysis and whole
      cell protein fingerprinting. 16S rDNA sequence analysis classified representative
      strains in the genus Streptococcus. Highest sequence similarity (95.9 %) was
      obtained with Streptococcus ovis. Growth characteristics, biochemical features,
      DNA-DNA hybridization and DNA G+C contents of selected strains demonstrated that
      they represent a single, novel streptococcal species. The name Streptococcus
      minor sp. nov. is proposed for the novel species; the type strain (ON59(T)=LMG
      21734(T)=CCUG 47487(T)) was isolated from a dog tonsil.

PMID- 15023959
TI  - Nocardiopsis aegyptia sp. nov., isolated from marine sediment.
AB  - An actinomycete, strain SNG49(T), was isolated from marine sediment of Abu Qir
      Bay, on the western seashore of Alexandria, Egypt. The bacterium was aerobic and
      Gram-positive. It produced beige to light-yellow aerial mycelium, brown substrate
      mycelium and straight to flexuous hyphae, but no specific spore chains. 16S rDNA
      sequence analysis and chemotaxonomic markers were consistent with classification
      of strain SNG49(T) in the genus Nocardiopsis, i.e. meso-diaminopimelic acid; no
      diagnostic sugars; phosphatidylcholine, phosphatidylmethylethanolamine,
      phosphatidylinositol, phosphatidylglycerol and diphosphatidylglycerol as polar
      lipids; menaquinones of the MK-10 series from MK-10(H(0)) to MK-10(H(8)); and
      iso/anteiso-branched and 10-methyl-branched fatty acids, the principal fatty
      acids being anteiso-17 : 0 and tuberculostearic acid. Nocardiopsis lucentensis
      and Nocardiopsis alba are the phylogenetic neighbours of strain SNG49(T),
      respectively showing 98.8 and 98.7 % 16S rRNA gene sequence similarity; however,
      moderate DNA-DNA reassociation values between these two species and strain
      SNG49(T) (44 and 60 %, respectively) showed that strain SNG49(T) could be clearly
      separated from them. These data, together with distinct physiological traits, led
      to the conclusion that this isolate represents a novel species within the genus
      Nocardiopsis, for which the name Nocardiopsis aegyptia is proposed. The type
      strain is SNG49(T) (=DSM 44442(T)=NRRL B-24244(T)).

PMID- 15023960
TI  - Deinococcus indicus sp. nov., an arsenic-resistant bacterium from an aquifer in
      West Bengal, India.
AB  - An arsenic- and radiation-resistant bacterium, strain Wt/1a(T), was isolated from
      water from an arsenic-contaminated aquifer located in the Chakdah district of
      West Bengal, India. The bacterium stains Gram-negative and is rod-shaped, non
      motile, non-sporulating and red-pigmented. Cell-wall peptidoglycan contains
      ornithine as the diamino acid, MK-8 is the major menaquinone, C(15 : 1) and C(16
      : 1) are the major fatty acids and the DNA G+C content of the organism is 65.8
      mol%. Based on these phenotypic and chemotaxonomic characteristics, strain
      Wt/1a(T) was identified as a member of the genus Deinococcus. Strain Wt/1a(T)
      exhibited maximum 16S rRNA gene sequence similarity (95 %) with Deinococcus
      grandis; however, strain Wt/1a(T) exhibited only 14 % similarity to D. grandis
      IAM 13005(T) at the DNA-DNA level. Furthermore, strain Wt/1a(T) (compared to D.
      grandis IAM 13005(T)) is more resistant to arsenate and arsenite, is positive for
      arginine dihydrolase, utilizes a number of carbon sources and exhibits
      quantitative differences in fatty acid composition and qualitative differences in
      lipid composition. Strain Wt/1a(T) is identified as a novel species of the genus
      Deinococcus, for which the name Deinococcus indicus sp. nov. is proposed. The
      type strain of Deinococcus indicus is Wt/1a(T) (=MTCC 4913(T)=DSM 15307(T)).

PMID- 15023961
TI  - Genetic evidence that Weissella kimchii Choi et al. 2002 is a later heterotypic
      synonym of Weissella cibaria Bjorkroth et al. 2002.
AB  - The taxonomic positions of Weissella kimchii and Weissella cibaria were examined
      using phenotypic tests, 16S rRNA gene sequencing and DNA-DNA hybridization. The
      two species displayed very similar sugar-fermentation patterns and produced the D
      form of lactic acid. Phylogenetic analysis showed that W. cibaria is the closest
      neighbour of W. kimchii, sharing about 99.7 % similarity in the 16S rRNA gene
      sequence. DNA-DNA hybridization experiments further reinforced these results,
      demonstrating a 98.2 % reassociation level between W. cibaria LMG 17699(T) and W.
      kimchii DSM 14295(T). On the other hand, strain RO5, an isolate from paddy rice
      silage, exhibited 99.4 % 16S rRNA gene sequence similarity and a DNA
      reassociation level of more than 97 % with both type strains. Therefore, it is
      proposed that the species W. kimchii should be reclassified as W. cibaria.

PMID- 15023962
TI  - Isolation from oil reservoirs of novel thermophilic anaerobes phylogenetically
      related to Thermoanaerobacter subterraneus: reassignment of T. subterraneus,
      Thermoanaerobacter yonseiensis, Thermoanaerobacter tengcongensis and
      Carboxydibrachium pacificum to Caldanaerobacter subterraneus gen. nov., sp. nov.,
      comb. nov. as four novel subspecies.
AB  - Novel thermophilic, anaerobic, Gram-positive, rod-shaped bacteria, strains SL9
      and OCA1, were isolated from oilfields in France and Australia, respectively.
      Both strains, together with Thermoanaerobacter yonseiensis KB-1(T) (=DSM
      13777(T)), Thermoanaerobacter tengcongensis MB4(T) (=DSM 15242(T)) and
      Carboxydibrachium pacificum JM(T) (=DSM 12653(T)), possessed genomic (DNA-DNA
      hybridization studies) and phylogenetic similarities with Thermoanaerobacter
      subterraneus SEBR 7858(T) (=DSM 13054(T)), which was isolated recently from an
      oilfield reservoir in south-west France. Marked phenotypic differences exist
      between the three oilfield isolates (T. subterraneus, strain OCA1 and strain
      SL9): they include temperature range for growth and substrates used. Differences
      were also observed in the DNA G+C contents of all organisms. Similarly to T.
      subterraneus, strains SL9 and OCA1, and also T. yonseiensis, T. tengcongensis and
      Carboxydibrachium pacificum, produced acetate and L-alanine as major end products
      of glucose metabolism [0.8-1.0 mol L-alanine produced (mol glucose consumed)(-1)]
      and reduced thiosulfate, but not sulfate, to sulfide. Because of these
      significant metabolic and phylogenetic differences between the oilfield isolates
      (T. subterraneus, strain OCA1 and strain SL9), T. yonseiensis, T. tengcongensis
      and Carboxydibrachium pacificum and other Thermoanaerobacter species, it is
      proposed to reassign them as a novel genus and species, Caldanaerobacter
      subterraneus gen. nov., sp. nov., comb. nov., with the creation of four novel
      subspecies, Caldanaerobacter subterraneus subsp. subterraneus subsp. nov., comb.
      nov., Caldanaerobacter subterraneus subsp. yonseiensis subsp. nov., comb. nov.,
      Caldanaerobacter subterraneus subsp. tengcongensis subsp. nov., comb. nov. and
      Caldanaerobacter subterraneus subsp. pacificus subsp. nov., comb. nov.

PMID- 15023963
TI  - Sulfitobacter delicatus sp. nov. and Sulfitobacter dubius sp. nov., respectively
      from a starfish (Stellaster equestris) and sea grass (Zostera marina).
AB  - On the basis of data from phenotypic and genotypic characterization and analysis
      of 16S rRNA gene sequences, two novel species belonging to the genus
      Sulfitobacter are described. Strains KMM 3584(T), a pale-yellowish, non-motile
      strain isolated from a starfish (Stellaster equestris), and KMM 3554(T), which is
      motile by means of a single subpolar flagellum and was isolated from sea grass
      (Zostera marina), are marine, Gram-negative, aerobic, rod-shaped organisms. Both
      strains have the ability to degrade gelatin, but not casein, chitin, agar, DNA,
      Tween 80 or starch. Strain KMM 3584(T) decomposed alginate and grew at NaCl
      concentrations of 1-8 % and temperatures of 12-37 degrees C, whereas strain KMM
      3554(T) grew in 1-12 % NaCl and at temperatures of 10-30 degrees C. The
      predominant fatty acid was 18 : 1omega7, amounting to up to 80 % of the total
      fatty acids. The other characteristic feature was the presence of 18 : 2 isomers.
      The DNA G+C contents of KMM 3584(T) and KMM 3554(T) were respectively 60.0 and
      63.7 mol%. The level of DNA similarity between the two strains was 33 %. DNA from
      KMM 3584(T) and KMM 3554(T) had hybridization values of 5-24 % and 10-41 %,
      respectively, with DNA from the type strains of Sulfitobacter pontiacus,
      Sulfitobacter brevis, Sulfitobacter mediterraneus and Staleya guttiformis. It is
      proposed that strains KMM 3584(T) (=LMG 20554(T)=ATCC BAA-321(T)) and KMM 3554(T)
      (=LMG 20555(T)=ATCC BAA-320(T)) represent two novel species, Sulfitobacter
      delicatus sp. nov. and Sulfitobacter dubius sp. nov., respectively.

PMID- 15023964
TI  - Aeromonas simiae sp. nov., isolated from monkey faeces.
AB  - Two Aeromonas strains, IBS S6874(T) and IBS S6652, were isolated from the faeces
      of two healthy monkeys (Macaca fascicularis) from Mauritius that were kept in
      quarantine in the Centre for Primatology, Strasbourg, France. Phylogenetic
      analysis based on 16S rRNA gene sequences showed that the two isolates formed an
      unknown genetic lineage within the genus Aeromonas. The two isolates had nearly
      identical sequences (0.1 % nucleotide substitution) that were related closely to
      those of recognized Aeromonas species (1.7-3.5 % nucleotide substitution). DNA
      DNA hybridization showed that strains IBS S6874(T) and IBS S6652 had high DNA-DNA
      similarity (89 %) to each other and a low level of DNA-DNA similarity to closely
      related taxa (18 % relatedness to Aeromonas trota and 16 % relatedness to
      Aeromonas schubertii). Phenotypically, the two monkey isolates differed from most
      previously described mesophilic Aeromonas species by their lack of haemolysis on
      sheep-blood agar and inability to produce indole, gas from glucose or acid from
      mannitol. They differed from the most closely related species, A. schubertii, by
      their ability to produce acid from D-cellobiose and D-sucrose and by their
      pyrazinamidase activity. The name Aeromonas simiae sp. nov. is proposed for these
      isolates; strain IBS S6874(T) (=CIP 107798(T)=CCUG 47378(T)) is the type strain.

PMID- 15023965
TI  - Shewanella gaetbuli sp. nov., a slight halophile isolated from a tidal flat in
      Korea.
AB  - A Gram-negative, motile, non-spore-forming, rod-shaped strain, TF-27(T) (=KCCM
      41648(T)=JCM 11814(T)), was isolated from a tidal flat in Korea. This organism
      grew well at 25-35 degrees C, with optimum growth at 30 degrees C. Strain TF
      27(T) grew optimally in the presence of 2 % NaCl; it did not grow without NaCl or
      in the presence of >8 % NaCl. Strain TF-27(T) simultaneously contained both
      menaquinones and ubiquinones as isoprenoid quinones. The predominant menaquinone
      was MK-7 and the predominant ubiquinones were Q-7 and Q-8. The major fatty acids
      in strain TF-27(T) were iso-C(15 : 0) (20.6 %) and iso-C(15 : 0) 2-OH and/or C(16
      : 1)omega7c (21.1 %). The DNA G+C content of strain TF-27(T) was 42 mol%.
      Phylogenetic analyses based on 16S rDNA sequences showed that strain TF-27(T)
      falls within the radiation of the cluster that is encompassed by the genus
      Shewanella. Levels of 16S rDNA sequence similarity between strain TF-27(T) and
      the type strains of Shewanella species were 93.2-96.8 %. On the basis of
      phenotypic properties and phylogenetic data, strain TF-27(T) should be placed in
      the genus Shewanella as a novel species, for which the name Shewanella gaetbuli
      sp. nov. is proposed.

PMID- 15023966
TI  - Molecular phylogeny of the heterocystous cyanobacteria (subsections IV and V)
      based on nifD.
AB  - The heterocystous cyanobacteria are currently placed in subsections IV and V,
      which are distinguished by cellular division in one plane (false branching) and
      in more than one plane (true branching), respectively. Published phylogenies of
      16S rRNA gene sequence data support the monophyly of the heterocystous
      cyanobacteria, with members of subsection V embedded within subsection IV. It has
      been postulated that members of subsection V arose from within subsection IV.
      Therefore, phylogenetic analysis of nucleotide sequences of the nitrogen-fixation
      gene nifD from representatives of subsections IV and V was performed by using
      maximum-likelihood criteria. The heterocystous cyanobacteria are supported as
      being monophyletic, with the non-heterocystous cyanobacteria as their closest
      relative. However, neither subsection IV nor subsection V is monophyletic, with
      representatives of both subsections intermixed in two sister clades. Analysis of
      nifD does not support recognition of two distinct subsections.

PMID- 15023967
TI  - Halomonas neptunia sp. nov., Halomonas sulfidaeris sp. nov., Halomonas axialensis
      sp. nov. and Halomonas hydrothermalis sp. nov.: halophilic bacteria isolated from
      deep-sea hydrothermal-vent environments.
AB  - To assess the physiological and phylogenetic diversity of culturable halophilic
      bacteria in deep-sea hydrothermal-vent environments, six isolates obtained from
      low-temperature hydrothermal fluids, sulfide rock and hydrothermal plumes in
      North and South Pacific Ocean vent fields located at 1530-2580 m depth were fully
      characterized. Three strains were isolated on media that contained oligotrophic
      concentrations of organic carbon (0.002 % yeast extract). Sequencing of the 16S
      rRNA gene indicated that all strains belonged to the genus Halomonas in the gamma
      subclass of the Proteobacteria. Consistent with previously described species, the
      novel strains were slightly to moderately halophilic and grew in media containing
      up to 22-27 % total salts. The isolates grew at temperatures as low as -1 to 2
      degrees C and had temperature optima of 30 or 20-35 degrees C. Both the minimum
      and optimum temperatures for growth were similar to those of Antarctic and sea
      ice Halomonas species and lower than typically observed for the genus as a whole.
      Phenotypic tests revealed that the isolates were physiologically versatile and
      tended to have more traits in common with each other than with closely related
      Halomonas species, presumably a reflection of their common deep-sea, hydrothermal
      vent habitat of origin. The G+C content of the DNA for all strains was 56.0-57.6
      mol%, and DNA-DNA hybridization experiments revealed that four strains
      (Eplume1(T), Esulfide1(T), Althf1(T) and Slthf2(T)) represented novel species and
      that two strains (Eplume2 and Slthf1) were related to Halomonas meridiana. The
      proposed new species names are Halomonas neptunia (type strain Eplume1(T)=ATCC
      BAA-805(T)=CECT 5815(T)=DSM 15720(T)), Halomonas sulfidaeris (type strain
      Esulfide1(T)=ATCC BAA-803(T)=CECT 5817(T)=DSM 15722(T)), Halomonas axialensis
      (type strain Althf1(T)=ATCC BAA-802(T)=CECT 5812(T)=DSM 15723(T)) and Halomonas
      hydrothermalis (type strain Slthf2(T)=ATCC BAA-800(T)=CECT 5814(T)=DSM 15725(T)).

PMID- 15023968
TI  - Microbacterium ulmi sp. nov., a xylanolytic, phosphate-solubilizing bacterium
      isolated from sawdust of Ulmus nigra.
AB  - A xylanolytic and phosphate-solubilizing bacterium isolated from sawdust of Ulmus
      nigra in Salamanca was characterized by a polyphasic approach. The novel strain,
      designated XIL02(T), was Gram-positive, aerobic, catalase- and oxidase-negative,
      rod-shaped and non-motile. Phylogenetically and chemotaxonomically, it was
      related to members of the genus Microbacterium. According to 16S rRNA gene
      sequence analysis, it is closely related to Microbacterium arborescens and
      Microbacterium imperiale; however, DNA-DNA hybridization showed reassociation
      values less than 70 % with the type strains of these species. In chemotaxonomic
      analyses, the major menaquinones detected were MK-12, MK-13 and MK-11 and the
      major fatty acids were anteiso-C(15 : 0), anteiso-C(17 : 0) and iso-C(16 : 0);
      the peptidoglycan was of the type B2beta. The G+C content determined was 69 mol%.
      Based on the present data, it is proposed that strain XIL02(T) (=LMG
      20991(T)=CECT 5976(T)) be classified as the type strain of a novel Microbacterium
      species, for which the name Microbacterium ulmi sp. nov. is proposed.

PMID- 15023969
TI  - Tenacibaculum skagerrakense sp. nov., a marine bacterium isolated from the
      pelagic zone in Skagerrak, Denmark.
AB  - A number of bacteria were isolated from sea water in Skagerrak, Denmark, at 30 m
      depth. Two of the isolates, strains D28 and D30(T), belonged to the
      Flavobacteriaceae within the Cytophaga-Flavobacterium-Bacteroides group.
      Sequencing of 16S rRNA genes of the two strains indicated strongly that they
      belonged to the genus Tenacibaculum and that they showed greatest similarity to
      the species Tenacibaculum amylolyticum and Tenacibaculum mesophilum. DNA-DNA
      hybridization values, DNA base composition and phenotypic characteristics
      separated the Skagerrak strains from the other species within TENACIBACULUM:
      Thus, it is concluded that the strains belong to a novel species within the genus
      Tenacibaculum, for which the name Tenacibaculum skagerrakense sp. nov. is
      proposed, with strain D30(T) (=ATCC BAA-458(T)=DSM 14836(T)) as the type strain.

PMID- 15023970
TI  - Yania halotolerans gen. nov., sp. nov., a novel member of the suborder
      Micrococcineae from saline soil in China.
AB  - A novel coccoid, halotolerant actinobacterium, designated strain YIM 70085(T),
      was isolated from a soil sample that was collected in Xinjiang Province, China,
      and characterized by using a polyphasic approach. Optimum growth temperature was
      28 degrees C and growth occurred optimally in culture media that contained 10 %
      KCl. The peptidoglycan type was A4alpha, L-lys-gly-L-Glu. Whole-cell sugars
      consisted of xylose, mannose and galactose. Phospholipids were
      diphosphatidylglycerol, phosphatidylglycerol, one unknown phospholipid, one
      unknown glycolipid and traces of phosphatidylinositol. Menaquinones were MK-8 (83
      %), MK-7 (12 %) and MK-9 (15 %). Predominant fatty acids were i-C(15 : 0) (44.29
      %), ai-C(15 : 0) (35.60 %) and ai-C(17 : 0) (9.74 %). The DNA G+C content was
      53.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that
      strain YIM 70085(T) occupies a branch that is distinct from, although very close
      to, the family Micrococcaceae in the suborder Micrococcineae. Based on its
      phenotypic characteristics, phylogenetic position (as determined by 16S rRNA gene
      sequence analysis) and 16S rDNA signature nucleotide data, it is concluded that
      the isolate represents a novel member of the suborder Micrococcineae, for which
      the name Yania halotolerans gen. nov., sp. nov. is proposed. The type strain is
      YIM 70085(T) (=CCTCC AA001023(T)=DSM 15476(T)).

PMID- 15023971
TI  - Cellulomonas xylanilytica sp. nov., a cellulolytic and xylanolytic bacterium
      isolated from a decayed elm tree.
AB  - A Gram-positive, aerobic, non-motile bacterium was isolated from a decayed elm
      tree. Phylogenetic analysis based on 16S rDNA sequences revealed 99.0 %
      similarity to Cellulomonas humilata. Chemotaxonomic data that were determined for
      this isolate included cell-wall composition, fatty acid profiles and polar
      lipids; the results supported the placement of strain XIL11(T) in the genus
      Cellulomonas. The DNA G+C content was 73 mol%. The results of DNA-DNA
      hybridization with C. humilata ATCC 25174(T), in combination with chemotaxonomic
      and physiological data, demonstrated that isolate XIL11(T) should be classified
      as a novel Cellulomonas species. The name Cellulomonas xylanilytica sp. nov. is
      proposed, with strain XIL11(T) (=LMG 21723(T)=CECT 5729(T)) as the type strain.

PMID- 15023972
TI  - Taxonomy of the canine Mollicutes by 16S rRNA gene and 16S/23S rRNA intergenic
      spacer region sequence comparison.
AB  - The taxonomy of canine Mollicutes is described, based on phylogenetic analysis of
      16S rRNA gene and 16S/23S rRNA intergenic spacer (IGS) region sequences. The
      nucleotide sequences of the 16S rRNA gene of two untyped mycoplasmas and the IGS
      region of 11 Mycoplasma species were determined and used for phylogenetic
      analysis. The two untyped Mycoplasma strains, HRC 689 and VJC 358, were found to
      be distinct from all known canine mycoplasmas and all published mycoplasma 16S
      rRNA gene sequences.

PMID- 15023973
TI  - 'Candidatus Rhabdochlamydia porcellionis', an intracellular bacterium from the
      hepatopancreas of the terrestrial isopod Porcellio scaber (Crustacea: Isopoda).
AB  - Intracellular bacteria were observed in the hepatopancreas of the terrestrial
      isopod Porcellio scaber. Comparative 16S rRNA gene sequence analysis and electron
      microscopic observations were used to determine the taxonomic position of these
      intracellular bacteria. Phylogenetic analysis and a complex developmental cycle
      affiliate these bacteria to the order Chlamydiales, within which they form a
      distinctive lineage, close to the family Simkaniaceae. They share <92 % 16S rRNA
      gene sequence similarity with their closest relative and <88 % similarity with
      other members of the order Chlamydiales. A specific signature oligonucleotide
      sequence was identified and used as a probe, enabling the identification of
      intracellular bacteria in infected hepatopancreatic tissue. According to the
      distinctive morphology of their elementary bodies, which are rod-shaped rather
      than spherical and contain translucent oblong structures, their genomic
      properties and their crustacean host, the name 'Candidatus Rhabdochlamydia
      porcellionis' is proposed for intracellular bacteria in the hepatopancreas of P.
      scaber.

PMID- 15023975
TI  - Xylanibacterium ulmi gen. nov., sp. nov., a novel xylanolytic member of the
      family Promicromonosporaceae.
AB  - A bacterial strain designated XIL08(T) was isolated from an elm tree affected by
      Dutch elm disease. Strain XIL08(T) is Gram-positive, aerobic, rod-shaped and non
      motile. The complete 16S rDNA sequence of this micro-organism was obtained and
      phylogenetic analysis based on the neighbour-joining method indicated that the
      closest related organism belongs to the genus Xylanimonas of the family
      Promicromonosporaceae, suborder Micrococcineae. Cell-wall analyses revealed the
      presence of type A4alpha, L-lys-L-ala-D-Glu peptidoglycan. The cell-wall sugars
      found were rhamnose in large amounts, fucose, mannose and galactose and traces of
      arabinose and glucose. HPLC analysis of menaquinones revealed two peaks, the main
      peak corresponding to MK-9(H(4)) and the smaller one to MK-8(H(4)). The major
      fatty acid found was anteiso-C(15 : 0). Mycolic acids were absent. The polar
      lipids detected were phosphatidylglycerol, diphosphatidylglycerol,
      phosphatidylinositol and phosphatidylinositol mannosides. The G+C content of the
      DNA was 72 mol%. Isolate XIL08(T) hydrolysed xylan but not cellulose. Growth was
      observed with many carbohydrates including acetate and xylan as the only carbon
      source. Catalase activity was not detected. The data from this polyphasic study
      suggest that this bacterium belongs to a novel genus of the family
      Promicromonosporaceae. It is proposed that isolate XIL08(T) (=LMG 21721(T)=CECT
      5731(T)) be classified in a new genus, Xylanibacterium gen. nov., as the type
      strain of Xylanibacterium ulmi sp. nov.

PMID- 15023974
TI  - Reclassification of Lactobacillus kefirgranum Takizawa et al. 1994 as
      Lactobacillus kefiranofaciens subsp. kefirgranum subsp. nov. and emended
      description of L. kefiranofaciens Fujisawa et al. 1988.
AB  - Fourteen homofermentative lactic acid bacteria that were isolated from kefir
      grains and kefir fermented milks were assigned to either Lactobacillus
      kefiranofaciens or Lactobacillus kefirgranum, based on their characteristic
      morphotypes, phenotypic features and SDS-PAGE profiles of whole-cell proteins.
      Further genotypic analyses on representative strains from both taxa demonstrated
      that L. kefiranofaciens and L. kefirgranum share 100 % 16S rDNA sequence
      similarity and belong phylogenetically to the Lactobacillus acidophilus species
      group. DNA-DNA binding values of >79 % and analogous DNA G+C contents of 37-38
      mol% showed that the strains studied belonged to one species: L. kefirgranum is a
      later synonym of L. kefiranofaciens. An emended description is proposed for L.
      kefiranofaciens. Due to the specific morphological and biochemical
      characteristics of these taxa in kefir grain formation, it is proposed that L.
      kefirgranum should be reclassified as L. kefiranofaciens subsp. kefirgranum
      subsp. nov.

PMID- 15023976
TI  - Nocardia inohanensis sp. nov., Nocardia yamanashiensis sp. nov. and Nocardia
      niigatensis sp. nov., isolated from clinical specimens.
AB  - Comparative 16S rDNA studies on six strains of actinomycete isolated from
      clinical specimens revealed that they belong to the genus Nocardia and are
      closely related to Nocardia seriolae, Nocardia otitidiscaviarum, Nocardia
      uniformis, Nocardia pseudobrasiliensis and Nocardia crassostreae. However, the
      novel organisms consistently formed a clade distinct from that of the five latter
      species. Determination of DNA-DNA relatedness indicated that these strains could
      be classified under three novel species. Based on their phenotypic and
      phylogenetic characters, three novel species of the genus Nocardia are
      established: Nocardia inohanensis sp. nov. for IFM 0092(T) (=NBRC 100128(T)=JCM
      11891(T)=DSM 44667(T)), Nocardia yamanashiensis sp. nov. for IFM 0265(T) (=NBRC
      100130(T)=JCM 11893(T)=DSM 44669(T)) and Nocardia niigatensis sp. nov. for IFM
      0330(T) (=NBRC 100131(T)=JCM 11894(T)=DSM 44670(T)), IFM 0260, IFM 0636 and IFM
      0833.

PMID- 15023977
TI  - Aestuariibacter salexigens gen. nov., sp. nov. and Aestuariibacter halophilus sp.
      nov., isolated from tidal flat sediment, and emended description of Alteromonas
      macleodii.
AB  - Two strictly aerobic, halophilic strains of the gamma-Proteobacteria, designated
      JC2042(T) and JC2043(T), were obtained from a sediment sample of getbol, the
      Korean tidal flat. Comparative 16S rDNA sequence studies revealed that the test
      strains were related most closely to the type strains of the genera Alteromonas
      (93.5-95.5 %) and Glaciecola (91.1-93.3 %). Phylogenetic analyses demonstrated
      that strains JC2042(T) and JC2043(T) formed a distinct monophyletic clade within
      the family Alteromonadaceae and clustered distantly with the genera Alteromonas
      and Glaciecola. Physiological, biochemical and chemotaxonomic data also indicated
      that the two getbol isolates were significantly different from members of these
      two genera and others with validly published names. Cells were rod-shaped and
      motile with a polar flagellum. The major isoprenoid quinone was Q8. The
      predominant cellular fatty acids were C(16 : 0), C(18 : 1)omega7c and a mixture
      of C(16 : 1)omega7c and iso-C(15 : 0) 2-OH. DNA G+C contents were 48-54 mol%. On
      the basis of this polyphasic study, Aestuariibacter gen. nov. is proposed with
      two novel species, Aestuariibacter salexigens sp. nov. (type strain,
      JC2042(T)=IMSNU 14006(T)=KCTC 12042(T)=DSM 15300(T)) and Aestuariibacter
      halophilus sp. nov. (type strain, JC2043(T)=IMSNU 14007(T)=KCTC 12043(T)=DSM
      15266(T)). Aestuariibacter salexigens is the type species of the genus. In
      addition, an emended description of Alteromonas macleodii is proposed.

PMID- 15023978
TI  - Streptomyces scabrisporus sp. nov.
AB  - The taxonomic position was determined for a soil actinomycete, isolate KM
      4927(T), that produced the antibiotic hitachimycin. The strain was assigned to
      the genus Streptomyces on the basis of 16S rDNA analysis, where it formed a
      separate clade. The strain is characterized by grey aerial cell mass, spiral
      spore chains and a rugose spore surface, menaquinones of the MK-9(H(4), H(2),
      H(6)) types and cell-wall chemotype I. DNA-DNA reassociation with 21
      phylogenetically neighbouring Streptomyces type strains showing similar
      morphological characteristics to strain KM-4927(T) indicated that this isolate is
      only moderately related to other Streptomyces species. On the basis of genomic
      and physiological properties, the novel species Streptomyces scabrisporus sp.
      nov. is proposed; the type strain is strain KM-4927(T) (=JCM 11712(T)=NRRL B
      24202(T)).

PMID- 15023979
TI  - Genetic diversity of Leptotrichia and description of Leptotrichia goodfellowii
      sp. nov., Leptotrichia hofstadii sp. nov., Leptotrichia shahii sp. nov. and
      Leptotrichia wadei sp. nov.
AB  - Sixty strains of Gram-negative, anaerobic, rod-shaped bacteria from human sources
      initially assigned to Leptotrichia buccalis (n=58) and 'Leptotrichia
      pseudobuccalis' (n=2) have been subjected to polyphasic taxonomy. Full-length 16S
      rDNA sequencing, DNA-DNA hybridization, RAPD, SDS-PAGE of whole-cell proteins,
      cellular fatty acid analysis and enzymic/biochemical tests supported the
      establishment of four novel Leptotrichia species from this collection,
      Leptotrichia goodfellowii sp. nov. (type strain LB 57(T)=CCUG 32286(T)=CIP
      107915(T)), Leptotrichia hofstadii sp. nov. (type strain LB 23(T)=CCUG
      47504(T)=CIP 107917(T)), Leptotrichia shahii sp. nov. (type strain LB 37(T)=CCUG
      47503(T)=CIP 107916(T)) and Leptotrichia wadei sp. nov. (type strain LB
      16(T)=CCUG 47505(T)=CIP 107918(T)). Light and electron microscopy showed that the
      four novel species were Gram-negative, non-spore-forming and non-motile rods. L.
      goodfellowii produced arginine dihydrolase, beta-galactosidase, N-acetyl-beta
      glucosaminidase, arginine arylamidase, leucine arylamidase and histidine
      arylamidase. L. shahii produced alpha-arabinosidase. L. buccalis and L.
      goodfellowii fermented mannose and were beta-galactosidase-6-phosphate positive.
      L. goodfellowii, L. hofstadii and L. wadei were beta-haemolytic. L. buccalis
      fermented raffinose. With L. buccalis, L. goodfellowii showed 3.8-5.5 % DNA-DNA
      relatedness, L. shahii showed 24.5-34.1 % relatedness, L. hofstadii showed 27.3
      36.3 % relatedness and L. wadei showed 24.1-35.9 % relatedness. 16S rDNA
      sequencing demonstrated that L. hofstadii, L. shahii, L. wadei and L.
      goodfellowii each formed individual clusters with 97, 96, 94 and 92 % similarity,
      respectively, to L. buccalis.

PMID- 15023980
TI  - Phylogenetic analysis of the genera Streptomyces and Kitasatospora based on
      partial RNA polymerase beta-subunit gene (rpoB) sequences.
AB  - The RNA polymerase beta-subunit genes (rpoB) of 67 Streptomyces strains,
      representing 57 species, five Kitasatospora strains and Micromonospora
      echinospora KCTC 9549 were partially sequenced using a pair of rpoB PCR primers.
      Among the streptomycetes, 99.7-100 % similarity within the same species and 90.2
      99.3 % similarity at the interspecific level were observed by analysis of the
      determined rpoB sequences. The topology of the phylogenetic tree based on rpoB
      sequences was similar to that of 16S rDNA. The five Kitasatospora strains formed
      a stable monophyletic clade and a sister group to the clade comprising all
      Streptomyces species. Although there were several discrepancies in the details,
      considerable agreement was found between the results of rpoB analysis and those
      of numerical phenetic classification. This study demonstrates that analysis of
      rpoB can be used as an alternative genetic method in parallel to conventional
      taxonomic methods, including numerical phenetic and 16S rDNA analyses, for the
      phylogenetic analyses of the genera Streptomyces and Kitasatospora.

PMID- 15023981
TI  - Nocardia neocaledoniensis sp. nov., a novel actinomycete isolated from a New
      Caledonian brown hypermagnesian ultramafic soil.
AB  - The taxonomic position of an actinomycete isolated from a hypermagnesian
      ultramafic soil was examined using a polyphasic approach. The strain, designated
      SBH(R) OA6(T), was shown to have chemical and morphological properties typical of
      members of the genus Nocardia. The organism was most closely associated with
      Nocardia asteroides using 16S rRNA gene sequence data. It showed a distinctive
      set of phenotypic properties that distinguished it from representatives of all
      species with validly published names classified in the genus Nocardia. The
      combined genotypic and phenotypic data show that strain SBH(R) OA6(T) (=DSM
      44717(T)=NCIMB 13955(T)) merits description as the type strain of a novel
      Nocardia species, Nocardia neocaledoniensis sp. nov.

PMID- 15023982
TI  - Arsenicicoccus bolidensis gen. nov., sp. nov., a novel actinomycete isolated from
      contaminated lake sediment.
AB  - An unknown Gram-positive, catalase-positive, facultatively anaerobic, non-spore
      forming, coccus-shaped bacterium originating from sediment was characterized
      using phenotypic, molecular chemical and molecular phylogenetic methods. Chemical
      studies revealed the presence of a cell-wall murein based on LL-diaminopimelic
      acid (type LL-Dpm-glycine(1)), a complex mixture of saturated, monounsaturated
      and iso- and anteiso-methyl-branched, non-hydroxylated, long-chain cellular fatty
      acids and tetrahydrogenated menaquinones with eight isoprene units [MK-8(H(4))]
      as the major respiratory lipoquinone. This combination of characteristics
      somewhat resembled members of the suborder Micrococcineae, but did not correspond
      to any currently described species. Comparative 16S rRNA gene sequencing
      confirmed that the unidentified coccus-shaped organism is a member of the
      Actinobacteria and represents a hitherto-unknown subline related to, albeit
      different from, a number of taxa including Intrasporangium, Janibacter,
      Terrabacter, Terracoccus and Ornithinicoccus. Based on phenotypic and
      phylogenetic considerations, it is proposed that the unknown bacterium
      originating from lake sediment be classified as a new genus and species,
      Arsenicicoccus bolidensis gen. nov., sp. nov. (type strain CCUG 47306(T)=DSM
      15745(T)).

PMID- 15023983
TI  - Cellulophaga pacifica sp. nov.
AB  - Three marine, heterotrophic, aerobic, agarolytic, pigmented and gliding bacteria
      were isolated in June 2000 from a sea water sample that was collected in the Gulf
      of Peter the Great, Sea of Japan, and analysed in a polyphasic taxonomic study.
      16S rDNA sequence analysis indicated that strains KMM 3664(T), KMM 3669 and KMM
      3915 were members of the family Flavobacteriaceae. Based on phenotypic,
      chemotaxonomic, genotypic and phylogenetic data, the isolates were classified in
      the genus Cellulophaga as members of a novel species, Cellulophaga pacifica sp.
      nov. The type strain is KMM 3664(T) (=JCM 11735(T)=LMG 21938(T)).

PMID- 15023984
TI  - Reclassification of Brevibacterium liquefaciens Okabayashi and Masuo 1960 as
      Arthrobacter nicotianae Giovannozzi-Sermanni 1959.
AB  - Brevibacterium liquefaciens ATCC 14929(T) was reclassified as Corynebacterium
      liquefaciens by Laneelle et al. (1980). A further study by Stackebrandt et al.
      (1983) described the same strain, indicating high genomic and chemotaxonomic
      relatedness to Arthrobacter nicotianae; however, reclassification was not
      formally proposed. Because of the discrepancies between their previous work and
      the data of Collins & Kroppenstedt (1983), Laneelle and colleagues re-examined B.
      liquefaciens and withdrew their recommendation for the assignment of B.
      liquefaciens to the genus Corynebacterium (Laneelle et al., 1984). Formal
      reclassification of B. liquefaciens as A. nicotianae is now proposed.

PMID- 15023985
TI  - Bacillus galactosidilyticus sp. nov., an alkali-tolerant beta-galactosidase
      producer.
AB  - A novel Bacillus isolate from raw milk and four strains from diverse origins that
      were identified previously as Bacillus lentus, Bacillus firmus and Bacillus
      circulans showed a high degree of similarity in amplified rDNA restriction
      analysis, SDS-PAGE and routine phenotypic tests, whilst 16S rDNA sequence
      comparisons and DNA relatedness data showed that this taxon was different from
      related Bacillus species. On the basis of these data, Bacillus galactosidilyticus
      sp. nov. is proposed, with the type strain LMG 17892(T) (=DSM 15595(T)=Logan
      B2188(T)=MB 800(T)).

PMID- 15023986
TI  - Malassezia nana sp. nov., a novel lipid-dependent yeast species isolated from
      animals.
AB  - Five isolates of a novel species of the yeast genus Malassezia were isolated from
      animals in Japan and Brazil. Phylogenetic trees based on the D1/D2 domains of the
      large-subunit (26S) rDNA sequences and nucleotide sequences of the internal
      transcribed spacer 1 region showed that the isolates were conspecific and
      belonged to the genus Malassezia. They were related closely to Malassezia
      dermatis and Malassezia sympodialis, but were clearly distinct from these two
      species and the other six species of Malassezia that have been reported,
      indicating that they should be classified as a novel species, Malassezia nana sp.
      nov. Morphologically and physiologically, M. nana resembles M. dermatis and M.
      sympodialis, but can be distinguished from these species by its inability to use
      Cremophor EL (Sigma) as the sole lipid source and to hydrolyse aesculin. The type
      strain of M. nana is NUSV 1003(T) (=CBS 9557(T)=JCM 12085(T)).

PMID- 15023992
TI  - Arginase plays a pivotal role in polyamine precursor metabolism in Leishmania.
      Characterization of gene deletion mutants.
AB  - The polyamine pathway of protozoan parasites has been successfully targeted in
      anti-parasitic therapies and is significantly different from that of the
      mammalian host. To gain knowledge into the metabolic routes by which parasites
      synthesize polyamines and their precursors, the arginase gene was cloned from
      Leishmania mexicana, and Deltaarg null mutants were created by double targeted
      gene replacement and characterized. The ARG sequence exhibited significant
      homology to ARG proteins from other organisms and predicted a peroxisomal
      targeting signal (PTS-1) that steers proteins to the glycosome, an organelle
      unique to Leishmania and related parasites. ARG was subsequently demonstrated to
      be present in the glycosome, whereas the polyamine biosynthetic enzymes, in
      contrast, were shown to be cytosolic. The Deltaarg knockouts expressed no ARG
      activity, lacked an intracellular ornithine pool, and were auxotrophic for
      ornithine or polyamines. The ability of the Deltaarg null mutants to proliferate
      could be restored by pharmacological supplementation, either with low putrescine
      or high ornithine or spermidine concentrations, or by complementation with an
      arginase episome. Transfection of an arg construct lacking the PTS-1 directed the
      synthesis of an arg that mislocalized to the cytosol and notably also
      complemented the genetic lesion and restored polyamine prototrophy to the
      Deltaarg parasites. This molecular, biochemical, and genetic dissection of ARG
      function in L. mexicana promastigotes establishes: (i) that the enzyme is
      essential for parasite viability; (ii) that Leishmania, unlike mammalian cells,
      expresses only one ARG activity; (iii) that the sole vital function of ARG is to
      provide polyamine precursors for the parasite; and (iv) that ARG is present in
      the glycosome, but this subcellular milieu is not essential for its role in
      polyamine biosynthesis.

PMID- 15023990
TI  - A tyrosine-based sorting signal regulates intracellular trafficking of protease
      activated receptor-1: multiple regulatory mechanisms for agonist-induced G
      protein-coupled receptor internalization.
AB  - Protease-activated receptor-1 (PAR1), a G protein-coupled receptor (GPCR) for
      thrombin, is irreversibly proteolytically activated, internalized, and then
      sorted to lysosomes and degraded. Internalization and lysosomal sorting of
      activated PAR1 is critical for termination of receptor signaling. We previously
      demonstrated that activated PAR1 is rapidly phosphorylated and internalized via a
      clathrin- and dynamin-dependent pathway that is independent of arrestins. Toward
      understanding the mechanisms responsible for activated PAR1 internalization
      through clathrin-coated pits we examined the function of a highly conserved
      tyrosine-based motif, YXXL, localized in the cytoplasmic carboxyl tail of the
      receptor. A mutant PAR1 in which tyrosine 383 and leucine 386 were replaced with
      alanines (Y383A/L386A) was significantly impaired in agonist-triggered
      internalization and degradation compared with wild-type receptor. In contrast,
      constitutive internalization, and recycling of unactivated PAR1 Y383A/L386A
      mutant was not affected, suggesting that tonic cycling of the mutant receptor
      remained intact. Strikingly, a PAR1 C387Z truncation mutant in which the YXXL
      motif was exposed at the C terminus constitutively internalized and degraded in
      an agonist-independent manner, whereas C387Z truncation mutant in which the
      critical tyrosine and leucine were mutated to alanine (C387Z-Y383A/L386A) failed
      to internalize. Inhibition of PAR1 C387Z mutant constitutive internalization with
      dominant-negative K44A dynamin blocked agonist-independent degradation of the
      mutant receptor. Together these findings strongly suggest that internalization of
      activated PAR1 is controlled by multiple regulatory mechanisms involving
      phosphorylation and a highly conserved tyrosine-based motif, YXXL. This study is
      the first to describe a function for a tyrosine-based motif, YXX, in GPCR
      internalization and reveal novel complexities in the regulation of GPCR
      trafficking.

PMID- 15023991
TI  - Activation of the redox-regulated chaperone Hsp33 by domain unfolding.
AB  - The molecular chaperone Hsp33 in Escherichia coli responds to oxidative stress
      conditions with the rapid activation of its chaperone function. On its activation
      pathway, Hsp33 progresses through three major conformations, starting as a
      reduced, zinc-bound inactive monomer, proceeding through an oxidized zinc-free
      monomer, and ending as a fully active oxidized dimer. While it is known that
      Hsp33 senses oxidative stress through its C-terminal four-cysteine zinc center,
      the nature of the conformational changes in Hsp33 that must take place to
      accommodate this activation process is largely unknown. To investigate these
      conformational rearrangements, we constructed constitutively monomeric Hsp33
      variants as well as fragments consisting of the redox regulatory C-terminal
      domain of Hsp33. These proteins were studied by a combination of biochemical and
      NMR spectroscopic techniques. We found that in the reduced, monomeric
      conformation, zinc binding stabilizes the C terminus of Hsp33 in a highly
      compact, alpha-helical structure. This appears to conceal both the substrate
      binding site as well as the dimerization interface. Zinc release without
      formation of the two native disulfide bonds causes the partial unfolding of the C
      terminus of Hsp33. This is sufficient to unmask the substrate-binding site, but
      not the dimerization interface, rendering reduced zinc-free Hsp33 partially
      active yet monomeric. Critical for the dimerization is disulfide bond formation,
      which causes the further unfolding of the C terminus of Hsp3 and allows the
      association of two oxidized Hsp33 monomers. This then leads to the formation of
      active Hsp33 dimers, which are capable of protecting cells against the severe
      consequences of oxidative heat stress.

PMID- 15023993
TI  - Activation of human TRPC6 channels by receptor stimulation.
AB  - The human TRPC6 channel was expressed in human embryonic kidney (HEK) cells, and
      activity was monitored using the giga-seal technique. Whole cell membrane
      currents with distinctive inward and outward rectification were activated by
      carbachol (CCh) in TRPC6-expressing cells, but not in lacZ-transfected controls.
      The effect of CCh was steeply dose-dependent with a K(0.5) of approximately 10
      microm and a Hill coefficient of 3-4. A steep concentration-response relationship
      was also observed when TRPC6 activity was measured using a fluorescence-based
      imaging plate reader (FLIPR) assay for membrane depolarization. Ionomycin,
      thapsigargin, and dialysis of the cell with inositol 1,4,5-trisphosphate via the
      patch pipette had no effect on TRPC6 currents, but exogenous application of 1
      oleoyl acetyl-sn-glycerol (OAG, 30-300 microm) produced a slow increase in
      channel activity. The PKC activator, phorbol 12-myristate 13-acetate (PMA, 0.5
      microm) had no significant acute effect on TRPC6, or on the subsequent response
      to OAG. In contrast, the response to CCh was blocked >90% by PMA pretreatment. To
      further explore the role of DAG in receptor stimulation, TRPC6 currents were
      monitored following the sequential addition of CCh and OAG. Surprisingly,
      concentrations of CCh that produced little or no response in the absence of OAG,
      produced increases in TRPC6 currents in the presence of OAG that were larger than
      the sum of either agent alone. Likewise, the response to OAG was superadditive
      following prior stimulation of the cells with near threshold concentrations of
      CCh. Overall, these results suggest that generation of DAG alone may not fully
      account for activation of TRPC6, and that other receptor-mediated events act
      synergistically with DAG to stimulate channel activity. This synergy may explain,
      at least in part, the steep dose-response relationship observed for CCh-induced
      TRPC6 currents expressed in HEK cells.

PMID- 15023994
TI  - On evolutionary conservation of thermodynamic coupling in proteins.
AB  - The inherent complexity of thermodynamic coupling in proteins presents a major
      challenge in understanding and engineering protein function. Recent work has
      argued that the study of proteins can be simplified by the use of correlated
      mutations in the evolutionary record to locate a small subset of
      thermodynamically coupled residues that participate in functionally important,
      evolutionarily conserved energetic pathways. To test this hypothesis, we examined
      the predictions of correlated mutation algorithms for a number of proteins for
      which coupling between residues has been determined by analysis of double mutant
      cycles. We find that correlated mutation algorithms can find residue pairs that
      are physically close and that physically close residue pairs tend to be
      thermodynamically coupled. We find little evidence, however, for the hypothesis
      that thermodynamic coupling is limited to the subset of evolutionarily
      constrained residue positions.

PMID- 15023996
TI  - Junction of RecQ helicase biochemistry and human disease.

PMID- 15023997
TI  - Structure and function of the glycine receptor and related nicotinicoid
      receptors.

PMID- 15023995
TI  - Activation of peroxisome proliferator-activated receptor gamma inhibits
      interleukin-1beta-induced membrane-associated prostaglandin E2 synthase-1
      expression in human synovial fibroblasts by interfering with Egr-1.
AB  - Membrane-associated prostaglandin (PG) E(2) synthase-1 (mPGES-1) catalyzes the
      conversion of PGH(2) to PGE(2), which contributes to many biological processes.
      Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand
      activated transcription factor and plays an important role in growth,
      differentiation, and inflammation in different tissues. Here, we examined the
      effect of PPARgamma ligands on interleukin-1beta (IL-1beta)-induced mPGES-1
      expression in human synovial fibroblasts. PPARgamma ligands 15-deoxy-Delta(12,14)
      prostaglandin J(2) (15d-PGJ(2)) and the thiazolidinedione troglitazone (TRO), but
      not PPARalpha ligand Wy14643, dose-dependently suppressed IL-1beta-induced PGE(2)
      production, as well as mPGES-1 protein and mRNA expression. 15d-PGJ(2) and TRO
      suppressed IL-1beta-induced activation of the mPGES-1 promoter. Overexpression of
      wild-type PPARgamma further enhanced, whereas overexpression of a dominant
      negative PPARgamma alleviated, the suppressive effect of both PPARgamma ligands.
      Furthermore, pretreatment with an antagonist of PPARgamma, GW9662, relieves the
      suppressive effect of PPARgamma ligands on mPGES-1 protein expression, suggesting
      that the inhibition of mPGES-1 expression is mediated by PPARgamma. We
      demonstrated that PPARgamma ligands suppressed Egr-1-mediated induction of the
      activities of the mPGES-1 promoter and of a synthetic reporter construct
      containing three tandem repeats of an Egr-1 binding site. The suppressive effect
      of PPARgamma ligands was enhanced in the presence of a PPARgamma expression
      plasmid. Electrophoretic mobility shift and supershift assays for Egr-1 binding
      sites in the mPGES-1 promoter showed that both 15d-PGJ(2) and TRO suppressed IL
      1beta-induced DNA-binding activity of Egr-1. These data define mPGES-1 and Egr-1
      as novel targets of PPARgamma and suggest that inhibition of mPGES-1 gene
      transcription may be one of the mechanisms by which PPARgamma regulates
      inflammatory responses.

PMID- 15023998
TI  - Lysophospholipid G protein-coupled receptors.
AB  - The many biological responses documented for lysophospholipids that include
      lysophosphatidic acid and sphingosine 1-phosphate can be mechanistically
      attributed to signaling through specific G protein-coupled receptors. At least
      nine receptors have now been identified, and the total number is likely to be
      larger. In this brief review, we note cogent features of lysophospholipid
      receptors, including the current nomenclature, signaling properties, development
      of agonists and antagonists, and physiological functions.

PMID- 15023999
TI  - My love affair with insulin.

PMID- 15024001
TI  - Ca(2+) homeostasis during mitochondrial fragmentation and perinuclear clustering
      induced by hFis1.
AB  - Mitochondria modulate Ca(2+) signals by taking up, buffering, and releasing
      Ca(2+) at key locations near Ca(2+) release or influx channels. The role of such
      local interactions between channels and organelles is difficult to establish in
      living cells because mitochondria form an interconnected network constantly
      remodeled by coordinated fusion and fission reactions. To study the effect of a
      controlled disruption of the mitochondrial network on Ca(2+) homeostasis, we took
      advantage of hFis1, a protein that promotes mitochondrial fission by recruiting
      the dynamin-related protein, Drp1. hFis1 expression in HeLa cells induced a rapid
      and complete fragmentation of mitochondria, which redistributed away from the
      plasma membrane and clustered around the nucleus. Despite the dramatic
      morphological alteration, hFis1-fragmented mitochondria maintained a normal
      transmembrane potential and pH and took up normally the Ca(2+) released from
      intracellular stores upon agonist stimulation, as measured with a targeted
      ratiometric pericam probe. In contrast, hFis1-fragmented mitochondria took up
      more slowly the Ca(2+) entering across plasma membrane channels, because the
      Ca(2+) ions reaching mitochondria propagated faster and in a more coordinated
      manner in interconnected than in fragmented mitochondria. In parallel cytosolic
      fura-2 measurements, the capacitative Ca(2+) entry (CCE) elicited by store
      depletion was only marginally reduced by hFis1 expression. Regardless of
      mitochondria shape and location, disruption of mitochondrial potential with
      uncouplers or oligomycin/rotenone reduced CCE by approximately 35%. These
      observations indicate that close contact to Ca(2+) influx channels is not
      required for CCE modulation and that the formation of a mitochondrial network
      facilitates Ca(2+) propagation within interconnected mitochondria.

PMID- 15024000
TI  - Human 1-D-myo-inositol-3-phosphate synthase is functional in yeast.
AB  - We have cloned, sequenced, and expressed a human cDNA encoding 1-d-myo-inositol-3
      phosphate (MIP) synthase (hINO1). The encoded 62-kDa human enzyme converted d
      glucose 6-phosphate to 1-d-myo-inositol 3-phosphate, the rate-limiting step for
      de novo inositol biosynthesis. Activity of the recombinant human MIP synthase
      purified from Escherichia coli was optimal at pH 8.0 at 37 degrees C and
      exhibited K(m) values of 0.57 mm and 8 microm for glucose 6-phosphate and NAD(+),
      respectively. NH(4)(+) and K(+) were better activators than other cations tested
      (Na(+), Li(+), Mg(2+), Mn(2+)), and Zn(2+) strongly inhibited activity.
      Expression of the protein in the yeast ino1Delta mutant lacking MIP synthase
      (ino1Delta/hINO1) complemented the inositol auxotrophy of the mutant and led to
      inositol excretion. MIP synthase activity and intracellular inositol were
      decreased about 35 and 25%, respectively, when ino1Delta/hINO1 was grown in the
      presence of a therapeutically relevant concentration of the anti-bipolar drug
      valproate (0.6 mm). However, in vitro activity of purified MIP synthase was not
      inhibited by valproate at this concentration, suggesting that inhibition by the
      drug is indirect. Because inositol metabolism may play a key role in the etiology
      and treatment of bipolar illness, functional conservation of the key enzyme in
      inositol biosynthesis underscores the power of the yeast model in studies of this
      disorder.

PMID- 15024003
TI  - Extracellular matrix-induced cyclooxygenase-2 regulates macrophage proteinase
      expression.
AB  - Chronic inflammatory diseases are characterized by the persistent presence of
      macrophages and other mononuclear cells, tissue destruction, cell proliferation,
      and the deposition of extracellular matrix (ECM). The tissue degradation is
      mediated, in part, by enhanced proteinase expression by macrophages. It has been
      demonstrated recently that macrophage proteinase expression can be stimulated or
      inhibited by purified ECM components. However, in an intact ECM the biologically
      active domains of matrix components may be masked either by tertiary conformation
      or by complex association with other matrix molecules. In an effort to determine
      whether a complex ECM produced by vascular smooth muscle cells (SMC) regulates
      macrophage degradative phenotype, we prepared insoluble SMC matrices and examined
      their ability to regulate proteinase expression by RAW264.7 and thioglycollate
      elicited peritoneal macrophages. Here we demonstrate that macrophage engagement
      of SMC-ECM triggers PKC-dependent activation of MAPK(erk1/2) leading to increased
      expression of cyclooxygenase (COX)-2 and prostaglandin (PG) E(2) synthesis. The
      addition of PGE(2) to macrophage cultures stimulates their expression of both
      urokinase-type plasminogen activator and MMP-9, and the selective COX-2 inhibitor
      NS-398 blocks ECM-induced proteinase expression. Moreover, ECM-induced PGE(2) and
      MMP-9 expression by elicited COX-2(-/-) macrophages is markedly reduced when
      compared with the response of either COX-2(+/-) or COX-2(+/+) macrophages. These
      data clearly demonstrate that SMC-ECM exerts a regulatory role on the degradative
      phenotype of macrophages via enhanced urokinase-type plasminogen activator and
      MMP-9 expression, and identify COX-2 as a targetable component of the signaling
      pathway leading to increased proteinase expression.

PMID- 15024002
TI  - A choline-deficient diet in mice inhibits neither the CDP-choline pathway for
      phosphatidylcholine synthesis in hepatocytes nor apolipoprotein B secretion.
AB  - Phosphatidylcholine is a major component of very low density lipoproteins (VLDLs)
      secreted by the liver. Hepatic phosphatidylcholine is synthesized from choline
      via the CDP-choline pathway and from the phosphatidylethanolamine N
      methyltransferase pathway. Elimination of the methyltransferase in male mice
      reduces hepatic VLDL secretion. Our objective was to determine whether inhibition
      of the CDP-choline pathway for phosphatidylcholine synthesis (by restricting the
      supply of choline) also impaired VLDL secretion. In mice fed a choline-deficient
      (CD), compared with a choline-supplemented, diet for 21 days, the amounts of
      plasma apolipoproteins (apo) B100 and B48 were reduced and the liver
      triacylglycerol content was increased. Hepatocytes were isolated from male mice
      that had been fed the CD diet for 3 or 21 days, and the cells were incubated with
      or without choline. The secretion of apoB100 and B48 from CD hepatocytes was not
      reduced, and triacylglycerol secretion was only modestly decreased, compared with
      that from cells supplemented with choline. Remarkably, in light of widely held
      assumptions, the rate of phosphatidylcholine synthesis from the CDP-choline
      pathway was not decreased in CD hepatocytes. Rather, there was a trend toward
      increased phosphatidylcholine synthesis that might be explained by enhanced
      CTP:phosphocholine cytidylyltransferase activity. Although the concentration of
      phosphocholine in CD hepatocytes was reduced, the size of the phosphocholine pool
      remained well above the K for the cytidylyltransferase. Moreover, the amount and
      m activity of the cytidylyltransferase and methyltransferase were increased. The
      reduction in plasma apoB in mice deprived of dietary choline cannot, therefore,
      be attributed to decreased apoB secretion.

PMID- 15024004
TI  - Cloning and characterization of diacylglycerol kinase iota splice variants in rat
      brain.
AB  - Diacylglycerol kinase (DGK) catalyzes phosphorylation of a second messenger
      diacylglycerol (DG) to phosphatidic acid in cellular signal transduction.
      Previous studies have revealed that DGK consists of a family of isozymes
      including our rat clones. In this study we isolated from rat brain cDNA library
      the cDNA clones for a rat homologue of DGKiota (rDGKiota-1) that contains two
      zinc finger-like sequences, the highly conserved DGK catalytic domain, a
      bipartite nuclear localization signal, and four ankyrin repeats at the carboxyl
      terminus. In addition, we found novel splice variants, which contain either
      insertion 1 (71 bp) or insertion 2 (19 bp) or both in the carboxyl-terminal
      portion. Each of the insertions causes a frameshift, and the resultant premature
      stop codons produce two truncated forms (termed rDGKiota-2 and -iota-3), the
      former lacking the ankyrin repeats at the carboxyl terminus and the latter
      lacking a part of the catalytic domain and the ankyrin repeats. Truncation of the
      carboxyl-terminal portion clearly exerts effects on the detergent solubility and
      enzymatic activity of the splice variants, although all three variants showed
      similar cytoplasmic localization in cDNA-transfected cultured neurons despite the
      continued presence of the nuclear localization signal sequence. Immunoblot
      analysis using anti-rDGKiota antibody raised against the common amino-terminal
      portion clearly shows that these rDGKiota variants are indeed expressed in the
      brain. These results suggest that the carboxyl-terminal truncated forms of
      rDGKiota-2 and -iota-3 that exhibit reduced enzymatic activities might show a
      dominant negative effect against the intact rDGKiota-1, and that the modulation
      of signal transduction by the splice variants may play some roles in the
      physiologic and/or pathologic conditions of neurons.

PMID- 15024005
TI  - Methionine metabolism in plants: chloroplasts are autonomous for de novo
      methionine synthesis and can import S-adenosylmethionine from the cytosol.
AB  - The subcellular distribution of Met and S-adenosylmethionine (AdoMet) metabolism
      in plant cells discloses a complex partition between the cytosol and the
      organelles. In the present work we show that Arabidopsis contains three
      functional isoforms of vitamin B(12)-independent methionine synthase (MS), the
      enzyme that catalyzes the methylation of homocysteine to Met with 5
      methyltetrahydrofolate as methyl group donor. One MS isoform is present in
      chloroplasts and is most likely required to methylate homocysteine that is
      synthesized de novo in this compartment. Thus, chloroplasts are autonomous and
      are the unique site for de novo Met synthesis in plant cells. The additional MS
      isoforms are present in the cytosol and are most probably involved in the
      regeneration of Met from homocysteine produced in the course of the activated
      methyl cycle. Although Met synthesis can occur in chloroplasts, there is no
      evidence that AdoMet is synthesized anywhere but the cytosol. In accordance with
      this proposal, we show that AdoMet is transported into chloroplasts by a carrier
      mediated facilitated diffusion process. This carrier is able to catalyze the
      uniport uptake of AdoMet into chloroplasts as well as the exchange between
      cytosolic AdoMet and chloroplastic AdoMet or S-adenosylhomocysteine. The obvious
      function for the carrier is to sustain methylation reactions and other AdoMet
      dependent functions in chloroplasts and probably to remove S-adenosylhomocysteine
      generated in the stroma by methyltransferase activities. Therefore, the
      chloroplastic AdoMet carrier serves as a link between cytosolic and chloroplastic
      one-carbon metabolism.

PMID- 15024006
TI  - Protein splicing of a Pyrococcus abyssi intein with a C-terminal glutamine.
AB  - Protein splicing involves the excision of an intervening polypeptide sequence,
      the intein, from a precursor protein and the concomitant ligation of the flanking
      polypeptides, the exteins, by a peptide bond. Most reported inteins have a C
      terminal asparagine residue, and it has been shown that cyclization of this
      residue is coupled to peptide bond cleavage between the intein and C-extein. We
      show that the intein interrupting the DNA polymerase II DP2 subunit in Pyrococcus
      abyssi, which has a C-terminal glutamine, is capable of facilitating protein
      splicing. Substitution of an asparagine for the C-terminal glutamine moderately
      improves the rate and extent of protein splicing. However, substitution of an
      alanine for the penultimate histidine residue, with either asparagine or
      glutamine in the C-terminal position, prevents protein splicing and facilitates
      cleavage at the intein N terminus. The intein facilitates in vitro protein
      splicing only at temperatures above 30 degrees C and can be purified as a
      nonspliced precursor. This temperature dependence has enabled us to characterize
      the optimal in vitro splicing conditions and determine the rate constants for
      splicing as a function of temperature.

PMID- 15024007
TI  - Replacement of amino acid sequence features of a- and c-subunits of ATP synthases
      of Alkaliphilic Bacillus with the Bacillus consensus sequence results in
      defective oxidative phosphorylation and non-fermentative growth at pH 10.5.
AB  - Mitchell's (Mitchell, P. (1961) Nature 191, 144-148) chemiosmotic model of energy
      coupling posits a bulk electrochemical proton gradient (Deltap) as the sole
      driving force for proton-coupled ATP synthesis via oxidative phosphorylation
      (OXPHOS) and for other bioenergetic work. Two properties of proton-coupled OXPHOS
      by alkaliphilic Bacillus species pose a challenge to this tenet: robust ATP
      synthesis at pH 10.5 that does not correlate with the magnitude of the Deltap and
      the failure of artificially imposed potentials to substitute for respiration
      generated potentials in energizing ATP synthesis at high pH (Krulwich, T. (1995)
      Mol. Microbiol. 15, 403-410). Here we show that these properties, in alkaliphilic
      Bacillus pseudofirmus OF4, depend upon alkaliphile-specific features in the
      proton pathway through the a- and c-subunits of ATP synthase. Site-directed
      changes were made in six such features to the corresponding sequence in Bacillus
      megaterium, which reflects the consensus sequence for non-alkaliphilic Bacillus.
      Five of the six single mutants assembled an active ATPase/ATP synthase, and four
      of these mutants exhibited a specific defect in non-fermentative growth at high
      pH. Most of these mutants lost the ability to generate the high phosphorylation
      potentials at low bulk Deltap that are characteristic of alkaliphiles. The
      aLys(180) and aGly(212) residues that are predicted to be in the proton uptake
      pathway of the a-subunit were specifically implicated in pH-dependent restriction
      of proton flux through the ATP synthase to and from the bulk phase. The evidence
      included greatly enhanced ATP synthesis in response to an artificially imposed
      potential at high pH. The findings demonstrate that the ATP synthase of extreme
      alkaliphiles has special features that are required for non-fermentative growth
      and OXPHOS at high pH.

PMID- 15024008
TI  - Neomycin prevents the wortmannin inhibition of insulin-stimulated Glut4
      translocation and glucose transport in 3T3-L1 adipocytes.
AB  - Insulin stimulates the movement of the facilitative glucose transporter glucose
      transporter-4 (Glut4) from an intracellular compartment to the plasma membrane in
      adipocytes and muscle cells, resulting in an increased rate of glucose uptake.
      Insulin-stimulated Glut4 translocation and glucose transport are abolished by
      wortmannin, a specific inhibitor of phosphatidylinositol 3'-kinase (PI3K). Here,
      we demonstrate that neomycin, a drug that masks the cellular substrate of PI3K,
      phosphatidylinositol 4,5-bisphosphate (PIP), prevents wortmannin inhibition of
      insulin-stimulated (2)Glut4 translocation and glucose transport without
      activating protein kinase B, a downstream effector of PI3K. These results suggest
      that PIP(2) may have an important regulatory function in insulin-stimulated Glut4
      translocation and glucose transport.

PMID- 15024009
TI  - Isolation and characterization of the early nodule-specific protein homologue
      (Hev b 13), an allergenic lipolytic esterase from Hevea brasiliensis latex.
AB  - Recurring reports of a highly allergenic 42-46-kDa protein in Hevea brasiliensis
      latex appeared to have been resolved with the discovery of a 43-kDa allergenic
      latex protein that was a homologue to patatin. However, the low to moderate
      prevalence of sensitization to the protein, designated Hev b 7, among latex
      allergic patients could not adequately explain the frequent observations of the
      42-46-kDa allergen. This led to the hypothesis that another, more allergenic
      protein of a similar molecular mass existed in Hevea latex. We report the
      isolation and purification of a 42.98-kDa latex glycoprotein showing homology to
      the early nodule-specific protein (ENSP) of the legumes Medicago sativa, Medicago
      truncatula, and Glycine max. The protein is allergenic, being recognized by
      immunoglobulin E (IgE) in sera from latex-allergic patients. The IgE epitope
      resides on the carbohydrate moiety of the protein, and the presence of a similar
      carbohydrate component on potato tuber patatin enables the latter to inhibit IgE
      binding to the ENSP homologue. The cDNA encoding the ENSP homologue was isolated
      by reverse transcription-PCR and cloned. The protein predicted from the cDNA
      sequence has 391 amino acids, the first 26 of which constitute a putative signal
      peptide. The deduced molecular mass of the mature protein is 40.40 kDa, while its
      isoelectric point is estimated at 5.0. The discrepancy between the predicted and
      observed molecular mass might be due to glycosylation, for which three N-sites on
      the protein are predicted. The purified protein showed lipase and esterase
      activities and may be involved in plant defense.

PMID- 15024010
TI  - Association of stomatin with lipid bodies.
AB  - The oligomeric lipid raft-associated integral protein stomatin normally localizes
      to the plasma membrane and the late endosomal compartment. Similar to the
      caveolins, it is targeted to lipid bodies (LBs) on overexpression. Endogenous
      stomatin also associates with LBs to a small extent. Green fluorescent protein
      tagged stomatin (StomGFP) and the dominant-negative caveolin-3 mutant DGV(cav3)HA
      occupy distinct domains on LB surfaces but eventually intermix. Studies of
      StomGFP deletion mutants reveal that the region for membrane association but not
      oligomerization and raft association is essential for LB targeting. Blocking
      protein synthesis leads to the redistribution of StomGFP from LBs to LysoTracker
      positive vesicles indicating a connection with the late endosomal/lysosomal
      pathway. Live microscopy of StomGFP reveals multiple interactions between LBs and
      microtubule-associated vesicles possibly representing signaling events and/or the
      exchange of cargo. Proteomic analysis of isolated LBs identifies adipophilin and
      TIP47, various lipid-specific enzymes, cytoskeletal components, chaperones, Ras
      related proteins, protein kinase D2, and other regulatory proteins. The
      association of the Rab proteins 1, 6, 7, 10, and 18 with LBs indicates various
      connections to other compartments. Our data suggest that LBs are not only
      involved in the storage of lipids but also participate actively in the cellular
      signaling network and the homeostasis of lipids.

PMID- 15024011
TI  - Role of mammalian vacuolar protein-sorting proteins in endocytic trafficking of a
      non-ubiquitinated G protein-coupled receptor to lysosomes.
AB  - Many signaling receptors require covalent modification by ubiquitin for agonist
      induced down-regulation via endocytic trafficking to lysosomes, a process that is
      mediated by a conserved set of endosome-associating proteins also required for
      vacuolar protein-sorting (VPS) in yeast. The delta opioid receptor (DOR) is a G
      protein-coupled receptor that can undergo agonist-induced proteolysis via
      endocytic trafficking to lysosomes but does not require covalent modification by
      ubiquitin to do so. This raises the question of whether lysosomal down-regulation
      of this "ubiquitination-independent" GPCR is mediated by a completely distinct
      biochemical mechanism or if similar VPS machinery is involved. Agonist-induced
      proteolysis of DOR was significantly inhibited by dominant negative mutant
      versions of Vps4/Skd1, an AAA-family ATPase required for a late step in lysosomal
      sorting of ubiquitinated membrane cargo. Furthermore, overexpression and
      interfering RNA-mediated knockdown indicated that lysosomal trafficking of opioid
      receptors is also dependent on Hrs, a VPS protein that mediates an early step in
      lysosomal sorting of ubiquitinated cargo. However, interfering RNA-mediated
      knockdown of Tsg101, a VPS protein that is essential for an intermediate step of
      the conserved lysosomal sorting mechanism, did not detectably affect agonist
      induced proteolysis of DOR in the same cells in which (ubiquitination-dependent)
      lysosomal trafficking of epidermal growth factor receptors was clearly inhibited.
      These results indicate that opioid receptors, despite their ability to undergo
      efficient agonist-induced trafficking to lysosomes in the absence of covalent
      modification by ubiquitin, utilize some (Vps4 and Hrs) but perhaps not all
      (Tsg101) of the VPS machinery required for lysosomal sorting of ubiquitinated
      membrane cargo.

PMID- 15024012
TI  - Xenopus laevis macrophage migration inhibitory factor is essential for axis
      formation and neural development.
AB  - Macrophage migration inhibitory factor (MIF) is an immunoregulatory cytokine
      involved in both acquired and innate immunity. MIF also has many functions
      outside the immune system, such as isomerase and oxidoreductase activities and
      control of cell proliferation. Considering the involvement of MIF in various
      intra- and extracellular events, we expected that MIF might also be important in
      vertebrate development. To elucidate the possible role of MIF in developmental
      processes, we knocked down MIF in embryos of the African clawed frog Xenopus
      laevis, using MIF-specific morpholino oligomers (MOs). For the synthesis of the
      MOs, we cloned a cDNA for a Xenopus homolog of MIF. Sequence analysis,
      determination of the isomerase activity, and x-ray crystallographic analysis
      revealed that the protein encoded by the cDNA was the ortholog of mammalian MIF.
      We carried out whole mount in situ hybridization of MIF mRNA and found that MIF
      was expressed at high levels in the neural tissues of normal embryos. Although
      early embryogenesis of MO-injected embryos proceeded normally until the gastrula
      stage, their neurulation was completely inhibited. At the tailbud stage, the MO
      injected embryos lacked neural and mesodermal tissues, and also showed severe
      defects in their head and tail structures. Thus, MIF was found to be essential
      for axis formation and neural development of Xenopus embryos.

PMID- 15024013
TI  - The role of N-glycosylation in function and surface trafficking of the human
      dopamine transporter.
AB  - The present study addressed the role of N-linked glycosylation of the human
      dopamine transporter (DAT) in its function with the help of mutants, in which
      canonical N-glycosylation sites have been removed (N181Q, N181Q,N188Q, and
      N181Q,N188Q,N205Q), expressed in human embryonic kidney-293 cells. Removal of
      canonical sites produced lower molecular weight species as did enzymatic
      deglycosylation or blockade of glycosylation, and all three canonical sites were
      found to carry sugars. Prevention of N-glycosylation reduced both surface and
      intracellular DAT. Although partially or non-glycosylated DAT was somewhat less
      represented at the surface, no evidence was found for preferential exclusion of
      such material from the plasma membrane, indicating that glycosylation is not
      essential for DAT expression. Non-glycosylated DAT was less stable at the surface
      as revealed by apparently enhanced endocytosis, consonant with weaker DAT
      immunofluorescence at the cell surface and stronger presence in cytosol in
      confocal analysis of the double and triple mutant. Non-glycosylated DAT did not
      transport dopamine as efficiently as wild-type DAT as judged from the sharp
      reduction in uptake V(max), and prevention of N-glycosylation enhanced the
      potency of cocaine-like drugs in inhibiting dopamine uptake into intact cells
      without changing their affinity for DAT when measured in membrane preparations
      prepared from these cells. Thus, non-glycosylated DAT at the cell surface
      displays appreciably reduced catalytic activity and altered inhibitor sensitivity
      compared with wild type.

PMID- 15024014
TI  - The Nudix hydrolase Ndx1 from Thermus thermophilus HB8 is a diadenosine
      hexaphosphate hydrolase with a novel activity.
AB  - The ndx1 gene, which encodes a Nudix protein, was cloned from the extremely
      thermophilic bacterium Thermus thermophilus HB8. This gene encodes a 126-amino
      acid protein that includes the characteristic Nudix motif conserved among Nudix
      proteins. Ndx1 was overexpressed in Escherichia coli and purified. Ndx1 was
      stable up to 95 degrees C and at extreme pH. Size exclusion chromatography
      indicated that Ndx1 was monomeric in solution. Ndx1 specifically hydrolyzed
      (di)adenosine polyphosphates but not ATP or diadenosine triphosphate, and it
      always generated ATP as the product. Diadenosine hexaphosphate (Ap(6)A), the most
      preferred substrate, was hydrolyzed to produce two ATP molecules, which is a
      novel hydrolysis mode for Ap(6)A, with a K(m) of 1.4 microm and a k(cat) of 4.1
      s(-1). These results indicate that Ndx1 is a (di)adenosine polyphosphate
      hydrolase. Ndx1 activity required the presence of the divalent cations Mn(2+),
      Mg(2+), Zn(2+), and Co(2+), whereas Ca(2+), Ni(2+), and Cu(2+) were not able to
      activate Ndx1. Fluoride ion inhibited Ndx1 activity via a non-competitive
      mechanism. Optimal activity for Ap(6)A was observed at around pH 8.0 and about 70
      degrees C. We found two important residues with pK(a) values of 6.1 and 9.6 in
      the free enzyme and pK(a) values of 7.9 and 10.0 in the substrate-enzyme complex.
      Kinetic studies of proteins with amino acid substitutions suggested that Glu-46
      and Glu-50 were conserved residues in the Nudix motif and were involved in
      catalysis. Trp-26 was likely involved in enzyme-substrate interactions based on
      fluorescence measurements. Based on these results, the mechanism of substrate
      recognition and catalysis are discussed.

PMID- 15024015
TI  - Dual functions of transcription factors, transforming growth factor-beta
      inducible early gene (TIEG)2 and Sp3, are mediated by CACCC element and Sp1 sites
      of human monoamine oxidase (MAO) B gene.
AB  - Monoamine oxidases (MAO) A and B catalyze the oxidative deamination of many
      biogenic and dietary amines. Abnormal expression of MAO has been implicated in
      several psychiatric and neurodegenerative disorders. Human MAO B core promoter (
      246 to -99 region) consists of CACCC element flanked by two clusters of
      overlapping Sp1 sites. Here, we show that cotransfection with transforming growth
      factor (TGF)-beta-inducible early gene (TIEG)2 increased MAO B gene expression at
      promoter, mRNA, protein, and catalytic activity levels in both SH-SY5Y and HepG2
      cells. Mutation of the CACCC element increased the MAO B promoter activity, and
      cotransfection with TIEG2 further increased the promoter activity, suggesting
      that CACCC was a repressor element. This increase was reduced when the proximal
      Sp1 overlapping sites was mutated. Similar interactions were found with Sp3.
      These results showed that TIEG2 and Sp3 were repressors at the CACCC element but
      were activators at proximal Sp1 overlapping sites of MAO B. Gel-shift and
      chromatin immunoprecipitation assays showed that TIEG2 and Sp3 bound directly to
      CACCC element and the proximal Sp1 sites in both synthetic oligonucleotides and
      natural MAO B core promoter. TIEG2 had a higher affinity to Sp1 sites than CACCC
      element, whereas Sp3 had an equal affinity to both elements. Thus, TIEG2 was an
      activator, but Sp3 had no effect on MAO B gene expression. This study provides
      new insights into MAO B gene expression and illustrates the complexity of gene
      regulation.

PMID- 15024016
TI  - PfPKB, a novel protein kinase B-like enzyme from Plasmodium falciparum: I.
      Identification, characterization, and possible role in parasite development.
AB  - Extracellular signals control various important functions of a eukaryotic cell,
      which is often achieved by regulating a battery of protein kinases and
      phosphatases. Protein Kinase B (PKB) is an important member of the
      phosphatidylinositol 3-kinase-dependent signaling pathways in several eukaryotes,
      but the role of PKB in protozoan parasites is not known. We have identified a
      protein kinase B homologue in Plasmodium falciparum (PfPKB) that is expressed
      mainly in the schizonts and merozoites. Even though PfPKB shares high sequence
      homology with PKB catalytic domain, it lacks a pleckstrin homology domain
      typically found at the N terminus of the mammalian enzyme. Biochemical studies
      performed to understand the mechanism of PfPKB catalytic activation suggested (i)
      its activation is dependent on autophosphorylation of a serine residue (Ser-271)
      in its activation loop region and (ii) PfPKB has an unusual N-terminal region
      that was found to negatively regulate its catalytic activity. We also identified
      an inhibitor of PfPKB activity that also inhibits P. falciparum growth,
      suggesting that this enzyme may be important for the development of the parasite.

PMID- 15024017
TI  - Structure-based design of selective and potent inhibitors of protein-tyrosine
      phosphatase beta.
AB  - Protein-tyrosine phosphatases (PTPs) are considered important therapeutic targets
      because of their pivotal role as regulators of signal transduction and thus their
      implication in several human diseases such as diabetes, cancer, and autoimmunity.
      In particular, PTP1B has been the focus of many academic and industrial
      laboratories because it was found to be an important negative regulator of
      insulin and leptin signaling, and hence a potential therapeutic target in
      diabetes and obesity. As a result, significant progress has been achieved in the
      design of highly selective and potent PTP1B inhibitors. In contrast, little
      attention has been given to other potential drug targets within the PTP family.
      Guided by x-ray crystallography, molecular modeling, and enzyme kinetic analyses
      with wild type and mutant PTPs, we describe the development of a general, low
      molecular weight, non-peptide, non-phosphorus PTP inhibitor into an inhibitor
      that displays more than 100-fold selectivity for PTPbeta over PTP1B. Of note, our
      structure-based design principles, which are based on extensive bioinformatics
      analyses of the PTP family, are general in nature. Therefore, we anticipate that
      this strategy, here applied to PTPbeta, in principle can be used in the design
      and development of selective inhibitors of many, if not most PTPs.

PMID- 15024018
TI  - CD86 and beta2-adrenergic receptor signaling pathways, respectively, increase Oct
      2 and OCA-B Expression and binding to the 3'-IgH enhancer in B cells.
AB  - Stimulation of CD86 (formerly known as B7-2) and/or the beta2-adrenergic receptor
      on a CD40 ligand/interleukin-4-activated B cell increased the rate of mature IgG1
      transcription. To identify the mechanism responsible for this effect, we
      determined whether CD86 and/or beta2-adrenergic receptor stimulation regulated
      transcription factor expression and binding to the 3'-IgH enhancer in vitro and
      in vivo. We showed that CD86 stimulation increased the nuclear localization of NF
      kappaB1 (p50) and phosphorylated RelA (p65) and increased Oct-2 expression and
      binding to the 3'-IgH enhancer, in a protein kinase C-dependent manner. These
      effects were lost when CD86-deficient or NF-kappaB1-deficient B cells were used.
      CD86 stimulation also increased the level of IkappaB-alpha phosphorylation but in
      a protein kinase C-independent manner. Beta2-adrenergic receptor stimulation
      increased CREB phosphorylation, OCA-B expression, and OCA-B binding to the 3'-IgH
      enhancer in a protein kinase A-dependent manner, an effect lost when beta2
      adrenergic receptor-deficient B cells were used. Also, the beta2-adrenergic
      receptor-induced increase in the level of mature IgG1 transcript was lost when
      OCA-B-deficient B cells were used. These data are the first to show that CD86
      stimulation up-regulates the expression of the transcription factor Oct-2 in a
      protein kinase C- and NF-kappaB1-dependent manner, and that beta2-adrenergic
      receptor stimulation up-regulates the expression of the coactivator OCA-B in a
      protein kinase A-dependent manner to cooperate with Oct-2 binding to the 3'-IgH
      enhancer.

PMID- 15024019
TI  - Interleukin 6 mediates the lysophosphatidic acid-regulated cross-talk between
      stromal and epithelial prostate cancer cells.
AB  - The interaction between stromal and epithelial cells is critical for the
      initiation and progression of prostate cancer, but the molecular determinants
      responsible for the cross-talk between these two cell types remain largely
      unknown. Here, we used a co-culture cell assay to identify messengers involved in
      the cross-talk between human prostate stromal PS30 and epithelial LNCaP cells.
      Stimulation with lysophosphatidic acid (LPA) activates the mitogenic ERK
      signaling pathway in PS30, but not LNCaP, cells. The co-culture of PS30 and LNCaP
      cells results in the activation of ERK in LNCaP cells and that is further
      increased in response to stimulation with LPA. Physiologic relevance of the
      interaction between PS30 and LNCaP cells is demonstrated using LNCaP xenograft
      tumor assays. Animals implanted with a mixture of both cell types develop larger
      tumors with higher frequency compared with those injected with LNCaP cells alone.
      Conditioned medium transfer experiments reveal the PS30-derived inducing factor
      is soluble and promotes mitogenic ERK and STAT3 signaling pathways in LNCaP
      cells. Protein analysis demonstrates that treatment of the PS30 cells with LPA
      induces synthesis of interleukin 6 (IL-6). Antibody neutralization experiments
      reveal that IL-6 is responsible for the LPA-induced mitogenic signaling and
      growth of the LNCaP cells. Our findings reveal that the LPA-regulated secretion
      of IL-6 is an important messenger linking stromal and epithelial prostate cells,
      which may be exploited for the effective treatment of patients with advanced
      prostate cancer.

PMID- 15024020
TI  - Small interfering RNA knockdown of calcium-independent phospholipases A2 beta or
      gamma inhibits the hormone-induced differentiation of 3T3-L1 preadipocytes.
AB  - Alterations in lipid secondary messenger generation and lipid metabolic flux are
      essential in promoting the differentiation of adipocytes. To determine whether
      specific subtypes of intracellular phospholipases A(2) (PLA(2)s) facilitate
      hormone-induced differentiation of 3T3-L1 cells into adipocytes, we examined
      alterations in the mRNA level, protein mass, and activity of three previously
      characterized mammalian intracellular PLA(2)s. Hormone-induced differentiation of
      3T3-L1 cells resulted in 7.3 +/- 0.5- and 7.4 +/- 1.4-fold increases of mRNA
      encoding the calcium-independent phospholipases, iPLA(2)beta and iPLA(2)gamma,
      respectively. In contrast, the temporally coordinated loss of at least 90% of
      cPLA(2)alpha mRNA was manifest. Western analysis demonstrated the near absence of
      both iPLA(2)beta and iPLA(2)gamma protein mass in resting 3T3-L1 cells that
      increased dramatically during differentiation. In vitro measurement of PLA(2)
      activities demonstrated an increase in both iPLA(2)beta and iPLA(2)gamma
      activities that were discriminated using the chiral mechanism based inhibitors
      (S)- and (R)-BEL, respectively. Remarkably, treatment of 3T3-L1 cells with small
      interfering RNA directed against either iPLA(2)beta or iPLA(2)gamma prevented
      hormone-induced differentiation. Moreover, analysis of the temporally programmed
      expression of transcription factors demonstrated that the small interfering RNA
      knockdown of iPLA(2)beta or iPLA(2)gamma resulted in down-regulation of the
      expression of peroxisome proliferator-activated receptor gamma and the CCAAT
      enhancer-binding protein alpha (C/EBPalpha). No alterations in the expression of
      the early stage transcription factors C/EBPbeta and C/EBPdelta were observed.
      Collectively, these results demonstrate prominent alterations in intracellular
      PLA(2)s during 3T3-L1 cell differentiation into adipocytes and identify the
      requirement of iPLA(2)beta and iPLA(2)gamma for the adipogenic program that
      drives resting 3T3-L1 cells into adipocytes after hormone stimulation.

PMID- 15024021
TI  - Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and
      phosphorylation.
AB  - Polo-like kinase 1 (Plk1) has an important role in the regulation of M phase of
      the cell cycle. In addition to its cell cycle-regulatory function, Plk1 has a
      potential role in tumorigenesis. Here we found for the first time that Plk1
      physically binds to the tumor suppressor p53 in mammalian cultured cells, and
      inhibits its transactivation activity as well as its pro-apoptotic function.
      During the cisplatin-induced apoptosis in human neuroblastoma SH-SY5Y cells, the
      expression level of Plk1 was significantly decreased both at mRNA and protein
      levels, whereas cisplatin treatment caused a remarkable stabilization of p53.
      Systematic immunoprecipitation analyses using a series of deletion mutants of p53
      revealed that a sequence-specific DNA-binding region of p53 is required and
      sufficient for the physical interaction with Plk1. The ectopically overexpressed
      Plk1 was co-localized with the endogenous p53 in mammalian cell nucleus, as shown
      by confocal laser microscopy. Expression of exogenous Plk1 and p53 in p53
      deficient lung carcinoma H1299 cells greatly decreased the p53-mediated
      transcription from the p53-responsive p21(WAF1), MDM2, and BAX promoters, whereas
      the kinase-deficient mutant form of Plk1 failed to reduce the transcriptional
      activity of p53. Consistent with the luciferase reporter analysis, Plk1 had an
      ability to block the p53-dependent induction of the endogenous p21(WAF1). In
      addition, Plk1 inhibited the pro-apoptotic function of p53 in H1299 cells.
      Intriguingly, Plk1-mediated repression of p53 was attenuated with ATM. Thus, our
      present findings strongly suggest that p53 is a critical target of Plk1, and its
      function is abrogated through the physical interaction with Plk1.

PMID- 15024022
TI  - Interference of mRNA function by sequence-specific endoribonuclease PemK.
AB  - In Escherichia coli, programmed cell death is mediated through the system called
      "addiction module," which consists of a pair of genes encoding a stable toxin and
      a labile antitoxin. The pemI-pemK system is an addiction module present on
      plasmid R100. It helps to maintain the plasmid by post-segregational killing in
      E. coli population. Here we demonstrate that purified PemK, the toxin encoded by
      the pemI-pemK addiction module, inhibits protein synthesis in an E. coli cell
      free system, whereas the addition of PemI, the antitoxin against PemK, resumes
      the protein synthesis. Further studies reveal that PemK is a sequence-specific
      endoribonuclease that cleaves mRNAs to inhibit protein synthesis, whereas PemI
      blocks the endoribonuclease activity of PemK. PemK cleaves only single-stranded
      RNA preferentially at the 5' or 3' side of the A residue in the "UAH" sequences
      (where H is C, A, or U). Upon induction, PemK cleaves cellular mRNAs to
      effectively block protein synthesis in E. coli. The pemK homologue genes have
      been identified on the genomes of a wide range of bacteria. We propose that PemK
      and its homologues form a novel endoribonuclease family that interferes with mRNA
      function by cleaving cellular mRNAs in a sequence-specific manner.

PMID- 15024023
TI  - Akt kinase activation blocks apoptosis in intestinal epithelial cells by
      inhibiting caspase-3 after polyamine depletion.
AB  - Apoptosis plays a critical role in the maintenance of gut mucosal homeostasis and
      is regulated by numerous factors including polyamines. Although the exact roles
      of polyamines in apoptotic pathway are still unclear, inhibition of polyamine
      synthesis promotes the resistance of intestinal epithelial cells to apoptosis.
      Akt is a serine-threonine kinase that has been established as an important
      intracellular signaling in regulating cell survival. The current studies test the
      hypothesis that polyamines are involved in the control of Akt activity in normal
      intestinal epithelial cells (IEC-6 line) and that activated Akt mediates
      suppression of apoptosis following polyamine depletion. Depletion of cellular
      polyamines by alpha-difluoromethylornithine induced levels of phosphorylated Akt
      and increased Akt kinase activity, although it had no effect on expression of
      total Akt, pERK, p38, and Bcl-2 proteins. This activated Akt was associated with
      both decreased levels of active caspase-3 and increased resistance to tumor
      necrosis factor-alpha/cycloheximide-induced apoptosis. Inactivation of Akt by
      either treatment with LY294002 or ectopic expression of a dominant negative Akt
      mutant (DNMAkt) not only enhanced the caspase-3 activation in polyamine-deficient
      cells but also prevented the increased resistance to tumor necrosis factor
      alpha/cycloheximide-induced apoptosis. Phosphorylation of glycogen synthase
      kinase-3, a downstream target of Akt, was also increased in alpha
      difluoromethylornithine-treated cells, which was prevented by inactivation of Akt
      by LY294002 or DNMAkt overexpression. These results indicate that polyamine
      depletion induces the Akt activation mediating suppression of apoptosis via
      inhibition of caspase-3 in normal intestinal epithelial cells.

PMID- 15024024
TI  - Cellular processing of cone photoreceptor cyclic GMP-gated ion channels: a role
      for the S4 structural motif.
AB  - We examined cellular protein processing and functional expression of
      photoreceptor cyclic nucleotide-gated (CNG) ion channels. In a mammalian cell
      line, wild type bovine cone photoreceptor channel alpha subunits (bCNGA3) convert
      from an unglycosylated state, at 90 kDa, to two glycosylated states at 93 and 102
      kDa as they transit within the cell to their final location at the plasma
      membrane. Glycosylation per se is not required to yield functional channels, yet
      it is a milestone that distinguishes sequential steps in channel protein
      maturation. CNG ion channels are not gated by membrane voltage although their
      structure includes the transmembrane S4 motif known to function as the membrane
      voltage sensor in all voltage-gated ion channels. S4 must be functionally
      important because its natural mutation in cone photoreceptor CNG channels is
      associated with achromatopsia, a human autosomal inherited loss of cone function.
      Point mutation of specific, not all, charged and neutral residues within S4 cause
      failure of functional channel expression. Cellular channel protein processing
      fails in every one of the non-functional S4 mutations we studied. Mutant proteins
      do not reach the 102-kDa glycosylated state and do not arrive at the plasma
      membrane. They remain trapped within the endoplasmic reticulum and fail to
      transit out to the Golgi apparatus. Coexpression of cone CNG beta subunit (CNGB3)
      does not rescue the consequence of S4 mutations in CNGA3. It is likely that an
      intact S4 is required for proper protein folding and/or assembly in the
      endoplasmic reticulum membrane.

PMID- 15024025
TI  - Protein trafficking and anchoring complexes revealed by proteomic analysis of
      inward rectifier potassium channel (Kir2.x)-associated proteins.
AB  - Inward rectifier potassium (Kir) channels play important roles in the maintenance
      and control of cell excitability. Both intracellular trafficking and modulation
      of Kir channel activity are regulated by protein-protein interactions. We adopted
      a proteomics approach to identify proteins associated with Kir2 channels via the
      channel C-terminal PDZ binding motif. Detergent-solubilized rat brain and heart
      extracts were subjected to affinity chromatography using a Kir2.2 C-terminal
      matrix to purify channel-interacting proteins. Proteins were identified with
      multidimensional high pressure liquid chromatography coupled with electrospray
      ionization tandem mass spectrometry, N-terminal microsequencing, and
      immunoblotting with specific antibodies. We identified eight members of the MAGUK
      family of proteins (SAP97, PSD-95, Chapsyn-110, SAP102, CASK, Dlg2, Dlg3, and
      Pals2), two isoforms of Veli (Veli-1 and Veli-3), Mint1, and actin-binding LIM
      protein (abLIM) as Kir2.2-associated brain proteins. From heart extract
      purifications, SAP97, CASK, Veli-3, and Mint1 also were found to associate with
      Kir2 channels. Furthermore, we demonstrate for the first time that components of
      the dystrophin-associated protein complex, including alpha1-, beta1-, and beta2
      syntrophin, dystrophin, and dystrobrevin, interact with Kir2 channels, as
      demonstrated by immunoaffinity purification and affinity chromatography from
      skeletal and cardiac muscle and brain. Affinity pull-down experiments revealed
      that Kir2.1, Kir2.2, Kir2.3, and Kir4.1 all bind to scaffolding proteins but with
      different affinities for the dystrophin-associated protein complex and SAP97,
      CASK, and Veli. Immunofluorescent localization studies demonstrated that Kir2.2
      co-localizes with syntrophin, dystrophin, and dystrobrevin at skeletal muscle
      neuromuscular junctions. These results suggest that Kir2 channels associate with
      protein complexes that may be important to target and traffic channels to
      specific subcellular locations, as well as anchor and stabilize channels in the
      plasma membrane.

PMID- 15024026
TI  - 15-deoxy-delta 12,14-prostaglandin J2 induces heme oxygenase-1 gene expression in
      a reactive oxygen species-dependent manner in human lymphocytes.
AB  - 15-Deoxy-delta(12,14)-prostaglandin J(2) (15dPGJ(2) has been recently proposed as
      a potent anti-inflammatory agent. However, the mechanisms by which 15dPGJ(2)
      mediates its therapeutic effects in vivo are unclear. We demonstrate that
      15dPGJ(2) at micromolar (2.5-10 microm) concentrations induces the expression of
      heme oxygenase-1 (HO-1), an anti-inflammatory enzyme, at both mRNA and protein
      levels in human lymphocytes. In contrast, troglitazone and ciglitazone, two
      thiazolidinediones that mimic several effects of 15dPGJ(2) through their binding
      to the peroxisome proliferator-activated receptor (PPAR)-gamma, did not affect HO
      1 expression, and the positive effect of 15dPGJ(2) on this process was mimicked
      instead by other cyclopentenone prostaglandins (PG), such as PGD(2) (the
      precursor of 15dPGJ(2)) and PGA(1) and PGA(2) which do not interact with PPAR
      gamma. Also, 15dPGJ(2) enhanced the intracellular production of reactive oxygen
      species (ROS) and increased xanthine oxidase activity in vitro. Inhibition of
      intracellular ROS production by N-acetylcysteine, TEMPO, Me(2)SO, 1,10
      phenanthroline, or allopurinol resulted in a decreased 15dPGJ(2)-dependent HO-1
      expression in the cells. Furthermore, buthionine sulfoximine, an inhibitor of
      reduced glutathione synthesis, or Fe(2+)/Cu(2+) ions enhanced the positive effect
      of 15dPGJ(2) on HO-1 expression. On the other hand, the inhibition of
      phosphatidylinositol 3-kinase or p38 mitogen-activated protein kinase, or the
      blockade of transcription factor NF-kappaB activation, hindered 15dPGJ(2)
      elicited HO-1 expression. Collectively, the present data suggest that 15dPGJ(2)
      anti-inflammatory actions at pharmacological concentrations involve the induction
      of HO-1 gene expression through mechanisms independent of PPAR-gamma activation
      and dependent on ROS produced via the xanthine/xanthine oxidase system and/or
      through Fenton reactions. Both phosphatidylinositol 3-kinase and p38 mitogen
      activated protein kinase signaling pathways also appear implicated in modulation
      of HO-1 expression by 15dPGJ(2).

PMID- 15024027
TI  - Stage I and II follicular non-Hodgkin's lymphoma: long-term follow-up of no
      initial therapy.
AB  - PURPOSE: To analyze the outcome of no initial therapy in stage I and II
      follicular small-cleaved (FSC) and follicular mixed (FM) non-Hodgkin's lymphoma
      (NHL) on overall survival, time to treatment, incidence and course of
      transformation, and cause of death. PATIENTS AND METHODS: This was a
      retrospective analysis. Criteria for selection were patients with stage I and IIA
      FSC and FM (grades 1 and 2) NHL with therapy deferred for at least 3 months after
      diagnosis and a minimum follow-up of 1 year. RESULTS: Forty-three patients were
      identified (11 stage I, 32 stage II), with a median age of 58 years. Reasons for
      no initial therapy included: physician choice (n = 20), large abdominal radiation
      field required (n = 10), advanced age (n = 7), concern for xerostomia (n = 4), or
      patient refusal (n = 2). At a median follow-up of 86 months, 27 patients (63%)
      had not been treated. The median time to treatment in the remaining 16 patients
      was 22 months. Four of 16 patients transformed to a higher-grade lymphoma. Nine
      patients died-six due to progressive lymphoma. Estimated survivals at 5, 10, and
      20 years were 97%, 85%, and 22%, respectively. CONCLUSION: In selected stage I
      and II follicular NHL patients, deferred therapy is an acceptable approach, as
      more than half of our patients remained untreated at a median of 6 or more years,
      and survival was comparable to that seen in reports with immediate treatment.

PMID- 15024028
TI  - Protein kinase Ciota is required for Ras transformation and colon carcinogenesis
      in vivo.
AB  - Protein kinase C iota (PKCiota) has been implicated in Ras signaling, however, a
      role for PKCiota in oncogenic Ras-mediated transformation has not been
      established. Here, we show that PKCiota is a critical downstream effector of
      oncogenic Ras in the colonic epithelium. Transgenic mice expressing
      constitutively active PKCiota in the colon are highly susceptible to carcinogen
      induced colon carcinogenesis, whereas mice expressing kinase-deficient PKCiota
      (kdPKCiota) are resistant to both carcinogen- and oncogenic Ras-mediated
      carcinogenesis. Expression of kdPKCiota in Ras-transformed rat intestinal
      epithelial cells blocks oncogenic Ras-mediated activation of Rac1, cellular
      invasion, and anchorage-independent growth. Constitutively active Rac1 (RacV12)
      restores invasiveness and anchorage-independent growth in Ras-transformed rat
      intestinal epithelial cells expressing kdPKCiota. Our data demonstrate that
      PKCiota is required for oncogenic Ras- and carcinogen-mediated colon
      carcinogenesis in vivo and define a procarcinogenic signaling axis consisting of
      Ras, PKCiota, and Rac1.

PMID- 15024029
TI  - A role for the actin cytoskeleton in cell death and aging in yeast.
AB  - Several determinants of aging, including metabolic capacity and genetic
      stability, are recognized in both yeast and humans. However, many aspects of the
      pathways leading to cell death remain to be elucidated. Here we report a role for
      the actin cytoskeleton both in cell death and in promoting longevity. We have
      analyzed yeast strains expressing mutants with either increased or decreased
      actin dynamics. We show that decreased actin dynamics causes depolarization of
      the mitochondrial membrane and an increase in reactive oxygen species (ROS)
      production, resulting in cell death. Important, however, is the demonstration
      that increasing actin dynamics, either by a specific actin allele or by deletion
      of a gene encoding the actin-bundling protein Scp1p, can increase lifespan by
      over 65%. Increased longevity appears to be due to these cells producing lower
      than wild-type levels of ROS. Homology between Scp1p and mammalian
      SM22/transgelin, which itself has been isolated in senescence screens, suggests a
      conserved mechanism linking aging to actin stability.

PMID- 15024030
TI  - Primary cilia of human endothelial cells disassemble under laminar shear stress.
AB  - We identified primary cilia and centrosomes in cultured human umbilical vein
      endothelial cells (HUVEC) by antibodies to acetyl-alpha-tubulin and capillary
      morphogenesis gene-1 product (CMG-1), a human homologue of the intraflagellar
      transport (IFT) protein IFT-71 in Chlamydomonas. CMG-1 was present in particles
      along primary cilia of HUVEC at interphase and around the oldest basal
      body/centriole at interphase and mitosis. To study the response of primary cilia
      and centrosomes to mechanical stimuli, we exposed cultured HUVEC to laminar shear
      stress (LSS). Under LSS, all primary cilia disassembled, and centrosomes were
      deprived of CMG-1. We conclude that the exposure to LSS ends the IFT in cultured
      endothelial cells.

PMID- 15024032
TI  - In vitro FRAP reveals the ATP-dependent nuclear mobilization of the exon junction
      complex protein SRm160.
AB  - We present a new in vitro system for characterizing the binding and mobility of
      enhanced green fluorescent protein (EGFP)-labeled nuclear proteins by
      fluorescence recovery after photobleaching in digitonin-permeabilized cells. This
      assay reveals that SRm160, a splicing coactivator and component of the exon
      junction complex (EJC) involved in RNA export, has an adenosine triphosphate
      (ATP)-dependent mobility. Endogenous SRm160, lacking the EGFP moiety, could also
      be released from sites at splicing speckled domains by an ATP-dependent
      mechanism. A second EJC protein, RNPS1, also has an ATP-dependent mobility, but
      SRm300, a protein that binds to SRm160 and participates with it in RNA splicing,
      remains immobile after ATP supplementation. This finding suggests that SRm160
      containing RNA export, but not splicing, complexes have an ATP-dependent
      mobility. We propose that RNA export complexes have an ATP-regulated mechanism
      for release from binding sites at splicing speckled domains. In vitro
      fluorescence recovery after photobleaching is a powerful tool for identifying
      cofactors required for nuclear binding and mobility.

PMID- 15024031
TI  - In vivo kinetics of Cajal body components.
AB  - Cajal bodies (CBs) are subnuclear domains implicated in small nuclear
      ribonucleoprotein (snRNP) biogenesis. In most cell types, CBs coincide with
      nuclear gems, which contain the survival of motor neurons (SMN) complex, an
      essential snRNP assembly factor. Here, we analyze the exchange kinetics of
      multiple components of CBs and gems in living cells using photobleaching
      microscopy. We demonstrate differences in dissociation kinetics of CB
      constituents and relate them to their functions. Coilin and SMN complex members
      exhibit relatively long CB residence times, whereas components of snRNPs, small
      nucleolar RNPs, and factors shared with the nucleolus have significantly shorter
      residence times. Comparison of the dissociation kinetics of these shared proteins
      from either the nucleolus or the CB suggests the existence of compartment
      specific retention mechanisms. The dynamic properties of several CB components do
      not depend on their interaction with coilin because their dissociation kinetics
      are unaltered in residual nuclear bodies of coilin knockout cells. Photobleaching
      and fluorescence resonance energy transfer experiments demonstrate that coilin
      and SMN can interact within CBs, but their interaction is not the major
      determinant of their residence times. These results suggest that CBs and gems are
      kinetically independent structures.

PMID- 15024033
TI  - Nesca, a novel adapter, translocates to the nuclear envelope and regulates
      neurotrophin-induced neurite outgrowth.
AB  - We provide the first characterization of a novel signaling adapter, Nesca, in
      neurotrophic signal transduction. Nesca contains a RUN domain, a WW domain, a
      leucine zipper, a carboxyl-terminal SH3 domain, and several proline-rich regions.
      Nesca is highly expressed in the brain, is serine phosphorylated, and mobilizes
      from the cytoplasm to the nuclear membrane in response to neurotrophin, but not
      epidermal growth factor, stimulation in a MEK-dependent process. Overexpression
      studies in PC12 cells indicate that Nesca facilitates neurotrophin-dependent
      neurite outgrowth at nonsaturating doses of nerve growth factor (NGF). Similarly,
      short interfering RNA studies significantly reduce NGF-dependent neuritogenesis
      in PC12 cells. Mutational analyses demonstrate that the RUN domain is an
      important structural determinant for the nuclear translocation of Nesca and that
      the nuclear redistribution of Nesca is essential to its neurite outgrowth
      promoting properties. Collectively, these works provide the first functional
      characterization of Nesca in the context of neurotrophin signaling and suggest
      that Nesca serves a novel, nuclear-dependent role in neurotrophin-dependent
      neurite outgrowth.

PMID- 15024034
TI  - An actin molecular treadmill and myosins maintain stereocilia functional
      architecture and self-renewal.
AB  - We have previously shown that the seemingly static paracrystalline actin core of
      hair cell stereocilia undergoes continuous turnover. Here, we used the same
      approach of transfecting hair cells with actin-green fluorescent protein (GFP)
      and espin-GFP to characterize the turnover process. Actin and espin are
      incorporated at the paracrystal tip and flow rearwards at the same rate. The flux
      rates (approximately 0.002-0.04 actin subunits s(-1)) were proportional to the
      stereocilia length so that the entire staircase stereocilia bundle was turned
      over synchronously. Cytochalasin D caused stereocilia to shorten at rates
      matching paracrystal turnover. Myosins VI and VIIa were localized alongside the
      actin paracrystal, whereas myosin XVa was observed at the tips at levels
      proportional to stereocilia lengths. Electron microscopy analysis of the
      abnormally short stereocilia in the shaker 2 mice did not show the characteristic
      tip density. We argue that actin renewal in the paracrystal follows a treadmill
      mechanism, which, together with the myosins, dynamically shapes the functional
      architecture of the stereocilia bundle.

PMID- 15024035
TI  - Cortactin is necessary for E-cadherin-mediated contact formation and actin
      reorganization.
AB  - Classical cadherin adhesion molecules are key determinants of cell-cell
      recognition during development and in post-embryonic life. A decisive step in
      productive cadherin-based recognition is the conversion of nascent adhesions into
      stable zones of contact. It is increasingly clear that such contact zone
      extension entails active cooperation between cadherin adhesion and the force
      generating capacity of the actin cytoskeleton. Cortactin has recently emerged as
      an important regulator of actin dynamics in several forms of cell motility. We
      now report that cortactin is recruited to cell-cell adhesive contacts in response
      to homophilic cadherin ligation. Notably, cortactin accumulates preferentially,
      with Arp2/3, at cell margins where adhesive contacts are being extended.
      Recruitment of cortactin is accompanied by a ligation-dependent biochemical
      interaction between cortactin and the cadherin adhesive complex. Inhibition of
      cortactin activity in cells blocked Arp2/3-dependent actin assembly at cadherin
      adhesive contacts, significantly reduced cadherin adhesive contact zone
      extension, and perturbed both cell morphology and junctional accumulation of
      cadherins in polarized epithelia. Together, our findings identify a necessary
      role for cortactin in the cadherin-actin cooperation that supports productive
      contact formation.

PMID- 15024036
TI  - Tumor cell alpha3beta1 integrin and vascular laminin-5 mediate pulmonary arrest
      and metastasis.
AB  - Arrest of circulating tumor cells in distant organs is required for hematogenous
      metastasis, but the tumor cell surface molecules responsible have not been
      identified. Here, we show that the tumor cell alpha3beta1 integrin makes an
      important contribution to arrest in the lung and to early colony formation. These
      analyses indicated that pulmonary arrest does not occur merely due to size
      restriction, and raised the question of how the tumor cell alpha3beta1 integrin
      contacts its best-defined ligand, laminin (LN)-5, a basement membrane (BM)
      component. Further analyses revealed that LN-5 is available to the tumor cell in
      preexisting patches of exposed BM in the pulmonary vasculature. The early arrest
      of tumor cells in the pulmonary vasculature through interaction of alpha3beta1
      integrin with LN-5 in exposed BM provides both a molecular and a structural basis
      for cell arrest during pulmonary metastasis.

PMID- 15024037
TI  - [3H]A-317491, a novel high-affinity non-nucleotide antagonist that specifically
      labels human P2X2/3 and P2X3 receptors.
AB  - A-317491 is a potent and selective antagonist of P2X3 and P2X(2/3) receptors. In
      the present studies, the ability of [3H]A-317491 to label recombinant human
      P2X(2/3) and P2X(3) receptors was characterized. Using membranes prepared from
      1321N1 cells expressing P2X(2/3) receptors, [3H]A-317491 specifically labeled
      high-affinity (Kd = 0.9 nM) recognition sites. High-affinity [3H]A-317491 binding
      was not detected in membrane preparations from native 1321N1 cells or cells
      expressing homomeric P2X1, P2X2, or P2X3 receptors. Specific [3H]A-317491 P2X3
      receptors could only be reliably detected following treatment of intact P2X3
      receptor-expressing cells with apyrase (1 U/ml) both before and during membrane
      preparation. Under these conditions, [3H]A-317491 also labeled high-affinity (Kd
      = 9 nM) binding sites. Lower affinity binding components (Kd values of 87-790 nM)
      were detected in both assays using higher ligand concentrations that likely
      represent nonfunctional recognition sites. [3H]A-317491 binding to both P2X(2/3)
      and P2X3 receptors was reversible, and ligand kinetic studies provided similar
      estimates of the high-affinity binding constants. Potent P2X3 receptor agonists 2
      methylthio-ATP, 2,3-O-(4-benzoylbenzoyl)-ATP, and alpha,beta-methylene adenosine
      triphosphate also potently inhibited specific [3H]A-317491 binding to both
      P2X(2/3) and P2X3 receptors. The pharmacological profile for P2X receptor
      antagonists to inhibit [3H]A-317491 binding to P2X(2/3) and P2X3 receptors was
      highly correlated (r = 0.98, P < 0.05), and a similar rank order of potency was
      observed for blockade of P2X(2/3) receptor-mediated calcium influx. These data
      demonstrate that [3H]A-317491 is the first useful radioligand for the specific
      labeling of P2X3-containing channels.

PMID- 15024038
TI  - Involvement of capsaicin-sensitive afferent nerves and cholecystokinin 2/gastrin
      receptors in gastroprotection and adaptation of gastric mucosa to Helicobacter
      pylori-lipopolysaccharide.
AB  - Lipopolysaccharide (LPS) is one of the virulence factors in the Helicobacter
      pylori (Hp)-infected stomach, but it remains unknown whether single and prolonged
      pretreatment with Hp-LPS can affect the course of gastric damage induced by
      aspirin (ASA). We compared the effects of Hp-LPS with those induced by LPSs
      isolated from intestinal Bacteroides fragilis, Yersinia enterocolitica, and
      Campylobacter jejuni applied for 4 days on acute ASA-induced gastric lesions in
      rats. The area of ASA-induced gastric lesions, gastric blood flow (GBF),
      expression of mRNA and protein of leptin and plasma leptin, gastrin, interleukin
      1beta, and tumor necrosis factor-alpha levels were examined. Single (once) or
      repeated (five times) i.p. injections of Hp-LPS (1 mg/kg) or intestinal LPSs
      failed to produce macroscopic gastric damage and did not affect the GBF when
      compared with vehicle. Hp-LPS injected repeatedly suppressed the gastric acid
      secretion, up-regulated leptin mRNA and protein, and increased plasma leptin and
      gastrin levels. Hp-LPS significantly reduced the ASA-induced gastric damage and
      the accompanying decline in the GBF, and these effects were significantly
      attenuated by capsaicin denervation and selective antagonism of cholecystokinin-B
      (CCK2) receptors by RPR-102681 [N-(metoxy-3 phenyl) N-(N-methyl N-phenyl
      carbamylmethyl) carbamoylmethyl]-3 ureido]-3 phenyl]-2 propronique] but not by
      loxiglumide, an antagonist of CCK1 receptors. We conclude that 1) daily
      application of Hp-LPS enhances gastric mucosal resistance against ASA damage due
      to the increase of GBF and the expression and release of leptin and gastrin
      exerting trophic and gastroprotective effects, and 2) this enhanced resistance to
      ASA damage in Hp-LPS-adapted stomach is mediated by the sensory afferents and
      specific CCK2/gastrin receptors.

PMID- 15024039
TI  - Differential effects of tyrosine kinase inhibitors on volume-sensitive chloride
      current in human atrial myocytes: evidence for dual regulation by Src and EGFR
      kinases.
AB  - To determine whether protein tyrosine kinase (PTK) modulates volume-sensitive
      chloride current (I(Cl.vol)) in human atrial myocytes and to identify the PTKs
      involved, we studied the effects of broad-spectrum and selective PTK inhibitors
      and the protein tyrosine phosphatase (PTP) inhibitor orthovanadate (VO(4)(-3)).
      I(Cl.vol) evoked by hyposmotic bath solution (0.6-times isosmotic, 0.6T) was
      enhanced by genistein, a broad-spectrum PTK inhibitor, in a concentration
      dependent manner (EC(50) = 22.4 microM); 100 microM genistein stimulated
      I(Cl.vol) by 122.4 +/- 10.6%. The genistein-stimulated current was inhibited by
      DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, 150 microM) and tamoxifen
      (20 microM), blockers of I(Cl.vol). Moreover, the current augmented by genistein
      was volume dependent; it was abolished by hyperosmotic shrinkage in 1.4T, and
      genistein did not activate Cl(-) current in 1T. In contrast to the stimulatory
      effects of genistein, 100 microM tyrphostin A23 (AG 18) and A25 (AG 82) inhibited
      I(Cl.vol) by 38.2 +/- 4.9% and 40.9 +/- 3.4%, respectively. The inactive analogs,
      daidzein and tyrphostin A63 (AG 43), did not alter I(Cl.vol). In addition, the
      PTP inhibitor VO(4)(-3) (1 mM) reduced I(Cl.vol) by 53.5 +/- 4.5% (IC(50) = 249.6
      microM). Pretreatment with VO(4)(-3) antagonized genistein-induced augmentation
      and A23- or A25-induced suppression of I(Cl.vol). Furthermore, the selective Src
      family PTK inhibitor PP2 (5 microM) stimulated I(Cl.vol), mimicking genistein,
      whereas the selective EGFR (ErbB-1) kinase inhibitor tyrphostin B56 (AG 556, 25
      microM) reduced I(Cl.vol), mimicking A23 and A25. The effects of both PP2 and B56
      also were substantially antagonized by pretreatment with VO(4)(-3). The results
      suggest that I(Cl.vol) is regulated in part by the balance between PTK and PTP
      activity. Regulation is complex, however. Src and EGFR kinases, distinct soluble
      and receptor-mediated PTK families, have opposing effects on I(Cl.vol), and
      multiple target proteins are likely to be involved.

PMID- 15024040
TI  - RYR2 proteins contribute to the formation of Ca(2+) sparks in smooth muscle.
AB  - Calcium release through ryanodine receptors (RYR) activates calcium-dependent
      membrane conductances and plays an important role in excitation-contraction
      coupling in smooth muscle. The specific RYR isoforms associated with this release
      in smooth muscle, and the role of RYR-associated proteins such as FK506 binding
      proteins (FKBPs), has not been clearly established, however. FKBP12.6 proteins
      interact with RYR2 Ca(2+) release channels and the absence of these proteins
      predictably alters the amplitude and kinetics of RYR2 unitary Ca(2+) release
      events (Ca(2+) sparks). To evaluate the role of specific RYR2 and FBKP12.6
      proteins in Ca(2+) release processes in smooth muscle, we compared spontaneous
      transient outward currents (STOCs), Ca(2+) sparks, Ca(2+)-induced Ca(2+) release,
      and Ca(2+) waves in smooth muscle cells freshly isolated from wild-type,
      FKBP12.6(-/-), and RYR3(-/-) mouse bladders. Consistent with a role of FKBP12.6
      and RYR2 proteins in spontaneous Ca(2+) sparks, we show that the frequency,
      amplitude, and kinetics of spontaneous, transient outward currents (STOCs) and
      spontaneous Ca(2+) sparks are altered in FKBP12.6 deficient myocytes relative to
      wild-type and RYR3 null cells, which were not significantly different from each
      other. Ca(2+) -induced Ca(2+) release was similarly augmented in FKBP12.6(-/-),
      but not in RYR3 null cells relative to wild-type. Finally, Ca(2+) wave speed
      evoked by CICR was not different in RYR3 cells relative to control, indicating
      that these proteins are not necessary for normal Ca(2+) wave propagation. The
      effect of FKBP12.6 deletion on the frequency, amplitude, and kinetics of
      spontaneous and evoked Ca(2+) sparks in smooth muscle, and the finding of normal
      Ca(2+) sparks and CICR in RYR3 null mice, indicate that Ca(2+) release through
      RYR2 molecules contributes to the formation of spontaneous and evoked Ca(2+)
      sparks, and associated STOCs, in smooth muscle.

PMID- 15024041
TI  - Influence of permeant ions on voltage sensor function in the Kv2.1 potassium
      channel.
AB  - We previously demonstrated that the outer vestibule of activated Kv2.1 potassium
      channels can be in one of two conformations, and that K(+) occupancy of a
      specific selectivity filter site determines which conformation the outer
      vestibule is in. These different outer vestibule conformations result in
      different sensitivities to internal and external TEA, different inactivation
      rates, and different macroscopic conductances. The [K(+)]-dependent switch in
      outer vestibule conformation is also associated with a change in rate of channel
      activation. In this paper, we examined the mechanism by which changes in [K(+)]
      modulate the rate of channel activation. Elevation of symmetrical [K(+)] or
      [Rb(+)] from 0 to 3 mM doubled the rate of on-gating charge movement (Q(on)),
      measured at 0 mV. Cs(+) produced an identical effect, but required 40-fold higher
      concentrations. All three permeant ions occupied the selectivity filter over the
      0.03-3 mM range, so simple occupancy of the selectivity filter was not sufficient
      to produce the change in Q(on). However, for each of these permeant ions, the
      speeding of Q(on) occurred with the same concentration dependence as the switch
      between outer vestibule conformations. Neutralization of an amino acid (K356) in
      the outer vestibule, which abolishes the modulation of channel pharmacology and
      ionic currents by the K(+)-dependent reorientation of the outer vestibule, also
      abolished the K(+)-dependence of Q(on). Together, the data indicate that the K(+)
      dependent reorientation in the outer vestibule was responsible for the change in
      Q(on). Moreover, similar [K(+)]-dependence and effects of mutagenesis indicate
      that the K(+)-dependent change in rate of Q(on) can account for the modulation of
      ionic current activation rate. Simple kinetic analysis suggested that K(+)
      reduced an energy barrier for voltage sensor movement. These results provide
      strong evidence for a direct functional interaction, which is modulated by
      permeant ions acting at the selectivity filter, between the outer vestibule of
      the Kv2.1 potassium channel and the voltage sensor.

PMID- 15024042
TI  - Overexpressed Ca(v)beta3 inhibits N-type (Cav2.2) calcium channel currents
      through a hyperpolarizing shift of ultra-slow and closed-state inactivation.
AB  - It has been shown that beta auxiliary subunits increase current amplitude in
      voltage-dependent calcium channels. In this study, however, we found a novel
      inhibitory effect of beta3 subunit on macroscopic Ba(2+) currents through
      recombinant N- and R-type calcium channels expressed in Xenopus oocytes.
      Overexpressed beta3 (12.5 ng/cell cRNA) significantly suppressed N- and R-type,
      but not L-type, calcium channel currents at "physiological" holding potentials
      (HPs) of -60 and -80 mV. At a HP of -80 mV, coinjection of various concentrations
      (0-12.5 ng) of the beta3 with Ca(v)2.2alpha(1) and alpha(2)delta enhanced the
      maximum conductance of expressed channels at lower beta3 concentrations but at
      higher concentrations (>2.5 ng/cell) caused a marked inhibition. The beta3
      induced current suppression was reversed at a HP of -120 mV, suggesting that the
      inhibition was voltage dependent. A high concentration of Ba(2+) (40 mM) as a
      charge carrier also largely diminished the effect of beta3 at -80 mV. Therefore,
      experimental conditions (HP, divalent cation concentration, and beta3 subunit
      concentration) approaching normal physiological conditions were critical to
      elucidate the full extent of this novel beta3 effect. Steady-state inactivation
      curves revealed that N-type channels exhibited "closed-state" inactivation
      without beta3, and that beta3 caused an approximately 40-mV negative shift of the
      inactivation, producing a second component with an inactivation midpoint of
      approximately -85 mV. The inactivation of N-type channels in the presence of a
      high concentration (12.5 ng/cell) of beta3 developed slowly and the time
      dependent inactivation curve was best fit by the sum of two exponential functions
      with time constants of 14 s and 8.8 min at -80 mV. Similar "ultra-slow"
      inactivation was observed for N-type channels without beta3. Thus, beta3 can have
      a profound negative regulatory effect on N-type (and also R-type) calcium
      channels by causing a hyperpolarizing shift of the inactivation without affecting
      "ultra-slow" and "closed-state" inactivation properties.

PMID- 15024043
TI  - Large diameter of palytoxin-induced Na/K pump channels and modulation of
      palytoxin interaction by Na/K pump ligands.
AB  - Palytoxin binds to Na/K pumps to generate nonselective cation channels whose pore
      likely comprises at least part of the pump's ion translocation pathway. We
      systematically analyzed palytoxin's interactions with native human Na/K pumps in
      outside-out patches from HEK293 cells over a broad range of ionic and nucleotide
      conditions, and with or without cardiotonic steroids. With 5 mM internal
      (pipette) [MgATP], palytoxin activated the conductance with an apparent affinity
      that was highest for Na(+)-containing (K(+)-free) external and internal
      solutions, lowest for K(+)-containing (Na(+)-free) external and internal
      solutions, and intermediate for the mixed external Na(+)/internal K(+), and
      external K(+)/internal Na(+) conditions; with Na(+) solutions and MgATP, the mean
      dwell time of palytoxin on the Na/K pump was about one day. With Na(+) solutions,
      the apparent affinity for palytoxin action was low after equilibration of patches
      with nucleotide-free pipette solution. That apparent affinity was increased in
      two phases as the equilibrating [MgATP] was raised over the submicromolar, and
      submillimolar, ranges, but was increased by pipette MgAMPPNP in a single phase,
      over the submillimolar range; the apparent affinity at saturating [MgAMPPNP]
      remained approximately 30-fold lower than at saturating [MgATP]. After palytoxin
      washout, the conductance decay that reflects palytoxin unbinding was accelerated
      by cardiotonic steroid. When Na/K pumps were preincubated with cardiotonic
      steroid, subsequent activation of palytoxin-induced conductance was greatly
      slowed, even after washout of the cardiotonic steroid, but activation could still
      be accelerated by increasing palytoxin concentration. These results indicate that
      palytoxin and a cardiotonic steroid can simultaneously occupy the same Na/K pump,
      each destabilizing the other. The palytoxin-induced channels were permeable to
      several large organic cations, including N-methyl-d-glucamine(+), suggesting that
      the narrowest section of the pore must be approximately 7.5 A wide. Enhanced
      understanding of palytoxin action now allows its use for examining the structures
      and mechanisms of the gates that occlude/deocclude transported ions during the
      normal Na/K pump cycle.

PMID- 15024044
TI  - PKCtheta signals activation versus tolerance in vivo.
AB  - Understanding the pathways that signal T cell tolerance versus activation is key
      to regulating immunity. Previous studies have linked CD28 and protein kinase C
      theta (PKCtheta) as a potential signaling pathway that influences T cell
      activation. Therefore, we have compared the responses of T cells deficient for
      CD28 and PKCtheta in vivo and in vitro. Here, we demonstrate that the absence of
      PKCtheta leads to the induction of T cell anergy, with a phenotype that is
      comparable to the absence of CD28. Further experiments examined whether PKCtheta
      triggered other CD28-dependent responses. Our data show that CD4 T cell-B cell
      cooperation is dependent on CD28 but not PKCtheta, whereas CD28 costimulatory
      signals that augment proliferation can be uncoupled from signals that regulate
      anergy. Therefore, PKCtheta relays a defined subset of CD28 signals during T cell
      activation and is critical for the induction of activation versus tolerance in
      vivo.

PMID- 15024045
TI  - Immunoprevention of basal cell carcinomas with recombinant hedgehog-interacting
      protein.
AB  - Basal cell carcinomas (BCCs) are driven by abnormal hedgehog signaling and highly
      overexpress several hedgehog target genes. We report here our use of one of these
      target genes, hedgehog-interacting protein (Hip1), as a tumor-associated antigen
      for immunoprevention of BCCs in Ptch1+/- mice treated with ionizing radiation.
      Hip1 mRNA is expressed in adult mouse tissues at levels considerably lower than
      those in BCCs. Immunization with either of two large recombinant Hip1
      polypeptides was well tolerated in Ptch1+/- mice, induced B and T cell responses
      detectable by enzyme-linked immunosorbent assay, Western blot, delayed type
      hypersensitivity, and enzyme-linked immunospot assay, and reduced the number of
      BCCs by 42% (P < 0.001) and 32% (P < 0.01), respectively. We conclude that
      immunization with proteins specifically up-regulated by hedgehog signaling may
      hold promise as a preventive option for patients such as those with the basal
      cell nevus syndrome who are destined to develop large numbers of BCCs.

PMID- 15024046
TI  - Sclerostin is an osteocyte-expressed negative regulator of bone formation, but
      not a classical BMP antagonist.
AB  - Sclerosteosis, a skeletal disorder characterized by high bone mass due to
      increased osteoblast activity, is caused by loss of the SOST gene product,
      sclerostin. The localization in bone and the mechanism of action of sclerostin
      are not yet known, but it has been hypothesized that it may act as a bone
      morphogenetic protein (BMP) antagonist. We show here that SOST/sclerostin is
      expressed exclusively by osteocytes in mouse and human bone and inhibits the
      differentiation and mineralization of murine preosteoblastic cells (KS483).
      Although sclerostin shares some of the actions of the BMP antagonist noggin, we
      show here that it also has actions distinctly different from it. In contrast to
      noggin, sclerostin did not inhibit basal alkaline phosphatase (ALP) activity in
      KS483 cells, nor did it antagonize BMP-stimulated ALP activity in mouse C2C12
      cells. In addition, sclerostin had no effect on BMP-stimulated Smad
      phosphorylation and direct transcriptional activation of MSX-2 and BMP response
      element reporter constructs in KS483 cells. Its unique localization and action on
      osteoblasts suggest that sclerostin may be the previously proposed osteocyte
      derived factor that is transported to osteoblasts at the bone surface and
      inhibits bone formation.

PMID- 15024047
TI  - In vivo targeting of antigens to maturing dendritic cells via the DEC-205
      receptor improves T cell vaccination.
AB  - The prevention and treatment of prevalent infectious diseases and tumors should
      benefit from improvements in the induction of antigen-specific T cell immunity.
      To assess the potential of antigen targeting to dendritic cells to improve
      immunity, we incorporated ovalbumin protein into a monoclonal antibody to the DEC
      205 receptor, an endocytic receptor that is abundant on these cells in lymphoid
      tissues. Simultaneously, we injected agonistic alpha-CD40 antibody to mature the
      dendritic cells. We found that a single low dose of antibody-conjugated ovalbumin
      initiated immunity from the naive CD4+ and CD8+ T cell repertoire. Unexpectedly,
      the alphaDEC-205 antigen conjugates, given s.c., targeted to dendritic cells
      systemically and for long periods, and ovalbumin peptide was presented on MHC
      class I for 2 weeks. This was associated with stronger CD8+ T cell-mediated
      immunity relative to other forms of antigen delivery, even when the latter was
      given at a thousand times higher doses. In parallel, the mice showed enhanced
      resistance to an established rapidly growing tumor and to viral infection at a
      mucosal site. By better harnessing the immunizing functions of maturing dendritic
      cells, antibody-mediated antigen targeting via the DEC-205 receptor increases the
      efficiency of vaccination for T cell immunity, including systemic and mucosal
      resistance in disease models.

PMID- 15024048
TI  - Positive selection of B cells expressing low densities of self-reactive BCRs.
AB  - B cell tolerance or autoimmunity is determined by selective events. Negative
      selection of self-reactive B cells is well documented and proven. In contrast,
      positive selection of conventional B cells is yet to be firmly established. Here,
      we demonstrate that developing self-reactive B cells are not always highly
      sensitive to the deletion mechanisms imposed by membrane-bound self-antigens. At
      low amounts, membrane-bound antigens allow survival of B cells bearing a single
      high affinity self-reactive B cell receptor (BCR). More importantly, we show that
      forced allelic inclusion modifies B cell fate; low quantities of self-antigen
      induce the selection and accumulation of increased numbers of self-reactive B
      cells with decreased expression of antigen-specific BCRs. By directly measuring
      antigen binding by intact B cells, we show that the low amounts of self-antigen
      select self-reactive B cells with a lower association constant. A fraction of
      these B cells is activated and secretes autoantibodies that form circulating
      immune complexes with self-antigen. These findings demonstrate that conventional
      B cells can undergo positive selection and that the fate of a self-reactive B
      cell depends on the quantity of self-antigen, the number of BCRs engaged, and on
      its overall antigen-binding avidity, rather than on the affinity of individual
      BCRs.

PMID- 15024049
TI  - A B cell receptor with two Igalpha cytoplasmic domains supports development of
      mature but anergic B cells.
AB  - B cell receptor (BCR) signaling is mediated through immunoglobulin (Ig)alpha and
      Igbeta a membrane-bound heterodimer. Igalpha and Igbeta are redundant in their
      ability to support early B cell development, but their roles in mature B cells
      have not been defined. To examine the function of Igalpha-Igbeta in mature B
      cells in vivo we exchanged the cytoplasmic domain of Igalpha for the cytoplasmic
      domain of Igbeta by gene targeting (Igbetac-->alphac mice). Igbetac-->alphac B
      cells had lower levels of surface IgM and higher levels of BCR internalization
      than wild-type B cells. The mutant B cells were able to complete all stages of
      development and were long lived, but failed to differentiate into B1a cells. In
      addition, Igbetac-->alphac B cells showed decreased proliferative and Ca2+
      responses to BCR stimulation in vitro, and were anergic to T-independent and 
      dependent antigens in vivo.

PMID- 15024050
TI  - Critical role for Kit-mediated Src kinase but not PI 3-kinase signaling in pro T
      and pro B cell development.
AB  - The Kit receptor functions in hematopoiesis, lymphocyte development,
      gastrointestinal tract motility, melanogenesis, and gametogenesis. To investigate
      the roles of different Kit signaling pathways in vivo, we have generated knock-in
      mice in which docking sites for PI 3-kinase (KitY719) or Src kinase (KitY567)
      have been mutated. Whereas steady-state hematopoiesis is normal in KitY719F/Y719F
      and KitY567F/Y567F mice, lymphopoiesis is affected differentially. The KitY567F
      mutation, but not the KitY719F mutation, blocks pro T cell and pro B cell
      development in an age-dependent manner. Thus, the Src family kinase, but not the
      PI 3-kinase docking site in Kit, mediates a critical signal for lymphocyte
      development. In agreement with these results, treatment of normal mice with the
      Kit tyrosine kinase inhibitor imatinib (Gleevec) leads to deficits in pro T and
      pro B cell development, similar to those seen in KitY567F/Y567F and KitW/W mice.
      The two mutations do not affect embryonic gametogenesis but the KitY719F mutation
      blocks spermatogenesis at the spermatogonial stages and in contrast the KitY567F
      mutation does not affect this process. Therefore, Kit-mediated PI 3-kinase
      signaling and Src kinase family signaling is highly specific for different
      cellular contexts in vivo.

PMID- 15024051
TI  - Molecular mechanism of suppression of testicular steroidogenesis by
      proinflammatory cytokine tumor necrosis factor alpha.
AB  - Tumor necrosis factor alpha (TNF-alpha) has been demonstrated to inhibit
      steroidogenesis in Leydig cells at the transcriptional level of steroidogenic
      enzymes. However, the molecular mechanism of this observed gene repression is not
      well understood. We now demonstrate that nuclear factor kappaB (NF-kappaB)
      activated by TNF-alpha inhibits the transactivation of orphan nuclear receptors,
      which regulate the expression of steroidogenic-enzyme genes. TNF-alpha treatment
      suppressed the luteinizing-hormone-induced or Nur77/SF-1-stimulated promoter
      activity of steroidogenic-enzyme genes in Leydig cells. The TNF-alpha-mediated
      gene suppression was blocked by treatment with an inhibitor of NF-kappaB. In
      addition, overexpression of the p65 (RelA) subunit of NF-kappaB showed the same
      effect as TNF-alpha and inhibited Nur77 transactivation, suggesting the
      involvement of NF-kappaB activation in the observed gene repression. Physical
      association of Nur77 with p65 was revealed by mammalian two-hybrid, GST pull
      down, and coimmunoprecipitation analyses. The NF-kappaB inhibition of Nur77
      transactivation was likely due to the competition of p65 for Nur77 binding with
      coactivators. Finally, chromatin immunoprecipitation assays revealed that TNF
      alpha treatment caused the recruitment of NF-kappaB to the promoter of the
      steroidogenic-enzyme p450c17 gene, supporting the hypothesis that the TNF-alpha
      mediated gene repression involves NF-kappaB inhibition of the transcriptional
      activity of Nur77 and other orphan nuclear receptors. These findings provide a
      molecular mechanism underlying the inhibition of testicular steroidogenesis by
      proinflammatory cytokines.

PMID- 15024052
TI  - Histone fold protein Dls1p is required for Isw2-dependent chromatin remodeling in
      vivo.
AB  - We report the identification of two new subunits of the Isw2 chromatin-remodeling
      complex in Saccharomyces cerevisiae. Both proteins, Dpb4p and Yjl065cp (named
      Dls1p), contain histone fold motifs and are homologous to the two smallest
      subunits of ISWI-containing CHRAC complexes in higher eukaryotes. Dpb4p is also a
      subunit of the DNA polymerase epsilon (polepsilon) complex, and Dls1p is
      homologous to another polepsilon subunit, Dpb3p. Therefore, these small histone
      fold proteins may fulfill functions that are required for both polepsilon and
      Isw2 complexes. We characterized the role of Dls1p in known roles of the Isw2
      complex in vivo. Transcriptional analyses reveal that the Isw2 complex requires
      Dls1p to various degrees at a wide variety of loci in vivo. Consistent with this,
      Dls1p is required for Isw2-dependent chromatin remodeling in vivo, although the
      requirement for this protein varies among Isw2 targets. Dls1p is likely required
      for functions of the Isw2 complex at steps subsequent to its interaction with
      chromatin, since a dls1 mutation does not affect cross-linking of Isw2 with
      chromatin.

PMID- 15024053
TI  - Protein kinase Cdelta selectively regulates protein kinase D-dependent activation
      of NF-kappaB in oxidative stress signaling.
AB  - Protein kinase D (PKD) participates in activation of the transcription factor NF
      kappaB (nuclear factor kappaB) in cells exposed to oxidative stress, leading to
      increased cellular survival. We previously demonstrated that phosphorylation of
      PKD at Tyr463 in the PH (pleckstrin homology) domain is mediated by the Src-Abl
      pathway and that it is necessary for PKD activation and subsequent NF-kappaB
      induction. Here we show that activation of PKD in response to oxidative stress
      requires two sequential signaling events, i.e., phosphorylation of Tyr463 by Abl,
      which in turn promotes a second step, phosphorylation of the PKD activation loop
      (Ser738/Ser742). We show that this is mediated by PKCdelta (protein kinase
      Cdelta), a kinase that is activated by Src in response to oxidative stress. We
      also show that other PKCs, including PKCepsilon and PKCzeta, do not participate
      in PKD activation or NF-kappaB induction. We propose a model in which two
      coordinated signaling events are required for PKD activation. Tyrosine
      phosphorylation in the PH domain at Tyr463, mediated by the Src-Abl pathway,
      which in turn facilitates the phosphorylation of Ser738/Ser742 in the activation
      loop, mediated by the Src-PKCdelta pathway. Once active, the signal is relayed to
      the activation of NF-kappaB in oxidative stress responses.

PMID- 15024054
TI  - N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts
      with TRAF2 and induces activation of the NF-kappaB signaling pathway.
AB  - Caspase 8 is required not only for death receptor-mediated apoptosis but also for
      lymphocyte activation in the immune system. FLIP(L), the long-splice form of c
      FLIP, is one of the specific substrates for caspase 8, and increased expression
      of FLIP(L) promotes activation of the NF-kappaB signaling pathway. The synthetic
      caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD
      fmk) markedly blocked NF-kappaB activation induced by overexpression of FLIP(L).
      FLIP(L) is specifically processed by caspase 8 into N-terminal FLIP(p43) and C
      terminal FLIP(p12). Only FLIP(p43) was able to induce NF-kappaB activation as
      efficiently as FLIP(L), and FLIP(p43)-induced NF-kappaB activation became
      insensitive to zVAD-fmk. In caspase 8-deficient cells, FLIP(p43) provoked NF
      kappaB activation only when procaspase 8 or caspase 8(p43) was complemented.
      FLIP(p43)-induced NF-kappaB activation was profoundly blocked by the dominant
      negative TRAF2. Moreover, endogenous TRAF2 interacted specifically with
      FLIP(p43), and the formation of the FLIP(p43)-caspase 8-TRAF2 tertiary complex
      was a prerequisite to induction of NF-kappaB activation. zVAD-fmk prevented the
      recruitment of TRAF2 into the death-inducing signaling complex. Thus, our present
      results demonstrate that FLIP(p43) processed by caspase 8 specifically interacts
      with TRAF2 and subsequently induces activation of the NF-kappaB signaling
      pathway.

PMID- 15024055
TI  - Identification of Staufen in the human immunodeficiency virus type 1 Gag
      ribonucleoprotein complex and a role in generating infectious viral particles.
AB  - Staufen is a host protein that is selectively incorporated into human
      immunodeficiency virus type 1 (HIV-1) particles in a poorly defined process that
      involves the selection of HIV-1 genomic RNA for encapsidation and the activity of
      its third double-stranded RNA-binding domain (dsRBD3). To better understand this,
      we characterized its interactions with pr55(Gag), the principal mediator of HIV-1
      genomic RNA encapsidation. Chimeric proviruses harboring wild-type or mutant
      forms of Staufen were expressed in 293T cells. Cell fractionation analyses
      demonstrated that Staufen cosedimented with pr55(Gag) within detergent-resistant,
      trypsin-sensitive complexes that excluded mature capsid and matrix proteins.
      Coimmunoprecipitation and bioluminescence resonance energy transfer assays
      demonstrated a specific and direct interaction between Staufen and the
      nucleocapsid domain of pr55(Gag) in vitro and in live cells. This interaction is
      shown here to be mediated by Staufen's dsRBD3, with a contribution from its C
      terminal domain. Immunoprecipitation and reverse transcription-PCR analyses
      showed that the 9-kb genomic RNA was found within Staufen-containing immune
      complexes. Spliced HIV-1 RNAs were not detected in these Staufen complexes,
      indicating a preferential association of Staufen with the 9-kb species. These
      results substantiate that Staufen and pr55(Gag) interact directly during HIV-1
      expression. Knockdown of Staufen expression by small interfering RNAs in HIV-1
      expressing cells demonstrated that this cellular protein was important for the
      generation of infectious virus. These data show that Staufen, pr55(Gag), and
      genomic RNA are part of the same intracellular complex and support a role for
      Staufen in pr55(Gag) function in viral assembly, genomic RNA encapsidation, and
      the generation of infectious viral particles.

PMID- 15024056
TI  - Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin
      complexes for phosphorylation-dependent recruitment of p300/CBP coactivators.
AB  - Previous liver regeneration studies demonstrated that the mouse forkhead box M1B
      (FoxM1B) transcription factor regulates hepatocyte proliferation through
      expression of cell cycle genes that stimulate cyclin-dependent kinase 2 (Cdk2)
      and Cdk1 activity. In this study, we demonstrated that disruption of the FoxM1B
      Cdk1/2 phosphorylation site at Thr residue 596 significantly reduced both FoxM1B
      transcriptional activity and Cdk phosphorylation of the FoxM1B T596A mutant
      protein in vivo. Retention of this FoxM1B 596 Cdk phosphorylation site was found
      to be essential for recruiting the histone acetyltransferase CREB binding protein
      (CBP) to the FoxM1B transcriptional activation domain. Consistent with these
      findings, dominant negative Cdk1 protein significantly reduced FoxM1B
      transcriptional activity and inhibited FoxM1B recruitment of the CBP coactivator
      protein. Likewise, Cdc25B-mediated stimulation of Cdk activity together with
      elevated levels of the CBP coactivator protein provided a 6.2-fold synergistic
      increase in FoxM1B transcriptional activity. Furthermore, mutation of the FoxM1B
      Leu 641 residue within an LXL motif (residues 639 to 641) inhibited recruitment
      of Cdk-cyclin complexes and caused significant reduction in both FoxM1B
      transcriptional activity and in vivo Cdk phosphorylation of the FoxM1B Thr 596
      residue. We demonstrated that FoxM1B transcriptional activity requires binding of
      either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk
      phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment
      of p300/CBP coactivator proteins.

PMID- 15024057
TI  - Basic helix-loop-helix proteins bind to TrkB and p21(Cip1) promoters linking
      differentiation and cell cycle arrest in neuroblastoma cells.
AB  - Differentiation of precursor into specialized cells involves an increasing
      restriction in proliferative capacity, culminating in cell cycle exit. In this
      report we used a human neuroblastoma cell line to study the molecular mechanisms
      that coordinate cell cycle arrest and neuronal differentiation. Exposure to
      retinoic acid (RA), a differentiation agent in many cell types, causes an
      upregulation of neurotrophin receptor TrkB and the cyclin kinase inhibitor
      p21(Cip1) at a transcriptional level. Full transcriptional activation of these
      two genes requires canonical E-box sequences found in the TrkB and p21(Cip1)
      promoters. As reported for other E-box-regulated promoters, ectopic expression of
      E47 and E12 basic helix-loop-helix (bHLH) proteins enhances RA-dependent
      expression of TrkB and p21(Cip1), whereas the inhibitory HLH Id2 exerts opposite
      effects. In addition, ectopic expression of E47 and NeuroD, a neuronal bHLH
      protein, is able to activate TrkB transcription in the absence of RA. More
      importantly, we show that E47 and NeuroD proteins bind the TrkB and p21(Cip1)
      promoter sequences in vivo. Since they establish a direct transcriptional link
      between a cell cycle inhibitor, p21(Cip1), and a neurotrophic receptor, TrkB,
      bHLH proteins would play an important role in coordinating key events of cell
      cycle arrest and neuronal differentiation.

PMID- 15024058
TI  - Inhibition of Mist1 homodimer formation induces pancreatic acinar-to-ductal
      metaplasia.
AB  - The pancreas consists of three main cell lineages (endocrine, exocrine, and duct)
      that develop from common primitive foregut precursors. The transcriptional
      network responsible for endocrine cell development has been studied extensively,
      but much less is known about the transcription factors that maintain the exocrine
      and duct cell lineages. One transcription factor that may be important to
      exocrine cell function is Mist1, a basic helix-loop-helix (bHLH) factor that is
      expressed in acinar cells. In order to perform a molecular characterization of
      this protein, we employed coimmunoprecipitation and bimolecular fluorescence
      complementation assays, coupled with electrophoretic mobility shift assay
      studies, to show that Mist1 exists in vivo as a homodimer complex. Analysis of
      transgenic mice expressing a dominant-negative Mist1 transgene (Mist1(mutant
      basic) [Mist1(MB)]) revealed the cell autonomous effect of inhibiting endogenous
      Mist1. Mist1(MB) cells become disorganized, exhibit a severe depletion of
      intercellular gap junctions, and express high levels of the glycoprotein
      clusterin, which has been shown to demarcate immature acinar cells. Inhibition of
      Mist1 transcriptional activity also leads to activation of duct-specific genes,
      such as cytokeratin 19 and cytokeratin 20, suggesting that alterations in the
      bHLH network produce a direct acinar-to-ductal phenotypic switch in mature cells.
      We propose that Mist1 is a key transcriptional regulator of exocrine pancreatic
      cells and that in the absence of functional Mist1, acinar cells do not maintain
      their normal identity.

PMID- 15024059
TI  - Rapid glucocorticoid receptor exchange at a promoter is coupled to transcription
      and regulated by chaperones and proteasomes.
AB  - Exchange of the glucocorticoid receptor (GR) at promoter target sites provides
      the only known system in which transcription factor cycling at a promoter is
      fast, occurring on a time scale of seconds. The mechanism and function of this
      rapid exchange are unknown. We provide evidence that proteasome activity is
      required for rapid GR exchange at a promoter. We also show that chaperones,
      specifically hsp90, stabilize the binding of GR to the promoter, complicating
      models in which the associated chaperone, p23, has been proposed to induce GR
      removal. Our results are the first to connect chaperone and proteasome functions
      in setting the residence time of a transcription factor at a target promoter.
      Moreover, our results reveal that longer GR residence times are consistently
      associated with greater transcriptional output, suggesting a new paradigm in
      which the rate of rapid exchange provides a means to tune transcriptional levels.

PMID- 15024060
TI  - Functional analysis of the Mad1-mSin3A repressor-corepressor interaction reveals
      determinants of specificity, affinity, and transcriptional response.
AB  - The recruitment of corepressors by DNA-bound repressors is likely to be a
      critical rate-limiting step in the transcriptional regulation of many genes. An
      excellent paradigm for such an interaction is the association of the basic helix
      loop-helix zipper protein Mad1 with the corepressor mSin3A. When bound together,
      the Sin3 interaction domain (SID) of Mad1 forms extensive hydrophobic contacts
      with the four-helix bundle formed by the paired amphipathic helix 2 (PAH2) domain
      of mSin3A. Using the costructure to predict the principle residues required for
      binding, we have carried out an extensive mutational analysis to examine the Mad1
      SID-mSin3A PAH2 interaction in vitro and in vivo. Bulky hydrophobic residues in
      the alpha1 (I308 and V311) and alpha2 (L329 and L332) helices of the PAH2 domain
      are necessary to accommodate the precise arrangement of bulky (L12) and short
      (A15 and A16) hydrophobic residues in the amphipathic Mad1 SID. We have also used
      phage display to derive an optimal SID, which shows an essentially identical
      arrangement of key residues. By manipulating these key residues, we have
      generated altered-specificity Mad1 SID mutants that bind only to a PAH2 domain
      with a reciprocal mutation, permitting us to demonstrate for the first time that
      these domains interact directly in vivo. We have also found that the integrity of
      the PAH1 domain affects the Mad1 SID-PAH2 interaction. It is conceivable that
      cross talk between different PAH domains and their binding partners helps to
      determine the subunit composition and order of assembly of mSin3A complexes.

PMID- 15024061
TI  - ATP-sensitive K(+) channels regulate the concentrative adenosine transporter CNT2
      following activation by A(1) adenosine receptors.
AB  - This study describes a novel mechanism of regulation of the high-affinity Na(+)
      dependent adenosine transporter (CNT2) via the activation of A(1) adenosine
      receptors (A(1)R). This regulation is mediated by the activation of ATP-sensitive
      K(+) (K(ATP)) channels. The high-affinity Na(+)-dependent adenosine transporter
      CNT2 and A(1)R are coexpressed in the basolateral domain of the rat hepatocyte
      plasma membrane and are colocalized in the rat hepatoma cell line FAO. The
      transient increase in CNT2-mediated transport activity triggered by (-)-N(6)-(2
      phenylisopropyl)adenosine is fully inhibited by K(ATP) channel blockers and
      mimicked by a K(ATP) channel opener. A(1)R agonist activation of CNT2 occurs in
      both hepatocytes and FAO cells, which express Kir6.1, Kir6.2, SUR1, SUR2A, and
      SUR2B mRNA channel subunits. With the available antibodies against Kir6.X, SUR2A,
      and SUR2B, it is shown that all of these proteins colocalize with CNT2 and A(1)R
      in defined plasma membrane domains of FAO cells. The extent of the purinergic
      modulation of CNT2 is affected by the glucose concentration, a finding which
      indicates that glycemia and glucose metabolism may affect this cross-regulation
      among A(1)R, CNT2, and K(ATP) channels. These results also suggest that the
      activation of K(ATP) channels under metabolic stress can be mediated by the
      activation of A(1)R. Cell protection under these circumstances may be achieved by
      potentiation of the uptake of adenosine and its further metabolization to ATP.
      Mediation of purinergic responses and a connection between the intracellular
      energy status and the need for an exogenous adenosine supply are novel roles for
      K(ATP) channels.

PMID- 15024062
TI  - Securin is a target of the UV response pathway in mammalian cells.
AB  - All eukaryotic cells possess elaborate mechanisms to protect genome integrity and
      ensure survival after DNA damage, ceasing proliferation and granting time for DNA
      repair. Securin is an inhibitory protein that is bound to a protease called
      Separase to inhibit sister chromatid separation until the onset of anaphase. At
      the metaphase-to-anaphase transition, Securin is degraded by the anaphase
      promoting complex or cyclosome, and Separase contributes to the release of
      cohesins from the chromosome, allowing for the segregation of sister chromatids
      to opposite spindle poles. Here we provide evidence that human Securin (hSecurin)
      has a novel role in cell cycle arrest after exposure to UV light or ionizing
      radiation. In fact, irradiation downregulated the level of hSecurin protein,
      accelerating its degradation via the proteasome and reducing hSecurin mRNA
      translation, but the presence of hSecurin is necessary for cell proliferation
      arrest following UV treatment. Moreover, an alteration of UV-induced hSecurin
      downregulation could lead directly to the accumulation of DNA damage and the
      subsequent development of malignant tumors.

PMID- 15024064
TI  - snRNAs contain specific SMN-binding domains that are essential for snRNP
      assembly.
AB  - To serve in its function as an assembly machine for spliceosomal small nuclear
      ribonucleoprotein particles (snRNPs), the survival of motor neurons (SMN) protein
      complex binds directly to the Sm proteins and the U snRNAs. A specific domain
      unique to U1 snRNA, stem-loop 1 (SL1), is required for SMN complex binding and U1
      snRNP Sm core assembly. Here, we show that each of the major spliceosomal U
      snRNAs (U2, U4, and U5), as well as the minor splicing pathway U11 snRNA,
      contains a domain to which the SMN complex binds directly and with remarkable
      affinity (low nanomolar concentration). The SMN-binding domains of the U snRNAs
      do not have any significant nucleotide sequence similarity yet they compete for
      binding to the SMN complex in a manner that suggests the presence of at least two
      binding sites. Furthermore, the SMN complex-binding domain and the Sm site are
      both necessary and sufficient for Sm core assembly and their relative positions
      are critical for snRNP assembly. These findings indicate that the SMN complex
      stringently scrutinizes RNAs for specific structural features that are not
      obvious from the sequence of the RNAs but are required for their identification
      as bona fide snRNAs. It is likely that this surveillance capacity of the SMN
      complex ensures assembly of Sm cores on the correct RNAs only and prevents
      illicit, potentially deleterious, assembly of Sm cores on random RNAs.

PMID- 15024063
TI  - Palm mutants in DNA polymerases alpha and eta alter DNA replication fidelity and
      translesion activity.
AB  - We isolated active mutants in Saccharomyces cerevisiae DNA polymerase alpha that
      were associated with a defect in error discrimination. Among them, L868F DNA
      polymerase alpha has a spontaneous error frequency of 3 in 100 nucleotides and
      570-fold lower replication fidelity than wild-type (WT) polymerase alpha. In
      vivo, mutant DNA polymerases confer a mutator phenotype and are synergistic with
      msh2 or msh6, suggesting that DNA polymerase alpha-dependent replication errors
      are recognized and repaired by mismatch repair. In vitro, L868F DNA polymerase
      alpha catalyzes efficient bypass of a cis-syn cyclobutane pyrimidine dimer,
      extending the 3' T 26000-fold more efficiently than the WT. Phe34 is equivalent
      to residue Leu868 in translesion DNA polymerase eta, and the F34L mutant of S.
      cerevisiae DNA polymerase eta has reduced translesion DNA synthesis activity in
      vitro. These data suggest that high-fidelity DNA synthesis by DNA polymerase
      alpha is required for genomic stability in yeast. The data also suggest that the
      phenylalanine and leucine residues in translesion and replicative DNA
      polymerases, respectively, might have played a role in the functional evolution
      of these enzyme classes.

PMID- 15024065
TI  - Meox homeodomain proteins are required for Bapx1 expression in the sclerotome and
      activate its transcription by direct binding to its promoter.
AB  - The axial skeleton of vertebrates derives from the sclerotomal compartment of the
      somites. Genetic analysis has demonstrated that the transcription factors Pax1,
      Pax9, Meox1, Meox2, and Bapx1 are all required for sclerotomal differentiation.
      Their hierarchical relationship is, however, poorly understood. Because Bapx1
      expression in the somites starts slightly later than that of the Meox genes, we
      asked whether Bapx1 is one of their downstream targets. Our analysis of Meox1;
      Meox2 mutant mice supports this hypothesis, as Bapx1 expression in the sclerotome
      is lost in the absence of both Meox proteins. Using transient-transfection
      assays, we show that Meox1 activates the Bapx1 promoter in a dose-dependent
      manner and that this activity is enhanced in the presence of Pax1 and/or Pax9.
      Furthermore, by electrophoretic mobility shift and chromatin immunoprecipitation
      experiments, we demonstrate that Meox1 can bind the Bapx1 promoter. The
      palindromic sequence TAATTA, present in the Bapx1 promoter, binds the Meox1
      protein in vitro and is necessary for Meox1-induced transactivation of the Bapx1
      promoter. Our data demonstrate that the Meox genes are required for Bapx1
      expression in the sclerotome and suggest that the mechanism by which the Meox
      proteins exert this function is through direct activation of the Bapx1 gene.

PMID- 15024066
TI  - The yeast split-ubiquitin membrane protein two-hybrid screen identifies BAP31 as
      a regulator of the turnover of endoplasmic reticulum-associated protein tyrosine
      phosphatase-like B.
AB  - In the past decade, traditional yeast two-hybrid techniques have identified a
      plethora of interactions among soluble proteins operating within diverse cellular
      pathways. The discovery of associations between membrane proteins by genetic
      approaches, on the other hand, is less well established due to technical
      limitations. Recently, a split-ubiquitin system was developed to overcome this
      barrier, but so far, this system has been limited to the analysis of known
      membrane protein interactions. Here, we constructed unique split-ubiquitin-linked
      cDNA libraries and provide details for implementing this system to screen for
      binding partners of a bait protein, in this case BAP31. BAP31 is a resident
      integral protein of the endoplasmic reticulum, where it operates as a chaperone
      or cargo receptor and regulator of apoptosis. Here we describe a novel human
      member of the protein tyrosine phosphatase-like B (PTPLB) family, an integral
      protein of the endoplasmic reticulum membrane with four membrane-spanning alpha
      helices, as a BAP31-interacting protein. PTPLB turns over rapidly through
      degradation by the proteasome system. Comparisons of mouse cells with a deletion
      of Bap31 or reconstituted with human BAP31 indicate that BAP31 is required to
      maintain PTPLB, consistent with a chaperone or quality control function for BAP31
      in the endoplasmic reticulum membrane.

PMID- 15024067
TI  - Mdt1, a novel Rad53 FHA1 domain-interacting protein, modulates DNA damage
      tolerance and G(2)/M cell cycle progression in Saccharomyces cerevisiae.
AB  - The Rad53 kinase plays a central role in yeast DNA damage checkpoints. Rad53
      contains two FHA phosphothreonine-binding domains that are required for Rad53
      activation and possibly downstream signaling. Here we show that the N-terminal
      Rad53 FHA1 domain interacts with the RNA recognition motif, coiled-coil, and
      SQ/TQ cluster domain-containing protein Mdt1 (YBl051C). The interaction of Rad53
      and Mdt1 depends on the structural integrity of the FHA1 phosphothreonine-binding
      site as well as threonine-305 of Mdt1. Mdt1 is constitutively threonine
      phosphorylated and hyperphosphorylated in response to DNA damage in vivo. DNA
      damage-dependent Mdt1 hyperphosphorylation depends on the Mec1 and Tel1
      checkpoint kinases, and Mec1 can directly phosphorylate a recombinant Mdt1 SQ/TQ
      domain fragment. MDT1 overexpression is synthetically lethal with a rad53
      deletion, whereas mdt1 deletion partially suppresses the DNA damage
      hypersensitivity of checkpoint-compromised strains and generally improves DNA
      damage tolerance. In the absence of DNA damage, mdt1 deletion leads to delayed
      anaphase completion, with an elongated cell morphology reminiscent of that of
      G(2)/M cell cycle mutants. mdt1-dependent and DNA damage-dependent cell cycle
      delays are not additive, suggesting that they act in the same pathway. The data
      indicate that Mdt1 is involved in normal G(2)/M cell cycle progression and is a
      novel target of checkpoint-dependent cell cycle arrest pathways.

PMID- 15024068
TI  - Secondary structure as a functional feature in the downstream region of mammalian
      polyadenylation signals.
AB  - Secondary structure within the downstream region of mammalian polyadenylation
      signals has been proposed to perform important functions. The simian virus 40
      late polyadenylation signal (SVLPA) forms alternate secondary structures in
      equilibrium. Their formation correlates with cleavage-polyadenylation efficiency
      (H. Hans and J. C. Alwine, Mol. Cell. Biol. 20:2926-2932, 2000; M. I. Zarudnaya,
      I. M. Kolomiets, A. L. Potyahaylo, and D. M. Hovorun, Nucleic Acids Res. 3:1375
      1386, 2003), and oligonucleotides that disrupt the secondary structure inhibit in
      vitro cleavage. To define the important features of downstream secondary
      structure, we first minimized the SVLPA by deletion, forming a downstream region
      with fewer, and more stable, stem-loop structures. Specific mutagenesis showed
      that both stem stability and loop size are important functional features of the
      downstream region. Stabilization of the stem, thus minimizing alternative
      structures, decreased cleavage efficiency both in vitro and in vivo. This was
      most deleterious when the stem was stabilized at the base of the loop,
      constraining loop size by inhibiting breathing of the stem. The significance of
      loop size was supported by mutants that showed increased cleavage efficiency with
      increased loop size and vice versa. A loop of at least 12 nucleotides promoted
      cleavage; U richness in the loop also promoted cleavage and was particularly
      important when the stem was stabilized. A mutation designed to eliminate
      downstream secondary structure still formed many relatively weak alternative
      structures in equilibrium and retained function. The data suggest that although
      the downstream region is very important, its structure is quite malleable and is
      able to tolerate significant mutation within a wide range of primary and
      secondary structural features. We propose that this malleability is due to the
      enhanced ability of GU- and U-rich downstream elements to easily form secondary
      structures with surrounding sequences.

PMID- 15024069
TI  - Phosphorylation controls Ikaros's ability to negatively regulate the G(1)-S
      transition.
AB  - Ikaros is a key regulator of lymphocyte proliferative responses. Inactivating
      mutations in Ikaros cause antigen-mediated lymphocyte hyperproliferation and the
      rapid development of leukemia and lymphoma. Here we show that Ikaros's ability to
      negatively regulate the G(1)-S transition can be modulated by phosphorylation of
      a serine/threonine-rich conserved region (p1) in exon 8. Ikaros phosphorylation
      in p1 is induced during the G(1)-S transition. Mutations that prevent
      phosphorylation in p1 increase Ikaros's ability to impede cell cycle progression
      and its affinity for DNA. Casein kinase II, whose increased activity in
      lymphocytes leads to transformation, is a key player in Ikaros p1
      phosphorylation. We thus propose that Ikaros's activity as a regulator of the
      G(1)-S transition is controlled by phosphorylation in response to signaling
      events that down-modulate its DNA binding activity.

PMID- 15024070
TI  - Cellular senescence requires CDK5 repression of Rac1 activity.
AB  - Cellular senescence is a tumor-suppressive process characterized by an
      irreversible cell cycle exit, a unique morphology, and expression of senescence
      associated beta-galactosidase (SA-beta-Gal). We report here a role for CDK5 in
      induction of senescent cytoskeletal changes. CDK5 activation is upregulated in
      senescing cells. The increased activity of CDK5 further reduces GTPase Rac1
      activity and Pak activation. The repression of the activity of the GTPase Rac1 by
      CDK5 is required for expression of the senescent phenotype. CDK5 regulation of
      Rac1 activity is necessary for actin polymerization accompanying senescent
      morphology in response to expression of pRb, activated Ras, or continuous
      passage. Inhibition of CDK5 attenuates SA-beta-Gal expression and blocks actin
      polymerization. These results point to a unique, nonneuronal role for CDK5 in
      regulation of Rac1 activity in senescence, illuminating the mechanisms underlying
      induction of senescence and the senescent shape change.

PMID- 15024071
TI  - DeltaFosB induces osteosclerosis and decreases adipogenesis by two independent
      cell-autonomous mechanisms.
AB  - Osteoblasts and adipocytes may develop from common bone marrow mesenchymal
      precursors. Transgenic mice overexpressing DeltaFosB, an AP-1 transcription
      factor, under the control of the neuron-specific enolase (NSE) promoter show both
      markedly increased bone formation and decreased adipogenesis. To determine
      whether the two phenotypes were linked, we targeted overexpression of DeltaFosB
      in mice to the osteoblast by using the osteocalcin (OG2) promoter. OG2-DeltaFosB
      mice demonstrated increased osteoblast numbers and an osteosclerotic phenotype
      but normal adipocyte differentiation. This result firmly establishes that the
      skeletal phenotype is cell autonomous to the osteoblast lineage and independent
      of adipocyte formation. It also strongly suggests that the decreased fat
      phenotype of NSE-DeltaFosB mice is independent of the changes in the osteoblast
      lineage. In vitro, overexpression of DeltaFosB in the preadipocytic 3T3-L1 cell
      line had little effect on adipocyte differentiation, whereas it prevented the
      induction of adipogenic transcription factors in the multipotential stromal cell
      line ST2. Also, DeltaFosB isoforms bound to and altered the DNA-binding capacity
      of C/EBPbeta. Thus, the inhibitory effect of DeltaFosB on adipocyte
      differentiation appears to occur at early stages of stem cell commitment,
      affecting C/EBPbeta functions. It is concluded that the changes in osteoblast and
      adipocyte differentiation in DeltaFosB transgenic mice result from independent
      cell-autonomous mechanisms.

PMID- 15024072
TI  - Overexpression of inducible cyclic AMP early repressor inhibits transactivation
      of genes and cell proliferation in pancreatic beta cells.
AB  - Transcriptional control mediated by the cyclic AMP-responsive element (CRE)
      represents an important mechanism of gene regulation. To test our hypothesis that
      increased inducible cyclic AMP early repressor (ICER) Igamma inhibits function of
      CRE-binding proteins and thus disrupts CRE-mediated transcription in pancreatic
      beta cells, we generated transgenic mice with beta-cell-directed expression of
      ICER Igamma, a powerful repressor that is greatly increased in diabetes. Three
      transgenic lines clearly show that increased ICER Igamma expression in beta cells
      results in early severe diabetes. From birth islets were severely disorganized
      with a significantly increased proportion of alpha cells throughout the islet.
      Diabetes results from the combined effects of impaired insulin expression and a
      decreased number of beta cells. The decrease in beta cells appears to result from
      impaired proliferation rather than from increased apoptosis after birth. Cyclin A
      gene expression is impaired by the strong inhibition of ICER; the suppression of
      cyclin A results in a substantially decreased proliferation of beta cells in the
      postnatal period. These results suggest that CRE and CRE-binding factors have an
      important role in pancreatic beta-cell physiology not only directly by regulation
      of gene trans-activation but also indirectly by regulation of beta-cell mass.

PMID- 15024073
TI  - Normal human fibroblasts are resistant to RAS-induced senescence.
AB  - Oncogenic stimuli are thought to induce senescence in normal cells in order to
      protect against transformation and to induce proliferation in cells with altered
      p53 and/or retinoblastoma (Rb) pathways. In human fibroblasts, RAS initiates
      senescence through upregulation of the cyclin-dependent kinase inhibitor
      p16INK4A. We show here that in contrast to cultured fibroblast strains, freshly
      isolated normal fibroblasts are resistant to RAS-induced senescence and instead
      show some characteristics of transformation. RAS did not induce growth arrest or
      expression of senescence-associated beta-galactosidase, and Rb remained
      hyperphosphorylated despite elevated levels of p16. Instead, RAS promoted
      anchorage-independent growth of normal fibroblasts, although expression of hTert
      with RAS increased colony formation and allowed normal fibroblasts to bypass
      contact inhibition. To test the hypothesis that p16 levels determine how cells
      respond to RAS, we expressed RAS in freshly isolated fibroblasts that expressed
      very low levels of p16, in hTert-immortalized fibroblasts that had accumulated
      intermediate levels of p16, and in IMR90 fibroblasts with high levels of p16. RAS
      induced growth arrest in cells with higher p16 levels, and this effect was
      reversed by p16 knockdown in the hTert-immortalized fibroblasts. These findings
      indicate that culture-imposed stress sensitizes cells to RAS-induced arrest,
      whereas early passage cells do not arrest in response to RAS.

PMID- 15024074
TI  - Silencing of chromatin assembly factor 1 in human cells leads to cell death and
      loss of chromatin assembly during DNA synthesis.
AB  - In eukaryotic cells, chromatin serves as the physiological template for gene
      transcription, DNA replication, and repair. Chromatin assembly factor 1 (CAF-1)
      is the prime candidate protein to mediate assembly of newly replicated DNA into
      chromatin. To investigate the physiological role of CAF-1 in vivo, we used RNA
      interference (RNAi) to silence the 60-kDa subunit of CAF-1 (p60) in human cells.
      Transfection of a small interfering RNA (siRNA) directed against p60 resulted in
      efficient silencing of p60 expression within 24 h. This silencing led to an
      induction of programmed cell death in proliferating but not in quiescent human
      cells. Concomitantly, proliferating cells lacking p60 accumulated DNA double
      strand breaks and increased levels of the phosphorylated histone H2A.X. Nuclear
      extracts from cells lacking p60 exhibited a 10-fold reduction of nucleosome
      assembly activity during DNA synthesis, which was restored upon addition of
      recombinant p60 protein. Nascent chromatin in cell nuclei lacking p60 showed
      significantly increased nuclease sensitivity, indicating chromatin assembly
      defects during DNA synthesis in vivo. Collectively, these data identify CAF-1 as
      an essential factor not only for S-phase-specific chromatin assembly but also for
      proliferating cell viability.

PMID- 15024075
TI  - A nonconserved surface of the TFIIB zinc ribbon domain plays a direct role in RNA
      polymerase II recruitment.
AB  - The general transcription factor TFIIB is a highly conserved and essential
      component of the eukaryotic RNA polymerase II (pol II) transcription initiation
      machinery. It consists of a single polypeptide with two conserved structural
      domains: an amino-terminal zinc ribbon structure (TFIIB(ZR)) and a carboxy
      terminal core (TFIIB(CORE)). We have analyzed the role of the amino-terminal
      region of human TFIIB in transcription in vivo and in vitro. We identified a
      small nonconserved surface of the TFIIB(ZR) that is required for pol II
      transcription in vivo and for different types of basal pol II transcription in
      vitro. Consistent with a general role in transcription, this TFIIB(ZR) surface is
      directly involved in the recruitment of pol II to a TATA box-containing promoter.
      Curiously, although the amino-terminal human TFIIB(ZR) domain can recruit both
      human pol II and yeast (Saccharomyces cerevisiae) pol II, the yeast TFIIB amino
      terminal region recruits yeast pol II but not human pol II. Thus, a critical
      process in transcription from many different promoters-pol II recruitment-has
      changed in sequence specificity during eukaryotic evolution.

PMID- 15024076
TI  - Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia
      inducible factor 1-dependent and -independent mechanisms and contributes to drug
      resistance.
AB  - Solid tumors with disorganized, insufficient blood supply contain hypoxic cells
      that are resistant to radiotherapy and chemotherapy. Drug resistance, an obstacle
      to curative treatment of solid tumors, can occur via suppression of apoptosis, a
      process controlled by pro- and antiapoptotic members of the Bcl-2 protein family.
      Oxygen deprivation of human colon cancer cells in vitro provoked decreased mRNA
      and protein levels of proapoptotic Bid and Bad. Hypoxia-inducible factor 1 (HIF
      1) was dispensable for the down-regulation of Bad but required for that of Bid,
      consistent with the binding of HIF-1alpha to a hypoxia-responsive element
      (positions -8484 to -8475) in the bid promoter. Oxygen deprivation resulted in
      proteosome-independent decreased expression of Bax in vitro, consistent with a
      reduction in global translation efficiency. The physiological relevance of Bid
      and Bax down-regulation was confirmed in tumors in vivo. Oxygen deprivation
      resulted in decreased drug-induced apoptosis and clonogenic resistance to agents
      with different mechanisms of action. The contribution of Bid and/or Bax down
      regulation to drug responsiveness was demonstrated by the relative resistance of
      normoxic cells that had no or reduced expression of Bid and/or Bax and by the
      finding that forced expression of Bid in hypoxic cells resulted in increased
      sensitivity to the topoisomerase II inhibitor etoposide.

PMID- 15024077
TI  - Translocation products in acute myeloid leukemia activate the Wnt signaling
      pathway in hematopoietic cells.
AB  - The acute myeloid leukemia (AML)-associated translocation products AML1-ETO, PML
      retinoic acid receptor alpha (RARalpha), and PLZF-RARalpha encode aberrant
      transcription factors. Several lines of evidence suggest similar pathogenetic
      mechanisms for these fusion proteins. We used high-density oligonucleotide arrays
      to identify shared target genes in inducibly transfected U937 cells expressing
      AML1-ETO, PML-RARalpha, or PLZF-RARalpha. All three fusion proteins significantly
      repressed the expression of 38 genes and induced the expression of 14 genes.
      Several of the regulated genes were associated with Wnt signaling. One of these,
      plakoglobin (gamma-catenin), was induced on the mRNA and protein level by all
      three fusion proteins. In addition, primary AML blasts carrying one of the fusion
      proteins significantly overexpressed plakoglobin. The plakoglobin promoter was
      cloned and shown to be induced by AML1-ETO, with promoter activation depending on
      the corepressor and histone deacetylase binding domains. The induction of
      plakoglobin by AML fusion proteins led to downstream signaling and
      transactivation of TCF- and LEF-dependent promoters, including the c-myc
      promoter, which was found to be bound by plakoglobin in vivo after AML1-ETO
      expression. beta-Catenin protein levels and TCF and LEF target genes such as c
      myc and cyclin D1 were found to be induced by the fusion proteins. On the
      functional level, a dominant negative TCF inhibited colony growth of AML1-ETO
      positive Kasumi cells, whereas plakoglobin transfection into myeloid 32D cells
      enhanced proliferation and clonal growth. Injection of plakoglobin-expressing 32D
      cells into syngeneic mice accelerated the development of leukemia. Transduction
      of plakoglobin into primitive murine hematopoietic progenitor cells preserved the
      immature phenotype during colony growth, suggesting enhanced self-renewal. These
      data provide evidence that activation of Wnt signaling is a common feature of
      several balanced translocations in AML.

PMID- 15024078
TI  - Growth factor-mediated induction of HDM2 positively regulates hypoxia-inducible
      factor 1alpha expression.
AB  - The hypoxia-inducible factor 1 (HIF-1) transcriptional complex is regulated by
      cellular oxygen levels and growth factors. The phosphoinosotide 3-kinase (PI-3K)
      Akt/protein kinase B (PKB) pathway has been shown to regulate HIF-1 activity in
      response to oncogenic signals and growth factors. We assessed whether the HDM2
      oncoprotein, a direct target of Akt/PKB, could regulate HIF-1alpha expression and
      HIF-1 activity under normoxic conditions. We found that growth factor
      stimulation, overexpression of Akt/PKB, or loss of PTEN resulted in enhanced
      expression of both HIF-1alpha and HDM2. Growth factor-mediated induction of HIF
      1alpha was ablated by transient expression of a dominant negative form of Akt/PKB
      or by treatment with LY294002. Transient expression of HDM2 led to increased
      expression of HIF-1alpha. Pulse-chase and cycloheximide experiments revealed that
      HDM2 did not significantly affect the half-life of HIF-1alpha. Growth factor
      induced HIF-1alpha and HDM2 proteins were localized to the nucleus, and induction
      of both proteins was observed in both p53(+/+) and p53(-/-) HCT116 cells to
      comparable levels. Importantly, insulin-like growth factor 1-induced HIF-1alpha
      expression was observed in p53-null mouse embryo fibroblasts (MEFs) but was
      significantly impaired in p53 Mdm2 double-null MEFs, indicating a requirement for
      Mdm2 in this process. Finally, we showed that phosphorylation at Ser166 in HDM2
      contributed in part to growth factor-mediated induction of HIF-1alpha. Our study
      has important implications for the role of the PI-3K-Akt/PKB-HDM2 pathway in
      tumor progression and angiogenesis.

PMID- 15024079
TI  - Brn-2 expression controls melanoma proliferation and is directly regulated by
      beta-catenin.
AB  - Constitutive activation of the Wnt/beta-catenin signaling pathway is a notable
      feature of a large minority of cases of malignant melanoma, an aggressive and
      increasingly common cancer. The identification of target genes downstream from
      this pathway is therefore crucial to our understanding of the disease. The POU
      domain transcription factor Brn-2 has been implicated in control of proliferation
      and melanoma survival, and its expression is strongly upregulated in melanoma. We
      show here that in vivo Brn-2 is expressed in melanocytes but not in embryonic day
      11.5 melanoblasts and that its expression is directly controlled by the Wnt/beta
      catenin signaling pathway in melanoma cell lines and in transgenic mice.
      Moreover, silent interfering RNA-mediated inhibition of Brn-2 expression in
      melanoma cells overexpressing beta-catenin results in significantly decreased
      proliferation. These results, together with the observation that BRAF signaling
      also induces Brn-2 expression, reveal that Brn-2 is a focus for the convergence
      of two key melanoma-associated signaling pathways that are linked to cell
      proliferation.

PMID- 15024080
TI  - The Brn-2 transcription factor links activated BRAF to melanoma proliferation.
AB  - Malignant melanoma, an aggressive and increasingly common cancer, is
      characterized by a strikingly high rate (70%) of mutations in BRAF, a key
      component of the mitogen-activated protein (MAP) kinase signaling pathway. How
      signaling events downstream from BRAF affect the underlying program of gene
      expression is poorly understood. We show that the Brn-2 POU domain transcription
      factor is highly expressed in melanoma cell lines but not in melanocytes or
      melanoblasts and that overexpression of Brn-2 in melanocytes results in increased
      proliferation. Expression of Brn-2 is strongly upregulated by Ras and MAP kinase
      signaling. Importantly, the Brn-2 promoter is stimulated by kinase-activating
      BRAF mutants and endogenous Brn-2 expression is inhibited by RNA interference
      mediated downregulation of BRAF. Moreover, silent interfering RNA-mediated
      depletion of Brn-2 in melanoma cells expressing activated BRAF leads to decreased
      proliferation. The results suggest that the high levels of Brn-2 expression
      observed in melanomas link BRAF signaling to increased proliferation.

PMID- 15024081
TI  - The essential WD repeat protein Swd2 has dual functions in RNA polymerase II
      transcription termination and lysine 4 methylation of histone H3.
AB  - Swd2, an essential WD repeat protein in Saccharomyces cerevisiae, is a component
      of two very different complexes: the cleavage and polyadenylation factor CPF and
      the Set1 methylase, which modifies lysine 4 of histone H3 (H3-K4). It was not
      known if Swd2 is important for the function of either of these entities. We show
      here that, in extract from cells depleted of Swd2, cleavage and polyadenylation
      of the mRNA precursor in vitro are completely normal. However, temperature
      sensitive mutations or depletion of Swd2 causes termination defects in some genes
      transcribed by RNA polymerase II. Overexpression of Ref2, a protein previously
      implicated in snoRNA 3' end formation and Swd2 recruitment to CPF, can rescue the
      growth and termination defects, indicating a functional interaction between the
      two proteins. Some swd2 mutations also significantly decrease global H3-K4
      methylation and cause other phenotypes associated with loss of this chromatin
      modification, such as loss of telomere silencing, hydroxyurea sensitivity, and
      alterations in repression of INO1 transcription. Even though the two Swd2
      containing complexes are both localized to actively transcribed genes, the allele
      specificities of swd2 defects suggest that the functions of Swd2 in mediating RNA
      polymerase II termination and H3-K4 methylation are not tightly coupled.

PMID- 15024082
TI  - A novel complex regulates cardiac actin gene expression through interaction of
      Emb, a class VI POU domain protein, MEF2D, and the histone transacetylase p300.
AB  - Expression of the mouse cardiac actin gene depends on a distal enhancer (-7 kbp)
      which has been shown, in transgenic mice, to direct expression to embryonic
      skeletal muscle. The presence of this distal sequence is also associated with
      reproducible expression of cardiac actin transgenes. In differentiated skeletal
      muscle cells, activity of the enhancer is driven by an E box, binding MyoD family
      members, and by a 3' AT-rich sequence which is in the location of a DNase I
      hypersensitive site. This sequence does not bind MEF2 proteins, or other known
      muscle transcription factors, directly. Oct1 and Emb, a class VI POU domain
      protein, bind to consensus sites on the DNA, and it is the binding of Emb which
      is important for activity. Emb binds as a major complex with MEF2D and the
      histone transacetylase p300. The form of Emb present in this complex and as a
      major form in muscle cell extracts is longer (80 kDa) than that previously
      described. These results demonstrate the importance of this novel complex in the
      transcriptional regulation of the cardiac actin gene and suggest a potential role
      in chromatin remodeling associated with muscle gene activation.

PMID- 15024083
TI  - Modular structure of the human lamin B2 replicator.
AB  - The cis-acting elements necessary for the activity of DNA replication origins in
      metazoan cells are still poorly understood. Here we report a thorough
      characterization of the DNA sequence requirements of the origin associated with
      the human lamin B2 gene. A 1.2-kb DNA segment, comprising the start site of DNA
      replication and located within a large protein-bound region, as well as a CpG
      island, displays origin activity when moved to different ectopic positions.
      Genomic footprinting analysis of both the endogenous and the ectopic origins
      indicates that the large protein complex is assembled in both cases around the
      replication start site. Replacement of this footprinted region with an unrelated
      sequence, maintaining the CpG island intact, abolishes origin activity and the
      interaction with hORC2, a subunit of the origin recognition complex. Conversely,
      the replacement of 17 bp within the protected region reduces the extension of the
      protection without affecting the interaction with hORC2. This substitution does
      not abolish the origin activity but makes it more sensitive to the integration
      site. Finally, the nearby CpG island positively affects the efficiency of
      initiation. This analysis reveals the modular structure of the lamin B2 origin
      and supports the idea that sequence elements close to the replication start site
      play an important role in origin activation.

PMID- 15024084
TI  - Apoptosis associated with deregulated E2F activity is dependent on E2F1 and
      Atm/Nbs1/Chk2.
AB  - The retinoblastoma protein (Rb)/E2F pathway links cellular proliferation control
      to apoptosis and is critical for normal development and cancer prevention. Here
      we define a transcription-mediated pathway in which deregulation of E2F1 by
      ectopic E2F expression or Rb inactivation by E7 of human papillomavirus type 16
      signals apoptosis by inducing the expression of Chk2, a component of the DNA
      damage response. E2F1- and E7-mediated apoptosis are compromised in cells from
      patients with the related disorders ataxia telangiectasia and Nijmegen breakage
      syndrome lacking functional Atm and Nbs1 gene products, respectively. Both Atm
      and Nbs1 contribute to Chk2 activation and p53 phosphorylation following
      deregulation of normal Rb growth control. E2F2, a related E2F family member that
      does not induce apoptosis, also activates Atm, resulting in phosphorylation of
      p53. However, we found that the key commitment step in apoptosis induction is the
      ability of E2F1, and not E2F2, to upregulate Chk2 expression. Our results suggest
      that E2F1 plays a central role in signaling disturbances in the Rb growth control
      pathway and, by upregulation of Chk2, may sensitize cells to undergo apoptosis.

PMID- 15024085
TI  - Obesity and endocrine dysfunction in mice with deletions of both neuropeptide Y
      and galanin.
AB  - Neuropeptide Y (NPY) and galanin have both been implicated in the regulation of
      body weight, yet mice bearing deletions of either of these molecules have
      unremarkable metabolic phenotypes. To investigate whether galanin and NPY might
      compensate for one another, we produced mutants lacking both neuropeptides (GAL(
      /-)/NPY(-/-)). We found that male GAL(-/-)/NPY(-/-) mice ate significantly more
      and were much heavier (30%) than wild-type (WT) controls. GAL(-/-)/NPY(-/-) mice
      responded to a high-fat diet by gaining more weight than WT mice gain, and they
      were unable to regulate their weight normally after a change in diet. GAL(-/
      )/NPY(-/-) mice had elevated levels of leptin, insulin, and glucose, and they
      lost more weight than WT mice during chronic leptin treatment. Galanin mRNA was
      increased in the hypothalamus of NPY(-/-) mice, providing evidence of
      compensatory regulation in single mutants. The disruption of energy balance
      observed in GAL(-/-)/NPY(-/-) double knockouts is not found in the phenotype of
      single knockouts of either molecule. The unexpected obesity phenotype may result
      from the dysregulation of the leptin and insulin systems that normally keep body
      weight within the homeostatic range.

PMID- 15024086
TI  - A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase
      modulates the activity of the kinase and its binding to calmodulin.
AB  - Eukaryotic elongation factor 2 (eEF2) kinase is an unusual calcium- and
      calmodulin-dependent protein kinase that is regulated by insulin through the
      rapamycin-sensitive mTOR pathway. Here we show that insulin decreases the ability
      of eEF2 kinase to bind calmodulin in a rapamycin-sensitive manner. We identify a
      novel phosphorylation site in eEF2 kinase (Ser78) that is located immediately
      next to its calmodulin-binding motif. Phosphorylation of this site is increased
      by insulin in a rapamycin-sensitive fashion. Regulation of the phosphorylation of
      Ser78 also requires amino acids and the protein kinase phosphoinositide-dependent
      kinase 1. Mutation of this site to alanine strongly attenuates the effects of
      insulin and rapamycin both on the binding of calmodulin to eEF2 kinase and on
      eEF2 kinase activity. Phosphorylation of Ser78 is thus likely to link insulin and
      mTOR signaling to the control of eEF2 phosphorylation and chain elongation. This
      site is not a target for known kinases in the mTOR pathway, e.g., the S6 kinases,
      implying that it is phosphorylated by a novel mTOR-linked protein kinase that
      serves to couple hormones and amino acids to the control of translation
      elongation. eEF2 kinase is thus a target for mTOR signaling independently of
      previously known downstream components of the pathway.

PMID- 15024087
TI  - Loss of translational control in yeast compromised for the major mRNA decay
      pathway.
AB  - The cytoplasmic fate of mRNAs is dictated by the relative activities of the
      intimately connected mRNA decay and translation initiation pathways. In this
      study, we have found that yeast strains compromised for stages downstream of
      deadenylation in the major mRNA decay pathway are incapable of inhibiting global
      translation initiation in response to stress. In the past, the paradigm of the
      eIF2alpha kinase-dependent amino acid starvation pathway in yeast has been used
      to evaluate this highly conserved stress response in all eukaryotic cells. Using
      a similar approach we have found that even though the mRNA decay mutants maintain
      high levels of general translation, they exhibit many of the hallmarks of amino
      acid starvation, including increased eIF2alpha phosphorylation and activated GCN4
      mRNA translation. Therefore, these mutants appear translationally oblivious to
      decreased ternary complex abundance, and we propose that this is due to higher
      rates of mRNA recruitment to the 40S ribosomal subunit.

PMID- 15024088
TI  - HBP1 repression of the p47phox gene: cell cycle regulation via the NADPH oxidase.
AB  - Several studies have linked the production of reactive oxygen species (ROS) by
      the NADPH oxidase to cellular growth control. In many cases, activation of the
      NADPH oxidase and subsequent ROS generation is required for growth factor
      signaling and mitogenesis in nonimmune cells. In this study, we demonstrate that
      the transcriptional repressor HBP1 (HMG box-containing protein 1) regulates the
      gene for the p47phox regulatory subunit of the NADPH oxidase. HBP1 represses
      growth regulatory genes (e.g., N-Myc, c-Myc, and cyclin D1) and is an inhibitor
      of G(1) progression. The promoter of the p47phox gene contains six tandem high
      affinity HBP1 DNA-binding elements at positions -1243 to -1318 bp from the
      transcriptional start site which were required for repression. Furthermore, HBP1
      repressed the expression of the endogenous p47phox gene through sequence-specific
      binding. With HBP1 expression and the subsequent reduction in p47phox gene
      expression, intracellular superoxide production was correspondingly reduced.
      Using both the wild type and a dominant-negative mutant of HBP1, we demonstrated
      that the repression of superoxide production through the NADPH oxidase
      contributed to the observed cell cycle inhibition by HBP1. Together, these
      results indicate that HBP1 may contribute to the regulation of NADPH oxidase
      dependent superoxide production through transcriptional repression of the p47phox
      gene. This study defines a transcriptional mechanism for regulating intracellular
      ROS levels and has implications in cell cycle regulation.

PMID- 15024089
TI  - Ribosomal S6 kinase (RSK) regulates phosphorylation of filamin A on an important
      regulatory site.
AB  - The Ras-mitogen-activated protein (Ras-MAP) kinase pathway regulates various
      cellular processes, including gene expression, cell proliferation, and survival.
      Ribosomal S6 kinase (RSK), a key player in this pathway, modulates the activities
      of several cytoplasmic and nuclear proteins via phosphorylation. Here we report
      the characterization of the cytoskeletal protein filamin A (FLNa) as a membrane
      associated RSK target. We show that the N-terminal kinase domain of RSK
      phosphorylates FLNa on Ser(2152) in response to mitogens. Inhibition of MAP
      kinase signaling with UO126 or mutation of Ser(2152) to Ala on FLNa prevents
      epidermal growth factor (EGF)-stimulated phosphorylation of FLNa in vivo.
      Furthermore, phosphorylation of FLNa on Ser(2152) is significantly enhanced by
      the expression of wild-type RSK and antagonized by kinase-inactive RSK or
      specific reduction of endogenous RSK. Strikingly, EGF-induced, FLNa-dependent
      migration of human melanoma cells is significantly reduced by UO126 treatment.
      Together, these data provide substantial evidence that RSK phosphorylates FLNa on
      Ser(2152) in vivo. Given that phosphorylation of FLNa on Ser(2152) is required
      for Pak1-mediated membrane ruffling, our results suggest a novel role for RSK in
      the regulation of the actin cytoskeleton.

PMID- 15024090
TI  - Chromatin-mediated restriction of nuclear factor 1/CTF binding in a repressed and
      hormone-activated promoter in vivo.
AB  - Mouse mammary tumor virus (MMTV) promoter-driven transcription is induced by
      glucocorticoid hormone via binding of the glucocorticoid receptor (GR). The MMTV
      promoter also harbors a binding site for nuclear factor 1 (NF1). NF1 and GR were
      expressed in Xenopus oocytes; this revealed GR-NF1 cooperativity both in terms of
      DNA binding and chromatin remodeling but not transcription. A fraction of NF1
      sites were occupied in a hormone-dependent fashion, but a significant and NF1
      concentration-dependent fraction were constitutively bound. Activation of the
      MMTV promoter resulted in an approximately 50-fold increase in the NF1
      accessibility for its DNA site. The hormone-dependent component of NF1 binding
      was dissociated by addition of a GR antagonist; however, the antagonist RU486,
      which supports partial GR-DNA binding, also maintained partial NF1 binding. Hence
      GR-NF1 cooperativity is independent of agonist-driven chromatin remodeling. NF1
      induced the formation of a micrococcal-nuclease-resistant protein-DNA complex
      containing the DNA segment from -185 to -55, the MMTV enhanceosome. Coexpression
      of NF1 and Oct1 resulted in a significant stimulation of hormone-induced MMTV
      transcription and also in increased basal transcription. We propose that hormone
      independent NF1 binding may be involved in maintaining transcriptional competence
      and establishment of tissue-specific gene networks.

PMID- 15024091
TI  - Inhibition of NF-kappaB activity by IkappaBbeta in association with kappaB-Ras.
AB  - IkappaBbeta, one of the major IkappaB proteins, is only partially degraded in
      response to most extracellular signals. However, the molecular mechanism of this
      event is unknown. We show here that IkappaBbeta exists in at least two different
      forms: one that is bound to the NF-kappaB dimer and the other bound to both NF
      kappaB and kappaB-Ras, a Ras-like small G protein. Removal of cellular kappaB-Ras
      enhances whereas excess kappaB-Ras blocks induced IkappaBbeta degradation.
      Remarkably, kappaB-Ras functions in both GDP- and GTP-bound states, and mutations
      of the conserved guanine-binding residues of kappaB-Ras abrogate its ability to
      block degradation of IkappaBbeta. kappaB-Ras also directly blocks the in vitro
      phosphorylation of IkappaBbeta by IKKbeta. These observations suggest that
      IkappaBbeta in the ternary complex is resistant to degradation by most signals.
      We suggest that specific signals, in addition to those that activate only IKK,
      are essential for the complete degradation of IkappaBbeta.

PMID- 15024092
TI  - p38 mitogen-activated protein kinase is the central regulator of cyclic AMP
      dependent transcription of the brown fat uncoupling protein 1 gene.
AB  - It is well established that catecholamine-stimulated thermogenesis in brown fat
      requires beta-adrenergic elevations in cyclic AMP (cAMP) to increase expression
      of the uncoupling protein 1 (UCP1) gene. However, little is known about the
      downstream components of the signaling cascade or the relevant transcription
      factor targets thereof. Here we demonstrate that cAMP- and protein kinase A
      dependent activation of p38 mitogen-activated protein kinase (MAPK) in brown
      adipocytes is an indispensable step in the transcription of the UCP1 gene in
      mice. By phosphorylating activating transcription factor 2 (ATF-2) and peroxisome
      proliferator-activated receptor gamma (PPARgamma) coativator 1alpha (PGC-1alpha),
      members of two distinct nuclear factor families, p38 MAPK controls the expression
      of the UCP1 gene through their respective interactions with a cAMP response
      element and a PPAR response element that both reside within a critical enhancer
      motif of the UCP1 gene. Activation of ATF-2 by p38 MAPK additionally serves as
      the cAMP sensor that increases expression of the PGC-1alpha gene itself in brown
      adipose tissue. In conclusion, our findings illustrate that by orchestrating the
      activity of multiple transcription factors, p38 MAPK is a central mediator of the
      cAMP signaling mechanism of brown fat that promotes thermogenesis.

PMID- 15024094
TI  - Catalytic asymmetric reactions for organic synthesis: the combined C-H
      activation/Cope rearrangement.
AB  - The development of new catalytic asymmetric reactions can lead to exciting new
      strategies for organic synthesis. This article describes the synthetic utility of
      the combined C-H activation/Cope rearrangement, achieved by dirhodium
      tetraprolinate-catalyzed reaction of vinyldiazoacetates with compounds containing
      allylic C-H bonds. The transformation is highly diastereoselective and
      enantioselective. The product distribution, however, is highly substrate
      dependent, the major side products being either direct C-H activation or
      cyclopropanation.

PMID- 15024093
TI  - Desymmetrization of enone-diones via rhodium-catalyzed diastereo- and
      enantioselective tandem conjugate addition-aldol cyclization.
AB  - Catalytic tandem conjugate addition-enolate trapping represents an effective
      strategy for the design of catalytic transformations that enable formation of
      multiple C-C bonds. Recently, using enantioselective rhodium-catalyzed conjugate
      addition methodology, we developed a catalytic tandem conjugate addition-aldol
      cyclization of keto-enones. Here, we report related desymmetrizations and
      parallel kinetic resolutions involving the use of diones as terminal
      electrophiles. The Rh-enolate generated on enone carbometallation effectively
      discriminates among four diastereotopic pi-faces of the appendant dione,
      ultimately providing products that embody four contiguous stereocenters,
      including two adjacent quaternary centers, with quantitative diastereoselection
      and high levels of enantiomeric excess. This methodology allows concise entry to
      optically enriched seco-B ring steroids possessing a 14-hydroxy cis-fused C-D
      ring junction, as found in naturally occurring cardiotonic steroids derived from
      digitalis.

PMID- 15024096
TI  - An unsupervised method for the extraction of propositional information from text.
AB  - Recent developments in question-answering systems have demonstrated that
      approaches based on propositional analysis of source text, in conjunction with
      formal inference systems, can produce substantive improvements in performance
      over surface-form approaches. [Voorhees, E. M. (2002) in Eleventh Text Retrieval
      Conference, eds. Voorhees, E. M. & Buckland, L. P.,
      http://trec.nist.gov/pubs/trec11/t11_proceedings.html]. However, such systems are
      hampered by the need to create broad-coverage knowledge bases by hand, making
      them difficult to adapt to new domains and potentially fragile if critical
      information is omitted. To demonstrate how this problem might be addressed, the
      Syntagmatic Paradigmatic model, a memory-based account of sentence processing, is
      used to autonomously extract propositional knowledge from unannotated text. The
      Syntagmatic Paradigmatic model assumes that people store a large number of
      sentence instances. When trying to interpret a new sentence, similar sentences
      are retrieved from memory and aligned with the new sentence by using String Edit
      Theory. The set of alignments can be considered an extensional interpretation of
      the sentence. Extracting propositional information in this way not only permits
      the model to answer questions for which the relevant facts are explicitly stated
      in the text but also allows the model to take advantage of "inference by
      coincidence," where implicit inference occurs as an emergent property of the
      mechanism. To illustrate the potential of this approach, the model is tested for
      its ability to determine the winners of tennis matches as reported on the
      Association of Tennis Professionals web site.

PMID- 15024097
TI  - Analytic models for mechanotransduction: gating a mechanosensitive channel.
AB  - Analytic estimates for the forces and free energy generated by bilayer
      deformation reveal a compelling and intuitive model for MscL channel gating
      analogous to the nucleation of a second phase. We argue that the competition
      between hydrophobic mismatch and tension results in a surprisingly rich story
      that can provide both a quantitative comparison with measurements of opening
      tension for MscL when reconstituted in bilayers of different thickness, and
      qualitative insights into the function of the MscL channel and other
      transmembrane proteins.

PMID- 15024099
TI  - Histone H1 and the origin of protamines.
AB  - We present evidence that chordate protamines have evolved from histone H1. During
      the final stages of spermatogenesis, the compaction of DNA in many organisms is
      accomplished by the replacement of histones with a class of arginine-rich
      proteins called protamines. In other organisms, however, condensation of sperm
      DNA can occur with comparable efficiency in the presence of somatic-type histones
      or, alternatively, an intermediate class of proteins called protamine-like
      proteins. The idea that the highly specialized sperm chromosomal proteins
      (protamines) and somatic chromosomal proteins (histones) could be related dates
      back almost to the discovery of these proteins. Although this notion has
      frequently been revisited since that time, there has been a complete lack of
      supporting experimental evidence. Here we show that the emergence of protamines
      in chordates occurred very quickly, as a result of the conversion of a lysine
      rich histone H1 to an arginine-rich protamine. We have characterized the sperm
      nuclear basic proteins of the tunicate Styela montereyensis, which we show
      consists of both a protamine and a sperm-specific histone H1 with a protamine
      tail. Comparison of the genes encoding these proteins to that of a sister
      protochordate, Ciona intestinalis, has indicated this rapid and dramatic change
      is most likely the result of frameshift mutations in the tail of the sperm
      specific histone H1. By establishing an evolutionary link between the chromatin
      condensing histone H1s of somatic tissues and the chromatin-condensing proteins
      of the sperm, these results provide unequivocal support to the notion that
      vertebrate protamines evolved from histones.

PMID- 15024100
TI  - The Nash equilibrium: a perspective.
AB  - In 1950, John Nash contributed a remarkable one-page PNAS article that defined
      and characterized a notion of equilibrium for n- person games. This notion, now
      called the "Nash equilibrium," has been widely applied and adapted in economics
      and other behavioral sciences. Indeed, game theory, with the Nash equilibrium as
      its centerpiece, is becoming the most prominent unifying theory of social
      science. In this perspective, we summarize the historical context and subsequent
      impact of Nash's contribution.

PMID- 15024102
TI  - Evolution and evolvability of proteins in the laboratory.

PMID- 15024101
TI  - Epitope-specific immunotherapy induces immune deviation of proinflammatory T
      cells in rheumatoid arthritis.
AB  - Modulation of epitope-specific immune responses would represent a major addition
      to available therapeutic options for many autoimmune diseases. The objective of
      this work was to induce immune deviation by mucosal peptide-specific
      immunotherapy in rheumatoid arthritis (RA) patients, and to dissect the related
      immunological mechanisms by using a technology for the detection of low-affinity
      class II-restricted peptide-specific T cells. A group of patients with early RA
      was treated for 6 months orally with dnaJP1, a peptide that induces
      proinflammatory T cell responses in naive RA patients. Immunological analysis at
      initial, intermediate and end treatment points showed an intriguing change from
      proinflammatory to regulatory T cell function. In fact, dnaJP1-induced T cell
      production of IL-4 and IL-10 increased significantly when initial and end
      treatment points were compared, whereas dnaJP1-induced T cell proliferation and
      production of IL-2, IFN-gamma, and tumor necrosis factor-alpha decreased
      significantly. The total number of dnaJP1-specific cells did not change over
      time, whereas expression of foxP3 by CD4+CD25(bright) cells increased, suggesting
      that the treatment affected regulatory T cell function. Thus, rather than clonal
      deletion, the observed change in immune reactivity to dnaJP1 was the outcome of
      treatment-induced emergence of T cells with a different functional phenotype.
      This study contributes to our knowledge of mechanisms and tools needed for
      antigen-specific immune modulation in humans, thus laying the foundation for
      exploitation of this approach for therapeutic purposes.

PMID- 15024103
TI  - Small interfering RNA production by enzymatic engineering of DNA (SPEED).
AB  - Small interfering RNAs (siRNAs) potently silence expression of target genes. In
      principle siRNA libraries can be used to perform effective genome-scale
      functional genetic screens in mammalian cells, but their development has been
      hampered by the need to chemically synthesize thousands of oligonucleotides and
      to incorporate them into expression vectors. We have developed a technology to
      efficiently convert a double-stranded cDNA library into a retroviral siRNA
      library in which 21-base siRNAs are produced in infected cells at high levels and
      efficiently block expression of their target genes. The key steps are the
      generation of random cDNA fragments that are fused to a hairpin linker, cleavage
      with the MmeI endonuclease that creates 20- to 21-bp cDNA fragments, conversion
      to a double-stranded DNA that contains two copies of the cDNA insert in a head-to
      head palindrome, and insertion of the construct downstream of a polymerase III
      promoter. We constructed a siRNA library with 3 x 10(6) clones from a mouse
      embryo cDNA library; siRNAs were found against many different genes; and multiple
      siRNAs can be generated from a single mRNA. We further showed that specific
      siRNAs were efficiently produced in stably infected mammalian cells and resulted
      in significant and specific reduction of their target mRNAs. Because no prior
      knowledge about target transcripts is needed, a cDNA-derived siRNA library will
      generate siRNAs against unknown transcripts and genes. Finally, cDNA-derived
      siRNA libraries can be readily generated from any cell type or species, enabling
      genome-wide functional screens in many biological systems.

PMID- 15024105
TI  - Membrane proteins: a new method enters the fold.

PMID- 15024108
TI  - Bacterial quorum-sensing signals are inactivated by mammalian cells.

PMID- 15024109
TI  - Functional and evolutionary genomics of Mycobacterium tuberculosis: insights from
      genomic deletions in 100 strains.
AB  - To better understand genome function and evolution in Mycobacterium tuberculosis,
      the genomes of 100 epidemiologically well characterized clinical isolates were
      interrogated by DNA microarrays and sequencing. We identified 68 different large
      sequence polymorphisms (comprising 186,137 bp, or 4.2% of the genome) that are
      present in H37Rv, but absent from one or more clinical isolates. A total of 224
      genes (5.5%), including genes in all major functional categories, were found to
      be partially or completely deleted. Deletions are not distributed randomly
      throughout the genome but instead tend to be aggregated. The distinct deletions
      in some aggregations appear in closely related isolates, suggesting a genomically
      disruptive process specific to an individual mycobacterial lineage. Other genomic
      aggregations include distinct deletions that appear in phylogenetically unrelated
      isolates, suggesting that a genomic region is vulnerable throughout the species.
      Although the deletions identified here are evidently inessential to the causation
      of disease (they are found in active clinical cases), their frequency spectrum
      suggests that most are weakly deleterious to the pathogen. For some deletions,
      short-term evolutionary pressure due to the host immune system or antibiotics may
      favor the elimination of genes, whereas longer-term physiological requirements
      maintain the genes in the population.

PMID- 15024111
TI  - Effect of hydrogen-switchable mirrors on the Casimir force.
AB  - We present systematic measurements of the Casimir force between a gold-coated
      plate and a sphere coated with a hydrogen-switchable mirror. Hydrogen-switchable
      mirrors are shiny metals that can become transparent upon hydrogenation. Despite
      such a dramatic change of the optical properties of the sphere, we did not
      observe any significant decrease of the Casimir force after filling the
      experimental apparatus with hydrogen. This counterintuitive result can be
      explained by the Lifshitz theory that describes the Casimir attraction between
      metallic and dielectric materials.

PMID- 15024110
TI  - E-box function in a period gene repressed by light.
AB  - In most organisms, light plays a key role in the synchronization of the circadian
      timing system with the environmental day-night cycle. Light pulses that phase
      shift the circadian clock also induce the expression of period (per) genes in
      vertebrates. Here, we report the cloning of a zebrafish per gene, zfper4, which
      is remarkable in being repressed by light. We have developed an in vivo
      luciferase reporter assay for this gene in cells that contain a light-entrainable
      clock. High-definition bioluminescence traces have enabled us to accurately
      measure phase-shifting of the clock by light. We have also exploited this model
      to study how four E-box elements in the zfper4 promoter regulate expression.
      Mutagenesis reveals that the integrity of these four E-boxes is crucial for
      maintaining low basal expression together with robust rhythmicity and repression
      by light. Importantly, in the context of a minimal heterologous promoter, the E
      box elements also direct a robust circadian rhythm of expression that is
      significantly phase-advanced compared with the original zfper4 promoter and lacks
      the light-repression property. Thus, these results reveal flexibility in the
      phase and light responsiveness of E-box-directed rhythmic expression, depending
      on the promoter context.

PMID- 15024114
TI  - Membrane-mediated structural transitions at the cytoplasmic face during integrin
      activation.
AB  - Cytoplasmic face-mediated integrin inside-out activation remains a paradigm in
      transmembrane signal transduction. Emerging evidence suggests that this process
      involves dissociation of the complex between the integrin cytoplasmic tails;
      however, a dynamic image of how it occurs on the membrane surface remains
      elusive. We show here that, whereas membrane-proximal helices of integrin
      alpha/beta cytoplasmic tails associate in cytoplasm-like aqueous medium, they
      become partially embedded into membrane-mimetic micelles when unclasped. Membrane
      embedding induces substantial structural changes of the cytoplasmic tails as
      compared to their aqueous conformations and suggests there may be an upward
      movement of the membrane-proximal helices into the membrane during their
      separation. We further demonstrate that the beta3 tail exhibits additional
      membrane binding site at its C terminus containing the NPLY motif. Talin, a key
      intracellular integrin activator, recognizes this site as well as the membrane
      proximal helix, thereby promoting cytoplasmic tail separation along the membrane
      surface. These data provide a structural basis of membrane-mediated changes at
      the cytoplasmic face in regulating integrin activation and signaling.

PMID- 15024115
TI  - A nuclear translation-like factor eIF4AIII is recruited to the mRNA during
      splicing and functions in nonsense-mediated decay.
AB  - In eukaryotes, a surveillance mechanism known as nonsense-mediated decay (NMD)
      degrades the mRNA when a premature-termination codon (PTC) is present. NMD
      requires translation to read the frame of the mRNA and detect the PTC. During pre
      mRNA splicing, the exon-exon junction complex (EJC) is recruited to a region 20
      24 nt upstream of the exon junction on the mature mRNA. The presence of a PTC
      upstream from the EJC elicits NMD. Eukaryotic initiation factor 4A (eIF4A) III is
      a nuclear protein that interacts physically or functionally with translation
      initiation factors eIF4G and eIF4B, respectively, and shares strikingly high
      identity with the initiation factors eIF4AI/II. Here we show that siRNA against
      eIF4AIII, but not against eIF4AI/II, inhibits NMD. Moreover, eIF4AIII, but not
      eIF4AI, is specifically recruited to the EJC during splicing. The observations
      that eIF4AIII is loaded onto the mRNA during splicing in the nucleus, has
      properties related to a translation initiation factor, and functions in NMD
      raises the possibility that eIF4AIII substitutes for eIF4AI/II during NMD.

PMID- 15024116
TI  - Synaptic activity-independent persistent plasticity in endogenously active
      mammalian motoneurons.
AB  - Potentiation and depression of glutamate receptor function in hippocampal,
      cerebellar, and cortical neurons are examples of persistent changes in synaptic
      function that underlie important behavioral adaptations such as learning and
      memory. Persistent changes in synaptic function relevant for motor behaviors have
      not been demonstrated in mammalian motoneurons. We demonstrate that adaptive
      changes in (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
      hydrobromide (AMPA) receptor function at endogenously active synapses occur in
      motoneurons in neonatal rodents. We found a form of serotonin (5-HT)-dependent
      synaptic plasticity in hypoglossal (XII) motoneurons, which control tongue
      muscles affecting upper airway function, that is metamodulated by metabotropic
      glutamate receptors. Episodic, but not continuous, activation of postsynaptic 5
      HT type 2 (5-HT(2)) receptors on hypoglossal (XII) motoneurons leads to long
      lasting increases in their AMPA receptor-mediated respiratory drive currents and
      associated XII nerve motor output. Antagonism of group-I metabotropic glutamate
      receptors blocks induction of the 5-HT-induced increase in excitability. We
      propose that this activity-independent postsynaptic 5-HT-mediated plasticity
      represents the cellular mechanism underlying long-term facilitation, i.e.,
      persistent increases in respiratory motor output and ventilation seen in humans
      and rodents in response to episodic hypoxia. Loss of activity in XII motoneurons
      is common during sleep causing snoring and, in serious cases, airway obstruction
      that interrupts breathing, a condition known as obstructive sleep apnea. These
      results may provide the basis for rationale development of therapeutics for
      obstructive sleep apnea in humans.

PMID- 15024119
TI  - Asymmetric hydrogenation of alpha,beta-unsaturated phosphonates with Rh-BisP* and
      Rh-MiniPHOS catalysts: scope and mechanism of the reaction.
AB  - Optically active 1,2-bis(alkylmethylphosphino)ethanes and
      bis(alkylmethylphosphino)methanes are unique diphosphine ligands combining the
      simple molecular structure and P-stereogenic asymmetric environment. This work
      shows that these ligands exhibit excellent enantioselectivity in rhodium
      catalyzed asymmetric hydrogenation of alpha,beta-unsaturated phosphonic acid
      derivatives. The enantioselective hydrogenation mechanism elucidated by NMR study
      is also described.

PMID- 15024118
TI  - CYP15A1, the cytochrome P450 that catalyzes epoxidation of methyl farnesoate to
      juvenile hormone III in cockroach corpora allata.
AB  - The molecular analysis of insect hormone biosynthesis has long been hampered by
      the minute size of the endocrine glands producing them. Expressed sequence tags
      from the corpora allata of the cockroach Diploptera punctata yielded a new
      cytochrome P450, CYP15A1. Its full-length cDNA encoded a 493-aa protein that has
      only 34% amino acid identity with CYP4C7, a terpenoid omega-hydroxylase
      previously cloned from this tissue. Heterologous expression of the cDNA in
      Escherichia coli produced >300 nmol of CYP15A1 per liter of culture. After
      purification, its catalytic activity was reconstituted by using phospholipids and
      house fly P450 reductase. CYP15A1 metabolizes methyl (2E,6E)-3,7,11-trimethyl-2,6
      dodecatrienoate (methyl farnesoate) to methyl (2E,6E)-(10R)-10,11-epoxy-3,7,11
      trimethyl-2,6-dodecadienoate [juvenile hormone III, JH III] with a turnover of 3
      5 nmol/min/nmol P450. The enzyme produces JH III with a ratio of approximately
      98:2 in favor of the natural (10R)-epoxide enantiomer. This result is in contrast
      to other insect P450s, such as CYP6A1, that epoxidize methyl farnesoate with
      lower regio- and stereoselectivity. RT-PCR experiments show that the CYP15A1 gene
      is expressed selectively in the corpora allata of D. punctata, at the time of
      maximal JH production by the glands. We thus report the cloning and functional
      expression of a gene involved in an insect-specific step of juvenile hormone
      biosynthesis. Heterologously expressed CYP15A1 from D. punctata or its ortholog
      from economically important species may be useful in the design and screening of
      selective insect control agents.

PMID- 15024122
TI  - Long-term human response to uncertain environmental conditions in the Andes.
AB  - Human interaction with the physical environment has increasingly transformed
      Earth-system processes. Reciprocally, climate anomalies and other processes of
      environmental change of natural and anthropogenic origin have been affecting, and
      often disrupting, societies throughout history. Transient impact events, despite
      their brevity, can have significant long-term impact on society, particularly if
      they occur in the context of ongoing, protracted environmental change. Major
      climate events can affect human activities in critical conjunctures that shape
      particular trajectories of social development. Here we report variable human
      responses to major environmental events in the Andes with a particular emphasis
      on the period from anno Domini 500-1500 on the desert north coast of Peru. We
      show that preindustrial agrarian societies implemented distinct forms of
      anticipatory response to environmental change and uncertainty. We conclude that
      innovations in production strategies and agricultural infrastructures in these
      indigenous societies reflect differential social response to both transient (El
      Nino-Southern Oscillation events) and protracted (desertification) environmental
      change.

PMID- 15024125
TI  - Synaptic organization in the adult honey bee brain is influenced by brood
      temperature control during pupal development.
AB  - Recent studies have shown that the behavioral performance of adult honey bees is
      influenced by the temperature experienced during pupal development. Here we
      explore whether there are temperature-mediated effects on the brain. We raised
      pupae at different constant temperatures between 29 and 37 degrees C and
      performed neuroanatomical analyses of the adult brains. Analyses focused on
      sensory-input regions in the mushroom bodies, brain areas associated with higher
      order processing such as learning and memory. Distinct synaptic complexes
      [microglomeruli (MG)] within the mushroom body calyces were visualized by using
      fluorophore-conjugated phalloidin and an antibody to synapsin. The numbers of MG
      were different in bees that had been raised at different temperatures, and these
      differences persisted after the first week of adult life. In the olfactory-input
      region (lip), MG numbers were highest in bees raised at the temperature normally
      maintained in brood cells (34.5 degrees C) and significantly decreased in bees
      raised at 1 degrees C below and above this norm. Interestingly, in the
      neighboring visual-input region (collar), MG numbers were less affected by
      temperature. We conclude that thermoregulatory control of brood rearing can
      generate area- and modality-specific effects on synaptic neuropils in the adult
      brain. We propose that resulting differences in the synaptic circuitry may affect
      neuronal plasticity and may underlie temperature-mediated effects on multimodal
      communication and learning.

PMID- 15024124
TI  - S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of
      methionine metabolism.
AB  - We report studies of a Croatian boy, a proven case of human S
      adenosylhomocysteine (AdoHcy) hydrolase deficiency. Psychomotor development was
      slow until his fifth month; thereafter, virtually absent until treatment was
      started. He had marked hypotonia with elevated serum creatine kinase and
      transaminases, prolonged prothrombin time and low albumin. Electron microscopy of
      muscle showed numerous abnormal myelin figures; liver biopsy showed mild
      hepatitis with sparse rough endoplasmic reticulum. Brain MRI at 12.7 months
      revealed white matter atrophy and abnormally slow myelination. Hypermethioninemia
      was present in the initial metabolic study at age 8 months, and persisted (up to
      784 microM) without tyrosine elevation. Plasma total homocysteine was very
      slightly elevated for an infant to 14.5-15.9 microM. In plasma, S
      adenosylmethionine was 30-fold and AdoHcy 150-fold elevated. Activity of AdoHcy
      hydrolase was approximately equal to 3% of control in liver and was 5-10% of the
      control values in red blood cells and cultured fibroblasts. We found no evidence
      of a soluble inhibitor of the enzyme in extracts of the patient's cultured
      fibroblasts. Additional pretreatment abnormalities in plasma included low
      concentrations of phosphatidylcholine and choline, with elevations of
      guanidinoacetate, betaine, dimethylglycine, and cystathionine. Leukocyte DNA was
      hypermethylated. Gene analysis revealed two mutations in exon 4: a maternally
      derived stop codon, and a paternally derived missense mutation. We discuss
      reasons for biochemical abnormalities and pathophysiological aspects of AdoHcy
      hydrolase deficiency.

PMID- 15024126
TI  - Substance P in the medial amygdala: emotional stress-sensitive release and
      modulation of anxiety-related behavior in rats.
AB  - Increasing evidence implicates the substance P (SP)/neurokinin-1 receptor system
      in anxiety and depression. However, it is not known whether emotional stimulation
      alters endogenous extracellular SP levels in brain areas important for processing
      of anxiety and mood, a prerequisite for a contribution of this neuropeptide
      system in modulating these behaviors. Therefore, we examined in rats whether the
      release of SP is sensitive to emotional stressors in distinct subregions of the
      amygdala, a key area in processing of emotions. By using in vivo micropush-pull
      superfusion and microdialysis techniques, we found a pronounced and long-lasting
      increase (150%) in SP release in the medial nucleus of the amygdala (MeA), but
      not in the central nucleus of the amygdala, in response to immobilization stress.
      SP release in the MeA was transiently enhanced (40%) in response to elevated
      platform exposure, which is regarded as a mild emotional stressor. Immobilization
      enhanced the anxiety-related behavior evaluated in the subsequently performed
      elevated plus-maze test. Bilateral microinjections of the neurokinin-1 receptor
      antagonist [2-cyclopropoxy-5-(5-(trifluoromethyl)tetrazol-1-yl)benzyl]-(2
      phenylpiperidin-3-yl)amine into the MeA blocked the stress-induced anxiogenic
      like effect, supporting a functional significance of enhanced SP release. In
      unstressed rats, the neurokinin-1 receptor antagonist displayed no significant
      anxiolytic effect but reversed the anxiogenic effect of SP microinjected into the
      MeA. Our findings identify the MeA as a critical brain area for the involvement
      of SP transmission in anxiety responses and as a putative site of action for the
      recently discovered therapeutic effects of SP antagonists in the treatment of
      stress-related disorders.

PMID- 15024128
TI  - Retinoblastoma protein functions as a molecular switch determining white versus
      brown adipocyte differentiation.
AB  - Adipocyte precursor cells give raise to two major cell populations with different
      physiological roles: white and brown adipocytes. Here we demonstrate that the
      retinoblastoma protein (pRB) regulates white vs. brown adipocyte differentiation.
      Functional inactivation of pRB in wild-type mouse embryo fibroblasts (MEFs) and
      white preadipocytes by expression of simian virus 40 large T antigen results in
      the expression of the brown fat-specific uncoupling protein 1 (UCP-1) in the
      adipose state. Retinoblastoma gene-deficient (Rb-/-) MEFs and stem cells, but not
      the corresponding wild-type cells, differentiate into adipocytes with a gene
      expression pattern and mitochondria content resembling brown adipose tissue. pRB
      deficient MEFs exhibit an increased expression of the Forkhead transcription
      factor Foxc2 and its target gene cAMP-dependent protein kinase regulatory subunit
      RIalpha, resulting in increased cAMP sensitivity. Suppression of cAMP-dependent
      protein kinase activity in Rb(-/-)MEFs blocked the brown adipocyte-like gene
      expression pattern without affecting differentiation per se. Immunohistochemical
      studies revealed that pRB is present in the nuclei of white but not brown
      adipocyte precursor cells at a developmental stage where both cell types begin to
      accumulate lipid and brown adipocytes express UCP-1. Furthermore, pRB rapidly
      undergoes phosphorylation upon cold-induced neodifferentiation and up-regulation
      of UCP-1 expression in brown adipose tissue. Finally, down-regulation of pRB
      expression accompanies transdifferentiation of white into brown adipocytes in
      response to beta3-adrenergic receptor agonist treatment. We propose that pRB acts
      as a molecular switch determining white vs. brown adipogenesis, suggesting a
      previously uncharacterized function of this key cell cycle regulator in adipocyte
      lineage commitment and differentiation.

PMID- 15024130
TI  - Mitochondrial localization of estrogen receptor beta.
AB  - Estrogen receptors (ERs) are believed to be ligand-activated transcription
      factors belonging to the nuclear receptor superfamily, which on ligand binding
      translocate into the nucleus and activate gene transcription. To date, two ERs
      have been identified: ERalpha and ERbeta. ERalpha plays major role in the
      estrogen-mediated genomic actions in both reproductive and nonreproductive
      tissue, whereas the function of ERbeta is still unclear. In this study, we used
      immunocytochemistry, immunoblotting, and proteomics to demonstrate that ERbeta
      localizes to the mitochondria. In immunocytochemistry studies, ERbeta was
      detected with two ERbeta antibodies and found to colocalize almost exclusively
      with a mitochondrial marker in rat primary neuron, primary cardiomyocyte, and a
      murine hippocampal cell line. The colocalization of ERbeta and mitochondrial
      markers was identified by both fluorescence and confocal microscopy. No
      translocation of ERbeta into the nucleus on 17beta-estradiol treatment was seen
      by using immunocytochemistry. Immunoblotting of purified human heart mitochondria
      showed an intense signal of ERbeta, whereas no signals for nuclear and other
      organelle markers were found. Finally, purified human heart mitochondrial
      proteins were separated by SDS/PAGE. The 50,000-65,000 M(r) band was digested
      with trypsin and subjected to matrix-assisted laser desorption/ionization mass
      spectrometric analysis, which revealed seven tryptic fragments that matched with
      those of ERbeta. In summary, this study demonstrated that ERbeta is localized to
      mitochondria, suggesting a role for mitochondrial ERbeta in estrogen effects on
      this important organelle.

PMID- 15024131
TI  - Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a
      haplotypic Hsp70-Hom variant.
AB  - Susceptibility to a clinically significant drug hypersensitivity syndrome
      associated with abacavir use seems to have a strong genetic component. We have
      previously shown that the presence of HLA-B*5701 strongly predicts abacavir
      hypersensitivity and have identified a potential susceptibility locus within a
      300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report
      the results of fine recombinant genetic mapping in an expanded patient population
      of 248 consecutive, fully ascertained, abacavir-exposed individuals in the
      Western Australian HIV Cohort Study, in which 18 cases of definite abacavir
      hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype
      mapping within patients with allelic markers of the 57.1 ancestral haplotype
      suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701
      was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds
      ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom
      (HspA1L, resulting from the substitution of residue M493T in the peptide-binding
      subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive
      cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with
      abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor
      expression in response to ex vivo abacavir stimulation, which was abrogated with
      CD8(+) T cell depletion. These data indicate that the concurrence of HLA-B*5701
      and Hsp70-Hom M493T alleles is necessary for the development of abacavir
      hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted
      immune response to abacavir.

PMID- 15024132
TI  - Corticosteroid treatment of experimental arthritis retards cartilage destruction
      as determined by histology and serum COMP.
AB  - OBJECTIVE: To examine if changes in serum cartilage oligomeric matrix protein
      (COMP) correlate with the development of cartilage damage, as measured by
      histological grading, in corticosteroid-treated animals with collagen-induced
      arthritis (CIA). METHODS: DA rats with established CIA were treated with
      corticosteroids (betamethasone, 0.1 mg/kg body weight) or placebo (saline)
      intraperitoneally once daily after reaching an arthritis score exceeding 1. The
      treatment continued throughout the study. Arthritis progression was monitored by
      clinical scoring of paws, serial measurements of serum COMP and fibrinogen, and
      histological grading of paws. RESULTS: Corticosteroid treatment reduced clinical
      signs of arthritis compared with placebo (arthritis score reduced, P < 0.01 at
      day 25). Corticosteroid treatment also reduced fibrinogen levels compared with
      placebo (P < 0.01). The morphological changes in the joint were less severe in
      the corticosteroid-treated animals (median cartilage score 4 in the placebo
      group, 0 in the corticosteroid-treated group; P < 0.01). The levels of COMP
      remained unchanged during treatment in the corticosteroid-treated arthritic
      animals, whereas an increase in levels of COMP was observed in rats treated with
      placebo (P < 0.01). There was a correlation between serum COMP and the extent of
      cartilage destruction at day 25 after immunization (r = 0.77, P < 0.001).
      CONCLUSIONS: Corticosteroids given therapeutically to arthritic rats diminish
      joint destruction histologically, and stable serum COMP levels reflect this
      effect.

PMID- 15024133
TI  - Effect of neutralizing antibodies to IL-10 and C5 on the renal damage caused by a
      pathogenic human anti-dsDNA antibody.
AB  - OBJECTIVES: There is considerable evidence suggesting that anti-double-stranded
      deoxyribonucleic acid (anti-dsDNA) antibodies are involved in the pathogenesis of
      lupus nephritis. It was shown previously using severe combined immune deficient
      (SCID) mice that when the hybridomas secreting human immunoglobulin G (IgG) anti
      dsDNA antibodies, RH14 and DIL-6, were implanted intraperitoneally the antibodies
      produced by RH14, but not DIL-6, deposited in the kidneys, caused pathological
      changes in the renal tissues and induced proteinuria. In this study we have
      further analysed the effect of activated terminal complement proteins and
      interleukin-10 (IL-10) in the pathogenesis of glomerulonephritis caused by the RH
      14. METHODS: SCID mice implanted with RH-14 or DIL-6 cell lines were treated with
      neutralizing antibodies to IL-10 (mAb B-S10) or anti-complement factor 5 (anti
      C5) (mAb BB5.1) intraperitoneally. Control groups received either an isotype
      control antibody (135.8) or phosphate-buffered saline (PBS). Serum human IgG
      levels and proteinuria were estimated and the extent of renal involvement was
      examined by histopathological and electron microscopic techniques. RESULTS: While
      there was a tendency to reduce proteinuria in the anti-IL-10 injected group the
      anti-C5 injected group showed a significant reduction in proteinuria (P<0.01)
      compared with the groups injected with either the control mAb or PBS. There was a
      considerable reduction in the serum human IgG levels in the anti-IL-10 but not in
      the anti-C5 treated animals. Both anti-IL-10 and anti-C5 treated groups showed
      significantly reduced renal impairment as revealed by histopathological
      examination and proteinuria assessment. CONCLUSION: The findings, while
      confirming the role of IL-10 and activated terminal complement component in the
      production of antibody at the cellular level and at the site of glomerular immune
      deposition in this model, respectively, also suggest the beneficial effect of a
      combined therapy using both anti-IL-10 and anti-C5 mAb to prevent or reduce the
      effect of the humoral immune response in lupus disease.

PMID- 15024134
TI  - Echocardiography and pulmonary function as screening tests for pulmonary arterial
      hypertension in systemic sclerosis.
AB  - OBJECTIVE: A prospective study to evaluate echocardiography and gas transfer
      (DLCO) by comparison with cardiac catheterization in discriminating between
      patients with and without systemic sclerosis-associated pulmonary arterial
      hypertension (SScPAH). METHOD: A total of 137 (52 with and 85 without pulmonary
      fibrosis) had echocardiography and lung function tests within 3 months of their
      definitive invasive study. RESULTS: At cardiac catheterization 99 of these
      patients were found to have PAH, while PAH was excluded in 38.
      Echocardiographically estimated tricuspid gradient (TG) showed a moderate
      positive correlation (r(2) = 0.44, P<0.005) with both mean pulmonary pressure and
      invasively determined tricuspid gradient. DLCO showed a weak correlation (r(2 )=
      0.09, P = 0.006), when compared with mean pulmonary arterial pressure. In total,
      97% of patients with an echocardiographically determined TG of > 45 mmHg were
      found to have pulmonary hypertension at catheterization. However, no threshold
      could be defined with either screening test that safely excluded PAH.
      CONCLUSIONS: The positive predictive accuracy of currently used non-invasive
      tests are adequate for the diagnosis of advanced PAH provided sufficiently high
      thresholds (TG > 45 mmHg or DLCO < 55% predicted) are used. These tests cannot be
      relied upon to exclude pulmonary hypertension where pre-test probability is high.

PMID- 15024135
TI  - Development, validation and use of a patient knowledge questionnaire (PKQ) for
      patients with early rheumatoid arthritis.
AB  - OBJECTIVES: To design and validate a patient knowledge questionnaire (PKQ) to use
      pre- and post-education programme for a group of early rheumatoid arthritis (RA)
      patients. The aim was to design a tool to assess knowledge acquisition before and
      after an arthritis information course (AIC). METHODS: The PKQ design incorporated
      12 multichoice questions. Validation procedures were undertaken. Following PKQ
      validation 30 patients were recruited from specialist practice having met the
      inclusion criteria. All patients attended the arthritis information course run by
      the multidisciplinary team. Demographic data such as age, gender, disease
      duration and educational level were evaluated for possible significance. RESULTS:
      The PKQ demonstrated test-retest stability with a Pearson's correlation
      coefficient of 0.965 and an intraclass single measure coefficient of 0.87.
      Internal consistency was demonstrated with a Cronbach's alpha of 0.62. The PKQ
      was sensitive to change with a statistically significant improvement following
      three 1-h education sessions (Mann-Whitney U-test P<0.001). No correlation was
      found between baseline PKQ scores and age or disease duration. However,
      significant correlation between educational level and pre-knowledge scores
      (Pearson's correlation r = 0.386, P = 0.035) was demonstrated. Change in PKQ
      score was not associated with age, disease duration or educational level.
      Patients with lower initial pre-scores obtained the most improvement post-AIC
      (chi(2)-test P = 0.003). CONCLUSIONS: The PKQ is a reliable, valid and sensitive
      instrument suitable for measuring the acquisition of RA knowledge in a group of
      early RA patients following arthritis information courses.

PMID- 15024136
TI  - Morbidity and mortality in rheumatoid patients during treatment with adalimumab
      and infliximab.

PMID- 15024137
TI  - Pneumococcal vaccination for RA patients on TNF-alpha antagonists.

PMID- 15024138
TI  - Painful hips in a shipyard worker.

PMID- 15024139
TI  - Treatment of myositis with etanercept (Enbrel), a recombinant human soluble
      fusion protein of TNF-alpha type II receptor and IgG1.

PMID- 15024140
TI  - Periodic fever due to a novel TNFRSF1A mutation in a heterozygous Chinese carrier
      of MEFV E148Q.

PMID- 15024141
TI  - Tuberculosis in a nine-year-old girl treated with infliximab for systemic
      juvenile idiopathic arthritis.

PMID- 15024142
TI  - ANCA-associated giant cell arteritis presenting with mononeuritis multiplex and
      central retinal artery occlusion: a case report.

PMID- 15024143
TI  - Refractory polymyositis responding to infliximab: extended follow-up.

PMID- 15024144
TI  - Infliximab in the treatment of refractory vasculitis secondary to hepatitis C
      associated mixed cryoglobulinaemia.

PMID- 15024145
TI  - Acute-onset thigh pain.

PMID- 15024147
TI  - Symptoms without pathology.

PMID- 15024148
TI  - Concurrence of interphalangeal osteoarthritis and rheumatoid arthritis.

PMID- 15024149
TI  - Musculoskeletal assessment of general medical inpatients.

PMID- 15024150
TI  - Microalbuminuria: is it a predictor of ischaemic heart disease in rheumatoid
      arthritis?

PMID- 15024155
TI  - Use of BAC end sequences for SNP discovery.

PMID- 15024156
TI  - Exon trapping for positional cloning and fingerprinting.

PMID- 15024157
TI  - Isolation of CpG islands from BAC clones using a methyl-CpG binding column.

PMID- 15024158
TI  - BAC microarray-based comparative genomic hybridization.

PMID- 15024159
TI  - Large DNA transformation in plants.

PMID- 15024160
TI  - Retrofitting BACs with a selectable marker for transfection.

PMID- 15024161
TI  - BAC modification using a RecA expressing shuttle vector system.

PMID- 15024162
TI  - Bacterial artificial chromosome engineering.

PMID- 15024163
TI  - ET recombination: DNA engineering using homologous recombination in E. coli.

PMID- 15024164
TI  - BAC engineering for the generation of ES cell-targeting constructs and mouse
      transgenes.

PMID- 15024165
TI  - Microinjection of BAC DNA into the pronuclei of fertilized mouse oocytes.

PMID- 15024166
TI  - Generation of BAC transgenic mice.

PMID- 15024167
TI  - BAC rescue: a tool for functional analysis of the mouse genome.

PMID- 15024168
TI  - Herpesviruses: a brief overview.

PMID- 15024169
TI  - Cloning of beta-herpesvirus genomes as bacterial artificial chromosomes.

PMID- 15024170
TI  - Construction of HSV-1 BACs and their use for packaging of HSV-1-based amplicon
      vectors.

PMID- 15024171
TI  - Mutagenesis of viral BACs with linear PCR fragments (ET recombination).

PMID- 15024172
TI  - Mutagenesis of herpesvirus BACs by allele replacement.

PMID- 15024173
TI  - Herpesvirus genome mutagenesis by transposon-mediated strategies.

PMID- 15024174
TI  - Protective DNA vaccination by particle bombardment using BAC DNA containing a
      replication-competent, packaging-defective genome of herpes simplex virus type I.

PMID- 15024175
TI  - Biliary ascariasis as a cause of post-cholecystectomy syndrome in an endemic
      area.
AB  - BACKGROUND: Post-cholecystectomy syndrome encompasses numerous biliary,
      pancreatic and other entities. Biliary ascariasis is a common cause of adult
      biliary disease in an endemic area. Post-cholecystectomy biliary ascariasis, a
      cause of post- cholecystectomy syndrome although not yet defined is frequently
      seen in this part of the world. METHOD: Between Jan. 1990 and Jan. 2001, 104
      cases of post-cholecystectomy biliary ascariasis were seen. Ultrasonography was
      found to be an excellent tool for diagnosing and monitoring of the worms inside
      the biliary tract. Endoscopic retrograde cholangiopancreatography had both
      diagnostic and therapeutic value. RESULTS: The majority (68.2%) of patients
      responded to conservative treatment. Surgical treatment was advocated in 18.2%,
      which included 2 patients with liver abscesses. Endoscopic extraction of worms
      was successful in 48.2%. CONCLUSION: Post-cholecystectomy biliary ascariasis as a
      cause of post-cholecystectomy syndrome needs to be included in the list of causes
      for post-cholecystectomy syndrome. Although the majority of patients respond to
      conservative treatment but endoscopic extraction or surgical intervention may be
      needed. Routine deworming of patients undergoing cholecystectomy both
      preoperatively and postoperatively should be done in all patients in endemic
      areas of ascariasis. Although this entity is rare in Europe and United States,
      due to population migration and increased travel, it is necessary for surgeons in
      these countries to be aware of this condition.

PMID- 15024176
TI  - Surgery for hilar cholangiocarcinoma: feasibility and results of parenchyma
      conserving liver resection.
AB  - BACKGROUND/AIM: Major liver resection has improved the resectability rate of
      hilar cholangiocarcinomas, but morbidity and mortality may be significant. The
      aim of this study was to assess the value of parenchyma-conserving liver
      resection (resection of bile duct with liver segments I and IVb; PCLR) in hilar
      cholangiocarcinoma. METHODS: Retrospective analysis of prospectively collected
      data. Factors influencing survival following three types of operations were
      studied by univariate and multivariate analyses. The three types of operations
      were: (1) local resection of the bile duct alone (LR); (2) major liver resection
      (resection of three or more segments, hepatic resection; HR), and (3) PCLR.
      RESULTS: Forty-six patients (21 males, 25 females; age range 35-77 years, mean
      age 57, median age 57 years) underwent surgery. There were 11 LR, 12 HR, and 23
      PCLR procedures. There were 3 deaths (mortality 6.5%). The mortality was higher
      following HR (3 out of 12; 25%) than following LR or PCLR (0 out of 34; p =
      0.01). Survival was longer following curative resection (median 27 months) than
      after palliative resection (median 15 months; p = 0.001). Lymph nodal and
      perineural involvement were adverse factors on univariate, but not on
      multivariate analysis. PCLR produced better survival (median 29 months) as
      compared with LR (median 15 months) or HR (median 22.5 months; p < 0.01).
      CONCLUSIONS: PCLR is applicable to selected patients with Bismuth-Corlette type
      III disease without major vascular involvement and produces survival rates
      comparable to those of LR and HR. PCLR may help avoid major liver resections in
      some patients with hilar cholangiocarcinoma.

PMID- 15024177
TI  - Hemoglobin content is increased in the human erythroleukemia K562 cell line by a
      56.2-kD peptide from uremic plasma.
AB  - BACKGROUND: Some abnormalities in porphyrin metabolism have been described in
      erythrocytes from patients with end-stage renal failure. A peptidic fraction of
      56.2 kD isolated from plasma of these patients was previously identified as an
      aminolevulinate dehydratase inhibitor. The aim of this study was to examine the
      in vitro effect of this peptide on heme synthesis in the erythroleukemia K562
      cells. METHODS: The 56.2-kD fraction was purified from uremic plasma by protein
      electroelution and, its action on the mitochondrial rate-limiting steps of heme
      synthesis, as well as the hemoglobin content during erythroid differentiation
      induced by sodium butyrate, was investigated in K562 cells. RESULTS: Two hours
      after addition of the 56.2-kD peptide, the activities of aminolevulinate acid
      synthase and aminolevulinate dehydratase were reduced while the activity of the
      ferrochelatase was enhanced, indicating that this peptide easily across the
      membranes. A 3-day incubation with this peptide enhanced approximately twofold
      the hemoglobin and porphyrin levels during erythroid differentiation of K562
      cells without variation of cell growth. CONCLUSION: This study shows that the
      addition of the 56.2-kD uremic factor to K562 cells was clearly implicated in
      heme disturbances existing in chronic renal failure but it did not play a
      negative role in the pathogenesis of the uremic anemia.

PMID- 15024178
TI  - Immune reconstitution and viral stimulation are required to restore HIV-specific
      CD8 T cell responses following advanced infection.
AB  - The extent to which highly active antiretroviral therapy (HAART) restores human
      immunodeficiency virus (HIV)-specific immunity in advanced infection is unknown.
      Therefore, we studied how effective therapy affected HIV-specific CD8(+) T cell
      responses in 4 individuals who had progressed to advanced infection. CD8(+) T
      cell responses were assessed by cytotoxicity and interferon-gamma (IFN-gamma)
      production. Proliferative CD4(+) T cell responses against HIV, Candida and
      mitogen were measured by (3)H-thymidine incorporation. Substantial immune
      reconstitution indicated by increased CD4(+) and CD8(+) T cell numbers followed
      suppression of viral replication. This was associated with emergence of HIV
      specific cytotoxic T lymphocytes (CTL), but only concurrent with detectable viral
      replication. Emergent anti-HIV CTL were similar to those at earlier stages of
      infection in terms of their specificity, function, and CD28 phenotype. However,
      they were very short-lived in the absence of detectable HIV replication. Antigen
      specific CD4(+) T cell responses remained severely compromised. Thus, effective
      antiretroviral therapy restores the capacity for HIV-specific CTL responses after
      advanced infection. However, the transient nature of these responses suggests
      failure to generate stable long-lived memory cells in the absence of HIV-specific
      helper T cell responses.

PMID- 15024179
TI  - Early impairment of CD8+ T cells immune response against Epstein-Barr virus (EBV)
      antigens associated with high level of circulating mononuclear EBV DNA load in
      HIV infection.
AB  - Immunodeficiency related to HIV may increase the incidence of EBV-associated
      lymphomas, by altering EBV-specific immune control and consequently favoring EBV
      reactivation. The aim of the present study was to assess the relationship between
      the decrease of EBV-specific cellular immunity and the increase of EBV
      reactivation in a prospective cohort of 72 unselected HIV-infected individuals.
      EBV-specific immunity was evaluated by a highly sensitive IFN-gamma ELISPOT assay
      using 22 peptides mimicking latent and lytic antigens, and circulating
      mononuclear (PBMC) EBV DNA load was quantified by real-time quantitative PCR. The
      mean circulating cell-associated EBV DNA load was higher in HIV-infected patients
      (639 copies/10(6) PBMC) than in healthy controls (21, n = 14) ( P = 0.005) and
      was higher in patients with CD4(+) T-cell count below 350/microL than that in
      patients harboring higher CD4(+) T-cell count (1112 vs. 389, P = 0.003). The mean
      intensity of EBV-specific cellular responses was lower in HIV-infected patients
      than in controls ( P = 0.001), even in patients with CD4(+) T-cell count above
      350/-microL ( P = 0.007). The number of EBV peptides recognized was lower in HIV
      infected patients than in controls (frequency: 0.44 vs. 0.67; P = 0.02),
      indicating reduced polyclonality in HIV-infected patients. The polyclonality was
      1.5-fold lower in HIV-infected patients with CD4(+) T-cell count below 350/
      microL ( P =0.007). For EBV load >1000 copies/10(6) PBMC, the levels of cell
      associated EBV DNA and those of EBV-specific cellular immunity, either in
      intensity or in polyclonality, or both, were inversely correlated. These findings
      demonstrate early impairment of the EBV-specific cellular immune control with
      progressive increase of EBV reactivation in the course of HIV infection. These
      observations likely provide a basis for appreciating the risk to develop non
      Hodgkin's lymphomas in HIV-infected individuals.

PMID- 15024180
TI  - Effect of IL-2 therapy on CD8+ cell noncytotoxic anti-HIV response during primary
      HIV-1 infection.
AB  - Early treatment intervention during human immunodeficiency virus (HIV) infection
      is a strategy aimed to preserve and/or enhance the developing anti-HIV immune
      responses. We report the effect of highly active antiretroviral therapy (HAART)
      combined with intermittent subcutaneous doses of Interleukin 2 (IL-2) on CD8(+)
      cell noncytotoxic anti-HIV responses (CNAR), as well as on viral loads and CD4(+)
      cell/CD8(+) cell numbers in subjects with primary HIV-1 infection. Twenty-four
      patients received HAART, 24 received a combination of HAART plus IL-2, and 12
      elected no-therapy. In comparison to HAART alone, IL-2 treatment led to
      significant increases in CD4(+) cell numbers through week 48 of the study. No
      effect was observed on viral loads or the CD8(+) cell population. The first cycle
      of IL-2 enhanced CNAR; later cycles showed no substantial effect. This study
      suggests that HAART combined with IL-2 could provide an immunologic benefit in
      the treatment of early HIV infection.

PMID- 15024181
TI  - Functional impairment of dendritic cells caused by murine hepatocellular
      carcinoma.
AB  - Immunosuppression in tumor-bearing hosts may be a major obstacle in eradicating
      tumors. This study investigated whether hepatocellular carcinoma suppressed the
      functions of dendritic cells to escape tumor surveillance. Dendritic cells (DC),
      propagated from C57BL/10J mice, were cocultured with or without murine hepatoma
      Hepa1-6 cells to examine the influence of hepatocellular carcinoma on dendritic
      cells. The results revealed that dendritic cells cocultured with hepatoma cells
      expressed low levels of costimulatory molecules, and the stimulatory capacity was
      decreased. The antigen-specific cytotoxic effects of T cells activated by the DC
      cocultured with hepatoma cells were also decreased. In ex vivo studies, the
      maturation and function of dendritic cells propagated from tumor-bearing mice
      were suppressed. The suppressive effect of Hepa1-6 cells on dendritic cells could
      be partially reversed by neutralizing IL-10. In conclusion, the maturation and
      stimulatory function of DC are suppressed by hepatocellular carcinoma. IL-10
      release may be one of the mechanisms employed by hepatocellular carcinoma to
      suppress dendritic cells.

PMID- 15024182
TI  - Circulating CD4+CD25+ T regulatory cells are not altered in multiple sclerosis
      and unaffected by disease-modulating drugs.
AB  - Experimental animal models for autoimmunity have demonstrated the existence and
      crucial role of CD4(+)CD25(+) T regulatory (Tr) cells in suppressing autoreactive
      T cells and promoting peripheral tolerance. Recent in vitro functional studies
      showed that Tr cells are enriched in the CD25(high) cell population among CD4(+)
      T cells, and that they totally inhibit proliferation and cytokine secretion by
      CD4(+) T cells. It is not yet known if circulating Tr cells are involved in
      multiple sclerosis (MS). This study was done firstly to determine whether
      alterations of the CD4 (+) CD25(high) T cells occur in MS, examining their
      frequencies. As it was reported that the suppressive activity of CD4(+)CD25(+) Tr
      cells is mainly through cell surface contact pathway, we secondly analyzed the
      expression of the functionally important cell surface molecules of
      CD4(+)CD25(high) Tr cells. Two- or three-colour flow cytometry was used to
      identify and quantify CD4(+)CD25(+) Tr cells and CD4(+)CD25(high) Tr cells among
      blood CD4(+) T cells in MS patients without treatment vs. patients treated with
      either interferon-beta (IFN-beta) or glatiramer acetate (GA) or IFN-beta + GA in
      combination vs. healthy controls (HC). Expression of functionally important
      surface molecules CD45RO, CD69, CD95, HLA-DR, and intracellular CTLA-4 and IL-10
      production by CD4(+)CD25(high) Tr cells were investigated. CD4(+)CD25(+) T cells
      constituted around 6% of CD4(+)T cells in all MS patient groups, and 7% in HC.
      There were also no changes in the proportions of CD4(+)CD25(+) Tr cells and
      CD4(+)CD25(high) Tr cells in a longitudinal follow-up of MS patients before and
      during IFN-beta treatment. Frequencies of circulating CD4(+)CD25(high)Tr cells
      among CD4(+) T cells were also similar and their surface or intracellular
      molecular expression did not vary in MS patients, irrespective of treatment,
      compared to HC. This study suggests that levels of circulating CD4(+)CD25(+) Tr
      cells and CD4(+)CD25(high) Tr cells are not altered in MS, and are unaffected by
      substances currently used to modulate the disease.

PMID- 15024183
TI  - Immune response against gene therapy vectors: influence of synovial fluid on
      adeno-associated virus mediated gene transfer to chondrocytes.
AB  - Intraarticular gene transfer with adeno-associated virus (AAV) vectors may allow
      efficient therapeutic transgene expression within the joint. In an effort to
      understand potential obstacles (particularly immunity against AAV vectors) to
      intraarticular gene therapy better, our objective was to determine whether
      synovial fluid (SF) influenced AAV-mediated gene transfer to chondrocytes. SF and
      sera from 21 patients with joint diseases were collected. Neutralizing activity
      against AAV/interleukin-4 (IL-4) was determined by assessing the ability of SF or
      serum to inhibit AAV/IL-4 transduction to the C20A4 chondrocytes. IgGs were
      purified from SF by salt-dependent chromatography. Anti-AAV IgG levels were
      determined by ELISA in the SF. SF and sera from all the patients inhibited AAV
      mediated gene transfer to chondrocytes. Six SF out of 21 exerted a stronger
      inhibition. Serum from healthy patients were also inhibitory. Purified IgGs from
      SF exhibited inhibition patterns similar to those seen with whole SF. Anti-AAV
      IgG were found in SF from 13 patients out of 18. Moreover, in the SF, anti-AAV
      IgG level was correlated with the neutralizing activity (p < 0.001, r = 0.716). A
      correlation was observed between levels of inhibition by the SF and serum (P <
      0.0001, r = 0.813). Inhibition of AAV/IL-4 infection of C20A4 cells by SF and
      sera was abolished by increasing the number of AAV/IL-4 particles. SF from
      patients with joint disease consistently inhibited AAV infection of chondrocytes
      in vitro. This effect was ascribable to IgG, most probably directed against AAV.
      In the future, these data may be useful for tailoring intraarticular AAV-mediated
      gene therapy to individual patients.

PMID- 15024184
TI  - The autoantibody repertoire against copper- or macrophage-modified LDL differs in
      normolipidemics and hypercholesterolemic patients.
AB  - We have analyzed the antibody repertoire from normo- and hypercholesterolemic
      subjects to investigate how it can be related to macrophage-dependent
      modification of low-density lipoproteins, in comparison to the commonly used
      copper-oxidized LDL. Preexisting natural antibodies in plasma from normo- and
      hypercholesterolemic individuals were tested for their reactivity against copper
      ion oxidized LDL and LDL modified by macrophages. A crosswise comparison between
      these two antigen preparations demonstrated a different antibody repertoire in
      normo- and hypercholesterolemic patients. This study suggest that the search for
      antibodies that can influence the progression or regression of an atherosclerotic
      process has to take into account the process by which LDL is modified, and the
      repertoire of antibodies that is generated in the normal population, in
      comparison to that with, or at risk for, coronary artery diseases.

PMID- 15024185
TI  - The expression of cytokine genes in the peritoneal macrophages and splenic CD4-
      and CD8-positive lymphocytes of the nonobese diabetic mice.
AB  - Type 1 diabetes is an autoimmune disease that results from the destruction of the
      insulin-producing pancreatic beta islet cells, probably via the influence of
      cytokines. However, direct correlation between the expression of selected
      cytokines by various immune cells at different time points during the progression
      of the disease has not yet been clearly demonstrated. In this study, we showed
      that the mRNA expression of the pro-inflammatory cytokines, TNF-alpha, IL-1 beta,
      IL-6, and GM-CSF, were increased while the anti-inflammatory cytokine, TGF-beta,
      decreased in the peritoneal macrophages of nonobese diabetic (NOD) mice. IL-6
      expression however decreased when the mice became diabetic. Surprisingly the
      expression of IFN-gamma and IL-2 by splenic CD4+ cells were lower in 5-week-old
      NOD mice as compared to the nonobese diabetic resistant (NOR) control mice, but
      their expression was higher in older NOD mice. The expression of IL-4 and IL-10
      decreased in splenic CD4-positive lymphocytes. Splenic CD8-positive lymphocytes
      expressed increased levels of IFN-gamma and IL-10 but the latter decreased
      sharply when diabetes occurred. The relevance of these findings to the
      pathogenesis of type 1 diabetes is discussed.

PMID- 15024186
TI  - Active Crohn's disease patients show a distinctive expansion of circulating
      memory CD4+CD45RO+CD28null T cells.
AB  - In a previous study we found an expansion of circulating memory (CD45RO(+))
      CD4(+) T cells in patients with Crohn's disease (CD). The aim of this work was to
      investigate the phenotypic and functional characteristics of this T-cell subset
      in CD. We analyzed in peripheral blood CD4(+)CD45RO(+) T cells from CD patients
      the expression of surface markers associated to immune activation, costimulation,
      and apoptosis. In sorted CD4(+)CD45RO(+) T cells apoptosis was quantified by
      fluorescent annexin V binding. Healthy subjects and patients with ulcerative
      colitis and acute bacterial enterocolitis served as control groups. An increased
      percentage of memory CD4(+)CD45RO(+) T cells lacking the expression of
      costimulatory receptor CD28 was detected in patients with active CD when compared
      to the other groups evaluated. This expanded CD4(+)CD45RO(+)CD28(null) T-cell
      subset expressed mostly the effector-cell marker CD57(+). Both CD28
      downregulation and CD57 expression correlated to CDAI and surrogate markers of
      disease activity. These phenotypic changes observed on CD4(+)CD45RO(+) T cells
      from active CD returned to values similar to healthy controls after clinical
      remission. Moreover, this memory CD28(null) T-cell subset might express more
      intracytoplasmic TNF and IFN-gamma than their CD28(+) counterpart. Significantly
      lower frequencies of memory CD4(+)CD45RO(+) T cells expressing CD95 apoptosis
      receptor were found in patients with active CD. Moreover, sorted
      CD4(+)CD45RO(+)and CD4(+)CD45RO(+) CD28(null) T cells from patients with active
      CD exhibited a lower apoptotic rate than that found in healthy controls and
      inactive CD patients. According to our data, circulating T lymphocytes from
      active CD patients show distinctive phenotypic and functional changes,
      characterized by an expansion of memory CD4(+)CD45RO(+)CD28(null) T cells
      expressing effector-associated cell surface molecules and displaying enhanced
      resistance to apoptosis.

PMID- 15024188
TI  - Gnathostomiasis: clinicopathologic study.
AB  - Gnathostomiasis is a systemic parasitic disease that is caused by the ingestion
      of contaminated raw fish, the intermediate host. Involvement of the skin is a
      common event, and when it does happen, it can produce a superficial or creeping
      eruption, pseudofurunculosis, and nodular migratory panniculitis. We carried out
      a retrospective study of 946 cases of gnathostomiasis; 66 of them had skin
      biopsies. The diagnosis was made based on clinical and epidemio-logic findings as
      well as the therapeutic response. The most common skin finding was nodular
      migratory panniculitis affecting the trunk. Most of the patients were males
      between 20 and 40 years of age. Histopathologically, we were able to see the
      larva and make a definitive diagnosis in 15 cases, and in 12 cases, the worm was
      retrieved during the surgical procedure. In remaining cases, despite of our
      inability to identify the larva, the histopathologic changes were quite
      characteristic and included: dermal and hypodermal edema with dense mixed
      infiltrates composed of eosinophils admixed with lymphocytes and neutrophils,
      eosinophilic vasculitis, flame figures, areas of necrosis, and hemorrhage. Thus,
      the presence of these histopathologic features in the context of a clinical
      picture suggestive of gnathostomiasis allows the pathologist to make the correct
      diagnosis.

PMID- 15024189
TI  - Alterations of basement membrane zone in bullous and non-bullous variants of
      extragenital lichen sclerosus.
AB  - The aim of the study was to compare alterations of various regions of the
      basement membrane zone (BMZ) in lichen sclerosus (LS) using laser scanning
      confocal microscopy. The study included three cases of bullous LS, one case of
      bullous LS that developed in the course of graft-versus-host disease (GVHD), and
      six cases of non-bullous LS. Three cases of morphea served as a control. Biopsies
      from patients' skin and control biopsies from normal human skin were cut into 30
      microm thick slides and labeled with antibodies against beta4-intergin (lamina
      lucida marker), collagen IV, and the N-terminal end of collagen VII (lamina densa
      markers) and the C-terminal end of collagen VII (sublamina densa marker) using
      routine immunofluorescence (IF). Three-dimensional (3D) reconstruction of various
      regions of the BMZ showed a decrease in the number and size of the dermal
      papillae in LS and morphea as compared with normal skin. In LS numerous
      invaginations and holes were present in the BMZ at the level of the lamina lucida
      and lamina densa. Computer animation of 3D projections revealed that the
      thickness of the lamina densa observed under the light microscopy is an optical
      artifact dependent on periodical tortion of the lamina densa along its axis.
      Torsions and invaginations of the BMZ are equally responsible for the phenomenon
      of artificial reduplication of the lamina densa observed at the ultrastructural
      level. IF labeling with antibody against the N-terminal end of collagen VII
      disclosed the presence of a large hole (up to 25 microm) in the lamina densa and
      the presence of granular material in deep dermis suggestive of partial
      degradation of lamina densa at the level of anchoring fibers. An IF mapping study
      showed blister formation below the lamina densa in three patients with bullous
      LS, whereas in a case of LS associated with GVHD, a blister formed through the
      basal layer of the epidermis. In morphea, there was flattening of BMZ at the
      level of lamina lucida, lamina densa, and sublamina densa but the continuity of
      BMZ was preserved. Three-dimensional reconstruction of dermal-epidermal junction
      in LS revealed alterations of the BMZ, most pronounced at the level of the lamina
      densa and sublamina densa.

PMID- 15024187
TI  - Effect of recombinant human keratinocyte growth factor (rHuKGF) on the
      immunopathogenesis of intestinal graft-vs.-host disease induced without a
      preconditioning regimen.
AB  - We studied the effect of rHuKGF on acute, lethal graft- vs.-host disease (GVHD)
      in the C57BL/6-->(C57BL/6 X DBA/2)F(1)-hybrid model. rHuKGF-treated recipients
      did not develop intestinal GVHD despite elevated levels of intestinal NO and TNF
      alpha, did not develop endotoxemia, and did not die. LPS augmented serum TNF
      alpha release and intestinal NO production, but did not induce intestinal
      epithelial cell apoptosis, a phenomenon associated with acute GVHD. These data
      suggest that KGF prevents the development of acute lethal GVHD by protecting
      epithelial cell injury mediated by TNF-alpha, NO, and other potential cytotoxic
      factors. We noted a moderate reduction in intestinal KGFR mRNA expression in
      untreated GVH mice on day 8, when IFN-gamma mRNA levels were highest. This
      reduction in KGFR mRNA levels was not seen in recipients of IFN-gamma gene
      knockout grafts, suggesting that IFN-gamma may be involved in reducing KGFR mRNA
      expression in the intestine. A similar reduction in intestinal KGFR mRNA
      expression was also seen in rHuKGF-treated recipients, suggesting that rHuKGF
      does not mediate its protective effect by maintaining KGFR at control levels. KGF
      treatment also redirected the cytokine response in acute GVH mice from Th1 to a
      mixed pattern of both Th1 and Th2 cytokines. This was associated with
      histopathologic changes resembling chronic GVHD.

PMID- 15024191
TI  - Inflammatory changes in vitiligo: stage I and II depigmentation.
AB  - Frequent failure of early studies to demonstrate inflammatory changes in vitiligo
      led many investigators to consider the disease as noninflammatory. However,
      others found an inflammatory element in vitiliginous lesions. In this study we
      tried to verify that assumption. Twenty-five patients (10 males and 15 females)
      with common vitiligo and 11 normal healthy individuals were included.
      Histopathologic studies were carried out using epon-embedded sections stained
      with modified toluidine blue stain. Comparisons of the results of histopathologic
      examination of the stained specimens of vitiliginous lesions (both stage I and
      II), marginal areas, and uninvolved normal skin of vitiligo patients with normal
      healthy control were performed. Focal spongiosis was observed in 48% of the
      specimens of vitiligo patients and largely limited to the marginal areas and
      stage I vitiligo lesions. Epidermal mononuclear cell infiltration was seen in 80%
      of both the marginal areas and stage I vitiligo specimens. The number of these
      cells was significantly higher than that in stage II lesions and uninvolved skin.
      Many of the epidermotropic lymphocytes were grouped together, forming clusters
      resembling Pautrier microabscesses. The extent of epidermal mononuclear cell
      invasion did not always parallel the density of the subjacent dermal infiltrate.
      Vitiligo is an inflammatory disease, and the epidermal lymphocytic infiltration
      is most likely the primary immunologic event.

PMID- 15024190
TI  - The anti-MAGE antibody B57 as a diagnostic marker in melanocytic lesions.
AB  - The differentiation of melanoma from certain benign melanocytic lesions on
      histologic grounds alone may sometimes be difficult. The anti-MAGE antibody 57B
      was suggested to be a useful adjunct in differentiating melanoma from nevi. Our
      aim was to study MAGE immunoreactivity with B57 in benign melanocytic lesions
      that have not been investigated to this end so far. One hundred six benign
      melanocytic lesions were stained with the monoclonal antibody 57B. They included
      deep-penetrating nevus (n = 6), desmoplastic nevus (n = 9), halo nevus (n = 10),
      persistent melanocytic nevus (n = 12), common blue nevus (n = 17), cellular blue
      nevus (n = 8), cellular blue nevus with microalveolar pattern (n = 3),
      desmoplastic cellular blue nevus (n = 6), epithelioid blue nevus (n = 2),
      sclerotic blue nevus (n = 3), and clonal nevus (n = 30). Fifty-two lesions (49%)
      demonstrated various patterns of MAGE immunoreactivity, with clonal nevi and deep
      penetrating nevi showing the most consistent staining. In conclusion, MAGE
      immunoreactivity detected by the monoclonal antibody 57B in formalin-fixed,
      paraffin-embedded tissue can be observed in benign melanocytic lesions, and
      therefore this antibody cannot be used in the differential diagnosis between
      melanoma and nevi.

PMID- 15024192
TI  - BCL-2-related apoptosis markers in cutaneous human papillomavirus-associated
      lesions.
AB  - BACKGROUND: Human papilloma virus (HPV) is an etiological agent in benign and
      malignant epithelial tumors. Resistance to apoptotic stimuli by viral strategies
      represents an immunologic escape mechanism during virus-induced tumor development
      and is critical for efficient replication of the virus. OBJECTIVE: The aim of the
      present study was to investigate a role of bcl-family proteins in the anti
      apoptotic pathways modulated by low-risk HPVs in the development of benign HPV
      associated cutaneous tumors. METHODS: Forty lesional biopsy specimens from HPV
      associated cutaneous lesions and 11 non-lesional control skin biopsies were
      studied by immunohistochemical analysis for the differential expressions of HPV
      antigens, the pro-apoptotic bax protein, and the anti-apoptotic bcl-2 and bcl-x
      proteins. RESULTS: Compared with the normal epidermis, bcl-2 and bcl-x expression
      were significantly reduced in the lesional epidermis. Bax was expressed in HPV
      associated cutaneous lesions, although the expression did not reveal a
      significant deviation from that in normal skin. CONCLUSION: These findings
      indicate a discordant expression of bcl-2/ bcl-x and bax proteins in HPV
      associated skin lesions and suggest that low-risk HPVs mediate other pathways
      that bypass the action of anti-apoptotic bcl-2 and bcl-x proteins. The presence
      of bax expression with a prominent decrease in bcl-2/ bax ratio and the lack of
      massive apoptosis in HPV-associated benign epithelial lesions may imply that
      interference with the pro-apoptotic proteins of bcl-family may constitute one of
      the several mechanisms mediated by HPV oncoproteins for the suppression of
      apoptotic process.

PMID- 15024193
TI  - Primary cutaneous immunocytoma/marginal zone B-cell lymphoma: a case with unusual
      course.
AB  - Although primary cutaneous immunocytoma/marginal zone B-cell lymphoma (PCI/MZBL)
      is considered as an indolent lymphoma with excellent prognosis, extracutaneous
      spread and even death due to disseminated disease have been reported. This is a
      case report of a PCI/MZBL showing dissemination to the regional lymph node and
      bone marrow, 22 months after the initial diagnosis. Furthermore, in the lymph
      node, there were focal areas of high-grade transformation. On the other hand, the
      bone marrow involvement displayed low-grade morphology. We suggest that it should
      be kept in mind that there is still a possibility of systemic involvement in
      PCI/MZBL.

PMID- 15024195
TI  - Histological features of kaposi sarcoma in a patient receiving highly active
      antiviral therapy.
AB  - The introduction of highly active anti-retroviral therapy (HAART) has changed the
      clinical presentation of skin diseases in patients with the Acquired Immune
      Deficiency Syndrome (AIDS). This occurs as a consequence of a newly recognized
      effect of this therapy known as the "Immune Reconstitution Syndrome," which
      develops with improvement of immunity. One manifestation of this syndrome is
      alteration of the natural history of Kaposi sarcoma (KS). While there are
      multiple reports of KS regression during HAART, there is little documentation of
      the histologic changes that occur. We present the case of a 55-year-old
      homosexual male with KS for over 4 years who underwent 6 biopsies over a 3-year
      period before, during, and after HAART. Kaposi sarcoma lesions prior to HAART
      were multinodular with ill-defined borders clinically and demonstrated typical
      features of nodular stage KS histologically. After initiation of HAART in this
      patient, lesions became uninodular, well circumscribed, and histologically were
      noted to be less cellular and surrounded by a dense fibrotic stroma. Although the
      mechanisms for these histologic changes are not clear, it may be due to activity
      of HAART against human herpesvirus type 8 (HHV-8), the causative agent of KS, to
      reconstitution of immunity due to diminution in HIV viral load, or both.

PMID- 15024194
TI  - Adult onset folliculocentric langerhans cell histiocytosis confined to the scalp.
AB  - Langerhans cell histiocytosis (LCH) is a pleomorphic disease entity characterized
      by local or disseminated atypical Langerhans cells found most commonly in bone,
      lungs, mucocutaneous structures, and endocrine organs. Cutaneous disease occurs
      in approximately one quarter of all cases. Cutaneous findings include soft-tissue
      swelling, eczematous changes, a seborrheic dermatitis-like appearance, and
      ulceration. We report a rare case of LCH confined to the scalp with
      folliculocentric infiltrates. This 32-year-old male patient presented with
      follicularly based erythema, scale, and pustules unresponsive to topicals and
      oral antibiotics. The patient's lesions mimicked lichen planopilaris and
      folliculitis decalvans during the disease process. On hematoxylin and eosin
      stain, scalp biopsy showed a perivascular interstitial patchy lichenoid
      mononuclear cell infiltrate that focally abutted follicular infundibula.
      Prominent mononuclear cells having reniform nuclei were present, and
      immunoperoxidase stains for CD1a confirmed Langerhans cell differentiation.
      Serological and imaging workup failed to display systemic involvement.

PMID- 15024196
TI  - Lymphomatoid papulosis histopathologically simulating angiocentric and cytotoxic
      T-cell lymphoma: a case report.
AB  - We report a patient presenting with a 20-year history of recurrent papulonecrotic
      lesions in which skin biopsy shows extensive vascular destruction. Atypical
      lymphoid cells surrounding the dermal vessels had a CD3+, CD4-, CD5-, CD8+, CD20
      , CD30+, CD56+, TIA-1+, and granzyme B immunophenotype implicating a natural
      killer/T origin. In situ hybridization was negative for Epstein-Barr virus
      transcripts. Analysis of T-cell receptor-gamma gene of 2 separate biopsy
      specimens detected an identical clone. The patient was treated with low-dose
      methotrexate and achieved complete resolution in a month. According to the
      clinical course, immunophenotype, clonality analysis and the excellent response
      to methotrexate, we conclude that this is an unusual case of lymphomatoid
      papulosis. We believe that this unusual presentation needs to be distinguished
      from other aggressive lymphomas, including the natural killer/T-cell and
      cytotoxic T-cell subsets.

PMID- 15024198
TI  - The findings do not conform precisely: fibrosing sarcoidal expressions of
      panniculitis as example.

PMID- 15024197
TI  - Cutaneous and subcutaneous fibrohistiocytic tumors of intermediate malignancy: an
      update.
AB  - The fibrohistiocytic tumors of intermediate malignancy are uncommon mesenchymal
      tumors, which typically occur in the skin and subcutis and which may pose
      significant problems for the dermatopathologist. This article reviews the
      clinical, histopathologic, and genetic features of dermatofibrosarcoma
      protuberans, giant cell fibroblastoma, angiomatoid (malignant) fibrous
      histiocytoma, plexiform fibrous histiocytoma, and soft tissue giant cell tumor
      (of low malignant potential). The differential diagnosis of these tumors with a
      variety of benign and fully malignant cutaneous soft tissue neoplasms is
      discussed.

PMID- 15024199
TI  - A progressive papular eruption on the chest and back.

PMID- 15024200
TI  - Alopecia mucinosa, inflammatory disease or mycosis fungoides: must we choose? And
      are there other choices?

PMID- 15024201
TI  - Argyrophilic staining of nucleolar organizer region count and morphometry in
      benign and malignant melanocytic lesions.

PMID- 15024203
TI  - Lessons from lumps.

PMID- 15024205
TI  - Memorable medical mentors: III. Howard Atwood Kelly (1858-1943).

PMID- 15024206
TI  - A guest editorial: Women's health care in correctional facilities: a lost colony.

PMID- 15024227
TI  - Female genital cutting: clinical and cultural guidelines.
AB  - Clinical guidelines for managing women who have undergone female genital cutting
      are essential in providing appropriate and culturally competent care. The
      objectives of this study were to review the literature, describe the types of
      female genital cutting, evaluate its immediate and long-term complications, and
      provide clinical guidelines for managing women who have undergone this procedure.
      We conducted an extensive literature search on the MEDLINE database (1966-2003)
      for articles pertaining to female circumcision/genital mutilation/cutting. The
      search was extended further by citations in these journals not identified in
      MEDLINE. National and international nongovernmental organizations provided
      articles not available in American libraries. The author has developed guidelines
      based on personal experience and recommendations from the literature. The major
      inclusion criteria limited the search to: 1) English language, 2) medical
      journals, 3) WHO publications, 4) medical society publications, 5) case studies
      and statistical data on medical complications, 6) infertility and sexual issues,
      7) U.S. legal practice, and 8) deinfibulation. The exclusion criteria pertained
      to articles: 1) reviewing the literature, 2) lacking epidemiologic data, 3)
      addressing political and ethical issues, and 4) discussing international
      concerns. Immediate complications include hemorrhage, infection, urinary
      dysfunction, shock, or death. Long-term complications include urinary
      complications, scarring, pain, infection, and infertility. Obstetric
      complications include lacerations, wound infections, postpartum hemorrhage, and
      sepsis. Fetal complications are rarely seen in Western countries. Women who have
      undergone female genital cutting can experience complications. Practitioners must
      recognize the type of circumcision, ensure cultural competency, and provide
      appropriate clinical care.

PMID- 15024228
TI  - Does hysteroscopy produce intraperitoneal spread of endometrial cancer cells?
AB  - Hysteroscopy is the tool of choice for the evaluation of the endometrial cavity,
      including the assessment of abnormal uterine bleeding (AUB). The combination of
      endometrial biopsy and diagnostic hysteroscopy could replace dilation and
      curettage in most patients. However, hysteroscopy might disseminate endometrial
      cells into the peritoneum, thereby potentially raising the stage and decreasing
      the survival of a patient with endometrial cancer. The purpose of this article is
      to explore the dilemma of whether hysteroscopy produces intraperitoneal spread of
      endometrial cancer cells, and, if the answer is yes, what is the prognostic
      significance of isolated malignant cells in the peritoneal cavity. We conducted a
      literature search using MEDLINE using the following key words: hysteroscopy,
      endometrial carcinoma, and dissemination for the years 1980 through 2001.
      Retrospective data shows a correlation between fluid-based hysteroscopy and the
      presence of cancer cells in the peritoneal cavity. It cannot, however, be
      determined whether positive peritoneal washings are the result of hysteroscopy or
      whether the endometrial cells are found in the peritoneum as a result of other
      mechanism. Because no prospective, randomized studies have been performed on the
      dissemination of cancer cells by diagnostic hysteroscopy, no definite conclusions
      can be made concerning the risk of diagnostic hysteroscopy. In addition, the
      prognostic significance of isolated malignant cells in the peritoneal cavity of
      women with endometrial cancer is unclear. Although there might be an increased
      risk of peritoneal contamination by cancer cells after hysteroscopy, there is
      currently no evidence that these patients face worse prognosis than patients who
      have undergone other diagnostic procedures.

PMID- 15024229
TI  - Management of single fetal demise in a multiple gestation.
AB  - Intrauterine fetal demise of 1 twin in a multiple gestation is a complex clinical
      situation. Chorionicity, gestational age at diagnosis, problems specific to the
      pregnancy, and the emotional needs of the patient can impact management.
      Strategies to optimize outcomes may include a multidisciplinary team approach and
      fetal surveillance. The following article reviews (1) adverse fetal and neonatal
      outcomes associated with intrauterine fetal demise of 1 twin, (2) the potential
      maternal impact, and (3) the strategies to possibly prevent poor outcomes. It is
      important to remember that even the most vigilant care may not avoid adverse
      sequelae in a portion of at-risk pregnancies.

PMID- 15024230
TI  - Effect of total abdominal hysterectomy on pelvic floor function.
AB  - Historically, hysterectomy is one of the oldest gynecologic operations, dating
      back to the 1840s. Currently, it is the most common gynecologic operation
      performed and is associated with marked improvement in the patients' quality of
      life. It is widely considered a safe procedure with an extremely low mortality
      rate (<0.1%). The majority of hysterectomies are done abdominally, with the vast
      majority being total abdominal hysterectomies. The effect of hysterectomy on
      pelvic floor function has been a subject of long debate. Various studies have
      reached different and rather contradictory results. Most of these studies lack
      stringent methodologic standards, being retrospective, observational, or
      uncontrolled. A recent excellent study assessed the effect of abdominal
      hysterectomy on pelvic floor function as 1 functional unit and concluded that
      both total and subtotal abdominal hysterectomies have no detrimental effect on
      the pelvic floor function up to 1 year postoperatively.

PMID- 15024235
TI  - Leadership and retention: research needed.

PMID- 15024236
TI  - Making a case for shared accountability.

PMID- 15024238
TI  - The "new age" of union organizing.

PMID- 15024237
TI  - Integrating research: into daily nursing practice.

PMID- 15024239
TI  - Licensed caregiver characteristics and staffing in California acute care hospital
      units.
AB  - PURPOSE: Concerns about declining quality of care and nurse staffing shortages
      led to legislation mandating minimum nurse-to-patient ratios in the state of
      California. Although research finds that better registered nurse (RN) staffing
      results in higher quality of care, little evidence exists on which to base
      specific nurse-patient ratios. The authors describe the results of a California
      survey characterizing licensed caregivers, identifying staffing levels by unit
      type, and describing how staffing levels vary across hospital types. METHODS: A
      stratified random sample of general acute care hospitals was surveyed to collect
      cross-sectional data on hospitals' nursing workforce and staffing practices and
      to assess the impact of potential patient-to-nurse staffing ratios. All academic
      medical centers; rural, private, and city/county hospitals; and hospitals
      affiliated with a large group-model health maintenance organization (HMO) were
      eligible for inclusion. RESULTS: Eighty hospitals were surveyed, representing all
      major metropolitan areas in the state. Acute care hospitals in California have
      diverse nursing staffs with variations in education, experience, and employment
      status. Considerable variations in skill mix were identified, with the proportion
      of RNs ranging from 30% to 84%, depending on the unit type surveyed. CONCLUSIONS:
      As states struggle with an anticipated critical shortage of RNs, these results
      have several implications for health and education policy. Future studies of this
      type will be needed to evaluate the impact of anticipated changes in the
      regulation of nurse staffing.

PMID- 15024240
TI  - Amplifying nursing's voice through a staff-management partnership.
AB  - Recommendations to decrease the nursing shortage often identify the need to
      strengthen nurses' autonomy and control in hospitals but do not describe specific
      mechanisms to accomplish this goal. The Nurse Practices Committee provides a
      forum for staff nurses and nurse executives at Robert Wood Johnson University
      Hospital to jointly make decisions about resource allocation. Committee members
      agree that this work has strengthened relationships by fostering mutual
      understanding, respect, and trust. As a result, nursing management and staff
      partners can advocate for patients and nurses with a single, more powerful voice.

PMID- 15024241
TI  - Decreasing turnaround time between general surgery cases: a six sigma initiative.
AB  - A major problem in the operating room is the length of turnaround time between
      surgical cases. By decreasing this turnaround, staff overtime can be reduced and
      more cases can be scheduled during the day shift. In an era when cost cutting for
      hospitals is vital to maintain an operating margin, solving this problem is
      crucial. In addition, this can be a great satisfier for surgeons who can increase
      their daily workload in a more orderly, organized manner. To achieve our goal of
      decreasing turnaround time in the operating room, the authors review the
      implementation and outcomes of the application of Six Sigma.

PMID- 15024242
TI  - Key ethical issues encountered in healthcare organizations: the perceptions of
      staff nurses and nurse leaders.
AB  - The authors compare the results of a May 2002 ethics issues survey of staff
      nurses who are members of the American Nurses Association (ANA) with those of a
      February 2000 survey of American Organization of Nurse Executives (AONE) nurse
      leaders. The findings reveal a common set of key ethical issues that result from
      the ineffective management of the conflict between clinical ethics and
      organizational ethics. Implications for healthcare professionals and the
      organizations that employ them are discussed.

PMID- 15024243
TI  - Preventing workplace violence from negligent hiring in healthcare.
AB  - Negligent hiring is emerging as one of the prime causes of healthcare employer
      liability for workplace violence. Healthcare administrators have been found
      liable for violent acts of employees both within and outside their normal scope
      of employment. The authors discuss negligent hiring doctrine and what the US
      courts have decided on negligent hiring cases. The discussion shows how liability
      in healthcare institutions can occur, and how the respondeat superior doctrine
      may no longer serve to limit employer liability. The authors suggest how to
      develop screening practices to reduce work-place violence and minimize negligent
      hiring lawsuits.

PMID- 15024268
TI  - Functional anatomy of the pelvic floor and lower urinary tract.

PMID- 15024269
TI  - Physiology of the lower urinary tract.

PMID- 15024270
TI  - Pathophysiology of the lower urinary tract: continence and incontinence.

PMID- 15024271
TI  - Epidemiology of lower urinary tract dysfunction.

PMID- 15024272
TI  - Clinical evaluation of women with lower urinary tract dysfunction.

PMID- 15024273
TI  - Testing in women with lower urinary tract dysfunction.

PMID- 15024274
TI  - Nonsurgical treatment of urinary incontinence.

PMID- 15024275
TI  - Pharmacologic therapy of lower urinary tract dysfunction.

PMID- 15024276
TI  - Surgical management of stress urinary incontinence.

PMID- 15024277
TI  - Research frontiers in the treatment of urinary incontinence.

PMID- 15024280
TI  - The rise in multiple births in the United States: who, what, when, where, and
      why.

PMID- 15024281
TI  - Outcomes of multifetal pregnancy reductions.

PMID- 15024282
TI  - Improving multiple pregnancy outcomes with nutritional interventions.

PMID- 15024283
TI  - Diagnosis and management of obstetrical complications unique to multiple
      gestations.

PMID- 15024284
TI  - The twin-twin transfusion syndrome.

PMID- 15024285
TI  - Prediction and prevention of preterm delivery in multiple gestations.

PMID- 15024286
TI  - Treatment of preterm labor in multiple gestations.

PMID- 15024287
TI  - Maternal complications associated with multiple pregnancy.

PMID- 15024288
TI  - Timing of delivery in multiple gestation.

PMID- 15024289
TI  - Intrapartum management of twins.

PMID- 15024290
TI  - Antenatal care for women with multiple pregnancies: the Liverpool approach.

PMID- 15024294
TI  - What is the role of biventricular pacing the transplant candidate?

PMID- 15024295
TI  - Destination therapy in late-stage heart failure.

PMID- 15024296
TI  - Surgical ventricular restoration: reshaping the adversely remodeled left
      ventricle.

PMID- 15024297
TI  - Cardiac xenotransplantation.

PMID- 15024298
TI  - Predictors of left ventricular thrombus formation in patients with dilated
      cardiomyopathy: role of activated protein C resistance.
AB  - OBJECTIVES: The aim of this study was to investigate the association between left
      ventricular thrombus formation and natural anticoagulant systems including the
      protein C, protein S and antithrombin in patients with dilated cardiomyopathy.
      MATERIALS AND METHODS: Sixty patients with dilated cardiomyopathy who met the
      inclusion criteria were included in the study. Patients were divided into two
      groups: group I consisted of 22 patients with left ventricular thrombus and group
      II consisted of 38 patients without left ventricular thrombus. Our main inclusion
      criteria were ejection fraction </= 35% and left ventricular end-diastolic
      diameter >/= 6.0 cm. These two groups were compared for clinical and hematologic
      parameters (activated protein C resistance, protein S and antithrombin). RESULTS:
      There were no statistically significant differences between patients with or
      without left ventricular thrombi with respect to left ventricular end-diastolic
      and end-systolic dimensions, ejection fraction, fractional shortening and left
      atrial diameter. There were no statistically significant differences between
      patients with and without left ventricular thrombus with respect to platelet
      count (252 +/- 64/mm3 x 10(3) compared with 260 +/- 74/mm3 x 10(3) respectively,
      P=0.68), prothrombin time (12.94 +/- 1.9 s compared with 12.86 +/- 1.3 s
      respectively, P=0.82), activated partial thromboplastin time (32 +/- 5 compared
      with 30 +/- 4 s respectively, P=0.32) and fibrinogen levels (36 +/- 9 mg/dl
      compared with 34 +/- 8 mg/dl respectively, P=0.41). None of the patients had
      protein S and antithrombin deficiency. Activated protein C resistance was found
      in 12 patients (12 out of 22, 54%) in group I and four patients (four out of 38,
      9.5%) in group II (P < 0.01). It was also shown to be an independent predictor of
      left ventricular thrombus (P < 0.05). CONCLUSION: Activated protein C resistance
      is found to be an independent predictor of left ventricular thrombus in patients
      with dilated cardiomyopathy who have ejection fractions less then 35% and left
      ventricular end-diastolic dimensions > 6.0 cm.

PMID- 15024299
TI  - Canadian Cardiovascular Society classification of effort angina: an angiographic
      correlation.
AB  - BACKGROUND: The Canadian Cardiovascular Society classification (CCSC) remains the
      standard for grading angina in patients with chronic stable angina. The utility
      value of this angina grading system in predicting the severity of coronary artery
      disease is not clear. AIM: We studied the relationship between the clinical
      angina grade and the angiographic severity of underlying coronary artery disease.
      MATERIALS AND METHODS: The participants in the study were 493 patients with
      stable angina who had undergone coronary angiography from 1998 to 2001. They were
      grouped according to their anginal grading and the number of vessels diseased.
      Significant lesions were defined as 50% narrowing for the left main and 70% for
      the left and right coronaries and their major branches. STATISTICAL ANALYSIS: The
      chi2-test was used for statistical analysis and a P-value <0.05 was taken as
      significant. RESULTS: There was no significant difference between the four angina
      class patients and the incidence of single-, double- and triple-vessel
      involvement. Class 1 patients had less left main trunk disease than class 4
      patients. Class 3 and 4 patients had significantly fewer normal coronary
      angiograms. CONCLUSIONS: There is generally little correlation between coronary
      artery disease and the CCSC of effort angina except for left main disease.
      Presence or absence of angina rather than the CCSC should indicate the need for
      coronary angiography.

PMID- 15024300
TI  - Rosuvastatin improves the atherogenic and atheroprotective lipid profiles in
      patients with hypertriglyceridemia.
AB  - BACKGROUND: We examined the effects of rosuvastatin treatment on triglyceride
      levels and lipid measures in a parallel-group multicenter trial (4522IL/0035) in
      patients with hypertriglyceridemia (Fredrickson Type IIb or IV). METHODS: After a
      6-week dietary lead-in period while on a National Cholesterol Education Program
      step I diet, 156 patients with fasting triglyceride levels >/= 300 and < 800
      mg/dl were randomized to 6 weeks of double-blinded treatment: once-daily
      rosuvastatin of 5, 10, 20, 40 or 80 mg or placebo. The primary end point was mean
      percentage change from baseline in total serum triglyceride levels at week 6 as
      determined by analysis of variance. RESULTS: Rosuvastatin at all doses produced
      significant mean reductions in triglycerides compared with placebo (-18 to -40
      compared with +2.9%, P </= 0.001); median reductions in triglycerides with
      rosuvastatin at 5-80 mg ranged from -21 to -46%. All doses of rosuvastatin
      significantly reduced levels of atherogenic lipoprotein and apolipoproteins over
      placebo, including low-density lipoprotein cholesterol, total cholesterol, non
      high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol,
      apolipoprotein B and apolipoprotein C-III. Statistically significant increases in
      high-density lipoprotein cholesterol were observed with rosuvastatin doses > 5
      mg. The occurrence of adverse events was generally low and not dose related,
      although some adverse events occurred more frequently in the rosuvastatin 80 mg
      group. CONCLUSIONS: Rosuvastatin reduced triglyceride levels and improved the
      overall atherogenic and atheroprotective lipid profiles in hypertriglyceridemic
      patients.

PMID- 15024301
TI  - Bibliography. Current world literature.

PMID- 15024302
TI  - Laparoscopic versus open gastric bypass in the treatment of morbid obesity: a
      randomized prospective study.
AB  - OBJECTIVE: The objective of the study was to compare the results of open versus
      laparoscopic gastric bypass in the treatment of morbid obesity. SUMMARY
      BACKGROUND DATA: Gastric bypass is one of the most commonly acknowledged surgical
      techniques for the management of morbid obesity. It is usually performed as an
      open surgery procedure, although now some groups perform it via the laparoscopic
      approach. PATIENTS AND METHODS: Between June 1999 and January 2002 we conducted a
      randomized prospective study in 104 patients diagnosed with morbid obesity. The
      patients were divided into 2 groups: 1 group with gastric bypass via the open
      approach (OGBP) comprising 51 patients, and 1 group with gastric bypass via the
      laparoscopic approach (LGBP) comprising 53 patients. The parameters compared were
      as follows: operating time, intraoperative complications, early (<30 days) and
      late (>30 days) postoperative complications, hospital stay, and short-term
      evolution of body mass index. RESULTS: Mean operating time was 186.4 minutes (125
      290) in the LGBP group and 201.7 minutes (129-310) in the OGBP group (P < 0.05).
      Conversion to laparotomy was necessary in 8% of the LGBP patients. Early
      postoperative complications (<30 days) occurred in 22.6% of the LGBP group
      compared with 29.4% of the OGBP group, with no significant differences. Late
      complications (>30 days) occurred in 11% of the LGBP group compared with 24% of
      the OGBP group (P < 0.05). The differences observed between the 2 groups are the
      result of a high incidence of abdominal wall hernias in the OGBP group. Mean
      hospital stay was 5.2 days (1-13) in the LGBP group and 7.9 days (2-28) in the
      OGBP group (P < 0.05). Evolution of body mass index during a mean follow-up of 23
      months was similar in both groups. CONCLUSIONS: LGBP is a good surgical technique
      for the management of morbid obesity and has clear advantages over OGBP, such as
      a reduction in abdominal wall complications and a shorter hospital stay. The
      midterm weight loss is similar with both techniques. One inconvenience is that
      LGBP has a more complex learning curve than other advanced laparoscopic
      techniques, which may be associated with an increase in postoperative
      complications.

PMID- 15024303
TI  - Laparoscopic verses open gastric bypass to treat morbid obesity.

PMID- 15024304
TI  - Learning curve for radiofrequency ablation of liver tumors: prospective analysis
      of initial 100 patients in a tertiary institution.
AB  - OBJECTIVE: This study aims to evaluate the effect of operator experience on the
      treatment outcomes of radiofrequency ablation (RFA) for malignant liver tumors.
      SUMMARY BACKGROUND DATA: RFA is gaining popularity as the ablative therapy of
      choice for liver tumors. It is generally considered a simple and safe technique,
      and little attention has been paid to the importance of operator experience in
      this treatment. A learning curve in this treatment modality has not been
      documented before. PATIENTS AND METHODS: The clinical data and treatment outcomes
      of the initial 100 patients undergoing RFA for liver tumors (hepatocellular
      carcinoma, n = 84; metastasis, n = 15; cholangiocarcinoma n = 1) were collected
      prospectively. All patients were managed by a single team of surgeons and
      interventional radiologists. The data of the first 50 patients (group I) and the
      second 50 patients (group II) were compared. RESULTS: RFA was performed by
      percutaneous (group I, n = 22; group II, n = 19), open (group I, n = 26; group
      II, n = 30) or laparoscopic (group I, n = 2; group II, n = 1) approach. In group
      I, 30 patients (60%) had a solitary tumor and 20 (40%) had multiple tumors; in
      group II, 35 patients (70%) had a solitary tumor and 15 (30%) had multiple tumors
      (P = 0.295). The size of the largest tumor was comparable between groups I and II
      (median, 2.8 cm in both groups; P = 0.508). Group II had significantly shorter
      hospital stay (median, 4.0 versus 5.5 days; P = 0.048), lower morbidity rate (4%
      versus 16%; P = 0.046) and higher complete ablation rate (100% versus 85.7%; P =
      0.006) than group I. There was 1 hospital death (2%) in group I and 0 in group
      II. By multivariate analysis, treatment period (group I versus group II) was an
      independent significant factor affecting the morbidity rate and complete ablation
      rate. CONCLUSIONS: A low complication rate and a high complete ablation rate
      could be achieved with the accumulated experience from the first 50 cases of RFA
      for liver tumors by a specialized team. This study demonstrates that there is a
      significant learning curve in RFA for liver tumors.

PMID- 15024305
TI  - Early and late complications after radiofrequency ablation of malignant liver
      tumors in 608 patients.
AB  - BACKGROUND: Radiofrequency ablation (RFA) has become a common treatment of
      patients with unresectable primary and secondary hepatic malignancies. We
      performed this prospective analysis to determine early (within 30 days) and late
      (more than 30 days after) complication rates associated with hepatic tumor RFA.
      METHODS: All patients treated between January 1, 1996 and June 30, 2002 with RFA
      for hepatic malignancies were entered into a prospective database. Patients were
      evaluated during RFA treatment, throughout the immediate post RFA course, and
      then every 3 months after RFA to assess for the development of treatment-related
      complications. RESULTS: A total of 608 patients, 345 men (56.7%) and 263 women
      (43.3%), with a median age of 58 years (range 18-85 years) underwent RFA of 1225
      malignant liver tumors. Open intraoperative RFA was performed in 382 patients
      (62.8%), while percutaneous RFA was performed in 226 (37.2%). The treatment
      related mortality rate was 0.5%. Early complications developed in 43 patients
      (7.1%). Early complications were more likely to occur in patients treated with
      open RFA (33 [8.6%] of 382 patients) compared with percutaneous RFA (10 [4.4%]
      226 patients, P < 0.01), and in patients with cirrhosis (25 [12.9%] complications
      in 194 patients) compared with noncirrhotic patients (31 [7.5%] complications in
      414 patients, P < 0.05). Late complications arose in 15 patients (2.4%) with no
      difference in incidence between open and percutaneous RFA treatment. The combined
      overall early and late complication rate was 9.5%. CONCLUSIONS: Hepatic tumor RFA
      can be performed with low mortality and morbidity rates. Though relatively rare,
      late complications can develop and physicians performing hepatic RFA must be
      cognizant of these delayed treatment-related problems.

PMID- 15024306
TI  - Minimizing complications with radiofrequency ablation for liver cancer: the
      importance of properly controlled clinical trials and standardized reporting.

PMID- 15024308
TI  - Systems approaches to surgical quality and safety: from concept to measurement.
AB  - OBJECTIVE: This approach provides the basis of our research program, which aims
      to expand operative assessment beyond patient factors and the technical skills of
      the surgeon; to extend assessment of surgical skills beyond bench models to the
      operating theater; to provide a basis for assessing interventions; and to provide
      a deeper understanding of surgical outcomes. SUMMARY BACKGROUND DATA: Research
      into surgical outcomes has primarily focused on the role of patient
      pathophysiological risk factors and on the skills of the individual surgeon.
      However, this approach neglects a wide range of factors that have been found to
      be of important in achieving safe, high-quality performance in other high-risk
      environments. The outcome of surgery is also dependent on the quality of care
      received throughout the patient's stay in hospital and the performance of a
      considerable number of health professionals, all of whom are influenced by the
      environment in which they work. METHODS: Drawing on the wider literature on
      safety and quality in healthcare, and recent papers on surgery, this article
      argues for a much wider assessment of factors that may be relevant to surgical
      outcome. In particular, we suggest the development of an "operation profile" to
      capture all the salient features of a surgical operation, including such factors
      as equipment design and use, communication, team coordination, factors affecting
      individual performance, and the working environment. Methods of assessing such
      factors are outlined, and ethical issues and other potential concerns are
      discussed.

PMID- 15024309
TI  - Improved survival for patients with upper and/or middle mediastinal lymph node
      metastasis of squamous cell carcinoma of the lower thoracic esophagus treated
      with 3-field dissection.
AB  - OBJECTIVE: To evaluate the outcomes with 2 and 3 lymph node dissection for
      patients with squamous cell carcinoma of the lower thoracic esophagus at a single
      institution. BACKGROUND: Extensive lymph node dissection, including the upper
      mediastinum, for carcinoma of the lower thoracic esophagus is advocated as a
      standard surgical procedure with curative intent in Japan. However, its efficacy
      remains controversial. METHODS: From January 1988 to December 1997, 532 patients
      with carcinomas of the thoracic esophagus underwent transthoracic esophagectomy
      and extensive lymph node dissection with curative intent at the National Cancer
      Center Hospital, Tokyo. Of these, 495 (93%) had squamous cell carcinomas. A total
      of 156 (29%) with tumors of the lower thoracic esophagus were retrospectively
      analyzed. RESULTS: Of the 156 patients, 55 (35%) underwent 2-field and 101 (65%)
      underwent 3-field lymph node dissection. The operative morbidity and 30-day and
      in-hospital mortality rates were 68.0%, 1.3%, and 2.6%, respectively. The overall
      5-year survival rate for the entire series was 49.3%. One hundred and seven (69%)
      had lymph node metastases. Upper and/or middle mediastinal lymph node metastases
      occurred in 42% of the series. The 5-year survival rate for patients with lymph
      node metastases in the upper and/or middle mediastinum was 23.3%. Among them, the
      values after 2- and 3-field lymph node dissection were 5.6% and 30.0%,
      respectively (P = 0.005). Thirteen (27%) of 48 patients with upper and/or middle
      mediastinal lymph node metastases treated with 3-field dissection had
      simultaneous cervical lymph node metastases and their 5-year survival rate was
      23.1%. CONCLUSION: The 3-field approach for extensive lymph node dissection
      provides better survival benefit for patients with squamous cell carcinoma of the
      lower thoracic esophagus compared to 2-field lymph node dissection when lymph
      node metastases are present in the upper and/or middle mediastinum.

PMID- 15024307
TI  - Ghrelin: integrative neuroendocrine peptide in health and disease.
AB  - OBJECTIVE: Ghrelin is a novel gastric hormone recognized in 1999 as a mediator of
      growth hormone release. Since growth hormone is anabolic, an important function
      of ghrelin may be to coordinate energy needs with the growth process. Newly
      discovered biologic roles of ghrelin imply that it may have other important
      physiological functions as well. This is a review of recent clinically relevant,
      yet less well-known, physiologic actions of ghrelin. SUMMARY BACKGROUND DATA:
      Ghrelin has profound orexigenic, adipogenic, and somatotrophic properties,
      increasing food intake and body weight. Secreted predominantly from the stomach,
      ghrelin is the natural ligand for the growth hormone secretagogue receptor in the
      pituitary gland, thus fulfilling criteria of a brain-gut peptide. The brain-gut
      axis is the effector of anabolism by regulating growth, feeding, and metabolism
      via vagal afferents mediating ghrelin signaling. However, the wide tissue
      distribution of ghrelin suggests that it may have other functions as well.
      METHODS: Systematic literature review of all PubMed citations between 1999 and
      August 2003 focusing on clinically relevant biochemical and physiological
      characteristics of ghrelin. RESULTS: Ghrelin is an important component of an
      integrated regulatory system of growth and metabolism acting via the vagus nerve,
      and is implicated in a variety of altered energy states such as obesity, eating
      disorders, neoplasia, and cachexia. It also enhances immune responses and
      potentially down-regulates anti-inflammatory molecules. Ghrelin's role as a brain
      gut peptide emphasizes the significance of afferent vagal fibers as a major
      pathway to the brain, serving the purpose of maintaining physiologic homeostasis.
      CONCLUSIONS: The discovery of ghrelin has increased our understanding of feeding
      regulation, nutritional homeostasis, and metabolic processes. Further
      characterization of ghrelin's functions will likely generate new pharmacological
      approaches to diagnose and treat different disease entities including those
      related to the over-nutrition of obesity and the catabolic response to surgical
      trauma.

PMID- 15024310
TI  - NF-kappaB activation in esophageal adenocarcinoma: relationship to Barrett's
      metaplasia, survival, and response to neoadjuvant chemoradiotherapy.
AB  - OBJECTIVE: To examine the expression of the transcription factor nuclear factor
      kappa B (NF-kappaB) in Barrett's epithelium and adenocarcinoma and the impact of
      NF-kappaB expression on tumor stage and response to neoadjuvant chemotherapy and
      radiation therapy. SUMMARY BACKGROUND DATA: Progression of Barrett's esophagus to
      adenocarcinoma is associated with a wide range of cellular and molecular
      abnormalities. Nuclear factor-kappa B (NF-kappaB) regulates several genes
      involved in inflammatory, immune and apoptotic responses, but its role in
      esophageal inflammation and tumorigenesis has not been reported. METHODS:
      Mobility shift assay was used to measure NF-kappaB activity in nuclear extracts
      of fresh-frozen biopsies from tumor and uninvolved tissues (n = 30) and
      esophageal cell lines OE33, SKGT-4, and OE21. RelA expression was assessed by
      immunohistochemical staining (n = 97). The NF-kappaB/RelA and IkappaB protein
      expressions were also examined by Western blotting. RESULTS: NF-kappaB was not
      expressed in normal esophageal squamous epithelium, in contrast to increased
      expression in 40% of patients with Barrett's epithelium. Sixty-one percent of
      resected tumors (n = 97) displayed NF-kappaB immunoreactivity, and 87.5% of the
      NF-kappaB-positive tumors were Stage IIb and III compared with only 12.5% of
      patients with Stage I and IIa disease (P < 0.05). The expression of NF-kappaB
      inversely correlated with major or complete pathologic responses to neoadjuvant
      chemotherapy and radiation therapy, with 15/20 (75%) responders in the NF-kappaB
      negative group compared with 7/38 (18%) in the NF-kappaB-positive group (P <
      0.00001). Moreover, incubation of esophageal cell lines OE33, SKGT-4, and OE21
      with deoxycholic acid or low pH induced NF-kappaB expression. CONCLUSIONS: Bile
      acids and low pH induce NF-kappaB expression in esophageal cell lines. NF-kappaB
      activation is common in esophageal adenocarcinoma. In patients with Barrett's
      epithelium and an associated esophageal adenocarcinoma, there is a progressive
      expression of NF-kappaB through Barrett's tumorigenesis. The absence of NF-kappaB
      expression in esophageal adenocarcinoma correlates with response to neoadjuvant
      chemoradiotherapy and may be of value in predicting response to neoadjuvant
      therapy.

PMID- 15024311
TI  - Lipopolysaccharide-induced changes in rat gastric H/K-ATPase expression.
AB  - OBJECTIVE: To evaluate lipopolysaccharide (LPS)-induced inhibition of gastric
      acid secretion. SUMMARY BACKGROUND DATA: Endotoxemia from LPS inhibits gastric
      acid secretion by an unknown mechanism. Bacterial overgrowth in the stomach
      caused by decreased acid secretion could be responsible for nosocomial pneumonia
      developing in critically ill intensive care unit patients. Because acid secretion
      is via the H/K-ATPase and the effects of LPS on this enzyme are unknown, we
      hypothesized that LPS causes inhibition of gastric acid secretion by down
      regulating the H/K-ATPase. METHODS: A rat model to study gastric acid secretion
      was created. Saline or LPS (0.05-20 mg/kg IP) was given for 1 hour, after which
      basal acid secretion was determined for 1 hour. Pentagastrin (PG; 10 microg/kg
      IV) or saline was then given and gastric acid output collected for another 2
      hours. RESULTS: LPS dose dependently inhibited basal and PG stimulated acid
      secretion. LPS increased alpha- and beta-H/K-ATPase subunit mRNA expression
      (Northern blot) in the absence of PG compared with saline. In the presence of PG,
      LPS did not have this effect. Western blot analysis did not show any difference
      in alpha- or beta-subunit immunoreactivity. Immunofluorescence analysis
      demonstrated that PG increased staining in the secretory membranes for H/K-ATPase
      subunits whereas in all LPS-treated rats, it appeared that H/K-ATPase subunits
      remained within the tubulovesicles. Furthermore, changes in H/K-ATPase mRNA
      expression may not be related to changes in NF-kappaB activity. CONCLUSIONS:
      These data suggest that inhibition of gastric acid secretion by LPS is due to
      inhibition of H/K-ATPase enzymatic function or changes in cytoskeletal
      rearrangements in H/K-ATPase subunits rather than by down-regulation of
      transcriptional or translational events.

PMID- 15024312
TI  - The value of bile replacement during external biliary drainage: an analysis of
      intestinal permeability, integrity, and microflora.
AB  - OBJECTIVE: To investigate the effect of bile replacement following percutaneous
      transhepatic biliary drainage, ie, external drainage, on intestinal permeability,
      integrity, and microflora in a clinical setting. SUMMARY BACKGROUND DATA: Several
      authors have reported that internal biliary drainage is superior to external
      drainage. However, it is unclear whether bile replacement following external
      drainage is beneficial. METHODS: Twenty-five patients with biliary cancer
      underwent percutaneous transhepatic biliary drainage (PTBD) as a part of
      presurgical management. All externally drained bile was replaced either per os or
      by administration through a nasoduodenal tube. The interval between PTBD and the
      beginning of bile replacement was 21.3 +/- 19.7 days, and the length of bile
      replacement was 20.7 +/- 9.6 days. The lactulose-mannitol test, measurement of
      serum diamine oxidase (DAO) activity, and analyses of fecal microflora and
      organic acids were performed before and after bile replacement. RESULTS: The
      volume of externally drained bile varied widely from patient to patient, ranging
      from 220 +/- 106 mL/d to 1616 +/- 394 mL/d (mean, 714 +/- 346 mL/d). Biliary
      concentrations of bile acids, cholesterol, and phospholipids increased
      significantly after bile replacement. The lactulose-mannitol (L/M) ratio
      decreased from 0.063 +/- 0.060 before bile replacement to 0.038 +/- 0.032 after
      bile replacement (P < 0.05). Serum DAO activity increased from 3.9 +/- 1.4 U/L
      before bile replacement to 5.1 +/- 1.6 U/L after bile replacement (P < 0.005),
      and the magnitude of change in serum DAO activity correlated with the length of
      bile replacement (r = 0.483, P < 0.05). Neither the L/M ratios nor serum DAO
      activities before bile replacement correlated with the interval between PTBD and
      the beginning of bile replacement. Fecal microflora and organic acids were
      unchanged. CONCLUSION: Impaired intestinal barrier function does not recover by
      PTBD without bile replacement. Bile replacement during external biliary drainage
      can restore the intestinal barrier function in patients with biliary obstruction,
      primarily due to repair of physical damage to the intestinal mucosa. Our results
      support the hypothesis that bile replacement during external drainage is
      beneficial.

PMID- 15024313
TI  - Saline-linked surface radiofrequency ablation: factors affecting steam popping
      and depth of injury in the pig liver.
AB  - SUMMARY BACKGROUND DATA: Saline-linked surface radiofrequency (RF) ablation is a
      new technique for applying RF energy to surfaces. The surface is cooled, which
      prevents charring and results in deeper coagulation. However, subsurface heating
      may lead to steam formation and a form of tissue disruption called steam popping.
      We determined parameters that predict steam popping and depth of tissue
      destruction under nonpopping conditions. A commercially available saline-linked
      surface RF cautery device (Floating Ball 3.0, TissueLink, Inc.) was used.
      METHODS: One hundred eighty circular lesions were created varying in lesion
      diameter, duration, power, and inflow occlusion. Variables affecting popping were
      determined. Then factors influencing lesion depth were studied at fixed
      nonpopping diameter/power combinations (1 cm/10W, 2 cm/15W, 4 cm/60W). Tissue
      viability was determined in selected samples by staining of tissue NADH. RESULTS:
      The probability of steam popping was directly related to power level and inflow
      occlusion, and indirectly related to lesion diameter. Depth of injury under safe
      nonpopping conditions was directly related to power, lesion size, and inflow
      occlusion. Maximum depth in excess of 20 mm was achieved using a 4 cm diameter at
      60W with inflow occlusion. Microscopy of NADH-stained tissues showed a complete
      cell killing in the macroscopically visible coagulated area. CONCLUSIONS: Steam
      popping can be avoided by selecting power level/lesion diameter combinations.
      Tissue destruction to 20 mm can be safely achieved with short periods of inflow
      occlusion. The device has promise as a treatment of superficial tumors and close
      resection margins.

PMID- 15024314
TI  - The NIH criteria for parathyroidectomy in asymptomatic primary
      hyperparathyroidism: are they too limited?
AB  - OBJECTIVE: To determine whether preoperative and postoperative symptoms and
      outcome differ in patients who meet or fail to meet the NIH criteria for
      parathyroidectomy. SUMMARY BACKGROUND DATA: The NIH Consensus Conference on
      primary hyperparathyroidism in 1990 defined criteria for surgical intervention
      suggesting that some patients can be safely managed without surgery. METHODS:
      Over a 3-year period, 202 consecutive patients undergoing parathyroidectomy for
      primary hyperparathyroidism at a tertiary referral center were prospectively
      given a questionnaire regarding their symptoms and associated conditions during
      their initial and follow-up office visits as were 63 thyroid control patients.
      The 178 patients who completed the follow-up questionnaire were assigned to 2
      groups according to the NIH criteria for parathyroidectomy. The frequency of
      preoperative symptoms and conditions associated with primary hyperparathyroidism
      as well as postoperative improvement in symptoms and surgical outcome were
      compared. RESULTS: Of the 178 parathyroid patients, 103 met the NIH criteria for
      parathyroidectomy whereas 75 did not. Patient profiles were similar in each group
      except mean ages, 55 versus 65, and preoperative serum calcium levels, 11.5 mg/dL
      versus 11.0 mg/dL (NIH and non-NIH groups, respectively; P < 0.001). The
      incidence of preoperative nonspecific somatic and neuropsychiatric symptoms and
      associated conditions was equivalent in both groups and more common than in the
      63 thyroid control patients. After parathyroidectomy, symptomatic improvement was
      dramatic and equal between the 2 parathyroid groups. Postoperative mean serum
      calcium levels were similar (8.78 mg/dL, NIH group, versus 8.75 mg/dL, non-NIH
      group). CONCLUSION: Symptoms were more common in patients with primary
      hyperparathyroidism versus thyroid controls, but were not different between those
      patients who met the NIH criteria for parathyroidectomy and those who did not.
      Patients in both parathyroid groups benefited symptomatically after successful
      parathyroidectomy.

PMID- 15024315
TI  - Latency period of thyroid neoplasia after radiation exposure.
AB  - OBJECTIVE: To determine the temporal sequence for developing benign and malignant
      thyroid neoplasms after radiation. SUMMARY BACKGROUND DATA: Therapeutic radiation
      is associated with thyroid neoplasms in humans and animals. Some question whether
      thyroid cancers develop de novo or from benign thyroid neoplasms. Little
      information, however, is available concerning the time to development of benign
      and malignant thyroid neoplasms after radiation exposure. METHODS: We
      retrospectively analyzed the records of 171 consecutive patients who had a
      history of exposure to radiation and were treated surgically at University of
      California, San Francisco-affiliated hospitals for thyroid neoplasms between 1960
      and 1999. RESULTS: There were 66 men and 105 women aged 9 to 80 years (mean, 47.0
      years). One hundred patients had benign and 71 had malignant tumors (58 papillary
      cancers, 10 follicular cancers, 1 Hurthle cell cancer, 1 medullary cancer, and 1
      carcinosarcoma). The mean latency period for benign tumors was longer than that
      for malignant lesions (mean, 34.1 and 28.4 years, P = 0.018; median, 38.0 years
      and 30.0 years, P = 0.001). Follicular carcinomas developed sooner (mean, 20.5
      years; median, 20 years) than did follicular adenomas (mean, 35.3 years; median,
      36.5 years; P = 0.003, P = 0.0009). Patients with papillary thyroid cancers
      presenting as occult papillary cancers (<1 cm) and as a dominant nodule had
      similar latency periods (mean, 34.0 and 28.0 years P = 0.29; median, 37.5 and
      30.5 years, P = 0.09), respectively. CONCLUSION: Although there could be
      selection bias regarding referral of patients, our data document that malignant
      thyroid tumors after radiation exposure, including follicular carcinomas, present
      earlier than do benign thyroid tumors. Occult and manifest papillary thyroid
      cancers present at about the same time interval after radiation exposure. Our
      findings question whether benign thyroid neoplasms progress to malignant thyroid
      neoplasms and that most occult thyroid cancers do not progress to malignant
      thyroid cancers in radiation-exposed patients.

PMID- 15024316
TI  - Correlation between preoperative lymphoscintigraphy and metastatic nodal disease
      sites in 362 patients with cutaneous melanomas of the head and neck.
AB  - OBJECTIVE: Lymphoscintigraphy for head and neck melanomas demonstrates a wide
      variation in lymphatic drainage pathways, and sentinel nodes (SNs) are reported
      in sites that are not clinically predicted (discordant). To assess the clinical
      relevance of these discordant node fields, the lymphoscintigrams of patients with
      head and neck melanomas were analyzed and correlated with the sites of metastatic
      nodal disease. METHODS: In 362 patients with head and neck melanomas who
      underwent lymphoscintigraphy, the locations of the SNs were compared with the
      locations of the primary tumors. The SNs were removed and examined in 136
      patients and an elective or therapeutic regional lymph node dissection was
      performed in 40 patients. RESULTS: Lymphoscintigraphy identified a total of 918
      SNs (mean 2.5 per patient). One or more SNs was located in a discordant site in
      114 patients (31.5%). Lymph node metastases developed in 16 patients with
      nonoperated SNs, all underneath the tattoo spots on the skin used to mark the
      position of the SNs. In 14 patients SN biopsy revealed metastatic melanoma. After
      a negative SN biopsy procedure 11 patients developed regional lymph node
      metastases during follow-up. Elective and therapeutic neck dissections
      demonstrated 10 patients with nodal metastases, all located in predicted node
      fields. Of the 51 patients with involved lymph nodes, 7 had positive nodes in
      discordant sites (13.7%). CONCLUSIONS: Metastases from head and neck melanomas
      can occur in any SN demonstrated by lymphoscintigraphy. SNs in discordant as well
      as predicted node fields should be removed and examined to optimize the accuracy
      of staging.

PMID- 15024317
TI  - Insulin treatment improves the systemic inflammatory reaction to severe trauma.
AB  - OBJECTIVE: Determine the effect of insulin on the systemic inflammatory response,
      pro- and anti-inflammatory cytokines and hepatic acute-phase-response in severely
      burned pediatric patients. SUMMARY BACKGROUND DATA: The systemic inflammatory and
      hepatic acute-phase-response contribute to hypermetabolism, multi-organ failure,
      and mortality. Insulin has been recently shown to decrease mortality and to
      prevent the incidence of multi-organ failure in critically ill patients; however,
      the underlying mechanisms have not been defined. METHODS: Thirteen thermally
      injured children received insulin to maintain blood glucose at a range from 120
      to 180 mg/dl, 15 children received no insulin with blood glucose levels also at
      range from 120 to 180 mg/dl and served as controls. Our outcome measures
      encompassed the effect of insulin on pro-inflammatory mediators, the hepatic
      acute-phase-response, fat, and the IGF-I system. RESULTS: Insulin administration
      decreased pro-inflammatory cytokines and proteins, while increasing constitutive
      hepatic proteins (P < 0.05). Burned children receiving insulin required
      significantly less albumin substitution to maintain normal levels compared with
      control (P < 0.05). Insulin decreased free fatty acids and serum triglycerides
      when compared with controls (P < 0.05). Serum IGF-I and IGFBP-3 significantly
      increased with insulin administration (P < 0.05). CONCLUSION: Insulin attenuates
      the inflammatory response by decreasing the pro-inflammatory and increasing the
      anti-inflammatory cascade, thus restoring systemic homeostasis, which has been
      shown critical for organ function and survival in critically ill patients.

PMID- 15024318
TI  - Enhancing the clinical skills of surgical residents through structured cancer
      education.
AB  - OBJECTIVE: To assess the short and long-term educational value of a highly
      structured, interactive Breast Cancer Structured Clinical Instruction Module
      (BCSCIM). SUMMARY BACKGROUND DATA: Cancer education for surgical residents is
      generally unstructured, particularly when compared with surgical curricula like
      the Advanced Trauma Life Support (ATLS) course. METHODS: Forty-eight surgical
      residents were randomly assigned to 1 of 4 groups. Two of the groups received the
      BCSCIM and 2 served as controls. One of the BCSCIM groups and 1 of the control
      groups were administered an 11-problem Objective Structured Clinical Examination
      (OSCE) immediately after the workshop; the other 2 groups were tested with the
      same OSCE 8 months later. The course was an intensive multidisciplinary,
      multistation workshop where residents rotated in pairs from station to station
      interacting with expert faculty members and breast cancer patients. RESULTS:
      Residents who took the BCSCIM outperformed the residents in the control groups
      for each of the 7 performance measures at both the immediate and 8-month test
      times (P < 0.01). Although the residents who took the BCSCIM had higher
      competence ratings than the residents in the control groups, there was a decline
      in the faculty ratings of resident competence from the immediate test to the 8
      month test (P < 0.004). CONCLUSIONS: This interactive patient-based workshop was
      associated with objective evidence of educational benefit as determined by a
      unique method of outcome assessment.

PMID- 15024319
TI  - Digital video capture and synchronous consultation in open surgery.
AB  - OBJECTIVE: To achieve real-time or simultaneous surgical consultation and
      education to students in distant locations, we report the successful integration
      of robotics, video-teleconferencing, and intranet transmission using currently
      available hardware and Internet capabilities. SUMMARY BACKGROUND DATA: Accurate
      visualization of the surgical field with high-resolution video imaging cameras
      such as the closed-coupled device (CCD) of the laparoscope can serve to insure
      clear visual observation of surgery and share the surgical procedure with
      trainees and, or consultants in a distant location. Prior work has successfully
      applied optics and technical advances to achieve precise visualization in
      laparoscopy. METHODS: Twenty-five thyroidectomy explorations in 15 patients were
      monitored and transmitted bidirectionally with audio and video data in real-time.
      Remotely located surgical trainees (n = 4) and medical students (n = 3) confirmed
      7 different anatomic landmarks during each surgical procedure. The study used the
      Socrates System (Computer Motion, Inc. [CMI], Goleta, CA), an interactive
      telementoring system inclusive of a telestration whiteboard, in conjunction with
      the AESOP robotic arm and Hermes voice command system (CMI). A 10-mm flat
      laparoscopic telescope was used to capture the optical surgical field. As voice,
      telestrator, or marker confirmed each anatomic landmark the image parameters of
      resolution, chroma (light position and intensity), and luminance were assessed
      with survey responses. RESULTS: Confirmation of greater than 90% was achieved for
      the majority of relevant anatomic landmarks, which were viewed by the remote
      audience. CONCLUSION: The data presented in this study support the feasibility
      for mentoring and consultation to a remote audience with visual transmission of
      the surgical field, which is otherwise very difficult to share. Additionally,
      validation of technical protocols as teaching tools for robotic instrumentation
      and computer imaging of surgical fields was documented.

PMID- 15024326
TI  - Nonagenarians on a rehabilitation unit: characteristics, progress, and outcomes.
AB  - OBJECTIVE: To determine the diagnostic, functional, and demographic
      characteristics and to review the progress of nonagenarians admitted to a general
      rehabilitation unit. In addition, to compare their outcomes with a selected group
      of younger patients. DESIGN: A 4-yr retrospective chart review of the 40 admitted
      nonagenarians. Functional status was assessed by means of the FIM instrument.
      RESULTS: The most common diagnostic category was hip or femur fracture. Only two
      of the 40 patients required a transfer back to an acute medical unit. Mean FIM
      gain was 14.42 points. Nineteen of the 40 patients were discharged directly to
      their homes. Discharge home was related to younger age, living situation before
      hospitalization, and whether the patient lived alone or with others
      prehospitalization. No admission FIM score was related to discharge disposition.
      Compared with younger hip or femur fracture patients, nonagenarians were more
      likely to be women, be unmarried, not lived at home before admission, and less
      likely to be discharged home. CONCLUSION: The majority of this select group of
      nonagenarians was able to complete a structured program on a rehabilitation unit.
      Their demographic and functional characteristics and long-term outcomes merit
      further study.

PMID- 15024324
TI  - Describing quality of life and psychosocial outcomes after traumatic brain
      injury.
AB  - OBJECTIVE: To describe the quality of life (QOL) and psychosocial outcomes of a
      sample of adults with traumatic brain injury in 50 community dwelling adults with
      traumatic brain injury and examine the associations among these variables.
      DESIGN: Cross-sectional. RESULTS: Mean QOL rating was low average. Standardized
      measures had acceptable internal reliability and normal distributions in this
      sample. Subjects had significantly lower QOL and social support, higher negative
      affect, and similar positive affect and spirituality compared with
      standardization and other nondisabled samples. They also had a significantly
      higher level of community integration than other traumatic brain injury samples.
      Regression analyses suggested that social support, community integration, and
      positive affect make a unique and significant contribution to the QOL variance
      with R of 0.492. The addition of spirituality reduced their respective unique
      variance, reducing positive affect to nonsignificant levels due to their high
      intercorrelation. CONCLUSIONS: Findings suggest that this sample experiences a
      wide range of QOL. Factors significantly associated with good QOL include
      community integration, positive affect, and social support; demographic variables
      had virtually no association with QOL. Evaluation of the sample's response to
      standardized scales not designed for a traumatic brain injury population support
      their use in similar QOL investigations.

PMID- 15024328
TI  - Changes of joint moments in the gait of normal subjects wearing laterally wedged
      insoles.
AB  - OBJECTIVE: The purpose of this study was to assess the kinematic and kinetic
      effects of wearing a laterally wedged insole on the knee joint moment during
      gait, specifically in the frontal plane, in normal healthy adults. DESIGN: Motion
      analyses were conducted with (1) a three-dimensional motion analysis system and
      (2) ground reaction force analysis using force platforms when subjects walked
      under three different insole conditions: no wedge, a low wedge with a 3-degree
      lateral angle, and a high wedge with a 6-degree lateral angle. RESULTS: The high
      wedge insole significantly reduced the knee joint varus moment during gait
      compared with the gait with the no-wedge insole. The actual segment angles at the
      subtalar and knee joints did not show any changes due to insole conditions. In
      contrast, the subtalar joint valgus moment increased for the high-wedge insole.
      This finding was correlated with a greater moment arm of the subtalar joint
      valgus moment with the high-wedge insole. CONCLUSIONS: These results indicate
      that, under dynamic conditions, the subjects wearing laterally wedged insoles had
      both changes of moments at the subtalar and knee joints via the more laterally
      shifted location of the center of pressure.

PMID- 15024329
TI  - Bone density loss after spinal cord injury: elite paraplegic basketball players
      vs. paraplegic sedentary persons.
AB  - OBJECTIVE: To compare the bone mineral density of elite paraplegic basketball
      players with the values obtained from their paraplegic sedentary counterparts.
      DESIGN: A total of 17 male paraplegic basketball players and 17 male paraplegic
      sedentary persons were included in the study. Bone mineral densities of the
      distal third of radius of the dominant arm, L2-L4 spine, and trochanters, Ward's
      triangles, and the femoral necks of both hips were measured. RESULTS: The
      densities of trochanters, Ward's triangles, and the femoral necks were found to
      be decreased in both groups, with no significant difference between them. The
      densities of lumbar and radial regions were found to be increased in both groups.
      Radial density was significantly higher in paraplegic basketball players than in
      paraplegic sedentary patients, whereas the groups were not significantly
      different for lumbar density. CONCLUSIONS: Wheelchair basketball in spinal cord
      injured patients was associated with greater bone density in distal radius
      compared with sedentary paraplegics. However, it was not associated with greater
      density below the injury level.

PMID- 15024330
TI  - Clinical effects of botulinum toxin A and phenol block on gait in children with
      cerebral palsy.
AB  - OBJECTIVE: To compare the treatment effectiveness of botulinum toxin type A (BTX
      A) and phenol blocks in managing lower limb spasticity and gait dysfunction in
      children with cerebral palsy. DESIGN: This is a case-controlled study that took
      place in a tertiary center's gait laboratory. A total of 27 ambulatory children
      with cerebral palsy spastic diplegia, aged from 3 to 7 yrs, and 20 normal
      children were recruited into this study. Sixteen children with cerebral palsy
      received BTX-A injections, and 11 received phenol motor point blocks. Gait
      analyses were assessed by a portable computer-assisted system (Computer
      DynoGraphy, Infotronic, The Netherlands). Both the BTX-A and phenol groups
      received gait analysis at 1 wk before and 2 mos after injection treatments.
      RESULTS: Significant improvements in gait variables of velocity and cadence were
      noted in children with cerebral palsy after BTX-A injections as compared with the
      phenol block group. Gaitline and cyclogram patterns also improved significantly
      in the BTX-A group. The adverse clinical effects of BTX-A injections were less
      severe as compared with phenol injections. CONCLUSIONS: BTX-A injections
      demonstrated superior treatment effects in improving gait variables and patterns
      in children with spastic diplegia as compared with phenol blocks. BTX-A
      injections also revealed fewer clinical side effects and were well tolerated by
      children with cerebral palsies.

PMID- 15024331
TI  - Effect of different methods of thermotherapy on skin microcirculation.
AB  - OBJECTIVE: The purpose of the study was to compare the effects of different
      methods of thermotherapy on skin microcirculation, skin temperature, and core
      temperature in patients with rheumatoid arthritis and in healthy persons. DESIGN:
      In 20 patients with rheumatoid arthritis and 20 healthy controls, the skin
      microcirculation was measured by means of laser-Doppler flowmetry before, at the
      end of, and 30 mins after completion of local thermotherapy (infrared light,
      paraffin, peat) in the lumbar area. In addition, skin and core temperature were
      recorded at the same point in time. The influence of previous intake of
      acetylsalicylic acid on skin microcirculation during thermotherapy was
      investigated. The controlled trial was conducted in an air-conditioned
      laboratory. RESULTS: All methods caused a significant increase in skin
      microcirculation (flow and vasomotion), skin temperature, and core temperature.
      The skin temperature showed the highest increase when infrared light was applied.
      The microcirculation became more intense when paraffin fango was used. There were
      no differences between the reactions of rheumatoid arthritis patients and healthy
      persons. The additional intake of 500 mg acetylsalicylic acid before treatment
      did not affect skin temperature or skin microcirculation. A tendency toward a
      sinusoidal rhythmization of vasomotion was detected. CONCLUSIONS: The effects of
      the three methods of thermotherapy differ quantitatively due to their physical
      attributes. The effects on circulation differ depending on the method chosen, and
      this is significant when selecting the least stressful method for a particular
      patient. Rheumatoid arthritis patients and healthy controls have the same
      increase of skin microcirculation in the lumbar area. Findings in the distal
      limbs might differ. All used therapies cause a rhythmization of the vasomotion
      and, as a consequence, a qualitative improvement of the microcirculation.

PMID- 15024332
TI  - Beneficial effect of etidronate therapy in immobilized hip fracture patients.
AB  - OBJECTIVES: Hip fracture is among the most common causes of acute immobilization
      in elderly patients leading to increased bone resorption, and elderly patients
      with hip fracture are at high risk for a subsequent hip fracture. DESIGN: In this
      double-blind, randomized, prospective study, 80 female patients who were
      immobilized because of a hip fracture were divided into two groups. The
      etidronate group received oral administration of 200 mg/day etidronate for 2 wks
      starting 1 day after the surgery. Then, after a 9-wk intermission, etidronate
      administration was resumed for 2 wks. The placebo group received placebo in a
      similar manner. RESULTS: At baseline, both groups had high serum concentrations
      of ionized calcium, high urinary deoxypyridinoline (D-Pyr) concentrations, and
      decreased calcitriol concentrations, suggesting immobilization-induced
      hypercalcemia and inhibition of renal synthesis of calcitriol. After treatment,
      serum calcitriol concentrations increased in the etidronate and placebo groups.
      The etidronate group had significant decreases in serum ionized calcium and
      urinary D-Pyr, and the placebo group had higher serum calcium and urinary D-Pyr
      concentrations. CONCLUSIONS: Etidronate therapy inhibits bone resorption and
      improves calcium balance, and such therapy may prevent bone loss and reduce the
      risk of subsequent hip fracture.

PMID- 15024333
TI  - Intraparotid injection of botulinum toxin A as a treatment to control sialorrhea
      in children with cerebral palsy.
AB  - OBJECTIVE: To determine the efficacy of botulinum toxin A in the management of
      drooling (sialorrhea) in children and young adults with cerebral palsy. DESIGN:
      Twenty-one children were enrolled in an open-label, nonblinded prospective study.
      Subjective and objective measures were used to determine the effect of botulinum
      toxin A on drooling and saliva production. Subjective measures included visual
      scales to document the child's severity and frequency of drooling. Objective
      measures included the number of bibs used per day and salivary secretion. At the
      initial visit, subjective and objective measures established the child's baseline
      drooling and saliva production. Fifteen units of botulinum toxin A was injected
      into each parotid glans. At each fellow-up visit of telephone survey, subjective
      and objective measures were recorded to monitor the child's drooling and saliva
      production. A postinjection questionnaire evaluated overall effect and caregiver
      satisfaction. RESULTS: The visual analog scales and number of bibs used per day
      demonstrated statistically significant reduction in severity and frequency of
      drooling at 2 wks, 1 mo and 2 mos. Salivary production was significantly reduced
      at 1-mo fellow-up. Eighty-nine percent of the caregivers reported and improvement
      of their child's drooling after botulinum toxin A injection. Severity-nine
      percent of caregivers were satisfied with the treatment and would perform the
      treatment again. CONCLUSION: Intraparotid injections of botulinum toxin A are
      efficacious in decreasing severity and frequency of drooling, the number of bibs
      used per day, and the production of saliva in children with cerebral palsy. The
      injections are relatively safe and adverse effects were observed in this study.

PMID- 15024334
TI  - Utility of head computed tomographic scans in functional decline late after
      traumatic brain injury.

PMID- 15024335
TI  - Risk adjusting rehabilitation outcomes: an overview of methodologic issues.
AB  - The complexity and mix of rehabilitation patients varies across clinicians and
      institutions. Comparisons of outcomes across providers must therefore adjust for
      differences in risk factors across patient populations. Research on risk
      adjustment has generally focused on acute care hospital outcomes, although
      techniques for risk adjusting financial outcomes are fairly well developed in
      rehabilitation, primarily to support Medicare and other prospective payment
      systems. This article reviews important methodologic issues in risk adjusting
      rehabilitation outcomes in observational studies of routine clinical practice or
      for management, such as assessing quality or costs of care. Risk adjusting
      rehabilitation outcomes is more difficult than risk adjusting other clinical
      results, such as outcomes of many acute care services. At the outset,
      characterizing rehabilitation interventions is frequently difficult. Furthermore,
      outcomes are diverse and depend on myriad factors, including patients' physical
      and cognitive abilities, underlying medical diseases, sensory and emotional
      factors, willingness to participate in care, and supportive environments. No risk
      adjustment approach can control for every factor affecting outcomes of care.
      Knowing which risk factors are missing helps guide interpretation of the results
      and determines how well risk-adjusted outcomes fairly compare providers or
      treatments.

PMID- 15024336
TI  - Herniated nucleus pulposus as a result of emesis in a 20-yr-old man.
AB  - The causes of herniated disc in vivo vary, and recent studies stress the role of
      intradiscal pressure as an important factor. Identifying causes of increased
      intradiscal pressure is difficult. This case report describes the diagnosis of a
      herniated nucleus pulposus in a 20-yr-old healthy man, with sudden onset of
      emesis. The diagnosis was made by a complete history, physical examination,
      electrodiagnostic studies, and magnetic resonance imaging. This etiology of
      herniated nucleus pulposus has not been described in the medical literature, and
      the severity of the symptoms, clinical examination, electrodiagnostic findings,
      and radiologic findings are discussed. Intradiscal pressures and their role in
      herniated nucleus pulposus are discussed, with a review of the medical literature
      on the measurement of intradiscal pressure. The amount of force required to
      produce a herniated nucleus pulposus is also discussed.

PMID- 15024337
TI  - Tibial nerve block with anesthetics resulting in achilles tendon avulsion.
AB  - Diagnostic tibial nerve block with anesthetics is a common and safe procedure for
      the management of the spastic equinovarus foot. Side effects have been rarely
      reported. We present the case of a hemiplegic patient with a spastic equinovarus
      foot who presented with an avulsion fracture of the calcaneum at the insertion of
      the Achilles tendon consecutive to a diagnostic tibial nerve block with
      anesthetic agents. Although rare, such a complication should be considered when
      the Achilles tendon is shortened and when the patient is suspected of bone
      osteoporosis or dystrophy.

PMID- 15024339
TI  - For better communication.

PMID- 15024344
TI  - Telomere biology of human hematopoietic stem cells.
AB  - BACKGROUND: Telomeres are protein DNA structures present at the ends of
      chromosomes and are essential for genetic stability and cell replication.
      Telomerase is the enzyme complex that maintains telomere integrity. Hematopoietic
      stem cells express telomerase and contain long telomeres, which become shorter as
      cells differentiate and mature. The extent of telomere shortening and the level
      of telomerase activity often correlate with the presence and severity of some
      hematopoietic diseases. METHODS: The fundamentals of telomeres and telomerase are
      reviewed, and the telomere biology of human hematopoietic cells is discussed.
      RESULTS: Telomere length and telomerase activity are important in the self
      renewal of hematopoietic stem cells. Changes within these compartments affect
      both normal hematopoietic cells and the generation of hematopoietic disease.
      Telomere length provides information pertaining to the proliferative history and
      potential of a hematopoietic cell. CONCLUSIONS: The role of telomerase and
      telomeres within the hematopoietic compartment needs further clarification.
      Advances in our knowledge in this field may improve clinical outcomes for the
      treatment of hematologic disease.

PMID- 15024345
TI  - Nonmyeloablative allogeneic stem cell transplantation using alternative donors.
AB  - BACKGROUND: The reduced intensity of nonmyeloablative stem cell transplant
      (NMSCT) has enabled older patients to benefit from allogeneic therapy.
      Identification of suitable donors remains an obstacle. The use of alternative
      donors for stem cell therapy is essential to ensure broad applicability of
      allogeneic therapy. METHODS: Clinical results using alternative hematopoietic
      stem cell donors are reviewed, including matched unrelated donors, partially
      matched family member donors, and unrelated partially matched umbilical cord
      blood. RESULTS: The successful use of NMSCT in the treatment of hematologic and
      nonhematologic diseases has increased the number of patients capable of receiving
      allogeneic therapy. However, the stem cell donor pool remains limited due to the
      infrequent number of patients with matched siblings. CONCLUSIONS: The use of
      alternative donor stem cell sources can expand the number of patients able to
      receive allogeneic therapy. Preliminary studies indicate that the use of
      alternative donors can provide reliable engraftment, although graft-vs-host
      disease remains a concern.

PMID- 15024346
TI  - Considerations for targeting malignant stem cells in leukemia.
AB  - BACKGROUND: Malignant stem cells have been identified in acute myelogenous
      leukemia, chronic myeloid leukemia, and some types of acute lymphoblastic
      leukemia. Like normal stem cells, these leukemic stem cells (LSCs) are able to
      self-renew, differentiate, and proliferate extensively. Evidence suggests that
      LSCs are critical for the initiation and perpetuation of leukemic disease.
      METHODS: We reviewed the literature describing the characteristic features of
      LSCs in various leukemias and the novel molecular approaches being used to
      specifically ablate the LSC population. RESULTS: Studies have demonstrated the
      potential importance of ablating LSCs when treating leukemia. The unique
      characteristics of LSCs that differentiate them from their normal counterparts
      can be exploited to specifically target the malignant population. CONCLUSIONS:
      Current therapeutic strategies may not effectively ablate the LSC, leaving the
      potential for disease progression or relapse. A better understanding of LSC cell
      and molecular biology will allow the design of more effective therapies.

PMID- 15024347
TI  - Stem cell transplantation in the fetus.
AB  - BACKGROUND: In utero transplantation (IUT) of hematopoietic stem cells has the
      potential to treat a large number of hematologic and metabolic diseases amenable
      to partial replacement of the hematopoietic system. METHODS: A review of the
      literature was conducted that focused on the clinical and experimental experience
      with IUT and, in this context, the development of the hematopoietic and immune
      systems. RESULTS: Successful application of IUT has been limited to the treatment
      of various types of immunodeficiencies that affect lymphocyte development and
      function. Other congenital defects such as the thalassemias have not resulted in
      clinically significant engraftment. Recent efforts at understanding and
      overcoming the barriers to engraftment in the fetus have focused on providing a
      selective advantage to donor stem cells and fostering immune tolerance toward the
      donor cells. The critical cellular components of the graft that promote
      engraftment and tolerance induction are being evaluated in animal models.
      Improvements in engraftment have resulted from the inclusion of T cells and/or
      dendritic cells in the graft, as well as a strategy of combined prenatal and
      postnatal transplantation. CONCLUSIONS: The advantages, necessity, and benefits
      of early treatment will continue to encourage development of IUT as a means to
      treat hematopoietic and other types of birth defects.

PMID- 15024349
TI  - Business education for dental professionals: how much is enough?

PMID- 15024348
TI  - Stem cell transplantation for multiple myeloma.
AB  - BACKGROUND: Multiple myeloma (MM) is the second most common hematologic
      malignancy, affecting approximately 14,000 new patients in the United State per
      year. The median overall survival is 5 years, and cure is a realistic goal for
      only a small minority of patients. METHODS: A review of the literature was
      conducted that focused on treatment strategies for MM involving administration of
      high doses of chemotherapy followed by autologous or allogeneic hematopoietic
      stem cell transplant. RESULTS: For over three decades, the standard treatment for
      MM has been a regimen of melphalan and prednisone (MP). Complete responses (CRs)
      have been rare, and 50% of patients have had disease that was resistant to
      treatment with MP. Attempts have been made to improve the outcome of MM by
      administering other combinations of standard doses of chemotherapy, but these
      treatments are equivalent in terms of overall survival. For patients who are
      candidates, high-dose therapy followed by autologous stem cell transplantation
      results in higher CR rates and improved long-term survival compared to treatment
      with standard doses of chemotherapy alone. While this strategy represents an
      advance in the treatment of MM, evidence-based reviews indicate that there are a
      number of issues to consider regarding the induction therapy, the collection of
      stem cells, and the timing, type, and number of high-dose therapies to use in
      this type of treatment strategy. CONCLUSIONS: Advances have been made in
      autologous transplantation, allogeneic transplantation, anti-MM agents, and
      immunotherapy for MM. Combining these different strategies to achieve synergistic
      responses is an exciting possibility.

PMID- 15024350
TI  - Mandibular unilocular radiolucency with ill-defined borders.

PMID- 15024351
TI  - Intralesional chemotherapy for head and neck carcinoma: a review of the
      literature.
AB  - In the last decade chemotherapy has gained widespread acceptance in the treatment
      of oral and pharyngeal cancer. Current standard treatment for advanced lesions
      consists of concomitant radiation and chemotherapy. This approach has provided
      marginal improvement of prognosis for Stage III-IV disease. Recent studies have
      explored the idea that locally delivered cytotoxic drugs could further improve
      prognosis in this patient population. We review this literature with the
      objective of popularizing these data and suggesting future directions for
      treatment and clinical research for head and neck cancer.

PMID- 15024352
TI  - Self-reinforced bioresorbable poly-L/DL-lactide [SR-P(L/DL)LA] 70/30 miniplates
      and miniscrews are reliable for fixation of anterior mandibular fractures: a
      pilot study.
AB  - OBJECTIVE: Bioresorbable osteofixation devices are being increasingly used in
      orthognathic surgery and in cases of trauma to avoid problems associated with
      conventional metal osteofixation devices. The aim of this clinical study was to
      assess the reliability and efficacy of bioresorbable self-reinforced poly-L/DL
      lactide (SR-P(L/DL)LA 70/30) plates and screws in the fixation of mandibular
      fractures in adults. STUDY DESIGN: Ten patients (20 to 49 years old) with
      isolated anterior mandibular parasymphyseal fractures were treated by means of
      open reduction and internal fixation using SR-P(L/DL)LA 70/30 bioresorbable
      plates and screws. RESULTS: During the minimum of 6 months of follow-up, no
      problems were encountered except for 1 case where a plate became exposed
      intraorally and infected. This required debridement and later excision of the
      exposed part of the plate. Despite this setback the fractured bone healed well.
      CONCLUSIONS: SR-P(L/DL)LA 70/30 plates and screws are reliable for internal
      fixation of anterior mandibular fractures in adults. Proper soft tissue coverage
      should be ensured to avoid plate exposure. Should implant exposure occur, it
      might be necessary to excise the exposed part after fracture healing (6-8 weeks
      postoperatively).

PMID- 15024353
TI  - Temporomandibular joint pathosis in patients with myofascial pain: a comparative
      analysis of magnetic resonance imaging and a clinical examination based on a
      specific set of criteria.
AB  - OBJECTIVE: We sought to determine the prevalence of joint diseases in patients
      with either of 2 forms of myofascial pain (with and without limited mouth
      opening) and to verify the accuracy of temporomandibular joint-related clinical
      diagnoses through the use of magnetic resonance imaging (MRI). STUDY DESIGN: On
      the basis of the results of a clinical examination carried out according to the
      Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD), 61
      patients were divided into 2 subgroups. The first group consisted of 36 patients
      who had myofascial pain with limited mouth opening (MPLO), whereas the other 25
      patients were diagnosed with myofascial pain without limited mouth opening. MRI
      was carried out on all patients. The clinical joint-related diagnoses from
      RDC/TMD were compared with MRI results. RESULTS: Patients with MPLO often had
      joint diseases that were not detected by means of a clinical examination alone.
      The kappa statistic was used to compare MRI and clinical diagnoses, confirming
      poor agreement in patients with MPLO (kappa=0.13) and acceptable agreement in
      patients with myofascial pain without limited mouth opening (kappa=0.72).
      CONCLUSION: Restricted mandibular mobility is frequently associated with
      temporomandibular joint diseases that were not identified during a clinical
      examination. Therefore, an adaptation of the classification scheme used for the
      RDC/TMDs may result in the improvement of the sensitivity of clinical joint
      related diagnoses, especially in patients with MPLO.

PMID- 15024354
TI  - Concrescence: report of a rare case.
AB  - Concrescence represents an uncommon developmental anomaly in which juxtaposed
      teeth are united in the cementum but not in the dentin. The incidence of
      concrescent teeth is reported to be highest in the posterior maxilla. The
      presence of concrescent teeth may influence surgical procedures as well as
      periodontal, endodontic and even orthodontic diagnoses and treatment. Therefore,
      consideration should be given to the possible occurrence, recognition, and
      implications of this anomaly in diagnosis and treatment planning. The purpose of
      this article is to report a case of concrescence between an impacted third molar
      and an erupted second molar that was identified postextraction.

PMID- 15024355
TI  - Primary non-Hodgkin's lymphoma of the sinonasal tract.
AB  - OBJECTIVES: We sought to review the records of patients seen at the Chaim Sheba
      Medical Center (Tel Hashomer, Israel) during a 10-year period with respect to the
      presenting features, management, and outcome of extranodal non-Hodgkin's lymphoma
      (NHL) of the sinonasal region. STUDY DESIGN: Eight patients were diagnosed with
      NHL of the paranasal sinuses from 1993 to 2003. The data were reviewed, and we
      noted the patient's age, sex, the presenting signs and symptoms, staging,
      histology, treatment, and outcome of NHL. RESULTS: The mean age was 61.75 years
      (range, 24-83 years), with a 1:1 male-to-female ratio. All cases involved the
      paranasal sinuses, and the most common symptom was nasal obstruction (6
      patients). All the patients had large B-cell lymphoma, and all were treated with
      combined chemotherapy and radiation. Three patients died from the disease, 3 were
      free of disease after 12 to 36 months of follow-up, and 1 had a recurrence after
      60 months. CONCLUSIONS: NHLs of the paranasal sinuses are uncommon. Early
      diagnosis and combined treatment are essential for achieving an optimal outcome.

PMID- 15024356
TI  - CO2-laser treatment of ulcerative lesions.
AB  - This article reports the successful use in our clinic of CO(2)-laser to reduce
      severe pain in the treatment of oral aphthosis. The patients, presenting stress
      related, chemoradiotherapy-induced, and immuno-related oral aphthosis, reported
      immediate pain relief and rapid recovery. Treatment technique and laser
      parameters are described.

PMID- 15024357
TI  - Abnormal oral mucosal light reflectance: a new clinical sign of Ehlers-Danlos
      syndrome.
AB  - Ehlers-Danlos syndrome (EDS) is a major inherited connective tissue disorder
      leading to an impaired extracellular matrix structure. Although several
      odontostomatologic signs have been reported, their diagnostic accuracy remains to
      be ascertained. We tested the hypothesis that EDS is associated with an abnormal
      reflectance of the oral mucosa. Twelve patients with EDS-II or EDS-III and 12 age
      and gender-matched controls were examined. Reflectance of the lower gingival and
      vestibular oral mucosa in the optical spectrum was measured using an imaging
      spectrophotometer. EDS patients showed significantly higher reflectance values in
      the 400-590 nm wavelengths (P<or=.0002) and significantly lower reflectance
      values in the red wavelengths (610-700 nm range, P<or=.025) than did controls. A
      reflectance cutoff value of >10.51% at the 400 nm wavelength identified the EDS
      patients with 100% sensitivity and 100% specificity. These findings indicate that
      an abnormal oral mucosal reflectance is a previously unrecognized clinical marker
      of EDS.

PMID- 15024358
TI  - Psychological profile in burning mouth syndrome.
AB  - Thirty-two patients with burning mouth syndrome and 32 matched control subjects
      were evaluated for their personality profile using a comprehensive, reliable, and
      validated inventory. All subjects were requested to complete the Neo PI-R
      questionnaire that measures the 5 dimensions of personality and their facets. A t
      test and univariate correlations (Pearson's correlation coefficient) were used to
      compare the 2 groups. Results show high significant differences in some
      personality factors. Neuroticism and all its facets, which include anxiety, angry
      hostility, depression, self-consciousness, impulsiveness and vulnerability, were
      significant at P<.001. Other domains like extraversion, openness, and
      conscientiousness showed significant differences also (P<.05). Many personality
      characteristics differentiate burning mouth syndrome patients from controllers
      according to the Neo PI-R and this should affect the treatment plan according to
      the identified characteristics.

PMID- 15024359
TI  - The effect of antiretroviral therapy on the prevalence of HIV-associated oral
      candidiasis in a Spanish cohort.
AB  - OBJECTIVE: To investigate the temporal changes in the prevalence of oral
      candidiasis in a cohort of Spanish human immunodeficiency virus (HIV)-infected
      individuals, before and after the introduction of highly active antiretroviral
      therapy (HAART). STUDY DESIGN: Retrospective analysis of a clinical database from
      "Carlos Haya" Hospital, Malaga, Spain, from 1995 to 2000. The prevalence of oral
      candidiasis was assessed in 807 HIV/AIDS patients and the temporal progression of
      its major variants evaluated using a linear regression model. RESULTS: Overall
      oral candidiasis was prevalent in 30.0% to 48.3% of the cohort throughout and no
      significant variation in its incidence was noted during the study period.
      Prevalence of erythematous candidiasis increased from 24.5% (1995) to 45.0%
      (2000) and pseudomembranous candidiasis decreased from 22.4% (1995) to 5.2%
      (2000) (P<.05). Hyperplastic candidiasis was not detected in the cohort after the
      introduction of HAART therapy. CONCLUSIONS: Although oral candidiasis in HIV
      infected Spanish individuals has not decreased significantly after the
      introduction of HAART, there appears to be a significant reduction in
      hyperplastic and pseudomembranous variants of the disease with a compensatory
      increase in erythematous candidiasis.

PMID- 15024360
TI  - Evaluation of the recurrence of denture stomatitis and Candida colonization in a
      small group of patients who received itraconazole.
AB  - OBJECTIVES: The aim of the study was to determine the recurrence rate of denture
      stomatitis and persistence of Candida in 22 patients (5 male and 17 female, mean
      age 71 years) over a 3-year period. STUDY DESIGN: Denture hygiene practice,
      denture cleanliness, and the presence of palatal erythema were assessed for each
      patient at the start of the study (baseline). The oral cavity was sampled for
      yeasts by imprint culture and denture discs. Ten patients received a capsular
      form of itraconazole (100 mg twice daily for 15 days) and 12 patients were
      provided with 100 mg of itraconazole in the form of a mouthwash (10 mL twice
      daily), which was then swallowed. No further antifungal treatment was
      administered to any of the patients. Clinical and microbiological assessments
      were repeated for each patient at 6 months and 3 years after the original
      appointment. Yeasts were identified by colony color on CHROMagar Candida, germ
      tube formation, and API-32C profiling. Selected isolates were then typed by inter
      repeat polymerase chain reaction (IR PCR). RESULTS: Candida albicans was isolated
      at baseline from all patients either alone (12 patients) or in combination with
      another species (10 patients). Other yeast species recovered were C glabrata (5
      patients), C tropicalis (1 patient), C guilliermondii (1 patient), C krusei (1
      patient), C parapsilosis (1 patient), C kefyr (1 patient), and Saccharomyces
      cerevisiae (2 patients). Candida albicans and/or C glabrata were recovered from
      11 of the 22 patients after 6 months or 3 years. A complete and consistent change
      of yeast species from baseline was observed in 6 patients after 6 months and at 3
      years. The remaining 5 patients were yeast-free at the follow-up assessments. PCR
      fingerprinting of C albicans and C glabrata indicated strain persistence over 6
      months in 10 patients and in 4 patients after 3 years. A switch in strain type
      occurred for 1 patient after 6 months and for 3 patients after 3 years.
      CONCLUSIONS: The recurrence of denture stomatitis in patients who maintained a
      high standard of denture cleanliness was low. Although itraconazole was
      beneficial in reducing the fungal load, there may be strain persistence or
      subsequent recolonization of the oral cavity by a broader range of potentially
      less sensitive yeast species.

PMID- 15024361
TI  - Oral metastasis of a hepatocellular carcinoma.
AB  - Hepatocellular carcinoma is a relatively common tumor that etiologically is
      closely linked to previous hepatitis B infection. Oral metastatic hepatocellular
      carcinoma is very rare, with only 61 cases reported in the literature. We
      describe a case of hepatocellular carcinoma metastatic to the anterior mandibular
      gingivae of a 60-year-old man. The patient also exhibited tumor metastases to the
      lungs, left knee, little finger of the left hand, scalp, and the skin of the
      neck. He died 6 months after the diagnosis of the oral metastasis because of
      systemic tumor dissemination.

PMID- 15024362
TI  - Dedifferentiated chondrosarcoma of the larynx.
AB  - Dedifferentiated chondrosarcoma is an uncommon malignant cartilaginous neoplasm
      of bone characterized by the presence of a malignant spindle cell neoplasm
      associated with a low- or medium-grade chondrosarcoma. Origin of this tumor in
      the cartilagenous framework of the larynx is very rare. A 60-year-old male with a
      2-year history of hoarseness and dyspnea was examined while presenting in acute
      airway distress. Direct laryngoscopy revealed a mass of the right side of the
      larynx. Histopathologic examination revealed a malignant cartilaginous tumor with
      a malignant spindle cell component. We report a case of dedifferentiated
      chondrosarcoma arising in the thyroid cartilage. This, to our knowledge, is the
      eleventh fully documented case of this neoplasm arising in the larynx.

PMID- 15024363
TI  - Recurrent oral herpes simplex virus infection presenting as a tongue mass.
AB  - Reactivation of herpes simplex virus resulting in oral infection is common after
      cardiac transplantation and usually occurs within the first month posttransplant.
      The clinical presentation, however, may be atypical. We present a case of a 48
      year-old female who presented with a large tongue mass 1 year after cardiac
      transplantation. Outpatient biopsies and viral stains were nondiagnostic. Because
      of the high suspicion for malignancy, an excisional biopsy was performed in the
      operating room. Pathologic analysis was consistent with herpes simplex virus type
      1 infection. The patient received antiviral therapy with resolution of infection
      at follow-up.

PMID- 15024364
TI  - Surface debris of canal walls after post space preparation in endodontically
      treated teeth: a scanning electron microscopic study.
AB  - PURPOSE: To evaluate surface cleanliness of root canal walls along post space
      after endodontic treatment using 2 different irrigant regimens, obturation
      techniques, and post space preparation for adhesive bonding. STUDY DESIGN: Forty
      teeth, divided into 4 groups, were instrumented, using Ni-Ti rotary files,
      irrigated with NaOCl or NaOCl+EDTA and obturated with cold lateral condensation
      (CLC) or warm vertical condensation (WVC) of gutta-percha. After post space
      preparation, etching, and washing procedure, canal walls were observed using a
      scanning electron microscope (SEM). Amount of debris, smear layer, sealer/gutta
      percha remnants, and visibility of open tubules were rated. RESULTS: Higher
      amounts of rough debris, large sealer/gutta-percha remnants, thick smear layer,
      and no visibility of tubule orifices were recorded in all the groups at apical
      level of post space. At middle and coronal levels areas of clean dentin,
      alternating with areas covered by thin smear layer, smaller debris, gutta-percha
      remnants, and orifices of tubules partially or totally occluded by plugs were
      frequently observed. CONCLUSIONS: After endodontic treatment, obturation, and
      post space preparation SEM analysis of canal walls along post space shows large
      areas (covered by smear layer, debris, and sealer/gutta-percha remnants) not
      available for adhesive bonding and resin cementation of fiber posts.

PMID- 15024366
TI  - SEM observations of the attachment of human periodontal ligament fibroblasts to
      non-demineralized dentin surface in vitro.
AB  - PURPOSE: The purpose of this investigation was to study in-vitro the attachment
      behavior of human periodontal ligament (HPDL) fibroblasts to nondemineralized
      dentin surface using scanning electron microscope. STUDY DESIGN: Thirty root
      slices of freshly extracted human teeth of 4 mm thickness as well as six 5x5 mm
      glass slides used as a control were used in this study. The dentin surface of the
      root slices was not treated with any chemicals to remove the smear layer. The
      root slices and the glass slides were placed in tissue culture clusters and an
      amount of 1 ml of HPDL fibroblast cell suspension was placed over the dentin
      surface of the root slices and the glass slides. They were then placed into an
      incubator at 37 degrees C and 100% humidity for 4, 24, and 72 hours. At the end
      of the incubation, the cells were fixed with glutaraldehyde and examined
      microscopically. RESULTS: Different shapes of fully spread cells were seen. The
      cells were attached firmly to the dentin surface by the cytoplasmic extension of
      the lamellipodia and microvilli which were seen extending inside the opening of
      the dentinal tubules. CONCLUSION: It was concluded that the human dentin surface
      provided an excellent surface for attachment of periodontal ligament fibroblasts.
      In addition, the smear layer did not affect the cell attachment.

PMID- 15024365
TI  - Evaluation of pH levels and calcium ion release in various calcium hydroxide
      endodontic dressings.
AB  - OBJECTIVE: The purpose of this study was to evaluate Ca(2+) release and pH of 3
      calcium hydroxide-based products used routinely as intracanal dressings, as well
      as the new gutta-percha points with calcium hydroxide. STUDY DESIGN: The pH and
      Ca(2+) release were assessed using Calen with camphorated paramonochlorophenol,
      saline calcium hydroxide paste, LC paste (Lopes and Costa paste-calcium hydroxide
      with olive oil), and calcium hydroxide containing gutta-percha points. The
      materials were inserted in polyethylene tubes and immersed in deionized water.
      The pH variation and Ca(2+) release were monitored periodically for 4 weeks.
      RESULTS: After 72 hours, materials 1 and 2 raise the pH from 9.6 and 8.2 to 11.4
      and 11.3, respectively, while a small change was observed for materials 3 and 4.
      The calcium concentration released from materials 1, 2, 3, and 4 after 72 hours
      was 6.54, 4.98, 1.31, and 1.74 mg/dL, respectively. CONCLUSION: Calen plus
      camphorated paramonochlorophenol and saline calcium hydroxide paste exhibited the
      highest calcium release and pH levels.

PMID- 15024368
TI  - The prevalence of calcified carotid atheromas on the panoramic radiographs of
      patients with dilated cardiomyopathy.
AB  - OBJECTIVE: Individuals with dilated cardiomyopathy (DCM) often die from heart
      failure without a transplant. Of those who do receive a transplant, a significant
      number suffer a perioperative stroke, although the cause is often in doubt. Our
      study attempts to determine whether the prevalence of calcified carotid artery
      atheromas, a known cause of stroke, is greater on the panoramic radiographs of
      individuals with DCM than it is among controls. STUDY DESIGN: Twenty-seven
      persons [mean age 62.3 years] enrolled in the UCLA Cardiac Transplantation
      Program were provided a panoramic radiograph. An age-matched, atherogenic risk
      matched cohort of 54 patients free of DCM served as controls. The radiographs of
      patients in each group were examined for the presence of calcified carotid
      atheromas. RESULTS: Nine of the 27 patients with DCM had calcified atheromas,
      whereas only 2 of the 54 patients in the control group had such lesions. This
      difference was statistically significant (P<.001). CONCLUSIONS: Panoramic
      radiographs may be helpful in identifying some DCM patients with occult carotid
      artery atherosclerosis who may be at risk for a subsequent stroke.

PMID- 15024367
TI  - Examination of the signal transduction pathways involved in matrix
      metalloproteinases-2 in human pulp cells.
AB  - OBJECTIVES: Matrix metalloproteinases (MMPs) play an important role in pulp
      tissue destruction. However, the mechanisms and signal transduction pathways
      involved in the production of MMPs in human pulp cells are not fully understood.
      The purpose of this study was to investigate the gelatinolytic activity in human
      pulp cells stimulated with various pharmacological agents. STUDY DESIGN: Human
      dental pulp cells were cultured using an explant technique obtained from impacted
      third molars with informed consent of the patients. The effects of p38 inhibitor
      SB203580, MEK inhibitor U0126, extracellular signal-regulated kinase (ERK)
      inhibitor PD098059, phosphatidylinositaol 3-kinase (PI3K) inhibitor LY294002,
      cyclooxygenase-2 (COX-2) inhibitor NS-398, nuclear factor kappa B (NF-kappaB)
      inhibitor dexamethasone, and tyrosine kinase inhibitor herbimycin A on the
      production and secretion of MMPs by human pulp cells were determined by gelatin
      zymography. RESULTS: The main gelatinase secreted by human pulp cells migrated at
      72 kd and represented MMP-2. Minor gelatinolytic bands were also observed at 92
      kd regions that correspond to MMP-9. After a 4-day culture period, NS-398,
      dexamethasone, and herbimycin A were found to depress MMP-2 production (P<.05).
      The inhibition decreased in an order of dexamethasone >NS-398>herbimycin A. Human
      pulp cells, however, treated with various pharmacological agents had no effect on
      the pattern of MMP-9 produced or secreted in either cell extracts or conditioned
      medium fractions (P>.05). CONCLUSION: These observations suggest that NS-398,
      dexamethasone, and herbimycin A can regulate MMP-2 produced by human pulp cells.
      The signal transduction pathways COX-2, NF-kappaB, and tyrosine kinase may be
      involved in the production of MMPs.

PMID- 15024369
TI  - Determination of the resolution of a digital system for panoramic radiography
      based on CCD technology.
AB  - OBJECTIVES: To determine Line Spread Functions (LSFs) and Modulation Transfer
      Functions (MTFs) for a digital system for panoramic radiography: the Dimax I
      (Planmeca Oy, Helsinki, Finland) based on Charge-Coupled Device (CCD) technology.
      STUDY DESIGN: A test object was specially designed having a gold foil positioned
      vertically. Images of the gold foil created edge functions that were used to
      determine LSFs and MTFs. The design of the test object made it possible to move
      the gold foil forward and backward relative to the central plane of the image
      layer by means of a micrometer screw. The experiment was carried out for
      different object depths in 5 different regions: the anterior, the canine, the
      premolar, the molar, and the TMJ regions. LSFs and MTFs were calculated using
      specially designed software. RESULTS: The results are presented graphically. LSFs
      and MTFs for the central plane were essentially the same for all regions. The
      MTFs for different object depths in the 5 investigated regions exhibited typical
      characteristics of MTFs for panoramic radiography with the exception for the
      functions for the molar region. CONCLUSIONS: The present findings indicate that
      the resolution of the Dimax I CCD system is comparable to that of film-based
      panoramic radiography.

PMID- 15024370
TI  - Foreword: the NINR research centers programs.

PMID- 15024371
TI  - The Center for Research on Cardiovascular and Respiratory Health: the development
      of a National Institute of Nursing Research-funded center.

PMID- 15024372
TI  - A cross-sectional examination of changes in anxiety early after acute myocardial
      infarction.
AB  - BACKGROUND: Anxiety is common after acute myocardial infarction (AMI). The
      assessment and treatment of anxiety early after AMI is important, because anxiety
      is associated with increased morbidity and mortality. Few data exist about
      anxiety early after AMI, the time when anxiety likely peaks. Furthermore, no
      researchers have evaluated potential gender differences in the evolution of
      anxiety after AMI. OBJECTIVES: The purpose of this study was to investigate the
      evolution of anxiety during the first 72 hours of hospitalization for AMI and to
      examine whether there is a gender difference in the pattern of anxiety early
      after AMI, from cross-sectional data. METHODS: In this cross-sectional study, 486
      patients with AMI were recruited from 4 urban university medical centers and 2
      private hospitals in the United States and 1 large university teaching hospital
      in Australia. The Spielberger State-Trait Anxiety Inventory was used to measure
      anxiety once in each patient within 72 hours of the patient's admission to the
      hospital. Patients were divided into 6 groups based on the time interval in which
      they were interviewed. RESULTS: The mean score of state anxiety was 39 +/- 13.
      Peak anxiety occurred within the first 12 hours after AMI (P<.05) and anxiety
      level differed among the time intervals (F [5, 474]=4.55, P<.001). There was a
      main effect of gender on anxiety (F [1, 474]=11.86, P<.001). Women reported
      higher anxiety than men at all time points except the time interval of 24.1 to 36
      hours after AMI. CONCLUSION: Prospective, longitudinal, repeated measures
      research is needed to confirm the trajectory of anxiety in AMI patients, but data
      from this study suggest that anxiety should be assessed and treated in the early
      stages of AMI to prevent potential complications that may be exacerbated by
      anxiety and to provide comfort to AMI patients.

PMID- 15024373
TI  - Duration of action of a single, early oral application of chlorhexidine on oral
      microbial flora in mechanically ventilated patients: a pilot study.
AB  - OBJECTIVE: The purpose of this study was to describe the effect of an early post
      intubation oral application of chlorhexidine gluconate on oral microbial flora
      and ventilator-associated pneumonia. METHODS: Thirty-four intubated patients were
      randomly assigned to chlorhexidine gluconate by spray or swab or to control
      group. Oral cultures were done at study admission, 12, 24, 48, and 72 hours,
      whereas the Clinical Pulmonary Infection Score (CPIS) was documented at study
      admission, 48, and 72 hours. RESULTS: Reductions in oral culture scores (less
      growth) were only found in the treatment groups (swab and spray); no reduction
      was found in the control group. There was a trend for fewer positive cultures in
      the combined treatment groups. The mean CPIS for the control group increased to a
      level indicating pneumonia (4.7 to 6.6), whereas the CPIS for the treatment group
      increased only slightly (5.17 to 5.57). CONCLUSIONS: Trends in the data suggest
      that use of chlorhexidine gluconate in the early post-intubation period may
      mitigate or delay the development of ventilator-associated pneumonia.

PMID- 15024374
TI  - Electronic voice-output communication aids for temporarily nonspeaking patients
      in a medical intensive care unit: a feasibility study.
AB  - BACKGROUND: The inability to speak during mechanical ventilation is recognized as
      a terrifying and isolating experience that is related to feelings of panic,
      insecurity, anger, worry, fear, sleep disturbances, and stress among critically
      ill patients. Alternative methods of communicating with temporarily nonspeaking
      patients in the intensive care unit (ICU) have received little study. Although
      electronic voice output communication aids (VOCAs) are available for disabled
      children and adults, the effectiveness of VOCA systems with adult medical ICU
      patients who may have multisystem illness, prolonged intubation, and longer ICU
      stays has not been explored. OBJECTIVES: The purpose of this pilot study was to
      describe (1) the characteristics of intubated MICU patients who use VOCAs, (2)
      the usage patterns (message categories, frequency, assistance required), (3)
      communication quality (ease, user satisfaction), and (4) barriers to
      communication with VOCAs. METHODS: This pilot study used participant observation,
      semi-structured interviews, questionnaires, and clinical record review in a
      complementary design to obtain data on communication events and VOCA use with 11
      critically ill adults. RESULTS: Study participants, 45.5 +/- 16.0 years of age
      with 13 +/- 1.9 years of education and moderately severe illness (APACHE III=27.5
      +/- 16.1), used the VOCA for 5.7 +/- 4.6 days. Ease of Communication Scale
      measurements showed significantly less difficulty with communication after device
      use (t>2.62; P=.047). Almost half (n=5) of the participants demonstrated some
      independent use of the device. VOCAS were used in one quarter of observed
      communication events. Patients used VOCAs most often to communicate with family
      visitors and initiated communication interactions more often when VOCAs were used
      than when communicating by other nonvocal methods. Poor device positioning,
      deterioration in patient condition, staff time constraints, staff unfamiliarity
      with device, and complex message screens were primary barriers to VOCA use.
      CONCLUSIONS: This study showed that use of VOCAs is possible with selected
      critically ill adults and may contribute to greater ease of communication during
      respiratory tract intubation particularly with family members. Further clinical
      research using control or comparison groups is needed.

PMID- 15024375
TI  - Descriptors of dyspnea by patients with chronic obstructive pulmonary disease
      versus congestive heart failure.
AB  - OBJECTIVES: The purpose of this study was to determine whether differences
      existed between reports of dyspnea in stable chronic obstructive pulmonary
      disease (COPD) and congestive heart failure (CHF) subjects. METHODS: Sixty stable
      COPD (n=30) and CHF (n=30) male, outpatient subjects were studied. Subjects were
      asked to both endorse (from a pre-designed list of descriptors) and volunteer
      terms that best described their breathing discomfort. Subjects also reported the
      frequency and the intensity of breathlessness (0-10 scale) using the Pulmonary
      Functional Status and Dyspnea Questionnaire. RESULTS: From the endorsed list of
      descriptors, my breath does not go out all the way, was significantly different
      (COPD=11, CHF=4, P<.05) between groups. The most common terms volunteered by COPD
      subjects were scary (n=5, P<.02), hard to breathe (n=5), shortness of breath
      (n=4), and cannot get enough air (n=4), whereas CHF subjects volunteered the
      terms, shortness of breath (n=9), gasping (n=6), and cannot get enough air (n=4).
      There was no difference in the frequency with which both groups experienced
      dyspnea or times per month they reported severe to very severe dyspnea. Subjects
      with COPD experienced a higher intensity of breathlessness on different occasions
      P<.05. CONCLUSIONS: Stable COPD and CHF patients use and recognize a variety of
      terms that describe their breathing distress. There was, however, only 1 unique
      term among the endorsed and volunteered terms, and that was among the COPD
      subjects. COPD and CHF subjects shared many common terms and also experienced
      dyspnea with similar frequency. The uniqueness of terms among the COPD group was
      less clear. The study highlights the variability of the dyspnea experience among
      COPD and CHF patients and the potential difficulty identifying unique dyspnea
      terms in these subjects.

PMID- 15024376
TI  - Expressions of hope in cystic fibrosis patients: a comparison with the general
      population.
AB  - PURPOSE: Hope was evaluated in Norwegian patients with cystic fibrosis (CF).
      PARTICIPANTS: The subjects were 87 Norwegian adults with CF and a control group
      of 1020 from the general population (GP). METHODS: Subjects completed a
      questionnaires that included the Herth Hope Index and demographic variables. Data
      on health-related variables were collected for the CF group. RESULTS: The mean
      age of the CF patients was 29 years (range 18-54). Almost 50% had a forced
      expiratory volume for one second percent predicted (FEV1%) below 50%, and 21%
      reported perceiving being in a bad phase of the disease. The CF patients reported
      lower (poorer) levels of hope than the GP sample, especially for the item scared
      about the future. However, they scored higher on inner strength and were younger,
      more often living alone, unmarried, not in paid work, but with similar
      educational levels. Levels of hope increased with increasing age in the CF
      patients but decreased for the GP subjects. The health variable that most
      affected hope in the CF sample was pulmonary function, not the presence of asthma
      or chronic lung infections. CONCLUSIONS: Persons growing up with CF experience
      many challenges. CF patients expressed slightly lower levels of hope and were
      more scared of the future. They scored higher on inner strength than the general
      population.

PMID- 15024377
TI  - Thoracic aortic aneurysm with aortobronchial fistula: a thirteen-year experience.
AB  - PURPOSE: This study investigated the causes of aortobronchial fistula, clinical
      features, diagnostic modalities, and prognostic factors. PARTICIPANTS: A
      retrospective analysis of 17 patients with aortobronchial fistula secondary to
      thoracic aortic aneurysm was studied. METHODS: Retrospective chart review was
      used. RESULTS: Atherosclerosis (47.1%), infection (23.5%), and previous thoracic
      vascular surgery (17.6%) accounted for most causes. Most patients (94.1%)
      experienced at least 1 episode of hemoptysis. Chest computer tomography is the
      most useful tool and revealed hematoma or consolidation around the aneurysm in
      more than half of our patients. Bronchoscopy and aortoangiogram frequently did
      not demonstrate an aortobronchial fistula. The 6 patients in the surgery group
      all survived, in contrast to 100% mortality in the non-surgery group. The average
      interval between initial presentation of hemoptysis and surgical intervention in
      the surgery group is 68 days, in contrast to 170 days between initial
      presentation of hemoptysis and death in the non-surgery group. CONCLUSIONS: A
      high index of suspicion will decrease delayed diagnosis. Early diagnosis and
      emergent surgery are 2 prognostic factors for survival.

PMID- 15024380
TI  - Intensity-modulated radiation therapy.

PMID- 15024378
TI  - FUO due to sarcoidosis-lymphoma syndrome.
AB  - This is a patient who presented as a fever of unknown origin (FUO) due to
      sarcoidosis-lymphoma syndrome. In favor of sarcoidosis was an elevated
      angiotensin-converting enzyme level, hypercalciuria, and bilateral hilar
      adenopathy on chest x-ray and chest CT. CT-guided biopsy of a hilar node revealed
      B-cell lymphoma. The differential diagnosis of sarcoidosis versus lymphoma and
      sarcoidosis-lymphoma syndrome as a cause of fever of unknown origin is discussed
      in this article.

PMID- 15024381
TI  - Age at onset: important marker of genetic heterogeneity in Alzheimer's disease.

PMID- 15024382
TI  - Pharmacogenetics in the treatment of breast cancer.

PMID- 15024383
TI  - A receptor for green tea polyphenol EGCG.
AB  - The major polyphenol in green tea, (-)-epigallocatechin-3-gallate (EGCG), has
      been shown to prevent carcinogenesis. We have identified a receptor that mediates
      the anticancer activity of EGCG. Expression of the metastasis-associated 67-kDa
      laminin receptor confers EGCG responsiveness to cancer cells at physiologically
      relevant concentrations. Experiments using surface plasmon resonance demonstrate
      binding of EGCG to the 67-kDa laminin receptor with a nanomolar K (d) value.

PMID- 15024384
TI  - A novel ADP- and zinc-binding fold from function-directed in vitro evolution.
AB  - A great challenge to biologists is to create proteins with novel folds and
      tailored functions. As an alternative to de novo protein design, we investigated
      the structure of a randomly generated protein targeted to bind ATP. The crystal
      structure reveals a novel alpha/beta fold bound to its ligand, representing both
      the first protein structure derived from in vitro evolution and the first
      nucleotide-binding protein stabilized by a zinc ion.

PMID- 15024385
TI  - p27 binds cyclin-CDK complexes through a sequential mechanism involving binding
      induced protein folding.
AB  - p27 controls cell proliferation by binding and regulating nuclear cyclin
      dependent kinases (CDKs). In addition, p27 interacts with other nuclear and
      cytoplasmic targets and has diverse biological functions. We seek to understand
      how the structural and dynamic properties of p27 mediate its several functions.
      We show that, despite showing disorder before binding its targets, p27 has
      nascent secondary structure that may have a function in molecular recognition.
      Binding to Cdk2-cyclin A is accompanied by p27 folding, and kinetic data suggest
      a sequential mechanism that is initiated by binding to cyclin A. p27 regulates
      CDK-cyclin complexes involved directly in cell cycle control and does not
      interact with other closely related CDKs. We show that p27-cyclin interactions
      are an important determinant of this specificity and propose that the homologous
      cell cycle regulators p21 and p57 function by a similar sequential, folding-on
      binding mechanism.

PMID- 15024386
TI  - The Mad2 spindle checkpoint protein has two distinct natively folded states.
AB  - The spindle checkpoint delays chromosome segregation in response to misaligned
      sister chromatids during mitosis, thus ensuring the fidelity of chromosome
      inheritance. Through binding to Cdc20, the Mad2 spindle checkpoint protein
      inhibits the target of this checkpoint, the ubiquitin protein ligase
      APC/C(Cdc20). We now show that without cofactor binding or covalent modification
      Mad2 adopts two distinct folded conformations at equilibrium (termed N1-Mad2 and
      N2-Mad2). The structure of N2-Mad2 has been determined by NMR spectroscopy. N2
      Mad2 is much more potent in APC/C inhibition. Overexpression of a Mad2 mutant
      that specifically sequesters N2-Mad2 partially blocks checkpoint signaling in
      living cells. The two Mad2 conformers interconvert slowly in vitro, but
      interconversion is accelerated by a fragment of Mad1, an upstream regulator of
      Mad2. Our results suggest that the unusual two-state behavior of Mad2 is critical
      for spindle checkpoint signaling.

PMID- 15024387
TI  - Expression profiling using a hexamer-based universal microarray.
AB  - We describe a transcriptional analysis platform consisting of a universal micro
      array system (UMAS) combined with an enzymatic manipulation step that is capable
      of generating expression profiles from any organism without requiring a priori
      species-specific knowledge of transcript sequences. The transcriptome is
      converted to cDNA and processed with restriction endonucleases to generate low
      complexity pools (approximately 80-120) of equal length DNA fragments. The
      resulting material is amplified and detected with the UMAS system, comprising all
      possible 4,096 (4(6)) DNA hexamers. Ligation to the arrays yields thousands of 14
      mer sequence tags. The compendium of signals from all pools in the array-of
      universal arrays comprises a full-transcriptome expression profile. The
      technology was validated by analysis of the galactose response of Saccharomyces
      cerevisiae, and the resulting profiles showed excellent agreement with the
      literature and real-time PCR assays. The technology was also used to demonstrate
      expression profiling from a hybrid organism in a proof-of-concept experiment
      where a T-cell receptor gene was expressed in yeast.

PMID- 15024388
TI  - Capturing and profiling adult hair follicle stem cells.
AB  - The hair follicle bulge possesses putative epithelial stem cells.
      Characterization of these cells has been hampered by the inability to target
      bulge cells genetically. Here, we use a Keratin1-15 (Krt1-15, also known as K15)
      promoter to target mouse bulge cells with an inducible Cre recombinase construct
      or with the gene encoding enhanced green fluorescent protein (EGFP), which allow
      for lineage analysis and for isolation of the cells. We show that bulge cells in
      adult mice generate all epithelial cell types within the intact follicle and hair
      during normal hair follicle cycling. After isolation, adult Krt1-15-EGFP-positive
      cells reconstituted all components of the cutaneous epithelium and had a higher
      proliferative potential than Krt1-15-EGFP-negative cells. Genetic profiling of
      hair follicle stem cells revealed several known and unknown receptors and
      signaling pathways important for maintaining the stem cell phenotype. Ultimately,
      these findings provide potential targets for the treatment of hair loss and other
      disorders of skin and hair.

PMID- 15024389
TI  - A nanoliter-scale nucleic acid processor with parallel architecture.
AB  - The purification of nucleic acids from microbial and mammalian cells is a crucial
      step in many biological and medical applications. We have developed microfluidic
      chips for automated nucleic acid purification from small numbers of bacterial or
      mammalian cells. All processes, such as cell isolation, cell lysis, DNA or mRNA
      purification, and recovery, were carried out on a single microfluidic chip in
      nanoliter volumes without any pre- or postsample treatment. Measurable amounts of
      mRNA were extracted in an automated fashion from as little as a single mammalian
      cell and recovered from the chip. These microfluidic chips are capable of
      processing different samples in parallel, thereby illustrating how highly
      parallel microfluidic architectures can be constructed to perform integrated
      batch-processing functionalities for biological and medical applications.

PMID- 15024390
TI  - Differentiating germ cells can revert into functional stem cells in Drosophila
      melanogaster ovaries.
AB  - Many tissues including blood, skin, gut and germ cells are continuously
      maintained by tissue stem cells. Under certain conditions, however, other organs
      can undergo repair using stem-cell-like progenitors generated by cell de
      differentiation. Cell fates have been broadened experimentally, but mechanisms
      allowing de-differentiation to a stem cell state are poorly known. Germline stem
      cells begin to differentiate by forming interconnected germ cell cysts
      (cystocytes), and under certain conditions male mouse cystocytes have been
      postulated to revert into functional progenitors. Here we report that four- and
      eight-cell Drosophila germline cystocytes generated either in second instar
      larval ovaries or in adults over-producing the BMP4-like stem cell signal
      Decapentaplegic efficiently convert into single stem-like cells. These de
      differentiated cells can develop into functional germline stem cells and support
      normal fertility. Our results show that cystocytes represent a relatively
      abundant source of regenerative precursors that might help replenish germ cells
      after depletion by genotoxic chemicals, radiation or normal ageing. More
      generally, Drosophila cystocytes now provide a system for studying de
      differentiation and its potential as a source of functional stem cells.

PMID- 15024391
TI  - A DNA vaccine induces SARS coronavirus neutralization and protective immunity in
      mice.
AB  - Public health measures have successfully identified and contained outbreaks of
      the severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), but concerns
      remain over the possibility of future recurrences. Finding a vaccine for this
      virus therefore remains a high priority. Here, we show that a DNA vaccine
      encoding the spike (S) glycoprotein of the SARS-CoV induces T cell and
      neutralizing antibody responses, as well as protective immunity, in a mouse
      model. Alternative forms of S were analysed by DNA immunization. These expression
      vectors induced robust immune responses mediated by CD4 and CD8 cells, as well as
      significant antibody titres, measured by enzyme-linked immunosorbent assay.
      Moreover, antibody responses in mice vaccinated with an expression vector
      encoding a form of S that includes its transmembrane domain elicited neutralizing
      antibodies. Viral replication was reduced by more than six orders of magnitude in
      the lungs of mice vaccinated with these S plasmid DNA expression vectors, and
      protection was mediated by a humoral but not a T-cell-dependent immune mechanism.
      Gene-based vaccination for the SARS-CoV elicits effective immune responses that
      generate protective immunity in an animal model.

PMID- 15024393
TI  - Perennial water ice identified in the south polar cap of Mars.
AB  - The inventory of water and carbon dioxide reservoirs on Mars are important clues
      for understanding the geological, climatic and potentially exobiological
      evolution of the planet. From the early mapping observation of the permanent ice
      caps on the martian poles, the northern cap was believed to be mainly composed of
      water ice, whereas the southern cap was thought to be constituted of carbon
      dioxide ice. However, recent missions (NASA missions Mars Global Surveyor and
      Odyssey) have revealed surface structures, altimetry profiles, underlying buried
      hydrogen, and temperatures of the south polar regions that are thermodynamically
      consistent with a mixture of surface water ice and carbon dioxide. Here we
      present the first direct identification and mapping of both carbon dioxide and
      water ice in the martian high southern latitudes, at a resolution of 2 km, during
      the local summer, when the extent of the polar ice is at its minimum. We observe
      that this south polar cap contains perennial water ice in extended areas: as a
      small admixture to carbon dioxide in the bright regions; associated with dust,
      without carbon dioxide, at the edges of this bright cap; and, unexpectedly, in
      large areas tens of kilometres away from the bright cap.

PMID- 15024394
TI  - Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a
      noncompetitive manner.
AB  - The serotonin type 3 (5-HT(3)) receptor is the only ligand-gated ion channel
      receptor for serotonin (5-HT). 5-HT(3) receptors play an important role in
      modulating the inhibitory action of dopamine in mesocorticolimbic brain regions.
      Neuroleptic drugs are commonly thought to exert their psychopharmacological
      action mainly through dopamine and serotonin type 2 (5-HT(2)) receptors. Except
      for clozapine, a direct pharmacological interaction of neuroleptics with 5-HT(3)
      receptors has not yet been described. Using the concentration-clamp technique, we
      investigated the effects of flupentixol, various phenothiazines, haloperidol,
      clozapine and risperidone on Na(+)-inward currents through 5-HT(3) receptors
      stably expressed in human embryonic kidney 293 cells, and through endogenous 5
      HT(3) receptors of murine N1E-115 neuroblastoma cells. In addition, we studied
      their effects on Ca(2+) influx, measured as a change in intracellular Ca(2+)
      concentrations ([Ca(2+)](i)). All neuroleptic drugs, but not risperidone,
      antagonized Na(+)- and Ca(2+)-inward currents evoked by 5-HT (10 microM for 2 s
      and 1 microM, respectively) in a voltage-independent manner. Only clozapine was a
      competitive antagonist, while all other compounds turned out to be
      noncompetitive. Fluphenazine and haloperidol affected membrane anisotropy at
      concentrations below their IC(50) values, indicating that a change in membrane
      anisotropy might contribute to their antagonistic effect at the 5-HT(3) receptor.
      Only structure analogues of flupentixol and fluphenazine with a lipophilic side
      chain were potent antagonists against 5-HT-evoked Na(+) and Ca(2+) currents.
      Since 5-HT(3) receptors modulate mesolimbic and mesocortical dopaminergic
      activity, the functional antagonism of neuroleptics at 5-HT(3) receptors may
      contribute to their antipsychotic efficacy and may constitute a not yet
      recognized pharmacological principle of these drugs.

PMID- 15024395
TI  - MAOA and persistent, pervasive childhood aggression.

PMID- 15024397
TI  - Long-term normalization of insulin sensitivity following biliopancreatic
      diversion for obesity.
AB  - OBJECTIVE: Assess insulin sensitivity and metabolic status of obese patients with
      stable weight loss at long term following biliopancreatic diversion (BPD).
      MATERIAL AND METHODS: The study was carried out in 36 nondiabetic severely obese
      patients undergoing BPD. Serum concentration of glucose, insulin and leptin were
      determined prior to and at 2 y following the operation. Insulin sensitivity was
      calculated according to the homeostatic model assessment (HOMA IR). RESULTS: At 2
      y following BPD, weight loss in all subjects corresponded to a marked drop in
      serum leptin concentration and improvement of insulin sensitivity within
      physiological range. Following the operation, HOMA IR values were positively
      correlated with serum leptin concentration independently of body mass index
      values. DISCUSSION: The stable weight loss following BPD at long term is
      accompanied by a complete reversal of the preoperative insulin resistance. Serum
      leptin concentration and HOMA IR data were positively related only
      postoperatively, suggesting that the action of factors that could influence the
      relation between leptin and insulin action in the obese status can be reverted.

PMID- 15024396
TI  - Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism
      spectrum disorder.
AB  - Mouse mutants of the homeobox transcription factor Engrailed2 (En2) and autistic
      individuals display similar cerebellar morphological abnormalities, which include
      hypoplasia and a decrease in the number of Purkinje cells. Human EN2 maps to
      7q36, a chromosomal region that has demonstrated suggestive linkage to autism
      spectrum disorder (ASD). To investigate EN2 for evidence of association with ASD,
      four single-nucleotide polymorphisms (SNPs) (rs3735653, rs1861972, rs1861973,
      rs2361689) that span the majority of the 8.0 kb gene were assessed by the
      transmission/disequilibrium test. Initially, 138 triads of autistic individuals
      and their parents were tested. Two intronic SNPs (rs1861972 and rs1861973)
      demonstrated significant association with autism (rs1861972, P=0.0018; rs1861973,
      P=0.0003; haplotype, P=0.000005). Flanking exonic SNPs (rs3735653 and rs2361689)
      did not display association. This analysis was then extended to include 167 small
      nuclear ASD pedigrees and significant association was again only observed for
      rs1861972 and rs1861973 under both the narrow and broad diagnostic criteria
      (narrow: rs1861972 P=0.0290, rs1861973 P=0.0073, haplotype P=0.0009; broad:
      rs1861972 P=0.0175, rs1861973 P=0.0107, haplotype P=0.0024). These data
      demonstrate association between a cerebellar patterning gene and ASD, suggesting
      a role for EN2 as a susceptibility locus and supporting a neurodevelopmental
      defect hypothesis in the etiology of autism.

PMID- 15024398
TI  - Association between indices of obesity and fasting hyperglycemia in Taiwan.
AB  - OBJECTIVE: To examine the association of body mass index (BMI), waist-hip ratio
      (WHR), and waist circumference (WC) with fasting hyperglycemia after adjustment
      for age, cigarette smoking, and alcohol use. DESIGN: A cross-sectional survey was
      conducted among individuals visiting four health-screening centers across Taiwan.
      SUBJECTS: A total of 61 568 subjects (28 734 men and 32 834 women) between 25 and
      64 years of age were included. Fasting hyperglycemia was defined as fasting
      plasma glucose > or =6.1 mmol/l or current diagnosis and use of insulin or
      hypoglycemic agent. RESULTS: Fasting hyperglycemia was found in 11.0% of men and
      8.3% of women. The factors significantly associated with fasting hyperglycemia in
      men were age, BMI, WHR, and heavy drinking, while for women these factors were
      age, educational level, BMI, WHR, and heavy smoking. For men, increased risk of
      fasting hyperglycemia started from age 30 to 34 years, BMI > or =25 kg/m2, and
      WHR > or =0.82. For women, increased risk of fasting hyperglycemia started from
      age 35 to 39 years, BMI > or =24 kg/m2, and WHR > or =0.74. WC lost its
      significance as a predictor of fasting hyperglycemia when WHR included in the
      model. CONCLUSION: This study found that central obesity and general obesity were
      both independently associated with increased risk of fasting hyperglycemia in
      Taiwanese. The relationship between fasting hyperglycemia and central fat
      accumulation (WHR) begins to appear at levels that would not be regarded as
      representing obesity in Western populations, suggesting the need to redefine
      cutoffs for central obesity in this population.

PMID- 15024399
TI  - Overweight and obesity in children with Attention-Deficit/Hyperactivity Disorder.
AB  - OBJECTIVE: Epidemiological studies suggest that adiposity in children may be
      associated with a reduced level of physical activity. Children with Attention
      Deficit/Hyperactivity Disorder (ADHD) are physically hyperactive as of early
      childhood and have been shown to exhibit higher levels of motor activity than
      normal. The aim of our study was to assess if the prevalence of overweight and
      obesity is lower in a population of boys with ADHD in comparison with the German
      healthy male reference population of the same age. DESIGN: Patients were
      investigated from 1999 until 2001 upon referral to the inpatient and outpatient
      unit of the Department of Child and Adolescent Psychiatry of the University of
      Aachen. SUBJECTS: A total of 97 male patients (mean age 10+/-2 y) with a
      diagnosis of ADHD according the Diagnostic and Statistical Manual of Mental
      Disorders (DSM-IV), who were free of potentially orexigenic medication and who
      had no further comorbid diagnosis apart from conduct disorder. MEASUREMENTS: BMI
      standard deviation scores (BMI-SDS) were calculated and compared to age-adapted
      reference value of the German population. RESULTS: Patients' mean BMI-SDS was
      significantly higher than the age-adapted reference values of the German
      population (P=0.038). Our sample included significantly more subjects than
      expected with a BMI > or =90th percentile (19.6%, P<0.001) and > or =97th
      percentile (7.2%, P=0.007). CONCLUSION: Surprisingly, being 'hyperactive' in the
      sense of the DSM-IV diagnosis of ADHD does not prevent the development or
      persistence of overweight and obesity in children. The examination of these
      children might be a helpful approach in the investigation of the relationship
      between obesity and its contributing psychological and behavioural factors.

PMID- 15024400
TI  - Plasma resistin concentration, hepatic fat content, and hepatic and peripheral
      insulin resistance in pioglitazone-treated type II diabetic patients.
AB  - OBJECTIVES: To study the effect of pioglitazone (PIO) on plasma resistin
      concentration, endogenous glucose production (EGP), and hepatic fat content (HFC)
      in patients with type II diabetes (T2DM). SUBJECTS: A total of 13 T2DM patients
      (age=51+/-2 y, BMI=29.7+/-1.1 kg/m(2), HbA(1c)=8.0+/-0.5%). METHODS: HFC
      (magnetic resonance spectroscopy) and basal plasma resistin concentration were
      quantitated before and after PIO treatment (45 mg/day) for 16 weeks. Subjects
      received a 3 h euglycemic insulin (100 mU/m(2)/min) clamp with 3-[(3)H] glucose
      to determine rates of EGP and tissue glucose disappearance (Rd) before and after
      PIO. RESULTS: PIO reduced fasting plasma glucose (10.3+/-0.7 to 7.6+/-0.6 mmol/l,
      P<0.001) and HbA(1c) (8.0+/-0.4 to 6.8+/-0.3%, P<0.001) despite increased body
      weight (83.2+/-3.4 to 86.3+/-3.4 kg, P<0.001). PIO improved Rd (4.9+/-0.4 to
      6.6+/-0.5 mg/kg/min, P<0.005) and reduced EGP (0.22+/-0.04 to 0.06+/-0.02
      mg/kg/min, P<0.01) during the insulin clamp. Following PIO, HFC decreased from
      21.1+/-3.5 to 11.2+/-2.1% (P<0.005), and plasma resistin decreased from 5.3+/-0.6
      to 3.5+/-0.3 ng/ml (P<0.01). Plasma resistin concentration correlated positively
      with HFC before (r=0.58, P<0.05) and after (r=0.55, P<0.05) PIO treatment. Taken
      collectively, plasma resistin concentration, before and after PIO treatment,
      correlated positively with hepatic fat content (r=0.66, P<0.001) and EGP during
      the insulin clamp (r=0.41, P<0.05). However, the plasma resistin concentration
      did not correlate with whole body glucose disposal (Rd) during the insulin clamp
      either before (r=-0.18, P=NS) or after (r=-0.13, P=NS) PIO treatment.
      CONCLUSIONS: PIO treatment in T2DM causes a significant decrease in plasma
      resistin concentration. The decrease in plasma resistin is positively correlated
      with the decrease in hepatic fat content and improvement in hepatic insulin
      sensitivity.

PMID- 15024401
TI  - Relationship of obesity to depression: a family-based study.
AB  - OBJECTIVE: To examine the relationship between obesity and depression in a sample
      of extremely obese individuals and their siblings and parents. SUBJECTS: A total
      of 1730 European Americans (558 men, 1172 women, aged 49.29+/-15.42 y, body mass
      index (BMI) of 35.57+/-11.53 kg/m(2)) and 373 African Americans (103 men, 270
      women, aged 44.85+/-15.08 years, BMI of 36.83+/-11.31 kg/m(2)) in a sample of 482
      nuclear families segregating extreme obesity and normal weight. MEASUREMENTS:
      Individual BMI, history of depression treatment and covariates (age, sex, race,
      education, marital status, socioeconomic status, chronic medical conditions and
      exercise program). RESULTS: Greater odds for depression were found for the obese,
      European American, women, the unmarried, the more educated, those with chronic
      physical disorder(s) and the offspring of depressed parents. A trend test found
      that the odds ratios for depression increased with BMI and number of chronic
      medical conditions (P<0.0001). Multivariate logistic regression analyses
      indicated that BMI, race, marital status, chronic medical conditions and family
      history were the predicators of depression for both the genders. Hierarchical
      analyses revealed that BMI significantly increased the risk above that predicated
      by the combined effects of all other variables. CONCLUSIONS: Extreme obesity was
      associated with the increased risk for depression across gender and racial
      groups, even after controlling for chronic physical disease, familial depression
      and demographic risk factors. More detailed research is needed to determine the
      underlying mechanisms.

PMID- 15024402
TI  - Intentional weight loss and smoking in young adults.
AB  - OBJECTIVE: To investigate whether current smoking and lifetime snuff use are
      associated with a lifetime history of major (>/=5 kg) intentional weight loss in
      young adults, and to examine the dependence of this association on familial
      factors. DESIGN: Cross-sectional population-based questionnaire survey of young
      adult Finnish twins participating in the fourth wave of the longitudinal FinnTwin
      16-study in 2000-2002. SUBJECTS: A total of 4521 young adult Finnish twins aged
      23-27 y. MEASUREMENTS: Questionnaire data on the number of intentional weight
      loss episodes and on body mass index (BMI), cigarette smoking and snuff use,
      educational level, and number of subjects' own children. RESULTS: Current daily
      smoking was strongly associated with a history of two or more intentional major
      weight-loss episodes (lost >/=5 kg twice or more lifetime) both in women odds
      ratio (OR 1.87; 95%; confidence interval (CI) 1.39-2.50) and in men (OR 2.00; 95%
      CI 1.37-2.90). Frequent lifetime snuff use was statistically significantly
      associated with recurrent intentional weight loss episodes in men (OR 1.51; 95%
      CI 1.08-2.13). Among the twin pairs discordant for daily smoking, the smoking
      twin was more likely than the nonsmoking co-twin to have recurrent intentional
      weight-loss episodes (OR 1.57; 95% CI 1.03-2.41). These episodes were also
      strongly associated with high BMI. Education was inversely related to recurrent
      intentional weight-loss episodes in men. CONCLUSION: Tobacco use is strongly
      associated with a lifetime history of recurrent intentional major weight-loss
      episodes in early adulthood. This represents a major challenge to existing
      attitudes on smoking prevention and the promotion of healthful weight control.

PMID- 15024403
TI  - Improved glucose homeostasis in mice overexpressing human UCP3: a role for AMP
      kinase?
AB  - OBJECTIVE: An unexplained phenotype of mice overexpressing human UCP3 is their
      improved glucose homeostasis. Since overexpression of UCP3 might affect the
      energy charge of the cell, we investigated whether these mice have an increased
      AMP-activated protein kinase (AMPK) activity. METHODS: Mitochondrial localisation
      of UCP3 was determined by immunoelectronmicroscopy and AMPK activity was measured
      in medial gastrocnemius of control mice and mice overexpressing human UCP3.
      RESULTS: Mice overexpressing human UCP3 had 5.8 fold higher levels of UCP3
      protein, for which mitochondrial localisation was confirmed by
      immunoelectronmicroscopy. The ATP/AMP ratio was significantly lower in mice over
      expressing UCP3 compared to the wild-type (10.9+/-1.6 vs 20.4+/-1.9 AU, P=0.03).
      Over-expression of UCP3 resulted in increased AMPK alpha1 activity (1.23+/-0.05
      vs 1.00+/-0.06 normalized values, P=0.004) and a tendency towards increased AMPK
      alpha2 activity (1.18+/-0.08 vs 1.00+/-0.10 normalized values, P=0.08).
      CONCLUSION: Increased AMPK activity provides a plausible explanation for the
      improved glucose tolerance characteristic for these mice.

PMID- 15024404
TI  - A nuclear function for armadillo/beta-catenin.
AB  - The Wnt signaling pathway provides key information during development of
      vertebrates and invertebrates, and mutations in this pathway lead to various
      forms of cancer. Wnt binding to its receptor causes the stabilization and nuclear
      localization of beta-catenin. Nuclear beta-catenin then functions to activate
      transcription in conjunction with the transcription factor TCF. A recent report
      has challenged this basic precept of the Wnt signaling field, arguing that the
      nuclear localization of beta-catenin may be unrelated to its function and that
      beta-catenin functions at the plasma membrane to activate this signaling pathway.
      Here we present evidence that the pathway in fact does depend on the nuclear
      localization of beta-catenin. We reexamine the functionality of various
      truncations of beta-catenin and find that only the most severe truncations are
      true signaling-null mutations. Further, we define a signaling-null condition and
      use it to show that membrane-tethered beta-catenin is insufficient to activate
      transcription. We also define two novel loss-of-function mutations that are not
      truncations, but are missense point mutations that retain protein stability.
      These alleles allow us to show that the membrane-bound form of activated beta
      catenin does indeed depend on the endogenous protein. Further, this activity is
      dependent on the presence of the C-terminus-specific negative regulator Chibby.
      Our data clearly show that nuclear localization of beta-catenin is in fact
      necessary for Wnt pathway activation.

PMID- 15024405
TI  - Sequence-specific inhibition of small RNA function.
AB  - Hundreds of microRNAs (miRNAs) and endogenous small interfering RNAs (siRNAs)
      have been identified from both plants and animals, yet little is known about
      their biochemical modes of action or biological functions. Here we report that 2'
      O-methyl oligonucleotides can act as irreversible, stoichiometric inhibitors of
      small RNA function. We show that a 2'-O-methyl oligonucleotide complementary to
      an siRNA can block mRNA cleavage in Drosophila embryo lysates and HeLa cell S100
      extracts and in cultured human HeLa cells. In Caenorhabditis elegans, injection
      of the 2'-O-methyl oligonucleotide complementary to the miRNA let-7 can induce a
      let-7 loss-of-function phenocopy. Using an immobilized 2'-O-methyl
      oligonucleotide, we show that the C. elegans Argonaute proteins ALG-1 and ALG-2,
      which were previously implicated in let-7 function through genetic studies, are
      constituents of a let-7-containing protein-RNA complex. Thus, we demonstrate that
      2'-O-methyl RNA oligonucleotides can provide an efficient and straightforward way
      to block small RNA function in vivo and furthermore can be used to identify small
      RNA-associated proteins that mediate RNA silencing pathways.

PMID- 15024408
TI  - Reason as our guide.

PMID- 15024411
TI  - Identifying protein function--a call for community action.

PMID- 15024412
TI  - The strange case of the armored scale insect and its bacteriome.

PMID- 15024409
TI  - Genetic and functional diversification of small RNA pathways in plants.
AB  - Multicellular eukaryotes produce small RNA molecules (approximately 21-24
      nucleotides) of two general types, microRNA (miRNA) and short interfering RNA
      (siRNA). They collectively function as sequence-specific guides to silence or
      regulate genes, transposons, and viruses and to modify chromatin and genome
      structure. Formation or activity of small RNAs requires factors belonging to gene
      families that encode DICER (or DICER-LIKE [DCL]) and ARGONAUTE proteins and, in
      the case of some siRNAs, RNA-dependent RNA polymerase (RDR) proteins. Unlike many
      animals, plants encode multiple DCL and RDR proteins. Using a series of insertion
      mutants of Arabidopsis thaliana, unique functions for three DCL proteins in miRNA
      (DCL1), endogenous siRNA (DCL3), and viral siRNA (DCL2) biogenesis were
      identified. One RDR protein (RDR2) was required for all endogenous siRNAs
      analyzed. The loss of endogenous siRNA in dcl3 and rdr2 mutants was associated
      with loss of heterochromatic marks and increased transcript accumulation at some
      loci. Defects in siRNA-generation activity in response to turnip crinkle virus in
      dcl2 mutant plants correlated with increased virus susceptibility. We conclude
      that proliferation and diversification of DCL and RDR genes during evolution of
      plants contributed to specialization of small RNA-directed pathways for
      development, chromatin structure, and defense.

PMID- 15024413
TI  - A spontaneous, recurrent mutation in divalent metal transporter-1 exposes a
      calcium entry pathway.
AB  - Divalent metal transporter-1 (DMT1/DCT1/Nramp2) is the major Fe(2+) transporter
      mediating cellular iron uptake in mammals. Phenotypic analyses of animals with
      spontaneous mutations in DMT1 indicate that it functions at two distinct sites,
      transporting dietary iron across the apical membrane of intestinal absorptive
      cells, and transporting endosomal iron released from transferrin into the
      cytoplasm of erythroid precursors. DMT1 also acts as a proton-dependent
      transporter for other heavy metal ions including Mn(2+), Co(2+), and Cu(2), but
      not for Mg(2+) or Ca(2+). A unique mutation in DMT1, G185R, has occurred
      spontaneously on two occasions in microcytic (mk) mice and once in Belgrade (b)
      rats. This mutation severely impairs the iron transport capability of DMT1,
      leading to systemic iron deficiency and anemia. The repeated occurrence of the
      G185R mutation cannot readily be explained by hypermutability of the gene. Here
      we show that G185R mutant DMT1 exhibits a new, constitutive Ca(2+) permeability,
      suggesting a gain of function that contributes to remutation and the mk and b
      phenotypes.

PMID- 15024414
TI  - Preferential duplication of conserved proteins in eukaryotic genomes.
AB  - A central goal in genome biology is to understand the origin and maintenance of
      genic diversity. Over evolutionary time, each gene's contribution to the genic
      content of an organism depends not only on its probability of long-term survival,
      but also on its propensity to generate duplicates that are themselves capable of
      long-term survival. In this study we investigate which types of genes are likely
      to generate functional and persistent duplicates. We demonstrate that genes that
      have generated duplicates in the C. elegans and S. cerevisiae genomes were 25%
      50% more constrained prior to duplication than the genes that failed to leave
      duplicates. We further show that conserved genes have been consistently prolific
      in generating duplicates for hundreds of millions of years in these two species.
      These findings reveal one way in which gene duplication shapes the content of
      eukaryotic genomes. Our finding that the set of duplicate genes is biased has
      important implications for genome-scale studies.

PMID- 15024415
TI  - No evidence of Neandertal mtDNA contribution to early modern humans.
AB  - The retrieval of mitochondrial DNA (mtDNA) sequences from four Neandertal fossils
      from Germany, Russia, and Croatia has demonstrated that these individuals carried
      closely related mtDNAs that are not found among current humans. However, these
      results do not definitively resolve the question of a possible Neandertal
      contribution to the gene pool of modern humans since such a contribution might
      have been erased by genetic drift or by the continuous influx of modern human DNA
      into the Neandertal gene pool. A further concern is that if some Neandertals
      carried mtDNA sequences similar to contemporaneous humans, such sequences may be
      erroneously regarded as modern contaminations when retrieved from fossils. Here
      we address these issues by the analysis of 24 Neandertal and 40 early modern
      human remains. The biomolecular preservation of four Neandertals and of five
      early modern humans was good enough to suggest the preservation of DNA. All four
      Neandertals yielded mtDNA sequences similar to those previously determined from
      Neandertal individuals, whereas none of the five early modern humans contained
      such mtDNA sequences. In combination with current mtDNA data, this excludes any
      large genetic contribution by Neandertals to early modern humans, but does not
      rule out the possibility of a smaller contribution.

PMID- 15024416
TI  - Taste perception: cracking the code.

PMID- 15024417
TI  - Interaction networks in yeast define and enumerate the signaling steps of the
      vertebrate aryl hydrocarbon receptor.
AB  - The aryl hydrocarbon receptor (AHR) is a vertebrate protein that mediates the
      toxic and adaptive responses to dioxins and related environmental pollutants. In
      an effort to better understand the details of this signal transduction pathway,
      we employed the yeast S. cerevisiae as a model system. Through the use of arrayed
      yeast strains harboring ordered deletions of open reading frames, we determined
      that 54 out of the 4,507 yeast genes examined significantly influence AHR signal
      transduction. In an effort to describe the relationship between these modifying
      genes, we constructed a network map based upon their known protein and genetic
      interactions. Monte Carlo simulations demonstrated that this network represented
      a description of AHR signaling that was distinct from those generated by random
      chance. The network map was then explored with a number of computational and
      experimental annotations. These analyses revealed that the AHR signaling pathway
      is defined by at least five distinct signaling steps that are regulated by
      functional modules of interacting modifiers. These modules can be described as
      mediating receptor folding, nuclear translocation, transcriptional activation,
      receptor level, and a previously undescribed nuclear step related to the
      receptor's Per-Arnt-Sim domain.

PMID- 15024418
TI  - Endosymbiosis: lessons in conflict resolution.

PMID- 15024421
TI  - NCEAS: promoting creative collaborations.

PMID- 15024422
TI  - Protein nanomachines.

PMID- 15024419
TI  - Phylogenomics of the reproductive parasite Wolbachia pipientis wMel: a
      streamlined genome overrun by mobile genetic elements.
AB  - The complete sequence of the 1,267,782 bp genome of Wolbachia pipientis wMel, an
      obligate intracellular bacteria of Drosophila melanogaster, has been determined.
      Wolbachia, which are found in a variety of invertebrate species, are of great
      interest due to their diverse interactions with different hosts, which range from
      many forms of reproductive parasitism to mutualistic symbioses. Analysis of the
      wMel genome, in particular phylogenomic comparisons with other intracellular
      bacteria, has revealed many insights into the biology and evolution of wMel and
      Wolbachia in general. For example, the wMel genome is unique among sequenced
      obligate intracellular species in both being highly streamlined and containing
      very high levels of repetitive DNA and mobile DNA elements. This observation,
      coupled with multiple evolutionary reconstructions, suggests that natural
      selection is somewhat inefficient in wMel, most likely owing to the occurrence of
      repeated population bottlenecks. Genome analysis predicts many metabolic
      differences with the closely related Rickettsia species, including the presence
      of intact glycolysis and purine synthesis, which may compensate for an inability
      to obtain ATP directly from its host, as Rickettsia can. Other discoveries
      include the apparent inability of wMel to synthesize lipopolysaccharide and the
      presence of the most genes encoding proteins with ankyrin repeat domains of any
      prokaryotic genome yet sequenced. Despite the ability of wMel to infect the
      germline of its host, we find no evidence for either recent lateral gene transfer
      between wMel and D. melanogaster or older transfers between Wolbachia and any
      host. Evolutionary analysis further supports the hypothesis that mitochondria
      share a common ancestor with the alpha-Proteobacteria, but shows little support
      for the grouping of mitochondria with species in the order Rickettsiales. With
      the availability of the complete genomes of both species and excellent genetic
      tools for the host, the wMel-D. melanogaster symbiosis is now an ideal system for
      studying the biology and evolution of Wolbachia infections.

PMID- 15024423
TI  - Circulation and chemotaxis of fetal hematopoietic stem cells.
AB  - The major site of hematopoiesis transitions from the fetal liver to the spleen
      and bone marrow late in fetal development. To date, experiments have not been
      performed to evaluate functionally the migration and seeding of hematopoietic
      stem cells (HSCs) during this period in ontogeny. It has been proposed that
      developmentally timed waves of HSCs enter the bloodstream only during distinct
      windows to seed the newly forming hematopoietic organs. Using competitive
      reconstitution assays to measure HSC activity, we determined the localization of
      HSCs in the mid-to-late gestation fetus. We found that multilineage
      reconstituting HSCs are present at low numbers in the blood at all timepoints
      measured. Seeding of fetal bone marrow and spleen occurred over several days,
      possibly while stem cell niches formed. In addition, using dual-chamber migration
      assays, we determined that like bone marrow HSCs, fetal liver HSCs migrate in
      response to stromal cell-derived factor-1alpha (SDF-1alpha); however, unlike bone
      marrow HSCs, the migratory response of fetal liver HSCs to SDF-1alpha is greatly
      increased in the presence of Steel factor (SLF), suggesting an important role for
      SLF in HSC homing to and seeding of the fetal hematopoietic tissues. Together,
      these data demonstrate that seeding of fetal organs by fetal liver HSCs does not
      require large fluxes of HSCs entering the fetal bloodstream, and that HSCs
      constitutively circulate at low levels during the gestational period from 12 to
      17 days postconception. Newly forming hematopoietic tissues are seeded gradually
      by HSCs, suggesting initial seeding is occurring as hematopoietic niches in the
      spleen and bone marrow form and become capable of supporting HSC self-renewal. We
      demonstrate that fetal and adult HSCs exhibit specific differences in chemotactic
      behavior. While both migrate in response to SDF-1alpha, fetal HSCs also respond
      significantly to the cytokine SLF. In addition, the combination of SDF-1alpha and
      SLF results in substantially enhanced migration of fetal HSCs, leading to
      migration of nearly all fetal HSCs in this assay. This finding indicates the
      importance of the combined effects of SLF and SDF-1alpha in the migration of
      fetal HSCs, and is, to our knowledge, the first demonstration of a synergistic
      effect of two chemoattractive agents on HSCs.

PMID- 15024425
TI  - Perceptual "read-out" of conjoined direction and disparity maps in extrastriate
      area MT.
AB  - Cortical neurons are frequently tuned to several stimulus dimensions, and many
      cortical areas contain intercalated maps of multiple variables. Relatively little
      is known about how information is "read out" of these multidimensional maps. For
      example, how does an organism extract information relevant to the task at hand
      from neurons that are also tuned to other, irrelevant stimulus dimensions? We
      addressed this question by employing microstimulation techniques to examine the
      contribution of disparity-tuned neurons in the middle temporal (MT) visual area
      to performance on a direction discrimination task. Most MT neurons are tuned to
      both binocular disparity and the direction of stimulus motion, and MT contains
      topographic maps of both parameters. We assessed the effect of microstimulation
      on direction judgments after first characterizing the disparity tuning of each
      stimulation site. Although the disparity of the stimulus was irrelevant to the
      required task, we found that microstimulation effects were strongly modulated by
      the disparity tuning of the stimulated neurons. For two of three monkeys,
      microstimulation of nondisparity-selective sites produced large biases in
      direction judgments, whereas stimulation of disparity-selective sites had little
      or no effect. The binocular disparity was optimized for each stimulation site,
      and our result could not be explained by variations in direction tuning, response
      strength, or any other tuning property that we examined. When microstimulation of
      a disparity-tuned site did affect direction judgments, the effects tended to be
      stronger at the preferred disparity of a stimulation site than at the
      nonpreferred disparity, indicating that monkeys can selectively monitor direction
      columns that are best tuned to an appropriate conjunction of parameters. We
      conclude that the contribution of neurons to behavior can depend strongly upon
      tuning to stimulus dimensions that appear to be irrelevant to the current task,
      and we suggest that these findings are best explained in terms of the strategy
      used by animals to perform the task.

PMID- 15024426
TI  - N-terminal phosphorylation of the dopamine transporter is required for
      amphetamine-induced efflux.
AB  - Amphetamine (AMPH) elicits its behavioral effects by acting on the dopamine (DA)
      transporter (DAT) to induce DA efflux into the synaptic cleft. We previously
      demonstrated that a human DAT construct in which the first 22 amino acids were
      truncated was not phosphorylated by activation of protein kinase C, in contrast
      to wild-type (WT) DAT, which was phosphorylated. Nonetheless, in all functions
      tested to date, which include uptake, inhibitor binding, oligomerization, and
      redistribution away from the cell surface in response to protein kinase C
      activation, the truncated DAT was indistinguishable from the full-length WT DAT.
      Here, however, we show that in HEK-293 cells stably expressing an N-terminal
      truncated DAT (del-22 DAT), AMPH-induced DA efflux is reduced by approximately
      80%, whether measured by superfusion of a population of cells or by amperometry
      combined with the patch-clamp technique in the whole cell configuration. We
      further demonstrate in a full-length DAT construct that simultaneous mutation of
      the five N-terminal serine residues to alanine (S/A) produces the same phenotype
      as del-22-normal uptake but dramatically impaired efflux. In contrast,
      simultaneous mutation of these same five serines to aspartate (S/D) to simulate
      phosphorylation results in normal AMPH-induced DA efflux and uptake. In the S/A
      background, the single mutation to Asp of residue 7 or residue 12 restored a
      significant fraction of WT efflux, whereas mutation to Asp of residues 2, 4, or
      13 was without significant effect on efflux. We propose that phosphorylation of
      one or more serines in the N-terminus of human DAT, most likely Ser7 or Ser12, is
      essential for AMPH-induced DAT-mediated DA efflux. Quite surprisingly, N-terminal
      phosphorylation shifts DAT from a "reluctant" state to a "willing" state for AMPH
      induced DA efflux, without affecting inward transport. These data raise the
      therapeutic possibility of interfering selectively with AMPH-induced DA efflux
      without altering physiological DA uptake.

PMID- 15024436
TI  - Role of infant feeding practices on the dental health of children.

PMID- 15024435
TI  - Promoting child social-emotional growth in primary care settings: using a
      developmental approach.
AB  - Clinicians are often faced with meaningful child/family mental health concerns,
      and yet suggesting a helpful course of action can be very challenging. While
      pediatricians routinely use a developmental framework to evaluate young
      children's cognitive, motor, and language skills, this occurs much less
      frequently for social-emotional development. Only recently have newer models of
      child development been put forth that emphasize the central role that emotions
      play in organizing the interactions among cognitive, motor, and language
      development across the lifespan. We review such a model of social-emotional
      growth and consider its implications for use in primary care settings.

PMID- 15024427
TI  - Extensive association of functionally and cytotopically related mRNAs with Puf
      family RNA-binding proteins in yeast.
AB  - Genes encoding RNA-binding proteins are diverse and abundant in eukaryotic
      genomes. Although some have been shown to have roles in post-transcriptional
      regulation of the expression of specific genes, few of these proteins have been
      studied systematically. We have used an affinity tag to isolate each of the five
      members of the Puf family of RNA-binding proteins in Saccharomyces cerevisiae and
      DNA microarrays to comprehensively identify the associated mRNAs. Distinct groups
      of 40-220 different mRNAs with striking common themes in the functions and
      subcellular localization of the proteins they encode are associated with each of
      the five Puf proteins: Puf3p binds nearly exclusively to cytoplasmic mRNAs that
      encode mitochondrial proteins; Puf1p and Puf2p interact preferentially with mRNAs
      encoding membrane-associated proteins; Puf4p preferentially binds mRNAs encoding
      nucleolar ribosomal RNA-processing factors; and Puf5p is associated with mRNAs
      encoding chromatin modifiers and components of the spindle pole body. We
      identified distinct sequence motifs in the 3'-untranslated regions of the mRNAs
      bound by Puf3p, Puf4p, and Puf5p. Three-hybrid assays confirmed the role of these
      motifs in specific RNA-protein interactions in vivo. The results suggest that
      combinatorial tagging of transcripts by specific RNA-binding proteins may be a
      general mechanism for coordinated control of the localization, translation, and
      decay of mRNAs and thus an integral part of the global gene expression program.

PMID- 15024437
TI  - Optimizing antibacterial therapy for community-acquired respiratory tract
      infections in children in an era of bacterial resistance.
AB  - The spread of antibacterial resistance in bacteria that commonly cause childhood
      community-acquired respiratory tract infections (RTIs), such as acute otitis
      media, community-acquired pneumonia, and acute pharyngitis, is a major healthcare
      problem. One of the foremost concerns is the rapid increase in penicillin,
      macrolide, and multidrug resistance in Streptococcus pneumoniae. There is also a
      rising prevalence of macrolide resistance in Streptococcus pyogenes in pockets of
      the United States, and beta-lactamase production in Haemophilus influenzae is
      widespread. Although data are limited, some evidence suggests that resistance to
      antibacterials can impair bacteriologic and clinical outcomes in childhood RTIs.
      Optimizing antibacterial use is important both in the care of individual patients
      and within strategies to address the wider problem of antibacterial resistance.
      This involves encouraging judicious antibacterial use (i.e., reducing overuse for
      viral infection and prophylaxis), and preventing misuse through the wrong choice,
      dosage, and duration of therapy. Given that initial therapy is usually empiric,
      antibacterials used to treat community-acquired RTIs in children should ideally
      have the following properties: an optimal targeted spectrum of activity; high
      clinical and bacteriologic efficacy against respiratory pathogens, including
      resistant strains; simple, short-course therapy; and good tolerability and
      palatability. New antibacterials will continue to have a role in the treatment of
      RTIs in children, especially where resistance compromises existing therapies.

PMID- 15024438
TI  - Can the diagnosis of pelvic inflammatory disease be excluded without a bimanual
      examination?
AB  - Now that urine-based tests are available for detection of Chlamydia and
      gonorrhea, we sought to determine whether history alone could be used to exclude
      pelvic inflammatory disease (PID) and thus preclude a bimanual examination. The
      study design was a retrospective chart review. The study population included
      females aged 15-24 years diagnosed with PID. Outcome measures were documentation
      of screening symptoms (abdominal pain, dyspareunia, or abnormal vaginal bleeding)
      in the medical record. Our primary analysis was sensitivity of screening symptoms
      for identifying patients with PID. At least 1 of the 3 screening symptoms was
      reported by 93% of the PID group. If absence of all 3 screening symptoms were
      used as a screening instrument to exclude a bimanual examination, many women with
      lower genital tract symptoms could be evaluated noninvasively. However, this
      approach could result in delayed diagnosis of PID in a small number of patients.
      Before this strategy is adopted, a large prospective study is needed.

PMID- 15024439
TI  - Diagnosis and management of acute otitis media in Michigan.
AB  - We surveyed pediatricians (PEDs), family physicians (FPs), otolaryngologists
      (ENTs), and emergency physicians (ERs) from across Michigan (100 each), as well
      as 30 nationally recognized experts about their clinical approach to acute otitis
      media (AOM). The overall response rate was 52%. There was substantial variation
      within each group with respect to diagnostic criteria and clinical decision
      making, but no significant differences among groups. The 63% of respondents who
      considered symptoms among their diagnostic criteria for AOM were 3.8-fold more
      likely to defer therapy for an asymptomatic toddler with a bulging, red, immobile
      tympanic membrane (TM) (95% Confidence Interval (CI) 1.53, 9.74), but 24% of
      respondents stated that they would prescribe oral antibiotics for a symptomatic
      child with a red TM, even in the absence of a middle ear effusion. These data
      suggest that diagnostic criteria are a major factor determining whether
      clinicians prescribe antibiotics to a particular patient.

PMID- 15024440
TI  - Dental infections as a cause of persistent fever in a patient with chronic
      granulomatous disease.

PMID- 15024442
TI  - Group A beta-hemolytic streptococcal vulvovaginitis: diagnosis by rapid antigen
      testing.

PMID- 15024441
TI  - Life-threatenting ceftriaxone-induced immune hemolytic anemia in a child with
      Crohn's disease.

PMID- 15024443
TI  - In-utero lead exposure after maternal ingestion of Mexican pottery: inadequacy of
      the lead exposure questionnaire.

PMID- 15024444
TI  - An asymptomatic middle-school-age boy with a blood lead concentration of 173
      microg/dL.

PMID- 15024446
TI  - Unusual rhythm problems in acute rheumatic fever: two patient reports.

PMID- 15024447
TI  - Metabolic acidosis and coma in a child with acetaminophen toxicity.

PMID- 15024445
TI  - Ribavirin for SARS in children.

PMID- 15024448
TI  - Fulminant hemorrhagic pneumonitis.

PMID- 15024449
TI  - Dilated cardiomyopathy.

PMID- 15024451
TI  - Wireless capsule endoscopy: light at the end of the tunnel for obscure
      gastrointestinal bleeding.

PMID- 15024452
TI  - Biostatistics 103: qualitative data - tests of independence.

PMID- 15024453
TI  - Audit of investigations in patients with iron deficiency anaemia.
AB  - BACKGROUND: Patients with iron deficiency anaemia (IDA) are commonly referred to
      the gastroenterologists for exclusion of gastrointestinal (GI) pathologies. The
      British Society of Gastroenterology (BSG) has published a guideline for
      management of IDA. As recommended by this guideline, all patients should have
      examinations of both upper and lower GI tract with the exception of pre
      menopausal women younger than 45 years old. The primary aim of this audit was to
      determine how thoroughly patients referred to our unit at the Singapore General
      Hospital had been investigated. The secondary aim was to determine the yield rate
      of gastroscopy and lower gastrointestinal investigations (colonoscopy or barium
      enema) in our patients. METHODS: We reviewed the case notes of patients who
      underwent gastroscopy for indication of anaemia between the period from April to
      December 1999. We classified iron deficiency anaemia as having haemoglobin of
      lower than reference range with either low ferritin level or iron/ TIBC ratio of
      less than 10%. RESULTS: Of a total of 326 patients reviewed, 172 patients (65
      men, 109 women) met the inclusion criteria of IDA. The median age for the group
      was 59 (Range 16 to 88) years old and there were 107 (62.2%) women. There were 31
      female patients younger than 45 years old (group A) and 141 patients in group B
      which included all the males and females older than 45 years old. Due to the
      method of data retrieval, all of the patients in group A fulfilled the standard
      set by the BSG guideline in that they all underwent gastroscopy. In this group,
      few gastrointestinal pathologies were found (one patient with peptic ulcer and
      two patients with colonic cancer). In terms of finding potential gastrointestinal
      causes of IDA, the yield rate of gastroscopy and colonoscopy were 3.2% and 13.6%
      respectively. In group B, 96 patients (68%) underwent upper and lower
      gastrointestinal investigations. Evaluation with gastroscopy showed peptic ulcer
      disease in 31 patients (21.7%) and gastric cancer in 9 patients (6.3%). Only 96
      patients (68.1%) in group B had lower gastrointestinal investigations. Twenty-six
      patients were found to have gastrointestinal disorders (12 patients with colon
      cancer, 10 colonic polyps, one Crohn's disease, one colonic tuberculosis and two
      haemorrhoids). The yield rate of gastroscopy and colonoscopy were 31.2% and 25%
      respectively. CONCLUSION: In this study of patients with confirmed IDA, we found
      much higher incidence of gastrointestinal disorders in the group of male and
      postmenopausal women than in the group with premenopausal women. Furthermore,
      over 30% of patients in this group did not undergo lower gastrointestinal tract
      investigations as recommended by the BSG guideline. We also found two cases of
      colonic cancer in the latter group. We would recommend bidirectional endoscopy
      for postmenopausal women and men with IDA. For premenopausal women, we would
      recommend similar approach unless there are clinical pointers to dietary iron
      deficiency or menorrhagia.

PMID- 15024454
TI  - An outbreak of acute haemorrhagic conjunctivitis in Melaka, Malaysia.
AB  - This paper reports a second outbreak of acute haemorrhagic conjunctivitis due to
      coxsackievirus A24 in peninsular Malaysia. Between June 2002 and early October
      2003, 10,327 patients, comprising 3,261 children and 7,066 adults, were treated
      for acute conjunctivitis in 11 government health clinics in the Melaka Tengah
      district of the state of Melaka. The figure grossly underestimates the size of
      the outbreak; as no patients treated in private clinics in the same district were
      included. Institution and household surveillance showed that the commonest
      presenting clinical feature of the illness was eye-discharge (91.2%), followed by
      foreign body sensation (81.8%), pain (78.3%) and subconjunctival haemorrhage
      (74.4%). The mean duration of illness was 6.5 and five days for patients with and
      without subconjunctival haemorrhage respectively.

PMID- 15024456
TI  - Patellar allografts in anterior cervical fusion - a two-year clinical and
      radiographic study.
AB  - Donor site morbidity, which occurs in 15% to 20% with the use of autografts for
      anterior cervical fusion, is eliminated with the use of allografts. While
      allografts from the iliac crest, ribs, fibula, femoral head and skull have been
      used in anterior cervical fusion, the use of patellar allografts has not been
      previously reported. Twenty-two patients underwent Cloward anterior cervical
      decompression and fusion using bicortical patellar allografts from 1993 to 1997.
      Fifteen patients, with a follow-up period of at least two years, were reviewed.
      Eleven patients (73.4%) had good or excellent results at an average of 42.8
      months after surgery. Fourteen patients (93.4%) achieved union. Two patients
      (13.3%) developed collapse of the graft with extrusion, one of whom still
      achieved union. These results are comparable to those reported of anterior
      cervical fusion using autografts or other types of allografts.

PMID- 15024455
TI  - Validation of a multiplex RT-PCR assay for screening significant oncogene fusion
      transcripts in children with acute lymphoblastic leukaemia.
AB  - In childhood acute lymphoblastic leukaemia (ALL), cytogenetics play an important
      role in diagnosis, allocation of treatment and prognosis. Conventional
      cytogenetic analysis, involving mainly karyotyping in our experience, has not
      been successful in a large proportion of cases due to inadequate metaphase
      spreads and poor chromosome morphology. Our aim is to develop a highly sensitive
      and specific method to screen simultaneously for the four most frequent fusion
      transcripts resulting from specific chromosomal translocations, namely, both the
      CML- and ALLtype BCR-ABL transcripts of t(9;22), E2A-PBX1 transcript of t(1;19),
      the MLL-AF4 transcript of t(4;11) and TEL-AML1 (also termed ETV6-CBFA2) of the
      cryptic t(12;21). A multiplex reverse transcription polymerase chain reaction
      protocol (RT-PCR) was developed and tested out on archival bone marrow samples
      and leukaemia cell lines. In all samples with a known translocation detected by
      cytogenetic techniques, the same translocation was identified by the multiplex
      PCR assay. Multiplex RT-PCR assay is an effective, sensitive, accurate and cost
      effective diagnostic tool which can improve our ability to accurately and rapidly
      risk-stratify patients with childhood ALL.

PMID- 15024457
TI  - Rising signal intensity observed in extra-axial brain tumours - a potential
      pitfall in perfusion MR imaging.
AB  - OBJECTIVE: Dynamic perfusion magnetic resonance (MR) techniques may be used to
      track the susceptibility effects of gadolinium contrast material as it passes
      through the brain. We describe three intracranial tumours that showed
      progressively rising signal intensity above the baseline during first-pass
      contrast-enhanced echo-planar imaging (EPI) MR imaging. METHODS: Multiphase
      acquisition using single-shot EPI was performed during rapid bolus contrast
      injection. Ten studies, using either spin-echo or gradient-echo EPI sequences,
      were carried out in eight patients with intracranial tumours. Time-signal
      intensity graphs and regional cerebral blood volume (rCBV) were reviewed.
      RESULTS: In seven studies, the signal intensity within the tumour showed initial
      signal drop and quick recovery to baseline and increased rCBV. Three studies
      revealed progressively rising signal intensity. These patients were all imaged
      using a spin-echo EPI method and subsequent histology revealed meningioma,
      hemangiopericytoma and pinealblastoma. CONCLUSION: Dynamic perfusion MR methods
      may be used to study intracranial tumours. However, in short relaxation time spin
      echo EPI, the T1- effect of gadolinium becomes noticeable during the first-pass
      acquisition in extra-axial tumours that lack a well-developed blood-brain
      barrier. Careful selection of patients and pulse sequence is essential to avoid
      this potential pitfall.

PMID- 15024458
TI  - Review of peripherally inserted central catheters in the Singapore acute-care
      hospital.
AB  - Peripherally inserted central catheters are frequently used whenever reliable
      central venous access is required for a prolonged period of time. The objective
      of this study was to review utilisation profile, complication rates and outcomes
      of patients who were treated in our hospital with the therapy that required
      placement of the peripherally inserted central catheter. We reviewed the medical
      records of all patients who had peripherally inserted central catheter placed
      between the beginning of July and the end of October 2002. Five patients who
      remained hospitalised at the time of review (six weeks after the last day of
      study period) were excluded. Seventy-eight patients with 94 peripherally inserted
      central catheters were analysed in detail. Sixty-four peripherally inserted
      central catheters (68.1%) were placed for prolonged antibiotic therapy, 27
      (28.7%) mainly to administer total parenteral nutrition and 3 (3.2%) were
      inserted for other reasons. Catheters were in place before removal for a mean
      17.2 days. Forty-eight catheters (51.1%) were removed after completion of therapy
      on average 20.2 days after insertion. Complications were frequent but minor.
      Thirty-three catheters (35.1%) were removed due to catheter-related
      complications. The most common complication were phlebitis followed by accidental
      removal. In summary, peripherally inserted central catheters proved to be
      reasonably safe and a reliable way of providing therapy requiring prolonged
      intravenous access. Complications were frequent but relatively minor.
      Complication rates in our study were similar to those reported in other studies
      on this subject. Peripherally inserted central catheters remain a convenient and
      reasonable alternative to other centrally or peripherally inserted venous
      devices.

PMID- 15024459
TI  - Conservative management of recurrent bilateral ovarian cysts in pregnancy: a case
      report.
AB  - This is a case report of recurrent bilateral ovarian cysts in pregnancy. From the
      clinical picture these are likely to be theca lutein cysts. A lookout for
      complications involving these cysts is important. Patients can be managed
      conservatively in the absence of complications. Likely mechanisms for the
      causation of this phenomenon are discussed.

PMID- 15024460
TI  - Paediatric acute epiglottitis re-visited.
AB  - INTRODUCTION: Paediatric acute epiglottitis is rare in Asia. The National
      University Hospital in Singapore has seen only two cases of paediatric acute
      epiglottitis in the last 10 years. The topic is re-visited here to remind
      physicians of its acutely dramatic progression. CLINICAL PICTURE: Both boys
      presented with a viral prodrome which progressed within hours to life-threatening
      upper airway obstruction. Examination revealed an inflamed epiglottitis.
      TREATMENT: They were successfully intubated and treated with intravenous
      antibiotics. OUTCOME: Both recovered uneventfully. CONCLUSION: Paediatric acute
      epiglottitis has declined markedly in the West with widespread vaccination
      against HiB. In contrast, the incidence of invasive HiB disease in Asia has
      always been low despite limited vaccination. Clinicians must remain vigilant of
      the possibility of acute epiglottitis in a child with "flu".

PMID- 15024461
TI  - Clinics in diagnostic imaging (90). Childhood nasopharyngeal carcinoma.
AB  - An 11-year-old boy presented with a nasopharyngeal mass that was thought to
      represent a juvenile angiofibroma based on the initial clinical and radiological
      evaluation. Partial tumour resection was performed. Resected specimen revealed
      histological diagnosis of undifferentiated carcinoma. Further evaluation of the
      tumour including MR imaging, radioisotope bone scan, CT thorax and abdomen were
      performed. Differential diagnoses of childhood nasopharyngeal masses were
      discussed. The differences between childhood NPC and adult NPC, rhabdomyosarcoma,
      malignant lymphoma and juvenile nasopharyngeal angiofibroma were also discussed.

PMID- 15024465
TI  - Mapping of AFLP markers linked to seed coat colour loci in Brassica juncea (L.)
      Czern.
AB  - Association mapping of the seed-coat colour with amplified fragment length
      polymorphism (AFLP) markers was carried out in 39 Brassica juncea lines. The
      lines had genetically diverse parentages and varied for seed-coat colour and
      other morphological characters. Eleven AFLP primer combinations were used to
      screen the 39 B. juncea lines, and a total of 335 polymorphic bands were
      detected. The bands were analysed for association with seed-coat colour using
      multiple regression analysis. This analysis revealed 15 markers associated with
      seed-coat colour, obtained with eight AFLP primer combinations. The marker E
      ACA/M-CTG(350 )explained 69% of the variation in seed-coat colour. This marker
      along with markers E-AAC/M-CTC(235 )and E-AAC/M-CTA(250) explained 89% of the
      total variation. The 15 associated markers were validated for linkage with the
      seed-coat colour loci using a recombinant inbred line (RIL) mapping population.
      Bands were amplified with the eight AFLP primer combinations in 54 RIL progenies.
      Of the 15 associated markers, 11 mapped on two linkage groups. Eight markers were
      placed on linkage group 1 at a marker density of 6.0 cM, while the remaining
      three were mapped on linkage group 2 at a marker density of 3.6 cM. Marker E
      ACA/M-CTG(350 )co-segregated with Gene1 controlling seed-coat colour; it was
      specific for yellow seed-coat colour and mapped to linkage group 1. Marker E
      AAC/M-CTC(235) (AFLP8), which had been studied previously, was present on linkage
      group 2; it was specific for brown seed-coat colour. Since AFLP markers are not
      adapted for large-scale applications in plant breeding, it is important to
      convert these to sequence-characterised amplified region (SCAR) markers. Marker E
      AAC/M-CTC(235) (AFLP8) had been previously converted into a SCAR. Work is in
      progress to convert the second of the linked markers, E-ACA/M-CTG(350), to a
      SCAR. The two linked AFLP markers converted to SCARs will be useful for
      developing yellow-seeded B. juncea lines by means of marker-assisted selection.

PMID- 15024462
TI  - [Diagnosis and follow-up management of postoperative bacterial osteitis].
AB  - Osteomyelitis is a term used to describe bone infection. As a complication, it
      can occur after open bone fracture and is associated with the implantation of
      foreign material. Acute disease after surgery starts after about 7 days to 4
      weeks, and is characterized by a suppurative infection. Chronic infection
      sometimes manifests even years after surgery with a purulent sinus tract.
      Diagnosis is based on clinical signs, microbiological culture, histological
      evidence of the presence of granulocytes, and on radiological signs of
      osteomyelitis. However, it is sometimes difficult to distinguish between merely
      soft tissue involvement and osteomyelitis, especially in the presence of
      implanted material. Management includes a thoroughly surgical debridement and
      antibiotic treatment. Though frequently used, bacterial cultures of swabs of
      superficial wounds or fistulas are often misleading, whereas needle biopsy or
      surgical sampling with at least three tissue samples provides more reliable
      information. Because of the prolonged antibiotic treatment, it is mandatory for a
      successful outcome to culture the microorganism in order to determine antibiotic
      susceptibility. In addition to conventional radiological approaches, magnetic
      resonance imaging has become useful for the diagnosis of osteomyelitis. Despite
      significant progress in antibiotic therapy and orthopedic surgery, osteomyelitis
      remains difficult to treat and often relapses, even after years.

PMID- 15024466
TI  - Comparative analysis of seeded and vegetative biotype buffalograsses based on
      phylogenetic relationship using ISSRs, SSRs, RAPDs, and SRAPs.
AB  - Buffalograss [ Buchloe dactyloides (Nutt.) Englem.] is the only native grass that
      is being used extensively as a turfgrass in the Great Plains region. Its low
      growth habit, drought resistance, and low-maintenance requirement make it
      attractive as a turfgrass species. Our objective was to obtain an overview on the
      genetic relatedness among and within seeded and vegetative biotype buffalograsses
      using inter-simple sequence repeats (ISSRs), random amplified polymorphic DNA
      (RAPDs), sequence-related amplified polymorphisms (SRAPs), and simple sequence
      repeats (SSRs) markers that were derived from related species (maize, pearl
      millet, sorghum, and sugarcane). Twenty individuals per cultivar were genotyped
      using 30 markers from each marker system. All buffalograss cultivars were
      uniquely fingerprinted by all four marker systems. Mean genetic similarities were
      estimated at 0.52, 0.51, 0.62, and 0.57 using SSRs, ISSRs, SRAPs, and RAPDs,
      respectively. Two main clusters separating the seeded-biotype from the vegetative
      biotype cultivars were produced using UPGMA analysis. Further subgroupings were
      unequivocal. The Mantel test resulted in a very good fit (SRAP=0.92, ISSR=0.90)
      to good fit (RAPD=0.86, SSR=0.88) of cophenetic values. Comparing the four marker
      systems to each other, RAPD and SRAP similarity indices were highly correlated (
      r=0.73), while Spearman's rank correlation coefficient between RAPDs and SSRs was
      r=0.24 and between ISSRs and SSRs was r=0.66. A genotype-assignment analytical
      approach might be useful for cultivar identification and property rights
      protection. Polymorphic SRAPs were abundant and demonstrated genetic diversity
      among closely related cultivars.

PMID- 15024467
TI  - [Difficult cases in pediatric urology. Treatment should be coordinated by a
      specialist center].

PMID- 15024468
TI  - [Competence network "community acquired pneumonia" (CAPNETZ). A first interim
      report].
AB  - Community acquired pneumonia (CAP) is a disease with high morbidity and mortality
      in Germany. However, no reliable data are available about spectrum and resistance
      of pathogens, course of the disease, evidence based guidelines for treatment, and
      pathogen-host interactions. The German Ministry of Education and Research
      recognized these deficits and therefore decided to fund CAPNETZ, a network of
      competence for community acquired pneumonia. CAPNETZ integrates components of
      health research as well as clinical and basic research (horizontal network) on
      one hand and supports cooperation among general practitioners, community
      hospitals and universities (vertical network). Since October 2002, 1547 patients
      with CAP have been recruited within the network. First results indicate, that new
      observations made in terms of symptoms, spectrum of pathogens involved, and
      treatment modalities will impact on the formulation of new guidelines for the
      management of community acquired pneumonia.

PMID- 15024470
TI  - [Painful ulcerating livid erythema in a 58-year old patient].

PMID- 15024469
TI  - [Stenosing gastric laryngitis in infancy].
AB  - A 2 month old female infant presented an aphonic voice and increasing inspiratory
      stridor due to a stenosing granulating laryngitis. A pathologically elevated
      gastroesophageal reflux was measured by means of 24-h pH-metry. After antireflux
      therapy (Cisaprid, sodium alginate and upright body positioning), the laryngitis
      was completely healed. This case confirms that an elevated gastroesophageal
      reflux in infants can cause chronic inflammatory diseases of the upper
      respiratory tract, especially of the larynx.

PMID- 15024471
TI  - [Repigmentation of persistent laser-induced hypopigmentation after tattoo
      ablation with the excimer laser].
AB  - Hypopigmented skin developed following tattoo removal with the Q-switched Nd:YAG
      laser. The hypopigmented area remained unchanged for over 4 years, until the use
      of the 308-nm xenon-chloride excimer laser induced a significant repigmentation
      in 40 sessions over 14 months. The excimer laser has the potential to influence
      the reduced activity of the melanocytes, as demonstrated with electron
      microscopy.

PMID- 15024472
TI  - [Graves disease. An important differential diagnostic consideration for systemic
      lupus erythematosus].
AB  - Graves disease is a frequent cause (30-40%) of hyperthyroidism. In addition to
      the classic clinical triad (goiter, exophthalmos and tachycardia), symptoms
      relating to other organ systems may be found at presentation. Cutaneous
      manifestations play an important role and may initially be the only clue to the
      endocrine disorder. A 40-year-old woman with Graves disease presented with
      features of systemic lupus erythematosus. She had a malar rash, as well as marked
      hematological changes (thrombocytopenia and leukocytopenia) and antinuclear
      antibodies (1:640). She also had hyperthyroidism and Graves disease-specific
      thyroid autoantibodies (TSIg). Her symptoms improved after initiation of
      antithyroid therapy. Because of overlapping clinical and laboratory criteria,
      Graves disease can mimic systemic lupus erythematosus. The differentiation
      requires careful laboratory evaluation. Moreover, both autoimmune diseases may
      occur in the same patient.

PMID- 15024474
TI  - [Belt and braces? The bad habit of redundant publication].

PMID- 15024473
TI  - [Surgical interdisciplinary cooperation].

PMID- 15024475
TI  - [Hans Gummel on the 30th anniversary of his death. 1954-1973 chief surgeon and
      director of the Robert-Rossle Clinic].

PMID- 15024479
TI  - [The changed approach to goiter, and struma resection respecting morphology and
      function. On Breitner B (1930), The goiter problem. Chirurg 2: 1009-1012 and
      Enderlen E (1932), Technique of goiter surgery. Chirurg 4: 293-300].

PMID- 15024477
TI  - [Laparoscopic esophagotomy without diverticular resection for treating epiphrenic
      diverticulum in hypertonic lower esophageal sphincter].
AB  - INTRODUCTION: As a rule, epiphrenic diverticulum occurs in combination with most
      diverse forms of dysfunction in the lower esophageal sphincter (LES) and/or in
      the esophagus itself. The main symptoms are dysphagia, pain, and regurgitation.
      The operation consists in myotomy, diverticulum resection, and partial
      fundoplication via abdominal or thoracic approach using conventional or minimally
      invasive technique. The main risk is postoperative suture dehiscence after
      diverticular resection. The present study was therefore undertaken to establish
      whether the operation succeeds in risk patients even without resection of the
      diverticulum. PATIENTS AND METHODS: In the period from 1998 to 2001, six patients
      were investigated preoperatively by means of esophageal manometry, endoscopy, and
      radiological barium swallow. The four risk patients underwent only myotomy of the
      LES, if appropriate, in combination with laparoscopic partial fundoplication.
      Resection of the diverticulum by thoracoscopy or with conventional thoracic
      technique was also performed in the two patients with normal risk. RESULTS: Three
      of the four risk patients showed normal postoperative courses after laparoscopic
      myotomy and rapidly became free of symptoms and were able to eat normally. One
      patient died perioperatively of pulmonary complications. After thoracic
      diverticulum resection, both patients developed postoperative suture dehiscence
      with a complicated course. Altogether, freedom from symptoms with regard to
      dysphagia and regurgitation could be attained in five out of six patients over a
      follow-up period of 6 to 25 months. CONCLUSION: In patients with epiphrenic
      diverticulum and disorder of LES function, myotomy alone without resection of the
      diverticulum may be sufficient to relieve or eliminate symptoms. Laparoscopy and
      the combination with partial fundoplication are the preferred techniques. In our
      opinion, this method must be considered in order to reduce the surgical risk in
      multimorbid and elderly patients.

PMID- 15024480
TI  - [PET scan diagnosis of lymph node metastases of esophageal carcinoma].

PMID- 15024481
TI  - [Surgery of primary inguinal hernias].

PMID- 15024483
TI  - A diagnostic expert system for structured reports, quality assessment, and
      training of residents in sonography.
AB  - BACKGROUND: The quality of medical reports on diagnostic procedures has a
      considerable impact on the quality of medical care. Handwritten or otherwise
      unstructured reports tend to be incomplete, whereas structured questionnaires are
      of limited flexibility and not considered case-adequate. Thus, medical reports of
      this kind may promote an incomplete and misleading documentation and, therefore,
      be problematic with respect to their reliability. METHODS: SonoConsult (SC), an
      expert system for structured and case-adequate documentation of sonographic
      findings with an additional diagnostic component, was evaluated with respect to
      user acceptance and suitability for enhancing the quality of reports and
      supporting sonographic beginners. The expectations and the attitudes of the users
      toward the program were evaluated by anonymous questionnaires. The documentation
      of findings and the diagnostic conclusions in 103 free text reports made by
      experienced examiners were evaluated by subjecting their information to a
      subsequent input into SC. Free text reports were checked for information that was
      asked by SC but not mentioned in the reports. In a series of 150 cases, the
      system diagnoses were blinded during input of findings into SC-questionnaires and
      the examiners' diagnostic conclusions were compared with the uncovered SC
      diagnoses with respect to forgotten diagnoses. RESULTS: The structured and data
      driven acquisition of information by the program was well accepted by the users.
      However, only a medium interest in the system-delivered diagnoses was noted. The
      program-generated reports were characterized by a more detailed description of
      the findings and a higher number of diagnoses in comparison to the unstructured
      reports before introduction of SC as the only documentation system. When unaware
      of the system diagnoses, information was entered into the questionnaires, and SC
      generated some diagnoses which were not mentioned by the examiners in their
      conclusions. The possibility to inspect the system diagnoses led to an
      enhancement of the number of diagnoses the examiners mentioned in their
      conclusions. By contrast, the examiners meant that the influence of the program
      on their conclusions was minimal or dispensable. Beginners in sonography
      acknowledged that the program led them to perform a complete examination in an
      adequate sequence. CONCLUSION: An expert system for the data-driven, case
      adequate information acquisition of abdominal ultrasound examinations may enhance
      the quality of the reports and, potentially, of the examinations at the same
      time. In addition, it may help beginners to learn a structured problem- and
      finding-adequate examination sequence.

PMID- 15024484
TI  - [Extraintestinal manifestations of inflammatory bowel disease].
AB  - Extraintestinal manifestations of Crohn's disease and ulcerative colitis are
      found in > 50% of all patients. These extraintestinal manifestations sometimes
      impair the overall life quality much more than the bowel-related symptoms.
      Extraintestinal manifestations need to be distinguished from secondary diseases
      or complications of inflammatory bowel diseases, as they require a different and
      specific therapy. Complications of the intestinal disease, such as vitamin
      deficiency or osteoporosis, can be treated specifically by substitution of
      vitamin D, calcium, or other vitamins. However, extraintestinal manifestations of
      Crohn's disease and ulcerative colitis, such as primary sclerosing cholangitis,
      arthritis or granulomatous inflammation of the skin, lung, or liver, are much
      more difficult to treat sufficiently. Almost every organ can be a localization of
      extraintestinal symptoms of inflammatory bowel diseases. It is important to
      acquire knowledge on these extraintestinal manifestations of Crohn's disease and
      ulcerative colitis to start the respective treatment early. Perhaps even more
      important, these extraintestinal symptoms can be the primary manifestation of
      Crohn's disease and ulcerative colitis. Therefore, they have to be recognized as
      extraintestinal manifestations to adequately treat the intestinal disease.

PMID- 15024485
TI  - [Systemic mastocytosis. Classification, symptoms, therapy].
AB  - BACKGROUND: Systemic mastocytoses are a group of diseases, which are
      characterized by accumulation and unusual growth of mast cells infiltrating two
      different organs or types of tissue. Two case reports are introduced.
      CLASSIFICATION: According to the new WHO classification of 2000, mastocytoses are
      separated into cutaneous and systemic mastocytoses. Systemic mastocytosis is
      subdivided into an indolent course with good prognosis and four subgroups with
      poor prognosis (systemic mastocytosis with associated clonal hematologic non-mast
      cell disease, aggressive systemic mastocytosis, mast cell leukemia, and mast cell
      sarcoma). GENETICS: Systemic mastocytoses are clonal disorders of mast cells and
      their progenitor cells, which may show point mutations of the protooncogene c
      kit. This gene codes for the stem cell receptor (CD117). THERAPY: Therapy of
      systemic mastocytosis depends on patient's symptoms. There is no known cure of
      the disease. Besides diet and avoidance of skin irritations, symptoms are treated
      with H(1)- or H(2)-blockers, steroids, leukotriene receptor antagonists, and PUVA
      therapy. If patients suffer from systemic reactions such as hypotension or
      syncope, epinephrine solution should be prescribed for emergency use.

PMID- 15024486
TI  - [Which drug interactions the general practitioner should know].

PMID- 15024488
TI  - [Acute infectious mononucleosis-like syndrome due to infection with
      cytomegalovirus in immunocompetence].
AB  - BACKGROUND: Infections by cytomegalovirus (CMV) cause substantial morbidity and
      mortality in immunocompromised patients, whereas immunocompetent individuals
      generally experience mild disease or remain asymptomatic. CASE REPORT: A 54-year
      old immunocompetent man undergoing CMV mononucleosis and hepatitis after primary
      infection is reported. Symptoms were pronounced with considerably reduced general
      condition and sustained highly febrile temperatures. Only therapy with
      intravenous ganciclovir led to rapid resolution of the disease. A second case
      describes a 31-year-old woman who, having had contact with a CMV-infected infant,
      developed a mononucleosis-like illness during her pregnancy. Due to the risk of
      congenital CMV infection, the exclusion of CMV-caused infection or the
      discrimination between primary and secondary infection is of particular
      importance, and the second case illustrates the relevant diagnostic difficulties
      and pitfalls. CONCLUSION: As demonstrated by the two cases, even in
      immunocompetent patients and pregnant women CMV should be considered in the
      differential diagnosis of symptomatic viral infections. Particularly during
      pregnancy and after organ transplantation, early diagnosis and prognostic markers
      are necessary because of possible severe complications such as congenital CMV
      infection and organ transplant failure.

PMID- 15024487
TI  - [Severe microangiopathic hemolytic anemia as first manifestation of a CUP
      syndrome. Rapid hematologic remission under polychemotherapy].
AB  - BACKGROUND: Microangiopathic hemolytic anemia (MAHA) represents a rare
      manifestation of malignant tumors. This complication, which is mainly lethal
      within a few weeks, is most commonly observed in association with mucin-producing
      adenocarcinomas, especially gastric cancer. The pathogenesis of tumor-associated
      mechanical hemolysis remains unclear. A standard therapy of this hematologic
      disturbance is not established. CASE REPORT: The authors report on a 51-year-old
      patient, who presented himself in their clinic with severe anemia, thrombopenia
      and deterioration of his general condition. Extensive investigations revealed
      signet-ring carcinoma metastases in the whole vertebral column, pelvis and bone
      marrow. The primary tumor could neither be located endoscopically nor in imaging
      examinations. Under palliative chemotherapy with cisplatin, epirubicin and 5
      fluorouracil continuous infusion, a rapid objective and subjective improvement
      could be achieved, which was reflected in normalization of the blood picture and
      regression of the osteoplastic bone metastases indicating partial remission. 9
      months later, the patient died because of a new progression of his disease.
      CONCLUSION: MAHA can be the first manifestation of malignant tumors. Upon the
      diagnosis of a MAHA, rapid diagnostics should be done to detect a possible
      underlying tumor, as effective antineoplastic therapy can induce both tumor and
      hematologic remission.

PMID- 15024489
TI  - [Pitfalls of DRG coding in pneumology].

PMID- 15024490
TI  - [Telemedicine in the maritime environment--hightech with a fine tradition].
AB  - Access to health care always has been one of the most critical issues for
      offshore crews. Therefore, telemedicine has a long and outstanding tradition in
      the maritime environment. Since 1931 Cuxhaven medical center (Medico Cuxhaven)
      operates as a hospital-based radio medical advice center (RMA) for ships
      worldwide providing one of the first routine telemedical services worldwide. For
      a long time this task was performed on a honorary basis by the hospital's
      physicians. In 1994 Germany accepted the IMO/ILO (International Maritime
      Organisation and International Labour Organisation) solution 164. Therefore, in
      1998 a formal contract of the German Ministry of Transport officially installed
      Medico Cuxhaven as the TMAS Center for Germany. According to IMO/ILO solution
      164, the RMA provides an expert level of care 24 h/day, 365 days/year. Cuxhaven
      hospital is a busy general hospital with departments of anesthesia and intensive
      care, internal medicine, surgery, gynecology and obstetrics, urology, pediatrics,
      ENT, radiology, and pain medicine. All physicians directly responding to TMAS
      calls have practical experience in maritime routine and emergency medicine. All
      incoming emergency calls are primarily handled by board-certified
      anesthesiologists, experienced in martime emergency medicine (e. g., staffing
      coastal SAR helicopters, working on rescue boats, carrying out repatriation
      services for sailors worldwide). If needed, other medical specialists are
      included. Today, Medico Cuxhaven takes an average workload of one to two
      emergency calls (response time < 20 s), two to three follow-up calls and
      approximately one informative call per day. Since 2000 transmission of digital
      photos has been used for routine RMA. Recently, a system for online and trenddata
      telemetry of twelve-lead ECG, NIBP (noninvasive blood pressure measurement),
      CO(2), SaO(2), pulse and respiration rates including the transmission of video
      images was developed. This system allows worldwide communications as it is
      capable of all possible means of telecommunication such as GSM, Inmarsat-ISDN or
      Iridium-Satellite-Transmission. So far, this system has been installed on board
      several German SAR rescue boats.However, radio telephone and the simple
      transmission of digital photography remain the basis of maritime radio medical
      advice service.

PMID- 15024494
TI  - Acute pancreatitis: the role of imaging and interventional radiology.
AB  - Acute pancreatitis can manifest as a benign condition with minimal abdominal pain
      and hyperamylasemia or can have a fulminant course, which can be life-threatening
      usually due to the development of infected pancreatic necrosis, and multisystem
      organ failure. Fortunately, 70-80% of patients with acute pancreatitis have a
      benign self-limiting course (figs. 1, 2, 4). The initial 24-48 hours after the
      initial diagnosis is usually the period that determines the subsequent course,
      and for many of the 20-30% of patients who subsequently have a fulminant course,
      this becomes apparent within this time frame. With reference to long-term outcome
      following acute pancreatitis, most cases recover without long-term sequelae with
      only a minority of cases progressing to chronic pancreatitis. In the initial
      management of acute pancreatitis, assessment of metabolic disturbances and
      systemic organ dysfunction is critical. However, the advent and continued
      refinement of cross-sectional imaging modalities over the past two decades has
      led to a prominent role for diagnostic imaging in assessing acute pancreatitis.
      Furthermore, these cross-sectional imaging modalities have enabled the
      development of diagnostic and therapeutic interventional techniques in the hands
      of radiologists. In this article we review the diagnostic features of acute
      pancreatitis, the clinical staging systems, complications and the role of
      imaging. The role of interventional radiology techniques in the management of
      acute pancreatitis will be discussed as well as potential complications
      associated with these treatments.

PMID- 15024496
TI  - Intraoperative dissemination of tumour cells in patients with Ewing tumours
      detected by RT-PCR.
AB  - Using reverse transcriptase polymerase chain reaction (RT-PCR) we evaluated the
      occurrence of tumour-cell ribonucleic acid (RNA) in the blood during surgery in
      patients with Ewing tumours. The patients received irradiation and chemotherapy
      according to the protocol of the European Intergroup Cooperative Ewing Sarcoma
      Study (EICESS) 92. Blood samples were taken from 15 patients. Intra-operative
      dissemination was found during 2/8 resections but showed no relation to patient
      survival. At second-look biopsy, detection of tumour-cell RNA was associated with
      relapse and metastases in 3/4 patients. The results suggest that pre-operative
      treatment did not completely prevent dissemination of tumour cells during surgery
      of Ewing tumours.

PMID- 15024499
TI  - The timing of tourniquet release and its influence on blood loss after total knee
      arthroplasty.
AB  - We performed a prospective, randomized study on 76 patients (82 knees) scheduled
      for total knee arthroplasty to determine the effect of tourniquet release and
      hemostasis on the peri- and postoperative blood loss. Patients were randomly
      divided in two groups. Posterior cruciate retaining tricompartmental total knee
      prostheses were used in all. In group 1, the tourniquet was deflated
      intraoperatively after the prosthetic components were settled and hemostasis was
      done. In group 2, the tourniquet was released after the wound was closed and a
      compressive bandage was applied. Mean blood drainage was 880.85 ml (320-1,315) in
      group 1 and 745.36 ml (220-1,175) in group 2 ( p=0.03). The mean number of blood
      transfusions given, hemoglobin and hematocrit values, operation time, and
      tourniquet time were similar in both groups. Intraoperative tourniquet release
      and hemostasis does not reduce total blood loss in total knee arthroplasty.

PMID- 15024500
TI  - Proximal humeral fractures with minimal displacement treated conservatively.
AB  - We reviewed 27 patients with a minimally displaced proximal humeral fracture
      treated conservatively after a mean follow-up of 25 (12-34) months. All fractures
      had united. Patients were evaluated using the Constant-Murley scoring system, and
      isokinetic muscle strength was tested using a Cybex dynamometer. Finally, all
      shoulders were examined ultrasonographically. The mean Constant score for all
      patients were 81 (54-100). Twenty-three patients had no or only mild pain, while
      three had moderate and one severe pain necessitating regular use of oral
      analgesics. Twenty patients were able to perform all activities of daily living,
      but seven had mild trouble in overhead activities and weight carrying. Only in
      one patient, the abduction peak torque equalled the one of the opposite shoulder.
      In all other patients, the peak torque was lower than, and in 14 patients below,
      50%. In nine patients, rotator cuff tears were seen at ultrasonography.

PMID- 15024501
TI  - Antitumor effects of fusions composed of dendritic cells and fibroblasts
      transfected with genomic DNA from tumor cells.
AB  - Based on several previous studies indicating that transfection of genomic DNA can
      stably alter the character of the cells that take up the exogenous DNA, we
      investigated antitumor immunity conferred by fusions of syngeneic dendritic cells
      (DCs) and allogeneic fibroblasts (NIH3T3) transfected with genomic DNA from B16
      tumor cells. Fusion cells (FCs) composed of dendritic and genetically engineered
      NIH3T3 cells were prepared with polyethylene glycol, and fusion efficiency was
      30.3%. Prior immunization with FCs prevented tumor formation upon challenge with
      B16 tumor cells. Efficacy was reduced when studies were performed in mice
      depleted of NK cells. Vaccination with FCs containing DCs and fibroblasts
      transfected with denatured DNA did not inhibit tumor growth. Cytotoxic T cell
      (CTL) activity of spleen cells from immunized mice against both Yac-1 and tumor
      cells was also stimulated by administration of FCs compared with the activity
      observed for cells obtained from naive mice. These data demonstrate the
      therapeutic efficacy of fusion cell-based vaccine therapy using syngeneic DCs and
      allogeneic fibroblasts transfected with tumor-derived genomic DNA.

PMID- 15024505
TI  - Renal artery stenosis: value of contrast-enhanced ultrasonography.
AB  - Renal artery stenosis is the most common cause of potentially curable secondary
      hypertension. For a long time, angiography has been considered the "gold
      standard" in screening for renal arterial occlusive disease, but it is expensive
      and invasive. Magnetic resonance angiography and spiral computed tomography are
      safer alternatives to angiography but are expensive and not widely available. Due
      to the fact that duplex scanning is noninvasive, it has been advocated since the
      early 1980s as a screening test for renal vascular disorders. Factors that make
      duplex ultrasound an attractive screening measure for renovascular disease are
      its safety, suitability for outpatient use, and low cost. However, the frequency
      of artery variants, lengthy examination time, and technically inadequate test
      conditions limit the use of the direct duplex ultrasound detection of renal
      artery stenosis. Advances in Doppler technology may alleviate some of the current
      problems related to examination of renal arteries. One such technique is the use
      of echo-enhancing agents, which increase Doppler signal strength and can improve
      the sensitivity and specificity in Doppler ultrasound detection of renal artery
      stenosis.

PMID- 15024510
TI  - Superselective embolization of lower gastrointestinal hemorrhage: a new paradigm.
AB  - In the past 5 years, there has been a rapid evolution in the endovascular
      treatment of lower gastrointestinal bleeding. Previously, most bleeding distal to
      the ligament of Treitz was managed with catheter-directed vasoconstrictive
      therapy. Currently, microcatheters allow superselective embolization of bleeding
      vessels, a technique that minimizes potential ischemic complications and obviates
      many drawbacks associated with vasopressin infusion. This article summarizes the
      current radiologic approach for patients with severe colonic hemorrhage.

PMID- 15024511
TI  - Peritoneal coccidioidomycosis: a potential CT mimic of peritoneal malignancy.
AB  - Peritoneal involvement is a rare extrapulmonary manifestation of
      coccidioidomycosis. We report a patient with meningeal coccidioidomycosis who was
      found to have multiple, globular, peripherally enhancing deposits in the
      peritoneal cavity at abdominal computed tomography, raising the consideration of
      peritoneal malignancy. Aspiration biopsy demonstrated peritoneal
      coccidioidomycosis. The particular computed tomographic findings of peritoneal
      coccidioidomycosis seen in this patient have not been previously described.

PMID- 15024512
TI  - Extrahepatic arterioportal fistula: three-dimensional reconstruction of
      computerized tomodensitometric scan for diagnosis and morphologic assessment.
AB  - Arterioportal fistulae (APFs) are rare. An asymptomatic APF was suspected by
      computed tomography. Multiplanar, maximum intensity projection, and surface
      shaded display reconstructions showed its anatomy. To our knowledge, this is the
      first report using such reconstructions to analyze the architecture of an
      extrahepatic APF. Complete assessment of APF can be achieved noninvasively, and
      initial endovascular treatment can be planned.

PMID- 15024513
TI  - Borderline Brenner tumor of the ovary: MRI findings.
AB  - Ovarian Brenner tumor is an uncommon epithelial tumor that accounts for 1.5% to
      2.5% of all ovarian neoplasms. These tumors are usually benign. Whereas the
      magnetic resonance imaging features of benign Brenner tumors have been described,
      reports of malignant findings are limited. We report a case of borderline
      malignant Brenner tumor that imaged as a cystic lesion with papillary projections
      and solid elements.

PMID- 15024514
TI  - Acute abdominal aortic thrombosis in cancer patients.
AB  - We report two cases of acute aortic thrombosis in cancer patients. Aortic
      thrombosis is rare in the absence of atherosclerosis, dissection, or aneurysm. On
      the one hand, hypercoagulable state related to cancer is a well-known risk factor
      for venous thrombosis. On the other hand, arterial thrombosis has been rarely
      reported in cancer patients. Recognition of aortic thrombosis is important
      because it is a dangerous condition; furthermore, it exposes at the patient to
      complications such as peripheral embolism. In addition, anticoagulation can
      result in resolution of thrombosis.

PMID- 15024515
TI  - Symptomatic giant Mullerian duct cyst in an infant: radiographic and CT findings.
AB  - We report an unusual case of Mullerian duct cyst in an 8-month-old infant who
      presented with frequent vomiting and recurrent urinary tract infections. Computed
      tomography showed a midline giant cyst in the pelvic floor. Delayed enhanced
      computed tomography demonstrated contrast filling of the cyst, indicating a
      communication with the urotract. Subsequent cystourethrogram and surgery
      confirmed a giant Mullerian duct cyst.

PMID- 15024516
TI  - Normal organ volume assessment from abdominal CT.
AB  - We determined the normal distribution of abdominal organ volumes measured from
      abdominal computed tomographic (CT) images. A total of 149 adult abdominal CT
      studies were selected, and 711 organs (388 from males, 323 from females) were
      outlined by hand on each CT image by using a computer. More than 18000 organ
      outlines were traced. The organs studied included left and right kidneys, left
      and right adrenals, spleen, pancreas, and liver, and the first lumbar vertebrae
      was also evaluated. Using the known pixel size and section thickness, organ
      volumes were computed. Organ volumes were corrected for height and weight for
      each sex. The normal and cumulative normal distributions for each organ studied
      were computed, demonstrating the range of organ volumes for each sex that exist
      in the normal adult population. Organ volumes ranged from a mean of 4.4 mL
      (female left adrenal) to 1710 mL (male liver). Mean organ volumes were 64.4,
      156.5, 179.8, and 1411 mL for the female pancreas, kidneys, spleen, and liver,
      respectively. Corresponding male volumes were 87.4, 193.1, 238.4, and 1710 mL,
      respectively. Tabular data are provided that indicate the relative size for each
      organ volume in terms of the cumulative probability distribution. Normative data
      are provided to allow physicians to estimate where in the normal range a
      particular organ volume lays. Organ volumes may be useful as quantitative indices
      of pathologic conditions.

PMID- 15024517
TI  - Wandering spleen with torsion of vascular pedicle: early diagnosis with
      multiplaner reformation technique of multislice spiral CT.
AB  - Wandering spleen is a rare clinical radiologic entity characterized by splenic
      hypermobility due to laxity or maldevelopment of the supporting splenic
      ligaments. The cause for hypermobility may be hormonal changes during pregnancy
      or failure of fusion of the dorsal peritoneum. Patients may be asymptomatic,
      present with a movable lump in the abdomen, or present with acute, chronic, or
      intermittent symptoms due to torsion of the wandering spleen. Early clinical
      diagnosis is difficult, so imaging modalities play an important role. We report a
      case of wandering spleen in which multiplanar reformation of thin maximum
      intensity projection images played a pivotal role in its precise diagnosis.

PMID- 15024518
TI  - Infradiaphragmatic pulmonary sequestration combined with cystic adenomatoid
      malformation: unusual postnatal computed tomographic features.
AB  - We present a surgically proven case of infradiaphragmatic pulmonary sequestration
      combined with cystic adenomatoid malformation. Prenatal magnetic resonance
      imaging revealed a well-defined hyperintense mass with a hypointense septum in
      the left infradiaphragmatic region. Postdelivery computed tomography (CT) and 3
      month follow-up CT showed replacement of intralesional cystic areas by solid
      content. Such unusual postnatal CT changes, to our knowledge, have not been
      previously documented.

PMID- 15024519
TI  - Intraperitoneal fat focal infarction of the lesser omentum: case report.
AB  - Intraperitoneal fat focal infarction (IFFI) represents a relatively rare acute
      abdominal condition essentially characterized by infarction and/or torsion of the
      greater omentum or an epiploic appendage. The spontaneous clinical evolution is
      favorable under medical treatment, and the imaging findings have been proved
      sufficiently typical to avoid unnecessary surgery in the great majority of cases.
      To our knowledge, we report the first case of IFFI of the lesser omentum. Despite
      the absence of definitive histologic proof, the diagnosis was possible through
      typical imaging findings extremely similar to those of more classic cases of IFFI
      but also through the spontaneous benign evolution.

PMID- 15024520
TI  - Malignant lymphoma with tumor thrombus in the portal venous system.
AB  - We report a case of malignant lymphoma presenting with tumor thrombus of the
      portal venous system. Computed tomography showed a mass in the portal vein and
      mesenteric lymphadenopathy. Filling defects in the dilated portal vein also were
      identified by angiography. This type of the lymphoma is extremely rare, but it
      should be considered in the differential diagnosis of portal vein thrombus.

PMID- 15024521
TI  - Adult ileocolic intussusception secondary to a submucosal cecal lipoma.
AB  - Intussusception is a relatively common cause of intestinal obstruction in
      children but a rare clinical entity in adults, representing fewer than 1% of
      intestinal obstructions in this patient population. We present a rare case of a
      44-year-old female patient with intestinal obstruction due to ileocolic and
      colocolonic intussusception secondary to an intramural cecal lipoma. Diagnosis
      was made by barium enema and abdominal computed tomography and was confirmed by
      colonoscopy. After failure of conservative treatment, the patient underwent
      surgery.

PMID- 15024522
TI  - Structural themes in ion channels.
AB  - The recent crystal structure of the prokaryotic inwardly rectifying potassium
      channel, KirBac1.1, revealed for the first time the structure of a K+ channel in
      the closed state plus the location of the activation gate. Comparison of the
      KirBac1.1 structure with other known ion channels reveals a number of common
      structural features. These common characteristics include the formation of the
      ion conduction pathway at the interface between adjacent subunits, non-fixed
      charges forming part of the ion pathway, electrostatic sinks drawing ions into
      the channel, helix dipoles, and hydrophobic gates that ultimately prevent ion
      movement. This review describes in detail common structural themes present in ion
      channels.

PMID- 15024524
TI  - Chronic hypoperfusion alters the content and structure of proteins and lipids of
      rat brain homogenates: a Fourier transform infrared spectroscopy study.
AB  - Arteriovenous malformations (AVMs), masses of abnormal blood vessels which grow
      in the brain, produce high flow shunts that steal blood from surrounding brain
      tissue, which is chronically hypoperfused. Hypoperfusion is a condition of
      inadequate tissue perfusion and oxygenation, resulting in abnormal tissue
      metabolism. Fourier transform infrared (FTIR) spectroscopy is used in this study
      to investigate the effect of hypoperfusion on homogenized rat brain samples at
      the molecular level. The results suggest that the lipid content increases, the
      protein content decreases, the lipid-to-protein ratio increases, and the state of
      order of the lipids increases in the hypoperfused brain samples. FTIR results
      also revealed that, owing to hypoperfusion, not only the protein synthesis but
      also the protein secondary structure profile is altered in favor of beta-sheets
      and random coils. These findings clearly demonstrate that, FTIR spectroscopy can
      be used to extract valuable information at the molecular level so as to have a
      better understanding of the effect of hypoperfusion on rat brain.

PMID- 15024523
TI  - Patterning of endocytic vesicles and its control by voltage-gated Na+ channel
      activity in rat prostate cancer cells: fractal analyses.
AB  - Fractal methods were used to analyze quantitative differences in secretory
      membrane activities of two rat prostate cancer cell lines (Mat-LyLu and AT-2) of
      strong and weak metastatic potential, respectively. Each cell's endocytic
      activity was determined by horseradish peroxidase uptake. Digital images of the
      patterns of vesicular staining were evaluated by multifractal analyses:
      generalized fractal dimension (Dq) and its Legendre transform f(alpha), as well
      as partitioned iterated function system -- semifractal (PIFS-SF) analysis. These
      approaches revealed consistently that, under control conditions, all multifractal
      parameters and PIFS-SF codes determined had values greater for Mat-LyLu compared
      with AT-2 cells. This would agree generally with the endocytic/vesicular activity
      of the strongly metastatic Mat-LyLu cells being more developed than the
      corresponding weakly metastatic AT-2 cells. All the parameters studied were
      sensitive to tetrodotoxin (TTX) pre-treatment of the cells, which blocked voltage
      gated Na+ channels (VGSCs). Some of the parameters had a "simple" dependence on
      VGSC activity, whereby pre-treatment with TTX reduced the values for the MAT-LyLu
      cells and eliminated the differences between the two cell lines. For other
      parameters, however, there was a "complex" dependence on VGSC activity. The
      possible physical/physiological meaning of the mathematical parameters studied
      and the nature of involvement of VGSC activity in control of
      endocytosis/secretion are discussed.

PMID- 15024525
TI  - Force generation by recombinant myosin heads trapped between two functionalized
      surfaces.
AB  - Fluorescence resonance energy transfer measurements have revealed that the lever
      arm domain of myosin swings when it hydrolyzes Mg-ATP. It is generally accepted
      that this swing of the lever arm of myosin is the molecular basis of force
      generation. On the other hand, the possibility that the force might be generated
      at the interface between actin and myosin cannot be ignored. However, there is a
      third possibility, namely, that myosin itself generates force without actin.
      Thus, using recombinant subfragment 1 molecules of Dictyostelium myosin II that
      were trapped between two functionalized surfaces of a surface-force apparatus, we
      determined whether myosin itself could actually generate force. Here, we report
      that, despite the absence of actin, myosin heads themselves have a capacity to
      generate a force (at least approximately 0.2 pN/molecule) that is coupled to the
      structural changes. Although the role of actin should not be neglected because
      muscle physiologically shortens as a result of the interaction between actin and
      myosin, in this work the focus is on the question of whether the catalytic domain
      of myosin has the capacity to generate force.

PMID- 15024526
TI  - Endovascular treatment of a congenital dural caroticocavernous fistula.
AB  - Carotico-cavernous sinus fistula is a rare anomaly in infancy. We report a 3
      month-old boy with progressive symptoms and threatened visual loss requiring
      urgent therapeutic intervention. Embolization using n-butyl 2-cyanoacrylate was
      performed with immediate and dramatic results.

PMID- 15024527
TI  - Use of a cutting balloon in the dilatation of caustic oesophageal stricture.
AB  - A 14-year-old boy was admitted with absolute dysphagia 1 year after he had
      swallowed drain cleaner. Contrast swallow showed a tight stricture of the whole
      of the oesophagus below the level of T2. Attempted dilatation to 8 mm using
      conventional balloons was performed on two occasions, but there was residual
      waisting. An 8-mm cutting balloon (Peripheral Cutting Balloon, Boston Scientific)
      was used to abolish this waisting, and full dilatation to 10 mm was performed in
      the same procedure. Subsequent serial dilatation to 20 mm has been successful and
      the patient is now able to swallow normal food with cessation of gastrostomy
      feeding. This is believed to be the first report of the use of a cutting balloon
      to treat an oesophageal stricture.

PMID- 15024528
TI  - Craniofacial differences according to AHI scores of children with obstructive
      sleep apnoea syndrome: cephalometric study in 39 patients.
AB  - BACKGROUND: Cephalometry is useful as a screening test for anatomical
      abnormalities in patients with obstructive sleep apnoea syndrome (OSAS).
      OBJECTIVE: To evaluate comprehensively the cephalometric features of children
      with OSAS, with or without adenotonsillar hypertrophy, and to elucidate the
      relationship between cephalometric variables and apnoea-hypopnoea index (AHI)
      severity. MATERIALS AND METHODS: The study population consisted of 39 children,
      aged 4-12 years, with OSAS. Cephalometry was analysed using 11 measurements of
      the bony structures, their relationships and the size of the airways.
      Additionally, adenoid and tonsillar hypertrophy were graded. RESULTS: Cranial
      base angles (BaSN and BaSPNS) were found to correlate with increasing levels of
      AHI scores (P<0.001). Protrusion of the maxilla (SNA) and mandible (SNB) did not
      correlate with AHI scores (P>0.05). The length of the mandibular plane (GnGo) and
      the minimal posterior airway space (MPAS) were inversely correlated with AHI
      scores (P<0.001). There was positive correlation between MPAS and GnGo (r=0.740,
      P<0.001), and negative correlation between MPAS and gonial angle (ArGoGn) (r=
      0.541, P<0.001). There was significant correlation between cephalometric data and
      adenotonsillar hypertrophy concerning BaSN, BaSPNS, ArGoGn, GnGoH, BaN-GnGo,
      MPAS, GnGO and MPH (P<0.001). CONCLUSIONS: There is significant correlation
      between cephalometric data and AHI score severity in children with OSAS.
      Adenotonsillar hypertrophy affects the cephalometric measurements adversely. The
      study clearly mandates the institution of early and effective therapy of
      adenotonsillar hypertrophy in children with OSAS.

PMID- 15024529
TI  - Intussusception.

PMID- 15024530
TI  - The effect of DA-8159 on corpus cavernosal smooth muscle relaxation and penile
      erection in diabetic rabbits.
AB  - A previous study showed that DA-8159, a potent type 5 phosphodiesterase
      inhibitor, enhanced the relaxation of the smooth muscles in the normal rabbit
      corpus cavernosum. In this study, we investigated the in vitro effects of DA-8159
      on cavernosal smooth muscle relaxation and the in vivo erectogenic potential in
      diabetic rabbits, since erectile dysfunction is a well-known sequela of diabetes
      mellitus. Diabetes mellitus was induced in male New Zealand White rabbits with
      alloxan monohydrate. Cavernosal strips from age-matched control and 8-week
      diabetic animals were mounted in organ baths. The relaxation responses to sodium
      nitroprusside (10(-9)--10(-5) M), a nitric oxide donor, were assessed in the
      presence or absence of DA-8159 (10(-9)--10(-6) M). For the penile erection test,
      DA-8159 was given orally (1-10 mg/kg) to diabetic rabbits and the length of the
      uncovered penile shaft was measured in a time-course manner in the presence or
      absence of intravenous sodium nitroprusside. The sodium nitroprusside-stimulated
      relaxations were significantly impaired in the corpus cavernosum from the
      diabetic group (IC(50)=1.07 x 10(-6) M following 8 weeks of diabetes mellitus;
      compared with 0.48 x 10(-6) M for age-matched controls). DA-8159 significantly
      and dose-dependently enhanced the sodium nitroprusside-stimulated relaxation in
      the diabetic groups. In addition, DA-8159 induced a dose-dependent penile
      erection in diabetic rabbits, which was potentiated by intravenous sodium
      nitroprusside. These results suggest that DA-8159 is an effective treatment for
      diabetic erectile dysfunction but further evaluation of the efficacy on human
      needs to be performed.

PMID- 15024532
TI  - Choice of cross size in stereology.

PMID- 15024531
TI  - Semicircular canal dehiscence: comparison of T2-weighted turbo spin-echo MRI and
      CT.
AB  - We assessed the value of MRI for delineation of dehiscence of the superior or
      posterior semicircular canal, as compared with CT, the current standard study for
      this entity. We reviewed heavily T2-weighted fast spin-echo images and high
      resolution CT of the temporal bones of 185 patients independently semicircular
      canal dehiscence and its extent. In 30 patients (19 men, 11 women) we identified
      dehiscence of the bone over the superior and/or posterior semicircular canal on
      MRI. In 27 of these cases CT also showed circumscribed bone defects. In one
      patient dehiscence of the superior semicircular canal was initially overlooked on
      MRI, but seen on CT. MRI imaging thus had a sensitivity of 96% and specificity of
      98%. Knowledge of the appearances of this entity on MRI may contribute to early
      diagnosis in patients with vertigo due to semicircular canal dehiscence.

PMID- 15024533
TI  - Patterns of psychotropic medicine use and related diseases across educational
      groups: national cross-sectional survey.
AB  - OBJECTIVE: To analyse whether the use of different groups of psychotropic
      medicines among educational groups in a general population was congruent with the
      occurrence of related diseases. METHODS: Data from The Danish Health and
      Morbidity Survey 2000 were analysed. The survey was conducted by face-to-face
      interviews with a representative sample of the Danish population aged 16 years
      and above ( n=16,690). The prevalence of four different types of psychotropic
      medicine use and related diseases in educational groups was analysed by indirect
      standardisation. Age and gender standardised prevalence ratios (SPRs) and 95%
      confidence intervals were calculated based on the total study population.
      RESULTS: In general, respondents in the two least-educated groups used
      psychotropic medicines more often and had a higher proportion reporting the
      related disease than could be expected according to indirect standardisation. The
      opposite picture appeared for respondents in the two highest educated groups
      (SPR<100). The overall patterns were similar for all four groups of psychotropic
      medicine users, although some of the SPRs were not significant. CONCLUSIONS: The
      results documented an uneven distribution of health problems in the general
      population. Psychotropic medicine use was congruent with the distribution of
      related health problems, which means that the least-educated groups in most need
      of treatment also had the most-frequent medicine use. Expenses incurred by the
      individual user did not seem to be a barrier to access to medicines, not even for
      specific groups of medicine ineligible for reimbursement in Denmark.

PMID- 15024535
TI  - Differential effects of hindlimb peripheral afferents on motoneurons innervating
      different parts of longissimus muscle in cats.
AB  - Previous studies (Wada and Kanda 2001, Exp Brain Res 136:263-263; Wada et al.
      1999, Exp Brain Res 128:543-549) demonstrated that input patterns from hindlimb
      muscles and cutaneous afferents vary among individual trunk muscle motoneurons.
      The purpose of the present study was to examine the relationship between the
      synaptic pattern from hindlimb afferents and the area innervated by motoneurons.
      Histologic study of m. longissimus lumborum (Long) indicated that the
      distribution of different fiber types (slow-twitch oxidative, SO; fast-twitch
      oxidative glycolytic, FOG; fast-twitch glycolytic, FG) depends on the area of the
      Long cross-section. The ventromedial area and dorsolateral area of the cross
      section possess a high content of SO and FG, respectively. The motoneurons
      innervating the dorsolateral area receive muscle afferent inputs mainly from the
      ipsilateral side, while the motoneurons innervating the ventromedial area often
      receive bilateral afferent inputs. The motoneurons innervating the dorsolateral
      area receive excitatory post-synaptic potentials from cutaneous nerves on both
      sides. These findings indicate that the effects of afferent inputs from the
      hindlimbs are related to motoneuron type or the area innervated by the
      motoneurons.

PMID- 15024534
TI  - Genetic polymorphism of cytochrome P450 2C9 in diphenylhydantoin-induced
      cutaneous adverse drug reactions.
AB  - BACKGROUND: Apart from allergic mechanisms, a lack or mutation of metabolic
      enzymes may cause adverse drug reactions. Patch testing has rarely been useful in
      cutaneous adverse drug reactions (CADRs) induced by diphenylhydantoin (DPH).
      Genetic polymorphisms leading to altered metabolic processes of cytochrome P(450)
      (CYP) 2C9, a main metabolic enzyme for DPH, may be the pathological mechanism for
      certain cases of DPH-induced CADRs. OBJECTIVE: To examine the effects of an
      altered CYP2C9 variant, CYP2C9*3, on DPH-induced CADRs. METHODS: Ten patients
      with DPH-induced CADRs were examined for CYP2C9 genetic polymorphisms. The
      results were compared with non-exposed controls and 39 neurological patients
      without DPH-induced CADRs despite exposure to DPH. The patients with DPH-induced
      CADRs were also patch tested with anti-epileptic drugs and the results were
      compared with 40 DPH-exposed and 58 non-exposed controls. RESULTS: A heterozygous
      CYP2C9*3 variant was found in three of the 10 DPH-induced CADR patients. The
      crude odds ratios (OR) of the patients compared with those of exposed and non
      exposed controls were 167 and 71, respectively. Only one neurological patient,
      who had never taken DPH, showed the variant in both exposed (P=0.007) and non
      exposed (P=0.001) controls. Positive patch-test results were displayed in three
      of the ten DPH-induced patients, but the patients with positive patch-test
      reactions to DPH differed from those with the CYP2C9*3 polymorphism. No patients
      and controls displayed a CYP2C9*2 variant. CONCLUSION: A CYP2C9*3 variant could
      play a role in the proportion of patients with DPH-induced CADRs that differ from
      patients with DPH-induced CADRs showing positive patch-test results.

PMID- 15024536
TI  - Coordinating degrees of freedom during interceptive actions in children.
AB  - The aim of the experiment was to examine how children coordinate the degrees of
      freedom of the arm and trunk when performing interceptive actions that correspond
      to daily life activities. For that purpose, children were required to reach and
      grasp a stationary ball while standing (condition C1), a stationary ball while
      walking (C2), and a moving ball while standing (C3). The resulting movements were
      measured in world-centered and body-centered coordinates, and then subjected to
      three-dimensional kinematic analysis. The different coordinate frames of
      reference were used to determine the interaction between arm and trunk movements.
      Children adapted their coordination in the two moving conditions (C2 and C3) by
      decelerating longer towards the ball and exhibiting more interaction between the
      arm and trunk movements than in the stationary condition (C1). These results
      indicate that, like adult participants, children adapt to the constraints imposed
      by complex, interceptive actions by recruiting additional degrees of freedom of
      the trunk, which are coordinated with the hand to produce a movement that
      preserves an appropriate level of impact at hand/object collision.

PMID- 15024537
TI  - Postural adjustments due to external perturbations during sitting in 1-month-old
      infants: evidence for the innate origin of direction specificity.
AB  - The aim of the study was to examine whether infants, at an age when they have no
      or little experience in sitting, can produce direction specific postural
      adjustments, i.e. synergies of muscle activity on the ventral side of the body
      during backward sway and on the dorsal side during forward sway. In addition, we
      addressed the question whether postural adjustments at this young age are
      restricted to single muscle responses or consist of a variable repertoire of
      muscle activation patterns including one during which all direction specific
      muscles participate ('complete' pattern). Postural adjustments due to external
      perturbations in a sitting position were studied in eight healthy infants aged 1
      month. Multiple surface EMGs of neck, trunk and leg muscles and kinematics were
      recorded while the infants were exposed to horizontal forward (Fw) and backward
      (Bw) displacements of the surface of support. Direction specific postural
      adjustments, defined as adjustments during which agonist activation or antagonist
      inhibition preceded antagonist activation, were present in 85% of Bw and 72% of
      Fw translations. The direction specific adjustments showed a large variability
      with the repertoire of adjustments including the activation of one, two or all of
      the recorded direction specific muscles. The finding of direction specific
      adjustments at 1 month of age support the opinion that the basic level of
      organisation of postural adjustments has an innate origin. The finding of a
      variable repertoire of muscle response patterns, including the 'complete'
      pattern, refutes the idea that the development of postural adjustments results
      from gradual addition of appropriate muscles to the synergies.

PMID- 15024538
TI  - Inter-hemispheric asymmetry of ipsilateral corticofugal projections to proximal
      muscles in humans.
AB  - Motor evoked potentials (MEPs) elicited in many proximal or truncal muscles by
      ipsilateral transcranial magnetic stimulation (TMS) are thought to be mediated by
      an oligosynaptic corticofugal pathway and not by uncrossed corticospinal
      collaterals. In the present study, we compared the input-output properties and
      scalp surface topography of the ipsilateral and contralateral projections to
      pectoralis major (PM) and latissimus dorsi (LD) in seven healthy subjects. In six
      subjects, ipsilateral MEPs evoked by stimulation of one hemisphere (dominant
      ipsilateral hemisphere) were markedly larger in amplitude than the MEPs evoked in
      the opposite hemisphere (non-dominant ipsilateral hemisphere). The dominant
      ipsilateral hemisphere MEPs were significantly larger than the non-dominant MEPs
      (p<0.02) by an average factor of 3.6 and 3.4 times in PM and LD, respectively.
      Similarly, there was significant asymmetry between hemispheres in the scalp
      surface area from which ipsilateral MEPs could be evoked. In contrast,
      contralateral projections were symmetric in both MEP amplitude and area. Neither
      the right nor left hemisphere was consistently the dominant ipsilateral
      hemisphere. The ipsilateral centre of gravity (CoG) for PM was located an average
      of 0.8+/-0.6 cm posterior to the contralateral CoG, but no significant
      differences were observed between ipsilateral and contralateral CoGs in LD. These
      results demonstrate that the excitability of ipsilateral corticofugal projections
      to PM and LD are asymmetric between hemispheres.

PMID- 15024539
TI  - Speed-accuracy of saccades, vergence and combined eye movements in children with
      vertigo.
AB  - Vergence abnormalities could lead to inappropriate vestibulo-ocular reflex (VOR),
      causing vertigo and imbalance (Brandt 1999). Indeed, a recent study by Anoh-Tanon
      et al. (2000) reported the existence of a population of children with symptoms of
      vertigo in the absence of vestibular dysfunction but with abnormal vergence
      findings in orthoptic tests. The purpose of this study was to examine in such
      children the accuracy, duration and mean velocity of vergence and saccades;
      additionally, for a few subjects, the effect of orthoptic vergence training on
      these parameters was also investigated. LEDs were used to stimulate saccades,
      pure vergence along the median plane and combined saccade-vergence movements.
      Movements from both eyes were recorded with a photoelectric device (Bouis). The
      results show that children with vertigo perform saccades as normal subjects of
      comparable age. In contrast, vergence, particularly convergence, shows
      abnormalities: poor accuracy, long duration and low speed. During combined
      movements, the well known reciprocal interaction between the saccade and the
      vergence is present only for saccades combined with divergence; for saccades
      combined with convergence such interaction is abnormal: the saccade is slowed
      down by the convergence but the convergence is not accelerated by the saccade.
      Orthoptic training improves significantly the accuracy of all eye movements; such
      improvement was significant for all types of eye movements except for divergence
      (pure and combined). Furthermore, convergence remains abnormal and the lack of
      acceleration by the saccade persists. These specific convergence deficits could
      be of both subcortical and cortical origin. Orthoptic training improves the
      accuracy presumably via visual attentional mechanisms, but cannot completely
      override deficits related to subcortical deficiencies.

PMID- 15024540
TI  - Finger coordination during moment production on a mechanically fixed object.
AB  - The moment production by several fingers on a mechanically fixed vertically
      oriented handle was studied under the systematic variations of task parameters
      such as (a) moment magnitude (1.0 Nm and 2.0 Nm) and (b) direction of moment
      production (into pronation and supination), as well as (c) vertical position of
      the handle from the moment axis, P (0, 2.0, 4.0, and 6.0 cm in both directions).
      The purpose of this study was twofold: to investigate the dependences between the
      task parameters and the performance variables and to test the mechanical
      advantage hypothesis. The performance variables changed symmetrically with P. In
      particular, magnitudes of the net horizontal and vertical forces both showed an S
      shape change. The position of the point of zero free moment (PZFM) was
      determined. In the intermediate grasp locations (when 0< P magnitude <PZFM), the
      contribution of M(free) (moment produced mainly by pronational or supinational
      effort) and the moment of the resultant force (moment generated mainly by
      pushing) into the total moment production scaled linearly with the P. The
      magnitudes of both agonist and antagonist moments (those acting in and against
      the direction of the required moment, respectively) of normal forces increased
      with P magnitudes while the magnitude of agonist moments of tangential forces
      decreased. For individual fingers, the ratio of finger force to its moment arm
      was not constant. The mechanical advantage hypothesis was successful in
      explaining some of the data but could not cope with other findings. We assume,
      therefore, that this hypothesis is limited in its applicability and may be task
      and effector specific.

PMID- 15024541
TI  - Motor strategies for initiating downward-oriented movements during standing in
      adults.
AB  - Sitting down and squatting are routine activities in daily living that lower the
      body mass by flexing the trunk and legs, but they obviously require different
      motor strategies for each goal posture. The former action must transfer the
      supporting surface onto a seat, whereas the latter must maintain the center of
      mass within the same base of both feet. By comparing the performance of both
      maneuvers, the mechanisms involved in initiating the downward-oriented movements
      and the process of optimizing the performance during their repetitions were
      studied. Twelve healthy subjects were asked to perform sitting-down and squatting
      actions immediately when a light cue was given, but at a natural speed.
      Electromyograms, angular movements of the joints of the right leg, and center of
      pressure (COP) displacement were recorded before and during each task. The
      initial mechanisms to initiate the break from the upright posture and the changes
      of postural adjustments during repetitive movements were analyzed separately. The
      sitting-down movement was achieved by a stereotyped motor strategy characterized
      by a gastrocnemius muscle burst coupled with deactivation of the erector spinae
      muscle. The former produced a transient COP displacement in the forward
      direction, and simultaneous unlocking of the trunk prevented a fall backward. By
      contrast, because of the absence of any need to produce momentum in a given
      direction, a variety of motor strategies were available to initiate squatting.
      The direction of initial COP displacement to initiate squatting varied with the
      muscles involved in unlocking the upright posture. During repetition of sitting
      down, the average COP position of the initial standing posture in the preparatory
      period was immediately shifted forward after the second trial. Simultaneously,
      the erector spinae muscle was deactivated earlier in the later trials. These
      resulted in a decreased momentum in the backward direction while the subjects
      were transferring themselves onto the seat. In the squatting task, however, these
      changes could not be identified, except for a slight flexed position of the knee
      during standing in the first trial. These findings suggest that in the case of
      transferring the body-mass to another supporting base the central nervous system
      immediately adjusts the size of the initial impetus to optimize the performance.

PMID- 15024543
TI  - Ion chromatography.

PMID- 15024542
TI  - Motor cortex inhibition induced by acoustic stimulation.
AB  - The influence of the brainstem motor system on cerebral motor areas may play an
      important role in motor control in health and disease. A new approach to
      investigate this interaction in man is combining acoustic stimulation activating
      the startle system with transcranial magnetic stimulation (TMS) over the motor
      cortex. However, it is unclear whether the inhibition of TMS responses following
      acoustic stimulation occurs at the level of the motor cortex through reticulo
      cortical projections or subcortically, perhaps through reticulo-spinal
      projections. We compared the influence of acoustic stimulation on motor effects
      elicited by TMS over motor cortical areas to those evoked with subcortical
      electrical stimulation (SES) through depth electrodes in five patients treated
      with deep brain stimulation for Parkinson's disease. SES bypasses the motor
      cortex, demonstrating any interaction with acoustic stimuli at the subcortical
      level. EMG was recorded from the contralateral biceps brachii muscle. Acoustic
      stimulation was delivered binaurally through headphones and used as a
      conditioning stimulus at an interstimulus interval of 50 ms. When TMS was used as
      the test stimulus, the area and amplitude of the conditioned motor response was
      significantly inhibited (area: 57.5+/-12.9%, amplitude: 47.9+/-7.4%, as
      percentage of unconditioned response) whereas facilitation occurred with SES
      (area: 110.1+/-4.3%, amplitude: 116.9+/-6.9%). We conclude that a startle-evoked
      activation of reticulo-cortical projections transiently inhibits the motor
      cortex.

PMID- 15024545
TI  - Chemical partitioning of aluminium in rocks, soils, and sediments acidified by
      mining activity.
AB  - The work presented describes the application of different analytical approaches
      for study of aluminium mobility in rock, soil, and sediment samples affected by
      mining activity (secondary quartzites with sulfidic deposits). For this purpose
      we used a combination of the single extractions, the optimized BCR three-step
      sequential extraction procedure (SEP), and reactive aluminium determination after
      chelating ion-exchange on Ostsorb (Iontosorb) Salicyl by a batch technique with
      flame atomic absorption spectrometry quantification. The single extraction agents
      H(2)O, KCl, NH(4)Cl, and BaCl(2) were found to be the best for the quantitative
      estimation of the aluminium mobility in rocks, soils, and sediments caused by
      acidification of the environment. This fact was confirmed by reactive aluminium
      determination in the same samples. The vast majority of the aluminium content of
      samples after application of the optimized BCR three-step SEP is in the residues.
      The available fraction of aluminium extracted by dilute CH(3)COOH in the first
      step of this procedure correlates with the reactive aluminium content. The
      amounts of aluminium released in the second and the third steps and the sums from
      steps 1-3 of this procedure are closely associated with the aluminium content
      values obtained by the single dilute HCl leach. The accuracy of results obtained
      was verified with only informative values for individual fractions of the BCR
      three-step SEP because of the absence of suitable certified or standard reference
      materials. The amounts of the reactive aluminium determined in samples was in the
      range 12-82% of total soluble Al in the filtered H(2)O extracts. It was confirmed
      that the acidified polluted samples contain the most of reactive Al content,
      which is responsible for its toxicity.

PMID- 15024544
TI  - Assessment of total effective xenoestrogen burden in adipose tissue and
      identification of chemicals responsible for the combined estrogenic effect.
AB  - Test systems to screen for estrogenicity and appropriate biomarkers of human
      exposure are required for epidemiological studies of endocrine disruption. We
      addressed these issues by developing and standardising a method to assess the
      total estrogenic xenobiotic burden in human adipose tissue. In this study, which
      is the continuation of a previous work, we have improved the protocol for
      extensive fractionation of a higher number of tissue samples in order to
      investigate bioaccumulated xenoestrogens that are candidates for estrogenicity
      and to assess their combined estrogenic effect. This was achieved by extensive
      HPLC separation of xenoestrogens from endogenous hormones followed by testing of
      individual fractions in the E-Screen test for estrogenicity. Organochlorine
      pesticides, PCBs and halogenated bisphenols and alkylphenols were collected in
      the most lipophilic fractions, followed by progestins, androgens and estradiol
      esters, and then by steroidal estrogens; phyto- and myco-estrogens were collected
      around the end of the run. These results were confirmed by exhaustive chemical
      analysis. In 458 human adipose tissue samples, the total effective xenoestrogen
      burden was positive in 75% of samples in the pooled fraction that contained
      organohalogenated xenoestrogens (mean 515.3 pM Eeq/g lipid; range 0-14.5 nM) and
      in 82% of samples in the pooled fraction where natural estrogens eluted (mean
      696.6 pM Eeq/g lipid; range 0-12.9 nM). Organochlorine pesticides emerged as
      candidate chemicals for the estrogenicity of the first pooled fraction, because
      DDT and derivatives were present in 98.3% of the samples. However, no correlation
      was found between the concentration of any single chemical and the estrogenicity
      determined in the bioassay. There may be several reasons for this lack of
      concordance: (i) the estrogenic effects depicted in the E-Screen bioassay are a
      consequence of the combined effect of several organohalogens or (ii) the
      proliferative effect is due to other chemicals not measured. Because additive,
      synergistic or antagonistic mechanisms may account for the final effect observed
      in the pooled fractions, the approach proposed in this work is more appropriate
      for exposure assessment in epidemiological studies than the determination of
      individual chemicals in human samples.

PMID- 15024546
TI  - Application of a simple and sensitive GC-MS method for determination of morphine
      in the hair of opium abusers.
AB  - Thirty hair samples were collected from male opioid abusers for whom the presence
      of morphine in their urine samples was confirmed by thin layer chromatography
      (TLC). The hair samples were decontaminated by washing with isopropanol,
      deionized water, and isopropanol, dried at room temperature, and cut into small
      pieces. Samples of the latter (30 mg ) were digested by incubation in a mixture
      of methanol-trifluoroacetic acid (9:1) for 18 h at 45 degrees C and sonicated to
      improve the extraction process. The methanolic phase was evaporated to dryness
      under a stream of nitrogen at 50 degrees C. The sample was derivatized by
      addition of N-methyl- N-trimethylsilyltrifluoroacetamide (MSTFA) and 1%
      trimethyliodosilane (TMIS) at 70 degrees C for 20 min, with sonication.
      Derivatized samples (1 microL) were injected into a gas chromatograph-mass
      spectrometer (GC-MS) system fitted with a capillary column; the Finnigan MS was
      operated in SIM mode. Naltrexone was used as internal standard (IS). The masses
      of the ions selected for morphine and naltrexone were 429 and 557, respectively.
      The limit of quantitation was set at 0.03 ng mg(-1) hair. By using the above
      procedure we detected morphine in all the samples examined, in the concentration
      range 0.26-10.31 ng mg(-1 )hair.

PMID- 15024547
TI  - In rats, acute morphine dependence results in antagonist-induced response
      suppression of intracranial self-stimulation.
AB  - RATIONALE: Lower (0.001-1.0 mg/kg) doses of the opioid antagonist naltrexone
      produce few behavioral effects in otherwise drug-free rats responding for ICSS,
      but reduce response rates by up to 75% after a single dose of morphine.
      OBJECTIVES: The present study represents an effort to verify that other opioid
      antagonists produce this acute opioid dependence effect, and to characterize
      their relative pharmacological profiles. METHODS: We implanted bipolar electrodes
      in the lateral hypothalamus of adult male rats, and then trained them to lever
      press on an "autotitration" ICSS schedule, where responding on a "reset" lever
      allows the rat to control the frequency of stimulation; performance stabilized at
      approximately 1.5 responses/s. RESULTS: During twice-weekly test sessions,
      cumulative doses of five of seven opioid antagonists produced significant
      response rate decreases (30-80%) in saline-pretreated rats; nalorphine (ED25=15.6
      mg/kg)> naltrexone (ED25=13.1 mg/kg)>naloxone (ED25=7.3 mg/kg)>levallorphan
      (ED25=13.96 mg/kg)>(-)cyclazocine (ED25=0.028 mg/kg). A single MOR pretreatment
      (10 mg/kg, 4 h) significantly enhanced the rate-decreasing effects of six of the
      seven agonists tested; by 10-fold (-) cyclazocine>13-fold (nalorphine)>93-fold
      (levallorphan)>972-fold (naloxone)>2190-fold (naltrexone). The pure non-selective
      antagonist diprenorphine potently decreased rates after MOR pretreatment (ED25=
      0.01 mg/kg), but did not after saline pretreatment. The mixed opioid agonist
      antagonist drug nalbuphine (1.0-30 mg/kg) did not affect responding after either
      saline or MOR. CONCLUSIONS: Antagonists with a high affinity for, and a lack of
      intrinsic activity at, the micro-opioid receptor precipitate the greatest
      behavioral changes in rats acutely dependent on MOR.

PMID- 15024549
TI  - A preliminary report on dopamine system reactivity in PKU: acute effects of
      haloperidol on neuropsychological, physiological, and neuroendocrine functions.
AB  - BACKGROUND: Classic phenylketonuria (PKU) is due to an inborn error of metabolism
      resulting in an inability to metabolize the amino acid phenylalanine. To avoid
      mental retardation, affected individuals observe a phenylalanine-restricted diet.
      When dietary control is poor, deficits in prefrontally mediated cognitive
      functions have been observed. It has been suggested that these deficits are due
      to disruptions in the mesocortical dopamine system that projects to the
      prefrontal cortex. METHODS: In this study, dopamine system reactivity was
      examined in individuals with PKU, relative to age-matched controls, using the non
      specific DA antagonist haloperidol, in a repeated measures placebo-controlled
      design. Outcome variables included neuroendocrine, physiological, and cognitive
      measures. RESULTS: Regardless of drug condition, PKU participants differed from
      control participants in their blood phenylalanine and tyrosine levels, and in
      their times to complete measures of attention and working memory. Also, relative
      to placebo, haloperidol influenced several variables irrespective of group
      status, including serum prolactin secretion, times to complete attention and
      working memory tasks, and accuracy of working memory performance. An interaction
      between group and drug condition was observed for the digit span task, where PKU
      participants exhibited greater relative impairments on haloperidol. When
      composite indices of impairment were derived, PKU participants demonstrated
      selective disruption in executive function on haloperidol relative to control
      subjects. CONCLUSIONS: Findings are consistent with the presence of
      frontostriatal dysfunction in PKU but are less consistent with the notion that
      PFC dopamine function is specifically affected.

PMID- 15024548
TI  - Rewarding effects elicited by cocaine microinjections into the ventral tegmental
      area of C57BL/6 mice: involvement of dopamine D1 and serotonin1B receptors.
AB  - RATIONALE: The role of ventral tegmental area (VTA) in mediating the rewarding
      effects of cocaine has not been extensively studied. OBJECTIVES: We used the
      intracranial self-administration (ICSA) procedure to assess the involvement of
      the VTA in the rewarding effects of cocaine, and the effect of dopamine (DA) D(1)
      and serotonin (5-HT)(1B)-receptor antagonists on ICSA of cocaine. METHODS: Adult
      male C57BL/6 mice were stereotaxically implanted, unilaterally, with a guide
      cannula either 1.5 or 2.3 mm above the VTA. After 1 week, mice were trained to
      discriminate between the two arms of a Y-maze over seven daily sessions, one arm
      being reinforced by intracranial cocaine microinjections. Starting from session
      8, the D(1) and 5-HT(1B)-receptor antagonists were injected IP pre-test each day
      over five consecutive sessions. RESULTS: Mice injected into the VTA rapidly
      exhibited a preference for the cocaine-reinforced arm, whatever the dose of
      cocaine available (30 pmol or 150 pmol per injection), reaching optimum ICSA
      performance within 5 days. In contrast, mice injected 0.8 mm above the VTA did
      not discriminate between the arms of the maze and performed at random, except for
      one subject. Once the ICSA response was acquired, systemic pre-injections of
      either the D(1) (SCH23390; 25 microg/kg IP) or 5-HT(1B) (GR127935; 0.5 mg/kg IP)
      antagonist disrupted this behavior. Replacement of each antagonist by vehicle led
      to the reinstatement of intra-VTA cocaine self-administration. CONCLUSIONS: The
      results of the present study suggest that VTA neurons play a critical role in
      mediating the rewarding effects of acute cocaine and that both D(1) and 5-HT(1B)
      receptors modulate these effects.

PMID- 15024550
TI  - The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP
      induced cognitive deficits in rats.
AB  - RATIONALE: Recent studies have shown that metabotropic glutamate receptor 5
      (mGluR5) can modulate N-methyl-D-aspartate (NMDA) receptor function in vivo. For
      example, the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) can
      potentiate PCP (phencyclidine)-evoked hyperactivity and PCP-induced disruptions
      in pre-pulse inhibition (PPI) in rats. OBJECTIVE: To extend these previous
      behavioral findings and determine whether the mGluR5 antagonist MPEP can modulate
      the disruptions in learning and memory induced by PCP in rats. METHODS: The
      effects of MPEP, alone and in combination with PCP, were evaluated in rats
      trained to perform a repeated acquisition procedure (learning) or a delayed non
      matching to position (DNMTP) radial maze task (spatial memory). RESULTS: In the
      repeated acquisition task, MPEP (0-10 mg/kg, IP) dose-dependently decreased
      response rates but had no effect on response accuracy. In contrast, PCP (0.625
      1.25 mg/kg, SC) reduced response rate and response accuracy in a dose-dependent
      manner. Although MPEP (10 mg/kg, IP) had no effect when administered alone, the
      mGluR5 antagonist potentiated the disruptions in learning induced by a low dose
      of PCP (0.625 mg/kg, SC). In the DNMTP maze task, MPEP (0-10 mg/kg, IP) had no
      effect on spatial memory, whereas PCP (1.25-2.5 mg/kg, SC) produced a dose
      dependent disruption. MPEP (10 mg/kg, IP) potentiated the impairments in memory
      induced by PCP (1.25 mg/kg, SC). CONCLUSION: The mGluR5 antagonist, MPEP,
      potentiated the disruptions in learning and memory induced by PCP. These
      behavioral data extend previous behavioral findings and further suggest that
      mGluR5 can modulate NMDA receptor function in vivo.

PMID- 15024551
TI  - In vivo affinity of [18F]fallypride for striatal and extrastriatal dopamine D2
      receptors in nonhuman primates.
AB  - RATIONALE: [18F]Fallypride is a new and promising radiotracer, suitable for
      imaging D2 receptors with Positron Emission Tomography (PET) in both striatal and
      extrastriatal regions. The high signal to noise ratio of [18F]fallypride has been
      attributed to its high affinity for D2 receptors (K(D) of 0.03 nM, measured in
      vitro at room temperature). OBJECTIVES: We sought to further characterize this
      tracer in terms of its in vivo affinity, possible affinity differences between
      brain regions and dependence of in vitro affinity on temperature. METHODS: PET
      scans were performed in baboons over a wide range of concentrations to measure
      the in vivo K(D) of [18F]fallypride in striatal and extrastriatal regions.
      Several analytical approaches were used, including nonlinear kinetic modeling and
      equilibrium methods. Also, in vitro assays were performed at 22 and 37 degrees C.
      RESULTS: No significant differences in the in vivo K(D) were detected between
      regions. In vivo K(D) of [18F]fallypride was 0.22+/-0.05 nM in striatum, 0.17+/
      0.05 nM in thalamus, and 0.21+/-0.07 nM in hippocampus. These values were
      intermediate between in vitro K(D) measured at 22 (0.04+/-0.03 nM) and 37 degrees
      (2.03+/-1.07 nM). CONCLUSION: The in vivo affinity of [18F]fallypride was not as
      high as previously estimated from in vitro values. This property might contribute
      to the favorable kinetic properties of the tracer. The in vivo affinity was
      similar between striatal and extrastriatal regions. This result indicates that
      the measured regional in vivo affinities of this tracer are not affected by
      putative regional differences in endogenous dopamine, and that [18F]fallypride is
      an appropriate tool to provide unbiased estimates of the occupancy of D2
      receptors by antipsychotic drugs in striatal and extrastriatal regions.

PMID- 15024554
TI  - Rhizobium etli maize populations and their competitiveness for root colonization.
AB  - Rhizobium etli, which normally forms nitrogen-fixing nodules on Phaseolus
      vulgaris (common bean), is a natural maize endophyte. The genetic diversity of R.
      etli strains from bulk soil, bean nodules, the maize rhizosphere, the maize root,
      and inside stem tissue in traditional fields where maize is intercropped with P.
      vulgaris-beans was analyzed. Based on plasmid profiles and alloenzymes, it was
      determined that several R. etli types were preferentially encountered as putative
      maize endophytes. Some of these strains from maize were more competitive maize
      root colonizers than other R. etli strains from the rhizosphere or from bean
      nodules. The dominant and highly competitive strain Ch24-10 was the most tolerant
      to 6-methoxy-2-benzoxazolinone (MBOA), a maize antimicrobial compound that is
      inhibitory to some bacteria and fungi. The R. tropici strain CIAT899,
      successfully used as inoculant of P. vulgaris, was also found to be a competitive
      maize endophyte in inoculation experiments.

PMID- 15024556
TI  - Loss of vertebral bone and mechanical strength in estrogen-deficient rats is
      prevented by long-term administration of zoledronic acid.
AB  - This study investigated the protective effect of long-term treatment with the
      bisphosphonate zoledronic acid on bone mass, structure, and strength in adult,
      estrogen-deficient rats. Rats were ovariectomized (OVX) at the age of 4 months
      and divided into four groups of 20 rats: one group of saline-treated OVX
      controls, and three groups of OVX rats treated with 0.3, 1.5, or 7.5
      microg/kg/week s.c. zoledronic acid (ZOL). An additional group of sham-operated,
      saline-treated rats served as normal controls. Biochemical assays were performed
      after 16 and 51 weeks, respectively, and bone mineral density (BMD)
      determinations after 17 and 52 weeks, respectively. Before the end of the
      experiment animals were injected with tetracyclines for the determination of
      dynamic bone indexes. Finally, animals were sacrificed after 52 weeks, and
      vertebral bones (LV5) were subjected to mechanical compression testing. LV4 were
      used for histology and LV2 for microcomputed tomography. ZOL treatment abolished
      the rise of osteocalcin and reduced urinary deoxypyridinoline excretion. BMD was
      reduced in the OVX group in comparison to sham controls, and the decline was dose
      dependently prevented by ZOL treatment. Tetracycline labeling showed a
      significant increase in bone formation rate (BFR) in OVX rats which was abolished
      by ZOL treatment. The same was observed for osteoid perimeter (Os.Pm) suggesting
      that ZOL diminished the high bone turnover associated with estrogen deficiency.
      Architectural parameters (BV/TV, Tb.Th*, Tb.N*, Tb.Sp*, SMI, CD) underwent the
      expected changes toward structural deterioration which was completely prevented
      by ZOL administration at doses of 1.5 and 7.5 microg/kg/week s.c. Similar results
      were obtained in compression testing: maximum stress fell significantly after
      OVX, and this effect was effectively prevented by ZOL treatment. Regression
      analysis suggests that in this rat model, SMI and Tb.Th* significantly contribute
      to compressive strength, albeit to a smaller degree than total cross-sectional
      area. The data further suggest that in the aged OVX rat, SMI and TB.Th* change in
      an interdependent way. ZOL prevents this process by inhibiting plate thinning and
      the transition into rod-shaped trabeculae.

PMID- 15024553
TI  - Inhibitors of ATP-sensitive potassium channels in guinea pig isolated ischemic
      hearts.
AB  - During heart ischemia, ATP-sensitive potassium channels in the sarcolemmal
      membrane (sarcK(ATP)) open and cause shortening of the action potential duration.
      This creates heterogeneity of repolarization, being responsible for the
      development of re-entry arrhythmias and sudden cardiac death. Therefore, the aim
      is to develop selective blockers of the cardiac sarcK(ATP) channel. In the
      present study we established an in vitro model and classified 5 K(ATP) channel
      inhibitors with respect to their potency and selectivity between cardiomyocytes
      and the coronary vasculature and compared the results with inhibition of
      Kir6.2/SUR2A channels expressed in HEK293 cells, recorded with the Rb(+)-efflux
      methods. We used Langendorff-perfused guinea pig hearts, where low-flow ischemia
      plus hypoxia was performed by reducing the coronary flow (CF) to 1.2 ml/min and
      by gassing the perfusion solution with N(2) instead of O(2). Throughout the
      experiment, the monophasic action potential duration at 90% repolarization
      (MAPD(90)) was recorded. In separate experiments, high-flow hypoxia was produced
      by oxygen reduction in the perfusate from 95% to 20%, which caused an increase in
      the coronary flow. Under normoxic conditions, the substances glibenclamide,
      repaglinide, meglitinide, HMR 1402 and HMR 1098 (1 microM each) reduced the CF by
      34%, 38%, 19%, 12% and 5%, respectively. The hypoxia-induced increase in CF was
      inhibited by the compounds half-maximally at 25 nM, approximately 200 nM, 600 nM,
      approximately 9 microM and >100 microM, respectively. In control experiments
      after 5 min low-flow ischemia plus hypoxia, the MAPD(90) shortened from 121+/-2
      to 99+/-2 ms ( n=29). This shortening was half-maximally inhibited by the
      substances at concentrations of 95 nM, 74 nM, 400 nM, 110 nM and 550 nM,
      respectively. In HEK293 cells the Rb(+)-efflux through KIR6.2/SUR2A channels was
      inhibited by the compounds with IC(50) values of 21 nM, 67 nM, 205 nM, 60 nM and
      181 nM, respectively. In summary, the present data demonstrate that the
      sulfonylurea glibenclamide, and the carbamoylbenzoic acid derivatives repaglinide
      and meglitinide are unselective blockers of K(ATP) channels in cardiac cells and
      in the cardiac vascular system, whereas the sulfonylthioureas HMR 1402, and
      especially HMR 1098 selectively blocked the cardiac sarcK(ATP) channel. Blockade
      of Kir6.2/SUR2A channels in HEK293 cells occurred with comparable efficacy as in
      the cardiac tissue, indicating that the expression system is suited for screening
      for novel inhibitors.

PMID- 15024558
TI  - Open-wedge high tibial osteotomy: a technical trick to avoid loss of reduction of
      the opposite cortex.
AB  - High tibial osteotomies for the treatment of gonarthrosis in young and active
      patients are well-accepted and frequently performed procedures. Several
      techniques are described to achieve good axial alignment with enough stability
      for early motion, but they come along with a considerable number of
      complications, such as insufficient or excessive axial correction, loss of
      reduction, delayed union, and pseudoarthrosis. We present a case of early loss of
      reduction in a medial opening-wedge high tibial osteotomy and a simple technical
      trick to avoid and treat this potential complication.

PMID- 15024559
TI  - A comparison of five tibial-fixation systems in hamstring-graft anterior cruciate
      ligament reconstruction.
AB  - The weak point in an ACL reconstruction immediately after surgery is the tibial
      fixation of the graft. This factor will often limit the return to load-inducing
      activities. Many new hamstring-graft fixation devices have been introduced for
      cruciate ligament reconstruction, but there is little comparative data on their
      performance. This work tested the hypotheses that some of these devices will
      resist graft slippage under cyclic loads better than others, and that some will
      have higher ultimate strength than others. Five devices were tested: WasherLoc,
      Intrafix fastener; and RCI, Delta Tapered, and Bicortical interference screws.
      Cyclic loads representing normal walking activity (1000 cycles from 70 to 220 N)
      and ultimate strength tests were done, using calf tibiae (similar bone density to
      young human tibiae) and four-strand tendon grafts, with eight tests of each
      device for each of cyclic and ultimate tensile strength tests. A series of graft
      creep tests under cyclic loads was also done. The results showed that there was
      no significant difference in graft construct elongation under cyclic loads (range
      0.7-1.3 mm) after allowing for 0.4 mm mean graft creep. The WasherLoc gave the
      highest ultimate strength (945 N, p<0.001, range 490-945 N). We concluded that
      all devices performed well under cyclic loads that represented normal walking
      activity, but the ultimate strengths differed. The performance under cyclic load
      was better than has been published for conventional interference screws. This
      evidence suggests that it may now be safe to mobilise younger patients less
      cautiously immediately after hamstring-graft ACL reconstruction.

PMID- 15024557
TI  - Effects of short-term cycling on knee joint proprioception in ACL-deficient
      patients.
AB  - It has previously been shown that knee injuries with ACL ruptures may lead to
      decreased proprioception and that exercise in a normal population, uninjured
      individuals, may reduce the proprioceptive ability. How proprioception is
      affected by exercise in patients with ACL deficiency has, to our knowledge, not
      been studied before. Knee joint proprioception was estimated in 36 patients, 18
      males and 18 females, with ACL deficiency by measuring thresholds for detection
      of slow passive motion before and after a short period of exercise on an
      ergometer bicycle. In addition, the results were compared with a control group of
      24 individuals of the same age. We found trends of enhanced proprioception
      towards extension in the patient group after cycling, but not in the control
      group. Towards flexion, both groups showed poorer proprioception after cycling.
      When difference scores of proprioceptive change in each group were compared, a
      trend towards different reaction upon cycling between the groups was seen in
      measurement towards extension from 20 degrees where the patients seemed to
      improve proprioception, which the controls did not. The results are not
      conclusive in this pilot study, but the possibility that ACL-deficient patients
      and controls may not react likewise to cycling, as regards their proprioceptive
      ability, is discussed.

PMID- 15024561
TI  - ACL surgery revisited.

PMID- 15024560
TI  - Fat-pad impingement after total knee arthroplasty with the LCS A/P-Glide system.
AB  - Early follow-up (15.8 months;1-48) of 230 knee replacements with an LCS A/P Glide
      component indicated an increased occurrence of anterior knee pain due to a fat
      pad impingement, necessitating early revision surgery. Unsatisfactory results
      were observed in 28 knees (12.2%). Thirteen knees (5.7%) were revised on finding
      the fat-pad impingement, and four knees (1.7%) were scheduled for later revision
      surgery; the remaining 11 subjects (4.8%) had revision surgery for a different
      reason. Twenty-six subjects (11.3%) complained about milder but typical symptoms
      of a fat-pad impingement, and 22 subjects (9.6%) had unspecific mild symptoms.
      151 knees (65.7%) were free of pain and demonstrated an excellent result. The
      total revision rate of 10.4% (24 knees) is higher than described for other
      implant systems. However, the revision needed to treat the fat-pad impingement
      (5.7%) consisted of minor surgery only, such as exchange of the mobile bearing or
      reduction of the fat pad by arthroscopy. The femoral and tibial components were
      able to be left untouched. Resection of the Hoffa's fat pad is recommended when
      such an implant system is used, and possible impingement should be investigated
      intraoperatively before closure.

PMID- 15024562
TI  - Dynamic in-vivo tibio-femoral and bearing motions in mobile bearing knee
      arthroplasty.
AB  - To determine the tibio-femoral and bearing motions in well functioning mobile
      bearing total knee arthroplasties, a quantitative analysis by means of
      fluoroscopy was carried out during stair ascending, chair rising-sitting and step
      up-down motor tasks. Femoral and tibial component positions were obtained using a
      CAD-model-based shape matching technique. Direct measurement of mobile bearing
      motion was carried out by tracking previously inserted tantalum beads. A
      relatively small motion of the bearing was observed. The advantage of self
      alignment claimed for the mobile bearing arthroplasty seems to be confirmed by
      subject-specific ranges of motion exhibited by these patients. It has also been
      demonstrated that these total knee arthroplasties, which are not fully conforming
      in flexion, provide little constraint to antero-posterior motion, leading to a
      kinematic pattern very similar to an ACL deficient knee.

PMID- 15024565
TI  - R3-survey of traumatic brain injury management in European Brain IT centres year
      2001.
AB  - OBJECTIVE: To obtain knowledge about the conditions and management of traumatic
      brain injury (TBI) in a collaborative network of Brain Information Technology
      centres. DESIGN: The Brain IT (Brain monitoring with Information Technology)
      survey comprised two parts: local conditions and policies (part A), and a case
      study part (part B). The information was gathered by written questionnaires
      followed by telephone interviews. PARTICIPANTS: Twenty-four Brain IT centres
      participated (two respondents from 18 sites). RESULTS: The average proportion of
      agreement between duplicate respondents was 0.79 (range 0.44-1.00). All Brain IT
      centres monitored ICP. The reported order of treatment for intracranial
      hypertension was: evacuation of mass-lesions and head elevation (1), increase of
      sedation and Mannitol scheme (2), hyperventilation (3), ventricular drainage (4),
      craniectomy and pentothal coma (5), and decompressive lobectomy (6). The
      respondents were less prone to evacuate expansive contusions in relation to extra
      cerebral hematomas. The most common suggested interventions (alone or in
      combination) for treatment of intracranial hypertension without mass lesions was
      the Mannitol scheme (included in 71% of the suggestions), CSF drainage (included
      in 56%), hyperventilation (included in 32%), and pentothal coma (included in
      22%). CONCLUSIONS: The suggested management of TBI was mainly in accordance with
      published guidelines, although a minor proportion of the answers deviated to some
      extent. The suggested order and combinations of different treatment interventions
      varied. Variation of treatment within the range of prescribed standards provides
      optimal conditions for an interesting future analysis of treatment and monitoring
      data as collected prospectively in a Brain IT database.

PMID- 15024563
TI  - Bilateral vs. unilateral spinal anesthesia for outpatient knee arthroscopies.
AB  - This prospective randomized study compared unilateral and bilateral spinal
      anesthesia with respect to intraoperative and postoperative complications, and
      time to discharge from hospital for knee arthroscopies in outpatients. We studied
      70 ASA I patients scheduled for elective outpatient knee arthroscopy. The
      patients were randomly allocated into two groups to receive either 3 ml (15 mg)
      0.5% hyperbaric bupivacaine (bilateral group) or 1.5 ml (7.5 mg) 0.5% hyperbaric
      bupivacaine (unilateral group). The duration of motor and sensory block and the
      time to discharge from the hospital were all recorded. Perioperative
      complications such as hypotension, bradycardia, nausea, vomiting, urinary
      retention, if present, were recorded. The patients were interviewed by telephone
      7 days later, and each patient was asked about headache or backache. The duration
      of motor and sensory block, and the time to discharge from hospital was shorter
      in the unilateral group than in the bilateral group. Three patients in the
      bilateral group were treated for hypotension. Bradycardia occurred in two
      patients in the bilateral group, and three patients required temporary bladder
      catheterization due to delay in recovery of spontaneous urination. Nausea and
      vomiting occurred in three patients in bilateral group. Nine patients in the
      bilateral group and six patients in the unilateral group developed postspinal
      headache. Backache occurred in five patients in the bilateral group and in six
      patients in the unilateral group. Our data indicate that the use of unilateral
      spinal block is a suitable technique for knee arthroscopies in outpatients.

PMID- 15024566
TI  - Mucociliary function deteriorates in the clinical range of inspired air
      temperature and humidity.
AB  - OBJECTIVE: To test whether a reduction in air temperature within the clinical
      range [37 degrees C to 30, 100% relative humidity (RH)] altered mucus transport
      velocity (MTV) and ciliary beat frequency (CBF) in an in vitro ovine tracheal
      model. DESIGN: Controlled laboratory study. SETTING: University research
      laboratory. SUBJECTS: Farm-reared sheep. INTERVENTIONS: Tracheae were mounted
      flat in an organ bath. Krebs Henseleit bathed the serosal surface and air at 100%
      (RH) was passed over the mucosal surface at 4 l/min. Cilial beat frequency (CBF)
      was measured photo-electrically and mucus transport velocity (MTV) by timing
      movement. After 2 h at 37 degrees C (100% RH) the tissue was either maintained
      with those settings (controls), or the air temperature reduced to 34 degrees C or
      30 degrees C. Tissue was taken for histology before and after each experiment.
      MEASUREMENTS AND RESULTS: CBF was 19.8+/-2.7 beats/s and MTV 5.7+/-2.6 mm/min in
      tissue exposed to air at 37 degrees C. Cilial activity continued for up to 6 h in
      the controls but mucus transport was more fragile. Reduction of the air
      temperature to either 34 degrees C or 30 degrees C led to a decrease in both CBF
      and MTV and, frequently, total mucociliary failure. There was a reduction in
      epithelial mucous cell numbers in all preparations. Tissues exposed to low
      temperature had additional abnormal histology. CONCLUSIONS: Delivery of inspired
      gas at 30 degrees C, or even 34 degrees C, with 100% RH may not be sufficient to
      prevent epithelial damage occurring during 6 h exposure.

PMID- 15024567
TI  - Identifying the potential organ donor: an audit of hospital deaths.
AB  - OBJECTIVE: To quantify the potential for organ donation in Victoria and identify
      missed opportunities for organ donation. DESIGN AND SETTING: Prospective medical
      record audit of all deaths in 12 Victorian hospitals. MEASUREMENTS: Data on
      deaths, total potential donors, organ donors and outcome of requests for organ
      donation were collected. Patients in whom brain death was confirmed or likely to
      occur and in whom organ donation was not requested (unrealised potential donors)
      were classified by an independent panel. Rates of organ donation and unrealised
      donors were determined as a proportion of total potential donors and hospital
      deaths and the maximal potential organ donor rate was estimated. RESULTS: Of 5551
      deaths, there were 112 potential donors, with 66 requests for organ donation
      resulting in 39 consents (consent rate of 59%) and 37 organ donors (33% of total
      potential donors; 0.7% of hospital deaths). Two consented potential donors did
      not donate due to failed physiological support (5%). There were 46 medically
      suitable unrealised potential donors; 3 with confirmed brain death. Approximately
      half of these patients had treatment withdrawn in the intensive care unit and
      half in the Emergency Department. The estimated maximal potential donor rate was
      30 per million population. CONCLUSIONS: The potential for organ donation in
      Victoria is relatively low compared with previous estimates in Australia and
      overseas. An increase in the organ donation rate may be possible through
      increasing consent and the identification and support of potential donors. This
      would require substantial changes in clinical practice that have resource and
      ethical implications.

PMID- 15024569
TI  - Transaminase levels in ventilated children with respiratory syncytial virus
      bronchiolitis.
AB  - OBJECTIVES: To compare disease severity as judged by duration of ventilation,
      inotrope use and mortality in children ventilated for respiratory syncytial virus
      (RSV)-positive lower respiratory tract infection (LRTI) with and without elevated
      transaminase levels and to determine the aetiology of elevated transaminase
      levels in this patient group. DESIGN: Prospective observational study. SETTING:
      Twenty-two-bed Paediatric Intensive Care Unit. PATIENTS: Forty-eight ventilated
      children with RSV-positive LRTI. MEASUREMENTS AND RESULTS: Alanine
      aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured
      daily. In patients with elevated transaminase levels infection with the following
      viruses was investigated: hepatitis A, B and C viruses, cytomegalovirus, Epstein
      Barr virus, adenovirus, influenza virus, and parainfluenza viruses (types I, II,
      and III). Elevated transaminase levels were detected in 22 (46%) patients. The
      duration of mechanical ventilation (geometric mean; 95% CI) was significantly (
      P<0.05) longer in the group with elevated transaminase levels: 10.6 (9.4; 11.7)
      days versus 3.5 (2.8; 4.2) days. This difference remained significant in patients
      without congenital heart disease. Inotrope use was more common and all deaths
      occurred in the group with elevated transaminase levels ( P<0.05). All patients
      who died and all but two patients with inotrope requirements had underlying
      congenital heart disease. One patient with elevated transaminase levels had a
      simultaneous infection with influenza A virus. CONCLUSIONS: RSV disease in
      ventilated children was more severe if transaminase levels were elevated.
      Transaminase level elevation was due to hepatitis in the majority of patients. In
      patients with congenital heart disease we also detected myocardial involvement.

PMID- 15024568
TI  - Effects of the angiotensin-converting enzyme inhibitor perindopril on endothelial
      injury and hemostasis in rabbit endotoxic shock.
AB  - OBJECTIVE: To assess the effects of the angiotensin-converting enzyme (ACE)
      inhibitor (ACEI) perindopril on prolonged endothelial cell dysfunction in a
      rabbit endotoxic model. DESIGN: Randomized, controlled, interventional trial.
      SETTING: University animal laboratory. SUBJECTS: A total of 65 male New Zealand
      White rabbits, randomly assigned to one of eight groups. INTERVENTIONS: Endotoxic
      shock was induced by a single lipopolysaccharide (LPS, serotype O55:B5) bolus
      (0.5 mg.kg(-1), i.v., Escherichia coli endotoxin). Coagulation factors and
      expression of monocyte tissue factor (TF) were determined by functional assay.
      Endothelium-dependent vascular relaxation was assessed by in vitro vascular
      reactivity. Immunohistochemical staining (CD31) was performed to assess
      endothelial injury of the abdominal aorta. These parameters were studied 5 days
      (D5) after the onset of endotoxic shock. Rabbits were randomized to receive
      perindopril (1 mg kg(-1) day(-1) orally) alone, or with N(G)-nitro-L-arginine
      methyl ester (L-NAME; 15 mg kg(-1) day(-1) orally), or L-NAME alone initiated 7
      days before the onset of endotoxic shock and maintained for 5 days afterward.
      MEASUREMENTS AND RESULTS: Perindopril prevented altered endothelium-dependent
      relaxation to acetylcholine induced by LPS injection (E(max)=75.6+/-3.7 vs 42.3+/
      9.4% in LPS group, p<0.05). This effect was inhibited by co-treatment with L
      NAME. Perindopril had no effect on either LPS-induced endothelial histological
      injury or monocyte TF expression. CONCLUSION: These data suggest that perindopril
      can prevent endothelial dysfunction in endotoxin-induced shock through an NO
      dependent mechanism.

PMID- 15024570
TI  - A short Chemical Sensitivity Scale for assessment of airway sensory
      hyperreactivity.
AB  - OBJECTIVES: A short version of the 21-item Chemical Sensitivity Scale (CSS),
      called the Chemical Sensitivity Scale for Sensory Hyperreactivity (CSS-SHR), was
      developed and evaluated for the quantifying of self-reported affective reactions
      to and behavioral disruptions in daily activities by odorous/pungent substances
      among patients with sensory hyperreactivity (SHR) for clinical and
      epidemiological studies. METHODS: Twenty-two patients with clinically diagnosed
      SHR and 124 control participants responded to the CSS and to additional questions
      about chemical sensitivity for the evaluation of the CSS-SHR. RESULTS: Eleven of
      the 21 items of the CSS were selected, on statistical grounds, to constitute the
      CSS-SHR, which was found to generate approximately normal distributions, have
      good test-retest reliability (r(xy)=0.87), satisfying internal consistency
      (r(alpha)=0.76-0.84) and predictive and concurrent validity, and to be uni
      dimensional. The metric properties of the CSS-SHR were, despite its few items,
      comparable with those of the CSS. A proposed diagnostic cut-off score for SHR
      demonstrated a high correct classification rate (92%) for the CSS-SHR.
      CONCLUSIONS: The favorable metric properties of the CSS-SHR and its
      sensitivity/specificity suggests that it is useful for clinical diagnosis and
      epidemiological study of sensory hyperreactivity in combination with other
      diagnostic tools.

PMID- 15024572
TI  - Comparison of unchanged n-hexane in alveolar air and 2,5-hexanedione in urine for
      the biological monitoring of n-hexane exposure in human volunteers.
AB  - INTRODUCTION AND AIM: Biological monitoring of n-hexane (HEX) is based on the
      measurement of urinary 2,5-hexanedione (2,5-HD). In 2001, the American Conference
      of Governmental Industrial Hygienists modified the biological exposure index
      (BEI) for HEX and suggested measuring free urinary 2,5-HD (without hydrolysis)
      (3.5 micromol/l) instead of total 2,5-HD (acid hydrolysis). This BEI value was
      derived from four field studies that involved worker exposures to variable
      concentrations of HEX and other solvents. This study was undertaken to
      characterize, for 5 consecutive days, the relationship between HEX exposure (25
      ppm and 50 ppm) and (1). 2,5-HD urinary excretion and (2). HEX in alveolar air.
      METHODS: Five volunteers (three women, two men) were exposed to HEX in an
      exposure chamber for 2 non-consecutive weeks (7 h/day). They were exposed to 50
      ppm HEX, during the first week and to 25 ppm during the second week. Alveolar air
      and urine samples were collected at different intervals before, during and after
      the exposures. The concentration of unchanged HEX in alveolar air and the
      concentration of urinary 2,5-HD under three analytical conditions (with acid, or
      enzymatic hydrolysis and without hydrolysis) were measured. RESULTS: The results
      show that the mean concentrations of HEX in alveolar air were 18 ppm (25 ppm) and
      37 ppm (50 ppm), which indicates that approximately 73% of inspired HEX was
      expired unchanged in alveolar air by the volunteers. The mean (+/- SD)
      concentrations of urinary 2,5-HD for the last 4 h of exposure at the end of the
      week (day 5) following exposure to 50 ppm HEX were 30.4 micromol/l (+/-7.8
      micromol/l) (acid hydrolysis); 5.8 micromol/l (+/-1.0 micromol/l) (enzymatic
      hydrolysis); 6.2 micromol/l (+/-0.9 micro mol/l) (without hydrolysis). Following
      the volunteers' exposure to 25 ppm HEX, the urinary excretion concentrations were
      15.2 micromol/l +/- 1.9 micromol/l, 3.1 micromol/l +/- 0.7 micromol/l and 3.7
      micromol/l +/- 0.5 micromol/l, respectively. CONCLUSION: Both free urinary 2,5-HD
      and HEX in alveolar air measurements could be used for the biological monitoring
      of HEX. Between these two indicators, HEX in alveolar air is less variable than
      2,5-HD in urine, but the sampling time is more critical. Therefore, biological
      monitoring of HEX based on the measurement of free urinary 2,5-HD is preferable
      to HEX in alveolar air. Additionally, we believe that the 2,5-HD values reported
      in this study better reflect the actual levels of exposure to HEX alone than what
      has been previously reported in studies that involved co-exposure to other
      solvents, and that the current BEI value for HEX is most likely more protective
      than what has been believed up until now.

PMID- 15024571
TI  - Neuropsychological function in manganese alloy plant workers.
AB  - OBJECTIVES: The objective was to investigate potential nervous system effects of
      manganese (Mn) exposure in workers employed in manganese-alloy-producing plants.
      METHODS: One hundred male Mn alloy plant workers were compared with 100 age
      matched referents. The subjects were examined with a comprehensive
      neuropsychological test battery. Exposure was assessed by measurement of Mn
      concentrations in the workroom air, blood and urine. RESULTS: The geometric mean
      (GM) concentration of inhalable Mn in workroom air was 301 microg/m(3). The GM
      concentration of Mn in whole blood (181 nmol/l vs 160 nmol/l) ( P=0.002) and
      urine (0.9 nmol/mmol creatinine vs 0.4 nmol/mmol creatinine) ( P<0.001) was
      higher among the exposed subjects than among the referents. The Mn-exposed
      subjects had increased postural tremor while conducting a visually guided tremor
      test (static steadiness test) compared with the referents (mean number of
      contacts 94 vs 59 ( P= 0.001); duration of contacts (in seconds) 5.1 vs 3.5 (
      P=0.003)). The tremor had larger frequency dispersion, indicating that the tremor
      included a wider variety of frequencies, among the exposed subjects than among
      the referents, assessed by the "TREMOR" test system. Smoking habits (self
      reported) influenced the tremor parameters significantly, the Mn-exposed smokers
      having more tremor than the non-smoking Mn-exposed subjects. No differences
      between the groups were found in tests for cognitive functions, reaction time or
      in symptom reporting. CONCLUSION: The Mn-exposed subjects had increased hand
      tremor compared with their referents. The tremor was related to exposure
      parameters. Smoking habits (self-reported) influenced the tremor parameters.

PMID- 15024573
TI  - Evidence for a possible NOS back-up system in the organ of Corti of the guinea
      pig.
AB  - Recently, the two Ca(2+)/calmodulin-regulated nitric oxide synthase isoforms,
      nNOS and eNOS, and NO itself have been identified in the cochlea of vertebrates
      using specific antibodies and a new fluorescence indicator. In order to acquire
      more information about the quantitative and spatial distribution of these two
      constitutively expressed NOS isoforms (cNOS) in the organ of Corti at the
      cellular and subcelluar levels, ultrathin sections of London resin (LR) White
      embedded cochleae of the guinea pig were incubated with various concentrations of
      commercially available antibodies to nNOS and eNOS. The immunoreactivity was
      visualized by a gold-labeled secondary antibody and the amount of the
      immunoreactions/microm(2) was quantified for different cell types and subcellular
      regions. Both NOS isoforms were identified to varying degrees in the same cell
      types and subcellular regions. A prominent eNOS immunoreactivity was identified
      in nearly every cell type. In all analyzed animals the highest number of gold
      coupled anti-eNOS antibodies was always seen in the cells of the reticular
      lamina, especially in the cuticular structures of outer and inner hair cells,
      pillar cells and apical Deiters' cells. Also the microtubuli-containing
      cytoplasmic regions of Deiters' cells were scattered with gold-coupled anti-eNOS
      antibodies. A clear eNOS immunoreaction was also found in the remaining cytoplasm
      of inner and outer hair cells and in the apical Deiters' cells. Numerous anti
      nNOS antibodies were located in the outer hair cells and in the cuticular
      structures of the apical Deiters' cells. The amount of the gold-labeled anti-nNOS
      antibodies in the cuticular plates of the pillar cells and outer hair cells and
      in the cytoplasm of inner hair cells and apical Deiters' cells were clearly less
      but still above unspecific background labeling. The spatial co-localization of
      the two NOS isotypes in the same cell regions was proven in double-labeling
      experiments. The spatial distribution of the two cNOS isoforms confirmed recent
      findings of other authors who localized NO distribution and production sites. The
      cNOS co-expression with similar function in the same cell type and subcellular
      regions may represent a functional "back-up system" in which one NOS isoform can
      replace the other in case of pathophysiological malfunction.

PMID- 15024575
TI  - Third degree perineal tears in a university medical center where midline
      episiotomies are not performed.
AB  - OBJECTIVE: Midline episiotomy is a known major risk factor for severe perineal
      lacerations. The study was aimed to define obstetric risk factors for third
      degree perineal tears in a university medical center where midline episiotomies
      are not performed. STUDY DESIGN: A comparison between vaginal deliveries
      complicated with third-degree perineal tears and deliveries without third-degree
      perineal tears was performed. Deliveries occurred between the years 1988-1999 in
      a tertiary medical center. Multiple gestations, preterm deliveries (<37 weeks'
      gestation), cesarean deliveries and cases of shoulder dystocia were excluded from
      the analysis. A multiple logistic regression model was constructed in order to
      find independent risk factors for third-degree perineal tears. Odds ratios (OR)
      and their 95% confidence interval (CI) were calculated from the regression
      coefficient. RESULTS: During the study period, 79 (0.1%) consecutive cases of
      third degree perineal tears were identified. Significant risk factors from the
      univariate analysis were fetal macrosomia (OR 2.7, 95% CI 1.2-5.5), nulliparity
      (OR 2.9, 95% CI 1.8-4.6), labor induction (OR 1.9, 95% CI 1.0-3.5), failure of
      labor to progress during the second stage (OR 10.8, 95% CI 5.4-21.1), non
      reassuring fetal heart rate patterns (OR 11.7, 95% CI 6.1-21.5), mediolateral
      episiotomy (OR 2.8, 95% CI 1.8-4.5), vacuum extraction (OR 10.6, 95% CI 6.1
      18.3), and forceps delivery (OR 29.2, 95% CI 7.3-97.2). However, using a
      multivariable analysis, only fetal macrosomia (OR 2.5, 95% CI 1.2-4.9), vacuum
      extraction (OR 8.2, 95% CI 4.7-14.5), and forceps delivery (OR 26.7, 95% CI 8.0
      88.5) remained as independent risk factors. The combined risk for instrumental
      deliveries of macrosomic newborns was 8.6 (95% CI 1.2-62.5; p=0.010).
      CONCLUSIONS: After adjustment for possible confounding variables, mediolateral
      episiotomy per se was not an independent risk factor for third-degree perineal
      tears. Instrumental vaginal deliveries of macrosomic fetuses should be avoided
      whenever possible to decrease the occurrence of third-degree perineal tears.

PMID- 15024576
TI  - An evaluation of maternal illnesses in the origin of neural-tube defects.
AB  - OBJECTIVE: The objective of the study was to estimate risk of acute and chronic
      maternal diseases during pregnancy in the origin of neural-tube defects.
      MATERIALS AND METHODS: Mothers with neural-tube defect fetuses/newborns (the NTD
      group), controls without any congenital defects (the normal control group) and
      controls with other defects (the other CA control group) were compared in the
      population-based data set of the Hungarian Case-Control Surveillance of
      Congenital Abnormalities, 1980-1996. Of 1,202 cases with neural tube defects, 559
      (49.8%) and 229 (19.1%) had mothers with one or more acute and chronic diseases,
      respectively. Of 38,151 mothers in the normal control group 14,004 (36.7%) and
      8,328 (21.8%) had mothers with one or more acute or chronic diseases,
      respectively. Of 22,475 mothers in the other CA control group, 8,999 (40.0%) and
      3,793 (16.9%) were affected with one or more acute or chronic maternal diseases,
      respectively. The prevalence of these diseases was evaluated in the 2nd months of
      gestation, however, if diseases occurred in the 1st month and continued in the
      2nd month were also included. RESULTS: There was a potential recall bias between
      the NTD group and the normal control group, but not between the NTD group and the
      other CA control group. CONCLUSIONS: We suggest that maternal fever is a possible
      cause of neural-tube defects. Thus, these fevers should be treated with
      antipyretics during pregnancy. Among chronic maternal diseases, the possible
      association of migraine-headache, on the one hand and neural tube defects
      (particularly anencephaly) on the other hand cannot be excluded.

PMID- 15024577
TI  - T cells in psoriatic lesional skin that survive conventional therapy with NB-UVB
      radiation display reduced IFN-gamma expression.
AB  - The type 1 T cell-derived cytokine interferon gamma (IFN-gamma) is overexpressed
      in psoriatic lesional skin. Recently, we have shown that a single high erythemal
      dose of broad-band ultraviolet B (UVB) irradiation reduces type 1 and favors type
      2, i.e. interleukin-4 (IL-4), cytokine expression in normal and psoriatic skin.
      In this study, we wanted to see whether conventional narrow-band UVB (NB-UVB)
      therapy (i.e. repeated exposure to nonerythemal doses) also affects type 1/type 2
      cytokine expression of T cells present in chronic plaque type psoriatic lesions.
      Staining of cryostat sections showed decreased expression of both IFN-gamma and
      IL-4 in situ after NB-UVB therapy. CD4(+) dermal T cell lines, derived from
      psoriatic lesional skin, displayed significantly decreased intracellular IFN
      gamma expression during and after NB-UVB therapy as compared to pretreatment
      values. Intracellular IL-4 expression was increased in most patients after
      therapy. Analysis of the supernatants of these stimulated dermal T cells revealed
      that IFN-gamma production decreased significantly following NB-UVB therapy,
      whereas IL-4 expression increased in the T cell supernatants from most patients,
      confirming the intracellular determinations. In addition, IL-10 and transforming
      growth factor-beta levels in the supernatants appeared to be increased in the
      majority of patients following UVB therapy. Apart from the well-known killing
      effect of UVB on T cells, our results show that the improvement in psoriatic skin
      following NB-UVB therapy is also due to a reduced capacity of the surviving
      dermal T cells to express the proinflammatory cytokine IFN-gamma.

PMID- 15024578
TI  - Involvement of RFX proteins in transcriptional activation from a Ras-responsive
      enhancer element.
AB  - The B10.RRE element has previously been shown to mediate induced transcription in
      response to an activated Ha- ras gene and epidermal growth factor in
      keratinocytes but not in fibroblasts. We report the identification of regulatory
      factor for X box 3 (RFX-3) as a B10.RRE-binding protein, using the yeast one
      hybrid assay. We showed that in vitro-translated RFX3, as well as RFX1 and RFX2,
      was able to bind B10.RRE in a sequence-specific manner. Furthermore, RFX proteins
      are part of the protein complex in HeLa and HepG2 cells that binds the B10.RRE
      element. Functional analysis in cell culture demonstrated that a truncated
      version of RFX1 (*RFX1) lacking the repressor domain was able to activate
      transcription from B10.RRE. Conversely, a dominant-negative form of RFX1 was able
      to block Ras-induced transcription. Taken together, these results suggest a novel
      role for the RFX family of transcription factors as modulators of Ras signalling
      in epithelial cells. Such an interaction is of potential relevance for cell
      growth and carcinogenesis in the skin.

PMID- 15024579
TI  - A model of soft-tissue graft anterior cruciate ligament reconstruction in sheep.
AB  - INTRODUCTION: Since there is to our knowledge no clinically valid and
      reproducible animal model of soft-tissue anterior cruciate ligament (ACL)
      reconstruction currently available, we developed one in sheep, in terms of graft
      suitability, postsurgical recovery, and knee stability. MATERIALS AND METHODS: To
      find a suitable graft, anatomical dissections of the hind limbs of 7 sheep were
      performed. After a pilot study in 3 sheep, we reconstructed the ACL with an
      ipsilateral, longitudinally split, superficial digital flexor tendon autograft
      and anatomic graft fixation in 42 sheep (study 1) and with a full, superficial
      digital flexor tendon autograft and extracortical graft fixation in 48 sheep
      (study 2). Follow-up examinations ranged from 6 to 104 weeks (study 1) and 3 to
      24 weeks (study 2). RESULTS: All animals tolerated the graft harvest well and
      returned to physiological movement after about 4 weeks. Only 1 out of 93 ACL
      reconstructions failed. At final follow-up, the anteroposterior (AP) drawer
      displacement in both studies had almost regained the value of the intact
      contralateral knee. Maximum load-to-failure improved over time in both studies
      but was significantly lower at all time points compared with the intact ACL and
      the graft tissues. Tensile stress was significantly lower at final follow-up in
      both studies compared with the intact ACL and graft tissues. It attained 43.3% of
      the intact ACL and 58.3% of the graft tissue in study 1 and 28.9% and 22.8% in
      study 2, respectively. CONCLUSION: The flexor tendon is suitable, and sheep
      appear to be an appropriate animal model for soft-tissue graft ACL
      reconstruction. They tolerate the graft harvest well and quickly return to full
      weight-bearing and physiological movement. Their knees become stable without
      showing signs of macroscopically evident osteoarthritis.

PMID- 15024580
TI  - The Lubinus patellofemoral arthroplasty: a series of 17 cases.
AB  - INTRODUCTION: The Lubinus patellofemoral arthroplasty was introduced in our
      institution in 1994. The first 17 patients were followed-up in order to identify
      the short-term outcome for this prosthesis. MATERIALS AND METHODS: The average
      age at surgery was 66 years (range 37-82 years). The mean follow-up was 19
      months. The indications for surgery were strictly limited to radiographically
      proven primary osteoarthritis affecting only the patellofemoral joint (13) and
      secondary arthritis due to maltracking, subluxation (3) or trauma to the patella
      (1). At review, the range of movement and Lysholm and Tegner scores were recorded
      and radiographs obtained. Patients were also asked if their outcome was
      satisfactory or unsatisfactory. RESULTS: At review, only 9 (53%) knees were
      classified as satisfactory by the patients. Further surgery had been carried out
      in 6 cases (35%) including revision to total knee arthroplasty in 4 (24%). Other
      complications included clicking and subluxation in 3 cases (18%), extension block
      in 3 (18%) and infection in 1 (6%). Progression of osteoarthritis to involve
      other compartments occurred in 2 cases (12%). CONCLUSIONS: Many of these early
      problems are related to the unforgiving nature of the prosthesis on insertion.
      These poor early results have led us to stop using the prosthesis.

PMID- 15024581
TI  - Occurrence of alpha-synuclein pathology in the cerebellum of Guamanian patients
      with parkinsonism-dementia complex.
AB  - Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a
      progressive neurodegenerative disease affecting the indigenous Chamorro
      population of Guam. Neuropathologically, PDC is characterized by neuronal loss in
      the substantia nigra pars compacta with severe widespread neurofibrillary tangles
      (NFTs) similar to those observed in Alzheimer's disease (AD), and is thus
      considered a tauopathy. Following reports of alpha-synuclein pathology in PDC
      patients of Guam, PDC has also been neuropathologically classified as a
      synucleinopathy. Recently, the presence of alpha-synuclein-positive bodies has
      been reported in the cerebellum of some patients with Parkinson's disease (PD),
      diffuse Lewy body disease (DLBD), or multiple system atrophy (MSA). Using
      immunohistochemical techniques, we investigated the deposition of alpha-synuclein
      in the cerebellum of Guamanian PDC patients. Numerous alpha-synuclein
      immunoreactive spherical structures were found in the molecular layer of the
      cerebellum of 63.6% of PDC patients. These structures were only seen in patients
      showing alpha-synuclein pathology in the amygdala. The average density of alpha
      synuclein-immunoreactive structures in the cerebellum of Guamanian PDC patients
      was almost an order of magnitude higher than in non-Guamanian PD patients, and
      this alpha-synuclein pathology was much more pronounced in the hemisphere than in
      the vermis. In addition, double immunohistochemistry revealed that cerebellar
      alpha-synuclein is co-localized with the neuronal marker calbindin and with glial
      fibrillary acidic protein, suggesting the involvement of Purkinje cells and
      Bergmann glia. These findings demonstrate that the alpha-synuclein pathology in
      PDC of Guam affects not only the amygdala, but also the cerebellum, where it
      appears to involve both Purkinje cells and specialized astrocytes.

PMID- 15024582
TI  - Histone deacetylase inhibitor, FK228, induces apoptosis and suppresses cell
      proliferation of human glioblastoma cells in vitro and in vivo.
AB  - We investigated the effects of FK228 on cell proliferation and apoptosis against
      human glioblastoma (GM) T98G, U251MG, and U87MG cells. Upon exposure to FK228,
      cell proliferation was inhibited, and apoptosis detected by the cleavage of CPP32
      was induced. FK228 increased the expression levels of p21 (WAF-1) and of pro
      apoptotic Bad protein in all GM cells. Furthermore, FK228 treatment also reduced
      the anti-apoptotic protein Bcl-xL in all GM cells and anti-apoptotic Bcl-2 in
      U87MG cells, thereby shifting the cellular equilibrium from life to death. An
      increased accumulation of histone H4 was detected in the p21 (WAF-1) promoter and
      the structural gene (exon 2) and the Bad structural gene (exon 2 and 3) upon
      treatment with FK228, as assessed by chromatin immunoprecipitation (ChIP) assay.
      Thus, the results indicated that an increased expression of p21 (WAF1) and Bad
      due to FK228 is regulated, at least in part, by the degree of acetylation of the
      gene-associated histone. We also found that FK228 inhibits cellular invasiveness
      and decreases MMP-2 activity. In addition, the growth of transplanted human GM m
      3 cells into the subcutaneous tissue of hereditary athymic mice was significantly
      inhibited, and apoptosis was induced with FK228 treatment. The results suggested
      that FK228 might be useful in the treatment of human GM, although further studies
      will be needed.

PMID- 15024583
TI  - Immunohistochemical study of tau accumulation in early stages of Alzheimer-type
      neurofibrillary lesions.
AB  - Accumulation of abnormally phosphorylated tau results in the formation of
      neurofibrillary tangles (NFTs) in the neuronal cell soma and neuropil threads
      (NTs) in the cell processes. In the present study, we used immunohistochemistry
      to investigate serially cut thick tissue sections from the brains of patients
      with Alzheimer's disease (AD) and non-demented elderly subjects. In the early
      stages of neurofibrillary pathology, clusters of NTs occurred occasionally in the
      cerebral cortex. Each NTs cluster, the entire extent of which was observed in the
      serial sections, corresponded to a dendritic tree that was arborized from a tau
      positive neuron. Adult human brain contains six tau isoforms with three having
      three carboxyl-terminal tandem repeat sequences that are encoded by exon 10 (3R
      tau) and the other three having four repeat sequences (4R-tau). Three isoform
      patterns, 3R-tau(+)/4R-tau(-), 3R-tau(-)/4R-tau(+) and 3R-tau(+)/4R-tau(+), were
      seen in NFTs in early stage AD lesions. In an individual neuron, the isoform
      pattern was consistent between the NFTs in the cell soma and the NTs in the cell
      processes. The results of this study indicate that, in early stages of AD and age
      associated neurofibrillary changes, tau accumulates simultaneously in the cell
      soma and cell processes of affected neurons. The process of AD and age-associated
      tau pathology is not tau-isoform-specific, but the ratio of 3R-tau and 4R-tau
      isoforms involved in the neurofibrillary changes varies and is specific to
      individual neurons.

PMID- 15024585
TI  - Nucleic acid-based modulation of cardiac gene expression for the treatment of
      cardiac diseases. Approaches and perspectives.
AB  - During the past few years major conceptual and technical advances have been made
      towards the therapeutic modulation of cardiac gene expression for the treatment
      of cardiac diseases. Among these are 1) the identification of new molecular
      therapy targets in cardiac disorders, often derived from genetic animal models.
      2) A better understanding of the molecular and cellular determinants of cardiac
      gene transfer in vivo, in animal models and in first clinical trials. 3) The
      development of novel regulatable and long-term stable vector systems. This review
      is focused on nucleic acid-based modulation of cardiac calcium homeostasis as a
      paradigm for the new gene therapeutic approaches, since recent landmark papers
      have suggested this to be a molecular target of key importance in heart failure.
      In particular, the development of severe heart failure in the genetic MLP(-/-)
      animal model could be completely abolished by the targeted ablation of
      phospholamban (PL), a key regulator of cardiac calcium homeostasis. This
      impressive effect of permanent germline PL ablation provides-in conjunction with
      former important work on disturbed calcium handling in the failing human heart-a
      rationale for the gene therapeutic approach of ad hoc suppression of PL by
      antisense strategies (antisense RNAs, ribozymes, RNA interference) or PL
      variants. Based on the broad spectrum of methods employed to characterize this
      general strategy, PL-targeted approaches may be considered as a paradigm of
      future genetic treatments of cardiac disorders, although the differences between
      animal models and humans must be kept in mind. High safety of any such therapy
      will be a prerequisite for any possible clinical application and therefore novel
      methods to improve control are being devised: 1) The regulation of gene therapy
      vectors by biochemical abnormalities associated with the target disease itself ("
      Induction-by-Disease" gene therapy). 2) External control of vector activity by
      the employment of drug-sensitive promotors. In addition, the important goal of
      cardiac long-term stability of the therapeutic vectors has recently been achieved
      in animal models using vectors derived from adeno-associated viruses (AAVs).

PMID- 15024584
TI  - Alzheimer disease pathology in amyotrophic lateral sclerosis.
AB  - Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and
      lower motor neurons. In some ALS patients, dementia or aphasia may be present
      (ALS-D). The dementia is most commonly a frontotemporal dementia (FTD), and many
      of these cases have ubiquitin-positive, tau-negative inclusions in neurons of the
      dentate gyrus and superficial layers of the frontal and temporal lobes. Identical
      inclusions have been found in cases presenting with FTD and have been designated
      motor neuron disease (MND)-inclusions. Cases of ALS-D without MND-inclusions have
      been reported to show neocortical gliosis, neuronal loss, and superficial
      spongiosis, but there have also been scattered case reports of ALS with
      Alzheimer's disease (AD). To determine whether AD pathology may play a role in
      the dementia or aphasia syndromes in ALS, we reviewed 30 cases of sporadic ALS
      diagnosed at the University of Pittsburgh Medical Center. A clinical history of
      ALS-D was found in 24.1% of the cases, of which 57% had MND-inclusions. Although
      the ALS-D cases with MND-inclusions typically had amyloid-beta (Abeta) plaques,
      there were no neuritic plaques. Three cases of ALS-D had no MND-inclusions, and
      two of these fulfilled pathological criteria for AD. One ALS-D case showed severe
      amyloid angiopathy but no neuritic plaques or MND-inclusions. MND-inclusions were
      not found in any ALS case without dementia; however, four patients without
      dementia or aphasia showed moderate or frequent numbers of neuritic plaques. In
      conclusion, we found that approximately 30% of ALS cases with dementia have AD
      and that some ALS cases without frank dementia have significant AD pathology.

PMID- 15024586
TI  - [Ventricular septal defect and aortic regurgitation-pathophysiological aspects
      and therapeutic consequences].
AB  - The development of aortic regurgitation (AI) is a rare but serious complication
      of subaortic ventricular septal defects (VSD). Over a period of 5 years we
      observed VSD-related AI in 24 patients, a frequency of 4.5% of all isolated VSD's
      encountered during that time frame. The location of the defects was in the
      infundibular septum in 59%, it was perimembranous in 25% and in the trabecular
      septum in 16%. Hemodynamically the defects were small except for 2 where the
      Q(p)/Q(s) ratio was > 2. Of the 24 pts, 16 had surgical closure of their VSD
      accompanied in 9 by aortic valvuloplasty. AI was caused by elongation or defect
      of the right coronary leaflet in 42%, of the noncoronary leaflet in 25% and a
      combination of both, in 8%. In 6 pts with infundibular VSD absence of part of the
      aortic valve ring above the defect was the underlying mechanism for AI.
      Postoperatively AI was improved to moderate in one pt and to none to trivial in
      15. LV end-diastolic diameter decreased significantly in all pts operated.
      Pathogenetic mechanisms for the development of AI are a deficiency in the aorto
      infundibular junction with prolaps of the right-or non-coronary leaflet,
      deficiency of the valve supporting structures including the valve ring as well as
      suction of the already elongated leaflet into the VSD with further damage to the
      antiregurgitant mechanism of the semilunar valve at risk. In perimembranous
      VSD's, late AI is probably related to turbulent flow through the adjacent LVOT.
      Surgical closure of isolated VSD's with a location immediately beneath the aortic
      valve is indicated regardless of their size to prevent the development of AI. If
      AI has occurred, VSD closure including aortic valvuloplasty improves the amount
      of regurgitation and normalizes LV enddiastolic dimension.

PMID- 15024587
TI  - Rings, slings and other vascular abnormalities. Ultrafast computed tomography and
      magnetic resonance angiography in pediatric cardiology.
AB  - Ultrafast CT and MR angiography are noninvasive, accurate and robust techniques
      for preoperative diagnosis and planning of congenital heart disease and vascular
      abnormalities in pediatric patients. While they seem to be equivalent to
      conventional catheter angiocardiography for detecting vascular abnormalities,
      they are more accurate for the diagnosis of potentially life-threatening
      complications, such as tracheal, bronchial or esophageal compression. The value
      of ultrafast CT and MR angiography is demonstrated in 22 pediatric patients with
      vascular rings, slings and other vascular abnormalities.

PMID- 15024588
TI  - [Cardiopulmonary exercise capacity increases after interventional ASD-closure].
AB  - BACKGROUND: In patients with atrial septal defects of the secundum-type (ASD),
      exercise tolerance is reduced. Generally, ASD closure is recommended in
      symptomatic patients and in patients with a relevant left-to-right shunt (Qp/Qs >
      1.5). Only few data are available concerning objective parameters of
      cardiopulmonary exercise capacity. The aim of this study was to evaluate exercise
      capacity as achieved by ergospirometry in adult patients with an ASD at baseline
      and in the long-term following transcatheter closure. METHODS AND RESULTS: Thirty
      consecutive patients (8 male; mean age 43.4 years; defect size 23.5 mm; pulmonary
      to-systemic flow ratio (Qp/Qs) 1.94) performed exercise testing on a supine
      bicycle ergometer. At baseline, oxygen consumption at maximal exercise (VO(2)
      peak) was 14.3 ml/min kg, oxygen consumption at the anaerobic threshold (VO(2)
      AT) was 11.2 ml/min/kg and maximal achieved workload was 86 Watt. At one and six
      months after ASD-closure, there was no relevant increase of the VO(2) peak, the
      VO(2)-AT or the maximal workload. After 12 months, there was a significant
      increase of the VO(2) peak (15.1 ml/min/kg, p = 0.049), the VO(2)-AT (13
      ml/min/kg, p < 0.001) and the maximal workload (99 Watt, p < 0.01). An increase
      of the oxygen consumption at the anaerobic threshold (Delta VO(2) AT) could be
      seen in 24 out of 30 patients and was independent of shunt volume (Q(p)/Q(s) < or
      = 2, 1.95 ml/ min/kg; Q(p)/Q(s) > 2, 2.13 ml/min/ kg; ns), defect size (defect <
      or = 24 mm, 2.0 ml/min/kg; defect > 24 mm, 1.5 ml/min/kg; ns), age (age < or = 44
      years, 1.97 ml/min/kg; age >44 years, 1.66 ml/min/kg; ns), gender (female 1.56
      ml/min/ kg; male 1.91 ml/min/kg; ns) and of the existence of a residual shunt.
      Highly symptomatic patients had a tendency to have greater benefit from ASD
      closure as compared to mildly symptomatic patients (NYHA 0/I 1.85 ml/min/kg; NYHA
      II 1.5 ml/min/ kg; NYHA III 2.7 ml/min/kg; ns). There was no correlation between
      shunt volume, shunt size, pulmonal arterial pressure and increase of the oxygen
      consumption at the anaerobic threshold (Delta VO(2) AT). CONCLUSION: There is no
      relevant improvement in exercise capacity early (1-6 months) after interventional
      ASD-closure, but late after ASD-closure (12 months) exercise capacity improves
      significantly. This improvement can be found in almost all patients independent
      of gender, age, symptoms, shunt volume and defect size.

PMID- 15024589
TI  - Comparison of complete and incomplete revascularization in CABG-patients with
      severely impaired left ventricular function (LVF).
AB  - OBJECTIVE: CABG-procedures in patients with depressed LV-ejection fraction (LVEF)
      may still cause complications. In patients with severely impaired LVEF, it is
      particularly unclear whether a complete revascularization (CR) leads to a better
      outcome than the possible advantage of a short period of ischemia. This may be
      reached by a possibly incomplete revascularization (ICR). METHODS: In our
      department, 263 patients with LVEF < 30% underwent a CABG-procedure between 1996
      and 2000. Patients were divided into two groups with regard to their
      revascularization: group A patients (n = 158) received all grafts that were
      thought to be necessary according to preoperative angiography, whereas in group B
      (n = 105) at least one graft could not be realized. RESULTS: Mean number of
      grafts per patient was 3.59 +/- 0.58 in group A and 2.92 +/- 0.47 in group B (p <
      0.05). Intraoperatively, 33% of group A patients needed catecholamines, compared
      to 48% in group B (p < 0.05). IABP was used more often in group B (n = 7 compared
      to n = 3 in group A) (p < 0.05). Postoperatively, there were also significant
      differences: duration of mechanical ventilation (A: 12.1 +/- 3.4 h; B: 20 +/- 5.2
      h) (p < 0.05) and stay on ICU (A: 3.0 +/- 0.6 days; B: 4.2 +/- 0.6 days) (p <
      0.05) were significantly prolonged in group B patients. Six patients from group B
      died during hospitalization (6%), compared to five from group A (3.2%) (p <
      0.05). CONCLUSIONS: In patients with a severely depressed LVEF, complete
      revascularization improves the outcome after CABG-procedures. A prolonged time of
      intraoperative ischemia and CPB can be accepted to realize an effective
      revascularization.

PMID- 15024590
TI  - [Influence of myocardial mass of the univentricular heart on exercise capacity in
      patients with functional single ventricle and Fontan surgery].
AB  - BACKGROUND: The Fontan operation causes an acute decrease of volume overload of
      the univentricular heart followed by changes in ventricular geometry. The
      postoperative increase of myocardial mass-volume-index (MVI) may alter
      ventricular diastolic function. In this study, we analysed whether the increase
      in MVI and changes of the ventricular geometry have an effect on the decrease of
      the exercise capacity in patients with Fontan surgery. METHODS: We examined the
      cardiopulmonary function of 24 patients with functional single ventricle and
      Fontan operation 3.63 +/- 1.97 years after surgery (m = 14, w = 10, age: 14.57 +/
      9.74 years) using a bicycle cardiopulmonary exercise testing. The parameters of
      exercise capacity and cardiopulmonary function were correlated with Magnetic
      Resonance Imaging (MRI) parameters such as the MVI, enddiastolic ventricular
      muscle mass (EDMM) und endsystolic volume (ESV). RESULTS: The exercise capacity
      was 2.06 +/- 0.54 W/kg (60.63 +/- 15.75% of the norm) and VO(2)max was 27.41 +/-
      8.87 ml/min/kg (60.91 +/- 19.7% of the norm). There was a positive correlation of
      exercise capacity and VO(2)max with ESV (r(2) = 0.2572, p = 0.033) and EDMM (r(2)
      = 0.2544, p = 0.024), but none with the MVI. CONCLUSION: Myocardial hypertrophy
      may influence the myocardial performance of the univentricular heart and thereby
      the physical performance in children and adults with Fontan circulation.

PMID- 15024591
TI  - Heart rate variability in patients suffering from structural heart disease and
      decreased AV-nodal conduction capacity. Insights into the formation of heart rate
      variability.
AB  - METHODS: Time and frequency domain analysis were conducted during a period of 600
      s each. We performed a special protocol consisting of five different "pacing"
      periods: 1) recording of normal sinus rhythm (SR1); 2) atrial pacing with a rate
      15% higher than the intrinsic heart rate; 3) ventricular pacing triggered by
      atrial activation (VAT, with a short AV-delay of 80 ms); 4) AV-sequential pacing
      with an atrial rate 15% higher than the intrinsic heart rate and a very short AV
      delay of 80 ms (DDD); 5) normal sinus rhythm (SR2). Only patients with normal AV
      nodal conduction or with AV-block I degrees were included. The influence of a
      structural heart disease as well as a non-sustained VT on Holter ECG and a
      depressed EF on HRV parameters were analyzed using a multivariate analysis. All
      patients were lying in a supine position. Blood pressure was measured
      continuously and the frequency of breathing was controlled. RESULTS: No
      differences in HRV between the two sinus rhythm periods SR1 versus SR2 could be
      detected. Neither SR1 vs VAT showed a significant difference for SDNN and r-MSSD.
      In contrast, HRV during SR1 compared to AAI, and HRV during VAT compared to AAI
      were significantly different (p < 0.001). When comparing HRV during DDD, which
      should be zero, and AAI, we found a significantly lower SDNN and r-MSSD (1.2 ms
      vs 4 ms, p < 0.04). The presence of structural heart disease, a non-sustained
      ventricular tachycardia, a depressed ejection fraction of less than 0.50 did not
      reveal a significant influence on the HRV parameters (multivariate analysis). The
      mean Wenckebach in patients with structural heart disease tended to be greater
      (437 ms vs 350 ms, p = 0.05); an increase in the Wenckebach was not correlated to
      a change in HRV parameters (p = ns). CONCLUSION: Heart rate variability derived
      from consecutive RR-intervals is predominantly caused by periodicity in sinus
      node impulse formation. A conduction variability of the AV-node exists, but is
      very low. The presence of a structural heart disease, a non-sustained ventricular
      tachycardia on Holter ECG, as well as a depressed ejection fraction of less than
      0.50 showed no significant influence on the HRV parameters. Therefore, one can
      apply the calculation of heart rate variability for risk stratification in
      patients suffering from structural heart disease and moderate AV-nodal conduction
      disturbances. Attenuation of the oscillation of the heart rate, i. e. heart rate
      variability (HRV), is associated with an increased risk for mortality in patients
      with structural heart disease. Many of these patients also suffer from conduction
      disturbances, e. g. AV-nodal conduction delays. Whether the calculation of HRV in
      those patients is recommendable has not been investigated yet. Therefore, we
      conducted a study consisting of 20 consecutive patients in order to determine the
      formation of HRV, the influence of structural heart disease, the presence of a
      nonsustained ventricular tachycardia (VT), and a reduced ejection fraction (EF)
      on the HRV parameters during an elective electrophysiologic study.

PMID- 15024592
TI  - [Levosimendan-long-term inodilation in an infant with myocardial infarction].
AB  - An infant with myocardial infarction due to congenital stenosis of the left
      coronary artery with consecutive left ventricular dysfunction and mitral
      regurgitation developed refractory pulmonary hypertension (PHT) and recurrent PHT
      crises. Catecholamines to support cardiac function, or pulmonary vasodilators
      like inhaled nitric oxide showed no effect. Treatment with Levosimendan (Simdax),
      a new inodilator, combining both inotropic and pulmonary vasodilating effects,
      improved left ventricular dysfunction, increased cardiac index, decreased
      pulmonary vascular resistance and reduced frequency and extent of the PHT crises.
      This case may suggest the use of Levosimendan as a long-term inotropic agent and
      pulmonary vasodilator in children with depressed cardiac function.

PMID- 15024594
TI  - Left ventricular hypertrabeculation/noncompaction-don't forget the
      myologist!Concerning the article "Isolated myocardial noncompaction als seltene
      Ursache einer Synkope im Kindesalter" by Binz G. et al. Z Kardiol 92:1039-1044
      (2003).

PMID- 15024597
TI  - An epidemic of isolated perforation: how can we stop it?

PMID- 15024596
TI  - New trends in the surgical treatment of outlet obstruction: clinical and
      functional results of two novel transanal stapled techniques from a randomised
      controlled trial.
AB  - BACKGROUND AND AIMS: A randomised trial was undertaken to compare the clinical
      and functional results of two novel transanal stapled techniques in patients with
      outlet obstruction syndrome. MATERIALS AND METHODS: Ninety-six females with
      outlet obstruction were treated with medical therapy and biofeedback for 2
      months; 67 non-responders were evaluated by the Constipation Scoring and
      Continence Grading Systems, clinical examination, endoscopy, dynamic
      defecography, anorectal manometry, transanal ultrasound and anal EMG, and 50 of
      them, all affected with descending perineum, intussusception and rectocele, were
      randomly assigned to two groups and operated on: 25 patients (mean age 53.2+/
      15.3 years) underwent a single Stapled Trans-Anal Prolapsectomy, associated with
      Perineal Levatorplasty (STAPL Group), and the other 25 (mean 54.6+/-14.2 years)
      underwent a double Stapled Trans-Anal Rectal Resection (STARR Group). Patients
      were followed-up for a mean period of 23.4+/-5.1 months in STAPL Group and 22.3+/
      4.8 in STARR Group. RESULTS: STARR Group showed a significantly (p<0.0001) lower
      pattern of postoperative pain and a greater decrease (P=0.0117) of the rectal
      sensitivity threshold volume; otherwise, no differences were found in operative
      time, hospital stay, or time of inability to work. Complications included delayed
      healing of the perineal wound (ten), dyspareunia (five), urinary retention (two)
      and stenosis (one) in STAPL Group, and urge to defecate (four), transitory
      incontinence to flatus (two), urinary retention (two), bleeding (one) and
      stenosis (one) in STARR Group. All constipation symptoms significantly improved
      without worsening of anal continence and with excellent/good outcome at 20 months
      in 76 and 88% of patients of STAPL Group and STARR Group, respectively. Seven
      patients of STAPL Group had a little residual rectocele, while both
      intussusception and rectocele were corrected in all patients of STARR Group.
      Neither operation modified anal pressures or caused lesions of anal sphincters.
      CONCLUSIONS: Both techniques are safe and effective in the treatment of outlet
      obstruction; nevertheless, the double Stapled Trans-Anal Rectal Resection seems
      to be preferable due to less pain, absence of dyspareunia, reduced rectal
      sensitivity threshold volume and absence of residual rectocele at defecography.

PMID- 15024598
TI  - A mass in the omental bursa secondary to biliary leakage: identification and
      management.

PMID- 15024599
TI  - Eosinophilic granuloma of the skull associated with epidural haematoma: a case
      report and review of the literature.
AB  - INTRODUCTION: Eosinophilic granuloma (EG), a benign bone lesion, represents a
      focal form of histiocytosis X. Here, the authors report a case of an extremely
      rare presentation of a solitary EG of the skull. CASE REPORT: A 9-year-old boy
      presented with headache and vomiting for 3 days. His examination was unremarkable
      except for a tender mass in his left occipital region. Radiological studies
      revealed a huge bilateral epidural haematoma under the occipital bone, extending
      supratentorially and infratentorially, and a nonenhanced, epidural, soft tissue
      mass overlying the left transverse sinus. Evacuation of the epidural haematoma
      was performed and it was noted that the left transverse sinus wall was eroded by
      the EG at one point with venous oozing. REVIEW OF THE LITERATURE: The acute
      presentation of a solitary EG of the skull with an epidural haematoma was
      described in only four cases in the literature. This is the first documented case
      in terms of the origin of an epidural haematoma.

PMID- 15024601
TI  - The role of positron emission tomography in germ cell cancer.
AB  - Positron emission tomography (PET) is a non-invasive tool for imaging regional
      metabolic processes, which adds another dimension to current anatomy-derived
      imaging techniques, i.e. metabolic imaging. To date, 2-(18)fluoro-2-deoxy-D
      glucose (FDG) has been the only tracer used for imaging germ cell tumors (GCT),
      which can be distinguished from normal tissue by their different glucose
      utilization. However, FDG PET has several limitations: (1) inflammatory and
      granulomatous tissues also show extensive FDG uptake, (2) lesions <1 cm in size
      can often not be detected, and (3) mature teratoma is indistinguishable from
      normal and necrotic tissue. Studies assessing the clinical role of FDG PET in GCT
      suggest that the technique has a place as a standard tool in evaluating post
      chemotherapy seminoma residuals. Whether it also improves the assessment of the
      risks carried by clinical stage I non-seminoma patients and the early prediction
      of response to salvage chemotherapy is still under investigation, or at least
      needs to be confirmed by further trials. In relapsing patients with a mismatch
      between tumor markers and imaging data, FDG PET appears to be useful whenever
      salvage surgery is considered, although systematic trials are not yet available.

PMID- 15024602
TI  - Preoperative breast MRI in patients with invasive lobular breast cancer.
AB  - To investigate the use of MRI in preoperative characterization of invasive
      lobular breast cancer (ILC) and in detection of multifocal/multicentric disease.
      We retrospectively reviewed T1-weighted FLASH 3D precontrast and postcontrast MR
      images together with subtraction images of 26 women with histopathologically
      proven invasive lobular cancer. Two experienced radiologists described tumor
      patterns of ILC independently. MR findings of unifocal, multifocal, single
      quadrant and multiquadrant disease were correlated with results of other imaging
      techniques and compared with histopathological findings as gold standard. Most
      ILC presented on MRI as a single spiculated/irregular, inhomogeneous mass
      (pattern 1, n=12) or as a dominant lesion surrounded by multiple small enhancing
      foci (pattern 2, n=8). Multiple small enhancing foci with interconnecting
      enhancing strands (pattern 3) and an architectural distortion (pattern 4) were
      both described in three cases. There was one case of a focal area of
      inhomogeneous enhancement (pattern 5) and one normal MR examination (pattern 6).
      Unifocal and multifocal lesions were identified on MRI in four patients with
      normal conventional imaging. In nine women, multiple additional lesions or more
      extensive multiquadrant disease were correctly identified only on MRI. MRI may
      play an important role in the evaluation of patients with ILC, which is often
      difficult to diagnose on clinical examination and conventional imaging and more
      likely occur in multiple sites and in both breasts. However, false-negative MR
      findings do occur in a small percentage of ILC.

PMID- 15024603
TI  - Biaxial total wrist arthroplasty in rheumatoid arthritis. Satisfactory functional
      results.
AB  - We reviewed 16 uncemented biaxial total wrist arthroplasties (TWA) in 14 patients
      with rheumatoid or juvenile arthritis. The mean follow-up was 25 months (range 5
      60). According to the Hospital for Special Surgery scoring system (HSS), good-to
      excellent results were accomplished in 69%, moderate in 19%, and poor in 12%. The
      mean pain score was 0.4 on a visual analog scale from 0-10 (0=no pain). The
      Wrightington activities of daily life assessment chart showed a 63% improvement,
      and we found a threefold increase in range of motion at follow-up. Four TWAs
      showed early dislocation, one of which was revised. Biaxial TWA yields good short
      term results in rheumatoid patients, although instability is a frequent
      complication.

PMID- 15024604
TI  - The impact of manipulations with cytoplasmically inherited factors on nuclear
      transmission and degradation in yeast heterokaryons.
AB  - Heterokaryotic zygotes in yeast provide a unique possibility to study the
      survival and transmission of two genetically diverse nuclei in one cell. Using
      partial pedigree analysis, we show that various treatments used to change
      cytoplasmic hereditary determinants can essentially affect nuclear transmission
      in yeast heterokaryons. This includes choice of nucleus to enter the first bud
      and incidence of various classes of mother/daughter pairs demonstrating nuclear
      degradation patterns in heterokaryotic zygotes. These treatments include
      guanidine hydrochloride, a prion-curing agent, ethidium bromide, an agent causing
      elimination of mitochondrial DNA, and cytoplasm replacement by cytoduction, which
      leads to mtDNA replacement and transfer of some other cytoplasmically inherited
      determinants. The genetic and cytological evidence obtained favors prion
      involvement in nuclear transmission and suggests apoptotic features in nuclear
      degradation in yeast heterokaryotic zygotes.

PMID- 15024605
TI  - A novel fungal prenyl diphosphate synthase in the dimorphic zygomycete Mucor
      circinelloides.
AB  - Two Mucor circinelloides structural genes involved in isoprenoid biosynthesis
      were isolated and characterised. The isoA gene encodes a typical eukaryotic
      farnesyl diphosphate synthase (EC 2.5.1.10), whereas the isoB gene deduced amino
      acid sequence shows similarity to fungal medium-chain prenyl diphosphate
      synthases. By functional complementation in Escherichia coli, the isoB gene
      product was shown to be a solanesyl diphosphate synthase (EC 2.5.1.11), which is
      the first fungal enzyme reported having this specificity. In addition, a M.
      circinelloides one-marker-per-chromosome map was completed by contour-clamped
      homogeneous electric field localisation of isoA, isoB and three other isoprenoid
      biosynthesis genes to individual chromosomes.

PMID- 15024606
TI  - Fever as a risk factor causing delayed elimination of methotrexate in pediatric
      patients receiving high doses of cancer chemotherapy.
AB  - PURPOSE: Delayed elimination of methotrexate (MTX) has been reported to be caused
      by a number of factors. In order to identify these causes, we retrospectively
      investigated the risk factors for delayed elimination in pediatric patients who
      received high doses of MTX. SUBJECTS AND METHODS: The study included 69 courses
      of therapy involving 22 patients who received more than 1000 mg/m(2) of MTX.
      Plasma MTX concentrations 48 h (C48) and 72 h (C72) after infusion were used as
      indices of MTX elimination. RESULTS: Neither C48 nor C72 was directly
      proportional to the dose of MTX infused. Both C48 and C72 were significantly
      higher in patients who developed fever of above 38 degrees C within a 10-day
      period (i.e., from 7 days before to 3 days after infusion) than in patients with
      no fever. Subgroup analysis revealed that C72 was significantly higher in
      patients who either developed fever and received antipyretics or developed fever
      but did not receive antipyretics than in patients who did not develop fever and
      did not receive antipyretics. Changes in the serum creatinine concentrations
      before and after MTX infusion revealed that renal function was significantly
      decreased in patients who developed fever compared to patients without fever.
      CONCLUSIONS: The present results suggest that the development of fever is one of
      the main risk factors for the delayed elimination of MTX.

PMID- 15024607
TI  - High incidence of complications after 2-chloro-2'-deoxyadenosine combined with
      cyclophosphamide in patients with advanced lymphoproliferative malignancies.
AB  - The combination of purine analogs with alkylating agents is able to produce a
      synergistic antitumoral effect. However, the addition of immunosuppressive and
      DNA-targeting agents might increase purine analog-related complications. The risk
      for serious complications was evaluated in 38 patients treated with 2-chloro-2'
      deoxyadenosine (CDA) and cyclophosphamide (CP). The diagnoses were chronic
      lymphocytic leukemia (CLL) in 15, Waldenstrom's macroglobulinemia in 4, mantle
      cell lymphoma in 6, follicular non-Hodgkin's lymphoma (NHL) in 10, and other low
      grade NHL in 3 patients. All patients were pretreated (median: 2 lines, range: 1
      5) and 23 (61%) were refractory. The patients received a median of two courses
      (range: 1-5) of 5.6 mg/m(2) CDA, followed by a median of 200 mg/m(2) CP, for 3
      days. The response rate was 51% [complete remission (CR): 14%, partial remission
      (PR): 38%]. Grade 3/4 infections occurred in 16 (42%) patients. Dose-limiting
      cytopenias were seen in 22 (58%) patients. In 12 (32%) patients, autoimmune
      manifestations developed requiring treatment in most of them. Second cancers
      arose in five (13%) patients (myelodysplastic syndrome/acute myelocytic leukemia
      in three, lung cancer in two). Multivariate analysis showed that cytopenias,
      gender (F), prior radiotherapy, and age (>65 years) predicted for the
      complications seen after CDA-CP. To conclude, because of the high incidence of
      complications, caution is warranted in selecting patients with advanced lymphoid
      malignancies for the CDA-CP protocol.

PMID- 15024608
TI  - Anatomic study of the tendinous insertion lamina of the temporalis muscle.
AB  - Lengthening temporalis myoplasty is indicated in long-standing and congenital
      facial paralysis. Its principle is the transfer of the coronoid tendinous
      insertions onto the lip and the nasolabial fold. Knowledge of the anatomy of this
      strong and wide tendon is necessary for successful use of its anatomic
      advantages. A study on 10 cadavers (20 temporalis muscles) confirmed the surgical
      anatomy found during lengthening temporalis myoplasty procedures: the strong
      tendon, when freed from the coronoid process, is 4-6 cm wide.

PMID- 15024609
TI  - Navigation for ankle arthroscopy: anatomical study of the anterolateral portal
      with reference to the superficial peroneal nerve.
AB  - We aimed to navigate the surgeon regarding the localization of the main
      anatomical structures at the anterior part of the ankle joint, in order to find
      easily the safest anatomical points with reference to the superficial peroneal
      nerve (SPN), in particular for anterolateral portal placement in ankle
      arthroscopy. Sixty-three ankles in 36 fresh cadavers were dissected. In all
      specimens we examined (1) the distance between the SPN bifurcation and the most
      distal point of the lateral malleolus; and at the level of ankle joint, (2) the
      number of SPN, (3) the distance between the medial and intermediate dorsal
      cutaneous nerves, which are branches of the SPN, (4) the localization of the
      peroneus tertius (PT) tendon in relation to the lateral malleolus, (5) the width
      of the extensor digitorum longus (EDL) tendon, (6) the relationship of the PT
      tendon and (7) the relationship of the extensor hallucis longus (EHL) tendon with
      the SPN. The results were as follows: (1) In 41 ankles with bifurcation (65%) the
      average distance was 71.8+/-35.3 mm. (2) There were two SPN branches in 39 (62%),
      three branches in seven (11%) and one branch in 17 (27%) cases. (3) In 39 ankles
      with two branches of the SPN, the mean distance was 15.2+/-7.1 mm. (4) The
      lateral border of the PT tendon was positioned a mean distance of 20.8+/-3.3 mm
      proximal and 25.2+/-5.8 mm medial to the reference points. (5) The mean width was
      10.1+/-2.9 mm. (6) In 42 ankles (67%) the distance between the lateral border of
      the PT tendon and the SPN was a mean of 6.2+/-6.6 mm, median of 3 mm (range 0-22
      mm lateral to the tendon). (7) In 56 cases (89%) a branch of the SPN was found a
      mean of 6.6+/-4 mm and a median of 6 mm lateral to the EHL tendon, and in seven
      cases (11%) on the tendon. According to our study, in ankle arthroscopy the risk
      of the SPN injury is maximal in the 0-3 mm lateral to the PT tendon. To avoid
      injury to the SPN, the safest placement of the anterolateral portal is 4 mm
      lateral to the PT tendon.

PMID- 15024610
TI  - Biodegradation of acid blue-15, a textile dye, by an up-flow immobilized cell
      bioreactor.
AB  - Acid blue-15, a complex and resonance-stabilized triphenylmethane (TPM) textile
      dye, resistant to transformation, was decolorized/degraded in an up-flow
      immobilized cell bioreactor. A consortium comprised of isolates belonging to
      Bacillus sp., Alcaligenes sp. and Aeromonas sp. formed a multispecies biofilm on
      refractory brick pieces used as support material. The TPM dye was degraded to
      simple metabolic intermediates in the bioreactor with 94% decolorization at a
      flow rate of 4 ml h(-1).

PMID- 15024611
TI  - Water-dispersed lamellar phases of symmetric poly(styrene)-block-poly(acrylic
      acid) diblock copolymers: model systems for flat dense polyelectrolyte brushes.
AB  - We investigate the static properties of a water-dispersed lamellar ( L) phase
      formed in the melt state with a nearly symmetric poly(styrene)-block-poly(acrylic
      acid) (PS- b-PAA) diblock copolymer. The PAA brush is considered as a model flat
      polyelectrolyte ( PE) brush of controlled surface density. Thanks to small-angle
      X-ray scattering, its behavior in water is studied as a function of (i) its
      ionization, through the pH of the dispersions which is increased by an addition
      of a known amount of a base, i.e. sodium hydroxyde NaOH, and (ii) in the presence
      of a monovalent salt, i.e. sodium chloride NaCl, of concentration C(S). At low
      pH, we find that the brush effectively behaves as a neutral brush. At high pH,
      the brush is in the so-called "osmotic regime", in which all sodium counterions
      are trapped within the brush volume and stretch the chains via an osmotic effect.
      The properties of such a brush in the presence of a monovalent salt, confirm this
      result, showing a C(S)(-1/3) dependence in the brush height L(O), in agreement
      with mean-field predictions. The L(O)- C(S) profiles at different ionizations
      give access to the actual brush internal charge fraction f. The results are found
      to be in very good quantitative agreement with experimental measures found in the
      literature, and can be completely and quantitatively described by Oosawa's
      approach to counterion condensation in a semi-dilute to concentrated solution of
      charged, rod-like chains.

PMID- 15024612
TI  - Conformation-dependent sequence design: evolutionary approach.
AB  - A new modification of evolutionary approach to sequence design of copolymers has
      been proposed. A model of step-by-step evolution of a two-letter ( HP) copolymer
      sequence has been studied by means of a coarse-grained Monte Carlo algorithm. The
      conditions for accepting a change in the primary sequence depend on the spatial
      conformation of HP-copolymer chain. This leads to a coupling between sequence and
      conformation and to formation of protein-like conformations and primary sequences
      (for some values of parameters of the model) independently of initial sequence
      and/or conformation. Simple theory describing these computer simulation
      observations is developed.

PMID- 15024613
TI  - Dynamic light scattering and 31P NMR study of the self-assembly of deoxyguanosine
      5'-monophosphate: the effect of added salt.
AB  - Self-assembling and dynamical properties of deoxyguanosine 5'-monophosphate in
      isotropic aqueous solutions were studied by (31)P NMR spectroscopy and dynamic
      light scattering (DLS). All solutions had the same c = 4 wt% guanosine
      concentration, while the added KCl molarity ranged from 0 to 1.5 M. (31)P NMR
      measurements show that potassium ions strongly enhance the stacking process of
      guanosine tetramers until a saturation is reached at 0.1 M KCl with more than 70%
      of the molecules aggregated. Polarized light scattering reveals the presence of a
      fast relaxation mode that arises from the translational dynamics of the self
      assembled stacks. The diffusion coefficient of this mode shows a strong
      dependence on molarity of added salt, which can be described in terms of the
      coupled mode and counterion condensation theories for polyelectrolyte solutions.
      Depolarized light scattering reveals the rotational dynamics of the self
      assembled stacks which exhibits a pronounced slowing down with increasing the
      added salt content.

PMID- 15024614
TI  - Continuous director-field transformation of nematic tactoids.
AB  - We theoretically investigate the director field inside spindle-shaped nematic
      droplets, known as tactoids. Tactoids typically form in dispersions of rod-like
      colloidal particles. By optimising the bulk elastic and surface energies, we find
      that the director field crosses over smoothly from a homogeneous to a bipolar
      configuration with increasing droplet size, in a process that we postulate to
      involve two virtual point defects that move in from infinity towards the poles on
      the surface of the droplet. Our calculations show that these hypothesised virtual
      defects become true surface point defects or boojums only in the limit of
      infinite droplet volume, and that the more elongated the droplets are, the larger
      their volume has to be before a uniform director field distorts so as to become
      discernibly bipolar. The theory agrees well with available experimental data on
      the size dependence of the aspect ratio of tactoids.

PMID- 15024615
TI  - Attraction of like-charged macroions in the strong-coupling limit.
AB  - Like-charged macroions attract each other as a result of strong electrostatic
      correlations in the presence of multivalent counterions or at low temperatures.
      We investigate the effective electrostatic interaction between i) two like
      charged rods and ii) two like-charged spheres using the recently introduced
      strong-coupling theory, which becomes asymptotically exact in the limit of large
      coupling parameter (i.e. for large counterion valency, low temperature, or high
      surface charge density on macroions). In contrast to previous applications of the
      strong-coupling theory, we deal with curved surfaces and an additional parameter,
      referred to as Manning parameter, is introduced, which measures the ratio between
      the radius of curvature of macroions to the Gouy-Chapman length. This parameter,
      together with the size of the confining box enclosing the two macroions and their
      neutralizing counterions, controls the counterion-condensation process that
      directly affects the effective interactions. For sufficiently large Manning
      parameters (weakly-curved surfaces), we find a strong long-ranged attraction
      between two macroions that form a closely-packed bound state with small surface
      to-surface separation of the order of the counterion diameter in agreement with
      recent simulations results. For small Manning parameters (highly-curved
      surfaces), on the other hand, the equilibrium separation increases and the
      macroions unbind from each other as the confinement volume increases to infinity.
      This occurs via a continuous universal unbinding transition for two charged rods
      at a threshold Manning parameter of Epsilon c = 2/3, while the transition is
      strongly discontinuous for spheres because of a pronounced potential barrier at
      intermediate distances. Unlike the cylindrical case, the attractive forces
      between spheres disappear slowly for increasing confinement volume due to the
      complete de-condensation of counterions. Scaling arguments suggest that for
      moderate values of coupling parameter, strong-coupling predictions remain valid
      for sufficiently small surface-to-surface separations.

PMID- 15024616
TI  - Electric field induced order reconstruction in a nematic cell.
AB  - We have experimentally observed the biaxial switching between two topologically
      distinct textures of a nematic liquid crystal cell submitted to a strong electric
      field. The effect is deduced from optical and electrical measurements across the
      cell. Above a static threshold, a bulk order reconstruction is observed, where
      the final nematic orientation in the centre becomes perpendicular to its initial
      one, inducing a total pi change of orientation across the cell. Using short
      electric field pulses, a higher dynamical threshold is observed. These
      experiments are explained by a Landau-de Gennes-Khalatnikov model. The threshold
      implies the local exchange of two eigenvalues of the nematic order tensor through
      intermediate biaxial states. The onset of the effect in a thin splay-bend wall
      decreases the static threshold by almost an order of magnitude. The model
      explains reasonably well the static and dynamic measurements within the present
      description of nematic biaxiality.

PMID- 15024617
TI  - Deformation of adhering elastic tubes.
AB  - Deformation of an elastic tube adhering onto a substrate due to van der Waals
      attractive force is investigated by means of numerical minimization and scaling
      theory. The onset of the deformation is determined by the critical value of
      Cb/Epsilon N2, where Cb is the bending constant, epsilon is the depth of the van
      der Waals potential, and N is the size of the tube. For a significantly deformed
      tube, we found a scaling behavior of the bending energy, which is explained
      within the shell theory.

PMID- 15024618
TI  - Power law polydispersity and fractal structure of hyperbranched polymers.
AB  - Using the complementary approaches of Flory theory and the overlap function, we
      study the molecular weight distribution and conformation of hyperbranched
      polymers formed by the melt polycondensation of A-R(N)(0)-B(f - 1) monomers in
      their reaction bath close to the mean field gel point p(A) = 1, where p(A) is the
      fraction of reacted A groups. Here f > or = 3, N(0) is the degree of
      polymerisation of the linear spacer linking the A group and the f-1 B groups and
      condensation occurs exclusively between the A and B groups. For Epsilon tripe
      bond (1-pA) <<1, we assume that the number density of hyperbranched polymers with
      degree of polymerisation N generally obeys the scaling form n(N) =N(- tau)f(N/Nl)
      and we explicitly show that this scaling assumption is correct in the mean field
      regime (here Nl is the largest characteristic degree of polymerisation and the
      function f (N/Nl) cuts off the power law sharply for N>Nl). We find the upper
      critical dimension for this system is d(c) = 4, so that for d> or = dc the mean
      field values for the polydispersity exponent and fractal dimension apply:
      tau=3/2, d(f) = 4. For d = 3, mean field theory is still correct for Epsilon >
      Epsilon G where Epsilon G approximately equal N -1 0 is the Ginzburg point; for
      Epsilon < Epsilon G, mean field theory applies on small mass scales N< N c but
      breaks down on larger mass scales N> N c where N c approximately equal N 3 0 is a
      cross-over mass. Within the Ginzburg zone (i.e., d< d(c) < Epsilon G), we show
      that the hyperbranched chains on mass scales N> N(c) are non-Gaussian with
      fractal dimension given by d(f) = d (for d = 2,3,4). Our results are
      qualitatively different from those of the percolation model and indicate that the
      polycondensation of AB(f-1), unlike polymer gelation, is not described by
      percolation theory. Instead many of our results are similar to those for a
      monodisperse melt of randomly branched polymers, a consequence of the fact that
      tau < 2 so that polydispersity is irrelevant for excluded volume screening in
      hyperbranched polymer melts.

PMID- 15024619
TI  - Nematic liquid crystal around a spherical particle: Investigation of the defect
      structure and its stability using adaptive mesh refinement.
AB  - We investigate the orientation profile and the structure of topological defects
      of a nematic liquid crystal around a spherical particle using an adaptive mesh
      refinement scheme developed by us previously. The previous work [J. Fukuda et
      al., Phys. Rev. E 65, 041709 (2002)] was devoted to the investigation of the fine
      structure of a hyperbolic hedgehog defect that the particle accompanies and in
      this paper we present the equilibrium profile of the Saturn ring configuration.
      The radius of the Saturn ring r(d) in units of the particle radius R(0) increases
      weakly with the increase of Epsilon, the ratio of the nematic coherence length to
      R(0). Next we discuss the energetic stability of a hedgehog and a Saturn ring.
      The use of adaptive mesh refinement scheme together with a tensor orientational
      order parameter Q (alpha, beta) allows us to calculate the elastic energy of a
      nematic liquid crystal without any assumption of the structure and the energy of
      the defect core as in the previous similar studies. The reduced free energy of a
      nematic liquid crystal, F= F/L1RO, with L(1) being the elastic constant, is
      almost independent of Epsilon in the hedgehog configuration, while it shows a
      logarithmic dependence in the Saturn ring configuration. This result clearly
      indicates that the energetic stability of a hedgehog to a Saturn ring for a large
      particle is definitely attributed to the large defect energy of the Saturn ring
      with a large radius.

PMID- 15024620
TI  - Towards efficient methods for the study of pattern formation in ferrofluid films.
AB  - Hexagonal and labyrinthine patterns appear in thin ferrofluid films after
      application of a magnetic field perpendicular to the film. The pattern size and
      the stability of the hexagonal and labyrinthine structures can be predicted by
      free energy approaches. Several approximations are used in the literature to
      accelerate the calculation of the magnetic energy. They are usually based on the
      use of a uniform, average or constant magnetization. In the uniform approximation
      the magnetization at all points in the pattern is assumed to be equal to its
      value at the center of the stripes or cylinders in the labyrinthine or hexagonal
      patterns. Recent papers indicate that this approximation gives qualitatively
      wrong results. This is corroborated here by a comparison with accurate results.
      When a volume- averaged magnetization is used during the calculation of the
      demagnetization field, from which the magnetic energy is evaluated, the
      theoretical results are only slightly modified with respect to the accurate
      results. Thus, we can propose a new method which gives results in good agreement
      with the accurate values and accelerates the calculations by a factor of 1000.
      The influence of the approximations is explained by a study of the evolution of
      the demagnetization field in the patterns. This study indicates that the volume
      averaged approximation might only be reliable for patterns with a homogeneously
      distributed magnetic fluid. Another approximation of a constant magnetization,
      which is widely used in the literature, assumes that the magnetization does not
      change during the pattern formation in contrast to the uniform and average
      approximations. A different way of computing the constant magnetization than that
      usually employed markedly improves the agreement with the accurate results. This
      is explained by the derivation of a direct relationship between the
      approximations of a constant and an average magnetization.

PMID- 15024621
TI  - Efficacy of directly observed treatment of HIV infection: experience in AIDS
      welfare homes.
AB  - With the objective of analyzing the efficacy of directly observed treatment (DOT)
      of HIV infection in the management of severely immunodepressed patients, this
      method was examined in individuals cared for in two social welfare facilities for
      HIV-infected persons and compared to self-administered therapy in outpatients.
      Forty-seven patients with registered HIV infection, stage C, were assigned to DOT
      for 9 months, the majority of whom had previously received antiretroviral
      therapy. A group of 51 HIV-infected outpatients, who attended day clinics
      attached to the reference hospitals, served as a comparison group. Together with
      increases in weight (9.2+/-7.5 kg) and Karnofsky scores (16.9+/-12.2) in the DOT
      group, a significant improvement of surrogate markers, such as CD4+ T-cell counts
      (increase in DOT group, 113.4+/-151.0 cells/microl; control group, -2.8+/-114.1
      cells/microl; P<0.001) and HIV load (decrease in DOT group, -1.7+/-2.3 log10
      copies/ml; control group, -0.4+/-1.5 log10 copies/ml; P<0.01) was detected in the
      DOT group. Morbidity and mortality were similar in both groups. The results
      indicate that such welfare facilities provide a useful framework not only for
      social objectives but also for healthcare purposes.

PMID- 15024622
TI  - Failure of broth-based tests to detect methicillin-resistant Staphylococcus
      aureus in a clinical specimen.

PMID- 15024624
TI  - Persistent colonization of nine cystic fibrosis patients with an Achromobacter
      (Alcaligenes) xylosoxidans clone.
AB  - The present study was conducted to investigate the increasing incidence of
      Achromobacter (previously Alcaligenes) xylosoxidans isolates being recovered from
      sputum samples of cystic fibrosis patients at a cystic fibrosis department for
      adults in Athens, Greece. During the 1-year study period, a total of 34 isolates
      were detected persistently in 9 of 71 cystic fibrosis patients. The isolates
      exhibited resistance to multiple antimicrobial agents. Isolates that were
      recovered repeatedly from each patient exhibited identical macrorestriction
      profiles with pulsed-field gel electrophoresis, indicating that the same strain
      persisted in the lungs of these patients. Isolates from five of the patients were
      genetically related, suggesting a common-source outbreak of Achromobacter
      xylosoxidans colonization or infection.

PMID- 15024625
TI  - Pharmacokinetic and pharmacodynamic issues in the treatment of mycobacterial
      infections.
AB  - The therapy of mycobacterial infections is challenging for a number of reasons.
      Because mycobacteria are not susceptible to many classes of antibacterial agents,
      treatment typically requires the use of antimicrobial drugs that are not commonly
      used and may have small therapeutic windows. For many species, procedures for
      drug susceptibility testing and optimal treatment regimens have yet to be
      defined. Finally, because mycobacteria are generally slow to succumb to
      antimicrobial agents, therapy must be given with multiple drugs for prolonged
      periods of time, making it necessary to monitor for drug toxicity, drug
      interactions, and patient nonadherence. Better understanding of the
      pharmacokinetics and pharmacodynamics of antimycobacterial agents should improve
      the therapy of mycobacterial infections. Using current treatment strategies for
      tuberculosis and Mycobacterium avium complex infections as examples, this review
      highlights basic pharmacokinetic and pharmacodynamic principles and the rationale
      for combination chemotherapy that should also be applicable to other
      mycobacterial infections.

PMID- 15024626
TI  - Risk factors for mortality in patients with anaerobic bacteremia.
AB  - Risk factors for mortality in anaerobic bacteremia have been incompletely
      defined. The aims of the present study were to determine clinical significance by
      pathogen for a broad range of obligate anaerobic organisms isolated from blood,
      and to define the factors independently associated with mortality among those
      with clinically significant bacteremia. All patients who had anaerobic bacteria
      isolated from blood over a 19-month period (from 1 September 1998 to 1 April
      2000) at two urban teaching hospitals were included in this study. Each case was
      analyzed for clinical significance by means of a retrospective medical record
      review using predetermined definitions. Information was collected on a broad
      range of clinical and microbiological factors, which were evaluated for their
      association with mortality using a Cox proportional hazards model. Among 166
      patients with obligate anaerobic bacteria isolated from blood, 73 (44%) were
      deemed to have clinically significant bacteremia. Clinical significance ranged
      from 0% (0/53) for Propionibacterium spp. to 96% (43/45) for Bacteroides spp. The
      crude mortality rate in patients with clinically significant anaerobic bacteremia
      was 25% (18/73). Mortality was significantly associated with age, polymicrobial
      infection, and underlying heart, kidney or liver disease in univariate analysis.
      Only the presence of liver disease (relative risk, 5.3; 95% confidence interval,
      1.7-16.0; P=0.003) and patient age (relative risk, 1.06/y; 95% confidence
      interval, 1.0-1.1; P=0.005) remained significant in multivariate analysis. Among
      patients with anaerobic bacteremia, clinical significance varies markedly by
      pathogen and mortality is independently associated with age and underlying liver
      disease.

PMID- 15024628
TI  - Identification of human Clock gene variants by denaturing high-performance liquid
      chromatography.
AB  - The human Clock gene ( hClock) encodes the CLOCK protein essential for the
      function of the circadian system. We have screened the entire coding region,
      including the 5' and 3' untranslated regions (UTRs) and the flanking intronic
      regions, of the hClock gene for sequence variations in 70 unrelated Chinese
      Singaporeans with denaturing high-performance liquid chromatography (dHPLC). A
      total of 15 sequence variations were detected, five of which were novel. All
      involved single base changes. There were 12 substitutions and three
      insertions/deletions. All except one were found in the introns or the UTRs.
      Frequencies of the minor allele for all 15 polymorphisms ranged from 0.7% to
      almost 50%. For the eight sites whose minor allele frequency was found to be at
      least 10%, pair-wise comparisons revealed that all except one were in almost
      complete linkage disequilibrium. Our identification of additional single
      nucleotide polymorphisms in the hClock gene would provide markers whose
      frequencies could be established in the selected population and used for further
      analysis of the phenotypic effects. Our results would also be useful for better
      planning in the selection of polymorphisms for future genetic association studies
      involving the hClock gene.

PMID- 15024627
TI  - Pharmacologic considerations in antimicrobial therapy, with emphasis on
      pharmacokinetics and pharmacodynamics: reviews for the practicing clinician.

PMID- 15024623
TI  - Economic impact of Candida colonization and Candida infection in the critically
      ill patient.
AB  - The objective of the study presented here was to assess the economic impact of
      Candida colonization and Candida infection in critically ill patients admitted to
      intensive care units (ICUs). For this purpose, a prospective, cohort,
      observational, and multicenter study was designed. A total of 1,765 patients over
      the age of 18 years who were admitted for at least 7 days to 73 medical-surgical
      ICUs in 70 Spanish hospitals between May 1998 and January 1999 were studied. From
      day 7 of ICU admission to ICU discharge, samples of tracheal aspirates,
      pharyngeal exudates, gastric aspirates and urine were collected every week for
      culture. Prolonged length of stay was associated with severity of illness,
      Candida colonization or infection, infection by other fungi, antifungal therapy,
      treatment with more than one antifungal agent, and toxicity associated with this
      therapy. Compared to non-colonized, non-infected patients (n=720), patients with
      Candida colonization (n=880) had an extended ICU stay of 6.2 days (OR, 1.69;
      95%CI, 1.53-1.87; P<0.001) and an extended hospital stay of 8.6 days (OR, 1.27;
      95%CI, 1.16-1.40; P<0.001). The corresponding figures for patients with Candida
      infection (n=105) were 12.7 days for ICU stay (OR, 2.13; 95%CI, 1.72-2.64;
      P<0.001) and 15.5 days for hospital stay (OR, 1.23; 95%CI, 0.99-1.52; P=0.060).
      Candida colonization resulted in an additional 8,000 EUR in direct costs and
      Candida infection almost 16,000 EUR. Both Candida colonization and Candida
      infection had an important economic impact in terms of cost increases due to
      longer stays in both the ICU and in the hospital.

PMID- 15024629
TI  - A novel alteration in metaxin 1, F202L, is associated with N370S in Gaucher
      disease.
AB  - The gene for glucocerebrosidase ( GBA), the enzyme deficient in Gaucher disease,
      is located in a gene-rich region on 1q21. Metaxin 1( MTX1) is a convergently
      transcribed gene contiguous to the 3' end of the GBA pseudogene. A single
      nucleotide alteration in MTX1, 628T-->C, resulting in the amino acid change
      F202L, was identified in patients with Gaucher disease in association with the
      common N370S mutation in GBA. The polymorphism was also present on 4.6% of 152
      control alleles, but could have functional consequences that have a modifying
      role in Gaucher disease.

PMID- 15024630
TI  - Tension-free mesh repair of umbilical hernia as a day case using local
      anaesthesia.
AB  - BACKGROUND: Umbilical hernias are a common surgical problem with a high
      recurrence rate using conventional suture techniques. This prospective study
      examined the feasibility of tension-free mesh repair as a day case using local
      anaesthetic (LA) for all primary umbilical hernias. METHOD: Fifty-four patients
      (eight women) were operated on; 49 using LA. Through a periumbilical skin
      incision the margins of the sac were freed from the edges of the defect, and a
      space was made in the extraperitoneal plane. In defects <3 cm in diameter, a cone
      of polypropylene (pp) mesh was inserted and attached with nonabsorbable sutures.
      In defects >3 cm, a flat piece of pp mesh was inserted into the extraperitoneal
      space as a sublay. No attempt was made to close the fascial defect. RESULTS:
      Postoperative pain was graded as mild ( n=37) and moderate ( n=17). No patient
      had severe postoperative pain. Seven superficial wound infections responded to
      oral antibiotics. In no case it was necessary to remove the mesh. There were no
      other complications. Patients were recalled between 2 and 6 years postopertively
      mean follow-up 43 months (28- 67). There were no recurrences. CONCLUSION:
      Umbilical hernia repair can be carried out safely and securely under LA with a
      tension-free mesh technique (cone or a sublay patch) with a low morbidity,
      negligible recurrence rate, and a high degree of patient satisfaction. It should
      be the procedure of choice for all such hernias.

PMID- 15024631
TI  - Appendicitis in incarcerated femoral hernia.
AB  - BACKGROUND: Femoral hernia can rarely present with the content of appendicitis.
      We report on an elderly female who was admitted to our emergency department with
      a painful groin mass. METHODS: An 85-year-old woman presented with a 7-day
      history of right groin pain and swelling. She also had complaints of nausea,
      vomiting, and right lower quadrant abdominal pain. Physical examination revealed
      a right groin mass in the femoral region, which was painful on examination.
      Abdominal examination ended with normal findings except bilateral lower quadrant
      tenderness. Ultrasonographic examination revealed a hernia sac containing
      suspected aperistaltic bowel segment with edematous wall. RESULTS: The patient
      underwent surgery. During exploration of the right groin region, a strangulated
      femoral hernia sac containing appendicitis was detected. CONCLUSION: Surgeons
      should be aware of the existence of this kind of atypical presentation of
      appendicitis.

PMID- 15024632
TI  - Normal coordinate analyses of 3,5-dichlorophenylcyanamide.
AB  - The structure of 3,5-dichlorophenylcyanamide c-C6H3Cl2-NHCN was investigated by
      DFT-B3LYP and ab initio MP2 calculations with the 6-311+G** basis set. The planar
      to perpendicular rotational barrier was calculated to be of about 5 kcal mol(-1)
      at both levels of calculation. The stability of the planar structure of the
      molecule was explained on the basis of conjugation effects between the cyanamide
      NHCN moiety and the phenyl c-C6H5 ring in agreement with earlier NMR results. The
      CNC and the HNC bond angles were calculated to be about 120 degrees especially by
      MP2 calculation, which is consistent with sp2 (planar -NH-CN group) and not sp3
      (pyramidal -NH-CN group) structure. The vibrational frequencies of the d0, d1 and
      d3 species of 3,5-dichlorophenylcyanamide and the potential energy distributions
      among symmetry coordinates of the normal modes of the parent molecule were
      computed at the DFT-B3LYP level. The calculated infrared and Raman spectra of the
      molecule were plotted. Complete vibrational assignments were made on the basis of
      isotopic substitution and normal coordinate calculations.

PMID- 15024633
TI  - Molecular modeling of dipeptide and its analogous systems with water.
AB  - Intermolecular hydrogen-bond interactions in the monohydrated complexes of
      formamide, N-methylacetamide and glycylglycine have been studied using ab initio
      and DFT methods. The geometries were optimized using second-order Moller-Plesset
      perturbation theory and the B3LYP DFT functional with the 6-311++G** basis set.
      It is observed that hydrogen-bond interactions at the carbonyl group of the
      peptide moiety are stronger than those at the amino group of the formamide and N
      methylacetamide molecules. Because of the presence of cyclic hydrogen-bonding
      interactions in glycylglycine, the interaction at the amino group is higher than
      at the carbonyl. The 13C and 15N NMR shielding values were calculated for the non
      hydrated and monohydrated complexes. Condensed Fukui functions have also been
      calculated for non-hydrated formamide, N-methylacetamide and glycylglycine
      molecules at the B3LYP/6-311++G** level of theory, and the results are discussed.

PMID- 15024634
TI  - Second primary tumours in oropharyngeal squamous cell carcinoma.
AB  - Improved diagnostic techniques and more effective treatment concepts have
      resulted in a growing number of patients with oropharyngeal cancer diagnosed with
      second primary tumours. In order to evaluate the relative number of patients with
      second primary tumours and to estimate the efficacy of diagnostic procedures, a
      retrospective evaluation of 981 patients with oropharyngeal cancer, who were
      treated during 20 years in one single medical centre, was performed. In total,
      9.2% of the patients were affected by secondary cancer, 1.5% from tertiary cancer
      and 0.2% from quartary cancer. Of the multiple cancers, 27.8% occurred
      synchronously and 72.2% metachronously. If the index tumour was located at the
      oral floor or the pharynx, the risk of second primary tumours was enhanced; if
      the index tumour was located at the lips or the tongue, the risk was reduced. The
      5-year survival of all examined patients was 34.1%; the survival of patients with
      multiple cancers was 62.3% at the diagnosis of the index tumour and dropped to
      30.5% at the diagnosis of an additional malignancy. Of the second primary
      tumours, 23.2% were diagnosed by panendoscopy. We conclude that among patients
      with oropharyngeal cancer, the presence of second primary tumours always has to
      be considered and that panendoscopy is a valuable tool for their diagnosis.

PMID- 15024635
TI  - Biophysical characterization and molecular modeling of the coordinative
      intercalative DNA monoadduct of a platinum-acridinylthiourea agent in a site
      specifically modified dodecamer.
AB  - The guanine- N7 monoadduct of [Pt(en)Cl(ACRAMTU)](NO(3))(2) (PT-ACRAMTU;
      en=ethane-1,2-diamine, ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3
      dimethylthiourea), a dual metalating/intercalating cytotoxic agent, was generated
      in a double-stranded dodecamer, d(CCTCTCG*TCTCC/GGAGACGAGAGG) (III*), and
      isolated by preparative reverse-phase high-performance liquid chromatography
      (HPLC). The adduct was characterized using matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), circular
      dichroism spectropolarimetry (CD), UV-melting curves, and NMR spectroscopy. In
      addition, a molecular mechanics/restrained molecular dynamics (MM/rMD) study was
      performed for this adduct using the AMBER force field. Monoadduction of the
      sequence leads to a pronounced increase in melting temperature, Delta T(m)=
      T(m)(III*)- T(m)(III)=9.7 degrees C. Because there is complete enthalpy-entropy
      compensation, binding occurs without noticeable thermodynamic destabilization.
      This feature and the CD (induced-ligand circular dichroism) and NMR (upfield
      shifts of aromatic acridine proton signals) data are indicative of a unique,
      nondenaturing dual-binding mode that involves partial intercalation of the
      acridine chromophore. An energy-minimized AMBER model ofIII* demonstrates that
      platination of G7- N7 of guanine in the major groove and partial insertion of the
      acridine moiety into the C6G19/G7C18 base step on the 5' face of the modified
      purine base is feasible and supportive of the experimental results. Differences
      in the biophysical properties betweenIII* and duplexes containing adducts of the
      clinical-drug cisplatin are outlined, and possible biological consequences are
      discussed.

PMID- 15024636
TI  - DNA modification by oxovanadium(IV) complexes of salen derivatives.
AB  - Oxovanadium(IV) complexes of hydroxysalen derivatives have been prepared and
      tested as DNA reactive agents. The nuclease activity has been investigated under
      oxidative or reducing conditions, on the basis of the various oxidation states of
      vanadium: V(III), V(IV) and V(V). In the absence of an activating agent, none of
      the compounds tested was able to induce cleavage of DNA, whereas in the presence
      of mercaptopropionic acid (MPA) or Oxone the four complexes induced DNA
      modifications. Under both conditions, the para-hydroxy complex was found to be
      the most active compound. Reaction of these salen complexes with DNA occurs
      essentially at guanine residues and is more efficient in the presence of Oxone
      than under reducing conditions. The extent of Oxone-mediated DNA oxidation by the
      four vanadyl complexes was clearly superior to VOSO(4) and was observed without
      piperidine treatment. EPR studies provided information on the reactive metal-oxo
      species involved under each conditions and a mechanism of reaction with DNA is
      discussed.

PMID- 15024637
TI  - Primary amyloidoma of the axis and acute spinal cord compression: a case report.
AB  - BACKGROUND: Localized primary amyloidosis is a disease characterized by a single
      tumor and localized amyloid deposit (amyloidoma) with no evidence of generalized
      amyloidosis. The occurrence of an amyloidoma in the spine is rare and only three
      cases affecting the axis have been previously reported. We describe the case of a
      79-year-old woman presenting with a mass involving the odontoid process,
      responsible for an acute tetraparesia. Diagnosis of local primary amyloidosis was
      made after surgical excision. RESULTS: Despite the critical presentation, outcome
      was excellent after total excision of the mass. This case can be classified as a
      primary localized amyloidoma. The patient did not exhibit any infection, tumor or
      inflammatory disease, and continued investigations failed to demonstrate other
      amyloid deposit after one-year follow-up. CONCLUSIONS: Amyloidoma must be
      discussed in presence of a tumor-like mass of the odontoid process and may be
      responsible, as in our case, for spinal cord compression.

PMID- 15024639
TI  - The invasive shrub, Lonicera maackii, reduces growth and fecundity of perennial
      forest herbs.
AB  - Effects of invasive plant species on native plant species are frequently assumed
      or inferred from comparisons, but rarely quantified experimentally. Such
      quantification is important to assessing risks and impacts of invasives. We
      quantified the effects of Lonicera maackii, an exotic shrub invasive in many
      eastern North American forests, on survival, growth, and reproduction of three
      perennial herbs: Allium burdickii, Thalictrum thalictroides , and Viola
      pubescens. We predicted that the spring ephemeral, A. burdickii , would be most
      impacted, due to early leaf expansion of L. maackii. Field experiments were
      carried out in two deciduous forest stands, one (Gregg's Woodlot, GW) disturbed
      and the other (Western Woods, WW) relatively undisturbed. In each stand,
      individual herbs were transplanted into a blocked design of 60 plots where L.
      maackii was present, absent, or removed, and monitored for 5 growing seasons.
      Lonicera maackii did not affect survival of transplants, but reduced growth and
      final size of individuals of all three species. For two of the species, A.
      burdickii and V. pubescens, L. maackii reduced the proportion of live plants
      flowering in both stands, and reduced the seed or fruit number per flowering
      individual in GW. For T. thalictroides the proportion flowering was not affected,
      but seed number per flowering plant was reduced by L. maackii in both stands. For
      all three species, cumulative seed production over the course of the study was
      reduced by L. maackii. Overall, effects on the spring ephemeral, A. burdickii,
      were similar to effects on the other herbs. Because mortality of these
      established individuals was not affected, short-term studies might conclude
      forest herbs are unaffected by invasive shrubs. However, the growth and
      reproduction impacts documented here suggest that populations are impacted in the
      long-term.

PMID- 15024640
TI  - A field test for competitive effects of Aedes albopictus on A. aegypti in South
      Florida: differences between sites of coexistence and exclusion?
AB  - We tested whether interspecific competition from Aedes albopictus had measurable
      effects on A. aegypti at the typical numbers of larval mosquitoes found in
      cemetery vases in south Florida. We also tested whether the effect of
      interspecific competition from A. albopictus on A. aegypti differed between sites
      where A. aegypti either persists or went extinct following invasion by A.
      albopictus. Similar experiments manipulating numbers of A. albopictus in cemetery
      vases were conducted at three sites of A. aegypti persistence and three sites
      where A. aegypti was apparently extinct. The experiments were done using numbers
      of larvae that were determined by observed numbers of larvae for each site, and
      with resources (leaf detritus) that accumulated in experimental vases placed into
      each field site. In both the early rainy season (when number of mosquito larvae
      was low) and the late rainy season (when number of mosquito larvae was high),
      there was a significant effect of treatment on developmental progress of
      experimental A. aegypti. In the late rainy season, when numbers of larvae were
      high, there was also a significant effect of treatment on survivorship of A.
      aegypti. However, the competition treatment x site type (A. aegyptipersists vs
      extinct) interaction was never significant, indicating that the competitive
      effect of A. albopictus on A. aegypti did not differ systematically between
      persistence versus extinction sites. Thus, although competition from A.
      albopictus is strong under field conditions at all sites, we find no evidence
      that variation in the impact of interspecific competition is associated with
      coexistence or exclusion. Interspecific competition among larvae is thus a viable
      explanation for exclusion or reduction of A. aegypti in south Florida, but
      variation in the persistence of A. aegypti following invasion does not seem to be
      primarily a product of variation in the conditions in the aquatic environments of
      cemetery vases.

PMID- 15024641
TI  - Genomic modulation of diabetes (db/db) and obese (ob/ob) mutation-induced
      hypercytolipidemia: cytochemical basis of female reproductive tract involution.
AB  - Infertility and hypercytolipidemic utero-ovarian involution are recognized
      consequences of the diabetes-obesity syndrome (DOS) in C57BL mice with either
      obese (ob/ob) or diabetes (db/db) single gene mutations. We have evaluated the
      interdependent deleterious influences of both mutation types and differences in
      the genomic background on utero-ovarian dysfunction in C57BL mice. Control ( +/?)
      C57BL mice were matched with littermate ob/ob and db/db mutants expressed on
      either the /KsJ or /6 background. Both ob/ob and db/db mutations increased body
      weights of /KsJ and /6 background strains relative to +/? groups. In contrast,
      uterine and ovarian weights were depressed by ob/ob and db/db mutations relative
      to +/?, regardless of the background strain, but especially when expressed on the
      /KsJ background. Functionally, both ob/ob and db/db mutations induced
      hyperglycemic-hyperinsulinemic states coupled with depressed serum estradiol-17
      beta and progesterone concentrations when expressed on a /KsJ background.
      Microscopic analysis of utero-ovarian tissue samples revealed marked
      hypercytolipidemia in the follicular granulosa and endometrial epithelial tissue
      layers of both ob/ob and db/db mutant groups relative to normal +/?
      cytoarchitecture. The db/db mutation consistently promoted more severe
      hypercytolipidemic profiles than the ob/ob mutation, regardless of background
      strain. Thus, the severity of utero-ovarian hypercytolipidemia following the
      expression of ob/ob and db/db mutations in C57BL mice is influenced, or
      moderated, by the genomic background on which the mutation is expressed.

PMID- 15024642
TI  - Differentiation capacity of epithelial cells in the sponge Suberites domuncula.
AB  - Sponges (phylum Porifera) represent the oldest metazoans. Their characteristic
      metazoan adhesion molecules and transcription factors enable them to establish a
      complex "Bauplan"; three major differentiated cell types (epithelial cells,
      skeletal cells/sclerocytes, and contractile cells) can be distinguished. Since no
      molecular markers are as yet available to distinguish these somatic cells or the
      corresponding embryonic cells from which they originate, we have selected the
      following three genes for their characterization: noggin (a signaling molecule in
      development), a caspase that encodes an apoptotic molecule, and silicatein.
      Silicatein is an enzyme that is involved in the synthesis of siliceous spicules
      and can hence be considered as a marker for scleroblasts. We have used the
      demosponge Suberites domuncula as a model system. During the hatching of the
      gemmules (asexual reproduction bodies) of S. domuncula, the expression of both
      noggin and caspase increases, whereas no transcripts for silicatein can be
      detected, irrespective of the presence of silicate or ferric iron (Fe3+) in the
      medium. In contrast, in adult specimens, silicate/Fe3+ cause an increased
      expression of these genes. In situ analysis has revealed that the first cells
      that express noggin, caspase, and silicatein lie in the epithelial layer of the
      pinacoderm. In a later phase, the noggin- and silicatein-positive cells migrate
      into the mesohyl, where they are found in association with spicules. Thus, the
      pinacoderm of sponges contains cells that have a differentiating capacity and
      from which somatic cells, such as skeletal cells/sclerocytes, derive.

PMID- 15024643
TI  - Parents of children with autosomal recessive diseases are not always carriers of
      the respective mutant alleles.
AB  - Classically, each parent of a child with an autosomal recessive disease has been
      considered to carry at least one copy of the abnormal allele. However, with the
      increasing ability to characterise the molecular basis of genetic diseases,
      several exceptions have been reported. The most frequent situation is that only
      one parent is a carrier of the mutation that is present in the patient in two
      copies either because of uniparental disomy or because of a de-novo mutation on
      the gene transmitted by the non-carrier parent. In order to give accurate genetic
      counselling, in particular when prenatal diagnosis is envisaged, molecular
      analysis of each of the parents of a child affected with an autosomal recessive
      disease must be routinely performed.

PMID- 15024644
TI  - Predicted ATP-binding cassette systems in the phytopathogenic mollicute
      Spiroplasma kunkelii.
AB  - Spiroplasma kunkelii is a cell wall-free, helical, and motile mycoplasma-like
      organism that causes corn stunt disease in maize. The bacterium has a compact
      genome with a gene set approaching the minimal complement necessary for cellular
      life and pathogenesis. A set of 21 ATP-binding cassette (ABC) domains was
      identified during the annotation of a draft S. kunkelii genome sequence. These 21
      ABC domains are present in 18 predicted proteins, and are components of 16
      functional systems, which account for 5% of the protein coding capacity of the S.
      kunkelii genome. Of the 16 systems, 11 are membrane-bound transporters, and two
      are cytosolic systems involved in DNA repair and the oxidative stress response;
      the genes for the remaining three hypothetical systems harbor nonsense and/or
      frameshift mutations, so their functional status is doubtful. Assembly of the 11
      multicomponent transporters, and comparisons with other known systems permitted
      functional predictions for the S. kunkelii ABC transporter systems. These
      transporters convey a wide variety of substrates, and are critical for nutrient
      uptake, multidrug resistance, and perhaps virulence. Our findings provide a
      framework for functional characterization of the ABC systems in S. kunkelii.

PMID- 15024646
TI  - Metachronous and multiple aneurysmal bone cysts: a rare variant of primary
      aneurysmal bone cysts.
AB  - In 1942, Jaffe and Lichtenstein introduced the term aneurysmal bone cyst (ABC).
      Primary ABC is characterized by the presence of spongy or multi-cameral cystic
      tissue filled with blood. The process is benign, but it is locally destructive
      and has a high propensity for recurrence. In this paper, we present the third
      case of multiple metachronous primary ABCs as a rare variant of ABC. We describe
      the 10-year history of a 12-year-old boy with metachronous multiple primary ABCs
      at five different sites (right proximal humerus, right ulna, bilateral distal
      radius and right lateral clavicle). Furthermore, our patient suffered from
      vascular malformations, such as aortic isthmus stenosis, hypoplastic thoraco
      abdominal aorta and bilateral renal artery stenosis. To date, in contrast to
      solitary ABC, the multiple lesions have been found more frequently in male
      individuals. Using interphase cytogenetics, we analyzed three of five of the
      patient's ABCs and one of these was also analyzed by GTG-banding. No chromosomal
      abnormalities were found. Significantly, we excluded the missense mutation of
      codon 201 in guanine nucleotide-binding protein 1 gene consistently found in
      McCune-Albright syndrome (MAS) and in non-MAS cases of polyostotic fibrous
      dysplasia of bone with or without secondary ABC.

PMID- 15024647
TI  - Endocardial location of familial myofibromatosis revealed by cerebral
      embolization: cardiac counterpart of the frequent intravascular growth of the
      disease?
AB  - Myofibromatosis is a rare infantile benign neoplasia, which may involve the heart
      in the rare and usually fatal generalized form of the disease. Diagnosis of
      endocardial myofibromas was made on two surgically excised lesions of the mitral
      valve that were reveled by a cerebral embolization in a 12-month-old female
      infant. Surprisingly, the patient had no other obvious lesion of myofibromatosis.
      However, her father had a histologically proven neonatal history of
      myofibromatosis. This case confirms the likely autosomal dominant mode of
      inheritance of myofibromatosis. It highlights the embolization risk of the
      previously unreported endocardial location. We suggest that these clinically
      isolated non-invasive endocardial myofibromas did not represent a true visceral
      form of myofibromatosis. They were, rather, similar to the frequent intravascular
      growth of the disease.

PMID- 15024645
TI  - Allelotype of ampulla of Vater cancer: highly frequent involvement of chromosome
      11.
AB  - PURPOSE: To determine the genetic differences/similarities in ampulla of Vater
      cancers (AVC) with respect to other pancreatic tumor types. METHODS: We analyzed
      eight cases of primary AVC by genome-wide allelotyping on DNA obtained from
      frozen tissue. A total of 372 microsatellite loci were used for each case, for a
      total of 2,976 microsatellites analyzed. RESULTS: Of the 2,159 informative
      markers, 400 were allelic losses and 1,759 markers were retained for an average
      fractional allelic loss of 0.19. Seven cases showed LOH on at least two markers
      on chromosomal arm 11p, while six cases showed allelic losses on 11q. The high
      frequency of LOH on chromosome 11 was also confirmed by analysis of an additional
      17 paraffin-embedded AVC. Frequent LOH (50% or greater) was also found on
      chromosome arms 5q, 6q, 9p, 13, 16p, 17p, and 18p. CONCLUSIONS: It can be
      inferred that the targets of inactivation on chromosomes 5q, 9p, and 17p appear
      to be APC, p16, and p53, respectively, while the critical target(s) of
      inactivation at the other frequently lost loci remain to be characterized. The
      resulting allelotype reveals that distinctive chromosomal alterations are present
      in these neoplasms, indicating that it is a tumor entity distinct from pancreatic
      adenocarcinoma.

PMID- 15024648
TI  - Size selectivity of aqueous pores in astomatous cuticular membranes isolated from
      Populus canescens (Aiton) Sm. leaves.
AB  - Little is known about the permeability of plant cuticles to ionic molecules with
      hydration shells that render them lipid insoluble and limit their diffusion to
      narrow aqueous pores. Therefore, the permeation of cuticular membranes to ionised
      calcium salts with anhydrous molecular weights ranging from 111 to 755 g mol(-1)
      was studied. Penetration was a first-order process and rate constants (k)
      (proportional to permeability) decreased exponentially with molecular weight.
      Plots of log k vs. molecular weight had slopes of -2.11x10(-3) and -2.80x10(-3),
      respectively, depending on the year in which the cuticular membranes were
      isolated. This corresponds to decreases in permeability by factors of about 7 to
      13 when molecular weight increased from 100 to 500 g mol(-1). This size
      selectivity is small compared to the dependence on molecular weight of solute
      mobility in Populus cuticles. A decrease in mobility of neutral molecules by more
      than 3 orders of magnitude has been reported [A. Buchholz et al. (1998) Planta
      206:322-328] for the same range of molecular weights. Hence, discrimination of
      large ionic species diffusing in aqueous pores (polar pathway) is much smaller
      than that for neutral solutes diffusing in cutin and waxes (lipophilic pathway).
      This indicates that formulating large solutes as ionic species would be
      advantageous.

PMID- 15024650
TI  - Abstracts of the 83rd Annual Meeting of the German Physiological Society (DPG).
      14-17 March 2004, Leipzig, Germany.

PMID- 15024649
TI  - Import of polyphenol oxidase by chloroplasts is enhanced by methyl jasmonate.
AB  - Polyphenol oxidase (PPO; EC 1.10.3.2 or EC 1.14.18.1) takes part in the response
      of tomato plants (Lycopersicon esculentum Mill.) to wounding and herbivore
      attack, mediated by the octadecanoid wound-signaling pathway. Wounding and methyl
      jasmonate (MeJA) induce expression of ppo genes and markedly increase the level
      of the enzyme. We report that pretreatment with MeJA also markedly increased the
      ability of isolated tomato chloroplasts to import and process PPO precursors
      (pPPO). Pea (Pisum sativum L.) chloroplasts showed no such response. Wounding or
      ethylene alone was ineffective but ethylene was synergistic with MeJA. Treatment
      with MeJA conferred a strong binding of pPPO, or its processing intermediate, to
      thylakoids and subsequent translocation into the lumen and processing to the
      mature protein. The effect on PPO import and translocation was evident after 8-16
      h exposure to MeJA. Membrane-bound pPPO was cross-linked to a proteinaceous
      component of the thylakoid translocation apparatus, apparently induced by MeJA.
      The import and processing of other nuclear-encoded thylakoid proteins were not
      affected by MeJA in tomato. A 90-kDa protein that co-fractionated with thylakoids
      was induced along with the increase in competence for PPO import, and was
      identified as the proteinase-inhibitor multicystatin. It is concluded that the 90
      kDa protein observed is part of the MeJA-induced defense response of tomato, not
      a component of the thylakoid translocation apparatus.

PMID- 15024659
TI  - Current options in prosthetic vascular graft infection: comparative analysis of
      63 consecutive cases.
AB  - PURPOSE: The study was conducted to compare the results of two different
      techniques of vascular reconstruction in patients after the removal of infected
      vascular prostheses. METHODS: Sixty-three patients with vascular prostheses
      infections underwent treatment. Either the infected fragments or the entire
      prosthesis was removed in all of the patients. Extra-anatomical grafts were
      implanted in 19 cases. Cryopreserved allogenic arterial grafts were applied for
      reconstruction in 44 patients. RESULTS: In a 19-patient group with extra
      anatomical grafts, two patients died (10.5%). In seven patients (36.8%) relapse
      symptoms of infection appeared. Primary and secondary patencies of the grafts
      after 3 years were 31.6% and 52.6% respectively. In a group of 44 patients with
      allogenic grafts no recurrence of infection was observed. Six patients died
      (13.6%). Primary and secondary patencies after 3 years were 63.6% and 81.8%
      respectively. CONCLUSIONS: The results reveal the benefits of the allogenic
      arterial grafts in revascularization in patients with major vascular prostheses
      infections. The differences in secondary patencies of the implanted allogenic
      grafts indicate the necessity of an early selection of patients for the complete
      removal of the infected prosthesis, during a time when patients are in general
      good health.

PMID- 15024658
TI  - Nitrosative stress and potassium channel-mediated neuronal apoptosis: is zinc the
      link?
AB  - Nitrosative stress has been implicated in a large number of neurological
      disorders. The molecular mechanisms underlying the neuronal injury associated
      with this stimulus, however, are not clearly understood. Emerging evidence
      suggests that the liberation of intracellular zinc as well as over-activation of
      potassium channels may be two important components of nitrosative stress-induced
      neuronal death.

PMID- 15024661
TI  - EMG recovery and ratings after back extensor fatigue in patients with lumbar disc
      herniation and healthy subjects.
AB  - This prospective study aimed to examine whether patients with lumbar disc
      herniation, before and after surgery, showed impaired recovery from fatigue
      measured with EMG and subjective ratings as compared to healthy subjects. Forty
      three patients due for, and after, lumbar disc surgery and 60 healthy subjects
      were fatigued using a modified Sorensen's test. Recovery of back extensor muscles
      was assessed using electromyography and the Borg scale ratings at 1, 2, 3, and 5
      minutes of recovery, and was further analyzed using an exponential time
      dependence model. The patients completed four questionnaires: the Oswestry, the
      Roland-Morris, a self-efficacy scale and the SF-36. The exponential time
      dependence model was successful for 14 of the 43 patients and 57 of the 60
      healthy subjects. The patients for whom the model succeeded had significantly
      better scores on the questionnaires than those for whom the model was
      unsuccessful. Specific items related to standing and lifting were identified. The
      patients' recovery was impaired compared to the healthy subjects, as determined
      by use of the exponential time-dependence model. The combination of fatigue and
      recovery measures was reflected in the questionnaire scores and is therefore
      important for evaluating patients with lumbar disc herniation.

PMID- 15024663
TI  - Effects of 20-s and 180-s double poling interval training in cross-country
      skiers.
AB  - The purpose of this study was to investigate the effect of upper body 20-s or 180
      s interval training, using a double poling ergometer, on upper body power output
      and selected physiological and biomechanical parameters in cross-country skiers.
      Twenty (12 male, 8 female) well-trained cross-country skiers took part. Two
      intervention groups, a 20-s interval training group (IT20; n=6) and a 180-s
      interval training group (IT180; n=7), underwent training three times a week for 6
      weeks on a double poling ergometer. A third group served as a control (CON; n=7)
      and followed the same training program as the IT20 and IT180 groups without the
      double poling ergometer interval training. The IT20 and IT180 groups
      significantly (P<0.05) increased both peak and mean power in a 30-s test and mean
      power in a 6-min test after double poling training. There was a significant
      improvement in work efficiency in both IT20 and IT180 (P<0.05) and, in IT180, a
      significant reduction (P<0.05) in blood lactate concentration at given sub
      maximal workloads. VO(2peak) increased significantly during double poling in
      IT180 ( P<0.05) only. VO(2max) did not change significantly in either group.
      There were no significant changes in any of the test variables in CON. In
      conclusion, this study shows that 6 weeks of 20-s or 180-s double poling interval
      training, three times a week, significantly increases power output in both 30-s
      and 6-min tests, as well as in selected physiological and biomechanical
      parameters in well-trained cross-country skiers.

PMID- 15024664
TI  - Pedalling rate affects endurance performance during high-intensity cycling.
AB  - The purpose of this study into high-intensity cycling was to: (1) test the
      hypothesis that endurance time is longest at a freely chosen pedalling rate
      (FCPR), compared to pedalling rates 25% lower (FCPR-25) and higher (FCPR+25) than
      FCPR, and (2) investigate how physiological variables, such as muscle fibre type
      composition and power reserve, relate to endurance time. Twenty males underwent
      testing to determine their maximal oxygen uptake (VO(2max)), power output
      corresponding to 90% of VO(2max) at 80 rpm (W90), FCPR at W90, percentage of slow
      twitch muscle fibres (% MHC I), maximal leg power, and endurance time at W90 with
      FCPR-25, FCPR, and FCPR+25. Power reserve was calculated as the difference
      between applied power output at a given pedalling rate and peak crank power at
      this same pedalling rate. W90 was 325 (47) W. FCPR at W90 was 78 (11) rpm,
      resulting in FCPR-25 being 59 (8) rpm and FCPR+25 being 98 (13) rpm. Endurance
      time at W90(FCPR+25) [441 (188) s] was significantly shorter than at W90(FCPR)
      [589 (232) s] and W90(FCPR-25) [547 (170) s]. Metabolic responses such as VO(2)
      and blood lactate concentration were generally higher at W90(FCPR+25) than at
      W90(FCPR-25) and W90(FCPR). Endurance time was negatively related to VO(2max),
      W90 and % MHC I, while positively related to power reserve. In conclusion, at
      group level, endurance time was longer at FCPR and at a pedalling rate 25% lower
      compared to a pedalling rate 25% higher than FCPR. Further, inter-individual
      physiological variables were of significance for endurance time, % MHC I showing
      a negative and power reserve a positive relationship.

PMID- 15024662
TI  - Movement performance and body size: the relationship for different groups of
      tests.
AB  - It has been shown that inconsistently applied normalization for body size could
      be an important methodological problem in testing physical performance in areas
      such as sports, physical education, ergonomy, or physical medicine and
      rehabilitation. The aim of this study was to evaluate a part of the recently
      proposed classification of physical performance tests (Jaric 2003) based on the
      role of body size in the tested performance. Presuming a normalization method
      P(n)= P/ S(b) based on an allometric relationship between the tested performance
      P and a selected index of body size S (P(n) performance normalized for body size;
      b allometric parameter), we specifically hypothesized that: (1) the tests of
      exertion of external force (e.g., lifting weight, pushing, pulling), (2) tests of
      rapid movements (jumping, sprinting, kicking) and (3) tests of supporting body
      weight (chin-ups, squats) would reveal the values of the allometric parameters
      b=0.67, b=0 and b=-0.33 when body size is expressed as body mass, or b=2, b=0 and
      b=-1 when body size is expressed as body height, respectively. Male physical
      education students (n=77) were tested on 18 standard physical performance tests
      belonging to the aforementioned three groups. The obtained values of the
      allometric parameters proved to be closely in line with the hypothesized ones.
      While the finding regarding the tests of exertion of external force (i.e., the
      tested force should be divided by m(0.67) in order to normalize the force for
      body size) have been already demonstrated by some authors, the findings related
      to the tests of rapid movements and, particularly, tests of supporting body
      weight are novel. Although the normalization methods discussed need further
      evaluation, a more accurate and consistently applied assessment of the body size
      independent indices of the evaluated groups of standard tests could improve the
      methodology of physical performance testing in general.

PMID- 15024665
TI  - Magnetic resonance imaging evaluation of cooling on blood flow and oedema in
      skeletal muscles after exercise.
AB  - This study assessed the effects of cooling on blood flow and intramuscular water
      content in human skeletal muscles after exercise using magnetic resonance
      imaging. In six male subjects, their legs were randomly assigned to be control or
      to be cooled. All subjects performed ankle dorsiflexion exercise inside an
      imaging magnet and after exercise, an ice bag was placed on the ankle
      dorsiflexors of the cooled leg. Flow-sensitive images, which reflect both
      perfusion and intramuscular water, were obtained before and up to 270 s post
      exercise at 30-s intervals. The flow-sensitive alternating inversion recovery
      (FAIR) images, which extract only the perfusion change, were also obtained.
      Signal intensity (SI) in the ankle dorsiflexors was estimated before and after
      exercise in both flow-sensitive and FAIR images. On the flow-sensitive images,
      the control leg increased SI 30-270 s after exercise (P<0.05), but the cooled leg
      showed no significant change. On the FAIR images, the control leg increased SI 30
      270 s post-exercise (P<0.05), while the cooled leg increased SI 30-150 s and 210
      s after exercise (P<0.05). The findings suggest that cooling attenuates the
      perfusion elevation and prevents the oedema formation in skeletal muscle
      immediately after exercise.

PMID- 15024666
TI  - Prolonged vitamin C supplementation and recovery from eccentric exercise.
AB  - We have previously shown that vitamin C supplementation affects recovery from an
      unaccustomed bout of demanding exercise, with the most pronounced effect being
      that on plasma interleukin-6 concentration. However, because of the proposed role
      of interleukin-6 in the regulation of metabolism, it was unclear whether this
      represented a reduced response to muscle damage or some form of interaction with
      the metabolic demands of the activity. Therefore, the aim of the present study
      was to investigate the effect of the same form of supplementation on a bout of
      exercise that initiated similar muscle damage but had a low metabolic cost.
      Fourteen male subjects were allocated to either a placebo (P) or a vitamin C (VC)
      group. The VC group consumed 200 mg of ascorbic acid twice a day for 14 days
      prior to a bout of exercise and for the 3 days after exercise. The P group
      consumed identical capsules that contained 200 mg lactose. Subjects performed 30
      min of downhill running at a gradient of -18% and recovery was monitored for up
      to 3 days after exercise. Plasma VC concentrations in the VC group increased
      following supplementation. Nevertheless, downhill running provoked a similar
      increase in circulating markers of muscle damage (creatine kinase activity and
      myoglobin concentration) and muscle soreness in P and VC groups. Similarly,
      although downhill running increased plasma interleukin-6, there was no effect
      from VC supplementation. These results suggest that vitamin C supplementation
      does not affect interleukin-6 concentrations following eccentric exercise that
      has a low metabolic component.

PMID- 15024667
TI  - Hormonal responses to three training protocols in rowing.
AB  - The aim of this study was to examine the acute responses of serum growth hormone,
      testosterone, and cortisol to three training protocols in rowing. Six young
      rowers, members of the national team, carried out three frequently used protocols
      in rowing, i.e., an endurance, a moderate interval, and a resistance protocol, on
      separate days in a counterbalanced design. Blood samples were collected before,
      immediately after, and 4 h after exercise for the determination of growth
      hormone, testosterone, cortisol, and creatine kinase. All three protocols caused
      marked increases in growth hormone, the most spectacular being that immediately
      after the endurance protocol. The change in testosterone concentration
      immediately after the endurance protocol was significantly higher than the
      changes after the other two protocols. Cortisol concentration was significantly
      higher immediately after the endurance protocol than after the other two
      protocols, but remained relatively low in all cases, suggesting that these
      protocols did not considerably promote catabolism in muscle tissue. Based on
      these data, endurance training caused greater responses of the three hormones
      studied compared to interval or resistance training. In fact, resistance training
      (at intensities above 85% of 1RM) did not cause any significant changes in the
      three hormones. We therefore propose that evaluation of training programmes
      designed for elite athletes should include measurements of hormonal changes in
      order to ascertain that the programmes do cause the expected adaptations.

PMID- 15024668
TI  - Reproducibility of the heart rate variability responses to graded lower body
      negative pressure.
AB  - The reproducibility of heart rate variability (HRV) measures during graded lower
      body negative pressure (LBNP) have not been studied in sufficient detail. Active
      college age men (n=14) underwent an orientation exposure and two trials of graded
      LBNP to presyncope or -100 mmHg, separated by 1 week. Heart rate, stroke volume
      (impedance cardiography), blood pressure (Finapres), and forearm blood flow were
      assessed, as was HRV in both time and frequency domains. The trial-to-trial
      responses to LBNP common to all subjects (LBNP< or =-60 mmHg and at test
      termination) showed parallel changes, suggesting similar responses between both
      trials. Good reproducibility estimates were found for the resting HRV data
      (lowest: R=0.62 for low frequency/high frequency ratio; highest: R=0.94 for
      standard deviation of normal R-R intervals). During LBNP, reproducibility
      estimates varied but were generally similar to that seen at rest. At test
      termination, they were unacceptably low (R<0.41) for the HRV data assessed in the
      frequency domain and expressed in absolute units. LBNP tolerance was lower in the
      first trial [LBNP tolerance index: 404 (21) versus 437 (15) mmHg min(-1); P<0.05]
      but the intraclass correlation coefficient was high (R=0.87). These data suggest
      that (1) HRV responses to submaximal LBNP up to -60 mmHg are consistent across
      trials, (2) the considerable variability seen in the HRV parameters at maximal
      LBNP can be reduced by expressing these data in either the time domain or using
      normalized units in the frequency domain, and (3) cardiovascular responses to sub
      and maximal LBNP are reproducible. Data are presented as mean (SEM) unless
      otherwise stated.

PMID- 15024671
TI  - Gynaecomastia in the adolescent: a surgically relevant condition.
AB  - BACKGROUND/PURPOSE: Gynaecomastia is a benign condition which is commonly seen in
      adolescent males. The aim of this study is to assess the complications and the
      cosmetic outcome of surgical treatment in the management of adolescent
      gynaecomastia. METHODS: Thirty-nine adolescent males had subcutaneous mastectomy
      for gynaecomastia at Booth Hall and Royal Manchester Children's Hospitals between
      1995 - 2001 inclusive. A retrospective analysis was performed and in addition to
      chart review, personal and telephone interviews were conducted to assess the
      patients' satisfaction with the cosmetic results of the procedure. RESULTS:
      Thirty-four patients (87%) had bilateral mastectomies and the remaining five
      (13%) had a unilateral procedure. The technique used was the standard
      subcutaneous mastectomy via a circumareolar skin incision (10). Early
      postoperative complications included haematoma (n = 3), seroma formation (n = 1),
      and wound infection (n = 1). Late complications included unequal breast sizes (n
      = 3) and redundant baggy appearance of the skin (n = 1). We contacted thirty
      three patients to assess their satisfaction with the cosmetic results of the
      procedure. Twenty-nine (88%) were satisfied with their cosmetic appearance,
      compared to four (12%) reported "not satisfied". CONCLUSION: Gynaecomastia in
      adolescent males is common and the majority of cases regress spontaneously within
      one year. Surgery is indicated if the condition fails to regress or if it is
      causing sufficient embarrassment to interfere with the patient's social life.
      Based on our experience, we believe that subcutaneous mastectomy through a
      circumareolar skin incision is a valid procedure for the treatment for adolescent
      gynaecomastia and provides satisfactory cosmetic results for this age group.

PMID- 15024669
TI  - Impact of sensorimotor training on the rate of force development and neural
      activation.
AB  - The ability to generate high muscular strength within short time periods is of
      functional importance not only as a basic quality in many sports disciplines but
      also for active stabilization of joints. The rate of force development (RFD) is
      generally used to describe this ability. The purpose of the present study was to
      examine the functional adaptations of a specific sensorimotor training on the
      explosive strength qualities of the leg extensor muscles during maximum isometric
      actions. Force and surface EMG were recorded in 17 subjects before and after a 4
      week sensorimotor training period. Maximum static leg press strength did not
      change [608.2 (47.0) N to 627.8 (48.4) N before/after training], whereas maximum
      RFD (RFD(max)) increased significantly from 4.95 (0.48) N/ms to 6.58 (0.76) N/ms
      (P<0.05). The gain in RFD(max) was accompanied by an increased EMG of the M.
      vastus medialis. Enhancement of neuromuscular activation was only prominent in
      the early phases of muscular action. Neither force nor EMG parameters revealed
      significant improvements for time phases beyond 100 ms following the onset of
      isometric action. Enhanced extrafacilitatory drive from the afferent system is
      discussed as a potential mechanism for the improved neural activation. From a
      more functional point of view, this type of adaptation may be helpful in various
      sport performances. Moreover, with regard to injury related situations, enhanced
      neuromuscular activation is of distinct relevance in order to stiffen joint
      complexes actively within short time periods.

PMID- 15024672
TI  - Necessity for surgery in children with gastrooesophageal reflux and
      supraoesophageal symptoms.
AB  - BACKGROUND/PURPOSE: The majority of gastrooesophageal reflux (GER) manifestations
      in children are supraoesophageal, and "spitting/posseting" is "the tip of the
      iceberg" because most reflux episodes are not regurgitated. Aim of the present
      study was to prospectively evaluate the incidence of gastrooesophageal reflux and
      the incidence of antireflux surgery in patients with difficult-to-treat
      respiratory symptoms. PATIENTS AND METHODS: Five hundred and ninety-five children
      with difficult-to-treat respiratory symptoms were prospectively enrolled in a
      blind study looking for the correlation between clinical presentation (asthma or
      non-asthma), oesophageal pH monitoring, X-ray barium meal, broncho-alveolar
      lavage, necessity for surgery, and outcome. RESULTS: pH monitoring was anomalous
      in 47% of patients with asthma (group A) and in 43% of those who did not have
      asthma as main symptom (group B). Overall, 48 patients finally underwent anti
      reflux surgery (8%) as anti-reflux medical treatment did not ensure stable
      benefits. No major surgical complications were experienced. Postoperatively,
      respiratory symptoms improved strongly (Visick 1) in 69% of cases, moderately
      (Visick 2) in 27%, while clinical worsening (Visick 4) was observed in 4%.
      CONCLUSIONS: The results of this study stress the importance of symptoms,
      clinical response to anti-reflux medical treatment and broncho-alveolar lavage
      compared to classical pH parameters in the decision-making process for patients
      with difficult-to-treat supraoesophageal symptoms. To date no single tool alone
      has proved to be diagnostic in these patients. Fundoplication is recommended only
      when a relationship between supraoesophageal symptoms and gastrooesophageal
      reflux is strongly suspected.

PMID- 15024674
TI  - Appendicular colic and the non-inflamed appendix: fact or fiction?
AB  - AIMS: Appendicoliths cause acute appendicitis and appendicular perforation. Do
      appendicoliths cause acute abdominal pain in the absence of acute appendicitis?
      METHODS: A retrospective observational study was undertaken of histology reports
      of all appendicectomy specimens from children < 16 years of age between January
      1995 and December 2001. Specimens were categorised as perforated or uncomplicated
      acute appendicitis, non-inflamed, and "incidental" (removed during abdominal
      surgery for other indications). The presence of an appendicolith was noted.
      Clinical details were supplemented by selected case note review. Specimens in
      which the diagnosis of appendicitis or the presence of an appendicolith were not
      clearly defined (n = 20) were reviewed by an experienced, independent
      pathologist. RESULTS: 601 consecutive appendicectomy reports were analysed. The
      mean age of the study population was 9 years (range 1 day - 15.9 years) and there
      were 357 boys. An appendicolith was identified in 31/118 (26%) cases of
      perforated appendicitis, 60/352 (17%) cases of uncomplicated appendicitis, 12/59
      (20%) cases of non-inflamed appendices, and only 1/72 (1%) cases of incidental
      appendicectomies. All patients with an appendicolith in the non-inflamed appendix
      group had presented with acute abdominal pain mimicking acute appendicitis. The
      frequency of an appendicolith in perforated appendicitis was significantly
      greater than in uncomplicated acute appendicitis (chi (2) = 4.8, 1 df, p < 0.05).
      There was no significant difference in the frequency of an appendicolith between
      non-inflamed appendices and acute appendicitis (either perforated or intact).
      Appendicoliths were rarely found in incidental appendicectomies, but these
      patients were younger. The frequency of appendicoliths in non-inflamed appendices
      was much greater than that expected from published autopsy data. CONCLUSION:
      Appendicoliths may cause acute abdominal pain that mimics acute appendicitis.

PMID- 15024673
TI  - Poor effect of glutamin and human-EGF on autologic-allotopic transplanted ileum
      mucosa.
AB  - INTRODUCTION: After establishing a new method of autologic-allotopic ileum mucosa
      transplantation as a therapy for short-bowel syndrome, the effects of glutamine
      and human epithelial growth factor (human EGF) on the transplanted ileum mucosa
      were evaluated. METHODS: Ileum mucosa was transplanted in 28 young beagle dogs in
      a demucosed vascularised transverse colon segment. The ileum mucosa was kept in
      place with silicone stents in all animals. Eight animals of the control group
      were irrigated with saline solution. In the second group with 10 animals, 100
      mg/kg glutamine were administered daily in the lumen. The 10 animals of the third
      group were treated with 25 microg/kg human EGF per day subcutaneously and
      irrigated with saline solution. 4 weeks later, histological specimens were
      harvested from the colon coat-ileum mucosa complex, the normal ileum and normal
      colon. Lumen diameter, percentage ileum mucosa uptake as well as mucosa and colon
      muscle coat thickness were evaluated. RESULTS: In all groups, the diameter of the
      lumen was larger than 10 mm after fixation, due to the silicone stent. The group
      with glutamine irrigation showed the largest lumen diameter. A complete mucosa
      lining of the inner surface of the colon muscle coat was achieved in none of the
      animals. The highest percentage of ileum mucosa uptake was found in the group
      with glutamine irrigation. In most animals, the transplanted ileum mucosa was
      markedly thinner than normal ileum mucosa. Only in the group with glutamine
      irrigation did we find two animals with nearly normal mucosa thickness. The
      longitudinal muscle of the transplanted colon coat was thicker in all three
      groups compared to normal colon. There were no differences in thickness of the
      circular muscle in all animals compared to normal colon. CONCLUSIONS: Silicone
      stents maintain a lumen after autologic-allotopic ileum mucosa transplantation.
      However, additional irrigation with glutamine, as well as treatment with human
      EGF subcutaneously could not provide a complete lining of the colon muscle coat
      with transplanted ileum mucosa. A modification of the operative procedure is
      necessary to achieve a colon muscle coat that is completely lined with ileum
      mucosa before the absorptive capacity of the transplanted colon coat-ileum mucosa
      complex can be evaluated.

PMID- 15024675
TI  - Short-stay open appendectomy.
AB  - PURPOSE: This report describes a minimally invasive short-stay open appendectomy
      technique which improves the length of stay in comparison to traditional open
      appendectomy and improves the cost of hospitalization in comparison to
      laparoscopic appendectomy. STUDY DESIGN: This retrospective analysis reviewed 100
      consecutive children treated with traditional open appendectomy and 100
      consecutive children treated with a minimally invasive short-stay open technique
      with local infiltration of bupivacaine hydrochloride. Data collected for each
      child included age, sex, diagnosis, operative time, return to activity time,
      complications, length of stay, and hospital charge. RESULTS: The mean length of
      stay (LOS) was reduced from 2.7 days for traditional open appendectomy patients
      to 1.0 day for minimally invasive short-stay open appendectomy. The mean hospital
      charge (HC) for this short-stay open appendectomy, US dollars 6795, was
      significantly less than the mean HC for traditional open appendectomy (US dollars
      8162), and for laparoscopic appendectomy (US dollars 7668). CONCLUSION: This
      short-stay open appendectomy technique offers an efficacious alternative to both
      traditional open appendectomy and laparoscopic appendectomy.

PMID- 15024676
TI  - Non-operative management of isolated solid organ injuries due to blunt abdominal
      trauma in children: a fifteen-year experience.
AB  - The purpose of this study was to evaluate essential prerequisites for a selective
      non-operative approach in children with solid organ injuries due to blunt
      abdominal trauma, and to determine the predictive value of two different trauma
      scoring systems: the Injury Severity Score (ISS) and the Paediatric Trauma Score
      (PTS). A retrospective review of children who were admitted with blunt abdominal
      solid organ injuries to a paediatric trauma centre between January 1986 and
      September 2001 was performed. Hepatic, splenic, and renal injuries were graded,
      based on the American Association for the Surgery of Trauma (AAST) Organ Injury
      Scale (ranged from grade I to IV). The patients were treated non-operatively or
      operatively and the two groups were compared for variables such as age, blood
      transfusion, ISS, PTS, length of hospitalisation, morbidity and mortality rate.
      Two hundred and five patients (147 boys and 58 girls) entered in this study.
      Median age was 7 years (1 - 15 yrs). The most common cause of trauma was falls
      (50%). Abdominal organ injuries were present in all patients with the spleen as
      the most commonly injured organ (111 patients). Fifty-one patients (32%) had
      additional extra-abdominal organ injuries. Thirty-five (17%) patients were
      treated operatively, while 170 (83%) were treated non-operatively. Post-traumatic
      complications developed in 10 patients treated operatively versus 4 patients
      treated non-operatively. Four patients died due to multiple organ failure (2 non
      operative, 2 operative). When compared to the non-operative group, higher
      transfusion requirements (p < 0.05), a higher ISS (p < 0.01), lower PTS values (p
      = 0.0001), a longer hospitalisation period (p = 0.0001), and a higher
      complication rate (p < 0.05) were observed in the operative group. In addition,
      the non-operative treatment approach was more common in the last five years
      compared to the previous ten years (p = 0.002). In conclusion, the appropriate
      non-operative management of injured children reduces the risks of blood
      transfusion and decreases the length of hospital stay compared with a surgical
      approach. The use of physiological parameters and radiological findings may be
      sufficient criteria for observing haemodynamically stable patients with isolated
      abdominal organ injuries, and thus intensive care unit costs may be avoided. In
      addition, a careful and close follow-up is essential in injured patients with a
      low PTS or high ISS.

PMID- 15024677
TI  - Morphology and urodynamics after longitudinal urethral plate incision in proximal
      hypospadias repairs: long-term results.
AB  - AIM: To determine whether longitudinal neourethra incision disturbs the healing
      and growth of the neourethra, and to see how it affects the urine flow after
      proximal hypospadias repairs. SUBJECTS AND METHODS: Nine patients were examined,
      in whom longitudinal incision had been performed 9 - 15 years earlier, after
      previous penis lengthening operations. Calibration, urethrography, endoscopy, and
      urodynamics were carried out in all patients. RESULTS: In all but 1 patient the
      external meatus had steadily been growing in width, and in 8 out of 9 it was
      within the normal size range. Urethroscopy showed single hairs growing into the
      lumen in 3 patients. No scarring was demonstrated in any patient. Saccular
      dilatation of the neourethra was found in 6 out of 9, urethral stricture was
      shown in only 1 patient. Peak flow rate was within 2 SD in 5 patients, and below
      2 SD in 3. Average flow rate was below 2 SD in 6 patients and in all patients it
      was markedly low. In the patient with urethral stricture both peak flow rate and
      average flow rate were well below normal. CONCLUSIONS: Although longitudinal
      neourethra incision allows for easy and safe closure, longitudinal incision may
      result in functional meatal stenosis with formation of a wide neourethra. This
      may be due to disproportional low resistance of the urethral wall, compared with
      external meatus, to urine flow.

PMID- 15024678
TI  - Changes in the threshold voltage and alterations of smooth-muscle physiology
      after bladder outlet obstruction.
AB  - The purpose of this study was to determine the resultant changes in the bladder
      function after partial bladder outlet obstruction (BOO), with particular emphasis
      on the threshold voltage and on the role of NO. A total of 12 adult rabbits were
      used in the study. New Zealand-type rabbits were subjected to no intervention and
      3 weeks duration of a partial outlet obstruction. They underwent an in vivo
      cystometric evaluation before and after the BOO, histological studies, bladder
      strip stimulation studies using acetylcholine, electrical field stimulation, and
      relaxation studies using NO donor nitroprusside. Statistical significance was
      determined by two-way ANOVA for multiple variations and Student's t-test.
      Histology sections demonstrated smooth-muscle hypertrophy, hyperemia of the
      vessels in the wall and widely set mononuclear cell infiltration in the rabbits
      with partial BOO. Cystometry showed markedly decreased bladder capacities, and
      decrease of compliance from 4.3 +/- 1.8 to 1.6 +/- 0.3 in the obstructed group.
      Tissue bath studies demonstrated no meaningful change with cholinergic
      stimulation, increased contractility in response to electrical field stimulation,
      and increased threshold voltage values from 57.5 to 93.3 compared to controls.
      Nitroprusside did not induce relaxation of the neostigmine and acetylcholine
      precontracted bladder in all animals. Hypertrophy was observed due to adaptation
      of the detrusor against the obstruction. During this adaptation period, bladder
      capacity decreases and the elasticity disappears, thus causing higher pressures
      with lesser volumes. In other words, compliance decreases. The neurogenic damage
      can be shown with increasing values of threshold voltage, and higher voltages are
      needed to start a contraction. Nitroprusside has no inhibitory effect on smooth
      muscle tone in the rabbit bladder.

PMID- 15024679
TI  - Ureterocystoneostomy (UCN) and subureteral collagen injection (SCIN): combined
      one-stage correction of high-grade bilateral vesicoureteral reflux (VUR) in
      children.
AB  - The treatment of vesicoureteral reflux (VUR) is still a controversial issue. The
      efficacy of medical treatment appears to be equal to that of operative procedures
      in avoiding new formation of renal scars. However, there are generally accepted
      indications for operative procedures including bilateral high-grade VUR,
      especially in young patients. Ureteral reimplantation (UCN) is the operative
      treatment of choice in cases with high-grade VUR. Alternatively in cases with
      lower-grade VUR, injection of bulking agents under the refluxive orifice can be
      performed. It is also generally accepted that UCN with extravesical preparation
      of the ureter and the bladder should not be done bilaterally in a one-stage
      procedure. Postoperative bladder dysfunction may result due to detrimental
      neurogenic effects. In this study we report on our operative procedure in cases
      with bilateral high-grade VUR, during which we perform intra/extravesical UCN
      (mod. Leadbetter-Politano) of the higher-grade refluxive ureter, and (open)
      subureteral collagen injection (SCIN) of the lower-grade refluxive orifice as a
      combined one-stage procedure. In this study 50% of the patients had no VUR on
      either side after the first combined procedure. 15% of the patients showed
      significant down-grading of VUR of the injected side. These patients underwent a
      2nd endoscopic SCIN. 35% of the patients showed no change of VUR of the injected
      side after the first procedure; these patients underwent reimplantation of this
      side in another operation. Accordingly, 50% of patients with bilateral high-grade
      VUR required a 2nd operative procedure under full anesthesia to achieve loss of
      VUR on both sides. None of the patients showed bladder dysfunction
      postoperatively. Mean follow-up after the last operative correction was 29.9
      months (6 - 84 months).

PMID- 15024680
TI  - Displaced fractures of the proximal humerus in children require open/closed
      reduction and internal fixation.
AB  - Fractures of the proximal humerus in children are rare and constitute only 3% of
      all epiphyseal injuries. From 1992 to 2002 sixteen patients aged 4 - 15 years
      with a displaced fracture of the proximal humerus were treated at our level I
      trauma unit. The mean follow-up of the patients was 23.8 months (8 - 72). Ten
      children had a metaphyseal fracture and six a Salter and Harris Type II injury.
      Only one metaphyseal fracture was treated conservatively; the other patients
      underwent surgery (ORIF [= open reduction internal fixation] in ten patients,
      CRIF [= closed reduction internal fixation] in five patients). Follow-up
      examination showed no shortening or major angulation of the humerus in any of the
      sixteen cases. Fifteen children showed excellent and good results. There was only
      one average result in a polytraumatized child with additional injuries in both
      upper extremities. Based on the results of this study we suggest performing
      ORIF/CRIF in displaced fractures of the proximal humerus in children.

PMID- 15024681
TI  - Fibroadenoma of the breast in an 11-year-old girl.
AB  - Fibroadenoma is the main cause of unilateral breast mass in teenagers and
      adolescents. 4% of these are a special form described as giant or juvenile
      fibroadenoma. For primary diagnosis, ultrasound is the method of choice. The MRI
      allows exact evaluation of size and location. The fibroadenoma must be
      distinguished from the phylloid tumour, which can be malignant. The latter occurs
      in patients of all ages, but peaks between the ages 40 and 50 years. Only 2% of
      all primary malignant breast lesions are found in women aged under 25. Metastases
      of other primary tumours must be excluded, especially with a history of prior
      malignancies. When planning the surgical excision, the final cosmetic result is
      important. Although the main reason of an asymmetrical breast enlargement of
      young girls is a benign mass, an early surgical excision is efficient with regard
      to the best possible cosmetic outcome.

PMID- 15024683
TI  - Mesenchymal hamartomas of the liver may be associated with increased serum alpha
      foetoprotein concentrations and mimic hepatoblastomas.
AB  - A mesenchymal hamartoma (MH) of the liver in a seven-month-old girl was
      associated with slightly elevated alpha fetoprotein (AFP) concentrations (320
      microg/L, normal < 25 after six months of age). Hepatocytes were abundant at the
      periphery of the tumour at histopathological examination. These were slightly
      atypical and expressed AFP immunohistochemically. In two other girls, aged 14
      months and two months respectively, with MH and increased serum AFP
      concentrations (320 microg/L and 7500 microg/L, respectively), hepatoblastomas
      were misdiagnosed preoperatively. MH of the liver with increased serum AFP
      concentrations may thus mimic hepatoblastoma radiologically if cysts are lacking,
      and foetal hepatoblastoma pathologically if a biopsy samples only the peripheral
      hepatocellular component of the MH.

PMID- 15024682
TI  - Complete pancreatic ectopia in a gastric duplication cyst: a case report and
      review of the literature.
AB  - Ectopic tissue can be histologically detected in gastric duplication cysts. The
      authors describe the case of a complete pancreatic ectopia in a prenatally
      diagnosed symptomatic gastric duplication cyst in a 6-month-old male infant.
      Surgical removal of the cystic formation was curative. In view of the rarity of
      the lesion, a full clinical and diagnostic classification of the condition proved
      possible only after radical surgical resection and histological examination.
      Immunohistochemical investigation enabled us to detect the complete pancreatic
      ectopia.

PMID- 15024684
TI  - Haematosalpinx of fallopian tube: isolated torsion with congenital abnormal
      vascularisation.
AB  - We report a case of haematosalpinx due to torsion of the Fallopian tube with
      congenital abnormal blood supply in a girl. The symptoms were not specific and
      the first diagnosis was a pelvic complex mass like a tumour. The authors discuss
      the possible aetiology.

PMID- 15024685
TI  - Tubo-ovarian abscess in a sexually inactive adolescent patient.
AB  - Tubo-ovarian abscess as a complication of acute salpingitis or salpingo
      oophoritis is very uncommon in pre-menarchal and/or sexually inactive girls. It
      is generally the result of a blood-borne or genitourinary infection. Early
      diagnosis and treatment are essential to prevent future sequelae causing
      infertility. Laparoscopic surgery which minimises postoperative complications
      should be the first option in the treatment of TOA.

PMID- 15024687
TI  - Novel analytical methods applied to type 1 diabetes genome-scan data.
AB  - Complex traits like type 1 diabetes mellitus (T1DM) are generally taken to be
      under the influence of multiple genes interacting with each other to confer
      disease susceptibility and/or protection. Although novel methods are being
      developed, analyses of whole-genome scans are most often performed with
      multipoint methods that work under the assumption that multiple trait loci are
      unrelated to each other; that is, most models specify the effect of only one
      locus at a time. We have applied a novel approach, which includes decision-tree
      construction and artificial neural networks, to the analysis of T1DM genome-scan
      data. We demonstrate that this approach (1) allows identification of all major
      susceptibility loci identified by nonparametric linkage analysis, (2) identifies
      a number of novel regions as well as combinations of markers with predictive
      value for T1DM, and (3) may be useful in characterizing markers in linkage
      disequilibrium with protective-gene variants. Furthermore, the approach outlined
      here permits combined analyses of genetic-marker data and information on
      environmental and clinical covariates.

PMID- 15024686
TI  - Crohn disease: frequency and nature of CARD15 mutations in Ashkenazi and
      Sephardi/Oriental Jewish families.
AB  - Crohn disease (CD), an inflammatory bowel disease, is a multifactorial trait with
      the highest frequency in Ashkenazi Jewish (AJ) individuals of Central European
      origin. Recently, three common predisposing CARD15 mutations (R702W, G908R, and
      1007fs) and a polymorphism (P268S) were identified. To determine whether CARD15
      mutations account for the higher prevalence of CD in AJ individuals, the
      haplotypes and allele frequencies of the common mutations and variants were
      assessed in 219 members of 50 AJ and 53 members of 10 Sephardi/Oriental Jewish
      (SOJ) multiplex families with CD, in 36 AJ patients with sporadic CD, and in 246
      AJ and 82 SOJ controls. A higher frequency of CARD15 mutations was found in AJ
      patients from multiplex families with CD from Central (44.0%) versus Eastern
      (24.0%) Europe, especially for G908R and 1007fs, and in SOJ patients (34.5%)
      compared with AJ (10.1%) or SOJ (5.4%) controls. Contrary to expectation, the
      frequency of the common mutations was slightly lower in AJ patients with CD
      (30.1%) than in SOJ patients with CD (34.5%). The 702W allele was associated with
      both the P268 and 268S alleles. CARD15 mutation frequencies were greater in
      affected sib pairs than in sporadic CD cases but actually decreased in families
      with three or more affected sibs, raising the possibility of genetic
      heterogeneity. Similarly, our linkage evidence on chromosome 16 was diminished in
      the families with three or more affected sibs compared with sib pairs. Screening
      the CARD15 gene for rare variants revealed five novel changes (D113N, D357A,
      I363F, L550V, and N852S) of which N852S occurred only in AJ individuals and may
      be disease predisposing. Also, there was no evidence for increased risk
      associated with the recently described IVS(+158) single-nucleotide polymorphism.
      Although the AJ controls appear to have a higher frequency of CARD15 mutations
      than the SOJ controls, it is unlikely that this difference fully explains the
      excess frequency of CD in the AJ population.

PMID- 15024689
TI  - Power for genetic association studies with random allele frequencies and genotype
      distributions.
AB  - One of the first and most important steps in planning a genetic association study
      is the accurate estimation of the statistical power under a proposed study design
      and sample size. In association studies for candidate genes or in fine-mapping
      applications, allele and genotype frequencies are often assumed to be known when,
      in fact, they are unknown (i.e., random variables from some distribution). For
      example, if we consider a diallelic marker with allele frequencies of 0.5 and 0.5
      and Hardy-Weinberg proportions, the three genotype frequencies are often assumed
      to be 0.25, 0.50, and 0.25, and the statistical power is calculated.
      Unfortunately, ignoring this source of variation can inflate the estimated power
      of the study. In the present article, we propose averaging the estimates of power
      over the distribution of the genotype frequencies to calculate the true estimate
      of power for a fixed allele frequency. For the usual situation, in which allele
      frequencies in a population are not known, we propose placing a prior
      distribution on the allele frequency, taking advantage of any available genotype
      information. This Bayesian approach provides a more accurate estimate of power.
      We present examples for quantitative and qualitative traits in cohort studies of
      unrelated individuals and results from an extensive series of examples that show
      that ignoring the uncertainty in allele frequencies can inflate the estimated
      power of the study. We also present the results from case-control studies and
      show that standard methods may also overestimate power. As discussed in this
      article, the approach of fixing allele frequencies even if they are not known is
      the common approach to power calculations. We show that ignoring the sources of
      variation in allele frequencies tends to result in overestimates of power and,
      consequently, in studies that are underpowered. Software in C is available at
      http://www.ambrosius.net/Power/.

PMID- 15024688
TI  - The western and eastern roots of the Saami--the story of genetic "outliers" told
      by mitochondrial DNA and Y chromosomes.
AB  - The Saami are regarded as extreme genetic outliers among European populations. In
      this study, a high-resolution phylogenetic analysis of Saami genetic heritage was
      undertaken in a comprehensive context, through use of maternally inherited
      mitochondrial DNA (mtDNA) and paternally inherited Y-chromosomal variation. DNA
      variants present in the Saami were compared with those found in Europe and
      Siberia, through use of both new and previously published data from 445 Saami and
      17,096 western Eurasian and Siberian mtDNA samples, as well as 127 Saami and
      2,840 western Eurasian and Siberian Y-chromosome samples. It was shown that the
      "Saami motif" variant of mtDNA haplogroup U5b is present in a large area outside
      Scandinavia. A detailed phylogeographic analysis of one of the predominant Saami
      mtDNA haplogroups, U5b1b, which also includes the lineages of the "Saami motif,"
      was undertaken in 31 populations. The results indicate that the origin of U5b1b,
      as for the other predominant Saami haplogroup, V, is most likely in western,
      rather than eastern, Europe. Furthermore, an additional haplogroup (H1) spread
      among the Saami was virtually absent in 781 Samoyed and Ob-Ugric Siberians but
      was present in western and central European populations. The Y-chromosomal
      variety in the Saami is also consistent with their European ancestry. It suggests
      that the large genetic separation of the Saami from other Europeans is best
      explained by assuming that the Saami are descendants of a narrow, distinctive
      subset of Europeans. In particular, no evidence of a significant directional gene
      flow from extant aboriginal Siberian populations into the haploid gene pools of
      the Saami was found.

PMID- 15024690
TI  - Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are
      associated with alcohol dependence and with brain oscillations.
AB  - Alcoholism is a complex disease with both genetic and environmental risk factors.
      To identify genes that affect the risk for alcoholism, we systematically
      ascertained and carefully assessed individuals in families with multiple
      alcoholics. Linkage and association analyses suggested that a region of
      chromosome 4p contained genes affecting a quantitative endophenotype, brain
      oscillations in the beta frequency range (13-28 Hz), and the risk for alcoholism.
      To identify the individual genes that affect these phenotypes, we performed
      linkage disequilibrium analyses of 69 single-nucleotide polymorphism (SNPs)
      within a cluster of four GABA(A) receptor genes, GABRG1, GABRA2, GABRA4, and
      GABRB1, at the center of the linked region. GABA(A) receptors mediate important
      effects of alcohol and also modulate beta frequencies. Thirty-one SNPs in GABRA2,
      but only 1 of the 20 SNPs in the flanking genes, showed significant association
      with alcoholism. Twenty-five of the GABRA2 SNPs, but only one of the SNPs in the
      flanking genes, were associated with the brain oscillations in the beta
      frequency. The region of strongest association with alcohol dependence extended
      from intron 3 past the 3' end of GABRA2; all 43 of the consecutive three-SNP
      haplotypes in this region of GABRA2 were highly significant. A three-SNP
      haplotype was associated with alcoholism, with P=.000000022. No coding
      differences were found between the high-risk and low-risk haplotypes, suggesting
      that the effect is mediated through gene regulation. The very strong association
      of GABRA2 with both alcohol dependence and the beta frequency of the
      electroencephalogram, combined with biological evidence for a role of this gene
      in both phenotypes, suggest that GABRA2 might influence susceptibility to alcohol
      dependence by modulating the level of neural excitation.

PMID- 15024691
TI  - Mutations in LRP5 or FZD4 underlie the common familial exudative
      vitreoretinopathy locus on chromosome 11q.
AB  - Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder of
      the retinal vascular system. Autosomal dominant FEVR is genetically
      heterogeneous, but its principal locus, EVR1, is on chromosome 11q13-q23. The
      gene encoding the Wnt receptor frizzled-4 (FZD4) was recently reported to be the
      EVR1 gene, but our mutation screen revealed fewer patients harboring mutations
      than expected. Here, we describe mutations in a second gene at the EVR1 locus,
      low-density-lipoprotein receptor-related protein 5 (LRP5), a Wnt coreceptor. This
      finding further underlines the significance of Wnt signaling in the
      vascularization of the eye and highlights the potential dangers of using multiple
      families to refine genetic intervals in gene-identification studies.

PMID- 15024692
TI  - High proportion of mutant osteoblasts is compatible with normal skeletal function
      in mosaic carriers of osteogenesis imperfecta.
AB  - Individuals with mosaicism for the autosomal dominant bone dysplasia osteogenesis
      imperfecta (OI) are generally identified by having more than one affected child.
      The mosaic carriers have both normal and mutant cell populations in somatic and
      germline tissues but are unaffected or minimally affected by the type I collagen
      mutation that manifests clinically in their heterozygous offspring. We determined
      the proportion of mutant osteoblasts in skeletal tissue of two mosaic carriers
      who each have a COL1A1 mutation in a high proportion of dermal fibroblasts. Both
      carriers had normal height and bone histology; the first carrier had normal
      lumbar spine measurements (L1-L4), as determined by dual-energy x-ray
      absorptiometry (Z = +1.17). In cultured cells from the first carrier, studied by
      labeled PCR and single-cell PCR over successive passages, the collagen mutation
      was present in 85% of fibroblasts and 50% and 75% of osteoblasts from her right
      iliac crest and left patella, respectively, with minimal selection. The second
      carrier was studied by PCR amplification of DNA from autopsy paraffin blocks. The
      proportion of heterozygous cells was 40% in calvarium, 65% in tracheal ring, and
      70% in aorta. Thus, in OI, substantially normal skeletal growth, density, and
      histology are compatible with a 40%-75% burden of osteoblasts heterozygous for a
      COL1A1 mutation. These data are encouraging for mesenchymal stem-cell
      transplantation, since mosaic carriers are a naturally occurring model for cell
      therapy.

PMID- 15024694
TI  - Novel truncating mutations in the polyglutamine tract binding protein 1 gene
      (PQBP1) cause Renpenning syndrome and X-linked mental retardation in another
      family with microcephaly.

PMID- 15024695
TI  - Extracellular matrix components in atherosclerotic arteries of Apo E/LDL receptor
      deficient mice: an immunohistochemical study.
AB  - During accelerated vascular remodeling such as in atherosclerosis, the
      composition of the extracellular matrix becomes altered. The matrix components of
      the diseased artery influence cellular processes such as adhesion, migration and
      proliferation. Furthermore, in atherosclerosis, the inability of the cells within
      the lesion to produce a mechanically stable matrix may lead to plaque rupture. In
      this immunohistochemical study of atherosclerotic mice aorta, we have reviewed
      the presence of ECM components with roles in maintaining tissue structure and
      function. These components include osteopontin and COMP as well as the leucine
      rich repeats proteins decorin, PRELP, and fibromodulin. Immunohistochemistry
      demonstrated presence of osteopontin, COMP, decorin, PRELP and fibromodulin in
      lesion areas of ApoE/LDLr deficient mice. Some advanced lesions exhibited areas
      of cartilage-like morphology and were shown to represent cartilage by their
      content of the cartilage specific proteins collagen II and aggrecan. The results
      suggest that cartilage-associated cell/collagen binding ECM proteins may be
      involved in the pathogenesis of atherosclerosis.

PMID- 15024693
TI  - Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.
AB  - Neuroblastoma (NB) is a frequent pediatric tumor for which recurrent somatic
      rearrangements are known. Germline mutations of predisposing gene(s) are
      suspected on the basis of rare familial cases and the association of NB with
      other genetically determined congenital malformations of neural crest-derived
      cells--namely, Hirschsprung disease (HSCR) and/or congenital central
      hypoventilation syndrome (CCHS). We recently identified the paired-like homeobox
      2B (PHOX2B) gene as the major disease-causing gene in isolated and syndromic
      CCHS, which prompted us to regard it as a candidate gene in NB. Here, we report
      on germline mutations of PHOX2B in both a familial case of NB and a patient with
      the HSCR-NB association. PHOX2B, therefore, stands as the first gene for which
      germline mutations predispose to NB.

PMID- 15024696
TI  - Neurotrophin and Trk receptor-like immunoreactivity in the frog gastrointestinal
      tract.
AB  - Nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and
      neurotrophin-3 (NT-3) are members of the neurotrophin family, which is involved
      in the differentiation, growth, repair, plasticity and maintenance of many
      neuronal populations. They act through three tyrosin-kinase (Trk) specific
      receptors: NGF bind to TrkA, BDNF to TrkB and NT3 to TrkC. Despite increasing
      evidence regarding the presence of neurotrophin and their receptors in many
      vertebrate species, in amphibians there are very few data concerning them. Thus,
      the aim of this study was to extend the investigation to the presence of both
      neurotrophins and their Trk receptors in the gut of an anuran amphibian, Rana
      temporaria. In the frog gut NT-3- like immunoreactivity (IR) was observed in both
      the nervous system and endocrine cells of the stomach and intestine, while NGF
      like IR was observed only in the enteric nervous system, and BDNF-like IR in the
      intestinal endocrine cells. TrkA- and TrkB-like IR was detected in both neurons
      and endocrine cells of the intestine, while TrkC-like IR was observed only in
      intestinal neurons. No Trk IR was detected in the stomach. The occurrence of the
      IR to neurotrophins and their receptors in the gut of the frog further confirms
      the well-conserved presence of this family of growth factors and Trk receptors
      during the evolution of vertebrates and suggests their complex involvement in the
      biology of the gastrointestinal neuro-endocrine system.

PMID- 15024697
TI  - Cholinergic, nitrergic and peptidergic (Substance P- and CGRP-utilizing)
      innervation of the horse intestine. A histochemical and immunohistochemical
      study.
AB  - The small and large intestine of adult horses were histochemically and
      immunohistochemically investigated in order to evidence components of the
      intramural nervous system. The general structural organization of the intramural
      nervous system was examined by using Nissl-thionin staining as well as the anti
      neurofilament 200 (NF200) immunoreaction, which demonstrated the presence of
      neurons in the submucous as well as myenteric plexuses. The additional presence
      of subserosal ganglia was shown in the large intestine. Acetylcholinesterase
      (AChEase) activity was observed in both the submucous and myenteric plexuses.
      Localization of acetylcholine-utilizing neurons was also evidenced by
      immunohistochemical reactions for choline acetyltransferase (ChAT) and vesicular
      acetylcholine transporter (VAChT). With both histochemistry and
      immunohistochemistry possible cholinergic nerve fibres were detected in the inner
      musculature. The two possible cholinergic co-mediators Calcitonin Gene-Related
      Peptide (CGRP) and Substance P (SP) have been investigated by an
      immunohistochemical approach. CGRP immunoreactivity was detected in roundish
      nerve cell bodies as well as in nerve fibres of the submucous plexus, whereas SP
      immunoreactivity was evidenced in nerve fibres of the tunica mucosa, in nerve
      cell bodies and fibres of the submucous plexus and in nerve fibres of the
      myenteric plexus. NADPH-diaphorase reactivity, which is linked to the synthesis
      and release of nitric oxide, was detected in nerve cell bodies and nerve fibres
      of both the submucous and myenteric plexuses as well as in a subserosal
      localization of the large intestine. The nitrergic components were confirmed by
      the anti-NOS (nitric oxide synthase) immunoreaction. Results are compared with
      those of other mammals and related to the complex intestinal horse physiology and
      pathophysiology.

PMID- 15024698
TI  - Cells from the inner mass of blastocyst as a source of neural derivates for
      differentiation studies.
AB  - Our results show that cells derived from the inner cell mass (ICM) show a clear
      tendency to differentiate into the neural lineage, showing both cells and
      structures in different degrees of differentiation. Among the experimental
      paradigms used to learn about neural differentiation, there have been several
      lines of investigation on stem cells, including embryonic stem (ES) cells
      isolated from the inner cell mass of embryo and also stem cells derived from
      embryonic carcinoma (EC). In this work, we have used a cellular line obtained
      from the inner cell mass of a blastocyst. The cells were cultured and after
      inoculated subcutaneously in syngenic mice. The neural differentiation was
      predominant, and could be observed both by morphological and immunohistochemical
      methods. It was represented by neural-tubes, neurons and glial cells, as
      expressed by the presence of Microtubule-associated protein-2 (MAP-2) and glial
      fibrilary acidic protein. Moreover, tyrosine hydroxilase positive labelling was
      found in neuron-like cells, which suggest the chatecolaminergic differentiation.
      These results show that isolation of cells from the inner mass of blastocyst
      represents an easy, reproducible and cheap source of neural derivates suitable
      for both in vivo and in vitro differentiation studies.

PMID- 15024699
TI  - Growth performance and histological intestinal alterations in piglets fed dietary
      raw and heated pigeon pea seed meal.
AB  - Histological intestinal villus alterations were studied in piglets fed raw (PM)
      or heated (HPM) pigeon pea seed meal. The trypsin inhibition rate was 99.15% in
      PM and 54.31% HPM. The PM and HPM were added into the basal diet (crude protein;
      176.3 g/kg, gross energy; 4.15 kcal/g, control) at 20% and 40% levels,
      respectively. The diets were formulated in order to adjust protein to 180 g/kg
      and gross energy to about 4.20 kcal/g. The feed intake was not different among
      groups. The daily body weight gain and feed efficiency tended to decrease with
      the increasing PM level, and they decreased significantly in the 40% PM group
      compared with the control group (P < 0.05). However, HPM groups showed a growth
      performance similar to the control. The villus height, cell area and cell mitosis
      tended to decrease with the increasing PM level, and they decreased significantly
      in the 40% PM group compared with the control group (P < 0.05). In HPM group,
      these villus height, cell area and cell mitosis were significantly higher than
      those of the 40% PM group (P < 0.05), and did not show a significant difference
      compared with the control. Compared with the duodenal villus surface of the
      control group, the PM groups had a smooth surface due to flat cells and the HPM
      group showed a rough surface due to protuberated cells. The current histological
      alterations of intestinal villi demonstrate that the villi might be atrophied in
      the piglets fed raw PM due to anti-nutritional factors, resulting in the
      decreased growth performance, and that heating PM might abolish such a harmful
      effect of the anti-nutritional factors on the villus function, resulting in a
      similar growth performance to the control. Raw PM could be incorporated under a
      level of 40%, but heated PM increases the incorporation rate up to the 40% level.

PMID- 15024700
TI  - A truncated isoform of the PP2A B56gamma regulatory subunit reduces irradiation
      induced Mdm2 phosphorylation and could contribute to metastatic melanoma cell
      radioresistance.
AB  - F10, a subline of the B16 mouse melanoma cell line, is itself the parent of the
      more metastatic BL6 line. BL6 cells differ from F10 cells by an alteration of the
      gene encoding the B56gamma regulatory subunit of protein phosphatase 2A (PP2A),
      which results in mRNA encoding a truncated variant of the subunit (deltagamma1).
      Expression of deltagamma 1 protein is detectable only when BL6 cells are
      transplanted into mice and then gamma-irradiated. Recently, B56gamma subunit
      containing PP2A holoenzymes have shown to dephosphorylate Mdm2, a negative
      regulator of p53. Thus, we assessed whether the expression of deltagamma1 affects
      irradiation-induced phosphorylation of Mdm2 and radioresistance of melanoma cells
      by perturbing the regulation of p53. Western blot analyses revealed that
      irradiated COS-7 and NIH3T3 cells stably expressing deltagamma1 showed
      significantly less irradiation-induced Mdm2 phosphorylation. Mdm2 phosphorylation
      reduces the ability of Mdm2 to target p53 for degradation, which probably
      explained why p53 protein levels in NIH3T3 cells expressing deltagamma1 were not
      significantly elevated by irradiation, unlike in wild-type cells. This was also
      true for F10 cells transfected with deltagamma1 (F10deltagamma1) when the cells
      expressed deltagamma1 after being irradiated in vivo. p53 mRNA levels in
      irradiated wild-type and deltagamma 1-expressing cells were both only slightly
      elevated, suggesting that Mdm2 regulates p53 levels by a post-transcriptional
      mechanism. p53-mediated induction of the pro-apoptotic gene encoding Bax was also
      significantly lower in F10deltagamma1 cells irradiated in vivo. Moreover,
      F10deltagamma1 and BL6 cells were less apoptotic than F10 cells when the cells
      were irradiated in vivo. The p53 in F10 cells appears to be as functional as that
      in NIH3T3 cells because irradiation-induced expression of p53-target genes was
      comparable in both cells. Collectively, deltagamma1 appears to reduce irradiation
      induced Mdm2 phosphorylation, which then blocks irradiation-stimulated p53
      accumulation. Defects, such as deltagamma1, in PP2A may thus contribute to
      melanoma cell radioresistance.

PMID- 15024701
TI  - Amplification of CDK4, MDM2, SAS and GLI genes in leiomyosarcoma, alveolar and
      embryonal rhabdomyosarcoma.
AB  - We evaluated amplification and overrepresentation of CDK4, MDM2, GLI and SAS
      genes of the 12q13-15 region, in a group of soft tissue sarcomas including
      leiomyosarcomas (LMS), alveolar rhabdomyosarcomas (ARMS) and embryonal
      (anaplastic and classic variants) rhabdomyosarcomas (ERMS), to ascertain genomic
      alterations and possible differences within histologic subtypes of
      rhabdomyosarcoma (RMS). Quantitative real-time PCR was performed on DNA samples
      from 29 LMS, 9 ARMS, 7 anaplastic ERMS and 6 classic ERMS. Alteration of one or
      more of the 12q13-15 genes was revealed in 13/29 LMS (45%) and 12/22 RMS (54%)
      including 5/9 ARMS (56%), 5/7 anaplastic ERMS (71%) and 2/6 classic ERMS (33%).
      The potential importance of overproduction of protein products in neoplastic
      development, led us also to study a possible high expression of cdk4, mdm2 and
      gli proteins in immunohistochemical staining experiments on paraffin-embedded
      tissue samples of the same cases. Among LMS and RMS most cases with CDK4, MDM2
      and GLI gene alterations also showed a simultaneous high expression of the
      relative protein. In summary, these results indicate that amplification or
      overerepresentation of genes at 12q13-15 region involve both LMS and RMS.
      Moreover these genes alterations reveal predominantly in the alveolar and in the
      anaplastic variant of the embryonal subtype. These two seem to have a more
      similar behavior than anaplastic and classic embryonal that are classified in the
      same subtype.

PMID- 15024702
TI  - Bone growth, modeling and remodeling in a supernumerary metatarsal bone
      associated with segmental gigantism in cutis marmorata telangiectatica congenita.
AB  - Skeletal structure and processes of bone growth, modeling and remodeling were
      studied in a supernumerary metatarsal surgically removed from a 3-year-old boy
      affected by Cutis Marmorata Telangiectatica Congenita (CMTC), associated with
      hypertrophy of the right upper and lower limbs and postaxial hexadactylism of the
      homolateral hand and foot. No other anomalies were observed. The excess of
      periosteal growth, due to congenital anomaly, induced an abnormal development of
      both modeling and remodeling processes. In bone modeling, osteoblast activity on
      the periosteal surface was not paralleled by osteoclast resorption along the wall
      of the medullary canal, and this enormously increased the cortical thickness. In
      bone remodeling, osteoclastic resorption cavities were not refilled by secondary
      Haversian systems, thus inducing a severe bone loss. While the alteration of bone
      growth and modeling can be ascribed to the congenital disease, the unbalanced
      bone remodeling appears mainly to depend on mechanical disuse of the
      supernumerary metatarsal.

PMID- 15024703
TI  - Human saphenous vein and coronary bypass surgery: ultrastructural aspects of
      conventional and "no-touch" vein graft preparations.
AB  - Coronary artery bypass graft surgery (CABG) is routinely used to restore blood
      flow to diseased cardiac muscle due to coronary artery disease. The patency of
      conventional grafts decreases with time, which is due to thrombosis and formation
      of neointima. A primary cause of graft failure is the mechanical damage inflicted
      to the graft during harvesting, including removal of surrounding tissue
      accompanied by high pressure saline distension to overcome vasospasm (both
      causing considerable mechanical trauma). The aim of this study was to compare the
      ultrastructural features of human saphenous vein (SV) grafts harvested
      conventionally and grafts prepared using an atraumatic 'no-touch' harvesting
      technique introduced by Souza (1996). The results of this study showed a better
      preservation of the lumenal endothelium and medial vascular smooth muscle (SM) in
      'no-touch' versus conventional grafts. A 'fast' (within 30 min) response of SM
      cells to conventional harvesting was noted where features of both SM cell
      division and apoptosis were observed. It is concluded that the 'preserved' nature
      of the 'no-touch' aortocoronary SV grafts renders them less susceptible to
      thrombotic and atherosclerotic factors than grafts harvested conventionally.
      These features are suggested to contribute to the improved early patency rate
      described using the no-touch technique of SV harvesting.

PMID- 15024704
TI  - Human articular chondrocytes, synoviocytes and synovial microvessels express
      aquaporin water channels; upregulation of AQP1 in rheumatoid arthritis.
AB  - Recent studies have shown that aquaporin water channels are expressed in human
      Meckel's cartilage. The aim of the present investigation was to determine if
      human articular chondrocytes and synoviocytes express aquaporin 1 (AQP1) water
      channels and to establish if there are any alterations in AQP1 expression in
      osteoarticular disorders such as osteoarthritis (OA) and rheumatoid arthritis
      (RA). Immunohistochemistry was employed semi-quantitatively to compare the
      expression of AQP1 in human chondrocytes derived from normal, OA and RA joints.
      PCR, cloning and sequencing confirmed the presence of AQP1 transcripts in
      chondrocytes. Normal human tissue microarrays including samples of kidney,
      choroid plexus and pancreas were used as positive controls for AQP1 expression.
      In most tissues AQP1 was expressed along endothelial barriers. In the kidney AQP1
      was present in the glomerular capillary endothelium, proximal tubule and
      descending thin limbs. AQP1 was also localized to pancreatic ducts and acini and
      the apical membrane domain of the choroid plexus. Immunohistochemistry showed
      that AQP1 is expressed in synovial micro-vessels, synoviocytes and predominantly
      in chondrocytes located in the deep zone of articular cartilage. Image analysis
      of normal, OA and RA cartilage suggested that AQP1 may be upregulated in RA. This
      is the first report of AQP1 mRNA and protein expression in articular chondrocytes
      and synoviocytes. These findings suggest a potential role for AQP1 and possibly
      other members of the AQP gene family in the movement of extracellular matrix and
      metabolic water across the membranes of chondrocytes and synoviocytes for the
      purposes of chondrocyte volume regulation and synovial homeostasis.

PMID- 15024705
TI  - Involution of seminiferous tubules in aged hamsters: an ultrastructural,
      immunohistochemical and quantitative morphological study.
AB  - In this study, we examined the age-related changes on morphometric parameters and
      ultrastructure of seminiferous tubules, and on the expression of extracellular
      matrix proteins in lamina propria of Syrian hamsters. A significant decrease in
      the percentage of normal tubules and an increase in the percentage of
      hypospermatogenic and arrested maturation tubules was observed with aging. Aged
      animals showed a decrease in tubular diameter, tubular lumen, seminiferous
      epithelium volume and total tubular volume. However, the total length of
      seminiferous tubules was significantly increased with aging. The most important
      ultrastructural changes with aging were the thickening of the lamina propria, the
      presence of diverse abnormalities in the spermiogenesis process, degeneration of
      germ cells, and vacuolization and flattening of Sertoli cells showing abundant
      lipofucsin droplets and residual bodies. Laminin immunoreactivity was found along
      the lamina propria of seminiferous tubules both in young and aged animals.
      Fibronectin immunoreactivity was found along the lamina propria and blood
      vessels. Both laminin and fibronectin total volume of immunostaining per testis
      was increased in aged hamsters. In conclusion, the age-related changes in
      seminiferous tubules of hamster include: a decrease in tubular width and an
      increase in tubular length; widening of the lamina propria caused by a more
      extensive connective matrix between the peritubular cells and the basal membrane;
      and a strong disarrangement of the seminiferous epithelium, including germ cell
      degeneration and important alterations in both spermiogenesis and Sertoli cell
      structure.

PMID- 15024706
TI  - Bcl-2 protein in normal, hyperplastic and neoplastic breast tissues. A metabolite
      of the putative stem-cell subpopulation of the mammary gland.
AB  - This investigation, though initially designed to examine the possible influence
      of the Bcl-2 protein on the node-metastasizing capacity of breast carcinomas, was
      amplified to study the expression of this anti-apoptotic protein in normal breast
      lobules and hyperplastic lesions. We examined paraffin sections of 508 breast
      carcinomas, stained for Bcl-2, estrogen (ER) and progesterone receptors (PgR) and
      epithelial membrane antigen, and occasionally for other antigens as well. Only a
      few cells showing a strong Bcl-2 positivity spotted the tubulo-lobular units of
      normal resting glands, whereas such cells were relatively numerous in atrophic
      lobules, and very scarce in the terminally differentiated lactating breast.
      Columnar and usual types of hyperplasia were exclusively, or almost exclusively,
      composed of Bcl-2(+), ER(+) and PgR(+) cells. The foci of carcinoma in situ and
      those of invasive carcinomas were respectively 83% and 66% positive for Bcl-2 in
      at least 25% of their cells. Even among the invasive carcinomas, Bcl-2(+) cases
      included 83% and 87% of the ER(+) and PgR(+) cases, respectively (p=0.0001).
      Though there was a statistically significant inverse relation between Bcl-2 and
      tumor grade (p=0.0001), no significant association was found between Bcl-2 and
      lymph node stage. In conclusion, we suggest that normal, hyperplastic and
      neoplastic breast epithelial cells expressing the anti-apoptotic protein Bcl-2
      are immature cells that ought to form part of the stem-cell subpopulation, which
      is committed to the development and to the maintenance of the normal gland and
      which gives rise to hyperplastic and neoplastic disorders when its proliferation
      is deregulated. In ductal proliferative changes Bcl-2 assays may be useful for
      diagnostic but not for prognostic purposes.

PMID- 15024707
TI  - p63 expression in benign and malignant breast lesions.
AB  - The p63 gene encodes six protein isoforms. The transactivating isoforms have
      similar actions with p53, while the N-isoforms inhibit transcription activation
      by p53 and transactivating isoforms. p63 is expressed in stratified epithelia and
      in basal cells of the prostate and salivary glands. In mammary epithelium p63 has
      been shown to be expressed only in the myoepithelial layer. In the present study
      we investigated the immunohistochemical expression of p63, in benign and
      malignant breast lesions, and compared it with known myoepithelial cell markers.
      Our material consisted of 140 benign and 126 malignant breast lesions. We used
      the antibodies anti-p63, anti-alpha-smooth muscle actin, anti-S-100 protein and
      anti-cytokeratin 14. In all benign lesions, p63 immunoreactivity was noted in the
      myoepithelial cell layer surrounding the luminal epithelial cells. A less
      continuous peripheral rim of myoepithelial cells was also highlighted with p63
      staining in all situ carcinomas. All invasive breast carcinomas were devoided of
      peripheral p63 staining. Interestingly, strong nuclear p63 immunoreactivity was
      noted in a small fraction (5-15%) of epithelial cells in all cases of
      papillomatosis, in 62.5% of in situ ductal papillary-type carcinomas and in 33.3%
      of invasive papillary carcinomas. Comparable staining was observed with S-100.
      The stromal cells were unreactive to p63. Our findings suggest that p63 is a
      sensitive and specific myoepithelial marker, and may be included in
      immunohistochemical panels aiming to identify myoepithelial cells in problematic
      breast lesions. Regarding papillary neoplasms, it is possible that tumor cells
      acquire and exhibit at least in part a myoepithelial differentiation program.

PMID- 15024708
TI  - Delayed remodeling in the early period of fracture healing in spontaneously
      diabetic BB/OK rats depending on the diabetic metabolic state.
AB  - Several clinical series, analyzing fracture healing in patients with insulin
      dependent type 1 diabetes (IDDM) demonstrated significant incidence of delayed
      union, non-union, and pseudarthrosis. The purpose of this study was to examine
      the detailed histomorphometry and histology of bone formation and remodeling
      during fracture healing depending on the diabetic metabolic state in
      spontaneously diabetic BB/O(ttawa)K(arlsburg) rats, a rat strain that represents
      a close homology to IDDM in man. A standardized fracture model was chosen and
      based on blood-glucose values at the time of surgery (mg%), postoperative blood
      glucose course (mg%) and postoperative insulin requirements (IU/kg), 100
      spontaneously diabetic BB/OK rats were divided into groups with well-compensated
      (n=50, 167+/-77 mg%; 244+/-68 mg%; 1.8+/-1.9 IU/kg) or poorly compensated (n=50,
      380+/-89 mg%; 415+/-80 mg%; 6.0+/-1.0 IU/kg) metabolic state. Fifty LEW.1A rats
      served as the normoglycemic controls (97+/-15 mg%). Ten animals from each group
      were killed 1, 2, 3, 4 and 6 weeks after fracture and specimens were processed
      undecalcified for quantitative histomorphometry and for qualitative light
      microscopy. In terms of bone histomorphometry, within the first four weeks after
      fracture, severe mineralization disorders occurred exclusively in the rats with
      poorly compensated diabetic metabolic states with a significantly decrease of all
      fluorochrome-based parameters of mineralization, apposition, formation and timing
      of mineralization in comparison to the spontaneously diabetic rats with well
      compensated metabolic states and to the control rats. This was confirmed
      histologically. Early fracture healing in the spontaneously diabetic BB/OK rats
      is delayed exclusively in poorly compensated diabetic metabolic states, and 6
      weeks after fracture, histomorphometrically significant deficits in the measured
      and dynamically calculated parameters remain. This study suggests that strictly
      controlled insulin treatment resulting in well-compensated diabetic metabolic
      states will ameliorate the impaired early mineralization and cell differentiation
      disorders of IDDM fracture healing.

PMID- 15024709
TI  - Identification of extraretinal photoreceptors in the teleost Phoxinus phoxinus.
AB  - The existence of cells capable of detecting changes of the photoperiod within the
      deep brain, the so-called deep brain photoreceptors, was proposed in the early
      years of the twentieth century. By using immunocytochemistry with antisera
      against phototransductory proteins on paraffin and vibratome sections, we have
      localized several positive areas in the brain of the teleost Phoxinus phoxinus.
      These areas were restricted to two encephalic regions: the epithalamus and the
      hypothalamus. Immunopositive (rod-opsin- and a-transducin-like) pinealocytes and
      parapinealocytes, as well as some sparse neurons in the habenula, were seen in
      the epithalamus. The immunoreaction of the hypothalamus was represented by a
      transducin-like positive (magnocellular and parvicellular) neurons of the Nucleus
      Preopticus, as well as by a-transducin- and arrestin-like positive fibers
      corresponding to the hypothalamic-hypophyseal tract and a few fibers running
      towards the basal telencephalon. These findings corroborate the data published on
      other teleost fish and fully support the hypothesis of the presence of
      photosensitive cells in the encephalon of lower vertebrates. The labelling with
      antisera against different components of the phototransductory cascade also
      strengthens the idea that such cells employ a biochemical mechanism similar to
      that in the retinal visual photoreceptor cells, rods and cones. Although the
      function is still unclear, the detection of the photoperiod seems to be the most
      likely role for these extraretinal photoreceptors.

PMID- 15024711
TI  - Relationships between stem cells and cancer stem cells.
AB  - Stem cells have been shown to exist in a variety of tissues. Recent studies have
      characterized stem cell gene expression patterns, phenotypes, and potential
      therapeutic uses. One of the most important properties of stem cells is that of
      self renewal. This raises the possibility that some of the clinical properties of
      human tumors may be due to transformed stem cells. Similar signaling pathways may
      regulate self renewal in normal and transformed stem cells. These rare
      transformed stem cells may drive the process of tumorigenesis due to their
      potential for self renewal. There are important ramifications for clinical cancer
      treatment if the growth of solid tumors is at least partially dependent on a
      cancer stem cell population. In the cancer stem cell model, tumor recurrence may
      be due to the non-targeted stem cell compartment repopulating the tumor. If
      cancer stem cells can be prospectively identified and isolated, it should be
      possible to identify therapies that will selectively target these cells.

PMID- 15024712
TI  - New insights into the normal menstrual cycle-regulatory molecules.
AB  - Although the growth and regression of the endometrium is primarily a function of
      the ovarian hormones, recent studies indicate a potential autocrine/paracrine
      role for regulatory molecules. Thus, growth factors, angiogenesis stimulating
      factors and proliferating cell markers are high in the proliferative phase
      endometrium contributing to its regeneration. At the same time, other proteins
      promote endometrial cell survival by preventing extracellular matrix degradation
      and apoptosis. As glandular proliferation persists in the early secretory phase
      of the menstrual cycle, the activity of some proteins stimulating growth remains
      unchanged, but declines significantly thereafter, shifting the balance between
      proliferation and apoptosis in favour of apoptosis. During this period, several
      other regulatory substances are expressed at high levels, suggesting a role in
      endometrial maturation. If, however, implantation of a fertilized ovum fails to
      take place, menstruation occurs probably as the result of matrix
      metalloprotinases which antagononizes the anti-degradation factors (inhibitors of
      metalloproteinases). This review examines the changing endometrial patterns of a
      normal menstrual cycle in relation to these regulatory molecules.

PMID- 15024710
TI  - Targeting WNT, protein kinase B, and mitochondrial membrane integrity to foster
      cellular survival in the nervous system.
AB  - Targeting essential cellular pathways that determine neuronal and vascular
      survival can foster a successful therapeutic platform for the treatment of a wide
      variety of degenerative disorders in the central nervous system. In particular,
      oxidative cellular injury can precipitate several nervous system disorders that
      may either be acute in nature, such as during cerebral ischemia, or more
      progressive and chronic, such as during Alzheimer disease. Apoptotic injury in
      the brain proceeds through two distinct pathways that ultimately result in the
      early externalization of membrane phosphatidylserine (PS) residues and the late
      induction of genomic DNA fragmentation. Degradation of DNA may acutely impact
      cellular survival, while the exposure of membrane PS residues can lead to
      microglial phagocytosis of viable cells, cellular inflammation, and thrombosis in
      the vascular system. Through either independent or common pathways, the
      Wingless/Wnt pathway and the serine-threonine kinase Akt serve central roles in
      the maintenance of cellular integrity and the prevention of the phagocytic
      disposal of cells "tagged" by PS exposure. By selectively governing the activity
      of specific downstream substrates that include GSK-3beta, Bad, and beta-catenin,
      Wnt and Akt serve to foster neuronal and vascular survival and block the
      induction of programmed cell death. Novel to Akt is its capacity to protect cells
      from phagocytosis through the direct modulation of membrane PS exposure.
      Intimately linked to the activation of Wnt signaling and Akt is the maintenance
      of mitochondrial membrane potential and the regulation of Bcl-xL, mitochondrial
      energy metabolism, and cytochrome c release that can lead to specific cysteine
      protease activation.

PMID- 15024713
TI  - Interaction between cell and extracellular matrix in heart disease: multiple
      roles of tenascin-C in tissue remodeling.
AB  - The heart remodels myocardial tissue in physiological and pathological response.
      The cell-extracellular matrix (ECM) interaction provides not only structural and
      mechanical support but also important biological signaling during tissue
      remodeling. Among various ECM molecules, tenascin-C (TNC) is well known as a
      regulator of multiple cellular functions during embryogenesis, wound healing or
      cancer progression. In the heart, TNC appears in several important steps of
      embryonic development such as the initial differentiation of cardiomyocytes or
      coronary vasculo/angiogenesis, but it is not detected in a normal adult
      myocardium. However, TNC is found to re-express after myocardial injury and may
      regulate cellular behavior during tissue remodeling by modulating the attachment
      of cardiomyocytes to connective tissue, by enhancing migration and
      differentiation of myofibroblasts, and by inducing matrix metallo-proteinases.
      TNC also interacts with other ECM molecules and may modulate progression of
      fibrosis. Furthermore, transient and site specific expression of TNC closely
      associated with myocardial injury and inflammation suggests not only its key
      roles during tissue remodeling but also that TNC can be a marker for myocardial
      disease activity.

PMID- 15024714
TI  - Glycosylation and lectins-examples of immunesurveillance and immune evasion.
AB  - Cell surface proteins are posttranslationally modified by tightly regulated
      enzymes of glycosylation. Typical patterns of glycosylation may signal
      pathological situations to the immune system. Here, carbohydrate receptors on the
      surface of cells in the immune system are involved in regulation of effector
      cells. Moreover, some lectins are circulating in the plasma and take part in host
      defense. The code of carbohydrate modifications is impaired in malignant cells
      and yet they are not eliminated. In this review, we focus on recent experimental
      evidence for regulatory functions of lectins and carbohydrate derivatives in the
      immune system and tumours.

PMID- 15024715
TI  - Structural pathways for macromolecular and cellular transport across the blood
      brain barrier during inflammatory conditions. Review.
AB  - This review presents an overview of the highlights of major concepts involving
      the anatomical routes for the transport of macromolecules and the transmigration
      of cellular elements across the blood-brain barrier (BBB) during inflammation.
      The particular focus will include inflammatory leukocytes, neoplastic cells and
      pathogenic microorganisms including specific types of viruses, bacteria and
      yeasts. The experimental animal models presented here have been employed
      successfully by the authors in several independent experiments during the past
      twenty-five years for investigations of pathologic alterations of the BBB after a
      variety of experimentally induced injuries and inflammatory conditions in
      mammalian and non-mammalian animal species. The initial descriptions of
      endothelial cell (EC) vesicles or caveolae serving as mini-transporters of fluid
      substances essentially served as a springboard for many subsequent discoveries
      during the past half century related to mechanisms of uptake of materials into
      ECs and whether or not pinocytosis is related to the transport of these materials
      across EC barriers under normal physiologic conditions and after tissue injury.
      In the mid-1970's, the authors of this review independently applied morphologic
      techniques (transmission electron microscopy-TEM), in conjunction with the plant
      protein tracer horseradish peroxidase (HRP) to investigate macromolecular
      transport structures that increased after the brain and spinal cord had been
      subjected to a variety of injuries. Based on morphologic evidence from these
      studies of BBB injury, the authors elaborated a unique EC system of modified
      caveolae that purportedly fused together forming transendothelial cell channels,
      and later similar EC profiles defined as vesiculo-canalicular or vesiculo-tubular
      structures (VTS, Lossinsky, et al., 1999). These EC structures were observed in
      association with increased BBB permeability of tracers including exogenously
      injected HRP, normally excluded from the intercellular milieu of the CNS.
      Subsequent studies of non-BBB-type tumor ECs determined that the EC VTS and other
      vesicular structures were defined by others as vesiculo-vacuolar organelles
      (VVOs, Kohn et al., 1992; Dvorak et al., 1996). Collectively, these structures
      appear to represent a type of anatomical gateway to the CNS likely serving as
      conduits. However, these CNS conduits become patent only in damaged ECs for the
      passage of macromolecules, and purportedly for inflammatory and neoplastic cells
      as well (Lossinsky et al., 1999). In this review, we focus attention on the
      similarities and differences between caveolae, fused racemic vesicular bundles,
      endothelial tubules and channels (VTS and the VVOs) that are manifest in normal,
      non-BBB-type blood vessels, and in the BBB after injury. This review will present
      evidence that the previous studies by the authors and other researchers
      established a framework for subsequent transmission (TEM), scanning (SEM) and
      high-voltage electron microscopic (HVEM) investigations concerning
      ultrastructural, ultracytochemical and immunoultra-structural alterations of the
      cerebral ECs and the mechanisms of the BBB transport that occurs after CNS
      injury. This review is not intended to include all of the many observations that
      might be included in a general historical overview of the development of the EC
      channel hypothesis, but it will discuss several of the major contributions. We
      have attempted to present some of the structural evidence that supports our early
      contributions and those made by other investigators by highlighting major
      features of these EC structures that are manifest in the injured BBB. We have
      focused on currently established concepts and principles related to mechanisms
      for the transendothelial transport of macromolecules after CNS injury and also
      offer a critical appraisal of some of this literature. Finally, we describe more
      recent concepts of transBBB avenues for viruses, including HIV-1, bacterial and
      mycotic organisms, as well as inflammatory and neoplastic cell adhesion and
      migration across the injured mammalian BBB. Data from studies of EC-related
      adhesion molecules, both from the literature and from the author's experimental
      results and observations made in other laboratories, as well as from personal
      communications underscore the importance of the adhesion molecules in
      facilitating the movement of leukocytic, neoplastic cell and human pathogens
      across the BBB during inflammatory and neoplastic events. Exciting, ongoing
      clinical trials are addressing possible therapeutic intervention in
      neuroinflammatory diseases, including multiple sclerosis, by blocking certain
      glycoprotein adhesion molecules before cells have the ability to adhere to the
      ECs and migrate across the BBB. Approaches whereby inflammation may be reduced or
      arrested using anti-adhesion molecules, by restructuring EC cytoskeletal,
      filamentous proteins, as well as remodeling cholesterol components of the
      modified VTS are discussed in the context of developing future therapies for BBB
      injury and inflammation. Understanding new concepts about the mechanism(s) by
      which inflammatory cells and a variety of pathogenic microorganisms are
      transported across the BBB can be expected to advance our understanding of
      fundamental disease processes. Taken together, the literature and the author's
      experiences during the past quarter of a century, will hopefully provide new
      clues related to the mechanisms of transendothelial cell adhesion and emigration
      across the injured BBB, issues that have been receiving considerable attention in
      the clinical arena. Learning how to chemically modulate the opening and/or
      closure of EC VTS and VVO structural pathways, or junctional complexes prior to
      cellular or microorganism adhesion and breaching the BBB presents challenging new
      questions in modern medicine. Future studies will be critically important for the
      development of therapeutic intervention in several human afflictions including
      traumatic brain and spinal cord injuries, stroke, cancer, multiple sclerosis and
      conditions where the immune system may be compromised including HIV infection,
      infantile and adult meningitis.

PMID- 15024716
TI  - Gastrointestinal stromal tumors: overview of pathologic features, molecular
      biology, and therapy with imatinib mesylate.
AB  - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of
      the gastrointestinal tract. These tumors develop at any site but are most
      commonly reported in the stomach. They originate from the neoplastic
      transformation of the intestinal pacemaker cell, the interstitial cell of Cajal.
      GISTs strongly express the receptor tyrosine kinase KIT and have mutations in the
      KIT gene, most frequently in exon 11 encoding the intracellular juxtamembranous
      region. Expression of KIT is seen in almost all GISTs, regardless of the site of
      origin, histologic appearance, or biologic behavior, and is therefore regarded as
      one of the key diagnostic markers. Distinction from smooth muscle tumors, such as
      leiomyosarcomas, and other mesenchymal tumors is very important because of
      prognostic differences and therapeutic strategies. Predicting the biologic
      behavior of GISTs is often difficult by conventional pathologic examination;
      tumor size and mitotic rate are the most important prognostic indicators. The
      prognostic significance of KIT mutations is controversial and thus far has not
      been clearly linked with biologic behavior. KIT mutations are associated with
      tumor development, and cytogenetic aberrations are associated with tumor
      progression. The pathogenesis of GISTs involves a gain-of-function mutation in
      the KIT proto-oncogene, leading to ligand-independent constitutive activation of
      the KIT receptor. KIT-wild-type GISTs have shown mutually exclusive platelet
      derived growth factor receptor (PDGFR) mutation and activation. The use of
      imatinib mesylate (also known as Gleevec or STI-571) has greatly increased the
      therapeutic efficacy for this otherwise chemotherapy-resistant tumor. GISTs with
      very low levels of KIT expression may respond to imatinib mesylate therapy if the
      receptors are activated by specific mechanisms. KIT-activating mutations fall
      into two groups: the regulatory type and the enzymatic site type. The regulatory
      type of mutation is conserved at the imatinib binding site, whereas the enzymatic
      site mutation has a structurally changed drug-binding site, resulting in drug
      resistance. Resistance to the drug is the major cause of treatment failure in
      cancer therapy, emphasizing the need for researchers to understand KIT signaling
      pathways so as to identify new therapeutic targets. This review summarizes the
      pathologic features of GISTs, recent advances in understanding their molecular
      and biologic features, and therapy with imatinib mesylate.

PMID- 15024717
TI  - Circulating nucleic acids in plasma and serum (CNAPS) and its relation to stem
      cells and cancer metastasis: state of the issue.
AB  - The presence of circulating cell-free nucleic acids has been demonstrated both in
      disease and health. In the last decade, a burst of papers about Circulating
      Nucleic Acids in Plasma and Serum (CNAPS) have been found in the literature,
      showing the scientific interest raised by this phenomenon and their putative
      clinical interest, especially in the field of cancer. Today, the detection of
      extracellular tumor-derived DNA and/or RNA is considered by many authors as a new
      molecular marker for situations such as cancer diagnosis, monitoring the outcome
      of a disease and, even, as a treatment response indicator. Furthermore, in some
      studies it has been suggested a possible role of tumor CNAPS in the development
      of metastasis. Specifically, the hypothesis known as the "genometastasis
      hypothesis" proposes that stem cells might be naturally transfected with dominant
      oncogenes as a result of dissemination of such genes in the plasma. On the other
      hand, current studies concerned with the biology of metastatic cells are
      increasingly being focused on the striking similarities found between these cells
      and stem cells. In this review we intend to expound and integrate two theories
      about metastatization: the "genometastasis hypothesis" and the idea of stem cells
      as cancer stem cells.

PMID- 15024718
TI  - To NO or not to NO: 'where?' is the question.
AB  - Nitric oxide (NO) is a gaseous radical with unique biological functions essential
      for the cardiovascular system, host defense and neuro-transmission. For two
      decades it was thought that NO was able to diffuse freely across relatively long
      distances and to traverse major parts of the cell, if not multiple cell layers.
      However, NO has been proven to be extremely reactive: it reacts with other
      reactive oxygen species, heavy metals, as well as with cysteine and tyrosine
      residues in proteins. In accordance, it is now widely accepted that once NO is
      generated, it is very short-lived and diffuses only over a short distance. This
      urges for the local production of NO and the localization of NO synthases in the
      proximity of their downstream targets. This review discusses the highly organized
      localization of NO synthases, with the endothelial isoform (eNOS) as its main
      focus, since from this synthase most is known about its subcellular localization
      and regulation.

PMID- 15024719
TI  - The system of cerebrospinal fluid-contacting neurons. Its supposed role in the
      nonsynaptic signal transmission of the brain.
AB  - Recent investigations confirm the importance of nonsynaptic signal transmission
      in several functions of the nervous tissue. Present in various periventricular
      brain regions of vertebrates, the system of cerebrospinal fluid (CSF)-contacting
      neurons seems to have a special role in taking up, transforming and emitting
      nonsynaptic signals mediated by the internal and external CSF and intercellular
      fluid of the brain. Most of the CSF-contacting nerve cells send dendritic
      processes into the internal CSF of the brain ventricles or central canal where
      they form terminals bearing stereocilia and a 9+0-, or 9+2-type cilium. Some of
      these neurons resemble known sensory cells of chemoreceptor-type, others may be
      sensitive to the pressure or flow of the CSF, or to the illumination of the brain
      tissue. The axons of the CSF-contacting neurons transmit information taken up by
      dendrites and perikarya to synaptic zones of various brain areas. By forming
      neurohormonal terminals, axons also contact the external CSF space and release
      various bioactive substances there. Some perikarya send their axons into the
      internal CSF, and form free endings there, or synapses on intraventricular
      dendrites, perikarya and/or on the ventricular surface of ependymal cells.
      Contacting the intercellular space, sensory-type cilia were also demonstrated on
      nerve cells situated in the brain tissue subependymally or farther away from the
      ventricles. Among neuronal elements entering the internal CSF-space, the
      hypothalamic CSF-contacting neurons are present in the magnocellular and
      parvicellular nuclei and in some circumventricular organs like the
      paraventricular organ and the vascular sac. The CSF-contacting dendrites of all
      these areas bear a solitary 9 x 2+0-type cilium and resemble chemoreceptors
      cytologically. In electrophysiological experiments, the neurons of the
      paraventricular organ are highly sensitive to the composition of the ventricular
      CSF. The axons of the CSF-contacting neurons terminate not only in the
      hypothalamic synaptic zones but also in tel-, mes- and rhombencephalic nuclei and
      reach the spinal cord as well. The supposed chemical information taken up by the
      CSF-contacting neurons from the ventricular CSF may influence the function of
      these areas of the central nervous system. Some nerve cells of the photoreceptor
      areas form sensory terminals similar to those of the hypothalamic CSF-contacting
      neurons. Special secondary neurons of the retina and pineal organ contact the
      retinal photoreceptor space and pineal recess respectively, both cavities being
      embryologically derived from the 3rd ventricle. The composition of these
      photoreceptor spaces is important in the photochemical transduction and may
      modify the activity of the secondary neurons. Septal and preoptic CSF-contacting
      neurons contain various opsins and other compounds of the phototransduction
      cascade and represent deep encephalic photoreceptors detecting the illumination
      of the brain tissue and play a role in the regulation of circadian and
      reproductive responses to light. The medullo-spinal CSF-contacting neurons
      present in the oblongate medulla, spinal cord and terminal filum, send their
      dendrites into the fourth ventricle and central canal. Resembling
      mechanoreceptors of the lateral line organ, the spinal CSF-contacting neurons may
      be sensitive to the pressure or flow of the CSF. The axons of these neurons
      terminate at the external CSF-space of the oblongate medulla and spinal cord and
      form neurohormonal nerve endings. Based on information taken up from the CSF, a
      regulatory effect on the production or composition of CSF was supposed for
      bioactive materials released by these terminals. Most of the axons of the
      medullospinal CSF-contacting neurons and the magno- and parvicellular
      neurosecretory nuclei running to neurohemal areas (neurohypophysis, median
      eminence, terminal lamina, vascular sac and urophysis) do not terminate directly
      on vessels, instead they form neurohormonal nerve terminals attached by half
      desmosomes on the basal lamina of the external and vascular surface of the brain
      tissue. Therefore, the bioactive materials released from these terminals
      primarily enter the external CSF and secondarily, by diffusion into vessels and
      the composition of the external CSF, may have a modulatory effect on the
      bioactive substances released by the neurohormonal terminals. Contacting the
      intercellular space, sensory-type cilia were also demonstrated on nerve cells
      situated subependymally or farther away from the ventricles, among others in the
      neurosecretory nuclei. Since tight-junctions are lacking between ependymal cells
      of the ventricular wall, not only CSF-contacting but also subependymal ciliated
      neurons may be influenced by the actual composition of the CSF besides that of
      the intercellular fluid of the brain tissue. According to the comparative
      histological data summarised in this review, the ventricular CSF-contacting
      neurons represent the phylogenetically oldest component detecting the internal
      fluid milieu of the brain. The neurohormonal terminals on the external surface of
      the brain equally represent an ancient form of nonsynaptic signal transmission.

PMID- 15024720
TI  - Localization of sex steroid receptors in human skin.
AB  - Sex steroid hormones are involved in regulation of skin development and functions
      as well as in some skin pathological events. To determine the sites of action of
      estrogens, androgens and progestins, studies have been performed during the
      recent years to accurately localize receptors for each steroid hormone in human
      skin. Androgen receptors (AR) have been localized in most keratinocytes in
      epidermis. In the dermis, AR was detected in about 10% of fibroblasts. In
      sebaceous glands, AR was observed in both basal cells and sebocytes. In hair
      follicles, AR expression was restricted to dermal papillar cells. In eccrine
      sweat glands, only few secretory cells were observed to express AR. Estrogen
      receptor (ER) alpha was poorly expressing, being restricted to sebocytes. In
      contrast, ERbeta was found to be highly expressed in the epidermis, sebaceous
      glands (basal cells and sebocytes) and eccrine sweat glands. In the hair
      follicle, ERbeta is widely expressed with strong nuclear staining in dermal
      papilla cells, inner sheath cells, matrix cells and outer sheath cells including
      the buldge region. Progesterone receptors (PR) staining was found in nuclei of
      some keratinocytes and in nuclei of basal cells and sebocytes in sebaceous
      glands. PR nuclear staining was also observed in dermal papilla cells of hair
      follicles and in eccrine sweat glands. This information on the differential
      localization of sex steroid receptors in human skin should be of great help for
      future investigation on the specific role of each steroid on skin and its
      appendages.

PMID- 15024721
TI  - Pathogenetic role of BCL6 translocation in B-cell non-Hodgkin's lymphoma.
AB  - Chromosomal translocation affecting the 3q27 band, where the BCL6 gene is
      localized, is one of the most common genetic abnormalities in non-Hodgkin's
      lymphoma of B-cell type (B-NHL). The translocation occurs within the major
      translocation cluster (MTC) of BCL6, and as the result of translocation either
      one of the three immunoglobulin (Ig) genes or a heterogeneous non-Ig gene is
      juxtaposed to the coding regions of BCL6. On the other hand, somatic
      hypermutation involves the BCL6 gene of not only B-NHL but also B-cells from
      normal individuals. The mutations are clustered within a region of the MTC,
      suggesting that a common molecular mechanism is operating for the two genetic
      lesions of BCL6. The Bcl-6 protein is a transcriptional repressor that is an
      important regulator of lymphoid development and function. The protein is
      preferentially expressed in germinal center (GC) B-cells of normal lymphoid
      tissues as well as in a variety of B-NHL subtypes derived from GC B-cells
      irrespective of whether the BCL6 is rearranged. Although there is no consensus on
      the effect of BCL6 translocation on the clinical outcome of B-NHL, many studies
      coincide in showing that a high-level of BCL6 expression at either or both the
      mRNA and protein levels is a favorable prognostic marker of diffuse large B-cell
      lymphoma. In vitro evidence suggests that non-Ig/BCL6 translocation transiently
      enhances the level of Bcl-6 expression, which may perturb a molecular network
      that controls the differentiation of GC B-cells to Ig-secreting plasma cells,
      thereby predisposing the B-cells to neoplastic transformation.

PMID- 15024722
TI  - Molecular imaging: Bridging the gap between neuroradiology and neurohistology.
AB  - Historically, in vivo imaging methods have largely relied on imaging gross
      anatomy. More recently it has become possible to depict biological processes at
      the cellular and molecular level. These new research methods use magnetic
      resonance imaging (MRI), positron emission tomography (PET), near-infrared
      optical imaging, scintigraphy, and autoradiography in vivo and in vitro. Of
      primary interest is the development of methods using MRI and PET with which the
      progress of gene therapy in glioblastoma (herpes simplex virus-thymidine kinase)
      and Parkinson's disease can be monitored and graphically displayed. The
      distribution of serotonin receptors in the human brain and the duration of
      serotonin-receptor antagonist binding can be assessed by PET. With PET, it is
      possible to localize neurofibrillary tangles (NFTs) and beta-amyloid senile
      plaques (APs) in the brains of living Alzheimer disease (AD) patients. MR
      tracking of transplanted oligodendrocyte progenitors is feasible for determining
      the extent of remyelinization in myelin-deficient rats. Stroke therapy in adult
      rats with subventricular zone cells can be monitored by MRI. Transgene expression
      (beta-galactosidase, tyrosinase, engineered transferrin receptor) can also be
      visualized using MRI. Macrophages can be marked with certain iron-containing
      contrast agents which, through accumulation at the margins of glioblastomas,
      ameliorate the visual demarcation in MRI. The use of near-infrared optical
      imaging techniques to visualize matrix-metalloproteinases and cathepsin B can
      improve the assessment of tumor aggressiveness and angiogenesis-inhibitory
      therapy. Apoptosis could be detected using near-infrared optical imaging
      representation of caspase 3 activity and annexin B. This review demonstrates the
      need for neurohistological research if further progress is to be made in the
      emerging but burgeoning field of molecular imaging.

PMID- 15024723
TI  - Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic
      telangiectasia in France.
AB  - Hereditary hemmorrhagic telangiectasia (HHT, or Osler-Rendu-Weber syndrome) is an
      autosomal dominant disease characterized by arteriovenous malformations,
      affecting 1 out of 10,000 individuals in France. The disease is caused by
      mutations of two genes: ENG and ALK1 (ACVRL1). We screened the coding sequence of
      ENG and ALK1 in 160 unrelated French index cases. A germline mutation was
      identified in 100 individuals (62.5%). A total of 36 mutations were found in ENG,
      including three nonsense mutations, 19 small insertions/deletions leading to a
      frameshift, two inframe deletions, seven missense mutations, and five intronic or
      splice-site mutations. Of the 36 mutations, 33 were novel mutations. A total of
      64 mutations were found in ALK1, including six nonsense mutations, 28 small
      insertions/deletions leading to a frameshift, one inframe deletion, 27 missense
      mutations, and two intronic or splice-site mutations. Of the 64 mutations, 27
      were novel mutations. Mutations were found in most parts of the coding sequence
      for both genes, except ALK1 exon 5 and ENG exons 12 to 14. Missense mutations in
      ALK1 were more frequent in exons 7, 8, and 10. ENG cDNA was sequenced for three
      intronic mutations: c.689+2T>C produced an abnormal transcript excluding exon 5,
      c.1103+3_1103+8del activated a cryptic splice site 22 bp upstream, and c.1428G>A
      produced two abnormal transcripts, one including intron 11 and the other
      excluding exon 10. Although most of the mutations were private, some recurrent
      mutations in ALK1 were of particular interest. Mutation c.1112_1113dupG
      (p.Gly371fsX391) was found in 17 unrelated individuals sharing a common
      haplotype, strongly suggesting a founder effect related to the concentration of
      patients previously reported in a specific French region (Rhone-Alpes). Three
      missense mutations involved the same codon: c.1231C>T (p.Arg411Trp), c.1232G>C
      (p.Arg411Pro), and c.1232G>A (p.Arg411Gln) were found in seven, two, and one
      patients, respectively. Haplotype analysis was in favor of both a founder effect
      and a mutation hot-spot.

PMID- 15024724
TI  - Variant late infantile neuronal ceroid lipofuscinosis in a subset of Turkish
      patients is allelic to Northern epilepsy.
AB  - Childhood-onset neuronal ceroid lipofuscinoses (NCL) are a group of autosomal
      recessive progressive encephalopathies characterized by the accumulation of
      autofluorescent material in various tissues, notably in neurons. Based on
      clinical features, the country of origin of patients, and the molecular genetic
      background of the disorder, at least seven different forms are thought to exist.
      Northern epilepsy is a novel form of NCL so far described only in Finland, where
      all patients are homozygous for a missense mutation in the CLN8 gene. A variant
      form of late infantile NCL (vLINCL) present in Turkish patients has been
      considered a distinct clinical and genetic entity among the NCL, the underlying
      gene (CLN7) being unknown. Recently, we reported homozygosity over the Northern
      epilepsy CLN8 gene region on 8p23 in four out of five Turkish vLINCL families
      studied. However, no common mutation in CLN8 was found in these families. We have
      now extended the Turkish vLINCL family panel to 18 families, of which only one is
      nonconsanguineous. Nine families were excluded from CLN8 by lack of homozygosity.
      In the remaining families, four CLN8 gene mutations were identified indicating
      that in a subset of patients with Turkish vLINCL, the disorder is allelic to
      Northern epilepsy. There is no apparent genotype-phenotype correlation among the
      Turkish patients with CLN8 mutations, although their phenotype is distinct from
      that of Finnish Northern epilepsy patients. The molecular genetic background of
      the Turkish vLINCL families not linked to CLN8 remains to be clarified.

PMID- 15024725
TI  - Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity,
      refinement of the clinical definition, and genotype-phenotype correlations as a
      strategy for molecular diagnosis.
AB  - Leber congenital amaurosis (LCA) is the earliest and most severe form of all
      inherited retinal dystrophies, responsible for congenital blindness. Disease
      associated mutations have been hitherto reported in seven genes. These genes are
      all expressed preferentially in the photoreceptor cells or the retinal pigment
      epithelium but they are involved in strikingly different physiologic pathways
      resulting in an unforeseeable physiopathologic variety. This wide genetic and
      physiologic heterogeneity that could largely increase in the coming years,
      hinders the molecular diagnosis in LCA patients. The genotyping is, however,
      required to establish genetically defined subgroups of patients ready for
      therapy. Here, we report a comprehensive mutational analysis of the all known
      genes in 179 unrelated LCA patients, including 52 familial and 127 sporadic
      (27/127 consanguineous) cases. Mutations were identified in 47.5% patients.
      GUCY2D appeared to account for most LCA cases of our series (21.2%), followed by
      CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1.7%), and CRX
      (0.6%). The clinical history of all patients with mutations was carefully
      revisited to search for phenotype variations. Sound genotype-phenotype
      correlations were found that allowed us to divide patients into two main groups.
      The first one includes patients whose symptoms fit the traditional definition of
      LCA, i.e., congenital or very early cone-rod dystrophy, while the second group
      gathers patients affected with severe yet progressive rod-cone dystrophy.
      Besides, objective ophthalmologic data allowed us to subdivide each group into
      two subtypes. Based on these findings, we have drawn decisional flowcharts
      directing the molecular analysis of LCA genes in a given case. These flowcharts
      will hopefully lighten the heavy task of genotyping new patients but only if one
      has access to the most precise clinical history since birth.

PMID- 15024726
TI  - Identification of a novel candidate gene, CASC2, in a region of common allelic
      loss at chromosome 10q26 in human endometrial cancer.
AB  - Allelic deletions, which are suggestive for the presence of tumor suppressor
      genes, represent a common event in endometrial cancer (EC). Previous loss-of
      heterozygosity studies for human chromosome 10q identified a candidate deletion
      interval at 10q25-q26, which we further narrowed to a 160-kb region at 10q26,
      bounded by markers D10S1236 and WIAF3299. Using a positional candidate approach,
      we identified three alternative transcripts of a novel human gene, CASC2 (cancer
      susceptibility candidate 2; formely C10orf5). One of such transcripts, CASC2a,
      encodes a short protein of 102 amino acids with no similarity to any other known
      gene product. Three (7%) CASC2a mutations were identified in tumor DNA from 44 EC
      patients. While c.-156G>T and c.22C>T (p.Pro8Ser) are sequence variants with
      unknown functional significance, c.84delA is a mutation with a truncation effect
      on the predicted protein (p. Asn28fsX50). Expression studies by real-time RT-PCR
      on several normal and tumor cells revealed that CASC2a mRNA is downregulated in
      cancer, suggesting that it may act as a potential tumor suppressor gene. The very
      low mutation rate seems to also indicate that inactivation of CASC2a might
      probably be due to mechanisms different from genetic alterations.

PMID- 15024727
TI  - Genetically heterogeneous selective intestinal malabsorption of vitamin B12:
      founder effects, consanguinity, and high clinical awareness explain aggregations
      in Scandinavia and the Middle East.
AB  - Selective intestinal malabsorption of vitamin B(12) causing juvenile
      megaloblastic anemia (MGA; MIM# 261100) is a recessively inherited disorder that
      is believed to be rare except for notable clusters of cases in Finland, Norway,
      and the Eastern Mediterranean region. The disease can be caused by mutations in
      either the cubilin (CUBN; MGA1; MIM# 602997) or the amnionless (AMN; MIM# 605799)
      gene. To explain the peculiar geographical distribution, we hypothesized that
      mutations in one of the genes would mainly be responsible for the disease in
      Scandinavia, and mutations in the other gene in the Mediterranean region. We
      studied 42 sibships and found all cases in Finland to be due to CUBN (three
      different mutations) and all cases in Norway to be due to AMN (two different
      mutations), while in Turkey, Israel, and Saudi Arabia, there were two different
      AMN mutations and three different CUBN mutations. Haplotype evidence excluded
      both CUBN and AMN conclusively in five families and tentatively in three
      families, suggesting the presence of at least one more gene locus that can cause
      MGA. We conclude that the Scandinavian cases are typical examples of enrichment
      by founder effects, while in the Mediterranean region high degrees of
      consanguinity expose rare mutations in both genes. We suggest that in both
      regions, physician awareness of this disease causes it to be more readily
      diagnosed than elsewhere; thus, it may well be more common worldwide than
      previously thought.

PMID- 15024728
TI  - Genetic variants in a haplotype block spanning IDE are significantly associated
      with plasma Abeta42 levels and risk for Alzheimer disease.
AB  - Risk for late onset Alzheimer disease (LOAD) and plasma amyloid beta levels
      (Abeta42; encoded by APP), an intermediate phenotype for LOAD, show linkage to
      chromosome 10q. Several strong candidate genes (VR22, PLAU, IDE) lie within the 1
      lod support interval for linkage. Others have independently identified haplotypes
      in the chromosome 10q region harboring IDE that show highly significant
      association with intermediate AD phenotypes and with risk for AD. To pursue these
      associations, we analyzed the same haplotypes for association with plasma Abeta42
      in 24 extended LOAD families and for association with LOAD in two independent
      case-control series. One series (MCR, 188 age-matched case-control pairs) did not
      show association (p=0.64) with the six haplotypes in the 276-kb region spanning
      three genes (IDE, KNSL1, and HHEX) previously shown to associate with LOAD. The
      other series (MCJ, 109 age-matched case-control pairs) showed significant
      (p=0.003) association with these haplotypes. In the MCJ series, the H4 (odds
      ratio [OR]=5.1, p=0.003) and H2(H7) haplotypes (OR=0.60, p=0.04) had the same
      effects previously reported. In this series, the H8 haplotype (OR=2.7, p=0.098)
      also had an effect similar as in one previous case control series but not in
      others. In the extended families, the H8 haplotype was associated with
      significantly elevated plasma Abeta42 (p=0.02). In addition, the H5(H10)
      haplotype, which is associated with reduced risk for AD in the other study is
      associated with reduced plasma Abeta42 (p=0.007) in our family series. These
      results provide strong evidence for pathogenic variant(s) in the 276-kb region
      harboring IDE that influence intermediate AD phenotypes and risk for AD.

PMID- 15024729
TI  - Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and
      diverse mutational mechanisms.
AB  - Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane
      conductance regulator gene (CFTR/ABCC7). Despite the extensive and enduring
      efforts of many CF researchers over the past 14 years, up to 30% of disease
      alleles still remain to be identified in some populations. It has long been
      suggested that gross genomic rearrangements could account for these unidentified
      alleles. To date, however, only a few large deletions have been found in the CFTR
      gene and only three have been fully characterized. Here, we report the first
      systematic screening of the 27 exons of the CFTR gene for large genomic
      rearrangements, by means of the quantitative multiplex PCR of short fluorescent
      fragments (QMPSF). A well-characterized cohort of 39 classical CF patients
      carrying at least one unidentified allele (after extensive and complete screening
      of the CFTR gene by both denaturing gradient gel electrophoresis and denaturing
      high-performance liquid chromatography) participated in this study. Using QMPSF,
      some 16% of the previously unidentified CF mutant alleles were identified and
      characterized, including five novel mutations (one large deletion and four
      indels). The breakpoints of these five mutations were precisely determined,
      enabling us to explore the underlying mechanisms of mutagenesis. Although non
      homologous recombination may be invoked to explain all five complex lesions, each
      mutation appears to have arisen through a different mechanism. One of the indels
      was highly unusual in that it involved the insertion of a short 41 bp sequence
      with partial homology to a retrotranspositionally-competent LINE-1 element. The
      insertion of this ultra-short LINE-1 element (dubbed a "hyphen element") may
      constitute a novel type of mutation associated with human genetic disease.

PMID- 15024730
TI  - Genetic variants of ABCA1 modify Alzheimer disease risk and quantitative traits
      related to beta-amyloid metabolism.
AB  - Linkage studies have provided evidence that one or more loci on chromosome 9q
      influence Alzheimer disease (AD). The gene encoding the ATP-binding cassette A1
      transporter (ABCA1) resides within proximity of previously identified linkage
      peaks and represents a plausible biological candidate for AD due to its central
      role in cellular lipid homeostasis. Several single nucleotide polymorphisms
      (SNPs) spanning ABCA1 have been genotyped and haplotype-based association
      analyses performed in four independent case-control samples, consisting of over
      1,750 individuals from three European populations representing both early and
      late-onset AD. Prominent effects were observed for a common (H2) and rarer
      haplotype (H5) that were enriched in AD cases across studied populations (odds
      ratio [OR] 1.59, 95% confidence interval [CI] 1.36-1.82; P<0.00001 and OR 2.90;
      95% CI 2.54-3.27; P<0.00001, respectively). Two other common haplotypes in the
      studied region (H1 and H3) were significantly under-represented in AD cases,
      suggesting that they may harbor alleles that decrease disease risk (OR 0.79, 95%
      CI 0.64-0.94; P=0.0065 and OR 0.70, 95% CI 0.46-0.93; P=0.011, respectively).
      While findings were significant in both early and late-onset samples, haplotype
      effects were more distinct in early-onset materials. For late-onset samples,
      ancillary evidence was obtained that both single marker alleles and haplotypes of
      ABCA1 contribute to variable cerebrospinal fluid tau and beta amyloid (Abeta42)
      protein levels, and brain Abeta load. Results indicate that variants of ABCA1 may
      affect the risk of AD, providing further support for a genetic link between AD
      and cholesterol metabolism.

PMID- 15024731
TI  - Rapid detection of subtelomeric deletion/duplication by novel real-time
      quantitative PCR using SYBR-green dye.
AB  - Telomeric chromosome rearrangements may cause mental retardation, congenital
      anomalies, miscarriages, and hematological malignancies. Automated detection of
      subtle deletions and duplications involving telomeres is essential for high
      throughput screening procedures, but impractical when conventional cytogenetic
      methods are used. Novel real-time PCR quantitative genotyping of subtelomeric
      amplicons using SYBR-green dye allows high-resolution screening of single copy
      number gains and losses by their relative quantification against a diploid
      genome. To assess the applicability of the technique in the screening and
      diagnosis of subtelomeric imbalances, we describe here a blinded study in which
      DNA from 20 negative controls and 20 patients with known unbalanced cytogenetic
      abnormalities involving at least one or more telomeres were analyzed using a
      novel human subtelomere-specific primer set, producing altogether 86 amplicons,
      in the SYBR-green I-based real-time quantitative PCR screening approach.
      Screening of the DNA samples from 20 unrelated controls for copy number
      polymorphism do not detect any polymorphism in the set of amplicons, but single
      copy-number gains and losses were accurately detected by quantitative PCR in all
      patients, except the copy number alterations of the subtelomeric p-arms of the
      acrocentric chromosomes in two cases. Furthermore, a detailed mapping of the
      deletion/translocation breakpoint was demonstrated in two cases by novel real
      time PCR "primer-jumping." Because of the simplicity and flexibility of the SYBR
      green I-based real-time detection, the primer-set can easily be extended, either
      to perform further detailed molecular characterization of breakpoints or to
      include amplicons for the detection and/or analysis of syndromes that are
      associated with genomic copy number alterations, e.g., deletion/duplication
      syndromes and malignant cancers.

PMID- 15024733
TI  - Rapid identification of female carriers of DMD/BMD by quantitative real-time PCR.
AB  - Recently developed PCR systems offer online-monitoring of amplification and allow
      simple and reliable DNA quantification. We have used the LightCycler system to
      develop a simple and rapid method for direct identification of female carriers of
      deletions and duplications in the dystrophin gene. The challenge resides in the
      ability to identify the presence of a deleted or duplicated allele over the
      background contributed by the normal allele. Quantification is based on the
      determination of the ratio between potentially deleted/duplicated dystrophin
      exons and non-deleted/-duplicated reference exons using the unspecific dsDNA-dye
      SYBRgreen I. In a retrospective study, we evaluated our method in female
      relatives of DMD/BMD patients with known carrier status by comparative analysis
      of deleted or duplicated versus non-deleted/-duplicated exons. Carrier status was
      accurately attributed in 100% of cases, the mean ratios being 0.52+/-0.12 for
      deletion carriers (expected value: 0.5) and 1.56+/-0.18 for duplication carriers
      (expected value: 1.5) vs. 1.022+/-0.17 for non-carriers (expected value: 1.0).
      The method proved to be simple, rapid, reliable, and cost-effective. It may be
      used for direct determination of deletions/duplications in potential DMD/BMD
      carriers and may easily be adapted for other genetic conditions involving
      deletions and duplications.

PMID- 15024732
TI  - Analysis of the allele-specific expression of the mismatch repair gene MLH1 using
      a simple DHPLC-Based Method.
AB  - Quantitative measures of allele-specific gene expression allow the indirect
      detection of mutations or sequence variants in regulatory elements or in other
      non-coding regions that may result in significant physiological or pathological
      changes of gene expression and may contribute to Mendelian or multifactorial
      disorders. We have devised a simple method, based on RT-PCR and single nucleotide
      primer extension (SNuPE) with unlabelled dideoxynucleotides, followed by DHPLC
      (denaturing high performance liquid chromatography). We established optimal
      conditions for separation of the extended products corresponding to the alleles
      of the c.655A>G (p.Ile219Val) SNP, which is the most frequent exonic polymorphism
      of MLH1. We then genotyped 99 unrelated control subjects and measured the allele
      specific MLH1 expression in the 40 heterozygous controls found in this group.
      This method allowed us to define a narrow range of normal biallelic expression of
      MLH1, each allele contributing between 44.7% and 55.3% of the total expression.
      We then measured the allele-specific expression in hereditary nonpolyposis
      colorectal cancer (HNPCC) patients with MLH1 mRNAs bearing different stop-codon
      or frame-shift mutations, or in-frame deletions, in order to detect the effects
      of nonsense-mediated mRNA decay (NMD). Defects that induce mRNA instability were
      identified unambiguously and the data were consistent with current models of NMD.
      This study provides a sensitive tool to identify indirectly MLH1 defects that may
      escape detection in genomic DNA screenings but result in a quantitative change at
      the mRNA level.

PMID- 15024734
TI  - Importance of standard nomenclature for SMN1 small intragenic ("subtle")
      mutations.

PMID- 15024737
TI  - Identification of four novel COL10A1 missense mutations in schmid metaphyseal
      chondrodysplasia: further evidence that collagen X NC1 mutations impair trimer
      assembly.
AB  - Schmid metaphyseal chondrodysplasia (SMCD) is an autosomal dominant disorder
      affecting the growth plate cartilage of long bones caused by heterozygous
      mutations in the gene for collagen X (COL10A1), a short-chain collagen expressed
      by hypertrophic chondrocytes of growth plate cartilage. In this paper we analyzed
      six unrelated patients clinically determined as affected by SMCD, and
      characterized four missense mutations, c.52G>A (p.G18R), c.1744T>G (p.Y582D),
      c.1792T>G (p.Y598D) and c.1958A>C (p.Q653P). These mutations were clustered in
      the two regions of the collagen X protein shown to contain all previous SMCD
      mutations; the signal sequence cleavage site (p.G18R), or the C-terminal NC1
      trimerization domain (p.Y582D, p.Y598D and p.Q653P). To determine the functional
      effect of the mutations we produced engineered p.Y582D, p.Y598D and p.Q653P cDNA
      and expressed these in vitro. Our data showed that while the wild-type collagen X
      assembled in vitro into trimers that were stable to SDS-PAGE analysis, p.Y582D
      (the most N-terminal of the SMCD NC1 mutations described), p.Q653P, and the
      previously analyzed p.Y598D impair collagen X trimerization. However, in two
      patients no mutations were detected despite complete sequence analysis of the
      COL10A1 coding region, the exon-intron splice consensus sequences and the 500bp
      gene promoter region. Heterozygosity for known polymorphisms ruled out major
      COL10A1 gene deletions and Southern analysis excluded major rearrangements. The
      data suggest that in these two patients, SMCD results from mutations at another
      gene locus. No mutations were detected in RMRP, the gene for cartilage-hair
      hypoplasia that has phenotypic overlap with SMCD.

PMID- 15024738
TI  - Biochemical characterization of two GALK1 mutations in patients with
      galactokinase deficiency.
AB  - Galactokinase (GALK1) deficiency is an autosomal recessive disorder, which causes
      cataract formation in children not maintained on a lactose-free diet.
      Galactokinase deficiency results from mutation in the GALK1 gene mapped on 17q24.
      Since GK1 cDNA was cloned about 20 mutations (prevalently deletions and missense)
      have been reported to date. Most of these reported mutations are confined to
      single families, and only one of them, P28T, has been referred as the founder
      Romani mutation. In this paper we report two novel missense mutations in GALK1
      gene, identified in two unrelated patients with galactokinase deficiency. One
      mutation, g.575G>A, substitutes a valine for a methionine at amino acid 32
      (p.V32M), while the other mutation, g.2839G>A, results in the arginine to
      glutamine substitution p.R239Q (GenBank sequence L76927). Biochemical studies
      demonstrate that these mutations led to a drastic modification in GALK activity
      when individual mutant cDNAs were expressed in an E. coli system. These findings
      indicate the pathogeneticity of these mutations causing GALK deficiency.

PMID- 15024739
TI  - Molecular analysis of the APC and MYH genes in Czech families affected by FAP or
      multiple adenomas: 13 novel mutations.
AB  - Familial adenomatous polyposis (FAP) is an autosomal dominant predisposition to
      colorectal cancer and is caused by germline mutations in the adenomatous
      polyposis coli gene. The most prominent clinical manifestation is the presence of
      hundreds to thousands of colorectal polyps. A milder phenotype is found in
      patients affected with AFAP/ multiple adenomas. We screened the entire APC coding
      region using the combination of DGGE, PTT and direct sequencing and identified
      causative mutations in 52 of 77 patients. Thirteen of the mutations found were
      novel. In addition, we also tested 21 APC mutation/negative probands for the two
      most common mutations in the MYH gene. Four patients showed neither dominant
      transmission of the disease nor evidence of APC mutations. In one of them the
      most common biallelic germline mutation in the MYH gene was detected.
      Correlations between the localization of germline mutations and clinical
      manifestations of the diseases are discussed.

PMID- 15024740
TI  - Novel TSC2 mutations and decreased expression of tuberin in cultured tumor cells
      with an insertion mutation.
AB  - Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized
      by hamartomas in many organs. Two genes responsible for TSC, TSC1 and TSC2, were
      recently identified. TSC1 and TSC2 encode the proteins hamartin and tuberin,
      respectively, and 337 different mutations have been reported in these genes thus
      far. Here, we report six novel TSC2 mutations including one missense mutation,
      two nonsense point mutations, two frameshifts, and an insertion mutation. The
      insertion mutation is unique because of its location at an exon/intron boundary
      that results in triplication of a 34-bp sequence. Cultured tumor cells from the
      patient with this insertion mutation exhibited a decreased level of tuberin as
      revealed by Western blotting, suggesting that the mRNA of TSC2 is not translated
      as efficiently or the translated protein exhibits reduced stability. Five novel
      polymorphisms of TSC2 were also identified. As previously reported, the missense
      mutations were located in the GTPase activating protein-related domain of TSC2
      encoded in exons 34-38. No TSC1 mutations were identified in the present
      subjects.

PMID- 15024741
TI  - BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian
      cancer in the Czech Republic.
AB  - Germline mutations in BRCA1 and BRCA2 account for majority of hereditary breast
      and ovarian cancer. The complete coding sequence analysis of both genes was
      carried out in 197 breast/ovarian cancer patients from high-risk families and 53
      patients with sporadic breast/ovarian cancer. In summary, 59 mutations (16
      different) in BRCA1 and 29 mutations (17 different) in BRCA2 were identified in
      unrelated breast and/or ovarian index cases. Using the BIC Database numbering,
      the most frequently found mutations in BRCA1 were c.5385dupC (22 cases),
      c.3819_3823delGTAAA (8 cases) and c.300T>G (6 cases). The most frequently found
      mutations in BRCA2 were c.8138_8142delCCTTT (7 cases) and c.8765_8766delAG (7
      cases). Altogether, these 5 mutations represented 56.8% of all detected
      mutations. A broad spectrum of other mutations was detected including four novel
      mutations (c.2881delA in BRCA1; and c. 6677_6678delAA, c.6982dupT and
      c.8397_8400dupTGGG in BRCA2). Deleterious mutations were found in 80 (40.6%) of
      197 high risk-families, in 6 (37.5%) of 16 patients with sporadic bilateral
      breast, ovarian or both cancers and in 2 (6.2%) of 32 women with sporadic early
      onset unilateral breast cancer. No mutation was detected in 5 cases of sporadic
      early-onset unilateral ovarian cancer.

PMID- 15024742
TI  - Wilson disease: novel mutations in the ATP7B gene and clinical correlation in
      Brazilian patients.
AB  - Wilson disease (WD) is a rare inherited autosomal recessive disorder caused by a
      defect in a metal transporting P-type ATPase, resulting in copper overload in
      various tissues and cells. The aim was to assess both the phenotype in Brazilian
      WD patients and the corresponding ATP7B genotype. Sixty subjects belonging to 46
      pedigrees diagnosed as WD were included in this study. Direct sequencing of all
      21 exons within ATP7B and their flanking introns was performed. Demographic,
      clinical, laboratory and histopathological data at the time of diagnosis were
      obtained. We identified twenty-five mutations, twelve of them reported for the
      first time. The c.3402delC mutation had the highest allelic frequency (30.8%),
      followed by the c.2123T>C (p.L708P) (16.7%). Exons 8 and 15 were the site of
      62.5% of the mutations. The common European mutation c.3207C>A (p.H1069Q) was not
      present at all. Phenotype varied greatly among individuals with the same ATP7B
      genotype. Our data confirm the heterogeneity of ATP7B genotype in Brazilian WD
      patients. The mutational spectrum is compatible with the Brazilian history of
      Mediterranean immigration; however, new mutations, and different frequencies and
      phenotype associated with the previously known mutations characterize this
      population. Exons 8 and 15 should be preferentially screened in WD cases from
      Brazil. Phenotype variation among subjects with the same ATP7B genotype suggests
      that modifying factors play an additional role in the pathogenesis of WD.

PMID- 15024743
TI  - Identification of the bruton tyrosine kinase (BTK) gene mutations in 20
      Australian families with X-linked agammaglobulinemia (XLA).
AB  - X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in
      the Bruton tyrosine kinase (BTK) gene. Twenty Australian patients with an XLA
      phenotype, from 15 unrelated families, were found to have 14 mutations. Five of
      the mutations were previously described c.83G>A (p.R28H), c.862C>T (p.R288W),
      c.904G>A (p.R302G), c.1535T>C (p.L512P), c.700C>T (p.Q234X), while nine novel
      mutations were identified: four missense c.82C>A (p.R28S), c.494G>A (p.C165Y),
      c.464G>A (p.C155Y), c.1750G>A (p.G584E), one deletion c.142_144delAGAAGA
      (p.R48_G50del), and four splice site mutations c.241-2A>G, c.839+4A>G, c.1350
      2A>G, c.1566+1G>A. Carrier analysis was performed in 10 mothers and 11 female
      relatives. The results of this study further support the notion that molecular
      genetic testing represents an important tool for definitive and early diagnosis
      of XLA and may allow accurate carrier status and prenatal diagnosis.

PMID- 15024745
TI  - Genetic and biochemical analyses of Israeli osteogenesis imperfecta patients.
AB  - Osteogenesis imperfecta (OI) is clinically characterized by abnormal bone
      fragility, with most patients harboring heterozygote germline mutations in the
      COL1A1 or COL1A2 genes that encode the chains of type I procollagen, the major
      protein in bone. More than 250 mutations in both genes in OI patients have been
      reported, mostly missense mutations affecting glycine residues in the triple
      helical domains of the two chains. These mutations disrupt protein folding and
      structure, and their effects often can be detected by the analysis of proteins
      synthesized but cultured fibroblasts or, less often, osteoblasts. In this study,
      mutational analysis of all the COL1A1 and part of the COL1A2 was performed using
      exon-specific PCR amplification followed by denaturing gradient gel
      electrophoresis (DGGE) analysis and complemented by DNA sequencing in 57 Israeli
      OI patients from 55 unrelated families. Protein analysis was also performed using
      cultured fibroblasts obtained from a subset of these OI patients. Of 57 OI
      patients analyzed, 35 had OI type 1, 12 has OI type III, 8 had OI type IV, and 2
      had OI type II. Fourteen different pathogenic mutations (10 novel) were
      identified in the COL1A1 gene: 3 missense, 5 nonsense, 3 insertion/deletion
      frameshift, 2 splice junction mutations, and 1 in frame deletion. We conclude
      that COL1A1 mutations underlie a subset of Israeli OI patients, that most
      commonly in OI type I, the mutations are contained within the COL1A1 gene, and
      that there are no predominant mutations in Jewish OI patients. Lastly, the use of
      protein analyses complements genetic analyses.

PMID- 15024744
TI  - The west side story: MEFV haplotype in Spanish FMF patients and controls, and
      evidence of high LD and a recombination "hot-spot" at the MEFV locus.
AB  - Mutations at the MEFV gene cause, with various degrees of penetrance, familial
      Mediterranean fever (FMF). This disease is more prevalent in the Middle East than
      elsewhere, and most studies have focused on those populations. However, FMF
      occurs also in the Western Mediterranean and these populations should be taken
      into account for a complete view of FMF. We have analyzed intragenic MEFV SNPs in
      Spanish and Chueta (descendants of converted Jews) FMF patients and controls, and
      this constitutes the first systematic survey of normal MEFV SNP haplotype
      structure and variability. Our findings have allowed us to systematize the
      nomenclature of MEFV haplotypes and show that there is strong linkage
      disequilibrium (LD) at the MEFV locus and an intragenic recombination hot spot.
      The high local LD, regardless the recombination hot spot, is responsible for the
      limited diversity of the MEFV control haplotypes found in the Spanish population
      and it suggests that it may be a common feature to all Mediterranean populations.
      The MEFV mutation spectrum in Spain is quite diverse, and similar to those of
      France and Italy. On the contrary, the Chueta spectrum was poorer and closer to
      that of North African Jews, suggesting a direct connection with the Jewish
      diaspora.

PMID- 15024747
TI  - HAMP gene mutation c.208T>C (p.C70R) identified in an Italian patient with severe
      hereditary hemochromatosis.
AB  - Hepcidin is a recently identified hormone peptide involved in regulation of iron
      homeostasis. HAMP gene mutations have been described to date in five families
      with iron overload. We have identified the c.208T>C (p.C70R) mutation in the HAMP
      gene in a patient affected by a severe form of hereditary hemochromatosis. The
      variant, occurring in a highly conserved amino acid, disrupts one of the 4
      intramolecular disulphide bonds present in hepcidin molecules of all vertebrates,
      and is presumably able to destabilize the peptide structure. The investigated
      patient was also found to harbor a heterozygous HFE c.845G>A (p.C282Y) mutation
      that may have contributed in increasing his iron burden.

PMID- 15024746
TI  - CYLD mutation causes multiple familial trichoepithelioma in three Chinese
      families.
AB  - Multiple familial trichoepithelioma (MFT) and familial cylindromatosis are two
      clinically distinct cancer syndromes. MFT patients developed mostly
      trichoepithelioma in the face while cylindromatosis patients developed
      cylindromas predominantly (approximately 90%) on the head and neck. However,
      multiple familial trichoepithelioma is occasionally associated with familial
      cylindromatosis while cylindromatosis patients can also develop
      trichoepithelioma. This has led to the speculation that the 2 types of dermatoses
      may be caused by dysfunction of a common pathway. Previously, a candidate MTF
      locus has been mapped to 9p21 while disease gene for familial cylindromatosis,
      the CYLD gene located on 16q21-13 has been identified. Here, we show that
      mutations in the CYLD gene are also the genetic basis for three different Chinese
      families with MFT. Sequence analysis reveal a single nucleotide deletion,
      c.1462delA (P.Ile488fsX9) in exon 9, a nonsense mutation, c.2128C>T (p. Gln710X)
      in exon 17, and a missense mutation, c.2822A>T (p. Asp941Val) in exon 21 in each
      of the three families respectively. This provides direct evidence that the
      mutations in CYLD can cause two clinically distinct cancer syndromes.

PMID- 15024748
TI  - Organization of the main olfactory bulbs of some mammals: musk shrews, moles,
      hedgehogs, tree shrews, bats, mice, and rats.
AB  - We immunohistochemically examined the organization of the main olfactory bulbs
      (MOBs) in seven mammalian species, including moles, hedgehogs, tree shrews, bats,
      and mice as well as laboratory musk shrews and rats. We focused our investigation
      on two points: 1) whether nidi, particular spheroidal synaptic regions subjacent
      to glomeruli, which we previously reported for the laboratory musk shrew MOBs,
      are also present in other animals and 2) whether the compartmental organization
      of glomeruli and two types of periglomerular cells we proposed for the rat MOBs
      are general in other animals. The general laminar pattern was similar among these
      seven species, but discrete nidi and the nidal layer were recognized only in two
      insectivores, namely, the mole and laboratory musk shrew. Olfactory marker
      protein-immunoreactive (OMP-IR) axons extended beyond the limits of the
      glomerular layer (GL) into the superficial region of the external plexiform layer
      (EPL) or the nidal layer in the laboratory musk shrew, mole, hedgehog, and tree
      shrew but not in bat, mouse, and rat. We observed, in nidi and the nidal layer in
      the mole and laboratory musk shrew MOBs, only a few OMP-IR axons. In the
      hedgehog, another insectivore, OMP-IR processes extending from the glomeruli were
      scattered and intermingled with calbindin D28k-IR cells at the border between the
      GL and the EPL. In the superficial region of the EPL of the tree shrew MOBs,
      there were a small number of tiny glomerulus-like spheroidal structures where OMP
      IR axons protruding from glomeruli were intermingled with dendritic branches of
      surrounding calbindin D28k-IR cells. Furthermore, we recognized the compartmental
      organization of glomeruli and two types of periglomerular cells in the MOBs of
      all of the mammals we examined. These structural features are therefore
      considered to be common and important organizational principles of the MOBs.

PMID- 15024749
TI  - Synaptic localization of P2X7 receptors in the rat retina.
AB  - The distribution of P2X(7) receptor (P2X(7)R) subunits was studied in the rat
      retina using a subunit-specific antiserum. Punctate immunofluorescence was
      observed in the inner and outer plexiform layers. Double labeling of P2X(7) and
      the horizontal cell marker, calbindin, revealed extensive colocalization in the
      outer plexiform layer (OPL). Significant colocalization of P2X(7)R and kinesin, a
      marker of photoreceptor ribbons, was also observed, indicating that this receptor
      may be expressed at photoreceptor terminals. Furthermore, another band of P2X(7)R
      puncta was identified below the level of the photoreceptor terminals, adjacent to
      the inner nuclear layer (INL). This band of P2X(7)R puncta colocalized with the
      active-zone protein, bassoon, suggesting that "synapse-like" structures exist
      outside photoreceptor terminals. Preembedding immunoelectron microscopy
      demonstrated P2X(7)R labeling of photoreceptor terminals adjacent to ribbons. In
      addition, some horizontal cell dendrites and putative "desmosome-like" junctions
      below cone pedicles were labeled. In the inner plexiform layer (IPL), P2X(7)R
      puncta were observed surrounding terminals immunoreactive for protein kinase C
      alpha, a marker of rod bipolar cells. Double labeling with bassoon in the IPL
      revealed extensive colocalization, indicating that P2X(7)R is likely to be found
      at conventional cell synapses. This finding was confirmed at the ultrastructural
      level: only processes presynaptic to rod bipolar cells were found to be labeled
      for the P2X(7)R, as well as other conventional synapses. These findings suggest
      that purines play a significant role in neurotransmission within the retina, and
      may modulate both photoreceptor and rod bipolar cell responses.

PMID- 15024750
TI  - Differential mRNA expression and protein localization of the SAP90/PSD-95
      associated proteins (SAPAPs) in the nervous system of the mouse.
AB  - The supramolecular anchoring/signaling complex at the postsynaptic density of
      glutamatergic synapses has been proposed to play a key role in regulating
      synaptic function and plasticity. One class of proteins present in the complex is
      the SAP90/PSD-95-associated protein family (SAPAPs). The SAPAPs, identified by
      their direct interaction with PSD-95 family proteins, were initially proposed to
      function in the anchoring/signaling complex as linker proteins between glutamate
      receptor binding proteins and the cytoskeleton. However, recent studies have
      indicated that the SAPAPs also bind to signaling molecules and may thus have
      multiple roles at synapses. Four homologous genes encoding SAPAP proteins have
      been previously identified. As a first step toward understanding the
      physiological function of the SAPAPs, we have investigated in detail, at both the
      mRNA and protein levels, the localization of the individual SAPAP genes in the
      adult murine nervous system. We find that the SAPAP mRNAs are highly, yet
      differentially, expressed in many regions of the brain, including the hippocampus
      and cerebellum. Furthermore, SAPAP3 mRNA is targeted to dendrites, whereas
      SAPAP1, -2, and -4 mRNAs are detected mainly in cell bodies. The SAPAP proteins
      are localized at synapses in a manner consistent with mRNA expression.
      Surprisingly, in addition to glutamatergic synapse localization, antibody
      staining also reveals that the SAPAP proteins are localized at cholinergic
      synapses, including neuronal cholinergic synapses and the neuromuscular junction.
      Together, these results indicate that the SAPAPs are general components of
      excitatory synapses and that each of these proteins may perform a distinct
      function.

PMID- 15024751
TI  - The postnatal developmental expression pattern of urocortin in the rat
      olivocerebellar system.
AB  - Urocortin belongs to the family of corticotropin-releasing factor (CRF)-like
      peptides, which play an important role in sensorimotor coordination. CRF induces
      locomotor activity, and urocortin has an inhibitory effect. Here, we document the
      regional and subcellular localization of urocortin in the developing rat
      cerebellum to compare it with CRF. During the first postnatal week, urocortin
      immunoreactivity (UCN-ir), within the white matter and cerebellar cortex, was
      strongest in vermal lobules I, II, IX, and X, closely followed by lobules IV, V,
      and VIII; lobules VI and VII showed the weakest labeling. Cortical
      immunoreactivity was in the form of puncta that encircled Purkinje cell somata.
      By postnatal day (PD) 12, UCN-ir had increased appreciably in all lobules. In
      Purkinje cells, labeling was spread throughout their somata and proximal
      dendrites. By PD 15, labeling in lobules I-IV appeared to wane, yet still
      prevailed in the central and posterior lobules. This anterior-to-posterior
      gradient persisted through to adulthood. The study shows that urocortin and CRF
      have similar regional distribution profiles during development, suggesting
      synergistic roles within the vestibulocerebellum. The onset of the adult
      distributional pattern of urocortin at the stage when rats are capable of fluent
      walking patterns further strengthens the correlation between CRF-like peptides
      and postural control. An important difference between urocortin and CRF is the
      localization of urocortin, and not CRF, within Purkinje cells, implying that
      urocortin probably has an additional role in modulating the signals emanating
      from the cerebellar cortex to the deep cerebellar nuclei.

PMID- 15024752
TI  - LIM-homeodomain genes as developmental and adult genetic markers of Xenopus
      forebrain functional subdivisions.
AB  - We have investigated the expression patterns of five LIM-homeodomain (LIM-hd)
      genes, x-Lhx1, x-Lhx2, x-Lhx5, x-Lhx7, and x-Lhx9 in the forebrain of the frog
      Xenopus laevis during larval development and in the adult. The results were
      analyzed in terms of neuromeric organization of the amphibian brain and of
      combinatorial LIM-hd code and showed that LIM-hd developmental transcription
      factors are particularly powerful to highlight the coherence of several groups or
      nuclei, to delineate subdivisions, and/or to clarify structures that are still a
      matter of debate. Among other findings, we bring substantial evidence for the
      following: (1) a dual origin of olfactory bulb neurons, based on x-Lhx5
      expression; (2) the existence of a ventral pallium in frog, based on x-Lhx9
      expression; (3) a multiple (pallial and subpallial) origin for the nuclei of the
      amygdaloid complex, based on distinct combinations of the five studied genes; (4)
      a clear homology between the Xenopus medial pallium and the mammalian
      hippocampus, based on x-Lhx2 pattern; and (5) a confirmed prosomeric organization
      of the diencephalon, based on alternating x-Lhx1/5 and x-Lhx2/9 expressions. In
      addition, the important expression levels for LIM-hd factors found throughout
      development and in the adult brain suggest a role for these genes in development
      and maintenance of neuronal specification and phenotype, as for example in the
      case of x-Lhx7 and cholinergic neurons. Moreover, following LIM-hd patterns
      throughout development points out to some of the migrations and morphogenetic
      movements, which give rise to the adult structures. Finally, the detailed
      description of the LIM-hd code in the developing and adult Xenopus forebrain
      provides interesting cues for the possible mechanisms of evolution of the
      vertebrate forebrain.

PMID- 15024753
TI  - The population of bipolar cells in the rabbit retina.
AB  - The population of bipolar cells in the rabbit retina was studied using Golgi
      impregnation and photocatalyzed filling of single cells with dihydrorhodamine, a
      quantitative sampling technique. The Golgi method revealed the morphology and
      stratification of cells in detail. The photofilling method allowed us to estimate
      the frequency of the cell types. From a sample of 243 Golgi-impregnated bipolar
      cells and 107 photofilled cells, we identified 1 type of rod bipolar cell and 12
      types of cone bipolar cells. An analysis based on retinal coverage indicates that
      this number of types could be contained within the number of bipolar cells known
      to exist. The dendrites of most cone bipolars contacted all the cones within the
      individual cone bipolar cell's dendritic field. Types of bipolar cell were
      encountered at roughly similar frequency, without any one type predominating. The
      rabbit retina thus contains about a dozen parallel and roughly equipotent through
      pathways.

PMID- 15024754
TI  - Engrailed-2 negatively regulates the onset of perinatal Purkinje cell
      differentiation.
AB  - The transcription factor Engrailed-2 is expressed in cerebellar Purkinje cells
      (PCs) throughout embryonic development but is downregulated in PCs after birth.
      Since the onset of PC differentiation coincides with this change of gene
      expression, we asked whether downregulation of Engrailed-2 is necessary for
      proper timing of PC differentiation. To investigate this, we used an L7En-2
      transgenic mouse model in which Engrailed-2 expression in PCs is maintained
      beyond the day of birth. In these L7En-2 mice the onset of parvalbumin expression
      was delayed in all PCs by about 3 days; the spatial expression pattern, however,
      remained comparable to wildtype cerebella. Furthermore, parvalbumin expression
      resembled the known pattern of normal PC maturation, suggesting a direct link
      between parvalbumin expression and PC differentiation. Consistent with a delay of
      PC differentiation, we found that PCs of L7En-2 cerebella displayed a reduced
      tendency to align in the typical monolayer. The average size of L7En-2 PCs was
      reduced and the dendritic arbor developed more slowly than in wildtype PCs. In
      contrast, major morphological features of PCs were comparable in L7En-2 and
      wildtype cerebella after postnatal day 11. In addition, we observed a transient
      reduction of PC survival in organotypic slice cultures of L7En-2 cerebella in
      comparison with wildtype slice cultures. Since PC survival parallels PC
      differentiation in vitro, we propose that the observed delay in PC
      differentiation upon Engrailed-2 overexpression is an intrinsic property of
      Engrailed-2 activity, and that downregulation of Engrailed-2 in wildtype PCs
      around the day of birth is critical for the timing of distinct steps of PC
      differentiation.

PMID- 15024755
TI  - Abnormal c-fos-like immunoreactivity in the superior colliculus and other
      subcortical visual centers of pigmented Royal College of Surgeons rats.
AB  - Neurons in the central nervous system often show a transient up-regulation of
      expression of the immediate early gene c-fos when presented with precise novel
      stimuli. In normal rats, neurons in most subcortical visual centers show low
      levels of fos-like immunoreactivity (FLI) expression, but there is a substantial
      and transient increase in FLI expression if the animal is exposed to a flashing
      light. This is especially evident in the superior colliculus (SC). We have
      examined here FLI expression in the subcortical visual centers of the Royal
      College of Surgeons rat, focusing specifically on the SC. In this animal, as a
      result of a genetic defect, there is early loss of rod photoreceptors over the
      first few months of life, along with slower disappearance of cones. Although
      light stimulation showed that FLI expression was very similar to that seen in
      normal rats, the basal levels of FLI expression under dark-maintained conditions
      were much higher than normal, even exceeding the levels seen after visual
      stimulation. In the SC, the elevation of FLI expression was already evident by 6
      weeks of age and reached a plateau by 17 weeks. Other subcortical visual centers
      also showed elevated basal levels of FLI expression, although in general the
      increases were less dramatic than the increase in the SC. The elevated FLI
      expression in dark-maintained condition seen in the SC was abolished by
      contralateral optic nerve section. It was also severely diminished by subretinal
      cell transplantation at 3 weeks of age with the objective of limiting
      photoreceptor loss over part of the retina. These results suggest that the
      elevated basal FLI expression is a retina-driven event. Although it correlates
      with the loss of rod photoreceptors, it is unlikely to reflect reduced
      photoreceptor drive but rather some form of bursting activity generated in the
      inner retina, as a result of circuit reorganization or receptor up-regulation.

PMID- 15024756
TI  - Rat brain vascular distribution of interleukin-1 type-1 receptor
      immunoreactivity: relationship to patterns of inducible cyclooxygenase expression
      by peripheral inflammatory stimuli.
AB  - Interleukin-1 beta (IL-1 beta) is thought to act on the brain to induce fever,
      neuroendocrine activation, and behavioral changes during disease through
      induction of prostaglandins at the blood-brain barrier (BBB). However, despite
      the fact that IL-1 beta induces the prostaglandin-synthesizing enzyme
      cyclooxygenase-2 (COX-2) in brain vascular cells, no study has established the
      presence of IL-1 receptor type 1 (IL-1R1) protein in these cells. Furthermore,
      although COX inhibitors attenuate expression of the activation marker c-Fos in
      the preoptic and paraventricular hypothalamus after administration of IL-1 beta
      or bacterial lipopolysaccharide (LPS), they do not alter c-Fos induction in other
      structures known to express prostaglandin receptors. The present study thus
      sought to establish whether IL-1R1 protein is present and functional in the rat
      cerebral vasculature. In addition, the distribution of IL-1R1 protein was
      compared to IL-1 beta- and LPS-induced COX-2 expression. IL-1R1-immunoreactive
      perivascular cells were mostly found in choroid plexus and meninges. IL-1R1
      immunoreactive vessels were seen throughout the brain, but concentrated in the
      preoptic area, subfornical organ, supraoptic hypothalamus, and to a lesser extent
      in the paraventricular hypothalamus, cortex, nucleus of the solitary tract, and
      ventrolateral medulla. Vascular IL-1R1-ir was associated with an endothelial cell
      marker, not found in arterioles, and corresponded to the induction patterns of
      phosphorylated c-Jun and inhibitory-factor kappa B mRNA upon IL-1 beta
      stimulation, and colocalized with peripheral IL-1 beta- or LPS-induced COX-2
      expression. These observations indicate that functional IL-1R1s are expressed in
      endothelial cells of brain venules and suggest that vascular IL-1R1 distribution
      is an important factor determining BBB prostaglandin-dependent activation of
      brain structures during infection.

PMID- 15024757
TI  - A randomized comparison of total or supracervical hysterectomy: surgical
      complications and clinical outcomes.

PMID- 15024758
TI  - Iatrogenic endometriosis caused by uterine morcellation during a supracervical
      hysterectomy.

PMID- 15024759
TI  - Three patients with actinic keratoses on atrophic balding scalps who experienced
      delayed healing after treatment.

PMID- 15024760
TI  - Infection control.

PMID- 15024761
TI  - Safe staffing initiatives get another boost in Congress.

PMID- 15024762
TI  - Environment health is public health.

PMID- 15024766
TI  - Acute hemorrhagic conjunctivitis epidemic--2003 in Nepal.
AB  - This rapid communication present the findings of nationwide outbreak of acute
      hemorrhagic conjunctivitis (AHC) epidemic occurred in Nepal during summer 2003.
      Only ten percent of samples showed bacterial and no fungus were grown. On the
      contrary, viruses were detected in 60.0% cases studied. Of the viruses detected,
      Adenovirus (ADV), Coxsackie virus (CA24v) and both accounted for 83.3% (30/36),
      11.1% (4/36) and 5.5% (2/36), respectively. Interestingly, ADV was detected also
      from one of the ten a Rupees bill.

PMID- 15024767
TI  - Articular branch of the axillary artery and its clinical implication.
AB  - Origin and course of the articular branch of the axillary artery was recorded in
      151 (43.9%) out of 344 axilla during the routine dissection. The branch was
      observed in 60.5% right side and 39.4% left side of male axilla, whereas in 55.5%
      right and 44.4% left side of female axilla and the difference was found
      significant (P < 0.001) among the gender. The orientation of the articular branch
      on right and left side was of similar proportion in both the sexes. The articular
      branch entered into the shoulder joint either upper, middle or lower part of the
      capsule of joint. This articular branch originated mostly from the lateral aspect
      of second part of the axillary artery below to the origin of the lateral thoracic
      artery. This is a rare observation and is of importance to clinicians dealing
      with the shoulder joint.

PMID- 15024768
TI  - Electrocardiographic prediction of left anterior descending coronary artery
      occlusion site in acute anterior myocardial infarction.
AB  - The complications, therapy and prognosis are significantly determined by the
      exact location of occlusion site in left anterior descending (LAD) coronary
      artery in anterior acute myocardial infarction (AMI). This study assessed the
      role of Electrocardiogram (ECG) as a predictor of coronary artery occlusion site
      in anterior AMI. Sixty two patients of anterior AMI were divided into two groups
      according to the occlusion site in relation to first septal and first diagonal
      branches, proximal--group A and distal--group B. Their initial ECG were analyzed
      and interpreted. The number of patients having ST elevation in leads aVR and aVL
      (> or = 0.5 mm) were significantly higher in proximal group compared to distal
      ones (42.3% vs 2.8% and 73.1% vs 22.2%; p < 0.001). Similarly the number of
      patients having ST depression in inferior leads, II (> or = 1 mm), III (> or = 1
      mm) and aVF (> or = 1 mm) were also significantly higher in proximal group (84.6%
      vs 22.2%, 88.5% vs 33.3% and 84.6% vs 22.2%; p < 0.001). The sensitivity of ST
      depression in inferior leads II (> or = 1 mm), III (> or = 1 mm) and aVF (> or =
      1 mm) to predict the proximal lesion were 85.0%, 88.0% and 85.0% respectively,
      whereas specificity were 78.0%, 67.0% and 78.0% respectively. The ST elevation in
      a VR had 42.0% sensitivity and 97.0% specificity to predict proximal lesion.
      Similarly ST elevation in aVL (> or = 0.5 mm) had 73% sensitivity and 78%
      specificity. In anterior AMI, ST elevation in aVR, aVL and ST depression in
      inferior leads can predict the occlusion site in LAD proximal to first diagonal
      and first septal branch.

PMID- 15024769
TI  - Subtenon's anesthesia in extracapsular cataract extraction.
AB  - To avoid sight threatening complications of retrobulbar and peribulbar blocks
      various new modalities of ophthalmic anesthesia have been developed. Subtenon's
      anesthesia has been found to be a safe and effective technique in
      phacoemulsification. This study aimed to see the efficacy of subtenon's block in
      extracapsular cataract extraction. Administration of the anesthetic agents was
      found to be comfortable in 137 (95.1%) patients. Surgical procedure was painless
      in 141 (98.0%) cases. Akinesia was satisfactory in 136 (94.5%) cases. Although
      minor events like chemosis and subconjunctival hemorrhage were seen in a
      significant number of patients but there was not a single case of major
      complication. Hence it is concluded that subtenon's anesthesia is a safe and
      efficient technique for ophthalmic anesthesia in extracapsular cataract
      extraction.

PMID- 15024770
TI  - Management of femur shaft fracture with close locked intramedullary nailing:
      comparison of Variwall and predrilled Kuntscher nail.
AB  - A prospective and comparative study of 44 cases of close locked static
      intramedullary (IM) nailing of Femur shaft fracture with two nailing systems was
      done. Comparing the cheap predrilled Kuntscher nail with standard but expensive
      Variwall nail of Biomet Company England, we found almost equal result in both
      groups regarding complications and healing of the fracture. Average healing time
      in Variwall and Kuntscher nailing were 16.4 and 16.1 weeks respectively, P value
      being in-significant. In Variwall nailing, stable fractures healed at the average
      of 13.5 weeks and unstable fractures at 17.2 weeks; open fractures at 18.4 weeks
      and close ones at 14.2 weeks; fractures due to Road Traffic Accident (RTA) at
      16.3 weeks, gunshot injury at 18.6 weeks and fractures due to fall at 14 weeks.
      Similarly in Kuntscher nailing these figures were 14 and 16.7 weeks; 19.6 and
      14.5 weeks; 16.6, 22 and 13 weeks respectively. Pre-drilled Kuntscher nail with
      good quality cortical screws for interlocking is recommended for any variety of
      femoral shaft fracture. It is cost effective, at the same time gives acceptable
      result as compared to standard interlocking intramedullary nail.

PMID- 15024771
TI  - Study on head and neck tumours presented in ENT OPD of Nepal Medical College
      Teaching Hospital.
AB  - This retrospective study was carried out to analyze the types of head and neck
      tumours on the basis of site and histopathological type. A total of 35 patients
      with head and neck tumours (M: 19 and F: 16; aged 15 to 68 years) were included.
      Thyroid neoplasm was the commonest (20.0%) patients followed by tumour of larynx
      (17.1%), oropharyngeal tumour and (14.3%), oral cavity tumour ranked number one
      (14.3%) followed by tumours of nose (11.4%) and others. All thyroid neoplasms
      were follicular type whereas all laryngeal tumours were squamous cell carcinoma.

PMID- 15024772
TI  - Prevention of carcinoma cervix: role of Pap smear screening.
AB  - This study was undertaken to evaluate the prevalence of Cervical precancerous and
      Cancer pick up by single pap smear test. A prospective study of pap smear test of
      three years duration 2000-2002 in Obstetrics and Gynecology department, NMCTH,
      Kathmandu. A total 800 cases were included Maximum number of patients are in the
      age group of active reproductive period (21-40 yr) with higher rate of an
      abnormal smear in Brahmin ethnic group. The main complaints are of lower
      abdominal pain and white discharge per vaginum. The main cervical pathology is
      cervicitis, cervical erosion and cervical hypertrophied with bleeding on touch.
      4.8% of the patients had abnormal smear including three patients with invasive
      cervical squamous cell carcinoma detected on pap smear test. This study shows
      that routine pap smear screening in patients attending gynecological OPD is the
      good method of detecting precancerous cervical intraepithelial neoplasia (CIN)
      lesion and early cervical cancer, which would go undiagnosed otherwise with worst
      morbidity and mortality. We should try to cover 100% screening if possible in an
      institution at least to begin with.

PMID- 15024773
TI  - Clinical importance of unusual patterns of tendinous intersections of rectus
      abdominis muscle.
AB  - The objective of the present study was to note the different patterns of
      tendinous intersections of rectus abdominis muscle and its surgical importance.
      The tendinous intersections of rectus abdominis muscle were studied in dissected
      46 human cadavers dissected over a span of 3 years. Only two unusual patterns of
      intersections; one with tendinous intersections arched, and the other with the
      intersections at different levels on the right and left sides of the same
      cadaver, were observed, in two different cadavers. The tendinous intersections
      are the sites of anastomosis of numerous blood vessels. Surgeons using the the
      Transverse Rectus Abdominis (TRAM) flap in autogenous breast constructive
      surgeries should be aware of such unusual patterns so as to design the TRAM flap
      accordingly. Biomechanics of rectus abdominis muscle may also be influenced by
      arched pattern of tendinous intersections instead of normal transverse pattern.

PMID- 15024774
TI  - Toxoplasma infection in selected patients in Kathmandu, Nepal.
AB  - Seroprevalence of Toxoplasma infections in 272 patients with ocular diseases
      (uveitis, retinochoroiditis), malignancy (including leukemia), women with bad
      obstetric history (BOH) and others (patients with fever, lymphadenitis and
      encephalitis) have been was studied. Toxoplasma antibodies were detected by
      microlatex agglutination and IgM ELISA techniques. Overall, 50.7% (138/272)
      patients included in this study had Toxoplasma antibodies, out of which 5.7%
      (8/138) had IgM antibodies. Patients with malignancy had highest positive rate
      [68.7% (22/32)] followed by group of others. Of the different groups, women with
      BOH had highest Toxoplasma IgM positive rate [25.0%; (2/8)].

PMID- 15024775
TI  - A study of symptom profile of depression following myocardial infarction.
AB  - Depression is common clinical manifestation following myocardial infarction (MI),
      the prevalence being 20.0-30.0% in different studies. Both biological factors and
      problems related to life threatening condition have been blamed as risk factors
      of depression following MI. Although the profile of symptomatology of depression
      after life threatening physical illnesses is similar in many aspects to that of
      depressive disorder in other individuals, there are substantial differences
      between them. Fifty-one patients with MI were studied using Hamilton Depression
      Rating Scale (HDRS) during first visit, and after one month, three months and six
      months period. The result showed that most of the symptoms were somatic type
      (45.0-57.0%), psychological category being the next (36.0-44.0%), whereas 7.0 to
      12.0% of the symptoms constituted motor.

PMID- 15024776
TI  - Study of social support in the spouses of depressives.
AB  - This study was conducted to asses the level of social support amongst the
      patients of disthymia and unipolar depression. A total of 80 patients with their
      spouses were included. Results showed no significant differences of social
      support in this study group. Spouses of patients with unipolar depression with
      psychotic features perceived lower social support compared with the spouses of
      unipolar depression without psychotic features. The severity of unipolar
      depression of the patients correlated negatively with the perceived social
      support of the spouses.

PMID- 15024777
TI  - Demographic assessment on vasectomy clients of Sankhuwasabha Nepal.
AB  - This paper presents the demographic status of vasectomy clients in Sankhuwasabha
      district in Eastern Nepal based on the 427 face-sheets taken at camps in district
      during 3 consecutive years. More than half (55.0%) of the clients were Brahmin
      and Chhetri. Major occupation of clients was agriculture (73.7%) with a literacy
      rate of 83.0%. Mean age of vasectomy clients and their wives was 32.5 and 28.7
      years, respectively. Average number of children of a client was 3.2. Age of
      youngest male child was 4.7 years and youngest female child was 3.9 years. Of the
      total, 55.8% couples have had used temporary contraceptives before having
      vasectomy. As a part screening procedure, blood pressure of more than half
      clients (54.6%) was measured and found to be within normal range.

PMID- 15024778
TI  - Seasonal variation of blood pressure in young normotensive.
AB  - In this study, the variation of blood pressure in young normotensive medical
      students has been recorded in winter and summer. Daytime blood pressure of young
      normotensive medical students has been measured in supine position. It has been
      found that both the systolic and diastolic pressure increases in low ambient
      temperature. It may be due to sympathetic stimulation and increase secretion of
      catecholamines in response to cold. Both sympathetic stimulation and
      catecholamines causes vasoconstriction leading to increased peripheral resistance
      and thereby increases diastolic pressure. At the same time the above mention
      stimuli increases heart rate and force of contraction of cardiac muscle causing
      increased cardiac output and thereby increases the systolic pressure.

PMID- 15024779
TI  - Is urinary tract infection a predisposing factor for renal stone formation?
AB  - The study was carried out to assess whether Urinary Tract Infection (UTI) is a
      predisposing factor for Renal Stones (RS) formation. A total of 836 subjects
      (males 300; females 536) attending Surgery Out Patient Department (OPD) of which
      were either diagnosed of UTI or had been detected of RS for a period of two years
      from January 2001 to December 2002 were included. Of the 836, 240 had UTI and 596
      were free from UTI. The prevalence of RS was higher without UTI (44.4%) than
      those with UTI (27.8%) in males. In case of females the result showed (17.6%) and
      (5.1%) in cases with and without UTI. Chi square test revealed statistically
      significant difference in the proportion of prevalence between subjects with and
      without UTI with (p < 0.01) in males and (p < 0.001) in females. Males had higher
      incidence of RS than females with a prevalence of (p < 0.0001). The higher
      occurrence of RS was observed in age group between 21-40 years for both genders.

PMID- 15024780
TI  - Unusual frontal bone injury.
AB  - A 12-year old girl presented 6 months after a forehead injury due to fall from
      height. She had a deformed forehead with a rectangular bone defect and a
      rectangular bicortical bone fragment impacted into the lower edge of the defect.
      There was no obvious skin or dural injury. The deformed forehead was exposed
      through a bi-coronal scalp flap. The bone fragment was reposited back into the
      defect. The forehead of the patient healed with a smooth contour.

PMID- 15024781
TI  - Solid and cystic tumor arising from an extrapancreatic site--a case report.
AB  - A case of solid and cystic tumor arising in the lesser Omentum of a 53 year old
      woman is presented. A well defined, encapsulated tumor measuring 7.5 x 6.5 x 6
      cms, weight 170 grams was histologically characterized by a combination of solid
      and pseudo papillary growth patterns of tumor cells with pale to eosinophilic
      cytoplasm. No pancreatic tissue was seen with or adjacent to the tumor. The
      patient was well with out recurrence 7 months after the diagnosis. It is
      important to include pseudo papillary solid cystic tumor in the differential
      diagnosis of omental tumors. The tumor is presented because of its rarity.

PMID- 15024782
TI  - Non-pharmacological therapy of hyperlipidaemia.
AB  - Hyperlipidaemia is one of the major contributors to atherosclerosis and Coronary
      Heart Disease (CHD) in our society. Numerous clinical and epidemiological studies
      have shown repeatedly that an elevated blood cholesterol level is one of the
      major modifiable risk factors associated with the development of CHD. In
      particular, these studies have demonstrated that low- density lipoprotein (LDL)
      cholesterol is the primary lipoprotein mediating atherosclerosis. Non
      pharmacological therapy especially dietary therapy and exercise remains the first
      line of treatment in hyperlipidaemia, with pharmacotherapy reserved for use in
      patients at high risk of coronary heart disease or patients who do not respond to
      non-pharmacological therapy.

PMID- 15024783
TI  - Update on the prevalence of malnutrition among children in Asia.
AB  - Approximately 70.0% of the world's malnourished children live in Asia, resulting
      in the region having the highest concentration of childhood malnutrition. About
      half of the preschool children are malnourished ranging from 16.0% in the
      People's Republic of China to 64.0% in Bangladesh. Prevalence of stunting and
      underweight are high especially in South Asia where one in every two preschool
      children is stunted. Besides protein-energy malnutrition, Asian children also
      suffer from micronutrient deficiency. Iron deficiency anaemia affects 40.0-50.0%
      of preschool and primary school children. Nearly half of all vitamin A deficiency
      and xeropthalmia in the world occurs in South and Southeast Asia, with large
      numbers of cases in India (35.3 million), Indonesia (12.6 million) and China
      (11.4 million). Another major micronutrient problem in the region is iodine
      deficiency disorders, which result in high goiter rates as manifested in India,
      Pakistan and parts of Indonesia. While under-nutrition problem persists,
      overweight problem in children has emerged in Asia, including Taiwan, Singapore
      and urban China and Malaysia. The etiology of childhood malnutrition is complex
      involving interactions of multiple determinants that include biological, cultural
      and socio-economic influences. Protein-energy malnutrition and micronutrient
      deficiency leading to early growth failure often can be traced to poor maternal
      nutritional and health care before and during pregnancy, resulting in
      intrauterine growth retardation and children born with low birth weight. While
      significant progress has been achieved over the past 30 years in reducing the
      proportion of malnourished children in developing countries, nonetheless,
      malnutrition persists affecting large numbers of children. The socio-economic
      cost of the malnutrition burden to the individual, family and country is high
      resulting in lower cognitive outcomes in children and lower adult productivity.
      Interventions that are cost-effective and culturally appropriate for the
      elimination of childhood malnutrition deserve the support of all.

PMID- 15024784
TI  - Tough choices and lack of funding confront Iowa legislators.

PMID- 15024785
TI  - HIPAA's next phase--security!

PMID- 15024786
TI  - Senator Grassley brings it home for Iowa physicians and their patients!

PMID- 15024787
TI  - Drugs detected in suspected pediatric ingestions: a three-year review.
AB  - Comprehensive toxicology testing can be a valuable resource when pediatric
      patients are suspected of having ingested unknown chemicals. In a recent 36-month
      period (January 2000-December 2002), the Analytical Toxicology Laboratory at the
      University of Mississippi Medical Center, Jackson, MS, tested 190 urine samples
      referred from the hospital's Pediatric Emergency Department for STAT toxicology
      testing. All samples were tested in parallel using an immunoassay technique for
      drugs of abuse and a comprehensive technique using gas chromatography/mass
      spectroscopy (GC/MS). With immunoassay, sixteen percent of the samples were
      positive for a drug of abuse. In comparison, drugs were detected in 85% of the
      samples using comprehensive GC/MS analysis. A total of 86 different
      pharmaceuticals were identified by GC/MS. This review shows that comprehensive
      toxicology testing provides the clinician significantly more information
      regarding the exposure of the pediatric patient presenting with an unknown
      chemical ingestion.

PMID- 15024788
TI  - 2003 Medicare law tweaks the system.

PMID- 15024789
TI  - Our children's obesity epidemic: can MSMA help legislatively mandate a cure?
      Responses to "what's your opinion, doctor?".

PMID- 15024790
TI  - Looking back: use and abuse of the nitrites in 1909.

PMID- 15024792
TI  - [Dental tours de force 5. Bimaxillary transverse distraction osteogenesis].
AB  - A narrow anterior apical base in both jaws can cause pronounced crowding, which
      can be corrected by extraction therapy (as a rule extraction of four premolars)
      or by transverse distraction osteogenesis therapy (as a rule bimaxillary),
      followed by orthodontic treatment. A case is reported of bimaxillary transverse
      distraction osteogenesis in an eleven-year old female patient. Alignment was
      performed with fixed orthodontic appliances. Correction of the skeletal Class II
      relationship was done with a functional appliance. The active treatment time was
      eighteen months.

PMID- 15024791
TI  - Avian influenza frequently asked questions.

PMID- 15024793
TI  - [Treatment strategies for anxious adults in general dental practice: guidelines
      for mild forms of anxiety].
AB  - In this article an attempt is made to formulate a number of general clinical
      guidelines, based on the currently available knowledge and clinical experience
      within the area of dental anxiety. It is concluded that, in case of mild forms of
      anxiety, a careful treatment approach of the dental practitioner--which is
      focused on a style of establishing trust, specific pharmacological support and
      the teaching of coping strategies--can reduce patients' anxiety level, thereby
      preventing avoidance behaviour and deterioration of the oral health.

PMID- 15024794
TI  - [Dissertations 25 years later. 1. Mesial drift of teeth by occlusal forces].
AB  - More than 25 years ago the thesis 'Functional occlusion and mesial drift, an
      experimental study of tooth migration in monkeys' was presented. A literature
      review was carried out to assess whether the results have withstood the test of
      time. It was confirmed that occlusion plays an important role in mesial drift,
      whilst no direct evidence for transseptal fibre contraction as a causal factor
      has been put forward. Mesial drift is not merely a compensatory mechanism for
      loss of tooth substance, but may cause crowding, depending on axial inclination
      and occlusal morphology. This phenomenon has implications for orthodontic and
      restorative treatments.

PMID- 15024795
TI  - [A patient with Prader-Willi syndrome. Characteristics, oral consequences and
      treatment options].
AB  - A dentist referred a 32-year-old man with the Prader-Willi syndrome to a center
      for special dental care because of the poor cooperation of the patient,
      progressive toothwear and advanced palatal trauma. The dental problems were,
      among others, caused by the disto-relation (Class II-2), a poor oral hygiene, the
      frequency of sugar intake, oesophageal reflux and a strongly reduced salivary pH
      of 5.5. Treatment of the dentition was established by minimal invasive and
      adhesive dentistry.

PMID- 15024796
TI  - Epidemiology and pathology of intraventricular tumors.
AB  - Tumors that primarily or exclusively involve the ventricular system constitute a
      rare and heterogeneous group. Certain histologic tumor types predominantly occur
      in children, whereas others are more common in adults. Tumor location provides
      additional clues to correct diagnosis. When used in conjunction with clinical and
      radiologic data, histopathologic features can distinguish among this wide range
      of possibilities to provide the correct diagnosis for optimal patient management.

PMID- 15024797
TI  - Intraventricular neurocytomas.
AB  - The literature to date on the treatment of CNC reflects an evolution of clinical
      practice in neurooncology. The advent of sophisticated tools, such as MRS and
      molecular pathology, has facilitated more efficient diagnosis of CNC. Decreased
      morbidity associated with surgical intervention has resulted in better outcomes
      in patients undergoing resection of CNC. Prospective monitoring of treated
      patients with MRI coupled with judicious use of radiosurgery will likely further
      decrease treatment-related morbidity.

PMID- 15024798
TI  - Surgical approaches to tumors of the lateral ventricle.
AB  - Lateral ventricular tumors are rare lesions of the central nervous system, and
      because most tumors are benign or low grade, permanent cure can be achieved with
      complete removal. After adequate preoperative imaging discloses a lateral
      ventricular mass, the neurosurgeon has several options to choose from when
      determining the ideal surgical approach to the tumor. The surgical approach
      cannot be standardized, because the specific location, size, and vascularization
      of these deep-seated tumors are fundamental elements influencing the choice of
      surgical approach. Although access to the lateral ventricles may require
      additional preoperative considerations and planning, the combination of proper
      knowledge of the cortical and intraventricular anatomy with the familiarity and
      selection of an appropriate surgical approach will optimize the surgical outcome.

PMID- 15024799
TI  - Surgical approaches to posterior third ventricular tumors.
AB  - A variety of surgical approaches to the posterior third ventricle and pineal
      region exist. The choice of approach is influenced by the exact location of the
      lesion, its expected pathologic findings, and the comfort level of the operating
      surgeon with the approach that is being considered. For most pineal region masses
      that are situated in the midline below the deep venous system, we favor the
      supracerebellar-infratentorial approach in the sitting position. For pineal
      region lesions that displace the deep venous system inferiorly or have
      significant lateral extension, we prefer the occipital-transtentorial approach in
      the three-quarter prone or sitting position. For lesions that are truly in the
      posterior third ventricle without extension posterior to the splenium, we prefer
      the interhemispheric-transcallosal approach in the lateral position.

PMID- 15024800
TI  - Endoscopic adjuncts to intraventricular surgery.
AB  - Recently, endoscopic intraventricular surgery has been performed successfully in
      several clinical series. Although the therapeutic results must be compared with
      conventional surgery, neuroendoscopy seems to be a safe surgical technique when
      performed by surgeons with appropriate experience and refined endoscopic tools.
      Rigid or flexible endoscopes equipped with various-sized working channels should
      be selected depending on the nature of the pathologic findings. The well-proven
      tenets of microsurgery must not be sacrificed for the sake of more rapid surgical
      time and noninvasiveness; thus, endoscopic surgery must adhere to the principles
      of microsurgery. The improved visualization and lower morbidity have established
      neuroendoscopy in the management of specific disease processes, such as
      obstructive hydrocephalus. Its further use in the management of intraventricular
      cysts and tumors is dependent on long-term follow-up and the development of even
      better instrumentation.

PMID- 15024801
TI  - Intraventricular meningiomas.
AB  - Intraventricular meningiomas are most often seen in the lateral ventricles of
      adults, more often on the left than on the right. A variety of surgical
      approaches can be selected depending on patient and tumor factors as well as on
      surgeon preference. Some of these approaches are complex and demand a thorough
      understanding of the ventricular and periventricular anatomy. When successful,
      surgery can be curative in most cases of total removal.

PMID- 15024802
TI  - Intraventricular gliomas.
AB  - Gliomas are the most common primary brain tumor in adults, and those within or
      relating to the ventricular surface represent a less common but important
      subcategory. The most common intraventricular gliomas include ependymomas, SEs,
      and SEGAs. Other less common varieties have been reported, including chordoid
      gliomas, glioblastoma multiforme, and mixed glial-neuronal tumors. Each type of
      intraventricular glioma is associated with its own unique constellation of
      epidemiologic, clinical, radiologic, and pathologic defining characteristics.
      Each tumor type has its own management considerations and nuances with unique
      prognostic indicators and outcomes. The outcome for certain intraventricular
      gliomas (especially ependymomas) remains relatively poor. Future advancements in
      surgical technique are likely to have only a modest impact on improvement of
      outcome. Translational research aiming to advance the knowledge of tumor biology
      into new targeted cellular and molecular therapies holds tremendous promise to
      improve the overall outcome. Additionally, more thorough delineation of
      prognostic factors as well as modifications and refinements to radiation and
      chemotherapy may help to improve the still significantly poor outcomes for
      patients harboring these lesions. Future cooperative intra- and
      interinstitutional efforts between scientists and clinicians will hopefully
      culminate in an improved outlook and eventual cure for patients with gliomas.

PMID- 15024803
TI  - Surgical resection of metastatic intraventricular tumors.
AB  - The ventricle is a rare site of brain metastases. Renal cell carcinoma has a
      higher propensity to metastasize to the ventricle compared with more common
      metastatic tumors (e.g., lung cancer). The trigone is the predominant location
      for intraventricular metastases, presumably because of the high concentration of
      choroid plexus in this region. Surgical resection is an important component of
      the management of these lesions, particularly if there is only a single
      intraventricular lesion. Despite the deep location of these tumors within the
      ventricle, survival in patients undergoing surgery for them is comparable to that
      in patients receiving surgery for intraparenchymal metastases.

PMID- 15024804
TI  - Intraventricular congenital lesions and colloid cysts.
AB  - Intraventricular congenital lesions and colloid cysts comprise a rather large
      spectrum of different pathologic conditions. In most cases, treatment in not
      warranted unless there is progressive ventricular obstruction with hydrocephalus
      or growth of the lesion itself, making tissue biopsy and histopathologic
      diagnosis necessary. Accordingly, a precise neuroradiologic evaluation is of the
      utmost importance, because most lesions, if not symptomatic, only require
      clinical and radiologic follow-up.

PMID- 15024805
TI  - Choroid plexus tumors in children.
AB  - Choroid plexus tumors represent a well-defined subset of brain tumors that occur
      mainly in young children. Surgical resection for papilloma is usually curative,
      although careful surgical planning is required to minimize the potential risks.
      Although adjunctive therapy for carcinoma includes chemotherapy or radiation, the
      long-term survival for carcinoma remains poor.

PMID- 15024806
TI  - Geriatric mental health. Preface.

PMID- 15024807
TI  - Epidemiology of late-life mental disorders.
AB  - This article reviews the prevalence and incidence of mental disorders in older
      adults. The authors outline the epidemiologic challenges in determining the
      frequency of mental disorders in late-life and discuss issues that are critical
      for understanding the prevalence of the disorders and for reviewing the evidence
      from epidemiologic studies of mental disorders in this population. The authors
      summarize the epidemiologic data for depression, anxiety, dementia,
      schizophrenia, and alcoholism. Also included is a discussion of risk factors and
      outcomes of these disorders and a discussion of the implications of these
      epidemiologic findings for geriatric medicine.

PMID- 15024808
TI  - Use of psychopharmacologic agents in the elderly.
AB  - Most psychiatric disorders in elderly patients are amenable to treatment,
      provided that intervention is thorough and intensive. Appropriate and judicious
      use of psychopharmacologic agents has a potential for dramatically improving the
      quality of life and functional status of many elderly patients with psychiatric
      disorders. The decision to prescribe a psychopharmacologic agent in elderly
      patients is a serious and complex issue. Several basic principles need to be
      followed (Table 6). Although some strides have been made in the last decade
      regarding safety and efficacy of many psychopharmacologic agents in elderly
      [table: see text] patients, for many psychopharmacologic agents, large randomized
      controlled studies to evaluate efficacy and safety in elderly patients are
      lacking. Sparse data are available regarding the long-term effects of
      psychopharmacologic agents in elderly patients. Important gaps remain in our
      knowledge concerning the optimal duration of treatment for most psychiatric
      disorders in elderly patients. The treatment data deficiency is most striking
      among the oldest old (patients aged 85 and older), frail medically ill elderly
      patients (such as nursing home residents), and ethnic minority groups. Future
      research should focus on these and other relevant issues related to the use of
      psychopharmacologic agents in elderly patients.

PMID- 15024809
TI  - Anxiety disorders in older adults.
AB  - Recent epidemiologic surveys indicate that anxiety disorders in older adults are
      more common than previously believed. Despite this, knowledge regarding the
      clinical characteristics of anxiety disorders in elderly patients is emerging
      slowly. In addition, detection of anxiety symptoms in elders is complicated by
      several factors, including a confounding of symptom picture by high medical
      comorbidity, frequent use of multiple prescribed and over-the-counter
      medications, difficulty of differentiating anxiety from depression, and a
      tendency of some older adults to resist psychiatric evaluation. Nonetheless, a
      comprehensive evaluation that includes a clinical interview, self-report
      measures, and laboratory results, can improve detection and accurate assessment
      of anxiety in elderly patients. Empirically validated knowledge regarding
      appropriate pharmacologic interventions in elderly patients is still sparse, and
      inferences from data in young and middle-aged populations typically form the
      basis of clinical practice in elderly patients. SSRIs and SNRIs are considered
      first-line interventions because of their efficacy and relative tolerability in
      elderly patients. Psychotherapy, particularly cognitive-behavioral therapy, also
      has been found to be efficacious for older adults with anxiety disorders.
      Collaborative care models that address physician, patient, and healthcare service
      delivery barriers, also hold promise for adequately treating anxiety disorders
      experienced by older adults.

PMID- 15024810
TI  - Diagnosis and treatment of alcohol dependence in older alcoholics.
AB  - Treatment of alcohol dependence among older alcoholic patients should be
      multidimensional to address as many potential relapse factors as possible. As the
      literature suggests, alcohol-related disorders often are under diagnosed and
      under treated. More efforts are needed to identify and improve diagnosis of these
      disorders in older alcoholic patients. For better outcomes, age-specific programs
      should be implemented. Furthermore, when treating elderly patients, basic
      therapeutic principles like respect for privacy and a respectful attitude should
      be adopted. Adequate medical, pharmacologic, and psychiatric treatment should be
      provided when appropriate. Medication to reduce cravings should be considered in
      patients without contraindications to its use. Participation in individual,
      group, and family therapy and attendance at self-help group meetings such as AA
      should be encouraged (Table 8). Despite the lack of empiric testing to validate
      these recommendations in an elderly population, clinical experience suggests that
      adherence to these recommendations will benefit elderly patients just as it has
      the general adult population. Research is necessary to explore the benefits of
      alcohol treatments in elderly patients. Until then, adherence to these
      recommendations should be the best available approach.

PMID- 15024811
TI  - Alzheimer disease and other dementias.
AB  - Dementias become more prevalent with increasing age. As the growth in the
      geriatric population increases, so does their incidence. Risk factor profiling,
      neuroimaging, and neurocognitive testing are helping provide objective evidence
      for determining between normal aging and cognitive deficit states. The diagnosis
      usually can be made, however, by a careful interview of the patient and a
      reliable informant and a detailed physical examination with emphasis on the
      neurologic and mental status examinations, followed by standard laboratory
      testing. Earlier therapeutic intervention can make a long-term difference in
      outcome. Distinguishing variants of dementias grants the clinician an opportunity
      of intervening based on etiology and similarities in neurotransmitter deficit
      states. Palliative ways of slowing progressive decline are available primarily by
      way of ChEIs, although no cures yet exist for the dementias. Optimizing current
      treatments makes sense in improving the quality of life of sufferers.

PMID- 15024812
TI  - Late-life mood disorders.
AB  - Mental disorders are not uncommon in late life. Although most psychiatric
      disorders occur less frequently in older populations compared with populations of
      younger adults, more than 10% of older adults have one or more psychiatric
      disorders. In addition, many older adults present with symptoms that do not meet
      the criteria for a specific disorder but nevertheless are clinically significant
      and affect quality of life. In this article the authors summarize the
      epidemiologic data for five psychiatric disorders and their subclinical forms:
      depression, anxiety, dementia, schizophrenia, and alcoholism. Also included is a
      discussion of risk factors and outcomes of these disorders.

PMID- 15024813
TI  - Behavioral and psychologic symptoms of dementia.
AB  - Although tremendous strides with regard to identification and treatment of BPSD
      have been made over the last several decades, much work remains. Presently, BPSD
      research opportunities are at their greatest. The increasing worldwide social and
      economic impact of BPSD, however, requires that researchers, clinicians, and
      scientists develop a global network focused on collaboration and innovation. In
      particular, research must address cross-culturally applicable methods for
      assessment, exploration of the environmental relationships of BPSD and the
      underlying biologic and psychologic substrates, longitudinal evaluation,
      determination of the frequency and underlying pathogenic mechanisms, and
      development of a clearly defined treatment method profile with specific reference
      to different types of BPSD [134].

PMID- 15024814
TI  - Electroconvulsive therapy in the elderly.
AB  - ECT is a safe, useful, and effective treatment for a variety of disorders and can
      be administered safely in elderly patients. Efforts need to be undertaken to
      increase the awareness and acceptability of ECT treatments. As Carl Salzman says
      in the January 1998 issue of the American Journal of Psychiatry, "Let us not
      perpetuate outmoded, nonscientific and incorrect attitudes toward ECT in our
      younger colleagues. Rather, let us stimulate scientific curiosity and research
      into this cost-effective and safe psychiatric treatment."

PMID- 15024815
TI  - End-of-life care in geriatric psychiatry.
AB  - Depression, anxiety and delirium are relatively common during the final stages of
      terminal disease, and each can profoundly impact the quality of those last days
      for both patient and involved family. In this article the authors review the
      assessment and treatment of each syndrome in the context of palliative care for
      older adults. Treatment of mental disorders at the end of life warrants special
      consideration due to the need to balance the benefits of treatment against the
      potential burden of the intervention, especially those that might worsen quality
      of life. Dementia and the complications of depression and behavioral disturbance
      within dementia are also discussed. Finally, caregivers of dying patients are
      vulnerable to stress, depression, grief, and complicated bereavement.
      Interventions for caregivers who are debilitated by these states are briefly
      summarized.

PMID- 15024817
TI  - Treating patients with amelogenesis imperfecta.

PMID- 15024816
TI  - News about HIV care.

PMID- 15024818
TI  - Importing drugs: is it legal?

PMID- 15024819
TI  - Don't assume your patients can't pay.

PMID- 15024820
TI  - ADA finances in good shape.

PMID- 15024821
TI  - Dr. George Eastman: a wonderful career!

PMID- 15024822
TI  - Brush with Coca-Cola!

PMID- 15024823
TI  - [Unruptured intracranial aneurysms].

PMID- 15024824
TI  - [Silent brain infarction and white matter lesion].

PMID- 15024825
TI  - [The management for asymptomatic stenoses of carotid and intracerebral arteries].

PMID- 15024826
TI  - [Asymptomatic brain tumor].

PMID- 15024827
TI  - [Diagnosis and therapy of spontaneous intracranial hypotension syndrome].

PMID- 15024828
TI  - [A study of the effect of donepezil hydrochloride on cognitive function in
      patients with dementia of Alzheimer's type using WAIS-R].
AB  - The present study aimed to assess the initial effects of donepezil hydrochloride
      (DPZ) on various aspects of cognitive function in patients with dementia of
      Alzheimer's type (DAT) using the Japanese version of the Wechsler Adult
      Intelligence Scale-Revised (WAIS-R). DPZ was administered to 47 patients with
      mild-to-moderate DAT (D group). The control group comprised 61 patients who had
      been followed up before DPZ was released for use (C group). Both groups underwent
      WAIS-R testing, before and after 10 months of treatment with DPZ for group D, and
      at time of diagnosis of DAT and 10 months later for group C. D and C groups did
      not differ significantly in terms of gender ratio, years of education, age at
      onset of DAT, age at administration of DPZ or at diagnosis of DAT, severity of
      dementia, MMSE score, presence of behavioral and psychological symptoms of
      dementia, concomitant use of psychotropic medication, or initiation of
      rehabilitation. No significant differences were found between D and C groups in
      verbal (V), performance (P) or full-scale (F) intelligence quotient (IQ), or in
      six verbal subtest scores of VIQ and five performance subtest scores of PIQ on
      WAIS-R, before administration of DPZ or at diagnosis of DAT. For differences
      between each score on WAIS-R at diagnosis of DAT or before administration of DPZ
      and 10 months later, DPZ inhibited decreases in FIQ and in VIQ, PIQ, vocabulary,
      similarities, picture arrangement and object assembly subtest scores on WAIS-R.
      These indices are related to concept formation and abstract thinking, which form
      part of executive function. DPZ effectively prevented decline of cognitive
      function, particularly executive function, in patients with DAT.

PMID- 15024829
TI  - [A case of spinocerebellar ataxia 6 accompanied with schizophrenia].
AB  - An abnormally expanded CAG repeats (25, normal; 4-20) was identified in the alpha
      1A voltage-dependent calcium channel (CACNA1A) gene of a 50-year-old Japanese man
      with 25 years history of schizophrenia. At age 45, he first noted unsteadiness of
      standing and gait, which gradually worsened subsequently. In addition to the
      psychiatric symptoms of schizophrenia, neurological examination revealed marked
      truncal ataxia and mild limb ataxia. Brain magnetic resonance imaging showed
      atrophy of the cerebellar vermis. Gene analysis confirmed the diagnosis of
      spinocerebellar ataxia type 6 (SCA 6). No family members showed similar
      neuropsychiatric symptoms except that the patient's father had been suffering
      from an unknown dementing disease. Occurrence of both schizophrenia and SCA 6 in
      the identical patient may be coincidental. However, growing evidence has shown
      that various mutations in the CACNA1A gene are associated with phenotypic
      variability, such as progressive ataxia, episodic ataxia, migraine, coma,
      epilepsy and mental retardation. Therefore, the schizophrenic symptoms,
      association of which with SCA 6 has previously reported in a few cases, may
      represent rare clinical features of the channelopathy associated with the
      mutation in the CACNA1A gene.

PMID- 15024831
TI  - [A case of polymyalgia rheumatica with improved steroid-responsibility after
      discontinuing carbamazepine].
AB  - A 70-year-old woman under anticonvulsive therapy with carbamazepine and valproate
      was diagnosed as polymyalgia rheumatica. She responded to the prednisolone
      therapy so poorly that she required high dose prednisolone and methotrexate, and
      it was difficult to reduce prednisolone. After discontinuing of carbamazepine,
      her steroid response improved immediately. Carbamazepine is known to induce
      hepatic enzyme CYP3A4 and alter metabolism of other drugs. In our case, the
      effect of prednisolone might have been reduced by carbamazepine. This case
      suggests more attention should be paid to the interaction between carbamazepine
      and prednisolone.

PMID- 15024830
TI  - [Riche-Cannieu anastomosis and a paradoxical preservation of thenar muscles in
      carpal tunnel syndrome: a case report].
AB  - A 72-year old woman had been suffered from a dysesthesia in the left median nerve
      distribution, followed by a dysesthesia in the right ulnar distribution.
      Neurological examination revealed weakness in the right intrinsic hand muscles
      with the ipsilateral thenar and hyothenar atrophy. Paradoxical preservation of
      the left thenar muscles was a clinical challenge. Nerve conduction studies
      disclosed bilateral carpal tunnel syndrome and the right cubital tunnel syndrome.
      In needle electromyography, however, the left abductor pollicis brevis and
      opponens pollicis muscles had normal motor unit potentials without denervation
      activity. The needle recording of the left abductor pollicis brevis muscle showed
      a good motor response with a negative deflection by the left ulnar nerve
      stimulation, indicating an ulnar to median nerve innervation, i.e., Riche-Cannieu
      anastomosis. A Riche-Cannieu anastomosis in a setting of a median or ulnar nerve
      injury can produce confusing clinical and electrodiagnostic findings. We reviewed
      clinical findings, electrophysiological data, and the impact of a Riche-Cannieu
      anastomosis in median nerve injury.

PMID- 15024832
TI  - [A case of skeletal muscle type very-long-chain-acyl CoA dehydrogenase(VLCAD)
      deficiency with repeated rhabdomyolysis].
AB  - We experienced a 24-year-old male patient with myalgia and myoglobuinuria
      followed by severe exercise from childhood. In 18 years old, he had severe
      myaglia after a long time-night trip by bus. He was diagnosed as acute renal
      failure induced by rhabdomyolysis and treated with hemodialysis. In 24 years old,
      he was admitted to our hospital because of repeated rhabdomyolysis. We performed
      muscle biopsy from right quadriceps femoris, however histological and
      immunohistochemistological studies were normal. Ischemic forearm exercise test
      showed the elevation of lactic acid in serum. Therefore, we performed the
      analysis of acylcarnitine in serum, and the measurement of enzyme in beta
      oxidation in muscle and white blood cells. These showed the lack of very-long
      chain-acyl coA dehydrogenase (VLCAD) activity. He was diagnosed as skeletal
      muscle type VLCAD deficiency. Under the guidance of high carbohydrate and low fat
      diet, creatine kinase was controlled around 400 IU/l. VLCAD deficiency is
      important to make a differential diagnosis of young cases with recurrent
      elevation of creatine kinase.

PMID- 15024833
TI  - [Two cases of transient global amnesia (TGA) immediately after coronary
      angiography: pathogenesis of the primary TGA].
AB  - Two cases of transient global amnesia (TGA) following coronary angiography are
      reported. Nonionic contrast media was used and injected at room temperature. Both
      cases showed sudden amnesia about 15 minutes after the left ventriculography. A
      clinical feature was typical to TGA, showing repeated questions with retrograde
      and antegrade memory disturbance without any other neurological abnormality.
      Diffusion-weighted images (DWI) of magnetic resonance imaging revealed no fresh
      lesion in both cases. The patients recovered from TGA attack within 24 hours.
      Some cases have been reported which display a manifested TGA following cerebral
      or coronary angiography. In these situations, embolism, the effect by the
      contrast media was suspected as the cause of TGA. Since most TGA cases in a
      classical meaning (primary TGA) showed no abnormality in both DWI and T2-weighted
      image (T2WI), the cerebral ischemia was not really considered to be the cause of
      the condition. Therefore, the pathogenesis of the TGA is suggested to be much
      more functional rather than anatomically abnormal. The pathogenesis of the
      primary TGA was thought to be some kind of hypersensitivity to the external
      stress or the stress reaction of the hippocampal cell. This stress may lead to
      cellular depolarization and the following repolarization (spreading depression),
      which showed transient abnormality in DWI and not a permanent abnormality in
      T2WI.

PMID- 15024835
TI  - [MRI and 1H-MRS findings of central pontine myelinolysis].

PMID- 15024834
TI  - [Clinical usefulness of thallium-201 single-photon emission CT in the patient
      with hypertrophic cranial pachymeningitis].
AB  - We report a 54-year-old female with rheumatoid factor-positive hypertrophic
      cranial pachymeningitis. At age of 51 years she developed headache, hearing loss,
      right vagal nerve palsy, and right accessory nerve palsy. MRI revealed thickening
      and gadolinium-enhancement of the cranial dura mater. The initial symptoms
      significantly improved with corticosteroid therapy. Two years later, she
      presented with severe headache and neck pain. Although gadolinium-enhanced MR
      images failed to show any change compared with those before recurrence, 201Tl
      single-photon emission CT (SPECT) showed a remarkable accumulation of thallium
      201 in the dura mater. Furthermore, the abnormal uptake of thallium-201 returned
      to normal after treatment with corticosteroid. 201T1-SPECT was a useful tool for
      the evaluation of disease activity in the patient with hypertrophic
      pachymeningitis.

PMID- 15024836
TI  - [Odontoid process fracture as the initial presentation of multiple myeloma].

PMID- 15024837
TI  - [Relationships between dioxin concentrations in deposited dust and those in serum
      of workers at municipal waste incineration plants].
AB  - Relationships between concentrations of polychlorodibenzo-p-dioxins (PCDDs) and
      polychlorodibenzofurans (PCDFs) in deposited dust and those in the serum of
      incinerator workers were examined at 13 municipal incineration plants. The
      following results were found. 1) Dust analysis showed that dominant constituents
      were octachlorodibenzo-p-dioxin (OCDD) and 1, 2, 3, 4, 6, 7, 8-heptachlorodibenzo
      p-dioxin (HpCDD) among PCDDs, and 1, 2, 3, 4, 6, 7, 8-heptachlorodibenzofuran
      (HpCDF) and octachlorodibenzofuran (OCDF) among PCDFs. The toxicity equivalents
      (TEQs) of total PCDDs and PCDFs in the deposited dust were 0.54 to 33 ngTEQ/g,
      which were about 1,000 to 10,000 times as high as those in general soil. 2) The
      mean of serum TEQ of PCDDs, that of PCDFs and that of total PCDDs and PCDFs in
      the incinerator workers were 16, 12 and 28 pg TEQ/g lipid, respectively, for all
      the incinerator workers. Concentrations of hexachlorodibenzofurans (HxCDFs) and
      HpCDFs in the serum were significantly higher in the incinerator workers than the
      general population, which suggests that these workers had inhaled these chemicals
      during their work. 3) The concentration of 1, 2, 3, 4, 6, 7, 8-HpCDF and the TEQ
      value of PCDFs and in the serum were positively correlated with those in dust
      except for three plants where large-scale remodeling of the equipment was
      conducted within the past seven years. Consequently, deposited dust analysis may
      be useful for judging whether health examination containing blood dioxin
      measurement is necessary or not.

PMID- 15024838
TI  - [Problems of management for workers with Brugada syndrome].

PMID- 15024840
TI  - [Virus infection and interferon system].

PMID- 15024839
TI  - [Investigation of the cause of contact dermatitis due to heavy metal in a metal
      spray process in a film-condenser factory].
AB  - To investigate causes of contact dermatitis in the metal spray process in a film
      condenser factory, we developed a questionnaire survey for workers exposed to
      metal dust, analyzed the metal dust, and conducted patch tests with the metal
      dust and its constituents. In the questionnaire survey, we identified 12 workers
      (12/26, 46.2%) who had had dermatitis. The main symptoms were itching, itchy red
      skin and itchy papules. Analysis of the metal dust showed that there was no
      copper oxide, but nickel, not contained in the materials of the metal spray, was
      detected. One worker with dermatitis had a positive reaction to 2.5% nickel
      sulphate. Some of the workers showed primary irritant reactions to 5% copper
      sulphate. As a result, we considered that these cases of dermatitis involved
      irritant contact dermatitis due to copper and/or allergic contact dermatitis due
      to nickel. To prevent dermatitis, we recommended improvement in ventilation,
      reducing the room temperature to reduce sweating, and to educate workers on the
      importance of frequent hand washing. Thereafter, the incidence of dermatitis
      decreased, and there were no cases requiring medication.

PMID- 15024841
TI  - [Virus interference with the host interferon-induction system].

PMID- 15024842
TI  - [Diversity of suppression mechanisms of JAK/STAT pathway by virus infection].

PMID- 15024843
TI  - [Molecular mechanisms on interferon resistance of hepatitis C virus].

PMID- 15024844
TI  - [Electron cryomicroscopy of the bacterial flagellar nanomachine].

PMID- 15024845
TI  - [Multiple roles of the actin family in the cell nucleus].

PMID- 15024847
TI  - [Legislation of MEXT guidelines for research involving recombinant DNA
      molecules].

PMID- 15024846
TI  - [Establishment of the bill on living modified organisms (LMOs) and its
      background].

PMID- 15024848
TI  - [Computational chemistry and bioinformatics: grid computing for protein
      simulation].

PMID- 15024849
TI  - [What can and cannot be patented: novel, non-obvious, and concrete invention].

PMID- 15024850
TI  - [In memory of Dr. Kosaku Maruyama].

PMID- 15024851
TI  - Avian influenza A(H5N1).

PMID- 15024853
TI  - Database of public health chemical incidents: first year pilot phase report.

PMID- 15024852
TI  - Monitoring the interruption of indigenous measles transmission, Cape Town
      meeting, 14 October 2003.

PMID- 15024854
TI  - Avian influenza A(H5N1) in humans and poultry, Vietnam.

PMID- 15024855
TI  - Announcement of suspected severe acute respiratory syndrome (SARS) case, southern
      China--update.

PMID- 15024856
TI  - Global Advisory Committee on Vaccine Safety, 3-4 December 2003.

PMID- 15024857
TI  - Porter Physiology Development Program 1967-2001: a retrospective study.
AB  - The Porter Physiology Development Program Fellowships have supported the
      predoctoral and postdoctoral studies of numerous minority students. All of the
      Fellows responding to the current survey continue to be involved in life sciences
      related work, primarily as physiologists-in-training or as physiologists working
      in academia, government, or industry. Following receipt of their degree, the
      large majority of Fellows completed a single postdoctoral fellowship and entered
      their first professional position. Most employed past-Fellows spent at least part
      of their time engaged in research and were also involved in teaching, management,
      and administration. Respondents felt strongly that the Porter Fellowship had
      contributed to the quality of their pre/postdoctoral training. They felt it gave
      them intellectual freedom to select research advisors and topics or postdoctoral
      positions. They also felt the financial freedom provided by the Fellowship
      allowed them to concentrate on their research, contributing both to the quality
      of their work and to their overall career commitment. Fellows strongly
      recommended continuation of the program and offered suggestions for expansion and
      increased communication. Finally, one of the most powerful benefits of the
      program is in its longitudinal impact. Past Fellows now serve as role models for
      a new generation of minority students aspiring to careers in biomedical research.
      Some have their own graduate students who have received the Porter Fellowship.
      One such Fellow emphasized the importance of this aspect of the program: I was
      always told by my colleagues that I would be a good role model to minority
      students. Having Fellowships like the Porter Development Fellowship insures the
      training of minority professionals. Young minority students have hope of becoming
      scientists when they see those of us who have made it. I have graduate students
      who tell me that they want a laboratory and to do research like I am doing which
      makes me feel that I have accomplished something [important]. As stated earlier,
      the goal of the Porter Physiology Fellowship Program is to encourage diversity
      among students pursuing full-time studies toward the PhD (or DSc) in the
      physiological sciences, and to encourage their participation in the APS. The
      findings of this retrospective study suggest that the program has been highly
      successful in both of these aspects.

PMID- 15024858
TI  - European welfare standards may affect US research.

PMID- 15024859
TI  - FY 04 funds await final Nod; FY 05 prospects are grim.

PMID- 15024860
TI  - [The SBU report on the treatment of depression can increase the quality of care.
      Hopefully it will be read!].

PMID- 15024861
TI  - [Breakthrough pain--analysis and therapy. A pilot study of a new drug,
      transmucosal fentanyl (Actiq)].

PMID- 15024863
TI  - [A video archive on the Internet for dissemination of knowledge of minimally
      invasive techniques].

PMID- 15024862
TI  - [Cognitive behavior therapy via Internet. Patients with tinnitus are helped to
      manage their problem--simpler and cheaper].
AB  - Cognitive-behavioural therapy (CBT) is effective in reducing distress in tinnitus
      patients. To make CBT more available, an Internet-based self-help treatment has
      been used since 1999 at the department of Audiology, Uppsala University hospital.
      After initial medical and psychological assessment the patients get access to the
      Internet treatment. The treatment programme is divided into six weeks, and each
      week the patient chooses treatment components, reads information and
      instructions, plans the training and then practises during one week. The patient
      prints out registration sheets and reports the progress at the web site,
      receiving E-mail feedback from the therapist. It is important to keep in contact
      with the patient. The efficacy of the treatment has been shown in two randomised
      controlled studies, showing significantly better result then a waiting-list
      control group and equal result compared to a CBT group treatment respectively. A
      recent replication showed that the results can be generalised to a clinical
      setting.

PMID- 15024864
TI  - [Emotional and physical pain are processed by the brain in a similar way].

PMID- 15024865
TI  - [Treatment of depressive disorders. A systematic literature review. The SBU's
      summary and conclusions].

PMID- 15024866
TI  - [Children's right of survival--vulnerable status in spite of progress].

PMID- 15024867
TI  - [Lack of willingness and resources are obstacles for better health among children
      and adolescents].

PMID- 15024868
TI  - [Depression--a gender-disease in drug advertisement].

PMID- 15024869
TI  - [Lakartidningen 70 years ago: homosexuality--a disease].

PMID- 15024870
TI  - [Frida Kahlo: "I'm a champion of the world when it comes to surgical
      interventions"].

PMID- 15024871
TI  - [Changed attitudes and increased control is necessary to reduce sick listing].

PMID- 15024872
TI  - [Get rid of sickness certificates, introduce health declaration].

PMID- 15024873
TI  - [A final reply: ask the men if they beat their women].

PMID- 15024875
TI  - [Sick listing--correct and more insurance-based assessment is necessary].

PMID- 15024874
TI  - [Work-related musculoskeletal problems--paradigmatic shift in research is
      necessary].

PMID- 15024876
TI  - [Physiotherapists should participate in sick listing].

PMID- 15024877
TI  - [Everything revealed!].

PMID- 15024878
TI  - [Mental health services' personnel and Anna Lindh's murderer--what does the
      Lakartidningen mean?].

PMID- 15024879
TI  - [Drug industry is not to be subsidized by the society].

PMID- 15024880
TI  - [The medical profession needs a strong voice and a clear message].

PMID- 15024881
TI  - [Organ procurement activities at the Karolinska University Hospital are going
      on].

PMID- 15024882
TI  - [Prohibit coloring agents in drugs].

PMID- 15024883
TI  - [New strategies in emergency treatment].

PMID- 15024884
TI  - Key developments in heart surgery.

PMID- 15024885
TI  - The heart in systemic disease.

PMID- 15024886
TI  - Pacemakers: a guide for GPs.

PMID- 15024887
TI  - A rational approach to hypertension.

PMID- 15024888
TI  - The GP's role in erectile dysfunction.

PMID- 15024889
TI  - Thyroid disease.
AB  - Evaluation and treatment of thyroid disease is a common feature of primary care
      medicine. Nevertheless, the dose of thyroid hormone used to treat hypothyroidism
      is frequently not titrated to normalize the TSH, engendering the risks of under-
      or overtreatment. Other hypothyroid patients remain symptomatic even with
      normalized TSH on levothyroxine alone. Some of these patients improve
      symptomatically when liothyronine is added to the treatment regimen. Subclinical
      hypothyroidism and hyperthyroidism are also relatively common in primary care
      medical practice, and appropriately selected patients probably benefit from
      treatment. In the follow-up of patients treated for thyroid cancer, the use of
      rhTSH improves patient comfort considerably while allowing sensitive screening
      for persistent or recurrent cancer.

PMID- 15024890
TI  - Management of dyslipidemias in the age of statins.
AB  - Evidence for the effectiveness of lipid-lowering therapy in reducing CHD risk
      continues to emerge. In primary prevention, clinical trials have demonstrated a
      benefit for middle-aged, high-risk men with high LDL cholesterol and, more
      recently, for men and women with "average" LDL and low HDL cholesterol. Although
      low HDL cholesterol, small dense LDL particles, elevated lipoprotein (a),
      elevated apolipoprotein B, and the dyslipidemia of the metabolic syndrome pose an
      increased in CHD risk in some patients, the risk reduction with lipid-lowering
      therapy has not been fully investigated. The CHD risk of isolated
      hypertriglyceridemia remains uncertain. Very high triglyceride levels, however,
      should be treated to prevent pancreatitis. A lipid-lowering diet and other
      appropriate lifestyle changes constitute safe advice for all patients with
      dyslipidemia. In initiating pharmacologic therapy, physicians should view
      potential risk reduction in the context of a patient's overall CHD risk. The
      selection of particular medications can be individualized, considering
      effectiveness evidence from clinical trials, lipid-lowering potency, adverse
      effects, drug interactions, costs, and patient preferences.

PMID- 15024891
TI  - Postmenopausal hormone therapy: a concise guide to therapeutic uses,
      formulations, risks, and alternatives.
AB  - Postmenopausal hormone replacement therapy is helpful in relieving menopausal
      vasomotor symptoms and vaginal atrophy and can prevent osteoporosis; however,
      attendant risks include breast cancer, thromboembolism, gallbladder disease,
      stroke, CHD, dementia, and hypertriglyceridemia. Decision making must weigh these
      risks and benefits and also include potential benefits on mood, colorectal cancer
      prevention, and hip fracture reduction. Some areas, such as ovarian cancer risk
      and the impact of combination estrogen-progestin versus unopposed estrogen on
      risk, remain unclear. The physician and patient need to carefully assess,
      discuss, and monitor the individual's symptoms and risks when considering HT use.
      For those with contraindications or concerns about HT, there are alternative
      therapies of variable efficacy for vasomotor symptoms and vaginal atrophy.

PMID- 15024892
TI  - Polycystic ovary syndrome: a review for primary providers.
AB  - PCOS is a metabolic syndrome that exists throughout the world with much clinical
      heterogeneity. PCOS is now appreciated as encompassing two interrelated metabolic
      phenomena--insulin resistance and hyperandrogenism. Patients present with oligo
      amenorrhea and clinical hyperandrogenism, and the diagnosis is based on clinical
      grounds with few laboratory tests necessary. Because patients are at higher than
      normal risk for diabetes, glucose intolerance, and hyperlipidemia, and perhaps at
      higher risk for coronary heart disease, newly diagnosed patients with PCOS should
      be evaluated for glucose intolerance and hyperlipidemia. The cornerstone of
      therapy today includes weight management, and further therapeutic intervention is
      focused on reproductive and cardiovascular health and treatment of insulin
      resistance. Clinical case continued The 17-year-old mentioned in the beginning of
      this article probably does have PCOS. She fits the clinical criteria: oligo
      ovulation and hyper-androgenism (the acne and hirsutism). In addition, she is
      obese, which is also associated with PCOS. Her TSH and prolactin were normal, and
      as her presentation was not suggestive of an adrenal tumor or congenital adrenal
      hyperplasia (she had mild hirsutism, and those diagnoses are associated with more
      severe hyperandrogenism), no further laboratory evaluation was deemed necessary.
      Once the diagnosis was made, she was screened for lipid abnormalities and for
      glucose intolerance. Her LDL was 150, HDL 35; oral glucose tolerance test (OGTT)
      was normal. A pregnancy test was negative, and she was started on OCPs. Devoting
      herself to exercise and dietary change, she lost 10 pounds in her first 3 months
      after diagnosis. Her hirsutism and acne have improved with the OCPs and weight
      loss, and her menses are regular. She has elected to defer oral insulin
      sensitizers until her weight loss has stabilized. Findings PCOS is common in
      reproductive-aged women. Diagnosis is clinical and is supported by lab findings;
      there is significant clinical heterogeneity. Insulin resistance is likely central
      to the pathophysiology along with androgen excess. Health implications include
      infertility, diabetes, endometrial cancer, hyperlipidemia, and possibly coronary
      heart disease. Treatment is evolving and includes weight loss, OCPs, and insulin
      sensitizers.

PMID- 15024893
TI  - Osteoporosis management in the new millennium.
AB  - The prevalence of osteoporosis in all US postmenopausal women is 17%, and it is
      as high as 30% in women older than 65. All postmenopausal women should be
      encouraged to have adequate daily calcium and vitamin D intake, to exercise
      regularly, and to avoid tobacco and excessive alcohol use. Although the clinical
      impact and cost-effectiveness of osteoporosis screening tools remain to be
      established, a rational approach based on current evidence involves using
      National Osteoporosis Foundation guidelines, Simple Calculated Osteoporosis Risk
      Estimation, or Osteoporosis Risk Assessment Instrument clinical decision rules to
      decide when a postmenopausal woman should undergo further evaluation.

PMID- 15024894
TI  - Male hypogonadism in the primary care clinic.
AB  - Hypogonadism is common in clinical practice but is frequently unrecognized and
      underdiagnosed. The common causes of male hypogonadism vary with the age of
      presentation. The overall prevalence of male hypogonadism based upon low serum
      total testosterone levels is high and increases with age. There are many pitfalls
      in making the diagnosis of male hypogonadism. First, male hypogonadism is
      sometimes difficult to recognize because the signs and symptoms are often
      nonspecific and overlap with other common syndromes. Second, the biochemical
      diagnosis of male hypogonadism is not straightforward because it might not be
      clear which testosterone assay to select from the many that are available.
      Finally, even after the diagnosis of male hypogonadism is made, the patient and
      clinician must weigh the potential benefits and risks of androgen replacement
      therapy. However, new diagnostic tools and therapies are making decisions easier.

PMID- 15024895
TI  - Diagnosis and management of pituitary tumors: recent advances.
AB  - In recent years, the medical therapy for prolactinomas and GH-secreting adenomas
      has greatly improved due to the availability of new, highly effective, long
      acting dopamine and somatostatin analogues. Although medical therapy has for some
      time been the first-line approach to prolactinoma management, the incidence of
      patients requiring surgery for resistance or intolerance/noncompliance is likely
      to decrease substantially with these new agents. Increasing efficacy and greater
      ease of administration of somatostatin analogues for GH, and for rare TSH,
      adenomas are also anticipated to lead to less reliance on surgery and radiation
      therapy as the primary therapy in these disorders. Although somewhat unclear at
      this time, GH antagonists hold promise for alternative or adjunct therapy for
      acromegaly. Given the significant morbidity and mortality associated with
      acromegaly, these advances are quite encouraging. Unfortunately, little if any
      progress has been made toward establishing an effective medical treatment for
      gonadotropin or nonsecreting tumors. However, new approaches to delivery of
      radiation therapy may reduce some of the inconvenience and risk of this treatment
      for patients when surgery alone is inadequate. In all of these disorders, the
      challenge to physicians and their patients remains one of choosing a rational
      combination of medical, surgical, and radiation therapy. Fortunately, for most
      patients, control, if not cure, of their pituitary adenoma is a reasonable
      expectation.

PMID- 15024896
TI  - Issues in the diagnosis of Cushing's syndrome for the primary care physician.
AB  - The diagnosis of Cushing's syndrome is one of the most difficult and yet one of
      the most important ones a primary care physician can make. The clinical
      presentation overlaps that of many other common diseases, but more specific signs
      such as unexplained osteoporosis, muscle weakness, ecchymoses, hypokalemia, and
      central obesity, the presence of multiple symptoms affecting different body
      systems, and a demonstrated change over time should prompt the screening
      evaluation. We recommend a step-wise approach to the diagnostic evaluation. Step
      1 involves demonstrating pathologic hypercortisolemia and thus making the
      diagnosis of Cushing's syndrome. In step 2, distinguishing ACTH-independent
      disease from ACTH-dependent disease and then adrenal imaging is done. Finally,
      for patients with ACTH-dependent disease, step 3 entails anatomic localization of
      the ACTH source by MRI, if unequivocal, or by IPSS or CSS. Only when the
      evaluation is done in a step-wise fashion can the clinician be assured that
      appropriate treatment recommendations can be made. Although a fair amount of the
      testing is complex, requiring special facilities and usually the assistance of an
      endocrinologist, the most critical step is that done by the primary care
      physician--considering the diagnosis and initiating the screening algorithm.

PMID- 15024897
TI  - Hyperaldosteronism and pheochromocytoma: new tricks and tests.
AB  - Hyperaldosteronism, previously thought to represent only 1% to 2% of cases of
      hypertension, may cause as much as 25% of hypertension in a primary care setting.
      The renin/aldosterone ratio is the best test for initial screening, followed by
      localization if possible. Aldosterone antagonists, such as spironolactone, and
      surgery are the mainstays of treatment. Pheochromocytomas are rare, but because
      they are a curable cause of hypertension and potentially fatal if not found,
      important to diagnose. Clinical presentation is variable; however, if symptoms
      are present, they usually include hypertension, hyperhydrosis, headaches, or
      palpitations sometimes occurring in dramatic fashion. Once a diagnosis is
      entertained, appropriate laboratory confirmation is essential. Positive
      laboratory confirmation then leads to localization of the tumor for eventual
      surgical removal. New biochemical tests and imaging procedures are making the
      difficult job of diagnosing and finding these tumors.

PMID- 15024898
TI  - Put suspension trauma in proper perspective.

PMID- 15024899
TI  - Investigate training requirements.

PMID- 15024900
TI  - Calibration using 'equivalent' gases.

PMID- 15024902
TI  - An inspector gadget.

PMID- 15024901
TI  - Assessing and defusing workplace threats of violence.

PMID- 15024903
TI  - Another simple method for estimating air delivery.

PMID- 15024904
TI  - Why warnings fail.

PMID- 15024905
TI  - Whose symbols are safer?

PMID- 15024906
TI  - Using PIDs in confined spaces.

PMID- 15024907
TI  - Alternative technologies and avoiding entry.
AB  - Specialized equipment, changes to procedures, non-entry by design, and
      customized/creative approaches can eliminate or reduce the frequency of the need
      to enter confined spaces. Consider the new safety hazards that may be created,
      but always remember: The safest entry is no entry at all!

PMID- 15024910
TI  - Enforcing PPE use.

PMID- 15024909
TI  - Who's buying the brands?

PMID- 15024908
TI  - Add impact to your program.

PMID- 15024912
TI  - Don't get burned.

PMID- 15024911
TI  - Security vulnerability assessments.

PMID- 15024913
TI  - WHO Expert Committee on Specifications for Pharmaceutical Preparations.
AB  - This report presents the recommendations of an international group of experts
      convened by the World Health Organization to consider matters concerning the
      quality assurance of pharmaceuticals and specifications for drug substances and
      dosage forms. Of particular relevance to drug regulatory authorities and
      pharmaceutical manufacturers, this report discusses the latest volume of The
      International Pharmacopoeia and quality specifications for pharmaceutical
      substances and dosage forms, as well as quality control of reference materials,
      good manufacturing practices (GMP), inspection, distribution and trade and other
      aspects of quality assurance of pharmaceuticals, and regulatory issues. The
      report is complemented by a number of annexes, including recommendations on good
      trade and distribution practices for pharmaceutical starting materials,
      guidelines on the WHO scheme for the certification of pharmaceutical materials
      moving in international commerce, draft procedures for assessing quality control
      laboratories and procurement agencies for use by United Nations agencies, and
      guidelines for preparing a laboratory information file and a procurement agency
      information file.

PMID- 15024914
TI  - Social work and end-of-life care for older people: a historical perspective.
AB  - End-of-life issues became increasingly complicated during the 20th century as
      profound shifts occurred in who died, how they died, and when they died. This
      article reviews societal changes related to death in the United States and
      chronicles the developments in social work practice with and for dying people and
      their families in the 20th century, leading up to the 1993 policy statement of
      the National Association of Social Workers on end-of-life decision making, which
      reinforced that client self-determination, a fundamental principle of social
      work, should apply to people planning for their deaths or undergoing a dying
      process. After identifying limitations in policies and practices, suggestions are
      offered to promote competent social work practice and enhance end-of-life care,
      particularly with reference to the dying process of older people.

PMID- 15024915
TI  - Factors that influence consideration of hastening death among people with life
      threatening illnesses.
AB  - Although the debate about whether an individual with a life-threatening illness
      should have the right to hasten his or her death continues, few researchers have
      examined why someone might consider such an option. This study examined factors
      that contribute to consideration of hastening death among people with life
      threatening illnesses. A discriminant function analysis was conducted to
      determine what factors distinguished between people who had self-identified as
      either contemplating or not contemplating hastening their deaths. Of the
      variables examined, depression, social support, and hope distinguished between
      the two groups. Pain and anxiety appeared to play no role in distinguishing
      between the two groups. The results are presented and implications for social
      work practice and research are discussed.

PMID- 15024916
TI  - Nurses' and social workers' attitudes and beliefs about and involvement in life
      sustaining treatment decisions.
AB  - Data were collected from 213 nurses and 61 social workers at major hospitals
      across Israel. Whereas nurses reported being more involved in the daily care of
      terminally ill patients, social workers reported being more involved in
      discussions with patients and family members. Nurses were more willing than
      social workers to use artificial feeding and less willing to use mechanical
      ventilation and CPR for all conditions. Social workers expressed stronger beliefs
      about their involvement in end-of-life issues. These findings, which reflect the
      differences in the professional values and experiences of both groups, encourage
      the use of interdisciplinary teams to improve end-of-life decision making.

PMID- 15024918
TI  - Hope as a strategy in supervising social workers of terminally ill patients.
AB  - This article focuses on supervision of social workers who feel despair and
      hopelessness in treating terminally ill patients. The emotional difficulties that
      may lead to these feelings are discussed. A special model of supervision that
      relates to hope as a strategy to help social workers cope with such difficulties
      is presented. The model suggests goals in supervising such social workers and
      outlines the means and techniques for achieving the goals.

PMID- 15024917
TI  - Oncology social workers' attitudes toward hospice care and referral behavior.
AB  - Members of the Association of Oncology Social Workers completed a survey, which
      included the Hospice Philosophy Scale (HPS) assessing the likelihood of the
      worker referring a terminally ill patient to hospice, background and experience,
      and demographics. The respondents held overwhelmingly favorable attitudes toward
      hospice philosophy and care, yet the average proportion of terminally ill
      patients whom they referred to hospice was only 49.5 percent. The worker's HPS
      score was related significantly, although weakly, to the likelihood of referral.
      A follow-up study was undertaken to determine the reasons for the discrepancy
      between the workers' self-reported favorable attitudes toward hospice and their
      relatively low rate of patient referral. The factor identified most frequently
      was resistance from families because of the requirement that hospice patients
      discontinue active treatment.

PMID- 15024919
TI  - The ambiguous dying syndrome.
AB  - More than one-half of the 2.4 million deaths that will occur in the United States
      in 2004 will be immediately preceded by a time in which the likelihood of dying
      can best be described as "ambiguous." Many people die without ever being
      considered "dying" or "at the end of life." These people may miss out on the
      opportunity to close important relationships and make financial and legal
      arrangements that can benefit themselves and their survivors. They may
      inadvertently forgo palliative care that is available to comfort them physically,
      emotionally, and spiritually. This article calls for a broader conceptualization
      of the end of life to include not just the time when death is foreseeable, but
      also the time when people are at a greatly increased risk of death, although the
      timing is highly uncertain. Social workers have much to offer people affected by
      the "ambiguous dying syndrome."

PMID- 15024920
TI  - Social workers' participation in the resolution of ethical dilemmas in hospice
      care.
AB  - Ethical dilemmas are inherent in every health care setting. A sample of hospice
      social workers with no direct access to a hospice ethics committee (N = 110) was
      surveyed regarding ethical issues in hospice care, how the issues were managed,
      and the extent to which social workers participated in resolution of ethical
      dilemmas. Common issues discussed were the patients' medical condition,
      involvement of family, and family denial of terminal illness. Difficult cases
      were discussed most often in interdisciplinary team meetings. Social workers were
      most involved in traditional social work activities, such as providing knowledge
      of community resources and patients' psychosocial histories and promoting self
      determination in policies.

PMID- 15024921
TI  - Improving our care at life's end: making a difference.

PMID- 15024922
TI  - Clinical trials in parasitic diseases.

PMID- 15024923
TI  - Real-time polymerase chain reaction diagnosis of leishmaniasis in Panama from
      both fresh and frozen tissue.
AB  - Skin biopsies stored in ethanol from 49 patients with suspected cutaneous
      leishmaniasis (CL) were tested in a real-time polymerase chain reaction (PCR)
      assay and compared with conventional diagnostic methods. With clinical diagnosis
      as the gold standard, PCR had a sensitivity of 96% (47/49) vs. 61% (30/49) for
      histopathology and 33% (16/49) for culture. In addition, DNA was extracted from
      70 frozen smears of lesions from suspected cases of CL and tested with the same
      assay. In these samples, the PCR had a sensitivity of 61% (43/70) vs. 56% (39/70)
      for histopathology and 41% (29/70) for culture. In this study, real-time PCR
      offered a rapid diagnosis with an enhanced sensitivity over conventional methods.
      Although the yield of PCR diagnosis was lower when testing frozen smears, the
      assay still outperformed existing diagnostic modalities.

PMID- 15024924
TI  - Combined field and laboratory evaluation of a long-term impregnated bednet,
      PermaNet.
AB  - For how long does the insecticidal effect of long-lasting nets achieve high
      Anopheles mortality? Four PermaNets tested previously in Colombia for wash
      resistance were bioassayed again after 3 years of use and 23 washes. The tests
      were done both in Colombia and a reference laboratory in Indonesia. Additionally
      the residual concentration of deltamethrin on the nets was chemically analysed.
      The results showed high Anopheles mortality and a mean deltamethrin concentration
      of 9.6 mg/m2. Discrepancies with other studies are discussed.

PMID- 15024926
TI  - American cutaneous leishmaniasis in two cats from Rio de Janeiro, Brazil: first
      report of natural infection with Leishmania (Viannia) braziliensis.
AB  - We describe the isolation of Leishmania (Viannia) braziliensis from two female
      cats with American cutaneous leishmaniasis in Rio de Janeiro, Brazil. The
      isolates were identified as L. (V.) braziliensis by isoenzyme electrophoresis.

PMID- 15024927
TI  - Compliance with 14-day primaquine therapy for radical cure of vivax malaria--a
      randomized placebo-controlled trial comparing unsupervised with supervised
      treatment.
AB  - The only available treatment that can eliminate the latent hypnozoite reservoir
      of vivax malaria is a 14 d course of primaquine (PQ). A potential problem with
      long-course chemotherapy is the issue of compliance after clinical symptoms have
      subsided. The present study, carried out at an Afghan refugee camp in Pakistan,
      between June 2000 and August 2001, compared 14 d treatment in supervised and
      unsupervised groups in which compliance was monitored by comparison of relapse
      rates. Clinical cases recruited by passive case detection were randomised by
      family to placebo, supervised, or unsupervised groups, and treated with
      chloroquine (25 mg/kg) over 3 days to eliminate erythrocytic stages. Individuals
      with glucose-6-phosphate dehydrogenase (G6PD) deficiency were excluded from the
      trial. Cases allocated to supervision were given directly observed treatment
      (0.25 mg PQ/kg body weight) once per day for 14 days. Cases allocated to the
      unsupervised group were provided with 14 PQ doses upon enrollment and strongly
      advised to complete the course. A total of 595 cases were enrolled. After 9
      months of follow up PQ proved equally protective against further episodes of P.
      vivax in supervised (odds ratio 0.35, 95% CI 0.21-0.57) and unsupervised (odds
      ratio 0.37, 95% CI 0.23-0.59) groups as compared to placebo. All age groups on
      supervised or unsupervised treatment showed a similar degree of protection even
      though the risk of relapse decreased with age. The study showed that a presumed
      problem of poor compliance may be overcome with simple health messages even when
      the majority of individuals are illiterate and without formal education.
      Unsupervised treatment with 14-day PQ when combined with simple instruction can
      avert a significant amount of the morbidity associated with relapse in
      populations where G6PD deficiency is either absent or readily diagnosable.

PMID- 15024925
TI  - Relative lack of clinical disease among household contacts of tuberculosis
      patients compared to leprosy households.
AB  - The incidence of clinical tuberculosis and clinical leprosy among household
      members of tuberculosis and leprosy patients in Sri Lanka was studied. The study
      period was approximately 20 years (January 1981 to December 2001) and the total
      number of patients and contacts were 325 and 968 for tuberculosis and 726 and
      3066 for leprosy, respectively. While none of the tuberculosis patient households
      had more than 1 patient nor any contacts who developed clinical disease during
      the observation period, 20% (148/726) of the leprosy patients had more than 1
      patient in the family and 0.9% (13/1403) of their contacts who were followed-up
      developed clinical leprosy during the observation period. Although the
      tuberculosis patient household contacts did not develop clinical disease, in 79%
      (88/112) of contacts who were tested by Western blot analysis, there was
      serologic evidence of Mycobacterium tuberculosis infection. These data show that
      in populations of comparable socio-economic, environmental and geographic
      locations, tuberculosis and leprosy show very different transmission patterns. In
      general, in tuberculosis household contacts, in spite of exposure, infection did
      not proceed to clinical disease. In contrast, a significant number of leprosy
      household contacts developed clinical leprosy. These findings have implications
      in the design and implementation of control programmes for these two diseases.

PMID- 15024928
TI  - Impact of two annual single-dose mass drug administrations with
      diethylcarbamazine alone or in combination with albendazole on Wuchereria
      bancrofti microfilaraemia and antigenaemia in south India.
AB  - A two-arm community-based lymphatic filariasis elimination trial is being carried
      out in Tamil Nadu state, India to assess the effect of 2 annual single-dose mass
      drug administrations of diethylcarbamazine + albendazole (DEC + ALB) on
      microfilaraemia and antigenaemia in one arm, and diethylcarbamazine(DEC) alone in
      the other arm. In a cross-sectional survey at each time-point, 450-650 subjects
      in childhood (2-9 years old) and young adulthood (10-25 years old) were screened
      from each treatment arm. After 2 annual mass drug administrations,
      microfilaraemia prevalence in the 2-drug arm was reduced by 54% and 62% in the 2
      9 year old and 10-25 year old groups respectively; and corresponding figures for
      the single-drug arm were 26% and 37%. Though higher reductions were recorded for
      geometric mean intensity of microfilaraemia in the 2-9 year old groups for both
      treatment arms, reduction was more pronounced in the 2-drug arm than the single
      drug arm (74% vs. 24%) in the 10-25 year old group. The reduction in the
      antigenaemia prevalence in the 2-9 year old group was evident in both treatment
      arms, but in the 10-25 year old group the reduction was only 16.8% in the 2-drug
      arm. Our results suggest that the annual, single-dose combination (DEC + ALB)
      mass treatment regimen has an enhanced effect against bancroftian filariasis
      compared to single-drug therapy.

PMID- 15024929
TI  - Optimising operational use of artesunate-mefloquine: a randomised comparison of
      four treatment regimens.
AB  - A randomised trial was conducted in adults and children (> 1 year old) with acute
      falciparum malaria in Western Myanmar to compare the operational effectiveness of
      4 different artesunate-mefloquine combinations. All regimens were well tolerated.
      During 42 days follow-up polymerase chain reaction genotyping-confirmed
      recrudescence occurred in 11 of 187 (5.9%) patients who received observed single
      low-dose mefloquine (15 mg/kg) and artesunate (4 mg/kg), 7 of 192 (3.6%) patients
      following observed single high-dose mefloquine (25 mg/kg) and artesunate (4
      mg/kg), 7 of 180 (3.9%) patients following observed artesunate 4 mg/kg on day 0
      plus self-administered mefloquine 15 mg/kg on day 1 and 10 mg/kg on day 2 with
      artesunate 4 mg/kg/day on day 1 and 2, and none of 177 patients who received this
      3 d regimen under direct observation (P = 0.01). Compared with 3 d treatment
      regimens, single dose treatments were followed by significantly more P vivax
      infections during the 42 d follow-up (P = 0.009). Post treatment anaemia
      (haemoglobin < 10 g/dL) was reduced by the 3 d regimens. Gametocyte appearance
      was low with all 4 regimens. Single dose observed mefloquine-artesunate regimens
      were very effective, but the 3 d artesunate-mefloquine regimen is the best
      treatment for acute falciparum malaria in Western Myanmar. Active measures to
      ensure absorption and improve adherence will be necessary to realise this
      advantage operationally.

PMID- 15024930
TI  - Case report: unusual presentation of Fasciolopsis buski in a Vietnamese child.
AB  - A Vietnamese child presented with a history of abdominal pain. Shortly
      afterwards, he vomited eight live trematode flukes that were collected and
      morphologically identified as Fasciolopsis buski. The identification was
      confirmed by DNA analysis. Adult worms of F. buski from humans are very rarely
      seen except at autopsy, and this is the first such report from Vietnam.

PMID- 15024931
TI  - [Gene therapy in pancreatic cancer].
AB  - Pancreatic cancer is the fifth cause of cancer death in the developed world. It
      is a highly malignant disease, characterised by aggressive local spread and early
      locoregional and hepatic metastasis. Surgery offers the only prospect of long
      term survival, but the resectability ratio is very low at the time of diagnosis.
      Conventional chemo- and radiotherapy are relatively ineffective, that is why
      development of newer therapeutic alternatives are encouraged. Gene therapy came
      into the limelight of interest. Authors discuss the fundamental scientific
      principle and clinical experience in connection with gene therapy of pancreatic
      cancer. Different targets include antisense strategies, gene-replacement, gene
      directed prodrug activation therapy, promoter gene strategies, as well as
      oncolytic viruses.

PMID- 15024932
TI  - [Lipid profile in patients with systemic lupus erythematosus, with special focus
      on lipoprotein(a) in lupus nephritis].
AB  - Systemic lupus erythematosus (SLE) is a multifactorial polysystemic autoimmune
      disorder. Although life expectance in SLE has been improved by adequate immune
      suppressive therapy, the importance of chronic renal failure has not been
      reduced. Among late complications of the disease accelerated atherosclerosis
      attempts increasing attention. Dyslipoproteinemia and increased concentration of
      lipoproteins are important risk factors of atherosclerotic cardiovascular
      complication in SLE. Serum lipid parameters of 50 patients with lupus were
      examined in the present work. Thirty patients had histologically proven lupus
      nephritis (LN+), while the other group did not have renal involvement (LN-).
      Serum triglyceride, total cholesterol, LDL-C and apolipoprotein B (apoB)
      concentrations were significantly higher in the lupus nephritis (LN+) group. On
      the other hand, HDL-C and apoAI levels were also elevated in patients with LN. As
      a consequence of that, LDL-C/HDL-C and the apoB/apoAI ratios did not differ
      between patients with or without kidney involvement. This concluded the authors
      to measure the concentration of lipoprotein (a) in SLE patients, as Lp(a) is
      known to be an independent risk factor of atherosclerosis. Results indicated a
      significantly increased Lp(a) concentration in patients with lupus nephritis as
      compared to the LN- group. All but 2 patients without kidney involvement had
      lower than 100 mg/L Lp(a) concentration, while 27% of patients with lupus
      nephritis has an Lp(a) level between 100-300 mg/L. Further more, Lp(a)
      concentration was higher than 300 mg/L in 13% of the LN+ group. In a good
      correlation of these observations patients with nephritis suffered more
      frequently from deep venous thrombosis and ischaemic heart disease. The
      frequencies of hypertension and non-insulin dependent diabetes mellitus were
      slightly elevated in patients with nephritis. Present results suggest the
      importance of elevated lipoprotein (a) concentration in patients with lupus
      nephritis, further increasing the risk of athero-thrombotic cardiovascular
      complications.

PMID- 15024933
TI  - [Child sexual abuse].
AB  - Authors review the epidemiology of child sexual abuse. They summarize the
      individual, social and medico-legal aspects of sexual violence. They present an
      achievable approach for managing and preventing sexual crime concerning the
      circumstances of public health and the current laws in Hungary. Searching for
      specific signs and symptoms will facilitate the recognition of the cases and the
      success of the official procedure. In order to explore and to prevent child
      sexual abuse an interdisciplinary instruction is recommended on different
      educational levels.

PMID- 15024934
TI  - [Dental fluorosis in children in Bar and Dunaszekcso in the 6-18 age group].
AB  - Extensive experimental ad clinical data have established that in a concentration
      of approximately 1 mg/L in drinking water fluoride is highly effective in
      reducing the incidence of dental caries and dental plaque. However because of its
      well established cariostatic property, fluoride is being added to dental care and
      dental health product. In Hungary, community water fluoridation has not occurred,
      and the fluoride concentration of the drinking water is generally minimal. 95% of
      the population live in areas of the country where the majority of the population
      ingests water containing fluoride at a concentration of less than 0.5 mg/L. There
      are, however, communities in which the natural fluoride concentration in the
      drinking water is 1.7 or 2.0 mg/L. These are Bar ad Dunaszekcso. This study is
      designed to evaluate both prevalence and intensity of dental fluorosis, oral
      hygiene and periodontal diseases in the children in communities with suboptimal,
      1.7x and 2x optimal fluoride concentration of drinking water. MATERIAL AND
      METHODS: 141 healthy school-children in the 6-18 age groups who were lifetime
      residents in the communities Bar and Dunaszekcso, and 140 from Budapest have been
      asked to participate in this cross-sectional study. The examinations were
      performed using; the Fluorosis Index of Dean and the Tooth Surface Index of
      Fluorosis of Horowitz et al. The prevalence and intensity of gingivitis and oral
      hygiene were determined by the Russell (PI)-index and the Greene Vermillion Oral
      Hygiene index (OHI-S). RESULTS: 1. The prevalence and intensity of gingivitis and
      oral hygiene were changing with fluoride concentration in the water supply. 2. On
      the basis of the number and distribution of the individual scores a community
      index of dental fluorosis (Fd) were in both community above 0.6, therefore it
      begins to constitute a public health problem warranting increasing consideration.
      3. The intensity of the fluorosis was changed with aging (p < 0.001). This was
      tested by comparing the fluorosis scores in 6-13 year old children, with the
      scores for those who were 14-18 years of age. 4. There were no differences in the
      oral hygiene status and in the intensity of gingivitis between children living in
      a high-fluoride city and those living in a low-fluoride city. CONCLUSION: The
      study supports the need of continuous monitoring of the prevalence of dental
      fluorosis in school-age children. Concerning the reduction in gingivitis and the
      oral hygiene status the authors found no differences between children living in a
      high-fluoride or in a low fluoride city.

PMID- 15024935
TI  - [Heterogeneity of small intestinal microcirculation].
AB  - INTRODUCTION: Microcirculatory disorders play important roles in the impairment
      of the mucosal barrier of the small intestine. Circulatory failures may increase
      the heterogeneity of microvascular perfusion, however, conventional methods are
      inadequate to describe an evolving heterogeneity in time or space. The authors
      aims were to examine and characterize the microcirculatory reactions in the
      mucosa and longitudinal muscle of the small intestine in clinically relevant
      experimental models of circulatory disorders. METHODS: Intravital videomicroscopy
      with orthogonal polarization spectral imaging technique was used to visualize the
      microcirculation. A mathematical approach was applied to describe the temporal
      variability in perfusion based on the calculation of average red blood cell
      velocity from the relative time periods of observed velocity, while spatial
      heterogeneity was calculated as a function of the perfused area. The authors'
      experiments were performed after 1. sham operation, 2. during hemorrhagic shock
      and crystalloid resuscitation, 3. during 2-hr endotoxin infusion, 4. in response
      to nitric oxide synthesis inhibition, and 5. after superior mesenteric artery
      occlusion and reperfusion. RESULTS: During hemorrhagic shock a fluctuating flow
      pattern appeared in the mucosa, the average red blood cell velocity decreased by
      40% in the villi and by 60% in the muscle. Ischemia caused 20% flow reduction in
      both layers, while endotoxin caused a temporary 20% decrease in the mucosa, and a
      persistent, over 25% decrease in the muscle layer. Nitric oxide synthesis
      inhibition resulted in a 40% decrease in both structures. CONCLUSIONS:
      Heterogeneity of microcirculatory perfusion may appeared both spatially (between
      or within anatomical layers) and in time (periodically) after the insults. A
      redistribution of blood flow favouring the mucosa evolves in the small intestine
      after systemic circulatory disorders. Heterogenous perfusion-related
      microcirculatory changes can be characterized with mathematical approaches, and
      these calculations should be taken into account during the comparison of the
      consequences of distinct circulatory failures involving the small intestine.

PMID- 15024936
TI  - [Chemotherapy in pancreatic cancer].

PMID- 15024937
TI  - [New antithrombotic principles approaching clinical use].

PMID- 15024938
TI  - ["Public information"--a mirror of the medical profession during 100 years].

PMID- 15024939
TI  - [Thrombolytic therapy in acute ischemic stroke. Critical analysis of current
      knowledge].
AB  - Thrombolysis is a highly promising treatment in acute ischaemic stroke. There is
      evidence of positive effects at least up to three hours and most probably up to
      six. The risk of intracranial haemorrhage is increased fourfold with
      thrombolysis; risk factors other than the treatment as such have not been
      identified for certain; the risk is not related to giving thrombolysis during the
      0-3 as opposed to the 3-6 hour time window. There is a non-significant excess of
      deaths, ranging from a small reduction to a substantial excess. There is not
      enough evidence to answer several questions regarding the influence of patient-
      and stroke characteristics on effectsize; death; and risk of intracranial
      haemorrhage. Giving priority to new large randomized controlled trials is
      essential to achieve this knowledge.

PMID- 15024940
TI  - [Thrombolytic therapy in stroke approved with reservation. Underlying evidence,
      practical guidelines and safety follow up].

PMID- 15024941
TI  - ["Save the brain"-network in the county of Uppsala for thrombolytic therapy in
      stroke].
AB  - "Save the brain" is a network for thrombolysis of stroke in the Uppsala County,
      Sweden. The network involves the ambulance services, the emergency ward, and the
      departments of medicine and neurology. The county has 298,655 inhabitants. During
      one year, 2001-2002, 184 "save the brain" transports were performed. After an
      initial clinical examination at the emergency ward, 67 of these patients (36%)
      were investigated with hyperacute CT. After a second clinical examination, 13
      patients (19%) received intravenous thrombolysis. The time lag from onset of
      symptoms to thrombolysis varied from one and a half hour to four hours.

PMID- 15024943
TI  - [Good guideline compliance among patients and health services when it comes to
      suspected SARS infection].

PMID- 15024942
TI  - [Avian influenza--next global infection threat from Asia].

PMID- 15024945
TI  - [Access to health services directed by needs or money?].

PMID- 15024944
TI  - [Usefulness of BNP in heart failure. Shortages of a current review reflect th
      complexity of the problem].

PMID- 15024946
TI  - [Sudanese cytogeneticists--vision of a new kind of assistance].

PMID- 15024947
TI  - [Computer tomography of the cranium in children--risk assessment].

PMID- 15024948
TI  - [Brain concussion and computer tomography of the cranium in children--clinical
      conclusions].

PMID- 15024949
TI  - [Swedish clinical research is the best in the world--but the warning bells ring].

PMID- 15024950
TI  - [The incapability of health services to follow the needs].

PMID- 15024951
TI  - [About poliomyelitis in Sweden].

PMID- 15024952
TI  - Molecular imaging of the brain: a historical perspective.
AB  - The rapid expansion of modern molecular imaging methods since the time of their
      initial conception in the 1970s has given rise to numerous discoveries of
      molecular mechanisms that underlie brain function in health and disease. Uses in
      clinical diagnosis and therapy monitoring are still evolving. Future clinical
      trials, in which molecular imaging is imbedded and correlated with clinical
      outcomes, will be critical to advancing new uses for patient management. Receptor
      occupancy studies are already well integrated into many drug development studies
      and clinical trials; such studies will provide a basis for new studies that will
      further advance clinical uses of brain molecular imaging.

PMID- 15024953
TI  - Instrumentation in positron emission tomography.
AB  - The past 40 years have seen PET scanning evolve from a tool that was used
      predominantly for research to a valued clinical, imaging modality. Current PET
      scanners must perform high quality, whole-body, as well as brain, PET. There are
      several levels of PET devices that range from the dedicated, high-end scanners
      down to the hybrid PET-SPECT systems that offer varying levels of performance.
      The incorporation of PET into single, hybrid, multi-modality units that can
      provide functional and anatomic information is becoming extremely popular.
      Several manufacturers now provide hybrid PET-CT scanners. There is also a growing
      interest in dedicated devices for specific applications, such as high-resolution
      scanners for imaging small animals.

PMID- 15024954
TI  - Positron emission tomography radiochemistry.
AB  - Factors that place constraints on radio-chemists who are seeking to design and
      develop radiopharmaceuticals for PET imaging studies include the short half-lives
      of 11C and 18F, minimum radiochemical yield and specific activity requirements,
      and high radiation fields that are associated with multi-Curie quantities of PET
      radionuclides. Nevertheless, during the past 20 years, considerable progress has
      been made in the development and application of a variety of PET radiotracers for
      a range of imaging studies in human subjects. We have highlighted a few areas of
      radiochemistry that focused on PET radiotracers that are described in this issue.
      Although the number of PET radiotracers synthesized is in the hundreds [6], much
      work remains to develop specific and useful PET radiotracers for a host of new
      and exciting noninvasive imaging applications.

PMID- 15024955
TI  - Principles of tracer kinetic analysis.
AB  - This article described basic ideas and concepts that are related to the
      performance and analysis of dynamic tracer kinetic PET studies of brain. There
      are many aspects of these studies that require careful consideration, because
      there is always a compromise between accuracy and precision [101]. Important
      issues that were not discussed in this article include the appropriate use of
      anatomic information for the interpretation and analysis of the functional PET
      imaging data, ROI sampling, or parametric image generation; statistical analyses
      of ROI and parametric data; as well as steps involved in the evaluation of novel
      radiotracers and the identification of an analysis-of-choice or issues related to
      methodologic optimization. Fig. 5 is a summary diagram that links these ideas and
      provides a more complete picture of the multiple components that are involved in
      tracer kinetic PET imaging research.

PMID- 15024956
TI  - Imaging the epileptic brain with positron emission tomography.
AB  - Positron emission tomography (PET) has an established role in the noninvasive
      localization of epileptic foci during presurgical evaluation.
      [18F]fluorodeoxyglucose (FDG) PET is able to lateralize and regionalize
      potentially epileptogenic regions in patients who have normal MR imaging and is
      also useful in the evaluation of various childhood epilepsy syndromes, including
      cryptogenic infantile spasms and early Rasmussen's syndrome. Novel PET tracers
      that were developed to image neurotransmission related to gamma-aminobutyric acid
      (GABA) [with [11C]flumazenil] and serotonin-mediated [with alpha-[11C]methyl-L
      tryptophan (AMT)] function provide increased specificity for epileptogenic cortex
      and are particularly useful when FDG PET shows large abnormalities of glucose
      metabolism. Detailed comparisons of PET abnormalities with intracranial
      electroencephalographic findings also improve our understanding of the
      pathophysiology of human epilepsy.

PMID- 15024957
TI  - Positron emission tomography imaging of brain tumors.
AB  - Energy metabolism and amino acid transport and incorporation are important
      components of the pathophysiology of gliomas, about which molecular imaging is
      providing regional biologic information that is useful to clinical practice.
      Imaging hypoxia is straightforward and proliferation imaging with FLT shows
      significant promise. Neither has been exploited thoroughly enough to allow
      judgement of their potential benefit to the practice of neuro-oncology. Although
      cell division is the most distinguishing function of growth in tumors, probing
      membrane biosynthesis with PET and 1-[11C]acetate or a choline tracer may yield
      information as helpful as protein or DNA synthesis. Because astrocytic gliomas
      frequently carry epidermal growth factor receptor mutations at a frequency that
      is related to grade, a PET tracer that is specific for this mutated receptor
      could be useful for grading and prognosis [35]. Methods for imaging angiogenesis
      are being developed; 18F-labeling of a cyclic RGD-containing glycopeptide, cyclo(
      Arg-Gly-Asp-D-Phe-Lys(sugar amino acid)-), with 4-nitro-phenyl 2
      [18F]fluoropropionate has been reported [136]. 18F-labeled annexin V is being
      tested as a new PET agent for quantitating tumor cell death and predicting
      response to therapy. Annexin V binds to surface membranes that have exposed
      phosphatidyl serine residues resulting from programmed cell destruction.
      Recently, a Tc-99m-labeled derivative has been shown to accumulate in late stage
      lung cancer and lymphoma in response to chemotherapy [137]. As molecular pathways
      leading to and sustaining neoplasia become better understood, so will our
      capacity improve to measure them in vivo and intervene to the patient's
      advantage.

PMID- 15024958
TI  - The use of positron emission tomography in cerebrovascular disease.
AB  - Even with rapid development of other neuroimaging modalities such as MR imaging
      and CT, PET is the only technique that provides accurate, quantitative
      measurements of regional hemodynamics and metabolism in human subjects. Through
      the use of these combined measurements, we have greatly expanded our knowledge of
      the pathophysiology of cerebrovascular disease of different types. It has been
      possible to document the compensatory responses of the brain to reductions in
      perfusion pressure and to directly relate these responses to prognosis. PET
      measurements of OEF identify a subgroup of patients who have carotid occlusion
      and who are at increased risk for recurrent stroke who cannot be identified by
      any other clinical or arteriographic means. These measurements of OEF are being
      used to identify high-risk patients for inclusion in a clinical trial to assess
      the efficacy of surgical revascularization in reducing the subsequence of
      ipsilateral ischemic stroke. In acute ischemic stroke, attempts have been made to
      define the "ischemic penumbra" and to predict tissue viability and clinical
      outcome, although the reliability of PET markers of ischemia in distinguishing
      viable from irreversibly damaged tissue needs to be confirmed with independent
      data sets. Much work has been devoted to the investigation of the metabolic
      effects of infarcts and hemorrhages on remote areas of the brain; the clinical
      importance of such findings appears to be minimal. Early studies of recovery from
      stroke suggested functional reorganization of the brain, but further
      investigations with more rigorous experimental design need to be performed. Given
      the case of performing such studies with functional MR imaging, it is likely that
      this technology will supplant PET for this specific indication. The importance of
      ischemia as a secondary mechanism of brain injury has been addressed in ICH and
      SAH. PET demonstrated that hematomas exert a primary depression of metabolism
      rather than inducing ischemia in the surrounding tissue. It also documented the
      integrity of autoregulation and provided clinically useful information regarding
      the safety of blood pressure reduction after ICH. Studies in SAH have
      differentiated the primary effects of the hemorrhage on cerebral hemodynamics and
      metabolism from those of vasospasm. PET studies are time-consuming, expensive,
      and require extensive facilities and technical support. In the field of
      cerebrovascular disease, PET has served as a specialized research tool at a few
      centers to help elucidate the pathophysiology of stroke. Up until now, however,
      PET scans in individual patients have not been demonstrated to be necessary for
      making patient care decisions. Whether the role of PET expands to impact the
      management of individual patients will depend on the results of investigations
      like the Carotid Occlusion Surgery Study that directly assess the ability of PET
      to influence patient outcome.

PMID- 15024959
TI  - Positron emission tomography imaging of the aging brain.
AB  - PET imaging provides a vital means to study the human brain in vivo in aging and
      early disease states. PET studies using selective markers for brain metabolism
      and neurotransmitter function have uncovered a wealth of information on healthy
      and pathologic brain aging, and its relationship to behavior and mood states.
      Recognition of inherent potential confounds in the use of PET in aging studies is
      essential to the proper interpretation of these data.

PMID- 15024960
TI  - Imaging Alzheimer's disease: clinical applications.
AB  - Extensive PET imaging research on AD has been conducted since PET scanners became
      available in the early 1980s. PET imaging using FDG, now commercially available,
      can detect early metabolic changes in AD and differential metabolic features of
      various dementing disorders. Image analysis techniques have also advanced in the
      field of functional brain imaging and permit accurate and consistent scan
      interpretation. PET studies that involve autopsy-confirmed cases suggest that the
      PET diagnosis of AD is no worse or may even be better than clinical diagnosis.
      Limited prospective studies demonstrated the effects of PET imaging in dementia
      management, which precludes the approval of FDG PET for more widespread,
      reimbursable use. Further evidence for the efficacy of PET imaging through well
      organized clinical studies, as well as continuing efforts in technologic
      development and basic research to characterize functional alterations in
      dementing disorders in living patients, are equally important to achieve the goal
      of better dementia care.

PMID- 15024961
TI  - Imaging the pathology of Alzheimer's disease: amyloid-imaging with positron
      emission tomography.
AB  - The steep rise in the incidence of Alzheimer's disease (AD) has further added to
      the considerable public health burden caused by aging of the United States
      population. Among the most characteristic pathologic hallmarks of AD are neuritic
      plaques and neurofibrillary tangles. The capability to use positron emission
      tomography and selective markers for amyloid protein deposition promises to
      substantially alter the way we diagnosis and manage patients who have AD.

PMID- 15024962
TI  - The role of positron emission tomography imaging in movement disorders.
AB  - PET imaging provides the means to study neurochemical, hemodynamic, or metabolic
      processes that underlie movement disorders in vivo. Because the extent of
      presynaptic nigrostriatal dopaminergic denervation can be quantified in PD even
      at an early or preclinical stage of the disease, PET imaging may allow the
      selection of at-risk subjects for neuroprotective intervention trials. These
      techniques may also provide markers to follow progression of disease or evaluate
      the effects of neurorestorative interventions in patients who have more advanced
      disease. PET is expected to play an increasing role in the selection of patients
      who have PD for deep brain stimulation. Dopaminergic studies may have a limited
      clinical role in the diagnosis of patients who have symptoms that suggestive of
      PD yet do not respond to typical dopaminergic drugs, such as patients who have
      vascular parkinsonism or ET with mild resting tremor who may have normal
      dopaminergic innervation. The differential diagnosis between PD and multiple
      system atrophy, progressive supranuclear palsy, or corticobasal degeneration is
      not yet clearly established by PET, but combined pre- and postsynaptic
      dopaminergic imaging may be able to distinguish early idiopathic PD from atypical
      parkinsonian disorders, in general. Huntington's chorea is characterized by more
      prominent striatal dopamine receptor loss, whereas nigrostriatal denervation is
      present to a lesser degree. Patients who have TS may have enhanced synaptic
      dopamine release in the putamen. Functional imaging studies have generally failed
      to demonstrate nigrostriatal denervation in essential tremor or idiopathic
      dystonia. Studies have shown striatal dopamine receptor loss in selected subtypes
      of dystonic patients. In conclusion, it is expected that PET will help us to
      better understand the pathophysiology of movement disorders, increase the
      diagnostic accuracy, allow preclinical diagnosis, monitor disease progression,
      and evaluate the efficacy of therapeutic agents. Pharmacologic radioligand
      displacement studies and the development of new nondopaminergic ligands may
      further aid in the unraveling of cerebral mechanisms that underlie movement
      disorders.

PMID- 15024963
TI  - Positron emission tomography imaging in depression: a neural systems perspective.
AB  - PET measures of regional glucose metabolism, although chemically nonspecific, are
      sensitive indices of brain function in the untreated state and following
      disparate treatments. The continued development of imaging and multivariate
      statistical strategies is expected to provide an important perspective toward the
      full characterization of the depression phenotype at the neural systems level. An
      additional goal is the development of routine, brain-based clinical algorithms
      that optimize diagnosis and treatment of individual depressed patients.

PMID- 15024965
TI  - Neuroimaging and mechanisms of drug abuse: interface of molecular imaging and
      molecular genetics.
AB  - Whereas ligand studies can inform the end-products of dysregulation of genetic
      expression, reporter gene imaging can provide the means to understand the genetic
      origin of these end-products. As with radioligand studies, in vivo direct
      measurement of gene expression will allow genetic processes to be monitored over
      time in the same subject, use of a subject as his/her own control in intervention
      studies (i.e., measurement before and after an intervention), and monitoring the
      spatial distribution of molecular events in the whole brain. Furthermore,
      reporter gene imaging, by advancing knowledge of the biologic mechanisms of
      disease states, has important clinical implications, particularly in the
      development and monitoring of treatments. We expect PET to play a prominent role
      in the elucidation of substance abuse mechanisms and contribute significantly to
      the development of innovative treatment strategies.

PMID- 15024964
TI  - Positron emission tomography and single photon emission CT molecular imaging in
      schizophrenia.
AB  - We reviewed findings from PET and SPECT studies that have contributed to our
      understanding of the pathophysiology and treatment of schizophrenia. The most
      robust set of findings pertains to imaging of presynaptic dopaminergic function
      in the striatum. The results of these studies have been consistent in showing
      that schizophrenia, at least during episodes of illness exacerbation, is
      associated with increased activity of DA neurons; this increased presynaptic
      activity is associated with positive symptoms and good therapeutic response.
      Studies of cortical DA function are less numerous and less consistent. In the
      future, technical advances in PET instrumentation and radioligand development
      should contribute to a clarification of the role of prefrontal DA in the
      cognitive impairment that is presented by these patients. An important drawback
      of the literature in this field is the generally low number of subjects that are
      included in studies (typically less than 20 per group). Small samples are
      necessitated by the cost of these investigations, but also, in some instances, to
      the difficulty in recruiting appropriate clinical subjects (such as drug-free
      patients who have schizophrenia). In conditions that are characterized by marked
      heterogeneity, such as major depressive disorders, this factor is bound to yield
      divergent results across studies. Another source of discrepancy is the variety of
      technical approaches to data acquisition and analysis. For example, analytical
      methods range from "empirical" or "semiquantitative" (typically a region of
      interest to a region of reference ratio measured at one time point) to model
      based methods that use an arterial input function. The limitations that are
      associated with empirical analytical methods might account for artifactual
      results, especially when the effect size of the between-group difference and the
      number of subjects are small [149]. In addressing these limitations it will be
      important to increase the availability of these techniques beyond a few academic
      centers, to promote multi-center studies in well-characterized populations, and
      to standardize analytical methods. Until recently, SPECT was the only widely
      available technique, and SPECT studies have provided a substantial contribution
      to this field. With the current increase in PET camera availability, the
      development of [18F]-based molecular imaging probes will provide unique
      opportunities for further dissemination of these techniques. The article reviewed
      seminal findings obtained with PET and SPECT molecular imaging of schizophrenia.
      These techniques do not play a major role in the diagnosis and treatment of this
      disorder, remain essentially research tools. The results that have been produced
      by this field to date suggest that PET will significantly contribute to
      unraveling the biologic bases of psychiatric disorders and may contribute to
      their clinical management. Moreover, it is foreseeable that PET will become
      increasingly involved in the development of new psychiatric medications.
      Expanding the availability of PET and the current radiopharmaceutical portfolio
      will be critical for these predictions to become reality.

PMID- 15024966
TI  - Positron emission tomography in central nervous system drug discovery and
      development.
AB  - Genetics, neuroscience, and imaging science have advanced greatly in the last few
      years. These advances can be brought together and applied in creative new ways to
      make available better drugs for treating neuropsychiatric disorders and for
      getting candidate drugs through the development process faster. One particular
      approach, built around [18F]fluordeoxyglucose positron emission tomography, is
      described.

PMID- 15024967
TI  - Pre-natal origins of childhood leukemia.
AB  - Chimeric fusion genes derived by chromosome translocation provide stable,
      sensitive and clone-specific markers for tracking the origins of leukemic cells
      and the natural history of disease and have been particularly informative in
      studies with twins concordant for leukemia and in retrospective scrutiny of
      archived neonatal blood spots. These data have indicated that in pediatric
      leukemia the majority, but not all, of the chromosome translocations arise, in
      utero, during fetal hemopoiesis, probably as initiating events. In most cases,
      functionally complementary and secondary genetic events are also required. These
      are acquired rapidly, and possibly in utero also, in infant acute lymphoblastic
      leukemia (ALL) but post-natally for most childhood ALL and acute myeloblastic
      leukemia (AML). An important consequence of the latter is a very variable and
      occasionally protracted post-natal latency (1-15 years). Another important
      corollary is that functional chromosomal translocations and pre-leukemic clones
      arise at a substantially higher frequency (approximately 100x) before birth than
      the cumulative incidence or risk of disease. These natural histories provide an
      important framework for consideration of key etiological events in pediatric
      leukemia.

PMID- 15024968
TI  - Congenital syndromes and leukemia: clues to pathogenesis.
AB  - The association of specific congenital syndromes with leukemia provides an
      opportunity to study the process of leukemogenesis on the background of known
      genetic alterations. The role of the intracellular DNA damage response system in
      suppressing leukemia is demonstrated by the congenital disorders of genomic
      instability. Specific collaborations between survival and differentiation
      pathways characterize the leukemias observed in Down, Noonan and
      neurofibromatosis syndromes. As these syndromes clearly reveal, childhood
      leukemia arises when the delicate balance between growth, development and
      differentiation of the fetal and early post-natal hematopoietic system is
      disrupted.

PMID- 15024969
TI  - Adolescents with acute lymphoblastic leukemia: a new "age".
AB  - Adolescents with acute lymphoblastic leukemia (ALL) have a higher incidence of T
      cell immunophenotype, a higher incidence of Philadelphia chromosome positive ALL,
      a lower incidence of high hyperdiploidy and TEL-AML1 translocation, and a lower
      incidence of extramedullary bulk disease compared to younger patients. There
      appears to be little difference between 10-15 and 16-21 year old patients.
      Adolescents with ALL have a lower event free survival (EFS) compared to younger
      patients. Adolescents 16-21 years of age treated on pediatric ALL trials have a
      significantly better EFS than those treated on adult trials. Pediatric treatment
      protocols utilize more vincristine, steroid and L-asparaginase compared to adult
      trials. In a recently completed Children's Cancer Group trial, adolescents 16-21
      years of age had a four-year EFS of 73.1%. Avascular necrosis of bone is an
      important complication of therapy in adolescents with ALL.

PMID- 15024970
TI  - RNA interference: new mechanisms for targeted treatment?
AB  - Nucleic acid-based sequence-specific therapeutic intervention offers the
      potential for treatment of particular cancers without side effects. RNA
      interference (RNAi) induced by small interfering RNA (siRNA) (19-21 bp) is a
      normal cellular mechanism leading to highly specific and extraordinarily
      efficient degradation of the corresponding mRNA. The mechanism of RNAi as well as
      strategies for the design and delivery of siRNA are described. The growing role
      of RNAi in target validation for cancer-specific genetic aberrations is
      discussed. We attempt an early assessment of the potential for using RNAi
      technologies to treat cancer directly, especially hematologic malignancies.
      Promising targets for specific gene silencing in hematologic oncology include
      oncogenic fusion proteins and oncogenes activated by point mutations. Potency and
      specificity of gene silencing are the major advantages of the new RNAi technology
      over other nucleic acid-based gene targeting approaches. Crucial questions for
      pharmaceutical interventions remain. Advances in the areas of delivery, systemic
      spreading and duration of the silencing effect are necessary before the
      methodology can enter clinical oncology.

PMID- 15024971
TI  - Minimal residual disease as a surrogate marker for risk assignment to ALL
      patients.
AB  - The use of minimal residual disease (MRD) measurement as a "surrogate" marker of
      molecular response to treatment, can potentially improve the evaluation of
      treatment response and enable estimates of the residual leukemic cell burden
      during clinical remission, thereby improving the selection of therapeutic
      strategies and, possibly, long-term clinical outcome. The most specific and
      sensitive methods for MRD monitoring currently available are polymerase chain
      reaction amplification of fusion transcripts and rearranged immunoglobulin or
      antigen-receptor genes, and flow cytometric detection of aberrant
      immunophenotypes. Several retrospective studies in childhood acute lymphoid
      leukemias (ALL) have used one of the different approaches for the detection of
      MRD. The strong association between MRD and risk of relapse was observed in
      children and adult patients irrespective of the methodology used. The promising
      results on the predictivity of MRD evaluation at the end of induction treatment
      has challenged the need for a new definition of remission. There is now urgent
      need to incorporate MRD data in clinical studies, properly designed to address
      treatment questions. In this context, several ongoing cooperative study groups
      have adopted a MRD-based risk group classification to explore whether a better
      tailored treatment would result in further improvement in cure rates for children
      with ALL.

PMID- 15024972
TI  - [Corynebacterium diphtheriae nontoxigenic strain carrying the gene of diphtheria
      toxin].
AB  - Among 828 C. diphtheriae nontoxigenic cultures isolated in different region of
      Russia in 1994-2002, 114 cultures (13.8%) had the gene of diphtheria toxin (gene
      tox) and were thus called nontoxigenic tox-carrying (NTTC) strains. All NTTC
      strains were found to belong to biovar mitis and formed neither normal, nor
      "defective" diphtheria toxin. The most of NTTC strains (94%) belonged to ribotype
      "Moskva", not occurring among C. diphtheriae toxigenic strains. The incapacity of
      NNTC strains of forming diphtheria toxin was caused by mutation: the deletion of
      one nucleotide which led to the shift of the open reading frame and to the
      formation of the stop codon. The results of these studies are indicative of the
      fact that a sufficiently homogeneous and isolated group of C. diphtheriae
      nontoxigenic strains is spread in Russia. These strains carry the nonexpressing
      gene of diphtheria toxin and are of no epidemic importance in diphtheria
      infection.

PMID- 15024974
TI  - [Experimental non-culturable Vibrio cholerae eltor and its biological
      properties].
AB  - In experiments with the cultivation of V. cholerae eltor under the conditions of
      high salt concentration, as well as low temperature and deficiency in nutrient
      substances, uncultivable forms (UF) of toxigenic and nontoxigenic vibrios were
      obtained. The absence of growth of seeded vibrios after the filtration of samples
      (with a filter of 0.22 micron), the preservation of specific antigenic
      determinants and the initial set of genes, changes in the morphology of cells
      (small size, coccoid form with the flagella retained) confirm the transition of
      V. cholerae eltor under study into the uncultivable state which, under
      unfavorable conditions, more rapidly develops in toxigenic vibrios than in
      nontoxigenic ones. The analysis of the INT-reductase activity of UF disintegrates
      revealed that they had endogenic respiration whose activity increased (4.5- to
      6.5-fold) in the presence of the exogenic intermediates of the Krebs cycle. The
      uncultivable forms of the vibrios retain genes responsible for pathogenicity, as
      well as their antigenic determinants.

PMID- 15024973
TI  - [Microorganism "Montezuma" of the order Rickettsiales: the potential causative
      agent of tick-borne disease in the Far East of Russia].
AB  - A new microorganism, tentatively named "Montezuma" was detected in ticks and in
      specimens (blood, bioptic specimens of the primary affect) taken from patients
      with an acute fever disease, etiologically linked with the bites of Ixodes ticks
      in the Far East of the Russian Federation. After sequencing the products of the
      amplification of DNA isolated from ticks with wide-spectrum primers new primers
      were developed, highly specific to the unusual sequence thus obtained. The study
      revealed that ticks of the species Ixodes persulcatus (97%) and Haemophysalis
      concinnae (5%) contained DNA of this microorganism. The same DNA was detected in
      materials taken from the patients. The phylogenetic analysis of the gene showed
      that this organism formed an independent and well defined branch within the order
      Rickettsiales. The nearest homology (89%) was observed with recently detected
      endosymbiotes Acanthamoeba. The similarity with their relatives from the families
      Rickettsiaceae and Anaplasmataceae of the order Rickettsiales was within 81-86%,
      which made it possible to infer the existence of, probably, only a new genus, but
      also a family. The isolated DNA belonged, supposedly, to the new microoganism
      which caused a tick-borne disease in humans, transmitted through bites of Ixodes
      ticks, and was, supposedly, widely spread in the southern area of the Khabarovsk
      Territory.

PMID- 15024975
TI  - [Viral hepatitis in different population groups of Republic of Sakha (Iakutia)].
AB  - A survey for the presence of markers of viral hepatitis B, delta, C and E among
      different groups of the population of the arctic and agricultural zones of the
      Republic of Sakha (Yakutia), as well as in Yakutsk, was carried out. The survey
      revealed that viral hepatitides with the parenteral mechanism of the transmission
      of infective agents were widely spread among the population. In the arctic zone
      HBsAg was detected in persons aged 20 years and older in 10.8-17.1% of cases. On
      the average, in the arctic zone antibodies to virus delta were detected in 2.4%
      of cases. In different regions of the agricultural zone the detection rate of
      HBsAg was also high (10.4-23.8%). In the Namsk and Vilyui regions delta infection
      was registered among adolescents (15-19 years of age) in 8.7 and 22.4% of cases
      respectively. In the Mountainous region anti-delta antibodies were detected among
      persons aged 20 years and older in 31% of cases. The survey showed the presence
      of considerable differences in the detection rate of the markers of hepatitis B,
      depending on the ethnic origin of the examined patients. Similar tendencies were
      found to exist with respect to delta infection.

PMID- 15024976
TI  - [The genome polymorphism of Vibrio cholerae ctxAB(-) strains, containing the
      proximal part of the CTX element].
AB  - The comparative analysis of the hybridization patterns of DNA restricts for 20 V.
      cholerae, groups 01 and non-01 (non-0139), containing the incomplete CTX element
      (ctxAB-) was carried out with the use of probes, complementary to the genes of
      the proximal part of the virulence cassettle and flanking its RS1 sequences. This
      group was found to be heterogeneous both in the number of copies of "truncated"
      CTX prophage and their localizations in the genome, as well as in the position of
      the sites of restriction endonucleases HindlII and BglII. Among 17 clinically
      noncholerigenic isolates, 5 etiologically dangerous clones were found, each of
      them characterized by the definite time and place of isolation. At least one of
      them proved to be the causative agent of the local outbreak of diarrheal diseases
      in Uzbekistan.

PMID- 15024978
TI  - [Typing of Mycobacterium tuberculosis cultures from Samara region by the variable
      number of tandem repeats].
AB  - To type Mycobacterium tuberculosis (MT) strains by the variable number of tandem
      repeats (VNTR), 136 MT cultures, isolated in 5 main general therapeutic
      laboratories and penitentiary antituberculosis institutions of the Samara region,
      were studied. Gene typing revealed that the greatest number of MT strains (73)
      belonged to VNTR type 42435. It was followed by VNTR type 22232, found in 13
      isolated cultures. Among the MT cultures of the most widely spread VNTR type
      42435, rifampicin-resistant strains prevailed (57 strains, i.e. 78%), while
      strains belonging to VNTR type 22232 were mainly sensitive to rifampicin (84%).
      VNTR typing of MT typing may be useful for epidemiological studies in the field
      of phthisiology.

PMID- 15024979
TI  - [Detection rate and distribution pattern of HIV infected patients in the
      emergency room of a hospital].
AB  - HIV positive patients needing urgent treatment have become reality in the
      clinical practice of the multiprofile hospital of the Sklifosovsky Research
      Institute of Emergency Aid. 243,030 patients and 55,163 donors were examined at
      the Laboratory of Clinical Immunology and AIDS Diagnostics during the period of
      1989-2001, and among the examinees 814 patients and 13 donors were found to be
      HIV-infected. The highest detection rate of HIV-infected patients was registered
      in the poisoning center, the somatic-psychiatric and endotoxicosis departments.
      After the period of a sharp rise in the number of HIV-positive patients (1997
      2000) a decrease in their proportion among hospitalized patients was registered
      in 2001.

PMID- 15024977
TI  - [Variable nucleotide tandem repeats (VNTR analysis) in Vibrio cholerae 0139
      isolated from humans and from water of surface reservoirs in Russia].
AB  - The comparative study of variable tandem repeats (VNTR analysis) in genomes of V.
      cholerae 0139 isolated from humans and from water samples taken from surface
      reservoirs was carried out. The results of the study of the allele state of 5
      loci of tandem repeats in 50 strains of vibrios, carried out in the double-primer
      polymerase chain reaction (PCR), as well as the earlier comparison of the same
      isolates in the single-primer PCR, showed essential differences and the absence
      of clonality in the cultures of the clinical and aqueous origin. The suggestion
      was made that vibrios with individual VNTR genotypes and having no genes ctx and
      tcpA, isolated from water samples, were epidemic unimportant representatives of
      the autochthonous microflora of water reservoirs.

PMID- 15024980
TI  - [Soluble HLA class I and HLA class II antigens in the blood of HIV infected
      patients].
AB  - The levels of HLA, class I, antigen and HLA-DR antigen in the blood sera of HIV
      infected persons were determined by the enzyme immunoassay. The levels of soluble
      antigens HLR-DR and of HLA, class I, in serum samples containing only antibodies
      to HIV were elevated, respectively, 1.8- and 1.3-fold in comparison with the
      norm. The level of soluble HLA-DR antigen in samples containing the markers of
      other infections (HBsAg, antibodies to hepatitis C virus, anti-IgM antibodies to
      cytomegalovirus) was significantly higher in comparison with samples containing
      only antibodies to HIV and serum samples from healthy donors (p < 0.05). The
      concentration of soluble HLA antigen, class I, in the samples containing
      antibodies to HIV and markers of other infections was also elevated, but the
      statistically authentic increase in comparison with the normal level was observed
      only in the presence of the markers of HIV infection, hepatitis C and
      cytomegalovirus infection.

PMID- 15024981
TI  - [Immunomodulation activity of new vaccines for pertussis prophylaxis--acellular
      pertussis vaccine and adsorbed DPT vaccine with acellular component].
AB  - The immunomodulating activity of acellular pertussis vaccine (APV) and adsorbed
      DPT vaccine with acellular pertussis component (DPTA vaccine) was studied. The
      study revealed that only large doses of APV, 10 immunizing doses (ID), suppressed
      humoral and cell-mediated response to sheep red blood cells (SRBC). 1 ID produced
      no influence on the formation of antibody producing cells, but increased the
      development of delayed hypersensitivity (DH) to SRBC. The modulation of cell
      mediated immune response, induced by APV, returned to normal after the injection
      of purified staphylococcal toxoid, used as immunomodulator, in doses of 0.15 BU
      per mouse and 1.5 BU per mouse. DPTA vaccine containing 1 ID, as well as 10 ID,
      produced no immunomodulating effect. This was established by the evaluation of
      humoral response to SRBC in CBA mice and the study of the formation of DH to SRBC
      in BALB/c mice. As indicated by the total of the presented data, the inclusion of
      APV into DPTA vaccine enhanced the immunological safety of its pertussis
      component.

PMID- 15024982
TI  - [Evaluation of influenza vaccine Vaxigrip in the combined immunization of
      conscripts during influenza seasons of 2002-2003].
AB  - The immunization properties of the influenza vaccine Vaxigrip, used in
      combination with vaccines against pneunococcal infection and hepatitis A
      (respectively, Pneumo 23 and Avaxim), were evaluated. In Central Russia in one of
      the units of the internal forces of the RF Ministry of Internal Affairs 3 groups
      totaling 755 servicemen were formed, depending on the complex of the introduced
      vaccines. Active medical observation and the registration of the complaints of
      the vaccinees at the postvaccinal period did not reveal unusual reactions and
      complications in none of the groups under observation. In the evaluation of the
      level of specific antibodies to the circulating influenza viruses prior to
      vaccination the low level of collective protection to influenza B virus was
      determined: protective antibody levels were registered only in 14-18% of the
      servicemen, while the corresponding data with respect of influenza viruses
      A(H1N1) and A(H3N2) were 45-50% and 56-63% respectively. At the same time, in
      seronegative persons the vaccine Vaxigrip exhibited high immunogenic activity
      with respect of all 3 influenza strains; seroconversion to them was determined in
      84-92% of the vaccines, and the level of protective antibody titers before the
      beginning of the epidemic season was 86-99% in the whole of the group. The
      characteristics of the prophylactic effectiveness of the vaccine Vaxigrip in
      relation to the influenza virus infection level 1 were 4.7 (index) and 79%
      (coefficient). In addition, the frequency of influenza cases, clinically
      pronounced and confirmed by laboratory methods, in patients who had been
      immunized with 3 vaccines was 6.7%, which was 10.3 times less frequent than
      number of cases in the groups of comparison (68.2% on the average). The
      coefficient of epidemiological effectiveness of the prophylaxis of influenza was
      90.2%. The complex use of 3 preparations did not affect the immunization
      properties of the vaccine Vaxigrip.

PMID- 15024983
TI  - [Antistaphylococcal activity of the complex of natural cytokines].
AB  - The in vitro study of the action of the complex of natural cytokines (CNC), or
      preparation Superlymph, on different microbial test strains (Staphylococcus
      aureus, Escherichia coli, yeast-like fungi of the genus Candida) was carried out.
      CNC suppressed the growth of S. aureus test culture, depending on the
      concentration of the preparation. The inhibiting effect was observed in the
      presence of Ca and Mg bivalent cations in the medium. Under the chosen conditions
      of the experiment CNC did not inhibit the growth of E. coli test cultures, as
      well as test cultures of yeast-like fungi of the genus Candida. In addition to
      its antibacterial effect, Superlymph also produced some effect on the release of
      cathepsin G, the lysosomal enzyme of human leukocyte granules.

PMID- 15024985
TI  - [Qualitative and quantitative composition of intestinal microflora in healthy
      young children].
AB  - The results of the qualitative and quantitative analysis of the microflora of the
      large intestine in 45 healthy children aged 6, 8, 10 months and 1 year, living in
      Moscow, are presented. During the first year of life high concentrations and
      detection rate of not only bifidobacteria, enterococci, nonpathogenic
      Escherichia, but also bacteria, commonly regarded as opportunistic were typical.
      The latter include lecithinase positive Clostridium, citrate assimilating
      enterobacteria, as well as Escherichia with low biochemical activity and capacity
      for hemolysin production. In addition, this group also includes coagulase
      positive staphylococci. Later on, as these children become older, opportunistic
      bacteria are partially or completely eliminated under normal conditions.
      Suggestion is made that the composition of intestinal microflora depends on
      protective and other systems of the host at different periods of life, as well as
      on the character of nutrition and the microbial contamination of the environment.

PMID- 15024986
TI  - [Diagnostic suspension for detection of the infective agent of tularemia].
AB  - The matrix for obtaining silica-based diagnosticum was selected, its activation
      with surfactant was optimized and its immobilization with tularemia
      immunoglobulins was carried out. In the glass suspension agglutination test (SAT)
      the sensitivity of the diagnosticum was 3.125 x 10(6) to 6.25 x 10(6) microbial
      cells per ml; the duration of SAT, including the evaluation of its results, was 1
      5 minutes.

PMID- 15024984
TI  - [Concentration and antiviral activity of interferon-alpha in the sera of patient
      with hepatic pathology].
AB  - The normalization of the antiviral activity of interferon-alpha (IFN-alpha) in
      the process of the treatment of patients with acute viral hepatitis (VH),
      simultaneously with the results of other clinico-laboratory tests, reflects the
      positive dynamics of the process. The prolonged preservation of the elevated
      level of the antiviral activity of IFN-alpha (up to 6 months and longer) is a
      prognostically unfavorable sign. In patients with chronic VH the growth of both
      the average concentration of IFN-alpha in the blood serum and its average
      antiviral activity can be observed. With the progress of the disease and the
      formation of the cirrhosis of the liver, the concentration of IFN-alpha in the
      blood serum remains to be elevated, while its antiviral activity drops.

PMID- 15024987
TI  - [Polyclonal antisera to birch pollen allergen for the air allergen screening].
AB  - The cross reactivity of the pollen allergens of birch (Betula pendula), hazel
      (Corylus avelana), alder (Alnus glutinosa), wormwood (Artemisia absinthium), oak
      (Quercus robur) and ashtree (Fraxinus excelsior) was studied by the methods of
      the enzyme immunoassay and gel diffusion with the use of rabbit polyclonal
      antisera (PAS) prepared against birch pollen allergen. PAS was shown to be
      greatly related to all above-mentioned allergens with the exception of oak pollen
      allergen. PAS was found capable of forming precipitates in the layer of agar gel
      only with birch pollen allergen. A proposal was made to use PAS, in view of the
      established specific features of its immunochemical properties, in the
      development of test systems for the ecological monitoring of biotopes.

PMID- 15024989
TI  - [Allergenic and immunogenic properties of industrial dust of the cotton factory].
AB  - The results of the determination of the allergenic and immunogenic properties of
      industrial dust of the cotton factory complex are presented. The antigen of
      industrial dust consists of, at least, 5 antigenic components. The presence of
      common antigenic determinants in the antigen of industrial dust and in cotton
      pollen antigen has been established. The administration of relatively large doses
      of the allergen according to a shortened schedule has been experimentally shown
      to enhance the curative effectiveness of specific therapy.

PMID- 15024988
TI  - [Clinical and immunological changes in atopic dermatitis patients treated with
      purified staphylococcal toxoid].
AB  - 32 patients with atopic dermatitis (AD), complicated by pyoderma, were treated
      with purified staphylococcal toxoid (PST). Changes in clinical and laboratory
      characteristics in the course of treatment were evaluated. PST was shown to
      produce a satisfactory therapeutic effect, arresting the symptoms of local
      staphylococcal infection. An increase in the levels of alpha- and gamma
      interferons and decreased content of CD25+ lymphocytes were found. Thus prospects
      appear for using this preparation as an interferon inductor, as well a for the
      immunotherapy of AD patients sensitized to Staphylococcus aureus.

PMID- 15024990
TI  - [Tuberculosis morbidity in Primor'e region].
AB  - The present epidemiological situation in tuberculosis in the Maritime Territory
      is described, including the spread of this infection among the population and the
      prognosis for the next year. Tuberculosis morbidity in HIV-infected patients is
      specially emphasized, with high growth rate of morbidity in these mixed
      infections. The conclusion has been made on the necessity of improving the
      diagnostic and prophylactic measures among the population of the Maritime
      Territory.

PMID- 15024993
TI  - [Cholera prevalence worldwide and in Ukraine].
AB  - In the course of the 7th pandemic cholera morbidity has been registered in 163
      countries of the world. 5 periods in the development of the pandemic hav been
      established. The pandemic process has a pronounced tendency to growth. The spread
      and dynamics of cholera morbidity have their specific features on each continent.
      In Asia the epidemic process is manifested as permanent morbidity. Africa
      determines the total morbidity level in the 7th pandemic. In America both the
      import of cholera infection and large local outbreaks due to the formation of the
      secondary foci are registered. In Europe the infection is mainly brought from
      different territories, and in a number of cases an epidemic spread of this
      infection occurs. The paths of the penetration of cholera to Europe and Ukraine
      are, probably, identical. In Ukraine 3 pandemic periods have been established,
      corresponding to the periods of pandemic spread.

PMID- 15024992
TI  - [Dysbacteriosis and preparations with probiotic function].
AB  - Information on intestinal microecological disturbances (dysbacteriosis) and the
      preparations of probiotics, prebiotics and synbiotics used for the correction of
      resident normal colon microflora is presented. Probiotics are preparations
      containing live microbes or substances of microbial origin that, when introduced
      by natural methods are expected to confer beneficial physiologic, biochemical and
      immune effects to the host through the stabilization and the optimization of
      functions of normal microflora. Prebiotics are preparations containing a non
      digestible food ingredient that beneficially affect the host by selectively
      stimulating the growth and the activity of a limited number of resident bacteria
      of normal microflora in the colon. Synbiotics are preparations obtained as the
      result of the rational combination of probiotics and prebiotics.

PMID- 15024991
TI  - [Potentialities of calcium dependent lectin receptors of antigen presenting cells
      for the immunotherapeutic preparation development].
AB  - Publications on C-lectin receptors, multifunctional surface molecules of antigen
      presenting cells are updated. The study of C-lectin receptors is stipulated by
      their role in antimicrobial protection. The importance of C-lectin receptors of
      dendrite cells in the system of the recognition of microbial carbohydrate as well
      as their properties of the targeted supply of tumor cell and other antigens to
      dendrite cells with the purpose of the formation of immunity against faintly
      immunogenic antigens is considered. Suggestion is made on the potential of their
      use as experimental preparations for immunotherapy.

PMID- 15024995
TI  - [Management experience on the prevention of occupational HIV infection in medical
      institutions of Sverdlovsk region].

PMID- 15024994
TI  - [Diagnostics of botulism in Ul'ianovsk region].

PMID- 15024996
TI  - [Etiological structure of enteric infection outbreaks in Moscow in 1993-2002].

PMID- 15024997
TI  - [Pleiotropic function of the phosphoenolpyruvate-dependent phosphotransferase
      system].
AB  - The final Communication III deals with the pleiotropicaction of the
      phosphotransferase system (PTS) focusing on the below issues related with the
      bacterial cell: PTS and the nitrous metabolism regulation, virulence, chemotaxis
      and sporulation. The factor of protein Mlc within the regulation of PTS itself,
      i.e. of permease PtsG and of system's general components, is described
      separately. Therefore, all practically valuable PTS functions involved in the
      vital activity of both gram-positive and gram-negative bacteria are elucidated;
      they are depicted in a generalized diagram, Fig. 2, Communication 1.

PMID- 15024998
TI  - [Use of PCR for identification of Burkholderia mallei].
AB  - Stimuli of glanders belong to the potential agents of biological terror. The
      possibility to use various primers in the identification of B. mallei was
      investigated and the significance of polymerase chain reaction (PCR) was defined
      within the scheme of laboratory glanders diagnosis in the offered paper. The
      constructed amplifying test-systems can be used to detect the glanders both in
      the environmental objects contaminated with B. mallei and in experimental
      clinical material.

PMID- 15024999
TI  - [Phytase activity in some groups of bacteria. Search for and cloning of genes for
      bacterial phytases].
AB  - A search for phytase genes in 9 Bacillus strains from the collection of IMGAN was
      implemented. The growth optimum of strains IX-22, IX-12B, K17-2, K18, IMG I, IMG
      II, M4 and M8 was 50-60 degrees C; the optimal growth temperature for Bacillus
      sp. 790 was 45-47 degrees C. According to the sequence data of 16S RNA genes,
      Bacillus sp. 790 belongs to the B. subtilis/amyloliquefaciens group. The other 8
      strains were identified as B. licheniformis. Selection of Bacillus strains,
      potentially containing the phytase genes, was performed via PCR with primers
      designed on the basis of the conserved sequence regions of the phyA gene from B.
      amyloliquefaciens FZB45 with chromosomal DNA being used as the template. The
      nucleotide sequences of all PCR fragments showed a high level of homology to the
      known Bacillus phytase genes. The gene libraries of B. licheniformis M8 and B.
      amyloliquefaciens 790 in E. coli were constructed and phytase-containing clones
      were selected from them. Twenty-four Pseudomonas strains of different species, 5
      Xanthomonas maltophilia strains and 1 Xanthomonas malvacearum (all from the
      mentioned collection) were tested for phytase activity. Such activity was found
      in 13 Pseudomonas strains and in 6 Xanthomonas strains. The accumulation of
      phytase in Pseudomonas was shown to take place at later (over 2 days') growth
      stages. The optimum pH for phytase from 3 Pseudomonas strains were established.
      The enzymes were found to be most active at pH 5.5.

PMID- 15025000
TI  - [Analysis of genomic polymorphism of typical and atypical strains of the plague
      pathogen using polymerase chain reaction with universal primers].
AB  - An analysis of genome polymorphism of the Y. pestis strains by using the method
      of polymerase chain reaction (PCR) for the tandem repeats of bacteriophage M13
      DNA revealed a species similarity of both typical and atypical (according to
      diagnostic signs) plague-microbe strains. Strain Y. pestis A-1726 with the
      atypical differential-and-diagnostic properties, without the amplicon specified
      for Y. pestis and sized 1000 b.p., was identified among 27 analyzed Y. pestis
      strains. The amplicon profiles of the basic Y. pestis subtype were found to be
      different from such profiles of other Y. pestis subtypes.

PMID- 15025001
TI  - [Detection of YMDD mutations in hepatitis B virus DNA with the use of allele
      specific polymerase chain reaction].
AB  - Antiviral drug lamivudine has been widely used in the treatment of hepatitis B.
      However, it was demonstrated recently, that therapy by the drug is related with
      the selection of viral strains carrying mutations in C-domain of DNA
      polymerase/reverse transcriptase (YMDD-mutation). The mutation is the cause of
      resistance to lamivudine. An increase of the mutant population in the course of a
      long-term lamivudine therapy makes the monotherapy by the discussed drug
      ineffective. Therefore, the monitoring of YMDD mutations is important in the
      treatment of chronic hepatitis B (CHB) by lamivudine. The results of using the
      allele-specific polymerase chain reaction (AS PCR) for the detection of YMDD
      mutations are presented in the offered case study. Sera from CHB patients were
      used in research. A system of allele-specific primers was designed for the HBV
      DNA region from base 720 to base 978, which enabled us to detect possible
      substitutions in an appropriate ATG-triplet, i.e. the YMDD-mutations locus-
      positions 741-743 of the HBV DNA nucleotide sequence. The obtained DNA fragments
      were analyzed by electrophoresis in the agar gel. AS PCR was used to test the
      sera of HBV patients. Samples were detected, which contained the "wild" virus
      type, different YMDD mutations and mixed (the "wild" type plus a mutation) HBV
      variants. It was shown that reliable AS PCR results could be obtained only in
      those sample, whose HBV titer is no more than 10(6) genome per ml. The offered AS
      PCR procedure can be applied in the detection of YMDD mutations of HBV DNA in
      sera of patients with hepatitis B. Sera with a high virus titer must be diluted,
      prior to testing, to 10(6) genomes per ml. to ensure the reliable AS PCR results.

PMID- 15025002
TI  - [Phylogenetic analysis of chemokine-binding protein gene from orthopoxviruses].
AB  - Poxviruses, belonging to the genus of Orthopoxviruses and Leporipoxviruses,
      express a protein that binds a wide spectrum of CC-chenokines. The above viral
      protein (vCCI) has no homology by the amino acid sequence with the known cellular
      receptors of chemokines or with any other proteins represented in databases.
      Sixty-nine nucleotide sequences of the vCCI protein gene of 4 Orthopoxviruses,
      which are pathogenic to man, and of 2 species, to whom man is immune, as well as
      16 of such sequences borrowed from GenBank were subjected to the phylogenetic
      analysis. Strains of Orthopoxviruses, except for cowpox viruses (CPXV), were
      found to cluster together in groups according to their specific attribute. CPXV
      isolates can be conditionally divided into 2 subgroups, which are much remote
      from one another evolutionally. Four subgroups were defined for smallpox virus
      with their strains originating from different geographic regions.

PMID- 15025003
TI  - [Laminin-binding protein as a cellular receptor for the equine Venezuelan
      encephalomyelitis virus: Report 2. Inhibition of replication of equine Venezuelan
      encephalomyelitis virus by blocking laminin-binding protein on the surface of
      Vero cells].
AB  - A possible inhibition of the Venezuelan equine encephalomyelitis (VEE) virus
      replication in Vero cells through the laminin-binding protein (LBP) blocking in
      the surface of such cells was investigated in order to verify the LBP value. It
      was demonstrated, on the basis of the flow scanning cytometry and FITC-labeled
      antibodies to LBP, that there are at least 263 thousand LBP molecules in the Vero
      cells' surface. Blocking of the molecules by rabbit polyclonal antibodies to 43
      kD of the recombinant LBP (rLBP) was shown to inhibit the VEE virus replication
      in Vero cells by more than 300,000 times, which made them virtually resistant to
      the possibility of VEE virus infection. This also confirmed that LBP is a target
      molecule for VEE virus in Vero cells with the interplay between VEE virus and LBP
      in the cells' surface being the initial stage of virions' penetration into the
      cell and of their replication inside the cell.

PMID- 15025004
TI  - Headache and facial pain. Preface.

PMID- 15025005
TI  - Anatomy of headache and facial pain.
AB  - In this article we review the neural and vascular supply contributing to headache
      and facial pain. A detailed review of the neuroanatomy, particularly of the
      trigeminal contribution, was formulated. Emphasis was placed on outlining the
      dural, supratentorial, and facial structures innervated. A detailed review of the
      vascular anatomy is performed, with demonstration of the trigeminal innervation
      of key vascular structures. An outline of pain-sensitive cranial structures is
      also described. The pathways examined in this article serve as the basis on which
      concepts of headache and facial pain will build.

PMID- 15025007
TI  - Migraine mechanism and management.
AB  - Migraine affects an estimated 10% to 15% of the population with greater or lesser
      regularity and throughout much of their lifetime. It causes disability, be it
      often temporary, and strains personal relationships and professional development.
      Little is known about it scientifically, and its treatment remains mostly
      empirical. This article describes the pathogenesis of migraine, as well as its
      management in terms of abortive and preventive treatment.

PMID- 15025006
TI  - Classification of headache and facial pain.
AB  - It is important for us as otolaryngologists to identify our critical role in
      diagnosing and treating the subset of patients that suffers from headaches. It is
      equally important for the layperson and the medical community to recognize the
      importance of a multidisciplinary team approach in the management of headache and
      facial pain. Despite its limitations, classification provides us with a starting
      point from which scientists, clinicians, and patients can begin to determine the
      success of diagnostic and therapeutic strategies. It also indicates future
      directions for research.

PMID- 15025008
TI  - Cranial neuralgias and headaches associated with cranial vascular disorders.
AB  - This article discusses various cranial neuralgias and headaches linked to
      vascular disorders, including trigeminal neuralgia, intracerebral hemorrhage,
      temporal arteritis, and central nervous system angiitis. Also discussed are
      diagnostic methods, treatment options, and pain management.

PMID- 15025009
TI  - Acute, subacute, and chronic headache.
AB  - Headaches are perhaps the most common ailment, affecting up to 80% of the
      population. They can be classified as acute, subacute, or chronic, depending on
      the time they have been present, either intermittently or continuously. This
      article describes the most common types of headaches, their causes, and various
      treatments available.

PMID- 15025010
TI  - Treatment and outcome of chronic daily headache.
AB  - Chronic daily headache (CDH) refers to the daily or almost daily occurrence of
      headache for a prolonged period of time, with lack of a well-defined attack
      pattern. It constitutes the vast majority of daily headaches. Hemicrania
      continua, a condition that closely resembles CDH, will be discussed as part of
      this article because the two are difficult, if not impossible, to distinguish
      solely on the basis of their presentations.

PMID- 15025011
TI  - Sinonasal facial pain.
AB  - Evaluation of the paranasal sinuses and nasal cavity in patients with headache
      and or facial pain must include a thorough medical and social history, with close
      attention to the pattern and character of the pain, a thorough physical
      examination that includes a palpation and nasal endoscopy, and imaging studies
      such as CT scans and Magnetic Resonance Imaging. The physician must remember that
      every pain in the face is not caused by sinusitis.

PMID- 15025012
TI  - Pain from the oral cavity.
AB  - The head, face, mouth, and throat collectively is the most frequent site of pain
      in humans. Facial pain is a particularly distressing problem because
      identification and effective treatment of the underlying cause is often
      challenging and sometimes elusive. This article focuses on the more common causes
      of facial pain that originate in the oral cavity and associated structures and
      outlines a general approach to diagnosis and management of these problems.

PMID- 15025013
TI  - Otalgia.
AB  - The patient presenting with otalgia poses a diagnostic challenge for which
      orderly and diligent evaluation and management is needed. The etiology of otalgia
      can be either primary or referred, and a detailed history and physical
      examination with directed studies as indicated can elucidate the cause of the
      pain.

PMID- 15025015
TI  - Pharmacological management of head and neck pain.
AB  - Careful selection of an effective analgesic regimen based on the amount and type
      of pain the patient is expected to have can prevent the stress and anxiety
      associated with breakthrough pain. When analgesics fail, it is not unusual for
      patients to go to desperate lengths to seek relief. The clinician can and should
      develop various effective, safe analgesic regimens based on estimates of
      anticipated pain intensity that apply sound pharmacological principles.

PMID- 15025014
TI  - Headache and facial pain in children and adolescents.
AB  - Headaches commonly affect children and adolescents. Proper diagnosis and
      management is dependent on thorough history taking and a comprehensive physical
      and neurological examination. Additional diagnostic testing is indicated in some
      cases. The second edition of the headache classification system by the
      International Headache Society has recently become available. The classification
      system is primarily based on adults, but we discussed the subtle distinctions
      made regarding children. In addition to the primary headache types of migraine,
      tension-type, and cluster headaches, we discussed selected symptomatic headaches.
      Emphasis was placed on migraine and tension-type headaches because these are the
      most common pediatric headache types. We briefly discussed genetic aspects of
      headaches. Genetic factors have been hypothesized for chronic tension headache
      and other forms of migraine, but genetic linkage has only been established for
      familial hemiplegic migraine. We reviewed the nonpharmacologic and pharmacologic
      therapies, including abortive and prophylactic medications for various age
      groups. Unlike headaches, facial neuralgias are rare in otherwise healthy
      children. Facial pain may be neurological, vascular, or dental in origin. We
      focused on trigeminal neuralgia, glossopharyngeal neuralgia, occipital neuralgia,
      and Bell's palsy as neurological causes of facial pain in children.

PMID- 15025016
TI  - Psychiatric perspectives on headache and facial pain.
AB  - For a subset of headache patients, an understanding of psychological antecedents
      and interpersonal difficulties is an important part of the headache evaluation.
      This subset includes patients with chronic headache, frequent headache, treatment
      refractory headache, analgesic misuse problems, and serious compliance issues.
      Inadequate coping with stress is central to the persistence of headache in many
      such patients. Other patients present to the headache specialist but actually
      suffer from a serious comorbid psychiatric disorder, such as major depression,
      panic disorder, substance abuse, or personality disorder. For successful
      treatment of headache, it is important that these related problems be detected
      and either treated (as outlined here) or referred to a specialist for treatment.

PMID- 15025017
TI  - Regional anesthesia and invasive techniques to manage head and neck pain.
AB  - Regional anesthesia of the head and neck is an effective method of obtaining
      surgical anesthesia for various procedures. Diagnostic and therapeutic head and
      neck blocks can also assist with the diagnosis and management of many chronic
      pain conditions, including headache, postherpetic neuralgia, and cancer pain in
      this region. Gamma knife surgery offers a unique approach to the management of
      refractory trigeminal neuralgia. Because of the proximity of so many critical
      structures adjacent to these nerves, a solid understanding of the anatomical
      basis of these nerve blocks is necessary. Appropriate patient selection,
      monitoring, proper injection technique, knowledge of the pharmacokinetics and
      pharmacodynamics of local anesthetics and vasoconstrictors, possible drug
      interactions, and recommended doses will ensure safe and successful application
      of head and neck nerve blockade.

PMID- 15025018
TI  - Alternative therapies in the management of headache and facial pain.
AB  - Complementary therapies are now becoming the rule rather than the exception in
      the management of headache and facial pain. It is incumbent on physicians to be
      aware of and to have a working knowledge of these increasingly popular
      modalities.

PMID- 15025019
TI  - Generic drugs. Does inexpensive mean cheap?

PMID- 15025020
TI  - What's up with soy?

PMID- 15025021
TI  - Get hooked on fish and seafood.

PMID- 15025022
TI  - Are you label-able?

PMID- 15025023
TI  - Pack a punch for lunch.

PMID- 15025024
TI  - How much do you know about staying hydrated?

PMID- 15025025
TI  - Sports & fitness. Improving your balance.

PMID- 15025026
TI  - H-B-A-1-C (what it is and why it matters).

PMID- 15025028
TI  - [Retraction. A case of ill smelling watery sputum].

PMID- 15025027
TI  - Supermarket smarts. Frozen cakes, pies, and cheesecake.

PMID- 15025029
TI  - Structural estimation of a principal-agent model: moral hazard in medical
      insurance.
AB  - Despite the importance of principal-agent models in the development of modern
      economic theory, there are few estimations of these models. I recover the
      estimates of a principal-agent model and obtain an approximation to the optimal
      contract. The results show that out-of-pocket payments follow a concave profile
      with respect to costs of treatment. I estimate the welfare loss due to moral
      hazard, taking into account income effects. I also propose a new measure of moral
      hazard based on the conditional correlation between contractible and
      noncontractible variables.

PMID- 15025030
TI  - Contracting with limited commitment: evidence from employment-based health
      insurance contracts.
AB  - Impediments to worker mobility serve to mitigate the attrition of healthy
      individuals from employer-sponsored insurance pools, thereby creating a de facto
      commitment mechanism that allows for more complete insurance of health risks than
      would be possible in the absence of such frictions. Using data on health
      insurance contracts obtained from the 1987 National Medical Expenditure Survey,
      we find that the quantity of insurance provided is positively related to the
      degree of worker commitment. These results illustrate the importance of
      commitment in the design of long-term contracts, and provide an additional
      rationale for the bundling of health insurance with employment.

PMID- 15025031
TI  - Assessing competition in hospital care markets: the importance of accounting for
      quality differentiation.
AB  - Quality differentiation is especially important in the hospital industry, where
      the choices of Medicare patients are unaffected by prices. Unlike previous
      studies that use geographic market concentration to estimate hospital
      competitiveness, this article emphasizes the importance of quality
      differentiation in this spatially differentiated market. I estimate a random
      coefficients discrete-choice model that predicts patient flow to different
      hospitals and find that demand responses to both distance and quality are
      substantial. The estimates suggest that patients do not substitute toward
      alternative hospitals in proportion to current market shares, implying that
      geographic market concentration is an inappropriate measure of hospital
      competitiveness.

PMID- 15025032
TI  - [Infant crying diary: a useful aid in distinguishing between normal and excessive
      crying behavior].
AB  - Three infant girls aged 9, 10 and 8 weeks, who cried excessively according to
      their parents, were referred by the general practitioner to the paediatrician.
      Using a crying diary it was possible to ascertain that one infant fulfilled the
      criteria of infantile colic. The diary showed that a second infant was not crying
      excessively and her mother could be reassured that her baby's behaviour was
      normal. The third infant proved to be suffering from an organic disease (Alpha-I
      antitrypsin deficiency), which had not been obvious at clinical assessment. The
      crying diary provided clues that warranted further investigation. The parents of
      all 3 infants were reassured and the crying lessened over a period of several
      weeks. When parents complain that their child cries excessively, it is useful to
      chart the amount of crying time in a diary. Registration for one week is
      sufficient. If the child does not suffer from an organic disease, the mainstay of
      treatment is to explain normal crying behaviour and that it often helps if the
      infant is not offered too many stimuli. Parents can be reassured that spontaneous
      resolution will generally occur at the age of three months.

PMID- 15025033
TI  - ["What is a dream?"].

PMID- 15025034
TI  - Intragastric balloon: another option for treatment of obesity and morbid obesity.
AB  - BACKGROUND/AIMS: The BioEnterics Intragrastric Balloon (BIB, BioEnterics, Santa
      Barbara, CA) in association with restricted diet has been used for the treatment
      of obesity and morbid obesity. METHODOLOGY: Since March 1998, 349 BIB were placed
      in 303 obese and morbidly obese patients; 95 patients were male and 208 female;
      mean age was 41.5 years (19-70); mean weight was 118.8 Kg (67-229); mean BMI was
      42 Kg/m2, % excess weight was 62.3% (4.6-216.3). The balloon was inserted and
      removed endoscopically under general anesthesia. Patients were given a balanced
      diet of 1000 Kcal/day. RESULTS: After 4 months of balloon treatment, the mean
      weight loss was 13.9 Kg and the mean reduction in BMI was 4.8 Kg/m2. Weight loss
      was greater in male patients. Weight loss was accompanied by an improvement of
      the diseases associated with obesity, in particular diabetes. CONCLUSIONS: The
      best indications for BIB were: morbidly obese (BMI >40) and super-obese patients
      (BMI >50) in preparation for bariatric operations; obese patients with BMI 35-40
      with co-morbidity in preparation for bariatric surgery; obese patients with BMI
      30-35 with a chronic disease otherwise unresolved; patients with BMI <30 only in
      a multidisciplinary approach.

PMID- 15025035
TI  - The effect of non-random loss to follow-up on group mean estimates in a
      longitudinal study.
AB  - Bias due to selective non-response is often neglected in large-scale
      epidemiological studies. And, although some recent techniques enable adjustment
      for selective non-response, these are rarely applied. The Maastricht Cohort
      Study, a study on fatigue at work among 12140 respondents at baseline, enabled us
      to estimate the degree of bias in a real life data set. After seven subsequent
      measurements, spanning a 2-year period, 8070 respondents remained in the cohort.
      Two traditional ways of presenting longitudinal mean levels (means using all
      data, and means using only complete cases) are compared with adjusted mean
      levels, using mixed models. The difference between the complete case and overall
      mean levels and the adjusted means were about 2% for the continuous fatigue score
      and 6% for the proportion of fatigued cases. For the company mean scores the
      observed bias due to selective non-response might be as much as 30% for some of
      the company means for the continuous fatigue score and up to 160% for the
      estimated number of fatigued cases. We therefore conclude that bias due to
      selective non-response needs serious attention. Next to making vigorous attempts
      to minimize longitudinal non-response, the use of statistical adjustment is also
      recommended.

PMID- 15025037
TI  - Cognitive and affective probes of the HPA axis: a SPECT study.

PMID- 15025036
TI  - Salmeterol decreases eosinophilic cationic protein and rescue medication in
      patients inhaling beclomethasone dipropionate: preliminary study in mild and
      moderate asthma in Trinidad, West Indies.
AB  - Activated eosinophils play a critical role in asthma pathogenesis, and eosinophil
      cationic protein (ECP) is a useful indicator of inflammation. Inhaled
      corticosteroids and long-acting beta2-agonists (LABA) effectively control asthma
      symptoms and improve airway function. Salmeterol's anti-inflammatory efficacy as
      add-on therapy to inhaled corticosteroids has not been evaluated in Caribbean
      populations. We investigated nine non-smoking subjects (three men and six women;
      mean age: +/- SE, 50.7 +/- 3.82 years) with stable mild and moderate persistent
      asthma who were inhaling > or = 500 microg beclomethasone dipropionate (BDP)
      daily. This was a with-in-patient controlled laboratory blind study performed
      over 8 weeks. Patients received BDP for 2 weeks, add-on salmeterol 100 microg in
      weeks 3-6 and BDP alone in weeks 7-8. Patients recorded daily morning and night
      symptoms. Morning peak expiratory flow rate was measured on entry to the study
      and with sputum ECP at the end of weeks 2, 4, 6 and 8. Salmeterol together with
      BDP decreased sputum ECP from a pretreatment median value of 897.84 microg/l to
      628.38 microg/l after 4 weeks, and ECP continued to decrease even after
      salmeterol withdrawal. Both drugs decreased the frequency of rescue medication
      use by approximately 50% and increased the median number of days per week without
      rescue salbutamol from 0 to 3 days. Salmeterol's bronchoprotective effect was
      maximal after 4 weeks and was sustained after its withdrawal. In conclusion, this
      study, performed in Trinidadian asthmatics, used ECP as a surrogate marker of
      bronchial inflammation and supports the recent Salmeterol Multi-center Asthma
      Research Trial (SMART) data recommending add-on salmeterol therapy to adequate
      anti-inflammatory medication such as inhaled corticosteroids for optimal asthma
      management. Further studies are required to evaluate the anti-inflammatory
      efficacy and possible tolerance to salmeterol in Caribbean patients.

PMID- 15025038
TI  - PDL neuron-associated neurotransmitters in orthodontic tooth movement:
      identification and proposed mechanism of action.
AB  - The remodeling of the PDL and alveolar bone that occurs during orthodontic tooth
      movement (OTM) has long been associated with an inflammatory process. The
      vascular and cellular changes that occur have been well documented, and several
      inflammatory mediators, growth factors and neuropeptides have been found in
      increased levels in the periodontal supporting tissues during orthodontic tooth
      movement. It recently was found that peripheral nerve fibers participate in the
      inflammatory process (neurogenic inflammation) by releasing various
      neuropeptides. Calcitonin gene-related peptide (CGRP) and substance P (SP), two
      PDL neuropeptides, play a role in inflammation by serving as vasodilators and
      inducing increased vascular permeability. They also stimulate plasma
      extravasation and proliferation of endothelial cells and fibroblasts; upregulate
      the expression of endothelial cell adhesion molecules; and act as
      neurotransmitters. The increase in concentration of these PDL neuropeptides
      during OTM indicates their importance to the process. This paper will review the
      current research and summarize the roles and proposed mechanism of these two main
      PDL neurotransmitters in OTM.

PMID- 15025039
TI  - Maternal deaths disproportionately high in developing countries.

PMID- 15025040
TI  - Multi-modality imaging data analysis with partial least squares.

PMID- 15025041
TI  - Auditory rCBF covariation with word rate during drug-induced sedation and
      unresponsiveness: a H2015 PET study.

PMID- 15025042
TI  - Electrophysiological study of working memory in mild cognitive impairment
      patients.

PMID- 15025043
TI  - Qualities of autobiographical memory modulate hippocampal activation during
      retrieval: preliminary findings of an fMRI study.

PMID- 15025044
TI  - The effects of prenatal and current marijuana exposure on response inhibition: a
      functional magnetic resonance imaging study.

PMID- 15025045
TI  - Localization of transient and steady-state auditory evoked responses using
      synthetic aperture magnetometry.

PMID- 15025046
TI  - Differential topography of Alzheimer's disease and frontotemporal dementia: an
      MRI volumetric analysis from Sunnybrook dementia study.

PMID- 15025047
TI  - Fusiform gyrus and possible impairment of the recognition of emotional expression
      in schizophrenia subjects with blunted affect: a fMRI preliminary report.

PMID- 15025048
TI  - Visual stimulation training in cerebral blindness due to hypoxia.

PMID- 15025049
TI  - The generator of MEG sleep spindle.

PMID- 15025050
TI  - Functional MRI of haptic face recognition.

PMID- 15025051
TI  - Abnormal prefrontal and anterior cingulate activation in major depressive
      disorder during episodic memory encoding of sad stimuli.

PMID- 15025052
TI  - Neural activity associated with failed inhibition: an event related fMRI study or
      performance monitoring.

PMID- 15025054
TI  - Simple linear and area MR measurements can help distinguish between Alzheimer's
      disease, frontotemporal dementia, and normal aging: the Sunnybrook dementia
      study.

PMID- 15025053
TI  - Medical devices; hematology and pathology devices; classification of the Factor V
      Leiden DNA mutation detection systems devices. Final rule.
AB  - The Food and Drug Administration (FDA) is classifying the Factor V Leiden
      deoxyribonucleic acid (DNA) mutation detections systems device into class II
      (special controls). The special control that will apply to the device is the
      guidance document entitled "Class II Special Controls Guidance Document: Factor V
      Leiden DNA Mutation Detection Systems." The agency is taking this action in
      response to a petition submitted under the Federal Food, Drug, and Cosmetic Act
      (the act) as amended by the Medical Device Amendments of 1976 (the 1976
      amendments), the Safe Medical Devices Act of 1990 (SMDA), the Food and Drug
      Administration Modernization Act of 1997 (FDAMA), and the Medical Device User Fee
      and Modernization Act of 2002. The agency is classifying this device into class
      II (special controls) in order to provide a reasonable assurance of safety and
      effectiveness of the device. Elsewhere in this issue of the Federal Register, FDA
      is publishing a notice of availability of a guidance document that is the special
      control for this device.

PMID- 15025055
TI  - Effect of mental imagery duration on functional brain mapping: an fMRI study.

PMID- 15025056
TI  - Neural correlates of conflict monitoring and error processing.

PMID- 15025057
TI  - fMRI studies of remote spatial memory in an amnesic person.

PMID- 15025058
TI  - New stimulation paradigm for simultaneous investigation of habituation and
      lateral inhibition effects in the central auditory system.

PMID- 15025060
TI  - Systems psychodynamics: the formative years of an interdisciplinary field at the
      Tavistock Institute.
AB  - Systems psychodynamics is an interdisciplinary field amalgamating a triad of
      influences -the practice of psychoanalysis, the theories and methods of the field
      of group relations, and the task and boundary awareness of open systems
      perspectives. Although systems psychodynamics is not a new field of study, there
      has been a general lack of awareness of its roots, how its formative elements
      have become intertwined over the years, and the role of the Tavistock Institute
      in developments in the field. This article provides a synthesis of this history
      and focuses, in particular,on the intellectual foundations of the Tavistock
      method of working experientially with groups and the application of this method
      to the study of organizations.

PMID- 15025061
TI  - Wellcome witnesses: the Medical Research Council Applied Psychology Unit.
AB  - A Witness Seminar brings together individuals involved in a significant event in
      the treatment of a medical condition to describe its background and to discuss,
      debate, or even to disagree with their peers' recollections. A brief description
      is given of the Witness Seminar, held in June 2001 by the Wellcome Trust Centre
      for the History of Medicine at University College London, which considered the
      history of Medical Research Council's Applied Psychology Unit (ABU) in Cambridge,
      United Kingdom. The APU was created in 1944 and produced more than 3,000 papers
      before it was renamed the Cognition and Brain Sciences Unite (CBU) in 1998.
      Photographs of key figures and purpose-built apparatus illustrate some of its
      early work as recorded in the published transcript of the meeting.

PMID- 15025059
TI  - In vivo plasma binding capacity for cyanocobalamin.

PMID- 15025062
TI  - Proton magnetic resonance spectroscopy and cognitive function in pediatric
      attention-deficit/hyperactive disorder.

PMID- 15025064
TI  - To test or not to test: do workplace drug testing programs discourage employee
      drug use?
AB  - Workplace drug testing programs are often met with intense criticism. Despite
      resistance among labor and consumer groups and a lack of rigorous empirical
      evidence regarding effectiveness, drug testing programs have remained popular
      with employers throughout the 1990s and into the current century. The present
      study analyzed nationally representative data on over 15,000 US households to
      determine whether various types of workplace drug testing programs influenced the
      probability of drug use by workers. The study estimated several empirical
      specifications using both univariate and bivariate probit techniques. The
      specification tests favored the bivariate probit model over the univariate probit
      model. Estimated marginal effects of drug testing on any drug use were negative,
      significant, and relatively large, indicating that drug testing programs are
      achieving one of the desired effects. The results were similar when any drug use
      was replaced with chronic drug use in the models. These results have important
      policy implications regarding the effectiveness and economic viability of
      workplace anti-drug programs.

PMID- 15025063
TI  - A spatiotemporal approach to cortical mapping using synthetic aperture
      magnetometry.

PMID- 15025065
TI  - The philosophical foundations of Aleksandr R. Luria's neuropsychology.
AB  - This article attempts to show that the cultural-historical psychological theory
      of Aleksandr R. Luria (Luriya) and his colleagues is based on the foundations of
      historical materialism. It argues in particular that Luria's psychology,
      neuropsychology, and brain theory are integrated in the same scientific research
      program and are based on the same philosophical premises, and that his theories
      must be interpreted in the Marxist context in which they are embedded. Luria's
      research program asserts that the development of higher mental functions depends
      on the appropriation of cultural means, particularly language, within social
      practice. Moreover, the brain structures underlying mental functions are also
      dependent on the appropriation of cultural means. Luria's clinical diagnosis and
      his program for rehabilitation of patients with brain lesions are based on his
      psychological theory and brain theory. The following analysis of Luria's
      comprehensive program will show that a socio-cultural non-reductive explanation
      of mental functions and their underlying brain structures may have implications
      for the philosophical discussion of the mind-brain problem.

PMID- 15025066
TI  - Streamlining drug discovery: finding the right drug against the right target to
      treat the right disease.

PMID- 15025067
TI  - The dangers of generalization in nanotechnology.

PMID- 15025068
TI  - Body counts and murder rates: the contested statistics of Western violence.
      [Review of: McKanna CV, Jr. Race and homicide in nineteenth-century California.
      Reno, University of Nevada Press, 2002; Peterson del Mar D. Beaten down: a
      history interpersonal violence in the West. Seattle, University of Washington
      Press, 2002].

PMID- 15025069
TI  - Apothecaries, "charlatans", and the medical marketplace in Italy, 1400-1750.

PMID- 15025070
TI  - Medicating with or without "scruples": the "professionalization" of the
      apothecary in sixteenth-century Venice.

PMID- 15025071
TI  - "For the protection of those who have both shop and home in this city". Relations
      between Italian charlatans and apothecaries.

PMID- 15025072
TI  - Pharmaceutical self-fashioning or how to get rich and famous in the Renaissance
      medical marketplace.

PMID- 15025073
TI  - MEWAs: the threat of plan insolvency and other challenges.

PMID- 15025074
TI  - Blood on demand. Transfusions used to be a bloody mess. A few dedicated doctors
      knew there had to be a better way.

PMID- 15025075
TI  - Alchemy in popular culture: Leonardo Fioravanti and the search for the
      philosopher's stone.
AB  - This article examines the alchemical ideas and practices of the sixteenth-century
      Italian surgeon Leonardo Fioravanti. I argue that Fioravanti's "search for the
      philosopher's stone" was as much an effort at self-fashioning as a search for
      alchemical gold. Exploiting the fashion for alchemical drugs, he framed a "new
      theory" of healing that relied on the use of distilled drugs as a means of
      purging bodily corruptions. His theory resonated with popular culture, and made
      him the focus of an alternative medical movement. I conclude that Fioravanti's
      alchemy was not Paracelsianism, but relied much more on more immediate sources
      such as Arnald of Villanova, the pseudo-Lull, and the contemporary Milanese
      alchemist Ettore Ausonio.

PMID- 15025076
TI  - Acute versus habitual exercise, thrombogenesis and exercise intensity.

PMID- 15025078
TI  - Evidence, logic, the rule and the exception in Renaissance law and medicine.
AB  - This article sets out to investigate aspects of the uptake of Renaissance law and
      medicine from some of the logical and natural-philosophical components of the
      university arts course. Medicine is shown to have a much laxer operative logic
      than law, reflecting its commitment to the theory of idiosyncrasy as opposed to
      the demands made upon the law by the need for a uniform application of justice.
      Symptomatic of the different uptake are the contrasting meanings of "regulariter"
      and "generaliter" in the two disciplines. Whereas the law treats the rule as
      inviolable and the exception as only valid if made explicit in due legal form,
      medicine is able to conceive of a nature as a field of knowledge broader than
      that encompassed by its rules of art. Both law and medicine approach evidence in
      ways which reflect their attempts to keep apart the process of information
      gathering from that of interpretation; this is exemplified by the legal
      computation of competing testimony on the one hand and by the various medical
      modes of sign interpretation on the other.

PMID- 15025077
TI  - TAFI: a promising drug target?

PMID- 15025079
TI  - Morbus-Locke's early essay on disease.
AB  - John Locke engaged in a systematic study of medicine from the late 1650's. In
      this period he acquainted himself with the three main competing natural
      philosophical theories of the time -Galenism, Paracelsianism and Mechanism. He
      was particularly interested in the work of Sennert, Helmont and Doyle. In 1666,
      just after the publication of Boyle's The Origine of Formes and Qualities, Locke
      wrote a short paper entitled Morbus. This paper gave Locke's own view of the
      nature of disease. Locke went out of his way to criticise Boyle's attempts to
      give mechanical explanations for biological phenomena. He endorsed Helmont's
      theory that disease was caused by "ferments" and "Archei" and re-introduced
      Galenic temperaments as factors of susceptibility in seminal diseases. Locke did
      not endorse a mechanical corpuscularianism at this stage in his career, when his
      contact with Boyle was most frequent. Consequently, Locke's espousal of the
      corpuscular philosophy in the Essay cannot be attributed to Locke's association
      with Boyle at this time.

PMID- 15025080
TI  - Readers' forum: orthodontic pain.

PMID- 15025081
TI  - Invisalign material studies.

PMID- 15025082
TI  - Enhanced learning through ARS.

PMID- 15025083
TI  - Early mixed dentition treatment.

PMID- 15025084
TI  - Elderly women more likely than men to be prescribed inappropriate drugs.

PMID- 15025085
TI  - Skeletodental patterns associated with missing teeth.

PMID- 15025086
TI  - Inadequate sigmoidoscopy more common in older patients and women.

PMID- 15025087
TI  - Hormone alternative doesn't worsen vasomotor symptoms or impact urinary
      incontinence in post-menopausal women.

PMID- 15025088
TI  - New study shows disparities in treatment of rectal cancer.

PMID- 15025089
TI  - Combined thrombopoietin and platelet response to altitude in a patient with
      autoimmune thrombocytopenia.

PMID- 15025090
TI  - What information should physicians be required to know?

PMID- 15025091
TI  - In memoriam: Alexandre G. Petrovic, 1925-2003.

PMID- 15025092
TI  - Medical ethics is whatever you say it is.

PMID- 15025093
TI  - In memoriam: Coenraad F.A. Moorrees, 1916-2003.

PMID- 15025094
TI  - Reflections of an idealistic pragmatist: on moving from a philosophy department
      to a clinical setting twenty years ago.

PMID- 15025095
TI  - Abstracts of the 6th Biennial Meeting of the Asian-Pacific Society for
      Neurochemistry. Hong Kong, 4-7 February 2004.

PMID- 15025096
TI  - My life in bioethics.

PMID- 15025097
TI  - Evidence that Armadillo transduces wingless by mediating nuclear export or
      cytosolic activation of Pangolin.

PMID- 15025098
TI  - Endothelial dysfunction: discovery and initial characterization.

PMID- 15025099
TI  - A philosopher in the land of bioethics.

PMID- 15025100
TI  - Abstracts of the 29th Annual Meeting of the American Society of Andrology. April
      17-20, 2004. Baltimore, Maryland, USA.

PMID- 15025101
TI  - Late expectations: clinical ethics and beyond.

PMID- 15025102
TI  - Experience and reflections.

PMID- 15025103
TI  - Fibrinolysis and proteolysis in a cellular context.

PMID- 15025104
TI  - Endovascular stent grafting for rupture of a thoracoabdominal aortic aneurysm
      after replacement of the entire aorta.

PMID- 15025105
TI  - Blue light special in a red light district.

PMID- 15025106
TI  - Needle embolism to the heart.

PMID- 15025108
TI  - Children as research subjects: guinea pigs or therapeutic orphans?

PMID- 15025107
TI  - Glucuronidation and susceptibility to chemical carcinogenesis.
AB  - The highlighted article in this issue of Toxicological Sciences, written by
      Zhuohan Hu and Peter Wells, addresses a subject that has received increasing
      scrutiny the past decade and a half--interindividual variation in detoxification
      enzyme activity as it relates to toxicity and cancer. Hu and Wells in their
      simple yet elegant study report variations in glucuronidation among normal
      individuals and provide data that define the potential impact of these variations
      on covalent binding and cytotoxicity of carcinogenic benzo[a]pyrene (BP)
      intermediates, gaining in the process important insights into individual
      potential to resist carcinogenesis by this and related compounds.

PMID- 15025109
TI  - Anatomizing the Renaissance. [Review of: Carlino A. Books of the body. Anatomical
      ritual and Renaissance learning. Chicago, University of Chicago Press, 2000;
      French R. Dissection and vivisection in the European Renaissance. Aldershot and
      Brookfield, VT, Ashgate, 1999; French R. Ancients and moderns in the medical
      sciences. From Hippocrates to Harvey. Aldershot and Brookfield, VT, Ashgate,
      2000].

PMID- 15025110
TI  - Cloning newspeak.

PMID- 15025111
TI  - High-tech medicine and the physician-patient relationship.

PMID- 15025112
TI  - Human embryos, human ingenuity, and government policy.

PMID- 15025113
TI  - Good, bad or offal? The evaluation of raw pancreas therapy and the rhetoric of
      control in the therapeutic trial, 1925.
AB  - In 1925 a debate erupted in the correspondence columns of the British Medical
      Journal concerning the effectiveness of eating raw pancreas as a treatment for
      diabetes. Enthusiasts were predominantly general practitioners (GPs), who claimed
      success for the therapy on the basis of their clinical impressions. Their
      detractors were laboratory-oriented 'biochemist-physicians,' who considered that
      their own experiments demonstrated that raw pancreas therapy was ineffective. The
      biochemist-physicians consistently dismissed the GPs' observations as
      inadequately 'controlled'. They did not define the meaning of 'control' in this
      context, although it clearly did not have the term's present-day meaning of a
      trial employing an untreated comparison group of patients. Rather, the physician
      biochemists' 'properly controlled' experiments involved careful regulation of
      their patients' diet and other environmental factors, and evaluation of the
      therapy's success through biochemical, rather than just clinical, criteria.
      However, my analysis suggests that these factors alone are inadequate to account
      for the biochemist-physicians' dismissal of the GPs' work as 'uncontrolled'. I
      suggest that the biochemist-physicians were deliberately exploiting the powerful
      rhetorical connotations of the term 'control'. Ultimately, they implied that only
      a trial which they themselves had conducted could be deemed 'adequately
      controlled'.

PMID- 15025114
TI  - Is it right or is it useful? Patenting of the human gene, Lockean property
      rights, and the erosion of the imago Dei.

PMID- 15025115
TI  - Withholding and withdrawing neonatal therapy: an alternative glance.

PMID- 15025116
TI  - Recent writing on health care history in Canada.
AB  - These are halcyon days for health care history in Canada. One routinely sees
      articles pertaining to health in leading Canadian and international history
      journals. The Canadian Bulletin of Medical History is a vibrant and important
      vehicle and there are a growing number of monographs. This essay reviews several
      of the maturing content areas that now characterize the writing of health history
      in Canada, including hospital history, nursing history, the history of mental
      health, and health and medicine in aboriginal settings. This essay seeks to
      highlight the accomplishments of the field, while reviewing some of the gaps.

PMID- 15025117
TI  - "Do everything!" Encountering "futility" in medical practice.

PMID- 15025118
TI  - [Medicine and health in French Canada: a historiography (1987-2000)].
AB  - In 1987, historian Jacques Bernier estimated that despite the publication between
      1876 and 1986 of a number of prominent papers, the history of medicine and health
      in French Canada was still in its infancy. Since then, this particular field of
      study has boomed. The present article examines published studies gathered
      according to the various themes which have been favored from 1987 to 2002 and
      concern the history of medicine and health in French Canada, so as to illustrate
      the gains of the past sixteen years. In our conclusion, we shall discuss the
      advancement of the history of medicine and health in French Canada in connection
      with the various elements suggested by historians Ludmilla Jordonova and Thomas
      Brown when considering the maturity of a given field of study. We shall identify
      a number of factors limiting its consolidation.

PMID- 15025119
TI  - Science on trial: conflicts of interest jeopardize scientific integrity and
      public health.

PMID- 15025121
TI  - Out of sight, out of mind: how Harvard University exploited rural Chinese
      villagers for their DNA.

PMID- 15025122
TI  - [Miasmas, germs and doctors: the diffusion of ancient and new ideas in the Union
      medicale du Canada: the case of typhoid fever (1872-1900)].
AB  - The final decades of the 19th century have become known as a period of important
      transition in the medical world. New discoveries revolutionized the way diseases
      were seen and fought. Germs, not miasmas, caused disease and sanitary measures of
      prevention not miracle treatments controlled them. The articles in l'Union
      medicale du Canada, from 1872 to 1900 concerning typhoid fever reveal that
      doctors rapidly accepted some important innovations. However, when it came to
      innovations refuting their former theories or risking to jeopardize their
      popularity with the public, certain doctors hesitated to adopt the new theories.
      This study presents the coexistance of new ideas with the older ideas, which
      continued to be presented, sometimes years after important discoveries. This
      paper looks at how they were finally won over to the newer ideas.

PMID- 15025120
TI  - The Cambridge model: how public oversight of biotech is good for everyone--even
      business.

PMID- 15025123
TI  - No task fit for a soldier? Canadian forces medical personnel and humanitarian
      relief missions since the Second World War.
AB  - Modern armies of the industrialized world operate in accordance with a doctrine,
      that is to say a philosophy linked to a series of procedures themselves
      determined by the tactical and strategic environment. These same armies, however,
      answer to civilian governments that do not limit their demands or instructions to
      the types of operations an army might list in its doctrine. For Canada's armed
      services, such seems to have been the case in regards to humanitarian operations
      which, even if they were not part of these services' operational philosophies,
      have nonetheless been of no little importance in the history of the air force,
      the navy, and the army since the end of the Second World War. This study will
      explore humanitarian operations from the second half of the 1940s to the
      formation and first missions of a unit specializing in such work in the 1990s. It
      will focus mainly on medical practice during these missions and attempt to
      determine whether medical practitioners had to change their basic approach to
      accomplish their tasks, or whether it sufficed to adapt procedures in accordance
      with the operational situation.

PMID- 15025124
TI  - Lee J. Cronbach.

PMID- 15025125
TI  - Ernest Ropiequet Hilgard.

PMID- 15025126
TI  - Women's illnesses - the Indian male perspective a search for linkage with Vedic
      concept of health & Hindu mythology.
AB  - A multicentric ICMR study was done in rural north India during 1996- 1999.
      Qualitative data was gathered from adult males of the study area regarding their
      views on women's illnesses. "Heat" emerged as the chief etiological factor for
      most of the reproductive health problems of women. Diet was told as the major
      source of this heat. A linkage between Vedic/Ayurvedic concepts of diet/heat and
      our respondents' view on women's illnesses has been described in the article.
      Similar references in western literature have also been quoted. As per Vedic
      concepts blood and bones are intermediary products of food assimilation between
      chyle and semen. Respondents view that, melting of bones leads to vaginal
      discharge (equated to semen) has been traced to this concept. Leucorrhea emerged
      as a significant morbidity of women. These views of the respondents reflect their
      culture. Any attempt to change these should take into account the overall
      cultural aspects of the concerned population.

PMID- 15025128
TI  - Gold foil restorations. An old friend whose time has come again.

PMID- 15025129
TI  - Inform all parties when coordinating benefits.

PMID- 15025127
TI  - Glimpses of the history of insulin.
AB  - The discovery of the insulin which took place at Toronto, Canada in 1921-22 is
      one of the most important medical discoveries of the modern age. For this
      miracle, Prof. John James Macleod and Frederic Grant Banting were Jointly awarded
      the Nobel Prize in 1923 for Physiology or Medicine. Frederick Sanger a British
      biochemist discovered the structure of insulin in 1958 and was awarded Nobel
      prize for chemistry. Diabetes mellitus is called Madhumeha in ancient Indian
      Ayurvedic medicine. Egyptians and Greeks knew about it. Greek physician Aretaeus
      of Capadocia first suggested the term "Diabetes" and described it. Though insulin
      was discovered about 80 years ago research interest in it still continues
      unabated. This paper also gives case details of the first patient on whom Insulin
      was first tried and chronology of research on pancreas and Insulin.

PMID- 15025130
TI  - Treatment of fevers in Camatkara Cintamani.
AB  - Utility of the various formulae of Camatkara Cintamani can not be minimised due
      to limited and easily available ingredients. Because the efficacy of the formulae
      in curing the various diseases has proved them very useful. Treatment of fevers
      cover near about 93 verses in Camatkara Cintamani. Therefore an attempt has been
      made to check the potency and usefulness of the formulae in treatment of fevers.

PMID- 15025131
TI  - Translation of the twelfth chapter of "Uyoonul Anba Fi Tabaqatil Atibba".
AB  - This is a translation of an Arabic book "Uyoonul Anba Fi Tabaqatil Atibba"
      compiled by Ibn-e-Abi Useibia, the famous writer of Abbaside's period of Baghdad
      in 13th century A.D. This book is in two volumes comprising of 15 chapters
      dealing with 388 biographies of world known physicians. Looking into the
      authenticity and importance of this work, the translation of its 12th chapter
      which is on Indian physicians is being submitted here in this article form. This
      portion provides information with regard to the Indian physicians, the way of
      their approach to Baghdad, their miraculous treatments and the literary works
      etc.

PMID- 15025132
TI  - [The heritage of anaphylaxis].
AB  - This text resumes the steps in Immunology that have followed the discovery of
      anaphylaxis in 1902 by P. Portier and C. Richet. Anaphylaxis was difficult to
      explain at the beginning of the 20th century where "phylactic" thinking
      predominated in Immunology. About one hundred years of research were necessary to
      identify the serum factor, IgE, the cellular actors with their IgE receptors as
      well as their activation mechanisms and to obtain an atomic view of the
      interaction between IgE and its receptor. Its also after one century that arrives
      the first treatment derived from biotechnological research that aims allergies
      which is the most commonly known expression of an anaphylactic reaction.

PMID- 15025133
TI  - Modified ultrafiltration for paediatric cardiac surgical patients: additional
      benefits and concerns.

PMID- 15025134
TI  - Regulatory evaluation of efficacy and safety of new drugs in China.

PMID- 15025135
TI  - [Immunology and allergy].

PMID- 15025136
TI  - Developmental and clinical aspects of surfactant-related neonatal lung disease.
      Proceedings and abstracts of the 18th International Workshop on Surfactant
      Replacement. Prague, June 5-7, 2003.

PMID- 15025137
TI  - [On the creativity of the researcher: the work of Charles Richet].
AB  - At the birth of the scientific thoughts, the degree of creativity of the searcher
      depends on his capacity to extract himself from the previously acquired notions
      in this domain. The discovery of anaphylaxis, by Charles Richet and Paul Portier,
      constitutes therefore an epistemological break off, knocking over the theory on
      organism defences and the universality of the biological response to different
      stimuli. In the light of the works of Charles Richet on hypnosis, renal
      physiology, thermoregulation and psychophysiology, we see that the most creative
      discoveries are also the most unexpected or the most difficult to impose. They
      require courage and initiative, severity of thought, a radical independence of
      mind and a certain distance concerning eventual practical consequences.

PMID- 15025138
TI  - [The life and times of Charles Richet].
AB  - In 1913 Charles Richet received the Nobel Prize of Medicine and Physiology for
      his work on anaphylaxis, which he discovered with Paul Portier in 1902. The 335
      letters received by Charles Richet shortly thereafter shed some light on his
      position in the European world at the time. In the field of biomedical sciences,
      he distinguished himself with his constant determination to blend physiology, and
      clinical studies, which irritated the fundamentalists and clinicians at the time;
      The circumspection of the latter in regard to anaphylaxis is evident in their
      letters. For wasn't anaphylaxis an experimental pathogen occurence, devoid
      obvious clinical correlations, in comparison to Pasteur's immunology with its
      serums and vaccinations, firmly relevant to modern medicine? An abundant non
      biological correspondence arrived from various horizons-cultural, literary,
      metapsychistnatalist, pacifist, as well as those concerned with civil justice and
      civil liberties, the Intellectuals. Strangely, Charles Richet, who was actively
      engaged in such struggles, is barely mentioned in the index of recent works
      devoted to the role played by these Intellectuals. Was Charles not an
      Intellectual? Or has the expression come to mean something different today?

PMID- 15025139
TI  - [A new collection discovered at the Academy of Medicine: the Bouquet collection].

PMID- 15025140
TI  - Proceedings of the 8th International Workshops on Opportunistic Protists and
      International Conference on Anaerobic Protists. Hilo, Hawaii, July 23-29, 2003.

PMID- 15025142
TI  - Bioinformatics: from sequence analysis to molecular structure. Proceedings of a
      symposium. May 30, 2002, Cagliari, Italy.

PMID- 15025141
TI  - Prokaryotic expression of Chinese bovine enterokinase catalytic subunit.
AB  - BACKGROUND: To express in vitro the bovine enterokinase catalytic subunit (EKL)
      protein, which could be used in the future for the cleavage and purification of
      fusion proteins. METHODS: Bovine enterokinase catalytic subunit cDNA was obtained
      by RT-PCR from duodenal mucosa of a bovine obtained at wholesale market, and then
      cloned into a pUCmT cloning vector and sequenced. The desired gene fragment was
      inserted into a pET39b expression plasmid and the recombinant vector pET39b-EKL
      was transformed into E. coli BL21 (DE3). Protein expression was induced using
      IPTG. The recombinant DsbA-EKL was purified with His.Tag affinity chromatography,
      and it bioactivity was analyzed. RESULTS: Compared with the sequence deposited in
      GenBank, the sequence of the EKL gene cloned in the present study is correct. It
      was also confirmed that the nucleotide sequence of expression plasmid pET39b-EKL
      was correct at the conjunction site between the recombinant DNA 5' terminal multi
      cloning site and the recombinant fragment. SDS-PAGE analysis indicated that the
      target product was about 65 kDa and represented 28% of total cell protein.
      Purified recombinant protein was obtained by metal chelating chromatography using
      Ni-IDA resin. After desalting and changing the buffer, the crude kinase was
      incubated at 21 degrees C overnight and shown to have a high autocatalytic
      cleavage activity. CONCLUSIONS: The EKL gene from Chinese bovine has been cloned
      successfully and expressed. This investigation has layed the foundation for
      future enterokinase activity research and for further large-scale application of
      expression products.

PMID- 15025143
TI  - Should the English National Health Service be freed from political control? The
      case against.

PMID- 15025144
TI  - I swear that ...

PMID- 15025145
TI  - Pets prevented from entering Britain when vaccinated 5 days too early.

PMID- 15025146
TI  - An ethicist's commentary on favoring veterinary students from agricultural
      backgrounds for admission.

PMID- 15025147
TI  - An outbreak of West Nile virus-associated disease in domestic geese (Anser anser
      domesticus) upon initial introduction to a geographic region, with evidence of
      bird to bird transmission.
AB  - West Nile virus activity in Manitoba was documented for the first time by the
      collection of an infected crow found on July 8, 2002, in Winnipeg. West Nile
      virus was identified as the cause of death for a large number of domestic geese
      at a single farm in southern Manitoba in August. Of the 5 differently aged
      cohorts on the affected farm, which included 2 breeding flocks and 3 growing
      flocks, the 6-week-old cohort was most severely affected with 692 of 2731
      goslings dying within a 10-day period. Seroprevalence of West Nile virus in 2
      clinically affected and recovered juvenile cohorts was 98% and 100%. In breeding
      geese without clinical disease, seroprevalence was 90% for 15-month-old birds and
      10% for 5-year-old birds. Seroreaction in 3 of 4 cohorts tested exceeded what
      would be expected by mosquito transmission alone.

PMID- 15025148
TI  - The selenium status of dairy herds in Prince Edward Island.
AB  - Bulk tank milk selenium (Se) concentration was compared with mean serum Se
      concentration in 15 herds and was found to be an accurate reflection of the herd
      Se status. The Se status of 109 Prince Edward Island (PEI) dairy herds was
      monitored for 1 year using bulk tank milk Se concentration. Fifty-nine percent of
      the herds surveyed were, at some point, found to be marginal or deficient in Se,
      putting them at risk of disease and suboptimal production. The periods of
      greatest risk of deficiency were fall and winter, at which time 5% and 4%,
      respectively, of herds sampled fell in the range considered truly deficient in
      Se. Herds in which Se supplementation was provided in the form of a commercial
      dairy concentrate were over 4 times more likely to be Se-adequate than herds not
      using this method, and adjusted average daily milk yield was 7.6% greater in
      herds determined to be Se-adequate when compared with Se-marginal herds. We
      conclude that many dairy producers in PEI are providing insufficient
      supplementary Se in the ration to meet the recommended Se intake for lactating
      cows.

PMID- 15025149
TI  - Clinical evaluation of a powder of quality elk velvet antler for the treatment of
      osteoarthrosis in dogs.
AB  - A powder of quality elk velvet antler (QEVA) was evaluated on client-owned dogs
      with osteoarthrosis (OA) in a clinical, double-blind, and placebo-controlled
      study. Thirteen dogs received a placebo for 30 days and then QEVA for 60 days.
      Twenty-five other dogs received QEVA for 60 days. Gait analysis measured with a
      force plate, clinical signs assessed by an orthopedic surgeon, performances in
      daily life activities and vitality assessed by the owners, and complete blood
      analyses were obtained at days 0, after 30 days of placebo and/or 60 days of
      QEVA. On placebo, the 13 dogs did not show significant improvement (P < 0.05);
      however, their gait, their performances in daily life activities, and their
      vitality were significantly improved on QEVA, based on changes in values
      exceeding those observed when placebo was administered. The 25 dogs on QEVA for
      60 days showed similar improvements. No clinical changes were revealed on blood
      analyses. Administration of QEVA was effective in alleviating the condition in
      arthritic dogs.

PMID- 15025150
TI  - The utility of ketoprofen for alleviating pain following dehorning in young dairy
      calves.
AB  - To determine if ketoprofen, in addition to local anaesthesia, reduces pain
      following dehorning, we experimentally dehorned dairy calves, less than 2 weeks
      of age, with (20 calves) or without (20 calves) intramuscular injections of
      ketoprofen. All calves received a local anesthetic (lidocaine) prior to dehorning
      and were dehorned with heat cauterization. Cortisol concentration was measured
      via jugular blood samples taken immediately before dehorning and at 3 and 6 hours
      following dehorning. Calf behavior was recorded between 0 and 2, 3 and 5, and 6
      and 8 hours following dehorning. There was no significant (P > 0.10) effect on
      creep feed consumption, cortisol concentration, or any of the behavioral measures
      during the time periods studied. However, the difference in cortisol
      concentrations from the time of dehorning until 3 hours later was significantly
      lower (P < 0.05) in the ketoprofen-treated group. These results suggest that
      ketoprofen, in addition to local anesthesia, may alleviate short-term pain
      following dehorning with a butane dehorning device in dairy calves less than 2
      weeks of age.

PMID- 15025152
TI  - Pregnancy toxemia in a ferret.
AB  - A late-gestation jill was presented for depression, anorexia, and weakness. The
      working diagnosis became pregnancy toxemia. Supportive care was initiated and an
      emergency cesarian section performed. Twelve live kits were delivered; however,
      all soon perished despite home care. Surgery and recovery are discussed,
      including information regarding pregnancy toxemia in general.

PMID- 15025151
TI  - Effects of ketanserin on hypergranulation tissue formation, infection, and
      healing of equine lower limb wounds.
AB  - The objective of this multicentre, randomized, controlled field study was to
      determine the efficacy of ketanserin gel in preventing exuberant granulation
      tissue formation (hypergranulation) and infection in equine lower limb wounds.
      Horses and ponies (n = 481) with naturally occurring wounds were randomized to
      either topical treatment with ketanserin gel (n = 242) or a positive control
      (Belgium, Germany: ethacridin lactate solution, n = 120; France, United Kingdom:
      malic, benzoic, and salicylic acid [MBS] cream, n = 119). Treatment continued
      until the wound healed (success), formed hypergranulation tissue (failure), or
      became infected (failure). Treatment was terminated after 6 months in all
      remaining animals. Ketanserin was successful in 88% of cases. Wounds treated with
      ketanserin were 2 and 5 times more likely to heal successfully than were those
      treated with MBS or ethacridin lactate, respectively. Ketanserin gel is thus more
      effective than these standard treatments in preventing hypergranulation tissue
      and infection of equine lower limb wounds.

PMID- 15025153
TI  - Headshaking in a 10-year-old Thoroughbred mare.
AB  - A 10-year-old Thoroughbred mare was presented with a 2.5-week history of
      headshaking. Based on a thorough physical examination, blood analysis, and a fine
      needle aspirate of an enlarged thyroid gland, a tentative diagnosis of seasonal
      idiopathic headshaking was made. Treatment with cyproheptadine was attempted.

PMID- 15025154
TI  - Practical bond considerations: acknowledging clients' physical limits.

PMID- 15025156
TI  - The Canadian Veterinary Medical Association benchmarking campaign to create
      awareness about and improve economics of the veterinary profession begins.

PMID- 15025155
TI  - The femoral head and neck ostectomy.

PMID- 15025157
TI  - Congenital hypothyroidism in a cat.

PMID- 15025158
TI  - Development of a fragment constant method for estimating the mixture toxicity.
AB  - Based on Group Contribution Theory, a fragment constant model to estimate mixture
      toxicity is proposed in this paper. The toxicity (EC50M) of 58 mixtures is
      determined using Photobacterium phosphoreum. Analysis of these EC50M and the mole
      fraction of the individual chemical fragments (Br, Cl, NO2, OH, NH2) helps work
      out the fragment toxicity contribution (deltaTi) to EC50M. Thus, a linear
      regression equation is established between the toxicity contribution deltaTi and
      the fragment constants of Hansch f(i), and this equation is so significant that
      it helps provide an approach for calculating EC50M.

PMID- 15025159
TI  - Effect of adsorption capacity of dissolved humic matter on leachability of
      dioxins from raw and treated fly ashes of municipal solid waste incinerators.
AB  - The purposes of this study are to obtain information on the leachability of
      dioxins depending on the samples, to confirm the effect of dissolved humic matter
      (DHM) on the leachability of dioxins, and to evaluate the suitability of the
      detoxification treatments specified by the Japanese government for the reduction
      of leachability of dioxins. In this study, the leachability of dioxins from raw
      and treated fly ash was evaluated by a 24-hour batch leaching test and by an
      extraction test repeated three times with DHM solution, whose concentration was
      determined to be 700 mg-OC/L as an initial concentration based on organic carbon
      (OC) from adsorption tests of DHM to fly ash. The leaching concentration from fly
      ash samples having high DHM adsorption capacity was low regardless of pH, and
      that from samples having relatively low adsorption capacity and high pH was
      largely increased. Therefore, it is expected that the leachability of dioxins
      from treated fly ashes would be reduced by avoiding high pH and enhancing the DHM
      adsorption capacity rather than by using the detoxification method specified. We
      also confirmed that increase of the leachability of HOPs due to DHM is not as
      large as known in condition that is composed of three phases of HOPs, DHM, and
      solid matrix.

PMID- 15025160
TI  - Biphasic dissipation kinetics for dislodgeable foliar residues in estimating
      postapplication occupational exposures to endosulfan.
AB  - Agricultural workers are exposed to pesticide residues via dermal contact with
      foliage upon entry of treated fields. Restricted Entry Intervals (REIs) are
      established based on both toxicity and exposure. Key factors for estimation of
      potential worker exposures are dislodgeable foliar residues (DFRs) and the manner
      in which DFRs dissipate over time. DFR dissipation curves vary in form and shape,
      and are often biphasic, reflecting different rate processes, chemical-physical
      influences, and partitioning. Biphasic dissipation behavior for endosulfan
      [6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9a-hexahydro-6,9-methano-2,4,3
      benzodioxathiepin 3-oxide] previously reported for tomatoes and peppers has been
      confirmed here for endosulfan on melon, grape, and peach foliage. Use of biphasic
      kinetics results in more robust r2 values for the regression curves that describe
      foliar dissipation of endosulfan compared to use of simple first-order kinetics.
      For endosulfan, the use of biphasic kinetics to describe the overall dissipation
      accurately predicts daily DFR values. In contrast, first order kinetics may
      overestimate DFRs and, potentially, postapplication worker exposures during the
      critical period when entry of treated fields is most likely to occur.

PMID- 15025161
TI  - Procedures for determining the pesticide sensitivity of indigenous soil algae: a
      possible bioindicator of soil contamination?
AB  - Soil algae are present in all kinds of soils, both arable and virgin, in large
      amounts and in great diversity. These photosynthetic microorganisms, which are
      concentrated in the top few centimeters of the soil profile, are organized in a
      community structure that varies depending on soil type, farming method and
      pesticide application. We first tested several extraction and conservation
      methods for soil algae, and a 14C incorporation procedure to evaluate the
      photosynthetic activity of these micro-organisms. In a second study, we assessed
      the sensitivity to atrazine of soil microalgae from two corn fields managed by
      different agricultural practices (conventional vs. organic). Changes in
      indigenous diatom communities were monitored, together with photosynthetic tests
      performed on the whole algal community. Comparison of the data for the treated
      field with those for the reference, untreated organic cornfield showed that
      previous atrazine application in the conventional cornfield had changed the
      species composition of the soil diatom communities. Short-term ecotoxicological
      tests, using photosynthetic activity as endpoint, also showed that the
      communities that had developed under pesticide stress were more tolerant to
      further atrazine application than the control communities. The stress caused by
      major environmental disturbances, such as ground dressing, was not sufficient to
      mask the difference between the two crops, suggesting that telluric microalgae
      could be used as indicators of xenobiotic contamination in soils. These initial
      findings about using soil microalgal communities as bioindicators are promising.
      In addition, their photosynthetic activity, which reflects their sensitivity to
      xenobiotic compounds, seems to be a relevant bioindicator of soil contamination.

PMID- 15025162
TI  - Comparison of the toxicity using body residues of DDE and select PCB congeners to
      the midge, Chironomus riparius, in partial-life cycle tests.
AB  - Due to the long time course required to achieve steady state with highly
      lipophilic contaminants such as PCBs (polychlorinated biphenyls), data derived
      from short-term toxicity tests may lead to an erroneous interpretation of hazard.
      In addition, PCBs bioaccumulated over time can cause sublethal impairments in
      organisms at concentrations much lower than required for mortality. Here, the
      body residues of 1,1-dichloro-2,2-bis-p-chlorophenyl ethane (DDE) and select PCB
      congeners associated with a spectrum of chronic effects in the midge, Chironomus
      riparius, were evaluated. The route of exposure was ingestion of the PCB
      contaminated alga, Chlorella vulgarus, and trout chow loaded with the selected
      test compound. Two separate exposures of midges were performed. In the first
      experiment, midges were exposed from the second instar to the pupal stage. In the
      second exposure, midges were exposed from the second instar to the adult stage. A
      variety of sublethal endpoints was monitored, including developmental time within
      a stadium, body weight, and fecundity for the female adult. The dose was assessed
      as the whole body residue concentration of the contaminant. Overall, the midge
      concentration increased with increasing exposure concentration in algae and trout
      chow. Body weight at the end of each stadium was the assessment parameter that
      was least significantly affected among the test endpoints monitored. In contrast,
      a significant increase in development time was the endpoint that was most
      frequently observed in response to contaminant exposure. Reduction in fecundity
      was found only for DDE-exposed midges. These data, in which chronic endpoints are
      related to body residues, suggest that body residues will be useful in defining
      sublethal hazards of DDE and some PCB congeners.

PMID- 15025163
TI  - Genetic determination of tolerance to lethal and sublethal copper concentrations
      in field populations of Daphnia longispina.
AB  - In order to study the effects of environmental pollution on the genetic diversity
      of natural populations, two field populations of the cladoceran Daphnia
      longispina were sampled: one in a reference site (uncontaminated) and the other
      in a site historically stressed with acid mine drainage (AMD). Five hypotheses
      were formulated: (1) the stressed population presents a higher tolerance to
      lethal levels of copper than the reference population, (2) differences in
      tolerance to lethal levels, observed between the two populations, are due to the
      loss of sensitive lineages, (3) differences in tolerance to lethal levels of
      copper between the two populations are due to the appearance of new genotypes,
      (4) the acquisition of tolerance to lethal levels of copper involved changes in
      life-history patterns and fitness costs under optimal conditions, and (5)
      historical contamination by AMD resulted in tolerance differences to sublethal
      levels between populations, within categories similarly tolerant to lethality,
      specifically, lineages with similar tolerance to lethal levels from both
      populations show differences in tolerance to sublethal levels, the stressed
      population being more tolerant to sublethal levels of contamination than the
      reference population. Over 125 acclimated cloned lineages, from each population,
      were exposed to different copper concentrations for 24 hours. At the end of each
      assay, mortality and feeding inhibition were monitored. Life-cycle traits under
      optimal conditions were also monitored (time to first brood, number of neonates
      per brood, inter-brood time, body length, and ingested algae). At lethal levels
      of copper, significant differences were found in the frequency of sensitive
      lineages between the two populations. The stressed population did not include the
      most sensitive lineages, though the most tolerant ones were also present in the
      reference population. Thus, the hypothesis of presence of new genotypes in the
      stressed population resulting in an overall increase tolerance of the population
      at lethal levels was rejected. Changes in life-history patterns were detected,
      though they were not fully consistent with predictions of life-history theory.
      Furthermore, these changes in life-history patterns did not involve fitness
      costs. The fifth hypothesis was rejected since, at sublethal levels of copper, no
      significant differences were found between the feeding inhibitions of similarly
      lethal tolerant lineages of the two populations, with only one exception.
      Therefore, the present study further confirmed the genetic erosion hypothesis and
      gave further support to the incorporation of genetic diversity measurements into
      risk assessments.

PMID- 15025164
TI  - A comparison of in situ and laboratory toxicity tests with the estuarine amphipod
      Eohaustorius estuarius.
AB  - Amphipod survival in laboratory and in situ exposures was assessed using the
      eastern Pacific Haustoriid species Eohaustorius estuarius. Toxicity test results
      were compared using intact (unhomogenized) and homogenized sediment samples in
      both field and laboratory exposures. Experiments were conducted in Moss Landing
      Harbor, California, an impaired waterbody under 303 (d) of the US Clean Water
      Act. Synoptic laboratory and in situ sediment toxicity tests were conducted at
      two stations: Sandholdt Bridge (SB), the most contaminated station in the harbor,
      and at the South Jetty (SJ), a more marine station near the mouth of the harbor.
      We found that Eohaustorius is amenable to in situ testing. Despite highly
      variable field salinity regimes (6-32 PSU at SB and 21-34 PSU at SJ), in situ
      control survival was 87% and 84% at SB and SJ, respectively. Amphipod survival
      was lower in the in situ exposures relative to the laboratory exposures at both
      sites. Survival at SB was 30% and 76% in the homogenized in situ and laboratory
      samples, respectively, and 40% and 64% in the intact (unhomogenized) in situ and
      laboratory samples, respectively. Neither the homogenized or intact samples from
      the SJ station were toxic in laboratory experiments, but amphipod survival was
      only 40% in the intact in situ exposure at this station, possibly due to
      predation. These experiments suggest that the interaction of contaminants and
      variable physical parameters such as salinity and temperature may have resulted
      in lower survival in the in situ exposures. Sediment homogenization prior to in
      situ deployment may have reduced effects of predators in some samples.

PMID- 15025165
TI  - Sublethal effects of trace metals (Cd, Cr, Cu, Hg) on embryogenesis and larval
      settlement of the ascidian Ciona intestinalis.
AB  - Toxicity of Cadmium (Cd), Chromium (Cr), Copper (Cu), and Mercury (Hg) on the
      early developmental stages of Ciona intestinalis was investigated. Developmental
      defects of larvae after exposure of gametes throughout their development to the
      larval stage were assessed. Gamete exposure to increasing metal concentrations
      resulted in a significant decrease of the percentage of normally hatched larvae,
      showing median effective concentrations (EC50) of 721 microg/L (6.42 microM) for
      Cd, 12772 microg/L (226 microM) for Cr, 36.6 microg/L (0.576 microM) for Cu, and
      44.7 microg/L (0.223 microM) for Hg. Larval attachment was significantly affected
      when gametes were exposed to the metals throughout development. The EC50 reducing
      larval attachment by 50% were 752 microg/L (6.7 microM) for Cd, 15026 microg/L
      (289 microM) for Cr, 67.8 microg/L (1.607 microM) for Cu, and 78.1 microg/L
      (0.389 microM) for Hg. Therefore, on a molar basis Hg is three times more toxic
      than Cu, 20-30 times more than Cd, and 700-1000 times more toxic than Cr, for
      both responses.

PMID- 15025166
TI  - Trace metals in the brown mussel Perna perna from the coastal waters off Yemen
      (Gulf of Aden): how concentrations are affected by weight, sex, and seasonal
      cycle.
AB  - The effects of seasonal cycle, sex of individuals, and changes of soft tissues
      weight on accumulated trace metal concentrations (Cd, Cu, Fe, Mn, Pb, Zn) were
      examined in the brown mussel Perna perna collected monthly from a natural rocky
      habitat in the coastal waters off Yemen, the Gulf of Aden, for a period of ten
      months. Basic hydrological parameters were recorded simultaneously. All metals
      analyzed displayed seasonal fluctuations with different temporal patterns and
      variable amplitudes. Similar seasonal cycles were observed for Cu, Mn, and Pb
      with an increase in accumulated concentration during the rainy period (NE
      monsoon), and a decrease thereafter. The concentrations of Cu, Mn, and partially
      Pb appeared to be related to environmental changes, the concentration of Pb
      possibly also being related to changes in body weight. Accumulated concentrations
      of Cu and Mn thus seem to reflect actual metal bioavailability in the ecosystem
      quite efficiently. The tissue levels of Fe and Cd changed inversely to
      fluctuations in body weight with additional variation due to monsoon-related
      environmental changes. The behaviors of Fe and Cd are therefore driven by
      seasonally changing body weight with a considerable contribution of external
      factors including fluctuations in hydrological conditions and metal exposure. The
      Zn concentrations tended to increase gradually throughout most of the year
      regardless of its concentration in the environment. Zinc is considered to be
      mainly regulated by physiological mechanisms in the mussel, making its
      accumulated metal concentration independent to some degree of environmental
      levels. Significant differences in trace metal concentrations between sexes (in
      favour of females) might have resulted from more intense formation of
      reproductive tissues and metal accumulation in sexual products of females during
      the prespawning and spawning periods.

PMID- 15025167
TI  - Differences in prey capture in grass shrimp, Palaemonetes pugio, collected along
      an environmental impact gradient.
AB  - The waterways and associated salt marshes along the western border of Staten
      Island, New York (Arthur Kill) have long been under environmental duress.
      Environmental threats include industrial and municipal discharges, oil spills,
      and possible leachate from landfills. These impacts are compounded due to the low
      flushing of this body of water. Grass shrimp, Palaemonetes pugio, inhabiting the
      Arthur Kill are, therefore, potentially at risk of exposure to metal and organic
      pollutants. Successful prey capture (of live brine shrimp, Artemia franciscana)
      was used to compare the relative health of shrimp collected from three sites
      along an environmental impact gradient. Study sites included a relatively
      unimpacted harbor (Great Kills Harbor, GK) and two creeks adjoining the Arthur
      Kill (Nassau Creek, NC, and Richmond Creek, RC). Shrimp originating from GK
      exhibited a rate of prey capture (6.3 prey h(-1)) that was about two times
      greater (p < 0.05) than that of shrimp originating from a creek behind a series
      of landfills (RC, 3.2 prey h(-1)). The rate of prey capture for shrimp collected
      from a creek impacted by historic smelting activities (NC) was intermediate (5.4
      prey h(-1)). Laboratory studies with shrimp from a pristine site (Tuckerton, NJ)
      exposed to RC conditions (i.e., sediment and water) for eight weeks indicate that
      reduced prey capture can be induced in healthy shrimp. Finally, video analysis
      suggests that reduced prey capture in RC shrimp may not be the result of less
      effort, but rather the combination of (1) 80% fewer (p < 0.05) prey being
      captured with a lunge type of attack and (2) a greater reliance (p < 0.05) on a
      less efficient grab type of foraging behavior (64% success rate for RC versus 87%
      success rate for GK; p = 0.058). These results indicate that sublethal toxicity
      in environmentally impacted populations can occur and that prey capture may be
      used to assay the relative health of field specimens. Additionally, impaired prey
      capture may have important implications for the energy flow within impacted
      environments.

PMID- 15025168
TI  - Respiratory and reproductive characteristics of eastern mosquitofish (Gambusia
      holbrooki) inhabiting a coal ash settling basin.
AB  - Coal fly ash and effluent from coal ash settling basins negatively affects
      metabolism and reproduction in a variety of organisms, including a number of fish
      species. Some species, most notably the eastern mosquitofish (Gambusia
      holbrooki), are known to maintain viable populations in areas contaminated by
      coal ash. While eastern mosquitofish are present in these systems, their degree
      of tolerance to coal ash has not been investigated using sublethal metrics of
      exposure. It is possible that eastern mosquitofish persist in habitats affected
      by coal ash, but experience significant costs such as changes in metabolism and
      fecundity. Thus, we investigated the effects of coal ash on standard metabolic
      rate and reproduction of eastern mosquitofish inhabiting a coal-ash contaminated
      settling basin. Standard metabolic rates of mosquitofish from the ash
      contaminated site and a reference site (mean O2 consumption = 0.286 mL/g x h +/-
      0.007 and 0.291 +/- 0.008 mL/g x h, respectively) were not significantly
      different. Despite elevated contaminant concentrations in ash basin females
      (selenium, arsenic, copper, and cadmium) and their offspring (selenium), brood
      sizes and offspring viability did not differ between clutches collected from ash
      basin and reference site females. Our data provide further evidence of the high
      degree of tolerance of eastern mosquitofish to exposure to aquatic coal ash
      disposal generated by power plants. However, the basis for such tolerance to ash
      remains unclear. Further investigations are required to determine whether such
      tolerance is a result of species-specific characteristics or population
      characteristics due to local adaptation.

PMID- 15025169
TI  - Synthetic musk toxicity to early life stages of zebrafish (Danio rerio).
AB  - Synthetic musk substances have been found in a number of environmental samples.
      Some of these chemicals have been detected in concentrations above 1 microg/L in
      water, which raises concern about possible effects on aquatic life. The toxicity
      of four synthetic musks, 4-tert-butyl-2,6-dimethyl-3,5-dinitrophenylethanone
      (musk ketone), 1-tert-butyl-3,5-dimethyl-2,4,6-trinitrobenzene (musk xylene), 1
      (5,6,7,8-tetrahydro-3,5,5,6,8,8-hexamethyl-2-naphthalenyl)ethanone (AHTN,
      tonalide) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-[g]-2
      benzopyrane (HHCB, galaxolide), were studied in zebrafish by the use of two
      different early life-stage methods. In the first method, specific developmental
      characteristics during the first 48 hours were studied. In the second method,
      hatching and survival times were studied on eggs and larvae. The results on heart
      rate in the first test gave the following LOECs: musk ketone 10 microg/L, musk
      xylene and AHTN 33 microg/L, and HHCB showed no effect up to 1000 microg/L. In
      the study of survival time, LOEC for musk ketone was 100 microg/L, for musk
      xylene 33 microg/L, and AHTN gave no effect on survival time up to 100 microg/L.
      The LOECs for musk ketone, musk xylene, and AHTN in this study are in the range
      of what has been measured in sewage effluents and recipients, and consequently
      these substances may have adverse impact on wild fish.

PMID- 15025170
TI  - Screening of organochlorines in freshwater fish collected from the Pearl River
      Delta, People's Republic of China.
AB  - HCHs, DDTs, and PCBs were analyzed in fish flesh collected from fish ponds in the
      Pearl River Delta and compared with those from the Mai Po Marshes (a nature
      reserve) in Hong Kong, which was considered an unpolluted area. The
      concentrations for these contaminants were <0.01-7.8 ng/g lipid for HCHs, 22.3
      381 ng/g lipid for DDTs, and 60-480 ng/g lipid for PCBs. Nevertheless, levels of
      HCHs and DDTs in fish flesh were lower than the China National Environmental
      Protection Agency maximum permissible limits set for foodstuffs. As for PCBs, 16%
      of fish collected from the Pearl River Delta exceeded the US EPA guideline
      concentration.

PMID- 15025172
TI  - Contamination by persistent organochlorines in cetaceans incidentally caught
      along Brazilian coastal waters.
AB  - Wide ranges of organochlorine residues were determined in the blubber of
      franciscana (Pontoporia blainvillei), estuarine dolphin (Sotalia guianensis),
      Atlantic spotted dolphin (Stenella frontalis), and long-beaked common dolphin
      (Delphinus capensis) incidentally caught along Brazilian coastal waters.
      Concentrations of DDTs and PCBs were the highest, followed by CHLs, TCPMOH,
      dieldrin, TCPMe, heptachlor epoxide, HCB, and HCHs. Unexpectedly, significant
      pollution of PCBs, DDTs, TCPMe, and TCPMOH were observed in cetaceans from
      Brazil, implying the occurrence of local sources in the Southern Hemisphere
      comparable to those in the Northern Hemisphere, probably by high
      industrialization in Brazil. On the other hand, CHLs, HCB, HCHs, heptachlor
      epoxide, and dieldrin residue levels in Brazilian dolphins were much lower than
      those in other species from the Northern Hemisphere. Significant correlations of
      TCPMe and TCPMOH were found along with PCBs and DDTs, indicating the highly
      bioaccumulative nature of all these compounds and/or possible similar pollution
      sources.

PMID- 15025171
TI  - Bioaccumulation profiles of chemical contaminants in fish from the lower
      Willamette River, Portland Harbor, Oregon.
AB  - Twenty-five PCBs (polychlorinated biphenyls), 15 organochlorine (OC) pesticides,
      and mercury were determined in fish from the Willamette River in Oregon,
      including a Portland Harbor superfund site. Fish were collected during the summer
      of 2000 along a 20-mile stretch of the lower Willamette River. Concentrations of
      sumPCBs (sum of 25 individually determined PCB congeners) and sumDDTs (sum of
      p,p'-DDT, p,p'-DDE, and p,p'-DDD) in fish ranged from 14 to 530 and from 18 to
      510 ng/g-wet weight, respectively. SumPCBs concentrations at all sites exceeded
      US EPA fish advisory's screening values. Hexachlorobiphenyl congener 153 was the
      most abundant of the PCBs detected and p,p'-DDE was the most abundant OC
      pesticide detected. Low levels of dieldrin were detected in fish at all sites
      with the highest concentration at the superfund site (4.6 ng/g-wet weight), while
      other OC pesticides tested were near or below detection limits (approximately 2
      ng/g). In general, organic chemical contaminant concentrations were highest in
      fish from the superfund site and were lower further upriver. Smallmouth bass had
      the highest levels of OC compounds of three fish species examined. They also had
      the largest site-to-site variations whereas black crappie had little variation
      throughout the study area. Mercury levels in fish ranged from 13 to 520 ng/g.
      Historical fish residue data are limited from the Portland Harbor superfund site,
      what data is available is over a decade old, generally consisted of only a few
      fish (< or = 3) and analyses quantified only a few PCB congeners (< 3).

PMID- 15025173
TI  - Efficient in vitro paraquat removal via irreversible immobilization into zeolite
      particles.
AB  - A new efficient mineral adsorbent, zeolite ZSM-5, has been evaluated for its
      ability to durably immobilize the herbicide paraquat in conditions simulating
      acute poisoning by oral ingestion of this toxic compound. The sorption properties
      have been studied in water, normal saline solution, as well as in artificial and
      simulated human gastric juices. Uptake kinetics and capacities have been
      determined and compared to the ion exchange resin Amberlite IR-120. Significant
      advantages of ZSM-5 over the resin have been demonstrated, especially with
      respect to long-term retention capability of the toxic herbicide. This solid is a
      promising primary treatment of acute paraquat poisoning.

PMID- 15025174
TI  - [Beta-adrenoceptor antagonists in the treatment of chronic heart failure].
AB  - Beta-Adrenoceptor antagonists in the treatment of chronic heart failure The
      incidence of chronic heart failure is high in the developed countries (1-4/1000
      per year). Treatment of chronic heart failure is a therapeutic challenge. A great
      improvement in mortality and morbidity of heart failure patients was achieved by
      the introduction of beta-adrenoceptor blockers in the treatment of chronic heart
      failure. However only 39% of heart failure patients are treated with a beta
      adrenoceptor blocker in Europe. This review outlines pathophysiology of the beta
      adrenergic system during human heart failure and its alterations induced by beta
      adrenoceptor blockade. Based on the results of large clinical trials,
      experimental-pharmacological properties of beta-adrenoceptor blockers as well as
      the main aspects of its clinical use are discussed.

PMID- 15025175
TI  - Synthesis and antifungal properties of compounds which target the alpha
      aminoadipate pathway.
AB  - Fungi synthesize lysine via the alpha-aminoadipate pathway, which is not found in
      plants or animals. This pathway has been proposed as a target for antifungal
      agents, but until now no reports have appeared to test this proposal. Hampering
      studies on the susceptibility of filamentous fungi such as those of the
      clinically important genus Aspergillus is the fact that growth quantitation is
      notoriously difficult. We have used the recently-reported XTT-based method of
      biomass quantitation to measure the susceptibility of Aspergillus nidulans strain
      A28 to growth suppression by novel compounds designed to target early steps in
      the alpha-aminoadipate lysine biosynthesis pathway, specifically those steps
      involving (R)-homocitrate and (2R,3S)-homoisocitrate. Three compounds show
      moderate inhibition of fungal growth, which can be partially restored by the
      presence of lysine in the growth medium.

PMID- 15025176
TI  - Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with
      an arylpiperazine moiety as ligands for 5-HT(1A) and 5-HT(2A) receptors, Part 2.
AB  - The synthesis of new of 4-aryl-hexahydro- (11-16) and (R,R)(S,S)4-aryl
      octahydropyrido[1,2-c]pyrimidine (23-27) derivatives bearing a aryl- or
      heteroarylpiperazinyl moiety in position 2 is described. The derivatives of 4
      aryl-hexahydro- (1-5) and (R,R)(S,S)4-aryl-octahydropyrido[1,2-c]pyrimidin-1,3
      dion (17-19) served as starting compounds for further synteses. The N-alkylation
      of the imide moiety in compounds 1-5 and 17-19 by 1,4-dibromobutane gave the
      respective monbromobutyl derivatives 6-10 and 20-22. The final derivatives 11-16
      and 23-27 have been produced by condensation of the obtained bromoderivatives
      with selected 1-aryl and 1-heteroarylpiperazines. Compounds 11-16 and 23-27 were
      tested for their affinity towards 5-HT(1A), 5-HT(2A) and alpha1 receptors, using
      a radioligand binding assay.

PMID- 15025177
TI  - Derivative-differential UV spectrophotometry and compensation technique for the
      simultaneous determination of zidovudine and lamivudine in human serum.
AB  - Three new simple, precise, rapid and selective determination methods are
      described for zidovudine (ZID) and lamivudine (LAM) in human serum and in
      pharmaceutical formulations. The first method, based on the compensation
      technique is presented for the derivative spectrophotometric determination of
      binary mixtures with overlapping spectra. Using ratios of the derivative maxima
      or the derivative minimum, the exact compensation of either component in the
      binary mixture and human serum can be achieved, followed by its determination.
      The second method, differential derivative spectrophotometry, comprised of
      measurement of the difference absorptivities derivatized in the first order
      (deltaD1) of a tablet extract in 0.1 N NaOH relative to that of an equimolar
      solution in methanol at wavelengths of 246 nm and 263 nm, respectively. Neither
      sample pretreatment nor separation were required. The third method is based on
      HPLC on a reversed-phase column using a mobile phase of 0.01M sodium dihydrogen
      phosphate : methanol : acetonitrile (4 : 2 : 3 v/v/v), with detection at 285 nm.
      Repeatability and reproducibility studies for each compound showed no significant
      differences at 95% confidence level. The proposed methods were used for the
      simultaneous determination of the drugs in human serum samples and binary
      mixtures with good recoveries.

PMID- 15025178
TI  - Kinetic spectrophotometric method for the determination of silymarin in
      pharmaceutical formulations using potassium permanganate as oxidant.
AB  - A new simple and sensitive kinetic spectrophotometric method for the
      determination of silymarin in pure form and in pharmaceutical formulations is
      described. The method is based on the oxidation of the drug with potassium
      permanganate at pH 7.0 +/- 0.2. The reaction is followed spectrophotometrically
      by measuring the decrease in the absorbance at 530 nm. The calibration graph is
      linear in the range of 18-50 microg x m(-1). The method has been successfully
      applied to the determination of silymarin in pharmaceutical formulations.
      Statistical comparison of the results with the reference method shows excellent
      agreement and indicates no significant difference in accuracy and precision.

PMID- 15025179
TI  - Solubility prediction in water-ethanol mixtures based on the excess free energy
      approach using a minimum number of experimental data.
AB  - The solubility of nalidixic acid in water-ethanol mixtures has been determined at
      25 degrees C. The generated solubility data sets have been used to assess the
      accuracy of different numerical analyses for the excess free energy model and a
      new numerical method for solubility prediction in water-ethanol mixtures based on
      four experimental determinations is proposed. The accuracy of a previously
      presented numerical method to fit all data points is compared with that of a
      proposed analysis using average percentage deviation (APD). The APD obtained are
      14.6 (+/- 8.0) and 8.4 (+/- 4.1), respectively for previous and proposed methods.
      A minimum number of three and four data points employed to train the original
      forms of the excess free energy model and the solubility at other solvent
      compositions were predicted. The APDs obtained were 61.4 and 23.0%, respectively.
      The APD produced for the proposed numerical method was 16.1%.

PMID- 15025181
TI  - Predicting blood-brain barrier penetration of drugs using an artificial neural
      network.
AB  - An artificial neural network model is developed to predict the ratios of the
      steady-state concentrations of drugs in the brain to those in the blood (log BB)
      from their molecular structural parameters. These molecular structural parameters
      are the molecular volume (V), the sum of the absolute values of the net atomic
      charges of oxygen and nitrogen atoms which are hydrogen-bond acceptors (Q(O, N)),
      and the sum of the net atomic charges of hydrogen atoms attached to oxygen or
      nitrogen atoms (Q(H)). For a training set of 56 compounds and a test set of 5
      compounds, root mean squared errors (RMSE) between experimental log BB values and
      calculated/predicted log BB values were 0.236 and 0.258, respectively. These
      molecular structural parameters can be obtained easily from quantum chemical
      calculations. The model is suitable for the rapid prediction of the blood-brain
      barrier penetration of drugs.

PMID- 15025180
TI  - Rheological evaluation of the influence of sterilisation on ocular gels using an
      experimental design.
AB  - Different rheological characterisation methods are employed to investigate the
      influence of the sterilisation method (autoclaving), the polymer concentration
      (0.50, 0.75 and 1.00%) and the dispersing medium (i.e. isotonic phosphate buffer
      and mannitol solution) on Carbopol 974 P NF dispersions, used as ocular gels. The
      evaluation of the different polyacrylic acid-based dispersions was performed
      using flow and oscillatory shear measurements, and herewith an experimental
      design was set up. The rheological data show that the choice of the dispersing
      medium has a significant influence on the rheological behaviour of the ocular
      gels prepared. The dispersions in mannitol exhibit higher elastic properties than
      those made in the phosphate buffer solution (PBS). Sterilisation increases only
      the elastic properties of the 0.50% (w/w) Carbopol 974 P NF/PBS dispersion but
      has no influence on the other dispersions prepared.

PMID- 15025182
TI  - Effect of Pluronic on cellular uptake of cationic liposomes- mediated antisense
      oligonucleotides.
AB  - Cationic liposomes modified by different Pluronic block copolymers were prepared.
      The influence of Pluronic on the cellular uptake of antisense oligonucleotides
      (ODN) based on cationic 3beta[N-(N', N'-dimethylaminoethan)-carbamoyl]
      cholesterol (DC-Chol) liposomes was studied by flow cytometric analysis. It
      showed that DC-Chol liposomes containing Pluronic gave 1.7-2.3 times higher
      capacity of cellular uptake of ODN, despite the diminution of ODN loading
      efficiency. The level of improvement by Pluronic is related to the hydrophobic
      propylene oxide (PO) units Pluronic contains as well as the lipophile/hydrophile
      value of the molecule. This preliminary study indicated that modifying liposomes
      with another excipient is a useful pharmaceutical technique to improve ODN
      delivery.

PMID- 15025184
TI  - Azathioprine transport through rat skin and its immunosuppressive effect.
AB  - The objective of this research was to study the in vitro and in vivo percutaneous
      absorption of azathioprine with and without the effect of penetration enhancers.
      In vitro permeation of azathioprine was studied using a Franz diffusion cell and
      rat skin. Both azathioprine and 6-mercaptopurine were detected in the receiver
      solution with a reversed phase HPLC system. The steady state flux of
      azathioprine, permeability coefficient, and lag time were reported. Penetration
      enhancers such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), and urea
      were added to the donor compartment to increase the skin permeation of
      azathioprine. The flux of azathioprine was increased by 20.7%, and 22.4% using
      dimethylsulfoxide, and dimethylformamide respectively. The in vivo permeation was
      determined by measurement of antibody titers by the slide latex agglutination
      test. The in vivo permeation study showed that the titers of antibody induced in
      the rats were not affected by topical application of azathioprine solution. The
      results show that azathioprine has low flux to exert a systemic effect with and
      without penetration enhancers. However these results may support the use of
      topical azathioprine for the treatment of some dermatological disorders with
      minimum side effects.

PMID- 15025183
TI  - Uptake of antigen encapsulated in polyethylcyanoacrylate nanoparticles by D1
      dendritic cells.
AB  - Polyethylcyanoacrylate (PECA) nanoparticles were prepared by interfacial
      polymerization of a water-in-oil microemulsion. Nanoparticles were isolated from
      the polymerization template by sequential ethanol washing and centrifugation. A
      nanocapsule preparation yielding the original particle size and distribution
      following redispersion in an aqueous solution was achieved by freeze-drying the
      isolated nanoparticles in a solution of 5% w/v sugar. The cytotoxicity and uptake
      of nanocapsules by dendritic cells was investigated using a murine-derived cell
      line (D1). PECA nanoparticles were found to adversely effect cell viability at
      concentrations greater than 10 microg/ml of polymer in the culture medium. In
      comparison to antigen in solution, cell uptake of antigen encapsulated within
      nanoparticles was significantly higher at both 4 and 37 degrees C. Following a 24
      h incubation period, the percentage of cells taking-up antigen was also increased
      when antigen was encapsulated in nanoparticles as compared to antigen in
      solution. The uptake of nanoparticles and the effect of antigen formulation on
      morphological cell changes indicative of cell maturation were also investigated
      by scanning electron microscopy (SEM). SEM clearly demonstrated the adherence of
      nanoparticles to the cell surface. Incubation of D1 dendritic cells with
      nanoparticles containing antigen also resulted in morphological changes
      indicative of cell maturation similar to that observed when the cells were
      incubated with lipopolysaccharide. In contrast, cells incubated with antigen
      solution did not demonstrate such morphological changes and appeared similar to
      immature cells that had not been exposed to antigen.

PMID- 15025186
TI  - In vitro investigation on the effect of a plant preparation with antiviral
      activity on the functions of mice phagocyte cells.
AB  - A polyphenol extract from the aerial roots of the medicinal plant Geranium
      sanguineum L. (PC) inhibited the reproduction of influenza viruses type A and B
      in vitro and in ovo and protected mice from mortality in the experimental
      influenza infection. The in vivo protective effect was connected with multiple
      biological activities of the preparation. The present paper focuses on the in
      vitro effects of the polyphenol extract on the functions of peritoneal and
      alveolar macrophages and blood polymorphonuclear leucocytes (PMNs), isolated from
      healthy ICR mice. It was found that PC in doses of 12.5 and 25 microg ml(-1)
      stimulated the phagocytic activity of peritoneal macrophages and blood PMNs. PC
      in the same doses did not significantly affect the phagocytic activity of
      alveolar macrophages, the migration of alveolar and peritoneal macrophages or the
      adherent activity of PMNs. Used in concentrations of 3.1-25.0 microg ml(-1), PC
      suppressed spontaneous NO production from peritoneal macrophages, while inducible
      NO production, provoked by LPS-, Ifn-gamma and LPS + Ifn-gamma inductions was not
      affected. The cell-toxic concentration of 100 microg ml(-1) increased spontaneous
      and LPS-inducible NO production. The experimental results demonstrated a
      stimulating effect of PC on the phagocytic activity of murine PMNs and peritoneal
      macrophages as well as a beneficial effect of the preparation on spontaneous NO
      production.

PMID- 15025185
TI  - Effects of Rumex patientia root extract on indomethacine and ethanol induced
      gastric damage in rats.
AB  - The effects of an aqueous root extract from Rumex patientia (D-1) compared to COX
      2 selective inhibitors on indomethacine and ethanol induced stomach ulcers were
      investigated. Adult male Wistar albino rats, weighing between 185-200 g were
      used. It was determined that D-1 does not show its gastroprotective activity via
      a COX enzyme in indomethacine induced ulcers. Antioxidant effects protect the
      gastrointestinal system. The effect of D-1 in ethanol induced ulcers may also be
      due to its antioxidant effect.

PMID- 15025187
TI  - Coadjustment of quercetin and hydrogen peroxide: the role of ROS in the
      cytotoxicity of quercetin.
AB  - Quercetin (QU) displays antioxidant and cell protective effects in most cell
      culture models, yet in some studies it is reported that QU shows prooxidant and
      cytotoxic effects. In order to explore the real role of ROS in QU's cytotoxicity,
      the cytotoxicity of QU and/or H2O2, as indicated by the proliferation and
      viability of HL-60 cells, was examined in this study. Both H2O2 and QU dose
      dependently induced cell proliferation arrest and cell death. The cytotoxicity of
      QU could be diminished by the supplement of H2O2 in the culture medium, at the
      same time, the addition of QU also significantly attenuated H2O2- caused
      cytotoxicity. These results indicated that certain amounts of ROS are critical
      for the proliferation and viability of HL-60 cells, QU scavenged the necessary
      ROS, and hence led to the proliferation arrest and cell death; on the contrary,
      the excessive ROS, such as H2O2, are obviously harmful to HL-60 cells, under
      these conditions, QU protected cells through diminishing the excessive ROS in
      vivo. Thus QU exerted its effects on cells, including its cytotoxic and
      protective effects, mainly through its antioxidant activity. The malondialdehyde
      (MDA, an index of ROS level) assay further confirmed this conclusion, as the
      effects of QU, H2O2, or their combination on HL-60 cells were closely related
      with the variation of MDA amounts in vivo.

PMID- 15025188
TI  - Toxicity of environmental lead and the influence of intestinal absorption in
      children.
AB  - Exposure to metals, particularly lead, remains a widespread issue that is
      associated with historical and current industrial practices. Whereas the toxic
      properties of metals are well described, exposure to metals per se is only one of
      many factors contributing to elevated blood metal concentrations and their
      consequent health effects in humans. The absorbed dose of metal is affected by
      geochemical, biochemical, and physiological parameters that influence the rate
      and extent of absorption. In children, the interplay among these factors can be
      of critical importance, especially when biochemical and physiological processes
      might not have matured to their normal adult status. Such immaturity represents
      an elevated risk to metal-exposed children because they might be more susceptible
      to enhanced absorption, especially via the oral route. This review brings
      together the more recent findings on the physiological mechanisms of metal
      absorption, especially lead, and examines several models that can be useful in
      assessing the potential for metal uptake in children.

PMID- 15025189
TI  - Occupation and lung cancer in nonsmokers.
AB  - Lung cancer remains a significant burden on society, with approximately 157,200
      deaths from this disease in 2003 occurring in the United States alone. Smoking
      causes the vast majority of cases (and deaths) from lung cancer, occupation may
      account for as many as 16,700 of such deaths. To examine the influence of
      occupation independent of smoking, we reviewed the literature on occupational
      lung cancer in nonsmokers. We found that most individual studies and summaries of
      occupational lung cancer are based on data having a heavy preponderance of male
      smokers. Relatively little data are available concerning females and nonsmokers.
      Specific dose-response information is often lacking. Although many studies have
      been adjusted for smoking, there remains a significant potential for residual
      confounding because of the overwhelming importance of smoking in the etiology of
      this disease. Our review has found some evidence that asbestos, environmental
      tobacco smoke, and radon decay products (progeny) are occupational carcinogens in
      nonsmokers. Increased risk for lung cancer might also occur in nonsmokers from
      occupational exposure to arsenic. Nevertheless, for many agents and occupations
      occupations or industries listed in the database of the International Agency for
      Research on Cancer (IARC), we could not locate any study that found them to be
      occupational risk factors for lung cancer in nonsmokers. Thus, considerable
      uncertainty exists about their ability to cause lung cancer in the nonsmoking
      working population. We discuss problems with the original occupational studies
      and the IARC list of carcinogens. Besides the absence of information on
      nonsmokers, these problems include lack of sufficient detail on exposure to the
      primary agent of concern and to other occupational lung carcinogens. Further
      research on occupational causes of lung cancer in nonsmokers should be given high
      priority.

PMID- 15025190
TI  - A review of time-series studies used to evaluate the short-term effects of air
      pollution on human health.
AB  - We review the methodology used in the analysis of time-series studies of ambient
      air pollution. Our focus is on mortality studies, in which daily counts of death
      are correlated with changes in air pollution. We first illustrate the methods by
      showing data from the 1950s, during which the effects of air pollution were much
      more pronounced, and then describe current methods that were developed to
      identify associations when the signal-to-noise ratio is much lower. We describe
      basic data sources, details of statistical methods, and current state of the art,
      especially as it refers to problems found recently with the fitting algorithm
      used in the generalized additive models. A summary of the findings from mortality
      studies is presented and the pre-eminent issues regarding methods,
      interpretation, and identification of susceptible populations are discussed. We
      conclude by describing possible biological mechanisms and suggesting other
      designs that will aid in the interpretation of data from studies of acute health
      effects.

PMID- 15025192
TI  - Route of nutrient delivery.
AB  - Nutritional intervention early in the course of critical illness in humans and
      animals can have a significant impact on morbidity and mortality. Enteral
      delivery of nutrients is less technically demanding, more physiologic, and less
      expensive than parenteral nutrition. Furthermore, as complete bowel rest during
      critical illness can be associated with detrimental intestinal structural and
      functional changes ultimately resulting in bacterial translocation from the gut,
      direct delivery of nutrients to the gastrointestinal tract is preferred in
      patients with sufficient gastrointestinal function to allow digestion and
      absorption of nutrients. Once the decision to "feed the gut" has been
      established, there are several routes of enteral nutrient delivery available. A
      sound knowledge of gastrointestinal function, anticipated duration of enteral
      support, and co-moribund conditions will help the clinician tailor a plan of
      nutrient delivery that optimally meets each patient's needs. This article will
      review available routes of nutrient delivery to the gastrointestinal tract, and
      discuss indications and contraindications for each.

PMID- 15025191
TI  - Nutritional requirements of the critically ill patient.
AB  - The presence or development of malnutrition during critical illness has been
      unequivocally associated with increased morbidity and mortality in people.
      Recognition that malnutrition may similarly affect veterinary patients emphasizes
      the need to properly address the nutritional requirements of hospitalized dogs
      and cats. Because of a lack in veterinary studies evaluating the nutritional
      requirements of critically ill small animals, current recommendations for
      nutritional support of veterinary patients are based largely on sound clinical
      judgment and the best information available, including data from experimental
      animal models and human studies. This, however, should not discourage the
      veterinary practitioner from implementing nutritional support in critically ill
      patients. Similar to many supportive measures of critically ill patients,
      nutritional interventions can have a significant impact on patient morbidity and
      may even improve survival. The first step of nutritional support is to identify
      patients most likely to benefit from nutritional intervention. Careful assessment
      of the patient and appraisal of its nutritional needs provide the basis for a
      nutritional plan, which includes choosing the optimal route of nutritional
      support, determining the number of calories to provide, and determining the
      composition of the diet. Ultimately, the success of the nutritional management of
      critically ill dogs and cats will depend on close monitoring and frequent
      reassessment.

PMID- 15025193
TI  - Nutritional plan: matching diet to disease.
AB  - Institution of appropriate, timely nutritional support in the anorexic or
      critically ill patient has become accepted medical practice in people and
      animals. This article focuses on the benefits of appropriate nutrient intake in
      critically ill animals, recommended nutrient requirements for dogs and cats
      receiving enteral feeding, and mechanics of food preparation and delivery for a
      variety of feeding tubes. General nutrient requirements for all patients,
      specific recommendations for certain illnesses such as renal failure,
      pancreatitis, and hepatic disease, and nutritional alterations for critical
      illness are reviewed. Commercial liquid diets manufactured for people and pets,
      and pet-food diets practical for formulation of gruel are presented. Institution
      of and weaning from feeding are explained.

PMID- 15025194
TI  - Esophageal and gastric feeding tubes in ICU patients.
AB  - Providing nutrition to critically ill patients is important to the healing
      process. This article will focus on selection and placement of nasoesophageal,
      nasogastic, esophagostomy, and gastrostomy tubes. Advantages and disadvantages of
      these tubes will be discussed, as well detailed instructions on the placement of
      the aforementioned tubes.

PMID- 15025195
TI  - Placement of jejunal feeding tubes for post-gastric feeding.
AB  - In veterinary patients, postgastric feeding is indicated for uncontrollable
      gastric vomiting, gastroparesis, biliary tract disease, pancreatitis, and for
      patients at increased risk for aspirating secondary to decreased mentation,
      prolonged recumbency, or an unprotected airway. Postgastric feeding may be
      implemented via the placement of a jejunal feeding tube. These tubes can be
      placed surgically (jejunostomy tubes) or with fluoroscopic or endoscopic
      guidance. This article will focus on methods of jejunal feeding-tube placement,
      advantages and disadvantages of the methods described, and complications
      associated with jejunal feeding.

PMID- 15025197
TI  - Preventing and managing complications of enteral nutritional support.
AB  - Complications of enteral nutritional support include mechanical problems related
      to the feeding device, gastrointestinal side effects, metabolic disturbances, and
      infectious complications. Although the sickest patients are often the ones that
      we feel will most likely benefit from nutritional support, they are generally
      more challenging to feed and least likely to tolerate complications arising from
      assisted feeding. Many of the problems that can occur with enteral nutritional
      support can be anticipated, which may allow them to be avoided or possibly aid in
      early detection and thereby minimize consequences to the patient. Therefore,
      knowledge of the types of complications that can occur with enteral nutritional
      support will aid in the process of deciding whether and how a patient should
      receive assisted feeding, and what parameters to monitor while a patient is
      receiving nutritional support.

PMID- 15025196
TI  - The problem of gastric atony.
AB  - Normal gastrointestinal motility is crucial for maintaining an appropriate
      balance of microorganisms within the gut. Disruption of this system results in
      bacterial overgrowth and associated complications such as bacterial
      translocation, aspiration pneumonia, and sepsis. Critically ill animals are at
      increased risk of developing gastroparesis caused by primary gastrointestinal
      disturbances or severe metabolic derangements that impact gastrointestinal
      function. In the intensive-care setting, delayed gastric emptying complicates
      enteral nutrition, and the catabolic effects of severe illness further deplete
      the patient's caloric reserves, resulting in impaired wound healing, decreased
      immune function, and increased morbidity and mortality. The use of promotility
      drugs in critically ill patients is a safe, effective means to circumvent the
      problem of gastric atony and improve patient recovery. Understanding the drugs
      available and their interaction with the receptors involved in neuromuscular
      transmission within the gastrointestinal tract will aid the clinician in
      selecting the optimal prokinetic therapy.

PMID- 15025198
TI  - [Dear colleagues].

PMID- 15025199
TI  - [The veterinarian Samuel Vollmar of Murten (1812-1874)].
AB  - The biography and family history of Samuel Vollmar author of "Chirurgie der
      Hausthiere" (1830) was discovered while researching the manuscript. The family
      history extends from the end of the 18th century to the present and reflects a
      small part of the developmental history of the veterinary profession. The
      manuscript is based on multiple sources. It remains unknown whether the
      manuscript was written at the veterinary school in Zurich or Bern.

PMID- 15025200
TI  - ["Look into the mouth of the horse...". Horse medicine of Captain Meinrad Tschudi
      1584].

PMID- 15025201
TI  - [Chronology of horseshoes found in Switzerland].
AB  - The horse was domesticated by a people in Central Asia. However, it is not known
      where and who invented horse shoeing, an invention that increased the
      possibilities for using horses. The word "horseshoe" was first mentioned in a
      document from 826 p.c. Up to now an archaeologist couldn't date an excavated
      horseshoe. I succeeded now to establish a chronology for horseshoes found in
      Switzerland. The first realisation is that in the course of more than thousand
      years of horse shoeing history three basic forms followed each other. Moreover,
      the existing horseshoes can be allocated to periodical types, each in use for
      approximately a quarter of a century.

PMID- 15025202
TI  - [The beginning of horse breeding in Switzerland: 1850-1910].

PMID- 15025203
TI  - [The Faculty of Veterinary Medicine of Berne: an old history].

PMID- 15025204
TI  - [Amyloidosis of the larynx. A clinical case and literature review].
AB  - The larynx is a rare site of deposition for amyloidosis. We are reporting the
      clinical case of a 73 years female with hoarseness of 2 years evolution due to a
      laryngeal mass which was informed as located primary amyloidosis after
      anatomopathologic exam (AP) and its extension study. A laryngeal microsurgery was
      performed and then we proceeded to send the patient to Internal Medicine Service
      with periodic controls by ORL. Surgery is the treatment of choice by
      microsurgery, laryngofissure or Laser with local excision. The prognosis of
      localized forms is better than systemic ones although recurrences are common and
      it is recommended a long-term follow-up. A bibliographic review about this
      pathology has been made.

PMID- 15025205
TI  - [Ten years of ENT surgery in the Toledo's outpatient surgery unit].
AB  - One of the Spain's pioneer out patient surgery units is the Toledo's one. We have
      realized a retrospective study of the 10th first years of its functioning. During
      this period, 4733 patients were operated, on tonsills and adenoids, laryngeal
      microsurgeries, septoplasties, miringotomies, and miringoplasties. We obtained a
      91.8% of discharge from hospital in the same day and few complications (5.5%
      without hospitalization and 0.7% with). Thanks to a questionary we know that the
      degree of satisfaction of the patients is high, and so, added to our good
      statistic results, stimulate us to follow in this working line.

PMID- 15025206
TI  - [Otogenic intracranial abscesses. Description of 6 cases].
AB  - We are reporting 6 clinical cases corresponding to admitted patients with
      intracranial abscesses (4 in brain and 2 in cerebellum) due to chronic otogenic
      pathology. Five were men and one woman with ages between 25 and 74 years. We have
      analysed in each case the initial symptoms, otoscopic exam, the otic and cranial
      CT informed, diagnosis, treatment and evolution. In all of them, it was performed
      a drainage of the abscess by Neurosurgery and Radical mastoidectomy by our
      Service with positive result. Although it is an uncommon complication nowdays,
      the abscesses of otological cause must be always suspected in uncontrolled
      chronic otitis or poor response to medical treatment. Symptoms can be no
      characteristics and must be asked for a CT or IRM in case of doubt.

PMID- 15025207
TI  - [The ductal parotid carcinoma. A rare malignant neoplasm].
AB  - The annual incidence of parotid neoplasms are between 0,4-13,5 for 100.000
      people, almost the fourth part of it with malignant histology. The ductal parotid
      carcinoma has a lower incidence and a high malignancy. In the last years, the
      imaging advances permit a better therapeutical approach, facilitating the
      realisation of more complex surgical techniques. We present a male patient 76
      years old with a ductal parotid carcinoma affecting all the gland and contacting
      the mastoid. We insist that precise preoperatory exams of the tumorals lesions of
      the parotid area are important for an adequate surgical interpretation and to try
      a complexe extirpation.

PMID- 15025208
TI  - [Post-tonsillectomy hemorrhage in adults. A retrospective study and literature
      review].
AB  - We are reporting a review of 21 adults admitted with diagnosis of post
      tonsillectomy hemorrhage between 1992 and 2001 (10 years). 14 were male and 7
      female with 29 years-old average. We have studied the number of days from
      intervention to hemorrhage beginning, bleeding location, urgent analysis, the
      medical or surgical treatment that was performed and clinical evolution. A 85.7%
      were late bleeding (5th day or afterwards) being two times more frequent on the
      left fossae. It was required a hemostasia under general anestesia in 57.14% of
      the cases and the incidence of bleeding post-tonsillectomy has been estimated in
      5.8% respect to global surgery of that kind.

PMID- 15025209
TI  - Osteopetrosis of temporal bone with blockage of the eustachian tube. A case
      report.
AB  - Osteopetrosis is an inherited disorder characterized by bone sclerosis. One of
      the more predominant feature of the disease in the temporal bone is conductive
      hearing loss due to anomalous bone formation in the middle ear and to otitis
      media. A 55-year-old woman affected by the adult type of osteopetrosis was
      referred to our department with a long history of otitis media. CT study
      demonstrated a narrowing of Eustachian tube due to abnormal deposition of
      sclerotic bone; this condition was confirmed during surgery. Tubotomy was
      performed during tympanoplastic surgery and there were no relapse of otitis after
      12 months of follow up. Timpanoplastic surgery should be considered in those
      cases where medical treatment has failed in dealing with otitis media. In our
      experience an enlargement of Eustachian tube shuld be performed in this kind of
      patients, thus helping the functional recovery and the potential well-being of
      the patient as we observed in our case.

PMID- 15025210
TI  - [Differential diagnosis of intrasinusal calcifications].
AB  - We present a case of a patient with a sinusitis of three months evolution. The CT
      scan showed an occupation of the middle meatus of the left nasal fossa with
      alergic polyps and a total opacification of the left maxillary sinus with
      calcifications, that makes to discard the metalic on dental nature of an
      intrasinusal body, and other chronic granulomatous processes. The correct
      surgical restauration of the osteomeotal complex obtained the complete resolution
      of the process.

PMID- 15025211
TI  - Cigarette smoking, periodontal disease: and chronic obstructive pulmonary
      disease.
AB  - BACKGROUND: Cigarette smoking is a significant risk factor for both chronic
      obstructive pulmonary disease (COPD) and periodontal disease. The goal of this
      study was to better understand the role of smoking in a possible relationship
      between periodontal disease and COPD. METHODS: The study population consisted of
      7,625 participants in the Third National Health and Nutrition Examination Survey
      (NHANES III) during 1988-1994 who were aged 30 years or older when examined and
      who received a spirometric examination. The data analysis employed logistic
      regression models and accounted for the complex sampling design used in NHANES
      III. RESULTS: After adjustment for potential confounders, there was no
      statistically significant association between periodontal disease and COPD among
      former or non-smokers. Current smokers with > or = 4 mm mean loss of attachment
      had an odds ratio of 3.71 (95% confidence interval: 1.74, 7.89). CONCLUSIONS:
      These results suggest that cigarette smoking may be a cofactor in the
      relationship between periodontal disease and chronic obstructive pulmonary
      disease. The key role played by smoking in the etiology of both periodontal
      disease and chronic obstructive pulmonary disease suggests that much of the
      observed increase in risk may actually reflect the exposure to smoking.
      Additional research into smoking-related effect modification is needed to clarify
      the role of periodontal disease in the etiology of smoking-related systemic
      diseases.

PMID- 15025212
TI  - The effect of cigarette smoking on gingival bleeding.
AB  - BACKGROUND: The purpose of this study was to investigate the dose-dependent
      effect of cigarette smoking upon gingival bleeding on probing (BOP) in a large
      representative sample of the United States population (National Health and
      Nutrition Examination Survey III). METHODS: Weighted multiple logistic regression
      was used to model bleeding on probing of 141,967 mesio-buccal sites in 12,385
      individuals with complete case records on all covariates. Adjustments were made
      for age, gender, race/ethnicity, number of missing teeth, tooth type/jaw, root
      caries, full crown coverage, socioeconomic status (poverty/income ratio), and
      survey characteristics. The model stratified by presence of calculus (CALC) and
      increased probing depth (PD > or = 4 mm). Generalized estimating equations were
      used to account for dependence of sites within subjects. RESULTS: Smoking had a
      strong suppressive effect on gingival bleeding. The effect was strongest in
      heavier smokers (> 10 cigarettes/day) and smallest in former smokers. In healthy
      sites (no CALC, PD < or = 3 mm), the odds ratio (OR) of bleeding for sites in
      heavier smokers compared to never-smokers was 0.56 (95% CI: 0.45-0.70). Sites
      with CALC and/or PD > or = 4 mm were more likely to bleed in never-smokers (OR:
      5.7; 95% CI: 4.3-7.6). This relationship was less evident among heavier smokers
      (OR: 1.3; 95% CI: 0.8-1.9). The effect of smoking did not differ between
      maxillary and mandibular molars, premolars, or incisors. CONCLUSION: Smoking
      exerts a strong, chronic, and dose-dependent suppressive effect on gingival
      bleeding on probing.

PMID- 15025213
TI  - Study of bacterial viability within human supragingival dental calculus.
AB  - BACKGROUND: There is evidence that supragingival calculus contains unmineralized
      channels and lacunae. The purpose of this study was to investigate the viability
      of bacteria within these areas. METHODS: Supragingival calculus harvested from
      patients with moderate to severe chronic periodontitis was immediately frozen to 
      70 degrees C. Six samples were cryosectioned, stained with a bacterial viability
      kit, and examined with fluorescence microscopy. Controls comprised heat treatment
      of cryosections prior to staining. Four additional samples were stained and
      examined whole in a confocal laser scanning microscope (CLSM). Nine additional
      samples were prepared for bacterial culture, after initial irradiation with
      ultraviolet light to kill viable organisms on the covering plaque layer. Test
      samples were crushed to expose internal bacteria, while two controls were used
      without crushing. RESULTS: Viable bacteria, as identified using the bacterial
      viability stain, were found within cavities/lacunae in supragingival calculus
      cryosections. Similar results were obtained from whole calculus samples using
      CLSM. Of the nine experimental samples where bacterial culture was attempted,
      five provided positive bacterial culture under both aerobic and anaerobic
      conditions; one showed positive growth under aerobic conditions only; while one
      showed no bacterial growth. The controls showed no bacterial growth. CONCLUSIONS:
      From this study, it appears that viable aerobic and anaerobic bacteria may be
      present within supragingival calculus, specifically within the internal channels
      and lacunae. Clinically, this may be important, since incomplete removal of
      supragingival calculus may expose these reservoirs of possible pathogenic
      bacteria and be a factor in the recurrence of periodontal diseases after
      treatment.

PMID- 15025214
TI  - Analysis of the interleukin-6 gene promoter polymorphisms in Czech patients with
      chronic periodontitis.
AB  - BACKGROUND: Chronic periodontitis is an inflammatory disease, which is a major
      cause of tooth loss. The proinflammatory cytokines interleukin-1 (IL-1) and
      interleukin-6 (IL-6) are key regulators of the host response to microbial
      infection and major modulators of extracellular matrix catabolism and bone
      resorption. The purpose of this study was to investigate the associations of
      chronic periodontitis with IL-6 gene polymorphisms (at positions -597 [G/A], -572
      [G/C], and -174 [G/C]). METHODS: We analyzed allele, genotype, and haplotype
      distributions of the IL-6 promoter variants in a case-control study involving 148
      patients with chronic periodontitis and 107 unrelated controls. RESULTS: Our
      results showed significant differences in the distributions of alleles and
      genotypes of the IL-6 (-572 G/C) polymorphism between patients and the control
      population (chi2 = 10.393, P= 0.001, P(corr) < 0.01). The difference was due to
      the underrepresentation of the -572 G/C heterozygotes in patients (6.1%) compared
      to controls (19.6%). Although no variant "CC" homozygotes were detected in our
      cases and controls, heterozygosity protected against chronic periodontitis,
      representing a 73% reduction of risk (odds ratio [OR] = 0.27, 95% confidence
      interval: 0.12-0.61) compared to wild-type homozygotes. However, there were no
      significant differences in genotype or allele frequencies between both groups for
      IL-6 -597 G/A and -174 G/C polymorphisms. CONCLUSION: This study is the first, to
      our knowledge, suggesting that the -572 G/C polymorphism of the IL-6 gene may be
      one of the protective factors associated with lower susceptibility to chronic
      periodontitis.

PMID- 15025215
TI  - Interleukin-11 and IL-17 and the pathogenesis of periodontal disease.
AB  - BACKGROUND: Interleukin (IL)-11 and IL-17 are cytokines that modulate the
      inflammatory process and have not been assessed within normal or inflamed
      gingival tissues. Our purpose was to compare concentrations of human IL-11 and IL
      17 within healthy and diseased human gingiva to determine their possible role in
      the initiation or progression of periodontal diseases. METHODS: Biopsies from
      healthy (non-hemorrhagic gingiva adjacent to a < or = 3 mm gingival sulcus) and
      diseased gingiva (hemorrhagic gingiva adjacent to a > or = 3 mm periodontal
      pocket) were studied. IL-11, IL-17, RANTES, and IL-6 concentrations were assessed
      within solubilized gingival biopsies by enzyme-linked immunosorbent assay. Data
      were compared by factorial analysis of variance and a post-hoc Tukey honestly
      significant difference (HSD) test. Regression analysis and partial correlation
      analysis (adjusted for sample weight) were also used to determine correlations
      between the variables. RESULTS: Interleukin-11 concentrations were highest within
      gingiva adjacent to 3 mm diseased pockets (P < 0.001), and IL-17 concentrations
      were highest at 4 to 5 mm sites compared to other sites (P < 0.001). Gingival
      concentrations of both cytokines were significantly lower in gingiva adjacent to
      a > or = 6 mm pocket. RANTES concentrations were significantly greater in gingiva
      adjacent to > or = 6 mm pockets than in tissues derived from other sites (P <
      0.001). IL-11, IL-6, and RANTES concentrations were significantly correlated with
      sulcular depth. CONCLUSIONS: Gingival concentrations of IL-11 and IL-17 are
      different in diseased gingiva adjacent to 3, 4 to 5, and > or = 6 mm pockets,
      suggesting that their concentrations change as a consequence of the progression
      of gingivitis to periodontitis and that both cytokines could have a significant
      role in this progression. These data may be useful for the design of procedures
      for prevention of periodontal disease.

PMID- 15025216
TI  - The clinical effect of acellular dermal matrix on gingival thickness and root
      coverage compared to coronally positioned flap alone.
AB  - BACKGROUND: The primary aim of this randomized, controlled, blinded, clinical
      investigation was to compare the coronally positioned flap (CPF) plus an
      acellular dermal matrix (ADM) allograft to CPF alone to determine their effect on
      gingival thickness and percent root coverage. METHODS: Twenty-four subjects with
      one Miller Class I or II buccal recession defect of > or = 3 mm were treated with
      a CPF plus ADM or a CPF alone. Multiple additional recession sites were treated
      with the same flap procedure, and all sites were studied for 6 months. Tissue
      thickness was measured at the sulcus base and at the mucogingival junction of all
      teeth, with an SDM ultrasonic gingival thickness meter. RESULTS: For the ADM
      sites, mean initial recession of 3.46 mm was reduced to 0.04 mm for defect
      coverage of 3.42 mm or 99% (P < 0.05). For the CPF group, mean initial recession
      of 3.27 mm was reduced to 1.08 mm for defect coverage of 2.19 mm or 67% (P <
      0.05). The difference between ADM and CPF groups was statistically significant (P
      < 0.05). Marginal soft-tissue thickness was increased by 0.40 mm (P < 0.05) for
      the ADM group, whereas the CPF group remained essentially unchanged. Keratinized
      tissue was increased for the ADM group by 0.81 mm (P < 0.05), whereas the CPF
      group increased by 0.33 mm (P > 0.05). No additional root coverage was gained due
      to creeping attachment between 2 and 6 months for either group. CONCLUSIONS:
      Treatment with a CPF plus an ADM allograft significantly increased gingival
      thickness when compared with a CPF alone. Recession defect coverage was
      significantly improved with the use of ADM.

PMID- 15025217
TI  - Efficacy of a fluoridated hydrogen peroxide-based mouthrinse for the treatment of
      gingivitis: a randomized clinical trial.
AB  - BACKGROUND: A randomized clinical trial was performed to test the efficacy of a
      fluoridated hydrogen peroxide-based mouthrinse on gingivitis and tooth whitening
      in a two-phase study. The first phase (28 days) included the experimental
      gingivitis phase; the second phase (5 months) was the oral hygiene phase, which
      included rinsing. METHODS: A total of 99 subjects were included in the study and
      were randomly assigned to receive either placebo or test mouthrinse. Clinical
      measures were chosen to reflect the gingival health and tooth whiteness in an
      intent-to-treat study design. Statistical analyses of clinical parameters related
      to gingival health and tooth color were conducted, using the method of
      generalized estimating equations (GEE), with an exchangeable working correlation
      to accommodate tooth-level data. Baseline differences between the groups were
      adjusted. Microbial samples taken at the beginning and at the end of the study
      were analyzed by DNA-DNA hybridization technique, to determine whether there was
      any adverse shift in supragingival flora. RESULTS: Eastman bleeding index,
      modified gingival index, intensity of stain, and extent of stain were
      significantly reduced in the test group at 6 months compared to baseline (P <
      0.05). In contrast, only the Eastman bleeding index was significantly reduced in
      the control group (P < 0.05). The reduction in the index of gingival inflammation
      for the test group was significantly greater than for the control group (P =
      0.004). Subjects using the test rinse were also six times more likely to exhibit
      an improvement in tooth color after 6 months than were subjects using placebo (P
      = 0.002). As a result of the clinical evaluations and microbial analysis, test
      mouthrinse was found to be safe during a 6-month period. CONCLUSION: The results
      of this study indicate that the fluoridated hydrogen peroxide-based mouthrinse
      effectively whitens teeth and significantly reduces gingivitis.

PMID- 15025218
TI  - P-15 cell-binding domain derived from collagen: analysis of MG63 osteoblastic
      cell response by means of a microarray technology.
AB  - BACKGROUND: P-15 is an analog of the cell-binding domain of collagen. P-15 has
      been shown to facilitate physiological processes in a way similar to collagen; to
      serve as an anchorage for cells; and to promote the binding, migration, and
      differentiation of cells. METHODS: Expression profiling by DNA microarray is a
      molecular technology that allows the analysis of gene expression in a cell
      system. By using DNA microarrays containing 19,200 genes, we identified in
      osteoblast-like cell line (MG-63) cultured with P-15 several genes whose
      expression was significantly up- or downregulated. RESULTS: The differentially
      expressed genes cover a broad range of functional activities: 1) signaling
      transduction, 2) differentiation, 3) apoptosis, and 4) cell-cycle regulation. It
      was also possible to detect some genes whose function is unknown. CONCLUSIONS:
      The data reported are, to our knowledge, the first genetic portrait of P-15
      effects. They can help us to better understand the molecular mechanism of
      osteogenesis and can serve as a model for comparing different cell cultures
      and/or other materials with similar effect.

PMID- 15025219
TI  - Telomere length in leukocytes and cultured gingival fibroblasts from patients
      with aggressive periodontitis.
AB  - BACKGROUND: The association of genetic risk factors with the pathogenesis of
      aggressive periodontitis (AgP) has been a focus of attention. Telomeres, which
      are nucleoprotein complexes at the ends of chromosomes, could be a genetic marker
      for Down's syndrome and Hutchinson-Gilford progeria, in which patients' premature
      aging is involved in the pathogenesis. It has been reported that these patients
      tend to experience severe periodontitis. Therefore, we investigated the telomere
      length of peripheral blood leukocytes (PBL) obtained from patients with AgP and
      that in the patients' gingival fibroblasts undergoing cellular aging in vitro.
      METHODS: Twenty-one patients with AgP and 50 age-matched, periodontally healthy
      subjects (HS) participated in this study. Genomic DNA from PBL and from human
      gingival fibroblasts (HGF) was analyzed by Southern blotting for telomere length.
      The percentage of HGF positive for beta-galactosidase (beta-gal), a marker for
      cellular senescence, was also investigated. RESULTS: There was no significant
      difference in the telomere length (P = 0.20, Student's t test) between the two
      groups, and wide interindividual variation was found (5.93 to 11.4 kbp, average
      8.35 +/- 1.19 kbp). The telomere length from PBL negatively correlated with donor
      age, but no significant difference in telomere loss between the two groups was
      observed. With HGF undergoing aging in culture, the mean telomere length of these
      cells from six patients with AgP and seven HS decreased an average of -67.5 bp
      and -81.0 bp, respectively. No association was found in the telomere length
      between PBL and HGF from the same donors (r = 0.56, P = 0.20). A significant
      association was found between the telomere length and the percentages of beta-gal
      positive HGF during cell passages (r = 0.70, P < 0.001). CONCLUSIONS: These
      results indicate that patients with AgP do not have excessive telomere loss and
      thus do not support the notion of the occurrence of a generalized premature
      cellular aging in patients with AgP. Further studies are required to investigate
      the association between telomere length and beta-gal in HGF.

PMID- 15025220
TI  - Vascular endothelial growth factor in gingival tissues and crevicular fluids of
      diabetic and healthy periodontal patients.
AB  - BACKGROUND: Periodontal disease is one of the major oral problems encountered in
      patients with diabetes mellitus (DM). Vascular changes, neutrophil dysfunction,
      altered collagen synthesis, and genetic predisposition observed in DM may
      contribute to periodontitis; and the vascular alterations observed in such
      patients may depend on vascular endothelial growth factor (VEGF) actions. Few
      reports are available about the mechanism of neovascularization and the
      angiogenic factors that contribute to the periodontal pathology and the role of
      VEGF in periodontal diseases. The aim of this study is to compare VEGF expression
      in healthy and periodontally diseased tissues with gingival crevice fluid (GCF)
      of healthy persons and diabetic patients. METHODS: Gingival tissue and GCF
      samples were collected from sites of periodontitis in 10 healthy subjects and in
      10 type 2 diabetic patients, and from the sites of healthy gingiva within the
      same groups. Therefore, each patient became his/her own control. Additionally, 10
      people without any systemic or periodontal diseases were enrolled, forming a
      negative control group. Thus, a total of 50 tissue and 50 GCF samples were
      provided. RESULTS: No VEGF staining was observed in the negative control group or
      in the systemically healthy people's healthy tissue samples, whereas four samples
      of diabetic patients showed positive staining (P < 0.05). However, VEGF was
      revealed in two tissue samples of periodontal sites of systemically healthy
      people and in six samples of the diabetic patients (P > 0.05). In all test
      groups, GCF VEGF levels were higher in periodontal sites (P < 0.05) than in
      healthy sites. CONCLUSION: The results of this study showed that VEGF is
      increased in all periodontal tissues of both groups and in the healthy sites of
      diabetic patients. Additionally, GCF VEGF values increased in periodontal sites
      of all test groups.

PMID- 15025221
TI  - The effect of occlusal discrepancies on gingival width.
AB  - BACKGROUND: A relationship between occlusal forces and gingival recession has
      been postulated in the past. However, minimal data are available to demonstrate a
      causal relationship between occlusal forces and recession. METHODS: The records
      from a private practice limited to periodontics were reviewed to find patients
      who had complete periodontal examination records, including occlusal analysis and
      gingival width, that were recorded at least 1 year apart. Patients who fit this
      criteria were divided into those who had none of the recommended treatment
      (untreated, n = 30), those who had only non-surgical treatment (partially
      treated, n = 20), and a control group who had completed all recommended surgical
      and non-surgical treatment (completely treated, n = 41). The data for each tooth
      of each patient, including occlusal status and gingival width, were placed in a
      database and analyzed for a relationship between occlusal discrepancies and
      changes in gingival width. RESULTS: No statistically significant relationship was
      detected between the presence of occlusal discrepancies and initial width of the
      gingival tissue (P = 0.414) or between occlusal treatment and changes in the
      width of the gingiva (P = 0.481). CONCLUSION: Based on the current study, there
      does not appear to be a relationship between occlusal discrepancies and gingival
      recession.

PMID- 15025222
TI  - The effect of adjunctive low-dose doxycycline therapy on clinical parameters and
      gingival crevicular fluid matrix metalloproteinase-8 levels in chronic
      periodontitis.
AB  - BACKGROUND: Low-dose doxycycline (LDD) is recognized to have non-antimicrobial
      properties that can therapeutically modulate the host response. The aim of the
      present randomized, double-blind, placebo-controlled, parallel-arm study was to
      examine the effectiveness of LDD in combination with non-surgical periodontal
      therapy, compared to non-surgical periodontal therapy alone, on gingival
      crevicular fluid (GCF) matrix metalloproteinase-8 (MMP-8) levels and clinical
      parameters over a 12-month period in patients with chronic periodontitis.
      METHODS: GCF samples were collected, and clinical parameters including probing
      depth (PD), clinical attachment level, gingival index (GI), and plaque index were
      recorded. Thirty chronic periodontitis patients were randomized either to a low
      dose doxycycline (LDD) or placebo group. The LDD group received low-dose
      doxycycline (20 mg) b.i.d. for 3 months plus scaling and root planing (SRP),
      while the placebo group was given placebo capsules b.i.d. for 3 months plus SRP.
      The patients were evaluated every 3 months during the 12-month study period. At
      each visit, all clinical measurements and GCF sampling were repeated. GCF MMP-8
      levels were determined by a time-resolved immunofluorescence assay. Intragroup
      comparisons were tested by the Friedman test followed by Wilcoxon signed-rank
      test to analyze significance of changes over time. The Mann-Whitney test was used
      to determine differences between the LDD and placebo groups. RESULTS: Significant
      improvements were observed in all clinical parameters in both groups over the 12
      month period (P < 0.0125). The LDD group showed a significantly greater reduction
      in mean PD scores at 9 and 12 months and in mean GI scores at all time points
      than the placebo group (P < 0.05). From baseline to 12 months, GCF MMP-8 levels
      were significantly reduced in both groups (P < 0.0125). The GCF MMP-8 level in
      the LDD group was significantly lower than that of the placebo group at 6 months
      (P < 0.05). CONCLUSIONS: The present results indicate that low-dose doxycycline
      therapy in combination with scaling and root planing can reduce GCF MMP-8 levels
      and improve clinical periodontal parameters in patients with chronic
      periodontitis. These results provide additional information about the usefulness
      of low-dose doxycycline therapy as an adjunct to non-surgical periodontal therapy
      in the long-term management of periodontal disease. The effectiveness and course
      of low-dose doxycycline therapy can be monitored conveniently by assessing GCF
      MMP-8 levels.

PMID- 15025223
TI  - The oral conditions and pregnancy study: periodontal status of a cohort of
      pregnant women.
AB  - BACKGROUND: Our objective was to describe the oral health of pregnant women, to
      determine oral health changes during pregnancy, and to determine factors
      associated with maternal periodontal health or disease. MATERIALS AND METHODS:
      Between December 1997 and July 2001, 1,224 pregnant women at < 26 weeks'
      gestation were enrolled in the study and oral health examinations were performed
      at enrollment and within 48 hours of delivery. Demographic, medical, and health
      behavior data were determined by chart abstraction and questionnaire. Comparisons
      between oral health at enrollment and delivery were made by student t test or
      Fisher's exact test. Ordinal logistic regression analysis was used to identify
      risk factors for maternal periodontal disease. RESULTS: Among 903 women, there
      was a significant increase in those with health/periodontal disease absence
      between enrollment and delivery (P < 0.001). However, we also observed a
      significant increase in women with four or more sites with attachment loss > or =
      2 mm or > or = 3 mm (P < 0.05, 0.001). Race, smoking, and insurance status were
      significantly associated with maternal periodontal disease. Black women were more
      likely than white women to have periodontal disease at enrollment (adj. odds
      ratio 2.9, 95% confidence interval 2.2 to 3.9) and delivery (adj. odds ratio 3.1,
      95% confidence interval 2.2 to 4.2), and experience incident disease (adj. odds
      ratio 2.3, 95% confidence interval 1.6 to 3.4). CONCLUSIONS: Oral health
      examinations were well accepted by pregnant women. An increase in attachment loss
      may represent active periodontal infection accelerated by pregnancy. Further
      study on racial disparity in oral health among pregnant women is needed.
      Continued efforts to evaluate and establish appropriate definitions of oral
      disease in pregnancy are warranted.

PMID- 15025225
TI  - The application of multilevel modeling in the analysis of longitudinal
      periodontal data--part II: changes in disease levels over time.
AB  - BACKGROUND: The aim of this study was to investigate the longitudinal
      relationships between the outcome measurements of changes in lifetime cumulative
      attachment loss (cLCAL) and changes in probing depth (cPD) in relation to
      potential risk factors or other risk markers for periodontal disease progression
      from a cohort of 100 young males. In order to account for the hierarchical data
      structure, and to explore explicitly the site, tooth, and subject levels
      simultaneously, multilevel modeling was undertaken. METHODS: The analyses were
      undertaken in two parts. Within a previous article, the absolute levels of
      disease were analyzed in relation to potential risk factors; within this article,
      changes in disease are analyzed in relation to these factors. Each analytical
      approach yielded substantively different insights. RESULTS: Subject-level risk
      factors had limited predictive value for cLCAL/cPD throughout the 30-month
      observation period. Tooth position demonstrated a near linear relationship for
      both outcomes, with disease increasing from anterior to posterior teeth.
      Supragingival plaque had no significant effect on cLCAL/cPD, while subgingival
      calculus and bleeding on probing were negatively associated with cLCAL/cPD. In
      contrast to the outcomes LCAL/PD, supragingival calculus had no significant
      protective effect on cLCAL/cPD. There was no significant influence of smoking in
      this cohort. CONCLUSIONS: This study provides, for a relatively young cohort,
      considerable insights into the factors associated with longitudinal patterns of
      early-life periodontal disease at all levels of the natural hierarchy of sites
      within teeth within subjects. Furthermore, it is demonstrated how multilevel
      modeling can provide considerable insight into some of the inconsistencies and
      controversies found in the previous periodontal literature.

PMID- 15025224
TI  - The application of multilevel modeling in the analysis of longitudinal
      periodontal data--part I: absolute levels of disease.
AB  - BACKGROUND: Statistical analyses of periodontal data that average site
      measurements to subject mean values are unable to explore the site-specific
      nature of periodontal diseases. Multilevel modeling (MLM) overcomes this, taking
      hierarchical structure into account. MLM was used to investigate longitudinal
      relationships between the outcomes of lifetime cumulative attachment loss (LCAL)
      and probing depth (PD) in relation to potential risk factors for periodontal
      disease progression. METHODS: One hundred males (mean age 17 years) received a
      comprehensive periodontal examination at baseline and at 12 and 30 months. The
      resulting data were analyzed in two stages. In stage one (reported here), the
      absolute levels of disease were analyzed in relation to potential risk factors;
      in stage two (reported in a second paper), changes in disease patterns over time
      were analyzed in relation to the same risk factors. Each approach yielded
      substantially different insights. RESULTS: For absolute levels of disease,
      subject-level risk factors (covariates) had limited prediction for LCAL/PD
      throughout the 30-month observation period. Tooth position demonstrated a near
      linear relationship for both outcomes, with disease increasing from anterior to
      posterior teeth. Sites with subgingival calculus and bleeding on probing
      demonstrated more LCAL and PD, and supragingival calculus had an apparently
      protective effect. Covariates had more "explanatory power" for the variation in
      PD than for the variation in LCAL, suggesting that LCAL and PD might be generally
      associated with a different profile of covariates. CONCLUSION: This study
      provides, for a relatively young cohort, considerable insights into the factors
      associated with early-life periodontal disease and its progression at all levels
      of the natural hierarchy of sites within teeth within subjects.

PMID- 15025226
TI  - Locally produced anti-phosphorylcholine and anti-oxidized low-density lipoprotein
      antibodies in gingival crevicular fluid from aggressive periodontitis patients.
AB  - BACKGROUND: Sera from patients with periodontal attachment loss contain higher
      concentrations of IgG anti-phosphorylcholine (anti-PC) than sera from healthy
      subjects. Furthermore, a large proportion of plaque bacteria bear PC-containing
      surface antigens, implicating the oral flora as a source of immunogen for anti
      PC. Additionally, anti-PC is cross-reactive with a variety of oral bacterial
      antigens and human antigens such as oxidized low-density lipoprotein (oxLDL). We
      hypothesized that, if the oral flora is a source of PC antigens, then we should
      be able to detect local anti-PC and anti-oxLDL production in gingival crevicular
      fluid (GCF). METHODS: To test this, we collected 66 GCF samples from 15 patients
      with aggressive periodontitis and examined both the GCF samples and serum samples
      for their content of IgG anti-PC, IgG anti-LDL, and IgG anti-oxLDL by enzyme
      linked immunosorbent assay. We also determined levels of anti-tetanus toxoid
      (anti-TT) as a non-oral antigen control. Serum and GCF concentrations of serum
      albumin (HSA) were also determined for use as a dilution marker. A conservative
      GCF:serum antibody ratio of greater than 1.5 was considered to be evidence of
      local antibody production. RESULTS: For the non-oral antigen TT, only one out of
      62 samples contained locally produced antibody. Eight out of 64 samples (7 from a
      single subject) demonstrated local production of anti-LDL. In contrast, 28 out of
      66 samples demonstrated local production of anti-PC, and 47 out of 66 samples
      contained locally produced anti-oxLDL. It was observed that A.
      actinomycetemcomitans strains containing or devoid of PC could absorb anti-oxLDL
      from human sera. Although there was a correlation between the ratios of anti-PC
      and anti-oxLDL (Spearman's rho = 0.35, P = 0.0037), local production of both
      antibodies was found in only 17 out of 65 samples, indicating that these
      antibodies are not always reflective of reactivity to the same antigens.
      CONCLUSION: The local production of anti-PC and anti-oxLDL further implicates the
      oral flora as a source of antigen that may mediate immune reactions of relevance
      to cardiovascular and other systemic diseases.

PMID- 15025228
TI  - Effects of tumor necrosis factor-alpha inhibitors pentoxifylline and thalidomide
      on alveolar bone loss in short-term experimental periodontal disease in rats.
AB  - BACKGROUND: Pentoxifylline (PTX) and thalidomide (TLD) have been shown to inhibit
      cytokine synthesis, mainly tumor necrosis factor (TNF)-alpha, in different
      inflammatory conditions. We studied the effects of these cytokine inhibitors in
      an experimental model of periodontitis. METHODS: Wistar rats were subjected to a
      ligature placement around the second upper right molars. Alveolar bone loss was
      evaluated by the sum of the distances between the cusp tip and the alveolar bone
      along the axis of each molar root, subtracting from the contralateral side.
      Histopathological analysis was based on cell influx, amount of alveolar bone, and
      cementum integrity. Animals were weighed daily, and total and differential
      peripheral white blood cell counts were performed at 6 hours and 1, 7, and 11
      days after induction of periodontitis. Groups were treated with saline (positive
      control), PTX, or TLD 1 hour before and daily up to 11 days after induction of
      periodontitis. RESULTS: Alveolar bone loss was inhibited 42%, 54%, and 69% by PTX
      at 5, 15, and 45 mg/kg, and 25%, 25%, 42%, and 54% by TLD at 5, 15, 45, and 90
      mg/kg, respectively, as compared to the control (P < 0.05; analysis of variance).
      Histological analysis showed that PTX and TLD reduced cell influx and alveolar
      bone and cementum destruction. PTX and TLD also reversed peripheral
      lymphomonocytosis but not weight loss, as compared to controls. These data showed
      that both PTX and TLD reduced alveolar bone loss in periodontitis. CONCLUSION:
      The data showed a protective effect of PTX and TLD on experimental periodontitis,
      suggesting a role for TNF-alpha in the pathophysiology of periodontitis.

PMID- 15025227
TI  - Cementoblast delivery for periodontal tissue engineering.
AB  - BACKGROUND: Predictable periodontal regeneration following periodontal disease is
      a major goal of therapy. The objective of this proof of concept investigation was
      to evaluate the ability of cementoblasts and dental follicle cells to promote
      periodontal regeneration in a rodent periodontal fenestration model. METHODS: The
      buccal aspect of the distal root of the first mandibular molar was denuded of its
      periodontal ligament (PDL), cementum, and superficial dentin through a bony
      window created bilaterally in 12 athymic rats. Treated defects were divided into
      three groups: 1) carrier alone (PLGA polymer sponges), 2) carrier + follicle
      cells, and 3) carrier + cementoblasts. Cultured murine primary follicle cells and
      immortalized cementoblasts were delivered to the defects via biodegradable PLGA
      polymer sponges, and mandibulae were retrieved 3 weeks and 6 weeks post-surgery
      for histological evaluation. In situ hybridization, for gene expression of bone
      sialoprotein (BSP) and osteocalcin (OCN), and histomorphometric analysis were
      further done on 3-week specimens. RESULTS: Three weeks after surgery, histology
      of defects treated with carrier alone indicated PLGA particles, fibrous tissue,
      and newly formed bone scattered within the defect area. Defects treated with
      carrier + follicle cells had a similar appearance, but with less formation of
      bone. In contrast, in defects treated with carrier + cementoblasts, mineralized
      tissues were noted at the healing site with extension toward the root surface,
      PDL region, and laterally beyond the buccal plate envelope of bone. No PDL-bone
      fibrous attachment was observed in any of the groups at this point. In situ
      hybridization showed that the mineralized tissue formed by cementoblasts gave
      strong signals for both BSP and OCN genes, confirming its nature as cementum or
      bone. The changes noted at 3 weeks were also observed at 6 weeks. Cementoblast
      treated and carrier alone-treated defects exhibited complete bone bridging and
      PDL formation, whereas follicle cell-treated defects showed minimal evidence of
      osteogenesis. No new cementum was formed along the root surface in the above two
      groups. Cementoblast-treated defects were filled with trabeculated mineralized
      tissue similar to, but more mature, than that seen at 3 weeks. Furthermore, the
      PDL region was maintained with well-organized collagen fibers connecting the
      adjacent bone to a thin layer of cementum-like tissue observed on the root
      surface. Neoplastic changes were observed at the superficial portions of the
      implants in two of the 6-week cementoblast-treated specimens, possibly due in
      part to the SV40-transformed nature of the implanted cell line. CONCLUSIONS: This
      pilot study demonstrates that cementoblasts have a marked ability to induce
      mineralization in periodontal wounds when delivered via polymer sponges, while
      implanted dental follicle cells seem to inhibit periodontal healing. These
      results confirm the selective behaviors of different cell types in vivo and
      support the role of cementoblasts as a tool to better understand periodontal
      regeneration and cementogen-

PMID- 15025229
TI  - Specific antibiotics in the treatment of periodontitis--a proposed strategy.
AB  - BACKGROUND: The purpose of the present study was to propose a strategy for the
      selection of antibiotics that specifically target complexes of periodontal
      pathogens present in patients with periodontitis. METHODS: Seven hundred seventy
      four (774) patients with various forms of periodontitis were included in the
      study. Subgingival plaque samples were taken from the deepest periodontal pockets
      in each quadrant using a sterile curet, and pooled. Actinobacillus
      actinomycetemcomitans, Porphyromonas gingivalis, Eikenella corrodens, Tannerella
      forsythensis, Prevotella intermedia, and Prevotella nigrescens were identified by
      polymerase chain reaction, and the prevalence of combinations of these pathogens
      was determined. To each pathogen complex (PC), i.e., combination of pathogens,
      those antibiotics were assigned that were most specific according to the
      published minimum inhibitory concentration (MIC90) values and the gingival
      crevicular fluid (GCF) concentrations achievable in vivo. Antibiotic GCF
      concentrations had to be at least 10 times the MIC90 values, and the narrowest
      spectrum was selected with respect to the assessed periodontal pathogens.
      RESULTS: Nine major PCs (each > or = 3% of all patients) were found in 73.4% of
      all patients, whereas 38 minor PCs (each < 3% of all patients) were distributed
      in 26.6% of all patients. Ten different antibiotic regimens were found to be
      specific for the total of 46 PCs; i.e., metronidazole and amoxicillin in 11 PCs
      (55.0% of all patients), metronidazole and amoxicillin/clavulanic acid or
      metronidazole and ciprofloxacin in 13 PCs (18.9%), amoxicillin in 4 PCs (8.3%),
      doxycycline in 2 PCs (6.1%), metronidazole in 8 PCs (4.1%),
      amoxicillin/clavulanic acid in 3 PCs (2.9%), clindamycin in 2 PCs (1.5%),
      ciprofloxacin in 2 PCs (0.4%), and tetracycline in 1 PC (0.3%). CONCLUSION: The
      results of the study indicate that there are at least 46 different combinations
      of the assessed periodontal pathogens in subjects with periodontitis, and at
      least 10 different antibiotic regimens might be required to specifically target
      the various pathogen complexes.

PMID- 15025230
TI  - Periodontal parameters around implants anchoring orthodontic appliances: a series
      of case reports.
AB  - BACKGROUND: Implants replacing missing teeth provide advantages over clinical
      orthodontic treatment as compensation for reaction forces is no longer necessary
      and the lack of teeth is immediately resolved. METHODS: A total of 38 two-stage
      implants were inserted (16 in maxilla, 22 in mandible) in 10 partially edentulous
      patients with orthodontic problems. Osseointegration and marginal bone levels
      were assessed via intra-oral radiographs taken at the abutment stage and at the
      completion of the orthodontic treatment and also via probing depth, measurement
      of recession toward the implant/abutment (I/A) interface, and sulcus bleeding
      index, recorded after completion of orthodontic treatment. RESULTS: In the
      maxilla, the cumulative survival rate was 87.1% after 2 years; for the mandible,
      it remained 100%. Mean amount of bone loss was 1.6 mm for maxilla and 0.8 mm for
      mandible. No correlation could be found between directions of orthodontic forces
      and marginal bone loss. Mean percentage of bleeding sites was 38.5% and 25%,
      respectively, for implants in the maxilla and mandible. Attachment level was 1.2
      mm (SD: 1.2) below I/A interface after completion of the orthodonic treatment.
      CONCLUSION: No significant marginal bone loss was present. Using implants during
      orthodontics can result in an easier and more predictable treatment.

PMID- 15025231
TI  - Sulfadiazine-induced nephrolithiasis detected by spiral CT scan.
AB  - Nephrolithiasis is a known complication of the use of sulfadiazine in the
      treatment of cerebral toxoplasmosis. Radiographic diagnosis of this complication
      has historically been challenging. Between March 1999 and June 2002, 11 patients
      were treated for cerebral toxoplasmosis with sulfadiazine-containing therapy.
      Four of these patients (36.4%) developed nephrolithiasis during this period. Case
      patients had received sulfadiazine for a median of 35.5 days prior to
      nephrolithiasis. All cases were diagnosed by spiral CT scans. Although studies
      are needed to evaluate the sensitivity and specificity of this modality, spiral
      CT may aid in the diagnosis of sulfadiazine-induced nephrolithiasis.

PMID- 15025232
TI  - The social impact of medicine--Chapter 16.
AB  - This paper, an overview of medical history, is based on a course I taught at the
      University of Delaware's Academy of Life Long Learning, "Medicine, the Old and
      the New." It will not be a chronology of medical events and discoveries, but a
      discussion of the social aspects of medicine, how medicine affected the everyday
      lives of people, from the religion-based medicine of antiquity to the super
      scientific medicine of today. This paper is a compilation of other historical
      papers including, but not limited to, those listed in the accompanying
      bibliography. It is not an original paper. This paper will consist of 25
      chapters. Dr. Peter V. Rocca, Editor-in-Chief of the Delaware Medical Journal
      (DMJ), is planning to publish one chapter in each successive issue of the DMJ.

PMID- 15025233
TI  - Volunteerism.

PMID- 15025235
TI  - Documenting the pesticide processes module of the ARS RZWQM agroecosystem model.
AB  - We describe the theory and current development state of the pesticide process
      module of the USDA-Agricultural Research Service Root Zone Water Quality Model,
      or RZWQM. Several processes which are significant in determining the fate of a
      pesticide application are included together in this module for the first time,
      including application technique, root uptake, ionic dissociation, soil depth
      dependence of persistence, volatilization, wicking upward in soil and aging of
      residues. The pesticide module requires a large number of parameters to run (as
      does the RZWQM model as a whole) and it is becoming clear that RZWQM will find
      most interest and use as part of a 'scenario' in which all data requirements are
      supplied and the predictions of the system compared with a real (usually partial)
      data set. Such a scenario may then be modified to examine the response of the
      system to changes in inputs. It also has significant potential as a technology
      transfer or teaching tool, providing detailed understanding of a specific
      agronomic system and its potential impacts on the environment.

PMID- 15025234
TI  - Application of the Root Zone Water Quality Model (RZWQM) to pesticide fate and
      transport: an overview.
AB  - Pesticide transport models are tools used to develop improved pesticide
      management strategies, study pesticide processes under different conditions
      (management, soils, climates, etc) and illuminate aspects of a system in need of
      more field or laboratory study. This paper briefly overviews RZWQM history and
      distinguishing features, overviews key RZWQM components and reviews RZWQM
      validation studies. RZWQM is a physically based agricultural systems model that
      includes sub-models to simulate: infiltration, runoff, water distribution and
      chemical movement in the soil; macropore flow and chemical movement through
      macropores; evapotranspiration (ET); heat transport; plant growth; organic
      matter/nitrogen cycling; pesticide processes; chemical transfer to runoff; and
      the effect of agricultural management practices on these processes. Research to
      date shows that if key input parameters are calibrated, RZWQM can adequately
      simulate the processes involved with pesticide transport (ET, soil-water content,
      percolation and runoff, plant growth and pesticide fate). A review of the
      validation studies revealed that (1) accurate parameterization of restricting
      soil layers (low permeability horizons) may improve simulated soil-water content;
      (2) simulating pesticide sorption kinetics may improve simulated soil pesticide
      concentration with time (persistence) and depth and (3) calibrating the pesticide
      half-life is generally necessary for accurate pesticide persistence simulations.
      This overview/review provides insight into the processes involved with the RZWQM
      pesticide component and helps identify model weaknesses, model strengths and
      successful modeling strategies.

PMID- 15025236
TI  - The pesticide module of the Root Zone Water Quality Model (RZWQM): testing and
      sensitivity analysis of selected algorithms for pesticide fate and surface
      runoff.
AB  - The Root Zone Water Quality Model (RZWQM) is a one-dimensional, numerical model
      for simulating water movement and chemical transport under a variety of
      management and weather scenarios at the field scale. The pesticide module of
      RZWQM includes detailed algorithms that describe the complex interactions between
      pesticides and the environment. We have simulated a range of situations with
      RZWQM, including foliar interception and washoff of a multiply applied
      insecticide (chlorpyrifos) to growing corn, and herbicides (alachlor, atrazine,
      flumetsulam) with pH-dependent soil sorption, to examine whether the model
      appears to generate reasonable results. The model was also tested using
      chlorpyrifos and flumetsulam for the sensitivity of its predictions of chemical
      fate and water and pesticide runoff to various input parameters. The model
      appears to generate reasonable representations of the fate and partitioning of
      surface- and foliar-applied chemicals, and the sorption of weakly acidic or basic
      pesticides, processes that are becoming increasingly important for describing
      adequately the environmental behavior of newer pesticides. However, the kinetic
      sorption algorithms for charged pesticides appear to be faulty. Of the 29
      parameters and variables analyzed, chlorpyrifos half-life, the Freundlich
      adsorption exponent, the fraction of kinetic sorption sites, air temperature,
      soil bulk density, soil-water content at 33 kPa suction head and rainfall were
      most sensitive for predictions of chlorpyrifos residues in soil. The latter three
      inputs and the saturated hydraulic conductivity of the soil and surface crusts
      were most sensitive for predictions of surface water runoff and water-phase loss
      of chlorpyrifos. In addition, predictions of flumetsulam (a weak acid) runoff and
      dynamics in soil were sensitive to the Freundlich equilibrium adsorption
      constant, soil pH and its dissociation coefficient.

PMID- 15025237
TI  - Modeling hydrology, metribuzin degradation and metribuzin transport in
      macroporous tilled and no-till silt loam soil using RZWQM.
AB  - Due to the complex nature of pesticide transport, process-based models can be
      difficult to use. For example, pesticide transport can be effected by macropore
      flow, and can be further complicated by sorption, desorption and degradation
      occurring at different rates in different soil compartments. We have used the
      Root Zone Water Quality Model (RZWQM) to investigate these phenomena with field
      data that included two management conditions (till and no-till) and metribuzin
      concentrations in percolate, runoff and soil. Metribuzin degradation and
      transport were simulated using three pesticide sorption models available in
      RZWQM: (a) instantaneous equilibrium-only (EO); (b) equilibrium-kinetic (EK,
      includes sites with slow desorption and no degradation); (c) equilibrium-bound
      (EB, includes irreversibly bound sites with relatively slow degradation). Site
      specific RZWQM input included water retention curves from four soil depths,
      saturated hydraulic conductivity from four soil depths and the metribuzin
      partition coefficient. The calibrated parameters were macropore radius, surface
      crust saturated hydraulic conductivity, kinetic parameters, irreversible binding
      parameters and metribuzin half-life. The results indicate that (1) simulated
      metribuzin persistence was more accurate using the EK (root mean square error,
      RMSE = 0.03 kg ha(-1)) and EB (RMSE = 0.03 kg ha(-1)) sorption models compared to
      the EO (RMSE = 0.08 kg ha(-1)) model because of slowing metribuzin degradation
      rate with time and (2) simulating macropore flow resulted in prediction of
      metribuzin transport in percolate over the simulation period within a factor of
      two of that observed using all three pesticide sorption models. Moreover, little
      difference in simulated daily transport was observed between the three pesticide
      sorption models, except that the EB model substantially under-predicted
      metribuzin transport in runoff and percolate >30 days after application when
      transported concentrations were relatively low. This suggests that when macropore
      flow and hydrology are accurately simulated, metribuzin transport in the field
      may be adequately simulated using a relatively simple, equilibrium-only pesticide
      model.

PMID- 15025238
TI  - Test of the Root Zone Water Quality Model (RZWQM) for predicting runoff of
      atrazine, alachlor and fenamiphos species from conventional-tillage corn
      mesoplots.
AB  - The Root Zone Water Quality Model (RZWQM) is a comprehensive, integrated
      physical, biological and chemical process model that simulates plant growth and
      movement of water, nutrients and pesticides in a representative area of an
      agricultural system. We tested the ability of RZWQM to predict surface runoff
      losses of atrazine, alachlor, fenamiphos and two fenamiphos oxidative degradates
      against results from a 2-year mesoplot rainfall simulation experiment. Model
      inputs included site-specific soil properties and weather, but default values
      were used for most other parameters, including pesticide properties. No attempts
      were made to calibrate the model except for soil crust/seal hydraulic
      conductivity and an adjustment of pesticide persistence in near-surface soil.
      Approximately 2.5 (+/- 0.9), 3.0 (+/- 0.8) and 0.3 (+/- 0.2)% of the applied
      alachlor, atrazine and fenamiphos were lost in surface water runoff,
      respectively. Runoff losses in the 'critical' events--those occurring 24 h after
      pesticide application--were respectively 91 (+/- 5), 86 (+/- 6) and 96 (+/- 3)%
      of total runoff losses for these pesticides. RZWQM adequately predicted runoff
      water volumes, giving a predicted/observed ratio of 1.2 (+/- 0.5) for all events.
      Predicted pesticide concentrations and loads from the 'critical' events were
      generally within a factor of 2, but atrazine losses from these events were
      underestimated, which was probably a formulation effect, and fenamiphos losses
      were overestimated due to rapid oxidation. The ratios of predicted to measured
      pesticide concentrations in all runoff events varied between 0.2 and 147, with an
      average of 7. Large over-predictions of pesticide runoff occurred in runoff
      events later in the season when both loads and concentrations were small. The
      normalized root mean square error for pesticide runoff concentration predictions
      varied between 42 and 122%, with an average of 84%. Pesticide runoff loads were
      predicted with a similar accuracy. These results indicate that the soil-water
      mixing model used in RZWQM is a robust predictor of pesticide entrainment and
      runoff.

PMID- 15025240
TI  - Photodegradation of bensulfuron-methyl on soil surface.
AB  - Photolysis of bensulfuron-methyl on soil surface was studied under sunlight and
      UV light. Seven photoproducts were isolated and characterised by spectroscopic
      methods. The major processes in the photolysis of bensulfuron-methyl in soil are
      cleavage of the sulfonylurea bridge, scission of the SO2NH bond and contraction
      of the sulfuronylurea bridge. The rates of photodegradation of bensulfuron-methyl
      on different soils followed first-order rate kinetics with half lives of 21.9,
      28.4, 36.9, 59.2 and 47.2 h (UV) and 23.1, 27.5, 29.1, 38.9 and 33.8 days
      (sunlight) for vertisol, alluvial, alfisol, red and laterite soils, respectively.
      The differences in rates of photodegradation were dependent upon the soil texture
      and organic matter content.

PMID- 15025239
TI  - Herbicide leaching as affected by macropore flow and within-storm rainfall
      intensity variation: a RZWQM simulation.
AB  - Within-event variability in rainfall intensity may affect pesticide leaching
      rates in soil, but most laboratory studies of pesticide leaching use a rainfall
      simulator operating at constant rainfall intensity, or cover the soil with ponded
      water. This is especially true in experiments where macropores are present-
      macroporous soils present experimental complexities enough without the added
      complexity of variable rainfall intensity. One way to get around this difficulty
      is to use a suitable pesticide transport model, calibrate it to describe
      accurately a fixed-intensity experiment, and then explore the affects of within
      event rainfall intensity variation on pesticide leaching through macropores. We
      used the Root Zone Water Quality Model (RZWQM) to investigate the effect of
      variable rainfall intensity on alachlor and atrazine transport through
      macropores. Data were used from an experiment in which atrazine and alachlor were
      surface-applied to 30 x 30 x 30 cm undisturbed blocks of two macroporous silt
      loam soils from glacial till regions. One hour later the blocks were subjected to
      30-mm simulated rain with constant intensity for 0.5 h. Percolate was collected
      and analyzed from 64 square cells at the base of the blocks. RZWQM was calibrated
      to describe accurately the atrazine and alachlor leaching data, and then a median
      Mid-west variable-intensity storm, in which the initial intensity was high, was
      simulated. The variable-intensity storm more than quadrupled alachlor losses and
      almost doubled atrazine losses in one soil over the constant-intensity storm of
      the same total depth. Also rainfall intensity may affect percolate-producing
      macroporosity and consequently pesticide transport through macropores. For
      example, under variable rainfall intensity RZWQM predicted the alachlor
      concentration to be 2.7 microg ml(-1) with an effective macroporosity of 2.2 E(
      4) cm(3) cm(-3) and 1.4 microg ml(-1) with an effective macroporosity of 4.6 E(
      4) cm(3) cm(-3). Percolate-producing macroporosity and herbicide leaching under
      different rainfall intensity patterns, however, are not well understood. Clearly,
      further investigation of rainfall intensity variation on pesticide leaching
      through macropores is needed.

PMID- 15025241
TI  - Metabolism of imidacloprid in Apis mellifera.
AB  - Biotransformation of imidacloprid and the appearance of olefin and 5
      hydroxyimidacloprid metabolites in the honeybee were studied by HPLC-MS/MS
      analysis. Honeybees were treated orally with imidacloprid at 20 and 50 microg kg(
      1) bee. Imidacloprid was metabolised relatively quickly and thoroughly. Twenty
      minutes after the beginning of imidacloprid ingestion, the sum of the residues
      from the three compounds amounted to only 70% of the actual given dose.
      Imidacloprid, 5-hydroxyimidacloprid and olefin represented, respectively, 50%, 9%
      and 8% of the actual ingested dose. Six and 24 h, respectively, after ingestion
      of imidacloprid at 20 and 50 microg kg(-1) bee, imidacloprid could no longer be
      detected in the honeybee. Imidacloprid had a half-life ranging between 4.5 and 5
      h and was rapidly metabolised into 5-hydroxyimidacloprid and olefin. Except 5
      hydroxyimidacloprid in the 20 microg kg(-1) treatment, these two metabolites
      presented a peak value 4 h after ingestion of the 20 and 50 microg kg(-1) doses.
      This time fully coincided with the appearance of mortality induced by
      imidacloprid after acute oral intoxication. These results suggested that the
      immediate neurotoxicity symptoms are due to the action of imidacloprid, whereas 5
      hydroxyimidacloprid and/or olefin are involved in honeybee mortality. In
      addition, it was likely that the 30% of residues undetected 20 min after
      intoxication were imidacloprid metabolites, although not 5-hydroxyimidacloprid or
      olefin. Thus, 5-hydroxyimidacloprid and olefin could not be the major metabolites
      in the worker bees.

PMID- 15025242
TI  - Sorption of aged dicamba residues in soil.
AB  - The effect of aging (residence time in soil) on dicamba (3,6-dichloro-2
      methoxybenzoic acid) and a major metabolite, 3,6-dichlorosalicylic acid (3,6
      DCSA) sorption was determined in an unamended and a carbon-amended sandy loam and
      in a silt loam soil. During the incubation, sequential solvent extraction with
      0.01 M calcium chloride solution and aqueous acetonitrile + hydrochloric acid was
      used to determine the solution and sorbed concentrations of dicamba and 3,6-DSCA,
      and sorption coefficients were calculated. Dicamba was weakly sorbed to soil (Kd
      < 0.7). In contrast to some other classes of pesticides, sorption of dicamba did
      not significantly increase with aging, at least not until < 15% of the applied
      dicamba remained. 3,6-DSCA was strongly sorbed to soil (Kd > 8) and the Kd-a
      value increased by a factor of 2-6 during a 28-day aging period. Addition of a
      carbon source to the soil had minimal effect on the strength of sorption of aged
      dicamba. However, it did appear to decrease 3,6-DSCA availability to soil micro
      organisms; once formed 3,6-DSCA was not further mineralized. While it appears
      that sorption can be well characterized for weakly sorbed pesticides using the
      batch equilibration method with freshly treated soils, this procedure may not be
      adequate for more strongly sorbed pesticides and their degradates.

PMID- 15025243
TI  - Effectiveness of twelve insecticides applied topically to diapausing larvae of
      the codling moth, Cydia pomonella L.
AB  - Dose-mortality curves were established for 12 insecticides administered by
      topical application to diapausing larvae from a susceptible codling moth strain.
      Toxicity varied greatly among the insecticides tested. LC50 values ranged from
      0.1 mg kg(-1) for fenoxycarb to over 2800 mg kg(-1) for diflubenzuron and
      indoxacarb. Discriminating dose levels were determined from dose-mortality
      reference curves for the detection of resistance in field-collected diapausing
      larvae.

PMID- 15025244
TI  - Hepatic encephalopathy syndromes.
AB  - Hepatic encephalopathy (HE) is a neuropsychiatric complication of acute and
      chronic liver failure. Its clinical spectrum ranges from minimal (subclinical) to
      overt encephalopathy. Psychometric and electrophysiological tests are helpful in
      diagnosing minimal HE. However, changes in metabolites in the brain, such as
      depletion of myo-inositol and accumulation of glutamine, appear to be very
      sensitive and specific in diagnosing this form. Positron emission tomography has
      been useful in studying brain ammonia metabolism. The main focus of medical
      treatment has been to modify ammonia metabolism. Reduction in ammonia production
      can be achieved by, among others, a diet rich in vegetable protein and
      carbohydrate, and oral lactulose, oral antibiotics and sodium benzoate. L
      ornithine-L-aspartate provides critical substrates for both ureagenesis and
      glutamine synthesis, the key pathways for ammonia detoxification. Recent trials
      have shown its effectiveness in the treatment of HE.

PMID- 15025245
TI  - Assessing the severity of hepatic encephalopathy.
AB  - The diagnosis of hepatic encephalopathy (HE) is based mostly on clinical
      criteria. It is important to assess the severity of HE quantitatively for both
      clinical practice and research; however, this remains a difficult and challenging
      problem. Modalities like psychometric tests, electroencephalography, evoked
      potentials, and several innovative biochemical indices have shown promise in this
      regard. No single parameter or index has yet been shown to be infallible in
      assessing the severity of HE.

PMID- 15025246
TI  - Pathogenesis of hepatic encephalopathy: update on molecular mechanisms.
AB  - Hepatic encephalopathy (HE) is a major neuropsychiatric complication of acute and
      chronic liver failure. Neuropathologically, HE in chronic liver failure is
      characterized by astrocytic (rather than neuronal) changes known as Alzheimer
      type II astrocytosis and in altered expression of key astrocytic proteins.
      Magnetic resonance imaging in cirrhotic patients reveals bilateral signal
      hyperintensities in globus pallidus on T1-weighted imaging, which appear to
      result from manganese deposition. Proton (1H) magnetic resonance spectroscopy
      shows an increase in glutamine resonance in brain, a finding that confirms
      previous biochemical studies and is consistent with increased uptake of ammonia
      by the brain (glutamine synthesis). Recent molecular biological studies show an
      increased expression of several genes coding for neurotransmitter-related
      proteins in chronic liver failure. Such genes include those for monoamine oxidase
      (MAO-A isoform), nitric oxide synthase (nNOS isoform) and the peripheral-type
      benzodiazepine receptor. Activation of these systems may lead to alterations of
      monoamine and amino acid neurotransmitter function and changes in cerebral blood
      flow in chronic liver failure.

PMID- 15025247
TI  - Newer aspects of hepatic encephalopathy.
AB  - Recently attempts have been made to standardize terminology in the field of
      hepatic encephalopathy. We are now facing a new problem. Chronic hepatitis C
      induced cirrhosis occurs in an older population; this may change the presentation
      pattern of hepatic encephalopathy in future. Ammonia has once again become
      prominent as the leading toxin likely to play a role in the pathogenesis of this
      syndrome. How ammonia interacts with other proposed mechanisms should be an area
      of active research. The treatment arena has seen some advances. Unfortunately,
      the economics of having newer treatments approved in the USA is formidable.
      Rifaximine, L-ornithine-L-aspartate, sodium benzoate and possibly flumazenil
      appear to be significant advances. More elective shunt suppression for selected
      patients will be seen. Liver transplantation remains the only option for truly
      intractable hepatic encephalopathy.

PMID- 15025248
TI  - Decompressive shunts and hepatic encephalopathy.
AB  - Encephalopathy is a major complication of all decompressive procedures done to
      reduce portal pressure. There are two major groups of decompressive procedures:
      surgical portosystemic shunts and transjugular intrahepatic portosystemic shunts
      (TIPS). Surgical decompressive shunts are of three types: total, partial and
      selective, depending on the amount of hepatopetal flow that is maintained in each
      of them. Encephalopathy with these shunts occurs because of reduction in
      hepatopetal flow. These shunts have failed to reduce mortality; in fact, some
      studies have shown an increase in mortality following shunts. TIPS has more or
      less replaced the need for surgical shunts, but their risk to cause
      encephalopathy is almost equivalent to that of selective shunts and in some
      series is even more. Lactulose, antibiotics and protein restriction can easily
      control severe encephalopathy as a consequence of decompressive shunts.

PMID- 15025249
TI  - Interplay of portal pressure, portal perfusion and hepatic arterial inflow in
      modulating expression of hepatic encephalopathy in patients with spontaneous or
      artificially created portosystemic shunts.
AB  - The major theme of this discussion is how portal pressure after portosystemic
      shunt procedures may modulate the expression of hepatic encephalopathy. Decades
      of emphasis on the paramount importance of maintaining portal venous perfusion
      after shunt procedures is now being re-examined. In countries where non-cirrhotic
      portal hypertension is common, physicians have long recognized that hepatic
      encephalopathy is rare even with total portosystemic shunting. However, once
      decompressive shunts are created, hepatic encephalopathy becomes a clinical
      problem. Why this occurs needs to be better understood. In the meantime, there
      has been virtual abandonment of surgical shunts in favor of endoscopic variceal
      ablation treatment. This is despite the fact that surgical shunts that only
      partially decompress the portal hypertension are associated with excellent long
      term control of variceal bleeding and low rates of hepatic encephalopathy. The
      time has come to once again examine the key relationship between portal pressure,
      portal perfusion with hepatic arterial inflow in inducing hepatic encephalopathy
      after creation of portosystemic shunts.

PMID- 15025251
TI  - Helicobacter pylori and hepatic encephalopathy.
AB  - Several extra-intestinal diseases have been associated with Helicobacter pylori
      infection. Hepatic encephalopathy has been linked to H. pylori infection because
      of the ammonia produced by the organism in the stomach. H. pylori infection is
      commoner in cirrhotic patients with hepatic encephalopathy than in those without.
      Increased ammonia levels have been observed in the gastric juice and blood more
      commonly in cirrhotics with H. pylori infection than in those without. Though the
      amount of ammonia produced by H. pylori may be too small to contribute to hepatic
      encephalopathy, eradication of H. pylori has been shown to improve the blood
      ammonia levels and hepatic encephalopathy.

PMID- 15025250
TI  - Role of trace elements in hepatic encephalopathy: zinc and manganese.
AB  - Apart from increased blood ammonia, alterations in various other substances have
      been implicated in the pathogenesis of hepatic encephalopathy (HE). The role of
      trace elements like zinc and manganese has been described recently. Zinc is an
      essential trace element and functions as an antioxidant. Low zinc concentrations
      have been reported in patients with cirrhosis of the liver, particularly those
      with HE. Patients with fulminant hepatic failure and subacute hepatic failure
      have also been shown to have low serum zinc levels. In animal experiments, zinc
      supplementation leads to a reduction in blood ammonia. Zinc deficiency also leads
      to alteration of neurotransmitters like gamma aminobutyric acid and
      norepinephrine. Zinc supplementation has been tried in HE. It may have a role in
      mild chronic HE, though further trials are necessary. Increased serum manganese
      levels have been shown in acute and chronic hepatitis, cirrhosis and congenital
      disorders like Alagille's syndrome. High manganese content has been reported in
      the globus pallidus in animals as well as brain tissues of patients dying of HE.
      Miners with chronic manganese exposure have encephalopathy and extra-pyramidal
      features similar to HE. It has been postulated that manganese impairs neuronal
      oxidative metabolism. The role of manganese in the pathogenesis of HE and the
      possibility of its chelation as treatment need further study.

PMID- 15025252
TI  - Animal models of hepatic encephalopathy.
AB  - Hepatic encephalopathy is a neuropsychiatric syndrome associated with acute liver
      failure, chronic parenchymal liver disease, or portosystemic anastomosis. Many
      approaches have been used to develop suitable models of hepatic encephalopathy,
      each with specific advantages and disadvantages. The most commonly used models
      have been the surgical hepatectomy and liver devascularization procedures, and
      hepatotoxins such as galactosamine and acetaminophen. Drug-toxicity models may be
      clinically more relevant. The specific requirements of experiments to study a
      particular aspect of encephalopathy also influence the choice of animal model.
      Animal models will play a central role in future research into hepatic
      encephalopathy to better understand its pathophysiology and to develop newer
      therapeutic modalities for this condition.

PMID- 15025253
TI  - Minimal hepatic encephalopathy: diagnosis by neuropsychological and
      neurophysiologic methods.
AB  - Minimal hepatic encephalopathy (mHE) consists of cognitive deficits found on
      neuropsychological and/or neurophysiologic methods in patients with liver
      disease, present most commonly in cirrhosis. Patients suffering from mHE may have
      psychomotor slowing and cognitive deficits affecting their ability to perform
      many activities of daily life, especially driving and other activities requiring
      subtle cognitive abilities. It has been now been shown that patients with mHE
      improve after treatment with agents like lactulose and other therapeutic
      interventions. Neuropsychological and neurophysiologic tests have been widely
      used and have shown the greatest promise for the detection of mHE. Commonly used
      psychometric tests include trailmaking tests (number and figure connection tests)
      and Wechsler Adult Intelligence Scale (WAIS) for verbal and performance skills.
      Among the various neuropsychological or psychometric tests, trailmaking tests and
      block design and digit symbol tests from WAIS-performance battery appear to be
      adequate for diagnosis of mHE. Standardized tests including NCT A and B, line
      tracing, serial dotting test and digits-symbol test (PSE syndrome test) validated
      in German patients need validation in other populations. Both exogenous evoked
      potentials and endogenous event-related potentials have been used extensively in
      diagnosing mHE. However, the event-related P300 wave is the most consistent wave
      and can be considered the electrophysiological counterpart of the psychometric
      tests as both involve active use of the cognitive faculties. Other new tests like
      the critical flicker frequency have shown some promise but further studies are
      required to substantiate initial results. In conclusion, a combination of at
      least two psychometric (trailmaking tests [NCT or FCT], block design and digit
      symbol test) and neurophysiological tests (P300 auditory evoked potential or
      electroencephalography with mean dominant frequency) appears to be optimal in
      detecting mHE.

PMID- 15025254
TI  - Minimal hepatic encephalopathy: natural history, impact on daily functioning, and
      role of treatment.
AB  - Cirrhosis of liver is often complicated by minimal hepatic encephalopathy (mHE),
      which is detected by neuropsychiatric and neurophysiological tests. mHE develops
      more commonly in cirrhotics with severe liver disease and in those with
      esophageal and gastric varices. On follow up, these patients more often develop
      overt encephalopathy as compared to cirrhotics without mHE. mHE may affect daily
      activities like sleep, driving ability, alertness, social interaction, and
      communication. It is probably also an independent predictor of survival. The most
      practical treatment strategy for mHE has not been established; however, it can be
      treated as effectively as overt encephalopathy with similar agents. Treatment
      improves mHE in terms of psychometric tests, but improvement in daily functioning
      has not been well documented.

PMID- 15025255
TI  - Magnetic resonance imaging and spectroscopy in hepatic encephalopathy.
AB  - Hepatic encephalopathy (HE) is a potentially reversible neuropsychiatric syndrome
      secondary to cirrhosis and other severe liver diseases. Magnetic resonance
      imaging (MRI) and MR spectroscopy (MRS) have been explored to provide new insight
      into the pathophysiology, diagnosis and treatment of HE. MRI shows brain atrophy
      especially in the frontal region. Globus pallidus, putamen and portions of the
      internal capsule appear hyperintense on T1-weighted images; this is likely to be
      due to deposition of manganese as a result of portosystemic shunting and liver
      dysfunction. MRS permits the detection and quantification of certain brain
      metabolites in vivo. There is decrease in myoinositol and choline concentrations
      and increase in glutamine concentrations. There is no change in n-acetyl
      aspartate. Depletion of myoinositol is the most sensitive and specific
      spectroscopic marker in HE. Its loss is most likely a compensatory mechanism for
      the accumulation of glutamine. In conclusion, MRI and MRS examine different
      aspects of hepatocerebral disease.

PMID- 15025256
TI  - Role of gut bacteria in the therapy of hepatic encephalopathy with lactulose and
      antibiotics.
AB  - The pathogenesis of hepatic encephalopathy is mediated to a large extent by
      ammonia, mainly derived from the gut. Both bacterial and nonbacterial mechanisms
      of ammoniagenesis have been shown, but ammoniagenesis mediated by colonic
      bacteria is probably of clinical significance. The therapy of hepatic
      encephalopathy is based on the putative etiological agents, including ammonia.
      Non-absorbable disaccharides and antibiotics have been shown to modify gut flora
      and decrease blood ammonia levels, but these are not necessarily related
      (indicating nonbacterial sources of ammonia, which may also be decreased by these
      compounds). A combination of these has been suggested but not consistently
      demonstrated to be beneficial in hepatic encephalopathy. Sodium benzoate is an
      alternate method of nonbacterial, non-hepatic metabolic binding pathway for
      ammonia disposal. Other mechanisms of gut bacterial modification may be achieved
      albeit transiently by the use of resistant bacteria like Enterococcus faecium.

PMID- 15025257
TI  - Management of agitation and convulsions in hepatic encephalopathy.
AB  - Hepatic encephalopathy represents a reversible decrease in neurological function
      caused by liver disease. Overall incidence of seizures in hepatic encephalopathy
      varies between 2% and 33%. Non-convulsive status epilepticus may be particularly
      common in these patients. Psychiatric disturbances manifest as agitation,
      personality change, delusions, etc. Aims of seizure management include treatment
      of basic disease, correction of precipitant factors, imaging of head, and choice
      of a pharmacologically safe agent. It is important to consider non-convulsive
      status epilepticus and rule it out by an EEG. Absolute data for safety profile of
      drugs in liver disease is still not clear, as changes of pharmacokinetics make
      choice of drugs difficult. Free drug concentrations may be higher, making plasma
      concentration monitoring essential in such circumstances. A single seizure may
      not require therapy. However when started, antiepileptic drugs are usually
      discontinued early. Drugs with sedative effects are best avoided because of a
      risk of precipitating coma. Phenytoin and gabapentin are relatively preferred
      drugs; however, monitoring of drug levels is desirable. Management of agitation
      includes physical restraint and medication. Benzodiazepines are best avoided.
      Haloperidol is a safer choice in the presence of liver disease. Overall
      management of neuropsychiatric state aims at management of underlying pathology,
      the resolution of which leads to improvement in the clinical symptomatology.

PMID- 15025258
TI  - Brain edema in acute liver failure.
AB  - Brain edema and consequent increase in intracranial pressure is a major
      complication of acute liver failure (ALF) and is a major cause of death in this
      condition. Rapid accumulation of ammonia in brain has been implicated in the
      pathogenesis of brain edema in ALF. Increased brain ammonia may cause brain
      swelling via the osmotic effects of an increase in astrocytic glutamine
      concentration or by inhibition of glutamate removal from brain extracellular
      space. Acute liver failure results in altered expression of several genes in the
      brain, some of which code for proteins involved in central nervous system
      function such as the glutamate transporter GLT-1, the astrocytic structural
      protein, glial fibrillary acidic protein, and the water channel protein,
      aquaporin IV. Loss of expression of GLT-1 results in increased extracellular
      brain glutamate. Therapeutic measures currently used to prevent and treat brain
      edema in acute liver failure include mannitol; strategies aimed at lowering of
      gut ammonia production are generally ineffective. Studies in experimental animals
      suggest that mild hypothermia or the use of L-ornithine-L-aspartate may be useful
      in the prevention of brain edema in these patients.

PMID- 15025259
TI  - Raised intracranial pressure in hepatic encephalopathy.
AB  - Intracranial hypertension secondary to cerebral edema is the cause of death in
      50%-80% of patients with fulminant hepatic failure (FHF). This is rarely seen in
      chronic hepatic failure. The genesis of cerebral edema in FHF is poorly
      understood. The grade of encephalopathy and coagulopathy are the most important
      predictors of outcome in FHF. However, it is important to emphasize that
      intracranial pressure (ICP) may not reflect clinical course. Decerebrate
      posturing may be seen with ICP recording of 16 mmHg, while a quarter of the
      patients may have brain damage without clinical signs of raised ICP. ICP
      monitoring is therefore vital. The gold standard for ICP monitoring is the
      intraventricular method. Non-invasive methods like computerized tomography scan
      and magnetic resonance imaging have poor correlation with ICP. Other methods like
      transcranial Doppler and jugular venous oximetry measurement of brain metabolites
      need evaluation. The main indications for ICP monitoring in FHF are (a) patients
      in grade III or IV encephalopathy and (b) patients undergoing liver
      transplantation. Generally, patients with an ICP >40 mmHg with cerebral perfusion
      pressure <50 mmHg for over 2 hours are poor subjects for liver transplant.

PMID- 15025260
TI  - Acute liver failure: prognostic markers.
AB  - Acute liver failure (ALF) is defined as liver failure occurring within one month
      of the occurrence of jaundice. The disease has a grim prognosis, with a mortality
      of 65% to 85%. The management of ALF has till recently been conservative, and
      newer therapeutic modalities like bioartificial liver, hepatocyte transplant, and
      extracorporeal liver assist devices have not yet been proven to be successful.
      Liver transplant has changed the gloomy outlook of the disease, and post
      transplant survival rates of 60%-70% have been reported from most centers.
      However liver transplant is expensive, necessitates life-long immunosupression,
      and is limited by a global shortage of available organs. It is thus necessary to
      select patients who are at greatest risk of death for liver transplantation.
      Prognostic criteria are based primarily either on clinical and laboratory
      (coagulation tests, serum bilirubin) parameters, or on other parameters like
      liver volume. Prognostic criteria have been developed both from the East and the
      West; these are essentially similar except that the Western criteria take into
      account etiology (drug overdose being the main cause of ALF there) as well as
      jaundice-encephalopathy interval as factors for prognostication. The King's
      College criteria were one of the first prognostic systems; it has two parts for
      both paracetamol as well as non paracetamol ALF. The criteria from our institute
      found prothrombin time >25 s, serum bilirubin >15 mg/dL, age >40 years, and
      cerebral edema to be bad prognostic markers. Criteria from the PGIMER, Chandigarh
      found age >50 years, raised intracranial pressure, prothrombin time >100 s, and
      onset of HE more than seven days after the jaundice as poor prognostic markers.
      All these clinical criteria have similar sensitivity and specificity.

PMID- 15025261
TI  - Bioartificial liver support for fulminant hepatic failure.
AB  - Mortality from fulminant hepatic failure (FHF) is high (50%-80%), although
      survivors have absolutely normal liver function. The only treatment option that
      is curative is liver transplantation. However, because of shortage of cadaveric
      organ donors and/or delay in their availability, only 10% of FHF patients
      ultimately receive a transplant. This has led to development of artificial liver
      support systems with an idea to bridge the time to transplantation and/or
      recovery from FHF. Initial support systems were based on the principles of
      hemodialysis, hemofiltration, plasma-exchange, and hemoperfusion through
      adsorbent media (e.g., charcoal). However, lack of clinical efficacy, problems of
      bioincompatibility and fear of loss of circulating hepatocyte-regeneration
      factors led to the search for alternate strategies. With the successful long-term
      propagation and culturing of human and pig hepatocytes, and the development of
      adequate biocompatible microcarrier modules, it is now possible to achieve
      sufficient density of hepatocytes per unit volume to develop bioartificial liver
      systems. These can be implanted transperitoneally but are subject to early
      destruction because of inadequate vascularization and immune attack from the
      host. Thus the major thrust is now to develop bioreactors, e.g., Extracorporeal
      Liver Assist Device (ELAD), Bioartificial Liver (BAL), etc. These contain human
      or pig hepatocytes implanted on hollow-fiber ultrafiltration cartridges. The
      patient's blood or plasma circulates through these bioreactors and after
      clearance of toxic compounds (via ultrafiltration and metabolism in hepatocytes)
      and addition of synthesized products, is returned to the patient. This article
      reviews the genesis, the pros and cons, and the clinical experience of BAL
      support for FHF.

PMID- 15025262
TI  - Results of liver transplantation in fulminant hepatic failure.
AB  - Liver transplantation has dramatically changed the management of patients with
      fulminant hepatic failure and subacute hepatic failure. A wide range of survival
      rates (55% to 90%) reported from different centers performing liver
      transplantation for fulminant hepatic failure reflects variations in patient
      selection and the centers' experience. Results of transplantation appear to be
      improving, with survival rates approaching 80% at 1 year in some series. The
      improved results are attributed to vigorous perioperative management, using
      intracranial pressure monitoring and continuous arteriovenous hemofiltration when
      required, early listing of patients with organ-sharing network, and exclusion of
      patients who are unlikely to recover neurologically after successful
      transplantation. Use of piggyback hepatectomy to minimize hemodynamic alterations
      during surgery has also contributed to better results in critically ill patients.
      Patients with acetaminophen toxicity have a more favorable outcome than those
      with viral hepatitis or non-acetaminophen drug hepatotoxicity. Because of limited
      availability of cadaveric organs, emergency living-related liver transplantation,
      use of ABO incompatible and marginal livers need consideration. Auxiliary liver
      transplantation is desirable for those who have a chance of spontaneous recovery,
      thus obviating life-long immunosuppression after recovery of the native liver.

PMID- 15025263
TI  - Hepatic encephalopathy in pregnancy.
AB  - Hepatic encephalopathy in pregnancy may be related to a wide variety of acute and
      chronic liver diseases, including acute viral hepatitis, acute fatty liver of
      pregnancy, pre-eclampsia-related liver injury, etc. Of these, hepatitis E virus
      infection is a particularly important cause in those developing countries where
      this infection is endemic. Etiological diagnosis can be made based on
      epidemiologic, clinical and laboratory findings. Treatment is usually similar to
      that of hepatic encephalopathy in the absence of pregnancy. Patients with acute
      fatty liver of pregnancy and pre-eclampsia-related liver injury may benefit from
      termination of pregnancy; the role of this treatment modality among patients with
      viral hepatitis has not been studied.

PMID- 15025264
TI  - [What are the therapeutic hopes for stem cell in neurological diseases?].
AB  - For several years, in Parkinson's disease patients, immature neuroblasts grafts
      could be realized. Those immature cells come from mesencephalic regions of six to
      ten weeks-old embryos. Given several technical problems, clinical outcome of the
      patients is not favourable and moreover, it appears that the cell source is very
      limited. That's the reason why the use of embryonic or somatic stem cells could
      be promising. Stem cells are able to self-renew, and could differentiate into
      several cell types. In this lecture, the author reviews the biological properties
      of different stem cells types in order to be used in cerebral graft in several
      neurological diseases. Given their recently unravelled phenotypic plasticity,
      somatic stem cells could be the best candidate for such a clinical use for
      autografts.

PMID- 15025265
TI  - The biology and epidemiology of variant Creutzfeldt-Jakob disease.

PMID- 15025266
TI  - [Cerebral vasospasm: molecular analysis].
AB  - Calcium concentration modifications in endothelial and smooth muscle cells,
      represent a key element in the pathogenesis of cerebral basilar artery vasospasm,
      induced by subarachnoid hemorrhage (SAH). These calcium concentration
      modifications induce, in turn activation of calcium-dependent PKCS. However,
      calcium antagonists, including nimodipine, exhibit weak clinical efficiency in
      this disease. Our data show that SAH-induced-cerebral vasospasm in a rat
      experimental model is accompanied not only by marked concentration modifications
      of several calcium-dependent PKCS, but also by marked concentration modifications
      of calcium-independent PKCS. Our data also evidence the fact that another group
      of calcium-dependent proteins, i.e. S100 proteins, exhibit marked modifications
      in their concentrations in the above mentioned rat model of cerebral vsospasm.
      All these data suggest that S100 proteins could represent a link by which calcium
      activates calcium-dependent as well as calcium-independent PKCS.

PMID- 15025268
TI  - [Demonstration and immunologic effect of an infection of the human thymus by the
      diabetogenic human Coxsackievirus B4].
AB  - Thymus exerts a prominent role in the establishment os central T-cell tolerance,
      as well as in the development of self major histocompatibility complex (MHC)
      restricted T lymphocytes. Like others autoimmune diseases, type 1 diabetes
      emergence implies central or peripheric self tolerance breakdown. Environmental
      factors, especially enterovirus infections, are supposed to be involved in
      diabetes pathophysiology. Epidemiological studies have highlighted a frequent
      association between enterovirus Coxsackievirus B4 (CVB4) and type 1 diabetes. The
      aim of our work was to study whether a thymus infection by CVB4 could induce
      modifications of thymic function. In primary cultures of thymic epithelial cells
      (TEC), we detected viral proteins, positive- and negative- strand RNA, and
      infectious virus in the supernatants, meaning that TEC cultures were susceptible
      to CVB4 infection and that CVB4 induced a persistent infection in those cells.
      CVB4 also modulated TEC proliferation and cytokine, such as IL-6, GM-CSF and LIF
      secretions. Studies using fetal organ thymus culture (FTOC) showed that CVB4
      induced a marked and progressive thymocytes depletion, in particular double
      positive (DP) and CD4+ cells. CVB4 replicated in those subpopulations, indeed
      positive- and negative-atrand RNA were detected. CVB4 also upregulated MHC class
      I expression on DP thymocytes. The upregulation of MHC expression required viral
      infection in DP cells. IL-6 and GM-CSF secretions were also involved in this
      phenomenom, but IFN-alpha was shown not to be involved. Taken together, our
      results showed the susceptibility of the human thymus to CVB4 infection, and an
      important thymic dysfuntion due to this infection. Our work is a novel approach
      in the understanding of the mechanisms of CVB4-induced type 1 diabetes.

PMID- 15025267
TI  - [What are the realistic hopes for remyelinization in the central nervous
      system?].
AB  - Up to now, there is no therapy in order to stimulate a remyelination in the adult
      central nervous system. So, the study the ontogenesis of oligodendrocytes at the
      cellular and molecular level could provide cues in order to design such a
      treatment that will be efficient to remyelinate patients after a multiple
      sclerosis relapse. In our work, we demonstrated that both neurotransmitters
      acting trough ionotropic receptors, expressed by oligodendrocytes precursors and
      some members of the neuregulin growth factors family, could modulate the
      proliferation and the differentiation of oligodendrocytes progenitors.
      Furthermore, we demonstrated that the graft of neural stem cells in experimental
      demyelinated lesion in adult animals is responsible for an efficient
      remyelination.

PMID- 15025269
TI  - [New studies of the physiopathologic mechanisms of disseminated lupus
      erythematosus].
AB  - Recent work about the role of cytokines in the pathogenesis of systemic lupus has
      shed new light on the important contribution of IL-10 and BAFF, to the production
      of pathogenic autoantibodies and the development of disease. Together with the
      advances in the biotechnologies, these contributions will allow to develop novel
      therapeutic approaches targeting the immune system of lupus patients.

PMID- 15025270
TI  - [Persistent neonatal hyperinsulinism: new pathological findings which clarify the
      physiopathology of the syndrome and direct the therapeutic approach].
AB  - Our morphological studies of the pancreas of patients suffering from neonatal
      persistent hyperinsulinemic hypoglycemia of infancy (PHHI), enabled us to
      discover the existence of two different forms of the syndrome, focal and diffuse.
      We defined precise morphological criteria allowing their differential diagnosis,
      even for intraoperative examination of frozen sections of small biopsies from the
      various areas of the pancreas. Together with selective venous catheterization,
      morphology can thus guide the surgeon when deciding between partial
      pancreatectomy in case of focal PHHI. and near-total pancreatectomy in case of
      diffuse PHHI. Among neonates affected by PHHI, about 40% suffer from the focal
      form of the syndrome and have clearly a better prognosis than those suffering
      from the diffuse form, in that they do not need a subtotal pancreatectomy with
      its complications. The second part of our work was devoted to analyze the
      pathogenesis of PHHI. We demonstrated that diffuse PHHI is not the result of an
      abnormal proliferation of b cells, and thus that nesidioblastosis is not the
      underlying pathological condition of the disease. By contrast, in total
      concordance with its genetic background, the focal PHHI lesion has a very high
      proliferation index, not observed in insulinomas, the other pancreatic endocrine
      lesion responsible for hyperinsulinemia. Comparing the focal lesion in focal PHHI
      with insulinomas, we found that not only their morphological features are
      different, but also their functional characteristics studied by morphological and
      quantitative approaches. However, some insulinomas share similarities in their
      molecular background with focal PHHI. Finally, we recently identified an atypical
      form of PHHI, characterized by a mosaicism of islets. This new form is currently
      under investigation.

PMID- 15025271
TI  - [Important antitumoral immunity and a favorable clinical outcome in two patients
      receiving an autologous vaccine].
AB  - The anti-tumor immune response was studied on two patients. The first patient is
      still alive, fifteen years after the diagnosis of a cutaneous melanoma and this,
      despite unique recurrent metastases. She receives regularly an autologous
      vaccine. The second patient is alive ten years after the diagnosis of a lung
      cancer, and benefit also of an autologous vaccine. The immune response of these
      two patients is mostly directed against a strictly tumor-specific antigen. These
      important responses are easily detectable in their blood using a new tool:
      soluble HLA-peptides complexes. Each time, there is an oligoclonal response where
      one clone is largely dominant. Moreover, there are some elements suggesting that
      these responses may have influenced the favorable clinical evolution of these two
      patients.

PMID- 15025272
TI  - [Regulation by ATP of a phospholipase D in the ductal cells of the submaxillary
      gland].
AB  - ATP increased the PLD activity of rat submandibular ductal cells in a
      concentration-dependent and calcium-sensitive manner. Among ATP analogs, BZATP
      and ATPgammaS were the only ones able to stimulate the PLD activity. ATP and BZ
      ATP also activated PLD in control mice, but not in mice lacking the P2X7
      receptors. Oxidized ATP, Coomassie blue, NiCl2 and MgCl2 inhibited the response
      to ATP. PLD stimulation by ATP was inhibited by calphostin C and chelerythrine,
      two PKC inhibitors. The PLD stimulation by BZ-ATP and TPA, a phorbol ester which
      activates PKC, were not additive. Purinergic agonists did not increase the
      phosphorylation of proteins on tyrosyl residues. We can conclude that the
      activation of P2X7 receptors in rat submandibular glands ductal cells, is coupled
      to the activation of PLD. This activation is partly mediated by PKC and is not
      secondary to the activation of a tyrosine kinase.

PMID- 15025273
TI  - [Autologous stem cell transplantation in addition to cardiomyoplasty in a porcine
      model of ischemic cardiomyopathy].
AB  - Autologuous stem cell transplantation within regional infarcted or ischemic
      myocardium is currently a focus of experimental research world-wide, and could
      provide a unique way to ensure myocardial functional recovery. In order to
      benefit from immediate access to bone marrow stromal cells at the time of
      myocardial injury, and thus avoid the delay rendered necessary by autologuous
      harvesting and clonal expansion, the use of allogeneic stem cell could be of
      major interest. This experimental work is based on a unique mini-swine model in
      which the histocompatibility antigens are known, and perfectly controlled,
      through inbreeding and investigate the survival and the induction of an immune
      tolerance to allogeneic stem cells injected into the infarcted myocardium with
      the use of transient immunosuppression (12 days).

PMID- 15025274
TI  - Pauci-immune crescentic glomerulonephritis.
AB  - Pauci-immune crescentic glomerulonephritis (PICGN) is a rapidly progressive
      condition leading to renal failure within days or weeks and is potentially life
      threatening. Majority of these patients have clinical or pathological evidence of
      systemic vasculitis. PICGN may occur as renal limited disease or as a component
      of systemic necrotising small vessel vasculitis. Majority of these cases are
      attributed to Wegener's granulomatosis (WG), microscopic polyangitis (MPA) or
      Churg Strauss syndrome (CSS). Renal involvement is encountered in 80 to 90% cases
      of WG and MPA and in about 45% cases of CSS. Approximately 80 to 90% patients of
      untreated WG or MPA and about 60% cases of CSS are positive for anti-neutrophilic
      cytoplasmic antibodies (ANCA). These diseases are therefore also called as ANCA
      associated vasculitis. Serial ANCA measurements provide useful information on
      disease activity. Renal transplant should be avoided in patients with clinical
      evidence of active vasculitis. Even though the treatment with oral
      corticosteroids and i.v. or oral cyclophosphamide results in complete long term
      remission in 70 to 75% patients, relapse occurs in >25% cases within a mean
      period of 18 months after cessation of therapy. Prognosis of untreated ANCA
      associated PICGN is poor.

PMID- 15025275
TI  - Transmission of filarial infection through blood transfusion.
AB  - Microfilariae can be transmitted by blood transfusion and they may be circulated
      in the recipient's blood but they do not develop into adult worms. Mortality
      associated with transfusion associated filarial infection is not documented but
      it may give rise to morbidity in transfusion recipients in terms of allergic
      reaction. The present study was carried out to investigate the association of
      post transfusion reactions and filarial infections in an endemic area. About
      11,752 transfusion recipients were followed up and in 15 months period, 47 (0.4%)
      post transfusion reactions (PTR) were reported. Routine investigations for post
      transfusion reaction were carried out in all 47 patients and their respective
      blood donor. Moreover, blood culture, microfilaria detection by concentration
      technique, filarial antibody and antigen detection (both by ELISA) were done in
      all subjects. Out of 47 patients showing post transfusion reaction, 29 (61.7%)
      patients developed allergic reaction. Eighteen (38.3%) patients having allergic
      reaction did not have previous history of blood transfusion and 14 (29.8%) of
      them received transfusion from blood donors who was either positive for
      microfilaria, filarial antigen or antibody. Microfilaremia was demonstrated in 4
      (8.5%) patients and 5 (10.6%) blood donors. Microfilaria was concurrently present
      in 2 patients and their respective donors. Filarial antibody was detected in 27
      (56.5%) patients and 26 (55.3%) blood donors but microfilaria was detected in 3
      (6.4%) and 4 (8.5%) subjects, respectively. Antigen detection test correlated
      with microfileraemic state of subjects. The result shows that transfusion
      associated filarial infection may be a probable cause for transfusion-associated
      morbidity in endemic areas. In 14 (29.8%) patients having allergic reactions, the
      probable cause was transfusion-associated filarial infection. Filarial antigen
      detection test was found to be more useful in detecting infections. Blood donors
      with active history of filarial infection should be deferred from donating blood.
      Filarial antigen detection test may be employed as screening test for blood
      donors, if possible.

PMID- 15025276
TI  - Study of nucleolar organizer regions (NORs) in lesions of gallbladder.
AB  - Tissue sections from 100 specimens of gallbladder including 40 cases of chronic
      cholecystitis, 30 cases of epithelial hyperplasia and 30 cases of well,
      moderately and poorly differentiated adenocarcinoma of gallbladder were studied
      for argyrophillic nucleolar organizer regions (AgNORs). The arithmetic mean +/-
      S.D. were calculated for each category. This showed NOR counts of chronic
      cholecystitis--(1.89+/-0.96), epithelial hyperplasia--(3.99+/-1.03), well
      differentiated adenocarcinoma (WDCA)--(7.04+/-1.34), moderately differentiated
      adenocarcinoma (MDCA)--(7.52+/-0.97) and poorly differentiated adenocarcinoma
      (PDCA)--(8.37+/-1.27). The study revealed increasing number of AgNORS from cases
      of chronic cholecystitis to epithelial hyperplasia to carcinoma gallbladder, but
      a considerable overlap in AgNOR counts of individual cases was observed
      suggesting that though AgNOR count cannot act as a specific diagnostic parameter
      for diagnosis of early carcinoma & dysplasia in isolated cases, they may prove to
      be a good adjunct to presently available imaging techniques and cytology.

PMID- 15025277
TI  - Red cell indices for distinguishing macrocytosis of aplastic anaemia and
      megaloblastic anaemia.
AB  - Megaloblastic anaemia and aplastic anaemia are important causes of pancytopenia
      in India. Since both may have presence of macrocytes, peripheral smear
      examination alone may pose a difficulty in distinction between the two in the
      absence of macro-ovalocytes and hypersegmented neutrophils. The present study was
      conducted to evaluate the role of red cell indices in differentiation between
      macrocytosis of aplastic anaemia and megaloblastic anaemia. Haemogram from 25
      cases each of biopsy proven megaloblastic anaemia and aplastic anaemia were
      reviewed. It was observed that MCV was greater than 97 fl in 15 cases of aplastic
      anemia (mean MCV 109.7 fl), and 25 cases of megaloblastic anaemia (mean MCV 113.2
      fl). Hb, MCV & MCHC were comparable in the two groups. However, mean RDW in
      megaloblastic anaemia (mean 87.7 fl) was significantly higher than those in
      aplastic anaemia (mean 71.4 fl). The difference in RDW of patients with
      megaloblastic anaemia and aplastic anaemia was statistically significant. We
      conclude that RDW can be of help to differentiate between the two conditions.

PMID- 15025278
TI  - Clinicopathological study of thymomas--correlation of histologic subtype to
      myasthenia gravis and prognosis.
AB  - Thymoma is the most common primary tumor of anterior superior mediastinum. Sixty
      cases of thymomas over a 12 year period were analysed and the histologic subtype,
      according to Marino and Muller-Hermilink, classification was correlated with
      presence or absence of myasthenia gravis (MG) and capsular invasion. Thirty four
      patients had myasthenia gravis associated with thymoma and there was one case of
      pure red cell aplasia. There were 3 (1) predominantly cortical, 28 (20) cortical,
      12 (9) mixed, 16 (4) medullary thymomas and 1 (0) thymic carcinoma (Figures in
      parenthesis indicate number of cases associated with MG). Capsular invasion was
      seen in 25 cases. Association with myasthenia gravis and capsular invasion were
      seen predominantly in cortical and mixed thymomas which were also associated with
      aggressive behaviour.

PMID- 15025279
TI  - Bone marrow involvement by metastatic solid tumors.
AB  - A five year experience with bone marrow aspirates and biopsies positive for
      metastatic carcinoma is reviewed. Marrow examination in 25 cases detected
      metastasis. The common primary tumors with marrow metastasis were neuroblastoma,
      carcinoma breast and prostate. In 56% cases primary site could not be ascertained
      from bone marrow as metastatic tumor showed undifferentiated morphology. The
      study demonstrates the usefulness of combining trephine biopsy with aspirate
      examination for increased detection of bone marrow metastasis.

PMID- 15025280
TI  - Triple approach method for screening of contralateral breast in treated cases of
      breast cancer.
AB  - A prospective study of 50 cases of treated breast cancer was undertaken to
      evaluate the status of the contralateral breast by combined physical examination,
      mammographic screening and mammographically directed FNAB (triple approach
      method). This study was done to assess the frequency of synchronous (cancers that
      were simultaneously diagnosed with a tumour in ipsilateral breast) or
      metachronous (those that occurred in contralateral breast subsequent to first
      cancer and not detected at the time of treatment of first cancer) malignancy
      and/or presence of preneoplastic lesions in the contralateral breast. Six percent
      cases had palpable lump in contralateral breast (synchronous or metachronous),
      10% of the cases showed mammographic abnormalities. Mammographically directed
      FNAB showed atypical/suspicious smears in 8% cases and malignancy in 2% cases, of
      which infiltrating duct carcinoma was the most frequent. In high-risk group
      patients triple approach method proved to be extremely important screening
      procedure for early detection of abnormalities in contralateral breast and helps
      in significantly reducing the morbidity and mortality associated with it.

PMID- 15025281
TI  - HPLC--how necessary is it for haemoglobinopathy diagnosis in India?
AB  - Cation exchange high performance liquid chromatography (HPLC) is emerging as the
      method of choice for the initial screening of thalassemias and
      haemoglobinopathies and quantification of Haemoglobins (Hbs) like HbA, HbA2 and
      HbF. Since it is expensive, the present study was conducted to evaluate the need
      for HPLC in Indian laboratories and identify situations where it would be
      imperative. Eighty three patients suspected to have thalassemia and
      haemoglobinopathies were analysed. Both HPLC and alkaline gel electrophoresis
      detected 14 cases of HbE syndrome and 14 cases of HbS syndrome. However of the 14
      cases diagnosed as HbD syndrome by alkaline electrophoresis, eight cases were
      diagnosed as Hb Q India, 1 case as HbD Iran and 5 cases of HbD Punjab on HPLC.
      Thirty-one cases were detected to have beta heterozygous thalassemia based on the
      high HbA2 levels (>3.9%) and eight cases were diagnosed as beta homozygous
      thalassemia by both HPLC and gel electrophoresis. One of them had an unknown Hb
      migrating in F-A region. Her mother also had same unknown Hb variant. In view of
      electrophoretic migration and retention time (RT) on HPLC, possibility of HbG-San
      Jose was considered. HPLC being an automated instrument is highly sensitive and
      specific, has high resolution and helps in quantification of various
      haemoglobins. However in a developing country like India where economical factors
      play a major role in planning for management of patients, the role of HPLC is
      limited.

PMID- 15025282
TI  - Telomerase and telomere length in normal and malignant human endometrium as
      prognostic markers.
AB  - Telomerase activation and telomere length maintainence are thought to be
      essential for cellular immortality and oncogenesis. Normal human endometrium
      expresses significant telomerase activity in a menstrual phase dependent manner.
      In this report, we have evaluated telomerase activity and telomere length in post
      menopausal endometrial hyperplasias and endometrial cancers to study their
      usefulness as prognostic markers. Telomerase activity was measured by the TRAP
      assay (Boehringer Mannheim, Germany) and telomere restriction fragment (trf) by
      the telomere length assay kit (BD Pharmingen). Proliferation markers PCNA and
      Bcl2 were studied by immunohistochemistry. Senescence associated Ogal activity
      was studied simultaneously and correlated with the above markers. Strong
      telomerase activity was observed in the proliferative phase of the normal
      endometrium, endometrial cancers and post-menopausal endometrial hyperplasias
      compared to normal, secretory and resting phases of the endometrium. PCNA and
      Bcl2 showed high positivity in telomerase positive cases. Telomerase activity was
      inversely proportional to Ogal activity. Mean trf lengths became shortened as the
      normal tissues underwent neoplastic changes. Our study suggests that high
      telomerase activity and short telomere lengths could be useful prognostic markers
      in human endometrium.

PMID- 15025283
TI  - Changing trends in malaria--a decade's experience at a referral hospital.
AB  - A 10 year study of malaria during 1989-98 recorded an increase in the incidence
      of malaria from 0.22 in 1989 to 1.3 in 1996 following which it has reached a
      plateau. The cases were chiefly from Karnataka, Andhra Pradesh and Tamil nadu.
      The P. falciparum infection and mixed infections (P. falciparum and vivax) were
      found to be on the rise. Peak of malaria cases were recorded in the months of
      June-July and in Oct-Nov coinciding with the rains showing a seasonal pattern.
      The common haematological findings were anemia, thrombocytopenia, pancytopenia
      and leucopenia. Complications noted in our study were haemolysis, renal failure,
      hepatopathy and cerebral malaria. The unusual cases were congenital malaria,
      malaria with sickle cell anemia, AIHA and G-6PD deficiency. Mortality due to
      cerebral malaria was found to be 13.5%.

PMID- 15025284
TI  - Ki-67 labelling as a proliferation marker in pre-invasive squamous epithelial
      lesions of cervix.
AB  - Study was conducted to evaluate proliferation in squamous intraepithelial lesions
      of cervix. 36 cases of cervical biopsies were chosen including unremarkable
      cervix, basal cell hyperplasia, cervical intraepithelial neoplasia (CIN I, CIN
      II, CIN III). Ki-67 immunostaining was performed by peroxidase-antiperoxidase
      method. Ki-67 labelling index in basal and parabasal layers of cervix showed
      progressive rise with increasing grade of lesion but may not be helpful in
      classification of individual lesion. Also extent of staining from the basement
      membrane increases with increasing grade. High basal Ki-67 reactivity might be of
      greater biological significance than surface differentiation.

PMID- 15025285
TI  - Pure red cell aplasia--report of 11 cases from eastern Nepal.
AB  - There were eleven cases of pure red cell aplasia diagnosed over a period of 2
      years (January 2000-December 2001). All the patients had anemia with pallor and
      weakness being the presenting complaints. Hematological profile depicted
      normocytic normochromic anemia, reticulocytopenia and marked paucity of erythroid
      precursors on bone marrow aspiration and biopsy studies. In the present study,
      one case was of congenital pure red cell aplasia, in one other case of pyrexia of
      unknown origin, no definitive diagnosis could be made. Other associated diseases
      seen with pure red cell aplasia were thymoma, septicemia, protein energy
      malnutrition, non-Hodgkin's lymphoma, juvenile rheumatoid arthritis, acute
      myeloid leukemia, tuberculosis and hepatitis C. The association of pure red cell
      aplasia with haematologic malignancies is rare. There are very few case reports
      on pure red cell aplasia with hepatitis C.

PMID- 15025286
TI  - Cytomorphology of polymorphous low grade adenocarcinoma--diagnosis and pitfalls.
AB  - Polymorphous Low Grade Adenocarcinoma (PLGA) arises characteristically in the
      minor salivary glands. Histological diagnosis of this tumour has improved
      following awareness and well characterized histologic features. However cytologic
      diagnosis is difficult. Ten cases of PLGA were identified on review of 61 cases
      of palatal salivary gland tumours aspirated over a 17 year period. Seven of these
      had been diagnosed as salivary gland tumours but had not been further
      characterized, while two cases had been diagnosed as adenoid cystic carcinoma
      initially. In only one case a differential diagnosis between pleomorphic adenoma
      and PLGA had been considered. Cytologic diagnosis of PLGA is difficult but
      possible if an attempt is made to identify specific cytologic criteria.

PMID- 15025287
TI  - Metastatic tumours of the ovary: a clinico-pathological study.
AB  - The ovary is a frequent site of metastasis. However the incidence of metastatic
      tumours to the ovary is not exactly known. The reported incidence in the
      literature varies from 2.95 to 27.8%. The gastrointestinal tract (GIT) and the
      breast have been reported to be the frequent primary sites of the metastatic
      deposits in the ovary. The aim of this study was to determine the incidence of
      metastatic ovarian tumours and analyse their detailed morphologic features. All
      the metastatic ovarian neoplasms diagnosed in the Department of Cytology and
      Gynaecologic Pathology, Post Graduate Institute of Medical Education and
      Research, Chandigarh from 1996 to 2000 were included in the study. Nineteen
      metastatic tumours out of a total of 363 ovarian neoplasms (5%) were identified.
      The patients frequently presented with abdominal distension and mass. The age
      ranged from 17 to 75 years. The primary site was unknown in ten cases. Uterus was
      the most common site (4 cases) followed by GIT (3 cases). Six Krukenberg's
      tumours were identified. In cases simulating the primary ovarian tumours, the
      following features were helpful to suggest the metastatic deposit in the ovary:
      bilaterality, no significant ovarian enlargement, vascular emboli, a Krukenberg's
      morphology, no omental deposits and the absence of transition from benign to
      malignant epithelium.

PMID- 15025288
TI  - Needle necropsy in AIDS.
AB  - The value of autopsy in understanding the natural course of any disease is beyond
      any argument. The reluctance of pathologists to perform autopsy in HIV infected
      cadavers is justified due to the risks involved to the prosector and the morgue
      attendants. A relative low risk needle necropsy protocol is proposed using fine
      needle aspiration cytology, tru-cut biopsies and microbiological examination.
      Diagnosis could be offered in all the forty-four needle necropsies performed.
      Disseminated tuberculosis in 18/44 (40.9%) cases, disseminated cryptococcosis in
      12/44 (27.2%) cases, poly-microbial infections in 27.2% cases and non-Hodgkin's
      lymphoma in 9% cases were detected in the study. Infectious agents like
      Histoplasma capsulatum, Isospora belli, tachyzoites of Toxoplasma gondii, Candida
      sp and Cryptococcus sp could be demonstrated in the samples obtained in the
      study. Lack of material for study of gross pathology, inaccessibility of deep
      seated lesions and risk of needle stick injury to the prosector though low are
      the limitations of this procedure.

PMID- 15025289
TI  - Study of haemoglobin S percentage and haematological parameters in sickle cell
      trait.
AB  - A total of 101 individuals who showed AS pattern on haemoglobin electrophoresis
      were included in this study and various haematological investigations were
      carried out on them. Of these, 79 cases were grouped as AS patients. Twenty two
      healthy relatives of sickle anemia patients were grouped as AS controls. Twenty
      AA controls were also included in this study. Haemoglobin S (HbS) and hemoglobin
      A (HbA) quantitation was carried out. The frequency distribution of HbS
      percentage showed that maximum subjects had HbS levels above 33%. A female
      predominance was seen in subjects of sickle cell trait. Haemoglobin levels and
      total red cell counts of AS patients were found to be significantly lower than
      those of AS controls. Reticulocyte counts and hematocrit values of AS patients
      were found to be significantly higher than AS controls. MCV and MCH values of AS
      patients were found to be significantly lower, but MCHC was not significantly
      altered.

PMID- 15025290
TI  - D-dimer test: diagnostic role in clinical and sub-clinical DIC.
AB  - D-dimer test is used as a diagnosis test for acute disseminated intravascular
      coagulation (DIC). This study was undertaken to find out its sensitivity and
      specificity in the diagnosis of acute DIC and its role in diagnosis of sub
      clinical DIC, as there is limited data available on the subject. Of the 29
      patients of clinically acute DIC, all had positive D-dimer test, and markedly
      prolonged PT, APTT and TT were seen in 24 (83%) of these patients. D-dimer test
      was found to be highly specific but less sensitive for the diagnosis of acute
      DIC. Of the 29 patients predisposed to sub-clinical DIC. D-dimer was positive is
      26 (90%) patients and PT, APTT and TT were mildly prolonged in 11 patients. It is
      suggested that D-dimer positivity for the diagnoses of sub-clinical DIC need to
      be considered with caution and to be supplemented by other coagulation test
      including serial follow up with d-dimer and coagulation tests.

PMID- 15025291
TI  - T-cell rich B-cell lymphoma--a case report.
AB  - T-Cell-Rich B-Cell lymphoma (TCRBCL) is a recently described variant of diffuse
      large B-cell lymphoma characterized by a predominance of reactive T-cells and a
      minority of neoplastic large cells which may resemble the Reed-Sternberg cell or
      its variants. TCRBCL is a notorious mimicker of both lymphocyte predominance
      Hodgkin's disease (LPHD) and peripheral T-cell lymphoma (PTCL).
      Immunohistochemistry is mandatory for a definitive diagnosis. We report a case of
      TCRBCL which was mistaken for HD both on fine needle aspiration cytology and
      histopathology due to the presence of RS like cells. Immunohistochemistry
      resolved the diagnostic dilemma.

PMID- 15025292
TI  - Isolated necrotizing vasculitis of gallbladder: a report of two cases and review
      of literature.
AB  - We report two cases of isolated necrotizing vasculitis of gallbladder without
      evidence of systemic involvement which was histologically indistinguishable from
      classic polyarteritis nodosa (PAN), displaying vascular lesions in different
      stages of progression like those of PAN. The literature has been reviewed in
      order to evaluate the significance and possible aetio-pathogenesis of gallbladder
      (GB) vasculitis. Localized PAN of gallbladder is a rare incidental postoperative
      finding, the serological work-up for autoantibodies may be negative and the
      disease is likely to remain self-limited.

PMID- 15025293
TI  - Leptospirosis--a case report.
AB  - Outbreaks of Leptospirosis have been reported from various parts of India
      including Maharashtra. We report a case of leptospirosis from Wardha District,
      Maharashtra from where the disease has not been reported so far.

PMID- 15025294
TI  - Polymerase chain reaction confirmed Mycoplasma pneumoniae arthritis: a case
      report.
AB  - We report here a case of polyarthritis caused by Mycoplasma pneumoniae in a 30
      years old male who initially triggered suspicion of tuberculosis. Synovial fluid
      subjected to AFB smear, culture and PCR for Mycobacterium tuberculosis along with
      culture for aerobic and anaerobic bacteria by standard methods were negative.
      Synovial fluid was found to be positive by PCR for M. pneumoniae amplifying 543
      bp fragment of P1 gene, however it could not be grown in culture. Specific IgG
      immunoglobulins to M. pneumoniae were also detected in synovial fluid as well as
      serum by ELISA which were further confirmed by IgG immunoblotting showing
      response to M. pneumoniae proteins specially immunodominant protein P1. The
      finding that both M. pneumoniae DNA and specific antibodies to M. pneumoniae are
      present in synovial fluid of the patient suggests that M. pneumoniae play an
      important role in arthritis. To the best of our knowledge, this is the first PCR
      confirmed M. pneumoniae infection in synovial fluid from a case of polyarthritis.

PMID- 15025295
TI  - Pneumatosis cystoides intestinalis: disease or sequel? A case report and review
      of theories regarding pathogenesis.
AB  - Pneumatosis cystoides intestinalis is an uncommon condition characterized by gas
      filled cysts within the bowel wall. We present a case of a 40-year old male who
      complained of abdominal pain and distension. The clinical diagnosis was
      intestinal obstruction and intraoperative impression was intestinal lymphangioma.
      The resected segment of the bowel showed multiple thin walled, tense, air-filled
      cysts on the serosal surface, which collapsed with a popping sound when pricked.
      The histologic diagnosis was pneumatosis cystoides intestinalis. Pneumatosis
      cystoides intestinalis has varied clinical manifestations, course and outcome
      depending on its benign or fulminant form. There are varying theories regarding
      its pathogenesis and it is seen in association with a variety of diseases. Hence
      it should be interpreted with relevance to its entire clinical context, as it may
      not be a disease in itself but a sequel to other conditions.

PMID- 15025296
TI  - Benign stromal fragments in metastases of squamous cell carcinoma in cytology--a
      report of two cases.
AB  - Benign stromal fragments or extracellular matrix can be seen in aspirates of
      invasive carcinomas. Although well documented on histology, this feature is
      rarely observed on fine needle aspirates and can create diagnostic difficulties
      on smears. Only three such cases have been reported so far. We report two more
      cases where stromal fragments were seen in association with invasive squamous
      cell carcinoma (SCC). Two cases of biopsy proved invasive SCC of the cheek and of
      the larynx presented with metastases to the submandibular salivary gland and to
      the cervical lymph node respectively. Aspirates of the metastatic sites showed
      two components: one of SCC and the other benign stroma, both in close
      approximation with one another. Both patients were treated with radiotherapy.
      Biopsy of the metastatic sites was not done. Benign stromal fragments can be
      encountered in aspirates of invasive carcinoma. These may be cellular or myxoid.
      Since such stromal fragments can also be seen in salivary tumours, adnexal
      tumours, fibroadenoma and phylloides tumour, their presence should be interpreted
      in the light of clinical findings of the patient, so that an erroneous diagnosis
      can be avoided.

PMID- 15025297
TI  - Sporotrichosis in Amritsar--a case report.
AB  - A case of cutaneous, lymphatic Sporotrichosis, in a farm labourer, is presented.
      The diagnosis was established by isolating fungus from the lesion. Dimorphic
      nature of the fungus was established in vitro by demonstrating the mycelial phase
      at 25-30 degrees C and yeast phase at 37 degrees C. The patient responded well to
      oral administration of Potassium iodide.

PMID- 15025298
TI  - Naevus lipomatosus superficialis: clinicopathological study of a case.
AB  - Naevus lipomatosus superficialis is an uncommon skin disorder characterized by
      the presence of fat cells in the dermis. It is clinically benign and said to be a
      developmental anomaly. The histological features and the theories of histogenesis
      have been discussed.

PMID- 15025299
TI  - Plasma cell leukaemia with papillary serous cystadenocarcinoma of ovary--a case
      report.
AB  - A rare case of plasma cell leukaemia and papillary serous cystadenacarcinoma of
      ovary in a 58-year-old female is reported.

PMID- 15025300
TI  - Intra-abdominal desmoplastic small cell tumour--a case report.
AB  - Intra-abdominal desmoplastic small cell tumour is a rare malignant neoplasm of
      childhood. We report a case of this uncommon tumour in a 14-year-old boy. The
      tumour originated from transverse mesocolon. The case is notable because there
      was no pain and ascites on presentation and there was transmural infiltration of
      the transverse colon.

PMID- 15025301
TI  - Allergic fungal rhinosinusitis--a case report.
AB  - Allergic fungal rhinosinusitis is a unique disorder characterised by specific
      immunological hypersensitivity to certain fungal antigens usually presenting with
      nasal polyps and characteristic CT findings. It is a noninvasive disease and on
      histopathology shows formation of allergic mucin containing numerous eosinophils,
      charcot leyden crystals and scattered fungal hyphae. Many cases have been
      reported in western journals but it has been rarely reported in Indian
      literature. This case is probably the first case in India. It is presented here
      for its rarity.

PMID- 15025302
TI  - Follicular dendritic cell tumour--a case report.
AB  - Follicular dendritic cell tumors are rare entities, which are however being
      increasingly recognised. One such tumor in the parapharyngeal region,
      diagnostically challenging, and with an unusual histological feature is reported,
      with a short review of the literature.

PMID- 15025303
TI  - Parachordoma of tibia--a case report.
AB  - A rare case of a 24-year old male patient with 'parachordoma' of left tibia
      having the characteristic histopathological and histochemical features of
      chordoma occurring in an unconventional site, which was clinically and
      radiologically diagnosed as osteoclastoma is presented here. The case is
      presented considering the extreme rarity of the lesion in literature in long
      bones.

PMID- 15025304
TI  - Sertoli Leydig cell tumour of ovary with heterologous element--a case report.
AB  - A 16 years old female who presented with abdominal swelling and secondary
      amenorrhoea was subsequently diagnosed as Sertoli Leydig cell tumour of ovary
      revealing intermediate differentiation with heterologous element. The case is
      reported in view of its rarity.

PMID- 15025305
TI  - Botryoid rhabdomyosarcoma of mesentery--a case report.
AB  - Botryoid rhabdodmyosarcomas are described predominantly in hollow visceral
      organs. We present case of an embryonal (botryoid) rhabdomyosarcoma arising in
      mesentery of a two year old male child.

PMID- 15025306
TI  - Prolymphocytic leukaemia--report of three cases.
AB  - Prolymphocytic leukaemia is a rare subtype of chronic lymphocytic leukaemia.
      Three such cases were reported here along with clinical details. All these cases
      were seen in males above 5th decade. These patients showed moderate to massive
      splenomegaly, inconspicuous lymphadenoapthy in two cases and one with minimal
      lymphadenopathy. Peripheral smear showed high leukocyte count with more than 55%
      of prolymphocytes. Bone marrow aspiration showed diffuse involvement and in one
      with minimal lymphadenopathy, lymphnode aspiration showed prolymphocytes. All the
      three patients died within a year after diagnosis.

PMID- 15025307
TI  - Benign teratoma of the lesser omentum--a case report.
AB  - Teratomas of the lesser omentum are extremely rare and all cases reported in the
      literature have been benign teratomas with mature tissue elements. A case of
      teratoma, which behaved in benign fashion in spite of immature elements in a 16
      year-old male, is reported. The patient remained free of disease 7 years after
      surgical resection of the tumour.

PMID- 15025308
TI  - Haemophagocytosis in tuberculosis--a case report.
AB  - Reactive histiocytosis with hemophagocytosis is most commonly associated with
      viral infections. Appearance of hemophagocytosis in the tissues is associated
      with a rapid progression of the underlying disease, and therefore it is important
      to diagnose and treat the etiological factor at the earliest. Hemophagocytosis is
      uncommonly associated with tuberculosis and we report one such case.

PMID- 15025309
TI  - A large pleomorphic adenoma of soft palate causing sleep apnea syndrome--a case
      report.
AB  - Pleomorphic adenoma of soft palate is extremely rare. A large tumour in soft
      palate is reported with sleep apnea syndrome. Diagnosis was made by fine needle
      aspiration cytology and intraoperative consultation by imprint smears, which were
      confirmed by histopathological and immunohistochemical studies.

PMID- 15025310
TI  - Nodular and diffuse fibrous proliferation of tunica vaginalis--a case report.
AB  - A case of nodular and diffuse fibrous proliferation (NDFP) of the tunica
      vaginalis testis occurring in a 40 year male is described. Immunohistochemistry
      confirmed fibroblastic origin. Histogenesis & differential diagnosis of this
      lesion is considered. Simple excision of this lesion is curative. The lesion is
      very rare but it is important that both surgeons & pathologists become aware of
      this entity to avoid radical orchiectomy in young patients.

PMID- 15025311
TI  - Multiple primary malignancies: synchronous and metachronous presentation--case
      report.
AB  - Reporting three rare cases of multiple primary cancers. Case one and two were a
      synchronous presentation of primary gastric carcinoma and renal carcinoma,
      gastric carcinoma and papillary carcinoma thyroid. Case 3 was metachronous
      presentation of squamous cell carcinoma of the oral cavity and hepatocellular
      carcinoma.

PMID- 15025312
TI  - Congenital cervical teratoma--an unusual presentation.
AB  - We report a case of congenital benign cervical teratoma in a female child. The
      unusual asymptomatic nature of the tumour and its relationship with the thyroid
      is highlighted.

PMID- 15025313
TI  - Unusual mesenchymal tumour of uterus--a case report with immunohistochemical
      findings.
AB  - This is a case report of a mesenchymal tumor of uterus in a 60 year female
      initially interpreted as myxoid leiomyosarcoma. Immunohistochemical studies were
      negative for smooth muscle actin, desmin and p53 but positive for S-100 protein.
      The tumor was therefore reclassified as a low grade malignant mesenchymal tumor
      of neural origin.

PMID- 15025314
TI  - Pleomorphic lipoma of the tonsillar fossa--a case report.
AB  - Pleomorphic lipoma is a benign adipocytic tumor, commonly located in the shoulder
      and posterior neck region. The presence of bizarre, hyperchromatic stromal cells
      along with multinucleated giant cells often poses difficulty in diagnosis,
      especially when it arises at an unusual site like tonsillar fossa.

PMID- 15025315
TI  - Primary angiosarcoma of the spleen--a case report.
AB  - Primary splenic angiosarcomas are rare neoplasms. They have aggressive behavior
      that frequently present with hematological abnormalities and metastatic disease.
      The diagnosis can only be made at surgery. Prognosis of this disease is poor. We
      present a rare case of primary splenic angiosarcoma with metastases in liver.

PMID- 15025316
TI  - Necrotising prostatic granulomas following transurethral resection--a case
      report.
AB  - Necrotising post surgical granulomatous prostatitis following transurethral
      resection of the prostate is a poorly recognized entity. It is often mistaken for
      other conditions like tuberculosis, allergic granulomatous prostatitis, etc. This
      case is being reported in order to increase the awareness of this condition. The
      relevant literature has also been reviewed.

PMID- 15025317
TI  - Von Hippel-Lindau disease: a case report.
AB  - Von Hippel Lindau (VHL) disease is a rare autosomal dominant condition manifested
      by central nervous system hemangioblastoma, retinal angiomas, cysts of pancreas,
      kidney and epididymis, pheochromocytomas and renal cell carcinoma. We present
      such a case in a 45 years old male patient.

PMID- 15025318
TI  - Plasma cell leukemia--a case report.
AB  - Plasma cell leukemia, occurring either de novo or in patients with long standing
      multiple myeloma, is the least common type of plasma cell dyscrasia.
      Histogenetically plasma cell leukemia is derived from terminally differentiated B
      cells. It is diagnosed by presence of absolute plasma cell count >2000/cm or >20%
      circulating plasma cells. Two cases of plasma-cell leukemia are reported here.
      Clinical spectrum and course of the disease, are discussed. Both cases (of
      primary plasma cell leukemia) had abrupt onset of disease, poor response to
      therapy and short survival time. Both presented with fatiguability and weakness.
      Evidence of organomegaly and radiological and hematological evidence of plasma
      cell leukemia, with thrombocytopenia and evidence of visceral involvement with
      leukemic cells, was seen in one case.

PMID- 15025319
TI  - Ulcerative post-kala azar mucosal leishmaniasis masquerading as a carcinoma--a
      case report.
AB  - Post kala-azar mucosal leishmaniasis (PKML) is relatively rare in the Indian
      subcontinent. We describe an ulcerative variant of PKML with nasal involvement in
      a Nepalese adult male. He had ulcerated plaque over the upper lip with extensive
      involvement of nasal columella and septum. He came from endemic area for kala
      azar and had a previous history of kala-azar. There were plenty of LD bodies in
      microsections and FNA of submandibular lymph node.

PMID- 15025320
TI  - Primary spinal paraganglioma--a case report.

PMID- 15025321
TI  - Intestinal helminthic infestation in children.
AB  - In this study of fecal samples from 1000 children below 6 years of age, 680
      (68.0%) detected to have intestinal helminthic infection. The incidence of
      intestinal helminthiasis in urban group of children was 56.8% (284 out of 500
      tested) while in rural group of children was 79.2% (396 out of 500 tested). Both
      in rural and urban population Ascaris lumbricoides was the single predominant
      species, whereas a combination of A. lumbricoides and Trichuris trichiura was
      common multiple infection. All cultures of fecal samples positive for hook worm
      ova revealed the prevalent species as Necator americanus in this area.

PMID- 15025322
TI  - Co-infection with hepatitis C virus and human immunodeficiency virus among
      patients with sexually transmitted diseases in Pondicherry, South India.
AB  - Hepatitis C virus (HCV), which is usually transmitted by blood and blood products
      is emerging as an important agent in the list of sexually transmitted diseases
      (STDs). The present study was undertaken to document the burden of HCV infection
      in individuals with STDs in this tertiary care hospital in South India. One
      hundred serum samples collected from individuals with STDs were tested for
      antibodies to HCV by a third generation ELISA. All the samples were also screened
      for HIV infection. Six out of 100 individuals were found to possess antibodies
      against HCV (95% confidence interval [CI=1.3-10.7%). Fourteen out of 100 samples
      were positive for HIV (95% CI=7-20.9%). The seroprevalence of HCV in HIV positive
      individuals was 21.4% (3/14) whereas the corresponding figure for HIV negative
      individuals was only 3.5% (3/86). The difference was found to be statistically
      significant (p<0.01).

PMID- 15025323
TI  - A steady decrease in occurrence of Salmonella typhi infection in Rourkela,
      Orissa.
AB  - Between January 1999 and December 2001, the isolation rate of Salmonella typhi in
      Rourkela was found to be under steady fall as compared to the isolation rate
      encountered between 1996 and 1998. Of 4378 blood samples tested, 254 were found
      positive for S. typhi giving an over all per cent positivity of 5.8. Enteric
      fever was found to occur almost through out the year. An over all 30.7 per cent
      of multi drug resistant (MDR) strains of S. typhi have appeared during this
      period. Proper and timely health education besides undertaking corrective
      measures in sanitary system and water supply management, appeared to have a
      cumulative effect in the steady reduction of enteric fever morbidity in this
      region.

PMID- 15025324
TI  - Isolation, characterisation and antibiogram of Enterococci from clinical samples.
AB  - During a one year study 2955 clinical specimens of pus, urine, wound swabs, blood
      cultures, discharges from fistula, peritoneal aspiration fluid, CSF and sputum
      were processed to find out the prevalence rate of enterococci. One hundred
      isolates (3.38%) of Enterococci were obtained which were speciated by
      conventional methods. The highest incidence was from isolates of urine (43%), pus
      (40%), wound swabs (11%), and the least incidence was noted in discharges from
      fistula (2%), blood cultures (2%) and peritoneal aspiration fluid (2%). 98% were
      Enterococci and among these 88% of the isolates were Enterococcus faecalis.
      Antibiogram of the isolates were done by Standard disc diffusion method and
      Vancomycin sensitivity was found to be 95%.

PMID- 15025325
TI  - Serum resistance of Escherichia coli strains causing urinary tract infection and
      diarrhoea in relation to alpha haemolysin production and O type.
AB  - A total of 46 alpha-hemolytic and 40 non-hemolytic clinical isolates of
      Escherichia coli were collected from pediatric patients with urinary tract
      infection and diarrhoea. Of 39 (84.7%) alpha-hemolytic strains and 27 (67.5%) non
      hemolytic strains were resistant to 10% serum and there was no significant
      difference between urinary and stool isolates. On the contrary when 100% serum
      was used, 22 (47.8%) of the alpha-hemolytic and 7 (17.5%) of the non-hemolytic
      strains were resistant (p<0.01). and significantly greater resistance was found
      in urinary tract infection than from the stool samples (47% versus 24%, p<0.01).
      Serum resistance was higher in serogroups O6, O18 and O75. Production of alpha
      hemolysin was more frequent in serogrops O2, O6, O8, O18 and O75. Thus, the
      resistance to human serum can determine clinical significance of Escherichia coli
      from different sources and alpha-hemolysin contributes to the virulence of
      Escherichia coli in initiation and perpetuation of clinical infection.

PMID- 15025326
TI  - Prevalence of aspergillosis in bronchogenic carcinoma.
AB  - Bronchoalveolar lavage of 42 patients of bronchogenic carcinoma was studied to
      find out the prevalence of aspergillosis. Sera of the patients were also analysed
      for presence of anti-Aspergillus antibodies by Immunodiffusion (ID), Enzyme
      linked immunosorbent assay (ELISA) and dot blot assay (DBA). Aspergillus was
      isolated in culture from 6 (14.2%) patients of bronchogenic carcinoma.
      Aspergillus fumigatus was the predominant species isolated. All the strains of
      Aspergillus were sensitive to itraconazole, ketoconazole and amphotericin B while
      resistance (33.3%) was found with fluconazole. Anti-aspergillus antibodies were
      detected equally by ID, ELISA and DBA in 9 (21.4%) cases. The present study
      revealed prevalence and seroprevalance of Aspergillus in bronchogenic carcinoma
      to be 14.2% and 21.4% respectively. Consistent reactivity against 18 kDa
      Aspergillus fumigatus antigen was noted in serologically positive cases.
      Antibodies against 18 kDa protein antigen in western blotting may be used as a
      reference marker for diagnosis of aspergillosis in bronchogenic carcinoma. It is
      also suggested that the simplest serological technique like ID may be performed
      along with culture for diagnosing Aspergillosis in patients of bronchogenic
      carcinoma since ID, ELISA and DBA showed similar sensitivity.

PMID- 15025327
TI  - Role of ELISA in H. pylori detection and its correlation with urease test.
AB  - Helicobacter pylori is one of the most common chronic bacterial infection in
      humans linked to acid peptic diseases, gastric carcinomas and lymphomas. The
      bacilli produces large amounts of urease and this property has formed the basis
      of detection of H. pylori by the Christensen's urease test. Where endoscopy is
      not clinically indicated, serology may be used to establish the diagnosis. This
      study was undertaken to diagnose H. pylori with the help of Christensen's urease
      test on endoscopic biopsy specimens & correlated with the detection in Sera, of
      IgG antibodies against H. pylori, by ELISA technique. The study was conducted on
      100 patients suffering from acid peptic disorders out of which 40 (40%) tested
      positive for H. pylori both by urease and serology. Christensen's urease and
      ELISA were found to have sensitivities of 85.7% & 90.9% and specificities of 96%
      and 87.5% respectively. Christensen's urease was taken as a standard method of
      diagnosis and its correlation with ELISA worked out to (+1) which meant there was
      a strong positive association between both the tests. Hence either test could be
      used for primary diagnosis of H. pylori instead of histopathological study and/or
      culture of H. pylori.

PMID- 15025328
TI  - C-reactive proteins as an indicator of sub-clinical infection in cases of
      premature rupture of membranes.
AB  - The present study was conducted on 25 cases of preterm, premature rupture of
      membranes and 25 patients preterm with intact membranes, between 28-36 weeks of
      gestation, admitted in the maternity ward of Obstetrics and Gynecology, PGIMS,
      Rohtak. The sensitivity and specificity of CRP determination was found to be 80%
      each as an early predictor of subclinical chorioamnionitis. TLC had a low
      sensitivity of 20% and specificity of 60% in detecting histopathological
      chorioamnionitis. So CRP estimation is a reliable marker for detection of early
      choriamnionitis, at the same time, it is quite affordable and reasonably simple.

PMID- 15025329
TI  - Comparison between conventional and QBC methods for diagnosis of malaria.
AB  - Stained blood film examination is a widely used technique for the diagnosis of
      malaria. Comparison of this technique was made with the QBC method, which is
      based on fluorescent staining of the blood cells and parasites. Of the 1435 blood
      samples studied, 57 (3.97%) samples were positive for malarial parasites by QBC
      method, while only 44 (3.07%) samples were positive by the blood film
      examination. Plasmodium vivax was detected in 27 (47.37%), P. falciparum in 26
      (45.61%) and mixed infection of P. vivax and P. falciparum in 4 (7.02%) cases.
      Samples with low levels of parasitaemia (QBC grades 1+ and 2+) were often found
      to be negative by blood film examination. QBC method was easy to perform, had a
      higher sensitivity and could be interpreted rapidly, as compared to the Leishman
      stained blood film examination.

PMID- 15025330
TI  - Enhanced detection of Mycobacteria stained with rhodamine auramine at 37 degrees
      C.
AB  - Sputum smear microscopy is the most efficient and rapid technique for detection
      of acid-fast bacilli (AFB). Fluorochrome method of staining is preferred for
      Mycobacteria in the overburdened laboratories as the fluorescing bacilli are more
      readily detected than the fuchsin stained bacilli in shorter period of time. A
      total of 300 sputum samples obtained from suspected cases of Tuberculosis were
      collected and were subjected to staining by rhodamine auramine at 37 degrees C
      and also at room temperature (conventional method). The smears were then blindly
      evaluated. Fifty-eight samples were positive by both methods and 5 were positive
      at 37 degrees C only. Staining at 37 degrees C increased the smear positivity by
      8.6% over conventional staining at room temperature. No smears were positive only
      with staining at room temperature alone. Out of 58 smears positive by both
      methods, 25 had equal number of AFB in both smears, 22 had more AFB in smear
      stained at 37 degrees C and 11 had greater number of AFB in smears stained at
      room temperature. Our study, therefore, indicates that rhodamine auramine
      staining at 37 degrees C is superior to conventional auramine method at room
      temperature for detecting AFB in sputum smears.

PMID- 15025331
TI  - Myristica fragrans [nutmeg] and its activity against the enteric pathogens.

PMID- 15025332
TI  - Antimicrobial susceptibility pattern of clinical isolates of non-fermentative
      bacteria.
AB  - 152 nonfermentative bacteria were isolated from a total number of 965 clinical
      samples processed routinely in the laboratory of Microbiology Department, M.K.C.G
      Medical College in South Orissa accounting to a prevalence rate of 15.75%.
      Pseudomonas spp. (both pigmented and non-pigmented strains) were isolated in
      maximum percentage (73.6%) followed by Acinetobacter spp. (19.7%) and Alkaligenes
      faecalis (4.6%). Rarely encountered species were Eikenella corrodens (1.3%) and
      Stenotrophomonas maltophila (0.6%). Pus from various sites was the major source
      (116; 76%). 81% of all isolates were sensitive to amikacin and 74% to ofloxacin.
      Sensitivity to cefotaxime, ciprofloxacin, tobramycin, gentamicin and netlimycin
      ranged from 53% to 68%. Least effective drugs were carbenicillin and ceftriaxone
      (48% each).

PMID- 15025333
TI  - Occurrence of group C Streptococci in children in a South Indian village.
AB  - Throat swabs were collected from 310 children aged 5-14 years attending a rural
      health camp at Orathur near Chennai. Group C Streptococci were isolated from
      13/310 (4.19%) cases. Seven out of 13 patients had symptoms of respiratory tract
      infection. Biochemical characterization of the isolates was done by hemolytic
      characteristics, Voges-Proskauer test, fermentation of trehalose and sorbitol and
      hydrolysis of 4-methylumbelliferyl-D-a-glucuronide. Four out of 13 strains were
      identified as S. equisimilis.

PMID- 15025334
TI  - Serodiagnosis of smear and culture-negative neurotuberculosis with enzyme linked
      immunosorbent assay for anti A-60 immunoglobulins.
AB  - Early diagnosis of neurotuberculosis (NTB), useful in prevention of mortality and
      morbidity, remains a challenge despite availability of several tests. An ELISA
      test to detect IgG and IgM antibodies against Mycobacterial antigen A-60 (Anda
      Biologicals, France) was done in 677 specimens; group 1 (NTB): 373 sera and 167
      cerebrospinal fluid (CSF), group 2: 100 sera from healthy subjects, group 3: 17
      CSF from patients undergoing neurosurgical operations for non-tubercular
      diseases. Anti-A 60 IgA estimation was done in 99 sera from group 1 and all 100
      from group 2. Working dilutions were 1:200 for serum and 1:10 for CSF. Serum IgM
      and IgG anti-A 60 antibodies were more often detected in group 1 than in 2 (50%
      Vs 10%, p<.001). Anti-IgG and IgM antibody were detected more often in group 1
      than in group 3 (33% Vs 6%, p<.001). In serum and CSF both IgM positivity was
      more than IgG in 2 subgroups of NTB and these are tubercular meningitis, spinal
      tuberculosis whereas in tuberculoma IgG positivity was more as compared to other
      2 groups. Sera were more often positive than CSF (50% Vs 33%, p<.001). Of 32
      patients, in whom magnetic resonance imaging (MRI) was done, 15/18 (83%) patients
      with suggestive findings in MRI had a positive ELISA (IgG or IgM). AntiA-60
      antibody is a useful aid in the diagnosis of NTB, especially in smear and culture
      negative NTB where one does not have much diagnostic opportunities to choose
      from.

PMID- 15025335
TI  - Acute myeloid leukemia manifested as intracerebral hemorrhage.

PMID- 15025336
TI  - Worrisome endothelial cells in peripheral smear: a diagnostic problem.

PMID- 15025337
TI  - Serum pooling for screening of blood donors for hepatitis C virus antibody.

PMID- 15025338
TI  - Sarcoidosis presenting as a case of acute intestinal obstruction.

PMID- 15025339
TI  - Nine-banded armadillo and leprosy research.
AB  - In this presentation an attempt has been made to describe the nine-banded
      armadillo as an animal model, probably the only one in which lepromatous leprosy
      similar to that found in humans can be experimentally produced. Some unique
      features of the physiology of the animal are mentioned. The pathology and the
      microbiology of leprosy in the armadillo are described in detail. The discovery
      of lepromatous leprosy in the wild armadillos in the southern parts of United
      States, the transmission of disease among them through trauma and thorn pricks
      and the pathogenesis of the disease are presented. The impact of leprosy in the
      wild animals may have on human leprosy is discussed.

PMID- 15025340
TI  - Histopathological evaluation of placentas in IUGR pregnancies.
AB  - Gross and microscopic examination was conducted on one hundred placentas. These
      included twenty five normal controls and seventy five from intrauterine growth
      retardation (IUGR) pregnancies. Weight of the placentas from IUGR pregnancies
      were less than those of normal placentas. The incidence of infarction,
      intervillous fibrin deposition were much higher in IUGR placentas on gross
      examination. Highly significant increase in the incidence of infarction,
      intervillous fibrin deposition, stromal fibrosis and syncytial knotting were
      found in IUGR placentas compared to full term normal placentas on microscopic
      examination. The incidence of basement membrane thickening and cytotrophoblastic
      hyperplasis were also higher in IUGR placentas. All the major histologic findings
      pointed towards reduced blood flow to the placentas resulting in the restriction
      of blood flow to fetus. The information obtained from their examination can be a
      useful adjunct in planning and management of future pregnancies.

PMID- 15025341
TI  - Histological profile of liver disease in patients with dual hepatitis B and C
      virus infection.
AB  - There is limited information on the histological profile of chronic liver disease
      due to dual infection with hepatitis B virus and hepatitis C virus infection. Few
      studies have indicated higher histological activity with dual infection as
      compared to HBV and HCV infection present alone. This study aims at reviewing the
      histological profile of liver biopsies in the three groups. Liver biopsies of 25
      patients serologically diagnosed as HBV and HCV dual infection (Group I), were
      compared with 25 age and sex matched cases of HBV infection (Group II) and HCV
      infection (Group III). RESULTS: Mean Histological Activity Score in group I was
      8, which was higher than the scores of group II (6.2) and group III (7.3). The
      mean stage of fibrosis was also slightly higher in group I (2.3) as compared to
      group II (1.9) and group III (1.7). However, when stage 3 and 4 fibrosis
      (extensive fibrosis) were combined and compared with the number of patients with
      stage 1 and 2 fibrosis in each group, we found Group I (dual infection) had
      larger number of patients with extensive fibrosis (48%) than in Groups II and III
      (20% and 36% respectively). In addition, there was no significant difference in
      presence of features like fatty change, bile duct injury and lymphoid aggregates
      in the three groups. CONCLUSION: Patients with dual HBV and HCV infection are
      more likely to have an advanced stage of disease than those with a single
      infection, however there is no significant difference in histologic activity or
      any other histological parameter between these groups.

PMID- 15025342
TI  - Breast lesions in young females--a 20-year study for significance of early
      recognition.
AB  - The aim of this case series is to evaluate the pattern of breast lumps in males
      and females with special reference to spectrum of lesions in females below 40
      years of age. A 20 years retrospective study was undertaken from the records of
      the department of Pathology, Bhopal. The lesions were classified into benign and
      malignant. In young females histological pattern was analyzed in various age
      groups. A total of 1824 cases were studied. 1724 (94.5%) cases were seen in
      females and 100 (5.5%) in males. There were 1276 (74%) females below 40 years of
      age and 448 (26%) were above 40 years of age. In young females 1136 (89%) lesions
      were benign and 140 (11%) were malignant lumps. Fibrocystic disease in 60 (49%)
      cases constituted the largest group of benign lumps followed by 30 (24.5%) cases
      of inflammatory lesion in older females. The mean age of malignant tumors was
      34.1 in young females and 51.4 in females above 40. Infiltrating duct carcinoma
      constituted 83.5% of malignant tumors in young females and 86.1% in older
      females.

PMID- 15025343
TI  - Contribution of iron deficiency to anemia in chronic renal failure.
AB  - Prevalence of iron deficiency in anemia of chronic renal failure (CRF) has long
      been the subject of interest, because the patients of CRF with coexistent iron
      deficiency anemia need to be treated with iron preparations before starting
      erythropoietin therapy. Prevalence of iron deficiency in CRF is higher in Indian
      patients as compared to the West. Diagnosis of iron deficiency in patients with
      CRF is difficult. Bone marrow iron which is considered to be the gold standard is
      a painful and invasive procedure. In the present study we used serum transferrin
      receptor and serum ferritin levels, since not much Indian data is available on
      this.

PMID- 15025344
TI  - Validity of hematologic parameters in identification of early and late onset
      neonatal infection.
AB  - This study was designed to evaluate the utility of hematological parameters and C
      reactive protein (CRP) to formulate a sepsis screen to detect sepsis in early and
      late onset infection. Hundred and fifty neonates clinically suspected of
      bacterial infection, based on risk factors and/or clinical features were selected
      for the study. Blood was collected by venipuncture at the time of admission in
      all neonates. A total leukocyte count (TLC), differential leukocyte count (DLC),
      its derivatives [Total neutrophil count (TNC or T), ratio of immature to total
      neutrophil count (I/T), ratio of immature to mature neutrophil count (I/M)] and
      CRP were obtained. TLC = 10x10(9)/L, TNC = 8x10(9)/L, I/T = 0.16, I/M = 0.25 and
      CRP = 0.6 mg/dl were found to be good parameters in detection of sepsis. During
      the first three days of life leukopenia, neutropenia, elevated I/T ratio,
      elevated I/M ratio and CRP were good diagnostic aids while after 3 days of life
      CRP was the best single test. This emphasizes use of multiple indicators for
      detection of sepsis. Using these parameters a sepsis screen was formulated which
      detected >90% of proven early and late onset sepsis suggesting that other
      neonates with positive sepsis screen but blood culture negativity may have been
      truly infected.

PMID- 15025345
TI  - Diagnostic utility of squash (smear) technique in the inflammatory lesions of
      central nervous system.
AB  - Smears of histologically verified inflammatory lesions of central nervous system
      (CNS) during 12 years were analysed to determine the diagnostic utility and
      accuracy of squash (smear) technique. Two hundred and sixteen (216) lesions were
      analysed. Smears could not be interpreted in 72 lesions (33.33%) as the tissue
      could not be spread or not representative. Tuberculosis was the commonest
      etiology (70.83%) followed by bacterial, fungal and parasitic infections. To
      conclude, smear technique is a useful modality in establishing diagnosis in
      inflammatory lesions of CNS, but its usefulness is limited by difficulties in
      spreading tissue.

PMID- 15025346
TI  - Proliferative activity in squamous intraepithelial and invasive lesions of
      cervix: analysis by AgNOR staining.
AB  - Proliferation potential of squamous intraepithelial lesions of cervix is the main
      factor affecting the biological aggressiveness of the lesion. The present study
      was aimed at assessing the proliferation in preinvasive and invasive squamous
      epithelial lesions of cervix using a simple and inexpensive proliferation marker:
      AgNOR (Argyrophilic nucleolar organizer regions). Fifty biopsy sections of
      various grades of preinvasive and invasive squamous epithelial lesions of cervix
      were taken for AgNOR staining. Single step staining technique using gelatin in
      formic acid solution was employed. Counting was done with the help of 'CAMERA
      LUCIDA' drawings. AgNOR counts/nucleus in parabasal and basal layer showed
      progressive rise in their mean value with increasing grade of lesion. Amongst
      invasive malignancies, highest mean of AgNORs/nucleus was observed in poorly
      differentiated squamous cell carcinoma of cervix. In conclusion, AgNORs can prove
      to be a simple inexpensive and reliable proliferation marker in lesions of
      cervix.

PMID- 15025347
TI  - An unusual platelet function defect: report of 19 cases.
AB  - Selective impairment in platelet responsiveness to epinephrine has been seen in
      certain acquired conditions and very rarely as a hereditary disorder. To the best
      of our knowledge this hereditary defect has been described in a single family and
      in two other individuals. We describe here 19 cases of this defect. Subjects with
      history of generalized bleeding with a prolonged bleeding time, PF3 availability
      or prothrombin consumption index and a normal platelet count, prothrombin time,
      activated partial thromboplastin time, clot solubility were subjected to platelet
      aggregation. Those of these who showed a normal aggregation with ADP, collagen,
      arachidonic acid and an absent aggregation with epinephrine were included in our
      study group. Subjects with history or findings suggestive of antiplatelet drug
      intake or any acquired condition giving rise to this abnormality were excluded
      from this study. 74% of the patients had onset of bleeding manifestations since
      childhood (<14 years) with a mean age at onset of 10.4 years. All patients
      presented with mild bleeding manifestations, the commonest symptom being
      appearance of recurrent ecchymotic spots. In females, menorrhagia was the
      commonest symptom. We present here probably the first report of the occurrence of
      hereditary platelet aggregation defect selectively with epinephrine in Indian
      patients.

PMID- 15025348
TI  - Vimentin expression in breast carcinomas.
AB  - Epithelial malignancies expressing mesenchymal markers and their prognostic
      implications have been studied by various authors. In view of this, we studied
      fifty cases of breast carcinomas for vimentin expression and correlated the
      various clinical and histopathological parameters. Eighteen percent (9/50) of all
      breast carcinomas expressed vimentin. Vimentin positive tumours were
      predominantly larger in size (mean greatest diameter 5.43 cm), of higher TNM
      stage, node negative (55.56%), poorly differentiated (66.66%, p=0.0458) with high
      mitotic rate (>10/hpf, p=0.0000), Estrogen (88.88%) and Progesterone (77.77%)
      receptor negative thus pointing towards aggressive biological behavior.
      Interestingly 20% of well differentiated and 9.09% of moderately differentiated
      tumours also expressed vimentin. One vimentin positive case had pulmonary
      metastases despite being node negative while another well differentiated vimentin
      positive tumour showed skeletal muscle infiltration. Hence, we conclude that
      vimentin expression is an indicator of biologically aggressive tumours.

PMID- 15025349
TI  - Proliferation in squamous cell carcinoma of cervix: a comparative assessment by
      two markers.
AB  - The study was aimed at assessing the cell proliferation in various grades of
      squamous cell carcinoma of cervix using two proliferation markers: AgNORs and Ki
      67. 18 biopsy sections of various grades of SCC of cervix were chosen. AgNORs
      staining was done by single step staining technique using gelatin. Ki-67
      immunostaining was done by Avidin--Biotin technique using DAB as a chromogen.
      Highest mean number of AgNORs was found in poorly differentiated squamous cell
      carcinoma and statistically significant difference was observed between well and
      poorly differentiated SCC and between moderately and poorly differentiated SCC.
      Highest mean Ki-67 LI was seen in poorly differentiated SCC. We observed
      correlation between histological grade and Ki-67 and AgNORs separately but no
      statistically significant correlation was found between Ki-67 and AgNOR counts.
      AgNORs and Ki-67 are both simple and easily performed techniques. They may prove
      to be a useful adjunct in estimating tumor proliferation and hence in determining
      the management strategy of the patients.

PMID- 15025350
TI  - Rapid staining using toluidine blue: a reliable method for quick diagnosis in
      ultrasound-guided aspiration cytology.
AB  - Rapid staining of ultrasound guided aspirates is an accepted procedure for
      evaluation of adequacy and rapid diagnosis (RD). We have assessed the reliability
      of Toluidine blue stain in this regard, which has not been previously reported.
      295 ultrasound guided aspirates performed over a 13 month period were studied. 59
      aspirates were inadequate for RD. 103 cases were called malignant on RD of which
      101 were confirmed, and 2 cases were considered highly suspicious on final
      diagnosis. Of 34 cases considered suspicious on RD, 32 were either signed out as
      malignant or considered highly suspicious while 2 cases were benign. Of 56 cases
      considered benign on RD, 49 were confirmed, 2 were suspicious for malignancy and
      5 cases had inadequate material on final diagnosis. All 43 inflammatory lesions
      on RD were confirmed. The overall sensitivity for a malignant/suspicious for
      malignancy diagnosis was 98.54% on RD while specificity was 97.99%. Sensitivity
      and specificity for an inflammatory condition was 100%. Toluidine blue staining
      is not only a reliable method for rapid staining and diagnosis, it also permits
      preservation of cytological material by destaining and restaining with permanent
      stains.

PMID- 15025351
TI  - Significance of mucin stain in differentiating benign and malignant lesions of
      prostate.
AB  - In an attempt to assess the significance of mucin stains in benign and malignant
      lesions of prostate, 200 prostatic biopsies in the department of Pathology, Pt.
      B.D. Sharma PGIMS, Rohtak were studied. All the biopsies were subjected to PAS
      and alcian blue staining along with H&E stain. Neutral mucin (PAS positive) was
      more frequently observed in benign prostatic lesions (93.3%) as compared to
      carcinoma (36%) while acid mucin (AB positive) was found more in carcinoma
      prostate (68%) as compared to benign prostatic lesions (16%). The positivity for
      acid mucin was more in well differentiating tumour decreasing significantly in
      high grade malignancies. With both types of mucin, luminal positivity was
      slightly more as compared to cytoplasmic positivity.

PMID- 15025352
TI  - Detection of HPV DNA in cervical carcinomas by PCR and hybrid capture assay.
AB  - HPV DNA was detected in exfoliated cervical cells of 73% (85/116) cervical cancer
      patients by PCR using HPV consensus primers and by hybrid capture assay (HC II)
      (Digene Corp., USA) in 77 of the 85 cases found HPV positive by PCR. Presence of
      HPV 16/18 DNA were investigated in the 79 cases by PCR using type specific
      primers. HPV 16 was detected in 31 (39%) patients, HPV 18 in 7 (8.8%), both HPV
      16 and 18 in 19 (24%) and HPVs other than 16/18 in 22 (27.8%) cases. Age and
      clinical stages had no significant effect on HPV prevalence. Double infection of
      HPV 16 and 18 was significantly (p<0.05) high in the older patients (56 years or
      more) compared to younger group. Results indicated that cervical cancers in India
      are strongly associated with high-risk type HPV infection. HC II assays and PCR
      results for detection of HPV in cervical smears were comparable.

PMID- 15025353
TI  - Epithelioid hemangioendothelioma of bone--a clinicopathologic and
      immunohistochemical study of 7 cases.
AB  - Epithelioid hemangioendothelioma is a rare vascular tumor of bone. Between 1987
      1999, seven cases of epithelioid hemangioendothelioma were recorded. The
      histopathological evaluation was done with hematoxylin and eosin stain and
      immunohistochemical stains along with the analysis of clinical data and X-ray
      findings. There were 4 males, 3 females between 15 to 48 years of age with
      complaints of pain and swelling. Long bones were involved in five of the seven
      patients and one was multifocal. Radiologically all seven patients showed
      osteolytic lesions. The histologic hall mark was the presence of eosinophilic,
      epithelioid cells with intracytoplasmic vacuoles. The tumor may be histologically
      confused with metastatic carcinoma, chondromyxoid fibroma and osteogenic sarcoma.
      Immunohistochemical reactivity was as follows: Vimentin (6/6 cases), Factor VIII
      related antigen (4/6 cases), Ulex Europeaus (5/6 cases), CD31 (3/5 cases), CD34
      (3/5 cases), epithelial membrane antigen (1/6 cases), cytokeratin (none).
      Treatment comprised curettage (4 cases), wide excision (2 cases), below knee
      amputation (1 case) and post operative radiotherapy (2 cases). At follow-up,
      (available in 4 patients) two were without disease at 18 months and 120 months.
      Of the remaining two, one developed local recurrence after 36 months; while the
      other died of lung metastasis (18 months). A lytic bone shadow, the presence of
      plump eosinophilic often vacuolated cells on a myxoid background and
      immunohistochemistry together help in the correct recognition of this tumor.

PMID- 15025354
TI  - Mast cells in Helicobacter pylori associated antral gastritis.
AB  - Mast cells are known to be effector cells in various inflammatory reactions, but
      their role in gastritis is unclear. The present study was undertaken to
      investigate the extent of mast cell involvement in antral gastritis with and
      without Helicobacter pylori (H. pylori) infection and thus evaluate the possible
      role of mast cells in the pathogenesis of H. pylori-associated gastritis. Antral
      mucosal biopsies were taken from 212 subjects with symptoms suggestive of acid
      peptic disease. Sections were assessed for inflammation. Modified Giemsa stain
      was used to detect H. pylori infection and 1% toluidine blue to count mast cells.
      Mast cell counts were significantly higher in the antral mucosa even in H. pylori
      negative gastritis (68.4 +/- 6.7/mm2), as compared to normal non-inflamed mucosa
      (45.7 +/- 5.8/mm2) (P < 0.05). However, with H. pylori infection, the mucosal
      mast cell count were markedly increased (123.8 +/- 4.7/mm2) as compared to normal
      mucosa (P < 0.01). and H. pylori-negative gastritis (P < 0.01) this increase was
      noticed uniformly in patients with H. pylori-positivity, irrespective of the
      presence or absence of a peptic ulcer. After cure of H. pylori infection, the
      mast cell density decreased significantly (44.9 +/- 4.6/mm2) to reach levels that
      were similar to those in normal mucosa. There was a positive correlation between
      the antral mucosal mast cell density and polymorphonuclear and mononuclear cell
      infiltration (rs = 0.61). H. pylori infection, and 0.73 respy. It was concluded
      that could be responsible for increasing the mast cell density in the gastric
      antrum. Probably by inducing castain mucosal cytokine.

PMID- 15025356
TI  - Bone marrow metastasis in solid tumors.
AB  - Bone marrow examination has been increasingly useful in documenting metastatic
      involvement of tumors. A retrospective analysis of 73 cases of bone marrow
      metastasis of solid tumors revealed 27 cases in the pediatric age group and 46
      cases in the adult age group. All 27 pediatric cases were that of neuroblastoma.
      In the adult bone marrow metastasis from carcinoma prostate were present in 22
      cases followed by carcinoma breast in 13 cases. Rest were 5 cases of carcinoma
      lung, 4 cases of carcinoma colon, 1 case each of carcinoma thyroid and renal cell
      carcinoma. A number of associated features were observed which may help to
      suggest bone marrow metastasis, in the absence of tumor cells in the bone marrow.

PMID- 15025355
TI  - Early diagnosis of neonatal septicemia by sepsis screen.
AB  - A study of 100 neonates with clinical suspicion of septicemia, admitted in
      neonatal intensive care unit of SCSM General Hospital, Solapur was carried out to
      assess the utility of various indices of sepsis screen. Bacterial and
      hematological profile of these neonataes was studied. Parameters of sepsis screen
      such as leukocyte count, band form to neutrophil ratio, neutrophils with toxic
      granulations, micro ESR and test for C-reactive protein were analysed to know
      their sensitivity and specificity.

PMID- 15025357
TI  - Use of the gel-based DiaMed-ID microtyping system for crossmatching enhances
      sensitivity.
AB  - A host of newer techniques have been introduced over the past decade in blood
      bank serological testing. One such technology which has been in vogue in the west
      since early 1990s is the gel test. The procedures used are standardized and they
      provide clear and stable reactions that improve result interpretation. The
      principle involves the differential passage of red cell agglutinates and free red
      blood cells through a dextran acrylamide gel. The results are stable and may be
      read even after many hours. The test is easy to perform, sensitive and
      reproducible. We report our experience in compatibility testing with use of the
      DiaMed micro typing system which is based on the gel technology. Over a one year
      period since this technology was introduced in our blood bank, we noticed a
      startling 65 fold rise (p<0.0001) in the reported number of incompatible units in
      one year which rose from a paltry 4 (0.02%) to 260 (1.6%). We found the DiaMed
      system easy to use and as our findings suggest it proved to be more sensitive
      than the conventional tube agglutination technique.

PMID- 15025358
TI  - Venous thrombosis: prevalence of prothrombotic defects in north Indian
      population.
AB  - 431 patients with thrombosis of different venous system were evaluated for
      underlying acquired and inherited prothrombotic states. Associated acquired risk
      factors were observed to be present in 28.7% patients and possible inherited in
      32.3%, in the rest, no cause could be identified. Major acquired risk factors
      included coexistence of liver disease (12.2%), oral contraceptives (4.1%),
      puerperium (2.5%), malignancy (2.3%) and lupus anticoagulant (2%). Low levels of
      protein C were detected in 21.1% and of which 11.3% were attributed to acquired
      factors. Protein S deficiency was found in 19.0% and of these 10.4% cases were
      associated with acquired risk factors. Antithrombin III (AT III) deficiency was
      detected in 6.4% of patients, of which 4.8% were secondary to acquired factors.
      In the rest, deficiency of protein C, protein S and AT III were attributed to
      inherited factors as no associated acquired risk factor was present. Activated
      protein C resistance (APC-R) was present in 12.5% cases.

PMID- 15025359
TI  - CD99 expression in hepatocellular carcinoma: an immunohistochemical study in the
      fibrolamellar and common variant of the tumour.
AB  - Histological diagnosis of hepatocellular carcinoma (HCC) in biopsy and fine
      needle aspiration material can pose difficult problems. This is particularly so
      in the fibrolamellar variant of the tumour (FLHCC) which has biological features
      distinctly different from those of common HCC (CHCC). Expression of CD99, a
      membrane localised glycoprotein which is known to be a feature of diagnostic
      importance in several malignant neoplasms was looked for in immunohistochemical
      preparation of tissue material from 18 cases of HCC, 6 FLHCC and 12 CHCC
      accessioned in our department. Positive staining of variable degrees and intesity
      was observed in all 18 cases. Non-neoplastic hepatocytes, normal or others and
      all the 18 other cases of non-HCC cancers outside the liver or metastatic within
      the liver were negative. In some cases, mostly of FLHCC, a definitive diagnosis
      could be suggested on the basis of CD99 positivity. It is concluded that in cases
      of HCC, particularly in small specimens and in FLHCC, immunostaining for CD99
      will be of significant help in diagnosis.

PMID- 15025360
TI  - Histopathological study of endometrium in infertility.
AB  - A study of 200 cases of primary and secondary infertility was carried out in the
      department of pathology, Dr. V.M. Medical College, Solapur. Endometrial specimens
      were evaluated in the light of menstrual history to find out the incidence of
      various endometrial changes in cases of infertility. All cases underwent
      endometrial biopsy premenstrually. Haematoxylin and eosin staining was done for
      dating of endometrium and diagnosis of corpus luteal defect and anovalutory
      cycles. PAS stain was done in 50 cases of infertility with control of 25 cases to
      detect the amount of glycogen. Menstrual problems were seen in 38.2% of patients.
      Anovulatory infertility was present in 28.2% cases. Luteal phase defect was seen
      in 20% cases. Cystoglandular hyperplasia was seen in 1.7% cases & tuberculous
      endometritis was present in 2.6% cases. Glycogen deficiency was seen in 30% cases
      of luteal phase defect.

PMID- 15025361
TI  - Solitary amyloid tumour of breast--a case report.
AB  - 45 years old woman with solitary amyloid tumor of breast is described.
      Clinically, the breast mass was hard and was suspicious of carcinoma.
      Microscopically there was no neoplasia. Instead there was extensive fibrosis with
      amyloid deposition in perivascular periductal areas and also in intervening
      stroma. The presence of amyloid was confirmed by Special stains and by Polarised
      microscope. Investigations revealed no evidence of systemic amyloidosis or
      amyloid related illness.

PMID- 15025362
TI  - Nevus lipomatosus cutaneous superficialis--a case report.
AB  - We report a case of nevus lipomatosus cutaneous superficialis, an uncommon
      hamartomatous disorder.

PMID- 15025363
TI  - Primary liposarcoma of the omentum: a case report and review of the literature.
AB  - A case of round cell liposarcoma of omentum in a 45-year-old man is reported. The
      patient presented with abdominal pain, swelling and fever of 4-month duration.
      Abdominal ultrasonography and computed tomogram confirmed the presence of an
      abdominal mass, but the omental origin of the tumour was revealed only on
      laparotomy. In addition to the main tumour mass, multiple nodules were present in
      the omentum. The tumour was excised with omentum. Histopathology of the tumour
      revealed a round cell liposarcoma. The patient expired 9 months after operation.
      Eight other cases of liposarcoma of omentum reported in English literature are
      reviewed.

PMID- 15025364
TI  - Proliferating Brenner tumour of ovary--a case report.
AB  - Transitional cell tumours or Brenner tumours of ovary are uncommon neoplasms. Out
      of all the Brenner tumours less than 2% are either proliferating or malignant
      type. Borderline or malignant tumours occur in women who are on an average 10
      years older than those with benign tumours. It is essential to categorise these
      tumours as benign, borderline or malignant type as the biologic behaviour and
      choice of surgery differs in all of the three categories. The gross and
      microscopic findings of a proliferating brenner tumour are reported here.

PMID- 15025365
TI  - Hepatoblastoma--report of three cases.
AB  - Hepatoblastoma accounts for only 0.5% of all paediatric tumours. The vast
      majority of these cases are seen under five years of age and a third of patients
      have some form of congenital anomaly syndrome or other childhood tumour. Most
      recent classification describes six subtypes of hepatoblastoma. Surgical
      resection is the best treatment preceded by accurate staging and chemotherapy or
      radiotherapy. Hepatoblastoma can be diagnosed by Fine Needle Aspiration Cytology
      (FNAC). We report here three cases of hepatoblastoma diagnosed by FNAC and
      subsequently confirmed by histopathology following resection of hepatic tumours.

PMID- 15025366
TI  - Epithelioid and retiform hemangioendothelioma of the skull bone--report of four
      cases.
AB  - Hemangioendothelioma (HE) is a borderline or intermediate type of vascular
      neoplasm. We report clinical and histopathological characteristics of four cases
      of HE arising from the skull bones because of its extreme rarity in this
      location. The age of the patients ranged from 6-45 years. Three patients
      presented with a painless swelling over the head and one case had sphenoid wing
      mass with dimness of vision and proptosis. Radiographic images showed a well
      demarcated, osteolytic lesion in the skull bone in all the four, one case in
      addition had sclerotic edges and another had specks of calcification. Grossly,
      the tumour was very vascular with hemorrhagic areas. Histologically, three cases
      showed features of an epithelioid variant of HE, with short strands and solid
      nests of rounded to slightly spindled, eosinophilic endothelial cells, some of
      them having small intracellular vacuoles. The stroma was myxoid--hyalinised with
      focal mixed inflammatory infiltrate. One case had features of a 'retiform'
      histological variant composed of numerous elongated vessels lined by a single
      layer of hobnail endothelial cells, focal lymphocytic infiltrate and papillae
      with hyaline collagenous cores. The tumour cells in all the four were immuno
      labelled by antibody to factor VIII-associated protein. The tumour cells lacked
      cytological atypia and mitosis was sparse. These features were important in
      prognostication as low-grade tumours can be cured by complete wide-resection.

PMID- 15025367
TI  - Pathology of Toxoplasma myocarditis in acquired immunodeficiency syndrome.
AB  - Involvement of the myocardium by Toxoplasma gondii is seen in patients of
      acquired immunodeficiency syndrome (AIDS), mostly in association with toxoplasma
      encephalitis. Only few patients die as a direct result of cardiac dysfunction.
      Clinico-pathological findings of three cases of toxoplasma myocarditis are
      reported, one of which presented and died due to massive pericardial effusion.
      All cases showed diffuse myocarditis with parasites on histopathological
      examination. Incidence of toxoplasma myocarditis in patients dying with AIDS was
      8.3% (3 out of 36 cases).

PMID- 15025368
TI  - Paraganglioma of the urinary bladder--a case report.
AB  - Paragangliomas of the urinary bladder are extremely rare tumors accounting for
      less than 1% of all bladder tumors. Males and females are affected roughly
      equally with an average age of 41 years. Hypertension and headache during or
      immediately after voiding in association with intermittent hematuria is virtually
      diagnostic of urinary bladder paragangliomas. A high index of clinical suspicion
      is required to diagnose these tumors. We present a case of a urinary bladder
      paraganglioma because of its rarity.

PMID- 15025370
TI  - Asymptomatic essential thrombocythemia: a case report.
AB  - Essential thrombocythemia (ET) is a clonal disorder of unknown etiology involving
      multipotent hematopoietic progenitor cell and belongs to the spectrum of chronic
      myeloproliferative disorders (CMPD). It is rarest of the CMPD with no case
      reported from India. The case being presented was detected incidentally during
      routine investigations in an adult female who presented with mild abdominal
      discomfort.

PMID- 15025371
TI  - Primary mixed germ cell tumour of the liver--a case report.
AB  - Germ cell tumours in liver are uncommon. Fewer than 20 cases have been reported
      in the literature. Primary mixed malignant germ cell tumours of liver are even
      rare. Here we describe a case of primary mixed malignant germ cell tumour of left
      lobe of liver in a two and half year old male boy. This is the first reported
      case of primary mixed malignant germ cell tumour with components of yolk sac
      tumour and mature teratoma in an infant. The patient complained of gradual
      increase in abdominal distension, upper abdominal pain and loss of weight.
      Ultrasonography and computed tomography of the abdomen revealed a large hepatic
      mass. Serum alpha-feto protein levels were raised. Left lobectomy of liver was
      done and chemotherapy was initiated. Histopathology of specimen disclosed yolk
      sac tumour and mature teratoma. Levels of serum alpha-feto protein declined
      rapidly. Widespread intrahepatic metastasis developed and patient died due to
      liver dysfunction after six months of left lobectomy.

PMID- 15025369
TI  - Cartilagenous choristoma of palatine tonsil--a case report.
AB  - Choristoma is defined as a histologically normal tissue proliferation or nodule
      of a tissue type not normally found in anatomic site of proliferation. Here a
      case of chronic tonsillitis is being reported where mature cartilage was found
      embedded in the tonsil, making the surgical removal of the tonsil difficult.
      Cartilaginous choristoma of the tonsil appears to be a developmental anomaly in
      the second pharyngeal arch and could be one of the causes of recurrent
      tonsillitis.

PMID- 15025372
TI  - Sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid--a case
      report.
AB  - We report a 55-year old female who presented with thyroid swelling for six
      months. She was clinically asymptomatic with normal thyroid functions.
      Thyroidectomy revealed the left lobe totally replaced by a well-circumscribed
      grey white homogenous tumor. Microscopically, the tumor comprised of cells
      arranged in adenoid pattern along with nests of cohesive intermediate cells, some
      also forming keratin pearls in a sclerotic and inflammatory background. The thin
      rim of thyroid at the periphery showed features of lymphocytic thyroiditis. No
      other associated malignancy was seen on thorough screening. The tumor cells were
      negative for thyroglobulin and calcitonin. The patient was thus diagnosed with
      Sclerosing mucoepidermoid carcinoma with eosinophilia, thyroid.

PMID- 15025373
TI  - Aplastic anaemia following varicella infection with coexistent microfilaremia of
      Wuchereria bancrofti--a case report.
AB  - Filariasis is a common public health problem in various regions of Indian
      subcontinent. There are many reports describing detection of microfilaria in
      different organ systems. There are limited number of reports available describing
      the presence of microfilaria in bone marrow. Here we report a young patient who
      developed aplastic anaemia following varicella infection. Peripheral blood and
      bone marrow showed many microfilariae of Wuchereria bancrofti. There are no
      reports describing this unique combination in the available literature.

PMID- 15025374
TI  - A case of TRAP sequence: acardiac twin.
AB  - Monochorionic twinning contributes significantly to neonatal morbidity and
      mortality. The twin-twin transfusion syndrome complicates 5-35% of monozygotic
      twin pregnancies with monochorionic placentation. The most severe and a rare
      manifestation of this condition is acardiac twinning which is seen in 1 in 35,000
      pregnancies. The acronym TRAP (Twin Reversed Arterial Perfusion) sequence is used
      to describe this condition. The acardiac twin does not survive while the
      mortality for the normal twin is about 50%. Proper timing of the delivery is of
      prime importance to survival of the normal fetus for which emphasis is placed on
      close sonographic monitoring for early antenatal diagnosis. We present such a
      case of TRAP sequence because of its rarity.

PMID- 15025375
TI  - Abnormal leukocyte histogram with a factitious automated white cell count due to
      Plasmodium vivax parasitemia--a case report.
AB  - Automated hematology analyzers are designed to produce accurate and precise blood
      counts on specimens which are either normal or show only numerical abnormalities.
      However they alert the operator in samples with unusual characteristics which
      could result in inaccurate measurement or require review of the blood smear. Even
      the most sophisticated instruments cannot recognize all the significant
      abnormalities that can be recognized by a human observer. Spurious automated
      white cell counts could result from platelet aggregates, nucleated red cells, non
      lysis of cells and a variety of other causes. We present a case with spurious
      leukocytosis due to Plasmodium vivax parasitemia which was flagged by the
      automated analyzer.

PMID- 15025376
TI  - Mucosal neuromas and prominent corneal nerves without MEN IIB.
AB  - Multiple endocrine neoplasia type II B or the mucosal neuroma syndrome is an
      autosomal dominant hamartoneoplastic syndrome. This is a report of a 17 year old
      female who presented with mucosal neuromas at age 7 years and had surgical
      excision of the lesion. Ten years later (at age 17 years) she had further
      recurrence of mucosal neuromas which were again surgically excised. She has been
      thoroughly investigated & followed, however to date she has no evidence of
      thyroid carcinoma which is a major complication of this syndrome.

PMID- 15025377
TI  - Squamous cell carcinoma of breast--report of two case.
AB  - Squamous cell carcinoma is an extremely rare variant of breast cancer. Presence
      of unequivocal squamous differentiation should be observed to diagnose a case as
      squamous cell carcinoma of breast since focal squamous metaplasia is frequently
      seen in common variants of breast carcinoma. We report here two cases of squamous
      cell carcinoma of breast, one a primary metaplastic type and the other one
      metastatic from a carcinoma of the cervix.

PMID- 15025378
TI  - Juvenile myelomonocytic leukaemia in a very young child--a case report.

PMID- 15025379
TI  - Co-existent massive renal replacement lipomatosis and xanthogranulomatous
      pyelonephritis--a case report.
AB  - Renal replacement lipomatosis is a benign condition that may assume major
      clinical significance by producing pyelocalyceal deformities that may be mistaken
      for true renal masses. While the number of reported cases of renal replacement
      lipomatosis has been relatively small, this entity's prevalence is probably
      underestimated. We report a case of co-existent massive renal replacement
      lipomatosis and xanthogranulomatous pyelonephritis.

PMID- 15025380
TI  - Methicillin resistant Staphylococcus aureus (MRSA): the associated risk factors.
AB  - Methicillin Resistant Staphylococcus Aureus (MRSA) infections are common among
      hospitalized patients in whom surgical/medical therapy provides easy and ample
      opportunity for infection. The present study was conducted to examine the
      incidence of MRSA amongst patients from burns and orthopaedic units which are
      high risk units, and to see the correlation of the risk factors associated with
      these infections. Four hundred and fifty patients from the above two units were
      included with complete clinical details. Pus samples/swabs were transported in
      glucose broth and subsequent identification of MRSA was based on standard
      techniques. The incidence of MRSA infection was found to be 17.5% while the nasal
      carriage of this pathogen was seen in 2.9% patients. The risk factors which were
      found to be significantly associated with these infections were prolonged
      hospital stay, (16.95+6.7d) previous history of hospitalization during the last
      three months (38%), intake of broad spectrum antibiotics within the last two
      weeks (39.2%), prior history of intake of any intravenous drug (6.3%) and
      carriage of Staphylococcus aureus (30.3%) particularly MRSA (61.5%) in nose.
      Since these risk factors were found to be significant, it is therefore essential
      to control and prevent these factors to minimize the spread of these multi drug
      resistant MRSA infections.

PMID- 15025381
TI  - Evidence of chlamydial infection in infertile women with fallopian tube
      obstruction.
AB  - The study was carried out to find the prevalence of Chlamydia trachomatis
      seropositivity among women with infertility of tubal origin. Forty women with
      tubal infertility (verified at hysterosalpingography and laproscopy), 20 women
      with infertility due to variety of other reasons and 20 healthy fertile women of
      reproductive age were enrolled in the study. It was found that the presence of
      Chlamydia specific IgG antibody was significantly higher (70%) in women with
      infertility of tubal origin as compared to 35% seropositivity in healthy fertile
      women and 55% seropositivity in infertile women with cause of infertility other
      than tubal factor. Seventy eight percent of women with frequency of coitus 3-4
      times/week were seropositive as compared to 34.7% when frequency of coitus was 1
      2 times/week. Study also showed the silent nature of this infection as history
      suggestive of past pelvic inflammatory disease (PID) was lacking in majority of
      the seropositive women (63.75%). In the study group, both the ends of the
      fallopian tubes (cornual and distal block) were involved with almost equal
      frequency. Eighty three percent of women with seropositivity had unilateral or
      bilateral hydrosalpinx and 75% of women had marked pelvic adhesions. These
      results support the fact that there is strong association between serum anti
      Chlamydial antibodies and tubal factor as a cause of infertility in infertile
      women.

PMID- 15025382
TI  - Seroanalysis of Chlamydia trachomatis and S-TORCH agents in women with recurrent
      spontaneous abortions.
AB  - Genital tract infections are an important cause of pregnancy loss, many of which
      are amenable to treatment. There is scarcity of literature on role of S-TORCH
      agents in recurrent spontaneous abortions (RSA) and available data on role of
      Chlamydia trachomatis (CT) is controversial. In a retrospective analysis, CT IgM,
      IgG and IgA antibodies were tested by indirect ELISA in 86, 53 and 30 sera
      samples respectively from women with RSA (= or > 3 abortions). IgM antibodies
      using m-capture ELISA for S-TORCH agents (Syphilis, tested by VDRL) were analysed
      in 47 sera from women with RSA. Results compared with 29 age matched normal
      pregnant women. Anatomical, endocrine, Rh incompatibility and chromosomal
      abnormality in the couple were ruled out prior to inclusion in the study. Serum
      anti-CT IgM positivity was 46.5% in RSA vs. 13.8% in control group (p < 0.001). S
      TORCH positivity in RSA group was 31.9% and nil in the control group (p < 0.005).
      Present study demonstrates a strong association between IgM antibodies to CT and
      S-TORCH agents in women with history of RSA.

PMID- 15025383
TI  - Primary rubella virus infection: prevalence and relationship to pregnancy
      wastage.
AB  - A total of 580 females (200 in prepubertal age and 380 in reproductive age group)
      were screened for primary rubella infection. Rubella specific serology (IgM and
      IgG) was studied by ELISA using commercially available diagnostic kits. IgM
      seropositivity was observed in 56 of 200 females (28%) of prepubertal age and 26
      of 380 females (6.84%) in reproductive age group. Out of 380 females in
      reproductive age, 183 presented with history of adverse pregnancy outcome and
      they showed a higher percentage of IgM seropositivity (10.38%) as compared to
      those with normal obstetric performance (3.55%). However, the difference was not
      statistically significant (p > 0.05). IgG seronegativity was found in 109 females
      (28.68%) in reproductive age suggesting their susceptibility to acquire primary
      rubella infection. Five of 380 (0.32%) females were seropositive for both IgG and
      IgM indicating reinfection.

PMID- 15025385
TI  - In vitro comparative kinetics of adhesive and haemolytic potential of T.
      vaginalis isolates from symptomatic and asymptomatic females.
AB  - The host parasite relationship and pathogenic mechanisms of the commonly reported
      sexually transmitted urogenital disease, trichomoniasis, are poorly understood.
      This study was planned to correlate the adhesion properties of Trichomonas
      vaginalis isolates from symptomatic and asymptomatic women to vaginal epithelial
      cells in vitro (in presence and absence of L. acidophilus) and to ascertain the
      haemolytic activity of the isolates, in order to assess these properties as
      possible markers of pathogenicity. Cytoadherence assay study shows the
      significant difference in adhesion only up to first 15 minutes of incubation in
      symptomatic versus asymptomatic isolates. The presence of L. acidophilus was
      found to be more effective in enhancing the attachment of T. vaginalis in a time
      dependent manner mostly operative through its pH lowering effect, whereas the
      excretory secretory products of L. acidophilus reduced the attachment in case of
      both symptomatic and asymptomatic isolates. Amount of haemoglobin released by
      isolates from symptomatic patients was significantly higher than by the isolates
      from asymptomatic women. This investigation forms the basis for future studies to
      explore the role of other known virulence factors of T. vaginalis in initiation
      and persistence of vaginal infection by the parasite.

PMID- 15025384
TI  - Occult hepatitis B virus (HBV) infection in healthy blood donors.
AB  - Blood transfusion is an important route of transmission of hepatitis B virus
      (HBV). Occult HBV infection can exist in the absence of HBsAg and can be detected
      by determining HBV DNA. To determine the occult HBV infection in healthy blood
      donors. One hundred adult healthy blood donors, negative for HBsAg, anti HCV, HIV
      1 and other risk factors were screened for HBV DNA by PCR. All the healthy blood
      donors were negative for HBV DNA by PCR. Occult HBV infection does not occur in
      the healthy blood donors in the population studied.

PMID- 15025386
TI  - Simplified panel of assimilation tests for identification of Acinetobacter
      species.
AB  - A total of 66 Acinetobacter isolates obtained from JIPMER hospital wards were
      subjected to phenotypic identification schemes involving 25-test and a simplified
      13-test panel of carbon utilization or assimilation tests. Reference strains
      belonging to different DNA groups (n=24) were also tested. Identification was
      done using numerical approach based on a matrix constructed of phenotypic data
      published elsewhere and the strains were assigned to different DNA groups
      according to classification of Tjernberg & Ursing. Sixty-six strains tested
      represented 10 DNA groups in matrix of large test panel; at a probability level
      of 0.95. Much simplified scheme of 13 assimilation test panel failed to
      differentiate some isolates with in A. calcoaceticus-A. baumannii complex (Acb
      complex) unlike extended panel. In all, from the large panel 95% of isolates were
      identified correctly among all the isolates and it did not identify 5% of
      isolates. From the small panel, a total of 89% of isolates were identified
      correctly and it could not identify 11% of isolates. Reduced number of
      assimilation tests to 13 from the large panel bought reduction in identification
      percentage rate by only 6%. It is impossible for many bacterial diagnostic labs
      worldwide to perform large panel of carbon utilization tests in routine practice.
      Simplified panel of assimilation tests suggested here seems to be the best
      alternative method for identification of Acinetobacter species.

PMID- 15025387
TI  - Primary lymphoma of the bone.

PMID- 15025388
TI  - Chair's introduction. Anaphylaxis.

PMID- 15025389
TI  - History and classification of anaphylaxis.
AB  - Anaphylaxis is the maximal variant of an acute allergic reaction involving
      several organ systems. The phenomenon itself is old, but it was recognized and
      named at the beginning of the 20th century by Richet and Portier. The clinical
      symptoms of anaphylaxis affect various organs, most commonly starting in the skin
      and proceeding to the respiratory tract, to gastrointestinal involvement and to
      cardiovascular symptoms, and finally to cardiac and/or respiratory arrest.
      Anaphylaxis stricto sensu is an immunological reaction, mostly mediated by IgE
      antibodies, but also by IgG or IgM antibodies (immune complex anaphylaxis). There
      are cases with similar clinical symptomatology without detectable immunological
      sensitization which are called pseudo-allergic or anaphylactoid reactions. In the
      newer nomenclature, some authors tend to include these under the heading of
      'anaphylaxis' which has then to be defined as an acute systemic hypersensitivity
      reaction. The most common elicitors of anaphylaxis include drugs, foods,
      additives, but also other allergens as well as physical factors (cold, heat, UV
      radiation). The clinical outcome--the intensity of the reaction--is not only
      influenced by the degree of sensitization, but also by concomitant other factors:
      sometimes, individuals only develop anaphylaxis after simultaneous exposure to
      the allergen and an infection, physical exercise, psychological stress or
      concomitant medication (e.g. beta blockers). The term 'summation anaphylaxis' has
      been proposed for this phenomenon which probably underlies many cases of so
      called idiopathic anaphylaxis. In patients with insect venom anaphylaxis,
      decreased levels of plasma angiotensin have been measured in inverse correlation
      to the severity of the reaction. Certain differential diagnoses have to be
      distinguished from anaphylaxis. Every patient with a history of anaphylaxis
      should undergo allergy diagnosis with the aim to detect the eliciting agent,
      characterize the relevant pathomechanism (e.g. IgE-mediated reaction) and to
      offer a tolerable alternative (in food or drug allergy). In clear-cut IgE
      mediated anaphylaxis, allergen-specific immunotherapy (hyposensitization) is the
      effective causal treatment, with success rates of 90% in insect venom
      anaphylaxis.

PMID- 15025391
TI  - The high affinity receptor for IgE, FcepsilonRI.
AB  - Progress in our understanding of the structure and function of the receptor with
      high affinity for IgE (FcepsilonRI) is already being applied in attempts to
      mitigate allergic reactions, specifically by using specific anti-IgEs to prevent
      sensitization. Investigations of the complex network of intracellular signals
      generated by FcepsilonRI and related receptors are proceeding. Although achieving
      a 'complete' description of the events will be a daunting task, the effort is
      likely to identify additional targets for therapeutic intervention along the way.

PMID- 15025390
TI  - Rethinking Th2 antibody responses and allergic sensitization.
AB  - Human Th2 cytokines (interleukins 4 and 13) induce co-expression of IgE and IgG4
      through sequential switching. The regulation of IgG4 responses and the role of
      these responses in the pathogenesis of allergy have not been characterized. We
      are addressing these issues by comparing and contrasting the expression of
      allergen-specific IgE and IgG4 in a population of European children thoroughly
      defined for lifestyle, environmental exposures and allergic phenotypes. The
      current analysis focused exclusively on children from non-farming families
      (n=493) in order to avoid potential effects of exposure to microbial products
      abundant in farming environments. We found that allergens induce Th2-mediated
      IgG4 and/or IgE responses in the majority of the population. Approximately two
      thirds of the children had allergen-specific IgG4 but not IgE, only a minority
      had both IgG4 and IgE, only a few were negative for both, and virtually none had
      only IgE. The prevalence of asthma and hay fever was dramatically higher in
      children with high IgG4 and IgE compared to children who only mounted IgG4 or low
      IgG4 and IgE responses. These results appear to recapitulate different stages of
      in vivo Th2-dependent sequential switching from IgG4 to IgE. These patterns of
      Th2-induced antibody responses may warrant a redefinition of the notion of
      allergen sensitization.

PMID- 15025392
TI  - Effector cells of anaphylaxis: mast cells and basophils.
AB  - Systemic anaphylaxis arises when mast cells, possibly along with other cell
      types, are provoked to secrete mediators that evoke a systemic response. Mast
      cells in perivascular, respiratory, gastrointestinal and cutaneous tissues are
      likely involved, regardless of whether IgE or non-IgE-dependent pathways are
      invoked. Alpha/beta tryptases are selectively and abundantly produced by mast
      cells. Tryptase levels in the circulation provide a precise indicator of mast
      cell involvement. Mature beta tryptase is stored in secretory granules and is
      released when the cells are activated to degranulate, as occurs in anaphylaxis.
      Alpha/beta pro/pro' tryptases are spontaneously secreted by mast cells.
      Consequently, mature tryptase levels in serum (normally 1 ng/ml) are elevated in
      systemic anaphylaxis. Total tryptase levels (mature plus precursor forms),
      normally 1-15 ng/ml in baseline serum samples, are elevated in patients with
      systemic mastocytosis (> 20 ng/ml), a disease that also predisposes one to
      anaphylactic reactions. The assessment of basophils in systemic anaphylactic
      reactions has been problematic, because an assay for a specific releasable marker
      from this cell type has not been developed. Nevertheless, in cases of anaphylaxis
      in which elevations of histamine, but not tryptase, have been detected, it is
      enticing to speculate that basophil-dependent anaphylaxis may have occurred.

PMID- 15025394
TI  - Patterns of anaphylaxis: acute and late phase features of allergic reactions.
AB  - Anaphylaxis is usually defined as a multi-system allergic reaction, but includes
      isolated shock or airway obstruction. Hives do not occur in 20-30% of cases.
      Gastrointestinal (GI) symptoms are more common with foods. Cardiac anaphylaxis
      can cause arrhythmias, bradycardia or chest pain with ECG changes. Plasma
      histamine level correlates with hives and GI symptoms. Serum tryptase is elevated
      less often in food allergy, and correlates poorly with plasma histamine level.
      Anaphylaxis occurs in 30/100,000 population/year (mortality 1-2%) and is caused
      by foods (35%), drugs/ biologicals (25%), insect stings (15%), exercise (5%) or
      is idiopathic (20%). Onset of anaphylaxis to stings or allergen injections is
      usually rapid: 70% begin in < 20 minutes and 90% in < 40 minutes. Food/ingestant
      anaphylaxis may have slower onset or slow progression. Rapid onset is associated
      with greater severity. Prolonged anaphylaxis can be resistant to epinephrine and
      i.v. fluids. Biphasic allergic reactions which recur some hours after the early
      phase of the reaction were reported in 25% of cases of fatal and near-fatal food
      reactions, and in 23% of drug/biological reactions. But they occurred in only 6%
      of anaphylaxis of mixed causes and are uncommon with insect stings. Late phase
      (biphasic) reactions rarely occur without initial hypotension or airway
      obstruction.

PMID- 15025393
TI  - Cytokine enhancement of anaphylaxis.
AB  - Two distinct pathways of anaphylaxis in the mouse have similar clinical features:
      the classical pathway in which antigen cross-linking of IgE bound to FcepsilonRI
      on mast cells induces histamine release, and a second pathway, in which cross
      linking of macrophage FcgammaRIII by antigen-IgG complexes induces release of
      platelet activating factor. IgG antibodies are a double-edged sword, blocking the
      first pathway but mediating the second. Both anaphylaxis pathways are
      considerably enhanced by interleukin (IL)4 or IL13 through a Stat6-dependent,
      gammac-independent mechanism. Enhancement is rapid, sensitive, and observed
      during infection with intestinal nematode parasites, where it probably
      contributes to parasite expulsion. Enhancement involves increased sensitivity to
      mediators (platelet activating factor, histamine, serotonin, and cysteinyl
      leukotrienes), rather than increased mediator production, and is mediated by a
      synergistic increase in vascular permeability by cytokine plus mediator. Basophil
      production of IL4 and IL13, which is more sensitive to FcepsilonRI cross-linking
      than mast cell release of mediators, may sensitize target cells to mediators
      prior to their release. Inhibitors of IL4 and IL13 may ameliorate allergy by
      rapidly blocking the sensitizing effects of these cytokines on the effector phase
      of the allergic response, as well as by more slowly blocking the induction phase
      of this response.

PMID- 15025395
TI  - Fatal anaphylaxis in the UK, 1992-2001.
AB  - Each year in the UK, around nine deaths are attributed to anaphylaxis to
      pharmaceuticals, six to food and four to stings. I have identified 214 deaths
      associated with anaphylaxis, and have sufficient information for 196 to determine
      that 88 deaths were due to shock, 96 to asphyxia. Five deaths followed
      epinephrine overdose, seven were complicated by disseminated intravascular
      coagulation. There will have been other unrecognized fatal antibiotic and
      asthmatic food reactions. For foods, peak age was 17-27 with a female and atopic
      predominance; the first arrest was commonly from asthma 25-35 minutes after the
      implicated food. For stings, peak age was 45-70 with male and non-atopic
      predominance; death was commonly from shock 10-15 minutes after the sting. A
      majority of deaths from pharmaceuticals in hospital took 5 minutes or less from
      dose to arrest; peak age was 60-75. Maximum time for any cause from trigger to
      first arrest was 6 hours. The danger of epinephrine overdose and its limitations
      in reversing anaphylaxis must be recognized. The patient should remain supine
      with legs raised throughout sting and other shock reactions. Prevention of fatal
      food reactions will depend on avoidance and optimal daily control of asthma.

PMID- 15025396
TI  - The human heart as a shock organ in anaphylaxis.
AB  - Human mast cells, by elaborating vasoactive mediators and cytokines, are the
      primary effector cells of anaphylaxis. A body of evidence implicates human heart
      mast cells (HHMCs) in anaphylaxis. These cells have been identified
      perivascularly, in dose proximity to myocytes and in the arterial intima in human
      heart tissue. The membrane surface of mast cells from human heart tissue of
      patients undergoing cardiac transplantation expresses the high affinity receptors
      for IgE (FcepsilonRI) and C5a receptors. Activation of HHMCs in vitro with anti
      IgE or anti-FcepsilonRI induced the release of preformed mediators (histamine,
      tryptase and chymase) and the de novo synthesis of LTC4 (approximately equal to
      18 ng/10(6) cells) and PGD2 (approximately equal to 18 ng/10(6) cells).
      Complement activation and anaphylatoxin formation occur during anaphylaxis in
      human. C5a caused rapid release of histamine and tryptase from HHMCs. These cells
      are activated in vitro by therapeutic (general anaesthetics, protamine, etc.) and
      diagnostic agents (radio contrast media, etc.) that may cause non-IgE-mediated
      anaphylactic reactions. Administration of low concentrations of histamine and
      cysteinyl leukotrienes in subjects undergoing diagnostic catheterization caused
      significant systemic and coronary haemodynamic effects. Taken together, these
      results indicate that the human heart can be both the site and the target of
      anaphylactic reactions.

PMID- 15025397
TI  - Food-induced anaphylaxis.
AB  - Food allergies affect approximately 2% of the population and are the single
      leading cause of anaphylaxis occurring outside of hospitals in westernized
      countries. Given the frequency of IgE-mediated food allergy, it is imperative
      that physicians appropriately diagnose food-allergic patients, educate them in
      the appropriate measures to prevent accidental ingestion of food allergens, teach
      them to recognize early signs of anaphylaxis, and arm them with medications and a
      treatment plan to utilize in case of the 'almost inevitable' accidental
      ingestion.

PMID- 15025398
TI  - Anaphylaxis to insect venom.
AB  - Systemic reactions to insect stings have a prevalence of about 1% in the adult
      population. The majority presents with urticaria and angioedema, and the number
      of deaths per year registered as due to insect stings is 0.1-0.5 per million in
      the general population. The venom contains peptides and low molecular weight
      substances such as histamine with an effect on blood vessels, smooth muscles and
      nerves. High molecular weight components in the venom often have enzyme activity
      and in addition can act as allergens. It can be difficult to separate allergic
      from vasovagal or psychogenic reactions based on the clinical history alone. Skin
      test reaction to venom and/or venom specific IgE in the blood indicate an allergy
      although a high proportion of people in the general population (up to 20%) with
      no previous reactions are positive in such tests. Test results can be used to
      identify the responsible insect species, since allergic reactions can occur
      against species-specific as well as common allergens in the venom. Following a
      systemic allergic reaction only about half of the patients will react
      systemically to a future sting. Immunotherapy with insect venom is effective but
      the duration of the treatment is still under debate.

PMID- 15025399
TI  - Anaphylaxis to anaesthetic drugs.
AB  - Severe anaphylactic reactions during anaesthesia increased dramatically in
      incidence in the mid 1970s. Studies performed in our unit over the subsequent 25
      years demonstrated the involvement of IgE in these reactions and the value and
      safety of intradermal and prick testing in the diagnosis and determination of the
      drug responsible. Radioimmunoassay studies demonstrated that neuromuscular
      blocking drugs produce anaphylaxis by cross-linking IgE molecules via their
      substituted ammonium groups. The IgE binding of these drugs leads to a high
      incidence of cross sensitivity. Mast cell tryptase measurement is highly
      sensitive and specific for anaphylaxis although it can be elevated in reactions
      due to direct histamine release. The reactions are unpredictable from the
      history. The heart is rarely a target organ in human anaphylaxis although the
      diseased heart is more likely to fail or produce serious arrhythmias than the
      normal heart. Colloid solutions produce a better response than crystalloid
      solutions in the treatment of hypotension. Anaesthetic allergy persists up to 27
      years. Subsequent anaesthesia based on the findings of skin testing is usually
      safe.

PMID- 15025401
TI  - Fatal course of Vespula venom immunotherapy: pretreatment withdrawl of the beta
      blocker may have been involved.

PMID- 15025400
TI  - The radiocontrast molecule in anaphylaxis: a surprising antigen.
AB  - X-ray contrast media are individually injected into human blood vessels in
      greater quantities than any other pharmacological substance. Adverse reactions to
      these substances have heretofore been considered anaphylactoid in nature. Others
      and we have demonstrated that the mechanisms involved are multifactorial and may
      involve activation of mast cells and basophils, activation of the complement
      system, activation of the contact system, and the conversion of L-arginine into
      nitric oxide. Appropriate pretreatment with corticosteriods will diminish the
      incidence of reactions. Most recently we have demonstrated that the contrast
      media function as 'pseudoantigens' (PsA). They can combine with antibodies, but
      cannot themselves produce antibodies. This property appears to be dependent on
      aggregation in high concentrations and varies with the individual media. It
      furthermore appears to be non-specific in relation to antibodies, and suggests
      that binding occurs to the Fc portion of immunoglobulins. We have now
      demonstrated that the least toxic of current media demonstrate the best antibody
      binding and in sufficient concentration can inhibit contrast induced mast cell
      activation and/or non-contrast antigen induced mast cell activation, apparently
      due to in vivo pseudoantigen excess. In lesser concentrations and/or lesser
      binding, the media can trigger mast cell activation.

PMID- 15025402
TI  - Epinephrine (adrenaline) in the first-aid, out-of-hospital treatment of
      anaphylaxis.
AB  - Epinephrine (adrenaline), the initial treatment of choice for systemic
      anaphylaxis, is an alpha- and beta-adrenergic agonist with bidirectional, cyclic
      adenosine monophosphate-mediated pharmacological effects on target organs, and a
      narrow therapeutic index. In a recent study, 0.95% of a geographically-defined
      population was found to have had epinephrine dispensed for out-of-hospital use;
      dispensing rates within this population varied from 1.44% for individuals under
      age 17 years to 0.32% for those older than 65 years. Although epinephrine is
      widely available in the community, it is not necessarily given in a timely manner
      when anaphylaxis occurs. Individuals with anaphylaxis may fail to respond to
      first-aid treatment with epinephrine for a variety of reasons. These include: (1)
      delay in treatment (in an animal model, epinephrine injection at the nadir of
      shock fails to provide sustained haemodynamic recovery); (2) administration of
      epinephrine by sub-optimal routes such as subcutaneous injection or inhalation
      from a pressurized metered-dose inhaler instead of intramuscular injection; (3)
      administration of an inappropriately low epinephrine dose due to the limitations
      currently imposed by the availability of only two fixed-dose auto-injectors:
      EpiPen Jr 0.15 mg or EpiPen 0.3 mg; and (4) injection of 'outdated' epinephrine,
      with inadvertent administration of an inadequate dose. Additional fixed-dose
      formulations of epinephrine are needed to facilitate optimal first-aid dosing in
      patients of all ages and sizes.

PMID- 15025403
TI  - New approaches for the treatment of anaphylaxis.
AB  - Anaphylaxis represents the most extreme form of life-threatening allergic
      reactions. However, effective long-term therapies for this condition are not
      currently available. A number of potential approaches have proven effective in
      murine models of peanut-induced anaphylaxis and are currently being considered in
      humans, including the use of vaccines containing 'engineered' recombinant food
      proteins and Chinese herbal medications. TNX-901 is a humanized IgG1 anti-IgE mAb
      that recognizes and masks an epitope in the CH3 region responsible for binding to
      the high affinity Fc epsilon receptor (FcepsilonRI) on basophils and mast cells.
      Recently, we conducted a double-blinded, placebo-controlled, randomized, dose
      escalation trial in 84 patients with a history of peanut allergy. Allergy was
      confirmed and the threshold dose of encapsulated peanut established by a double
      blinded, placebo-controlled oral food challenge (DBPCOFC) at screening. Patients
      were randomized 3:1 in three dose groups to receive either TNX-901 (150, 300 and
      450 mg) or placebo subcutaneously every four weeks for four doses. They underwent
      a final open food challenge within 2-4 weeks after the last dose of study
      medication. From mean baseline values of 178-436 mg in the various treatment
      groups, the mean increases in the open food challenge threshold were 710, 913,
      1650 and 2627 mg for the placebo, 150, 300 and 450 mg for TNX-901 dose groups,
      respectively (P = 0.0004, 450 mg vs. placebo; P = 0.0008 for trend with dose).
      TNX-901 was well tolerated. TNX-901 at a dosage of 450 mg significantly increased
      the threshold of sensitivity to peanut by open food challenge from a level of
      about half a peanut (178 mg) to almost nine peanuts (2805 mg). These studies
      suggest that treatment of patients with anti-IgE therapy may represent an
      effective long-term approach for management of food-induced anaphylaxis.

PMID- 15025404
TI  - Patient's perspective and public policy regarding anaphylaxis.
AB  - It is estimated that dose to 7 million Americans have food allergy. The incidence
      of food allergy, particularly peanut allergy, is believed to be on the rise.
      Several studies have shown that in spite of a patient's best efforts to avoid
      ingesting the allergy-causing food, reactions will occur. These reactions occur
      from incorrect ingredient information in food service or restaurant settings,
      incorrect product labels, or mistakes in label reading. In the hospital setting,
      patients are sometimes treated for an anaphylactic reaction in the emergency room
      but are not given instructions to see a specialist to determine the cause of
      their reaction, nor are they given a prescription for epinephrine to arm them to
      treat future allergic emergencies. Two studies of fatal and near fatal allergic
      reactions concluded that a delay in administration of epinephrine could have been
      a factor in the fatal outcomes. However, schools often do not have written
      emergency action plans in place for children with documented food allergy, and
      patients and caregivers often report not knowing when to use the epinephrine kit
      or how to use it. Until there is a cure for food allergy and anaphylaxis,
      avoidance of the allergen is key. There is much work to be done in education and
      public policy regarding anaphylaxis.

PMID- 15025405
TI  - Advances in cancer research and practice.
AB  - The cure and management of patients with cancer are constantly evolving. The
      rapid translation of scientific findings into clinical therapeutics has resulted
      in a variety of efficacious cancer agents. Results from recently completed and
      ongoing clinical trials continue to demonstrate the efficacy and tolerability of
      many of these new cancer therapies. This supplement aims to provide the oncology
      nurse with a better understanding of the pathophysiology and management of a
      variety of cancers. Each article provides practical information to the nurse
      treating cancer in clinical practice. At the conclusion of this educational
      activity, the participant should be able to discuss the most recent advances in
      the medical management of leukemia as well as lung, breast, and ovarian cancer;
      to describe the role and report the results of new molecular-targeted therapies
      in treating malignancies; to review new therapies for managing chemotherapy
      related hematologic toxicities, cognitive impairment, fatigue, and pain; and to
      recognize the need and discuss the measures used to improve symptom control and
      supportive care in the palliative setting.

PMID- 15025406
TI  - New developments in endocrine therapy: role of adjuvant therapy for early breast
      cancer.
AB  - Tamoxifen has become the standard of care in relation to hormonal therapy for
      women with hormone-sensitive tumors. However, recently completed and ongoing
      studies indicate that third-generation aromatase inhibitors may be more effective
      than tamoxifen for a wide range of patients with breast cancer. Drugs in this
      class currently are approved as first-line endocrine therapy for postmenopausal
      women with metastatic hormone-dependent breast cancer, and as second-line
      endocrine therapy after failure of antiestrogen therapy alone or multiple
      hormonal therapies. The interim results from the Arimidex, Tamoxifen Alone or in
      Combination Trial support the use of an aromatase inhibitor as an alternative to
      tamoxifen for adjuvant therapy in postmenopausal women with operable breast
      cancer that is hormone positive. In this trial, anastrozole had a favorable side
      effect profile, with fewer cases of endometrial cancer and fewer thromboembolic
      events than tamoxifen. Other recent studies have indicated that an aromatase
      inhibitor may be superior to tamoxifen as preoperative treatment for women with
      hormone-sensitive, primary breast cancer. Numerous clinical trials currently are
      comparing the efficacy of aromatase inhibitors with that of tamoxifen used as
      adjuvant therapy for postmenopausal women who have early-stage breast cancer. The
      results of these trials will provide additional information about the best ways
      to use these powerful agents for patients with breast cancer.

PMID- 15025407
TI  - Clinical trials update: Medical management of advanced breast cancer.
AB  - Selection of treatment for metastatic breast cancer depends on several factors:
      the status of estrogen receptors or progesterone receptors on breast cancer cells
      and the expression levels of human epidermal growth factor receptor-2. The
      presence of estrogen or progesterone receptors typically indicates slower-growing
      tumors that may be amenable to hormonal manipulation, which provides significant
      disease control while offering a better toxicity profile than conventional
      chemotherapy. The understanding of hormonal therapies in patients with
      postmenopausal metastatic breast cancer has advanced greatly in the past several
      decades. Aromatase inhibitors, although used initially as second-line therapy,
      recently have proved to be as effective as tamoxifen, if not superior to it, as
      first-line therapy for metastatic breast cancer. New data also suggest that
      letrozole provides significantly better objective responses than anastrozole as
      second-line therapy. Exemestane, a steroidal aromatase inhibitor, is an effective
      third-line therapy. Fulvestrant, an estrogen receptor antagonist with no known
      agonist effect, provides a new option for hormonal therapy. For patients with
      metastatic breast cancer and overexpression of human epidermal growth factor
      receptor-2 on tumor cells, the monoclonal antibody trastuzumab is the preferred
      option, either in combination with paclitaxel as first-line treatment, or as a
      single agent for second-line therapy. By extending the sequence of hormonal
      therapy, disease progression and the need for chemotherapy may be significantly
      delayed, potentially extending patient survival rates and improving quality of
      life.

PMID- 15025408
TI  - Treatment advances in ovarian cancer.
AB  - Ovarian cancer is the fifth leading cause of cancer death among women. Although
      many patients respond to initial surgery and platinum-based chemotherapy
      regimens, recurrence is common, and many individuals require treatment with
      multiple agents. A number of drugs not cross-reactive with platinums or taxanes
      are effective as secondary treatment for women with recurrent ovarian cancer. For
      this reason, ovarian cancer now is considered a chronic disease with treatment
      aimed at control of disease, palliation of symptoms, and quality-of-life
      maintenance. Achievement of these goals requires selection of effective therapies
      (eg, liposomal preparations) that minimize toxicities and effectively manage both
      short- and long-term adverse reactions. Novel therapeutic approaches are aimed at
      increasing the efficacy and tolerability of therapy for patients with ovarian
      cancer. Some of these therapies include intraperitoneal drug administration
      designed to achieve higher drug concentrations at tumors as well as agents that
      target underlying disease processes (eg, anticancer vaccines, monoclonal
      antibodies directed against cancer antigens, gene therapy, and antiangiogenic
      treatments). This report reviews both current and developing approaches to the
      treatment of this malignancy.

PMID- 15025409
TI  - Epidermal growth factor receptor tyrosine kinase inhibitors: application in non
      small cell lung cancer.
AB  - Despite treatment advances over the past decade, long-term survival for patients
      with non-small cell lung cancer (NSCLC) remains poor, and treatment options
      available after second-line therapy are limited. Increased understanding of
      cancer biology has led to the identification of several potential targets for
      treatment. The epidermal growth factor receptor (EGFR) belongs to a family of
      plasma membrane receptor tyrosine kinases that controls many important cellular
      functions, from growth and proliferation to cell death. This receptor is a
      particularly promising therapeutic target because it often is overexpressed in
      patients with NSCLC and has been implicated in the pathogenesis as well as the
      proliferation, invasion, and metastasis of lung cancer and other malignancies.
      New agents developed to inhibit EGFR function include small-molecule tyrosine
      kinase inhibitors, monoclonal antibodies to EGFR, and pan-EGFR inhibitors.
      Completed and ongoing clinical trials have shown that EGFR inhibitors have
      remarkable efficacy for patients with relapsed NSCLC. Among these, two phase 2
      trials have shown that ZD1839 is effective when used as monotherapy. The response
      rates are comparable with those for docetaxel given in the second-line setting.
      Another phase 2 trial has shown that OSI-774 is effective in the same setting.
      Data from phase 3 trials indicate that adding an EGFR tyrosine kinase inhibitor
      to chemotherapy does not provide an additional survival benefit, as compared with
      standard chemotherapy alone for first-line treatment of NSCLC. It appears that
      EGFR tyrosine kinase inhibitors are safe and well tolerated by patients with
      cancer. Further studies will elucidate how these new agents can best be used for
      NSCLC and other tumor types.

PMID- 15025410
TI  - Innovations in the management of leukemia: role of biologic therapies.
AB  - Chronic myelogenous leukemia (CML) results from clonal proliferation of malignant
      hematologic progenitor cells and is responsible for 7% to 15% of all adult
      leukemias. The hallmark of CML is a genetic translocation between chromosomes 9
      and 22 (the Philadelphia chromosome), which creates the abnormal bcr-abl gene and
      a continuously activated Bcr-Abl protein. Bcr-Abl tyrosine kinase activity leads
      to signal transduction and cell growth. Traditional therapies for CML include
      allogeneic stem cell transplantation, interferon alfa, and oral chemotherapeutic
      agents. However, because Bcr-Abl is the causative abnormality in CML, it
      represents an ideal target for rational biologic therapy. Imatinib mesylate is an
      orally available tyrosine kinase inhibitor that specifically blocks Bcr-Abl
      function. Clinical trials have demonstrated that imatinib mesylate produces rapid
      responses in patients with all stages of CML, including those who were resistant
      to interferon alfa therapy or intolerant of it. When imatinib mesylate therapy
      was initiated early in the course of CML, there was a complete hematologic
      response in 98% of the patients and a complete cytogenetic response in 72% of the
      patients. Although long-term safety and survival data are not yet available,
      imatinib mesylate is a promising new treatment option for CML that targets the
      molecular cause of the disease.

PMID- 15025411
TI  - Managing hematologic toxicities: novel therapies.
AB  - Myelosuppression associated with cancer chemotherapy may lead to neutropenia,
      anemia, or both, resulting in an increased risk for infection, fatigue,
      diminished quality of life, and reduced survival. In addition, neutropenia
      specifically has been shown to result in dose reductions, treatment delays, or
      both in subsequent chemotherapy cycles. Hematopoietic growth factors have been
      used effectively as supportive therapy to reduce chemotherapy-associated
      neutropenia and anemia. New preparations have the potential to improve treatment
      outcome dramatically. Results from recently reported studies indicate that
      patients at risk for neutropenia can be safely and effectively treated with
      pegfilgrastim once per chemotherapy cycle, and that those with anemia can be
      managed with weekly or biweekly darbepoetin alfa therapy. These new treatments
      have the potential to reduce the morbidity and mortality associated with
      opportunistic infections, decrease the requirement for potentially dangerous
      blood transfusions, and improve the quality of life for patients undergoing
      cancer chemotherapy. The longer dosing intervals offered by these new
      preparations may decrease healthcare expenses and enhance patient adherence.

PMID- 15025412
TI  - Anemia in the oncology patient: cognitive function and cancer.
AB  - Cancer-related anemia often develops from the infiltration of marrow by malignant
      cells, impaired hemoglobin (Hb) production related to chemotherapy or radiation
      therapy, iron deficiency, or low endogenous erythropoietin levels. Patients with
      cancer-related anemia may experience cognitive dysfunction including decreased
      mental alertness, poor concentration, and memory problems. Anemia-mediated
      cerebral hypoxia may cause symptoms such as headache, vertigo, tinnitus, and
      dizziness. These symptoms often are exacerbated in the elderly patient with
      cancer and related to underlying low Hb concentrations. Restoring Hb levels via
      the administration of iron supplements, blood transfusions, or, more recently,
      erythropoiesis-stimulating therapy (epoetin alfa) results in significant
      improvement of cognitive function. The use of epoetin alfa as a treatment option
      for patients with chemotherapy-associated anemia and an Hb concentration less
      than 10 g/dL has been recommended by the American Society of Clinical Oncology
      and the American Society of Hematology. Erythropoiesis-stimulating therapies are
      a promising treatment option for cancer-related anemia that may improve cognitive
      function and quality of life for patients with cancer.

PMID- 15025413
TI  - The price of HIV treatment.
AB  - The burden of HIV on society in the developing world and the price for treatment
      is enormous. The recent agreement between the Clinton Foundation and generic
      pharmaceutical companies is a major step forward. Also the cost-effectiveness is
      superior to treatment of for example hypercholesterolaemia. However, there are
      other prices to be paid, since drugs may induce unfavourable and unwanted side
      effects. For the future the challenge remains to keep all prices for HIV
      treatment as low as possible. Only an affordable and harmless HIV treatment might
      bring the progress of the HIV pandemic to a halt.

PMID- 15025414
TI  - Antiretroviral therapy in HIV patients: aspects of metabolic complications and
      mitochondrial toxicity.

PMID- 15025415
TI  - Pathophysiology of ANCA-associated vasculitides: are ANCA really pathogenic?
AB  - The strong relation between antineutrophil cytoplasmic autoantibodies (ANCA) and
      primary vasculitic syndromes suggests a pathophysiological role for ANCA.
      Experimental evidence for the pathogenic potential of ANCA has been derived from
      in vitro studies that demonstrate that ANCA can activate tumour necrosis factor
      alpha primed neutrophils, monocytes and/or endothelial cells. The binding of ANCA
      to primed neutrophils results in activation of these cells by a process that is
      largely dependent on engagement of beta-2 integrins and on the interaction of the
      Fc portion of ANCA. An Fc-independent mechanism is, however, also operative. In
      experimental animal models, it has been demonstrated that immunisation with
      myeloperoxidase (MPO) induces MPO-ANCA. The induction of ANCA, however, is not
      sufficient to induce vasculitis in rats since immune complexes first have to be
      deposited along the vessel wall before lesions develop. When MPO-deficient mice
      are, however, immunised with murine MPO, anti-MPO immunoglobulins are purified
      and subsequently injected into mice that are not deficient for MPO, systemic
      vasculitis and glomerulonephritis is induced. These experiments suggest that ANCA
      indeed induces vasculitis. Risk factors for breaking self-tolerance to ANCA
      antigens are genetic factors, drugs, chemical substances and/or infectious
      agents.

PMID- 15025417
TI  - A man with a bulging mass in his left lumbar region.

PMID- 15025416
TI  - Immune restoration disease in HIV-infected individuals receiving highly active
      antiretroviral therapy: clinical and immunological characteristics.
AB  - BACKGROUND: HIV-infected patients responding to HAART can show a diverse spectrum
      of symptoms caused by inflammatory reaction. The pathogenesis of this phenomenon,
      called immune restoration disease (IRD), is unclear. This study describes the
      spectrum of IRD and analyses the immunological and clinical parameters that could
      be related to its development. METHODS: In a retrospective, matched case-control
      study, 17 HIV-infected individuals who developed inflammatory symptoms < 12
      months after initiation of HAART were included. HIV-infected controls were
      matched for age, gender and CDC classification. Factors included in the analysis
      were: CD4+ and CD8+ cell counts, deltaCD4+ and deltaCD8+, CD4/CD8 ratios, HIV-1
      RNA load (VL), AVL and the number of CDC events prior to HAART. RESULTS: The
      median time after initiation of HAART and developing IRD (n = 17) was 72 days
      (range 2-319). In nine cases (53%) a mycobacterial infection was identified as
      the underlying cause. HAART was started at a mean CD4+ count (+/- SD) of 55 x
      10(6) /l (+/- 59) and 85 x 10(6) /l (+/- 78.0) for cases and controls,
      respectively (p = 0.13). After initiation of HAART, the CD4+ count showed a 10.6
      fold increase at the onset of IRD in the cases and a 2.7 fold increase in the
      controls in an equal period of time (p = 0.020). The other parameters analysed
      did not differ significantly between cases and controls. CONCLUSION: We conclude
      that the risk of developing IRD is associated with a high-fold increase in CD4+
      lymphocytes. In this study, mycobacteria are the pathogens most frequently
      associated with IRD.

PMID- 15025418
TI  - Successful treatment of metastatic esthesioneuroblastoma.
AB  - This case report describes a patient with a metastasised olfactorial
      esthesioneuroblastoma Hyams grade 4 who has been treated with debulking surgery
      and radiotherapy. After relapse in lymph node, lung and brain, he received
      additional irradiation and six cycles of carboplatin, vincristine and
      cyclophosphamide intravenously every three weeks. The patient has now been
      disease free for 7.8 years. Our data suggest that metastatic
      esthesioneuroblastoma is sensitive to platinum-based chemotherapy. This patient
      illustrates that this tumour is very sensitive to platinum-based chemotherapy and
      that durable complete response can be achieved, even in a metastatic ENB.

PMID- 15025419
TI  - Acute renal failure due to carnitine palmitoyltransferase II deficiency.
AB  - Carnitine palmitoyltransferase II (CPT-II) deficiency is the most common long
      chain fatty acid oxidation defect, resulting in rhabdomyolysis and acute renal
      failure (ARF). There are three forms of CPT-II deficiency: the neonatal,
      infantile and adult form. We report an adult form of CPT-II deficiency in a
      patient who presented with attacks of exercise-induced rhabdomyolysis and ARF.

PMID- 15025420
TI  - Optimisation of the antibiotic guidelines in The Netherlands. VII. SWAB
      guidelines for antimicrobial therapy in adult patients with infectious
      endocarditis.
AB  - The Working Party on Antibiotic Policy (Dutch acronym is SWAB) is a Dutch
      organisation that develops guidelines for in-hospital antimicrobial therapy of
      bacterial infectious diseases. This present guideline describes the antimicrobial
      treatment for adult patients with infective endocarditis. The choice and duration
      of antimicrobial therapy is determined by the infecting micro-organism,
      sensitivity of this micro-organism for antimicrobial therapy, location of the
      endocarditis, left-sided or right-sided, and presence of intracardial prosthetic
      material. In this guideline, the empirical therapy for endocarditis is discussed
      as well as the therapy for the most frequent causative organisms: streptococci,
      enterococci, staphylococci and HACEK micro-organisms.

PMID- 15025421
TI  - Renal replacement therapy for acute renal failure on the ICU: coming of age?

PMID- 15025422
TI  - Platelet serotonin 5-HT2A receptor binding in patients with carcinoid tumor.

PMID- 15025423
TI  - Platelet serotonin 5-HT2A receptor binding in patients with carcinoid tumor.
AB  - BACKGROUND: As carcinoid tumors produce and secrete serotonin, various serotonin
      markers in blood, plasma and urine have been used as diagnostic tools, and
      quantification of the urinary excretion of the serotonin metabolite 5
      hydroxyindoleacetic acid (5-HIAA) is the method most frequently used. METHODS:
      [3H]lysergic acid diethylamide ([3H]LSD) binding to the platelet serotonin 5-HT2A
      receptor was investigated in nine patients with carcinoid tumors. The possible
      effect of serotonin-rich food on the receptor binding was also investigated.
      RESULTS: B(max) for [3H]LSD binding was significantly lower in the carcinoid
      group than in the control group (mean +/- SD: 17.6 +/- 1.3 vs. 23.9 +/- 5.2
      fmol/mg protein; p = 0.007). Kd for [3H]LSD binding was significantly higher in
      the carcinoid group than in the control group (median: 1.14 vs. 0.71 nmol/L; p =
      0.03). B(max) was inversely related to the urinary 5-HIAA excretion, but the
      correlation did not reach statistical significance (r(s) = -0.57; p = 0.14).
      Intake of five bananas per day for one week had no effect on B(max) or Kd in
      healthy volunteers. CONCLUSIONS: The results are consistent with a down
      regulation of the 5-HT2A receptor as a response to the high serotonin levels
      found in patients with carcinoid tumors. Intake of serotonin-rich food does not
      affect the receptor characteristics. Further studies are needed to determine
      whether the platelet 5-HT2A receptor status can be used as a supplement to
      urinary 5-HIAA and other biochemical variables in carcinoid tumors.

PMID- 15025424
TI  - Synovial concentrations of the angiogenic peptides bFGF and VEGF do not
      discriminate rheumatoid arthritis from other forms of inflammatory arthritis.
AB  - OBJECTIVES: To investigate whether concentrations of basic fibroblast growth
      factor (bFGF) and vascular endothelial growth factor (VEGF) in aspirated synovial
      fluid can be used to distinguish rheumatoid arthritis from other forms of
      inflammatory arthritis. METHODS: bFGF and VEGF concentrations were measured in
      aspirated synovial fluid and serum samples from 66 patients with active arthritis
      (clinical diagnoses: rheumatoid arthritis (35 patients), psoriatic arthritis (9),
      reactive arthritis (11) and arthritis UNS (11)) utilizing commercial ELISA kits.
      RESULTS: In comparison with controls, elevated concentrations of VEGF were found
      in synovial fluid compared with in serum in all forms of arthritis. There were no
      significant differences in synovial fluid bFGF or VEGF concentrations between
      rheumatoid arthritis and the other forms of inflammatory arthritis. CONCLUSION:
      Both serum bFGF and VEGF concentrations were increased in patients with
      rheumatoid arthritis. Patients treated with steroids had lower synovial fluid
      bFGF concentrations. Synovial fluid levels of bFGF and VEGF were elevated but
      could not be used to distinguish rheumatoid arthritis from other forms of
      inflammatory arthritis.

PMID- 15025425
TI  - Relationship between urinary albumin and albumin/creatinine ratio during normal
      pregnancy and pre-eclampsia.
AB  - Pre-eclampsia is a serious complication of pregnancy and it is important to
      detect the condition as early as possible. Albuminuria is an important symptom of
      pre-eclampsia and repeated urine analyses to screen for the condition are part of
      the standard antenatal care. The purpose of this study was to investigate whether
      measurement of the urine albumin/creatinine ratio in spot samples could be a
      complement to the dipstick method and could reduce the need for 24-h urine
      collections. Urine samples were collected for 24 h in weeks 12, 24 and 36 of
      pregnancy from both normotensive women and women who developed hypertension or
      who had pregnancy-induced hypertension (PIH) when they entered the study. The 24
      h albumin excretion was significantly correlated to the albumin/creatinine ratio
      in all measurements (Pearson correlation coefficient). In week 12, the values
      were: n = 44, r = 0.964, p < 0.001 (normotensive group) and in the PIH group: n =
      8, r = 0.789, p < 0.05. In week 24, the correlation values were r = 1.0 and p <
      0.001 in both the normotensive group (n = 41) and in the PIH group (n = 11). In
      week 36 the correlation values were r = 0.791 and p < 0.001 in the normotensive
      group (n = 39) and r = 1.0 and p < 0.001 in the PIH group (n = 16).
      Microalbuminuria was defined as urine albumin excretion higher than 30 mg/24 h
      and this corresponded to an albumin/creatinine ratio of 2.9. Microalbuminuria was
      found in three persons in the PIH group and in two persons in the normotensive
      group. Overt albuminuria (> 300 mg/24 h) was found in one of the 46 normotensive
      women (2%) and in 3 of the 19 PIH women (16%). In all these women the high
      albumin values had been detected by using the albumin/creatinine ratio method. In
      conclusion, it has been found that the albumin excretion in urine correlates
      significantly to the albumin/creatinine ratio during pregnancy. The urinary
      albumin/creatinine ratio appears to be a good alternative to the dipstick method
      and to 24-h urine collections.

PMID- 15025426
TI  - Calculation of glomerular filtration rate expressed in mL/min from plasma
      cystatin C values in mg/L.
AB  - The Cockcroft Gault formula is often used to calculate the glomerular filtration
      rate (GFR) from plasma creatinine results. In Sweden this calculation is not
      usually done in the laboratory, but locally in the wards. These manual
      calculations could cause erroneous results. In several studies plasma cystatin C
      has been shown to be superior to plasma creatinine for estimation of GFR. One
      limitation of using cystatin C as a GFR marker is that there is no conversion
      formula transforming cystatin C expressed as mg/L to GFR expressed as mL/min. In
      this study plasma creatinine and cystatin C were compared with iohexol clearance.
      A stronger correlation (p < 0.0001) was found between cystatin C and iohexol
      clearance (r2 = 0.91) than between creatinine and iohexol clearance (r2 = 0.84).
      From the correlation data a formula was calculated to convert cystatin C
      expressed as mg/L to GFR (mL/min). The formulas y = 77.24x(-1.2623) (Dade Behring
      cystatin C calibration) or y = 99.43x(-1.5837) (DakoCytomation cystatin C
      calibration) are used to calculate GFR expressed in mL/min from the cystatin C
      value in mg/L and both results are reported to the referral doctor. These
      formulas can provide the clinicians with reliable and readily available GFR data
      based on single measurements of cystatin C concentrations.

PMID- 15025427
TI  - Reconstitution of ATP-dependent cGMP transport into proteoliposomes by membrane
      proteins from human erythrocytes.
AB  - The cellular efflux of cGMP from human erythrocytes has previously been
      characterized in functional studies. The purpose of the present study was to find
      membrane proteins with the ability to restore ATP-dependent uptake of cGMP into
      proteoliposomes. Human erythrocyte membranes were solubilized with CHAPS (3-([3
      cholamidopropyl]dimethylammonio)-1-propanesulfonate) and gel filtration gave
      three protein fractions with the ability to restore active transport. Only two of
      these fractions were retained on a lentil lectin column. By using these two
      purification steps, active transport was 11 times higher in the first fraction
      compared to the original material and SDS-PAGE showed the presence of proteins
      with sizes of 145 kDa and 165 kDa. The second fraction gave 20 times higher
      active transport after purification and comprised proteins with sizes of 145 kDa
      and 180 kDa. At present three members of the MRP (multi-resistance associated
      protein) family have been detected in human erythrocytes: MRPI, MRP4 and MRP5.
      The last two proteins have been shown to transport cyclic nucleotides. The
      present findings are compatible with MRP4 as the 145 kDa protein, MRP5 as the 165
      kDa protein and MRP1 as the 180 kDa protein. However, the 145 kDa protein could
      also be SMRP (short multi-resistance protein), the gene splice variant of MRP5.
      Immunoprecipitation of MRP5 from CHAPS-solubilized extract reduced active
      transport and specific binding by about 45% and 40%, respectively. This shows
      that MRP5 is an important cGMP-transporting protein in human erythrocytes.

PMID- 15025428
TI  - Production and characterization of antibodies for the specific determination of
      the opioid peptide Met5-Enkephalin-Arg6-Phe7.
AB  - Endogenous opioids serve as modulators of neuroendocrine and immune system
      processes, the investigation of which calls for high-specificity
      radioimmunoassays (RIAs). This study focuses on the development and use of a
      specific radioimmunoassay for the opioid peptide Met5-Enkephalin-Arg6-Phe7
      (MEAP), the C-terminus part of proenkephalin A. Antibodies were raised in four
      rabbits and investigated in terms of titre, avidity and specificity, followed by
      finding ideal conditions for these antibodies in RIA. MEAP concentrations were
      determined in crude extracts of rat hypothalamus, dorsal root ganglia, adrenals
      and ankle using this standardized assay after an oxidizing process. At reverse
      phase high-pressure liquid chromatography (HPLC), the position of immunoreactive
      material from rat hypothalamus eluted as two peaks out of which one was
      compatible with that of synthetic MEAP. All rabbits exhibited individual
      differences in relative immune response and time of its onset. The avidity
      constant was 10 times higher on a molar basis for ab 4108 compared with ab 4182.
      There was no cross-reactivity for ab 4182 to related peptides, such as
      enkephalins and dynorphin B, and negligible background values for ab 4108. The
      relative levels ofimmunoreactive MEAP from the CNS versus peripheral tissues
      contrasted in accordance with current knowledge. It is suggested that reports
      with RIA results should include characterization of antibodies, extraction
      procedures, standard curves and compositions of buffers. Furthermore, the results
      should preferably be expressed in relation to total protein content.

PMID- 15025429
TI  - Serum levels of chitotriosidase as a marker of disease activity and clinical
      stage in sarcoidosis.
AB  - BACKGROUND: Sarcoidosis is a systemic granulomatous disease characterized by T
      lymphocyte activation and lymphocyte migration into involved organs, usually the
      lungs. The amounts of a number of biochemical markers, such as angiotensin
      converting enzyme (ACE) activity, increase in the serum of patients with
      sarcoidosis. Chitotriosidase is an enzyme secreted by activated macrophages able
      to catalyze the hydrolysis of both chitin and chitin-like substrates.
      Chitotriosidase is involved in defense against, and in degradation of chitin
      containing pathogens such as fungi, nematodes, and insects. METHODS: Forty-three
      patients affected by chronic sarcoidosis, in active (23 patients) or inactive (20
      patients) phase, were studied. Serum levels of chitotriosidase and ACE activity
      were evaluated and compared with those of 32 healthy subjects. Serum
      chitotriosidase concentration and ACE activity were also correlated with
      radiographic stage of disease. RESULTS: Individuals with chronic sarcoidosis have
      higher serum chitotriosidase concentrations and ACE activity than those of normal
      subjects. Sarcoidosis patients in the active phase of the disease had
      significantly higher chitotriosidase and ACE levels than those in the inactive
      phase. In contrast to serum ACE activity, a significant relationship between
      serum levels of chitotriosidase and the four radiographic stages of the disease
      was observed. CONCLUSION: Although the data need to be validated by further
      investigation, the observations made in this study seem to indicate that serum
      chitotriosidase concentrations may be a useful marker for monitoring sarcoidosis
      disease activity and prognosis.

PMID- 15025430
TI  - Results of intraperitoneal microdialysis depend on the location of the catheter.
AB  - BACKGROUND AND OBJECTIVE: Intraperitoneal microdialysis was recently described as
      a method for early detection of visceral ischemia. The method seems safe and
      accurate. The intra-abdominal catheter used may imply variations in results
      depending on the location of the catheter. The aim of the study was to
      investigate possible differences in metabolic parameters obtained depending on
      various locations of the intra-abdominal catheter, compared with using the
      subcutaneous reference catheter. METHOD: After right-sided hemicolectomy in 12
      patients, three catheters were placed and fixed intraperitoneally: one at the
      anastomosis, one in the omentum and one embedded between the small intestinal
      loops. A subcutaneous catheter placed in the pectoral region was used as
      reference. Analyses of lactate/pyruvate ratio and glucose and glycerol levels
      were done during a period of 45 hours postoperatively. RESULTS: Lactate/pyruvate
      ratio decreased numerically at all three intraperitoneal locations during the
      study while the subcutaneous lactate/pyruvate ratio increased slightly.
      Significant differences between intraperitoneal and subcutaneous locations were
      found as well as differences between the three intraperitoneal locations. Highest
      values of the lactate/pyruvate ratio were found at the anastomosis, while the
      widest range was found at the small intestine. Subcutaneous glucose levels were
      lower while glycerol levels were higher compared with intraperitoneal values.
      CONCLUSIONS: In evaluating postoperative metabolism, intraperitoneal
      microdialysis is influenced by the location of the microdialysis catheter. The
      same pattern is, however, recorded over time. The juxta-anastomotic region and
      the small intestinal loop area seem to be the most reasonable locations for
      measurements.

PMID- 15025431
TI  - Oxygen affinity is decreased in patients with polycythaemia vera and essential
      thrombocythaemia.
AB  - The plasma erythropoietin (EPO) concentration is subnormal in the vast majority
      of all patients at the time of diagnosis of polycythaemia vera (PV) and in 33-50%
      of patients with essential thrombocythaemia (ET). At equivalent haemoglobin
      concentrations patients with PV and a substantial number of ET patients have
      subnormal EPO concentrations compared with those of healthy subjects. A possible
      explanation could be altered haemoglobin (Hb) oxygen affinity. Plasma EPO
      concentration and the oxygen pressure at 50% Hb saturation (p50) were measured in
      29 patients with PV, 23 patients with ET and 34 healthy controls. There was no
      significant correlation between p50 and plasma EPO concentration. However, the
      mean p50 for PV patients exceeded the mean for healthy controls (p = 0.004).
      Furthermore, the mean p50 for ET patients significantly (p = 0.012) exceeded the
      mean for controls but there was no significant difference in p50 between patients
      with PV and ET. It could be hypothesized that the lower oxygen affinity to Hb in
      PV and ET patients partly explains the decreased EPO production.

PMID- 15025432
TI  - Cytometry in the diagnosis of acute urinary tract infections: one year's
      experience.

PMID- 15025433
TI  - An operational supramolecular nanovalve.
AB  - A functioning nanomachine in the form of a supramolecular nanovalve that opens
      and closes the orifices to molecular-sized pores and releases a small number of
      molecules on demand is reported. The nanovalve, which is used to open and close
      the nanocontainer, is a pseudorotaxane composed of two components-a long thread
      containing a 1,5-dioxnaphthalene donor unit, which is attached to the solid
      support, and the moving part, the tetracationic cyclophane acceptor/receptor,
      cyclobis(paraquat-p-phenylene), which controls access to the interior of the
      nanopore. The nanocontainer is made out of mesoporous silica by using a dip
      coating method. Operating the nanovalve involves three steps: (i) filling the
      container, (ii) closing the valve, and (iii) opening the valve to release the
      contents of the container on demand. The tubular pores, which are approximately 2
      nm wide, are filled with stable luminescent Ir(ppy)3 molecules by allowing them
      to diffuse into the open pores. The orifices are then closed by pseudorotaxane
      formation. An external reducing reagent (NaCNBH3) is used to effect dethreading
      of the pseudorotaxane so as to unlock the tubes and allow the guest molecules to
      be released. This nanovalve is a supramolecular machine consisting of a solid
      framework with moving parts capable of doing useful work.

PMID- 15025434
TI  - Self-assembling peptide nanotubes from enantiomeric pairs of cyclic peptides with
      alternating D and L amino acid residues.
AB  - Cyclic peptides with alternating d- and l-amino acid residues containing tert
      leucine residues in every second position can form peptide nanotubes only when
      both enantiomers of the peptide are present in the solution. These results
      strongly indicate the formation of peptide nanotubes that assemble with one
      enantiomer in every second position, thereby forming a lamellar structure.

PMID- 15025435
TI  - Nanoassembly of biodegradable microcapsules for DNA encasing.
AB  - A new microcontainer for DNA delivery based on biocompatible poly[beta-glucuronic
      acid-(1 --> 3)-N-acetyl-beta-galactosamine-6-sulfate-(1 --> 4)](chondroitin
      sulfate)/poly(-l-arginine) microcapsules with 40 nm thick molecularly organized
      shell was proposed. DNA molecules were deposited as DNA/sperimidine complex on
      the surface of template 4 mum core particles followed by layer-by-layer
      nanoassembly of protective chondroitin sulfate/poly(-l-arginine) shell. After
      template core dissolution, DNA molecules were captured inside microcapsules
      retaining a natural double-helix structure. The developed DNA encapsulation
      approach can be employed for targeted delivery of plasmid DNA in living cells.

PMID- 15025436
TI  - Photon antibunching from oriented semiconducting polymer nanostructures.
AB  - Fluorescence intensity correlation measurements reveal that z-oriented
      nanostructures from single chains of a cyano-substituted polyphenylene vinylene
      (CN-PPV) polymer act as single-quantum emitters. Photon antibunching is observed
      for the first time on individual polymer nanostructures with a modulation depth
      exceeding 90%, providing definitive proof that radiative recombination of
      molecular excitons occurs at a single localized site within the folded polymer
      chain.

PMID- 15025437
TI  - High-performance semiconducting polythiophenes for organic thin-film transistors.
AB  - Conjugated polymers have been widely studied as potential semiconductor materials
      for organic thin-film transistors (TFTs). However, they have provided
      functionally poor transistor properties when the TFTs are fabricated in air. We
      have developed a class of liquid crystalline regioregular polythiophenes, PQTs,
      that possess sufficient air stability to enable achievement of excellent TFT
      properties under ambient conditions. These polythiophenes exhibit unique self
      assembly ability and form highly structured thin films when deposited from
      solution under appropriate conditions. TFTs fabricated in air with PQT channel
      layers have provided high field-effect mobility to 0.14 cm2 V-1 s-1 and high
      current modulation to over 107, together with other desirable transistor
      properties. These high-performance polythiophenes will therefore help bring the
      long-standing concept of low-cost organic/polymer transistor circuits closer to
      commercial reality.

PMID- 15025438
TI  - Sandwich-like complexes based on "all-metal" (Al 4 2-) aromatic compounds.
AB  - We report a new sandwich-like structure (Al4TiAl42-) based on the recently
      synthesized all-metal aromatic Al42- squares. This structure has two aromatic
      squares (-2 charged each) trapping a titanium +2 cation. These all-metal aromatic
      squares have been detected by various metallic counterions, with a global charge
      of -1. Thus, we have also characterized a similar sandwich-like structure
      interacting with one and two sodium atoms with global charges of -1 and 0. The
      properties of these compounds strongly support the idea that they may be formed
      by Al42- aromatic squares.

PMID- 15025439
TI  - Polymorph selectivity under nanoscopic confinement.
AB  - Polymorph selectivity has been achieved during crystallization of anthranilic
      acid (AA) and 5-methyl-2-[(2-nitrophyenyl)amino]-3-thiophenecarbonitrile (ROY),
      both considered benchmarks of polymorphic behavior, within nanoporous glass beads
      and polymer monoliths. Whereas polymorph III of AA crystallizes from the melt on
      nonporous glass beads or within larger pores, the metastable polymorph II
      crystallizes in pores with diameters <23 nm, with the selectivity toward this
      form increasing with decreasing pore size. Of the six ROY polymorphs
      characterized by single-crystal X-ray diffraction, the yellow form (Y)
      crystallizes during evaporation of pyridine solutions imbibed by the 30-nm
      cylindrical pores of porous polycyclohexylethylene (p-PCHE) monoliths. Although
      both R and ON grow from the melt on the external surfaces of PCHE, only the red
      form (R) crystallizes in the pores. Amorphous ROY also forms in p-PCHE pores
      during evaporation from pyridine solutions, subsequently crystallizing to the R
      nanocrystals upon heating. Although heterogeneous nucleation on the pore walls
      may play a role, these observations suggest that nucleation and polymorph
      selectivity is governed by critical size constraints imposed by the ultrasmall
      pores. The ability to achieve polymorph selectivity in both glass and polymer
      matrices suggests wide-ranging compatibility with various organic crystalline
      solids, promising a new approach to controlling polymorphism and searching for
      unknown polymorphs.

PMID- 15025440
TI  - A high-resolution probe of protein folding.
AB  - Protein folding is a central problem in the biological sciences. To generate
      residue-specific information on the equilibrium folding of cytochrome c, we have
      semisynthesized the protein with specifically deuterated residues. The C-D bonds
      may be easily visualized in an otherwise transparent region of the IR spectra,
      even at high protein and denaturant concentrations. Plotted as a function of
      added guanidine hydrochloride denaturant, the absorption intensities reveal that
      the protein undergoes a conformational change at the protein-based ligand, Met80,
      which is then followed by a more global unfolding at 2.3 M denaturant.
      Deuteration and characterization of other residues in cytochrome c, or other
      protein of interest, should provide complete views of folding with residue
      specific detail that is capable of resolving even the most rapidly
      interconverting intermediates.

PMID- 15025442
TI  - Convergent synthesis and photophysics of [60]fullerene/porphyrin-based rotaxanes.
AB  - A series of Sauvage-type rotaxanes containing [60]fullerene and
      tetraarylporphyrin moieties has been synthesized by a convergent route.
      Photoinduced energy-transfer and electron-transfer reactions in these rotaxanes
      yield long-lived change-separated states, in agreement with the large distance
      between the fullerene and porphyrin chromophores.

PMID- 15025441
TI  - Shotgun annotation of histone modifications: a new approach for streamlined
      characterization of proteins by top down mass spectrometry.
AB  - Eukaryotic histones serve as prototypical examples of posttranslational
      complexity with diverse modifications (PTMs) on many different residues that
      comprise a "Histone Code". To help crack this code more efficiently, we
      demonstrate a new strategy for protein characterization wherein complete PTM
      descriptions are obtained by database retrieval instead of manual interpretation
      of information-rich data from high-resolution tandem mass spectrometry (MS/MS). A
      database of nearly 50 000 modified histone H4 sequences was created and queried
      with 91 fragment ions from electron capture dissociation of a histone form +112
      Da (versus unmodified mass) selectively accumulated in a quadrupole Fourier
      transform hybrid mass spectrometer. The correct form atop the retrieval list
      indicated dimethylation at Lys20, acetylation at the N terminus, and acetylation
      at Lys16 (resolved from trimethylation, Deltam = 0.036 Da). A statistical
      evaluation reveals the critical role of mass accuracy and that PTM "isomers" are
      retrieved as next-best matches. The applicability of shotgun annotation to forms
      of H4 with up to six PTMs is demonstrated, with extensibility to other histones
      (e.g., H2A, H2B, H3) and other protein classes projected.

PMID- 15025443
TI  - Conformational changes in a photosensory LOV domain monitored by time-resolved
      NMR spectroscopy.
AB  - Phototropins are light-activated kinases from plants that utilize light-oxygen
      voltage (LOV) domains as blue light photosensors. Illumination of these domains
      leads to the formation of a covalent linkage between the protein and an
      internally bound flavin chromophore, destabilizing the surrounding protein and
      displacing an alpha-helix from its surface. Here we use a combination of
      spectroscopic tools to monitor the kinetic processes that spontaneously occur in
      the dark as the protein returns to the noncovalent ground state. Using time
      resolved two-dimensional (2D) NMR methods, we measured the rate of this process
      at over 100 independent sites throughout the protein, establishing that
      regeneration of the dark state occurs cooperatively within a 1.6-fold range of
      observed rates. These data agree with other spectroscopic measurements of the
      kinetics of protein/FMN bond cleavage and global conformational changes,
      consistent with these processes experiencing a common rate-limiting step.
      Arrhenius analyses of the temperature dependence of these rates suggest that the
      transition state visited during this regeneration has higher energy than the
      denatured form of this protein domain despite the fact that there is no global
      unfolding of the domain during this process.

PMID- 15025444
TI  - Nitrilotriacetic acid-modified magnetic nanoparticles as a general agent to bind
      histidine-tagged proteins.
AB  - Using Nalpha,Nalpha-bis(carboxymethyl)lysine to react with FePt magnetic
      nanoparticles, we synthesized the FePt-NTA conjugate, which immobilizes Ni2+ ions
      and selectively binds to histidine-tagged proteins at concentration as low as 0.5
      pM. This simple system serves as a useful alternative to existing protocols for
      protein separation and also acts as a versatile agent for transporting and
      anchoring proteins.

PMID- 15025445
TI  - A highly potent and selective PKCalpha inhibitor generated via combinatorial
      modification of a peptide scaffold.
AB  - A potent and highly selective inhibitor of protein kinase C alpha has been
      generated via the combinatorial modification of a consensus sequence peptide. The
      inhibitor displays a Ki of 800 pM versus variable peptide substrate and good
      selectivity versus other members of the PKC family, including PKCbeta (385-fold),
      PKCgamma (580-fold), PKCdelta (2730-fold), PKCepsilon (600-fold), PKCeta (1310
      fold), PKCtheta (1210-fold), PKCiota (940-fold), and PKCzeta (640-fold). The
      parallel synthesis strategy employed is easily automated and straightforward to
      implement.

PMID- 15025446
TI  - Bifunctional nanocrystalline MgO for chiral epoxy ketones via Claisen-Schmidt
      condensation-asymmetric epoxidation reactions.
AB  - Design and development of a truly nanobifunctional heterogeneous catalyst for the
      Claisen-Schmidt condensation (CSC) of benzaldehydes with acetophenones to yield
      chalcones quantitatively followed by asymmetric epoxidation (AE) to afford chiral
      epoxy ketones with moderate to good yields and impressive ee's is described. The
      nanomagnesium oxide (aerogel prepared) NAP-MgO was found to be superior over the
      NA-MgO and CM-MgO in terms of activity and enantioselectivity as applicable in
      these reactions. An elegant strategy for heterogenization of homogeneous
      catalysts is presented here to evolve single-site chiral catalysts for AE by a
      successful transfer of molecular chemistry to surface metal-organic chemistry
      with the retention of activity, selectivity/enantioselectivity. Bronsted
      hydroxyls are established as sole contributors for the epoxidation reaction,
      while they add on to the CSC, which is largely driven by Lewis basic O2-sites.
      Strong hydrogen-bond interactions between the surface -OH on MgO and -OH groups
      of diethyl tartrate are found inducing enantioselectivity in the AE reaction.
      Thus, the nanocrystalline NAP-MgO with its defined shape, size, and accessible OH
      groups allows the chemisorption of TBHP, DET, and olefin on its surface to
      accomplish single-site chiral catalysts to provide optimum ee's in AE reactions.

PMID- 15025447
TI  - A limiting speed for protein folding at low solvent viscosity.
AB  - Because protein folding dynamics are heavily overdamped, Kramers theory predicts
      the rate of folding to scale inversely with the reaction friction, which is
      usually interpreted to mean the solvent viscosity. This does not mean, however,
      that the speed of folding can increase without limit as solvent viscosity
      decreases. We show that, in a sufficiently fast-folding protein, the folding
      speed approaches a finite limit at low solvent viscosity, indicating a reaction
      controlled by internal friction.

PMID- 15025448
TI  - Direct detection of homocysteine.
AB  - Homocysteine (Hcy) is a biomarker for significant disorders including Alzheimer's
      and cardiovascular disease. The monitoring of Hcy levels in plasma is of current
      concern. We describe highly selective colorimetric methods for the direct
      detection of Hcy. Inexpensive, commercially available materials are employed. The
      results show potential application for the detection of Hcy in human blood
      plasma.

PMID- 15025449
TI  - Presteady-state kinetic evidence for a ring-opening activity in fructose-1,6
      (bis)phosphate aldolase.
AB  - Fructose 1,6-bisphosphate aldolase, a glycolytic enzyme, catalyzes the cleavage
      of fructose 1,6-bisphosphate, resulting in two three-carbon products. The
      reaction of the class I enzymes, which utilize a Schiff-base intermediate,
      requires that the hexose be in the open-chain form. This form comprises only 1-2%
      of the sugar at equilibrium. The chemical form of the substrate that binds to
      aldolase and begins the catalytic cycle has not been unequivocally demonstrated.
      Transient-state kinetics in single-turnover experiments of fructose 1,6
      bisphosphate with aldolase in excess reveals the rates of the intermediate steps
      in the cleavage reaction, including those from initial binding to Schiff-base
      formation. The rate of hexose Schiff-base formation was faster than the
      uncatalyzed rate for ring-opening of either the alpha- or beta-furanose at 4
      degrees C. In addition, approach-to-equilibrium experiments reveal that aldolase
      binds and reacts first with 70% of fructose-1,6-bisphosphate in a fast reaction,
      consistent with the amount of beta-anomer in solution, and with the remaining
      30%, presumably the alpha-anomer, in a slow reaction. These results indicate that
      aldolase must catalyze the ring-opening step and that there may be a previously
      unrecognized second active site on the enzyme for catalyzing this reaction.

PMID- 15025450
TI  - Vinyl sulfones: inhibitors of SrtA, a transpeptidase required for cell wall
      protein anchoring and virulence in Staphylococcus aureus.
AB  - Several small molecule vinyl sulfones were found to exhibit irreversible time
      dependent inhibition of the Staphylococcus aureus sortase SrtA in vitro. A
      representative of these compounds was shown to impair the ability of S. aureus
      bacteria to bind fibronectin-coated surfaces through in vivo inhibition of SrtA
      mediated linkage of fibronectin to the cell surface. These data highlight the
      potential use of small molecule vinyl sulfones as chemotherapeutics to prevent
      adhesion to and colonization of host tissues during S. aureus infection.

PMID- 15025451
TI  - C-H to N substitution dramatically alters the sequence-specific DNA alkylation,
      cytotoxicity, and expression of human cancer cell lines.
AB  - We designed and synthesized sequence-specific alkylating conjugates 1 and 2,
      which selectively alkylate matched sequences at nanomolar concentrations.
      Conjugates 1 and 2 differ only in that the C-H is substituted by an N in the
      second ring, which precisely recognizes and effectively alkylates DNA according
      to the recognition rule of Py-Im polyamides. We investigated sequence-specific
      DNA alkylation, cytotoxicity in 39 human cancer cell lines, and the effect on
      expression levels in cancer cell lines by Py-Im conjugates 1 and 2. The COMPARE
      analysis of the mean graphs showed that conjugates 1 and 2 did not correlate well
      with each other (r = 0.65) despite having a common DNA alkylating mechanism
      (purine N3 alkylation). Array-based gene expression analysis demonstrated that
      there are several oppositely regulated genes. The results suggest the intriguing
      possibility that DNA alkylating agents recognizing longer base-pair sequences may
      provide a promising approach for developing new types of antigene agents.

PMID- 15025452
TI  - PtCl 2-catalyzed cycloisomerizations of allenynes.
AB  - The PtCl2-catalyzed cycloisomerization of allenyne systems has been examined.
      This process is a highly versatile tool for obtaining products that cannot be
      attainable with other metals. Simple adjustment of the allene or alkyne
      substitution can direct the reactivity in a selective manner and give birth to
      important carbocyclic frameworks (hydrindenes, cyclic vinylallenes, and trienes).

PMID- 15025454
TI  - Oxidation of sulfide, phosphine, and benzyl substrates tethered to N-donor
      pyridine ligands in carboxylate-bridged diiron(II) complexes.
AB  - Substituted pyridines were employed to prepare a series of terphenylcarboxylate
      bridged diiron(II) compounds to mimic aspects of the chemistry at the active
      sites of bacterial multicomponent monooxygenases, including soluble methane
      monooxygenase (sMMO) and toluene monooxygenase (ToMO). Complexes of general
      formula [Fe2(O2CArTol)4L], L = 2, 3, or 4-pyridyldiphenylphosphine, 2
      pyridylphenylsulfide, or 2-benzylpyridine and ArTol = 2,6-di(p-tolyl)benzoate,
      were synthesized and characterized by X-ray crystallography. Upon exposure of
      these compounds to dioxygen, ligand oxidation ensued and, in one case, proceeded
      catalytically.

PMID- 15025455
TI  - Resonance Raman spectra of electrons solvated in liquid alcohols.
AB  - Resonance Raman spectra of electrons solvated in liquid methanol, ethanol, and n
      propanol are presented. At least five distinct solvent modes exhibit resonantly
      enhanced scattering, including the OH torsion, CO/CC stretches, the OH in-plane
      bend, methyl deformations, and the OH stretch. The 200-350 cm-1 frequency
      downshift of the OH stretch indicates a strong H-bond interaction between the
      electron and the hydroxyl group. The multiple modes including alkyl vibrations
      that are coupled to the electronic transition of the solvated electron reveal the
      extension of the electron's wavefunction into the alkyl solvent environment.

PMID- 15025453
TI  - Structures and energetics of models for the active site of acetyl-coenzyme a
      synthase: role of distal and proximal metals in catalysis.
AB  - Acetyl-coenzyme A (CoA) synthase/carbon monoxide dehydrogenase (ACS/CODH) is a
      bifunctional enzyme that generates CO from carbon dioxide in the C-cluster of the
      beta subunit and synthesizes acetyl-CoA from carbon monoxide (CO), CoA, and CH3+
      at the active site of the A-cluster in the alpha subunit. On the basis of density
      functional calculations, we predict that methylation of Nip occurs first, and CO
      then adds to the NipII-CH3 species to form the intermediate, NipII(CO)(CH3), in
      which Nip deligates one of its SNid bonds. The CO-insertion/CH3-migration occurs
      on one metal, the proximal Ni, forming the trigonal planar NipII-acetyl
      intermediate. The thiolate can bind to NipII and reductively eliminate the
      thioester. Our calculations disfavor the unprecedented bimetallic CO
      insertion/CH3-migration. Ni in the proximal site produces a better catalyst than
      does Cu.

PMID- 15025456
TI  - Intramolecular arylation reactions of alkenes: a flexible approach to chromans
      and tetrahydroquinoline derivatives.
AB  - A metal-free approach to chroman derivatives by the reaction of different
      allylphenyl ethers with Ipy2BF4 is described. The access to this frame, by direct
      cyclization of the starting materials, takes place smoothly. In addition, an
      unusual and selective sequence that comprises initial rearrangement and further
      cyclization could be accomplished, with temperature as an excellent element of
      control. The process can be extended to the synthesis of tetrahydroquinolines
      when using allylamines. Also, two cascade reactions, leading to relevant oxygen
      and nitrogen-containing skeletons, have been devised.

PMID- 15025457
TI  - Chiral proton catalysis: a catalytic enantioselective direct aza-Henry reaction.
AB  - Despite Nature's longstanding ability to use a proton, the most prevalent Lewis
      acid, to both activate and orient a substrate during an enantioselective
      reaction, this work represents the first example of this phenomenon outside of a
      protein. A chiral, nonracemic BisAMidine (BAM) ligand was designed, synthesized,
      and complexed to the proton of a Bronsted acid. The resulting coordination
      compound catalyzed the production of enantioenriched product from the combination
      of a Schiff base and nitroalkane (the aza-Henry reaction). This particular
      reaction is also considered a model for many analogous carbon-carbon bond-forming
      reactions catalyzed by enzymes (e.g., the Mannich reaction). This discovery
      suggests the use of ionic hydrogen bonds in asymmetric catalysis may not only be
      more general than previously thought, but also a viable "green" approach to
      single-enantiomer organic compounds.

PMID- 15025458
TI  - Valence electron orbitals of an oligo(p-phenylene-ethynylene)thiol on gold.
AB  - This communication reports measurement of one-photon (21.2 eV) and one-color, two
      photon (3.2-4.5 eV) photoemission spectra of 4,4'-bis-(phenylethynyl)benzenethiol
      chemisorbed on gold. Four features are observed in these spectra: two occupied,
      predominantly molecular levels below the Fermi level and two unoccupied,
      predominantly molecular levels above the Fermi level. The occupied and unoccupied
      bands closest to the Fermi level are assigned to delocalized pi-bands, and the
      other occupied and unoccupied bands, to localized pi-bands. With this assignment,
      the hole- and electron-injection barriers and the transport gap for those levels
      are deduced.

PMID- 15025459
TI  - A simple and general method for the synthesis of multicomponent Na2V6O16.3H2O
      single-crystal nanobelts.
AB  - Multicomponent Na2V6O16.3H2O (barnesite) single-crystalline nanobelts were
      synthesized by a direct reaction-crystallization growth of bulk V2O5 and NaF
      powders under hydrothermal treatment without using any templates or catalysts.
      This new strategy could be extended to prepare other one-dimensional
      multicomponent nanomaterials including ammonium, alkali-metal or alkali-earth
      metal vanadium oxide bronzes and other transition metal oxyfluorides. This is an
      efficient and mild solution method with clear advantages over the traditional
      high-temperature approach for the large-scale production of 1D multicomponent
      nanomaterials. The applicability of this approach toward the preparation of other
      inorganic systems, such as tungstates and molybdates, will be explored.

PMID- 15025460
TI  - On the electronic structure of molecular UO2 in the presence of Ar atoms:
      evidence for direct U-Ar bonding.
AB  - Calculations via scalar-relativistic density functional theory (DFT) and ab
      initio CCSD(T) methodologies are used to explore the possibility of direct
      interactions between molecular UO2 and Ar atoms. The 3Hg electronic state of UO2,
      which is an excited state of the isolated molecule, exhibits significant bonding
      to Ar in the model complexes UO2(Ar) and UO2(Ar)5. The calculated vibrational
      frequencies of ground-state 3Phiu UO2 and UO2(Ar)5 with an (fphi)1(fdelta)1
      electron configuration agree well with the observed frequencies of UO2 in solid
      neon and solid argon, respectively. The results strongly suggest that the ground
      electron configuration of UO2 changes from 5f17s1 to 5f2 when the matrix host is
      changed from neon to argon.

PMID- 15025461
TI  - Enzymatic cyclization of 22,23-dihydro-2,3-oxidosqualene into euph-7-en-3beta-ol
      and bacchar-12-en-3beta-ol by recombinant beta-amyrin synthase.
AB  - Recombinant beta-amyrin synthase from Pisum sativum converted 22,23-dihydro-2,3
      oxidosqualene, a substrate analogue lacking the terminal double bond of 2,3
      oxidosqualene, into a 4:1 mixture of euph-7-en-3beta-ol and bacchar-12-en-3beta
      ol. This is the first demonstration of the enzymatic formation of the baccharene
      skeleton with a six-membered D-ring. In the absence of the terminal double bond,
      the proton-initiated cyclization first generated the tetracyclic dammarenyl
      cation, followed by a backbone rearrangement with loss of H-7alpha leading to the
      formation of euph-7-en-3beta-ol, while D-ring expansion to the baccharenyl cation
      and subsequent 1,2-hydride shifts with H-12alpha elimination yielded bacchar-12
      en-3beta-ol. It is remarkable that the formation of the anti-Markovnikov six
      membered D-ring did not depend on the participation of the terminal pi-electrons.

PMID- 15025462
TI  - De novo synthesis of oligosaccharides using a palladium-catalyzed glycosylation
      reaction.
AB  - The natural all d- and/or unnatural all l-1,4- and 1,6-oligosaccharides were
      synthesized from furan alcohols using a palladium-catalyzed glycosylation
      reaction. The 1,4- and 1,6-alpha-manno-disaccharides were achieved in seven total
      steps starting from chiral furan alcohols. Similarly, 1,4- and 1,6-alpha-manno
      trisaccharides were also synthesized in nine total steps. Key to the overall
      efficiency of this process was the use of highly diastereoselective palladium
      catalyzed glycosylations, reductions, and dihydroxylations.

PMID- 15025463
TI  - Porphyrins with four monodisperse oligofluorene arms as efficient red light
      emitting materials.
AB  - A family of red light-emitting star-shaped porphyrins with four monodisperse
      conjugated oligofluorene arms was prepared by using two key reactions: Lindsey
      condensation and Suzuki-Miyaura cross coupling reactions. All porphyrins exhibit
      high quantum yields (about 0.22) and good solubility in common organic solvents,
      and form high-quality solid films. Optical studies showed that the star-shaped
      oligomers could absorb blue light and emit saturated red light via efficient
      energy transfer from the fluorene segments to the porphyrin core.

PMID- 15025464
TI  - Elimination of R-H from iridium acyl hydrides without loss of CO: evidence for
      the intervention of metal cation/carbanion pairs.
AB  - Instead of reductive elimination of aldehyde, or decarbonylation to give a
      trifluoroalkyl hydride, heating Cp*(PMe3)Ir(H)[C(O)CF3] leads to the quantitative
      formation of Cp*(PMe3)Ir(CO) and CF3H. Kinetic experiments, isotope-labeling
      studies, solvent effect studies, and DFT calculations support a mechanism which
      involves dissociation of trifluoromethyl anion to give the transient ion-pair
      intermediate [Cp*(PMe3)Ir(H)(CO)]+[CF3]-. Further evidence for the ability of CF3
      to act as a leaving group came from investigation of the analogous methyl and
      chloride derivatives Cp*(PMe3)Ir(Me)[C(O)CF3] and Cp*(PMe3)Ir(Cl)[C(O)CF3]. Both
      of these compounds undergo a similar loss of trifluoromethyl anion, generating an
      iridium carbonyl cation and CF3D in CD3OD.

PMID- 15025465
TI  - Carbolithiation for the generation of cyclooctadienyl anions and tandem
      electrocyclization/alkylation to functionalized cis-bicyclo[3.3.0]octenes.
AB  - A powerful cascade reaction process for the construction of functionalized cis
      bicyclo[3.3.0]octenes has been developed. Carbolithiation of 3-methylene-1,4
      cyclooctadiene with 1 degrees , 2 degrees , or 3 degrees alkyllithium reagents
      leads to cyclooctadienyl anions, which undergo disrotatory electrocyclization and
      subsequent trapping with carbon, oxygen, sulfur, or silicon electrophiles to
      provide functionalized cis-bicyclo[3.3.0]octenes. Transmetalation of the
      allyllithium intermediates allowed access to the cuprate manifold of reactivity.
      The rapid construction of a linear triquinane using this methodology demonstrates
      the potential for synthetic applications.

PMID- 15025466
TI  - Formation of hypervalent complexes of PhCCSiF3 with pyridine through
      intermolecular silicon...nitrogen interaction.
AB  - We report here the synthesis of trifluoro-phenylethynyl-silane (1) that forms
      with pyridine (Py), through intermolecular Si...N interaction, the
      pentacoordinate 1.Py complex and at low temperatures also the hexacoordinate
      1.Py2 complex. 1H, 19F, 29Si, and 15N NMR spectra, as well as the first report
      for an intermolecular 29Si...15N one-bond spin-spin coupling, are presented for
      the two complexes. Quantum mechanical ab initio calculations (MP2/6-31G*) suggest
      a distorted trigonal bipyramid structure for the 1.Py complex and a nearly ideal
      octahedral structure for the 1.Py2 complex. The hypervalent complexes of 1 with
      Py described here imply a possible application of such Si...N intermolecular
      interactions in supramolecular chemistry.

PMID- 15025467
TI  - Asymmetric benzoin condensation catalyzed by chiral rotaxanes tethering a
      thiazolium salt moiety via the cooperation of the component: can rotaxane be an
      effective reaction field?
AB  - Although some reactions on rotaxanes have been reported, the characteristic
      features of the rotaxanes providing unique reaction fields have hardly been
      studied, especially as catalyst. In our continuous studies on interlocked
      molecules such as rotaxanes and catenanes, we have noticed the importance of such
      interlocked structures with high freedom in functionalized materials such as
      molecular catalyst. For catalytic asymmetric benzoin condensations, two optically
      active rotaxanes possessing thiazolium salt moieties were prepared using the
      binaphthyl group as the chiral auxiliary. The benzoin condensations of aromatic
      aldehydes catalyzed by the chiral rotaxanes as catalysts gave optically active
      benzoins with ca. 30% ee in moderate to high chemical yields depending upon the
      structure of rotaxane and the reaction conditions employed. From the results, two
      intrarotaxane chirality transfers are confirmed: (i) through-space chirality
      transfer from wheel to axle and (ii) through-bond chirality transfer controlled
      with an achiral wheel. Because these asymmetric reaction fields are specific to
      the rotaxane structure, the importance and possibility of the "rotaxane field" as
      a particular reaction field is demonstrated in this work.

PMID- 15025468
TI  - Photocatalytic hydrogen production from hantzsch 1,4-dihydropyridines by
      platinum(II) terpyridyl complexes in homogeneous solution.
AB  - 1,4-Dihydropyridines have been photocatalytically oxidized to pyridines by
      platinum(II) terpyridyl complexes with the generation of hydrogen in homogeneous
      solution. The hydrogen production proceeds in quantitative yield and with great
      catalytic turnover.

PMID- 15025469
TI  - Cooperative effects in the activation of molecular oxygen by anionic silver
      clusters.
AB  - A novel size dependence in the adsorption reaction of multiple O2 molecules onto
      anionic silver clusters Agn- (n = 1-5) is revealed by gas-phase reaction studies
      in an rf-ion trap. Ab initio theoretical modeling based on DFT method provides
      insight into the reaction mechanism and finds cooperative electronic and
      structural effects to be responsible for the size selective reactivity of Agn-
      clusters toward one or more O2. In particular, Agn- clusters with odd n have
      paired electrons and therefore bind one O2 only weakly, but they are
      simultaneously activated to adsorb a strongly bound second oxygen molecule. For
      the clusters Ag3O4- and Ag5O4-, this cooperative effect results in a superoxo
      like, doubly bound O2 subunit with potentially high activity in catalytic silver
      cluster oxidation processes.

PMID- 15025470
TI  - An unusual reverse turn structure adopted by a furanoid sugar amino acid
      incorporated in gramicidin S.
AB  - A new reverse turn, replacing one of the native type II' beta-turns in the cyclic
      peptide antibiotic gramicidin S, induced by a furanoid sugar amino acid is
      revealed. The C3-hydroxyl function plays a pivotal role by acting as a H-bond
      acceptor, consequently flipping the amide bond between residues i and i + 1, as
      was established by NMR and X-ray crystallographic analysis.

PMID- 15025472
TI  - Ligating DNA with DNA.
AB  - Cloning DNA typically involves the joining of target DNAs with vector constructs
      by enzymatic ligation. A commonly used enzyme for this reaction is bacteriophage
      T4 DNA ligase, which requires ATP as the energy source to catalyze the otherwise
      unfavorable formation of a phosphodiester bond. Using in vitro selection, we have
      isolated a DNA sequence that catalyzes the ligation of DNA in the absence of
      protein enzymes. We have used the action of two catalytic DNAs, an ATP-dependent
      self-adenylating deoxyribozyme (AppDNA) and a self-ligating deoxyribozyme, to
      create a ligation system that covalently joins oligonucleotides via the formation
      of a 3',5'-phosphodiester linkage. The two-step process is conducted in separate
      reaction vessels wherein the products of deoxyribozyme adenylation are purified
      before their use as substrates for deoxyribozyme ligation. The final ligation
      step of the deoxyribozyme-catalyzed sequence of reactions mimics the final step
      of the T4 DNA ligase reaction. The initial rate constant (k(obs)) of the
      optimized deoxyribozyme ligase was found to be 1 x 10(-)(4) min(-)(1). Under
      these conditions, the ligase deoxyribozyme promotes DNA ligation at least 10(5)
      fold faster than that generated by a simple DNA template. The self-ligating
      deoxyribozyme has also been reconfigured to generate a trans-acting construct
      that joins separate DNA oligonucleotides of defined sequence. However, the
      sequence requirements of the AppDNA and that of the 3' terminus of the
      deoxyribozyme ligase limit the range of sequences that can be ligated.

PMID- 15025471
TI  - Fluorescence-based approach for detecting and characterizing antibiotic-induced
      conformational changes in ribosomal RNA: comparing aminoglycoside binding to
      prokaryotic and eukaryotic ribosomal RNA sequences.
AB  - Aminoglycoside antibiotics bind specifically to a conserved sequence of the 16S
      ribosomal RNA (rRNA) A site and interfere with protein synthesis. One model for
      the mechanism underlying the deleterious effects of aminoglycosides on protein
      synthesis invokes a drug-induced conformational change in the rRNA that involves
      the destacking of two adenine residues (A1492 and A1493 in Escherichia coli) at
      the A site. We describe here a fluorescence-based approach for detecting and
      characterizing this drug-induced conformational change in the target rRNA. In
      this approach, we insert the fluorescent base analogue 2-aminopurine in place of
      A1492 in an E. coli 16S rRNA A-site model oligonucleotide (EcWT) as well as in a
      mutant form of this oligomer (A1408G) in which A1408 has been replaced with a
      guanine. The presence of guanine at 1408 instead of adenine represents one of the
      major sequence differences between prokaryotic and eukaryotic A sites, with the
      latter A sites being resistant to the deleterious effects of aminoglycosides.
      Binding of the aminoglycoside paromomycin to the 2AP-substituted forms of EcWT
      and A1408G induced changes in fluorescence quantum yield consistent with drug
      induced base destacking in EcWT but not A1408G. Isothermal titration calorimetry
      studies reveal that paromomycin binds to the EcWT duplex with a 31-fold higher
      affinity than the A1408G duplex, with this differential affinity being enthalpic
      in origin. In the aggregate, these observations are consistent with both rRNA
      binding affinity and drug-induced base destacking being important determinants in
      the prokaryotic specificity of aminoglycosides. Combining fluorescence quantum
      yield and lifetime data allows for quantification of the extent of drug-induced
      base destacking, thereby providing a convenient tool for evaluating the relative
      impacts of both novel and existing A-site targeting ligands on rRNA conformation
      and potentially for predicting relative antibiotic activities and specificities.

PMID- 15025473
TI  - A wrench-shaped synthetic molecule that modulates a transcription factor
      coactivator interaction.
AB  - Development of synthetic molecules that provide external control over the
      transcription of a given gene represents a challenge in medicinal and bioorganic
      chemistry. Here we report design and analysis of wrenchnolol, a wrench-shaped
      synthetic molecule that impairs the transcription of the Her2 oncogene by
      disrupting association of transcription factor ESX with its coactivator Sur-2.
      The "jaw" part of the compound mimics the alpha-helical interface of the
      activation domain of ESX, and the "handle" region accepts chemical modifications
      for a range of analysis. A water-soluble handle permitted NMR study in aqueous
      solution; a biotinylated handle verified the selectivity of the interaction, and
      a fluorescent handle confirmed the cell permeability of the compound. The case
      study of wrenchnolol foreshadows the promise and the challenge of targeting
      protein-protein interactions in the nucleus and may lead to the development of
      unique synthetic modulators of gene transcription.

PMID- 15025474
TI  - Solid-phase ATRP synthesis of peptide-polymer hybrids.
AB  - A versatile methodology to prepare hybrid biomaterials by atom transfer radical
      polymerization from resin-supported peptides has been established. As an example,
      we have synthesized a GRGDS-functionalized poly(2-hydroxyethyl methacrylate). The
      peptide-polymer was characterized by solid-state (13)C NMR and GPC and found to
      have a number average molecular weight of 4420 and a polydispersity of 1.47.
      These values are comparable to those obtained from solution-phase syntheses,
      suggesting the ATRP reaction is successful from a peptide-conjugated solid
      support. Solid-state (13)C NMR was used to characterize multiple steps in the
      reaction, and the synthesis was found to be near quantitative. We have performed
      cell adhesion experiments and observed the GRGDS sequence-promoted cell adhesion,
      whereas unfunctionalized poly(2-hydroxyethyl methacrylate) did not. By
      incorporating cell-signaling moieties in materials with defined molecular
      architecture, it will be possible to control the interactions between polymeric
      materials and biological systems.

PMID- 15025475
TI  - Directed self-assembly of monodisperse phospholipid bilayer Nanodiscs with
      controlled size.
AB  - Using a recently described self-assembly process (Bayburt, T. H.; Grinkova, Y.
      V.; Sligar, S. G. Nano Letters 2002, 2, 853-856), we prepared soluble
      monodisperse discoidal lipid/protein particles with controlled size and
      composition, termed Nanodiscs, in which the fragment of
      dipalmitoylphosphatidylcholine (DPPC) bilayer is surrounded by a helical protein
      belt. We have customized the size of these particles by changing the length of
      the amphipathic helical part of this belt, termed membrane scaffold protein
      (MSP). Herein we describe the design of extended and truncated MSPs, the
      optimization of self-assembly for each of these proteins, and the structure and
      composition of the resulting Nanodiscs. We show that the length of the protein
      helix surrounding the lipid part of a Nanodisc determines the particle diameter,
      as measured by HPLC and small-angle X-ray scattering (SAXS). Using different
      scaffold proteins, we obtained Nanodiscs with the average size from 9.5 to 12.8
      nm with a very narrow size distribution (+/-3%). Functionalization of the N
      terminus of the scaffold protein does not perturb their ability to form
      homogeneous discoidal structures. Detailed analysis of the solution scattering
      confirms the presence of a lipid bilayer of 5.5 nm thickness in Nanodiscs of
      different sizes. The results of this study provide an important structural
      characterization of self-assembled phospholipid bilayers and establish a
      framework for the design of soluble amphiphilic nanoparticles of controlled size.

PMID- 15025477
TI  - Mechanism and activity of ruthenium olefin metathesis catalysts: the role of
      ligands and substrates from a theoretical perspective.
AB  - The reaction mechanism of olefin metathesis by ruthenium carbene catalysts is
      studied by gradient-corrected density functional calculations (BP86). Alternative
      reaction mechanisms for the reaction of the "first-generation" Grubbs-type
      catalyst (PCy(3))(2)Cl(2)Ru=CH(2) (1) for the reaction with ethylene are studied.
      The most likely dissociative mechanism with trans olefin coordination is
      investigated for the metathesis reaction between the "first-" and the "second
      generation" Grubbs-type catalysts 1 and (H(2)IMes)(PCy(3))Cl(2)Ru=CH(2) (2) with
      different substrates, ethylene, ethyl vinyl ether, and norbornene, and a profound
      influence of the substrate is found. In contrast to the degenerate reaction with
      ethylene, the reactions with ethyl vinyl ether and norbornene are strongly
      exergonic by 8-15 kcal/mol, and this excess energy is released after passing
      through the metallacyclobutane structure. While the metallacyclobutane is in a
      deep potential minimum for degenerate metathesis reactions, the energy barrier
      for the [2+2] cycloreversion vanishes for the most exergonic reactions. On the
      free energy surface under typical experimental conditions, the rate-limiting
      steps for the overall reactions are then either metallacyclobutane formation for
      1 or phosphane ligand dissociation for 2.

PMID- 15025476
TI  - Rate of enolate formation is not very sensitive to the hydrogen bonding ability
      of donors to carboxyl oxygen lone pair acceptors; a ramification of the principle
      of non-perfect synchronization for general-base-catalyzed enolate formation.
AB  - Two series of structures (1 and 2) possessing intramolecular hydrogen bonds to
      the lone-pair electrons of carbonyl oxygens have been examined to reveal the
      influence of the pK(a) of the hydrogen-bond donor on the rate of general-base
      catalyzed enolate formation. The geometry of the hydrogen bonds is well accepted
      to be appropriate for intramolecular hydrogen-bond formation. Yet, as revealed by
      Bronsted plots, both series show very little dependence of the rate of enolate
      formation on the hydrogen-bond donor ability. The intramolecular hydrogen bonds
      give rate enhancements only on the order of 10-100-fold, and corrected Bronsted
      alpha-values are slightly below 0.1. The results can be understood by
      interpreting them in light of the Principle of Non-Perfect Synchronization. The
      results are consistent with the proton transfer occurring through an asynchronous
      transition state with the developing negative charge localized on carbon. We
      postulate that catalysts of enolate formation will be most effective if the
      binding groups are focused on stabilizing negative charge that is forming on the
      enolate carbon rather than on the enolate oxygen.

PMID- 15025478
TI  - 1,4-hydroxybiradical behavior revealed through crystal structure-solid-state
      reactivity correlations.
AB  - Structure-reactivity correlations for triplet 1,4-hydroxybiradicals in solution
      are made difficult by the presence of multiple reactive conformers and the
      possibility of conformation-dependent intersystem crossing. These problems can be
      overcome by working in the crystalline state, where the conformations of the 1,4
      hydroxybiradicals are fixed and determinable by X-ray crystallography of the
      parent ketones, assuming that hydrogen atom abstraction occurs with little or no
      change in conformation. This approach is applied to 15 bi- and tricyclic ketones
      designed to have slightly different biradical conformations, so that the effect
      of small and incremental changes in geometry on biradical behavior can be tested.
      The results indicate that, while geometry does have a strong influence on 1,4
      hydroxybiradical partitioning between cyclization, cleavage, and reverse hydrogen
      transfer, a full understanding of the results requires that the strain involved
      in forming the cyclization products be taken into account.

PMID- 15025479
TI  - Dynamics of positive charge carriers on Si chains of polysilanes.
AB  - The transient absorption of radical cations of a variety of substituted
      polysilanes is discussed quantitatively in terms of the molar extinction
      coefficient and oscillator strength by nanosecond pulse radiolysis. Oxygen
      saturated polysilane solutions in benzene exhibit a strong transient absorption
      band ascribed to the polysilane radical cation. The transient species react with
      N,N,N',N'-tetramethyl-p-phenylene-diamine (TMPD) to produce TMPD radical cations.
      On the basis of the molar extinction coefficient of the TMPD radical cation, the
      molar extinction coefficients for the radical cations of polysilanes are found to
      increase in the range 3.3 x 10(4) to 2.0 x 10(5) M(-)(1) cm(-)(1) with increasing
      polymer segment length. The stepwise increase in the total oscillator strength
      with an increase in the number of phenyl rings directly bonded to the Si skeleton
      suggests the delocalization of the positive polaron state and/or the SOMO state
      over the phenyl rings, indicating the importance of phenyl rings in
      intermolecular hole transfer processes.

PMID- 15025481
TI  - Enantioselective synthesis of (--)-gilbertine via a cationic cascade cyclization.
AB  - Described is the first enantioselective synthesis of (-)-gilbertine (2), a member
      of the uleine-type family, and the determination of the absolute configuration of
      this natural product is reported. The key step employs a cationic cascade
      reaction for a tetrahydropyrane and piperidine ring formation and the
      construction of the pentacyclic framework in one step. The synthetic strategy
      utilizes the Shibasaki reaction to build up the first stereogenic center. A
      formylation reaction of a 3-substituted cyclohexanone derivative was achieved,
      giving only the desired regioisomer. The Japp-Klingemann Fischer indole protocol
      was used successfully as a convergent synthetic approach for the construction of
      the desired tetrahydrocarbazole (20). Furthermore, an unexpected behavior of this
      2,3-disubstituted cyclohexanone derivative during an epimerization process was
      investigated, resulting in different chemical behavior of the enantiomers and the
      racemate. The diastereomeric resolution was achieved via the cationic cascade
      reaction, demonstrating the versatility of this approach. Significantly, the
      synthetic 17-step sequence was easy to execute, giving (-)-gilbertine in 5.5%
      overall yield.

PMID- 15025480
TI  - Synthesis of medium ring nitrogen heterocycles via a tandem copper-catalyzed C-N
      bond formation-ring-expansion process.
AB  - A simple method for the preparation of medium ring heterocycles (7-, 8-, 9-, and
      10-membered) has been developed. The process employs a Cu-catalyzed coupling of a
      beta-lactam with an aryl bromide or iodide followed by intramolecular attack of a
      pendant amino group. In some instances, the intermediate beta-lactam is
      observable but can be converted to the aza-heterocycle by catalysis. Acetic acid
      was found to be superior to transition metal complexes as a catalyst for this
      ring-expansion process.

PMID- 15025482
TI  - X-ray diffraction analysis of nonequilibrium states in crystals: observation of
      an unstable conformer in flash-cooled crystals.
AB  - Some molecules with a molecular skeleton similar to that of stilbenes and
      azobenzenes show orientational disorder in the crystals. If the disorder is
      dynamic, a conformational interconversion takes place through a pedal motion. In
      this study X-ray diffraction analyses of (E)-stilbene (1) and azobenzene (2) were
      carried out at various temperatures. We succeeded in observing thermodynamic
      nonequilibrium states that were generated by fast freezing of the conformational
      interconversion at low temperatures. The populations of the two conformers in
      crystals of 1 at 90 K varied with the cooling rate. Flash cooling of a crystal of
      2 from room temperature to 90 K made it possible to observe the minor unstable
      conformer that does not exist in the equilibrium state at the same temperature.

PMID- 15025483
TI  - Ion-driven ATP pump by self-organized hybrid membrane materials.
AB  - We report new hybrid organic-inorganic materials, based on macrocyclic receptors
      1-3 self-organized in tubular superstructures prepared by sol-gel process.
      Fourier transform infrared (FTIR) and NMR spectroscopic analyses demonstrate that
      the self-organization by hydrogen bonding of organogel superstructures of 2 and 3
      were preserved in the hybrid materials throughout the sol-gel process. The
      molecular arrangement of heteroditopic receptors defines a particularly
      attractive functional transport device for both cation (tubular macrocycles) and
      anion (sandwich-urea) directional-diffusion transport mechanism in the hybrid
      membrane material. This system has been employed successfully to design a solid
      dense membrane, functioning as an ion-powered adenosine triphosphate (ATP(2)(-))
      pump, and illustrates how a self-organized hybrid material performs interesting
      and potentially useful functions.

PMID- 15025484
TI  - Self-assembly of rod-coil molecules into molecular length-dependent organization.
AB  - A series of rod-coil molecules (n-x, where n represents the number of repeating
      units in a PPO coil and x the number of phenyl groups in a rod segment) with
      variation in the molecular length, but an identical rod to coil volume ratio was
      synthesized, and their self-assembling behavior was investigated by using DSC and
      X-ray scatterings. The molecule with a short rod-coil molecule (16-4) shows a 3-D
      tetragonal structure based on a body-centered symmetry of the discrete bundles in
      addition to a lamellar structure. This 3-D lattice, on heating, collapses to
      generate a disordered micellar structure. Remarkably, the molecules based on
      longer molecular length (21-5 and 24-6) were observed to self-organize into, on
      heating, lamellar, tetagonally perforated lamellar, 2-D hexagonal columnar and
      finally disordered micellar structures. Further increase in the molecular length
      as in the case of 29-7 and 32-8 induces a 3-D hexagonally perforated lamellar
      structure as an intermediate structure between the lamellar and tetragonally
      perforated lamellar structures. Consequently, these systems demonstrate the
      ability to regulate the domain nanostructure, from 2-dimensionally continuous
      layers, long strips to discrete bundles via periodic perforated layers by small
      changes in the molecular length, at an identical rod-to-coil volume fraction.

PMID- 15025485
TI  - Fluorescent and circular dichroic detection of monosaccharides by molecular
      sensors: bis[(pyrrolyl)ethynyl]naphthyridine and
      bis[(indolyl)ethynyl]naphthyridine.
AB  - The push-pull conjugated molecules 2,7-bis-(1H-pyrrol-2-yl)ethynyl-1,8
      naphthyridine (BPN) and 2,7-bis(1H-indol-2-yl)ethynyl-1,8-naphthyridine (BIN)
      adopting daad relays of proton donors (d) and acceptors (a) form multiple
      hydrogen-bonding complexes with various monosaccharides that possess
      complementary adda sequences. Although the free BPN emits blue light at
      lambda(max) = 475 nm in CH(2)Cl(2), its complexation with octyl beta-d
      glucopyranoside gives green fluorescence at lambda(max) = 535 nm. The excellent
      photophysical properties make BPN a highly sensitive probe for monitoring
      glucopyranoside to a detection limit of approximately 100 pM. On the other hand,
      the CD-silent BIN molecule binds with monosaccharides to form the CD-active
      multiple hydrogen-bonding complexes, which exhibit the remarkable chirality
      dependent helicities consistent with the prediction by the ab initio approaches.
      On the basis of the similar daad cleft and hence the binding property, the
      fluorescence and CD absorption methods in BPN and BIN, respectively, are
      complementary, which, in combination with computational molecular modeling, not
      only give a detailed insight into the structures of the receptor-saccharide
      complexes in solution, but also differentiate octyl beta-d-glucopyranoside from
      its enantiomer and other monosaccharides.

PMID- 15025486
TI  - Self-assembly of electron donor-acceptor dyads into ordered architectures in two
      and three dimensions: surface patterning and columnar "double cables".
AB  - We report the synthesis and characterization of covalent dyads and multiads of
      electron acceptors (A) and donors (D), with the purpose of exploiting their
      nanophase separation behavior toward (a) two-dimensional (2D) surface patterning
      with well-defined integrated arrays of dissimilar molecular electronic features
      and (b) bulk self-assembly to noncovalent columnar versions of the so-called
      "double cable" systems, the likes of which could eventually provide side-by-side
      percolation pathways for electrons and holes in solar cells. Soluble, alkylated
      hexa-peri-hexabenzocoronenes (HBCs) bearing tethered anthraquinones (AQs) are
      shown by scanning tunneling microscopy (STM) to self-assemble at the solution
      graphite interface into either defect-rich polycrystalline monolayers or extended
      2D crystalline domains, depending on the number of tethered AQs. In the bulk, the
      thermal stability of the room-temperature HBC columnar phase is increased, which
      is attributed to the desired nanotriphase separation of HBC columns, insulating
      alkyl sheaths, and AQ units. Homeotropic alignment (columns normal to surfaces),
      predicted to be ideal for potential exploitation of such "double cables" in
      photovoltaic devices, is demonstrated.

PMID- 15025487
TI  - Exceptionally stable, hollow tubular metal-organic architectures: synthesis,
      characterization, and solid-state transformation study.
AB  - An effective solvothermal procedure has been developed to synthesize the new
      three-dimensional metal-organic framework, [ZnF(AmTAZ)].solvents, using either 3
      amino-1,2,4-triazole (AmTAZ) or 3-amino-1,2,4-triazole-5-carboxylic acid
      (AmTAZAc) and a choice of several Zn(II) salts as starting materials. The three
      dimensional structure displays open-ended, hollow nanotubular channels that are
      formed by hexanuclear metallamacrocyclic Zn(6)F(6)(AmTAZ)(6) rings. The framework
      integrity is maintained to 350 degrees C, at which point most of the guest
      solvent molecules have been removed, as evidenced by single-crystal X-ray
      analyses, (1)H solid-state NMR, and TGA measurements. At higher temperatures, the
      framework is converted either to zinc oxide (ZnO) when heated in air or to zinc
      cyanamide (ZnCN(2)) when heated in an inert atmosphere. In both cases, the as
      grown, rodlike crystal shape is maintained during the solid-state transformation,
      suggesting a possible route for preparing one-dimensional crystalline
      nanomaterials.

PMID- 15025488
TI  - Crystal structure and microstructure of some La(2/3-x)Li 3xTiO3 oxides: an
      example of the complementary use of electron diffraction and microscopy and
      synchrotron X-ray diffraction to study complex materials.
AB  - Three representative oxides of the La(2/3)(-)(x)()Li(3)(x)()TiO(3) system have
      been studied by selected area electron diffraction (SAED), high-resolution
      transmission electron microscopy (HRTEM), and powder synchrotron X-ray
      diffraction. HRTEM showed that the materials have a complex microstructure. The
      SAED and HRTEM results have allowed us to propose a model to refine the crystal
      structure of these oxides that also accounts for their microstructure. The
      materials have a perovskite-related structure with a diagonal unit cell ( radical
      2a(p) x radical 2a(p) x 2a(p)) as a consequence of the tilting of the TiO(6)
      octahedra. Ordering of lanthanum and lithium ions and vacancies along the 2a(p)
      axis, as well as displacements of titanium ions from the center of the octahedra,
      have been determined. The size and shape of the domains have been obtained from
      the synchrotron X-ray diffraction data; in addition, other extended defects such
      as strains and compositional fluctuations have been detected.

PMID- 15025489
TI  - Electronic structure of tubular aromatic molecules derived from the metallic
      (5,5) armchair single wall carbon nanotube.
AB  - All-electron static and time-dependent DFT electronic calculations, with complete
      geometrical optimization, are performed on tubular molecules up to C(210)H(20)
      that are finite sections of the (5,5) metallic single wall carbon nanotube with
      hydrogen termination at the open ends. We find pronounced C-C bond reconstruction
      at the tube ends; this initiates bond alternation that propagates into the tube
      centers. For the especially low band gap molecules C(120)H(20), C(150)H(20), and
      C(180)H(20), alternation increases, and a second nearly isoenergic structural
      isomer of different alternation is found. A small residual C-C bond alternation
      and band gap may be present in the infinite tube. The van Hove band gap forms
      quickly with length, while the metallic Fermi point (at the crossing of linear
      bands) forms very slowly with length. There are no end-localized states at
      energies near the Fermi energy. The HOMO-LUMO gap and the lowest singlet excited
      state, whose energies show a periodicity with length as previously calculated,
      are optically forbidden. However, each molecule shows an intense visible "charge
      transfer" transition, not present in the infinite tube, whose energy varies
      smoothly with length; this transition should be an identifying signature for
      these molecules. The static axial polarizability per unit length increases
      rapidly with N as the "charge transfer" transition moves into the infrared; this
      indicates increasing metallic character. However, the ionization potential,
      electron affinity, chemical hardness, and relative energetic stability all show
      the length periodicity seen in the HOMO-LUMO gap, in contrast to the optical
      "charge transfer" transition and the static axial polarizability. These
      periodicities, due to a one-dimensional quantum size effect as originally modeled
      by Coulson in 1938, nevertheless cancel in the calculated Fermi energy, which
      varies smoothly toward a predicted bulk work function near 3.9 eV. A detailed
      study of C(190)H(20) with up to eight extra electrons or holes shows the total
      energy is closely fit by a simple classical charging model, as is commonly
      applied to metallic clusters.

PMID- 15025490
TI  - Os(II)-nitrosyl and Os(II)-dinitrogen complexes from reactions between Os(VI)
      nitrido and hydroxylamines and methoxylamines.
AB  - Reactions between the Os(VI)-nitrido salts (e.g., trans
      [Os(VI)(tpy)(Cl)(2)(N)]PF(6) (tpy = 2,2':6',2"-terpyridine), cis
      [Os(VI)(tpy)(Cl)(2)(N)]PF(6), and fac-[Os(VI)(tpm)(Cl)(2)(N)]PF(6) (tpm =
      tris(pyrazol-1-yl)methane)) and the hydroxylamines (e.g., H(2)NOH and MeHNOH) and
      the methoxylamines (e.g., H(2)NOMe and MeHNOMe) in dry MeOH at room temperature
      give three different types of products. They are Os(II)-dinitrogen (e.g., trans-,
      cis-, or fac-[Os(II)-N(2)]), Os(II)-nitrosyl [Os(II)-NO](+) (e.g., trans- or cis
      [Os(II)-NO](+)), Os(IV)-hydroxyhydrazido (e.g., cis-[Os(IV)-N(H)N(Me)(OH)](+)),
      and Os(IV)-methoxyhydrazido (e.g., trans-/cis-[Os(IV)-N(H)N(H)(OMe)](+), and
      trans-/cis-[Os(IV)-N(H)N(Me)(OMe)](+)) adducts. The products depend in a subtle
      way on the electron content of the starting nitrido complexes, the nature of the
      hydroxylamines, the nature of the methoxylamines, and the reaction conditions.
      Their appearance can be rationalized by invoking the formation of a series of
      related Os(IV) adducts which are stable or decompose to give the final products
      by two different pathways. The first involves internal 2-electron transfer and
      extrusion of H(2)O, MeOH, or MeOMe to give [Os(II)-N(2)]. The second which gives
      [Os(II)-NO](+) appears to involve seven-coordinate Os(IV) intermediates based on
      the results of an (15)N-labeling study.

PMID- 15025491
TI  - Alumina-supported vanadium nanoparticles: structural characterization and CO
      adsorption properties.
AB  - Alumina-supported vanadium particles were prepared under ultrahigh vacuum (UHV)
      conditions and characterized with respect to their structural and CO adsorption
      properties. As supporting oxide, we used a thin, well-ordered alumina film grown
      on NiAl(110). This allows the application of scanning tunneling microscopy (STM),
      infrared reflection-absorption spectroscopy (IRAS), and X-ray photoelectron
      spectroscopy (XPS) without charging effects. Vanadium evaporation under UHV
      conditions leads to the growth of nanometer-sized particles which strongly
      interact with the alumina support. At very low vanadium coverages, these
      particles are partially incorporated into the alumina film and get oxidized
      through the contact to alumina. Low-temperature CO adsorption in this coverage
      regime permits the preparation of isolated vanadium carbonyls, of which we have
      identified mono-, di-, and tricarbonyls of the V(CO)(y)() type. A charge
      frequency relationship was set up which allows one to quantify the extent of
      charge transfer from vanadium to alumina. It turns out that this charge transfer
      depends on the V nucleation site.

PMID- 15025492
TI  - Kinetics, thermodynamics, and effect of BPh3 on competitive C-C and C-H bond
      activation reactions in the interconversion of allyl cyanide by [Ni(dippe)].
AB  - Reaction of [(dippe)Ni(micro-H)](2) with allyl cyanide at low temperature
      quantitatively generates the eta(2)-olefin complex (dippe)Ni(CH(2)=CHCH(2)CN)
      (1). At ambient temperature or above, the olefin complex is converted to a
      mixture of C-CN cleavage product (dippe)Ni(eta(3)-allyl)(CN) (3) and the olefin
      isomerization products (dippe)Ni(eta(2)-crotonitrile) (cis- and trans-2), which
      form via C-H activation. The latter are the exclusive products at longer reaction
      times, indicating that C-CN cleavage is reversible and the crotononitrile
      complexes 2 are more thermodynamically stable than eta(3)-allyl species 3. The
      kinetics of this reaction have been followed as a function of temperature, and
      rate constants have been extracted by modeling of the reaction. The rate
      constants for C-CN bond formation (the reverse of C-CN cleavage) show a stronger
      temperature dependence than those for C-CN and C-H activation, making the
      observed distribution of C-H versus C-CN cleavage products strongly temperature
      dependent. The activation parameters for the C-CN formation step are also quite
      distinct from those of the C-CN and C-H cleavage steps (larger DeltaH(++) and
      positive DeltaS(++)). Addition of the Lewis acid BPh(3) to 1 at low temperature
      yields exclusively the C-CN activation product (dippe)Ni(eta(3)-allyl)(CNBPh(3))
      (4). Independently prepared (dippe)Ni(crotononitrile-BPh(3)) (cis- and trans-7)
      does not interconvert with 4, indicating that 4 is the kinetic product of the
      BPh(3)-mediated reaction. On standing in solution at ambient temperature, 4
      decomposes slowly to complex 5, with structure [(dippe)Ni(eta(3)-allyl)(N triple
      bond C-BPh(3)), while addition of a second equivalent of BPh(3) immediately
      produces [(dippe)Ni(eta(3)-allyl)](+)[Ph(3)BC triple bond NBPh(3)](-) (6).
      Comparison of the barriers to pi-sigma allyl interconversion (determined via
      dynamic (1)H NMR spectroscopy) for all of the eta(3)-allyl complexes reveals that
      axial cyanide ligands facilitate pi-sigma interconversion by moving into the
      P(2)Ni square plane when the allyl group is sigma-bound.

PMID- 15025493
TI  - Why are olefins oxidized by RuO4 under cleavage of the carbon-carbon bond whereas
      oxidation by OsO4 yields cis-diols?
AB  - Quantum chemical calculations using gradient-corrected (B3LYP) density functional
      theory have been carried out to investigate the mechanism of the oxidative
      cleavage of alkenes by ruthenium tetraoxide. The initial reaction of the
      tetraoxide with the olefin occurs via a [3+2] cycloaddition as in the case of
      osmium tetraoxide. The results clearly show that the bond cleavage does not take
      place at the primary adduct, but much later in the reaction path. After the
      formation of the ruthenium(VI)dioxo-2,5-dioxolane, the reaction proceeds with the
      addition of a second olefin to yield ruthenium(IV)-bis(2,5-dioxolane), which in
      turn becomes oxidized first to rutheniumoxo(VI)-bis(2,5-dioxolane) 6(Ru) and then
      to ruthenium(VIII)-dioxo-bis(2,5-dioxolane) 7(Ru). Only in complexes containing
      the metal center in the formal oxidation state +VIII are low activation barriers
      for C-C bond cleavage and exothermic formation of carbonyl compounds as products
      calculated. The lowest activation barrier, DeltaH(++) = 2.5 kcal/mol, is
      calculated for the C-C bond breaking reaction of 7(Ru) which is predicted as the
      pivotal intermediate of the oxidation reaction. The calculations of the oxidation
      reaction with OsO(4) show that those reactions where the oxidation state of the
      metal increases have larger activation barriers for M = Ru than for M = Os, while
      reactions which reduce the oxidation state have a lower activation barrier for
      ruthenium compounds. Also, reactions which increase the oxidation state of the
      metal are in the case of M = Os more exothermic than for M = Ru. In this work,
      all important points of the potential energy surface (PES) are reported, and the
      complete catalytic cycle for the oxidative cleavage of olefins by ruthenium
      tetraoxide is presented.

PMID- 15025494
TI  - 13C nuclear overhauser polarization-magic-angle spinning nuclear magnetic
      resonance spectroscopy in uniformly 13C-labeled solid proteins.
AB  - A recently introduced (13)C polarization technique based on the nuclear
      Overhauser effect in rotating solid (nuclear Overhauser polarization-magic-angle
      spinning, NOP-MAS) (Takegoshi, K.; Terao, T. J. Chem. Phys. 2002, 117, 1700-1707)
      is applied to uniformly (13)C, (15)N-labeled proteins. NOP enhancement factors
      per scan of 1.5 approximately 2.0 are obtained, while that by cross polarization
      (CP) is less than 1.0. We show that uniform enhancement of all (13)C signals by
      CP is difficult to attain, while it is easily achieved by NOP, thus enabling
      quantitative comparison of signal intensities. NOP is easy to carry out under
      fast MAS and works well even for somewhat mobile molecules, for which CP does not
      work. Moreover, in labeled protein samples containing nonlabeled additives, NOP
      can eliminate the latter signals. For these features, NOP is superior to CP in
      many uniformly (13)C labeled proteins.

PMID- 15025495
TI  - The bond-forming reactions of atomic dications with neutral molecules: formation
      of ArNH+ and ArN+ from collisions of Ar2+ with NH3.
AB  - An experimental and computational study has been performed to investigate the
      bond-forming reactivity between Ar(2+) and NH(3). Experimentally, we detect two
      previously unobserved bond-forming reactions between Ar(2+) and NH(3) forming
      ArN(+) and ArNH(+). This is the first experimental observation of a triatomic
      product ion (ArNH(+)) following a chemical reaction of a rare gas dication with a
      neutral. The intensity of ArNH(+) was found to decrease with increasing collision
      energy, with a corresponding increase in the intensity of ArN(+), indicating that
      ArN(+) is formed by the dissociation of ArNH(+). Key features on the potential
      energy surface for the reaction were calculated quantum chemically using CASSCF
      and MRCI methods. The calculated reaction mechanism, which takes place on a
      singlet surface, involves the initial formation of an Ar-N bond to give Ar
      NH(3)(2+). This complexation is followed by proton loss via a transition state,
      and then loss of the two remaining hydrogen atoms in two subsequent
      activationless steps to give the products (3)ArN(+) + H(+) + 2H. This calculated
      pathway supports the sequential formation of ArN(+) from ArNH(+), as suggested by
      the experimental data. The calculations also indicate that no bond-forming
      pathway exists on the ground triplet surface for this system.

PMID- 15025496
TI  - TiO2 films loaded with silver nanoparticles: control of multicolor photochromic
      behavior.
AB  - Ag-TiO(2) films exhibiting multicolor photochromism were prepared by
      photoelectrochemical reduction of Ag(+) to Ag nanoparticles in nanoporous TiO(2)
      films under UV light. Color of the Ag-TiO(2) film, initially brownish-gray,
      changes under a colored visible light to the color of the light and reverts to
      brownish-gray under UV light. Their chromogenic properties were improved by
      simultaneous irradiation for Ag deposition with UV and blue lights to suppress
      the formation of anisotropic Ag particles. Nonvolatilization of a color image was
      also achieved by removing Ag(+) that was generated during the irradiation with a
      colored light. Once nonvolatilized, the image can be reproduced by UV light, even
      after the image is discolored under white light. This new effect evidenced that
      nanopores in the TiO(2) film determine the resonance wavelengths of the Ag
      particles, as their molds. In addition, solvatochromic behavior of the Ag-TiO(2)
      film proved that nanospaces left around the Ag nanoparticles affect the resonance
      wavelengths of the Ag particles.

PMID- 15025497
TI  - Mass spectrometric investigation of the mechanism of inactivation of hamster
      arylamine N-acetyltransferase 1 by N-hydroxy-2-acetylaminofluorene.
AB  - Arylamine N-acetyltransferases (NATs) are expressed in most mammalian tissues.
      NATs catalyze the N-acetylation of primary arylamines, the O-acetylation of N
      arylhydroxylamines, and the N,O-transacetylation of N-arylhydroxamic acids. The
      latter two reactions result in formation of reactive, electrophilic N
      acetoxyarylamines, which are considered to be the ultimate carcinogenic
      metabolites of certain environmental and dietary arylamines. Incubation of
      various N-(aryl)acetohydroxamic acids, such as N-hydroxy-2-acetylaminofluorene (N
      OH-AAF) with hamster NAT1, results in time-dependent, concentration-dependent,
      and kinetically first-order irreversible inactivation of the enzyme. N-OH-AAF
      also causes in vivo inactivation of NAT1. The purpose of this research was to
      investigate the molecular mechanism of NAT1 inactivation by identifying the amino
      acid residues that undergo covalent modification upon NAT1-catalyzed
      bioactivation of N-OH-AAF and by characterizing the chemical structures of the
      adducts. Electrospray ionization quadrupole time-of-flight mass spectrometric
      analysis of NAT1 that had been incubated with N-OH-AAF revealed that the mass of
      the major adduct (+195 Da) was consistent with a (2-fluorenyl)sulfinamide
      modification. The major adduct underwent hydrolysis to yield a protein with a
      molecular mass that corresponded to a sulfinic acid-modified NAT1. Treatment of
      NAT1 with 2-nitrosofluorene resulted in a modification (+195 Da) that was
      identical in mass to that obtained with N-OH-AAF-inactivated enzyme. Matrix
      assisted laser desorption-ionization quadrupole time-of flight tandem mass
      spectrometric (MALDI Q-TOF MS/MS) analysis revealed that the modified residue was
      the catalytically essential Cys68. MALDI Q-TOF MS/MS sequencing of peptides from
      protease digests of inactivated NAT1 also identified two minor adducts at Tyr17
      and Tyr186, each of which was covalently conjugated with 2-aminofluorene. Thus,
      the mechanism of inactivation of NAT1 by N-OH-AAF involves NAT1-catalyzed
      deacetylation to afford N-hydroxy-2-aminofluorene, which after oxidative
      conversion to 2-nitrosofluorene, forms a sulfinamide adduct by reacting with
      Cys68. GSH had little effect on the inactivation of NAT1 by N-OH-AAF, although
      high concentrations of cysteine attenuated both the extent of inactivation and
      the sulfinamide adduct formation.

PMID- 15025499
TI  - Detection of O6-carboxymethyl-2'-deoxyguanosine in DNA following reaction of
      nitric oxide with glycine and in human blood DNA using a quantitative immunoslot
      blot assay.
AB  - Previous research has shown that a range of nitrosated glycine derivatives react
      with DNA to form O6-carboxymethylguanine and O6-methylguanine DNA adducts
      [Harrison et al. (1999) Chem. Res. Toxicol. 12, 106-111). Nitrosated glycine
      derivatives may be formed in the gastrointestinal tract from the reaction of
      dietary glycine with nitrosating agents. The aim of this study was to further
      investigate the role of dietary glycine in the formation of O6-guanine adducts at
      physiologically relevant concentrations. In vitro studies were performed by
      reacting 10 microM to 50 mM glycine with nitric oxide in the presence of oxygen.
      An HPLC assay was developed to measure the resulting nitrosated glycine
      derivative, diazoacetate anion. The amount of nitrosating agent present in the
      reaction mixture was determined by colorimetric measurement of nitrite, the
      hydrolysis product of N2O3. Diazoacetate anion formation depended linearly on
      glycine concentration. Solutions of nitrosated glycine reacted with 2'
      deoxyguanosine and calf thymus DNA to give O6-carboxymethyl-2'-deoxyguanosine
      and, at high concentrations of glycine and nitric oxide, O6-methyl-2'
      deoxyguanosine. At physiological concentrations of glycine and nitric oxide,
      diazoacetate anion was not detectable. Studies with synthetic diazoacetate anion
      showed that concentrations < 14 microM did not give detectable O6
      carboxyethylguanine in DNA, even when a sensitive immunoslot blot assay was used.
      However, O6-carboxymethylguanine was detected in human blood DNA samples obtained
      from three volunteers consuming a standardized high meat diet, using the
      immunoslot blot assay. O6-Carboxymethylguanine levels ranged from 35 to 80
      (detection limit = 15) O6-carboxymethylguanine per 10(8) bases. These studies
      provide further evidence that nitrosated amino acids may be risk factors for
      gastrointestinal tract cancers.

PMID- 15025500
TI  - Protein binding and metabolism influence the relative skin sensitization
      potential of cinnamic compounds.
AB  - Skin protein modification (haptenation) is thought to be a key step in the
      manifestation of sensitization to low molecular mass chemicals (<500 g/mol). For
      sensitizing chemicals that are not protein reactive, it is hypothesised that
      metabolic activation can convert such chemicals into protein reactive toxins
      within the skin. trans-Cinnamaldehyde, alpha-amyl cinnamaldehyde, and trans
      cinnamic alcohol are known sensitizers with differing potencies in man, where the
      former two are protein reactive and the latter is not. Here, we have used
      immunochemical methods to investigate the extent of protein-cinnamaldehyde
      binding in rat and human skin homogenates that have been incubated (for either 5,
      15, 30, or 60 min) at 37 degrees C with cinnamaldehyde, alpha-amyl cinnamaldehyde
      (at concentrations of between 1 and 40 mM), and cinnamic alcohol (at higher
      concentrations of 200 or 400 mM). Cinnamaldehyde specific antiserum was raised
      specially. A broad range (in terms of molecular mass) of protein-cinnamaldehyde
      adducts was detected (as formed in a time- and concentration-dependent manner) in
      skin treated with cinnamaldehyde and cinnamic alcohol but not with alpha-amyl
      cinnamaldehyde. Mechanistic observations have been related to relative skin
      sensitization potential, as determined using the local lymph node assay (LLNA) as
      a biological read-out. The work presented here suggests that there is a common
      hapten involved in cinnamaldehyde and cinnamic alcohol sensitization and that
      metabolic activation (to cinnamaldehyde) is involved in the latter. Conversely,
      there does not appear to be a common hapten for cinnamaldehyde and alpha-amyl
      cinnamaldehyde. Such mechanistic work on protein modification is important in
      understanding the early mechanisms of skin sensitization. Such knowledge can then
      be used in order that effective and appropriate in vitro/in silico tools for
      predicting sensitization potential, with a high confidence, can be developed.

PMID- 15025498
TI  - Effects of cadmium(II) on (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide-induced
      DNA damage response in human fibroblasts and DNA repair: a possible mechanism of
      cadmium's cogenotoxicity.
AB  - Cadmium, a widespread environmental pollutant and a cigarette smoke constituent,
      enhances the genotoxicity of benzo[a]pyrene (BP). The mechanism(s) underlying the
      potentiation of BP-induced genotoxicity by Cd2+ is not clearly understood. Our
      studies of the effects of noncytotoxic concentrations of Cd2+ on the levels of
      p53 and p21 in (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE)-treated
      human fibroblasts showed that Cd2+ decreased BPDE-induced p21 levels in a dose
      dependent manner whereas p53 accumulation is attenuated only at higher
      noncytotoxic concentrations of cadmium. These findings suggest that both the
      activity and the accumulation of p53 in response of BPDE treatment are inhibited
      by Cd2+ although the possibility of p53-independent p21 transactivation cannot be
      ruled out. Exposure of synchronized human fibroblast cells to 0.5 microM of BPDE
      caused 72% of the cells remaining in G1 phase as compared to 52% in the case of
      untreated cells. Treatment of the cells with CdCl2 prior to exposing them to BPDE
      caused a decrease in the G1 population (72 to 54%) in a dose-dependent manner. An
      in vitro repair assay of BPDE-damaged pUC18 plasmid DNA using untreated and
      cadmium-treated nucleotide excision repair (NER) proficient HeLa extract showed
      that cadmium impaired the ability of HeLa cell extract to repair BPDE-damaged
      pUC18 DNA. Our findings indicate that cadmium not only inhibits NER pathway
      dependent repair of BPDE-damaged DNA but also impairs p53 and p21 responses and
      overrides BPDE-induced G1-S cell cycle arrest. The effect of cadmium on these
      processes may explain, at least partly, the potentiating effect of the metal on
      the genotoxicity of BP.

PMID- 15025502
TI  - Mutation of the Phe20 residue in Alzheimer's amyloid beta-peptide might decrease
      its toxicity due to disruption of the Met35-cupric site electron transfer
      pathway.
AB  - It has been proposed that the Met residue in the C-terminal domain of the
      Alzheimer's disease beta-amyloid peptide (betaA) serves as a source of electrons
      for the Cu(II)-catalyzed reduction of molecular oxygen to hydrogen peroxide.
      Mechanistically, this process would require the long distance electron transfer
      from the thioether sulfur to the peptide-bound copper. Therefore, the electron
      transfer pathways between the Met35 sulfur atom and the cupric site in the N
      terminus of betaA congeners have been analyzed applying semiclassical models of
      long distance electron transfer. Simulations performed for several betaA
      conformers collected along the 6 ns Langevin Dynamics trajectories suggest that
      the presence of the Phe20 residue in the peptide is required for feasibility of
      the electron transfer. Thus, I would like to propose the mutation Phe20Ala in
      betaA as a potential way to reduce its neurotoxicity.

PMID- 15025501
TI  - Structural and stereoisomer effects of model estrogen quinone-derived DNA
      adducts: N6-(2-hydroxyestron-6(alpha,beta)-yl)-2'-deoxyadenosine and N2-(2
      hydroxyestron-6(alpha,beta)-yl)-2'-deoxyguanosine.
AB  - An extensive conformational analysis has been carried out for two
      diastereoisomeric pairs of model estrogen quinone-derived DNA adducts, N6-(2
      hydroxyestron-6(alpha,beta)-yl)-2'-deoxyadenosine (2-OHE1-6(alpha,beta)-N6-dA)
      and N2-(2-hydroxyestron-6(alpha,beta)-yl)-2'-deoxyguanosine (2-OHE1-6(alpha,beta)
      N2-dG), in a B-DNA duplex and at a primer-template junction in a pol alpha family
      DNA polymerase. In vitro primer extension studies in pol alpha [Terashima, I., et
      al. (1998) Biochemistry 37, 13807-13815] have shown that the adenine adducts can
      incorporate dT, together with a small proportion of the incorrect base dC
      opposite the lesion, and they block less strongly than the guanine adducts. We
      have carried out conformational searches with energy minimization for four DNA
      duplexes containing 2-OHE1-6alpha-N6-dA, 2-OHE1-6beta-N6-dA, 2-OHE1-6alpha-N2-dG,
      or 2-OHE1-6beta-N2-dG. Our searches revealed that the four-ring nonplanar 2
      hydroxyestrone (2-OHE1) moiety strongly prefers to reside in the major groove of
      the adenine adducts or the minor groove of the guanine adducts in a B-DNA duplex,
      with stereochemistry-dependent orientational differences in each case. No low
      energy conformations involving intercalation of the 2-OHE1 moiety were located in
      the searches. This stems from the largely nonplanar, nonaromatic nature of the 2
      OHE1 ring system and implies that the proclivity for such bulky, nonplanar
      adducts to reside at the DNA helix exterior is a plausible conformational feature
      of other structurally similar estrogen quinone-derived DNA adducts, independent
      of base sequence context. In addition, the adenine adduct isomers, located in the
      major groove, manifest serious disturbance to the Watson-Crick base pairs at and
      near the lesion site, suggesting repair susceptibility. Possible structures of
      these adducts in a pol alpha family polymerase were also investigated through
      molecular modeling. The results rationalized the experimental in vitro primer
      extension studies. In addition, poor accommodation of the beta-stereoisomers
      within the polymerase was noted, suggesting that these stereoisomers would be
      more prone to cause blockage. Stereochemistry-dependent differences in adduct
      orientation could be expected to produce different biochemical effects, as has
      been observed in adducts derived from polycyclic aromatic hydrocarbons.

PMID- 15025503
TI  - Supercoiled DNA promotes formation of intercalated cis-N2-deoxyguanine adducts
      and base-stacked trans-N2-deoxyguanine adducts by (+)-7R,8S-dihydrodiol-9S,10R
      epoxy-7,8,9,10-tetra- hydrobenzo[a]pyrene.
AB  - The highly reactive and mutagenic benzo[a]pyrene metabolite, (+)-7R,8S-dihydroxy
      9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), forms predominantly N2
      deoxyguanine DNA adducts in two stereoisomeric configurations (cis and trans). In
      previous in vitro assays using oligonucleotide substrates site specifically
      modified with cis- and trans-BPDE adducts, the nucleotide excision repair (NER)
      systems of eukaryotes and prokaryotes incise cis-BPDE adducts more efficiently
      than trans-BPDE adducts [Hess, et al. (1997) Mol. Cell Biol 17, 7069; Zou, et al.
      (2001) Biochemistry 40, 2923). We investigated the influence of DNA secondary
      structure on stereospecificity of BPDE adduct formation, and incision of BPDE
      adducts by the prokaryotic UvrABC NER endonuclease was examined. BPDE adducts
      formed at low density on supercoiled plasmids were incised 6-7-fold better by the
      thermoresistant Bacillus caldotenaxUvrABC than were BPDE adducts formed on linear
      DNA. Linearizing supercoiled plasmid DNAs after BPDE adduct formation did not
      diminish incision efficiency. These results suggested that configuration and/or
      conformation of adducts formed on linear and supercoiled DNAs differed. This
      hypothesis was confirmed by low temperature fluorescence spectroscopy of adducted
      supercoiled and linear DNAs. Spectroscopic results indicated that intercalated
      cis-BPDE adducts as well as base-stacked trans-BPDE adducts formed more
      abundantly in supercoiled DNA than in linear DNA. A higher cis to trans adduct
      ratio in supercoiled DNA was confirmed by high resolution [32P]postlabeling
      analyses. These results demonstrate that DNA secondary structure influences both
      configuration and conformation of BPDE adducts formed at low density
      (approximately 1 adduct/kbp) and suggests that the ratio of cis- to trans-BPDE
      adducts and amount of base-stacked trans adducts formed under physiological
      exposure conditions may be higher than inferred from high dose experiments.

PMID- 15025505
TI  - Structure-activity relationships for the toxicity of polychlorinated
      dibenzofurans: approach through density functional theory-based descriptors.
AB  - The applicability of various density functional theory (DFT)-based descriptors-
      chemical softness, electronegativity, and electrophilicity index--for
      quantitative structure--activity relationships (QSARs) was investigated for
      polychlorinated dibenzofurans (PCDFs). The DFT descriptors were obtained by using
      the three parameter hybrid density functional, B3LYP, with the 6-311G(d,p) basis
      set. QSARs were developed relating aryl hydrocarbon receptor (AhR) binding
      affinities, aryl hydrocarbon hydroxylase and ethoxyresorufin O-deethylase
      induction potencies of PCDFs with DFT descriptors, hydrophobicity, and steric
      parameters. These QSARs explain around 75% of variation in AhR binding affinities
      of PCDFs. Congeners with higher toxicity values had larger softness values.
      Studies also showed that the most toxic isomer of tetrachlorodibenzofurans
      (TCDFs) and dibenzo-p-dioxins (TCDDs), respectively, had the largest chemical
      softness value in its respective group. The results show that DFT descriptors
      could be used as useful electronic descriptors in QSARs for the prediction of
      toxicity of PCDFs. Overall, 85 congeners of PCDFs and TCDDs were considered in
      this study.

PMID- 15025506
TI  - Reactions of the putative neurotoxin tryptamine-4,5-dione with L-cysteine and
      other thiols.
AB  - Tryptamine-4,5-dione (1) is formed by oxidation of 5-hydroxytryptamine by
      reactive oxygen and reactive nitrogen species. Dione 1 is a powerful electrophile
      that can covalently modify cysteinyl residues of proteins and deactivate key
      enzymes. Thus, 1 has been suggested to play a role in the degeneration of
      serotonergic neurons in brain disorders such as Alzheimer's disease or evoked by
      amphetamine drugs. However, if formed in the brain, it is also likely that 1
      would react with low molecular weight thiols such as cysteine (CySH) and
      glutathione (GSH). The resulting metabolites might not only contribute to the
      degeneration of serotonergic neurons but also, perhaps, serve as biomarkers of
      such neurodegeneration. In this investigation, it is shown that in oxygenated
      buffer at pH 7.4 dione 1 reacts with CySH and other low molecular weight
      sulfhydryls such as GSH, N-acetylcysteine, and cysteamine to form, first, the
      corresponding 7-S-thioethers of the dione. However, unlike the glutathionyl and N
      acetylcysteinyl conjugates of 1, the 7-S-cysteinyl conjugate is very unstable at
      pH 7.4 forming a number of novel products, the nature of which are dependent on
      the relative concentrations of 1 and CySH. These products have been isolated, and
      spectroscopic and other evidence is provided in support of their proposed
      chemical structures.

PMID- 15025504
TI  - Toxicity of hydroxylated and quinoid PCB metabolites: inhibition of gap
      junctional intercellular communication and activation of aryl hydrocarbon and
      estrogen receptors in hepatic and mammary cells.
AB  - In the present study, a series of 32 hydroxy- and dihydroxy-polychlorinated
      biphenyls (OH-PCBs) and PCB-derived quinones were prepared and evaluated for
      their in vitro potencies to downregulate gap junctional intercellular
      communication (GJIC) and to activate the aryl hydrocarbon receptor (AhR) and the
      estrogen receptor alpha (ER) in well-established liver and mammary cell models.
      The rat liver epithelial cell line WB-F344 was used for in vitro determination of
      GJIC inhibition; the AhR-inducing activity was determined in the rat hepatoma
      H4IIE.Luc cells stably transfected with a luciferase reporter gene; ER-mediated
      activity was measured in two breast carcinoma cell lines, MVLN and T47D.Luc,
      stably transfected with luciferase under the control of estrogen responsive
      element. Acute inhibition of GJIC, potentially associated with tumor promotion,
      was detected after treatment with all OH-PCBs under study, with the persistent OH
      PCBs being the strongest ones. Several compounds were found to significantly
      induce the AhR-mediated activity, including 4'-OH-PCB 79, a metabolite of PCB 77,
      and 2-(4'-chloro)- and 2-(3',4'-dichloro)-1,4-benzoquinones and 1,4
      hydroquinones. Low molecular weight OH-PCBs, such as 3'-hydroxy, 4'-, and 3',4'
      dihydroxy-4-chlorobiphenyl, elicited significant estrogenic activity and
      potentiated effect of 17beta-estradiol. Antiestrogenic potencies, determined in
      the presence of 17beta-estradiol, were found for persistent 4-OH-PCB 187, 4-OH
      PCB 146, and some low chlorinated PCB derivatives. However, no apparent
      association between induction of AhR activity and antiestrogenicity was observed.
      The majority of the OH-PCBs suppressed the 17beta-estradiol response only at
      cytotoxic concentrations. Spearman's rank correlations were calculated for these
      biological data and the physicochemical descriptors, hydrophobicity (log P),
      molar volume, pKa, log D, and dihedral angle. Significant correlations were found
      between potency to downregulate GJIC and log P and molar volume (R = -0.7, p <
      0.0001). Antiestrogenic effects were also negatively correlated with
      hydrophobicity and molar volume. No significant correlations among other
      biological end points and the physicochemical descriptors were observed for the
      entire set of compounds. These results show that oxygenated PCB metabolites are
      capable of multiple adverse effects, including gap junction inhibition, AhR
      mediated activity, and (anti)estrogenicity. The inhibition of GJIC by OH-PCBs
      represents a novel mode of action of both the lower chlorinated and the
      persisting high molecular weight OH-PCBs.

PMID- 15025507
TI  - Detection of nitrated benzene metabolites in bone marrow of B6C3F1 mice treated
      with benzene.
AB  - Benzene, a constituent of cigarette smoke, is a human leukemogen and induces bone
      marrow toxicity. The mechanism of benzene-induced toxicity is not well
      established. We hypothesized that relatively high levels of nitric oxide formed
      in bone marrow can react with oxygen and/or superoxide anion that is generated
      during redox cycling of ring-hydroxylated benzene metabolites to yield
      peroxynitrite as well as other NO-derived intermediates. Peroxynitrite can either
      directly damage cellular macromolecules or form nitrated toxic metabolites.
      Toward this end, we investigated whether nitro derivatives of benzene are formed
      in bone marrow of mice treated with benzene. First, we have characterized
      products formed during activation of benzene in Fenton's system in the absence or
      presence of NO-releasing compound in vitro by GC/MS. The result of above
      experiment prompted us to determine whether similar products can be formed in
      vivo. Groups of B6C3F1 male mice, eight weeks of age, were given a single
      intraperitoneal dose of [14C]benzene (400 mg/kg body wt, 9.7 mCi/mmol) or an
      equal dose of unlabeled benzene in corn oil, and the mice were killed 0.5 or 1 h
      posttreatment. The control group received only vehicle injections. Organic
      solvent extractable metabolites from bone marrow, liver, lungs, and blood of mice
      treated with [14C]benzene were identified by comparison of their respective
      retention times under two different HPLC conditions with authentic standard
      samples. These metabolites were further characterized by comparison of their
      GC/MS properties to those of reference standards. Nitro metabolites, namely,
      nitrobenzene, nitrobiphenyl, and nitrophenol isomers, were detected in the bone
      marrow of the mice 1 h after benzene treatment. Formation of nitro derivatives in
      other tissues was either not observed or was significantly less than that formed
      in bone marrow. This study clearly demonstrates that nitric oxide is a
      contributor to benzene metabolism and can form nitrated derivatives that may, in
      part, account for bone marrow toxicity.

PMID- 15025508
TI  - 2,6-diarylaminotetrahydropyrans from reactions of glutaraldehyde with anilines:
      models for biomolecule cross-linking.
AB  - Glutaraldehyde reacts with weakly nucleophilic anilines, e.g., 3-fluoro-4
      nitroaniline, which are models for amino groups in DNA, to give meso-2,6
      disubstituted tetrahydropyrans, e.g., meso-2,6-di-(3-fluoro-4
      nitroanilino)tetrahydropyran, that were characterized spectroscopically and by X
      ray crystal structure analysis. This contrasts with the outcome of reactions with
      more strongly nucleophilic amines, which give rise to N-substituted 1,4
      dihydropyridines. The mechanism of formation of the tetrahydropyrans is proposed
      to involve initial attack of the amine on one of the aldehyde groups of
      glutaraldehyde to give a carbinolamine intermediate. The ensuing cyclization to a
      tetrahydropyran, rather than dehydration to an imine leading to a
      dihydropyridine, is explained as a result of a competition between the lone pair
      of the amino function of the carbinolamine and the two lone pairs of the hydroxyl
      group. The formation of the tetrahydropyran is more likely with an amino function
      of low nucleophilicity, whereas dehydration to an imine leading to a
      dihydropyridine is favored with an amino function of higher nucleophilicity. The
      formation of tetrahydropyrans may be relevant to the toxicology of glutaraldehyde
      by providing a mechanistic basis for DNA adduction or DNA-protein cross-linking.

PMID- 15025509
TI  - Reactions of N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil) with
      2'-deoxycytidine, 2'-deoxy-5-methylcytidine, and thymidine.
AB  - N,N-Bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil, 1; 2.5 mM) was
      allowed to react with 2'-deoxycytidine, 2'-deoxy-5-methylcytidine, and thymidine
      (16.1 mM) at physiological pH (cacodylic acid, 50% base), and the reactions were
      followed by HPLC and HPLC-MS technique. Although the predominant reaction
      observed was chlorambucil hydrolysis, 1 reacted with various heteroatoms of the
      nucleosides. The principal site of alkylation with all pyrimidine nucleosides was
      N3, as judged by 1H NMR and HPLC-MS analyses. Also, several other adducts were
      detected, which could be tentatively characterized by means of HPLC-MS and MS/MS.
      As expected, thymidine was the least reactive pyrimidine nucleoside studied, and
      in addition of the N3 derivative, it reacted only at the carbohydrate moiety.
      Overall reactivity of cytosine nucleosides with 1 was considerably higher. The N3
      adducts of dCyd and 5-Me-dCyd partially deaminated under the reaction conditions
      employed, but the reaction was not catalyzed by the participation of the omega
      hydroxy function of the alkyl substituent but presumably by the nitrogen atom of
      the chlorambucil moiety. In the case of cytosine nucleosides, the O2 derivatives
      were the second most abundant species. 5-Me-dCyd reacted more readily at O2 than
      dCyd. These O2 adducts were labile under acidic, neutral, and basic conditions.
      No N4 derivatives or cross-links were detected, but dCyd reacted also at C5,
      although the yield of this derivative was very low. The role of chlorambucil
      pyrimidine 2'-deoxyribonucleoside adducts on the cytotoxicity and mutagenity of 1
      is also discussed.

PMID- 15025510
TI  - Contrasting effects of metal ions on S-nitrosoglutathione, related to
      coordination equilibria: GSNO decomposition assisted by Ni(II) vs stability
      Increase in the presence of Zn(II) and Cd(II).
AB  - Complex formation between nitrosoglutathione (GSNO) and Zn(II), Cd(II), and
      Ni(II) ions was studied by potentiometry and spectroscopic techniques. GSNO forms
      simple ML and ML2 type complexes (L = GSNO) with these ions. The stability of
      GSNO in HEPES buffer solution, pH 7.4, increased in the presence of both Zn(II)
      and Cd(II), due to an indirect mechanism. A concentration-dependent
      destabilization of GSNO by Ni(II) ions was found to be linearly dependent on the
      NiL complex concentration. NiL forms ternary complexes readily. The NiLA-
      stoichiometry was found for l-His, and NiHLB3- and NiLB4- complexes were detected
      for GSSG as the second ligand. The formation of these complexes was found to
      inhibit GSNO decay, by limiting the concentration of the NiL complex. The
      mechanism of Ni(II)-assisted GSNO decomposition contains several steps, with a
      hypothetical ternary complex with GSH as a likely active form. These results
      provide experimental evidence for the stabilization of GSNO in solution by metal
      ions, which may provide an additional level of control and/or impairment of
      cellular redox signaling. The Ni(II)-dependent destabilization of GSNO may
      constitute a novel epigenetic mechanism in nickel carcinogenesis.

PMID- 15025511
TI  - Endogenous reductants support the catalytic function of recombinant rat cyt19, an
      arsenic methyltransferase.
AB  - The postulated scheme for the metabolism of inorganic As involves alternating
      steps of oxidative methylation and of reduction of As from the pentavalent to the
      trivalent oxidation state, producing methylated compounds containing AsIII that
      are highly reactive and toxic. S-Adenosyl-L-methionine:AsIII methyltransferase
      purified from rat liver catalyzes production of methyl and dimethyl arsenicals
      from inorganic As. This protein is encoded by the cyt19 gene orthologous with
      cyt19 genes in mouse and human. The reductants dithiothreitol or tris(2
      carboxylethyl)phosphine support catalysis by recombinant rat cyt19 (rrcyt19).
      Coupled systems containing an endogenous reductant (thioredoxin/thioredoxin
      reductase/NADPH, glutaredoxin/glutathione/glutathione reductase/NADPH, or lipoic
      acid/thioredoxin reductase/NADPH) support inorganic As methylation by rrcyt19.
      Although glutathione alone does not support rrcyt19's catalytic function, its
      addition to reaction mixtures containing other reductants increases the rate of
      As methylation. Aurothioglucose, an inhibitor of thioredoxin reductase, reduces
      the rate of As methylation by rrcyt19 in thioredoxin-supported reactions.
      Addition of guinea pig liver cytosol, a poor source of endogenous As
      methyltransferase activity, to reaction mixtures containing rrcyt19 shows that
      endogenous reductants in cytosol support the enzyme's activity. Methylated
      compounds containing either AsIII or AsV are detected in reaction mixtures
      containing rrcyt19, suggesting that cycling of As between oxidation states is a
      component of the pathway producing methylated arsenicals. This enzyme may use
      endogenous reductants to reduce pentavalent arsenicals to trivalency as a
      prerequisite for utilization as substrates for methylation reactions. Thus, cyt19
      appears to possess both AsIII methyltransferase and AsV reductase activities.

PMID- 15025512
TI  - Pyridoxamine: an extremely potent scavenger of 1,4-dicarbonyls.
AB  - 1,4-Dicarbonyl compounds, which include 2,5-hexanedione and recently discovered
      endogenous 4-ketoaldehydes (levuglandins, isoketals, and neuroketals), exhibit
      severe toxicity. The key step in the toxicity of these compounds is their
      reaction with the lysyl residues of proteins to form pyrrole adducts. To screen
      for effective scavengers of these toxic compounds, we determined the reaction
      rates of pyrrole formation for a series of primary amines with a model 4
      ketoaldehyde, 4-oxopentanal (OPA). We found pyridoxamine (PM) to react extremely
      rapidly, with a second-order rate constant at physiological pH being
      approximately 2300 times faster than that of Nalpha-acetyllysine. The extreme
      reactivity of PM was unique to 1,4-dicarbonyls, as its reactions with
      methylglyoxal and 4-hydroxy-2(E)-nonenal were much slower and only slightly
      faster than with Nalpha-acetyllysine. The phenolic group of PM was found to be
      essential to its high reactivity, and the rate constant for pyrrole formation
      with OPA exhibited a maximum at pH 7.5, close to the second pKa of PM. We
      therefore propose a mechanism involving transfer of the phenolic proton to the
      carbonyl of the initially formed hemiacetal, which facilitates subsequent
      nucleophilic attack and ring closure. Only 1,4-dicarbonyls are likely to
      participate in the proposed mechanism, thereby conferring unique sensitivity of
      this class of compounds to scavenging by PM.

PMID- 15025513
TI  - Nitrosation of glycine ethyl ester and ethyl diazoacetate to give the alkylating
      agent and mutagen ethyl chloro(hydroximino)acetate.
AB  - Whereas nitrosation of secondary amines produces nitrosamines, amino acids with
      primary amino groups and glycine ethyl ester were reported to react with nitrite
      to give unidentified agents that alkylated 4-(p-nitrobenzyl)pyridine to produce
      purple dyes and be direct mutagens in the Ames test. We report here that
      treatment of glycine ethyl ester at 37 degrees C with excess nitrite acidified
      with HCl, followed by ether extraction, gave 30-40% yields of a product
      identified as ethyl chloro(hydroximino)acetate [ClC(=NOH)COOEt, ECHA] and a 9%
      yield of ethyl chloroacetate. The ECHA was identical to that synthesized by a
      known method from ethyl acetoacetate, strongly alkylated nitrobenzylpyridine, and
      may have arisen by N-nitrosation of glycine ethyl ester to give ethyl
      diazoacetate, which was C-nitrosated and reacted with chloride to give ECHA.
      Nitrosation of ethyl diazoacetate also yielded ECHA. Ethyl nitroacetate was not
      an intermediate as its nitrosation did not produce ECHA. ECHA reacted with
      aniline to give ethyl (hydroxamino)(phenylimino)acetate [PhN=C(NHOH)CO2Et]. This
      product was different from ethyl [(phenylamino)carbonyl]carbamate
      [PhNHC(=O)NHCO2Et], which was synthesized by reacting ethyl isocyanatoformate
      (OCN.CO2Et) with aniline. ECHA reacted with guanosine to give a derivative, which
      may have been a guanine-C(=NOH)CO2Et derivative. ECHA showed moderate toxicity
      and weak but significant mutagenicity without activation in Salmonella
      typhimurium TA-100 (mean, 1.31 x control value for 12-18 microg/plats) and for
      V79 mammalian cells (1.5-1.7 x control value for 60-100 microM). In conclusion,
      gastric nitrosation of glycine derivatives such as peptides with a N-terminal
      glycine might produce ECHA analogues that alkylate bases of gastric mucosal DNA
      and thereby initiate gastric cancer.

PMID- 15025514
TI  - The repair of the tobacco specific nitrosamine derived adduct O6-[4-Oxo-4-(3
      pyridyl)butyl]guanine by O6-alkylguanine-DNA alkyltransferase variants.
AB  - The tobacco specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
      (NNK), a potent pulmonary carcinogen, both methylates and pyridyloxobutylates
      DNA. Both reaction pathways generate promutagenic O6-alkylguanine adducts. These
      adducts, O6-methylguanine (O6-mG) and O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O6
      pobG), are repaired by O6-alkylguanine-DNA alkyltransferase (AGT). In this
      report, we demonstrate that pyridyloxobutyl DNA adducts are repaired by AGT in a
      reaction that results in pyridyloxobutyl transfer to the active site cysteine.
      Because minor changes within the binding pocket of AGT can alter the ability of
      this protein to repair bulky O6-alkylguanine adducts relative to O6-mG, we
      explored the ability of AGTs from different species as well as several human AGT
      variants and mutants to discriminate between O6-mG or O6-pobG adducts. We
      incubated proteins with equal molar amounts of oligodeoxynucleotides containing
      site specifically incorporated O6-mG or O6-pobG and measured repair. Bacterial
      AGTs poorly repaired O6-pobG. Mouse and rat AGT repaired both adducts at
      comparable rates. Wild-type human AGT, variant I143V/K178R, and mutant N157H
      repaired O6-mG approximately twice as fast as O6-pobG. Human variant G160R and
      mutants P140K, Y158H, G156A, and E166G did not repair O6-pobG until all of the O6
      mG was removed. To understand the role of adduct structure on relative repair
      rates, the competition experiments were repeated with two other bulky O6
      alkylguanine adducts, O6-butylguanine (O6-buG) and O6-benzylguanine (O6-bzG). The
      proteins displayed similar repair preference of O6-mG relative to O6-buG as
      observed with O6-pobG. In contrast, all of the mammalian proteins, except the
      mutant P140K, preferentially repaired O6-bzG. These studies indicate that the
      rate of repair of O6-pobG is highly dependent on protein structure. Inefficient
      repair of O6-pobG by bacterial AGT explains the high mutagenic activity of this
      adduct in bacterial systems. In addition, differences observed in the repair of
      this adduct by mammalian proteins may translate into differences in sensitivity
      to the mutagenic and carcinogenic effects of NNK or other pyridyloxobutylating
      nitrosamines.

PMID- 15025515
TI  - Sulfoxidation of cysteine and mercapturic acid conjugates of the sevoflurane
      degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether
      (compound A).
AB  - The volatile anesthetic sevoflurane is degraded in anesthesia machines to the
      haloalkene fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE), which
      can cause renal and hepatic toxicity in rats. FDVE is metabolized to S-[1,1
      difluoro-2-fluoromethoxy-2-(trifluoromethyl)ethyl]-L-cysteine (DFEC) and (E) and
      (Z)-S-[1-fluoro-2-fluoromethoxy-2-(trifluoromethyl)vinyl]-L-cysteine [(E,Z)
      FFVC], which are N-acetylated to N-Ac-DFEC and (E,Z)-N-Ac-FFVC S-conjugates. Some
      haloalkene S-conjugates undergo sulfoxidation. This investigation tested the
      hypothesis that FDVE S-conjugates can also undergo sulfoxidation, by evaluating
      sulfoxide formation by human and rat liver and kidney microsomes and expressed
      P450s and flavin monooxygenases. Rat, and at lower rates human, liver microsomes
      oxidized (Z)-N-Ac-FFVC and N-Ac-DFEC to the corresponding sulfoxides. Much lower
      rates of (Z)-N-Ac-FFVC, but not N-Ac-DFEC, sulfoxidation occurred with rat and
      human kidney microsomes. In human liver microsomes, the P450 inhibitor 1
      aminobenzotriazole completely inhibited S-oxidation, while heating to inactivate
      FMO decreased (Z)-N-Ac-FFVC and N-Ac-DFEC sulfoxidation only 0 and 30%,
      respectively. Of the various cytochrome P450s examined, P450s 3A4 and 3A5 had the
      highest S-oxidase activity toward (Z)-N-Ac-FFVC; P450 3A4 was the predominant
      enzyme forming N-Ac-DFEC-SO. The P450 3A inhibitors troleandomycin and
      ketoconazole inhibited >95% of (Z)-N-Ac-FFVC sulfoxidation by P450 3A4 and 3A5
      and 40-100% of (Z)-N-Ac-FFVC sulfoxidation by human liver microsomes and 15-85%
      of N-Ac-DFEC sulfoxidation by human liver microsomes. Sulfoxidation of DFEC was
      also examined in human liver microsomes. Substantial amounts of sulfoxide were
      observed, even in the absence of NADPH or protein, while enzymatic formation was
      comparatively minimal. These results show that FDVE S-conjugates undergo P450
      catalyzed and nonenzymatic sulfoxidation and that enzymatic sulfoxidation of (Z)
      N-Ac-FFVC and N-Ac-DFEC is catalyzed predominantly by P450 3A. The extent of FDVE
      sulfoxidation in vivo and the toxicologic significance of FDVE sulfoxides remain
      unknown and merit further investigation.

PMID- 15025516
TI  - Influence of uranium speciation on normal rat kidney (NRK-52E) proximal cell
      cytotoxicity.
AB  - Uranium is a naturally occurring heavy metal. Its extensive use in the nuclear
      cycle and for military applications has focused attention on its potential health
      effects. Acute exposures to uranium are toxic to the kidneys where they mainly
      cause damage to proximal tubular epithelium. The purpose of this study was to
      investigate the biological consequences of acute in vitro uranyl exposure and the
      influence of uranyl speciation on its cytotoxicity. NRK-52E cells, representative
      of rat kidney proximal epithelium, were exposed to uranyl-carbonate and -citrate
      complexes, which are the major complexes transiting through renal tubules after
      acute in vivo contamination. Before NRK-52E cell exposure, these complexes were
      diluted in classical or modified cell culture media, which can possibly modify
      uranyl speciation. In these conditions, uranium cytotoxicity appears after 16 h
      of exposure. The CI50 cytotoxicity index, the uranium concentration leading to
      50% dead cells after 24 h of exposure, is 500 microM (+/-100 microM) and strongly
      depends on uranyl counterion and cell culture medium composition. Computer
      modeling of uranyl speciation is reported, enabling one to draw a parallel
      between uranyl speciation and its cytotoxicity.

PMID- 15025517
TI  - A novel method for the N-terminal modification of native proteins.
AB  - The formation of structurally defined bioconjugates of proteins hinges on their
      regioselective modification. Toward this goal a novel method is described here
      using the commercial IgA protease to attach a nonnatural peptidic moiety to the N
      terminus of predisposed proteins by means of a kinetically controlled reverse
      proteolysis in water. The process requires an H-Ala-Pro N-terminal sequence and
      then furnishes a selectively modified conjugate under nondenaturing and
      nondestructive conditions in acceptable yield. The method lends itself to the N
      terminal introduction of orthogonal moieties that may be elaborated further.

PMID- 15025518
TI  - 90Y and 111In complexes of a DOTA-conjugated integrin alpha v beta 3 receptor
      antagonist: different but biologically equivalent.
AB  - 90Y-TA138 is a (90)Y-labeled nonpeptide integrin alpha(v)beta(3) receptor
      antagonist that binds with high affinity and specificity to integrin
      alpha(v)beta(3) receptors overexpressed on both endothelial and tumor cells.
      (90)Y-TA138 has demonstrated significant therapeutic effects in several
      preclinical tumor-bearing animal models. Since (90)Y is a pure beta-emitter,
      (111)In-TA138 has been chosen as the imaging surrogate for dosimetry
      determination of (90)Y-TA138. This report describes the synthesis of (111)In
      TA138 and biological evaluations of both (111)In-TA138 and (90)Y-TA138 in the c
      neu Oncomouse model. The HPLC data shows that (111)In-TA138 is more hydrophilic
      with the retention time approximately 4.5 min shorter than that of (90)Y-TA138
      under identical chromatographic conditions. Since the only difference between
      (111)In-TA138 and (90)Y-TA138 is the metal ion, the HPLC retention time
      difference strongly suggests that indium and yttrium chelates do not share the
      same coordination sphere in solution even though they are coordinated by the same
      DOTA conjugate. Despite their differences in lipophilicity and solution
      structure, biodistribution data in the c-neu Oncomouse model clearly showed that
      (111)In-TA138 and (90)Y-TA138 are biologically equivalent with respect to their
      uptake in tumors and other major organs. Therefore, (111)In-TA138 is useful as an
      imaging surrogate for (90)Y-TA138 and should be able to predict the radiation
      dosimetry of (90)Y-TA138, a therapeutic radiopharmaceutical for treatment of
      rapidly growing tumors.

PMID- 15025519
TI  - A dual fluorochrome probe for imaging proteases.
AB  - Near-infrared fluorescence (NIRF) optical probes have been able to provide a
      noninvasive assessment of enzyme activity for a number of different enzymes and
      types of pathology. Here we describe a dual fluorochrome enzyme-activatable probe
      featuring one NIRF fluorochrome that is activated by protease activity and a
      second fluorochrome that is protease resistant and serves as an internal
      standard. The probe was prepared by attaching Cy7 directly to an amino-CLIO, an
      amine functional cross-linked iron oxide (CLIO) nanoparticle carrier, in a
      protease resistant manner. Cy5.5 was attached to a protease sensitive
      polyarginine peptide spacer, also attached to amino-CLIO. In vitro and in vivo
      the ratio of the Cy5.5 to Cy7 fluorescence was increased by protease, reflecting
      the increase in Cy5.5 fluorescence by protease in the vicinity of the probe. In
      vitro and in vivo the absolute values of the Cy5.5 and Cy7 fluorescence reflected
      lesion size and the distance of lesions from the surface, while the ratio of
      Cy5.5 to Cy7 fluorescence obtained was constant and independent of lesion size
      and depth. The dual fluorochrome probe, and related dual wavelength imaging
      method, represents a novel approach for imaging protease activity in vivo.

PMID- 15025521
TI  - NMR structure determination of a modified DNA oligonucleotide containing a new
      intercalating nucleic acid.
AB  - The intercalating nucleic acid (INA) presented in this paper is a novel 1-O-(1
      pyrenylmethyl)glycerol DNA intercalator that induces high thermal affinity for
      complementary DNA. The duplex examined contained two INA intercalators, denoted
      X, inserted directly opposite each other:
      d(C(1)T(2)C(3)A(4)A(5)C(6)X(7)C(8)A(9)A(10)G(11)C(12)T(13)):d(A(14)G(15)C(16)T(17
      -T(18)G(19)X(20)G(21)T(22)T(23)G(24)A(25)G(26)). Unlike most other nucleotide
      analogues, DNA with INA inserted has a lower affinity for hybridizing to
      complementary DNA with an INA inserted directly opposite than to complementary
      unmodified DNA. In this study we used two-dimensional (1)H NMR spectroscopy to
      determine a high-resolution solution structure of the weak INA-INA duplex. A
      modified ISPA approach was used to obtain interproton distance bounds from NOESY
      cross-peak intensities. These distance bounds were used as restraints in
      molecular dynamics (rMD) calculations. Twenty final structures were generated for
      the duplex from a B-type DNA starting structure. The root-mean-square deviation
      (RMSD) of the coordinates for the 20 structures of the complex was 1.95 A. This
      rather large value, together with broad lines in the area of insertion, reflect
      the high degree of internal motion in the complex. The determination of the
      structure revealed that both intercalators were situated in the center of the
      helix, stacking with each other and the neighboring nucleobases. The
      intercalation of the INAs caused an unwinding of the helix in the insertion area,
      creating a ladderlike structure. The structural changes observed upon
      intercalation were mainly of local character; however, a broadening of the minor
      groove was found throughout the helix.

PMID- 15025520
TI  - Long-term expression with a cationic polymer derived from a natural
      polysaccharide: schizophyllan.
AB  - Among the various synthetic gene carriers based on biomaterials, cationic
      polymers with polysaccharide backbones have long been studied as nonviral vectors
      due to their low immunogenicity and high water solubility. Schizophyllan, a beta
      (1,3)-glucan, is one of the various polysaccharides that are clinically
      administered. Furthermore, its safety in the human body has already been
      confirmed. Various functional groups can be selectively introduced into the side
      chain, not into the main chain of schizophyllan. Therefore, we have synthesized
      various oligoamine conjugates from schizophyllan. It was confirmed that their in
      vitro transfection efficiencies are superior to that of polyethylenimine by
      adjusting the molecular weight and the degree of amination of cationic
      schizophyllan. While it was possible to reduce cytotoxicity by adjusting the
      amount of DNA complex per cell, as seen with poly-L-lysine, polyethylenimine, and
      chitosan, PEGylation was the most effective means of reducing toxicity.
      Furthermore, using cationic schizophyllan carriers, it was also possible to
      express a reporter protein for a long period of time due to a long residence time
      of plasmid DNA in cells.

PMID- 15025522
TI  - Antigenic prenylated peptide conjugates and polyclonal antibodies to detect
      protein prenylation.
AB  - Posttranslational modification of proteins with farnesyl and geranylgeranyl
      groups is a required modification for signaling proteins that includes the small
      GTPases in the Ras, Rho, and Rab families, heterotrimeric G proteins, and nuclear
      lamin proteins. To develop antibodies capable of detecting and distinguishing
      prenylated proteins, we synthesized two antigens, succinylglycine
      (geranylgeranyl)cysteine methyl ester (SuccG-(gg)CMe, 1) and succinylglycine
      (farnesyl)cysteine methyl ester (SuccG-(f)CMe, 2). These prenylated peptides were
      covalently coupled to bovine serum albumin (BSA) and to keyhole limpet hemocyanin
      (KLH) to produce polyvalent, immunogenic bioconjugates. Immunization of rabbits
      with these immunogens generated polyclonal antisera that contained significant
      titers of anti-geranylgeranyl and anti-farnesyl antibodies. The selectivity of
      the polyclonal antisera was examined using ELISA and dot blotting methods. The
      anti-farnesyl and anti-geranylgeranyl antisera crossreacted with both antigens.
      Attempts to purify the polyclonal antisera by either positive or negative
      immunoaffinity selection protocols failed to produce selective anti
      geranylgeranyl and anti-farnesyl antibodies. Moreover, both crude antisera and
      purified antibodies also crossreacted with myristoylated and palmitoylated BSA
      conjugates. Immunofluorescence staining of EYFP-CVLL or EYFP-CVIM transfected CHO
      K1 cells with rabbit polyclonal antisera showed colocalized membrane
      fluorescence. Thus, an important caveat for the use of antibodies raised against
      aliphatic antigens is that extensive controls must be performed to determine
      selectivity.

PMID- 15025523
TI  - Dimers of D-myo-inositol 1,4,5-trisphosphate: design, synthesis, and interaction
      with Ins(1,4,5)P3 receptors.
AB  - The design and synthesis of dimeric versions of the intracellular signaling
      molecule d-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] are reported.
      Ins(1,4,5)P(3) dimers in a range of sizes were constructed by conjugation of a
      partially protected 2-O-(2-aminoethyl)-Ins(1,4,5)P(3) intermediate with activated
      oligo- and poly(ethylene glycol) (PEG) tethers, to give benzyl-protected dimers
      with amide or carbamate linkages. After deprotection, the resulting water-soluble
      Ins(1,4,5)P(3) dimers were purified by ion-exchange chromatography. The
      interaction of the Ins(1,4,5)P(3) dimers with tetrameric Ins(1,4,5)P(3) receptors
      was explored, using equilibrium [(3)H]Ins(1,4,5)P(3)-binding to membranes from
      cerebellum, and (45)Ca(2+)-release from permeabilized hepatocytes. The results
      showed that dimers, even when they incorporate large PEG tethers, interact
      potently with Ins(1,4,5)P(3) receptors, and that the shorter dimers are more
      potent than Ins(1,4,5)P(3) itself. A very small dimer, consisting of two
      Ins(1,4,5)P(3) motifs joined by a short N,N'-diethylurea spacer, was synthesized.
      Preliminary studies of (45)Ca(2+) release from the intracellular stores of
      permeabilized hepatocytes showed this shortest dimer to be almost as potent as
      adenophostin A, the most potent Ins(1,4,5)P(3) receptor ligand known. Possible
      interpretations of this result are considered in relation to the recently
      disclosed X-ray crystal structure of the type 1 Ins(1,4,5)P(3) receptor core
      binding domain.

PMID- 15025524
TI  - Cellular uptake of antisense morpholino oligomers conjugated to arginine-rich
      peptides.
AB  - Although the sequence specificity, biostability, and low toxicity of PMO
      (phosphorodiamidate morpholino oligomers) make them good antisense agents to
      study gene function, their limited ability to cross cell membranes limits their
      use in cell culture. In this paper we show that conjugation to arginine-rich
      peptides significantly enhanced the cellular uptake of PMO. The factors that
      affect the conjugate's cellular uptake and its antisense activity toward a
      targeted mRNA were investigated. Factors studied include the number of arginines
      in the peptide, the choice of cross-linker, the peptide conjugation position, the
      length of the PMO, and the cell culture conditions. Delivery of PMO to the cell
      nucleus and cytosol required conjugation rather than complexation of peptides to
      PMO. R(9)F(2)C was best suited to deliver a PMO to its target RNA resulting in
      the strongest antisense effect. By simply adding the R(9)F(2)C-PMO conjugate into
      the cell culture medium at low microM concentration, missplicing of pre-mRNA was
      corrected. This particular peptide-conjugated PMO was more effective than the PMO
      conjugated to the transmembrane transport peptides of HIV-1 Tat protein,
      Drosophila antennapedia protein, or to peptides with fewer arginines. Length of
      PMO did not affect a peptide's delivery efficacy, but all other factors were
      important. R(9)F(2)C peptide provided a simple and efficient delivery of PMO to a
      RNA target. Conjugation of peptide to PMO enhances the opportunities to evaluate
      gene functions in cell cultures.

PMID- 15025525
TI  - Molecular binding behavior of pyridine-2,6-dicarboxamide-bridged bis(beta
      cyclodextrin) with oligopeptides: switchable molecular binding mode.
AB  - Bridged bis(beta-cyclodextrin) 1 with a pyridine-2,6-dicarboxamide linker was
      synthesized, and its inclusion complexation behavior with some aliphatic
      oligopeptides was investigated in aqueous buffer solution of pH 2.0 and 7.2 at 25
      degrees C by means of circular dichroism, fluorescence, and 2D NMR techniques.
      The results show that the resulting inclusion complexes of 1 with oligopeptides
      adopt a cooperative "cyclodextrin-guest-cyclodextrin" sandwich binding mode in a
      neutral media, but a "guest-linker-cyclodextrin" coinclusion binding mode in an
      acidic media. These switchable binding modes consequently rationalize the binding
      ability of bis(beta-cyclodextrin) 1 at different pH values; that is, 1 shows the
      stronger association with oligopeptides in a neutral media. Because of the
      simultaneous contributions of hydrophobic, hydrogen bond, and electrostatic
      interactions, bis(beta-cyclodextrin) 1 affords length-selectivity up to 4.7 for
      the Gly-Gly/Gly-Gly-Gly pair at pH 2.0 and sequence-selectivity up to 4.2 for the
      Gly-Leu/Leu-Gly pair at pH 7.2. These phenomena are discussed from the viewpoint
      of the size-fit concept and the multipoint recognitions between host and guest.

PMID- 15025526
TI  - Peptide-protein microarrays for the simultaneous detection of pathogen
      infections.
AB  - We describe novel peptide-protein microarrays, which were fabricated using
      semicarbazide glass slides that permitted the immobilization of glyoxylyl
      peptides by site-specific ligation and the immobilization of proteins by
      physisorption. The arrays permitted the simultaneous serodetection of antibodies
      directed against hepatitis C virus (HCV core p21 15-45 peptide, NS4 1925-1947
      peptide, core, NS3, NS4, and mixture of core, NS3, NS4, and NS5 antigens),
      hepatitis B virus (HBc, HBe, and HBs), human immunodeficiency virus (Gp41 and
      Gp120 for HIV-I and Gp36 for HIV-II), Epstein-Barr virus (VCAp18 153-176
      peptide), and syphilis (rTpN47 and rTpN17) antigens using an immunofluorescence
      assay. Peptide-protein microarrays displayed high signal-to-noise ratios,
      sensitivities, and specificities for the detection of antibodies as revealed by
      the analysis of a collection of human sera referenced against these five
      pathogens.

PMID- 15025527
TI  - Polypeptide semicarbazide glass slide microarrays: characterization and
      comparison with amine slides in serodetection studies.
AB  - We have described in the accompanying article the preparation of peptide-protein
      semicarbazide microarrays and their use for the simultaneous serodetection of
      antibodies directed against different pathogens. Here, we present a comparative
      study between semicarbazide and amine glass slides in an immunofluorescent
      serodetection assay using HIV (Gp120, Gp41), HCV (mix-HCV, core, NS3, and NS4),
      and HBV (HBs) recombinant antigens. Amine and semicarbazide surfaces displayed
      the same sensitivity for antibodies detection just after printing. However, the
      reactivity of protein antigens changed rapidly upon aging on amine slides but not
      on semicarbazide slides. Peptide or protein semicarbazide microarrays were found
      to be remarkably stable for months. Additional data concerning the
      characterization of the semicarbazide surface (homogeneity of the slides,
      chemical stability, contact angle measurements, atomic force microscopy studies,
      reproducibility of serodetection results) are also presented and discussed.

PMID- 15025528
TI  - Gene transfer into human hepatoma cells by receptor-associated protein/polylysine
      conjugates.
AB  - Receptor-associated protein (RAP) is a ligand for all members of low-density
      lipoprotein (LDL) receptor families. RAP is internalized into cells via receptor
      mediated endocytic trafficking, making it an attractive mechanism for efficient
      gene delivery. In this study, we have developed a gene delivery system using RAP
      as a targeting ligand. A RAP cDNA lacking a C-terminal heparin-binding domain was
      amplified by polymerase chain reaction (PCR) from a human liver cDNA library and
      was reamplified by using a primer containing a cysteine codon at its carboxyl end
      to facilitate its conjugation to polylysine (polyK). RAP was purified using a
      bacterial expression system and coupled to poly-D-lysine (PDL) or poly-L-lysine
      (PLL) of average MW 50 kDa via the heterobifunctional cross-linker SPDP. Using
      fluorescence-labeled RAP ligand, cellular uptake of the transfection complexes
      into HepG2 cells was shown to be highly efficient and more specific to PDL
      conjugated RAP compared with PLL-conjugated one. Plasmid DNA containing a
      luciferase reporter gene was condensed with either RAP-PDL or RAP-PLL. In vitro
      transfection into HepG2 cells with RAP-PDL conjugate resulted in significantly
      higher luciferase expression levels in comparison to either nonconjugated PDL, or
      RAP-PLL, or LipofecAMINE/DNA complexes in the presence of 10% fetal bovine serum.
      Luciferase expression was inhibited by the addition of excess RAP. Treatment of
      the cells with Lovastatin, which inhibits HMG-Co reductase and increases
      expression of LDL receptor, stimulates luciferase expression, suggesting that the
      gene delivery is specifically mediated by LDL receptor. Thus, RAP-PDL conjugates
      have the potential to be used as a new nonviral gene delivery vector.

PMID- 15025530
TI  - Preparation of bionanoreactor based on core-shell structured polyion complex
      micelles entrapping trypsin in the core cross-linked with glutaraldehyde.
AB  - Recently, the polyion complex (PIC) micelle has been suggested as a promising
      carrier system for peptide and proteins. However, its utilities are limited by
      its sensitivity to the environment such as dilution and ionic strength of the
      solution. In this study, to overcome these obstructions, PIC micelles prepared
      from an anionic block copolymer, poly(ethylene glycol)-poly(alpha,beta-aspartic
      acid), and a cationic protein, trypsin, were cross-linked with glutaraldehyde
      through the Schiff base formation. On the basis of a light scattering technique,
      the results revealed an efficient resistance of the cross-linked PIC micelle to a
      high salt concentration, which was a key parameter controlling the structure of
      the PIC micelles. Moreover, the stability of trypsin after cross-linking was
      remarkably improved. Evidently, as a bionanoreactor and/or bionanoreservoir, the
      PIC micelles entrapping protein molecules in the cross-linked core reveal an
      improved stability, allowing their wide application in the fields of
      biotechnology and pharmaceutical sciences.

PMID- 15025529
TI  - Immobilization of a novel antibacterial agent on solid phase and subsequent
      isolation of EF-Tu.
AB  - Screening of our compound collection identified PNU-92560, a 2
      [1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxamide, as a novel antibacterial
      agent. Extensive analogue development identified that the 2-position of the
      thiadiazole could be functionalized with a linker that would allow the compound
      to be attached to a solid support. The extreme insolubility of the analogues
      prevented the mechanism of action for these compounds to be determined utilizing
      traditional methodology. The solid-supported compounds were utilized as affinity
      columns to identify elongation factor Tu (EF-Tu) as a putative target for this
      class of compounds. The activity of the compounds in a metabolic labeling
      experiments and in translation assay supports the identity of the target for
      these compounds to be EF-Tu.

PMID- 15025531
TI  - Synthesis of novel, multivalent glycodendrimers as ligands for HIV-1 gp120.
AB  - Multivalent neoglycoconjugates are valuable tools for studying carbohydrate
      protein interactions. To study the interaction of HIV-1 gp120 with its reported
      alternate glycolipid receptors, galactosyl ceramide (GalCer) and sulfatide,
      galactose- and sulfated galactose-derivatized dendrimers were synthesized,
      analyzed as ligands for rgp120 by surface plasmon resonance, and tested for their
      ability to inhibit HIV-1 infection of CXCR4- and CCR5-expressing indicator cells.
      Four different series of glycodendrimers were made by amine coupling spacer-arm
      derivatized galactose residues, either sulfated or nonsulfated, to
      poly(propylenimine) dendrimers, generations 1-5. One series of glycodendrimers
      was prepared from the ceramide saccharide derivative of purified natural GalCer,
      and another was from chemically synthesized 3-(beta-D
      galactopyranosylthio)propionic acid. Synthesis of 3-sulfogalactopyranosyl
      derivatized dendrimers was accomplished using the novel compound, 3-(beta-D-3
      sulfogalactopyranosylthio)propionic acid. The fourth series was made by random
      sulfation of the 3-(beta-D-galactopyranosylthio)propionic acid functionalized
      dendrimers. Structures of the carbohydrate moieties were confirmed by NMR, and
      the average molecular weights and polydispersities of the different
      glycodendrimers were determined using MALDI-TOF MS. Surface plasmon resonance
      studies found that rgp120 IIIB bound to the derivatized dendrimers tested with
      nanomolar affinity, and to dextran sulfate with picomolar affinity. In vitro
      studies of the effectiveness of these compounds at inhibiting infection of U373
      MAGI-CCR5 cells by HIV-1 Ba-L indicated that the sulfated glycodendrimers were
      better inhibitors than the nonsulfated glycodendrimers, but not as effective as
      dextran sulfate.

PMID- 15025532
TI  - A novel, high-affinity, fluorescent progesterone receptor antagonist. Synthesis
      and in vitro studies.
AB  - The present paper describes the chemical synthesis and in vitro characterization
      of a novel, high-affinity, fluorescent progesterone receptor (PR) antagonist. The
      three-step synthesis was carried out starting from mifepristone. After
      demethylation with calcium oxide, the methylamino group was alkylated with 6
      bromohexanol, and the resulting compound was reacted with fluorescein 5
      isothiocyanate, yielding the fluorescein-mifepristone conjugate. Interaction of
      the conjugate as well as of its precursors with PR was determined in cell culture
      (alkaline phosphatase assay and transactivation assay). Antiprogestagenic
      activity of the intermediates were comparable to that of the parent compound.
      Even after attachment of the bulky fluorescein moiety, considerable
      antiprogestagenic activity was maintained. Microscopic studies revealed that
      fluorescence of the conjugate was almost confined to the nuclei of steroid
      hormone receptor-positive cells, whereas the nuclei of steroid hormone receptor
      negative cells remained unstained. To our knowledge, this is the first report on
      a fluorescent ligand for PR suitable for studies in living cells. It is proposed
      that the present fluorescent PR antagonist might serve as a lead compound for the
      development of contrast agents for PR imaging, e.g., by near-infrared optical
      imaging.

PMID- 15025533
TI  - Optimized conjugation of a fluorescent label to proteins via intein-mediated
      activation and ligation.
AB  - Intein-mediated ligation provides a site-specific method for the attachment of
      molecular probes to proteins. The method is inherently flexible with regard to
      either the protein sequence or the attached probe, but practical difficulties
      have limited the widespread use of this valuable labeling system for the
      attachment of small- to medium-sized molecules. We report herein studies to
      improve the efficiency and practical application of these reactions, including
      the assembly of plasmids for the expression of target-intein fusion proteins and
      the analysis of their reaction with a fluorescent cysteine derivative under a
      range of conditions. Optimal ligation of the fluorophore to the target protein is
      critically dependent on the degree of oxidation of the fluorescent cysteine
      derivative. Efficient ligation has been achieved with freshly prepared
      fluorescent cysteine derivative under rigorously anaerobic conditions. Similar
      ligation yields have also been achieved using more practically convenient
      conditions including anaerobic reaction with addition of thiophenol, or aerobic
      reaction with the further addition of tricarboxyethylphosphine.

PMID- 15025534
TI  - Production of [F-18]fluoroannexin for imaging apoptosis with PET.
AB  - Recombinant human-annexin-V was conjugated with 4-[F-18]fluorobenzoic acid (FBA)
      via its reaction with the N-hydroxysuccinimidyl ester (FBA-OSu) at pH 8.5. A
      series of reactions using varying amounts of annexin-V, unlabeled FBA-OSu, and
      time produced products with different conjugation levels. Products were
      characterized by mass spectrometry and a cell-binding assay to assess the effect
      of conjugation. In each case, the conjugated protein was a mixture of proteins
      with a range of conjugation. Annexin-V could be conjugated with an average of two
      FBA mole equivalents without decreasing its affinity for red blood cells (K(d) 6
      10 nM) with exposed phosphatidylserine. An average conjugation of 7.7 (range 3
      13) diminished the binding 3-fold. Large-scale production and purification of [F
      18]FBA-OSu from [F-18]fluoride was accomplished within 90 min and in 77%
      radiochemical yield (decay-corrected to the end of cyclotron bombardment). The
      conjugation reaction of annexin with [F-18]FBA-OSu was studied with respect to
      activity level, protein mass, and concentration. Under the most favorable
      conditions, >25 mCi [F-18]fluoroannexin (FAN) was isolated in 64% yield (decay
      corrected for a 22 min conjugation process) from labeling 1.1 mg of annexin-V. A
      pilot PET imaging study of [F-18]fluoroannexin in normal rats showed high uptake
      in the renal excretory system and demonstrated sufficient clearance from most
      other internal organs within 1 h. [F-18]Fluoroannexin should prove useful in
      imaging targeted apoptosis.

PMID- 15025535
TI  - Design and synthesis of visible isotope-coded affinity tags for the absolute
      quantification of specific proteins in complex mixtures.
AB  - Identification of proteins in complex mixtures by mass spectrometry is most
      useful when quantitative data is also obtained. We recently introduced isotope
      coded affinity tags (ICAT reagents) for the relative quantification of proteins
      present in two or more biological samples. In this report, we describe a new
      generation of ICAT reagents that contain the following additional features: (1) a
      visible tag that allows the electrophoretic position of tagged peptides during
      separation to be easily monitored; (2) a photocleavable linker that allows most
      of the tag to be removed prior to mass spectrometric analysis; (3) an isotope tag
      that contains carbon-13 and nitrogen-15 atoms instead of deuterium to ensure
      precise comigration of light and heavy tagged peptides by reverse-phase HPLC.
      These reagents contain an iodoacetyl group that selectively reacts with peptide
      cysteine residues. Peptide modification chemistry is also reported that allows
      tagging of peptides that are devoid of cysteine. The synthesis of these visible
      isotope-coded affinity tags (VICAT reagents), and their reaction with peptides
      are described in this report. VICAT reagents containing a carbon-14 visible probe
      or an NBD fluorophore are described. These reagents are most useful for the
      determination of the absolute quantity of specific target proteins in complex
      protein mixtures such as serum or cell lysates.

PMID- 15025537
TI  - Synthesis of ultrasmall superparamagnetic iron oxides using reduced
      polysaccharides.
AB  - Investigation into the effect of the reducing sugar of dextran on formation and
      stability of dextran-coated ultrasmall superparamagnetic iron oxides (USPIO) has
      demonstrated that reduction of the terminal reducing sugar can have a significant
      effect on particle size, coating stability, and magnetic properties. Four aspects
      of polysaccharide-coated USPIO particle synthesis were investigated: (i) the
      effect reduction of the terminal polysaccharide sugar has upon polysaccharide
      usage, particle size, stability, and magnetic susceptibility; (ii) the effect an
      exogenous reducing sugar can have upon particle synthesis; (iii) the effect the
      molecular weight of the reduced polysaccharide has on particle synthesis; and
      (iv) the effectiveness of reduced and native dextrans in stabilizing a preformed
      magnetic sol. For low molecular weight dextrans (MW <or=10 kDa), reduction
      resulted in a 10 fold or greater decrease in the carbohydrate-to-iron ratio
      necessary during particle formation to produce the desired particle size (<20
      nm). Particles prepared at the equivalent dextran-to-iron ratio using the
      equivalent native dextrans yielded larger particles except for a 70 kDa dextran
      where reduced and native dextran yielded identical particles with respect to size
      and magnetic properties. The stability of particle size and coating was studied
      using 10 kDa native and reduced dextran. Particles prepared with reduced dextran
      yielded a more stable coating as evidenced by stability on autoclaving. For
      native dextrans (MW < 70 kDa), small (<or=30 nm) particles could be obtained at
      much higher dextran-to-iron ratios, but only the 10 kDa dextran gave a particle
      with comparable magnetic properties (susceptibility > 20,000 x 10(-6) cgs).
      Similar results were obtained with a 12 kDa pullulan. The effect of
      polysaccharide molecular weight on particle size was studied, wherein higher
      molecular weight reduced dextrans produced larger particles. The effectiveness of
      the reduced and native dextrans in stabilizing a preformed magnetic sol was
      compared. Reduced dextrans were found to be superior for stabilizing the magnetic
      sol. The observed effects of reduction of the terminal sugar in dextran compared
      with the native dextran were modeled using the Langmuir adsorption isotherm. A
      good fit of experimental data with this model was found.

PMID- 15025536
TI  - A Tc-99m-labeled long chain fatty acid derivative for myocardial imaging.
AB  - C-11- and I-123-labeled long chain fatty acid derivatives have been reported as
      useful radiopharmaceuticals for the estimation of myocardial fatty acid
      metabolism. We have reported that Tc-99m-labeled N-[[[(2
      mercaptoethyl)amino]carbonyl]methyl]-N-(2-mercaptoethyl)-6-aminohexanoic acid
      ([(99m)Tc]MAMA-HA), a medium chain fatty acid derivative, is metabolized by beta
      oxidation in the liver and that the MAMA ligand is useful for attaching to the
      omega-position of fatty acid derivatives as a chelating group for Tc-99m. On the
      basis of these findings, we focused on developing a Tc-99m-labeled long chain
      fatty acid derivative that reflected fatty acid metabolism in the myocardium. In
      this study, we synthesized a dodecanoic acid derivative, MAMA-DA, and a
      hexadecanoic acid derivative, MAMA-HDA, and performed radiolabeling and
      biodistribution studies. [(99m)Tc]MAMA-DA and [(99m)Tc]MAMA-HDA were prepared
      using a ligand-exchange reaction. Biodistribution studies were carried out in
      normal mice and rats. Then, a high initial uptake of Tc-99m was observed,
      followed by a rapid clearance from the heart. The maximum heart/blood ratio was
      3.6 at 2 min postinjection of [(99m)Tc]MAMA-HDA. These kinetics were similar to
      those with postinjection of p-[(125)I]iodophenylpentadecanoic acid. Metabolite
      analysis showed [(99m)Tc]MAMA-HDA was metabolized by beta-oxidation in the body.
      In conclusion, [(99m)Tc]MAMA-HDA is a promising compound as a long chain fatty
      acid analogue for estimating beta-oxidation of fatty acid in the heart.

PMID- 15025538
TI  - O6-3-[131I]iodobenzylguanine: improved synthesis and further evaluation of a
      potential agent for imaging of alkylguanine-DNA alkyltransferase.
AB  - O(6)-Benzylguanine derivatives with suitable radionuclides attached to the benzyl
      ring are potentially useful in the noninvasive imaging of the DNA repair protein,
      alkylguanine-DNA alkyltransferase (AGT). Previously, O(6)-3
      [(131)I]iodobenzylguanine ([(131)I]IBG) was prepared using a two-step approach;
      we now report its synthesis in a single step by the radioiododestannylation of
      O(6)-3-(trimethylstannyl)benzylguanine in 85-95% radiochemical yield. The in
      vitro specific uptake of [(131)I]IBG in DAOY human medulloblastoma cells, in TE
      671 human rhabdomyosarcoma cells and a CHO cell line transfected to express AGT
      was linear (r(2) = 0.9-1.0) as a function of cell density. After intravenous
      injection of [(131)I]IBG in athymic mice bearing TE-671 xenografts, tumor uptake
      was 1.38 +/- 0.34% ID/g at 0.5 h and declined at 2 and 4 h. Preadministration of
      O(6)-(3-iodobenzyl)guanine (IBG) at 0.5 h increased uptake not only in tumor but
      also in several normal tissues. Notable exceptions were thyroid (p < 0.05), lung
      (p <0.05) and stomach. After intratumoral injection of [(131)I]IBG in the same
      xenograft model, the uptake in tumors that were depleted of AGT by BG treatment
      (165.8 +/- 27.5% ID/g) was about 60% of that in control mice (272.4 +/- 48.2%
      ID/g; p < 0.05).

PMID- 15025539
TI  - Silicon nanoparticles as a luminescent label to DNA.
AB  - We successfully conjugated 1-2 nm diameter silicon nanoparticles to a 5'-amino
      modified oligonucleotide (60mer) that contains a C6 linker between amide and
      phosphate groups. The conjugation was implemented via two photoinduced reactions
      followed by a DNA labeling step through formation of a carboxamide bond.
      Photoluminescence of the conjugates is dominated by two blue bands (400 and 450
      nm maximal) under 340 nm excitation. The quantum yield of oligonucleotide
      conjugated nanoparticles was determined to be 0.08 as measured against quinine
      sulfate in 0.1 M HClO(4) as a reference standard. We report a conjugation process
      that allows labeling of Si nanoparticles to an oligonucleotide in aqueous
      solutions. Ways to further optimize the procedure in order to achieve narrower
      and brighter photoluminescence are discussed.

PMID- 15025540
TI  - AMD3100 conjugates as components of targeted nonviral gene delivery systems:
      synthesis and in vitro transfection efficiency of CXCR4-expressing cells.
AB  - We describe the synthesis of a series of AMD3100-lipid and AMD3100-polycationic
      conjugates which were used as components of targeted lipoplexes (in conjunction
      with (poly)cationic lipids) and polyplexes, respectively, for mediating specific
      gene transfer into cells expressing CXCR4 which displays a high affinity for
      AMD3100. Transfection studies were investigated with suspension CXCR4(+) human
      lymphoma Jurkat cells and with adherent CXCR4(-) human glioblastoma T98G and
      human lung carcinoma A549 cells lines in order to demonstrate a receptor-mediated
      endocytosis pathway and to minimize nonspecific transfection pathways.
      Altogether, our results show that polyplexes formulated with AMD-labeled polymers
      constitute, under certain conditions, specific gene transfer systems into
      suspension CXCR4(+) Jurkat cells. This is more particularly the case when the
      nonspecific transfection pathways are minimized (i.e. for N/P <or= 2.5 AMD
      labeled polyplexes) and in the presence of phorbol myristate acetate which
      triggers CXCR4 receptor endocytosis of the AMD-labeled polyplexes to a larger
      extent than that of their respective nonlabeled ones. Although encouraging, the
      transfection specificities and efficiencies obtained with these compounds should
      however be improved. This study also illustrates the difficulties to demonstrate
      and to obtain a specific and efficient gene transfer system with cationized
      ligand-labeled DNA particles which also provide receptor-independent nonspecific
      gene transfer to cells, and more particularly to adherent cells.

PMID- 15025541
TI  - Synthesis of heterotelechelic poly(ethylene glycol) derivatives having alpha
      benzaldehyde and omega-pyridyl disulfide groups by ring opening polymerization of
      ethylene oxide using 4-(diethoxymethyl)benzyl alkoxide as a novel initiator.
AB  - New heterotelechelic PEG-containing benzaldehyde and 2-pyridyldithio endgroup
      (CHO-Bz-PEG-SSpyl) was synthesized with high efficiency and high selectivity. An
      alpha-benzylacetal-omega-methansulfonyl PEG was prepared as the first step to CHO
      Bz-PEG-SSpyl through the ring-opening polymerization of ethylene oxide (EO)
      initiated by potassium 4-(diethoxymethyl)benzyl alkoxide (PDA), followed by the
      successive conversion of the end-alkoxide group to a methanesulfonyl group and
      then to dithiocarbonate derivative. Further, deprotection of the dithiocarbonate
      derivative and subsequent conversion to the 2-pyridyldithio group at the omega
      end was successfully performed through a one-step reaction to form alpha
      benzylacetal-omega-2-pyridyldithio PEG (aceBz-PEG-SSpyl). The aceBz-PEG-SSpyl was
      then treated with an aqueous HCl solution (pH 5.0) to generate the benzaldehyde
      group at the alpha-end. Molecular functionalities of the benzaldehyde and the 2
      pyridyldithio end group of the heterotelechelic PEG (CHO-Bz-PEG-SSpyl) thus
      prepared were characterized by (1)H and (13)C NMR, showing that the reaction
      proceeded almost quantitatively. The benzaldehyde end group is available to
      conjugate various ligands having a primary amino group by forming the pH
      sensitive imine linkage (-N=CHC(6)H(4)-).

PMID- 15025542
TI  - Incorporation of chemoselective functionalities into peptoids via solid-phase
      submonomer synthesis.
AB  - A simple route to the introduction of a number of chemoselective functional
      groups into peptoids (oligo(N-substituted glycines)) by an extension of the
      standard solid-phase submonomer method is reported. The following groups were
      introduced: aminooxyacetamide, N-(carbamoylmethyl)acetohydrazide,
      mercaptoacetamide, 2-pyridinesulfenylmercaptoacetamide, and aldehyde-terminated
      peptoids. The method uses commercially available reagents, is fully compatible
      with standard peptoid submonomer synthesis conditions, is easily automated, and
      generates the desired functionalized peptoid in high yield and purity. Peptoids
      with suitable pairs of chemoselective ligation groups were joined in high yield.

PMID- 15025543
TI  - Disseminated mycobacterium avium-intracellulare complex (MAC) infection in the
      era of effective antiretroviral therapy: is prophylaxis still indicated?
AB  - Before highly active antiretroviral therapies (HAART) were available for the
      treatment of persons with HIV infection, disseminated Mycobacterium avium
      intracellulare complex (MAC) infection was one of the most common opportunistic
      infections that affected people living with AIDS. Routine use of chemoprophylaxis
      with a macrolide has been advocated in guidelines for the treatment of HIV
      infected individuals if they have a circulating CD4+ cell count of < or =50
      cells/microL. In addition, lifelong prophylaxis for disease recurrence has been
      recommended for those with a history of disseminated MAC infection. The
      introduction of HAART has resulted in a remarkable decline in the incidence of
      opportunistic infections and death among persons living with AIDS. Considerable
      reconstitution of functional immune responses against opportunistic infections
      can be achieved with HAART. In the case of infection with MAC, there has been a
      substantial reduction in the incidence of disseminated infections in the HAART
      era, even in countries where the use of MAC prophylaxis was never widely
      accepted. Moreover, the clinical picture of MAC infections in patients treated
      with potent antiretroviral therapies has shifted from a disseminated disease with
      bacteraemia to a localised infection, presenting most often with lymphadenopathy
      and osteomyelitis. Data from several recently conducted randomised, double-blind,
      placebo-controlled trials led to the current practice of discontinuing primary
      and secondary prophylaxis against disseminated MAC infections at stable CD4+ cell
      counts >100 cells/microL. These recommendations are still conservative as primary
      or secondary disseminated MAC infections are only rarely seen in patients who
      respond to HAART, despite treatment initiation at very low CD4+ cell counts.
      Potential adverse effects of macrolide therapy and drug interactions with
      antiretrovirals also metabolised via the cytochrome P450 enzyme system must be
      critically weighed against the marginal benefit that MAC prophylaxis may provide
      in addition to treatment with HAART. These authors feel that, unless patients who
      initiate HAART at low CD4+ cell counts do not respond to HIV-treatment, routine
      MAC prophylaxis should not be recommended. Nevertheless, the patient population
      for whom MAC prophylaxis may still be indicated in the era of HAART needs to be
      identified in prospectively designed clinical trials.

PMID- 15025544
TI  - Challenges in the management of HIV and hepatitis C virus co-infection.
AB  - Hepatitis C virus (HCV) has become a significant contributor to morbidity and
      mortality to those infected with HIV since the introduction of highly active
      antiretroviral therapy (HAART). The presence of HIV clearly has a negative effect
      on the natural history of HCV, although there is some debate over whether HCV
      influences the natural history of HIV. Given the prevalence of co-infection and
      the accelerated liver damage from HCV, treatment of chronic HCV infection is an
      important consideration in patients co-infected with HIV. There are few studies
      of pegylated interferon and ribavirin in co-infected populations, but it seems
      that the treatment is well tolerated, although it is possibly less effective in
      this group. HAART in the setting of HCV infection also requires some special
      consideration, namely an increased incidence of hepatotoxicity. Treatment of co
      infected patients requires close monitoring as current therapies are not ideal in
      terms of effectiveness, and toxicity may be severe.

PMID- 15025545
TI  - Adverse metabolic effects associated with atypical antipsychotics: literature
      review and clinical implications.
AB  - Adverse metabolic effects, such as diabetes mellitus, lipid abnormalities and
      weight gain, have increasingly been recognised with the use of the newer, so
      called atypical antipsychotic drugs. This article reviews the current literature
      in the field and attempts to answer the question of whether the atypical
      antipsychotics differ in their effects on glucose-insulin homeostasis and lipid
      metabolism. It also addresses how then to manage the use of the atypical
      antipsychotics that do interfere with these metabolic systems. Differences in
      effects of atypical antipsychotics on leptin levels are also summarised and put
      into context; bodyweight gain associated with atypical antipsychotics is reviewed
      elsewhere. In summary, there are no large controlled trials published quantifying
      the prevalence of adverse effects on glucose-insulin homeostasis and lipid
      metabolism in patients receiving atypical antipsychotics. Nevertheless, the
      published articles and case reports reviewed in this article give a fairly good
      view of those adverse effects occurring with clozapine, olanzapine and
      risperidone, whereas little data are available regarding quetiapine, ziprasidone
      and zotepine, and no data exist for amisulpride and aripiprazole. Estimated
      rankings of the atypical agents, based on the available literature, show that the
      relative risk of glucose intolerance/diabetes mellitus, hyperlipidaemia and
      hyperleptinaemia is highest for clozapine and olanzapine, moderately high for
      quetiapine, rather low for risperidone and lowest for ziprasidone. Since adverse
      metabolic effects of atypical antipsychotics may have a negative influence on
      both the antipsychotic treatment outcome as well as the physical health of the
      patient, these effects have to be recognised and adequately managed. In this
      review, recommendations for prevention and treatment of the adverse metabolic
      effects are outlined.

PMID- 15025547
TI  - Ethinylestradiol/chlormadinone acetate.
AB  - Ethinylestradiol/chlormadinone acetate 0.03/2mg (EE/CMA) is a combined monophasic
      contraceptive pill with antiandrogenic properties. In a large, noncomparative,
      multicentre trial (< or =24 cycles of treatment per woman) and two (6- and 12
      cycle) postmarketing surveillance studies, EE/CMA was effective in preventing
      pregnancy. EE/CMA was significantly more effective than EE/levonorgestrel
      0.03/0.15 mg/day in treating women with mild-to-moderate papulopustular acne of
      the face and related disorders in a randomised, single-blind, multicentre trial.
      EE/CMA was well tolerated in clinical trials and the postmarketing surveillance
      studies. Adverse events were those commonly reported with oral contraceptives. As
      expected, the most common menstrual disturbances were breakthrough bleeding,
      spotting and amenorrhoea.

PMID- 15025546
TI  - The anabolic androgenic steroid oxandrolone in the treatment of wasting and
      catabolic disorders: review of efficacy and safety.
AB  - There has been increasing interest in the development of effective agents that
      can be safely used to promote anabolism in the clinical setting for patients with
      chronic wasting conditions as well as in the prevention and treatment of frailty
      associated with loss of muscle tissue in aging (sarcopenia). One such agent is
      the anabolic androgenic steroid (AAS) oxandrolone, which has been used in such
      clinical situations as HIV-related muscle wasting, severe burn injury, trauma
      following major surgery, neuromuscular disorders and alcoholic hepatitis for over
      30 years. In the US, oxandrolone is the only AAS that is US FDA-approved for
      restitution of weight loss after severe trauma, major surgery or infections,
      malnutrition due to alcoholic cirrhosis, and Duchenne's or Becker's muscular
      dystrophy. Our review of the use of oxandrolone in the treatment of catabolic
      disorders, HIV and AIDS-related wasting, neuromuscular and other disorders
      provides strong evidence of its clinical efficacy. Improvements in body
      composition, muscle strength and function, status of underlying disease or
      recovery from acute catabolic injury and nutritional status are significant in
      the vast majority of well designed trials. However, oxandrolone has not yet been
      studied in sarcopenia.Unlike other orally administered C17alpha-alkylated AASs,
      the novel chemical configuration of oxandrolone confers a resistance to liver
      metabolism as well as marked anabolic activity. In addition, oxandrolone appears
      not to exhibit the serious hepatotoxic effects (jaundice, cholestatic hepatitis,
      peliosis hepatis, hyperplasias and neoplasms) attributed to the C17alpha
      alkylated AASs. Oxandrolone is reported to be generally well tolerated and the
      most commonly documented adverse effects are transient elevations in transaminase
      levels and reductions in high density lipoprotein cholesterol level.However,
      optimal risk:benefit ratios for oxandrolone and other agents in its class will
      need to be refined before widespread clinical acceptance of AASs as a therapeutic
      option in sarcopenia and other chronic wasting conditions.

PMID- 15025555
TI  - Aprepitant: a review of its use in the prevention of chemotherapy-induced nausea
      and vomiting.
AB  - Aprepitant (Emend) is the first commercially available drug from a new class of
      agents, the neurokinin NK(1) receptor antagonists. Oral aprepitant, in
      combination with other agents, is indicated for the prevention of acute and
      delayed chemotherapy-induced nausea and vomiting (CINV) associated with highly
      emetogenic chemotherapy in adults. In three randomised, double-blind, placebo
      controlled trials comparing aprepitant (125 mg day 1, 80mg once daily on days 2
      and 3 or 2-5) plus standard therapy (intravenous ondansetron and oral
      dexamethasone) with standard therapy plus placebo, overall complete responses
      (primary endpoint, defined as no emesis and no rescue therapy) were seen in
      significantly more patients in the aprepitant arms (63-73% versus 43-52%, p <
      0.01 for all comparisons). Complete responses and complete protection during the
      acute and delayed phase, and overall complete protection were also observed in
      significantly more patients in the aprepitant arms. The difference between
      treatment groups was more marked in the overall and delayed phases than in the
      acute phase. The antiemetic efficacy of aprepitant plus standard therapy in the
      prevention of CINV was maintained for up to six cycles of chemotherapy. Where
      assessed, more patients in the aprepitant plus standard therapy arms than the
      standard therapy plus placebo arms reported no impact of CINV on daily life, as
      assessed by the Functional Living Index-Emesis. Aprepitant is generally well
      tolerated. The most common adverse events in randomised trials were asthenia or
      fatigue. Other adverse events experienced by aprepitant recipients include
      anorexia, constipation, diarrhoea, nausea (after day 5 of the study) and hiccups.
      In addition to being a substrate for cytochrome P450 (CYP) 3A4, aprepitant is
      also a moderate inhibitor and inducer of this isoenzyme as well as an inducer of
      CYP2C9. Thus, aprepitant has the potential to interact with other agents
      metabolised by hepatic CYP isoenzymes. In one trial, there was a higher incidence
      of serious infection or febrile neutropenia in the aprepitant plus standard
      therapy arm than the standard therapy plus placebo arm; this was attributed to a
      pharmacokinetic interaction between aprepitant and dexamethasone. In subsequent
      trials, a modified dexamethasone regimen was used. In conclusion, when added to
      standard therapy (a serotonin 5-HT(3) receptor antagonist and a corticosteroid),
      aprepitant is effective and generally well tolerated in the prevention of CINV
      associated with highly emetogenic chemotherapy in adults. Despite marked advances
      in the prevention of CINV, standard therapy does not protect all patients. The
      addition of aprepitant to standard therapy provides an advance in the prevention
      of both acute and delayed CINV in adults with cancer.

PMID- 15025551
TI  - Inhaled iloprost: in primary pulmonary hypertension.
AB  - Iloprost is a stable prostacyclin analogue with a pharmacokinetic profile
      allowing nebulised administration in patients with primary pulmonary hypertension
      (PPH). Inhaled iloprost is a potent acute pulmonary vasodilator with a duration
      of action of about 60 minutes. It may exert additional long-term benefit through
      antiproliferative and antithrombotic effects. Inhaled iloprost 2.5 or 5 microg
      six or nine times daily for 12 weeks (n = 101) significantly (p < 0.01) improved
      a combined clinical endpoint of a > or =10% increase in distance walked in 6
      minutes and an improvement of > or =1 class in New York Heart Association
      functional class without clinical deterioration or death (16.8 versus 4.9% of
      placebo recipients, n = 102) in patients with severe PPH or selected forms of
      nonprimary pulmonary hypertension. Statistical analysis of the response for the
      PPH subgroup (20.8 versus 5.5% with placebo; n = 51 and 51) was not reported.
      Improvements from baseline in exercise capacity and haemodynamic/gas exchange
      variables have been reported in patients with PPH with continued use of inhaled
      iloprost. In addition, improvement in preinhalation vascular resistance occurred
      after 12 weeks of inhaled iloprost (p < 0.01 versus placebo) in a large
      randomised trial. Increased cough, headache, flushing and an influenza-like
      syndrome were the most common adverse events in the largest trial of patients
      receiving inhaled iloprost. Headache, flushing and jaw pain occurred
      significantly more frequently with inhaled iloprost than with placebo.

PMID- 15025556
TI  - Requirements for superoxide-dependent tyrosine hydroperoxide formation in
      peptides.
AB  - Superoxide reacts rapidly with other radicals, but these reactions have received
      little attention in the context of oxidative stress. For tyrosyl radicals,
      reaction with superoxide is 3-fold faster than dimerization, and forms the
      addition product tyrosine hydroperoxide. We have explored structural requirements
      for hydroperoxide formation using tyrosine analogues and di- and tri-peptides.
      Superoxide and phenoxyl radicals were generated using xanthine oxidase,
      peroxidase and the respective tyrosine derivative, or by gamma-radiation.
      Peroxides were measured using FeSO4/Xylenol Orange. Tyrosine and tyramine formed
      stable hydroperoxides, but N-acetyltyrosine and p-hydroxyphenylacetic acid did
      not, demonstrating a requirement for a free amino group. Using [14C]tyrosine, the
      hydroperoxide and dityrosine were formed at a molar ratio of 1.8:1. Studies with
      pre-formed hydroperoxides, and measurements of substrate losses, indicated that,
      in the absence of a free amino group, reaction with superoxide resulted primarily
      in restitution of the parent compound. With dipeptides, hydroperoxides were
      formed only on N-terminal tyrosines. However, adjacent lysines promoted
      hydroperoxide formation, as did addition of free lysine or ethanolamine. Results
      are compatible with a mechanism [d'Alessandro, Bianchi, Fang, Jin, Schuchmann and
      von Sonntag (2000) J. Chem. Soc. Perkin Trans. II, 1862-1867] in which the
      phenoxyl radicals react initially with superoxide by addition, and the
      intermediate formed either releases oxygen to regenerate the parent compound or
      is converted into a hydroperoxide. Amino groups favour hydroperoxide formation
      through Michael addition to the tyrosyl ring. These studies indicate that tyrosyl
      hydroperoxides should be formed in proteins where there is a basic molecular
      environment. The contribution of these radical reactions to oxidative stress
      warrants further investigation.

PMID- 15025558
TI  - Reversion of protein aggregation mediated by Sso7d in cell extracts of Sulfolobus
      solfataricus.
AB  - In eukaryotic cells and in Escherichia coli, reversion of protein aggregation is
      mediated by the network of chaperones belonging to Hsp70 and Hsp100 families
      [Weibezahn, Bukau and Mogk (2004) Microb. Cell Fact. 3, 1-12]. The thermophilic
      prokaryotes of the archaea domain lack homologues of these chaperone families,
      and the mechanisms they use to rescue aggregated proteins are unknown [Macario,
      Malz and Conway de Macario (2004) Front. Biosci. 9, 1318-1332]. In the present
      study, we show that stable protein aggregates can be detected in extracts of
      starved cells of the thermophilic archaeon Sulfolobus solfataricus, and that the
      protein Sso7d interacts with the aggregates and mediates the disassembly of the
      aggregates and the re-activation of insolubilized beta-glycosidase in the
      presence of ATP hydrolysis. Furthermore, we report that heat-induced protein
      aggregates in extracts of exponential cells of S. solfataricus contain Sso7d that
      rescues insolubilized proteins in the presence of ATP hydrolysis. Results of
      these experiments performed in cell extracts are consistent with an in vivo role
      of Sso7d in reverting protein aggregation.

PMID- 15025557
TI  - Deuterium isotope effect on the oxidation of monophenols and o-diphenols by
      tyrosinase.
AB  - A solvent deuterium isotope effect on the catalytic affinity (km) and catalytic
      constant (kcat) of tyrosinase in its action on different monophenols and o
      diphenols was observed. The catalytic constant decreased in all substrates as the
      molar fraction of deuterated water in the medium increased, while the catalytic
      affinity only decreased for the o-diphenols with an R group in C-1 [-H, -CH3 and 
      CH(CH3)2]. In a proton inventory study of the oxidation of o-diphenols, the
      representation of kcat fn/kcat f0 against n (atom fractions of deuterium), where
      kcat fn is the catalytic constant for a molar fraction of deuterium (n) and kcat
      f0 is the corresponding kinetic parameter in a water solution, was linear for all
      substrates, indicating that only one of the four protons transferred from the
      hydroxy groups of the two molecules of substrate, which are oxidized in one
      turnover, is responsible for the isotope effects, the proton transferred from the
      hydroxy group of C-4 to the peroxide of the oxytyrosinase form (Eox). However, in
      the representation of Km fn/Km f0 against n, where Km fn represents the catalytic
      affinity for a molar fraction of deuterium (n) and Km f0 is the corresponding
      kinetic parameter in a water solution, a linear decrease was observed as n
      increased in the case of o-diphenols with the R group [-H, -CH3 and -CH(CH3)2],
      and a parabolic increase with other R groups, indicating that more than one
      proton is responsible for the isotope effects on substrate binding. In the case
      of monophenols with six protons transferred in the catalytic cycle, the isotope
      effect occurs in the same way as for o-diphenols. In the present paper, the
      fractionation factors of different monophenols and o-diphenols are described and
      possible mechanistic implications are discussed.

PMID- 15025560
TI  - Increased levels of insulin and insulin-like growth factor-1 hybrid receptors and
      decreased glycosylation of the insulin receptor alpha- and beta-subunits in
      scrapie-infected neuroblastoma N2a cells.
AB  - We have previously shown that ScN2a cells (scrapie-infected neuroblastoma N2a
      cells) express 2-fold- and 4-fold-increased levels of IR (insulin receptor) and
      IGF-1R (insulin-like growth factor-1 receptor) respectively. In addition, the IR
      alpha- and beta-subunits are aberrantly processed, with apparent molecular masses
      of 128 and 85 kDa respectively, as compared with 136 and 95 kDa in uninfected N2a
      cells. Despite the 2-fold increase in IR protein, the number of (125)I-insulin
      binding sites was slightly decreased in ScN2a cells [Ostlund, Lindegren,
      Pettersson and Bedecs (2001) Brain Res. 97, 161-170]. In order to determine the
      cellular localization of IR in ScN2a cells, surface biotinylation was performed,
      showing a correct IR trafficking and localization to the cell surface. The
      present study shows for the first time that neuroblastoma N2a cells express
      significant levels of IR-IGF-1R hybrid receptors, and in ScN2a cells the number
      of hybrid receptors was 2-fold higher than that found in N2a cells, potentially
      explaining the apparent loss of insulin-binding sites due to a lower affinity for
      insulin compared with the homotypic IR. Furthermore, the decreased molecular mass
      of IR subunits in ScN2a cells is not caused by altered phosphorylation or
      proteolytic processing, but rather by altered glycosylation. Enzymic
      deglycosylation of immunoprecipitated IR from N2a and ScN2a cells with
      endoglycosidase H, peptide N-glycosidase F and neuraminidase all resulted in
      subunits with increased electrophoretic mobility; however, the 8-10 kDa shift
      remained. Combined enzymic or chemical deglycosylation using anhydrous
      trifluoromethane sulphonic acid treatment ultimately showed that the IR alpha-
      and beta-subunits from ScN2a cells are aberrantly glycosylated. The increased
      formation of IR-IGF-1R hybrids in ScN2a cells may be part of a neuroprotective
      response to prion infection. The degree and functional significance of aberrantly
      glycosylated proteins in ScN2a cells remain to be determined.

PMID- 15025559
TI  - SLI1 (YGR212W) is a major gene conferring resistance to the sphingolipid
      biosynthesis inhibitor ISP-1, and encodes an ISP-1 N-acetyltransferase in yeast.
AB  - ISP-1 (myriocin) is a potent inhibitor of serine palmitoyltransferase, the
      primary enzyme of sphingolipid biosynthesis, and is a useful tool for studying
      the biological functions of sphingolipids in both mammals and yeast
      (Saccharomyces cerevisiae). In a previous study, we cloned yeast multicopy
      suppressor genes for ISP-1, and one of these, YPK1/SLI2, was shown to encode a
      serine/threonine kinase which is a yeast homologue of mammalian SGK1
      (serum/glucocorticoid-regulated kinase 1). In the present study, another gene,
      termed SLI1 (YGR212W; GenBank accession number CAA97239.1), was characterized.
      Sli1p has weak similarity to Atf1p and Atf2p, which are alcohol
      acetyltransferases. Although a sli1-null strain grew normally, the IC50 of ISP-1
      for the growth of this strain was markedly decreased compared with that for the
      parental strain, indicating that Sli1p is a major contributor to ISP-1 resistance
      in yeast. On a sli1-null background, the increase in resistance to ISP-1 induced
      by YPK1 gene transfection was almost abolished. These data indicate that Sli1p co
      operates with Ypk1p in mediating resistance to ISP-1 in yeast. Sli1p was found to
      convert ISP-1 into N-acetyl-ISP-1 in vitro. Furthermore, N-acetyl-ISP-1 did not
      share the ability of ISP-1 to inhibit the growth of yeast cells, and the serine
      palmitoyltransferase inhibitory activity of N-acetyl-ISP-1 was much lower than
      that of ISP-1. These data suggest that Sli1p inactivates ISP-1 due to its N
      acetyltransferase activity towards ISP-1.

PMID- 15025561
TI  - Expression, intracellular distribution and basis for lack of catalytic activity
      of the PDE4A7 isoform encoded by the human PDE4A cAMP-specific phosphodiesterase
      gene.
AB  - PDE4A7 is an isoform encoded by the human PDE4A cAMP-specific phosphodiesterase
      gene that fails to hydrolyse cAMP and whose transcripts are widely expressed.
      Removal of either the N- or C-terminal unique portions of PDE4A7 did not
      reconstitute catalytic activity, showing that they did not exert a chronic
      inhibitory effect. A chimera (Hyb2), formed by swapping the unique N-terminal
      portion of PDE4A7 with that of the active PDE4A4C form, was not catalytically
      active. However, one formed (Hyb1) by swapping the unique C-terminal portion of
      PDE4A7 with that common to all active PDE4 isoforms was catalytically active.
      Compared with the active PDE4A4B isoform, Hyb1 exhibited a similar K(m) value for
      cAMP and IC50 value for rolipram inhibition, but was less sensitive to inhibition
      by Ro-20-1724 and denbufylline, and considerably more sensitive to thermal
      denaturation. The unique C-terminal region of PDE4A7 was unable to support an
      active catalytic unit, whereas its unique N-terminal region can. The N-terminal
      portion of the PDE4 catalytic unit is essential for catalytic activity and can be
      supplied by either highly conserved sequence found in active PDE4 isoforms from
      all four PDE4 subfamilies or the unique N-terminal portion of PDE4A7. A discrete
      portion of the conserved C-terminal region in active PDE4A isoforms underpins
      their aberrant migration on SDS/PAGE. Unlike active PDE4A isoforms, PDE4A7 is
      exclusively localized to the P1 particulate fraction in cells. A region located
      within the C-terminal portion of active PDE4 isoforms prevents such exclusive
      targeting. Three functional regions in PDE4A isoforms are identified, which
      influence catalytic activity, subcellular targeting and conformational status.

PMID- 15025562
TI  - Ligand-dependent autophosphorylation of the insulin receptor is positively
      regulated by Gi-proteins.
AB  - Previously, we have shown that the human insulin receptor (IR) interacts with
      G(i)2, independent of tyrosine kinase activity and stimulates NADPH oxidase via
      the Galpha subunit of G(i)2. We have now investigated the regulatory role of
      G(i)2-proteins in IR function. For the experiments, isolated IRs from plasma
      membranes of human fat cells were used. The activation of IR autophosphorylation
      by insulin was blocked by G-protein inactivation through GDPbetaS (guanosine 5'
      [beta-thio]disphosphate). Consistently, activation of G-proteins by micromolar
      concentrations of GTPgammaS (guanosine 5'-[gamma-thio]triphosphate) induced
      receptor autophosphorylation 5-fold over baseline and increased insulin-induced
      autophosphorylation by 3-fold. In the presence of 10 microM GTPgammaS, insulin
      was active at picomolar concentrations, indicating that insulin acted via its
      cognate receptor. Pretreatment of the plasma membranes with pertussis toxin
      prevented insulin- and GTPgammaS-induced autophosphorylation, but did not disrupt
      the IR-G(i)2 complex. The functional nature of the IR-G(i)2 complex was made
      evident by insulin's ability to increase association of G(i)2 with the IR. This
      leads to an augmentation of maximal receptor autophosphorylation induced by
      insulin and GTPgammaS. The specificity of this mechanism was further demonstrated
      by the use of isolated preactivated G-proteins. Addition of G(i)2alpha and
      Gbetagamma mimicked maximal response of insulin, whereas Galphas or Galphao had
      no stimulatory effect. These results define a novel mechanism by which insulin
      signalling mediates tyrosine kinase activity and autophosphorylation of the IR
      through recruitment of G(i)-proteins.

PMID- 15025564
TI  - Agonist-dependent up-regulation of thyrotrophin-releasing hormone receptor
      protein.
AB  - To study the effect of agonist on the TRH (thyrotrophin-releasing hormone)
      receptor protein, an epitope-tagged receptor was stably expressed in HEK-293
      cells (human embryonic kidney 293 cells) and receptor levels were measured by
      immunoblotting. TRH caused a 5-25-fold increase in receptor protein during 48 h,
      which was half-maximal at 1 nM and was slowly reversible after hormone
      withdrawal. Chlordiazepoxide, an inverse agonist, had no effect. TRH up
      regulation was mimicked by phorbol ester and blocked by the protein kinase C
      inhibitor GF109203X in combination with thapsigargin, which prevents a calcium
      response. TRH and phorbol ester increased the density of immunoreactive receptors
      localized at the cell surface and [3H]MeTRH (where MeTRH stands for [N3-methyl
      His]TRH) binding. TRH also increased the concentration of a truncated,
      internalization-defective receptor. Analysis of cell lines stably expressing TRH
      receptors fused to the green fluorescent protein on a fluorescence-activated cell
      sorter showed that TRH and phorbol ester caused 2.7- and 6.8-fold increases in
      fusion protein expression respectively. TRH receptor up-regulation was only
      partially accounted for by changes in receptor mRNA, which increased 1.7-fold.
      TRH caused a small increase in receptor concentration in the presence of
      cycloheximide, actinomycin D or MG132. In contrast with the results obtained with
      the TRH receptor, agonist decreased the concentration of stably expressed b2
      adrenergic receptors. These results show that TRH increases receptor
      concentration by a complex mechanism that requires signal transduction but not
      receptor endocytosis.

PMID- 15025563
TI  - Regulation of the human involucrin gene promoter by co-activator proteins.
AB  - Stratified squamous epithelial cells undergo an orderly process of terminal
      differentiation that is characterized by specific molecular and morphological
      changes, including expression of the cornified envelope protein involucrin.
      Significant progress has been made in characterizing the upstream regulatory
      region of the involucrin gene. Binding sites for AP-1 (activator protein 1) and
      Sp1 transcription factors were shown to be important for involucrin promoter
      activity and tissue-specific expression. Defective terminal differentiation is
      often characterized by decreased or lack of involucrin expression. Recently, a
      dominant-negative construct of the transcriptional co-activator P/CAF [p300/CBP
      associated factor, where CBP stands for CREB (cAMP-response-element-binding
      protein)-binding protein] was shown to inhibit involucrin expression in
      immortalized keratinocytes [Kawabata, Kawahara, Kanekura, Araya, Daitoku, Hata,
      Miura, Fukamizu, Kanzaki, Maruyama and Nakajima (2002) J. Biol. Chem. 277, 8099
      8105]. Loss of expression or inactivation of other co-activators has also been
      demonstrated [Suganuma, Kawabata, Ohshima, and Ikeda (2002) Proc. Natl. Acad.
      Sci. U.S.A. 99, 13073-13078]. In the present study, we re-expressed CBP and P/CAF
      in immortalized keratinocyte lines that had lost expression of these co-activator
      proteins. Re-expression of these proteins restored calcium- and RA (retinoic
      acid)-responsive involucrin expression in these cells. RA and calcium signalling
      induced exchange of CBP and P/CAF occupancy at the AP-1 sites of the involucrin
      promoter. CBP and P/CAF inductions of the involucrin expression were not
      dependent on MEK (mitogen-activated protein kinase/extracellular-signal-regulated
      kinase kinase), p38, protein kinase C or CaM kinase (calcium/calmodulin-dependent
      kinase) signalling. Kinase-induced changes in involucrin promoter activity
      directly resulted from changes in AP-1 protein expression. We concluded that CBP
      and P/CAF are important regulators of involucrin expression in stratified
      squamous epithelial cells.

PMID- 15025566
TI  - A linkage map of Atlantic salmon (Salmo salar) reveals an uncommonly large
      difference in recombination rate between the sexes.
AB  - A genetic linkage map of the Atlantic salmon (Salmo salar) was constructed, using
      54 microsatellites and 473 amplified fragment length polymorphism (AFLP) markers.
      The mapping population consisted of two full-sib families within one paternal
      half-sib family from the Norwegian breeding population. A mapping strategy was
      developed that facilitated the construction of separate male and female maps,
      while retaining all the information contributed by the dominant AFLP markers. By
      using this strategy, we were able to map a significant number of the AFLP markers
      for which all informative offspring had two heterozygous parents; these markers
      then served as bridges between the male and female maps. The female map spanned
      901 cM and had 33 linkage groups, while the male spanned 103 cM and had 31
      linkage groups. Twenty-five linkage groups were common between the two maps. The
      construction of the genetic map revealed a large difference in recombination rate
      between females and males. The ratio of female recombination rate vs. male
      recombination rate was 8.26, the highest ratio reported for any vertebrate. This
      map constitutes the first linkage map of Atlantic salmon, one of the most
      important aquaculture species worldwide.

PMID- 15025567
TI  - Genetic characterization of four strains of Nile tilapia (Oreochromis niloticus
      L.) using microsatellite markers.
AB  - Four domesticated strains of Nile tilapia (Oreochromis niloticus L.) were
      genetically characterized using 14 microsatellite markers and 64 animals per
      strain. Two strains, Chitralada (AIT) and International Development Research
      Centers (IDRC) were obtained from the AIT institute, Bangkok, Thailand. The GIFT
      strain (5th generation) came from NAGRI, Thailand, and the GOTT strain was
      supplied by the University of Gottingen, Germany. The average numbers of alleles
      per marker were 5.0 (GOTT), 5.4 (AIT), 5.6 (IDRC) and 7.5 (GIFT). Private alleles
      were found at all markers with the exception of two. No fixation of alleles was
      found at any marker. Population differentiation, FST, was 0.178 (great genetic
      differentiation) and confirmed grouping of the animals in strains. The expected
      level of heterozygosity ranged from 0.624 to 0.711, but the observed level of
      heterozygosity significantly deviated from the expected level in three strains.
      This was probably because of small population size. Moderate to great genetic
      differentiation was found between strains. A phylogenetic tree reflected the
      strains known histories. Application of the Weitzman approach showed that all
      strains have added value for the total genetic diversity and thus should be
      retained.

PMID- 15025565
TI  - The vaccinia virus-stimulated mitogen-activated protein kinase (MAPK) pathway is
      required for virus multiplication.
AB  - Early events play a decisive role in virus multiplication. We have shown
      previously that activation of MAPK/ERK1/2 (mitogen-activated protein
      kinase/extracellular-signal-regulated kinase 1/2) and protein kinase A are
      pivotal for vaccinia virus (VV) multiplication [de Magalhaes, Andrade, Silva,
      Sousa, Ropert, Ferreira, Kroon, Gazzinelli and Bonjardim (2001) J. Biol. Chem.
      276, 38353-38360]. In the present study, we show that VV infection provoked a
      sustained activation of both ERK1/2 and RSK2 (ribosomal S6 kinase 2). Our results
      also provide evidence that this pattern of kinase activation depends on virus
      multiplication and ongoing protein synthesis and is maintained independently of
      virus DNA synthesis. It is noteworthy that the VGF (VV growth factor), although
      involved, is not essential for prolonged ERK1/2 activation. Furthermore, our
      findings suggest that the VV-stimulated ERK1/2 activation also seems to require
      actin dynamics, microtubule polymerization and tyrosine kinase phosphorylation.
      The VV-stimulated pathway MEK/ERK1/2/RSK2 (where MEK stands for MAPK/ERK kinase)
      leads to phosphorylation of the ternary complex factor Elk-1 and expression of
      the early growth response (egr-1) gene, which kinetically paralleled the kinase
      activation. The recruitment of this pathway is biologically relevant, since its
      disruption caused a profound effect on viral thymidine kinase gene expression,
      viral DNA replication and VV multiplication. This pattern of sustained kinase
      activation after VV infection is unique. In addition, by connecting upstream
      signals generated at the cytoskeleton and by tyrosine kinase, the MEK/ERK1/2/RSK2
      cascade seems to play a decisive role not only at early stages of the infection,
      i.e. post-penetration, but is also crucial to define the fate of virus progeny.

PMID- 15025568
TI  - A microsatellite linkage map for Atlantic salmon (Salmo salar).
AB  - A linkage map of the Atlantic salmon is described here consisting of 15 linkage
      groups containing 50 microsatellite loci with a 14 additional unlinked markers
      (including three allozymes). The map shows the largest sex-specific recombination
      rate differences so far found in any vertebrate species (3.92:1 female:male).
      Homologies with previous linkage mapping studies of Atlantic salmon and rainbow
      trout are described. An in silico search of the Genbank database carried out
      using the microsatellites used in the mapping process identified significant
      matches between the flanking regions of the microsatellite SS11 and the calcium
      binding mitochondrial carrier protein, 'Aralar1'.

PMID- 15025569
TI  - Genetic diversity and differentiation in Portuguese cattle breeds using
      microsatellites.
AB  - Genotype data from 30 microsatellites were used to assess genetic diversity and
      relationships among 10 native Portuguese cattle breeds, American Charolais and
      the Brazilian Caracu. Hardy-Weinberg equilibrium was observed for all
      loci/population combinations except for five loci in Brava de Lide and one locus
      in Alentejana that exhibited heterozygote deficiency. Estimates of average
      observed and expected heterozygosities, total number of alleles (TNA) per breed
      and mean number of alleles (MNA) per locus/population were obtained. A total of
      390 alleles were detected. TNA among Iberian cattle ranged from 170 to 237 and
      MNA ranged from 5.67 to 8.07. The highest observed heterozygosities were found in
      the Caracu, Maronesa, Garvonesa and Arouquesa and the lowest in Brava de Lide and
      Mirandesa. Estimation of population subdivision using Wright's FST index showed
      that the average proportion of genetic variation explained by breed differences
      was 9%. Neighbour-joining phylogenetic trees based on DA distances showed that
      the genetic relationships of present-day Portuguese native breeds are consistent
      with historical origins in the Brown Concave (Arouquesa, Mirandesa, Marinhoa) and
      Red Convex (Mertolenga, Alentejana, Garvonesa, Minhota) evolutionary groups. The
      Iberian Black Orthoide group, represented by Brava de Lide and Maronesa, and the
      Barrosa breed appeared to be more closely related to the Brown Concave group but
      may represent a separate lineage. The Caracu breed was not found to be closely
      associated with any of the native Portuguese breeds.

PMID- 15025572
TI  - Determination of PRKAG1 coding sequence and mapping of PRKAG1 and PRKAG2
      relatively to porcine back fat thickness QTL.
AB  - PRKAG1, PRKAG2 and PRKAG3 encode three isoforms of AMP-activated protein kinase
      gamma chain. A major effect on meat quality and a medium effect on back fat
      thickness of the RN- mutation in the PRKAG3 gene has previously been reported. We
      have now mapped PRKAG1 and PRKAG2 at expected locations on SSC5 and SSC18 by
      analysis of radiation hybrids (IMpRH panel). PRKAG2 has been mapped in a region
      where no quantitative trait loci (QTL) has been reported. PRKAG1 has been mapped
      close to (but probably outside) a region containing a QTL influencing fatness
      traits. We have determined the full coding sequence of PRKAG1. No missense
      mutation was identified when comparing the coding sequence of one Meishan and one
      Large White boars. Further work is, however, required to determine if a
      polymorphism in PRKAG1 could be responsible for a part of the variability
      observed on fatness traits.

PMID- 15025570
TI  - Differential expression of iodothyronine deiodinase type 2 in growth plates of
      chickens divergently selected for incidence of tibial dyschondroplasia.
AB  - Tibial dyschondroplasia (TD) is a genetic leg defect in broilers with a lesion of
      avascular, non-calcified cartilage below the growth plate of the proximal
      tibiatarsus. This disease is considered to result from the inability of
      chondrocytes to undergo terminal differentiation. Thyroid hormones are required
      for chondrocyte differentiation. The thyroid gland produces and secrets mostly L
      thyroxine or T4 and T4 plays most of its biological activities through conversion
      to triiodothyronine or T3 in local tissues by iodothyronine deiodinases type 1 or
      type 2, which are tissue specific. In this study, no differences were found in
      the plasma concentrations of total T3 and T4 between two chicken lines
      divergently selected for the incidence of TD. Plasma T4 was higher than T3,
      especially in older chickens. Younger birds had much higher T3 than older birds,
      but there were no significant age differences in T4. The expression level of
      deiodinase type 2 in the growth plates of broilers with TD was one-eighth of
      those birds without the disease. The expression levels of deiodinase type 2
      (DIO2) in commercial broilers without the disease were much higher than those
      with TD and lower than those without the disease in the susceptible and resistant
      lines, respectively. These results indicate that the inadequate expression of
      DIO2 in the growth plates contributes to the pathogenesis of TD in broilers and
      that TD is a tissue-specific hypothyroidism.

PMID- 15025573
TI  - Comparison of GNRH3 genes across salmonid genera.
AB  - Genomic sequences of gonadotropin-releasing hormone genes were amplified and
      examined for sequence divergence among members of three different genera of the
      subfamily Salmoninae: rainbow trout (Oncorhynchus mykiss), Atlantic salmon (Salmo
      salar), and Arctic charr (Salvelinus alpinus). Sequences of GNRH3A and GNRH3B
      (formerly known as sGnRH1 and sGnRH2) were 97-99% similar in coding regions and
      94-98% similar in non-coding regions among genera, but comparisons within species
      between GNRH3A and GNRH3B were only 90-92% similar in coding regions and 83-89%
      similar in non-coding regions. Polymorphisms in the parents of mapping families
      for each species allowed for linkage mapping of the GNRH3B gene in all three
      species and the GNRH3A gene in rainbow trout. GNRH3B maps to linkage group 6 in
      rainbow trout, linkage group 16 in Atlantic salmon and linkage group 25 in Arctic
      charr. GNRH3A mapped to linkage group 30 in rainbow trout.

PMID- 15025571
TI  - Native antiviral specificity of chicken Mx protein depends on amino acid
      variation at position 631.
AB  - An attempt was made to determine whether amino acid variation at position 631 in
      the chicken Mx protein definitely influences antiviral specificity, using an
      artificial mutation technique by which a single amino acid was reciprocally
      substituted between Ser (AGT) and Asn (AAT) at position 631 of the negative and
      positive chicken Mx, respectively. Using permanently transfected 3T3 cell lines,
      the antiviral potential of chicken Mx against vesicular stomatitis virus
      infection was analysed. The results indicated that the phenotype of antiviral
      activity depends on the amino acid difference at position 631; that is, the
      genotype coding Asn at position 631 corresponds to the positive antiviral
      phenotype, and the genotype coding Ser corresponds to the negative phenotype. The
      present study has confirmed that the antiviral specificity of chicken Mx protein
      is determined by an amino acid substitution at the carboxy terminus.

PMID- 15025574
TI  - Characterization of a new BAC library for rainbow trout: evidence for multi-locus
      duplication.
AB  - A 10X rainbow trout bacterial artificial chromosome (BAC) library was constructed
      to aid in the physical and genetic mapping efforts of the rainbow trout genome.
      The library was derived from the Swanson clonal line (YY male) and consists of
      184,704 clones with an average insert size of 137,500 bp (PFGE) or 118,700 bp
      (DNA fingerprinting). The clones were gridded onto 10 large nylon membranes to
      produce high-density arrays for screening the library by hybridization. The
      library was probed with 11 cDNAs from the NCCCWA EST project chosen because of
      interest in their homology to known gene sequences, seven known genes, and a Y
      specific sex marker. Putative positive clones identified by hybridization were re
      arrayed and gridded for secondary confirmation. FPC analysis of HindIII and EcoRV
      DNA fingerprinting was used to estimate the level of redundancy in the library,
      to construct BAC contigs and to detect duplicated loci in the semi-duplicated
      rainbow trout genome. A good correlation (R2 = 0.7) was found between the number
      of hits per probe and the number of contigs that were assembled from the positive
      BACs. The average number of BACs per contig was 9.6, which is in good agreement
      with 10X genome coverage of the library. Two-thirds of the loci screened were
      predicted to be duplicated as the positive BACs for those genes were assembled
      into two or three different contigs, which suggests that most of the rainbow
      trout genome is duplicated.

PMID- 15025575
TI  - Assignment of the appaloosa coat colour gene (LP) to equine chromosome 1.
AB  - A single autosomal dominant locus, leopard complex (LP) controls the presence of
      appaloosa pigmentation patterns in the horse. The causative gene for LP is
      unknown. This study was undertaken to map LP in the horse. Two paternal half sib
      families segregating for the LP locus and including a total of 47 offspring were
      used to perform a genome scan which localized LP to horse chromosome 1 (ECA1). LP
      was linked to ASB08 (LOD = 9.99 at Theta = 0.02) and AHT21 (LOD = 5.03 at Theta =
      0.14). To refine the map position of LP, eight microsatellite markers on ECA1
      (UM041, LEX77, 1CA41, TKY374, COR046, 1CA32, 1CA43, and TKY002) were analysed in
      the two half sib families. Results from this linkage analysis showed LP was
      located in the interval between ASB08 and 1CA43. Tight junction protein (TJP1),
      which lies within the LP interval on ECA1, was used to determine the homologous
      chromosomes in humans (HSA15) and mice (mouse chromosome 7). We propose that the
      pink eyed dilution (p) gene and transient receptor potential cation channel
      subfamily M, member 1 (TRPM1) are positional candidate genes for LP.

PMID- 15025576
TI  - A missense mutation in the bovine leptin receptor gene is associated with leptin
      concentrations during late pregnancy.
AB  - The leptin receptor (LEPR) gene consists of 20 exons divided over 1.75 Mb. Parts
      of bovine LEPR exon 4 (79 bp), exon 11 (95 bp) and exon 20 (513 bp) of 20 cows
      (Holstein-Friesian) were sequenced (AJ580799; AJ580800; AJ580801) in an attempt
      to find polymorphisms. In exons 4 and 11 no SNPs were found. In exon 20, a T to C
      missense mutation was found at nucleotide 115, which causes an amino acid
      substitution at residue 945 (T945M). Frequencies for alleles C and T were 0.93
      and 0.07 respectively, in a population of 323 Holstein-Friesian cows and TT
      animals were not detected. Using genotypes of these cows an association study was
      performed for leptin concentrations during late pregnancy and lactation. Leptin
      concentrations were determined by radioimmunoassay (RIA). The T945M mutation
      showed an association with circulating leptin concentrations only during late
      pregnancy (P < 0.05) but not during lactation (P > 0.05). The CC genotype had
      higher concentrations than the CT genotype during this period. A combined effect
      with previously described leptin polymorphisms on prepartum leptin concentrations
      was observed, with one genotype combination having significantly lower levels of
      leptin up to 50 days, but interaction effects were not significant. The T945M
      polymorphism may have induced a structural change in the intracellular domain of
      the LEPR, which may have influenced the signal transduction pathway. However, the
      effect was found only for the heterozygous genotype because the TT genotype was
      not detected in this population of 323 Holstein-Friesian cows.

PMID- 15025577
TI  - Mapping of the FES and FURIN genes to porcine chromosome 7.

PMID- 15025578
TI  - Assignment of the phosphoglycerate kinase 1 (PGK1) gene to porcine chromosome
      Xq12-q13 by fluorescence in situ hybridization and hybrid panel analyses.

PMID- 15025579
TI  - Identification of three microsatellite loci on bovine chromosome 19.

PMID- 15025580
TI  - Assignment of the SIAT4A gene to bovine chromosome 14 by linkage mapping of an
      associated microsatellite.

PMID- 15025581
TI  - Construction of six linkage groups in the guppy (Poecilia reticulata).

PMID- 15025582
TI  - Refined localization of the chicken KITLG, MGP and TYR genes on GGA1 by FISH
      mapping using BACs.

PMID- 15025583
TI  - Partial cloning of the T-cell receptor-alpha gene and assignment of TRA and TRB
      genes to the catfish linkage map.

PMID- 15025584
TI  - Sequencing, SNP identification and mapping of the porcine PTHLH gene to
      chromosome 5.

PMID- 15025585
TI  - A previously unreported DraI polymorphism within the regulatory region of the
      bovine growth hormone gene and its association with growth traits in Korean
      Hanwoo cattle.

PMID- 15025586
TI  - Mapping of the GATA4, NEIL2, FDFT1 genes and CTSB-associated microsatellites to
      the centromeric region of BTA8.

PMID- 15025587
TI  - Linkage mapping of the porcine cathepsin F (CTSF) gene close to the QTL regions
      for meat and fat deposition traits on pig chromosome 2.

PMID- 15025588
TI  - Assignment of bovine trophinin (TRO) to the q arm of the X chromosome by
      fluorescence in situ hybridization.

PMID- 15025589
TI  - Linkage mapping of inhibitor of apoptosis protein-1 (IAP 1) to chicken chromosome
      1.

PMID- 15025591
TI  - SNP identification and genetic mapping of chicken ephrin type-B receptor 2 gene
      to linkage group E54.

PMID- 15025590
TI  - Radiation hybrid mapping of 63 previously unreported equine microsatellite loci.

PMID- 15025592
TI  - Physical mapping of the stearoyl-CoA desaturase (SCD) locus in sheep.

PMID- 15025593
TI  - Physical and linkage mapping of the lymphocyte antigen 86 (LY86) gene to porcine
      chromosome 7.

PMID- 15025594
TI  - Chicken tubby-like protein 1 (TULP1) gene maps to chromosome 26.

PMID- 15025596
TI  - Haemodynamic responses to intubation: what more do we have to know?

PMID- 15025595
TI  - Mapping and microsatellite marker development for the porcine GRB2-associated
      binding protein 1 (GAB1) gene.

PMID- 15025597
TI  - Effect of remifentanil on intracranial pressure and cerebral blood flow velocity
      in patients with head trauma.
AB  - BACKGROUND: Remifentanil, an ultra-short-acting opioid, is used as an on-top
      analgesic in head trauma patients during transient painful procedures, e.g.
      endotracheal suctioning, physiotherapy, on the intensive care unit. However,
      previous studies have shown that opioids may increase intracranial pressure and
      decrease cerebral blood flow. METHODS: The present study investigates the effect
      of remifentanil on mean arterial blood pressure, intracranial pressure measured
      with intraparenchymal or epidural probes, and on cerebral blood flow velocity
      assessed by transcranial Doppler flowmetry in 20 head trauma patients sedated
      with propofol and sufentanil. Ventilation was adjusted for a target PaCO2 of 4.7
      5.1 kPa. After baseline measurements a bolus of remifentanil (0.5 microg x kg(-1)
      i.v.) was administrated followed by a continuous infusion of remifentanil (0.25
      microg x kg(-1) x min(-1) i.v.) for 20 min. RESULTS: There was no change in mean
      arterial blood pressure, intracranial pressure, and cerebral blood flow velocity
      in response to remifentanil infusion over time. Statistical analysis was
      performed using the Wilcoxon Signed Rank test. CONCLUSIONS: These data suggest
      that remifentanil can be used for on-top analgesia in head trauma patients
      without adverse effects on cerebrovascular haemodynamics, cerebral perfusion
      pressure or intracranial pressure.

PMID- 15025598
TI  - Desflurane results in higher cerebral blood flow than sevoflurane or isoflurane
      at hypocapnia in pigs.
AB  - BACKGROUND: In clinical neuroanaesthesia, the increase in cerebral blood flow
      (CBF) and intracranial pressure caused by the cerebral vasodilative effects of an
      inhalational anaesthetic agent is counteracted by the cerebral vasoconstriction
      induced by hypocapnia. Desflurane and sevoflurane may have advantages over the
      more traditionally used isoflurane in neuroanaesthesia but their dose-dependent
      vasodilative effects at hypocapnia have not been compared in the same model using
      truly equipotent minimal alveolar concentrations (MACs). METHOD: Desflurane,
      sevoflurane and isoflurane were administered in a randomized order to six pigs at
      0.5 and 1.0 MAC. The intra-arterial xenon clearance technique was used to
      calculate CBF. Blood pressure was invasively monitored. Cerebral and systemic
      physiological variables were recorded first at normocapnia (PaCO2 5.6 kPa) and
      then at hypocapnia (PaCO2 3.5 kPa). Electroencephalographic (EEG) activity was
      continuously recorded. RESULTS: None of the three agents abolished
      cerebrovascular reactivity to hyperventilation, and at 0.5 MAC all had similar
      effects on CBF at hypocapnia. Desflurane at 1.0 MAC was associated with 16%
      higher CBF (P = 0.027) at hypocapnia than isoflurane, and with 24% higher CBF (P
      = 0.020) than sevoflurane. There was no seizure activity in the EEG. CONCLUSION:
      More cerebral vasodilation at hypocapnia with high doses of desflurane than with
      sevoflurane or isoflurane indicates that desflurane might be less suitable for
      neuroanaesthesia than sevoflurane and isoflurane.

PMID- 15025599
TI  - Convulsions on anaesthetic induction with sevoflurane in young children.
AB  - Increased worldwide use for paediatric anaesthesia of the volatile anaesthetic
      agent sevoflurane has mainly resulted from its low blood-gas partition
      coefficient and low airway irritability, providing smooth conditions for rapid
      induction of anaesthesia. Nevertheless, there are several clinical and
      experimental reports suggesting a correlation between exposure to sevoflurane and
      generalized clonic or tonic seizure activity. We report two clinical episodes of
      convulsions associated with the induction of sevoflurane anaesthesia in young
      children. CASE 1: during induction of anaesthesia with sevoflurane by facemask in
      a 3-year-old healthy boy, there were symmetrical clonic seizure-like movements of
      the upper extremities for 60 s. CASE 2: on re-induction of anaesthesia with
      sevoflurane because of profuse bleeding following nasal adenoidectomy in a 4-year
      old healthy girl with a family history of epilepsy, there were symmetrical tonic
      and clonic seizure-like movements for 30-40 s in the upper and lower extremities.
      Both episodes ceased spontaneously. Although no EEG was recorded, it cannot be
      excluded that both episodes resulted from seizure activity within the CNS. Based
      on our observations and reports by others we suggest that, until further notice,
      sevoflurane should be avoided or at least used cautiously in patients where
      clinical epileptic activity has been verified or is strongly suspected.

PMID- 15025601
TI  - Retrograde tracheal intubation: beyond fibreoptic endotracheal intubation.
AB  - BACKGROUND: Flexible fibreoptic laryngoscopy is the method of choice for coping
      with difficult tracheal intubations, a leading cause of catastrophic outcomes in
      anaesthesia. However, this technique is not always available or feasible.
      Retrograde intubation is a minimally invasive airway management technique with a
      flat learning curve and a high level of skill retention. METHODS: A retrospective
      review of the anaesthesia records of 24 patients who underwent retrograde
      intubation. The success rate and the incidence of complications were recorded.
      RESULTS: Retrograde tracheal intubation was successful in all 24 patients. In 21
      patients it succeeded on the first attempt. In two patients it succeeded when the
      technique was changed from sliding over a guide wire to a pulling technique. The
      most common complication was a sore throat in almost 60% of the patients. Two
      patients had mild subcutaneous emphysema and one had minimal bleeding at the
      puncture site. CONCLUSIONS: In these patients retrograde tracheal intubation was
      easy to perform, had a high success rate and a low incidence of complications. It
      is a reliable alternative when fibreoptic intubation is precluded, fails or is
      unavailable.

PMID- 15025600
TI  - Effect of aminophylline on bispectral index.
AB  - BACKGROUND: The aim of the present study was to investigate the effects of
      aminophylline on BIS as well as clinical recovery in patients anesthetized with
      sevoflurane. METHODS: Sixty patients with status of ASA I-II scheduled for
      elective surgery were enrolled in this study. Anesthesia was induced by 2 mg kg(
      1) of propofol and 0.5 mg kg(-1) of atracurium, maintained with 1:1 ratio of
      oxygen and nitrous oxide and 2-2.5% sevoflurane, keeping BIS values at 50 +/- 5.
      During the last 30 min of the operation no muscle relaxant was given and
      anesthesia was continued without decreasing anesthetic concentration. After
      sevoflurane discontinuation, saline was given to Group P, and 5 mg kg(-1) of
      aminophylline was given to Group A. Bispectral index values, heart rate, blood
      pressure and oxygen saturation were determined in all the patients before and
      every min after injection of the test drug for 15 min. The following variables
      were measured in both groups: eye opening, extubation time, response to command,
      Aldrete scores, and performing three simple arithmetic calculations. RESULTS:
      Between groups there was no statistically significant difference in mean arterial
      blood pressure, SpO2 and anesthesia time. Heart rate was found to be
      statistically higher (P < 0.001) at 2 to 6 min in Group A when compared with
      group P. Eye opening, verbal response, extubation and arithmetic calculation
      times were significantly shorter (P < 0.001) in Group A. Bispectral index scores
      were significantly higher in Group A at 1 to 12 min after aminophylline injection
      when compared with placebo (P < 0.001). CONCLUSION: Recovery from sevoflurane
      anesthesia and BIS scores are improved in early period when aminophylline is
      given at emerging from anesthesia.

PMID- 15025602
TI  - Outcome of the elderly critically ill after intensive care in an era of cost
      containment.
AB  - BACKGROUND: Economical constraints have, in many countries, led to a reduction in
      provision of health care services, including care of the critically ill, after
      decades of expansion. We hypothesized that elderly critically ill patients may be
      particularly vulnerable to these changes. The purpose of the present study was to
      examine survival of patients > or = 75 years between 1993 and 1999 when overall
      staff and ICU/HDU-beds were stepwise reduced, but the nurse/bed ratio increased.
      METHODS: Patient demographics, reason for admission, APACHE II and TISS scores
      were retrieved from a prospectively collected clinical database, and 180-day
      mortality was secured from a national database. Multivariate logistic regression
      was used to determine the role of year of admission on outcome. RESULTS: The
      annual number of elderly admissions (mean 656, range 611-702) and their APACHE II
      derived probability of death (mean 0.25, range 0.24-0.26) did not alter
      significantly during the period. For patients admitted after anesthesia and
      surgery, length of stay was significantly shorter (P < 0.001) and TISS points per
      admission were fewer (P < 0.05) at the end of the period, whereas 180-day
      survival remained unchanged (mean 27.5%, range 25.3-29.3%). Year of admission had
      no explanatory power with an odds ratio of 1.0 (95% CI 0.9-1.1) per year.
      CONCLUSION: Reduction of intensive care services led to shorter stay and lower
      TISS allocation for elderly critically ill without any significant increase in
      180-day mortality.

PMID- 15025603
TI  - Fiber-type composition and fiber size of the human cricopharyngeal muscle and the
      pharyngeal constrictor muscle.
AB  - BACKGROUND: Despite a similar density of nicotinic acetylcholine receptors, the
      upper esophageal sphincter is sensitive to partial neuromuscular block, whereas
      the pharyngeal constrictor muscle is more resistant. In order to postulate
      possible mechanisms behind this difference in pharmacological response, basic
      knowledge of morphological and physiological features of these muscles is needed.
      The aim of this study was to compare the muscle fiber-type composition, the size
      and the morphology of the muscle fibers of the cricopharyngeal muscle, the main
      component of the upper esophageal sphincter, with that of the pharyngeal
      constrictor muscle. METHODS: Muscle specimens were obtained from five patients
      undergoing surgery with laryngectomy. Muscle fiber type was determined by myosin
      heavy chain immunohistochemistry and the muscle fiber cross-sectional area was
      measured for each fiber type by planimetry. Morphology of muscle fibers was
      evaluated by histochemistry. RESULTS: The muscle fiber cross-sectional area was
      generally smaller in the cricopharyngeal muscle compared with the pharyngeal
      constrictor muscle (P < 0.001). The composition of fiber types showed a large
      interindividual variability with no distinct difference between the studied
      muscles. Aberrant histological features were common in both the cricopharyngeal
      muscle and the pharyngeal constrictor muscle. CONCLUSION: The main morphological
      difference between the neuromuscular blocking agents sensitive cricopharyngeal
      muscle and the more resistant pharyngeal constrictor muscle is a uniformly
      smaller size of contributing fiber types in the cricopharyngeal muscle than in
      the pharyngeal constrictor muscle. The muscle fiber-type composition does not
      differ between the two studied muscles.

PMID- 15025604
TI  - Changes in diaphragm structure following prolonged mechanical ventilation in
      piglets.
AB  - BACKGROUND: Prolonged mechanical ventilation and inactivity negatively affect
      muscle function. The mechanisms for this dysfunction are unclear and clinical
      studies of respiratory muscle are difficult to carry out. An animal model
      simulating the critical care environment was used to investigate the effects of 5
      days' mechanical ventilation and diaphragm inactivity on diaphragm muscle
      morphology. METHODS: Twelve 2-4-month-old piglets weighing 23-30 kg were studied.
      Seven animals received controlled mechanical ventilation and sedation such that
      spontaneous breathing efforts were inhibited over 5 days. Five control animals
      were ventilated for only 4-6 h following surgical preparation. Diaphragm biopsies
      were obtained from the left costal region at the end of all experiments. RESULTS:
      Morphometric, morphologic, electron microscopic and enzyme histochemical
      examination of costal diaphragm biopsies was carried out. Contractile properties
      were studied over 5 days and the results have been previously reported. Cross
      sectional area of alI fiber types was increased compared with controls. The
      proportion of type IIb/x fibers increased following inactivity (P < 0,05) and the
      proportion of type I and IIa fibers tended to decrease although not
      significantly. Focal areas of diaphragm fiber regeneration were found without
      signs of inflammation. Increased appearance of cytoplasmic vacuoles consisting of
      lipid accumulation was noted in type I fibers. Several study animals developed
      focal areas with weak myofibrillar ATPase activity and disrupted fiber
      organization. There were areas of myofibrillary destruction and loss of
      sarcomeric pattern, without evidence of selective thick filament loss or a change
      in the myosin to actin ratio. CONCLUSION: Five days' mechanical ventilation with
      sedation and complete diaphragm inactivity resulted in changes in muscle fiber
      structure. A causal relationship can not be concluded but the acute changes in
      fiber type distribution and structure suggest that previously reported diaphragm
      contractile impairment occurs at the level of muscle fibers.

PMID- 15025605
TI  - Effects of sodium benzoate on the complications of 1.5% glycine solution using
      two different intravesical pressures during bladder irrigation.
AB  - BACKGROUND: In this experimental study we researched the effects of sodium
      benzoate on the complications of 1.5% glycine solution using with two different
      intravesical pressures during bladder irrigation. METHODS: Thirty-six male adult
      New Zealand rabbits with body weight ranging from 1500 to 2800 g were used in the
      experiments. The rabbits were randomly allocated to four groups. In groups 1 and
      2, 500 ml of 1.5% gylcine was used as irrigating fluid during 30 min, but only
      group 2 received 500 mg kg(-1) of sodium benzoate treatment by oral route
      immediately after irrigation. In groups 3 and 4, 500 ml of 1.5% glycine was used
      as irrigating fluid during 60 min, but only group 4 received the same treatment
      as group 2. Ammonia, urea, sodium, potassium, hemoglobin, hemotocrit and platelet
      levels were studied at preirrigation and postirrigation on the 4 h and 24 h. Also
      electrocardiographic (ECG) changes were monitored at the same time with blood
      parameters. RESULTS: At 4 h postirrigation, Na+ levels were decreased
      significantly in group 1 and non-significantly in group 3 when compared with
      preirrigation levels. But these levels were not changed in groups 2 and 4. Both
      at 4 h and 24 h, ammonia and urea levels were significantly increased in groups 1
      and 3. Ammonia level was decreased but the urea level was not changed in groups 2
      and 4 at the same time points. K+ level was significantly changed only in group 1
      at 4 h and 24 h. Hemoglobin and hemotocrit concentrations were decreased both at
      4 h and 24 h compared with preirrigation levels in all groups. Also there were
      ECG changes between the treated and untreated groups. CONCLUSION: Sodium benzoate
      was very effective against the complications of 1.5% glycine during bladder
      irrigation experimentally. But this needs further investigation, especially for
      the applicability of this new treatment model in human TURP syndrome.

PMID- 15025606
TI  - Increased spillover of norepinephrine to the portal vein during CO
      pneumoperitoneum in pigs.
AB  - BACKGROUND: Elevated intra abdominal pressure (IAP) during CO2-insufflation has
      been associated with increased catecholamine concentrations in plasma. We have
      previously indicated that this may be due to a regional increased spillover from
      the abdominal region. In this experimental study we investigated catecholamine
      spillover from the drainage area of the portal vein during CO2-pneumoperitoneum.
      METHODS: Eight pigs under general anesthesia were investigated before and after
      CO2-pneumoperitoneum with an IAP of 15 mmHg. Regional spillover of catecholamines
      was determined by measuring plasma catecholamine concentrations and flow
      simultaneously. Plasma concentrations of catecholamines were measured from the
      portal and femoral veins, the pulmonary and carotid arteries. Flow data were
      collected with laser-Doppler transit time flow probes around the portal and
      femoral veins. Cardiac output was measured by the thermo-dilution technique.
      Estimated spillover was calculated by the veno-arterial difference multiplied by
      flow. RESULTS: We found a significant increase in estimated spillover of
      norepinephrine from the drainage area of the portal vein from 10 (-1.2, 78) ng x
      min(-1) to 27 (1.8, 475) ng x min(-1)[median (range)] (P = 0.05), but no change
      in estimated spillover of norepinephrine from the drainage area of the femoral
      vein. Plasma concentrations of norepinephrine increased in central venous and
      arterial blood. There was no significant change in epinephrine concentrations in
      arterial blood. CONCLUSION: Estimated norepinephrine spillover from the drainage
      area of the portal vein increased during CO2-pneumoperitoneum in pigs. This may
      indicate that the increased norepinephrine concentrations found in arterial
      plasma reflects a local activation of sympathetic nerves in the region of the
      portal drainage area.

PMID- 15025607
TI  - Percutaneous tracheostomy: Ciaglia Blue Rhino versus Griggs' Guide Wire Dilating
      Forceps. A prospective randomized trial.
AB  - BACKGROUND: Percutaneous tracheostomy (PT) has gained widespread acceptance to
      control the airway in patients requiring prolonged mechanical ventilation. Since
      1985, new techniques for PT have been described. It was the aim of this
      investigation to compare two different PT techniques: the Ciaglia Blue Rhino
      (CBR) and the Guide Wire Dilating Forceps (GWDF). METHODS: A prospective
      randomized trial was performed in four intensive care units. After informed
      consent, 53 consecutive patients were randomized to undergo CBR or GWDF.
      Procedural complications were evaluated and specific symptoms of the upper airway
      tract in survivors were assessed. RESULTS: Twenty-seven patients were randomly
      assigned to CBR and 26 to GWDF. Patients mean ages were 62.7 +/- 15.8 years and
      62.2 +/- 18.3, respectively. Mean APACHE II scores were 20.6 +/- 6.8 and 21.2 +/-
      7.2, respectively. Median duration of the procedure was 7 min (range: 4-17 min)
      with GWDF and 9 min (range: 5-32 min) with CBR (P = 0.16). Seven patients in the
      group undergoing GWDF had complications (desaturation: two; mild bleeding: one;
      infected stoma: one; inability to complete the procedure: three). Two patients
      had complications in the group undergoing CBR (mild bleeding) (P = 0.07).
      Survivors were followed up after discharge. Three patients (all of them having
      undergone GWDF) were symptomatic (two with mild hoarseness and one with a
      persistent foreign body sensation), but laryngotracheoscopy was negative.
      CONCLUSIONS: Our results show no differences between both techniques regarding
      surgical duration or procedural complications. Late symptoms were encountered in
      three patients undergoing GWDF, however, laryngotracheoscopy failed to document
      anatomical or functional abnormalities.

PMID- 15025608
TI  - Practices of anaesthesiologists with regard to withholding and withdrawal of life
      support from the critically ill in Turkey.
AB  - BACKGROUND: To determine practices of Turkish anaesthesiologists with regard to
      withholding and withdrawal of life support from the critically ill. METHODS: An
      anonymous questionnaire consisting of 18 questions was mailed to 439 members of
      the Turkish Society of Anaesthesiology and Reanimation. RESULTS: Three hundred
      and 69 questionnaires were returned (84% response). Over 90% of the respondents
      indicated that they were Muslim. We found that 66% of respondents had initiated
      written or oral do-not-resuscitate orders, most frequently after discussion with
      colleagues (82%). CONCLUSIONS: While a number of similarities were found between
      Turkish anaesthesiologists and those from other countries, some specific
      differences could be identified, particularly related to consensus decision
      making and sharing information with other providers and the value of Ethics
      Committees in the decision-making process.

PMID- 15025609
TI  - Respiratory changes during prolonged increased intra-abdominal pressure in pigs.
AB  - BACKGROUND: Increased intra-abdominal pressure (IAP) elevates thoracic pressure
      and airway pressures and reduces lung compliance in humans and laboratory
      animals. We studied respiratory alterations and arterial blood gas changes in
      pigs with IAP maintained at 20 mmHg or 30 mmHg for 3 h. METHODS: Domestic pigs of
      both sexes weighing 30.0 +/- 5.1 kg (mean +/- SD) (n = 21) were divided into
      three groups. The animals were anesthetized and kept at 20 mmHg IAP (n = 7) or 30
      mmHg IAP (n = 7) for 3 h. The third group (n = 7) served as control without an
      elevated IAP. We recorded respiratory alterations and changes in acid-based
      parameters at baseline and after 90 min and 180 min of increased IAP. RESULTS: No
      significant hypoxia or hypercarbia was found in animals with an IAP of 20 mmHg
      IAP. At an IAP of 30 mmHg, pO2 decreased to an average 19.6 kPa and pCO2
      increased to about 6 kPa, and the animals were slightly acidotic. Airway pressure
      increased significantly and lung compliance decreased in both groups of elevated
      IAP. CONCLUSION: In our porcine model, an IAP of 20 mmHg or higher for 3 h is
      harmful for the respiratory function of the animals due to deterioration of
      respiratory parameters, increased airway pressure and decreased lung compliance.

PMID- 15025610
TI  - Biochemical markers for brain damage after carbon monoxide poisoning.
AB  - BACKGROUND: Carbon monoxide poisoning is associated with high mortality and a
      substantial risk for brain damage in survivors. Evidence for acute brain
      dysfunction may be obtained by measuring concentrations of suitable biochemical
      markers. We hypothesized that increased serum concentrations of Neuron-specific
      enolase (NSE) and S-100beta protein could be detected after carbon monoxide
      poisoning and that the concentration would correlate with the severity of
      intoxication. METHODS: Prospective non-interventional study in the university
      hospital. We included 20 patients admitted for hyperbaric treatment due to carbon
      monoxide poisoning. Serum levels of NSE and S-100beta protein were measured in
      all patients on admission and after 12, 24, 36 and 48 h. As a control group, we
      included 20 patients who underwent elective hyperbaric treatment. RESULTS: Serum
      concentrations of NSE and S-100beta protein were not significantly different from
      the controls, with median values at admission being 10.6 vs. 9.7 microg l(-1) and
      0.15 vs. 0.13 microg l(-1), respectively (P = 0.82 and P = 0.38). The
      concentrations did not change significantly during the sampling period. We were
      unable to show any significant relation to level of consciousness. CONCLUSION:
      Blood concentrations of NSE and S-100beta protein were not significantly
      increased after carbon monoxide poisoning and do not seem to be related to a
      history of unconsciousness.

PMID- 15025611
TI  - Comparison of 27-gauge (0.41-mm) Whitacre and Quincke spinal needles with respect
      to post-dural puncture headache and non-dural puncture headache.
AB  - BACKGROUND: The incidence of headache after spinal anaesthesia has varied greatly
      between studies. We compared the incidence of postoperative headache in general
      and postdural puncture headache (PDPH) when using 27-gauge (G) (outer diameter
      0.41 mm) Quincke and Whitacre spinal needles in ambulatory surgery performed
      under spinal anaesthesia. METHODS: In a prospective, randomized study, 676 ASA
      physical status I-II day-case outpatients were given a spinal anaesthetic through
      either a 27-G (0.41 mm) Quincke or a 27-G (0.41 mm) Whitacre spinal needle. The
      incidence of any type of postoperative headache was assessed and the type of
      headache defined using a standardized questionnaire including PDPH criteria. The
      severity of the headache was defined using a 100-mm visual analogue scale.
      RESULTS: For the final analysis, 529 patients were available (259 patients in the
      Quincke group and 270 patients in the Whitacre group). The overall incidence of
      postoperative headache was 20.0%, but the incidence of true PDPH was very low
      (1.51%). The incidence of PDPH in the Quincke group was 2.70%, while in the
      Whitacre group it was only 0.37% (P < 0.05). The overall incidence of non-dural
      puncture headache was 18.5% and did not differ between the study groups.
      CONCLUSIONS: True PDPH seldom occurs when a 27-G (0.41 mm) spinal needle is used,
      although postoperatively a non-specific headache is common. Using the 27-G (0.41
      mm) Whitacre spinal needle further reduced the incidence of PDPH. Thus, we
      recommend routine use of the 27-G (0.41 mm) Whitacre spinal needle when
      performing spinal anaesthesia.

PMID- 15025612
TI  - Analgesia and discharge following preincisional ilioinguinal and iliohypogastric
      nerve block combined with general or spinal anaesthesia for inguinal
      herniorrhaphy.
AB  - BACKGROUND: Preincisional ilioinguinal and iliohypogastric nerve block (IINB)
      reduces postoperative analgesics after inguinal herniorrhaphy. The effect of an
      IINB on postoperative pain and discharge profile was therefore studied in day
      surgery patients undergoing inguinal herniorrhaphy with general or spinal
      anaesthesia. METHODS: Seventy ASA I-II adult patients scheduled for inguinal
      herniorrhaphy received an IINB before the surgical incision with 15 ml of 0.5%
      bupivacaine. In a randomized fashion half of them received general anaesthesia
      with spontaneous breathing via a laryngeal mask (GA-group) and the other half
      received spinal anaesthesia with 5 mg of bupivacaine diluted with sterile water
      to 2.5-ml volume (SPIN-group). In the postanaesthesia care unit (PACU), pain was
      assessed on a scale from 0 to 10 (VAS) and ketorolac 30 mg i.v. (VAS < 5), or
      fentanyl 0.05 mg i.v. (VAS > or = 5) was administered as scheduled. In the day
      surgery unit and at home the analgesic was a tablet of ibuprofen 200 mg + codeine
      30 mg (VAS > or = 3). RESULTS: Patients in the SPIN-group reported lower
      postoperative pain scores at 30, 60 min (P < 0.0001) and 120 min (P < 0.05) after
      surgery, and longer time to first analgesic use (P < 0.0001). Patients in the GA
      group had a shorter time to discharge without voiding (P < 0.001) and with
      voiding (P < 0.05). After discharge, there were no significant differences
      between the groups regarding pain scores at rest and at walking, or the doses of
      analgesic. Adverse events were rare in both groups. CONCLUSION: Only a relatively
      short immediate analgesic benefit could be demonstrated by a combination of IINB
      with spinal anaesthesia compared with IINB combined with general anaesthesia. The
      use of general anaesthesia facilitated an earlier postoperative discharge than
      spinal anaesthesia.

PMID- 15025613
TI  - Development and validation of a brief, descriptive Danish pain questionnaire
      (BDDPQ).
AB  - BACKGROUND: A new pain questionnaire should be simple, be documented to have
      discriminative function, and be related to previously used questionnaires.
      METHODS: Word meaning was validated by using bilingual Danish medical students
      and asking them to translate words taken from the Danish version of the McGill
      pain questionnaire into English. Evaluative word value was estimated using a
      visual analog scale (VAS). Discriminative function was assessed by having
      patients with one of six painful conditions (postherpetic neuralgia, phantom limb
      pain, rheumatoid arthritis, ankle fracture, appendicitis, or labor pain) complete
      the questionnaire. RESULTS: We were not able to find Danish words that were
      reliably back-translated to the English words 'splitting' or 'gnawing'. A simple
      three-word set of evaluative terms had good separation when rated on a VAS scale
      ('let' 17.5+/-6.5 mm; 'moderat' 42.7+/-8.6 mm; and 'staerk' 74.9+/-9.7 mm). The
      questionnaire was able to discriminate among the six painful conditions with 77%
      accuracy by just using the descriptive words. The accuracy of the questionnaire
      increased to 96% with the addition of evaluative terms (for pain at rest and with
      activity), chronicity (acute vs. chronic), and location of the pain. CONCLUSIONS:
      A Danish pain questionnaire that subjects and patients can self-administer has
      been developed and validated relative to the words used in the English McGill
      Pain questionnaire. The discriminative ability of the questionnaire among some
      common painful conditions has been tested and documented. The questionnaire may
      be of use in patient care and research.

PMID- 15025614
TI  - Improved application of Lidocaine/Prilocaine cream in children. A randomized and
      prospectively controlled study of two application regimes.
AB  - Intravenous cannulation in children aged 6-12 years is less painful after a 90
      min application of a Lidocaine/ Prilocaine cream followed by a 30-min interval
      without cream, than cannulation immediately after a 60-min application.
      BACKGROUND: Sixty-min application of an eutectic mixture of 25 mg g(-1) Lidocaine
      and 25 mg g(-1) Prilocaine cream is widely used in both adults and children to
      alleviate pain related to intravenous cannulation. However, studies have shown
      that this is not the optimal procedure in adults. Inspired by the results from
      these studies, the aim of the present study was to find an improved application
      regime for children. METHODS: In this prospective, randomized, and single-blind
      study 60 Caucasian children, aged 6-12 years, presenting for an i.v. cannulation
      were included. The children were allocated to either a 60-min application of
      anaesthetic cream followed by i.v. cannulation (Group A) or to a 90-min
      application followed by an interval of 30 min before cannulation (Group B). No
      sedatives or analgesics were given. The children scored their pain by a faces
      scale with four faces. RESULTS: The i.v. cannulations in Group B were less
      painful than the cannulations in Group A (Mann-Whitney test, P = 0.01). There was
      no difference between the two groups as regards problems when performing the
      cannulations. CONCLUSION: i.v. cannulation after application of anaesthetic cream
      for 90 min followed by a 30-min interval is less painful than the widely used 60
      min application directly followed by cannulation.

PMID- 15025615
TI  - The analgesic effect of intravenous ketamine and lidocaine on pain after spinal
      cord injury.
AB  - BACKGROUND: Pain following spinal cord injury (SCI) is a therapeutic challenge.
      Only a few treatments have been assessed in randomized, controlled trials. The
      primary objective of the present study was to examine the analgesic effect of
      ketamine and lidocaine in a group of patients with neuropathic pain below the
      level of spinal cord injury. We also wanted to assess sensory abnormalities to
      see if this could help us to identify responders and if treatments resulted in
      changes of sensibility. METHODS: Ten patients with spinal cord injury and
      neuropathic pain below the level of injury were included. The analgesic effect of
      ketamine 0.4 mg kg(-1) and lidocaine 2.5 mg kg(-1) was investigated. Saline was
      used as placebo. The drugs were infused over 40 min. A randomized, double-blind,
      three-period, three-treatment, cross-over design was used. Systemic plasma
      concentrations of ketamine and lidocaine were assessed. Pain rating was performed
      using a visual analogue scale (VAS). Sensory function was assessed with a
      combination of traditional sensory tests and quantitative measurement of
      temperature thresholds. RESULTS: Response to treatment, defined as 50% reduction
      in VAS-score during infusion, was recorded in 5/10 in the ketamine, 1/10 in the
      lidocaine and 0/10 in the placebo groups. Neither ketamine nor lidocaine changed
      temperature thresholds or assessments of mechanical; dynamic and static
      sensibility. Nor could these sensory assessments predict response to treatment in
      this setting. Lidocaine and particularly ketamine were associated with frequent
      side-effects. CONCLUSION: Ketamine but not lidocaine showed a significant
      analgesic effect in patients with neuropathic pain after spinal cord injury. The
      pain relief was not associated with altered temperature thresholds or other
      changes of sensory function.

PMID- 15025616
TI  - Painful neuropathy alters the effect of gabapentin on sensory neuron excitability
      in rats.
AB  - BACKGROUND: Pain following peripheral nerve injury is associated with increased
      excitability of sensory neurons. Gabapentin (GBP), a novel anticonvulsant with an
      uncertain mechanism of action, is an effective treatment for neuropathic pain. We
      therefore investigated the effect of GBP on dorsal root ganglion (DRG) neurons
      from normal rats and those with painful peripheral nerve injury. METHODS: Dorsal
      root ganglions were excised from rats with neuropathic pain behaviour following
      chronic constriction injury (CCI) of the sciatic nerve, and from normal rats.
      Intercellular recordings were made from myelinated sensory neuron somata using a
      microelectrode technique from DRGs bathed in artificial CSF with or without GBP
      (100 microM). RESULTS: Compared with normal neurons, injury decreased the
      refractory interval (RI) for repeat action potential (AP) generation increased
      the number of APs during sustained depolarization, and shortened the after
      hyperpolarization following an AP. In normal neurons, GBP decreased the RI and
      increased the AP number during sustained depolarization. In an opposite fashion,
      the result of GBP application to injured neurons was a decreased number of APs
      during depolarization and no change in RI. In injured neurons only, GBP increased
      the time-to-peak for AP depolarization. CONCLUSIONS: Nerve injury by CCI is
      associated with increased sensory neuron excitability, associated with a
      decreased AHP. In normal peripheral sensory neurons, GBP has pro-excitatory
      effects, whereas GBP decreases excitability in injured neurons, possibly on the
      basis of altered sodium channel function.

PMID- 15025617
TI  - Spinal anesthesia for arthroscopic knee surgery.
AB  - BACKGROUND AND OBJECTIVE: The purpose of the study was to compare the effects of
      adding 50 microg of morphine, 25 microg of fentanyl or saline to 6 mg of
      hyperbaric bupivacaine on postoperative analgesia and time to urination in
      patients undergoing arthroscopic knee surgery under spinal anesthesia. METHODS:
      The study was designed in a prospective, randomized, double-blinded and placebo
      controlled manner. Sixty ASA I-II patients were randomized into the following
      three groups: Group BM: 6 mg of bupivacaine and 50 microg of morphine, Group BF:
      6 mg of bupivacaine and 25 microg of fentanyl, and Group BS: 6 mg of bupivacaine
      and saline. Selective spinal anesthesia was performed in a lateral decubitus
      position, with the operative knee dependent for 10 min. RESULTS: In all groups
      satisfactory anesthesia was provided during the operation. There was a
      statistically significant difference between all the groups in times to voiding
      [Group BM 422 +/- 161 min; Group BF 244 +/- 163 min; Group BS 183 +/- 54 min
      (mean +/- SD)]. The incidence of pruritus was significantly greater in Group BM
      (80%) and BF (65%) in comparison with Group BS (no pruritus) (P < 0.05). The
      incidence of nausea was significantly increased in Group BM (35%) in comparison
      with Group BF (10%) and Group BS (P < 0.05). Analgesic consumption was
      significantly greater in Group BS in comparison with Groups BM and BF (P < 0.01).
      CONCLUSIONS: We conclude that during spinal anesthesia even mini-dose intrathecal
      morphine is not acceptable for outpatient surgery due to side-effects, especially
      severely prolonged time to urination.

PMID- 15025618
TI  - Anaesthetic considerations in Kartagener's syndrome -- a case report.
AB  - Kartagener's syndrome is a rare disorder characterized by the triad of situs
      inversus, including dextrocardia, bronchiectasis and paranasal sinusitis. We
      report the anaesthetic management of a patient with Kartagener's syndrome and
      postrenal transplant immunosuppression, presenting for repair of uterovaginal
      prolapse. Combined spinal epidural anaesthesia was administered to this patient.
      The anaesthetic considerations of this rare disorder and the relative advantages
      of the regional technique over general anaesthesia in this situation are
      discussed.

PMID- 15025619
TI  - Survival of acute hemorrhage and extreme dilutional anemia in the presence of
      high-graded aortic valve stenosis.

PMID- 15025622
TI  - Caution when using cuffed tracheal tubes for fibreoptic intubation through
      paediatric-sized laryngeal mask airways.

PMID- 15025620
TI  - Milrinone improves lung compliance.

PMID- 15025631
TI  - The influence of amphotericin B and neomycin on the effect of human relaxin-2 on
      foetal membranes and isolated myometrium.
AB  - In vitro studies have documented effects of relaxin on utero-placental tissues.
      Previously unpublished experiments indicate that neomycin and amphotericin B in
      vitro influences the effect of human relaxin-2 on the strength of human foetal
      membranes. The aim of the current study was to investigate the interaction
      between neomycin and amphotericin B and human relaxin-2 using human foetal
      membranes, human myometrium and rat myometrium. Chloramphenicol, erythromycin and
      penicillin were also examined. Human foetal membranes were stretched until
      rupture in a materials-testing machine while the contractility of rat and human
      myometrium were examined by myography. Human relaxin-2 (hrlx-2, 10(-9) M) induced
      a decreased strength in human foetal membranes, although this effect of hrlx-2
      was inhibited after co-incubation with neomycin and amphotericin B. Hrlx-2 (10(
      9) M) in combination with chloramphenicol induced a decreased strength of human
      foetal membranes. Hrlx-2 (10(-9) M) decreased myometrial contractility on
      amplitude and frequency in the rat myometrium, but had no effect on baseline
      tension. After exposure to amphotericin B, hrlx-2 induced a more pronounced
      decrease in amplitude, increased baseline tension and increased the frequency of
      contractions of the rat myometrium. Hrlx-2 (10(-9) M) had no effect on the human
      myometrium. However, after exposure to amphotericin B or neomycin+amphotericin B,
      hrlx-2 induced an increase in baseline tension and a decrease in amplitude.
      Amphotericin B and neomycin+amphotericin B increased the frequency of
      contractions and this effect was further enhanced by the addition of hrlx-2. We
      therefore conclude that amphotericin B and neomycin + amphotericin B may have an
      influence on relaxin's effect on isolated foetal membranes and myometrium.

PMID- 15025634
TI  - Can item response theory help us improve our tests?

PMID- 15025633
TI  - Can training and service survive the European Working Time Directive?

PMID- 15025635
TI  - Trainee to trained: helping senior psychiatric trainees make the transition to
      consultant.
AB  - PURPOSE: To describe the contents and results of a series of annual fora for
      senior psychiatric trainees in New Zealand. These fora were designed to address a
      perceived gap in the training of psychiatrists in non-clinical skills.
      PROCEDURES: The contents of the fora are described, and qualitative and
      quantitative feedback from participants is reported, These data were gathered
      from participants for the purposes of quality improvement, using questionnaires
      designed for this setting. Issues addressed included participants' self-ratings
      of gains in knowledge, as well as their ratings of tutor effectiveness, the forum
      overall and the extent to which their needs were met. Qualitative feedback
      included suggestions for improvements and identification of key learning gains.
      MAIN FINDINGS: There was an increase in understanding in all topic areas as
      assessed by the participants. In addition, participants made unanticipated gains
      in confidence and their sense of empowerment. The opportunity to meet with peers
      and the increased sense of collegiality were valued. Suggestions for improvements
      were incorporated into fora held in successive years. PRINCIPAL CONCLUSIONS: Non
      clinical skills can be taught successfully to senior trainees in a forum setting,
      which can also facilitate development of peer support and empowerment. More time
      for practice and discussion of how the teachers coped with challenging situations
      would improve the forum. It is recommended that such non-clinical skills also be
      incorporated into the teaching of senior trainees in the workplace.

PMID- 15025636
TI  - Experiences from psychiatric rotation for pre-registration house officers:
      contributions to subjective learning.
AB  - SETTING: The clinical experience and the subjective learning of pre-registration
      house officers who completed 4 months' psychiatric rotation are described.
      METHOD: The study was cross-sectional and based on self-report. The participants
      had responded to an anonymous questionnaire at the completion of their 4 months'
      psychiatric rotation in the period 1999-2001. Of those eligible (n = 137), 85
      (61%) completed the questionnaire. The relationships between individual
      background variables, different factors of the learning environment, and good
      learning outcome were explored. CONCLUSIONS: The subjective learning benefit and
      positive learning environment were most related to the amount of practical
      experience, the degree of tailoring of the tasks to the house officers'
      competence, and to the formal intramural teaching programme. Supervision, gender,
      previous experience, and prior interest in psychiatry did not have significant
      impact on subjective learning. The findings are discussed in terms of the
      learning model that was developed.

PMID- 15025637
TI  - Clinical skills in junior medical officers: a comparison of self-reported
      confidence and observed competence.
AB  - BACKGROUND: The intern year is a key time for the acquisition of clinical skills,
      both procedural and cognitive. We have previously described self-reported
      confidence and experience for a number of clinical skills, finding high levels of
      confidence among Australian junior doctors. This has never been correlated with
      an objective measure of competence. AIMS AND HYPOTHESIS: We aimed to determine
      the relationship between self-reported confidence and observed competence for a
      number of routine, procedural clinical skills. METHODS: A group of 30 junior
      medical officers in their first postgraduate year (PGY1) was studied. All
      subjects completed a questionnaire concerning their confidence and experience in
      the performance of clinical skills. A competency-based assessment instrument
      concerning 7 common, practical, clinical skills was developed, piloted and
      refined. All 30 PGY1s then completed an assessment using this instrument.
      Comparisons were then made between the PGY1s' self-reported levels of confidence
      and tutors' assessments of their competence. RESULTS: A broad range of competence
      levels was revealed by the clinical skills assessments. There was no correlation
      between the PGY1s' self-ratings of confidence and their measured competencies.
      CONCLUSIONS: Junior medical officers in PGY1 demonstrate a broad range of
      competence levels for several common, practical, clinical skills, with some
      performing at an inadequate level. There is no relationship between their self
      reported level of confidence and their formally assessed performance. This
      observation raises important caveats about the use of self-assessment in this
      group.

PMID- 15025638
TI  - Assessing student reflection in medical practice. The development of an observer
      rated instrument: reliability, validity and initial experiences.
AB  - INTRODUCTION: This study describes the development of an instrument to measure
      the ability of medical students to reflect on their performance in medical
      practice. METHODS: A total of 195 Year 4 medical students attending a 9-hour
      clinical ethics course filled in a semi-structured questionnaire consisting of
      reflection-evoking case vignettes. Two independent raters scored their answers.
      Respondents were scored on a 10-point scale for overall reflection score and on a
      scale of 0-2 for the extent to which they mentioned a series of perspectives in
      their reflections. We analysed the distribution of scores, the internal validity
      and the effect of being pre-tested with an alternate form of the test on the
      scores. The relationships between overall reflection score and perspective score,
      and between overall reflection score and gender, career preference and work
      experience were also calculated. RESULTS: The interrater reliability was
      sufficient. The range of scores on overall reflection was large (1-10), with a
      mean reflection score of 4.5-4.7 for each case vignette. This means that only 1
      or 2 perspectives were mentioned, and hardly any weighing of perspectives took
      place. The values over the 2 measurements were comparable and were strongly
      related. Women had slightly higher scores than men, as had students with work
      experience in health care, and students considering general practice as a career.
      CONCLUSIONS: Reflection in medical practice can be measured using this
      semistructured questionnaire built on case vignettes. The mean score allows for
      the measurement of improvement by future educational efforts. The wide range of
      individual differences allows for comparisons between groups. The differences
      found between groups of students were as expected and support the validity of the
      instrument.

PMID- 15025639
TI  - The interactive examination: assessing students' self-assessment ability.
AB  - BACKGROUND: The ability to self-assess one's competence is a crucial skill for
      all health professionals. The interactive examination is an assessment model
      aiming to evaluate not only students' clinical skills and competence, but also
      their ability to self-assess their proficiency. METHODS: The methodology utilised
      students' own self-assessment, an answer to a written essay question and a group
      discussion. Students' self-assessment was matched to the judgement of their
      instructors. As a final task, students compared their own essay to one written by
      an "expert". The differences pointed by students in their comparison documents
      and the accompanying arguments were analysed and categorised. Students received
      individual feedback on their performance and learning needs. The model was tested
      on 1 cohort of undergraduate dental students (year 2001, n = 52) in their third
      semester of studies, replacing an older form of examination in the discipline of
      clinical periodontology. RESULTS: Students' acceptance of the methodology was
      very positive. Students tended to overestimate their competence in relation to
      the judgement of their instructors in diagnostic skills, but not in skills
      relevant to treatment. No gender differences were observed, although females
      performed better than males in the examination. Three categories of differences
      were observed in the students' comparison documents. The accompanying arguments
      may reveal students' understanding and methods of prioritising. CONCLUSIONS:
      Students tended to overestimate their competence in diagnostic rather than
      treatment skills. The interactive examination appeared to be a convenient tool
      for providing deeper insight into students' ability to prioritise, self-assess
      and steer their own learning.

PMID- 15025640
TI  - Changes in student approaches to learning with the introduction of computer
      supported problem-based learning.
AB  - OBJECTIVES: To study changes in student approaches to learning following the
      introduction of computer-supported, problem-based learning. SETTING: Medical
      students at the University of Oslo undertake a 12-week period of clinical
      placement during their 10th term. In this period they continue to undertake
      problem-based learning (PBL) in the form of distributed problem-based learning
      (DPBL) in a computer-supported learning environment. DESIGN: A questionnaire
      focusing on learning styles, PBL, and information and communication technology
      (ICT) was distributed before and after the DPBL period. SUBJECTS: All students in
      their 10th term at the University of Oslo (n = 61). RESULTS: The introduction of
      DPBL did not seem to affect the participants' use of regulating strategies or
      their mental models of learning. After the DPBL period, group discussion and
      tutor input were reported to have less influence on students' self-study, while
      the students perceived themselves as being less active in groups and as expecting
      less from tutors. There was a relationship between perceived tutor influence and
      students' familiarity with ICT. The DPBL period seemed to increase students' task
      related web accesses and use of experts, and to decrease their task-related use
      of textbooks and discussions with students outside the group. CONCLUSIONS:
      Students' general approaches to learning were not affected by the introduction of
      DPBL. However, there was a decrease in students' expectations concerning activity
      in the group and the importance of the tutor. These changes were related to
      students' familiarity with the use of computers. Web-based resources and experts
      became more important resources to the students during the DPBL period.

PMID- 15025641
TI  - Good wine may need to mature: a critique of accelerated higher specialist
      training. Evidence from cognitive neuroscience.
AB  - CONTEXT: Higher specialist training in the UK is to be further shortened in the
      absence of any valid educational evidence for the wisdom of this move. Some
      practitioners/teachers are becoming increasingly concerned at this. THESIS AND
      DISCUSSION: Whereas the optimum length of time for such training is as yet
      undetermined, there is much in medical practice that resonates with the thinking
      of recent authors, who recommend slow incubation and facilitated reflection on
      experience, which steeps the learner in a hidden curriculum of practice, and
      entrains intuitive, "slow mode" thinking. This engagement necessarily takes time.
      The author has surveyed some of the recent literature on problem solving,
      cognitive neuroscience, artificial intelligence and learning for practice, and
      discusses his conclusions. These are unsettling. CONCLUSION: Further truncation
      of the length of higher specialist training must be supported by robust
      educational evidence that supports this reduction. The author advises caution.

PMID- 15025642
TI  - Social and behavioural science education in UK medical schools: current practice
      and future directions.
AB  - INTRODUCTION: The increasing importance accorded the social and behavioural
      sciences in medical education presents opportunities for developing new and
      innovative forms of teaching and learning in this field. Yet social and
      behavioural scientists often feel isolated and marginalized. This research was
      designed to build a network of such practitioners to share and compare current
      practice, and to develop better models and resources. METHODS: Questionnaire
      survey and workshop discussions describe current practice among social and
      behavioural scientists in UK medical education, and identify current and future
      issues. RESULTS: Most UK medical curricula feature a significant social and
      behavioural science component, often in multidisciplinary contexts. Questions of
      core content, and how this relates to desired learning outcomes, particularly in
      the attitudinal sphere, remain unresolved. Identity problems result from
      differing perspectives of medics and social and behavioural scientists, staffing
      constraints, assessment regimes, and relationships with external examiners.
      DISCUSSION: This project identified barriers and opportunities for providing
      adequate training in the social and behavioural sciences in medical schools. Some
      of the barriers are common to higher education generally. Through our network, a
      database of core cases and assessments can be developed that would be available
      to all for teaching purposes. CONCLUSION: Social and behavioural scientists
      involved in medical education show commonality and difference in the extent and
      scope of their input. While they have made great progress, there remains much to
      achieve.

PMID- 15025643
TI  - Teaching anatomy without cadavers.
AB  - BACKGROUND: Anatomy learning is generally seen as essential to medicine, and
      exposure to cadavers is generally seen as essential to anatomy learning around
      the world. Few voices dissenting from these propositions can be identified. AIMS:
      This paper aims to consider arguments relating to the use of cadavers in anatomy
      teaching, and to describe the rationale behind the decision of a new UK medical
      school not to use cadaveric material. DISCUSSION: First, the background to use of
      cadavers in anatomy learning is explored, and some general educational principles
      are explored. Next, arguments for the use of human cadaveric material are
      summarised. Then, possible arguments against use of cadavers, including
      educational principles as well as costs, hazards and practicality, are
      considered. These are much less well explored in the existing literature. Next,
      the rationale behind the decision of a new UK medical school not to use cadaveric
      material is indicated, and the programme of anatomy teaching to be employed in
      the absence of the use of human remains is described. Curriculum design and
      development, and evaluation procedures, are briefly described. Issues surrounding
      pathology training by autopsy, and postgraduate training in surgical anatomy, are
      not addressed in this paper. FUTURE DIRECTIONS: Evidence relating to the effect
      on medical learning by students not exposed to cadavers is scant, and plainly
      opportunities will now arise through our programme to gather such evidence. We
      anticipate that this discussion paper will contribute to an ongoing debate, in
      which virtually all previous papers on this topic have concluded that use of
      cadavers is essential to medical learning.

PMID- 15025644
TI  - An empirical study of the predictive validity of number grades in medical school
      using 3 decades of longitudinal data: implications for a grading system.
AB  - Context It is important to establish the predictive validity of medical school
      grades. The strength of predictive validity and the ability to identify at-risk
      students in medical schools depends upon assessment systems such as number
      grades, pass/fail (P/F) or honours/pass/fail (H/P/F) systems. Objective This
      study was designed to examine the predictive validity of number grades in medical
      school, and to determine whether any important information is lost in a shift
      from number to P/F and H/P/F grading systems. Subjects The participants in this
      prospective, longitudinal study were 6656 medical students who studied at
      Jefferson Medical College over 3 decades. They were grouped into 10 deciles based
      on their number grades in Year 1 of medical school. Methods Participants were
      compared on academic accomplishments in Years 2 and 3 of medical school, medical
      school class rank, delayed graduation and attrition, performance on medical
      licensing examinations and clinical competence ratings in the first postgraduate
      year. Results Results supported the short- and longterm predictive validity of
      the number grades. Ratings of clinical competence beyond medical school were
      predicted by number grades in medical school. We demonstrated that small
      differences in number grades are statistically meaningful, and that important
      information for identifying students in need of remedial education is lost when
      students who narrowly meet faculty's expectations are included with the rest of
      the class in a broad 'pass' category. Conclusions The findings refute the
      argument that knowledge of sciences basic to medicine is not critical to
      subsequent performance in medical school and beyond if an appropriate evaluation
      system is used. Furthermore, the results of this study raise questions about
      abandoning number grades in favour of a pass/fail system. Consideration of these
      findings in policy decisions regarding assessment systems of medical students is
      recommended.

PMID- 15025645
TI  - The impact of evidence-based education on a perinatal capacity-building
      initiative in Macedonia.
AB  - CONTEXT: The perinatal mortality rate (PMR) in Macedonia is among the highest in
      Europe. The World Bank supported a consultant (HEJ) to collaborate with a
      Macedonian team to develop a national perinatal strategy with the goal of
      reducing the PMR. Education was given priority in the form of a hospital-based
      initiative to develop the capacity of health professionals to introduce evidence
      based perinatal practice into 16 participating hospitals. A "train the teachers"
      approach was used, with trainees introduced to modern education and clinical
      practice in Sydney and subsequently supported to train their colleagues in
      Skopje. OBJECTIVES: To describe the development, implementation and evaluation of
      the educational intervention. METHODS: A curriculum, based on specific Macedonian
      needs, was developed in order to integrate teaching in the knowledge, skills and
      attitudinal domains of learning, using small group, interactive techniques.
      Twenty-five Macedonian doctors and nurses participated in 4-month (phase 1a) and
      6-month (phase 1b) teaching programmes at a tertiary perinatal unit in Sydney.
      Australian staff conducted 4 2-week modules for 36 trainees in Macedonia (phase
      2). The phase 1 trainees conducted 8 modules for 57 colleagues in Skopje (phase
      3). The intervention was evaluated by trainee questionnaires, assessments of
      competence, changes in hospital practice and pre- (1997-99) and post-intervention
      (2000-01) comparisons of PMR. RESULTS: A total of 115 doctors and nurses
      graduated from the programme. Positive responses to the education programme
      exceeded 80%. Evidence-based practice in 16 participating hospitals (covering 91%
      of all Macedonian births) was verified in 6 key areas of neonatology. The PMR
      fell significantly from 27.4 to 21.5 per 1000 births (RR 0.79, 95% CI 0.73,
      0.85). The early neonatal death rate in babies weighing over 1000 g fell by 36%.
      CONCLUSIONS: The intervention has increased the capacity of Macedonians to
      practise best-evidence perinatal medicine and improve outcomes. Sustainability is
      predicted by the "train the teachers" approach, with concurrent strengthening of
      the infrastructure and organisational framework.

PMID- 15025646
TI  - Contextual tensions of the clinical environment and their influence on teaching
      and learning.
AB  - BACKGROUND: Academic medical centres face major challenges, and finding creative,
      effective strategies to support patient care and teaching are critical for
      survival. At the centre of these challenges is clinical teaching. AIM: To
      characterise how context influences clinical teaching. METHODS: Multiple embedded
      case-study design analysed 3 internal medicine in-patient teams. Direct
      observations, interviews and documents were data sources. Triangulated data,
      audit trails and member checks enhanced trustworthiness. RESULTS: Three tensions
      influenced clinical teaching: 1, patient census; 2, time sensitivity of the
      context; and 3, the multiple and conflicting commitments of participants. Patient
      census exhibited the greatest influence and was the catalyst for teaching,
      learning, and the allocation of total time. Time functioned as an important
      element influencing the pace of action, reflective and interpretative cognitive
      processes of the team, time available for action, and the general fatigue of the
      team. Conflicts among the multiple roles of ward team members disrupted
      individual and team teaching and learning. CONCLUSION: Clinical teaching is an
      open system influenced by multiple forces. Learning, teaching and patient care
      were very closely coupled, and learning knowledge and using knowledge were parts
      of the same process within the clinical context.

PMID- 15025647
TI  - A junior doctor's dismay at a full shift system.

PMID- 15025648
TI  - Simulated patient versus clinician marking of doctors' performance: which is more
      accurate?

PMID- 15025649
TI  - The scientific standard of Journal of Oral Rehabilitation.

PMID- 15025650
TI  - Oral kinesiology. A new postgraduate programme in the Netherlands.
AB  - As one of the dental differentiations in The Netherlands, temporomandibular
      disorders (TMD) focuses on the diagnosis and treatment of pain and dysfunction of
      the masticatory system. Bruxism (i.e. tooth clenching and/or grinding) is thought
      to play an important aetiological role in TMD. Among others, bruxism may result
      in TMD pain and dental attrition. The close relationship between TMD, bruxism,
      and attrition necessitates an integrated approach to these clinical problems.
      This could be achieved through the multidisciplinary differentiation 'oral
      kinesiology', that covers not only the diagnosis and treatment of TMD and bruxism
      but also the restoration of worn dentitions. This article focuses on the
      background of oral kinesiology, as well as on the rationale to develop a
      curriculum for the postgraduate training of dentist-kinesiologists in the
      Netherlands. Further, the oral kinesiology curriculum of the Academic Centre for
      Dentistry Amsterdam will be introduced. This curriculum will ensure that
      specialized professionals, who are able to approach the different aspects of oral
      kinesiology in an integrated manner, are available not only for general dental
      practice but also for centres for special dental care and university departments.
      This will lead to improved care for patients, whose management is until now
      dispersed between various dental specialists.

PMID- 15025651
TI  - The role of oral sensorimotor function in masticatory ability.
AB  - In order to investigate the relationship between oral sensorimotor ability and
      masticatory function, an oral stereognosis ability (OSA) test, masticatory
      performance and efficiency was employed for 15 dentate subjects. Subjects were
      instructed to orally identify OSA test pieces blindly. The response score and sum
      of the duration time for identification were used for analysis as OSA score and
      OSA response time. Masticatory function was evaluated using a sieving method with
      3 g of peanuts. Masticatory performance was calculated with the weight percentage
      of portions finer than 1700 microm by the total volume after 20 chewing strokes.
      Masticatory efficiency was calculated by the declination rate of median particle
      size which is defined by the Rosin-Rammler equation. To analyse the relationship
      between OSA variables and masticatory ability, the correlation coefficient was
      calculated. The results summarized as a significant correlation was found only
      between OSA score and masticatory efficiency. However, a significant correlation
      could not be found between other OAS variables and masticatory ability. It was
      revealed that positive correlation existed between oral stereognosis ability and
      masticatory ability. It was suggested that the role of oral sensorimotor function
      might affect the masticatory function.

PMID- 15025652
TI  - The development of a new index for measurement of incisal/occlusal tooth wear.
AB  - A number of indices have been developed for the measurement of tooth surface loss
      but they have not achieved universal acceptance. The aim of this study was to
      develop a new index suitable for the monitoring of incisal/occlusal tooth wear on
      serial study models. The new index recorded incisal/cuspal wear for individual
      teeth. Each tooth was scored on a six-point scale ranging from 0-5. Six assessors
      evaluated the index and it was applied to baseline and sequential models taken
      after 20 years. The study demonstrated the value of maintaining long-term dental
      records in the form of study models for monitoring progressive tooth wear.

PMID- 15025653
TI  - Comparison of deep bite and open bite cases: normative data for condylar
      positions, paths and radiographic appearances.
AB  - To compare normal overbite, deep bite and open bite cases with clinically healthy
      temporomandibular joints (TMJ) regarding the difference between condylar
      positions in centric relation (CR) and habitual or centric occlusion (CO),
      condylar paths and radiographic findings of condylar appearance in order to
      establish normative data. Three study groups of normal overbite, deep bite and
      open bite cases consisted each of 30 subjects with no detectable clinical signs
      of temporomandibular disorder. The CR-CO differences and axiographic tracings
      were recorded using the School Artikulator of Mack (SAM) diagnostic system.
      Condylar shape was evaluated on panoramic radiographs. The CR-CO differences were
      greater in the vertical plane in open bite cases, and direction of movements from
      CR to CO showed great variability. Open bite cases had significantly shorter
      condylar paths. Radiographic findings exhibited that 23% of the total sample
      showed evidence of erosion and 83% evidence of flattening of condyles. The
      erosion rates were higher in the open bite group, but flattening was seen more
      often in the deep bite group. Results of this study showed that open bite cases
      show larger vertical CR-CO slides and, shorter protrusion paths than normal and
      deep overbite cases. The radiographic appearance of condyles in non-patients may
      also differ significantly according to vertical incisor guidance type. Deep bite
      cases demonstrated a higher incidence of condylar flattening. This study
      indicates that the clinician should be paying special attention to the TMJ status
      of open bite patients.

PMID- 15025654
TI  - Effects of occlusal load on cervical lesions.
AB  - Toothbrush abrasion has been considered to cause cervical lesions. However, some
      investigators have proposed that occlusal loading factors direct tensile stresses
      at the cervical area, resulting in wedge-shaped abfraction defects. The purpose
      of this study is to investigate the role of axial and non-axial load on the
      development of cervical lesions. Matched paired premolars, extracted for
      orthodontic purposes, were used in a custom-fabricated toothbrushing apparatus. A
      periodontal sulcus width of 0b1 mm with 1 mm gingival recession was simulated
      with denture base resin. In phase 1, eight matched premolar pairs were subjected
      to 80 h (1b4 million strokes) of brushing and 300 g of toothbrush force.
      Toothpaste slurry was applied continuously through the toothbrush. One specimen
      in each pair was subjected to 250 h and 45 kg of continuous axial load, while the
      other unloaded tooth served as a negative control. In phase 2, 10 matched
      premolar pairs were subjected to the same conditions; however, the experimental
      teeth were subjected to 250 h and 45 kg of intermittent non-axial load, directed
      at a 45 degrees angle to the buccal cusp. Rubber impressions were made of the
      cervical lesions, then trimmed, weighed, and compared to determine the amount of
      tooth material lost. When teeth were loaded axially, there was significantly less
      tooth material loss (P < 0b02); however, when teeth were loaded non-axially,
      there was no significant difference (P =0b80) when compared with controls.
      Optical and scanning electron microscopy did not reveal any significant
      differences in the morphology between pairs. Our data suggest that the
      application of occlusal load may not necessarily play a significant role in the
      progression of cervical tooth wear commonly referred to as abfraction.

PMID- 15025655
TI  - Finite element analysis of four thread-form configurations in a stepped screw
      implant.
AB  - The purpose of this study was to determine the optimal thread form configuration
      for an experimental stepped screw implant. Two-dimensional finite element
      analysis was applied to model the experimental stepped screw implant in a
      standard cross-section of the posterior human mandible digitized from a CT
      generated patient data set. Four different thread form configurations: v-thread
      (V), thin-thread (T), and two square-thread forms of 0.24 mm (S1) and 0.36 mm
      (S2) thread width were compared under oblique load in normal cortical bone
      condition. The support-type constraint position changed from middle to the base
      of the bone segment. In middle support-type constraint position only the thin
      thread (T) model demonstrated significantly different stress distribution from
      the other three models, however, in base support-type constraint position T and
      S1 models demonstrated significantly different stress distribution from the other
      two models. The results implies that v-thread (V) or large square-thread (S2) are
      optimal thread form for the experimental stepped screw implant. While, minimal
      support constraints allow clearer differentiation of the stress picture between
      the different stepped screw types at the trabecular bone-implant interface.

PMID- 15025656
TI  - Effects of calcium hydroxide paste medication on coronal leakage.
AB  - The purpose of this in vitro study was to examine the coronal leakage of canals
      medicated with Ca(OH)(2) compared with the canals which did not receive Ca(OH)(2)
      medication before obturation with laterally condensed gutta-percha points and
      sealer. Sixty-one single rooted permanent canines and premolars were used. The
      crowns were removed from the cemento-enamel junction. After the canals were
      chemomechanically prepared, the roots were divided into three experimental groups
      as group 1, 2 and 3. The canals in group 1 and 2 were treated with
      ethylenediaminetetraacetic acid (EDTA) and NaOCl in order to remove the smear
      layer and then the canals were filled with Ca(OH)(2) paste. The coronal 3 mm of
      the cavities were sealed with Cavit and the samples were kept in an incubator at
      37 degrees C for 7 days. No intra-canal medication was applied in group 3. The
      root canals were irrigated with NaOCl in group 1 and with EDTA and NaOCl in group
      2, in order to remove Ca(OH)(2) before obturation. Two samples from group 1 and
      two from group 2 were examined under SEM in order to reveal the removal of
      Ca(OH)(2) paste. Following this, the canals in the experimental groups were
      obturated with gutta-percha and sealer. The roots were placed in India ink for 7
      days and the linear dye penetration was evaluated. No significant statistical
      difference was found in the amount of coronal dye leakage between experimental
      groups (P > 0.05). The results of the present study indicated that the
      application of Ca(OH)(2) as a temporary dressing material had no effect on
      coronal leakage.

PMID- 15025657
TI  - Clinical evaluation of ferric oxalate in relieving dentine hypersensitivity.
AB  - Previous in vitro permeability and scanning electron microscopic (SEM) studies
      have demonstrated the effectiveness of the oxalate ion in dentine permeability
      reduction and effective tubule occlusion. The aim of this randomized double
      blind, split mouth 4-week clinical study, therefore was to determine whether a 1
      min application of ferric oxalate (Sensodyne Sealant) on exposed root dentine was
      effective in reducing dentine hypersensitivity (DH). Thirteen subjects [8F:5M,
      mean age 46.2 (s.d. 4.15) years] completed the study. The subjective response was
      evaluated by tactile, thermal and evaporative methods of assessment. Data were
      collected at baseline and post-application at +5 min and 4 weeks. Analysis was
      based on paired t-test (P=0.05) and Wilcoxon-Mann-Whitney tests. No statistically
      significant differences were noted between ferric oxalate and placebo
      preparations at +5 min and 4 weeks for any of the test stimuli. There was,
      however, a clear trend towards immediate reduction (+5 min) in DH reverting back
      to baseline values at 4 weeks with the exception of the Biomat Thermal Probe mean
      values, which maintained the reductions in DH compared with placebo. The results
      of the present study demonstrated that a 1-min application of ferric oxalate is
      both rapid and effective in reducing DH although its long-term effectiveness
      still needs to be determined.

PMID- 15025658
TI  - Clinical performance of a resin-modified glass-ionomer and two polyacid-modified
      resin composites in cervical lesions restorations: 1-year follow-up.
AB  - The aim of this study was to assess the clinical performance of a resin-modified
      glass-ionomer cement (Vitremer) and two polyacid-modified resin composites (F2000
      and Freedom) over 1 year. Nineteen patients with at least three cervical lesions
      were selected, providing an initial sample size of 87 restorations (29 per
      material), being 78 to non-carious and nine to carious lesions. Restorations were
      evaluated at baseline, 6 months and 1 year after placement, using modified US
      Public Health Service criteria: colour match, marginal discoloration, caries,
      anatomical form, marginal integrity and surface texture. At baseline,
      restorations were considered as acceptable for all criteria. At 1-year recall, 21
      restorations per material were re-examined. Freedom was rated Bravo or Charlie
      for all the examined criteria and Vitremer earned an Alfa rating solely for the
      criterion caries. On the contrary, F2000 showed the best overall results,
      although presenting significant alteration in colour match. Statistical analysis
      of data was performed using chi-square and Mc Nemar tests. As to the evaluated
      periods, significant difference was observed solely between baseline and 1-year
      recall. Freedom and Vitremer were statistically different (P < 0.01) as to
      anatomical form and surface texture. For F2000, significant difference (P < 0.05)
      was noticed as to colour match and anatomical form. After 1-year follow-up, F2000
      showed the most acceptable results as to the analysed criteria.

PMID- 15025659
TI  - Effects of various light curing methods on the leachability of uncured substances
      and hardness of a composite resin.
AB  - The purpose of this study was to evaluate the effect of the various light curing
      units (plasma arc, halogen and light-emitting diodes) and irradiation methods
      (one-step, two-step and pulse) using different light energy densities on the
      leachability of unreacted monomers (Bis-GMA and UDMA) and the surface hardness of
      a composite resin (Z250, 3M). Leachability of the specimens immersed for 7 days
      in ethanol was analysed by HPLC. Vicker's hardness number (VHN) was measured
      immediately after curing (IC) and after immersion in ethanol for 7 days. Various
      irradiation methods with three curing units resulted in differences in the amount
      of leached monomers and VHN of IC when light energy density was lower than 17.0 J
      cm(-2) (P = 0.05). However, regardless of curing units and irradiation methods,
      these results were not different when the time or light energy density increased.
      When similar light energy density was irradiated (15.6-17.7 J cm(-2)), the
      efficiency of irradiation methods was different by the following order: one-step
      > or = two-step > pulse. These results suggest that the amount of leached
      monomers and VHN were influenced by forming polymer structure in activation and
      initiation stages of polymerization process with different light source energies
      and curing times.

PMID- 15025660
TI  - A microleakage study of ceramic laminate veneers by autoradiography: effect of
      incisal edge preparation.
AB  - The purpose of this study was to evaluate the microleakage characteristics of
      laminate veneers with different incisal edge preparation. Two groups of 20
      extracted human maxillary central incisors were used for fabricating laminate
      veneers. The cervical margin of all veneers were placed 1 mm above the
      cementoenamel junction. The incisal finish line of 20 teeth was placed at the
      incisal edge (window type preparation). The incisal finish line of the other 20
      teeth was placed linguoincisally (incisal edge overlapped type preparation). All
      veneers were fabricated according to the manufacturer's instructions with vacuum
      fired porcelain and cemented with dual-cure resin cement. The autoradiographic
      method was used for determination of microleakages. Microleakages at the
      interface of the laminate veneer and tooth were determined according to the scale
      described in the manuscript. Mc Nemar test was used for comparison of
      microleakages at cervical margins. Microleakage grades at other areas were
      compared in percentage. In the two preparation types the cervical microleakages
      were of similar degree. The incisal microleakages in the overlapped laminate
      veneers were greater than in the window type veneers. In conclusion, the window
      preparation type was more effective in terms of prevention of microleakage at the
      incisal margin than the overlapped type laminates.

PMID- 15025663
TI  - The concept of quality of life: what we know and do not know.
AB  - BACKGROUND: Over the past two decades the concept of quality of life (QOL) has
      increasingly become a focus for research and application in the fields of
      education/special education, health care (physical and behavioural), social
      services (disabilities and ageing), and families. METHODS: This article
      summarizes our current understanding of the construct of individual QOL as it
      pertains to persons with intellectual disabilities (ID). The article's three
      major sections discuss what we know, what we are beginning to understand, and
      what we still do not know about the QOL construct. RESULTS: We currently know the
      importance of the QOL construct as a service delivery principle, along with its
      current use and multidimensional nature. We are beginning to understand the
      importance of methodological pluralism in the assessment of QOL, the multiple
      uses of quality indicators, the predictors of assessed QOL, the effects of
      different data collection strategies, and the etic (universal) and emic (culture
      bound) properties of the construct. We have yet to understand fully the use of
      QOL-related outcomes in programme change, how to best evaluate the outcomes of
      QOL-related services, and how to use the concept of QOL to impact public and
      disability reform. CONCLUSION: The article concludes with a brief discussion of
      future challenges related to demonstrating the concept's social validity and
      positive impact on the lives of persons with ID.

PMID- 15025662
TI  - Adherence of Streptococcus mutans to various restorative materials in a
      continuous flow system.
AB  - A continuous flow system was developed to evaluate the adhesion of Streptococcus
      mutans ATCC 25175 to filling materials (Ariston, Tetric, Dyract, Compoglass,
      Vitremer, Aqua Ionofil, Ketac Fil, amalgam, Galloy and ceramics as controls).
      Streptococcus mutans was added to saliva-coated test specimens, and a nutrient
      broth permanently supplied over a time period of 48 h and then the weight of
      plaque, the number and viability of the bacteria adhering to the materials were
      determined. The weights of artificial plaque on all filling materials tested were
      higher than those on ceramics, the highest values were measured on the glass
      ionomers. The amount of plaque correlates with the surface roughness, whereas
      there was no correlation of the surface roughness with the number of colony
      forming units (CFU) of S. mutans. The CFU of adhering S. mutans also depends on
      the viability of the bacteria. The plaque on Ketac Fil contained a high number of
      viable bacteria. The fluorides of glass-ionomers do not efficiently prevent the
      attachment and the viability of S. mutans.

PMID- 15025661
TI  - Parameters affecting retentive force of conus crowns.
AB  - The aim of this study was to determine the values of the retentive forces of the
      telescopic crowns. At the first step of the study, the samples having different
      heights and angles were compared in relation to retentive force. At the second
      step, the samples were subjected to removal procedures having a pre-determined
      speed, force and number. The obtained retention values were compared. Ninety dies
      were prepared in order to measure the retention of the conus crowns. The removal
      tests were performed with the insertion/separation device. The speed of the test
      device was 100 cm min(-1) providing the placement of the pieces with 5 kgf in
      100, 200, 300, 500, 1000, 5000 and 10 000 cycles. The mean of the retention
      values of the changes of the angles were found to be statistically different (P <
      0.01). According to the results of the variant analysis, the differences in the
      changes of the height were statistically significant (P < 0.01). The differences
      between the changes of the number of procedures of all groups were statistically
      significant (P < 0.01). The number of procedures, height and angle interactions
      were statistically insignificant (P = 0.758). According to the results of this
      study, the effect of the angle and height factors in terms of retention among the
      groups were not independent of each other. In equal angles, as the height
      increased, increased retention measurements were obtained. In more acute angles,
      the increase in retention was more obvious. It was also found that an accessory
      device was necessary to maintain retention capabilities after a long-term use.

PMID- 15025664
TI  - Are caregivers' reports of motivation valid? Reliability and validity of the
      Reiss Profile MR/DD.
AB  - BACKGROUND: Sensitivity theory proposes that there are wide individual
      differences in what motivates people with intellectual disability. The Reiss
      Profile MR/DD is a rating scale that measures 15 fundamental motives. This study
      examined the internal consistency and interrater reliability of the 15 subscales
      as well as the validity of motivational profiles. METHOD: The study consisted of
      two distinct but related steps. First, the interrater reliability of the rating
      scale was established by having pairs of raters evaluate 48 individuals. Second,
      raters were presented with three different motivational profiles and asked to
      identify which one corresponded to the individual they had rated 4 weeks earlier.
      RESULTS: Results indicated good internal consistency (average alpha=0.84),
      significant variability in the interrater reliability (average intraclass
      correlation coefficient=0.52), and excellent validity (95% of the correct
      profiles were chosen). Average discrepancies between pairs of raters are
      presented. CONCLUSIONS: Interrater reliability is an important topic for
      professionals working in the field of intellectual disability and results are
      discussed in terms of the factors that affect it. This is the first published
      study to report on the interrater reliability of the Reiss Profile MR/DD.

PMID- 15025665
TI  - Predictors of parent-child language during novel task play: a comparison between
      typically developing children and individuals with Down syndrome.
AB  - Three questions were asked that explored the linguistic fine-tuning hypothesis
      and how parents might model language: (i) do parents significantly tune to their
      children's productive language or non-verbal cognition during play? (ii) is the
      level of the linguistic tuning different in the Down syndrome (DS) population
      compared to a typically developing (TD)-match group population? and (iii) do the
      two populations differ in requests for labels and the scaffolding responses to
      the requests? In an exploratory play condition, parents of children with DS used
      a mean length of utterance (MLU) significantly higher than the MLU used by the
      parents of younger TD children who were matched for MLU. Thus, the DS parents
      have a higher baseline MLU, but the non-significant correlations in the DS group
      do not support parental MLU tuning. There was evidence, however, for parental
      tuning to the children's lexicon using a number of different words when the DS
      children were at lower and average levels of receptive syntax and non-verbal
      cognition. In addition, DS and TD parents requested labels for novel toys with
      the same frequency, perhaps indicating that all groups of parents are still
      probing and building their children's lexicons. This is an important finding
      because it may help to explain why adolescents and young adults with DS have
      vocabulary comprehension skills greater than one would predict from measures of
      their production and non-verbal cognition.

PMID- 15025666
TI  - Smoking prevalence and knowledge of associated risks in adult attenders at day
      centres for people with learning disabilities.
AB  - BACKGROUND: Increased longevity among people with learning disabilities is
      accompanied by an increase in morbidity. A possible explanation is that living in
      the community and a move to greater independence may bring higher health risks
      through obesity and smoking. The study aimed to see if rates of smoking have
      increased from earlier published rates and to ascertain the awareness of the
      risks of smoking among people with learning disabilities. METHODS: A total of 435
      people attending four social services day centres in a large urban area were
      assisted to complete a questionnaire. RESULTS: Twenty-seven (6.2%) reported that
      they currently smoked. Those with mild disabilities were much more likely to
      smoke than those with more severe disabilities and they also reported smoking
      more heavily. For those with mild levels of learning disability, a higher than
      expected proportion living in hospital and staffed housing smoked, a lower
      proportion living with parents smoked but for those living independently the
      proportion who smoked was no higher than expected. Smokers were more
      knowledgeable about the risks than non-smokers even if the level of learning
      disability was controlled for. Only a third of smokers were concerned about the
      risks. CONCLUSIONS: The study provides no evidence that rates of smoking are
      increasing among people with learning disabilities nor that those living
      independently were more likely to smoke. Knowledge of health risks is poor across
      the group, but higher among the smokers who were unlikely to express concern
      about the risks. This may indicate that more support may be needed along with
      health education in this group.

PMID- 15025667
TI  - Effectiveness of immediate verbal feedback on trainer behaviour during
      communication training with individuals with intellectual disability.
AB  - The effect of immediate verbal feedback on trainer behaviour during communication
      training sessions with individuals with intellectual disability (ID) was
      assessed. Trainers were six undergraduate university students majoring in
      psychology. The procedure consisted of interrupting the sequence of trials of
      training by the supervisor and then giving brief corrective feedback. Feedback
      was focused on the accuracy of the following procedural aspects: (1) entry
      behaviour; (2) prompt level and order of presenting response prompts; (3) use of
      reinforcement; (4) pace of presenting trials; and (5) if this occurred, handling
      trainee's disruptive behaviour during training. Data were collected in a
      nonconcurrent multiple baseline design. Results indicated a statistically
      significant increase of the percentage correct trainer behaviour as compared to
      the baseline phase. Maintenance of effect of feedback was recorded during post
      training and follow-up.

PMID- 15025668
TI  - An exploratory study into health care policy for persons with intellectual
      disabilities in Taiwan.
AB  - BACKGROUND: Although Taiwan has already had a higher quality of health care
      compared with other countries, there still is a need to review the quality and
      effectiveness of services provided. The lack of health care policy for persons
      with disabilities is a reflection of health care provision in Taiwan. Health care
      provision problems will limit persons with disabilities in their access to the
      health care system. The purpose of the present study was to examine the general
      beliefs about the current health care policies for persons with intellectual
      disabilities (ID) in Taiwan. METHODS: Data were obtained from two sources, namely
      government policies analysis and interviews with representatives for key
      stakeholders in the field of ID. RESULTS: The results illustrate that health care
      service problems for persons with ID include: how to enforce the discovery system
      and early intervention service, disability evaluation system, National Health
      Insurance medical payment and medical care resource development are still
      confining their quality of care. Furthermore, the links between social welfare,
      education and health care have been lost because the different roles and
      perspectives of people in these fields are fundamentally at odds with one
      another. Health care professionals have become less reform-minded as a
      consequence of the conditions of their work. Consequently, a complete and
      coordinated health care policy for persons with ID has become unattainable in
      society. The present paper draws on evidence from research and policies to
      explore the problems and potential of service development for persons with ID,
      and to identify review and action points for managing its implementation.

PMID- 15025669
TI  - Autism and intellectual disability: a study of prevalence on a sample of the
      Italian population.
AB  - BACKGROUND: In 1994, the American Association on Mental Retardation with the DSM
      IV has come to a final definition of pervasive developmental disorders (PDD), in
      agreement with the ICD-10. Prevalence of PDD in the general population is 0.1
      0.15% according to the DSM-IV. PDD are more frequent in people with severe
      intellectual disability (ID). There is a strict relationship between ID and
      autism: 40% of people with ID also present a PDD, on the other hand, nearly 70%
      of people with PDD also have ID. We believe that in Italy PDD are underestimated
      because there is no agreement about the classification system and diagnostic
      instruments. METHOD: Our aim is to assess the prevalence of PDD in the Italian
      population with ID. The Scale of Pervasive Developmental Disorder in Mentally
      Retarded Persons (PDD-MRS) seems to be a very good instrument for classifying and
      diagnosing PDD. RESULTS: The application of the PDD-MRS and a clinical review of
      every individual case on a sample of 166 Italian people with ID raised the
      prevalence of PDD in this population from 7.8% to 39.2%. CONCLUSIONS: The study
      confirms the relationship between ID and autism and suggests a new approach in
      the study of ID in order to elaborate a new integrated model for people with ID.

PMID- 15025670
TI  - Burnout in direct care staff in intellectual disability services: a factor
      analytic study of the Maslach Burnout Inventory.
AB  - BACKGROUND: There is gathering research interest in the well-being of staff
      working in services for people with intellectual disability (ID), including the
      assessment of burnout and its correlates. However, no previous studies have
      considered the applicability of the main three dimensions of burnout to staff in
      ID services. METHODS: Data were analysed from two samples of staff (total n=184)
      who participated in research studies that included completion of the Maslach
      Burnout Inventory (MBI). RESULTS: Nineteen of the MBI items loaded clearly onto
      factors closely resembling the three original subscales: emotional exhaustion,
      depersonalization and personal accomplishment. Internal consistency for the three
      MBI subscales was fair to good (range 0.68-0.87). CONCLUSIONS: The original three
      MBI dimensions were found to be highly relevant to the present sample of staff.
      The analyses support the construct validity and reliability of the MBI for staff
      in ID services.

PMID- 15025671
TI  - Urinary compounds in autism.
AB  - BACKGROUND: Although earlier claims to identify specific compounds in the urine
      of people with autism had been discredited, it was subsequently suggested that
      there might be biochemical characteristics that were specific to early childhood,
      particularly in those who also did not have a severe degree of intellectual
      disability This study was to establish whether autism might have a distinctive
      chromatographic profile on urinary analysis. METHOD: Thirty-four prepubertal boys
      with autism were matched with two groups of boys without autism--one on ability
      and chronological age and the other on chronological age alone, being within the
      normal range of ability. Laboratory analysis of their urine samples was carried
      out blind as to the clinical diagnosis. RESULTS: The analysis correctly
      identified 53% of the autism group as against misidentifying 33% and 18% of the
      other two groups. When children with a severe learning disability (both with and
      without autism) were excluded from the comparisons, the laboratory then
      identified 77% of the 13 boys left in the autism group and misidentified 8% and
      18% of the other two groups. CONCLUSIONS: The results would support the idea of a
      biological marker in prepubertal children and that it may be absent in, or
      obscured by the presence of severe LD.

PMID- 15025673
TI  - Heart and ocular anomalies in children with Down's syndrome.

PMID- 15025674
TI  - Glutathione depletion and cardiomyocyte apoptosis in viral myocarditis.
AB  - BACKGROUND: The course of viral myocarditis is highly variable. Oxidative stress
      and Bcl-2 family genes may play a role in its pathogenesis by regulating the
      amount of cardiomyocyte apoptosis. Apoptosis is difficult to detect and quantify
      in vivo. Therefore, we set to look for indicators of this potentially preventable
      form of cell death during various phases of experimental murine coxsackievirus B3
      myocarditis. METHODS: BALB/c mice were infected with the cardiotropic
      coxsackievirus B3 variant. Glutathione (HPLC), cardiomyocyte apoptosis (TUNEL and
      caspase-3 cleavage), Bax and Bcl-X(L) mRNA expression (real time RT-PCR),
      histopathology and viral replication (plaque assay and real time RT-PCR) were
      measured from day 3 to day 20 after infection. RESULTS: Infection caused severe
      myocarditis and led to progressive decrease of plasma glutathione levels.
      Myocardial mRNA levels of pro-apoptotic Bax and antiapoptotic Bcl-X(L) were
      significantly increased from day 3 onwards. Bax mRNA and ratio of Bax to Bcl-X(L)
      correlated with cardiomyocyte apoptosis (r = 0.77, P = < 0.001 and r 0.51, P <
      0.01, respectively). Cardiomyocyte apoptosis was highest on day 5, coinciding
      with a rapid decline in plasma glutathione (r = -0.52, P = 0.003). CONCLUSIONS:
      Systemic oxidative stress as indicated by decreased plasma glutathione levels
      coincides with cardiomyocyte apoptosis in experimental coxsackievirus
      myocarditis. Decreased plasma glutathione levels and changes in cardiac Bax and
      Bcl-X(L) mRNA expression identify a phase of myocarditis in which the potentially
      preventable cardiomyocyte apoptosis is mostly observed.

PMID- 15025675
TI  - Fatty acid metabolism assessed by 125I-iodophenyl 9-methylpentadecanoic acid
      (9MPA) and expression of fatty acid utilization enzymes in volume-overloaded
      hearts.
AB  - BACKGROUND: The peroxisome proliferator-activated receptor (PPAR) alpha is a
      member of the nuclear receptor superfamily and regulates gene expression of fatty
      acid utilization enzymes. In cardiac hypertrophy and heart failure by pressure
      overload, myocardial energy utilization reverts to the fetal pattern, and
      metabolic substrate switches from fatty acid to glucose. However, myocardial
      metabolism in volume-overloaded hearts has not been rigorously studied. The aim
      of the present study was to examine fatty acid metabolism and protein expressions
      of PPARalpha and fatty acid oxidation enzymes in volume-overloaded rabbit hearts.
      METHODS: Volume-overload was induced by carotid-jugular shunt formation. Sham
      operated rabbits were used as control. Chronic volume-overload increased left
      ventricular weight and ventricular cavity size, and relative wall thickness was
      decreased, indicating eccentric cardiac hypertrophy. (125)I-iodophenyl 9
      methylpentadecanoic acid (9MPA) was intravenously administered, and animals were
      sacrificed at 5 min after injection. The 9MPA was rapidly metabolized to
      iodophenyl-3-methylnonanoic acid (3MNA) by beta-oxidation. Lipid extraction from
      the myocardium was performed by the Folch method, and radioactivity distribution
      of metabolites was assayed by thin-layer chromatography. The protein was
      extracted from the left ventricular myocardium, and levels of PPARalpha and fatty
      acid oxidation enzymes were examined by Western blotting. RESULTS: Myocardial
      distribution of 9MPA tended to be more heterogeneous in shunt than in sham
      rabbits (P = 0.06). In volume-overloaded hearts by shunt, the conversion from
      9MPA to 3MNA by beta-oxidation was faster than the sham-control hearts (P <
      0.05). However, protein levels of PPARalpha and fatty acid utilization enzymes
      were unchanged in shunt rabbits compared with sham rabbits. CONCLUSIONS: These
      data suggest that myocardial fatty acid metabolism is enhanced in eccentric
      cardiac hypertrophy by volume-overload without changes in protein expressions of
      PPARalpha and fatty acid utilization enzymes. Our data may provide a novel
      insight into the subcellular mechanisms for the pathological process of cardiac
      remodelling in response to mechanical stimuli.

PMID- 15025676
TI  - Intracellular lipid accumulation, low-density lipoprotein receptor-related
      protein expression, and cell survival in vascular smooth muscle cells derived
      from normal and atherosclerotic human coronaries.
AB  - BACKGROUND: Vascular smooth muscle cell (VSMC) regulation during atherosclerotic
      plaque progression is determinant for plaque stability. AIMS: To study lipid
      accumulation, low-density lipoprotein receptor-related protein (LRP) expression,
      and cell survival in VSMCs isolated from nonatherosclerotic areas (normal VSMCs)
      and advanced atherosclerotic plaques (plaque-VSMCs) of human coronaries. DESIGN:
      Normal or plaque-VSMCs were obtained from the intima by modification of the
      explant technique. RESULTS: Aggregated low-density lipoprotein (agLDL) (100 micro
      g mL(-1)) internalization induced higher intracellular cholesteryl ester (CE)
      accumulation in plaque-VSMC compared with normal VSMCs (89.28 +/- 6.1 vs. 60.34
      +/- 4.1 micro g CE mg(-1) of protein; P < 0.05). This internalization was
      associated with LRP expression, as plaque-VSMCs show higher levels of LRP mRNA
      (6.06 +/- 0.55 vs. 3.87 +/- 0.28; P < 0.05) and LRP protein expression than
      normal VSMCs. However, plaque-VSMCs showed a lower proliferative response than
      normal VSMCs (6536 +/- 636 vs. 11151 +/- 815 c.p.m. [(3)H]thymidine; P < 0.05)
      and did not respond to platelet-derived growth factor BB (PDGF-BB) stimulus. In
      agreement, the Bcl(2)/BAX ratio was significantly lower in plaque-VSMCs compared
      with normal VSMCs (0.14 +/- 0.05 vs. 0.51 +/- 0.07; P < 0.05) and it was
      independent of lipid loading. CONCLUSIONS: These results indicate that higher
      intracellular lipid deposition in plaque-VSMCs is related to higher LRP
      expression levels. However, LRP-mediated agLDL internalization is not directly
      related to the reduced survival of plaque-VSMCs.

PMID- 15025677
TI  - Changes in blood carnitine and acylcarnitine profiles of very long-chain acyl-CoA
      dehydrogenase-deficient mice subjected to stress.
AB  - BACKGROUND: In humans with deficiency of the very long-chain acyl-CoA
      dehydrogenase (VLCAD), C14-C18 acylcarnitines accumulate. In this paper we have
      used the VLCAD knockout mouse as a model to study changes in blood carnitine and
      acylcarnitine profiles under stress. DESIGN: VLCAD knockout mice exhibit stress
      induced hypoglycaemia and skeletal myopathy; symptoms resembling human VLCADD. To
      study the extent of biochemical derangement in response to different stressors,
      we determined blood carnitine and acylcarnitine profiles after exercise on a
      treadmill, fasting, or exposure to cold. RESULTS: Even in a nonstressed, well-fed
      state, knockout mice presented twofold higher C14-C18 acylcarnitines and a lower
      free carnitine of 72% as compared to wild-type littermates. After 1 h of intense
      exercise, the C14-C18 acylcarnitines in blood significantly increased, but free
      carnitine remained unchanged. After 8 h of fasting at 4 degrees C, the long-chain
      acylcarnitines were elevated 5-fold in knockout mice in comparison with
      concentrations in unstressed wild-type mice (P < 0.05), and four out of 12
      knockout mice died. Free carnitine decreased to 44% as compared with unstressed
      wild-type mice. An increase in C14-C18 acylcarnitines and a decrease of free
      carnitine were also observed in fasted heterozygous and wild-type mice.
      CONCLUSIONS: Long-chain acylcarnitines in blood increase in knockout mice in
      response to different stressors and concentrations correlate with the clinical
      condition. A decrease in blood free carnitine in response to severe stress is
      observed in knockout mice but also in wild-type littermates. Monitoring blood
      acylcarnitine profiles in response to different stressors may allow systematic
      analysis of therapeutic interventions in VLCAD knockout mice.

PMID- 15025678
TI  - Correlates of total homocysteine plasma concentration in type 2 diabetes.
AB  - BACKGROUND: Although well-defined in the general population, correlates of total
      homocysteine (tHcy) plasma concentration have not been sufficiently evaluated in
      diabetes. We investigated factors potentially associated with tHcy concentration
      in a cohort of type 2 diabetic subjects. MATERIALS AND METHODS: The common
      methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism, fasting tHcy,
      vitamin B12 and folate plasma levels were assessed in 312 diabetic subjects,
      whose clinical, metabolic and lifestyle information was also available. RESULTS:
      The MTHFR genotype distribution was comparable to the Hardy-Weinberg equilibrium,
      with an overall TT homozygous frequency of 22%. Fasting tHcy concentration was
      significantly higher in men than in women (P < 0.001). Multivariate-adjusted tHcy
      concentration was significantly different across the quartiles of age (P <
      0.001), folate (P = 0.01), vitamin B12 (P = 0.03), creatinine concentrations (P =
      0.001) and smoking (P = 0.02). Overall, significant trends were noted for
      creatinine clearance (P for trend = 0.02) and systolic blood pressure (BP)
      (unadjusted P for trend = 0.01), whereas no differences were noted according to
      BMI, diastolic BP, presence of hypertension, and diabetes-related variables, such
      as diabetes duration, fasting glucose and glycated haemoglobin concentrations,
      current treatment and diabetes long-term complications. Total homocysteine levels
      significantly correlated with age, systolic BP, vitamin B12, creatinine and
      creatinine clearance, but only age, creatinine, folate and vitamin B12 levels
      were independently associated with tHcy concentration in stepwise regression
      analysis. CONCLUSIONS: Age, creatinine, folate, vitamin B12, and to a minor
      extent, sex, smoking, TT genotype and systolic BP were significantly associated
      with Hcy plasma concentration in type 2 diabetes, whereas no significant
      associations were noted with diabetes-related variables.

PMID- 15025679
TI  - Improved metabolic control decreases platelet activation markers in patients with
      type-2 diabetes.
AB  - BACKGROUND: Cardiovascular disease is associated with platelet dysfunction in
      patients with diabetes. Hyperglycaemia is known as an independent risk factor for
      micro- and macrovascular complications, and improvement of metabolic control has
      shown beneficial effects on diabetic late complications. Our study attempts to
      clarify the effect of improved metabolic control on platelet activation markers
      in patients with type-2 diabetes. MATERIALS AND METHODS: Thirty patients were
      studied at baseline and 3 months after improvement of metabolic control and
      compared with an age-matched nondiabetic control group. Platelet activation
      markers (CD31, CD36, CD49b, CD62P and CD63) were assessed by flow cytometry
      analysis. RESULTS: Significantly more activated platelets were detected in
      patients with diabetes compared with controls. After 3 months' improvement of
      metabolic control, a significant decline of all platelet activation markers
      except CD36 was noted. Furthermore a significant correlation between CD62P, CD63
      and HbA(1c) levels was observed. CONCLUSIONS: We conclude therefore that
      improvement of metabolic control has a beneficial effect on platelet activation.
      This may have an implication in the pathogenesis of vascular disease in patients
      with type-2 diabetes.

PMID- 15025680
TI  - Use of an artificial neural network to predict Graves' disease outcome within 2
      years of drug withdrawal.
AB  - BACKGROUND: Graves' disease (GD) is an autoimmune disorder characterized by
      hyperthyroidism, which can relapse in many patients after antithyroid drug
      treatment withdrawal. Several studies have been performed to predict the clinical
      course of GD in patients treated with antithyroid drugs, without conclusive
      results. The aim of this study was to define a set of easily achievable variables
      able to predict, as early as possible, the clinical outcome of GD after
      antithyroid therapy. METHODS: We studied 71 patients with GD treated with
      methimazole for 18 months: 27 of them achieved stable remission for at least 2
      years after methimazole therapy withdrawal, whereas 44 patients relapsed. We used
      for the first time a perceptron-like artificial neural network (ANN) approach to
      predict remission or relapse after methimazole withdrawal. Twenty-seven variables
      obtained at diagnosis or during treatment were considered. RESULTS: Among
      different combinations, we identified an optimal set of seven variables available
      at the time of diagnosis, whose combination was useful to efficiently predict the
      outcome of the disease following therapy withdrawal in approximately 80% of
      cases. This set consists of the following variables: heart rate, presence of
      thyroid bruits, psycological symptoms requiring psychotropic drugs, serum TGAb
      and fT4 levels at presentation, thyroid-ultrasonography findings and cigarette
      smoking. CONCLUSIONS: This study reveals that perceptron-like ANN is potentially
      a useful approach for GD-management in choosing the most appropriate therapy
      schedule at the time of diagnosis.

PMID- 15025681
TI  - Bradycardia and sinus arrest during percutaneous ethanol injection therapy for
      hepatocellular carcinoma.
AB  - BACKGROUND: Percutaneous ethanol injection (PEI) is an established method in the
      treatment of hepatocellular carcinoma (HCC) and considered a safe procedure, with
      severe complications occurring rarely. Cardiac arrhythmias have not been reported
      to date. Aim of the study was to investigate the occurrence of dysrhythmias
      during PEI. PATIENTS AND METHODS: Twenty-six consecutive patients with inoperable
      HCC were included. During ultrasound-guided PEI with 95% ethanol,
      electrocardiogram (ECG) monitoring was performed before starting and continuously
      during PEI. RESULTS: During PEI a significant reduction in mean heart rate (>
      20%) was seen in 15 of 26 (58%) patients. In 11 of 26 patients (42%) occurrence
      of sinuatrial block (SAB) or atrioventricular block (AVB) was observed after a
      median time of 9 s (range 4-50) from the start of PEI with a median length of 24
      s (range 12-480). Clinical symptoms were seen in two patients, including episodes
      of unconsciousness, seizure-like symptoms in both and a respiratory arrest during
      PEI in one patient, requiring mechanical ventilation. In four of 12 patients with
      repeat interventions, dysrhythmias were reproducible during monthly performed
      procedures. There was a significant association between the occurrence of SAB or
      AVB and the amount of instilled alcohol (P = 0.03) and post-PEI serum ethanol
      levels (P = 0.03). CONCLUSIONS: Bradycardia and block formation occur frequently
      during PEI. These symptoms could be explained by a vasovagal reaction and/or the
      direct effect of ethanol on the sinus node or the right atrial conduction system.
      Ethanol dose is an important factor for the occurrence of SAB/AVB. ECG-monitoring
      seems mandatory during PEI. Prophylactic use of intravenously administered
      Atropine might be useful.

PMID- 15025682
TI  - Gender, age and seasonal effects on IgA deficiency: a study of 7293 Caucasians.
AB  - BACKGROUND: The frequency of serum IgA deficiency (SIgAD) differs between
      populations. We examined the prevalence of SIgAD in healthy Caucasians. MATERIALS
      AND METHODS: Serum immunoglobulin A (SIgA) was measured in 7293 volunteers (2264
      women, 5029 men) aged 30 +/- 14.2 years (mean +/- SD; range: 12-66). Serum
      immunoglobulin A and subnormal SIgA levels were defined by a SIgA level < 0.07 g
      L(-1), and between 0.07 and 0.7 g L(-1), respectively. Means were compared by
      analysis of variance (anova) and analysis of covariance (ancova); frequencies by
      the chi(2) test. RESULTS: Fifteen subjects (0.21%; one woman, 14 men) had SIgAD.
      Subnormal SIgA levels were found in 155 persons (2.13%): 21 females (0.93% of the
      females) and 134 males (2.66% of the males; difference: 1.74%; 95% CI: 1.12
      2.33%; P < 0.001). Males were more likely to have subnormal SIgA levels or SIgAD
      (odds ratio 3.09, 95% CI: 1.97-4.85). The prevalence of SIgAD and subnormal SIgA
      was lowest in winter (chi(2) = 14.8; P = 0.002; 3 d.f.; and chi(2) = 43.2; P <
      0.001; 3 d.f., respectively). Serum immunoglobulin A concentrations were
      significantly higher during winter. Serum immunoglobulin A levels increased with
      age on average by 0.2 +/- 0.06 g L(-1) per decade of life (P < 0.001). Taking
      into account the influence of age, SIgA concentration was lower in females as
      compared with males. CONCLUSION: The prevalence of SIgAD and subnormal SIgA
      levels is increased in males. There exists a significant influence of gender, age
      and seasons on SIgA levels.

PMID- 15025683
TI  - Association between human-Pneumocystis infection and small-cell lung carcinoma.
AB  - BACKGROUND: Tobacco smoking is the most important but not the only risk factor in
      lung carcinoma. There is evidence that certain infections, which cause chronic
      inflammatory reactions, can also induce tumour development. It has recently been
      shown that patients with chronic pulmonary diseases present a high rate of
      subclinical Pneumocystis infection, and that the latter is able to induce
      inflammatory responses and alveolar cell alterations. The possible role of
      Pneumocystis infection in the development of lung neoplasms thus deserves
      consideration. MATERIAL AND METHODS: Polymerase chain reaction has been used to
      analyze the presence of DNA of two independent loci of the Pneumocystis genome:
      the mitochondrial region (mtLSU rRNA) and the gene encoding for the
      dihydropteroate synthase enzyme, in paraffin-embedded tissue blocks of 10 cases
      of small cell lung carcinoma (SCLC) and 10 cases of nonsmall cell lung carcinoma
      (NSCLC) with similar demographic and clinical characteristics. Five cases without
      lung pathology, and two cases of Pneumocystis pneumonia were also analyzed as
      controls. RESULTS: DNA of the microorganism was found in all the cases of SCLC
      but in only two of the NSCLC, and in none of the controls without pulmonary
      disease - thus implying a statistically significant association (P < 0.0001)
      between subclinical Pneumocystis infection and SCLC. CONCLUSIONS: While the
      nature of this association is not clear, it nevertheless constitutes an important
      finding - either the infection is specifically facilitated by this tumour or
      induces the development of this type of neoplasm in combination with other
      factors. Eur J Clin Invest 2004; 34 (3): 229-335

PMID- 15025684
TI  - Fabry disease defined: baseline clinical manifestations of 366 patients in the
      Fabry Outcome Survey.
AB  - BACKGROUND: Fabry disease is a rare X-linked disorder caused by deficient
      activity of the lysosomal enzyme alpha-galactosidase A. Progressive accumulation
      of the substrate globotriaosylceramide in cells throughout the body leads to
      major organ failure and premature death. In response to the recent introduction
      of enzyme replacement therapy, the Fabry Outcome Survey (FOS) was established to
      pool data from European clinics on the natural history of this little-known
      disease and to monitor the long-term efficacy and safety of treatment. This paper
      presents the first analysis of the FOS database and provides essential baseline
      data against which the effects of enzyme replacement can be measured. DESIGN:
      Baseline data from a cohort of 366 patients from 11 European countries were
      analysed in terms of demography and clinical manifestations of Fabry disease.
      RESULTS: Misdiagnosis of Fabry disease is common, and the mean delay from onset
      of symptoms to correct diagnosis was 13.7 and 16.3 years in males and females,
      respectively. Although previously thought to have serious manifestations only in
      hemizygous men, the FOS database has confirmed that females heterozygous for
      Fabry disease are similarly affected. Furthermore, signs and symptoms of Fabry
      disease may be present from early childhood. CONCLUSIONS: With the advent of
      enzyme replacement therapy, it is important that general practitioners and
      physicians in a range of specialties recognize the signs and symptoms of Fabry
      disease so that effective treatment can be given. Baseline data from FOS
      demonstrate that enzyme replacement therapy should not be restricted to
      hemizygous men, but should be considered for both heterozygous females and
      children.

PMID- 15025685
TI  - Adjunctive chromosomal abnormalities in Philadelphia-negative cells of CML
      patients treated with Imatinib.

PMID- 15025686
TI  - Long-term effects of intensified lifestyle modification on cardiovascular
      complications after successful coronary angioplasty.

PMID- 15025687
TI  - Prevalence of traumatic injuries to the permanent incisors in candidates for
      orthodontic treatment.
AB  - The dental records made on presentation of 1367 consecutive patients (731 females
      and 636 males) for orthodontic treatment at a private orthodontic practice
      between 1998 and 2002 were examined for data relating to trauma to the permanent
      incisors. The results showed that 10.3% of these patients had suffered from
      dental trauma before the onset of orthodontic treatment. The highest prevalence
      of dental trauma was determined in the 11-15 years age group, corresponding to
      the dental developmental stage of the late mixed dentition. The most frequently
      affected teeth were the maxillary central incisors (79.6%), and the most common
      types of trauma were fracture of enamel-dentin without pulpal involvement (42.7%)
      and fracture of enamel (33.8%). Compared to patients with normal overjet and
      adequate lip coverage, the frequency of dental trauma was significantly higher in
      patients with increased overjet and adequate lip coverage (P = 0.028) or with
      increased overjet and inadequate lip coverage (P = 0.003). The results of the
      present study indicate that a significant percentage of candidates for
      orthodontic treatment, and especially those with increased overjet and inadequate
      lip coverage, suffer trauma to their permanent incisors before the onset of
      orthodontic treatment. It might also be concluded that preventive orthodontic
      treatment of such patients should be initiated and completed before the age of
      11, i.e. in the early to middle mixed dentition.

PMID- 15025688
TI  - The association between incisor trauma and occlusal characteristics in
      individuals 8-50 years of age.
AB  - To explore the association between incisal trauma and occlusal characteristics
      using oral examination and health interview data from the Third National Health
      and Nutrition Examination Survey 1988-1994 (NHANES III). Incisal trauma
      examinations were performed on 15 364 individuals 6-50 years of age using an
      ordinal scale developed by the National Institute of Dental and Craniofacial
      Research. Occlusal examinations were performed on 13 057 individuals 8-50 years
      of age. We fitted separate multivariate logistic regression models for maxillary
      and mandibular incisor trauma adjusting for socio-demographic variables (age,
      gender, race-ethnicity) and occlusal characteristics (overbite, overjet, open
      bite). 23.45% of all individuals evidenced trauma on at least one incisor, with
      trauma more than four times more prevalent on maxillary (22.59%) than on
      mandibular incisors (4.78%). Males (OR = 1.67) had greater odds of trauma than
      females; Whites (OR = 1.37) and non-Hispanic Blacks (OR = 1.37) had greater odds
      of trauma than Mexican-Americans. The odds of trauma increased with age, peaked
      from age 21 to 30 (OR = 2.92), and declined. As overjet increased, so did the
      odds of trauma. Compared to individuals with < or =0-mm overjet, odds of trauma
      increased from 1-3 mm (OR = 1.42) to 4-6 mm (OR = 2.42) to 7-8 mm (OR = 3.24) to
      >8 mm (OR = 12.47). Trauma to incisors is prevalent but mostly limited to enamel.
      Trauma to maxillary incisors is associated with overjet, gender, race-ethnicity,
      and age, while trauma to mandibular incisors is associated with gender, age, and
      overbite.

PMID- 15025689
TI  - Pulp revascularization of replanted immature dog teeth after treatment with
      minocycline and doxycycline assessed by laser Doppler flowmetry, radiography, and
      histology.
AB  - This study investigated the effect of topical antibiotic treatment on pulp
      revascularization in replanted teeth. Thirty-four immature teeth were selected
      from three young dogs. Baseline radiographs and laser Doppler flowmetry (LDF)
      readings were obtained. Specimens were randomly divided into four groups: Thirty
      eight teeth were extracted, kept dry for 5 min, and either (Group 1) covered with
      minocycline mixture (G1, n = 11), (Group 2) soaked in doxycycline (G2, n = 11),
      or (Group 3) soaked in saline (G3-negative control, n = 6), and replanted. Teeth
      in Group 4 were not extracted (positive control, n = 6). Postoperative
      radiographs and LDF readings were obtained for 2 months after replantation. After
      sacrifice, the jaws were collected and processed for light microscopy. Pre- and
      postreplantation LDF readings and radiographs, and histologic findings were
      analyzed to assess revascularization. Pulp revascularization occurred in 91%
      (G1), 73% (G2), and 33% (G3) of the specimens. In conclusion, minocycline
      facilitates pulp revascularization in replanted immature teeth after
      replantation.

PMID- 15025690
TI  - A quantitative analysis of Propolis: a promising new storage media following
      avulsion.
AB  - Both length of extra-alveolar time and type of storage media are significant
      factors that can affect the long-term prognosis of replanted teeth. Numerous
      studies have examined various media in an attempt to determine the ideal material
      for storage of the avulsed tooth. The purpose of this study was to use a
      Collagenase-Dispase assay to investigate the potential of a new storage media,
      Propolis, in maintaining viable periodontal ligament (PDL) cells on simulated
      avulsed teeth. Seventy freshly extracted human teeth were divided into five
      experimental groups and two control groups. The positive and negative controls
      corresponded to 0-min and an 8-h dry time, respectively. The experimental teeth
      were stored dry for 30 min and then immersed in one of the five media (Hank's
      balanced salt solution (HBSS), milk, saline, Propolis 50%, and Propolis 100% for
      45 min). The teeth were then treated with dispase grade II and collagenase for 30
      min. The number of viable PDL cells were counted with a hemocytometer and
      analyzed. Statistical analysis demonstrated that both Propolis groups kept
      significantly more PDL cells viable compared to either milk, saline, or HBSS.
      Within the parameters of this study, it appears that Propolis may be a better
      alternative to HBSS, milk, or saline in terms of maintaining PDL cell viability
      after avulsion and storage.

PMID- 15025692
TI  - Tooth replantation after traumatic avulsion: a 27-year follow up.
AB  - This report presents a case of replantation of a traumatically avulsed central
      incisor in a 32-year-old woman. The tooth was replanted after a 30-min extra
      alveolar period. Emergency unconventional immobilization was performed, using 2-0
      chromic gut, and a restorative composite made Gunning-type splint. The tooth is
      still in place 27 years after replantation (1976 to date) without marked
      resorption.

PMID- 15025691
TI  - Stress-strain response in human dentine: rethinking fracture predilection in
      postcore restored teeth.
AB  - In this study, the biomechanical perspective of fracture predilection in post
      core restored teeth is investigated using computational, experimental, and
      fractographic analyses. The computational finite element analysis and the
      experimental tensile testing are used to evaluate the stress-strain response in
      structural dentine. The fractographic evaluations are conducted using laser
      scanning confocal microscopy and scanning electron microscopy to examine the
      topography of dentine from experimentally fractured specimens, and clinically
      fractured post-core restored teeth specimens. These experiments aided in
      correlating the stress-strain response in structural dentine with cracks and
      catastrophic fractures in post-core restored teeth. It was observed from these
      experiments that the inner dentine displayed distinctly high strains
      (deformations), while the outer dentine demonstrated high stresses during tensile
      loading. This implies that the energy fed into the material as it is extended
      will be spread throughout the inner dentine, and there is less possibility of
      local increase in stress at the outer dentine, which can lead to the failure of
      dentine structure. During post-endodontic restoration with increase in loss of
      inner dentine, the fracture resistance factor contributed by the inner dentine is
      compromised, and this in turn predisposes the tooth to catastrophic fracture.

PMID- 15025693
TI  - Chronic osteomyelitis: 20 years after mandible fracture.
AB  - Chronic osteomyelitis is a persistent abscess of the bone that is characterized
      by the usual complex of inflammatory processes, including necrosis of mineralized
      and marrow tissues, suppuration, resorption, sclerosis, and hyperplasia. The
      purpose of this paper is to report a case of chronic osteomyelitis seen 20 years
      after mandible fracture.

PMID- 15025694
TI  - Aspects of pulp capping of teeth in dogs.

PMID- 15025696
TI  - Return-to-work barriers for workers with contact dermatitis.
AB  - There is little information available regarding barriers to return-to-work (RTW)
      in workers with contact dermatitis. The purpose of this study was to survey
      occupational health and safety personnel to determine their perceptions regarding
      RTW barriers for workers with contact dermatitis. The study was conducted during
      an occupational health and safety research conference attended by stakeholders
      from labour, management, injured workers, government, safety associations,
      occupational health and safety practitioners and researchers. The attendees were
      presented with 3 pictures of varying degrees of work-related hand contact
      dermatitis and were asked to list the 3 key barriers or challenges in RTW for
      individuals with contact dermatitis. 21 individuals completed the survey. Issues
      identified in descending order of frequency were concern of ongoing dermatitis,
      ability to do the job safely, appearance, ability to accommodate, personal
      protective equipment, fear that the rash was contagious, workplace attitudes and
      pain. While some of these issues are potentially common to RTW situations in
      general, others are more specific to health problems which have a visible
      manifestation. Increased awareness of and attention to these possible barriers to
      RTW may lead to better RTW outcomes.

PMID- 15025698
TI  - Occupational allergic contact dermatitis from bisphenol A in vinyl gloves.
AB  - Allergic contact dermatitis caused by polyvinyl chloride gloves is rarely
      reported, and in only 2 cases was bisphenol A considered to be the responsible
      sensitizer. We report a patient with occupational hand dermatitis after the use
      of a new type of high-density vinyl (HDV) gloves. Patch tests showed positive
      (++) reactions to both used and new HDV gloves and to bisphenol A. Chemical
      analysis by gas chromatography-mass spectrometry demonstrated the presence of
      bisphenol A in the HDV gloves. Replacement by nitrile rubber gloves resulted in
      complete clearance of the hand dermatitis.

PMID- 15025697
TI  - Delayed-type hypersensitivity skin reactions due to heparins and heparinoids.
      Tolerance of recombinant hirudins and of the new synthetic anticoagulant
      fondaparinux.
AB  - Eczema-like, infiltrated plaques at subcutaneous heparin-injection sites are well
      documented side effects of these anticoagulants. They are due to delayed-type
      hypersensitivity. In 4 patients, patch, intradermal and subcutaneous tests were
      performed with a panel of unfractionated heparins (UFHs), low-molecular-weight
      heparins (LMWHs), heparinoids, recombinant hirudins and a new synthetic
      pentasaccharide anticoagulant fondaparinux sodium, to find safe alternatives. 3
      patients were sensitized to all the UFHs and LMWHs. The LMWH tinzaparin sodium
      and the heparinoid pentosan polysulfate were found to be a possible substitute in
      patient no. 1 and 2, respectively. The recombinant hirudins and fondaparinux
      sodium were tolerated without any side effects in all patients tested.
      Fondaparinux is a synthetic copy of a pentasaccharide sequence in the heparin
      molecule. It is the first in a new class of antithrombotic agents. Our study
      suggests that it is a new safe alternative in patients with eczema-like,
      infiltrated plaques at subcutaneous heparin-injection sites.

PMID- 15025699
TI  - Marking patch tests sites: description of a practical, clean, durable and
      inexpensive method.
AB  - We propose an original method to mark patch test sites. A transparency is applied
      on the patient's back, surrounding patch tests, immediately after their
      application. Marks are performed with an erasable pen on test sites and on
      permanent skin lesions like naevi. For further readings performed after patch
      test removal, the transparency applied on the patient's back permits the
      attribution of a positive reaction. This method is clean (without ink marks on
      skin and without contamination of clothing), more comfortable for the patient
      (allowing back washing immediately after the 1st reading, never inducing allergy
      to inks), durable (permitting delayed readings after several days or weeks) and
      inexpensive (because transparencies can be reused).

PMID- 15025701
TI  - Fixed drug eruption from sodium benzoate.
AB  - We report a fixed drug eruption caused by a syrup containing sodium benzoate. Our
      patient gave a positive reaction to a patch test and to a provocation test after
      15 h ingestion, but no patch test reaction in the interdigital area where the
      patient had previous lesions.

PMID- 15025700
TI  - Patch testing with fine fragrances: comparison with fragrance mix, balsam of Peru
      and a fragrance series.
AB  - High frequencies of contact allergy to fragrance ingredients have been reported
      in recent years. Only approximately 70-80% are detected by fragrance allergens in
      the standard patch test series. This investigation compares the patch test
      reactions to fine fragrances with reactions to fragrance mix (FM), balsam of Peru
      (BP) (Myroxylon pereirae resin) and a fragrance series. 641 consecutive patients
      with eczema were patch tested with the European standard series and with selected
      fine fragrances. Those who were positive to 1 of the fine fragrances or the FM or
      BP were also tested with the fragrance series. 95 (14.8%) patients were found to
      have a positive patch test reaction to FM or BP; 41 (6.4%) had positive results
      to fragrance no. 1 and 29 (4.5%) to no. 2. 9 (9.5% of the 95 positive patients)
      had a positive reaction to fine fragrances and a negative reaction to all other
      fragrance allergens in the standard series. These findings indicate that testing
      with fine fragrances can add to our evaluation of fragrance-sensitive patients.

PMID- 15025702
TI  - Responsive corneosurfametry following in vivo skin preconditioning.
AB  - Skin is subjected to many environmental threats, some of which altering the
      structure and function of the stratum corneum. Among them, surfactants are
      recognized factors that may influence irritant contact dermatitis. The present
      study was conducted to compare the variations in skin capacitance and
      corneosurfametry (CSM) reactivity before and after skin exposure to repeated
      subclinical injuries by 2 hand dishwashing liquids. A forearm immersion test was
      performed on 30 healthy volunteers. 2 daily soak sessions were performed for 5
      days. At inclusion and the day following the last soak session, skin capacitance
      was measured and cyanoacrylate skin-surface strippings were harvested. The latter
      specimens were used for the ex vivo microwave CSM. Both types of assessments
      clearly differentiated the 2 hand dishwashing liquids. The forearm immersion test
      allowed the discriminant sensitivity of CSM to increase. Intact skin capacitance
      did not predict CSM data. By contrast, a significant correlation was found
      between the post-test conductance and the corresponding CSM data. In conclusion,
      a forearm immersion test under realistic conditions can discriminate the
      irritation potential between surfactant-based products by measuring skin
      conductance and performing CSM. In vivo skin preconditioning by surfactants
      increases CSM sensitivity to the same surfactants.

PMID- 15025703
TI  - Foot dermatitis caused by the textile dye Basic Red 46 in acrylic blend socks.
AB  - 17 male subjects are described with foot dermatitis in association with positive
      patch test reactions to the textile dye Basic Red 46. Chromatographic analysis of
      the socks of 2 affected patients confirmed the presence of Basic Red 46.
      Withdrawal of the acrylic blend socks suspected of having been dyed with Basic
      Red 46 resulted in the improvement of symptoms in 12 of 17 patients (70.6%).
      However, equivocal or negative patch test results to their own socks were
      frequently noted in those patients. A highly significant association between the
      presence of foot dermatitis and a positive Basic Red 46 patch test reaction was
      noted in 555 patients from a patch test clinic population (P < 0.001). The
      prevalence of positive patch test reactions to Basic Red 46 was 1.2%. We suggest
      that patients with foot dermatitis be routinely patch tested for textile dyes. In
      particular, testing with Basic Red 46 should be considered in those with a
      history of use of dark-coloured acrylic and/or acrylic blend socks.

PMID- 15025704
TI  - Contact allergy to the mild surfactant decylglucoside.

PMID- 15025705
TI  - Dithiocarbamate-induced allergic contact dermatitis.

PMID- 15025706
TI  - Contact dermatitis from lacquer in a 'Go' player.

PMID- 15025707
TI  - Compound allergy to Unguentum M.

PMID- 15025708
TI  - An unusual case of mercurial baboon syndrome from metallic mercury in a broken
      industrial barometer.

PMID- 15025710
TI  - Xanthelasma palpebrarum following allergic contact dermatitis from para
      phenylenediamine in a black eyelash-tinting product.

PMID- 15025711
TI  - Allergic contact dermatitis from rubber bands in 3 postal workers.

PMID- 15025709
TI  - Contact dermatitis in a bagpipes maker.

PMID- 15025712
TI  - Contact dermatitis from peppermint and menthol in a local action transcutaneous
      patch.

PMID- 15025713
TI  - Contact dermatitis due to cyclohexanone: a further case.

PMID- 15025714
TI  - Reproductive epigenetics.
AB  - Epigenetics refers to covalent modifications of DNA and core histones that
      regulate gene activity without altering DNA sequence. To date, the best
      characterized DNA modification associated with the modulation of gene activity is
      methylation of cytosine residues within CpG dinucleotides. Human disorders
      associated with epigenetic abnormalities include rare imprinting diseases, molar
      pregnancies, and childhood cancers. Germ cell development and early embryo
      development are critical times when epigenetic patterns are initiated or
      maintained. This review focuses on the epigenetic modification DNA methylation
      and discusses recent progress that has been made in understanding when and how
      epigenetic patterns are differentially established in the male and female
      germlines, the mouse, and human disorders associated with abnormalities in
      epigenetic programming in germ cells and early embryos, as well as genetic and
      other modulators (e.g. nutrition and drugs) of reproductive epigenetic events.

PMID- 15025718
TI  - A new model for prediction of the age of onset and penetrance for Huntington's
      disease based on CAG length.
AB  - Huntington's disease (HD) is a neurodegenerative disorder caused by an unstable
      CAG repeat. For patients at risk, participating in predictive testing and
      learning of having CAG expansion, a major unanswered question shifts from "Will I
      get HD?" to "When will it manifest?" Using the largest cohort of HD patients
      analyzed to date (2913 individuals from 40 centers worldwide), we developed a
      parametric survival model based on CAG repeat length to predict the probability
      of neurological disease onset (based on motor neurological symptoms rather than
      psychiatric onset) at different ages for individual patients. We provide
      estimated probabilities of onset associated with CAG repeats between 36 and 56
      for individuals of any age with narrow confidence intervals. For example, our
      model predicts a 91% chance that a 40-year-old individual with 42 repeats will
      have onset by the age of 65, with a 95% confidence interval from 90 to 93%. This
      model also defines the variability in HD onset that is not attributable to CAG
      length and provides information concerning CAG-related penetrance rates.

PMID- 15025719
TI  - Utilization of prenatal genetic testing by Israeli Moslem women: a national
      survey.
AB  - The number of prenatal genetic tests that are being offered to women is
      constantly increasing. However, there is little national data as to who is
      performing the tests and the reasons for doing or not doing so. The aim of the
      study was to evaluate the proportion of Israeli Moslem women who perform the
      various prenatal genetic tests and the factors affecting the performance of these
      tests. A 2-day survey was conducted in all the maternity departments in Israel
      based on a structured interview. Of the 242 women interviewed, 74.2% underwent
      the triple test (TT), 15.8% of the women older than 35 years who were eligible to
      take the test free of charge underwent amniocentesis and only 1.5% underwent
      fragile-X (FX) carrier testing which costs 100 dollars privately. In the stepwise
      regression analysis, having fewer children and having had a higher education
      affected the performance of the TT. None of the sociodemographic factors were
      associated with the performance of amniocentesis or FX carrier testing, but the
      sample sizes were small. The main reason reported by the women for not performing
      the TT and FX carrier testing was not being referred for testing. The main reason
      for not performing amniocentesis was that they chose not to perform the test (the
      majority of these women were religious or ultrareligious). Consideration should
      be given to providing first-trimester prenatal diagnosis when termination of
      pregnancy in the Moslem population is more acceptable. In addition, consideration
      should be given to including state-subsidized FX testing as there is a low rate
      of FX testing partly due to the cost. Primary care givers should be educated
      about the importance of prenatal genetic testing.

PMID- 15025720
TI  - Novel CFTR mutations in black cystic fibrosis patients.
AB  - Cystic fibrosis (CF) is considered as a rare disease in black Africans. In fact,
      this disease is likely to be underestimated since clinical features consistent
      with CF diagnosis are often ascribed to environmental factors such as
      malnutrition. Very little is known about CFTR mutations in affected patients from
      Central Africa. We report here four novel mutations, i.e., IVS2 + 28 (intron 2),
      459T > A (exon 4), EX17a_EX18del (exons 17-18), and IVS22 + IG > A (intron 22),
      in such patients. An update of CFTR mutations reported in black patients from
      various ethnies is included. These data might be helpful for genetic counselling
      regarding CF in black patients.

PMID- 15025721
TI  - Mutational spectrum in Usher syndrome type II.
AB  - Usher syndrome type II is an autosomal recessive disorder characterized by
      moderate to severe hearing impairment and progressive visual loss due to
      retinitis pigmentosa (RP). We carried out a mutation screening of the USH2A gene
      in 88 probands with Usher syndrome type II to determine the frequency of USH2A
      mutations as a cause for USH2. Six mutations, including 2299delG, 921-922insCAGC,
      R334W, N346H, R626X, and N357T were identified, with 2299delG mutation being the
      most frequent (16.5% of alleles), accounting for 77.5% of the pathologic alleles.
      Thirty-five percent (31/88) of the probands had a USH2A mutation. Nine of them
      carried two pathogenic mutations: six cases were homozygotes and three were
      compound heterozygotes. Twenty-two probands (25%) were found to carry only single
      USH2A mutations. One new missense mutation (N357T) occuring within the laminin N
      terminal (type VI) domain of usherin was identified. Eight polymorphisms were
      found, five of which are novel. Our data support the view that the 2299delG is
      the most common mutation in USH2A.

PMID- 15025722
TI  - Terminal deletion of the long arm of chromosome 10.
AB  - The case of two female patients with de novo terminal deletion of the long arm of
      chromosome 10, one with del(10)(q26.2) and the other with del(10)(q26.3), is
      reported. Both presented with megabladder associated with urinary tract
      abnormalities. The case of four similar patients has been previously reported
      with bladder dilatation secondary to urinary obstruction. These new cases
      highlight the possible involvement of the bladder and the urethra in the syndrome
      of chromosome 10q terminal deletion, suggesting a careful renal and urinary tract
      evaluation in such situations. Moreover, the possibility of monosomy 10qter
      syndrome should be borne in mind in the case of prenatal diagnosis of apparently
      isolated bladder obstruction, especially in females.

PMID- 15025724
TI  - Current clinical selection strategies for identification of hereditary non
      polyposis colorectal cancer families are inadequate: a meta-analysis.
AB  - Present guidelines to identify hereditary non-polyposis colorectal cancer (HNPCC)
      families are criticized for limitations in accuracy. The Amsterdam criteria I and
      II (AC I and AC II) are used to predict a germline mutation in one of the
      mismatch repair genes. In families not fulfilling the AC I and AC II criteria,
      individual indications to test cancer specimens for microsatellite instability
      (MSI) are guided by the Bethesda Guidelines (BG). Germline mutation testing is
      then performed in patients who conform to the BG and show MSI. We investigated
      the sensitivity and specificity of AC I, AC II, and BG. A meta-analysis of
      studies on the value of the AC I and AC II criteria for predicting germline
      mutation, as well as a meta-analysis of BG for the detection of MSI was
      performed. For the AC I, sensitivity varied from 54 to 91% and specificity varied
      from 62 to 84%. For the AC II, the pooled sensitivity was 78% and specificity
      ranged between 46 and 68%. Post-test probabilities of a positive test result were
      0.61 and 0.46 for the AC I and AC II, respectively. Post-test probabilities of a
      negative test result were 0.17 and 0.21 for the AC I and AC II, respectively. For
      the BG, the pooled sensitivity was 89% and pooled specificity was 53%. Post-test
      probability of a positive test result was 41%, and post-test probability of a
      negative test result was 9%. The sensitivity and specificity of the Amsterdam
      criteria for predicting a germline mutation that causes HNPCC is not sufficient.
      The BG are useful for the detection of MSI in a group of patients suspected of
      having familial colorectal cancer (CRC), but sensitivity is very low in the total
      group of newly diagnosed CRC patients. Therefore, a new strategy is needed for
      the identification of HNPCC.

PMID- 15025725
TI  - Molecular diagnosis of hereditary hemochromatosis: application of a newly
      developed reverse-hybridization assay in the South African population.
AB  - A recently developed strip-assay for hemochromatosis provides a rapid method for
      simultaneous detection of multiple mutations, which among others includes the HFE
      gene mutations V53M, V59M, H63D, H63H, S65C, Q127H, E168Q, and C282Y, previously
      detected in the general South African population using gel-based mutation
      screening methods. The objective of the study was to determine the frequency of
      the relatively rare mutations in samples selected for altered iron parameters or
      a family history of hereditary hemochromatosis (HH) as part of the validation
      process of the assay for routine diagnostic purposes. The study population
      consisted of 451 individuals previously screened for mutations C282Y and H63D by
      restriction enzyme analysis in order to confirm or possibly exclude a diagnosis
      of HH. These individuals were subjected to mutation screening using the
      commercially available hemochromatosis strip-assay. Previous positive results for
      mutations C282Y and H63D in 233 individuals confirmed the accuracy of the reverse
      hybridization assay. Mutation S65C was detected in 13 Caucasians, including three
      compound heterozygotes. These constituted 2% (13/600) of the chromosomes without
      mutations C282Y or H63D. The African-specific HFE mutation V53M was detected in
      one out of 11 (9%) African subjects screened. Mutation E168Q was detected in a
      single Caucasian individual together with mutation H63D. Our data demonstrate the
      value of the strip-based technology in providing a rapid and reliable
      comprehensive test for simultaneous analysis of multiple mutations.

PMID- 15025723
TI  - The Mainz Severity Score Index: a new instrument for quantifying the Anderson
      Fabry disease phenotype, and the response of patients to enzyme replacement
      therapy.
AB  - Anderson-Fabry disease (AFD) is an X-linked disorder caused by deficient activity
      of the lysosomal enzyme alpha-galactosidase A. The availability of enzyme
      replacement therapy (ERT) for this debilitating condition has led to the need for
      a convenient and sensitive instrument to monitor clinical effects in an
      individual patient. This study aimed to develop a scoring system--the Mainz
      Severity Score Index (MSSI)--to measure the severity of AFD and to monitor the
      clinical course of the disease in response to ERT. Thirty-nine patients (24 males
      and 15 females) with AFD were assessed using the MSSI immediately before and 1
      year after commencing agalsidase alfa ERT. Control data were obtained from 23
      patients in whom AFD was excluded. The MSSI of patients with AFD was
      significantly higher than that of patients with other severe debilitating
      diseases. The MSSI indicated that, although more men than women had symptoms
      classified as severe, overall, the median total severity scores were not
      significantly different between male and female patients. One year of ERT with
      agalsidase alfa led, in all patients, to a significant (p < 0.001) reduction in
      MSSI score (by a median of nine points). This study has shown that the MSSI score
      may be a useful, specific measure for objectively assessing the severity of AFD
      and for monitoring ERT-related treatment effects.

PMID- 15025726
TI  - Detection of RAG mutations and prenatal diagnosis in families presenting with
      either T-B- severe combined immunodeficiency or Omenn's syndrome.
AB  - It has been recently shown that mutations in both of the recombination activating
      genes RAG1 and RAG2 are involved in each of the two different types of severe
      combined immunodeficiency (SCID) syndromes: T-B- SCID and Omenn's syndrome (OS).
      The objective of the study was to search for novel mutations in the RAG genes and
      to offer prenatal diagnosis for families that have been identified as at risk of
      T-B- SCID or OS. Mutation analyses of polymerase chain reaction products of
      RAG1/RAG2 genes were performed in 14 cases (T-B- SCID = 6 and OS = 8).
      Consanguinity was reported in seven (50%) families. Four missense mutations in
      the RAG2 gene in six of eight OS patients and in four of six T-B- SCID patients
      were detected. The C1845T transition leading to a Tre215Ile substitution is a
      novel mutation. All but one of the patients were homozygous for the detected
      mutations, possibly reflecting the consanguinity in these families and the
      relative rarity of the disease-causing mutations. In addition, three putative
      polymorphic sites were found. Prenatal diagnosis was offered to seven families,
      but three of them declined genetic counseling for religious reasons. In the
      remaining families, four pregnancies were successfully completed, and in one
      case, the family chose to have an abortion because of a homozygous mutation.
      Mutations in RAG1/RAG2 genes were detected in only some of the T-B- SCID or OS
      patients, and the molecular basis for the remaining cases has yet to be
      elucidated. Important factors such as religious beliefs need to be considered
      when offering prenatal diagnosis to certain families.

PMID- 15025727
TI  - Cognitive, language, and adaptive behavior profiles in individuals with a
      diagnosis of Cohen syndrome.
AB  - Although the physical characteristics of Cohen syndrome have been studied in
      considerable detail, data on other aspects of development are relatively limited.
      We report findings on cognitive, linguistic, and adaptive profiles in a group of
      45 individuals clinically diagnosed with Cohen syndrome when aged between 4 and
      49 years. The profile of skills observed was consistent with other recent
      findings. Thus, independence levels generally were poor, but socialization skills
      as assessed by the Vineland were relatively less impaired. This particular area
      of strength probably underlies the 'sociable' temperament typically associated
      with Cohen syndrome. However, the range of cognitive ability was wider than
      reported in most previous research, raising the issue of whether mental
      retardation should be considered as a necessary component of the phenotype. The
      implications for genetic testing are discussed.

PMID- 15025728
TI  - Low frequency of myocilin mutations in Indian primary open-angle glaucoma
      patients.
AB  - Glaucoma is one of the major causes of blindness in the Indian population.
      Mutations in the myocilin (MYOC) gene have been reported in different
      populations. However, reports on MYOC mutations in Indian primary open-angle
      glaucoma (POAG) patients and juvenile open-angle glaucoma (JOAG) patients are
      sparse. We therefore screened 100 unrelated POAG/JOAG patients for MYOC
      mutations. Patients with POAG/JOAG were clinically diagnosed. Genomic DNA from
      such patients was collected and studied for MYOC mutations by direct sequencing.
      Nucleotide variations were compared with unrelated healthy controls by
      restriction enzyme digestion. Secondary structure prediction for the sequence
      variants was performed by Chou-Fasman method. A novel mutation in exon 1 (144 G-
      >Alpha) resulting in Gln48His substitution was observed in 2% of the patients.
      Four other polymorphisms were also observed. The novel mutation was seen in four
      other affected family members of a JOAG patient. The novel mutation was found to
      alter the secondary structure in the glycosaminoglycan initiation site of the
      protein. MYOC mutations were found in 2% of the population studied. MYOC gene may
      not be playing a significant role in causing POAG in the Indian population.

PMID- 15025729
TI  - The frequency of GJB2 and GJB6 mutations in the New York State newborn
      population: feasibility of genetic screening for hearing defects.
AB  - In the US, approximately one in every 1000 children has hearing loss sufficiently
      severe to interfere with the acquisition of normal speech [Ann NY Acad Sci 630
      (1991) 16]. The causes of non-syndromic hearing loss (NSHL) are known to be
      heterogeneous, with genetic factors accounting for 50-75%[Am J Med Genet 46
      (1993) 486]. Often individuals with NSHL thought to be caused by mutations in
      GJB2 have only one detectable mutant allele [Am J Hum Genet 62 (1998) 792, Hum
      Mol Genet 6 (12) (1997) 2173]. Another gene that has been identified as a
      possible cause of NSHL is GJB6 that codes for the gap junction protein, connexin
      30. A consecutive series of anonymous newborn dried blood specimens (n = 2089)
      was tested for two GJB2 mutations: (i) 35delG, a pan-ethnic mutation; and (ii)
      167delT, a mutation more frequently found in individuals of Ashkenazi Jewish and
      Mediterranean descents. Mutation detection was validated using allele-specific
      oligonucleotide hybridization in single wells. Once the positive samples had been
      identified, the samples were pooled and retested. All positives in the individual
      experiment were correctly identified in the pooled experiment. The same random
      set of anonymous newborn dried blood specimens plus some additional samples were
      tested (n = 2112) for the 342-kb deletion in the GJB6 gene.

PMID- 15025730
TI  - Genetic counseling of medullary breast cancer patients.

PMID- 15025733
TI  - Drug interactions-information, education, and the British National Formulary.

PMID- 15025734
TI  - Recent advances in drug action and therapeutics: relevance of novel concepts in G
      protein-coupled receptor and signal transduction pharmacology.
AB  - PROBLEM STATEMENT: During especially the past two decades many discoveries in
      biological sciences, and in particular at the molecular and genetic level, have
      greatly impacted on our knowledge and understanding of drug action and have
      helped to develop new drugs and therapeutic strategies. Furthermore, many
      exciting new drugs acting via novel pharmacological mechanisms are expected to be
      in clinical use in the not too distant future. SCOPE AND CONTENTS OF REVIEW: In
      this educational review, these concepts are explained and their relevance
      illustrated by examples of drugs used commonly in the clinical setting, with
      special reference to the pharmacology of G-protein-coupled receptors. The review
      also addresses the basic theoretical concepts of full and partial agonism,
      neutral antagonism, inverse agonism and protean and ligand-selective agonism, and
      the relevance of these concepts in current rational drug therapy. Moreover, the
      mechanisms whereby receptor signalling (and eventually response to drugs) is fine
      tuned, such as receptor promiscuity, agonist-directed trafficking of receptor
      signalling, receptor trafficking, receptor 'cross-talk' and regulators of G
      protein signalling (RGSs) are discussed, from theory to proposed therapeutic
      implications. CONCLUSIONS: It is concluded that the understanding of molecular
      receptor and signal transduction pharmacology enables clinicians to improve their
      effective implementation of current and future pharmacotherapy, ultimately
      enhancing the quality of life of their patients.

PMID- 15025737
TI  - Retrospective population pharmacokinetic analysis of cetirizine in children aged
      6 months to 12 years.
AB  - AIMS: To evaluate retrospectively the population pharmacokinetics of cetirizine,
      a second-generation antihistamine, in children. METHODS: Data were pooled from
      six clinical trials, in which cetirizine was administered orally in various
      formulations and in single and multiple dosage regimens. The population consisted
      of 112 children (33 female and 79 male) aged 6 months to 12 years. A one
      compartment open model with first-order absorption and elimination was fitted to
      the plasma concentration-time profiles using nonlinear mixed effects modelling
      with first-order estimation. RESULTS: A linear association was found between
      apparent clearance (CL/F) and age with the former increasing by 0.12 l h(-1) per
      year. The intercept of the relationship was slightly lower for female children
      (0.59 vs. 0.77 l h(-1) in male). The population estimate of CL/F for an average
      age of 7 years was 1.61 and 1.43 l h(-1) for male and female children,
      respectively. A linear association was found between apparent volume of
      distribution (V/F) and age with the former increasing by 1.4 l year(-1), with an
      intercept of 4.0 l. The population estimate of V/F for an average age of 7 years
      was 13.9 l. The magnitudes of interpatient variability were 35.6% for CL/F and
      19.7% for V/F. The magnitude of residual variability in cetirizine concentrations
      was 26.9%. CONCLUSIONS: Population analysis predicts a linear increase in
      cetirizine CL/F and V/F with age, with CL/F being slightly lower in female
      children, relative to males of the same age. However, this gender difference
      probably has no clinical consequences. Since V/F increased more rapidly with age
      than CL/F, a nonlinear increase in half-life was seen, from < 4 h in infants to
      near the adult value at 12 years of age. The current recommended dosing regimens
      that younger children should receive lower but more frequent doses, are confirmed
      by the present analysis.

PMID- 15025735
TI  - The presence of emphysema does not affect the systemic bioactivity of inhaled
      fluticasone in severe chronic obstructive pulmonary disease.
AB  - AIMS: To assess the systemic bioactivity of fluticasone proprionate (FP) 2000
      micro g daily on sensitive adrenal and bone markers in severe chronic obstructive
      pulmonary disease (COPD) patients with or without significant emphysema. METHODS:
      Ten patients without emphysema (COPD group: age 55 years, FEV(1) 51% predicted
      and DL(CO) 83% predicted) and 10 patients with emphysema (COPDE group: age 59
      years, FEV(1) 43% predicted and DL(CO) 49% predicted) received FP 2000 micro g
      daily via a spacer for 2 weeks. There was a 1-week washout period prior to FP
      treatment where patients were given salmeterol and oxitropium, after stopping
      their usual inhaled corticosteroids for the duration of the study. Measurements
      including overnight 10 h urinary cortisol excretion corrected for creatinine
      (OUCC) and serum osteocalcin concentrations were performed at baseline following
      washout and after 2 weeks of FP. RESULTS: Values for OUCC and serum osteocalcin
      concentrations pre- and post-FP were not significantly different between the COPD
      and COPDE groups. There was significant suppression of OUCC (nmol mmol(-1)) by FP
      treatment within the COPD group (P = 0.03): 7.86 vs 4.64 (95% CI on the
      difference 0.47, 5.98), and within the COPDE group (P = 0.006): 7.13 vs 4.27 (95%
      CI on the difference: 1.03, 4.69). Likewise, there was significant suppression of
      osteocalcin concentration (nmol l(-1)) by FP treatment within the COPD group (P =
      0.04): 7.24 vs 6.34 (95% CI on the difference: 0.01, 1.78), and within the COPDE
      group (P = 0.03): 6.92 vs 5.72 (95% CI on the difference: 0.12, 2.29).
      CONCLUSIONS: Severe COPD patients who are receiving high dose FP are susceptible
      to the development of systemic adverse effects, irrespective of the presence of
      emphysema.

PMID- 15025736
TI  - Effects of a nonpeptide motilin receptor antagonist on proximal gastric motor
      function.
AB  - AIM: To assess the effects of the motilin receptor antagonist RWJ-68023 on basal
      and motilin-stimulated proximal gastric volume. METHODS: Eighteen healthy male
      volunteers received RWJ-68023 in two different doses or placebo for 135 min.
      After 45 min, subjects received a motilin infusion for 90 min. Proximal gastric
      volume was measured with a barostat at constant pressure and during isobaric
      distensions. Abdominal symptoms were scored using visual analogue scales. Motilin
      and RWJ-68023 concentrations were assessed by radioimmunoassay and liquid
      chromatography-mass spectrometry, respectively. RESULTS: Both dosages of RWJ
      68023 were safe and well tolerated. The most common adverse events were of
      gastrointestinal origin. RWJ-68023 did not affect basal proximal gastric volume,
      but the high-dose RWJ-68023 reduced the contractile effect of motilin on the
      stomach. This antagonizing effect of RWJ-68023 was only significant (P = 0.014)
      during the distension procedure. CONCLUSIONS: The RWJ-68023 doses used in this
      study were selected to accomplish plasma concentrations that would block the
      motilin effect entirely. However, the antagonizing effect of RWJ-68023 was
      partial and only present when the tonic condition of the stomach was modulated by
      motilin.

PMID- 15025738
TI  - Pharmacokinetics of levosimendan and its circulating metabolites in patients with
      heart failure after an extended continuous infusion of levosimendan.
AB  - AIMS: The purpose of the study was to characterize the pharmacokinetics of
      levosimendan and its metabolites OR-1855 and OR-1896 in patients with congestive
      heart failure. METHODS: Levosimendan was administered as a continuous intravenous
      infusion for 7 days. Twelve subjects received the drug at an infusion rate of
      0.05 micro g kg(-1) min(-1) and 12 at a rate 0.1 micro g kg(-1) min(-1). RESULTS:
      Steady state concentrations of levosimendan were achieved within 4 h. Peak
      concentrations of the metabolites occurred after termination of the infusion. The
      mean (+/- SD) half-life of the active metabolite OR-1896 was 81 +/- 37 h after
      the lower dose and 81 +/- 28 h after the higher dose (P = 0.992, 95% confidence
      interval on the difference -27.5, 27.7). CONCLUSIONS: The metabolites of
      levosimendan, OR-1855 and OR-1896, were formed and eliminated slowly, their peak
      concentrations occurring after termination of the 7-day infusion of the drug.

PMID- 15025740
TI  - Blood-brain barrier transport of morphine in patients with severe brain trauma.
AB  - AIMS: In experimental studies, morphine pharmacokinetics is different in the
      brain compared with other tissues due to the properties of the blood-brain
      barrier, including action of efflux pumps. It was hypothesized in this clinical
      study that active efflux of morphine occurs also in human brain, and that brain
      injury would alter cerebral morphine pharmacokinetics. METHODS: Patients with
      traumatic brain injury, equipped with one to three microdialysis catheters in the
      brain and one in abdominal subcutaneous fat for metabolic monitoring, were
      studied. The cerebral catheter locations were classified as 'better' and 'worse'
      brain tissue, referring to the degree of injury. Morphine (10 mg) was infused
      intravenously over a 10-min period in seven patients in the intensive care
      setting. Tissue and plasma morphine concentrations were obtained during the
      subsequent 3-h period with microdialysis and regular blood sampling. RESULTS: The
      area under the concentration-time curve (AUC) ratio of unbound morphine in brain
      tissue to plasma was 0.64 (95% confidence interval 0.40, 0.87) in 'better' brain
      tissue (P < 0.05 vs. the subcutaneous fat/plasma ratio), 0.78 (0.49, 1.07) in
      'worse' brain tissue and 1.00 (0.86, 1.13) in subcutaneous fat. The terminal half
      life and T(max) were longer in the brain vs. plasma and fat, respectively. The
      relative recovery for morphine was higher in 'better' than in 'worse' brain
      tissue. The T(max) value tended to be shorter in 'worse' brain tissue.
      CONCLUSIONS: The unbound AUC ratio below unity in the 'better' human brain tissue
      demonstrates an active efflux of morphine across the blood-brain barrier. The
      'worse' brain tissue shows a decrease in relative recovery for morphine and in
      some cases also an increase in permeability for morphine over the blood-brain
      barrier.

PMID- 15025739
TI  - Population pharmacokinetics of raltitrexed in patients with advanced solid
      tumours.
AB  - AIMS: To investigate the population pharmacokinetics of raltitrexed in patients
      with advanced solid tumours and to identify patient covariates contributing to
      the interpatient variability in the pharmacokinetics of raltitrexed. METHODS:
      Patient covariate and concentration-time data were collected from patients
      receiving 0.1-4.5 mg m(-2) raltitrexed during the early clinical trials of
      raltitrexed. Data were fitted using nonlinear mixed effects modelling to generate
      population mean estimates for clearance (CL) and central volume of distribution
      (V). The relationship between individual estimates of the pharmacokinetic
      parameters and patient covariates was examined and the influence of significant
      covariates on the population parameter estimates and their variance was
      investigated using stepwise multiple linear regression. The performance of the
      developed model was tested using an independent validation dataset. All patient
      data were pooled in the total cohort to refine the population pharmacokinetic
      model for raltitrexed. RESULTS: three-compartment pharmacokinetic model was used
      to fit the concentration-time data of raltitrexed. Estimated creatinine clearance
      (CL(CR)) was found to influence significantly the CL of raltitrexed and explained
      35% of variability in this parameter, whilst body weight (WT) and serum albumin
      concentrations (ALB) accounted for 56% of the variability in V. Satisfactory
      prediction (mean prediction error 0.17 micro g l(-1) and root mean square
      prediction error 4.99 micro g l(-1)) of the observed raltitrexed concentrations
      was obtained in the model validation step. The final population mean estimates
      were 2.17 l h(-1)[95% confidence interval (CI) 2.06, 2.28] and 6.36 l (95% CI
      6.02, 6.70) for CL and V, respectively. Interpatient variability in the
      pharmacokinetic parameters was reduced (CL 28%, V 25%) when influential
      covariates were included in the final model. The following covariate
      relationships with raltitrexed parameters were described by the final population
      model: CL (l h(-1)) = 0.54 + 0.02 CL(CR) (ml min(-1)) and V (l) = 6.64 + 0.08 WT
      (kg) - 0.16 ALB (g l(-1)). CONCLUSIONS: A population pharmacokinetic model has
      been developed for raltitrexed in patients with advanced cancer. Pharmacokinetic
      parameters of raltitrexed are markedly influenced by the patient's renal
      function, body weight and serum albumin levels, which may be taken into account
      in dose individualization. The use of influential covariates to guide anticancer
      dosage selection may result in less variability in drug exposure and potentially
      a better clinical outcome.

PMID- 15025741
TI  - Therapeutic drug monitoring of lopinavir/ritonavir given alone or with a non
      nucleoside reverse transcriptase inhibitor.
AB  - AIMS: To evaluate the interindividual variability in the plasma concentrations of
      lopinavir in the context of routine monitoring with or without treatment with a
      non-nucleoside reverse transcriptase inhibitor and to assess the interaction
      between the coformulation of lopinavir/ritonavir and efavirenz or nevirapine.
      METHODS: Plasma trough and peak concentrations (C(trough), C(max)) of lopinavir
      from 182 HIV-1-infected patients were analysed by high-performace liquid
      chromatography. Three lopinavir/ritonavir regimens were assessed, namely (A) 400
      mg lopinavir/100 mg ritonavir twice daily given alone (n = 125), (B) 400/100 mg
      twice daily together with a non-nucleoside reverse transcriptase inhibitor (n =
      25), and (C) 533/133 mg twice daily together with a non-nucleoside reverse
      transcriptase inhibitor (n = 32). RESULTS: Median (ng ml(-1)) C(trough) and
      C(max) lopinavir (interquartile range, CV) were: (A) 4852 (3198-6891, 56%) and
      8501 (6333-11 584, 41%), (B) 2979 (1704-5186, 74%) and 5612 (3362-11 704, 76%)
      and (C) 5082 (2696-7226, 74%) and 9757 (4883-12 963, 60%). Median C(trough) of
      lopinavir was lower in patients taking both efavirenz [P = 0.01, 95% confidence
      interval (CI) for difference between medians 343, 2713] and nevirapine (P =
      0.019, 95% CI for difference between medians 354, 3681) compared with those
      taking lopinavir/ritonavir alone. A higher interindividual variability was
      observed when lopinavir/ritonavir was given with a non-nucleoside reverse
      transcriptase inhibitor. The risk of achieving a 'suboptimal'C(trough) of
      lopinavir (below a threshold of 3000 ng ml(-1)) was statistically higher in
      patients treated with a non-nucleoside reverse transcriptase inhibitor (P <
      0.001, 95% CI for difference between percentages 8.8, 43.1%) compared with those
      receiving lopinavir/ritonavir alone. CONCLUSIONS: Our results confirmed the
      interaction between lopinavir and efavirenz, and also demonstrated a significant
      interaction between the former drug and nevirapine, resulting in lower C(trough)
      of lopinavir. The wide interpatient variability in this interaction suggests that
      therapeutic drug monitoring may be useful in optimizing the dose of lopinavir.

PMID- 15025742
TI  - The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of
      repaglinide in healthy subjects.
AB  - AIMS: Our aim was to investigate the effect of the CYP2C8 inhibitor trimethoprim
      on the pharmacokinetics and pharmacodynamics of the antidiabetic drug
      repaglinide, and to examine the influence of the former on the metabolism of the
      latter in vitro. METHODS: In a randomized, double-blind, crossover study with two
      phases, nine healthy volunteers took 160 mg trimethoprim or placebo orally twice
      daily for 3 days. On day 3, 1 h after the last dose of trimethoprim or placebo,
      they ingested a single 0.25 mg dose of repaglinide. Plasma repaglinide and blood
      glucose concentrations were measured for up to 7 h post-dose. In addition, the
      effect of trimethoprim on the metabolism of repaglinide by human liver microsomes
      was investigated. RESULTS: Trimethoprim raised the AUC(0, infinity ) and C(max)
      of repaglinide by 61% (range, 30-117%; P= 0.0008) and 41% (P = 0.005),
      respectively, and prolonged the t((1/2)) of repaglinide from 0.9 to 1.1 h (P =
      0.001). Trimethoprim had no significant effect on the pharmacokinetics of its
      aromatic amine metabolite (M1), but decreased the M1 : repaglinide AUC(0,
      infinity ) ratio by 38% (P = 0.0005). No effect of trimethoprim on the blood
      glucose-lowering effect of repaglinide was detectable. In vitro, trimethoprim
      inhibited the metabolism of (220 nm) repaglinide in a concentration-dependent
      manner. CONCLUSIONS: Trimethoprim raised the plasma concentrations of repaglinide
      probably by inhibiting its CYP2C8-mediated biotransformation. Although the
      interaction did not significantly enhance the effect of repaglinide on blood
      glucose concentration at the drug doses used, the possibility of an increased
      risk of hypoglycaemia should be considered during concomitant use of trimethoprim
      and repaglinide in patients with diabetes.

PMID- 15025743
TI  - Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin
      in Japanese.
AB  - AIMS: To investigate the effects of repeated grapefruit juice (GFJ) intake on the
      pharmacokinetics of atorvastatin and pravastatin in Japanese subjects. METHODS:
      Two randomized, two-way crossover studies were performed. GFJ or water was given
      to two groups of 10 subjects each three times daily for 2 days. On the third day,
      single 10 mg doses of atorvastatin or pravastatin were orally administered with
      GFJ or water, and an additional 250 ml of GFJ or water was taken before lunch and
      dinner. Plasma concentrations of atorvastatin and its metabolites were determined
      over 48 h postdosing and of pravastatin and its metabolites over 24 h postdosing.
      RESULTS: Compared with in the water group, the AUC(0,48 h) of atorvastatin acid
      significantly increased by 1.40 fold (95% CI 1.02, 1.92; P < 0.05) when
      atorvastatin was taken with GFJ. AUC(0,48 h) and C(max) of atorvastatin lactone
      significantly increased by 1.56 (95% CI 1.33, 1.83; P < 0.001) and 1.29 fold (95%
      CI 1.09, 1.51; P < 0.01), respectively, when atorvastatin was taken with GFJ. No
      significant changes were detected in any pravastatin pharmacokinetic parameter
      examined when pravastatin was taken with GFJ. However, AUC(0,24 h) of pravastatin
      lactone increased 1.31 fold (95% CI 1.01, 1.71; P < 0.05) with GFJ intake.
      CONCLUSIONS: GFJ was confirmed to significantly affect the pharmacokinetics of
      atorvastatin but had little or no effect on those of pravastatin in Japanese
      subjects.

PMID- 15025744
TI  - Clinical inhibition of CYP2D6-catalysed metabolism by the antianginal agent
      perhexiline.
AB  - AIMS: Perhexiline is an antianginal agent that displays both saturable and
      polymorphic metabolism via CYP2D6. The aim of this study was to determine whether
      perhexiline produces clinically significant inhibition of CYP2D6-catalysed
      metabolism in angina patients. METHODS: The effects of perhexiline on CYP2D6
      catalysed metabolism were investigated by comparing urinary total
      dextrorphan/dextromethorphan metabolic ratios following a single dose of
      dextromethorphan (16.4 mg) in eight matched control patients not taking
      perhexiline and 24 patients taking perhexiline. All of the patients taking
      perhexiline had blood drawn for CYP2D6 genotyping as well as to measure plasma
      perhexiline and cis-OH-perhexiline concentrations. RESULTS: Median (range)
      dextrorphan/dextromethorphan metabolic ratios were significantly higher (P <
      0.0001) in control patients, 271.1 (40.3-686.1), compared with perhexiline
      treated patients, 5.0 (0.3-107.9). In the perhexiline-treated group 10/24
      patients had metabolic ratios consistent with poor metabolizer phenotypes;
      however, none was a genotypic poor metabolizer. Interestingly, 89% of patients
      who had phenocopied to poor metabolizers had only one functional CYP2D6 gene.
      There was a significant negative linear correlation between the log of the
      dextrorphan/dextromethorphan metabolic ratio and plasma perhexiline
      concentrations (r(2) = 0.69, P < 0.0001). Compared with patients with at least
      two functional CYP2D6 genes, those with one functional gene were on similar
      perhexiline dosage regimens but had significantly higher plasma perhexiline
      concentrations, 0.73 (0.21-1.00) vs. 0.36 (0.04-0.69) mg l(-1) (P = 0.04), lower
      cis-OH-perhexiline/perhexiline ratios, 2.85 (0.35-6.10) vs. 6.51 (1.84-11.67) (P
      = 0.03), and lower dextrorphan/dextromethorphan metabolic ratios, 2.51 (0.33
      39.56) vs. 11.80 (2.90-36.93) (P = 0.005). CONCLUSIONS: Perhexiline significantly
      inhibits CYP2D6-catalysed metabolism in angina patients. The plasma cis-OH
      perhexiline/perhexiline ratio may help to both phenotype patients and predict
      those in whom perhexiline may be most likely to cause clinically significant
      metabolic inhibition.

PMID- 15025745
TI  - Potential for drug interactions involving cytochromes P450 2D6 and 3A4 on general
      adult psychiatric and functional elderly psychiatric wards.
AB  - AIMS: To assess the potential for interactions involving cytochromes P450 2D6
      (CYP2D6) and 3A4 (CYP3A4) between drugs prescribed in a city in-patient
      psychiatric service. METHODS: Prescription information was obtained from all 236
      patients in general adult wards and all 87 patients in functional elderly wards
      under a city psychiatric service. The frequencies with which combinations of
      drugs expected to interact via CYP2D6 or CYP3A4 were documented and compared
      between these two settings. RESULTS: All 2089 drug prescriptions, of which 1237
      (59%) were administered, were analyzed. One hundred and seventy-two patients
      (73%) on adult wards and 59 (68%) on functional elderly wards were prescribed at
      least one drug metabolized by and/or inhibiting CYP2D6, the difference being
      nonsignificant (95% confidence interval on the difference -6.3%, 16.4%).
      Anticipated interactions from 62/82 CYP2D6-related combinations prescribed on
      adult wards (27/100 patients) and 19/30 prescribed to elderly patients (22/100
      patients) were judged to be clinically important or potentially clinically
      important. The proportion of patients on functional elderly wards prescribed at
      least one drug interacting with CYP3A4 (87%) was significantly greater than that
      for patients on adult wards (57%, P < 0.001). The frequency of interactions
      involving CYP3A4 was significantly greater on functional elderly than adult wards
      (43/100 vs 22/100 patients, P < 0.025, 95% confidence interval on the difference
      4, 38/100). CONCLUSIONS: Our findings confirm extensive polypharmacy on general
      adult psychiatric and functional elderly psychiatric wards. A substantial
      proportion of patients were receiving combinations of drugs that interact with
      CYP2D6 and/or CYP3A4, many of which are known to produce clinically important
      interactions. Doctors practising in old age psychiatry should be aware that
      patients on functional elderly wards are at increased risk of clinically
      important CYP3A4 interactions. Psychiatrists should consider the pharmacokinetic
      implications of drugs prescribed for use 'as needed', because of the potential
      for unpredictable interactions.

PMID- 15025746
TI  - Database analyses for the prediction of in vivo drug-drug interactions from in
      vitro data.
AB  - AIMS: In theory, the magnitude of an in vivo drug-drug interaction arising from
      the inhibition of metabolic clearance can be predicted using the ratio of
      inhibitor concentration ([I]) to inhibition constant (K(i)). The aim of this
      study was to construct a database for the prediction of drug-drug interactions
      from in vitro data and to evaluate the use of the various estimates for the
      inhibitor concentrations in the term [I]/K(i). METHODS: One hundred and ninety
      three in vivo drug-drug interaction studies involving inhibition of CYP3A4,
      CYP2D6 or CYP2C9 were collated from the literature together with in vitro K(i)
      values and pharmacokinetic parameters for inhibitors, to allow calculation of
      average/maximum systemic plasma concentration during the dosing interval and
      maximum hepatic input plasma concentration (both total and unbound
      concentration). The observed increase in AUC (decreased clearance) was plotted
      against the estimated [I]/K(i) ratio for qualitative zoning of the predictions.
      RESULTS: The incidence of false negative predictions (AUC ratio > 2, [I]/K(i) <
      1) was largest using the average unbound plasma concentration and smallest using
      the hepatic input total plasma concentration of inhibitor for each of the CYP
      enzymes. Excluding mechanism-based inhibition, the use of total hepatic input
      concentration resulted in essentially no false negative predictions, though
      several false positive predictions (AUC ratio < 2, [I]/K(i) > 1) were found. The
      incidence of true positive predictions (AUC ratio > 2, [I]/K(i) > 1) was also
      highest using the total hepatic input concentration. CONCLUSIONS: The use of the
      total hepatic input concentration of inhibitor together with in vitro K(i) values
      was the most successful method for the categorization of putative CYP inhibitors
      and for identifying negative drug-drug interactions. However this approach should
      be considered as an initial discriminating screen, as it is empirical and
      requires subsequent mechanistic studies to provide a comprehensive evaluation of
      a positive result.

PMID- 15025748
TI  - Effect of St John's wort on the activities of CYP1A2, CYP3A4, CYP2D6, N
      acetyltransferase 2, and xanthine oxidase in healthy males and females.
AB  - AIMS: To investigate the influence of St. John's wort (SJW) on CYP3A4, CYP1A2,
      CYP2D6, N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO) activities in
      healthy males and females. METHODS: Eight males and eight females were treated
      with SJW extract (3 x 300 mg day(-1)) for 14 days. Assessment of CYP1A2, NAT2,
      XO, CYP2D6, and CYP3A4 activities was performed before and at the end of the
      study period, using caffeine, dextromethorphan, and endogenous cortisol as
      probes. The corresponding metabolic ratios measured were 17MX/137MX in saliva and
      (AFMU+1MX+1MU)/17MU in urine for CYP1A2, AFMU/1MX for NAT2, 1MU/1MX for XO,
      DOR/DMO for CYP2D6, 3MM/DMO and 6OHC/C for CYP3A4, all determined in urine.
      RESULTS: The ratios of the treatment to baseline values for CYP3A4 using cortisol
      as the probe were 1.5 [95% confidence interval (CI) 1.3, 1.9] for males, and 1.9
      (1.1, 3.0) for females. The corresponding ratios using dextromethorphan as the
      probe for CYP2D6 were 0.9 (95% CI 0.5, 2.1) for males and 1.9 (1.3, 3.2) for
      females. For CYP1A2, a significant increase in the metabolic ratios was found
      only for females (ratio of values 1.2; 95% CI 1.1, 1.4). No influence of SJW on
      CYP2D6, NAT2, and XO activities was observed. CONCLUSIONS: An induction of CYP3A4
      by SJW was confirmed. CYP1A2 appears to be induced by SJW only in females. The
      activities of CYP2D6, NAT2, and XO were not affected by SJW.

PMID- 15025747
TI  - Different inhibitory effect of fluvoxamine on omeprazole metabolism between
      CYP2C19 genotypes.
AB  - AIMS: Omeprazole is mainly metabolized by the polymorphic cytochrome P450 (CYP)
      2C19. The inhibitory effect of fluvoxamine, an inhibitor of CYP2C19 as well as
      CYP1A2, on the metabolism of omeprazole was compared between different genotypes
      for CYP2C19. METHODS: Eighteen volunteers, of whom six were homozygous extensive
      metabolizers (EMs), six were heterozygous EMs and six were poor metabolizers
      (PMs) for CYP2C19, participated in the study. A randomized double-blind, placebo
      controlled crossover study was performed. All subjects received two six-day
      courses of either daily 50 mg fluvoxamine or placebo in a randomized fashion with
      a single oral 40 mg dose of omeprazole on day six in both cases. Plasma
      concentrations of omeprazole and its metabolites, 5-hydroxyomeprazole, omeprazole
      sulphone, and fluvoxamine were monitored up to 8 h after the dosing. RESULTS:
      During placebo administration, geometric means of peak concentration (C(max)),
      under the plasma concentration-time curve from 0 to 8 h (AUC(0,8 h)) and
      elimination half-life (t(1/2)) of omeprazole were 900 ng ml(-1), 1481 ng ml(-1)
      h, and 0.6 h in homozygous EMs, 1648 ng ml(-1), 4225 ng ml(-1) h, and 1.1 h in
      heterozygous EMs, and 2991 ng ml(-1), 11537 ng ml(-1) h, and 2.8 h in PMs,
      respectively. Fluvoxamine treatment increased C(max) of omeprazole by 3.7-fold
      (95%CI, 2.4, 5.0-fold, P < 0.01) and 2.0-fold (1.4, 2.6-fold, P < 0.01), AUC(0,8
      h) by 6.0-fold (3.3, 8.7-fold, P < 0.001) and 2.4-fold (1.7, 3.2-fold, P < 0.01),
      AUC(0, infinity ) by 6.2-fold (3.0, 9.3-fold, P < 0.01) and 2.5-fold (1.6, 3.4
      fold, P < 0.001) and prolonged t((1/2)) by 2.6-fold (1.9, 3.4-fold, P < 0.001)
      and 1.4-fold (1.02, 1.7-fold, P < 0.05), respectively. However, no
      pharmacokinetic parameters were changed in PMs. The AUC(0,8 h) ratios of 5
      hydroxyomeprazole to omeprazole were decreased with fluvoxamine in homozygous EMs
      (P < 0.05) and heterozygous EMs (P < 0.01). CONCLUSIONS: Even a low dose of
      fluvoxamine increased omeprazole exposure in EMs, but did not increase omeprazole
      exposure in PMs after a single oral dose of omeprazole. These findings confirm a
      potent inhibitory effect of fluvoxamine on CYP2C19 activity. The bioavailability
      of omeprazole might, to some extent, be increased through inhibition of P
      glycoprotein during fluvoxamine treatment.

PMID- 15025749
TI  - Acute otitis media in children: a retrospective analysis of physician prescribing
      patterns.
AB  - BACKGROUND: Acute otitis media (AOM) is one of the most common infectious
      diseases of childhood and the most frequent indication for antibiotic use in
      children. Aim To better understand the prescribing patterns and appropriateness
      of AOM therapy. METHODS: We investigated a historical cohort of children aged <
      or = 6 years who had a first AOM episode between June 1999 and June 2002, using
      the Regie de l'assurance maladie du Quebec (RAMQ) administrative databases.
      Conformity of prescription was based on the consensus guidelines on AOM treatment
      from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. These
      recommendations suggested amoxicillin as the first-line drug, and amoxicillin
      clavulanic acid or cefuroxime for children who had received antibiotics in the
      previous month. Data were analysed using descriptive statistics, chi(2) test and
      logistic regression. RESULTS: During the study period, 60 513 children < or = 6
      years of age experienced their first AOM episode with a mean age of 2.6 years.
      They were seen by 4708 physicians [87% general practitioners (GPs), 9%
      paediatricians, and 3% ENT specialists]. Amoxicillin was the antibiotic that was
      prescribed the most (43%), followed by cefprozil and azithromycin. Overall, 42%
      of physicians adhered to antibiotic guideline recommendations. Compared with GPs,
      paediatricians were almost as likely to prescribe in conformity with the
      consensus guidelines, whereas ENT specialists were 50% less likely to prescribe
      an antibiotic recommended by the guidelines. CONCLUSION: Continuing medical
      education is necessary to ensure appropriate adherence to antibiotic guidelines.

PMID- 15025750
TI  - Low body mass index is associated with an increased risk of neuropsychiatric
      adverse events and concentration impairment in women on mefloquine.
AB  - AIMS: We performed a prospective cohort study to gain more insight into risk
      factors for neuropsychiatric effects of mefloquine among tourists travelling to
      tropical areas. METHODS: We enrolled all patients who consulted the Travel Clinic
      of the Havenziekenhuis & Institute for Tropical Diseases Rotterdam for mefloquine
      prophylaxis during the period between 1 May 1999 and 7 March 2000. Each patient
      was followed from baseline (prior to starting mefloquine) up to 3 weeks after
      starting weekly intake of 250 mg mefloquine. We compared the intraindividual
      change in scores between baseline and follow-up visit on the Dutch shortened
      Profile of Mood States, and on the Continuous Performance Test (CPT) which
      measures sustained attention. RESULTS: The final cohort consisted of 151 subjects
      with a mean age of 38 years. In this population, a significant impairment of mood
      state was observed in those with a body mass index (BMI) < or = 20 kg m(-2).
      Stratification for gender showed that the total mood disturbance in females in
      the lowest BMI category significantly increased by 8.42 points [95% confidence
      interval (CI) 3.33, 13.50], whereas BMI did not affect the risk in males.
      Stratification for history of use of mefloquine showed that the risks were
      highest in first-time users. Analyses of the CPT showed that reaction time in
      women with a BMI < or = 20 kg m(-2) increased significantly by 22.5 ms (95% CI
      7.80, 37.20), whereas reaction time in men showed a slight and nonsignificant
      decrease. CONCLUSION: Risk factors for mefloquine-associated neuropsychiatric
      adverse events and concentration impairment are female gender, low BMI, and first
      time use. The frequency of neuropsychiatric effects is highest in women with a
      BMI < or = 20 kg m(-2).

PMID- 15025752
TI  - Overanticoagulation associated with combined use of lactulose and acenocoumarol
      or phenprocoumon.
AB  - Some medical textbooks on drug interactions take note of the potential
      interaction between laxatives and coumarin anticoagulants, but epidemiological
      evidence that this interaction is of practical importance is lacking. We
      conducted a follow-up study in a large population-based cohort to investigate
      which laxatives are associated with overanticoagulation during therapy with
      coumarins. Of the 1124 patients in the cohort, 351 developed an International
      Normalized Ratio > or = 6.0. The only laxative with a moderate but significantly
      increased relative risk of overanticoagulation was lactulose (relative risk 3.4,
      95% confidence interval 2.2, 5.3). In view of the widespread use of lactulose,
      especially among the elderly, awareness of this potential drug interaction is
      required.

PMID- 15025751
TI  - A prospective multicentre study of pharmacist initiated changes to drug therapy
      and patient management in acute care government funded hospitals.
AB  - AIMS: To determine the cost savings of pharmacist initiated changes to
      hospitalized patients' drug therapy or management in eight major acute care
      government funded teaching hospitals in Australia. METHODS: This was a
      prospective study performed in eight hospitals examining resource implications of
      pharmacists' interventions assessed by an independent clinical panel. Pharmacists
      providing clinical services to inpatients recorded details of interventions,
      defined as any action that directly resulted in a change to patient management or
      therapy. An independent clinical review panel, convened at each participating
      centre, confirmed or rejected the clinical pharmacist's assessment of the impact
      on length of stay (LOS), readmission probability, medical procedures and
      laboratory monitoring and quantified the resultant changes, which were then
      costed. RESULTS: A total of 1399 interventions were documented. Eight hundred and
      thirty-five interventions impacted on drug costs alone. Five hundred and eleven
      interventions were evaluated by the independent panels with three quarters of
      these confirmed as having an impact on one or more of: length of stay,
      readmission probability, medical procedures or laboratory monitoring. There were
      96 interventions deemed by the independent panels to have reduced LOS and 156
      reduced the potential for readmission. The calculated savings was $263 221 for
      the eight hospitals during the period of the study. This included $150 307 for
      length of stay reduction, $111 848 for readmission reduction. CONCLUSIONS: The
      annualized cost savings relating to length of stay, readmission, drugs, medical
      procedures and laboratory monitoring as a result of clinical pharmacist initiated
      changes to hospitalized patient management or therapy was $4 444 794 for eight
      major acute care government funded teaching hospitals in Australia.

PMID- 15025753
TI  - Professional athletes suffering from familial hypercholesterolaemia rarely
      tolerate statin treatment because of muscular problems.
AB  - AIMS: Muscular problems are the major group of side-effects during statin
      treatment. They are known to occur much more frequently during and after
      exercise. METHODS AND RESULTS: For the last 8 years we have monitored 22
      professional athletes in whom, because of familial hypercholesterolaemia,
      treatment with different statins was attempted. Only six out of the 22 finally
      tolerated at least one member of this family of drugs. In three of these six the
      first statin prescribed allowed training performance without any limitation.
      Changing the drug demonstrated that only two tolerated all the four or five
      statins examined (atorvastatin, fluvastatin, lovastatin, pravastatin,
      simvastatin). Cerivastatin was not among the statins prescribed. CONCLUSIONS:
      These findings indicate that in top sports performers only about 20% tolerate
      statin treatment without side-effects. Clinical decision making as to lipid
      lowering therapy thus becomes a critical issue in this small subgroup of
      patients.

PMID- 15025754
TI  - Protein binding and alpha : beta anomer ratio of dihydroartemisinin in vivo.
AB  - AIMS: To determine the ratio of alpha : beta anomers and the protein binding of
      dihydroartemisinin (DHA) in vivo. METHODS: 10-[(3)H]-DHA was synthesized by
      reduction of artemisinin with sodium boro-[(3)H]-hydride and purified with
      preparative thin layer chromatography. A solution of (3)H-DHA (2000 ng in 20
      micro l) was added to 2 ml whole blood from 15 healthy volunteers and 22
      Vietnamese patients with falciparum or vivax malaria. The blood was centrifuged
      and the plasma stored at -25 degrees C until analysed by HPLC with
      radiochromatographic detection. Protein-free ultrafiltrate of the plasma was
      assayed to determine the free fraction of DHA and the in vivo ratio of alpha-DHA
      : beta-DHA. RESULTS: The DHA fraction unbound (mean +/- SD) was 0.068 +/- 0.032
      in Vietnamese patients with falciparum malaria (n = 17), 0.065 +/- 0.009 in
      Vietnamese patients with vivax malaria (n = 5), 0.117 +/- 0.015 in Vietnamese
      volunteers (n = 7) and 0.092 +/- 0.020 in Caucasian volunteers (n = 8). The
      ratios of alpha-DHA : beta-DHA for the four groups were 6.3 +/- 0.9, 6.9 +/- 0.8,
      6.9 +/- 0.6 and 5.4 +/- 0.8, respectively. CONCLUSIONS: DHA is approximately 93%
      protein-bound in patients with malaria infection and there is a preferential
      existence in vivo of the alpha-DHA anomer. Knowledge of this stereochemistry may
      be valuable in elucidation of the mechanisms of DHA action and/or toxicity, and
      in the synthesis of new trioxane antimalarials.

PMID- 15025758
TI  - Innovations in technology for critical care medicine.
AB  - This new section in Critical Care presents a selection of clinically important
      examples of advances in critical care health technology. This article is divided
      into two main areas: diagnostics and monitoring. Attention is given to how
      bedside echocardiography can alter the cardiovascular physical examination, and
      to novel imaging techniques such as virtual bronchoscopy. The monitoring section
      discusses recent claims of improved efficiency with telemedicine for intensive
      care units.

PMID- 15025759
TI  - Inhaled nitric oxide: another weapon in our armamentarium in the battle against
      acute hypoxic respiratory failure in preterm infants.
AB  - Acute hypoxic respiratory failure (AHRF) remains a significant cause of death in
      intensive care units. With the realization that pathophysiologic abnormalities in
      AHRF involve surfactant abnormalities as well as inflammatory and vascular
      changes, it is not surprising that nitric oxide (NO) has been investigated as an
      adjunct to the multiple ventilatory strategies adopted in the management of this
      disorder. Since the enthusiastic reports of Roussaint in 1993 showing improved
      survival with inhaled NO in the management of AHRF, several well-designed studies
      have been published, all designed to investigate the utility of NO in neonatal,
      pediatric and adult patients. Michael Schreiber and colleagues evaluated 207
      preterm infants with AHRF in a randomized, double-blind placebo-controlled study.
      Inhaled NO was administered at a constant low dose for up to 6 days in the NO
      group. Patients were further randomized to conventional ventilation and to high
      frequency oscillatory ventilation. The patients showed a statistically
      significant improvement in their primary endpoint of the incidence of chronic
      lung injury and death in the inhaled NO group. There was no increase in the
      incidence of intraventricular hemorrhage between the study and placebo groups.
      Schreiber and colleagues concluded that early treatment with inhaled NO would
      improve long-term pulmonary outcomes in premature infants with respiratory
      distress syndrome, decreasing the incidence of chronic lung disease and death.
      Prior to this study no prospective randomized trial had demonstrated any benefits
      in clinical outcomes such as the length of hospital stay or death. This study
      supports the belief that the majority of patients will experience, at a minimum,
      a short-term benefit from inhaled NO therapy, but also suggests that inhaled NO
      may influence clinical outcomes as well. The recognition that AHRF is often the
      result of a multifactorial process makes it unlikely that one treatment modality
      will have a major beneficial effect on mortality and morbidity.

PMID- 15025761
TI  - The ethical analysis of risk in intensive care unit research.
AB  - Research in the intensive care unit (ICU) is commonly thought to pose 'serious
      risk' to study participants. This perception may be at the root of a variety of
      impediments to the conduct of clinical trials in the ICU setting. Component
      analysis offers a promising approach to the ethical analysis of ICU research.
      Because clinical trials commonly involve a mixture of study interventions,
      therapeutic and nontherapeutic procedures must be analyzed separately.
      Therapeutic procedures must meet the requirement of clinical equipoise. Risks
      associated with nontherapeutic procedures must be minimized consistent with sound
      scientific design, and be deemed reasonable in relation to the knowledge to be
      gained. When research involves a vulnerable population, such as adults incapable
      of providing informed consent, nontherapeutic risks are limited to a minor
      increase over minimal risk. Understood in this way, the incremental risk posed by
      participation in ICU research may be minimal. This realization has important
      implications for review by institutional review boards of such research and for
      the informed consent process.

PMID- 15025760
TI  - Ethics roundtable debate: withdrawal of tube feeding in a patient with persistent
      vegetative state where the patients wishes are unclear and there is family
      dissension.
AB  - The decision to withdraw or withhold life supporting treatment in moribund
      patients is difficult under any circumstances. When the patient becomes
      incompetent to clarify their wishes regarding continued maintenance in long-term
      facilities, surrogates sometimes cannot agree, further clouding the issue. We
      examine a case where the State's interests come into play, forcing a
      controversial resolution.

PMID- 15025762
TI  - To plug or not to plug?
AB  - Coronary artery disease remains a common problem in industrialized countries.
      Percutaneous coronary interventions are usually performed utilizing the femoral
      approach. Arterial puncture-closing devices have been developed in hope to avoid
      manual compression and shortening the period of rest. In a recent meta-analysis
      in the Journal of the American Medical Association these devices have shown only
      marginal benefits over manual compression. Further, well designed studies are
      necessary to document the comparative effects of these devices versus manual
      compression.

PMID- 15025763
TI  - Blood management in intensive care medicine: CRIT and ABC--what can we learn?
AB  - In 284 US intensive care units the CRIT study (Anemia and blood transfusion in
      the critically ill--Current clinical practice in the United States) assessed
      allogeneic red blood cell (RBC) transfusion and outcome in 4892 patients. As in
      the former European ABC study (Anemia and blood transfusion in the critically
      ill), the mean pretransfusion hemoglobin was approximately 8.5 g/dl and RBC
      transfusions were independently associated with an increased mortality. These
      studies were purely observational and, therefore, despite the finest statistical
      models indicating that RBC transfusions were independently associated with a
      higher mortality, it remains possible that this adverse outcome is not due to a
      harmful effect of RBC transfusion in itself, but merely reflects the fact that
      transfused patients were sicker to start with. The definitive call is still out,
      but one mechanism by which RBC transfusion might be harmful now appears less
      likely; namely, storage lesion. In the CRIT study, mortality was not increased in
      patients receiving 'old' RBCs (>14 days stored) versus 'fresh' RBCs. The effect
      of leukoreduction could not be assessed since mainly nonleukoreduced RBCs were
      transfused. The evidence is mounting, however, that RBC transfusions are
      efficacious only when oxygen delivery is compromised. What can be done to
      diminish the use of RBC transfusions, its costs and side effects in intensive
      care medicine? There are two important options available today: decreasing blood
      loss for diagnostic purposes using pediatric sampling tubes, and establishing
      restrictive multidisciplinary transfusion guidelines and implementing them in
      daily clinical practice.

PMID- 15025764
TI  - Recently published papers: choose well, treat well, get well--which matters most?

PMID- 15025766
TI  - Increased blood lacate levels: an important warning signal in surgical practice.
AB  - Both in emergency and elective surgical patients increased blood lactate levels
      warn the physician that the patient is at risk of increased morbidity and
      decreased changes of survival. Prompt therapeutic measures to restore the balance
      between oxygen demand and supply are warranted in these patients.

PMID- 15025767
TI  - Coagulation in sepsis: all bugs bite equally.
AB  - Sepsis almost invariably leads to hemostatic abnormalities, ranging from
      insignificant laboratory changes to severe disseminated intravascular
      coagulation. There is compelling evidence from clinical and experimental studies
      that disseminated intravascular coagulation is involved in the pathogenesis of
      microvascular dysfunction and contributes to organ failure. Data from the PROWESS
      phase III clinical trial of recombinant activated protein C in patients with
      severe sepsis confirm this notion and demonstrate that the vast majority of
      patients with severe sepsis have increased markers for systemic coagulation
      activation, decreased physiological anticoagulant proteins and depressed
      fibrinolysis. There is no correlation between the type of microorganism that has
      caused the infection and the presence or severity of the coagulation disorder.

PMID- 15025765
TI  - Is there a place for N-acetylcysteine in the treatment of septic shock?
AB  - Excessive inflammatory responses and impaired oxygen utilization because of
      microcirculatory failure are implicated in septic shock. Recent studies have
      pointed out some beneficial effects in the treatment of septic shock of several
      vasodilators that exert anti-inflammatory properties. In particular, the
      antioxidant N-acetylcysteine has been demonstrated to enhance cardiac
      performance, and to improve hepatosplanchnic perfusion and liver function in
      patients with established septic shock. These clinical observations may lead us
      to examine further the role of antioxidant agents in developing novel therapies
      for septic shock.

PMID- 15025768
TI  - Partitioning the work-sparing effects of partial ventilatory support in airflow
      obstruction.
AB  - Sweeping conclusions regarding the utility or nonutility of elevating expiratory
      pressure are not warranted. The effects of manipulating airway pressure in the
      setting of airflow obstruction depend heavily on the nature and severity of
      disease, as well as on the presence of airflow limitation during tidal breathing.

PMID- 15025769
TI  - Understanding the lingering consequences of what we treat and what we do.
AB  - Granja and colleagues have helped us by showing that long-term follow-up is
      feasible and by trying to tease out whether select intensive care unit patient
      populations are at particular risk of adverse outcomes. This work gives us clues
      for future investigations which will hopefully interrogate further the potential
      mechanisms of action that underlie poor long-term outcomes. In the meantime, we
      can hope that this quality of follow-up will move from the research arena to
      become a part of routine clinical care.

PMID- 15025770
TI  - Pro/con clinical debate: steroids are a key component in the treatment of SARS.
      Pro: Yes, steroids are a key component of the treatment regimen for SARS.
AB  - SARS (severe acute respiratory syndrome) proved an enormous physical and
      emotional challenge to frontline health care workers throughout the world in late
      2002 through to mid 2003. A large percentage of patients (many being health care
      workers themselves) became critically ill. Unfortunately, clinicians caring for
      these individuals did not have the advantage of previous experience or research
      data on which to base treatment decisions. As a result, at least early in the
      outbreak, a 'best guess approach' and/or anecdotes drove therapy. In many centres
      systemic steroids, which carry many potential downsides, became a mainstay of
      therapy. In this issue of Critical Care, two groups that have frontline
      experience of SARS debate the role of steroids. Let us hope and pray together
      that we never have the patient population needed to resolve the questions the two
      sides raise.

PMID- 15025771
TI  - Bench-to-bedside review: treating acid-base abnormalities in the intensive care
      unit--the role of renal replacement therapy.
AB  - Acid-base disorders are common in critically ill patients. Metabolic acid-base
      disorders are particularly common in patients who require acute renal replacement
      therapy. In these patients, metabolic acidosis is common and multifactorial in
      origin. Analysis of acid-base status using the Stewart-Figge methodology shows
      that these patients have greater acidemia despite the presence of hypoalbuminemic
      alkalosis. This acidemia is mostly secondary to hyperphosphatemia,
      hyperlactatemia, and the accumulation of unmeasured anions. Once continuous
      hemofiltration is started, profound changes in acid-base status are rapidly
      achieved. They result in the progressive resolution of acidemia and acidosis,
      with a lowering of concentrations of phosphate and unmeasured anions. However, if
      lactate-based dialysate or replacement fluid are used, then in some patients
      hyperlactatemia results, which decreases the strong ion difference and induces an
      iatrogenic metabolic acidosis. Such hyperlactatemic acidosis is particularly
      marked in lactate-intolerant patients (shock with lactic acidosis and/or liver
      disease) and is particularly strong if high-volume hemofiltration is performed
      with the associated high lactate load, which overcomes the patient's metabolic
      capacity for lactate. In such patients, bicarbonate dialysis seems desirable. In
      all patients, once hemofiltration is established, it becomes the dominant force
      in controlling metabolic acid-base status and, in stable patients, it typically
      results in a degree of metabolic alkalosis. The nature and extent of these acid
      base changes is governed by the intensity of plasma water exchange/dialysis and
      by the 'buffer' content of the replacement fluid/dialysate, with different
      effects depending on whether lactate, acetate, citrate, or bicarbonate is used.
      These effects can be achieved in any patient irrespective of whether they have
      acute renal failure, because of the overwhelming effect of plasma water exchange
      on nonvolatile acid balance. Critical care physicians must understand the nature,
      origin, and magnitude of alterations in acid-base status seen with acute renal
      failure and during continuous hemofiltration if they wish to provide their
      patients with safe and effective care.

PMID- 15025772
TI  - Clinical review: the implications of experimental and clinical studies of
      recruitment maneuvers in acute lung injury.
AB  - Mechanical ventilation can cause and perpetuate lung injury if alveolar
      overdistension, cyclic collapse, and reopening of alveolar units occur. The use
      of low tidal volume and limited airway pressure has improved survival in patients
      with acute lung injury or acute respiratory distress syndrome. The use of
      recruitment maneuvers has been proposed as an adjunct to mechanical ventilation
      to re-expand collapsed lung tissue. Many investigators have studied the benefits
      of recruitment maneuvers in healthy anesthetized patients and in patients
      ventilated with low positive end-expiratory pressure. However, it is unclear
      whether recruitment maneuvers are useful when patients with acute lung injury or
      acute respiratory distress syndrome are ventilated with high positive end
      expiratory pressure, and in the presence of lung fibrosis or a stiff chest wall.
      Moreover, it is unclear whether the use of high airway pressures during
      recruitment maneuvers can cause bacterial translocation. This article reviews the
      intrinsic mechanisms of mechanical stress, the controversy regarding clinical use
      of recruitment maneuvers, and the interactions between lung infection and
      application of high intrathoracic pressures.

PMID- 15025773
TI  - Clinical review: corticotherapy in sepsis.
AB  - The use of glucocorticoids (corticotherapy) in severe sepsis is one of the main
      controversial issues in critical care medicine. These agents were commonly used
      to treat sepsis until the end of the 1980s, when several randomized trials casted
      serious doubt on any benefit from high-dose glucocorticoids. Later, important
      progress in our understanding of the role played by the hypothalamic-pituitary
      adrenal axis in the response to sepsis, and of the mechanisms of action of
      glucocorticoids led us to reconsider their use in septic shock. The present
      review summarizes the basics of the physiological response of the hypothalamic
      pituitary-adrenal axis to stress, including regulation of glucocorticoid
      synthesis, the cellular mechanisms of action of glucocorticoids, and how they
      influence metabolism, cardiovascular homeostasis and the immune system. The
      concepts of adrenal insufficiency and peripheral glucocorticoid resistance are
      developed, and the main experimental and clinical data that support the use of
      low-dose glucocorticoids in septic shock are discussed. Finally, we propose a
      decision tree for diagnosis of adrenal insufficiency and institution of cortisol
      replacement therapy.

PMID- 15025774
TI  - Statistics review 9: one-way analysis of variance.
AB  - This review introduces one-way analysis of variance, which is a method of testing
      differences between more than two groups or treatments. Multiple comparison
      procedures and orthogonal contrasts are described as methods for identifying
      specific differences between pairs of treatments.

PMID- 15025775
TI  - Pleural drainage: an evolving area.

PMID- 15025777
TI  - Anti-inflammatory effects of the antibiotics ceftazidime and tobramycin in
      porcine endotoxin shock: are they really anti-inflammatory?

PMID- 15025779
TI  - Occult hypoperfusion is associated with increased mortality in hemodynamically
      stable, high-risk, surgical patients.
AB  - BACKGROUND: Our aim was to examine whether serial blood lactate levels could be
      used as predictors of outcome. METHODS: We prospectively studied 44 high-risk,
      hemodynamically stable, surgical patients. Blood lactate values, mean arterial
      pressure, heart rate and urine output were obtained at patient admission to the
      study, at 12, 24 and 48 hours. RESULTS: The nonsurvivors (n = 7) had similar
      blood lactate levels initially (3.1 +/- 2.3 mmol/l versus 2.2 +/- 1.0 mmol/l, P =
      not significant [NS]), but had higher levels after 12 hours (2.9 +/- 1.7 mmol/l
      versus 1.6 +/- 0.9 mmol/l, P = 0.012), after 24 hours (2.1 +/- 0.6 mmol/l versus
      1.5 +/- 0.7 mmol/l, P = NS) and after 48 hours (2.7 +/- 1.8 mmol/l versus 1.9 +/-
      1.4 mmol/l, P = NS) as compared with the survivors (n = 37). Arterial bicarbonate
      concentrations increased significantly in survivors and were higher than in
      nonsurvivors after 24 hours (22.9 +/- 5.2 mEq/l versus 16.7 +/- 3.9 mEq/l, P =
      0.01) and after 48 hours (23.1 +/- 4.1 mEq/l versus 17.6 +/- 7.1 mEq/l, P = NS).
      The PaO2/FiO2 ratio was higher in survivors initially (334 +/- 121 mmHg versus
      241 +/- 133 mmHg, P = 0.03) and remained elevated for 48 hours. There were no
      significant differences in mean arterial pressure, heart rate, and arterial blood
      oxygenation at any time between survivors and nonsurvivors. The intensive care
      unit stay (40 +/- 42 hours versus 142 +/- 143 hours, P < 0.001) and the hospital
      stay (12 +/- 11 days versus 24 +/- 17 days, P = 0.022) were longer for
      nonsurvivors than for survivors. The Simplified Acute Physiology Score II score
      was higher for nonsurvivors than for survivors (34 +/- 9 versus 25 +/- 14, P =
      NS). The urine output was slightly lower in the nonsurvivor group (P = NS). The
      areas under the receiving operating characteristic curves were larger for initial
      values of Simplified Acute Physiology Score II and blood lactate for predicting
      death. CONCLUSION: Elevated blood lactate levels are associated with a higher
      mortality rate and postoperative complications in hemodynamically stable surgical
      patients.

PMID- 15025780
TI  - N-acetylcysteine decreases lactate signal intensities in liver tissue and
      improves liver function in septic shock patients, as shown by magnetic resonance
      spectroscopy: extended case report.
AB  - BACKGROUND: N-acetylcysteine (NAC) has been shown to improve splanchnic blood
      flow in experimental studies. This report evaluates the effects of NAC on liver
      perfusion and lactate signal intensities in the liver tissue of septic shock
      patients using proton magnetic resonance imaging and spectroscopy. Furthermore,
      the monoethylglycinexylidide (MEGX) test was used to investigate hepatic
      function. METHODS: Five septic shock patients received 150 mg/kg body weight NAC
      as an intravenous bolus injection over 15 min. Lidocaine was injected both prior
      to and following NAC administration in order to determine MEGX formation.
      Measurements (hemodynamics, oxygen transport-related variables, blood samples for
      lactate, liver-related markers) were performed 1 hour before and 1 hour after NAC
      injection. In addition to the proton magnetic resonance imaging patients received
      two proton magnetic resonance spectra, one prior to and one 30 min subsequent to
      the onset of the NAC infusion at a 1.5 Tesla clinical scanner, for measurement of
      liver perfusion and liver lactate signal intensity. MAIN FINDINGS: Following NAC
      infusion, the lactate signal intensity in the liver tissue showed a median
      decrease of 89% (11-99%), there was a median increase in liver perfusion of 41% (
      14 to 559%), and the MEGX serum concentration increased three times (1.52-5.91).
      CONCLUSIONS: A decrease in the lactate signal intensity in the liver tissue and
      an increase in the MEGX serum concentration and in liver perfusion might indicate
      improved liver function as a result of NAC administration. Patients with
      compromised hepatosplanchnic function, such as patients with septic shock due to
      peritonitis, may therefore benefit from NAC therapy.

PMID- 15025781
TI  - Effects of the components of positive airway pressure on work of breathing during
      bronchospasm.
AB  - INTRODUCTION: Partial assist ventilation reduces work of breathing in patients
      with bronchospasm; however, it is not clear which components of the ventilatory
      cycle contribute to this process. Theoretically, expiratory positive airway
      pressure (EPAP), by reducing expiratory breaking, may be as important as
      inspiratory positive airway pressure (IPAP) in reducing work of breathing during
      acute bronchospasm. METHOD: We compared the effects of 10 cmH2O of IPAP, EPAP,
      and continuous positive airwaypressure (CPAP) on inspiratory work of breathing
      and end-expiratory lung volume (EELV) in a canine model of methacholine-induced
      bronchospasm. RESULTS: Methacholine infusion increased airway resistance and work
      of breathing. During bronchospasm IPAP and CPAP reduced work of breathing
      primarily through reductions in transdiaphragmatic pressure per tidal volume
      (from 69.4 +/- 10.8 cmH2O/l to 45.6 +/- 5.9 cmH2O/l and to 36.9 +/- 4.6 cmH2O/l,
      respectively; P < 0.05) and in diaphragmatic pressure-time product (from 306 +/-
      31 to 268 +/- 25 and to 224 +/- 23, respectively; P < 0.05). Pleural pressure
      indices of work of breathing were not reduced by IPAP and CPAP. EPAP
      significantly increased all pleural and transdiaphragmatic work of breathing
      indices. CPAP and EPAP similarly increased EELV above control by 93 +/- 16 ml and
      69 +/- 12 ml, respectively. The increase in EELV by IPAP of 48 +/- 8 ml (P <
      0.01) was significantly less than that by CPAP and EPAP. CONCLUSION: The
      reduction in work of breathing during bronchospasm is primarily induced by the
      IPAP component, and that for the same reduction in work of breathing by CPAP,
      EELV increases more.

PMID- 15025782
TI  - Universal changes in biomarkers of coagulation and inflammation occur in patients
      with severe sepsis, regardless of causative micro-organism [ISRCTN74215569].
AB  - INTRODUCTION: PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation
      in Severe Sepsis) was a phase III, randomized, double blind, placebo controlled,
      multicenter trial conducted in patients with severe sepsis from 164 medical
      centers. Here we report data collected at study entry for 1690 patients and over
      the following 7 days for the 840 patients who received placebo (in addition to
      usual standard of care). METHODS: Nineteen biomarkers of coagulation activation,
      anticoagulation, fibrinolysis, endothelial injury, and inflammation were analyzed
      to determine the relationships between baseline values and their change over
      time, with 28-day survival, and type of infecting causative micro-organism.
      RESULTS: Levels of 13 of the 19 biomarkers at baseline correlated with Acute
      Physiology and Chronic Health Evaluation II scores, and nearly all patients
      exhibited coagulopathy, endothelial injury, and inflammation at baseline. At
      study entry, elevated D-dimer, thrombin-antithrombin complexes, IL-6, and
      prolonged prothrombin time were present in 99.7%, 95.5%, 98.5%, and 93.4% of
      patients, respectively. Markers of endothelial injury (soluble thrombomodulin)
      and deficient protein C, protein S, and antithrombin were apparent in 72%, 87.6%,
      77.8%, and 81.7%, respectively. Impaired fibrinolysis (elevated plasminogen
      activator inhibitor-1) was observed in 44% of patients. During the first 7 days,
      increased prothrombin time (which is readily measurable in most clinical
      settings) was highly evident among patients who were not alive at 28 days.
      CONCLUSION: Abnormalities in biomarkers of inflammation and coagulation were
      related to disease severity and mortality outcome in patients with severe sepsis.
      Coagulopathy and inflammation were universal host responses to infection in
      patients with severe sepsis, which were similar across causative micro-organism
      groups.

PMID- 15025783
TI  - Quality of life of survivors from severe sepsis and septic shock may be similar
      to that of others who survive critical illness.
AB  - INTRODUCTION: The objective of the present study was to compare the health
      related quality of life (HR-QoL) of survivors from severe sepsis and septic shock
      with HR-QoL in others who survived critical illness not involving sepsis.
      METHODS: From March 1997 to March 2001, adult patients in an eight-bed
      medical/surgical intensive care unit (ICU) of a tertiary care hospital admitted
      with severe sepsis or septic shock (sepsis group; n = 305) were enrolled and
      compared with patients admitted without sepsis (control group; n = 392). Patients
      younger than 18 years (n = 48) and those whose ICU stay was 1 day or less (n =
      453) were excluded. In addition, patients exhibiting nonsevere sepsis on
      admission were excluded (n = 87). Finally, patients who developed nonsevere
      sepsis or severe sepsis/septic shock after admission were also excluded (n = 88).
      RESULTS: In-hospital mortality rates were 34% in the sepsis group and 26% in the
      control group. There were no differences in sex, age, main activity (work
      status), and previous health state between groups. Survivors in the sepsis group
      had a significantly higher Acute Physiology and Chronic Health Evaluation II
      score on admission (17 versus 12) and stayed significantly longer in the ICU. A
      follow-up appointment was held 6 months after ICU discharge, and an EQ-5D
      (EuroQol five-dimension) questionnaire was administered. A total of 104 sepsis
      survivors and 133 survivors in the control group answered the EQ-5D
      questionnaire. Sepsis survivors reported significantly fewer problems only in the
      anxiety/depression dimension. Although there were no significant differences in
      the other dimensions of the EQ-5D, there was a trend towards fewer problems being
      reported by sepsis survivors. CONCLUSION: Evaluation using the EQ-5D at 6 months
      after ICU discharge indicated that survivors from severe sepsis and septic shock
      have a similar HR-QoL to that of survivors from critical illness admitted without
      sepsis.

PMID- 15025784
TI  - Case mix, outcome and length of stay for admissions to adult, general critical
      care units in England, Wales and Northern Ireland: the Intensive Care National
      Audit & Research Centre Case Mix Programme Database.
AB  - INTRODUCTION: The present paper describes the methods of data collection and
      validation employed in the Intensive Care National Audit & Research Centre Case
      Mix Programme (CMP), a national comparative audit of outcome for adult, critical
      care admissions. The paper also describes the case mix, outcome and activity of
      the admissions in the Case Mix Programme Database (CMPD). METHODS: The CMP
      collects data on consecutive admissions to adult, general critical care units in
      England, Wales and Northern Ireland. Explicit steps are taken to ensure the
      accuracy of the data, including use of a dataset specification, of initial and
      refresher training courses, and of local and central validation of submitted data
      for incomplete, illogical and inconsistent values. Criteria for evaluating
      clinical databases developed by the Directory of Clinical Databases were applied
      to the CMPD. The case mix, outcome and activity for all admissions were briefly
      summarised. RESULTS: The mean quality level achieved by the CMPD for the 10
      Directory of Clinical Databases criteria was 3.4 (on a scale of 1 = worst to 4 =
      best). The CMPD contained validated data on 129,647 admissions to 128 units. The
      median age was 63 years, and 59% were male. The mean Acute Physiology and Chronic
      Health Evaluation II score was 16.5. Mortality was 20.3% in the CMP unit and was
      30.8% at ultimate discharge from hospital. Nonsurvivors stayed longer in
      intensive care than did survivors (median 2.0 days versus 1.7 days in the CMP
      unit) but had a shorter total hospital length of stay (9 days versus 16 days).
      Results for the CMPD were comparable with results from other published reports of
      UK critical care admissions. CONCLUSIONS: The CMP uses rigorous methods to ensure
      data are complete, valid and reliable. The CMP scores well against published
      criteria for high-quality clinical databases.

PMID- 15025786
TI  - Human primary osteoclasts: in vitro generation and applications as
      pharmacological and clinical assay.
AB  - Osteoclasts are cells of hematopoietic origin with a unique property of
      dissolving bone; their inhibition is a principle for treatment of diseases of
      bone loss. Protocols for generation of human osteoclasts in vitro have been
      described, but they often result in cells of low activity, raising questions on
      cell phenotype and suitability of such assays for screening of bone resorption
      inhibitors. Here we describe an optimized protocol for the production of stable
      amounts of highly active human osteoclasts. Mononuclear cells were isolated from
      human peripheral blood by density centrifugation, seeded at 600,000 cells per 96
      well and cultured for 17 days in alpha-MEM medium, supplemented with 10% of
      selected fetal calf serum, 1 microM dexamethasone and a mix of macrophage-colony
      stimulating factor (M-CSF, 25 ng/ml), receptor activator of NFkappaB ligand
      (RANKL, 50 ng/ml), and transforming growth factor-beta1 (TGF-beta1, 5 ng/ml).
      Thus, in addition to widely recognized osteoclast-generating factors M-CSF and
      RANKL, other medium supplements and lengthy culture times were necessary. This
      assay reliably detected inhibition of osteoclast formation (multinucleated cells
      positive for tartrate-resistant acid phosphatase) and activity (resorbed area and
      collagen fragments released from bone slices) in dose response curves with
      several classes of bone resorption inhibitors. Therefore, this assay can be
      applied for monitoring bone-resorbing activity of novel drugs and as an clinical
      test for determining the capacity of blood cells to generate bone-resorbing
      osteoclasts. Isolation of large quantities of active human osteoclast mRNA and
      protein is also made possible by this assay.

PMID- 15025787
TI  - A note on the use of sensitivity analysis to explore the potential impact of
      declining institutional care utilisation on disability prevalence.
AB  - Many health and disability surveys are conducted using the non-institutionalised
      population as a sampling frame. Consequently, it is possible that changes in the
      utilisation of institutional care could account for all or part of any change in
      the observed prevalence of functional limitation, disability or other health
      state, based on samples from the non-institutionalised population. Using
      conditional probability arguments, I present an adjustment formula for computing
      health state prevalences for the non-institutionalised population under a
      scenario in which health state prevalences are held constant except for movement
      into the non-institutionalised population of individuals who would formerly have
      been in institutional care. By comparing the adjusted prevalence with observed
      non-institutionalised health state prevalences the contribution of changes in
      institutionalisation to observed changes in the non-institutionalised health
      state prevalence can be assessed.

PMID- 15025785
TI  - Characteristics and outcome for admissions to adult, general critical care units
      with acute severe asthma: a secondary analysis of the ICNARC Case Mix Programme
      Database.
AB  - INTRODUCTION: This report describes the case mix, outcome and activity (duration
      of intensive care unit [ICU] and hospital stay, inter-hospital transfer, and
      readmissions to the ICU) for admissions to ICUs for acute severe asthma, and
      investigates the effect of case mix factors on outcome. METHODS: We conducted a
      secondary analysis of data from a high-quality clinical database (the Intensive
      Care National Audit and Research Centre [ICNARC] Case Mix Programme Database) of
      129,647 admissions to 128 adult, general critical care units across England,
      Wales and Northern Ireland over the period 1995-2001. RESULTS: Asthma accounted
      for 2152 (1.7%) admissions, and in 57% mechanical ventilation was employed during
      the first 24 hours in the ICU. A total of 147 (7.1%) patients died in intensive
      care and 199 (9.8%) died before discharge from hospital. The mean age was 43.6
      years, and the ratio of women to men was 2:1. Median length of stay was 1.5 days
      in the ICU and 8 days in hospital. Older age, female sex, having received
      cardiopulmonary resuscitation (CPR) within 24 hours before admission, having
      suffered a neurological insult during the first 24 hours in the ICU, higher heart
      rate, and hypercapnia were associated with greater risk for in-hospital death
      after adjusting for Acute Physiology and Chronic Health Evaluation II score. CPR
      before admission, neurological insult, hypoxaemia and hypercapnia were associated
      with receipt of mechanical ventilation after adjusting for Acute Physiology and
      Chronic Health Evaluation II score. CONCLUSION: ICU admission for asthma is
      relatively uncommon but remains associated with appreciable in-hospital
      mortality. The greatest determinant of poor hospital survival in asthma patients
      was receipt of CPR within 24 hours before admission to ICU. Clinical management
      of these patients should be directed at preventing cardiac arrest before
      admission.

PMID- 15025788
TI  - Fine needle aspiration biopsy of liver - an update.

PMID- 15025789
TI  - Social function in schizophrenia and schizoaffective disorder: associations with
      personality, symptoms and neurocognition.
AB  - BACKGROUND: Research has indicated that stable individual differences in
      personality exist among persons with schizophrenia spectrum disorders predating
      illness onset that are linked to symptoms and self appraised quality of life.
      Less is known about how closely individual differences in personality are
      uniquely related to levels of social relationships, a domain of dysfunction in
      schizophrenia more often linked in the literature with symptoms and
      neurocognitive deficits. This study tested the hypothesis that trait levels of
      personality as defined using the five-factor model of personality would be linked
      to social function in schizophrenia. METHODS: A self-report measure of the five
      factor model of personality was gathered along with ratings of social function,
      symptoms and assessments of neurocognition for 65 participants with schizophrenia
      or schizoaffective disorder. RESULTS: Univariate correlations and stepwise
      multiple regression indicated that frequency of social interaction was predicted
      by higher levels of the trait of Agreeableness, fewer negative symptoms, better
      verbal memory and at the trend level, lesser Neuroticism (R2 =.42, p <.0001). In
      contrast, capacity for intimacy was predicted by fewer negative symptoms, higher
      levels of Agreeableness, Openness, and Conscientiousness and at the trend level,
      fewer positive symptoms (R2 =.67, p <.0001). CONCLUSIONS: Taken together, the
      findings of this study suggest that person-centered variables such as
      personality, may account for some of the broad differences seen in outcome in
      schizophrenia spectrum disorders, including social outcomes. One interpretation
      of the results of this study is that differences in personality combine with
      symptoms and neurocognitive deficits to affect how persons with schizophrenia are
      able to form and sustain social connections with others.

PMID- 15025790
TI  - One-step concentration of malarial parasite-infected red blood cells and removal
      of contaminating white blood cells.
AB  - BACKGROUND: Isolation of a concentrated, living preparation of malarial parasite
      infected red blood cells (PRBCs) that have low contamination of white blood cells
      (WBCs) facilitates research on the molecular, biochemical and immunological
      aspects of malarial parasites. This is currently carried out by a two-step
      method, including the concentration of PRBCs using density gradient
      centrifugation through Percoll or Nycodenz, followed by the removal of host WBCs
      using a cellulose powder column or a commercially available filtration unit.
      These two-step methods can help isolate sufficient PRBCs, but they are laborious.
      In this study, a simplified one-step procedure that takes advantage of the
      difference between diamagnetic low-spin oxyhaemoglobin and paramagnetic haemozoin
      (haem polymer) was described. The paramagnetic polymer is deposited in the food
      vacuoles of the parasite, allowing the use of magnetic separation to efficiently
      and rapidly concentrate PRBCs while removing contaminating host WBCs. METHODS:
      The magnetic removal of WBCs using a commercial LD column (MACS) was evaluated as
      a new method for concentrating and purifying PRBCs. To compare this method with
      the two density gradient centrifugation methods using Percoll or Nycodenz, we
      analysed the quantities of enriched PRBCs and contaminating host WBCs as well as
      the viability of malarial parasites in the final preparations. RESULTS: The
      quantity of PRBCs and the viability of malarial parasites in the isolated PRBCs
      were similar between magnetic and centrifugation methods. However, 90-99% of the
      contaminating WBCs were removed from the starting material using a magnetic
      column, whereas WBC content did not change using the Percoll or Nycodenz methods.
      CONCLUSION: The use of a commercially available magnetic LD column is effective,
      safe and easy for the one-step purification of PRBCs. This simple method does not
      affect the viability of malarial parasites.

PMID- 15025791
TI  - Cetuximab targeted therapy: a new treatment paradigm for advanced colorectal
      cancer.

PMID- 15025792
TI  - Update on adjuvant trials in the treatment of high-risk colorectal cancer.

PMID- 15025793
TI  - Ovarian neoplasms in patients with colorectal cancer: understanding the role of
      prophylactic oophorectomy.
AB  - Although the role of prophylactic oophorectomy is currently under debate and not
      well defined, it is of increasing and considerable relevance, especially in
      premenopausal women, particularly those with identifiable hereditary cancer
      syndromes. Patients with colorectal cancer with ovarian metastases are often
      symptomatic, require surgery, and have poor survival. Prophylactic oophorectomy
      abolishes the increased risk of primary ovarian cancer in these patients, resects
      synchronous metastases, and prevents development of metachronous ovarian
      metastases. Prophylactic oophorectomy trials, mostly conducted in postmenopausal
      women, have not shown survival advantage. In patients with ovarian metastases of
      colorectal cancer, maximal cytoreductive surgery followed by adjuvant therapy
      employing newer chemotherapeutic agents, whole abdominal irradiation with
      chemosensitization, or hyperthermic intraperitoneal chemotherapy may improve
      outcomes in selected patients.

PMID- 15025794
TI  - Biologic basis of ovarian metastasis of colorectal cancer.

PMID- 15025795
TI  - Dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms and their
      association with 5-fluorouracil/leucovorin chemotherapy in colorectal cancer.
AB  - The causes of interpatient variation in severe toxicity resulting from treatment
      with weekly 5-fluorouracil (5-FU)/ leucovorin (LV) are poorly understood. This
      study was undertaken to examine the contribution of commonly occurring
      polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene to interpatient
      variability in 5-FU pharmacokinetics and toxicity. Patients with stage III/IV
      colorectal cancer were treated by bolus intravenous (I.V.) injection with 500
      mg/m2 doses of 5-FU and LV once every week. The pharmacokinetics of 5-FU was
      determined on weeks 1 and 4. Genotyping assays were developed for 8 polymorphisms
      in the DPYD gene. A well-characterized functional polymorphism in the 5'
      untranslated region of the thymidylate synthase (TS) gene was also analyzed. A
      cohort of 22 patients (15 male, 7 female) with a median age of 61 years was
      evaluated. Although there was no relationship between the area under the plasma
      concentration time curve (AUC) for the first dose of 5-FU and worst-grade
      toxicity during the first cycle of therapy, 3 of the 4 patients in whom the AUC
      on week 4 was more than equal to 5 microgram/h/mL greater than the value for the
      first dose experienced grade 3/4 toxicity during subsequent treatment. Among the
      8 polymorphisms in the DPYD gene, 7 were found to vary in the study population
      but none were significantly associated with the AUC of 5-FU. There was no
      relationship between the DPYD and TS genotypes examined and 5-FU toxicity.
      Extensive polymorphism in the DPYD gene was observed; however, no conclusive
      correlations existed between the DPYD and TS genotype and 5-FU pharmacokinetics
      or toxicity. Decreases in 5-FU clearance in certain patients may provide insight
      into the increased toxicity following repetitive cycles of treatment with weekly
      I.V. bolus 5-FU. The present study offers useful themes for undertaking larger
      prospective pharmacogenetic studies in the future.

PMID- 15025796
TI  - Phase III study of mitomycin-C with protracted venous infusion or circadian-timed
      infusion of 5-fluorouracil in advanced colorectal carcinoma.
AB  - The combination of protracted venous infusion (PVI) fluorouracil (5-FU) and
      mitomycin-C has previously been shown to be superior to PVI 5-FU alone in terms
      of response rate and failure-free survival. This study explores the effect of
      dose intensification by circadian timing of 5-FU in this combination on response,
      toxicity, and survival. Patients with advanced colorectal carcinoma were
      randomized to receive PVI 5-FU 300 mg/m2 daily or circadian-timed infusion (CTI)
      of 5-FU, beginning at 600 mg/m2 and subsequently reduced to 450 mg/m2, delivered
      as a flat-rate infusion from 10:15 PM to 9:45 AM. Both groups received mitomycin
      C at a dose of 7 mg/m2 given every 6 weeks. From April 1996 to August 1998, 320
      patients were randomized, including 263 with metastatic disease and 21 with
      circumferential margin involvement. The overall response rate for the PVI 5-FU
      group was 38%, compared with 30.3% for the CTI group (P = 0.176). There was no
      statistically significant difference in terms of failure-free survival (8.0
      months vs. 9.9 months; P = 0.131) or overall survival (15.8 months vs. 16.3
      months; P = 0.275) between the treatment groups. There were no differences in
      global quality of life. Grade 3/4 diarrhea occurred significantly more frequently
      with CTI 5-FU (6.5% vs. 19.8%; P < 0.001); a nonsignificant trend toward
      increased incidences of grade 3/4 infection and palmar plantar erythema were
      observed with CTI 5-FU. This study confirms the high response rate and overall
      survival figures for the combination of PVI 5-FU and mitomycin-C in colorectal
      cancer. However, dose intensification of 5-FU using a circadian-timed, flat-rate
      infusion did not lead to improved response or survival.

PMID- 15025797
TI  - Cyclooxygenase-2 expression in right- and left-sided colon cancer: a rationale
      for optimization of cyclooxygenase-2 inhibitor therapy.
AB  - Cyclooxygenase-2 (COX-2) has been identified as a potential target for prevention
      and therapy of human colorectal cancers (CRC) and other cancers. Because right
      sided colon cancers (RSCCs) exhibit clinicopathologic and genetic differences
      from left-sided colorectal cancers (LSCRCs), determination of COX-2 status in
      these subsets of CRCs may be clinically relevant in designing COX-2 inhibitor
      trials for CRC and in subsequent assessment of objective therapeutic response to
      such therapy. Thirty-six primary CRC resection specimens (18 left, 18 right) from
      36 patients were evaluated. Representative tumor sections were subjected to
      immunohistochemical analysis of COX-2. A semiquantitative system was used to
      score cytoplasmic COX-2 immunostaining. The tumors were considered COX-2 positive
      if more than 10% tumor cells showed COX-2 staining. Clinicopathologic and COX-2
      data were compared for LSCRCs versus RSCCs. All 18 LSCRCs and 13 of 18 (72%)
      RSCCs were well to moderately differentiated. Overall rates of COX-2 positivity
      for the LSCRCs versus RSCCs were 67% (12 of 18) and 33% (6 of 18), respectively
      (P = 0.04). Furthermore, 11 of 12 (92%) COX-2 positive LSCRCs and 3 of 6 (50%)
      COX-2 positive RSCCs were stage II-IV at resection. All 12 COX-2 positive LSCRCs
      were associated with advanced primary tumor and 4 of 12 (33%) LCRCs had distant
      metastases. These associations could not be evaluated for the RSCCs because of
      the limited number of COX-2 positive cases. The more frequent expression of COX-2
      in LSCRCs as compared with RSCCs supports the hypothesis that COX-2 expression
      may be related to genetic alterations specific to right- or left-sided CRCs.
      Further studies are needed to elucidate such relationships. Our data also suggest
      that stratification of patients with CRC into right- and left-sided subsets may
      be important in optimal patient selection for COX-2 inhibitor therapy and for
      subsequent assessment of objective therapeutic response.

PMID- 15025798
TI  - Renal stone analysis: why and how?
AB  - Upper urinary tract stone disease is widespread in the developed world. On both
      clinical and economic grounds it is now accepted that evidence-based medical
      intervention is the only approach likely to make a significant impact on the
      incidence, and more importantly, the recurrence rates of this disease. Targeted
      medical prophylaxis requires reliable information on stone type which, when
      combined with relevant blood and urine analyses, allows identification of
      treatable risk factors. Data from an external quality assurance scheme indicate
      that stone analysis is poorly performed in many laboratories, and it is probable
      that this results in ill-informed patterns of investigation, inappropriate
      therapy, missed diagnoses of rarer causative disorders and wasteful further
      investigation of 'non-renal' stone artefacts. Renal stone analysis is a
      specialist investigation requiring appropriate analytical and interpretative
      expertise if the information is to be used to enhance patient care. For those
      laboratories not able to offer this, for whatever reason, referral is the only
      defensible approach to service provision. The methods currently employed in many
      departments have no place in modern clinical biochemistry practice.

PMID- 15025799
TI  - Cholinesterase: phenotyping and genotyping.
AB  - The plasma enzyme butyrylcholinesterase (BChE) is of clinical interest because of
      the occurrence of genetic variants with decreased ability to hydrolyse, and
      therefore inactivate, muscle-relaxant drugs such as suxamethonium. Analysis of
      BChE involves the determination of both enzyme activity and biochemical
      phenotypes which are used to determine the risk of so-called 'scoline apnoea'.
      Problems in analysis arise from both the lack of a universally accepted reference
      method and the variety of substrates and conditions employed for the
      determination of activity and phenotypes. Phenotype is determined by the use of
      specific enzyme inhibitors that produce phenotype-specific patterns of 'inhibitor
      numbers'. DNA analysis is now possible, and true genotypes can be obtained. The
      nomenclature in use for cholinesterase studies can cause problems in
      interpretation and reporting as there is poor understanding of the difference
      between phenotype and genotype, and terms are often, inappropriately, transposed.
      Techniques for both biochemical and molecular analysis of the enzyme are
      discussed.

PMID- 15025800
TI  - Measurement of urinary cystatin C by particle-enhanced nephelometric immunoassay:
      precision, interferences, stability and reference range.
AB  - BACKGROUND: Urinary excretion of the low molecular weight protein cystatin C is a
      marker of renal disorders and a good predictor of the severity of acute tubular
      necrosis. We evaluated the measurement of urinary cystatin C and determined its
      reference range. METHODS: Measurement of urinary cystatin C by particle-enhanced
      nephelometric immunoassay (PENIA) in 102 patients with various renal disorders
      and 133 healthy controls. We assessed the influence of pH and temperature,
      interferences on urinary cystatin C measurement, as well as cystatin C adsorption
      to plastic. RESULTS: The upper reference value for urinary cystatin C was 0.28
      mg/L, independent of age and gender. Accuracy and linearity (r(2)=0.996) were
      excellent. Intra- and inter-assay precision were < or =4.8% and < or =5.2%,
      respectively. Albumin (< or =160 g/L), bilirubin (< or =500 micromol/L) and
      haemoglobin (< or =210 micromol/L) did not show interferences. Urinary cystatin C
      was stable, at urine pH> or =5, at -20 degrees C and 4 degrees C for 7 days, and
      at 20 degrees C for 48 h. Freezing and thawing did not influence urinary cystatin
      C concentration. There was no adsorption of cystatin C to plastic. CONCLUSION:
      Urinary cystatin C measurement by PENIA is precise. High stability and no
      interference add to the practicability of urinary cystatin C as a routine
      biochemical test.

PMID- 15025801
TI  - Spurious hyperphosphataemia caused by an IgA paraprotein: a topic revisited.
AB  - BACKGROUND: There are reports in the literature describing artefactually raised
      phosphate concentrations in serum samples of patients with myeloma. However, IgA
      paraproteins have been reported only rarely as a potential cause. METHODS:
      Following the detection of a grossly elevated phosphate concentration in a
      patient with an IgA paraprotein and another with an IgG paraprotein, we estimated
      phosphate concentrations in a further 73 patients with paraproteins using the
      Bayer ADVIA 1650 and Ortho Vitros 950 analysers. The latter method has been
      reported to be unaffected by pseudohyperphosphataemia. RESULTS: Deproteinization
      of the serum samples containing the IgA and IgG paraproteins showed that they
      were responsible for the interference. No significant difference in serum
      phosphate concentrations measured by the two analysers was noted for the larger
      study of serum IgG or IgM paraproteins. However, a statistically significant but
      clinically trivial difference in phosphate concentration was noted for serum IgA
      paraproteins, with the Ortho Vitros 950 giving slightly higher phosphate
      concentrations. Deproteinization of these samples yielded similar phosphate
      concentrations. Phosphate estimation in serum samples without paraproteins using
      both analysers yielded results that were not statistically different. CONCLUSION:
      On occasion, serum samples containing IgA paraproteins may give rise to erroneous
      phosphate concentrations when the Bayer ADVIA is used

PMID- 15025802
TI  - Serum amyloid A, C-reactive protein and remnant-like lipoprotein particle
      cholesterol in type 2 diabetic patients with coronary heart disease.
AB  - BACKGROUND: Serum amyloid A (SAA) and C-reactive protein (CRP) have been
      suggested to be involved in the process of coronary heart disease (CHD) and to be
      potential markers and/or predictors of CHD. Remnant-like lipoprotein particles
      (RLPs), which are regarded as atherogenic remnant lipoprotein, are reported to be
      increased in type 2 diabetic patients. We assessed the association of CHD with
      SAA, CRP and RLP-cholesterol in type 2 diabetic patients. METHODS: One hundred
      and twenty-six diabetic patients without CHD and 41 patients with CHD were
      recruited from our hospital. Plasma SAA was measured by the latex agglutination
      nephelometric immunoassay. Plasma high-sensitivity CRP was measured by a latex
      immunoturbidity method. Plasma RLP-cholesterol was measured by an
      immunoabsorption enzyme method. RESULTS: The mean standard deviation values of
      RLP-cholesterol in patients with and without CHD were 0.22 (0.26) mmol/L and 0.15
      (0.10) mmol/L, respectively (P <0.05). Median (interquartile ranges) for SAA in
      patients with and without CHD were 7.4 (4.2-11.2) mg/L and 3.9 (2.2-5.9) mg/L,
      respectively (P <0.001). Median (interquartile ranges) for CRP in patients with
      and without CHD was 1.14 (0.45-2.08) mg/L and 0.43 (0.19-1.25) mg/L, respectively
      (P <0.001). For all patients, the Spearman rank correlation statistics for RLP
      cholesterol compared with SAA and with CRP were 0.213 (P <0.05) and 0.301 (P
      <0.01), respectively. CONCLUSION: These data suggest that SAA, CRP and RLP
      cholesterol are increased in type 2 diabetic patients with CHD, and that the
      inflammatory proteins correlate with remnant lipoprotein.

PMID- 15025803
TI  - Genotyping of hepatitis C virus by melting curve analysis with SYBR Green I.
AB  - BACKGROUND: Recent studies have focused on whether different hepatitis C virus
      (HCV) genotypes are associated with different profiles of pathogenicity,
      infectivity, and response to antiviral therapy. We needed to develop a convenient
      screening test for HCV genotypes 1 and 2. METHOD: We tested 55 patients with
      known chronic HCV infection. Viral RNA was extracted from serum samples using an
      automatic viral RNA purification system, and HCV genotypes were determined by
      reverse transcriptase-polymerase chain reaction using LightCycler melting curve
      analysis with SYBR Green I. RESULTS: HCV RNA was detected in all samples and each
      genotype was determined. The mean (standard deviation) melting temperatures for
      subtypes 1b (n = 32), 2a (n = 15) and 2b (n = 8) were 93.14 degrees C (0.51
      degrees C), 91.08 degrees C (0.49 degrees C) and 91.77 degrees C (0.27 degrees
      C), respectively. Genotypes 1 and 2 were differentiated within 3 h by this
      method. CONCLUSIONS: Our melting curve analysis is a rapid and convenient
      screening test for differential identification of HCV genotypes 1 and 2.

PMID- 15025804
TI  - Assessment of thrombin in the urine of glomerulonephritic patients by enzyme
      linked immunosorbent assay.
AB  - BACKGROUND: Accumulating evidence suggests that blood clotting occurs in inflamed
      glomeruli, although its role in the pathophysiology of glomerulonephritis remains
      to be elucidated. To address this issue, a simple and reliable method for
      evaluating clotting in glomeruli is necessary. Here, we developed an enzyme
      linked immunosorbent assay (ELISA) for thrombin in urine to evaluate the degree
      of clotting activation in diseased glomeruli. METHODS: Monoclonal antibodies
      against human alpha-thrombin were raised and used for sandwich ELISA to measure
      thrombin. Thrombin was measured in urine samples from normal volunteers and from
      patients with glomerulonephritis or disseminated intravascular coagulation (DIC).
      RESULTS: Thrombin antigen was not detected in the urine of healthy volunteers or
      of patients with DIC, but was detected in the urine from two-thirds of
      glomerulonephritic patients. The average concentration in positive samples was
      3.79 microg/L. Urinary thrombin concentrations measured by ELISA correlated well
      with thrombin activities measured by hydrolysis of a synthetic substrate.
      CONCLUSION: We suggest that thrombin antigen in urine measured by ELISA is not
      affected by systemic thrombin production in the vessels, and reflects blood
      clotting activation in glomerulonephritic lesions. A close relationship between
      urinary thrombin and glomerulonephritis indicates a possible involvement of
      clotting in disease development, and measurement of urinary thrombin may provide
      a real-time marker for monitoring renal diseases.

PMID- 15025805
TI  - Micronutrient concentrations in patients with malignant disease: effect of the
      inflammatory response.
AB  - BACKGROUND: Micronutrient deficiencies may occur in patients with malignancy due
      to a variety of possible causes, including unbalanced dietary intake and adverse
      effects of treatment. In addition, many patients show signs of a chronic
      inflammatory response, which can affect circulating concentrations of certain
      vitamins and trace elements. Our aim was to examine the effect of the
      inflammatory response, as determined by plasma C-reactive protein (CRP)
      concentrations, on a range of micronutrients in patients with malignancy.
      METHODS: Blood samples were collected from 50 patients with various malignancies
      for the measurement of vitamins A, E, C and B(1), the trace elements copper,
      zinc, selenium and manganese and the inflammatory marker CRP. Vitamin A was
      measured as retinol and vitamin E as alpha-tocopherol. Vitamin C measurement
      included both ascorbic acid and dehydroascorbic acid. The vitamins were assayed
      by high-performance liquid chromatography and the trace elements by atomic
      absorption spectroscopy. RESULTS: Concentrations of zinc and selenium below their
      respective reference ranges and copper and manganese above their respective
      reference ranges were commonly found in the cancer group. However, none of these
      elements showed any significant correlation with CRP (P >0.01). Reduced levels of
      vitamin A, C and B(1) were commonly found in the cancer group. Vitamins A and C
      showed a significant negative correlation with CRP (r(s)=-0.66, P <0.0001 and
      r(s)=-0.53, P = 0.0005, respectively). Vitamin E showed no correlation with CRP.
      CONCLUSION: The inflammatory response is a major consideration in the
      interpretation of vitamin A and C concentrations in patients with malignancy.

PMID- 15025806
TI  - The predictive value of cumulative lactate dehydrogenase release within the first
      72 h of acute myocardial infarction in patients treated with primary angioplasty.
AB  - BACKGROUND: In patients with acute myocardial infarction, estimation of infarct
      size by cumulative lactate dehydrogenase release at 72 h (LDHQ(72)) is a simple
      and widely used method. Our objective was to study the value of estimating
      infarct size, by the cumulative release of LDH over 72, 60, 48 and 36 h in
      predicting left ventricular ejection fraction (LV(ef)) and cardiac death at 1
      year. METHODS: In the Zwolle Infarction Study infarct size estimated as LDHQ was
      calculated in 1224 patients treated with primary percutaneous coronary
      intervention for acute myocardial infarction between December 1993 and June 2001.
      Patients were categorized as having small (LDHQ(72)<800 U/L), medium (LDHQ(72)
      800-2500 U/L) or large (LDHQ(72)>2500 U/L) myocardial infarction. RESULTS:
      LDHQ(72) was closely correlated with LDHQ(60), LDHQ(48) and LDHQ(36) (r = 0.998,
      0.993 and 0.987, respectively, P <0.0001). The relations between LDHQ infarct
      size classification and mean LV(ef) (51% vs 45% vs 35%, P <0.001) or cardiac
      death at 1 year (0-0.3% vs 0.7-1% vs 6-8%) showed a similar pattern, irrespective
      of whether LDH was measured up to 36, 48, 60 or 72 h. CONCLUSION: Infarct size
      classification based on LDHQ(36) is an objective and widely available method for
      early risk stratification in patients treated with primary angioplasty for acute
      ST-segment elevation myocardial infarction.

PMID- 15025807
TI  - Major method-specific differences in the measurement of intact parathyroid
      hormone: studies in patients with and without chronic renal failure.
AB  - BACKGROUND: Following the introduction of two-site immunometric assays for
      parathyroid hormone (PTH), the expectation of good inter-assay agreement has not
      been fulfilled. The reasons for this may include differences in standardization
      as well as fragment recognition between the assays. METHODS: PTH values for
      healthy individuals, patients with renal failure and patients with normal renal
      function and elevated parathyroid hormone (hPTH) were compared using two
      commercial two-site immunochemiluminometric assays (Bayer Magic-lite and DPC
      Immulite 2000). RESULTS: Immulite results had a mean value 50.4% greater than the
      corresponding Magic-lite values for the whole study population with individual
      values ranging from 17.5% below to 118.3% above the corresponding Magic-lite
      value. There was no significant difference in inter-assay bias between patients
      with renal failure and those with normal renal function, suggesting that variable
      cross-reactivity with circulating disease-specific PTH fragments was not the
      primary cause of the observed discrepancy. Cross-reactivity with the synthetic
      fragment hPTH (7-84) was 34+/-5% for Magic-lite and 62+/-2% for Immulite. We also
      studied the stability of synthetic hPTH on storage. CONCLUSION: The instability
      of synthetic hPTH over extended storage periods may affect primary standard
      material. The consistent inter-assay differences and the over-recovery observed
      in external quality assessment programmes for the Immulite assay may have best
      been explained by differences in calibration and the relative cross-reactivities
      and/or kinetics of the two assay systems for specific parathyroid fragments.

PMID- 15025808
TI  - Pseudohyperkalaemia at commercial laboratories in Japan: a questionnaire survey.
AB  - BACKGROUND: Pseudohyperkalaemia caused by recentrifugation after storage or delay
      in separation of serum from blood cells is not uncommon. The purpose of this
      study was to audit pseudohyperkalaemia at commercial laboratories in Japan.
      METHODS: A questionnaire asking about how samples are handled for potassium
      measurement and information on pseudohyperkalaemia was sent to 431 commercial
      laboratories. RESULTS: A total of 263 (response rate 61%) questionnaires were
      returned and suitable for analysis. Pseudohyperkalaemia caused by
      recentrifugation was seen at 145 (70%) laboratories. Pseudohyperkalaemia caused
      by delay in separation of serum was also seen in many laboratories. Blood samples
      were centrifuged on site in only 46% of hospitals and in 17% of clinics served by
      these laboratories. The longest average time from venesection to centrifugation
      was 18 h. Although half the laboratories had asked their client facilities to
      centrifuge blood samples on site, very few complied. CONCLUSION:
      Pseudohyperkalaemia is not uncommon at commercial laboratories in Japan. Further
      efforts are necessary to avoid inappropriate handling at blood collection sites
      and in laboratories.

PMID- 15025809
TI  - New approaches towards laboratory diagnosis of isolated sulphite oxidase
      deficiency.
AB  - BACKGROUND: Molybdenum cofactor deficiency (resulting in combined deficiencies of
      the enzymes sulphite oxidase, xanthine dehydrogenase and aldehyde dehydrogenase)
      and isolated sulphite oxidase deficiency are inherited metabolic diseases which
      follow an autosomal recessive trait of inheritance. Detection of these diseases
      in selective screening for inborn errors of metabolism is not easy because
      relevant metabolites are either not routinely determined or are unstable.
      METHODS: We have searched for additional markers for these diseases and studied
      plasma total homocysteine (determined by enzyme immunoassay) and S-sulphonation
      of transthyretin (assessed by electrospray ionization mass spectrometry). RESULTS
      AND CONCLUSION: We found total homocysteine concentrations below the limit of
      quantification (<1 micromol/L) in all samples of patients with sulphite oxidase
      deficiency studied in this regard and that the proportion of S-sulphonated
      transthyretin is clearly increased in such samples. Our observations suggest
      additional tools for selective screening and diagnostic work-up of patients
      suspected of having sulphite oxidase deficiency.

PMID- 15025810
TI  - 2,8-Dihydroxyadenine renal stones in a 41-year-old man.
AB  - A case is presented of a 41-year-old man with a history of recurrent renal stones
      over 10 years. Analysis of the stone showed that, although it gave a positive
      reaction with the non-specific phosphotungstic acid test, uricase failed to
      identify any urate present. Analysis in a reference laboratory confirmed its
      composition as dihydroxyadenine. Patients who are homozygous for the rare
      autosomal-recessive adenine phosphoribosyltransferase deficiency, excrete large
      amounts of 2,8-dihydroxyadenine, which has poor solubility at normal urinary pH.
      Treatment with the xanthine oxidase inhibitor allopurinol induces a total
      cessation of stone formation. Increased awareness of the condition and knowledge
      of the limitations of some methods of laboratory analysis for renal stones should
      help to identify this type of stone and prevent renal damage.

PMID- 15025811
TI  - The role of the biochemistry department in the diagnosis of pituitary apoplexy.
AB  - A 47-year-old man presented with severe clinical hypoglycaemia. He had long
      standing insulin-dependent diabetes with previously good glycaemic control.
      Intense headaches and vomiting initiated hospitalization. A brain computed
      tomography (CT) scan was normal, and a lumbar puncture showed elevated
      cerebrospinal fluid (CSF) protein [0.67 g/L; normal range (NR) 0.15-0.45 g/L],
      suggesting resolving viral meningitis. Routine thyroid function tests were
      abnormal (free thyroxine 10.6 pmol/L, NR 9-22.5 pmol/L; thyroid-stimulating
      hormone 0.16 mU/L, NR 0.35-5 mU/L). In the absence of evident thyroid therapy,
      the laboratory policy required an urgent cortisol assay to be added; this was
      very abnormal (42 nmol/L), suggesting hypopituitarism. Later analysis showed that
      concentrations of gonadotrophins and adrenocorticotrophin were low. An urgent
      pituitary magnetic resonance imaging scan revealed an unsuspected pituitary
      tumour with recent haemorrhage (pituitary apoplexy). The patient was given
      intravenous hydrocortisone and then stabilized on oral hydrocortisone, thyroxine
      and mesterolone. He made a full recovery and the hypoglycaemia resolved. The
      normal brain CT scan was falsely reassuring and the CSF protein was not due to
      viral meningitis but to haemorrhage into the pituitary tumour. If laboratory
      policy had not required the urgent cortisol assay be added, the diagnosis of
      hypopituitarism would have been delayed or even missed altogether. This could
      have led to the death of the patient.

PMID- 15025812
TI  - Topiramate increases biochemical risk of nephrolithiasis.
AB  - The incidence of renal stone disease in patients receiving topiramate (Topamax)
      is 2-4 times that expected in the background population. This has been attributed
      to a weak carbonic anhydrase inhibitor effect, but published data are scant.
      Following three cases of renal stones in patients receiving topiramate, we
      evaluated biochemical risk for nephrolithiasis in eight further unselected
      patients. Most patients demonstrated inadequate urinary acidification and
      hypocitraturia; in some cases citrate was undetectable. Several patients also had
      other risk factors for nephrolithiasis, including increased urinary sodium,
      calcium and oxalate excretion. The biochemical changes induced by topiramate
      appear highly penetrant. Experience with this drug is relatively short-lived and
      it is being prescribed for long-term use in (often) relatively young patients.
      This report highlights the significantly increased metabolic risk of stone
      formation in patients receiving topiramate.

PMID- 15025813
TI  - Molecular diagnostics in routine practice.

PMID- 15025814
TI  - Interference caused by the contents of serum separator tubes in the Vitros CRP
      assay.

PMID- 15025815
TI  - Routine transferrin saturation measurements in liver clinic patients increases
      detection of hereditary haemochromatosis.

PMID- 15025819
TI  - The plasma kallikrein/kinin and renin angiotensin systems in blood pressure
      regulation in sepsis.
AB  - The hemodynamics of septic shock after endotoxinemia is influenced by the plasma
      kallikrein/kinin and the renin angiotensin systems. In recent years, new
      information has improved understanding of the protein/biologically active peptide
      interactions between these two systems. The plasma kallikrein/kinin system, more
      commonly known as the contact system, has undergone a re-evaluation as to how it
      assembles on cell membranes for physiological and pathophysiological activation
      and as to its role in Gram-negative sepsis. It has been proposed that it
      counterbalances the plasma renin angiotensin system. Furthermore, more knowledge
      about the renin angiotensin system has become available on how it either opposes
      the actions of the kallikrein/kinin system or, in some cases, summates with it.
      Understanding the interactions between these two systems may lead to development
      of better pharmacological treatments for endotoxin-induced shock.

PMID- 15025821
TI  - Characteristic biological activities of lipopolysaccharides from Sinorhizobium
      and Mesorhizobium.
AB  - The biological actions of lipopolysaccharides (LPSs) from Sinorhizobium meliloti,
      Mesorhizobium loti and Escherichia coli were compared. In biological activities
      including lethality, production of tumor necrosis factor (TNF)-alpha and nitric
      oxide (NO), adjuvant action and Limulus activity, LPS from S. meliloti exhibited
      stronger actions than LPS from M. loti, but had a weaker action than LPS from E.
      coli. On the other hand, M. loti LPS showed a higher activity to activate human
      complement than S. meliloti LPS. Further, there was a significant difference in
      polymyxin B binding between S. meliloti LPS and M. loti LPS, suggesting a
      difference in the lipid A structure. LPSs from S. meliloti and M. loti seem to
      exhibit characteristic biological actions that may be dependent on the difference
      in the lipid A structure.

PMID- 15025820
TI  - Molecular cloning and characterization of mouse LITAF cDNA: role in the
      regulation of tumor necrosis factor-alpha (TNF-alpha) gene expression.
AB  - The inflammatory response to bacteria and bacterial products, such as
      lipopolysaccharides (LPSs), is mediated by a variety of secreted factors, but
      cytotoxic effects of LPS have been ascribed to the tumor necrosis factor alpha
      (TNF-alpha) activity. TNF-alpha is probably the most pleiotropic cytokine and,
      given the deleterious effects to the host of this factor, it has been postulated
      that its expression must be tightly regulated. Our laboratory has recently
      isolated, cloned and characterized a novel human transcription factor named LITAF
      or LPS-induced TNF-alpha factor. The present study reports the isolation, cloning
      and characterization of the mouse LITAF cDNA. Chromosomal localization revealed
      that mouse LITAF mapped to mouse chromosome 16, in a region highly homologous
      with the area on which human LITAF was previously located. Northern blot analysis
      shows that mouse LITAF is already expressed at embryonic day 7 of development,
      and is highly expressed in adult liver, heart and kidney. Moreover, upon LPS
      stimulation, we show that: (i) LITAF expression is increased in a mouse
      monocyte/macrophage cell line; and (ii) TNF-alpha expression is reduced in ES
      cell-derived macrophages lacking one copy of LITAF gene. Taken together, these
      results highlight the important role of LITAF in the regulation of TNF-alpha gene
      expression and suggest a potential role of LITAF in mouse organogenesis.

PMID- 15025822
TI  - Butyrate enhances the production of nitric oxide in mouse vascular endothelial
      cells in response to gamma interferon.
AB  - The effect of butyrate, a natural bacterial product of colonic bacterial flora,
      on nitric oxide (NO) production in murine vascular endothelial cell line END-D in
      response to IFN-gamma and/or LPS was studied. Butyrate significantly augmented NO
      production in END-D cells in response to IFN-gamma or IFN-gamma + LPS, but not
      LPS alone. The NO production was augmented by the addition of butyrate until 6 h
      after the stimulation with IFN-gamma or IFN-gamma + LPS. The augmentation was
      abolished by the removal of butyrate from the cultures. Butyrate enhanced the
      expression of inducible type NO synthase (iNOS) in the stimulated END-D cells.
      Furthermore, butyrate-enhanced NO production in the presence of various signal
      inhibitors down-regulating the signal pathways using nuclear factor (NF)-kappaB,
      mitogen-activated protein (MAP) kinases and Janus tyrosine kinase. The putative
      mechanism of butyrate-induced augmentation of NO production in response to IFN
      gamma or IFN-gamma + LPS is discussed.

PMID- 15025823
TI  - Fever onset is linked to the appearance of lipopolysaccharide in the liver.
AB  - To assess the relative contributions of different phagocytes to the febrile
      response of guinea pigs to intravenous (i.v.) and intraperitoneal (i.p.)
      bacterial endotoxic lipopolysaccharide (LPS), we injected fluorescein
      isothiocyanate (FITC)-labeled LPS at doses of 37.5, 75, 150, 300 and 900
      microg/kg, and measured its distribution and corresponding core temperature
      (T(c)) changes before and at 15, 30, 60, 90, and 120 min after injection. At all
      times, i.v. FITC-LPS appeared as granular fluorescent patches in circulating
      leukocytes and hepatic macrophages; its density was proportional to dose. At all
      doses, the density of i.v. FITC-LPS labeling decreased from its peak 15 min after
      injection at a rate commensurate with its dose. Intraperitoneal FITC-LPS was also
      present dose- and time-dependently in peritoneal macrophages, but it appeared
      later and accumulated more slowly except at the highest dose. Compared with i.v.
      FITC-LPS, its maximal appearance was always lower in density. No labeling was
      found at any time in brain and kidney following any dose of i.v. or i.p. FITC-LPS
      injection. The initiation of T(c) rises was best correlated with the presence of
      FITC-LPS in liver, irrespective of its route of injection. Pretreatment with
      gadolinium chloride 3 days before LPS injection attenuated the febrile response
      and reduced FITC-LPS labels in liver. These results suggest that the Kupffer
      cells may be central to the initiation of the febrile response of guinea pigs to
      i.v. and i.p. LPS.

PMID- 15025824
TI  - Endotoxin induces leukocyte transmigration and changes in permeability of the
      airway epithelium via protein-kinase C and extracellular regulated kinase
      activation.
AB  - Lipopolysaccharide (LPS) endotoxin of Gram-negative bacteria compromises the
      integrity of the airway epithelial barrier and initiates migration of leukocytes
      across the epithelium. The goal of the present study was to identify the role of
      extracellular regulated kinase (ERK1/2) transduction pathways in these processes.
      The first aim was to determine whether LPS induces ERK1/2 activation and changes
      in epithelial permeability in epithelial cells alone or only in the presence of
      immune cells. The second aim was to determine whether the changes in the
      epithelial permeability were diminished by ERK1/2 blockade. The third aim was to
      investigate the role of protein kinase C (PKC) activation as an upstream event in
      activation of ERK1/2. In vitro 20 microg/ml LPS challenge reduced epithelial
      barrier function, and induced ERK1/2 phosphorylation in primary cultures of
      bovine tracheal epithelium and in the transformed human airway epithelial cell
      line, Calu-3. LPS initiated migration of neutrophil-like and monocyte-like
      transformed HL-60 cell across sheets of Calu-3 cells. The migration rate and the
      associated changes in the electrical resistance, permeability to albumin, and
      ERK1/2 phosphorylation were all blocked by calphostin C, the specific blocker of
      PKC and by PD98059 (2'-amino-3'-methoxyflavone), a selective cell-permeable
      inhibitor of MAP kinase kinase. In rats, in vivo perfusion of the lumen of an
      isolated segment of trachea with LPS (0.1 mg/ml) initiated migration of
      neutrophils and increased the permeability to albumin. Again, these effects were
      markedly inhibited by PD98059 and calphostin C (by > 50%). We conclude that
      epithelial ERK1/2 is activated by endotoxin via PKC and is an important pathway
      in regulation of epithelial permeability.

PMID- 15025825
TI  - The shape of neural dependence.
AB  - The product-moment correlation coefficient is often viewed as a natural measure
      of dependence. However, this equivalence applies only in the context of
      elliptical distributions, most commonly the multivariate gaussian, where linear
      correlation indeed sufficiently describes the underlying dependence structure.
      Should the true probability distributions deviate from those with elliptical
      contours, linear correlation may convey misleading information on the actual
      underlying dependencies. It is often the case that probability distributions
      other than the gaussian distribution are necessary to properly capture the
      stochastic nature of single neurons, which as a consequence greatly complicates
      the construction of a flexible model of covariance. We show how arbitrary
      probability densities can be coupled to allow greater flexibility in the
      construction of multivariate neural population models.

PMID- 15025826
TI  - On the phase reduction and response dynamics of neural oscillator populations.
AB  - We undertake a probabilistic analysis of the response of repetitively firing
      neural populations to simple pulselike stimuli. Recalling and extending results
      from the literature, we compute phase response curves (PRCs) valid near
      bifurcations to periodic firing for Hindmarsh-Rose, Hodgkin-Huxley, FitzHugh
      Nagumo, and Morris-Lecar models, encompassing the four generic (codimension one)
      bifurcations. Phase density equations are then used to analyze the role of the
      bifurcation, and the resulting PRC, in responses to stimuli. In particular, we
      explore the interplay among stimulus duration, baseline firing frequency, and
      population-level response patterns. We interpret the results in terms of the
      signal processing measure of gain and discuss further applications and
      experimentally testable predictions.

PMID- 15025828
TI  - Investigation of possible neural architectures underlying information-geometric
      measures.
AB  - A novel analytical method based on information geometry was recently proposed,
      and this method may provide useful insights into the statistical interactions
      within neural groups. The link between informationgeometric measures and the
      structure of neural interactions has not yet been elucidated, however, because of
      the ill-posed nature of the problem. Here, possible neural architectures
      underlying information-geometric measures are investigated using an isolated pair
      and an isolated triplet of model neurons. By assuming the existence of
      equilibrium states, we derive analytically the relationship between the
      information-geometric parameters and these simple neural architectures. For
      symmetric networks, the first- and second-order information-geometric parameters
      represent, respectively, the external input and the underlying connections
      between the neurons provided that the number of neurons used in the parameter
      estimation in the log-linear model and the number of neurons in the network are
      the same. For asymmetric networks, however, these parameters are dependent on
      both the intrinsic connections and the external inputs to each neuron. In
      addition, we derive the relation between the information-geometric parameter
      corresponding to the two-neuron interaction and a conventional cross-correlation
      measure. We also show that the information-geometric parameters vary depending on
      the number of neurons assumed for parameter estimation in the log-linear model.
      This finding suggests a need to examine the information-geometric method
      carefully. A possible criterion for choosing an appropriate orthogonal coordinate
      is also discussed. This article points out the importance of a model-based
      approach and sheds light on the possible neural structure underlying the
      application of information geometry to neural network analysis.

PMID- 15025827
TI  - Estimating the entropy rate of spike trains via Lempel-Ziv complexity.
AB  - Normalized Lempel-Ziv complexity, which measures the generation rate of new
      patterns along a digital sequence, is closely related to such important source
      properties as entropy and compression ratio, but, in contrast to these, it is a
      property of individual sequences. In this article, we propose to exploit this
      concept to estimate (or, at least, to bound from below) the entropy of neural
      discharges (spike trains). The main advantages of this method include fast
      convergence of the estimator (as supported by numerical simulation) and the fact
      that there is no need to know the probability law of the process generating the
      signal. Furthermore, we present numerical and experimental comparisons of the new
      method against the standard method based on word frequencies, providing evidence
      that this new approach is an alternative entropy estimator for binned spike
      trains.

PMID- 15025829
TI  - Robustifying AdaBoost by adding the naive error rate.
AB  - AdaBoost can be derived by sequential minimization of the exponential loss
      function. It implements the learning process by exponentially reweighting
      examples according to classification results. However, weights are often too
      sharply tuned, so that AdaBoost suffers from the nonrobustness and overlearning.
      Wepropose a new boosting method that is a slight modification of AdaBoost. The
      loss function is defined by a mixture of the exponential loss and naive error
      loss functions. As a result, the proposed method incorporates the effect of
      forgetfulness into AdaBoost. The statistical significance of our method is
      discussed, and simulations are presented for confirmation.

PMID- 15025835
TI  - Use of transdermal fentanyl without prior opioid stabilization in patients with
      cancer pain.
AB  - OBJECTIVE: To determine the safety and efficacy of transdermal fentanyl for pain
      relief in cancer patients and to compare the effects on patients according to
      whether they had previously received strong opioids, weak opioids or non-opioid
      analgesia. METHODS: Cancer patients requiring strong analgesia were recruited
      into an open-label, multicentre study, conducted in eight countries. Patients
      received transdermal fentanyl treatment for 28 days. Pain severity, overall
      satisfaction with pain control, convenience of use of patches and treatment
      preferences were recorded daily. RESULTS: Of the 292 participants, 135 had
      previously received a strong opioid, 84 had previously received a weak opioid and
      73 had received no regular opioids. Thirty-eight patients did not complete the
      study, mainly due to adverse events. For all groups the proportion of patients
      with 'good to excellent' pain control increased after transdermal fentanyl
      treatment. Transdermal fentanyl was well tolerated, with the most common
      treatment-related adverse events being nausea, vomiting and constipation. The
      percentage of strong-opioid-tolerant patients with constipation decreased
      following transdermal fentanyl treatment and increased slightly in the strong
      opioid-naive groups. Most patients rated the convenience of the patches as 'good
      to excellent', and most preferred transdermal fentanyl to their previous therapy.
      CONCLUSIONS: Transdermal fentanyl is an effective and well-tolerated treatment
      for cancer-related pain for patients regardless of whether they have previously
      received opioids. Previous guidelines have often advocated initial dose finding
      with short-acting opioids but this study demonstrates that such a complex
      titration and conversion schedule may not be necessary,and that treatment may be
      initiated directly with long-acting formulations such as transdermal fentanyl
      when previous analgesic therapy fails to provide adequate relief.

PMID- 15025836
TI  - Eletriptan for the acute treatment of migraine: results of bridging a Japanese
      study to Western clinical trials.
AB  - OBJECTIVE: To compare the efficacy, safety and tolerability of eletriptan (20, 40
      and 80 mg) to placebo when given to Japanese and Western patients for the acute
      treatment of migraine. METHODS: A double-blind, randomized, parallel-group trial
      with the aforementioned therapeutic objectives was conducted in Japan (N = 321).
      By bridging analysis, data from this study were compared to two migraine trials
      previously conducted in the US (N = 1190) and Europe (N = 563). RESULTS: The 2-h
      post-dose headache response rates (i.e., the primary efficacy endpoint) of
      Japanese migraineurs to eletriptan 20, 40 and 80 mg were 64, 67 and 76%,
      respectively; European and American migraineurs showed similar trends and, in
      these studies, eletriptan was significantly superior to placebo (p < 0.05).
      Japanese patients did demonstrate a higher placebo response than Westerners,
      possibly due to differences in previous triptan exposure or expectation. Adverse
      events were generally mild to moderate, were comparable in all three studies, and
      showed a modest dose-response effect. CONCLUSION: The efficacy and tolerability
      of eletriptan for the acute treatment of migraine is comparable in Japan, Europe
      and the US.

PMID- 15025837
TI  - AII antagonists in hypertension, heart failure, and diabetic nephropathy: focus
      on losartan.
AB  - The goal of antihypertensive therapy is to prevent cardiovascular complications
      of hypertension, such as heart failure, stroke, end stage renal disease, and
      death, not just to normalize blood pressure. Recently, several clinical trials
      investigated the beneficial effects of angiotensin II antagonists (AIIAs) in
      patients with hypertension, heart failure or diabetic nephropathy utilizing
      proven clinical outcomes (e.g., all-cause mortality) rather than surrogate
      outcomes (e.g., blood pressure or proteinuria). The AIIAs may offer therapeutic
      advantages with respect to particular outcomes in certain types of patients.
      Evidence is also emerging that losartan may possess beneficial pharmacological
      properties such as effects on uric acid, platelets, sexual dysfunction, and
      cognitive function, that may set it apart from other members of the AIIA class.
      However, further studies are needed to delineate fully these potential
      pharmacological differences among the AIIAs and their possible clinical
      relevance. This paper reviews recent AIIA outcomes studies in patients with
      hypertension, heart failure, or diabetic nephropathy and also examines data
      suggesting that molecular differences exist within the AIIA class, differences
      that may assist in explaining the outcomes achieved in these recent trials.

PMID- 15025838
TI  - Obesity as the core of the metabolic syndrome and the management of coronary
      heart disease.
AB  - The global burden of coronary heart disease (CHD) has led to the introduction of
      international guidelines to minimize the morbidity and mortality that result from
      this condition. These guidelines recognize the contribution of multiple risk
      factors to the development of CHD and advocate a multifaceted approach to
      treatment. Obesity, particularly visceral adiposity, contributes to the
      clustering of many other risk factors, such as hypertension, insulin
      resistance/type 2 diabetes and dyslipidemia, within individual patients. The
      molecular mechanisms underlying the metabolic abnormalities induced by visceral
      adiposity have yet to be fully elucidated; however, adipocytokines such as
      adiponectin, tumor necrosis factor-alpha and resistin seem to play an important
      role in this process. Obesity is a major modifiable CHD risk factor, and the
      benefits of weight loss are numerous, leading to improvements in several co
      morbidities. Guidelines advocate lifestyle changes to correct excess bodyweight
      and improve the CHD risk factor profile. In addition, pharmacologic therapy is
      recommended for the management of other risk factors, such as hypertension and
      dyslipidemia, which may not be adequately controlled by lifestyle changes alone.
      Lowering low-density lipoprotein cholesterol (LDL-C) levels is the primary target
      for drug therapy for CHD prevention, and statins are first-line lipid-modifying
      therapy. The introduction of more efficacious statins with favorable effects on
      the lipid profile will optimize the control of dyslipidemia. Combining these new
      treatments with lifestyle changes and drug therapies for managing other CHD risk
      factors, as part of a multifaceted approach to treatment, will have benefits for
      CHD prevention.

PMID- 15025839
TI  - Economic impact and quality-of-life burden of allergic rhinitis.
AB  - Allergic rhinitis can be a debilitating condition which, if untreated, can result
      in considerable health-related and economic consequences. A review of the
      published literature was conducted, with quantitative/qualitative analysis as
      appropriate, to explore the direct, indirect, and hidden costs of allergic
      rhinitis, as well as the quality-of-life burdens that the disease presents to
      patients and to the healthcare system. Lack of treatment, undertreatment, or
      nonadherence to treatment in allergic rhinitis were seen to increase direct and
      indirect costs, reinforcing the need for patient education and for physicians to
      implement existing evidence-based guidelines for prevention and treatment. It was
      concluded that greater awareness of the total economic burden of allergic
      rhinitis should encourage appropriate intervention and ultimately ensure
      clinically favorable and cost-effective outcomes.

PMID- 15025840
TI  - Surveying general practitioners: a new avenue.
AB  - BACKGROUND: The validity of opinions expressed in questionnaire surveys
      diminishes with lower response rates. Recent research suggests that general
      practitioners (GPs) are more likely to respond to questionnaire surveys if they
      are motivated to do so because the subject of the survey is perceived as relevant
      to the practitioner at the time of the survey, and there is an opportunity to
      respond without encroaching on existing obligations or interests. AIM: To compare
      the results of a questionnaire survey administered by two routes: a postal survey
      with reminders and after an educational meeting with no reminders. METHODS: A
      validated questionnaire with 19 questions using a Likert scale seeking views
      about the ideal contents of a referral letter to colorectal surgeons was
      administered to GPs attending a monthly educational meeting in one locality in
      the UK and by post to a different group in a second locality. The response rate
      and demographic characteristics of the GPs were compared for respondents, non
      respondents, attenders and non-attenders to the educational meeting. The mean
      responses to the questions on the Likert scale were used to produce a schedule to
      score the contents of referral letters. The schedules produced by the two methods
      (postal/educational meeting) were used to score 551 referral letters at one
      district general hospital. Mean scores calculated using the two schedules derived
      by the postal and educational routes were compared. Cases diagnosed with
      'significant organic pathology' as defined in a previous study were identified.
      The predictive value of the scores in identifying these cases was compared.
      RESULTS: 88% (138/157) of GPs in the locality attended the educational meeting
      and were invited to participate in the survey. Non-attenders were more likely to
      be assistants, locums or part-time practitioners. Overall 71% (98) of the GPs
      responded to the survey. There were no significant demographic differences
      between the respondents and non-respondents to the survey. Response rates to the
      survey conducted by the two routes were similar. Referral letter 'quality' scores
      derived via the two alternative routes were equally valuable in predicting which
      patients had significant organic pathology. CONCLUSIONS: Responses to
      questionnaire surveys are equally valid when administered via an educational
      meeting or by post. The value of the educational meeting approach was the
      relative ease of administering the questionnaire and the rapid turn around of
      replies. However this method may exclude the views of part-time practitioners who
      were more likely to fail to attend. These practitioners may need to be targeted
      by alternative routes in questionnaire surveys.

PMID- 15025841
TI  - Bioequivalence of ximelagatran, an oral direct thrombin inhibitor, as whole or
      crushed tablets or dissolved formulation.
AB  - OBJECTIVE: To investigate whether crushed or dissolved tablets of the oral direct
      thrombin inhibitor ximelagatran are bioequivalent to whole tablet administration.
      Ximelagatran is currently under development for the prevention and treatment of
      thromboembolic disorders. RESEARCH DESIGN AND METHODS: This was an open-label,
      randomised, three-period, three-treatment crossover study in which 40 healthy
      volunteers (aged 20-33 years) received a single 36-mg dose of ximelagatran
      administered in three different ways: I swallowed whole, II crushed, mixed with
      applesauce and ingested and III dissolved in water and administered via
      nasogastric tube. RESULTS: The plasma concentrations of ximelagatran, its
      intermediates and the active form melagatran were determined. Ximelagatran was
      rapidly absorbed and the bioavailability of melagatran was similar after the
      three different administrations, fulfilling the criteria for bioequivalence. The
      mean area under the plasma concentration-versus-time curve (AUC) of melagatran
      was 1.6 micromol.h/L (ratio 1.01 for treatment II/I and 0.97 for treatment
      III/I), the mean peak concentration (C(max)) was 0.3 micromol/L (ratio 1.04 for
      treatment II/I and 1.02 for treatment III/I) and the mean half-life (t(1/2)) was
      2.8 h for all treatments. The time to C(max) (t(max)) was 2.2h for the whole
      tablet and approximately 0.5 h earlier when the tablet was crushed or dissolved
      (1.7-1.8 h), due to a more rapid absorption. The study drug was well tolerated as
      judged from the low incidence and type of adverse events reported. CONCLUSION:
      The present study showed that the pharmacokinetics (AUC and C(max)) of melagatran
      were not significantly altered whether ximelagatran was given orally as a crushed
      tablet mixed with applesauce or dissolved in water and given via nasogastric
      tube.

PMID- 15025842
TI  - Advances in the treatment of diabetic renal disease: focus on losartan.
AB  - Diabetic nephropathy is the leading cause of end stage renal disease (ESRD), and
      given that treating this condition is a considerable economic burden, the
      prevention of ESRD is a major public health goal. The renin-angiotensin system
      (RAS) is aberrantly activated in patients with diabetes. Angiotensin II (AII), a
      downstream effector of the RAS, has haemodynamic and non-haemodynamic effects
      that contribute to the development and progression of nephropathy. For patients
      with type 2 diabetes mellitus (T2DM) and hypertension, an AII receptor blocker
      (AIIRB) is recommended as the first drug that should be used. This review will
      focus on the rationale for the use of losartan as a treatment for nephropathy
      associated with T2DM. In animal models of diabetes, losartan reduced proteinuria
      and conferred renal protection. In RENAAL (Reduction in Endpoints in Non-Insulin
      Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan), the
      first major randomised trial that investigated the benefit of losartan in
      patients with T2DM and nephropathy, losartan significantly reduced the risk of a
      doubling of serum creatinine and progression to ESRD, significantly lowered the
      levels of proteinuria and slowed the rate of decline in glomerular filtration
      rate. This review also discusses other clinical trials of losartan and other
      AIIRBs in T2DM, and considers alternative mechanisms by which losartan may be
      exerting its effects. The collective experience in treatment trials highlighted
      in this review indicate that losartan and other AIIRBs can reduce blood pressure
      and the progression of proteinuria in diabetic renal disease. However, losartan
      is thus far the only AIIRB that has been shown to reduce significantly the risk
      of ESRD and cardiovascular events in patients with T2DM. Its use in hypertensive
      patients with T2DM and nephropathy may play an important role in reducing the
      burden of ERSD.

PMID- 15025843
TI  - Is bone mineral density predictive of fracture risk reduction?
AB  - Bone mineral density (BMD) measurement is a widely available noninvasive means of
      identifying individuals with osteoporosis and, possibly, those at high risk for
      fracture. This nonsystematic review examines the relationship between BMD
      increase and fracture risk reduction in clinical trials evaluating osteoporosis
      therapy. The trials examined here are predominantly in postmenopausal women. BMD
      increase correlates poorly with fracture risk reduction in clinical trials of
      osteoporosis therapy conducted in postmenopausal women. Although BMD may increase
      with therapy, the increase is not measurable until later, and the overall
      increase is too small to account for the timing and magnitude of fracture risk
      reduction. BMD is only one of many contributors to bone strength and fracture
      risk reduction. Bone strength is derived from bone quantity, which consists of
      density and size, and bone quality, which, in turn, consists of structure (micro-
      and macroarchitecture), material properties, and turnover. Data are beginning to
      accrue suggesting that changes in bone turnover markers may be an accurate
      predictor of fracture risk reduction. Future research will elucidate the link
      between changes in bone turnover markers and bone architecture as a measure of
      osteoporosis treatment efficacy. Until then, physicians will continue to rely on
      fracture risk reduction data from well-designed clinical trials when judging the
      efficacy of different treatments for osteoporosis.

PMID- 15025844
TI  - Antiresorptive treatment of postmenopausal osteoporosis: review of randomized
      clinical studies and rationale for the Evista alendronate comparison (EVA) trial.
AB  - Standard pharmacological antiresorptive therapy for the prevention and/or
      treatment of postmenopausal osteoporosis now consists of four categories of
      drugs: estrogens, a selective estrogen receptor modulator (SERM), bisphosponates,
      and calcitonin. All of these drugs have been studied in randomized controlled
      trials, but meaningful comparisons of the efficacy of drugs have been difficult
      due to differences in baseline risks for fracture and differences in study
      design, including calcium and vitamin D supplementation, definition of fracture,
      and discontinuation rates. The current paper reviews results from pivotal studies
      of antiresorptive therapies with fracture as a primary endpoint, as well as head
      to-head trials comparing these therapies using surrogate markers of fracture
      risk, and introduces the first head-to-head trial with fracture as a primary
      endpoint. The Evista Alendronate Comparison (EVA) trial, a multi-center, double
      blind, double-dummy, randomized trial with two active treatment arms is currently
      underway to compare directly the osteoporotic fracture risk reduction efficacy of
      raloxifene and alendronate in postmenopausal women with osteoporosis as defined
      by bone mineral density. The results from this trial will permit more informed
      judgment by practitioners and provider groups concerning the relative clinical
      utility of these two drugs.

PMID- 15025845
TI  - Selective imidazoline agonist moxonidine plus the ACE inhibitor ramipril in
      hypertensive patients with impaired insulin sensitivity: partners in a successful
      MARRIAGE?
AB  - Hypertension in combination with clinically overt diabetes mellitus is recognized
      as a particularly powerful combination of risk factors that greatly increases
      cardiovascular vulnerability. There is also evidence that presumed pre-diabetic
      conditions such as insulin resistance, hyperinsulinaemia and compensatory
      hyperglycaemia may amplify overall cardiovascular risk in patients with
      hypertension, especially when encountered as part of the condition known as
      metabolic syndrome X (Reaven's syndrome). The long-term benefits of
      antihypertensive therapy may be compromised if these drugs exert adverse effects
      on metabolic parameters such as insulin sensitivity, or if they promote a
      transition from pre-diabetes to overt diabetes. Class differences in the effects
      of antihypertensives on metabolic indices may therefore be an important
      consideration when choosing treatment for patients who exhibit these
      characteristics. Experience from clinical trials suggests that drugs that target
      the renin-angiotensin system may have metabolic advantages over drugs such as
      beta-blockers and diuretics, but this conclusion has not been proved
      definitively. Moxonidine, which selectively targets imidazoline type-1 receptors
      in the sympathetic vasomotor centres of the rostral-ventrolateral medulla, is an
      effective antihypertensive and has been reported to exert favourable metabolic
      effects in preclinical and clinical studies. The MARRIAGE study (Moxonidine And
      Ramipril Regarding Insulin And Glucose Evaluation) will extend these preliminary
      observations by comparing the effects of moxonidine and the ACE inhibitor
      ramipril--and the combination of both drugs--on metabolic and haemodynamic
      parameters in patients with hypertension and impaired fasting glycaemia. A
      description is provided of the design and conduct of MARRIAGE.

PMID- 15025846
TI  - Uric acid: role in cardiovascular disease and effects of losartan.
AB  - A substantial body of epidemiological and experimental evidence suggests that
      serum uric acid is an important, independent risk factor for cardiovascular and
      renal disease especially in patients with hypertension, heart failure, or
      diabetes. Elevated serum uric acid is highly predictive of mortality in patients
      with heart failure or coronary artery disease and of cardiovascular events in
      patients with diabetes. Further, patients with hypertension and hyperuricemia
      have a 3- to 5-fold increased risk of experiencing coronary artery disease or
      cerebrovascular disease compared with patients with normal uric acid levels.
      Although the mechanisms by which uric acid may play a pathogenetic role in
      cardiovascular disease is unclear, hyperuricemia is associated with deleterious
      effects on endothelial dysfunction, oxidative metabolism, platelet adhesiveness,
      hemorheology, and aggregation. Xanthine oxidase inhibitors (e.g., allopurinol) or
      a variety of uricosuric agents (e.g., probenecid, sulfinpyrazone, benzbromarone,
      and benziodarone) can lower elevated uric acid levels but it is unknown whether
      these agents reversibly impact cardiovascular outcomes. However, the findings of
      the recent LIFE study in patients with hypertension and left ventricular
      hypertrophy suggest the possibility that a treatment-induced decrease in serum
      uric acid may indeed attenuate cardiovascular risk. LIFE showed that
      approximately 29% (14% to 107%, p = 0.004) of the treatment benefit of a losartan
      based versus atenolol-based therapy on the primary composite endpoint (death,
      myocardial infarction, or stroke) may be ascribed to differences in achieved
      serum uric acid levels. Overall, serum uric acid may be a powerful tool to help
      stratify risk for cardiovascular disease. At the very least, it should be
      carefully considered when evaluating overall cardiovascular risk.

PMID- 15025847
TI  - Clinical and economic comparison of epoetin alfa and darbepoetin alfa.
AB  - BACKGROUND: The pharmacoeconomics of erythropoietic therapy for the treatment of
      anemia is receiving renewed attention due to the current availability of two
      agents. Epoetin alfa has been the standard of therapy for patients with renal
      disease and cancer-related anemia for more than a decade. Darbepoetin alfa, an
      alternative agent, is now approved for anemia resulting from renal disease and
      cancer chemotherapy. METHODOLOGY: Although direct comparative trials have not
      been performed with these agents, information published in the last several years
      regarding their clinical efficacy, safety, and dosing is sufficient, in most
      cases, to compare costs. With the disclaimer that any efficacy comparison of
      competing products using published reports has certain limitations, a cost
      minimization approach from a provider's perspective was conducted. RESULTS: To
      provide background for the economic evaluation, pharmacokinetic and
      pharmacodynamic data for these two agents are discussed. Recent clinical trials
      in the nephrology and oncology therapeutic areas are summarized, highlighting
      study designs, dosing regimens, patient entry criteria, study endpoints, and
      published results. Cost data, based on average wholesale prices (AWP) in 2003,
      are compared and calculated from available clinical data with an emphasis on
      efficacy. CONCLUSION: These evaluations largely conclude that epoetin alfa is the
      better pharmacoeconomic value of the two currently available erythropoietic
      agents.

PMID- 15025848
TI  - The bioequivalence of liquid and freeze-dried formulations of recombinant human
      chorionic gonadotrophin.
AB  - OBJECTIVE: To compare the bioavailability and tolerability of liquid and freeze
      dried formulations of recombinant human chorionic gonadotrophin (r-hCG). SUBJECTS
      AND METHODS: In an open-label, randomised, single-centre, Phase I study, healthy
      adult volunteers (18-50 years of age) received single injections of r-hCG 250
      microg from reconstituted freeze-dried (1.0 mL of 250 microg/mL) and liquid (0.5
      mL of 250 microg/0.5 mL) formulations in random order, separated by a 10-day wash
      out period. Pharmacokinetics (C(max), AUC, AUC(last), t(max)) and local and
      systemic tolerability were assessed. RESULTS: Pharmacokinetic properties of the
      two formulations were very similar, with mean C(max) 125 mIU/mL (liquid
      formulation) vs 129 mIU/mL (freeze-dried formulation), mean AUC 10,350 mIU.h/mL
      vs 10,480 mIU(.)h/mL, mean AUC(last) 10,050 mIU.h/mL vs 10,210 mIU.h/mL, and
      median t(max) 20 vs 24h. The 90% confidence intervals of the ratios of the
      treatment means for C(max), AUC and AUC(last) all fell within the pre-defined FDA
      acceptance range of 0.8-1.25, demonstrating the bioequivalence of the two
      formulations. Both formulations were equally well tolerated; the most frequent
      adverse events were headache and nausea. CONCLUSION: The liquid formulation of r
      hCG was shown to be bioequivalent to the freeze-dried formulation, with no
      clinically significant differences in tolerability. The liquid formulation of r
      hCG can be expected to provide the same efficacy and tolerability as the freeze
      dried formulation when used to trigger final follicular maturation in women
      undergoing therapies for assisted reproduction, together with a greater
      convenience of use.

PMID- 15025849
TI  - Evaluation of the efficacy of polydeoxyribonucleotides in the healing process of
      autologous skin graft donor sites: a pilot study.
AB  - OBJECTIVE: The article presents the results of a pilot study performed to
      evaluate the efficacy of polydeoxyribonucleotides (PDRNs) in shortening the
      healing times of autologous skin graft donor sites. RESEARCH DESIGN, METHODS: Two
      groups of patients were studied, the PDRN group (n = 20) and a control group (n =
      20). In the control group dressings were performed with non-adherent gauzes and
      bulky gauzes with cloramine solution, whereas in the PDRN group a PDRN ointment
      was spread under the same medication as the controls. RESULTS: In the PDRN group,
      dressing procedures were not painful (whereas in the controls they often were),
      re-epithelialisation occurred earlier (12.5 vs 24.45 days) and there were no
      infections (9 in the controls). CONCLUSIONS: Results are encouraging for the use
      of PDRNs in shortening the healing times of autologous skin graft donor sites,
      although further studies are necessary to obtain clinically relevant results.

PMID- 15025850
TI  - Assessment of the therapeutic activity of a combination of almitrine and
      raubasine on functional rehabilitation following ischaemic stroke.
AB  - BACKGROUND AND OBJECTIVES: Stroke is a major cause of disability. Certain
      experimental studies have suggested that a combination of almitrine + raubasine
      (Duxil) increases the supply of oxygen to cerebral tissues and may be beneficial
      in post-stroke rehabilitation. This multicentre clinical study was carried out in
      order to assess the efficacy of this combination on poststroke rehabilitation.
      METHODS: The trial was a randomised, double-blind, placebo-controlled study.
      Patients that had experienced an ischaemic cerebrovascular accident (confirmed by
      CT scan) were included 4-6 weeks after the acute onset and received randomised
      treatment of either almitrine + raubasine or placebo 2 tablets daily for 3
      months. Before treatment, there was a 2-week washout period for stopping all
      other drugs, except for antihypertensive and antidiabetic drugs. We assessed the
      patients by Barthel Index (BI), Neurological Functional Deficit Scores (NFDS),
      and Hasagawa Dementia Scales (HDS) each month after treatment. RESULTS: A total
      of 83 patients were entered into the study and data were available for 74. Of
      these, 38 patients received almitrine + raubasine and 36 received placebo. The
      baseline characteristics were comparable between both groups. Almitrine +
      raubasine was significantly more effective than placebo at increasing BI at 1, 2
      or 3 months (14.6 +/- 13.8 versus 3.3 +/- 13.2, p = 0.01; 19.3 +/- 13.6 versus
      8.8 +/- 14.0, p = 0.02; 22.6 +/- 14.7 versus 10.7 +/- 17.0, p = 0.02
      respectively) and reducing NFDS at 1 month (3.6 +/- 3.2 versus 1.9 +/- 3.5, p =
      0.034) after treatment. More almitrine + raubasine-treated patients' NFDS had
      improved compared with placebo-treated patients at 2 and 3 months (97 versus 78%,
      p = 0.013; 100 versus 86%, p = 0.023 respectively). Compared with pretreatment,
      there was a strong tendency towards an improvement of HDS with almitrine +
      raubasine. The number of adverse events reported was low for the almitrine +
      raubasine-treated group and the placebo group and all events were mild, of short
      duration and resolved without treatment. Almitrine + raubasine had no clinically
      significant effect on blood pressure, heart rate or other laboratory tests.
      CONCLUSION: The results indicate that almitrine + raubasine can accelerate
      neurological function recovery after stroke to some degree and is well tolerated.

PMID- 15025851
TI  - General practitioners' greater choice for sentinel node biopsy than patients in
      the UK.

PMID- 15025852
TI  - Histatins: antimicrobial peptides with therapeutic potential.
AB  - Histatins are a group of antimicrobial peptides, found in the saliva of man and
      some higher primates, which possess antifungal properties. Histatins bind to a
      receptor on the fungal cell membrane and enter the cytoplasm where they target
      the mitochondrion. They induce the non-lytic loss of ATP from actively respiring
      cells, which can induce cell death. In addition, they have been shown to disrupt
      the cell cycle and lead to the generation of reactive oxygen species. Their mode
      of action is distinct from those exhibited by the conventional azole and polyene
      drugs, hence histatins may have applications in controlling drug-resistant fungal
      infections. The possibility of utilising histatins for the control of fungal
      infections of the oral cavity is being actively pursued with the antifungal
      properties of topical histatin preparations and histatin-impregnated denture
      acrylic being evaluated. Initial clinical studies are encouraging, having
      demonstrated the safety and efficacy of histatin preparations in blocking the
      adherence of the yeast Candida albicans to denture acrylic, retarding plaque
      formation and reducing the severity of gingivitis. Histatins may represent a new
      generation of antimicrobial compounds for the treatment of oral fungal infections
      and have the advantage, compared with conventional antifungal agents, of being a
      normal component of human saliva with no apparent adverse effects on host tissues
      and having a mode of action distinct to azole and polyene antifungals.

PMID- 15025853
TI  - Human skin permeation of Delta8-tetrahydrocannabinol, cannabidiol and cannabinol.
AB  - The purpose of this study was to quantify the in-vitro human skin transdermal
      flux of Delta8-tetrahydrocannabinol (Delta8-THC), cannabidiol (CBD) and
      cannabinol (CBN). These cannabinoids are of interest because they are likely
      candidates for transdermal combination therapy. Differential thermal analysis and
      in-vitro diffusion studies with human tissue were completed for the compounds.
      Heats of fusion, melting points and relative thermodynamic activities were
      determined for the crystalline compounds, CBD and CBN. Flux, permeability, tissue
      concentration and lag times were measured in the diffusion experiments. CBN had a
      lower heat of fusion and corresponding higher calculated relative thermodynamic
      activity than CBD. Ethanol concentrations of 30 to 33% significantly increased
      the transdermal flux of Delta8-THC and CBD. Tissue concentrations of Delta8-THC
      were significantly higher than for CBN. Lag times for CBD were significantly
      smaller than for CBN. The permeabilities of CBD and CBN were 10-fold higher than
      for Delta8-THC. Combinations of these cannabinoids with ethanol will be further
      studied in transdermal patch formulations in vitro and in vivo, as significant
      flux levels of all the drugs were obtained. CBD, the most polar of the three
      drugs, and other more polar cannabinoids will also be the focus of future drug
      design studies for improved transdermal delivery rates.

PMID- 15025854
TI  - Effect of lubricant type and concentration on the punch tip adherence of model
      ibuprofen formulations.
AB  - A model formulation, comprising ibuprofen and direct compression lactose
      (Tablettose 80) was used to assess the influence of two lubricants, magnesium
      stearate and stearic acid, on punch tip adherence. Lubricant concentrations were
      varied from 0.25% to 2% w/w. Formulations in the presence and absence of 0.5% w/w
      colloidal silica (Aerosil 200) were examined, to assess the influence of the
      glidant on the anti-adherent effects of the lubricants. Differential scanning
      calorimetry (DSC) was used to examine the effect of the lubricants on the melting
      temperature of ibuprofen. Tablets were compacted using a single punch tablet
      press at 10 kN using hard chrome-plated punches or at 40 kN using uncoated steel
      punches, tooling was 12.5-mm diameter in each case. The upper punch faces were
      characterized by obtaining Taylor Hobson Talysurf surface profiles. Following
      compaction, ibuprofen attached to the face was quantified by spectroscopy. At low
      concentrations of each lubricant, the levels of sticking observed were similar.
      Whilst sticking increased at magnesium stearate concentrations above 1%, sticking
      with stearic acid remained relatively constant at all concentrations. DSC
      revealed that the melting temperature of ibuprofen was lowered by the formation
      of eutectic mixtures with both lubricants. However, the onset temperature of
      melting and melting point were lowered to a greater extent with magnesium
      stearate compared with stearic acid. When using uncoated tooling at 40 kN, the
      deleterious effects of magnesium stearate on the tensile strength of the tablets
      also contributed to sticking. When using chrome-plated punches at 10 kN, the
      tensile strength reduction by the presence of magnesium stearate was less
      pronounced, as was the level of sticking.

PMID- 15025855
TI  - The emulsification and solubilisation properties of polyglycolysed oils in self
      emulsifying formulations.
AB  - Self-emulsifying drug delivery systems (SEDDS), whereby drugs are dispersed in an
      oil-surfactant mix that emulsifies on contact with water, represent a highly
      promising approach for enhancing oral bioavailability. However, the choice of
      formulation is, at present, largely empirical both in terms of the composition
      dependence of the emulsification process and the solubilisation of the drug in
      the initial oil-surfactant mixture. In this investigation, a range of chemically
      related self-emulsifying systems have been studied, based on the Labrafil family
      of polyglycolysed oils, using Tween 80 and Tween 20 as surfactants. The ease of
      emulsification, the particle size distribution and the appearance of the emulsion
      droplets were studied as a function of composition, while the solubility of
      danazol and mefenamic acid in the various oil-surfactant mixes was measured. It
      was noted that dilution of the emulsions led to apparent change in particle size
      distribution. The more hydrophilic oil-surfactant mixes showed a greater ease of
      emulsification and a lower particle size. It was also noted that multiple
      emulsions could be formed using systems of lower polarity. A linear relationship
      was observed between the hydrophile-lipophile balance (HLB) of the mix and the
      solubility of both danazol and mefenamic acid, with more hydrophilic mixes
      showing greater drug solubility values. The study has indicated that, within the
      range studied, more hydrophilic mixes tend to result in superior emulsification
      properties and greater drug solubility.

PMID- 15025856
TI  - Pharmacokinetic interaction of ibuprofen enantiomers in rabbits.
AB  - The potential interaction between two ibuprofen enantiomers was studied after
      intravenous administration of R-(-)-, S-(+)- and racemic ibuprofen to rabbits.
      The total body clearance values calculated by compartmental model analysis (0.65
      +/- 0.21 for R-(-)-ibuprofen and 0.63 +/- 0.34 for S-(+)-ibuprofen) after
      intravenous administration of the racemate of ibuprofen were significantly
      smaller than those of individual enantiomers (0.95 +/- 0.23 for R-(-)-ibuprofen
      and 1.03 +/- 0.23 for S-(+)-ibuprofen), indicating that the enantiomer-enantiomer
      interaction results in a mutual inhibition. The enantiomeric interaction in the
      pharmacokinetic behaviour of ibuprofen after racemic administration is considered
      to be a result of an alteration in the metabolic or excretion phase (or both)
      rather than stereoselective protein binding in the systemic distribution.

PMID- 15025857
TI  - Pharmacokinetics and distribution of sodium 3,4-diaminonaphthalene-1-sulfonate, a
      Congo Red derivative active in inhibiting PrP(res) replication.
AB  - Sodium 3,4-diaminonaphthalene-1-sulfonate (CRA) is a compound, synthesised by our
      group from Congo Red (CR), that is active in preventing the pathological
      conversion of normal prion protein (PrP). As the precise mechanisms controlling
      the ways in which prions are distributed and infect the brain and other organs
      are not fully understood, studying the pharmacokinetics of drugs that are active
      against prions may clarify their targets and their means of inhibiting prion
      infection. This paper describes the pharmacokinetics of CRA in plasma, spleen and
      brain after single or repeated intraperitoneal or subcutaneous administration, as
      determined by means of specific and sensitive fluorimetric HPLC. A single
      intraperitoneal administration led to peak plasma CRA concentrations after 15
      min, followed by biphasic decay with an apparent half-life of 4.3 h. After
      subcutaneous administration, T(max) was reached after 30 min, and was followed by
      a similar process of decay: Cmax and the AUC0-last were 25% those recorded after
      intraperitoneal administration. The mean peak concentrations and AUCs of CRA
      after a single intraperitoneal or subcutaneous administration in peripheral
      tissue (spleen) were similar to those observed in blood, whereas brain
      concentrations were about 2% those in plasma. After repeated intraperitoneal or
      subcutaneous doses, the Cmax values in plasma, brain and spleen were similar to
      those observed at the same times after a single dose. After repeated
      intraperitoneal doses, CRA was also found in the ventricular cerebrospinal fluid
      at concentrations of 1.8 +/- 0.2 microg(-1) mL, which is similar to, or slightly
      higher than, those found in brain. Brain concentrations may be sufficient to
      explain the activity of CRA on PrP reproduction in the CNS. However, peripheral
      involvement cannot be excluded because the effects of CRA are more pronounced
      after intraperitoneal than after intracerebral infection.

PMID- 15025859
TI  - Quantitative structure-pharmacokinetic relationship modelling: apparent volume of
      distribution.
AB  - The purpose of this study was to develop a quantitative structure-activity
      relationship (QSAR) for the prediction of the apparent volume of distribution
      (Vd) in man for a heterogeneous series of drugs. The relationship of many
      computed, and some experimental, structural descriptors with Vd, and the Vd
      corrected for protein binding (unbound Vd), was investigated. Models were
      constructed using stepwise regression analysis for all the 70 drugs in the
      dataset, as well as for acidic drugs and basic drugs separately. The predictive
      power of the models was assessed using half the chemicals as a test set, and
      revealed that the models for Vd yielded lower prediction errors than those
      constructed for the unbound Vd (mean fold error of 2.01 for Vd compared with 2.28
      for unbound Vd). Moreover, the separation of the compounds into acids and bases
      did not reduce the prediction error significantly.

PMID- 15025858
TI  - Small intestinal glucose absorption in cystic fibrosis: a study in human and
      transgenic DeltaF508 cystic fibrosis mouse tissues.
AB  - Intestinal transport is disturbed in cystic fibrosis (CF), with both defective Cl
      secretion and changes in absorption being reported. We have examined the effects
      of the disease on Na(+)-dependent glucose absorption by the small intestine.
      Active glucose absorption was monitored as changes in short-circuit current (SCC)
      in intact and stripped intestinal sheets from normal (Swiss) and transgenic CF
      (Cftr(tm1Eur) and Cftr(tm2Cam)) mice with the DeltaF508 mutation, and in jejunal
      biopsies from children with CF and normal controls. Na(+)-dependent glucose
      uptake at the luminal membrane was measured in brush-border membrane vesicles
      (BBMVs). Intact and stripped sheets of jejunum and midintestine from Swiss mice
      exhibited a concentration-dependent increase in SCC with glucose. Apparent Km
      values were similar in the two preparations, but the apparent Vmax was greater in
      stripped sheets. This difference was not due to a loss of neural activity in
      stripped sheets as tetrodotoxin did not influence the glucose-induced SCC in
      intact sheets. Similar results were observed in stripped sheets of jejunum and
      mid-intestine from wild-type Cftr(tm1Eur) mice, but in tissues from CF mice the
      apparent Vmax value was reduced significantly. A lower Vmax was also obtained in
      intact sheets of mid-intestine from CF (Cftr(tm2Cam)) mice. Jejunal biopsies from
      CF patients however, exhibited an enhanced glucose-dependent rise in SCC. Na(+)
      dependent uptake by BBMVs from CF (Cftr(tm1Eur)) mice was not reduced compared
      with wild-type and Swiss BBMVs. It was concluded that, in contrast to human
      intestine, intestinal glucose absorption was reduced in transgenic mouse models
      of CF with the DeltaF508 mutation, but that this could not be detected in an
      isolated preparation of brush-border membranes. Transgenic mouse models of CF may
      not accurately reflect all aspects of intestinal dysfunction in the human
      disease.

PMID- 15025860
TI  - Systemic and ocular pharmacokinetics of N-4-benzoylaminophenylsulfonylglycine
      (BAPSG), a novel aldose reductase inhibitor.
AB  - To better develop N-[4-(benzoylamino)phenylsulfonyl]glycine (BAPSG), a potent and
      selective aldose reductase inhibitor capable of delaying the progression of
      ocular diabetic complications, the objective of this study was to assess its
      pharmacokinetics. The plasma pharmacokinetics of BASPG was assessed in male
      Sprague-Dawley rats following intravenous, intraperitoneal and oral routes of
      administration and its distribution to various tissues including those of the eye
      was studied following intraperitoneal administration. In addition, rat plasma
      protein binding of BAPSG was studied using ultracentrifugation method and its
      ocular tissue disposition was assessed following topical administration in
      rabbits. Plasma and tissue levels of BAPSG were analysed using an HPLC assay.
      BAPSG exhibited dose-proportionate AUC0 --> infinity (area under the plasma
      concentration-time curve) following both intravenous and intraperitoneal
      administration over the dose range (5-50 mg kg(-1)) studied and an erratic oral
      absorption profile with low oral bioavailability. The fraction bioavailability
      following oral and intraperitoneal administration was 0.06 and 0.7-1,
      respectively. BAPSG exhibited short plasma elimination half-lives in the range
      0.5-1.5 h. BAPSG was bound to rat plasma proteins and the percent protein binding
      ranged from 83 to 99.8%. BAPSG was better distributed to cornea, lens and retina
      than to brain, following intraperitoneal administration in rats. However, the
      distribution was lower compared with kidney and liver. Following topical
      administration in rabbits, BAPSG delivery to the surface ocular tissues, cornea
      and conjunctiva was higher compared with intraocular tissues, aqueous humour,
      iris-ciliary body and lens. Thus, BAPSG was distributed to ocular tissues
      following systemic and topical modes of administration.

PMID- 15025861
TI  - Melatonin reverses urinary system and aorta damage in the rat due to chronic
      nicotine administration.
AB  - We have evaluated the changes in contractile activity and oxidant damage of
      corpus cavernosum, urinary bladder, kidney and aorta after chronic nicotine
      administration in rats. The effects of melatonin on these parameters were
      investigated also. Male Wistar albino rats were injected intraperitoneally with
      nicotine hydrogen bitartrate (0.6 mg kg(-1) daily for 21 days) or saline.
      Melatonin (10 mg kg(-1), i.p.) was administered either alone or with nicotine
      injections. Corpus cavernosum, bladder and aorta were used for contractility
      studies, or stored with kidneys for the measurement of malondialdehyde and
      glutathione levels. Corpus cavernosum, bladder, and aorta samples were examined
      histologically and the extent of microscopic tissue damage was scored. In the
      nicotine-treated group, the contraction of corpus cavernosum, bladder and aorta
      samples and the relaxation of corporeal and aorta tissues decreased significantly
      compared with controls. However, melatonin treatment restored these responses. In
      the nicotine-treated group, there was a significant increase in the
      malondialdehyde levels of the corporeal tissue, bladder, kidney and aorta, with
      marked reductions in glutathione levels compared with controls. Melatonin
      treatment reversed these effects also. Melatonin administration to nicotine
      treated animals caused a marked reduction in the microscopic damage of the
      tissues compared with those of the untreated group. In this study, nicotine
      induced dysfunction of the corpus cavernosum, bladder and aorta of rats was
      reversed by melatonin treatment. Moreover, melatonin, as an antioxidant,
      abolished elevation in lipid peroxidation products, and reduction in the
      endogenous antioxidant glutathione, and protected the tissues from severe damage
      due to nicotine exposure.

PMID- 15025862
TI  - Effect of P-glycoprotein inhibition on methadone analgesia and brain distribution
      in the rat.
AB  - Methadone is an opiate drug that has been identified as an in-vitro substrate of
      the efflux pump P-glycoprotein (P-gp), active in the intestinal epithelium and in
      the blood-brain barrier (BBB), among other sites. The objective of this study was
      to test in vivo, in the rat model, the role of P-gp modulation on the analgesic
      effect and brain uptake of methadone, as well as identify the most relevant site
      via dual oral and intravenous (i.v.) experiments. The P-gp specific inhibitor
      (valspodar or PSC833) was preadministered (10 mg kg(-1) i.v.) to test groups.
      Analgesia was measured using the tailflick test. The ED50 for oral methadone (2,
      3, 6 and 8 mg kg(-1)) decreased three-fold in valspodar groups compared with
      controls (2.23 +/- 0.002 mg kg(-1) and 6.07 +/- 0.07 mg kg(-1); P < 0.0001). The
      overall analgesic effect (% antinociception) was elevated 3.1 times in pretreated
      compared with control rats (90.65% +/- 0.22 vs 29.23% +/- 14.0; P < 0.01) after 6
      mg kg(-1) oral methadone and 2.8 times after i.v. (0.35 mg kg(-1)) administration
      (91.75% +/- 4.27 vs 32.45% +/- 9.0; P < 0.01). The brain:plasma distribution
      ratio was higher in pretreated animals and AUCbrain (overall brain concentration)
      was 6 times higher after oral methadone and 4 times higher after i.v. compared
      with controls, disproportionally increased relative to plasma, implying an active
      process at the BBB. P-gp, and hence substrate comedication, plays a critical role
      in the evolution of the methadone analgesic effect and in its brain uptake,
      independent of the administration route.

PMID- 15025863
TI  - Inhibition of acetylcholinesterase by Tea Tree oil.
AB  - Pediculosis is a widespread condition reported in schoolchildren. Treatment most
      commonly involves the physical removal of nits using fine-toothcombs and the
      chemical treatment of adult lice and eggs with topical preparations. The active
      constituents of these preparations frequently exert their effects through
      inhibition of acetylcholinesterase (AChE, EC 3.1.1.7). Increasing resistance to
      many preparations has led to the search for more effective treatments. Tea Tree
      oil, otherwise known as Melaleuca oil, has been added to several preparations as
      an alternative treatment of head lice infestations. In this study two major
      constituents of Tea Tree oil, 1,8-cineole and terpinen-4-ol, were shown to
      inhibit acetylcholinesterase at IC50 values (inhibitor concentrations required to
      give 50% inhibition) of 0.04 and 10.30 mM, respectively. Four samples of Tea Tree
      oil tested (Tisserand, Body Treats, Main Camp and Irish Health Culture
      Association Pure Undiluted) showed anticholinesterase activity at IC50 values of
      0.05, 0.10, 0.08 and 0.11 microL mL(-1), respectively. The results supported the
      hypothesis that the insecticidal activity of Tea Tree oil was attributable, in
      part, to the anticholinesterase activity of Tea Tree oil.

PMID- 15025864
TI  - Medicinal plants in Suriname: hypotensive effect of Gossypium barbadense.
AB  - In traditional medicine Gossypium barbadense L. is used against hypertension.
      Looking for a scientific basis for this use, the blood-pressure-lowering effect
      of the decoction of the leaves was confirmed. Fraction II (frII) of the crude
      extract of G. barbadense showed a dose-dependent hypotensive effect in
      anaesthetized rats. In hexamethonium-treated rats, the blood-pressure-lowering
      effect of frII was almost abolished. A small decrease of the blood-pressure
      lowering effect was followed by an increase in the blood pressure. Phentolamine
      antagonized the increase in blood pressure in hexamethoniumtreated rats. High
      doses of atropine (4 mg/rat) suppressed both depressor and heart effects. In
      vitro experiments revealed that atropine did not antagonize the contraction of
      the ileum of the rat. Tripelennamine in a concentration of 100 microg could not
      influence the contraction either, whereas 300 microg did. In the guinea-pig ileum
      10 microg tripelennamine did not reduce the contraction significantly. In the
      mechanism of action of frII, acetylcholine receptors could be involved, but not
      histaminergic or adrenergic receptors. Although it is still not known which
      compound(s) in G. barbadense is (are) the active substance(s), the results
      obtained may explain the use of this plant in traditional medicine in Suriname.

PMID- 15025865
TI  - Central activity of hydroalcoholic extracts from Erythrina velutina and Erythrina
      mulungu in mice.
AB  - This work studied the central behavioural effects of hydroalcoholic extracts from
      the stem bark of Erythrina velutina and Erythrina mulungu on the elevated plus
      maze, open field, and rota rod tests in mice. These medicinal plants belong to
      the Fabaceae family and are popularly used in Brazil for their effects on the
      central nervous system. Single doses of the extracts were administered orally
      (200, 400 or 800 mg kg(-1)) or intraperitoneally (200 or 400 mg kg(-1)) to female
      mice. A reduction of the locomotor activity was observed in the open field test
      with both hydroalcoholic extracts after intraperitoneal treatment with all doses,
      but only with the highest dose after oral administration. In addition, oral and
      intraperitoneal administration of the extracts decreased the incidence of rearing
      and grooming. Decreases in the number of entries in the open (NEOA) and closed
      (NECA) arms of the elevated plus maze were observed after the administration of
      the highest dose (800 mg kg(-1), p.o.) of both hydroalcoholic extracts, and this
      effect may be due to the decrease in locomotor activity. These hydroalcoholic
      extracts failed to affect the motor coordination in the rota rod test. In
      conclusion, we showed that the hydroalcoholic extracts of E. velutina and E.
      mulungu have depressant effects on the central nervous system, which, at least
      partially, corroborates the popular use of these species as tranquilizers in
      Brazilian popular medicine.

PMID- 15025866
TI  - Blocking actions of glibenclamide on ATP-sensitive K+ channels in pig urethral
      myocytes.
AB  - The inhibitory effects of glibenclamide on the levcromakalim-induced ATP
      sensitive K+ (K(ATP)) channels were investigated with cell-attached configuration
      in pig proximal urethra. Application of 10 microM glibenclamide reversibly
      inhibited the activity of the 100 microM levcromakalim-induced K(ATP) channel,
      decreasing not only the channel open probability but also the amplitude of
      unitary current. The inhibitory concentration-response curve of the glibenclamide
      induced sublevel conductance of K(ATP) channel was shifted to the right (IC50 =
      4.7 microM), compared with the levcromakalim-induced K(ATP) channel (full
      conductance, IC50 = 0.5 microM). Glibenclamide is the first reported
      sulphonylurea to selectively block K(ATP) channel, not only by decreasing the
      channel activity but also by reducing the unitary amplitude in smooth muscle.

PMID- 15025867
TI  - Pretreatment with Ginkgo biloba extract weakens the hypnosis action of
      phenobarbital and its plasma concentration in rats.
AB  - In a previous study, we found that orally administered Ginkgo biloba extract
      (GBE) induced hepatic cytochrome P450 (CYP) in rats, especially the CYP2B type.
      This fact suggested that GBE influenced the availability and safety of drugs that
      were metabolized via CYP2B type enzymes. To confirm this possibility, in this
      study we examined the effect of feeding a 0.1, 0.5 and 1.0% GBE diet for 2 weeks
      on the pharmacokinetics and pharmacological action of phenobarbital, which is
      known to be metabolized by CYP2B in Wistar rats. The feeding of GBE markedly
      shortened the sleeping time in rats. Furthermore, the maximal phenobarbital
      plasma concentration (Cmax) and the 24-h area under the curve (AUC0-24) were
      decreased in rats fed GBE. These findings indicate that GBE reduces the
      therapeutic potency of phenobarbital via enhancement of cytochrome P450
      expression, and raises the possibility that GBE and drug interactions may occur
      clinically.

PMID- 15025869
TI  - Science and healing: from bioelectromagnetics to the medicine of light.
      Implications, phenomena, and deep transformation.

PMID- 15025868
TI  - Polymeric nanoparticles composed of fatty acids and polyvinylalcohol for topical
      application of sunscreens.
AB  - Benzophenone-3 (BZP) or oxybenzone is widely used in many cosmetic formulations,
      such as sunscreen lotions or emulsions, shampoos and hair sprays. The nature of
      the vehicle used can enhance or block the percutaneous absorption of UV filter.
      In this work, we hydrophobically modified polyvinylalcohol 10 000 (PVA) with
      fatty acids (FAs) to obtain PVA-FA derivatives for the preparation of lipophilic
      polymeric nanoparticles able to prevent BZP movement towards the skin.
      Synthesized PVA-FA derivatives were confirmed by H1 NMR. Nanoparticles loaded
      with BZP were prepared using a solvent extraction method. The particle size was
      monitored by means of dynamic light scattering measurements. In-vitro skin
      permeation studies were performed.

PMID- 15025870
TI  - Energy medicine: from knowledge to practice.

PMID- 15025871
TI  - Wisdom, knowledge, and information: have we lost our way in our understanding and
      practice of medicine?

PMID- 15025872
TI  - The practitioner as medicine.

PMID- 15025873
TI  - Exploring new horizons in electromedicine.

PMID- 15025874
TI  - Healing with water.

PMID- 15025875
TI  - Biophoton images of plants: revealing the light within.

PMID- 15025876
TI  - Consciousness and quantum information processing: uncovering the foundation for a
      medicine of light.
AB  - Great progress has been made by Russian and German researchers in recent years
      (Popp, Voeikov, and others) to examine the biophysical aspects of biophotonic
      processes in humans. This paper suggests that there is a many-body reality to the
      way biophysical light interacts with the human self-organization of information
      that may be achieved by means of biomolecular, metabolic, or neural
      communication. These systems may merge as mobile energy relay systems similar to
      what is seen as qi processes in acupuncture science, suggesting a "holomovement"
      that seeks to confirm itself and increasingly retrieves and uses only the
      information that serves its exchanges with the environment. This coevolution of
      evolutionary process levels, expressed in process terms, can be seen as a
      foundation for a Medicine of Light integrating hidden variables in consciousness
      studies with functional differentiation and new findings in the biologic
      sciences.

PMID- 15025877
TI  - Toward an electromagnetic paradigm for biology and medicine.
AB  - Work by Lund, Burr, Becker, and others leads to the inescapable conclusion that
      organisms tend to express quasisystemic electric changes when perturbed, and,
      conversely, will tend toward wellness either through endogenous repair currents
      or the application of equivalent external currents. We show that an all-inclusive
      electromagnetic field representation for living systems is fully consistent with
      this extensive body of work. This electrogenomic field may provide the basis for
      a new paradigm in biology and medicine that is radically different from the
      present emphasis on molecular biology and biochemistry. An electromagnetic field
      description also enables a more rational transformation from the genome than the
      present endpoint, universally stated in terms of the so-called visible
      characteristics. Furthermore, once the organism is described as an
      electromagnetic entity, this strongly suggests the reason for the efficacy of the
      various electromagnetic therapies, namely as the most direct means of restoring
      the body's impacted electromagnetic field to its normal state.

PMID- 15025879
TI  - Bioinformation within the biofield: beyond bioelectromagnetics.
AB  - This review article extends previous scientific definitions of the biofield
      (endogenous energy fields of the body) to include nonclassical and quantum energy
      fields. The biofield is defined further in terms of its functional property to
      act as a resonance target for external forms of energy used as treatment
      modalities in energy medicine. The functional role of the biofield in the body's
      innate self-healing mechanisms is hypothesized, based on the concept of
      bioinformation which, mediated by consciousness, functions globally at the
      quantum level to supply coherence, phase, spin, and pattern information to
      regulate and heal all physiologic processes. This model is used to explain a wide
      variety of anomalies reported in the scientific literature, which can not be
      explained by traditional biophysics and bioelectromagnetics.

PMID- 15025878
TI  - Assessing biophysical energy transfer mechanisms in living systems: the basis of
      life processes.
AB  - OBJECTIVE: To explain the energetic physiologic basis for acupuncture
      electroconductance effects and for gas discharge visualization (GDV) assessment
      methods, using a quantum biophysical model of entropy and information flows.
      DESCRIPTION: The main reservoir of free energy in biologic processes is electron
      excited states of complex molecular systems. Communities of delocalized excited
      pi-electrons in protein macromolecules are the basis of this energy reservoir.
      Specific structural-protein complexes within the mass of the skin provide
      channels of heightened electron conductivity, measured at acupuncture points on
      the surface. Stimulated impulse emissions from the skin are also developed mainly
      by transport of delocalized pi-electrons. Stimulated by high voltage impulses,
      optical emissions, with amplification in gaseous discharge, are registered by
      optical sensors (GDV). This quantum model supports an argument that GDV
      techniques provide indirect judgment about the level of energy resources at the
      molecular level of functioning in structural-protein complexes. Several years of
      GDV research have provided clinical correlations with well-accepted physiologic
      parameters. For example, postsurgery recovery progress is correlated with GDV
      parameters and GDV assessments provide independent diagnostic measures of
      psychophysical reserves in athletes. CONCLUSION: GDV methods for investigating
      human functional states, by assessing electro-optical parameters of the skin, are
      based on the registration of physical processes emerging from electron components
      of tissue conductivity.

PMID- 15025880
TI  - Quanta and coherence effects in water and living systems.
AB  - OBJECTIVE: To review the progress the author has made over the past 5 years in
      understanding coherence effects in water and living systems using quantum
      mechanical models. BACKGROUND: The implications of existing theoretical work on
      water are discussed. METHODS: Available techniques for the measurement of
      frequencies imprinted in water are described or referenced. RESULTS: The
      importance of frequency is shown in respect of the understanding of the
      mechanisms of homeopathy, acupuncture and how bio-information may be stored in
      water and also in respect of chemical and electrical sensitivities or
      hypersensitivities; hypersensitivity being that degree of sensitivity that
      seriously interferes with normal functioning. CONCLUSION: Water and living
      systems have macroscopic quantum properties that can give rise to a memory for
      frequencies, long-range effects, and entanglement between separated systems.

PMID- 15025881
TI  - What does it mean to practice an energy medicine?
AB  - The concepts that energy exists and moves and that health is homeodynamic form
      the core assumptions of medical practices such as acupuncture that are known as
      energy medicines. These assumptions lead logically to practice characteristics
      that distinguish energy medicines from materialist medicines.

PMID- 15025882
TI  - Are we close to a theory of energy medicine?
AB  - Critical phenomena offer an attractive new theoretical resource for biophysics.
      Physical instabilities result in fluctuations, the quantum properties of which
      can be applied to regulatory control mechanisms in living organisms with
      promising results. Many aspects of energy medicine can be scientifically modeled,
      in agreement with previous theoretical ideas and speculation, such as the
      existence of macroscopic quantum coherence in living systems. Light is shed on
      areas of complementary and alternative medicine (CAM) such as Ayurveda,
      naturopathy, and the nature and action of potentized medicines in homeopathy and
      other aspects of vibrational medicine.

PMID- 15025883
TI  - Energy medicine: an osteopath's personal view.

PMID- 15025884
TI  - An introduction to Kundalini yoga meditation techniques that are specific for the
      treatment of psychiatric disorders.
AB  - The ancient system of Kundalini yoga includes a vast array of meditation
      techniques and many were discovered to be specific for treating the psychiatric
      disorders as we know them today. One such technique was found to be specific for
      treating obsessive-compulsive disorder (OCD), the fourth most common psychiatric
      disorder, and the tenth most disabling disorder worldwide. Two published clinical
      trials are described here for treating OCD using a specific Kundalini yoga
      protocol. This OCD protocol also includes techniques that are useful for a wide
      range of anxiety disorders, as well as a technique specific for learning to
      manage fear, one for tranquilizing an angry mind, one for meeting mental
      challenges, and one for turning negative thoughts into positive thoughts. Part of
      that protocol is included here and published in detail elsewhere. In addition, a
      number of other disorder-specific meditation techniques are included here to help
      bring these tools to the attention of the medical and scientific community. These
      techniques are specific for phobias, addictive and substance abuse disorders,
      major depressive disorders, dyslexia, grief, insomnia and other sleep disorders.

PMID- 15025885
TI  - Measuring effects of music, noise, and healing energy using a seed germination
      bioassay.
AB  - OBJECTIVE: To measure biologic effects of music, noise, and healing energy
      without human preferences or placebo effects using seed germination as an
      objective biomarker. METHODS: A series of five experiments were performed
      utilizing okra and zucchini seeds germinated in acoustically shielded, thermally
      insulated, dark, humid growth chambers. Conditions compared were an untreated
      control, musical sound, pink noise, and healing energy. Healing energy was
      administered for 15-20 minutes every 12 hours with the intention that the treated
      seeds would germinate faster than the untreated seeds. The objective marker was
      the number of seeds sprouted out of groups of 25 seeds counted at 12-hour
      intervals over a 72-hour growing period. Temperature and relative humidity were
      monitored every 15 minutes inside the seed germination containers. A total of 14
      trials were run testing a total of 4600 seeds. RESULTS: Musical sound had a
      highly statistically significant effect on the number of seeds sprouted compared
      to the untreated control over all five experiments for the main condition (p <
      0.002) and over time (p < 0.000002). This effect was independent of temperature,
      seed type, position in room, specific petri dish, and person doing the scoring.
      Musical sound had a significant effect compared to noise and an untreated control
      as a function of time (p < 0.03) while there was no significant difference
      between seeds exposed to noise and an untreated control. Healing energy also had
      a significant effect compared to an untreated control (main condition, p <
      0.0006) and over time (p < 0.0001) with a magnitude of effect comparable to that
      of musical sound. CONCLUSION: This study suggests that sound vibrations (music
      and noise) as well as biofields (bioelectromagnetic and healing intention) both
      directly affect living biologic systems, and that a seed germination bioassay has
      the sensitivity to enable detection of effects caused by various applied
      energetic conditions.

PMID- 15025886
TI  - Strength of vital force in classical homeopathy: bio-psycho-social-spiritual
      correlates within a complex systems context.
AB  - OBJECTIVE: To explore associations between a global rating for the classical
      homeopathic construct of vital force and clinician and patient ratings on
      previously validated bio-psycho-social-spiritual questionnaires. METHODS: Sixty
      two (62) community-recruited patients with fibromyalgia (FM) were assessed at
      baseline prior to a clinical trial of individualized homeopathy. Two homeopaths
      jointly performed case-taking interviews. A conventional medical provider
      independently evaluated patients with a standardized history and physical
      examination. Homeopaths rated each patient's vital force (five-point Likert
      scale, with 1 = very weak to 5 = very strong). Homeopaths and the conventional
      medical provider rated their Clinical Global Impression (CGI) of the severity of
      illness (1 = normal; 7 = among the most extremely ill). Patients completed self
      rating scales on pain, global health, mood, quality of life, coping style, health
      locus of control, multidimensional well-being, spirituality, sense of coherence,
      positive states of mind, and social desirability. RESULTS: Greater vital force
      ratings (mean 2.9 standard deviation [SD] 0.6) correlated moderately (p < or =
      0.005) with less severe CGI illness ratings by the homeopaths (r =-0.59),
      decreased patient-rated mental confusion (r =-0.43), higher vigor (r = 0.38), and
      greater positive states of mind (r = 0.36). Vital force also showed correlations
      (p < 0.05) with lower CGI ratings by the conventional medical provider (r =
      0.32), better selfrated quality of life (r = 0.33), lesser fatigue (r =-0.31),
      better global health (r = 0.29), greater sense of coherence (r = 0.28), powerful
      others health locus of control (r = 0.27), increased emotional well-being (r =
      0.27), and higher social desirability (r = 0.27), but not with age, pain, or
      illness duration. CONCLUSION: Homeopathic vital force ratings reflect better
      perceived mental function, energy, and positive dimensions of the individual,
      beyond absence of disease.

PMID- 15025887
TI  - Electrophysiological evidence of intuition: part 1. The surprising role of the
      heart.
AB  - OBJECTIVES: This study aims to contribute to a scientific understanding of
      intuition, a process by which information normally outside the range of conscious
      awareness is perceived by the psychophysiological systems. The first objective,
      presented in two empirical papers (Part 1 and Part 2), was to replicate and
      extend the results of previous experiments demonstrating that the body can
      respond to an emotionally arousing stimulus seconds before it is actually
      experienced. The second objective, to be presented in a third paper (Part 3), is
      to develop a theory that explains how the body receives and processes information
      involved in intuitive perception. DESIGN: The study used a counterbalanced
      crossover design, in which 30 calm and 15 emotionally arousing pictures were
      presented to 26 participants under two experimental conditions: a baseline
      condition of normal psychophysiologic function and a condition of physiological
      coherence. Primary measures included: skin conductance; the electroencephalogram
      (EEG), from which cortical event-related potentials and heartbeat-evoked
      potentials were derived; and the electrocardiogram (ECG), from which cardiac
      decelerations/accelerations were derived. These measures were used to investigate
      where and when in the brain and body intuitive information is processed. RESULTS:
      The study's results are presented in two parts. The main findings in relation to
      the heart's role in intuitive perception presented here are: (1) surprisingly,
      the heart appears to receive and respond to intuitive information; (2) a
      significantly greater heart rate deceleration occurred prior to future emotional
      stimuli compared to calm stimuli; (3) there were significant gender differences
      in the processing of prestimulus information. Part 2 will present results
      indicating where in the brain intuitive information is processed and data showing
      that prestimulus information from the heart is communicated to the brain. It also
      presents evidence that females are more attuned to intuitive information from the
      heart. CONCLUSIONS: Overall, we have independently replicated and extended
      previous research documenting prestimulus responses. It appears that the heart is
      involved in the processing and decoding of intuitive information. Once the
      prestimulus information is received in the psychophysiologic systems, it appears
      to be processed in the same way as conventional sensory input. This study
      presents compelling evidence that the body's perceptual apparatus is continuously
      scanning the future. To account for the results presented in Parts 1 and 2, Part
      3 will develop a theory based on holographic principles explaining how intuitive
      perception accesses a field of energy into which information about future events
      is spectrally enfolded.

PMID- 15025888
TI  - Toward general experimentation and discovery in conditioned laboratory spaces:
      Part I. Experimental pH change findings at some remote sites.
AB  - OBJECTIVES: To fulfill the general scientific method requirement for one of our
      earlier Minnesota experiments, namely that laboratory spaces operated by other
      investigators at different sites in the United States can be conditioned to a
      higher electromagnetic gauge symmetry state than our normal background state and
      such a space can be specifically tuned so that the pH of purified water in
      equilibrium with air will be increased by approximately 1.0 pH unit with no
      chemical additions. DESIGN: Insertion of a specific intention imprinted
      electrical device (IIED) into the space for a period of at least 3 months while
      continuously monitoring the pH of purified water wherein the water was replaced
      and the pH-electrode recalibrated on a 2-week cycle. Control sites were
      associated with each IIED site. SETTING/LOCATION: Offices in homes and clinics.
      SUBJECTS: Three IIED sites plus three control sites. INTERVENTIONS: None. OUTCOME
      MEASURES: Continuously recorded pH and temperature. RESULTS: (1) Linear and
      exponential pH(t) variations with time at IIED sites, with the Delta pH-values
      increasing with each 2-week cycle up to a value of approximately 0.8-1.0 pH
      units, (2) control sites, 2-20 miles distant from the IIED sites exhibited
      similar behavior but with smaller Delta pH-values, and (3) a new information
      transfer mechanism in nature has been demonstrated. CONCLUSIONS: Human
      consciousness, at least under some conditions, can strongly influence well
      designed target experiments in physical reality and the primary data are
      reproducible in other laboratories provided the specific protocol is followed.

PMID- 15025889
TI  - A case study of simultaneous recovery from multiple physical symptoms with
      medical qigong therapy.
AB  - BACKGROUND: It is well known that qigong practice is beneficial to human health,
      but it is less known, even in China, that qigong may also be an effective therapy
      to treat various diseases. This report documents the story of a 58-year-old
      Caucasian male patient with a series of chronic conditions, including high
      prostate-specific antigen (PSA) levels (but not a confirmed cancer), atrial
      septal defect, asthma, allergies, multiple injuries following an automobile
      accident, high blood pressure, and edema in the legs. Can medical qigong help
      such a patient to cure multiple symptoms simultaneously? METHOD: The intensive
      qigong workshop involved the training and practice of gathering qi, magnifying qi
      energy and using it for self-healing with visualization and guided imaginary;
      plus supervised energetic fasting. The patient practiced qigong 4-plus hours per
      day during intensive training, and approximately 1 to 2 hours daily thereafter.
      About 10 sessions of external qi healing were performed by a qigong master for
      his pain and systematic adjustment. SETTINGS/LOCATION: The intensive medical
      qigong workshop took place in the World Institute for Self-Healing, Inc. (WISH)
      office at Middlesex, NJ; and the patient practiced qigong at home for the rest of
      time. RESULTS: After the workshop and qigong therapy, the patient discontinued
      all medications (8 in total) and lost 35 pounds; his blood pressure dropped from
      220/110 with medication to 120/75 without medication (in 2 weeks); pulse rate
      dropped from 88 beats per minute resting to 68 beats per minute in the mornings
      and 55 bpm in the evening; the edema in his legs went away; symptoms of asthma or
      allergies disappeared; the PSA level dropped from 11 to 4 (normal), all without
      any medications. CONCLUSION: This kind of simultaneous recovery from multiple
      "incurable" conditions and other documented successes cannot be explained by any
      known medical theories, and call for formal clinical trials to closely examine
      the qigong self-healing therapy.

PMID- 15025890
TI  - Commentary: Multifaceted health benefits of medical qigong.

PMID- 15025892
TI  - Recommendations regarding definitions and standards in healing research.

PMID- 15025891
TI  - Biofield detection: role of bioenergy awareness training and individual
      differences in absorption.
AB  - OBJECTIVE: To measure health care providers' capacity to detect biofields before
      and after bioenergy awareness training in relation to individual differences in
      the personality trait of absorption. METHODS: Twenty-seven (27) physicians,
      psychologists, and nurses participated in a 5-day intensive bioenergy healing
      training course with Rev. Rosalyn Bruyere. The course was part of the Associate
      Fellows Program in the Program in Integrative Medicine at the University of
      Arizona. Blindfolded participants received a 24-trial hand biofield detection
      test (HBDT) pretraining and post-training. The experimenter placed his or her
      dominant hand a few inches above the participant's left or right hand for 30
      second trials. After each trial, the participant guessed which hand was being
      tested. Blocks contained two right- and two left-hand trials in different orders.
      Participants filled out Tellegen's Absorption Scale, a measure of the capacity to
      focus attention in tasks. RESULTS: Percent HBDT accuracy for the entire sample
      was 50.8% (standard deviation [SD] = 12.24) at pretraining (50% is chance);
      accuracy increased to 55.5% (SD = 12.38) at post-training (t = p = 2.08, p <
      0.05). Pretraining absorption (mean = 23.9; SD = 5.52) was significantly
      correlated with degree of detection accuracy increase (r = 0.42, n = 22, p <
      0.05). High absorption (mean = 28.2 n = 11) participants increased to 58.3%
      compared to 52.7% for low absorption (mean = 19.2 n = 11) participants.
      CONCLUSION: The findings support claims of energy healers that (1) training can
      improve bioenergy awareness, and (2) there are substantial individual differences
      in response to training.

PMID- 15025894
TI  - Yamamoto's scalp acupuncture seminar: a presentation of innovative skills.
AB  - Description of a continuing education seminar that provides a model for the
      effective demonstration of needling techniques.

PMID- 15025901
TI  - The contribution of metaphor and metonymy to delusions.
AB  - This article investigates the possible role of metaphorical thinking in psychotic
      delusions. Twenty-five participants with delusions were asked to give an account
      of how their ideas had formed and to describe recent experiences relevant to
      their delusional beliefs. The data suggest that for some participants there may
      have been a crucial period when the person has unusual experiences, psychosocial
      difficulties, and made attempts involving metaphor/metonymy to understand these
      experiences. Furthermore, some participants reported very recent unusual
      experiences using metaphorical terms, and we speculate on the possibility that
      the content of the metaphors contributes to a continuation of psychotic
      experience. The data form a series of case illustrations and are exploratory. No
      generalizations can be made, but the presence of significant metaphors and
      metonymy in 11 out of 25 case histories suggests the process may be an important
      one. We end by outlining a theoretical model of how metaphors might contribute to
      the formation of delusions: it is suggested that delusional statements are
      intended to be literal statements, but report on experiences transformed by
      metaphorical meaning. This transformation involves the 'fusion' of conceptual
      domains.

PMID- 15025902
TI  - The quest for well-being: a qualitative study of the experience of taking
      antipsychotic medication.
AB  - Antipsychotic medication is integral to the treatment of severe and enduring
      mental health problems (e.g. schizophrenia). Such medication is associated with
      significant adverse side effects that can affect treatment adherence. To date
      there have been few attempts to analyse qualitatively service users' experience
      of taking antipsychotic medication. This study, conducted in Exeter, South West
      England, investigates the subjective experience of side effects of antipsychotic
      medication to gain a greater understanding of service users' experiences and to
      gain insights into adherence issues. Data were analysed using a variant of
      grounded theory (Glaser and Strauss, 1967) and a model of the experience of
      taking antipsychotic medication was constructed. The interview schedule was then
      refined and further interviews (including a focus group) were conducted among a
      diverse sample recruited from local day centres. Results indicated that people
      taking antipsychotic medication do not see side effects and symptoms as separate
      issues. Instead, they describe drugs as 'good' or 'terrible'-an indication of the
      total impact of their treatment. The model constructed reflects this, having the
      core concept of Well-being: that is, normality of function, feeling and
      appearance to the outside world. Major themes relating to this core category were
      managing treatment, evaluating treatment and understanding of the situation.
      Implications for medication adherence and clinical practice, including drug
      choice, are discussed, and the doctor-patient relationship is also considered.

PMID- 15025903
TI  - An examination of parenting experiences in male perpetrators of domestic
      violence: a qualitative study.
AB  - Early experiences have been found to have an enduring long-term impact on adult
      relationships. The coexistence of love and violence is evident in attachment
      patterns across the life-span, and in adulthood is particularly apparent in
      domestically violent partnerships. The aim of the study was to examine in depth
      the early parenting experiences of men who are domestically violent. Seven male
      participants who were on probation orders for domestic violence were interviewed
      using the Adult Attachment Interview. The data were analysed qualitatively and
      the results indicated that all of the men had experienced unloving, rejecting and
      dangerous parenting. Participants minimized their own violence upon their female
      partners despite having recently completed an anti-violence training
      intervention. Clinical implications, particularly the need to examine the
      efficacy of treatment with domestically violent men, are discussed.

PMID- 15025904
TI  - Personality disorder clusters and the Defence Style Questionnaire.
AB  - This research examined the relative contribution of 20 defence mechanisms
      assessed by the 40-item Defence Style Questionnaire (DSQ-40) as discriminating
      variables in predicting membership in personality disorder (PD) clusters. The
      odd, dramatic and anxious clusters of DSM-III-R and the detached, dependent,
      independent and ambivalent groups of Millon were used as PD types. PDs were
      assessed by the Coolidge Axis II Inventory and the Millon Clinical Multiaxial
      Inventory-II in a non-clinical sample. Results of discriminant function analysis
      provide empirical support for the usefulness of both DSM and Millon
      classification schemes. The DSM's odd cluster and Millon's ambivalent types are
      classified most accurately with the CATI. The MCMI-II classifies most accurately
      the DSM's odd and dramatic, and Millon's independent and ambivalent, personality
      types.

PMID- 15025907
TI  - Client-centred therapy, post-traumatic stress disorder and post-traumatic growth:
      theoretical perspectives and practical implications.
AB  - In practice it is not unusual for client-centred therapists to work with people
      who have experienced traumatic events. However, client-centred therapy is not
      usually considered within texts on traumatic stress and questions have been
      raised over the appropriateness of client-centred therapy with trauma survivors.
      The present study shows how, although he was writing well before the introduction
      of the term 'post-traumatic stress disorder', Carl Rogers provided a theory of
      therapy and personality that contains an account of threat-related psychological
      processes largely consistent with contemporary trauma theory. Rogers' theory
      provides the conceptual underpinnings to the client-centred and experiential ways
      of working with traumatized people. Furthermore, Rogers' theory provides an
      understanding of post-traumatic growth processes, and encourages therapists to
      adopt a more positive psychological perspective to their understanding of how
      people adjust to traumatic events.

PMID- 15025905
TI  - The big idea: clients' perspectives of change processes in cognitive therapy.
AB  - This study reports on analyses carried out by the authors on five 'end of
      therapy' evaluations conducted with clients who had received a brief course of
      cognitive therapy for depression. The clients' evaluation was based on Elliott's
      (1996) Change Interview Schedule. The transcripts were then analysed using
      grounded theory methods, and arranged into 10 categories and three category
      clusters. The category clusters included 'the listening therapist', 'the big
      idea' and 'feeling more comfortable with self'. Clients' reported cognitive and
      emotional processes fit with Stiles et al.'s (1990) assimilation model.

PMID- 15025906
TI  - Validity of a measure of readiness to recover in Spanish adolescent patients with
      anorexia nervosa.
AB  - The objective of the present study was to evaluate readiness to recover in
      adolescent patients with anorexia nervosa with a Spanish version of the Anorexia
      Nervosa Stages of Change Questionnaire (ANSOCQ). Three measures-the ANSOCQ, the
      Eating Disorders Inventory-2 (EDI-2) and the Beck Depression Inventory (BDI)-were
      administered to a group of 70 anorexia nervosa patients (mean age = 15.6 yrs) who
      were receiving treatment at a specialized eating disorder unit and had reached
      different stages of the treatment programme. The ANSOCQ was administered again
      after one week in 42 patients to evaluate test-retest reliability. The ANSOCQ
      demonstrated good internal consistency (Cronbach's alpha =.94) and one week test
      retest reliability (r =.90). Negative, significant correlations were found
      between the ANSOCQ and several scales on the EDI-2 (r between -.50 and -.72) and
      the BDI (r = -.68). The Spanish version of the ANSOCQ seems a reliable instrument
      to evaluate readiness to recover in adolescents with anorexia nervosa.

PMID- 15025908
TI  - Effect of the destructive disagreement belief on relationship satisfaction with a
      romantic partner or closest friend.
AB  - This study tested the rational-emotive-behaviour theory hypothesis that, when
      imagining having a serious disagreement with one's romantic partner or closest
      friend, imagining believing the rational belief that disagreement is not
      destructive will lead to less dissatisfaction with either relationship than
      imagining endorsing the irrational belief that disagreement is destructive. The
      influence of demand characteristics on such an effect was assessed with two
      counter-demand control conditions. Undergraduates (106 women and 44 men) were
      assigned randomly to one of five conditions in a pretest/posttest design. The
      belief appeared to be effectively manipulated. Post-test relationship
      satisfaction was significantly higher in the rational condition than in the
      control or irrational condition. These results were not affected by the counter
      demand instructions and suggest that this rational belief may reduce relationship
      dissatisfaction during disagreements.

PMID- 15025910
TI  - The translation start codon region is sensitive to antisense PNA inhibition in
      Escherichia coli.
AB  - Antisense peptide nucleic acids (PNA) can inhibit bacterial gene expression with
      gene and sequence specificity. Using attached carrier peptides that aid cell
      permeation, the antisense effects when targeting essential genes are sufficient
      to prevent growth and even kill bacteria. However, many design uncertainties
      remain, including the difficult question of target sequence selection. In this
      study, we synthesized 90 antisense peptide-PNAs to target sequences in a head to
      tail manner across the entire length of the mRNA encoding beta-lactamase. The
      results from this scan pointed to the start codon region as most sensitive to
      inhibition. To confirm and refine the result, a higher-resolution scan was
      conducted over the start codon region of the beta-lactamase gene and the
      essential Escherichia coli acpP gene. For both genes, the start codon region,
      including the Shine-Dalgarno motif, was sensitive, whereas antisense agents
      targeted outside of this region were largely ineffective. These results are in
      accord with natural antisense mechanisms, which typically hinder the start codon
      region, and the sensitivity of this region should hold true for most bacterial
      genes as well as for other RNase H-independent antisense agents that rely on a
      steric blocking mechanism. Therefore, although other design parameters are also
      important, the start codon region in E. coli mRNA is the most reliable target
      site for antisense PNAs.

PMID- 15025911
TI  - A structure-activity study of the inhibition of HIV-1 Tat-dependent trans
      activation by mixmer 2'-O-methyl oligoribonucleotides containing locked nucleic
      acid (LNA), alpha-L-LNA, or 2'-thio-LNA residues.
AB  - The HIV-1 trans-activation responsive element (TAR) RNA stem-loop interacts with
      the HIV trans-activator protein Tat and other cellular factors to stimulate
      transcriptional elongation from the viral long terminal repeat (LTR). Inhibitors
      of these interactions block full-length transcription and, hence, would
      potentially inhibit HIV replication. We have studied structure-activity
      relationships in inhibition of trans-activation by steric block 2'-O-methyl (OMe)
      oligonucleotides chimeras (mixmers) containing locked nucleic acid (LNA) units.
      Inhibition was measured both in Tat-dependent in vitro transcription from an HIV
      1 DNA template directed by HeLa cell nuclear extract and in a robust HeLa cell
      reporter assay that involves use of stably integrated plasmids to express firefly
      luciferase Tat dependently and Renilla luciferase Tat-independently. OMe
      oligonucleotides with optimally 40%-50% LNA units and a minimum of 12 residues in
      length were active in the cellular assay when delivered with cationic gemini
      surfactant GS11 at 50% inhibitory concentrations of 230 +/- 40 nM, whereas
      activity in the in vitro transcription assay was observed down to 9 residues. No
      cellular activity was observed for OMe oligonucleotides of 12 or 16 residues,
      which was shown to be due to poor cellular uptake. Both 12-mer mixmers containing
      alpha -L-LNA or 2'-thio-LNA (S-LNA) were also active in in vitro transcription
      and the former in cellular reporter inhibition assays, demonstrating that the
      property of promotion of cellular uptake by LNA is not due to specific sugar
      conformational effects. Covalent conjugates of OMe/LNA chimeras with Kaposi
      fibroblast growth factor (K-FGF) or Transportan peptides failed to enter HeLa
      cells without a delivery agent but were fully active when delivered by cationic
      gemini surfactant, showing that in principle, peptide conjugation does not
      interfere with cellular activity. Thus, OMe/LNA mixmers are powerful reagents for
      use as steric block inhibitors of gene expression regulated by protein-RNA
      interactions within HeLa cell nuclei.

PMID- 15025912
TI  - Selection of DNA aptamers that bind the RNA-dependent RNA polymerase of hepatitis
      C virus and inhibit viral RNA synthesis in vitro.
AB  - The RNA-dependent RNA polymerase (NS5B) of the hepatitis C virus (HCV) plays a
      key role in the life cycle of the virus. In order to find inhibitors of the HCV
      polymerase, we screened a library of 81 nucleotide (nt)-long synthetic DNA
      containing 35 random nucleotides by the Systematic Evolution of Ligands by
      Exponential enrichment (SELEX) approach. Thirty ligands selected for their
      binding affinity to the NS5B were classified into four groups on the basis of
      their sequence homologies. Among the selected molecules, two were able to inhibit
      in vitro the polymerase activity of the HCV NS5B. These aptamers appeared to be
      specific for HCV polymerase, as no inhibition of poliovirus 3D polymerase
      activity was observed. The binding and inhibitory potential of one aptamer (27v)
      was associated with the 35 nt-long variable region. This oligonucleotide
      displayed an apparent dissociation constant (K(d)) in the nanomolar range. Our
      results showed that it was able to compete with RNA templates corresponding to
      the 3'-ends of the (+) and the (-) HCV RNA for binding to the polymerase. The
      fact that a DNA aptamer could interfere with the binding of natural templates of
      the enzyme could help in performing structure-function analysis of the NS5B and
      might constitute a basis for further structure-based drug design of this crucial
      enzyme of HCV replication.

PMID- 15025913
TI  - Short pyrimidine stretches containing mixed base PNAs are versatile tools to
      induce translation elongation arrest and truncated protein synthesis.
AB  - Recently, we showed that antisense peptide nucleic acids (PNA) containing a short
      pyrimidine stretch (C(4)TC(3)) invade Ha-ras mRNA hairpin structures to form
      highly stable duplex and triplex complexes that contribute to the arrest of
      translation elongation. The antisense PNA targeted to codon 74 of Ha-ras was
      designed to bind in antiparallel configuration (the N-terminal of the PNA faces
      the 3'-end of target mRNA), as PNA/RNA duplexes are most stable in this
      configuration. In order to show that different sequences in the coding region
      could be targeted successfully with antisense PNAs, we extended our study to
      three other purine-rich targets. We show that the tridecamer PNA (targeted to
      codon 149) containing a CTC(3)T pyrimidine stretch forms with the complementary
      oligoribonucleotide (ORN) a stable (PNA)(2)/ORN triplex at neutral pH (T(m) = 50
      degrees C) and arrests Ha-ras mRNA translation elongation. Interestingly, the
      thermal stability of triplexes formed with PNAs designed to bind to the
      complementary ORN in a parallel orientation (the N-terminal of the PNA faces the
      5'-end of target) was higher than that formed with antiparallel oriented PNAs
      (T(m) = 58 degrees C). Because parallel and antiparallel PNAs form stable
      triplexes with target sequence, they act as translation elongation blockers.
      These duplex-forming and partly triplex-forming PNAs targeted to Ha-ras mRNA also
      arrested translation elongation at specific polypurine sites contained in the
      mRNA coding for HIV-integrase protein. Furthermore, the tridecamer PNA containing
      the C(3)TC(4) motif was more active than a bis-PNA in which the Hoogsteen
      recognizing strand was linked to the Watson-Crick recognizing strand by a
      flexible linker. Pyrimidine-rich, short PNAs that form very stable duplexes with
      target Ha-ras mRNA inhibit translation by a mechanism that does not involve
      ribosome elongation arrest, whereas PNAs forming duplex and triplex structures
      arrest ribosome elongation. The remarkable efficacy of the tridecamer PNAs in
      arresting translation elongation of HIV-1 integrase mRNA is explained by their
      ability to form stable triplexes at neutral pH with short purine sequences.

PMID- 15025914
TI  - Base pairing properties of D- and L-cyclohexene nucleic acids (CeNA).
AB  - Cyclohexene nucleic acids (CeNA) with a D-like configuration form very stable
      self-complementary duplexes and stable duplexes with RNA. An increased duplex
      stability with Delta T(m)/mod of +1.2 degrees C is observed. The duplex with DNA
      is less stable. Excellent mismatch discrimination has been observed as well for
      the duplex with DNA as for the duplex with RNA. The results obtained with mixed
      CeNA sequences warrant antisense studies with CeNA. The CeNAs of opposite
      chirality constitute a self-pairing system on their own, resembling L-RNA
      sequences.

PMID- 15025915
TI  - P-chirality-dependent immune activation by phosphorothioate CpG
      oligodeoxynucleotides.
AB  - Many of the biologic activities of phosphorothioate oligodeoxynucleotides (PS
      oligos) are affected by the sense of chirality of the phosphorus atoms of the
      internucleotide linkages. Some of the activities are increased by the Rp
      stereoisomer, and others are increased by the Sp stereoisomer. In previous
      studies, we showed that PS-oligos containing unmethylated CpG dinucleotides in
      particular sequence contexts can stimulate B cells and other immune cells. These
      CpG PS-oligos trigger mitogenactivated protein kinase (MAPK) signaling pathways,
      causing the induction of B cell proliferation and cytokine and immunoglobulin
      secretion. We investigated whether the immune stimulation by CpG PS-oligos
      depends on the sense of their P-chirality. CpG PS-oligos synthesized with
      internucleotide phosphorothioates of Rp configuration at P-atom showed much
      stronger MAPK activation and induction of I kappa B degradation after 40 minutes
      of stimulation compared with PS-oligos synthesized with Sp linkages. In order to
      determine if the enhanced stimulatory effects of the Rp stereoisomer may result
      from differential cellular uptake, we examined the rates at which fluorescently
      labeled Rp or Sp CpG PS-oligos were taken up by B cells, but these were found to
      be identical to each other and to stereorandom PS-oligos. The stronger
      stimulatory effect of the R stereoisomer did not last for 48 hours, and (3)H
      thymidine incorporation assays at this point showed that only the S stereoisomer
      was active--to approximately the same level as induced by PS-oligos with
      stereorandom phosphorothioate linkages. This loss of activity of the R
      stereoisomer most likely resulted from rapid degradation of the oligonucleotides
      rather than from reduced interaction with the CpG receptor because PS-oligos in
      which only the CpG dinucleotide was stereodefined were most stimulatory when the
      CpG was Rp but not when the CpG was Sp. These studies demonstrate that the sense
      of Pchirality of PS-oligos plays a major role in determining the biologic
      activities of CpG motifs. Rp-chirality at the CpG is preferred for best
      stimulation at early time points, but Sp-chirality of the PS-oligo appears to
      improve stability and may provide more durable effects in prolonged tissue
      culture systems.

PMID- 15025916
TI  - MD studies of the DIS/DIS kissing complex solution and x-ray structures.
AB  - As in all retroviruses, human immunodeficiency virus (HIV) genomic RNA is
      packaged into virions as a dimer. The two copies of the genome are noncovalently
      linked by their 5'-ends in the dimerization initiating site (DIS), which folds as
      a hairpin containing an apical autocomplementary sequence. In vitro, DIS is able
      to dimerize in two conformations: a kissing complex and an extended dimer. Both
      conformations have been resolved by NMR and x-ray diffraction. Here, we report
      molecular dynamics (MD) studies of the two available structures for the DIS/DIS
      kissing complex in aqueous solution and in the presence of sodium counterions.
      The two structures behave in two different manners. On one hand, the NMR
      structure displays a very stable behavior, and the simulated structure remains
      very close to the starting structure. On the other hand, the structure issued
      from crystallography displays a more dynamic behavior, in which residues A8 and
      A9 are seen in a new and surprising bulge-in conformation. The transition from
      the bulge-out to the bulge-in conformation is analyzed, and a new and simple
      dimerization process is proposed.

PMID- 15025917
TI  - Analysis of thermal melting curves.
AB  - T(m) is defined as Temperature of melting or, more accurately, as temperature of
      midtransition. This term is often used for nucleic acids (DNA and RNA,
      oligonucleotides and polynucleotides). A thermal denaturation experiment
      determines the stability of the secondary structure of a DNA or RNA and aids in
      the choice of the sequences for antisense oligomers or PCR primers. Beyond a
      simple numerical value (the T(m)), a thermal denaturation experiment, in which
      the folded fraction of a structure is plotted vs. temperature, yields important
      thermodynamic information. We present the classic problems encountered during
      these experiments and try to demonstrate that a number of useful pieces of
      information can be extracted from these experimental curves.

PMID- 15025918
TI  - Oligonucleotide-based strategies to inhibit human hepatitis C virus.
AB  - Hepatitis C virus (HCV) infection represents a worldwide problem, and current
      antiviral regimens are not satisfactory. The need to develop novel, specific,
      anti-HCV antiviral drugs is clear. Antisense oligonucleotides (AS-ON), ribozymes,
      and more recently, small interfering RNAs (siRNAs) have been widely used to
      control gene expression, and several clinical trials are in progress. The
      potential to use AS-ON as tools to control HCV infection, either by promoting an
      RNase H mediated cleavage of viral genomic RNA or by interfering with the
      assembly of a translation initiation complex on the internal ribosome entry site
      (IRES) is reviewed. Extensive knowledge of IRES structure and conservation among
      HCV genotypes have rendered the HCV IRES (and, in particular, its IIId loop)
      particularly attractive for antisense approaches. Encouraging data have been
      obtained with IRES-targeted RNase H-competent and incompetent ON analogs. We
      demonstrate here that very short steric blocking ONs can inhibit the formation of
      translation preinitiation complexes on the IRES and block IRES-mediated
      translation in a cell-free translation assay and in a transfected hepatoma cell
      line.

PMID- 15025921
TI  - Toward oxidative lipidomics of cell signaling.
AB  - Involvement and role of oxidatively modified lipids become increasingly evident
      in different signaling pathways, although specific mechanisms remain to be
      explored. The current forum focuses on several aspects of signaling by
      oxidatively modified lipid molecules during apoptosis and implications of
      different oxidized phospholipids in elimination of apoptotic cells and regulation
      of inflammatory response. Studies of signaling mechanisms by oxidatively modified
      lipids represent a rapidly expanding field of oxidative lipidomics, a new and
      exciting research focus at the interface of traditional lipid/membrane
      biochemistry and biophysics with free radical chemistry and cell biology.

PMID- 15025922
TI  - Thiol oxidation enforces phosphatidylserine externalization in apoptosis
      sensitive and -resistant cells through a deltapsim/cytochrome C release-dependent
      mechanism.
AB  - Previous studies have shown that unlike most apoptotic cells, Raji cells do not
      externalize phosphatidylserine (PS) upon apoptosis. Here we show that Raji cells
      are resistant to intrinsic apoptogenic agents, but sensitive to extrinsically
      triggered Fas-induced apoptosis. Treatment of intrinsic apoptosis-competent
      Jurkat cells with vitamin E implicated reactive oxygen species in intrinsic
      apoptosis because, like Raji cells, they became resistant to actinomycin D- but
      not Fas-triggered apoptosis. Oxidation of sulfhydryls in both cell types with N
      ethylmaleimide resulted in rapid disruption of the mitochondrial membrane
      potential, release of cytochrome c from the mitochondria to the cytoplasm, and
      externalization of PS by a mechanism that was not inhibited by the pan caspase
      inhibiter zVAD-fmk. These results suggest that although cell death and PS
      externalization are both cytochrome c-dependent, they are distinct and separable
      processes.

PMID- 15025923
TI  - The plasma membrane is the site of selective phosphatidylserine oxidation during
      apoptosis: role of cytochrome C.
AB  - Phosphatidylserine (PS) externalization, a functional end point of apoptosis that
      triggers phagocytic recognition of dying cells, may be modulated by oxidative
      stress in biological membranes. We previously observed selective oxidation of PS
      during apoptosis, but the intracellular location and molecular mechanisms
      responsible for PS oxidation remain to be described. Peroxidation in individual
      classes of cellular phospholipids was monitored in whole cells and various
      subcellular fractions obtained from HL-60 cells undergoing apoptosis in response
      to tert-butyl hydroperoxide (t-BuOOH) after metabolic acylation of phospholipids
      with the oxidation-sensitive fluorescent fatty acid, cis-parinaric acid.
      Nonrandom selective oxidation of PS was observed in whole cells, as well as in
      plasma membrane. PS in mitochondria appeared selectively resistant to oxidation
      during apoptosis. All phospholipids in nuclear membranes appeared resistant to
      oxidation after t-BuOOH treatment. Selective PS oxidation was accompanied by
      cytochrome c release and PS externalization. PS oxidation and externalization
      were followed by caspase activation and other end points of apoptosis. HL-60
      cells "loaded" with exogenous cytochrome c by mild sonication showed selective
      oxidation of PS in both the absence and presence of t-BuOOH. Cytochrome
      c/hydrogen peroxide could effectively oxidize purified PS but not
      phosphatidylcholine in a cell-free model system. Selective plasma membrane-based
      PS oxidation and subsequent externalization during oxidant-induced apoptosis may
      be mediated through the redox activity of cytochrome c.

PMID- 15025924
TI  - Vitamin E inhibits anti-Fas-induced phosphatidylserine oxidation but does not
      affect its externalization during apoptosis in Jurkat T cells and their
      phagocytosis by J774A.1 macrophages.
AB  - Apoptosis and phagocytosis of apoptotic cells provide for effective and harmless
      clearance of unwanted or damaged cells in the body. Preferential oxidation of one
      particular class of phospholipids, phosphatidylserine (PS), is a typical trait of
      both oxidant- and nonoxidant-induced apoptosis. PS oxidation is likely to play an
      important role in phagocytosis either by affecting PS externalization acting as
      an "eat me" signal or by more effective recognition of apoptotic cells by
      macrophage receptors. This implies that antioxidants effective in inhibiting PS
      oxidation may affect PS externalization and/or effective removal of apoptotic
      cells. Therefore, it is essential to determine whether vitamin E, the major lipid
      soluble antioxidant of membranes, inhibits PS oxidation, and hence blocks
      apoptosis/phagocytosis. To test this, we studied the effects of vitamin E on PS
      oxidation and signaling using a model of anti-Fas-triggered apoptosis in Jurkat T
      cells. We found that incubation of cells with vitamin E (0.25-50 micro M)
      resulted in its integration into cells to reach physiologically relevant
      concentrations. Using labeling of cell phospholipids with oxidation-sensitive and
      fluorescent cis-parinaric acid (PnA), we found that anti-Fas exposure caused
      significant and selective oxidation of PnA-PS in Jurkat T cells (22 +/- 2.1% of
      its content in nonexposed cells). Vitamin E protected PnA-PS against oxidation in
      a concentration-dependent way such that at 25 micro M and 50 micro M, a complete
      inhibition of anti-Fas-induced PS oxidation was achieved. At all concentrations
      used, vitamin E had no effect on either biomarkers of anti-Fas-induced apoptosis
      (PS externalization, nuclear fragmentation) or phagocytosis of anti-Fas-induced
      apoptotic cells by J774A.1 macrophages. We conclude that vitamin E does not
      significantly interfere with extrinsic (death receptor-triggered) pathways of
      apoptosis and does not affect phagocytosis of anti-Fas-triggered apoptotic cells.

PMID- 15025925
TI  - Role of beta2-glycoprotein I, LDL-, and antioxidant levels in
      hypercholesterolemic elderly subjects.
AB  - The levels of electronegative low-density lipoprotein (LDL-), LDL cholesterol
      oxidability, and plasma levels of molecular antioxidants and of beta(2)
      glycoprotein I (beta(2) GPI) were studied in a group of 10 hypercholesterolemic
      (HC) and 10 normocholesterolemic (NC) elderly subjects. HC subjects showed
      significantly higher levels of cholesterol, LDL cholesterol, LDL-, and beta(2)GPI
      than NC, whereas high-density lipoprotein cholesterol and alpha-tocopherol levels
      were lower in HC as compared with NC subjects. Correlations among LDL- levels,
      LDL oxidation lag time, beta(2)GPI, and antioxidant plasma levels were studied in
      100 HC elderly subjects. Lag time for in vitro LDL oxidation positively
      correlated with ubiquinol-10 levels (p = 0.008), but not with other antioxidants
      studied or beta(2)GPI. LDL- and alpha-tocopherol levels showed an inverse and
      significant correlation (p = 0.018). beta(2)GPI and LDL cholesterol levels were
      correlated (p = 0.001), whereas no significance was found between LDL- and
      beta(2)GPI levels (p = 0.057). The physiological significance of alpha-tocopherol
      and ubiquinol-10 levels on LDL- levels, and the presence of high levels of
      beta(2)-GPI, are discussed in terms of protective mechanisms operating during the
      overall atherosclerosis process.

PMID- 15025926
TI  - Endothelial cell proliferation associated with abrupt reduction in shear stress
      is dependent on reactive oxygen species.
AB  - We have shown previously that flow-adapted endothelial cells respond to cessation
      of flow with cell membrane depolarization and increased production of reactive
      oxygen species, resulting in activation of transcription factors and increased
      DNA synthesis. This study utilized flow cytometry to evaluate cellular
      proliferation with ischemia and to determine the role of reactive oxygen species
      and apoptosis. PKH26-labeled rat pulmonary microvascular endothelial cells were
      seeded in an artificial capillary system and subjected to flow at 5 dynes/cm(2)
      for 96 h or for 72 h followed by 24 h of simulated "ischemia." Ischemia resulted
      in a 2.5-fold increase in the cellular proliferation index. Cell-cycle analysis
      showed G0/G1 arrest and decreased S plus G2/M during flow adaptation, whereas
      ischemia resulted in a three-fold increase of cells in S plus G2/M phases.
      Apoptotic cells as detected by TUNEL and annexin V binding assays were ~5% of
      total cells with no differences between static, flow-adapted, and "ischemic"
      groups. Reactive oxygen species production during a 1-h period following onset of
      ischemia was confirmed by oxidation of the fluorophore, dichlorofluorescein, and
      was inhibited by cromakalim, a K(ATP) channel agonist, or diphenyleneiodonium, a
      flavoprotein inhibitor. Cromakalim and diphenyleneiodonium also markedly
      inhibited cell proliferation in the flow-adapted ischemic cells, but had no
      effect on subconfluent cells cultured under static conditions. These results
      indicate reactive oxygen species-dependent endothelial cell proliferation in flow
      adapted microvascular endothelial cells as a response to ischemia and indicate
      that this response is not a consequence of apoptosis.

PMID- 15025927
TI  - Utilization of yeast to investigate the role of lipid oxidation in cell death.
AB  - The yeast Saccharomyces cerevisiae is a powerful tool to investigate several
      aspects of the molecular mechanisms underlying programmed cell death, namely, the
      events involving mitochondria. Yeast has allowed new information to be gained
      about crucial aspects of the interaction between proapoptotic proteins Bax and
      Bid and mitochondria, namely, their addressing and insertion into the
      mitochondrial outer membrane and their ability to induce the relocalization of
      cytochrome c. Going one step further, the prooxidant effect of Bax can also be
      studied in yeast. Bax expression induces both the accumulation of reactive oxygen
      species and lipid oxidation. Lipid oxidation is involved in Bax-induced cell
      death and may be required for optimal insertion of Bax in mitochondria. The easy
      modulation of lipid composition in yeast is a powerful tool to investigate this
      process further, and studies can be extended to other regulators of apoptosis,
      such as proapoptotic Bid or antiapoptotic Bcl-x(L). Also, yeast is a model for
      the study of other types of cell death, such as autophagy-related forms of death,
      for which a role of lipid oxidation has also been evidenced.

PMID- 15025928
TI  - Plasma membrane alterations during apoptosis: role in corpse clearance.
AB  - Apoptosis is a program of cellular self-destruction culminating in the clearance
      of cell corpses by neighboring macrophages. Studies in recent years have served
      to characterize a number of structural and molecular plasma membrane alterations
      that act in concert to mediate efficient engulfment of cell corpses. Hence, "eat
      me" signals, including the anionic phospholipid phosphatidylserine (PS) and its
      oxidized counterpart, PS-OX, as well as the PS-binding protein, annexin I, are
      exposed on the surface of effete cells and function to mediate engulfment by
      neighboring phagocytic cells. Plasma membrane blebbing (zeiosis), a common
      feature of the apoptotic program, provides a structural context for the
      exposition of recognition signals insofar as PS molecules aggregate on the
      surface of these membrane protrusions. Apoptotic cells also secrete chemotactic
      factors ("seek me" signals), such as the phospholipid lysophosphatidylcholine,
      that recruit phagocytes to the site of the apoptotic lesion. Taken together,
      these events serve to mediate the disposal of effete cells prior to their
      necrotic disintegration, thus preventing the inflammation and tissue scarring
      that would otherwise ensue.

PMID- 15025929
TI  - Essential cellular regulatory elements of oxidative stress in early and late
      phases of apoptosis in the central nervous system.
AB  - The generation of reactive oxygen species and subsequent oxidative stress in the
      central nervous system is now considered to be one of the primary etiologies of a
      host of neurodegenerative disorders, such as Alzheimer disease, Parkinson
      disease, and cerebral ischemia. On a cellular level, oxidative stress leads to an
      apoptotic early phase that involves cellular membrane phosphatidylserine (PS)
      exposure and a late phase that pertains to the degradation of genomic DNA. The
      translocation of membrane PS from the inner cellular membrane to the surface is a
      critical component for both microglial activation and cellular disposal of
      injured cells. During oxidative stress, this early phase of apoptosis is
      intimately controlled by neuronal PS exposure and microglial PS receptor
      expression. The late phase of apoptosis that involves a loss of genomic DNA
      integrity can result as a function of an ill-fated attempt to enter the cell
      cycle in postmitotic neurons. By using a cascade of pathways that involve
      cysteine proteases to modulate programmed cell death, protein kinase B (Akt)
      surfaces as a key regulatory element of both extrinsic pathways of inflammation
      and intrinsic pathways of cellular integrity. Further understanding of the
      cellular mechanisms modulating neuronal cellular integrity and phagocytic cell
      disposal during oxidative stress may form the basis for the future development of
      cytoprotective strategies in the nervous system.

PMID- 15025931
TI  - Role of lipid hydroperoxides in photo-oxidative stress signaling.
AB  - Photosensitized peroxidation of membrane lipids has been implicated in skin
      pathologies such as phototoxicity, premature aging, and carcinogenesis, and may
      play a role in the antitumor effects of photodynamic therapy. Lipid
      hydroperoxides (LOOHs) are prominent early products of photoperoxidation that
      typically arise via singlet oxygen ((1)O(2)) attack. Nascent LOOHs can have
      several possible fates, including (i) iron-catalyzed one-electron reduction to
      chain-initiating free radicals, which exacerbate peroxidative damage, (ii)
      selenoperoxidase-catalyzed two-electron reduction to relatively innocuous
      alcohols, and (iii) translocation to other membranes, where reactions noted in
      (i) or (ii) might take place. In addition, LOOHs, like other stress-associated
      lipid metabolites/peroxidation products (e.g., arachidonate, diacylglycerol,
      ceramide, 4-hydroxynonenal), may act as signaling molecules. Intermembrane
      transfer of LOOHs may greatly expand their signaling range. When photogenerated
      rapidly and site-specifically, e.g., in mitochondria, LOOHs may act as early
      mediators of apoptotic cell death. This review will focus on these various
      aspects, with special attention to the role of LOOHs in photooxidative signaling.

PMID- 15025930
TI  - Antioxidant role of glutathione S-transferases: protection against oxidant
      toxicity and regulation of stress-mediated apoptosis.
AB  - It has been known that glutathione S-transferases (GSTs) can reduce lipid
      hydroperoxides through their Se-independent glutathione peroxidase activity and
      that these enzymes can also detoxify lipid peroxidation end products such as 4
      hydroxynonenal (4-HNE). In this article, recent studies suggesting that the Alpha
      class GSTs provide a formidable defense against oxidative stress are critically
      evaluated and the role of these enzymes in the regulation of oxidative stress
      mediated signaling is reviewed. Available evidence from earlier studies together
      with results of recent studies in our laboratories strongly suggests that lipid
      peroxidation products, particularly hydroperoxides and 4-HNE, are involved in the
      mechanisms of stress-mediated signaling and that it can be modulated by the Alpha
      class GSTs through the regulation of the intracellular concentrations of 4-HNE.

PMID- 15025933
TI  - Redox control of cardiac preconditioning.

PMID- 15025932
TI  - Apoptotic cells as sources for biologically active oxidized phospholipids.
AB  - Acute inflammation is characterized by an accumulation of polymorphonuclear cells
      (PMNs), generation of reactive oxygen species, subsequent apoptosis of PMNs, and
      finally phagocytosis of apoptotic cells by macrophages. Recently, it has been
      demonstrated that during apoptosis oxidation of membrane phospholipids,
      especially phosphatidylserine, occurs. Moreover, we have shown that membrane
      vesicles released from apoptotic cells contain biologically active oxidized
      phospholipids. The involvement of oxidized phospholipids in the development of
      atherosclerosis, which is described as a chronic inflammatory disease, is
      increasingly recognized. These oxidized phospholipids were shown to induce
      several proinflammatory genes, such as monocyte chemoattractant protein 1 or
      interleukin-8, and it is hypothesized that lipid oxidation products also play a
      role in other chronic inflammatory disorders. On the other hand, oxidized
      phospholipids were shown to exert antiendotoxin effects by inhibiting
      lipopolysaccharide-induced signaling, representing a possible feedback loop
      during gram-negative infection. Additionally, it has been described that oxidized
      phospholipids are capable of inducing genes such as heme oxygenase-1 that are
      important for the resolution of acute inflammation. Moreover, oxidized
      phospholipids serve as recognition signals on apoptotic cells facilitating
      phagocytosis. In this review, we discuss the hypothesis that oxidized
      phospholipids generated in apoptotic cells (a) propagate chronic inflammation and
      (b) contribute to the resolution of acute inflammation.

PMID- 15025934
TI  - Preconditioning in intact and previously diseased myocardium: laboratory or
      clinical dilemma?
AB  - We studied the effects of various cycles of preconditioning (PC) (one cycle, 1 x
      PC; two cycles, 2 x PC; three cycles, 3 x PC; and four cycles, 4 x PC) on cardiac
      function, infarct size, and the incidence of reperfusion-induced arrhythmias in
      isolated hearts obtained from rabbits with hypercholesterolemia. After 8 weeks of
      hypercholesterolemia, hearts were subjected to 30 min of ischemia followed by 120
      min of reperfusion. Various cycles of PC resulted in a "cycle-dependent"
      reduction in infarct size in the age-matched nonhypercholesterolemic group. In
      the 8-week hypercholesterolemic group, increasing cycles of PC resulted in a
      significant increase in infarct size from their nonpreconditioned
      ischemic/reperfused control value of 44 +/- 5% to 45 +/- 6%, 49 +/- 5%, 59 +/- 6%
      (p < 0.05), and 58 +/- 5% (p < 0.05), respectively. PC increased the
      vulnerability of the myocardium to reperfusion-induced arrhythmias in
      hypercholesterolemics indicating that PC may be an "intact heart" phenomenon. The
      effects of PC appear currently to be a dilemma in laboratories and clinics. The
      solution to the problem of PC in intact and diseased myocardium requires further
      data from two different sources: (a) previously "diseased" animals, and (b)
      diseased human myocardium from clinics. Once these data are available, then the
      effects under which PC will be beneficial rather than harmful could be
      established and the dilemma solved.

PMID- 15025935
TI  - Role of adenosine receptor activation in antioxidant enzyme regulation during
      ischemia-reperfusion in the isolated rat heart.
AB  - The aim of the present study was to investigate the protective role of
      pharmacological preconditioning on antioxidant enzymes using A(1) and A(3)
      adenosine receptor agonists in the recovery of the isolated myocardium after
      cardioplegic ischemia. Two different modes of preconditioning were studied:
      isolated rat hearts were perfused with A(1) receptor agonist 2-chloro-N(6)
      cyclopentyladenosine (CCPA) or A(3) 2-chloro-N(6)-(3-iodobenzyl) adenosine-5'-N
      methyluronamide (Cl-IB-MECA) (1 nM), followed by cardioplegic ischemia and
      reperfusion (30 min each) (perfusion mode), or CCPA or Cl-IB-MECA (100 micro
      g/kg) were injected intravenously 24 h before the experiment (injection mode).
      Hearts treated with CCPA improved in terms of mechanical function, infarct size,
      ATP levels, superoxide dismutase, and catalase (p < 0.005) in both modes of
      administration. Cl-IB-MECA was beneficial mainly in the injected group. Reduced
      damage to the mitochondria in the CCPA-treated hearts was observed using electron
      microscopy evaluation. In the Cl-IB-MECA-injected hearts, mitochondrial damage
      was moderate. CCPA in both modes of treatment and Cl-IB-MECA in the injected mode
      were beneficial in protecting the perfused isolated rat heart, subjected to
      normothermic cardioplegic ischemia. This protection was partially related to the
      higher myocardial activity of superoxide dismutase and catalase.

PMID- 15025936
TI  - Cellular control of nitric oxide synthase expression and activity in rat
      cardiomyocytes.
AB  - Potential ortho- and pathophysiological roles for nitric oxide synthases (NOS) in
      cardiac functions have been and are continuing to be described. However, cellular
      signaling mechanisms controlling nitric oxide (NO) production in the heart remain
      obscure. The aim of this study was to investigate signaling mechanisms involved
      in regulation of NOS expression and NO generation in cardiomyocytes. Using
      immunocytochemical methods in conjunction with western blotting, we have found
      that cultured neonatal rat cardiomyocytes express constitutively all three NOS
      isoforms targeted predominantly to the particulate component of cardiomyocytes -
      mitochondria and along contractile fibers, as well as along plasma membrane
      including T-tubules. Biochemical assay of NO generation has shown that exposure
      of cultured neonatal rat cardiac cells to isoproterenol (beta-adrenergic
      stimulation), iloprost [stable prostaglandin I(2) (PGI(2)) analogue], as well as
      inflammatory cytokines and dibutyryl adenosine-3',5'-monophosphate (db-cAMP),
      resulted in a marked up-regulation of NOS expression by cardiomyocytes. In db
      cAMP-stimulated cells, inhibition of protein kinase A (PKA) and protein kinase C
      (PKC) reduced immunolabeling of NOS and concomitantly lowered NO production.
      Taken together, these data point to an involvement of beta-adrenergic mechanisms,
      cytokine and PGI(2) receptors, adenylyl cyclase, PKA, and PKC in the control of
      NO generation and expression of NOS in rat cardiomyocytes.

PMID- 15025937
TI  - Distinct roles of Ca2+, calmodulin, and protein kinase C in H2O2-induced
      activation of ERK1/2, p38 MAPK, and protein kinase B signaling in vascular smooth
      muscle cells.
AB  - We have shown earlier that extracellular signal-regulated kinases 1 and 2
      (ERK1/2) and protein kinase B (PKB), two key mediators of growth-promoting and
      proliferative responses, are activated by hydrogen peroxide (H(2)O(2)) in A10
      vascular smooth muscle cells (VSMC). In the present studies, using a series of
      pharmacological inhibitors, we explored the upstream mechanisms responsible for
      their activation in response to H(2)O(2). H(2)O(2) treatment of VSMC stimulated
      ERK1/2, p38 mitogen-activated protein kinase (MAPK), and PKB phosphorylation in a
      dose- and time-dependent fashion. BAPTA-AM and EGTA, chelators of intracellular
      and extracellular Ca(2+), respectively, inhibited H(2)O(2)-stimulated ERK1/2, p38
      MAPK, and PKB phosphorylation. Fluphenazine, an antagonist of the Ca(2+)-binding
      protein calmodulin, also suppressed the enhanced phosphorylation of ERK1/2, p38
      MAPK, and PKB. In contrast, the protein kinase C (PKC) inhibitors Go 6983 and Ro
      31-8220 attenuated H(2)O(2)-induced ERK1/2 phosphorylation, but had no effect on
      p38 MAPK and PKB phosphorylation. Taken together, these data demonstrate that the
      activation of Ca(2+)/calmodulin-dependent pathways represents a key component
      mediating the stimulatory action of H(2)O(2) on ERK1/2, p38 MAPK, and PKB
      phosphorylation. On the other hand, PKC appears to be an upstream modulator of
      the increased ERK1/2 phosphorylation, but not of p38 MAPK and PKB in response to
      H(2)O(2) in VSMC.

PMID- 15025938
TI  - Peroxisome proliferator ameliorates endocardial endothelial and muscarinic
      dysfunction in spontaneously hypertensive rats.
AB  - Spontaneously hypertensive rats (SHR) develop hypertension (HT) at the age of 2-6
      weeks. Endocardial endothelial (EE) dysfunction, autonomic suppression, left
      ventricle hypertrophy (LVH), and fibrosis are hallmarks of HT. The mechanism of
      EE dysfunction, LVH, and fibrosis in SHR is largely unknown. It is known,
      however, that the levels of peroxisome proliferator-activated receptor gamma
      (PPARgamma) are negatively correlated with EE function, LVH, and HT. PPARgamma
      ameliorates EE dysfunction and LVH, in part, by increasing endothelial nitric
      oxide (eNO) and muscarinic activity. Male SHR and normotensive Wistar rats (NWR)
      at 1 week of age were administered 8 micro g/ml ciglitazone (CZ), a PPARgamma
      agonist, in drinking water. The rats were grouped as follows: NWR, NWR+CZ, SHR,
      SHR+CZ, at 2 and 6 weeks (n = 6 in each group). The levels of PPARgamma were low
      in the nuclear extracts of the left ventricle (LV) in SHR, but increased in CZ
      treated rats, measured by western analysis. The contractile response to
      norepinephrine in cardiac rings prepared from the above groups of rats, measured
      in tissue myobath and normalized by tissue weight, demonstrated no difference in
      the maximum response to norepinephrine in any group. However, the EC(50) was
      significantly lower in SHR at 2 weeks (SHR2wk) than in any other groups, and CZ
      normalized this decrease. The response to acetylcholine demonstrated no
      difference in EC(50); however, the maximum response was attenuated in SHR2wk, and
      substantially increased in SHR6wk as compared with age-matched NWR, suggesting
      that early in HT eNO dysfunction in SHR2wk leads to depression of autonomic
      muscarinic cholinergic receptor in SHR6wk. The PPARgamma agonist ameliorated both
      the early eNO dysfunction and late autonomic suppression in HT. The response to
      nitroprusside demonstrated no change in EC(50); however, the maximum response was
      attenuated only in SHR6wk. There were significant fibrosis, LVH, and increased LV
      pressure in SHR6wk compared with any other group, and CZ regressed LVH and LV
      pressure. Results suggest that early in HT, except for eNO dysfunction, other
      contractile responses are preserved; however, at 6 weeks there is significant
      nonendothelial cell dysfunction, and treatment with CZ reverses this
      nonendothelial dysfunction as well.

PMID- 15025939
TI  - Sublethal simulated ischemia promotes delayed resistance against ischemia via ATP
      sensitive (K+) channels in murine myocytes: role of PKC and iNOS.
AB  - In this study, we examined whether sublethal simulated ischemia (SSI) induces
      delayed cellular protection in mouse cardiac myocytes, and whether the delayed
      cellular protection depends on the activation of protein kinase C-epsilon (PKC
      epsilon), inducible nitric oxide synthase (iNOS), and ATP-sensitive K(+) (K(ATP))
      channels against subsequent sustained simulated ischemia (SI). The following
      groups of mouse cardiac myocytes were studied: (a) SI: incubation with SI buffer
      for 1 h; (b) SSI: incubation with SSI buffer for 30 min; (c) SSI + PKC inhibitor,
      chelerythrine chloride (CCl): SSI and 1 micro M CCl; (d) SSI + iNOS inhibitor, S
      methylthiourea (SMT): SSI and 100 nM SMT; (e) SSI + K(ATP) channel blocker,
      glibenclamide (Glb): SSI and 50 micro M Glb; (f) SSI + mitochondrial K(ATP)
      channel blocker, 5-hydroxydecanoate (5-HD): SSI and 50 micro M 5-HD. The release
      of lactate dehydrogenase into the medium and the amount remaining in the cells
      was measured, and A(1) adenosine receptor, PKC-epsilon, and iNOS were detected
      through western blot analysis. The delayed cellular protection acquired due to
      SSI showed a decreased release of lactate dehydrogenase (%) from 46.51 +/- 1.60
      to 37.00 +/- 1.34 (p < 0.001) and was blocked by CCl (47.08 +/- 0.95), SMT (48.08
      +/- 1.18), Glb (45.88 +/- 1.31), and 5-HD (47.20 +/- 1.56). Simultaneously, SSI
      induced up-regulation of A(1) adenosine receptor, PKC-epsilon, iNOS, and opening
      of both membrane and mitochondrial K(ATP) channels also was observed compared
      with controls.

PMID- 15025940
TI  - Redox modulation of Gi protein expression and adenylyl cyclase signaling: role of
      nitric oxide.
AB  - Nitric oxide (NO) has been shown to regulate a variety of physiological
      functions, including vascular tone. The inhibition of NO synthase by N(omega)
      nitro-L-arginine methyl ester (L-NAME) has been reported to increase arterial
      blood pressure. The present studies were undertaken to investigate if the
      increased blood pressure by L-NAME is associated with enhanced expression of Gi
      proteins, implicated in the pathogenesis of hypertension. L-NAME was administered
      orally into Sprague-Dawley rats for a period of 4 weeks. Control rats were given
      plain tap water only. The systolic blood pressure was enhanced in L-NAME-treated
      rats as compared with control rats; however, the heart-to-body weight ratio was
      not different in the two groups. The levels of Gialpha-2 and Gialpha-3 proteins
      and their mRNA as determined by western and northern blotting, respectively, were
      significantly augmented in hearts from L-NAME-treated rats, whereas the levels of
      Gsalpha and Gbeta were unaltered. In addition, the effect of low concentrations
      of GTPgammaS on forskolin-stimulated adenylyl cyclase activity (receptor
      independent functions of Gialpha) was significantly enhanced, whereas the
      receptor-dependent inhibitions of adenylyl cyclase were completely attenuated in
      L-NAME-treated rats. Whereas cholera toxin-mediated stimulation of adenylyl
      cyclase was unaltered in both group of rats, the stimulatory effects of some
      agonists on adenylyl cyclase activity were diminished in L-NAME-treated rats.
      These results suggest the implication of NO in the modulation of Gi protein
      expression and associated adenylyl cyclase signaling.

PMID- 15025941
TI  - Role of reactive oxygen species in ischemic preconditioning of subcellular
      organelles in the heart.
AB  - Ischemic preconditioning (IPC) is an endogenous adaptive mechanism and is
      manifested by early and delayed phases of cardioprotection. Brief episodes of
      ischemia-reperfusion during IPC cause some subtle functional and structural
      alterations in sarcolemma, mitochondria, sarcoplasmic reticulum, myofibrils,
      glycocalyx, as well as nucleus, which render these subcellular organelles
      resistant to subsequent sustained ischemia-reperfusion insult. These changes
      occur in functional groups of various receptors, cation transporters, cation
      channels, and contractile and other proteins, and may explain the initial effects
      of IPC. On the other hand, induction of various transcriptional factors occurs to
      alter gene expression and structural changes in subcellular organelles and may be
      responsible for the delayed effects of IPC. Reactive oxygen species (ROS), which
      are formed during the IPC period, may cause these changes directly and indirectly
      and act as a trigger of IPC-induced cardioprotection. As ROS may be one of the
      several triggers proposed for IPC, this discussion is focused on the current
      knowledge of both ROS-dependent and ROS-independent mechanisms of IPC.
      Furthermore, some events, which are related to functional preservation of
      subcellular organelles, are described for a better understanding of the IPC
      phenomenon.

PMID- 15025942
TI  - Thioredoxin regulation of ischemic preconditioning.
AB  - Thioredoxins are a class of small redox-regulating proteins that appear to play a
      crucial role in many oxidative stress-inducible degenerative diseases. A recent
      study demonstrated a reduction of thioredoxin-1 (Trx1) protein in the ischemic
      reperfused myocardium. When the same heart was adapted to ischemic stress by
      preconditioning with repeated cyclic episodes of small duration of ischemia and
      reperfusion, there was an increased induction of Trx1 expression. Inhibition of
      Trx1 expression resulted in reduced postischemic ventricular recovery and
      increased myocardial infarct size in the preconditioned heart. Corroborating
      these findings, transgenic mouse hearts overexpressing Trx1 were resistant to
      ischemic reperfusion injury as compared with the hearts from wild-type mice.
      Thus, it appears that thioredoxin plays a crucial role in cardioprotection
      induced by preconditioning.

PMID- 15025943
TI  - Ischemic preconditioning mediated angiogenic response in the heart.
AB  - Angiogenesis represents a major focus for novel therapeutic approaches to the
      prevention and treatment of multiple diseases, most notably ischemic
      cardiovascular disease and cancer. Therapeutic angiogenesis achieved either
      through the use of discreet angiogenic proteins or by gene therapy is fast
      emerging as a highly attractive treatment modality for ischemic heart disease.
      The purpose of this review is to address this important clinical issue through
      the identification of potential signaling mechanisms by which a short episode of
      sublethal ischemia known as ischemic preconditioning causes angiogenesis and
      subsequently improves myocardial salvage following coronary artery occlusion.

PMID- 15025944
TI  - Oxidative stress and adaptation of the infant heart to hypoxia and ischemia.
AB  - The potential contribution of oxidative stress to cardioprotection in infants
      induced by adaptation to chronic hypoxia and by ischemic preconditioning is
      poorly understood. Under conditions of oxidative stress, reactive oxygen species
      and reactive nitrogen species may contribute to phenotypic changes in hearts
      adapted to chronic hypoxia and to the pathogenesis of myocardial injury during
      both ischemia/reperfusion and hypoxia/reoxygenation. Hearts from infant rabbits
      normoxic from birth can be preconditioned by brief periods of ischemia. In
      contrast, hearts from infant rabbits adapted to hypoxia from birth appear
      resistant to ischemic preconditioning. Chronically hypoxic infant rabbit hearts
      are already resistant to ischemia compared with age-matched normoxic controls,
      and thus additional cardioprotection by ischemic preconditioning may not be
      possible. Endothelial nitric oxide synthase (NOS3) protein and its product nitric
      oxide are increased, but not NOS3 message, in chronically hypoxic infant hearts
      to protect against ischemia. Chronic hypoxia from birth also increases
      cardioprotection of infant hearts by increasing association of heat shock protein
      90 with NOS3. Normoxic infant hearts also generate more superoxide by an N(omega)
      nitro-L-arginine methyl ester-inhibitable mechanism than chronically hypoxic
      hearts. Thus, NOS3 appears to be critically important in adaptation of infant
      hearts to chronic hypoxia and in resistance to subsequent ischemia by regulating
      the production of reactive oxygen and nitrogen species.

PMID- 15025945
TI  - Ethanol, wine, and experimental cardioprotection in ischemia/reperfusion: role of
      the prooxidant/antioxidant balance.
AB  - It is now well established that oxidative stress resulting from reactive oxygen
      species (ROS) that are generated in cardiac myocytes subjected to
      ischemia/reperfusion plays a causative role in the development of heart failure
      and may contribute to promote cell death. During the last decade, several groups
      have reported that, in animal models of myocardial ischemia/reperfusion, certain
      nutrients, including ethanol and nonethanolic components of wine, may have a
      specific protective effect on the myocardium, independent of the classical risk
      factors implicated in vascular atherosclerosis and thrombosis. Mechanisms through
      which the consumption of alcoholic beverages protects against ischemia-induced
      cardiac injury are still unknown. One major open question is whether ethanol and
      nonethanolic components of wine are cardioprotective, at least in part, by
      interfering with the myocardial prooxidant/antioxidant balance. Important
      concepts, such as cardiac preconditioning, are now entering the field of
      nutrition, and recent experimental evidence suggests that ethanol and/or
      nonethanolic components of wine might exert preconditioning effects in animal
      models of myocardial ischemia/reperfusion. There is no doubt that such an
      observation, if confirmed in human subjects, might open new perspectives in the
      prevention and treatment of ischemic coronary heart disease.

PMID- 15025947
TI  - Reactive oxygen species as mediators of signal transduction in ischemic
      preconditioning.
AB  - Ischemic preconditioning (IPC) is a most powerful endogenous mechanism for
      myocardial protection against ischemia/reperfusion injury. It is now apparent
      that reactive oxygen species (ROS) generated in the mitochondrial respiratory
      chain act as a trigger of IPC. ROS mediate signal transduction in the early phase
      of IPC through the posttranslational modification of redox-sensitive proteins.
      ROS-mediated activation of Src tyrosine kinases serves a scaffold for interaction
      of proteins recruited by G protein-coupled receptors and growth factor receptors
      that is necessary for amplification of cardioprotective signal transduction.
      Protein kinase C (PKC) plays a central role in this signaling cascade. A crucial
      target of PKC is the mitochondrial ATP-sensitive potassium channel, which acts as
      a trigger and a mediator of IPC. Mitogen-activated protein (MAP) kinases
      (extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun NH(2)-terminal
      kinase) are thought to exist downstream of the Src-PKC signaling module, although
      the role of MAP kinases in IPC remains undetermined. The late phase of IPC is
      mediated by cardioprotective gene expression. This mechanism involves redox
      sensitive activation of transcription factors through PKC and tyrosine kinase
      signal transduction pathways that are in common with the early phase of IPC. The
      effector proteins then act against myocardial necrosis and stunning presumably
      through alleviation of oxidative stress and Ca(2+) overload. Elucidation of IPC
      mediated complex signaling processes will help in the development of more
      effective pharmacological approaches for prevention of myocardial
      ischemia/reperfusion injury.

PMID- 15025946
TI  - Cardiac preconditioning by volatile anesthetic agents: a defining role for
      altered mitochondrial bioenergetics.
AB  - Volatile anesthetic agents, such as halothane, isoflurane, and sevoflurane, are
      the drugs most commonly used to maintain the state of general anesthesia. They
      have long been known to provide some protection against the effects of cardiac
      ischemia and reperfusion. Several mechanisms likely contribute to this
      cardioprotection, including coronary vasodilation, reduced contractility with
      corresponding decreased metabolic demand, and a direct effect to decrease
      myocardial Ca(2+) entry through L-type Ca(2+) channels. Recently, a memory phase
      to cardioprotection has been observed by these agents, which is inhibited by ATP
      sensitive potassium channel inhibition. These features suggest a pathway that
      shares components with those required for ischemic preconditioning, despite the
      remarkable differences between these two stimuli, and the term anesthetic
      preconditioning (APC) has been adopted. Scavengers of reactive oxygen species
      (ROS) abrogate APC, suggesting an effect of anesthetic agents to cause ROS
      formation. Such an effect has recently been directly demonstrated. The mechanism
      by which these drugs induce ROS formation is unclear. However, direct inhibition
      of mitochondrial electron transport system enzymes, and altered mitochondrial
      bioeneregtics in hearts preconditioned by volatile anesthetics, strongly
      implicate the mitochondria as the target for these effects. Furthermore,
      decreased mitochondrial ROS formation during ischemia and reperfusion in hearts
      preconditioned by volatile anesthetics might underlie the improved postischemic
      structure and function. APC presents a safe mode to apply preconditioning to
      human hearts. This review summarizes the major developments in a field that is
      exciting to clinicians and basic scientists alike.

PMID- 15025948
TI  - Effects of acute gamma-hexachlorocyclohexane intoxication in relation to the
      redox regulation of nuclear factor-kappaB, cytokine gene expression, and liver
      injury in the rat.
AB  - gamma-Hexachlorocyclohexane-induced hepatotoxicity is associated with oxidative
      stress. We tested the hypothesis that gamma-hexachlorocyclohexane triggers the
      redox activation of nuclear factor-kappaB (NF-kappaB), leading to proinflammatory
      cytokine expression. Liver NF-kappaB activation (electrophoretic mobility shift
      assay), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1alpha (IL
      1alpha) mRNA expression (reverse transcription-polymerase chain reaction), and
      their serum levels (enzyme-linked immunosorbent assay) were measured at different
      times after gamma-hexachlorocyclohexane treatment (50 mg/kg). The relationship
      between these and hepatic O(2) uptake, glutathione and protein carbonyl levels,
      and sinusoidal lactate dehydrogenase (LDH) efflux in liver perfusion studies was
      determined. gamma-Hexachlorocyclohexane increased liver NF-kappaB DNA binding at
      14-22 h after treatment, concomitantly with significant glutathione depletion and
      an increase in the rate of O(2) consumption, the content of protein carbonyls,
      and the sinusoidal LDH efflux. In these conditions, the expression of TNF-alpha
      and IL-1alpha is enhanced, with maximal increases in their respective mRNA
      content and serum levels of the cytokines being elicited at 18 h after gamma
      hexachlorocyclohexane treatment. All these changes are suppressed by the
      administration of alpha-tocopherol (100 mg/kg) or the Kupffer cell inactivator
      gadolinium chloride (10 mg/kg) prior to gamma-hexachlorocyclohexane. gamma
      Hexachlorocyclohexane-induced TNF-alpha levels in serum are suppressed by
      pretreatment with an antisense oligonucleotide (ASO TJU-2755; daily doses of 10
      mg/kg for 2 days) targeting the primary transcript for the cytokine, whereas
      those of IL-1alpha are not modified. It is concluded that gamma
      hexachlorocyclohexane-induced liver oxidative stress triggers the DNA binding
      activity of NF-kappaB, with the consequent increase in the expression of NF
      kappaB-dependent genes for TNF-alpha and for IL-1alpha, factors that may mediate
      the hepatotoxicity of the insecticide.

PMID- 15025949
TI  - Circadian expression of dihydropyrimidine dehydrogenase, thymidylate synthase, c
      myc and p53 mRNA in mouse liver tissue.
AB  - BACKGROUND & OBJECTIVE: Anti-cancer effect of 5-Fluorouracil (5-FU) is mediated
      mainly by inhibition of the thymidylate synthase (TS), while dihydropyrimidine
      dehydrogenase (DPD) is an initial and a rate-limiting catabolic enzyme of 5-FU.
      In this study, the mRNA expression profiles of TS, DPD, p53 and c-myc were
      investigated in mouse liver. METHODS: A total of 24 male B6D2F1 mice were
      involved in this study. All the mice were synchronized with an alternation of 12
      h of light (L) and 12 h of darkness (D) (LD12:12) for 4 weeks. Body temperature
      and rest-activity were monitored with an intra-peritoneal sensor. All the mice
      were sacrificed at 3, 7, 11, 15, 19, 23 HALO (hours after light onset)
      respectively and liver samples were obtained and immediately frozen in liquid
      nitrogen. Total RNA was extracted from the frozen liver samples and one-step real
      time quantitive RT-PCR was performed using LightCycler - RNA Amplification Kit
      SYBR Green I system. RESULTS: Both body temperature and rest-activity displayed
      similarly rhythmic patterns with peak times located in darkness, while the trough
      time was located in the light span. DPD showed a circadian expression in mRNA
      level with a peak at about 16 HALO (P=0.0012). TS showed a trend for a circadian
      rhythm, with a peak during light (P=0.079). Neither c-myc nor p53 displayed
      significant circadian rhythm. CONCLUSION: The 24-h patterns in DPD and TS
      expression were approximately 12 h out of phase, supporting a coordinated
      regulation of both transcriptional pathways relevant for 5-FU chronopharmacology.

PMID- 15025950
TI  - [Expression of fascin 1 gene in the process of the immortalized esophageal
      carcinoma carcinogenesis].
AB  - BACKGROUND & OBJECTIVE: Fascin 1 is the 55kDa F-actin- binding cytoskeleton
      protein. Fascin 1 gene was cloned from a human teratocarcinoma. Up to now, the
      carcinogenesis mechanism of esophageal squamous cell carcinoma is unclear. The
      study was designed to identify the differentially expressed proteins and mRNAs
      between the human immortalized esophageal epithelial cell line (SHEE) transfected
      by human papillomavirus type 18 E6E7 and the malignant transformation cell line
      (SHEEmt), which is derivated from SHEE, and to further understand the
      carcinogenesis mechanisms of esophageal squamous cell carcinoma. METHODS:
      Cellular proteins were separated by two-dimensional electrophoresis and
      differentially expressed proteins were identified by matrix-assisted laser
      desorption/ionization time of flying mass spectrometry (MALDI-TOF-MS). The mRNA
      of fascin 1 gene was assayed by reverse transcription polymerase chain reaction
      (RT-PCR) and its product was analyzed by sequencing assay. RESULTS: The results
      manifested 9 genes expressed differently in the progress of malignant
      transformation of SHEE to SHEEmt, fascin 1 protein increased about 3.64 times and
      its mRNA increased about 16.17 times. CONCLUSION: The upregulated expression of
      fascin 1 gene may be correlated with the malignant transformation of SHEE to
      SHEEmt.

PMID- 15025951
TI  - [Cloning and identification of fibrinogen gamma polypeptide (FGG) gene
      differentially expressed in human hepatocellular carcinoma].
AB  - BACKGROUND & OBJECTIVE: Abnormal expression of genes is related to development
      and progression of hepatocellular carcinoma (HCC); however, the detailed
      mechanism is unclear yet because the known genetic information is not sufficient
      at present. This study was to explore cloning and identification of fibrinogen
      gamma polypeptide (FGG) gene differentially expressed in human hepatocellular
      carcinoma. METHODS: The suppression subtractive hybridization was used to obtain
      subtracted cDNA products of HCC, then the products were cloned by T/A method. The
      differential expression of gene in HCC was identified by DNA sequencing analysis,
      Northern blot analysis, rapid amplification of cDNA end (RACE), and reverse
      transcription polymerase chain reaction (RT-PCR). RESULTS: Firstly, a cDNA
      fragment of 787 nucleotides was screened from the subtracted cDNA clones, and it
      was further discovered that the expression of the cDNA fragment was higher
      significantly in human hepatocellular carcinoma cell strains of SMMC-7721 and
      HepG2 than in normal hepatocytes by Northern blot analysis. The RACE was carried
      out and the gene of 1 597 bp containing polyA in 3'end was obtained, which has an
      entire open reading frame encoding 437 amino acids. Homology analysis showed that
      this was a gene encoding human FGG. RT-PCR analysis of FGG showed that the
      amplification of cancerous tissues, especially in metastasis of HCC, was raised
      as compared to that of adjacent non-cancerous tissues. CONCLUSION: Overexpression
      of FGG was discovered in SMMC-7721 and HepG2 cells. The up-regulation of FGG may
      be associated with the pathogenesis of HCC.

PMID- 15025952
TI  - [Expression of cellular FLICE inhibitory protein (cFLIP) in endometrial
      adenocarcinoma].
AB  - BACKGROUND & OBJECTIVE: Cellular FLICE inhibitory protein (cFLIP) is a new-found
      member of the inhibitors of apoptosis. It has been reported to be overexpressed
      in various human cancers. We investigated the expression of cFLIP in endometrial
      adenocarcinoma and its association with clinicopathological features and
      proliferating cell nuclear antigen-labeling index (PCNA-LI). METHODS: cFLIP and
      PCNA-LI were determined in endometrial tissue samples including 42 endometrial
      adenocarcinoma tissues, 20 normal proliferative endometrial tissues, and 40
      hyperplastic tissues with (n=10) or without (n=30) atypia by
      immunohistochemistry. RESULTS: The positive rates of cFLIP expression in normal
      proliferative samples of endometrium, hyperplastic samples, and endometrial
      adenocarcinomas were (55.0+/-11.4)%, (72.5+/-7.1)%, and (83.3+/-5.8)%,
      respectively. Scoring on the basis of the percentage of positive cells and the
      intensity of positive immunostaining indicated that the expression level of cFLIP
      was significantly higher in adenocarcinoma than in normal proliferative
      endometrium (P< 0.01) and hyperplastic endometrium with or without atypia (P<
      0.05);but no significant difference was found between the later two groups. PCNA
      LI were (12.01+/-2.07)%,(20.26+/-6.99)%, (27.10+/-3.01)%, and (41.65+/-10.16)%,
      respectively in the adenocarcinoma groups with different cFLIP levels showed as 
      , +, ++, +++. Statistical analysis showed that cFLIP expression was significantly
      associated with PCNA-LI (r=0.7471,P< 0.01). In addition, cFLIP expression was
      also significantly associated with clinical stage (P< 0.05), the presence of
      invasion to >1/2 myometrium (P< 0.05) and positive lymph node metastasis (P<
      0.01) of endometrial adenocarcinomas. CONCLUSION: Overexpression of cFLIP is
      tumor specific, which may be a late event in the tumor development of endometrial
      adenocarcinoma.

PMID- 15025953
TI  - [Association of TGFalpha and cyclin E expression in gastric carcinoma and
      precancerous lesions].
AB  - BACKGROUND & OBJECTIVE: Previous studies have indicated that increased expression
      of TGFalpha and cyclin E are correlated with the oncogenesis and progress of
      cancer; however, their expression patterns in gastric precancerous lesions have
      been not clear yet. In addition, the association between expression of TGFalpha
      and cyclin E has not been reported. This study was designed to investigate the
      expression of TGFalpha and cyclin E in chronic superficial gastritis (CSG),
      gastric precancerous lesions, and gastric carcinoma (GCA), and analyze the
      association of TGFalpha and cyclin E expression, and the relationship between
      their expression and different development stages of oncogenesis of GCA. METHODS:
      The expression of TGFalpha and cyclin E in CSG, intestinal metaphases (IM),
      atypical hyperplasia (AH), and GCA were examined using immunohistochemical
      staining. The association of TGFalpha and cyclin E expression was also
      statistically analyzed. RESULTS: The expression rates of TGFalpha and cyclin E
      were 15.1%, 53.6%, 51.7%, 61.7%, and 7.5%, 28.6%, 37.9%, 42.6% in tissue samples
      of CSG, IM, AH and GCA, respectively. The positive expression rates of TGFalpha
      and cyclin E were higher in IM, AH, GCA than in CSG; the difference was
      significant (each P< 0.05). In addition, the positive expression rates of
      TGFalpha and cyclin E were higher in low differential adenocarcinoma (TGFalpha
      81.0%, cyclin E 57.1%) than in mediate to high differential one (TGFalpha 41.7%,
      cyclin E 16.7%) (P< 0.05,for both TGFalpha and cyclin E). It is also revealed
      that the expression of TGFalpha and cyclin E were closely associated (P< 0.001
      for the tissue of gastric chronic inflammation, and P=0.005 for gastric
      carcinoma, respectively). CONCLUSION: In the tissues of CSG, IM, AH, and GCA, the
      expression rates of TGFalpha and cyclin E are increased gradually with the
      severity of the pathological lesions and the malignancy of GCA. In addition, the
      expression of TGFalpha and cyclin E were obviously associated.

PMID- 15025954
TI  - [Study of genes related to gastric cancer and its premalignant lesions with
      fluorescent differential display].
AB  - BACKGROUND & OBJECTIVE: It is generally recognized that development of gastric
      cancer arises gradually from premalignant lesions (chronic atrophic gastritis,
      intestinal metaplasia and dysplasia). Differential display of mRNA is a valuable
      tool for the identification of differentially expressed genes in human
      carcinogenesis and development. The search for differentially expressed genes in
      gastric cancer and its premalignant lesions may help to define molecular
      alterations in the gastric mucosa tissue that may precede the development of
      gastric cancer. METHODS: The differentially expressed cDNA bands were isolated
      and identified by fluorescent differential display in 2 gastric cancer, 2
      premalignant lesions, and 2 normal gastric mucosa tissues and then reamplified by
      PCR. After being cloned, all cDNA fragments were sequenced. Through BLAST
      software, the sequencing results were compared with GenBank database for homology
      analysis. Expression of SPTAN1 in 7 gastric cancer tissues, 7 premalignant
      lesions, and 7 normal gastric mucosa tissues were identified by RT-PCR. RESULTS:
      Four differentially expressed cDNA fragments were found. Three of them were over
      expressed in the gastric cancer tissue. One of them was over-expressed in
      premalignant lesions and normal gastric mucosa tissue. One cDNA fragment over
      expressed in gastric cancer was homologous to SPTAN1 and its over-expression in
      gastric cancer was confirmed by RT-PCR. The other three cDNA fragments showed
      significant homology to known gene sequences in GenBank but their functions are
      unknown. CONCLUSION: Three of the four differentially expressed genes over
      expressed in gastric cancer. SPTAN1gene was significantly higher in gastric
      cancer tissue than in normal gastric mucosa tissue and dysplasia tissue.

PMID- 15025955
TI  - [Analysis of gene expression of ribonuclease inhibitor in human breast cancer
      tissue].
AB  - BACKGROUND & OBJECTIVE: Ribonuclease inhibitor (RI), which is rich in human
      placenta, is a multi-functional acidic glycoprotein. Our previous studies showed
      that the growth of some solid tumors (S180 sarcoma, Ca761 breast cancer, and H22
      hepatoma) could be significantly inhibited by RI extracted and purified from
      human placenta. This study was designed to observe the change of RI gene
      expression in human breast cancer tissue. METHODS: The expression level of RI
      mRNA was determined by reverse transcription-polymerase chain reaction (RT-PCR)
      and capillary electrophoresis (CE). The RI content was determined by Western blot
      analysis. RESULTS: The electrophoretic stripes of the RT-PCR products of the
      breast cancer tissues were narrower and the plaques of Western blot of the breast
      cancer tissues were smaller compared with the control breast tissues. The peak
      altitude and width of capillary electrophoretic absorptive curve of the RT-PCR
      product of the breast cancer tissue were clearly smaller than that of the control
      breast tissue. The capillary electrophoresis integral values of the absorptive
      peak areas of RT-PCR product of the breast cancer tissue and the control breast
      tissue were (3.320+/-0.365)x10(6) and (4.385+/-0.880)x10(6), respectively. The
      comparison between two groups reveals a remarkably difference (P< 0.01).
      CONCLUSION: The gene expression of RI is clearly down-regulated in human breast
      cancer tissue that the RI mRNA level is remarkably lower and RI content also
      reduces significantly in human breast cancer tissue.

PMID- 15025956
TI  - [Expression and significance of telomerase reverse transcriptase and its
      regulators in non-small cell lung carcinoma].
AB  - BACKGROUND & OBJECTIVE: Telomerase is a ribonucleoprotein complex, which is
      silent in normal human somatic cells but may be reactivated by a series of
      regulators, and cause tumorigenesis. As a critical factor of telomerase activity,
      much progression has been achieved in the study of regulation of human telomerase
      reverse transcriptase, but the detail mechanism is still not clear. This study
      was designed to investigate the relationship of expression of human telomerase
      reverse transcriptase mRNA (hTERT mRNA) and its regulators including c-myc,
      mutant p53, protein kinase C alpha (PKCalpha) with clinicopathological
      significance of expression of the four markers in non-small cell lung carcinoma
      (NSCLC). METHODS: The expression of hTERT mRNA in 113 NSCLC specimens were
      detected by in situ hybridization, and the expression of c-myc, mutant p53, and
      PKCalpha in the same specimens were detected by immunohistochemistry. RESULTS:
      The positive rates of 113 NSCLC samples for hTERT mRNA, c-myc, mutant p53, and
      PKCalpha were 80.5%, 68.1%, 61.9%, and 85.0%, respectively. The differences were
      statistically significant among the expression of hTERT mRNA, c-myc, and PKCalpha
      (P< 0.05 or P< 0.01), but was not significant between the expression of mutant
      p53 and hTERT mRNA, c-myc as well as PKCalpha. The expression of mutant p53 was
      associated with carcinoma cell differentiation (P< 0.05), and its positive rate
      gradually increased with the extend of differentiation of carcinoma cell. The
      expression of hTERT mRNA, c-myc, and PKCalpha were not associated with carcinoma
      cell differentiation. There was no relationship of expression of the four markers
      with histological types, TNM stages, and lymph node metastasis status.
      CONCLUSION: C-myc and PKCalphawere associated with the expression of telomerase.

PMID- 15025957
TI  - [Correlation between expression of vascular endothelial growth factor-C in tumor
      associated macrophages and lymphatic metastasis in oral cancer].
AB  - BACKGROUND & OBJECTIVE: Previous study shows that both vascular endothelial
      growth-C (VEGF-C) and tumor-associated macrophages (TAMs) are related to
      lymphatic metastasis. This study aimed to explore the correlation between the
      expression of VEGF-C in TAMs and lymphatic metastasis in human oral squamous-cell
      carcinoma (OSCC). METHODS: After immunohistochemical staining, light microscope
      was used for counting macrophages and automated image analysis quantification was
      used to determine VEGF-C expression,which was reflected by positive index (PI).
      In addition,the double staining was also used to determine VEGF-C expression in
      TAMs. RESULTS: VEGF-C expression was higher in lymphatic metastasis group
      (PI=12.169+/-2.778) than in no-metastasis group (PI=8.498+/-2.674, P< 0.05). TAMs
      counts was related to VEGF-C expression in OSCC (r=0.370, P< 0.05). The result of
      double staining indicated that macrophage with positive VEGF-C expression
      accounted for about 22.8% of the total. CONCLUSION: Not only tumor cells but also
      TAMs secrete the VEGF-C in OSCC, and TAMs may play a major role in peritumoral
      lymphatic neoangiogenesis and lymphatic metastasis.

PMID- 15025958
TI  - [Construction of carcinoembryonic antigen (CEA) gene vaccine and stable
      coexpression with an immune adjuvant].
AB  - BACKGROUND & OBJECTIVE: Carcinoembryonic antigen (CEA) positive cancers are
      poorly responded to different kinds of treatments. Gene vaccines are promising in
      research of gene immunotherapy for these tumors. In this study, a CEA gene
      vaccine with hIL-2 as an immune adjuvant was constructed into a pVAX1 vector for
      synchronous expression, so as to explore experimentally a new biotherapy strategy
      against tumors. METHODS: Using reverse transcription polymerase chain reaction
      (RT-PCR), CEA cDNA was obtained from a large intestine carcinoma tissue; its
      encoded protein was compared with the CEA presented in GenBank using the protein
      analysis software. The acquired CEA cDNA fragment was linked to hIL-2 cDNA via an
      IRES site and cloned into the pVAX1 vector. The recombinant plasmid was estimated
      by CEA luminometry assay and hIL-2 ELISA measurement respectively. RESULTS: The
      nucleotide sequences of the target gene fragments of the recombinant plasmid were
      verified. The acquired CEA sequence is highly homologous with M29540 and M17303
      (99.8%) in GenBank; and the PCR sequence of hIL-2 is coincident with the original
      cDNA (100%) provided. The antigenicity,membrane-spanning segments, signal
      cleavage sites, secondary structure and 3D structure of the acquired CEA protein
      were similar to the original proteins of M29540 and M17303 predicted by the
      protein analysis software. Results showed the recombinant could steadily express
      CEA antigen and hIL-2 protein synchronously in CHO cells in vitro. CONCLUSION:
      The CEA cDNA was obtained from the tumor tissue and the CEA gene vaccine with hIL
      2 coexpression was constructed successfully. It has provided a possible method
      for immunotherapy against CEA positive cancers in vivo.

PMID- 15025959
TI  - [Expression of DeltaNp63 protein in nasopharyngeal carcinoma and its
      significance].
AB  - BACKGROUND & OBJECTIVE: The molecular etiology of nasopharyngeal carcinoma is
      currently unknown. It was reported that DeltaNp63 is dominant-negative toward
      transactivation of p53, and associated with the malignant hyperplasia and
      dedifferentiation of the squamous cells. This study was designed to investigate
      the expression and significance of DeltaNp63 protein in NPC tissues. METHODS:
      Immunohistochemical method was used to determine the expression of DeltaNp63 in
      60 cases of NPC, 37 cases of nearby mucosa of the carcinoma, and 30 cases of
      chronic inflammation of nasopharyngeal mucosa. The classification of the 60 NPC
      cases were as follows: 3 cases of keratinizing squamous cell carcinomas, 57 cases
      of nonkeratinizing carcinomas including 12 cases of undifferentiated carcinomas.
      RESULTS: All 60 NPC cases showed DeltaNp63 positive reaction. Keratinizing
      squamous cell carcinomas showed weakly positive expression; 66.67% (38/57) of
      nonkeratinizing carcinomas showed strongly positive reaction, and 83.33% (10/12)
      of undifferentiated carcinomas showed strongly positive reaction. Chronic
      inflammation mucosas and cancer nearby mucosas showed positive reaction only in
      their basal and superbasal cells. CONCLUSION: DeltaNp63 protein was found to be
      closely associated with cell malignant hyperplasia. DeltaNp63 protein has
      distinct tendency to the infantile or anaplastic squamous cells, and DeltaNp63
      protein is a valuable diagnostic marker for anaplastic squamous cells.

PMID- 15025960
TI  - [Primary study of genes related to uterine leiomyoma].
AB  - BACKGROUND & OBJECTIVE: The occurrence of uterine leiomyoma is related to the
      abnormal expression of some genes, but the molecular mechanism has not been
      clarified yet, the study screened genes related to uterine leiomyoma by comparing
      different genes expressed in uterine leiomyoma tissues with normal myometrium
      uterine tissues. METHODS: To compare different genes expressed in uterine
      leiomyoma tissues with normal myometrium uterine tissues by fluorescent
      differential display reverse transcription polymerase chain reaction (FDD-RTPCR).
      Four sets of anchor primers and three sets of arbitrary primers, totally twelve
      primer combinations, were used for FDD-RTPCR amplification. Differentially
      expressed cDNA fragments were cloned, sequenced, and analyzed in origin. And one
      of differentially expressed bands was analyzed by RT-PCR. RESULTS: Twenty-seven
      cDNA fragments were isolated from uterine leiomyoma. N(568) cDNA fragment shared
      96% homology with the sequence of GCRG114 gene. RT-PCR confirmed that this gene
      was expressed lowlier in uterine leiomyoma tissues than in normal myometrium
      uterine tissues. CONCLUSION: N(568) cDNA fragment is highly homologous with the
      sequence of GCRG114 gene, and it may be related to the development of uterine
      leiomyoma.

PMID- 15025961
TI  - [Clinical analysis of surgery for rectal cancer in 122 elderly patients].
AB  - BACKGROUND & OBJECTIVE: Patients with rectal carcinoma in the elderly are usually
      complicated with coexisting diseases. For selection of operative procedure, it is
      necessary to consider the various factors. The aim of this study was to assess
      the treatment and prognosis of rectal carcinoma in patients over 65 years of age.
      METHODS: The data of 122 such patients treated from January 1987 to December 1998
      in Cancer Hospital of Chinese Academy of Medical Sciences was analyzed
      retrospectively. Curative resection was performed for all patients, including
      abdominoperineal resection (45), anterior resection (66), Hartmann's operation
      (7), and transanal local excision (4). Postoperative complication developed in 10
      patients (8.2%). No death occurred within 30 days post operation. Survival
      analysis was estimated using the Kaplan-Meier method and compared using the log
      rank test. Cox regression was used in multivariate analysis. RESULTS: The overall
      3- and 5- year survival rates were 76.4% and 61.0% for the whole group, 81.6% and
      70.6% for the lymph node negative group (Dukes A, B), 60.9% and 40.4% for the
      lymph node positive group (Dukes C), respectively. The difference between the two
      groups was highly significant (Chi(2)=10.1, P< 0.01). However, histological type,
      coexisting disease, and tumor size had no significant association with prognosis
      (P< 0.05). Cox regression showed that lymph node metastasis was an important
      prognostic factor. CONCLUSION: Suitable radical surgery are crucial for long-term
      survival of the elderly patients wtih rectal carcinoma. Lymph node metastasis is
      an important prognostic factor for rectal carcinoma in the elderly patients.

PMID- 15025962
TI  - [Analysis of prognostic factors of rectal cancer in the elderly].
AB  - BACKGROUND & OBJECTIVE: The relation between patient age and outcomes from
      colorectal cancer surgery is complex. It is generally believed that age should
      not be a determinant in consideration of prognosis for colorectal cancer patient.
      But there were few studies on the prognostic factors of rectal cancer in the
      elderly. We therefore performed a retrospective analysis of clinicopathologic
      characteristics of rectal cancer in 343 old patients with rectal cancer by
      univariate and multivariate analysis. METHODS: A total of 343 patients (older
      than 60 years) with rectal cancer were treated surgically during a period of 10
      years. R0, R1, and R2 operations were carried out in 261 patients (76.09%), 29
      patients (8.45%), and 53 patients (15.45%), respectively. Low anterior resection
      was performed in 116 patients; 169 patients underwent Miles operation; 58
      patients underwent the other operations. RESULTS: The operation mortality was
      0.87%; 149 patients died of occurrence or metastases of the tumor within 108
      months postoperatively. Liver, lung, and bone metastases were occurred in 17, 18,
      and 1 patients, respectively. The mean survival time for all patients was 72.12+/
      2.60 months and the overall 3-, 5-, and 10-year survival rates were 69.62%,
      55.73%, and 34.23%, respectively. Univariate analysis showed that the predictors
      of survival were type of operations, radical resection, histological type,
      diameter of the tumors, depth of tumor invasion, lymphatic invasion, distance
      metastases, liver and lung metastases. Multivariate analysis showed that only
      radical resection, lymphatic invasion, liver and lung metastases were independent
      factors. CONCLUSION: The follow prognostic factors can influence the survival of
      rectal cancer in the elderly: type of operations, nature of operation,
      histological type, diameter of the tumors, depth of tumor invasion, lymphatic
      invasion, distance metastases, liver and lung metastases. The independent factors
      were nature of operation, lymphatic invasion, liver and lung metastases.

PMID- 15025963
TI  - [Expression of thymidine phosphorylase in human colorectal carcinoma and its
      clinical significance].
AB  - BACKGROUND & OBJECTIVE: Angiogenesis has been well known to be a factor related
      to the tumor growth and metastasis. Recent studies have reported that thymidine
      phosphorylase (TP) is identical with platelet-derived endothelial cell growth
      factor. It not only plays a role in the induction of the tumor angiogenesis, but
      also enhances the chemotherapeutical sensitivity of the tumor cells to prodrug of
      5-fluorouracil. However, until now, the complete identity of view about the
      function of TP expression in colorectal carcinoma and its prognostic significance
      has not been reached. The present study was to explore the TP expression level in
      human colorectal carcinoma and its clinical significance. METHODS: Seventy
      archived samples of the patients with colorectal carcinoma were detected by
      immunohistochemical staining. These patients had undergone radical surgical
      treatment at the First Hospital of Xi'an Jiaotong University and had been
      followed up for 5 years after operation. RESULTS: TP expression was predominantly
      observed in the cytoplasm of the tumor cells. The positive rate was
      57.14%(40/70). TP expression levels in the patients with different Dukes, stages
      and histopathological grades showed obvious difference (P=0.007 and 0.002,
      respectively). By Kaplan-Meier methods, the survival of TP positive expression
      group was shorter than that of TP negative expression group, and the five-year
      survival rates of TP positive expression group and TP negative expression group
      were 33.33% and 73.33% (P=0.000). The results indicated that the prognosis of the
      patients with TP positive expression was poorer than that of patients with TP
      negative expression. CONCLUSION: These findings suggest that TP expression might
      be one of the important prognostic indicators for colorectal carcinoma patients,
      and TP detection in colorectal carcinoma patients might served as a parameter for
      designing therapeutic schedule and choosing prodrug of 5-fluorouracil.

PMID- 15025964
TI  - [Expression and clinical significance of survivin gene and PTEN protein in
      colorectal adenocarcinoma].
AB  - BACKGROUND & OBJECTIVE: The occurrence of colorectal adenocarcinoma is resulted
      from multiple factors and both survivin gene and PTEN protein take part in these
      courses. They all regulate cell cycle and apoptosis, but their biological effects
      are adverse. It is not completely elucidated about their function and
      relationship in colorectal adenocarcinoma. This study was designed to investigate
      the role of survivin gene and PTEN protein in the pathogenesis of colorectal
      adenocarcinoma and their correlation. METHODS: To determine the survivin mRNA in
      42 colorectal adenocarcinoma and 20 adjacent normal colorectal tissue samples, we
      used reverse transcription polymerase chain reaction (RT-PCR) to determine the
      expression of survivin mRNA, and immunohistochemical evaluation was used to
      determine the expression of PTEN protein. RESULTS: The positive expression rate
      of survivin was 54.8% in colorectal adenocarcinoma, while no expression was
      detected in adjacent normal tissue. The expression of survivin gene was
      significantly correlated with histological differentiation and Dukes stage, but
      not with gender or lymph node metastasis. The positive rate of PTEN protein in
      colorectal carcinoma was lower (47.6%) than that in adjacent normal tissue
      (90.0%). The difference between them was significant (P< 0.01). There was no
      relationship between PTEN protein and gender, while the expression of PTEN was
      positively correlated with histological differentiation and lymph node
      metastasis, and possibly correlated with Dukes stage. With the progress of tumor
      in malignancy, negative correlation was observed between survivin and PTEN
      expression in colorectal adenocarcinoma. CONCLUSION: Survivin gene and PTEN
      protein are significantly correlated with the clinicopathological characteristics
      and biologic behaviors in colorectal adenocarcinoma. Detection of survivin
      together with PTEN is valuable for diagnosing colorectal adenocarcinoma, and
      evaluating malignancy extent and prognosis.

PMID- 15025965
TI  - [Abnormal expression of fragile histidine triad (FHIT) and Mut S homolog 2 (MSH2)
      proteins in human sporadic colorectal carcinoma and their clinical significance].
AB  - BACKGROUND & OBJECTIVE: Frequent loss of fragile histidine triad (FHIT)
      expression in human gastrointestinal tract carcinomas has been reported; however,
      there were divergent opinions regarding FHIT expression in colorectal carcinoma.
      Recent studies have suggested that FHIT inactivation can be a consequence of
      defects in mismatch repair proteins, particularly mut S homolog 2 (MSH2). This
      study was designed to investigate the expression and clinical significance of
      FHIT and MSH2 proteins in human sporadic colorectal carcinoma (SCC). METHODS:
      Immunohistochemistry SP method was used to determine the expression of FHIT and
      MSH2 in surgically resected specimens of 84 SCC and its corresponding paratumor
      normal colorectal tissues, and 23 cases of colonic adenomas. RESULTS: The
      positive expression rates of FHIT protein were 48.81%, 73.91%, and 100% in SCC,
      colonic adenomas, and adjacent normal colorectal tissues, respectively. The
      positive expression rates of FHIT protein showed increasing trend from SCC,
      colonic adenomas, to paratumor normal colorectal tissues; and the difference was
      statistically significant (P< 0.05). The expression levels of FHIT were not
      associated with age, gender, tumor site, and histological type (P >0.05), but
      were correlated with tumor invasive depth, differentiation degree, Dukes,stage,
      and lymph node metastasis (P< 0.05). The tumor tissues of deeper invade depth,
      lower differentiation degree, later Ducks,stage and with lymph node metastasis
      showed more reduction of FHIT protein expression. The expression level of MSH2
      was only related to Dukes, stage (P< 0.05). FHIT expression was closely
      associated with MSH2 expression in SCC (r=0.3728,P< 0.01). CONCLUSION: (1) Loss
      or reduction of FHIT protein expression plays an important role in the
      development and progression of SCC. The expression levels of FHIT protein are
      related to the malignant degree of SCC and may be a valuable biological indicator
      for predicting the potent invasion and metastasis of SCC. (2) FHIT protein
      expression is in a positive correlation fashion with MSH2 protein expression in
      SCC.

PMID- 15025966
TI  - [Preliminary study of astrocytic tumors by diffusion tensor imaging].
AB  - BACKGROUND & OBJECTIVE: Diffusion tensor imaging (DTI) is an advanced
      quantitative form of diffusion-weighted imaging. It could be used to calculate
      not only the apparent diffusion coefficient (ADC) of average water diffusion for
      each vowel, but also the diffusion anisotropic index of diffusion. Diffusion
      weighted imaging is used in most of the studies of the brain tumors abroad. We
      used DTI method to measure the ADC, fractional anisotropy (FA) and relative
      anisotropy (RA), values of different tumor tissues and to evaluate the usefulness
      of ADC, FA, and RA in differentiating solid tumor, necrotic region, edema region,
      normal brain tissue, and in grading the malignancy of cerebral astrocytomas.
      METHODS: Fourteen cases of astrocytomas diagnosed (10 cases of grade 1-2
      astrocytomas and 4 cases of grade 3-4 astrocytomas) were studied by DTI. ADC, FA,
      and RA values of different tumor tissue were measured. RESULTS: When all cases
      were analyzed as a group, significant differences of ADC were found in enhancing
      solid tumor (1.14+/-0.13x10(-3) mm(2)/s), necrotic region (2.04+/-0.50x10(-3)
      mm(2)/s), edema region (1.55+/-0.19x10(-3) mm(2)/s) compared with normal brain
      tissue (0.74+/-0.08x10(-3) mm(2)/s)(P< 0.05). Significant differences of ADC were
      also found in solid tumor (enhancing tissue:1.14+/-0.13x10(-3) mm(2)/s, non
      enhancing tissue:1.01+/-0.25x10(-3) mm(2)/s) compared with necrotic region and
      edema region, respectively (P< 0.05). Significant differences of FA and RA were
      found in solid enhancing region (FA:0.21+/-0.08; RA:0.23+/-0.07), necrotic region
      (FA: 0.14+/-0.06, RA: 0.16+/-0.07), edema region (FA:0.16+/-0.04, RA:0.16+/-0.02)
      compared with normal brain tissue (FA: 0.37+/-0.06, RA: 0.38+/-0.07) (P< 0.05).
      No difference of FA and RA was found in solid tumor (including enhancing and non
      enhancing tissue). Significant differences of ADC (P< 0.05), not FA and RA, were
      found between grade 1-2 astrocytomas (1.07+/-0.04x10(-3) mm(2)/s) and grade 3-4
      astrocytomas (1.32+/-0.08x10(-3) mm(2)/s). CONCLUSION: Determination of ADC can
      be used to differentiate normal brain tissue from enhancing solid tumor, necrotic
      region, and edema region. Determination of FA and RA can be used to differentiate
      solid enhancing tumor, necrotic region, and edema region from normal brain
      tissue, but can not be used to differentiate solid tumor, necrotic region, and
      edema region. The ADC values, not FA and RA, may predict the degree of malignancy
      of astrocytic tumors.

PMID- 15025968
TI  - [Relationship between expression of matrix metalloproteinase-9 (MMP-9) and
      angiogenesis in renal cell carcinoma].
AB  - BACKGROUND & OBJECTIVE: Matrix metalloproteinase-9 (MMP-9) is closely related to
      tumor invasion and metastasis. It has been recently found that MMP-9 also plays a
      role in tumor angiogenesis. This study was designed to investigate the
      relationship between MMP-9 and angiogenesis in renal cell carcinoma (RCC) and its
      clinical significance. METHODS: SP immunohistochemistry was used to determine the
      expression of MMP-9, vascular endothelial growth factor (VEGF), and microvessel
      density (MVD) in 78 RCC tissues. RESULTS: The expression of MMP-9 was related to
      the pathological stage and the histological grade in RCC (P< 0.05). The MVD value
      in MMP-9-positive group (110.46+/-50.16) was much higher than that in MMP-9
      negative group (84.77+/-44.52)(P< 0.05). There was a positive correlation between
      the intensity of the expression of MMP-9 and that of VEGF in RCC tissues
      (r=0.4096,P< 0.01). MMP-9 and VEGF took synergistic effect on angiogenesis in
      RCC. CONCLUSION: MMP-9 is associated with angiogenesis in RCC, and can serve as a
      biomarker for the potentialities of invasion and metastasis of RCC.

PMID- 15025967
TI  - [Expression of topoisomerase IIalpha in nasopharyngeal carcinoma and its clinical
      significance].
AB  - BACKGROUND & OBJECTIVE: TopoisomeraseIIalpha (TopoIIalpha) is a protein in
      eukaryotic cell with many different roles in DNA duplication and repair. It was
      reported that the expression level of TopoIIalpha was related to the prognosis of
      many malignant tumors. The aim of this study was to investigate the relationship
      of expression of TopoIIalpha in nasopharyngeal carcinoma (NPC) with
      clinicopathologic factors and its prognostic significance. METHODS: The
      expression of TopoIIalpha was observed in 114 NPC cases using immunohistochemical
      staining. All of the patients were divided into two groups according to the
      expression level of TopoIIalpha. Kaplan-Meier survival analysis was used to
      analyze the relationship of expression of TopoIIalpha with recurrence and
      metastasis of tumor after radiotherapy. Cox proportional hazards model analysis
      was used to analyze the factors related to local recurrence of tumor. RESULTS:
      The expression of TopoIIalpha in NPC cells ranged from 0 to 90%; the average
      percentage was (22.63+/-21.92)%. The positive rate of TopoIIalpha was 43.9%
      (50/114) when 20% was used as the cut-off point. The positive rate of TopoIIalpha
      was not related to the sex, age, pathological type, and clinical staging. The 3
      year relapse-free survival rates of negative group and positive group were 93.1%
      and 74.3%, respectively (P=0.0027). The 3-year disease-free survival rates of the
      two groups were 77.9% and 58.9%, respectively (P=0.0091). The metastasis-free
      survival rates of the two groups were 81.1% and 77.6%, respectively (P=0.566).
      Cox proportional hazards model analysis showed that the local recurrence of tumor
      was independently affected by the expression of TopoIIalpha. CONCLUSION: There is
      a high expression level of TopoIIalpha in a part of NPC.NPC patients with high
      expression of TopoIIalpha have a higher local recurrence rate and worse
      prognosis.

PMID- 15025969
TI  - [Efficiency of combined multiple organs resection in advanced gastric carcinoma].
AB  - BACKGROUND & OBJECTIVE: Presently, 26.05% of cases with gastric carcinoma
      hospitalized in Cancer Center of Sun Yat-sen University were revealed adjacent
      organs involvement in varying degrees in exploration. There have been many
      arguments about the issue of surgery therapy on these advanced gastric carcinomas
      for a long time. This study was designed to demonstrate the feasibility of
      combined multiple organs resection in such cases. METHODS: Clinical data of 44
      advanced gastric cancer patients received combined multiple organs resections
      from 1985 to 1995 in Cancer Center of Sun Yat-sen University were enrolled
      retrospectively. Among them, 34 cases received curative resection and 10 cases
      received palliative resection. The effects of two kinds of operations were
      analyzed. RESULTS: Median survival time was 588 days (average is 1 676 days) in
      radical combined multiple organs resection group and 344 days (average is 1 045
      days) in palliative resection group respectively (P >0.05). In addition, no
      serious complication occurred and no patients died of extended resection.
      CONCLUSION: Combined multiple organs resection is practicable in curative therapy
      for gastric carcinoma; even palliative resection may have better treatment
      effect. So, if permission, radical combined multiple organs resection should be
      top-priority.

PMID- 15025970
TI  - [Expression of PTEN, p16, p21, and p53 proteins in lung cancer using tissue
      microarray and their clinical significance].
AB  - BACKGROUND & OBJECTIVE: The genesis of lung cancer was associated with mutation
      or abnormal expression of PTEN, p16, p21, and p53. Tissue microarray provides a
      high throughout tool for genes expression. But little is reported about
      expression of PTEN, p16, p21, and p53 in lung cancers with tissue microarray. The
      aim of this study was to investigate the expression of PTEN, p16, p21, and p53
      proteins and to analyze their relationship with the pathogenesis, invasion, and
      metastasis in lung cancer. METHODS: The expression of the antioncogene proteins
      in 100 cases of lung cancer and corresponding adjacent tissues were determined by
      tissue microarray combined with immunohistochemistry. RESULTS: The positive
      expression rates of PTEN, p16, p21, and p53 proteins were 31% (31/100), 38%
      (38/100), 42% (42/100), 53% (53/100) in lung cancer tissues, and were 85%
      (85/100), 72% (72/100), 80% (80/100), and 23% (23/100) in the adjacent cancer
      tissues, respectively, showing a low expression of PTEN, p16, p21 in cancer
      tissues, and high expression of p53 outside of them (P< 0.05, P< 0.01).
      Furthermore, the expression of PTEN, P16, and p53 proteins showed positive
      correlation with the clinical degrees and pathological stages of lung squamous
      carcinomas and adenocarcinomas (P< 0.05,P< 0.01). In lung cancer with lymph node
      metastasis, the expression of PTEN, p16, and p21 were low, but the expression of
      p53 increased significantly (P< 0.05, P< 0.01). CONCLUSION: Tissue microarray
      provided a useful high-throughout tool for multigene expression in large-scale
      investigations. There existed low expression of PTEN, p16, p21 proteins and over
      expression of mutated p53 protein. Coexpression of these antioncogenes played an
      important role in invasion and metastasis in lung cancer.

PMID- 15025971
TI  - [Western blot analysis and flow cytometric analysis of estrogen and progesterone
      receptors in fixed breast cancer cells].
AB  - BACKGROUND & OBJECTIVE: Quantitative and qualitative detection of estrogen
      receptor (ER) and progesterone receptor (PR) levels are very important for
      predicting prognosis and evaluating the outcome of endocrine therapy of breast
      cancer patients. Western blot analysis and Flow cytometry (FCM) are important
      means for quantitative and qualitative analysis of proteins, but conventional
      Western blot analysis need to extract proteins from fresh cells. The present
      study was designed to establish Western blot analysis of human estrogen receptor
      (ER) and progesterone receptor (PR) in fixed breast cancer cells, and to explore
      the possibility of ER and PR analysis in fixed cells by flow cytometry and
      Western blot analysis simultaneously. METHODS: Proteins extracted from fresh and
      fixed cells of different exponentially growing breast cancer cell lines were
      labelled using 1D5 and PgR636, which were monoantibodies to ERalpha and PR,
      respectively. The expression of ER and PR were determined using Western blot
      analysis, and the results were compared with that of fixed cells measured with
      flow cytometry. RESULTS: Clear and correct ERalpha bands were observed with
      Western blot analysis in cell lines T-47d, MCF-7, and ZR-75-1, and the band
      density of fixed T-47d and ZR-75-1 was higher than that of fresh cells. The
      expression of ERalpha in MM231 cells was negative. Clear and correct PR bands
      were visible in T-47d and ZR-75-1 cells with Western blot analysis, and the band
      density of fixed cells was higher than that of fresh cells. And the expression of
      PR in MM231 and MCF-7 cells were negative. In addition, positive expression of ER
      and PR in different cell lines measured by flow cytometry were the same with that
      analyzed by Western blot analysis. CONCLUSION: After fixed with 0.25%
      paraformaldehyde and 75% ethanol, breast cancer cells can be used for not only
      quantitative measurement of ER and PR, but also Western blot analysis of ER and
      PR.

PMID- 15025973
TI  - [Clinical evaluation of three methods of fine-needle aspiration, large-core
      needle biopsy and frozen section biopsy with focus staining for non-palpable
      breast disease].
AB  - BACKGROUND & OBJECTIVE: Early detection of breast cancer is crucial to improve
      the therapeutic effect and to increase the survival rate. However, it is
      difficult because breast cancer in early stage was usually occult, impalpable,
      and could not be detected by laboratory test. This study was designed to compare
      the effectiveness of three methods for diagnosis of non-palpable breast cancer.
      METHODS: Twenty-four patients with impalpable breast mass suggested by computer
      aided stereotactic mammography were performed with three kinds of methods,
      including fine-needle aspiration cytology (FNAC), large-core needle biopsy
      (LCNB), and frozen section biopsy (FSB) with focus staining. The results were
      compared with postoperative pathology. RESULTS: Compared with postoperative
      pathology results, the diagnostic consistent rates of FNAC, LCNB and FSB with
      staining focus were 75%, 92%, and 100%, respectively (P< 0.05). CONCLUSION:
      Frozen section with focus staining guided by computer-aided stereotactic
      mammography was the effective diagnostic technique for non-palpable breast
      cancer.

PMID- 15025972
TI  - [A study on the method of DNA extraction from unbuffered formalin-fixed and
      paraffin-embedded samples].
AB  - BACKGROUND & OBJECTIVE: Unbuffered formalin is widely used to fix resected
      specimens in China. The DNA in unbuffered formalin-fixed and paraffin-embedded
      tissues is usually degraded seriously, so the extraction of DNA from these
      samples is difficult. This study was conducted to seek an optimal method to
      extract DNA from these samples. METHODS: Fifteen blocks of esophageal carcinoma
      resected in Fourth Hospital of Hebei Medical University in 2000 were selected.
      The cells were lyzed by proteinase K digestion or heating under different pH
      values, then DNA was extracted by phenol:chloroform. After that, four parameters
      (deparaffined by xylene or histolene; digested for 48 h or 72 h at 37 degrees C
      or 56 degrees C; extracted by salting-out or phenol:chloroform) were optimized
      according to the principle of cross design. At last, the quality of obtained DNA
      was analyzed with electrophoresis and PCR amplification. RESULTS: The quality and
      quantity of DNA obtained by proteinase K digestion (the average yield is 17.88
      microg) were better than that of heating under different pH (7-12)(P< 0.05). The
      quality and quantity of DNA digested at 56 degrees C were better than that at 37
      degrees C, and similarly, digestion for 72 hours was better than that for 48
      hours. The methods of deparaffin and extraction had no obvious influence on the
      quality and quantity of DNA. CONCLUSION: By means of NaCl salting-out after
      proteinase K digestion, more reliable quality of DNA can be obtained from
      unbuffered formalin-fixed and paraffin-embedded samples. Furthermore,digestion
      for three days at 56 degrees C is more likely to obtain DNA with high quality and
      quantity.

PMID- 15025974
TI  - [Advantage of dual-energy technique in diagnosis of chest tubercular diseases].
AB  - BACKGROUND & OBJECTIVE: X-ray radiography is the first choice for detecting chest
      diseases. However, "visual obstacles" caused by the overlaps between ribs and
      lung in chest radiography affects the observation and analysis of chest diseases.
      The objective of this study was to investigate the value of direct digital
      radiography (DR) dual-energy technique in diagnosis of chest disease located in
      the overlaps between ribs and lung. METHODS: Thirty-five cases of chest
      tubercular diseases located in the overlaps between ribs and lung were examined
      using direct digital radiography (DR) dual-energy technique. RESULTS: Ratings of
      dual-energy technique radiography in detecting chest tubercular diseases were
      94.3% whereas the ratings of DR radiography were 45.7%. Bone and soft tissue can
      be separated in the radiography using dual-energy technique. CONCLUSION: DR dual
      energy technique not only increases the visibility towards chest tubercular
      disease, but also discriminates the location (ribs or lung) of chest tubercular
      disease.

PMID- 15025975
TI  - [Recent progress in molecular mechanisms of chromosome instability and their
      association with carcinogenesis].
AB  - The persistent presence of chromosome instability (CIN) has been demonstrated in
      majority of human cancers, particularly in solid cancers. Recent progress in
      molecular and cellular biology as well as cytogenetic has shed light on the
      possible molecular mechanisms and their association with carcinogenesis.
      Chromosome instability may result from various causes, including defects of
      mitotic spindle checkpoint, centrosome aberration, failure of cell cycle
      checkpoint, DNA double strand break, telomeres dysfunction, hypomethylation and
      so on. The researches broaden new insight in molecular mechanisms of
      carcinogenesis and provided new ideas in diagnoses, therapy, classification, and
      prognosis of cancer.

PMID- 15025976
TI  - [Electron arc therapy: application of chest wall irradiation after mastectomy].
AB  - With the development of multidisciplinary treatment for cancer, great changes
      have taken place in the therapeutic strategy of breast cancer. However,
      radiotherapy as a method of local management, still plays an important role in
      the combined treatment of breast cancer. The recurrence in the chest wall ranks
      the first, accounting for 44-69% of the total local-regional relapse, therefore,
      the chest wall is commonly regarded as the most important target of radiotherapy
      after mastectomy. The traditional irradiation techniques cannot reach an ideal
      dose distribution due to the irregular shape of the chest wall. Electron arc
      therapy, by using the electron characteristics of dose distribution, combining
      the shape of thorax and the depth of target volume, make the dose distribution of
      target volume more reasonable, decreases the dose of heart or lung and has more
      clinical benefit than traditional techniques. On the other hand, it had been
      demonstrated by some clinical research that irradiation with electron arc could
      provide a high rate of local control and generally acceptable acute and long-term
      toxicity, comparing with the traditional irradiation techniques.

PMID- 15025977
TI  - [The pericardium. A structure in need of more detailed study].

PMID- 15025978
TI  - [Analysis of 73 cases of significant pericardiac effusion].
AB  - Seventy-three patients with significant pericardiac effusion (SPE) are analyzed
      retrospectively. The results concerning etiology, clinical findings, evolution,
      echocardiography findings and pericardiac effusion (PE) findings are summarized.
      Conclusions drawn are: 1) the pericardiac effusion (PE) is a difficult diagnosis
      without the assistance of the echocardiogram; 2) the echocardiogram signs of
      hemodynamic alterations have prognostic value; 3) the most frequent causes of SPE
      are: tumors, idiopathic acute pericarditis, and iatrogenesis; 4) in an important
      percentage of DPS patients the cause is not identified; 5) the clinical
      presentation as pericardiac tamponade (PT) is most frequent in the tumors; 6) the
      analysis of the PE has a low yield, which means that diagnostic pericardicentesis
      is not justified in all patients with SPE; 7) the pericardiac biopsy hasa low
      diagnostic yield; 8) the predictive mortality factors are: presentation as PT and
      tumor etiology, and 9) because of the dynamic character of the SPE, it is
      important to carry out a progress follow-up of it.

PMID- 15025979
TI  - [Validation of the Spanish version of the Rhinoconjunctivitis Quality of Life
      Questionnaire (RQLQ)].
AB  - OBJECTIVE: Validate the questionnaire Rhinoconjunctivitis Quality of Life
      Questionnaire (RQLQ) in conditions of regular clinical practice. METHODS: Two
      hundred and eighty four adult patients with a diagnosis of rhinoconjunctivitis
      (RC) cared in 37 centers of specialized health care in allergy or
      otorhinolaryngology services in Spain were analyzed. Patients with RC were
      included in two groups: clinically non-stable patients who received treatment
      with an oral second generation antihistaminic (group A), and clinically stable
      patients (group B). Sociodemographic and clinical variables were collected and
      the questionnaires RQLQ and EQ-5D were administered in the initial visit and in
      the second visit 15 days after. Feasibility, validity, reliability and
      sensitivity related to the change of the RQLQ were analyzed. RESULTS: The mean
      period (standard deviation) of administration was 9.67 (6.25) minutes and 85.6%
      of patients needed assistance in order to fill the RQLQ, especially the selection
      of the characteristics (62.5%). The dimensions of the RQLQ showed a greater
      association with the dimensions of the EQ-5D that assessed similar aspects and
      the symptoms in which a greater relation was expected. The alpha Cronbach
      coefficient of the scorings of the RQLQ fluctuated between 0.85 and 0.96 and the
      intraclass correlation coefficient fluctuated between 0.68 and 0.89. The
      sensitivity to the change of the dimensions of the RQLQ, evaluated through the
      magnitude of the effect between the two visits, ranged between 0.76 and 1.46.
      CONCLUSIONS: The Spanish version of the RQLQ proved to be a valid instrument for
      assessing the Health-Related Quality of Life (HRQL) in adult patients with
      seasonal or perennial RC.

PMID- 15025980
TI  - [Evaluation of the clinical manifestations in patients with reactions to the
      rabies vaccine or serum in the Ciego de Avila province (Cuba)].
AB  - The present design is a descriptive study in which people bitten by animals,
      rabies treatment used and the reactions to it are described. The frequency of
      adverse effects to the vaccine and to the serum are pointed out. The forms of
      clinical presentation and the clinical symptoms of the reactions observed in the
      Ciego de Avila province, Cuba, in the period from 1981 to 2001, were evaluated.
      In this period prevailed the reactions to the heterologous serum and the
      reactions caused by the human rabies vaccine. Local reactions to the vaccine were
      more common than the systemic ones. Four neuroparalytic reactions produced by the
      vaccines were observed. The most frequent symptoms and signs of the patients with
      reaction to the vaccine were pruritus, rash, localized urticaria, papule in the
      point of injection and local pain. The clinical manifestations considered as
      reactions to the heterologous serum that prevailed in the patients were rash in
      gluteal regions, pruritus, local erythyema and fever. No patient was detected
      with neurological manifestations caused by the heterologous serum.

PMID- 15025981
TI  - [Hepatitis A seroprevalence in Navarra].
AB  - BACKGROUND: Determine the hepatitis A seroprevalence in Navarra. Because of the
      improvement in the hygienic-sanitary conditions, we hope to find a decline of the
      total prevalence. METHODS: Population and random sample of Navarra, obtained by
      stratified sampling with proportional allocation of sex, age, and area of health
      care: 1,440 individuals over 15 years of age. Detection of total antibodies by
      enzyme immunoassay of microparticles. RESULTS: Global seroprevalence: 79.24%. By
      age: 9.09% (16-19 years), 35.32% (20-29 years), 77.78% (30-39 years), 97.31% (40
      49 years), 98.58% (50-59 years), 97.51% (60-69 years), 99.33% (70-79 years) and
      100% (>79 years). By gender: 78.76% in men and 79.7% in women. Rural area 82.04%
      and urban area 75.77%. Areas of health care: Tafalla, 89.06%; Estella, 87.91%;
      Tudela, 82.88%; northern, 77.22%; Pamplona, 75.05%, and eastern, 70.97%.
      CONCLUSIONS: The global prevalence is 79.24% and increasing progressively with
      the age. Greater seroprevalence in rural areas and in people in contact with
      livestock. Characteristics of the persons with seroprevalence for HAV in Navarra:
      inhabitant of the average area, of rural area, with average age and in contact
      with livestock.

PMID- 15025983
TI  - [Chronobiology and medicine: from theory to clinical reality].

PMID- 15025982
TI  - [Allergy to latex].

PMID- 15025984
TI  - [Non-steroid antiinflammatory-related dyspepsia. An unresolved subject].

PMID- 15025985
TI  - [Antisecretor treatment of digestive hemorrhage associated to peptic ulcer: an
      approximation to the available evidence].

PMID- 15025986
TI  - [Desquamative violet nodules disseminated in limbs].

PMID- 15025987
TI  - [A 55-year-old male with Raynaud's phenomenon, cutaneous lesions and focal
      seizures].

PMID- 15025988
TI  - [A 65-year-old woman with mediastinal enlargement].

PMID- 15025989
TI  - [Spontaneous pneumothorax secondary to lung infarct in patient with protein S
      deficiency].

PMID- 15025990
TI  - HIV-associated asymmetric lipodystrophy syndrome.

PMID- 15025991
TI  - [Lung adenocarcinoma with rapid evolution in a 35-year-old patient].

PMID- 15025992
TI  - [Adaptation of the clinical history as quality of care control].

PMID- 15025994
TI  - Peptidomics.
AB  - Peptides occur in the whole animal kingdom, from the least evolved phyla with a
      very simple nervous system (coelenterates) to the highest vertebrates and are
      involved in most, if not all, physiological processes in animals. Knowing the
      amino acid sequence of peptide hormones or neurotransmitters is important since
      this allows for synthesis of large quantities of peptides to perform further
      functional analysis. Immunocytochemistry, radioimmunoassays (RIA), enzyme-linked
      immunosorbant assays (ELISA) and mass spectrometry can then provide information
      on the temporal and spatial distribution and quantification of the
      (neuro)peptide. Ever since the 1970s, a wealth of peptides has been discovered
      and investigated and this flow seems to be far from over. This is partially due
      to the use of new approaches mainly based on chromatographical purifications as
      well as molecular biological techniques. Surprisingly, peptides have so far been
      neglected in most proteomic studies. The finalization of the genome projects has
      opened new opportunities for rapid identification and functional analysis of
      (neuro)peptides as well. In analogy with the proteomics technology, where all
      proteins expressed in a cell or tissue are analyzed, the peptidomic approach aims
      at the simultaneous visualization and identification of the whole peptidome of a
      cell or tissue, i.e. all expressed peptides with their post-translational
      modifications (PTMs). This technology provides us with a fast and efficient tool
      to analyze the peptides from any tissue. This paper reviews the approaches that
      have been used so far to achieve this.

PMID- 15025995
TI  - Differential polypeptide display: the search for the elusive target.
AB  - Proteomics, as a tool to identify proteins in biological samples, is gaining
      rapidly importance in the postgenomic era. Here we discuss the current and
      potential role of different techniques in the field of proteomics such as two
      dimensional gel electrophoresis off-line coupled to MALDI-MS (2D-PAGE-MALDI-MS),
      high performance liquid chromatography mass spectrometry (HPLC-MS), surface
      enhanced laser desorption/ionization mass spectrometry (SELDI-MS) and a newly
      developed technique, capillary electrophoresis mass spectrometry (CE-MS). The
      developments of the last years are presented discussed.

PMID- 15025996
TI  - Methodological advances in the discovery of protein and peptide disease markers.
AB  - The quest for biomarkers has seen a renaissance due to the application of newly
      developed separation methodologies and advances in biomolecular mass
      spectrometry. It can be argued that each disease influences the physiology of an
      organism and that these changes should be measurable. Many diagnostic and
      therapeutic decisions are supported by measurable biochemical or cellular changes
      in plasma, serum or urine but it is unquestionable that there is a great lack in
      better markers for early disease detection and prevention. In this review we
      cover recent developments in the areas of separation science, sample preparation
      and mass spectrometry as applied to biomarker discovery. We focus, in particular,
      on the use of LC-MS and SELDI-TOF-MS as two approaches that have seen an upswing
      in recent years. While validation of newly discovered biomarkers or biomarker
      patterns and their introduction into diagnostic practice will be a long process,
      it is our believe that many future diagnostic tests will be based on markers
      discovered through novel profiling technologies as those outlined in this
      article.

PMID- 15025997
TI  - Bioactive peptides from marine sources: pharmacological properties and isolation
      procedures.
AB  - Marine organisms represent a valuable source of new compounds. The biodiversity
      of the marine environment and the associated chemical diversity constitute a
      practically unlimited resource of new active substances in the field of the
      development of bioactive products. In this paper, the molecular diversity of
      different marine peptides is described as well as information about their
      biological properties and mechanisms of action is provided. Moreover, a short
      review about isolation procedures of selected bioactive marine peptides is
      offered. Novel peptides from sponges, ascidians, mollusks, sea anemones and
      seaweeds are presented in association with their pharmacological properties and
      obtainment methods.

PMID- 15025998
TI  - Proteomics of the venom from the Amazonian scorpion Tityus cambridgei and the
      role of prolines on mass spectrometry analysis of toxins.
AB  - Scorpion venom are complex mixtures of peptides, known to cause impairment of ion
      channel function in biological membranes. This report describes the separation of
      approximately 60 different components by high performance liquid chromatography
      and the characterization by Edman degradation and mass spectrometry of 26
      peptides from the soluble venom of the Amazonian scorpion Tityus cambridgei. One
      of these peptides, named Tc48a, was fully characterized. It contains 65 amino
      acid residues, the C-terminal residue is amidated and it affects Na(+)-channels
      with a K(d) of about 82 nM. Furthermore, this report shows the thermo-instability
      of scorpion toxins subjected to electron spray ionization-mass spectrometry (ESI
      MS). When a proline residue is located near the N-terminal region of the toxin,
      not stabilized by disulfide bridges, artificial components are generated by the
      mass spectrometer conditions, due to the cleavage of the peptide bond at the
      proline positions. This phenomenon was confirmed by using four model proteins
      (variable regions of immunoglobulins) studied by ESI-MS and matrix assisted laser
      desorption ionization-time of flight (MALDI-TOF)/MS.

PMID- 15025999
TI  - Structure-function study of a chlorotoxin-chimer and its activity on Kv1.3
      channels.
AB  - Chlorotoxin has been isolated from the venom of the scorpion Leiurus
      quinquestriatus and characterized as a 4.1kDa peptide, containing a lysine at
      position 27 that is also present in many Kv-blocking toxins. Because chlorotoxin
      shows no affinity for Kv-channels, we intended to design, express and purify a
      chlorotoxin-chimer, containing the active binding site (beta-sheet) of a very
      potent Kv1-channel blocking peptide, agitoxin 2, by mutating three original
      residues in the chlorotoxin molecule. Several derivatives of the chimer,
      gradually missing one additional amino acid residue at the N-terminal side of the
      peptide, were produced and identified chromatographically. In contrast to
      chlorotoxin, these chimer derivatives are capable of blocking cloned Kv1
      channels.

PMID- 15026000
TI  - Recombinant production, purification and biochemical characterization of domain 6
      of LEKTI: a temporary Kazal-type-related serine proteinase inhibitor.
AB  - Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a 15-domain serine
      proteinase inhibitor which is of pathophysiological relevance for skin diseases
      and atopy. Domains 2 and 15 of LEKTI contain six cysteine residues and match the
      Kazal-type inhibitor motif almost exactly. The other 13 domains seem to be Kazal
      type derived but lack the cysteines in positions 3 and 6 usually conserved within
      this family of inhibitors. Here, we report the recombinant production and
      comprehensive biochemical characterization of the 7.7 kDa LEKTI domain 6 (LD-6).
      Testing a selected number of different serine proteinases, we show that both
      native and recombinant LD-6 exhibit a significant but temporary inhibitory
      activity on trypsin. Furthermore, the relation of LEKTI domain 6 to Kazal-type
      inhibitors is confirmed by determining its disulfide bond pattern (1-4/2-3) and
      its P(1) site located after the second Cys residue of LD-6. The established
      strategy for the recombinant production of LEKTI domain 6 will enable further
      investigation of its mode of action and its physiological role.

PMID- 15026002
TI  - Simultaneous determination of incretin hormones and their truncated forms from
      human plasma by immunoprecipitation and liquid chromatography-mass spectrometry.
AB  - The incretins, glucose-dependent insulinotropic peptide (GIP(1-42)) and glucagon
      like peptide 1 (GLP-1(7-36)), are involved in regulation of gastric emptying,
      glucose homeostasis, body fat regulation and the glucose-induced insulin
      secretion from the endocrine pancreas. After release in the circulation both
      peptides are rapidly degraded by the exopeptidase dipeptidyl peptidase IV (DP IV)
      to the inactive polypeptides GIP(3-42) and GLP-1(9-36). In vivo stabilization of
      the active incretins by orally available DP IV-inhibitors is now widely accepted
      as a new therapeutic approach in antidiabetic treatment. In order to demonstrate
      the pharmacodynamic effect of DP IV-inhibitors, it is necessary to measure the
      plasma levels of active and inactive forms of GIP and GLP-1. We previously
      described an immunoprecipitation method as sample preparation and concentration
      in combination with a LC-MS analysis for determination of active and inactive
      GIP. We could improve the efficiency and suitability of this method by reduction
      of the necessary sample volume to 1.0 ml and simultaneous measurement of GIP(1
      42), GIP(3-42) and GLP-1(7-36), GLP-1(9-36), without loss of sensitivity. An LOQ
      of approximately 5 and 11 pmol/l was maintained for GIP and GLP-1, respectively.

PMID- 15026001
TI  - Quantitative analysis of [Dmt(1)]DALDA in ovine plasma by capillary liquid
      chromatography-nanospray ion-trap mass spectrometry.
AB  - The synthetic opioid peptide analog Dmt-D-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA; [Dmt=
      2',6'-dimethyltyrosine) is a highly potent and selective mu opioid-receptor
      agonist. A very sensitive and robust capillary liquid chromatography/nanospray
      ion-trap (IT) mass spectrometry method has been developed to quantify
      [Dmt(1)]DALDA in ovine plasma, using deuterated [Dmt(1)]DALDA as the internal
      standard. The standard MS/MS spectra of d(0)- and d(5)-[Dmt(1)]DALDA were
      obtained, and the collision energy was experimentally optimized to 25%. The
      product ion [ M + 2H-NH(3)](2+) (m/z 312.2) was used to identify and to quantify
      the synthetic opioid peptide analog in ovine plasma samples. The MS/MS detection
      sensitivity for [Dmt(1)]DALDA was 625 amol. A calibration curve was constructed,
      and quantitative analysis was performed on a series of ovine plasma samples.

PMID- 15026003
TI  - Optimization of reversed-phase microcapillary liquid chromatography for
      quantitative proteomics.
AB  - Currently, the field of shotgun proteomics relies primarily on the separation of
      peptides by reversed-phase microcapillary chromatography (RP-microLC) combined
      with either electrospray ionization (ESI) or matrix-assisted laser desorption
      ionization (MALDI) and tandem mass spectrometry (MS/MS) for protein
      identification as well as quantification. For this purpose we herein describe
      construction of a RP-microLC-ESI column-emitter along with optimized microLC
      conditions for using the device to quantify pair-wise changes in protein
      expression via the isotope coded affinity tag (ICAT) method that also maximize
      peak capacity. These optimized RP-microLC parameters required a balance be
      reached between the disparate needs of quantification which requires good peak
      shape and identification (i.e. proteome coverage) of proteins via peptide
      collision induced dissociation (CID) which requires peak capacity be maximized. A
      complex biological sample from a study of murine acetaminophen toxicity in
      hepatocyes was chosen for method development because of the high level
      complexity, but the biological results are not the focus of this manuscript.

PMID- 15026004
TI  - Identification and analysis of phosphopeptides.
AB  - Reversible phosphorylation of serine, threonine and tyrosine residues in proteins
      is one of the key events in signal transduction. To understand the process of
      signal transduction on a molecular level, it is imperative to identify
      phosphorylation sites in proteins. In this review, we offer an overview of the
      different methods/technologies currently available to identify protein
      phosphorylation sites.

PMID- 15026005
TI  - Automated multi-dimensional liquid chromatography: sample preparation and
      identification of peptides from human blood filtrate.
AB  - A comprehensive on-line sample clean-up with an integrated two-dimensional HPLC
      system was developed for the analysis of natural peptides. Samples comprised of
      endogenous peptides with molecular weights up to 20 kDa were generated from human
      hemofiltrate (HF) obtained from patients with chronic renal failure. The (poly
      )peptides were separated using novel silica-based restricted access materials
      with strong cation-exchange functionalities (SCX-RAM). The size-selective sample
      fractionation step is followed by cation-exchange chromatography as the first
      dimension. The subsequent second dimension of separation is based on hydrophobic
      interaction using four parallel short reversed-phase (RP) columns implemented via
      a fully automated column switching technique. More than 1000 peaks were resolved
      within the total analysis time of 96 min. Substances of selected peaks were
      sampled to analyse their molecular weights by off-line MALDI-TOF mass
      spectrometry and to determine their amino acid sequence by Edman degradation. The
      potential for comprehensive peptide mapping and identification is demonstrated.

PMID- 15026006
TI  - Protein identification by liquid chromatography-mass spectrometry using retention
      time prediction.
AB  - Liquid chromatography has been coupled with mass spectrometry to improve the
      dynamic range and to reduce the complexity of sample introduced to the mass
      spectrometer at any given time. The chromatographic separation also provides
      information on the analytes, such as peptides in enzymatic digests of proteins;
      information that can be used when identifying the proteins by peptide mass
      fingerprinting. This paper discusses a recently introduced method based on
      retention time prediction to extract information from chromatographic separations
      and the applications of this method to protein identification in organisms with
      small and large genomes.

PMID- 15026007
TI  - Evaluation and comparison of tailor-made stationary phases based on spherical
      silica-based beads for capillary electrochromatography via peptide separation
      analysis.
AB  - Small cyclic peptides have been employed to elucidate the performance of novel
      sorbents as stationary phases in capillary electrochromatography (CEC). In this
      paper chain length dependencies for ordinary liquid chromatographic sorbents are
      reported together with findings acquired on beads specifically designed to suit
      CEC. The latter, tailor-made, spherical, porous silica exhibits a distinguished
      surface modification to meet the criteria anticipated to enhance performance
      profiles in CEC. With well-characterised peptides resembling the analytes,
      probing of the CEC system in a systematic manner (predominantly via the organic
      modifier content of the background electrolyte (BE)) reveals insight into the
      complex interplay occurring in such analytical systems at the molecular and sub
      molecular level in particular upon various modes of interaction.

PMID- 15026008
TI  - Optimization of capillary coating by hydroxyethyl methacrylate for capillary zone
      electrophoresis of proteins.
AB  - This work describes further improvements of coating fused silica capillaries with
      2-hydroxyethyl methacrylate (HEMA) by atom transfer radical polymerization
      (ATRP). First, endcapping with a sterically less bulky silanyl reagent reduces
      the electrosmotic flow (EOF) by 25% in addition to the 40% EOF reduction caused
      by HEMA coating compared to a bare fused silica capillary. An additional
      hydrolysis step was introduced into the preparation of HEMA coated capillaries
      and leads to better reproducible migration times. The influence of the solvent
      during ATRP and the resulting polymer coating was investigated by replacement of
      DMF with water or water-methanol mixtures. The quality of the optimized coating
      was characterized by protein separations at pH 3. HEMA coated capillaries reveal
      up to 746000 plates. The polyvinyl alcohol (PVA) coated capillary provides only
      half of this efficiency. A long-term test at pH 9 shows good stability of the
      HEMA coated capillaries in basic medium. Also the numbers of plates in this
      medium was about 30% higher than for separations with the PVA capillary. In
      addition, the phosphate buffer was replaced by a volatile ammonium acetate buffer
      for later use with mass spectrometry (MS).

PMID- 15026009
TI  - General method allowing the use of 100% aqueous loading conditions in reversed
      phase liquid chromatography.
AB  - Reversed-phase HPLC purification of peptides, using n-alkyl modified spherical
      silica, has become a widely used technique within the pharmaceutical industry.
      One drawback of these materials is the necessity of having at least 5% organic
      modifier in the mobile phase, in order to avoid de-wetting of the porous
      stationary phase. For some preparative reversed-phase separations, it is an
      advantage if the feed solution can be loaded onto the column under 100% aqueous
      conditions. This study describes the use of post-column pressure control to avoid
      de-wetting of regular reversed-phase stationary phases when operated under 100%
      aqueous conditions. The applicability of post-column pressure control as a means
      of maintaining the column fully wetted is demonstrated with various buffers and
      with packing materials having different alkyl-chain lengths. Two peptides,
      insulin and oxytocin, in overloaded quantities, were loaded under 100% aqueous
      conditions onto a regular C8 column, and then eluted by a acetonitrile gradient
      following standard procedures. The retention volume and the peak shape showed
      that the separation was satisfactory, and proved that post-column pressure
      control can be used to overcome wettability problems, which are otherwise often
      observed for reversed-phase packing materials with high ligand density.

PMID- 15026010
TI  - Mass spectrometric strategy for primary structure determination of N-terminally
      blocked peptides.
AB  - The mass spectrometric strategy including three steps is presented for primary
      structure determination of the N-terminally blocked peptides. First, the C
      terminal sequencing is performed by using matrix-assisted laser
      desorption/ionization (MALDI) mass spectrometry coupled with carboxypeptidase Y
      digestion. Then, the peptide is cleaved according to the obtained C-terminal
      sequence information and the resulting peptides are identified by mass
      spectrometry and Edman degradation after fractionation by reverse-phase
      chromatography. Finally, the N-terminal fragment is sequenced by tandem mass
      spectrometry. The strategy was successfully applied to the sequence determination
      of two novel N-terminally blocked peptides named EAFP1 and EAFP2.

PMID- 15026011
TI  - Placenta cryosections for study of the adhesion of Plasmodium falciparum-infected
      erythrocytes to chondroitin sulfate A in flow conditions.
AB  - The adhesion of Plasmodium falciparum-infected erythrocytes (IEs) to chondroitin
      4-sulfate (CSA) via the PfEMP1-CSA parasite ligand domain is correlated with
      placental malaria in primigravidae. The recent identification of parasite genes
      encoding CSA adhesion molecules and the development of pan-reactive monoclonal
      antibodies against the Pf(CSA) ligand have opened up new avenues for the
      development of anti-IE sequestration therapies for the prevention of placental
      malaria. A model closely mimicking placental sequestration of IEs during
      pregnancy is needed for the preclinical and clinical evaluation of candidate
      molecules for the induction of antibodies that could protect pregnant women from
      placental malaria. We found that normal placenta cryosections were a specific and
      highly consistent support for the binding of IEs to CSA in flow conditions under
      physiological conditions. This model makes possible the quantitative and
      qualitative analysis of IE adhesion. We identified distinct CSA-binding
      phenotypes within the FCR3(CSA)-selected parasites in flow analyses, but not in
      static analyses. We also analyzed inhibitors of placental parasite binding such
      as soluble CSA and antibodies directed against the Pf(CSA) ligand. Our data
      demonstrate that placenta cryosections could be used to standardize assays
      between laboratories, potentially advancing the development of therapies against
      placental malaria.

PMID- 15026013
TI  - T cell subpopulations mediating inhibition of feline immunodeficiency virus
      replication in mucosally infected cats.
AB  - Feline immunodeficiency virus (FIV) infection induces an increase in two
      subpopulations (CD8alpha(+)beta(low) and CD8alpha(+)beta(-)) within CD8(+)
      peripheral blood lymphocytes (PBLs) of cats. It is known that depletion of CD8(+)
      cells often results in augmentation of FIV proliferation in PBL culture,
      similarly to the case of human immunodeficiency virus. In this study, we
      attempted to define PBL subpopulations mediating antiviral activity in five cats
      intravaginally infected with a molecularly cloned FIV isolate. Several
      subpopulations (CD8alpha(+)beta(+), CD8alpha(+)beta(-), and CD4(+) cells) were
      shown to participate in inhibition of the FIV replication, at least in part, in a
      major histocompatibility complex-unrestricted manner. Moreover, the
      subpopulations showing anti-FIV activity were different among the individual
      cats.

PMID- 15026012
TI  - Neuromodulation of experimental Shigella infection reduces damage to the gut
      mucosa.
AB  - Bacillary dysentery arises when Shigella invades the colonic and rectal mucosae
      of the human gut and elicits a strong inflammatory response, which may lead to
      life-threatening complications. Hence, downregulation of the host inflammatory
      response is an appealing therapeutical alternative. The gastrointestinal tract is
      densely innervated, and nerve endings are often found in the vicinity of
      leukocytes. We have assessed the impact of experimental Shigella infection on
      levels of neuropeptides in the intestinal mucosa of rabbits. Ligated small
      intestinal loops were created in rabbits, and either live, pathogenic Shigella
      flexneri, a nonpathogenic mutant of Shigella, or NaCl was injected into the
      loops. Infection was allowed to proceed for 8 or 16 h, after which the rabbits
      were sacrificed and intestinal biopsies collected. Tissue destruction, fluid
      secretion and degree of bacterial invasion were monitored. Intestinal biopsies
      were homogenized, and levels of the neuropeptides calcitonin gene-related
      peptide, substance P, peptide YY (PYY), vasoactive intestinal peptide,
      somatostatin, galanin, motilin and neurotensin were measured by radioimmunoassay.
      Loops exposed to invasive Shigella had 5.7 times lower levels of PYY (P = 0.0095)
      than loops exposed to NaCl, after 16 h of infection. The levels of the other
      neuropeptides tested were unchanged. Inhibition of nicotinic cholinergic
      neurotransmission partly protected the intestinal mucosa from destruction
      elicited by invasive Shigella. These findings indicate that a tissue-invasive
      bacterium such as Shigella, which is strictly localized to the intestinal mucosa,
      activates intramural nerve reflexes that presumably involve a nicotinic synapse
      as well as the neuropeptide PYY.

PMID- 15026014
TI  - Genetic characterization of the Guinea-Bissau family of Mycobacterium
      tuberculosis complex strains.
AB  - In a previous study of Mycobacterium tuberculosis complex isolates from Guinea
      Bissau in West Africa, we identified a unique group of strains, designated here
      as the Guinea-Bissau family of strains, which, although genotypically closely
      related, phenotypically demonstrated a considerable heterogeneity. We conducted
      here a detailed genotypic analysis of a subset (n = 35) of these isolates. Based
      on the data obtained, and by comparison of known corresponding genes in
      mycobacteria outside the M. tuberculosis complex, we propose that the Guinea
      Bissau strains belong to a unique branch of the M. tuberculosis complex tree in
      between classical M. tuberculosis and classical M. bovis. These observations are
      discussed in their significance in M. tuberculosis complex classification.

PMID- 15026016
TI  - Genomic-scale analysis of Pasteurella multocida gene expression during growth
      within liver tissue of chickens with fowl cholera.
AB  - We have recently reported the gene expression profile of Pasteurella multocida
      during growth in the blood of chickens with fowl cholera. Here we report the gene
      expression profile of P. multocida during growth in the livers of similarly
      infected chickens. We compared expression profiles of bacteria harvested from the
      livers of infected chickens with late-stage fowl cholera with those of bacteria
      grown in rich medium. Independent analysis of bacterial expression profiles from
      three individual chickens indicated that 93 P. multocida genes were always
      differentially expressed during growth in liver tissue. Of these 93 genes, 49
      were upregulated and 44 downregulated in the host. Many of the upregulated genes
      were involved in energy production and conversion (9/49) and carbohydrate
      transport and metabolism (8/49), and a number of these have been shown to be
      induced under anaerobic conditions in other species. The downregulated genes were
      generally of unknown or poorly characterised functions (14/44). Comparison of the
      differentially regulated gene sets identified for growth in liver with those
      identified previously for growth in blood allowed the identification of a core
      set of 13 upregulated and 16 downregulated genes that were differentially
      regulated in at least five of the six infections studied.

PMID- 15026015
TI  - Genetic analysis of Indian HIV-1 nef: subtyping, variability and implications.
AB  - HIV-1 subtype C is predominant in India and globally. In the present study, we
      analyze HIV-1 subtype C regulatory protein Nef sequences from five recent Indian
      seroconverters and five long-term survivors (LTSs) for variability at crucial
      functional domains. Sequence analysis suggested the possibility of using
      regulatory gene sequences for viral subtyping and evolutionary studies apart from
      structural genes. In the phylogenetic tree, Indian nef sequences segregated away
      from other reported subtype C sequences, forming an Indian subclade within
      subtype C. Our studies also suggested no evidence for the association of
      truncated Nef with slow progression of disease, as all LTSs had intact Nef. We
      could identify some variations in juxtapositions to crucial functional domains,
      especially in seroconverter sequences, when comparing them with others. In
      phylogenetic analysis, specifically for the base-pair regions 411-428 and 478
      525, our seroconverter sequences segregated away from those reported earlier in
      the literature, indicating specific evolutionary changes in these conserved
      regions of nef in currently circulating viruses. But the dN/dS ratio for our
      samples was less than one on comparing them with reported subtype C and
      representative sequences of different clades, strongly emphasizing the necessity
      of sequence conservation at different disease stages and even across clades. HLA
      I binding epitope predictions for common Indian HLAs indicated that specific
      mutations in seroconverter Nef may alter the intensity of epitope binding, which
      may alter the outcome of the immune response. Hence these data would be useful in
      designing Nef epitopes to be included in multi-epitope HIV-1 vaccine for the
      Indian population and would also be of immense help in HIV-1 evolutionary
      studies.

PMID- 15026017
TI  - Lyme borreliosis agents and the genetics and sex of their vector, Ixodes ricinus.
AB  - The tick Ixodes ricinus is responsible for the transmission and maintenance of a
      wide variety of pathogenic organisms in the Northern Hemisphere, among which Lyme
      disease represents a major threat to humans. Despite numerous studies, the
      epidemiology of the different bacterial species responsible for this disease
      remains unclear. Recent evidence for a sex-biased genetic structure of its
      European vector leads us to analyse the consequences of this pattern on Borrelia
      transmission. Here we show that male and female ticks are not equivalently
      infected by Borrelia burgdorferi, that Borrelia afzelii affects tick migration
      capabilities, especially for the most vagile sex (i.e., male) and that Lyme
      borreliosis agents are consequently vectorised in a much more complex way than
      usually thought. Such results change the epidemiological perception of Lyme
      borreliosis and suggest new co-evolutionary pathways between the ticks and the
      borrelia.

PMID- 15026018
TI  - Don't forget about Streptococcus pyogenes! (comment on Microbes Infect. 5 (2003)
      1329-1335).

PMID- 15026020
TI  - Partitioning of TSE infectivity during ethanol fractionation of human plasma.
AB  - The practice of validating processes for their capacity to inactivate a range of
      non-enveloped and enveloped viruses also provides confidence that plasma products
      will be safe from emerging viral pathogens with known aetiology. Of greater
      concern are diseases of unknown or poorly defined aetiology such as the group of
      neurological diseases collectively called the transmissible spongiform
      encephalopathies (TSEs), or prion diseases, for which the best known human
      disease is Creutzfeldt-Jakob Disease (CJD) and its variant form (vCJD). The goal
      of the current study was to investigate the potential for manufacturing steps
      used in the production of albumin and immunoglobulin products by Kistler
      Nitschmann fractionation, and the utility of nanofiltration of immunoglobulin to
      remove TSE agents. Two different scrapie model systems were used. In the first
      system infectious material used for spiking was scrapie sheep brain homogenate
      with infectivity titres being measured in hamsters. In the second system purified
      scrapie agent was used (PrP fibrils) with Western blot analysis measuring
      reduction in the proteinase K resistant form being used as a measure of removal.
      The data demonstrated substantial removal of the infectious agent by the
      manufacturing process in both model systems although some differences were
      observed in partitioning of the two different infectious materials. The hamster
      infectivity studies were shown to be approximately 1000 fold more sensitive than
      the Western Blot assay. The data from both studies provide added confidence that
      these plasma products are safe with respect to their potential to transmit TSE.

PMID- 15026021
TI  - Detection of O-acetylated Vi polysaccharide of Salmonella enterica subspecies
      typhi by enzyme immunoassay.
AB  - Immunisation with capsular Vi polysaccharide (Vi PS) of Salmonella enterica
      serovar Typhi (S. typhi) protects against typhoid. This protection depends on the
      presence of O-acetyl groups on the Vi PS, which form an immunodominant epitope.
      An antiserum raised against conjugated Vi PS was used as the basis for an
      indirect Enzyme Immunoassay (EIA). The antiserum did not react with
      lipopolysaccharide of five gram negative bacteria including S. typhi. Vi PS from
      three different sources was tested, and all but one of 18 native Vi PS
      preparations had EIA values comparable to a standard Vi PS preparation. The
      sensitivity of the EIA for the detection of O-acetyl groups on Vi PS was compared
      to an NMR spectroscopy assay (Biologicals 28 (2000) 17-24). The EIA distinguished
      between O-acetylated and de-O-acetylated Vi PS preparations. However,
      significantly lower EIA reactivity was observed only for samples which had O
      acetylation levels of 25% or less. This assay should facilitate batch control of
      Vi vaccines.

PMID- 15026022
TI  - Validation of the anthrax lethal toxin neutralization assay.
AB  - A validation of the performance characteristics of a toxin neutralization assay
      is presented. This in vitro assay measures the functional ability of antisera,
      containing antibodies to anthrax lethal toxin, to specifically protect J774A.1
      cells against Bacillus anthracis lethal toxin cytotoxicity. This colormetric
      assay is based upon the reduction of MTT by living cells. Human and rabbit
      antisera produced against anthrax vaccine absorbed (AVA) were used to validate
      the assay. Results showed a high level of repeatability and reproducibility,
      particularly for a bio-assay. Inter-assay variability in absorbance values was
      the most prominent negative finding however, an acceptable level was demonstrated
      with a ratio [neutralization ratio (NR)] of the test serum 50% effective dose
      (ED(50)) to the reference standard ED(50). Accuracy was maintained, even in
      samples with minimal neutralizing capacity, and linearity was noted when sample
      dilutions resulted in accurate prediction of the Y(max)and Y(min). Specificity
      tests demonstrated that normal sera did not have an observable effect on the
      ability of the reference standard to neutralize toxin. The assay remained stable
      against time, temperature, and freeze/thaw effects on the reference standards,
      but not on the toxin. The assay also remained stable against media and solution
      storage effects. Cell passage number and cell plating density were two critical
      parameters identified during the robustness studies that may be responsible for
      inter-assay variability in absorbance values. The work was performed in
      accordance with the FDA's Bioanalytical Method Validation Guidance for Industry
      and the FDA's Good Laboratory Practice for Nonclinical Laboratory Studies (21 CFR
      Part 58).

PMID- 15026023
TI  - Verification of components of acellular pertussis vaccines that have been
      distributed solely, been in routine use for the last two decades and contributed
      greatly to control of pertussis in Japan.
AB  - An ideal acellular pertussis vaccine is now under investigation worldwide. We
      have had acellular pertussis vaccines available for the last 22 years, which
      contributed greatly to the control of pertussis in Japan, although it has not
      been known whether they are one of ideal acellular pertussis vaccines or not.
      Moreover, the formulations of acellular pertussis vaccines that we have been
      using have not been widely recognized. Serum samples were taken from recipients
      of the T type, B type, and two-component acellular pertussis vaccine and assayed
      by ELISA for anti-PT, anti-FHA, and anti-69 kD OMP antibody levels and by the
      agglutination test. Although it was shown that T type vaccine contained four
      components (PT, FHA, 69 kD OMP, agglutingen), B type vaccine contained three
      components (PT, FHA, 69 kD OMP) and the two-component vaccine contained PT and
      FHA, it was concluded that PT and FHA were essential and common antigens
      contained in all three acellular pertussis vaccines in Japan. The national
      monitoring system for adverse effects of routine immunization demonstrated low
      reactogenicity of DTaP in Japan. This resulted in high acceptance rates of DTaP
      and in virtual control of pertussis.

PMID- 15026024
TI  - Human serum inactivates non-glycosylated but not glycosylated granulocyte colony
      stimulating factor by a protease dependent mechanism: significance of
      carbohydrates on the glycosylated molecule.
AB  - It has previously been reported that the biological activity of the human
      hematopoetic cytokine granulocyte colony stimulating factor (G-CSF) was reduced
      following incubation with human serum. The mechanism of action of serum has
      remained elusive although a number of possible mechanisms have been suggested
      including inactivation due to binding to the serum protein alpha(2)-macroglobulin
      (alpha(2)M) and degradation by serum proteases. The aim of this study was to
      clarify the conditions required by serum to reduce the biological activity of the
      cytokine and to define the mechanism involved. It has also been noted that G-CSF
      obtained from a CHO expression system (and therefore considered a glycosylated
      molecule) was resistant to serum inactivation unlike G-CSF obtained from an E.
      coli expression system (considered to be non-glycosylated). We used an enzymatic
      approach to remove the carbohydrate residues from glycosylated G-CSF and tested
      this material for its stability in serum. We additionally used a mutated G-CSF
      lacking glycosylation sites. We concluded that glycosylation was important in
      protecting against serum inactivation. We observed that serum reduced the
      biological activity of non-glycosylated G-CSF in a dose, and temperature
      dependent manner and deduced that the mechanism of action was dependent upon
      alpha(2)M bound serum protease enzymes.

PMID- 15026025
TI  - A freeze-dried fibrin disc as a biodegradable drug release matrix.
AB  - A fibrin clot loaded with soluble tetracycline (TET) was prepared and lyophilized
      to make discs of a size and shape to use as a drug delivery matrix. On
      subcutaneous implantation of these discs in mice, they were found to have
      degraded in 15 days as evidenced by gross and histological examination. The in
      vitro discharge kinetics of tetracycline from the disc into phosphate buffered
      saline (PBS) and human serum were compared. It was observed that the release rate
      of tetracycline from the matrix into serum remained steady from day 1 to day 12,
      maintaining sufficient concentration that may be required to control microbial
      growth in the medium. Two different concentrations of fibrinogen were used to
      fabricate discs denoted as FG200 and FG100, and in both cases the retention rate
      was comparable when the study medium was serum. In contrast, when suspended in
      PBS instead of serum, the delivery of the drug into the medium was found to be
      high for up to the 3rd day when a sharp decline in discharge was observed. The
      fibrinogen used is a factor that determines not only the longevity of discharge
      but also fibrinolysis. The degradation of the disc in vitro was visible when the
      discs were suspended in the buffer, and correspondingly fibrin degradation
      product (FDP) measured in the medium using an antibody-based assay system was
      high. Fibrin disc is haemostatic and biodegradable in vivo, and in vitro release
      of a small molecule at a controlled rate is demonstrated here. Hence, it may be a
      suitable candidate as a drug delivery implant for short-term use.

PMID- 15026026
TI  - Mitogenic activity of Cratylia mollis lectin on human lymphocytes.
AB  - The mitogenic effect of Cratylia mollis seed lectin preparations containing two
      (Cramoll 1,4) or one molecular form (Cramoll 1) showed activity similar to the
      well known T-cell mitogen, concanavalin A (Con A). The effect on human
      lymphocytes was analyzed through a colorimetric assay using 3-(4,5
      dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). Inhibition of
      lymphocyte proliferation with methyl-alpha-d-mannoside (both preparations)
      indicated that the mitogenic effect involved carbohydrate lectin binding sites.

PMID- 15026027
TI  - Endothelium-dependent hyperpolarizations: the history.
AB  - Endothelial cells control the tone and the growth of the underlying vascular
      smooth muscle by releasing Nitric Oxide (NO). This introduction summarizes the
      early experiments which first suggested and then demonstrated the existence of an
      alternative pathway, endothelium-dependent hyperpolarization. It reviews why
      endothelium-derived hyperpolarizing factor (EDHF) is not likely to be either NO
      or prostacyclin. It sets the stage for the other contributions of this special
      issue devoted to EDHF that will discuss in depth the current knowledge concerning
      endothelium-dependent hyperpolarizations.

PMID- 15026028
TI  - Prostacyclin and endothelium-dependent hyperpolarization.
AB  - Prostacyclin released from the endothelium is capable of relaxing vascular smooth
      muscle. Here, we review the mechanisms underpinning this relaxation, with a focus
      on the role of smooth muscle hyperpolarization. The contribution of endothelium
      derived prostacyclin to overall blood pressure is discussed. The role of
      prostacyclin in determining vasodilation in different vascular beds, especially
      in relation to sex steroid status and in pregnancy, is also discussed.
      Interactions between prostacyclin and other endothelium-derived vasodilators are
      reviewed. The synthetic pathway for prostanoid production, including
      prostacyclin, is upregulated in many diseases and drugs that interfere with this
      pathway are in widespread use. Emerging information suggests that these drugs may
      impact on endothelial prostacyclin production, with less than optimal
      consequences for thrombus formation and vasodilation.

PMID- 15026029
TI  - 14,15-EET analogs: characterization of structural requirements for agonist and
      antagonist activity in bovine coronary arteries.
AB  - Arachidonic acid metabolites contribute to the regulation of vascular tone and
      therefore tissue blood flow. The vascular endothelium metabolizes arachidonic
      acid by cytochrome P450 epoxygenases to epoxyeicosatrienoic acids or EETs. The
      placement of the epoxide group can occur on any of the double bonds of
      arachidonic acid resulting in four EET regioisomers; 5,6-, 8,9-, 11,12- and 14,15
      EET. In the vasculature, EETs are key components of cellular signaling cascades
      that culminate in the activation of smooth muscle potassium channels to induce
      membrane hyperpolarization and vascular relaxation. In some vasculatures such as
      bovine coronary arteries, EET regioisomers are equipotent in inducing
      relaxations, while in other arteries, a specific EET regioisomer induces
      relaxation while others do not. Therefore, the position of the double bonds
      and/or the epoxide group may alter vascular agonist activity. This observation
      suggests that small alterations in the chemical structure of EETs can
      significantly impact vascular activity. To explore this hypothesis, we
      synthesized a series of EET analogs and characterized their vasodilator agonist
      and antagonist activity in bovine coronary arteries. In this chapter, we first
      review the mechanisms of EET-dependent relaxations in bovine coronary arteries to
      familiarize the reader with the role of EETs in these arteries. The second
      component is a synopsis of the functional characterization of the 14,15-EET
      analogs and the resulting description of structural components required for
      vascular dilator activity. Lastly, we discussed the characterization of three
      14,15-EET analogs with specific EET-antagonist activity and compared this to the
      activity of similar 11,12-EET analogs. These studies have revealed that specific
      structural components of the 14,15-EET molecule are critical for dilator activity
      and that alteration of these components influences agonist activity and may
      confer antagonist properties.

PMID- 15026030
TI  - Cytochrome P450 epoxygenases as EDHF synthase(s).
AB  - The metabolism of arachidonic acid by cytochrome P450 (CYP) epoxygenases
      generates epoxyeicosatrienoic acids (EETs) which affect numerous cellular process
      including Ca(2+) signaling and the activity of Ca(2+)-dependent K(+) channels.
      The expression of the CYP epoxygenase(s) that generate EETs in endothelial cells
      is not constitutive but is determined by a number of physical (fluid shear stress
      and cyclic stretch) and pharmacological stimuli which also affect responses
      attributed to an endothelium-derived hyperpolarizing factor (EDHF). This review
      summarizes the role played by EETs, and the enzymes that generate and metabolize
      them, in EDHF-mediated responses.

PMID- 15026032
TI  - Hydrogen peroxide as an endothelium-derived hyperpolarizing factor.
AB  - Vascular endothelium plays an important role in maintaining vascular homeostasis
      by synthesizing and releasing several vasodilating factors, such as prostacyclin,
      nitric oxide (NO), and a yet unidentified endothelium-derived hyperpolarizing
      factor (EDHF). Possible candidates for EDHF include epoxyeicosatrienoic acids
      (EETs), endothelium-derived potassium ions (K(+)), and as we have recently
      identified, hydrogen peroxide (H2O2). Electrical communication between
      endothelial and smooth muscle cells through gap junctions has also been suggested
      to be involved in endothelium-dependent hyperpolarization. Among the above
      candidates, the H2O2 hypothesis well explains the pathophysiological interactions
      between NO and EDHF and re-highlights the physiological roles of the reactive
      oxygen species (ROS) in endothelium-dependent vascular responses. This brief
      review summarizes our current knowledge about H2O2 as an EDHF, with special
      reference to its production by the endothelium, its action on membrane potentials
      and its pathophysiological roles.

PMID- 15026031
TI  - Potassium and potassium clouds in endothelium-dependent hyperpolarizations.
AB  - A small increase in extracellular K(+) acts as a local, physiological regulator
      of blood flow to certain vascular beds. The K(+) derives from active tissues such
      as contracting skeletal muscle and brain and increases blood supply to these
      organs by the activation of Na(+)/K(+)-ATPases and/or inwardly-rectifying K(+)
      channels on the vascular myocytes. K(+) liberated from the vascular endothelium
      also acts as an endothelium-derived hyperpolarizing and relaxing factor within
      blood vessels. The K(+) effluxes from endothelial cell intermediate- and small
      conductance, Ca(2+)-sensitive K(+) channels which open in response to stretch and
      local hormones. In many vessels, endothelium-derived hyperpolarizing factor
      (EDHF) seems identical to the K(+) derived from endothelial cells; it activates
      Na(+)/K(+)-ATPases (particularly those containing alpha2 and alpha3 subunits) and
      inward rectifiers (particularly Kir2.1) located on the vascular myocytes.
      Vasospastic agents generate "potassium clouds" around vascular smooth muscle
      cells via the efflux of this ion through large conductance, Ca(2+)-sensitive K(+)
      channels on the myocytes. These potassium clouds can reduce the hyperpolarizing
      actions of endothelium-derived K(+) by effectively saturating the Na(+)/K(+)
      ATPases and inward rectifiers on the muscle cells and they may be of clinical
      significance in vasospastic conditions.

PMID- 15026033
TI  - The obligatory link: role of gap junctional communication in endothelium
      dependent smooth muscle hyperpolarization.
AB  - Although an endothelium-derived hyperpolarizing factor (EDHF) has often been
      hypothesized to underpin vascular relaxations that are independent of nitric
      oxide (NO) and prostanoids, bioassay techniques have failed to confirm the
      existence of a freely transferable EDHF in a consistent fashion. Indeed,
      observations that inhibitors of direct cell-cell coupling such as connexin
      mimetic peptides (e.g. Gap 26 and 27) and glycyrrhetinic acid derivatives
      attenuate "EDHF-type" smooth muscle hyperpolarizations and relaxations suggest
      that an electrotonic spread of endothelial hyperpolarization via myoendothelial
      and homocellular smooth muscle gap junctions plays an obligatory role in such
      responses. The endothelial hyperpolarization that initiates relaxation results
      from the opening of K(Ca) channels and is sustained by capacitative Ca(2+) entry
      triggered by the depletion of intracellular Ca(2+) stores in the endoplasmic
      reticulum. EDHF-type relaxations are also associated with a prostanoid
      independent synthesis of cAMP that increases the conductance of gap junction
      channels and enhances the transmission of endothelial hyperpolarization through
      the vascular wall in a permissive fashion. This review will discuss the roles of
      these interacting signalling pathways in the mediation of the EDHF phenomenon.

PMID- 15026034
TI  - EDHF: new therapeutic targets?
AB  - Besides cyclooxygenase and NO-synthase, another distinct endothelial pathway,
      endothelium-dependent hyperpolarization (EDHF), is involved in the relaxation of
      the vascular smooth muscle cells. EDHF has been demonstrated unequivocally in
      various blood vessels from different species, including human, and is likely to
      play an important role in cardiovascular physiology. This alternative pathway
      involves the activation of two populations of endothelial potassium channels, the
      small conductance and intermediate conductance calcium-activated potassium
      channels (SK(Ca) and IK(Ca), respectively). EDHF-mediated responses are clearly
      altered in various pathological conditions (ageing, hypertension,
      atherosclerosis, hypercholesterolemia, heart failure, ischemia-reperfusion,
      angioplasty, eclampsia, diabetes, sepsis). Therapeutic or adjutant interventions
      (angiotensin converting enzyme inhibitors, antagonist of the angiotensin
      receptor, estrogen, omega-3 polyunsaturated fatty acids, polyphenol derivatives,
      potassium and/or calcium intake) can restore these responses, suggesting that the
      improvement of the EDHF pathway contributes to the observed beneficial effect of
      these various substances. However, the improvement or restoration of EDHF
      responses has not been, yet, the direct purpose of any pharmaceutical effort.
      Activating endothelial IK(Ca) and/or SK(Ca) or increasing their expression as
      well as improving myo-endothelial communication, for instance by increasing the
      expression of connexin(s), could become interesting therapeutic targets.

PMID- 15026035
TI  - The synthesis and structure-activity relationships of 3-amino-4-benzylquinolin-2
      ones; discovery of novel KCNQ2 channel openers.
AB  - 3-amino-4-benzylquinolin-2-ones have been identified as a novel class of KCNQ2
      channel openers. Synthesis and SAR is described along with their
      electrophysiological evaluation as activators of the cloned mKCNQ2 channel
      expressed in Xenopus laevis oocytes. The preliminary SAR data suggest the
      importance of both the trifluoromethylsulfonamido group and electron-withdrawing
      substituents on the quinolone nucleus for expression of KCNQ2 channel opening
      properties.

PMID- 15026036
TI  - Discovery and SAR of trisubstituted thiazolidinones as CCR4 antagonists.
AB  - Substituted thiazolidinones were identified as CCR4 antagonists from high
      throughput screening. Subsequent lead optimization efforts resulted in defined
      structure-activity relationships and the identification of potent antagonists
      (compounds 90 and 91) that inhibited the chemotaxis of Th2 T-cells in vitro.

PMID- 15026037
TI  - Evidences for the formation of bisbenzamidine-heme complexes in cell-free
      systems.
AB  - Infrared and colorimetry data suggest that bisbenzamidines connected by various
      rigid or flexible linkers are able to interact with heme in cell-free systems. At
      pH 5.0 the inhibition of formation of beta-hematin could be ascertained by
      infrared spectroscopy whereas at pH 7.0 the interaction yielded insoluble
      complexes for which a sandwich-type structure of stoichiometry 2:1, heme-drug, is
      tentatively proposed.

PMID- 15026038
TI  - Femtosecond time-resolved guanine oxidation in acridine modified alanyl peptide
      nucleic acids.
AB  - Alanyl peptide nucleic acids have been designed to generate linear and rigid
      pairing complexes. Femtosecond time resolved electron transfer dynamics studies
      of alanyl-PNA double strands where both strands contain an intercalated 9-amino-6
      chloro-2-methoxy-acridine in its protonated state reveal a strong similarity to
      nearest neighbor interstrand/intrastrand guanine oxidation in the corresponding B
      DNA fragment. This observation implies that the combined influence of electronic
      couplings and energetic parameters, driving force and reorganization energy, on
      electron transfer dynamics is similar in both structures. With respect to the
      alanyl-PNA structure, this result is consistent with the notion of stacking
      distances in the nucleobase staple similar to the one in B-DNA and thus provides
      additional structural evidence for nucleobase stacking in alanyl-PNA double
      strands.

PMID- 15026039
TI  - Biosynthesis of vitamin B6: direct identification of the product of the PdxA
      catalyzed oxidation of 4-hydroxy-l-threonine-4-phosphate using electrospray
      ionization mass spectrometry.
AB  - PdxA (E.C. 1.1.1.262) catalyzes a key step in the biosynthesis of vitamin B(6):
      the nicotinamide-dependent oxidation of 4-hydroxy-l-threonine-4-phosphate (HTP)
      to a product tentatively identified as 3-amino-1-hydroxyacetone 1-phosphate
      (AHAP). To date, the evidence for the formation of AHAP, while self-consistent,
      has been largely circumstantial, and does not exclude the possibility that the
      actual product of the enzyme-catalyzed oxidation of HTP might be 2-amino-3-oxo-4
      hydroxybutyric acid 4-phosphate which could undergo rapid, non-enzyme-catalyzed
      decarboxylation once released from the protein. Use of negative ion electrospray
      ionization mass spectrometry (ESI-MS) and tandem mass spectrometric analysis (MS
      MS) confirms that AHAP is the product of the PdxA-catalyzed reaction.

PMID- 15026040
TI  - Synthesis of N tau-arylhistidine derivatives via direct N-arylation.
AB  - N(tau)-Aryl-histidine derivatives were synthesized using a modified one-step Cu
      catalyzed coupling of aryl halides and N-acetylhistidine methyl ester. The latter
      is much less reactive than imidazole toward aryl halides. p-Chloroiodobenzene
      coupled with iodine displacement only, whereas m- and p-bromoiodobenzene both
      gave mixtures of bromo- and iodophenyl products.

PMID- 15026041
TI  - Synthesis of a novel intercalator based on 2,2'-binaphthalene bearing
      dimethylammonium groups.
AB  - A novel type of DNA intercalator, 8,8'-bis(dimethylaminomethyl)-2,2'
      binaphthalene (1) based on 2,2'-binaphthalene skeleton, was prepared via
      homocoupling of 7-bromo-1-methylnaphthalene as a key step. The binding ability of
      1 for calf thymus (CT) DNA was evaluated by UV-vis and fluorescence spectroscopic
      titrations and the melting temperature of CT DNA. The apparent association
      constant of 1 with CT DNA was larger than that of ethidium bromide (EB).

PMID- 15026043
TI  - Synthesis, characterization and evaluation of pro-drugs of VLA-4 antagonists.
AB  - A pro-drug strategy to identify orally efficacious VLA-4 antagonists is
      described. Potential pro-drugs were evaluated for their physical chemical
      characteristics and in vitro properties, including solubility, stability,
      permeability and plasma stability. Based on this characterization, promising
      compounds were identified for in vivo pharmacokinetic evaluation. These studies
      resulted in the identification of a pro-drug that exhibited desirable blood
      levels in PK studies in several different species.

PMID- 15026042
TI  - Discovery of N-propylurea 3-benzylpiperidines as selective CC chemokine receptor
      3 (CCR3) antagonists.
AB  - The discovery of novel and selective small molecule antagonists of the CC
      Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3
      benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT(2A)
      receptor. Chiral resolution and exploration of mono- and disubstitution of the N
      propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding
      IC(50)s under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays
      for these compounds ranged from high picomolar to low nanomolar EC(50)s and
      correlated well with antagonist binding IC(50)s.

PMID- 15026044
TI  - Lactams as EP4 prostanoid receptor subtype selective agonists. Part 1: 2
      Pyrrolidinones-stereochemical and lower side-chain optimization.
AB  - A series of 7-[(5R)-substituted 2-oxo-1-pyrrolidinyl]-heptanoic acids were
      prepared, their isomeric purity determined, and pharmacologically evaluated.
      Lactams with affinity for the EP(4) receptor displayed agonist behavior. The
      lower side-chain of the lactam template could be substituted to afford ligands
      (e.g., 17, 24, 30, 31, and 33) of high potency and greater than 1000-fold
      affinity for EP(4) versus the other EP prostanoid receptors.

PMID- 15026045
TI  - Synthesis and evaluation of analogues of S-adenosyl-L-methionine, as inhibitors
      of the E. coli cyclopropane fatty acid synthase.
AB  - Analogues of S-adenosyl-L-methionine were synthesized and evaluated as inhibitors
      of the purified E. coli cyclopropane fatty acid synthase, a model for M.
      tuberculosis cyclopropane synthases that are potential targets for
      antituberculous drugs. Our results show that the presence of the adenosine
      moiety, in the inhibitor, is required for strong binding, but that the sulfonium
      charge is less important. The best inhibitors found were S-adenosyl-l
      homocysteine and its sulfoxides.

PMID- 15026046
TI  - New synthesis of (S)-dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethenedioxy-biphenyl
      2,2'-dicarboxylate by configuration transform.
AB  - (R/S)-4,4'-Dimethoxy-5,6,5',6'-dimethenedioxy-2,2'-di-(4(S)-methyl-oxazoline-1)
      biphenyl has been synthesized from dimethyl-4,4'-dimethoxy-5,6,5',6'
      dimethenedioxy-biphenyl-2,2'-dicarboxylate, and then the diastereoisomer mixture
      was almost fully converted to a single diastereoisomer with S-configuration ((S)
      3) through the key configuration transform promoted by CuI, which was confirmed
      by CD, HPLC and (13)C NMR. The C(2)-symmetric biphenyl, (S)-dimethyl-4,4'
      dimethoxy-5,6,5',6'-dimethenedioxy-biphenyl-2,2'-dicarboxylate was prepared
      easily via the hydrolysis and ester exchange of (S)-3.

PMID- 15026047
TI  - Inhibitory activities against topoisomerase I and II by polyhydroxybenzoyl amide
      derivatives and their structure-activity relationship.
AB  - o-, m-, p-Phenylenediamines having 2,3,4-trihydroxy, 3,4 dihydroxy, and 4
      hydroxybenzoyl moieties were prepared and their inhibitory activities were
      measured against topoisomerase I and II. More hydroxy groups on two aromatic
      rings increased the activities. Bis(trihydroxybenzoyl)-o-phenylenediamide showed
      IC(50)=0.90 and 0.09 microM against topoisomerase I and II, respectively.
      Compounds with hydroxy groups protected by acetyl moiety still had the
      activities. Less hydroxy groups decreased their activities. Benzothiazole
      derivatives also indicated the activities.

PMID- 15026048
TI  - Design and synthesis of macrocyclic inhibitors of phosphatase cdc25B.
AB  - Based on molecular modeling studies, macrocyclic inhibitors of phosphatase cdc25B
      were synthetically derived from steroids. A preliminary SAR for this new template
      was elaborated. A series of compounds shows inhibition of cdc25B in the low
      micromolar range and good selectivity versus other phosphatases. The compounds
      did not show a significant antiproliferative effect in MaTu or HaCaT cells.

PMID- 15026050
TI  - Methanesulfonamide group at position-4 of the C-5-phenyl ring of 1,5
      diarylpyrazole affords a potent class of cyclooxygenase-2 (COX-2) inhibitors.
AB  - The effect of methanesulfonamide (MeSO(2)NH) group on COX-2 inhibitory activity
      of 1,5-diarylpyrazole is described. While this group being at position-4 of the
      N(1)-phenyl ring was found to be ineffective, its installation at position-4 of
      the C-5 phenyl ring offered several potent and selective inhibitors of COX-2 with
      IC(50) as low as 30 nM.

PMID- 15026049
TI  - Tricyclic pyridones as functionally selective human GABAA alpha 2/3 receptor-ion
      channel ligands.
AB  - A series of tricyclic pyridones has been evaluated as benzodiazepine site ligands
      with functional selectivity for the alpha(3) over the alpha(1) containing subtype
      of the human GABA(A) receptor ion channel. This investigation led to the
      identification of a high affinity, functionally selective, orally bioavailable
      benzodiazepine site ligand that demonstrated activity in rodent anxiolysis models
      and reduced sedation relative to diazepam.

PMID- 15026051
TI  - Pi-delocalized beta-carbolinium cations as potential antimalarials.
AB  - Several beta-carboline compounds including natural products and their
      corresponding salts were synthesized and evaluated for antimalarial activity and
      cytotoxicity levels. Quaternary carbolinium cations showed much higher potencies
      than neutral beta-carbolines and a good correlation was observed between pi
      delocalized lipophilic cationic structure and antimalarial efficacy.

PMID- 15026052
TI  - N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thioureas as
      potent vanilloid receptor antagonistic ligands.
AB  - A series of N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butylbenzyl
      thioureas were prepared for the study of their agonistic/antagonistic activities
      to the vanilloid receptor in rat DRG neurons. Their structure-activity
      relationship reveals that there is a space for another hydrophobic binding
      interaction around 2-position in 4-tert-butylbenzyl region. Among the prepared
      derivatives, 6n show the highest antagonistic activity against the vanilloid
      receptor (IC(50)=15 nM).

PMID- 15026053
TI  - Complestatin synthetic studies; the effect of the amino acid configuration on
      peptide backbone conformation in the common western BCD macrocycle.
AB  - The synthesis and structural analysis, involving X-ray crystallographic, nuclear
      magnetic resonance, and computational studies of four diastereomers of the common
      western BCD diarylether macrocycle of the complestatins, a family of HIV entry
      inhibitors, has been achieved exploiting a ruthenium-promoted intramolecular
      S(N)Ar reaction. The stereogenicity of the individual phenylglycines (residues C
      and D) results in remarkable effects on the backbone conformation.

PMID- 15026054
TI  - Meridianins, a new family of protein kinase inhibitors isolated from the ascidian
      Aplidium meridianum.
AB  - Meridianins are brominated 3-(2-aminopyrimidine)-indoles which are purified from
      Aplidium meridianum, an Ascidian from the South Atlantic (South Georgia Islands).
      We here show that meridianins inhibit various protein kinases such as cyclin
      dependent kinases, glycogen synthase kinase-3, cyclic nucleotide-dependent
      kinases and casein kinase 1. Meridianins prevent cell proliferation and induce
      apoptosis, a demonstration of their ability to enter cells and to interfere with
      the activity of kinases important for cell division and cell death. These results
      suggest that meridianins constitute a promising scaffold from which more potent
      and selective protein kinase inhibitors could be designed.

PMID- 15026055
TI  - The design and preparation of metabolically protected new arylpiperazine 5-HT1A
      ligands.
AB  - New arylpiperazines related to buspirone, gepirone and NAN-190 were designed and
      screened in silico for their 5-HT(1A) affinity and potential sites of metabolism
      by human cytochrome p450 (CYP3A4). Modifications to these structures were
      assessed in silico for their influence on both 5HT(1A) affinity and metabolism.
      Selected new molecules were synthesized and purified in a parallel chemistry
      approach to determine structure activity relationships (SARs). The resulting
      molecules were assessed in vitro for their 5HT(1A) affinity and half-life in a
      heterologously expressed human CYP3A4 assay. Molecular features responsible for 5
      HT(1A) affinity and CYP3A4 stability are described.

PMID- 15026056
TI  - Small molecule biaryl FSH receptor agonists. Part 1: Lead discovery via encoded
      combinatorial synthesis.
AB  - High-throughput screening of two million compounds in 37 distinct encoded
      combinatorial libraries using FSH receptor transfected cells provided small
      molecule agonists such as 1 (EC(50)=3 microM) and 2 (EC(50)=3.9 microM), based on
      which a focused combinatorial library with a total of 31372 compounds was
      designed, synthesized, and screened to reveal 72 novel biaryl FSH receptor
      agonists such as 8a-c as well as a unique combinatorial SAR.

PMID- 15026057
TI  - Small molecule biaryl FSH receptor agonists. Part 2: Lead optimization via
      parallel synthesis.
AB  - Potent small molecule biaryl diketopiperazine FSH receptor agonists such as 10c
      (EC(50)=13 nM) and 11f (EC(50)=1.2 nM) were discovered through the design,
      synthesis and evaluation of three biaryl diketopiperazine optimization libraries
      with over 300 compounds. These libraries were prepared via solid-phase parallel
      synthesis using a cyclization-release method.

PMID- 15026059
TI  - Betuligenol derivative with growth inhibition and antifeedant activity.
AB  - The title chiral amine, 3-(4-methoxyphenyl)-1-methylpropylamine 5 has been
      synthesized from naturally abundant betuligenol 1 in three steps and also in good
      yield. Furthermore, the versatile intermediate 3 could be manipulated for the
      preparation of chiral disulphide 7. The amine derivative 5 prepared from (-)
      betuligenol showed significant growth inhibition and antifeedant activity.

PMID- 15026058
TI  - Differentiation of in vitro transcriptional repression and activation profiles of
      selective glucocorticoid modulators.
AB  - The SAR at C-5 of the 10-methoxy-2,2,4-trimethylbenzopyrano[3,4-f]quinoline core
      leading to identification of (-) anti 1-methylcyclohexen-3-yl as the optimum
      substituent that imparts minimal GR mediated in vitro transcriptional activation
      while maintaining full transcriptional repression is described. The in vitro
      profile of these candidates in human cell assays relevant to the therapeutic
      window of glucocorticoid modulators is outlined.

PMID- 15026060
TI  - Synthesis and anti-inflammatory activity of some [4,6-(4-substituted aryl)-2
      thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetic acid derivatives.
AB  - A series of [4,6-(substituted aryl)-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]
      acetic acid (4a-r) has been synthesized by the base catalyzed condensation of
      beta-aroylpropionic acid, thiourea with aldehyde in ethanol. Structures of the
      new compound were established on the basis of (1)H NMR and IR spectral data. Anti
      inflammatory activity in vivo were evaluated and compared with standard drug
      diclofenac sodium. Some compounds have shown moderate activity.

PMID- 15026061
TI  - The inhibition of metallo-beta-lactamase by thioxo-cephalosporin derivatives.
AB  - The 8-thioxocephalosporins are poor substrates for the B. cereus metallo beta
      lactamase (k(cat)/K(m)=61.4M(-1) s(-1)) and act as weak competitive inhibitors
      (K(i) approximately 700 microM). The hydrolysis product of thioxocephalosporin, a
      thioacid, also inhibits the enzyme competitively with a K(i)=96 microM, whereas
      the cyclic thioxo-piperazinedione, formed by intramolecular aminolysis of
      thioxocephalexin has a K(i) of 29 microM.

PMID- 15026062
TI  - Carbazates as potent inhibitors of hormone-sensitive lipase.
AB  - The central role of adipose tissue hormone-sensitive lipase in regulating fatty
      acid metabolism makes it a potential pharmacological target for the prevention of
      peripheral insulin resistance in obese, prediabetic and diabetic individuals. The
      synthesis of a new series of carbazates is presented. Modification of the
      phenolic 4-position in a series of 1,2,3,4-tetrahydroisoquinoline and morpholine
      derived carbazates, yielded inhibitors of the catalytic activity of this enzyme
      with nanomolar potency.

PMID- 15026063
TI  - 6-aryl-2,4-dioxo-5-hexenoic acids, novel integrase inhibitors active against HIV
      1 multiplication in cell-based assays.
AB  - A series of 6-aryl-2,4-dioxo-5-hexenoic acids, were synthesized and tested
      against HIV-1 in cell-based assays and against recombinant HIV-1 integrase (rIN)
      in enzyme assays. Compound 8a showed potent antiretroviral activity (EC(50)=1.5
      microM) and significant inhibition against rIN (strand transfer: IC(50)=7.9
      microM; 3'-processing: IC(50)=7.0 microM). A preliminary molecular modeling study
      was carried out to compare the spatial conformation of 8a with those of L-731988
      (4) and 5CITEP (7) in the IN core.

PMID- 15026064
TI  - Chain-branched 1,3-dibenzylthioureas as vanilloid receptor 1 antagonists.
AB  - A series of chain-branched 1,3-dibenzylthiourea derivatives were synthesized, and
      tested their antagonist activity against vanilloid receptor 1. Chain-branching
      led to a significant change in the mode of action and the potency. (R)-Methyl or
      ethyl-branched 1,3-dibenzylthiourea derivatives showed the most potent antagonist
      activity up to the IC(50) value of 0.05 microM which is 10-fold more potent than
      capsazepine.

PMID- 15026065
TI  - A prodrug approach to COX-2 inhibitors with methylsulfone.
AB  - 2,2-dimethyl-4-phenyl-5-[4-(methylsulfinyl)phenyl]-3(2H)furanone derivatives, 3
      and 6, were shown to be effectively transformed in vivo into the corresponding
      methylsulfone derivatives 1 and 4, when orally administered to rats.
      Pharmacological implications for use of sulfoxide analogues 3 and 6 are discussed
      as prodrugs to potent selective COX-2 inhibitors 1 and 4.

PMID- 15026066
TI  - Synthesis and evaluation of substituted 4-alkoxy-2-aminopyridines as novel
      neuropeptide Y1 receptor antagonists.
AB  - A series of substituted 4-alkoxy-2-aminopyridines 2, which were formally derived
      from neuropeptide Y1 antagonist 1 by replacing the morpholino portion with alkoxy
      groups, were synthesized and evaluated as neuropeptide Y Y1 receptor antagonists.
      Primary structure-activity relationships and identification of potent 4-alkoxy
      derivatives are described.

PMID- 15026067
TI  - Protein-dynamics of the putative HCV receptor CD81 large extracellular loop.
AB  - The human CD81 protein is a likely receptor for the binding of hepatitis C virus
      (HCV) to hepatocytes and therefore a possible target for novel anti-HCV drugs.
      The two published X-ray structures of the HCV binding region of CD81 (1G8Q and
      1IV5) have, particularly in a substructure that is formed by two helices, a
      slightly different conformation. The abovementioned substructure is a candidate
      target region for virtual screening approaches. We present here a molecular
      dynamics study of the two X-ray structures. Our results indicate that the
      conformation of the two helical regions in one of the X-ray structures (1G8Q) is
      affected by crystallographic contacts and most likely does not represent the
      native state of the protein.

PMID- 15026068
TI  - N-acyl substituted 7-amino-4-chloroisocoumarin: a peptide degradation model via
      an imide mechanism.
AB  - During the coupling reaction between 3-alkoxy-7-amino-4-chloroisocoumarin and N
      acyl alanine dipeptide, an unexpected deamidation reaction was observed. The
      proposed mechanism for this reaction involved the formation of an imide
      intermediate which after cleavage led to the release of amino acid moiety. The
      described deamidation reaction represents the first chemical model involving a
      non-peptidic moiety, which mimics biological and chemical deamidation processes
      occurring in proteins or peptides incorporating an asparagine or a glutamine
      residue.

PMID- 15026069
TI  - Synthesis and nicotinic acetylcholine receptor binding affinities of 2- and 3
      isoxazolyl-8-azabicyclo[3.2.1]octanes.
AB  - A series of epiboxidine homologues, 2- and 3-isoxazole substituted 8
      azabicyclo[3.2.1]octane derivatives was synthesized and evaluated as potential
      ligands for neuronal nicotinic acetylcholine receptors in [(3)H]cytisine labeled
      rat brain. The 2beta-isoxazolyl-8-azabicyclo[3.2.1]octane 9b (K(i)=3 nM) was the
      most potent compound of the series with a binding affinity twice that of
      nicotine. The 3beta-isoxazolyl-8-azabicyclo[3.2.1]octane 15b (K(i)=148 nM)
      exhibited moderate affinity while the corresponding 2alpha- and 3alpha-isomers
      exhibited micromolar binding affinity.

PMID- 15026070
TI  - Different hydroxyl radical scavenging activity of water-soluble beta-alanine C60
      adducts.
AB  - Three C(60) derivatives [C(60) (NHCH(2)CH(2)COONa)(n)(H)(n)], n=1, 5, 9] (A, B,
      C) with different additional number of beta-alanine were synthesized by the
      control of relative amount of C(60) and beta-alanine added. Hydroxyl radical
      scavenging activity of the adducts was evaluated in a copper-catalyzed Haber
      Weiss reaction by chemiluminescence technology. The 50% inhibition concentrations
      (IC(50)'s) of A, B, and C were 147.2 micromol/L, 76.3 micromol/L, and 96.2
      micromol/L, respectively. The difference should be closely related to the numbers
      of residual C=C bonds in C(60), steric effect and electron-withstanding effect of
      amino group especially.

PMID- 15026071
TI  - Cyclodextrin trimers as receptors for arranging ester and catalyst at optimized
      location to achieve enhancement of hydrolytic activity.
AB  - Two novel trimer receptor molecules (AC and AD trimers) consisting of two alpha
      cyclodextrins (alpha-CDs) and one beta-cyclodextrin (beta-CD) have been designed
      and synthesized in order to make an optimum arrangement between a substrate and a
      catalyst. In the reaction systems that use trimer receptors as host molecules,
      the substrate and the catalyst are thought to be accommodated by two alpha-CDs
      and one beta-CD, respectively. The rate for the hydrolytic reaction of a long
      shaped ester was largely increased, when the trimer receptors were used as
      receptor molecules or molecular flasks, which provided optimum location between
      the substrate and the catalyst.

PMID- 15026072
TI  - Synthesis and stability studies of phosphonoformate-amino acid conjugates: a new
      class of slowly releasing foscarnet prodrugs.
AB  - Prodrugs of phosphonoformic acid (PFA), an anti-viral agent used clinically as
      the trisodium salt (foscarnet), are of interest due to the low bioavailability of
      the parent drug, which severely limits its utility. Neutral PFA triesters are
      known to be susceptible to P-C bond cleavage under hydrolytic de-esterification
      conditions, and it was previously found that P,C-dimethyl PFA P-N conjugates with
      amino acid ethyl esters did not release PFA at pH 7, and could not be fully
      deprotected under either acid or basic conditions, which led, respectively, to
      premature cleavage of the P-N linkage (with incomplete deprotection of the PFA
      ester moiety), or to P-C cleavage. Here we report that novel, fully deprotected
      PFA-amino acid P-N conjugates 4 can be prepared via coupling of C-methyl PFA
      dianion 2 with C-ethyl-protected amino acids using aqueous EDC, which gives a
      stable monoanionic intermediate 3 that resists P-C cleavage during subsequent
      alkaline deprotection of the two carboxylate ester groups. At 37 degrees C, the
      resulting new PFA-amino acid (Val, Leu, Phe) conjugates (4a-c) undergo P-N
      cleavage near neutral pH, cleanly releasing PFA. A kinetic investigation of 4a
      hydrolysis at pH values 6.7, 7.2, and 8.5 showed that PFA release was first-order
      in [4a] with respective t(1/2) values of 1.4, 3.8, and 10.6 h.

PMID- 15026073
TI  - Isopropyl amide derivatives of potent and selective muscarinic M2 receptor
      antagonists.
AB  - Low molecular weight amide derivatives were synthesized and evaluated as M(2)
      receptor antagonists for the treatment of Alzheimer's disease. Isopropyl amides
      19 and 31 are highly potent, selective and low molecular weight M(2) receptor
      antagonists with structural features different from our clinical candidate 1.

PMID- 15026075
TI  - Synthesis of methylphenidate analogues and their binding affinities at dopamine
      and serotonin transport sites.
AB  - The rhodium(II)-catalyzed intermolecular C-H insertion of methyl
      aryldiazoacetates with either N-Boc-piperidine or N-Boc-pyrrolidine followed by
      deprotection with trifluoroacetic acid is a very direct method for the synthesis
      of methylphenidate analogues. By using either dirhodium tetraacetate or dirhodium
      tetraprolinate derivatives as catalyst, either the racemic or enantioenriched
      methylphenidate analogues can be prepared. The binding affinities of the
      methylphenidate analogues to both the dopamine and the serotonin transporters are
      described. The most notable compounds are the erythro-(2-naphthyl) analogues
      which display high binding affinity and selectivity for the serotonin
      transporter.

PMID- 15026074
TI  - Syntheses and structure-activity relationship studies of piperidine-substituted
      quinolones as nonpeptide gonadotropin releasing hormone antagonists.
AB  - Syntheses and structure-activity relationships of piperidine-substituted
      quinolones as nonpeptide gonadotropin releasing hormone antagonists are
      described. Some of substituents on the piperidine ring that were investigated
      included a fused phenyl group, a (6R)-trifluoromethyl group, (6S) and (6R)-methyl
      group. This study showed that GnRH binding potency was tolerated by a small group
      at the 6-position of the piperidine, and blocking the 6-position by a
      trifluoromethyl group reduced clearance rate and increased oral bioavailability.

PMID- 15026076
TI  - Efficient and chemoselective N-acylation of 10-amino-7-ethyl camptothecin with
      poly(ethylene glycol).
AB  - A new poly(ethylene glycol) (PEG) conjugate of 10-amino-7-ethyl camptothecin, a
      potent antitumor analogue of camptothecin, has been synthesized and preliminary
      in vivo tests have been performed. Successful chemoselective N-acylation of 10
      amino-7-ethyl camptothecin was accomplished using phenyl dichlorophosphate, a
      coupling reagent used in esterification of alcohols, while other coupling methods
      failed, due to the low nucleophilicity of the amino group in position 10. The
      conjugate was tested against P388 murine leukemia cell lines and resulted
      equipotent to CPT-11, a camptothecin analogue already in clinical use.

PMID- 15026077
TI  - Synthesis of potent sigma-1 receptor ligands via fragmentation of
      dextromethorphan.
AB  - Treatment of dextromethorphan 1 with various alkylating agents followed by base
      treatment led to Hoffman-type elimination reactions to produce a series of
      tricyclic derivatives, 6. These derivatives were characterized in vitro as sigma
      1 receptor ligands.

PMID- 15026078
TI  - Preliminary in vitro studies on two potent, water-soluble trimethoprim analogues
      with exceptional species selectivity against dihydrofolate reductase from
      Pneumocystis carinii and Mycobacterium avium.
AB  - 2,4-Diamino-5-[3',4'-dimethoxy-5'-(5-carboxy-1-pentynyl)]benzylpyrimidine (6) and
      2,4-diamino-5-[3',4'-dimethoxy-5'-(4-carboxyphenylethynyl)benzylpyrimidine (7)
      were synthesized from 2,4-diamino-5-(5'-iodo-3',4'-dimethoxybenzyl)pyrimidine (9)
      via a Sonogashira reaction with appropriate acetylenic esters followed by
      saponification, and were tested as inhibitors of dihydrofolate reductase (DHFR)
      from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma),
      and rat in comparison with the widely used antibacterial agent 2,4-diamino-5
      (3',4',5'-trimethoxybenzyl)pyrimidine (trimethoprim, TMP). The selectivity index
      (SI) for each compound was calculated by dividing its 50% inhibitory
      concentration (IC(50)) against rat DHFR by its IC(50) against Pc, Tg, or Ma DHFR.
      The IC(50) of 6 against Pc DHFR was 1.0 nM, with an SI of 5000. Compound 7 had an
      IC(50) of 8.2 nM against Ma DHFR, with an SI of 11000. By comparison, the IC(50)
      of TMP was 12000 nM against Pc, 300 nM against Ma, and 180000 against rat DHFR.
      The potency and selectivity values of 6 and 7 were not as high against Tg as they
      were against Pc or Ma DHFR, but nonetheless exceeded those of TMP. Because of the
      outstanding selectivity of 6 against Pc and of 7 against Ma DHFR, these novel
      analogues may be viewed as promising leads for further structure-activity
      optimization.

PMID- 15026079
TI  - Selective non-steroidal inhibitors of 5 alpha-reductase type 1.
AB  - The enzyme 5 alpha-reductase (5 alpha R) catalyses the reduction of testosterone
      (T) into the more potent androgen dihydrotestosterone (DHT). The abnormal
      production of DHT is associated to pathologies of the main target organs of this
      hormone: the prostate and the skin. Benign prostatic hyperplasia (BPH), prostate
      cancer, acne, androgenetic alopecia in men, and hirsutism in women appear related
      to the DHT production. Two isozymes of 5 alpha-reductase have been cloned,
      expressed and characterized (5 alpha R-1 and 5 alpha R-2). They share a poor
      homology, have different chromosomal localization, enzyme kinetic parameters, and
      tissue expression patterns. Since 5 alpha R-1 and 5 alpha R-2 are differently
      distributed in the androgen target organs, a different involvement of the two
      isozymes in the pathogenesis of prostate and skin disorders can be hypothesized.
      High interest has been paid to the synthesis of inhibitors of 5 alpha-reductase
      for the treatment of DHT related pathologies, and the selective inhibition of any
      single isozyme represents a great challenge for medical and pharmaceutical
      research in order to have more specific drugs. At present, no 5 alpha R-1
      inhibitor is marketed for the treatment of 5 alpha R-1 related pathologies but
      pharmaceutical research is very active in this field. This paper will review the
      major classes of 5 alpha R inhibitors focusing in particular on non-steroidal
      inhibitors and on structural features that enhance the selectivity versus the
      type 1 isozyme. Biological tests to assess the inhibitory activity towards the
      two 5 alpha R isozymes will be also discussed.

PMID- 15026080
TI  - Molecular determinants of ER alpha and ER beta involved in selectivity of 16
      alpha-iodo-7 beta estradiol.
AB  - The two known estrogen receptors, ER alpha and ER beta, are hormone inducible
      transcription factors that have distinct roles in regulating cell proliferation
      and differentiation. The natural ligand, 17 beta-estradiol (E2), binds with high
      affinity to both ER alpha and ER beta. However, a close analogue, 16 alpha-iodo
      17 beta-estradiol (16 alpha IE2) showed about 10-fold selectivity for ER alpha
      over ER beta. From X-ray studies, it has been shown that the ligand-binding
      domains (LBD) of the two receptors are strikingly similar, and that only two
      changes fall within the binding cavity (ER alpha Leu384 to ER beta Met336, and ER
      alpha Met421 to ER beta Ile373). To understand the molecular basis for the ER
      alpha selectivity of 16 alpha IE2, mutants and chimeras of ER alpha and ER beta
      were generated, and ligand-binding and transactivation functions were studied.
      The ER alpha Leu384 Met mutant behaved like ER alpha WT in the presence of 16
      alpha IE2; whereas the profile of the ER alpha Met421 Ile mutant was similar to
      that of ER beta WT. The ER beta mutant Ile373 Met behaved like ER alpha with 16
      alpha IE2. The results clearly demonstrate the role of ER alpha Met421 in the ER
      alpha selectivity of 16 alpha IE2.

PMID- 15026081
TI  - Aryl hydrocarbon receptor-mediated inhibition of LNCaP prostate cancer cell
      growth and hormone-induced transactivation.
AB  - LNCaP prostate cancer cells express the aryl hydrocarbon receptor (AhR), and
      treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein
      and an Ah-responsive reporter gene. Similar results were obtained with the
      selective AhR modulator 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF); however,
      TCDD but not 6-MCDF induced degradation of the AhR protein. TCDD and 6-MCDF
      inhibited growth of LNCaP cells, and inhibitory AhR-androgen receptor (AR)
      crosstalk was investigated in cells transfected with constructs containing the
      androgen-responsive probasin promoter (-288 to +28) (pPB) or three copies of the 
      244 to -96 region of this promoter (pARR(3)). Ten nanomolar dihydrotestosterone
      (DHT) and 17 beta-estradiol (E2) induced transactivation in LNCaP cells
      transfected with pPB or pARR(3); however, inhibitory AhR-AR crosstalk was
      observed only with the latter construct. 6-MCDF and TCDD did not inhibit DHT- or
      E2-induced transactivation in ZR-75 human breast cancer cells, indicating that
      these interactions were promoter and cell context-dependent. Both E2 and DHT
      stabilized AR protein in LNCaP cells; however, cotreatment with TCDD or 6-MCDF
      decreased AR protein levels. These results indicate that inhibitory AhR-AR
      crosstalk in prostate cancer cells is complex and for some responses, AR protein
      stability may play a role.

PMID- 15026082
TI  - The proliferative effects of 5-androstene-3 beta,17 beta-diol and 5 alpha
      dihydrotestosterone on cell cycle analysis and cell proliferation in MCF7, T47D
      and MDAMB231 breast cancer cell lines.
AB  - Epidemiological studies suggest that precursor steroids are implicated in the
      aetiology of breast cancer. However, our understanding of the role of precursor
      steroids in breast cancer is complicated by fact that there are many precursor
      steroids, which are metabolically inter-related and have divergent proliferative
      activities on the growth of breast cancer cell lines. In this study the
      proliferative affects of 5 alpha-dihydrotestosterone and 5-androstene-3 beta,17
      beta-diol, which may be considered true metabolites acting at a tissue level, on
      MCF7, T47D and MDAMB231 breast cancer cell lines have been examined by a flow
      cytometric technique. DNA cell cycle analysis demonstrates that 5-androstene-3
      beta,17 beta-diol stimulates the proliferation of hormone-dependent cell lines at
      physiological levels by an oestrogen receptor mediated mechanism whereas 5 alpha
      dihydrotestosterone does not affect the proliferation of MCF7 and T47D cell lines
      at physiological levels over short (48 h) incubations. Both 5 alpha
      dihydrotestosterone and 5-androstene-3 beta,17 beta-diol stimulate proliferation
      of hormone-dependent cell lines at pharmacological levels via and interaction
      with the oestrogen receptor. In long (6-9 days) incubations both 5 alpha
      dihydrotestosterone and 5-androstene-3 beta,17 beta-diol inhibit the 17 beta
      oestradiol induced proliferation of MCF7 and T47D cell lines, however, 5 alpha
      dihydrotestosterone inhibits while 5-androstene-3 beta,17 beta-diol stimulates
      basal proliferation. These cell line studies suggest a model for the role of
      precursor steroids in pre- and postmenopausal breast cancer.

PMID- 15026083
TI  - Effects of environmental estrogenic chemicals on AP1 mediated transcription with
      estrogen receptors alpha and beta.
AB  - There has been much discussion concerning endocrine disrupting chemicals
      suspected of exerting adverse effects in both wildlife and humans. Since the
      majority of these compounds are estrogenic, a large number of in vitro tests for
      estrogenic characteristics have been developed for screening purpose. One
      reliable and widely used method is the reporter gene assay employing estrogen
      receptors (ERs) and a reporter gene with a cis-acting estrogen responsive element
      (ERE). Other elements such as AP1 also mediate estrogenic signals and the manner
      of response could be quite different from that of ERE. Since this has yet to be
      explored, the ER mediated AP1 activity in response to a series of environmental
      estrogens was investigated in comparison with ERE findings. All the compounds
      exhibited estrogenic properties with ERE-luc and their AP1 responses were quite
      similar. These was one exception, however, p,p'-DDT (1,1,1,-trichloro-2,2-bis(p
      chlorophenyl)ethane) did not exert any AP1-luc activity, while it appeared to be
      estrogenic at 10(-7) to 10(-5)M with the ERE action. None of the compounds
      demonstrated ER beta:AP1 activity. These data suggest that significant
      differences can occur in responses through the two estrogen pathways depending on
      environmental chemicals.

PMID- 15026084
TI  - Aging alters the functional expression of enzymatic and non-enzymatic anti
      oxidant defense systems in testicular rat Leydig cells.
AB  - In aged rats, trophic hormone-stimulated testosterone secretion by isolated
      Leydig cells is greatly reduced. The current studies were initiated to establish
      a functional link between excess oxidative stress and the age-related decline in
      steroidogenesis. Highly purified Leydig cell preparations obtained from 5-month
      (young mature) and 24-month (old) Sprague-Dawley rats were employed to measure
      and compare levels of lipid peroxidation, non-enzymatic (alpha-tocopherol,
      ascorbic acid, and reduced/oxidized glutathione) and enzymatic (Cu, Zn-superoxide
      dismutase, Cu, Zn-SOD; Mn-superoxide dismutase, Mn-SOD; glutathione peroxidase-1,
      GPX-1, and catalase, CAT) anti-oxidants. The extent of lipid peroxidation
      (oxidative damage) in isolated membrane fractions was quantified by measuring the
      content of thiobarbituric acid-reactive substances (TBARS) under basal
      conditions, or in the presence of non-enzymatic or enzymatic pro-oxidants.
      Membrane preparations isolated from Leydig cells from old rats exhibited two- to
      three-fold enhancement of basal TBARS formation. However, aging had no
      significant effect on TBARS formation in response to either non-enzymatic or
      enzymatic pro-oxidants. Among the non-enzymatic anti-oxidants, the levels of
      reduced glutathione were drastically reduced during aging, while levels of alpha
      tocopherol and ascorbic acid remained unchanged. Both steady-state mRNA levels
      and catalytic activities of Cu, Zn-SOD, Mn-SOD, and GPX-1 were also significantly
      lower in Leydig cells from 24-month-old rats as compared with 5-month-old control
      rats. In contrast, neither mRNA levels nor enzyme activity of catalase was
      sensitive to aging. From these data we conclude that aging is accompanied by
      reduced expression of key enzymatic and non-enzymatic anti-oxidants in Leydig
      cells leading to excessive oxidative stress and enhanced oxidative damage (lipid
      peroxidation). It is postulated that such excessive oxidative insult may
      contribute to the observed age-related decline in testosterone secretion by
      testicular Leydig cells.

PMID- 15026085
TI  - Endogenous human prolactin and not exogenous human prolactin induces estrogen
      receptor alpha and prolactin receptor expression and increases estrogen
      responsiveness in breast cancer cells.
AB  - Prolactin (PRL) and estrogen act synergistically to increase mammary gland
      growth, development, and differentiation. Based on their roles in the normal
      gland, these hormones have been studied to determine their interactions in the
      development and progression of breast cancer. However, most studies have
      evaluated only endocrine PRL and did not take into account the recent discovery
      that PRL is synthesized by human mammary cells, permitting autocrine/paracrine
      activity. To examine the effects of this endogenous PRL, we engineered MCF7 cells
      to inducibly overexpress human prolactin (hPRL). Using this Tet-On MCF7hPRL cell
      line, we studied effects on cell growth, PRLR, ER alpha, and PgR levels, and
      estrogen target genes. Induced endogenous hPRL, but not exogenous hPRL, increased
      ER alpha levels as well as estrogen responsiveness in these cells, suggesting
      that effects on breast cancer development and progression by estrogen may be
      amplified by cross-regulation of ER alpha levels by endogenous hPRL. The long
      PRLR isoform was also upregulated by endogenous, but not exogenous PRL. This
      model will allow investigation of endogenous hPRL in mammary epithelial cells and
      will enable further dissection of PRL effects on other hormone signaling pathways
      to determine the role of PRL in breast cancer.

PMID- 15026086
TI  - Expression of cytochrome P450scc mRNA and protein in the rat kidney from birth to
      adulthood.
AB  - The expression of cytochrome P450scc, encoded by the CYP11A gene, was
      investigated in the rat kidney from birth to adulthood. In the male and female
      rat kidneys, the corresponding mRNA was detected by semi-quantitative reverse
      transcriptase and polymerase chain reaction (RT-PCR) analysis with specific
      primers, resulting in higher levels of expression during the first 15 days from
      birth. RT-PCR and sequence analysis showed that the P450scc mRNA coding region
      was the same for both kidney and testis, whereas 5'-RACE analysis (rapid
      amplification of cDNA ends) demonstrated that the renal transcription utilizes a
      distal transcription start site (TSS) located 76 b upstream of that used in
      ovarian and testicular P450scc mRNA expression, which is placed 43 b upstream of
      the first ATG. The 5'-UTR sequence of renal P450scc cDNA exactly matched the
      contiguous upstream untranslated region of the gene, suggesting that alternative
      splicing was not involved in the synthesis of this transcript. Northern
      hybridization detected a specific transcript only in the newborn male, but not in
      adult rat kidney, confirming the higher levels of expression in the first days of
      the rat's life. Positive immunodetections of cytochrome P450scc were found in
      renal cortical distal tubules and the results were confirmed by Western blotting
      analysis. As demonstrated by semi-quantitative RT-PCR, the male kidney also
      expresses the messengers corresponding to the steroidogenic acute regulatory
      (StAR) and steroidogenic factor 1 (SF-1) proteins, which are normally required
      for steroidogenesis in steroidogenic tissues, such as gonads and adrenal cortex.
      These studies suggest that the rat kidney has the capability for local steroid
      hormone production, although the physiological significance of the pregnenolone
      eventually produced remains to be established.

PMID- 15026087
TI  - Identification of a novel steroid inducible gene associated with the beta hsd
      locus of Comamonas testosteroni.
AB  - Comamonas testosteroni is a soil bacterium, which can use a variety of steroids
      as carbon and energy source. Even if it can be estimated that the complete
      degradation of the steroid nucleus requires more than 20 enzymatic reactions, the
      complete molecular characterization of the genes encoding these steroid
      degradative enzymes as well as the genetic organization of them remain to be
      elucidated. We have previously reported the cloning and nucleotide sequence of
      two steroid-inducible genes, beta hsd and stdC encoding 3 beta-17 beta
      hydroxysteroid dehydrogenase and a hypothetical protein respectively, located in
      both ends of a 3.2kb HindIII fragment. Herein, we report the cloning and
      characterization of another steroid-inducible gene, called sip48 (steroid
      inducible protein), located between these two genes. The analysis of Sip48 amino
      acid sequence predicts a protein of 438 amino acids with a molecular mass of 48.5
      kDa. This protein bears high homology with conserved hypothetical proteins of
      unknown function described in Pseudomonas aeruginosa, Pseudomonas syringae,
      Pseudomonas putida, Burkholderia fungorum, Shewanella oneidensis, Pseudomonas
      fluorescens and Thauera aromatica. The predicted protein shows a typical
      structure of a leader peptide at its N-terminus. A 48.5 kDa protein encoded by
      the recombinant plasmid was detected by SDS-PAGE analysis of in vitro [35S]
      methionine labeled polypeptides. Analysis of gene expression indicates that Sip48
      is tightly controlled at the transcriptional level by several steroid compounds.
      In addition, transcriptional analysis of sip48 and beta hsd in a sip48 mutant
      strain, indicates that both genes are transcribed as a polycistronic mRNA. lacZ
      transcriptional fusions integrated into the chromosome of C. testosteroni
      demonstrate that a steroid-inducible promoter located upstream of sip48 regulates
      the expression of both genes.

PMID- 15026088
TI  - High glucose blocks the effects of estradiol on human vascular cell growth:
      differential interaction with estradiol and raloxifene.
AB  - Because diabetic women appear not to be protected by estrogen in terms of
      propensity to cardiovascular disease, we tested the possibility that chronic
      hyperglycemia modulates the effects of E(2) on vascular cell growth in vitro.
      Human endothelial cells (E304) and vascular smooth muscle cells (VSMC) were grown
      in normal glucose (5.5 mmol/l), high glucose (22 mmol/l) or high manitol (22
      nmol/l; an osmotic control) for 7 days. In endothelial cells glucose per se
      stimulated DNA synthesis. However E(2)- (but not RAL-) stimulated [3H] thymidine
      incorporation was attenuated in the presence of high glucose. In parallel, E(2)
      dependent MAP-kinase-kinase activity was blocked in the presence of high glucose.
      High glucose increased basal creatine kinase (CK) specific activity, but E(2)
      stimulated CK was not significantly impaired in the presence of high glucose. In
      VSMC, high glucose prevented the inhibitory effect of high E(2) (but not of high
      RAL) concentrations on DNA synthesis. High glucose also prevented E(2)-induced
      MAP-kinase-kinase activity. In contrast, while high glucose augmented basal CK,
      the relative E(2)-induced changes were roughly equal in normal and high high
      glucose media. Hence, high glucose blocks several effects of E(2) on vascular
      cell growth, which are mediated, in part, via the MAP-kinase system and are
      likely contributors to E(2)'s anti-atherosclerotic properties. Since RAL's
      estrogen-mimetic effects on human vascular cell growth were independent of MAP
      kinase activation and were not affected by hyperglycemia, the potential use of
      RAL to circumvent the loss of estrogen function induced by hyperglycemia and
      diabetes in the human vasculature should be further explored.

PMID- 15026089
TI  - Comparison of direct observational methods for measuring stereotypic behavior in
      children with autism spectrum disorders.
AB  - We compared partial-interval recording (PIR) and momentary time sampling (MTS)
      estimates against continuous measures of the actual durations of stereotypic
      behavior in young children with autism or pervasive developmental disorder-not
      otherwise specified. Twenty-two videotaped samples of stereotypy were scored
      using a low-tech duration recording method, and relative durations (i.e.,
      proportions of observation periods consumed by stereotypy) were calculated. Then
      10, 20, and 30s MTS and 10s PIR estimates of relative durations were derived from
      the raw duration data. Across all samples, PIR was found to grossly overestimate
      the relative duration of stereotypy. Momentary time sampling both over- and under
      estimated the relative duration of stereotypy, but with much smaller errors than
      PIR (Experiment 1). These results were replicated across 27 samples of low,
      moderate and high levels of stereotypy (Experiment 2).

PMID- 15026091
TI  - Behavioral function effects on intervention acceptability and effectiveness for
      self-injurious behavior.
AB  - A variety of variables have been found to augment perceived social validity of
      behavioral interventions. In the present study, potential effects of behavioral
      function were evaluated. Sixty students inexperienced in work with people with
      mental retardation, and 60 experienced staff watched one of two carefully matched
      acted videos depicting self-injury maintained by attention or escape from task
      demands. Participants were also told whether the self-injury depicted typically
      led to mild or severe consequences for the person filmed. Participants rated six
      interventions in terms of their acceptability and effectiveness for the behavior
      depicted. A hierarchy of acceptability was replicated: reinforcement-based
      procedures were rated as more acceptable and effective. There were also effects
      of behavior severity and rater experience. However, few effects of behavioral
      function were found. Potential implications of staff undifferentiated attitudes
      towards functional treatments are discussed.

PMID- 15026090
TI  - Self concept in people with Williams syndrome and Prader-Willi syndrome.
AB  - This study explored self concepts in matched groups of adolescents and adults
      with Williams syndrome (WS) and Prader-Willi syndrome (PWS), using Damon and
      Hart's semi-structured interview. The main findings were that the WS participants
      were more productive in their responses to the interview, providing more self
      characteristics. The WS group also used more social and psychological categories
      in describing their self concept, and their responses were in general at a higher
      level than the responses for the PWS group. There were significant age-group
      differences, with the adolescents offering more self descriptions that were coded
      as physical and active, whereas the adults gave more social and psychological
      responses. Different themes were emphasized in the interviews from the two
      groups. These themes reflected the distinct phenotypes associated with these
      disorders, the participants life experiences, and their overall attitudes toward
      their syndrome.

PMID- 15026092
TI  - Assessing visual attention in young children and adolescents with severe mental
      retardation utilizing conditional-discrimination tasks and multiple testing
      procedures.
AB  - To effectively reduce overselective attention, a fine-grained analysis of the
      control exhibited by compound training cues is first needed. Computer software
      was developed in this study to administer two different stimulus control-testing
      procedures to assess how three young children of normal development and three
      adolescents with severe mental retardation attended to stimulus compounds when
      conditional-discrimination tasks were provided. One test assessed stimulus
      control by determining response accuracy for each component of the S+ compounds.
      The other testing procedure measured the response topographies of the compound
      stimuli using a touch screen attached to a computer monitor screen. After
      pretraining each stimulus component, all three children attended simultaneously
      to two elements in a conditional-discrimination task with few errors occurring.
      The adolescents with mental retardation eventually attended to both elements
      simultaneously but required more pretraining and exposure to the conditional
      discrimination tasks before simultaneous attention occurred. Since the
      adolescents with severe mental retardation learned to simultaneously attend to
      multiple cues in the conditional-discrimination tasks, this demonstrated that
      restricted attention is not an unmodifiable perceptual characteristic among
      individuals with developmental disabilities. Recording response topographies with
      a touch screen was also discovered to be a sensitive measure of stimulus
      preferences for both groups. Utilizing touch-screen technology may prove to be
      critical for accurately identifying stimulus preferences and contribute to the
      understanding and treatment of overselective attention in students with
      attentional deficits.

PMID- 15026094
TI  - Aging among persons with intellectual disability in Israel in relation to type of
      residence, age, and etiology.
AB  - This study was conducted to compare aging phenomena of persons with intellectual
      and developmental disability (ID) aged 40 years and older living in community
      residence (N = 65) with those living with their families (N = 43) in Jerusalem,
      Israel. All 108 persons and care givers were interviewed to ascertain health
      problems, sensory impairment, activity of daily living (ADL), cognitive skills,
      and leisure activities. Health problem had already developed by age 40 years. The
      most frequent were visual (33%), hearing impairments (20%) and dental problems
      (30%). The community residence group displayed more medical problems, whereas
      individuals living at home had more dental problems. Health problems in persons
      with Down syndrome were significantly higher. ADL functioning for all
      participants was high, but persons with Down syndrome and cerebral palsy had more
      dependence. A decline in functioning in both residential groups was observed
      concerning leisure time, but scores for social life leisure activities were
      better for the community residential group. The data provided in this study can
      serve as information to develop geriatric services for persons with ID and
      provide a basis for comparison with peers in the general population in Israel.
      Dental service to persons with ID living at home should be improved.

PMID- 15026095
TI  - Mindful caregiving increases happiness among individuals with profound multiple
      disabilities.
AB  - Happiness is a critical indicator of quality of life in humans. A few studies
      have measured levels of happiness displayed under different conditions by
      individuals with profound multiple disabilities. We were interested in
      determining whether increasing the mindfulness of caregivers would result in
      increased levels of happiness in adults with these conditions. Using alternating
      treatments embedded within a multiple baseline across caregivers design, we
      measured baseline levels of happiness displayed by three adults with profound
      multiple disabilities when they engaged in leisure activities, each by a
      different pair of caregivers. Then, we taught mindfulness methods to one of each
      pair and measured the levels of happiness displayed by the individuals during the
      8-weeks training for the caregivers. Finally, we measured the levels of happiness
      displayed by the three individuals for 16 weeks following the termination of
      mindfulness training. We found that, regardless of whether the level of happiness
      was initially observed to be high or low in the presence of a caregiver, it
      increased markedly when an individual interacted with a caregiver who received
      training in mindfulness when compared to the control caregiver, who did not
      receive such training. Our study provides evidence that increasing the
      mindfulness of a caregiver can produce a substantial increase in the levels of
      happiness displayed by individuals with profound multiple disabilities.

PMID- 15026093
TI  - Using computer systems as microswitches for vocal utterances of persons with
      multiple disabilities.
AB  - We assessed the effects of two computer systems used as microswitches for the
      vocal utterances of an adolescent and a young adult with multiple disabilities.
      The systems were to respond to three one-syllable utterances of the first
      participant and nine word-like utterances of the second participant by presenting
      favorite stimuli linked to those utterances. The computer system used for the
      first participant relied on a software program developed specifically for this
      study. The computer system used for the second participant combined a new
      software program with a commercially available speech recognition program.
      Results showed that both participants increased the frequencies of their target
      utterances and obtained high levels of stimulation. Positive performance was
      maintained at post-intervention checks. Technical and practical implications of
      the data are discussed.

PMID- 15026096
TI  - The effects of antiepileptic medications on the social skills of individuals with
      mental retardation.
AB  - Prevalence rates of epilepsy are much higher among persons with developmental
      disabilities compared to the general population. Anticonvulsant medication is the
      most common method of treating seizure disorders. Many of these antiepileptic
      medications (AEDs) are associated with various side effects, which may have
      detrimental effects on the social skills of those with developmental
      disabilities. The present study investigated the effects of AEDs on the social
      skills of individuals with mental retardation (MR) residing in an institutional
      facility. The social skills of 130 individuals were assessed by the Matson
      Evaluation of Social Skills for Individuals with sEvere Retardation (MESSIER).
      Sixty-five of these individuals were diagnosed with a seizure disorder and
      received only one AED at the time of this study. These individuals were taking
      one of three AEDs (carbamazepine, valproic acid, or phenytoin). Participants
      belonging to one of these three medication groups were matched with residents for
      age, gender, level of MR and race, who did not have seizures or receive AEDs.
      MESSIER scores of each medication group were compared to its respective control
      group. Those individuals receiving phenytoin presented less positive social
      skills than their matched counterparts in the phenytoin-control group.

PMID- 15026097
TI  - Increased incidence of inflicted traumatic brain injury in children after a
      natural disaster.
AB  - BACKGROUND: The incidence of child abuse following natural disasters has not been
      studied thoroughly. However, parental stress and decreased social support have
      been linked to increased reports of child maltreatment. We hypothesized that a
      large-scale natural disaster (North Carolina's Hurricane Floyd) would increase
      the incidence of inflicted traumatic brain injury (TBI) in young children.
      METHODS: An ecologic study design was used to compare regions affected to those
      regions unaffected by the disaster. Cases of inflicted TBI resulting in admission
      to an intensive care unit or death from September 1998 through December 2001 in
      North Carolina were ascertained. Poisson regression modeling was employed to
      calculate rate ratios of injury for each geographic area by time period. RESULTS:
      Inflicted TBI in the most affected counties increased in the 6 months post
      disaster in comparison to the same region pre-disaster (rate ratio 5.1, 95%
      confidence interval [CI]=1.3-20.4), as did non-inflicted TBI (rate ratio 10.7,
      95% CI=2.0-59.4). No corresponding increased incidence was observed in counties
      less affected or unaffected by the disaster. The rate of inflicted injuries
      returned to baseline in the severely affected counties 6 months post-hurricane;
      however, the rate of non-inflicted injuries appeared to remain elevated for the
      entire post-hurricane study period. CONCLUSIONS: Families are vulnerable to an
      elevated risk of inflicted and non-inflicted child TBI following a disaster. This
      information may be useful in future disaster planning.

PMID- 15026098
TI  - Traumatic deaths during U.S. Armed Forces basic training, 1977-2001.
AB  - BACKGROUND: A Recruit Mortality Registry, linked to the Department of Defense
      Medical Mortality Registry, was created to provide comprehensive medical
      surveillance data for deaths occurring during enlisted basic military training.
      METHODS: Recruit deaths from 1977 through 2001 were identified and confirmed
      through redundant sources. Complete demographic, circumstantial, and medical
      information was sought for each case and recorded on an abstraction form.
      Mortality rates per 100,000 recruit-years were calculated by using recruit
      accession data from the Defense Manpower Data Center. RESULTS: There were 276
      recruit deaths from 1977 through 2001 and age-specific recruit mortality rates
      were less than half of same-age U.S. civilian mortality rates. Only 28% (77 of
      276) of recruit deaths were classified as traumatic (suicide, unintentional
      injury, and homicide), in comparison to three quarters in both the overall active
      duty military population and the U.S. civilian population (ages 15-34 years). The
      age-adjusted traumatic death rates were highest in the Army (four times higher
      than the Navy and Air Force, and 80% higher than the Marine Corps). The majority
      (60%) of traumatic deaths was due to suicide, followed by unintentional injuries
      (35%), and homicide (5%). The overall age-adjusted traumatic mortality rate was
      more than triple for men compared with women in all military services (rate
      ratio=3.9; p=0.01). CONCLUSIONS: There was a lower proportion of traumatic deaths
      in recruits compared to the overall active duty military population and same-age
      U.S. civilian population. This finding could be attributed to close supervision,
      emphasis on safety, and lack of access to alcohol and motor vehicles during
      recruit training.

PMID- 15026099
TI  - Nontraumatic deaths during U.S. Armed Forces basic training, 1977-2001.
AB  - BACKGROUND: A Recruit Mortality Registry, linked to the Department of Defense
      Medical Mortality Registry, was created to provide comprehensive medical
      surveillance data for deaths occurring during enlisted basic military training.
      METHODS: Recruit deaths from 1977 through 2001 were identified and confirmed
      through redundant sources. Complete demographic, circumstantial, and medical
      information was sought for each case and recorded on an abstraction form.
      Mortality rates per 100,000 recruit-years were calculated by using recruit
      accession data from the Defense Manpower Data Center. RESULTS: There were 276
      recruit deaths from 1977 through 2001 and age-specific recruit mortality rates
      were less than half of same-age U.S. civilian mortality rates. The majority (72%)
      of recruit deaths were classified as nontraumatic and 70% of these deaths (139 of
      199) were related to exercise. Of the exercise-related deaths, 59 (42%) were
      cardiac deaths, and heat stress was a primary or contributory cause in at least
      46 (33%). Infectious agents accounted for only 49 (25%) of the nontraumatic
      deaths. Nontraumatic death rates increased with age (rate ratio is 2.5 for 25+ v
      <25 years; p<0.001). The age- and gender-adjusted nontraumatic death rates were
      2.6 times higher for African American than non-African American recruits
      (p<0.001). CONCLUSIONS: Although recruit mortality rates are lower than the same
      age U.S. civilian population, preventive measures focused on reducing heat stress
      during exercise might be effective in decreasing the high proportion of exercise
      related death. The availability of 25 years of comprehensive recruit mortality
      data will permit the ongoing evaluation of cause-of-death trends, effectiveness
      of preventive measures, and identification of emerging threats during basic
      military training.

PMID- 15026100
TI  - Risk behaviors and healthcare coverage among adults by frequent mental distress
      status, 2001.
AB  - BACKGROUND: Given the increased emphasis on chronic diseases in the United
      States, physicians and health survey analysts are now gathering information on
      patients' subjective measures of health, also known as health-related quality-of
      life measures. Studies indicate that these measures can be more powerful
      predictors of chronic disease-related morbidity and mortality than objective
      measures. METHODS: The Behavioral Risk Factor Surveillance System (BRFSS) is an
      ongoing, state-based, random-digit-dialed telephone survey of the non
      institutionalized U.S. population aged 18 years or older. This study examined
      frequent mental distress (FMD), defined as self-reported 14 or more mentally
      unhealthy days in the past 30 days, and its association with adverse health
      behaviors and lack of healthcare coverage. RESULTS: In 2001, approximately 10% of
      adults reported FMD. Persons reporting FMD had a higher prevalence of smoking,
      drinking heavily, physical inactivity, and obesity than did persons without FMD.
      They were also more often without healthcare coverage. In addition, persons with
      FMD were more likely to engage in multiple adverse behaviors than were persons
      without FMD. CONCLUSIONS: Persons reporting FMD are at higher risk of chronic
      diseases because they engage in risky health behaviors and lack healthcare
      coverage. This study provides further support that mental health screening as
      well as physical health screening is important in clinical practice. Further
      research is needed to identify therapeutic or mental health-promoting
      interventions to reduce mental distress and reinforce healthy behaviors.

PMID- 15026101
TI  - Risk to self versus risk to others: how do older drivers compare to others on the
      road?
AB  - BACKGROUND: The objective of this study was to assess the risk of death or
      nonfatal injury drivers aged >/=65 pose to themselves and to other road users as
      compared with drivers in younger age groups. METHODS: Crash-related deaths and
      injuries were separated into two categories: those occurring among the drivers
      themselves, and those occurring among others, such as passengers, bicyclists, or
      pedestrians. RESULTS: The number of deaths among others varied by driver's age,
      with deaths among others decreasing as the driver's age increased. The proportion
      of deaths among others compared with deaths among drivers also varied by age. For
      drivers in the youngest three age groups, about two thirds of the deaths were
      among others (ages 16 to 19, 63.1%; ages 20 to 34, 68.1%; and ages 35 to 59,
      66.6%). This proportion declined with age, reaching a low among drivers aged
      >/=85 years (ages 60 to 74, 52.2%, ages 75 to 84, 37.9%, ages >/=85, 18.9%). When
      calculating deaths among others per 100 million miles driven, crashes among young
      (16 to 19) and older (aged >74) drivers were associated with more deaths to
      others than were crashes among drivers aged 20 to 74. The number of nonfatal
      injuries among others also declined as age of the driver increased. The number of
      injuries among others per 100 million miles driven was highest among the youngest
      (16 to 19) and oldest (>/=85) drivers. CONCLUSIONS: Our findings suggest that
      older drivers make relatively small contributions to crash-related morbidity and
      mortality; moreover, their contributions are generally a result of injuries to
      self rather than to others.

PMID- 15026102
TI  - Impact of an educational program on the safety of high-risk, visually impaired,
      older drivers.
AB  - BACKGROUND: Older drivers (licensed drivers aged 60 years and older) have among
      the highest rates of motor vehicle collision involvement per mile driven of all
      age groups. Educational programs that promote safe driving strategies among
      seniors are a popular approach for addressing this problem, but their safety
      benefit has yet to be demonstrated. The objective of this study was to determine
      whether an individualized educational program that promoted strategies to enhance
      driver safety reduces the crash rate of high-risk older drivers. DESIGN/ SETTING:
      Randomized, controlled, single-masked intervention evaluation at an ophthalmology
      clinic. PARTICIPANTS: A total of 403 older drivers with visual acuity deficit or
      slowed visual processing speed or both who were crash-involved in the previous
      year, drove at least 5 days or 100 miles per week or both, and were at least 60
      years old. INTERVENTION: Patients were randomly assigned to usual care
      (comprehensive eye examination) or usual care plus an individually tailored and
      administered educational intervention promoting safe-driving strategies. MAIN
      OUTCOME MEASURE: Police-reported vehicle collision rate, expressed both in terms
      of person-years of follow-up and person-miles of travel for 2 years
      postintervention. RESULTS: The intervention group did not differ significantly
      from the usual care only group in crash rate per 100 person-years of driving
      (relative risk [RR], 1.08; 95% confidence interval [CI], 0.71-1.64) and per 1
      million person-miles of travel (RR, 1.40; 95% CI, 0.92-2.12). The intervention
      group reported more avoidance of challenging driving maneuvers and self
      regulatory behaviors during follow-up than did the usual care only group
      (p<0.0001). CONCLUSIONS: An educational intervention that promoted safe-driving
      strategies among visually impaired, high-risk older drivers did not enhance
      driver safety, although it was associated with increased self-regulation and
      avoidance of challenging driving situations and decreased driving exposure by
      self-report.

PMID- 15026103
TI  - Binge drinking and health-related quality of life: do popular perceptions match
      reality?
AB  - BACKGROUND: Popular culture (movies, television shows, advertising) often
      portrays drinking to the point of intoxication as either humorous or associated
      with enjoyable social activities that enhance quality of life. This study
      examined the association between binge drinking (consuming five or more alcoholic
      drinks on one occasion) and health-related quality of life (HRQOL) among U.S.
      adults. METHODS: Data are from the Behavioral Risk Factor Surveillance System, a
      continuous random-digit-dial telephone survey of adults aged >/=18 years
      conducted in all states. This survey included questions about alcohol consumption
      and HRQOL. RESULTS: In 2001, 52% of U.S. adults were current drinkers (one or
      more drinks in the past 30 days). Of current drinkers, 11% were frequent binge
      drinkers (three or more episodes in past month) and 14% were infrequent binge
      drinkers (one to two episodes in past month). After adjusting for confounding
      factors, frequent binge drinkers were more likely than non-binge drinkers to
      experience >/=14 unhealthy days (physical or mental) in the past month (adjusted
      odds ratio [AOR]=1.39, 95% confidence interval [CI]=1.24-1.56), primarily because
      they had more mentally unhealthy days than non-binge drinkers (AOR=1.52, 95%
      CI=1.32-1.75). CONCLUSIONS: Frequent binge drinking is associated with
      significantly worse HRQOL and mental distress, including stress, depression, and
      emotional problems. Effective interventions to prevent binge drinking should be
      widely adopted and may help improve quality of life.

PMID- 15026104
TI  - Physician response rates to a mail survey by specialty and timing of incentive.
AB  - BACKGROUND: Historically, achieving a high response rate on physician surveys has
      been a challenging task. Given such concerns, understanding research strategies
      that facilitate adequate response rates is important. Primary care physician
      responses to a mail survey on smoking cessation are summarized by physician
      specialty and timing of incentive. METHODS: A stratified random-sample design,
      stratified by patient populations-adults, adolescents, and pregnant women-was
      used. The sampling frame included New Jersey internists, general practitioners,
      family physicians, pediatricians, and obstetrician-gynecologists. A total of 2100
      physicians, 700 physicians from each patient strata, were sampled and mailed a
      smoking-cessation survey in summer 2002. The sample was randomized by incentive
      timing: Half received the incentive (i.e., 25 dollars gift card) with the first
      survey mailing, and half received the incentive on receipt of their completed
      survey. RESULTS: The promised-incentive group achieved a significantly lower
      response rate (56%) compared with the up-front-incentive group (71.5%). Response
      rates by medical specialty varied overall and within incentive groups. The
      difference between the incentive groups was greatest among obstetrician
      gynecologists (i.e., 20.2 percentage points) and was least among pediatricians
      (i.e., 5.8 percentage points). CONCLUSIONS: Physician response rates to mail
      surveys are greatly improved, especially among certain medical specialties, by
      using up-front incentives.

PMID- 15026105
TI  - Population health technologies: emerging innovations for the health of the
      public.
AB  - At the beginning of the 21st century, we are at the dawn of a possibly
      unprecedented era of scientific discovery and promise. Emerging technologies,
      including information and communication technologies, genomics,
      microelectromechanical systems, robotics, sensors, and nanotechnologies, provide
      enormous opportunities for population health improvement. Population health
      technology refers to the application of an emerging technology to improve the
      health of populations. Emerging technologies present an opportunity for
      addressing global health challenges-in both developed and developing countries.
      Health issues ripe for the application of new technologies include disease
      surveillance and control, environmental monitoring and pollution prevention, food
      safety, health behavior change, self-care, population screening, and chronic
      disease and injury prevention and control. If appropriately applied, population
      health technologies may greatly enhance existing health intervention models.
      However, potential adverse consequences could arise related to privacy,
      confidentiality, and security; quality and effectiveness; sustainability; and the
      technology divide. To ensure the optimal development and diffusion of population
      health technologies will require balancing these risks and benefits while
      simultaneously adopting new mechanisms of public and private support for research
      and development in this potentially important new domain of public health.

PMID- 15026106
TI  - Why population attributable fractions can sum to more than one.
AB  - BACKGROUND: Population attributable fractions (PAFs) are useful for estimating
      the proportion of disease cases that could be prevented if risk factors were
      reduced or eliminated. For diseases with multiple risk factors, PAFs of
      individual risk factors can sum to more than 1, a result suggesting the
      impossible situation in which more than 100% of cases are preventable. METHODS: A
      hypothetical example in which risk factors for a disease were eliminated in
      different sequences was analyzed to show why PAFs can sum to more than 1.
      RESULTS: PAF estimates assume each risk factor is the first to be eliminated,
      thereby describing mutually exclusive scenarios that are illogical to sum, except
      under special circumstances. PAFs can sum to more than 1 because some individuals
      with more than one risk factor can have disease prevented in more than one way,
      and the prevented cases of these individuals could be counted more than once.
      Upper and lower limits of sequential attributable fractions (SAFs) can be
      calculated to describe the maximum and minimum proportions of the original number
      of disease cases that would be prevented if a particular risk factor were
      eliminated. CONCLUSIONS: Improved descriptions of the assumptions that underlie
      the PAF calculations, use of SAF limits, or multivariable PAFs would help avoid
      unrealistic estimates of the disease burden that would be prevented after
      resources are expended to reduce or eliminate multiple risk factors.

PMID- 15026107
TI  - Unnecessary losses: deaths in military recruit training.

PMID- 15026108
TI  - Practical methods for public health practitioners.

PMID- 15026109
TI  - Applied epidemiology elective at the Centers for Disease Control and Prevention,
      1997-2002.

PMID- 15026110
TI  - In response to the 2003, Vol. 25, No. 1 article entitled "Alcohol consumption
      patterns and work-related injuries among Colorado farm residents".

PMID- 15026112
TI  - Endothelin B receptor deficient transgenic rescue rats: a rescue phenomenon in
      the brain.
AB  - Homozygous endothelin B receptor deficiency leads to congenital aganglionosis of
      the gut in rats and mice, equivalent to human Hirschsprung disease. Homozygous
      endothelin B receptor deficient rats (spotting lethal rats, sl/sl) are
      characterized not only by this developmental disorder of the enteric nervous
      system, which limits their life span to 3-4 weeks, but exhibit an increased rate
      of apoptosis in the dentate gyrus compared to wildtype (+/+) rats. Recently,
      endothelin B receptor deficient transgenic rescue rats (sl/sl, tg/tg) were
      created to further investigate the role of the endothelin B receptor in mature
      animals. Linkage of the human dopamine-beta-hydroxylase promoter to the rat
      endothelin B receptor gene and expression of this transgenic construct results in
      normal development of the enteric nervous system. We investigated the expression
      pattern of this transgenic construct in the brain by using reverse transcriptase
      polymerase chain reaction. Unexpectedly, transgene mRNA expression was not
      restricted to the brain stem where adrenergic and noradrenergic nuclei are known
      to be present but, in addition, was also detectable in hippocampus and cortex.
      Using in situ tailing technique, cleaved caspase-3 immunohistochemistry and
      analysis of hematoxylin-eosin-stained serial sections, we found that all studied
      transgenic animals were rescued from the increased rate of apoptosis in the
      dentate gyrus characteristic for non-transgenic sl/sl rats. This finding supports
      our previous observation that the endothelin B receptor might be an important
      regulatory element supporting cellular survival in the hippocampus during
      postnatal development. The endothelin B receptor deficient transgenic rescue rats
      used here are rescued from developmental disorders both in the gut and in the
      brain.

PMID- 15026113
TI  - Marked regional differences of brain human apolipoprotein E expression in
      targeted replacement mice.
AB  - We used three human apolipoprotein (apo) E targeted replacement mouse lines, each
      expressing one of the three common human apoE isoforms to study the pattern of
      apoE expression in the central nervous system (CNS). Immunocytochemistry on brain
      sections from all three lines of targeted replacement mice, wild type mice,
      African green monkeys, and humans show a predominantly glial pattern of apoE
      expression. The levels of human apoE protein in hippocampus and frontal cortex
      were similar between targeted replacement mice and non-demented human tissue.
      Within a given brain region, the levels of apoE were very similar amongst all
      three isoforms, which contrasts sharply with plasma, where apoE2 levels are 16
      fold higher than apoE3 and E4 levels. Across brain regions, cerebellar apoE
      levels were significantly higher than cerebral apoE levels. In conclusion, we
      provide detailed analysis of a human apoE animal model system that recapitulates
      both the pattern and level of apoE expression in non-demented humans. The
      neurobiology of human apoE isoforms can now be studied in both the normal and
      post-injury state, since all apoE regulatory sequences are intact. Finally, the
      differences in apoE levels we observed may explain the regional vulnerability of
      neuronal degeneration in Alzheimer's disease.

PMID- 15026114
TI  - Memory consolidation and reconsolidation of an inhibitory avoidance response in
      mice: effects of i.c.v. injections of hemicholinium-3.
AB  - The immediate post-training i.c.v. administration of hemicholinium-3 (HC-3) (1
      microg), a specific inhibitor of the high-affinity choline uptake (HACU) in brain
      cholinergic neurons, impaired retention test performance of a one-trial step
      through inhibitory avoidance response in adult male CF-1 mice. The effect was
      observed in mice that received a footshock (0.8 mA, 50 Hz, 1 s) on the learning
      trial, and not only 48 h after training, but also 7 days after it. After the
      completion of the retention test at each of the training-test interval that were
      studied, the HACU in the hippocampus of HC-3-treated mice was not significantly
      different from that of saline-injected (1 microl) control groups. Mice that were
      over-reinforced (1.2 mA, 50 Hz, 1 s) on the learning trial, exhibited a high
      retention performance 48 h after training. The immediate i.c.v. injection of HC-3
      (1 microg) after the retention test, that is, after memory reactivation,
      significantly impaired retention performance over 4 consecutive days, whereas the
      saline-injected control group shown a slight, but significant performance
      decrease only at the last retention test. Retention performance was unchanged in
      HC-3-treated mice not undergoing memory reactivation session. These results,
      taken together, indicate that HC-3, not only impaired consolidation, but also
      reconsolidation of an inhibitory avoidance task in mice, suggesting a critical
      participation of central cholinergic mechanisms in both memory processes.

PMID- 15026115
TI  - Intraparenchymal nerve growth factor improves behavioral deficits while
      minimizing the adverse effects of intracerebroventricular delivery.
AB  - Nerve growth factor (NGF) delivered via intracerebroventricular (ICV) infusion
      restores behavioral and biochemical deficits in animal models of cholinergic
      hypofunction. However, ICV infusion of NGF induces an array of adverse events
      including weight loss, thermal hyperalgesia, and Schwann cell hyperplasia. We
      compared ICV administration with three different doses of intraparenchymally
      delivered NGF with cytochrome C infusion serving as a control. The goal of the
      study was to determine whether direct infusion of NGF would result in a more
      restricted topographical distribution of NGF leading to a reduction or
      elimination of the adverse events while still augmenting cholinergic functioning
      sufficiently to restore spatial mnemonic processing. Subsequent to bilateral
      ibotenic acid lesions of the nucleus basalis magnocellularis (NBM), NGF was
      delivered into the lateral ventricle or adjacent to the NBM for 11 weeks.
      Ibotenic acid lesions resulted in reductions in choline acetyltransferase (ChAT)
      activity in the cortex. The highest and medium dose of NGF led to significant
      restoration in ChAT activity on par with ICV infusion. The lowest dose was
      ineffective in altering ChAT activity in any region assayed. Similarly, the two
      highest doses did not alter weight gain, but ICV-NGF led to a significant weight
      loss. Intraparenchymal infusion resulted in a dose-dependent attenuation of the
      development of thermal hyperalgesia. However, the highest dose of
      intraparenchymal NGF induced Schwann cell hyperplasia at the level of the medulla
      and upper cervical spinal cord. ICV-NGF was able to completely restore spatial
      learning and memory as predicted while only the highest intraparenchymal dose was
      able to able to restore the mnemonic deficits. These data suggest that
      intraparenchymal infusion of growth factors may provide a viable delivery method
      in clinical trials using this mode of drug delivery once an optimal dose has been
      established.

PMID- 15026116
TI  - Heparin-binding epidermal growth factor-like growth factor: a component in
      chromaffin granules which promotes the survival of nigrostriatal dopaminergic
      neurones in vitro and in vivo.
AB  - Chromaffin cells can restore function to the damaged nigrostriatal dopaminergic
      system in animal models of Parkinson's disease. It has been reported that a
      protein which is released from chromaffin granules can promote the survival of
      dopaminergic neurones in vitro and protect them against N-methylpyridinium ion
      toxicity. This neurotrophic effect has been found to be mediated by astroglial
      cells and blocked by inhibitors of the epidermal growth factor (EGF) receptor
      signal transduction pathway. Here we report the identification of bovine heparin
      binding EGF-like growth factor (HB-EGF) in chromaffin granules and the cloning of
      the respective cDNA from bovine-derived adrenal gland. Protein extracts from
      bovine chromaffin granules were found to promote the survival of embryonic
      dopaminergic neurones in culture, to the same extent as recombinant human HB-EGF.
      Furthermore, the neurotrophic action of the chromaffin granule extract could be
      abolished by antiserum to recombinant human HB-EGF. We also show that
      intracerebral injection of recombinant human HB-EGF protected the nigrostriatal
      dopaminergic system in an in vivo adult rat model of Parkinson's disease.
      Intracerebral administration of this protein at the same time as a 6
      hydroxydopamine lesion of the medial forebrain bundle was found to spare dopamine
      levels in the striatum and tyrosine hydroxylase-immunopositive neurones in the
      midbrain. This study has found that the main component in chromaffin granules
      responsible for their neurotrophic effect on dopaminergic neurones is HB-EGF.
      Furthermore, HB-EGF has significant protective effects on nigrostriatal
      dopaminergic neurones in vivo, making it a potential candidate for use in the
      treatment of Parkinson's disease.

PMID- 15026118
TI  - Evidence that a major site of expression of the RHO-GTPASE activating protein,
      oligophrenin-1, is peripheral myelin.
AB  - Oligophrenin-1 is a recently discovered Rho-GTPase activating protein, mutation
      of which is associated with X-linked mental retardation. Since little is known
      about the cellular localization of oligophrenin-1 in central and peripheral
      neurons, we investigated its expression by RT-PCR and immunochemical analysis.
      Oligophrenin-1 immunoreactivity was found in glial cells forming myelin sheaths
      in the vagus nerve, sciatic nerve and dorsal roots of guinea-pig, rat and human,
      in chromaffin cells of the adrenal medulla, and in chromaffin cells associated
      with sympathetic ganglia. No immunoreactivity was detected in sympathetic
      neurons, in glial cells surrounding these neurons, in optic nerve or in spinal
      cord myelin. The full length cDNA sequence was determined from guinea-pig sciatic
      nerve. The translated amino acid sequence was 99% identical to the published
      human oligophrenin-1 sequence. Western blotting revealed two protein forms which
      were expressed to different relative extents in different tissues. A 91 kDa form
      was predominant in extracts of sciatic nerve whereas a 36 kDa form was relatively
      more abundant in adrenal medulla and brain. Greater amounts of the full length
      oligophrenin-1 protein occurred in the sciatic nerve of adult rats, compared with
      P2 rats, which reflects the development of myelination. The presence of multiple
      forms does not appear to be due to alternative mRNA splicing since RT-PCR
      products amplified from a variety of tissues were identical and only a single
      mRNA transcript of 7.4 kb was identified by Northern analysis. These findings
      demonstrate that a major site of oligophrenin-1 expression is peripheral myelin.

PMID- 15026117
TI  - Characterisation of matrix metalloproteinases and the effects of a broad-spectrum
      inhibitor (BB-1101) in peripheral nerve regeneration.
AB  - The effect of treatment with a broad-spectrum inhibitor (BB1101) of the matrix
      metalloproteinases (MMPs) on nerve regeneration and functional recovery after
      nerve crush was examined. Drug treatment had no effect on latency but from 63
      days the compound muscle action potential was significantly increased and was no
      different to that in the sham-operated controls at 72 days. Levels of MMP mRNA
      expression, and the localisation and activity of MMP proteins, were examined in
      rats for a 2 month period following a nerve crush injury, and compared with sham
      operated controls. The mRNA of all the MMPs studied was up-regulated by 5-10 days
      after nerve crush, and they remained up-regulated for 40-63 days, except for MMP
      9 which was down-regulated by 10 days. MMP immunoreactivity was localised to
      Schwann cells, macrophages and endothelial cells, and with the exception of
      membrane type 1-MMP (MT1-MMP), it was more intense after nerve crush compared
      with sham-operated controls. Regenerating axons showed immunoreactivity for MMP-2
      and MMP-3. In situ zymography confirmed that the activity of MMPs in the nerve
      was increased following crush but that the activity was greatly reduced in rats
      treated with BB-1101. Thus despite the inhibition of MMPs by BB-1101, the drug
      did not appear to essentially affect nerve degeneration or regeneration following
      nerve crush but that it could be beneficial in promoting the more effective
      reinnervation of muscles possibly by actions at the level of the muscles.

PMID- 15026119
TI  - Rhythmic melatonin secretion does not correlate with the expression of
      arylalkylamine N-acetyltransferase, inducible cyclic amp early repressor, period1
      or cryptochrome1 mRNA in the sheep pineal.
AB  - The pineal gland, through nocturnal melatonin, acts as a neuroendocrine
      transducer of daily and seasonal time. Melatonin synthesis is driven by rhythmic
      activation of the rate-limiting enzyme, arylalkylamine N-acetyltransferase (AA
      NAT). In ungulates, AA-NAT mRNA is constitutively high throughout the 24-h cycle,
      and melatonin production is primarily controlled through effects on AA-NAT enzyme
      activity; this is in contrast to dominant transcriptional control in rodents. To
      determine whether there has been a selective loss of circadian control of AA-NAT
      mRNA expression in the sheep pineal, we measured the expression of other genes
      known to be rhythmic in rodents (inducible cAMP early repressor ICER, the
      circadian clock genes Period1 and Cryptochrome1, as well as AA-NAT). We first
      assayed gene expression in pineal glands collected from Soay sheep adapted to
      short days (Light: dark, 8-h: 16-h), and killed at 4-h intervals through 24-h. We
      found no evidence for rhythmic expression of ICER, AA-NAT or Cryptochrome1 under
      these conditions, whilst Period1 showed a low amplitude rhythm of expression,
      with higher values during the dark period. In a second group of animals, lights
      out was delayed by 8-h during the final 24-h sampling period, a manipulation that
      causes an immediate shortening of the period of melatonin secretion. This did not
      significantly affect the expression of ICER, AA-NAT or Cryptochrome1 in the
      pineal, whilst a slight suppressive effect on overall Per1 levels was observed.
      The attenuated response to photoperiod change appears to be specific to the ovine
      pineal, as the first long day induced rapid changes of Period1 and ICER
      expression in the hypothalamic suprachiasmatic nuclei and pituitary pars
      tuberalis, respectively. Overall, our data suggest a general reduction of
      circadian control of transcript abundance in the ovine pineal gland, consistent
      with a marked evolutionary divergence in the mechanism regulating melatonin
      production between terrestrial ruminants and fossorial rodents.

PMID- 15026120
TI  - Patterns of colocalization of neuronal nitric oxide synthase and somatostatin
      like immunoreactivity in the mouse hippocampus: quantitative analysis with
      optical disector.
AB  - In some brain regions, previous studies reported the frequent coexistence between
      neuronal nitric oxide synthase (nNOS) and somatostatin (SOM). In the hippocampus,
      nNOS and SOM were mainly expressed in GABAergic nonprincipal neurons. Here we
      estimated the immunocytochemical colocalization of nNOS and SOM in the mouse
      hippocampus using the optical disector. Both in the Ammon's horn and dentate
      gyrus, we encountered only a few nNOS-immunoreactive (IR)/SOM-like immunoreactive
      (LIR) neurons. They were mainly located in the stratum oriens of the Ammon's horn
      and in the dentate hilus. The nNOS-IR/SOM-LIR neurons usually showed
      characteristic large somata with thick dendrites, whereas the majority of nNOS
      IR/SOM-negative neurons showed small somata with thin dendrites. Quantitative
      data revealed that the double-labeled cells represented only 4% and 7% of nNOS-IR
      neurons and SOM-LIR neurons, respectively, in the whole area of the hippocampus.
      We also found the laminar and dorsoventral differences in the degree of
      colocalization between nNOS and SOM. The percentages of nNOS-IR neurons
      containing SOM-like immunoreactivity were relatively high in the stratum oriens
      of the ventral CA1 region (24%), stratum lucidum of the dorsal CA3 region (29%)
      and dorsal dentate hilus (32%), but they were quite low in the other layers. On
      the other hand, the percentages of SOM-LIR neurons containing nNOS
      immunoreactivity were somewhat high in the stratum lucidum of the dorsal CA3
      region (19%) and dorsal dentate hilus (28%), whereas they were very low in the
      other layers. Immunofluorescent triple labeling of axon terminals for nNOS, SOM
      and glutamic acid decarboxylase indicated that some nNOS-IR/SOM-LIR neurons might
      be dendritic inhibitory cells. The present results show the infrequent
      colocalization of nNOS and SOM in the mouse hippocampus, and also suggest that
      the double-labeled cells may be a particular subpopulation of hippocampal
      GABAergic nonprincipal neurons.

PMID- 15026122
TI  - Rat nicotinic acetylcholine receptor alpha2beta2 channels: comparison of
      functional properties with alpha4beta2 channels in Xenopus oocytes.
AB  - Rat hippocampal interneurons express diverse subtypes of nicotinic acetylcholine
      receptors (nAChRs), including alpha7- and non-alpha7-containing receptors.
      Although the major subtype of non-alpha7 nAChRs in the hippocampus is thought to
      be composed of alpha4beta2 subunits, the molecular makeup of these non-alpha7
      receptors is likely to be more complicated. Previously, we reported a high level
      of expression of the alpha2 nAChR subunit in individual rat hippocampal CA1
      stratum oriens interneurons. In addition, the non-alpha7 nAChRs from these
      neurons are less sensitive to block by dihydro-beta-erythroidine (DHbetaE; the
      broad spectrum non-alpha7 nAChR antagonist) than that expected for alpha4beta2
      receptors. We studied the functional properties of rat alpha2beta2 channels
      expressed in Xenopus oocytes using two-electrode voltage-clamp, and compared
      these to those properties of the more widely expressed and studied alpha4beta2
      channels. Dose-response curves for both receptor subtypes indicated that there
      are at least two different affinity sites for ACh, the fractional contribution of
      which depended on the ratio of injected RNA. DHbetaE blocked both receptor
      subtypes, although the sensitivity to block of alpha4beta2 channels was
      significantly higher than that for alpha2beta2. Finally, the current-voltage (I
      V) relationship for the alpha2beta2 channels more strongly rectified than for the
      alpha4beta2 channels. These data suggest that functional properties, in
      particular the sensitivity to block by DHbetaE, might be useful indicators to
      differentiate between native alpha4beta2 and alpha2beta2 channels. In addition,
      these data suggest that the relative balance between the high- and low-affinity
      components being determined by the relative levels of the alpha and beta subunits
      might be a general property of the heteromeric non-alpha7 nAChRs. By comparing
      the properties of expressed nAChRs with those of the native channels, we might be
      able to learn what role alpha2-containing nAChRs may be playing in forming
      functional channels in the hippocampus.

PMID- 15026121
TI  - Estrogen-mediated regulation of cholinergic expression in basal forebrain neurons
      requires extracellular-signal-regulated kinase activity.
AB  - Beyond the role estrogen plays in neuroendocrine feedback regulation involving
      hypothalamic neurons, other roles for estrogen in maintaining the function of CNS
      neurons remains poorly understood. Primary cultures of embryonic rat neurons
      together with radiometric assays were used to demonstrate how estrogen alters the
      cholinergic phenotype in basal forebrain by differentially regulating sodium
      coupled high-affinity choline uptake and choline acetyltransferase activity. High
      affinity choline uptake was significantly increased 37% in basal forebrain
      cholinergic neurons grown in the presence of a physiological dose of estrogen (5
      nM) from 4 to 10 days in vitro whereas choline acetyltransferase activity was not
      significantly changed in the presence of 5 or 50 nM estrogen from 4 to 10 or 10
      to 16 days in vitro. Newly-synthesized acetylcholine was significantly increased
      35% following 6 days of estrogen treatment (10 days in vitro). These effects are
      in direct contrast to those found for nerve growth factor; that is, nerve growth
      factor can enhance the cholinergic phenotype through changes in choline
      acetyltransferase activity alone. This is most surprising given that mitogen
      activated protein kinase and extracellular-signal-regulated kinase1/2, kinases
      also activated in the signaling pathway of nerve growth factor, were found to
      participate in the estrogen-mediated changes in the cholinergic phenotype.
      Likewise, general improvement in the viability of the cultures treated with
      estrogen does not account for the effects of estrogen as determined by lactate
      dehydrogenase release and nerve growth factor-responsiveness. These findings
      provide evidence that estrogen enhances the differentiated phenotype in basal
      forebrain cholinergic neurons through second messenger signaling in a manner
      distinct from nerve growth factor and independent of improved survival.

PMID- 15026123
TI  - Efficient expansion and gene transduction of mouse neural stem/progenitor cells
      on recombinant fibronectin.
AB  - Neural stem/progenitor cells (NSCs) are commonly grown as floating neurospheres
      in medium containing basic fibroblast growth factor and epidermal growth factor.
      Under these conditions, about 1% of the cells retain multipotentiality. We
      developed a protocol based on culture of NSCs in adherence on recombinant
      fibronectin (rFN) to transduce up to 90% NSCs at a multiplicity of infection of 2
      with no need for viral concentration or production of serum-free retroviral
      supernatants. NSCs grew faster on rFN than as neurospheres on tissue culture
      plastic and did not lose their stem cell nature or multipotentiality.
      Furthermore, retroviral-mediated transgene expression was sustained with time in
      culture and upon differentiation into neurons and astrocytes. These experimental
      conditions may be utilized to study the function of various genes in NSCs, and to
      manipulate NSCs for gene and cell therapy of several neurological diseases.

PMID- 15026124
TI  - Expression of WW domain-containing oxidoreductase WOX1 in the developing murine
      nervous system.
AB  - WW domain-containing oxidoreductase WOX1, also known as WWOX or FOR, is a
      proapoptotic protein and a putative tumor suppressor. Hyaluronidases such as PH
      20, Hyal-1 and Hyal-2 induce the expression of WOX1, and hyaluronidases and
      hyaluronan are involved in the embryonic development. In the present study, we
      document the expression of WOX1 in the developing murine nervous system.
      Immunohistochemical analysis revealed that WOX1 was differentially expressed in
      early dividing cells from all three germ layers from embryonic to perinatal
      stages. In murine fetuses, WOX1 was present prevalently in the brainstem, spinal
      cord and peripheral nerve bundles, but its expression decreased after birth. In
      parallel, the expression of WOX1, as determined by Western blotting, was
      significantly reduced in the brain stem and spinal cord of adult mice. Notably,
      high levels of WOX1 immunoreactivity was observed in the neural crest-derived
      structures such as cranial and spinal ganglia and cranial mesenchyme during the
      late fetal stage. In the adult brain, WOX1 is abundant in the epithelial cells of
      the choroids plexus and ependymal cells, while a low to moderate level of WOX1 is
      observed within white matter tracts, such as axonal profiles of the corpus
      callosum, striatum, optic tract, and cerebral peduncle. WOX1 is shown to mediate
      apoptosis synergistically with p53 in vitro. Nonetheless, the expression profiles
      of WOX1 were found to be similar in both p53 wild type and knockout mice,
      suggesting that WOX1 expression is not controlled by p53-mediated gene
      transcription. Taken together, in this study we have shown the expression and
      distribution of WOX1 in developing and adult murine nervous system. The potential
      role of WOX1 in the neuronal differentiation is discussed.

PMID- 15026125
TI  - Mice deficient for the extracellular matrix glycoprotein tenascin-r show
      physiological and structural hallmarks of increased hippocampal excitability, but
      no increased susceptibility to seizures in the pilocarpine model of epilepsy.
AB  - Recognition molecules provide important cues for neuronal survival, axonal
      fasciculation, axonal pathfinding, synaptogenesis, synaptic plasticity, and
      regeneration. Our previous studies revealed a link between perisomatic inhibition
      and the extracellular matrix glycoprotein tenascin-R (TN-R). Therefore, we here
      studied neuronal excitability and epileptic susceptibility in mice constitutively
      deficient in TN-R. In vitro analysis of populational spikes in hippocampal slices
      of TN-R-deficient mice revealed a significant increase in multiple spikes in the
      CA1 region, as compared with wild-type mice. This difference between genotypes
      was only partially reduced after blockade of GABA(A) receptors with picrotoxin,
      indicating a deficit in GABAergic inhibition and an increase in intrinsic
      excitability of CA1 pyramidal cells in TN-R-deficient mice. Using a battery of
      immunohistochemical markers and histological stainings, we were able to identify
      two abnormalities in the hippocampus of TN-R-deficient mice possibly related to
      increased excitability: the high number of glial fibrillary acidic protein
      positive astrocytes and low number of calretinin-positive interneurons in the CA1
      and CA3 regions. In order to test whether the revealed abnormalities give rise to
      increased susceptibility to seizures in TN-R-deficient mice, we used the
      pilocarpine model of epilepsy. No genotype-specific differences were found with
      regard to the time-course of pilocarpine-induced and spontaneous seizures,
      neuronal cell loss, aberrant sprouting and distribution of synaptic and
      inhibitory interneuron markers. However, pilocarpine-induced astrogliosis and
      reduction in calretinin-positive interneurons were less pronounced in TN-R
      mutants, thereby resulting in an occlusion of effects induced by TN-R deficiency
      and pilocarpine. Thus, TN-R-deficient mutants show several electrophysiological
      and morphological hallmarks of increased neuronal excitability, which, however,
      do not give rise to more accelerated or severe epileptogenesis in the pilocarpine
      model of epilepsy.

PMID- 15026126
TI  - Regulation of the phosphodiesterase PDE4B3-isotype during long-term potentiation
      in the area dentata in vivo.
AB  - Hippocampal long-term potentiation (LTP) is the most prominent cellular model
      underlying learning and memory formation. However, which cellular processes are
      involved in maintaining LTP remains largely unknown. We have previously detailed
      temporal modulations of cyclic adenosine monophosphate (cAMP) and a cAMP-specific
      phosphodiesterase, PDE4B3, after LTP-induction and its maintenance in hippocampal
      area CA1 in vitro. To test whether other hippocampal sub-structures are
      characterised by similar mechanisms, tissue from the area dentata of freely
      moving rats was analysed at different LTP-time points. The tissue was
      fractionated into three components, where PDE4B-levels and cAMP-concentrations
      were measured. In contrast with data obtained in area CA1, we now detail an LTP
      specific translational, but not transcriptional regulation of PDE4B3 within the
      first 8 h after tetanization and present spatio-temporal changes of PDE4B
      proteins and cAMP that is LTP-specific.

PMID- 15026127
TI  - Hippocampal CA1 region neurodegeneration produced by ethanol withdrawal requires
      activation of intrinsic polysynaptic hippocampal pathways and function of N
      methyl-D-aspartate receptors.
AB  - Long-term intake of ethanol produces adaptive alterations in multiple transmitter
      systems in the hippocampal formation that likely contribute to ethanol withdrawal
      induced seizure and excitotoxicity. The present studies were designed to examine
      the role of N-methyl-d-aspartate receptor activation and cytosolic Ca(2+)
      accumulation in the neurotoxic effects of ethanol withdrawal. Further, these
      studies investigated the role of hippocampal network excitation in promoting both
      Ca(2+) accumulation and neurotoxicity during ethanol withdrawal. Chronic,
      continuous (11 day) exposure to ethanol (91 mM starting concentration) did not
      produce neurotoxicity in any region of organotypic hippocampal explants, as
      measured by uptake of the non-vital fluorescent marker propidium iodide.
      Withdrawal from chronic (10 day) ethanol exposure was associated with rapid (30
      min) and significant increases in intracellular Ca(2+), assessed by visualization
      of Calcium-Orange fluorescence, in each region of hippocampal explants. However,
      neurotoxicity was observed 24 h after initiation of withdrawal and was only seen
      in the cornu ammonis 1 (CA1) region. Exposure to MK-801 (20 microM) at the start
      of ethanol withdrawal markedly attenuated Ca(2+) entry in all regions, as well
      as, CA1 region neurodegeneration. Further, treatment of explants with
      tetrodotoxin (500 nM) as well as surgical transection of mossy fiber or Schaffer
      collateral projections immediately prior to ethanol withdrawal blocked both
      regional increases in Ca(2+) accumulation and CA1 neurotoxicity. These data
      suggest that neurodegeneration observed during ethanol withdrawal is dependent
      upon polysynaptic propagation of action potentials ("network excitation") and
      whole-hippocampal excitation of glutamatergic systems.

PMID- 15026128
TI  - Kappa opioid receptors in rat spinal cord: sex-linked distribution differences.
AB  - Activation of kappa opioid receptors (KORs) in the spinal cord can diminish
      nociception. Humans and rodents show sex differences in the analgesia produced by
      KOR agonists, and female rats show fluctuations in KOR density and sensitivity
      across the estrous cycle. However, it is unclear whether there are sex
      differences in the amount and/or distribution of spinal KORs. In the present
      study, immunocytochemically labeled KORs were examined in laminae I and II of the
      lumbosacral spinal dorsal horn of male and normally cycling female Sprague-Dawley
      rats. The basic pattern of KOR labeling was determined in both sexes using
      qualitative electron microscopy (EM), and sex-linked differences in the density
      and subcellular distribution of KOR immunoreactivity were determined with
      quantitative EM and light microscopy. KOR labeling was visualized with
      immunoperoxidase for optimally sensitive detection, or with immunogold for
      precise subcellular localization. By EM, the general pattern of KOR
      immunoreactivity was similar in males and females. KOR immunoreactivity was
      common in dendrites, axons, and axon terminals, and was in a few glia and
      neuronal somata. Most KOR-immunoreactive (-ir) axons were fine-diameter and
      unmyelinated. Most KOR-ir terminals were small or medium-sized, and a minority
      formed asymmetric or symmetric synapses with unlabeled dendrites. KOR
      immunoreactivity was associated both with the plasma membrane and with
      cytoplasmic organelles, notably including dense core vesicles in terminals. Light
      microscopic densitometry revealed that KOR immunoreactivity was significantly
      denser in estrus and proestrus females than in males. By EM, the distribution of
      KOR-immunogold labeling within axon terminals differed, with a greater proportion
      of cytoplasmic KOR labeling in estrus females compared with males. In contrast,
      the abundance and types of KOR-immunoperoxidase-labeled profiles did not show sex
      linked differences. We conclude that in both sexes, KORs are positioned to
      influence both pre- and postsynaptic neurotransmission and are present in
      morphologically heterogeneous neuron populations. These findings are consistent
      with complex consequences of KOR activation in the spinal cord. In addition, the
      presence of increased KOR density and proportionally elevated intracellular KORs
      in proestrus/estrus females suggests a basis for sex-linked differences in KOR
      mediated antinociception.

PMID- 15026130
TI  - Radioligand binding analysis of knockout mice reveals 5-hydroxytryptamine(7)
      receptor distribution and uncovers 8-hydroxy-2-(di-n-propylamino)tetralin
      interaction with alpha(2) adrenergic receptors.
AB  - In the present autoradiographic study, we took advantage of 5
      hydroxytryptamine(7) (5-HT(7)) receptor knockout mice to analyze the brain
      distribution of 5-HT(7) receptor binding sites using [(3)H]5
      carboxamidotryptamine (5-CT; a 5-HT(1A/1B/1D/5/7) receptor ligand) and [(3)H]8
      hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; a 5-HT(1A/7) receptor ligand).
      Low to moderate densities of [(3)H]5-CT (2 nM) binding sites insensitive to
      pindolol (10 microM, for 5-HT(1A/1B) receptor blockade) and GR-127935 (1 microM;
      for 5-HT(1D) receptor blockade) were observed in wild-type mice (mainly in
      thalamus and hypothalamus) but not in 5-HT(7) receptor knockout mice.
      Surprisingly, moderate to high densities of [(3)H]8-OH-DPAT (10 nM) binding sites
      insensitive to pindolol (10 microM) remained in 5-HT(7) receptor knockout mouse
      brain. These non-5-HT(1A), non-5-HT(7) binding sites were found to be adrenergic
      alpha(2A) receptor binding sites. In alpha(2A) receptor knockout mice low to
      moderate densities of [(3)H]8-OH-DPAT binding sites insensitive to pindolol but
      sensitive to the selective 5-HT(7) receptor antagonist SB-269970 (300 nM) were
      observed mainly in thalamus and hypothalamus. Therefore, in addition to 5-HT(1A)
      and 5-HT(7) binding sites, [(3)H]8-OH-DPAT also binds to alpha(2A) receptor
      binding sites in wild-type mouse brain. [(3)H]8-OH-DPAT (in the presence of
      pindolol and 1 microM RX-821002 for alpha(2) receptor blockade) and [(3)H]5-CT
      (in the presence of pindolol and GR-127935) bind to a similar receptor binding
      population corresponding to 5-HT(7) binding sites. Detailed anatomical mapping of
      5-HT(7) receptor binding sites in wild-type mouse brain was then performed using
      both radioligands in the presence of suitable pharmacological agents for non-5
      HT(7) receptor binding sites blockade. The mapping revealed binding sites
      consistent with the mRNA distribution with the highest densities found in
      anterior thalamic nuclei.

PMID- 15026129
TI  - Cyclooxygenase 2 expression in the spared nerve injury model of neuropathic pain.
AB  - Cyclooxygenase-2 (COX-2) after induction peripherally, and within the CNS, plays
      an important role in producing inflammatory pain. However, its role in
      neuropathic pain models is controversial. Recently a robust and persistent model
      of partial nerve injury pain, the spared nerve injury (SNI) model, has been
      developed. The aim of the present study was to examine the regulation of COX-2 in
      the rat SNI model and to evaluate the effectiveness of the selective COX-2
      inhibitor rofecoxib in preventing neuropathic allodynia and hyperalgesia. RNase
      protection assays revealed only a very small and transient increase in COX-2 mRNA
      in the dorsal horn of the spinal cord in the SNI model with a maximum change at
      24 h. Immunohistochemical analysis showed a small increase in COX-2 protein in
      the deep layers of the dorsal horn 10 h following SNI surgery. Rofecoxib (100
      microM) did not affect spontaneous excitatory postsynaptic currents or alpha
      amino-3-hydroxy-5-methyl-4-isoxazole propanoic acid (AMPA) and N-methyl-d
      aspartate (NMDA) responses in lamina II neurons from spinal cords of animals with
      SNI indicating no detectable action on transmitter release or postsynaptic
      activity. Furthermore, rofecoxib treatment (1 and 3.2 mg/kg for 5 and 3 days
      respectively starting on the day of surgery) failed to modify the development of
      allodynia and hyperalgesia in the SNI model. However, rofecoxib significantly
      reduced inflammatory hypersensitivity evoked by injection of complete Freund's
      adjuvant into one hindpaw, indicating that the doses used were pharmacologically
      active. The pain hypersensitivity produced by the SNI model is not COX-2
      dependent.

PMID- 15026131
TI  - An investigation of the effects of ruthenium red, nitric oxide and endothelin-1
      on infrared receptor activity in a crotaline snake.
AB  - The infrared (IR) receptors in the pit organ of crotaline snakes are very
      sensitive to temperature. The vasculature of the pit organs, which is located in
      close proximity to IR-sensitive terminal nerve masses (IR receptors), is finer,
      flatter, and more convoluted than that of other sensory organs. Using
      extracellular recording in vivo from IR-sensitive primary afferent trigeminal
      ganglion (TG) neurons of the crotaline snake Trimeresurus flavoviridis, I studied
      the response to IR warming (24-25 degrees C) and to various chemicals: an
      exogenous vasoactive substance nitric oxide donor (sodium nitroprusside, SNP),
      endothelin-1 (ET-1), a transient receptor potential vanilloid (TRPV)1 agonist
      (capsaicin, CAP) and antagonist (capsazepine, CZP), and Ruthenium Red (RR), an
      antagonist of the TRPV family. IR-sensitive primary afferent TG neurons display
      regular background firing at 10-25 impulses per second at 24-25 degrees C. At
      this temperature, Ruthenium Red and endothelin-1 clearly suppressed the frequency
      of background firing, while sodium nitroprusside injected into the bloodstream
      significantly increased the frequency of discharges (P<0.01) and caused regular
      bursts of firing in IR-sensitive TG neurons. By contrast, capsaicin and
      capsazepine had no effect on the infrared responses. The possibility that these
      opposite responses result from their vasoactive effects on the unusual pit
      vasculature or from their chemical effects on the thermoreceptors of IR-sensitive
      nerve terminals in the pit organ, like those of the TRPV family, is discussed.

PMID- 15026134
TI  - The effects of endogenous interleukin-10 on gray matter damage and the
      development of pain behaviors following excitotoxic spinal cord injury in the
      mouse.
AB  - Interleukin-10 (IL-10) has been utilized as a neuroprotective agent in
      experimental models of spinal cord injury because of its potent anti-inflammatory
      properties. Previous studies have delivered a single dose (5 microg) of IL-10
      following experimental spinal cord injury in the rat, and demonstrated various
      degrees of neuroprotection. However, the role of endogenous production of IL-10
      has not been considered. Therefore, the purpose of the current study was to
      establish the role of endogenous IL-10 and demonstrate the true potential of
      exogenous IL-10 administration through the use of IL-10((-/-)) mice. Using the
      quisqualic acid model of spinal cord injury, we examined the extent of gray
      matter damage and onset of injury-induced pain behaviors at various time points
      following injury in wild-type vs. IL-10((-/-)) mice. Additionally, IL-10 was
      reconstituted in IL-10 deficient mice by the intraperitoneal administration of 50
      ng recombinant murine (rm) IL-10 30 min following quisqualic acid injection.
      Animals were observed daily following injury for the onset of pain-behaviors. At
      days 1, 7, and 14 following injection, lesion analysis revealed a greater extent
      of damage at early time points (1 day, 7 days) following injury in the IL-10((-/
      )) animals as compared with wild-type animals. However, by 14 days post
      experimental spinal cord injury, the extent of damage between the two groups was
      not significant. IL-10((-/-)) animals that received the single (50 ng) rmIL-10
      injection following injury displayed gray matter damage patterns similar to wild
      type animals. The pronounced early damage noted in the IL-10((-/-)) animals was
      associated with an approximately two-fold increase in peripheral neutrophils, an
      index of an innate immune response to injury, compared with wild-type mice. In
      addition, wild type and IL-10((-/-)) animals receiving rmIL-10 demonstrated a
      delay in the onset of injury-induced pain behaviors. However, by 14 days post
      experimental spinal cord injury the overall incidence of pain behaviors was
      similar between all treatment groups. Therefore, the absence of IL-10 expression
      accelerates the kinetics of lesion expansion, the onset of pain behaviors, and
      the peripheral immune response to spinal cord injury. Endogenous IL-10 and low
      doses of exogenous IL-10 are neuroprotective at 1 and 7 days following injury.
      Therefore, the results of the current study suggest that low dose IL-10
      administration acutely following spinal cord injury has potential as a
      therapeutic agent for limiting tissue loss following injury.

PMID- 15026133
TI  - Selective neuroinhibitory effects of taurine in slices of rat main olfactory
      bulb.
AB  - Taurine is abundant in the main olfactory bulb, exceeding glutamate and GABA in
      concentration. In whole-cell patch-clamp recordings in rat olfactory bulb slices,
      taurine inhibited principal neurons, mitral and tufted cells. In these cells,
      taurine decreased the input resistance and caused a shift of the membrane
      potential toward the chloride equilibrium potential. The taurine actions were
      sustained under the blockade of transmitter release and were reversible and dose
      dependent. At a concentration of 5 mM, typically used in this study, taurine
      showed 90% of its maximal effect. GABA(A) antagonists, bicuculline and
      picrotoxin, blocked the taurine actions, whereas the glycine receptor antagonist
      strychnine and GABA(B) antagonists, CGP 55845A and CGP 35348, were ineffective.
      These findings are consistent with taurine directly activating GABA(A) receptors
      and inducing chloride conductance. Taurine had no effect on periglomerular and
      granule interneurons. The subunit composition of GABA(A) receptors in these
      cells, differing from those in mitral and tufted cells, may account for taurine
      insensitivity of the interneurons. Taurine suppressed olfactory nerve-evoked
      monosynaptic responses of mitral and tufted cells while chloride conductance was
      blocked. This action was mimicked by the GABA(B) agonist baclofen and abolished
      by CGP 55845A; CGP 35348, which primarily blocks postsynaptic GABA(B) receptors,
      was ineffective. The taurine effect most likely was due to GABA(B) receptor
      mediated inhibition of presynaptic glutamate release. Neither taurine nor
      baclofen affected responses of periglomerular cells. The lack of a baclofen
      effect implies that functional GABA(B) receptors are absent from olfactory nerve
      terminals that contact periglomerular cells. These results indicate that taurine
      decreases the excitability of mitral and tufted cells and their responses to
      olfactory nerve stimulation without influencing periglomerular and granule cells.
      Selective effects of taurine in the olfactory bulb may represent a physiologic
      mechanism that is involved in the inhibitory shaping of the activation pattern of
      principal neurons.

PMID- 15026135
TI  - Leading role of the piriform cortex over the neocortex in the generation of
      spontaneous interictal spikes during block of GABA(A) receptors.
AB  - Interictal spikes are generated in the cerebral cortex during certain
      pathological conditions. In normal tissue, interictal spikes are triggered by
      blocking GABA(A) receptors. We studied the propensity of different areas of the
      cerebral cortex (including neocortex and piriform cortex) to generate spontaneous
      interictal spikes during block of GABA(A) receptors in slices of adult mice. Ten
      sequential brain slices were studied spanning most of the cerebral hemisphere.
      During block of GABA(A) receptors spontaneous interictal spikes were observed in
      all slices. Interestingly, interictal spikes recurred at different frequencies in
      different slices; posterior slices had a higher rate than the frontal slices
      (approximately 0.2 vs. 0.1 Hz, posterior vs. frontal). Multi-site recordings
      allowed to monitor discharges traveling across each slice and to derive cross
      correlations. It became apparent that for the slices with higher frequency (i.e.
      posterior slices) the discharges originated in the piriform cortex and spread to
      the neocortex. A correlation between the frequency of the spontaneous discharges
      and the probability of events originating from piriform cortex was positive and
      significant. A further demonstration of this site of origin was provided by
      severing the connections between the neocortex and the piriform cortex. After
      interrupting these connections all the neocortical sites in the posterior slices
      displayed a lower frequency of discharges; similar to slower frontal slices.
      Meanwhile, the isolated piriform cortex of the posterior slices continued to
      produce higher frequency discharges. Thus, the higher frequency activity
      displayed by the posterior slices is intrinsically generated in the posterior
      piriform cortex from where it spreads to the neocortex. The results indicate that
      the neocortex and the piriform cortex have a distinct propensity to generate
      spontaneous interictal spikes, and that the more prone areas impose their
      activity on the less prone areas during disinhibition.

PMID- 15026132
TI  - Co-localization of the vanilloid capsaicin receptor and substance P in sensory
      nerve fibers innervating cochlear and vertebro-basilar arteries.
AB  - Evidence suggests that capsaicin-sensitive substance P (SP)-containing trigeminal
      ganglion neurons innervate the spiral modiolar artery (SMA), radiating
      arterioles, and the stria vascularis of the cochlea. Antidromic electrical or
      chemical stimulation of trigeminal sensory nerves results in neurogenic plasma
      extravasation in inner ear tissues. The primary aim of this study was to reveal
      the possible morphological basis of cochlear vascular changes mediated by
      capsaicin-sensitive sensory nerves. Therefore, the distribution of SP and
      capsaicin receptor (transient receptor potential vanilloid type 1-TRPV1) was
      investigated by double immunolabeling to demonstrate the anatomical relationships
      between the cochlear and vertebro-basilar blood vessels and the trigeminal
      sensory fiber system. Extensive TRPV1 and SP expression and co-localization were
      observed in axons within the adventitial layer of the basilar artery, the
      anterior inferior cerebellar artery, the SMA, and the radiating arterioles of the
      cochlea. There appears to be a functional relationship between the trigeminal
      ganglion and the cochlear blood vessels since electrical stimulation of the
      trigeminal ganglion induced significant plasma extravasation from the SMA and the
      radiating arterioles. The findings suggest that stimulation of paravascular
      afferent nerves may result in permeability changes in the basilar and cochlear
      vascular bed and may contribute to the mechanisms of vertebro-basilar type of
      headache through the release of SP and stimulation of TPVR1, respectively. We
      propose that vertigo, tinnitus, and hearing deficits associated with migraine may
      arise from perturbations of capsaicin-sensitive trigeminal sensory ganglion
      neurons projecting to the cochlea.

PMID- 15026136
TI  - Induction of FOS expression by acute immobilization stress is reduced in locus
      coeruleus and medial amygdala of Wistar-Kyoto rats compared to Sprague-Dawley
      rats.
AB  - Activation of the brain noradrenergic system during acute stress is thought to
      play an important integrative function in coping and stress adaptation by
      facilitating transmission in many brain regions involved in regulating behavioral
      and physiologic components of the stress response. Compared with outbred control
      Sprague-Dawley (SD) rats, inbred Wistar-Kyoto (WKY) rats exhibit an exaggerated
      hypothalamic-pituitary-adrenal (HPA) response as well as increased susceptibility
      to certain forms of stress-related pathology. However, we have also shown
      previously that WKY rats exhibit reduced anxiety-like behavioral reactivity to
      acute stress, associated with reduced activation of the brain noradrenergic
      system. Thus, to understand better the possible neurobiological mechanisms
      underlying dysregulation of the stress response in WKY rats, we investigated
      potential strain differences in stress-induced neuronal activation in brain
      regions that are both involved in regulating behavioral and neuroendocrine stress
      responses, and are related to the noradrenergic system, either as targets of
      noradrenergic modulation or as sources of afferent innervation of noradrenergic
      neurons. This was accomplished by visualizing stress-induced expression of Fos
      immunoreactivity in the paraventricular nucleus of the hypothalamus, lateral bed
      nucleus of the stria terminalis, central nucleus of the amygdala, and medial
      nucleus of the amygdala (MeA), as well as the noradrenergic nucleus locus
      coeruleus (LC). Stress-induced Fos expression was found to be decreased in the LC
      and MeA of WKY rats compared with similarly stressed SD rats, whereas no strain
      differences were observed in any of the other brain regions. This suggests that
      strain-related differences in activation of the MeA may be involved in the
      abnormal neuroendocrine and behavioral stress responses exhibited by WKY rats.
      Moreover, as the MeA is both an afferent as well as an efferent target of the
      brainstem noradrenergic system, reduced MeA activation may either be a source of
      reduced noradrenergic reactivity seen in WKY rats, or possibly a consequence.
      Nonetheless, understanding the mechanisms underlying altered stress reactivity in
      models such as the WKY rat may contribute to a better understanding of stress
      related psychopathologies such as depression, post-traumatic stress disorder or
      other anxiety disorders.

PMID- 15026137
TI  - Functional organization of preoptic vasotocin and isotocin neurons in the brain
      of rainbow trout: central and neurohypophysial projections of single neurons.
AB  - Preoptic magnocellular neurosecretory cells (NSCs) in the brain of rainbow trout
      show synchronization of periodic Ca(2+) pulses, patterns of which differ between
      vasotocin (VT) and isotocin (IT) neurons. To provide neuroanatomical bases of the
      synchronized periodic Ca(2+) pulses and their biological implications, we
      examined the organization of preoptic VT and IT neurons in the brain of rainbow
      trout. The cytoarchitecture of the preoptic neurosecretory system was
      characterized by a confocal double-color immunofluorescence. Two to five VT
      neurons, and also IT neurons, aggregate to form cell-type specific clusters. VT
      clusters tend to localize medially, while IT clusters laterally. VT neurons are
      closely apposed at the proximal neuronal processes. A Golgi-like
      immunohistochemistry demonstrated that VT and IT fibers distribute widely in the
      brain, such as ventral telencephalon, diencephalon, and various mesencephalic
      structures, in addition to the neurohypophysial projections. Projections from
      single VT and IT neurons were examined by an intracellular staining with biocytin
      injection in a sagittally hemisected brain preparation, which contains the entire
      forebrain region. Single VT and IT neurons project toward the pituitary and the
      extrahypothalamic regions. Some IT neurons, but not VT neurons, were dye-coupled.
      These results support the idea that the same types of NSCs are connected to form
      cell-type-specific networks responsible for the synchronization of periodic
      Ca(2+) pulses. The organization of the preoptic neurosecretory system shown in
      the present study is suitable for the simultaneous control of neurohypophysial
      and extrahypothalamic outputs through the synchronization of electrical activity.

PMID- 15026138
TI  - Voluntary exercise protects against stress-induced decreases in brain-derived
      neurotrophic factor protein expression.
AB  - Exercise is increasingly recognized as an intervention that can reduce CNS
      dysfunctions such as cognitive decline, depression and stress. Previously we have
      demonstrated that brain-derived neurotrophic factor (BDNF) is increased in the
      hippocampus following exercise. In this study we tested the hypothesis that
      exercise can counteract a reduction in hippocampal BDNF protein caused by acute
      immobilization stress. Since BDNF expression is suppressed by corticosterone
      (CORT), circulating CORT levels were also monitored. In animals subjected to 2 h
      immobilization stress, CORT was elevated immediately following, and at 1 h after
      the cessation of stress, but remained unchanged from baseline up to 24 h post
      stress. The stress protocol resulted in a reduction in BDNF protein at 5 and 10 h
      post-stress that returned to baseline at 24 h. To determine if exercise could
      prevent this stress-induced reduction in BDNF protein, animals were given
      voluntary access to running wheels for 3 weeks prior to the stress. Stressed
      animals, in the absence of exercise, again demonstrated an initial elevation in
      CORT (at 0 h) and a subsequent decrease in hippocampal BDNF at the 10 h time
      point. Exercising animals, both non-stressed and stressed, demonstrated
      circulating CORT and hippocampal BDNF protein levels that were significantly
      elevated above control values at both time points examined (0 and 10 h post
      stress). Thus, the persistently high CORT levels in exercised animals did not
      affect the induction of BDNF with exercise, and the effect of immobilization
      stress on BDNF protein was overcome. To examine the role of CORT in the stress
      related regulation of BDNF protein, experiments were carried out in
      adrenalectomized (ADX) animals. BDNF protein was not downregulated as a result of
      immobilization stress in ADX animals, while there continued to be an exercise
      induced upregulation of BDNF. This study demonstrates that CORT modulates stress
      related alterations in BDNF protein. Further, exercise can override the negative
      effects of stress and high levels of CORT on BDNF protein. Voluntary physical
      activity may, therefore, represent a simple non-pharmacological tool for the
      maintenance of neurotrophin levels in the brain.

PMID- 15026139
TI  - Conformational and inframolecular studies of the protonation of adenophostin
      analogues lacking the adenine moiety.
AB  - Four adenophostin analogues lacking the adenine moiety were subjected to 31P- and
      1H-NMR titrations in order to determine the acid-base behaviour of the individual
      ionisable groups of the molecules and the complex interplay of intramolecular
      interactions resulting from the protonation process. For the two
      trisphosphorylated compounds, the curve pattern of the phosphorus nuclei
      corresponds to the superimposition of the titration curves of a
      monophosphorylated polyol and a polyol carrying two vicinal phosphates,
      suggesting that the two phosphate moieties behave independently. Also, the
      general shape of 1H-NMR titration curves of the studied compounds is very close
      to that of adenophostin A, indicating that the adenine moiety does not
      specifically interact with the phosphorylated sugar moieties. The curves show,
      however, that both trisphosphorylated compounds adopt slightly different
      preferential conformations which could contribute to explain the difference in
      their affinity for Ins(1,4,5)P3 receptor. Their macroscopic as well as the
      microscopic protonation constants are higher than those of adenophostin A,
      indicating that the adenine moiety plays a base-weakening effect on the phosphate
      groups. Further analysis of the microscopic protonation constants confirms that
      the compound whose conformation is the closest to that of adenophostin A also
      shows the highest biological activity. The two bisphosphorylated analogues
      studied behave very similarly, suggesting that the deletion of the hydroxymethyl
      group on the pentafuranosyl ring only weakly influences the protonation process
      of the phosphate groups that bear the glucopyranose moiety.

PMID- 15026140
TI  - Mitogenic activity of edible mushroom lectins.
AB  - A special group of lectins were isolated from three popular Asian edible
      mushrooms: Volvariella volvacea, Pleurotus flabellatus and Hericium erinacium,
      and their mitogenic activities towards mouse T cells were compared to the
      extensively investigated Agaricus bisporus lectin (ABL) and the Jack bean lectin,
      Concanavalin A (Con A). Among the four mushroom lectins tested, V. volvacea
      lectin (VVL) exhibited strong mitogenic activity as demonstrated by 3H-thymidine
      incorporation, which was at least 10-fold more effective than that of Con A, and
      the other mushroom lectins did not exhibit any proliferative activity. Treatment
      with VVL and ABL resulted in activation of the protein tyrosine kinase, p56lck,
      and expression of early activation markers, CD69 and CD25, but only VVL induced
      intracellular calcium influx while ABL triggered cell death. The calcium influx
      was sensitive to calcium channel antagonists such as nifedipine and verapamil.
      The P. flabellatus lectin (PFL) and H. erinacium lectin (HEL) did not stimulate
      p56lck expression and cell proliferation. Neither of these lectins interfered
      with Con A-mediated lymphocyte proliferation, which further indicated that both
      PFL and HEL were non-mitogenic. Taken all results together, VVL induced
      mitogenesis through T cell receptors and the subsequent calcium signaling
      pathway.

PMID- 15026141
TI  - A simple model for the study of effects of the extracellular matrix on the cell
      morphology in vitro.
AB  - In the present work, a simple technique is proposed to study the effects of
      native extracellular matrix (ECM) of one cell type on the properties of other
      cell types. It is based on a procedure in which, after cells of one type are
      removed from the substrate, cells of another type are seeded on the same
      substrate. To obtain preparations of native ECM, cells were removed from the
      substrate by 0.02% EDTA only, without any proteolytic enzymes. Cells were placed
      on coverslips in standard Petri dishes and incubated in a culture medium for a
      time sufficient for adhesion and spreading, but not long enough to undergo
      mitosis. Up to four coverslips per Petri dish can be incubated, and various
      combinations of ECM and cell types can be used in one dish. It is important,
      therefore, that the different "ECM-cell" combinations are present in the same
      culture medium. For evaluation of ECM effects, the area occupied by the cell on a
      substrate and the perimeter of the cell were measured, and frequencies of cell
      distribution were calculated according to these parameters.

PMID- 15026142
TI  - Peroxisomal localization in the developing mouse cerebellum: implications for
      neuronal abnormalities related to deficiencies in peroxisomes.
AB  - In subjects with Zellweger syndrome, the most severe phenotype of peroxisomal
      biogenesis disorder, brain abnormalities include cortical dysplasia, neuronal
      heterotopia, and dysmyelination. To clarify the relationship between the lack of
      peroxisomes and neuronal abnormalities, we investigated peroxisomal localization
      in the mouse cerebellum, using double immunofluorescent staining for peroxisomal
      proteins. On immunostaining for peroxisomal matrix protein, while there are few
      peroxisomes in Purkinje cells, many locate in astroglia, especially soma of
      Bergmann glia. Clusters of peroxisomes were seen on the inferior side of the
      Purkinje cell layer in mice on postnatal days 3-5, and with time there was a
      shift to the superior side. The peroxisomal punctate pattern was seen to be
      radial and co-localized with Bergmann glial fibers. In cultured cells from the
      mouse cerebellum, peroxisomes were few in Purkinje cells, whereas many were
      evident in glial fibrillary acidic protein-positive cells. On the other hand, on
      immunostaining for peroxisomal membrane protein Pex14p, many particles were seen
      in Purkinje cells during all developmental stages, which means Purkinje cells
      possessed empty peroxisomal structures similar to findings of fibroblasts from
      the Zellweger patients. As peroxisomes in glial cells may control the development
      of neurons, the neuron-glial interaction and mechanisms of developing central
      nervous systems deserve ongoing attention.

PMID- 15026143
TI  - The biosynthesis of anticoagulant heparan sulfate by the heparan sulfate 3-O
      sulfotransferase isoform 5.
AB  - The role of heparan sulfate (HS) in regulating blood coagulation has a wide range
      of clinical implications. In this study, we investigated the role of 3-O
      sulfotransferase isoform 5 (3-OST-5) in generating anticoagulant HS in vivo. A
      Chinese hamster ovary cell line (3OST5/CHO) stably expressing 3-OST-5 was
      generated. The expression of 3-OST-5 in 3OST5/CHO cells was confirmed by Northern
      blot analysis, RT-PCR, and the disaccharide analyses of the HS from the cells. We
      also determined the effects of the HS from 3OST5/CHO on antithrombin-mediated
      inhibition of factor Xa. Fluorescently labeled antithrombin bound to the surface
      of 3OST5/CHO cells, suggesting that the antithrombin-binding HS is indeed present
      on the cell surface. Our results demonstrate that the 3-OST-5 gene is capable of
      synthesizing anticoagulant HS in CHO cells and has the potential to contribute to
      the biosynthesis of anticoagulant HS in humans.

PMID- 15026144
TI  - Induction of cytokines by toxins that have an identical RNA N-glycosidase
      activity: Shiga toxin, ricin, and modeccin.
AB  - Shiga toxin (Stx) has an A1-B5 subunit structure, and the A subunit is an RNA N
      glycosidase that inhibits cellular protein synthesis. We previously reported that
      in Caco-2 cells Stx induced cytokines and that the RNA N-glycosidase activity was
      essential for the cytokine induction. It is known that the binding of the Stx-B
      subunit to its receptor glycolipid, Gb3, mediates an A subunit-independent signal
      in some types of cells, but the involvement of this signal in the cytokine
      induction is unclear. In this study, we investigated whether RNA N-glycosidase
      itself induces cytokines. IL-8 production was enhanced by Stx, ricin, and
      modeccin, three toxins that inhibit protein synthesis through an identical RNA N
      glycosidase activity, but not by two other types of protein synthesis inhibitors,
      diphtheria toxin and cycloheximide. The RNA N-glycosidase-type toxins showed a
      similar induction pattern of cytokine mRNAs. Brefeldin A, a Golgi apparatus
      inhibitor, completely suppressed the cytokine induction by the toxins. Analysis
      by using inhibitors of toxin binding and also Stx-B subunit showed that the
      cytokine-inducing activity was independent of Gb3-mediated signaling. These
      results indicate that RNA N-glycosidase itself induces the cytokine production
      and that intracellular transport of toxins through the Golgi apparatus is
      essential for the activity.

PMID- 15026145
TI  - Modulation of insulin effects on phosphorylation of protein kinase B and glycogen
      synthesis by tumor necrosis factor-alpha in HepG2 cells.
AB  - The effects of tumor necrosis factor-alpha (TNF-alpha) on insulin-induced
      phosphorylation of protein kinase B-alpha (PKB-alpha) and downstream enzyme
      glycogen synthase kinase-3 beta (GSK-3 beta) was examined in HepG2 liver cells.
      The exogenous treatment of HepG2 cells with TNF-alpha for 1 h caused
      phosphorylation of Ser473 and Thr308 residues of PKB-alpha. The maximal
      phosphorylation (approximately 4-fold) was obtained with 1 ng/ml TNF-alpha and no
      further increase was observed with higher concentrations of this cytokine. The
      cells pretreated with TNF-alpha for 1 h followed by incubation with insulin (10
      nM) showed near additive effect on phosphorylation of PKB-alpha and downstream
      enzyme GSK-3 beta. The long-term (4, 8, 24 h) exogenous treatment of cells with
      optimal (1 ng/ml) concentration of TNF-alpha also caused phosphorylation of PKB
      alpha, albeit to a lesser degree. However, long-term pretreatments of cells with
      TNF-alpha reduced insulin-stimulated phosphorylation of PKB-alpha and GSK-3 beta.
      Short- and long-term preincubation of HepG2 cells with TNF-alpha also resulted in
      parallel changes in glycogen synthesis in the presence of insulin. In fact, long
      term preincubation with TNF-alpha completely abolished the insulin-induced
      glycogen synthesis. These results suggest that short-term exposure to TNF-alpha
      augments insulin effects whereas long-term exposure causes insulin resistance in
      HepG2 cells.

PMID- 15026146
TI  - Degradation of the tumor antigen epitope gp100(280-288) by fibroblast-associated
      enzymes abolishes specific immunorecognition.
AB  - Degradation of the tumor antigen epitope gp100(280-288) (YLEPGPVTA) was
      investigated in the presence of cultured human fibroblasts, and acellular
      supernatants obtained from these cells; the possible effect of substrate
      degradation on in vitro immunorecognition was also addressed. In the presence of
      fibroblasts, gp100(280-288) was degraded to free amino acids with a half-life of
      less than 4 min; hydrolysis data support the hypothesis that substrate
      degradation was mainly caused by the activity of cell-expressed amino- and
      carboxypeptidases. Gp100(280-288) was also degraded in the presence of acellular
      supernatants: under these conditions, the hydrolysis pattern was similar to that
      observed in the presence of whole cells, but degradation kinetics was slower. As
      a result of these phenomena, immunorecognition of gp100(280-288)-specific
      cytotoxic T lymphocyte (CTL) clones was severely hampered, and was totally
      suppressed after 90 min. In conclusion, the high activity of fibroblast-expressed
      proteases, and the presence of wide-scope soluble enzymes, may explain, at least
      in part, the low activity of peptide-based antineoplastic vaccines, as well as
      the transient effectiveness of subcutaneously administered peptides in general.

PMID- 15026147
TI  - Inhibition of Na+/Ca2+ exchanger by peroxynitrite in microsomes of pulmonary
      smooth muscle: role of matrix metalloproteinase-2.
AB  - Treatment of bovine pulmonary artery smooth muscle microsomes with peroxynitrite
      (ONOO-) (100 microM) markedly stimulated matrix metalloproteinase-2 (MMP-2)
      activity and also enhanced Ca2+ATPase activity and ATP-dependent Ca2+ uptake.
      Pretreatment of the microsomes with vitamin E (1 mM) and TIMP-2 (50 microg/ml)
      preserved the increase in MMP-2 activity, Ca2+ATPase activity and also ATP
      dependent Ca2+ uptake in the microsomes. In contrast, Na(+)-dependent Ca2+ uptake
      in the microsomes was inhibited by ONOO- and this was found to be reversed by
      vitamin E (1 mM) and TIMP-2 (50 microg/ml). However, changes caused by ONOO- in
      MMP-2 activity, ATP-dependent Ca2+ uptake and Na(+)-dependent Ca2+ uptake were
      not reversed upon pretreatment of the microsomes with a low concentration of 5
      microg/ml of TIMP-2 which, on the contrary, reversed MMP-2 (1 microg/ml)-mediated
      alteration on these parameters. The inhibition of Na(+)-dependent Ca2+ uptake by
      ONOO- and MMP-2 overpowered the stimulation of ATP-dependent Ca2+ uptake in the
      microsomes. Treatment with ONOO- abolished the inhibitory effect of TIMP-2 (5
      microg/ml) on MMP-2 (1 microg/ml) causing 14C-gelatin degradation. Overall, the
      present study suggests that ONOO- inactivated TIMP-2, the ambient inhibitor of
      MMP-2, leading to activation of the ambient proteinase, MMP-2, and subsequently
      stimulated Ca2+ATPase activity and ATP-dependent Ca2+ uptake, but inhibited Na(+)
      dependent Ca2+ uptake, resulting in a marked decrease in Ca2+ uptake in
      microsomes of bovine pulmonary artery smooth muscle.

PMID- 15026149
TI  - A lamin A/C beta-strand containing the site of lipodystrophy mutations is a major
      surface epitope for a new panel of monoclonal antibodies.
AB  - Using a phage-displayed peptide library, we have identified the epitope
      recognized by a new panel of five monoclonal antibodies (mAbs) raised against
      full-length recombinant human lamin A. The mAbs were found to recognize both
      lamin A and C by Western blotting and immunolocalization at the nuclear rim. A
      nine-amino acid consensus sequence PLLTYRFPP in the common immunoglobulin-like
      (Ig-like) domain of lamin A/C contains the binding site for all five mAbs. Three
      dimensional structure of the Ig-like domain of lamin A/C shows this sequence is a
      complete beta-strand. This sequence includes arginine-482 (R482) which is mutated
      in most cases of Dunnigan-type familial partial lipodystrophy (FPLD). R482 may be
      part of an interaction site on the surface of lamin A/C for lamin-binding
      proteins associated with lipodystrophy.

PMID- 15026148
TI  - Effect of secretagogues and pH on intestinal transport in guanylin-deficient
      mice.
AB  - The small and large intestine secrete guanylin, a peptide homologous to heat
      stable enterotoxin (STa) elaborated by enterotoxigenic Escherichia coli.
      Guanylin's role in intestinal electrolyte transport was investigated in guanylin
      deficient knockout mice and heterozygous littermate controls. Segments of mid
      jejunum, distal ileum, and proximal and distal colon were studied in Ussing
      chambers in HCO3- Ringer under short circuit conditions. We found that (1) under
      basal conditions, all segments in control and knockout mice absorb Na+, and the
      knockout mouse proximal colon secretes Cl-; (2) all segments except the jejunum
      of knockout mice respond by increasing absorption in response to reductions in pH
      from 7.6 to 7.1; (3) all segments exhibit decreased absorption in response to 1
      mM cAMP; (4) the jejunum and ileum of knockout and control mice, and the proximal
      colon of control mice (but not knockout mice) respond to the mucosal addition of
      50 nM STa with decreases in absorption; and (5) mucosal guanylin caused similar
      decreases in proximal colon absorption in control and guanylin-deficient mice.
      These findings suggest that guanylin deficiency causes basal Cl- secretion and
      reduced responsiveness to STa in mouse proximal colon. The effectiveness of
      guanylin in this segment suggests a difference in the intestinal secretory
      actions of STa and guanylin.

PMID- 15026150
TI  - Isolation, characterization, and cDNA sequencing of alpha-1-antiproteinase-like
      protein from rainbow trout seminal plasma.
AB  - Seminal plasma of teleost fish contains serine proteinase inhibitors related to
      those present in blood. These inhibitors can be bound to Q-Sepharose and
      sequentially eluted with a NaCl gradient. In the present study, using a two-step
      procedure, we purified (73-fold to homogeneity) and characterized the inhibitor
      eluted as the second fraction of antitrypsin activity (inhibitor II) from Q
      Sepharose. The molecular weight of this inhibitor was estimated to be 56 kDa with
      an isoelectric point of 5.4. It effectively inhibited trypsin and chymotrypsin
      but was less effective against elastase. It formed SDS-stable complexes with cod
      and bovine trypsin. Inhibitor II appeared to be a glycoprotein. Carbohydrate
      content was determined to be 16%. N-terminal Edman sequencing allowed
      identification of the first 30 N-terminal amino acids
      HDGDHAGHTEDHHHHLHHIAGEAHPQHSHG and 25 amino acids within the reactive loop
      IMPMSLPDTIMLNRPFLLFILEDST. The N-terminal sequence did not match any known
      sequence, however, the sequence within the reactive loop was significantly
      similar to carp and mammalian alpha1-antiproteinases. Both sequences were used to
      construct primers and obtain a cDNA sequence from liver. The mRNA coding the
      protein is 1675 nt in length including a single open reading frame of 1281 nt
      that encodes 426 amino acid residues. Analysis of this sequence indicated the
      presence of putative conserved serpin domains and confirmed the similarity to
      carp alpha1-antiproteinase and mammalian alpha1-antiproteinase. Our results
      indicate that inhibitor II belongs to the serpin superfamily and is similar to
      alpha1-antiproteinase.

PMID- 15026151
TI  - Synergistic activation of the central pattern generator for locomotion by l-beta
      3,4-dihydroxyphenylalanine and quipazine in adult paraplegic mice.
AB  - L-beta-3,4-Dihydroxyphenylalanine (L-DOPA) and quipazine, respectively
      dopamine/noradrenaline precursor and serotonergic (5-HT(2)) receptor agonist,
      were injected intraperitoneally in low-thoracic spinal mice at 7 days post
      spinalization. In mice pre-treated with decarboxylase and monoamine oxydase
      inhibitors, L-DOPA (30-100 mg/kg) was found not to induce air-stepping. On the
      other hand, L-DOPA (40 mg/kg) consistently triggered locomotor-like movements if
      combined with low doses of quipazine (0.4-0.7 mg/kg) or if mice were placed on a
      motor-driven treadmill running at low speed. However, twitches, spasms, and other
      non-locomotor movements were also induced, especially on the treadmill. These
      results suggest that (1) spinal catecholaminergic and serotonergic receptors
      interact synergistically to generate locomotor-like movements in chronic spinal
      mice, and that (2) hindlimb afferent inputs associated with the treadmill
      conditions contribute to the genesis of locomotor-like and non-locomotor
      movements induced by these drugs.

PMID- 15026152
TI  - Inosine reverses the inhibitory effects of the L-type Ca2+ channel antagonist, DM
      BODIPY-dihydropyridine, on neuritogenesis in an in vitro rat superior cervical
      ganglia axotomy model.
AB  - It has recently been demonstrated that L-type calcium channel antagonism with the
      fluorescent dihydropyridine DM-BODIPY-dihydropyridine (DMBD) inhibits neurite
      regeneration in rat superior cervical ganglia (SCG). The neuritogenic effects of
      inosine have been described in various models and the mechanism is thought to be
      N-kinase dependent. Because of the final common pathway between calcium dependent
      and N-kinase dependent neurite regeneration it was hypothesized that inosine
      would increase regeneration in normally regenerating SCG and reverse the
      inhibitory effects of DMBD on regenerating SCG. An in vitro model of rat SCG
      injury, where mature neurites are transected and observed at 2 and 24 h, was used
      to assess the effects of inosine on DMBD treated neurons. Results demonstrate a
      significant inhibition of growth in DMBD treated cultures, significantly
      increased growth in the inosine + DMBD treated SCG over DMBD treated cells and
      significantly increased growth in the inosine alone treated group over control
      cells. There is also evidence that inosine + DMBD treatment promotes linear
      growth of neurites. The implications of the findings are discussed.

PMID- 15026153
TI  - Melanocortin 4 receptor is expressed in the dorsal root ganglions and down
      regulated in neuropathic rats.
AB  - Recent reports have demonstrated effectiveness of melanocortin antagonists as
      potent analgesics, and have suggested that the spinal melanocortin 4 receptor
      (MC4-R) mediates their effects on pain transmission. These findings prompted us
      to investigate the changes in MC4-R mRNA level in the spinal cord and dorsal root
      ganglia (DRG) of neuropathic animals at different time points after sciatic nerve
      injury by quantitative real-time PCR. The spinal MC4-R mRNA level was not
      affected by sciatic nerve injury. In contrast, down-regulation of MC4-R mRNA in
      DRG developed 2 weeks after the injury and was parallel with the attenuated
      effectiveness of MC4-R ligands in neuropathic animals. The MC4-R adaptation in
      DRG observed in neuropathic rats indicates their important role in presynaptic
      modulation of activity of the primary afferents in neuropathic pain.

PMID- 15026154
TI  - Is there a transfer of postural ability from specific to unspecific postures in
      elite gymnasts?
AB  - The purpose of this study was to investigate the transfer of postural ability by
      comparing the level of performance and postural control of elite gymnasts in
      postures specifically trained or not. Fifteen elite gymnasts were asked to stand
      as still as possible with eyes opened in three conditions: bipedal, unipedal and
      handstand. Surface and mean velocity of the centre of pressure motions were used
      to quantify respectively performance and postural control. A ranking was made for
      each parameter to determine the level of each subject. As a whole, the subject's
      level of postural performance and control in one condition was not correlated to
      the corresponded level in another condition. Therefore, postural ability of elite
      gymnasts in the handstand is not transferable to upright standing postures.

PMID- 15026155
TI  - Acupuncture attenuates repeated nicotine-induced behavioral sensitization and c
      Fos expression in the nucleus accumbens and striatum of the rat.
AB  - Repeated injections of nicotine can produce behavioral sensitization, as
      evidenced by an enhanced locomotor response to a subsequent injection of the
      drug. Behavioral sensitization has been suggested as a model for studying drug
      addiction. Acupuncture as a therapeutic intervention is widely used for treatment
      for many functional disorders, such as substance abuse and mental dysfunction. We
      examined the effect of acupuncture on nicotine-induced behavioral locomotor
      activity and c-fos expression in the nucleus accumbens and striatum utilizing the
      immunocytochemical detection of the Fos protein. The rats were given repeated
      daily nicotine injections (0.4 mg/kg s.c., twice daily for 7 days) followed by
      one challenging injection on the 4th day after the last daily injection.
      Acupuncture at zusanli (ST36), but not control, significantly attenuated expected
      increase in nicotine-induced locomotor activity and Fos-like-immunoreactivity in
      the nucleus accumebns and striatum to subsequent nicotine challenge. These
      findings suggest that acupuncture has a therapeutic effect on nicotine addiction,
      possibly by modulating postsynaptic neuronal activity in the nucleus accumbens
      and the striatum.

PMID- 15026156
TI  - Vasoactive intestinal polypeptide phase-advances the rat suprachiasmatic nuclei
      circadian pacemaker in vitro via protein kinase A and mitogen-activated protein
      kinase.
AB  - The firing activity of suprachiasmatic nuclei (SCN) neurones in vitro shows a
      circadian rhythm with the peak in average firing frequency during the middle of
      the projected day. Vasoactive intestinal polypeptide (VIP), which is abundant in
      the rat SCN, phase-advances the time of peak in SCN neuronal activity when
      applied in vitro during the late projected night; an effect most likely mediated
      via the VPAC(2) receptor. Employing extracellular single-unit electrophysiology,
      we investigated the influence of protein kinase A (PKA) inhibitor KT5720 or
      mitogen-activated protein kinase kinase (MAPKK) inhibitor U0126 on phase advances
      evoked during the late projected night by VIP or Ro 25-1553, a VPAC(2) receptor
      agonist. Both inhibitors blocked VIP or Ro 25-1553-induced phase advances,
      indicating that the late-night resetting actions of VIP via the VPAC(2) receptor
      require PKA and MEK.

PMID- 15026158
TI  - Intracerebroventricular administration of urotensin II promotes anxiogenic-like
      behaviors in rodents.
AB  - We identified urotensin II (U-II) as the endogenous ligand for the orphan G
      protein-coupled receptor GPR14 or SENR. Both U-II and GPR14 are expressed not
      only in peripheral tissues but also in the brain of rodents, suggesting that U-II
      plays a physiological role in the central nervous system. In the present study,
      we investigated the central effects of U-II in rodents. Intracerebroventricular
      administration of U-II induced anxiogenic-like behaviors in the elevated plus
      maze test and the hole-board test in mice in a dose-dependent manner, as did
      corticotropin releasing factor (CRF). The effective doses of U-II were 10-100
      fold higher than these of CRF in these tests. Our results suggest that U-II is a
      candidate for the mediator of some aspect of stress or anxiety in the central
      nervous system.

PMID- 15026157
TI  - Comparative analyses of alpha-synuclein expression levels in rat brain tissues
      and transfected cells.
AB  - alpha-Synuclein may have a role in the genesis of Parkinson's disease (PD) and
      other neurodegenerative diseases, and overexpression of alpha-synuclein in
      endogenously expressing systems and transfected cell lines has been linked to its
      cytotoxicity. Because there is no definition of what constitutes normal or high
      expression levels of alpha-synuclein, the current studies were undertaken.
      Protein levels of alpha-synuclein, and its binding partner, the dopamine
      transporter (DAT), were examined and semi-quantified in different rat brain
      regions and compared to the amounts of alpha-synuclein expressed in Ltk(-) cells
      after transfection with known amounts of DNA. Of the regions tested, alpha
      synuclein expression was lowest in dopamine-producing brain areas, substantia
      nigra and ventral tegmental area; conversely, the expression of DAT was the
      highest in these tissues. Areas that do not normally degenerate in PD, such as
      cerebellum, nucleus accumbens and thalamus, expressed the highest levels of alpha
      synuclein and very low DAT. Expression of DAT and alpha-synuclein to levels
      similar to those observed in rat substantia nigra were obtained after
      transfection of Ltk(-) cells with 1-2 microg each of alpha-synuclein and DAT
      DNAs, indicating that such transfection conditions produce normal expression
      levels of these proteins.

PMID- 15026159
TI  - Stimulation of the nucleus basalis of Meynert increases diameter of the
      parenchymal blood vessels in the rat cerebral cortex.
AB  - To verify the hypothesis that stimulation of the nucleus basalis of Meynert (NBM)
      induces vasodilation in the cerebral cortical parenchyma, we investigated whether
      the diameter of parenchymal blood vessels of rat parietal cortex is increased
      during stimulation of NBM using histological techniques. The parietal cortex was
      fixed by immersion fixation in situ during focal electrical stimulation of the
      NBM, which increased cortical blood flow. Cortical tissues were sectioned
      horizontally to the cortical surface, and the parenchymal blood vessels were
      morphometrically analyzed using electron microscopy. Mean inner diameter of the
      parenchymal blood vessels in NBM stimulated rats (5.51+/-0.33 microm) was
      significantly larger than that in non-stimulated control rats (4.93+/-0.23
      microm). The result suggests that functional vasodilation in the cortical
      parenchyma during NBM stimulation correlates with histologically observed
      vasodilation in the cortical parenchyma.

PMID- 15026160
TI  - A novel haplotype of spinocerebellar ataxia type 6 contributes to the highest
      prevalence in western Japan.
AB  - The highest prevalence rate of spinocerebellar ataxia type 6 (SCA6) in the
      worldwide population is in the Chugoku and Kansai areas of Western Japan, but the
      reason of this geographic characteristics is unclear. We investigated the
      predisposing haplotypes and their geographic distribution. Genotyping of five
      microsatellite markers and three single nucleotide polymorphisms linked to the
      CACNA1A gene in 150 Japanese SCA6 patients from unrelated 118 families revealed
      three major haplotypes, carrying a pool of one common haplotype core. A founder
      chromosome was thought to have historically diverged into at least three types.
      One of the major haplotypes newly identified showed a strong geographical cluster
      around the Seto Inland Sea in the Chugoku and Kansai areas of Western Japan,
      whereas the others were widely distributed throughout Japan. The distribution of
      predisposing haplotypes contributes to the geographical differences in prevalence
      of SCA6.

PMID- 15026161
TI  - Activation of imidazoline receptor by agmatine to lower plasma glucose in
      streptozotocin-induced diabetic rats.
AB  - In the present study, we use agmatine, an endogenous ligand, to investigate the
      role of imidazoline receptor in plasma glucose regulation in streptozotocin
      induced diabetic rats (STZ-diabetic rats). After injection into the central
      lateral ventral (i.c.v.) of fasting STZ-diabetic rats for 30 min, agmatine
      produced plasma glucose lowering action in a concentration-dependent manner
      without alteration the mean arterial pressure (MAP). However, the plasma glucose
      was markedly raised in STZ-diabetic rats receiving similar injection of clonidine
      at dose (1 micromol/rat, i.c.v.) sufficient to lower MAP. Mediation of alpha(2)
      adrenoceptor in this action of agmatine seems unlikely. The plasma glucose
      lowering action of agmatine (1 micromol/rat, i.c.v.) was abolished by the
      pretreatment with BU-224 at concentration (100 nmol/rat) sufficient to block
      cerebral I(2)-imidazoline receptors. Also, this action of agmatine in STZ
      diabetic rats disappeared by spinal cord truncation between C6 and C7. Activation
      of cerebral I(2)-imidazoline receptor by agmatine can thus be considered for the
      lowering of plasma glucose. In conclusion, we suggest that an activation of I(2)
      imidazoline receptors in the brain may lower plasma glucose without insulin in
      animal.

PMID- 15026162
TI  - The role of anticipatory postural adjustments in a rocking on heels movement.
AB  - We studied the anticipatory postural adjustments (APAs) associated with a
      voluntary rocking on heels movement performed in a self-paced manner. Ground
      reaction forces and the EMG activity of the leg muscles were recorded. Such a
      movement shifted the centre of gravity (CG) backwards, due to APAs on the lower
      limbs. It is generally assumed that APAs only generate corrections in the
      opposite direction to the perturbation due to the focal movement. However, our
      study shows that APAs, by creating the initial backward oriented impulse,
      displace the CG backwards and generate the dynamic conditions required to move.

PMID- 15026163
TI  - Involvement of amygdalar extracellular zinc in rat behavior for passive
      avoidance.
AB  - On the basis of the evidence that zinc is released from glutamatergic neuron
      terminals in the amygdala, the effect of chelation of amygdalar extracellular
      zinc on glutamate release from the neuron terminals was studied by using in vivo
      microdialysis. When the amygdala was perfused with 100 microM CaEDTA to chelate
      extracellular zinc, glutamate concentration in the perfusate was decreased
      significantly, whereas that tended to be increased by perfusion with 100 microM
      ZnEDTA as a control. The effect of CaEDTA on extracellular glutamate levels was
      different between the amygdala and hippocampus, implying that modulation of
      glutamate signaling by zinc is different between them. To evaluate chelation of
      zinc in rat behavior, perfusion of the amygdala with CaEDTA was started 40 min
      before behavioral test for passive avoidance. The behavior for passive avoidance
      was impaired during perfusion with CaEDTA. On the other hand, the behavior during
      perfusion with ZnEDTA was more rapidly developed than that with vehicle only.
      These results suggest that amygdalar extracellular zinc is involved in the
      behavior for passive avoidance.

PMID- 15026164
TI  - High affinity D- and L-serine transporter Asc-1: cloning and dendritic
      localization in the rat cerebral and cerebellar cortices.
AB  - System asc transporter Asc-1, expressed in the brain, transports D- and L-serine
      with high affinity. To determine the localization of Asc-1 in the rat brain, we
      isolated a cDNA for the rat orthologue of Asc-1. The encoded protein designated
      as rAsc-1 (rat Asc-1) exhibited 98% sequence identity to mouse Asc-1 (mAsc-1).
      Based on amino acid sequences of rAsc-1 and mAsc-1, two polyclonal antibodies
      against Asc-1 were generated and used for the immunohistochemical analysis on the
      cerebral and cerebellar cortices of rats and mice. Asc-1 immunoreactivity was
      detected in neurons, including cerebellar Purkinje neurons and pyramidal neurons
      in the neocortex and hippocampus. It was clearly localized in dendrites as well
      as somata. The localization of Asc-1 in brain suggests the significant
      contribution of Asc-1 to amino acid mobilization in brains including the synaptic
      clearance of D-serine and the neuronal uptake of L-serine that is essential for
      survival and dendrite growth of Purkinje neurons in particular.

PMID- 15026165
TI  - Somatostatin induces striatal dopamine release and contralateral turning
      behaviour in the mouse.
AB  - Application of somatostatin to the striatum of the anaesthetized rat has
      previously been shown to elicit large increases in extracellular levels of
      dopamine and GABA via a glutamate-dependent mechanism. These actions have been
      ascribed to the SSTR2 receptor. Here we describe experiments designed to
      investigate whether these effects occur in C57Bl6 mice and if they elicit
      rotational behaviours associated with increased dopamine in the striatum.
      Application of somatostatin resulted in increased concentrations of dopamine in
      striatum, hippocampus and amygdala of anaesthetized mice. Unilateral striatal
      infusions of the peptide by retrodialysis increased locomotion. Application of N
      methyl-D-aspartate and AMPA to the freely-moving mouse striatum resulted in
      increased dopamine release; however, only AMPA caused increased locomotion. These
      results further confirm that somatostatin can play a role in the control of
      locomotor function by modulating striatal dopamine release.

PMID- 15026166
TI  - Displaced granule cells in the molecular layer of the cerebellar cortex in mice
      treated with methylazoxymethanol.
AB  - To study the effect of a reduced granule cell number on the development of the
      cerebellum, mice were administered with methylazoxymethanol (MAM) at birth and
      examined histologically at 21 days of age. In these mice, green fluorescent
      protein had been knocked in within the glutamic acid decarboxylase 67 gene,
      resulting in fluorescent GABAergic neurons. In severe cases, granule cells were
      greatly reduced in number and mixed with Purkinje cells instead of forming
      layers. In about 10% of the MAM-treated mice, an ectopic cell layer consisting of
      granule cells was observed within the molecular layer. Concomitantly, basket
      cells disappeared. The transient interruption of granule cell production in the
      external granular layer presumably resulted in their incomplete migration through
      the molecular layer.

PMID- 15026167
TI  - Modulation of taste peripheral signal through interpapillar inhibition in
      hamsters.
AB  - Single taste buds from fungiform papillae were iontophoretically stimulated with
      chemicals filling glass microelectrodes while a single unit was recorded in the
      taste pore of a neighbor papilla. High signal-to-noise ratio responses were
      observed in the recorded papilla as antidromic action potentials. These responses
      were possibly modulated by the simultaneous stimulation of another adjacent
      papilla. A decrease in the frequency of firing and/or both decrementing spikes
      were observed during such dual papillae stimulations. These inhibitory effects
      were not modified by the section of the chordo-lingual nerve, suggesting the
      tongue is able to process the gustatory information thanks to interpapillar
      negative feedback, prior to transmitting the signal to the central nervous
      system. Branched chorda tympani fibers can account for responses observed for
      single papillae stimulations; inhibitions and decrementing spikes may suggest the
      contribution of another mechanism of interaction between two different single
      fibers.

PMID- 15026168
TI  - Candidate gene association studies of the alpha 4 (CHRNA4) and beta 2 (CHRNB2)
      neuronal nicotinic acetylcholine receptor subunit genes in Alzheimer's disease.
AB  - Consistent deficits in the cholinergic system are evident in Alzheimer's disease
      (AD) patients, including selective loss of alpha4beta2 nicotinic acetylcholine
      receptors in the brains of AD patients. Knockout mice for the beta2 subunit have
      impaired neuronal survival in ageing. Accordingly, we have analysed polymorphisms
      in the genes that encode the alpha4 and beta2 subunits, CHRNA4 and CHRNB2
      respectively, for genetic associations with late-onset AD. A significant
      association for disease was observed for a non-coding polymorphism in CHRNB2
      (odds ratio=0.57, 95% confidence interval=0.35-0.95, P=0.024). Replication
      analysis was performed in two further sample sets. While these did not
      individually yield significant results, a significant association remained when
      all samples were pooled (odds ratio=0.70, 95% confidence interval=0.52-0.95,
      P=0.019). These data suggest that this variant warrants further examination in
      large case-control series.

PMID- 15026169
TI  - Halloween genes encode P450 enzymes that mediate steroid hormone biosynthesis in
      Drosophila melanogaster.
AB  - Mutation of members of the Halloween gene family results in embryonic lethality.
      We have shown that two of these genes code for enzymes responsible for specific
      steps in the synthesis of ecdysone, a polyhydroxylated sterol that is the
      precursor of the major molting hormone of all arthropods, 20-hydroxyecdysone.
      These two mitochondrial P450 enzymes, coded for by disembodied (dib) (CYP302A1)
      and shadow (sad) (CYP315A1), are the C22 and C2 hydroxylases, respectively, as
      shown by transfection of the gene into S2 cells and subsequent biochemical
      analysis. These are the last two enzymes in the ecdysone biosynthetic pathway. A
      third enzyme, necessary for the critical conversion of ecdysone to 20
      hydroxyecdysone, the 20-monooxygenase, is encoded by shade (shd) (CYP314A1). All
      three enzymes are mitochondrial although shade has motifs suggesting both
      mitochondrial and microsomal locations. By tagging these enzymes, their
      subcellular location has been confirmed by confocal microscopy. Shade is present
      in several tissues as expected while disembodied and shadow are restricted to the
      ring gland. The paradigm used should allow us to define the enzymes mediating the
      entire ecdysteroid biosynthetic pathway.

PMID- 15026170
TI  - A shift in steroidogenesis occurring in ovarian follicles prior to oocyte
      maturation.
AB  - Gonadotropins (GTHs; FSH and LH) require two major steroidal mediators, estradiol
      17 beta (E(2)) and 17 alpha,20 beta-dihydroxy-4-pregnen-3-one (17 alpha,20 beta
      DP) to act as critical hormones to execute oocyte growth and maturation,
      respectively. A two-cell type model has been proposed, where the theca cells
      provide the precursor steroids, and the granulosa cells produce the two steroidal
      mediators under the direct influence of FSH and LH. A distinct shift in
      steroidogenesis, i.e. from E(2) to 17 alpha,20 beta-DP as well as the
      steroidogenic enzyme genes from ovarian cytochrome P450 aromatase (oP450arom) to
      20 beta-hydroxysteroid dehydrogenase (20 beta-HSD), occurs in the granulosa
      layers of ovarian follicles prior to oocyte maturation. The triggering of the
      steroidogenic shift by GTHs in granulosa cells occurs through the subjugation of
      Ad4BP/SF-1 expression in respect of oP450arom, followed by an over-expression of
      20 beta-HSD probably through the CREB.

PMID- 15026171
TI  - Identification and characterization of 17 beta-hydroxysteroid dehydrogenases in
      the zebrafish, Danio rerio.
AB  - The 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) are key enzymes in the
      final steps of steroid hormone synthesis. 17beta-HSD type 1 (HSD17B1) catalyzes
      the reduction of estrone to estradiol, while type 3 (HSD17B3) performs the
      conversion of androstenedione to testosterone. Here we present a functional
      genomics study of putative candidates of these enzymes in the zebrafish. By an in
      silico screen of zebrafish EST databases we identified three candidate homologs
      for both HSD17B1 and HSD17B3. Phylogenetic analysis, unique expression patterns
      (RT-PCR) during embryogenesis and adulthood, as well as activity measurements
      revealed that one of the HSD17B1 candidates is the zebrafish homolog, while the
      other two are paralogous photoreceptor-associated retinol dehydrogenases. All
      three HSD17B3 candidate genes showed nearly identical, ubiquitous expressions in
      embryogenesis and adult tissues and were identified to be paralogs of HSD17B12
      and a yet uncharacterized putative steroid dehydrogenase. Phylogenetic analysis
      shows that HSD17B3 and HSD17B12 are descendants from a common ancestor.

PMID- 15026172
TI  - Vitamin D and barrier function: a novel role for extra-renal 1 alpha-hydroxylase.
AB  - Much recent attention has focused on the positive health benefits of vitamin D
      beyond its established role in calcium homeostasis. Epidemiology has highlighted
      the link between vitamin D deficiency and prevalent diseases such as common
      cancers and autoimmune disease. Furthermore, studies in vitro have shown that the
      active form of vitamin D, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is a
      potent antiproliferative and immunosuppressive agent. The net effect of this has
      been the generation and analysis of synthetic analogues of vitamin D for
      potential use in the treatment of cancers and other disorders including
      psoriasis. However, there is increasing interest in the impact that vitamin D may
      have on normal physiology above and beyond its classical effects on calcium
      homeostasis and bone metabolism. We have postulated that these 'non-calcemic'
      effects of vitamin D are dependent on extra-renal synthesis of 1,25(OH)(2)D(3)
      via the enzyme 1 alpha-hydroxylase at barrier sites throughout the body. Here we
      present a review of the mechanisms associated with extra-renal 1 alpha
      hydroxylase, and we also speculate on how this 'new' physiological role for
      vitamin D may actually reflect an ancient function for this pluripotent
      secosteroid.

PMID- 15026173
TI  - Regulation of aromatase expression by the nuclear receptor LRH-1 in adipose
      tissue.
AB  - Aromatase is the enzyme responsible for estrogen production, and is the product
      of the CYP19 gene. This gene is under the control of many tissue-specific
      promoters, each of which is regulated by different cohorts of factors. In normal
      breast adipose tissue, relatively low levels of aromatase are expressed via the
      action of the adipose specific promoter I.4. Breast tumor-derived factors such as
      prostaglandin E(2) (PGE(2)) strongly stimulate aromatase expression via an
      alternative promoter, promoter II, leading to increased estrogenic drive and
      tumor growth. Understanding the mechanisms that regulate promoter II activity in
      tumorous breast may therefore identify new targets for breast cancer drug
      discovery. The current study describes the role of the orphan nuclear receptor
      LRH-1 and its co-regulators in modulating aromatase expression in breast adipose
      tissue.

PMID- 15026174
TI  - 11 beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic
      syndrome.
AB  - 11 beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyses the in vivo
      conversion of inactive to active glucocorticoids. It is a widespread, highly
      regulated enzyme which amplifies the ligand available for intracellular
      glucocorticoid receptors. Excessive glucocorticoid exposure causes central
      obesity, hypertension, dyslipidaemia and insulin resistance, as seen with
      elevated plasma cortisol in Cushing's syndrome. Transgenic mice over-expressing
      11HSD1 in their white adipose tissue are obese, hypertensive, dyslipidaemic and
      insulin resistant. Further, 11HSD1 knockout mice are protected from these
      metabolic abnormalities. In human idiopathic obesity, circulating cortisol levels
      are not elevated but 11HSD1 mRNA and activity is increased in subcutaneous
      adipose. The impact of increased adipose 11HSD1 on pathways leading to metabolic
      complications remains unclear in humans. Pharmacological inhibition of 11HSD1 has
      been achieved in liver with carbenoxolone, which enhances hepatic insulin
      sensitivity. Newer selective 11HSD1 inhibitors are in development, which may
      achieve reduced cortisol action in adipose tissue and confer therapeutic benefit
      in obese patients.

PMID- 15026175
TI  - Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and
      sex steroid receptors.
AB  - Receptors for the adrenal and sex steroids arose by a series of gene duplications
      from an ancestral nuclear receptor in a primitive vertebrate, at least 540
      million years ago. Sequence analysis indicates many steroidogenic and steroid
      inactivating enzymes, including cytochrome P450s and hydroxysteroid
      dehydrogenases (HSDs), arose at the same time. The estrogen receptor (ER) appears
      to be the ancestral steroid receptor. Initially, the redundant duplicated ER had
      a low specificity for its new ligand. This raises the question: "How was
      specificity for responses to different steroids regulated early in the evolution
      of steroid receptors?" Selective expression of these steroid-metabolizing enzymes
      provided specificity for different steroid responses in primitive vertebrates. 17
      beta-Hydroxysteroid dehydrogenase-type 1 (17 beta-HSD-type 1) and 17 beta-HSD
      type 2, which preferentially catalyze the reduction and oxidation at C17 of
      androgens and estrogens, respectively, provide an example of this mechanism.
      Selective expression of either 17 beta-HSD-type 1 or 17 beta-HSD-type 2 can
      regulate synthesis or inactivation of androgens or estrogens in specific cells.
      Steroids also were important in the evolution of land animals, which began about
      400 million years ago. Steroidogenic and steroid-inactivating enzymes were
      recruited to regulate steroid-mediated responses as organ function became more
      complex. For example, in the kidney 11 beta-HSD-type 2 prevents binding of
      glucocorticoids to the mineralocorticoid receptor (MR), which is crucial for
      aldosterone-mediated regulation of electrolyte transport in the distal tubule. We
      propose that Delta 5 steroids, such as dehydroepiandrosterone and its
      metabolites, were the ligands for the ancestral ER. Understanding the actions of
      Delta 5 steroids in amphioxus and lamprey may shed light on adrenarche and
      neurosteroid actions in humans.

PMID- 15026176
TI  - Structure-function of human 3 alpha-hydroxysteroid dehydrogenases: genes and
      proteins.
AB  - Four soluble human 3 alpha-hydroxysteroid dehydrogenase (HSD) isoforms exist
      which are aldo-keto reductase (AKR) superfamily members. They share 86% sequence
      identity and correspond to: AKR1C1 (20 alpha(3 alpha)-HSD); AKR1C2 (type 3 3
      alpha-HSD and bile-acid binding protein); AKR1C3 (type 2 3 alpha-HSD and type 5
      17 beta-HSD); and AKR1C4 (type 1 3 alpha-HSD). Each of the homogeneous
      recombinant enzymes are plastic and display 3-, 17- and 20-ketosteroid reductase
      and 3 alpha- 17 beta- and 20 alpha-hydroxysteroid oxidase activities with
      different k(cat)/K(m) ratios in vitro. The crystal structure of the
      AKR1C2.NADP(+).ursodeoxycholate complex provides an explanation for this
      functional plasticity. Ursodeoxycholate is bound backwards (D-ring in the A-ring
      position) and upside down (beta-face of steroid inverted) relative to the
      position of 3-ketosteroids in the related rat liver 3 alpha-HSD (AKR1C9)
      structure. Transient transfection indicates that in COS-1 cells, AKR1C enzymes
      function as ketosteroid reductases due to potent inhibition of their oxidase
      activity by NADPH. By acting as ketosteroid reductases they may regulate the
      occupancy of the androgen, estrogen and progesterone receptors. RT-PCR showed
      that AKRs are discretely localized. AKR1C4 is virtually liver specific, while
      AKR1C2 and AKR1C3 are dominantly expressed in prostate and mammary gland. AKR1C
      genes are highly conserved in structure and may be transcriptionally regulated by
      steroid hormones and stress.

PMID- 15026177
TI  - Structure/function aspects of human 3beta-hydroxysteroid dehydrogenase.
AB  - Separate genes encode the human type 1 (placenta, breast tumors, other peripheral
      tissues) and type 2 (gonad, adrenal) isoforms of 3 beta-hydroxysteroid
      dehydrogenase/isomerase (3 beta-HSD1, 3 beta-HSD2). Mutagenesis of 3 beta-HSD1
      produced the Y154F, H156Y and K158Q mutant enzymes in the probable Y(154)-P
      H(156)-S-K(158) catalytic motif. The H(156)Y mutant of the 3 beta-HSD1 created a
      chimera of the 3 beta-HSD2 motif (Y(154)-P-Y(156)-S-K(158)) in 3 beta-HSD1. The
      D241N, D257L, D258L and D265N mutants are in the potential isomerase site of the
      3 beta-HSD1 enzyme. Homology modeling with UDP-galactose-4-epimerase predicted
      that Asp(36) in the Rossmann-fold domain is responsible for the NAD(H)
      specificity of human 3 beta-HSD1, and our D36A/K37R mutant tested that
      assignment. The H(156)Y mutant of the 3 beta-HSD1 enzyme shifted the substrate
      (DHEA) kinetics to the 14-fold higher K(m) value measured for the 3 beta-HSD2
      activity. From Dixon analysis, epostane inhibited the 3 beta-HSD1 activity with
      17-fold greater affinity compared to 3 beta-HSD2 and H(156)Y. The mutants of
      Tyr(154) and Lys(158) exhibited no dehydrogenase activity and appear to be
      catalytic 3 beta-HSD residues. The D257L and D258L mutations eliminated isomerase
      activity, suggesting that Asp(257) or Asp(258) may be catalytic residues for
      isomerase activity. The D36A/K37R mutant shifted the cofactor preference of both
      3 beta-HSD and isomerase from NAD(H) to NADP(H). In addition to characterizing
      catalytic residues, these studies have identified the structural basis (His(156))
      for an exploitable difference in the substrate and inhibition kinetics of 3 beta
      HSD1 and 3 beta-HSD2. Hence, it may be possible to selectively inhibit human 3
      beta-HSD1 to slow the growth of hormone-sensitive breast tumor cells and control
      placental steroidogenesis near term to prevent premature labor.

PMID- 15026178
TI  - 17 beta-hydroxysteroid dehydrogenases--their role in pathophysiology.
AB  - 17 beta-Hydroxysteroid dehydrogenases (17HSDs) regulate the biological activity
      of sex steroid hormones in a variety of tissues by catalyzing the
      interconversions between highly active steroid hormones, e.g. estradiol and
      testosterone, and corresponding less active hormones, estrone and
      androstenedione. Epidemiological and endocrine evidence indicates that estrogens
      play a role in the etiology of breast cancer, while androgens are involved in
      mechanisms controlling the growth of normal and malignant prostatic cells. Using
      LNCaP prostate cancer cell lines, we have developed a cell model to study the
      progression of prostate cancer. In the model LNCaP cells are transformed in
      culture condition into more aggressive cells. Our data suggest that substantial
      changes in androgen and estrogen metabolism occur in the cells, leading to
      increased production of active estrogens during the process. In breast cancer,
      the reductive 17HSD type 1 activity is predominant in malignant cells, while the
      oxidative 17HSD type 2 mainly seems to be present in non-malignant breast
      epithelial cells. Deprivation of an estrogen response by using specific 17HSD
      type 1 inhibitors is a tempting approach in treating estrogen-dependent breast
      cancer. Our recent studies demonstrate that in addition to sex hormone target
      tissues, estrogens may be important in the development of cancer in some other
      tissues previously not considered to be estrogen target tissues, such as the
      gastrointestinal tract.

PMID- 15026180
TI  - Function of Cyp11a1 in animal models.
AB  - CYP11A1 encodes the P450scc enzyme that catalyzes the first and rate-limiting
      step of steroid biosynthesis. It is expressed in the adrenals and gonads under
      the control of pituitary peptide hormones. Transcription factor SF-1, which binds
      to the CYP11A1 promoter, plays an important role in the tissue-specific and
      hormonally regulated expression. Transgenic mouse experiments linking the CYP11A1
      promoter to a reporter gene demonstrate the importance of the SF-1-binding site
      in directing balanced CYP11A1 gene expression. In addition, targeted mutagenesis
      of Cyp11a1 also reveals the importance of this gene in steroid secretion, gene
      regulation, and development of genitalia. Zebrafish cyp11a1 is expressed in the
      gonads and interrenal glands in the adults, similar to mammals. In addition, it
      is expressed in yolk syncytial layer during early embryogenesis. These two animal
      models complement each other for the understanding of gene regulatory pathways in
      human diseases related to steroid imbalance.

PMID- 15026179
TI  - Tissue-specific knockouts of steroidogenic factor 1.
AB  - Targeted gene disruption has produced knockout (KO) mice globally deficient in
      the orphan nuclear receptor steroidogenic factor 1 (SF-1). These SF-1 KO mice
      lacked adrenal glands and gonads, and also had impaired expression of
      gonadotropins in pituitary gonadotropes and marked structural abnormalities of
      the ventromedial hypothalamic nucleus (VMH). To define the roles of SF-1 within
      discrete sites of the hypothalamic-pituitary-steroidogenic organ axis, we have
      sought to make tissue-specific SF-1 KO mice (as reviewed here). We first used
      adrenal transplants to restore adrenal function in global SF-1 KO mice, providing
      a physiological form of a "VMH-specific" KO to study the roles of SF-1 in weight
      regulation. These adrenal-transplanted SF-1 KO mice became obese due to decreased
      locomotor activity, providing a novel model of hypothalamic obesity. Mice with a
      pituitary-specific KO of SF-1 mediated by the Cre-loxP recombination strategy
      exhibited hypogonadotropic hypogonadism, revealing essential roles of SF-1 in
      pituitary function in vivo. Ongoing studies seek to inactivate SF-1 in the brain
      or specific gonadal cell types, thereby defining its roles in development and
      function at these sites. In addition, we review our use of bacterial artificial
      chromosome transgenesis to develop a fluorescent marker for cells that express SF
      1.

PMID- 15026181
TI  - Expression of adenylyl cyclase-4 (AC-4) in Y1 and forskolin-resistant adrenal
      cells.
AB  - Forskolin-resistant mutants of a mouse adrenocortical cell line present a complex
      phenotype in which adenylyl cyclase (AC) is resistant to activation by forskolin
      and by ACTH. ACTH-resistance results from a defect affecting transcription of the
      ACTH receptor and can be overcome by transfecting mutant cells with expression
      vectors encoding G beta/gamma. Forskolin-resistance results from an AC-4
      deficiency. We now demonstrate that the AC-4 deficiency in forskolin-resistant
      mutants results from a transcription defect affecting the promoter activity of
      the AC-4 gene. Furthermore, the underlying defect leading to AC-4 deficiency and
      forskolin-resistance can be overcome by transfection of mutant clones with
      expression vectors encoding G beta/gamma. These data support our hypothesis that
      AC-4 is a preferred target of forskolin action in Y1 cells, demonstrate novel
      roles for G beta/gamma in gene expression and indicate that a common underlying
      defect, suppressible by G beta/gamma, accounts for both the resistance to ACTH
      and to forskolin.

PMID- 15026182
TI  - ACTH induces TIMP-1 expression and inhibits collagenase in adrenal cortex cells.
AB  - To identify genes that are induced by corticotropin (ACTH) in adrenal cortex
      cells, we carried out a differential hybridization screening of adrenal cortex
      cDNA libraries. Some of the clones we identified represented tissue inhibitor of
      metalloproteinase 1 (TIMP-1) mRNA. We examined ACTH dependence of the expression
      of TIMP-1 in vitro in cultured bovine adrenocortical cells, and in ACTH-treated
      rats. Northern blot analysis of total RNA from cells showed that the level of
      TIMP-1 mRNA increases sharply within 3h after ACTH stimulation. Since TIMP-1
      inhibits some cell matrix metalloproteinases (MMPs) of the collagenase type, we
      examined the effect of ACTH on collagenase activity in bovine adrenocortical
      cells. Exposure of confluent cultures to ACTH for 24h showed dose-dependent
      inhibition of collagenase activity. Northern blot analysis of total RNA from rat
      adrenal zona fasciculata-reticularis and zona glomerulosa showed that in both of
      these zones TIMP-1 expression was induced within 12h after ACTH injection. Long
      term (9 days) treatment with ACTH increased TIMP-1 mRNA levels nearly sixfold in
      zona fasciculata-reticularis. Overall, our results show that ACTH causes
      induction of TIMP-1 and suppression of collagenase activity, and suggest that
      ACTH may modulate the activities of MMPs and hence cell matrix remodeling.

PMID- 15026183
TI  - The effect of cytoplasmic Ca2+ signal on the redox state of mitochondrial
      pyridine nucleotides.
AB  - As first observed in rat adrenal glomerulosa cells, cytoplasmic Ca(2+) signal,
      induced by K(+), angiotensin II or vasopressin, evokes an increase in the level
      of reduced mitochondrial pyridine nucleotides, NADH and NADPH. Prostaglandin
      F(2)alpha and extracellular ATP exert similar effects in rat ovarian luteal
      cells. This coupling of cytoplasmic Ca(2+) concentration and mitochondrial
      metabolism occurs also when the stimuli are applied at physiological
      concentration and under conditions when no formation of high-Ca(2+)
      perimitochondrial microdomains may be presumed. We present evidence that low
      submicromolar Ca(2+) signals in the cytoplasm can increase mitochondrial Ca(2+)
      concentration and activate mitochondrial dehydrogenation processes. Several
      observations support the assumption that intramitochondrial Ca(2+) signals play a
      significant role in the stimulation of steroid hormone production.

PMID- 15026184
TI  - Regulation of transcription of the steroidogenic acute regulatory protein (StAR)
      gene: temporal and spatial changes in transcription factor binding and histone
      modification.
AB  - We examined the binding of transcription factors and histone modifications
      associated with induction of expression of the steroidogenic acute regulatory
      protein (StAR) gene in MA-10 cells using a quantitative chromatin
      immunoprecipitation (ChIP) assay. GATA-4, SF-1/Ad4BP, and cyclic AMP response
      element binding protein binding protein (CBP) bind rapidly to the StAR proximal
      promoter, but in different patterns following 8-Br-cAMP stimulation.
      Concomitantly, histone modifications occur in a spatial and temporal sequence
      including increased association of acetylated histone H3 with the proximal
      promoter region, increased association of dimethylated lysine 4 histone H3 with
      exonic sequences, a modification that marks actively transcribed regions, and
      reduced association of a marker linked to gene silencing (lysine 9 dimethylated
      histone H3). Our findings demonstrate that transcription factors and coactivators
      are rapidly associated with the StAR proximal promoter, that the patterns of
      binding differ which has implications for postulated direct interactions among
      these factors, and that multiple histone modifications are demonstrable in a
      spatially- and temporally-specific pattern along the StAR gene. These
      observations suggest that a combinatorial code of transcription factors including
      reciprocal changes in histone modifications associated with active transcription
      and gene silencing control StAR gene expression.

PMID- 15026185
TI  - Phosphorylation of the hamster adrenal steroidogenic acute regulatory protein as
      analyzed by two-dimensional polyacrylamide gel electrophoreses.
AB  - Post-translational modifications such as phosphorylation and specific proteolysis
      affect the steroidogenic acute regulatory protein (StAR) activity. We have found
      that in pcDNA3.1-StAR-transfected COS-1 cells, StAR was phosphorylated on S55,
      S56 and S194 (Fleury et al., unpublished). In this study, we are comparing the
      two-dimensional gel electrophoresis (2D-PAGE) characteristics of the WT StAR with
      those of the S194A and S55A/S56A/S194A-StAR mutants under control and (Bu)(2)
      cAMP stimulation, using an anti-StAR antibody and an anti-phospho-(Ser/Thr) PKA
      substrate antibody. The 2D-PAGE migration pattern of the WT StAR analyzed by
      immunoblotting with the anti-StAR antibody revealed many StAR species with
      different pI and different molecular weights. In the (Bu)(2)-cAMP-WT
      preparations, except for three, all these StAR species were also recognized by
      the anti-phospho-(Ser/Thr) PKA substrate antibody; in contrast, less
      phosphorylated species were found in the non-stimulated WT preparations. The two
      dimensional (2D) patterns of StAR revealed by the anti-StAR and the anti-phospho
      (Ser/Thr) PKA substrate antibodies were modified for the S194A mutant and further
      modified for the S55A/S56A/S194A mutant. Whereas many species could still be
      detected by the anti-StAR antibody in the triple mutant S55A/S55A/S194A, none of
      these could be revealed by the anti-phospho-(Ser/Thr) PKA substrate antibody.
      Finally we found that, in addition to phosphorylation, the formation of different
      StAR species was also due to the hydrolysis of the molecule at its N-terminal and
      to a lesser degree at its C-terminal.

PMID- 15026186
TI  - Cytokines and steroidogenesis.
AB  - Cytokines interfere with steroidogenesis at the level of the adrenals, testes,
      and ovaries. Within the adrenal, macrophages, and lymphocytes, physiologically
      widely infiltrating the adrenal cortex, and adrenocortical, and chromaffin cells
      produce cytokines, as IL-1, IL-6, TNFalpha, leukemia inhibitory factor (LIF), and
      IL-18 which have a key role in the immune-adreno-cortical communication. In
      addition to cytokines interacting with adrenal function, cytokine independent
      mechanisms are responsible for a cell to cell-mediated immune regulation of the
      adrenal. The importance of this immune-endocrine cross-talk becomes evident in
      the case of autoimmune and inflammatory diseases being necessary for an adequate
      adrenal stress response. Secretory products of macrophages are involved in the
      regulation of steroidogenesis, Sertoli cell activity, and germ cell survival in
      the human testes. In rats, IL-1 is involved in the paracrine regulation of Leydig
      cell steroidogenesis. IL-6 has been suggested to exert adverse effects on the
      male reproductive function, inducing persistent testicular resistance to
      luteinizing hormone (LH) action and/or suppression of Leydig cell
      steroidogenesis. Cytokines such as IL-8 and MCP-1 (monocyte chemotactic protein
      1) are involved in follicular development and atresia, ovulation,
      steroidogenesis, and corpus luteum function. In undifferentiated ovarian cells
      TNF and IL-1 inhibit steroidogenesis, whereas in differentiated ovaries these
      cytokines stimulate progesterone synthesis. Some ovarian cancer cells secrete TNF
      and IL-1 which stimulate growth of these cells. In conclusion, cytokines interact
      with steroidogenesis in a systemic and complex manner, influencing development,
      function, and hormone production of the adrenals, testes, and ovaries.

PMID- 15026187
TI  - Characterization of the adrenal-specific antigen IZA (inner zone antigen) and its
      role in the steroidogenesis.
AB  - Inner zone antigen (IZA) is a protein specifically expressed in the zona
      fasciculata and reticularis of the adrenal cortex. The cDNA encoding IZA was
      found to be identical to that encoding the previously reported putative membrane
      associated progesterone receptor (MPR) and the TCDD-induced 25kDa protein (25
      Dx). From its structure, MPR was classed as a member of a protein family
      containing a haem-binding domain, and progesterone was proposed to be a ligand of
      this domain. Indeed, when GST-tagged IZA was expressed in Escherichia coli and
      purified, the purified GST-IZA had a brown colour with maximum absorbance at 400
      nm. The addition of dithionate shifted the absorbance peak to 420 nm, suggesting
      a haem-binding function. The possible role of IZA in steroidogenesis has been
      addressed, and the inhibition of adrenal steroidogenesis by the addition of an
      anti-IZA monoclonal antibody has been reported. When COS-7 cells were transformed
      with plasmids for appropriate steroidogenic enzymes in the presence or absence of
      an IZA expression plasmid and tested for their steroidogenic activities, 21
      hydroxylation of progesterone was found to be specifically activated by IZA
      overexpression, suggesting the involvement of IZA in progesterone metabolism.
      Taken together, the available evidence suggests that IZA may have an important
      role in the functions of the adrenal zona fasciculata and reticularis.

PMID- 15026189
TI  - Putative F-G loop is involved in association with the membrane in P450scc (P450
      11A1).
AB  - Cytochrome P450scc (P450 11A1) catalyzes the conversion of cholesterol to
      pregnenolone, the first step in overall steroid hormone biosynthesis in
      steroidogenic tissues. On the basis of alignment with structurally characterized
      cytochromes P450 (P450s), we have identified the putative F-G loop of P450 11A1
      and mutated amino acid residues in this region. Wild type and mutant P450s 11A1
      were expressed in E. coli and compared with respect to subcellular distribution
      and turnover number. About 30% of the wild type P450 was found in the bacterial
      cytosol indicating loose association of the enzyme with the membrane. The
      N210S/V211M and L218R/F219Y replacements increased the fraction of P450 in the
      bacterial cytosol 1.5-1.7-fold and the latter mutant also showed an almost two
      fold increase of the turnover number. These data indicate that the putative F-G
      loop is the site of attachment to the membrane in P450 11A1 and changes in the
      enzyme-membrane interactions may affect the rate of catalysis.

PMID- 15026188
TI  - Modulation of aldosterone and cortisol synthesis on the molecular level.
AB  - CYP11B1 and the closely related CYP11B2 are involved in the production of adrenal
      steroid hormones. Although in human their primary structure is 93% identical they
      are involved in the biosynthesis of functionally diverse products, such as
      glucocorticoids and mineralocorticoids, respectively. In contrast, bovine CYP11B1
      combines both activities in one single enzyme. The CYP11B family belongs to class
      I cytochromes P450 that have been described in bacteria and mitochondria and
      receive their electrons from a low molecular weight iron sulphur protein which is
      reduced by a NADPH-dependent FAD-containing reductase. In this review, we
      summarise the current knowledge on the modulation of aldosterone and cortisol
      synthesis by transcriptional regulation, on the molecular level as consequence of
      mutations found in patients suffering from steroid hormone-related diseases as
      well as introduced by site-directed mutagenesis and as consequence of protein
      protein interaction with both CYP11A1 and the natural redox partner adrenodoxin.

PMID- 15026192
TI  - On the behavior of solutions in viral dynamical models.
AB  - We consider simple mathematical models for the early population dynamics of the
      human immunodefficiency type 1 virus (HIV-1). Although these systems of
      differential equations may be solved by numerical methods, few general
      theoretical results are available due to nonlinearities. We analyze a model whose
      components are plasma densities of uninfected CD4+ T-cells and infected cells
      (assumed in this model to be proportional to virion density). In addition to
      analyzing the nature of the equilibrium points, we show that there are no
      periodic or limit-cycle solutions. Depending on the values of the parameters,
      solutions either tend without oscillation to an equilibrium point with zero
      virion density or to an equilibrium point in which there are a nonzero number of
      virions. In the latter case the approach to equilibrium may be through damped
      oscillations or without oscillation.

PMID- 15026190
TI  - CYP51--the omnipotent P450.
AB  - Sterol 14 alpha-demethylase (CYP51) is the single cytochrome P450 (CYP) required
      for sterol biosynthesis in different phyla, and it is the most widely distributed
      P450 gene family being found in all biological kingdoms. It catalyzes the first
      step following cyclization in sterol biosynthesis such as removal of the 14 alpha
      methyl group from lanosterol in the cholesterol biosynthetic pathway, leading to
      formation of the initial substrate in steroid hormone biosynthesis. CYP51 from
      different phyla have low sequence similarity across kingdoms and contain only
      about 40 conserved amino acid residues in the whole family. An attempt to predict
      the possible role of these conserved residues is being made by a combination of
      the results of site-directed mutagenesis and information from the known crystal
      structure of sterol 14 alpha-demethylase from Mycobacterium tuberculosis.

PMID- 15026194
TI  - Adaptive methods for growing electronic circuits on an imperfect synthetic
      matrix.
AB  - Living systems can adapt to injuries and even heal themselves, an ability
      desirable also in synthetic systems. A method is presented for dynamically
      adapting the construction of an electronic circuit to hardware defects by
      formulating the process as a series of interactions between identical but
      specialized structures called supercells. The circuit components, including
      wires, can occupy any place in the hardware that has been determined to be free
      of defects. The circuit specification is reduced to a connected graph, with no
      positional information, and provided as a code repeated in each supercell. Using
      the code, supercells differentiate into circuit components in a late stage of the
      process, with highly adaptable physical location and organization; supercells
      also form the wires between circuit components. The structure and function of the
      system at three major levels is presented, the lowest cellular level, the
      supercell, and the target circuit level. Adaptation of circuit construction to
      defective hardware was observed for this method. Results obtained from this
      development process on simulated and real hardware with a variety of defect types
      and defect patterns are presented, as well as higher level simulations of the
      algorithm and its response to a wider range of defect patterns, amounts of
      hardware, and hardware to fault ratios.

PMID- 15026193
TI  - Global change in Escherichia coli gene expression in initial stage of symbiosis
      with Dictyostelium cells.
AB  - Genome-wide gene expression profiling was performed to investigate the early
      formation of symbiosis using an artificial symbiosis of Escherichia coli and
      Dictyostelium discoideum. We have previously reported that when these two species
      were allowed to grow on minimal agar plates, they achieved a stable state of
      coexistence, in which the emerging E. coli colonies housing Dictyostelium cells
      were of a mucoidal nature that was not observed originally. We used this
      microbiological system as a model to study the initial stages of the development
      of the symbiotic relationship. The E. coli gene expression profiles of symbiotic
      cells and non-symbiotic cells captured using GeneChip technology were compared.
      It was clearly shown that the gene expression profile was substantially altered
      in E. coli cells undergoing symbiotic transition. The genes responsible for
      central energy metabolism as well as those responsible for translation apparatus
      were down-regulated in symbiotic E. coli. The transcriptional patterns of genes
      coding for the E. coli cell surface structure were drastically altered, and this
      alteration may determine the mucoidal nature and unique structure of coexisting
      colonies. General stress inducible genes were expressed at low levels in
      symbiotic E. coli. These observed changes in the transcription profile indicate
      that the central metabolism of symbiotic E. coli is attenuated as a whole, and
      the cells are probably under less stress because of the benefits brought by
      coexistence with the symbiotic counterpart Dictyostelium.

PMID- 15026195
TI  - A method to explore the possibility of nonlocal correlations between brain
      electrical activities of two spatially separated animal subjects.
AB  - It now appears possible to design an experiment which might reveal whether
      nonlocal correlations exist between brain electrical activities of spatially
      separated animal subjects, with initial emphasis on primates and dolphins. This
      would have the advantage of being based upon research presently being conducted
      at the University of Washington-Bastyr University and the University of Freiburg,
      which appears to reveal that a visual evoked potential elicited in the brain of
      one human subject via patterned photostimulation, can induce a nonlocal
      transferred potential in the brain of a second human subject, without any
      apparent classical neural or electromagnetic intervention, since both subjects
      are in Faraday chambers. An observation of nonlocality may also make it possible
      to investigate if consciousness or mental experiences exist in various nonhuman
      animal subjects.

PMID- 15026196
TI  - The potential impact of drug transporters on nucleoside-analog-based antiviral
      chemotherapy.
AB  - Several ATP-binding cassette (ABC) transporters can transport drugs out of cells
      against steep concentration gradients resulting in resistance to the drugs
      transported. Recent work has shown that at least three members of the family of
      human Multidrug Resistance-associated Proteins (MRPs), MRP4, 5 and 8, are able to
      transport some nucleoside-monophosphate analogs. This can result in resistance to
      the base, nucleoside or nucleotide precursors of these results, at least in cell
      lines with high levels of transporter. The affinity of these transporters for the
      nucleotide analogs studied thus far is relatively low (millimolar rather than
      micromolar), and this limits their potential impact on the resistance. We briefly
      review how ABC transporters in general, and MRPs in particular, could affect the
      disposition and cellular accumulation of antiviral compounds.

PMID- 15026197
TI  - Synergistic drug combinations against the in vitro replication of Coxsackie B1
      virus.
AB  - The existence of synergistic drug combinations against the in vitro replication
      of poliovirus type 1 (Mahoney) (PV-1) had been established in our previous work.
      The objective of the present study was to test the combined effects of the
      different drugs against another representative of the enterovirus genus, i.e.
      Coxsackievirus B1 (CBV-1). Dual combinations of enviroxime, disoxaril, arildone,
      PTU-23, HBB and S-7 were evaluated. The susceptibility of CBV-1 to the individual
      effects of the inhibitors was compared to that of PV-1. CBV-1 was more sensitive
      to enviroxime, S-7, PTU-23 and HBB and less sensitive to the effects of disoxaril
      and arildone. The effect of most dual drug combinations tested against CBV-1
      replication was additive or synergistic. Enviroxime and S-7, enviroxime and PTU
      23, disoxaril and HBB, disoxaril and PTU-23, arildone and HBB, arildone and PTU
      23, S-7 and HBB revealed a strong synergistic effect. Synergy against CBV-1
      replication was stronger as compared to that noted for the same drug combinations
      against PV-1 replication.

PMID- 15026198
TI  - A simple assay for determining antiviral activity against Crimean-Congo
      hemorrhagic fever virus.
AB  - Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus that is
      emerging as a significant human pathogen in many regions of the world, including
      Africa, Asia, and Europe. In this report, we describe a simple screening method
      for discovering new antiviral compounds directed against CCHFV. Antiviral
      activity was determined by assaying infected SW-13 cells (human adrenal gland
      carcinoma) for protection from cytopathic effect (CPE). By using an in vitro
      neutral red uptake assay, we were able to quantitatively measure CPE induced by
      CCHFV. As a proof of concept, we used this method to evaluate the antiviral
      activity of ribavirin and a series of structural analogs (ribamidine, 6
      azauridine, selenazofurin, and tiazofurin) against four geographically diverse
      strains of CCHFV. Ribavirin inhibited the replication of CCHFV as reported
      previously using plaque reduction assays. One drug, ribamidine, showed antiviral
      activity that was 4.5- to 8-fold less than that of ribavirin, and the other three
      drugs (6-azauridine, selenazofurin, and tiazofurin) did not show significant
      antiviral activity. There were no significant differences in drug sensitivities
      among the CCHFV strains. Development of this simple and reliable assay will
      potentially allow high-throughput screening for discovering additional antiviral
      drugs to combat this important public health threat.

PMID- 15026199
TI  - A quantitative bioassay for HIV-1 gene expression based on UV activation: effect
      of glycyrrhizic acid.
AB  - Previous reports have shown that HIV-LTRcat constructs stably transfected in HeLa
      cells are inducible after exposure to UV light. We have optimized this system for
      studying the effect of drugs on HIV-1 gene expression. The maximum UV response
      was observed in quiescent stationary cells stimulated with fresh medium for 3h.
      Glycyrrhizic acid suppressed UV-induced HIV gene expression in a concentration
      dependent manner. The inhibitory effect was strongest when GL was added
      immediately after UV exposure; it was still evident when GL was added at 5 h, it
      was completely lost at 10 h, after UV exposure. The inhibitory effect was even
      more pronounced if the cells were pretreated with sub-effective dose (0.0012 mM)
      of GL prior to UV exposure. The IC50 values with and without pretreatment were
      0.04 and 0.38 mM, respectively. Cell proliferation and viability were not
      affected by GL at doses as high as 2.4 mM. The inhibitory effect of GL on UV
      induced CAT activity correlated with the complete inhibition of binding
      activities of NF-kappaB p65, NF-kappaB p50, c-Fos, and c-Rel. Thus, the UV-based
      bioassay as proposed here can be exploited for the routine screening of the
      compounds that interfere with HIV-1 gene expression.

PMID- 15026200
TI  - Susceptibility of human influenza viruses from Australasia and South East Asia to
      the neuraminidase inhibitors zanamivir and oseltamivir.
AB  - Human influenza viruses isolated from Australasia (Australia and New Zealand) and
      South East Asia were analysed to determine their sensitivity to the NA inhibitor
      drugs, zanamivir and oseltamivir. A total of 532 strains isolated between 1998
      and 2002 were tested using a fluorescence-based assay to measure the relative
      inhibition of NA activity over a range of drug concentrations. Based on median
      IC50 values, influenza A viruses (with neuraminidase subtypes N1 and N2) were
      more sensitive to both the NA inhibitors than were influenza B strains. Influenza
      A viruses with a N1 subtype and influenza B strains both demonstrated a greater
      sensitivity to zanamivir than to oseltamivir carboxylate, whereas influenza A
      strains with a N2 subtype were more susceptible to oseltamivir carboxylate. For
      each of the neuraminidase types, IC50 values for viruses from Australasia and
      South East Asia were found to be comparable. Based on the data prior to and
      following the licensing of the drugs into the respective regions, the use of the
      NA inhibitors did not appear to have a significant impact on the susceptibility
      of the viruses tested to zanamivir or oseltamivir carboxylate.

PMID- 15026201
TI  - Opportunities for early therapy of respiratory syncytial virus (RSV) infection:
      what happens before hospitalization.
AB  - RSV loads of infants are already declining near the time of hospitalization. For
      optimal effect, antiviral and other RSV therapeutics therefore may need to be
      applied before this occurs. 134 RSV-hospitalized infants were studied to
      determine the timing of events and their healthcare seeking behavior prior to
      hospitalization. Sixty-two percent of infants had contact with a health care
      professional > or = 1 day prior to hospitalization and 46% had such a contact on
      > or = 2 different days prior to hospitalization. The mean (S.D.) duration of RSV
      symptoms prior to hospitalization was 3.9 +/- 2.3 days and prior to first health
      care contact was 2.6 +/- 1.8 days. RSV-hospitalized infants routinely have
      contact with health care professionals at significantly early time points in
      their illness. These contacts are potential opportunities for initiation of early
      anti-RSV therapy.

PMID- 15026202
TI  - Lopinavir/ritonavir vs. indinavir/ritonavir in antiretroviral naive HIV-infected
      patients: immunovirological outcome and side effects.
AB  - We compared immunovirological outcomes and toxicities of HAART regimens including
      LPV/r and IDV/r in antiretroviral naive HIV-1 patients. We retrospectively
      selected 55 patients starting LPV/r and 52 starting IDV/r as first-line HAART.
      Immunovirological and metabolic parameters were recorded at baseline and every 3
      months as were side effects, AIDS-defining events and deaths. Demographic
      characteristics and NRTIs included in the regimens were comparable. Both groups
      reached undetectable HIV-RNA plasma viremia from third month and maintained
      during follow-up. However, patients receiving IDV/r had a lower probability to
      obtain virological success (RH: 0.46). Patients receiving IDV/r patients showed a
      greater increase of total cholesterol (P = 0.01). Three patients on LPV/r and 21
      on IDV/r discontinued the drug for toxicity, leading to a 8.40 higher risk of
      discontinuation in the latter group. In our clinical setting IDV/r showed to be
      less effective and more toxic than LPV/RTV as first-line HAART.

PMID- 15026203
TI  - Investigating the effects of stereochemistry on incorporation and removal of 5
      fluorocytidine analogs by mitochondrial DNA polymerase gamma: comparison of D-
      and L-D4FC-TP.
AB  - Enantiomers of beta-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (D/L-D4FC) are
      nucleoside analog reverse transcriptase inhibitors (NRTIs) currently under
      investigation as antiviral agents. One of the major problems of NRTIs is toxicity
      to mitochondria. It has been shown that mitochondrial toxicity of NRTIs can
      correlate with incorporation and removal of these compounds by mitochondrial DNA
      polymerase (Pol gamma). Mechanistic studies have shown that, if activated, NRTIs
      are incorporated more efficiently by HIV-1 reverse transcriptase (RT) and less
      efficiently by Pol gamma, the corresponding nucleosides are considered to be more
      selective. In the present study, in order to predict potential DNA Pol gamma
      related mitochondrial toxicity of D- and L-D4FC, the incorporation and removal of
      the monophosphate form of these compounds by Pol gamma were studied using
      transient kinetic methods. Our cell-free results showed that Pol gamma
      incorporated the natural D-isomer significantly more efficiently than the
      unnatural L-isomer. However, the removal rates of these enantiomers from the
      chain-terminated primers were almost identical. While these results suggest that
      D-D4FC may present more mitochondrial toxicity than L-D4FC in cell-free assays,
      we have previously shown that HIV-1 RT prefers D-D4FC-TP as a substrate over the
      L-isomer, particularly in the case of mutant forms of RT associated with
      nucleoside drug resistance such as M184V. Since the effectiveness of NRTIs is a
      balance between efficiency of incorporation by wild-type and drug-resistant forms
      of HIV-1 RT and mitochondrial toxicity, our kinetic results suggest that both
      enantiomers may show promise as potential therapeutics.

PMID- 15026205
TI  - Comparison of six methods for the extraction of lipids from serum in terms of
      effectiveness and protein preservation.
AB  - The present work compares six biochemical methods for extraction of lipids from
      human serum. Although some organic solvents were good lipid extractors, they
      precipitated most of the total proteins and albumin. On the other hand,
      methodologies using Triton X-114 and silica were efficient for extraction of
      lipids, while sparing the protein fraction.

PMID- 15026204
TI  - Synthesis, characterization and antiviral activity against influenza virus of a
      series of novel manganese-substituted rare earth borotungstates
      heteropolyoxometalates.
AB  - A series of novel manganese-substituted mixed-valence rare earth borotungsto
      heteropoly blues, Ln2H3[BW9(VI)W2(V)Mn(H2O)O39] x 12H2O (Ln(2), Ln = La, Ce, Pr,
      Nd, Sm, Eu and Gd), as well as their corresponding heteropoly acids (Ln(0)), have
      been prepared and characterized by cyclic voltammetry (CV), infrared (IR),
      ultraviolet (UV), thermal gravimetric (TG) and differential thermal (DTA)
      analysis, X-ray photoelectron spectroscopy (XPS) and electrochemistry. It's shown
      that the heteropoly blues anion in Ln(2) still retains the alpha-Keggin structure
      but with a slight distortion as heteropoly acids do, and Mn and W atoms
      distribute statistically in the whole molecular. At the same time, the cell
      toxicity and antiviral activity of these rare earth borotungstateheteropoly blues
      against influenza virus type A and type B in MDCK cells have been investigated
      using plaque reduction assay. The results elucidated that these complexes exhibit
      a significantly inhibitory activity and almost no cytotoxicity comparable with
      those obtained from virazole, and the anti-virus activity depend on the structure
      of these complexes.

PMID- 15026206
TI  - Effects of pH, salt and time on ligand binding properties of overexpressed
      melanocortin 4 receptor.
AB  - The G-protein coupled melanocortin 4 receptor (MC4r) plays an important role in
      the energy metabolism. We overexpressed the MC4r in CHO cells and performed
      characterisation studies on the cell membranes to determine functional stability
      and ligand binding properties of the receptor. The affinity for the ligands
      [Nle4, d-Phe7]-alphaMSH and MTII was lost below pH 6 but could be restored by
      returning to physiological pH. Increasing NaCl concentration up to 1 M had little
      influence on the binding of either ligand. At neutral pH, physiological salt
      concentration and 4 degrees C the ligand affinity of the receptor was stable for
      up to 6 days. These findings will facilitate design of purification methods for
      the receptor.

PMID- 15026207
TI  - The methanol method for the quantification of ascorbic acid and dehydroascorbic
      acid in biological samples.
AB  - We present a fast to perform spectrophotometric method for the quantification of
      ascorbic acid and its oxidized form dehydroascorbic acid in biological samples.
      The assay detects a chromophore formed during the reaction of dehydroascorbic
      acid with methanol in phosphate/citrate buffer. This reaction can also be
      employed for the determination of ascorbate (vitamin C) in the presence of
      ascorbate oxidase. The major advantage of the developed protocol for the
      determination of both forms of vitamin C is a simple spectrophotometrical single
      end point determination. It is demonstrated that the methanol method is an
      improvement compared with a commercially available test kit for the determination
      of vitamin C. Using the methanol method, a dose-dependent increase in
      intracellular ascorbic acid was determined upon incubation of L-929 cells and RAW
      264.7 macrophages with increasing concentrations of extracellular ascorbate. In
      blood serum, vitamin C was determined at concentrations between 46 and 97 microM.
      Supplementation with different amounts of ascorbate showed satisfying recovery.
      In L-929 cells, even unphysiologically high amounts of reactive nitrogen species
      were unable to completely oxidize intracellular vitamin C.

PMID- 15026208
TI  - Abnormal spectra alteration observed in Triton calibration method for measuring
      [Ca2+]i with fluorescence indicator, fura-2.
AB  - We compared two commonly used calibration methods for measuring the concentration
      of intracellular free calcium ([Ca2+]i) by ratiometric fluorescence dye, fura-2
      in mouse neuroblastoma-rat glioma hybrid cells (NG108-15). One calibration
      method, the Triton method, employs detergent Triton X-100, while the other, the
      Ionomycin method, uses a calcium-specific ionophore, Ionomycin. In the Triton
      method, we observed that at excitation 380 nm, the fura-2 fluorescence intensity
      of steady-state cells abnormally situated beyond the limiting intensity for
      calibration. By excitation scan, we demonstrated that this abnormality was caused
      by the change of fura-2 isosbestic points, which in turn was due to cell lysis
      after the addition of Triton X-100. This problem was resolved in the Ionomycin
      method by avoidance of cell lysis. Our results showed the correlation between
      inconsistent isosbestic points and cell lysis. As the basis for [Ca2+]i
      calibration, the proportionality between the fluorescence intensity and the
      concentration of dye species was impaired because of inconsistent isosbestic
      points. This inconsistency can be eliminated by a preliminary experiment of
      excitation scan to test the feasibility of different calibration methods.

PMID- 15026209
TI  - Ratiometric and nonratiometric Ca2+ indicators for the assessment of
      intracellular free Ca2+ in a breast cancer cell line using a fluorescence
      microplate reader.
AB  - Transporters of Ca2+ are potential drug targets and Ca2+ is a useful signal in
      the assessment of G-protein-coupled receptor activation. Assays involving the
      assessment of intracellular Ca2+ using microplate readers most often use Ca2+
      indicators which do not exhibit a spectra shift on Ca2+ binding (e.g. fluo-3).
      Indicators that do exhibit a spectral shift upon Ca2+ binding (e.g. fura-2) offer
      potential advantages for the calibration of intracellular Ca2+ levels. However,
      experimental limitations may limit the use of ratiometric dyes in microplate
      readers capable of screening. In this study, we compared the assessment of
      intracellular Ca2+ in adherent breast cancer cells using ratiometric and
      nonratiometric Ca2+ indicators. Our results demonstrate that both fluo-3 and fura
      2 detect ATP dose-dependent increases in intracellular Ca2+ in the MCF-7 breast
      cancer cell line and that some of the limitations in the use of fura-2 appear to
      be overcome by the use of glass bottom microplates. The calibrated intracellular
      Ca2+ levels derived using fura-2 are consistent with those from microscopy and
      cuvette-based studies. Fura-2 may be useful in microplate studies, where cell
      lines with different properties are compared or where screening treatments lead
      to differences in the number of cells or dye loading.

PMID- 15026210
TI  - Microanalysis of non-heme iron in animal tissues.
AB  - The method recommended by the Iron Panel of the International Committee for the
      Standardization in Haematology for measurement of serum iron was adapted for
      measurement of non-heme iron in animal tissues. The method developed was designed
      specifically to facilitate measurement of non-heme iron using as little as 10 mg
      of tissue, in a final reaction volume of 60 microl. In this assay, tissue
      homogenates are treated with hydrochloric acid and trichloroacetic acid and
      heated at 95 degrees C. Non-heme iron is released and protein is precipitated.
      Following centrifugation, iron in the supernatant is reacted with ferrozine in
      the presence of the reducing agent thioglycolic acid, and the complex is
      quantified by spectrophotometry. The method was validated by analysis of two
      Standard Reference Materials (bovine liver), comparing results of this assay
      against certified values and concentrations determined by flame atomic absorption
      spectrometry following acid digestion. Results using this method for analysis of
      non-heme iron in guinea pig tissues (liver, kidney and heart) compared favorably
      with those obtained using micro-scale adaptations of three published reference
      methods. The new method was more sensitive, required less time, and was less
      cumbersome than the three published methods to which it was compared.

PMID- 15026212
TI  - Gestural overlap in consonant clusters: effects on the fluent speech of
      stuttering and non-stuttering subjects.
AB  - This study was designed to investigate if persons who stutter differ from persons
      who do not stutter in the coproduction of different types of consonant clusters,
      as measured in the number of dysfluencies and incorrect speech productions, in
      speech reaction times and in word durations. Based on the Gestural Phonology
      Model of Browman and Goldstein, two types of consonant clusters were formed:
      homorganic and heterorganic clusters, both intra-syllabic (CVCC) and inter
      syllabic (CVC#CVC). Overall, the results indicated that homorganic clusters
      elicited more incorrect speech productions and longer reaction times than the
      heterorganic clusters, but there was no difference between the homorganic and the
      heterorganic clusters in the word duration data. Persons who stutter showed a
      higher percentage dysfluencies and a higher percentage incorrect speech
      productions than PWNS but there were no main group effects in reaction times and
      word durations. However, there was a significant three-way interaction effect
      between group, cluster type and cluster place: homorganic clusters elicited
      longer reaction times than heterorganic clusters, but only in the inter-syllabic
      condition and only for persons who stutter. These results suggest that the
      production of two consonants with the same place of articulation across a
      syllable boundary puts higher demands on motor planning and/or initiation than
      producing the same cluster at the end of a syllable, in particular for PWS. The
      findings are discussed in light of current theories on speech motor control in
      stuttering. EDUCATIONAL OBJECTIVES: The reader will be able to describe: (1) the
      effect of gestural overlap between consonant clusters on speech reaction time and
      word duration of people who do and do not stutter and be able to (2) identify the
      literature in the field of gestural overlap between consonant clusters.

PMID- 15026213
TI  - Measuring role entrapment of people who stutter.
AB  - The purpose of this study was to explore whether people who stutter experience
      role entrapment in the form of vocational stereotyping. To accomplish this, 385
      university students reported their perceptions of appropriate career choices for
      people who stutter. Direct survey procedures, utilizing the newly developed
      Vocational Advice Scale (VAS), were used in this study. Comparisons for the main
      effect of speaker status (person who stutters and person who does not stutter)
      were conducted using a one-way analysis of variance (ANOVA). Results of this
      analysis suggested that the university students reported an overall perception
      that stuttering affected career opportunities and that 20 careers were judged to
      be inappropriate choices for people who stutter. Conversely, 23 careers were
      judged to be appropriate choices for people who stutter. Findings of this study
      provide initial data that supports that people who stutter may suffer from role
      entrapment related to career choices. EDUCATIONAL OBJECTIVES: The reader will be
      able to: (1) provide the definitions of stereotyping, role entrapment, and how
      these relate to people who stutter; (2) discuss the career choices that college
      students perceive as appropriate and inappropriate for people who stutter; and
      (3) summarize the needs for future research in this area.

PMID- 15026214
TI  - Subjective Screening of Stuttering severity, locus of control and avoidance:
      research edition.
AB  - This article describes the Subjective Screening of Stuttering (SSS): research
      edition that is designed to quantify the selected self-reports of people who
      stutter (PWS) prior to, during, and following their treatment. The three areas
      screened by the SSS are perceived stuttering severity, the level of internal or
      external locus of control, and reported word or situation avoidance. Each of the
      areas has two or three items rated for three audiences on a one to nine rating
      scale. Other available measures were reviewed and the need for a single
      instrument that provides quantified screening of each of the areas was
      recognized. Results of a research project using the SSS with 16 PWS indicated
      that percent of syllables stuttered correlated with stuttering severity (r=0.75)
      and with locus of control (r=0.43) but did not correlate with avoidance. These
      results were interpreted to indicate a need for other types of therapy following
      the experimental treatment studied. Reliability and validity of the SSS were
      judged adequate for research and clinical screening. The possible role of
      screening self-reports of PWS in combination with more extensive self-report
      instruments and with objective measures of stuttering is discussed. EDUCATIONAL
      OBJECTIVES: The reader will be able to (1) assess the perception of stuttering
      severity, avoidance and locus of control of people who stutter (PWS), and (2)
      determine from the PWS the self-reported outcome of treatment.

PMID- 15026215
TI  - Performance on phonological and grammatical awareness metalinguistic tasks by
      children who stutter and their fluent peers.
AB  - This study was undertaken to examine the performance of 23 children who stutter
      (CWS) and 23 children who do not stutter (CWNS) on three metalinguistic tasks.
      These included two phonological awareness assessment procedures (The Lindamood
      Auditory Conceptualization Test (LAC) and a Phoneme Reversal Task) and one
      modified Grammar Judgments Task where syntactic and semantic appropriateness of
      sentences was evaluated. Differences between groups were significant for the
      grammar judgment task, where CWNS outperformed CWS in judging syntactically and
      semantically anomalous sentences. Group differences were not significant for the
      phonological awareness tasks. The results underscore the importance of examining
      metalinguistic abilities of CWS through a variety of tasks. EDUCATIONAL
      OBJECTIVES: The reader will learn about and be able to: (1) recognize the
      relevance of examining metalinguistic abilities within the context of research on
      language-stuttering dynamics; and (2) identify measures of metalinguistic
      abilities that can be used to compare the performances of CWS and CWNS.

PMID- 15026220
TI  - The boron-organic carbon correlation in water.
AB  - A linear correlation between boron and organic carbon has been identified for
      groundwater and surface water. The boron to organic carbon ratio is found to be
      higher for groundwaters than for surface waters, since surface waters are more
      heavily loaded with natural organic matter. This correlation in water might
      result from the complexation of boron with polar organic compounds, not adsorbed
      on activated carbon, or from independent species. Any deviation from the
      boron/organic carbon ratio is used to identify pollution events for both boron or
      organic compounds, and to characterise the origin of unusual water chemistries.
      Moreover, such a correlation could be used to define natural water pristine
      conditions in order to restore good quality of water resources.

PMID- 15026219
TI  - Mesophilic and thermophilic temperature co-phase anaerobic digestion compared
      with single-stage mesophilic- and thermophilic digestion of sewage sludge.
AB  - The performance of thermophilic and mesophilic temperature co-phase anaerobic
      digestions for sewage sludge, using the exchange process of the digesting sludge
      between spatially separated mesophilic and thermophilic digesters, was examined,
      and compared to single-stage mesophilic and thermophilic anaerobic digestions.
      The reduction of volatile solids from the temperature co-phase anaerobic
      digestion system was dependent on the sludge exchange rate, but was 50.7-58.8%,
      which was much higher than 46.8% of single-stage thermophilic digestion, as well
      as 43.5% of the mesophilic digestion. The specific methane yield was 424-468 mL
      CH(4) per gram volatile solids removed, which was as good as that of single-stage
      mesophilic anaerobic digestion. The process stability and the effluent quality in
      terms of volatile fatty acids and soluble chemical oxygen demand of the
      temperature co-phase anaerobic digestion system were considerably better than
      those of the single-stage mesophilic anaerobic processes. The destruction of
      total coliform in the temperature co-phase system was 98.5-99.6%, which was
      similar to the single-stage thermophilic digestion. The higher performances on
      the volatile solid and pathogen reduction, and stable operation of the
      temperature co-phase anaerobic system might be attributable to the well
      functioned thermophilic digester, sharing nutrients and intermediates for
      anaerobic microorganisms, and selection of higher substrate affinity anaerobic
      microorganisms in the co-phase system, as a result of the sludge exchange between
      the mesophilic and thermophilic digesters.

PMID- 15026221
TI  - Initial contaminant removal performance factors in horizontal flow reed beds used
      for treating urban wastewater.
AB  - This study evaluates the effect of hydraulic loading rate (HLR), aspect ratio,
      granular medium size and water depth on the removal of selected contaminants
      during the start up of horizontal subsurface flow reed beds (HFRBs). Experiments
      were carried out in a pilot-scale HFRB system comprising four pairs of lined beds
      of almost equal surface area (54-56 m(2) each bed), with the following aspect
      ratios: 1:1, 1.5:1, 2:1 and 2.5:1. The size of the granular medium of each pair
      varied from coarse granitic gravel ( D(60) = 10mm, C(u) = 1.6) to small granitic
      gravel (D(60) = 3.5 mm, C(u) = 1.7). The beds of the pair with longest aspect
      ratio were made shallower (0.27 m) than the rest (0.5m) The system was sampled
      weekly from May 2001 to January 2002. The results indicate that HLR and water
      depth are determining factors in the performance of the HFRBs. Beds with a water
      depth of 0.27 m removed more COD (70-80%), BOD(5) (70-85%), ammonia (40-50%) and
      dissolved reactive phosphorus (DRP) (10-22%) than beds with a depth of 0.5m (60
      65% for COD, 50-60% for BOD(5), 25-30% for ammonia, and 2-10% for DRP). The
      higher efficiency observed shallower beds was related to their less reducing
      conditions (average redox potential (E) ranging from -351 to -338 mV) than beds
      with a depth of 0.5m (-390 to -358 mV). The difference in E status between two
      bed types seems to lead to differences in the biochemical processes. In fact,
      denitrification was estimated to be a significant reaction in shallower beds.

PMID- 15026222
TI  - Stirring bar sorptive extraction in the determination of PAHs in drinking waters.
AB  - The application of a new extraction technique which is known as stir bar sorptive
      extraction (SBSE), followed by high-performance liquid chromatography with a
      fluorescence detector, was assessed for determining eight polycyclic aromatic
      hydrocarbons (PAHs) in water samples. The extraction conditions such as
      acetonitrile addition; effects of temperature and salt; and finally, extraction
      and desorption time profiles were studied. Once SBSE was optimized, analytical
      method parameters such as linearity (r(2)>0.991), precision (<9%), detection (0.5
      7.3 ng/L) and quantitation (1.0-22 ng/L) limits were estimated. To correct for
      the 43-57% absolute recovery depending on the PAH, calibration was done with a
      line obtained submitting standard-spiked blank tap waters to the complete sample
      treatment and analysis. Consequently, relative recovery was about 100% because
      all water samples (those for calibration purposes and those for recovery
      estimation) were processed in the same way and the absolute recovery remained
      constant. SBSE method characteristics were checked with the analysis of real
      drinking waters in the search for PAHs.

PMID- 15026224
TI  - Biocenosis of BAC(F)s used for groundwater treatment.
AB  - The studies on the biocenosis of biologically active carbon filters (BAC(F)) used
      in treatment of Miocene water revealed the presence of protozoa of the group of
      flagellates and ciliates (Glaucoma sp., Opercularia sp.), saprophytic bacteria,
      phase I and II nitrifying bacteria, Fe(II) and Mn(II) oxidizing bacteria of the
      family Siderocapsaceae, Leptothrix ochracea and Pedomicrobium sp., as well as
      microscopic fungi. The stratification of biofilter colonisation by these
      microorganisms was found to be similar to that occurring in biofilters applied in
      sewage treatment. A hypothetical model of microbiological transformations in
      BAC(F)s, brought about by various physiological groups of microorganisms, is
      presented. It is shown that ozone pre-treatment of water dosed to the biofilter
      reduces the number of saprophytic bacteria and moulds in its upper layer, as well
      as Fe(II) oxidizing bacteria of the family Siderocapsaceae across the full
      section of the biofilter; it does not, however, influence the abundance of
      nitrifying phase I and II autotrophic bacteria and Mn(II) oxidizing bacteria of
      the family Siderocapsaceae. The abundance of microorganisms in the biofilter
      outflow is increased in comparison with that in untreated water; they do not,
      however, create a health hazard for human beings.

PMID- 15026223
TI  - Formaldehyde degradation in an anaerobic packed-bed bioreactor.
AB  - The development of appropriate technologies for the treatment of formaldehyde
      discharged into the environment is important to minimize its impact. Aerobic
      systems have been employed, although alternative anaerobic treatments have also
      been widely studied, mainly due to their low energy consumption and sludge
      production. However, toxic substances can lead to disturbances in anaerobic
      reactors. Some research has already been developed on formaldehyde anaerobic
      biological treatment, but no consensus has yet been reached about its behavior
      nor has the most efficient system been identified. Aiming at finding supporting
      evidence for this issue, therefore, this study investigated the degradation and
      toxicity of formaldehyde in a Horizontal-Flow Anaerobic Immobilized Sludge
      Reactor. Formaldehyde concentrations of 26.2-1158.6 mg HCHO/L were applied in the
      reactor, resulting in formaldehyde and chemical oxygen demand removal
      efficiencies of 99.7% and 92%, respectively. Volatile fatty acids with up to five
      carbons, found during the degradation of formaldehyde, are believed to indicate
      that the degradation followed routes unlike those suggested in the literature,
      which reports the formation of intermediates such as methanol and formic acid.
      The Monod kinetic model adhered to the experimental data well, with apparent
      kinetic parameters estimated as r(app)max) = 2.79 x 10(-3) mg HCHO/mg SSVh and K
      (app)(s) = 242.8 mg HCHO/L.

PMID- 15026225
TI  - Emission of volatile organic compounds during composting of municipal solid
      wastes.
AB  - The objective of this study was to identify and quantify volatile and semi
      volatile organic compounds (VOCs) produced during composting of the organic
      fraction of municipal solid wastes (MSW). A laboratory experiment was conducted
      using organic components of MSW that were decomposed under controlled aerobic
      conditions. Mixed paper primarily produced alkylated benzenes, alcohols and
      alkanes. Yard wastes primarily produced terpenes, alkylated benzenes, ketones and
      alkanes, while food wastes primarily produced sulfides, acids and alcohols. Among
      13 aromatic VOCs found in MSW composting facilities, toluene, ethylbenzene, 1,4
      dichlorobenzene, p-isopropyl toluene, and naphthalene were in the largest
      amounts. Unseeded mixed paper, seeded mixed paper, seeded yard wastes, unseeded
      yard wastes, seeded food wastes and unseeded food wastes produced approximately
      6.5, 6.1, 2.1, 0.83, 2.5 and 0.33 mg of 13 volatile and semi-volatile aromatic
      organic compounds combined, respectively, per dry kg. All VOCs were emitted early
      during the composting process and their production rates decreased with time at
      thermophilic temperatures.

PMID- 15026226
TI  - Application of multiway ICA for on-line process monitoring of a sequencing batch
      reactor.
AB  - Multiway principal component analysis has been shown to be a powerful monitoring
      tool in many industrial batch processes. However, it has the shortcomings that
      all batch lengths should be equal, the measurement variables must be normally
      distributed and that future values of the current batch must be estimated to
      allow on-line monitoring. In this work, it is shown that multiway independent
      component analysis (MICA) can be used to overcome these drawbacks and obtain
      better monitoring performance. The on-line MICA monitoring of batch processes is
      based on a new unfolding method and independent component analysis (ICA). ICA
      provides better monitoring performance than PCA in cases with non-Gaussian data
      because it is not based on the assumption that the latent variables are normally
      distributed. The MICA algorithm does not require any estimation of future batch
      values and can also be applied to non-equal batch length data sets. This article
      describes the application of on-line MICA monitoring of a sequencing batch
      reactor (SBR). It is successfully applied to an 80L SBR for biological wastewater
      treatment, which is characterized by a variety of disturbance sources with non
      Gaussian characteristics. The SBR poses an interesting challenge from the point
      of process monitoring characterized by non-stationary, batchwise, multiscale, and
      non-Gaussian characteristics. The results of the bench-scale SBR monitoring
      clearly showed the power and advantages of MICA monitoring in comparison to
      conventional monitoring methods.

PMID- 15026227
TI  - Characterization and distribution of polycyclic aromatic hydrocarbon
      contaminations in surface sediment and water from Gao-ping River, Taiwan.
AB  - The concentrations of 16 polycyclic aromatic hydrocarbons (PAHs) in water and
      sediment samples collected from 12 locations in Gao-ping River, Taiwan were
      analyzed. Molecular ratios and principal component analysis (PCA) were used to
      characterize the possible pollution sources. Concentrations of total 16 PAHs
      (SigmaPAHs) in water samples ranged from below method detection limits (<MDLs) to
      9.4 microg/L with the mean value of 0.43+/-0.75 microg/L ( n=48), which were
      predominated by two- and three-ring PAHs. The SigmaPAH concentrations in
      sediments ranged from 8 to 356 ng/g-dry weight with the mean value of 80.6+/-31.8
      ng/g (n=48). Three- and four-ring PAHs including phenanthrene, anthracene and
      pyrene were the dominant species in sediment samples. High contents of PAHs were
      found in the estuary of the river and in the vicinity of industrial areas. Ratios
      of specific PAH compounds including phenanthrene/anthracene (Phe/Ant),
      fluoranthene/pyrene (FL/Pyr), chrysene/benzo[a] anthracene (Chr/BaA), low
      molecular-weight PAH/high-molecular-weight PAH (LPAH/HPAH) were calculated to
      evaluate the possible sources of PAH contamination. These ratios reflect a mixed
      pattern of pyrolytic and petrogenic inputs of PAHs in Gao-ping River. The
      petrogenic PAHs may be mainly from the leakage of crude oil and the refined
      products from urban vehicle traffic, while the pyrolytic PAH input is located in
      the proximity near the mouth of estuary of the River. The PCA analysis confirmed
      that petrochemical industrial parks located in the vicinity of estuary of Gao
      ping River might be the possible source for the PAH input.

PMID- 15026228
TI  - Selective removal of gallium (III) from aqueous solutions containing zinc or
      aluminum using sodium di-(n-octyl) phosphinate.
AB  - Gallium was removed selectively from aqueous solutions containing zinc or
      aluminum using sodium di-(n-octyl) phosphinate as a ligand (NaL). At low pH or
      low mole ratios, the gallium was removed by complexation with the ligand as
      GaL(3(S)), while the zinc or the aluminum remained in the solution. Nearly
      complete separation of gallium was obtained. By increasing the amount of ligand
      or by increasing the pH, the zinc or aluminum remaining in the solution was then
      removed as a solid complex: ZnL(2(S)) or AlL(3(S)), respectively. At a pH between
      1.5 and 2 and a mole ratio ligand to total metals of 0.75 for zinc solutions and
      1.0 for aluminum solutions, more than 98% of the gallium was selectively removed
      with a high molar selectivity, alpha(Ga/Zn) and alpha(Ga/Al), respectively. Over
      95% of gallium was recovered from the solid GaL(3(S)) complex by treatment of the
      complex with a 3M NaOH solution and diethyl ether. The gallium was concentrated
      in the aqueous solution to 4 times its initial concentration and the ligand was
      extracted into the ether phase. After evaporation of the ether, 95% of the ligand
      was regenerated in its sodium form as a solid.

PMID- 15026229
TI  - Land inputs of trace metals, major elements, particulate organic carbon and
      suspended solids to an industrial coastal bay of the NE Atlantic.
AB  - Rivers, streams and municipal and industrial effluents flowing into the Ferrol
      Ria (NW Spain) were analyzed for dissolved and particulate trace elements (Cd,
      Cu, Pb, Zn), particulate major elements (Al, Fe, Si), particulate organic carbon
      and nitrogen (POC and PON), and total suspended solids. Trace metal clean
      techniques were applied. Mean annual fluxes of these components were calculated.
      Dissolved trace metal concentrations in the major freshwater inputs were found to
      be within typical values for uncontaminated rivers: Cd: 0.020-0.035 nM; Cu: 11.7
      19.2 nM; Pb: 0.40-0.71 nM and Zn: 18-54 nM. Two sources of suspended particulate
      matter (SPM) were observed: (i). a detrital SPM, which becomes more important at
      high river discharges, with metal concentrations tending to lithogenic values;
      (ii). an organic- and metal-rich SPM, which becomes dominant at low discharges.
      Municipal and industrial effluents in the northern shore, despite of constitute a
      minor freshwater contribution to the bay, were responsible for more than 50% of
      total inputs of Cu, Cd, Pb, Zn, POC and PON. The fluxes of trace metals obtained
      for the Ferrol Ria are in the range of other inhabited world semi-enclosed
      embayments.

PMID- 15026230
TI  - Organochlorine pesticides sequestered in the aquatic macrophyte Schoenoplectus
      californicus (C.A. Meyer) Sojak from a shallow lake in Argentina.
AB  - This study was conducted in Los Padres Lake from Argentina in order to assess the
      ability of Schoenoplectus californicus to bioconcentrate organochlorine
      pesticides (OCPs). Bulrush tissues, superficial and near root sediments were
      collected from the input and the output creek areas. OCP analyses were carried
      out by GC-ECD. Samples from the input creek area showed the higher OCP levels as
      a result of contaminants washed down from upstream agricultural fields. Bulrush
      roots accumulated the highest concentrations of pollutants (30.2-45.7ngg(-1) dry
      weight). DDTs and chlordanes predominated in sediments and roots besides
      endosulfan sulfate. The sediments constitute the main source for these OCPs
      partitioning to bulrush. Stems mainly exposed to water column accumulated
      preferentially the less hydrophobic pesticides, such as HCHs and endosulfans. We
      have confirmed the important role of S. californicus in the contaminant removal
      from sediments. Therefore, this macrophyte can be used as a tool for field
      studies of OCP pollution monitoring and remediation.

PMID- 15026231
TI  - Investigation of impact of water type on borate ore flotation.
AB  - In this work, the impact of water type on borate ore flotation was investigated,
      while various physical parameters during flotation were considered in order to
      compare the results. Two different colemanite samples from Emet deposits of
      Turkey, named as Emet-A and Emet-B contained 44% B(2)O(3) and 40% B(2)O(3),
      respectively. The flotation tests were performed at feed particle size range of 
      210 +20 microm. Optimal consumption values for the reagents were determined as
      2000 gt(-1) for AeroPromoter R825 from Cytec Company, a sulphonate type
      collector, 1500 gt(-1) for Procol CA927 from Allied Colloids Company, a
      sulphosuccinamate type collector and 100 gt(-1) for AeroFrother 70 from Cytec
      Company, an alcohol-type frother. In the tests, the impeller speed of the Denver
      type flotation machine was set to 1200 rpm and the samples were fed into a litre
      cell at 25% solid/liquid ratio and at natural pH value of the slurry at room
      temperature. The flotation results obtained from the tests with use of tap water,
      demineralised water and the artificial water prepared with Ca(2+) and Mg(2+)
      cations deliberately added into demineralised water were compared to each other
      in optimal flotation conditions.

PMID- 15026232
TI  - Some aspects of water quality in a polluted lowland river in relation to the
      intracellular chemical levels in planktonic and epilithic diatoms.
AB  - Changes in elemental concentrations of diatoms and river water from the river Erh
      Jen were determined using scanning electron microscopy energy-dispersive X-ray
      microanalysis and inductively coupled plasma mass spectrometry. Relatively large
      amounts of copper and lead found in both planktonic and epilithic diatoms implied
      these algae might play an important role in biogeochemical cycles and in the
      transfer of those elements to higher trophic levels in the aquatic environment.
      Changes in elemental concentrations within diatom cells were found to vary with
      other elements within cells and the same or different elements in water.
      Planktonic and epilithic cells showed different correlation patterns. For
      epilithic diatoms, negative correlations were found between concentrations of
      total phosphorus and phosphate in water and those of phosphorus within cells, and
      between concentrations of lead in water and in cells. Concentrations of chromium
      and mercury within planktonic cells and those of phosphorus, manganese and lead
      within epilithic ones were found to be easily influenced by other elements in
      river water, indicating appearance of the competitive manner on uptake of such
      elements by algal cells. Relatively high concentration factors (CFs) for cadmium,
      mercury and lead by diatoms in this study suggested they are good accumulators
      for these heavy metals. Significant negative corrections were found between the
      CFs of diatoms and the concentrations of elements in river water.

PMID- 15026233
TI  - Adsorption of phenol and reactive dye from aqueous solution on activated carbons
      derived from solid wastes.
AB  - Activated carbons were produced from several solid wastes, namely, waste PET,
      waste tires, refuse derived fuel and wastes generated during lactic acid
      fermentation from garbage. Activated carbons having various pore size
      distributions were obtained by the conventional steam-activation method and via
      the pre-treatment method (i.e., mixture of raw materials with a metal salt,
      carbonization and acid treatment prior to steam-activation) that was proposed by
      the authors. The liquid-phase adsorption characteristics of organic compounds
      from aqueous solution on the activated carbons were determined to confirm the
      applicability of these carbons, where phenol and a reactive dye, Black5, were
      employed as representative adsorbates. The hydrophobic surface of the carbons
      prepared was also confirmed by water vapor adsorption. The characteristics of a
      typical commercial activated carbon were also measured and compared. It was found
      that the activated carbons with plentiful mesopores prepared from PET and waste
      tires had quite high adsorption capacity for large molecules. Therefore they are
      useful for wastewater treatment, especially, for removal of bulky adsorbates.

PMID- 15026234
TI  - Biomass growth and activity in a membrane bioreactor with complete sludge
      retention.
AB  - This work reports the main results of a bench scale membrane bioreactor operated
      for more than 100 days without sludge withdrawal and fed on real municipal
      wastewater. The experiments were oriented towards three main objectives. Firstly,
      the performance of the system was evaluated under two different volumetric
      loading rates (0.8 and 1.7 g CODL(react.)(-1)d(-1)). Secondly, biomass growth and
      accumulation of solids were assessed and a relationship between sludge
      concentration and volumetric loading rates was proposed. Thirdly, biomass
      activity was evaluated through respirometric tests, and endogenous and maximum
      respiration rates of heterotrophic and nitrifying bacteria were determined. The
      experimental campaign showed that these systems are easy to manage and very rapid
      to start-up. The SS concentrations under equilibrium conditions for both
      experimental periods were slightly lower than 10 times the volumetric loading
      rates, and the organic loading rates reached the same equilibrium value of 0.12 g
      CODgTSS(-1)d(-1). Furthermore, under equilibrium conditions the system showed
      very limited sludge production (0.12 g VSSgCOD(rem)(-1)) and low biomass
      activity, although it readily responded to load variations. Further work is being
      carried out to evaluate the performance over the long term.

PMID- 15026235
TI  - Aspects of decision support in water management--example Berlin and Potsdam
      (Germany) I--spatially differentiated evaluation.
AB  - Decisions about sustainable development demand spatially differentiated
      evaluations. As an example, we demonstrate the evaluation of water management
      strategies in the cities of Berlin and Potsdam (Germany) with respect to their
      ecological effects in 14 sections of the surface water system. Two decision
      support systems were compared, namely PROMETHEE, which is designed to obtain a
      clear decision (linear ranking), and Hasse Diagram Technique (HDT), normally
      providing more than one favourable solution (partial order). By PROMETHEE, the
      spatial differentiation had unwanted effects on the result, negating the
      stakeholders determined weighting of indicators. Therefore, the stakeholder can
      barely benefit from the convenience of obtaining a clear decision (linear
      ranking). In contrast, the result obtained by HDT was not influenced by spatial
      differentiation. Furthermore, HDT provided helpful tools to analyse the
      evaluation result, such as the concept of antagonistic indicators to discover
      conflicts in the evaluation process.

PMID- 15026236
TI  - Toxic effects of some major polyaromatic hydrocarbons found in crude oil and
      aquatic sediments on Scenedesmus subspicatus.
AB  - The green alga, Scenedesmus subspicatus was exposed for 7 days to a series of
      PAHs (polyaromatic hydrocarbons) of increased molecular weight from two to five
      rings [naphthalene (Nap), anthracene (Ant), phenanthrene (Phe), pyrene (Pyr) and
      benzo(a)pyrene (BaP)]. The toxicity measured as population growth inhibition by
      individual PAH to the S. subspicatus followed the order: BaP>Pyr>Ant>Phe>Nap.
      These results confirmed that the toxicity potential of PAHs seems to be strongly
      influenced by their physico-chemical properties (aqueous solubility, K(ow),
      coefficient of volatilization, etc.) and the conditions of algae culture (light,
      presence of nitrate ions, etc.). Consequently, Nap, Phe and Ant having low k(ow)
      values and low coefficient of volatilization values were less toxic than BaP with
      the highest k(ow) value, indicating for example why Nap with the lowest EC(50)
      value was nearly 2 x 10(5) times lower than that of BaP. Moreover, nitrate ions
      seemed to act directly on the degree of hydroxylated radical reactivity of PAHs,
      since BaP always remained the most toxic of the compounds tested. The results
      were also agreed with the QSAR model for toxicity prediction of PAHs to many
      aquatic organisms.

PMID- 15026237
TI  - Stimulation of microbial sulphate reduction in a constructed wetland:
      microbiological and geochemical analysis.
AB  - Microbial sulphate reduction was stimulated successfully in enclosures installed
      in a constructed wetland. When sucrose (2.4mM) and NH(4)Cl (600 microM) were
      added to water in the test enclosures, the indigenous microbial community was
      able to remove over 90% of the sulphate, present as a contaminant from nearby
      mining activity at a concentration of 384 mg x l(-1) (4mM), over 50 days. Over
      90% of the sucrose was also removed. Sulphate was not reduced in control
      enclosures containing no added sucrose or NH(4)Cl. Fermentation of sucrose by
      obligate anaerobes including Clostridium sp. and Bacteriodes sp. preceded
      sulphate reduction in the test enclosures. Sulphate reduction was biphasic, with
      maximum rates noted between 2-5 and 23-27 days after the addition of the growth
      substrates. Relatively unbiased 16S rDNA analysis suggested that nitrogen-fixing
      bacteria were important constituents of the microbial community in the test
      enclosures at day 23, suggesting that soluble nitrogen was limiting in the
      amended test enclosures during the experiment.

PMID- 15026238
TI  - The persistence and removal of enteric pathogens in constructed wetlands.
AB  - Sedimentation is thought to be one of the mechanisms of microbial reduction from
      wetlands used for wastewater treatment. This study compared the occurrence and
      survival of enteric indicator microorganisms and pathogens in the water column
      and sediments of two constructed surface flow wetlands in Arizona. On a
      volume/wet weight basis the concentration of fecal coliforms and coliphage in the
      water column and sediment was similar. However, on a volume/dry weight basis the
      numbers were one to two orders of magnitude higher in the sediment. Giardia cyst
      and Cryptosporidium oocyst concentrations were one to three orders of magnitude
      greater in the sediment compared to the water column. The die-off rates of all
      the bacteria and coliphage were greater in the water column than the sediment.
      The die-off rates of fecal coliforms in the water and sediment were
      0.256log(10)day(-1) and 0.151log(10)day(-1), respectively. The die-off rates of
      Salmonella typhimurium in the water and sediment were 0.345log(10)day(-1) and
      0.312log(10)day(-1), respectively. The die-off rates of naturally occurring
      coliphage in water column and sediment were 0.397log(10)day(-1) and
      0.107log(10)day(-1), respectively, and the die-off rates of and PRD-1 in water
      and sediment were 0.198log(10)day(-1) and 0.054log(10)day(-1), respectively. In
      contrast Giardia die-off in the sediment was greater compared to the water
      column. The die-off rates of Giardia in water and sediment were 0.029log(10)day(
      1) and 0.37log(10)day(-1), respectively. Coliphage survived the longest of any
      group of organisms in the sediment and the least in the water column. In contrast
      Giardia survived best in the water column and least in the sediment.

PMID- 15026239
TI  - Decolorization and toxicity of reactive anthraquinone textile dyes under
      methanogenic conditions.
AB  - Reductive decolorization of two anthraquinone reactive dyes (Reactive Blue 4,
      RB4; Reactive Blue 19, RB19) under methanogenic conditions was performed using a
      mixed, methanogenic culture. Decolorization of the two anthraquinone dyes was
      investigated to evaluate the rate and extent of color removal as well as to
      assess possible toxic effects of the dyes and their decolorization product(s) on
      the methanogenic culture as a function of initial dye concentration ranging from
      50 to 300 mg x L(-1). A dextrin/peptone mixture was used as the carbon and
      electron source. A high rate and extent of color removal was achieved ranging
      from 4.3 to 29.9 mg x L(-1)h(-1) and 73-91% for RB4, and 13.0-74.4 mg x L(-1)h(
      1) and 90-95% for RB19. Initial RB4 concentrations up to 100 mg x L(-1) did not
      result in any significant inhibition. Both the 200 and 300 mg x L(-1) RB4-amended
      cultures, and all RB19-amended cultures resulted in severe inhibition of both
      acidogenesis and methanogenesis. Sequential dye addition at 300 mg x L(-1) for
      both RB4 and RB19 resulted in accumulation of volatile fatty acids (VFAs) and a
      very low methane production at the end of the first dye addition after 44 days of
      incubation. However, at the end of the second dye addition, after a relatively
      long incubation (384 days), recovery of methanogens in the RB4-amended culture
      was observed in contrast to the complete inhibition of methanogenesis in the RB19
      amended culture. Therefore, RB19 resulted in a higher degree of inhibition of
      both acidogenesis and methanogenesis than RB4. Addition of dextrin/peptone to dye
      inhibited cultures resulted in acidogenesis and a gradual recovery of
      methanogenesis (mainly aceticlastic methanogenesis) in the RB4-inhibited culture,
      and a slow recovery of acidogenesis but no recovery of methanogenesis in the RB19
      inhibited culture. In contrast, addition of 80% H(2)-20% CO(2) gas to dye
      inhibited cultures resulted in recovery of hydrogenotrophic methanogenesis in
      both the RB4- and RB19-inhibited cultures. In spite of the relatively severe
      inhibition of the two anthraquinone dyes on the mixed, methanogenic culture, a
      high extent of color removal was achieved.

PMID- 15026240
TI  - Laboratory modelling of manganese biofiltration using biofilms of Leptothrix
      discophora.
AB  - Laboratory biofilters (pilot-scale, 20 l and laboratory-scale, 5l) were
      constructed in order to model the bioaccumulation of manganese (Mn) under flow
      conditions similar to those occurring in biofilters at groundwater treatment
      sites. The biofilters were operated as monocultures of Leptothrix discophora, the
      predominant organism in mature Mn oxidising biofilms. Biologically mediated Mn
      bioaccumulation was successfully modelled in both filter systems. The data
      obtained showed that in the small-scale biofilter, the Mn concentrations that
      gave the highest rate of Mn bioaccumulation, shortest maturation time, highest
      optical density (biomass) and growth rate were between 2000 and 3000 microg x l(
      1). The non-problematic scale-up of the process from the laboratory-scale to the
      pilot-scale biofilter model suggests that Mn biofilters may be 'seeded' with
      laboratory grown cultures of L. discophora. By initially operating the biofilter
      as a re-circulating batch culture, with an initial Mn concentration of
      approximately 2500 microg x l(-1), it is hoped to reduce the filter maturation
      time from months to days.

PMID- 15026241
TI  - The use of multicomponent statistical analysis in hydrogeological environmental
      research.
AB  - The present article examines the possibilities of investigating NO(3)(-) spread
      in aquifers by applying multicomponent statistical methods (factor, cluster and
      discriminant analysis) on hydrogeological, hydrochemical, and environmental
      parameters. A 4-R-Mode factor model determined from the analysis showed its
      useful role in investigating hydrogeological parameters affecting NO(3)(-)
      concentration, such as its dilution by upcoming groundwater of the recharge
      areas. The relationship between NO(3)(-) concentration and agricultural
      activities can be determined sufficiently by the first factor which relies on
      NO(3)(-) and SO(4)(2-) of the same origin-that of agricultural fertilizers. The
      other three factors of R-Mode analysis are not connected directly to the NO(3)(-)
      problem. They do however, by extracting the role of the unsaturated zone, show an
      interesting relationship between organic matter content, thickness and saturated
      hydraulic conductivity. The application of Hirerarchical Cluster Analysis, based
      on all possible combinations of classification method, showed two main groups of
      samples. The first group comprises samples from the edges and the second from the
      central part of the study area. By the application of Discriminant Analysis it
      was shown that NO(3)(-) and SO(4)(2-) ions are the most significant variables in
      the discriminant function. Therefore, the first group is considered to comprise
      all samples from areas not influenced by fertilizers lying on the edges of
      contaminating activities such as crop cultivation, while the second comprises all
      the other samples.

PMID- 15026242
TI  - Effect of shear on concentrated hydrous ferric floc rheology.
AB  - The primary interest of this work is to determine the effect of continuous shear,
      variable shear rate, and shear history on concentrated hydrous ferric floc
      rheology. The floc suspensions are strongly shear degrading with the behaviour
      being adequately described by a power law model. This is supported by images of
      the floc particles, which indicate a breakdown in floc structure, with the
      release of water and formation of smaller particles, after the application of
      shear. A shear rate sweep of the sample produces a hysteresis loop due to the
      time dependency of the samples. Higher shear rates are shown to destroy more
      structure, resulting in an overall decrease in floc viscosity. This is
      irreversible, and occurs due to a breakdown in floc structure to release trapped
      water and produce smaller floc particles. Shear also causes an instantaneous
      reduction in viscosity. This effect is instantaneously recoverable, and is due to
      a decrease in floc particle aggregation. Floc behaviour within the shear rate
      range 20-250 s(-1) is also adequately modelled by the Sisko model.

PMID- 15026243
TI  - Effect of synthetic iron colloids on the microbiological NH(4)(+) removal process
      during groundwater purification.
AB  - Subsurface aeration is used to oxidise Fe in situ in groundwater that is used to
      make drinking water potable. In a groundwater system with pH>7 subsurface
      aeration results in non-mobile Fe precipitate and mobile Fe colloids. Since
      originally the goal of subsurface aeration is to remove iron in situ, the
      formation of non-mobile iron precipitate, which facilitates the metal's removal,
      is the desired result. In addition to this intended effect, subsurface aeration
      may also strongly enhance the microbiological removal of ammonium (NH(4)(+)) in
      the purification station. Mobile iron colloids could be the link between
      subsurface aeration and the positive effect on the NH(4)(+) removal process.
      Therefore, the objective of this study was to assess whether synthetic iron
      colloids could improve the NH(4)(+) removal process. The effect of synthetic iron
      colloids on the NH(4)(+) removal process was studied using an artificial
      purification set-up on a laboratory scale. Columns that purified groundwater with
      or without added synthetic iron colloids were set up in duplicate. The results
      showed that the NH(4)(+) removal was significantly ( alpha = 0.05 ) increased in
      columns treated with the synthetic iron colloids. Cumulative after 4 months about
      10% more NH(4)(+) was nitrified in the columns that was treated with the
      groundwater containing synthetic iron colloids. The results support the
      hypothesis that mobile iron colloids could be the link between subsurface
      aeration and the positive effect on the NH(4)(+) removal process.

PMID- 15026245
TI  - Origins and implications of drinking water odours in lakes and reservoirs of
      British Columbia, Canada.
AB  - The relationship between commonly measured limnological parameters and odours was
      examined in 16 reservoirs and lakes used as sources for drinking water and three
      reference lakes. Odour analysis was conducted using flavour profile analysis
      (FPA) and, on select lakes, gas chromatography ion-trap mass spectrometry (GC
      ITMS) for target compounds. Total phosphorus (TP) was the best single predictor
      of FPA intensity and multiple regression models accounted for 37-39% of intensity
      variance in the epilimnion and metalimnion, respectively. Earthy odours were more
      prevalent in reservoirs and lakes with higher TP, whereas decomposing vegetation
      and green vegetation+grassy odours almost exclusively occurred when TP was lower
      (<13 microg P/L). Only geosmin was identified with GC-ITMS, and it was found to
      occur in lakes and reservoirs of higher trophic status (e.g. more algal biomass).
      Infrequent episodic events in the Greater Victoria's principal reservoir (e.g.
      algal blooms) have previously been linked with taste and odour problems in their
      tap water. However, analysis of odours under the conditions of this study (i.e.
      no strong odour episodes in the source reservoir) suggest that typical odours
      prevalent in tap water originating from Sooke Lake Reservoir are derived from
      treatment processes or the distribution system, not directly from the reservoir.
      This study demonstrates the utility of employing relatively simple and
      established methods to better understand management issues of a drinking water
      system.

PMID- 15026244
TI  - Removal of zinc, copper and lead by natural zeolite-a comparison of adsorption
      isotherms.
AB  - An uptake of zinc (Zn), copper (Cu), and lead (Pb) from aqueous solutions by ion
      exchange on natural zeolitic tuff has been studied. The Croatian zeolite
      clinoptilolite from the Donje Jesenje deposit has been used as a natural ion
      exchanger. The efficiency of removal is higher for Pb and Cu than for Zn ions.
      Measured concentrations of Si in the liquid phase identify the detachment of the
      aluminosilicate structure during ion exchange in the presence of H(+) and OH(-)
      ions. The adsorption isotherm equations; Langmuir-Freundlich, Redlich-Petersen,
      Toth, Dubinin-Radushkevich, modified Dubinin-Radushkevich, and Lineweawer-Burk
      were derived from the basic empirical equations, and used for calculation of ion
      exchange parameters. The best fitting of experimental results to the proposed
      isotherms was observed in models that assume that ionic species bind first at
      energetically most favorable sites, with multi-layer adsorption taking place
      subsequently.

PMID- 15026246
TI  - A study on stack configuration of continuous electrodeionization for removal of
      heavy metal ions from the primary coolant of a nuclear power plant.
AB  - This study investigated the production of high-purity water in the primary
      coolant of a nuclear power plant via the continuous electrodeionization (CEDI)
      process, using ion exchange resins as ion-conducting media between ion exchange
      membranes. The effectiveness of this method was examined with respect to the
      removal of heavy metals. The study was carried out on a laboratory scale with an
      effective area of 20 cm(2). The CEDI system was operated with a layered bed of
      cation exchange resins, anion exchange resins, and mixed-bed ion exchange resins.
      The stack configuration was designed to prevent a reaction between metal ions and
      hydroxide ions. The CEDI operation with the layered bed removed more than 99% of
      the ions at 30% of the current efficiency. The results showed that, with an inlet
      conductivity of 40 microScm(-1), a linear velocity of 4.17 cms(-1), and an
      applied current density of 17 mAcm(-2), the CEDI process yielded an outlet
      conductivity of 0.5 microScm(-1), thereby preventing the precipitation of metal
      ions. This study therefore successfully demonstrated the feasibility of the CEDI
      operation for the removal of heavy metals at a very low concentration.

PMID- 15026247
TI  - Biological treatment of Mn(II) and Fe(II) containing groundwater: kinetic
      considerations and product characterization.
AB  - In the present article, the treatment of groundwater containing Mn(II) and Fe(II)
      has been investigated. The biological oxidation of Mn(II) and Fe(II) in upflow
      filtration units comprised the applied experimental technique. The oxidation
      processes were mediated by specific bacteria, namely the Leptothrix ochracea and
      Gallionella ferruginea, which belong to the general category of manganese and
      iron oxidizing bacteria. This work was focused on the characterization of the
      products of biological oxidation and to the examination of the kinetics of Mn(II)
      removal as compared with Fe(II) removal from groundwaters. The products of
      biological oxidation were characterized using the spectroscopic techniques XRD,
      XPS and SEM-EDS and comprised a mixture of biogenic hydrous manganese and iron
      oxides. The oxidation state of manganese in the precipitates was found to be
      between 3 and 4. Iron oxides were mainly in the form of amorphous ferrihydrite.
      The kinetic results indicated that the rates of manganese and iron oxidation were
      several orders of magnitude greater than the respective for abiotic oxidation.
      The bacterially mediated oxidation of iron was faster than manganese oxidation,
      presenting half-lives of reaction 0.9 and 3.98 min, respectively.

PMID- 15026248
TI  - The effect of pretreatment to ultrafiltration of biologically treated sewage
      effluent: a detailed effluent organic matter (EfOM) characterization.
AB  - Ultrafiltration alone can remove only a portion of the effluent organic matter
      (EfOM) from biologically treated sewage effluent (BTSE). Use of pretreatment not
      only improves the EfOM removal but also reduces the membrane fouling. In this
      research, NTR 7410 ultrafiltration membrane was employed to remove EfOM from
      BTSE. Different pretreatments namely FeCl(3) flocculation and powder activated
      carbon adsorption were evaluated. The highest removal of organic matter was
      observed when flocculation followed by adsorption was used as pretreatment. The
      flocculation and adsorption removed 68.5% and 71.4% of hydrophobic organics,
      respectively. The molecular weight (MW) of the EfOM in BTSE ranged from 300 to
      about 400000 Da. After the flocculation pretreatment, the majority of large MW
      organic matter was removed. The pretreatment of the flocculation followed by
      adsorption led to very high removal of both small and large organic matter.
      Further, this pretreatment led to practically no filtration flux decline.

PMID- 15026249
TI  - Commentary on "Alpha-synuclein and mitochondria: a tangled skein".

PMID- 15026250
TI  - Adult human olfactory neural progenitors cultured in defined medium.
AB  - Neurosphere-forming cells (NSFCs) derived from primary cultures of adult human
      olfactory epithelium were established in minimum essential medium (MEM) with
      Hanks balanced salts and 10% heat-inactivated fetal bovine serum (FBS). A totally
      defined medium (DM) was employed to examine their proliferation, lineage
      restriction and differentiation. DMEM/F12 (DF) was found to support NSFCs and
      served as the base medium for this study. NSFCs were adapted to the DM through
      serial serum reductions at successive feedings. NSFCs in DF supplemented with N2,
      B27 or insulin attained saturation density and formed extensive processes.
      Immunolocalization of lineage specific markers [i.e., nestin, beta-tubulin III,
      peripherin, neural cell adhesion molecule, A2B5, O4, microtubule-associated
      protein-2 (MAP2) and glial fibrillary acidic protein], as well as 3-[4,5
      dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide and ornithine
      decarboxylase assays were employed to characterize the NSFCs. The effects of
      trophic factors including epidermal growth factor (EGF), nerve growth factor
      (NGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor
      (CNTF), neurotrophic factors (NT-3), and basic fibroblast growth factor (bFGF)
      were evaluated. With the reduction of serum and the addition N2, B27, and other
      nutrients, there was a change in lineage restriction including an increase the
      expression of A2B5 and other glial markers as well as the expression of mature
      neuronal markers with a simultaneous reduction of nestin reactivity. NSFCs
      proliferated and maintained their pluripotency for over a year in the DM. Further
      studies will determine the utility of NSFCs for cell replacement therapy.

PMID- 15026251
TI  - Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat
      optic nerve.
AB  - The optic nerve is a CNS pathway containing molecules capable of inhibiting axon
      elongation. The growth program in embryonic retinal ganglion cell (RGC) neurons
      enables axons to regenerate in the optic nerve through at least two mechanisms.
      Namely, high cyclic AMP (cAMP) levels abrogate the ability of CNS molecules to
      inhibit elongation, and the pattern of gene expression enables axons to undergo
      rapid, sustained, and lengthy elongation. In adult mammals, recovery of visual
      function after optic nerve injury is limited by both the death of most RGC
      neurons and the inability of surviving axons to regenerate. We now report that a
      single intraocular injection of the membrane-permeable cAMP analogue dibutyryl
      cAMP (db cAMP) promotes the regeneration of RGC axons in the optic nerves of
      adult rats, but does not prevent the death of RGC neurons. This regeneration in
      optic nerves crushed within the orbit (2 mm from the eye) was equally effective
      either 1 day before or 1 day after db cAMP injection. The number of regenerating
      axons, which was maximal 14 days after crush, declined with increasing time after
      injury (i.e., 28, 56, and 112 days) and distance beyond the crush site (i.e.,
      0.25, 0.5, and 1.0 mm). Thus, db cAMP promotes optic nerve regeneration without
      increasing the survival of axotomized RGC neurons. Furthermore, since db cAMP
      does not enable axons to undergo rapid, sustained, and lengthy elongation,
      strategies that increase survival and promote these changes in elongation may
      critically complement the ability of db cAMP to promote regeneration.

PMID- 15026252
TI  - Hematopoietic origin of microglial and perivascular cells in brain.
AB  - BACKGROUND: Bone marrow (BM)-derived cells differentiate into a wide variety of
      cell types. BM contains a heterogeneous population of stem and progenitor cells
      including hematopoietic stem cells, marrow stromal cells, and perhaps other
      progenitor cells. To establish unequivocally the transdifferentiation capability
      of a hematopoietic cell to a nonhematopoietic cell (endothelial cells, neurons,
      and glial cells), it is imperative to demonstrate that a single cell or clone of
      that single cell (clonal analysis) differentiates into cells comprising vessels
      or other cells in the brain. METHODS: We generated mice that exhibited a high
      level of hematopoietic reconstitution from a single enhanced green fluorescent
      protein (EGFP) stem cell. To achieve this, we combined FACS sorting and cell
      culture to generate a population of cells derived from a single hematopoietic
      stem cell (Lin-, CD34-, c-kit+, and Sca-1+). Clonal populations of cells were
      then transplanted into lethally irradiated recipient mice. After 3-4 months of
      engraftment, some mice underwent middle cerebral artery (MCA) suture occlusion.
      EGFP immunocytochemistry and dual labeling was performed with cell-specific
      markers on tissue from various time points. RESULTS: In all transplanted mice,
      EGFP+ highly ramified cells were seen in the brain parenchyma. These cells
      stained with RCA120 lectin and had the characteristics of parenchymal microglial
      cells. In brains without infarction and in uninfarcted brain regions of mice that
      underwent MCA occlusion, there were many EGFP+ cells in a perivascular
      distribution, associated with both small and larger blood vessels. The cells were
      tightly apposed to the vessel wall and some had long processes that enveloped the
      endothelial cells. After MCA occlusion, there was an influx of EGFP expressing
      cells in the ischemic tissue that colocalized with the "neovascularization."
      These EGFP+ cells were wrapped around endothelial cells in an albuminal location
      and did not coexpress von Willebrand Factor or CD31. We detected rare dual
      labeled EGFP and NeuN-expressing cells. We detected two staining patterns. The
      more frequent pattern was phagocytosis of NeuN cells by EGFP expressing cells.
      However, we also detected rarer cells where the EGFP and NeuN appeared to be
      colocalized by confocal microscopy. CONCLUSIONS: HSC differentiate into
      parenchymal microglial cells and perivascular cells in the brain. The numbers of
      these cells increase after cerebral ischemia. The HSC is therefore one source of
      parenchymal microglial cells and a source for perivascular cells. After a
      cerebral infarction, there are rare HSC-derived cells that stain with the
      neuronal marker, NeuN. However, the more common pattern appears to represent
      phagocytosis of damaged neurons by EGFP+ microglial cells.

PMID- 15026253
TI  - Limbic pallidal adaptations following long-term cessation of dopaminergic
      transmission: lack of upregulation of dopamine receptor function.
AB  - Neurons in the ventral pallidum (VP) exhibit robust responding to activation of
      dopamine (DA) receptors of the D1 class. To determine if the VP adapts to chronic
      cessation of DA transmission, the present studies examined D1 receptor-mediated
      responses in the VP recorded extracellularly in chloral-hydrate anesthetized rats
      following destruction of DA neurons with 6-hydroxydopamine (6-OHDA) or long-term
      treatment with the D1 antagonist SCH23390. Indices of basal spiking (i.e.,
      spontaneous firing rate and pattern) recorded 10-21 days after unilateral 6-OHDA
      treatment did not differ from controls. Moreover, DA depletion did not alter the
      proportion of VP neurons whose rate was enhanced with i.v. injections of the D1
      agonist SKF38393, and the functional efficacy (Emax) and potency (ED50) were
      similar to controls. There also was no change in the direction of responses, the
      Emax or the ED50 measure of sensitivity (ECur50) to iontophoretic application of
      DA or SKF38393 in VP neurons. Forty-eight hours after 21 once-daily treatments
      with SCH23390, the number of [3H]SCH23390-labeled D1 receptors was increased in
      the striatum, but unchanged in the VP, globus pallidus, or septum. Accordingly,
      there was no functional upregulation of VP responses to i.v. SKF38393. Indeed,
      the proportion of SKF38393-sensitive neurons was decreased after chronic
      SCH23390. Distinguishing the VP from other forebrain regions, these findings
      indicate that basal spiking is not altered in the VP following chronic DA
      depletion, and that no upregulation of VP DA receptor function occurs following
      either dopaminergic lesions or chronic antagonism of D1 receptors.

PMID- 15026255
TI  - Nociceptive response to innocuous mechanical stimulation is mediated via
      myelinated afferents and NK-1 receptor activation in a rat model of neuropathic
      pain.
AB  - Peripheral nerve injury in humans can produce a persistent pain state
      characterized by spontaneous pain and painful responses to normally innocuous
      stimuli (allodynia). Here we attempt to identify some of the neurophysiological
      and neurochemical mechanisms underlying neuropathic pain using an animal model of
      peripheral neuropathy induced in male Sprague-Dawley rats by placing a 2-mm
      polyethylene cuff around the left sciatic nerve according to the method of
      Mosconi and Kruger. von Frey hair testing confirmed tactile allodynia in all cuff
      implanted rats before electrophysiological testing. Rats were anesthetized and
      spinalized for extracellular recording from single spinal wide dynamic range
      neurons (L(3-4)). In neuropathic rats (days 11-14 and 42-52 after cuff
      implantation), ongoing discharge was greater and hind paw receptive field size
      was expanded compared to control rats. Activation of low-threshold sensory
      afferents by innocuous mechanical stimulation (0.2 N for 3 s) in the hind paw
      receptive field evoked the typical brief excitation in control rats. However, in
      neuropathic rats, innocuous stimulation also induced a nociceptive-like
      afterdischarge that persisted 2-3 min. This afterdischarge was never observed in
      control rats, and, in this model, is the distinguishing feature of the spinal
      neural correlate of tactile allodynia. Electrical stimulation of the sciatic
      nerve at 4 and at 20 Hz each produced an initial discharge that was identical in
      control and in neuropathic rats. This stimulation also produced an afterdischarge
      that was similar at the two frequencies in control rats. However, in neuropathic
      rats, the afterdischarge produced by 20-Hz stimulation was greater than that
      produced by 4-Hz stimulation. Given that acutely spinalized rats were studied,
      only peripheral and/or spinal mechanisms can account for the data obtained; as
      synaptic responses from C fibers begin to fail above approximately 5-Hz
      stimulation [Pain 46 (1991) 327], the afterdischarge in response to 20-Hz
      stimulation suggests a change mainly in myelinated afferents and a predominant
      role of these fibers in eliciting this afterdischarge. These data are consistent
      with the suggestion that peripheral neuropathy induces phenotypic changes
      predominantly in myelinated afferents, the sensory neurons that normally respond
      to mechanical stimulation. The NK-1 receptor antagonist, CP-99,994 (0.5 mg/kg,
      i.v.), depressed the innocuous pressure-evoked afterdischarge but not the brief
      initial discharge of wide dynamic range neurons, and decreased the elevated
      ongoing rate of discharge in neuropathic rats. These results support the concept
      that following peripheral neuropathy, myelinated afferents may now synthesize and
      release substance P. A result of this is that tonic release of substance P from
      the central terminals of these phenotypically altered neurons would lead to
      ongoing excitation of NK-1-expressing nociceptive spinal neurons. In addition,
      these spinal neurons would also exhibit exaggerated responses to innocuous
      pressure stimulation. The data in this study put forth a possible
      neurophysiological and neurochemical basis of neuropathic pain and identify
      substance P and the NK-1 receptor as potential neurochemical targets for its
      management.

PMID- 15026254
TI  - Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein
      transgenic mice after treatment with MPTP.
AB  - Recent studies have implicated alpha-synuclein (alpha-S) in the pathogenesis of
      Parkinson's disease (PD). The mechanisms underlying PD are not completely
      understood; however, mitochondrial complex I inhibition and oxidative injury may
      be involved. Because the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
      (MPTP) is a potent complex I inhibitor that can cause oxidative injury and mimic
      many aspects of PD in treated animals, we sought to determine whether the
      overexpression of alpha-S in transgenic (tg) mice (alpha-S-tg) would enhance the
      substantia nigra (SN) pathology resulting from treatment with MPTP. For this
      purpose, alpha-S-tg mice were produced expressing high levels of wild-type (wt)
      human alpha-S under the control of the neuron-specific Thy-1 promoter. Alpha-S-tg
      mice and non-tg controls were treated with MPTP (15 mg/kg ip, twice a week for 2
      weeks) or saline (Sal) and then examined 2 weeks after completion of treatment by
      transmission electron microscopy (EM). We found that alpha-S-tg mice treated with
      MPTP had extensive mitochondrial alterations, increases in mitochondrial size,
      filamentous neuritic aggregations, axonal degeneration, and formation of electron
      dense perinuclear cytoplasmic inclusions in the SN that did not occur in the
      hippocampus or neocortex, nor in MPTP-treated non-tg mice or Sal-treated alpha-S
      tg mice. These findings support the potential involvement of alpha-S expression
      in the vulnerability of SN neurons to toxicity from mitochondrial complex I
      inhibitors and the subsequent development of neurodegenerative pathology.

PMID- 15026256
TI  - Intrathecal xenogeneic chromaffin cell grafts reduce nociceptive behavior in a
      rodent tonic pain model.
AB  - Adrenal medullary chromaffin cells synthetize and secrete a combination of pain
      reducing neuroactive compounds including catecholamines and opioid peptides.
      Previous reports have shown that implantation of chromaffin cells into the spinal
      subarachnoid space can reduce both acute and chronic pain in several animal
      models. We recently demonstrated that human chromaffin cell grafts in the
      cerebrospinal fluid (CSF) could alleviate intractable cancer pain after failure
      of systemic opiates. However, wider application of this approach was limited by
      the limited availability of allogeneic donor material. Alternatively, chromaffin
      cells from xenogeneic sources such as bovine adrenal medulla were successful in
      the experimental treatment of pain, but recent concern over risk of prion
      transmission precluded use of bovine grafts in human clinical trials. The
      objective of the present study was to investigate the possibility of developing a
      new xenogeneic porcine source of therapeutic chromaffin cells because this
      strategy is currently considered the safest for transplantation in man. In the
      present study, we report the isolation and the characterization of primary
      porcine chromaffin cells (PCC) compared to bovine cells. We show, for the first
      time, that these cells grafted in the rat subarachnoid space can attenuate pain
      related behaviors as assessed by the formalin test, a model of tonic pain.
      Moreover, in addition to behavioral studies, immunohistochemical analysis
      revealed robust survival of chromaffin cells 35 days after transplantation. Taken
      together, these results support the concept that porcine chromaffin cells may
      offer an alternative xenogeneic cell source for transplants delivering pain
      reducing neuroactive substances.

PMID- 15026257
TI  - Electrophysiological and behavioral effects of zolpidem in rat globus pallidus.
AB  - The globus pallidus is believed to play a critical role in the normal function of
      the basal ganglia, and abnormal activity of its neurons may underlie some basal
      ganglia motor symptoms. A high density of benzodiazepine binding sites on GABAA
      receptors has been reported in the rat globus pallidus. The present study
      investigates the effect of activating the benzodiazepine site by the agonist
      zolpidem. In in vitro slices, 100 nM of zolpidem significantly prolonged the half
      decay time of both miniature and spontaneous inhibitory postsynaptic currents by
      30.1 +/- 3.0% (n=12) and 17.8 +/- 2.4% (n=16), respectively, with no effect on
      their amplitudes and frequencies. In the behaving animal, when zolpidem was
      microinjected into the globus pallidus unilaterally, it caused a robust
      ipsilateral rotation (26.4 +/- 2.4 turns/30 min, n=8), significantly higher than
      that of control animals receiving vehicle injection (1.3 +/- 1.6 turns/30 min,
      n=6). This effect was in agreement with the in vitro effect of zolpidem in
      enhancing the action of GABA on postsynaptic GABAA receptors. All the effects of
      zolpidem, in vitro or in vivo, were sensitive to the benzodiazepine antagonist
      flumazenil, confirming the specificity on the benzodiazepine site. This finding
      on the effect of zolpidem on motor behavior provides a rationale for further
      investigations into its potential in the treatment of motor disorders originating
      from the basal ganglia.

PMID- 15026258
TI  - Alterations in IGF-I, BDNF and NT-3 levels following experimental brain trauma
      and the effect of IGF-I administration.
AB  - The effects of a unilateral, penetrating brain trauma on IGF-I, BDNF and NT-3
      were studied immunocytochemically in the rat. BDNF and NT-3 were decreased in the
      peritraumatic area, but increased in the adjacent region, 4 and 12 h post-injury.
      One week following the trauma, BDNF remained low in the peritraumatic area, but
      was restored to normal levels in the adjacent, while no effect of injury on NT-3
      levels was detected in either area. Injury resulted in an increase in IGF-I
      levels in the peritraumatic area, which was most pronounced 1 week following the
      trauma, indicating that IGF-I could participate in endogenous repair processes.
      We thus administered IGF-I immediately following the trauma and investigated its
      effects on injury-induced changes in neurotrophin levels. Administration of IGF-I
      partially reversed the injury-induced decrease in BDNF and NT-3 in the
      peritraumatic area observed 4 and 12 h post-injury, while at the same time
      points, it completely cancelled the effects of injury in the adjacent region. One
      week after the trauma, BDNF levels were dramatically increased in both the
      peritraumatic and adjacent area, reaching levels even higher than those of the
      sham-operated animals, following IGF-I administration. Our results showing that
      IGF-I not only counteracts injury-induced changes in neurotrophins, but can also
      further increase their levels, indicate that this growth factor could mediate
      repair and/or protective processes, following brain trauma.

PMID- 15026259
TI  - Chronic administration of rotenone increases levels of nitric oxide and lipid
      peroxidation products in rat brain.
AB  - The complex I inhibitor rotenone is a neurotoxin that has been proposed to induce
      Parkinson-like degeneration. As the mechanisms of rotenone toxicity are not fully
      understood, the present study addresses the question of whether rotenone induces
      NO production and lipid peroxidation-like products, that is, thiobarbituric acid
      reactive substances (TBARS). Rotenone at a dose of 1.5 mg kg(-1) i.p. was
      administered to rats daily for 10, 20, 30, and 60 days, and NO and TBARS were
      measured in the frontal cortex and in the striatum. On the 1st and 10th day,
      there were no increases in NO and TBARS levels, after 20 days, the NO and TBARS
      levels were increased in the striatum. After 30 and 60 days, NO and TBARS levels
      were increased in striatum and frontal cortex. Behaviorally, on days 30 and 60,
      the rats exhibited akinesia and rigidity in the catalepsy test. These results
      show that chronic administration of rotenone over a long period is capable of
      increasing NO and TBARS in the cortex and striatum and mimics Parkinson's disease
      (PD)-like behavioral symptoms that are akinesia and rigidity in rats.

PMID- 15026260
TI  - Kynurenine aminotransferase in the supratentorial dura mater of the rat: effect
      of stimulation of the trigeminal ganglion.
AB  - Electrical stimulation of the trigeminal ganglion has been widely used as a model
      of nociception, characterizing migraine. This treatment is known to evoke release
      of neuropeptides and neurotransmitters from nerve fibers of the dura mater. On
      the basis of immunocytochemical investigations, we found that under normal
      conditions, surface membranes of Schwann cells surrounding nerve fibers in the
      supratentorial dura mater display kynurenine aminotransferase-immunoreaction (KAT
      IR); also KAT-IR are the granules of mast cells and the cytoplasms of macrophages
      (histiocytes). In consequence of stimulation of the trigeminal ganglion, Schwann
      cells in the dura mater became conspicuously swollen while their KAT-IR decreased
      considerably; also KAT-IR of mast cells and macrophages decreased significantly.
      At the same time, nitric oxide synthase (NOS)-IR of nerve fibers in the dura
      mater increased, suggesting release of nitric oxide (NO), this is known to be
      involved in NMDA receptor activation leading to vasodilation followed by
      neurogenic inflammation. Because kynurenic acid (KYNA) is an antagonist of NMDA
      receptors, we hypothesize that KYNA and its synthesizing enzyme, KAT, may play a
      role in the prevention of migraine attacks.

PMID- 15026261
TI  - Optimal delivery of minocycline to the brain: implication for human studies of
      acute neuroprotection.
AB  - Minocycline is currently under development as a neuroprotective agent in many
      different brain diseases. In more than a dozen experimental investigations in
      various models of brain injury, high doses of minocycline have been administered
      intraperitoneally. This report details new concerns with this route of
      administration and makes a case for intravenous dosing in experimental animals,
      particularly for acute neuroprotection, to optimize delivery to the brain and
      facilitate translation to human studies.

PMID- 15026262
TI  - Peripheral markers of blood-brain barrier damage.
AB  - Neurological diseases are often associated with cerebrovascular dysfunction and
      changes in blood-brain barrier (BBB) function. This is important for two
      seemingly conflicting reasons. On the one hand, a leaky BBB may lead to brain
      disease by allowing extravasation of cells and molecules normally segregated in
      the periphery, while on the other hand an intact BBB may hamper drug delivery to
      the ailing brain. Under both circumstances, it would be desirable to follow
      closely over time BBB "tightness". Several lines of evidence have suggested that
      the astrocytic protein S100beta is a potentially useful peripheral marker of BBB
      permeability. Other markers of brain-to-blood barriers have been recently
      discovered by a proteomic approach. These proteins are virtually absent in normal
      blood, appear in serum from patients with cerebral lesions, and can be easily
      detected. We will present clinical and laboratory evidence supporting the use of
      these markers as modern neurodiagnostic tools.

PMID- 15026263
TI  - Electropharmacological actions of Ginkgo biloba extract on vascular smooth and
      heart muscles.
AB  - Ginkgo biloba extract (GBE) is composed mostly of two constituents: One is
      terpenoids (such as bilobalide, ginkgolides A, B and C), and the other is
      flavonoids (such as quercetin and rutin). After oral administration of GBE (160
      mg) to healthy volunteers, the plasma concentrations of ginkgolides A and B and
      bilobalide are 41.8, 5.6 and 37.6 ng/ml, respectively. GBE and bilobalide cause a
      potent concentration-dependent relaxation. NG-Monomethyl-l-arginine acetate (l
      NMMA), an NO synthesis inhibitor, reduces the vasodilation induced by GBE.
      Furthermore, the vasorelaxation of GBE is attenuated in Ca2+-free medium.
      Bilobalide possesses similar mechanisms. The other constituents also produce
      vasorelaxation. On the other hand, all the compounds markedly modify the action
      potential configuration in guinea pig ventricular cardiomyocytes. GBE prolongs
      the action potential duration (APD), whereas bilobalide shortens the APD. In
      patch-clamp experiments, GBE markedly inhibits the Ca2+ current (ICa), the
      delayed rectifier K+ current (IK) and the inwardly rectifying K+ current (IK1).
      On the contrary bilobalide enhances the ICa and IK currents concentration
      dependently. The other constituents do not cause their actions in a uniform
      direction. In the rat sino-atrial (SA) node, GBE causes a negative chronotropic
      effect. These results indicate that GBE and the constituents produce effective
      electropharmacological actions in the cardiomyocytes and cause vasodilation,
      mainly due to the inhibitions of Ca2+ influx through the Ca2+ channel and the
      activation of NO release in the endothelium and aortic vascular muscles.

PMID- 15026265
TI  - Cysteine proteases as disease markers.
AB  - This review comprises issues concerning cysteine cathepsins (CCs): human
      peptidases belonging to papain family (C1) of clan CA of cysteine proteases:
      cathepsins B, L, H, S, K, F, V, X, W, O and C. The involvement of these enzymes
      in physiological and pathological processes is described, especially with respect
      to their application as diagnostic and prognostic markers. They participate in
      precursor protein activation (including proenzymes and prohormones), MHC-II
      mediated antigen presentation, bone remodeling, keratinocytes differentiation,
      hair follicle cycle, reproduction and apoptosis. Cysteine cathepsins upregulation
      has been demonstrated in many human tumors, including breast, lung, brain,
      gastrointestinal, head and neck cancer, and melanoma. Besides cancer diseases,
      they have been implied to participate in inflammatory diseases, such as
      inflammatory myopathies, rheumatoid arthritis, and periodontitis. Also, certain
      hereditary disorders are connected with mutations in CCs genes, what is observed
      in pycnodysostosis resulted from catK gene mutation and Papillon-Lefevre and Haim
      Munk syndrome caused by catC gene defect. The potential application of cysteine
      cathepsins in diagnosis and/or prognosis is discussed in cancer diseases (breast,
      lung, head and neck, ovarian, gastrointestinal cancers, melanoma), as well as
      other disorders (periodontitis, rheumatoid arthritis, osteoarthritis).

PMID- 15026264
TI  - Systematic reviews in laboratory medicine: principles, processes and practical
      considerations.
AB  - BACKGROUND: Systematic reviews and meta-analyses are generally accepted to
      represent the highest level of evidence, and are a cornerstone in practising
      evidence-based medicine. So far, these efforts have been largely confined to the
      evaluation of the efficacy and effectiveness of therapeutic and preventive
      interventions. Systematic reviews in laboratory medicine are scarce and many of
      them do not meet essential quality criteria [Clin. Chem. Lab. Med. 38 (2000)
      577]. Most of these problems are related to the poor design and heterogeneity of
      primary research, and that there are no agreed methods or quality standards for
      making systematic reviews in laboratory medicine. AIMS AND OBJECTIVES: For better
      evidence in laboratory medicine, not only higher quality primary studies but also
      standardized methodologies for designing, conducting and reporting systematic
      reviews in diagnostics are needed. The aim of this review is to present the
      general principles and provide a step-by-step process of systematic reviewing in
      laboratory medicine. METHODS: This narrative review is based on the overview of
      the medical literature on the methodology of systematic reviewing and that of the
      "state of the art" of evidence-based diagnosis. RESULTS: Systematic reviews of
      diagnostic interventions differ from that of therapeutic interventions in the
      methods of question formulation, the choice of study design, the assessment of
      study quality and the statistical methods used to combine results. Therefore, the
      general principles of systematic reviewing are adapted to the specialist field of
      laboratory medicine. The process of systematic reviewing consists of six key
      steps: (1) preparation for the review, (2) systematic search of the primary
      literature, (3) selection of papers for review, (4) critical appraisal of the
      selected literature, (5) analysis and synthesis of data, and (6) interpretation
      of data. The most important technical and methodological aspects of each step and
      the essential elements of a good systematic review in laboratory medicine are
      presented. CONCLUSIONS: Systematic reviews of diagnostic interventions support
      clinical and policy decisions, the development of practice guidelines, clinical
      audit, technology assessment, economic evaluations, education and training, and
      identify gaps in our knowledge for future research. Systematic reviewing of
      laboratory data is expected to result in better, bigger and more reliable primary
      studies, which hopefully will support the diffusion of new diagnostic
      technologies with scientifically proven efficacy and effectiveness in the future.

PMID- 15026266
TI  - Detection of autoantibody against carbonic anhydrase II in various liver diseases
      by enzyme-linked immunosorbent assay using appropriate conditions.
AB  - BACKGROUND: Immunoglobulin G autoantibody against carbonic anhydrase (CA) II has
      been detected in the sera of patients with a variety of autoimmune diseases.
      Antibody against CAII has also been described as a serological marker for
      distinguishing between cases of autoimmune cholangitis (AIC) and those of primary
      biliary cirrhosis (PBC). However, the optimal antibody measurement conditions
      (enzyme-linked immunosorbent assay: ELISA) have not yet been established.
      Moreover, we also found that a small amount of an IgG-like material exists in
      purchased CAII reagents, which causes pseudopositive reactions. METHODS: The sera
      of 96 patients with liver disease were examined for the presence of anti-CAII
      antibody using antigen (CAII) not containing the IgG-like material as the most
      suitable measurement conditions. Compared with the anti-CAII antibody prevalence
      of 3.8% found in normal subjects, a significantly higher seroprevalence of the
      antibody was detected in patients with PBC (31.0%, P<0.02), autoimmune hepatitis
      (AIH) (50.0%, P<0.01) and chronic viral hepatitis (27.5%, P<0.01). But, in cases
      of PBC, no significant correlation was noted between the level of anti-CAII
      antibody and the presence of anti-mitochondrial antibodies (AMA). CONCLUSIONS:
      While CAII may be a target antigen in autoimmune diseases, the anti-CAII antibody
      is not likely to be a specific marker of AIC. The optimum measurement conditions
      for the ELISA for anti-CAII antibody would provide us with valuable information
      to elucidate the underlying immunological abnormalities in liver diseases.

PMID- 15026267
TI  - Reference values for cardiac troponins I and T in a goal-oriented concept of
      health: cardiac marker values in a series of outpatients without acute coronary
      syndromes.
AB  - BACKGROUND: Cardiac troponins are part of the new definition of acute myocardial
      infarction (AMI) by the European Society of Cardiology and the American College
      of Cardiology (ESC/ACC). In the new guidelines, it was suggested to establish
      reference values for cardiac troponins to calculate the 0.99 quantile (Q99) as
      cutoff for AMI diagnosis. PATIENTS AND METHODS: We run a prospective series of
      troponin measurements in unselected outpatients who had no suspicion of cardiac
      ischemia. The selection of patients as reference population is based on a "goal
      oriented concept of health". One hundred and ninety-five patients agreed that 10
      ml additional blood was drawn at the occasion of the venous puncture done
      routinely in the evaluation of their case. Cardiac troponin I was measured using
      a point of care (POCT) device (Stratus CS, DadeBehring, TNI-PO). Additionally,
      heparin-plasma was obtained and immediately deep-frozen to -80 degrees C for
      later batch measurement of cardiac troponin T (Elecsys 2010, Roche Diagnostics,
      TnT) and troponin I (Centaur, Bayer, TnI-CL). RESULTS: The Q99 values were 0.14
      microg/l for TnI-PO, 0.023 microg/l for TnT and 0.07 microg/l for TnI-CL in
      patients with creatinine levels below 1.5 mg/dl. These values lay above those
      obtained from people at good health for reference study purposes. On the level of
      our cutoffs, CVs were 7.5%, 6.4% and 23.7% for TnI-PO, TnT and TnI-CL,
      respectively. CONCLUSIONS: Only the TnI-PO and TnT tests fulfilled the
      imprecision criteria in our study. TnI-PO values between 0.10 and 0.14 microg/l
      and TnT values between 0.01 and 0.03 microg/l have to be interpreted carefully.
      Patients presenting with chest pain will be possibly true positives, but patients
      without chest pain and nondiagnostic ECGs should be subjected to repetitive
      troponin measurements and further noninvasive investigation and maybe not
      directly sent to the cardiac catheter laboratory.

PMID- 15026268
TI  - Brain natriuretic peptide levels during cardiac reperfusion: comparison between
      percutaneous coronary angioplasty and aorto-coronaric bypass.
AB  - BACKGROUND: Several studies have documented brain natriuretic peptide (BNP)
      behavior during cardiac ischemia and after myocardial necrosis. Peptide levels
      have been shown to be increased during acute phase of cardiac ischemia and during
      late ventricular remodelling; however, there are fewer data about hormone levels
      during percutaneous transluminal coronary angioplasty (PTCA) and aorto-coronaric
      by pass (CABG). METHODS: Aim of this study was to investigate plasma BNP during
      acute or sub-acute myocardial ischemia in patients undergoing to PTCA or CABG,
      taking blood samples before and after both procedures. We studied 59 consecutive
      subjects, 25 submitted to coronary by-pass and 34 submitted to coronary
      angioplasty. Blood BNP levels were measured the day before intervention and after
      3, 7 and 90 days from the procedures. RESULTS: Peptide levels were significantly
      different just before intervention (GABG group 118.7+/-81 pg/ml vs. PTCA group
      34.8+/-15 pg/ml, p<0.01). This difference was increased after 3 days (CABG group
      403.2+/-185 pg/ml vs. PTCA group 105.3+/-56 pg/ml, p<0.0001) and after 7 days
      (CABG group 252.2+/-93 pg/ml vs. PTCA group 69.8+/-36 pg/ml, p<0.00001). These
      results trend to converge after 90 days (CABG group +/-93 pg/ml vs. PTCA group +/
      36 pg/ml, p<0.05). CONCLUSIONS: Plasma BNP shows a different behavior during and
      after different myocardial reperfusion procedures. PTCA causes only mild and
      temporary elevation of peptide levels, otherwise CABG demonstrates a more
      enhancing of BNP release not only in early phase but also after one week;
      increased levels tend to return towards the reference range after few weeks from
      cardiac surgery.

PMID- 15026269
TI  - The inflammatory markers C-reactive protein and serum amyloid A in refugees with
      and without posttraumatic stress disorder.
AB  - BACKGROUND: "Stress" is associated with changes in many systems of the body. The
      aim was to study the markers of the innate immune system, Serum amyloid A (SAA)
      and C-reactive protein (CRP), in subjects with and without posttraumatic stress
      disorder (PTSD). METHODS: Subjects were refugees from Iraq in the age range of 18
      48 years who participated in a longitudinal study focusing on life events. Blood
      samples were taken in the morning and analysed for Serum amyloid A and high
      sensitivity C-reactive protein (hsCRP). RESULTS: Contrary to expectations, serum
      SAA and hsCRP were lower in PTSD than in non-PTSD subjects. Levels of SAA and CRP
      were further inversely correlated with serum DHEA-s, but not with cortisol. In
      cases with PTSD at baseline, there was an inverse relationship between difference
      in self-rated symptoms of PTSD and difference in log-transformed SAA-thus
      increasing PTSD intensity was associated with decreasing SAA. No such patterns
      were obvious with regard to CRP. CONCLUSIONS: Changes in the innate immune
      system, as measured by acute phase proteins of hepatic origin, seem to be a
      feature of PTSD. Further, the inverse correlation between DHEA-s, which has been
      shown to be changed in PTSD, and the acute phase proteins is of interest.

PMID- 15026270
TI  - Plasma adenosine concentrations increase in women with hyperemesis gravidarum.
AB  - BACKGROUND: Adenosine is an important metabolic modulator and adenosine
      concentrations are affected by sympathetic nerve stimulation and cytokine
      production. Since hyperemesis gravidarum is characterized by overactivation of
      sympathetic nerves and enhanced production of tumor necrosis factor (TNF)-alpha,
      plasma adenosine concentrations may be altered. The present study evaluated
      plasma adenosine concentrations and their relation with norepinephrine and TNF
      alpha concentrations in hyperemesis gravidarum. METHODS: Plasma concentrations of
      adenosine, norepinephrine, and TNF-alpha were measured in 34 healthy nonpregnant
      women, and 34 women with hyperemesis gravidarum and normal pregnancies, matched
      for age, parity and gestational week. The relationships between plasma adenosine,
      and norepinephrine and TNF-alpha concentrations in hyperemesis gravidarum were
      evaluated. RESULTS: Mean plasma adenosine, norepinephrine, and TNF-alpha
      concentrations were significantly increased in women with hyperemesis gravidarum
      compared to those in nonpregnant and normal pregnant women (p<0.05). The increase
      in plasma adenosine concentrations correlated with the increase of norepinephrine
      and TNF-alpha in hyperemesis gravidarum (r=0.50, p<0.05 and r=0.43, p<0.05,
      respectively). CONCLUSIONS: Adenosine is an established suppressor of excessive
      sympathetic nerves activation and cytokine production, so the increase in plasma
      adenosine in hyperemesis gravidarum might serve to counteract further progression
      of hyperemesis gravidarum.

PMID- 15026271
TI  - Lower doses of vanadate in combination with trigonella restore altered
      carbohydrate metabolism and antioxidant status in alloxan-diabetic rats.
AB  - BACKGROUND: Vanadate treatment to diabetic rats has been reported to correct the
      altered carbohydrate metabolism and antioxidant status. However, vanadate exerts
      these effects at relatively high doses and several toxic effects are produced. We
      used low doses of vanadate in combination with Trigonella foenum graecum seed
      powder (TSP) and evaluated their effect on the enzyme changes in diabetic rats.
      METHODS: Alloxan-diabetic rats were treated separately with insulin, vanadate
      (0.6 mg/ml), TSP and a combined dose of Vanadate (0.2 mg/ml) and TSP for 21 days.
      At the end of the experimental period, blood glucose levels and activities of
      pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (PEPCK), glutathione
      peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and
      catalase (CAT) were measured in cytosolic fraction in the liver and kidney.
      RESULTS: Blood glucose levels increased markedly in diabetic rats. Treatment with
      antidiabetic compounds resulted in the reduction of glucose levels. Rats treated
      with combined dose of vanadate and trigonella had glucose levels comparable to
      control ones. Similar results were obtained with the activities of PK, PEPCK,
      SOD, GPx, GR, and CAT in liver and kidney of diabetic rats. Combined dose of
      vanadate and Trigonella was found to be most effective in correcting these
      alterations. CONCLUSIONS: Lower doses of vanadate could be used in combination
      with TSP to effectively counter diabetic alterations without any toxic side
      effects.

PMID- 15026272
TI  - A competitive nucleic acid sequence-based amplification assay for the
      quantification of human MDR1 transcript in leukemia cells.
AB  - BACKGROUND: Because clinical drug resistance is caused by low-grade expression of
      a responsible gene, highly sensitive methods are desirable for its detection in
      clinical settings. We developed a quantitative nucleic acid sequence-based
      amplification (NASBA) assay for multidrug resistance-1 (MDR1) transcripts, and
      applied it to clinical samples. METHOD: MDR1 transcripts were amplified using the
      NASBA technique combined with sandwich hybridization of amplified MDR1 mRNA
      followed by chemiluminescence detection on an automated analyzer. Quantification
      of MDR1 mRNA was achieved through competitive coamplification of in vitro
      generated RNA, which acts as an internal control. RESULTS: The competitive NASBA
      assay exhibited higher sensitivity (reliable detection limit was 100 copies of
      MDR1 mRNA) and linearity over a broader dynamic range (7 logarithmic orders) than
      the competitive reverse transcription-polymerase chain reaction assay. All 33
      clinical samples obtained from patients with leukemia were successfully assayed,
      demonstrating its feasibility. MDR1 expression-compensated with beta-actin
      expression-ranged from 1.4 x 10(2) to 2.5 x 10(6) (median 4.8 x 10(5))
      copies/microg RNA, while the range of MDR1 expression in peripheral blood samples
      from 15 healthy adults was from 8.9 x 10(4) to 5.2 x 10(5) (median 2.2 x 10(5))
      copies/microg RNA. MDR1 expression in 8 of 33 clinical samples exceeded the
      median of healthy adult samples. CONCLUSIONS: The competitive NASBA assay is
      applicable to MDR1 mRNA quantification in clinical samples and would contribute
      to detection of clinical multidrug resistance.

PMID- 15026273
TI  - Serum cytochrome c level as a prognostic indicator in patients with systemic
      inflammatory response syndrome.
AB  - BACKGROUND: Apoptosis may play an important role in the development of systemic
      inflammatory response syndrome (SIRS) and progression to multiple organ
      dysfunction syndrome (MODS). To quantify the extent of apoptosis in these
      morbidities, we developed a sandwich ELISA system to measure serum cytochrome c
      (cyt-c) levels and we investigated the prognostic significance of cyt-c
      concentration in SIRS/MODS patients. METHODS: Cyt-c concentrations in patients
      with SIRS (n=53) with or at risk for MODS were measured and compared with those
      of control subjects (n=14). RESULTS: Cyt-c concentrations in SIRS/MODS patients
      increased (0.24-210 ng/ml), whereas those in control subjects were under
      detection limits (0.1 ng/ml). Cyt-c concentrations in non-survivors increased
      significantly compared with those in survivors both on the day of admission and
      on the fifth hospital day. A significant positive correlation was found between
      cyt-c concentration and two representative organ dysfunction scores, APACHE II
      and multi-organ failure (MOF) score. Cyt-c concentrations increased earlier than
      MOF score during the exacerbation phase and rapidly decreased during the
      convalescence phase in a survivor, but the level continued to be high in a non
      survivor. CONCLUSIONS: Determination of serum cyt-c concentrations may be useful
      to assess the severity of organ dysfunction and to predict the prognosis of
      SIRS/MODS patients.

PMID- 15026274
TI  - Use of pyrosequencing to detect clinically relevant polymorphisms of genes in
      basal cell carcinoma.
AB  - BACKGROUND: Pyrosequencing is a new method to detect single nucleotide
      polymorphisms (SNPs). Basal cell carcinoma (BCC) is one of the most common
      neoplasms in the world, and its incidence has been increasing worldwide in recent
      years. BCC is caused by an interplay between genetic and environment factors.
      METHODS: Pyrosequencing and restrict fragment length polymorphism (RFLP) were
      used in the study. We conducted a case-control association study in BCC cases and
      controls from Sweden. For SNPs in IL-6, IL-10 and IL-1beta, 241 cases were at the
      age of 27-70 years (mean 50 years) and 260 healthy controls were 26-71 years
      (mean 48 years), 241 cases were 27-70 years (mean 50 years) and 574 healthy
      controls were 22-74 years (mean 52 years) for cyclin D1 G870A, 197 cases were 29
      69 years (mean 47 years) and 574 healthy controls were 22-74 years (mean 52
      years) for MTHFR C677T and A1298C. Nine SNPs for IL-6-174G/C, -634G/C and 
      597G/A; IL-10-1082G/A and -592C/A; IL-1beta-511C/T; cyclin D1 G870A; MTHFR C677T
      and A1298C were analyzed. RESULTS: Most genotype distributions were in accordance
      with Hardy-Weinberg equilibrium (HWE), except IL-10-1082G/A, which had a
      significantly deviation from HWE in BCC cases (P<0.05). Linkage disequilibrium
      was observed between the -174 and -597 alleles in the IL-6 gene in the studied
      populations. The differences for cyclin D1 G870A and methylenetetrahydrofolate
      reductase (MTHFR) C677T were found between BCC cases group and control group
      (P<0.05, OR=1.34, 95% CI, 1.00-1.74; P<0.05, OR=1.67, 95% CI, 1.13-2.47,
      respectively). CONCLUSIONS: Cyclin D1 G870A and MTHFR C677T were associated with
      BC cases from Sweden, the other SNPs studied here were not associated with BCC,
      but chance cannot be excluded.

PMID- 15026275
TI  - Colorimetric silver detection of methylation using DNA microarray coupled with
      linker-PCR.
AB  - BACKGROUND: Aberrant DNA methylation of CpG site is among the earliest and most
      frequent alterations in cancer. Detection of promoter hypermethylation of cancer
      related genes may be useful for cancer diagnosis or the detection of recurrence.
      Recently, several DNA microarray methods have been developed to detect the
      methylation status of the multiple genes. However, the microarrays are currently
      detected in fluorescence using a sophisticated laser-based scanner. These methods
      are limited by their lower sensitivity. METHODS: We present a sensitive
      colorimetric silver method coupled with linker-PCR to detect methylation status
      of four genes, including p16, E-cadherin, VHL, and hMLH1. The signal generated
      with this method results from the precipitation of silver onto nanogold particles
      bound to streptavidin used to detect biotinylated DNA. RESULTS: We show that p16,
      E-cadherin, VHL, and hMLH1 were all methylated in the positive control. However,
      no methylation was found in these genes for the negative control. P16 gene was
      only methylated in the sample, whereas others were not methylated. Furthermore,
      as little as 0.1 fmol of target DNA amplicons could be detected on the arrays.
      The results were further validated by methylation-specific PCR (MSP) and
      bisulfite DNA sequencing. CONCLUSIONS: The colorimetric silver detection of DNA
      microarray could be used as an inexpensive, useful, and sensitive tool to detect
      methylation status of the multiple genes in the future.

PMID- 15026276
TI  - Analysis of protein absorbed by LDL column (Liposorber) with special reference to
      complement component factor D.
AB  - BACKGROUND: A dextran sulfate column (Liposorber) has been developed and proven
      effective in LDL apheresis for removing LDL from patients with hyperlipemia.
      Chronic renal failure (CRF) patients with arteriosclerosis obliterans (ASO)
      treated with Liposorber have been shown good results. METHODS: We analyzed
      proteins absorbed by Liposorber in CRF patients with ASO by means of 2
      dimensional electrophoresis and found some noteworthy protein spots. One of these
      proteins was purified by Sephacryl S-100 column and DEAE Sepharose fast flow
      column chromatography. RESULTS: The purified protein was finally identified as
      complement factor D by Western blotting. The average of recovery amount from
      three experiments was 6.5 mg. The total recovered amount of factor D was
      calculated to be about 21.7% out of the estimated amount of factor D in the
      plasma of CRF patients with ASO receiving LDL apheresis using Liposorber.
      CONCLUSIONS: These results indicate that Liposorber absorbs factor D remarkably
      well.

PMID- 15026277
TI  - Hydrophobic nature of rat lymph chylomicrons.
AB  - BACKGROUND: A typical molecular structure of a lipoprotein is composed of
      hydrophobic lipids at the core and hydrophilic apolipoprotein side chains and
      lipid head groups at the surface. Some of the hydrophobic characteristics of rat
      lymph chylomicrons were investigated. METHODS: Thoracic duct was cannulated and
      lymph was collected overnight. Chylomicrons (>100 nm) were isolated by
      ultracentrifugation at 4 x 10(6)xg min. Since particle aggregation is a
      characteristic of hydrophobic nature of lipoproteins, as an index of aggregation,
      the turbidity generated by vortexing and storage of chylomicrons was measured
      spectrophotometrically at 680 nm. We also assessed the ability of chylomicrons to
      interact with five different hydrophobic interaction chromatography (HIC) media.
      RESULTS: Neither shaking nor prolonged storage at 4 degrees C produced an
      increase in the optical density of chylomicron solution indicating no aggregation
      took place. Typical elution profiles of chylomicrons through octyl, phenyl (high
      substance) and butyl sepharose columns showed two peaks. Peak I material emerged
      with 4 mol/l NaCl in a position corresponding to the void volume and peak II
      material eluted with water. Phenyl sepharose (high performance) media exhibited
      the maximum binding strength towards chylomicrons among the five different media.
      In the case of phenyl sepharose (low substance) column, an additional material
      was eluted with 3 mol/l NaCl between peaks I and II. These results indicate the
      heterogeneity of chylomicron surface hydrophobicity. CONCLUSION: Since particle
      aggregation is a characteristics of hydrophobicity of lipoproteins and believed
      to be an underlying cause of atherosclerosis, fractionation of lipoproteins by
      hydrophobic interaction chromatography may introduce a new approach into the
      assessment of lipoprotein atherogeneicity.

PMID- 15026278
TI  - Analytical and clinical evaluation of the Bayer ADVIA Centaur homocysteine assay.
AB  - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in the
      United States. Elevations in homocysteine (Hcy) have been associated with
      increased risk of acute coronary syndrome, stroke and peripheral vascular
      disease. Increased utilization of Hcy as a risk marker has prompted the need for
      high throughput methods that are simple to use and analytically accurate and
      precise. METHODS: We report the performance characteristics of the automated
      Bayer ADVIA Centaur chemiluminescent Hcy assay. Centaur Hcy is based on a three
      step procedure: (1) reduction of Hcy disulfides to free Hcy, (2) enzymatic
      conversion of free Hcy to S-adenosyl Hcy (SAH) and (3) quantitation of SAH in a
      competitive immunoassay (labeled anti-SAH antibody: magnetic particles coupled
      with SAH). RESULTS: Total assay precision ranged from 3.5% to 6.8% at 4.9-62
      micromol/Hcy; linearity undiluted from 0 to 65 micromol/l, up to 650 micromol/l
      with automatic dilution. Method comparisons with fluorescent polarization
      immunoassay and high-performance liquid chromatography (HPLC) gave linear
      regression equations with slopes between 0.95 and 1.0. Measurement of Hcy
      concentrations in apparently healthy populations yielded middle 95th percentile
      of 9.7 micromol/l, consistent with epidemiologic studies suggesting that 9-10
      micromol/l represents the lower threshold of a population at risk of CVD.
      CONCLUSIONS: The Centaur Hcy assay is a sensitive and precise assay for the
      measurement of Hcy.

PMID- 15026279
TI  - Plasma and urinary free amino acid concentrations in preeclamptic women in
      northern Nigeria.
AB  - BACKGROUND: Preeclampsia/eclampsia is one of the major causes of maternal and
      fetal mortality in Nigeria and many other countries in sub-Saharan Africa. We
      determined if serum and urine concentrations of amino acids were abnormal in
      women with this disorder of pregnancy in Gombe, Nigeria. METHODS: Free amino
      acids were measured in serum and urine of women (ages, 15 to 40 years) with
      preeclampsia/eclampsia (n=37) and their pregnant age and gestational age matched
      controls (n=16). RESULTS: The concentrations of 19 of the 20 serum amino acids
      that are common in proteins were not significantly different between the control
      and preeclamptic groups. Phenylalanine was increased in the preeclamptic women
      compared to the controls (p<0.05); however, the difference between the two values
      was small (119 vs. 104 umol/l, respectively). The concentrations of urine free
      amino acids were indexed to urine creatinine (i.e., nmol/mg creatinine). Five
      amino acids were significantly elevated in the urine of preeclamptic patients vs.
      the control group: proline (100%, p<0.05), the branched amino acids, valine (80%,
      p<0.05), leucine (61%, p<0.05), isoleucine (49%, p=0.01), and methionine (52%,
      p<0.005). On the other hand, the concentrations of a nutritionally non-essential
      amino acid, glycine (p=0.01), and an essential amino acid, histidine (p=0.01),
      were both reduced by about one-third in the urine of the preeclamptic women.
      CONCLUSIONS: Our findings indicate that there are disturbances in urinary amino
      acid excretion but not in the serum amino acid profile in the preeclamptic
      patients. The degree of aminoaciduria is probably not sufficient to significantly
      affect overall nitrogen balance or precipitate a deficiency of one or more of the
      essential amino acids.

PMID- 15026280
TI  - Possible link between glycated hemoglobin and lipid peroxidation in
      hyperthyroidism.
AB  - BACKGROUND: Glycated hemoglobin (HbA1C) levels are enhanced by elevated glucose
      concentrations. Glycation of hemoglobin is also modulated by lipid peroxides,
      ascorbic acid and reduced glutathione (GSH). We determined the strength of the
      relationships among these variables in a group of hyperthyroid patients. METHODS:
      Twenty-two untreated hyperthyroid patients and 17 healthy controls were recruited
      for the study. Whole blood GSH, HbA1C, plasma lipid peroxides, ascorbic acid and
      fasting glucose were analyzed in both the groups. Direct and partial correlation
      analysis was performed to explore the possible relationships between these
      variables. RESULTS: In hyperthyroid patients, HbA1C and lipid peroxides levels
      were found to be significantly increased than the controls. Ascorbic acid and GSH
      were decreased significantly in the test group when compared with the healthy
      control group. With partial correlation analysis, fasting glucose and lipid
      peroxides were found to have a significant positive correlation with HbA1C.
      Ascorbic acid and GSH showed no significant association with HbA1C levels.
      CONCLUSION: These data suggest that HbA1C levels are closely associated with
      fasting glucose and lipid peroxides in hyperthyroid patients. Therefore, serum
      lipid peroxides level should be kept in mind while interpreting HbA1C as a long
      term glycemic index in hyperthyroid cases.

PMID- 15026281
TI  - Acanthoic acid inhibits IL-8 production via MAPKs and NF-kappaB in a TNF-alpha
      stimulated human intestinal epithelial cell line.
AB  - BACKGROUND: Intestinal epithelial cells (IECs) can produce cytokines and
      chemokines that play an important role in the mucosal immune response. Regulation
      of this production is important to prevent inflammatory tissue damage. The root
      and stem barks of Acanthopanax species have been used as a tonic and sedative as
      well as in the treatment of rheumatism and diabetes. The aim of this study was to
      examine the inhibitory effect of acanthoic acid isolated from Acanthopanax
      koreanum (Araliaceae), on IL-8 production via mitogen-activated protein kinases
      (MAPKs) and nuclear factor-kappa B (NF-kappaB) in TNF-alpha-stimulated human
      colon epithelial cells. METHODS: HT29 cells were stimulated with TNF-alpha in the
      presence or absence of acanthoic acid. IL-8 production was measured by enzyme
      linked immunosorbent assay (ELISA) and reverse transcription-PCR (RT-PCR). MAPK
      activation and IkappaB/NF-kappaB expression were assessed by Western blot
      analysis. NF-kappaB activation was determined using immunofluorescence
      localization and electrophoretic mobility shift assay (EMSA). RESULTS: Acanthoic
      acid suppressed TNF-alpha-induced IL-8 production in a dose-dependent manner.
      Furthermore, acanthoic acid inhibited TNF-alpha-induced MAPKs (p38, JNK1/2, and
      ERK1/2) activation, IkappaB degradation, NF-kappaB nuclear translocation, and NF
      kappaB/DNA binding activity. CONCLUSION: Acanthoic acid might inhibit TNF-alpha
      mediated IL-8 production by blocking in both the MAPKs and NF-kappaB pathways in
      HT29 cells.

PMID- 15026282
TI  - Effect of coconut cake on the bacterial enzyme activity in 1,2-dimethyl hydrazine
      induced colon cancer.
AB  - BACKGROUND: Colon cancer is one of the most common forms of malignant tumors in
      humans, and its incidence is increasing. Since the intestinal microflora is
      directly in contact with the colonic cells, the enzymes of the bacterial
      microflora may also play a role in colon carcinogenesis. We studied the activity
      of bacterial enzymes in experimental colon cancer. METHODS: Twenty milligrams per
      kilogram body weight of 1,2-dimethyl hydrazine (DMH) was administered
      subcutaneously once a week for first 15 weeks and then discontinued. Coconut cake
      (25%) was mixed in the diet and given to 30 rats to study the diet effect
      throughout the experimental period. After 30 weeks, the macroscopic findings in
      the colon as well as the incidence of tumors in 30 rats was recorded in each
      group and the activity of beta-glucuronidase and mucinase was estimated in the
      tissues, colon and fecal contents of 10 rats per group. RESULTS: Average number
      of tumors in the colon as well as the incidence of cancer was significantly
      increased in DMH-treated rats which was markedly reduced on supplementing coconut
      cake. DMH injections significantly elevated both the activities of beta
      glucuronidase (distal colon, distal intestine, liver and colon contents) and
      mucinase (colon and fecal contents) as compared to the control rats. The increase
      in beta-glucuronidase activity may augment the hydrolysis of glucuronide
      conjugates, liberating the toxins, while the increase in mucinase activity may
      enhance the hydrolysis of the protective mucins in the colon. Coconut cake
      supplementation to DMH-treated rats significantly decreased the incidence and
      number of tumors as well as the activity of beta-glucuronidase and mucinase.
      CONCLUSIONS: Coconut cake has a protective effect against DMH induced colon
      cancer by virtue of its ability to lower the activities of the microbial enzymes
      beta-glucuronidase and mucinase.

PMID- 15026284
TI  - Simultaneous analysis of coenzyme Q10 in plasma, erythrocytes and platelets:
      comparison of the antioxidant level in blood cells and their environment in
      healthy children and after oral supplementation in adults.
AB  - BACKGROUND: Coenzyme Q10 (CoQ10) originates from food intake as well as from
      endogenous synthesis. While plasma concentrations may be influenced by dietary
      uptake, little is known whether concentrations in plasma reflect or influence
      intracellular concentrations. METHODS: For clinical routine investigation of
      intracellular CoQ10 contents, blood erythrocytes and platelets were isolated by
      Ficoll separating solution and CoQ10 analysed using HPLC. The intracellular
      concentrations were compared to environmental plasma concentrations of 50
      clinically healthy infants and additionally after exogenous pharmaceutical
      supplementation of CoQ10 (3 mg/kg/day) to 12 adult probands for 14 days. RESULTS:
      In healthy children, no correlation between plasma concentration and content in
      blood cells was found. A negative correlation exists between the year of life of
      the infants and CoQ10 concentrations in plasma correlated to cholesterol content.
      Probands supplemented with CoQ10 showed a distinct response in plasma
      concentrations after 14 days. While excessive environmental supplementation was
      without influence on erythrocyte concentrations, a positive correlation exists
      between plasma content and concentrations in platelets as mitochondria containing
      cell lines. CONCLUSIONS: Under physiologically normal conditions, blood cells or
      organs may regulate their CoQ10 content independently from environmental supply.
      Effects may be expected in situations of deficiency or excessive supply.
      Erythrocyte concentration of CoQ10 keeps independent from environmental supply.
      Thus incorporation into outer cell membranes may be limited. However, an
      excessive environmental supply may influence inner compartments like
      mitochondrial membranes.

PMID- 15026283
TI  - Serum iron, ferritin, transferrin, total iron binding capacity, hs-CRP, LDL
      cholesterol and magnesium in children; new reference intervals using the Dade
      Dimension Clinical Chemistry System.
AB  - BACKGROUND: We studied serum/Plasma iron, ferritin, transferrin concentrations,
      and total iron binding capacity (TIBC) in addition to highly sensitive C-reactive
      protein (hs-CRP), low-density lipoprotein (LDL) cholesterol and magnesium
      concentrations in a population of 800 in- and outpatients and defined new 95%
      reference intervals for pediatrics using the Dade Behring RxL Dimension Clinical
      Chemistry System. METHODS: Plasma/serum concentrations of the above analytes were
      determined on patient samples accrued from January to June 2003 and the data were
      analyzed employing a computer adapted Hoffmann approach. RESULTS AND CONCLUSIONS:
      New pediatric reference intervals on the Dade RxL Dimension were obtained for
      serum iron, ferritin, transferrin, TIBC, hs-CRP, LDL-cholesterol and magnesium.
      This work represents the first hs-CRP data for children <3 years old. The values
      for all the analytes were established on new data (n=800). These values are new
      for hs-CRP and LDL cholesterol, while for iron, ferritin and magnesium these
      intervals are more reliable than those previously published by our group which
      had used regression equations on samples measured by the old (Vitros/Immuno1)
      methods for which intervals were available.

PMID- 15026285
TI  - Assessment of hyperinsulinaemia at the termination of the prolonged fast.
AB  - BACKGROUND: Traditional criteria to diagnose hyperinsulinaemic hypoglycaemia are
      based on insulin measurements by unspecific insulin assays. This study was
      performed to test whether these traditional criteria can be applied when insulin
      is measured by specific immunoassays. METHODS: 29 consecutive patients undergoing
      a prolonged fast were included; 11 patients with insulinoma and 18 healthy
      individuals. We determined plasma glucose, insulin, C-peptide, proinsulin, and
      beta-hydroxybutyrate concentrations at the termination of the fast. Insulin was
      measured by an unspecific radioimmunoassay (RIA) and a specific enzyme-linked
      immunosorbent assay (ELISA). RESULTS: In 11 insulinoma patients, insulin
      concentrations at median plasma glucose concentration of 2.1 (range 1.3-2.5)
      mmol/l were 170 (76-340) pmol/l measured by RIA and 61 (11-156) pmol/l by ELISA.
      Insulin concentrations measured by RIA confirmed hyperinsulinaemia (i.e., >36
      pmol/l, the proposed cut-off value for traditional insulin assays) in all
      insulinoma patients, whereas insulin concentrations measured by ELISA were <36
      pmol/l in four patients. In three insulinoma patients, insulin concentrations
      measured by ELISA were <18 pmol/l, a proposed cut-off level to diagnose
      hyperinsulinaemia for specific insulin assays. CONCLUSION: When insulin
      concentrations are measured by specific immunoassays in patients evaluated for
      fasting hypoglycaemia, traditional reference values cannot be applied.

PMID- 15026287
TI  - In situ monitoring techniques for concentration polarization and fouling
      phenomena in membrane filtration.
AB  - Membrane fouling and subsequent permeate flux decline are inevitably associated
      with pressure-driven membrane processes. Despite the myriad of studies on
      membrane fouling and related phenomena--concentration polarization, cake
      formation and pore plugging--the fundamental mechanisms and processes involved
      are still not fully understood. A key to breakthroughs in understanding of
      fouling phenomena is the development of novel, non-invasive, in situ
      quantification of physico-chemical processes occurring during membrane
      filtration. State-of-the-art in situ monitoring techniques for concentration
      polarization, cake formation and fouling phenomena in pressure-driven membrane
      filtration are critically reviewed in this paper. The review addresses the
      physical principles and applications of the techniques as well as their strengths
      and deficiencies. Emphasis is given to techniques relevant to fouling phenomena
      where particles and solutes accumulate on the membrane surface such that pore
      plugging is negligible. The relevance of the techniques to specific processes and
      mechanisms involved in membrane fouling is also elaborated and discussed.

PMID- 15026286
TI  - Serum and urinary fucose concentrations in hepatitis B-related cirrhosis and
      acute liver diseases.

PMID- 15026288
TI  - In situ Fourier-transform infrared spectroscopy studies of inorganic ions
      adsorption on metal oxides and hydroxides.
AB  - In this work, the studies describing the use of attenuated total reflection
      infrared spectroscopy to obtain information on the sorption mechanism of
      inorganic ions on metal oxy-hydroxides are reviewed. ATR-IR is amongst the rare
      techniques which allow to analyze the sorption phenomena in situ and led to
      several results about the speciation of sorbed anions (sulfate, carbonate,
      phosphate, perchlorate, ...) or ternary inorganic complexes since it is able to
      distinguish outer-sphere and inner-sphere complexes. The principles of this
      method are summarized, and the experimental protocols, the results and the
      limitations are elaborated. The sample deposition method, initially based on a
      paste or a concentrated suspension, has evolved towards the coating of the ATR
      crystal by a colloid layer, increasing the sensibility and the reproducibility of
      the measurements. Observed absorption frequencies of ions sorbed on metal oxy
      hydroxides (goethite, hematite, alumina, silica, TiO2, ...) are reported to help
      the identification of peaks in new experimental works. This method, characterized
      by an in situ analysis performed with a special cell used in a widespread
      instrumentation (IR spectrometer), is very recent but its advantages suitable for
      the current problems in the sorption field should help its rapid development for
      the next years.

PMID- 15026289
TI  - Degradation of kinetically-stable o/w emulsions.
AB  - This article summarizes the studies on the degradation of the thermodynamically
      unstable o/w (nano)emulsion--a dispersion of one liquid in another, where each
      liquid is immiscible, or poorly miscible in the other. Emulsions are unstable
      exhibiting flocculation, coalescence, creaming and degradation. The physical
      degradation of emulsions is due to the spontaneous trend toward a minimal
      interfacial area between the dispersed phase and the dispersion medium.
      Minimizing the interfacial area is mainly achieved by two mechanisms: first
      coagulation possibly followed by coalescence and second by Ostwald ripening.
      Coalescence is often considered as the most important destabilization mechanism
      leading to coursing of dispersions and can be prevented by a careful choice of
      stabilizers. The molecular diffusion of solubilizate (Ostwald ripening), however,
      will continuously occur as soon as curved interfaces are present. Mass transfers
      in emulsion may be driven not only by differences in droplet curvatures, but also
      by differences in their compositions. This is observed when two or more
      chemically different oils are emulsified separately and the resulting emulsions
      are mixed. Compositional ripening involves the exchange of oil molecules between
      emulsion droplets with different compositions. The stability of the
      electrostatically- and sterically-stabilized dispersions can be controlled by the
      charge of the electrical double layer and the thickness of the droplet surface
      layer formed by non-ionic emulsifier. In spite of the similarities between
      electrostatically- and sterically-stabilized emulsions, there are large
      differences in the partitioning of molecules of ionic and non-ionic emulsifiers
      between the oil and water phases and the thickness of the interfacial layers at
      the droplet surface. The thin interfacial layer (the electrical double layer) at
      the surface of electrostatically stabilized droplets does not create any steric
      barrier for mass transfer. This may not be true for the thick interfacial layer
      formed by non-ionic emulsifier. The interactive sterically-stabilized oil
      droplets, however, can favor the transfer of materials within the intermediate
      agglomerates. The stability of electrosterically-stabilized emulsion is
      controlled by the ratio of the thickness of the non-ionic emulsifier adsorption
      layer (delta) to the thickness of the electrical double layer (kappa(-1)) around
      the oil droplets (delta/(kappa(-1))) = (deltakappa). The monomer droplet
      degradation can be somewhat depressed by transformation of coarse emulsions to
      nano-emulsion (miniemulsion) by intensive homogenization and by the addition of a
      surface active agent (coemulsifier) or/and a water-insoluble compound
      (hydrophobe). The addition of hydrophobe (hexadecane) to the dispersed phase
      significantly retards the rate of ripening. A long chain alcohol (coemulsifier)
      resulted in a marked improvement in stability, as well, which was attributed to a
      specific interaction between alcohol and emulsifier and to the alcohols tendency
      to concentrate at the o/w interface to form stronger interfacial film. The rate
      of ripening, according to the Lifshitz-Slyozov-Wagner (LSW) model, is directly
      proportional to the solubility of the dispersed phase in the dispersion medium.
      The increased polarity of the dispersed phase (oil) decreases the stability of
      the emulsion. The molar volume of solubilizate is a further parameter, which
      influences the stability of emulsion or the transfer of materials through the
      aqueous phase. The interparticle interaction is expected to favor the transfer of
      solubilizate located at the interfacial layer. The kinetics of solubilization of
      non-polar oils by ionic micelles is strongly related to the aqueous solubility of
      the oil phase (the diffusion approach), whilst their solubilization into non
      ionic micelles can be contributed by interparticle collisions.

PMID- 15026291
TI  - New policy on reports of randomized clinical trials.

PMID- 15026292
TI  - A randomized pilot test of "Moms on the Move": a physical activity intervention
      for WIC mothers.
AB  - BACKGROUND: Sedentary mothers are important to reach with physical activity
      promotion. PURPOSE: This study pilot tested "Moms on the Move," a
      Transtheoretical Model (TTM)-derived physical activity (PA) intervention for low
      income mothers enrolled in the Women, Infants, and Children (WIC) program.
      METHOD: Sedentary mothers (N = 44) were randomized to (a). Moms on the Move (PA
      intervention) or (b). counseling on self-breast examination (control). Pre- and
      posttest measurement (baseline and 2 weeks after the 8-week interventions)
      included (a). stage of PA behavior change, (b). PA behavior, (c). selected TTM
      constructs, and (d). social support. Pre- and postdifference scores, chi-square,
      and one-way analyses of variance (ANOVAs) were used. RESULTS: The experimental
      group progressed in stage of change more than control, chi2(1, N = 44) = 20.50, p
      <.001. The experimental group had greater PA behavior: weekly minutes of PA, F(1,
      42) = 46.85, p <.001; daily energy expenditure (EE), F(1, 42) = 23.01, p <.001;
      and weekly moderate PA EE, F(1, 42) = 32.63, p <.001. Experimental subgroup (n =
      11) step counts increased pre-post, t(10) = 6.16, p <.001. An ANOVA showed that
      the experimental group had greater improvements in all TTM constructs and social
      support, ps <.001. CONCLUSIONS: WIC mothers are at risk for sedentary living and
      have not been targeted for PA behavior change using a provider-counseled
      approach. Although further testing is needed, Moms on the Move appears to be
      efficacious.

PMID- 15026293
TI  - How neighborhoods and physical functioning are related: the roles of neighborhood
      socioeconomic status, perceived neighborhood strain, and individual health risk
      factors.
AB  - BACKGROUND: Increasing attention is being paid to the impact of neighborhood
      residence on individual health status. PURPOSE: This study examined pathways
      through which low neighborhood socioeconomic status (SES) and associated
      subjective neighborhood characteristics may be associated with self-reported
      physical functioning. METHODS: A sample of 658 adults responded to a
      questionnaire survey sent to residents of lower and higher SES neighborhoods.
      Measures of neighborhood social cohesion and problems were obtained and
      individual deprivation, social integration, sense of control, and financial
      strain were assessed with standard measures. Physical functioning was assessed
      with the MOS 36-item Short Form health survey. RESULTS: Structural equation
      modeling analyses showed that living in a lower socioeconomic neighborhood was
      associated with greater perceived neighborhood strain, which, in turn, was
      associated with poorer physical functioning. Lower neighborhood SES and greater
      perceived neighborhood strain were associated with poorer physical functioning of
      individuals through less social integration, less perceived control, and greater
      financial strain. Individual deprivation was also related to less social
      integration, less perceived control, and greater financial strain. CONCLUSIONS:
      Neighborhood SES and associated perceptions of neighborhoods are associated with
      physical functioning to some extent through the shaping of the social and
      psychological experiences of individuals living within them.

PMID- 15026294
TI  - The weight loss experience: a descriptive analysis.
AB  - BACKGROUND: Six months of loss followed by gradual regain to baseline is
      descriptive of most weight loss attempts. PURPOSE: This study sought to identify
      thoughts and feelings accompanying weight loss that might explain the phenomenon.
      METHODS: Thoughts, feelings, and body weight were measured weekly for 6 months in
      41 women receiving behavioral treatment for obesity. RESULTS: Overall, the weight
      loss experience of these women was positive, requiring modest time and effort and
      being associated with more positive than negative thoughts and experiences. Over
      time, however, positive but not negative reactions to the weight loss experience
      decreased, as did the strength of beliefs that the benefits of weight loss were
      worth the effort. In addition, we found no relation between the women's
      perception of effort and weight loss results. CONCLUSIONS: Inadequate long-term
      rewards for behaviors needed for weight control may be an important cause of
      frequent weight loss failures.

PMID- 15026295
TI  - Psychological and cognitive function: predictors of adherence with cholesterol
      lowering treatment.
AB  - BACKGROUND: Failure to adhere to medication regimes is a significant problem in
      clinical and research settings yet reliable, consistent identification of key
      psychosocial predictors remains elusive. Studies of mood and personality related
      to adherence show mixed results-compliance and objectively measured cognitive
      function are intuitively related but empirical support is lacking. PURPOSE: This
      study is a secondary analysis to examine the relations between adherence with a
      medication regime for lowering serum cholesterol and several domains of
      psychological and cognitive functioning. METHODS: Participants in the initial
      study completed a measure of personality and a battery of neuropsychological
      measures at baseline; anxiety and depression were measured at baseline and at 4
      week intervals. Medication adherence was tracked with electronic cap monitors for
      24 weeks. RESULTS: Only 23% of the sample was fully adherent to medication
      regimes at least 80% of the time over the 6-month study period.
      Conscientiousness, according to the Five Factor Theory of Personality, and
      estimated IQ remained robust predictors of adherence in hierarchical regression
      analyses. Depression and anxiety, mental flexibility, and visuospatial
      constructional ability were less robust but statistically significant (p <.05)
      correlates of adherence. CONCLUSIONS: Although results of this analysis explain
      only a portion of the variance in adherence, they demonstrate the importance of
      trait psychological and cognitive factors in adherence research.

PMID- 15026296
TI  - Risk perceptions and their relation to risk behavior.
AB  - BACKGROUND: Because risk perceptions can affect protective behavior and
      protective behavior can affect risk perceptions, the relations between these 2
      constructs are complex and incorrect tests often lead to invalid conclusions.
      PURPOSE: To discuss and carry out appropriate tests of 3 easily confused
      hypotheses: (a). the behavior motivation hypothesis (perceptions of personal risk
      cause people to take protective action), (b). the risk reappraisal hypothesis
      (when people take actions thought to be effective, they lower their risk
      perceptions), and (c). the accuracy hypothesis (risk perceptions accurately
      reflect risk behavior). METHODS: Longitudinal study with an initial interview
      just after the Lyme disease vaccine was made publicly available and a follow-up
      interview 18 months later. Random sample of adult homeowners (N = 745) in 3
      northeastern U.S. counties with high Lyme disease incidence. Lyme disease
      vaccination behavior and risk perception were assessed. RESULTS: All 3 hypotheses
      were supported. Participants with higher initial risk perceptions were much more
      likely than those with lower risk perceptions to get vaccinated against Lyme
      disease (OR = 5.81, 95% CI 2.63-12.82, p <.001). Being vaccinated led to a
      reduction in risk perceptions, chi2(1, N = 745) = 30.90, p <.001, and people
      vaccinated correctly believed that their risk of future infection was lower than
      that of people not vaccinated (OR =.44, 95% CI.21-.91, p <.05). CONCLUSIONS: The
      behavior motivation hypothesis was supported in this longitudinal study, but the
      opposite conclusion (i.e., that higher risk led to less protective behavior)
      would have been drawn from an incorrect test based only on cross-sectional data.
      Health researchers should take care in formulating and testing risk-perception
      behavior hypotheses.

PMID- 15026297
TI  - Does nondipping of blood pressure at night reflect a trait of blunted
      cardiovascular responses to daily activities?
AB  - BACKGROUND: Individuals who fail to show a decline in blood pressure (BP) when
      asleep or at night (labeled nocturnal nondippers) are at elevated risk for
      hypertension and associated target-organ damage. PURPOSE: We tested whether the
      well-established changes in BP exhibited in response to daily activities are also
      blunted in nocturnal nondippers. METHODS: Cross-sectional study of 41 women and
      56 men, aged 27 to 71 years, residing in Benin, Nigeria, enrolled in a health
      survey of civil servants. Ambulatory 24-hr BP monitoring was performed with
      concurrent diary recordings of physical activity level, posture, location, state
      of mental activity, interpersonal interaction, and mood obtained during the
      waking hours. RESULTS: Nocturnal nondippers exhibited smaller cardiovascular
      responses to changes in posture (from lying to sitting or to standing, ps <.02),
      location (from home to work or to driving/riding in a car, ps <.02), mental
      activity (from relaxed to active, p =.02), and mood (from feeling mellow to
      feeling elated-happy, p =.05) than did dippers. Statistical controls for posture
      substantially reduced the effects of nondipping status on responses to other
      daily activities and mood. Lack of systolic BP responsiveness to postural changes
      during the day is a strong predictor of nondipping status. CONCLUSIONS:
      Nondipping at night appears to extend to decreased cardiovascular responses to
      changes in activities during daytime hours.

PMID- 15026298
TI  - Effect sizes and statistical testing in the determination of clinical
      significance in behavioral medicine research.
AB  - BACKGROUND: The interpretation of clinical significance continues to be an
      obstacle for researchers in behavioral medicine. PURPOSE: To review selected
      behavioral medicine research to critically examine the perception among
      investigators that behavioral effects on health are small based on common metrics
      of clinical significance. METHODS: Using quantitative findings from recent
      behavioral medicine research in medical and psychiatric journals, we explored
      results in terms of several statistical metrics to assess potential clinical
      significance: r coefficients, risk ratios, risk difference measures, and
      attributable risk. RESULTS: Translated into r coefficients, even established
      health predictors such as smoking, obesity, and fitness had only modest effects
      (rs =.03-.22), and the range of effect sizes were comparable with those based on
      psychological predictors including depression and stress-reactivity (rs =.06
      .22). In contrast, effects for both classes of predictors were suggestive of
      clinical significance based on public health statistics. CONCLUSIONS: Our choice
      of statistics for defining "small" and "large" effect sizes affects the perceived
      importance of behavioral health findings. In the assessment of health outcomes
      with low incidence rates, effects expressed as correlations using even the most
      robust predictors will often appear small. In these instances, we challenge
      researchers to move beyond conventional data analysis approaches and to expand
      their clinical interpretation efforts by employing additional statistical methods
      favored in medicine and public health.

PMID- 15026299
TI  - New aspects in floral development of Papilionoideae: initiated but suppressed
      bracteoles and variable initiation of sepals.
AB  - BACKGROUND AND AIMS: The increase of molecular data and the resulting insights
      into legume systematics make the search for new morphological characters and a
      careful re-investigation of already stated characters necessary. Bracteoles are
      small, reduced leaves borne close to the base of lateral branches. Although they
      seem unimportant in older buds, they have an ecological function in protecting
      the sepal primordia. Furthermore, a morphogenetic function in mediating the onset
      of sepal initiation is suspected in the literature. The occurrence of bracteoles
      varies within Papilionoideae, and their distribution is used in legume
      systematics. But this is open to criticism, because there is a tendency to use
      'absent' for 'caducous'. Thus attention here was paid to the initiation of
      bracteoles as well as to the sequence of sepal initiation. METHODS: The floral
      development of 30 taxa out of 15 tribes of Papilionoideae was investigated using
      scanning electron microscopy (SEM). KEY RESULTS: In five taxa the bracteoles
      initiated, but suppressed early. Furthermore, a broad variability of sepal
      initiation was found. Besides the widely stated unidirectional pattern, modified
      unidirectionality, tendencies towards whorled, fully whorled, bidirectional and
      successive initiation of sepals were all found. CONCLUSION: Initiated but
      suppressed bracteoles are presented as a 'new' character in Papilionoideae.
      Considering the presence of bracteoles as a plesiomorphy, their suppression can
      be seen as a step towards completely reduced bracteoles. The remarkable
      variability of the sequence of sepal initiation questions the widely stated
      unidirectionality of organ initiation in Papilionoideae. The different modes of
      sepal initiation are deducible from the helical pattern of some caesalpinioids,
      which is seen as a developmental link of the flowers of Papilionoideae and
      Caesalpinioideae. The bidirectional sepal initiation is possibly a consequence of
      the morphogenetic function of bracteoles, although bidirectionality is not found
      in all taxa with reduced bracteoles.

PMID- 15026300
TI  - Microgeographic genome size differentiation of the carob tree, Ceratonia siliqua,
      at 'Evolution Canyon', Israel.
AB  - BACKGROUND AND AIMS: We tested whether the local differences in genome size
      recorded earlier in the wild barley, Hordeum spontaneum, at 'Evolution Canyon',
      Mount Carmel, Israel, can also be found in other organisms. As a model species
      for our test we chose the evergreen carob tree, Ceratonia siliqua. METHODS:
      Genome size was measured by means of DAPI flow cytometry. KEY RESULTS: In adults,
      significantly more DNA was recorded in trees growing on the more illuminated,
      warmer, drier, microclimatically more fluctuating 'African' south-facing slope
      than in trees on the opposite, less illuminated, cooler and more humid,
      'European' north-facing slope in spite of an interslope distance of only 100 m at
      the canyon bottom and 400 m at the top. The amount of DNA was significantly
      negatively correlated with leaf length and tree circumference. In seedlings,
      interslope differences in the amount of genome DNA were not found. In addition,
      the first cases of triploidy and tetraploidy were found in C. siliqua.
      CONCLUSIONS: The data on C. siliqua at 'Evolution Canyon' showed that local
      variability in the C-value exists in this species and that ecological stress
      might be a strong evolutionary driving force in shaping the amount of DNA.

PMID- 15026301
TI  - An apical K(+)-dependent HCO(3)- transport pathway opposes transepithelial HCO(3)
      absorption in rat medullary thick ascending limb.
AB  - Absorption of HCO(3)(-) in the medullary thick ascending limb (MTAL) is mediated
      by apical membrane Na(+)/H(+) exchange. The identity and function of other apical
      acid-base transporters in this segment have not been defined. The present study
      was designed to examine apical membrane HCO(3)(-)/OH(-)/H(+) transport pathways
      in the rat MTAL and to determine their role in transepithelial HCO(3)(-)
      absorption. MTALs were perfused in vitro in Na(+)- and Cl(-)-free solutions
      containing 25 mM HCO(3)(-), 5% CO(2). Lumen addition of either 120 mM Cl(-) or 50
      mM Na(+) (50 microM EIPA present) had no effect on intracellular pH (pH(i)).
      Lumen Cl(-) addition also had no effect on pH(i) in the presence of 145 mM Na(+)
      or in the nominal absence of HCO(3)(-)/CO(2). Thus there was no evidence for
      apical Cl(-)/HCO(3)(-) (OH(-)) exchange, Na(+)-dependent Cl(-)/HCO(3)(-)
      exchange, or Na(+)-HCO(3)(-) cotransport. In contrast, in tubules studied in
      Na(+)- and Cl(-)-free solutions containing 25 mM HCO(3)(-), 5% CO(2) and 120 mM
      K(+), removal of luminal K(+) induced a rapid and pronounced decrease in pH(i)
      (DeltapH(i) = 0.56 +/- 0.06 pH U). pH(i) recovered following lumen K(+)
      readdition. The initial rate of net base efflux induced by lumen K(+) removal was
      decreased 85% at the same pH(i) in the nominal absence of HCO(3)(-)/CO(2),
      indicating a dependence on HCO(3)(-)/CO(2) and arguing against apical K(+)/H(+)
      exchange. A combination of the apical K(+) channel blockers quinidine (0.1 mM)
      and glybenclamide (0.25 mM) had no effect on the lumen K(+)-induced pH(i)
      changes, arguing against electrically coupled K(+) and HCO(3)(-) conductances.
      The effect of lumen K(+) on pH(i) was inhibited by 1 mM H(2)DIDS. In addition,
      lumen addition of DIDS increased transepithelial HCO(3)(-) absorption from 10.7
      +/- 0.7 to 14.9 +/- 0.7 pmol x min(-1) x mm(-1) (P < 0.001) and increased pH(i)
      slightly in MTAL studied in physiological solutions (25 mM HCO(3)(-) and 4 mM
      K(+)). Lumen DIDS stimulated HCO(3)(-) absorption in the absence and presence of
      furosemide. These results are consistent with an apical membrane K(+)-dependent
      HCO(3)(-) transport pathway that mediates coupled transfer of K(+) and HCO(3)(-)
      from cell to lumen in the MTAL. This mechanism, possibly an apical K(+)-HCO(3)(-)
      cotransporter, functions in parallel with apical Na(+)/H(+) exchange and opposes
      transepithelial HCO(3)(-) absorption.

PMID- 15026302
TI  - Renal expression of osmotically responsive cation channel TRPV4 is restricted to
      water-impermeant nephron segments.
AB  - TRPV4, a nonselective cation channel of the transient receptor potential (TRP)
      family, is gated by hypotonicity. Expression of TRPV4 mRNA has been detected in
      the circumventricular organs of the brain responsible for sensing systemic
      tonicity and in the kidney distal convoluted tubule (DCT), among other sites. No
      analysis of TRPV4 expression at the protein level has been undertaken and no
      systematic analysis of expression of this channel has been reported in the
      kidney. Via RNAse protection assay and immunoblotting, abundant expression of
      TRPV4 was detected in the cortex, medulla, and papilla. The expression pattern of
      TRPV4 was characterized in both rat and mouse kidney, which revealed similar
      patterns of immunoreactivity. TRPV4 expression was absent from the proximal
      tubule (PT) and descending thin limb (DTL), whereas the strongest expression was
      observed in the ascending thin limb (ATL). The thick ascending limb (TAL) was
      strongly positive as was the DCT and connecting tubule. Importantly, the water
      permeant cells of the macula densa were unstained. Moderate TRPV4 expression was
      noted in all collecting duct portions and in papillary epithelium; intercalated
      cells (type A) exhibited a particularly strong signal. In all positive segments,
      TRPV4 expression was concentrated at the basolateral membrane. Therefore, TRPV4
      is expressed in only those nephron segments that are constitutively (i.e., ATL,
      TAL, and DCT) or conditionally (i.e., collecting duct) water impermeant and where
      generation of a substantial transcellular osmotic gradient could be expected.
      TRPV4 expression is absent from nephron segments exhibiting constitutive water
      permeability and unregulated apical aquaporin expression (i.e., PT and DTL).
      These data, although circumstantial, are consistent with a role for TRPV4 in the
      response to anisotonicity in the mammalian kidney.

PMID- 15026303
TI  - Insulin-independent effects of GLP-1 on canine liver glucose metabolism: duration
      of infusion and involvement of hepatoportal region.
AB  - Whether glucagon-like peptide-1 (GLP-1) has insulin-independent effects on
      glucose disposal in vivo was assessed in conscious dogs by use of tracer and
      arteriovenous difference techniques. After a basal period, each experiment
      consisted of three periods (P1, P2, P3) during which somatostatin, glucagon,
      insulin, and glucose were infused. The control group (C) received saline in P1,
      P2, and P3, the PePe group received saline in P1 and GLP-1 (7.5 pmol.kg(-1).min(
      1)) peripherally (Pe; iv) in P2 and P3, and the PePo group received saline in P1
      and GLP-1 peripherally (iv) (P2) and then into the portal vein (Po; P3). Glucose
      and insulin concentrations increased to two- and fourfold basal, respectively,
      and glucagon remained basal. GLP-1 levels increased similarly in the PePe and
      PePo groups during P2 ( approximately 200 pM), whereas portal GLP-1 levels were
      significantly increased (3-fold) in PePo vs. PePe during P3. In all groups, net
      hepatic glucose uptake (NHGU) occurred during P1. During P2, NHGU increased
      slightly but not significantly in all groups. During P3, NHGU increased in PePe
      and PePo groups to a greater extent than in C, but no significant effect of the
      route of infusion of GLP-1 was demonstrated (16.61 +/- 2.91 and 14.67 +/- 2.09
      vs. 4.22 +/- 1.57 micromol.kg(-1).min(-1), respectively). IN CONCLUSION: GLP-1
      increased glucose disposal in the liver independently of insulin secretion; its
      full action required long-term infusion. The route of infusion did not modify the
      hepatic response.

PMID- 15026304
TI  - Role of renal D-amino-acid oxidase in pharmacokinetics of D-leucine.
AB  - d-Amino acids are now recognized to be widely present in mammals. Renal d-amino
      acid oxidase (DAO) is associated with conversion of d-amino acids to the
      corresponding alpha-keto acids, but its contribution in vivo is poorly understood
      because the alpha-keto acids and/or l-amino acids formed are indistinguishable
      from endogenous compounds. First, we examined whether DAO is indispensable for
      conversion of d-amino acids to their alpha-keto acids by using the stable isotope
      tracer technique. After a bolus intravenous administration of d-[(2)H(7)]leucine
      to mutant mice lacking DAO activity (ddY/DAO(-)) and normal mice (ddY/DAO(+)),
      elimination of d-[(2)H(7)]leucine and formation of alpha-[(2)H(7)]ketoisocaproic
      acid ([(2)H(7)]KIC) and l-[(2)H(7)]leucine in plasma were determined. The
      ddY/DAO(-) mice, in contrast to ddY/DAO(+) mice, failed to convert d
      [(2)H(7)]leucine to [(2)H(7)]KIC and l-[(2)H(7)]leucine. This result clearly
      revealed that DAO was indispensable for the process of chiral inversion of d
      leucine. We further investigated the effect of renal mass reduction by partial
      nephrectomy on elimination of d-[(2)H(7)]leucine and formation of [(2)H(7)]KIC
      and l-[(2)H(7)]leucine. Renal mass reduction slowed down the elimination of d
      [(2)H(7)]leucine. The fraction of conversion of d-[(2)H(7)]leucine to
      [(2)H(7)]KIC in sham-operated rats was 0.77, whereas that in five-sixths
      nephrectomized rats was 0.25. The elimination behavior of d-[(2)H(7)]leucine
      observed in rats suggested that kidney was the principal organ responsible for
      converting d-leucine to KIC.

PMID- 15026305
TI  - Insulin suppresses PDK-4 expression in skeletal muscle independently of plasma
      FFA.
AB  - Starvation and experimental diabetes induce a stable increase in pyruvate
      dehydrogenase kinase (PDK) activity in skeletal muscle, which is largely due to a
      selective upregulation of PDK-4 expression. Increased free fatty acid (FFA) level
      has been suggested to be responsible for the upregulation. Because these
      metabolic states are also characterized by insulin deficiency, the present study
      was designed to examine whether insulin has a significant effect to regulate PDK
      mRNA expression in rat skeletal muscle. In study 1, overnight-fasted rats
      received an infusion of saline or insulin for 5 h (n = 6 each). During the
      insulin infusion, plasma glucose was clamped at basal levels (euglycemic
      hyperinsulinemic clamp). A third group (n = 6) received Intralipid infusion
      during the clamp to prevent a fall in plasma FFA. PDK-2 mRNA level in
      gastrocnemius muscle was not altered by insulin or FFA (i.e., Intralipid
      infusion). In contrast, PDK-4 mRNA level was decreased 72% by insulin (P < 0.05),
      and Intralipid infusion prevented only 20% of the decrease. PDK-4 protein level
      was decreased approximately 20% by insulin (P < 0.05), but this effect was not
      altered by Intralipid infusion. In study 2, overnight-fasted rats were refed or
      received an infusion of saline or nicotinic acid (NA, 30 micromol/h) for 5 h (n =
      5 each). During the refeeding and NA infusion, plasma FFA levels were similarly
      (i.e., 60-70% vs. saline control) lowered. Muscle PDK-4 mRNA level decreased 77%
      after the refeeding (P < 0.05) but not after the NA infusion. In conclusion, the
      present data indicate that insulin had a profound effect to suppress PDK-4
      expression in skeletal muscle and that, contrary to previous suggestions,
      circulating FFA had little impact on PDK-4 mRNA expression, at least within 5 h.

PMID- 15026306
TI  - Possible involvement of the alpha1 isoform of 5'AMP-activated protein kinase in
      oxidative stress-stimulated glucose transport in skeletal muscle.
AB  - Recent studies have suggested that 5'AMP-activated protein kinase (AMPK) is
      activated in response to metabolic stresses, such as contraction, hypoxia, and
      the inhibition of oxidative phosphorylation, which leads to insulin-independent
      glucose transport in skeletal muscle. In the present study, we hypothesized that
      acute oxidative stress increases the rate of glucose transport via an AMPK
      mediated mechanism. When rat epitrochlearis muscles were isolated and incubated
      in vitro in Krebs buffer containing the oxidative agent H(2)O(2), AMPKalpha1
      activity increased in a time- and dose-dependent manner, whereas AMPKalpha2
      activity remained unchanged. The activation of AMPKalpha1 was associated with
      phosphorylation of AMPK Thr(172), suggesting that an upstream kinase is involved
      in the activation process. H(2)O(2)-induced AMPKalpha1 activation was blocked in
      the presence of the antioxidant N-acetyl-l-cysteine (NAC), and H(2)O(2)
      significantly increased the ratio of oxidized glutathione to glutathione
      (GSSG/GSH) concentrations, a sensitive marker of oxidative stress. H(2)O(2) did
      not cause an increase in the conventional parameters of AMPK activation, such as
      AMP and AMP/ATP. H(2)O(2) increased 3-O-methyl-d-glucose transport, and this
      increase was partially, but significantly, blocked in the presence of NAC.
      Results were similar when the muscles were incubated in a superoxide-generating
      system using hypoxanthine and xanthine oxidase. Taken together, our data suggest
      that acute oxidative stress activates AMPKalpha1 in skeletal muscle via an AMP
      independent mechanism and leads to an increase in the rate of glucose transport,
      at least in part, via an AMPKalpha1-mediated mechanism.

PMID- 15026308
TI  - Pituitary control of lipoprotein and bile acid metabolism in male rats: growth
      hormone effects are not mediated by prolactin.
AB  - Previous studies have established that growth hormone (GH) has many important
      effects on the regulation of cholesterol and lipoprotein metabolism. However,
      human GH (hGH) can also bind to prolactin receptors, eliciting prolactin receptor
      mediated effects. In this study, we evaluated whether hGH can exert such
      responses in currently used animal models and whether prolactin affects
      lipoprotein and/or hepatic cholesterol metabolism. Normal and hypophysectomized
      (Hx) male rats were given either hGH or bovine GH, the latter unable to bind to
      the prolactin receptor. The hormones were continuously infused by use of
      subcutaneous osmotic mini-pumps for 7 days; blood and livers were collected after
      euthanasia. Both hormones stimulated hepatic LDL receptor expression and bile
      acid synthesis to a similar extent and normalized the altered plasma lipoprotein
      pattern in Hx rats. Prolactin, injected twice daily to Hx male rats, did not
      exert any effects on the plasma lipoprotein pattern or on cholesterol metabolism.
      We conclude that previously established effects of hGH on cholesterol metabolism
      are not mediated by prolactin in male rats.

PMID- 15026307
TI  - Nmp4/CIZ regulation of matrix metalloproteinase 13 (MMP-13) response to
      parathyroid hormone in osteoblasts.
AB  - Parathyroid hormone (PTH) regulation of matrix metalloproteinase-13 (MMP-13)
      expression in osteoblasts contributes to normal bone turnover. The PTH response
      region of the rat MMP-13 gene spans nucleotides (nt) -148 to -38 and supports
      binding of numerous transcription factors, including Runx2, necessary for
      osteoblast differentiation, c-Fos/c-Jun, and Ets-1. These trans-acting proteins
      mediate hormone induction via incompletely defined combinatorial interactions.
      Within this region, adjacent to the distal Runx2 site, is a homopolymeric(dA:dT)
      element (-119/-110 nt) that conforms to the consensus site for the novel
      transcription factor nuclear matrix protein-4/cas interacting zinc finger protein
      (Nmp4/CIZ). This protein regulates bone cell expression of type I collagen and
      suppresses BMP2-enhanced osteoblast differentiation. The aim of this study was to
      determine whether Nmp4/CIZ contributes to MMP-13 basal transcription and PTH
      responsiveness in osteoblasts. Electrophoretic mobility shift analysis confirms
      Nmp4/CIZ binding within the MMP-13 PTH response region. Mutation of the Nmp4/CIZ
      element decreases basal activity of an MMP-13 promoter-reporter construct
      containing the first 1329 nt of the 5'-regulatory region, and overexpression of
      Nmp4/CIZ protein enhances the activity of the wild-type promoter. The same
      mutation of the homopolymeric(dA:dT) element enhances the MMP-13 response to PTH
      and PGE(2). Overexpression of Nmp4/CIZ diminishes hormone induction. Mutation of
      both the homopolymeric(dA:dT) element and the adjacent Runx2 site further
      augments the PTH response. On the basis of these data and previous studies, we
      propose that Nmp4/CIZ is a component of a multiprotein assemblage or enhanceosome
      within the MMP-13 PTH response region and that, within this context, Nmp4/CIZ
      promotes both basal expression and hormonal synergy.

PMID- 15026310
TI  - Retinoic acid controls blood vessel formation by modulating endothelial and mural
      cell interaction via suppression of Tie2 signaling in vascular progenitor cells.
AB  - Inhibition by all-trans retinoic acid (atRA) of the microvasculature formation in
      chicken chorioallantoic membrane (CAM) accompanied remarkably reduced numbers of
      endothelial cells (ECs) and increased numbers of mural cells (MCs) under the
      chorionic epithelial layer. Ro41-5253 (retinoid antagonist) exerted the opposite
      effect. Although atRA did not affect the differentiation of murine embryonic stem
      cell-derived vascular progenitor cells (VPCs) into ECs or MCs, atRA suppressed EC
      MC interaction, leading to impaired branching. In both atRA-treated VPC cultures
      and CAM tissues underneath the chorionic epithelial layer, the expression of
      angiopoietin-2 (Ang-2; competitor for Ang-1) was enhanced, whereas that of Tie2
      (a receptor for Angs) was reduced. Simultaneous treatment with Ang-1 partially
      blocked RA induction of EC-MC malinteraction and reduction in blood vessel
      formation. These results suggest that retinoid(s) may reduce EC-MC interaction by
      down-regulating Tie2 signaling as well as decreased EC numbers, which lead to
      impaired vascular remodeling.

PMID- 15026311
TI  - Dominant factor XI deficiency caused by mutations in the factor XI catalytic
      domain.
AB  - The bleeding diathesis associated with hereditary factor XI (fXI) deficiency is
      prevalent in Ashkenazi Jews, in whom the disorder appears to be an autosomal
      recessive condition. The homodimeric structure of fXI implies that the product of
      a single mutant allele could confer disease in a dominant manner through
      formation of heterodimers with wild-type polypeptide. We studied 2 unrelated
      patients with fXI levels less than 20% of normal and family histories indicating
      dominant disease transmission. Both are heterozygous for single amino acid
      substitutions in the fXI catalytic domain (Gly400Val and Trp569Ser). Neither
      mutant is secreted by transfected fibroblasts. In cotransfection experiments with
      a wild-type fXI construct, constructs with mutations common in Ashkenazi Jews
      (Glu117Stop and Phe283Leu) and a variant with a severe defect in dimer formation
      (fXI-Gly350Glu) have little effect on wild-type fXI secretion. In contrast,
      cotransfection with fXI-Gly400Val or fXI-Trp569Ser reduces wild-type secretion
      about 50%, consistent with a dominant negative effect. Immunoprecipitation of
      cell lysates confirmed that fXI-Gly400Val forms intracellular dimers. The data
      support a model in which nonsecretable mutant fXI polypeptides trap wild-type
      polypeptides within cells through heterodimer formation, resulting in lower
      plasma fXI levels than in heterozygotes for mutations that cause autosomal
      recessive fXI deficiency.

PMID- 15026313
TI  - Bleeding risks associated with inheritance of the Quebec platelet disorder.
AB  - Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder
      associated with increased urokinase-type plasminogen activator in platelets and
      alpha-granule protein degradation. To determine bleeding risks and common
      manifestations of QPD, a history questionnaire was developed and administered to
      127 relatives in a family with QPD. Data entry was done blinded to affected and
      unaffected status, determined by assays for platelet urokinase-type plasminogen
      activator (u-PA) and fibrinogen degradation. Odds ratios (ORs), with 95%
      confidence intervals (CIs), were determined for items queried. Summative bleeding
      scores for each individual were calculated using items with OR more than 1. Mean
      ages (34 years; range, 1-89 years) were similar for affected (n = 23) and
      unaffected (n = 104) family members. Affected individuals had higher mean
      bleeding scores (P <.0001) and a much higher likelihood (OR > 20) of having
      bleeding that led to lifestyle changes, bruises that spread lower or as large or
      larger than an orange or both, joint bleeds, bleeding longer than 24 hours after
      dental extractions or deep cuts, and received or been recommended other
      treatments (fibrinolytic inhibitors) for bleeding. Individuals with QPD and
      exposure(s) to hemostatic challenges had experienced excessive bleeding only when
      fibrinolytic inhibitors had not been used. These data illustrate that QPD is
      associated with increased risks of bleeding that can be modified by fibrinolytic
      inhibitors.

PMID- 15026312
TI  - Altered leukocyte response to CXCL12 in patients with warts
      hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome.
AB  - The chemokine receptor CXCR4 and its functional ligand, CXCL12, are essential
      regulators of development and homeostasis of hematopoietic and lymphoid organs.
      Heterozygous truncating mutations in the CXCR4 intracellular tail cause a rare
      genetic disease known as WHIM syndrome (warts, hypogammaglobulinemia, infections,
      myelokathexis), whose pathophysiology remains unclear. We report CXCR4 function
      in 3 patients with WHIM syndrome carrying heterozygous truncating mutations of
      CXCR4. We show that CXCR4 gene mutations in WHIM patients do not affect cell
      surface expression of the chemokine receptor and its internalization upon
      stimulation with CXCL12. Moreover, no significant differences in calcium
      mobilization in response to CXCL12 are found. However, the chemotactic response
      of both polymorphonuclear cells and T lymphocytes in response to CXCL12 is
      increased. Furthermore, immunophenotypic analysis of circulating T and B
      lymphocytes reveals a decreased number of memory B cells and of naive T cells and
      an accumulation of effector memory T cells associated with a restricted T-cell
      repertoire. Based on our results, we suggest that the altered leukocyte response
      to CXCL12 may account for the pathologic retention of mature polymorphonuclear
      cells in the bone marrow (myelokathexis) and for an altered lymphocyte
      trafficking, which may cause the immunophenotyping abnormalities observed in WHIM
      patients.

PMID- 15026314
TI  - The contribution of inherited and acquired thrombophilic defects, alone or
      combined with antiphospholipid antibodies, to venous and arterial thromboembolism
      in patients with systemic lupus erythematosus.
AB  - Systemic lupus erythematosus (SLE) is associated with an increased risk of venous
      (VTE) and arterial thromboembolism (ATE). Lupus anticoagulant (LA) and
      anticardiolipin antibodies (ACAs) are established risk factors. We assessed the
      contribution of deficiencies of antithrombin, protein C, total protein S, factor
      V Leiden, the prothrombin G20210A mutation and APC resistance, either alone or in
      various combinations with LA and/or ACAs, to the thrombotic risk in a cohort of
      144 consecutive patients with SLE. Median follow-up was 12.7 years. VTE had
      occurred in 10% and ATE in 11% of patients. LA,ACAs, factor V Leiden, and the
      prothrombin mutation were identified as risk factors for VTE. Annual incidences
      of VTE were 2.01 (0.74-4.37) in patients with one of these disorders and 3.05
      (0.63-8.93) in patients with 2 disorders. The risk of VTE was 20- and 30-fold
      higher, respectively, compared with the normal population. In contrast with LA
      and ACAs, thrombophilic disorders did not influence the risk of ATE. In
      conclusion, factor V Leiden and the prothrombin mutation contribute to the risk
      of VTE in patients with SLE, and potentiate this risk when one of these
      thrombophilic defects are combined with LA and/or ACAs.

PMID- 15026316
TI  - Antigen-induced regulatory T cells.
AB  - Regulatory T cells participate in immunologic homeostasis by active suppression
      of inappropriate immune responses. Regulatory T lymphocytes expressing CD4 and
      CD25 antigens and naturally present in the peripheral blood were the first to be
      phenotypically characterized. However, their small number and antigen nonspecific
      suppression has prompted efforts to identify and dissect antigen-specific
      regulatory T cells. In this review we discuss how antigen-specific regulatory T
      cells can be identified, the cellular and molecular mechanisms underlying their
      induction and activity, and the challenges facing their potential clinical
      application.

PMID- 15026315
TI  - Effects of inflammatory cytokines on the release and cleavage of the endothelial
      cell-derived ultralarge von Willebrand factor multimers under flow.
AB  - ADAMTS13 cleaves ultralarge and hyperreactive von Willebrand factor (ULVWF)
      freshly released from activated endothelial cells to smaller and less active
      forms. This process may be affected by the amount of ULVWF released and the
      processing capacity of ADAMTS13, contributing to the development of thrombotic
      diseases. We examined the effects of inflammatory cytokines on the release and
      cleavage of ULVWF to evaluate potential links between inflammation and
      thrombosis. Human umbilical vein endothelial cells were treated with interleukin
      6 (IL-6), IL-8, or tumor necrosis factor alpha (TNF-alpha), and the formation of
      platelet-decorated ULVWF strings was quantitated. IL-8 and TNF-alpha
      significantly stimulated the release of ULVWF in a dose-dependent manner. IL-6
      induced ULVWF release only when it was in complex with the soluble IL-6 receptor.
      IL-6, but not IL-8 nor TNF-alpha, inhibited the cleavage of ULVWF strings by
      ADAMTS13 under flowing, but not static, conditions. These results suggest that
      inflammatory cytokines may stimulate the ULVWF release (IL-8 and TNF-alpha) and
      inhibit the ULVWF cleavage (IL-6), resulting in the accumulation of hyperreactive
      ULVWF in plasma and on the surface of endothelial cells to induce platelet
      aggregation and adhesion on the vascular endothelium. The findings describe a
      potential linkage between inflammation and thrombosis that may be of therapeutic
      importance.

PMID- 15026317
TI  - Erythropoietin regulation of Raf-1 and MEK: evidence for a Ras-independent
      mechanism.
AB  - Stimulation of the erythropoietin (EPO) receptor triggers a cascade of signaling
      events. We reported that EPO upregulates c-myc expression through 2 pathways in
      BaF3-EpoR cells--a phosphatidylinositol 3-kinase (PI3K) pathway operating on
      transcriptional initiation and a Raf-1-mitogen-activated protein kinase (MAPK)
      pathway affecting elongation. We now show that EPO induces phosphorylation of Raf
      1 at serine 338 and within the carboxy-terminal domain, resulting in an
      electrophoretic mobility change (hyperphosphorylation). Importantly, MEK 1
      inhibitor PD98059 blocked only the hyperphosphorylation of Raf-1 but not the
      phosphorylation at serine 338. This inhibition of Raf-1 hyperphosphorylation
      resulted in increased kinase activity of Raf-1 and increased phosphorylation of
      MEK, suggesting that the hyperphosphorylation of Raf-1 inhibits its MEK kinase
      activity. Deletion of the first 184 amino acids of Raf-1, which are involved in
      its interaction with Ras, had no effect on EPO-induced phosphorylation.
      Introducing the dominant-negative N17Ras or GAP had no effect on EPO-induced
      kinase activity of Raf-1 and ELK activation. N17Ras failed to inhibit ELK
      activation in another cell line-Rauscher murine erythroleukemia- which expresses
      the EPO receptor endogenously and differentiates in response to the hormone.
      These results indicate the presence of a Ras-independent mechanism for Raf-1 and
      MEK activation in these cells.

PMID- 15026318
TI  - Insulin-like growth factor binding protein-3 antagonizes the effects of retinoids
      in myeloid leukemia cells.
AB  - Insulin-like growth factor binding protein-3 (IGFBP-3) can cause growth
      suppressive and proapoptotic effects on retinoids in many types of cancer cells.
      However, the expression and effects of IGFBP-3 in myeloid leukemia cells have not
      been elucidated. In this study, we found no IGFBP-3 expression in the human
      myeloid leukemia cell lines either at baseline or after stimulation with all
      trans retinoic acid (ATRA). Human recombinant IGFBP-3 induced growth arrest and
      apoptosis of HL-60 and NB4 cells. We have previously identified RXR alpha as a
      nuclear receptor for IGFBP-3 and have proceeded to examine further the role of
      this interaction in leukemia cell lines. In signaling assays, IGFBP-3 potently
      suppressed RAR- and VDR-mediated signaling while enhancing RXR signaling.
      Interestingly, when IGFBP-3 was administered to these cells in combination with
      an RAR-selective ligand, the ability of these retinoids to induce differentiation
      was blunted. On the other hand, IGFBP-3 enhanced the effect of an RXR-selective
      ligand to induce differentiation of HL-60 and NB4 cells. Further studies showed
      that IGFBP-3 down-regulated (at the transcriptional level) the retinoid-induced
      expression of C/EBP epsilon in NB4 cells. Taken together, these results indicate
      that IGFBP-3 has antiproliferative activity against myeloid leukemia cells; while
      it enhances signaling through RXR/RXR, it blunts signaling by activated RAR/RXR.

PMID- 15026320
TI  - Reactive oxygen species (ROS), troublemakers between nuclear factor-kappaB (NF
      kappaB) and c-Jun NH(2)-terminal kinase (JNK).
AB  - Nuclear factor-kappaB (NF-kappaB) and c-Jun NH(2)-terminal kinase (JNK) are
      activated simultaneously under a variety of stress conditions. They also share
      several common signaling pathways for their activation in response to cytokines
      or growth factors. Recent studies, however, demonstrated a new form of interplay
      between these two allies. Inhibition of NF-kappaB by ikkbeta or rela gene
      deficiency sensitizes stress responses through enhanced or prolonged activation
      of JNK. Conversely, sustained activation of NF-kappaB inhibits cytokine-induced
      JNK activation. The mechanisms of how NF-kappaB and JNK become rivals for each
      other are under extensive debate.

PMID- 15026322
TI  - FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of
      urothelial cell carcinoma.
AB  - Fibroblast growth factor receptor 3 (FGFR3) and P53 mutations are frequently
      observed in bladder cancer. We here describe the distribution of FGFR3 mutations
      and P53 overexpression in 260 primary urothelial cell carcinomas. FGFR3 mutations
      were observed in 59% and P53 overexpression in 25%. Interestingly, FGFR3 and P53
      alterations were mutually exclusive, because they coincided in only 5.7% of
      tumors. Consequently, we propose that they characterize two alternative genetic
      pathways in urothelial cell carcinoma pathogenesis. The genetic alterations were
      reflected in the pathology and the clinical outcome, i.e., FGFR3 mutations were
      found in low-stage/-grade tumors and were associated with a favorable disease
      course, whereas P53 alterations were tied to adverse disease parameters.

PMID- 15026321
TI  - Angiogenesis and tumor proliferation/metastasis of human colorectal cancer cell
      line SW620 transfected with endocrine glands-derived-vascular endothelial growth
      factor, as a new angiogenic factor.
AB  - Endocrine glands-derived-vascular endothelial growth factor (EG-VEGF) was
      recently cloned as a new angiogenic factor that selectively acts on the
      endothelium of endocrine gland cells. We evaluated the involvement of EG-VEGF in
      colorectal cancer. The expression of EG-VEGF was confirmed in all of the
      colorectal cancer cell lines. (On the other hand, the expression of EG-VEGF mRNA
      was not detected in colorectal normal mucosae.) Stable EG-VEGF infectors of
      colorectal cancer cell line SW620 were produced, EG-VEGF transfectants were
      implanted into cecum and s.c., and cell proliferation was evaluated. Angiogenesis
      was evaluated by dorsal air sac method. Liver metastasis was evaluated after the
      implantation of EG-VEGF transfectants into the mouse spleen. Tumor proliferation
      (cecum, s.c.) was significantly higher in the EG-VEGF transfectants than in the
      control cells. The small vessels were significantly increased in EG-VEGF
      transfectants as compared with those in control cells. Also, liver metastatic
      ratio was higher in the EG-VEGF transfectants than in the control cells. In this
      study, EG-VEGF, a new angiogenic factor, may lead to angiogenesis, promoting cell
      proliferation and liver metastasis in colorectal cancers. When the EG-VEGF gene
      overexpressing colorectal cancer cell line that had been treated with
      phosphorothioate antisense EG-VEGF oligonucleotides was injected s.c. into mice,
      angiogenesis and tumor growth were inhibited. Although the novel angiogenesis
      factor EG-VEGF was not expressed in the normal colorectal mucosa, it was
      expressed in colorectal cancer cells, which indicates that it is a cancer
      specific and possibly tissue-specific angiogenesis factor in the large intestine,
      and which suggests that it can be targeted by a novel antiangiogenesis therapy.

PMID- 15026323
TI  - An antiapoptotic role for gastrin and the gastrin/CCK-2 receptor in Barrett's
      esophagus.
AB  - Mechanisms by which premalignant Barrett's metaplasia (BM) progresses to
      esophageal adenocarcinoma are currently being sought. This study investigated the
      role played by the polypeptide hormone gastrin, specifically its antiapoptotic
      effects through activation of protein kinase B/Akt (PKB/Akt). In esophageal cell
      lines with low basal levels of activated PKB/Akt, phosphorylation could be
      induced by exogenous amidated gastrin. High basal levels of activated PKB/Akt
      were linked to endogenous gastrin expression and were reduced by treatment with a
      cholecystokinin-type 2 receptor (CCK-2R) antagonist. Expression of a
      constitutively active splice variant of the CCK-2R additionally increased basal
      activation of PKB/Akt. It is proposed that gastrin acting in an autocrine and
      endocrine manner via a CCK-2R isoform may activate PKB/Akt and that with
      expression of gastrin and CCK-2R isoforms increasing in BM samples, gastrin may
      aid progression of BM through amplification of antiapoptotic pathways. Evidence
      for this proposal was provided through the observed specific up-regulation of
      PKB/Akt in BM samples.

PMID- 15026324
TI  - USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst.
AB  - Aneurysmal bone cyst (ABC) is a locally aggressive osseous lesion that typically
      occurs during the first two decades of life. ABC was regarded historically as a
      nonneoplastic process, but recent cytogenetic data have shown clonal
      rearrangements of chromosomal bands 16q22 and 17p13, indicating a neoplastic
      basis in at least some ABCs. Herein we show that a recurring ABC chromosomal
      translocation t(16;17)(q22;p13) creates a fusion gene in which the osteoblast
      cadherin 11 gene (CDH11) promoter region on 16q22 is juxtaposed to the entire
      ubiquitin-specific protease USP6 (Tre2) coding sequence on 17p13. CDH11-USP6
      fusion transcripts were demonstrated only in ABC with t(16;17) but other ABCs had
      CDH11 or USP6 rearrangements resulting from alternate cytogenetic mechanisms.
      CDH11 is expressed strongly in bone, and our findings implicate a novel oncogenic
      mechanism in which deregulated USP6 transcription results from juxtaposition to
      the highly active CDH11 promoter.

PMID- 15026325
TI  - Pol iota is a candidate for the mouse pulmonary adenoma resistance 2 locus, a
      major modifier of chemically induced lung neoplasia.
AB  - In this study, we performed systematic candidate gene analyses of the Pulmonary
      adenoma resistance 2 locus. Differential gene expression in lung tissues and
      nucleotide polymorphisms in coding regions between A/J and BALB/cJ mice were
      examined using reverse transcription-PCR and direct sequencing. Although not all
      genes in the interval were analyzed at this moment due to the recent database
      updating, we have found that the Pol iota gene, encoding the DNA polymerase iota,
      contains 25 nucleotide polymorphisms in its coding region between A/J and BALB/cJ
      mice, resulting in a total of ten amino acid changes. Primer extension assays
      with purified BALB/cJ and A/J proteins in vitro demonstrate that both forms of
      Pol iota are active but that they may differ in substrate discrimination, which
      may affect the formation of Kras2 mutations in mouse lung tumors. Altered
      expression of POL iota protein and an amino acid-changing nucleotide polymorphism
      were observed in human lung cancer cells, suggesting a possible role in the
      development of lung cancer. Thus, our data support the Pol iota gene as a
      modifier of lung tumorigenesis by altering DNA polymerase activity.

PMID- 15026326
TI  - B-Raf is dispensable for K-Ras-mediated oncogenesis in human cancer cells.
AB  - Oncogenic mutations in B-Raf and Kirsten-Ras (K-Ras) are mutually exclusive
      during human cancer pathogenesis. In an effort to study the biological basis of
      this epistasis, gene targeting was used to create isogenic sets of human cancer
      cells differing only in presence or absence of endogenous oncogenic K-Ras or wild
      type B-Raf. Whereas cells lacking the K-Ras oncogene were unable to efficiently
      form xenograft tumors, isogenic cells retaining activated K-Ras but deleted for B
      Raf remained highly tumorigenic. Deletion of oncogenic K-Ras failed to reduce the
      activation state of B-Raf or ERK1/2, despite the requirement of oncogenic K-Ras
      for tumorigenesis. Genechip analysis revealed numerous genes in which the
      regulation by oncogenic K-Ras did not require B-Raf. These studies suggest that
      despite the mutual exclusivity of K-Ras and B-Raf mutations in human cancer and
      the well-described role for Raf proteins as Ras effectors, B-Raf is dispensable
      for K-Ras-mediated oncogenesis in a human cancer cell line. Additional studies
      are required to demonstrate the generalizability of these unexpected findings.

PMID- 15026327
TI  - Accelerated induction of bladder cancer in patched heterozygous mutant mice.
AB  - The PATCHED (PTC) gene is recognized as a tumor suppressor in basal cell
      carcinoma. Mapping of a minimal region of deletion at 9q22.3 and observation of a
      decreased PTC expression in superficial papillary bladder tumors led us to
      hypothesize that it could also be involved in this cancer. To further investigate
      this hypothesis, we submitted Ptc(+/-) heterozygous mutant mice and their wild
      type littermates to chemical carcinogenesis by adding N-butyl-N-(4-hydroxybutyl)
      nitrosamine to their drinking water. Preneoplastic and neoplastic changes were
      observed significantly earlier in the Ptc(+/-) than in the wild-type mice. Our
      data support the hypothesis of Ptc acting as a tumor suppressor gene in bladder
      cancer.

PMID- 15026328
TI  - Cannabinoids induce cancer cell proliferation via tumor necrosis factor alpha
      converting enzyme (TACE/ADAM17)-mediated transactivation of the epidermal growth
      factor receptor.
AB  - Cannabinoids, the active components of marijuana and their endogenous
      counterparts were reported as useful analgetic agents to accompany primary cancer
      treatment by preventing nausea, vomiting, and pain and by stimulating appetite.
      Moreover, they have been shown to inhibit cell growth and to induce apoptosis in
      tumor cells. Here, we demonstrate that anandamide, Delta(9)-tetrahydrocannabinol
      (THC), HU-210, and Win55,212-2 promote mitogenic kinase signaling in cancer
      cells. Treatment of the glioblastoma cell line U373-MG and the lung carcinoma
      cell line NCI-H292 with nanomolar concentrations of THC led to accelerated cell
      proliferation that was completely dependent on metalloprotease and epidermal
      growth factor receptor (EGFR) activity. EGFR signal transactivation was
      identified as the mechanistic link between cannabinoid receptors and the
      activation of the mitogen-activated protein kinases extracellular signal
      regulated kinase 1/2 as well as prosurvival protein kinase B (Akt/PKB) signaling.
      Depending on the cellular context, signal cross-communication was mediated by
      shedding of proAmphiregulin (proAR) and/or proHeparin-binding epidermal growth
      factor-like growth factor (proHB-EGF) by tumor necrosis factor alpha converting
      enzyme (TACE/ADAM17). Taken together, our data show that concentrations of THC
      comparable with those detected in the serum of patients after THC administration
      accelerate proliferation of cancer cells instead of apoptosis and thereby
      contribute to cancer progression in patients.

PMID- 15026329
TI  - p53 pathway in renal cell carcinoma is repressed by a dominant mechanism.
AB  - Renal cell carcinoma (RCC) rarely acquires mutations in p53 tumor suppressor
      gene, suggesting that p53 signaling in this tumor type might be repressed by some
      other mechanism. In fact, all four RCC-derived cell lines we tested maintained
      wild-type p53 but were not capable of transactivating p53-responsive reporters
      and endogenous p53-responsive genes. p53 protein in RCC showed normal response to
      genotoxic stress, including accumulation, nuclear translocation, and activation
      of specific DNA binding. Functional and expression analysis of Mdm2, MdmX, and
      Arf showed lack of involvement of these p53 regulators in the observed defect of
      p53 function in RCC. However, activation of p53-mediated transactivation could be
      achieved by extremely high levels of p53 attained by lentivirus vector-driven
      transduction, suggesting the involvement of a dominant inhibitor in repression of
      p53-dependent transactivation in RCC. Consistently, p53 inactivation prevailed in
      the hybrids of RCC cells with the cells possessing fully functional p53.
      Remarkably, cells of normal kidney epithelium also caused partial p53 repression
      in cell fusion experiments, suggesting that RCC-specific p53 repression may be
      based on an unknown dominant mechanism also acting in normal kidney tissue.

PMID- 15026330
TI  - Brca2 deficiency does not impair mammary epithelium development but promotes
      mammary adenocarcinoma formation in p53(+/-) mutant mice.
AB  - Brca2 is an important tumor suppressor associated with susceptibility to breast
      cancer. Although increasing evidence indicates that the primary function of Brca2
      is to facilitate the repair of DNA damage via the homologous recombination
      pathway, how Brca2 prevents breast cancer is largely unknown. To study the role
      of Brca2 specifically in mammary epithelium development, we crossed mice bearing
      the conditionally deficient allele Brca2(flox9-10) to mouse mammary tumor virus-
      or whey acidic protein-Cre transgenic lines. Analysis of these animals showed
      that Brca2 is not required for epithelial expansion in mammary glands of pregnant
      mice. In addition, examination of mammary gland involution revealed normal
      kinetics of mammary alveolar cell apoptosis after weaning of litters.
      Nevertheless, Brca2-deficient mice developed mammary adenocarcinomas after a long
      latency (average, 1.6 years). Detailed histopathological analysis of four of
      these tumors demonstrated that three of them showed abnormal p53 protein
      expression. A mutation in the p53 gene was detected in one case. Moreover,
      homozygosity versus heterozygosity for the Brca2 mutation heavily skewed the
      tumor spectrum toward mammary adenocarcinoma development in p53(+/-) mice. Our
      data indicate that Brca2 is not essential for mammary epithelium development but
      that Brca2 deficiency and down-regulated p53 expression can work jointly to
      promote mammary tumorigenesis.

PMID- 15026331
TI  - Comprehensive scanning of somatic mitochondrial DNA alterations in acute leukemia
      developing from myelodysplastic syndromes.
AB  - Myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by
      ineffective hematopoiesis resulting in refractory cytopenias. Transformation
      resulting in acute myeloblastic leukemia is the final stage in the multistep
      process of MDS evolution. Functional relevant mutations of mitochondrial DNA
      (mtDNA) have been related to sideroblastic anemia and MDS. To investigate the
      role of mtDNA in malignant transformation to acute leukemia, we used high
      resolution techniques such as single-strand conformational polymorphism and
      fluorescence sequencing for investigation of the whole mitochondrial genome from
      blood cells of 10 patients with MDS. Functionally relevant point mutations in
      mitochondrial RNA and polypeptide-encoding genes were detected in 50% of patients
      with MDS. Their increasing mutation load connects MDS and the developing acute
      myeloid leukemias. Several point mutations of mtDNA, including secondary point
      mutations for Leber's hereditary optic neuropathy, occur in one bone marrow and
      may synergically affect bone marrow stem cells by an apoptotic pathway.

PMID- 15026332
TI  - A susceptibility locus at chromosome 3p21 linked to familial nasopharyngeal
      carcinoma.
AB  - Nasopharyngeal carcinoma (NPC) poses one of the serious health problems in
      southern Chinese, with an incidence rate ranging from 15 to 50/100,000.
      Chromosome translocation t(1;3) and frequent loss of heterogeneity on short arms
      of chromosome 3 and 9 have been reported to be associated with NPC, and a genome
      wide scan identified an NPC susceptibility locus on chromosome 4p15.1-q12
      recently. In our study, we collected samples from 18 families at high risk of NPC
      from the Hunan province in southern China, genotyped with a panel of polymorphic
      markers on short arms of chromosomes 3, 9, and 4p15.1-q12. A locus on 3p21 was
      identified to link to NPC with a maximum logarithm of odds for linkage score of
      4.18. Fine mapping located the locus to a 13.6-cM region on 3p21.31-21.2, where a
      tumor suppressor gene cluster resided. Our findings identified a novel locus for
      NPC and provided a map location for susceptibility genes candidates. In contrast
      to a recent study, no significant evidence for NPC linkage to chromosomes 4 and 9
      was observed.

PMID- 15026333
TI  - Hypermethylation of CpG islands in primary and metastatic human prostate cancer.
AB  - Aberrant DNA methylation patterns may be the earliest somatic genome changes in
      prostate cancer. Using real-time methylation-specific PCR, we assessed the extent
      of hypermethylation at 16 CpG islands in DNA from seven prostate cancer cell
      lines (LNCaP, PC-3, DU-145, LAPC-4, CWR22Rv1, VCaP, and C42B), normal prostate
      epithelial cells, normal prostate stromal cells, 73 primary prostate cancers, 91
      metastatic prostate cancers, and 25 noncancerous prostate tissues. We found that
      CpG islands at GSTP1, APC, RASSF1a, PTGS2, and MDR1 were hypermethylated in >85%
      of prostate cancers and cancer cell lines but not in normal prostate cells and
      tissues; CpG islands at EDNRB, ESR1, CDKN2a, and hMLH1 exhibited low to moderate
      rates of hypermethylation in prostate cancer tissues and cancer cell lines but
      were entirely unmethylated in normal tissues; and CpG islands at DAPK1, TIMP3,
      MGMT, CDKN2b, p14/ARF, and CDH1 were not abnormally hypermethylated in prostate
      cancers. Receiver operator characteristic curve analyses suggested that CpG
      island hypermethylation changes at GSTP1, APC, RASSF1a, PTGS2, and MDR1 in
      various combinations can distinguish primary prostate cancer from benign prostate
      tissues with sensitivities of 97.3-100% and specificities of 92-100%.
      Hypermethylation of the CpG island at EDNRB was correlated with the grade and
      stage of the primary prostate cancers. PTGS2 CpG island hypermethylation
      portended an increased risk of recurrence. Furthermore, CpG island
      hypermethylation patterns in prostate cancer metastases were very similar to the
      primary prostate cancers and tended to show greater differences between cases
      than between anatomical sites of metastasis.

PMID- 15026334
TI  - Cyr61 is overexpressed in gliomas and involved in integrin-linked kinase-mediated
      Akt and beta-catenin-TCF/Lef signaling pathways.
AB  - Cyr61 is a member of the CCN family of growth factors; these proteins are
      secreted and can act as ligands of distinct integrins. We show that Cyr61 can
      enhance tumorigenicity of glioma cells acting through activated integrin-linked
      kinase (ILK) to stimulate beta-catenin-TCF/Lef and Akt signaling pathways.
      Overexpression of Cyr61 occurred in highly tumorigenic glioma cell lines and in
      68% of the most malignant glioblastoma multiforme brain tumors. Forced expression
      of Cyr61 in U343 glioma cells accelerated their growth in liquid culture,
      enhanced their anchorage-independent proliferation in soft agar, and
      significantly increased their ability to form large, vascularized tumors in nude
      mice. Overexpression of Cyr61 in the U343 cells led to the up-regulation of
      distinct integrins, including beta1 and alphanubeta3, which have been shown to
      interact with Cyr61 and ILK. The activity of ILK was increased dramatically in
      these cells. Overexpression of Cyr61 also resulted in the phosphorylation of
      glycogen synthase kinase-3beta and accumulation and nuclear translocation of beta
      catenin, leading to activation of the beta-catenin-TCF/Lef-1 signaling pathway.
      Furthermore, forced expression of Cyr61 in the glioma cells activated
      phosphatidylinositol 3'-kinase pathway, resulting in prominent phosphorylation of
      Akt and the antiapoptotic protein Bad. Cyr61 appears to stimulate several
      signaling pathways in the development of gliomas.

PMID- 15026335
TI  - A polymorphism in the CDKN1B gene is associated with increased risk of hereditary
      prostate cancer.
AB  - The loss of cell cycle control is believed to be an important mechanism in the
      promotion of carcinogenesis. CDKN1B (p27) belongs to the Cip/Kip family and
      functions as an important cell cycle gatekeeper. Several lines of evidence from
      clinical studies and laboratory experiments demonstrate that CDKN1B is an
      important tumor suppressor gene in prostate cancer etiology. In addition, a case
      control study has shown that the 326T/G (V109G) polymorphism in CDKN1B is
      associated with advanced prostate cancer. In light of the evidence for linkage
      between the chromosomal location of the CDKN1B gene (12p13) and prostate cancer
      susceptibility in several hereditary prostate cancer (HPC) populations, we
      hypothesized that sequence variants of CDKN1B play a role in HPC. To test this
      hypothesis, we first resequenced this gene in 96 HPC probands to identify germ
      line mutations and sequence variants. We then genotyped the identified sequence
      variants among all family members of 188 HPC families and tested for their
      cosegregation with prostate cancer. In total, 10 sequence variants were
      identified, including three nonsynonymous changes. A family-based test, which is
      free from the effects of population stratification, revealed a significant
      association between single nucleotide polymorphism (SNP) -79C/T and prostate
      cancer (with a nominal P of 0.0005). The C allele of -79C/T was overtransmitted
      from parents to their affected offspring. Evidence for this association was
      primarily contributed by affected offspring whose age at diagnosis was <65 years.
      Together with the previous association study in a sporadic prostate cancer
      population, our new findings additionally suggest that germ-line variants of this
      gene play a role in prostate cancer susceptibility.

PMID- 15026336
TI  - Hypermethylation of the 5' CpG island of the FHIT gene is associated with
      hyperdiploid and translocation-negative subtypes of pediatric leukemia.
AB  - The human FHIT (fragile histidine triad) gene is a putative tumor suppressor gene
      located at chromosome region 3p14.2. Previous studies have shown that loss of
      heterozygosity, homozygous deletions, and abnormal expression of the FHIT gene
      are involved in several types of human malignancies. A CpG island is present in
      the 5' promoter region of the FHIT gene, and methylation in this region
      correlates with loss of FHIT expression. To test whether aberrant methylation of
      the FHIT gene may play a role in pediatric leukemia, we assessed the FHIT
      methylation status of 10 leukemia cell lines and 190 incident population-based
      cases of childhood acute lymphocytic and myeloid leukemias using methylation
      specific PCR. Conventional and fluorescence in situ hybridization cytogenetic
      data were also collected to examine aneuploidy, t(12, 21), and other chromosomal
      rearrangements. Four of 10 leukemia cell lines (40%) and 52 of 190 (27.4%) bone
      marrows from childhood leukemia patients demonstrated hypermethylation of the
      promoter region of FHIT. Gene expression analyses and 5-aza-2'-deoxycytidine
      treatment showed that promoter hypermethylation correlated with FHIT
      inactivation. Among primary leukemias, hypermethylation of FHIT was strongly
      correlated with acute lymphoblastic leukemia (ALL) histology (P = 0.008), high
      hyperdiploid (P < 0.0001), and translocation-negative (P < 0.0001) categories.
      Hyperdiploid B-cell ALLs were 23-fold more likely to be FHIT methylated compared
      with B-cell ALL harboring TEL-AML translocations. FHIT methylation was associated
      with high WBC counts at diagnosis, a known prognostic indicator. These results
      suggest that hypermethylation of the promoter region CpG island of the FHIT gene
      is a common event and may play an important role in the etiology and
      pathophysiology of specific cytogenetic subtypes of childhood ALL.

PMID- 15026337
TI  - Role of the Grb2-associated binder 1/SHP-2 interaction in cell growth and
      transformation.
AB  - Grb2-associated binder 1 (Gab1) is a docking protein that is tyrosine
      phosphorylated following the activation of multiple cytokine receptors and
      receptor tyrosine kinases. Its function then is to recruit and activate multiple
      signaling molecules. In our previous work, we showed that Gab1 enhances cell
      growth and induces the transformed phenotype in NIH3T3 cells downstream of the
      epidermal growth factor (EGF) receptor. In this report, we analyze how it
      produces these effects. Because SHP-2 is the major binding partner of Gab1, we
      mutated its binding site in the Gab1 cDNA (Gab1/DeltaSHP-2). This construct was
      stably overexpressed in NIH3T3 cells (3T3-Gab1/DeltaSHP-2) and in the wild-type
      Gab1 cDNA (3T3-Gab1) or an empty expression vector (3T3-CTR). Our findings show
      that after EGF stimulation, Gab1/DeltaSHP-2 has a higher level of tyrosine
      phosphorylation at early time points than Gab1. Gab1/DeltaSHP-2 recruits more
      phosphatidylinositol 3'-kinase than Gab1 after EGF triggering, which accounts for
      a higher and more sustained AKT activation in 3T3-Gab1/DeltaSHP-2 cells relative
      to 3T3-Gab1 fibroblasts. Moreover, 3T3-Gab1/DeltaSHP-2 cells demonstrate a higher
      level of extracellular-regulated kinase 1 activation at early time points of EGF
      stimulation. However, there was an unexpected decrease in c-fos promoter
      induction in 3T3-Gab1/DeltaSHP-2 cells when compared with 3T3-Gab1 cells.
      Additionally, the 3T3-Gab1/DeltaSHP-2 cells show a reversion of the transformed
      phenotype, including fewer morphologic changes, an increase in stress fiber
      cytoskeletal organization, and a decrease in cell proliferation and anchorage
      independent growth. These results reveal that the Gab1/SHP-2 interaction is
      essential for cell growth and transformation but that this must occur through a
      novel pathway that is independent of extracellular-regulated kinase or AKT. On
      the basis of its role in growth and transformation, the Gab1/SHP-2 interaction
      may become an attractive target for the pharmacologic intervention of malignant
      cell growth.

PMID- 15026338
TI  - Cancer and the microenvironment: myeloma-osteoclast interactions as a model.
AB  - We have investigated the interaction between tumor cells and specific cells in
      their microenvironment using myeloma as a model. The role of myeloma-induced
      osteoclastogenesis in the disease was studied ex vivo. Myeloma plasma cells
      freshly purified from patients' bone marrow attracted committed osteoclast (OC)
      precursors (n = 9; P < 0.01) and in 22 experiments directly induced their
      differentiation to multinucleated, bone-resorbing OCs (P < 0.00002) in a receptor
      activator of nuclear factor-kappaB ligand-mediated mechanism that was inhibited
      by the receptor activator of nuclear factor-kappaB (RANK-Fc) in 13 experiments by
      71 +/- 12% (P < 0.008). In contrast, myeloma cells did not induce differentiation
      of peripheral blood mononuclear cells. Myeloma plasma cells cocultured with OCs
      retained their viability and proliferative activity for >13 weeks. After 14 days
      in coculture, the plasma cells from 29 patients had higher viability (P < 2 x 10(
      6)), fewer apoptotic cells (P < 4 x 10(-15)), and a higher bromodeoxyuridine
      labeling index (P < 0.0006) than controls. Physical contact between OCs and
      myeloma cells was required for these effects to take place. No differences were
      observed between OCs from healthy donors and those from myeloma patients.
      Blocking interleukin 6 activity, while reducing survival of myeloma cells, had no
      effect on their proliferative activity. These results support data obtained from
      animal models and clinical observations on the essential role of the
      microenvironment in tumor sustenance and progression.

PMID- 15026339
TI  - Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the
      oral cavity.
AB  - Carcinoma cells of epithelial origin are predisposed to acquire a fibroblastic
      feature during progression of neoplasm referred to as the epithelial-mesenchymal
      transition. HMGA2 is an architectural transcriptional factor that is expressed in
      the undifferentiated mesenchyme and initiates mesenchymal tumor formation.
      However, the biological consequence of the expression in the pathology of
      epithelial-type carcinomas is controversial. The present study was conducted to
      dissect the expression pattern in oral squamous cell carcinomas. HMGA2 was
      detected exclusively in carcinoma cell lines and tissues, but not in normal
      keratinocytes and gingival, by conventional reverse transcription-PCR.
      Quantitative real-time reverse transcription-PCR demonstrated 160-fold more HMGA2
      expression in carcinoma tissues than in normal gingiva and 11-fold more HMGA2
      expression in carcinoma cell lines than in normal keratinocytes. HMGA2 expression
      was observed by immunohistochemistry in 73.8% of 42 carcinomas and localized to
      the invasive front, where the cells exhibit the epithelial-mesenchymal
      transition. Fourteen patients who had been classified into a group without lymph
      node metastasis were positive for HMGA2 staining, and the disease recurred.
      Furthermore, carcinomas from all 23 patients who died of tumor recurrence stained
      for HMGA2, and HMGA2 staining was correlated to long-term survival of patients (P
      < 0.01). Multivariate risk factor analysis demonstrated that HMGA2 expression was
      an independent prognostic value for disease-specific overall survival (P < 0.01).
      These results suggest that HMGA2 contributes to the aggressiveness of carcinoma
      and that detection of HMGA2 expression is a useful predictive and prognostic tool
      in clinical management of oral carcinomas.

PMID- 15026340
TI  - Celecoxib inhibits vascular endothelial growth factor expression in and reduces
      angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1
      transcription factor activity.
AB  - The aggressive biology of human pancreatic adenocarcinoma has been linked with
      overexpression of vascular endothelial growth factor (VEGF). Constitutive
      activation of the transcription factor Sp1 plays a critical role in VEGF
      overexpression. Recent studies indicated that celecoxib, a selective
      cyclooxygenase-2 inhibitor, exhibits potent antitumor activity. However, the
      underlying molecular mechanisms of this activity remain unclear. In the present
      study, we used a pancreatic cancer model to determine the role of Sp1 in the
      antitumor activity of celecoxib. Treatment of various pancreatic cancer cells
      with celecoxib suppressed VEGF expression at both the mRNA and protein level in a
      dose-dependent manner. VEGF promoter deletion and point mutation analyses
      indicated that a region between nucleotide -109 and -61 and its intact Sp1
      binding sites were required for the inhibition of VEGF promoter activity by
      celecoxib. Also, celecoxib treatment reduced both Sp1 DNA binding activity and
      transactivating activity. This decreased activity correlated with reduced Sp1
      protein and its phosphorylation as determined using Western blot analysis.
      Furthermore, in an orthotopic pancreatic cancer animal model, celecoxib treatment
      inhibited tumor growth and metastasis. The antitumor activity was consistent with
      inhibition of angiogenesis as determined by evaluating tumor microvessel
      formation, which correlated with decreased Sp1 activity and VEGF expression.
      Collectively, our data provide a novel molecular mechanism for the antitumor
      activity of celecoxib and may help further improve its effectiveness in
      controlling pancreatic cancer growth and metastasis.

PMID- 15026341
TI  - Human T-cell lymphotropic virus type I-infected cells extravasate through the
      endothelial barrier by a local angiogenesis-like mechanism.
AB  - Extravasation of tumor cells through the endothelial barrier is a critical step
      in cancer metastasis. Human T-cell lymphotropic virus type I (HTLV-I)-associated
      adult T-cell leukemia/lymphoma (ATL) is an aggressive disease characterized by
      visceral invasion. We show that ATL and HTLV-I-associated myelopathy patients
      exhibit high plasma levels of functional vascular endothelial growth factor and
      basic fibroblast growth factor. The viral oncoprotein Tax transactivates the
      promoter of the gap-junction protein connexin-43 and enhances gap-junction
      mediated heterocellular communication with endothelial cells. The interaction of
      HTLV-I-transformed cells with endothelial cells induces the gelatinase activity
      of matrix metalloproteinase (MMP)-2 and MMP-9 in endothelial cells and down
      regulates the tissue inhibitor of MMP. This leads to subendothelial basement
      membrane degradation followed by endothelial cell retraction, allowing neoplastic
      lymphocyte extravasation. We propose a model that offers a mechanistic
      explanation for extravasation of HTLV-I-infected cells: after specific adhesion
      to endothelia of target organs, tumor cells induce a local and transient
      angiogenesis-like mechanism through paracrine stimulation and direct cell-cell
      communication with endothelial cells. This culminates in a breach of the
      endothelial barrier function, allowing cancer cell invasion. This local and
      transient angiogenesis-like sequence that may facilitate visceral invasion in ATL
      represents a potential target for ATL therapy.

PMID- 15026342
TI  - Cell surface expression of epidermal growth factor receptor and Her-2 with
      nuclear expression of Her-4 in primary osteosarcoma.
AB  - There is controversy over the role of Her-2 in osteosarcoma, with some
      investigators reporting association between expression and adverse outcome,
      whereas others point to the lack of gene amplification and membranous expression
      by immunohistochemistry (IHC) as inconsistent with biological significance. Her-2
      normally requires pairing with epidermal growth factor receptor (EGFR), Her-3, or
      Her-4, but these have been less well studied in osteosarcoma. We evaluated the
      expression of each of these receptors in osteosarcoma and their potential to
      contribute to pathogenesis by examining a panel of low-passage primary
      osteosarcoma cell lines, comparing these with archival tumor specimens. Her-2
      immunoreactivity was seen frequently in the diffuse staining pattern described
      previously. We observed EGFR in all samples by IHC. Her-3 expression was not
      observed. Her-4 expression was nuclear in distribution in all tumor samples and
      many cell line samples, consistent with activation and cleavage of the receptor.
      Quantified expression of Her-2 and EGFR mRNA by quantitative, real-time PCR in
      cell lines correlated with IHC for Her-2 but not for EGFR. Western blot
      identified full-length receptors for EGFR and Her-2 in all expected cell lines
      and showed Her-4 to be predominantly in the p80 form. Flow cytometry identified
      cell surface Her-2 and EGFR in all lines with receptor expression by IHC. We
      conclude that the cell surface expression of Her-2 and EGFR and the nuclear
      localization of the activated p80 fragment of Her-4 suggest that all three may be
      contributing to osteosarcoma pathogenesis. Therapy directed against this family
      of receptors may be beneficial for patients with osteosarcoma.

PMID- 15026343
TI  - Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine
      model of human cervical carcinoma.
AB  - An orthotopic mouse model of cervical carcinoma has been used to investigate the
      relationship between acute (cyclic) hypoxia and spontaneous lymph node metastasis
      in vivo. The human cervical carcinoma cell line ME-180 was stably transfected to
      express the fluorescent protein DsRed2, which allowed the in vivo optical
      monitoring of tumor growth and metastasis by fluorescent microscopy. The
      surgically implanted primary tumors metastasize initially to local lymph nodes
      and later to lung, a pattern consistent with the clinical course of the disease.
      The effect of acute hypoxia on the growth and spread of these tumors was examined
      by exposing tumor-bearing mice to treatment consisting of exposure to 12 cycles
      of 10 min 7% O(2) followed by 10 min air (total 4 h) daily during tumor growth.
      After 21 days, the tumors were excised, lymph node and lung metastases were
      quantified, and the hypoxic fraction and relative vascular area of the primary
      tumors were assessed by immunohistochemical staining for the hypoxic marker drug
      EF5 [2-(2-nitro-1H-imidazole-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] and
      the vascular marker CD31, respectively. In untreated mice, the primary tumor size
      was directly correlated with lymph node metastatic burden. The acute hypoxia
      treatment resulted in a significant decrease in the size of the primary tumors at
      the time of excision. However, the mice in the acute hypoxia group had an
      increased number of positive lymph nodes (2-4) as compared with control mice (1
      3). Lung metastasis was not affected. The acute hypoxia treatment also decreased
      the relative vascular area in the primary tumors but did not affect the hypoxic
      fraction. These results suggest that fluctuating oxygenation in cervical
      carcinoma tumors may reduce tumor growth rate, but it may also enhance the
      ability of tumor cells to metastasize to local lymph nodes.

PMID- 15026344
TI  - Evidence of antiangiogenic and antimetastatic activities of the recombinant
      disintegrin domain of metargidin.
AB  - Metargidin, a transmembrane protein of the adamalysin family, and integrins,
      e.g., alpha5beta1 and alphav, are preferentially expressed on endothelial cells
      on angiogenesis. Furthermore, metargidin interacts with these integrins via its
      disintegrin domain. In this study, recombinant human disintegrin domain (RDD) was
      produced in Escherichia coli by subcloning its cDNA into the pGEX-2T vector, and
      the effect of purified RDD on different steps of angiogenesis was evaluated. At
      concentrations of 2-10 micro g/ml, RDD exhibited inhibitory activities in a
      variety of in vitro functional assays, including endothelial cell proliferation
      and adhesion on the integrin substrates fibronectin, vitronectin, and fibrinogen.
      RDD (10 micro g/ml) totally abrogated endothelial cell migration and blocked most
      capillary formation in a three-dimensional fibrin gel. To test RDD efficacy in
      vivo, the RDD gene inserted into pBi vector containing a tetracycline-inducible
      promoter was electrotransferred into nude mouse muscle. RDD was successfully
      synthesized by muscle cells in vivo as shown by immunolabeling and Western
      blotting. In addition, 78% less MDA-MB-231 tumor growth, associated with strong
      inhibition of tumor angiogenesis, was observed in athymic mice bearing
      electrotransferred RDD. Moreover, in the presence of RDD, 74% fewer B16F10
      melanoma lung metastases were found in C57BL/6 mice. Taken together, these
      results identified this RDD as a potent intrinsic inhibitor of angiogenesis,
      tumor growth, and metastasis, making it a promising tool for use in anticancer
      treatment.

PMID- 15026345
TI  - Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity.
AB  - One of the fundamental principles of pharmacology is that most drugs have side
      effects. Although considerable attention is paid to detrimental side effects,
      drugs can also have beneficial side effects. Given the time and expense of drug
      development, it would be particularly exciting if a systematic method could be
      applied to reveal all of the activities, including the unappreciated actions, of
      a potential drug. The present study takes the first step along this path. An
      activity-based proteomics strategy was used to simultaneously identify targets
      and screen for their inhibitors in prostate cancer. Orlistat, a Food and Drug
      Administration-approved drug used for treating obesity, was included in this
      screen. Surprisingly, we find a new molecular target and a potential new
      application for Orlistat. Orlistat is a novel inhibitor of the thioesterase
      domain of fatty acid synthase, an enzyme strongly linked to tumor progression. By
      virtue of its ability to inhibit fatty acid synthase, Orlistat halts tumor cell
      proliferation, induces tumor cell apoptosis, and inhibits the growth of PC-3
      tumors in nude mice.

PMID- 15026346
TI  - Reduced infiltration of class A scavenger receptor positive antigen-presenting
      cells is associated with prostate cancer progression.
AB  - The class A macrophage scavenger receptor (SR-A) is expressed in antigen
      presenting cells and is involved in host immune responses. Germ-line mutation of
      this gene has been associated with increased risk of human prostate cancer.
      However, there is little known about its expression in normal or neoplastic human
      prostate tissues. Double immunofluorescent labeling with monoclonal antibodies to
      SR-A and specific macrophage and dendritic cell markers was used to identify
      cells expressing SR-A in human prostate tissues. SR-A immunohistochemical
      staining was performed on paraffin sections of normal prostate, prostatic
      intraepithelial neoplasia (PIN) lesions, and prostate cancers from radical
      prostatectomy specimens. SR-A was expressed in a subset of macrophages and
      dendritic cells that infiltrated prostatic tissues. The majority of SR-A-positive
      cells coexpressed CD68, and a relatively low percentage expressed S100 protein.
      The number of SR-A-positive cells was significantly increased in PIN as compared
      with normal prostatic tissue (P = 0.0176). In contrast, the number of SR-A
      positive cells decreased with tumor progression. A lower SR-A-positive cell
      density was associated with higher clinical stage (rho = -0.26; P = 0.0234).
      Inverse associations were also found between SR-A density and positive lymph
      nodes (rho = -0.23; P = 0.0437), tumor size (rho = -0.31; P = 0.0100) and
      preoperative PSA levels (rho = -0.32; P = 0.0057). SR-A density is a significant
      predictor of disease-free survival after surgery univariately (P = 0.0003), as
      well as multivariately, adjusted for known clinical and pathological markers
      including preoperative prostate-specific antigen, clinical stage, Gleason score,
      surgical margin, extraprostatic extension, and seminal vesicle invasion, as well
      as lymph node metastasis (P = 0.0021). The preferential accumulation of SR-A
      positive cells in PIN suggests a role for SR-A in the APC response to early
      malignancy. A reduction in the number of SR-A-positive cells demarcates tumor
      progression as indicated by clinical and pathological correlations. Our results
      additionally indicate that systematic measurement of SR-A density is a strong
      prognostic marker for clinical outcome after surgery.

PMID- 15026347
TI  - Prostate cancer cell adhesion to bone marrow endothelium: the role of prostate
      specific antigen.
AB  - Bone metastasis is the most frequent complication of prostate cancer (PC).
      Elucidation of the biological basis of this specificity is required for the
      development of approaches for metastatic inhibition. We investigated the
      possibility that the preferential attachment of PC cells to bone marrow
      endothelium (as opposed to endothelium from other organs) affects this
      specificity. We selected, from peptide phage-displayed libraries, peptide ligands
      to surfaces of PC cells (C4-2B) attenuated (30-40%) binding of C4-2B cells to
      bone marrow endothelial cells (BMECs). We then determined the molecules on the
      surface of C4-2B cells interacted with the selected peptides using column
      affinity chromatography and a cDNA expression phage-displayed library generated
      from C4-2B cells in T7 phage. We identified a phage from the cDNA library that
      specifically bound to one of the selected peptides-L11. This phage displayed the
      amino acid sequence homologous for the COOH-terminal portion of prostate-specific
      antigen (PSA). To examine the possible direct involvement of PSA in the
      interactions between PC and BMECs, we performed a cell-cell adhesion assay.
      Antibodies to PSA attenuated PC cells adhesion to BMECs. In addition, exogenous
      proteolytically active PSA modulated this adhesion. Finally, inactivation of mRNA
      coding PSA by a small interfering RNA (siRNA) diminished C4-2B cell adhesion to
      BMECs. These results indicate that PSA expressed as secreted and surface
      associated molecules in C4-2B cells is involved in cell-cell interactions and/or
      digests components of bone marrow endothelium for preferential adhesion and
      penetration of PC cells. The suggested experimental approach is a promising
      strategy for identification of cell surface molecules involved in intercellular
      interactions.

PMID- 15026349
TI  - Pharmacogenomic identification of targets for adjuvant therapy with the
      topoisomerase poison camptothecin.
AB  - The response of tumor cells to the unusual form of DNA damage caused by
      topoisomerase poisons such as camptothecin (CPT) is poorly understood, and
      knowledge regarding which drugs can be effectively combined with CPT is lacking.
      To better understand the response of tumor cells to CPT and to identify potential
      targets for adjuvant therapy, we examined global changes in mRNA abundance in
      HeLa cells after CPT treatment using Affymetrix U133A GeneChips, which include
      all annotated human genes (22,283 probe sets). Statistical analysis of the data
      using a Bayesian/Cyber t test and a modified Benjamini and Hochberg correction
      for multiple hypotheses testing identified 188 probe sets that are induced and
      495 that are repressed 8 h after CPT treatment at a False Discovery Rate of <0.05
      and a minimum 3-fold change. This pharmacogenomic approach led us to identify two
      pathways that are CPT induced: (a) the epidermal growth factor receptor; and (b)
      nuclear factor-kappaB-regulated antiapoptotic factors. Experiments using HeLa
      cells in our lab and prior animal model studies performed elsewhere confirm that
      inhibitors of these respective pathways super-additively enhance CPT's
      cytotoxicity, suggesting their potential as targets for adjuvant therapy with
      CPT.

PMID- 15026348
TI  - Binding and cytotoxicity of conjugated and recombinant fusion proteins targeted
      to the gonadotropin-releasing hormone receptor.
AB  - Pokeweed antiviral protein (PAP) is a plant-derived, highly potent ribosome
      inactivating protein that causes inhibition of protein translation and rapid cell
      death. We and others have delivered this protein to various cell types, including
      cancer cells, using hormones to specifically target cells bearing the hormone
      receptor. Here, we compare binding and cytotoxicity of GnRH-PAP hormonotoxins
      prepared either by protein conjugation (GnRH-PAP conjugate) or through
      recombinant DNA technology (GnRH-PAP fusion). Although GnRH-PAP conjugate protein
      bound specifically to and caused cell death in cells bearing the gonadotropin
      releasing hormone (GnRH) receptor, we could not detect binding or cytotoxicity
      using two different versions of the fusion protein in receptor-positive cells. We
      conclude that generation of an active GnRH-PAP fusion protein may not be feasible
      either because both ends of the GnRH molecule are required for receptor binding,
      but only the NH(2) terminus is free in the fusion protein and/or that more potent
      analogues of GnRH (inclusion of which is not feasible in the fusion protein) are
      needed for efficient targeting. In contrast, the GnRH-PAP conjugate shows promise
      as a novel anticancer agent, capable of targeting cancer cells expressing the
      GnRH receptor such as prostate, breast, ovarian, endometrial, and pancreatic
      cells. It may also be useful as a therapeutic agent to eliminate pituitary
      gonadotrophs, eliminating the need for chronic GnRH analogue administration to
      treat hormone-sensitive diseases.

PMID- 15026350
TI  - Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human
      glioblastoma cells in brain xenografts by an apoptosis-like mechanism and
      prolongs survival.
AB  - Malignant brain tumors present a major therapeutic challenge because no selective
      or efficient treatment is available. Here, we demonstrate that intratumoral
      administration of human alpha-lactalbumin made lethal to tumor cells (HAMLET)
      prolongs survival in a human glioblastoma (GBM) xenograft model, by selective
      induction of tumor cell apoptosis. HAMLET is a protein-lipid complex that is
      formed from alpha-lactalbumin when the protein changes its tertiary conformation
      and binds oleic acid as a cofactor. HAMLET induces apoptosis in a wide range of
      tumor cells in vitro, but the therapeutic effect in vivo has not been examined.
      In this study, invasively growing human GBM tumors were established in nude rats
      (Han:rnu/rnu Rowett, n = 20) by transplantation of human GBM biopsy spheroids.
      After 7 days, HAMLET was administered by intracerebral convection-enhanced
      delivery for 24 h into the tumor area; and alpha-lactalbumin, the native, folded
      variant of the same protein, was used as a control. HAMLET reduced the
      intracranial tumor volume and delayed the onset of pressure symptoms in the tumor
      bearing rats. After 8 weeks, all alpha-lactalbumin-treated rats had developed
      pressure symptoms, but the HAMLET-treated rats remained asymptomatic. Magnetic
      resonance imaging scans revealed large differences in tumor volume (456 versus 63
      mm(3)). HAMLET caused apoptosis in vivo in the tumor but not in adjacent intact
      brain tissue or in nontransformed human astrocytes, and no toxic side effects
      were observed. The results identify HAMLET as a new candidate in cancer therapy
      and suggest that HAMLET should be additionally explored as a novel approach to
      controlling GBM progression.

PMID- 15026351
TI  - Molecular imaging of drug-modulated protein-protein interactions in living
      subjects.
AB  - Networks of protein interactions mediate cellular responses to environmental
      stimuli and direct the execution of many different cellular functional pathways.
      Small molecules synthesized within cells or recruited from the external
      environment mediate many protein interactions. The study of small molecule
      mediated interactions of proteins is important to understand abnormal signal
      transduction pathways in cancer and in drug development and validation. In this
      study, we used split synthetic renilla luciferase (hRLUC) protein fragment
      assisted complementation to evaluate heterodimerization of the human proteins FRB
      and FKBP12 mediated by the small molecule rapamycin. The concentration of
      rapamycin required for efficient dimerization and that of its competitive binder
      ascomycin required for dimerization inhibition were studied in cell lines. The
      system was dually modulated in cell culture at the transcription level, by
      controlling nuclear factor kappaB promoter/enhancer elements using tumor necrosis
      factor alpha, and at the interaction level, by controlling the concentration of
      the dimerizer rapamycin. The rapamycin-mediated dimerization of FRB and FKBP12
      also was studied in living mice by locating, quantifying, and timing the hRLUC
      complementation-based bioluminescence imaging signal using a cooled charged
      coupled device camera. This split reporter system can be used to efficiently
      screen small molecule drugs that modulate protein-protein interactions and also
      to assess drugs in living animals. Both are essential steps in the preclinical
      evaluation of candidate pharmaceutical agents targeting protein-protein
      interactions, including signaling pathways in cancer cells.

PMID- 15026352
TI  - Choice of oxygen-conserving treatment regimen determines the inflammatory
      response and outcome of photodynamic therapy of tumors.
AB  - The rate of light delivery (fluence rate) plays a critical role in photodynamic
      therapy (PDT) through its control of tumor oxygenation. This study tests the
      hypothesis that fluence rate also influences the inflammatory responses
      associated with PDT. PDT regimens of two different fluences (48 and 128 J/cm(2))
      were designed for the Colo 26 murine tumor that either conserved or depleted
      tissue oxygen during PDT using two fluence rates (14 and 112 mW/cm(2)). Tumor
      oxygenation, extent and regional distribution of tumor damage, and vascular
      damage were correlated with induction of inflammation as measured by interleukin
      6, macrophage inflammatory protein 1 and 2 expression, presence of inflammatory
      cells, and treatment outcome. Oxygen-conserving low fluence rate PDT of 14
      mW/cm(2) at a fluence of 128 J/cm(2) yielded approximately 70-80% tumor cures,
      whereas the same fluence at the oxygen-depleting fluence rate of 112 mW/cm(2)
      yielded approximately 10-15% tumor cures. Low fluence rate induced higher levels
      of apoptosis than high fluence rate PDT as indicated by caspase-3 activity and
      terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. The
      latter revealed PDT-protected tumor regions distant from vessels in the high
      fluence rate conditions, confirming regional tumor hypoxia shown by 2-(2
      nitroimidazol-1[H]-yl)-N-(3,3,3-trifluoropropyl) acetamide staining. High fluence
      at a low fluence rate led to ablation of CD31-stained endothelium, whereas the
      same fluence at a high fluence rate maintained vessel endothelium. The highest
      levels of inflammatory cytokines and chemokines and neutrophilic infiltrates were
      measured with 48 J/cm(2) delivered at 14 mW/cm(2) ( approximately 10-20% cures).
      The optimally curative PDT regimen (128 J/cm(2) at 14 mW/cm(2)) produced minimal
      inflammation. Depletion of neutrophils did not significantly change the high cure
      rates of that regimen but abolished curability in the maximally inflammatory
      regimen. The data show that a strong inflammatory response can contribute
      substantially to local tumor control when the PDT regimen is suboptimal. Local
      inflammation is not a critical factor for tumor control under optimal PDT
      treatment conditions.

PMID- 15026353
TI  - Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody
      dependent cellular cytotoxicity shows potent therapeutic activity to T-cell
      leukemia and lymphoma.
AB  - Human IgG1 antibodies with low fucose contents in their asparagine-linked
      oligosaccharides have been shown recently to exhibit potent antibody-dependent
      cellular cytotoxicity (ADCC) in vitro. To additionally investigate the efficacy
      of the human IgG1 with enhanced ADCC, we generated the defucosylated chimeric
      anti-CC chemokine receptor 4 (CCR4) IgG1 antibody KM2760. KM2760 exhibited much
      higher ADCC using human peripheral blood mononuclear cells (PBMCs) as effector
      cells compared with the highly fucosylated, but otherwise identical IgG1, KM3060.
      In addition, KM2760 also exhibited potent ADCC in the presence of lower
      concentrations of human PBMCs than KM3060. Because CCR4 is a selective marker of
      T-cell leukemia/lymphoma, the effectiveness of KM2760 for T-cell malignancy was
      evaluated in several mouse models. First, to compare the antitumor activity of
      KM2760 and KM3060, we constructed a human PBMC-engrafted mouse model to determine
      ADCC efficacy with human effector cells. In this model, KM2760 showed
      significantly higher antitumor efficacy than KM3060, indicating that KM2760
      retains its high potency in vivo. Second, KM2760 suppressed tumor growth in both
      syngeneic and xenograft mouse models in which human PBMCs were not engrafted.
      Although murine effector cells exhibited marginal ADCC mediated by KM2760 and
      KM3060, KM2760 unexpectedly showed higher efficacy than KM3060 in a syngeneic
      mouse model, suggesting that KM2760 functions in murine effector system in vivo
      via an unknown mechanism that differs from that in human. These results indicate
      that defucosylated antibodies with enhanced ADCC as well as potent antitumor
      activity in vivo are promising candidates for the novel antibody-based therapy.

PMID- 15026354
TI  - A link between benzyl isothiocyanate-induced cell cycle arrest and apoptosis:
      involvement of mitogen-activated protein kinases in the Bcl-2 phosphorylation.
AB  - In the present study, we clarified the molecular mechanism underlying the
      relationship between benzyl isothiocyanate (BITC)-induced cell cycle arrest and
      apoptosis and the involvement of mitogen-activated protein kinases (MAPKs). The
      exposure of Jurkat human T-cell leukemia cells to BITC resulted in the inhibition
      of the G(2)-M progression that coincided with the apoptosis induction. The
      experiment using the phase-specific synchronized cells demonstrated that the G(2)
      M phase-arrested cells are more sensitive to undergoing apoptotic stimulation by
      BITC than the cells in other phases. We also confirmed that BITC activated c-Jun
      N-terminal kinase (JNK) and p38 MAPK, but not extracellular signal-regulated
      kinase, at the concentration required for apoptosis induction. An experiment
      using a JNK-specific inhibitor SP600125 or a p38 MAPK inhibitor SB202190
      indicated that BITC-induced apoptosis might be regulated by the activation of
      these two kinases. Conversely, BITC is likely to confine the Jurkat cells in the
      G(2)-M phase mainly through the p38 MAPK pathway because only the p38 MAPK
      inhibitor significantly attenuated the accumulation of inactive phosphorylated
      Cdc2 protein and the G(2)-M-arrested cell numbers. We reported here for the first
      time that the antiapoptotic Bcl-2 protein was phosphorylated by the BITC
      treatment without significant alteration of the Bcl-2 total protein amount. This
      was abrogated by a JNK specific inhibitor SP600125 at the concentration required
      for specific inhibition of the c-Jun phosphorylation. Moreover, the spontaneous
      phosphorylation of antiapoptotic Bcl-2 in the G(2)-M synchronized cells was
      enhanced synergistically by the BITC treatment. Involvement of the MAPK
      activation in the Bcl-2 phosphorylation and apoptosis induction also was observed
      in HL-60 and HeLa cells. Thus, we identified the phosphorylated Bcl-2 as a key
      molecule linking the p38 MAPK-dependent cell cycle arrest with the JNK activation
      by BITC.

PMID- 15026356
TI  - CD30 is involved in inhibition of T-cell proliferation by Hodgkin's Reed
      Sternberg cells.
AB  - CD30 is expressed on Hodgkin's Reed-Sternberg (H-RS) cells, the tumor cells in
      Hodgkin's disease. Increased levels of serum CD30 are observed in Hodgkin's
      disease patients and are a good marker for predicting a poor prognosis and a poor
      response to therapy. In this study, we addressed the effect of CD30 on T cells.
      We showed that CD30, either as a membranous protein on H-RS cells and Chinese
      hamster ovary cells or as a plate-bound chimeric protein, inhibited T-cell
      proliferation. Anti-CD3-stimulated T cells in the presence of CD30 failed to
      increase tritium uptake and failed to express CD25 and CD26 and to produce
      interleukin 2. The inhibition of T-cell proliferation was, however, reversed with
      addition of exogenous interleukin 2 or pretreatment of H-RS cells with anti-CD30.
      Inability of T cells to express CD25 and CD26 in cocultures with H-RS cells or a
      plate-bound CD30 chimeric protein is in accordance with the results of
      immunohistochemistry on disease-involved tissues. We conclude that H-RS cells are
      able to inhibit the proliferation and activation of T cells through CD30-related
      interaction. The outcome of CD30-related interaction is an ineffective antitumor
      immunity, which is clearly in favor of the growth and survival of the tumor
      cells.

PMID- 15026355
TI  - Vitamin D receptor and p21/WAF1 are targets of genistein and 1,25
      dihydroxyvitamin D3 in human prostate cancer cells.
AB  - We investigated mechanisms by which genistein and 1,25-dihydroxyvitamin D(3)
      [1,25(OH)(2)D(3)] act synergistically to inhibit the growth of the human prostate
      cancer cell line LNCaP. We demonstrate that 1,25(OH)(2)D(3) and genistein
      cooperate to up-regulate the vitamin D receptor protein by increasing the
      stability of the vitamin D receptor. Genistein and 1,25(OH)(2)D(3) also cooperate
      to up-regulate the levels of p21/WAF1 (p21). Small interfering RNA-mediated
      knockdown of p21 expression showed that p21 is essential for significant growth
      inhibition of LNCaP cells in response to either compound or their combination. We
      conclude that one mechanism of synergism between genistein and 1,25(OH)(2)D(3) is
      through genistein modulation of vitamin D signaling.

PMID- 15026357
TI  - Human telomerase reverse transcriptase-transduced human cytotoxic T cells
      suppress the growth of human melanoma in immunodeficient mice.
AB  - Immunotherapy of melanoma by adoptive transfer of tumor-reactive T lymphocytes
      aims at increasing the number of activated effectors at the tumor site that can
      mediate tumor regression. The limited life span of human T lymphocytes, however,
      hampers obtaining sufficient cells for adoptive transfer therapy. We have shown
      previously that the life span of human T cells can be greatly extended by
      transduction with the human telomerase reverse transcriptase (hTERT) gene,
      without altering antigen specificity or effector function. We developed a murine
      model to evaluate the efficacy of hTERT-transduced human CTLs with antitumor
      reactivity to eradicate autologous tumor cells in vivo. We transplanted the human
      melanoma cell line melAKR or melAKR-Flu, transduced with a retrovirus encoding
      the influenza virus/HLA-A2 epitope, in RAG-2(-/-) IL-2Rgamma (-/-) double
      knockout mice. Adoptive transfer of the hTERT-transduced influenza virus-specific
      CTL clone INFA24 or clone INFA13 inhibited the growth of melAKR-Flu tumors in
      vivo and not of the parental melAKR melanoma cells. Furthermore, the hTERT
      transduced CTL clone INFA13 inhibited tumor growth to the same extent in vivo as
      the untransduced CTL clone, as determined by in vivo imaging of luciferase gene
      transduced melAKR-Flu tumors, indicating that hTERT did not affect the in vivo
      function of CTL. These results demonstrate that hTERT-transduced human CTLs are
      capable of mediating antitumor activity in vivo in an antigen-specific manner.
      hTERT-transduced MART-1-specific CTL clones AKR4D8 and AKR103 inhibited the
      growth of syngeneic melAKR tumors in vivo. Strikingly, melAKR-Flu cells were
      equally killed by the MART-1-specific CTL clones and influenza virus-specific CTL
      clones in vitro, but only influenza-specific CTLs were able to mediate tumor
      regression in vivo. The influenza-specific CTL clones were found to produce
      higher levels of IFNgamma on tumor cell recognition than the MART-1-specific CTL
      clones, which may result from the higher functional avidity of the influenza
      virus-specific CTL clones. Also, melAKR-Flu tumors were growing faster than
      melAKR tumors, which may have surpassed the relatively modest antitumor effect of
      the MART-1-specific CTL, as compared with the influenza virus-specific CTL. Taken
      together, the adoptive transfer model described here shows that hTERT-transduced
      T cells are functional in vivo, and allows us to evaluate the balance between
      functional activity of the CTL and tumor growth rate in vivo, which determines
      the efficacy of CTLs to eradicate tumors in adoptive transfer therapy.

PMID- 15026358
TI  - A mimic of tumor rejection antigen-associated carbohydrates mediates an antitumor
      cellular response.
AB  - Tumor-associated carbohydrate antigens are typically perceived as inadequate
      targets for generating tumor-specific cellular responses. Lectin profile
      reactivity and crystallographic studies demonstrate that MHC class I molecules
      can present to the immune system posttranslationally modified cytosolic peptides
      carrying O-beta-linked N-acetylglucosamine (GlcNAc). Here we report that a
      peptide surrogate of GlcNAc can facilitate an in vivo tumor-specific cellular
      response to established Meth A tumors that display native O-GlcNAc glycoproteins
      on the tumor cell surface. Peptide immunization of tumor-bearing mice had a
      moderate effect on tumor regression. Inclusion of interleukin 12 in the
      immunization regimen stimulated complete elimination of tumor cells in all of the
      mice tested, whereas interleukin 12 administration alone afforded no tumor growth
      inhibition. Adoptive transfer of immune T cells into tumor-bearing nude mice
      indicates a role for CD8+ T cells in tumor regression. This work postulates that
      peptide mimetics of glycosylated tumor rejection antigens might be further
      developed for immune therapy of cancer.

PMID- 15026359
TI  - Epstein-Barr virus infection of human natural killer cell lines and peripheral
      blood natural killer cells.
AB  - Although considerable part of natural killer (NK) cell neoplasms possess EBV
      genome, there has been no direct evidence that EBV infects human NK cells in
      vitro. In this study, we demonstrated EBV entry into NK cells using a recombinant
      EBV, which contains enhanced green fluorescent protein (EGFP) gene in its genome
      (EGFP-EBV). After 48 h of exposure to EGFP-EBV, we detected EGFP signals in
      approximately 30% of NK-92 and NKL cells and >40% of peripheral blood NK cells
      from three healthy volunteers. Reverse transcription-PCR analysis of various EBV
      associated genes confirmed EBV infection. In situ hybridization for EBERs and
      BHLFs showed that latent and lytic infections coexisted at the early phase of EBV
      infection in two NK cell lines. Although BHLF-positive cells in the early lytic
      phase were round-shaped, EBER-positive cells in latent EBV infection tended to
      show a bizarre shape. Flow cytometric analysis of EGFP-EBV-exposed NK cell lines
      showed that most of EBV-infected cells entered early apoptosis after 72 h of EBV
      exposure, which explains the difficulties to establish EBV-carrying NK clones.
      Flow cytometry and reverse transcription-PCR analysis indicated that two NK cell
      lines may fuse with EBV using HLA class II after binding to the virus through a
      distinct molecule from CD21. We established two EBV-carrying NKL clones showing
      latency types I and II, both of which are recognized in EBV-associated NK cell
      neoplasms. Because EBV-infected NKL cells showed only type I latency during the
      early phase of infection, the temporal profile of latent gene expression is
      similar to that of T cells. We first report in vitro EBV infection of human NK
      cells and establishment of EBV-carrying NK clones, which should contribute to
      elucidate the role of EBV in the development of NK cell neoplasms.

PMID- 15026360
TI  - Ovarian carcinoma expresses the NKG2D ligand Letal and promotes the survival and
      expansion of CD28- antitumor T cells.
AB  - The role of the NKG2D immunoreceptor and its ligands in antitumor immune response
      is incompletely understood. Here, we report that effector immune cells
      infiltrating ovarian carcinoma are mostly CD8+ lymphocytes lacking CD28 but
      expressing the NKG2D costimulatory receptor. Human ovarian carcinoma expresses
      the novel NKG2D ligand lymphocyte effector cell toxicity-activating ligand
      (Letal). Letal was found to be an independent prognosticator of improved survival
      in advanced ovarian cancer. Higher levels of tumor-derived Letal were associated
      with stronger lymphocyte infiltration. Letal exerted marked costimulatory effects
      and induced type-1 polarization in CD8+CD28- tumor-infiltrating lymphocytes ex
      vivo. Letal engagement increased the expression of the glucose transporter Glut
      1, enhanced glucose up-take, and protected CD8+ lymphocytes from cisplatin
      induced killing. Letal also down-regulated the expression of Fas in CD8+ cells
      and rendered them resistant to Fas ligand-induced apoptosis. Our results indicate
      that Letal promotes tumor immune surveillance by promoting the survival and
      intratumoral expansion of antitumor cytotoxic lymphocytes. We propose that Letal
      could be used for the ex vivo expansion of apoptosis-resistant tumor-reactive
      cytotoxic lymphocytes for adoptive transfer.

PMID- 15026361
TI  - Donor cell cycling, trafficking, and accumulation during adoptive immunotherapy
      for murine lung metastases.
AB  - Adoptive cellular immunotherapy treats metastatic cancer by infusing cultured T
      cells derived from resected tumors or primed lymph nodes. The infused cells must
      accumulate in metastatic lesions to suppress growth; however, this process and
      the resulting clinical response are dynamic and evolve during the days and weeks
      following cell infusion. This study used novel experimental techniques to
      determine the fate of infused, cultured tumor-draining lymph node (TDLN) cells
      during the treatment of murine pulmonary micrometastases. After infusion, the
      cultured TDLN cells accumulated in the pulmonary vasculature, systemic lymph
      nodes, and spleen. Donor cells were initially confined to alveolar capillaries
      with no movement into metastases. Within 4 h, TDLN cells began migrating across
      pulmonary postcapillary venules and first appeared within metastases. After 24 h,
      most donor cells in the lung were associated with tumor nodules. Donor cell
      proliferation within the lung and lymphoid organs was detected within 24 h of
      infusion and continued throughout the 5-day period of observation. Furthermore,
      those proliferating in lymphoid organs trafficked back to the tumor-bearing
      lungs, accounting for approximately 50% of the donor cells recovered from these
      sites after 5 days. Finally, donor T cells entering metastases both early (within
      1-2 days) and late (after 2 days) suppressed tumor growth, but the early recruits
      accounted for most of the therapeutic response. Thus, cultured TDLN cells migrate
      directly into tumor-bearing organs and seed the recirculating pool of lymphocytes
      after infusion. Small fractions of the later differentiate in lymphoid organs and
      migrate into the lungs but appear less effective than effector cells in the
      initial bolus.

PMID- 15026362
TI  - Selective accumulation of mature DC-Lamp+ dendritic cells in tumor sites is
      associated with efficient T-cell-mediated antitumor response and control of
      metastatic dissemination in melanoma.
AB  - The clinical relevance of dendritic cells (DCs) at the tumor site remains a
      matter of debate concerning their role in the generation of effective antitumor
      immunity in human cancers. We performed a comprehensive immunohistochemical
      analysis using a panel of DC-specific antibodies on regressing tumor lesions and
      sentinel lymph nodes (SLNs) in melanoma patients. Here we show in a case report
      involving spontaneous regression of metastatic melanoma that the accumulation of
      DC-Lamp+ DCs, clustered with tumor cells and lymphocytes, is associated with
      local expansion of antigen-specific memory effector CTLs. These findings were
      extended in a series of 19 melanoma-positive SLNs and demonstrated a significant
      correlation between the density of DC-Lamp+ DC infiltrates in SLNs with the
      absence of metastasis in downstream lymph nodes. This study, albeit performed in
      a limited series of patients, points to a pivotal role of mature DCs in the local
      expansion of efficient antitumor T-cell-mediated immune responses at the initial
      sites of metastasis and may have important implications regarding the prognosis,
      staging, and immunotherapy of melanoma patients.

PMID- 15026363
TI  - NY-ESO-1 expression and immunogenicity in malignant and benign breast tumors.
AB  - NY-ESO-1 is a cancer/testis antigen expressed in normal adult tissues solely in
      the testicular germ cells of normal adults and in various cancers. It induces
      specific humoral and cellular immunity in patients with NY-ESO-1-expressing
      cancer. The aim of this study was to determine the frequency of NY-ESO-1 mRNA and
      protein expression in malignant and benign breast tumors. NY-ESO-1 mRNA
      expression was detected by conventional reverse transcription-PCR and real-time
      PCR, and that of the protein expression by immunohistochemistry and Western blot
      analysis. Expression of NY-ESO-1 mRNA was detected in 37 of 88 (42%) cancer
      specimens, whereas that of the NY-ESO-1 protein was detected only in 1 mRNA
      positive specimen. In the latter case, expression level of NY-ESO-1 mRNA relative
      to that in the testis was relatively high (75% of testicular expression) and to
      the other among breast cancer specimens. In benign breast lesions, 21 of 31 (68%)
      specimens expressed low levels of NY-ESO-1 mRNA. In 1 case of fibroadenoma, NY
      ESO-1 mRNA was 8% of the testicular level, and protein was detected by Western
      blot analysis. Only 1 breast cancer patient had detectable antibody at time of
      surgery, which disappeared within 2 years. Tumor specimen from this patient was
      both NY-ESO-1 mRNA and protein positive, and NY-ESO-1-specific CD8 T cells were
      detected in this patient by IFN-gamma enzyme-linked immunospot assay using NY-ESO
      1 recombinant adeno and vaccinia virus. A higher rate of NY-ESO-1 expression was
      noted in breast cancer with high histological grade and negative hormone receptor
      status, suggesting NY-ESO-1 as a potential tumor antigen for immunotherapy in
      patients with breast cancer and poor prognosis.

PMID- 15026364
TI  - Surgical removal of primary tumor reverses tumor-induced immunosuppression
      despite the presence of metastatic disease.
AB  - Immunotherapy is a promising approach for the management of malignancies. It may
      be particularly useful for tumors that do not respond to conventional therapies,
      such as many metastatic cancers. The efficacy of immunotherapy will depend on
      many factors, one of which is the immunocompetence of the host. Patients with
      large primary tumors frequently are immunosuppressed, making them poor candidates
      for immunotherapy. Although a few studies have reported that surgical removal of
      primary tumor reverses immunosuppression, it is not known whether metastatic
      disease in postsurgery patients inhibits this recovery. To determine the role of
      metastatic disease, we examined tumor-free mice versus mice with primary tumor
      and metastatic disease versus mice whose primary tumors were removed surgically
      but who had metastatic disease. We have used the mouse 4T1 mammary carcinoma, a
      BALB/c-derived transplantable tumor that shares many characteristics with human
      breast cancer and is an established model for spontaneous, metastatic cancer.
      Cell-mediated and humoral adaptive immunity, as measured by rejection of
      allogeneic tumor, antigen-specific T-cell proliferation, and antigen-specific
      antibody responses, was suppressed in 4T1-bearing nonsurgery mice relative to
      tumor-free mice. Surgical removal of primary tumor resulted in rebounding of
      antibody and cell-mediated responses, even in mice with metastatic disease.
      Macrophage activity, as measured by lipopolysaccharide responsiveness, and
      dendritic cell function, as measured by nominal and alloantigen presentation,
      were not suppressed in tumor-bearing mice. Therefore, the presence of primary
      tumor suppresses T-cell and antibody responses; however, surgical removal of
      primary tumor restores immunocompetence even when disseminated metastatic disease
      is present.

PMID- 15026365
TI  - Dysregulation of sterol response element-binding proteins and downstream
      effectors in prostate cancer during progression to androgen independence.
AB  - Androgen ablation, the most common therapeutic treatment used for advanced
      prostate cancer, triggers the apoptotic regression of prostate tumors. However,
      remissions are temporary because surviving prostate cancer cells adapt to the
      androgen-deprived environment and form androgen-independent (AI) tumors. We
      hypothesize that adaptive responses of surviving tumor cells result from
      dysregulated gene expression of key cell survival pathways. Therefore, we
      examined temporal alterations to gene expression profiles in prostate cancer
      during progression to androgen independence at several time points using the
      LNCaP xenograft tumor model. Two key genes, sterol response element-binding
      protein (SREBP)-1 and -2 (SREBP-1a,-1c, and -2), were consistently dysregulated.
      These genes are known to coordinately control the expression of the groups of
      enzymes responsible for lipid and cholesterol synthesis. Northern blots revealed
      modest increased expression of SREBP-1a, -1c, and -2 after castration, and at
      androgen independence (day 21-28), the expression levels of both SREBP-1a and -1c
      were significantly greater than precastrate levels. Changes in SREBP-1 and -2
      protein expression were observed by Western analysis. SREBP-1 68-kDa protein
      levels were maintained throughout progression, however, SREBP-2 68-kDa protein
      expression increased after castration and during progression (3-fold). SREBPs are
      transcriptional regulators of over 20 functionally related enzymes that
      coordinately control the metabolic pathways of lipogenesis and cholesterol
      synthesis, some of which were likewise dysregulated during progression to
      androgen independence. RNA levels of acyl-CoA-binding protein/diazepam-binding
      inhibitor and fatty acid synthase decreased significantly after castration, and
      then, during progression, increased to levels greater than or equal to
      precastrate levels. Expression of farnesyl diphosphate synthase did not decrease
      after castration but did increase significantly during progression to androgen
      independence. Levels of SREBP cleavage-activating protein, a regulator of SREBP
      transcriptional activity, decreased after castration and increased significantly
      at androgen independence. In clinical prostate cancer specimens from patients
      with varying grades of disease, the stained tissue sections showed high levels of
      SREBP-1 protein compared with noncancerous prostate tissue. After hormone
      withdrawal therapy, tumor levels of SREBP-1 decreased significantly after 6
      weeks. AI tumors expressed significantly higher levels of SREBP-1. In summary,
      the LNCaP xenograft model of human prostate cancer as well as clinical specimens
      of prostate cancer demonstrated an up-regulation of SREBPs and their downstream
      effector genes during progression to androgen independence. As the AI phenotype
      emerges, enzymes critical for lipogenesis and cholesterol synthesis are activated
      and likely contribute significantly to cell survival of AI prostate cancer.

PMID- 15026366
TI  - Menin inactivation leads to loss of transforming growth factor beta inhibition of
      parathyroid cell proliferation and parathyroid hormone secretion.
AB  - Primary hyperparathyroidism is a common endocrine disorder caused by parathyroid
      gland enlargement and excessive parathyroid hormone (PTH) secretion. However, the
      precise mechanisms of tumorigenesis of the parathyroids are unknown. Here we have
      investigated the roles of transforming growth factor (TGF)-beta and menin, the
      product of the multiple endocrine neoplasia type 1 (Men1) gene, in the
      proliferation and PTH production of parathyroid cells from either patients with
      secondary hyperparathyroidism or Men1. TGF-beta was expressed in the parathyroid
      endocrine cells. Addition of TGF-beta to parathyroid cells from patients with
      secondary hyperparathyroidism inhibited their proliferation and PTH secretion.
      These responses to TGF-beta were lost when menin was specifically inactivated by
      antisense oligonucleotides. Moreover, TGF-beta did not affect the proliferation
      and PTH production of parathyroid cells from a Men1 patient. These results
      indicate that menin is required for TGF-beta action in the parathyroid. We
      conclude that TGF-beta is an important autocrine/paracrine negative regulator of
      parathyroid cell proliferation and PTH secretion and that loss of TGF-beta
      signaling due to menin inactivation contributes to parathyroid tumorigenesis.

PMID- 15026367
TI  - Insulin-like growth factor-binding protein 3 induces caspase-dependent apoptosis
      through a death receptor-mediated pathway in MCF-7 human breast cancer cells.
AB  - Insulin-like growth factor-binding protein (IGFBP)-3 has been shown to potently
      inhibit cell proliferation in various cell systems. However, the specific
      mechanisms involved in the antiproliferative action of IGFBP-3 have yet to be
      elucidated. In the present study, we demonstrate that IGFBP-3 induces apoptosis
      in an insulin-like growth factor (IGF)-independent manner through the activation
      of caspases involved in a death receptor-mediated pathway in MCF-7 human breast
      cancer cells. Induction of IGFBP-3 using an ecdysone-inducible expression system
      inhibited DNA synthesis in an IGF-IGF receptor axis-independent fashion and
      resulted in the subsequent induction of apoptosis and an increase in caspase
      activity. Similar results were obtained when cells were transfected with GGG
      IGFBP-3, an IGFBP-3 mutant unable to bind IGFs, corroborating the IGF-independent
      action of IGFBP-3. Additional caspase activity studies and immunoblot analyses
      using specific caspase substrates and/or caspase inhibitors revealed that the
      growth-inhibitory effect of IGFBP-3 results mainly from its induction of
      apoptosis (in particular, activation of caspase-8 and -7). Analyses of caspase-9
      activity and release of cytochrome c into the cytosol confirmed that the
      mitochondria-mediated pathway is not involved. Taken together, these results show
      that IGFBP-3 expression leads to the induction of apoptosis through the
      activation of caspases involved in a death receptor-mediated pathway and that
      IGFBP-3 functions as a negative regulator of breast cancer cell growth,
      independent of the IGF-IGF receptor axis.

PMID- 15026368
TI  - Progestin-dependent induction of vascular endothelial growth factor in human
      breast cancer cells: preferential regulation by progesterone receptor B.
AB  - The progesterone receptor (PR) is a ligand-dependent transcription factor that
      promotes progestin-stimulated expression of target genes. Two functional PR
      isoforms, PRA and PRB, are expressed in progestin-responsive cells. PRA and PRB
      have distinct roles in gene expression and in mammary gland development. One role
      of PRs in T47-D cells is regulating expression of vascular endothelial growth
      factor (VEGF), a potent angiogenic growth factor. This study explores the isoform
      specificity of this PR function using parental T47-Dco cells that express both
      PRA and PRB and clonal derivatives that express either PRA (YA cells) or PRB (YB
      cells) or lack PR (Y cells). Treatment with progesterone induces VEGF mRNA and
      protein approximately 2-fold in T47-Dco and YA cells and 3-7-fold in YB cells,
      suggesting that PRA inhibits PRB-dependent induction of VEGF. This is consistent
      with the observation that clinically relevant progestins induce a much higher
      level of VEGF in YB cells than in YA cells. Another novel finding in this report
      is that estradiol (10(-8) M) induces VEGF production from YB cells. However, this
      induction is not blocked by 100-fold excess tamoxifen or ICI-182,780. Moreover,
      both tamoxifen (10(-6) M) and ICI-182,780 (10(-6) M) function as agonists for
      VEGF in YB cells. Small interfering RNA against PR or estrogen receptor abrogated
      estradiol and tamoxifen induction, indicating that the agonist-like response of
      these compounds in YB cells is estrogen receptor and PR dependent. Estradiol,
      tamoxifen, and ICI-182780 also induce VEGF in BT-474 cells when their PRB levels
      were elevated by transfecting an expression plasmid for PRB, but not when the
      cells were transfected with vector alone. These results indicate that (a) PRB
      preferentially regulates VEGF expression in breast cancer cells and (b) PRB
      enriched tumor cells may produce more VEGF, have a better developed vasculature,
      and potentially are more resistant to tamoxifen and ICI-182,780 than cells that
      express an equivalent or higher level of PRA than PRB. These results imply that
      PRB-enriched breast tumors may respond well to anticancer therapies that include
      inhibitors of angiogenesis.

PMID- 15026369
TI  - Allelic imbalance of 12q22-23 associated with APAF-1 locus correlates with poor
      disease outcome in cutaneous melanoma.
AB  - Cutaneous melanoma is a highly aggressive tumor that is relatively resistant to
      chemotherapy and radiotherapy. This resistance may be in part due to inhibition
      of apoptosis. Apoptotic protease activating factor-1(APAF-1), a candidate tumor
      suppressor gene, mediates p53-induced apoptosis, and its loss promotes oncogenic
      transformation. To determine whether loss of the APAF-1 locus influences tumor
      progression, we assessed loss of heterozygosity microsatellites on the APAF-1
      locus (12q22-23) in 62 primary and 112 metastatic melanomas. We discovered that
      frequency of allelic imbalance was significantly higher in metastatic tumors (n =
      36 of 98; 37%) than in primary melanomas (n = 10 of 54; 19%; P = 0.02). In
      metastatic melanomas, APAF-1 loss significantly correlated with a worse prognosis
      (P < 0.05) in the patients, and its loss during melanoma tumor progression
      suggests that APAF-1 is a tumor suppressor gene. Furthermore, loss of
      heterozygosity was frequent in the 12q22-23 chromosome region centromeric to the
      APAF-1 locus suggesting that other tumor-related genes may be present in the
      12q22-23 region. In summary, the study demonstrates that allelic imbalance in the
      12q22-23 region is a genomic surrogate of poor disease outcome for cutaneous
      melanoma patients.

PMID- 15026370
TI  - An evolutionary perspective on single-nucleotide polymorphism screening in
      molecular cancer epidemiology.
AB  - Given that there are millions of single-nucleotide polymorphisms (SNPs) in the
      entire human genome, a major difficulty faced by scientists in planning costly
      population-based genotyping is to choose target SNPs that are most likely to
      affect phenotypic functions and ultimately contribute to disease development.
      Although it is widely accepted that sequences with important functionality tend
      to be less variable across species because of selective pressure, to what extent
      evolutionary conservation is mirrored by epidemiological outcome has never been
      demonstrated. In this study, we surveyed odds ratios detected for 46 SNPs in 39
      different cancer-related genes from 166 molecular epidemiological studies. The
      conservation levels of amino acid that these SNPs affected were calculated as a
      tolerance index by comparing sequences from different species. Our results
      provide evidence of a significant relationship between the detected odds ratios
      associated with cancer risk and the conservation levels of the SNP-affected amino
      acids (P = 0.002; R(2) = 0.06). Tolerance indices were further calculated for 355
      nonsynonymous SNPs identified in 90 human DNA repair genes, of which 103 caused
      amino acid changes in very conserved positions. Our findings support the concept
      that SNPs altering the conserved amino acids are more likely to be associated
      with cancer susceptibility. Using such a molecular evolutionary approach may hold
      great promise for prioritizing SNPs to be genotyped in future molecular
      epidemiological studies.

PMID- 15026371
TI  - Impact of types of lymphocyte chromosomal aberrations on human cancer risk:
      results from Nordic and Italian cohorts.
AB  - The frequency of cells with structural chromosomal aberrations (CAs) in
      peripheral blood lymphocytes is the first genotoxicity biomarker that has shown
      an association with cancer risk. CAs are usually divided into chromosome-type
      (CSAs) and chromatid-type aberrations (CTAs), with different mechanisms of
      formation. From a mechanistic point of view, it is of interest to clarify whether
      the cancer predictivity of CAs is different with respect to CSAs and CTAs. We
      report here cancer risk for cytogenetically tested, healthy subjects with respect
      to frequency of CAs, CSAs, and CTAs in peripheral blood lymphocytes, using Nordic
      (1981 subjects with CA data, 1871 subjects with CSA/CTA data) and Italian (1573
      subjects with CA data, 877 subjects with CTA/CSA data) cohorts, with a median
      follow-up of 17 years. High levels of CAs at test were clearly associated with
      increased total cancer incidence in the Nordic cohorts and increased total cancer
      mortality in the Italian cohort. In the Nordic cohorts, significantly elevated
      cancer risks were observed for subjects with both high CSAs and high CTAs at
      test, and these variables showed equally strong cancer predictivity. The results
      of the Italian cohort did not indicate any clear-cut difference in cancer
      predictivity between the CSA and CTA biomarkers. There was no significant effect
      modification by age at test, gender, country, or time since test. The results
      suggest that both DNA double-strand breaks and other initial DNA lesions
      responsible for CSAs and CTAs are associated with cancer risk.

PMID- 15026372
TI  - Characterization of the t(14;18) BCL2-IGH translocation in farmers occupationally
      exposed to pesticides.
AB  - Increasing incidence of non-Hodgkin's lymphoma have been associated repeatedly
      with farming occupation and particular attention focused on the role of pesticide
      exposure to potentially explain part of this trend. A genetic hallmark of non
      Hodgkin's lymphoma is the presence of recurrent chromosomal translocations
      involving the immunoglobulin heavy chain gene. Of these, the t(14;18), which
      deregulates BCL2 expression and inhibits apoptosis, is the most frequent in
      follicular lymphoma and has been detected consistently in peripheral blood
      lymphocytes of healthy individuals. As BCL2-IGH translocation represents an early
      step of the malignant process, we evaluated the occurrence and molecular
      characteristics of BCL2-IGH translocation in 56 individuals occupationally
      exposed to pesticides in open field farming They were selected from a
      representative cohort of farmers with a well-defined assessment of pesticide
      exposure taking into account potential confounding factors, smoking, sunlight,
      and age. Our results suggest that occupational exposure to pesticides would
      increase BCL2-IGH prevalence together with the frequency of BCL2-IGH-bearing
      cells especially during the high pesticide use period. Distribution of BCL2 or
      IGH breakpoint positions seemed to be independent of pesticide exposure and was
      similar to those found in other healthy populations or lymphoma patients.
      Finally, these results provide additional evidence that BCL2-IGH translocation
      measurements could be a measure of acquired genetic instability in relation to
      genotoxic exposure in a gene directly relevant in term of lymphomagenesis.

PMID- 15026373
TI  - Prostate pathology of genetically engineered mice: definitions and
      classification. The consensus report from the Bar Harbor meeting of the Mouse
      Models of Human Cancer Consortium Prostate Pathology Committee.
AB  - The Pathological Classification of Prostate Lesions in Genetically Engineered
      Mice (GEM) is the result of a directive from the National Cancer Institute Mouse
      Models of Human Cancer Consortium Prostate Steering Committee to provide a
      hierarchical taxonomy of disorders of the mouse prostate to facilitate
      classification of existing and newly created mouse models and the translation to
      human prostate pathology. The proposed Bar Harbor Classification system is the
      culmination of three meetings and workshops attended by various members of the
      Prostate Pathology Committee of the Mouse Models of Human Cancer Consortium. A 2
      day Pathology Workshop was held at The Jackson Laboratory in Bar Harbor, Maine,
      in October 2001, in which study sets of 93 slides from 22 GEM models were
      provided to individual panel members. The comparison of mouse and human prostate
      anatomy and disease demonstrates significant differences and considerable
      similarities that bear on the interpretation of the origin and natural history of
      their diseases. The recommended classification of mouse prostate pathology is
      hierarchical, and includes developmental, inflammatory, benign proliferative, and
      neoplastic disorders. Among the neoplastic disorders, preinvasive, microinvasive,
      and poorly differentiated neoplasms received the most attention. Specific
      criteria were recommended and will be discussed. Transitions between neoplastic
      states were of particular concern. Preinvasive neoplasias of the mouse prostate
      were recognized as focal, atypical, and progressive lesions. These lesions were
      designated as mouse prostatic intraepithelial neoplasia (mPIN). Some atypical
      lesions were identified in mouse models without evidence of progression to
      malignancy. The panel recommended that mPIN lesions not be given histological
      grades, but that mPIN be further classified as to the absence or presence of
      documented associated progression to invasive carcinoma. Criteria for recognizing
      microinvasion, for classification of invasive gland-forming adenocarcinomas, and
      for characterizing poorly differentiated tumors, including neuroendocrine
      carcinomas, were developed and are discussed. The uniform application of defined
      terminology is essential for correlating results between different laboratories
      and models. It is recommended that investigators use the Bar Harbor
      Classification system when characterizing new GEM models or when conducting
      experimental interventions that may alter the phenotype or natural history of
      lesion progression in existing models.

PMID- 15026374
TI  - Obesity: the new worldwide epidemic threat to general health and our complete
      lack of effective treatment.

PMID- 15026375
TI  - Human embryonic stem cells assemble and fulfill their developmental destiny.

PMID- 15026376
TI  - Hormone resistance: it's SMRT to fight repression.

PMID- 15026377
TI  - Endocrine-related resources from the National Institutes of Health.

PMID- 15026378
TI  - National Hormone Peptide Program (NHPP): new recombinant hormones, hypothalamic
      peptides, natural hormones, new antisera, expanded hormone assay services
      available.

PMID- 15026379
TI  - Scientists take aim at angiogenesis to treat degenerative eye diseases.

PMID- 15026380
TI  - Efforts needed to foster participation of blacks in stroke studies.

PMID- 15026388
TI  - ApoA-1 Milano and regression of atherosclerosis.

PMID- 15026389
TI  - ApoA-1 Milano and regression of atherosclerosis.

PMID- 15026390
TI  - Whole-body imaging for cancer staging.

PMID- 15026391
TI  - Relationship between patient mortality and nurses' level of education.

PMID- 15026392
TI  - Relationship between patient mortality and nurses' level of education.

PMID- 15026393
TI  - Relationship between patient mortality and nurses' level of education.

PMID- 15026394
TI  - Relationship between patient mortality and nurses' level of education.

PMID- 15026395
TI  - Relationship between patient mortality and nurses' level of education.

PMID- 15026396
TI  - Relationship between patient mortality and nurses' level of education.

PMID- 15026397
TI  - Echinacea for treating colds in children.

PMID- 15026398
TI  - Echinacea for treating colds in children.

PMID- 15026399
TI  - Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy.
AB  - CONTEXT: Salvage radiotherapy may potentially cure patients with disease
      recurrence after radical prostatectomy, but previous evidence has suggested that
      it is ineffective in patients at the highest risk of metastatic disease
      progression. OBJECTIVE: To delineate patients who may benefit from salvage
      radiotherapy for prostate cancer recurrence by identifying variables associated
      with a durable response. DESIGN, SETTING, AND PATIENTS: Retrospective review of a
      cohort of 501 patients at 5 US academic tertiary referral centers who received
      salvage radiotherapy between June 1987 and November 2002 for detectable and
      increasing prostate-specific antigen (PSA) levels after radical prostatectomy.
      MAIN OUTCOME MEASURE: Disease progression after salvage radiotherapy, defined as
      a serum PSA value > or =0.1 ng/mL above the postradiotherapy PSA nadir confirmed
      by a second PSA measurement that was higher than the first by any amount, by a
      continued increase in PSA level after treatment, or by the initiation of androgen
      deprivation therapy after treatment. RESULTS: Over a median follow-up of 45
      months, 250 patients (50%) experienced disease progression after treatment, 49
      (10%) developed distant metastases, 20 (4%) died from prostate cancer, and 21
      (4%) died from other or unknown causes. The 4-year progression-free probability
      (PFP) was 45% (95% confidence interval [CI], 40%-50%). By multivariable analysis,
      predictors of progression were Gleason score of 8 to 10 (hazard ratio [HR], 2.6;
      95% CI, 1.7-4.1; P<.001), preradiotherapy PSA level greater than 2.0 ng/mL (HR,
      2.3; 95% CI, 1.7-3.2; P<.001), negative surgical margins (HR, 1.9; 95% CI, 1.4
      2.5; P<.001), PSA doubling time (PSADT) of 10 months or less (HR, 1.7; 95% CI,
      1.2-2.2; P =.001), and seminal vesicle invasion (HR, 1.4; 95% CI, 1.1-1.9; P
      =.02). Patients with no adverse features had a 4-year PFP of 77% (95% CI, 64%
      91%). When treatment was given for early recurrence (PSA level < or =2.0 ng/mL),
      patients with Gleason scores of 4 to 7 and a rapid PSADT had a 4-year PFP of 64%
      (95% CI, 51%-76%) and of 22% (95% CI, 6%-38%) when the surgical margins were
      positive and negative, respectively. Patients with Gleason scores of 8 to 10,
      positive margins, and receiving early salvage radiotherapy had a 4-year PFP of
      81% (95% CI, 57%-100%) when the PSADT was longer than 10 months and of 37% (95%
      CI, 16%-58%) when the PSADT was 10 months or less. CONCLUSIONS: Gleason score,
      preradiotherapy PSA level, surgical margins, PSADT, and seminal vesicle invasion
      are prognostic variables for a durable response to salvage radiotherapy. Selected
      patients with high-grade disease and/or a rapid PSADT who were previously thought
      to be destined to develop progressive metastatic disease may achieve a durable
      response to salvage radiotherapy.

PMID- 15026400
TI  - Patient-controlled transdermal fentanyl hydrochloride vs intravenous morphine
      pump for postoperative pain: a randomized controlled trial.
AB  - CONTEXT: Patient-controlled analgesia (PCA) with morphine is commonly used to
      provide acute postoperative pain control after major surgery. The fentanyl
      hydrochloride patient-controlled transdermal system eliminates the need for
      venous access and complicated programming of pumps. OBJECTIVE: To assess the
      efficacy and safety of an investigational patient-controlled iontophoretic
      transdermal system using fentanyl hydrochloride compared with a standard
      intravenous morphine patient-controlled pump. DESIGN, SETTING, AND PATIENTS:
      Prospective randomized controlled parallel-group trial conducted between
      September 2000 and March 2001 at 33 North American hospitals, enrolling 636 adult
      patients who had just undergone major surgery. INTERVENTIONS: In surgical
      recovery rooms, patients were randomly assigned to intravenous morphine (1-mg
      bolus every 5 minutes; maximum of 10 mg/h) by a patient-controlled analgesia pump
      (n = 320) or iontophoretic fentanyl hydrochloride (40- microg infusion over 10
      minutes) by a patient-controlled transdermal system (n = 316). Supplemental
      analgesia (morphine or fentanyl intravenous boluses) was administered as needed
      before and for the first 3 hours after activation of the PCA treatments. Patients
      then used the PCA treatments without additional analgesics for up to 72 hours.
      MAIN OUTCOME MEASURES: The primary efficacy variable was patient global
      assessment of the method of pain control during the first 24 hours. Additional
      efficacy measures were the proportion of patients discontinuing the study because
      of inadequate analgesia for any reason, patient-reported pain intensity scores on
      a 100-mm visual analog scale (VAS), and patient global assessments at 48 and 72
      hours. Adverse effects were also recorded. RESULTS: Ratings of good or excellent
      after 24 hours of treatment for the method of pain control were given by 73.7% of
      patients (233/316) who used transdermal fentanyl PCA and 76.9% of patients
      (246/320) who used intravenous morphine PCA; treatment difference was -3.2% (95%
      confidence interval, -9.9% to 3.5%; P =.36). Early patient discontinuations
      (25.9% fentanyl vs 25.0% morphine; P =.78) and last pain intensity scores (32.7
      fentanyl vs 31.1 morphine on the VAS; P =.45) were not different between the 2
      treatments. With continued treatment for up to 48 or 72 hours, more than 80% of
      patient assessments in each treatment group were good or excellent. The incidence
      of opioid-related adverse events was similar between the groups. CONCLUSION: An
      investigational PCA transdermal system using iontophoresis to deliver fentanyl
      provided postsurgical pain control equivalent to that of a standard intravenous
      morphine regimen delivered by a PCA pump.

PMID- 15026401
TI  - Cardiovascular prognosis of "masked hypertension" detected by blood pressure self
      measurement in elderly treated hypertensive patients.
AB  - CONTEXT: Blood pressure (BP) measurement in clinicians' offices with a mercury
      sphygmomanometer has numerous drawbacks. In contrast, the use of home BP
      measurement improves measurement precision and reproducibility. However, data
      about its prognostic value are lacking. OBJECTIVE: To assess the prognostic value
      of home vs office BP measurement by general practitioners in a European
      population of elderly patients being treated for hypertension. DESIGN, SETTING,
      AND PARTICIPANTS: Office and home BP and cardiac risk factors were measured at
      baseline in a cohort of 4939 treated hypertensive patients (mean age, 70 [SD,
      6.5] years; 48.9% men) who were recruited and followed up by their usual general
      practitioners without specific recommendations about their management. The cohort
      was then followed up for a mean of 3.2 (SD, 0.5) years. The thresholds defining
      uncontrolled hypertension were at least 140/90 mm Hg for office BP and 135/85 mm
      Hg for home BP. MAIN OUTCOME MEASURES: The primary end point was cardiovascular
      mortality. Secondary end points were total mortality and the combination of
      cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke,
      transient ischemic attack, hospitalization for angina or heart failure,
      percutaneous transluminal coronary angioplasty, or coronary artery bypass graft
      surgery. RESULTS: At the end of follow-up, clinical status was known for 99.9% of
      patients. At least 1 cardiovascular event had occurred in 324 (incidence,
      22.2/1000 patient-years). For BP self-measurement at home, each 10-mm Hg increase
      in systolic BP increased the risk of a cardiovascular event by 17.2% (95%
      confidence interval [CI], 11.0%-23.8%) and each 5-mm Hg increase in diastolic BP
      increased that risk by 11.7% (95% CI, 5.7%-18.1%). Conversely, for the same
      increase in BP observed using office measurement, there was no significant
      increase in the risk of a cardiovascular event. In a multivariable model with
      patients having controlled hypertension (normal home and office BP) as the
      referent, the hazard ratio of cardiovascular events was 1.96 (95% CI, 1.27-3.02)
      in patients with uncontrolled hypertension (high BP with both measurement
      methods), 2.06 (95% CI, 1.22-3.47) in patients with normal office BP and elevated
      home BP, and 1.18 (95% CI, 0.67-2.10) in patients with elevated office BP and
      normal home BP. CONCLUSIONS: Our findings suggest that home BP measurement has a
      better prognostic accuracy than office BP measurement. Blood pressure should
      systematically be measured at home in patients receiving treatment for
      hypertension.

PMID- 15026402
TI  - Prehospital hypertonic saline resuscitation of patients with hypotension and
      severe traumatic brain injury: a randomized controlled trial.
AB  - CONTEXT: Prehospital hypertonic saline (HTS) resuscitation of patients with
      traumatic brain injury (TBI) may increase survival but whether HTS improves
      neurological outcomes is unknown. OBJECTIVE: To determine whether prehospital
      resuscitation with intravenous HTS improves long-term neurological outcome in
      patients with severe TBI compared with resuscitation with conventional fluids.
      DESIGN, SETTING, AND PATIENTS: Double-blind, randomized controlled trial of 229
      patients with TBI who were comatose (Glasgow Coma Scale score, <9) and
      hypotensive (systolic blood pressure, <100 mm Hg). The patients were enrolled
      between December 14, 1998, and April 9, 2002, in Melbourne, Australia.
      INTERVENTIONS: Patients were randomly assigned to receive a rapid intravenous
      infusion of either 250 mL of 7.5% saline (n = 114) or 250 mL of Ringer's lactate
      solution (n = 115; controls) in addition to conventional intravenous fluid and
      resuscitation protocols administered by paramedics. Treatment allocation was
      concealed. MAIN OUTCOME MEASURE: Neurological function at 6 months, measured by
      the extended Glasgow Outcome Score (GOSE). RESULTS: Primary outcomes were
      obtained in 226 (99%) of 229 patients enrolled. Baseline characteristics of the
      groups were equivalent. At hospital admission, the mean serum sodium level was
      149 mEq/L for HTS patients vs 141 mEq/L for controls (P<.001). The proportion of
      patients surviving to hospital discharge was similar in both groups (n = 63 [55%]
      for HTS group and n = 57 [50%] for controls; P =.32); at 6 months, survival rates
      were n = 62 (55%) in the HTS group and n = 53 (47%) in the control group (P
      =.23). At 6 months, the median (interquartile range) GOSE was 5 (3-6) in the HTS
      group vs 5 (5-6) in the control group (P =.45). There was no significant
      difference between the groups in favorable outcomes (moderate disability and good
      outcome survivors [GOSE of 5-8]) (risk ratio, 0.99; 95% confidence interval, 0.76
      1.30; P =.96) or in any other measure of postinjury neurological function.
      CONCLUSION: In this study, patients with hypotension and severe TBI who received
      prehospital resuscitation with HTS had almost identical neurological function 6
      months after injury as patients who received conventional fluid.

PMID- 15026403
TI  - Comprehensive discharge planning with postdischarge support for older patients
      with congestive heart failure: a meta-analysis.
AB  - CONTEXT: Comprehensive discharge planning plus postdischarge support may reduce
      readmission rates for older patients with congestive heart failure (CHF).
      OBJECTIVE: To evaluate the effect of comprehensive discharge planning plus
      postdischarge support on the rate of readmission in patients with CHF, all-cause
      mortality, length of stay (LOS), quality of life (QOL), and medical costs. DATA
      SOURCES: We searched MEDLINE (1966 to October 2003), the Cochrane Clinical Trials
      Register (all years), Social Science Citation Index (1992 to October 2003), and
      other databases for studies that described such an intervention and evaluated its
      effect in patients with CHF. Where possible we also contacted lead investigators
      and experts in the field. STUDY SELECTION: We selected English-language
      publications of randomized clinical trials that described interventions to modify
      hospital discharge for older patients with CHF (mean age > or =55 years),
      delineated clearly defined inpatient and outpatient components, compared efficacy
      with usual care, and reported readmission as the primary outcome. DATA
      EXTRACTION: Two authors independently reviewed each report, assigned quality
      scores, and extracted data for primary and secondary outcomes in an unblinded
      standardized manner. DATA SYNTHESIS: Eighteen studies representing data from 8
      countries randomized 3304 older inpatients with CHF to comprehensive discharge
      planning plus postdischarge support or usual care. During a pooled mean
      observation period of 8 months (range, 3-12 months), fewer intervention patients
      were readmitted compared with controls (555/1590 vs 741/1714, number needed to
      treat = 12; relative risk [RR], 0.75; 95% confidence interval [CI], 0.64-0.88).
      Analysis of studies reporting secondary outcomes found a trend toward lower all
      cause mortality for patients assigned to an intervention compared with usual care
      (RR, 0.87; 95% CI, 0.73-1.03; n = 14 studies), similar initial LOS (mean [SE]:
      8.4 [2.5] vs 8.5 [2.2] days, P =.60; n = 10), greater percentage improvement in
      QOL scores compared with baseline scores (25.7% [95% CI, 11.0%-40.4%] vs 13.5%
      [95% CI, 5.1%-22.0%]; n = 6, P =.01), and similar or lower charges for medical
      care per patient per month for the initial hospital stay, administering the
      intervention, outpatient care, and readmission (-359 dollars [95% CI, -763
      dollars to 45 dollars]; n = 4, P =.10 for non-US trials and -536 dollars [95% CI,
      -956 dollars to -115 dollars]; n = 4, P =.03, for US trials). CONCLUSION:
      Comprehensive discharge planning plus postdischarge support for older patients
      with CHF significantly reduced readmission rates and may improve health outcomes
      such as survival and QOL without increasing costs.

PMID- 15026404
TI  - Evaluation of vaginal complaints.
AB  - CONTEXT: Vaginal symptoms are one of the most common reasons for gynecological
      consultation. Clinicians have traditionally diagnosed vaginal candidiasis,
      bacterial vaginosis, and vaginal trichomoniasis using some combination of
      physical examination, pH, the wet mount, and the whiff test. OBJECTIVES: To
      evaluate the role of the clinical examination and determine the positive and
      negative likelihood ratios (LRs) for the diagnosis of vaginal candidiasis,
      bacterial vaginosis, and vaginal trichomoniasis. DATA SOURCES: Using a structured
      literature review, we abstracted information on sensitivity and specificity for
      symptoms, signs, and office laboratory procedures. We chose published (1966 to
      April 2003) articles that appeared in the MEDLINE database and were indexed under
      the combined search terms of diagnosis with vaginitis, vaginal discharge,
      candidiasis, bacterial vaginosis, and trichomoniasis. STUDY SELECTION: Included
      studies of symptomatic premenopausal women seen in primary care settings. Tests
      were evaluated only if they would provide diagnostic information during the
      office visit and were compared with an acceptable criterion standard. DATA
      EXTRACTION: All 3 authors extracted the data and computed sensitivity and
      specificity from each article independently. The absence of standard definitions
      for symptoms and signs made it impossible to combine results across studies. DATA
      SYNTHESIS: Symptoms alone do not allow clinicians to distinguish confidently
      between the causes of vaginitis. However, a patient's lack of itching makes
      candidiasis less likely (range of LRs, 0.18 [95% confidence interval [CI], 0.05
      0.70] to 0.79 [95% CI, 0.72-0.87]) and lack of perceived odor makes bacterial
      vaginosis unlikely (LR, 0.07 [95% CI, 0.01-0.51]). Similarly, physical
      examination signs are limited in their diagnostic power. The presence of
      inflammatory signs is associated with candidiasis (range of LRs, 2.1 [95% CI, 1.5
      2.8] to 8.4 [95% CI, 2.3-31]). Presence of a "high cheese" odor on examination is
      predictive of bacterial vaginosis (LR, 3.2 [95% CI, 2.1-4.7]) while lack of odor
      is associated with candidiasis (LR, 2.9 [95% CI, 2.4-5.0]). Office laboratory
      tests, particularly microscopy of vaginal discharge, are the most useful way of
      diagnosing these 3 conditions. CONCLUSIONS: The cause of vaginal complaints may
      be easily diagnosed when typical findings appear in microscopy. However, the poor
      performance of individual symptoms, signs, and office laboratory tests often
      makes it problematic to identify the cause of vaginal symptoms.

PMID- 15026405
TI  - Salvage radiotherapy for recurrent prostate cancer: the earlier the better.

PMID- 15026406
TI  - Prehospital care of the multiply injured patient: the challenge of figuring out
      what works.

PMID- 15026407
TI  - JAMA patient page. Vaginal symptoms.

PMID- 15026408
TI  - Distribution, sequence homology, and homing of group I introns among T-even-like
      bacteriophages: evidence for recent transfer of old introns.
AB  - Self-splicing group I introns are being found in an increasing number of
      bacteriophages. Most introns contain an open reading frame coding for a homing
      endo-nuclease that confers mobility to both the intron and the homing
      endonuclease gene (HEG). The frequent occurrence of intron/HEG has raised
      questions whether group I introns are spread via horizontal transfer between
      phage populations. We have determined complete sequences for the known group I
      introns among T-even-like bacteriophages together with sequences of the intron
      containing genes td, nrdB, and nrdD from phages with and without introns. A
      previously uncharacterized phage isolate, U5, is shown to contain all three
      introns, the only phage besides T4 found with a "full set" of these introns.
      Sequence analysis of td and nrdB genes from intron-containing and intronless
      phages provides evidence that recent horizontal transmission of introns has
      occurred among the phages. The fact that several of the HEGs have suffered
      deletions rendering them non-functional implies that the homing endonucleases are
      of no selective advantage to the phage and are rapidly degenerating and probably
      dependent upon frequent horizontal transmissions for maintenance within the phage
      populations. Several of the introns can home to closely related intronless phages
      during mixed infections. However, the efficiency of homing varies and is
      dependent on homology in regions flanking the intron insertion site. The
      occurrence of optional genes flanking the respective intron-containing gene can
      strongly affect the efficiency of homing. These findings give further insight
      into the mechanisms of propagation and evolution of group I introns among the T
      even-like bacteriophages.

PMID- 15026409
TI  - Role of protein-protein interactions during herpes simplex virus type 1
      recombination-dependent replication.
AB  - Recombination-dependent replication is an integral part of the process by which
      double-strand DNA breaks are repaired to maintain genome integrity. It also
      serves as a means to replicate genomic termini. We reported previously on the
      reconstitution of a recombination-dependent replication system using purified
      herpes simplex virus type 1 proteins (Nimonkar A. V., and Boehmer, P. E. (2003)
      Proc. Natl. Acad. Sci. U. S. A. 100, 10201-10206). In this system, homologous
      pairing by the viral single-strand DNA-binding protein (ICP8) is coupled to DNA
      synthesis by the viral DNA polymerase and helicase-primase in the presence of a
      DNA-relaxing enzyme. Here we show that DNA synthesis in this system is dependent
      on the viral polymerase processivity factor (UL42). Moreover, although DNA
      synthesis is strictly dependent on topoisomerase I, it is only stimulated by the
      viral helicase in a manner that requires the helicase-loading protein (UL8).
      Furthermore, we have examined the dependence of DNA synthesis in the viral system
      on species-specific protein-protein interactions. Optimal DNA synthesis was
      observed with the herpes simplex virus type 1 replication proteins, ICP8, DNA
      polymerase (UL30/UL42), and helicase-primase (UL5/UL52/UL8). Interestingly,
      substitution of each component with functional homologues from other systems for
      the most part did not drastically impede DNA synthesis. In contrast,
      recombination-dependent replication promoted by the bacteriophage T7 replisome
      was disrupted by substitution with the replication proteins from herpes simplex
      virus type 1. These results show that although DNA synthesis performed by the T7
      replisome is dependent on cognate protein-protein interactions, such interactions
      are less important in the herpes simplex virus replisome.

PMID- 15026410
TI  - Calpain-dependent endoproteolytic cleavage of PrPSc modulates scrapie prion
      propagation.
AB  - Previous studies using post-mortem human brain extracts demonstrated that PrP in
      Creutzfeldt-Jakob disease (CJD) brains is cleaved by a cellular protease to
      generate a C-terminal fragment, referred to as C2, which has the same molecular
      weight as PrP-(27-30), the protease-resistant core of PrP(Sc) (1). The role of
      this endoproteolytic cleavage of PrP in prion pathogenesis and the identity of
      the cellular protease responsible for production of the C2 cleavage product has
      not been explored. To address these issues we have taken a combination of
      pharmacological and genetic approaches using persistently infected scrapie mouse
      brain (SMB) cells. We confirm that production of C2 is the predominant cleavage
      event of PrP(Sc) in the brains of scrapie-infected mice and that SMB cells
      faithfully recapitulate the diverse intracellular proteolytic processing events
      of PrP(Sc) and PrP(C) observed in vivo. While increases in intracellular calcium
      (Ca(2+)) levels in prion-infected cell cultures stimulate the production of the
      PrP(Sc) cleavage product, pharmacological inhibitors of calpains and
      overexpression of the endogenous calpain inhibitor, calpastatin, prevent the
      production of C2. In contrast, inhibitors of lysosomal proteases, caspases, and
      the proteasome have no effect on C2 production in SMB cells. Calpain inhibition
      also prevents the accumulation of PrP(Sc) in SMB and persistently infected ScN2A
      cells, whereas bioassay of inhibitor-treated cell cultures demonstrates that
      calpain inhibition results in reduced prion titers compared with control-treated
      cultures assessed in parallel. Our observations suggest that calpain-mediated
      endoproteolytic cleavage of PrP(Sc) may be an important event in prion
      propagation.

PMID- 15026411
TI  - Roles of heme axial ligands in the regulation of CO binding to CooA.
AB  - CooA is a CO-dependent transcription factor of the bacterium Rhodospirillum
      rubrum that contains a six-coordinate heme. It has as its heme axial ligands
      Pro(2) and Cys(75) in the ferric state and Pro(2) and His(77) in the ferrous
      state. To probe the regulation of CO binding and the ligand switching mechanism
      in CooA, we have prepared site-directed mutants in which the residues
      contributing the axial ligands are substituted. The properties of these mutants
      were investigated by resonance Raman and CO titration methods. Wild-type CooA
      binds CO with a modest dissociation constant (K(d)) of 11 microm, this value
      being typical for gas-sensing heme proteins. The K(d) value was greatly decreased
      in the P2H mutant, indicating that Pro(2) coordination fine tunes CO sensing in
      CooA. The bound CO in P2H gives rise to a nu(Fe-CO) stretching Raman line at 490
      cm(-1), which is similar to that in wild-type CooA. Thus, Pro(2) is the ligand
      that is replaced by exogenous CO. In the H77A mutant, equilibrium CO binding is
      biphasic, and at high CO pressures two CO molecules occupy both axial sites. The
      nu(Fe-CO) stretching Raman line for the first CO molecule was observed at 497 cm(
      1). Some of the His(77) mutants showed an additional nu(Fe-CO) line at 525 cm(
      1). The binding affinity of the second CO molecule correlates with the five
      coordinate component in the ferrous His(77) mutants and also with the acidity of
      the side chain at position 77. Thus, we propose the Cys(75)-His(77) ligand switch
      is controlled by His(77) acting as a proton reservoir.

PMID- 15026412
TI  - Epidermal growth factor-mediated T-cell factor/lymphoid enhancer factor
      transcriptional activity is essential but not sufficient for cell cycle
      progression in nontransformed mammary epithelial cells.
AB  - Because beta-catenin target genes such as cyclin D1 are involved in cell cycle
      progression, we examined whether beta-catenin has a more pervasive role in normal
      cell proliferation, even upon stimulation by non-Wnt ligands. Here, we
      demonstrate that epidermal growth factor (EGF) stimulates T-cell factor/lymphoid
      enhancer factor (Tcf/Lef) transcriptional activity in nontransformed mammary
      epithelial cells (MCF-10A) and that its transcriptional activity is essential for
      EGF-mediated progression through G1/S phase. Thus, expression of dominant
      negative Tcf4 blocks EGF-mediated Tcf/Lef transcriptional activity and
      bromodeoxyuridine uptake. In fact, the importance of EGF-mediated Tcf/Lef
      transcriptional activity for cell cycle progression may lie further upstream at
      the G1/S phase transition. We demonstrate that dominant-negative Tcf4 inhibits a
      reporter of cyclin D1 promoter activity in a dose-dependent manner. Importantly,
      dominant-negative Tcf4 suppresses EGF-mediated cell cycle activity specifically
      by thwarting EGF-mediated Tcf/Lef transcriptional activity, not by broader
      effects on EGF signaling. Thus, although expression of dominant-negative Tcf4
      blocks EGF-mediated TOPFLASH activation, it has no effect on either EGF receptor
      or ERK phosphorylation, further underscoring the fact that Tcf/Lef-mediated
      transcription is essential for cell cycle progression, even when other pro
      mitogenic signals are at normal levels. Yet, despite its essential role, Tcf/Lef
      transcriptional activity alone is not sufficient for cell cycle progression.
      Serum also stimulates Tcf/Lef transcriptional activation in MCF-10A cells but is
      unable to promote DNA synthesis. Taken together, our data support a model wherein
      EGF promotes Tcf/Lef transcriptional activity, and this signal is essential but
      not sufficient for cell cycle activity.

PMID- 15026413
TI  - Beta-synuclein regulates Akt activity in neuronal cells. A possible mechanism for
      neuroprotection in Parkinson's disease.
AB  - Recent studies have shown that the neurodegenerative process in disorders with
      Lewy body formation, such as Parkinson's disease and dementia with Lewy bodies,
      is associated with alpha-synuclein accumulation and that beta-synuclein might
      protect the central nervous system from the neurotoxic effects of alpha
      synuclein. However, the mechanisms are unclear. The main objective of the present
      study was to investigate the potential involvement of the serine threonine kinase
      Akt (also known as protein kinase B) signaling pathway in the mechanisms of beta
      synuclein neuroprotection. For this purpose, Akt activity and cell survival were
      analyzed in synuclein-transfected B103 neuroblastoma cells and primary cortical
      neurons. Beta-synuclein transfection resulted in increased Akt activity and
      conferred protection from the neurotoxic effects of rotenone. Down-regulation of
      Akt expression resulted in an increased susceptibility to rotenone toxicity,
      whereas transfection with a lentiviral vector encoding for beta-synuclein was
      protective. The effects of beta-synuclein on the Akt pathway appear to be by
      direct interaction between these molecules and were independent of upstream
      signaling molecules. Taken together, these results indicate that the mechanisms
      of beta-synuclein neuroprotection might involve direct interactions between beta
      synuclein and Akt and suggest that this signaling pathway could be a potential
      therapeutic target for neurological conditions associated with parkinsonism and
      alpha-synuclein aggregation.

PMID- 15026414
TI  - Inhibition of NFkappaB increases the efficacy of cisplatin in in vitro and in
      vivo ovarian cancer models.
AB  - Whether or not inhibition of NFkappaB increases the efficacy of cisplatin in in
      vitro and in vivo ovarian cancer models was investigated. We compared the basal
      levels of phosphorylation of IkappaBalpha and activity of NFkappaB between
      cisplatin-sensitive A2780 cells and cisplatin-resistant Caov-3 cells. The basal
      levels of phosphorylation of IkappaBalpha and activity of NFkappaB in Caov-3
      cells were significantly higher than those in A2780 cells. Cisplatin caused a
      more marked decrease in the phosphorylation of IkappaBalpha and activity of
      NFkappaB in A2780 cells than in Caov-3 cells. Thus, high basal levels of
      phosphorylation of IkappaBalpha and activation of NFkappaB and less marked
      inhibition of the phosphorylation of IkappaBalpha and activation of NFkappaB by
      cisplatin seem to reduce the sensitivity of cells to cisplatin. Inhibition of
      NFkappaB activity either by treatment with the IkappaBalpha phosphorylation
      inhibitor (BAY 11-7085) or a specific NFkappaB nuclear translocation inhibitor
      (SN-50) or by transfection of p50DeltaNLS (which lacks the nuclear localization
      signal domain) increased the efficacy of both the cisplatin-induced attenuation
      of IkappaBalpha phosphorylation and NFkappaB activity and the cisplatin-induced
      apoptosis. In addition, treatment with BAY 11-7085 increased the efficacy of the
      cisplatin-induced attenuation of both the expression of X-linked inhibitor of
      apoptosis protein (XIAP) and cell invasion through Matrigel. Moreover, treatment
      with BAY 11-7085 increased the efficacy of the cisplatin-induced inhibition of
      the intra-abdominal dissemination and production of ascites using athymic nude
      mice inoculated intraperitoneally with Caov-3 cells. These results suggest that
      combination therapy of cisplatin with the NFkappaB inhibitor should increase the
      therapeutic efficacy of cisplatin.

PMID- 15026415
TI  - Distribution and transport of cholesterol-rich membrane domains monitored by a
      membrane-impermeant fluorescent polyethylene glycol-derivatized cholesterol.
AB  - Cholesterol-rich membrane domains function in various membrane events as diverse
      as signal transduction and membrane traffic. We studied the interaction of a
      fluorescein ester of polyethylene glycol-derivatized cholesterol (fPEG-Chol) with
      cholesterol-rich membranes both in cells and in model membranes. Unlike filipin
      and other cholesterol probes, this molecule could be applied as an aqueous
      dispersion to various samples. When added to live cells, fPEG-Chol distributed
      exclusively in the outer plasma membrane leaflet and was enriched in microdomains
      that dynamically clustered by the activation of receptor signaling. The surface
      bound fPEG-Chol was slowly internalized via clathrin-independent pathway into
      endosomes together with lipid raft markers. Noteworthy, fPEG-Chol could be
      microinjected in the living cells in which we found Golgi apparatus as the sole
      major organelle to be labeled. PEG-Chol, thus, provides a novel, sensitive probe
      for unraveling the dynamics of cholesterol-rich microdomains in living cells.

PMID- 15026416
TI  - Linkage between Werner syndrome protein and the Mre11 complex via Nbs1.
AB  - The Werner syndrome and the Nijmegen breakage syndrome are recessive genetic
      disorders that show increased genomic instability, cancer predisposition,
      hypersensitivity to mitomycin C and gamma-irradiation, shortened telomeres, and
      cell cycle defects. The protein mutated in the premature aging disease known as
      the Werner syndrome is designated WRN and is a member of the RecQ helicase
      family. The Nbs1 protein is mutated in Nijmegen breakage syndrome individuals and
      is part of the mammalian Mre11 complex together with the Mre11 and Rad50
      proteins. Here, we show that WRN associates with the Mre11 complex via binding to
      Nbs1 in vitro and in vivo. In response to gamma-irradiation or mitomycin C, WRN
      leaves the nucleoli and co-localizes with the Mre11 complex in the nucleoplasm.
      We detect an increased association between WRN and the Mre11 complex after
      cellular exposure to gamma-irradiation. Small interfering RNA and complementation
      experiments demonstrated convergence of WRN and Nbs1 in response to gamma
      irradiation or mitomycin C. Nbs1 is required for the Mre11 complex promotion of
      WRN helicase activity. Taken together, these results demonstrate a functional
      link between the two genetic diseases with partially overlapping phenotypes in a
      pathway that responds to DNA double strand breaks and interstrand cross-links.

PMID- 15026417
TI  - The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth
      factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration.
AB  - Previous studies have shown that the adaptor protein Shb is involved in receptor
      tyrosine kinase signaling. In this study, we demonstrate that Shb is
      phosphorylated in an Src-dependent manner upon vascular endothelial growth factor
      (VEGF) stimulation using porcine aortic endothelial cells expressing the human
      VEGF receptor 2 (VEGFR-2) (KDR). In co-immunoprecipitation experiments, we could
      detect an interaction between Shb and the VEGFR-2 in human telomerase
      immortalized microvascular endothelial cells. Furthermore, in a glutathione S
      transferase pull-down assay, the Src homology 2 domain of Shb was shown to
      interact with phosphorylated tyrosine 1175 in the C-terminal tail of VEGFR-2.
      VEGF-induced Shb phosphorylation was lost in porcine aortic endothelial cells
      expressing a chimeric murine VEGFR-2 (Flk-1) with a mutation at the corresponding
      position. Shb expression was specifically decreased by 80%, in a transient
      manner, by using the short interfering RNA technique. Reduced Shb expression led
      to a loss of stimulation of phosphatidylinositol 3-kinase, phosphorylation of
      focal adhesion kinase at tyrosine 576, the generation of focal adhesions, and
      stress fiber formation in response to VEGF. Furthermore, we show that VEGF
      induced migration is inhibited in Shb short interfering RNA-treated cells. Our
      data demonstrate that Shb is important for VEGF signaling in endothelial cells.
      This is achieved by Shb binding to tyrosine 1175 in the VEGFR-2, which regulates
      VEGF-induced formation of focal adhesions and cell migration, of which the latter
      occurs in a phosphatidylinositol 3-kinase-dependent manner.

PMID- 15026418
TI  - Initial events in the photocycle of photoactive yellow protein.
AB  - The light-induced isomerization of a double bond is the key event that allows the
      conversion of light energy into a structural change in photoactive proteins for
      many light-mediated biological processes, such as vision, photosynthesis,
      photomorphogenesis, and photo movement. Cofactors such as retinals, linear
      tetrapyrroles, and 4-hydroxy-cinnamic acid have been selected by nature that
      provide the essential double bond to transduce the light signal into a
      conformational change and eventually, a physiological response. Here we report
      the first events after light excitation of the latter chromophore, containing a
      single ethylene double bond, in a low temperature crystallographic study of the
      photoactive yellow protein. We measured experimental phases to overcome possible
      model bias, corrected for minimized radiation damage, and measured absorption
      spectra of crystals to analyze the photoproducts formed. The data show a
      mechanism for the light activation of photoactive yellow protein, where the
      energy to drive the remainder of the conformational changes is stored in a
      slightly strained but fully cis-chromophore configuration. In addition, our data
      indicate a role for backbone rearrangements during the very early structural
      events.

PMID- 15026419
TI  - Identification of a novel rat microsomal vitamin D3 25-hydroxylase.
AB  - Vitamin D3 requires the 25-hydroxylation in the liver and the subsequent 1alpha
      hydroxylation in the kidney to exert its biological activity. Vitamin D3 25
      hydroxylation is hence an essential modification step for vitamin D3 activation.
      Until now, three cytochrome P450 molecular species (CYP27A1, CYP2C11, and
      CYP2D25) have been characterized well as vitamin D3 25-hydroxylases. However,
      their physiological role remains unclear because of their broad substrate
      specificities and low activities toward vitamin D3 relative to other substrates.
      In this study, we purified vitamin D3 25-hydroxylase from female rat liver
      microsomes. The activities of the purified fraction toward vitamin D3 and 1alpha
      hydroxyvitamin D3 were 1.1 and 13 nmol/min/nmol of P450, respectively. The
      purified fraction showed a few protein bands in a 50-60-kDa range on SDS-PAGE,
      typical for a cytochrome P450. The tryptic peptide mass fingerprinting of a
      protein band (56 kDa) with matrix-assisted laser desorption ionization/time of
      flight mass spectrometry identified this band as CYP2J3. CYP2J3 was
      heterologously expressed in Escherichia coli. Purified recombinant CYP2J3 showed
      strong 25-hydroxylation activities toward vitamin D3 and 1alpha-hydroxyvitamin D3
      with turnover numbers of 3.3 and 22, respectively, which were markedly higher
      than those of P450s previously characterized as 25-hydroxylases. Quantitative PCR
      analysis showed that CYP2J3 mRNA is expressed at a level similar to that of
      CYP27A1 without marked sexual dimorphism. These results strongly suggest that
      CYP2J3 is the principal P450 responsible for vitamin D3 25-hydroxylation in rat
      liver.

PMID- 15026420
TI  - Stimulation of capacitative calcium entry in HL-60 cells by nanosecond pulsed
      electric fields.
AB  - Nanosecond pulsed electric fields (nsPEFs) are hypothesized to affect
      intracellular structures in living cells providing a new means to modulate cell
      signal transduction mechanisms. The effects of nsPEFs on the release of internal
      calcium and activation of calcium influx in HL-60 cells were investigated by
      using real time fluorescent microscopy with Fluo-3 and fluorometry with Fura-2.
      nsPEFs induced an increase in intracellular calcium levels that was seen in all
      cells. With pulses of 60 ns duration and electric fields between 4 and 15 kV/cm,
      intracellular calcium increased 200-700 nM, respectively, above basal levels
      (approximately 100 nM), while the uptake of propidium iodide was absent. This
      suggests that increases in intracellular calcium were not because of plasma
      membrane electroporation. nsPEF and the purinergic agonist UTP induced calcium
      mobilization in the presence and absence of extracellular calcium with similar
      kinetics and appeared to target the same inositol 1,4,5-trisphosphate- and
      thapsigargin-sensitive calcium pools in the endoplasmic reticulum. For cells
      exposed to either nsPEF or UTP in the absence of extracellular calcium, there was
      an electric field-dependent or UTP dose-dependent increase in capacitative
      calcium entry when calcium was added to the extracellular media. These findings
      suggest that nsPEFs, like ligand-mediated responses, release calcium from similar
      internal calcium pools and thus activate plasma membrane calcium influx channels
      or capacitative calcium entry.

PMID- 15026421
TI  - Functional analysis of the combined role of the O-linked branching enzyme core 2
      beta1-6-N-glucosaminyltransferase and dimerization of P-selectin glycoprotein
      ligand-1 in rolling on P-selectin.
AB  - Leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) is expressed as a homodimer
      and mediates leukocyte rolling through interactions with endothelial P-selectin.
      Previous studies have shown that PSGL-1 must be properly modified by specific
      glycosyltransferases including alpha1,3-fucosyltransferase-VII, core 2 beta1-6-N
      glucosaminyltransferase (C2GlcNAcT-I), one or more alpha2,3-sialytransferases,
      and a tyrosulfotransferase. In addition, dimerization of PSGL-1 through its sole
      extracellular cysteine (Cys(320)) is essential for rolling on P-selectin under
      shear conditions. In this report, we measured the contributions of both C2GlcNAcT
      I glycosylation and dimerization of PSGL-1 to adhesive bonds formed during
      tethering and rolling of transfected cell lines on purified P-selectin. Tethering
      to P-selectin under flow increased with dimerization compared with cells
      expressing monomeric PSGL-1 (referred to as C320A). The rolling defects
      (decreased cellular accumulation, PSGL-1/P-selectin bond strengths and tethering
      rates, and increased velocities and skip distance) demonstrated by transfectants
      expressing monomeric PSGL-1 could be overcome by increasing the substrate P
      selectin site density and by overexpressing C2GlcNAcT-I in C320A transfectants.
      Two molecular weight variants of PSGL-1 were isolated from cell lines transfected
      with PSGL-1, C320A, and/or C2GlcNAcT-I cDNAs, and these differences in
      electrophoretic mobility appeared to correlate with C2GlcNAcT-I expression. C320A
      transfectants expressing low molecular weight PSGL-1 had lower C2GlcNAcT-I levels
      (measured by reactivity to core 2 specific linkage antibody, CHO-131) and
      compromised rolling on P-selectin (regardless of site density) compared with
      C320A cells with high levels of C2GlcNAcT-I and high molecular weight PSGL-1.
      Both C2GlcNAcT-I glycosylation and PSGL-1 dimerization increased the rate of
      tethering to P-selectin under flow, whereas C2GlcNAcT-I levels primarily
      influenced tether bond strength.

PMID- 15026423
TI  - Molecular structure of human galactose mutarotase.
AB  - Galactose mutarotase catalyzes the conversion of beta-d-galactose to alpha-d
      galactose during normal galactose metabolism. The enzyme has been isolated from
      bacteria, plants, and animals and is present in the cytoplasm of most cells. Here
      we report the x-ray crystallographic analysis of human galactose mutarotase both
      in the apoform and complexed with its substrate, beta-d-galactose. The
      polypeptide chain folds into an intricate array of 29 beta-strands, 25 classical
      reverse turns, and 2 small alpha-helices. There are two cis-peptide bonds at Arg
      78 and Pro-103. The sugar ligand sits in a shallow cleft and is surrounded by Asn
      81, Arg-82, His-107, His-176, Asp-243, Gln-279, and Glu-307. Both the side chains
      of Glu-307 and His-176 are in the proper location to act as a catalytic base and
      a catalytic acid, respectively. These residues are absolutely conserved among
      galactose mutarotases. To date, x-ray models for three mutarotases have now been
      reported, namely that described here and those from Lactococcus lactis and
      Caenorhabditis elegans. The molecular architectures of these enzymes differ
      primarily in the loop regions connecting the first two beta-strands. In the human
      protein, there are six extra residues in the loop compared with the bacterial
      protein for an approximate longer length of 9 A. In the C. elegans protein, the
      first 17 residues are missing, thereby reducing the total number of beta-strands
      by one.

PMID- 15026422
TI  - A shear-restricted pathway of platelet procoagulant activity is regulated by
      IQGAP1.
AB  - Circulating blood platelets regulate the initial phase of the hemostatic response
      through adhesive and aggregatory events and by providing the necessary
      procoagulant surface for prothrombinase complex assembly and thrombin generation.
      The signaling pathway(s) that regulate platelet procoagulant activity are largely
      unknown, although they are distinct from platelet aggregatory signals linked to
      fibrinogen ligation to the conformationally active alpha(IIB)beta(3) integrin. We
      describe a novel intracellular signaling mechanism involving platelet IQGAP1 that
      specifically regulates the development of platelet procoagulant activity under
      conditions of mechanical shear stress. Murine platelets that are deficient in
      IQGAP1 demonstrate increased prothrombinase activity compared with wild-type
      littermate controls when activated by a physiological shear stress of 16
      dynes/cm(2) (shear rates of 1600 s(-1)) (p < 0.0001), corresponding to
      approximately 2.5 times the normal shear stress, or approximately 40% degree of
      stenosis in coronary arteries. The exaggerated prothrombinase activity is not
      associated with enhanced platelet microvesiculation (cytoskeletal proteolysis)
      and occurs independently of the intracellular calcium release, [Ca(2+)](i), but
      it is specifically coupled to the alpha-granule exocytic pathway without
      concomitant effects on aminophospholipid exposure. These observations identify
      platelet IQGAP1 as an important modulator of normal hemostasis and as an
      appropriate pharmacological target for control of platelet procoagulant function.

PMID- 15026424
TI  - A Bacillus thuringiensis crystal protein with selective cytocidal action to human
      cells.
AB  - Bacillus thuringiensis crystal proteins, well known to be toxic to certain
      insects but not pathogenic to mammals, are used as insecticidal proteins in
      agriculture and forest management. We here identified a crystal protein that is
      non-insecticidal and non-hemolytic but has strong cytocidal activity against
      various human cells with a markedly divergent target specificity, e.g. highly
      cytotoxic to HepG2 and Jurkat and less cytotoxic to the normal hepatocyte (HC)
      and HeLa. In slices of liver and colon cancer tissues, the toxin protein
      preferentially killed the cancer cells, leaving other cells unaffected. The
      cytocidal effect of the protein is non-apoptotic with swelling and fragmentation
      of the susceptible cells, although the apoptotic process does occur when the cell
      damage proceeded slowly. The amino acid sequence deduced from the nucleotide
      sequence of the cloned gene of the protein has little sequence homology with the
      insecticidal crystal proteins of B. thuringiensis. These observations raise the
      presence of a new group of the B. thuringiensis toxin and the possibility of new
      applications for the protein in the medical field.

PMID- 15026425
TI  - Differential regulation of cytosolic and peroxisomal bile acid amidation by PPAR
      alpha activation favors the formation of unconjugated bile acids.
AB  - In human liver, unconjugated bile acids can be formed by the action of bile acid
      CoA thioesterases (BACTEs), whereas bile acid conjugation with taurine or glycine
      (amidation) is catalyzed by bile acid-CoA:amino acid N-acyltransferases (BACATs).
      Both pathways exist in peroxisomes and cytosol. Bile acid amidation facilitates
      biliary excretion, whereas the accumulation of unconjugated bile acids may become
      hepatotoxic. We hypothesized that the formation of unconjugated and conjugated
      bile acids from their common substrate bile acid-CoA thioesters by BACTE and
      BACAT is regulated via the peroxisome proliferator-activated receptor alpha
      (PPARalpha). Livers from wild-type and PPARalpha-null mice either untreated or
      treated with the PPARalpha activator WY-14,643 were analyzed for BACTE and BACAT
      expression. The total liver capacity of taurochenodeoxycholate and taurocholate
      formation was decreased in WY-14,643-treated wild-type mice by 60% and 40%,
      respectively, but not in PPARalpha-null mice. Suppression of the peroxisomal
      BACAT activity was responsible for the decrease in liver capacity, whereas
      cytosolic BACAT activity was essentially unchanged by the treatment. In both
      cytosol and peroxisomes, the BACTE activities and protein levels were upregulated
      5- to 10-fold by the treatment. These effects caused by WY-14,643 treatment were
      abolished in PPARalpha-null mice. The results from this study suggest that an
      increased formation of unconjugated bile acids occurs during PPARalpha
      activation.

PMID- 15026426
TI  - Surfactant lipid peroxidation damages surfactant protein A and inhibits
      interactions with phospholipid vesicles.
AB  - The goal of these studies was to examine the effect of lipid peroxidation (LPO)
      on the function of surfactant protein A (SP-A). First, the optimal dialysis
      conditions for quantitative removal of EDTA and redoxactive metals from reagents
      were established. Surfactant phospholipids were incubated with free radical
      generators in the absence or presence of the SP-A or with BSA as a control. We
      found that SP-A inhibited copper-initiated LPO to an extent similar to BSA (P <
      0.05). Exposure of SP-A to LPO was associated with an increase in the level of SP
      A-associated carbonyl moieties and a marked reduction in SP-A-mediated
      aggregation of liposomes. LPO initiated by an azo-compound also resulted in
      enhanced protein oxidation and markedly inhibited SP-A-mediated liposome
      aggregation. The kinetics of aggregation of auto-oxidized and nonoxidized
      liposomes by nonoxidized SP-A was similar, suggesting that SP-A has similar
      affinities for oxidized and nonoxidized lipids. Oxidative inactivation of SP-A
      did not occur upon direct incubation of the protein with malondialdehyde alone.
      We conclude that exposure of SP-A to LPO results in oxidative modification and
      functional inactivation of SP-A by phospholipid radicals.

PMID- 15026427
TI  - Relationship between cholesteryl ester transfer protein and LDL heterogeneity in
      familial hypercholesterolemia.
AB  - Small, dense LDL particles have been associated with an increased risk of
      coronary artery disease, and cholesteryl ester transfer protein (CETP) has been
      suggested to play a role in LDL particle remodeling. We examined the relationship
      between LDL heterogeneity and plasma CETP mass in familial hypercholesterolemia
      (FH). LDL particles were characterized by polyacrylamide gradient gel
      electrophoresis in a total of 259 FH heterozygotes and 208 nonFH controls. CETP
      mass was measured by enzyme-linked immunosorbent assay in a subgroup of 240
      participants, which included 120 FH patients matched with 120 controls. As
      compared with controls, FH subjects had an 11% higher CETP mass. Moreover, LDL
      peak particle diameter (LDL-PPD) was significantly smaller in FH heterozygotes
      than in controls (258.1 +/- 4.8 vs. 259.2 +/- 4.1 A; P = 0.01) after adjustment
      for covariates. There was also an inverse relationship between LDL-PPD and CETP
      mass (R = -0.15; P = 0.02), and this relationship was abolished by adjustment for
      the FH/control status, indicating that LDL-PPD changes in FH are mediated, at
      least in part, by an increase in plasma CETP mass concentrations. These results
      suggest that increased plasma CETP mass concentrations could lead to significant
      LDL particle remodeling in FH heterozygotes and could contribute to the
      pathogenesis of atherosclerosis.

PMID- 15026429
TI  - Tackling health inequalities since the Acheson inquiry.

PMID- 15026428
TI  - The ATP-binding cassette transporter 1 mediates lipid efflux from Sertoli cells
      and influences male fertility.
AB  - The liver X receptor/retinoid X receptor (LXR/RXR)-regulated gene ABCA1 effluxes
      cellular cholesterol and phospholipid to apolipoprotein A1 (apoA1), which is the
      rate-limiting step in high-density lipoprotein synthesis. The RXR pathway plays a
      critical role in testicular lipid trafficking, and RXRbeta-deficient male mice
      are sterile and accumulate lipids in Sertoli cells. Here, we demonstrate that
      ABCA1 mRNA and protein are abundant in Sertoli cells, whereas germ cells express
      little ABCA1. LXR/RXR agonists stimulate ABCA1 expression in cultured Sertoli
      MSC1 and Leydig TM3 cell lines. However, Sertoli TM4 cells lack ABCA1, and TM4
      cells or primary Sertoli cells cultured from ABCA1(-/-) mice both fail to efflux
      cholesterol to apoA1. Expression of exogenous ABCA1 restores apoA1-dependent
      cholesterol efflux in Sertoli TM4 cells. In vivo, ABCA1-deficient mice exhibit
      lipid accumulation in Sertoli cells and depletion of normal lipid droplets from
      Leydig cells by 2 months of age. By 6 months of age, intratesticular testosterone
      levels and sperm counts are significantly reduced in ABCA1(-/-) mice compared
      with wild-type (WT) controls. Finally, a 21% decrease (P = 0.01) in fertility was
      observed between ABCA1(-/-) males compared with WT controls across their
      reproductive lifespans. These results show that ABCA1 plays an important role in
      lipid transport in Sertoli cells and influences male fertility.

PMID- 15026430
TI  - When I'm 64... will you still need me? Epidemiology in country practice: W H
      Pickles, 1939.

PMID- 15026432
TI  - A definition of causal effect for epidemiological research.
AB  - Estimating the causal effect of some exposure on some outcome is the goal of many
      epidemiological studies. This article reviews a formal definition of causal
      effect for such studies. For simplicity, the main description is restricted to
      dichotomous variables and assumes that no random error attributable to sampling
      variability exists. The appendix provides a discussion of sampling variability
      and a generalisation of this causal theory. The difference between association
      and causation is described-the redundant expression "causal effect" is used
      throughout the article to avoid confusion with a common use of "effect" meaning
      simply statistical association-and shows why, in theory, randomisation allows the
      estimation of causal effects without further assumptions. The article concludes
      with a discussion on the limitations of randomised studies. These limitations are
      the reason why methods for causal inference from observational data are needed.

PMID- 15026435
TI  - Ethnic inequalities in campylobacter infection in Birmingham, UK: descriptive
      study of notified cases.

PMID- 15026434
TI  - An outbreak of gastroenteritis from a non-chlorinated community water supply.
AB  - STUDY OBJECTIVE: To determine the source and the extent of a community wide
      outbreak of gastroenteritis. DESIGN: A matched case-control study with postal
      questionnaires. Subtyping of campylobacter strains by pulsed field gel
      electrophoresis (PFGE). SETTING: A rural municipality with a population of 8600
      in southern Finland, August 2000. Two thirds of the population receive non
      chlorinated ground water from the municipal water supply. PARTICIPANTS: Cases
      were randomly selected among residents of the municipality who contacted the
      municipal health centre because of gastroenteritis and had illness onset between
      31 July and 20 August 2000. Community controls were identified from the
      population registry and matched according to sex, year of birth, and postal code.
      MAIN RESULTS: Four hundred and sixty three persons contacted the municipal health
      centre because of gastroenteritis. Campylobacter jejuni was isolated from stool
      samples of 24 persons. One hundred and thirty seven cases and 388 controls were
      enrolled in the case-control study. In multivariate analysis, drinking unboiled
      water from the municipal supply was significantly associated with illness (odds
      ratio 11.1, 95% confidence interval 1.4 to 90.2). C jejuni was isolated from one
      tap water sample. The water isolate and all but one of the patient isolates were
      indistinguishable by PFGE. CONCLUSIONS: Combining epidemiological investigation
      with molecular subtyping methods provided strong evidence that water was the
      source of the outbreak. Non-chlorinated small ground water systems may be
      susceptible to waterborne outbreaks and constitute a risk to rural populations.

PMID- 15026436
TI  - Is smallpox "in" again?

PMID- 15026437
TI  - Putting public health evidence into practice: increasing the prevalence of
      working smoke alarms in disadvantaged inner city housing.
AB  - STUDY OBJECTIVES: The UK government recommends that local authorities install
      battery operated smoke alarms to prevent fire related injury. However, a
      randomised controlled trial of smoke alarm installation in local authority
      housing found a low level of working alarms at follow up. Qualitative work, which
      accompanied the trial explored barriers and levers to the use of this public
      health intervention. DESIGN: Semi-structured group and individual interviews were
      conducted with a sample of the adult participants in a randomised controlled
      trial of free smoke alarm installation. Group interviews and "draw and write"
      exercises were conducted with children at a local primary school. PARTICIPANTS: A
      sample of trial participants and primary school children in the trial
      neighbourhood. SETTING: An inner city housing estate in central London. MAIN
      RESULTS: The main barrier to smoke alarm use was the distress caused by false
      alarms. Although trial participants considered themselves to be at high risk for
      fires and would recommend smoke alarms to others, respondents' reports on the
      distress caused by false alarms suggest that people balance immediate and longer
      term risks to their health and wellbeing when they disable alarms. CONCLUSIONS:
      This study identified some of the reasons for the low level of functioning smoke
      alarms, and problems experienced with alarms. The results have implications for
      the implementation of this public health intervention. The effectiveness of smoke
      alarm installation could be improved if alarm manufacturers and those responsible
      for implementation programmes considered ways of tackling the issues raised in
      this study.

PMID- 15026439
TI  - Impact of injecting drug use on the interruption of antiretroviral therapies.

PMID- 15026440
TI  - Effect of dietary advice to increase fruit and vegetable consumption on plasma
      flavonol concentrations: results from a randomised controlled intervention trial.

PMID- 15026441
TI  - Avoidable mortality in Europe (1980-1997): a comparison of trends.
AB  - STUDY OBJECTIVE: To analyse international variations of trends in "avoidable"
      mortality (1980-1997). DESIGN: A multilevel model was used to study trends in
      avoidable and "non-avoidable" mortality and trends by cause of death. SETTING:
      Fifteen countries of the European Union, the Czech Republic, and Hungary.
      PARTICIPANTS: 19 avoidable causes of death among men and women aged 0-64 years.
      Mortality and population data were derived from the WHO mortality database; and
      perinatal mortality rates, from the Health for All statistical database. MAIN
      RESULTS: Avoidable mortality declined (1980-1997) in all the countries except
      Hungary. The difference between the trends in avoidable and non-avoidable
      mortality was small (-2.4% compared with -1.5%) and diminished over time. The
      largest trend variations between countries are attributable to causes mainly or
      partly amenable to prevention. For five of the 19 causes of death the
      international variations diminished over time. Various countries show trends that
      deviate significantly (p<0.003) from the mean trend. CONCLUSIONS: One explanation
      for the small and diminishing difference between avoidable and non-avoidable
      mortality is that some large avoidable causes show unfavourable trends. Another
      possible explanation is that the category of non-avoidable mortality is
      "polluted" by causes that have become avoidable with time. It is therefore
      suggested that Rutstein's lists of avoidable outcomes (1976) be updated to enable
      the appropriate monitoring of healthcare effectiveness. In countries that show
      unfavourable developments for specific avoidable causes, further research must
      unravel the causes of these trends.

PMID- 15026442
TI  - Increasing inequalities in premature mortality in Great Britain.
AB  - STUDY OBJECTIVE: To describe inequalities in all cause premature mortality
      between and within regions of Great Britain and how these inequalities have
      changed between 1979 and 1998. DESIGN: Retrospective study using routine
      population and death data aggregated into five year age and sex groups for each
      of 20 years. SETTING: All 459 local authority districts (England and Wales) and
      local government districts (Scotland). PARTICIPANTS: Estimated population and
      registered deaths aged 0-64. MAIN OUTCOME MEASURES: Indirectly standardised
      mortality ratios for all cause mortality; percentages of deaths that would be
      avoided if there were no inequalities between and within regions. RESULTS: The
      decrease in premature mortality of 36% seen in Great Britain ranged from 42% in
      Wales to 33% in Scotland and 31% in London. Differences between regions led to
      excess mortality of about 25% in Scotland, the North East, and the North West. In
      London excess mortality increased from 14% to 19%. Inequalities within regions
      increased in most parts of Great Britain, the exceptions being Wales, London, and
      the South West. The largest increase was seen in Scotland where the percentage of
      excess deaths increased from 23% to 33%. CONCLUSIONS: A decrease in premature
      mortality in Great Britain was seen in all regions, although less pronounced in
      London, but the gap between regions remained. Inequalities between districts
      within regions vary from one region to another and have increased in nearly every
      part of Great Britain.

PMID- 15026443
TI  - The demographic and social class basis of inequality in self reported morbidity:
      an exploration using the Health Survey for England.
AB  - STUDY OBJECTIVES: To assess the relative contribution of age and social class to
      variations in the prevalence of a selection of self reported health problems. To
      examine the implications of observed variations for research on health
      inequalities. DESIGN: Secondary analysis of the Health Survey for England (1991
      1997) using morbidities that are particularly prone to class effects. A
      statistical measure of the "relative class effect" is introduced to compare the
      effects of adjusting for social class and age. MAIN RESULTS: There is substantial
      variation in the relative importance of the age and class distributions of
      different diseases. Age effects often overshadow those of class even for
      conditions where an apparently strong social gradient exists. Only for self
      reported mental health among women does the social gradient exceed the age
      gradient. Within the context of a dominating age gradient, social gradients are
      relatively high for mental health and general health for both sexes. Variation in
      the relative strengths of the social gradients between the sexes are observed for
      angina symptoms. CONCLUSIONS: Given variations in the "relative class effect",
      analysis recognising the distinct contributions of age, sex, and social class to
      specific morbidities is advocated as a transparent and robust approach to the
      assessment of morbidity based inequality.

PMID- 15026444
TI  - Trends in socioeconomic health inequalities in Korea: use of mortality and
      morbidity measures.
AB  - STUDY OBJECTIVE: To examine trends in educational mortality and morbidity
      inequalities in Korea. DESIGN: Census data (1990, 1995, 2000) and death
      certificate data (1990-91, 1995-96, 2000-01) were used for mortality. For
      morbidity, four waves (1989, 1992, 1995, and 1999) of Social Statistics Survey
      from Korea's National Statistical Office were used. Morbidity indicators were
      self rated health and self reported illness in the past two weeks. Trends were
      studied using indices for both the relative and absolute size of socioeconomic
      inequalities in health. SETTING: South Korea. Patients (or Participants):
      Representative annual samples of the adult population aged 30-59 in Korea. MAIN
      RESULTS: Based on trends in relative index of inequalities, the relative level of
      socioeconomic mortality inequality remained virtually unchanged in men and women
      in the past 10 years. Meanwhile, inequalities in self rated health have increased
      over time in both sexes. Most of the total increase in health inequalities
      happened between 1995 and 1999. Inequalities in self reported acute illness
      increased in the past 10 years. CONCLUSIONS: The rise in inequalities in
      morbidity requires increased social discourse and policy discussions about health
      inequalities in Korean society.

PMID- 15026447
TI  - Sickness absence as a predictor of mortality among male and female employees.
AB  - OBJECTIVE: To determine the extent to which sickness absence is predictive of
      mortality. DESIGN: Prospective cohort study. Data on medically certified long
      term absences (>3 days), self certified short term absences (1-3 days), and sick
      days were derived from employers' records and data on mortality from the national
      mortality register. SETTING: 10 towns in Finland. PARTICIPANTS: 12821 male and
      28915 female Finnish municipal employees with a job contract of five consecutive
      years. The mean follow up was 4.5 years. MAIN RESULTS: After adjustment for age,
      occupational status, and type of employment contract, the overall mortality rate
      was 4.3 (95% confidence intervals 2.6 to 7.0) and 3.3 (2.1 to 5.3) times greater
      in men and women with more than one long term absences per year than in those
      with no absence. The corresponding hazard ratios for more than 15 annual sick
      days were 4.7 (2.3 to 9.6) and 3.7 (1.5 to 9.1). Both these measures of sickness
      absence were also predictive of deaths from cardiovascular disease, cancer,
      alcohol related causes, and suicide. Associations between short term sickness
      absences and mortality were weaker and changed to non-significant after
      adjustment for long term sickness absence. CONCLUSIONS: These findings suggest
      that measures of sickness absence, such as long term absence spells and sick
      days, are strong predictors of all cause mortality and mortality due to
      cardiovascular disease, cancer, alcohol related causes, and suicide.

PMID- 15026446
TI  - Effects of education and other socioeconomic factors on middle age mortality in
      rural Bangladesh.
AB  - STUDY OBJECTIVE: To examine socioeconomic gradients in mortality in adult women
      and their husbands in Bangladesh, paying particular attention to the independent
      effects of the educational status of each spouse. DESIGN: Historical cohort
      study. SETTING: Matlab, a rural area 60 km south east of Dhaka, the capital of
      Bangladesh. PARTICIPANTS: 14803 married women aged 45 or over and their husbands
      who were resident in the Matlab Demographic Surveillance area between 30 June
      1982 and 31 December 1998. MAIN RESULTS: Mortality was lower in women with formal
      or Koranic education compared with those with none (adjusted rate ratio for
      formal education = 0.68, 95% CI 0.53 to 0.86; adjusted rate ratio for Koranic
      schooling = 0.82, 95% CI 0.66 to 1.00). After adjusting for her own education,
      the husband's level of education or occupation did not have an independent effect
      on a woman's survival. Men who had attended formal education had lower mortality
      than those without any education (adjusted rate ratio = 0.84, 95% CI 0.75 to
      0.93), but men whose wives had been educated had an additional survival advantage
      independent of their own education and occupation (adjusted rate ratio = 0.76,
      95% CI 0.67 to 0.87). Mortality in both sexes was also significantly associated
      with marital status and the percentage of surviving children, and in men was
      associated with the man's occupation, religion, area of residence. CONCLUSIONS:
      The data suggest that socioeconomic status has a strong influence on mortality in
      adults in Bangladesh. They also illustrate how important the continued promotion
      of education, particularly for women, may be for the survival of both women and
      men in rural Bangladesh.

PMID- 15026449
TI  - Pathways between socioeconomic determinants of health.
AB  - STUDY OBJECTIVE: Many previous studies on socioeconomic inequalities in health
      have neglected the causal interdependencies between different socioeconomic
      indicators. This study examines the pathways between three socioeconomic
      determinants of ill health. DESIGN, SETTING, AND PARTICIPANTS: Cross sectional
      survey data from the Helsinki health study in 2000 and 2001 were used. Each year
      employees of the City of Helsinki, reaching 40, 45, 50, 55, and 60 years received
      a mailed questionnaire. Altogether 6243 employees responded (80% women, response
      rate 68%). Socioeconomic indicators were education, occupational class, and
      household income. Health indicators were limiting longstanding illness and self
      rated health. Inequality indices were calculated based on logistic regression
      analysis. MAIN RESULTS: Each socioeconomic indicator showed a clear gradient with
      health. Among women half of inequalities in limiting longstanding illness by
      education were mediated through occupational class and household income.
      Inequalities by occupational class were largely explained by education. A small
      part of inequalities for income were explained by education and occupational
      class. For self rated health the pathways were broadly similar. Among men most of
      the inequalities in limiting longstanding illness by education were mediated
      through occupational class and income. Part of occupational class inequalities
      were explained by education. Two thirds of inequalities by income were explained
      by education and occupational class. CONCLUSIONS: Parts of the effects of each
      socioeconomic indicator on health are either explained by or mediated through
      other socioeconomic indicators. Analyses of the predictive power of socioeconomic
      indicators on health run the risk of being fruitless, if interrelations between
      various indicators are neglected.

PMID- 15026450
TI  - Places, people, and their physical and mental functional health.
AB  - STUDY OBJECTIVE: To investigate the impact of area of residence on functional
      health as represented by medical outcomes study SF-36 physical and mental
      component summary scores. DESIGN: Multilevel analysis of cross sectional data
      from the European Prospective Investigation into Cancer and Nutrition in Norfolk,
      UK (EPIC-Norfolk). PARTICIPANTS: A community dwelling cohort of 18399 men and
      women, aged 41 to 80 and resident in 162 electoral wards in Norfolk, UK. MAIN
      RESULTS: Significant residual variation in physical functional health was
      observed at the area level after controlling for important individual level
      socioeconomic factors (p<0.001). However, the extent of this variation was modest
      when compared with that at the individual level (representing 0.6% of the total).
      About half of this variation could be explained by area deprivation. Area
      deprivation was associated with impaired mental functional health but residual
      variation at the area level (adjusted for individual level factors) was observed
      only for men (0.5% of total, p = 0.02). CONCLUSIONS: Area of residence was
      associated with physical functional health, albeit with modest effect size.
      Evidence for an association between area of residence and mental functional
      health was weak.

PMID- 15026452
TI  - Social capital and collective efficacy in Hungary: cross sectional associations
      with middle aged female and male mortality rates.
AB  - OBJECTIVES: Social capital, collective efficacy, and religious involvement have
      each been linked to population health. This study examined the relations between
      these measures and male/female mortality rates in Hungary. DESIGN: Cross
      sectional, ecological study. SETTING: 150 sub-regions of Hungary. PARTICIPANTS
      AND METHODS: 12643 people were interviewed in 2002 (the "Hungarostudy 2002"
      survey). Social capital was measured by lack of social trust, reciprocity between
      citizens, and membership in civil organisations. Collective efficacy was measured
      by survey items from the Project on Human Development in Chicago Neighborhoods.
      Religious involvement was measured by church attendance. MAIN OUTCOME MEASURE:
      Gender specific all cause mortality rates for the middle aged population (45-64
      years) in the 150 sub-regions of Hungary, provided by the Central Statistical
      Office (CSO). RESULTS: Social capital, collective efficacy, as well as religious
      involvement were each significantly associated with middle age mortality. After
      education, collective efficacy showed the strongest association with mortality in
      both men and women. Among men, socioeconomic status, collective efficacy, social
      distrust, competitive attitude, reciprocity, and membership of civic
      organisations explained 68.0% of the sub-regional variations in mortality rates.
      Among women the same variables explained only 29.3% of the variance in mortality
      rates. Religious involvement was protective among women. CONCLUSION: Collective
      efficacy and social capital are significant predictors of mortality rates in both
      men and women across sub-regions of Hungary. Gender differences in the relative
      importance of social factors may help to explain the differential impact of
      economic transformation on mortality rates for men and women in Central-Eastern
      European countries.

PMID- 15026453
TI  - Racial segregation and county level intentional injury in Pennsylvania: analysis
      of hospital discharge data for 1997-1999.
AB  - STUDY OBJECTIVE: This study examined whether high levels of racial segregation
      are associated with high county level intentional injury rates. DESIGN: Multiple
      linear regression was used to assess the association between county racial
      segregation (measured by the Gini coefficient) and intentional injury rates.
      Multicollinearity was assessed with Eigenvalues and condition indices. SETTING:
      State of Pennsylvania. PATIENTS: County level intentional injury rates for 1995
      to 1997 were calculated from hospital discharge data. MAIN RESULTS: After
      controlling for other known county level risk factors, higher levels of racial
      segregation in a county were significantly related to higher intentional injury
      rates. Multicollinearity was not a problem. Population size and density, family
      stability and median income, together with the percentage male, unemployed, in
      poverty, divorced men, and high school graduates of the county were controlled.
      CONCLUSIONS: Racial segregation is an important factor in the rate of intentional
      injury in a community. These results may be important for municipal and state
      agencies when developing public policies to prevent violence and promote racial
      integration.

PMID- 15026454
TI  - Images of body weight among young men and women: evidence from Beirut, Lebanon.

PMID- 15026455
TI  - Standardised QALYs and DALYs are more understandable, avoid misleading units of
      measurement, and permit comparisons.

PMID- 15026456
TI  - Previous trials of dissemination were identified.

PMID- 15026457
TI  - No place for modesty.

PMID- 15026459
TI  - Betting odds and genetic associations.

PMID- 15026460
TI  - The certainties and the uncertainties of ductal carcinoma in situ.

PMID- 15026461
TI  - For telomeres, longer is not always better.

PMID- 15026462
TI  - Funding cuts for public health projects in Europe may affect international cancer
      effort.

PMID- 15026463
TI  - High expectations for mammography at heart of many breast cancer malpractice
      cases.

PMID- 15026465
TI  - Stat bite: Cigarette smoking among U.S. adults, 1999-2001.

PMID- 15026464
TI  - Study evaluates information on breast cancer Web sites.

PMID- 15026466
TI  - Psychosocial care integral for breast cancer patients, report concludes.

PMID- 15026468
TI  - Assessing the probability that a positive report is false: an approach for
      molecular epidemiology studies.
AB  - Too many reports of associations between genetic variants and common cancer sites
      and other complex diseases are false positives. A major reason for this
      unfortunate situation is the strategy of declaring statistical significance based
      on a P value alone, particularly, any P value below.05. The false positive report
      probability (FPRP), the probability of no true association between a genetic
      variant and disease given a statistically significant finding, depends not only
      on the observed P value but also on both the prior probability that the
      association between the genetic variant and the disease is real and the
      statistical power of the test. In this commentary, we show how to assess the FPRP
      and how to use it to decide whether a finding is deserving of attention or
      "noteworthy." We show how this approach can lead to improvements in the design,
      analysis, and interpretation of molecular epidemiology studies. Our proposal can
      help investigators, editors, and readers of research articles to protect
      themselves from overinterpreting statistically significant findings that are not
      likely to signify a true association. An FPRP-based criterion for deciding
      whether to call a finding noteworthy formalizes the process already used
      informally by investigators--that is, tempering enthusiasm for remarkable study
      findings with considerations of plausibility.

PMID- 15026469
TI  - Trends in the treatment of ductal carcinoma in situ of the breast.
AB  - BACKGROUND: An increase in incidence of ductal carcinoma in situ (DCIS) of the
      breast has been documented, and concerns regarding overly aggressive treatment
      have been raised. This study was designed to evaluate the use of surgery and
      radiation therapy in treating DCIS. METHODS: We used the National Cancer
      Institute's Surveillance, Epidemiology, and End Results database to assess
      treatment of patients with DCIS with no evidence of microinvasion who were
      diagnosed from January 1, 1992, through December 31, 1999. We assessed the rates
      of mastectomy, breast reconstruction, radiation therapy after lumpectomy, and
      axillary dissection. Associations were analyzed by logistic regression. RESULTS:
      During the study period, 25 206 patients met selection criteria. The incidence of
      DCIS dramatically increased with time; however, the incidence of comedo lesions
      did not change. The rate of mastectomy decreased from 43% in 1992 to 28% in 1999,
      after controlling for age, race, tumor size, comedo histology, and geographic
      location. However, because of the increase in the diagnosis of DCIS, the age
      adjusted incidence of mastectomy for DCIS in the population did not change (7.8
      per 100 000 women in 1992 and 1999). Almost half the patients undergoing
      lumpectomy did not undergo radiation therapy (55% in 1992 and 46% in 1999); in
      those with comedo histology, 33% did not undergo radiation therapy after
      lumpectomy, even in 1999. Overall, patients were less likely to have axillary
      dissection over time (34% in 1992 versus 15% in 1999), yet the rate of axillary
      dissection was still high (30%) in patients undergoing mastectomy in 1999. Large,
      statistically and clinically significant variation by geographic location was
      found in treatment. CONCLUSIONS: Treatment of DCIS changed in a clinically
      significant fashion between 1992 and 1999. Throughout this study, many patients
      were found to undergo aggressive surgical therapy, including mastectomy and
      axillary dissection, whereas others appeared to be undertreated, e.g., not
      receiving radiation therapy after lumpectomy, even in the presence of adverse
      histologic features. Variation in demographic and geographic factors indicates
      that at least some of these treatment differences reflect individual and
      institutional practice patterns that may be modifiable.

PMID- 15026470
TI  - Human papillomavirus in oral exfoliated cells and risk of head and neck cancer.
AB  - BACKGROUND: Human papillomavirus (HPV) has been associated with the development
      of head and neck cancers. In this study, we investigated whether the risk factors
      for head and neck cancer in relation to HPV infection are different from those in
      the absence of HPV infection and whether HPV detected in oral exfoliated cells is
      an independent predictor of head and neck cancer risk. METHODS: We conducted a
      case-control study in 201 head and neck cancer case patients and 333 control
      subjects, frequency matched for age and sex. Oral exfoliated cells and tumor
      tissue were evaluated for HPV using polymerase chain reaction and DNA sequencing
      to type HPV. Logistic regression was used to calculate odds ratios (ORs) for head
      and neck cancer with HPV infection and 95% confidence intervals (CIs), adjusted
      for age, tobacco use, and alcohol consumption. RESULTS: Oncogenic, or high-risk
      (HR), HPV types were detected in oral cells from 22.9% of case patients and 10.8%
      of control subjects. HPV16 was the most frequently detected type (19% versus 10%
      of case patients and control subjects, respectively). After adjusting for age,
      tobacco use, and alcohol consumption, the risk of head and neck cancer was
      statistically significantly greater in individuals with HPV-HR types (adjusted OR
      = 2.6, 95% CI = 1.5 to 4.2) but not in individuals with nononcogenic HPV types
      (adjusted OR = 0.8, 95% CI = 0.4 to 1.7) compared with HPV-negative individuals.
      Compared with individuals who were HPV-negative and did not use alcohol or
      tobacco, there was a statistically significant synergistic effect between
      detection of HPV-HR and heavy alcohol consumption (OR = 18.8, 95% CI = 5.1 to
      69.5) but an additive effect between detection of HPV-HR and tobacco use (OR =
      5.5, 95% CI = 2.1 to 14.1). HPV-HR types detected in oral exfoliated cells were
      predictive of HPV-HR types in tumor tissue. CONCLUSION: Infection of oral
      exfoliated cells with HPV-HR types is a risk factor for head and neck cancer,
      independent of alcohol and tobacco use, and acts synergistically with alcohol
      consumption. HPV testing of an oral rinse may be predictive of an HPV-related
      head and neck cancer.

PMID- 15026471
TI  - Therapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in a
      breast cancer model.
AB  - BACKGROUND: The antiestrogen tamoxifen has potent activity against estrogen
      receptor-positive breast cancer, but two nonsteroidal aromatase inhibitors,
      letrozole and anastrozole, show considerable advantages over tamoxifen with
      respect to patient survival and tolerability. To determine the optimal way to use
      letrozole and tamoxifen, we studied their effects on a breast tumor xenograft
      model, MCF-7Ca, that is responsive to both antiestrogens and aromatase
      inhibitors. METHODS: Female ovariectomized BALB/c athymic nude mice carrying
      xenograft tumors were treated daily subcutaneously with one of the following
      first-line therapies for varying durations: no drug (control), tamoxifen (100
      microg/day) alone, letrozole (10 microg/day) alone, both drugs at the same time,
      or alternating 4-week courses of each drug (beginning with a course of tamoxifen
      or beginning with a course of letrozole). Tumor volumes and weights were
      estimated using linear mixed-effects models. The time to tumor doubling was
      calculated, and tumor weights in the treatment groups were compared, with
      adjustments for multiple comparisons being made with either Tukey's or Dunnett's
      procedure. Second-line therapies (with tamoxifen, letrozole, or fulvestrant) were
      initiated when tumors doubled in size under first-line therapies. All statistical
      tests were two-sided. RESULTS: The times for doubling of tumor volume were as
      follows: control, 3-4 weeks; tamoxifen alone, 16 weeks; tamoxifen alternating
      with letrozole, 17-18 weeks; tamoxifen plus letrozole, 18 weeks; letrozole
      alternating with tamoxifen, 22 weeks; letrozole alone, 34 weeks. First-line
      treatment with letrozole was superior to treatment with tamoxifen alone or with
      the two drugs combined (at week 16, both P<.001). Alternating tamoxifen and
      letrozole and alternating letrozole and tamoxifen were also not as effective as
      letrozole alone (at week 16, P =.002 and P<.001, respectively). Tumors
      progressing on tamoxifen remained sensitive to second-line therapy with letrozole
      compared with those remaining on tamoxifen at the end of treatment (week 28,
      P<.001), whereas tumors progressing on letrozole were unaffected by second-line
      treatment with the antiestrogens tamoxifen or fulvestrant. CONCLUSIONS: First
      line letrozole therapy extends time for tumor progression in this model relative
      to the other treatment regimens tested. However, further studies are needed to
      determine the most effective second-line therapy for tumors that progress on
      letrozole.

PMID- 15026473
TI  - Melatonin and breast cancer: a prospective study.
AB  - BACKGROUND: Experimental data from animals suggest a protective role for the
      pineal hormone melatonin in the etiology of breast cancer, but results from the
      few retrospective case-control studies that examined the association in humans
      have been inconsistent. To determine whether low levels of endogenous melatonin
      are associated with an increased risk for developing breast cancer, we conducted
      a prospective nested case-control study among British women. METHODS:
      Concentrations of 6-sulfatoxymelatonin, the main metabolite of melatonin in urine
      and a validated marker of circulating melatonin levels, were measured by
      radioimmunoassay in 24-hour urine samples collected from women shortly after
      enrollment in the prospective Guernsey III Study. Levels of 6-sulfatoxymelatonin
      were compared among 127 patients diagnosed with breast cancer during follow-up
      and among 353 control subjects, matched for age, recruitment date, menopausal
      status, and day of menstrual cycle for premenopausal women or number of years
      postmenopausal for postmenopausal women. Associations were examined by analyses
      of covariance and conditional logistic regression. All tests of statistical
      significance were two-sided. RESULTS: No statistically significant differences in
      urinary 6-sulfatoxymelatonin concentrations were observed between women who
      developed breast cancer and control subjects among premenopausal or
      postmenopausal women (P=.8 and P=.9, respectively). When data from premenopausal
      and postmenopausal women were combined in a multivariable analysis adjusted for
      potential confounders and grouped into three categories defined by 6
      sulfatoxymelatonin tertiles of control subjects, the level of 6
      sulfatoxymelatonin excreted was not statistically significantly associated with
      the risk of breast cancer (odds ratio [OR] for breast cancer = 0.95, 95%
      confidence interval [CI] = 0.55 to 1.65, comparing the middle category with the
      lowest category of 6-sulfatoxymelatonin concentration, and OR = 0.99, 95% CI =
      0.58 to 1.70, comparing the highest category with the lowest category).
      CONCLUSION: We found no evidence that the level of melatonin is strongly
      associated with the risk for breast cancer.

PMID- 15026472
TI  - Estrogen signaling in livers of male mice with hepatocellular carcinoma induced
      by exposure to arsenic in utero.
AB  - BACKGROUND: Exposure of pregnant mice to inorganic arsenic induces a spectrum of
      tumors, including hepatocellular carcinoma (HCC), in their adult offspring
      similar to that induced by exposing adult mice to estrogenic compounds. To
      investigate whether arsenic exposure in utero causes altered estrogen signaling,
      we examined expression of estrogen receptor-alpha (ER-alpha), cyclin D1 (an
      estrogen-responsive hepatic oncogene), and several cytochrome P450 genes (with
      sexually dimorphic liver expression patterns) in livers from adult male mice with
      in utero arsenic-induced HCC. METHODS: Quantitative real-time reverse
      transcription-polymerase chain reaction was used to evaluate gene expression in
      livers of adult male mice that had (i.e., exposed mice; n = 8) or had not (i.e.,
      control mice; n = 5) been exposed to arsenic in utero. DNA methylation status of
      portions of the ER-alpha and cyclin D1 gene promoters in liver tissue was
      measured using methylation-specific polymerase chain reaction. Statistical tests
      were two-sided. RESULTS: ER-alpha mRNA levels were 3.1-fold (95% confidence
      interval [CI] = 2.0-fold to 4.3-fold) higher in livers of exposed mice than in
      those of control mice, and cyclin D1 levels were 3.0-fold (95% CI = 1.7-fold to
      4.3-fold) higher. Exposed mice showed a feminized expression pattern of several
      cytochrome P450 genes, expressing the female-dominant CYP2A4 (P =.017 versus
      control) and CYP2B9 (P<.001) genes at 8.7 and 10.5 times, respectively, the level
      in control mice and expressing the male-dominant CYP7B1 at approximately one
      fourth the level in control mice(P =.0012). Exposed mice exhibited reduced (by
      approximately 90%) methylation of the ER-alpha gene promoter in liver DNA as
      compared with control mice; the cyclin D1 gene promoter was not methylated in
      either exposed or control mice. CONCLUSION: Altered estrogen signaling may play a
      role in induction of HCC by arsenic exposure in utero. Specifically,
      overexpression of ER-alpha, potentially through promoter region hypomethylation,
      in livers of such mice may be linked to the hepatocarcinogenicity of arsenic.

PMID- 15026474
TI  - Hypermethylation and transcriptional downregulation of the carboxyl-terminal
      modulator protein gene in glioblastomas.
AB  - The carboxyl-terminal modulator protein (CTMP) has been identified as a negative
      regulator of protein kinase B/Akt. Aberrant Akt signaling is frequently observed
      in glioblastomas, the most common and most malignant glial brain tumors. Because
      loss of CTMP function and/or expression may remove the inhibitory effects on Akt
      and promote tumorigenesis, we studied 93 primary glioblastomas and nine
      glioblastoma cell lines for CTMP deletion, mutation, promoter hypermethylation,
      and mRNA expression. None of the tumors or cell lines had CTMP-homozygous
      deletions or coding sequence mutations. However, CTMP mRNA expression was lower
      by at least 50% relative to non-neoplastic brain tissue in 37 (40%) glioblastomas
      and six (67%) glioma cell lines. Reduced CTMP mRNA levels were closely associated
      with hypermethylation of the CTMP promoter. Furthermore, treatment of CTMP
      hypermethylated A172 glioma cells with the demethylating agent 5-aza-2'
      deoxycytidine and the histone deacetylase inhibitor trichostatin A resulted in
      partial demethylation of the CTMP promoter and increased CTMP mRNA expression.
      Thus, epigenetic downregulation of CTMP transcription is a common aberration in
      glioblastomas.

PMID- 15026475
TI  - Re: New guidelines to evaluate the response to treatment in solid tumors (ovarian
      cancer).

PMID- 15026476
TI  - Case report of a generalized seizure related to Paclitaxel infusion.

PMID- 15026477
TI  - Is systemic disease in the coelomic epithelium associated with BRCA1 germline
      mutations?

PMID- 15026478
TI  - Perspectives on classic article: metastasis suppressor genes.

PMID- 15026486
TI  - Attention deficit hyperactivity disorder in adulthood.

PMID- 15026487
TI  - The MS Symptom and Impact Diary (MSSID): psychometric evaluation of a new
      instrument to measure the day to day impact of multiple sclerosis.

PMID- 15026488
TI  - Grey hair and grey matter.

PMID- 15026489
TI  - Recommendations for CSF analysis in subarachnoid haemorrhage.

PMID- 15026491
TI  - Inhibition of ongoing responses in patients with Parkinson's disease.
AB  - OBJECTIVES: We investigated the involvement of the basal ganglia in inhibiting
      ongoing responses in patients with Parkinson's disease (PD). METHODS: Thirty two
      patients with PD and 31 orthopaedic controls performed the stop signal task,
      which allows an estimation of the time it takes to inhibit an ongoing reaction
      (stop signal reaction time, SSRT). RESULTS: Patients with PD showed significantly
      longer SSRTs than the controls. This effect seemed to be independent of global
      cognitive impairment and severity of PD. Furthermore, in the PD patients, there
      was no significant relation between general slowing and inhibitory efficiency.
      CONCLUSIONS: Our results provide evidence for involvement of the basal ganglia in
      the inhibition of ongoing responses.

PMID- 15026492
TI  - Sir Charles Scott Sherrington (1857-1952) and the synapse.

PMID- 15026490
TI  - Functional genomics and proteomics: application in neurosciences.
AB  - The sequencing of the complete genome for many organisms, including man, has
      opened the door to the systematic understanding of how complex structures such as
      the brain integrate and function, not only in health but also in disease. This
      blueprint, however, means that the piecemeal analysis regimes of the past are
      being rapidly superseded by new methods that analyse not just tens of genes or
      proteins at any one time, but thousands, if not the entire repertoire of a cell
      population or tissue under investigation. Using the most appropriate method of
      analysis to maximise the available data therefore becomes vital if a complete
      picture is to be obtained of how a system or individual cell is affected by a
      treatment or disease. This review examines what methods are currently available
      for the large scale analysis of gene and protein expression, and what are their
      limitations.

PMID- 15026493
TI  - The L-dopa response in vascular parkinsonism.
AB  - OBJECTIVE: To determine whether a positive L-dopa response in vascular
      parkinsonism (VP) is correlated with the presence of nigrostriatal pathology due
      to either vascular damage or neuronal cell loss. METHODS: Seventeen patients with
      pathologically confirmed VP were selected from the pathological collection of the
      Queen Square Brain Bank for Neurological Disorders, and their L-dopa response
      during life was compared with the presence of macroscopic vascular damage in the
      nigrostriatal pathway and microscopic substantia nigra cell loss. RESULTS: Ten of
      the twelve patients with a good or excellent response had macroscopic infarcts or
      lacunae caused by enlarged perivascular spaces in the basal ganglia or
      microscopic neuronal cell loss in the substantia nigra. In contrast, only one of
      the five patients with a moderate or no response had lacunae in the putamen, and
      none had lacunar infarcts or substantia nigra cell loss. CONCLUSION: These
      results suggest that a substantial number of patients with clinically suspected
      VP may respond with benefit to dopaminergic therapy, especially those with
      lesions in or close to the nigrostriatal pathway.

PMID- 15026494
TI  - Hippocampal size and memory function in the ninth and tenth decades of life: the
      Sydney Older Persons Study.
AB  - OBJECTIVES: The purpose of this study was to define magnetic resonance imaging
      (MRI) correlates of normal brain ageing, with the specific objective of
      investigating whether the size of the hippocampus is selectively correlated with
      age related memory performance in non-demented individuals in their ninth and
      tenth decades of life. METHODS: Hippocampal size was estimated using MRI based
      volumetry and qualitative visual assessment in 102 community dwelling individuals
      aged between 81 and 94 years. Participants were evaluated on a variety of
      clinical and experimental instruments, including a comprehensive
      neuropsychological test battery. All participants underwent neurological
      examination, an extensive medical history was obtained, and an informant
      confirmed details of each participant's functional ability. RESULTS: Both visual
      and volumetric hippocampal measures were identified as robust predictors of
      memory performance, even when the influence of age related illnesses and
      sociodemographic variables was accounted for. When the sample was reduced to
      include the most cognitively healthy participants who were rated by an informant
      as showing no evidence of cognitive decline, the left hippocampal measures
      remained significant predictors of delayed retention of verbal material.
      CONCLUSIONS: These findings suggest that hippocampal volumes are selectively
      correlated with memory functioning in both normal and successful ageing.

PMID- 15026496
TI  - Scalp metastasis from glioblastoma.

PMID- 15026495
TI  - Motor cortex hyperexcitability to transcranial magnetic stimulation in
      Alzheimer's disease.
AB  - OBJECTIVES: Recent transcranial magnetic stimulation (TMS) studies demonstrate
      that motor cortex excitability is increased in Alzheimer's disease (AD) and that
      intracortical inhibitory phenomena are impaired. The aim of the present study was
      to determine whether hyperexcitability is due to the impairment of intracortical
      inhibitory circuits or to an independent abnormality of excitatory circuits.
      METHODS: We assessed the excitability of the motor cortex with TMS in 28 patients
      with AD using several TMS paradigms and compared the data of cortical
      excitability (evaluated by measuring resting motor threshold) with the amount of
      motor cortex disinhibition as evaluated using the test for motor cortex
      cholinergic inhibition (short latency afferent inhibition) and GABAergic
      inhibition (short latency intracortical inhibition). The data in AD patients were
      also compared with that from 12 age matched healthy individuals. RESULTS: The
      mean resting motor threshold was significantly lower in AD patients than in
      controls. The amount of short latency afferent inhibition was significantly
      smaller in AD patients than in normal controls. There was also a tendency for AD
      patients to have less pronounced short latency intracortical inhibition than
      controls, but this difference was not significant. There was no correlation
      between resting motor threshold and measures of either short latency afferent or
      intracortical inhibition (r = -0.19 and 0.18 respectively, NS). In 14 AD patients
      the electrophysiological study was repeated after a single oral dose of the
      cholinesterase inhibitor rivastigmine. Resting motor threshold was not
      significantly modified by the administration of rivastigmine. In contrast, short
      latency afferent inhibition from the median nerve was significantly increased by
      the administration of rivastigmine. CONCLUSIONS: The change in threshold did not
      seem to correlate with dysfunction of inhibitory intracortical cholinergic and
      GABAergic circuits, nor with the central cholinergic activity. We propose that
      the hyperexcitability of the motor cortex is caused by an abnormality of
      intracortical excitatory circuits.

PMID- 15026497
TI  - Cognitive impairment and functional outcome after stroke associated with small
      vessel disease.
AB  - OBJECTIVES: Although stroke associated with small vessel disease (SSVD) can
      induce both motor and cognitive impairment, the latter has received less
      attention. We aimed to evaluate the frequency of the varying severity levels of
      cognitive impairment, the determinants of severe cognitive impairment, and the
      association of cognitive impairment with functional outcome after SSVD. METHODS:
      Consecutive patients admitted to hospital because of SSVD were assessed at 3
      months after stroke. We performed a semi-structured clinical interview to screen
      for cognitive symptoms. Severity of cognitive symptoms was graded according to
      the Clinical Dementia Rating Scale (CDR). Performance on psychometric tests (Mini
      Mental State Examination, Alzheimer's Disease Assessment Scale (cognition
      subscale), Mattis Dementia Rating Scale (initiation/perseverence subscale; MDRS
      I/P)) of patients of different CDR gradings was compared with that of 42 healthy
      controls. Basic demographic data, vascular risk factors, stroke severity
      (National Institute of Health Stroke Scale; NIHSS), pre-stroke cognitive decline
      (Informant Questionnaire on Cognitive Decline in the Elderly; IQCODE), functional
      outcome (Barthel index; BI), Instrumental Activities Of Daily Living; IADL), and
      neuroimaging features (site of recent small infarcts, number of silent small
      infarcts, white matter changes) were also compared among the groups. Regression
      analyses were performed to find predictors of severe cognitive impairment and
      poor functional outcome. RESULTS: Among the 75 included patients, 39 (52%)
      complained of cognitive symptoms. The number of patients in each CDR grading was
      as follows: 39 (52%) had a CDR of 0, 26 (34.7%) had a CDR of 0.5, 10 (13.3%) had
      a CDR of > or =1. Pre-stroke IQCODE and previous stroke predicted CDR> or =1. The
      NIHSS was associated with more impaired BI. The NIHSS and MDRS I/P contributed
      most to impaired IADL. CONCLUSIONS: Half of the patients with SSVD complained of
      varying severity of cognitive problems 3 months after stroke. Pre-stroke
      cognitive decline and previous stroke predict severe cognitive impairment post
      stroke. Stroke severity and executive dysfunction contribute most to a poor
      functional outcome.

PMID- 15026498
TI  - Stroke in Devon: knowledge was good, but action was poor.
AB  - BACKGROUND AND AIM: Effective implementation of early treatment strategies for
      stroke requires prompt admission to hospital. There are several reasons for
      delayed admission. Good awareness should facilitate early admission. We
      identified local targets for education. METHODS: Four groups, each of 40 people,
      completed questionnaires to determine their knowledge of stroke symptoms and risk
      factors, and the action they took or would take in the event of a stroke. The
      groups were: patients with a diagnosis of stroke or TIA (within 48 hrs of
      admission); patients at risk of stroke; the general population; and nurses.
      RESULTS: Forty per cent of stroke patients identified their stroke. Median time
      from onset of symptoms to seeking medical help was 30 minutes. Medical help was
      sought by the patient themselves in only 15% of cases. In 80% of cases the GP was
      called rather than an ambulance. Of the at risk group, 93% were able to list at
      least one symptom of acute stroke, as were 88% of the general population. An
      ambulance would be called by 73% of the at risk group in the event of a stroke.
      Patients with self reported risk factors for stroke were largely unaware of their
      increased risk. Only 7.5% of at risk patients acquired their stroke information
      from the medical profession. CONCLUSIONS: Public knowledge about stroke is good.
      However, stroke patients access acute services poorly. At risk patients have
      limited awareness of their increased risk. A campaign should target people at
      risk, reinforcing the diagnosis of stroke and access to medical services.

PMID- 15026499
TI  - Latitudinal variation in the prevalence of multiple sclerosis in Ireland, an
      effect of genetic diversity.
AB  - BACKGROUND: Northern Ireland has a high and rising prevalence rate of multiple
      sclerosis (MS). The most recent survey in 1996 found a rate of 168.7/100 000.
      Recorded prevalence rates for the south of Ireland, including County Wexford,
      have been markedly lower and seemed to suggest the existence of a prevalence
      gradient within the island. OBJECTIVES: To compare the prevalence of multiple
      sclerosis in Co. Wexford in the south east of Ireland and Co. Donegal in the
      north west, and to establish whether a variation in prevalence of MS exists
      within Ireland. METHODS: Patients were referred from multiple sources. Review of
      clinical case records and/or patient examination confirmed the diagnosis.
      RESULTS: In Co. Wexford, 126 patients were found to have clinically definite or
      probable multiple sclerosis with a prevalence rate of 120.7/100 000 (95%
      confidence intervals (CI) 100.6 to 143.8), which is similar to other areas of
      similar latitude within the British Isles. In Co. Donegal, 240 people had
      clinically definite or probable MS with a prevalence rate of 184.6/100 000 (95%
      CI 162.0 to 209.5). The difference in prevalence rates is statistically
      significant (Z = 3.94, p = <0.001). CONCLUSION: There is a latitudinal variation
      in the prevalence rate of MS between the north and the south of Ireland. The
      increased prevalence of MS seen in Co. Wexford is likely to represent better case
      ascertainment and improved diagnostic accuracy rather than an actual increase in
      prevalence. The north/south variation in prevalence may represent a variation in
      the genetic predisposition to MS between the background populations of the two
      counties.

PMID- 15026501
TI  - Lluis Barraquer i Roviralta and the origins of torsion dystonia.

PMID- 15026500
TI  - The MS Symptom and Impact Diary (MSSID): psychometric evaluation of a new
      instrument to measure the day to day impact of multiple sclerosis.
AB  - OBJECTIVES: This study aimed to develop further a diary originally devised to
      measure the impact of multiple sclerosis (MS) as part of a cost utility study of
      beta interferon, and to evaluate its reliability, validity, and responsiveness in
      an outpatient sample of people with MS. METHODS: The original diary was further
      developed using qualitative and quantitative methods to ensure that it addressed
      the views of people with MS. The psychometric properties of the MS Symptom and
      Impact Diary (MSSID) were evaluated in a sample of 77 people who completed the
      MSSID daily for 12 weeks. Internal and test-retest reliability, discriminant and
      convergent validity, and responsiveness were assessed using traditional
      psychometric methods. RESULTS: The MSSID formed three, internally consistent
      scales that measured mobility, fatigue, and the overall impact of MS. The test
      retest reliability of the mobility scale was adequate for individual comparisons
      (ICC>0.90) and the fatigue and overall impact scales were adequate for group
      comparisons (ICC>0.70). The MSSID was able to distinguish between clinical groups
      depending on clinical course, indoor ambulation status, and relapse status. It
      demonstrated associations with other single point instruments in the expected
      direction. Compared with single point instruments, its responsiveness was similar
      or better, especially in detecting short term improvements in functioning.
      CONCLUSIONS: The MSSID may provide a useful complement to currently available
      instruments to measure the outcomes of MS within clinical trials. Further
      research is needed to explore its feasibility in the context of a randomised
      controlled trial and its utility for clinicians.

PMID- 15026503
TI  - Patients with extratemporal lobe epilepsy do not differ from healthy subjects
      with respect to subcortical volumes.
AB  - BACKGROUND: Evidence from previous volumetric magnetic resonance studies has
      revealed that patients with chronic temporal lobe epilepsy show atrophy of
      distinct subcortical nuclei, predominantly ipsilateral to the focus side. We were
      interested to find out if there is also selective subcortical atrophy in patients
      suffering from long standing extratemporal lobe epilepsy. METHODS: Thirty one
      patients in whom pre-surgical evaluation unambiguously localised an extratemporal
      focus were included in this study. Using high resolution magnetic resonance
      imaging, the volumes of the caudate nuclei, putamen, pallidum, and thalamus were
      measured bilaterally in both hemispheres and compared with measurements obtained
      in 15 healthy volunteers. RESULTS: No significant difference in volumes was found
      between the two subject groups, or in any subgroup of extratemporal lobe epilepsy
      patients, nor was there any relation to clinical variables such as age of onset,
      overall seizure frequency, or disease duration. However, patients who had no or
      only rare generalised tonic-clonic seizures seemed to differ from the other
      patients and controls in that they had smaller putamen volumes bilaterally
      (p<0.001). CONCLUSION: We concluded that extratemporal lobe epilepsy in general
      is not associated with diminished volumes in the studied subcortical structures,
      which contrasts with findings in temporal lobe epilepsy patients. Thus, both
      entities differ both cortically and subcortically. However, we found that small
      putamen volume was bilaterally associated with absent or rare generalised tonic
      clonic seizures, implicating the putamen in the control of the most disabling
      seizure type, independent of the site of neocortical focus.

PMID- 15026502
TI  - Cognitive changes after epilepsy surgery in the posterior cortex.
AB  - OBJECTIVE: The relationship between the posterior cortex and cognitive functions
      is still a relatively open field. There are no studies on populations in which
      functions of posterior structures were examined by a standardised
      neuropsychological examination before and after posterior resections. Changes in
      cognitive performance are regularly observed after epilepsy surgery in the
      temporal lobe. However, information about neuropsychological impairments after
      resections in the posterior cortex is poor, owing to the relatively low
      proportion of cortical resections in this area. METHODS: We retrospectively
      studied changes in cognition in the neuropsychological data of 28 patients prior
      to and 6 months after posterior cortical resections. RESULTS: Cognition
      significantly showed differences in performance intelligence quotient compared
      with verbal intelligence quotient. Post-operative verbal intelligence
      consistently increased, whereas performance intelligence decreased. There was no
      effect regarding the lesion side, continuation of seizures, or reduction of
      visual field after surgery. Epilepsy surgery in this area did not lead to
      significant differences in general intelligence after surgery. CONCLUSION:
      Functions of posterior areas could be described by standardised
      neuropsychological measures. Posterior regions contribute to explicit attentional
      and visuoconstructional abilities. Epilepsy surgery in the posterior cortex bears
      no risk for substantial decline in general cognition although some discrete
      impairment in performance intelligence may occur.

PMID- 15026504
TI  - Emotional memory and perception in temporal lobectomy patients with amygdala
      damage.
AB  - BACKGROUND: The human amygdala is implicated in the formation of emotional
      memories and the perception of emotional stimuli--particularly fear--across
      various modalities. OBJECTIVES: To discern the extent to which these functions
      are related. METHODS: 28 patients who had anterior temporal lobectomy (13 left
      and 15 right) for intractable epilepsy were recruited. Structural magnetic
      resonance imaging showed that three of them had atrophy of their remaining
      amygdala. All participants were given tests of affect perception from facial and
      vocal expressions and of emotional memory, using a standard narrative test and a
      novel test of word recognition. The results were standardised against matched
      healthy controls. RESULTS: Performance on all emotion tasks in patients with
      unilateral lobectomy ranged from unimpaired to moderately impaired. Perception of
      emotions in faces and voices was (with exceptions) significantly positively
      correlated, indicating multimodal emotional processing. However, there was no
      correlation between the subjects' performance on tests of emotional memory and
      perception. Several subjects showed strong emotional memory enhancement but poor
      fear perception. Patients with bilateral amygdala damage had greater impairment,
      particularly on the narrative test of emotional memory, one showing superior fear
      recognition but absent memory enhancement. CONCLUSIONS: Bilateral amygdala damage
      is particularly disruptive of emotional memory processes in comparison with
      unilateral temporal lobectomy. On a cognitive level, the pattern of results
      implies that perception of emotional expressions and emotional memory are
      supported by separate processing systems or streams.

PMID- 15026507
TI  - Reliability of self-reported diagnoses in patients with neurologically
      unexplained symptoms.
AB  - BACKGROUND: Patients with neurologically unexplained symptoms (NUS) often have a
      previous history of other medically unexplained symptoms. A past history of such
      symptoms can help make a positive diagnosis of a somatoform or affective
      disorder, and enable appropriate management strategies. However, information on
      past medical diagnoses is primarily obtained from patient interviews and may be
      inaccurate, particularly in patients with NUS. OBJECTIVE: To assess the
      reliability of past medical diagnoses reported by patients with NUS compared with
      patients with confirmed neurological disease (ND) without suspicion of somatoform
      illness. METHODS: 21 patients with NUS and 16 patients with ND were interviewed
      about their current and past medical problems and diagnoses. The accuracy of the
      reported diagnoses was assessed through examination of their complete general
      practice notes. RESULTS: The median number of previous diagnoses reported by
      patients with NUS was significantly higher than in controls (7 v 3, p = 0.001).
      There was no difference in the median number of confirmed diagnoses between the
      two groups (2 v 2.5); however, the median percentage of reported diagnoses
      confirmed by investigations was significantly smaller in the NUS group (22% v
      80%, p = 0.001). The additional diagnoses reported by patients with NUS not only
      comprised functional syndromes such as irritable bowel syndrome or non-cardiac
      chest pain (6% v 0%, p = 0.01), but also organic diagnoses which had either been
      unequivocally excluded (5% v 0%, p = 0.006), were based on equivocal findings
      often found after multiple investigations (9% v 0%, p = 0.01), or had not been
      investigated before a clinical diagnosis was made (50% v 18%, p = 0.04).
      CONCLUSION: Reported previous diagnoses should not be taken at face value when
      the current differential diagnosis includes a functional/somatoform neurological
      syndrome, particularly if the list of past medical diagnoses is long.
      Confirmation of previous diagnoses from alternative sources may contribute to a
      diagnosis of somatoform disorder, allowing appropriate management strategies for
      the current (and past) complaints to be initiated.

PMID- 15026506
TI  - Neuropsychological effects associated with temporal lobectomy and
      amygdalohippocampectomy depending on Wada test failure.
AB  - OBJECTIVE: To compare the neuropsychological effects of temporal lobectomy (TL)
      and amygdalohippocampectomy (AH), depending on whether the patients had passed or
      failed the Wada test. METHODS: We compared changes in neuropsychological scores
      in patients who underwent TL (n = 91) or AH (n = 15), and had passed or failed
      the Wada test. Comparisons were carried out in all 106 patients and among the 20
      patients who failed the Wada test (12 who had TL and 8 who had AH). RESULTS: No
      patient became globally amnesic after surgery. Among all patients, no differences
      were found in pre-surgical or change scores (percentage of change after surgery
      compared with preoperative values) of neuropsychological tests between patients
      who underwent TL or AH. Among patients who failed the Wada test, those in the TL
      group showed higher visual memory impairment (p<0.05). There was a strong trend
      suggesting that TL is associated with higher verbal memory deficits than AH (p =
      0.07). Of those TL patients who failed the Wada test, the contralateral Wada
      score correlated with change scores in verbal intelligence quotient (p<0.01), and
      there was a strong trend towards a correlation with the logical memory immediate
      recall version subtest of the Wechsler Memory Scale (p = 0.06). CONCLUSIONS: No
      profound changes in intelligence quotient or memory scores were found after TL or
      AH. Nevertheless, patients who underwent TL and failed the Wada test showed more
      deficits than those who passed the test or those who had AH. The presence of a
      correlation between contralateral Wada scores and verbal deficits in TL patients
      who failed the Wada test but not among AH patients suggests that, if temporal
      surgery is required, AH might be preferred to TL in patients who fail the Wada
      test.

PMID- 15026508
TI  - Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation
      depends on the origin and the site of pain.
AB  - OBJECTIVE: Drug resistant neurogenic pain can be relieved by repetitive
      transcranial magnetic stimulation (rTMS) of the motor cortex. This study was
      designed to assess the influence of pain origin, pain site, and sensory loss on
      rTMS efficacy. PATIENTS AND METHODS: Sixty right handed patients were included,
      suffering from intractable pain secondary to one of the following types of
      lesion: thalamic stroke, brainstem stroke, spinal cord lesion, brachial plexus
      lesion, or trigeminal nerve lesion. The pain predominated unilaterally in the
      face, the upper limb, or the lower limb. The thermal sensory thresholds were
      measured within the painful zone and were found to be highly or moderately
      elevated. Finally, the pain level was scored on a visual analogue scale before
      and after a 20 minute session of "real" or "sham" 10 Hz rTMS over the side of the
      motor cortex corresponding to the hand on the painful side, even if the pain was
      not experienced in the hand itself. RESULTS: and discussion: The percentage pain
      reduction was significantly greater following real than sham rTMS (-22.9% v 
      7.8%, p = 0.0002), confirming that motor cortex rTMS was able to induce antalgic
      effects. These effects were significantly influenced by the origin and the site
      of pain. For pain origin, results were worse in patients with brainstem stroke,
      whatever the site of pain. This was consistent with a descending modulation
      within the brainstem, triggered by the motor corticothalamic output. For pain
      site, better results were obtained for facial pain, although stimulation was
      targeted on the hand cortical area. Thus, in contrast to implanted stimulation,
      the target for rTMS procedure in pain control may not be the area corresponding
      to the painful zone but an adjacent one. Across representation plasticity of
      cortical areas resulting from deafferentation could explain this discrepancy.
      Finally, the degree of sensory loss did not interfere with pain origin or pain
      site regarding rTMS effects. CONCLUSION: Motor cortex rTMS was found to result in
      a significant but transient relief of chronic pain, influenced by pain origin and
      pain site. These parameters should be taken into account in any further study of
      rTMS application in chronic pain control.

PMID- 15026509
TI  - Email triage of new neurological outpatient referrals from general practice.
AB  - OBJECTIVES: To determine whether an email triage system between general
      practitioners and a neurologist for new outpatient referrals is feasible,
      acceptable, efficient, safe, and effective. METHODS: This was a prospective
      single cohort study on the interface between primary care practitioners and the
      neurology clinic of a district general hospital. Seventy six consecutive patients
      with neurological symptoms from nine GPs, for whom a specialist opinion was
      deemed necessary, were entered in the study. The number of participants managed
      without clinic attendance and the reduction in neurologist's time compared with
      conventional consultation was measured, as was death, other specialist referral,
      and change in diagnosis in the 6 months after episode completion. The
      acceptability for GPs was ascertained by questionnaire. RESULTS: Forty three per
      cent of participants required a clinic appointment, 45% were managed by email
      advice alone, and 12% by email plus investigations. GP satisfaction was high.
      Forty four per cent of the neurologist's time was saved compared with
      conventional consultation. No deaths or significant changes in diagnosis were
      recorded during the 6 month follow up period. CONCLUSIONS: Email triage is
      feasible, acceptable to GPs, and safe. It has the potential for making the
      practice of neurologists more efficient, and this needs to be tested in a larger
      randomised study.

PMID- 15026510
TI  - MR venography in idiopathic intracranial hypertension: unappreciated and
      misunderstood.
AB  - BACKGROUND: Venous sinus disease must be excluded before diagnosing idiopathic
      intracranial hypertension but is found only rarely in typical cases. Magnetic
      resonance venography (MRV) is the technique of choice for investigating this, and
      provides images that are diagnostic and easy to interpret. However, recent work
      using more invasive techniques has documented pressure gradients and stenoses in
      the lateral venous sinuses in many cases of idiopathic intracranial hypertension.
      OBJECTIVE: To examine the reason for this discrepancy and to establish whether
      there are characteristic appearances on MRV in idiopathic intracranial
      hypertension that are routinely overlooked in clinical practice. METHODS: MRVs
      from 20 patients with idiopathic intracranial hypertension were reviewed,
      unblinded, by two neuroradiologists, and their appearances rated for focal
      narrowings and signal gaps. A control group of 40 asymptomatic volunteers,
      matched for age and sex with the patient group, was recruited prospectively for
      MRV, and their scans rated in the same way. RESULTS: The lateral sinuses
      presented a range of appearances with quite different distributions in the two
      groups (p<0.001). Bilateral lateral sinus flow gaps were seen in 13 of 20
      patients with idiopathic intracranial hypertension and in none of 40 controls.
      CONCLUSIONS: A historical failure to use normal healthy controls to establish the
      boundaries between imaging artefact, normal anatomical variant, and disease means
      that the pathological significance of the different appearances of the lateral
      sinuses on MRV has not so far been appreciated.

PMID- 15026512
TI  - Progressive auditory neuropathy in patients with Leber's hereditary optic
      neuropathy.
AB  - OBJECTIVE: To investigate auditory neural involvement in patients with Leber's
      hereditary optic neuropathy (LHON). METHODS: Auditory assessment was undertaken
      in two patients with LHON. One was a 45 year old woman with Harding disease
      (multiple-sclerosis-like illness and positive 11778mtDNA mutation) and mild
      auditory symptoms, whose auditory function was monitored over five years. The
      other was a 59 year old man with positive 11778mtDNA mutation, who presented with
      a long standing progressive bilateral hearing loss, moderate on one side and
      severe to profound on the other. Standard pure tone audiometry, tympanometry,
      stapedial reflex threshold measurements, stapedial reflex decay, otoacoustic
      emissions with olivo-cochlear suppression, auditory brain stem responses, and
      vestibular function tests were undertaken. RESULTS: Both patients had good
      cochlear function, as judged by otoacoustic emissions (intact outer hair cells)
      and normal stapedial reflexes (intact inner hair cells). A brain stem lesion was
      excluded by negative findings on imaging, recordable stapedial reflex thresholds,
      and, in one of the patients, olivocochlear suppression of otoacoustic emissions.
      The deterioration of auditory function implied a progressive course in both
      cases. Vestibular function was unaffected. CONCLUSIONS: The findings are
      consistent with auditory neuropathy-a lesion of the cochlear nerve presenting
      with abnormal auditory brain stem responses and with normal inner hair cells and
      the cochlear nucleus (lower brain stem). The association of auditory neuropathy,
      or any other auditory dysfunction, with LHON has not been recognised previously.
      Further studies are necessary to establish whether this is a consistent finding.

PMID- 15026513
TI  - Concurrent hereditary haemochromatosis and idiopathic Parkinson's disease: a case
      report series.
AB  - Hereditary haemochromatosis (HH) is a genetic disorder in which abnormal iron
      handling leads to excessive iron accumulation in systemic tissues. Magnetic
      resonance imaging studies suggest excess iron deposition in the basal ganglia of
      patients with HH. The symptoms of neurological complications of HH include
      cognitive decline, gait difficulties, cerebellar ataxia, and extrapyramidal
      dysfunction, but idiopathic Parkinson's disease, in which brain iron deposition
      is normal, has not been reported. We describe four patients with concurrent HH
      and IPD. Although three of the cases had risk factors for cerebrovascular and
      cardiovascular disease, computed tomography did not show ischaemic changes in the
      basal ganglia. We speculate that in these cases, abnormal deposition of iron in
      the basal ganglia induced the symptoms of IPD.

PMID- 15026515
TI  - Are men at greater risk for Parkinson's disease than women?
AB  - Parkinson's disease seems to occur more commonly in men than women based
      primarily on studies of death rates and prevalence. In recent years, several
      population based incidence studies of Parkinson's disease that included sex data
      have been conducted in a variety of populations around the world. To investigate
      whether these incidence studies suggest an increased risk of Parkinson's disease
      in men, a meta-analysis was performed of the differences in incidence of
      Parkinson's disease between men and women reported in seven studies that met the
      inclusion criteria. A significantly higher incidence rate of Parkinson's disease
      was found among men with the relative risk being 1.5 times greater in men than
      women. Possible reasons for this increased risk of Parkinson's disease in men are
      toxicant exposure, head trauma, neuroprotection by oestrogen, mitochondrial
      dysfunction, or X linkage of genetic risk factors.

PMID- 15026514
TI  - Increased systemic levels of norsalsolinol derivatives are induced by levodopa
      treatment and do not represent biological markers of Parkinson's disease.
AB  - Endogenously synthesised norsalsolinol derivatives are elevated in Parkinson's
      disease (PD) and have been considered potentially useful biological markers of
      the disease. However, little is known about the impact of dopaminergic drugs on
      the formation of these compounds. We prospectively examined the urine
      concentrations of norsalsolinol, N-methyl-norsalsolinol and salsolinol in 47 PD
      patients and 14 control subjects. Patients and control subjects were re-examined
      after approximately 1 year to assess long term changes. Norsalsolinol derivatives
      were low in controls and untreated patients with early PD. Increased urine
      concentrations of norsalsolinol derivatives were significantly associated with
      levodopa treatment. They were elevated more markedly in the urine of patients
      treated with high (>600 mg daily) doses of levodopa compared with patients
      receiving medium (300-600 mg) or low (<300 mg) doses of the drug. There was no
      correlation with disease parameters such as the severity of motor disability or
      deficits in the cognitive performance. In the patient group, the concentrations
      of all three norsalsolinol derivatives declined over the period of investigation,
      however, they still remained elevated compared with the control group. We
      conclude that systemic levels of norsalsolinol derivatives in treated patients
      with PD are likely to derive from the metabolism of levodopa and cannot be
      regarded as intrinsic markers of the disease. The limited ability of
      norsalsolinol derivatives to pass the blood-brain barrier prevents an
      intracerebral accumulation of these possibly harmful compounds, which are
      biochemically similar to the neurotoxin 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine.

PMID- 15026516
TI  - Religiosity is associated with hippocampal but not amygdala volumes in patients
      with refractory epilepsy.
AB  - OBJECTIVE: To assess the relationship between the behavioural triad of hyper
      religiosity, hypergraphia and hyposexuality in epilepsy, and volumes of the
      mesial temporal structures. METHOD: Magnetic resonance images were obtained from
      33 patients with refractory epilepsy and mesial temporal structure volumes
      assessed. Amygdala and hippocampal volumes were then compared in high and low
      scorers on the religiosity, writing, and sexuality sub-scales of the
      Neurobehavioural Inventory. RESULTS: Patients with high ratings on the
      religiosity scale had significantly smaller right hippocampi. Religiosity scores
      rated by both patient and carer showed a significant negative correlation with
      right hippocampal volumes in this group. There were no other differences in
      amygdala or hippocampal volumes between these groups, or between high and low
      scorers on the writing and sexuality sub-scales. CONCLUSIONS: These findings
      suggest that right hippocampal volumes are negatively correlated with religiosity
      in patients with refractory epilepsy.

PMID- 15026517
TI  - Brain tissue loss occurs after suppression of enhancement in patients with
      multiple sclerosis treated with autologous haematopoietic stem cell
      transplantation.
AB  - To assess whether brain tissue loss occurs after profound and sustained
      suppression of magnetic resonance imaging (MRI) enhancement, we measured brain
      volume changes from 10 patients with rapidly evolving secondary progressive
      multiple sclerosis (MS) treated with autologous haematopoietic stem cell
      transplantation and followed up for 24 months. An average yearly decrease of
      brain volume of about 1.9% was observed despite only five enhancing lesions seen
      on triple dose follow up scans of two patients. This indicates that, in MS,
      progressive loss of tissue can occur independently of concomitant MRI-visible
      inflammation.

PMID- 15026518
TI  - Percutaneous radiological gastrostomy: a safe and effective method of nutritional
      tube placement in advanced ALS.
AB  - BACKGROUND: Enteral nutrition may be required in amyotrophic lateral sclerosis
      (ALS), and is usually achieved by percutaneous endoscopic gastrostomy (PEG). As
      PEG is not indicated in patients with severe respiratory impairment, an
      alternative is percutaneous radiological gastrostomy (PRG), involving air
      insufflation into the stomach under fluoroscopic guidance for tube insertion.
      OBJECTIVE: To evaluate the safety of PRG and its effect on survival and
      respiratory function in ALS patients with respiratory failure. METHODS: 25
      consecutive ALS patients with severe dysphagia and forced vital capacity (FVC)
      <50% underwent PRG after October 2000. They were compared with 25 consecutive ALS
      patients with FVC <50% who underwent PEG before October 2000. Respiratory
      function was evaluated before and after the procedure. RESULTS: The two groups
      were similar for all relevant characteristics. PRG was successful in all cases,
      PEG in 23/25. One patient in each group died after the procedure. The mean
      survival time after the procedure was 204 days in the PRG group and 85 days in
      the PEG group (p<0.004). Respiratory function decreased more in the PEG group
      than in the PRG group (p<0.02). CONCLUSIONS: PRG appears to be safer than PEG in
      ALS patients with moderate or severe respiratory impairment, and is followed by a
      longer survival.

PMID- 15026519
TI  - Facial expression recognition and subthalamic nucleus stimulation.
AB  - BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN)
      improves motor signs in Parkinson's disease. However, clinical studies suggest
      that DBS of the STN may also affect cognitive and emotional functions. OBJECTIVE:
      To study the impact of STN stimulation in Parkinson's disease on perception of
      facial expressions. RESULTS: There was a selective reduction in recognition of
      angry faces, but not other expressions, during STN stimulation. CONCLUSIONS: The
      findings may have important implications for social adjustment in these patients.

PMID- 15026520
TI  - Reversible corpus callosum lesion in legionnaires' disease.
AB  - Legionnaires' disease is often associated with neurological findings. Despite
      such findings, computed tomography and neuropathological investigations are
      typically normal. This report describes a reversible lesion of the corpus
      callosum identified on magnetic resonance imaging (MRI) in a patient with
      legionnaires' disease. MRI may show previously undocumented neuropathology in
      acute legionnaires' disease. Legionella pneumophila infection should be included
      in the differential diagnosis of conditions associated with reversible lesions of
      the corpus callosum.

PMID- 15026521
TI  - Late onset MLD with normal nerve conduction associated with two novel missense
      mutations in the ASA gene.
AB  - Metachromatic leukodystrophy (MLD) rarely has its clinical onset in young adults,
      with a combination of cognitive and behavioural symptoms and peripheral
      neuropathy. Here we present an exceptional case with very late onset at 42 years
      of age and no clinical or neurophysiological sign of peripheral neuropathy.
      Molecular analysis revealed compound heterozygosity for two novel missense
      mutations affecting conserved residues in the arylsulphatase A (ASA) sulphatase
      and carboxyterminal domains, resulting in an 89% loss of enzymatic activity. This
      case indicates that MLD needs to be considered in the differential diagnosis of
      very late onset white matter diseases, even if not accompanied by peripheral
      nerve involvement.

PMID- 15026522
TI  - Intracranial hypotension caused by traumatic intrasacral meningocele.

PMID- 15026523
TI  - Transient ischaemic attack preceding anterior circulation infarction is
      independently associated with favourable outcome.

PMID- 15026524
TI  - Multiple cranial neuropathy and HIV-2.

PMID- 15026525
TI  - Progressive encephalomyelitis with rigidity associated with anti-amphiphysin
      antibodies.

PMID- 15026526
TI  - Central pontine myelinolysis associated with hypokalaemia in anorexia nervosa.

PMID- 15026534
TI  - Secondary structure and stability of the selenocysteine insertion sequences
      (SECIS) for human thioredoxin reductase and glutathione peroxidase.
AB  - We have used high resolution NMR and thermodynamics to characterize the secondary
      structure and stability of the selenocysteine insertion sequences (SECIS) of
      human glutathione peroxidase (58 nt) and thioredoxin reductase (51 nt). These
      sequences are members of the two classes of SECIS recently identified with two
      distinct structures capable of directing selenocysteine incorporation into
      proteins in eukaryotes. UV melting experiments showed a single cooperative and
      reversible transition for each RNA, which indicates the presence of stable
      secondary structures. Despite their large size, the RNAs gave well resolved NMR
      spectra for the exchangeable protons. Using NOESY, the imino protons as well as
      the cytosine amino protons of all of the Watson-Crick base pairs were assigned.
      In addition, a number of non-canonical base pairs including the wobble G.U pairs
      were identified. The interbase-pair NOEs allowed definition of the hydrogen
      bonded structure of the oligonucleotides, providing an experimental model of the
      secondary structure of these elements. The derived secondary structures are
      consistent with several features of the predicted models, but with some important
      differences, especially regarding the conserved sequence motifs.

PMID- 15026535
TI  - A novel strategy for selection of allosteric ribozymes yields RiboReporter
      sensors for caffeine and aspartame.
AB  - We have utilized in vitro selection technology to develop allosteric ribozyme
      sensors that are specific for the small molecule analytes caffeine or aspartame.
      Caffeine- or aspartame-responsive ribozymes were converted into fluorescence
      based RiboReporter trade mark sensor systems that were able to detect caffeine or
      aspartame in solution over a concentration range from 0.5 to 5 mM. With read
      times as short as 5 min, these caffeine- or aspartame-dependent ribozymes
      function as highly specific and facile molecular sensors. Interestingly,
      successful isolation of allosteric ribozymes for the analytes described here was
      enabled by a novel selection strategy that incorporated elements of both modular
      design and activity-based selection methods typically used for generation of
      catalytic nucleic acids.

PMID- 15026536
TI  - The alpha4 residues of human DNA topoisomerase IIalpha function in enzymatic
      activity and anticancer drug sensitivity.
AB  - We introduced a series of Pro substitutions within and near the alpha4 helix, a
      part of the breakage/rejoining region, in human DNA topoisomerase IIalpha, and
      analyzed if this region is involved in determination of anti-cancer drug
      sensitivity in a temperature- sensitive yeast strain (top2-4 allele). Among the
      19 mutants generated, H759P and N770P showed resistance to etoposide and
      doxorubicin at the non-permissive temperature, where cell growth depends on
      activity of the human enzyme. For these residues, mutants with an Ala
      substitution were further created, in which H759A also showed resistance to
      etoposide. H759P, H759A and N770P were expressed, purified and subjected to in
      vitro measurement of drug sensitivity. They generated lower amounts of the
      etoposide-induced cleavable complexes, and were also found to have lower
      decatenation activity than the wild-type. In the crystal structure, the yeast
      equivalent of His759 is found in the vicinity of the Arg713, a putative anchoring
      residue of the 3'-side of cleaved DNA strands. These results suggest that His759
      and the other alpha4 helix residues are involved in the enzymatic activity and
      drug sensitivity of human DNA topoisomerase IIalpha, via interaction with cleaved
      DNA.

PMID- 15026539
TI  - Relaxin potentiates the expression of inducible nitric oxide synthase by
      endothelial cells from human umbilical vein in in vitro culture.
AB  - The hormone relaxin (RLX), which can be detected in human venous cord blood, has
      been shown to be a potent vasodilator, acting through increased expression of
      inducible nitric oxide synthase (NOS II) and nitric oxide (NO) generation. This
      study aims at clarifying whether RLX, at concentrations of 100 and 1000 ng/ml for
      6 or 12 h of exposure, can influence the expression of NOS isoforms in human
      umbilical vein endothelial cells (HUVEC) cultured in vitro. NOS mRNA expression
      was studied by quantitative real-time RT-PCR, NOS protein expression and activity
      was studied by Western blot and nitrite assay, and immunoreactive NOS
      localization was performed by confocal microscopy. Untreated HUVEC expressed all
      the NOS isoforms, especially the constitutive, endothelial-type NOS III and, to a
      lesser extent, NOS II and NOS I. RLX-treated cells showed an increased expression
      of NOS II, attaining a maximum with 1000 ng/ml RLX, which gave rise to increased
      NO generation, as shown by nitrite assay. This effect of RLX appears to be
      mediated by activation of NOS II transcription factor NF-kappaB, since it was
      abolished by the NF-kappaB inhibitors curcumin-95 and dexamethasone. These
      findings suggest that RLX in the umbilical vein might contribute to the NO
      dependent regulation of vascular tone.

PMID- 15026538
TI  - siRNA relieves chronic neuropathic pain.
AB  - Double stranded, short interfering RNAs (siRNA) of 21-22 nt length initiate a
      sequence-specific, post-trancriptional gene silencing in animals and plants known
      as RNA interference (RNAi). Here we show that RNAi can block a pathophysiological
      pain response and provide relief from neuropathic pain in a rat disease model by
      down regulating an endogenous, neuronally expressed gene. Rats, intrathecally
      infused with a 21 nt siRNA perfectly complementary to the pain-related cation
      channel P2X3, showed diminished pain responses compared to missense (MS) siRNA
      treated and untreated controls in models of both agonist-evoked pain and chronic
      neuropathic pain. This form of delivery caused no adverse effects in any of the
      animals receiving P2X3 siRNA, MS siRNA or vehicle. Molecular analysis of tissues
      revealed that P2X3 mRNA expressed in dorsal root ganglia, and P2X3 protein
      translocated into the dorsal horn of the spinal cord, were significantly
      diminished. These observations open a path toward use of siRNA as a genetic tool
      for drug target validation in the mammalian central nervous system, as well as
      for proof of concept studies and as therapeutic agents in man.

PMID- 15026540
TI  - Gonadotrophin-induced gene regulation in human granulosa cells obtained from IVF
      patients. Modulation of steroidogenic genes, cytoskeletal genes and genes coding
      for apoptotic signalling and protein kinases.
AB  - Gonadotrophins exert a major effect on ovarian development and on the control of
      fertilization. By stimulating cells with forskolin (FK), it is possible to study
      which genes are activated by gonadotrophins via the cAMP cascade, and which by
      alternative pathways. Using RNA isolated from stimulated cells, we found that 59%
      of the total genes modulated by LH were also modulated by FK, while 69% of the
      genes modulated exclusively by FSH were also modulated by FK. Gene transcripts
      involved in steroidogenesis/progesterone production were highly elevated, while
      17beta-hydroxysteroid dehydrogenase was down-regulated. This suggests that a
      decrease in the conversion of androstenedione to testosterone and estrone to
      estradiol occurs during luteinization. Down-regulation of genes coding for actin
      cytoskeleton proteins and cytokeratin 18 was observed in response to
      gonadotrophin and cAMP stimulation. Several of the genes coding for the
      microtubule network were also modulated, implying that rearrangement of the
      cytoskeletal proteins permits better coupling between organelles involved in
      steroidogenesis. A dramatic change in gene transcripts coding for signalling
      enzymes was observed following LH stimulation. This includes the down-regulation
      of adenylyl cyclase 7 and 9, elevation of cAMP-dependent phosphodiesterase, and
      the up-regulation of a negative regulator of G-protein signalling (RGS16) that
      may negate gonadotrophin signalling via guanine nucleotide binding proteins. Thus
      luteinized cells, despite increased gene transcripts to LH/chorionic
      gonadotrophin (CG) receptors, respond inefficiently to gonadotrophin stimulation,
      due to attenuation of signal transduction in the cAMP cascade at multiple steps.
      Novel genes involved in the regulation of apoptosis were found for the first time
      to be up-regulated by gonadotrophin stimulation, including: BAX inhibitor-1,
      granulysin and apoptosis repressor with caspase recruitment domain (ARC). These
      proteins may be involved in a unique alternative pathway of ovarian cell death.
      Such a pathway could temporarily preserve the mitochondria and progesterone
      production during the initial stages of granulosa cell apoptosis.

PMID- 15026541
TI  - Aberrant gene expression associated with recurrent pregnancy loss.
AB  - Recent studies indicate that a number of factors including chromosomal
      abnormalities, immunological feto-maternal rejection, hormonal irregulation and
      anatomical factors are involved in provoking recurrent pregnancy loss (RPL). This
      indicates that normal cellular regulation of these factors is required for
      maintaining normal pregnancy. In addition, it is expected that biological
      processes for maintaining normal pregnancy require a series of differential gene
      expression. As expected, our previous investigations revealed that there are
      >/=30 genes showing different levels of expression between normal and RPL
      patients. In addition, other research groups have also identified a number of
      genes that are expressed aberrantly in pregnancy failure. In this review, recent
      study on aberrant expression levels of genes, which are grouped as immunity
      related, angiogenesis-related, apoptosis-related and other groups of genes, will
      be discussed.

PMID- 15026537
TI  - Enhanced transfection efficiency of a systemically delivered tumor-targeting
      immunolipoplex by inclusion of a pH-sensitive histidylated oligolysine peptide.
AB  - Successful cancer gene therapy depends on the development of non-toxic,
      efficient, tumor cell- specific systemic gene delivery systems. Our laboratory
      has developed a systemically administered, ligand-liposome complex that can
      effectively and preferentially deliver its therapeutic payload to both primary
      and metastatic tumors. To further improve the transfection efficiency of this
      targeting complex, a synthetic pH-sensitive histidylated oligolysine K[K(H)KKK]5
      K(H)KKC (HoKC), designed to aid in endosomal escape and condensation of DNA, was
      included in the complex. The presence of HoKC increased the in vitro transfection
      efficiency over that of the original complex. Moreover, no increase in
      cytotoxicity was observed due to the presence of the HoKC peptide. In a DU145
      human prostate cancer xenograft tumor model in athymic nude mice, inclusion of
      the HoKC peptide did not interfere with the tumor targeting specificity of the
      i.v. administered ligand/liposome/DNA complex. Most importantly, the level of
      transgene expression was significantly elevated in the tumors, but not in the
      normal tissue in those animals receiving the complex incorporating HoKC. The in
      vivo enhancement of transfection efficiency by this modified gene delivery
      vehicle could lead to a reduction in the number of administrations required for
      antitumor efficacy.

PMID- 15026542
TI  - Nucleotide-based therapies targeting clusterin chemosensitize human lung
      adenocarcinoma cells both in vitro and in vivo.
AB  - INTRODUCTION: Lung cancer is highly lethal and resistant to most anticancer
      interventions. Treatment resistance is mediated, in part, by enhanced expression
      of cell survival proteins that help facilitate tumor progression. Clusterin is a
      stress-associated cytoprotective protein up-regulated by various apoptotic
      triggers in many cancers and confers treatment resistance when overexpressed. The
      objectives in this study were to evaluate clusterin expression levels in human
      lung cancer tissue, and to test effects of clusterin silencing using antisense
      oligonucleotides (ASOs) and short interfering double-stranded RNAs (siRNAs) on
      chemosensitivity in human lung cancer A549 cells. METHODS: Clusterin
      immunostaining was evaluated in a tissue microarray of 149 spotted human lung
      cancers. The effects of clusterin ASO or siRNA treatment on clusterin expression
      and chemosensitivity to paclitaxel was examined in A549 cells in vitro while the
      ability of clusterin ASO to chemosensitize in vivo was evaluated in
      immunocompromised mice bearing A549 tumors. RESULTS: More than 80% of human non
      small cell lung cancers are immunoreactive for clusterin. Clusterin ASO or siRNA
      decreased clusterin mRNA expression in A549 cells >75% in a dose-dependent,
      sequence-specific manner, and significantly enhanced chemosensitivity to
      paclitaxel in vitro. Characteristic apoptotic DNA laddering was observed after
      combined treatment with ASO plus paclitaxel, but not with either agent alone. In
      vivo administration of clusterin ASO, compared to mismatch control
      oligonucleotide, synergistically enhanced the effects of paclitaxel or
      gemcitibine to significantly delay A549 tumor growth. CONCLUSION: These findings
      identify clusterin as a valid therapeutic target in strategies employing novel
      multimodality therapy for advanced lung cancer.

PMID- 15026543
TI  - Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of
      hypoxia-inducible factor-1alpha.
AB  - The hypoxia-inducible factor-1 (HIF-1) transcription factor is an important
      regulator of tumor response to hypoxia that include increased angiogenesis,
      glycolytic metabolism, and resistance to apoptosis. HIF-1 activity is regulated
      by the availability of the HIF-1alpha subunit, the levels of which increase under
      hypoxic conditions. PX-478 (S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl
      propionic acid N-oxide dihydrochloride) is an inhibitor of constitutive and
      hypoxia-induced HIF-1alpha levels and thus HIF-1 activity. We report that PX-478
      given to mice suppresses HIF-1alpha levels in HT-29 human colon cancer xenografts
      and inhibits the expression of HIF-1 target genes including vascular endothelial
      growth factor and the glucose transporter-1. PX-478 shows antitumor activity
      against established (0.15-0.40 cm(3)) human tumor xenografts with cures of SHP-77
      small cell lung cancer and log cell kills up to 3.0 for other tumors including HT
      29 colon, PC-3 prostate, DU-145 prostate, MCF-7 breast, Caki-1 renal, and Panc-1
      pancreatic cancers. Large (0.83 cm(3)) PC-3 prostate tumors showed 64%
      regression, which was greater than for smaller tumors. The antitumor response to
      PX-478 was positively correlated with tumor HIF-1alpha levels (P < 0.02) and was
      accompanied by massive apoptosis. The results show that PX-478 is an inhibitor of
      HIF-1alpha and HIF-1 transcription factor activity in human tumor xenografts and
      has marked antitumor activity against even large tumor xenografts, which
      correlates positively with HIF-1alpha levels.

PMID- 15026544
TI  - Small molecule inhibition of hypoxia inducible factor-1alpha: a viable
      therapeutic approach?

PMID- 15026545
TI  - A new class of peroxisome proliferator-activated receptor gamma (PPARgamma)
      agonists that inhibit growth of breast cancer cells: 1,1-Bis(3'-indolyl)-1-(p
      substituted phenyl)methanes.
AB  - 1,1-Bis(3'-indolyl)-1-(p-trifluoromethylphenyl)methane (DIM-C-pPhCF(3)) and
      several p-substituted phenyl analogues have been investigated as a new class of
      peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Structure
      activity studies in PPARgamma-dependent transactivation assays in MCF-7 breast
      cancer cells show that 5-20 micro M concentrations of compounds containing p
      trifluoromethyl, t-butyl, cyano, dimethylamino, and phenyl groups were active,
      whereas p-methyl, hydrogen, methoxy, hydroxyl, or halogen groups were inactive as
      PPARgamma agonists. Induction of PPARgamma-dependent transactivation by 15-deoxy
      Delta12,14-prostaglandin J2 (PGJ2) and DIM-C-pPhCF(3) was inhibited in MCF-7
      cells cotreated with the PPARgamma-specific antagonist N-(4'-aminopyridyl)-2
      chloro-5-nitrobenzamide. In mammalian two-hybrid assays, DIM-C-pPhCF(3) and PGJ2
      (5-20 micro M) induced interactions of PPARgamma with steroid receptor
      coactivator (SRC) 1, SRC2 (TIFII), and thyroid hormone receptor-associated
      protein 220 but not with SRC3 (AIB1). In contrast, DIM-C-pPhCF(3), but not PGJ2,
      induced interactions of PPARgamma with PPARgamma coactivator-1. C-substituted
      diindolylmethanes inhibit carcinogen-induced rat mammary tumor growth, induce
      differentiation in 3T3-L1 preadipocytes, inhibit MCF-7 cell growth and G(0)/G(1)
      S phase progression, induce apoptosis, and down-regulate cyclin D1 protein and
      estrogen receptor alpha in breast cancer cells. These compounds are a novel class
      of synthetic PPARgamma agonists that induce responses in MCF-7 cells similar to
      those observed for PGJ2.

PMID- 15026546
TI  - Novel peptidomimetic inhibitors of signal transducer and activator of
      transcription 3 dimerization and biological activity.
AB  - The critical role of signal transducer and activator of transcription 3 (Stat3)
      in the growth and survival of human tumor cells identifies it as a promising
      target for cancer drug discovery. We previously identified a Stat3 SH2 domain
      binding phosphopeptide, PY*LKTK, and its tripeptide derivatives, PY*L and AY*L
      (where Y* represents phosphotyrosine), which inhibit Stat3 biochemical activity
      and biological function. Here, we report novel peptidomimetic compounds based on
      PY*L (or AY*L) with substitution of the Y-1 residue by benzyl, pyridyl, or
      pyrazinyl derivatives that are selective and greater than 5-fold more potent in
      disrupting Stat3 activity in vitro than lead tripeptides. The biological
      activities of these derivatives mirror that originally observed for peptides. In
      this context, the representative peptidomimetic ISS 610 with 4-cyanobenzoate
      substitution inhibits constitutive Stat3 activity in Src-transformed mouse
      fibroblasts and human breast and lung carcinoma cells. This effect is not evident
      with the non-phosphorylated counterpart, ISS 610NP, consistent with interaction
      of peptidomimetics with the SH2 domain of Stat3. Moreover, ISS 610 induces cell
      growth inhibition and apoptosis of Src-transformed fibroblasts that contain
      persistently active Stat3. We present the first report of a peptidomimetic
      approach to design of small-molecule inhibitors of Stat3 that are also among the
      first examples of disruptors of transcription factor dimerization with the
      potential for novel cancer therapy.

PMID- 15026547
TI  - Regulation of Vinca alkaloid-induced apoptosis by NF-kappaB/IkappaB pathway in
      human tumor cells.
AB  - Antimicrotubule Vinca alkaloids, such as vinblastine and vincristine, interfere
      with the dynamics of microtubules and have shown significant cell killing
      activity in a variety of tumor cells through induction of apoptosis. The
      mechanism by which Vinca alkaloids induce apoptosis is not entirely clear. In
      this study, we found that glucocorticoids inhibit Vinca alkaloid-induced
      apoptosis without affecting G(2)-M arrest in human breast cancer BCap37 cells and
      human epidermoid tumor KB cells, suggesting that Vinca alkaloid-induced apoptosis
      may occur via a pathway independent of cell cycle arrest. Further analyses
      indicated that Vinca alkaloids cause significant degradation of IkappaBalpha,
      which in turn results in nuclear factor-kappaB (NF-kappaB) activation.
      Transfection of antisense IkappaBalpha in BCap37 cells sensitizes Vinca alkaloid
      induced apoptosis. Moreover, in vitro kinase assays show that the activity of
      IkappaB kinase (IKK) was activated by Vinca alkaloids and was not affected by
      glucocorticoids. Stable transfection of dominant-negative deletional mutant
      IkappaBalpha, which is insensitive to IKK-mediated phosphorylation and
      degradation, resulted in the inhibition of Vinca alkaloid-induced NF-kappaB
      activation and reduced sensitivity of tumor cells to Vinca alkaloid-induced
      apoptosis. These findings suggest that the NF-kappaB/IkappaB signaling pathway
      may contribute to the mediation of Vinca alkaloid-induced apoptosis in human
      tumor cells.

PMID- 15026548
TI  - The proteasome inhibitor bortezomib synergizes with gemcitabine to block the
      growth of human 253JB-V bladder tumors in vivo.
AB  - Bortezomib (PS-341, Velcade) is a dipeptidyl boronic acid inhibitor of the 20S
      proteasome that was developed as a therapeutic agent for cancer. Here, we
      investigated the effects of bortezomib on the growth of human 253JB-V bladder
      cancer cells. Although the drug did not stimulate significant increases in levels
      of apoptosis, it inhibited cell growth in a concentration-dependent fashion and
      augmented the growth inhibitory effects of gemcitabine in vitro. These effects
      were associated with accumulation of p53 and p21 and suppression of cyclin
      dependent kinase 2 activity. Bortezomib also inhibited secretion of the
      proangiogenic factors matrix metalloproteinase-9, interleukin-8 (IL-8), and
      vascular endothelial growth factor (VEGF). In vivo studies with 253JB-V tumors
      growing in nude mice demonstrated that bortezomib (1 mg/kg) did not inhibit tumor
      growth when it was delivered as a single agent, although it reduced tumor
      microvessel density and inhibited expression of VEGF and IL-8. However,
      combination therapy with bortezomib plus gemcitabine produced synergistic tumor
      growth inhibition associated with strong suppression of tumor cell proliferation.
      Together, our results demonstrate that bortezomib has significant
      antiproliferative activity in aggressive bladder cancer cells, which is best
      exploited within the context of combination chemotherapy.

PMID- 15026549
TI  - Antiproliferative effect of nitrosulindac (NCX 1102), a new nitric oxide-donating
      non-steroidal anti-inflammatory drug, on human bladder carcinoma cell lines.
AB  - Non-steroidal anti-inflammatory drugs (NSAIDs) are potent antitumoral agents but
      their side effects limit their clinical use. A novel class of drugs, nitric oxide
      donating NSAIDs (NO-NSAIDs), was found to be safer and more active than classical
      NSAIDs. This study explored the effect of the NO-donating sulindac derivative,
      NCX 1102, on three human urothelial epithelial carcinoma cell lines (T24, 647V,
      and 1207) and primary cultures of normal urothelial cells. Cytotoxicity,
      antiproliferative effect, cell cycle alterations, morphological changes, and
      apoptosis were investigated after treatment with NCX 1102 in comparison with the
      native molecule. After treatment, there was a cytotoxic effect (with IC(50) at 48
      h of 23.1 micro M on 647V, 19.4 micro M on T24, and 14.5 micro M on 1207) and an
      antiproliferative effect on all three cell lines with NCX 1102 but not with
      sulindac. No effect was detected on normal urothelial cells. Flow cytometric
      analysis showed a differential NCX 1102-induced accumulation of cells in various
      phases of the cell cycle, depending on cell line and concentration. NCX 1102
      induced an occurrence of multinucleated cells in all cell lines and mitotic
      arrest in 647V and 1207. NCX 1102-treated T24 and 647V cell lines showed a
      significant difference of apoptotic cell amount when compared to controls. Our
      results demonstrated a greater antiproliferative potency of NCX 1102 compared to
      its parent molecule sulindac, and suggested that this new NO-NSAID may have
      therapeutic impact in the management of bladder cancer.

PMID- 15026551
TI  - Acyclic retinoid activates retinoic acid receptor beta and induces
      transcriptional activation of p21(CIP1) in HepG2 human hepatoma cells.
AB  - Acyclic retinoid (ACR), a novel synthetic retinoid, has recently been
      demonstrated by us to inhibit the in vitro growth of human hepatoma cells, and
      this effect was associated with decreased expression of cell cycle-related
      molecules. These results, taken together with previous in vitro and clinical
      studies with ACR, suggest that this agent may be useful in the chemoprevention
      and therapy of hepatoma and possibly other human malignancies. In the present
      study, we further examined the molecular effects of ACR on the HepG2 human
      hepatoma cell line, focusing on the expression of nuclear retinoid receptors and
      the cell cycle inhibitor protein p21(CIP1). Reverse transcription-PCR assays and
      Western blot analyses indicated that these cells express retinoic acid receptors
      (RARs) alpha, beta, and gamma, retinoid X receptors (RXRs) alpha and beta, and
      peroxisome proliferator-activated receptors (PPAR) gamma mRNA. Treatment with ACR
      caused a rapid induction within 3 h of RARbeta mRNA and the related protein, but
      there was no significant change in the levels of the mRNA or proteins for RARs
      alpha and gamma, RXRs alpha and beta, and PPARgamma. There was also a rapid
      increase in p21(CIP1) mRNA and protein in HepG2 cells treated with ACR, and this
      induction occurred via a p53-independent mechanism. In transient transfection
      reporter assays, we cotransfected the retinoic acid response element
      chloramphenicol acetyltransferase (CAT) reporter gene into HepG2 cells together
      with a RARbeta expression vector. RARbeta expression markedly stimulated CAT
      activity (up to about 4-fold) after the addition of ACR. However, CAT activity in
      the presence of ACR was only about 2-fold higher than that in the absence of ACR,
      when cells were cotransfected with RARs alpha and gamma or RXRalpha. These
      findings suggest that the growth inhibitory effects of ACR are mediated at least
      in part through RARbeta and that both RARbeta and p21(CIP1) play critical roles
      in the molecular mechanisms of growth inhibition induced by ACR.

PMID- 15026550
TI  - The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and
      induces apoptosis in human cholangiocarcinoma cells.
AB  - The expression of cyclooxygenase (COX)-2 is increased in human cancers including
      cholangiocarcinoma. This study was designed to evaluate the effect and mechanisms
      of the selective COX-2 inhibitor celecoxib in the growth control of human
      cholangiocarcinoma cells. Immunohistochemical analysis using human
      cholangiocarcinoma tissues showed increased levels of COX-2 as well as phospho
      Akt (Thr (308)), a protein kinase activated by COX-2-mediated prostaglandins, in
      human cholangiocarcinoma cells. Treatment of cultured human cholangiocarcinoma
      cells (HuCCT1, SG231, and CCLP1) with celecoxib resulted in a dose- and time
      dependent reduction of cell viability. Fluorescence microscopy, Western blot, and
      caspase activity assays demonstrated that celecoxib induced morphological
      features of apoptosis, activation of caspase-9 and caspase-3, and release of
      cytochrome c. The celecoxib-induced cell death was significantly blocked by N
      benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone, a wide-spectrum caspase
      inhibitor. Furthermore, cholangiocarcinoma cells treated with celecoxib showed
      significant reduction of Akt phosphorylation, whereas the levels of Bcl-2 and Bax
      were not altered. Inhibition of Akt activation by LY294002 significantly
      decreased the viability of human cholangiocarcinoma cells. These findings suggest
      that celecoxib inhibits cholangiocarcinoma growth partly through induction of
      apoptosis and inhibition of Akt phosphorylation.

PMID- 15026552
TI  - Antitumor histone deacetylase inhibitors suppress cutaneous radiation syndrome:
      Implications for increasing therapeutic gain in cancer radiotherapy.
AB  - Radiotherapy is an effective treatment for head and neck, skin, anogenital, and
      breast cancers. However, radiation-induced skin morbidity limits the therapeutic
      benefits. A low-toxicity approach to selectively reduce skin morbidity without
      compromising tumor killing by radiotherapy is needed. We found that the antitumor
      agents known as histone deacetylase (HDAC) inhibitors (phenylbutyrate,
      trichostatin A, and valproic acid) could suppress cutaneous radiation syndrome.
      The effects of HDAC inhibitors in promoting the healing of wounds caused by
      radiation and in decreasing later skin fibrosis and tumorigenesis were correlated
      with suppression of the aberrant expression of radiation-induced transforming
      growth factor beta and tumor necrosis factor alpha. Our findings implicate that
      the inhibition of HDAC may provide a novel strategy to increase the therapeutic
      gain in cancer radiotherapy by not only inhibiting tumor growth but also
      protecting normal tissues.

PMID- 15026553
TI  - Down-regulation of Bcl-2 is associated with cisplatin resistance in human small
      cell lung cancer H69 cells.
AB  - Overexpression of the anti-apoptotic protein Bcl-2 has been associated with
      several malignancies, including small cell lung cancer (SCLC). In the present
      study, we have investigated if Bcl-2 contributes to the emergence of cisplatin
      resistance in SCLC H69 cells. The ability of cisplatin to induce apoptosis was
      decreased in H69 cells that acquired resistance to cisplatin (H69/CP). The level
      of Bcl-2 was, however, substantially reduced in H69/CP cells compared to parental
      H69 cells. There was little change in Bcl-2 content in H69 cells that were
      resistant to etoposide (VP-16) or Taxol. Bcl-2 was constitutively phosphorylated
      at serine 70 in H69 cells but not in H69/CP cells and cisplatin had little effect
      on Bcl-2 phosphorylation. The level of procaspase-3 was elevated in H69/CP cells
      but the ability of cisplatin to induce mitochondrial depolarization, caspase-9
      activation, and poly(ADP-ribose) polymerase (PARP) cleavage was compromised in
      H69/CP cells. The level of the anti-apoptotic protein Bcl-x(L) and the pro
      apoptotic protein Bax was slightly reduced in H69/CP cells but the ratio of pro
      apoptotic and anti-apoptotic Bcl-2 family proteins was not sufficient to explain
      cellular resistance to cisplatin. These results suggest that the acquisition of
      cisplatin resistance by H69 cells was not due to an increase in the
      level/phosphorylation status of the anti-apoptotic protein Bcl-2.

PMID- 15026554
TI  - TNP-470 promotes initial vascular sprouting in xenograft tumors.
AB  - TNP-470 (AGM-1470), an analogue of fumagillin, was one of the first molecules
      proposed to have antiangiogenic properties. This concept was based on its ability
      to inhibit both endothelial proliferation in vitro and tumor growth in vivo in a
      number of xenograft models. Yet, subsequent investigations indicated that the
      biochemical activities associated with TNP-470 are not selective for endothelial
      cells. Moreover, recent evidence suggests that this agent inhibits tumor growth
      in vivo, but without a corresponding decrease in angiogenesis. Therefore, we
      performed a detailed comparison of TNP-470 to a validated antiangiogenic agent, a
      VEGF inhibitor termed VEGF-Trap, using a xenograft model of Wilms tumor.
      Treatment with TNP-470 for 5 weeks significantly suppressed xenograft growth
      (83%). Surprisingly, this inhibition was not associated with a decrease in
      angiogenesis, but instead with an increase in tiny neovessels. To determine
      whether this was a direct effect of TNP-470 on tumor vessels, we examined its
      effect in a short-term assay using large tumors with established vasculature. In
      contrast to treatment with VEGF-Trap, which led to rapid vessel regression and
      tumor hypoxia, tumors exposed to TNP-470 for 1 day displayed increased capillary
      sprouting, with significantly increased microvessel density, vessel length, and
      branch points. TNP-470 did not induce tumor hypoxia as demonstrated by minimal
      pimonidazole staining and VEGF expression. TNP-470 did, however, cause a marked
      increase in apoptosis of tumor cells. Our results indicate that the antitumor
      effects of TNP-470 cannot be attributed to prevention of neoangiogenesis, but
      instead to its direct action on tumor cells.

PMID- 15026555
TI  - Retinoic acid-induced CD38 antigen as a target for immunotoxin-mediated killing
      of leukemia cells.
AB  - A major obstacle in the successful delivery of antibody-based therapeutics to
      tumor cells is the heterogeneity of target antigen expression. We reported
      previously that retinoic acid (RA) is a potent and selective inducer of the cell
      surface antigen CD38 in myeloid leukemia cells. The purpose of this study was to
      determine whether the RA-induced CD38 antigen could be a target for an anti-CD38
      based immunotoxin to induce selective killing of leukemia cells. The combination
      of RA and the anti-CD38 gelonin immunotoxin induced a synergistic killing of
      leukemia cells. Thus, coculture of myeloid leukemia cells and cell lines with as
      little as 1 nM RA in the presence of immunotoxin induced substantial killing
      (>90%) of leukemia cell clones. More importantly, the blasts of myeloid leukemia
      patients, irrespective of their morphological and phenotypic features, also
      responded to the RA and immunotoxin combination when cultured ex vivo. A similar
      synergistic effect between RA and immunotoxin was observed against a multidrug
      resistant variant subline of HL-60 cells. However, another variant of HL-60
      cells, HL-60R, in which the retinoid receptor function has been abrogated by a
      trans-dominant-negative mutation, exhibited complete resistance to the
      immunotoxin-induced killing effect in the presence or absence of RA. Our results
      suggest that RA combined with anti-CD38-based therapeutic agent may offer
      exciting opportunities for the treatment of myeloid leukemias despite their
      multiplicity of genetic and clinical varieties.

PMID- 15026556
TI  - Cassette dosing pharmacokinetics of a library of 2,6,9-trisubstituted purine
      cyclin-dependent kinase 2 inhibitors prepared by parallel synthesis.
AB  - Determination of pharmacokinetic properties in the intact animal remains a major
      bottleneck in drug discovery. Cassette dosing involves administration of a
      cocktail of drugs to individual animals. Here we describe the cassette dosing
      properties of a 107-membered library of 2,6,9-trisubstituted purine cyclin
      dependent kinase 2 (CDK2) inhibitors. A three-step parallel synthesis approach
      produced compounds with purity ranging from 63% to 100%. Cassette dosing was
      validated by comparing the pharmacokinetic parameters obtained following i.v.
      administration of a mixture of olomoucine, R-roscovitine (CYC202), and bohemine,
      each at 16.6 mg/kg, with results for administration of single agents at 50 mg/kg.
      No significant difference was observed between the pharmacokinetic parameters of
      agents when dosed in combination compared with those of individual compounds.
      CYC202 showed the highest area under the curve (AUC) and the longest elimination
      half-life (t(1/2)). Further cassettes evaluated the library of trisubstituted
      purines with CYC202 and purvalanol A included as pharmacokinetic standards in a
      validated limited sampling strategy. The ratios of pharmacokinetic parameters to
      that of CYC202 [AUC, maximum concentration (C(max)), and t(1/2)] remained similar
      when compounds were tested in two different cassettes or as individual compounds.
      Following dosing of the same cassette on three different days, there was less
      than 20% variation in pharmacokinetic parameters between days. The structure
      pharmacokinetics relationship showed that the favored purine substituents are
      benzylamine and veratrylamine at position 6, amino-2 propanol at position 2, and
      methylpropyl or hydroxyethyl at position 9. Without cassette dosing, this study
      would have used 3 times as many animals and would have taken 4 times longer,
      illustrating the power of this method in lead optimization.

PMID- 15026557
TI  - Cytochrome P450 enzymes: novel options for cancer therapeutics.
AB  - The concept of overexpression of individual forms of cytochrome P450 enzymes in
      tumor cells is now becoming well recognized. Indeed, a growing body of research
      highlights the overexpression of P450s, particularly CYP1B1, in tumor cells as
      representing novel targets for anticancer therapy. The purpose of this review is
      to outline the novel therapeutic options and opportunities arising from both
      enhanced endogenous expression of cytochrome P450 in tumors and cytochrome P450
      mediated gene therapy.

PMID- 15026558
TI  - Calcitriol in cancer treatment: from the lab to the clinic.
AB  - 1,25-Dihydroxyvitamin D (calcitriol), the most active metabolite of vitamin D,
      has significant antineoplastic activity in preclinical models. Several mechanisms
      of activity have been proposed. These include inhibition of proliferation
      associated with cell cycle arrest and, in some models, differentiation, reduction
      in invasiveness and angiogenesis, and induction of apoptosis. Proposed mechanisms
      differ between tumor models and experimental conditions, and no unifying
      hypothesis about the mechanism of antineoplastic activity has emerged.
      Synergistic and/or additive effects with cytotoxic chemotherapy, radiation, and
      other cancer drugs have been reported. Significantly supraphysiological
      concentrations of calcitriol are required for antineoplastic effects. Such
      concentrations are not achievable in patients when calcitriol is dosed daily due
      to predictable hypercalcemia and hypercalcuria; however, phase I trials have
      demonstrated that intermittent dosing allows substantial dose escalation and has
      produced potentially therapeutic peak calcitriol concentrations. Recently, a
      phase II study reported encouraging levels of activity for the combination of
      high-dose calcitriol and docetaxel administered on a weekly schedule in patients
      with androgen-independent prostate cancer. This regimen is now under study in a
      placebo-controlled randomized trial in androgen-independent prostate cancer and
      in phase II studies in several other tumor types. Further work is needed to
      elucidate the molecular mechanisms of antineoplastic activity and optimal
      clinical applications of calcitriol in cancer.

PMID- 15026559
TI  - Correspondence re: DC Lev et al., Dacarbazine causes transcriptional up
      regulation of interleukin 8 and vascular endothelial growth factor in melanoma
      cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther,
      2003;2(8):753-63.

PMID- 15026561
TI  - High-versus low-dose ACE inhibitor therapy in chronic heart failure.
AB  - OBJECTIVE: To discuss the controversy associated with the optimal dosing of
      angiotensin-converting enzyme (ACE) inhibitors in the management of patients with
      systolic heart failure; specifically, to review data related to the use of high
      dose ACE inhibitors related to both neurohormonal and clinical outcomes
      associated with doses similar to, lower than, and higher than those used in the
      large, randomized clinical trials. DATA SOURCES: Primary, review, and meta
      analysis articles were identified by MEDLINE search (1987-September 2002) and
      through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the
      articles identified from the data sources were evaluated, and all information
      deemed relevant was included in this discussion. All available comparative dose
      trials, both prospective and retrospective, were evaluated for clinical and
      neurohormonal outcomes. DATA SYNTHESIS: The majority of data comparing the effect
      of high- with low-dose ACE inhibitors on neurohormonal outcomes demonstrate dose
      related reduction in various neurohormonal measurements including plasma ACE,
      aldosterone, atrial natriuretic peptide, B-type natriuretic peptide, and
      interleukin-6 levels. Clinical endpoints including New York Heart Association
      class and heart failure-related hospitalizations were reduced by higher doses,
      but a dose-related survival benefit has not been demonstrated. Differences in
      duration of therapy and study design may account for variability in neurohormonal
      and morbidity results among various studies. CONCLUSIONS: Despite documented
      underutilization in clinical practice of doses of ACE inhibitors demonstrated in
      large controlled trials to improve morbidity and mortality, clinicians should
      attempt to reach these target doses if possible in patients with heart failure.
      Higher doses may improve surrogate markers for heart failure without impacting
      survival.

PMID- 15026560
TI  - Linkage of myostatin pathway genes with knee strength in humans.
AB  - This study was the first to explore the potential role of the myostatin (GDF8)
      pathway in relation to muscle strength and estimated muscle cross-sectional area
      in humans using linkage analysis with a candidate gene approach. In young male
      sibs (n = 329) 11 polymorphic markers in or near 10 candidate genes from the
      myostatin pathway were genotyped. Muscle mass was estimated by anthropometric
      measurements, and maximal knee strength was evaluated using isokinetic
      dynamometers (Cybex NORM). Single-point nonparametric variance components and
      linear quantitative trait locus regression linkage analysis methods were used.
      Linkage patterns were observed between knee extension and flexion peak torque
      with markers D2S118 (GDF8), D6S1051 (CDKN1A), and D11S4138 (MYOD1), and a maximum
      LOD score of 2.63 (P = 0.0002) was observed with D2S118. The ratios of peak
      torque over muscle and bone area of the midthigh of the lower contraction
      velocity (60 degrees/s) showed more frequently significant LOD scores than the
      torques at high velocity (240 degrees/s). Although myostatin is physiologically
      more related to muscle mass through possible effects of hyperplasia and
      hypertrophy than it is to strength, only two estimated muscle cross-sectional
      areas were marginally linked (LOD 1.06 and 1.07, P = 0.01) with marker D2S118
      near GDF8 (2q32.2). The present results gave suggestive evidence that the
      myostatin pathway might be important for strength phenotypes, and GDF8, CDKN1A,
      and MYOD1 are potential candidate regions for a further and denser mapping with
      respect to these phenotypes.

PMID- 15026562
TI  - Lichenoid drug eruption probably associated with rofecoxib.
AB  - OBJECTIVE: To report a case of lichenoid drug eruption (LDE) probably induced by
      rofecoxib. CASE SUMMARY: A 73-year-old woman was prescribed rofecoxib 25 mg/day
      for rheumatoid arthritis in addition to other medications on which the patient
      had been stabilized. Six months after initiation of rofecoxib, linear plaques
      over the infra-orbital and bitemporal areas of both eyes were observed. Several
      itchy violaceous papules also developed on her right wrist and dorsum of the left
      foot. She also had a hyperpigmented macule on her right buccal mucosa. As the
      skin rash was localized and the patient was initially unwilling to undergo skin
      biopsy, rofecoxib was continued and a topical steroid was started. One month
      later, the patient was seen in the dermatology clinic, and the improvement of her
      skin reaction was significant. A skin biopsy performed during this visit was
      consistent with LDE. On the next day, her rheumatologist decided to discontinue
      the offending drug, rofecoxib. Two months later, all skin lesions had completely
      resolved. No rechallenge with rofecoxib was attempted. DISCUSSION: LDE is a rare
      skin reaction that can be associated with several drugs. Rofecoxib, a
      cyclooxygenase-2 inhibitor, has never before been reported to cause LDE. An
      objective causality assessment indicates that rofecoxib was the probable cause of
      the skin reaction. CONCLUSIONS: As of this writing, to our knowledge, this is the
      first case report in the English literature in which rofecoxib had led to the
      development of LDE.

PMID- 15026563
TI  - Tibolone: a unique version of hormone replacement therapy.
AB  - OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of
      tibolone in the treatment of menopausal symptoms and the prevention of
      osteoporosis. DATA SOURCES: Information was obtained from a MEDLINE search (1966
      July 2003) and from Organon International. The bibliographies of reviewed
      literature were searched for additional studies. STUDY SELECTION AND DATA
      EXTRACTION: Studies and review articles evaluating tibolone were evaluated. Since
      tibolone has been available for many years in Europe and has an extensive
      literature base, this review emphasizes information from studies published after
      1995. DATA SYNTHESIS: Tibolone possesses estrogenic activity and is effective for
      treating the symptoms and osteoporosis associated with menopause. While the
      impact of tibolone on the risk of breast cancer or cardiovascular and
      thromboembolic events is not well defined, its unique pharmacologic profile may
      provide a safer alternative to traditional hormone replacement therapy. Although
      widely used for many years in other countries, tibolone has not been approved for
      use in the US. CONCLUSIONS: Results of recent trials have led to questions
      regarding the safety of established hormone replacement therapies in peri- and
      postmenopausal women. Tibolone appears to be an attractive alternative to these
      traditional regimens. Additional studies will determine whether the promise of
      increased safety with tibolone will be realized.

PMID- 15026564
TI  - Combined exchange transfusion and chelation therapy for neonatal lead poisoning.
AB  - OBJECTIVE: To describe the results of combined exchange transfusion and chelation
      therapy in a neonate with an elevated blood lead level (BLL). CASE SUMMARY: A 34
      year-old Latina woman with a long history of pica (eating glazed pottery) gave
      birth to a healthy-appearing girl at 40 weeks of gestation. The mother's
      preconception BLL was 117 microg/dL and remained elevated throughout pregnancy.
      At parturition, the mother's BLL was 87 microg/dL and the infant's cord BLL was
      100 microg/dL. The infant underwent single-volume exchange transfusion within 12
      hours of birth. BLL was 28 microg/dL following the exchange, and a 5-day course
      of chelation with dimercaprol and CaNa2 ethylenediamine tetraacetic acid was
      initiated at 36 hours of life. The infant's BLL was 37 microg/dL at the end of
      inpatient chelation. DISCUSSION: Long-term neurologic disability from in utero
      lead exposure is well described, but the optimal treatment of elevated neonatal
      BLLs in healthy-appearing infants at the time of birth is not established. This
      strategy of combined chelation and exchange transfusion therapy was well
      tolerated and resulted in decreased lead levels, but the long-term neurologic
      efficacy of our combination strategy remains to be seen. CONCLUSIONS: Combined
      exchange transfusion and chelation therapy resulted in rapidly decreased lead
      levels in a neonate with chronic in utero lead exposure.

PMID- 15026565
TI  - Clinical experience with moxifloxacin in patients with respiratory tract
      infections.
AB  - BACKGROUND: Moxifloxacin is an advanced-generation fluoroquinolone used primarily
      for the treatment of respiratory tract infections. OBJECTIVE: To further
      investigate moxifloxacin's general and cardiac safety and evaluate its efficacy
      in the community practice setting in a large surveillance study. METHODS: A total
      of 18,409 outpatients with suspected bacterial episodes of acute sinusitis, acute
      exacerbation of chronic bronchitis, or community-acquired pneumonia of mild to
      moderate severity were enrolled at 3377 community practice sites. Patients with
      sinusitis or pneumonia received once-daily oral moxifloxacin 400 mg for 10 days;
      those with bronchitis received 5 days' treatment. At follow-up, within 48 hours
      after the end of treatment, adverse event information was collected. An external
      safety committee assessed possible cardiac-related events. Efficacy was also
      evaluated at follow-up via the degree of resolution of clinical signs and
      symptoms. RESULTS: Of 18,374 safety-valid patients, 17.7% experienced adverse
      events and 14.3% experienced drug-related adverse events. The most common drug
      related adverse events were nausea (5.3%), diarrhea (2.2%), and dizziness (2.0%).
      There was no clinical evidence of increased risk of cardiac arrhythmias with
      moxifloxacin treatment. Of 17,137 patients included in the efficacy analysis,
      92.9% overall experienced clinical cure or improvement (92.8% with sinusitis,
      92.9% with bronchitis, 94.1% with pneumonia). CONCLUSIONS: Once-daily oral
      moxifloxacin 400 mg was shown to be safe and effective in this trial for the
      treatment of respiratory tract infections of suspected bacterial origin in the
      clinical practice setting.

PMID- 15026566
TI  - Possible association of acute lateral-wall myocardial infarction and bitter
      orange supplement.
AB  - OBJECTIVE: To report a possible incidence of acute lateral-wall myocardial
      infarction (MI) coinciding with the use of a Citrus aurantium L. (bitter orange)
      containing dietary supplement in a patient with undetected coronary vascular
      disease. CASE SUMMARY: A 55-year-old white woman presented to the emergency
      department with symptoms of dull aching shoulder and chest pain. A review of
      medications during cardiac rehabilitation revealed the patient had ingested a
      multicomponent dietary supplement for weight loss containing 300 mg of bitter
      orange (Edita's Skinny Pill) for the past year. Although the patient's past
      medical history did not include hypertension, coronary disease, or
      hyperlipidemia, an arteriogram revealed a lesion in the left main coronary
      artery. She did have a smoking history. She was diagnosed with acute lateral-wall
      MI and hospitalized for 4 days. DISCUSSION: Consumers generally consider dietary
      supplements safe. However, some supplements taken for weight loss contain
      ingredients that have been associated with cardiovascular events. Although
      consumers are becoming more aware of the serious adverse effects secondary to
      products containing ingredients such as Ma huang and ephedra, reports involving
      other ingredients are increasing. Bitter orange or synephrine, found in bitter
      orange, has been associated with adverse cardiovascular reactions. Based on the
      Naranjo probability scale, C. aurantium is possibly associated with this
      cardiovascular event. CONCLUSIONS: The use of C. aurantium-containing supplements
      may present as a risk for cardiovascular toxicity; however, additional
      studies/case reports are needed to validate this conclusion.

PMID- 15026567
TI  - Implementation and evaluation of cultural competency training for pharmacy
      students.
AB  - BACKGROUND: The demographic composition of the US population is rapidly changing.
      As a result, pharmacists increasingly face the need to interact effectively with
      and provide care for patients whose ethnic or cultural background may differ from
      their own. While schools implement curricula to provide pharmacy students with
      cultural awareness, knowledge, and communication skills they will need in
      practice, few assessment tools exist to evaluate the impact or effectiveness of
      such training. OBJECTIVE: To implement and assess the impact of a cultural
      competency training course designed specifically for pharmacy students. METHODS:
      An 8-hour elective course offering basic cultural competency training was
      provided to 60 first-through fourth-year pharmacy students in 2003. A 12-item
      survey assessing students' perceived awareness, knowledge, and communication
      skills in the areas of cultural competence and cross-cultural communication
      skills was administered immediately prior to and upon completion of the course.
      Surveys were linked, enabling estimation of within-student change as a result of
      exposure to the program. RESULTS: Fifty-six paired surveys (96.6% of
      participants) were analyzable. Responses to all survey items (p < 0.05) and total
      scores (t55 = 16.27; p < 0.001) increased significantly from pre- to
      posttraining. The mean +/- SD 12-item pretraining scale score was 33.35 +/- 5.48
      (range 21-44), and the mean posttraining scale score was 47.88 +/- 4.90 (range 36
      59). CONCLUSIONS: Survey results suggest that the course successfully raised
      student awareness of diversity and provided basic knowledge and skills pertaining
      to cultural competence and cross-cultural communication.

PMID- 15026568
TI  - Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS
      injury.
AB  - The unprocessed precursor of the neurotrophin nerve growth factor (NGF), proNGF,
      has been suggested to be a death-inducing ligand for the neurotrophin receptor
      p75. Whether proNGF is a true pathophysiological ligand that is secreted, binds
      p75, and activates cell death in vivo, however, has remained unknown. Here, we
      report that after brain injury, proNGF was induced and secreted in an active form
      capable of triggering apoptosis in culture. We further demonstrate that proNGF
      binds p75 in vivo and that disruption of this binding results in complete rescue
      of injured adult corticospinal neurons. These data together suggest that proNGF
      binding to p75 is responsible for the death of adult corticospinal neurons after
      lesion, and they help to establish proNGF as the pathophysiological ligand that
      activates the cell-death program by means of p75 after brain injury. Interference
      in the binding of proNGF to p75 may provide a therapeutic approach for the
      treatment of disorders involving neuronal loss.

PMID- 15026576
TI  - UPSIDE: Uniform principle for sharing integral data and materials expeditiously.

PMID- 15026570
TI  - Highly enantioselective alkyne additions to aldehydes in the presence of 1,1'-bi
      2-naphthol and hexamethylphosphoramide.
AB  - It is found that the addition of hexamethylphosphoramide to the solution of an
      alkyne, Et(2)Zn, and (S)-1,1'-bi-2-naphthol in methylene chloride allows the
      generation of an alkynylzinc at room temperature and shows highly
      enantioselective additions to aldehydes. The mild condition for the formation of
      the alkynylzinc reagent enables the use of functional alkynes in this asymmetric
      reaction with excellent enantioselectivity. It avoids the reflux of the toluene
      solutions of the alkynes and Et(2)Zn as previously reported.

PMID- 15026569
TI  - Activation of human medial prefrontal cortex during autonomic responses to
      hypoglycemia.
AB  - Studies in humans implicate the medial prefrontal cortex (MPFC) in complex
      cognitive and emotional states. We measured regional cerebral blood flow (CBF)
      four times each during euglycemia (5.2 +/- 0.2 mmol/liter) and hypoglycemia (3.0
      +/- 0.3 mmol/liter) in nine normal human volunteers. Autonomic responses during
      hypoglycemia were manifested by increases in neurogenic symptoms, heart rate, and
      plasma levels of epinephrine, norepinephrine, and pancreatic polypeptide. Typical
      symptoms of hypoglycemia were mild, and none reflected evidence of cognitive or
      emotional stress. Quantitative CBF fell 6-8% in the cerebrum, brainstem, and
      cerebellum. Analysis of regional CBF differences identified neuronal activation
      during hypoglycemia in bilateral MPFC (areas 24 and 32) and bilateral thalamus.
      These results provide evidence that the MPFC participates in the autonomic
      responses to simple physiological stimuli in humans.

PMID- 15026577
TI  - Coordinate enhancers share common organizational features in the Drosophila
      genome.
AB  - The evolution of animal diversity depends on changes in the regulation of a
      relatively fixed set of protein-coding genes. To understand how these changes
      might arise, we examined the organization of shared sequence motifs in four
      coordinately regulated neurogenic enhancers that direct similar patterns of gene
      expression in the early Drosophila embryo. All four enhancers possess similar
      arrangements of a subset of putative regulatory elements. These shared features
      were used to identify a neurogenic enhancer in the distantly related Anopheles
      genome. We suggest that the constrained organization of metazoan enhancers may be
      essential for their ability to produce precise patterns of gene expression during
      development. Organized binding sites should facilitate the identification of
      regulatory codes that link primary DNA sequence information with predicted
      patterns of gene activity.

PMID- 15026578
TI  - Sensing cellular stress: another new function for the nucleolus?
AB  - Recent research suggests that the nucleolus communicates with the p53 regulatory
      system and acts as a stress sensor. Cellular stress causes nucleolar disruption,
      triggering the release of regulatory factors to the nucleoplasm. These factors,
      especially ARF (alternative reading frame), inhibit the degradation of p53,
      thereby facilitating its intracellular accumulation.

PMID- 15026580
TI  - Recovery of function in osteoarthritic chondrocytes induced by p16INK4a-specific
      siRNA in vitro.
AB  - OBJECTIVE: To demonstrate the roles of p16(INK4a) in the senescence of human
      chondrocytes and the progression of osteoarthritis (OA). METHODS:
      Immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR)
      were performed to examine p16(INK4a) expression in fetal, normal age-matched and
      OA cartilage, and Western blot was used in primary cultured chondrocytes from
      different origins. To explore a functional p16(INK4a) knockdown in OA
      chondrocytes, the primary cultured cells were treated with p16(INK4a)-specific
      small interfering ribonucleic acids (siRNAs). Expression of p16(INK4a), p14(ARF)
      and p53 was observed by Western blot and RT-PCR. The phosphorylation status of
      pRb, senescence-associated beta-galactosidase (SA-beta-gal), cell G1/S transition
      and cell proliferation were studied by Western blot, histological staining, 3H
      thymidine incorporation and cell counts respectively. Expression of the collagen
      I, collagen II and aggrecan genes was measured by semiquantitative RT-PCR. To
      establish the response of chondrocytes to cytokines, cells were treated with
      transforming growth factor-beta1 (TGF-beta1) or interleukin-1alpha (IL-1alpha)
      and examined for incorporation of 3H-thymidine, 3H-proline and 35S-sulphate
      respectively. RESULTS: A significant increase of p16(INK4a) was detected in OA
      chondrocytes compared with normal age-matched and fetal chondrocytes (P<0.01) in
      vivo and in vitro. Treated with p16(INK4a)-specific siRNAs, OA chondrocytes
      displayed a significant decrease in p16(INK4a) expression with an increase of
      phosphorylated pRb, but no alteration of p14(ARF) and p53 expression, followed by
      decreases of senescent features and increases in the expression of some
      chondrocyte-specific genes and overall repair capacity. CONCLUSIONS: p16(INK4a)
      is instrumental in the senescence of human articular chondrocytes or OA. The
      reduction of p16(INK4a) by RNA interference (RNAi) contributed to the recovery of
      osteoarthritic chondrocytes, suggesting that p16(INK4a) may be a viable future
      therapeutic candidate.

PMID- 15026579
TI  - Promiscuity rules? The dispensability of cyclin E and Cdk2.
AB  - The canonical view of the mammalian cell cycle arose from studies of cultured
      cells rather than mutant organisms. It depicts the many complexes of cyclin and
      Cdk (cyclin/Cdk) as fulfilling unique and essential steps that dictate the
      sequential order of cell cycle events. Recent analyses of knockout mice challenge
      this view. Cdk2 and cyclin E, long thought to be essential, are largely
      dispensable. Here, we discuss the phenotypes of these and other cyclin/Cdk
      mutants in genetically tractable metazoa (mouse, fly, and nematode) and explore
      possible reasons behind similarities and differences among experimental systems
      and cell types.

PMID- 15026581
TI  - Nailfold videocapillaroscopic patterns and serum autoantibodies in systemic
      sclerosis.
AB  - BACKGROUND: Microvascular lesions are a predominant feature in systemic sclerosis
      (SSc) and seem to play a central pathogenetic role. Recently, we graded
      scleroderma microangiopathy by nailfold videocapillaroscopy (NVC) into three NVC
      patterns (early, active and late). The aim of the present study was to confirm,
      in a larger number of SSc patients, the presence of three patterns of
      microvascular damage, and to detect any possible relationship between these
      patterns and both specific serum autoantibodies and the subsets of cutaneous
      involvement. METHODS: Two hundred and forty-one consecutive patients (227 women
      and 14 men) affected by SSc were recruited. One hundred and forty-eight patients
      were affected by limited cutaneous SSc (lSSc) and 93 patients by diffuse
      cutaneous SSc (dSSc). The ages at onset of Raynaud's phenomenon (RP) and SSc, the
      durations of RP and SSc, ANA and antitopoisomerase I (anti-Scl70) and
      anticentromere (ACA) antibodies were investigated in all patients. The SSc
      patients were subdivided on the basis of the NVC pattern into three groups.
      RESULTS: A statistically significant correlation was found between the NVC
      patterns and the durations of both RP and SSc (P<0.001). Enlarged and giant
      capillaries, together with haemorrhages, constituted the earliest NVC finding in
      SSc (early NVC pattern). These abnormalities were mostly expressed in the active
      NVC pattern. Loss of capillaries, ramified capillaries and vascular architectural
      disorganization were increased in the late NVC pattern. Age and the duration of
      both RP and SSc were lower in 24 patients complaining of RP alone. Anti-Scl70
      antibodies were statistically less frequent in the early vs both the active and
      the late NVC pattern, whereas no significant correlation was found between the
      presence of anti-Scl70 antibodies and the duration of either RP or SSc. ACA
      positivity was more frequent in patients with longer RP duration. Patients with
      lSSc had shorter SSc duration and showed the early or active NVC pattern more
      frequently. Conversely, patients with dSSc showed longer disease duration and
      mostly showed the late NVC pattern. CONCLUSIONS: NVC is an appropriate tool for
      differential diagnosis between primary and secondary RP through the clear
      recognition of the early NVC scleroderma pattern. This study confirms, in a large
      number of SSc patients, the existence of three distinct NVC patterns that might
      reflect the evolution of SSc microangiopathy. The presence of anti-Scl70
      antibodies seems be related to earlier expression of the active and late NVC
      patterns of SSc microvascular damage. The presence of ACA seems to be related to
      delayed expression of the late NVC pattern.

PMID- 15026582
TI  - Assessment of endothelial function in complex regional pain syndrome type I using
      iontophoresis and laser Doppler imaging.
AB  - OBJECTIVES: To assess microvascular endothelial function in patients with complex
      regional pain syndrome type I (CRPS) compared with healthy controls, as measured
      by iontophoresis of vasoactive chemicals and laser Doppler imaging. METHODS:
      Microvascular blood flow was stimulated locally in affected and contralateral
      limbs of patients with CRPS (n = 17) and in control subjects (n = 16) using
      iontophoresis of the endothelial-dependent vasodilator acetylcholine (ACh) and
      the endothelial-independent vasodilator sodium nitroprusside (NaNP). Changes in
      blood flow were measured using laser Doppler imaging. Comparisons were made
      between right and left limbs and between patients and controls. RESULTS: No
      significant differences in blood flow [expressed as a median percentage increase
      from baseline (interquartile range)] were detected between affected and
      contralateral limbs in patients with CRPS for ACh [affected 237 (95-344);
      unaffected 251 (152-273)] or for NaNP [affected 102 (49-300); unaffected 190 (53
      218)]. In addition, there were no significant differences between patients and
      healthy controls [controls, ACh 216 (119-316); controls, NaNP: 122 (48-249)].
      CONCLUSIONS: In this pilot study, CRPS was not associated with impairment of
      microvascular endothelial function. This may be a true result or may reflect the
      diversity of the CRPS disease process.

PMID- 15026583
TI  - Efficacy and safety of leflunomide 10 mg versus 20 mg once daily in patients with
      active rheumatoid arthritis: multinational double-blind, randomized trial.
AB  - OBJECTIVE: To compare the efficacy and safety profile of two daily maintenance
      doses of leflunomide, 10 mg and 20 mg, for the treatment of active rheumatoid
      arthritis (RA). METHODS: In this multinational, randomized, double-blind,
      parallel-group study, 402 RA patients were randomized equally to receive daily
      doses of 10 mg leflunomide (n = 202; loading dose on day 3, 100 mg) or 20 mg
      leflunomide (n = 200; loading dose on day 1-3, 100 mg) for 24 weeks. The study
      was designed to demonstrate non-inferiority of the efficacy of 10 mg compared
      with 20 mg by calculating 95% confidence intervals for differences in changes in
      tender joint count (TJC), swollen joint count (SJC) and Health Assessment
      Questionnaire Disability Index (HAQ DI), comparing these confidence intervals
      with predefined bounds. RESULTS: In the intent-to-treat population, mean
      improvements at the end-point in the 10 and 20 mg groups respectively were: TJC, 
      7.57 and -8.89 (P = 0.061); SJC, -6.38 and -6.96 (P = 0.304); and HAQ DI, 0-0.37
      and 0-0.49 (P = 0.095). By American College of Rheumatology (ACR) > or =20%
      criteria, response rates were 49.8 and 56.6% respectively (P = 0.1724). Adverse
      events (AEs) resulting in treatment withdrawal were higher in the 10 mg (15.3%)
      than in the 20 mg treatment group (12.0%), as were serious adverse events (SAEs):
      12.9 vs 10.0%. CONCLUSIONS: This study rejected the hypothesis of non-inferiority
      of 10 mg compared with 20 mg daily maintenance doses of leflunomide. More AEs
      resulting in treatment discontinuation and SAEs in patients receiving 10 mg
      leflunomide daily also support a better efficacy profile for the 20 mg daily
      dose.

PMID- 15026584
TI  - Long-term treatment with etanercept significantly reduces the number of
      proinflammatory cytokine-secreting peripheral blood mononuclear cells in patients
      with rheumatoid arthritis.
AB  - OBJECTIVES: To determine the influence of etanercept treatment on the number of
      peripheral blood mononuclear cells (PBMC) secreting immunoregulatory key
      cytokines and the correlation of these cell counts with treatment response in
      patients with rheumatoid arthritis (RA). METHODS: Nineteen patients with RA were
      treated with etanercept as monotherapy. Frequencies of PBMC secreting cytokines
      were determined by ELISPOT analysis before and after 9 months of therapy and
      compared with values for healthy controls (HC). The clinical outcome was assessed
      as defined by the ACR criteria. RESULTS: Fifteen patients fulfilled the ACR20,
      seven patients the ACR50 and two patients the ACR70 criteria. Initially elevated
      numbers of tumour necrosis factor-alpha- and interleukin (IL)-1beta-secreting
      PBMC were reduced to HC levels, and normal or low numbers of IL-6- and interferon
      gamma (IFN-gamma)-secreting PBMC were reduced below HC levels. The number of IL
      10-secreting PBMC did not differ from that in HC and did not change significantly
      over time. The pretreatment IFN-gamma:IL-10 ratio correlated to reduction in the
      tender and swollen joint counts. CONCLUSIONS: Long-term treatment with etanercept
      in patients with RA significantly reduces the numbers of proinflammatory cytokine
      secreting PBMC, while the number of IL-10-secreting cells is unaffected. Although
      the changes described did not affect the safety or efficacy of etanercept
      therapy, these alterations may account for the long-term systemic effects. The
      pretreatment IFN-gamma:IL-10 ratio may be of prognostic value in predicting the
      improvement in joint symptoms.

PMID- 15026585
TI  - CT with 3D rendering of the tendons of the foot and ankle: technique, normal
      anatomy, and disease.
AB  - Three-dimensional rendering of computed tomographic data with volume rendering
      (VR), shaded surface display (SSD), and maximum intensity projection has been
      performed for over 20 years. In the foot and ankle, no one image reformatting
      technique is satisfactory for displaying every anatomic relationship or disease
      process. Two-dimensional multiplanar reformatted (MPR) images are the basic
      images used for diagnosis. MPR images are especially useful for identifying small
      fractures. VR is useful for demonstrating the relationships between ankle tendons
      and the underlying osseous structures, and SSD is useful when fractures extend to
      the articular cortex and a disarticulated view is desired. Three-dimensional
      images are helpful in patients with congenital deformities, arthritis, and
      trauma.

PMID- 15026586
TI  - Normal and abnormal US findings at the mastectomy site.
AB  - Evaluation of a mastectomy site is more effective with ultrasonography (US) than
      with either mammography or chest computed tomography because abnormalities are
      usually small and close to the skin surface. US does not involve the use of
      ionizing radiation and has a multiplanar scanning capability. The technique is
      readily available and inexpensive, and it allows real-time monitoring of needle
      tip placement during biopsy of a lesion. Normal US anatomy of the chest wall
      after mastectomy usually consists of four layers: skin, subcutaneous fat,
      pectoral muscles, and rib and intercostal muscle. The axilla is changed in
      appearance after lymph node dissection, but it remains the same in patients who
      have undergone simple mastectomy. US can accurately depict benign and malignant
      conditions in the mastectomy site, including fluid collection, fibrosis, local
      recurrent tumor, and metastatic lymphadenopathy, and can enable accurate
      diagnosis based on findings at fine needle aspiration biopsy.

PMID- 15026587
TI  - Hemangioma from head to toe: MR imaging with pathologic correlation.
AB  - Hemangioma is a common benign vascular neoplasm that closely resembles normal
      vessels and can be found in all organs of the human body. Vascular lesions can be
      classified as infantile hemangiomas or vascular malformations on the basis of
      their natural history, location, cellular turnover, and histologic
      characteristics. The magnetic resonance (MR) imaging features of vascular
      malformations of the central nervous system depend on the pathologic subtype.
      Soft-tissue vascular malformations can be categorized with combined MR imaging
      and MR angiography as either high- or low-flow. Osseous vascular malformations
      commonly demonstrate a high-signal-intensity trabecular pattern at both T1- and
      T2-weighted MR imaging. A group of more aggressive vascular neoplasms, including
      hemangioendothelioma, hemangiopericytoma, and glomus tumor, have a nonspecific
      appearance at MR imaging. In the liver and spleen, hemangiomas are typically
      hyperintense at T2-weighted MR imaging, with a centripetal filling pattern after
      administration of gadopentetate dimeglumine. Vascular lesions can involve several
      organs or systems in angiomatous syndromes. MR imaging allows characterization of
      a hemangioma with typical features, which vary depending on anatomic location.
      Familiarity with these features facilitates diagnosis and management of these
      anomalies.

PMID- 15026588
TI  - Spectrum of germ cell tumors: from head to toe.
AB  - Germ cell tumors (GCTs) occur most frequently in the gonads and are relatively
      rare in other sites, such as the pineal gland, neurohypophysis, mediastinum, and
      retroperitoneum. GCTs are thought to originate from primordial germ cells, which
      migrate to the primitive gonadal glands in the urogenital ridge. Extragonadal
      GCTs might also originate from these cells when the cells are sequestered during
      their migration. Pathologic subtypes of GCTs vary, and the prevalence of mixed
      tumors is high. These factors produce a diversity of radiologic findings and make
      prospective radiologic diagnosis difficult in many cases. However, similar
      radiologic findings have been observed in pathologically equivalent tumors in
      varying sites. Seminomas appear as uniformly solid, lobulated masses with
      fibrovascular septa that enhance intensely. Nonseminomatous GCTs appear as
      heterogeneous masses with areas of necrosis, hemorrhage, or cystic degeneration.
      Fat and calcifications are hallmarks of teratomas, most of which are benign. In
      immature teratomas, scattered fat and calcification within larger solid
      components are occasionally seen. These imaging characteristics reflect the
      pathologic features of each tumor, and histologically similar GCTs at varying
      sites have similar radiologic features. Knowledge of the pathologic appearances
      of GCTs and their corresponding radiologic appearances will allow radiologists to
      diagnose these tumors correctly.

PMID- 15026590
TI  - Splenogonadal fusion: a rare extratesticular scrotal mass.

PMID- 15026589
TI  - Amyloidosis: review and CT manifestations.
AB  - Amyloidosis is a collection of disease entities that produce considerable
      morbidity and mortality and are increasing in prevalence. The imaging findings
      are problematically nonspecific and diverse. This lack of specificity is
      compounded by the fact that amyloidosis is strongly associated with and
      frequently coexists with many other chronic disease states that have their own
      imaging findings. Amyloidosis can involve any organ singly or in conjunction with
      other organs and can do so in the form of a focal, tumorlike lesion or an
      infiltrative process. In the proper clinical setting, that is, in a patient with
      chronic inflammatory disease and especially in a patient with multiple myeloma,
      amyloidosis should be considered as a possible cause of worsening or new symptoms
      or imaging findings. Occasionally, the radiologic findings may precede the
      clinical findings, thus providing the radiologist with the opportunity to
      contribute to the patient's care. However, to make a difference in patient care,
      the radiologist must be familiar with the diverse imaging findings of amyloidosis
      as well as the patient's clinical history, which could raise the suspicion of
      amyloidosis.

PMID- 15026591
TI  - Patterns of lymphadenopathy in thoracic malignancies.
AB  - There are different lymphatic drainage pathways in the thorax that are relevant
      in the staging of lung cancer, breast cancer, lymphoma, esophageal cancer, and
      malignant mesothelioma. To properly search for metastatic spread, it is important
      to carefully evaluate the specific nodal stations that drain the thoracic
      structures from which a primary tumor originates. Because size criteria have
      limitations in the prediction of nodal status, pathologic confirmation is
      essential for accurate staging. Computed tomography (CT) is useful in helping the
      surgeon or interventional radiologist determine the most appropriate approach for
      nodal sampling. Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography
      (PET) has an increasing role in detection of diseased lymph nodes that appear
      normal at CT alone, particularly when FDG PET images are fused with CT images.
      However, the role of radiologic imaging extends beyond initial staging and the
      guidance of interventions to include posttreatment assessment and the detection
      of recurrent disease. Therefore, at all levels of cancer imaging, it is essential
      to identify the relevant lymph node regions and their relations to the primary
      tumor.

PMID- 15026592
TI  - CT and MR imaging of the adrenal glands in ACTH-independent cushing syndrome.
AB  - Adrenocorticotropic hormone (ACTH)-independent hypercortisolism accounts for 15%
      20% of cases of Cushing syndrome and always arises from primary adrenal disease.
      Computed tomographic (CT) and magnetic resonance (MR) imaging findings in 37
      patients with primary adrenal Cushing syndrome were analyzed and correlated with
      pathologic findings. Hyperfunctioning adenomas (n = 24), together with
      functioning carcinomas (n = 10), accounted for 92% of cases. Adenomas had a
      significantly smaller mean size (3.5 vs 14.5 cm) and lower mean unenhanced CT
      attenuation value (11 vs 28 HU) than did carcinomas. The presence of necrosis,
      hemorrhage, and calcification favored a diagnosis of carcinoma. Six of 10
      carcinoma patients had metastases at presentation. Two adenomas were seen within
      a myelolipoma, which was recognized at both CT and MR imaging due to its fat
      content, and two adenomas were of uncertain malignant potential. Bilateral
      disease--primary pigmented nodular adrenal dysplasia (PPNAD) (n = 2) and ACTH
      independent macronodular adrenal hyperplasia (AIMAH) (n = 1)--had characteristic
      imaging features. In PPNAD, multiple tiny (2-5-mm) nodules were visible
      bilaterally, with no overall glandular enlargement and normal intervening adrenal
      tissue. In AIMAH, both glands were grossly enlarged and contained nodules up to 3
      cm in diameter. Familiarity with the range of imaging appearances of the adrenal
      glands in primary adrenal Cushing syndrome may help establish the underlying
      diagnosis.

PMID- 15026593
TI  - Multi-detector row CT evaluation of living renal donors prior to laparoscopic
      nephrectomy.
AB  - Since its introduction in 1995, laparoscopic nephrectomy has become the preferred
      technique at many medical centers for the harvesting of kidneys from living
      donors for transplantation. Because the field of view at laparoscopic surgery is
      limited, preoperative radiologic evaluation of the donor's anatomy---the renal
      veins and arteries, collecting system, and parenchyma--is critical. Spiral
      computed tomographic (CT) angiography is a fast, safe, minimally invasive, and
      generally accepted method for preoperative evaluation of the renal vessels. Multi
      detector row CT scanners offer shorter image acquisition time, narrower
      collimation, better spatial resolution, and less tube heating than do single
      detector row CT scanners. Multi-row scanners also provide more complete anatomic
      coverage, increased contrast enhancement of the arteries, and greater
      longitudinal spatial resolution--all of which are important both for accurate
      imaging of the renal vasculature and for three-dimensional postprocessing of
      image data. Dual-phase multi-detector row CT angiography combined with three
      dimensional postprocessing enables minimally invasive and highly accurate
      depiction of the preoperative donor anatomy. To make the most effective use of
      this method, radiologists must be familiar with its technical aspects,
      advantages, and potential pitfalls. They also must be able to identify variations
      in vasculature and in renal and extrarenal anatomy that are important for
      laparoscopic donor nephrectomy.

PMID- 15026595
TI  - Nontraumatic emergent abdominal vascular conditions: advantages of multi-detector
      row CT and three-dimensional imaging.
AB  - In the past decade, great strides have been made in the development of helical
      computed tomography (CT) that have led to shorter scanning time and higher
      spatial resolution. A wide range of traumatic and nontraumatic emergent
      conditions may be quickly and accurately diagnosed with multi-detector row CT.
      Multi-detector row CT angiography is the preferred method for imaging in emergent
      abdominal vascular conditions because it enables the acquisition of high-spatial
      resolution volumetric image data during a single breath hold. Unlike catheter
      angiography, multi-detector row CT angiography not only depicts the vessels but
      also allows assessment of perfusion in adjacent organs. To make the most
      effective diagnostic use of multi-detector row CT angiography and three
      dimensional image postprocessing, radiologists must be familiar with the optimal
      CT angiographic protocols and with the typical CT findings in various emergent
      vascular conditions. This article describes the protocols used in 11 patients
      with conditions including ruptured abdominal aortic aneurysm, secondary
      aortoduodenal fistula, splanchnic segmental arterial mediolysis, and Wegener-type
      vasculitis with visceral involvement. All of the diagnoses in these 11 cases were
      made in the emergency department, and the delay between imaging and diagnosis was
      decreased considerably by avoiding the transfer of patients for catheter
      angiography.

PMID- 15026594
TI  - Popliteal artery disease: diagnosis and treatment.
AB  - The popliteal artery is a relatively short vascular segment but is affected by a
      unique set of pathologic conditions. These conditions, which may be common
      throughout the arterial system or exclusive to the popliteal artery, include
      atherosclerosis, popliteal artery aneurysm, arterial embolus, trauma, popliteal
      artery entrapment syndrome, and cystic adventitial disease. The clinical
      manifestations, imaging appearances, and treatment options associated with these
      pathologic conditions differ significantly. Consequently, the radiologist should
      be familiar with these conditions to direct imaging for accurate diagnosis and
      treatment and to prevent loss of limb.

PMID- 15026596
TI  - Slow flow or no flow? Color and power Doppler US pitfalls in the abdomen and
      pelvis.
AB  - Color and power Doppler ultrasonography allow rapid assessment of tissue
      vascularity. Motion sensitivity to phenomena such as flow along the edge of
      gallstones, urinary jets, and placentation abnormalities can result in
      artifactual flow patterns that require corroboration with spectral analysis.
      Similar artifacts have also been noted at the edge of bone and along the bowel
      wall secondary to bowel motion. These artifacts fall into four categories: (a)
      twinkle artifacts, which occur behind reflectors; (b) edge artifacts, which occur
      along strongly reflective interfaces; (c) flash artifacts, which occur due to
      tissue or fluid motion; and (d) pseudoflow, which occurs due to nonvascular flow
      of other fluids such as urine or ascites. Knowledge of the most common sites of
      color and power Doppler artifacts, familiarity with the typical appearances of
      these artifacts, and liberal use of spectral analysis will help prevent
      misinterpretation of these findings and may lead to improved diagnostic accuracy.

PMID- 15026597
TI  - The infant skull: a vault of information.
AB  - The art of interpreting skull radiographs is slowly being lost as trainees in
      radiology see fewer plain radiographs and depend more heavily on computed
      tomography and magnetic resonance imaging. Nevertheless, skull radiographs still
      provide significant information that is helpful in finding pathologic conditions
      and appreciating their extents. Abnormalities in the skull may be reflected as
      variations in the density, size, and shape of the skull, as well as skull
      defects. Skeletal dysplasias may manifest as a generalized decrease in calvarial
      density (hypophosphatasia, osteogenesis imperfecta), a generalized increase in
      calvarial density (osteopetrosis), or a focal increase in density
      (frontometaphyseal dysplasia). Diffusely decreased or increased calvarial density
      is usually associated with a process that affects the entire skeleton. Therefore,
      correct differentiation among these dysplasias depends on other concurrent
      features. Decreased size of the cranial vault at birth generally implies an
      underlying insult to the brain, including fetal alcohol syndrome and the so
      called TORCH infections (toxoplasmosis, rubella, cytomegalovirus infection,
      herpes simplex). Macrocephaly may result from skeletal dysplasia or an increase
      in the intracranial volume (eg, due to underlying anomalies of the brain such as
      hydrocephalus).

PMID- 15026599
TI  - Scenes from the past: x-ray mania: the x ray in advertising, Circa 1895.

PMID- 15026598
TI  - An introduction to PET-CT imaging.
AB  - Cancer is one of the leading causes of morbidity and mortality in developed
      countries such as the United States. Complex clinical decisions about treatment
      of oncologic patients are largely guided by imaging findings, among other
      factors. Most radiologic procedures map the anatomy and morphology of tumors with
      little or no information about their metabolism. Positron emission tomography
      (PET) performed with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) has proved
      valuable in providing important tumor-related qualitative and quantitative
      metabolic information that is critical to diagnosis and follow-up. PET-computed
      tomography (CT) is a unique combination of the cross-sectional anatomic
      information provided by CT and the metabolic information provided by PET, which
      are acquired during a single examination and fused. FDG PET-CT offers several
      advantages over PET alone; the most important is the ability to accurately
      localize increased FDG activity to specific normal or abnormal anatomic
      locations, which may be difficult or even impossible with PET alone.
      Understanding the principles of FDG PET-CT and the optimal scanning techniques
      and recognizing the potential pitfalls and limitations are important for
      advantageous use of this imaging modality.

PMID- 15026600
TI  - Radiologic pattern of disease in patients with severe acute respiratory syndrome:
      the Toronto experience.
AB  - Severe acute respiratory syndrome (SARS) is a transmissible febrile respiratory
      illness caused by a recently discovered coronavirus. Various patterns of disease
      progression may be observed that have different implications for the prognosis in
      those affected by SARS. The appearance of the lungs on chest radiographs of
      patients with this condition may be normal or may include focal airspace opacity
      or multifocal or diffuse opacities. Thoracic computed tomography (CT) is more
      sensitive in depicting SARS than is conventional chest radiography, and CT images
      obtained in patients with normal chest radiographs may show extensive disease and
      airspace consolidation. However, because the radiologic appearance of SARS is not
      distinct from that of other diseases that cause lower respiratory tract
      infection, early identification of SARS will depend in part on the prompt
      recognition of clusters of cases of febrile respiratory tract illness. To aid in
      the differential diagnosis and management of SARS, radiologists must be familiar
      with the typical clinical and histopathologic findings, as well as the radiologic
      features of the disease.

PMID- 15026601
TI  - From the archives of the AFIP. Meckel diverticulum: radiologic features with
      pathologic Correlation.
AB  - Meckel diverticulum is the most common congenital anomaly of the gastrointestinal
      tract, occurring in 2%-3% of the population. It results from improper closure and
      absorption of the omphalomesenteric duct. Meckel diverticulum is the most common
      end result of the spectrum of omphalomesenteric duct anomalies, which also
      include umbilicoileal fistula, umbilical sinus, umbilical cyst, and a fibrous
      cord connecting the ileum to the umbilicus. The formation of Meckel diverticulum
      occurs with equal frequency in both sexes, but symptoms from complications are
      more common in male patients. Sixty percent of patients come to medical attention
      before 10 years of age, with the remainder of cases manifesting in adolescence
      and adulthood. Heterotopic gastric and pancreatic mucosa are frequently found
      histologically within the diverticula of symptomatic patients. The most common
      complications are hemorrhage from peptic ulceration, small intestinal
      obstruction, and diverticulitis. Although the clinical, pathologic, and
      radiologic features of the complications of Meckel diverticulum are well known,
      the diagnosis of Meckel diverticulum is difficult to establish preoperatively.

PMID- 15026602
TI  - Best cases from the AFIP: cystic nephroma.

PMID- 15026603
TI  - Posterior mediastinal ganglioneuroma.

PMID- 15026604
TI  - Oligoastrocytoma.

PMID- 15026605
TI  - An extensible software-based platform for reconstruction and evaluation of CT
      images.
AB  - A collection of software applications dedicated to clinical x-ray computed
      tomography (CT) has been developed. These tools are designed for routine and
      scientific work and represent a complete platform, which is called syngo
      Explorer. The user can reconstruct, process, and view CT images in a personal
      computer environment independently of specialized hardware. To manage patient
      data and to allow full database access, the system uses the syngo platform
      (Siemens Medical Solutions, Erlangen, Germany), which serves as a framework for
      the management and visualization of Digital Imaging and Communications in
      Medicine (DICOM) images. Part of the philosophy behind syngo Explorer is to
      quickly provide specialized solutions and to be able to respond to user requests
      at once. Thus, syngo Explorer was built by choosing a modular setup that
      comprises standard and specific reconstruction algorithms as well as various
      artifact reduction techniques; it also helps one attain better insights into dose
      issues. Various raw data formats of commercial CT scanners are supported.
      Reconstruction algorithms equivalent to those on the manufacturer's scanner
      console are provided. A non-syngo Windows XP (Microsoft, Redmond, Wash) version
      of the application is available.

PMID- 15026607
TI  - Ligation of the inferior mesenteric artery in the surgery of rectal cancer:
      anatomical considerations.
AB  - BACKGROUND: No agreement has been found in the literature concerning the safest
      point of ligation of the inferior mesenteric artery (ima) in order to avoid nerve
      damage during the surgery of rectal cancer. STUDY DESIGN: The distance between
      the origin of the ima and the left paraortic trunk was measured, as was the
      distance between the left paraortic trunk and the origin of the left colic artery
      (lca). The measurements were carried out on 20 cadavers and during 22 operations
      for rectal cancer. RESULTS: The left paraortic trunk always runs posterior to the
      ima: its distance from the origin of the ima is on average 1.2 cm; the distance
      of the left paraortic trunk from the origin of the lca is on average 0.4 cm. The
      point at which the ima and the left paraortic trunk cross varies greatly, but it
      is never near the origin of the ima. CONCLUSIONS: From an anatomical point of
      view the safest point of ligation of the ima is at its origin. At this point, the
      left paraortic trunk never runs; so there isn't any risk to damage the nerve
      involving it during the ligation of the artery.

PMID- 15026606
TI  - Importance and effects of altered workplace ergonomics in modern radiology
      suites.
AB  - The transition from a film-based to a filmless soft-copy picture archiving and
      communication system (PACS)-based environment has resulted in improved work flow
      as well as increased productivity, diagnostic accuracy, and job satisfaction.
      Adapting to this filmless environment in an efficient manner requires seamless
      integration of various components such as PACS workstations, the Internet and
      hospital intranet, speech recognition software, paperless electronic hospital
      medical records, e-mail, office software, and telecommunications. However, the
      importance of optimizing workplace ergonomics has received little attention.
      Factors such as the position of the work chair, workstation table, keyboard,
      mouse, and monitors, along with monitor refresh rates and ambient room lighting,
      have become secondary considerations. Paying close attention to the basics of
      workplace ergonomics can go a long way in increasing productivity and reducing
      fatigue, thus allowing full realization of the potential benefits of a PACS.
      Optimization of workplace ergonomics should be considered in the basic design of
      any modern radiology suite.

PMID- 15026608
TI  - Prognostic variables for cancer-related survival in node-negative colorectal
      carcinomas.
AB  - BACKGROUND/AIM: The efficacy of adjuvant treatment in node-negative colorectal
      carcinoma is unproven. The purpose of this study was to analyze the prognostic
      value of routinely detectable clinicopathological variables in order to identify
      subgroups of node-negative colorectal cancer patients at a high risk of a
      recurrence. METHODS: Seventy-three patients who did not receive radio- or
      chemotherapy were selected among 112 node-negative colorectal cancer patients who
      underwent curative resection. Follow-up was a minimum of 5 years or until death.
      The influence of 17 demographic, clinical, and pathological variables on the 5
      year cancer-related survival was assessed using univariate and multivariate
      analyses. RESULTS: The compliance with follow-up was 99%. The 5-year survival
      rate was 81%. Univariate analysis showed that T4 lesions (p < 0.001), age >70
      years (p = 0.008), lymphatic invasion (p = 0.001), and neural invasion (p = 0.02)
      were significantly associated with a decreased survival. T4 stage (hazard ratio
      12.75, p < 0.001) and age >70 (hazard ratio 3.08, p = 0.04) significantly
      affected the cancer-related survival on multivariate analysis. CONCLUSIONS: Node
      negative colorectal cancer patients with T4 carcinoma or those aged over 70 years
      have a higher risk of recurrences after resection. They should receive adjuvant
      or neoadjuvant treatment compatible with their performance status.

PMID- 15026609
TI  - Genetic predisposition to neurological symptoms in lacunar infarction.
AB  - OBJECTIVE: Lacunar infarction is a unique stroke entity with characteristic
      symptoms. However, it is often silent clinically. The possible genetic
      predisposition to symptoms of lacunar infarction was investigated. METHODS: One
      hundred and fifty-one patients with lacunar stroke were consecutively recruited.
      Lacunar stroke was diagnosed based on both neurological symptoms and lacunar
      lesion(s), demonstrated by MRI, that were responsible for the symptoms. One
      hundred and fifty control subjects with MRI-proven lacunar lesions without
      neurological symptoms served as controls. There was no significant difference in
      age, sex and prevalence of known risk factors between cases and controls.
      Insertion and deletion polymorphisms of the angiotensin-converting enzyme gene
      (ACE), M235T substitution of the angiotensinogen gene (AGT), and A1133C
      substitution of type 1 receptor of the angiotensin II gene were determined.
      RESULTS: The frequency of ACE D allele was significantly higher in symptomatic
      patients compared with asymptomatic subjects (0.44 vs. 0.36, p < 0.05). The
      genotype distribution of AGT was significantly different between symptomatic and
      asymptomatic patients (chi(2) = 6.6, p = 0.037). Multiple logistic regression
      analysis revealed that ACE gene and AGT genotypes were independently associated
      with the neurological manifestation of lacunar infarction. In subjects with 1
      lacuna, the odds ratio of the ACE DD genotype for symptomatic manifestation was
      4.98 (95% CI 1.25-19.9). In subjects with 4 or more lacunae, the odds ratio of
      the ACE II genotype for symptomatic manifestation was 0.24 (95% CI 0.10-0.56).
      Furthermore, the ACE gene polymorphism was significantly different between
      symptomatic patients with a single lacuna and asymptomatic subjects with 4 or
      more multiple lacunar infarctions (chi(2) = 10.6, p = 0.005). CONCLUSION: These
      findings suggest that 2 subtypes of lacunar infarction, single symptomatic lacuna
      and multiple asymptomatic lacunae, may possess different genetic backgrounds.
      Subjects with the ACE DD genotype could be more predisposed to be symptomatic in
      first-ever lacunar stroke, while the ACE II genotype may convey resistance to
      symptoms even after multiple lacunar strokes. Polymorphism of genes of the renin
      angiotensin system could be involved in the manifestation of neurological
      symptoms of lacunar infarction.

PMID- 15026610
TI  - Common carotid artery intima-media thickness in patients with brain infarction
      and intracerebral haemorrhage.
AB  - An increase in the intima-media thickness of the common carotid artery (CCA-IMT)
      is generally considered as an early marker of atherosclerosis and has been
      associated with a higher risk of stroke and myocardial infarction. There is no
      evidence of an association between the IMT and cerebral bleeding. We investigated
      cross-sectionally the diagnostic ability of vascular risk factors, including CCA
      IMT, to distinguish between brain infarction (BI) and intracerebral haemorrhage
      (ICH). Patients suffering from BI (n = 126) had significantly (p < 0.05) higher
      CCA-IMT when compared to the ICH population (n = 30). The multinomial logistic
      regression procedure selected CCA-IMT as an independent factor able to
      discriminate between BI and ICH. The risk of BI versus ICH increased continuously
      with increasing CCA-IMT. After adjustment for cardiovascular risk factors the
      odds ratio for BI per 0.1 mm CCA-IMT increase was 1.29 (95% CI: 1.03-1.61). The
      present results demonstrate the possible predictive power of non-invasive
      measurement of the CCA-IMT with respect to BI versus ICH and deserve further
      investigation.

PMID- 15026611
TI  - Mechanisms of single and multiple borderzone infarct: transcranial Doppler
      ultrasound/magnetic resonance imaging correlates.
AB  - BACKGROUND AND PURPOSE: Hemodynamic patterns after borderzone (BZ) infarction are
      variable and dynamic. However, stroke mechanisms in different types of BZ
      infarctions have not been systematically studied by magnetic resonance
      angiography (MRA) and transcranial Doppler ultrasonography (TCD). METHODS: Forty
      nine patients who experienced a stroke limited to the territory of either the
      superficial or internal borderzone proved on MRI included in our registry,
      corresponding to 4% of 1,200 patients with ischemic stroke, were studied. All
      these patients underwent MRA, extracranial Doppler ultrasonography, TCD and other
      investigations from the standard protocol of our registry. Twenty of them (41%)
      had a posterior BZ infarct, 14 (29%) an anterior BZ infarct, 10 (20%) a
      subcortical BZ infarct and 5 (10%) bilateral BZ infarcts. RESULTS: Unilateral
      internal carotid artery (ICA) tight stenosis or occlusion ipsilateral to the
      lesion was present in 14 patients (70%) with a posterior BZ infarct, in 72% of
      those with an anterior BZ infarct, in 80% of those with a subcortical BZ infarct
      and in 80% of those with bilateral BZ infarcts. TCD showed cross-filling of the
      middle cerebral artery via the anterior communicating artery in 5 patients (25%)
      with a posterior BZ infarct and 10% had an increased mean flow velocity (MFV) in
      the ipsilateral P1 posterior cerebral artery (PCA). In patients with an anterior
      BZ infarct, 3 (23%) had an MFV increase in the contralateral A1 anterior cerebral
      artery (ACA), and 2 (15%) had a higher MFV in the ipsilateral PCA. An elevated
      velocity at midline depths with reversed A1 ACA flow direction was seen in 2
      patients (20%) with a subcortical infarct, and 1 patient (10%) had an MFV
      increase in the ipsilateral P1 PCA. Left ventricular systolic dysfunction
      (ejection fraction <40%) was present in 50% of patients with a posterior BZ
      infarct, in 36% of those with an anterior BZ infarct, in 20% of those with a
      subcortical BZ infarct and bilateral BZ infarcts each. CONCLUSION: The
      association of severe ICA stenosis or occlusion with cardiopathies and left
      ventricular dysfunction may play a critical role in those with BZ infarcts having
      inadequate collateral supply, while a cardioembolism or acute ICA dissection may
      also cause BZ infarction due to the rapidity of the occlusive process and the
      inability of the cerebral vasculature to recruit collateral pathways quickly
      enough.

PMID- 15026612
TI  - What is the lowest dose of aspirin for maximum suppression of in vivo thromboxane
      production after a transient ischemic attack or ischemic stroke?
AB  - BACKGROUND: There is still worldwide disagreement about the optimal lowest dose
      of aspirin to be used in patients after a transient ischemic attack (TIA) or
      nondisabling stroke. We measured the urinary 11-dehydro-thromboxane-B(2)
      (uTXB(2)) excretion to compare the degree of suppression of in vivo platelet
      activation by various low doses of aspirin. METHODS: 60 patients were randomly
      allocated to treatment with either 30, 50, 75 or 325 mg of aspirin. All patients
      received a 413-mg loading dose of carbasalate calcium (equivalent to 325 mg of
      aspirin) on day 0. The study population was stratified into a subgroup with acute
      ischemic stroke (AIS; n = 20; onset of symptoms <48 h) and a subgroup with a
      recent TIA or minor stroke (TIA/mS; n = 40) with onset of symptoms beyond 30
      days, but less than a year previously. Urine samples were collected on day 0, 1,
      5, 11 and 28 in patients with AIS, and on day 0, 11 and 28 in the patients with a
      TIA/mS. RESULTS: On day 28, mean uTXB(2) levels were 241, 130, 217 and 187
      pmol/mmol creatinine in the four treatment groups (ANOVA, p = 0.43). In the AIS
      subgroup, uTXB(2) remained suppressed on days 5 and 11 in all except the patients
      with the lowest dose (mean uTXB(2) on days 5 and 11: 475 and 392 pmol/mmol
      creatinine; log-transformed ANOVA, p = 0.05). CONCLUSION: In patients with a TIA
      or nondisabling stroke, a daily dose of 30 mg of aspirin provides sufficient
      suppression of thromboxane synthesis. No indication of a dose-effect relationship
      was found. However, whether such a low dose adequately suppresses thromboxane
      synthesis in patients with acute stroke is uncertain.

PMID- 15026613
TI  - Incidence of cerebral hemorrhage in the Changsha community. A prospective study
      from 1986 to 2000.
AB  - BACKGROUND AND PURPOSE: Intracranial hemorrhage (ICH) constitutes an important
      subtype of stroke. In a prior study, we found that the city of Changsha, People's
      Republic of China, not only had a high incidence of stroke, but also had almost
      the highest incidence of cerebral hemorrhage. To provide information for
      preventing and managing ICH, we undertook this study supervising and determining
      the annual first-ever average incidence of cerebral hemorrhage from 1986 to 2000
      in Changsha. METHODS: In January 1986, people from 6 well-defined communes in the
      Kai-fu district in Changsha were selected as the study population. Since 1991, we
      added another 18 well-defined communes of the same district. Data on these
      residents were obtained from the census register of the local administrative
      office. Persons who had a history of stroke were excluded from our study at the
      beginning. Every year, we checked up on the population and carried out door-to
      door inquiries to verify the new cases of ICH and stroke. If the patients were
      diagnosed in hospital, as many as possible were examined with CT and/or MRI. The
      incidence rate adjusted to the World population in 1985 for age and sex, as well
      as the prevalence of risk factors were calculated. RESULTS: An accumulative total
      of 551,163 people were supervised in 15 years (from 1986 to 2000); the annual
      average incidences of stroke and ICH were 236.6/100,000 (adjusted rate: 154.7)
      and 131.0/100,000 (adjusted rate: 73.1), respectively. From 1986 to 2000, the
      total annual average rate of stroke confirmed by CT and/or MRI in Changsha was
      70.8%, and for ICH it was 64.7%. The incidences of stroke and ICH confirmed by
      image analysis were 167.5 (adjusted rate: 110.8) and 84.7 (adjusted rate: 55.1),
      respectively. The mean annual mortality rate of ICH was 78.3/100,000 (adjusted
      rate: 49.3) and that of stroke was 124.5/100,000 (adjusted rate: 97.0). The
      percentage of ICH among stroke cases was 55.4%. Among patients with ICH, 79.8%
      had hypertension, 30.6% had cardiovascular disease, 7.6% had diabetes mellitus,
      and 12.5% had an abnormal high level of lipid. Among patients with other subtypes
      of stroke apart from ICH, the percentages were 76.6, 40.6, 15.5, and 22.5%.
      CONCLUSIONS: The incidence of ICH in Changsha is very high, so is the proportion
      of ICH among all stroke cases. Changsha is an area with a high incidence of ICH
      in the world. Hypertension is the prominent risk factor. The study demonstrated
      the importance of ICH as a significant subtype of stroke.

PMID- 15026614
TI  - Mycoplasma pneumoniae in elderly patients with stroke. a case-control study on
      the seroprevalence of M. pneumoniae in elderly patients with acute
      cerebrovascular disease - the M-PEPS Study.
AB  - BACKGROUND AND PURPOSE: Previous studies have suggested certain infections as
      potential risk factors for stroke. Chlamydia pneumoniae, an atypical respiratory
      pathogen, has been linked to atherosclerotic vascular diseases. Mycoplasma
      pneumoniae, another atypical respiratory micro-organism, can rarely cause stroke.
      We investigated whether serological markers of M. pneumoniae infection were
      associated with acute stroke or transient ischaemic attack (TIA) in elderly
      patients. METHODS: This case-control study was nested within the C-PEPS study - a
      case-control study on the seroprevalence of C. pneumoniae in elderly stroke and
      medical patients. Ninety-five incident cases of patients admitted consecutively
      with acute stroke or TIA, and 82 control subjects admitted concurrently with
      acute non-cardiopulmonary, non-infective disorders, were included in this study
      (both groups aged 65 years or older). Using commercial enzyme-linked
      immunosorbent assay (ELISA) kits, the presence of M. pneumoniae immunoglobulins
      IgA, IgG and IgM in patients' sera was determined. RESULTS: The seroprevalence of
      M. pneumoniae IgA, IgG and IgM in the stroke or TIA group (median age = 80) were
      79, 61 and 6%, respectively. In the control group (median age = 80), the
      seroprevalence of respective M. pneumoniae IgA, IgG and IgM were 84, 50 and 11%.
      Using a logistic regression statistical model, adjusting for history of
      hypertension, smoking, diabetes mellitus, age and sex, history of ischaemic heart
      disease, and ischaemic electrocardiogram, the odds ratios of having a stroke or
      TIA in relation to M. pneumoniae IgA, IgG and IgM were 0.63 (95% confidence
      interval (CI) = 0.26-1.52, p = 0.31), 1.32 (95% CI = 0.66-2.64, p = 0.43) and
      0.52 (95% CI = 0.14-1.92, p = 0.32), respectively. CONCLUSIONS: The study showed
      a high seroprevalence of M. pneumoniae in an elderly hospital population, using
      ELISA. Although the study ruled out M. pneumoniae seropositivity as a major risk
      factor for stroke in this elderly population, a smaller effect could not be
      excluded due to the small sample size. Future larger studies may be required to
      determine the precise role of M. pneumoniae infection in the pathogenesis of
      different subtypes of ischaemic stroke, in all age groups, and in different
      ethnic populations.

PMID- 15026615
TI  - The prognostic significance of changes in lesion size of established cerebral
      infarcts on computed tomography of the brain.
AB  - BACKGROUND: As a second part of our prospective study, we assessed the size of
      the infarct lesion on computed tomography (CT) of the brain at two fixed time
      points after stroke in order to investigate its influence on the clinical
      outcome. METHODS: From 220 consecutive stroke patients, admitted within 24 h
      after onset with symptoms lasting more than 24 h, we selected 150 displaying an
      anterior circulation infarct or syndrome. All included patients had CT scans
      without contrast enhancement on day 3 (+/- 8 h) and on day 10 (+/- 8 h) after
      stroke onset. The size of the X-ray hypoattenuation zone was determined by
      superimposing the CT slices on digital cerebral vascular maps, on which the
      contours of the infarct area were delineated. The lesion size was expressed as
      the fraction of the total surface area of these digital cerebral maps. The
      patients were divided into four groups according to their degree of disability at
      3 months on the modified Rankin (R) scale as follows : R 0-1, R 2-3, R 4-5, R 6.
      RESULTS: There was a clear association between lesion size on CT, on day 3 and on
      day 10, and the clinical outcome. Lesion size decreased between day 3 and day 10
      in the groups R 0-1 and R 2-3, remained unchanged in the group R 4-5 and further
      increased in group R 6. CONCLUSION: Lesion size on CT is a significant predictor
      of stroke outcome. It decreases from day 3 to day 10 in patients with no or low
      disability at 3 months, but increases in those who do not survive their stroke.

PMID- 15026616
TI  - Georg Friedrich Handel's strokes.
AB  - Georg Friedrich Handel was a musical giant and probably the first composer to be
      the manager and promoter of his own works. The story of his life and illnesses is
      full of myths, invented and embellished by various biographies. Existing
      pathographies written by authors from various specialities suggested he suffered
      from psychiatric diseases like cyclothymia or mania and rheumatologic disorders
      like arthritis, while others tended to interpret his recurrent palsies as typical
      sequelae of ischemic strokes. During the last years of life, Handel was struck
      with blindness, which in his era was interpreted as being due to cataracts. This
      led to three 'coucher' operations, all of them without lasting effect. Although a
      definite diagnosis cannot be inferred from the original sources, the most
      plausible explanation for Handel's palsies and visual impairment may be
      cerebrovascular disease. The possible differential diagnosis will be discussed in
      this paper.

PMID- 15026617
TI  - Congenital oral mucosal abnormalities in true umbilical cord knots.
AB  - OBJECTIVE: The pathogenesis and clinical significance of true umbilical cord
      knots remain controversial. Here, we tested the hypothesis of the presence of
      congenital oral mucosal changes in newborns with true umbilical cord knots. STUDY
      DESIGN: Seven consecutive infants with true umbilical cord knots and 50
      gestational age- and sex-matched controls were enrolled. The proportion of oral
      frenulum abnormalities and the two-dimensional vascular network geometry [fractal
      dimension, D, at two scales: D(1-46), and D(1-15), with the relative Lempel-Ziv
      complexity, (L-Z)], were analyzed. RESULTS: Infants with true umbilical cord
      knots showed significantly higher proportions of mandibular frenulum agenesis
      compared to controls (p = 0.000006). The oral vascular networks of these infants
      exhibited a significantly higher D(1-46) and D(1-15) (p < 0.0001, respectively),
      and higher L-Z values (p < 0.0001) than control networks. CONCLUSION: These
      findings indicate the presence of significant congenital oral mucosal changes in
      newborn infants with true umbilical cord knots, thus suggesting a previously
      unrecognized association between true umbilical cord knots and a subclinical
      extracellular matrix disorder.

PMID- 15026618
TI  - BAG-1 expression correlates with Bcl-2, p53, differentiation, estrogen and
      progesterone receptors in invasive breast carcinoma.
AB  - BAG-1, a recently identified anti-apoptotic protein, is overexpressed in the
      majority of invasive breast carcinomas. Overexpression of BAG-1 is important for
      both multi-step oncogenesis and resistance of cancer cells to apoptosis induced
      by DNA-damaging alkylating agents. BAG-1 protein species are localized
      differentially; nuclear expression may be associated with a shorter disease-free
      and overall survival in early stage breast cancer, while cytoplasmic expression
      has been associated with longer survival in non-small cell lung cancer. Growing
      evidence suggests that Bcl-2 and p53 are also involved in the oncogenesis of
      breast cancer. Since BAG-1 interacts with Bcl-2 and is upregulated by mutant p53
      in vitro, it would be interesting to determine if their expressions are
      correlated with each other and with other clinical prognostic factors in invasive
      breast cancer. To address this question we conducted a large scale retrospective
      study of BAG-1, Bcl-2 and p53 in 185 breast cancer patients. Our study again
      showed that BAG-1 is overexpressed in the majority of breast cancer patients. In
      addition, it demonstrated that the expression of BAG-1 correlates with that of
      Bcl-2, p53, differentiation, estrogen and progesterone receptors. Our clinical
      study supports the preclinical finding of the interaction between BAG-1 and Bcl
      2, p53 and estrogen and progesterone receptors. Further experiments to explore
      the prognostic and therapeutic role of BAG-1 in breast cancer are warranted.

PMID- 15026619
TI  - Her-2/neu gene amplification and protein expression in primary male breast
      cancer.
AB  - The role of HER-2/ neu in male breast cancer is not well defined. The purpose of
      the current study was to measure the frequency of HER-2/ neu expression in
      primary male breast cancer, to demonstrate HER-2/ neu gene amplification in cases
      found to be positive for protein overexpression, and to correlate HER-2/ neu
      positivity with clinicopathological variables. Formalin-fixed, paraffin-embedded
      archival material from 99 primary male breast carcinomas was evaluated by
      immunohistochemistry (IHC) using the HercepTest (DAKO Corp., Hamburg, Germany).
      Scoring was performed according to established guidelines. All cases
      demonstrating HER-2/ neu staining by IHC (1+/2+ and 3+) were analyzed for HER-2/
      neu gene amplification by fluorescence in situ hybridization (FISH) utilizing the
      PathVysion assay (Vysis Corp., Downers Grove, Illinois) to assess HER-2/ neu
      amplification status. The immunohistochemical staining of the HER-2/ neu protein
      revealed HER-2/ neu positivity in 15/99 (15.1%) cases, eight tumors showed 2+ and
      7 tumors 3+ staining. HER-2/ neu gene amplification was observed in 11/99 cases
      (11,1%), and all of the 3+ and 4/8 from the 2+ cases were amplified. HER-2/ neu
      gene amplification/protein overexpression did not correlate with tumor state,
      histological grade or estrogen/progesterone receptor status nor the axillary
      lymph node status. This is the first comprehensive study of HER-2/ neu gene
      amplification by FISH analysis in primary male breast cancer. Compared to female
      primary breast cancer the percentage of HER-2/ neu positivity in our study was
      lower. Our data provide first evidence for HER-2/ neu gene amplification in male
      breast cancer. Further studies should be addressed on the potential application
      of the monoclonal rhuMAB HER-2/ neu antibody for treatment of HER-2/ neu positive
      male breast cancer.

PMID- 15026620
TI  - Insulin-like growth factor (IGF)-system mRNA quantities in normal and tumor
      breast tissue of women with sporadic and familial breast cancer risk.
AB  - The insulin-like growth factor (IGF)-system plays a role in breast cancer
      susceptibility as well as in growth and progression of breast carcinomas. So far,
      findings have been based on serum IGF-I levels and semi-quantitative assessment
      of IGF-system expression levels in model systems and human tissue. Quantitative
      data on mRNA expression in different types of human breast tissue are lacking.
      Breast tissue samples ( n = 83) were available from 72 women. Messenger RNA
      expression of IGF-I, IGF-II, and their receptors (IGF-1R and IGF-2R) was assessed
      by real-time RT-PCR. We found a large variation in mRNA levels. Expression of
      each gene was significantly higher in normal tissue than in tumor tissue (median
      for normal and tumor tissue, respectively (arbitrary units); IGF-I: 25.2 and 1.4;
      IGF-II: 5.9 and 0.6; IGF-1R: 0.18 and 0.07; IGF-2R: 1.8 and 0.9; p < 0.0001, Mann
      Whitney test). Interestingly, in tumor tissue from patients with a strong family
      history of breast cancer, expression of both receptors was higher than in
      sporadic patients (IGF-1R: 0.13 and 0.05, p = 0.04; IGF-2R: 1.1 and 0.8, p =
      0.04). For cancer-free controls, expression of IGF-II and IGF-2R in normal breast
      tissue was also higher in women with a family history of breast cancer than in
      women without such a family history (IGF-II: 7.2 and 1.5, p = 0.02; IGF-2R: 2.6
      and 1.5, p = 0.09). Our study quantitatively shows that mRNA expression levels of
      IGF-system components in the breast are generally higher in normal tissue
      compared with tumor tissue, and higher in tissue from women with a family history
      of breast cancer. A basis has therefore been created for studies aimed at
      understanding IGF as a breast cancer risk factor, the relationship between IGF
      systems in serum and tissues, and effects of lifestyle factors on the IGF-system.

PMID- 15026621
TI  - Estrogen disrupts chemokine-mediated chemokine release from mammary cells:
      implications for the interplay between estrogen and IP-10 in the regulation of
      mammary tumor formation.
AB  - Chemokines are pro-inflammatory cytokines that function to attract immune cells
      to the sites of tissue inflammation, injury or infection. We have formulated the
      hypothesis that release of one chemokine can serve, in a local paracrine or
      endocrine fashion, to induce the release of other chemokines from neighboring
      mammary cells. We set out to investigate whether specific chemokines could
      promote the release of other chemokine members from mammary cells, and whether
      estrogen could serve to disrupt the release of these chemokines from mammary
      cells. We found that treatment with the chemokine IP-10 resulted in significant
      increases in the amount of MIP-1alpha and MCP-1/JE released from murine mammary
      cells. Estrogen co-treatment significantly blocked the ability of IP-10 to
      trigger the release of MIP-1alpha and MCP-1/JE. Suppressive effects of estrogen
      were reversed upon co-treatment with 4-hydroxytamoxifen. Estrogen treatment
      significantly decreased expression of proteins corresponding to the chemokine
      receptors CXCR3 and CCR5 on mammary cells. Exposure of female mice to IP-10 in
      vivo significantly decreased the ability of estrogen to support the growth of CCL
      51-based tumors in mammary tissue. Our results suggest that exposure of mammary
      tissue to estrogen may decrease the release of local chemokines from mammary
      cells, potentially increasing the risk of tumor growth through decreased immune
      surveillance. Ongoing studies are investigating the possible mechanisms through
      which IP-10 stimulates the release of chemokines from mammary cells, and how the
      action of IP-10 may serve to decrease mammary tumor formation.

PMID- 15026622
TI  - CXCR4 is expressed in ductal carcinoma in situ of the breast and in atypical
      ductal hyperplasia.
AB  - Recent evidence attributed important influence of chemokines and their receptors
      on motility, homing, and proliferation of cancer cells at specific metastatic
      sites. Here we report that the CXCL12 (SDF-1alpha) chemokine receptor CXCR4 is
      expressed in human ductal carcinoma in situ (DCIS) as well as in atypical ductal
      hyperplasia. CXCR4 was expressed in pure DCIS and DCIS with concurrent invasive
      disease. In 66% of the samples, atypical ductal hyperplasia was present, and >
      92% exhibited positive CXCR4-staining. Expression of CXCR4 at this very early
      step of tumor development indicates a role of this receptor in providing a
      selective advantage to such cells on their way to metastasizing carcinomas. These
      results strengthen the ideas to target chemokine networks involved in tumor
      progression and metastatis as a therapeutic approach in malignant disease or as a
      chemoprevention strategy, blocking the transition from premalignancy to
      malignancy.

PMID- 15026623
TI  - Perillyl alcohol inhibits human breast cancer cell growth in vitro and in vivo.
AB  - The effect of monoterpene perillyl alcohol (POH) on cell growth, cell cycle
      progression, and expression of cell cycle-regulatory proteins in estrogen
      receptor (ER)-positive (KPL-1 and MCF-7) and ER-negative (MKL-F and MDA-MB-231)
      human breast cancer cell lines was examined. POH inhibited cell proliferation in
      a dose-dependent manner in all cell lines tested. POH at a dose of 500 micro M
      had a cytostatic effect, in which growth inhibition was due to accumulation of
      cells in G1-phase. Cell cycle progression was preceded by a decrease in G1
      cyclins (cyclin D1 and E), followed by an increase in p21(Cip1/Waf1) and a
      decrease in proliferating cell nuclear antigen level. Levels of p53 and cyclin A
      were unchanged. POH at a dose of 75 mg/kg administered intraperitoneally three
      times a week throughout the entire 6-week experimental period suppressed
      orthotopically transplanted KPL-1 tumor cell growth and regional lymph node
      metastasis in a nude mouse system. POH inhibited both ER-positive and -negative
      human breast cancer cell growth in vitro, and suppressed growth and metastasis in
      vivo.

PMID- 15026624
TI  - Current controversies concerning sentinel lymph node biopsy for breast cancer.
AB  - BACKGROUND AND METHODS: The objectives of this article are to review existing
      controversies regarding sentinel lymph node (SLN) biopsy and to identify
      potential areas of consensus in order to eliminate routine axillary lymph node
      dissection (ALND). RESULTS: A combination of peritumoral injection with
      radioisotopes and subdermal or subareolar injection with blue dye may result in
      enhanced success rates of SLN identification. Preoperative lymphoscintigraphy is
      most useful for detecting an internal mammary SLN, but the practicability of
      internal mammary SLN biopsy is still in the investigative stage. Intraoperative
      diagnosis of SLN is useful because patients with SLN metastases may be treated
      immediately with ALND, but it is unreasonable to expect that either examination
      of frozen sections or imprint cytology will detect every metastatic disease. SLN
      micrometastases may be of prognostic importance and these can be identified with
      H and E staining on permanent sections of 200 micro m intervals. While ALND is
      preferable for patients even with a small tumor (T1) and SLN micrometastases,
      radiation therapy is an acceptable alternative. SLN biopsy may be indicated for
      patients with DCIS detected as a palpable mass or those with large calcification
      areas in the breast. The accuracy of SLN biopsy after neoadjuvant chemotherapy is
      considered to be unproven. CONCLUSION: Since SLN biopsy has been adopted by
      surgeons around the world, consistency of technique and case selection has
      attained great significance.

PMID- 15026625
TI  - The effect of environment on breast cancer risk.
AB  - Environmental factors are believed to explain a large proportion of breast cancer
      incidence. Known risk factors for breast cancer, which are related to the
      reproductive life of women, and other factors, such as inheritance and
      socioeconomic status, explain only about half of the breast cancer cases in the
      US. Ionizing radiation is a well established environmental risk factor for breast
      cancer. Chemicals that induce mammary cancer in rodents have served as leads for
      studies in humans, but occupational and environmental exposure to these chemicals
      have for the most part lacked association with breast cancer risk. However, there
      is recent evidence in rats that cadmium at very low doses acts as an estrogen
      mimic, indicating a need to investigate the effects of metals on breast cancer
      risk. Studies suggest that circadian rhythm disruption is linked with breast
      cancer, but too few studies have been done to be conclusive. Over the years,
      cigarette smoking as a risk factor for breast cancer has remained controversial.
      However, recent research has found passive smoke exposure to be associated with
      increased breast cancer risk, which is hypothesized to be accounted for on the
      basis of an antiestrogenic effect of smoking. Solar radiation has been noted to
      be associated with reduced breast cancer, supporting the hypothesis that vitamin
      D plays a protective role in reducing this risk. Although, most of the
      environmental factors discussed in this review have not been convincingly found
      to influence breast cancer risk, research suggests that environmental exposure in
      combination with genetic pre-disposition, age at exposure, and hormonal milieu
      have a cumulative effect on breast cancer risk.

PMID- 15026627
TI  - An epidemic of breast cancer among models of famous artists.

PMID- 15026626
TI  - No hypersensitive estrogen receptor-alpha mutation (K303R) in Japanese breast
      carcinomas.
AB  - Recently, a common somatic mutation, A-to-G transition at nucleotide 908, in the
      estrogen receptor-alpha (ERalpha) gene has been reported. This mutation causes an
      amino acid change in the ER hinge domain (lysine 303 to arginine, K303R) and
      confers an increased sensitivity to estrogen and an increased cellular
      proliferative potential. This mutation has been observed more frequently in
      breast cancers than in premalignant lesions. According to the previously
      published reports, the mutation was found in 62% of invasive breast cancers, 85%
      of the node-positive tumors, and 30% of proliferative breast hyperplasias in the
      study of US women. The purpose of our study was to investigate whether or not
      this mutation is present in breast cancers found in Japanese women. We performed
      mutation analysis using the genomic PCR and direct sequencing in 101 cases of
      breast cancer and eight cases of benign breast lesions. No K303R mutation was
      found in the ERalpha gene in these breast lesions obtained from Japanese
      patients.

PMID- 15026664
TI  - Practice-based research networks: the laboratories of primary care research.
AB  - Medical research has traditionally been based in academic centers, and the
      findings are frequently not applicable in community primary care settings. The
      result is a large gap between the possible and the practical in delivering high
      quality primary medical care in the United States. Practice-based research
      networks (PBRNs), laboratories for primary care clinical research, are the
      appropriate vehicles for uniting the worlds of community primary care practice
      and clinical research. Although they have received little attention in the
      mainstream of clinical and health services research, PBRNs have already reported
      a variety of findings useful for primary care providers, and these networks have
      helped to identify key issues in healthcare delivery that affect important
      outcomes. In this report, we outline the rationale for and history of PBRNs. We
      describe the organization and work of several productive PBRNs, giving examples
      of their studies that have changed the standards of modern primary care practice.
      Finally, we describe a developing electronic process for identifying research
      questions obtained directly from primary care providers that can be used to focus
      the national primary care research agenda on questions of clinical relevance and
      importance. As electronic technologies are fully developed and tested, they will
      facilitate communication between clinicians and researchers, thereby improving
      the effectiveness and efficiency of practice-based research.

PMID- 15026665
TI  - Outcomes research priorities in chronic care: a private purchaser perspective.
AB  - Private purchasers would benefit from outcomes research in chronic care that
      could inform their purchasing activities, including benefit design decisions.
      This article presents 1 purchaser's perspective on 10 areas of research of
      interest to the purchasing community.

PMID- 15026666
TI  - Research in long-term care: issues, dilemmas, and challenges from the public
      purchaser's perspective.
AB  - Expenditures for long-term care for older Americans are sizable and likely to
      increase as the population ages. As the largest purchaser of health care for this
      group of citizens, the Centers for Medicare & Medicaid Services (CMS) is working
      to improve the quality of the long-term care services it purchases through
      quality monitoring and enforcement, providing information to beneficiaries about
      quality of care and enhancing resources to improve quality. Although CMS has used
      the best scientific information available to inform the planning of quality
      initiative projects, there are a number of issues, dilemmas, and challenges for
      which the research base is insufficient to fully answer programmatic needs. In
      many instances, research needs in the long-term care setting differ substantially
      from those in acute care. Using the Nursing Home Quality Initiative as an
      example, this article presents a descriptive, conceptual discussion of strategic
      issues and a summary of research that would be valuable in informing critical
      areas of decision-making in quality and outcomes research over the next decade.
      The issues, dilemmas, and challenges discussed are grouped into 5 categories:
      measurement methods and tools, uses of quality data, organizational and cultural
      factors, information and informatics, and impact evaluation and research.

PMID- 15026667
TI  - Outcomes research on children, adolescents, and their families: directions for
      future inquiry.
AB  - Children have been poorly represented in clinical studies and health services
      research. However, this situation is changing rapidly, and the number of research
      studies focusing on child outcomes is steadily increasing. The special
      characteristics of childhood related to health care-developmental change,
      dependency on adults, different disease epidemiology from adults, and unique
      demographic characteristics-pose methodologic challenges to researchers. These
      characteristics also argue for an expanded concept of outcomes research that is
      centered on a child-specific model of the production of health, its determinants,
      and its relationship to healthcare services. This article proposes priorities for
      future inquiry, including developing new measures specific to children; examining
      the influence of medical, public health, and other community interventions on
      children's long-term health trajectories; increasing attention to risk behaviors
      and resiliency factors that influence children's future health status;
      reconsidering the value of routine child healthcare and pediatric specialty care;
      examining the financing and organization of children's health care; exploring the
      importance of family influences on child and adolescent health; and addressing
      optimal treatment strategies for managing common childhood health problems.

PMID- 15026668
TI  - Strategies to control costs and quality: a focus on outcomes research for disease
      management.
AB  - Rapid adoption of disease management has outpaced systematic evaluation of its
      net value in improving health outcomes and mitigating healthcare cost. This
      article identifies areas in which outcomes research in disease management is
      needed to demonstrate its value or to enhance its performance. Patient
      identification for disease management relies on administrative database queries
      but the trade-offs in sensitivity, specificity, and predictive value of
      alternative queries are not well known. Large-scale deployment, rapid patient
      engagement, and repeated interactions between patients and nurses could be
      important attributes for attaining measurable improvements in quality and cost
      reduction over short periods of time, but these hypothesis need to be tested.
      There is a trend toward integration of multiple chronic disease management
      programs onto a single platform. To support this trend, there is a need for a
      corresponding set of integrated clinical guidelines or "meta-guidelines" that
      combine the contents of individual practice guidelines. The relative contribution
      of various disease management interventions in improving clinical results,
      lowering costs, and their respective ease of implementation is not known.
      Research leading to a better understanding of tradeoffs could lead to more
      rational resource allocation and better overall outcomes. Coordination between
      disease management programs and physician practices is lacking. Research aimed at
      defining operational and technical interfaces and cultural and behavioral
      professional adjustments necessary to achieve integration and coordination is
      needed. The lack of a consistent analytical framework for evaluating clinical and
      financial outcomes has made comparisons of reported results impossible and has
      rendered many reports unreliable. Theoretical work on a standard methodology that
      integrates clinical and financial outcomes and empiric validation is needed.

PMID- 15026669
TI  - Leadership and management principles for outcomes-oriented organizations.
AB  - Outcomes and effectiveness research has provided a wealth of information about
      interventions that can improve patient experience and outcomes. The challenges
      facing healthcare leaders today highlight the need for new research on how
      leadership and management principles can enable healthcare providers and systems
      to deploy this knowledge swiftly and effectively. The Baldrige National Quality
      Program (BNQP) is an education and award program established by the U.S. Congress
      in 1987 that supports American businesses seeking to improve product and service
      quality, customer and workforce satisfaction, efficiency, financial results, and
      overall capacity to perform and respond to changing circumstances. Award
      recipients show a constellation of strengths that suggest that certain basic
      leadership and management practices are correlated with a fundamental ability to
      achieve desired results. This article describes characteristics of highly
      effective organizations based on a review of Baldrige Award recipients, focuses
      on the application of these characteristics to healthcare settings, illustrates
      their application with best practices from SSM Health Care, the first-ever
      healthcare recipient in 2002, and presents several priorities for outcomes and
      effectiveness research to inform healthcare leadership and administration.

PMID- 15026670
TI  - Formularies, therapeutics, and outcomes: new opportunities.
AB  - The increasing prominence of drug therapies in health care and their rapidly
      rising costs have led to a dramatic escalation of interest in the use of outcomes
      data for therapeutics and formulary decisions. The expanded use of formulary
      submission dossiers, effectiveness data, health outcomes analysis, and
      pharmacoeconomic modeling has created an urgent need for outcomes research to
      investigate topics especially relevant for health plan drug therapy coverage
      decisions. This article examines the evolving use of outcomes data on drug
      formulary and other therapeutic decisions, and outlines several priority areas
      for outcomes research. These include research into surrogate measures of long
      term health and economic outcomes, evaluations of new formulary submission
      programs, and research on the impact of pharmaceutical cost-sharing arrangements
      on health outcomes. The article also discusses the importance of evaluating
      patient compliance and health outcomes after implementation of a Medicare
      prescription drug benefit, and the need for new types of clinical trials that can
      respond to changing demands of pharmacy and therapeutics committees and providers

PMID- 15026671
TI  - Outcomes research: priorities for an evolving field.

PMID- 15026672
TI  - A comprehensive clinical assessment tool to inform policy and practice:
      applications of the minimum data set.
AB  - The Minimum Data Set (MDS) for nursing home (NH) resident assessment, designed to
      assess elders functional status and care needs, exemplifies how the information
      needs of clinical practice are congruent with those of research. Building on a
      review of the published literature, this article describes the development of the
      MDS, its reliability and validity testing, as well as the variety of different
      policy and research uses to which it has been applied. Interrater reliability of
      items and internal consistency of MDS summary scales is generally good to
      excellent. Validation studies reveal good correspondence to research quality
      instruments for cognition, activities of daily living, and diagnoses with more
      variable results for vision, pain, mood, and behavior scales. To date, no
      consistent evidence suggests that applications of MDS data for case-mix
      reimbursement and quality indicator monitoring systematically bias the data.
      Although facility variation in data quality could compromise some applications,
      creation of the MDS as a clinical tool for care planning provides an example of
      how assessment tools with clinical use can be used in administrative databases
      for research and policy applications.

PMID- 15026695
TI  - [Can type II diabetes be avoided?].

PMID- 15026696
TI  - [Patients' duties].

PMID- 15026697
TI  - [Ductal carcinoma in situ of the breast. Analysis of 882 cases].
AB  - OBJECTIVE: This study assesses the results of "current clinical practice" among
      882 women treated in nine French Cancer Centers from 1985 to 1995 for pure ductal
      carcinoma in situ (DCIS) of the breast. METHOD: Median age was 53 years (range 21
      87); 177 (20%) patients underwent mastectomy (M), 190 (22%) conservative surgery
      alone (CS) and 515 (58%) conservative surgery with radiotherapy (CS + RT).
      RESULTS: The crude 7-year local relapse (LR) rates were 2%, 31% and 13% among the
      M, CS and CS+RT subgroups (p<0.0001). All four LR after M were invasive as well
      as 31 (52%) out of 59 and 40 (61%) out of 66 in the CS and CS+RT groups. Distant
      metastases occurred in 1%, 3% and 1% of the three treatment groups. No LR factors
      were found in the M group. Among women treated with CS, the 7-year LR rates were
      36%, 31% and 30% among women aged 40 or less, 41 to 60 and 61 or more (NS). For
      women treated by CS+RT, the LR rates in these age subgroups were 33%, 13% and 8%,
      respectively (p<0.0001). Patients with negative, positive or uncertain margins
      had 7-year LR rates of 26%, 56% and 29% respectively if treated with CS (p=0.02)
      and 11%, 23% and 9% if treated with CS+RT (p=0.0008). RT reduced LR rates by 65%
      in all histological subgroups, but more particularly in comedocarcinoma and mixed
      cribriform/papillary subgroups. The 7-year rate of contralateral breast cancer
      was 7%, identical in all subgroups. CONCLUSION: Mastectomy remains the safest
      treatment for women with DCIS, with a 98% 7-year control rate. After conservative
      surgery, RT reduces very significantly LR rates, according to the NSABP B-17 and
      EORTC 10853 randomized trial results. The RT benefit is present in all
      clinical/histological subgroups, but its magnitude varies. Young age (<40 years)
      and incomplete excision are the most important LR risk factors.

PMID- 15026698
TI  - [Survey on the measures of asepsis taken by general practitioners].
AB  - CURRENT STATE OF THE QUESTION: Many legislative and administrative texts rule
      asepsis and prophylaxis in health care centres. The deontological code provides
      the guidelines for medical corps. OBJECTIVE: To identify the measures set-up to
      prevent the transmission of infections in general practitioners' consulting rooms
      and to compare them with the data in the literature. METHOD: A postal survey
      using a questionnaire was sent to a representative sample of 119 general
      practitioners in the Loire-Atlantique area in France. RESULTS: The response rate
      was of 69%. The majority of physicians declared that had a wash basin in the
      consulting room, 43% declared that they did not systematically wash their hands
      between 2 patients in their consulting rooms and 78% during home visits, 23% used
      an ordinary soap, 49% a hydro-alcoholic solution, and 62% wiped their hands with
      a cotton towel. Blood interventions were performed with gloves by more than 80%
      of the participants, complete decontamination procedures of the material were
      performed by 6%, but more than 80% used single use material. Although 45%
      believed they had changed their habits, 23% remained wary of any eventual
      recommendations and 43% made no comments. DISCUSSION: This survey method collects
      declarative data and remains limited with regard to information. In-depth
      analysis of the daily activity of the participants would be useful for an
      approach of performance criteria, in view of the fact that some consultations do
      not include any, or even partial, clinical examination. The investments required
      for the purchase of the material compatible with the specifications applicable to
      health care centres may appear excessive for their current activity. The
      generalisation of the use of single use material represents a great progress in
      the field of prevention. Comparison with similar earlier studies shows the good
      progress made and the improvement in quality. Nevertheless, studies using a
      strict methodology are necessary to establish guidelines to be applied in general
      medical practice. The drawing-up of Referentials requires great rigour and the
      participation of the practitioners in their development and organisation would
      lead to substantial benefits.

PMID- 15026699
TI  - [Desmoid cervical tumour following the placing of an internal jugular catheter].
AB  - INTRODUCTION: A desmoid tumour is a rare fibroblastic tumour and generally
      located in the abdomen. However, it can also develop on surgical scars.
      OBSERVATION: A 36 year-old woman on chronic dialysis consulted for a cervical
      mass on the left side that was progressively increasing in volume, on the site of
      a scar of an internal jugular catheter placed 7 months earlier. Histological
      analysis of a sample of this mass concluded in a benign fibroblastic
      proliferation and led to the diagnosis of a desmoid tumour. Study of the
      patient's history revealed that a left jugular catheter had been placed on two
      occasions to be used for the hemodialysis approach, the lesion provoked by the
      latter would explain the development of the desmoid tumour. COMMENTS: The
      potential severity of this tumour is related to its proximity with the carotid,
      trachea and base of the skull. In general, desmoid tumours, rare benign tumours
      of the connective tissue, exhibit a complex multifactor etiopathogenesis. A
      surgical trauma can often trigger-off such tumours.

PMID- 15026700
TI  - [Hepatic abscess in diabetics, 2 case reports].
AB  - INTRODUCTION: Over the past few years, the hepatic abscess appears as a
      privileged septic localisation in the case of diabetes mellitus, particularly in
      the elderly. OBSERVATIONS: Two, 75 year-old and 82 year-old, diabetic patients
      were hospitalised for non-ketonic decompensation of type 2 diabetes mellitus.
      Examination revealed a sub-febrile state, the absence of clinical hepatic signs
      and a biological infectious syndrome The abscesses were discovered during the
      systematic hepatic sonography. Liver puncture was only possible in one patient
      and revealed Klebsiella oxytoca. The progression with antibiotics alone in one
      patient, and associated with surgical draining in the other, was positive. The
      origin appeared to be bilary in one patient and arterial on the other. COMMENTS:
      These case reports underline the interest of the systematic evocation of an
      abscessed hepatic localisation in cases of imbalance in diabetes, particularly
      when associated with an unexplained infectious syndrome.

PMID- 15026701
TI  - [Two cases of mis-diagnosis of tuberculosis due to polymerisation chain
      reaction].

PMID- 15026702
TI  - [Iatrogenic complications with a neuroleptic during an attack of dementia].

PMID- 15026703
TI  - [Regressive erythema: an uncommon progression during HIV infection].

PMID- 15026704
TI  - [A disease accessible to treatment].

PMID- 15026705
TI  - [Mode of action of bronchodilators in COPD. Aims of their use and criteria of
      assessment].
AB  - THERAPEUTIC POSSIBILITIES: Chronic obstructive pulmonary disease (COPD) remains
      under-diagnosed and under-treated despite its growing impact on public health.
      However several treatments, either pharmacological or not (pulmonary
      rehabilitation with exercise training), can improve quality of life
      significantly, even if they can not modify the natural history of the disease, as
      reflected by the decline in FEV1, which smoking cessation is the only way to
      alter. THE ACTION OF BRONCHODILATORS: Bronchodilators represent the first-line
      pharmacological treatment. Their clinical efficacy cannot be predicted by the
      inconstant changes in FEV1, since their main mechanism of action is the reduction
      in lung hyperinflation. Besides decreasing dyspnea, they reduce the number of
      exacerbations and improve quality of life.

PMID- 15026707
TI  - [Bioterrorism with brucellosis].
AB  - A CONTAMINATING SPRAY: Brucellosis is a zoonosis due to a bacteria of the
      Brucella. B. melitensis species and is the principle agent of human brucellosis.
      The interest of Brucella as a biological weapon resides in the fact that
      transmission through a spray is possible, as has been reported with human
      contamination during abortion of infected animals or bacterial spraying in
      laboratories. The bacteria is highly contagious. It is suggested that 10 to 100
      bacteria would be sufficient to produce a contaminating spray for humans. THE
      MENACE: In 1954, B. suis was the first infectious agent used as a biological
      weapon in the United States. Several other countries have been suspected of
      studying the agent as a biological weapon, but to date, no use of Brucella in a
      bioterrorist attack has been reported. THE EXTENT OF RISK: Brucella, and notably
      B. melitensis and B. suis, are considered as agents unlikely to be used as
      biological weapons: their incubation is long, the majority of infections are
      asymptomatic and mortality is low. However, the morbidity of this agent should
      not be underrated since it leads to chronic and disabling pathologies.

PMID- 15026706
TI  - [Bronchodilators in COPD: latest recommendations, recent data and perspectives].
AB  - DEMONSTRATED EFFICACY: Inhaled bronchodilators improve the quality of life of
      COPD patients by reducing dyspnea and exacerbation frequency. There is no data
      supporting the superiority of one of the families of inhaled bronchodilators
      (i.e. beta 2 agonists and anticholinergic agents) over the other. Thus, the
      choice has to be based on the individual symptomatic response. These agents can
      be combined. OTHER POSSIBILITIES: Long-acting beta 2 agonists are already
      available and long-acting anticholinergics should be marketed soon. Theophylline
      has a lower efficacy/tolerance ratio than inhaled bronchodilators but can provide
      additional benefits when associated with the latter in some patients.
      Phosphodiesterase inhibitors with both bronchodilating and anti-inflammatory
      effect are being developed. THE BENEFITS OF CORTICOSTEROIDS: Finally, in
      symptomatic patients with FEV1<50% predicted and repeated exacerbations despite
      bronchodilators, inhaled corticosteroids can be added.

PMID- 15026708
TI  - [Pseudo-hypoaldosteronisms].
AB  - TWO FORMS: Pseudohypoaldosteronisms (PHA) are characterized by end-organ
      resistance to aldosterone inducing hyperkalemia and hyperaldosteronism. There are
      two forms of PHA classified according to the level of blood pressure with either
      hypotension (Type 1 PHA or PHA 1) or hypertension (Type 2 PHA or PHA 2). PHA 1:
      The association with hypotension and high renin level (PHA 1) is responsible for
      type 4 tubular acidosis and should suggest congenital or acquired excessive salt
      loss. Acquired forms are associated with salt wasting of urinary (nephropathy) or
      digestive (colon resection + ileostomy) origin. Congenital neonatal forms are
      either sporadic or autosomal dominant or recessive. Sporadic or autosomal
      dominant forms are caused by mutations in the mineralocorticoid receptor gene and
      generally remit with age. Autosomal recessive forms are caused by mutations in
      the gene encoding the amiloride-sensitive sodium channel and are clinically more
      severe with pulmonary symptoms. PHA 2: The association of
      hyperkalemia/hyperaldosteronism with high blood pressure should suggest PHA 2 or
      Gordon's syndrome, still called familial hyperkalemic hypertension. This form of
      low-renin hypertension is caused by mutations in the WNK genes (WNK 1 for PHA 2C
      and WNK 4 for PHA 2B), but other genes located on different loci are also
      involved. These WNK kinases constitute a new signalisation pathway that would
      regulate blood pressure and homeostasy of Na+, K+, H+ and Cl- ions.

PMID- 15026709
TI  - [Control scale of antibiotic prescriptions in intensive care].
AB  - THE PROBLEM TO BE SOLVED: The improvement in the prescription of antibiotics (PA)
      is currently one of the stages necessary for the management of bacterial
      resistances. Patients admitted to intensive care, because of an acute affection
      or fragile territory, are frequently administered an antibiotic. The
      inappropriate nature of the PA is noted in 30 to 50% of cases. The inadequacy of
      the initial antibiotic therapy leads to an excessive increase in mortality and
      morbidity. THE DEVELOPMENT OF A CONTROL TOOL: In order to improve our habits and
      help the prescribers, a panel of experts discussed the subject of the
      prescription of antibiotics during the 3rd day of the Outcomerea Group. At the
      end of this meeting, practical guidelines together with a scale for the control
      of the prescription of antibiotics had been established. COMMENTS: We targeted
      our discussion on the importance of empirical treatment and the need to document
      the infectious episode. Moreover, we discussed the choice of the antibiotic
      molecule and the crucial need to reassess the treatment set-up. We also approach
      the place of combinations of antibiotics and their indications in our units as
      well as the optimal duration of the treatments.

PMID- 15026710
TI  - [The attitude towards a patient with chronic hepatitis B].

PMID- 15026711
TI  - [A long walk].

PMID- 15026712
TI  - [Familial genetic data and medical secrecy].

PMID- 15026713
TI  - [Revelation of a coronary spasm using the Methergin test].

PMID- 15026714
TI  - [Illicit love (or some thoughts on the relationship between psychiatry and
      justice)].

PMID- 15026715
TI  - [Excess mortality in people over 65 years old during summer heat waves in
      Marseille. Comparison before and after a preventive campaign].
AB  - INTRODUCTION: High temperatures induce excess mortality in the population, even
      in our country. The 1983 heat wave in Marseille led to the development of warning
      messages in a preventive campaign since 1984. OBJECTIVE: To compare mortality of
      people over 65 years old during summer heat waves before and after a campaign in
      Marseille. METHOD: The INSEE mortality data were analysed according to the mean
      temperatures supplied by the National Meteorological Office from 1968 to 1997. A
      mortality index was developed to limit the effect of the progression in mortality
      over the last 30 years. The heat wave was defined as a temperature >or=26 degrees
      C lasting for 2 days during the months of June to August. RESULTS: The mean
      summer temperature in Marseille has increased from 22 to 23 degrees C in 30
      years. The number of days of heat wave has also increased during this period. The
      mean index of daily excess mortality has dropped from 3.27 (1968-82) to 1.32
      (1984-97) (p=0.008). CONCLUSION: The effects of global warming have been noted in
      Marseilles over the last 30 years. There has been no disappearance in excess
      mortality, but the warning messages appear to have been partially effective, even
      if other factors may have intervened (air-conditioning...). This prevention, like
      that for the risks related to air pollution, should be generalized because it is
      inexpensive, although assessment of its efficacy is difficult.

PMID- 15026716
TI  - [Treatment of Graves' disease: 300 cases].
AB  - OBJECTIVE: To try to select the best treatment among synthetic anti-thyroid
      agents, surgery and radioiodine in the case of Graves' disease. METHOD: We
      present a retrospective study of therapeutic and progressive aspects of 300 cases
      of Graves' disease. RESULTS: At the time of the diagnosis, the patients' mean age
      was of 38.17 years. Female sex predominated (70.7%). Medical treatment was
      prescribed in 25.7% of cases. Agranulocytosis occurred in one patient who died
      from septic shock. Surgery was performed in 29.3% of patients and 41% were
      treated with radioactive iodine. After a mean follow-up of 53.7 months, a
      progression towards euthyroidism was noted in 60, 22.7 and 21.7% of patients
      treated respectively with antithyroid drugs, surgery and radioiodine.
      Hypothyroidism was noted in around 40% of cases, 57.8% of which were treated
      surgically. Recurrent hyperthyroidism is more frequent with antithyroid drugs.
      CONCLUSION: Medical treatment increases the risk of relapse. It is therefore
      preferable to apply radical treatments in order to obtain permanent remission
      from hyperthyroidism.

PMID- 15026717
TI  - [A serious complication of sternal puncture: penetrating injury of the ascending
      thoracic aorta].
AB  - INTRODUCTION: Penetrating thoracic aorta wounds are rare but responsible for a
      high mortality when medical and surgical management is delayed. OBSERVATION: We
      report the case of a 71 year-old patient with malignant lymphoma who sustained an
      accidental penetrating injury of the ascending thoracic aorta while undergoing
      trephine biopsy of the sternum. He was successfully treated with emergency
      sternotomy and aortic suture-repair. CONCLUSION: This case report highlights the
      limits of sternal trephine biopsy, notably in patients whose bones are weakened
      by a malignant haematological process, and proposes preventive measures in order
      to avoid accidents.

PMID- 15026719
TI  - [Diagnosis of an HIV primary infection: the interest and limits of serological
      tests].

PMID- 15026718
TI  - [Necrotizing fasciitis of the thigh].
AB  - INTRODUCTION: Necrotizing fasciitis is a rare and severe infectious disease with
      infectious necrosis often extending in depth to the subcutaneous tissue in the
      absence of rapid medical-surgical treatment. We report two cases of necrotizing
      fasciitis of the thigh, which underline the principle clinical and therapeutic
      characteristics of this often underrated disease. OBSERVATION: The first case
      concerns a young 21 year-old woman without remarkable medical history who,
      following injury from the thorn of a palm tree, developed an aerobic germ
      necrotizing fasciitis which regressed following medical-surgical treatment. The
      second case concerned a 46 year-old man suffering from diabetes and arteritis,
      who having presented an infection following the amputation of the large toes,
      developed fatal necrotizing fasciitis. COMMENTS: This disease corresponds to
      infectious necrosis of the subcutaneous tissue and is essentially characterized
      by its rapid, occasionally violent, progression. It represents a surgical
      emergency and requires early and extensive incision in order to avoid severe
      functional after effects, or even death of the patient. Only enhanced education
      of the physicians leading to rapid clinical diagnosis will improve the prognosis
      which still remains fearsome.

PMID- 15026720
TI  - [A case of Mycoplasma pneumoniae lung disease with septic shock].

PMID- 15026722
TI  - [Temporal arteritis in elderly patients is still a "notorious disease"].

PMID- 15026721
TI  - [Hepatic hydatidosis].

PMID- 15026723
TI  - [Physiopathological data of Horton's syndrome].
AB  - GREAT PROGRESS: The understanding of the physiopathology of Horton's syndrome has
      been made in view of the prevalence of the disease, the access to affected tissue
      and new molecular biology techniques. And it is now possible to specify the
      intricacy between the genetic, immunological and vascular components. HORTON'S
      SYNDROME, A GENETIC DISEASE: The preferential association of the disease with
      some alleles pf the HLA DR4 group has helped to emphasize the fundamental role of
      a few amino acids of the second hypervariable area of the HLA-DR molecule. An
      immunogenetic predisposition appears favourable, or even necessary, for the
      development of the disease. HORTON'S SYNDROME, AN IMMUNOLOGICAL DISEASE: The
      temporal arteries of patients presenting with Horton's syndrome are infiltrated
      by polymorphous inflammatory cells, fundamentally including CD4 T-cell
      lymphocytes, macrophages, and a few giant cells. Some CD4 lymphocytes have
      undergone clonal proliferation and show signs of recent antigenic recognition. A
      fraction of them secrete interferon gamma, which plays a crucial role in the
      onset, maintenance and orientation of the immunological response. The macrophages
      play multiple roles notably in maintaining the inflammatory reaction, but also in
      the destruction of certain structures of the arterial wall. HORTON'S SYNDROME, A
      VASCULAR DISEASE: The destruction of the arterial wall at the acute stage of the
      disease appears responsible, sometimes later on, for aneurismal dilatations
      observed on the aorta of certain patients. Moreover, intimal hyperplasia
      (mediated by the PDGF (platelet derived growth factor) A and B) and thrombosis
      (related to the inflammation) join up in reducing the arterial flow and enhancing
      the risk of ischemic complications during the acute stage. PATHOGENESIS,
      HYPOTHESES: Various candidate-antigens have been incriminated in the onset of the
      inflammatory reaction during Horton's syndrome. Some epidemiological and
      molecular studies are in favour of an exogenous antigen, possibly infectious, but
      no evidence has been demonstrated in the studies published. A parietal,
      endogenous antigen might also be at the origin of the cascade of events described
      during this disease.

PMID- 15026724
TI  - [Simple Horton's syndrome: modalities of treatment].
AB  - IN GENERAL: Corticosteroids remain the basis of treatment of Horton's syndrome,
      with prednisone the molecule of choice, since they improve the symptoms and
      considerably reduce the risk of blindness. Several clinical forms of the disease
      must be distinguished in order to specify the modalities of corticosteroid
      treatment and any eventual associated treatments. SIMPLE HORTON'S SYNDROME: The
      simple forms of the disease are defined by the absence of ocular involvement, the
      absence of clinical involvement of the large arteries, the absence of
      corticosteroid resistance and the absence of corticosteroid dependence (simple
      forms subsequently complicated). MODALITIES OF CORTICOSTEROID THERAPY: These
      simple forms justify an attack treatment with 0.7 mg/kg/d of prednisone although
      cortisone assaults do not have a specific justification. Initiation with lower
      daily doses of prednisone at 0.5/mg/kg or even less appear to expose the patient
      to a higher risk of progression of the disease, but merit assessment. SATELLITE
      QUESTIONS: The iatrogeneity of corticosteroids raises problems in corticosteroid
      dependent patients and those receiving prolonged attack treatment. The risk of
      cortisone-induced osteoporosis is particularly high during Horton's syndrome.
      There is still no prospective study specifying the indications for treatment of
      the disease with anticoagulants or platelet antiaggregants.

PMID- 15026725
TI  - [Complicated Horton's syndrome: therapeutic modalities].
AB  - FORMS THAT RAISE THERAPEUTIC PROBLEMS: The complicated forms of Horton's syndrome
      regroup various situations: ocular involvement at the start, large vein
      involvement, corticosteroid resistance (rare), corticosteroid dependence
      preventing the reduction in the daily dose of prednisone to less than 15 mg, high
      rate of morbidity with prolonged corticosteroid therapy. GENERAL PRINCIPLES: The
      ocular forms and those with large vein involvement, require a minimal attack
      treatment with 1mg/kg/d of prednisone. Cortisone assaults are often prescribed
      despite the fact that their efficacy remains to be demonstrated. Curative
      treatment with heparin (calcic or of low molecular weight) should be prescribed
      for 5 to 7 days with later relay to a platelet anti-aggregant, without any
      randomised study having validated this proposition. THE CASE OF CORTICOSTEROID
      DEPENDENCE: The iatrogenic risk of corticosteroids is high and alternative
      treatments should be proposed: azathioprine, methotrexate, dapsone or
      hydroxychloroquine. Osteoporosis is the most frequent complication of
      corticosteroid therapy and must be avoided by the administration of a
      biphosphonate.

PMID- 15026726
TI  - [Optimising the management of anaemia of renal origin: what benefits for the
      patient?].

PMID- 15026727
TI  - [Hypereosinophilia of the blood].

PMID- 15026728
TI  - Spinal dysraphism: MR imaging rationale.
AB  - Spinal cord development occurs through the three consecutive periods of
      gastrulation (weeks 2-3), primary neurulation (weeks 3-4), and secondary
      neurulation (weeks 5-6). Spinal cord malformations derive from defects in these
      early embryonic stages, and are collectively called spinal dysraphisms. Spinal
      dysraphisms may be categorized clinically into open and closed, based on whether
      the abnormal nervous tissue is exposed to the environment or covered by skin.
      Open spinal dysraphisms include myelomeningocele and other rare abnormalities
      such as myelocele, hemimyelomeningocele, and hemimyelocele, and are always
      associated with a Chiari II malformation. Closed spinal dysraphisms are further
      divided into two subsets based on whether a subcutaneous mass is present in the
      low back. Closed spinal dysraphisms with mass comprise lipomyelocele,
      lipomyelomeningocele, meningocele, and myelocystocele. Closed spinal dysraphisms
      without mass comprise simple dysraphic states (tight filum terminale, filar and
      intradural lipomas, persistent terminal ventricle, and dermal sinuses) and
      complex dysraphic states. The latter category involves abnormal notochordal
      development, either in the form of failed midline integration (ranging from
      complete dorsal enteric fistula to neurenteric cysts and diastematomyelia) or of
      segmental agenesis (caudal agenesis and spinal segmental dysgenesis). Magnetic
      resonance imaging is the imaging modality of choice for evaluation of this
      complex group of disorders.

PMID- 15026729
TI  - [Diffusion, perfusion and activation functional MRI studies of brain
      arteriovenous malformations].
AB  - The management of Brain Arteriovenous Malformations continues to be challenged by
      a lack of understanding and control of pathophysiological processes implied in
      the clinical symptoms. New data from functional MRI with diffusion-weighted,
      perfusion-weighted and neuronal activation highlight abnormal brain areas near or
      remote to the AVM nidus. Moreover, these techniques are able to show hemodynamic
      and neuronal adaptative phenomena involved in brain plasticity. They reflect the
      instantaneous hemodynamic brain conditions that may help to correlate the
      clinical symptoms with the anatomical and functional substratum and to influence
      any invasive therapy.

PMID- 15026730
TI  - [Spinal cord ischemia].
AB  - Traditional data and recent advances in the field of spinal cord ischemia are
      reviewed, with special attention to clinical and radiological features, as well
      as underlying etiology, outcome, and pathophysiology. Acute spinal cord ischemia
      includes arterial and venous infarction and global ischemia resulting from
      cardiac arrest or severe hypotension. MRI has become the technique of choice for
      the imaging diagnosis of spinal cord infarction. Correlation of clinical and MRI
      data has allowed diagnosis of clinical syndromes due to small infarcts in the
      central or peripheral arterial territory of the spinal cord. Diffusion-weighted
      MR imaging may increase the sensitivity and specificity for diagnosis of acute
      spinal cord infarction. Diagnosis of venous spinal cord infarction remains
      difficult. As for global ischemia, neuropathological studies demonstrated a great
      sensitivity of spinal cord to ischemia, with selective vulnerability of
      lumbosacral neurons. Chronic spinal cord ischemia results in a syndrome of
      progressive myelopathy. The cause is usually an arteriovenous malformation. Most
      often, diagnosis may be suspected on MRI, leading to diagnostic, and eventually
      therapeutic, spinal angiography.

PMID- 15026732
TI  - Endovascular treatment of posterior cerebral aneurysm associated with Moyamoya
      disease.
AB  - PURPOSE: A patient with moyamoya disease associated with a ruptured posterior
      cerebral artery aneurysm treated by endovascular embolization is presented. CASE
      REPORT: A 47-year-old woman was admitted with severe headache to our hospital.
      Computed tomography demonstrated subarachnoid haemorrhage. Cerebral angiography
      revealed evidence of moyamoya disease and a saccular aneurysm at the P1 segment
      of the left posterior cerebral artery. CONCLUSION: Endovascular embolization was
      performed using Guglielmi detachable coil (GDC), and the aneurysm was completely
      occluded with preservation of the parent artery. Endovascular treatment using GDC
      seems comparatively safe and effective for the treatment of cerebral saccular
      aneurysms in patients with moyamoya disease.

PMID- 15026731
TI  - [Management of cerebrospinal fluid fistulae: physiopathology, imaging and
      treatment].
AB  - Cerebrospinal fluid (CSF) fistulae can produce leakage through a defect in the
      bony skull and meninges into the contiguous air-filled cavities at the base of
      the skull. The major risk is central nervous system infection. When abundant
      clear rhinorrhea or otorrhea is present, the diagnosis is obvious and imaging is
      used to localize the fistula. Computed tomography (CT) with millimetric slices
      and magnetic resonance imaging (MRI) are the most effective diagnostic tools. CT
      cisternography, an invasive procedure, should only be used when the diagnosis
      remains uncertain following CT scan and MRI. When CSF leakage is sparse or
      intermittent, the diagnosis can be made by measuring beta-2 transferrine in the
      escaping fluid. CT scan followed by MRI are also useful for making the diagnosis
      and locating the fistula when exterior leakage is absent. CT scan alone is
      effective for assessing isolated otorrhea. If the diagnosis remains uncertain
      after all these studies have been used, the patient should be closely followed
      clinically and isotopic study or surgery should be considered.

PMID- 15026733
TI  - Fatal subarachnoid hemorrhage after carotid stenting.
AB  - BACKGROUND AND PURPOSE: Cerebral hyperperfusion syndrome with intracerebral
      hemorrhage (ICH) following carotid angioplasty and stent placement (CAS) of the
      internal carotid artery (ICA) is well known. We report the occurrence of fatal
      subarachnoid hemorrhage in a patient undergoing CAS. CASE REPORT: A 77-year-old
      woman experiencing a left-hemispheric transient ischemic attack underwent CAS for
      a 95% stenosis of the left ICA. CAS was performed without acute complications. At
      5 hours the patient suddenly deteriorated. Her level of consciousness changed and
      she developed neck stiffness. CT of the brain revealed diffuse SAH with acute
      hydrocephalus. CONCLUSIONS: Like ICH, SAH may develop as a severe complication
      after CAS. There are no reliable clinical symptoms preceding this fatal
      complication. However, several factors such as long-standing severe carotid
      stenosis with contralateral occlusion and increasing blood pressure after CAS
      accompanied by the extensive use of antithrombotic agents may predispose to this
      fatal complication.

PMID- 15026734
TI  - [What is your diagnosis?].

PMID- 15026735
TI  - Diffusion MRI findings in neonatal brain abscess.
AB  - In neonates and infants, bacterial brain abscess is rare, and the diffusion
      weighted MR imaging appearance of such abscesses has not been reported. We report
      the diffusion weighted MR findings of a brain abscess in a 25-day-old boy. The
      lesion initially had a large cystic component with some high-signal pyogenic
      material inside on diffusion-weighted (b=1000 sec/mm(2))images. The ADC value of
      this material was low (0.59 x 10(-3) mm(2)/sec), compared to the value from
      normal cerebellar parenchyma (0.78 x 10(-3) mm(2)/sec). The unusual initial
      appearance mimicked a cystic tumor. The lesion markedly decreased in size over 20
      days after antibiotic therapy with persistent high-signal pyogenic material. In
      addition, at the initial presentation b=1000 sec/mm(2) images revealed high
      signal changes in the brain parenchyma compressed by markedly dilated ventricles,
      consistent with ischemia. Also, ADC values of perilesional vasogenic edema (1.74
      x 10(-3) mm(2)/sec), and that of transependymal resorption of CSF (1.56 x 10(-3)
      mm(2)/sec) were noted at the initial stage.

PMID- 15026736
TI  - [Sub occipital Pott's disease: report of 8 cases].
AB  - Craniocervical Pott's disease remains exceptional, and may cause spinal
      instability and severe cervicomedullary complications. We report eight cases of
      tuberculous spondylodiscitis at the craniocervical junction revealed by signs of
      spinal cord compression, torticollis and dysphagia. The value of CT and MR
      imaging is discussed.

PMID- 15026737
TI  - [Rhinocerebral mucormycosis].
AB  - We report a case of a rhinocerebral mucormycosis with extensive cavernous sinus
      thrombophlebitis and internal carotid artery thrombosis. This case illustrates
      the usual clinical and imaging features of the disease, which is a potentially
      devastating infection in immunocompromised patients.

PMID- 15026739
TI  - [Why Mohs micrographic surgery?].

PMID- 15026740
TI  - [Micrographic surgery].

PMID- 15026738
TI  - [Anterior spinal epidural hematoma: a case report].
AB  - PURPOSE: to present a case of post traumatic anterior spinal epidural hematoma.
      CASE REPORT: a 55-year-old man presented with abrupt onset of paraparesia
      following a motor vehicle accident. Magnetic resonance imaging showed an anterior
      lumbar epidural hematoma. Surgical evacuation of the hematoma resulted in
      complete recovery.

PMID- 15026742
TI  - [Treatment of dermatofibroma protuberans with fixed Mohs' micrographic surgery].
AB  - INTRODUCTION: Dermatofibrosarcoma protuberans is a tumor of intermediate
      malignancy characterized by its aggressive local growth due to pseudopodium-like
      outgrowths and marked propensity to recur after surgical excision. To achieve
      complete cure with conventional surgery, surgical margins up to 5 cm are
      required, leading to wide scars. Mohs' micrographic surgery is used for the
      removal of certain malignant tumors, both ensuring complete excision by
      examination of all margins as well as minimizing normal tissue loss. However,
      differentiating minimal residual tumor from normal skin can be difficult on the
      frozen sections used in Mohs' micrographic surgery. Our aim was to develop a
      procedure of Mohs' micrographic surgery in conjunction with rush formalin-fixed,
      paraffin-embedded tangential sections. PATIENTS AND METHODS: Ten consecutive
      cases have been prospectively treated since 1998. Under local anesthesia, the
      tumor was first excised including lateral margin of 1 cm and a deep margin
      including the underlying muscle aponevrosis. A 2 to 3 mm thick horizontal section
      of the surgical bed was then removed, rush formalin-fixed, paraffin-embedded,
      tangentially sectioned, hematin-eosin stained, and eventually stained with an
      anti-CD34 monoclonal antibody. While waiting for pathology results, the surgical
      bed was not definitively closed. If excision was incomplete, an oriented
      complementary excision was performed. RESULTS: Excision was complete after the
      first stage in 7 patients and incomplete only deeply in 3. Lateral surgical
      margins were reduced to 1.3 cm in all patients, facilitating wound closure:
      direct suture (5 patients), controlled wound healing (3 patients) or flap
      coverage (2 patients). No recurrence has been observed after a mean follow-up of
      26 months. DISCUSSION: The use of Mohs' micrographic surgery in conjunction with
      rush formalin-fixed, paraffin-embedded tangential sections reduce surgical
      margins in dermatofibrosarcoma protuberans. This procedure would be interesting
      in difficult sites, such as the genitalia, the breast, or the periarticular
      regions. Other cases, and longer follow-up are however necessary to validate this
      promising technique.

PMID- 15026741
TI  - [The cost of Mohs micrographic surgery for basal cell carcinoma. The Ambroise
      Pare hospital's experience (Boulogne, France)].
AB  - OBJECTIVE: Mohs'micrographic surgery is generally considered as the best
      procedure for the treatment of difficult basal cell carcinomas. It is supposed to
      be costly, but an economic evaluation, with a cost-outcome analysis, is necessary
      to estimate the actual contribution of this procedure in skin cancer treatment,
      in comparison with the reference procedure, i.e. traditional surgical excision.
      Our aim was to evaluate the actual cost of Mohs'surgery applied on basal cell
      carcinoma treatment in France. METHODS: The charts of 97 patients treated by
      Mohs'surgery between january 1997 and july 2001 in a teaching hospital near Paris
      (Ambroise Pare hospital, Boulogne), where Mohs'surgery is exclusively performed
      in France, were reviewed. Direct costs were derived from resource utilization of
      staff and material required for Mohs'surgery, estimated by a micro-costing
      method. Indirect costs and total costs were then calculated. RESULTS: When adding
      surgery and pathology facility costs, mean direct and total costs per basal cell
      carcinoma were 776.0 (range: 538.4-1273.9), and 1014.6 Euros (range: 777-1512.4),
      respectively. When including costs of diagnosis, the average total cost per
      procedure was 1084.3 Euros. DISCUSSION: These costs appear higher than those
      obtained with other methods of valuation of hospital costs used in France, but
      they are slightly lower than those found in the literature. The next stage will
      be to estimate, in the same way, the cost of traditional surgical excision for
      the same type of lesions, and to calculate the incremental cost-effectiveness
      ratio between the two procedures, with rate of recurrence at five years as the
      effectiveness outcome.

PMID- 15026743
TI  - [Atopic dermatitis: which are the diagnostic criteria used in medical
      literature?].
AB  - INTRODUCTION: Diagnosis of atopic dermatitis currently relies on diagnostic
      criteria scales developed by Hanifin and Rafka in 1980 and by the "United Kingdom
      Working party" in 1994. Some authors have proposed: "AEDS" [sM1] and "Atopiform
      Dermatitis", which has led to the distinction between different sub-populations
      and the exclusion of certain diseases from the diagnosis of atopic dermatitis.
      The aim of our study was to collect the criteria retained in the scientific
      medical literature during the year 2002 for the definition of atopic dermatitis
      and to try to understand not only the interest but also the questions that the
      various definitions lead to. METHOD: A PubMed research was launched with the key
      word "atopic dermatitis" from January to September of 2002. All the scientific
      articles either in French or in English were studied. RESULTS: Hanifin and
      Rafka's criteria were selected in 44 p. 100 of the scientific articles, and the
      "United Kingdom Working Party" criteria in 12 p. 100. Personal definitions were
      used in 21 p. 100 of the articles; these were based on the level of total and
      specific IgE or on personal clinical criteria. For twenty-three p. 100 of the
      authors, the definition of atopic dermatitis was not specified. DISCUSSION: There
      was not just one definition of atopic dermatitis. This may affect the
      interpretation of diagnostic or therapeutic papers concerning the disease,
      because there has been no proof that these definitions cover the same population
      of patients.

PMID- 15026745
TI  - [Mohs' micrographic surgery: history, principles, critical analysis of its
      efficacy and indications].
AB  - OBJECTIVES: To systematically review the literature for studies reporting on the
      role of Mohs' micrographic (MMS) surgery in the treatment of skin tumors. To show
      how it is performed in France. DESIGN: We reviewed with a quality grid all
      studies indexed in MEDLINE before 2003/01/01 and published in English or French.
      Data were extracted by two independent reviewers. MAIN OUTCOME MEASURES: Quality
      of clinical studies, recurrence rates, number of patients lost to follow-up.
      RESULTS: No randomized study was found among the 493 references found. Studies of
      lower quality, on procedures similar to MMS, or previous systematic reviews were
      therefore selected. In tumors such as basal (BCC) or spinous (SCC) cell
      carcinoma, microcystic adnexal carcinoma, dermatofibrosarcoma protuberans, and
      Merkel cell carcinoma, MMS commonly induced lower recurrence rates than figures
      reported for conventional treatments and/or reduced surgical margins. Studies on
      melanoma were of low quality. CONCLUSIONS: Although no evidence-based guidelines
      could be developed, MMS should be used mainly for larger, morphea, micronodular
      or infiltrative-type, or recurrent BCCs located in danger zones, but also
      (sometimes with a slightly modified procedure) in microcystic adnexal carcinomas,
      dermatofibrosarcoma protuberans, Merkel cell carcinoma, and in aggressive forms
      of SCC. Randomized, controlled studies should be performed.

PMID- 15026744
TI  - [Characteristics and evolution of consultants, their risk factors and their
      behavior at the free anonymous HIV screening center of Colmar (France)].
AB  - INTRODUCTION: Data collected in free anonymous HIV screening centers (Centre
      d'Information et de Depistage Anonyme et Gratuit du VIH, CIdAG) are numerous but
      poorly exploited. The characteristics of the consultants, their risk factors and
      their behavior were rarely analyzed previously. MATERIAL AND METHODS: Data of
      3995 patients attending the CIdAG of Colmar between January 93 and February 99
      were prospectively analyzed. Two 18-month periods at the beginning and end of the
      study were compared. RESULTS: The activity of the center was stable. Nine HIV
      infections were detected (2 p. 1000 consulting). The male/female ratio was 1.2
      and the mean age was 26 years. The proportion of very young patients (<20 years)
      was 30 p. 100 and increased significantly between the two periods. Six per cent
      of the consultants were male homo/bisexuals and 2 p. 100 used intravenous drugs.
      A regular use of condoms when having occasional sexual relations was reported by
      40 p. 100 of consultants before 20 years of age, but this proportion decreased
      regularly as the age increased. It was minimal among intravenous drug users (19
      p. 100), and greater among male homo/bisexuals (46 p. 100) than among male
      heterosexuals (37 p. 100) and women (33 p. 100). This proportion increased
      significantly during the study period in heterosexual men and women but not in
      male homo/bisexuals. The number of sexual partners did not vary but the knowledge
      of the partners'status for HIV infection and drug addiction progressed
      significantly. Some subjects who attended the centre several times were
      identified anonymously. They differed from the other consultants by an older age
      (mean: 31), a higher proportion of male homo/bisexuals (14 p. 100) and a less
      regular use of condom (26 p. 100). COMMENTS: In some French anonymous HIV
      screening centers, information and prevention currently appears to prevail over
      detecting new HIV infections. Modifying at-risk behaviour is difficult. Current
      messages for prevention must be improved.

PMID- 15026746
TI  - [Unusual cutaneous lesions of familial Mediterranean fever].
AB  - BACKGROUND: Familial mediterranean fever belongs to the periodic fever syndromes.
      During the attacks, fever is associated with abdominal pain, arthralgia, or both.
      Cutaneous involvement occurs in 7 to 46 p. 100 of cases and mainly consists in
      erysipelas-like erythema. We report on three patients treated for familial
      Mediterranean fever who developed unusual cutaneous lesions. OBSERVATIONS: All
      the patients had long past history of familial mediterranean fever without
      cutaneous involvement except, for the third patient who had pseudo-erysipela. The
      first patient had diffuse Sweet's syndrome-like lesions, the second developed
      long lasting panniculitis of the thigh and the third had a persistent and
      lichenified erysipela-like plaque. In two patients, skin histology revealed an
      inflammatory infiltrate with neutrophils. In all cases, an increase in the
      colchicine dose led to the rapid resolution of the lesions. DISCUSSION: In our 3
      case reports, the lesions were particular because of their atypical clinical
      appearance, their long duration, and they differed from the usual pseudo
      erysipela aspect. Histopathologically, the lesions were similar to pseudo
      erysipela, which has led some authors to hypothesize that cutaneous lesions of
      familial mediterranean fever belong to neutrophilic dermatoses. This hypothesis
      is supported by the response to the increase in colchicine doses.

PMID- 15026747
TI  - [Neurotropic metastasis of squamous cell carcinoma].
AB  - INTRODUCTION: Epidermoid skin carcinoma is the second most frequent skin cancer.
      It is rarely considered as aggressive. Other than its extension through the blood
      of lymph circulation, perineural invasion is also a significant form of tumoral
      invasion. We report a case of recurrent epidermoid skin carcinoma beginning with
      a neurological symptomatology. OBSERVATION: A 77 year-old man with a history of
      right fronto-temporal epidermoid skin carcinoma turned up at our clinic with a
      ptosis of the right eyelid and hypoesthesia in the nerve VI area. He later
      developed pain in the arch of the eyebrow and diplopia. Five weeks later, two
      subcutaneous nodules appeared. Histology revealed a neuro-invasive epidermoid
      carcinoma explaining the clinical picture. Re-loading of the histological
      sections of the first injury confirmed the clearly differentiated invasive
      epidermoid carcinoma. However, renewed classified sections revealed neoplastic
      cells surrounding the nerve branches in the deep dermis. DISCUSSION: Other than
      the extension through the blood or lymph circulation, epidermoid cutaneous
      cancers exhibit varying invasion of the nerve structures. Neurotropism is an
      aggressiveness marker. Only the pathologico-anatomic investigation enables an
      early diagnosis. In the case of recurrence, neurological symptomatology can
      precede skin injuries and make diagnosis difficult. The follow-up of the carriers
      of this type of tumor must include a neurological examination.

PMID- 15026749
TI  - [Dapsone treatment of folliculitis decalvans].
AB  - BACKGROUND: Folliculitis decalvans consists of recurrent patchy painful
      folliculitis of the scalp causing scarring alopecia. The physiopathology of this
      condition is still unclear, but is likely a manifestation of chronic neutrophilic
      bacterial folliculitis. Numerous topical and systemic treatments
      (corticosteroids, antistaphylococcal antibiotics) have been used with variable
      results. Based on the dapsone antimicrobial activity and its anti-inflammatory
      action especially directed to the neutrophil metabolism, we treated two patients
      with severe folliculitis decalvans with this drug. CASE REPORTS: The patients
      were treated with dapsone at a daily dose of 75 and 100 mg, respectively for 4 to
      6 months. After 1 and 2 months, pustular folliculitis progressively cleared,
      leaving a residual non inflammatory cicatricial alopecia. When maintaining a
      dapsone dosage at 25 mg/day no relapse occurred during 3 years and 1 year,
      respectively. No important adverse effect to dapsone was evidenced. After dapsone
      withdrawal, a moderate relapse of the disease with pruritus and folliculitis
      occurred after a few weeks in both cases. The disease relapse rapidly cleared
      after dapsone reintroduction at a daily dose of 25 mg. COMMENTS: Dapsone at
      moderate dosage was well tolerated and rapidly effective in treating the two
      cases of folliculitis decalvans. A long term and low dose (25 mg daily)
      maintenance treatment avoided disease relapses.

PMID- 15026748
TI  - [Infective dermatitis and recurrent strongyloidiasis in a child].
AB  - INTRODUCTION: Infective dermatitis is a chronic childhood dermatosis, associated
      with HTLV-1 infection. We report the observation of a young Haitian girl in
      French Guyana. OBSERVATION: An 8 year-old girl presented recurring dermatosis on
      the scalp and armpits since she was 2 years old. The initial clinical examination
      showed the presence of centro-facial micro-papules, associated with a nasal
      pyodermatitis. A bacteriological culture isolated a Staphylococcus aureus.
      Phenotypic analysis did not indicate any production of exfoliatin or leucocidin.
      Serologic tests for HTLV1 were positive. In addition, the child presented
      recurring symptomatic anguillulosis, despite numerous antihelmintic treatments. A
      clinical and parasitological cure was obtained with a monthly treatment of
      ivermectin. COMMENTS: This is the first case of infective dermatitis reported in
      french Guyana. The clinical analysis that led to this diagnosis showed a minor
      form of this dermatosis. The phenotypic analysis of the Staphylococcus aureus
      isolated from the cutaneous lesions did not indicate any factors of virulence
      habitually associated with pyodermatitis in Guyana. This is the first case of
      chronic digestive anguillulosis (a parasitic complaint usually associated with an
      adult HTLV-1 infection) associated with an infective dermatitis.

PMID- 15026750
TI  - [Mycobacterium fortuitum skin infection occurring after a facelift].
AB  - INTRODUCTION: Mycobacterium fortuitum skin infections are rare and usually
      iatrogenic. We report a case with cervical involvement following a facelift.
      OBSERVATION: A 65 year-old woman, without past history, underwent bilateral
      surgical facelift, complicated by cutaneous necrosis and treated with directed
      healing at home. Six weeks later, an abscessed nodule appeared under the left
      maxillary and was drained surgically. Then other pre-auricular and left cervical
      inflammatory nodules appeared without adenopathy or fever. M. fortuitum was
      isolated in bacteriological samples. The initially probabilistic antibiotherapy
      with carithromycin, subsequently adapted with amikacine and cirprofloxacine and
      then imipeneme for a total duration of 3 months, led to the clinical cure.
      DISCUSSION: Mycobacterium fortuitum is a rapidly growing, ubiquitous,
      mycobacteria responsible for nosocomial infections in immunocompetent patients,
      notably following plastic surgery. Contamination occurs where there has been a
      rupture in the skin barrier through contact with a vector (water, surgical
      material, antiseptic.). Treatment, which is not codified, consists in the
      association of surgery and antibiotics for several months.

PMID- 15026752
TI  - [Multiple cutaneous plasmocytoma treated with topical applications of
      miltefosine].

PMID- 15026751
TI  - [Photochemotherapy for pityriasis lichenoides: 3 cases].
AB  - BACKGROUND: Pityriasis lichenoides is a rare cutaneous disorder of unknown origin
      that mainly affects children and young people. The disease consists of two
      variants: pityriasis lichenoides et varioliformis acuta, characterized by papular
      lesions evolving into necrosis and pityriasis lichenoides chronica characterized
      by scaly papules that may last from several months to several years. Various
      types of therapy have been proposed for pityriasis lichenoides, to our
      knockledge, photochemotherapy has never been used. We report the first 3 cases of
      pityriasis lichenoides treated by photochemotherapy. CASE REPORTS: Three
      patients, 6, 15 and 18 years old, presented respectively with a 1 month, 2 years
      and 3 months history of numerous, papular and necrotic lesions or squally papular
      lesions. Clinical appearance and histopathologic examination of biopsy were
      consistent with pityriasis lichenoides et varioliformis acuta (patients 1 and 3)
      and with pityriasis lichenoides chronica (patient 2). They had received different
      treatments without significant effect: topical corticosteroids, antibiotic, UVB
      therapy and dapsone. Acitretin associated with PUVA were dramatically effective
      within few weeks. DISCUSSION: Pityriasis lichenoides can be a severe scarring
      disease with significant social, psychological and physical consequences. In our
      opinion, photochemotherapy, which has never been used in pityriasis lichenoides,
      is effective. Therapeutic modalities have to be define.

PMID- 15026753
TI  - [Alopecia areata and occipital angioma: fortuitous association or predictive
      factor?].

PMID- 15026754
TI  - [Black nodules on the foot].

PMID- 15026755
TI  - [Congenital exfoliative erythroderma].

PMID- 15026756
TI  - [Erythropoietic protoporphyria].

PMID- 15026757
TI  - [The common wart].

PMID- 15026758
TI  - [Interpreting a confidence interval].

PMID- 15026759
TI  - [Lichen sclerosis and atrophicus].

PMID- 15026760
TI  - [Meleda-type palmo-plantar keratoderma is caused by mutations in the gene coding
      the SLURP protein].

PMID- 15026761
TI  - [Side-effects of anti-TNF alpha agents].

PMID- 15026763
TI  - Strategies for staffing your case management department.

PMID- 15026764
TI  - Supreme court reviews drug addiction case.

PMID- 15026765
TI  - The NCCAM and new research priorities.

PMID- 15026766
TI  - Contemporary trends in case management.

PMID- 15026767
TI  - Member-centered disease management yields measurable results.

PMID- 15026769
TI  - Congenital heart disease and treatment options.

PMID- 15026771
TI  - Postacute neurobehavioral treatment: current perspectives on incidence,
      demographics, and contemporary delivery systems.

PMID- 15026770
TI  - The evolving role of case management in consumer-centric health plans.

PMID- 15026772
TI  - How case management affects medical stop loss insurance.

PMID- 15026773
TI  - Do associations between airborne particles and daily mortality in Mexico City
      differ by measurement method, region, or modeling strategy?
AB  - We evaluated whether associations between PM10 and daily mortality in Mexico City
      differ by the PM10 measurement device or by regional differences in particle
      composition. Additionally, we reanalyzed previously collected data in light of
      recent insights about flaws in commonly used time series analysis techniques. We
      examined daily associations between mortality and four indicators of ambient PM10
      using Poisson regression, controlling for temperature and time trends with cubic
      natural splines. Associations were calculated for five subregions corresponding
      to five monitoring sites and pooled for the entire metropolitan area. PM10 was
      measured with three methods: Tapered Element Oscillating Microbalance (TEOM),
      Sierra-Anderson High Volume (Hi-Vol) and Harvard Impactor (HI), the latter only
      at one site. In addition, predicted values of daily PM10 were developed using the
      Hi-Vol measurements, which were taken every sixth day, and weather, visibility
      and other pollutant data. We assigned deaths to the exposure from the monitor
      nearest to their residence. We also re-evaluated the HI PM2.5 and mortality
      association in southwest Mexico City, which was estimated previously using
      nonparametric statistical models. Slight decreases in effect estimates were
      observed (a 1.45% increase (95% CI: 0.09%, 2.83%) in total mortality per 10
      microg/m(3) increment of PM2.5 at lag 0) compared to a 1.68% change (95% CI:
      0.45%, 2.93%) using the previously employed nonparametric approach. Using data
      pooled over all the regions, PM10 measured by the TEOM and the predicted PM10
      values showed little association with mortality at any of the lags examined. The
      pooled estimates for Hi-Vol PM10 (using one sixth of the data) were positive
      across all lags examined and significant for lags 3 and 5. No consistent patterns
      of differing associations were seen across regions that would correspond with
      particle toxicity or composition. Particulate air pollution, measured with
      gravimetric methods, is associated with daily mortality and presents a risk to
      health in Mexico City. The reanalysis suggests that previous research is robust
      to statistical method and likely to yield the same overall conclusions about the
      short-term effects of airborne particles on mortality.

PMID- 15026774
TI  - The EXPOLIS study: implications for exposure research and environmental policy in
      Europe.
AB  - Exposure analysis is a crucial part of effective management of public health
      risks caused by pollutants and chemicals in our environment. During the last
      decades, more data required for exposure analysis has become available, but the
      need for direct population based measurements of exposures is still clear. The
      current work (i) describes the European EXPOLIS study, designed to produce this
      kind of exposure data for major air pollutants in Europe, and the database
      created to make the collected data available for researchers (ii) reviews the
      exposure analysis conducted and results published so far using these data and
      (iii) discusses the implications of the results from the point of view of
      research and environmental policy in Europe. Fine particle (with 37 elements and
      black smoke), nitrogen dioxide, volatile organic compounds (30 compounds) and
      carbon monoxide inhalation exposures and exposure-related questionnaire data were
      measured in seven European cities during 1996-2000. The EXPOLIS database has been
      used for exposure analysis of these pollutants for 4 years now and results have
      been published in approximately 30 peer-reviewed journal papers, demonstrating
      the versatility, usability and scientific value of such a data set. The
      multipollutant exposure data from the same subjects in the random population
      samples allows for analyses of the determinants, microenvironments and sources of
      exposures to multipollutant mixtures and associations between the different air
      pollutants. This information is necessary and useful for developing effective
      policies and control strategies for healthier environment.

PMID- 15026775
TI  - Cotinine and N-(2-hydroxyethyl)valine as markers of passive exposure to tobacco
      smoke in children.
AB  - Large segments of populations, including children, are exposed to environmental
      tobacco smoke (ETS), a risk factor for lung cancer and heart, circulatory and
      respiratory diseases. Recently, ETS was classified as a class A carcinogen by
      USEPA, as carcinogenic to humans by IARC (group 1) and by the National Toxicology
      Program of the US National Institutes of Health. Cotinine, a product of the
      metabolism of nicotine, is measurable in urine and, correlates strictly and
      directly to ETS exposure, therefore representing a well-known internal dose
      marker. Another marker of active tobacco smoking is the N-(2-hydroxyethyl) valine
      (HOEtVal) which results from the reaction between ethylene oxide (EtO) and the N
      terminal valine of hemoglobin. The aim of this study was the evaluations of ETS
      markers, namely urinary cotinine and HOEtVal measured in blood in 100 children
      with ages ranging between 3 and 13 years. Experimental findings show that
      cotinine, as a specific internal dose marker, and HOEtVal, as a nonspecific
      biological effective dose marker, both depend on the passive exposure to ETS as
      well as on the active habit of smoking.

PMID- 15026776
TI  - Exposure assessment in epidemiologic studies of adverse pregnancy outcomes and
      disinfection byproducts.
AB  - A major challenge in studies that examine the association between disinfection
      byproducts in drinking water and pregnancy outcomes is the accurate
      representation of a subject's exposure. We used household water samples and
      questionnaire information on water-use behavior to examine several aspects of
      exposure assessment: (i) the distribution and correlation of specific
      disinfection byproducts, (ii) spatial distribution system and temporal variation
      in byproduct levels, and (iii) the contribution of individual water-use behavior.
      The level of specific trihalomethanes (THMs) and haloacetic acids (HAAs) was
      determined for 360 household water samples in Eastern Ontario and Nova Scotia.
      Subjects were interviewed regarding tap water ingestion and showering and bathing
      practices. In both provinces, total THMs correlated highly with chloroform
      (correlation coefficient (r) >0.95) and less so with total HAAs (r = 0.74 in Nova
      Scotia and r = 0.52 in Ontario). The correlation between total THMs and
      bromodichloromethane was high in Nova Scotia (r = 0.63), but low in Ontario (r =
      0.26). The correlation was between THM level in individual household samples, and
      the mean THM level during the same time period from several distribution system
      samples was 0.63, while a higher correlation in THM level was observed for
      samples taken at the same location 1 year apart (r = 0.87). A correlation of 0.73
      was found between household THM level and a total exposure measure incorporating
      ingestion, showering, and bathing behaviors. These results point to the
      importance of: measurement of different classes of byproducts; household rather
      than distribution system sampling; and, incorporation of subject behaviors in
      exposure assessment in epidemiologic studies of disinfection byproducts and
      adverse pregnancy outcomes.

PMID- 15026777
TI  - Seasonal pesticide use in a rural community on the US/Mexico border.
AB  - An environmental measurement and correlation study of infant and toddler exposure
      to pesticides was carried out in a colonia south of the city of Laredo, Texas. As
      part of the study, homes were visited during the late spring or summer, and
      during the winter of 2000-2001. At each visit, families reported on their use of
      pesticides in and around the home and floor wipe samples were collected and
      analyzed for 14 organophosphate and triazine pesticides. Selection of homes was
      based on the presence of infants and toddlers. A total of 27 homes participated
      in both seasonal visits. The interval between visits was 6 +/- 1.4 months.
      Univariate and multivariate nonparametric analyses were carried out using SPSS
      statistical software. Pesticide use within the home was more often reported than
      outside use and showed seasonal variation in use patterns. Indoor use was
      primarily associated with ants and cockroaches, and secondarily with rodents. The
      primary room treated was the kitchen, and the primary structures treated were the
      floors, lower walls, and dish cupboards. Seasonal variations were not found in
      the use of pesticides used outside the home and outdoor use was primarily
      associated with ant control. Based on parent reports, most pesticides used in the
      homes were pyrethroids. Several of the pesticides measured in floor wipe samples,
      Azinphos methyl, Fonofos, and Simazine, also showed seasonal variations. However,
      these pesticides are used in agriculture and were not associated with reported
      house and yard use patterns.

PMID- 15026778
TI  - Determinants of exposure to volatile organic compounds in four Oklahoma cities.
AB  - To begin to develop generalized models for estimating personal exposure to
      ambient air pollutants within diverse populations, the design of the Oklahoma
      Urban Air Toxics Study incorporated eight dichotomous macroenvironmental and
      household factors that were hypothesized to be potential determinants of
      exposure. Personal, indoor, and outdoor samples of volatile organic compounds
      (VOCs) were collected over 24-h monitoring periods in 42 households, together
      with activity diaries and data on the participants' residences. The distributions
      of the VOC concentrations were moderately to highly left-censored, and were
      mostly bimodal. The ATSDR minimal risk level (MRL) was exceeded in a small number
      of the samples. Personal and indoor concentrations tended to be higher than
      outdoor concentrations, indicating that indoor exposures were dominated by indoor
      sources. However, indoor concentrations were not correlated with the permeability
      of the residence, suggesting that the observed indoor concentrations reflected
      mostly localized, short-term emissions. The influence of the eight dichotomous
      factors and of the presence of an attached garage was evaluated using the
      Wilcoxon rank-sum test and by comparison of "excursion fractions", that is, the
      fractions of each distributions exceeding 10% of the MRL. Dry weather and absence
      of children in the household were found to be associated with higher exposures in
      personal or indoor exposures. Given the small sample size, it is possible that
      these factors were confounded with unidentified household characteristics or
      activities that were the true determinants of exposure.

PMID- 15026779
TI  - Comparison of arsenic levels in fingernails with urinary As species as biomarkers
      of arsenic exposure in residents living close to a coal-burning power plant in
      Prievidza District, Slovakia.
AB  - The associations between As levels in fingernails with both As concentrations in
      urine and environmental samples are reported. The participants (aged 20-80 years,
      mean 66 years) lived in the vicinity of a coal-burning power plant with high As
      emissions in the Prievidza District, Slovakia. Samples were taken in 1999 and
      2000. The As levels in fingernails (n = 524) were measured after washing and
      digestion with microwave heating by hydride generation atomic absorption
      spectrometry. The spot urine samples (n = 436) were speciated for inorganic As
      (As(inorg)), monomethylarsonic (MMA) and dimethylarsinic acid (DMA) by hydride
      cryogenic trap-atomic absorption spectrometry. The geometric mean As level in
      fingernails was 0.10 mug/g (range, <0.01-2.94 microg/g). There was a clear
      association between As in fingernails and the distance of the home to the power
      plant (P<0.001). Geometric mean As levels were: 0.17 microg/g distance < or = 5
      km, 0.10 microg/g 6-10 km and 0.08 microg/g > 10 km. The association between the
      distance to the power plant and total urinary As (As(sum)) (n = 436, no fish
      consumption during the last 3 days before sample collection) was less pronounced
      (P = 0.018). The As levels in fingernails were positively correlated to As in
      soil (n = 207, r = 0.23, P<0.001) and to As in house dust (n = 209, r = 0.30,
      P<0.001). The associations between urinary As(sum) and As concentrations in soil
      (n = 159, r = 0.13, P<0.105) and in house dust (n = 162, r = 0.14, P<0.081) were
      quite similar. As levels in fingernails were associated with urinary As(sum) and
      with the different As species in urine. It is concluded that As levels in
      fingernails are a reliable marker of environmental As exposure, and that As
      concentrations in fingernails reflect the As exposure in a similar manner
      compared with urinary As(sum) and As species.

PMID- 15026780
TI  - Heritability of nectar production in Echium vulgare.
AB  - Heritabilities of nectar production in the wild species Echium vulgare were
      estimated as realised heritability under controlled and field conditions. The
      nectar production of offspring from high- and low-nectar-producing parents was
      significantly different in both controlled and field conditions, indicating that
      nectar production is in part genetically determined. The present study is the
      first one to report a genetic component of variation of nectar production in a
      wild plant species in the field. Heritability estimated under controlled
      conditions was 0.13 and therewith less than the heritability estimated under
      field conditions, which amounted to 0.26. Offspring of high-nectar-producing
      plants produced comparable amounts of nectar in the growth chamber (1.28 microl)
      and in the field (1.22 microl). In contrast, the nectar production of offspring
      of low-nectar-producing plants was significantly higher in the growth chamber
      (0.95 microl) than in the field (0.55 microl), indicating a genotype by
      environment interaction. The level of heritability of nectar production was
      dependent on the environment. Under less favourable conditions, like those in the
      field, heritability of nectar production increased. Nectar production was not
      correlated with any of the vegetative or reproductive traits measured, and hence
      no costs of nectar production could be detected. Results obtained stress the
      importance of field measurements in determining heritabilities.

PMID- 15026781
TI  - Neighbour joining trees, dominant markers and population genetic structure.
AB  - Population genetic theory for 'traditional' codominant loci showing low levels of
      allelic diversity (eg allozymes) has been well characterised and evaluated. In
      contrast, appropriate methods for the analysis of data from more recently
      developed marker systems are still being refined. For multilocus dominant markers
      such as amplified fragment length polymorphisms (AFLPs) and randomly amplified
      polymorphic DNA (RAPDs), the methods of data analysis can be split into two main
      categories. In population-based approaches, population allele frequencies are
      compared to obtain some measure of the partitioning of genetic diversity into
      within- and between-population components. In contrast, individual-based
      approaches use individual multilocus genotypes as the unit of analysis.
      Inferences on population processes such as gene flow are based on inter
      relationships among individual samples as visualised on phenetic diagrams such as
      neighbour joining trees. Using a simulation approach coupled with neighbour
      joining analyses, we show that while the underlying population genetic structure
      is an important determinant of tree shape in the analysis of dominant data, the
      number of loci examined also affects the topology. At low levels of population
      differentiation (eg FST=0.07), mutually exclusive clustering of individuals into
      their respective populations can occur when sufficiently large numbers of loci
      are scored (eg 250 loci, typical of many AFLP studies). In contrast, unresolved
      star-shaped topologies can be recovered at higher levels of population
      differentiation (FST= >0.15) when lower numbers of loci are employed (eg 50 loci,
      typical of many RAPD studies). Thus, the relationship between tree topology and
      the extent of genetic structuring of populations is contingent upon the number of
      dominant loci scored. The consequences of these findings for the biological
      interpretation of individual-based analysis of dominant data sets are discussed.

PMID- 15026782
TI  - Haplotype study in Dutch SCA3 and SCA6 families: evidence for common founder
      mutations.
AB  - This pilot study was initiated to show the existence of founder effects in the
      Dutch autosomal dominant cerebellar ataxia (ADCA) population. The ADCAs comprise
      a clinically heterogeneous group of neurodegenerative disorders and the estimated
      prevalence in the Netherlands is approximately 3:100 000 individuals. Here, we
      focused on the SCA3 and SCA6 genes because mutations in these genes occur most
      frequently in the Netherlands. We were able to determine a common origin of the
      CAG repeat expansions in the majority of Dutch SCA3 and SCA6 families. Haplotype
      analysis and linkage disequilibrium studies with polymorphic markers revealed
      shared haplotypes surrounding the SCA3 and SCA6 genes. These results strongly
      suggest that ADCA families can be traced back to common ancestors in particular
      parts of the Netherlands.

PMID- 15026783
TI  - Glycerol kinase deficiency: residual activity explained by reduced transcription
      and enzyme conformation.
AB  - Four unrelated patients with glyceroluria ranging from 7 to 170 mmol/l were
      studied. The activity of glycerol kinase (GK) in cultured fibroblasts was
      determined with a specific enzyme assay and with two indirect methods, that is,
      incorporation into macromolecules of [(14)C] from [(14)C]glycerol and its
      oxidation to [(14)C]CO(2). Exon amplification and RT-PCR were used to identify
      mutations. In patient 1, with low activity in all three assays, we identified a
      c.1194A>C (E398D) missense mutation. In patient 2 with a considerable activity of
      the GK enzyme (22% of reference), oxidation to [(14)C]CO(2) (37%) and a high
      incorporation of [(14)C] into macromolecules (92%), we identified a c.182T>C
      (L61P) mutation that causes the enzyme to have a higher K(m) for glycerol (
      approximately 300 microM) than normals (2-8 microM). In patient 3, the GK
      activity estimated by the three different methods ranged from 16 to 22% of
      reference. Analysis of mRNA from the GK gene revealed three alternatively spliced
      transcripts. A mutation in intron 3 (g.16835G>A) resulted in an insertion of a
      cryptic exon between exon 2 or 3 and exon 4. Patient 4 with minor glyceroluria (7
      mmol/l) and normal plasma glycerol concentration had normal activity with all
      three assay methods, thus excluding GK deficiency (GKD) as a cause of slight
      glyceroluria. To evaluate fully patients with glyceroluria, one needs to measure
      the GK activity and relate this and the clinical data to genetic findings.
      Residual enzyme activities in cultured fibroblasts can be found in GKD patients
      with severe clinical symptoms.

PMID- 15026784
TI  - A comparison of different metaphase CGH methods for the detection of cryptic
      chromosome aberrations of defined size.
AB  - An increasing body of evidence indicates that submicroscopic gene dose
      alterations may cause mental impairment and malformations. During the last
      decade, comparative genomic hybridization (CGH) has become a useful tool in the
      detection and mapping of chromosome aberrations. Modifications of CGH with
      increased resolution down to 3-5 Mb have been reported and CGH is now offered as
      a diagnostic procedure in the evaluation of patients with idiopathic mental
      retardation (MR). In order to increase the resolution, we modified the CGH
      protocol using freshly prepared high-quality metaphase slides and chemical
      labeling, and tested the method on a set of patients with well-defined
      submicroscopic chromosome abnormalities with confirmed size 1.3-20.5 Mb.
      Subsequently, a completely blinded test was performed to compare the performance
      of the chemical labeling CGH to the commercially available HR-CGH. Using the two
      different CGH methods, we were able to detect chromosome imbalances down to 2-3
      Mb approximately. The HR-CGH method detected all aberrations >6 Mb and a few
      smaller, while the modified CGH method was able to detect all but three
      aberrations >1.8 Mb. The modified CGH method was superior in the detection of
      terminal imbalances, while the HR-CGH software was more successful in the
      detection of imbalances located very close to the centromeric regions. In
      conclusion, the resolution of metaphase CGH may be as high as 2-3 Mb but is most
      likely depending on the chromosomal region involved, a clear limitation when used
      as a screening method for chromosome aberrations in patients with idiopathic MR.

PMID- 15026785
TI  - Haplotype diversity and SNP frequency dependence in the description of genetic
      variation.
AB  - Haplotype diversity is controlled by a variety of processes, including mutation,
      recombination, marker ascertainment and demography. Understanding the extent to
      which genetic variation at physically linked loci is co-inherited is crucial for
      the design of the HapMap project and the correct interpretation of the resulting
      data. In the absence of an analytical theory extensive coalescent simulations are
      used to disentangle the influence of all of these factors on haplotype diversity.
      In addition to these qualitative insights, this study also demonstrates (i) that
      marker spacing and frequency profoundly influence observed levels of haplotype
      diversity; (ii) that the spectrum of haplotypes contains information about how
      exhaustively genetic variation in a region is described by a given marker set;
      and (iii) that so-called haplotype blocks can be generated due by the
      stochasticity inherent in the recombination process without having to assume
      variation in the recombination rate.

PMID- 15026787
TI  - Establishing a tumour bank: banking, informatics and ethics.
AB  - The six divisions of the Cooperative Human Tissue Network in the USA bank and
      distribute tens of thousands of tissue specimens to researchers annually. Major
      operational concerns include: maintaining tissue integrity, managing informatics,
      and protecting patient confidentiality. Increasing molecular genetics testing is
      also resulting in an increased demand for high-quality nucleic acids.

PMID- 15026786
TI  - Expression profiling of small cellular samples in cancer: less is more.
AB  - Expression profiling of tumours from cancer patients has uncovered several genes
      that are critically important in the progression of a normal cell to an oncogenic
      phenotype. Leading the way in these discoveries is the use of microarrays, a
      technology that is currently in transition from basic science applications to use
      in the clinic. Microarrays can determine the global gene regulation of an
      individual cancer, which may be useful in formulating an individualised therapy
      for the patient. Currently, cells used in breast cancer microarray studies often
      come from either homogenous cultures or heterogeneous biopsy samples. Both cell
      sources are at a disadvantage in determining the most accurate gene profile of
      cancer, which often consists of multiple subspecies of cancerous cells within a
      background of normal cells. Therefore, acquisition of small, but highly specific
      biopsies for analysis may be required for an accurate expression analysis of the
      disease. Amplification methods, such as polymerase chain reaction (PCR) and
      amplified antisense RNA (aRNA) amplification, have been used to amplify the mRNA
      signal from very small samples, which can then be used for microarray analysis.
      In this study, we describe the acquisition, amplification, and analysis of very
      small samples (<10000 cells) for expression analysis and demonstrate that the
      ultimate resolution of cancer expression analysis, one cell, is both feasible and
      practical.

PMID- 15026788
TI  - Molecular profiling of breast cancer: clinical implications.
AB  - Breast cancers are routinely subcategorised on the basis of clinical stage,
      cellular morphology and immunohistochemical analysis of a small number of
      markers. The recent development of gene expression microarray and related
      technologies provides an opportunity to perform more detailed profiling of the
      disease. It is anticipated that the molecular classification arising from such
      studies will be more powerful than its pathological predecessor at confining
      treatment to those patients who are most likely to benefit. It is likely that
      this will result in a much less frequent use of adjuvant chemotherapy.
      Furthermore, of those who do receive it, a higher proportion will benefit. If
      adopted, this will offer considerable patient benefits in terms of reducing
      unnecessary toxicity and have major health economic implications.

PMID- 15026789
TI  - Phase I study of cisplatin analogue nedaplatin (254-S) and paclitaxel in patients
      with unresectable squamous cell carcinoma.
AB  - The recommended phase II dose of paclitaxel 180 mg m(-2) given as a 3-h infusion
      followed by nedaplatin 100 mg m(-2) in a 1-h infusion every 3-4 weeks was
      determined in 52 chemo-naive patients with unresectable squamous cell carcinoma
      (SCC), with a promising response rate for lung SCC of 55%.

PMID- 15026790
TI  - The response of leptin, interleukin-6 and fat oxidation to feeding in weight
      losing patients with pancreatic cancer.
AB  - At baseline, weight-losing pancreatic cancer patients (n=7) had lower leptin
      (P<0.05) but higher cortisol, interleukin-6, resting energy expenditure and fat
      oxidation than healthy subjects (n=6, P<0.05). Over a 4 h feeding period, the
      areas under the curve for glucose, cortisol and interleukin-6 were greater
      (P<0.05), but less for leptin in the cancer group (P<0.05). Therefore, it would
      appear that low leptin concentrations, increased fat oxidation and insulin
      resistance are associated with increased concentrations of cortisol and
      interleukin-6 in weight-losing patients with pancreatic cancer.

PMID- 15026791
TI  - Oral ibandronate reduces the risk of skeletal complications in breast cancer
      patients with metastatic bone disease: results from two randomised, placebo
      controlled phase III studies.
AB  - Although intravenous (i.v.) bisphosphonates are the standard of care for
      metastatic bone disease, they are less than ideal for many patients due to
      infusion-related adverse events (AEs), an increased risk of renal toxicity and
      the inconvenience of regular hospital visits. The use of oral bisphosphonate
      therapy is limited by concerns over efficacy and gastrointestinal (GI) side
      effects. There remains a clinical need for an oral bisphosphonate that offers
      equivalent efficacy to i.v. bisphosphonates, good tolerability and dosing
      convenience. Oral ibandronate, a highly potent, third-generation
      aminobisphosphonate, has been evaluated in phase III clinical trials of patients
      with bone metastases from breast cancer. In two pooled phase III studies,
      patients with breast cancer and bone metastases were randomised to receive oral
      ibandronate 50 mg (n=287) or placebo (n=277) once daily for up to 96 weeks. The
      primary end point was the skeletal morbidity period rate (SMPR), defined as the
      number of 12-week periods with new skeletal complications. Multivariate Poisson's
      regression analysis was used to assess the relative risk of skeletal-related
      events in each treatment group during the study period. Oral ibandronate 50 mg
      significantly reduced the mean SMPR compared with placebo (0.95 vs 1.18,
      P=0.004). There was a significant reduction in the mean number of events
      requiring radiotherapy (0.73 vs 0.98, P<0.001) and events requiring surgery (0.47
      vs 0.53, P=0.037). Poisson's regression analysis confirmed that oral ibandronate
      significantly reduced the risk of a skeletal event compared with placebo (hazard
      ratio 0.62, 95% CI=0.48, 0.79; P=0.0001). The incidence of mild treatment-related
      upper GI AEs was slightly higher in the oral ibandronate 50 mg group compared
      with placebo, but very few serious drug-related AEs were reported. Oral
      ibandronate 50 mg is an effective, well-tolerated and convenient treatment for
      the prevention of skeletal complications of metastatic bone disease.

PMID- 15026792
TI  - Survival of women with breast cancer in Ottawa, Canada: variation with age,
      stage, histology, grade and treatment.
AB  - This study examined the 5-year survival of 2192 breast cancer women diagnosed
      between 1994 and 1997 in Ottawa, Canada, by age, TNM stage, histology, grade and
      treatment, including assessment of the independent value of variables in defining
      prognosis. Our results showed that age, stage, treatment and grade significantly
      influenced outcome regardless of the confounding factors considered, with
      histology failing to achieve significant independent prognostic information. The
      survival rates were highest at ages 50-69 years for stage I and at ages 40-49
      years for stages II-IV. The rates were lowest at ages <or=39 years for stages I
      II and at ages >or=70 years for stages III-IV. The differences in survival
      between grade 1 and grade 3 were 9% in stage I and 20% in stage II. The treatment
      leading to the best survival was surgery plus radiation for stages I-II and
      surgery combined with chemotherapy for stages III-IV. Lobular carcinoma had a
      better prognosis than ductal carcinoma; this can be explained by more grade 1 and
      less grade 3 cases in lobular carcinoma. The worse prognosis for young patients
      than other ages can be explained by their higher proportion of poorly
      differentiated cancers. Stage I patients aged 50-69 years having the best
      survival is likely due to the earlier diagnosis achieved through screening.

PMID- 15026793
TI  - Patient's needs and preferences in routine follow-up after treatment for breast
      cancer.
AB  - The purpose of the study was to analyse the needs of women who participated in a
      routine follow-up programme after treatment for primary breast cancer. A cross
      sectional survey was conducted using a postal questionnaire among women without
      any sign of relapse during the routine follow-up period. The questionnaire was
      sent 2-4 years after primary surgical treatment. Most important to patients was
      information on long-term effects of treatment and prognosis, discussion of
      prevention of breast cancer and hereditary factors and changes in the untreated
      breast. Patients preferred additional investigations (such as X-ray and blood
      tests) to be part of routine follow-up visits. Less satisfaction with
      interpersonal aspects and higher scores on the Hospital Anxiety and Depression
      Scale (HADS) scale were related to stronger preferences for additional
      investigation. Receiving adjuvant hormonal or radiotherapy was related to a
      preference for a more intensive follow-up schedule. There were no significant
      differences between patients treated with mastectomy compared to treated with
      breast-conserving therapy. During routine follow-up after a diagnosis of breast
      cancer, not all patients needed all types of information. When introducing
      alternative follow-up schedules, individual patients' information needs and
      preferences should be identified early and incorporated into the follow-up
      routine care, to target resources and maximise the likelihood that positive
      patient outcomes will result.

PMID- 15026794
TI  - Long-term follow-up of patients treated with radiotherapy alone for early-stage
      histologically aggressive non-Hodgkin's lymphoma.
AB  - Historically localised aggressive non-Hodgkin's lymphoma (NHL) has been treated
      with involved field radiotherapy (RT), chemotherapy, or a combination of both
      modalities. The current weight of evidence supports a preference for combined
      modality treatment (CMT). Increased patient age at diagnosis is well recognised
      as a poor prognostic indicator in NHL, but despite this some perceive CMT as too
      toxic for use in the elderly. As a result, some older patients continue to be
      offered RT alone. Here, we present long-term follow-up of 377 adults of all ages
      treated with RT alone for early-stage diffuse large-cell lymphoma on British
      National Lymphoma Investigation trials between 1974 and 1997. 10-year cause
      specific survival in patients older than 60 years was poor and significantly
      inferior to that in younger patients (47 and 75% respectively; P<0.001). There is
      growing evidence that short-course chemotherapy, with or without RT, is superior
      to RT alone in early-stage aggressive NHL, in elderly as well as in younger
      patients. Increased age alone should not exclude patients from systemic treatment
      for early-stage aggressive NHL.

PMID- 15026796
TI  - A population-based study of pain and quality of life during the year before death
      in men with prostate cancer.
AB  - In order to explore how health-related quality of life changes towards the end of
      life, a questionnaire including the EuroQOl form and the Brief Pain Inventory
      form was sent to all men with prostate cancer in the county of Ostergotland,
      Sweden, in September 1999. Responders who had died prior to 1 January 2001 were
      later identified retrospectively. Of the 1442 men who received the questionnaire,
      1243 responded (86.2%). In the group of responders, 167 had died within the study
      period, 66 of prostate cancer. In multivariate analysis, pain as well as death
      within the period of study were found to predict decreased quality of life
      significantly. Of those who died of prostate cancer, 29.0% had rated their worst
      pain the previous week as severe. The same figure for those still alive was
      10.5%. On a visual analogue scale (range 0-100), the mean rating of quality of
      life for those who subsequently died of prostate cancer was 54.0 (95% confidence
      interval +/-5.2) and those still alive was 70.0 (+/-1.2). In conclusion, health
      related quality of life gradually declines during the last year of life in men
      with prostate cancer. This decline may partly be avoided by an optimised pain
      management.

PMID- 15026795
TI  - Safety and efficacy of subcutaneous and continuous intravenous infusion rIL-2 in
      patients with metastatic renal cell carcinoma.
AB  - A retrospective analysis was conducted on data from four open-label,
      nonrandomised, phase II trials of recombinant interleukin-2 (rIL-2) in patients
      with metastatic renal cell carcinoma to compare the safety and efficacy of
      administration by subcutaneous (s.c.) and continuous intravenous (c.i.v.)
      infusion (n=103 s.c. and n=225 c.i.v.). No statistically significant differences
      were found between the cohorts in terms of overall response rate (s.c.: 13.6% vs
      c.i.v.: 12.4%, P=0.77), response duration (s.c.: 9.8 months vs c.i.v.: 10.1
      months, P=0.99), and overall survival (P=0.08). Compared with c.i.v.
      administration, more patients in the s.c. cohort experienced stable disease (50.5
      vs 29.8%) and fewer underwent disease progression (35.0 vs 43.6%). Subcutaneous
      administration was associated with a significantly lower incidence of grade 3 or
      4 adverse events (46 vs 76%; P<0.001), and fewer s.c. patients required dose
      reductions because of toxicity (20 vs 82%). At the doses and within the schedules
      tested, this comparative analysis did not detect any difference in efficacy
      between s.c. and c.i.v. administration of rIL-2 in terms of overall survival,
      duration of response and response rate in patients with metastatic renal cell
      carcinoma. However, s.c. delivery of rIL-2 was associated with improved
      tolerability.

PMID- 15026798
TI  - Survival of patients with nonseminomatous germ cell cancer: a review of the IGCC
      classification by Cox regression and recursive partitioning.
AB  - The International Germ Cell Consensus (IGCC) classification identifies good,
      intermediate and poor prognosis groups among patients with metastatic
      nonseminomatous germ cell tumours (NSGCT). It uses the risk factors primary site,
      presence of nonpulmonary visceral metastases and tumour markers alpha-fetoprotein
      (AFP), human chorionic gonadotrophin (HCG) and lactic dehydrogenase (LDH). The
      IGCC classification is easy to use and remember, but lacks flexibility. We aimed
      to examine the extent of any loss in discrimination within the IGCC
      classification in comparison with alternative modelling by formal weighing of the
      risk factors. We analysed survival of 3048 NSGCT patients with Cox regression and
      recursive partitioning for alternative classifications. Good, intermediate and
      poor prognosis groups were based on predicted 5-year survival. Classifications
      were further refined by subgrouping within the poor prognosis group. Performance
      was measured primarily by a bootstrap corrected c-statistic to indicate
      discriminative ability for future patients. The weights of the risk factors in
      the alternative classifications differed slightly from the implicit weights in
      the IGCC classification. Discriminative ability, however, did not increase
      clearly (IGCC classification, c=0.732; Cox classification, c=0.730; Recursive
      partitioning classification, c=0.709). Three subgroups could be identified within
      the poor prognosis groups, resulting in classifications with five prognostic
      groups and slightly better discriminative ability (c=0.740). In conclusion, the
      IGCC classification in three prognostic groups is largely supported by Cox
      regression and recursive partitioning. Cox regression was the most promising tool
      to define a more refined classification. British Journal of Cancer (2004) 90,
      1176-1183. doi:10.1038/sj.bjc.6601665 www.bjcancer.com Published online 24
      February 2004

PMID- 15026797
TI  - Paclitaxel-containing high-dose chemotherapy for relapsed or refractory
      testicular germ cell tumours.
AB  - High-dose regimes containing etoposide, carboplatin and an oxazaphospharine can
      salvage 30-40% of patients with relapsed or refractory male germ cell tumours
      (GCTs). The additional benefit of paclitaxel in such high-dose therapy has not
      been tested. Between March 1995 and November 2002, 36 male GCT patients were
      treated with Carbop-EC-T (paclitaxel 75 mg x m(-2), etoposide 450 mg x m(-2),
      carboplatin AUC 10 on days -7, -5 and -3 and cyclophosphamide 60 mg x kg(-1) on
      days -5 and -3) followed by peripheral blood stem cell infusion (day 0). The 1
      year overall survival rate for all patients is 67% (median follow-up 29 months).
      For the 24 patients with cisplatin-sensitive disease, the 1-year overall and
      event-free survivals are 88 and 64%, respectively. For those with cisplatin
      refractory or absolutely refractory disease, the 1-year overall survival is 25%.
      In all, 12 patients relapsed at a median duration of 5 months, 11 of whom have
      died. There were also six treatment-related deaths, five associated with
      pneumonitis. Pulmonary toxicity has been reported with paclitaxel in other high
      dose regimes. Since altering our protocol so that paclitaxel is infused over 24 h
      with steroid prophylaxis, only one of 18 patients (13 testicular GCTs and five
      other tumour types) has had a treatment-related death. Our results suggest that
      Carbop-EC-T may enable a greater proportion of patients with relapsed and
      refractory GCTs to enter long-term remission.

PMID- 15026799
TI  - Phase I/II study of cisplatin combined with weekly paclitaxel in patients with
      advanced non-small-cell lung cancer.
AB  - To determine the maximum-tolerated dose (MTD) and the recommended dose (RD) of
      paclitaxel administered weekly with a fixed dose of cisplatin, and to assess the
      toxicity and activity of this combination, we conducted a phase I/II trial in
      patients with advanced non-small-cell lung cancer (NSCLC). In this study,
      patients with stage IIIB/IV NSCLC were eligible. Paclitaxel, at a starting dose
      of 40 mg x m(-2) week(-1) on days 1, 8, and 15, was combined with a fixed dose of
      cisplatin 80 mg x m(-2) on day 1. Chemotherapy was given in a 4-week cycle. In
      this phase I/II study, 38 patients were enrolled. Dose-limiting toxicities (DLT)
      were neutropenia, fatigue, and omission of treatment due to leucopenia,
      thrombocytopenia, or febrile neutropenia. The MTD and RD were estimated to be 70
      mg x m(-2). Of the 37 assessable patients, 23 had a partial response and one had
      a complete response. Overall response rate was 62.1% (95% confidence interval
      (CI): 46.5-77.7%). The progression-free survival, the median survival time, and
      the 1-year survival rate were 5.5 months, 13.7 months, and 56.9%, respectively.
      This regimen is tolerable and very active against advanced NSCLC, and its
      efficacy should be confirmed in a phase III study.

PMID- 15026800
TI  - Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated
      efficacy data and novel analyses from two large, randomised, phase III trials.
AB  - This study evaluates the efficacy of capecitabine using data from a large, well
      characterised population of patients with metastatic colorectal cancer (mCRC)
      treated in two identically designed phase III studies. A total of 1207 patients
      with previously untreated mCRC were randomised to either oral capecitabine (1250
      mg m(-2) twice daily, days 1-14 every 21 days; n=603) or intravenous (i.v.) bolus
      5-fluorouracil/leucovorin (5-FU/LV; Mayo Clinic regimen; n=604). Capecitabine
      demonstrated a statistically significant superior response rate compared with 5
      FU/LV (26 vs 17%; P<0.0002). Subgroup analysis demonstrated that capecitabine
      consistently resulted in superior response rates (P<0.05), even in patient
      subgroups with poor prognostic indicators. The median time to response and
      duration of response were similar and time to progression (TTP) was equivalent in
      the two arms (hazard ratio (HR) 0.997, 95% confidence interval (CI) 0.885-1.123,
      P=0.95; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV, respectively).
      Multivariate Cox regression analysis identified younger age, liver metastases,
      multiple metastases and poor Karnofsky Performance Status as independent
      prognostic indicators for poor TTP. Overall survival was equivalent in the two
      arms (HR 0.95, 95% CI 0.84-1.06, P=0.48; median 12.9 vs 12.8 months,
      respectively). Capecitabine results in superior response rate, equivalent TTP and
      overall survival, an improved safety profile and improved convenience compared
      with i.v. 5-FU/LV as first-line treatment for MCRC. For patients in whom
      fluoropyrimidine monotherapy is indicated, capecitabine should be strongly
      considered. Following encouraging results from phase I and II trials, randomised
      trials are evaluating capecitabine in combination with irinotecan, oxaliplatin
      and radiotherapy. Capecitabine is a suitable replacement for i.v. 5-FU as the
      backbone of colorectal cancer therapy.

PMID- 15026802
TI  - Allelic loss at 19q12 and Xq11-12 predict an adverse clinical outcome in patients
      with mucinous ovarian tumours of low malignant potential.
AB  - Ovarian tumours of low malignant potential (LMP) are intermediate between
      adenomas and ovarian carcinomas. These tumours are often associated with a
      significantly better prognosis than ovarian carcinomas. However, a subset of
      these tumours can progress and become lethal. In order to seek sensitive
      diagnostic tools for monitoring patients after surgical operation, we performed a
      genome-wide scan for loss of heterozygosity (LOH) in 41 mucinous LMPs using 91
      polymorphic microsatellite markers at an average interval of 50 cM across all of
      the human chromosomes and 25 LOH markers reportedly associated with ovarian
      carcinoma. In addition, we assessed whether clinicopathological parameters,
      microvessel density, Ki-67 labeling index, apoptotic index or p53 overexpression
      would be useful for predicting the postoperative outcome of LMP patients. Of the
      116 markers examined, 19q12 and Xq11-12 showed significant correlation between
      postoperative progression-free survival time and LOH status (P<0.05). Patients
      with a high Ki-67 labeling index had a significantly poorer progression-free
      survival time than those with lower levels (P=0.042). Other clinicopathological
      factors and immunohistochemical analysis had no correlation with progression-free
      survival time in this series of patients. When the combination of LOH at 19q12
      and/or Xq11-12 was assessed using Cox's regression analysis, patients with
      tumours that showed LOH at these positions were at greatest risk of progression
      (P=0.0073). These findings suggest that the identification of LOH at 19q12 and/or
      Xq11-12 in former mucinous LMP sites should alert the clinician to the presence
      of a potentially aggressive lesion in the coelomic epithelium, even if a
      distinction between second primary tumours or recurrence could not be determined.

PMID- 15026801
TI  - Overexpression of Id-1 is significantly associated with tumour angiogenesis in
      human pancreas cancers.
AB  - It has been suggested that Id-1 has a critical role in the tumour progression and
      aggressiveness of several human cancers. However, the clinicopathological and
      biological significance of Id-1 overexpression remains unclear in human primary
      cancer. To investigate the association between Id-1 expression and cell
      proliferation or tumour angiogenesis, we examined the cell cycle kinetic indices
      (the proliferation and apoptotic indices, PI and AI) and intratumoral microvessel
      density (MVD) in 65 human pancreatic cancers. We also investigated the
      relationship between its expression and various clinicopathological factors to
      determine the clinical significance of Id-1 overexpression. Out of a total 65
      cases, 32 (49.3%) showed overexpression of Id-1 vs normal tissues. Id-1
      expression was found to be significantly associated with MVD (P=0.002). In
      further analysis of subgroups with higher and lower Id-1 expression, tumours with
      higher Id-1 expression (scores 4 and 5) showed significantly higher MVD than
      tumours with lower expression of Id-1 (scores 2 and 3) (111.18+/-57.14 vs 64.13+/
      28.19, P<0.001). However, no significant association was found between Id-1
      overexpression and patient survival rate. No significant association was also
      found between Id-1 expression and cell cycle kinetic indices (PI or AI) in
      pancreatic cancer. Moreover, the overexpression of Id-1 protein was not
      correlated with any significant clinicopathologic factors. These findings
      indicate that Id-1 overexpression is closely related with tumour angiogenesis and
      a higher density of intratumoral vessel, but that it is not associated with a
      poorer prognosis of survival or a higher cell proliferative potential in human
      pancreatic cancer.

PMID- 15026803
TI  - Quantitation of circulating DNA in the serum of breast cancer patients by real
      time PCR.
AB  - The purpose of this study was to quantify the level of serum DNA in different
      groups of primary breast cancer patients and in healthy controls using real-time
      quantitative PCR in order to determine whether such measurements have diagnostic
      or prognostic value. A total of 96 serum samples of patients with primary breast
      cancer before surgery (with positive or negative lymph nodes and with high or low
      relapse-free survival) as well as 24 healthy controls were analysed. DNA
      concentrations in the serum of the patients differed significantly from the
      concentration of serum DNA in the controls (medians were 221 and 63 ng x ml(-1),
      respectively, P<0.001 M-W test). However, no statistically significant difference
      was observed between the patient groups (P=0.87, M-W test). The serum DNA levels
      were elevated independently of the size of primary tumour or lymph node
      metastases. The overall survival of patients with serum DNA concentrations >221
      ng x ml(-1) was better than patients with serum DNA concentration <or=221 ng ml(
      1) (Kaplan-Meier, P=0.028).

PMID- 15026804
TI  - Prediction of metastasis risk (11 year follow-up) using VEGF-R1, VEGF-R2, Tie
      2/Tek and CD105 expression in breast cancer (n=905).
AB  - Neoangiogenesis in tumours contributes to the development of blood-borne
      metastases, and can be evaluated by markers of activated endothelial cells in
      preference to panendothelial markers. Our purpose was to document the prognostic
      significance of VEGF-R1, VEGF-R2, Tie-2/Tek and CD105 immunoexpression in breast
      carcinoma frozen samples (n=905, follow-up=11.7 years). We observed that: (i).
      CD105 (P=0.001) and Tie-2/Tek (P=0.025) (but not VEGF-R1 and VEGF-R2)
      overexpression correlated with a shorter survival, and were (Cox's model)
      independent histoprognostic indicators; (ii). only CD105 marked expression
      correlated (P=0.035) with a shorter survival of node-negative patients; (iii).
      three markers - CD105 (P=0.001), Tie-2/Tek (P=0.01), VEGF-R1 (P=0.001), but not
      VEGF-R2 - correlated with metastatic risk in node-negative patients in univariate
      analysis; and (iv). VEGF-R1 (P=0.01) expression correlated with high local
      recurrence risk. It is concluded that CD105 and to a lesser extent Tie-2/Tek and
      VEGF-R1, but not VEGF-R2 are endowed with prognostic significance that may be
      useful for patient monitoring, particularly CD105 expression for selecting node
      negative patients for more aggressive postsurgery therapy.

PMID- 15026807
TI  - Gene array of VHL mutation and hypoxia shows novel hypoxia-induced genes and that
      cyclin D1 is a VHL target gene.
AB  - Gene expression analysis was performed on a human renal cancer cell line (786-0)
      with mutated VHL gene and a transfectant with wild-type VHL to analyse genes
      regulated by VHL and to compare with the gene programme regulated by hypoxia.
      There was a highly significant concordance of the global gene response to hypoxia
      and genes suppressed by VHL. Cyclin D1 was the most highly inducible transcript
      and 14-3-3 epsilon was downregulated. There were some genes regulated by VHL but
      not hypoxia in the renal cell line, suggesting a VHL role independent of hypoxia.
      However in nonrenal cell lines they were hypoxia regulated. These included
      several new pathways regulated by hypoxia, including RNase 6PL, collagen type 1
      alpha 1, integrin alpha 5, ferritin light polypeptide, JM4 protein, transgelin
      and L1 cell adhesion molecule. These were not found in a recent SAGE analysis of
      the same cell line. Hypoxia induced downregulation of Cyclin D1 in nonrenal cells
      via an HIF independent pathway. The selective regulation of Cyclin D1 by hypoxia
      in renal cells may therefore contribute to the tissue selectivity of VHL
      mutation.

PMID- 15026805
TI  - Differential expression of telomerase reverse transcriptase (hTERT) in lung
      tumours.
AB  - Human telomerase reverse transcriptase is a ribonucleoprotein that synthesises
      telomeric sequences, which decrease at each cell division. In cancer cells, its
      activity is linked to telomere maintenance leading to unlimited cellular
      proliferation and immortality. To evaluate the prognostic value of the catalytic
      subunit telomerase reverse transcriptase (hTERT), we analysed its expression by
      immunohistochemistry in 122 formalin-fixed lung tumours including 42 squamous
      cell carcinoma (SCC), 43 adenocarcinoma (ADC), 19 basaloid carcinoma (BC) and 18
      small-cell lung carcinoma (SCLC) in comparison with detection of hTERT mRNA by in
      situ hybridisation and relative telomerase activity by TRAP assay in a subset of
      tumours. We observed a high concordance between hTERT protein expression and
      detection of hTERT mRNA and telomerase activity. Telomerase expression varied
      according to histology (P=0.0002) being significantly lower in ADC than in SCC,
      BC and SCLC (P<0.0001). Adenocarcinoma and SCC exhibited either a nuclear or a
      nucleolar staining in contrast with a diffuse nuclear staining observed in most
      BC and all SCLC (P=0.01). In stage I NSCLC telomerase expression was lower than
      in other stages (P=0.04), and a nucleolar staining was correlated with a short
      survival (P=0.03). We concluded that telomerase expression and pattern are
      distinctive among histopathological classes of lung cancer and convey prognostic
      influence.

PMID- 15026806
TI  - Loss of heterozygosity on 10q and mutational status of PTEN and BMPR1A in
      colorectal primary tumours and metastases.
AB  - We investigated the possible role of chromosome 10q losses in colorectal cancer
      metastasis by carrying out an allelic imbalance study on a series of
      microsatellite instability-negative (MSI-) primary tumours (n=32) and metastases
      (n=36) from 49 patients. Our results demonstrate that 10q allelic losses are
      associated with a significant proportion (25%) of MSI- colorectal tumours, but
      are not involved in the metastatic process. PTEN and BMPR1A, two genes located in
      the common deleted region, were screened for mutations in samples with loss of
      heterozygosity. The absence or low frequency of mutations indicates that the
      inactivation of these genes by deletion of one allele and mutation of the other
      one plays only a minor role in MSI- tumours.

PMID- 15026809
TI  - Fusion of HIV-1 Tat protein transduction domain to poly-lysine as a new DNA
      delivery tool.
AB  - Effective gene therapy depends on the efficient transfer of therapeutic genes to
      target cells. None of the current technologies, however, satisfy all of the
      requirements necessary for gene therapy, because the plasma and nuclear membranes
      of mammalian cells are tight barriers against gene transfer using synthetic
      delivery systems. The protein transduction domain (PTD) of human immunodeficiency
      virus type 1 (HIV-1) Tat protein greatly facilitates protein transfer via
      membrane destabilisation. We synthesised polylysine peptides containing Tat PTD
      (TAT-pK), or other sequences, and investigated their potential as agents for gene
      transfer. The synthesised polypeptide TAT-pK retains DNA binding function and
      mediates delivery of a reporter gene to cultured cells. RGD motif binds with low
      affinity to alpha integrins which induce cell activation. Two control
      polypeptides, GGG-pK and RGD-pK, were synthesised and tested, but their gene
      transfer abilities were weaker than those of TAT-pK. TAT-pK-mediated gene
      transfer was enhanced in the presence of chloroquine or ammonium chloride, to a
      greater extent than that of cationic lipid-mediated gene transfer in most cancer
      cell lines tested. These data suggest that TAT-pK may be a potent candidate
      delivery vehicle that promotes gene transfer, dependent on the endocytic pathway.
      We conclude that the TAT-pK/DNA complex is useful as a minimal unit to package
      therapeutic genes and to transduce them into mammalian cells.

PMID- 15026808
TI  - BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian
      breast/ovarian cancer families.
AB  - Worldwide variation in the distribution of BRCA1 and BRCA2 mutations is well
      recognised, and for the Belgian population no comprehensive studies about BRCA1/2
      mutation spectra or frequencies have been published. We screened the complete
      coding region of both genes in 451 individuals from 349 Belgian families referred
      to a family cancer clinic and identified 49 families with a BRCA1 and 26 families
      with a BRCA2 mutation. Six major recurrent mutations (BRCA1 IVS5+3A>G, 2478
      2479insG, E1221X and BRCA2 IVS6+1G>A, 6503-6504delTT, 9132delC) accounted for
      nearly 60% of all mutations identified. Besides 75 true pathogenic mutations, we
      identified several variants of unknown clinical significance. In combination with
      a family history, an early average age of female breast cancer diagnosis
      (P<0.001), and the presence of a relative with ovarian cancer (P<0.0001) or
      multiple primary breast cancers (P=0.002), increased the chance for finding a
      mutation. Male breast cancer was indicative of a BRCA2 mutation segregating in
      the family (P=0.002). Mutations in the 5'-end of BRCA1 and BRCA2 were associated
      with a significantly increased risk for ovarian cancer relative to the central
      portion of the gene. Our study suggests a role for additional breast cancer
      susceptibility genes in the Belgian population, since mutation detection ratios
      were low in high-risk breast cancer-only families as compared to breast-ovarian
      cancer families. Given the large proportion of recurring mutations, molecular
      testing can now be organised in a more cost-effective way. Our data allow
      optimisation of genetic counselling and disease prevention in Belgian
      breast/ovarian cancer families.

PMID- 15026810
TI  - In vivo bioluminescence imaging of locally disseminated colon carcinoma in rats.
AB  - Animal tumour models using orthotopic tumours for the evaluation of cancer
      therapies are of greater clinical relevance than subcutaneous models, but they
      also pose greater difficulties for measuring tumour size and quantifying response
      to treatment. In this study, we used noninvasive bioluminescence imaging to
      monitor the intraperitoneal growth of luciferase-transfected CC531 colorectal
      cells in adult WAG/RIJ rats. The bioluminescence signal correlated well with post
      mortem assessment of tumour load by visual inspection of the peritoneal cavity at
      specific follow-up times. Using bioluminescence imaging, we were able to monitor
      peritoneal tumour growth sequentially in time and to calculate a tumour growth
      rate for each animal; this is not possible with invasive methods of evaluating
      tumour load. Bioluminescence imaging of rats treated with a single dose of
      cisplatin (4 mg x kg(-1), i.p.) demonstrated a significant delay in peritoneal
      tumour growth relative to saline controls (mean 45.0+/-s.d. 13.0 vs 28.2+/-10.3
      days; P=0.04). Similar protocols evaluated by visual scoring of tumour load at 40
      days after inoculation supported these findings, although no quantitative
      assessment of treatment-induced growth delay could be made by this method. This
      study shows that in vivo imaging of luciferase-transfected tumour cells is a
      useful tool to investigate the dynamics of disseminated tumour growth and
      efficacy of anticancer treatment in orthotopic models of peritoneal cancer in
      rats. It offers an attractive alternative to invasive methods, and requires fewer
      animals for measuring tumour response to therapy.

PMID- 15026811
TI  - Snail and SIP1 increase cancer invasion by upregulating MMP family in
      hepatocellular carcinoma cells.
AB  - Loss of E-cadherin (E-cad) triggers invasion, metastasis, and dedifferentiation
      in various epithelial carcinomas. Recently, it has been reported that two
      transcription factors, Snail and SIP1 (Smad interacting protein 1), directly
      repress transcription of the E-cad gene by binding E-box on E-cad promoter. Our
      aim is to solve the molecular mechanism of Snail and SIP1 in hepatocellular
      carcinoma (HCC). We first showed an inverse correlation between E-cad and
      Snail/SIP 1 expression among five HCC lines with different phenotypes. The result
      indicated that undifferentiated, but not differentiated type expressed
      Snail/SIP1. Then, we established transfectants stably expressing Snail and SIP1
      in two differentiated cells with E-cad expression. Suppressed expression of E
      cad, morphologic change into fibroblastoid feature, and remarkable acceleration
      of invasion activity were observed in the transfectants. In reverse transcription
      polymerase chain reaction series of genes relating to motility and invasion, we
      demonstrated striking evidence that matrix metalloproteinase (MMP-1), MMP-2, MMP
      7, and MT1-MMP expressions were strongly upregulated by Snail. On the other hand,
      MMP-1, MMP-2, and MT1-MMP expressions were enhanced by SIP1 transfection,
      however, the intensity was weaker than that in Snail transfection. In conclusion,
      Snail or SIP1 expression may be induced during HCC progression, where Snail/SIP1
      directly represses E-cad gene transcription and activates cancer invasion via the
      upregulation of the MMP gene family.

PMID- 15026812
TI  - Role of lipid-mobilising factor (LMF) in protecting tumour cells from oxidative
      damage.
AB  - Lipid-mobilising factor (LMF) is produced by cachexia-inducing tumours and is
      involved in the degradation of adipose tissue, with increased oxidation of the
      released fatty acids through an induction of uncoupling protein (UCP) expression.
      Since UCP-2 is thought to be involved in the detoxification of free radicals if
      LMF induced UCP-2 expression in tumour cells, it might attenuate free radical
      toxicity. As a model system we have used MAC13 tumour cells, which do not produce
      LMF. Addition of LMF caused a concentration-dependent increase in UCP-2
      expression, as determined by immunoblotting. This effect was attenuated by the
      beta3 antagonist SR59230A, suggesting that it was mediated through a beta3
      adrenoreceptor. Co-incubation of LMF with MAC13 cells reduced the growth
      inhibitory effects of bleomycin, paraquat and hydrogen peroxide, known to be free
      radical generators, but not chlorambucil, an alkylating agent. There was no
      effect of LMF alone on cellular proliferation. These results indicate that LMF
      antagonises the antiproliferative effect of agents working through a free radical
      mechanism, and may partly explain the unresponsiveness to the chemotherapy of
      cachexia-inducing tumours.

PMID- 15026815
TI  - PTHrP on MCF-7 breast cancer cells: a growth factor or an antimitogenic peptide?

PMID- 15026813
TI  - TNF autovaccination induces self anti-TNF antibodies and inhibits metastasis in a
      murine melanoma model.
AB  - TNF is a proinflammatory cytokine involved in the pathogenesis of chronic
      inflammatory diseases, but also in metastasis in certain types of cancer. In
      terms of therapy, TNF is targeted by anti-TNF neutralising monoclonal antibodies
      or soluble TNF receptors. Recently, a novel strategy based on the generation of
      self anti-TNF antibodies (TNF autovaccination) has been developed. We have
      previously shown that TNF autovaccination successfully generates high anti-TNF
      antibody titres, blocks TNF and ameliorates collagen-induced arthritis in DBA/1
      mice. In this study, we examined the ability of TNF autovaccination to generate
      anti-TNF antibody titres and block metastasis in the murine B16F10 melanoma
      model. We found that immunisation of C57BL/6 mice with TNF autovaccine produces a
      100-fold antibody response to TNF compared to immunisation with phosphate
      buffered saline vehicle control and significantly reduces both the number
      (P<0.01) and size of metastases (P<0.01) of B16F10 melanoma cells. This effect is
      also observed when an anti-TNF neutralising monoclonal antibody is administered,
      confirming the essential role TNF plays in metastasis in this model. This study
      suggests that TNF autovaccination is a cheaper and highly efficient alternative
      that can block TNF and reduce metastasis in vivo and trials with TNF
      autovaccination are already underway in patients with metastatic cancer.

PMID- 15026818
TI  - Metallosupramolecular squares: from structure to function.
AB  - Metallosupramolecular squares have been successfully evolved over the past years
      as versatile substitutes of the conventional organic macrocycles owing to the
      development of reliable synthetic protocols and abundant structural variability
      (metals and ligands). In this review we have presented the fundamental aspects of
      metallosupramolecular squares such as the strategies for their construction (self
      assembly vs. kinetically controlled macrocyclization) and characterization. The
      major emphasis of this tutorial review lies on the function of
      metallosupramolecular squares. Thus, the introduction of functionality into these
      systems has been discussed in detail by highlighting the recent progress toward
      application in various fields, including molecular recognition, enantioselective
      sensing, photoluminescence, redox activity and electrochemical sensing, and
      homogeneous catalysis.

PMID- 15026814
TI  - A modified p53 enhances apoptosis in sarcoma cell lines mediated by doxorubicin.
AB  - Mdm2 is frequently overexpressed in sarcoma cells and may contribute to drug
      resistance by increasing p53 degradation. We investigated the induction of
      apoptosis in sarcoma cells via adenovirus-mediated gene transfer of wild-type p53
      and two modified p53 genes, p53 14/19 and p53 22/23, whose protein products are
      resistant to Mdm2-mediated degradation. We found that adenovirus-wt p53 (Ad-wt
      p53) induces significant apoptosis in HT1080 fibrosarcoma cells expressing low
      levels of Mdm2, but fails to induce apoptosis in SJSA osteosarcoma cells
      expressing high levels of Mdm2. In contrast, Ad-p53 14/19 induces significant
      apoptosis in both cell lines. Interestingly, Ad-p53 22/23, a vector encoding a
      transcription-defective p53 mutant, causes limited apoptosis in both cell lines.
      We demonstrate that doxorubicin induces phosphorylation of both wt p53 and p53
      14/19 protein at multiple sites. We tested the efficacy of doxorubicin and
      cisplatin with either Ad-wt p53, Ad-p53 22/23 or Ad-p53 14/19. SJSA cells,
      although harbouring endogenous wt p53, did not undergo significant apoptosis
      following doxorubicin or cisplatin exposure alone or combined with Ad-wt p53. In
      contrast, doxorubicin or cisplatin plus Ad-p53 14/19 induced significant
      apoptosis. Gene transfer of p53 14/19 in combination with the administration of
      doxorubicin or cisplatin is a potential therapeutic approach for cancers
      expressing high levels of Mdm2.

PMID- 15026819
TI  - From ruthenium(II) to iridium(III): 15 years of triads based on bis-terpyridine
      complexes.
AB  - In order to mimic the photosynthetic reaction centre and better understand
      photoinduced electron transfer processes, a family of compounds has been studied
      for the past 15 years. These are transition metal complexes, M(tpy)(2) where tpy
      is a 2,2':6',2" terpyridine based ligand, bearing on one side a donor group and
      on the other side an acceptor group. The resulting triad molecules or their two
      component reference compounds (donor-M(tpy)(2) and M(tpy)(2-acceptor) can contain
      Ru, Os, Rh or Ir as the metal centre and both visible-light non absorbing groups
      and porphyrins as donor and acceptor groups. This tutorial review will briefly
      present the different systems studied and the reasons that led to the preparation
      of new systems with improved performances.

PMID- 15026820
TI  - Excitement in f block: structure, dynamics and function of nine-coordinate chiral
      lanthanide complexes in aqueous media.
AB  - Lanthanide complexation chemistry has been studied intensively over the past 15
      years and progress has been stimulated by the advent of well-defined, kinetically
      robust systems tailored to applications as bioactive probes for magnetic
      resonance and luminescence. In this tutorial review, the extent to which an
      enhanced understanding of the relationship between complex structure and spectral
      properties is emerging is discussed, together with an examination of the
      mechanism of ligand exchange processes. Such issues are aiding the development of
      responsive probes, ranging from simple sensors to more complex studies defining
      water structure and exchange dynamics.

PMID- 15026821
TI  - Imido-osmium(VIII) compounds in organic synthesis: aminohydroxylation and
      diamination reactions.
AB  - Imido complexes of osmium tetroxide are versatile compounds for olefin
      functionalisation. This tutorial review offers a brief historical overview on
      these compounds and discusses the electronic properties and reactivities of
      isolated imido osmium compounds in what had been the original stoichiometric
      aminohydroxylation reaction. The recently emerging catalytic Sharpless
      aminohydroxylation is discussed with special emphasis on mechanistic details. The
      final section deals with diamination of olefins, which relies on the chemistry of
      bisimido and trisimido osmium complexes.

PMID- 15026822
TI  - Elongated dihydrogen complexes: what remains of the H-H bond?
AB  - Of the several hundred examples of transition metal dihydrogen complexes that
      have been reported to date, the vast majority have H-H distances of less than 1.0
      Angstrom. A small number of complexes have been reported with distances in the
      range of 1.1 to 1.5 Angstrom. These complexes have been termed elongated
      dihydrogen complexes. In this review, experimental methods for structure
      determination of such complexes are summarized, along with computational
      approaches which have proven useful in understanding the structures of these
      molecules.

PMID- 15026823
TI  - Ruthenium-catalysed carbenoid cyclopropanation reactions with diazo compounds.
AB  - The transition-metal catalysed cyclopropanation of olefinic bonds using diazo
      compounds as a carbene source is among the best developed and most useful
      transformations available to the synthetic organic chemist. Nevertheless, the
      quest for new catalyst/ligand systems continues in order to further extend the
      scope of this method and to identify more economical catalytic systems. In this
      tutorial review, several different ruthenium complexes are presented which have
      recently emerged as suitable catalysts for carbenoid cyclopropanation. For the
      model reaction--cyclopropanation of styrene(s) with diazoacetates--and also for
      some intramolecular cyclopropanation reactions highly remarkable results in terms
      of catalyst efficiency, product yields, dia- and enantioselectivity have been
      reported.

PMID- 15026825
TI  - Proceedings of the 4th International Workshop on Biosignal Interpretation (BSI
      2002).

PMID- 15026824
TI  - Metal ion complexes of antivirally active nucleotide analogues. Conclusions
      regarding their biological action.
AB  - Acyclic nucleoside phosphonates (ANPs), i.e., analogues of (2'-deoxy)nucleoside
      5'-monophosphates, have been studied during the past 15 years for their potential
      as antiviral drugs. One of these compounds, 9-[2-(phosphonomethoxy)ethyl]adenine
      (PMEA; Adefovir) was recently approved in the form of its
      bis(pivaloyloxymethyl)ester (Adefovir dipivoxil) for use in hepatitis B therapy,
      a disease evoked by a DNA virus. Diphosphorylated PMEA(2-), i.e., PMEApp(4-), is
      initially recognized by nucleic acid polymerases as an excellent substrate, but
      after insertion in the growing nucleic acid chain, this is terminated due to the
      lack of a 3'-hydroxy group. Based on the metal ion-binding properties of PMEApp(4
      ) it can be explained why the ether oxygen in the aliphatic chain, R-CH(2)-O
      CH(2)-PO(3)pp(4-), is compulsory for a useful biological activity. Consequently,
      this critical review presents an overview on the coordination chemistry of
      various ANPs and correlates this to their biological properties.

PMID- 15026826
TI  - Marker identification and classification of cancer types using gene expression
      data and SIMCA.
AB  - OBJECTIVES: High-throughput technologies are radically boosting the understanding
      of living systems, thus creating enormous opportunities to elucidate the
      biological processes of cells in different physiological states. In particular,
      the application of DNA micro-arrays to monitor expression profiles from tumor
      cells is improving cancer analysis to levels that classical methods have been
      unable to reach. However, molecular diagnostics based on expression profiling
      requires addressing computational issues as the overwhelming number of variables
      and the complex, multi-class nature of tumor samples. Thus, the objective of the
      present research has been the development of a computational procedure for
      feature extraction and classification of gene expression data. METHODS: The Soft
      Independent Modeling of Class Analogy (SIMCA) approach has been implemented in a
      data mining scheme, which allows the identification of those genes that are most
      likely to confer robust and accurate classification of samples from multiple
      tumor types. RESULTS: The proposed method has been tested on two different
      microarray data sets, namely Golub's analysis of acute human leukemia and the
      small round blue cell tumors study presented by Khan et al.. The identified
      features represent a rational and dimensionally reduced base for understanding
      the biology of diseases, defining targets of therapeutic intervention, and
      developing diagnostic tools for classification of pathological states.
      CONCLUSIONS: The analysis of the SIMCA model residuals allows the identification
      of specific phenotype markers. At the same time, the class analogy approach
      provides the assignment to multiple classes, such as different pathological
      conditions or tissue samples, for previously unseen instances.

PMID- 15026827
TI  - A sequential method for discovering probabilistic motifs in proteins.
AB  - OBJECTIVES: This paper proposes a greedy algorithm for learning a mixture of
      motifs model through likelihood maximization, in order to discover common
      substrings, known as motifs, from a given collection of related biosequences.
      METHODS: The approach sequentially adds a new motif component to a mixture model
      by performing a combined scheme of global and local search for appropriately
      initializing the component parameters. A hierarchical clustering scheme is also
      applied initially which leads to the identification of candidate motif models and
      speeds up the global searching procedure. RESULTS: The performance of the
      proposed algorithm has been studied in both artificial and real biological
      datasets. In comparison with the well-known MEME approach, the algorithm is
      advantageous since it identifies motifs with significant conservation and
      produces larger protein fingerprints. CONCLUSION: The proposed greedy algorithm
      constitutes a promising approach for discovering multiple probabilistic motifs in
      biological sequences. By using an effective incremental mixture modeling
      strategy, our technique manages to successfully overcome the limitation of the
      MEME scheme which erases motif occurrences each time a new motif is discovered.

PMID- 15026828
TI  - Averaging signals with random time shift and time scale fluctuations.
AB  - OBJECTIVES: Our main objective was to propose an alternative to the technique of
      signal averaging (SA) to avoid shape distortions due to jittering and scale
      fluctuations, leading to a mean shape signal rather than to an average one.
      METHODS: In case of both time shift and time scale fluctuations of the individual
      signals, the first point was to show what model makes it possible to interpret
      their expected action as a linear shift invariant filter followed by a scale
      invariant one. So, even in the case of equal shape signals, the average is
      clearly not the same shape. The second point was to propose another averaging
      process, using the normalized integrals and called Shape Averaging (ShA) which
      provides, in this case, a mean signal preserving the common shape. RESULTS: The
      performances of ShA were firstly shown by simulation. Shifted and scaled versions
      of a given signal, without and with additive noise, have been generated at
      random. The mean shape signal obtained by ShA was compared to the shifted and
      scaled signal using the exact average values of the shifts and scale factors. A
      very good reconstruction of the mean shape signal is obtained for SNR = 20 dB and
      quite good for 8 dB, especially compared to SA. The method was then applied to a
      series of M-waves coming from surface EMG signals. In this case, the comparison
      of ShA with SA makes it possible to appreciate the validity of equal shape signal
      hypothesis.

PMID- 15026829
TI  - Automatic decomposition of Wigner distribution and its application to heart rate
      variability.
AB  - OBJECTIVE: We introduce an algorithm for the automatic decomposition of Wigner
      Distribution (WD) and we applied it for the quantitative extraction of Heart Rate
      Variability (HRV) spectral parameters during non-stationary events. Early
      response to tilt was investigated. METHODS: Quantitative analysis of multi
      components non-stationary signals is obtained through an automatic decomposition
      of WD based on least square (LS) fitting of the instantaneous autocorrelation
      function (ACF). Through this approach the different signal and interference terms
      which contributes to the ACF may be separated and their parameters (instantaneous
      frequency and amplitude) quantified. A beat-to-beat monitoring of HRV spectral
      components is obtained. RESULTS: Analysis of simulated signals demonstrated the
      capability of the proposed approach to track and separate the signal components.
      Analysis of HRV data evidenced different dynamics in the early Autonomic Nervous
      System (ANS) response to tilt. CONCLUSIONS: The novel approach to the
      quantification of the beat-to-beat HRV spectral parameters obtained from
      decomposition of Wigner distribution was demonstrated to be effective in the
      analysis of HRV data. Relevant physiological information about the dynamics of
      the early sympathetic response to tilt were obtained. The method is a general
      approach which may be employed for a quantitative time-frequency analysis of non
      stationary biological signals.

PMID- 15026830
TI  - Estimating respiratory pattern variability by symbolic dynamics.
AB  - OBJECTIVES: The traditional techniques of data analysis are often not sufficient
      to characterize the complex dynamics of respiration. In this study the
      respiratory pattern variability was analyzed using symbolic dynamics. METHODS: A
      group of 20 patients on weaning trials from mechanical ventilation were studied
      at two different pressure support ventilation levels. Breath duration (T(TOT))
      time series and the relation T(I)/T(TOT), that contains the influence of
      inspiratory time (T(I)), were considered. Length-3 words and 3 different symbols
      were proposed. The incidence of the overlapping tau and the parameter alpha were
      analyzed. RESULTS: From the breath duration time series, the distribution of
      words with probability of occurrence higher than 6% was concentrated on one word
      for low respiratory variability, whereas high variability was characterized by 4
      words, presenting a statistically significant difference (p </= 0.0005). The
      probability occurrence of words "110" and "111" was also significantly different
      (p</= 0.0005) when comparing both variabilities. CONCLUSION: The analysis carried
      out obtained discriminant functions able to correctly classify all the testing
      set series. These results permit the consideration of symbolic dynamics as a
      promising methodology to study the respiratory pattern variability.

PMID- 15026831
TI  - Decreased fractal correlation in diurnal physical activity in chronic fatigue
      syndrome.
AB  - OBJECTIVES: Our objectives were to study the temporal correlation of physical
      activity time series in patients with chronic fatigue syndrome (CFS) during
      normal daily life and to examine if it could identify the altered physical
      activity in these patients. METHODS: Fractal scaling exponents of diurnal and
      nocturnal physical activity time series in 10 CFS patients and 6 healthy control
      subjects (CON) were calculated by the detrended fluctuation analysis (DFA) and
      the wavelet transform modulus maxima (WTMM) method. We hypothesized that, due to
      their illness- and/or fatigue-induced resting episodes, altered physical activity
      patterns in CFS patients might be observed at the interruption of activity
      bursts. Thus, we further developed a new method, the wavelet transform negative
      modulus maxima (WTNMM) method, which could evaluate the temporal correlation at
      the interruption of activities. We compared the fractal scaling exponents for CFS
      and CON by each method. RESULTS: Both for CFS and CON, we found the fractal time
      structures in their diurnal physical activity records for at least up to 35
      minutes. No group difference was found in nocturnal activities. The WTNMM method
      revealed that, in diurnal activities, CFS patients had significantly (p < 0.01)
      smaller fractal scaling exponent (0.87 +/- 0.03) compared to controls (1.01 +/-
      0.03). Such a difference was identified neither by the DFA nor WTMM method.
      CONCLUSIONS: CFS patients had more abrupt interruptions of voluntary physical
      activity during diurnal periods in normal daily life, probed by the decreased
      correlation in the negative modulus maxima of the wavelet-transformed activity
      data, possibly due to their exaggerated fatigue.

PMID- 15026832
TI  - Surface EMG crosstalk evaluated from experimental recordings and simulated
      signals. Reflections on crosstalk interpretation, quantification and reduction.
AB  - OBJECTIVES: Surface EMG crosstalk is the EMG signal detected over a non-active
      muscle and generated by a nearby muscle. The aim of this study was to analyze the
      sources of crosstalk signals in surface EMG recordings and to discuss methods
      proposed in the literature for crosstalk quantification and reduction. METHODS:
      The study is based on both simulated and experimental signals. The simulated
      signals are generated by a structure based surface EMG signal model. Signals were
      recorded with both intramuscular and surface electrodes and single motor unit
      surface potentials were extracted with the spike triggered averaging approach.
      Moreover, surface EMG signals were recorded from electrically stimulated muscles.
      RESULTS: From the simulation and experimental analysis it was clear that the main
      determinants of crosstalk are non-propagating signal components, generated by the
      extinction of the intracellular action potentials at the tendons. Thus, crosstalk
      signals have a different shape with respect to the signals detected over the
      active muscle and contain high frequency components. CONCLUSIONS: Since crosstalk
      has signal components different from those dominant in case of detection from
      near sources, commonly used methods to quantify and reduce crosstalk, such as the
      cross-correlation coefficient and high-pass temporal filtering, are not reliable.
      Selectivity of detection systems must be discussed separately as selectivity with
      respect to propagating and non-propagating signal components. The knowledge about
      the origin of crosstalk signal constitutes the basis for crosstalk
      interpretation, quantification, and reduction.

PMID- 15026833
TI  - Analysis of vocal tract characteristics for near-term suicidal risk assessment.
AB  - OBJECTIVES: Among the many clinical decisions that psychiatrists must make,
      assessment of a patient's risk of committing suicide is definitely among the most
      important, complex and demanding. One of the authors reviewing his clinical
      experience observed that successful predictions of suicidality were often based
      on the patient's voice independent of content. The voices of suicidal patients
      exhibited unique qualities, which distinguished them from non-suicidal patients.
      In this study we investigated the discriminating power of lower order mel
      cepstral coefficients among suicidal, major depressed, and non-suicidal patients.
      METHODS: Our sample consisted of 10 near-term suicidal patients, 10 major
      depressed patients, and 10 non-depressed control subjects. Gaussian mixtures were
      employed to model the class distributions of the extracted features. RESULTS AND
      CONCLUSIONS: As a result of two-sample ML classification analyses, first four mel
      cepstral coefficients yielded exceptional classification performance with correct
      classification scores of 80% between near-term suicidal patients and non
      depressed controls, 75% between depressed patients and non-depressed controls,
      and 80% between near-term suicidal patients and depressed patients.

PMID- 15026834
TI  - Effects of subthreshold shocks on wavelet propagation during atrial fibrillation
      in humans.
AB  - OBJECTIVES: Our objectives are: first to investigate the effects of internal
      cardioversion energies on the wave fronts propagation in the right atrium
      immediately after the energy delivery; second, to track the time course of these
      effects. METHODS: The study is based on a measure of organization of the
      endoatrial electrograms obtained by a multipolar basket catheter inserted in the
      right atrium. We estimated the level of organization by computing the percentage
      of points laying on the signal baseline (i.e., number of occurrences, NO). NO
      values were computed on two-second long windows. Six non-overlapped windows were
      selected, one just before and five just after the last unsuccessful shock.
      RESULTS: Immediately after the shock most of the patients exhibited an increase
      in the organization patterns. This increase was more evident in those patients
      with rather disorganized patterns and higher energy threshold. This effect fades
      within a few seconds after the shock delivery. CONCLUSIONS: Our data confirm the
      idea that the electrical shock causes a widespread extinction of electrical
      wavefronts, which regenerates after the shock. Since an increase of organization
      may lead to a reduction of energy threshold, a potential application of these
      findings might consist in the delivery of multiple subthreshold shocks instead of
      a single one.

PMID- 15026835
TI  - Time course of ECG depolarization and repolarization changes during ischemia in
      PTCA recordings.
AB  - OBJECTIVES: In this work we studied the temporal evolution of changes in the
      electrocardiogram (ECG) as a consequence of the induced ischemia during prolonged
      coronary angioplasty, comparing the time course of indexes reflecting
      depolarization and those reflecting repolarization. METHODS: We considered both
      local (measured at specific points of the ECG) and global (obtained from the
      Karhunen-Loeve transform) indexes. In particular, the evolution of Q, R and S
      wave amplitudes during ischemia was analyzed with respect to classical indexes
      such as ST level. As a measurement of sensitivity we used an Ischemic Changes
      Sensor (ICS), which reflects the capacity of an index to detect changes in the
      ECG. RESULTS: The results showed that, in leads with low-amplitude ST-T
      complexes, the S wave amplitude was more sensitive in detecting ischemia than was
      the commonly used index ST60. It was found that in such leads the S wave
      amplitude initially exhibited a delayed response to ischemia when compared to
      ST60, but its performance was better from the second minute of occlusion. The
      global indexes describing the ST-T complex were, in terms of the ICS, superior to
      the S wave amplitude for ischemia detection. CONCLUSIONS: Ischemic ECG changes
      occur both at repolarization and depolarization, with alterations in the
      depolarization period appearing later in time. Local indexes are less sensitive
      to ischemia than global ones.

PMID- 15026836
TI  - Fetal heart rate variability due to vibroacoustic stimulation: linear and
      nonlinear contribution.
AB  - OBJECTIVES: This work aims at characterizing the variation of fetal heart rate
      (FHR) provoked by vibroacoustic stimulation (VAS). The FHR signal is analyzed by
      means of a multiparametric approach consisting of linear and nonlinear indices.
      METHODS: The FHR signals of 13 fetuses were collected through a US standard CTG
      monitor (HP1351A) and were sampled at a frequency of 2 Hz. The VAS was provided
      after a period of quiet of 10 minutes. The analysis was performed on the quiet
      period and on two successive time windows of 10 minutes each, after the
      stimulation. FHR classical parameters (delta, short term variability, long term
      irregularity, accelerations and decelerations) as well as power spectral density
      (PSD) and approximate entropy (ApEn) were computed for each period. RESULTS:
      Results confirm that there is a significant change in fetal conditions after the
      stimulus is applied. This change can be clearly observed either in time domain
      parameters and in the regularity index (ApEn). Individual data are all consistent
      with an increase of variability and a decrease of regularity after VAS.
      CONCLUSIONS: The obtained results give further strength to the hypothesis that
      vibratory stimuli tests represent a reliable method for monitoring the neural
      development of the fetus during pregnancy.

PMID- 15026837
TI  - A theoretical appraisal of the dependence of respiratory sinus arrhythmia on
      gradual vagal blockade.
AB  - MOTIVATION: The high frequency (HF) indices of heart rate variability (HRV),
      which reflect the magnitude of respiratory sinus arrhythmia (RSA), have been
      repeatedly used as measures of cardiac vagal tone. Recent studies, however, have
      shown experimentally that variations in these indices do not necessarily reflect
      proportional changes in cardiac parasympathetic outflow. OBJECTIVE: The goal of
      this study was to obtain a physiological-based theoretical evaluation of the
      relationship between RSA and cardiac vagal tone, which will help explain
      conflicting experimental results previously published. METHODS: We derived a
      theoretical model for heart rate (HR) response to gradual vagal blockade. The
      model implements the integral-pulse-frequency-modulation (IPFM) approach to
      sinoatrial (SA) node physiology. The level of vagal blockade was simulated by the
      addition of a cardio-selective muscarinic antagonist. RESULTS AND CONCLUSION: The
      derivations of the model lead to a closed set of equations, from which the
      dependence of the HF indices on the level of vagal blockade is deduced. It is
      shown that several aspects of the physiological condition may have a substantial
      effect on this relationship: the level of baseline vagal activity, the
      relationship between vagal tone and the fluctuations in its traffic, the level of
      sympathetic activity, etc em leader Hence, changes in the HF indices of HRV
      provide a plausible assessment of the changes in cardiac vagal tone only under a
      specific range of physiological conditions.

PMID- 15026838
TI  - ECG analysis for sleep apnea detection.
AB  - OBJECTIVES: The objective of our study was to find out whether obstructive sleep
      apnea (OSA) may be detected on ECGs recorded during sleep. METHODS: We have
      analyzed 70 eight-hour single-channel ECG recordings taken at polysomnographia.
      The 70 data sets were annotated for definition of regular sleep and phases with
      sleep apnea. From the 70 data sets, 35 have been used as a learning set. Our
      analysis is based on spectral components of heart rate variability. Frequency
      analysis was performed using Fourier and wavelet transformation with appropriate
      application of the Hilbert transform. Classification is based on four frequency
      bands: ULF band (0-0.013 Hz), VLF band (0.013-0.0375 Hz), LF band (0.0375-0.06
      Hz) and the HF band (0.17-0.28 Hz). Linear discriminant functions were applied
      using mainly spectral components derived from the records. Classification of
      cases was based on three variables. RESULTS: For the Testing Set, a sensitivity
      (Se) for apnea of 92.3% at a specificity (Sp) of 94.6% was achieved. For the
      minutes allocation on the Learning Set Se was 90.8% at Sp 92.7%. CONCLUSION: ECG
      analysis is useful for the detection of sleep apnea and may help to differentiate
      causes of cardiac arrhythmias.

PMID- 15026839
TI  - Assessment of cardiovascular autonomic control by the empirical mode
      decomposition.
AB  - OBJECTIVES: Heart-rate variability (HRV) is an interesting tool for assessing
      cardiac autonomic system control, but nonstationarities raise problematic issues.
      The objective of this paper is to show that adapted signal processing tools may
      cope with nonstationary situations and improve the analysis of HRV. METHODS: We
      propose to use the recent method of Empirical Mode Decomposition (EMD), so as to
      analyze the cardiac sympatho-vagal balance on automatically extracted modes. The
      method, which is fully data-adaptive, consists in an iterative decomposition
      based on the idea that any signal can be locally represented as an oscillation
      superimposed to a more regular trend. When a signal is composed of distinct
      nonstationary components, EMD therefore achieves a time-varying filtering which
      effectively separates them. RESULTS: The method has been applied to situations
      where postural changes occur, provoking instantaneous changes in heart rate as a
      result of autonomic modifications. In the considered application where the
      sympatho-vagal balance is quantified by comparing the low-frequency (LF) and high
      frequency (HF) components of RR intervals, EMD automatically achieves a
      separation of these components upon which further processing can be carried.
      Visualizing the decomposition in the time-frequency plane, we can identify local
      events due to the postural changes, and we can assess a (time-varying) HF vs. LF
      discrimination without resorting to some fixed high-pass/low-pass filtering.
      CONCLUSION: Assessing cardiovascular autonomic control by resorting to LF/HF
      measurements may prove difficult in nonstationary situations where the use of a
      priori fixed filters can be questioned. Because it is both local and fully data
      adaptive, EMD appears as an appealing and versatile pre-processing technique for
      overcoming some of the limitations that conventional spectral methods are faced
      with in nonstationary situations.

PMID- 15026840
TI  - Cortical potential imaging of brain electrical activity by means of parametric
      projection filter.
AB  - OBJECTIVES: The objective of this study was to explore suitable spatial filters
      for inverse estimation of cortical potentials from the scalp
      electroencephalogram. The effect of incorporating noise covariance into inverse
      procedures was examined by computer simulations and tested in human experiment.
      METHODS: The parametric projection filter, which allows inverse estimation with
      the presence of information on the noise, was applied to an inhomogeneous three
      concentric-sphere model under various noise conditions in order to estimate the
      cortical potentials from the scalp potentials. The method for determining the
      optimum regularization parameter, which can be applied for parametric inverse
      techniques, is also discussed. RESULTS: Human visual evoked potential experiment
      was carried out to examine the performance of the proposed restoration method.
      The parametric projection filter gave more localized inverse solution of cortical
      potential distribution than the truncated SVD and Tikhonov regularization.
      CONCLUSION: The present simulation results suggest that incorporation of
      information on the noise covariance allows better estimation of cortical
      potentials, than inverse solutions without knowledge about the noise covariance,
      when the correlation between the signal and noise is low.

PMID- 15026841
TI  - Time-frequency analysis of brain electrical activity--adaptive approximations.
AB  - OBJECTIVES: We present an approach to time-frequency analysis of bioelectrical
      signals. METHODS: The method relays on the decomposition of the signal into a set
      of waveforms that have good localization both in time and in frequency. The
      waveforms belong to a highly redundant set of functions - allowing for a very
      accurate description of signal components. RESULTS: Properties of the method are
      illustrated by simulations and applications to EEG. CONCLUSION: The presented
      method delivers a common formalism suitable for describing both gross statistical
      properties of structures present in bioelectrical signals, as well as
      microstructure of chosen phenomena.

PMID- 15026842
TI  - Independent component analysis compared to Laplacian filtering as "deblurring"
      techniques for event related desynchronization/synchronization.
AB  - OBJECTIVES: The aim of the work was to compare two different approaches - one
      model-dependent, the other data-dependent - for "deblurring" EEG data, in order
      to improve the estimation of Event-Related Desynchronization/Synchronization.
      METHODS: Realistic Surface Laplacian filtering (SL) and Infomax Independent
      Component Analysis (ICA) were applied on multivariate scalp EEG signals (SL: 128
      electrodes with MRI-based realistic modeling; ICA: a subset of 19 electrodes, no
      MRI) prior to beta Event Related Synchronization (ERS) estimation after finger
      movement in 8 normal subjects. ERS estimation was performed using standard band
      pass filtering. ERS peak amplitudes and latencies in the most responsive channel
      were calculated and the effect of the two methods above was evaluated by one-way
      analysis of variance (ANOVA) and Sheffe's test. RESULTS: Both methods and their
      combination significantly improved ERS estimation (greater ERS peak amplitude, p
      <0.05). The results obtained after ICA on 19 electrodes were not significantly
      different than the ones obtained with Realistic SL using 128 electrodes and MRI
      for scalp modeling (p >0.89). CONCLUSIONS: The "low cost" of ICA (19 electrodes,
      no MRI) imposes such method as a valid alternative to SL filtering. The employ of
      ICA after SL filtering suggests that the "ideal EEG deblurring method" would
      unify the two approaches, depending on both the scalp model and the data.

PMID- 15026843
TI  - Inclusion of signal analysis in a hybrid medical decision support system.
AB  - OBJECTIVES: Signal analysis has played an important role in cardiac diagnosis,
      both as a separate entity and in conjunction with clinical parameters. Hybrid
      systems are an effective method for developing higher-order decision models in
      which biomedical signal data can be incorporated. METHODS: The hybrid system
      components include a knowledge-based system that utilizes approximate reasoning
      techniques, a neural network model based on a potential function approach to
      supervised learning that uses the general class of Cohen orthogonal functions as
      potential functions, and a signal analysis component that relies on continuous
      chaotic modeling to produce a degree of variability in the time series. The
      hybrid system is illustrated in an application for differentiation among
      different types of dementia. RESULTS: Application of this method to cardiac
      diagnosis shows that chaotic parameters alone contribute significantly to correct
      classification while the addition of clinical parameters increases the
      sensitivity, specificity, and accuracy. Applications to electroencephalogram
      analysis indicate that the second-order difference plots display significant
      differences for the different types of EEG waves identifiable by frequency, both
      in shape and degree of dispersion. Hence the identification of these waves, and
      the duration of their occurrence, may provide suitable variables for chaotic
      analysis. CONCLUSIONS: Results from studies in cardiology demonstrate that using
      chaotic measures for ECG analysis provide useful information for classification.
      Sensitivity, specificity, and accuracy are increased if these methods are
      combined with other clinical parameters in a hybrid system. This approach has
      been extended to new applications based on EEG analysis combined with other
      relevant information.

PMID- 15026844
TI  - EuCliD--a medical registry.
AB  - OBJECTIVES: The European Clinical Database EuCliD small star, filled has been
      developed as a tool for supervising selected quality indicators of about 200
      European dialysis centers. Major efforts had to be made to comply with local and
      European laws regarding data security. METHOD: EuCliD is a Lotus Notes based flat
      file database currently containing medical data of more than 14,000 dialysis
      patients from 10 European countries. Another 15,000 patients from 150 centers in
      4 South-American countries will be added soon. Data are entered either manually
      or by means of interfaces to existing local data managing systems. This
      information is transferred to a central Lotus Notes Server. Data evaluation was
      performed with statistical tools like SPSS. RESULTS: EuCliD is used as a part of
      the CQI (Continuous Quality Improvement) management system of Fresenius Medical
      Care (FMC) dialysis units. Each participating dialysis center receives (currently
      every half year) benchmarking reports at a regular interval. The benchmark for
      all quality parameters is the weighted mean of the corresponding data of all
      centers. CONCLUSIONS: An obvious impact of data sampling and data evaluation on
      the quality of the treatments could be observed within the first one and a half
      years of working with EuCliD. This also concerns important outcome predictors
      like Kt/V and hemoglobin concentration as the outcome itself expressed in
      hospitalization days and survival rates. With the help of EuCliD the user is able
      to sample clinical data, identify problems, search for solutions with the aim of
      improving the dialysis treatment quality and guarantee a high-class treatment
      quality for all patients.

PMID- 15026845
TI  - A nonlinear circuit architecture for magnetoencephalographic signal analysis.
AB  - OBJECTIVES: The objective of this paper was to face the complex spatio-temporal
      dynamics shown by Magnetoencephalography (MEG) data by applying a nonlinear
      distributed approach for the Blind Sources Separation. The effort was to
      characterize and differ-entiate the phases of a yogic respiratory exercise used
      in the treatment of obsessive compulsive disorders. METHODS: The patient
      performed a precise respiratory protocol, at one breath per minute for 31
      minutes, with 10 minutes resting phase before and after. The two steps of
      classical Independent Component Approach have been performed by using a Cellular
      Neural Network with two sets of templates. The choice of the couple of suitable
      templates has been carried out using genetic algorithm optimization techniques.
      RESULTS: Performing BSS with a nonlinear distributed approach, the outputs of the
      CNN have been compared to the ICA ones. In all the protocol phases, the main
      components founded with CNN have similar trends compared with that ones obtained
      with ICA. Moreover, using this distributed approach, a spatial location has been
      associated to each component. CONCLUSIONS: To underline the spatio-temporal and
      the nonlinearly of the neural process a distributed nonlinear architecture has
      been proposed. This strategy has been designed in order to overcome the
      hypothesis of linear combination among the sources signals, that is
      characteristic of the ICA approach, taking advantage of the spatial information.

PMID- 15026846
TI  - Automatic Paroxysmal Atrial Fibrillation Based on not Fibrillating ECGs.
AB  - OBJECTIVES: The objective of the paper is to describe an automatic algorithm for
      Paroxysmal Atrial Fibrillation (PAF) Detection, based on parameters extracted
      from ECG traces with no atrial fibrillation episode. The modular automatic
      classification algorithm for PAF diagnosis is developed and evaluated with
      different parameter configurations. METHODS: The database used in this study was
      provided by Physiobank for The Computers in Cardiology Challenge 2001. Each ECG
      file in this database was translated into a 48 parameter vector. The modular
      classification algorithm used for PAF diagnosis was based on the nearest K
      neighbours. Several configuration options were evaluated to optimize the
      classification performance. RESULTS: Different configurations of the proposed
      modular classification algorithm were tested. The uni-parametric approach
      achieved a top classification rate value of 76%. A multi-parametric approach was
      configured using the 5 parameters with highest discrimination power, and a top
      classification rate of 80% was achieved; different functions to typify the
      parameters were tested. Finally, two automatic parametric scanning strategies,
      Forward and Backward methods, were adopted. The results obtained with these
      approaches achieved a top classification rate of 92%. CONCLUSIONS: A modular
      classification algorithm based on the nearest K-neighbours was designed. The
      classification performance of the algorithm was evaluated using different
      parameter configurations, typification functions and number of K-neighbors. The
      automatic parametric scanning techniques achieved much better results than
      previously tested configurations.

PMID- 15026847
TI  - Nonlinear dynamics of respiratory patterns during maturation.
AB  - OBJECTIVES: In this paper, we quantify the fractal scaling characteristics of
      phrenic neurograms during eupnea in piglets, the output of the respiratory neural
      network that accompany maturation We also attempt to investigate whether the
      fractal properties are altered with maturation. METHODS: The phrenic neurogram in
      piglets was recorded from the C5 phrenic nerve during eupnea at four postnatal
      ages; the 3-6 days, the 7-14 days, 15-21 days and the 26-31 days age groups and
      analyzed using the maximum likelihood estimator (MLE). RESULTS: Our results
      suggest that the mean fractal measures over a recording of five consecutive
      breaths during eupnea for each piglet in each group were higher during the first
      6 days and slightly decreased for the 7-14 days and significantly decreased for
      the 15-21 days and significantly increased for subsequent maturation (the 26-31
      days old group). CONCLUSIONS: We suggest that there is a significant alteration
      in the fractal organization in piglet respiratory patterns during maturation and
      a decrease in the fractal value is unique to the 15-21 days old group.

PMID- 15026848
TI  - Hydrophobicity analysis of protein primary structures to identify helical
      regions.
AB  - OBJECTIVES: A wavelet based approach for the hydrophobicity analysis of protein
      primary structures is proposed to predict the presence of alpha helices in the
      secondary structure. METHODS: The information about hydropathy profile
      periodicity content together with a score of probability of occurrence of a
      single amino acid allows the localization of alpha helices. RESULTS: The accuracy
      is comparable to other consolidated predictors based on different techniques
      (i.e.: neural networks, hidden markov models). CONCLUSION: This method is
      particularly suitable to capture the amphiphilic character of the helical
      structures.

PMID- 15026849
TI  - Prediction of cardiovascular risk in hemodialysis patients by data mining.
AB  - OBJECTIVES: The objective of this work was to contribute to the development,
      validation and application of data mining methods for prediction in decision
      support systems in medicine. The particular focus was on the prediction of
      cardiovascular risk factors in hemodialysis patients, specifically the
      interventricular septum (IVS) thickness of the heart of individual patients as an
      important quantitative indicator to diagnose left ventricular hypertrophy. The
      work was based on data from 63 long-term hemodialysis patients of the KfH
      Dialysis Centre in Jena, Germany. METHODS: The approach applied is based on data
      mining methods and involves four major steps: data based clustering, cluster
      based rule extraction, rulebase construction and cluster and rule based
      prediction. The methods employed include crisp and fuzzy algorithms. At each
      step, logical and medical validation of results was carried out. Different sets
      of randomly selected patient data were used to train, test and optimize the
      clusterbases and rulebases for prediction. RESULTS: Using the best
      clusterbase/rulebase combination designed, the IVS thickness cluster ('small' or
      'large') was predicted correctly for 30 of the 35 patients with known IVS values
      in the training data set; no patient was predicted incorrectly and 5 were parity
      predicted. For the test data set, 4 of the 6 patients with known IVS values were
      predicted correctly, no patient incorrectly and 2 parity. These results did not
      substantially differ from those obtained using the second best
      clusterbase/rulebase combination which was finally recommended for use based on
      further performance criteria. The prediction of the IVS thickness clusters of the
      22 patients with unknown IVS values also yielded good results that were (and
      could only be) validated by a medical individual risk assessment of these
      patients. CONCLUSIONS: The approach applied proved successful for the cluster and
      rule based prediction of a quantitative variable, such as IVS thickness, for
      individual patients from other variables relevant to the problem. The results
      obtained demonstrate the high potential of the approach and the methods developed
      and validated to support decision-making in hemodialysis and other fields of
      medicine by individual risk prediction.

PMID- 15026851
TI  - Characterization of heart rate variability changes following asphyxia in rats.
AB  - OBJECTIVES: A non-invasive method to monitor the functioning of the autonomous
      nervous system consists in heart rate variability (HRV) analysis. The aim of this
      study was to investigate the changes on HRV after an asphyxia experiment in rats,
      using several linear (time and frequency domain) and nonlinear parameters
      (approximate entropy, SD1 and SD2 indices derived from Poincare plots). METHODS:
      The experiments involved the study of HRV changes after cardiac arrest (CA)
      resulting from 5 min of hypoxia and asphyxia, followed by manual resuscitation
      and return of spontaneous circulation. 5 min stationary periods of RR intervals
      were selected for further analysis from 5 rats in following distinct situations:
      1) baseline, 2) 30 min after CA, 3) 60 min after CA, 4) 90 min after CA, 5) 120
      min after CA, 6) 150 min after CA. The ANS contribution has been delineated based
      on time and frequency domain analysis. RESULTS AND CONCLUSIONS: The results
      indicate that the recovery process following the asphyxia cardiac arrest reflects
      the impaired functioning of the autonomic nervous system. Both linear and
      nonlinear parameters track the different phases of the experiment, with an
      increased sensitivity displayed by the approximate entropy (ApEn). After 150 min
      the ApEn RRI parameter recovers to its baseline value. The results forward the
      ApEn as a more sensitive parameter of the recovery process following the
      asphyxia.

PMID- 15026850
TI  - EEG deblurring techniques in a clinical context.
AB  - OBJECTIVES: EEG scalp potential distributions recorded in humans are affected by
      low spatial resolution and by the dependence on the electrical reference used.
      High resolution EEG technologies are available to drastically increase the
      spatial resolution of the raw EEG. Such technologies include the computation of
      surface Laplacian (SL) of the recorded potentials, as well as the use of
      realistic head models to estimate the cortical sources via linear inverse
      procedure (low resolution brain electromagnetic tomography, LORETA). However,
      these deblurring procedures are generally used in conjunction with EEG recordings
      with 64-128 scalp electrodes and with realistic head models obtained via
      sequential magnetic resonance images (MRIs) of the subjects. Such recording setup
      it is not often available in the clinical context, due to both the unavailability
      of these technologies and the scarce compliance of the patients with them. In
      this study we addressed the use of SL and LORETA deblurring techniques to analyze
      data from a standard 10-20 system (19 electrodes) in a group of Alzheimer disease
      (AD) patients. METHODS: EEG data related to unilateral finger movements were
      gathered from 10 patients affected by AD. SL and LORETA techniques were applied
      for source estimation of EEG data. The use of MRIs for the construction of head
      models was avoided by using the quasi-realistic head model of the Brain Imaging
      Neurology Institute of Montreal. RESULTS: A similar cortical activity estimated
      by the SL and LORETA techniques was observed during an identical time period of
      the acquired EEG data in the examined population. CONCLUSIONS: The results of the
      present study suggest that both SL and LORETA approaches can be usefully applied
      in the clinical context, by using quasi-realistic head modeling and a standard 10
      20 system as electrode montage (19 electrodes). These results represent a
      reciprocal cross-validation of the two mathematically independent techniques in a
      clinical environment.

PMID- 15026852
TI  - Chronic obstructive lung disease: from structure to pathology.
AB  - Chronic obstructive pulmonary disease (COPD) is a complex disease characterized
      by progressive and irreversible airway obstruction and ubiquitous chronic
      inflammation in the lung. It is the end result of accumulated damage to many
      parts of the lung by many types of noxious agents, a destructive exhaustion of
      the lung reserve. Recent increases in the incidence of COPD have occurred mainly
      in older age groups, in non-smokers, and in females. Pathologically, COPD is
      characterized by chronic inflammation which perpetuates and accumulates locally.
      Discrete areas interact with each other, in the locus resistentia minoris (LRM),
      the sites of weak resistance of the lung, suggesting that insidious destruction
      with exhaustion of pulmonary reserves is still the main culprit of COPD.
      Traditional treatments of COPD are useful in symptomatic control but do not
      prevent progression of the disease. Prevention is still the best way to manage
      COPD. New pharmaceutical agents and bioengineered products using molecular or
      genetic techniques to block inflammatory mediators or their receptors may contain
      the inflammatory and noxious agents in the LRM and prevent their propagation.
      Methodologies involving structural approaches, such as devices to estimate the
      status of airways and associated vessels and the remaining lung reserve, creation
      of collateral or bypass ventilation pathways, and reduction of volume of over
      inflated areas may be effective. The balance between exposure and clearance,
      injury and repair, ultimately decides how quickly the great reserves of the lung
      are depleted.

PMID- 15026853
TI  - Natural history and risk stratification of discrete subaortic stenosis in
      children: an echocardiographic study.
AB  - BACKGROUND AND PURPOSE: Discrete subaortic stenosis (DSS) is considered an
      acquired cardiac defect. However, its clinical course and pathogenesis have not
      been well defined. This study used echocardiography to investigate the natural
      history of DSS and identify the possible anatomic abnormalities leading to its
      development. METHODS: We reviewed the medical records of 12 children with a
      diagnosis of DSS between 1988 and 2002. Data on the age at initial diagnosis of
      DSS was collected and the sequential changes of left ventricular outflow tract
      obstruction (LVOTO) and aortic regurgitation (AR) were analyzed by serial
      echocardiographic studies. Patients were divided into 2 subgroups according to
      the latest or presurgical (in patients with operations for DSS) Doppler-derived
      peak instantaneous left ventricular outflow tract gradient (deltaP; cut-off
      point: deltaP 50 mm Hg, our institutional criterion of operation for DSS). The
      indexed mitral valve (MV)-aortic valve (AV) distance, aortoseptal angle (ASA),
      indexed DSS-AV distance, and whether the anterior MV leaflet was involved were
      also determined. The DSS patients were compared with an age- and lesion-matched
      control group (12 patients). RESULTS: The mean age at initial diagnosis of DSS
      was 4.9 +/- 3.7 years. Nine children had disease characterized by milder LVOTO
      (latest deltaP < 50 mm Hg) and slower progression of LVOTO (mean increase of
      deltaP, 7.1 +/- 4.4 mm Hg/year) and AR (</= grade I), while 3 children had
      disease characterized by more severe LVOTO (presurgical deltaP > 50 mm Hg) and
      more rapid progression of LVOTO (mean increase of deltaP, 27.8 +/- 8.4 mm
      Hg/year) and AR (>/= grade II). Compared with the control group, the study group
      had a significantly longer indexed MV-AV distance and a steeper ASA. Compared
      with the patients with milder disease, patients with more severe disease had a
      significantly shorter indexed DSS-AV distance and more frequent involvement of
      the anterior MV leaflet. CONCLUSIONS: These data indicate that DSS may present
      with 2 distinct clinical courses. A shorter indexed DSS-AV distance and the
      involvement of the anterior MV leaflet might be predictive of more rapidly
      progressive DSS. Longer indexed MV-AV distance and steeper ASA might be useful to
      evaluate primary cardiac defects and thus to identify patients who are at risk
      for developing DSS.

PMID- 15026854
TI  - Developmental function of very-low-birth-weight infants and full-term infants in
      early childhood.
AB  - BACKGROUND AND PURPOSE: Despite general recognition that surviving very-low-birth
      weight (VLBW) infants are at risk for neurodevelopmental impairments and
      educational achievement difficulties, there has been relatively little study on
      their functional status in areas such as locomotion, communication, cognition,
      self-care, and interpersonal relationships. This study assessed the functional
      status of VLBW infants and full-term infants in early childhood, and sought to
      identify risk factors for functional morbidity. METHODS: A total of 238 VLBW
      infants and 91 full-term infants were included in this prospective follow-up
      study. The functional status of the infants was assessed using the Chinese Child
      Development Inventory (CCDI) and neurodevelopment was evaluated using the Bayley
      Scales of Infant Development, second version (BSID-II) at 3 years of corrected
      age. Perinatal and sociodemographic data were collected through review of medical
      records. RESULTS: The VLBW infants had lower scores on all the CCDI measures
      compared with the full-term infants. Functional limitation (defined as more than
      2 standard deviations below the means of the full-term infants) occurred more
      frequently in the VLBW infants than in the full-term infants: gross motor, 23% vs
      3%; fine motor, 12% vs 1%; expressive language, 21% vs 2%; comprehension
      conceptual, 23% vs 4%; situation comprehension, 17% vs 4%; self-help, 17% vs 1%;
      and personal-social, 19% vs 3% (all p < 0.01). Significant risk factors
      associated with functional morbidity included gestational age < 30 weeks, grade
      III-IV intraventricular hemorrhage, chronic lung disease, stage III-IV
      retinopathy of prematurity, male gender, and maternal education below high
      school. CONCLUSION: VLBW infants have a higher risk of functional morbidity than
      their full-term counterparts in early childhood. Infants with functional
      limitations on CCDI screening might require comprehensive developmental
      assessment and continued follow-up.

PMID- 15026856
TI  - Congenital nasal pyriform aperture stenosis and single central maxillary incisor:
      preoperative evaluation with three-dimensional computed tomography.
AB  - BACKGROUND AND PURPOSE: Congenital nasal pyriform aperture stenosis (CNPAS) is an
      uncommon cause of nasal airway obstruction in neonates and infants. It is
      frequently associated with a single central maxillary incisor (SCMI). The purpose
      of this study was to assess whether 3-dimensional spiral computed tomography (3D
      spiral CT) could be used for the diagnosis of CNPAS and for detecting SCMI in
      CNPAS patients before tooth eruption. METHODS: From January 1996 to December
      2001, 16 patients (mean age, 2 +/- 3 months) with clinically suspected CNPAS and
      13 normal control subjects (mean age, 28 +/- 32 months) were studied
      prospectively by 3D spiral CT. On the 3D CT image of each subject, the middle
      pyriform aperture width (MPAW), upper 1/4 PA width (UPAW), and middle internasal
      process width (MINPW) were measured. In addition, the ratios of MINPW to MPAW and
      of MINPW to UPAW were calculated. SCMI was identified as a bigger tooth with
      singular convexity. RESULTS: SCMI was diagnosed in 11 of the 16 CNPAS patients.
      In the CNPAS patient group, the mean MINPW (5 +/- 1 mm) was significantly shorter
      than the mean MPAW (9 +/- 1 mm) and the mean UPAW (8 +/- 1 mm) [p < 0.001].
      However, in the normal control group, the mean UPAW (13 +/- 2 mm) was
      significantly shorter than the mean MPAW (16 +/- 3 mm) and the mean MINPW (16 +/-
      3 mm) [p < 0.01]. In the CNPAS patients, the mean ratios of both MINPW to MPAW
      (0.5 +/- 0.1) and of MINPW to UPAW (0.6 +/- 0.1) were significantly lower than
      the corresponding mean ratios in the normal control subjects (1.0 +/- 0.1 and 1.3
      +/- 0.2, respectively; both p < 0.001). CONCLUSION: Our results indicate that
      CNPAS is frequently associated with a SCMI and CNPAS patients have a significant
      reduction in the MINPW and in the ratios of MINPW to MPAW and of MINPW to UPAW.
      We conclude that 3D spiral CT can be used for diagnosis of CNPAS and for
      detecting SCMI in CNPAS patients before tooth eruption.

PMID- 15026855
TI  - Molecular epidemiology and control of nosocomial methicillin-resistant
      Staphylococcus aureus infection in a teaching hospital.
AB  - BACKGROUND AND PURPOSE: Nosocomial methicillin-resistant Staphylococcus aureus
      (MRSA) infection is difficult to control. Due to a dramatic increase in the
      nosocomial MRSA infection rate at our hospital from 2000 to 2001, this study was
      conducted to identify the source of these infections and the effectiveness of
      control measures. METHODS: 179 healthcare workers (HCWs) were screened for
      carriage of MRSA. Starting in April 2001, all patients with MRSA infection or
      colonization were put in strict contact and cohort isolation. The bacterial
      isolates of HCW carriers and patients with MRSA infection from April 2001 to
      September 2001 were subjected to antimicrobial susceptibility testing by disk
      diffusion method and molecular typing by pulsed-field gel electrophoresis (PFGE).
      RESULTS: Fifteen HCWs were found to be carriers of MRSA. They were all given
      topical mupirocin treatment. After these interventions, the nosocomial MRSA
      infection rate decreased from 1.23 to 0.53 per 1000 patient-days. All 61 MRSA
      isolates available for antimicrobial susceptibility testing and molecular typing
      were multidrug resistant. PFGE study revealed 2 predominant types, type C and
      type Y, comprising 36 and 12 isolates, respectively. CONCLUSIONS: The current
      study demonstrates the importance of measures to control nosocomial MRSA
      infections in hospitals that already have a high incidence of endemic MRSA
      infection. Elimination of carriage by healthcare workers, and strict contact and
      cohort isolation are the main effective measures.

PMID- 15026857
TI  - Lymphoscintigraphy and intraoperative gamma probe-directed sentinel lymph node
      mapping in patients with malignant melanoma.
AB  - BACKGROUND AND PURPOSE: Lymphoscintigraphy has been considered a useful tool for
      sentinel lymph node (SLN) mapping for malignant melanoma. This study evaluated
      the usefulness of SLN detection by lymphoscintigraphy and excision with
      intraoperative gamma probe in Taiwanese patients with malignant melanoma.
      METHODS: Thirty six malignant melanoma patients in clinical stage I and II were
      enrolled. The Breslow thickness of the primary melanomas was </= 1.0 mm in 8
      patients, 1.01 to 2.0 mm in 12 patients, 2.01 to 4.0 mm in 9 patients, >/= 4 mm
      in 3 patients, and unknown in 4 patients who were transferred from other
      hospitals and had no nodal or distant metastasis. SLN lymphoscintigraphy was
      performed with filtered 99mTc-sulfur colloid. An intraoperative gamma probe was
      used to identify the SLN for dissection. RESULTS: A total of 44 SLNs were
      detected in 36 patients, with a mean of 1.22 SLNs per patient. The SLN detection
      rate by lymphoscintigraphy was 100%. During surgery, 39 of the 44 SLNs (88.6%) in
      33 of 36 patients (91.7%) were identified. SLN metastasis was found in 8 of 39
      dissected SLNs (20.5%) or in 8 of 36 patients (22.2%). The SLN metastatic rate in
      the patients with primary melanoma with Breslow thickness </= 2.0 mm was 10.0%
      (2/20), and in patients with Breslow thickness > 2.0 mm was 41.7% (5/12).
      CONCLUSIONS: Lymphoscintigraphy and intraoperative gamma probe are useful in
      localizing and dissecting SLN in patients with malignant melanoma. SLN mapping
      changed the clinical stage in 22.2% of melanoma patients.

PMID- 15026858
TI  - Effect of a systematic discharge nursing plan on mothers' knowledge and
      confidence in caring for infants with congenital heart disease at home.
AB  - BACKGROUND AND PURPOSE: Mothers who are separated from their infants due to the
      necessity of surgical treatment for congenital heart disease (CHD) may develop
      lack of confidence in their ability to care for their infant. This research
      developed a systematic discharge nursing plan (SDNP) for mothers to care for
      their infants with CHD and evaluated the effects of this plan on maternal
      knowledge and confidence in caring for their infant with CHD at home. METHODS: A
      quasi-experimental design was adopted for the study. Subjects were recruited by
      purposive sampling from mothers who had a hospitalized infant with CHD aged from
      0 to 6 months. There were 20 mothers in the control group and 15 mothers in the
      intervention group. Control group subjects received current nursing instruction
      and were followed at the outpatient department after discharge of the infant from
      the hospital whereas the intervention group completed the SDNP in addition to
      current nursing instruction. Evaluations of these 2 groups based on the mother's
      knowledge of infant care and confidence to provide adequate care were conducted
      twice, at 1 week and 1 month after the infant's discharge from the hospital.
      RESULTS: The intervention group had better confidence than the control group at 1
      week and 1 month after the infants' discharge (p < 0.05). There was no
      significant difference of improvement in knowledge of infant care score between
      the 2 groups. No significant relation was found between knowledge of infant care
      and maternal confidence. CONCLUSIONS: This research showed that an SDNP improved
      maternal confidence in caring for an infant with CHD. Thus, an SDNP may be a
      valuable part of standard clinical practice in caring for infants with CHD.

PMID- 15026859
TI  - Nosocomial infection of Aeromonas hydrophila presenting as necrotizing fasciitis.
AB  - Aeromonas hydrophila is infrequently reported as a causative organism of
      necrotizing fasciitis. We report a case of necrotizing fasciitis due to A.
      hydrophila in a 44-year-old man with Marfan syndrome who underwent valve
      replacement surgery twice. He was admitted due to a 2-day history of fever. The
      fever was attributed to hepatitis, and ingestion of herbal medication was
      suspected to be the cause. The fever relapsed on the 28th day of hospitalization
      with rapidly progressive erythematous patches on the bilateral lower extremities.
      Septic shock developed within a few hours, and 2 small diagnostic incisions on
      the skin lesions suggested necrotizing fasciitis. Surgical exploration further
      revealed extensive necrosis of the subcutaneous tissue and fascia, but the muscle
      was spared. Blood cultures and cultures of the debrided tissue all yielded A.
      hydrophila. Pathological examination showed necrosis and degeneration of the soft
      tissue. Although appropriately managed with broad-spectrum antibiotics,
      fasciotomies and debridement, the patient's condition deteriorated rapidly and
      resulted in death 11 hours after the surgery. This case indicates that A.
      hydrophila can be a causative organism of nosocomial necrotizing fasciitis.

PMID- 15026860
TI  - Symptomatic granular cell tumor of the neurohypophysis.
AB  - Symptomatic granular cell tumors of the neurohypophysis or infundibulum are very
      rare neoplasms which are difficult to diagnose before operation. We report a case
      of symptomatic granular cell tumor of the neurohypophysis in a 36-year-old woman
      who had suffered from amenorrhea and general malaise for more than 1 year. No
      definite visual or neurological deficit was found. Laboratory examination
      revealed hyperprolactinemia and decrease of other pituitary hormones. T1-weighted
      magnetic resonance imaging (MRI) revealed an isointense sellar mass with
      suprasellar extension. Transsphenoidal subtotal tumor removal was performed and
      pathological examination revealed a granular cell tumor of the neurohypophysis
      composed of densely packed polygonal cells with abundant eosinophilic, granular
      cytoplasm. The granules were periodic acid-Schiff-positive and diastase
      resistant. Immunohistochemical study showed positive reaction for S-100 protein
      and antitrypsin antibodies. Electron microscopic examination showed numerous
      lysosomes in the cytoplasm of tumor cells. The postoperative MRI showed the
      residual tumor to be just behind the pituitary stalk and that the tumor should
      arise from the posterior lobe of the pituitary gland. The postoperative course
      was smooth and there were no sequelae during 30 months of regular follow-up. We
      believe surgery remains the treatment of choice and even partial removal of the
      tumor may benefit the patient.

PMID- 15026861
TI  - Follicular mucinosis occurring after bone marrow transplantation in a patient
      with acute lymphoblastic leukemia.
AB  - Follicular mucinosis (FM) is characterized histologically by mucinous
      degeneration of the outer root sheath of the hair follicle and sebaceous gland,
      accompanied by inflammatory infiltrate. It can occur as a primary idiopathic
      disorder or in association with benign or malignant diseases, most notably
      mycosis fungoides. In addition, it also can be found incidentally on histology.
      We describe an unusual case of follicular mucinosis in a 19-year-old man with
      acute lymphoblastic leukemia (ALL). One month after bone marrow transplantation,
      he developed cutaneous graft-versus-host disease (GVHD) involving the palms and
      soles, which was followed 12 days later by the appearance of multiple
      erythematous follicular papules and plaques on his face, auricles, and
      postauricular area. Biopsy of follicular plaque revealed changes of follicular
      mucinosis without evidence of graft-versus-host disease or leukemia cutis. The
      follicular rash was associated with prominent peripheral eosinophilia. The rash
      and eosinophilia resolved after 2 and 4 weeks, respectively. In conclusion, we
      report a case of FM occurring as a transient reaction during the course of
      cutaneous GVHD following bone marrow transplantation for ALL. Awareness of this
      condition may avoid undue concern that the rash might represent a manifestation
      of GVHD, cutaneous relapse of the hematological malignancy, or a drug allergy.

PMID- 15026862
TI  - Use of extracorporeal membrane oxygenation to rescue a newborn with early-onset
      group B streptococcal sepsis and cardiopulmonary failure.
AB  - Group B streptococcal (GBS) infection is an important cause of perinatal
      morbidity and mortality. We report the use of extracorporeal membrane oxygenation
      (ECMO) to rescue a newborn with refractory GBS sepsis and meningitis who
      developed cardiopulmonary failure. This 2-day-old infant weighed 2640 g and was
      born to a healthy mother at full term. Respiratory distress, hypotension, and
      persistent pulmonary hypertension developed on the second day of life. The
      clinical condition deteriorated rapidly despite conventional treatment, and
      venoarterial ECMO was established to rescue this moribund newborn. During ECMO,
      the patient regained stable hemodynamics and good oxygenation, and infection was
      controlled. ECMO was used for 90 hours and the baby was weaned smoothly.
      Neurologic assessment after ECMO revealed hydrocephalus, abnormal
      electroencephalogram, and increased brain auditory evoked potential threshold.
      This report emphasizes that ECMO may be considered to rescue neonatal patients
      with cardiopulmonary failure due to GBS sepsis. Possible neurologic complications
      after ECMO should be carefully monitored.

PMID- 15026863
TI  - Denys-Drash syndrome.
AB  - We report a case of Denys-Drash syndrome, a disorder characterized by male
      pseudohermaphroditism, congenital nephrotic syndrome, and early renal failure.
      The patient received dialysis therapy from 15 days of age until his death at the
      age of 6 months. DNA analysis was performed on the WT1 gene, and a missense point
      mutation was detected in exon 8 (R366H). After prenatal confirmation of normal
      WT1 gene in the family's next child, they had a healthy baby 14 months after the
      patient's death.

PMID- 15026864
TI  - Spinal cord stimulation in the treatment of peripheral vascular disease: results
      of a single-center study of 258 patients.
AB  - This report is of a retrospective study of data from 258 patients who received
      spinal cord stimulation (SCS) for the treatment of peripheral vascular disease as
      a result of arteriosclerosis. The patients' clinical outcomes were monitored over
      a period of 18 months. In patients with a low baseline transcutaneous oxygen
      pressure (TcPO(2)) value of <10 mm Hg, limb survival at 18 months of follow-up
      (estimated by use of Kaplan-Meier survival analysis) was 77.8%, and this was even
      higher, at 89.5%, in patients with a medium baseline TcPO(2) value of 10-30 mm
      Hg. This successful treatment was accompanied by a sustained increase in TcPO(2)
      values to approximately 30 mm Hg in both of these groups. In looking at diabetic
      and nondiabetic patients, there is no difference in limb survival as a result of
      the treatment. It is concluded that SCS is an effective therapy in improving limb
      survival in patients with peripheral vascular disease. In addition, TcPO(2)
      values at baseline may be a useful predictor of treatment outcome.

PMID- 15026865
TI  - Time-resolved contrast-enhanced magnetic resonance angiography of the lower
      extremity.
AB  - The aim of this prospective study was to evaluate the feasibility and clinical
      use of time-resolved magnetic resonance angiography (MRA) of the lower extremity
      compared to intraarterial digital subtraction angiography (IA-DSA). Twenty-two
      patients suffering from peripheral arterial occlusive disease underwent MRA and
      IA-DSA. MRA examinations were performed on a 1.5 T system equipped with a 4
      element-array coil. The area from the distal abdominal aorta to the distal lower
      limb was covered by 2-3 examination steps. A T1-weighted gradient echo sequence
      with a temporal resolution of 7-10 s was used. Single-dose contrast material (0.1
      mm/kg) was injected with a flow rate of 2 mL/s, followed by a 40 mL saline flush.
      Pre and post contrast images were subtracted, and the subtracted data set was
      postprocessed with maximum intensity projection (MIP). In all patients diagnostic
      images could be obtained. Problems with venous overlay or incomplete arterial
      filling were not present. Sensitivity for the detection of relevant stenoses
      (>50%) was 96.7%, specificity was 97%. Concerning the detection of occlusions,
      sensitivity was 97.8%, specificity was 99.2%. Time-resolved contrast-enhanced MRA
      of the lower extremity is a robust procedure with high accuracy in the detection
      of relevant stenoses and occlusions.

PMID- 15026866
TI  - Validation of a new method of detecting peripheral artery disease by
      determination of ankle-brachial index using an automatic blood pressure device.
AB  - Peripheral artery disease (PAD) is a predictor of total and cardiovascular
      mortality; its most valuable simple index is the ankle-brachial index (ABI). The
      present study was designed to assess whether a commercially available automatic
      device could be used to determine ABI in comparison with the classical Doppler
      method. The ABI was defined as the ratio of systolic blood pressure at each ankle
      to the maximal brachial systolic pressure, a pathological index being defined for
      a ratio <0.90. The ABI were calculated in 219 consecutive patients (aged 55 +/-19
      years) with systolic blood pressure measured either by using a mercury sphygmo
      manometer and a continuous-wave Doppler probe or an automatic manometer Omron M4.
      This device has been validated for measurements in upper limbs, and so the
      authors undertook validation in the lower limbs versus intraarterial
      measurements. There was an excellent correlation between intraarterial
      measurements and automatic readings in the range of 70-220 mm Hg, r=0.99,
      p<0.001. The systolic pressures measured in upper limbs correlated well in the
      right (r=0.87, p<0.001) and the left (r=0.89, p<0.001) upper limbs; and in the
      left (r=0.72, p<0.001) and the right (r=0.68, p<0.001) lower limbs. Correlations
      between ABI in both methods were good in the left (r=0.66, p<0.001) and the right
      (r=0.61, p<0.001) lower limbs. The sensitivity (76%), specificity (95%), positive
      predictive value (86%), negative predictive value (90%), and global accuracy
      (89%) of a pathological automatic index to predict an abnormal Doppler index were
      good. The use of a simple, automatic blood pressure device to determine ABI
      appears feasible, easy, and precise. It would provide a practical tool for
      physicians not trained in Doppler to detect PAD.

PMID- 15026867
TI  - Dyslipoproteinemia and peripheral arterial occlusive disease.
AB  - Peripheral arterial occlusive disease (PAOD) is common in older age. PAOD is
      associated with an increased risk of vascular events (eg, myocardial infarction
      or stroke). Therefore, the prevention and treatment of PAOD is important,
      especially at a time when the elderly population is increasing. There is an
      association between lipid abnormalities and the risk of developing PAOD. However,
      it is not yet definitively established that early intervention with lipid
      lowering drugs prevents the development of PAOD. There is evidence that vascular
      events in patients with PAOD can be significantly reduced by statins and that the
      symptoms associated with PAOD are improved by this treatment. There is an urgent
      need for appropriately designed lipid-lowering trials in patients with PAOD.

PMID- 15026868
TI  - Large-artery hemodynamics after acute alcohol administration in young, healthy
      volunteers.
AB  - The objective of the present study was to investigate the acute effects of
      alcohol on blood flow volume and velocity, on wall motion of superficial large
      arteries, and on systemic hemodynamics in humans. In 10 healthy volunteers small
      doses of alcohol were administered either orally (0.3 g/kg in 250 mL water) or
      intravenously (7.5 mg/kg/minute in 250 mL saline in 40 minutes). The effects of
      alcohol were compared with those of saline 250 mL infused for 40 minutes (6.25
      mL/min). Blood velocity and systodiastolic changes of wall diameter were measured
      in the common carotid, femoral, and brachial arteries simultaneously with cardiac
      output and finger blood pressure. Skin temperature was measured at the cheek,
      hand, and toe. Ethanol administration caused a transitory blood pressure increase
      accompanied by a rise in peripheral resistances at 20 minutes. Arterial blood
      flow was not changed by either mode of alcohol administration at any of the
      measurement sites. However, this result was achieved through different
      compensatory mechanisms in each artery. In fact, mean carotid diameter increased
      after both oral and intravenous ethanol administration but remained unchanged at
      the brachial and femoral level. Mean blood velocity was reduced after alcohol
      administration at the carotid but was unchanged at the brachial and femoral level
      after oral or intravenous alcohol administration. Skin temperature increased 20
      minutes after alcohol administration at all sites. This study shows that although
      acute alcohol administration does not change blood flow in superficial large
      arteries, it causes different autoregulatory local responses of vessel walls.

PMID- 15026869
TI  - Calcium dobesilate for chronic venous insufficiency: a systematic review.
AB  - Chronic venous insufficiency (CVI) causes much discomfort and sick leave. Many
      randomized clinical trials (RCTs) have shown a beneficial effect of calcium
      dobesilate, but consensus is lacking about efficacy and safety. The authors
      report a meta-analysis of the effectiveness and safety of calcium dobesilate in
      CVI. Ten RCTs (778 patients) in which calcium dobesilate for CVI was compared
      with placebo met the inclusion criteria. Only 3 trials (608 patients) were of
      good methodological quality. Calcium dobesilate significantly improved night
      cramps and discomfort nearly twice as well as placebo, with the number needed to
      treat (NNT) being 8 (95% CI 4-50) and 4 (95% CI 3-7), respectively. Frequency of
      adverse events was not significantly different from placebo. Subgroup analysis
      found a differential response with respect to disease severity, with greater
      improvements in pain, heaviness, and malleolar swelling being seen in the severe
      group than in the mild group. Calcium dobesilate improved paresthesias
      significantly more than placebo in the severe but not in the mild group and the
      effect on leg volume was also significantly better in the severe group (-7.2% vs 
      1.6%). No difference in effect was found for different doses of calcium
      dobesilate (1,000 or 1,500 mg/day). Sensitivity analyses did not affect the
      results. Current evidence suggests that calcium dobesilate is more effective than
      placebo in improving some CVI symptoms, that there is higher efficacy in more
      severe disease, and that a dose of 1,000 mg/day is as effective and safe as 1,500
      mg/day. Further adequately powered trials are needed to further evaluate these
      hypotheses.

PMID- 15026870
TI  - Sex difference in the effect of ACE-DD genotype on the risk of premature
      myocardial infarction.
AB  - In this association study the authors compared the insertion/deletion (I/D)
      angiotensin-I converting enzyme (ACE) gene polymorphism in females and males with
      premature myocardial infarction (MI). I/D ACE gene polymorphism was tested in 738
      subjects: 302 patients with MI (151 men and 151 women) and 436 healthy subjects
      (207 men and 229 women). In women the ACE-DD genotype was not associated with MI
      (OR 1.1, 95% CI 0.6-2.1, p=0.6), whereas the ACE-DD genotype conferred a 2-fold
      independent risk for MI in men (95% CI=1.2-3.4; p=0.013) after adjustment for
      cardiovascular risk factors. The authors found evidence for the sex difference in
      the effect of the ACE-DD genotype on MI risk. The ACE-DD genotype conferred a 2
      fold independent risk for premature MI in males.

PMID- 15026872
TI  - Angiographic and long-term outcomes of "rescue" stenting versus PTCA in failed
      thrombolysis in acute myocardial infarction.
AB  - Percutaneous transluminal coronary angioplasty (PTCA), when performed early after
      clinically failed thrombolysis, improves acute infarct-artery patency in up to
      90% of cases. Limited data are available regarding the role of rescue stenting in
      this setting. From January 1995 to December 1999, the authors studied all
      consecutive patients treated with rescue PTCA or rescue stenting within 12 hours
      of onset of chest pain and clinically failed thrombolytic therapy at their
      institution. Baseline demographic characteristics, infarct-related artery
      location, lesion class, left ventricular function, and incidence of multivessel
      disease were similar between groups (23 patients in each group). Preprocedural
      TIMI flow 0 was more common in PTCA patients (p=0.025). Quantitative coronary
      analysis revealed similar incidence of calcification, thrombus burden, minimal
      lumen diameter (MLD), and lesion length between groups. Post-procedural TIMI 3
      flow was more common in stent patients; however, this was not statistically
      significant (p=0.18). Greater final MLD (p<0.001), less residual stenosis
      (p<0.001), and a trend toward larger reference vessel diameter (p=0.13) were
      observed in favor of stent patients. At 6-month follow-up, there was no
      difference in the incidence of death, myocardial infarction, or readmission for
      unstable angina between groups. More stent patients (60% vs 27%, p=0.06) were
      angina free as compared to PTCA patients. Despite similar in-hospital clinical
      outcomes, the study suggests better angiographic results and 6-month orbidity
      with rescue stenting.

PMID- 15026871
TI  - Effects of afterload increase on systolic and diastolic functions of the
      myocardium after myocardial infarction.
AB  - The evaluation of noninfarcted zone function after myocardial infarction by the
      use of noninvasive methods is very important. The authors speculated that
      phenylephrine, which increases systemic vascular resistance and blood pressure
      and has no effect on central ischemic and border-zone myocardium but does have an
      effect on remote myocardium, could be used as a stress agent as information is
      gathered about the functional capacity of the left ventricle and the status of
      coronary arteries in patients with recent myocardial infarction. Forty-six
      patients with recent myocardial infarction (5 women, 41 men; mean age: 53.6 +/
      9.3 years) and 15 individuals with normal findings from coronary angiography and
      ventriculography (9 women and 6 men; mean age: 39.0 +/-11.2 years) were included
      in the study. The study was performed on the 4th or 5th day of the myocardial
      infarction. Preejection period/left ventricular ejection time (PEP/LVET),
      diastolic mitral flow velocity, isovolumic relaxation time (IVRT), and
      deceleration time (DT), were measured before and after the phenylephrine
      infusion, with M-mode, pulse wave, and continuous-wave echocardiography. After
      pressor stress with phenylephrine infusion, all the parameters were measured
      again. Coronary angiography and ventriculography were performed on all the
      patients on the 7th to 10th day of the myocardial infarction. All the patients
      were grouped according to their ejection fraction and the number of involved
      coronary arteries. The increase in the PEP/LVET ratio in Group 1 (left ventricle
      ejection fraction [EF] below 40%) and multivessel coronary artery lesion group
      was significant (p<0.01). PEP/LVET ratio decreased significantly in both Group C
      (patients with normal-appearing coronary arteries and ventriculographies) and the
      single-vessel coronary disease group. Although the early diastole flow/atrial
      systole flow (E/A) ratio increased significantly in the 3 groups, the 0.5 and
      more increase in E/A ratio had high sensitivity (86%) and specificity (80%) in
      differentiating the low EF group. The 0.5 and more increase in E/A ratio had 65%
      sensitivity and 69% specificity in differentiating the multivessel coronary
      stenosis group. A deceleration time of 130 msec and below in basal conditions had
      a high sensitivity (86%) and specificity (92%) for detecting the group in which
      EF was below 40%. After phenylephrine infusion, the shortening of IVRT was
      significant in Group 1 (p<0.01). Phenylephrine, which has been shown to be an
      alpha-1 receptor agonist in low doses and effective only on remote myocardial
      function, may be given with low complication rates in the early postinfarction
      period. The increase in PEP/LVET ratio, 0.5 and more increase in E/A ratio, and
      shortening of DT and IVRT after phenylephrine infusion may be indicators of low
      LV functional capacity and widespread coronary artery disease. This test may
      suggest performance of early invasive detection of coronary artery disease and
      early revascularization. This study may also be interesting from a
      pathophysiological point of view.

PMID- 15026873
TI  - Prospective evaluation of von Willebrand factor release after multiple and single
      stenting.
AB  - The hypothesis that von Willebrand factor (vWf) release after multiple coronary
      stenting may be higher than release after single coronary stenting was tested.
      Preliminary data suggest that multiple stenting is a predictor of thrombosis, and
      vWf levels in the coronary sinus reflect coronary endothelial injury. Therefore
      vWf as an indicator of thrombogenesis and endothelial injury was studied. vWf
      levels were obtained in the coronary sinus at the prestenting and poststenting
      period in 50 patients with ischemic heart disease who underwent elective coronary
      stenting (25 patients in single stent group and 25 patients in multiple stent
      group). Eight subjects who underwent diagnostic coronary angiography were used as
      controls. vWf levels increased significantly after multiple stenting and vWf
      levels were significantly different from vWf levels after single stenting. In
      single stent group, vWf levels in type C lesions were significantly different
      from levels detected in type A and B lesions. Multiple coronary stenting induces
      a rapid increase in vWf expression in the coronary circulation. These changes may
      contribute to the pathogenesis of acute or subacute stent thrombosis and
      restenosis after multiple stenting.

PMID- 15026874
TI  - An epidemiologic study of acute coronary syndromes in northwestern Greece.
AB  - Acute coronary syndromes (ACS) represent the most common cause of morbidity and
      mortality in the Western world. Relative epidemiologic data for Greece, a
      Mediterranean country, are sparse. The aim of the study was to determine the
      incidence and the clinical presentations of ACS. Over a 1-year period we
      conducted a prospective, population-based survey of ACS cases in an isolated area
      of northwestern (NW) Greece with 170,000 inhabitants. Every patient living in the
      study area, aged <80 years, without history of coronary artery disease, who
      presented with symptoms suspicious for ACS and was hospitalized for at least 24
      hours was eligible for inclusion in the study. For sudden cardiac deaths,
      relative information was obtained from the autopsy report or the physician who
      documented death. Additional information regarding timing and associated
      conditions was obtained from relatives. The diagnosis and classification of the
      studied cases was performed according to World Health Organization and European
      Society of Cardiology criteria. The authors identified 352 patients (265 men, 87
      women, mean age 62.5 +/-10 and 68 +/-9.5 years, respectively) with first-appeared
      ACS (174 non-ST elevation, 105 ST elevation, 73 sudden cardiac deaths). Fifty-six
      patients with other forms of ischemic heart disease (stable angina, heart
      failure, and silent ischemia) were not included in the analysis. Moreover, 154
      patients with chest pain and normal appearing EGG at rest, normal values for
      enzymes (CK, troponin), and negative exercise testing, as well as 77 patients
      with normal findings from coronary angiography studies, were also excluded. The
      annual incidence for the age group of 30-79 was 39/10,000 inhabitants (60.6 for
      men and 19 for women). The incidence of ACS increased with age in both sexes and
      was higher in men even after the age of 70. About one third of the ACS and half
      of the sudden cardiac deaths occurred in the age group of 70-79. Only 3 patients
      were successfully resuscitated. ACS are common in this area of NW Greece and the
      majority of them present in a form amenable to therapeutic manipulations. Twenty
      percent of patients died suddenly, and a very small percentage of these were
      successfully resuscitated. Preventive measures and acute management facilities
      need to be improved, even in a Mediterranean country where the incidence of
      ischemic heart disease is relatively lower than in northern European countries.

PMID- 15026875
TI  - Effects of AT1 receptor antagonist losartan on sICAM-1 and TNF-alpha levels in
      uncomplicated hypertensive patients.
AB  - This study was designed to determine whether the levels of soluble intercellular
      adhesion molecule-1 (sICAM-1) and tumor necrosis factor-alpha (TNF-alpha) were
      elevated in subjects with uncomplicated hypertension who presented with no other
      risk factors or evidence of athero-sclerosis. The effects of administration of an
      angiotensin type-1 antagonist (losartan) on the serum concentrations of these
      molecules were also examined. Twenty hypertensive (HT) subjects (12 men and 8
      women, mean age 49.1 +/-7.2 years) without other risk factors or cardiovascular
      disease received placebo for 4 weeks. The patients were then treated with
      losartan (50 mg/day) for 24 weeks. After 4, 12, and 24 weeks of losartan
      treatment, sICAM-1 and TNF-alpha levels were measured. The same parameters were
      measured in 20 normotensive control subjects (C), matched for sex and age. HT had
      sICAM-1 and TNF-alpha basal values higher than C (respectively 351.7 +/-97.4 vs
      201.6 +/-32.3 ng/mL, p<0.001 and 31.8 +/-2.4 vs 15.3 +/-2.2 pg/mL, p<0.001).
      There was a positive correlation between sICAM-1 and TNF-alpha levels, but no
      correlation in HT between the average diastolic and systolic blood pressure
      (clinic and ambulatory monitoring) and the sICAM-1 or TNF-alpha levels was
      observed. Losartan treatment caused a significant decrease of sICAM-1 levels at
      the end of the first month of treatment (300.2 +/-64.4 ng/mL, p<0.05), but the
      values reverted to the basal levels at the following time points. No variation of
      TNF-alpha levels during losartan treatment was observed. These results show that
      patients with uncomplicated mild essential hypertension presented with high
      plasma ICAM-1 and TNF-alpha concentrations. Although all the patients were
      responsive to the antihypertensive treatment with losartan, their plasma
      concentrations of TNF-alpha were not modified, and sICAM-1 concentrations
      decreased only for a short period of time. This suggests that in uncomplicated
      hypertension other factors besides the blood pressure modulate the endothelial
      inflammation.

PMID- 15026876
TI  - Successful intervention for high-output cardiac failure caused by massive renal
      arteriovenous fistula-a case report.
AB  - Renal arteriovenous fistula is a rare clinical entity that may produce high
      output cardiac failure. This report describes the case of an 81-year-old woman in
      whom recurrent episodes of congestive heart failure developed over a relatively
      short time. A massive renal arteriovenous fistula was visualized by CT scan and
      arteriography. Successful embolization was performed under hemodynamic monitoring
      with complete resolution of the patient's symptoms.

PMID- 15026877
TI  - Subclavian steal syndrome in acute myocardial infarction masquerading as acute
      embolism to left upper extremity-a case report.
AB  - Subclavian steal syndrome is an uncommon entity diagnosed with angiography after
      neurologic symptoms occur during activity with the upper extremity. Cardiac
      symptoms or silent ischemia have been described in patients who have undergone
      cardiac bypass using the ipsilateral internal mammary artery. Our patient
      presented with acute chest pain radiating to the left upper extremity and a
      diminished pulse. Angiography to rule out an acute embolus instead revealed
      subclavian artery occlusion. As atherosclerosis is the most common cause, the
      ipsilateral subclavian artery should be carefully evaluated, particularly in
      cardiac patients undergoing coronary angiography. Recognition of coexisting
      subclavian artery occlusion could prevent cardiac complications that may occur
      with use of the ipsilateral internal mammary artery during coronary artery bypass
      surgery.

PMID- 15026878
TI  - Right atrial extension of primary venous leiomyosarcoma: pulmonary embolism and
      Budd-Chiari syndrome at presentation-a case report.
AB  - Venous leiomyosarcomas are rare and arise predominantly in the inferior vena cava
      (IVC). The clinical findings are nonspecific and may precede the diagnosis by
      several years. IVC leiomyosarcoma is predominantly seen in women. Intracavitary
      extension of vascular tumors tends to result from embolization or propagation
      along great veins, and this is a serious risk factor for pulmonary embolism and
      sudden death when it reaches the right heart. Modern imaging modalities using
      computed tomography, magnetic resonance imaging, individually or in combination
      with cavography, ultrasound, and echocardiography, allow an early and accurate
      preoperative diagnosis, resulting in a higher rate of surgical resection and
      improved survival. The authors present a 72-year-old woman who presented with
      pulmonary embolism and Budd-Chiari syndrome. Pathological examination revealed a
      leiomyosarcoma. The tumor, involving the IVC, was diagnosed with imaging
      techniques that showed intracardiac extension of a primary venous leiomyosarcoma.
      The literature discussing leiomyosarcoma of the IVC is briefly reviewed.

PMID- 15026879
TI  - Bridge over troubling spasm: is the association of myocardial bridging and
      coronary artery spasm a distinct entity? Three case reports.
AB  - The association of coronary artery spasm and myocardial bridging is very uncommon
      and may represent a distinct clinical entity. Three patients are described,
      presenting with acute coronary syndrome associated with myocardial bridging and
      coronary artery spasm. The relationship and respective roles of myocardial
      bridging and spasm, however, remain uncertain and may be consequent to a direct
      effect on endothelial function from the compressive effect of myocardial
      bridging. The role of intracoronary nitroglycerin in these patients is
      unresolved.

PMID- 15026880
TI  - Hypereosinophilic syndrome associated with heterozygous factor V gene mutation:
      an unusual combination resulting in an acute coronary syndrome and recurrent
      cerebral stroke-a case report.
AB  - The authors report the first case of a patient with a hypereosinophilic syndrome
      associated with heterozygous factor V gene mutation, resulting in an acute
      coronary syndrome and recurrent cerebral stroke despite effective
      anticoagulation. A 40-year-old man presented with an acute coronary syndrome
      accompanied by a brachiofacial right-sided hemiparesis and dysarthria. Diagnosis
      of a hypereosinophilic syndrome was established by blood testing, myocardial
      biopsy, and bone marrow analysis. Eosinophilic infiltration was present in the
      myocardium, accompanied by proliferation in the endomyocardium and a pneumonic
      infiltrate. Although effective anticoagulation with heparin was administered, a
      recurrent stroke occurred while blood eosinophils were being normalized by
      corticosteroid treatment. A coexisting heterozygosity of the factor V mutation
      was demonstrated, and it is hypothesized that this might have contributed to the
      recurrent thromboembolic episodes. In patients with hypereosinophilic syndrome
      and recurrent thromboembolic episodes, other thrombophilic diseases, including
      factor V mutations, should be considered, and long-term coagulation should be
      contemplated.

PMID- 15026881
TI  - Cerebral infarction due to giant cell arteritis-three case reports.
AB  - The objective of this report was to explore the clinical features of patients
      with cerebral infarction due to giant cell (temporal) arteritis (GCA) and its
      characteristic changes in pathology, and on computed tomography (CT) and magnetic
      resonance imaging (MRI). Three cases of cerebral infarction due to GCA, treated
      during the past 2 years, were analyzed. Their clinical manifestations were
      observed carefully, their temporal artery biopsies were performed, their
      immunohistochemistries were done, and CT as well as MRI were used. The results
      showed that all the patients had new-onset headache and temporal artery
      abnormality when the disease began, and there was tremor on the right limbs of 1
      patient; temporal artery biopsies revealed evidence of inflammatory cell
      infiltration in the arterial wall, mainly including T-lymphocytes and
      macrophages; small cerebral infarction foci were found on CT and MRI; and the
      responses to corticosteroid therapies were good. The results suggest that it is
      important to recognize the clinical features of cerebral infarction due to GCA,
      including the changes of pathology and on CT and MRI. In some cases, special
      attention is paid to differentiating between atherosclerotic infarction and
      infections to avoid misdiagnosis.

PMID- 15026893
TI  - Does laparoscopic fundoplication provide long-term control of gastroesophageal
      reflux related cough?
AB  - BACKGROUND: Of patients with chronic cough, 21% have GERD. Up to half of these
      patients may not respond adequately to medical, but the long-term results of
      antireflux surgery for cough is unknown. METHODS: A total of 905 patients (209
      with respiratory symptoms, mainly cough) underwent laparoscopic Nissen
      fundoplication. Preoperatively patients underwent esophageal motility studies, 24
      h pH monitoring, and symptom evaluation using a validated scale. Of eligible
      patients, 81% were followed at 6 months, 73% at 2 years, and 60% at 5 years.
      RESULTS: Before surgery, 83% of respiratory patients (RP) and 51% of
      nonrespiratory patients (NRP) had cough. RP had higher cough scores ( p <
      0.0001), but improvement in cough compared to baseline was similar in the RP and
      NRP ( p = 0.1105 at 6 months, 0.4206 at 2 years, and 0.1348 at 5 years). Cough
      improved in 83% at 6 months, 74% at 2 years, and 71% at 5 years. CONCLUSIONS:
      Laparoscopic Nissen fundoplication is successful in the long-term control of GERD
      related cough, even in patients who fail medical therapy.

PMID- 15026894
TI  - Laparoscopic adrenalectomy for pheochromocytoma. A comparison to aldosteronoma
      and incidentaloma.
AB  - BACKGROUND: Laparoscopic adrenalectomy is a safe and effective treatment for most
      surgical diseases of the adrenal gland. However it has been suggested that
      catecholamine effects associated with pheochromocytoma render the laparoscopic
      approach a more challenging and a more morbid procedure. The purpose of this
      study was to compare the operative characteristics and outcomes of laparoscopic
      adrenalectomy for pheochromocytoma to those of aldosteronoma and incidentaloma.
      METHOD: Patient records and operative reports were retrospectively reviewed for
      demographics, diagnoses, operative management, and outcomes for patients
      undergoing laparoscopic adrenalectomy between June 1994 and July 2002 at two
      academic medical centers. A total of 74 patients were included and analyzed by
      diagnosis. Differences were considered statistically significant at p < 0.05.
      RESULTS: Twenty-eight patients with pheochromocytoma, 27 with aldosteronoma, and
      19 with incidentally discovered nonfunctioning adrenal masses underwent
      laparascopic adrenalectomy. Patients undergoing resection for pheochromocytoma
      trended toward more operative blood loss (150 ml) compared to aldosteronoma (88
      ml) and incidentaloma (75 ml). Eight patients were converted to an open procedure
      for a 10.8% conversion rate. The mean operative time was 171 min and there was a
      10.8% perioperative complication rate. The mean hospital stay was 3.4 days. These
      results were not statistically significant between diagnostic groups. CONCLUSION:
      Despite concern about increased operative times and morbidity associated with
      pheochromocytoma, our experience supports that laparoscopic adrenalectomy may be
      performed as safely as, and achieve outcomes similar to, those for other
      diseases.

PMID- 15026895
TI  - Robotic-assisted thoracoscopic resection of esophageal leiomyoma.
AB  - Esophageal leiomyoma represents 70-80% of all benign esophageal tumors but only
      approximately 0.5% of all esophageal neoplasms; optimal surgical treatment
      consists of local resection. We present the first reported robotic-assisted
      thoracoscopic resection of two patients with esophageal leiomyoma using the
      daVinci Surgical System. Operative technique and technical considerations are
      presented.

PMID- 15026896
TI  - Botulinum toxin injection versus laparoscopic myotomy for the treatment of
      esophageal achalasia: economic analysis of a randomized trial.
AB  - BACKGROUND: The treatment of esophageal achalasia is still controversial: current
      therapies are palliative and aim to relieve dysphagia by disrupting or relaxing
      the lower esophageal sphincter muscle fibers with botulinum toxin. The aim of
      this study was to compare the clinical and economic results of two such
      treatments: laparoscopic myotomy and botulinum toxin injection. METHODS: A total
      of 37 patients with esophageal achalasia were randomly assigned to receive
      laparoscopic myotomy (20) or two Botox injections 1 month apart (17). All
      patients were treated at the same hospital and were part of a larger multicenter
      study. Symptom score, lower esophageal sphincter pressure, and esophageal
      diameter at barium swallow were compared. The economic analysis was performed
      considering only the direct costs (cost per treatment and cost effectiveness,
      i.e., cost per patient healed). RESULTS: Mortality and morbidity were nil in both
      groups. The actuarial probability of being asymptomatic at 2 years was 90% for
      surgery and 34% for Botox (p < 0.05). The initial cost was lower for Botox (1,245
      Euros) than for surgery (3,555 Euros), but when cost effectiveness at 2 years was
      considered, this difference nearly disappeared: Botox 3,364 Euros, surgery 3,950
      Euros. CONCLUSION: Botox is still the least costly treatment, but the minimal
      difference in the longer term does not justify its use, given that surgery is a
      risk-free, definitive treatment.

PMID- 15026897
TI  - Partial laparoscopic decapsulation of congenital splenic cysts. A medium-term
      evaluation proves the efficiency in children.
AB  - BACKGROUND: In children, laparoscopic decapsulation of large congenital splenic
      cysts has occasionally been advocated, but substantial series focusing on its
      long-term success are still lacking. We report the follow-up experiences from two
      pediatric surgical centers. METHODS: The decision to proceed to surgery was based
      on patient symptoms and cyst size (>4 cm and/or progression), after strictly
      exclusion of a parasitic cause (by serology and CT scan). With the use of three
      ports (5-10-mm) and a Harmonic Scalpel, the epithelial portion of the cyst was
      radically excised. The remaining hilar epithelium was coagulated carefully. After
      discharge, the children were examined regularly by ultrasound to detect
      recurrences. RESULTS: From 1998 until 2002, eight children (mean age, 11.1 years;
      range, 3.1-16.4) were treated for cysts ranging from 4 to 15 cm in diameter. All
      procedures were completed without significant intraoperative complications (no
      major bleeding, no conversions). The mean operating time was 75 min (range, 56
      184). Postoperatively, one child developed a cystic remnant (2 cm), which
      remained unchanged during 30 months of observation. After a mean follow-up of 2.2
      years (range, 13-38 months), none of the patients showed any evidence of
      recurrent growth, and all of them had healthy splenic remnants. CONCLUSION:
      Partial laparoscopic decapsulation is an advantageous approach to large splenic
      cysts in children, because it is effective, preserves splenic tissue, and
      provides good medium-term results.

PMID- 15026898
TI  - Totally laparoscopic transhiatal esophago-gastrectomy without thoracic or
      cervical access. The least invasive surgery for adenocarcinoma of the cardia?
AB  - BACKGROUND: The recent progress of minimally invasive surgery has allowed
      esophagectomy to be performed by both combined laparoscopic/thoracoscopic and
      totally laparoscopic transhiatal approaches. All these techniques imply a
      thoracic and/or cervical access for the creation of the esophagogastric
      anastomosis. METHODS: Five surgical ports are introduced in the abdomen. The
      stomach is mobilized, divided, and tubulized, preserving the right arteries. The
      lymphadenectomy of the celiac trunk and the hepatic pedicle is achieved. The
      dissection and resection of distal esophagus and a two-fields mediastinal
      lymphadenectomy are performed by means of harmonic scalpel. The realization of
      the intrathoracic esophago-gastrostomy is accomplished by means of a circular
      stapler. RESULTS: Three patients underwent the procedure. Mean operating time and
      blood loss were 347 min and 360 cc. There were no intraoperative or postoperative
      complications. Mean postoperative stay was 9 days. CONCLUSION: In selected cases,
      it is possible to perform a distal esophagectomy entirely by laparoscopy, without
      the need for any thoracic or cervical access.

PMID- 15026899
TI  - Prevention of adhesion formation to polypropylene mesh by collagen coating: a
      randomized controlled study in a rat model of ventral hernia repair.
AB  - INTRODUCTION: In laparoscopic incisional hernia repair with intraperitoneal mesh,
      concern exists about the development of adhesions between bowel and mesh,
      predisposing to intestinal obstruction and enterocutaneous fistulas. The aim of
      this study was to assess whether the addition of a collagen coating on the
      visceral side of a polypropylene mesh can prevent adhesion formation to the mesh.
      METHOD: In 58 rats, a defect in the muscular abdominal wall was created, and a
      mesh was fixed intraperitoneally to cover the defect. Rats were divided in two
      groups; polypropylene mesh (control group) and polypropylene mesh with collagen
      coating (Parieten mesh). Seven and 30 days postoperatively, adhesions and amount
      and strength of mesh incorporation were assessed. Wound healing was studied by
      microscopy. RESULTS: With Parieten mesh, the mesh surface covered by adhesions
      was reduced after 30 days (42% vs 69%, p = 0.01), but infection rate was
      increased after both 7 (p = 0.001) and 30 days (p = 0.03), compared to the
      polypropylene group with no mesh infections. If animals with mesh infection were
      excluded in the analysis, the mesh surface covered by adhesions was reduced after
      7 days (21% vs 76%, p = 0.02), as well as after 30 days (21 vs 69%, p < 0.001).
      Percentage of mesh incorporation was comparable in both groups. Mean tensile
      strength of mesh incorporation after 30 days was higher with Parieten mesh.
      CONCLUSION: Although the coated Parieten mesh was more susceptible to mesh
      infection in the current model, a significant reduction of adhesion formation was
      still seen with the Parieten mesh after 30 days, with comparable mesh
      incorporation in the abdominal wall.

PMID- 15026900
TI  - Early feeding after laparoscopic pyloromyotomy: the pros and cons.
AB  - BACKGROUND: Early feeding after pyloromyotomy for hypertrophic pyloric stenosis
      (HPS) has been advocated because this would lead to earlier discharge. However,
      some authors remain reluctant to introduce early feeding because of concern about
      postoperative vomiting. This study aimed to clarify the effects of early versus
      later feeding after laparoscopic pyloromyotomy on postoperative vomiting, time
      required to reach full oral feeding, hospital stay, and follow-up evaluation.
      METHODS: During the period from October 1993 through March 2002, 185 infants
      underwent laparoscopic pyloromyotomy for HPS. Of these patients, 164 patients
      were included in the study. The initial feeding was within 4 h after surgery in
      group A and after 4 hours in group B. The outcome variables were postoperative
      vomiting subdivided into vomiting requiring adjustment of the feeding schedule or
      not, time required to reach full feeding, hospital stay, and vomiting as well as
      weight gain at follow-up assessment. RESULTS: In 23% of the 62 patients of group
      A and in 6% of the 102 patients of group B (p = 0.003), vomiting was so severe
      that it necessitated modification of the feeding schedule. Th time required to
      reach full feeding and the postoperative hospital stay were similar in the two
      groups. Analysis of the subgroups that required modification of the feeding
      schedule because of vomiting showed a significant delay in time required to reach
      full feedings as well as a significant delay in hospital discharge. There was an
      11% incidence of ongoing vomiting after discharge irrespective of early or later
      feeding. Weight gain at follow-up assessment did not differ significantly between
      the two groups, and did not bear any relations to in-hospital vomiting.
      CONCLUSIONS: Feeding within 4 h postoperatively leads to more severe vomiting
      than later feeding. Vomiting leads to discomfort for the child, anxiety for the
      parents, a prolonged time required to achieve full oral feeding, and a prolonged
      postoperative hospital stay. However, clinical outcome after discharge is not
      adversely affected by early feeding. According to this study, it appears that it
      would be better to withhold feeding for the first 4 h after surgery.

PMID- 15026901
TI  - Endoscopic management of pancreatic fistulas secondary to intraabdominal
      operation.
AB  - BACKGROUND: Pancreatic fistulas may arise secondary to several disorders of the
      pancreas. Although approximately 70% of pancreatic fistulas close with
      nonoperative management, this course of treatment usually takes several weeks or
      even months. To reduce this long period, closures with fibrin glue have been
      attempted in the past. In this study, we describe the course, management, and
      outcome of eight patients with postoperative external pancreatic fistulas of the
      pancreatic body and tail that arose after oncologic operations in the upper
      abdomen. METHODS: All eight cases were treated by external drainage, insertion of
      an endoprosthesis into the pancreatic duct, and closure of the fistula with
      fibrin glue. RESULTS: Immediately after this intervention, secretion from the
      fistulas was absent in all cases. None of the patients developed abscesses,
      recurrent fistulas, or complications associated with the fibrin glue. CONCLUSION:
      The early endoscopic management of postoperative pancreatic fistula with an
      approach combining internal drainage of the pancreatic duct and external
      occlusion of the fistula with fibrin glue is expeditious and beneficial.

PMID- 15026902
TI  - Novel technique of laparoscopic azygoportal disconnection for treatment of
      esophageal varicosis: preliminary experience with five patients.
AB  - BACKGROUND: Liver cirrhosis leads frequently to the development of ascites and a
      formation of varicose veins in the esophagus. The latter presents increased
      mortality risk. Recently, significant progress in laparoscopic technology enabled
      devascularization of the proximal stomach in a less invasive way. The results
      experienced by five patients are presented. METHODS: Laparoscopic azygoportal
      disconnection was performed by means of novel technique (Danis procedure) in five
      men with esophagus varices bleeding (2nd to 11th events) and liver cirrhosis
      stage Child-Pugh B and C. This procedure was performed after all other methods
      had either failed to prevent recurrent bleeding or were refused by the patient.
      Five ports were positioned on the upper abdominal wall. The veins in the lesser
      omentum were divided by means of the LigaSure-Atlas device. The stomach coronary
      vein was visualized, and all the proximal branches toward the esophagus as well
      as the short gastric vessels were divided. The diaphragm hiatus was opened, and
      the distal esophagus was dissected. The paraesophageal venous collaterals also
      were divided, and the remaining varicose veins of the esophagus were interrupted
      by transmural stitching. RESULTS: All the patients survived the minimally
      invasive procedure. Two of them died 9 and 16 months after surgery, respectively,
      because of liver insufficiency. No bleeding event from varicose veins in the
      esophagus occurred postoperatively. CONCLUSION: Laparoscopic azygoportal
      disconnection is a less invasive method for prevention of rebleeding from
      varicose veins in the esophagus. Further studies are necessary to confirm these
      preliminary results.

PMID- 15026903
TI  - Laparoscopic approach to postoperative adhesive obstruction.
AB  - BACKGROUND: Some authors have assessed the feasibility of laparoscopy in the
      treatment of postoperative adhesive obstruction, but conclusions about its
      effectiveness are related to different selection criteria used for surgery. This
      paper reports on our experience in laparoscopic adhesiolysis and analyses the
      results on the basis of the selection criteria used. METHODS: From January 1993
      to December 2001, 65 patients were submitted to laparoscopic adhesiolysis for
      small bowel obstruction according to specific selection criteria. Of the 65
      patients, 40 were admitted for acute obstruction and 25 for chronic or recurrent
      transit disturbances. Correlation between historical and clinical data and the
      results of surgical treatment were statistically analyzed. RESULTS: The procedure
      was completed by laparoscopy in 52 patients (conversion rate: 20%). Mean
      postoperative stay was 4.4 days with a 12.3% morbidity and no mortality.
      Recurrence rate was 15.4%; a single correlation was found between recurrence and
      age. CONCLUSIONS: Laparoscopic adhesiolysis in the treatment of small bowel
      obstructions seems to be effective; further studies are required to define
      selection criteria for surgery and confirm real advantages in terms of
      recurrences.

PMID- 15026904
TI  - Laparoscopic appendectomy using endoloops: a prospective, randomized clinical
      trial.
AB  - BACKGROUND: Inadequate closure of the appendix stump can lead to abscess
      formation or peritonitis. This prospective randomized clinical trial was
      performed to evaluate the number of endoloops needed in laparoscopic
      appendectomy. METHODS: A total of 208 patients were randomized in two groups: 109
      in group 1 using one and 99 in group 2 using two proximal endoloops. The groups
      were compared in terms of intra- and postoperative complications. RESULTS:
      Postoperative complications were found in five patients (4.6%) in group 1,
      consisting of intraabdominal abscesses (three patients), pulmonary embolism (one
      patient), and persisting port-site pain (one patient). In group 2, postoperative
      complications were found in five patients (5.1%), consisting of intraabdominal
      abscesses (four patients) and prolonged percutaneous drainage (one patient).
      There was no significant difference between the two groups. DISCUSSION: In acute
      appendicitis, a minimal inflamed appendix base can be safely divided using one
      endoloop.

PMID- 15026911
TI  - Efficacy and safety of reuse of disposable laparoscopic instruments in
      laparoscopic cholecystectomy: a prospective randomized study.
AB  - BACKGROUND: The aim of this prospective randomized study was to investigate the
      efficacy and safety of the reuse of disposable laparoscopic instruments (DLI) in
      laparoscopic cholecystectomy. METHODS: A total of 125 consecutive patients with
      symptomatic cholelithiasis were randomly assigned to undergo laparoscopic
      cholecystectomy with single-use DLI (group 1, n = 62) or DLI that were reused
      (group 2, n = 63) after high-level disinfection by alkalinized 2% glutaraldehyde.
      Operative and postoperative outcomes were investigated. RESULTS: There was no
      significant difference between group 1 and group 2 in mean operating time, linear
      analogue pain scale score, duration and amount of analgesic administration, or
      hospital stay. Total incidence of complications (3.2% vs 4.8%, p = 0.50) and
      infection rates (1.6% vs 3.2%, p = 0.57) were also similar when group 1 was
      compared to group 2. CONCLUSION: This study showed that reusing DLI did not
      change the operative and postoperative outcomes or the infection rate for
      laparoscopic cholecystectomy when strict rules for disinfection were followed.

PMID- 15026905
TI  - Laparoscopic nephrectomy for autosomal dominant polycystic kidney disease.
AB  - BACKGROUND: The authors reviewed their experience with laparoscopic nephrectomy
      for autosomal dominant polycystic kidney disease to evaluate whether patient
      related or surgery-related factors influence operative outcomes. METHODS: A
      retrospective review was carried out of 22 consecutive laparoscopic nephrectomies
      performed by one surgeon in a university setting between March 1998 and March
      2003. The impact of patient factors (body mass index, preoperative hemoglobin
      level, preoperative blood urea nitrogen and creatinine, kidney size and side,
      prior abdominal surgery, dialysis) and surgical factors (surgeon experience and
      preoperative embolization) on short-term outcomes (estimated blood loss,
      transfusion requirements, operative time, conversion, intra- and postoperative
      complications and length of stay) was analyzed using the Student's t-test,
      Pearson correlation, and Mann-Whitney and Fisher tests. RESULTS: A total of 19
      patients underwent 22 nephrectomies. The average patient age was 49 years (range,
      36-65 years) and the average body mass index was 31.4 kg/m2 (range, 20.4-64.5
      kg/m2). Fourteen patients (68%) were receiving dialysis. Fifteen right (68%) and
      7 left (32%) nephrectomies were performed. The median kidney size was 22 cm
      (range, 8-50 cm). Five patients (23%) had preoperative embolization. The median
      operative time was 255 min (range, 95-415 min). There were no mortalities. The
      intraoperative complication rate was 18% (1 vena cava laceration, 1 cecal
      perforation, 1 dialysis fistula thrombosis, 1 intrarenal bleeding requiring
      conversion), and the postoperative complication rate was 32% (1 myocardial
      infarction, 1 urgent laparotomy for clinical peritonitis, 1 minor bile fistula, 1
      AV fistula thrombosis, 2 incisional hernias, 1 urinary retention). Four
      procedures (18%) were converted (1 for vena cava laceration, 1 for cecal
      perforation, 1 for intrarenal bleeding, 1 for adhesions). The median blood loss
      was 400 ml (range, 100-5000 ml). Eight patients (36%) received transfusions
      (median, 2 units). The median length of stay was 4 days. The patients who
      required blood transfusions had lower preoperative hemoglobin levels.
      Preoperative embolization did not affect surgical outcome. However, surgeon
      experience significantly reduced operative time. CONCLUSIONS: Laparoscopic
      nephrectomy for autosomal dominant polycystic kidney disease is a safe procedure,
      providing patients with a short hospital stay. Complication and conversion rates
      are relatively high.

PMID- 15026913
TI  - Laparoscopic total extraperitoneal (TEP) inguinal hernia repair: overcoming the
      learning curve.
AB  - BACKGROUND: Total extraperitoneal (TEP) laparoscopic inguinal hernia repair is
      preferred to the transabdominal preperitoneal (TAPP) repair since it preserves
      peritoneal integrity. However, in general it is considered to be more difficult
      than the latter because of the peculiarity of anatomy and limitation of working
      space. Therefore it has been assigned with a "steep learning curve" that the
      surgeon needs to climb steadily and slowly. This paper offers a working protocol,
      which is aimed at reducing the steep limb of this curve. METHODS: A total of 61
      patients were studied between April 2000 and September 2002. Of these, five
      patients had a open unilateral Stoppa's preperitoneal operation to learn the
      detailed anatomy of the extraperitoneal space. Thereafter, laparoscopic TEP
      procedure was started in the following 56 cases by P.L. In case of difficulty,
      the procedure was to be converted to the open preperitoneal operation only. Of
      the first 10 cases, five were converted to unilateral Stoppa's preperitoneal
      operation for various reasons, and one case was converted after 30 cases. Thus a
      total of 11 cases were completed by open unilateral Stoppa's preperitoneal
      operation and 50 cases were completed laparoscopically. The first 30 cases
      started initially as laparoscopic operations were analyzed in groups of 10 each
      and compared to another study from Netherlands (evaluating four surgeons) wherein
      the initial laparoscopic procedures were started with the assistance of a surgeon
      well experienced in laparoscopic TEP operation. RESULTS: The comparison of our
      first 30 cases with the Netherlands group showed that while the conversions (five
      cases) to open operation were higher in the first 10 cases, there were no
      conversions in the next 20 cases. Also, there were no complications or
      recurrences in the present study, in striking contrast to three recurrences and
      10 complications in the comparative study. The following 26 cases were associated
      with no recurrence or major complication. CONCLUSION: In this study we performed
      a total of 11 open unilateral Stoppa's preperitoneal procedures in our attempt to
      learn the anatomy of this extraperitoneal space better, and in the absence of any
      surgeon experienced in laparoscopic TEP procedure. We were able to place a large
      mesh in each and every case and also recognize double hernias in six cases, thus
      preventing recurrences and complications. We strongly recommend a minimum of 10
      open Stoppa's preperitoneal procedures, to enable a trained laparoscopic surgeon
      to start laparoscopic TEP operation independently and in the absence of another
      trained laparoscopic hernia surgeon, whose presence may not prevent complications
      and recurrences.

PMID- 15026912
TI  - A technique for real-time digital measurements in laparoscopic surgery.
AB  - BACKGROUND: The current techniques for the measurement of intracorporeal targets
      in laparoscopic surgery are relatively cumbersome and imprecise. METHODS: A
      structured light technique was used to obtain the length and width of two defects
      and an object in a laparoscopic training box. These measurements were compared
      against two current and standard laparoscopic techniques of intracorporeal
      measurement: the introduction of a plastic ruler and the use of an opened end of
      a laparoscopic instrument to approximate 2 cm. The time needed to measure the
      defects and object was recorded. RESULTS: Structured light-derived measurements
      were closest to the criterion standard, followed by plastic ruler measurements,
      then by instrument-end measurements. Digital measurements were quickest, followed
      by the instrument-end method, then by the plastic ruler. CONCLUSIONS: This report
      describes a novel structured light technique for laparoscopic measurement of
      intracorporeal targets capable of producing results superior to those of current
      techniques.

PMID- 15026914
TI  - Analysis of errors in laparoscopic surgical procedures.
AB  - BACKGROUND: The determination of laparoscopic surgeon ability is essential to
      training error avoidance. The present study describes a practical method of
      surgical error analysis. METHODS: After review of practice videotapes of the
      excisional phase of laparoscopic cholecystectomy, consensus on the identification
      of eight errors was achieved. Interrater agreement at the end of this phase was
      84-96%. Fourteen study videotapes of gallbladder excision were then observed
      independently by expert reviewers blinded to surgical team identity. Procedures
      were assessed using a scoring matrix of 1-min segments with each error reported
      each minute. RESULTS: Interrater agreement was 84-100% for all error categories.
      CONCLUSIONS: The present study demonstrates that excellent interrater agreement
      of procedural errors can be achieved by carefully defining and training
      recognition of targeted events. Extension of this simple and reliable analysis
      tool to other procedures should be feasible to define behaviors leading to
      adverse clinical outcomes.

PMID- 15026915
TI  - The Surgical Recovery Index.
AB  - BACKGROUND: We developed a tool, the Surgical Recovery Index (SRI), specifically
      to measure surgical recovery. We then tested the ability of the SRI to
      discriminate between patients undergoing laparoscopic (L) operations and patients
      undergoing open (O) operations. METHODS: We surveyed 50 patients drawn from the
      practice of a single surgeon to establish the types of activities that define
      recovery from surgery. Their responses were used to construct the SRI, a self
      administered questionnaire using a numerical rank-order scale format. A total
      score and two subscale scores (pain and activity resumption) were calculated for
      each patient. Mean and median scores were calculated for each patient group. Chi
      square tests were used to evaluate group differences for individual questions; t
      tests and Kruskal-Wallis tests were used to evaluate group differences for
      summary scores. RESULTS: In all, 149 patients completed the SRI (60 L, 89 O).
      Cronbach's alphas were 0.91 for pain questions and 0.97 for activity resumption
      questions. The scores for pain level with time (L vs O, 1-10 scale) at week 1
      (mean, 4.42 vs 6.06, p = 0.03), week 2 (mean, 3.08 vs 4.38, p = 0.04), week 3
      (mean, 2.03 vs 3.16, p = 0.02), and week 4 (mean, 1.18 vs 2.28, p = 0.00) all
      favored laparoscopy. The scores for pain level with activity (L vs O, 1-3 scale)
      for getting out of bed (mean, 1.62 vs 1.85, p = 0.04), hygiene activities (mean,
      1.38 vs 1.65, p = 0.04), and computer work (mean, 1.15 vs 1.56, p = 0.00) were
      all significant, although pain with exertion (mean, 1.87 vs 2.10, p = 0.13) was
      not. Delay until return to activity (L vs O, 1-4 scale) was significant, favoring
      L for 13 activities (all p < 0.02), but it was not significant for three
      activities. The scores for subscales for pain (L vs O, mean, 20.7 vs 34.4,
      respectively) and activity resumption delay (mean, 44.3 vs 62.0), as well as
      total scores (mean, 33.0 vs 49.0), were also significant (all p = 0.00). The same
      differences were observed when median scores were considered instead of mean
      scores, suggesting the robustness of the group difference. CONCLUSIONS: Reduction
      in time to full recovery (i.e., pain resolution and activity resumption) is a
      fundamental advantage of laparoscopic surgery, yet there are no tools designed to
      specifically measure recovery. These data provide preliminary evidence of the
      reliability and validity of the new SRI as a measure of recovery in patients
      undergoing laparoscopic operations.

PMID- 15026918
TI  - Use of a laparoscopic hand-assist device for accessory splenectomy.
AB  - BACKGROUND: The use of a laparoscopic hand-assist device may aid in the
      identification of accessory spleens (ASs) and provide similar benefits to a
      conventional laparoscopic procedure. A patient with previous splenectomy for
      immune thrombocytopenic pupusa (ITP) and recurrent thrombocytopenia is reported.
      METHOD: A computed tomography scan and RBC scan identified several nodules
      consistent with ASs. Initial laparoscopic exploration could not identify all the
      ASs seen on preoperative imaging. A hand-assist device was placed and a total of
      five nodules of splenic tissue were identified without conversion to laparotomy.
      RESULTS: The patient had a brief and uncomplicated postoperative course with a
      return of platelet counts to 350,000 at 1-month follow-up. CONCLUSION: We propose
      that in the scenario of recurrent ITP following laparoscopic splenectomy, repeat
      laparoscopy is the first step once an AS is identified by preoperative imaging.
      If the AS is not identified at laparoscopy, the insertion of a hand-assist device
      is an alternative to a full laparotomy.

PMID- 15026921
TI  - Laparoscopic total colectomy: hand-assisted vs standard technique.
AB  - BACKGROUND: Although hand-assisted laparoscopic surgery (HALS) has been proposed
      as an alternative to laparoscopically assisted surgery (LAP), little is known
      about its role in total colectomy. The objectives of the study were to compare
      the outcomes in patients undergoing total colectomy via either HALS or LAP and to
      determine what benefits HALS might have in extensive colorectal procedures.
      METHODS: We reviewed the data for 23 patients who underwent total proctocolectomy
      (TPC) or total abdominal colectomy (TAC) using either a HALS or LAP technique.
      RESULTS: There were 12 HALS (five TPC, seven TAC) and 11 LAP (seven TPC, four
      TAC) for ulcerative colitis (n = 17), familial polyposis (n = 5), and colonic
      inertia (n = 1). One LAP was converted (9.1%). The operative time was shorter for
      HALS than for LAP (210 vs 273 min; p = 0.03). Blood loss and incision length were
      similar. Postoperative recovery and morbidity rates were comparable. CONCLUSION:
      HALS reduces the operative time but patient morbidity rates and recovery are
      similar to LAP. HALS may be preferable for extensive colorectal procedures such
      as TPC and TAC.

PMID- 15026920
TI  - Suprapancreatic and periportal lymph nodes are normally larger than 1 cm by
      laparoscopic ultrasound evaluation.
AB  - BACKGROUND: Laparoscopic and endoscopic ultrasound is used to assess
      resectability of gastrointestinal malignancies. Lymph node size greater than 1 cm
      is a criterion used to identify suspicious nodes. We define size and echo
      characteristics of suprapancreatic and periportal nodes to determine if this
      criterion is reliable for suprapancreatic and periportal lymph nodes. METHODS: A
      prospective study of 21 patients with nonacute gallbladder disease was performed.
      Each underwent laparoscopic cholecystectomy with intraoperative ultrasound. The
      suprapancreatic and periportal nodes were evaluated in a transverse and
      longitudinal axis. Length and width measurements were taken in both orientations.
      Length-to-width ratios were calculated. Shape and echo textures were
      characterized. RESULTS: The mean size of both nodes was greater than 1 cm in the
      transverse and longitudinal orientation. Two nodes were "round." Remaining nodes
      were "oblong." All nodes had a hyperechoic center with a hypoechoic rim.
      CONCLUSION: In suprapancreatic and periportal lymph nodes, size greater than 1 cm
      should not be used as criterion for malignancy.

PMID- 15026922
TI  - Anal ultrasound and endosonographic measurement of perineal body thickness: a new
      evaluation for fecal incontinence in females.
AB  - BACKGROUND: Perineal body thickness (PBT) is measured by endoanal
      ultrasonography. The literature has shown that women with obstetric trauma to the
      anal sphincter have decreased PBT, and a measurement of 10 mm or less has been
      proposed as abnormal. Therefore, this study aimed to compare the proposed
      definitions of normal to pathologic findings in patients with fecal incontinence
      (FI) and to correlate PBT with anorectal physiologic findings. METHODS: All
      female patients who had endoanal ultrasonography and PBT measurement for
      evaluation of FI were assessed and divided into three groups on the basis of PBT:
      10 mm or less, 10 to 12 mm, more than 12 mm. The degree of FI (0 = complete
      continence; 20 = complete incontinence) was correlated with PBT. RESULTS: For
      this study, 83 female patients with a mean age of 59.7 years (range, 30-88 years)
      had endoanal ultrasonography and PBT measurement. Sphincter defects were
      suggested by endoanal ultrasonography in 77% of the patients in the three groups
      as follows: 57 (97%) of 59 patients, 4 (36%) of 11 patients, and 3 (23%) of 13
      patients. The mean external sphincter defect angle was 110 degrees (range, 45-170
      degrees ), and the mean FI score was 13.8. For 89% of the patients there was a
      history of vaginal delivery. As reported, 35% had undergone one or more prior
      perineal surgeries, 27% had both, and 4% denied having had either. A significant
      correlation between sphincter defect and PBT (p < 0.001) was noted. External
      sphincter defect angles were negatively correlated with PBT (p = 0.001).
      CONCLUSION: A PBT of 10 mm or less is considered abnormal, whereas a PBT of 10 mm
      to 12 mm is associated with sphincter defect in one-third of patients with FI.
      Those with a PBT of 12 mm or more are unlikely to harbor a defect unless they
      previously have undergone reconstructive perineal surgery.

PMID- 15026923
TI  - Hand-assisted laparoscopic colectomy vs open colectomy: a prospective randomized
      study.
AB  - BACKGROUND: We compared the perioperative parameters and outcomes achieved with
      hand-assisted laparoscopic colectomy (HALC) vs open colectomy (OC) for the
      management of benign and malignant colorectal disease, including cancer patients
      treated with curative intent. METHODS: Sixty eligible patients were randomized to
      either HALC (n = 30) or OC (n = 30) treatment groups. We used Pearson's chi
      square and two-sample t-tests to compare the differences in demographics and
      perioperative parameters. RESULTS: There were no significant differences in age,
      gender distribution, disease pattern, operative procedure, comorbidity, or
      history of abdominal surgery. The HALC patients had significantly shorter
      hospital stays and incision lengths, faster recovery of gastrointestinal
      function, less analgesic use and blood loss, and lower pain scores on
      postoperative days 1, 3, and 14. There were no significant differences in
      operative time, complications, or time to return to normal activity. CONCLUSION:
      Hand-assisted laparoscopic colectomy (HALC) is safe and produces better
      therapeutic results in terms of perioperative parameters than OC.

PMID- 15026924
TI  - Clinical outcome of laparoscopic antireflux surgery for patients with irritable
      bowel syndrome.
AB  - BACKGROUND: The prevalence of irritable bowel syndrome (IBS) is higher among
      subjects with gastroesophageal reflux disease (GERD). This study aimed to assess
      the effect of IBS on the postoperative outcome of antireflux surgery. METHODS:
      For this study, 102 patients who underwent laparoscopic fundoplication were
      screened preoperatively for IBS with the Rome II criteria. There were 32 patients
      in the IBS group and 70 patients in the non-IBS group. Most of the patients (97%)
      (31 of 32 IBS and 68 of 70 non-IBS patients) had both pre- and postoperative IBS
      evaluation. A visual analog GERD-specific scoring scale was used to evaluate GERD
      symptoms prospectively. RESULTS: In both groups, GERD symptom scores were
      statistically improved postoperatively. Of the 31 IBS patients 25 (80.6%) showed
      a reduction in their symptoms below the Rome II criteria for IBS diagnosis
      postoperatively. CONCLUSION: Irritable bowel syndrome does not have a negative
      effect on the outcome of laparoscopic antireflux surgery. Surgical correction of
      GERD may improve the severity of irritable bowel symptoms.

PMID- 15026925
TI  - Discriminative validity of the Minimally Invasive Surgical Trainer in Virtual
      Reality (MIST-VR) using criteria levels based on expert performance.
AB  - BACKGROUND: Increasing constraints on the time and resources needed to train
      surgeons have led to a new emphasis on finding innovative ways to teach surgical
      skills outside the operating room. Virtual reality training has been proposed as
      a method to both instruct surgical students and evaluate the psychomotor
      components of minimally invasive surgery ex vivo. METHODS: The performance of 100
      laparoscopic novices was compared to that of 12 experienced (>50 minimally
      invasive procedures) and 12 inexperienced (<10 minimally invasive procedures)
      laparoscopic surgeons. The values of the experienced surgeons' performance were
      used as benchmark comparators (or criterion measures). Each subject completed six
      tasks on the Minimally Invasive Surgical Trainer-Virtual Reality (MIST-VR) three
      times. The outcome measures were time to complete the task, number of errors,
      economy of instrument movement, and economy of diathermy. RESULTS: After three
      trials, the mean performance of the medical students approached that of the
      experienced surgeons. However, 7-27% of the scores of the students fell more than
      two SD below the mean scores of the experienced surgeons (the criterion level).
      CONCLUSIONS: The MIST-VR system is capable of evaluating the psychomotor skills
      necessary in laparoscopic surgery and discriminating between experts and novices.
      Furthermore, although some novices improved their skills quickly, a subset had
      difficulty acquiring the psychomotor skills. The MIST-VR may be useful in
      identifying that subset of novices.

PMID- 15026926
TI  - A mathematical model for preoperative planning of radiofrequency ablation of
      hepatic tumors.
AB  - BACKGROUND: Radiofrequency ablation (RFA) is rapidly evolving as an effective
      minimally invasive technique for the treatment of small and unresectable liver
      tumors. A potential cause of treatment failure is the inability to determine the
      optimum number of overlapping ablations needed to completely destroy tumors
      larger than the size of a single ablation. To clarify this relationship, we
      performed a mathematical evaluation that enables us to accurately estimate the
      number of ablations needed to completely ablate larger tumors. METHODS: This
      estimation is based on the assumptions that complete ablation of the surface of a
      target tumor, including its blood supply, would completely destroy the tumor and
      that the tumor and ablations produced are perfectly spherical. The smallest
      possible number of partially overlapping ablations that would completely cover
      the surface of the target tumor is the same as the number of faces on a regular
      polyhedron that has a circumscribing diameter equal to or greater than the
      diameter of the target sphere. RESULTS: This mathematical analysis shows that for
      a 5-cm ablation device, tumors with diameters ranging between 3.01 and 3.30 cm
      will require at least four ablations. Tumors between 3.31 and 4.12 cm require six
      overlapping ablations, and tumors between 4.13 and 6.23 cm require 12 overlapping
      ablations. The number of ablations needed for larger tumors and for 3-, 4-, 6-,
      and 7-cm ablation devices are also determined. CONCLUSION: The smallest number of
      ablations required to completely ablate a spherical target tumor larger than the
      size of the ablation sphere increases dramatically as tumor size increases.
      Because this model is geometrically optimized, even a small change in the
      position of the ablation spheres with respect to the target sphere can leave
      potentially unablated tumor and thus result in treatment failure.

PMID- 15026927
TI  - Modified devascularization surgery for isolated gastric varices assessed by
      endoscopic ultrasonography.
AB  - BACKGROUND: This study aimed to assess the role of endoscopic ultrasonography
      (EUS) in the surgical management of isolated gastric varices (IGV), and to report
      the authors' experience in the treatment of IGV with modified devascularization
      surgery. METHODS: In this study, 26 cirrhotic patients with IGV were treated with
      devascularization surgery for variceal hemorrhage. Preoperatively, percutaneous
      transhepatic portography (PTP) and EUS were used to determine the mode of therapy
      for IGV. Fundectomy was performed for 14 patients with fundic IGV, whereas 12
      patients with cardiac IGV underwent proximal gastrectomy. RESULTS: A
      significantly higher proportion of patients with cardiac varices showed grade 3
      IGV on preoperative EUS than those who had fundic varices (p < 0.05). No major
      complications were observed during or after the operation, and only one patient
      died of prolonged shock and massive transfusion. Postoperatively, gastric varices
      had been eradicated completely in 25 of 26 patients, as determined by EUS study.
      During a mean follow-up period of 50 months, two patients had recurrent varices
      without bleeding, as demonstrated by EUS. The overall 5-year survival rate for
      the fundic IGV group was 67.9%, whereas that for the cardiac IGV group was 64.3%
      (p > 0.05). CONCLUSIONS: This study showed that devascularization surgery is
      highly effective for the prevention of recurrent bleeding from IGV and provides
      an alternative treatment method. Preoperatively, EUS is very helpful in detailed
      devascularization of patients with specific IGV, and may be used also for
      postoperative follow-up evaluation.

PMID- 15026928
TI  - Disruptive visions: surgical education.
AB  - Technological change, decreased financial support for medical education, and
      social oversight (in the form of the "To Err Is Human" report, HIPPA, and reduced
      work hours) are forcing a rethinking of the traditional model of surgical
      education to improve patient safety. New approaches to evaluating surgical
      competence, such as objective assessment, in combination with new technologies,
      such as the Internet and surgical simulators, provide the tools to effect a
      revolution in surgical education and training. Competency based upon quantifiable
      criteria measures must replace the traditional subjective assessment. The
      implementation requires accurately defining the elements of training,
      establishing new quantifiable metrics, stringently measuring performance against
      criterion, and reporting outcomes throughout the career of a surgeon.

PMID- 15026929
TI  - Flexible light guide for thoracoscopic surgery: snake light adapter.

PMID- 15026930
TI  - Disruptive visions: a robot is not a machine...systems integration for surgeons.
AB  - The discipline of surgery has become even more complex with the rapid
      introduction of revolutionary technologies. Laparoscopic surgery is just the
      simplest and first of these new directions. Robotic surgery and image-guided
      therapy are the next generation. As biosurgery and other modalities are
      introduced, the complexity will increase exponentially. In order to understand
      and utilize the new technologies, surgeons need to be grounded in the science of
      systems integration. The pervasive influence of this new requirement, as well as
      the skills, education, training, and assessment needs, are defined.

PMID- 15026931
TI  - Complications of laparoscopic incisional-ventral hernia repair: the experience of
      a single institution.
AB  - BACKGROUND: Laparoscopic incisional-ventral hernia repair (LIVH) is used with
      increasing frequency for the morbidly obese and for complex and recurrent
      hernias. The experience of a single institution with this technique is reviewed
      and the findings and complications are presented. METHODS: Data were collected
      retrospectively for a single surgeon's series of patients undergoing LIVH at the
      institution described in this report. RESULTS: The review showed a complication
      rate of 15.2%, a recurrence rate of 2%, and a prosthetic infection rate of 2%.
      Patients with a body mass index greater than 30 cm/m2 accounted for 73% of the
      complications and made up 62.2% of the patients. CONCLUSIONS: The LIVH procedure
      may be safely performed with low complication and recurrence rates even for the
      obese, allowing ventral hernia repair to be performed safely with good results.
      The LIVH technique should be considered for the repair of all incisional and
      ventral hernias requiring repair with a mesh prosthesis.

PMID- 15026932
TI  - Laparoscopic repair of parastomal hernias: early results.
AB  - BACKGROUND: Open repair of parastomal hernias is associated with high rates of
      morbidity and recurrence. Laparoscopic repair with mesh has been described, and
      good results have been reported in small case series with short-term follow-up.
      The purpose of this study was to review our institution's experience with the
      laparoscopic repair of parastomal hernias. METHODS: Nine patients with
      symptomatic parastomal hernias (five ileal conduits, two ileostomies, and two
      sigmoid colostomies) underwent laparoscopic repair with mesh between April 1998
      and September 2001. Demographics, operative details, postoperative complications,
      and hernia recurrences were recorded retroprospectively. RESULTS: All of the
      patients were men; their average age was 66 years (range, 53-77). A single piece
      of Gore-Tex Dual Mesh with a slit to accommodate the stoma was used in seven of
      nine repairs; in the other two patients, two pieces of mesh were used. Concurrent
      incisional hernias were repaired in three of nine patients (33.3%). The average
      operating time was 243 min (range, 136-360). The average postoperative length of
      stay was 4.7 days (range, 2-7). Immediate postoperative complications occurred in
      three patients (33.3%) (one ileus, one urinary retention, and one ulnar
      neuropathy). Recurrences developed in four patients (44.4%), and in one patient
      (11.1%) the stoma prolapsed; all of these failures occurred within 6 months of
      the operation. One patient died 10 months postoperatively, without evidence of
      hernia recurrence. Three patients are without evidence of recurrence after 18,
      21, and 33 months (average, 24) of follow-up, respectively. CONCLUSION: In this
      series, laparoscopic repair of parastomal hernia failed in 56% of patients, all
      within 6 months of the operation. Although the laparoscopic approach has
      potential advantages compared to the conventional open methods, the initial
      results are disappointing. Advances in the technique may improve the early
      results, and further prospective studies are needed to determine the efficacy of
      this approach.

PMID- 15026933
TI  - Inspired oxygen concentrations during positive pressure therapy.
AB  - OBJECTIVES: This study examined the effects of various factors that might
      influence the fraction of oxygen in inspired air (FiO (2)) in a human and in a
      model system during nasal positive pressure treatments. DESIGN AND METHODS: A
      healthy male volunteer and a mannequin head were each outfitted with a nasal
      continuous positive air pressure mask and pressure source (BiPAP S, Respironics,
      Murrysville, PA). Oxygen was added through either a side port in the mask or a
      port near the machine. Flow and FiO (2) were measured while varying inspiratory
      and expiratory pressures. Measurements were repeated with a leak added to the
      system and using different sites of oxygen administration. RESULTS: In both the
      human and in the model system, increasing inspiratory pressure, thereby
      increasing flow, decreased FiO (2) inside the mask. In the model system, addition
      of a fixed leak caused an increase in flow and decrease in FiO (2) at any given
      level of inspiratory and expiratory pressure. CONCLUSION: In patients using nasal
      positive pressure therapy, variables of pressure, leak around the mask, and the
      site of oxygen delivery determine the inspired oxygen concentration when giving
      oxygen supplementation.

PMID- 15026934
TI  - CPAP compliance in sleep apnea patients with and without laboratory CPAP
      titration.
AB  - Advances in auto-adjusting positive airway pressure technology for obstructive
      sleep apnea now permit this treatment to be initiated outside of the sleep
      laboratory environment, bypassing the need for laboratory-based titration
      studies. Thus far, little research has addressed how such developments may affect
      compliance to continuous positive airway pressure (CPAP). We tested the effect of
      laboratory CPAP exposure and technologist support in a retrospective chart review
      of 98 veterans with obstructive sleep apnea to determine whether patients who
      received standard laboratory CPAP titration complied better with CPAP than did
      patients who received no laboratory CPAP titration. Fifty patients underwent
      standard technician-attended polysomnography (PSG) with CPAP titration, and 48
      patients underwent unattended PSG with no laboratory trial of CPAP (first CPAP
      exposure was at home). Objective CPAP compliance measures were obtained from CPAP
      units at follow-up visits. Attended-PSG patients wore CPAP significantly longer
      per night on average (5.0 hours vs 3.9 hours) and tended to wear CPAP on more
      nights (76.5% vs 64.2%) compared with unattended-PSG patients. These findings
      suggest that patients' sleep laboratory experience with CPAP and the support and
      education provided by sleep technologists are important factors in facilitating
      CPAP compliance.

PMID- 15026936
TI  - Plasma adenosine during investigation of hypoxic ventilatory response.
AB  - Adenosine, an endogenous nucleoside, is released by hypoxic tissue, causes
      vasodilation, and influences ventilation. Its effects are mediated by P1
      purinoceptors. We examined to what extent the plasma adenosine concentration in
      the peripheral venous blood correlates with hypoxic ventilatory response (HVR)
      and ventilatory drive P0.1 to find out whether endogenously formed adenosine has
      an influence on the individual ventilatory drive under hypoxic conditions. While
      investigating the HVR of 14 healthy subjects, the ventilatory drive P0.1 was
      measured with the shutter of a spirometer. Determination of the ventilatory drive
      P0.1(RA) started under room air conditions (21% O (2)) and then inspiratory gas
      was changed to a hypoxic mixture of 10% O (2) in N (2) to determine P0.1(Hyp). At
      the time of the P0.1 measurements, two blood samples were taken to determine the
      adenosine concentrations. After removal of cellular components and proteins,
      samples were analyzed by high-pressure liquid chromatography (HPLC). Both
      adenosine concentrations in plasma under room air (r = 0.59, p < 0.05) and
      adenosine concentrations under hypoxia (r = 0.75, p < 0.01) correlated
      significantly with the ventilatory drive P0.1. In addition, plasma adenosine
      concentrations during hypoxic conditions showed a significant correlation with
      HVR on the 0.01 level (r = 0.71, p < 0.01). The results indicate a possible role
      of endogenous adenosine in the regulation of breathing in humans. We assume that
      endogenous adenosine influences the HVR and the ventilatory drive, probably by
      modulating the carotid body chemoreceptor response to hypoxia.

PMID- 15026937
TI  - Improvement in obstructive sleep apnea in the supine knees-up position.
AB  - We report a 38-year-old man with obstructive sleep apnea whose sleep-disordered
      breathing was substantially reduced by sleep in the supine, "knees-up" position,
      relative to his sleep in the customary supine, "knees-down" position. No obvious
      anatomic or pathophysiologic alterations explained this phenomenon. The effect
      was reproducible in the patient 4 years later. Potential mechanisms underlying
      such improvement, including alterations in upper airway/lung volume dependence
      and venous supply to upper airway vasculature, are discussed. This manipulation
      could be an important adjunctive treatment for a subset of obstructive sleep
      apnea patients demonstrating such an effect.

PMID- 15026935
TI  - Refractory insomnia and sleep-disordered breathing: a pilot study.
AB  - OBJECTIVE: To assess an uncontrolled, open-label trial of sleep-disordered
      breathing (SDB) treatment on two different samples of chronic insomnia patients.
      METHOD: In Study 1 (Retrospective), data from one diagnostic and one continuous
      positive airway pressure (CPAP) titration polysomnogram were compiled from 19
      chronic insomnia patients with SDB. Objective polysomnogram indicators of sleep
      and arousal activity and self-reported sleep quality were measured. In Study 2
      (Prospective), clinical outcomes were assessed after sequential cognitive
      behavioral therapy (CBT) and SDB therapy (CPAP, oral appliances, or bilateral
      turbinectomy) were provided to 17 chronic insomnia patients with SDB. Repeat
      measures included the Insomnia Severity Index, Functional Outcomes of Sleep
      Questionnaire, Pittsburgh Sleep Quality Index, and self-reported insomnia indices
      and CPAP use. RESULTS: In Study 1, seven objective measures of sleep and arousal
      demonstrated or approached significant improvement during one night of CPAP
      titration. Sixteen of 19 patients reported improvement in sleep quality. In Study
      2, Insomnia Severity Index, Functional Outcomes of Sleep Questionnaire, and
      Pittsburgh Sleep Quality Index improved markedly with CBT followed by SDB
      treatment and achieved an average outcome equivalent to curative status.
      Improvements were large for each treatment phase; however, of 17 patients, only 8
      attained a nonclinical level of insomnia after CBT compared with 15 patients
      after SDB therapy was added. Self-reported insomnia indices also improved
      markedly, and self-reported SDB therapy compliance was high. CONCLUSIONS: In one
      small sample of chronic insomnia patients with SDB, objective measures of
      insomnia, arousal, and sleep improved during one night of CPAP titration. In a
      second small sample, validated measures of insomnia, sleep quality, and sleep
      impairment demonstrated clinical cures or near-cures after combined CBT and SDB
      therapies. These pilot results suggest a potential value in researching the
      pathophysiological relationships between SDB and chronic insomnia, which may be
      particularly relevant to patients with refractory insomnia.

PMID- 15026938
TI  - Resolution of severe sleep-disordered breathing with a nasopharyngeal obturator
      in 2 cases of nasopharyngeal stenosis complicating uvulopalatopharyngoplasty.
AB  - Obstructive sleep apnea-hypopnea syndrome (OSAHS) is characterized by episodic
      decrements in airflow due to upper airway obstruction. Uvulopalatopharyngoplasty
      (UPPP) is a potential therapy for OSAHS. Nasopharyngeal stenosis is a rare
      complication of UPPP that worsens OSAHS. We report two patients referred for
      OSAHS worsened by nasopharyngeal stenosis complicating UPPP. Both patients were
      treated with carbon dioxide laser release of adhesions and placement of a
      nasopharyngeal obturator. Follow-up polysomnograms demonstrated resolution of
      OSAHS correlating with subjective resolution of symptoms. Nasopharyngeal stenosis
      complicating UPPP can be successfully treated with scar removal and
      nasopharyngeal stenting. Polysomnographic demonstration of the effectiveness of
      this therapy has not previously been reported. Future questions include duration
      of nasopharyngeal stenting and timing of follow-up polysomnography.

PMID- 15026941
TI  - [Computer assistance in clinical image-based diagnosis and therapy: a challenge
      for German research].

PMID- 15026939
TI  - Treatment of long-standing nocturnal enuresis by mandibular advancement.
AB  - Enuresis, the involuntary release of urine during sleep, is one of the most
      common disorders of childhood. More common in boys than girls, this condition is
      characterized by night-time wetting in the presence of normal urinalysis and
      physical examination. At present, treatment can be divided into behavioral
      modification and pharmacological therapy, despite which many enuretic children
      remain untreated or are treated ineffectively. Treatment of long-standing chronic
      enuresis by orthodontic appliances could be used more frequently to give relief
      to those not responding to conventional treatment. Mandibular advancement therapy
      is especially beneficial in the treatment of enuretic patients presenting with
      anteroposterior skeletal discrepancies.

PMID- 15026943
TI  - [Stroke MRI: pathophysiology, potential and perspectives].
AB  - Magnetic resonance imaging (MRI) is increasingly utilized as the primary imaging
      modality in major stroke centers. The ability to depict several aspects of
      individual pathophysiology makes the use of MRI in stroke both attractive and
      complex. Profound knowledge of the pathophysiology of the imaging findings is
      crucial for a rational diagnostic workup. The pathophysiology of MRI in stroke
      will be reviewed considering recent experiences in clinical application, and the
      potential of stroke MRI will be assessed. Further perspectives like application
      of "blood oxygen level dependent" (BOLD) and the use of multiparametric
      prediction maps will be discussed.

PMID- 15026942
TI  - [Tumor simulating lesions on cranial MR imaging].
AB  - Statistically tumors are the most likely cause of space-occupying intracranial
      lesions. However, many non-neoplastic diseases also manifest as mass lesions and
      may be indistinguishable from tumors. The most common of these are inflammatory
      and dysplastic lesions, which intraaxially imitate mostly glioma, lymphoma, and
      metastases and extraaxially meningeoma and neurinoma. Aside from a willingness on
      the part of the diagnostic radiologist to question the most obvious diagnosis, on
      clinical history and findings are prerequisites for a sound radiological
      differential diagnosis. The aim of this article is to provide a practical
      overview of the differential diagnosis of intracranial mass lesions with emphasis
      on non-neoplastic abnormalities.

PMID- 15026944
TI  - Multipolar radiofrequency ablation: first clinical results.
AB  - Common systems of radiofrequency ablation (RFA) are monopolar devices which
      require grounding pads on the thighs in order to close the electrical circuit.
      Bipolar RFA does not require grounding pads, because both electrodes are located
      on one probe and alternating current circuit is confined within the target
      tissue. In this paper we report on the first clinical application of a new
      ablation device which enables both, bipolar (1 probe) and multipolar (up to 3
      internally cooled probes simultaneously) radiofrequency ablation. We report on bi
      and multipolar applications in liver tumors (9 patients), osteoid osteoma (2
      patients) and renal cell cancer (1 patient).

PMID- 15026945
TI  - [Contrast-enhanced 3D MR perfusion of the lung: application of parallel imaging
      technique in healthy subjects].
AB  - PURPOSE: Evaluation of lung perfusion by contrast-enhanced 3D MRI using partial
      parallel imaging techniques. MATERIALS AND METHODS: Eight healthy volunteers were
      examined using a contrast-enhanced dynamic FLASH 3D sequence with partial
      parallel imaging technique at 1.5 T MRI with a TA of 1.5 sec. The whole lung was
      covered by 36 coronal slices. A ventral, middle and dorsal slice of each lung was
      manually segmented and signal-to-time curves were computed. For absolute
      quantification of blood flow through the right and left pulmonary artery, phase
      contrast flow measurements were performed. RESULTS: No significant difference was
      found between the signal intensity in the right (8.9 +/- 2.6) and left (8.0 +/-
      3.5) lung, corresponding to a left-to-right signal intensity ratio of 0.9. A
      significantly higher signal intensity was found in the dorsal regions of the
      lungs (p = 0.01) compared to the ventral regions. The time to peak of the signal
      intensity was significantly shorter in the dorsal (15.3 sec) and middle (15.7
      sec) regions of the lungs (p = 0.03 and p = 0.04, respectively) than in the
      ventral regions (16.3 sec). The ratio between blood flow through the left (2.2
      L/min) and right (2.7 L/min) lung was 0.84. CONCLUSION: Partial parallel image
      acquisition can assess the perfusion of the lungs at high temporal resolution.
      The perfusion is slightly higher on the right than on the left. The signal
      increases faster and has a higher peak in the dorsal lung regions.

PMID- 15026946
TI  - [HRCT and bronchial asthma: visualization of the pathophysiologic changes of the
      pulmonary parenchyma after inhalation provocation].
AB  - PURPOSE: To characterize parenchymal lung affections morphologically in patients
      with asthma and healthy subjects by high -resolution computed tomography (HRCT)
      subsequent to histamine-triggered inhalation bronchoprovocation and salbutamol
      induced broncholysis, and to compare the results with pulmonary function tests.
      MATERIALS AND METHODS: Fifteen asthmatics with bronchial hyperreactivity, with a
      > 20% decrease in FEV1 and a > 10 mmHg decrease in PaO(2) after
      bronchoprovocation (PC20%+), twelve asthmatics with a < 20% decrease in FEV1 and
      a > 10 mmHg decrease in PaO(2) after bronchoprovocation (PC20%-), and eight
      healthy persons without bronchial hyperreactivity underwent inhalation
      bronchoprovocation and broncholysis. Spirometer-triggered HRCT at high lung
      volumes was performed, and total and peripheral lung densities and the amount of
      solid lung structures, representing predominantly vessels, were measured.
      RESULTS: After bronchoprovocation, we observed significant decreases in total and
      peripheral lung densities in all groups (p < 0.0005), and a significant increase
      in lung densities subsequent to bronchodilation (p < 0.0002). The morphological
      alterations in solid lung structure were not significantly different after
      bronchoprovocation or broncholysis (p > 0.05), as compared to the baseline
      measurements. In hyperreactive patients, PaO(2) significantly decreased after
      provocation and significantly increased after lysis (p < 0.05). In PC20%+
      asthmatics, a mean reduction of 27.8% in FEV1 was observed, which was < 20% in
      the other groups. No significant correlations were observed between radiological
      data and the results of pulmonary function tests. In healthy persons, we
      demonstrated highly significant parenchymal response to bronchoprovocation and
      broncholysis, which was not otherwise documented by pulmonary function tests.
      CONCLUSION: In both PC20%+ and PC20%- patients as well as in healthy individuals,
      HRCT was efficient in the evaluation of pathoanatomical alterations of the lung
      parenchyma subsequent to inhalation provocation. In healthy individuals, these
      parenchymal alterations were not documented by pulmonary function tests.

PMID- 15026947
TI  - [Biventricular MR volumetric analysis and MR flow quantification in the ascending
      aorta and pulmonary trunk for quantification of valvular regurgitation].
AB  - PURPOSE: To test the value of biventricular volumetric analysis and the
      combination of biventricular volumetric analysis with flow quantification in the
      ascending aorta (Ao) and pulmonary trunk (Pu) for quantification of regurgitation
      volume and cardiac function in valvular regurgitation (VR) according to location
      and presence of single or multivalvular disease. MATERIALS AND METHODS: In 106
      patients, the stroke volumes were assessed by measuring the biventricular volumes
      and the forward-stroke volumes in the great and small circulation by measuring
      the flow in the Ao and Pu. Valve regurgitation volumes and quotients were
      calculated for single and multivalvular disease and correlated with
      semiquantitative 2D-echocardiography (grade I-IV). For the assessment of the
      cardiac function in VR, the volumetric parameters of ejection fraction and end
      diastolic (EDV) and end-systolic (ESV) volumes were determined. RESULTS: The
      detection rate was 49% for left ventricular (LV) VR and 42% for right ventricular
      (RV) VR. Low LV VR and RV VR usually could not be detected quantitatively, with
      the detection rate improving with echocardiographically higher insufficiency
      grades. Quantitative MRI could detect a higher grade solitary aortic valve
      insufficiency (> or = 2) in 11 of 12 patients and higher grade mitral valve
      insufficiency in 4 of 10 patients. A significant increase in RV and LV
      ventricular EDV and ESV was seen more often with increased MR regurgitation
      volumes. Aortic stenosis did not interfere with flow measurements in the Ao.
      CONCLUSIONS: Biventricular volumetry combined with flow measurements in Ao and Pu
      is a robust, applicable and simple method to assess higher grade regurgitation
      volumes and the cardiac function in single and multivalvular regurgitation at
      different locations. It is an important application for the diagnosis of VR by
      MRI.

PMID- 15026948
TI  - [TrueFISP MR imaging to determine the influence of hemodialysis on the myocardial
      functional parameters in patients with terminal renal insufficiency].
AB  - PURPOSE: To assess the characteristic signs of uremic cardiomyopathy in patients
      with chronic renal failure (CRF) in comparison with healthy volunteers and to
      determine changes of left ventricular (LV) functional parameters in patients
      undergoing hemo-dialysis (HD). METHODS AND MATERIALS: Using a 1.5 T Magnetom
      Sonata system (Siemens, Erlangen), cardiac MR imaging was performed on 26
      patients (20 men, 6 women, mean age 54.7 years) and 14 volunteers (8 men, 6
      women, mean age 27.7 years). Single-slice true FISP sequences (TR 3.2 ms, TE 1.6
      ms, flip angel 58 degrees, matrix 256 x 208, slice thickness 5 mm) were used to
      obtain contiguous short axis slices covering the whole left ventricle. Patients
      were examined before and immediately after HD. Cardiodynamic parameters [end
      diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection
      fraction (EF), myocardial mass (MM), cardiac output (CO)] were calculated using
      the modified Simpson's rule (Argus Software, Siemens). Patient data were compared
      to reference values taken from healthy volunteers. RESULTS: As a consequence of
      HD, significant differences (p < 0.01) were observed for EDV (150 + 47 ml/114 +
      49 ml), ESV (71 + 46 ml/60 + 56 ml), SV (79 + 25 ml/57 + 27 ml) and CO (3.6 + 1.0
      l/min*m (2)/2.6 + 1.1 l/min*m (2)). Although EF (56 + 15 %/53 + 18 %) was
      decreased after HD, values did not differ significantly (p > 0.05). MM (148 + 47
      g/148 + 52 g) and myocardial mass index (80.7 +/- 27.4 g/m (2)/80.1 +/- 9.1 g/m
      (2)) did not change before and after HD. In all patients, signs of LV-hypertrophy
      (LVH) and increased CO were diagnosed compared to reference values. In 8 of 26
      patients, additional pathology, such as valvular dysfunction or global cardiac
      insufficiency, was detected. CONCLUSION: Cardiac MRI is an accurate tool to
      identify uremic cardiomyopathy in patients with chronic renal failure undergoing
      HD. LV functional parameters could be monitored reliably.

PMID- 15026949
TI  - [Grading of carotid artery stenosis using high resolution dynamic magnetic
      resonance angiography in comparison to intraarterial digital subtraction
      angiography. Are stenoses over 70% reliably detectable?].
AB  - PURPOSES: Evaluation of high resolution dynamic magnetic resonance angiography
      (ceMRA) in detection and graduation of carotid artery stenosis in comparison to
      intraarterial digital subtraction angiography. MATERIALS AND METHODS: Magnetic
      resonance angiography and intraarterial digital subtraction angiography was
      performed in 65 patients with suspected carotid artery stenosis by ultrasound
      examination. Detection and graduation of carotid artery stenosis by magnetic
      resonance angiography were compared to those of intraarterial digital subtraction
      angiography after stenosis grading according to NASCET criteria. RESULTS: All
      magnetic resonance angiographies were of excellent quality, with 46 stenoses type
      I and II and 12 stenoses type III NASCET correctly identified and classified by
      magnetic resonance angiography. Overestimation was found in 4 cases and
      underestimation in 2 cases. Both modalities detected 13 occlusions. Sensitivity
      and specificity of ceMRA were 92%. The positive predictive value was 86% and the
      negative predictive value 96%. CONCLUSION: High resolution dynamic magnetic
      resonance angiography is suitable in detecting and classifying carotid artery
      stenoses over 70% with high sensitivity and specificity in comparison to
      intraarterial digital subtraction angiography. Intraarterial digital subtraction
      angiography should only be performed in critical cases.

PMID- 15026950
TI  - [Part-body hyperthermia with a radiofrequency multiantenna applicator under
      online control in a 1.5 T MR-tomograph].
AB  - Objective of this study is the integration of a multiantenna applicator for part
      body hyperthermia (BSD 2000/3D) in a 1.5 T MR-tomograph (Siemens Magnetom
      Symphony) in order to perform noninvasive MR monitoring in real time to increase
      safety and effectiveness of heat treatments. The positioning unit is mechanically
      coupled to the MR gantry from the back side and the body coil is utilised for
      imaging. For that purpose, the hyperthermia antenna system (100 MHz, 1.500 W) and
      the MR receiver (63.9 MHs) have to be decoupled in terms of high frequency
      (filter) and electromagnetically (emc). The processing of MR data sets is
      performed in a hyperthermia planning system. A simultaneous operation of
      radiofrequency hyperthermia and MR system is possible at clinically relevant
      power levels. MR imaging is used for tumor-diagnostics (standard spin echo
      sequences), for hyperthermia planning (T1-weighted gradient echo sequences in
      equal- and opposed-phase techniques), and for temperature measurements according
      to the proton resonance frequency method (PRF method, phase evaluation
      registration using a gradient echo sequence with long echo time). In 33 patients
      with advanced pelvic and abdominal tumors we performed 150 heat sessions under MR
      monitoring. For 70% of these patients a visualisation of temperature sensitive
      data during treatment was possible. The evaluated difference images represent a
      superposition of real temperature -increase and a (temperature-induced) perfusion
      elevation. The -hybrid approach renders development of part body hyperthermia
      possible as an MR-controlled intervention in radiology.

PMID- 15026951
TI  - [Chemoembolization of hepatocellular carcinomas: which factors determine
      therapeutic response and survival?].
AB  - PURPOSE: To determine independent prognostic factors influencing the survival of
      patients with hepatocellular carcinoma (HCC) treated with transcatheter arterial
      chemoembolization (TACE). MATERIALS AND METHODS: Ninety-one patients with
      unresectable HCC were treated with 269 repetitive TACE. The dosages of epirubicin
      (40-60 mg) and ethiodized oil (8-20 ml) were adjusted to tumor size and liver
      function. The impact of tumor size, macroscopic tumor type, tumor location,
      portal vein infiltration, capsular infiltration, tumor vascularization, uptake of
      ethiodized oil within the tumors, Child-Pugh-Class and Okuda-Stage on patient
      survival were evaluated by means of univariate and multivariate regression
      analysis. RESULTS: The following independent prognostic factors were found: tumor
      type (nodular vs. infiltrating, p = 0 008), tumor size (p = 0.01), Child-Pugh
      Class (A vs. B; p = 0.02) and grade of tumor vascularization (p = 0.04). In 57
      patients with HCC of the nodular type, the median survival time was significant
      longer than in 32 patients with HCC of the infiltrating type (17.0 months vs. 7.9
      months; p < 0.003; 2 tumors could not be classified). The 1-, 2- and 3-year
      survival rates were significantly higher in 57 patients with Okuda-Stage I
      disease, compared to 34 patients with Okuda-Stage II and III disease (73%, 31%
      and 8% vs. 23%, 6% and 4% p < 0.0001). CONCLUSIONS: Tumor type, tumor size and
      grade of liver cirrhosis have an independent impact on prognosis of patients with
      HCC treated by TACE. An appropriate selection of patients is necessary to improve
      patients survival.

PMID- 15026952
TI  - [Ultrasound- and fluoroscopy-guided implantation of peripherally inserted central
      venous catheters (PICCs)].
AB  - PURPOSE: Evaluation of ultrasound- and fluoroscopy-guided implantation of
      peripherally inserted central venous catheters (PICCs). MATERIALS AND METHODS: In
      32 patients (12 males, 20 females; mean age 64.1 +/- 11.9 years) with clinical
      indication for long term central venous catheter (chemotherapy: N = 5; parenteral
      nutrition and fluid substitution: N = 26; parenteral pain therapy: N = 1) a PICC
      was placed by an interventional radiologist using ultrasound guidance. RESULTS:
      The placement of the PICC was technically successful in 31 (96.9%) patients, with
      placement of 20 single-lumen 5F PICCs, 4 double-lumen 6F PICCs and 7 double-lumen
      7F PICCs. The mean duration of catheter usage was 28.4 (2 - 161) days with a
      total of 910 catheter days. No catheter occlusions were recorded. Two patients
      developed a superficial venous thrombosis of the upper extremity. The resulting
      thrombotic rate was 2.2 per 1000 catheter days. No catheter associated infection
      was recorded. CONCLUSION: The ultrasound guided placement of peripherally
      inserted central venous catheters (PICCs) via a superficial vein of the upper
      extremity is a practical alternative to central catheters via central veins.

PMID- 15026953
TI  - [Staff requirements in medical radiation physics for diagnostic radiology in
      Germany: results of a questionnaire].
AB  - To get a general idea of the actual staffing situation in medical radiation
      physics, all active members of the German Society of Medical Physics (DGMP) were
      surveyed by the task force "staff requirements" ("Personalbedarf") of the DGMP in
      1999. Of the 322 forms sent out, 173 could be evaluated. The staff requirements
      in medical radiation physics were calculated from the major elements of the
      radiology equipment and from the staff responsibilities as defined in the DGMP
      Reports 8 and 10, and compared with the actual number of staff members. The data
      of this spot check were then extrapolated for the entire Federal Republic of
      Germany. The calculation revealed a deficit of 89% for the entire staff in
      diagnostic radiology and of 84% for physicists. Considering the age distribution
      of the DGMP members, a training capacity of about 100 medical physicists per year
      is needed to eliminate the calculated deficit within the next 10 years.

PMID- 15026954
TI  - [Liposome-mediated transfection of thrombomodulin in vascular smooth muscle cells
      -a gene therapy concept to inhibit recurrent stenosis].
AB  - PURPOSE: Thrombomodulin (TM), an integral endothelial receptor, is known for its
      anticoagulant functions. Moreover, there is evidence of growth-modulating effects
      of this cell surface -protein. The aim of our study was to establish by in vitro
      transfection a stable cell line of vascular smooth muscle cells with
      overexpression of TM for further investigations concerning the influence of TM on
      cellular proliferation and its potential role during the formation of restenosis.
      METHODS: Aortic smooth muscle cells of the rat were transfected with cDNA of
      mouse TM or one of its three mutants (M1, M2, M4) by a liposome-mediated
      technique. The expression of mouse TM mRNA in the selected clones was proven with
      the help of RT-PCR. Changes of cell proliferation were determined by
      proliferation kinetics over 24 days. The quantification of the total protein TM
      was made by Western blots. RESULTS: In 44 of 100 cases the RT-PCR confirmed a
      successful transfection of mouse-TM. The clones with transfected TM, M1 or M2
      showed an inhibited cell growth, whereas M4 demonstrated an increased
      proliferation compared with controls. The comparison of amounts of total TM with
      cell growth of individual clones resulted in a negative correlation between
      proliferation and TM-expression (coefficient of correlation for TM -0.87, for M1 
      0.59). CONCLUSIONS: It is possible to reproduce stable cell-lines of vascular
      smooth muscle cells with overexpression of TM by the presented model of in vitro
      transfection. Thus, a basis exists for detailed examinations of growth-regulating
      mechanisms by TM.

PMID- 15026955
TI  - [Dose dependent effects of the combined beta-gamma-emitter 188Rhenium on the
      growth of human vessel wall cells].
AB  - PURPOSE: To evaluate the dose of (188)Re that completely suppresses growth and
      clonogenic activity of human aortic smooth muscle cells (haSMC) since these cells
      are mainly responsible for restenosis occurring after PTA. For comparison, growth
      and clonogenic activity of endothelial cells (EC) were investigated with
      corresponding doses. MATERIALS AND METHODS: Two days after plating, haSMC and EC
      were incubated with (188)Re for five days. The doses applied ranged from 4 to 16
      Gy. Cell growth was observed for a period of 20 days (EC) or 30 days (haSMC),
      respectively. Clonogenic activity was monitored over a period of 20 days for both
      cell lines. RESULTS: Irradiation caused dose-depend-ent inhibition of cell growth
      and clonogenic activity both in haSMC and in EC. HaSMC growth was completely
      blocked with 8 Gy, while EC still showed some proliferation even with 16 Gy. The
      clonal activity of haSMC was also completely blocked with 8 Gy while EC still
      showed little clonal activity even with 16 Gy. CONCLUSION: Cell growth of both
      haSMC and EC can be effectively suppressed in a dose-dependent manner. Only haSMC
      showed a complete growth arrest with 8 Gy while EC were able to proliferate even
      with 16 Gy. HaSMC colony formation was completely suppressed after application of
      8 Gy, while the EC still showed colony formation activity with 16 Gy. (188)Re has
      some advantageous properties for intravascular irradiation in comparison to other
      radionuclides making it an interesting radionuclide for stent coating to prevent
      restenosis.

PMID- 15026957
TI  - [Ruptured intraventricular dermoid cyst].

PMID- 15026956
TI  - [Quantification of atelectases in artificial respiration: spiral-CT versus
      dynamic single-slice CT].
AB  - PURPOSE: Dynamic CT (dCT) allows visualization and quantification of ventilated
      lung and atelectases with high temporal resolution during continuous ventilation.
      This study compares a quantitative image analysis in a subcarinal single slice
      dCT series versus a whole lung spiral-CT, in order to analyze, whether the
      distribution of atelectasis of a single dCT series is representative for the
      whole lung. MATERIALS AND METHODS: dCT in sliding windows technique (slice
      thickness 1 mm, temporal increment 100 ms) was performed in 8 healthy pigs 3 cm
      caudal to the carina during continuous mechanical ventilation. Subsequently, a
      spiral-CT of the whole lung (slice thickness 2 mm; pitch 1.5; increment 2 mm) was
      acquired during inspiratory breath hold (airway pressure 20 mbar). Lung
      segmentation and planimetry of predefined density ranges were achieved using a
      dedicated software tool in both data-sets. Thus, the fractions of the following
      functional lung compartments were averaged over time: hyperinflated lung (- 1024
      to - 910 HE), normal ventilated lung -900 to -300 HE) and atelectasis (-300 to
      +200 HE). RESULTS: Quantitative analysis of dCT-series during continuous
      respiration correlated with the density analysis in spiral-CT as follows:
      hyperinflated lung r = 0.56; normal ventilated lung r = 0.83 and atelectases r =
      0.84. Analysis of spiral-CT showed the following distribution of functional lung
      compartments: hyperinflated lung 3.1% normal ventilated lung 77.9% and
      atelectasis 19.0%. In dCT, hyperinflated lung represented 6.4%, normal ventilated
      lung 65.2% and atelectasis 28.4% of total the lung area. CONCLUSION: The results
      of our study demonstrate that dCT allows monitoring of atelectasis formation in
      response to different ventilatory strategies. However, a deviation between dCT
      and spiral-CT has to be taken into account. In subcarinal dCT series,
      hyperinflated lung areas and atelectases were overestimated due to a craniocaudal
      gradient of atelectases, whereas normal ventilated lung was underestimated.

PMID- 15026958
TI  - [Septic abscess-forming pneumonia with osseous and hepatic involvement caused by
      Streptococcus intermedius].

PMID- 15026959
TI  - [SARS (Severe Acute Respiratory Syndrome)].

PMID- 15026960
TI  - [Focal fatty liver -- often difficult differential diagnosis of liver
      metastasis].

PMID- 15026961
TI  - [Eye muscle metastasis of neuroendocrine tumor of the pancreas].

PMID- 15026962
TI  - [Long-term course of reflux symptoms following Helicobacter pylori eradication].
AB  - BACKGROUND AND OBJECTIVE: Conflicting data regarding new onset or deterioration
      of gastroesophageal reflux disease (GORD) following eradication of Helicobacter
      pylori infection have been reported. Successful eradication therapy may influence
      gastric acid output. The study aimed to to investigate whether patients with pre
      existing GORD or peptic ulcer disease may experience deterioration of GORD.
      PATIENTS AND METHODS: 75 consecutive patients of a prospective longitudinal study
      (median age 66 years, n = 45 males) had received successful H. pylori eradication
      therapy because of the following main diagnosis: peptic ulcer (n = 37), GORD (n =
      16), functional dyspepsia (n = 22). Two to three years later, they had an
      interview regarding the course of their dyspeptic and reflux symptoms. Negative
      H. pylori status at present was confirmed by (13)C-urea breath test in all
      patients. Ten patients were excluded because of proton pump inhibitor treatment.
      RESULTS: Patients with deterioration of GORD (new onset or increasing reflux
      symptoms) were found significantly more frequently in the group with functional
      dyspepsia (36 %) compared to pre-existing GORD (16 %) or peptic ulcer disease (5
      %). Improvement of pre-existing reflux complaints were reported mostly by
      patients with peptic ulcer disease. There was no significant impact of initial
      reflux manifestations like reflux symptoms or reflux oesophagitis on the course.
      CONCLUSIONS: During long-term follow-up after H. pylori eradication, patients
      experience improvement as frequently as deterioration of reflux symptoms. There
      is a tendency towards improvement of reflux symptoms if peptic ulcer disease had
      been the indication for eradication, but towards deterioration in patients with
      initial functional dyspepsia. A clinical relevant prediction, however, is not
      feasible.

PMID- 15026963
TI  - [The role of plastic and reconstructive surgery within an interdisciplinary
      treatment concept for diabetic ulcers of the foot].
AB  - BACKGROUND AND OBJECTIVE: Diabetes mellitus and its sequelae such as the
      "diabetic foot" are increasing in incidence and pose a challenging medical and
      financial problem. Interdisciplinary teams have been formed to prevent and treat
      these problems, consisting of diabetic nurses and physicians, nutritionists,
      podiatrists, specialist shoemakers, general, orthopaedic and vascular surgeons.
      However, hardly mentioned in the literature are the surgical options offered by
      plastic and reconstructive surgeons. The aim of this study was to analyse the
      outcome of plastic surgical treatment for soft tissue defect coverage of the
      diabetic foot ulcer and to define the role of plastic and reconstructive surgery
      within an interdisciplinary treatment concept. PATIENTS AND METHODS: In a
      retrospective cohort study the charts of 38 diabetic patients (female n = 14/male
      n = 24) with an average age of 68.6 years and with 45 defects on the foot or
      ankle were analysed regarding the patient profile, defect etiology and size,
      operative procedures, complications and outcome results. RESULTS: Defect coverage
      was performed using 20 split skin grafts, 19 local flaps and 6 free flaps as well
      as 27 amputations. At the time of discharge 25 of 45 defects were closed (56 %),
      15 patients had an amputation and in 3 cases a small defect remained. The success
      rate of defect coverage decreased with increasing comorbidity. Whereas 71 % of
      the defects were covered in ASA stage 2 patients, only 50 % of the defects could
      be covered in ASA stage 3 patients and only 33 % in ASA stage 4 patients.
      CONCLUSIONS: Despite a high complication rate, plastic surgical techniques in
      many cases prevented an amputation in this negatively preselected patient group.
      These results provide justification for plastic and reconstructive surgery being
      in any case part of an interdisciplinary treatment approach of the diabetic
      ulcer.

PMID- 15026964
TI  - [Simulation of a colon carcinoma: diuretic-induced ulcerative-stricturing
      ischemic colitis].
AB  - HISTORY AND ADMISSION FINDINGS: A 49-year-old man was admitted to hospital with
      lower gastro-intestinal bleeding. He complained of fatigue, weight loss and
      bloody stools for a few days. There was no history of abdominal pain, but he had
      irregular bowel movements for some weeks with alternating constipation and
      diarrhea. He regularly took furosemide and ACE inhibitors for hypertension. The
      abdominal investigation was unremarkable. INVESTIGATIONS: Laboratory
      investigations showed a significant anemia (Hb 6,3 g/dl), WBC, C-reactive protein
      and lactic acid were normal, carcino-embryonic antigen was 38 ng/ml and thus
      increased (normal value: < 5 ng/ml). Colonoscopy revealed a circular stricturing
      and ulcerating tumor at 70 cm, which looked highly suspicious for malignancy and
      could not be passed endoscopically. Biopsies showed high-grade dysplasia and
      colon contrast x-ray confirmed a stricturing tumor. TREATMENT AND COURSE:
      Laparotomy was performed for a bleeding colon carcinoma. However, besides
      multiple inflammatory-stenosing strictures of different parts of the right colon,
      no tumor was found. Perfusion of the small and large bowel was normal. A right
      colectomy was performed and multiple deep ulcerations and strictures were found
      inside the resected colon. A cecal ulceration was the origin of the bleeding.
      After stopping furosemide intake no further bleeding or colonic ulceration
      occurred. CONCLUSION: This is an unusual case of drug related non-occlusive,
      ulcerative-stricturing, ischemic colitis, masquerading as colonic cancer.
      Although diuretic-induced non-occlusive ischemic colitis is a very rare finding,
      it should be taken into account in young patients with ischemic colitis, when
      other risk factors have been excluded and intake of diuretics is reported.

PMID- 15026966
TI  - [Nuclear cardiology: will we need it in the future?].

PMID- 15026965
TI  - [Hereditary neuroendocrine gastroenteropancreatic tumors and multiple endocrine
      neoplasia type 1].

PMID- 15026967
TI  - [Comorbidity between cardiovascular disease and affective illness].

PMID- 15026968
TI  - [Sedation in end-of-life care - ethical aspects].
AB  - Sedation in the final stages of life plays an increasing role to control
      refractory physical and psychological symptoms and to diminish distress and
      anxiety in palliative care. In the debate on euthanasia and self determination
      also in Germany the issue of "terminal sedation" has evoked ethical concerns and
      is discussed controversially. With respect for personal needs the intentions,
      aims and indications for medical sedation should be carefully reflected under
      ethical aspects to clarify its position in end-of-life care

PMID- 15026969
TI  - [Physician's duty to inform regarding the responsibility for treatment error.
      Decision of the Appeal Court Koblenz, l/15/2004].

PMID- 15026970
TI  - [What significance has the C(2) value in the treatment with cyclosporin A?].

PMID- 15026971
TI  - Orientation of the genetic variance-covariance matrix and the fitness surface for
      multiple male sexually selected traits.
AB  - Stabilizing selection has been predicted to change genetic variances and
      covariances so that the orientation of the genetic variance-covariance matrix (G)
      becomes aligned with the orientation of the fitness surface, but it is less clear
      how directional selection may change G. Here we develop statistical approaches to
      the comparison of G with vectors of linear and nonlinear selection. We apply
      these approaches to a set of male sexually selected cuticular hydrocarbons (CHCs)
      of Drosophila serrata. Even though male CHCs displayed substantial additive
      genetic variance, more than 99% of the genetic variance was orientated 74.9
      degrees away from the vector of linear sexual selection, suggesting that open
      ended female preferences may greatly reduce genetic variation in male display
      traits. Although the orientation of G and the fitness surface were found to
      differ significantly, the similarity present in eigenstructure was a consequence
      of traits under weak linear selection and strong nonlinear (convex) selection.
      Associating the eigenstructure of G with vectors of linear and nonlinear
      selection may provide a way of determining what long-term changes in G may be
      generated by the processes of natural and sexual selection.

PMID- 15026972
TI  - Limits on the evolution of tail ornamentation in birds.
AB  - In birds, elongated tails are one of the most common and most studied ornaments.
      However, the tail also has an aerodynamic function, playing a role in turning and
      slow flight. If a tail is to function as an ornament, then there will be an
      inevitable conflict between the aerodynamic role and the signaling role.
      Aerodynamic theory has developed to the point where it is possible to predict the
      aerodynamic and mechanical consequences of ornamental tails of different sizes
      and shapes. Tail elongation will influence many different mechanical and
      aerodynamic parameters. For at least some and possibly all of these parameters,
      there will be limits that are placed by the bird's anatomy, morphology, or
      physiology on the extent to which the effect of tail elongation could be
      tolerated. For example, if a particular tail morphology meant that the power
      required to fly exceeded the power available from the flight muscles, then the
      bird would obviously be unable to fly with such a tail. To examine whether these
      considerations could limit the development of ornamental tails, the effect of
      long tails of different shapes was examined on three parameters: static balance,
      lift-to-drag ratio, and the cost of flight. All three of these parameters were
      found to limit the range of possible tail morphologies that could be developed by
      birds. These limits were most acute for small birds, which may not be able to
      operate with a long tail of any shape. Slightly larger birds would be able to
      develop elongated streamers and forked tails but not pintails or wedge-shaped
      tails. Medium to large birds are less constrained and could develop a much wider
      range of tails than small birds, but there will always be limits to the sizes of
      tail ornament that could be developed. Thus the physical consequences of
      ornamentation on ecology and behavior are likely to be responsible for some of
      the patterns of ornamentation observed in nature.

PMID- 15026973
TI  - Foraging by deep-diving birds is not constrained by an aerobic diving limit: a
      model of avian depth-dependent diving metabolic rate.
AB  - The theoretical aerobic diving limit (tADL) specifies the duration of a dive
      after which oxygen reserves available for diving are depleted. The tADL has been
      calculated by dividing the available oxygen stores by the diving metabolic rate
      (DMR). Contrary to diving mammals, most diving birds examined to date exceed the
      tADL by a large margin. This discrepancy between observation and theory has
      engendered two alternative explanations suggesting that dive duration is extended
      either anaerobically or by depressing aerobic metabolism. Current formulations of
      tADL uncritically assume that DMR is independent of depth. However, diving birds
      differ from other vertebrate divers by having a larger respiratory system volume
      and by retaining air in their plumage while diving, thereby elevating buoyancy.
      Because air compresses with depth, diving power requirement decreases with depth.
      Following this principle, we modeled DMR to depth for Adelie and little penguins
      and reformulated the tADL accordingly. The model's results suggest that <
      approximately 5% of natural dives by Adelie penguins exceed the reformulated
      tADL(d), or maximal aerobic depth, and none in the more buoyant little penguin.
      These data suggest that, for both small and large species, deep diving birds
      rarely if ever exceed tADL(d).

PMID- 15026974
TI  - The synergistic effects of stochasticity and dispersal on population densities.
AB  - Using laboratory experiments, simulation models, and analytical techniques, we
      examined the impact of dispersal on the mean densities of patchily distributed
      populations. Even when dispersal leads to no net additions or removals of
      individuals from a population, it may nonetheless increase mean population
      densities if the net immigration rate is positive when populations are growing
      and negative when they are declining. As a model system for exploring this
      phenomenon, we used the yeastlike fungus Aureobasidium pullulans. In a laboratory
      experiment, we showed that dispersal can both ensure persistence and increase
      mean population densities even when dispersal among populations causes no direct
      addition or loss of fungal cells. From the laboratory data, we constructed a
      plausible model of A. pullulans dynamics among apple leaves within an orchard.
      This simulation model demonstrated that the effect of dispersal on mean densities
      is enhanced by three factors: weak density dependence of the dynamics within
      populations, high environmental variability affecting population growth rates,
      and lack of synchrony among the fluctuations of populations. Using an analytical
      model, we showed that the underlying mechanisms for this phenomenon are general,
      suggesting that a large effect of dispersal on mean population densities is
      possible in many natural systems.

PMID- 15026975
TI  - Begging and sibling competition: how should offspring respond to their rivals?
AB  - Godfray's influential model of competitive begging predicted that offspring
      should respond to each other's behavior, displaying more intensely when competing
      with needier rivals. Empirical tests of this prediction have, however, yielded
      equivocal results. Here, I develop a series of evolutionarily stable strategy
      models of begging as a signal of need, which show that this prediction holds only
      for competitive aspects of display that influence the division of food among the
      brood. No such response is expected for cooperative begging (which influences the
      total level of provisioning by the parent), and the models even predict the
      opposite trend under some circumstances (where the indirect costs of extracting
      additional resources from the parent are high). These contrasting sets of
      predictions may help to explain the varying empirical results obtained by studies
      of sibling interaction. Cooperative (as opposed to competitive) begging is likely
      to be of greater significance in cases where dominant young can gain direct
      control of allocation (or enjoy some competitive advantage). Dominants are then
      predicted to parasitize the efforts of their weaker rivals and reduce their own
      investment in cooperative signaling while continuing to claim a
      disproportionately large share of the resources provided by the parent.

PMID- 15026976
TI  - Exploring rarity using a general model for distribution and abundance.
AB  - We describe a simple model for changes in the distribution and abundance of a
      metapopulation and use it to explore the conditions leading to different types of
      rarity. The model suggests that localized populations (those with low patch
      occupancy but high local abundance) arise from low dispersal, low heterogeneity
      in extant population size, and frequent local extinctions relative to the
      potential for recolonization. Scarce populations (with low distribution and
      abundance) arise when relative local extinction rate is low to moderate and
      heterogeneity is high or successful dispersal is relatively low. Sparse
      populations (widespread, but with low local abundance) arise when relative local
      extinction rate is very low and either spatial heterogeneity or mortality through
      unsuccessful dispersal is high. In sparse or common species, there may be
      unstable as well as stable equilibria, implying a threshold distribution and
      abundance for persistence. The model supports a general correlation between
      distribution and abundance and suggests that persistence may be threatened by
      dispersal rates being either too high or too low. The model provides a new
      perspective on rarity and suggests a simple theoretical foundation for
      understanding the population-dynamic mechanisms that determine distribution and
      abundance.

PMID- 15026977
TI  - Did natural selection or genetic drift produce the cranial diversification of
      neotropical monkeys?
AB  - A central controversy among biologists is the relative importance of natural
      selection and genetic drift as creative forces shaping biological diversification
      (Fisher 1930; Wright 1931). Historically, this controversy has been an effective
      engine powering several evolutionary research programs during the last century
      (Provine 1989). While all biologists agree that both processes operate in nature
      to produce evolutionary change, there is a diversity of opinion about which
      process dominates at any particular organizational level (from DNA and proteins
      to complex morphologies). To address this last level, we did a broadscale
      analysis of cranial diversification among all living New World monkeys.
      Quantitative genetic models yield specific predictions about the relationship
      between variation patterns within and between populations that may be used to
      test the hypothesis that genetic drift is a sufficient explanation for
      morphological diversification. Diversity at several levels in a hierarchy of
      taxonomic/phylogenetics relationship was examined from species within genera to
      families within superfamilies. The major conclusion is that genetic drift can be
      ruled out as the primary source of evolutionary diversification in cranial
      morphology among taxa at the level of the genus and above as well as for
      diversification of most genera. However, drift may account for diversification
      among species within some Neotropical primate genera, implying that morphological
      diversification associated with speciation need not be adaptive in some
      radiations.

PMID- 15026978
TI  - Effects of body size and temperature on population growth.
AB  - For at least 200 years, since the time of Malthus, population growth has been
      recognized as providing a critical link between the performance of individual
      organisms and the ecology and evolution of species. We present a theory that
      shows how the intrinsic rate of exponential population growth, rmax, and the
      carrying capacity, K, depend on individual metabolic rate and resource supply
      rate. To do this, we construct equations for the metabolic rates of entire
      populations by summing over individuals, and then we combine these population
      level equations with Malthusian growth. Thus, the theory makes explicit the
      relationship between rates of resource supply in the environment and rates of
      production of new biomass and individuals. These individual-level and population
      level processes are inextricably linked because metabolism sets both the demand
      for environmental resources and the resource allocation to survival, growth, and
      reproduction. We use the theory to make explicit how and why rmax exhibits its
      characteristic dependence on body size and temperature. Data for aerobic
      eukaryotes, including algae, protists, insects, zooplankton, fishes, and mammals,
      support these predicted scalings for rmax. The metabolic flux of energy and
      materials also dictates that the carrying capacity or equilibrium density of
      populations should decrease with increasing body size and increasing temperature.
      Finally, we argue that body mass and body temperature, through their effects on
      metabolic rate, can explain most of the variation in fecundity and mortality
      rates. Data for marine fishes in the field support these predictions for
      instantaneous rates of mortality. This theory links the rates of metabolism and
      resource use of individuals to life-history attributes and population dynamics
      for a broad assortment of organisms, from unicellular organisms to mammals.

PMID- 15026979
TI  - Optimal body size and energy expenditure during winter: why are voles smaller in
      declining populations?
AB  - Winter is energetically challenging for small herbivores because of greater
      energy requirements for thermogenesis at a time when little energy is available.
      We formulated a model predicting optimal wintering body size, accounting for the
      scaling of both energy expenditure and assimilation to body size, and the trade
      off between survival benefits of a large size and avoiding survival costs of
      foraging. The model predicts that if the energy cost of maintaining a given body
      mass differs between environments, animals should be smaller in the more
      demanding environments, and there should be a negative correlation between body
      mass and daily energy expenditure (DEE) across environments. In contrast, if
      animals adjust their energy intake according to variation in survival costs of
      foraging, there should be a positive correlation between body mass and DEE.
      Decreasing temperature always increases equilibrium DEE, but optimal body mass
      may either increase or decrease in colder climates depending on the exact effects
      of temperature on mass-specific survival and energy demands. Measuring DEE with
      doubly labeled water on wintering Microtus agrestis at four field sites, we found
      that DEE was highest at the sites where voles were smallest despite a positive
      correlation between DEE and body mass within sites. This suggests that variation
      in wintering body mass between sites was due to variation in food
      quality/availability and not adjustments in foraging activity to varying risks of
      predation.

PMID- 15026980
TI  - Limits to trophic levels and omnivory in complex food webs: theory and data.
AB  - While trophic levels have found broad application throughout ecology, they are
      also in much contention on analytical and empirical grounds. Here, we use a new
      generation of data and theory to examine long-standing questions about trophic
      level limits and degrees of omnivory. The data include food webs of the
      Chesapeake Bay, U.S.A., the island of Saint Martin, a U.K. grassland, and a
      Florida seagrass community, which appear to be the most trophically complete food
      webs available in the primary literature due to their inclusion of autotrophs and
      empirically derived estimates of the relative energetic contributions of each
      trophic link. We show that most (54%) of the 212 species in the four food webs
      can be unambiguously assigned to a discrete trophic level. Omnivory among the
      remaining species appears to be quite limited, as judged by the standard
      deviation of omnivores' energy-weighted food-chain lengths. This allows simple
      algorithms based on binary food webs without energetic details to yield
      surprisingly accurate estimates of species' trophic and omnivory levels. While
      maximum trophic levels may plausibly exceed historically asserted limits, our
      analyses contradict both recent empirical claims that these limits are exceeded
      and recent theoretical claims that rampant omnivory eliminates the scientific
      utility of the trophic-level concept.

PMID- 15026981
TI  - Body size of insular carnivores: little support for the island rule.
AB  - Large mammals are thought to evolve to be smaller on islands, whereas small
      mammals grow larger. A negative correlation between relative size of island
      individuals and body mass is termed the "island rule." Several mechanisms--mainly
      competitive release, resource limitation, dispersal ability, and lighter
      predation pressure on islands, as well as a general physiological advantage of
      modal size--have been advanced to explain this pattern. We measured skulls and
      teeth of terrestrial members of the order Carnivora in order to analyze patterns
      of body size evolution between insular populations and their near mainland
      conspecifics. No correlations were found between the size ratios of
      insular/mainland carnivore species and body mass. Only little support for the
      island rule is found when individual populations rather than species are
      considered. Our data are at odds with those advanced in support of theories of
      optimal body size. Carnivore size is subjected to a host of selective pressures
      that do not vary uniformly from place to place. Mass alone cannot account for the
      patterns in body size of insular carnivores.

PMID- 15026982
TI  - Impact of supply-side ecology on consumer-mediated coexistence: evidence from a
      meta-analysis.
AB  - Studies of marine nearshore hard substrates have demonstrated that consumers and
      abiotic disturbances can remove biomass, clearing space for species that are
      competitively subordinate and subsequently increasing diversity. However, studies
      often examine the impact of these space-opening forces on diversity in isolation
      from other potentially interacting factors. In marine systems, space can be
      closed by recruitment decoupled from local populations. Therefore, we
      investigated how recruitment influences the impacts of consumers on diversity
      with a meta-analysis of 27 experiments of community development involving sessile
      species on marine hard substrates. These studies allowed quantification of
      recruitment rates, consumer pressure, and species richness of primary space
      occupants. This meta-analysis demonstrated that consumers generally increase
      diversity at high levels of recruitment but decrease diversity at low levels of
      recruitment. Therefore, species diversity of sessile species is controlled by the
      interaction between forces that open (predation and herbivory) and close
      (recruitment) space.

PMID- 15026983
TI  - The mid-domain effect and species richness patterns:what have we learned so far?
AB  - If species' ranges are randomly shuffled within a bounded geographical domain
      free of environmental gradients, ranges overlap increasingly toward the center of
      the domain, creating a "mid-domain" peak of species richness. This "mid-domain
      effect" (MDE) has been controversial both in concept and in application.
      Empirical studies assess the degree to which the evolutionary, ecological, and
      historical processes that undeniably act on individual species and clades produce
      geographical patterns that resemble those produced by MDE models. MDE models that
      resample empirical range size frequency distributions (RSFDs) balance the risk of
      underestimating and overestimating the role of MDE, whereas theoretical RSFDs are
      generally biased toward underestimating MDE. We discuss the inclusion of
      nonendemic species in MDE models, rationales for setting domain limits, and the
      validity of one- and two-dimensional MDE models. MDE models, though null models,
      are not null hypotheses to be simplistically rejected or accepted. They are a
      means of estimating the expected effect of geometric constraints within the
      context of multiple causality. We call for assessment of MDE on an equal
      statistical footing with other candidate explanations for richness gradients.
      Although some critics have categorically dismissed MDE, an overview of the 21 MDE
      studies published to date reveals a substantial signature of MDE in natural
      patterns and justifies continued work.

PMID- 15026984
TI  - Branching and self-organization in marine modular colonial organisms: a model.
AB  - Despite the universality of branching patterns in marine modular colonial
      organisms, there is neither a clear explanation about the growth of their
      branching forms nor an understanding of how these organisms conserve their shape
      during development. This study develops a model of branching and colony growth
      using parameters and variables related to actual modular structures (e.g.,
      branches) in Caribbean gorgonian corals (Cnidaria). Gorgonians exhibiting
      treelike networks branch subapically, creating hierarchical mother-daughter
      relationships among branches. We modeled both the intrinsic subapical branching
      along with an ecological-physiological limit to growth or maximum number of
      mother branches (k). Shape is preserved by maintaining a constant ratio (c)
      between the total number of branches and the mother branches. The size frequency
      distribution of mother branches follows a scaling power law suggesting self
      organized criticality. Differences in branching among species with the same k
      values are determined by r (branching rate) and c. Species with r<<c had a
      sigmoid logistic-like growth with a long asymptotic period before reaching k.
      Gorgonians exhibit c and r values in the range of the conditions for a stable
      equilibrium (c>r/2 or c>r>0). Ecological/physiological constraints limit growth
      without altering colony form or the interaction between r and c. The model
      described the branching dynamics giving the form to colonies and how colony
      growth declines over time without altering the branching pattern. This model
      provides a theoretical basis to study branching as a simple function of the
      number of branches independently of ordering- and bifurcation-based schemes.

PMID- 15026986
TI  - Biodistribution of the RD114/mammalian type D retrovirus receptor, RDR.
AB  - BACKGROUND: The limited expression of viral receptors on target cells is a
      recognized barrier to therapeutic gene transfer. Previous analysis of receptor
      expression has been performed using indirect methods due to a lack of receptor
      specific antibodies. METHODS: In this report we have used anti-RDR antiserum to
      provide direct histochemical and flow cytometric analysis of the expression of
      RDR, which is the cognate receptor for RD114-pseudotyped vectors as well as being
      a neutral amino acid transporter. RESULTS: RDR was present on a range of normal
      tissues with relevance to gene therapy including: colon, testis, ovary, bone
      marrow and skeletal muscle. It was also highly expressed on immature cells
      present in the squamous epithelia of skin, cervix, nasal mucosa, bronchus and
      tonsil. Of relevance to possible germline gene transfer, we demonstrated a lack
      of RDR expression on male or female germ cells. RDR expression on mature
      hemopoietic cell subsets showed up to 5-fold variability between individuals
      within each lineage-with some individuals expressing low levels of RDR across all
      blood lineages. Both myeloid and monocytic lineages contained the highest
      fraction of cells expressing RDR, whereas lymphoid lineages showed the lowest.
      Coexpression of CD34 and RDR ranged from 2.04 to 0.44% in G-CSF-mobilized
      peripheral blood samples. CONCLUSIONS: As a means to optimize gene transfer
      protocols, biodistribution studies such as these are fundamental to enable
      targeting of the virus receptor most abundantly expressed on relevant
      populations. The inter-individual variation of receptor expression seen here also
      raises the possible requirement for tailor-made gene therapy protocols.

PMID- 15026987
TI  - An essential role for the His-8 residue of the SDF-1alpha-chimeric, tropism
      redirected Env protein of the Moloney murine leukemia virus in regulating
      postbinding fusion events.
AB  - BACKGROUND: To use retroviral vectors for the cell-specific delivery of genes, it
      is necessary to redirect their receptor tropism to cell-specific receptors.
      Previously, we reported that a Moloney murine leukemia virus (MLV) retroviral
      vector containing a human stromal-derived factor-1alpha (SDF-1alpha)-chimeric
      envelope protein (Env) (S3) acquired the ability to transduce human cells via
      CXCR4, the cognate receptor for SDF-1alpha, while retaining the ability to
      transduce mouse cells via mCAT1. METHODS: We constructed expression plasmids for
      derivatives of the S3 Env protein; S3-D84K containing an Asp-84-to-Lys (D84K)
      substitution, S3-H8R-D84K containing D84K and an additional His-8-to-Arg
      substitution, and S3-D84K-RY containing D84K and additional Gln-227-to-Arg plus
      Asp-243-to-Tyr substitutions which have been suggested to suppress the loss of
      function of His-8. Cellular expression, virion incorporation, and entry functions
      of these derivatives were investigated. RESULTS: All three derivatives were
      incorporated into virions. The S3-D84K vector lost its ecotropism, but could
      transduce CXCR4-expressing human and mouse cells at titers of 10(3) to 10(4)
      colony-forming units (cfu)/ml. The S3-H8R-D84K vector did not show transduction,
      although its Env protein could bind to CXCR4. The transduction titer of the S3
      D84K-RY vector via CXCR4 was slightly lower than that of the S3-D84K vector.
      These results indicate that the His-8 residue of the S3-D84K Env protein is
      indispensable and may be fully functional in postbinding membrane fusion.
      CONCLUSIONS: Insertion of a ligand at Pro-79 of the Moloney MLV Env protein has
      proved to be a valuable strategy for constructing direct targeting retroviral
      vectors, since it permits the formation of a redirected Env protein without
      ecotropism, and it does not disrupt the function of the essential His-8 residue.

PMID- 15026988
TI  - Expression of HIV-1 integrase in CEM cells inhibits HIV-1 replication.
AB  - BACKGROUND: HIV-1 integrase (IN) is an interesting target for the gene therapy of
      AIDS. Although the in vivo functions are not well characterized, it is thought
      that IN has pleiotropic effects and plays a central role in the interplay between
      the virus and the host cell. Expression of IN in mammalian cells has proven
      difficult. We have previously established a 293T-derived cell line that stably
      expresses high levels of HIV-1 IN from a synthetic gene. We now have constructed
      CEM-derived cell lines stably expressing the enzyme or its different domains and
      studied the impact of IN expression on HIV-1 replication. METHODS: The CEM cell
      lines were selected following transduction with a retroviral vector encoding the
      full-length IN, the N-terminal domain, the catalytic core or the C-terminal
      domain. Stable IN expression in CEM cell lines was verified by Western blotting.
      The impact of IN expression on HIV-1 replication and HIV-1 vector transduction
      was studied. RESULTS: A marked inhibitory effect on HIV-1 replication was
      observed in CEM cells expressing IN. Expression of IN interfered with both
      particle production and integration. Expression of the N-terminal domain alone
      was sufficient for the inhibiting of HIV-1 replication. CONCLUSIONS: Expression
      of IN in CEM cells inhibits HIV-1 replication by a cumulative inhibitory effect
      on integration and particle production, in accord with the known pleiotropic
      interactions of IN. The inhibition of HIV-1 replication in CEM cells expressing
      the N-terminal domain of IN may lead to a novel approach for the gene therapy of
      AIDS.

PMID- 15026989
TI  - Transgene expression in hypertrophied and aged skeletal muscle in vivo by
      lentivirus delivery.
AB  - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1)-based lentiviral vectors
      can infect dividing and non-dividing cells. The purpose of this study was to
      investigate the efficacy of lentiviral transfer of the green fluorescent protein
      (eGFP) gene into post-mitotic quail skeletal muscle and into fibers undergoing
      hypertrophy and hyperplasia via addition of satellite cell nuclei. METHODS: A
      vesicular stomatitis virus G-protein (pMFG)-pseudotyped lentiviral vector
      encoding the eGFP gene coding sequence, flanked by two long terminal repeats
      (LTRs) (pHR-CMV-eGFP-Wsin-18) and an optional plasmid (pRSVrev), was generated in
      293T cells by means of the three-plasmid system. The resulting lentiviral vector,
      LtV/eGFP, was injected in vivo into the patagialis muscles of young (6 weeks of
      age) and senescent (100 weeks of age) Japanese quail. Polybrene (10 micro
      g/muscle) was injected in the right patagialis muscles of some birds. A weight
      was attached to the left wing of birds immediately following LtV/eGFP injection
      for 7, 14 or 21 days to induce hypertrophy in the patagialis muscle via satellite
      cell activation. A time-released bromodeoxyuridine (BrdU) pellet was implanted in
      some birds to identify satellite cells that had proliferated during stretch
      overload. Control and experimental muscles were examined 7, 14 or 21 days
      following injection and wing loading. RESULTS: Seven days post-injection proved
      to be insufficient to visualize and quantify the eGFP signal. EGFP-positive
      fibers were evident 14 and 21 days after injection of LtV/eGFP. As expected, wing
      weighting resulted in hypertrophy of the patagialis of senescent and young birds
      and an increase in collagen and other connective tissue in muscles of old birds.
      Nevertheless, this did not interfere with expression levels or intensity of the
      eGFP vector because the area of eGFP-positive fibers normalized to total muscle
      area was similar in control and overloaded muscles, and in muscles that were
      injected with the lentivirus vector but not loaded. Polybrene improved eGFP
      expression by 41% as compared with muscles that received only the lentivirus.
      CONCLUSIONS: These findings provide the first evidence that this lentivirus
      vector is an efficient tool for gene transfer and expression in mature (non
      growing) fibers of adult birds, sarcopenic fibers of senescent birds and
      hypertrophying skeletal muscle fibers of both young adult and old birds. This
      system could be useful for tissue engineering, or treating aging-associated
      muscle-wasting diseases such as sarcopenia, especially when exercise/overload are
      added to gene therapy approaches to combat muscle loss with aging.

PMID- 15026990
TI  - In situ generation of pseudotyped retroviral progeny by adenovirus-mediated
      transduction of tumor cells enhances the killing effect of HSV-tk suicide gene
      therapy in vitro and in vivo.
AB  - BACKGROUND: Hybrid adeno-retroviral vector systems utilize the high efficiency of
      adenovirus transduction to direct the in situ production of retroviral progeny.
      In this study, we show that a single-step transduction of glioma cells with trans
      complementing hybrid adeno-retroviral vectors effectively turns these cells into
      retrovirus vector-producing cells, which in turn facilitates the transduction of
      adjacent cells. METHODS: We have adapted the adeno-retroviral hybrid viral vector
      system to enhance the ganciclovir (GCV) killing of glioma cells following
      transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene. To assess
      the effect of the in situ production of retroviral vectors on the transduction
      efficiency of glioma cells, 9L cells were transduced with adeno-retroviral hybrid
      vectors that separately express a retroviral genome (AVC2.GCEGFP or AVC2.GCTK)
      and retroviral packaging proteins (AxTetGP and AxTetVSVG). The generation of an
      integrated HSV-tk provirus by trans-complementation of the adeno-retroviral
      vectors was verified by analysis of the flanking retroviral LTR sequences. Tumors
      established on nu/nu mice were injected with the viruses followed by
      intraperitoneal injections of either PBS or GCV. We also estimated the copy
      numbers of the HSV-tk transgene present in the tumors of the treated mice. To
      determine the expression pattern of the HSV-tk transcripts within a tumor, in
      situ hybridization analysis was performed using an RNA probe specific for HSV-tk.
      RESULTS: The co-transduction of rat 9L glioma cells with AVC2.GCEGFP together
      with vectors expressing packaging proteins of retroviruses increased the
      transduction efficiency. Transduction with AVC2.GCTK together with packaging
      vectors increased the in vitro sensitivity of cells to the pro-drug GCV by one
      log compared with control cells that were incapable of generating retrovirus. In
      vivo, the injection of established subcutaneous 9L tumors on athymic mice with a
      combination of AVC2.GCTK and packaging vectors followed by GCV treatment resulted
      in complete tumor regression in 50% of tumors at day 22, while no tumor
      regression was observed in control animals. Retroviral sequences diagnostic of 3'
      LTR reduplication in vivo were detected in genomic DNA extracted from the
      transduced tumors, indicating pro-viral integration of the retroviral genome
      derived from the adeno-retroviral hybrid vector. Furthermore, the relative copy
      number of the HSV-tk gene in tumors treated with the adeno-retroviral vectors was
      up to approximately 250-fold higher than in control tumors. In situ hybridization
      suggested dispersion of the HSV-tk product across a wider area of the tumor than
      in control tumors, which indicates the spread of the in situ generated
      retroviruses. CONCLUSIONS: Although the efficacy of this system has to be
      evaluated in orthotopic models, our observations suggest that this hybrid adeno
      retroviral vector system could improve the suicide gene therapy of tumors.

PMID- 15026991
TI  - In vitro and in vivo characterisation of endothelial cell selective adenoviral
      vectors.
AB  - BACKGROUND: Both viral and non-viral gene transfer vectors transduce vascular
      endothelial cells (EC) with low efficiency compared with other cell types such as
      hepatocytes. Generation of EC-selective vectors would enhance the clinical
      utility of gene therapy for diverse vascular-targeted applications. METHODS:
      12mer peptides derived by in vitro phage display with EC binding specificity
      [MTPFPTSNEANL (MTP) and MSLTTPPAVARP (MSL)] were inserted at position T542 in the
      exposed HI loop of the adenovirus (Ad) serotype 5 fiber using overlapping
      oligonucleotides; in combination with a double point mutation (KO1) to ablate
      virus : cell binding via the coxsackie-adenovirus receptor (CAR). The resulting
      modified viruses were tested in vitro and in vivo for their ability to direct
      endothelial-specific gene transfer. RESULTS: Peptide insertion was not
      deleterious to fiber trimerisation or virion maturation. In vitro gene transfer
      studies using a panel of cell types demonstrated that both peptide-targeted Ad
      vectors mediated efficient CAR-independent gene transfer to vascular EC compared
      with non-modified Ads. Neither peptide supported gene delivery to non-EC. Upon
      systemic injection into mice and subsequent evaluation of transgene expression we
      failed to observe a reduction in hepatic Ad accumulation but observed a
      significant elevation in beta-galactosidase in blood vessels with the
      MSLTTPPAVARP-targeted Ad vector. CONCLUSIONS: We have genetically engineered two
      novel Ads that transduce human EC selectively in vitro, one of which leads to
      altered Ad biodistribution in vivo. The successful generation of genetically
      engineered tropism for EC has broad implications for cardiovascular gene therapy.
      Further modifications to the Ad capsid will be required to improve in vivo
      biodistribution profiles.

PMID- 15026992
TI  - Adenovirus vectors targeting alphaV integrin or heparan sulfate receptors display
      different distribution of transgene activity after intramuscular injection.
AB  - BACKGROUND: Modification of the fiber proteins in replication-deficient
      adenoviral (Ad) vectors through incorporation of specific receptor-binding motifs
      may represent a strategy to enhance their tissue targeting capabilities. METHODS:
      In this study, we compared an unmodified Ad (GV10) with two mutated vectors
      obtained by insertion of specific target sequences that redirect binding, either
      toward alpha(V) integrin (RGD) or heparan sulfate (UTV) cellular receptors, for
      reporter gene expression spatial distribution in the rabbit skeletal muscle. In a
      first series of experiments, injection volume was kept constant and activity of a
      lacZ transgene was evaluated 48 h after injection of the Ad vectors at different
      doses. In separate experiments, the effects of different volumes of injection at
      a constant dose of Ad vector were monitored. RESULTS: All vectors evaluated
      showed a significant increase in the number of lacZ-positive muscle segments,
      with increasing vector dose. However, in muscles treated with the UTV vector,
      fewer muscle fibers were beta-gal-positive than in GV10 or RGD vector treated
      animals. In fact, total beta-gal activity increased in a dose-dependent fashion
      in the GV10- and RGD-treated muscles, but not in the UTV-treated ones.
      Remarkably, in samples from UTV-treated animals, a volume-dependent enhancement
      of transgene expression was observed during experiments performed at the same
      dose and different injection volumes. CONCLUSIONS: The results of the present
      study demonstrate that altering Ad affinity for cellular receptors modulates the
      level and distribution of transgene activity, conferring characteristics that may
      allow for treatment customization.

PMID- 15026993
TI  - Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by
      adenovirus-mediated expression of NK4.
AB  - BACKGROUND: To improve the prognosis of patients with gastric cancer it is
      important to develop novel treatment modalities targeting the malignant behavior
      of tumor cells. Concerning this, NK4, which acts as HGF-antagonist and
      angiogenesis inhibitor, might be a potential therapeutic agent for gastric
      cancer. The HGF-c-MET pathway plays a pivotal role in gastric tumor growth,
      invasion, metastasis and angiogenesis. Therefore, the current study investigates
      whether adenoviral vector-mediated NK4 gene therapy has therapeutic potential for
      gastric cancer. METHODS: Expression of HGF and c-MET in normal and (pre
      )malignant gastric tissue was studied by immunohistochemistry. The effects of
      adenoviral vector-mediated expression of NK4 on the biological behavior of
      gastric cancer cells were studied in vitro and in vivo. RESULTS: The majority of
      gastric cancers, i.e. 76%, express c-MET and in all carcinomas HGF is expressed
      in either tumor or stromal cells. Normal gastric epithelial cells do not express
      either of these proteins. Transduction of gastric cancer cells with the
      replication-deficient adenoviral vector AdCMV.NK4 resulted in efficient
      production and secretion of NK4. Consequently, proliferation, migration and
      invasion of gastric cancer cells were significantly inhibited. In addition,
      significantly reduced proliferation of vascular endothelial cells and efficient
      inhibition of angiogenesis were achieved. Finally, treatment of established human
      gastric tumor xenografts with AdCMV.NK4 resulted in significant tumor growth
      delay and significant reduction of intratumoral microvessel density. CONCLUSIONS:
      The present study shows that adenoviral vector-mediated expression of NK4 is a
      promising strategy to treat human gastric cancer by simultaneous interfering with
      primary tumor growth, metastasis and angiogenesis.

PMID- 15026994
TI  - Gene transfection into fetal sheep airways in utero using guanidinium-cholesterol
      cationic lipids.
AB  - BACKGROUND: Over the last several years, we have developed a novel class of
      cationic lipids, cholesterol derivatives characterized by polar head groups with
      guanidinium functions. We have in particular shown that bis(guanidinium)-tren
      cholesterol/dioleoylphosphatidylethanolamine (BGTC/DOPE) cationic liposomes can
      mediate efficient gene transfection into the mouse airways in vivo via direct
      intratracheal administration or intranasal instillation. As prenatal gene therapy
      may be necessary for the treatment of a variety of congenital lung diseases, we
      have explored in the present work the feasibility of BGTC-mediated gene
      transfection into the respiratory tract of fetal sheep in utero. METHODS: Thus,
      BGTC/DOPE liposomes were complexed with plasmids expressing the Escherichia coli
      chloramphenicol acetyltransferase (CAT) reporter gene and the resulting
      lipoplexes were administered to fetal sheep at 70 days of gestation via surgical
      replacement of the airway fluid by the transfection mixture followed by tracheal
      occlusion. The fetal lungs and tracheas were harvested at 72 h and examined for
      CAT expression and evidence of toxicity. RESULTS: CAT expression was detected in
      both lung and trachea homogenates, no CAT expression being observed in control
      fetuses receiving naked plasmid DNA. Immunohistochemical analysis showed that
      airway epithelial cells and some mesenchymal cells were transfected. Pulmonary
      histopathology of varied severity was however observed under our transfection
      conditions and manifested as focal epithelial and mesenchymal lesions.
      CONCLUSIONS: These results show that BGTC/DOPE liposomes can mediate gene
      transfection into the fetal sheep airway epithelium. They also invite the
      development of optimized BGTC-based formulations and administration conditions
      with a view to future prenatal gene transfer experiments involving therapeutic
      genes.

PMID- 15026995
TI  - Polymer-coated polyethylenimine/DNA complexes designed for triggered activation
      by intracellular reduction.
AB  - BACKGROUND: Site-specific gene delivery requires vectors that combine stability
      in the delivery phase with substantial biological activity within target cells.
      The use of biological trigger mechanisms provides one promising means to achieve
      this, and here we report a transfection trigger mechanism based on intracellular
      reduction. METHODS: Plasmid DNA was condensed with thiolated polyethylenimine
      (PEI-SH) and the resulting nanoparticles surface-coated using thiol-reactive
      poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) with 2-pyridyldisulfanyl or
      maleimide groups, forming reducible disulphide-linked or stable thioether-linked
      coatings, respectively. RESULTS: Both sets of polymer-coated complexes had
      similar size and were stable to a 250-fold excess of the polyanion poly(aspartic
      acid) (PAA). Reduction with dithiothreitol (DTT) allowed complete release of DNA
      from disulphide-linked coated complexes, whereas complexes with thioether-linked
      coating remained stable. Disulphide-linked complexes showed 40-100-fold higher
      transfection activity than thioether-linked ones, and activity was selectively
      further enhanced by boosting intracellular glutathione using glutathione
      monoethyl ester or decreased using buthionine sulfoximine. The chloroquine- and
      serum-independent transfection activity of disulphide-linked coated complexes
      suggests this system may provide a viable trigger mechanism to enable site
      specific transfection in complex biological settings. CONCLUSIONS: Linkage of
      hydrophilic polymer coating to PEI/DNA complexes via reducible disulphide bonds
      offers a means of fulfilling the contradictory requirements for extracellular
      stability and intracellular activity.

PMID- 15026996
TI  - Lactosylated polyethylenimine for gene transfer into airway epithelial cells:
      role of the sugar moiety in cell delivery and intracellular trafficking of the
      complexes.
AB  - BACKGROUND: As we have previously shown that lactosylated polyethylenimine (PEI)
      is the most efficient glycosylated PEI for gene transfer into human airway
      epithelial cells in primary culture, we have studied here the role of the lactose
      residue in the enhancement of gene transfer efficiency observed with lactosylated
      PEI as compared with unsubstituted PEI in immortalized (Sigma CFTE29o- cells) and
      primary human airway epithelial cells. METHODS AND RESULTS: After three
      transfections of 1 h performed daily, 60% of Sigma CFTE29o- cells were
      transfected with lactosylated PEI, whereas 25% of cells were transfected with
      unsubstituted PEI (p < 0.05). Cell viability was 1.8-fold greater with
      lactosylated PEI as compared with unsubstituted PEI (p < 0.05). As assessed by
      flow cytometry, the cellular uptake of lactosylated complexes was greater than
      that of complexes made with unsubstituted PEI (p < 0.05) and involved mostly a
      receptor-mediated endocytosis. The study of the intracellular trafficking in
      airway epithelial cells of complexes showed an endosomal and lysosomal
      accumulation of lactosylated complexes. In the presence of a proton pump
      inhibitor, the level of lactosylated and unsubstituted PEI-mediated gene
      expression was reduced more than 20-fold, whereas the cell viability increased to
      almost 100%. For both complexes, a nuclear localization was observed for less
      than 5% of intracellular complexes. CONCLUSIONS: Our results show that the
      greater gene transfer efficiency observed for lactosylated complexes may be
      attributed to a higher amount of lactosylated complexes incorporated by airway
      epithelial cells and a lower cytotoxicity that might be related to reduced
      endosomolytic properties. However, the lactose residues substituting the PEI did
      not promote the entry of the plasmid into the nucleus.

PMID- 15026997
TI  - LIM kinase-2 targeting as a possible anti-metastasis therapy.
AB  - BACKGROUND: Metastatic properties of tumors involve movement of cancerous cells
      from one place to another and tissue invasion. Metastatic cells have altered cell
      adhesion and movement that can be examined by in vitro chemotaxis assays. The
      Rho/ROCK/LIM kinase pathway is one of the major signaling pathways involved in
      tumor metastasis. It is involved in the regulation of the actin cytoskeleton.
      Using the randomized ribozyme library, we initially found that metastatic human
      fibrosarcoma cells harboring ribozyme specific for ROCK lose their metastatic
      properties. In this study, we have determined the effect of ribozymes specific
      for LIM kinase-2 on metastatic and proliferative phenotypes of human fibrosarcoma
      cells. METHODS: We attempted to target LIM kinase-2 (LIMK-2) expression by
      hammerhead ribozymes (Rz) in human metastatic fibrosarcoma cells. An effective
      ribozyme was selected based on the expression analysis. Cells were stably
      transfected with Rz specifically effective for LIMK-2 and were examined for
      metastatic and proliferative properties. RESULTS: Analyses of cellular phenotypes
      such as cell proliferation, cell migration and colony-forming efficiency revealed
      that the suppression of LIMK-2 expression in human fibrosarcoma cells limits
      their migration and dense colony-forming efficiency without affecting cell
      proliferation rate or viability. CONCLUSIONS: Specific targeting of metastatic
      and malignant properties of tumor cells by LIMK-2 ribozyme may serve as an
      effective therapy for invasive tumors with minimum effect on the surrounding
      normal cells.

PMID- 15026999
TI  - Interrupting transmission of genital herpes.

PMID- 15027001
TI  - Specific recognition of virus-infected cells by paired NK receptors.
AB  - NK cells show cytotoxicity and cytokine production upon recognition of virus
      infected cells and play an important role in conferring protective immunity
      against virus infection. Patients who lack functional NK cells are susceptible to
      severe infectious diseases such as herpesvirus infection. In addition, when NK
      cells are removed from cytomegalovirus-resistant mice, the virus titre after
      infection is markedly increased and the mice are likely to die due to infection.
      However, the exact mechanism of how NK cells recognise virus-infected cells has
      remained unclear for a long time. Recent findings of the presence of virus
      specific NK cell receptors and their ligands on virus-infected cells have
      provided a new vision of a protective role of NK cells in virus infection.
      Furthermore, the recognition of virus-infected cells by paired receptors
      consisting of activating and inhibitory receptors was found to correlate with the
      degree of host susceptibility to virus infection. Current topics on the role of
      NK cells in anti-virus immunity are reviewed.

PMID- 15027000
TI  - Rotavirus typing methods and algorithms.
AB  - Vaccination is the current strategy for control and prevention of severe
      rotavirus infections, a major cause of acute, dehydrating diarrhoea in young
      children worldwide. Public health interventions aimed at improving water, food
      and sanitation are unlikely adequately to control the disease. The development of
      vaccines against severe rotavirus diarrhoea is based upon homotypic or
      heterotypic protection provided against either a single common G serotype
      (monovalent vaccines) or against multiple serotypes (multivalent vaccines).
      Rotavirus strain surveillance has a high priority in disease control programmes
      worldwide. The continued identification of the most common G and P serotypes for
      inclusion in vaccines is an important priority. And subsequent to the
      introduction of a vaccine candidate, not only monitoring of circulating strains
      is recommended, but also surveillance of potential reassortment of animal
      rotavirus genes from the vaccine into human rotavirus strains is critical.
      Conventional methods used in the characterisation of rotavirus strains, such as
      enzyme immunoassay serotyping and reverse-transcription PCR-based genotyping
      often fail to identify uncommon and newly appearing strains. The application of
      newer molecular approaches, including sequencing and oligonucleotide microarray
      hybridisation, may be required to characterise such strains. The present paper
      presents a brief overview of the variety of standard methods available, followed
      by suggestions for a systematic approach for routine rotavirus strain
      surveillance as well as for characterisation of incompletely typed rotavirus
      strains. Improved detection and characterisation of incompletely typed strains
      will help to develop a comprehensive strain surveillance that may be required for
      tailoring effective rotavirus vaccines.

PMID- 15027002
TI  - Epidemiological and clinical aspects of human papillomavirus detection in the
      prevention of cervical cancer.
AB  - Cervical cancer is a major cause of death, and the second most frequent cancer in
      women worldwide. Many studies have indicated a causal relation between genital
      human papillomavirus (HPV) infections and cervical cancer. High-risk HPV
      genotypes have been detected in almost 100% of all cervical cancers, and the
      process of HPV mediated carcinogenesis has been partly clarified. The concept
      that HPV is a obligatory cause in cervical cancer development has lead to
      extensive research regarding the incorporation of HPV detection in (1) cervical
      cancer prevention programs, (2) triage of women with abnormal cervical scrapes in
      the screening program, and (3) follow-up of patients treated for cervical
      intraepithelial neoplasia (CIN). Epidemiological studies indicate that 50% of
      women becoming sexually active contract a genital HPV infection within 2 years.
      The lifetime risk of a genital HPV infection is estimated to be 80%, but very few
      of these women will develop cervical cancer. Several studies have shown that the
      persistence of genital HPV infections is especially related to the development of
      cervical cancer. As a result, HPV detection at a single moment was shown to be of
      limited clinical value in the triage of patients with abnormal cervical scrapes,
      or during follow-up after treatment for CIN. Furthermore, major variations in the
      sensitivity of different HPV detection methods, as well as differences in HPV
      detection related to the menstrual cycle, have shown that many facts regarding
      HPV transmission, replication, and detection need to be clarified, before HPV
      detection can be of clinical value.

PMID- 15027003
TI  - The molecular basis of HIV capsid assembly--five years of progress.
AB  - The assembly of HIV is relatively poorly investigated when compared with the
      process of virus entry. Yet a detailed understanding of the mechanism of assembly
      is fundamental to our knowledge of the complete life cycle of this virus and also
      has the potential to inform the development of new antiviral strategies. The
      repeated multiple interaction of the basic structural unit, Gag, might first
      appear to be little more than concentration dependent self-assembly but the
      precise mechanisms emerging for HIV are far from simple. Gag interacts not only
      with itself but also with host cell lipids and proteins in an ordered and
      stepwise manner. It binds both the genomic RNA and the virus envelope protein and
      must do this at an appropriate time and place within the infected cell. The
      assembled virus particle must successfully release from the cell surface and,
      whilst being robust enough for transmission between hosts, must nonetheless be
      primed for rapid disassembly when infection occurs. Our current understanding of
      these processes and the domains of Gag involved at each stage is the subject of
      this review.

PMID- 15027004
TI  - Valency of antibody binding to virions and its determination by surface plasmon
      resonance.
AB  - All IgGs are homobivalent, but their ability to bind bivalently to the surface of
      a virus particle depends mainly on a favourable spacing of cognate epitopes and
      the angle that the FAb arm makes with the virus surface. If the angle of binding
      forces the second FAb arm to point into solution, monovalent binding is
      inevitable. This IgG will have the same affinity as its FAb, will be less stably
      bound than if it were bound bivalently, cannot cross-link epitopes on the surface
      of a virion, and cannot neutralise by cross-linking surface proteins. However, at
      moderate IgG concentrations, monovalently bound IgG can reduce infectivity by
      aggregating virions, a phenomenon that cannot occur with IgG bound bivalently.
      This review describes how surface plasmon resonance can be used to determine the
      valency of IgG binding to enveloped and non-enveloped virus particles, and
      discusses the implications of this new methodology.

PMID- 15027005
TI  - The future of ultrasound: viewing the dark side of the moon?

PMID- 15027006
TI  - High-intensity focused ultrasound: a revolution in non-invasive ultrasound
      treatment?

PMID- 15027007
TI  - Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the 11-14
      week scan.
AB  - OBJECTIVE: To update the likelihood ratio for trisomy 21 in fetuses with absent
      nasal bone at the 11-14-week scan. METHODS: Ultrasound examination of the fetal
      profile was carried out and the presence or absence of the nasal bone was noted
      immediately before karyotyping in 5918 fetuses at 11 to 13+6 weeks. Logistic
      regression analysis was used to examine the effect of maternal ethnic origin and
      fetal crown-rump length (CRL) and nuchal translucency (NT) on the incidence of
      absent nasal bone in the chromosomally normal and trisomy 21 fetuses. RESULTS:
      The fetal profile was successfully examined in 5851 (98.9%) cases. In 5223/5851
      cases the fetal karyotype was normal and in 628 cases it was abnormal. In the
      chromosomally normal group the incidence of absent nasal bone was related first
      to the ethnic origin of the mother, being 2.2% for Caucasians, 9.0% for Afro
      Caribbeans and 5.0% for Asians; second to fetal CRL, being 4.7% for CRL of 45-54
      mm, 3.4% for CRL of 55-64 mm, 1.4% for CRL of 65-74 mm and 1% for CRL of 75-84
      mm; and third to NT, being 1.6% for NT < or = 95th centile, 2.7% for NT > 95th
      centile-3.4 mm, 5.4% for NT 3.5-4.4 mm, 6% for NT 4.5-5.4 mm and 15% for NT > or
      = 5.5 mm. In the chromosomally abnormal group there was absent nasal bone in
      229/333 (68.8%) cases with trisomy 21 and in 95/295 (32.2%) cases with other
      chromosomal defects. Logistic regression analysis demonstrated that in the
      chromosomally normal fetuses significant independent prediction of the likelihood
      of absent nasal bone was provided by CRL, NT and Afro-Caribbean ethnic group, and
      in the trisomy 21 fetuses by CRL and NT. The likelihood ratio for trisomy 21 for
      absent nasal bone was derived by dividing the likelihood in trisomy 21 by that in
      normal fetuses. CONCLUSION: At the 11-14-week scan the incidence of absent nasal
      bone is related to the presence or absence of chromosomal defects, CRL, NT and
      ethnic origin.

PMID- 15027008
TI  - Two- and three-dimensional sonographic assessment of the fetal face. 1. A
      systematic analysis of the normal face.
AB  - OBJECTIVES: To detail fetal facial examination in utero using ultrasound, to
      distinguish between requirements for routine screening and those for precise
      analysis of fetal facial features, and to assess the use of three-dimensional
      (3D) ultrasound imaging in fetal facial examination. METHODS: This was a
      retrospective study, based on the examination of approximately 10,500 fetuses.
      The usual age at screening ultrasound examination was 22 +/- 1 gestational weeks.
      RESULTS: The sonographic anatomy of the normal fetal face was depicted, and the
      relevance of the three reference scanning planes, sagittal, coronal and axial,
      was specified. CONCLUSIONS: At routine screening using two-dimensional
      sonography, at least two selected views must be imaged: the mid-sagittal plane
      (search for facial dysmorphology) and the anterior 'nose-mouth' coronal plane
      (search for disruption in lip continuity or deformation of the narinal bend).
      Precise analysis of fetal facial anomalies requires visualization and thorough
      step-by-step analysis in the three planes. The difference between routine
      screening and precise facial features' analysis has been greatly decreased since
      3D and 4D sonography have become readily available. Using this modality, after
      surface analysis of the fetal face, the three reference planes are simultaneously
      imaged, using the multiplanar modality, and detailed. 3D/4D ultrasound imaging
      allows easier, more rapid screening and more precise evaluation of the different
      facial features.

PMID- 15027009
TI  - Assessment of the fetal nasal bone at 11-14 weeks of gestation by three
      dimensional ultrasound.
AB  - OBJECTIVE: To evaluate the benefit of three-dimensional (3D) ultrasound in the
      examination of the fetal nasal bone at 11-14 weeks of gestation. METHOD: We
      examined the fetal nasal bone in 120 stored volumes acquired transabdominally
      with a 3D scanner from singleton pregnancies at 11-14 weeks of gestation. The
      volume acquisition had been performed following conventional ultrasound
      examination that had demonstrated presence of the fetal nasal bone. The volumes
      were obtained with two-dimensional (2D) start images in transverse, coronal mid
      sagittal, parasagittal and oblique longitudinal sections of the fetal head.
      RESULTS: In the transverse and coronal sections, a satisfactory image
      demonstrating presence of the nasal bone was achieved in only three and one,
      respectively, of the 20 volumes that we obtained. In mid-sagittal sections, the
      nasal bone was always visible when the angle was within a range of 30-60 degrees,
      without the need for sectional image analysis. None of the images with an angle
      >60 degrees or <30 degrees was satisfactory. In the parasagittal sections with
      the fetal profile at 45 degrees, a good-quality image of the nasal bone was
      possible in all cases that were examined, irrespective of the distance from the
      mid-sagittal plane. In the oblique longitudinal sections with the fetal profile
      at 45 degrees, there were 10 volumes where the 2D start section was at 0-25
      degrees from the midline and in all these cases the nasal bone was successfully
      visualized. In contrast, only 5/20 cases where the 2D start section was at 25-90
      degrees from the midline provided a satisfactory image demonstrating the nasal
      bone. In 5/10 volumes obtained with the fetus facing downwards the nasal bone was
      visible in both the 2D and 3D images. CONCLUSION: In a 3D volume the extent to
      which the nasal bone can be demonstrated to be present in a given reconstructed
      section is entirely dependent on obtaining a good initial 2D view.

PMID- 15027010
TI  - Umbilical cord diameter at 11-14 weeks of gestation: relation to chromosomal
      defects.
AB  - OBJECTIVE: To determine the potential value of measuring umbilical cord diameter
      (UCD) at 11-14 weeks of gestation in screening for chromosomal defects. METHODS:
      The UCD was measured in 1323 fetuses immediately before chorionic villus sampling
      for karyotyping at 11-14 weeks of gestation. In the group of chromosomally normal
      fetuses, regression analysis was used to determine the association between UCD
      and crown-rump length (CRL). UCD was compared in normal fetuses and those with
      chromosomal abnormalities. RESULTS: The median gestation was 12 (range, 11-14)
      weeks. The UCD was successfully measured in all cases. The fetal karyotype was
      normal in 1150 pregnancies and abnormal in 173, including 97 cases of trisomy 21.
      In the chromosomally normal group the UCD increased significantly with CRL from a
      mean of 2.9 mm at a CRL of 45 mm to 4.4 mm at a CRL of 84 mm. The UCD in the
      group of fetuses with trisomy 21 was significantly smaller than normal.
      Conversely, there were no significant differences from normal in the UCD of
      fetuses with other chromosomal abnormalities. CONCLUSION: At 11-14 weeks of
      gestation the UCD of fetuses with trisomy 21 is significantly smaller than normal
      but the magnitude of the difference is too small for useful inclusion of this
      measurement in screening.

PMID- 15027011
TI  - Affective state of women following a prenatal diagnosis: predictors of a negative
      psychological outcome.
AB  - OBJECTIVE: The benefits of prenatal diagnostic procedures are well documented.
      However, the investigation of psychological consequences related to these
      procedures has remained a surprisingly neglected area of research. The main aim
      of the present study was to investigate the potential relationship between
      psychological outcome and associated (socio-demographic, psychological and
      obstetric) variables in women attending a tertiary referral center for prenatal
      diagnosis and therapy for ultrasound scanning (due to the suspicion of a fetal
      malformation raised by the gynecologist in private practice), amniocentesis or
      chorionic villus sampling. METHODS: Affective state was assessed by means of
      standardized measures of anxiety and depression (State-Trait Anxiety Inventory;
      Mood Scale) in 77 consecutive, unselected women. A follow-up investigation,
      including an additional assessment of coping mechanisms, took place 6 months
      after the first contact. Given the considerable number of intervening and
      correlating factors, a path analysis was undertaken. RESULTS: We found that all
      women in our sample experienced acute distress, not only those with proven fetal
      malformations, genetic disorders or intrauterine fetal death, but also those with
      the diagnosis of a sonographic sign. At baseline (i.e. immediately after the
      diagnostic procedure), mood and anxiety scores in our sample were found to be
      comparable to those of patients with a major depressive episode. A high trait
      anxiety level, implementation of negative coping strategies and loss of the child
      during pregnancy were found to be predictive of a negative psychological outcome
      at follow-up. Socio-demographic variables did not have a significant predictive
      function for the psychological outcome. CONCLUSIONS: We assume that a
      considerable number of women undergoing prenatal diagnostic procedures experience
      psychological distress, which may be underestimated by workers in prenatal care.
      Establishment of interdisciplinary treatment settings, in which access to
      psychological support is facilitated, may be extremely beneficial for women
      following a prenatal diagnosis.

PMID- 15027012
TI  - Cesarean scar pregnancy: issues in management.
AB  - OBJECTIVE: To evaluate our experience with the diagnosis and treatment of
      Cesarean scar pregnancy. METHODS: During a 6-year period, 12 cases of Cesarean
      scar pregnancy were diagnosed using transvaginal color Doppler sonography and
      treated conservatively to preserve fertility. Incidence, gestational age,
      sonographic findings, beta-human chorionic gonadotropin ( beta-hCG) levels, flow
      profiles of transvaginal color Doppler ultrasound, and methods of treatment were
      recorded. RESULTS: The incidence of Cesarean scar pregnancy was 1:2216 and its
      rate was 6.1% in women with an ectopic pregnancy and at least one previous
      Cesarean section. Gestational age at diagnosis ranged from 5 + 0 to 12 + 4 weeks.
      The time interval from the last Cesarean section to the diagnosis of Cesarean
      scar pregnancy ranged from 6 months to 12 years. High-velocity and low-impedance
      subtrophoblastic flow (resistance index, 0.38) persisted until beta-hCG declined
      to normal. Patients were treated as follows: transvaginal ultrasound-guided
      injection of methotrexate into the embryo or gestational sac (n = 3),
      transabdominal ultrasound-guided injection of methotrexate (n = 2),
      transabdominal ultrasound-guided injection of methotrexate followed by systemic
      methotrexate administration (n = 2), systemic methotrexate administration alone
      (n = 2), dilatation and curettage (n = 2), or local resection of the gestation
      mass (n = 1). Eleven of the 12 patients preserved their reproductive capacity;
      the remaining patient, treated by dilatation and curettage, underwent a
      hysterectomy because of profuse vaginal bleeding. The Cesarean scar mass
      regressed from 2 months to as long as 1 year after treatment. Uterine rupture
      occurred in one patient during the following pregnancy at 38 + 3 weeks'
      gestational age. CONCLUSION: Ultrasound-guided methotrexate injection emerges as
      the treatment of choice to terminate Cesarean scar pregnancy. Surgical or
      invasive techniques, including dilatation and curettage are not recommended for
      Cesarean scar pregnancy due to high morbidity and poor prognosis.

PMID- 15027013
TI  - Do maternal cerebral vascular changes assessed by transcranial Doppler antedate
      pre-eclampsia?
AB  - OBJECTIVE: To determine whether maternal transcranial Doppler (TCD) evaluation of
      the middle cerebral artery identifies changes in the cerebral circulation prior
      to the development of pre-eclampsia. METHODS: In a nested, case-controlled study
      developed from a previous prospective cohort study, 20 pre-eclamptic and 40
      normotensive pregnancies, matched for maternal age, were assessed with the
      traditional middle cerebrovascular Doppler parameters (pulsatility index, mean
      cerebral blood flow velocity), together with non-traditional Doppler parameters
      including time taken to achieve end systole (EST) and percentage time to achieve
      end systole (% EST). Assessments done at 20-24 and 28-32 weeks' gestational age
      were compared using Student's t-tests. Significance was set at the P < 0.05
      level. RESULTS: In the second trimester (20-24 weeks) there were no significant
      differences in any of the Doppler waveform characteristics in either group. In
      the third trimester (28-32 weeks) there was a significant increase in the % EST
      in the group who subsequently developed pre-eclampsia (45.2 +/- 4.2 vs. 42.3 +/-
      4.1; P < 0.01). CONCLUSIONS: Patients who subsequently develop pre-eclampsia show
      a significant lengthening in the EST in the third trimester as a late finding,
      which indicates an increase in the cerebrovascular resistance. Earlier prediction
      of pre-eclampsia using TCD waveform analysis will require more provocative
      testing (i.e. hand grip and CO(2) reactivity).

PMID- 15027014
TI  - Time domain measurement of blood flow in the human fetal aorta during normal
      pregnancy.
AB  - OBJECTIVE: To evaluate blood-volume flow-rate measurement in the fetal descending
      thoracic aorta using a non-invasive, non-Doppler, ultrasound technique. METHODS:
      This was a cross-sectional, observational study. Volume flow measurements were
      obtained from the descending thoracic aorta in 59 human fetuses between 20 and 40
      weeks' gestation. These were uncomplicated pregnancies that resulted in the live
      births of appropriately grown infants. The measurements were obtained using a
      time domain processing technique: color velocity imaging quantification (CVI-Q).
      RESULTS: The blood-volume flow rate increased consistently from the second
      trimester until term. The mean values ranged between 100 mL/min at 20 weeks'
      gestation and approximately 350 mL/min at term. The normalized (weight-adjusted)
      volume flow rates decreased with increasing gestation, from a maximum of 626
      mL/min/kg at 23 weeks to a minimum of 45.6 mL/min/kg at 37 weeks. CONCLUSIONS:
      The regular measurement of blood-volume flow in the descending fetal thoracic
      aorta is feasible using CVI-Q. Although there is a considerable learning curve,
      with adequate training there are potential clinical applications for this non
      Doppler technique. However, limitations exist with the currently available
      technology for clinical use in fetal vascular studies.

PMID- 15027016
TI  - The 'iris effect': how two-dimensional and three-dimensional ultrasound can help
      us understand anti-incontinence procedures.
AB  - OBJECTIVE: The objective of this prospective, observational study in patients
      after tension-free vaginal tape (TVT) implantation was to describe the spatial
      relationship between suburethral sling implants, urethra and bony pelvis with the
      help of translabial two-dimensional and three-dimensional (3D) ultrasound.
      METHODS: A total of 141 women were examined by translabial ultrasound, supine and
      after voiding. The TVT sling is highly echogenic and easily identified posterior
      to the urethra. Tape location was described in the mid-sagittal plane relative to
      bladder neck and inferoposterior symphyseal margin, at rest and on Valsalva
      maneuver. In a subset of 83 women, 3D volume ultrasound was performed. RESULTS:
      The cranial tape margin was situated on average 9.3 mm above and 16.5 mm
      posterior to the symphyseal margin (Valsalva: 3.9 mm below and 9.6 mm behind the
      symphysis); the average tape movement on Valsalva was 16 (range, 2-34.2) mm. The
      distance between tape and inferoposterior symphyseal margin narrowed highly
      significantly from 20.4 +/- 4.3 mm at rest to 12.9 +/- 3.9 mm on Valsalva (P <
      0.001). When a fitted line plot was placed through tape coordinates on an x-y
      coordinate system, it became evident that tape movement occurs in an arc around
      the fulcrum of the posterior symphysis pubis. The result is an increasing
      reduction in the gap between tape and symphysis pubis (termed the 'iris effect'),
      implying mechanical compression of the urethra. CONCLUSIONS: The curative effect
      of the TVT on stress incontinence is likely to be due to mechanical compression
      of the urethra between implant and symphysis pubis. A large variation in tape
      location and movement explains its wide margin of clinical safety and efficacy.

PMID- 15027015
TI  - High-intensity focused ultrasound in the treatment of postpartum hemorrhage: an
      animal model.
AB  - OBJECTIVE: To investigate the use of high-intensity focused ultrasound (HIFUS) to
      reduce uterine artery blood flow in ewes in the postpartum period. METHODS: HIFUS
      was applied to the uterine arteries of seven ewes in the postpartum period.
      Arterial flow velocities were measured before and after the procedure at the site
      of HIFUS application (target), as well as 3 cm upstream and 3 cm downstream from
      the target. The uterine arteries were then removed for macroscopic and
      histological examination. RESULTS: Maximum flow velocities in the target area
      increased after the procedure by 350% and those upstream from the target
      decreased by 65%. Macroscopically, the vessel diameter was shown to have reduced
      at the site of HIFUS application. Microscopically, both the endothelium and media
      showed thermal lesions. Tissues surrounding the arteries were macroscopically and
      microscopically normal. CONCLUSION: Exposure of uterine arteries to HIFUS reduces
      the vessel diameter and thus induces a dramatic increase in the maximum flow
      velocities within the target area. HIFUS may have a role in the treatment of
      postpartum hemorrhage.

PMID- 15027017
TI  - Correlating structure and function: three-dimensional ultrasound of the urethral
      sphincter.
AB  - OBJECTIVE: Three-dimensional (3D) ultrasound facilitates assessment of the
      anatomy of the urethral sphincter, a decrease in sphincter volume being
      associated with stress incontinence. Urethral pressure profilometry (UPP) is used
      to assess urethral sphincter function although it is not diagnostic of stress
      incontinence. The aim of this pilot study was to determine whether 3D sphincter
      volume can be correlated with the area under the UPP curve. METHODS: Primigravid
      women were recruited antenatally between 32 and 42 weeks' gestation. 3D
      transvaginal ultrasound scans of the urethra were performed in modified lithotomy
      position with a comfortably full bladder. Length and cross-sectional area were
      measured allowing the sphincter volume to be calculated. UPP measurements were
      performed with a Gaeltec solid-state pressure transducer and the area under the
      curve mapped out and calculated. All scans and measurements were repeated between
      3 and 6 months postpartum. RESULTS: Nineteen women participated in the study.
      Antenatal and postnatal data were available in all cases. There was a
      statistically significant correlation between antenatal sphincter volumes and
      area under the UPP curve although this relationship was lost following delivery.
      CONCLUSIONS: There appears to be a correlation between structural anatomy and
      functional anatomy in the antenatal period although following delivery this is
      lost.

PMID- 15027018
TI  - Introital ultrasound of the lower genital tract before and after colposuspension:
      a 4-year objective follow-up.
AB  - OBJECTIVE: To assess the topography of the bladder neck by introital ultrasound
      before and after open colposuspension. METHODS: Three hundred and ten women with
      urodynamically proven stress urinary incontinence were included in this long-term
      study to investigate the position and function of the bladder neck at rest and
      during straining. Height (H), distance (D), and urethrovesical angle of the
      bladder neck (beta) were measured by means of preoperative and postoperative
      introital ultrasound. Women were followed up; 152 of them (49%) completed 48
      months of follow-up. RESULTS: At the 6-month follow-up examination, 90.0% of the
      women were continent (279/310), 3.5% (11/310) showed voiding difficulties, 3.5%
      (11/310) had urgency, and 1.6% (5/310) had developed de novo urge incontinence.
      At the 48-month follow-up, 76.8% of the patients were still continent. All
      postoperative measurements yielded significantly lower values for angle beta at
      rest and during straining compared with the preoperative results (P < 0.0001).
      The median linear movement of the bladder neck during straining decreased from
      18.0 mm before surgery to 6.4 mm at the 48-month follow-up (P < 0.0001). The
      median level of ventrocranial elevation of the vesicourethral junction was 14.3
      mm immediately after surgery, 9.9 mm after 6 months and 6.6 mm after 48 months.
      The degree of surgical bladder-neck elevation was associated with postoperative
      urgency/de novo urge incontinence (P < 0.0001) and voiding difficulty (P <
      0.0001). CONCLUSIONS: The colposuspension procedure reduces angle beta at rest
      and during straining, restricts linear movement with straining, and elevates the
      bladder neck. Perioperative introital ultrasound improves understanding of this
      surgical procedure and might help to prevent postoperative complications.

PMID- 15027019
TI  - Transvaginal sonographic appearance of peritoneal pseudocysts.
AB  - OBJECTIVE: To describe the sonographic features of peritoneal pseudocysts (PPCs)
      in order to determine the particular aspects that distinguish them from true
      ovarian cysts. METHODS: Thirty-one women with PPCs were investigated using
      transvaginal sonography immediately before surgery. The diameters of the cysts
      were measured, and the shape, margins, content, location, presence of septa and
      echogenic portions were analyzed. RESULTS: The PPCs were monolateral in 20 (65%)
      and bilateral in 11 (35%) women. A well-defined cystic structure was found in
      only six (19%) women, while in the other 25 (81%) women the PPCs showed blurred,
      undefined margins and a bizarre morphology, giving them a star-like tubular or
      lumpy shape. The ipsilateral ovary was identified in 26 (84%) cases either
      external to the cyst or entrapped within it like a 'spider in a web'. Septa were
      present in 25 (81%) cases and were often mobile, resembling a 'flapping sail'
      when touched by the endovaginal probe. CONCLUSION: Despite having a gross
      morphology resembling that of a true ovarian cyst, PPCs present some
      characteristic sonographic findings that allow a correct differential diagnosis
      in the vast majority of cases.

PMID- 15027020
TI  - Cesarean section scar evaluation by saline contrast sonohysterography.
AB  - OBJECTIVE: To investigate the frequency of images suggesting the existence of a
      dehiscence at the site of the uterine scar after Cesarean section. METHODS:
      Thirty-three women with a past history of Cesarean section who were planning a
      further pregnancy were involved in the study. Saline contrast sonohysterography
      (SCSH) was performed a minimum of 3 months following Cesarean section. The
      thickness of the residual myometrium, the thickness of the myometrium bordering
      the scar and the depth of the filling defect in the scar (i.e. the 'niche',
      defined as a triangular, anechoic area at the presumed site of incision) were
      recorded in each case. A 'dehiscence' was defined as a niche whose depth was at
      least 80% of the anterior myometrium. RESULTS: In 19/33 (57.5%) patients a niche
      with a depth of 4.2 +/- 2.5 (range, 1.2-11.7) mm was identified. In these
      patients the residual myometrium measured 6.5 +/- 2.7 (range, 0-10.9) mm vs. 8.9
      +/- 2.0 (range, 6.9-13.9) mm in the remaining 14 patients without a niche. Within
      the 19 niches, two dehiscences were identified. CONCLUSION: Niches can be
      identified by SCSH following a Cesarean section in about 60% of patients. The
      prevalence of scar dehiscence (in the present series 2/33 or 6%) is much higher
      than the reported risk of uterine rupture (0.4%).

PMID- 15027022
TI  - Ultrasound diagnosis of intra-urethral tension-free vaginal tape (TVT) position
      as a cause of postoperative voiding dysfunction and retropubic pain.
AB  - Intra-urethral Prolene tape erosion is a rare postoperative complication of
      tension-free vaginal tape (TVT) plasty. In cases reported in the literature,
      intra-urethral tape positioning has been diagnosed by urethroscopy as late as 3
      12 months after the procedure. Introital ultrasound using a vaginal sector
      scanner allows for the non-invasive assessment of the position of the Prolene
      tape in relation to the urethra. Postoperative introital ultrasound might shorten
      the interval between surgery and the time of diagnosis of an intra-urethrally
      placed tape and thus significantly shorten the duration of symptoms. We present a
      patient with urethral pain syndrome and dysuria following TVT plasty. In this
      case, introital ultrasound was not performed until 8 months after surgery, when
      it demonstrated intra-urethral Prolene tape positioning as the cause of the
      patient's complaints. All symptoms disappeared after surgical removal of the
      intra-urethrally placed parts of the tape. The patient is continent, suggesting
      that the remaining para-urethral portions of the Prolene tape depicted
      sonographically ensured adequate stabilization of the mid-urethra in this case.
      The case report emphasizes the role of introital ultrasound in assessing Prolene
      tape position relative to the urethra on sagittal and transverse angulated views
      in the postoperative diagnostic evaluation of functional disturbances occurring
      after TVT plasty.

PMID- 15027021
TI  - Enlarged adrenal glands as a prenatal marker of congenital adrenal hyperplasia: a
      report of two cases.
AB  - We report the prenatal findings of congenital adrenal hyperplasia (CAH) in two
      consecutive fetuses of one family. The first pregnancy was terminated at 23
      weeks' gestation due to the presence of a complex heart anomaly. The adrenal
      glands appeared enlarged on prenatal ultrasound examination and autopsy confirmed
      CAH. The parents were subsequently examined and were found to be heterozygous for
      nucleotide 656 of the CYP21B gene. In a subsequent pregnancy, chorionic villus
      sampling at 11 weeks confirmed CAH in the male fetus. At this gestational age,
      mild body edema was present and the nuchal translucency measured 2.1 mm. From 14
      weeks onwards, enlargement of the adrenal glands was the only sign of CAH. These
      findings suggest that enlarged adrenal glands may be a prenatal sign for CAH. In
      fetal medicine, when a pregnancy is terminated due to fetal malformations,
      autopsy should be performed because it can provide additional information that is
      helpful in counseling women with regard to subsequent pregnancies.

PMID- 15027023
TI  - Sonographic findings in a case of voiding dysfunction secondary to the tension
      free vaginal tape (TVT) procedure.
AB  - The tension-free vaginal tape (TVT) procedure was introduced as a minimally
      invasive surgical technique for treating female stress urinary incontinence. This
      procedure is supposed to be associated with less postoperative voiding
      dysfunction because the vaginal tape, theoretically, remains tension-free.
      Nevertheless, significant voiding dysfunction or complete urinary retention has
      been reported to complicate 2.8% to 7.6% of TVT procedures. We report a case of
      voiding dysfunction following a TVT procedure. Two-dimensional sonography
      revealed the tape situated beneath the mid-urethra. The spatial orientation
      between the vaginal tape and the urethral structure was clearly demonstrated on
      three-dimensional scanning. The urethra was indented from the posterior by the
      vaginal tape, resulting in acute constriction of the hypoechogenic region of the
      urethra. Urethral dilation was performed using Hegar dilators. Thereafter, the
      patient's voiding difficulty improved dramatically and the residual urine volume
      decreased. One week later, repeat sonography showed the hypoechogenic region of
      the urethra to have a normal configuration with a lesser degree of urethral
      indentation.

PMID- 15027025
TI  - Cesarean scar pregnancy: diagnosis with three-dimensional (3D) ultrasound and 3D
      power Doppler.

PMID- 15027024
TI  - A case of agnathia, tetramelia and diaphragmatic hernia at 18 weeks' gestation.

PMID- 15027026
TI  - Intramural pregnancy embedded in a previous Cesarean section scar treated
      conservatively.

PMID- 15027027
TI  - Assessment of fetal body composition.

PMID- 15027028
TI  - Diastrophic dysplasia: prenatal three-dimensional ultrasound findings.

PMID- 15027029
TI  - The substrate recognition mechanisms in chaperonins.
AB  - Chaperonins are a family of proteins devoted to assisting the folding of other
      proteins. They are large oligomers assembled into ring structures that enclose a
      cavity in which folding takes place. For this process to occur, the chaperonin
      must first recognize and interact with the unfolded polypeptide, then undergo a
      conformational change upon nucleotide binding that results in the closure of the
      cavity which in turn mediates the folding reaction inside the cavity. Although
      this general mechanism seems to apply to every chaperonin studied so far, there
      exist two different modes of interaction between the chaperonin and the
      substrate. The first occurs mainly through the interaction between the exposed
      hydrophobic residues of the unfolded polypeptides and those of the chaperonin
      substrate binding site, as elucidated for the chaperonin GroEL from E. coli. The
      second type of mechanism has been described so far only for the cytosolic
      chaperonin CCT (Chaperonin Containing TCP-1) and here the interaction seems to be
      of a more specific nature, involving charged and polar residues in both the
      chaperonin and the substrate, which interacts with CCT in a structured, quasi
      native conformation.

PMID- 15027030
TI  - Synthesis and receptor binding of IgG1 peptides derived from the IgG Fc region.
AB  - The IgG binding Fcgamma receptors (FcgammaRs) play a key role in defence against
      pathogens by linking humoral and cell-mediated immune responses. Impaired
      expression and/or function of FcgammaR may result in the development of
      pathological autoimmunity. Considering the functions of FcgammaRs, they are
      potential target molecules for drug design to aim at developing novel anti
      inflammatory and immunomodulatory therapies. Previous data mostly obtained by X
      ray analysis of ligand-receptor complexes indicate the profound role of the CH2
      domain in binding to various FcgammaRs. Our aim was to localize linear segments,
      which are able to bind and also to modulate the function of the low affinity
      FcgammaRs, like FcgammaRIIb and FcgammaRIIIa. To this end a set of overlapping
      octapeptides was prepared corresponding to the 231-298 sequence of IgG1 CH2
      domain and tested for binding to human recombinant soluble FcgammaRIIb. Based on
      these results, a second group of peptides was synthesized and their binding
      properties to recombinant soluble FcgammaRIIb, as well as to FcgammaRs expressed
      on the cell surface, was investigated. Here we report that peptide representing
      the Arg(255)-Ser(267) sequence of IgG1 is implicated in the binding to
      FcgammaRIIb. In addition we found that peptides corresponding to the Arg(255)
      Ser(267), Lys(288)-Ser(298) or Pro(230)-Val(240) when presented in a multimeric
      form conjugated to branched chain polypeptide in uniformly oriented copies
      induced the release of TNFalpha, a pro-inflammatory cytokine from MonoMac
      monocyte cell line. These findings indicate that these conjugated peptides are
      able to cluster the activating FcgammaRs, and mediate FcgammaR dependent
      function. Peptide Arg(255)-Ser(267) can also be considered as a lead for further
      functional studies.

PMID- 15027031
TI  - Kinetic and thermodynamic characterization of HIV-1 protease inhibitors.
AB  - Interaction kinetic and thermodynamic analyses provide information beyond that
      obtained in general inhibition studies, and may contribute to the design of
      improved inhibitors and increased understanding of molecular interactions. Thus,
      a biosensor-based method was used to characterize the interactions between HIV-1
      protease and seven inhibitors, revealing distinguishing kinetic and thermodynamic
      characteristics for the inhibitors. Lopinavir had fast association and the
      highest affinity of the tested compounds, and the interaction kinetics were less
      temperature-dependent as compared with the other inhibitors. Amprenavir,
      indinavir and ritonavir showed non-linear temperature dependencies of the
      kinetics. The free energy, enthalpy and entropy (DeltaG, DeltaH, DeltaS) were
      determined, and the energetics of complex association (DeltaG(on), DeltaH(on),
      DeltaS(on)) and dissociation (DeltaG(off), DeltaH(off), DeltaS(off)) were
      resolved. In general, the energetics for the studied inhibitors was in the same
      range, with the negative free energy change (DeltaG < 0) due primarily to
      increased entropy (DeltaS > 0). Thus, the driving force of the interaction was
      increased degrees of freedom in the system (entropy) rather than the formation of
      bonds between the enzyme and inhibitor (enthalpy). Although the DeltaG(on) and
      DeltaG(off) were in the same range for all inhibitors, the enthalpy and entropy
      terms contributed differently to association and dissociation, distinguishing
      these phases energetically. Dissociation was accompanied by positive enthalpy
      (DeltaH(off) > 0) and negative entropy (DeltaS(off) < 0) changes, whereas
      association for all inhibitors except lopinavir had positive entropy changes
      (DeltaS(on) > 0), demonstrating unique energetic characteristics for lopinavir.
      This study indicates that this type of data will be useful for the
      characterization of target-ligand interactions and the development of new
      inhibitors of HIV-1 protease.

PMID- 15027032
TI  - The role of flexibility and hydration on the sequence-specific DNA recognition by
      the Tn916 integrase protein: a molecular dynamics analysis.
AB  - The N-terminal domain of the Tn916 integrase protein (INT-DBD) is responsible for
      DNA binding in the process of strand cleavage and joining reactions required for
      transposition of the Tn916 conjugative transposon. Site-specific association is
      facilitated by numerous protein-DNA contacts from the face of a three-stranded
      beta-sheet inserted into the major groove. The protein undergoes a subtle
      conformational transition and is slightly unfolded in the protein-DNA complex.
      The conformation of many charged residues is poorly defined by NMR data but
      mutational studies have indicated that removal of polar side chains decreases
      binding affinity, while non-polar contacts are malleable. Based on analysis of
      the binding enthalpy and binding heat capacity, we have reasoned that dehydration
      of the protein-DNA interface is incomplete. This study presents results from a
      molecular dynamics investigation of the INT-DBD-DNA complex aimed at a more
      detailed understanding of the role of conformational dynamics and hydration in
      site-specific binding. Comparison of simulations (total of 13 ns) of the free
      protein and of the bound protein conformation (in isolation or DNA-bound) reveals
      intrinsic flexibility in certain parts of the molecule. Conformational adaptation
      linked to partial unfolding appears to be induced by protein-DNA contacts. The
      protein-DNA hydrogen-bonding network is highly dynamic. The simulation identifies
      protein-DNA interactions that are poorly resolved or only surmised from the NMR
      ensemble. Single water molecules and water clusters dynamically optimize the
      complementarity of polar interactions at the 'wet' protein-DNA interface. The
      simulation results are useful to establish a qualitative link between
      experimental data on individual residue's contribution to binding affinity and
      thermodynamic properties of INT-DBD alone and in complex with DNA.

PMID- 15027033
TI  - Identification of differences in the specificity-determining residues of
      antibodies that recognize antigens of different size: implications for the
      rational design of antibody repertoires.
AB  - Studies of antibodies of known three-dimensional structure have revealed that
      insertion and deletion of amino acids at the hypervariable loops change the
      canonical structures, thus generating differences in the antigen-binding site
      topography. Such differences determine the size of the antigen with which the
      antibody interacts. Here, 59 unique antibodies determined at a resolution of 3.0
      A or below, including 19 in complex with proteins, 18 with peptides and 22 with
      haptens, were analyzed to identify and characterize differences in the residues
      that are directly involved in the interaction with antigen, so-called specificity
      determining residues (SDRs). It was found that antibodies use a similar number of
      SDRs to recognize proteins and peptides but contact haptens with five SDRs less.
      By using a score of SDR usage, differences in the location of the SDRs, depending
      on the type of antigen recognized, were then identified with precision. An
      analysis of the surface generated by the SDRs usage indicates that the
      differences found correlate well with the size of the antigen. Anti-protein
      antibodies have the largest SDR surface, with SDRs of high usage located in the
      edge of the surface. The SDR surface of anti-hapten antibodies is the smallest,
      with hot spots of contacts in the interior of the binding surface and buried in
      the V(L):V(H) interface. The SDR surface of anti-peptide antibodies has a size in
      between anti-protein and anti-hapten antibodies, with the SDRs of high usage
      located in the interior of the antigen-binding site but do not buried as in anti
      hapten antibodies. These findings led to a fine-tuning of the model correlating
      differences in the antigen-binding site topography with its preference to
      recognize antigens of different size. Therefore, it is discussed how this
      knowledge should help to design antibody repertoires biased toward the
      recognition of antigens of predefined size.

PMID- 15027034
TI  - Validity and reliability of the newly translated Hellenic Neuropsychiatric
      Inventory (H-NPI) applied to Greek outpatients with Alzheimer's disease: a study
      of disturbing behaviors among referrals to a memory clinic.
AB  - CONTEXT: No rating scales of the neuropsychiatric symptoms of patients with
      dementia and Alzheimer's disease (AD) have previously been developed or
      translated. OBJECTIVES: To develop a Hellenic translation of the Neuropsychiatric
      Inventory (NPI), to evaluate it's reliability and validity, and to compare NPI
      results in Greek patients referred to a neuropsychiatry clinic for either of two
      reasons: disturbing behaviors evoking embarrassment and disturbing behaviors
      evoking fear in the caregiver. METHODS: The Hellenic translations of the NPI,
      Brief Psychiatric Rating Scale (BPRS), and Emotional Distress Scale (EDS) were
      compared in evaluating 29 consecutive referrals of patients with AD. RESULTS: The
      Hellenic NPI (H-NPI) demonstrated a high degree of internal consistency
      reliability, and of concurrent validity when compared to the BPRS or the EDS.
      Patients referred for behaviors evoking embarrassment presented with higher
      scores on NPI ratings of apathy. However, patients referred for behaviors evoking
      fear presented with higher scores on NPI ratings of aggression and irritability.
      CONCLUSIONS: These results indicate that the H-NPI is a reliable instrument, able
      to detect differences in clinically referred groups of AD patients.

PMID- 15027036
TI  - Differential age-related change of prose memory in older Hong Kong Chinese of
      higher and lower education.
AB  - BACKGROUND: Memory difficulty is one of the most common complaints of older
      people, with or without psychiatric conditions. It is therefore of utmost
      important to understand how normal ageing process impacts upon prose memory so as
      to gain insight into ways to differentiate pathological vs normal age-related
      changes of the recall of prose observed among older people. OBJECTIVES: To
      understand the differential age-related change of prose memory in older Hong Kong
      Chinese of higher and lower education. METHOD: Forty-eight normal, healthy
      Cantonese-speaking Chinese were recruited. Seventeen of them were younger, highly
      educated participants. Among the 31 older people recruited, 19 of them received
      education comparable with the younger participants and 12 were older people of
      low education. A prose passage was constructed to measure the different processes
      of prose memory, including learning efficiency, rate of forgetting, recall
      accuracy, accuracy of temporal sequence of information recalled, distortions, and
      recognition memory. RESULTS: As expected, ageing affected all the processes of
      prose memory measured, except the rate of forgetting. Apart from learning
      efficiency and rate of forgetting, education was observed to modify the effect of
      ageing on all the processes studied. CONCLUSIONS: Changes of prose memory
      associated with ageing and the differential effect of education on prose recall
      among older people were discussed. The findings seem to suggest that prose memory
      is a multifaceted construct.

PMID- 15027035
TI  - Differential associations of Head and Body Symptoms with depression and physical
      comorbidity in patients with cognitive impairment.
AB  - OBJECTIVE: To test the hypothesis that physical symptoms referred to the head
      might be specifically associated with depression in patients with cognitive
      impairment. METHODS: Subjects were taken from those enrolled in 'The Mild
      Project' a prospective study on the natural history of mild dementia (Mini Mental
      State Examination > or = 18) and with a diagnosis of Alzheimer's disease,
      vascular dementia, and mild cognitive impairment. A total of 129 subjects were
      included in the study. Physical symptoms were assessed with a checklist
      investigating nine different body organs or apparati. Physical symptoms were
      grouped into those referred to the head (Head Symptoms: ear and hearing; eyes and
      sight; and head and face) and all the others (Body Symptoms). Depressive symptoms
      were assessed with the Geriatric Depression Scale (GDS) and physical comorbidity
      with Greenfield's Index of Disease Severity (IDS). RESULTS: The number of
      patients reporting one or more Head Symptoms linearly increased with increasing
      depression severity (Mantel-Haenszel test = 6.497, df = 1, p = 0.011), while the
      number of patients reporting one or more Body Symptoms linearly increased with
      increasing physical comorbidity (Mantel-Haenszel test = 4.726, df = 1, p =
      0.030). These associations were confirmed in multivariate logistic regression
      models with adjustment for potential confounders (age, gender, education,
      cognitive performance, daily function, and diagnosis). CONCLUSIONS: Head Symptoms
      are specifically associated with depression while Body Symptoms with physical
      comorbidity, in patients with cognitive impairment. Recognizing these
      associations in individual patients may help clinicians decide whether to
      initiate or continue antidepressant therapy or whether to carry out physical
      instrumental investigations.

PMID- 15027037
TI  - No effects of a combination of caregivers support group and memory training/music
      therapy in dementia patients from a memory clinic population.
AB  - OBJECTIVES: To evaluate the impact of a combination of caregiver support group
      and memory training/music therapy in dementia patients on behavioural and
      psychological symptoms (BPSD) and caregiver burden compared to a control group.
      METHOD: Eighteen patient-carer-dyads in the treatment group and 18 patient-carer
      dyads as controls were studied in the setting of a memory clinic of a psychiatric
      university hospital over a period of 2 years. Controls were matched for age,
      gender, diagnosis, dementia severity, living arrangement and medication. The
      interventions were conducted once per week for 1 hour run by a clinical
      psychogeriatric team. Outcome measures were patients' cognitive and functional
      status as well as BPSD and caregivers subjective burden and depression measured
      by validated scales. Data were obtained 6, 12 and 24 months after baseline.
      RESULTS: There were no significant differences between the intervention and
      control group neither after 6, 12 nor after 24 months treatment. CONCLUSIONS: The
      lack of a positive impact in alleviating caregiver burden or BPSD after intensive
      psychological interventions may result from extensive care in the routine
      clinical management including individual counselling for patients and families.
      The effect of 'treatment as usual' needs to be taken into account when comparing
      an intervention and control group, as well as the dosage of the intervention.

PMID- 15027038
TI  - Assessing the cognitive abilities that differentiate patients with Alzheimer's
      disease from normals: single and multiple factor models.
AB  - BACKGROUND: Understanding the structure of cognitive abilities in Alzheimer's
      disease (AD) has considerable practical and theoretical importance. Some
      investigators have argued that a single cognitive process underlies the deficits
      seen in AD, while others have argued for multiple cognitive processes. As
      deficits in cognitive abilities may reflect the pathological process or processes
      occurring in AD, determination of the structure of abilities in AD is important.
      OBJECTIVES: The purpose of this study was to assess the utility of single and
      multiple ability factor models in differentiating patients with AD from normals.
      RESULTS: Findings show that although a single factor model accounts for a large
      part of the variability of a battery of measures used to differentiate patients
      and normals, a multiple factor model performed substantially better based on
      multiple fit criteria. CONCLUSIONS: At least in this sample, a multiple ability
      factor model of cognitive abilities fit data better than a single factor model in
      differentiating patients with AD from normals.

PMID- 15027039
TI  - Efficacy of rivastigmine in subjects with moderately severe Alzheimer's disease.
AB  - BACKGROUND: Cholinesterase (ChE) inhibitors are primarily used in the treatment
      of mild to moderate Alzheimer's disease (AD), but may also be effective in more
      severe disease. OBJECTIVE: To evaluate the dual ChE inhibitor, rivastigmine, in
      more severe dementia. METHODS: We retrospectively analysed pooled data from three
      randomised, placebo-controlled, double-blind, 6-month trials, involving 2126 AD
      subjects. Subjects were selected according to baseline Mini-Mental State
      Examination (MMSE) score to identify subjects with more severe cognitive
      impairment (10-12 MMSE points). One-hundred-and-seventeen subjects were included
      who had been treated with rivastigmine 6-12 mg/day or placebo. The AD Assessment
      Scale-Cognitive Subscale (ADAS-Cog), the MMSE, a six-item subscore of the
      Progressive Deterioration Scale (PDS) and the BEHAVE-AD assessed efficacy.
      Tolerability was assessed by recording adverse events (AEs) and the relative risk
      (RR) of discontinuation. RESULTS: This group of subjects responded well to
      rivastigmine. After 6 months, the mean ADAS-Cog score declined by 6.3 points in
      the placebo group and increased by 0.2 points in the rivastigmine group (observed
      cases; p<0.001). Clinical benefits were also observed with the MMSE, the six-item
      PDS score and items of the BEHAVE-AD. Rivastigmine showed the same pattern of AEs
      as in other studies, but the RR of dropping out due to AEs was lower than in
      subjects with milder AD. CONCLUSION: Current treatment guidelines do not
      recommend treating individuals with severe AD with ChE inhibitors. However, this
      retrospective analysis suggests that rivastigmine 6-12 mg/day may benefit
      subjects with more severe disease, as well as subjects with mild to moderate
      impairment.

PMID- 15027040
TI  - Topographical disorientation in community-residing patients with Alzheimer's
      disease.
AB  - BACKGROUND: Based on the hypothesis that declarative memory and navigation
      ability depend on hippocampal integrity, and the fact that declarative memory
      declines early in Alzheimer's disease (AD), the authors suggest that
      topographical disorientation (TD) will be an early manifestation of AD. SUBJECTS
      AND METHODS: Patients diagnosed with AD based on DSM-IV criteria, residing at
      home, were studied in a clinic at a 1000-bed referral medical center. Patient
      characteristics, disease condition, performance on neuropsychological tests, and
      navigation function were compared between patients with and without current TD.
      Information regarding the extent and duration of TD and the level of current
      navigational function were collected during a clinical interview. RESULTS: 112
      patients (61 males and 51 females) with mean age of 74 years and disease duration
      of 37 months completed the study. Among them, 61 currently experienced TD, 20 had
      required an escort to their home by others, and 28 had TD as an incipient
      symptom. Those with current TD tended to have a longer disease duration, required
      an escort to their home by others, and reported a history of repeated change of
      residence, TD as an incipient symptom, a restricted spatial range within which
      they felt comfortable (safety range), and disorientation when they were out of
      familiar territory. In addition, care-givers reported a high level of concern for
      the safety of those with TD when he or she traveled alone. CONCLUSION: TD in
      community-dwelling AD patient is common. Caregivers should pay attention to those
      with longer disease duration and try to avoid changing residence. Developing a
      brief and valid test for topographical orientation will be helpful for the early
      detection of TD.

PMID- 15027041
TI  - Patient versus informant perspectives of Quality of Life in Mild Cognitive
      Impairment and Alzheimer's disease.
AB  - BACKGROUND: Prior studies on Quality of Life (QOL) in Alzheimer's disease (AD)
      have rarely included control participants, or participants with very mild levels
      of cognitive impairment. Furthermore, there is little data to indicate whether or
      not mildly impaired patients can provide self-report QOL data or if informant
      reports are needed. OBJECTIVES: This study compared QOL ratings from informants
      and patients with mild AD (n = 26), Mild Cognitive Impairment (MCI, n = 30), and
      elderly controls (n = 23). METHODS: Participants (aged 60-91 years) were
      recruited from an outpatient memory disorder clinic. Elderly controls were
      recruited from the community. Measures about patients were the Dementia Quality
      of Life scale, the Neuropsychiatric Inventory-Questionnaire, Instrumental of
      Activities of Daily Living, and Mini-mental State Exam. Informant depression was
      assessed with the Geriatric Depression Scale. RESULTS: Results indicated that
      overall patient-informant agreement for MCI (M=0.24), AD (M=0.48), and controls
      (M=0.49) did not differ significantly. Self-reported QOL did not differ
      significantly across the 3 groups. For caregiver-reports, QOL in MCI again did
      not differ from controls but was significantly greater than QOL in AD for 2 of 6
      scales, and QOL in controls was greater than AD for 4 of 6 scales. Regression
      analyses indicated that neuropsychiatric symptoms were the most consistent
      predictors of QOL. CONCLUSIONS: In summary, informant- and self-perceptions of
      QOL differed substantially. Results suggest that future investigators should
      carefully consider gathering QOL information from both informants and patients
      because they provide unique information regarding patient QOL and, to date,
      neither source of information has been established to be superior.

PMID- 15027042
TI  - Measuring Alzheimer's disease progression with transition probabilities in the
      Taiwanese population.
AB  - BACKGROUND: The transition probability of Alzheimer's disease (AD) is defined as
      the likelihood that the disease progresses from one stage to another in a given
      time period. OBJECTIVE: To estimate the separate stage-to-stage and stage-to
      death transition probabilities for Taiwanese patients with AD and to evaluate the
      hazard ratios of age, sex, behavioral symptoms, and medications on disease
      progression. METHOD: We examined data (severity of dementia, hallucinations or
      delusions, use of cholinesterase inhibitors [CEIs], survival) in 365 patients
      with probable AD at baseline and at follow-Gup (mean +/- SD 29 +/- 17 months,
      range 3-109 months). RESULTS: Modified survival analysis revealed that transition
      probabilities of Taiwanese patients were similar to those of Western patients.
      The probability of dementia remaining at the same stage was higher in patients
      taking CEIs than in other. Men had a higher probability of dying in the mild
      stage. CONCLUSION: Transition probabilities can be used to measure AD
      progression. CEIs used to treat AD might alter the disease course.

PMID- 15027043
TI  - Delirium among patients with and without dementia: does the diagnosis according
      to the DSM-IV differ from the previous classifications?
AB  - BACKGROUND: Different diagnostic criteria differ in their capacity to identify
      subjects as delirious. It is not known how DSM-IV classification, compared with
      the DSM-III, DSM-III-R, and ICD-10, identifies delirium among individuals with
      and without dementia and whether the symptom profiles differ between these two
      subgroups. METHODS: A cross-sectional study was performed on patients (age > or =
      70 years) in seven acute geriatric wards (n = 230) and in seven nursing-homes (n
      = 195) in Helsinki, Finland. Delirium was diagnosed according to the
      operationalized criteria according to the DSM-III, DSM-III-R, DSM-IV, and
      clinical criteria of ICD-10. Dementia was defined according to consensus judgment
      among three geriatricians with concise information including: prior dementia
      diagnoses, Clinical Dementia Rating Scale, operationalized criteria according to
      the DSM-IV, nurses and/or caregivers interviews, and the results of the brain
      CT/MRI and prior Mini-Mental State Examination scores, when available. RESULTS:
      According to the DSM-III, DSM-IIIR, DSM-IV and ICD-10 criteria of delirium 22.7,
      23.5, 25.9 and 14.9% of the demented, and 12.9, 13.5, 23.5 and 2.9% of the non
      demented, respectively, were diagnosed as delirious. In stepwise logistic
      regression analysis clouding of consciousness, perceptual disturbances, and
      disorganized thinking were the most significant contributors to delirium
      diagnosis according to the DSM-IV among individuals with dementia, whereas
      perceptual disturbances, motor disturbances, and disorientation were the most
      significant contributors among those without dementia. CONCLUSIONS: DSM-IV
      criteria of delirium identify new, often non-demented, subjects as being
      delirious, while ICD-10 is overly restrictive. The symptom profile of delirium
      was slightly different among individuals with and without dementia.

PMID- 15027044
TI  - Can we trust depression screening instruments in healthy 'old-old' adults?
AB  - OBJECTIVE: Despite a growing understanding of late-life depression, few studies
      focus on the old-old, those 75 years and over. We wished to characterize
      depressive symptoms and determine the accuracy of two common screening
      instruments for major and minor depression in a population of old-old retirees.
      METHODS: Participants lived independently in one of two Continuing Care
      Retirement Communities and volunteered for an in-home interview about cancer
      screening attitudes. As part of this baseline interview, they were screened with
      the Geriatric Depression Scale (GDS) and the Center for Epidemiologic Studies
      Depression (CES-D) scale. Those agreeing to a second interview received an
      evaluation using the Structured Clinical Interview for DSM-IV (SCID-IV),
      performed by a geriatric psychiatrist within two weeks of the initial interview.
      RESULTS: In an educated and cognitively intact group of retirees averaging 80
      years of age, the GDS and CES-D performed poorly using standard cutpoints in
      detecting both major (sensitivity 60% for both) and minor (sensitivity 33% and
      50%, respectively) depression. One in five participants had significant
      depression as confirmed by SCID-IV evaluation. Twelve percent had major
      depression and 7% had minor depression. Most participants had their first episode
      of either after age 60. CONCLUSIONS: Contrary to most studies evaluating the GDS
      and CES-D for accuracy in detecting late-life depression, these instruments at
      standard cutpoints performed poorly in this group of healthy older adults. The
      healthy old-old may require novel screening interventions to detect clinically
      significant depression.

PMID- 15027045
TI  - The effect of ethnicity and gender on first-contact rates for schizophrenia-like
      psychosis in Bangladeshi, Black and White elders in Tower Hamlets, London.
AB  - BACKGROUND: A recent study of very-late onset schizophrenia-like psychosis (SLP)
      in South London showed an increase in first contact rates amongst African- and
      Caribbean-born elders compared to British-born ones. This study investigates
      incident first contact rates in an area of East London with a high Bangladeshi
      population, to investigate if Bangladeshi-born elders also have an increased
      referral rate for SLP. METHOD: Retrospective case note review of first contacts
      to the old age psychiatry service from 1997 to 2002 identifying cases of
      schizophrenia-like psychosis. In addition, a one-year review of first contacts
      for all diagnostic categories was completed. Gender, ethnicity and place of birth
      were established from the case notes. RESULTS: Among the African- and Caribbean
      born, but not the Bangladeshi-born, the odds ratio (OR) of being referred with
      SLP was significantly higher than for the British-born population. We observed a
      loss of the reported effect of female gender. For Whites the odds ratio for
      female gender and psychosis was 2.5 (1.0-6.1) and for non-Whites 0.8 (0.3-2.7)
      which was a trend away from the expected male to female ratio. In the one-year
      review there was a higher rate of referrals for organic disease in Bangladeshi
      men compared to Bangladeshi women and British-born men and women. CONCLUSIONS:
      Bangladeshi elderly migrants do not have an increased rate of SLP compared to
      indigenous elders. The usual female preponderance of SLP is not apparent in this
      elderly migrant population. Old age psychiatry services in the UK should take
      into account the increasing needs of Bangladeshi elders with dementia.

PMID- 15027046
TI  - The relationship between cholesterol levels and depression in the elderly.
AB  - OBJECTIVE: This study was undertaken to evaluate the possible association between
      low levels of serum cholesterol and depression in the elderly. BACKGROUND: The
      alteration of cholesterol content of synoptosomal membrane in response to low
      serum cholesterol levels has been shown to decrease the serotonin receptors in
      depressed patients. Previous studies suggest that low levels of serum cholesterol
      may be associated with the increased risk of depression in the elderly. SUBJECTS
      AND METHODS: This was a cross-sectional study where 189 subjects over 65 years
      old of both sexes were enrolled. Serum total cholesterol, HDL-cholesterol (HDL
      C), LDL-cholesterol (LDL-C), and triglycerides were measured. Cognitive functions
      were evaluated with mini mental state examination survey (MMSES) and depression
      was assessed with Structured Clinical Interview for DSM-IV Axis I Disorders (SCID
      I). RESULTS: Of the 189 subjects, 42 were affected by depression. Low serum
      cholesterol level (cut-off < or =160 mg/dl) as well as the levels of HDL-C, LDL-C
      and triglycerides were not associated with depression in older men or women.
      CONCLUSIONS: In the present cross sectional study, there was no association
      between depression and low serum cholesterol levels after adjusted for
      confounding factors. Further studies are needed to clarify this suggestion with
      larger number of patients.

PMID- 15027048
TI  - Historical notes on botulism, Clostridium botulinum, botulinum toxin, and the
      idea of the therapeutic use of the toxin.
AB  - Food-borne botulism probably has accompanied mankind since its beginning.
      However, we have only few historical sources and documents on food poisoning
      before the 19th century. Some ancient dietary laws and taboos may reflect some
      knowledge about the life-threatening consumption of poisoned food. One example of
      such a dietary taboo is the 10th century edict of Emperor Leo VI of Byzantium in
      which manufacturing of blood sausages was forbidden. Some ancient case reports on
      intoxications with Atropa belladonna probably described patients with food-borne
      botulism, because the combination of dilated pupils and fatal muscle paralysis
      cannot be attributed to an atropine intoxication. At the end of the 18th century,
      some well-documented outbreaks of "sausage poisoning" in Southern Germany,
      especially in Wurttemberg, prompted early systematic botulinum toxin research.
      The German poet and district medical officer Justinus Kerner (1786-1862)
      published the first accurate and complete descriptions of the symptoms of food
      borne botulism between 1817 and 1822. Kerner did not succeed in defining the
      suspected "biological poison" which he called "sausage poison" or "fatty poison."
      However, he developed the idea of a possible therapeutic use of the toxin. Eighty
      years after Kerner's work, in 1895, a botulism outbreak after a funeral dinner
      with smoked ham in the small Belgian village of Ellezelles led to the discovery
      of the pathogen Clostridium botulinum by Emile Pierre van Ermengem, Professor of
      bacteriology at the University of Ghent. The bacterium was so called because of
      its pathological association with the sausages (Latin word for sausage =
      "botulus") and not-as it was suggested-because of its shape. Modern botulinum
      toxin treatment was pioneered by Alan B. Scott and Edward J. Schantz.

PMID- 15027049
TI  - Molecular targets of botulinum toxin at the mammalian neuromuscular junction.
AB  - The molecular targets of botulinum neurotoxins (BoNTs) are SNARE (soluble N
      ethylmaleimide-sensitive factor-attachment protein-receptor) proteins necessary
      for neurotransmitter release. BoNT are powerful therapeutic agents in the
      treatment of numerous neurological disorders. The goals of this study were to (1)
      assess toxin diffusion by measuring substrate cleavage in adjacent and distant
      muscles, and (2) characterize the clinical course using SNARE protein chemistry.
      A small volume of BoNT/A was injected unilaterally into the mouse gastrocnemius
      muscle. Motor impairment was limited to the toxin-treated limb. No systemic
      illness or deaths occurred. At five time points, a subset of mice were killed,
      and muscles from both hindlimbs, and the diaphragm, were collected. Protein
      samples were examined for changes in SNAP-25 (synaptosomal-associated protein of
      Mr = 25 kDa) using immunochemistry. SNAP-25 cleavage product was noted in the
      toxin-treated limb as early as 1 day postinjection and continued through day 28.
      Onset and peak levels of substrate cleavage corresponded to the onset and peak
      clinical response. Cleavage was observed in adjacent and distant muscles,
      demonstrating that substrate cleavage is a sensitive indicator of toxin
      diffusion. Significant increases in full-length SNAP-25 and vesicle-associated
      membrane protein II were evident early in the impaired limb and continued through
      day 28. The increased SNARE protein most likely originates from nerve terminal
      sprouts.

PMID- 15027050
TI  - Structure and enzymatic activity of botulinum neurotoxins.
AB  - The structure of botulinum neurotoxin type B (BoNT/B) is analyzed, and it is
      demonstrated that the carbonyl oxygen of the scissile bond comes close to the
      zinc ion to form a Michaelis complex. The hydrated carbonyl is activated by the
      nucleophilic water, which moves closer to Glu 230 to form hydrogen bonds to side
      chain carboxylate. This process frees up the lone pair, which forms a bond with
      carbonyl carbon, corresponding to the tetrahedral transition state. The hydrated
      peptide oxygen is stabilized by a zinc ion and a water molecule close by. The
      proton from the nucleophile moves to NH of the scissile bond. The other proton is
      shuttled by Glu 230 to the NH2 group to make it NH3+ and allows it to leave. This
      mechanism is consistent with that proposed for thermolysin and BoNT/A. On the
      basis of these studies, we have shown that Tyr372 or Arg369 may not have any
      significant role in catalytic activity except for a secondary role such as
      stabilizing the transition state. Thus, the sulfate ion mimics the transition
      state of the scissile carbonyl carbon atom. However, the sulfate ion by itself
      does not inhibit the toxicity.

PMID- 15027051
TI  - Is the light chain subcellular localization an important factor in botulinum
      toxin duration of action?
AB  - Botulinum neurotoxins (BoNT) are therapeutic proteins that are specific, potent,
      and effective. They are highly specific in binding to motor neurons but do not
      bind to other non-neuronal cells. These proteins are zinc-dependent
      endopeptidases that inhibit exocytosis by specific cleavage of the SNARE (soluble
      N-ethylmaleimide-sensitive factor-attachment protein-receptor) proteins involved
      in vesicle docking and fusion. The therapeutic effect of BoNT/A in humans lasts
      from 3 to 12 months, depending upon the condition treated. Data from animal and
      cell culture models suggests that the long-lasting duration of inhibition of
      neurotransmitter release induced by BoNT/A maybe due to the persistence of the
      endopeptidase activity of the light chain (LC/A) in cells, interactions of the
      cleaved substrates, and/or the response of the nerve to the temporary disruption
      of communication with its target tissue. We have analyzed the subcellular
      localization of the light chains from serotypes A, B, and E and have demonstrated
      that each light chain displays a distinct distribution within cells. LC/A
      localizes at the plasma membrane, LC/B is dispersed throughout the cell including
      the nucleus, and LC/E is mainly cytosolic. Localization is similar in non
      neuronal cell lines, suggesting that the signals involved in proper subcellular
      localization are within the LC sequences and the moiety the light chain interacts
      with is present in both neuronal and non-neuronal cells.

PMID- 15027052
TI  - BotDB: A database resource for the clostridial neurotoxins.
AB  - BotDB is a database designed to encapsulate the rapidly expanding amount of
      information about the structure and function of the botulinum (BoNT) and tetanus
      neurotoxins and to track a variety of basic and applied research efforts. The
      AceDB management system was chosen for this project because of its flexibility in
      manipulating semistructured data sets and for its information retrieval query
      languages. In addition to storing amino and nucleic acid sequences of the
      clostridial neurotoxin genes and proteins, BotDB provides sequence data for new
      classes of objects, including neurotoxin mutants, substrates and their mutants,
      associated nontoxic proteins, and C-fragment vaccine candidates. New data types
      provide information on detection assays for the neurotoxins and on structural
      data from X-ray crystallographic and circular dichroism spectroscopic studies.
      Kinetic parameters from biochemical experiments include reaction rates for
      substrate cleavage and block of neurotransmission. The structures and kinetic
      characteristics of presently known chemical inhibitors are also being archived.
      All of these data are associated with citations of the relevant literature for on
      line annotation. Graphics viewer programs are provided to display stored images
      and three-dimensional representations of protein structures. BotDB is in the
      alpha test phase of development and will become a publicly available Web site.

PMID- 15027053
TI  - Retargeted clostridial endopeptidases: inhibition of nociceptive neurotransmitter
      release in vitro, and antinociceptive activity in in vivo models of pain.
AB  - Clostridial neurotoxins potently and specifically inhibit neurotransmitter
      release in defined cell types. Previously reported data have demonstrated that
      the catalytically active LH(N) endopeptidase fragment of botulinum neurotoxin
      type A (termed LH(N)/A) can be retargeted to a range of cell types in vitro to
      lead to inhibition of secretion of a range of transmitters. Here, we report the
      synthesis of endopeptidase conjugates with in vitro selectivity for nociceptive
      afferents compared to spinal neurons. Chemical conjugates prepared between
      Erythrina cristagalli lectin and LH(N)/A are assessed in vitro and in in vivo
      models of pain. Chemical conjugates prepared between E. cristagalli lectin and
      either natively sourced LH(N)/A, or recombinant LH(N)/A purified from Escherichia
      coli are assessed, and equivalence of the recombinant material is demonstrated.
      The duration of action of inhibition of neurotransmitter release by the conjugate
      in vitro is also assessed and is comparable to that observed with Clostridium
      botulinum neurotoxin. Selectivity of targeting and therapeutic potential have
      been confirmed by in vivo electrophysiology studies. Furthermore, the analgesic
      properties of the conjugate have been assessed in in vivo models of pain and
      extended duration effects observed. These data provide proof of principle for the
      concept of retargeted clostridial endopeptidases as novel analgesics.

PMID- 15027054
TI  - Roads from vaccines to therapies.
AB  - Over the past decade, we have demonstrated that various recombinant fragments of
      botulinum neurotoxin are highly immunogenic, stimulating notable levels of
      protective antibodies in mice, guinea pigs, and nonhuman primates. One of the
      fragments evaluated, the fragment C, is a potential next-generation vaccine
      candidate to replace the current pentavalent botulinum toxoid vaccine. Synthetic
      genes encoding the carboxyl-terminal regions (approximately 50 kDa) of toxin
      types A, B, C1, E, and F were expressed in Pichia pastoris, and manufacturing
      processes were developed for producing highly purified vaccines. These vaccines
      were shown to be safe, highly efficacious, stable, and amenable to high-level
      industrial production. Recombinant vaccines are now being produced in accordance
      with current Good Manufacturing Practices for use in future clinical trials. As
      our discovery-based program on vaccine development is diminishing, it is
      concurrently being replaced with a program focused on developing therapeutic
      interventions to botulism. Synthetic genes encoding the light chains of botulinum
      toxin have been expressed in Escherichia coli, and purified. These
      proteolytically active light chains are being used in high-throughput assays to
      screen for inhibitors of its catalytic activity. Other resources developed as
      part of the vaccine initiative, likewise, are finding utility in the quest to
      develop therapies for botulism.

PMID- 15027055
TI  - Different types of botulinum toxin in humans.
AB  - In humans, botulinum neurotoxin (BoNT) serotype A (BoNT/A) is a useful
      therapeutic tool, but different BoNT serotypes may be useful when a specific
      immune resistance related to BoNT/A is proved. BoNT serotype F (BoNT/F) was
      injected into human muscles but its effects are shorter compared to BoNT/A,
      whereas BoNT serotype B (BoNT/B) is effective in humans only if injected at very
      high doses. BoNT serotype C (BoNT/C) has a general profile of action similar to
      BoNT/A. Nevertheless, a comparison between these different BoNTs in human has not
      yet been reported. To establish the general profile of these different BoNTs in
      humans and the spread in near and untreated muscles we conducted an
      electrophysiological evaluation in 12 healthy volunteers by injecting BoNT/A
      (BOTOX 15MU), BoNT/B (NeuroBloc 1500MU), BoNT/F (15MU), BoNT/C (15MU) and a
      saline solution (placebo) in the abductor digiti minimi muscle (ADM) in a double
      blind manner. The compound muscle action potential (CMAP) amplitude variation,
      before and at 2, 4, 6 and 8 weeks after the injections, was evaluated in the ADM,
      the fourth dorsal interosseus, the first dorsal interosseus and the abductor
      pollicis brevis APB. We detected an earlier recovery for BoNT/F when compared to
      the other BoNTs. No significant differences in the local or distant BoNT spread
      was observed among the different serotypes. We conclude that in humans, BoNT/B
      and BoNT/C have a general profile similar to BoNT/A and as such these serotypes
      could be alternative therapies to BoNT/A. BoNT/F might be useful when only a
      short duration of neuromuscular blockade is required.

PMID- 15027056
TI  - Central effects of botulinum toxin type A: evidence and supposition.
AB  - No convincing evidence exists that botulinum toxin type A (BT-A) injected
      intramuscularly at therapeutic doses in humans acts directly on central nervous
      system (CNS) structures. Nevertheless, several studies, using various approaches,
      strongly suggest that BT-A affects the functional organization of the CNS
      indirectly through peripheral mechanisms. By acting at alpha as well as gamma
      motor endings, BT-A could alter spindle afferent inflow directed to spinal
      motoneurons or to the various cortical areas, thereby altering spinal as well as
      cortical mechanisms. Muscle afferent input is tightly coupled to motor cortical
      output, so that the afferents from a stretched muscle go to cortical areas where
      they can excite neurons capable of contracting the same muscle. The BT-A-induced
      reduction in spindle signals could, therefore, alter the balance between afferent
      input and motor output, thereby changing cortical excitability.

PMID- 15027057
TI  - Pharmacokinetic properties of different formulations of botulinum neurotoxin type
      A.
AB  - Although the relative potency measured by the number of units per nanogram of the
      toxin is different for the three preparations (BOTOX = 20 U/ng; Dysport = 40
      U/ng, and CS-BOT = 15.2 U/ng), the effective dose for CS-BOT is similar to that
      of BOTOX (Allergan, Irvine, CA). Despite the twofold difference in potency per
      nanogram, it appears that the clinically observable activity of 1 U of BOTOX is
      roughly equivalent to 3 U of the Dysport (Inamed, Santa Barbara, CA) product.
      Using quantitative analysis of regional paralysis produced by local injections
      into the gastrocnemius muscles of mice, prior studies estimated the potency ratio
      between Dysport and BOTOX to be 4.2 to 1. In a single-blind, randomized
      comparison study of Dysport and BOTOX in 91 patients with blepharospasm or
      hemifacial spasm, it was found that 4:1 dose ratio produced similar benefits. A
      similar 4:1 Dysport:BOTOX ratio was found to produce equivalent beneficial
      effects in a double-blind study in patients with blepharospasm, but the frequency
      of side effects, particularly of ptosis, was lower in the BOTOX group. In a study
      of 73 patients with cervical dystonia treated either with Dysport or BOTOX, it
      was concluded that a 3:1 ratio provides equivalent results. But a recent study
      concluded that the appropriate conversion factor between BOTOX and Dysport is
      less than 3. Therefore, there is some controversy about the relative potencies of
      the two preparations, with one study proposing that 1 unit of BOTOX corresponds
      to 1 unit of Dysport.

PMID- 15027058
TI  - Basic immunological aspects of botulinum toxin therapy.
AB  - Previous studies in this laboratory had mapped the immune recognition profile of
      the regions recognized antibodies (Abs) and by T cells on the protective H(C)
      domain (C-terminal fragment corresponding to residues 855-1296 of the heavy
      chain) of botulinum neurotoxin serotype A (BoNT/A). The localization of these
      regions has several potential applications and has provided a basis for the
      understanding of immunoresistance to treatment. We briefly outline these
      localized regions and discuss the impact of these findings on the
      immunotherapeutic applications of BoNT/A. Immunoresistance to toxin therapy can
      appear in some patients after a few injections with the toxin. Our epitope
      mapping studies have shown that several factors can influence the immune response
      to the toxin. These factors include dose, duration of treatment, frequency of
      immunization, and quality of the toxin. The immune response to the whole toxin is
      under genetic control, and the response to each epitope is under separate genetic
      control. Therefore, the appearance of blocking Abs (i.e., immunoresistance) in
      patients might be controlled by the major histocompatability of the host. Once a
      patient becomes immunoresistant to one toxin then switching to another toxin will
      most often be of limited and short-lived benefit, because the patient becomes
      rapidly immunoresistant to the second toxin. Finally, because of the considerable
      structural homology between tetanus neurotoxin (TeNT) and BoNTs, it is possible,
      although not certain, that a prior active immune response to TeNT might play some
      role in the early appearance on anti-BoNT Abs in some patients.

PMID- 15027059
TI  - Detection of antibodies against botulinum toxins.
AB  - After immunisation with botulinum vaccine, antibodies to multiple epitopes are
      produced. Only some of these will have the capacity to neutralise the toxin
      activity. In fact, the ability of toxoid vaccine to induce toxin neutralising
      antibodies has provided the basis for the use of therapeutic antitoxins and
      immunoglobulins for the prophylaxis and treatment of diseases caused by bacterial
      toxins. Increasing indications for the chronic use of botulinum toxin for therapy
      have inevitably resulted in concern for patients becoming unresponsive because of
      the presence of circulating toxin-specific antibodies. Highly sensitive and
      relevant assays to detect only clinically relevant toxin neutralising antibodies
      are essential. Although immunoassays often provide the sensitivity, their
      relevance and specificity is often questioned. The mouse protection LD(50)
      bioassay is considered most relevant but can often only detect 10 mIU/ml of
      antitoxin. This sensitivity, although sufficient for confirming protective
      immunity, is inadequate for patients undergoing toxin therapy. An intramuscular
      paralysis assay improves the sensitivity to ca. 1 mIU/ml, and a mouse ex vivo
      diaphragm assay, with sensitivity of < 0.5 mIU/ml, is the most sensitive
      functional assay to date for this purpose. Alternative approaches for the
      detection of antibodies to botulinum toxin have included in vitro endopeptidase
      activity neutralisation. Unlike any other functional assay, this approach is not
      reliant on serotype-specific antibodies for specificity. Most recent promising
      developments are focused on cellular assays utilising primary rat embryonic cord
      cells or more conveniently in vitro differentiated established cell lines such as
      human neuroblastoma cells.

PMID- 15027060
TI  - Clinical presentation and management of antibody-induced failure of botulinum
      toxin therapy.
AB  - Therapy with botulinum toxin (BT) can fail due to numerous reasons, including
      failure due to formation of antibodies against BT (BT-AB, AB-TF). AB-TF is a
      secondary therapy failure, i.e. it occurs during the course of an ongoing BT
      therapy. It can be subjective or objective, temporary or permanent, and partial
      or complete. Complete AB-TF is usually preceded by injection series with partial
      AB-TF in which the therapeutic effect is reduced in its intensity and duration.
      AB-TF usually occurs within 2 or 3 years after initiation of BT therapy. After 4
      years it is rare. BT-AB are neutralising or blocking by definition, i.e. they are
      directly interfering with BT's biological mechanism of action. Non-neutralizing
      or non-blocking antibodies occur. BT-AB can be detected by the mouse diaphragm
      assay, the mouse protection assay, and by patient-based tests such as the
      sternocleidomastoid test, the extensor digitorum brevis test, and the frowning
      test. Enzyme-linked immunosorbent assays (ELISA) have a low specificity and a low
      sensitivity for detection of BT-AB. BT-AB titres drop spontaneously after
      cessation of BT therapy but latencies are too long to be compatible with an
      effective BT therapy. BT dosage increase can be successful to overcome AB-TF when
      AB-TF is partial and when BT-AB titres are low. Usage of alternative BT type A
      preparations fail to overcome AB-TF. Alternative BT types, such as BT type B and
      BT type F, are initially successful in AB-TF, but stimulate formation of
      antibodies against the alternative BT types after few applications. BT-AB
      reduction with immunosuppressants and inactivation of BT-AB by intravenous
      immunoglobuline application has not yet been achieved. Extraction of BT-AB by
      plasmapheresis and immunoadsorption is possible but is associated with
      substantial logistic problems. Prevention of BT-AB formation, therefore, is of
      paramount importance. Identified risk factors for BT-AB formation must be taken
      into account when BT therapy is planned. The most interesting perspective seems
      to be the development of new BT preparations with reduced antigenicity.

PMID- 15027061
TI  - Deciphering antibody properties that lead to potent botulinum neurotoxin
      neutralization.
AB  - Monoclonal antibodies (mAbs) have been developed that bind to the toxin binding
      domain (H(C)) of botulinum toxin type A. These mAbs recognize with high affinity
      nonoverlapping epitopes on native toxin. The potency of a combination of three of
      the mAbs is almost 100 times greater than that reported for human polyclonal
      botulinum immune globulin. Potency appears to result largely from a marked
      increase in binding affinity for toxin that results when antibodies are combined.
      Precise epitope, or even domain recognized, seems to be of much less importance.
      The very high affinity required for toxin neutralization suggests why single mAbs
      that potently neutralize toxin have not been reported. Such affinities are not
      typically generated by the immune response.

PMID- 15027062
TI  - Treatment of cervical dystonia with botulinum toxin.
AB  - Cervical dystonia (CD) is the most common form of dystonia encountered in a
      movement disorders clinic. The treatment of this focal dystonia has improved
      markedly with the advent on botulinum toxin (BTX) injections, which has now
      become the treatment of choice. Initial studies, even double-blind controlled
      trials, failed to show robust effect, largely as a result of poor design, often
      using fixed dosage and site of administration. When the BTX treatment is
      customized to the needs of the individual patients and the most involved muscles
      are targeted, the effects can be quite dramatic and the improvement usually lasts
      3 to 4 months. Experience and improved skills can largely prevent the adverse
      effects such as dysphagia and neck weakness. Although there is no evidence that
      BTX slows the progression of the disease, as a result of early intervention with
      BTX, many of the long-term complications of CD, such as contractures and
      radiculopathy, have been largely eliminated.

PMID- 15027063
TI  - Botulinum toxin treatment of occupational and focal hand dystonia.
AB  - Botulinum toxin is now the first-line therapy for writer's cramp and other
      occupational dystonias, with well-established efficacy and safety. Future studies
      will allow us to understand better the physiological effects of injection and to
      refine and enhance our treatment of focal hand dystonia.

PMID- 15027064
TI  - Physiological effects of botulinum toxin in spasticity.
AB  - There is considerable evidence that injection of botulinum toxin (BTX) into
      muscles with spastic overactivity reduces resistance to passive movement in
      joints supplied by the injected muscles. The demonstration of improvement in
      active performance of the paretic limbs has been only anecdotal to date, and
      represents the most difficult challenge in research on BTX therapy in spastic
      paralysis. Data are reviewed that indicate several neurophysiological actions of
      BTX, other than the blocking of acetylcholine release at the neuromuscular
      ending: effects on the central nervous system, including retrograde axonal
      transport, reduced motoneuronal excitability, action on central synapses such as
      decreased Renshaw inhibition and increased presynaptic inhibition; action on
      gamma motoneuronal endings; action on most active terminals; spread of BTX to
      neighboring muscles; spread of BTX effects to remote muscles. Several of these
      neurophysiological actions are likely to contribute to improvement in active
      movements, as they may antagonize the primary mechanisms of functional impairment
      in patients with spastic paralysis: weakness, spastic cocontraction, spastic
      dystonia, and muscle shortening. We review the evidence for reduction of spastic
      cocontraction in both the injected muscle and its antagonist, and for improvement
      of antagonist weakness after BTX injection. The capacity of intramuscular BTX to
      reduce spastic dystonia and lengthen shortened muscles is also discussed based on
      prior literature. When injected into the more overactive of a pair of spastic
      antagonists around a joint, BTX should affect all the main mechanisms impairing
      active function around the joint.

PMID- 15027065
TI  - Clinical comparability of marketed formulations of botulinum toxin.
AB  - The majority of pharmaceutical products are patented in early phases of their
      discovery to preclude competition by similar products. Due to unusual
      circumstances (botulinum toxin is an unpatentable natural product and it is
      considered to be a biological weapon), technology know-how for botulinum toxin
      production was classified rather then available in the scientific community.
      Botulinum toxin type A was marketed in two pharmaceutical distinct formulations
      from competitor companies. Serendipity proved that the two formulations were not
      equipotent in terms of mouse units. From a regulatory point of view, differences
      in potency of distinct formulations are not a matter of concern because each
      formulation is licensed based on its own set of data. As far as the data in each
      case is sufficient to prove that a particular formulation is safe and efficacious
      at its defined dosage, a license for use can be granted. On the other hand,
      generation of data on comparability is the only way that clinicians and managers
      can ascertain which product (formulation, serotype) is most cost-effectiveness
      and to determine whether there are relevant differences in their safety profiles.
      The results of the systematic review of head-to-head randomised trials comparing
      BOTOX to Dysport suggest that the two formulations are not bioequivalent whatever
      the dose relationship. Data on comparative immunogenicity are not available. The
      indirect comparison of the results obtained in randomised clinical trials
      comparing BOTOX to placebo and Dysport to placebo support that intrinsic
      differences are present in the two products. It is concluded that comparative
      economic evaluations of different botulinum toxin formulations should move away
      from cost-minimization approaches based on the presumption of bioequivalence and
      move toward cost-effectiveness or cost-utility models.

PMID- 15027066
TI  - Botulinum toxin treatment of secretory disorders.
AB  - Botulinum neurotoxin serotype A (BoNT/A) has revolutionised the treatment of a
      variety of autonomic hypersecretory disorders. Several open and controlled
      studies indicate that BoNT/A is a safe and effective treatment for focal
      hyperhidrosis of the axillae and palms, for gustatory sweating, and for some
      other rare conditions associated with focal hyperhidrosis. There is class I
      evidence for the efficacy of botulinum toxin in axillary hyperhidrosis and class
      II evidence for palmar hyperhidrosis and gustatory sweating. BoNT/A has the
      potential to replace current invasive and surgical techniques and should at least
      be considered as a viable alternative. The results of pilot studies to treat
      sialorrhea are encouraging. However, the optimal dose, best mode of application,
      side effects, and duration of BoNT/A action in this condition remain uncertain.
      We need further formal clinical trials to evaluate risks and benefits of BoNT/A
      for palliative treatment in of sialorrhea in Parkinson's disease and in bulbar
      amyotrophic lateral sclerosis. Based on the few reports published, BoNT/A
      injections into the lacrimal gland for hyperlacrimation may be an elegant method
      to treat this sometimes disabling condition. Again, larger studies are needed to
      evaluate the risks and long-term benefits of this treatment option.

PMID- 15027067
TI  - Botulinum toxin in neuro-urological disorders.
AB  - Botulinum toxin has been used in urology since the end of the 1980s. However,
      this therapeutic option has not been firmly established yet. Valid studies have
      merely been conducted on detrusor sphincter dyssynergia (DSD) and on detrusor
      overactivity (hyperreflexia), but even those findings do not allow final
      conclusions. Success rates in DSD are between 58% and 88%, in detrusor
      overactivity approximately 80%. Further possible indications for botulinum toxin
      are motor and sensory urge, urethrospasm, spasticity of the pelvic floor,
      neobladder, and even chronic prostatic pain. To reach firmer conclusions,
      controlled studies with well-defined patient populations and using validated and
      reproducible outcome measures are needed. In addition, we also need information
      on repeated injections over a long period of time. These data are not available
      to date. At present, the application of botulinum toxin should be reserved for
      experienced users only.

PMID- 15027068
TI  - Treatment with botulinum neurotoxin of gastrointestinal smooth muscles and
      sphincters spasms.
AB  - Local injections of botulinum neurotoxin are now considered an efficacious
      treatment for neurological and non-neurological conditions. One of the most
      recent achievements in the field is the observation that botulinum neurotoxin
      provides benefit in diseases of the gastrointestinal tract. Botulinum neurotoxin
      inhibits contraction of gastrointestinal smooth muscles and sphincters; it has
      also been shown that the neurotoxin blocks cholinergic nerve endings in the
      autonomic nervous system, but it does not block nonadrenergic responses mediated
      by nitric oxide. This aspect has further promoted the interest to use botulinum
      neurotoxin as a treatment for overactive smooth muscles, such as the anal
      sphincters to treat anal fissure and outlet-type constipation, or the lower
      esophageal sphincter to treat esophageal achalasia. Knowledge of the anatomical
      and functional organization of innervation of the gastrointestinal tract is a
      prerequisite to understanding many features of botulinum neurotoxin action on the
      gut and the effects of injections placed into specific sphincters. This review
      presents current data on the use of botulinum neurotoxin to treat diseases of the
      gastrointestinal tract and summarizes recent knowledge on the pathogenesis of
      disorders of the gut due to a dysfunction of the enteric nervous system.

PMID- 15027069
TI  - New therapeutic indications for botulinum toxins.
AB  - The efficacy of botulinum toxin (BTX) without systemic effects has led to the
      rapid development of applications in neuromuscular disorders, hyperactivity of
      sudomotor cholinergic-mediated glandular function, and pain syndromes. The
      successful use of BTX in conditions with muscle overactivity, such as dystonia
      and spasticity, has been established and new areas in the field of movement
      disorders such as tics, tremor, myoclonic jerks, and stuttering has been explored
      with satisfactory results. Strategies to temporarily inactivate muscle function
      after orthopaedic or neurosurgery have also been developed. BTX treatment of
      hyperhidrosis was followed by its application in other hypersecretory conditions
      (hyperlacrimation and nasal hypersecretion) and in excessive drooling. Studies
      are in progress, aimed at optimising the technique and protocol of
      administration. Other applications for BTX have been proposed in
      gastroenterological and urogenital practice; it appears to be effective in
      replacing standard surgical procedures. Trials of BTX in painful conditions are
      ongoing mainly on refractory tension headache, migraine, and backache as well as
      dystonia-complex regional pain syndrome and myofascial pain with promising
      results. Recently, the fastest growing use for BTX toxin has been in the cosmetic
      applications. Clearly, the indications for the use of BTX are expanding, but
      further clinical trials will be needed in many different areas.

PMID- 15027070
TI  - Use of botulinum toxin in pediatric spasticity (cerebral palsy).
AB  - Local injection of botulinum toxin (BT) is a well-established treatment option
      for spastic movement disorders in children. BT blocks the release of
      acetylcholine from the axon terminal into the synaptic cleft of the motor
      endplate resulting in paresis of the injected musculature. Such localised,
      temporary chemodenervation of affected muscles can lead to functional gains and
      may improve the child's daily routine and rehabilitative care. We summarise state
      of-the-art treatment of spasticity in children with BT type A, addressing
      critical issues and introducing recent advances, such as sonography-guided
      injection of BT and the distal injection of the psoas muscle without the need for
      general anaesthesia. First-hand experience with BT type B in children is
      presented.

PMID- 15027072
TI  - The role of lipoxygenase products on the endocytosis of yolk proteins in insects:
      participation of cAMP.
AB  - The participation of eicosanoids and second messengers in the regulation of
      endocytosis by the ovaries was investigated using the uptake of Rhodnius heme
      binding protein (RHBP) as an experimental model. The rate of RHBP uptake
      decreased up to 40% in the presence of BWA4C and NDGA, 5 and 12-lipoxygenase
      inhibitors, respectively, suggesting the involvement of lipoxygenase products in
      endocytosis regulation. Addition of Leukotriene B4 (LTB(4); one product of the 5
      lipoxygenase pathway) increased in vitro the uptake of RHBP by 30%. The content
      of cAMP in the Rhodnius' ovaries were monitored after treatment with different
      eicosanoids and inhibitors of eicosanoids synthesis. The amount of cAMP decreased
      in the presence of indomethacin (by 50%), while treatment with PGE(2) induced an
      increase of 85% of this messenger in the ovaries. The presence of LTB(4) in the
      medium inhibited in 60% the content of cAMP in the ovaries, while BWA4C induced a
      100% increase of this messenger in the ovaries. Addition of 1 microM DBcAMP in
      the medium resulted in a 30% decrease in the rate of RHBP uptake. Taken together,
      these data show that cyclooxygenase and lipoxygenase products participate in the
      control of protein internalization by modulation of cAMP levels.

PMID- 15027071
TI  - Bacillus thuringiensis delta-endotoxin binding to brush border membrane vesicles
      of rice stem borers.
AB  - The receptor binding step in the molecular mode of action of five delta
      endotoxins (Cry1Ab, Cry1Ac, Cry1C, Cry2A, and Cry9C) from Bacillus thuringiensis
      was examined to find toxins with different receptor sites in the midgut of the
      striped stem borer (SSB) Chilo suppressalis (Walker) and yellow stem borer (YSB)
      Scirpophaga incertulas (Walker) (Lepidoptera: Pyralidae). Homologous competition
      assays were used to estimate binding affinities (K(com)) of (125)I-labelled
      toxins to brush border membrane vesicles (BBMV). The SSB BBMV affinities in
      decreasing order was: Cry1Ab = Cry1Ac > Cry9C > Cry2A > Cry1C. In YSB, the order
      of decreasing affinities was: Cry1Ac > Cry1Ab > Cry9C = Cry2A > Cry1C. The number
      of binding sites (B(max)) estimated by homologous competition binding among the
      Cry toxins did not affect toxin binding affinity (K(com)) to both insect midgut
      BBMVs. Results of the heterologous competition binding assays suggest that Cry1Ab
      and Cry1Ac compete for the same binding sites in SSB and YSB. Other toxins bind
      with weak (Cry1C, Cry2A) or no affinity (Cry9C) to Cry1Ab and Cry1Ac binding
      sites in both species. Cry2A had the lowest toxicity to 10-day-old SSB and Cry1Ab
      and Cry1Ac were the most toxic. Taken together, the results of this study show
      that Cry1Ab or Cry1Ac could be combined with either Cry1C, Cry2A, or Cry9C for
      more durable resistance in transgenic rice. Cry1Ab should not be used together
      with Cry1Ac because a mutation in one receptor site could diminish binding of
      both toxins.

PMID- 15027073
TI  - Expression and localization of the Spodoptera frugiperda allatotropin (Spofr-AT)
      and allatostatin (Spofr-AS) genes.
AB  - Manduca sexta allatotropin and allatostatin were the first corpora allata (CA)
      regulating neuropeptides identified from Lepidoptera. Recently, we cloned the
      allatotropin (Spofr-AT) and the allatostatin (Spofr-AS) genes from the fall
      armyworm Spodoptera frugiperda. Using one-step RT-PCR for semi-quantification of
      the gene expression, we now demonstrate that three mRNA isoforms of the Spofr-AT
      gene and the Spofr-AS gene are expressed in brain, digestive tract, and
      reproductive organs of larvae, pupae, and adults in a time- and tissue-specific
      manner. Expression rates in the brain and in various parts of the digestive tract
      prove the dual role of the peptides as brain/gut (neuro)peptides. The functional
      meaning of ovarian and testes expression of the genes is not yet clear, although
      myoregulatory properties of the peptides are probable. The tissue-specific
      localization of the prohormone expression, as demonstrated by whole mount in situ
      hybridization, confirms the overall distribution of the prohormones as shown by
      RT-PCR and supports the pleiotropic functions of the peptides.

PMID- 15027074
TI  - Isolation, characterization, and recombinant expression of multiple serpins from
      the cat flea, Ctenocephalides felis.
AB  - Several clones encoding serine protease inhibitors were isolated from larval and
      adult flea cDNA expression libraries by immunoscreening and PCR amplification.
      Each cDNA contained an open reading frame encoding a protein of approximately 45
      kDa, which had significant sequence similarity with the serpin family of serine
      protease inhibitors. The thirteen cDNA clones isolated to date encode serpin
      proteins, which share a primary structure that includes a nearly identical
      constant region of about 360 amino acids, followed by a C-terminal variable
      region of about 40-60 amino acids. The variable C-terminal sequences encode most
      of the reactive site loop (RSL) and are generated by mutually exclusive
      alternative exon splicing, which may confer unique protease selectivity to each
      serpin. Utilization of an alternative exon splicing mechanism has been verified
      by sequence analysis of a flea serpin genomic clone and adjacent genomic
      sequences. RNA expression patterns of the cloned genes have been examined by
      Northern blot analysis using variable region-specific probes. Several putative
      serpins have been overexpressed using the cDNA clones in Escherichia coli and
      baculovirus expression systems. Two purified baculovirus-expressed recombinant
      proteins have N-terminal amino acid sequences identical to the respective
      purified native mature flea serpins indicating that appropriate N-terminal
      processing occurred in the virus-infected insect cells.

PMID- 15027075
TI  - Estimating equations for association structures.
AB  - This paper investigates generalized estimating equations for association
      parameters, which are frequently of interest in family studies, with emphasis on
      covariance estimation. Separate link functions are used to connect the mean, the
      scale, and the correlation to linear predictors involving possibly different sets
      of covariates, and separate estimating equations are proposed for the three sets
      of parameters. Simulations show that the robust 'sandwich' variance estimator and
      the jackknife variance estimator for the correlation parameters are generally
      close to the empirical variance for the sample size of 50 clusters. The results
      contradict Ziegler et al. and Kastner and Ziegler, where the 'sandwich' estimator
      obtained from the software MAREG was shown to be unsuitable for practical usage.
      The problem appears to arise because the MAREG variance estimator does not
      account for variability in estimation of the scale parameters, but may be valid
      with fixed scale. We also find that the formula for the approximate jackknife
      variance estimator in Ziegler et al. is deficient, resulting in systematic
      deviations from the fully iterated jackknife variance estimator. A general
      jackknife formula is provided and performs well in numerical studies. Data from a
      study on the genetics of alcoholism is used to illustrate the importance of
      reliable variance estimation in biomedical applications.

PMID- 15027079
TI  - Comparing completely and stratified randomized designs in cluster randomized
      trials when the stratifying factor is cluster size: a simulation study.
AB  - Stratified randomized designs are popular in cluster randomized trials (CRTs)
      because they increase the chance of the intervention groups being well balanced
      in terms of identified prognostic factors at baseline and may increase
      statistical power. The objective of this paper is to assess the gains in power
      obtained by stratifying randomization by cluster size, when cluster size is
      associated with an important cluster level factor which is otherwise unaccounted
      for in data analysis. A simulation study was carried out using a CRT where UK
      general practices were the randomized units as a template. The results show that
      when cluster size is strongly associated with a cluster level factor which is
      predictive of outcome, the stratified randomized design has superior power
      results to the completely randomized design and that the superiority is related
      to the number of clusters.

PMID- 15027078
TI  - On the estimation of the binomial probability in multistage clinical trials.
AB  - Due to the optional sampling effect in a sequential design, the maximum
      likelihood estimator (MLE) following sequential tests is generally biased. In a
      typical two-stage design employed in a phase II clinical trial in cancer drug
      screening, a fixed number of patients are enrolled initially. The trial may be
      terminated for lack of clinical efficacy of treatment if the observed number of
      treatment responses after the first stage is too small. Otherwise, an additional
      fixed number of patients are enrolled to accumulate additional information on
      efficacy as well as on safety. There have been numerous suggestions for design of
      such two-stage studies. Here we establish that under the two-stage design the
      sufficient statistic, i.e. stopping stage and the number of treatment responses,
      for the parameter of the binomial distribution is also complete. Then, based on
      the Rao-Blackwell theorem, we derive the uniformly minimum variance unbiased
      estimator (UMVUE) as the conditional expectation of an unbiased estimator, which
      in this case is simply the maximum likelihood estimator based only on the first
      stage data, given the complete sufficient statistic. Our results generalize to a
      multistage design. We will illustrate features of the UMVUE based on two-stage
      phase II clinical trial design examples and present results of numerical studies
      on the properties of the UMVUE in comparison to the usual MLE.

PMID- 15027080
TI  - Construction and validation of a prognostic model across several studies, with an
      application in superficial bladder cancer.
AB  - Many models for clinical prediction (prognosis or diagnosis) are published in the
      medical literature every year but few such models find their way into clinical
      practice. The reason may be that since in most cases models have not been
      validated in independent data, they lack generality and/or credibility. In this
      paper we consider the situation in which several compatible, independent data
      sets relating to a given disease with a time-to-event endpoint are available for
      analysis. The aim is to construct and evaluate a single prognostic model.
      Building a multivariable model from the available prognostic factors is
      accomplished within the Cox proportional hazards framework, stratifying by study.
      Non-linear relationships with continuous predictors are modelled by using
      fractional polynomials. To assess the discrimination or separation of a survival
      model, we use the D statistic of Royston and Sauerbrei. D may be interpreted as
      the separation (log hazard ratio) between the survival distributions for two
      independent prognostic groups. To evaluate the generality of a prognostic model
      across the data sets, we propose 'internal-external cross-validation' on D: each
      study is omitted in turn, the model parameters are estimated from the remaining
      studies and D is evaluated in the omitted study. Because the linear predictor of
      a survival model tells only part of the story, we also suggest a method for
      investigating heterogeneity in the baseline distribution function across studies
      which involves fitting completely specified, flexible parametric survival models
      (Royston and Parmar). Our final models combine the prognostic index (obtained
      with stratification by study) with the pooled baseline survival distribution
      (estimated parametrically). By applying this methodology, we construct two
      prognostic scores in superficial bladder cancer. The simpler of the two scores is
      more suited to clinical application. We show that a three-group prognostic
      classification scheme based on either score produces well-separated survival
      curves for each of the data sets, despite identifiable heterogeneity among the
      baseline distribution functions and to a lesser extent among the prognostic
      indexes for the individual studies.

PMID- 15027081
TI  - Predicting meningococcal disease outbreaks in structured populations.
AB  - Rational decision making on whether some form of intervention would be necessary
      to control the spread of a meningococcal epidemic is based on predictions
      concerning its potential natural progression. Unfortunately, reliable predictions
      are difficult to make during the early stages of an outbreak. A stochastic
      discrete time epidemic model was applied to adaptively predict the development of
      outbreaks of meningococcal disease in 'closed' populations such as military
      garrisons or boarding schools, which are further divided into subgroups called
      'units'. The performance of the adaptive method was assessed by using 3 simulated
      epidemics representing substantially different realizations in a 'garrison' of 20
      units, with 68 men in each. Predictions of the weekly number of disease cases, of
      the number of carriers, and of the number of new infections were computed.
      Simulations suggest that predictions based only on the observed numbers of
      disease cases are generally inaccurate. These predictions can be improved if
      temporal observations on asymptomatic carriers in different units are utilized
      together with observed time series of the disease. A sample of 15 per cent from
      all units can be sufficient for a major improvement if the alternative is to
      obtain a full sample of only some units. Exploiting fully such information
      requires computer intensive Markov chain Monte Carlo methods.

PMID- 15027083
TI  - Modelling of cardiac imaging data with spatial correlation.
AB  - Cardiac imaging with single photon emission computed tomography (SPECT) is a
      common approach for quantifying myocardial perfusion. Fusing serial SPECT studies
      allows detection and quantification of changes in myocardial perfusion such as
      those resulting from disease progression or successful treatment therapy for
      patients with coronary artery disease. The abundance of data for each subject
      along with the inherent intra-subject correlation due to spatial proximity of
      multiple perfusion measurements present special analytical challenges. We utilize
      a standard physiological model of the left ventricle (LV) to construct a general
      statistical model for cardiac perfusion that incorporates spatial correlation. We
      illustrate the use of mixed effects models and linear models with correlated
      errors to estimate myocardial perfusion counts and to compare these counts across
      serial studies. We address different types of spatial correlation among perfusion
      measurements in the LV, and we consider various parametric structures for these
      correlations. We apply the model to data from serial SPECT studies conducted
      while subjects were in both restful and stressful states approximately two days
      and one year following a myocardial infarction.

PMID- 15027082
TI  - Pseudo-likelihood estimation for a marginal multivariate survival model.
AB  - In this paper, we propose a multivariate Plackett-Dale model for survival
      outcomes. A pseudo-likelihood method for the estimation of the parameters is
      proposed and these ideas are applied to two case studies. The modelling approach
      is similar in spirit but different from Parner's approach. The first study is in
      AIDS, where the overall survival time and different opportunistic infections in
      HIV-infected patients are studied. The second study is on adoption data where the
      association of the survival times within families is modelled, illustrating the
      use of the proposed methodology for the context of population genetics.

PMID- 15027084
TI  - Estimation of magnitude in gene-environment interactions in the presence of
      measurement error.
AB  - The design of studies aimed at identifying the interaction between genetic and
      environmental determinants in disease risk is attracting increased attention. In
      this paper, we study the effect of errors on measuring exposures and the effect
      of assessing genotype at one locus on the association of a continuous outcome
      measure with continuous exposures and genotype. The estimation of
      misclassification errors in assessing genotypes from a separate study is
      proposed. If the exposure measurement error is substantial, then even relatively
      small errors in genotyping within limits that are often quoted can have an
      appreciable effect on interaction estimates. We, thus, consider a method for
      correcting the measurement errors when the interaction between the exposures and
      the genetic factor is significant. Finally, we present an epidemiological example
      to demonstrate the importance of correcting measurement errors.

PMID- 15027086
TI  - Research data closer to expectation than compatible with random sampling.

PMID- 15027085
TI  - Goodness-of-fit tests for ordinal response regression models.
AB  - It is well documented that the commonly used Pearson chi-square and deviance
      statistics are not adequate for assessing goodness-of-fit in logistic regression
      models when continuous covariates are modelled. In recent years, several methods
      have been proposed which address this shortcoming in the binary logistic
      regression setting or assess model fit differently. However, these techniques
      have typically not been extended to the ordinal response setting and few
      techniques exist to assess model fit in that case. We present the modified
      Pearson chi-square and deviance tests that are appropriate for assessing goodness
      of-fit in ordinal response models when both categorical and continuous covariates
      are present. The methods have good power to detect omitted interaction terms and
      reasonable power to detect failure of the proportional odds assumption or
      modelling the wrong functional form of a continuous covariate. These tests also
      provide immediate information as to where a model may not fit well. In addition,
      the methods are simple to understand and implement, and are non-specific. That
      is, they do not require prespecification of a type of lack-of-fit to detect.

PMID- 15027088
TI  - New perspectives in primate cognitive ecology.
AB  - The papers in this issue are from a symposium presented at the 71st Annual
      Meeting of the American Association of Physical Anthropologists held in Buffalo,
      New York, in April 2002. In the light of recent theoretical and methodological
      advances and debates in the study of cognition, this symposium addressed
      questions concerning primate cognitive ecology and decision-making from a variety
      of perspectives. These include ontogenetic patterns of brain growth and learning,
      paleoecology and evolution, sensory adaptations, foraging strategies, tool-using
      behavior, and concepts derived from the study of human cognition, such as
      schemata, planning, and rehearsal of activities. In this issue, data are
      presented on New World monkeys, Old World monkeys, apes, and humans. It is argued
      that the ability to make decisions based on the recognition that tertiary
      relationships in one context can be used to understand cause-and-effect
      relationships in an unrelated context may enable nonhuman primates to effectively
      reduce uncertainty and solve problems in changing social and ecological
      environments.

PMID- 15027090
TI  - Wild capuchins (Cebus capucinus) fail to use tools in an experimental field
      study.
AB  - From September through November 2000 we conducted an experimental field study of
      tool use in a group of 15 wild white-faced capuchins (Cebus capucinus) in Costa
      Rica. The problem presented to the capuchins involved the use of wooden dowels as
      probes to obtain a food reward (two bananas) located inside a clear Plexiglas
      box. Specifically, the task required the capuchins to manually insert a dowel
      into any of six holes drilled into the box in order to push the bananas off a
      shelf. The banana could then be retrieved through a large opening at the bottom
      of the box. The capuchins visited the tool-use platform 702 times over the course
      of 55 consecutive days and under several experimental conditions. During the
      first 21 days of the study, they explored the box but made no attempt to touch or
      pick up the dowels. Even after we placed the dowels in the holes, the capuchins
      only occasionally manipulated them. Overall, the results indicate that the
      capuchins did not use a tool to solve this novel foraging problem.

PMID- 15027089
TI  - Brain growth, life history, and cognition in primate and human evolution.
AB  - This study investigates brain size ontogeny in a sample of seven anthropoid
      primate species (including humans) in order to evaluate longstanding ideas about
      the relations between brain size, brain ontogeny, life history, and cognition.
      First, this analysis tests the hypothesis that primate brain growth patterns vary
      across species. Second, the relations between the duration of the brain growth
      period and the duration of the pre-adult period are evaluated. Brain growth data,
      derived from a number of sources, are analyzed through parametric and
      nonparametric regressions. The results indicate that primates are characterized
      by significant variation in patterns of brain growth. In addition, the degree to
      which brain growth is allocated to either the pre- or the postnatal period varies
      substantially. Analyses of phylogenetically adjusted data show no correlation
      between the lengths of the brain growth period and the juvenile period, but there
      are correlations with other life-history variables. These results are explained
      in terms of maternal metabolic adaptations. Specifically, primates appear to
      present at least two major metabolic adaptations. In the first, brain growth
      occurs mainly during the prenatal period, reflecting heavy maternal investment.
      In the second, brain growth occupies large portions of the postnatal period.
      These differing patterns have important implications for maturation age,
      necessitating late maternal maturation in the first case and enabling relatively
      early maternal maturation in the second. Overall, these adaptations represent
      components of distinctive life-history adaptations, with potentially important
      implications for the evolution of primate cognition.

PMID- 15027092
TI  - Significance of color, calories, and climate to the visual ecology of
      catarrhines.
AB  - Here we describe correlations among visual ecology and the physiochemical
      properties of fruits and leaves consumed by four species of catarrhine primate:
      Cercopithecus ascanius, Colobus guereza, Pan troglodytes, and Piliocolobus
      badius. Collectively, their diet was diverse, with each species relying on fruits
      and leaves to different extents. The mean chromaticity of both foods, as
      perceived by the green-red and yellow-blue signals that catarrhines decode, was
      distinct from background foliage. However, selection on the basis of color was
      evident only for leaves. Primates consumed leaves with higher green-red values
      than the leaves they avoided-sensory mechanism that correlated with key
      nutritional variables, such as increased protein and reduced toughness. Moreover,
      the monkeys ingested leaves near dusk, when reddish targets may be more salient.
      Similar patterns were never observed with respect to edible fruits, the
      chromaticities of which did not differ from unconsumed fruits or correlate with
      nutritional properties. We also found that primate biomass is higher in seasonal
      sites. We conclude that these findings are consistent with the notion that
      routine trichromatic vision evolved in a context where seasonal folivory was
      pivotal to survival.

PMID- 15027091
TI  - Use of spatial, visual, and olfactory information during foraging in wild
      nocturnal and diurnal anthropoids: A field experiment comparing Aotus,
      Callicebus, and Saguinus.
AB  - Early in their evolution, the ancestors of anthropoid primates radiated from a
      nocturnal to a diurnal niche. Foraging during the night differs from foraging
      during the day in terms of the availability of light and color cues, and in the
      movement of odor molecules through the canopy. In this study, we compared the
      ability of nocturnal and diurnal New World monkeys to use perceptual cues (i.e.,
      the sight or smell of food) and spatial information (place predictability) in
      within-patch foraging decisions. An experimental field study was conducted on
      wild groups of night monkeys (Aotus nigriceps), tamarins (Saguinus imperator
      imperator and S. fuscicollis weddelli), and titi monkeys (Callicebus cupreus) at
      the Zoobotanical Park/UFAC, Rio Branco, Brazil. Our research design included the
      construction of feeding stations located in the home range of the study groups.
      Each feeding station consisted of eight visually identical feeding platforms
      located in a circular arrangement. In all test settings, two platforms at each
      feeding station contained a food reward (banana), and the remaining six platforms
      contained a sham reward (yellow plastic or inaccessible banana). In the night
      monkey experiments, each feeding platform was illuminated by a 40-W red bulb to
      aid the researcher in observing their behavior. When the location of reward sites
      was predictable over time, individuals in all four species successfully relocated
      food rewards based solely on spatial information. Each species was also
      successful in using visual information to distinguish real from sham food
      rewards. However, only night monkeys and one group of emperor tamarins used
      olfactory information alone to locate food rewards. Overall, the species'
      performances did not clearly differentiate Aotus from diurnal New World primates
      in these experiments.

PMID- 15027093
TI  - Paleoenvironmental basis of cognitive evolution in great apes.
AB  - A bias favoring tree-dominated habitats and ripe-fruit frugivory has persisted in
      great ape evolution since the early Miocene. This bias is indicated by fossil ape
      paleoenvironments, molar morphology, dental microwear, the geographic pattern of
      extinctions, and extant apes' reliance on wooded settings. The ephemeral aspect
      of high-quality fruit has placed a premium on cognitive and social means of
      finding and defending food sources, and appears related to great apes' affinity
      since the Miocene for wooded, fruit-rich environments. These habitats have,
      however, undergone a severe withdrawal toward the low latitudes of Africa and
      Southeast Asia since the late Miocene, corresponding to a decline in the
      diversity of great apes beginning 9.5 million years ago. Plio-Pleistocene records
      imply that wooded settings of Africa and SE Asia were prone to substantial
      fragmentation and coalescence. Once apes were confined to equatorial settings,
      therefore, habitat instability heightened the spatial/temporal uncertainty of
      ripe-fruit sources. Prolonged learning, the assignment of attributes to distant
      places, mental representation, and reliance on fallback foods were all favored in
      this dynamic environmental context. These abilities helped sustain forest
      frugivory in most lineages. Fluid social grouping afforded the animals
      opportunities to locate ephemeral foods in continuous and fragmented forests.
      Fission-fusion grouping also magnified the problems of object impermanence (of
      individuals) and dispersion manifested by food sources in the ecological realm.
      Thus the spatial and temporal dynamics of fruit and wooded habitats since the
      Miocene are reflected in important components of great ape cognition, foraging,
      and sociality. In contrast to great apes, cercopithecoid monkeys have increased
      their plant dietary options and diversified in seasonal environments since the
      late Miocene. Early hominins eventually severed the habitat bias that
      characterized the evolution of great apes, and later expanded into diverse
      environments.

PMID- 15027094
TI  - Human cognitive ecology: an instructive framework for comparative primatology.
AB  - In this review, research on human cognitive ecology is compared with studies of
      the cognitive ecologies of apes-especially the common chimpanzee. The objective
      was to assess the feasibility of extending an activity-theory framework developed
      in studies of humans to an integrated approach for studying the cognitive
      accomplishments and skills of other primates living in the wild. Six
      generalizations were abstracted from studies of humans: 1) Social and material
      environments are arranged to facilitate production. 2) Human activity is shaped
      by conceptual and cultural principles that provide underlying logic for working
      knowledge and practice. 3) Schemata (multimodal, mental representations of
      procedures, strategies, and techniques) govern performance in a domain. 4)
      Working knowledge, skills, and social identities are co-constructed in
      communities of practice. 5) Rehearsal improves skilled performances, from which
      reputations as well as material products are derived. 6) Planning and emergence
      are in productive tension in human practices. These generalizations are applied
      to findings in the literature regarding the behavior of chimpanzees and other
      apes in the wild to assess the potential utility of a situated-activity approach
      for comparative studies of primate cognition. It is argued in the Discussion that
      schemata constitute a common core of higher primate intelligence. Planning,
      emergence, and alterations of the environment to facilitate production further
      characterize human and chimpanzee or gorilla behaviors to varying degrees. Less
      apparent in the nonhuman-primate literature is evidence of governing principles,
      rehearsal, and skill-based reputations or identities entailing theories of mind.
      Nonetheless, recent observations in the wild suggest that further research is
      warranted to explore the rudiments of each of these components to enhance our
      understanding of the ecology of primate cognition and its evolutionary history.

PMID- 15027095
TI  - Signal transduction via the NF-kappaB pathway: a targeted treatment modality for
      infection, inflammation and repair.
AB  - Activation of transcription factors plays a pivotal role in many signal
      transduction pathways. Of particular interest is NF-kappaB, which is present in
      the cytoplasm in an inactive form, where it can be activated in response to many
      different stress conditions such as infection, inflammation, heat shock etc. It
      has also been associated with apoptosis and tissue repair. Modulation of signal
      transduction events that mediate activation of NF-kappaB seems to have a great
      potential in not only treating many disease conditions, but also in tissue
      repair. The present review article is an attempt to put together many different
      conditions where the NF-kappaB activation pathway appears to be crucial in
      transducing signals under stress conditions, and to explore the possibility of
      its modulation as a targeted treatment modality.

PMID- 15027096
TI  - The investigation of the ultrastructural neutrophil changes in alloxan-induced
      diabetes in rats: response to a chemotactic challenge.
AB  - Experimental diabetes is one of the most popular conditions in which to study the
      relation between neutrophil leukocyte activity and periodontal destruction. The
      aetiology of neutrophil dysfunction in the gingival tissue associated with
      diabetes has yet to be clarified. Diabetes in rats decreases neutrophil
      chemotactic activity in proportion to the severity of this systemic disorder. The
      present study was carried out to evaluate the relationship between the severity
      of diabetes and the neutrophil response to two chemotactic agents, and to
      correlate the observed neutrophil defects with the degree of diabetes. In this
      study two chemotactic agents, casein (0.2 microl, 2 mg ml(-1)) or N
      formylmethionylleucylphenylalanine (FMLP; 0.2 microl, 10(-4) M), were placed into
      the gingival crevices of alloxan-induced diabetic rats. Gingival biopsies were
      taken 15 min later and then at 5-min intervals up to 45 min and investigated by
      electron microscopy. Adherence and migration were observed in the rats with
      moderate diabetes 30 min after the application of casein. There was chemotaxis
      after 35 min of administration of the peptide FMLP. By 40 min neutrophils with
      pyknotic nuclei were observed. At 45 min neutrophils with a decreased number of
      granules were present. As the severity of the diabetes increased, the neutrophils
      degenerated and were structurally distorted. In the rats which had alloxan
      induced diabetes there was abnormal periodontal damage. This damage is thought to
      be related to dysfunctional neutrophils. These findings many contribute to an
      answer to the following question: why is there an apparent variability in the
      susceptibility of periodontal breakdown in diabetics?

PMID- 15027097
TI  - Tyrosine aminotransferase and gamma-glutamyl transferase activity in human fetal
      hepatocyte primary cultures under proliferative conditions.
AB  - The ontogeny of gamma-glutamyl transferase (GGTase; E.C.2.3.2.2) and tyrosine
      aminotransferase (TAT; E.C.2.6.1.5) activities in 14 to 36 weeks gestational and
      neonatal hepatocytes during development of human fetal liver was studied.
      Subsequently, 20-24 weeks gestational hepatocytes were cultured in media
      supplemented with epidermal growth factor (EGF) and insulin with or without
      glucagon and dexamethasone to investigate the proliferation and differentiation
      of fetal hepatocyte in vitro using GGTase and TAT as biochemical markers. During
      the development of the liver, the activity of GGTase increased continuously from
      the first trimester through the third trimester and decreased (p < 0.001) in
      neonates. A low basal level of TAT activity was seen only during the third
      trimester, which then increased significantly (p < 0.001) in neonates. Fetal
      hepatocytes, in the presence of EGF and insulin, undergo proliferation from the
      fourth to 10th day with an increase in cell number (p < 0.001) and concomitant
      increase (p < 0.001) in GGTase activity. As the cells attain confluence, enzyme
      activity decreased significantly (p < 0.001) from the 10th to 16th day. Maximal
      TAT activity (p < 0.001) was observed at 48 h of culture, which decreased, but
      not significantly, during cell proliferation and the enzyme activity was regained
      as the cultures attained confluence. Furthermore, TAT activity was induced
      synergistically (p<0.001) in the presence of glucagon and dexamethasone, while
      GGTase was inhibited (p<0.001). These results indicate that GGTase increases with
      proliferation, whereas TAT, once it has been expressed, is not suppressed during
      cell proliferation. In conclusion, human fetal hepatocytes undergo enzymic
      differentiation by 48 h of culture, and proliferate with an increase in GGTase in
      the presence of growth factors with maintenance of differentiated status up to
      the studied 16 days of culture.

PMID- 15027098
TI  - The protective effect of ursodeoxycholic acid in alloxan-induced diabetes.
AB  - The purpose of this work was to study the effect of ursodeoxycholic acid (UDCA)
      on the morphological and functional alterations in pancreatic islet beta-cells in
      rats with diabetes induced by alloxan (150 mg kg(-1), i.p.). UDCA (40 mg kg(-1),
      i.g.) was administered daily from the fifth to the 35th day after the alloxan
      treatment. The treatment of diabetic rats with UDCA improved the pancreatic
      morphology disturbed by the alloxan treatment: UDCA increased the number of
      pancreatic islets and beta-cells, the beta-/alpha-cell ratio and decreased the
      number of alpha-cells. As the morphometric data suggest, the treatment of
      diabetic animals with UDCA significantly increased the area of beta-cell
      cytoplasmatic granules stained by paraldehyde-fuchsin. The concentration of blood
      glucose in diabetic rats was gradually decreased after the UDCA treatment, and at
      the end of the experiment reached the control value. The treatment with UDCA
      raised the serum insulin level in diabetic rats about 2.5-fold, but this
      concentration was significantly lower as compared to the control group. The
      content of lipid peroxidation end-products, hydroxyalkenals and malondialdehyde,
      was significantly elevated in the alloxan-treated rats, whereas the treatment
      with UDCA normalized these parameters. The present data indicate that UDCA acts
      as an effective antidiabetic agent in alloxan-induced diabetes and its beneficial
      effects in diabetic rats can be related to the antioxidant properties of UDCA.

PMID- 15027099
TI  - Induction of myeloperoxidase and nitrotyrosine formation in a human eosinophilic
      leukemia cell line, EoL-1.
AB  - The human eosinophilic leukemia cell line, EoL-1, differentiated with butyrate as
      an eosinophilic cellular model was evaluated for peroxidase-dependent tyrosine
      nitration. Butyrate suppressed cell growth and induced eosinophilic granules in
      EoL-1 cells after 9 days of culture. Peroxidase activity was detected
      biochemically and histochemically from 3-day cultures and it increased in a time
      dependent manner. This peroxidase activity was inhibited by cyanide.
      Nitrotyrosine formation catalysed by peroxidase using hydrogen peroxide and
      nitrite was detected at a high level similar to that of mature eosinophils.
      However, no expression of eosinophil peroxidase (EPO) was detected by RT-PCR or
      immunocytochemistry. In contrast, the induction of myeloperoxidase (MPO) by
      butyrate was clearly detected by RT-PCR, Northern blot, and immunocytochemical
      staining. These results suggest that butyrate induces MPO rather than EPO in EoL
      1 cells and that the formation of nitrotyrosine in butyrate-induced cells is
      dependent on MPO.

PMID- 15027100
TI  - The effects of dietary flaxseed on the Fischer 344 rat: I. Development,
      behaviour, toxicity and the activity of liver gamma-glutamyltranspeptidase.
AB  - The effect of exposure to, followed by consumption of, 10% flax chow from the
      18th day of gestation to the 86th day after birth was examined in male and female
      Fischer 344 rats. Growth curves of the flax chow-fed rats were identical to those
      of regular chow-fed rats, as were such developmental milestones as pinna
      development, growth of hair and eye opening. Acoustical startle and the righting
      reflexes, developmental behavioural indices, were also the same. Blood glucose
      levels were comparable in flax chow-fed and regular chow-fed rats at all stages
      of development, indicating that flax is without effect on glucose balance. There
      were no signs of toxicity in the flax chow-fed rats since their plasma levels of
      alanine aminotransferase and gamma-glutamyltranspeptidase (gammaGT) were the same
      as those of regular chow-fed rats. The activity of gammaGT displayed an increase
      in the livers of flax chow-fed rats after puberty, more so in the male-four-fold
      than in the female-1.38-fold. This is suggestive of an estrogenic effect which
      implicates an effect of an estrogenic flax lignan. An hepatobeneficial effect of
      the flax-induced increase in liver gammaGT is discussed. In summary, dietary 10%
      flax chow is without long-term effect on growth, development and behaviour, is
      non-toxic and may be hepatoprotective.

PMID- 15027101
TI  - Protective effect of glycine supplementation on the levels of lipid peroxidation
      and antioxidant enzymes in the erythrocyte of rats with alcohol-induced liver
      injury.
AB  - We studied the effect of glycine supplementation on lipid peroxidation and
      antioxidants in the erythrocyte membrane, plasma and hepatocytes of rats with
      alcohol-induced hepatotoxicity. Administering ethanol (20%) for 60 days to male
      Wistar rats resulted in significantly elevated levels of erythrocyte membrane,
      plasma and hepatocyte thiobarbituric acid reactive substances (TBARS) as compared
      with those of the experimental control rats. Decreased activities of superoxide
      dismutase (SOD), catalase (CAT), reduced glutathione (GSH), glutathione
      peroxidase (GPx) and glutathione reductase (GR) were also observed on alcohol
      supplementation as compared with those of the experimental control rats. Glycine
      was administered at a dose of 0.6 g kg(-1) body weight to rats with alcohol
      induced liver injury, which significantly decreased the levels of TBARS and
      significantly elevated the activities of SOD, CAT, GSH, GPx and GR in the
      erythrocyte membrane, plasma and hepatocytes as compared to that of untreated
      alcohol supplemented rats. Thus, our data indicate that supplementation with
      glycine offers protection against free radical-mediated oxidative stress in the
      erythrocyte membrane, plasma and hepatocytes of animals with alcohol-induced
      liver injury.

PMID- 15027103
TI  - Reduced basis set for the gold atom in cluster complexes.
AB  - To extend the metal cluster size used in interfacing between bulk metals and
      molecules in ab initio studies of molecular electronics and chemisorption, a
      reduced size atomic orbital basis set for the gold atom has been generated. Based
      on the SKBJ relativistic effective core potential set, the three component 5d
      Gaussian orbital basis set is completely contracted. Comparisons between the full
      and reduced basis set in Au atom clusters and cluster complexes for geometry,
      bond distances, dipole moments, atomic charges, spin, bond dissociation energies,
      lowest energy harmonic frequencies, electron affinities, ionization energies, and
      density of states distributions show the contracted set to be a viable
      replacement for the full basis set. This result is obtained using both the B3LYP
      and BPW91 exchange-correlation potentials in density functional theory.

PMID- 15027102
TI  - The effects of isosorbide dinitrate on methemoglobin reductase enzyme activity
      and antioxidant states.
AB  - Isosorbide dinitrate (ISDN) has been used in the treatment of ischaemic
      cardiovascular diseases for many years. ISDN is the most popular nitric oxide
      donor and causes methemoglobinemia as an important side-effect. The purpose of
      this study was to examine antioxidant states and methemoglobin reductase activity
      after giving ISDN and ISDN plus vitamin E. Rats were divided into three groups
      according to the treatment: control group, ISDN group and ISDN plus vit. E group.
      We measured reduced glutathione in blood (GSH), plasma malondialdehyde (MDA),
      erythrocyte superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase
      (GPx) and NADH-dependent methemoglobin reductase activities. In the ISDN group,
      plasma MDA levels were significantly high compared to the control and ISDN + vit.
      E groups (p < 0.001). In the ISDN and ISDN + vit. E groups, blood GSH levels were
      higher than those of the control group (p < 0.05). Changes of SOD and GPx
      activities were not significant. In the ISDN and ISDN + vit. E groups the
      erythrocyte catalase and NADH-dependent methemoglobin reductase activities were
      significantly higher than that in the control group (p < 0.001). We conclude that
      oxidant drugs such as ISDN need to be carefully used because of lipid
      peroxidation and methemoglobinemia. These findings support the notion that
      vitamine E protects tissues against oxidative stress.

PMID- 15027104
TI  - The arsenic clusters Asn (n = 1-5) and their anions: structures, thermochemistry,
      and electron affinities.
AB  - The molecular structures, electron affinities, and dissociation energies of the
      As(n)/As(-) (n) (n = 1-5) species have been examined using six density functional
      theory (DFT) methods. The basis set used in this work is of double-zeta plus
      polarization quality with additional diffuse s- and p-type functions, denoted
      DZP++. These methods have been carefully calibrated (Chem Rev 2002, 102, 231) for
      the prediction of electron affinities. The geometries are fully optimized with
      each DFT method independently. Three different types of the neutral-anion energy
      separations reported in this work are the adiabatic electron affinity (EA(ad)),
      the vertical electron affinity (EA(vert)), and the vertical detachment energy
      (VDE). The first dissociation energies D(e)(As(n-1)-As) for the neutral As(n)
      species, as well as those D(e)(As(-) (n-1)-As) and D(e) (As(n-1)-As(-)) for the
      anionic As(-) (n) species, have also been reported. The most reliable adiabatic
      electron affinities, obtained at the DZP++ BLYP level of theory, are 0.90 (As),
      0.74 (As(2)), 1.30 (As(3)), 0.49 (As(4)), and 3.03 eV (As(5)), respectively.
      These EA(ad) values for As, As(2), and As(4) are in good agreement with
      experiment (average absolute error 0.09 eV), but that for As(3) is a bit smaller
      than the experimental value (1.45 +/- 0.03 eV). The first dissociation energies
      for the neutral arsenic clusters predicted by the B3LYP method are 3.93 eV
      (As(2)), 2.04 eV (As(3)), 3.88 eV (As(4)), and 1.49 eV (As(5)). Compared with the
      available experimental dissociation energies for the neutral clusters, the
      theoretical predictions are excellent. Two dissociation limits are possible for
      the arsenic cluster anions. The atomic arsenic results are 3.91 eV (As(-) (2) -->
      As(-) + As), 2.46 eV (As(-) (3) --> As(-) (2) + As), 3.14 eV (As(-) (4) --> As(-)
      (3) + As), and 4.01 eV (As(-) (5) --> As(-) (4) + As). For dissociation to
      neutral arsenic clusters, the predicted dissociation energies are 2.43 eV (As(-)
      (3) --> As(2) + As(-)), 3.53 eV (As(-) (4) --> As(3) + As(-)), and 3.67 eV (As(-)
      (5) --> As(4) + As(-)). For the vibrational frequencies of the As(n) series, the
      BP86 and B3LYP methods produce good results compared with the limited
      experiments, so the other predictions with these methods should be reliable.

PMID- 15027105
TI  - Calculation of electrostatic interaction energies in molecular dimers from atomic
      multipole moments obtained by different methods of electron density partitioning.
AB  - Accurate and fast evaluation of electrostatic interactions in molecular systems
      is still one of the most challenging tasks in the rapidly advancing field of
      macromolecular chemistry, including molecular recognition, protein modeling and
      drug design. One of the most convenient and accurate approaches is based on a
      Buckingham-type approximation that uses the multipole moment expansion of
      molecular/atomic charge distributions. In the mid-1980s it was shown that the
      pseudoatom model commonly used in experimental X-ray charge density studies can
      be easily combined with the Buckingham-type approach for calculation of
      electrostatic interactions, plus atom-atom potentials for evaluation of the total
      interaction energies in molecular systems. While many such studies have been
      reported, little attention has been paid to the accuracy of evaluation of the
      purely electrostatic interactions as errors may be absorbed in the semiempirical
      atom-atom potentials that have to be used to account for exchange repulsion and
      dispersion forces. This study is aimed at the evaluation of the accuracy of the
      calculation of electrostatic interaction energies with the Buckingham approach.
      To eliminate experimental uncertainties, the atomic moments are based on
      theoretical single-molecule electron densities calculated at various levels of
      theory. The electrostatic interaction energies for a total of 11 dimers of alpha
      glycine, N-acetylglycine and L-(+)-lactic acid structures calculated according to
      Buckingham with pseudoatom, stockholder and atoms-in-molecules moments are
      compared with those evaluated with the Morokuma-Ziegler energy decomposition
      scheme. For alpha-glycine a comparison with direct "pixel-by-pixel" integration
      method, recently developed Gavezzotti, is also made. It is found that the
      theoretical pseudoatom moments combined with the Buckingham model do predict the
      correct relative electrostatic interactions energies, although the absolute
      interaction energies are underestimated in some cases. The good agreement between
      electrostatic interaction energies computed with Morokuma-Ziegler partitioning,
      Gavezzotti's method, and the Buckingham approach with atoms-in-molecules moments
      demonstrates that reliable and accurate evaluation of electrostatic interactions
      in molecular systems of considerable complexity is now feasible.

PMID- 15027106
TI  - Hybrid boundary element and finite difference method for solving the nonlinear
      Poisson-Boltzmann equation.
AB  - A hybrid approach for solving the nonlinear Poisson-Boltzmann equation (PBE) is
      presented. Under this approach, the electrostatic potential is separated into (1)
      a linear component satisfying the linear PBE and solved using a fast boundary
      element method and (2) a correction term accounting for nonlinear effects and
      optionally, the presence of an ion-exclusion layer. Because the correction
      potential contains no singularities (in particular, it is smooth at charge sites)
      it can be accurately and efficiently solved using a finite difference method. The
      motivation for and formulation of such a decomposition are presented together
      with the numerical method for calculating the linear and correction potentials.
      For comparison, we also develop an integral equation representation of the
      solution to the nonlinear PBE. When implemented upon regular lattice grids, the
      hybrid scheme is found to outperform the integral equation method when treating
      nonlinear PBE problems. Results are presented for a spherical cavity containing a
      central charge, where the objective is to compare computed 1D nonlinear PBE
      solutions against ones obtained with alternate numerical solution methods. This
      is followed by examination of the electrostatic properties of nucleic acid
      structures.

PMID- 15027107
TI  - Geometric algorithms for the conformational analysis of long protein loops.
AB  - The efficient filtering of unfeasible conformations would considerably benefit
      the exploration of the conformational space when searching for minimum energy
      structures or during molecular simulation. The most important conditions for
      filtering are the maintenance of molecular chain integrity and the avoidance of
      steric clashes. These conditions can be seen as geometric constraints on a
      molecular model. In this article, we discuss how techniques issued from recent
      research in robotics can be applied to this filtering. Two complementary
      techniques are presented: one for conformational sampling and another for
      computing conformational changes satisfying such geometric constraints. The main
      interest of the proposed techniques is their application to the structural
      analysis of long protein loops. First experimental results demonstrate the
      efficacy of the approach for studying the mobility of loop 7 in amylosucrase from
      Neisseria polysaccharea. The supposed motions of this 17-residue loop would play
      an important role in the activity of this enzyme.

PMID- 15027108
TI  - First-principles pair potentials across the metal-ceramic interface.
AB  - Systematic approaches are presented to invert the first-principle binding energy
      to obtain the pair potentials across the metal/ceramic interfaces. The
      conformation characteristics of two virtual interface models suitable for the
      inversion are summarized: (1) the positions of one kind of ceramic ions stay
      unchanged, but those of the other change; or, (2) there is no change in the
      relative positions of the ceramic ions to the metal atoms but the positions of
      two kinds of ceramic ions are all exchanged each other. As an example, we derive
      the pair potentials of Ni-Zr(4+) and Ni-O(2-) across the Ni/ZrO(2) interface with
      this method, which exhibit comparable accuracy to the first-principle results.
      This provides direct evidence that the interfacial potentials obtained from this
      method can reasonably describe the general features of bondings across the metal
      ceramic interface. The limitation of this method is also discussed.

PMID- 15027109
TI  - Conformational fluctuations and electronic properties in myoglobin.
AB  - In this article we use the recently developed perturbed matrix method (PMM) to
      investigate the effect of conformational fluctuations on the electronic
      properties of heme in Myoglobin. This widely studied biomolecule has been chosen
      as a benchmark for evaluating the accuracy of PMM in a large and complex system.
      Using a long, 80-ns, molecular dynamics simulation and unperturbed Configuration
      Interaction (CISD) calculations in PMM, we reproduced the main spectroscopic
      features of deoxy-Myoglobin. Moreover, in line with our previous results on a
      photosensitive protein, this study reveals a clear dynamical coupling between
      electronic properties and conformational fluctuations, suggesting that this
      correlation could be a general feature of proteins.

PMID- 15027110
TI  - Ensemble variance in free energy calculations by thermodynamic integration:
      theory, optimal "Alchemical" path, and practical solutions.
AB  - Thermodynamic integration is a widely used method to calculate and analyze the
      effect of a chemical modification on the free energy of a chemical or biochemical
      process, for example, the impact of an amino acid substitution on protein
      association. Numerical fluctuations can introduce large uncertainties, limiting
      the domain of application of the method. The parametric energy function
      describing the chemical modification in the thermodynamic integration, the
      "Alchemical path," determines the amplitudes of the fluctuations. In the present
      work, I propose a measure of the fluctuations in the thermodynamic integration
      and an approach to search for a parametric energy path minimizing that measure.
      The optimal path derived with this approach is very close to the theoretical
      minimum of the measure, but produces nonergodic sampling. Nevertheless, this path
      is used to guide the design of a practical and efficient path producing correct
      sampling. The convergence with this practical path is evaluated on test cases,
      and compares favorably with that of other methods such as power or polynomial
      path, soft-core van der Waals, and some other approaches presented in the
      literature.

PMID- 15027111
TI  - On the applicability of the HSAB principle through the use of improved
      computational schemes for chemical hardness evaluation.
AB  - Finite difference schemes, named Compact Finite Difference Schemes with Spectral
      like Resolution, have been used for a less crude approximation of the analytical
      hardness definition as the second-order derivative of the energy with respect to
      the electron number. The improved computational schemes, at different levels of
      theory, have been used to calculate global hardness values of some probe bases,
      traditionally classified as hard and soft on the basis of their chemical
      behavior, and to investigate the quantitative applicability of the HSAB
      principle. Exchange acid-base reactions have been used to test the HSAB principle
      assuming the reaction energies as a measure of the stabilization of product
      adducts.

PMID- 15027112
TI  - Inhaled particles and lung cancer. Part A: Mechanisms.
AB  - Both occupational and environmental exposure to particles is associated with an
      increased risk of lung cancer. Particles are thought to impact on genotoxicity as
      well as on cell proliferation via their ability to generate oxidants such as
      reactive oxygen species (ROS) and reactive nitrogen species (RNS). For
      mechanistic purposes, one should discriminate between a) the oxidant-generating
      properties of particles themselves (i.e., acellular), which are mostly determined
      by the physicochemical characteristics of the particle surface, and b) the
      ability of particles to stimulate cellular oxidant generation. Cellular ROS/RNS
      can be generated by various mechanisms, including particle-related mitochondrial
      activation or NAD(P)H-oxidase enzymes. In addition, since particles can induce an
      inflammatory response, a further subdivision needs to be made between primary
      (i.e., particle-driven) and secondary (i.e., inflammation-driven) formation of
      oxidants. Particles may also affect genotoxicity by their ability to carry
      surface-adsorbed carcinogenic components into the lung. Each of these pathways
      can impact on genotoxicity and proliferation, as well as on feedback mechanisms
      involving DNA repair or apoptosis. Although abundant evidence suggests that
      ROS/RNS mediate particle-induced genotoxicity and mutagenesis, little information
      is available towards the subsequent steps leading to neoplastic changes.
      Additionally, since most of the proposed molecular mechanisms underlying particle
      related carcinogenesis have been derived from in vitro studies, there is a need
      for future studies that evaluate the implication of these mechanisms for in vivo
      lung cancer development. In this respect, transgenic and gene knockout animal
      models may provide a useful tool. Such studies should also include further
      assessment of the relative contributions of primary (inflammation-independent)
      and secondary (inflammation-driven) pathways.

PMID- 15027113
TI  - Inhibition of MUC1 expression by indole-3-carbinol.
AB  - MUC1 is a large transmembrane glycoprotein overexpressed by a majority of
      carcinomas. High expression of MUC1 is associated with aggressive tumors, and
      MUC1 antigen is used as a marker to monitor disease progression in breast cancer
      patients. Several lines of evidence strongly suggest that the overexpression of
      MUC1 contributes to cancer progression and metastasis. In this report, we
      demonstrate that the naturally occurring cancer preventative, indole-3-carbinol
      (I3C), inhibits the expression of MUC1 in breast cancer cells. I3C inhibited both
      MUC1 mRNA and protein levels in a dose- and time-dependent manner. This
      inhibition was seen in the estrogen responsive MCF-7 cells as well as
      unresponsive MDA-MB-468 cells, indicating that the inhibitory pathway is
      independent of estrogen receptor. Gene expression studies using the human MUC1
      gene promoter connected to a luciferase reporter demonstrated that I3C inhibits
      the transcription of the MUC1 gene. Promoter deletion studies indicate that the
      region containing up to 600 bp upstream (-600) of the initiation site is
      sufficient for inhibition by I3C. Furthermore, I3C represses the activation of
      transcription mediated by the region between -600 and -450 bp. A putative
      xenobiotic response element was located within this region but the binding of
      AhR/Arnt heterodimer to this site was undetectable by electrophoretic mobility
      shift assays. Our results may point to the existence of a novel pathway of
      transcriptional inhibition by I3C in cancer cells as well as a new mechanism of
      MUC1 gene inhibition. Our findings might have implications in the use of I3C as a
      preventative as well as a therapeutic agent for breast cancer.

PMID- 15027114
TI  - Synergistic effect of lymphotactin and interferon gamma-inducible protein-10
      transgene expression in T-cell localization and adoptive T-cell therapy of
      tumors.
AB  - The lack of efficient T-cell infiltration of tumors is a major obstacle to
      successful adoptive T-cell therapy. We have previously demonstrated that
      adenovirus (AdV)-mediated transgene lymphotactin (Lptn) or IP-10 expression in
      tumors can significantly enhance T-cell tumor infiltration. In this study, active
      OVA-specific CD8+ T cells were prepared by coculturing naive OVA-specific CD8+ T
      cells from transgenic OT I mice with OVA-I peptide-pulsed dendritic cells in
      vitro. These XCR-1- and CXCR3-expressing T cells predominantly secreted IFN-gamma
      and displayed significant killing activity (84% at effector:target cell ratio of
      1.5) against OVA-expressing EG7 tumor cells through perforin-mediated pathway.
      Our data also showed that chemokine Lptn and IP-10 not only can chemoattract, but
      also stimulate proliferation of CD8+ T cells in vitro, and that a mixture of Lptn
      and IP-10 can more efficiently chemoattract CD8+ T cells than either one of them.
      Furthermore, we demonstrated that the transferred CD8+ T cells detected in group
      of tumors treated with both AdVLptn and AdVIP-10 (group a) are around 4 and 2
      times more than that in groups of tumors treated with control AdVpLpA (group b)
      and either AdVIP-10 (group c) or AdVLptn (group d), respectively. Around 87.5% of
      mice in group a were tumor-free compared to the aggressive tumor growth in all 8
      mice of group b and 25% or 37.5% cured mice seen in groups c and d (p<0.05).
      Thus, our results indicate that enhancement of adoptive T-cell therapy can be
      obtained by double tranmsgene Lptn and IP-10 expression, which facilitates CD8+ T
      cell tumor localization through proliferation and chemoattraction of the
      transferred CD8+ T cells by in situ chemokine transgene expressions in the
      tumors. Collectively, our data provide solid evidence of a potent synergy between
      adoptive T-cell therapy and adenovirus-mediated Lptn and IP-10 gene transfer into
      tumor tissues, which culminated in the T-cell tumor localization and eradication
      of well-established tumor masses.

PMID- 15027115
TI  - Effect of serum deprivation on constitutive production of granulocyte-colony
      stimulating factor and granulocyte macrophage-colony stimulating factor in lung
      cancer cells.
AB  - We previously established 2 lung cancer cell lines, OKa-C-1 and MI-4, which
      constitutively produce an abundant dose of granulocyte-colony stimulating factor
      (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF). Many other
      cases with G-CSF or GM-CSF producing tumors have been reported up to the present.
      However, the biological properties of the overproduction of G-CSF and GM-CSF by
      tumor cells have not been well known. Several reports demonstrated the presence
      of an autocrine growth loop for G-CSF and GM-CSF in nonhematopoietic tumor cells.
      We showed that exogenous G-CSF and GM-CSF stimulated cell growth in a dose
      dependent manner in OKa-C-1 and MI-4 cells. We could detect the presence of G-CSF
      and GM-CSF receptors in both cell lines by RT-PCR analysis. We have previously
      shown that inflammatory cytokines, tumor necrosis factor (TNF)-alpha and
      interleukin (IL)-1beta enhance the expression of G-CSF and GM-CSF in the cell
      lines. However, the factors that regulate constitutive production of G-CSF or GM
      CSF by tumor cells are still unknown well. In our study, we first reported that
      serum deprivation stimulated constitutive production of G-CSF and GM-CSF by lung
      tumor cells through activation of nuclear factor (NF)-kappaB and p44/42 mitogen
      activated protein kinase (MAPK) pathway signaling. We suggest that G-CSF and GM
      CSF constitutively produced by tumor cells could grow tumor itself and rescue
      tumor cells from the cytotoxicity of serum deprivation.

PMID- 15027116
TI  - Expression, regulation and function of autotaxin in thyroid carcinomas.
AB  - Autotaxin (ATX/NPP2) is a tumor cell motility-stimulating factor that displays
      both a nucleotide pyrophosphatase/phosphodiesterase activity and a recently
      described lysophospholipase D (lysoPLD) activity. The precise function of ATX in
      tumor cells and the role of ATX in thyroid carcinoma remains unclear. We have
      quantified ATX mRNA expression in thyroid carcinoma cell lines and in tissues of
      patients with thyroid carcinomas. ATX gene activity was significantly higher in
      undifferentiated anaplastic thyroid carcinoma cell lines (UTC) and tumor tissues
      as compared to follicular thyroid carcinoma (FTC) cell lines, FTC tissues or
      goiter tissues that were used as a control. In the thyroid carcinoma cell line
      1736, EGF and bFGF stimulated ATX mRNA expression, whereas the cytokines IL-4, IL
      1beta and TGF-beta reduced ATX transcriptional levels. FTC-133 cells, stably
      transfected with an expression vector for ATX, showed a higher lysoPLD activity,
      a higher proliferation rate and an increased migratory behavior. In addition, ATX
      also displayed a paracrine stimulatory effect on the motility of different
      thyroid carcinoma cell lines. Overexpression of ATX in the stably transfected FTC
      133 resulted in down-regulation of CD54/ intercellular adhesion molecule-1 (ICAM
      1) gene expression and augmented gene activity of the pro-angiogenic chemokine IL
      8. We conclude that ATX may be regarded as a new tissue marker for
      undifferentiated human thyroid carcinoma cells. ATX increases the proliferation
      and migration of thyroid carcinoma cell lines and may also affect the angiogenic
      potential of thyroid carcinoma cells. Further studies are needed to provide
      insight into the role of ATX in the normal and neoplastic thyroid gland.

PMID- 15027117
TI  - RASSF1A is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma.
AB  - Deletion on the short arm of chromosome 3 is one of the most important genetic
      abnormalities in the tumorigenesis of nasopharyngeal carcinoma (NPC). Both
      physical mapping and functional studies have targeted an NPC-related tumor
      suppressor gene(s) to chromosome 3p21.3. We have reported recently that RASSF1A
      gene, located on a 120-kb minimal deletion region on 3p21.3, was frequently
      inactivated by promoter hypermethylation in NPC. We further confirmed that
      RASSF1A is the critical target tumor suppressor from 3p21.3, with the evidence
      that loss of expression and aberrant methylation of the other 8 candidate
      genes/transcripts (HYAL2, FUS1, RASSF1C, BLU, NPRL2, 101F6, PL6 and CACNA2D2) in
      this 120-kb region were rare in NPC samples. The contribution of RASSF1A in NPC
      tumorigenesis was investigated by restoring its expression in a RASSF1A deficient
      cell line, C666-1. Transient transfection of wild-type RASSF1A resulted in marked
      growth inhibition in NPC cells. Isolated stable clones expressing wild-type
      RASSF1A demonstrated retarded cell proliferation in vitro. Soft-agar assay also
      showed decreased number and sizes of colony formed in these clones. In vivo nude
      mice assay demonstrated the dramatic reduction of tumorigenic potential in the
      RASSF1A-transfected clones. Our results provide strong evidence to support
      RASSF1A as a target tumor suppressor gene on 3p21.3 in NPC.

PMID- 15027119
TI  - Role for dipeptidyl peptidase IV in tumor suppression of human non small cell
      lung carcinoma cells.
AB  - Lung cancer is the leading cause of cancer death. Lung cancers produce a variety
      of mitogenic growth factors that stimulate tumor cell proliferation and
      migration. The cell surface protease, dipeptidyl peptidase IV (DPPIV), is
      involved in diverse biologic functions, including peptide-mediated cellular
      growth and differentiation. DPPIV is expressed in various normal tissues,
      including lung tissue, and its expression is lost in many types of human cancers.
      DPPIV expression and its enzymatic activity are detected in normal bronchial and
      alveolar epithelium but different histologic subtypes of lung carcinomas lose
      DPPIV expression. To investigate the role of DPPIV in lung carcinoma, we examined
      the expression of DPPIV at both mRNA and protein levels in non small cell lung
      cancer (NSCLC) cell lines and normal human bronchial epithelial cells. DPPIV
      expression was detectable in normal lung epithelial cells, but was absent or
      markedly reduced in all NSCLC cell lines at both mRNA and protein levels.
      Restoration of DPPIV expression in NSCLC cells resulted in profound morphologic
      changes, inhibition of cell proliferation, anchorage-independent growth, in vitro
      cell migration and tumorigenicity in nude mice. DPPIV reexpression also
      correlated with increased p21 expression, leading to induction of apoptosis and
      cell cycle arrest in G1 stage. These effects were accompanied by increased
      expression of cell surface proteins, fibroblast-activating protein (Fapalpha) and
      CD44 that are associated with suppression of tumor growth and metastasis. Thus,
      DPPIV functions as a tumor suppressor, and its downregulation may contribute to
      the loss of growth control in NSCLC cells.

PMID- 15027118
TI  - ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan
      treated metastases.
AB  - Overcoming drug resistance has become an important issue in cancer chemotherapy.
      Among all known mechanisms that confer resistance, active efflux of
      chemotherapeutic agents by proteins from the ATP-binding cassette family has been
      extensively reported. The aim of the present study was to determine the
      involvement of ABCG2 in resistance to SN38 (the active metabolite of irinotecan)
      in colorectal cancer. By progressive exposure to increasing concentrations of
      SN38, we isolated 2 resistant clones from the human colon carcinoma cell line
      HCT116. These clones were 6- and 53-fold more resistant to SN38 than the HCT116
      derived sensitive clone. Topoisomerase I expression was unchanged in our
      resistant variants. The highest resistance level correlated with an ABCG2
      amplification. This overexpression was associated with a marked decrease in the
      intracellular accumulation of SN38. The inhibition of ABCG2 function by Ko143
      demonstrated that enhanced drug efflux from resistant cells was mediated by the
      activity of ABCG2 protein and confirmed that ABCG2 is directly involved in
      acquired resistance to SN38. Furthermore, we show, for the first time in clinical
      samples, that the ABCG2 mRNA content in hepatic metastases is higher after an
      irinotecan-based chemotherapy than in irinotecan-naive metastases. In conclusion,
      this study supports the potential involvement of ABCG2 in the development of
      irinotecan resistance in vivo.

PMID- 15027120
TI  - c-Jun NH2-terminal kinase pathway is involved in constitutive matrix
      metalloproteinase-1 expression in a hepatocellular carcinoma-derived cell line.
AB  - Transcription factor c-Jun serves for cellular proliferation, survival,
      differentiation and transformation and is recognized as an important factor in
      cancer development, including hepatocellular carcinoma (HCC). The purpose of
      present study is to determine the involvement of c-Jun in matrix
      metalloproteinase-1 (MMP-1) expression, which is previously reported by us to be
      expressed only in the early stage of human HCC showing stromal invasion. Of 5
      human HCC cell lines examined, only HLE cells revealed mRNA and protein
      expression as well as enzymatic activity of MMP-1. Transient transfection of an
      MMP-1 promoter/luciferase construct (including 4.4 kb full promoter region) into
      HLE and HCC-T cells (MMP-1 nonproducer) showed that high promoter activity was
      observed only in HLE cells without inducers, and that this promoter activity was
      still observed when a shorter 0.6 kb proximal promoter construct was transfected.
      The 0.6 kb promoter region contained 3 AP-1 sites, and c-jun mRNA was
      constitutively expressed in HLE cells without inducers. Furthermore,
      phosphorylated c-Jun and c-Jun NH2-terminal kinase (JNK) were detected in HLE
      cells. Promoter activity of the 0.6 kb construct was suppressed with SP600125, a
      potent inhibitor of JNK, but not with PD98059 and SB203580, potent inhibitors of
      MEK1/2 and p38, respectively. The inhibitory effect of SP600125 was also observed
      at protein expression level and in enzymatic activity of MMP-1. Taken together,
      this study suggests that the JNK pathway is involved in the expression of MMP-1
      in HCC cells and may represent a new functional role of c-Jun for HCC
      development.

PMID- 15027121
TI  - Identifying progression-associated genes in adult T-cell leukemia/lymphoma by
      using oligonucleotide microarrays.
AB  - Adult T-cell leukemia/lymphoma (ATL) is associated with human T-lymphotropic
      virus type-1 (HTLV-1). To understand the changes in expression that occur in the
      progression of chronic phase of ATL to acute crisis, the gene expression profiles
      of fresh ATL cells were compared in 4 pairs of samples (progression of chronic to
      acute phase in 3 patients, as well as 1 typical chronic phase sample vs. 1
      typical acute phase sample) using high-density oligonucleotide DNA arrays. We
      identified 203 genes that were commonly upregulated in acute vs. chronic phase
      samples including ribosomal proteins, proteosome subunits, eukaryotic translation
      factors, immunophilins, heat shock proteins and genes important for DNA
      replication. Additionally, we identified 91 commonly downregulated genes
      including immune molecules related to MHC and a phosphatase. Several of the genes
      were previously identified to be associated with the Tax protein of HTLV-1. Some
      of the upregulated genes were located in amplified regions identified by
      comparative genomic hybridization in the corresponding chronic/acute ATL sample.
      Using real-time quantitative PCR, we confirmed the array-results in those
      specimens analyzed by microarray. These results demonstrated that distinct sets
      of genes that are known to be critical in cellular transformation and/or
      activation are up- or down-regulated during the transition to the acute phase of
      ATL.

PMID- 15027122
TI  - D-PCa-2: a novel transcript highly overexpressed in human prostate and prostate
      cancer.
AB  - Identification of genes selectively expressed in tumors or individual tissues is
      a crucial prerequisite for molecular diagnosis and treatment of cancer by
      addressing molecular targets. By screening an expression database, we identified
      the novel gene D-PCa-2 (Dresden prostate carcinoma 2), which is highly
      overexpressed in normal prostate tissue and prostate carcinoma (PCa). The
      corresponding transcript contained an open reading frame of 453 nucleotides
      encoding a putative protein of 150 amino acids. A large part of exon 8 of the D
      PCa-2 gene shows strong similarity to the high-mobility-group nucleosomal binding
      protein 2 (HMGN2) cDNA. The highly specific transcription of the D-PCa-2 gene in
      normal and malignant prostate tissues and in a few additional tumors was
      demonstrated by using multiple tissue dot blot, cancer profiling dot blot and
      real-time PCR analyses. Examination of 18 pairs of tumorous and nontumorous
      prostate tissues from PCa patients by quantitative RT-PCR revealed D-PCa-2
      transcripts in all specimens. The potential usefulness of D-PCa-2 as a sensitive
      marker for metastatic prostate carcinoma cells in lymph nodes was demonstrated by
      the detection of one LNCaP cell in 1 x 10(5) normal lymph node cells using real
      time RT-PCR. Examination of 22 lymph nodes from PCa patients either containing
      metastatic prostate cancer cells or diagnosed as cancer-free was in full
      concordance with histopathologic diagnoses. These results validate D-PCa-2 as a
      transcript with high tissue specificity and with a potential application in the
      diagnosis of PCa.

PMID- 15027123
TI  - Invariant natural killer T cells are preserved in patients with glioma and
      exhibit antitumor lytic activity following dendritic cell-mediated expansion.
AB  - Brain tumors carry a poor prognosis, and newer approaches to their therapy are
      urgently needed. Natural killer T (NKT) cells are distinct innate lymphocytes
      with antitumor potentials. Defects in NKT cell function have been observed in
      patients with other forms of cancer. Here we show that both the frequency and
      interferon-gamma-producing function of NKT cells are well preserved in adult
      patients with glioma (n=9) and comparable to findings in healthy controls (n=9).
      These cells can be readily expanded in culture using autologous mature dendritic
      cells loaded with the NKT ligand, alpha-galactosyl ceramide. The expanded NKT
      cells from glioma patients are functional and, importantly, kill glioma cells in
      a ligand- and CD1d-dependent manner. Expression of CD1d is detected both on
      primary glioma cells as well as endothelial cells in infiltrating new blood
      vessels by immunohistochemistry of glioma tissue sections. These data suggest
      that targeting NKT cells may provide a novel strategy for immunotherapy of
      glioma.

PMID- 15027124
TI  - Beta-glucan enhanced killing of renal cell carcinoma micrometastases by
      monoclonal antibody G250 directed complement activation.
AB  - Metastases from renal cell carcinomas (RCC) are resistant to radiation and
      chemotherapy but are relatively immunogenic. We have investigated the possibility
      to eliminate human RCC micrometastases using MAb G250. G250 penetrates human
      micrometastases completely in a spheroid model and induces complement deposition
      rapidly on the outmost cell layers. However, complement dependent cytotoxicity
      (CDC) was barely detected using either (51)chromium release assays or confocal
      microscopy, due to relatively low expression of the G250 antigen and the effect
      of membrane bound complement regulatory proteins. Addition of blocking anti-CD59
      MAbs enhanced formation of C5b-9 and consequently complement mediated lysis
      (13%). Complement assisted cellular cytotoxicity (CACC) was not detectable,
      although the iC3b ligand and CR3 receptor were present on respectively target and
      effector cells. Addition of soluble beta-glucan induced the killing of MAb and
      iC3b opsonized spheroids by effector cells (6-21%). Despite a lower affinity for
      G250 antigen, a bispecific anti-G250*anti-CD55 MAb enhanced cell killing in
      spheroids comparable to the parental G250 MAb. Our results suggest that
      complement-activating G250 in combination with anti-mCRP MAbs is able to kill
      human RCC cells in micrometastasis in vitro. For CACC the presence of CR3-priming
      beta-glucan seems to be obligatory. In vivo, bi-MAb may be more effective as
      therapeutic agent due to its increased C5a generating properties.

PMID- 15027125
TI  - Human Mena protein, a serex-defined antigen overexpressed in breast cancer
      eliciting both humoral and CD8+ T-cell immune response.
AB  - Screening of a cDNA expression library from a primary breast tumor with the
      autologous patient serum led to the isolation of 6 cDNA clones corresponding to 3
      different genes, including a novel gene that maps to chromosome 1 and encodes the
      human homologue of mouse Mena (hMena, cDNA clone RMNY-BR-55), a protein of the
      Ena/VASP family involved in the regulation of cell motility and adhesion. A
      cancer-restricted antibody response against hMena was demonstrated, since 18/93
      cancer patient sera, the majority (10/52) from breast cancer, showed anti-hMena
      specific IgG, while no antibodies were present in healthy donors. When hMena
      protein expression was analyzed by Western blot and immunohistochemistry, the
      antigen was overexpressed in the majority of breast cancer cell lines and in 75%
      of primary breast tumor lesions evaluated. Furthermore, when HLA-A2-restricted
      peptides from the hMena sequence were used to stimulate CD8+ T cells, an hMena
      specific response was found in 9 out of 12 HLA-A2+ breast cancer patients. In 4
      patients, this cell-mediated immune response was concomitant with antibody
      response to hMena. Furthermore, an hMena-specific T-cell line was established
      from an HLA-A2+ breast cancer patient whose primary tumor lesion overexpressed
      the hMena protein. The present findings highlight the emerging role that
      overexpression of cytoskeleton regulatory components may have in the induction of
      a specific antitumor immune response.

PMID- 15027127
TI  - Expression of GLUT-1 glucose transfer, cellular proliferation activity and grade
      of tumor correlate with [F-18]-fluorodeoxyglucose uptake by positron emission
      tomography in epithelial tumors of the ovary.
AB  - We evaluated whether tracer FDG uptake, quantified as an SUV by PET in ovarian
      epithelial tumors, correlates with clinical stage, tumor grade, cell
      proliferation and glucose metabolism, all of which are biomarkers for response to
      chemotherapy, prognosis and overall survival in ovarian cancer patients.
      Seventeen patients suspected of having ovarian cancer by physical examination,
      tumor marker analysis and anatomic imaging (such as sonography, CT and/or MRI)
      underwent whole-body FDG-PET within the 2 weeks prior to surgery. Seventeen
      epithelial ovarian tumor specimens (13 malignant tumors, 5 at stage I, 2 at stage
      II, 6 at stage III; 2 borderline tumors; and 2 benign lesions) were available for
      pathologic evaluation. They were graded histopathologically, and
      immunohistochemistry for MIB-1 (proliferation index marker) and GLUT-1 was
      performed. Correlation between FDG uptake and clinical stage, GLUT-1 expression,
      MIB-1 LI and histologic grading score was determined. No positive correlation was
      observed between FDG uptake and clinical stage (p=0.14). Intensity of GLUT-1
      expression (r=0.76, p=0.001), MIB-1 LI (r=0.457, p=0.014) and histologic grading
      score (r=0.692, p=0.005) showed statistically significant positive correlations
      with FDG uptake. Stepwise logistic regression analysis revealed that expression
      of GLUT-1 transporters was the strongest parameter (r=0.760, p=0.0004) by which
      to predict positive FDG uptake. Therefore, glucose consumption, as determined by
      analysis of SUVs in FDG-PET, may be a noninvasive biomarker for ovarian
      epithelial tumors.

PMID- 15027126
TI  - Phenotypic alterations induced by the Hong Kong-prevalent Epstein-Barr virus
      encoded LMP1 variant (2117-LMP1) in nasopharyngeal epithelial cells.
AB  - Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma
      (NPC), a common cancer in Hong Kong. The EBV-encoded LMP1 protein is believed to
      play an important role in cell transformation. We have previously identified a
      prevalent LMP1 variant (2117-LMP1) that is expressed in 86% of primary NPC in
      Hong Kong. In this study, the biologic phenotypes induced by 2117-LMP1 were
      compared with those of the prototypic B95.8-LMP1 in an immortalized
      nasopharyngeal epithelial cell line, NP69. The 2117-LMP1 could induce cell
      proliferation and resistance to apoptosis induced by growth factor deprivation.
      Expression of 2117-LMP1 also suppressed expression of p16, p21 and Bax but
      induced expression of CDK2 and A20. Compared with B95.8-LMP1, 2117-LMP1 could
      induce a higher migration ability in NP69 cells but was less efficient in
      inducing morphologic changes, anchorage-independent growth and cell invasion.
      Relatively weaker ability of 2117-LMP1 than B95.8-LMP1 in upregulation of
      vimentin, VEGF and MMP9 as well as in downregulation of E-cadherin was observed.
      2117-LMP1 could activate higher level of NF-kappaB activity in HEK 293 cells than
      B95.8-LMP1. The present study supports a role of 2117-LMP1 in NPC development by
      enhancing cell proliferation, cell death inhibition and migration in premalignant
      nasopharyngeal epithelial cells. Furthermore, our study reveals significant
      functional differences between 2117-LMP1 and the prototypic B95.8-LMP1. Our
      results provide insights into the pathologic significance of this prevalent LMP1
      variant, 2117-LMP1, in the development of NPC in the Hong Kong population.

PMID- 15027128
TI  - Flavaglines: a group of efficient growth inhibitors block cell cycle progression
      and induce apoptosis in colorectal cancer cells.
AB  - Flavaglines are flavonol-cinnamate-derived cyclopenta[b]benzofurans, so far
      reported only for the genus Aglaia of the plant family Meliaceae. They represent
      a group of highly bioactive metabolites already known for their strong
      antileukemic activities. To assess their suitability as chemotherapeutic drugs in
      colorectal cancer, their cytostatic effects and the underlying mechanisms of
      action were analyzed in colorectal tumor cell lines. Aglaiastatin was the most
      active flavagline, inhibiting growth and inducing apoptosis at nanomolar
      concentrations in SW480 and HT29/HI1 carcinoma cells, while the premalignant
      adenoma cell lines VACO235 and LT97 as well as the normal intestinal epithelial
      cell line IEC18 were 1,000 times less sensitive (IC50>10 microM). In SW480 cells,
      aglaiastatin caused cell cycle block in early mitosis, demonstrated by a shift of
      cell cycle distribution 24 and 48 hr after addition of aglaiastatin and by an
      increased content of cyclin B after 6 hr together with a decreased level of
      cyclin A as early as 2 hr after exposure. In addition, induction of apoptosis
      could be shown by the characteristic morphology of apoptotic nuclei, loss of MMP
      and downmodulation of bcl(xl). Strong activation of p38 was observed after 2 hr
      of exposure, indicating that apoptosis may be induced via a p38-mediated stress
      pathway.

PMID- 15027130
TI  - Abortions and breast cancer: record-based case-control study.

PMID- 15027129
TI  - Women smoking and testicular cancer: one epidemic causing another?
AB  - In many countries the incidence of testicular cancer has increased epidemically,
      but the aetiology remains obscure. Maternal smoking during pregnancy has been
      suggested to be a cause, but a satisfactorily valid assessment of the hypothesis
      is still lacking. To evaluate the epidemiological relevance, we assessed the
      ecological correlation between female smoking habits and testicular cancer
      incidence in the Nordic countries. Data on smoking prevalence among women in 5
      year birth cohorts 1910-1940, at 25-29 years of age, were obtained through past
      studies of smoking habits in Sweden, Denmark, Norway and Finland. Testicular
      cancer incidence in the presumed offspring birth cohorts 1938-1968, was
      calculated using data from the respective cancer registries. For comparison, a
      similar analysis of male smoking and testicular cancer in the presumed offspring
      cohorts was carried out. The Pearson correlation coefficient between female
      smoking prevalence and testicular cancer incidence in the generation of the
      presumed offspring was 0.9 (p<0.0001) for all countries combined. With the
      exception of Finland, the country-specific correlations were of the same
      magnitude. In multivariate analysis, there was no correlation with male smoking.
      The strong geographical and temporal correlations between female smoking and
      testicular cancer indicate that if smoking during pregnancy is a cause of
      testicular cancer in the offspring, part of the increasing trends could be
      explained, and more importantly: avoided, by primary prevention.

PMID- 15027136
TI  - [Children: first consumers of antibiotics, first target of resistance].

PMID- 15027132
TI  - Omega-6 polyunsaturated fatty acid gamma-linolenic acid (18:3n-6) is a selective
      estrogen-response modulator in human breast cancer cells: gamma-linolenic acid
      antagonizes estrogen receptor-dependent transcriptional activity,
      transcriptionally represses estrogen receptor expression and synergistically
      enhances tamoxifen and ICI 182,780 (Faslodex) efficacy in human breast cancer
      cells.

PMID- 15027138
TI  - [Alzheimer's disease, conquering fear and solitude].

PMID- 15027137
TI  - [Alzheimer's disease. The importance of early diagnosis].

PMID- 15027139
TI  - [Hepatitis b, the strong return of the vaccine].

PMID- 15027141
TI  - ["Home care" for the homeless. Interview by Anne Hebel].

PMID- 15027140
TI  - [Living with a viral hepatitis: in the words of patients].

PMID- 15027142
TI  - [Management of the patient with multiple sclerosis].

PMID- 15027143
TI  - [Migraine: knowledge, research].

PMID- 15027145
TI  - [Handicapped persons: a humanist project at Tarbes].

PMID- 15027144
TI  - [Ketoprofen in gel form].

PMID- 15027146
TI  - [Easier bookkeeping].

PMID- 15027147
TI  - [Apoptosis in T-lymphocytes and its significance].
AB  - Apoptosis is an integral process of the immune system development and existence.
      Due to the ability of lymphocytes to follow the apoptotic pathway a very negative
      effect--the escape of tumor cells population from the immune system control is
      observed. Multiplying malignant cells during the tumor progression cause the
      synergic effect of tumor cells apoptosis blocation and unfavourable T-lymphocytes
      apoptosis induction. The lymphocyte cells apoptosis can be induced by the tumor
      produced substances as well as the receptor spectrum exprimated by the tumor
      cells. Physical and chemical anti-cancer therapy causing the non-selective
      apoptosis induction also contributes substantially to the immune system
      weakening. Fas-receptor (FasR) is constitutionally expressed on the activated T
      lymphocyte surface. The common sign of the lung, colorectal, breast and other
      carcinomas is the presence of the surfacial Fas-ligand (FasL). During the
      infiltration process of tumor by the lymphocytes the FasR/FasL interaction is
      present, which is probably the most effective trigger mechanism of the T cells
      apoptosis. The contact of T-lymphocytes and tumor cells for the active antitumor
      immunity is inevitable. The apoptotic pathways modulation of T-lymphocytes
      provides a space for FasR/FasL induction influence and thus the anticancer
      immunity efficiency determination.

PMID- 15027148
TI  - [Arterial hemodynamics and pulse wave propagation].
AB  - The pulse wave (PW) is a complex physiological phenomenon observed and detected
      in blood circulation. In the cardiac systole, a specified volume of blood is
      ejected and it moves in arteries due to transformation of the potential and
      kinetic energy of the ejected blood. In an artery or in a vein where the pulse
      wave is propagating, three dependable phenomena can be observed: blood streaming
      (streaming pulse), the increase of blood pressure (pressure pulse) and distension
      of the transverse profile (profile or volume pulse). The invasive method as well
      as several non-invasive methods is available to detect the PW. The PW shape
      varies in different parts of circulation. It depends on physiological or
      pathophysiological conditions of the organism. To the physiological factors the
      heart rate, the body height and the age belong. The pathological conditions like
      arteriosclerosis or diabetes can change the arterial elasticity. Hypertension or
      some heart diseases influence the PW velocity.

PMID- 15027149
TI  - [Early postdenervation depolarization: effect of NO, acetylcholine and glutamates
      on chloride transporter and a general view of nerve functions].
AB  - The survey of the original papers by Vyskocil and his co-workers draws attention
      to their contribution not only to the classic theory of neuromuscular
      transmission, but it discusses them especially in relation to some general
      principles of nervous functions. The mechanisms of synaptic plasticity, co
      localization of various types of receptors in a single synapse, as well as
      practical therapeutic implications could serve as examples. The regulatory
      functions connected with NO synthase and calcineurin are then discussed in a
      broader context.

PMID- 15027150
TI  - [Caveolar functions and caveolin structural proteins].
AB  - Caveolae are small invaginations of the plasma membrane found in a variety of
      cells. The major components of caveolae are cholesterol, sfingolipids and
      structural proteins named caveolins. Three caveolin isoforms are known: caveolin
      1, caveolin-2 and caveolin-3. Adipocytes, endothelial cells, pneumocytes and
      fibroblasts express caevolin-1 and-2, whereas caveolin-3 expression is limited to
      muscle cells types. Caveolae and caveolins have diverse functions including
      vesicular transport, cholesterol homeostasis, signal transduction or tumor
      suppression. The aim of the present review is to explain what is known about
      caveolae and caveolins.

PMID- 15027152
TI  - [Nicotine receptors, the hippocampus and schizophrenia].
AB  - This paper deals with nicotinic receptor abnormalities of hippocampus in
      schizophrenia. It reviews genetic, electrophysiologic and anatomical studies and
      possible therapeutic use of such findings. Short summation of hippocampal
      physiology and functional anatomy is presented. In schizophrenia there is a
      defect of information processing--sensory gating, a function under nicotinic
      control. Role of cholinergic enhancement in the treatment of schizophrenia is
      also mentioned.

PMID- 15027153
TI  - [History of Czech physiology].

PMID- 15027151
TI  - [Injection anesthesia administered in the mid-anesthesia period after ether
      induction in laboratory rats].
AB  - Our experience with anaesthetic combination of butyrophenone derivative
      droperidol (D, 0.8 mg/kg b.w.) + alpha-2-agonist xylazine (X, 5 mg/kg b.w.) +
      ketamine (X, 35 mg/kg b.w.), in 28 rats (12 female, 8 + 8 male) is described.
      Anaesthesia protocol started with ether inhalation (5 ml/l air) in a glass bell.
      When the effect of anaesthesia was evident, droperidol and xylazine with ketamine
      were administered in an intramuscular injection. At the same time as
      anaesthetics, atropine (0.05 mg/kg b.w.) was injected subcutaneously. Average
      time of induction of ether anaesthesia was 45 +/- 30 s. and duration of the
      surgical stage was 64 +/- 16 s. Average time of recurrence of the position reflex
      was 120 min. D + X + K anaesthetic combination is safe, cost effective, and it
      induces good analgesia and myorelaxation. Anaesthetic effect is possible to
      prolong with half dose of ketamine with half dose of droperidol or xylazine in 30
      to 40 min. interval and the next prolongation is possible in 20 min. interval.
      The presented combination of anaesthetic was used for the soft tissue surgery
      (laparotomy, thoracotomy, and cannulation of large vessels--a. carotis, v.
      jugularis), both in experiments and clinical praxis.

PMID- 15027154
TI  - Baldrige award winners track quality with clinical indexes.

PMID- 15027155
TI  - Doctors use web tool to compare practice based on case mix, acuity.
AB  - Physicians are still learning the ins and outs of using their own practice data
      to perform a range of functions, from validating their population case mix to
      monitoring their care patterns across a patient population. CareAdvantage, Inc.
      uses inpatient, outpatient, and pharmacy claims and encounter data to offer a
      vast array of reporting capabilities through a web-based portal. The company's
      RightPath Navigator is designed to help provider groups and health plans
      understand and forecast resource consumption, risks, and costs associated with
      their member populations.

PMID- 15027156
TI  - Health plan's sales team visits hospitals to boost website use.
AB  - Health plans have invested millions in websites that can automatically process
      claims, authorize procedures, and confirm member eligibility. But despite their
      ease of use, these websites have been underutilized as many hospital employees
      continue to pick up the phone when they need to do business with a managed care
      company.

PMID- 15027157
TI  - 'Voice mail on steroids' enhances communication, productivity of radiologists'.
AB  - Radiologists who discover an urgent medical problem with a patient are accustomed
      to picking up the phone to immediately contact the referring physician. But in
      today's busy world it may take several tries to get through to the other doctor,
      and occassionaly the message may not be received at all.

PMID- 15027158
TI  - The contingent valuation method in health care. An economic evaluation of
      Alzheimer's disease.

PMID- 15027159
TI  - [Nutritional support in the surgical field. Introduction].

PMID- 15027160
TI  - [Advance and perspective of clinical nutrition].
AB  - Although nutritional support using nutrient enemas was recorded almost 3,500
      years ago, the modern era of clinical dietetics commenced with the development of
      intravenous hyperalimentation by Dudrick et al. and the development of the
      chemically defined diet by Greenstein et al. Thereafter, clinical nutritional
      support became widely accepted as one of the basic tools of patient care, and
      knowledge of the metabolism of nutrients has been extended. In particular, the
      significance of micronutrients in systemic function, importance of gut function
      on the systemic metabolism and immune system, and involvement of amino acids and
      fat elements in the development and amelioration of specific disease status such
      as renal and hepatic failure have been recognized, and specific nutritional
      support has been created as a treatment strategy. In addition to knowledge of
      renal and hepatic failure or metabolic disorders, accumulated information on
      tumor metabolism and pathophysiology in cancer cachexia has also enabled cancer
      treatment using a nutritional approach. An enteral diet containing certain amino
      acids such as arginine or glutamate, omega-3 unsaturated fatty acids, and nucleic
      acids has been developed, and its clinical application under the new concept of
      "immunonutrition" has demonstrated reduction of the incidence of infection and
      shortening of hospital stay. Many questions on Immunonutrition remain to be
      answered such as its mechanism or optimal composition, although it is a promising
      field for future evolution. Currently, the assessment of nutritional status and
      gut function is required through lifelong education of medical doctors as well as
      the popularization of nutritional support teams. In the near future, tailor-made
      nutritional support will be required based on gene polymorphisms.

PMID- 15027161
TI  - [Recent trends in the clinical practice of nutritional support in Japan: results
      of a national survey carried out in 2001].
AB  - Nutritional support has advanced and patients can now be given more effective
      nutritional care. On the other hand, some problems remain, such as inadequate
      administration of total parenteral nutrition (TPN), catheter-related sepsis, etc.
      The Committee of the National Survey on Nutritional Support, established under
      the Japanese Society for Parenteral and Enteral Nutrition, investigated the
      recent trends in the clinical practice of nutritional support in Japan by mailing
      a questionnaire containing 90 questions to a total of 6,500 physicians in 10
      medical departments. The results showed that: 1) surgeons have more interest in
      nutritional support than physicians in other fields. 2) More than 90% of
      physicians in Japan still use intravenous hyperalimentation(IVH) instead of TPN
      and they place more focus on the central venous catheter and insertion of the
      central venous catheter than on hyperalimentation in the term IVH. 3) There
      remains a tendency for surgeons to prefer parenteral nutrition to enteral
      nutrition. This tendency is supported by data showing that the rate of
      administering TPN to gastroenterological surgical patients as a postoperative
      management method is high. To the question, "How did you learn about nutritional
      support?," only 18.3% of physicians answered that they studied it in medical
      school. We may conclude this to be the most important problem in nutritional
      support in Japan.

PMID- 15027162
TI  - [The roles of a nutrition support team].
AB  - In 1998, a new system called the potluck party method (PPM) for the operation of
      nutrition support teams (NSTs) was developed. In the PPM, just as at a potluck
      party where each participant brings a single dish of food to share, the NST is
      operated and managed by each department contributing a small amount of staff and
      resources at one time. Based on the PPM, 1 or 2 staff members are selected from
      each department and each ward and carry out the work of the NST as they continue
      to go about their routine duties. The roles of the NST are 1) nutritional
      assessments, 2) checking whether the nutritional support provided is adequate, 3)
      recommending the best nutritional therapy for each patient, 4) preventing
      complications during nutritional therapy, and 5) responding to consultations on
      nutritional support. NST performance based on the PPM have proven effective as
      demonstrated by the following results: 1) decreases in the number of problem
      cases in terms of nutritional management; 2) reductions in the incidence of
      catheter sepsis; 3) reductions in the numbers of patients with poor food intake;
      4) prevention of pressure ulceration; 5) attempts to eradicate nosocomial
      infections; 6) decreases in mean length of hospital stay; and 7) a total cost
      benefit of at least 120,000,000 yen (US$1,000,000) per year.

PMID- 15027163
TI  - [Immunonutrition].
AB  - Several specific nutritional substrates have been shown to augment and/or
      modulate host immune function. Some enteral formulas enriched with specific
      immune-modulating nutrients are presently available for clinical use in Japan.
      Such nutrients include n-3 fatty acids, arginine, glutamine and nucleotides.
      Recent meta-analyses of clinical trials showed risk of infection, length of
      hospital stay and medical costs to be reduced by immunonutrition. The benefits of
      enteral immunonutrition to be most pronounced in GI surgical patients. However,
      in critical illness, it is difficult to draw any conclusion on the effect of
      immunonutrition because of the heterogeneity of the critically ill patients and
      few clinical trials Further clinical trials to determine which groups of patients
      are indicated for immunonutrition, as well as what is the optimal combinations of
      specific nutrients, are needed. Studies are also required to determine the safety
      of immunonutrition.

PMID- 15027164
TI  - [Perioperative nutrition for gastrointestinal surgery].
AB  - In elective gastrointestinal (GI) surgery, the patients' nutritional status
      should be assessed and if protein-energy malnutrition exists, preoperative
      nutritional support should be scheduled 7 to 14 days before surgery. In
      malnourished patients in particular, preoperative nutrition with total parenteral
      nutrition (TPN) reduces postoperative complication rates of infection.
      Preoperative enteral nutrition (EN) is considered to be as effective as TPN in
      improving postoperative surgical outcome. Many prospective randomized trials or
      meta-analyses comparing postoperative EN and TPN have revealed that postoperative
      EN improves surgical outcomes and lowers postoperative complication rates of
      infection to a degree similar to TPN. Although two recent prospective multicenter
      randomized trials in malnourished patients undergoing elective GI cancer surgery
      are controversial, no evidence that EN was less effective than TPN was
      recognized. Thus postoperative EN, prior to TPN, is recommended in patients with
      malnutrition or insufficient oral intake for 7 days or more after surgery. When
      TPN is administered, hyperglycemia due to overfeeding should be carefully
      controlled. Patients who undergo distal gastrectomy or colectomy can start oral
      intake 3 to 4 days after surgery, with pertinent peripheral infusion.
      Immunonutrition containing immune-enhancing nutrients such as arginine, n-3
      polyunsaturated fatty acid, glutamine, etc., especially administered
      preoperatively, is a promising nutritional therapy for reducing postoperative
      infectious complications.

PMID- 15027165
TI  - [Nutritional support in various disease states. B. Nutritional support in severe
      infection].
AB  - Within one decade the concept of clinical nutritional support has changed. It was
      once thought that total parenteral nutrition was an all-purpose panacea, and then
      that role was played by enteral nutrition. Recently, however, immunonutrition has
      emerged as a new methodology for nutritional support. Because of the pathologic
      complexity, numerous problems remain in nutritional support for surgical patients
      with severe infection. The best route of nutrition in the acute phase, actual
      efficacy of immune system-enhancing diets, and the prevention of bacterial
      translocation (BT) and Ventilator-associated pneumonia (VAP) should be resolved.
      This paper describes concerns in the clinical nutritional management of patients
      with severe infection and examines how the remaining questions are being
      resolved.

PMID- 15027167
TI  - [Private hospitals with specialized surgical practice].

PMID- 15027168
TI  - [Strategy of public hospital for thyroid disease].

PMID- 15027169
TI  - [What we can learn from a case of medical malpractice].

PMID- 15027166
TI  - [Specialized nutrition support for the patients with advanced or recurrent
      carcinoma of the gastrointestinal tract].
AB  - Various nutritional disorders can occur in patients with advanced or recurrent
      carcinoma of the gastrointestinal tract due to the disease itself or the absence
      of the organs after surgery. Routine parenteral nutrition for cancer patients who
      undergo chemotherapy results in no benefit and troublesome complications such as
      catheter sepsis. Consequently, it is important to provide sufficient and proper
      specialized nutritional support to patients who need it, taking into account the
      pathologic status resulting from malignant disease. Patients with advanced or
      recurrent carcinoma of the gastrointestinal tract are likely to be deficient in
      folate and/or vitamin B12 for various reasons. Neurological disorders in vitamin
      B12 deficiency should worsen when folate is administered without supplementation
      of vitamin B12. This phenomenon should be avoided when 5-fluorouracil is used
      with reduced folate in cancer chemotherapy. The indications for specialized
      nutritional support for patients with advanced or recurrent carcinoma of the
      gastrointestinal tract are the same as for malnourished patients without cancer.
      The initial dose and formula of nutrition for cancer patients with malnutrition
      and various metabolic disorders should be calculated to avoid overloading. The
      oral intake of normal food is desirable for such patients. The placement of a
      central venous catheter to prevent the toxicity of chemotherapy or for venous
      access is contraindicated. Jejunal feeding or percutaneous endoscopic gastrostomy
      is performed in patients who cannot eat even a liquid diet. Total parenteral
      nutrition should be introduced when these accesses cannot be used. If any bowel
      obstruction occurs in the small intestine and/or colon, it is necessary to
      discuss the efficacy of surgery to resolve the obstruction.

PMID- 15027170
TI  - [The cortico-thalamic theory for generalised spike-wave discharges].
AB  - The origin of generalized absence epilepsy is still not known. In the last
      century, four theories have dominated the debate about the origin of the
      bilateral synchronous generalized spike-wave discharges associated with absence
      seizures: the "centrencephalic" theory [Penfield and Jasper], the "cortical"
      [Bancaud, Niedermeyer, Luders], the "cortico-reticular" theory [Gloor,
      Kostop[oulos, Avoli] and the "thalamic clock" theory [Buzsaki]. There is now some
      evidence that absence epilepsy, as studied in the WAG/Rij model, is a
      corticothalamic type of epilepsy. A new hypothesis is proposed which suggests
      that a cortical focus in the somatosensory cortex is driving the widespread
      corticothalamic networks during spontaneous absence seizures. This modern theory
      was given the name "hot spot' theory" [Meeren et al., 2002]. According to the
      present view three brain structures are critically involved and their integrity
      seems a minimal and sufficient condition for the occurrence of spike-wave
      discharges. Firstly, the reticular thalamic nucleus is involved and most likely
      its rostral pole. Secondly, the thalamocortical relay cells in the ventrobasal
      complex play a role and, thirdly and most importantly, the cerebral cortex with
      its epileptic zone. The zone in which the epileptic focus seems to be localised
      is located on the somato-sensory cortex, and more precisely in the area on which
      the peri-oral region including the upper lip, projects.

PMID- 15027171
TI  - [The general physiological mechanisms of glutamate influence on the central
      nervous system].
AB  - The L-Glutamate, is dicarboxilic amino acid which plays the important role in
      maintenance of normal functioning of the central nervous system (CNS) in
      invertebrate and vertebrate animals. It carrying out functions of amphibolic
      intermediate in biosynthesis and degradation of amino acids and some nitrogenous
      substances. Besides, L-Glutamate acid possesses a significant role in the
      regulation of the bioenergetics processes that proceeding in nervous system, due
      to direct or indirect participations in the reactions of glycolysis,
      gluconeogenesis, synthesis of ketone bodies and formation of glycogen. Also, L
      Glutamate accepts direct participation in realization of a citrate cycle
      reactions, a respiratory circuit; in conversion of ammonia and it excretion from
      an organism. However the most important function of the L-Glutamate--its
      participation in the processes of nervous regulation as excitatory neuromediator
      in the CNS of invertebrate and vertebrate animals.

PMID- 15027172
TI  - [Dysregulation pathology of hemopoietic and immune systems under infectious
      process].
AB  - Blood system and immune system play the crucial role in maintenance of anti
      infectious defence of macroorganism. Meanwhile, infectious agents, differencing
      by their nature, have marked mutafacient effect on immunocompetent cells of
      blood. Dysregulation of DNK-reparation systems, apoptosis and immunity,
      maintaining genetic homeostasis of organism, is considered to be the basic reason
      of cytogenetic instability under infectious process. It has been established,
      that disturbances in blood and immunity systems, following infectious process,
      are caused by not only direct or indirect action of infectious agents on mature
      immunocytes, but else by their stimulating or suppressed influence on functional
      properties of early cells-precursors of hemo- and immunopoesis and hemopoietic
      microenvironment.

PMID- 15027173
TI  - [Disorders in molecular organization of erythrocyte membrane in patients with
      somatic and mental pathology].
AB  - The article describes general laws and peculiarities of structural and functional
      changes of erythrocyte's membrane in patients with somatic and mental pathology.
      Considering our own investigations and reports in medical journals, conclusions
      are made supposing an existence of typical molecular disorders of erythrocyte
      membrane in pathological process of different genesis. It is suggested that a
      universal reaction of circulating pool of erythrocytes on different pathological
      affects is evolutionary formed.

PMID- 15027174
TI  - [Role of nitric oxide in tumor growth].
AB  - This review article will analyze the role of nitric oxide in antiblastomous
      organism resistance, in particular some mechanisms of NO-mediated apoptosis in
      different cells and NO involvement in etiological mechanisms as well as tumor
      growth promotion. The possible mechanisms of nitric oxide dual effect are
      discussed. The data about NO as a mediator in different methods of cancer
      treatment are given. In conclusion, we have determined some principles of
      application of NO-modulating agents in cancer therapy.

PMID- 15027175
TI  - [The neurotropic activity of food-derived opioid peptides beta-casomorphins].
AB  - In the review the history of food-derived opioid peptides beta-casomorphins (beta
      cas) discovery is given. The beta-cas formation in gastrointestinal tract during
      the beta-casein degradation and the following penetration into the blood are
      described, in the first place in newborn mammals. The attention is focused on
      neurotropic activity of beta-cas: their influence on the pain sensitivity,
      locomotion, anxiety and learning of experimental animals. The beta-cas ability to
      change the characteristics of mother-infant interaction is specially analysed.
      The necessity to take into consideration of beta-cas physiological effects on
      nursing dams and newborns behaviour is noted.

PMID- 15027176
TI  - [Further studies on the relationship between benign prostatic hyperplasia and
      prostatitis].
AB  - Benign prostatic hyperplasia(BPH) and prostatitis are two common diseases in
      aging men. In recent years, the study of correlation between these two diseases
      has been paid more and more attention to. Some researchers presumed that
      inflammation is one of the most important causations of BPH, however, it is not
      profound enough on this etiologic hypothesis at present. The writer, on the base
      of his clinical experiences, dissertated the etiology of BPH, the pathologic
      figures of coexistence of BPH and prostatitis, and the presumption of
      inflammation promoting BPH on the molecular biology level. We hope our colleagues
      pay attention to this problem, and do more study on it.

PMID- 15027177
TI  - [Electron microscopic study on Trichomonas vaginalis adhering to and
      phagocytizing male genitourinary epithelial cells].
AB  - OBJECTIVE: To observe Trichomonas vaginalis (T. vaginalis) adhering to and
      phagocytizing male genitourinary epithelial cells in order to study the
      pathogenetic mechanism of male trichomoniasis. METHODS: Cultured T. vaginalis
      bodies were incubated with male genitourinary epithelial cells, and then the
      ultrastructure was observed with transmission electron microscopy. RESULTS: T.
      vaginalis adhered to epithelial cells like amoeba, and formed pseudopodium or
      surface invagination surrounding or nibbling other parts of the epithelial
      cytoplasm. CONCLUSIONS: T. vaginalis has the speciality of adhering to and
      phagocytizing to male genitourinary epithelial cells. Genitourinary epithelial
      cells may be injured directly by the phagocytosis of T. vaginalis. Attention has
      to be paid to the correlation.

PMID- 15027178
TI  - [Detection of sperm chromosomes in Robertsonian translocation carriers by dual
      color fluorescence in situ hybridization].
AB  - OBJECTIVE: To study the technique of dual-color fluorescence in situ
      hybridization(D-FISH) and its application value in sperm chromosomes of
      Robertsonian translocation carriers. METHODS: The technique of dual-color
      fluorescence in situ hybridization was used. Biotin labelled 13q14.3 specific
      probe and Digoxigenin labeled 14q11.1 specific probe were used for in situ
      hybridization of sperm specimens in 2 Robertsonian translocation carriers.
      Hybridization signals for chromosomes 13 and 14 in the sperm interphase nucleus
      were counted. RESULTS: Under the microscope, Biotin labeled 13q 14.3 specific
      probe showed 1 green hybridization signal and Digoxigenin labeled 14q 11.1
      specific probe showed 1 red hybridization signal. Interphase nucleus counter
      stained with DAPI showed blue. From the total of 3,000 sperm interphase nuclei,
      the positive rate for 1 green hybridization signal and 1 red hybridization signal
      was 13q/14q(39.33%), for 1 green and 2 red was 13q/14q, 14q(11.57%), for 1 green
      was 13q/-(9.27%), for 2 green and 1 red was 13q,13q/14q(12.87%), for 1 red was 
      /14q(9.87%) and for 2 green and 2 red was 13q,13q/14q, 14q(12.26%). CONCLUSIONS:
      D-FISH of the human sperm interphase nucleus can be applied to the determination
      of sperm chromosomes of Robertsonian translocation carriers and the analysis of
      the laws of chromosomal segregation in the meiosis. The technique can be widely
      used in such aspects of human reproduction as insemination under the microscope
      and preimplantation embryos genetic diagnosis.

PMID- 15027179
TI  - [Seminiferous tubule scores used for quantitative assessment of spermatogenic
      function of patients with azoospermia].
AB  - OBJECTIVE: To investigate the clinical reliability of quantitative evaluation by
      seminiferous tubule scores on spermatogenesis dysfunction, using the testis
      tissues of azoospermia patients for analysis of histological changes. METHODS:
      One hundred and twelve Chinese patients with azoospermia underwent open
      testicular biopsy and their testicular biopsy specimens were evaluated by 10
      score (on testicular biopsy) and 5-Grade (on seminiferous tubule spermatogenesis)
      scale. The 112 patient, 22 to 46 years old [(29.0 +/- 4.4) years old] included
      105 cases of obstructive and 7 cases non-obstructive azoospermia. Of the total
      number, there were 96 primary infertile cases and 16 secondary infertile cases
      with infertile marriage of 2-12 years [(4.0 +/- 2.8) years]. Various seminiferous
      tubule characteristics were categorized by 10-score as follows: [1] degenerating
      Sertoli cells and no germinal epithelium; [2] no germ cells and only Sertoli
      cells; [3] no spermatids and primary spermatocytes and only spermatogonia; [4] no
      spermatids and few primary spermatocytes; [5] no spermatids and numerous primary
      spermatocytes; [6] no mature spermatids and few round immature spermatids; [7] no
      mature spermatids and numerous round immature spermatids; [8] < 20 mature
      spermatids/tubules, germinal epithelium height < 80 microns and spermiation
      absent; [9] > 20 mature spermatids/tubules, germinal epithelium height < 80
      microns and spermiation rarely < 80 microns; [10] > 20 mature spermatids/tubule
      and germinal epithelium height 80 microns and spermiation common. Seminiferous
      tubule spermatogenesis was catagorized by 5-Grade scale as follows: [1] tubular
      sclerosis; [2] sertoli cell only; [3] arrested spermatogenesis; [4] reduced
      spermatogenesis; [5] intact spermatogenesis. RESULTS: In terms of the 10-score
      scale on testicular biopsy, scores of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10
      corresponded with total patient numbers of 5 (4.5%), 38(33.9%), 2(1.8%), 6(5.4%),
      2(1.8%), 17(15.2%), 6(5.4%), 19(17%), 10(8.9%) and 7(6.3%), respectively.
      According to the 5-Grade scale on the seminiferous tubule spermatogenesis, Grades
      1, 2, 3, 4 and 5 corresponded with 5(4.5%), 38(33.9%), 33(29.5%), 29(25.9%) and 7
      (6.3%), respectively. Tubular diameter, the thickness of the lamina propria, the
      height of the germinal epithelium and serum FSH correlated with the average
      seminiferous tubule scores (P < 0.01). CONCLUSION: The seminiferous tubule scores
      obtained through testicular biopsy may provide important quantitative information
      concerning the etiology and pathogenesis and of azoospermia may serve as a
      helpful guide to the fundamental, clinical and therapeutical study of element,
      clinic and therapy.

PMID- 15027180
TI  - [Concealed penis and its surgical correction: a report of 63 cases].
AB  - OBJECTIVE: To evaluate the basic principles of surgical correction of concealed
      penis. METHODS: From Jan. 1999 to Dec. 2002, 63 cases of concealed penis, aged
      from 1 year and 6 months to 19 years with a mean age of 7 years and 2 months,
      were corrected with two different approaches: 37 cases of group A with obesity
      were corrected by anchoring micrus tissue onto the pubis at the base of the
      penis, and 26 cases of group B by fixing the subcutateous tissues at both sides
      of the penile shaft to the deep tunica albuginea at the penile root. Then prepuce
      plasty was carried out. RESULTS: Six-month postoperative follow-up found adequate
      exposure of the penis in all of group A, prepuce oedema in 7 cases, abdomen fat
      liquidization in 3 cases, unsatisfactory recovery of incision hollow in 3 cases
      and patchy numbness of the glans in 1 case. The 25 cases of group B had
      satisfactory exposure of the penis, with no obvious prepuce oedema, 1 case with
      retraction of the penis 7 days after operation. CONCLUSIONS: Various surgical
      procedures could be adopted for concealed penis, and the key to the satisfactory
      appearance is the restoration of penile tunicae and the fixation at the base of
      the penis. Further study is needed to determine the natural history of these
      disorders as well as which conditions and what age will benefit most from
      surgical intervention.

PMID- 15027181
TI  - [Effects of growth hormone on erectile function and number of nNOS-containing
      nerve fibers in internal iliac arterial ligation rats].
AB  - OBJECTIVE: To investigate the effects of growth hormone (GH) on the erectile
      function and the number of nNOS-containing nerve fibers in internal iliac
      arterial ligation rats. METHODS: Thirty-six mature male Wistar rats were
      randomized into 3 groups: GH intervention group, internal iliac arterial ligation
      group and sham operation group. After four weeks and eight weeks of treatment,
      one jalf of the rats of each group were selected respectively and tested for
      erectile function and then sacrificed for the detection of nNOS-containing nerve
      fibers by streptaridin-peroxidase immunohistochemistry techniques(SP method).
      RESULTS: After four weeks, the erection frequency and the number of nNOS
      containing never fibers in the sham operation group significantly increased
      compared with the other two groups, which showed no significant difference(P >
      0.05). There was no significant difference in erection rate among the three
      groups. After eight weeks, the number of nNOS-containing never fibers in corpus
      carvosum in the internal iliac arterial ligation group decreased compared with
      the other two groups, between which there was no significant difference. And
      there was no significant difference in erection frequency and erection rate among
      the three groups. CONCLUSION: Growth hormone can improve erectile function of
      internal iliac arterial ligation rats, which can be explained by the increase in
      the number of nNOS-containing never fibers in corpus carvosum of rats.

PMID- 15027182
TI  - [The mechanism of tetragametic chimerism in a true hermaphroditism with 46, XX/46
      ,XY].
AB  - OBJECTIVE: To report a true hermaphroditism due to a teragametic chimerism and to
      discuss the pathogenesis of tetragametic chimerism. METHODS: Chromosomal analysis
      and fluorescence in situ hybridization(FISH) were carried out on the lymphocytes
      from the blood and on the fibroblasts from the cultured skin and on fibroblasts
      from two different kinds of gonadal tissues of the patient with ambiguous
      genitalia respectively. Blood groups, human leukocyte antigen (HLA) haplotyping
      and 77 short tandem repeat (STR) microsatellite markers were tested. The two
      kinds of tissues in the gonad were detected by histopathological examination.
      Blood groups, HLA haplotying and 77 STR microsatellite markers parents of the
      patient's were also analyzed. RESULTS: Either 46,XX or 46,XY karyotype was found
      in the lymphocytes of the blood and in the fibroblasts of the cultured skin and
      of the two different kinds of gonadal tissues. Two X chromosome-specific signals
      or one X and one Y signal were detected in each interphase nucleus by FISH from
      the lymphocytes of the blood and the fibroblasts of three different tissue
      cultures. The karyotype of the 46,XY cell line predominated in all cultures
      except the cultured-fibroblasts from yellow gonadal tissues. STR marker analysis,
      ABO grouping and HLA study from the patient were identified a single haplotype in
      the patient from the mother and two different haplotypes from the father. Two
      kinds of tissues in the gonad were observed by histopathological examination. The
      yellow tissue was ovary and the white one was testis. CONCLUSIONS:
      Histopathological examination and chromosomal analysis combined with FISH are
      very useful methods for the diagnosis of true hermaphroditism. Blood typing, HLA
      and short tandem repeat microsatellite markers afford strong evidence for
      confirming tetragametic chimerism. The mechanism of tetragametic chimerism in
      true hermaphroditism can be explained by a parthenogenetic division of a haploid
      nucleu into two identical gametes, followed by fertilization with both X and Y
      spermatozoa and then developed into an organism.

PMID- 15027183
TI  - [Psychological hindrance and its treatment in chronic prostatitis patients].
AB  - OBJECTIVE: To improve the knowledge of psychological hindrance in chronic
      prostatitis (CP) patients and study the treatment strategy of it. METHODS: Two
      hundred and fifty-eight CP patients with psychological hindrance, aged 16 to 65
      years (average 33 years), were divided into the psychotherapy group (148 cases)
      and the control (110 cases). The control were only treated with antibiotics and
      Chinese traditional medicines, while the psychotherapy group were treated with
      cognitive therapy besides the above medicines. RESULTS: The symptoms in the
      psychotherapy group were improved obviously compared with those in the control.
      Both the cure rate (P < 0.05) and the effective rate (P < 0.001) of the
      psychotherapy group were higher than those of the control. CONCLUSION:
      Psychotherapy is an effective way to treat CP patient with psychological
      hindrance.

PMID- 15027184
TI  - [Urodynamic analysis of urinary incontinence after transurethral resection of
      prostate].
AB  - OBJECTIVE: To investigate the value of urodynamic test in the diagnosis of
      postoperative incontinence after transurethral resection of the prostate(TURP).
      METHODS: Thirty-seven patients with urinary incontinence after TURP received
      urodynamic tests, including cystometry(CMG), pressure-flow study, rest urethral
      pressure profilometry(RUPP) and stress leak-point pressure (SLPP) measurement.
      Urethrocystography was taken when necessary. RESULTS: Of the 37 cases, 16 were
      diagnosed as motor urge urinary incontinence, 2 as sensory urge urinary
      incontinence, 17 as stress urinary incontinence and 2 as overflow urinary
      incontinence. CONCLUSION: Different types of urinary incontinence after TURP can
      be clearly distinguished by urodynamic tests, which provides objective basis for
      the choice of adequate treatment.

PMID- 15027185
TI  - [Efficacy of local injection of bacillus calmette-guerin polysaccharide nucleic
      acid following CO2 laser resection on condyloma acuminatum].
AB  - OBJECTIVE: To observe the efficacy of local injection of bacillus calmette-guerin
      polysaccharide-nuclear acid (BCG-PSN) following CO2 laser resection on condyloma
      acuminatum (CA). METHODS: One hundred and six patients with CA were randomized
      into BCG-PSN group (60 cases) and interferon group (46 cases), treated
      respectively with BCG-PSN local injection and interferon subcutaneous injection
      following CO2 laser resection and followed up for 3 months. RESULTS: The healing
      rate of the BCG-PSN group was 88.3% and that of the interferon group was 71.7%.
      CONCLUSION: The BCG-PSN local injection following CO2 laser resection is
      effective for CA patients.

PMID- 15027186
TI  - [Combined open prostatectomy and preperitoneal inguinal herniorrhaphy: a 21-case
      report].
AB  - OBJECTIVE: To evaluate the effect of simultaneous open prostatectomy and
      preperitoneal inguinal herniorrhaphy. METHODS: Twenty-one patients with benign
      prostatic hyperplasia(BPH) and inguinal hernia, underwent simultaneous suprapubic
      or retropubic prostatectomy and preperitoneal inguinal herniorrhaphy through
      Pfannenstiel's incision. In 4 cases with bigger inguinal mass, hernia repair was
      performed with polypropylene meshwork (PPM). RESULTS: The 21 patients were
      followed up for 6 months to 7 years. There were 2 cases of recurrence (9.5%),
      with no morbidity and mortality in the other 19 cases. CONCLUSIONS: Open
      prostatectomy and preperitoneal inguinal herniorrhaphy can be performed during
      the same session without increasing infection and recurrence. The operation
      method is simple and the effect is positive, especially for older men.

PMID- 15027187
TI  - [Male urogenital tract mycoplasma infection and drug-resistance evolution].
AB  - OBJECTIVE: To investigate the male urogenital tract mycoplasma infection and drug
      resistance evolution in 2001 and 2003. METHODS: The results of mycoplasma culture
      and drug sensitivity tests were explored in 2001 and 2003, and the differences of
      drug sensitivity between the two years were analysed. RESULTS: Of the 109
      mycoplasma positive cases in 2001, 86.2% were infected with Ureaplasma
      urealyticum (Uu), 3.8% with Mycoplasma hominis (Mh), 10.1% with both Uu and Mh;
      and of the 134 mycoplasma positive cases in 2003, Uu infection accounted for
      79.1%, Mh infection 4.48% and Uu and Mh infection 16.4%. Compared with 2001, the
      drug-resistance rates to roxithromycin, azithromycin, levofloxacin, ofloxacin and
      clindamycin rose obviously in 2003; but the drug-resistance rates to josamycin,
      minomycin and doxycycline did not change significantly. As far as the drug
      sensitivity rate is concerned, josamycin ranked the first, and doxycycline the
      second. CONCLUSIONS: Mycoplasma was a high rate of drug-resistance, and the drug
      sensitivity evolves with the time. Treatment for mycoplasma should be based on
      the results of drug sensitivity tests. Josamycin can be used as the first choice.

PMID- 15027188
TI  - [Present research on the male germ cell differentiation in vitro].
AB  - Several culture systems such as tissue and organ culture system, seminiferous
      tubules culture system, co-culture systems of Sertoli cells and germ cells for
      male germ cell differentiation studies in vitro have been established. The
      importance of the blood-testis barrier and the polarity of testicular cells have
      been emphasized recently. And then the bicameral chambers culture system that can
      mimic the compartmental structure of testes and the calcium algmate culture
      system that can provide three-dimensional support have been primarily set up.
      These culture systems are powerful tools for facilitating the understanding to
      the spermatogenesis. The entire meiotic part of spermatogenesis in some animals
      has been achieved in vitro by different laboratories, but little is known about
      the regulation mechanism of the meiotic step of spermatogenesis in detail. This
      review focuses on the present studies on the differentiation of male germ cells,
      especially the meiotic step of the differentiation.

PMID- 15027189
TI  - [Advances in the study of signal transduction in cavernous smooth muscle].
AB  - The signal transduction pathways within corporal smooth muscle cells are the
      intracellular molecular mechanisms of corporal smooth muscle tone regulation.
      Various neurotransmitters activate the membrane receptor proteins or
      intracellular enzyme pathways and result in the production of extracellular
      chemical signals. Second messenger molecules and ions transmit and amplify the
      signals, and subsequently induce the relaxation of smooth muscle cells and penile
      erection. Therefore, the study of signal transduction in cavernous smooth muscle
      play an important role in understanding the physiology of erection and the
      pathophysiology of erectile dysfunction as well as in developing new selective
      drugs for the treatment of erectile dysfunction.

PMID- 15027190
TI  - [Structure, localization and characterization of lipocalin-type prostaglandin D
      synthase].
AB  - Lipocalin-type prostaglandin D synthase (L-PGDS), an N-glycosylated dual
      functional monomeric protein, acts as a PGD2-producing enzyme and also as a
      lipophilic ligand-binding protein. L-PGDS is localized in the central nervous
      system, male genital organs of various mammals and in the human and monkey heart,
      and secreted into the cerebrospinal fluid, seminal plasma and blood plasma. The L
      PGDS concentrations in these body fluids are useful for the diagnosis of several
      neurological disorders, dysfunction of sperm formation, cardiovascular and renal
      diseases.

PMID- 15027191
TI  - [Progress of erectile in the treatment dysfunction following peripheral nerve
      injury].
AB  - Trauma and surgery sometimes cause erectile dysfunction because of injury to
      pelvic nerves and cavernous nerves of the penis. The ideal treatment is to make
      the injured nerves regenerate themselves and erectile function recover
      completely. This paper reviews the recent advances in the studies of erigentes
      regeneration and plerosis following injury in order to find the best method to
      enhance erigentes regeneration.

PMID- 15027192
TI  - [Advances in clinical application of nocturnal penile tumescence monitoring to
      diagnosis and treatment of erectile dysfunction].
AB  - Nocturnal penile tumescence is a normal physiological behavior of males.
      Nocturnal penile tumescence monitoring is one of the most effective methods to
      differentiate between organic and psychological erectile dysfunctions. Nocturnal
      penile tumescence monitoring has reportedly been applied to the diagnosis and
      treatment of erectile dysfunction as well as to the researches on the mechanism
      of nocturnal penile tumescence.

PMID- 15027193
TI  - [Effect of Qianlie Huichun on prostate tissue VEGF expression in rats].
AB  - OBJECTIVE: To investigate the effect of Qianlie Huichun on the expression of
      vascular endothelial growth factor(VEGF) in prostate tissues and expound its anti
      prostatomegaly action in model rats with prostatic hypertrophy induced by
      injected testosterone. METHODS: A total of 60 male rats were eventy randomized
      into six groups. All were gelded except the normal control group. After a week,
      the gelded rats were injected with testosterone(4 mg/kg/d), meanwhile the first
      group were fed with a small dosage of Qianlie Huichun(0.4 g/kg/d), the second
      group with a medium dosage(0.8 g/kg/d), the third group with a large dosage(1.6
      g/kg/d), and the fourth group injected with estriol(2.5 mg/kg/d), all for a
      month. The fifth group were model controls, and the sixth the normal controls,
      both fed with the same amount of pure water for a month. Then all the six groups
      of rats were killed and their prostate glands were resected for the examination
      of the expression rate of VEGF by immunohistochemical method. RESULTS: The
      difference of VEGF expression between Qianlie Huichun groups and the model group
      was significant(P < 0.01), and so was it between the medium and large dosage
      middle, large amount of Qianlie Huichun groups and the estriol group(P < 0.01).
      CONCLUSION: Qianlie Huichun depressed the VEGF expression of the prostate gland
      in model rats, and the expression rate decreased with the increased amount of the
      drug, which shows that Qianlie Huichun has a definite therapeutic effect on
      prostatic hypertrophy by depressed the vascular growth of the vessel in the
      prostate gland.

PMID- 15027194
TI  - [Effects of ZJG on the quality of sperm in male rat epididymis].
AB  - OBJECTIVE: To observe the effects of Chinese herbal composition Zengjing Granule
      (ZJG) on the quality of sperm in the epididymis of infertile rats, and to study
      its therapeutic mechanisms of improving sperm quality. METHODS: A total of 40 GTW
      infertile rats were divided into 4 groups of 10 rats each, including an
      infertility group[GTW 2 mg/(ml.100 g)], a high-dosage group[ZJG 0.67 g/(ml.100 g)
      + GTW 2 mg/(ml.100 g)], a medium-dosage group[ZJG 0.33 g/(ml.100 g) + GTW 2
      mg/(ml.100 g)], a low-dosage group[ZJG 0.17 g/(ml.100 g) + GTW 2 mg/(ml.100 g)],
      and a normal control group(1% CMC). This study consisted of a 3-week modeling
      period and a 3-week ZJG period. The changes of sperm quality, the thickness of
      the epididymal gland canal wall and sexual organ coefficient were detected after
      3-week ZJG period. RESULTS: Of the 3 ZJG groups, the sperm density was (59.6 +/-
      3.72), (63.3 +/- 5.70) and (69.7 +/- 6.91) x 10(6)/ml, the sperm motility rates
      were (65.4 +/- 6.33)%, (69.3 +/- 10.96)% and (72.6 +/- 9.61)%, the sperm
      deformity rates were (52.3 +/- 7.47)%, (46.2 +/- 7.73)% and (33.2 +/- 7.97)%
      respectively. The ZJG groups showed significant difference from the infertility
      group (P < 0.05), whose sperm density, motility and deformity were (13.1 +/-
      6.81) x 10(6)/ml, (7.6 +/- 5.87)%, and (77.2 +/- 8.75)% respectively. But there
      was no significant difference between ZJG groups and the normal control group (P
      > 0.05), whose sperm density, motility and deformity were (75.6 +/- 10.82) x
      10(6)/ml, (83.00 +/- 8.02)%, and (8.80 +/- 3.49)% respectively. The thickness of
      the epididymal gland canal wall was (37.07 +/- 3.38), (37.16 +/- 6.69) and (43.42
      +/- 10.23) nm in the three ZJG groups respectively, different from the
      infertility group[(28.65 +/- 6.96) nm] (P < 0.05) significantly, but not from the
      normal control group [(45.79 +/- 11.13) nm] (P > 0.05). The ZJG groups showed an
      increase in the organ coefficient of the epididymal gland canal wall. And these
      was obvious statistical difference compared with the infertility group (P <
      0.05), but no statistical significance compared with the normal control group (P
      > 0.05). CONCLUSIONS: ZJG can obviously improve the sperm quality of infertile
      rats. Its therapeutic mechanisms can be summed up as follows: restoring the
      thickness of epididymal gland wall, increasing the organ coefficient of testes
      and epididymis, and hence improving the spermatozoa maturing function of
      epididymis of infertile rats.

PMID- 15027195
TI  - [Molecular-genetic characteristics of a medieval population from the northern
      Russian territory].
AB  - Forty-seven individual mitochondrial DNA (mtDNA) samples isolated from bones
      samples found in the Nefedyevo, Minino, and Shuygino gravesites have been
      analyzed to perform molecular genetic study of the medieval (12th to 13th
      centuries AD) human population from the vicinity of Lake Beloe (Vologda oblast,
      northern Russia). The mitotypic structure of the population has been determined
      on the basis of sequencing the mtDNA hypervariable-region segment I (HVSI;
      positions 15,989-16,410). Three mitotypes characterizing the population studied
      have been found in the 47 representatives of the medieval population: mitotype 1
      corresponding to the Cambridge reference sequence, mitotype 2 (transition G-A at
      position 16,129), and mitotype 3 (transitions G-A and C-T at loci 16,129 and
      16,223, respectively). Mitotypes 1, 2, and 3 have been found in 91.6, 4.2, and
      4.2% of the individual samples studied. This high frequency of the Cambridge
      mitotype is considerably higher than its mean frequencies in European
      populations. The frequencies of other mitotypes found correspond to their mean
      European values. The absence of a Mongoloid component has been demonstrated for
      the female lineage of the population. Comparison of the molecular genetic
      characteristics of contemporary European ethnic groups and the population studied
      has demonstrated that it may be assigned to the European population group. The
      high homogeneity of the mitochondrial pool suggests a strong founder effect,
      which agrees with the view of archeologists and anthropologists that the first
      migrant settlers were very few.

PMID- 15027196
TI  - [Structural-functional analysis of the promoter region of Escherichia coli udp
      gene].
AB  - Effect of mutations in the -10 and -35 regions of the udp gene promoter on the
      nature of its regulation by CytR and CRP proteins was studied. In studies of
      expression of mutant promoters, competition between RNA polymerase and the CytR
      repressor for the promoter region of the udp gene was shown. In the presence of
      the improved -10 region, the introduction of a substitution 15C-->T (that is the
      presence of the elongated Pribnow block) resulted in the CRP-independent
      transcription of the udp gene promoter. The binding site CRP2 was shown to be
      indispensable for the maximum promoter activation by the transcription-activating
      cAMP-CRP complex. Both positive (cAMP-CRP complex) and negative (CytR) regulation
      of the promoter was virtually fully abolished after the introduction of mutations
      leading to the creation of canonical sequences in -10 and -35 promoter regions.

PMID- 15027197
TI  - [Effect of superexpression of DNA-binding protein heterochromatin Abp1p on
      frequency of loss of minichromosomes and growth of Schizosaccharomyces pombe with
      mutations of the gene coding cofactor D].
AB  - Mitotic chromosome segregation is partly determined by interaction between
      microtubules (MTs) and the kinetochores of sister chromatids. The precise
      mechanism of the interaction between kinetochores and MTs remains unclear. This
      process has been studied in fission yeast Schizosaccharomyces pombe by analyzing
      interaction between genes encoding kinetochore components, such as DNA-binding
      protein Abp1p, and genes whose protein products affect the dynamics of MTs, such
      as cofactor D of tubulin dimer assembly. Analysis of cell growth and
      minichromosome loss frequency has demonstrated that mutations in the gene of
      cofactor D, especially mutation tsm1-512, increase the rate of minichromosome
      loss and the sensitivity to changes in Abp1p concentration in cells compared to
      wild-type cells Probably, mutations alp1-1315 and tsm1-512 of the cofactor D gene
      cause defects in the kinetochore-MT interaction.

PMID- 15027198
TI  - [Syringa species: molecular marking of species and cultivars].
AB  - RAPD analysis was carried out with 22 accessions of the genus Syringa, including
      six species, one interspecific hybrid, and 15 cultivars. In total, 500
      polymorphic fragments were detected; species-specific and cultivar-specific
      markers were identified. For the first time, genetic polymorphism and genome
      similarity coefficients were estimated and phylogenetic relationships were
      established for the genus Syringa.

PMID- 15027199
TI  - [Dependence of the efficacy of transfecting muscle fibers in vivo on
      electroporation conditions].
AB  - This study is a survey of in vivo experiments on transfection of laboratory mouse
      muscle fibers by electroporation using an original device generating electric
      impulses. Transfection efficiency proved to depend on DNA dose and the number of
      electric impulses. It can be increased significantly by electroporation at
      varying pulse burst polarity. At both direct electrode application to muscles and
      electroporation through the skin, the muscle fiber transfection was more
      efficient under electroporation conditions much milder than those usually
      reported. The use of electroporation method for gene therapy of Duchenne muscular
      dystrophy is discussed.

PMID- 15027200
TI  - [Comparative cytogenetic variability of polytene chromosomes from salivary glands
      of Chironomus riparius Mg., 1804 (Diptera, Chironomidae) from two polluted
      biotopes in Bulgaria and Russia].
AB  - The structural-functional variation of Chironomus riparius salivary gland
      polytene chromosomes was studied in two geographically isolated Palearctic
      regions, Bulgaria (village Pancharevo) and Russia (St. Petersburg). The two
      biotopes, where larvae were collected, were polluted with various heavy metals
      from anthropogenic sources. Hereditary paracentric heterozygous inversions were
      characteristic of the Russian population, whereas somatic paracentric or
      pericentric heterozygous inversions were more common in the Bulgarian one. All
      inversions occurred at low frequencies. Other aberrations found in the two
      populations included somatic deletions resulting in a pompon structure of
      chromosome IVG, heterozygous translocation between chromosomes IVG and IIIF,
      enlargement of individual disks, and the appearance of a heterozygous block close
      to the centromere of chromosome IVG. In addition, changes in functional activity
      of the nucleolus organizer and Balbiani rings (BRc/BRb) were observed. Several
      aberration breakpoints proved to coincide with satellites of the Alu and Hinf
      families.

PMID- 15027201
TI  - [Identification and registration of corn genotypes using molecular markers].
AB  - In plant genetics and breeding, second-generation molecular markers allow
      detailed characterization of plant genotypes. Unique genotypes at ten simple
      sequence repeat (SSR) loci were established for 40 maize accessions by means of
      PCR. For every locus, SSR analysis revealed heterozygotes among simple hybrids,
      which made it possible to identify the parental forms with a high probability of
      exclusion of nonparental forms. A system was proposed for registration of maize
      genotypes in the form of genetic formulas reflecting the allelic state of
      microsatellite loci, in order to catalog, preserve, and effectively employ the
      existing maize gene pool in breeding.

PMID- 15027202
TI  - [Linkage of genes, controlling morphological signs with isozyme markers of rye
      chromosomes].
AB  - Data on linkage of 12 rye genes controlling morphological traits (el, Vs, ln, w,
      np, ct2, Hs, Ddw, cb, mn, vil, mp) with one or several isozyme markers of
      individual rye chromosomes (2R-7R) are presented. Linkage of the following gene
      pairs was established: chromosome 2R: Est3/5-el, el-beta-Glu, Sod2-el, Sod2-Vs;
      chromosome 3R: ln-Got4; chromosome 4R: w-Got1, np-Got1; chromosome 5R: Est4-ct2,
      Est6/9-ct2, ct2-Est2, ct2-Aco2, Est2-Hs, Aco2-Hs, Est2-Ddw, Aco2-Ddw; chromosome
      6R: Lap2-cb, cb-Aco1, Est10-mn; chromosome 7R: Acph2/3-vi1, Got2-vi1, mp-Acph2/3.
      The reasons for mapping a very small number of genes in rye in spite of high
      intraspecific variability of this species are discussed. An approach is suggested
      to improve this situation by simultaneous identification and mapping of all
      diverse spontaneous mutations maintained in heterozygous state in various rye
      cultivars.

PMID- 15027203
TI  - [Genetic-physiologic features of reproduction in prolific animals].
AB  - Genetic and physiological functional relationships between major reproductive
      parameters were studied in domestic prolific mammals with special reference to
      selection-induced changes in fertility and mothering ability in ten generations
      of pigs of sino-European Tiameslan composite line, which was first bred in
      France. Based on our hypothesis, balance equations were derived describing highly
      adaptive functional coadaptations of reproductive traits. Properties of these
      equations were examined with regard to natural selection. Selection changes of
      secretory traits of mammary glands were shown to play a leading role in a
      correlated increase of biological fertility. Genetically controlled regulatory
      relationships maintained by natural stabilizing selection were established
      between fertility, sow milk production, perinatal survival, and survival to
      weaning. Thus, a system of simple complementary equations characterizing an
      independent integrative reproductive physiological mother-young(s) system was
      obtained, which had not been previously published. The self-regulated homeostatic
      mother-young(s) system, studied for the first time ever, ensured homeostatic
      development of suckling piglets, compensatory regulation, and stabilization at
      the optimal level of biological (11.6 +/- 0.17 piglets at birth) and actual (10.0
      +/- 0.08 piglets at weaning) fertility in the Tiameslan line.

PMID- 15027204
TI  - [Identification of the hereditary variants of skin melanoma].
AB  - The identification of hereditary variants of cutaneous melanoma and analysis of
      the role of hereditary factors and syndromes predisposing to cutaneous melanoma
      were carried out. The involvement of individual nevus phenotypes in the
      development of this disease was determined. Based on a survey of recent molecular
      biological data and our studies, the etiological and genetic heterogeneity of
      cutaneous melanoma is reported. In relatives of patients with cutaneous melanoma
      and persons with multiple pigmented nevi, the malignant tumors proved to be
      differentiated in the direction of the neural crist tissues and/or derivatives of
      cutaneous mesenchyma. Based on the evidence obtained, the approaches have been
      developed to formation of risk groups for the purpose of early diagnostics of
      cutaneous melanoma.

PMID- 15027205
TI  - [Analysis of the association of HLA-DQ1 alleles with mutation of the 21
      hydroxylase gene in patients with congenital adrenal hyperplasia].
AB  - In 96 patients with congenital adrenal hyperplasia (CAH) and 50 healthy donors
      from northwestern Russia the distribution of the HLA-DQA1 alleles and the
      mutation spectrum and frequency at the CYP21B gene were examined. In the patients
      with nonclassical (NC) CAH, the distribution of the HLA-DQA1 polymorphic alleles
      was similar to that in the population sample. In the patients with the salt
      wasting form of the disease a statistically significant decrease of the *0401 or
      *501 major allele frequency was observed. The prevalence of certain HLA-DQA1
      genotypes, namely, HLA5, HLA3, and HLA4, was observed in the patients with the
      NC, salt-wasting (SW), and simple virilizing CAH, respectively. Each clinical
      group was characterized by a specific spectrum of clinically valuable mutations.
      An association between the CYP21B mutations most frequently found in case of SW
      and SV CAH (delB, I2splice, and I172N) and certain HLA-DQA1 alleles was
      demonstrated. The necessity of more precise clinical diagnostics of the NC CAH
      cases along with detailed examination of this group for determination of the
      major mutations typical of the NC CAH cases from northwestern Russia is
      discussed.

PMID- 15027206
TI  - [Deletional polymorphism of the 11th intron of the human c-fms gene: allele
      frequency in certain Russian populations and possible functional significance].
AB  - Analysis of deletion polymorphism of human c-fms gene intron 11 (approximately
      425-bp deletion) is of particular interest because of the increased proportion of
      the deletion heterozygotes among the infants born from the parents, one of which
      lacks the deletion allele, and the other is heterozygous for the deletion. In
      this study, allele and haplotype frequencies of the polymorphism examined were
      assessed in a number of Caucasoid and Mongoloid populations of Russia. In all
      populations tested, relatively high prevalence of the deletion-bearing allele,
      ranging from 9.45% in ethnic Germans to 20.75% in Altaians, was detected.
      Russians and Kazakhs were characterized by intermediate frequencies of the rare
      allele, constituting in these populations 12.89 and 14.93%, respectively. Hardy
      Weinberg expectations were met in all populations examined, pointing to a stable
      level of polymorphism at the c-fms intron 11. It was established by the context
      analysis of DNA of the deleted fragment along with the flanking sequences that
      this region contained a number of transcription factor motifs (Ets, SRF, and
      Myc), potentially capable of the regulation of the M-CFF-dependant c-fms
      transcription. The deletion breakpoint was localized within the CArG motif,
      which, together with the neighboring ets motif, form the potential CArG/ets
      composite element. It was suggested that allele lacking the fragment of intron 11
      could be restricted in its ability to modulate the level of the c-fms
      transcription in response to the action of M-CSF. The data of molecular
      epidemiological survey serve as the indirect evidence favoring the suggestion on
      the possible functional value of this gene fragment. It was demonstrated that in
      the samples of acute bronchitis and trichomoniasis patients allelic and genotype
      frequencies were statistically significantly different from those in the
      population sample. In case of trichmoniasis, the frequency of rare allele was 2.4
      times lower, and in case of acute bronchitis it was 2.1 times higher than in the
      control sample.

PMID- 15027207
TI  - [Strategy of production and utilization of immortal cells].
AB  - The current methods of production of conditionally immortal cells in vivo and in
      vitro have been considered, including the method based on transgenesis of
      animals. Examples are given for utilization of conditionally immortal cells
      obtained in vivo from tissues of transgenic mice and rats carrying the gene of
      mutant T-antigen tsA58 SV40. The recent studies were analyzed, which concern the
      investigation and utilization of embryonic and regional stem cells, as well as
      immortal cells obtained through transfection of the recombinant construct of
      telomerase gene into human cells. The main problems of cell biotechnology are
      discussed.

PMID- 15027208
TI  - [Variability of flavonol contents during floral morphogenesis in Papaver
      somniferum L].
AB  - We studied the contents of flavonols (kaempferol and quercetin) in the meristem
      of vegetative and generative apices of the main plant shoot in floral Papaver
      somniferum mutants, as well as in the normal plants at successive stages of
      flower development. Five stages of flower development were distinguished.
      Flavonols (kaempferol and quercetin) were present in all flower organs at all
      stages of floral morphogenesis we studied. However, their contents and
      distribution in different organs and at different stages of flower development
      markedly varied. No significant differences were found in the contents of
      flavonols in the meristems of vegetative and generative apices of the main shoot
      in the lines of floral mutants, as well as between the lines with different
      amounts of vegetative phytomeres. In the plants with normal flower structure, the
      contents of flavonols (kaempferol + quercetin) sharply increased with the
      beginning of differentiation of flower organs, i.e. from stage 3, to reach a
      maximum in the open flower, when gametogenesis is terminated and fertilization
      takes place. The level of flavonol contents in the petals (upper part) and stamen
      was at a maximum at all stages of flower development, while that in the gynaecium
      was at a minimum. The kaempferol: quercetin ratio shifted towards quercetin at
      successive stages of flower development, most significantly in the stamens. The
      involvement of flavonols in the regulation of floral morphogenesis at stages of
      flower organs differentiation and functioning is discussed.

PMID- 15027209
TI  - [Effect of catecholamines on migration and differentiation of gonadotropin
      releasing hormone-neurons in rats].
AB  - The GnRH producing neurons are the key link of neuroendocrine regulation of the
      adult reproductive system. Synthesis and secretion of GnRH are, in turn, under
      the afferent catecholaminergic control. Taking into account that catecholamines
      exert morphogenetic effects on target cells during ontogenesis, this study was
      aimed at investigation of the effects of catecholamines on development of GnRH
      neurons in rats during ontogenesis. We carried out comparative quantitative and
      semiquantitative analyses of differentiation and migration of GnRH neurons in
      fetuses of both sexes under the conditions of normal metabolism of catecholamines
      (administration of saline) or their pharmacologically induced deficiency
      (administration of alpha-methylparatyrosine). The inhibition of catecholamine
      synthesis from day 11 of embryogenesis led to an increasing number of GnRH
      neurons in rostral regions of the trajectory of their migration over the brain:
      in the area of olfactory tubercles on day 17 and in the area of olfactory bulb on
      days 18 and 21. In addition, the optical density of GnRH neurons located in the
      rostral regions of migration was higher in the fetuses after administration of
      alpha-methylparatyrosine during embryogenesis, as compared to the control. It has
      been concluded that catecholamines stimulate the migration of GnRH neurons and
      affect their differentiation.

PMID- 15027210
TI  - [Eggs fertilizability in domestic hens Gallus gallus domesticus as a function of
      the yolk surface area].
AB  - The increase of egg mass and reliable decrease of egg fertilizability were
      observed when the mass surface area of yolk (egg) increased. The results obtained
      suggest that, in addition to the number of viable spermatozoa penetrating across
      the perivitelline membrane within 15-20 min after ovulation, the probability of
      fertilization depends on the area of egg surface, which approximately corresponds
      to the area of perivitelline membrane. Apparently, the ratio of receptors'
      numbers and spermatozoa, which contact with them on the germ disc surface, to
      their number on the rest part of perivitelline membrane decreases with the
      increase of yolk size. The decreased egg fertilizability concomitant with the
      increased area of perivitelline membrane suggests that the egg size is one of the
      factors of fertility of the female gametes as concerns both variability of the
      egg composition and age.

PMID- 15027211
TI  - [Cytogenetic approach to estimation of developmental stability of the natural
      population of coregonid fishes].
AB  - A comparative cytogenetic analysis of coregonid fish was carried out in the river
      and lake ecosystems of the northern Tyumen' District. The occurrence of
      chromosomal aberrations in embryonic cells of fish steadily increased during the
      period from 1989 until 2001. Possible causes of this dynamic are discussed.

PMID- 15027212
TI  - [Orthologs of arabidopsis CLAVATA 1 gene in cultivated Brassicaceae plants].
AB  - In arabidopsis (Arabidopsis thaliana), the CLAVATA1 (CLV1) gene is involved in
      maintaining the balance between the stem cells in the central zone of the stem
      apical meristem and the determined cells at its periphery. However, CLV1 has not
      been previously characterized in other Brassicaceae. Using the direct
      amplification of genomic DNA, we obtained a full-length CLV1 ortholog from canola
      plants (Brassica napus), and also three CLV1 fragments from rape (B. rapa),
      canola (B. napus), and false flax (Camelina sativa), which corresponded to the
      transmembrane domain and a part of the kinase domain of the CLAVATA1 protein. The
      nucleotide and deduced amino acid sequences of the full-size CLV1 ortholog from
      B. napus were similar by 81 and 87% to the prototype gene from arabidopsis; in
      the case of shorter gene fragments, the similarity was as high as 91-93 and 98%,
      respectively. By their primary structure, the CLV1 genes in the Brassicaceae
      considerably differ from its putative structural homologs beyond this family.

PMID- 15027213
TI  - [Effect of parental age on endoreduplication of giant chromosomes and some
      quantitative traits in Drosophila melanogaster descendants].
AB  - We studied the influence of parental age on the degree of polyteny of giant
      chromosomes and expressivity of mutation eyeless in Drosophila melanogaster
      descendants. The parental age equal to six days exerted an adverse effect on the
      function of endoreduplication of giant chromosomes in strain eyeless. The highest
      degree of polyteny was observed in descendants of four- and ten-day imago. The
      maximum reduction of eye facets was observed in descendants of four-day imago,
      while in the progeny of older parents, the mutation expressivity was sharply
      reduced. Relations between the changes in chromosome polyteny, expressivity of
      mutation eyeless, and earlier studied components of adaptation were statistically
      analyzed in descendants of aging parents of this Drosophila strain.

PMID- 15027214
TI  - [Characteristics of phenotypic expression of autosomal monosomies during
      pathological postimplantation human development].
AB  - Autosomal monosomies represent a severe form of genomic disbalance which
      determines elimination of human embryos already at the preimplantation stages. As
      a rule, they occur very rarely in the materials of spontaneously aborted embryos
      and fetuses. Molecular-cytogenetic studies were carried out on the karyotype of
      cells of 60 spontaneous abortuses of I trimester of pregnancy with cell
      degeneration or absence of cell proliferation in the cultures, as a result of
      which the cells could not be studied using the standard metaphase analysis. The
      embryos were characterized by an unexpectedly high frequency of mosaic variants
      of monosomies for chromosomes 7, 15, 21, and 22, which amounted to 19% of all
      chromosome aberrations. Lethal forms of monosomies for human chromosomes 7 and 15
      were described for the first time, since they are not found in spontaneous
      abortuses by standard cytogenetic methods. A hypothesis was proposed which
      accounts for the possibility of early postimplantation lethality of the embryos
      with mosaic forms of autosomal monosomies. The differences were found between the
      cells with monosomies for different autosomes in the mechanisms of origin,
      intertissue localization, and phenotypic effects. It was shown that monosomies
      for chromosomes 7, 15, 21, and 22 in a mosaic state with the normal cell line can
      be compatible with the early stages of postimplantation differentiation of the
      cytotrophoblast. Predominant compartmentalization of the cells with monosomies
      for chromosomes 21 and 22 in the extraembryonic mesoderm, a derivative of
      epiblast, can be a critical factor, which makes it impossible the normal
      morphogenesis of embryonic structures.

PMID- 15027216
TI  - Restraint training plan needed urgently.

PMID- 15027215
TI  - [Age-related characteristics of cataractogenesis in salmon fry. II. Biochemical
      characteristics of eye lens during cataractogenesis].
AB  - We studied biochemical features of the lipid and phospholipid composition and
      patter of fatty acid spectra in lenses of one and two year old salmons bearing
      cataracts. The lipid complex of lenses of diseased fish underwent significant
      changes. Cataractogenesis was accompanied by enhanced free radical oxidation and
      accumulation of malone dialdehyde in lenses of salmons of various age. The
      intensification of oxidative processes was synchronized with the decreased level
      of antioxidant protection (reduced glutathione, vitamins A and E). The activity
      of Ca(2+)-dependent proteolytic enzymes in lenses was determined and its decrease
      in the case of cataract was shown.

PMID- 15027217
TI  - Nurses divided over racism findings.

PMID- 15027218
TI  - Mental health nursing faces a future of cultural change.

PMID- 15027219
TI  - How I coped with ... cancer.

PMID- 15027220
TI  - Nurses lead the way.

PMID- 15027221
TI  - 'We help patients learn from each other'.

PMID- 15027222
TI  - Repetitive strain injury: causes, treatment and prevention.
AB  - Repetitive strain injury (RSI) has become increasingly prevalent with the growth
      of computer-based and automated occupations. While environmental factors such as
      work stations and repetitive tasks are primary causes, a number of secondary
      causes can increase a person's risk of RSI. Various treatments provide relief but
      the rate of recovery varies widely. Prevention involves adopting a range of
      measures that will also promote recovery in those with RSI.

PMID- 15027223
TI  - What you need to know about ... insulin.

PMID- 15027224
TI  - Using computer-aided systems to provide patient information.
AB  - Patient information should be tailored to suit the learning style of each person.
      Benefits and constrains of the method of information delivery should be taken
      into consideration. Using computer-aided systems to provide for patients'
      information needs is not a new concept. Studies have shown positive results in
      well-being when such systems are used and nurses act as facilitators.

PMID- 15027225
TI  - A nurse-led intervention for patients on CABG waiting lists.
AB  - Patients on coronary artery bypass graft (CABG) waiting lists experience numerous
      emotional disturbances. This article reports on the introduction of a nurse-led
      presurgical intervention that comprises home visits and follow-up calls from a
      specialist cardiac nurse based at the hospital. An improvement in patients'
      anxiety and depression levels and modifiable coronary heart disease risk factors
      was observed following the intervention.

PMID- 15027226
TI  - Strategies to enhance privacy and dignity in care of older people.
AB  - Respecting and enabling an individual's right to privacy and dignity is an
      essential part of professional practice. Older people and their supporters face
      many challenges as part of the ageing process. The key role of nurses is to
      ensure that, as part of their therapeutic care, people can expect freedom from
      intrusion and be regarded as worthy of respect. This paper outlines some
      strategies that enable privacy and dignity to be put into practice.

PMID- 15027227
TI  - A new role to reduce the incidence of health care-associated infection.
AB  - There have been many initiatives to improve cleanliness and infection control in
      UK hospitals over the years. These include the establishment of dedicated
      infection control teams and, more recently, the introduction of modern matrons,
      who have the authority--and budget--to take action to improve cleanliness in
      clinical areas.

PMID- 15027228
TI  - The implementation of a commode cleaning and identification system.
AB  - The epic Project guidelines (Pratt et al, 2001) state that: 'Where a piece of
      equipment is used for more than one patient, for example a commode, it must be
      cleaned following each and every episode of use.' As a ward sister and infection
      control link nurse in a private hospital, part of my role is to train staff about
      infection control and monitor standards and practice within the hospital.

PMID- 15027229
TI  - Establishing a system to improve hand-hygiene compliance.
AB  - Hand hygiene is one of the most important means of reducing the transmission of
      infection. At University Hospital Lewisham, efforts to improve hand hygiene have
      included better sink, soap and towel provision, and the distribution of posters,
      leaflets, badges, balloons and pens. There are signs pointing to the nearest
      sink, and hand decontaminants at the end of most beds.

PMID- 15027230
TI  - Working towards an NHS standard for aseptic non-touch technique.
AB  - Despite increased NHS funding, health care-associated infection (HCAI) remains a
      major problem. Polarising the issue is the media's favourite 'superbug'-
      methicillin-resistant Staphylococcus aureus (MRSA). Incidence of MRSA in the UK
      continues to rise at a higher rate than in other European countries. The National
      Audit Office estimates the cost of hospital-acquired infection to be 1 bn Pound a
      year, and it causes 5,000-15,000 deaths annually (NAO, 2000).

PMID- 15027231
TI  - The control of urinary tract infection in hospitalised older people.
AB  - Urinary tract infection (UTI) can be symptomatic, asymptomatic, complicated or
      uncomplicated. A symptomatic UTI is identified by the presence of clinical
      symptoms that can be attributed to the presence of bacteria in the urinary tract.
      This may present as an acute uncomplicated UTI or an acute non-obstructive
      pyelonephritis (bacterial infection of the kidney).

PMID- 15027232
TI  - How to ... be a reflective practitioner.

PMID- 15027233
TI  - 'It's a wonderful job'. Interview by Adele Waters.

PMID- 15027235
TI  - Talking to children. Interview by Jo Carlowe..

PMID- 15027237
TI  - We are worth it.

PMID- 15027236
TI  - Crossing the divide.

PMID- 15027238
TI  - Ringing the changes.

PMID- 15027239
TI  - Transrectal ultrasound and prostate biopsy clinic.
AB  - This article examines one of the most common outpatient diagnostic procedures
      carried out in urology--the transrectal ultrasound (TRUS) and prostatic biopsy.
      Following an exploration of the aetiology, anatomy and physiology of prostate
      disease, an explanation is given regarding the clinical investigations that
      inform the decision-making process and precipitate the procedure. Technical,
      clinical and ethical issues will be explored before a through examination of the
      TRUS and biopsy procedure and the crucial role of the registered nurse and
      healthcare assistant. References are made to the elements of nursing care
      required throughout this most invasive of procedures. These include counselling,
      discharge information and the maintenance of patient dignity in relation to
      gender-sensitive care.

PMID- 15027240
TI  - Nurse education in the university setting.

PMID- 15027241
TI  - Improving services for people with learning disabilities.
AB  - People with learning disabilities encounter numerous barriers when using health
      services. The authors discuss ways to ensure that the health needs of these
      patients are met in mainstream settings.

PMID- 15027242
TI  - Pressure ulcers in infants and children.
AB  - Although there is no agreement about the size of the problem, there is evidence
      that critically ill children are more at risk of pressure ulcers than the general
      paediatric population. In addition to tissue damage associated with immobility,
      equipment and objects pressing or rubbing on the child's skin have also been
      implicated in the development of pressure ulcers. To prevent disfiguring and
      potentially life-threatening pressure ulcers, it is important that risk factors
      are identified and minimised.

PMID- 15027243
TI  - Minimising pain at dressing changes.
AB  - This article emphasises the importance of preventing pain in wound management. It
      describes the physiology and aetiology of wound pain, discusses how to assess for
      pain and outlines strategies to prevent and manage wound pain.

PMID- 15027244
TI  - The evidence base in wound healing.
AB  - The evidence base for wound healing management is lacking. This article discusses
      the methods of assessing evidence base and makes the plea for more research.

PMID- 15027250
TI  - [Hematopoietic stem cell transplantation in 2003].

PMID- 15027251
TI  - [Coordination of hematopoietic stem cell collection].

PMID- 15027252
TI  - [Liver transplantation in children].

PMID- 15027253
TI  - [Liver transplant procurement].

PMID- 15027254
TI  - [Intensive care stay after a liver transplantation, a difficult step].

PMID- 15027256
TI  - [A new liver for Theo].

PMID- 15027255
TI  - [Education and support of children after liver transplantation].

PMID- 15027257
TI  - [A long hospitalization for an infant, what role for the brothers and sisters?].

PMID- 15027258
TI  - [7/7 Putting the patient in an inclined or orthostatic position].

PMID- 15027259
TI  - [III--differed emergencies. 3/ Lower anorectal abnormality].

PMID- 15027261
TI  - Standards to assure quality in nursing research.
AB  - The focus of this article is quality assurance in nursing research. Due to well
      established problems regarding the education of nursing research and increasing
      pressure to take responsibility for the quality of all educational activities,
      departments of nursing are obliged to initiate actions to assure quality in
      nursing research. A nursing department functions within a well-defined external
      context. The external context comprises of various aspects such as role player
      expectations and current educational and professional legislation. Standards are
      the basic components of any quality assurance system (Booyens, 1996:305).
      Standards give direction to the practitioner and must be compiled within the
      context of the country's cultural, philosophical and ethical value systems, as
      well as its social economic and political development. The premise of the study
      was that if the education of nursing research, indeed the total management of
      nursing research within the department, is subjected to quality assurance, the
      outcome of the in terms of nursing research will be positive. The research
      objective addressed in the study was to formulate and validate standards against
      which quality in nursing research in a nursing department can be judged. Muller's
      phases of standard formulation were used as the methodological basis for the
      study. Optimal, specific standards were formulated using a deductive process and
      validated by implementing the standards in a department of nursing.

PMID- 15027262
TI  - The prevention of intrapartum HIV/AIDS transmission from mother to child.
AB  - The transmission of HIV/AIDS from mother to child is the main cause of HIV/AIDS
      in children and child mortality. Two-thirds of children with HIV/AIDS are
      infected in the intrapartum period (Farley, 2000:1-2). Midwives, through
      effective practices, can lower the transmission of HIV/AIDS from mother to child
      in the intrapartum period. The aim of the study was to determine which preventive
      practices registered midwives in provincial labour wards in Bloemfontein,
      implement to lower the risk of mother to child transmission of HIV/AIDS and in
      doing so to lower child mortality. A descriptive research design was used. Fifty
      one midwives completed questionnaires to determine what preventive practices are
      used. The study showed that most of the midwives did not implement the
      interventions that could lower the chances of HIV/Aids transmission from mother
      to child during the intrapartum period. Midwives therefore may not have a
      positive impact on child mortality. The researchers concluded that midwives do
      not implement the interventions mentioned in the study because of a lack of
      knowledge and skills. Of the midwives who completed questionnaires, 67% completed
      their training between 1990 and 2000. This lack of knowledge may be due to a lack
      in the curriculum of training institutions and of an up-to-date policy concerning
      the transmission of HIV/Aids in provincial institutions in Bloemfontein. It is
      recommended that all affordable interventions should be incorporated in the
      policy.

PMID- 15027263
TI  - Selected outcomes of community-oriented, problem-based nursing programmes in
      South Africa.
AB  - Whilst there is a significant body of research on the outcomes of problem-based
      learning (PBL) programmes (Albanese and Mitchell, 1993; Vernon and Blake, 1993),
      there is little information regarding the outcomes of community-oriented
      programmes (COL) for nursing students. Between 1994 and 1997, four university
      schools of nursing implemented problem-based, community-oriented learning (COL)
      programmes. This research sought to describe, evaluate and compare the outcomes
      of graduates from these four universities with graduates who had followed
      conventional programmes. RESEARCH OBJECTIVES: These were to describe and explore
      the incorporation of illness prevention and health promotion of graduates from
      PBL/COL programmes and non-PBL/COL programmes in South Africa, as described by
      the graduates and their supervisors. Secondly, to describe whether and how the
      graduates from PBL/COL and non-PBL/COL programmes engaged themselves in continued
      learning. RESEARCH METHODOLOGY: This was a qualitative evaluation study, which is
      descriptive and comparative in nature. In-depth interviews were held with the
      graduates and their supervisors about six months after completion of their
      training. Use was made of Miller and Crabtree's (1994) Template Analysis Style
      and of Benner's (1984) interpretative approach to analyze data. Analysis was done
      using the NVIVO computer programme. This programme was used to manage the
      categories which were developed with regard to each concept as the analysis
      proceeded. FINDINGS: Both the graduates and the supervisors appeared to have
      difficulty describing activities relating to health promotion and illness
      prevention. Only three types of health promotion were described--mass education,
      increasing personal skills and creating a supportive environment. The most
      commonly mentioned means of illness prevention were health education and medical
      surgical asepsis. A few graduates described activities which indicated that they
      had taken context into consideration during patient care.

PMID- 15027264
TI  - A job analysis of selected health workers in a district health system in KwaZulu
      Natal. Part One: Job analysis of nurses in hospital settings.
AB  - The aim of this descriptive survey was to do a job analysis of different
      categories of nurses in a District Health System in order to clarify job
      expectations, describe current practice of nurses in hospitals and clinics and to
      make recommendations about skills mix in district services. A mail questionnaire
      requested the sampled nurses to rate the frequency and importance of the tasks
      they perform. Only 19% of the nurses (41 nurses of all categories) returned the
      questionnaire, and an index taking into account frequency and importance, was
      calculated. The self-report data was compared with data from non-participant
      observation done over 19 days in 14 units in all three hospitals. A total of 39
      tasks were done more than six times per week, of which most (16) were in the
      category of clinical assessment and recording. Counselling and teaching (8
      tasks), were the second most frequent type of task. Only two tasks were rated as
      very important (giving injections and assessing respiratory status). When
      frequency and importance were combined into a Task Index, a large number of tasks
      scored in the middle range, with very few very high or low. Respondents
      identified 33 tasks that did not appear on the questionnaire. The observations
      showed that all categories of nurses shared many tasks in hospital settings.
      However, Registered Nurses were involved in specialized treatment and care, as
      well as administration of the unit. The specialists type tasks of Registered
      Nurses were also clear in Operating Theatre settings. The implications of the
      study are discussed and recommendations are made.

PMID- 15027265
TI  - A job analysis of selected health workers in a district health system in KwaZulu
      Natal. Part Two: Job analysis of nurses in primary health care settings.
AB  - The aim of this descriptive survey was to do a job analysis of different
      categories of nurses in a District Health System in order to clarify job
      expectations, describe current practice of nurses in hospitals and clinics and to
      make recommendations about skills mix in district services. This article deals
      with the clinics only. A mail questionnaire requested the sampled nurses to rate
      the frequency and importance of the tasks they perform. A total of 71% of the
      nurses (60 nurses of all categories) returned the questionnaire, and an index
      taking into account frequency and importance, was calculated. The self-report
      data was compared with data from non-participant observation done over 11 days in
      five clinics. The respondents rated 11 tasks as being performed more than six
      times per week, and no task as being important in that more than 70% of
      respondents felt it could never be omitted. However, on the task index, which
      combines frequency and importance, 57 tasks received the highest possible score
      of ten, and few (25%) were rated below five. The work context of nurses in PHC
      settings and hospitals was compared using Exhaustion-Disengagement Model and it
      was proposed that hospital nurses had higher job demands and lower job resources,
      and therefore ran a higher risk of both exhaustion and disengagement. A clear
      difference in the roles of different categories of nurses was found, although
      they have many tasks in common.

PMID- 15027266
TI  - A job analysis of selected health workers in a district health system in KwaZulu
      Natal. Part three: Other categories of health workers.
AB  - This article described the third part of a study aimed at doing a job analysis of
      nurses and non-professional health workers in a district health system. This
      article describes the tasks of five categories of workers, their training and
      their work-load over an ordinary week. Interviews were done with 52 workers from
      three hospitals and five clinics, of whom 14 were men and 38 women. The three PHC
      guards had a much more varied job than the hospital security staff (also three).
      All of them have had specific task related training. The six General Assistants
      in Primary Health Care settings were almost exclusively involved in cleaning,
      while the 23 in hospitals added food and drink management and running errands to
      their work. Only one had training pertaining to the specific tasks. All three
      clerks were found in the PHC setting, and their tasks were mainly that of
      receptionist. None had specific task related training. The three Ground's Men
      worked at gardening and cleaning at PHC clinics, but a range of other tasks were
      added from time to time. Porters, of whom ten were interviewed, did mainly
      transporting of patients and running errands. GA's and security staff were also
      used to control violent patients and visitors, something for which none of them
      have had training. Recommendations were made about training and work redesign in
      the district.

PMID- 15027267
TI  - [Profile of baccalaureate curriculum graduate students in 1997].
AB  - The purpose of this study is to describe the profile of the B.Cur. graduates who
      completed their studies in 1997 at the Rand Afrikaans University. Theoretical
      points of departures were used, such as Muller's career management description
      (Muller, 1998: 353-362) and Northeastern University's five-step model career
      services (Northeastern University, sa:1). After taking all the factors into
      consideration that play a role in career management, the researcher will be able
      to compile a complete profile of the B.Cur. graduates of 1997. It is important to
      the nursing education institution to know the profile of the graduates, in order
      to adapt the programme to the needs of the students. With a quantitative survey
      design, data was gathered telephonically, through a self-composed questionnaire.
      The structured questionnaire has content validity in terms of conceptualization.
      Of the thirty-one students, data was gathered on twenty-nine of them. Descriptive
      statistics were used to analyze the data. The profile of the graduates is
      described according to fourteen factors from the questionnaire.

PMID- 15027269
TI  - Perception of the health of children living and working on the streets of
      Sunnyside. Part 2: Methodology, interpretation and recommendations.

PMID- 15027268
TI  - Perception of the health of children living and working on the streets of
      Sunnyside. Part 1: Literature review and methodology.
AB  - The phenomenon of street children is generating increasing concern in South
      Africa. The number of street children has grown because of the current economic
      hardship in South Africa, increasing levels of violence and widespread family and
      community disruption. In terms of health, it is clear that street children may be
      vulnerable to a range of severe risks. The street child's view of health may
      differ considerably from that of the researcher. Discrepancies exist between the
      perceptions of the street children, and those of community health workers. This
      can have serious consequences when planning health promotion strategies (Jenkins
      & Emmet 1997:427). The purpose of the study was to describe the perceptions of
      street children concerning their own health. A qualitative descriptive design was
      followed in this study. Focus groups were used to obtain data. The findings of
      this research revealed five categories: Influences the environment has on street
      children's wellness Paths of homelessness of street children of Sunnyside that
      play a leading role in their wellness Wellness seeking behaviors of the street
      children of Sunnyside and the access to care they make use of Sources of advice
      and wellness education the street children of Sunnyside make use of Illnesses
      perceived by the street children of Sunnyside.

PMID- 15027270
TI  - A needs assessment of persons suffering from schizophrenia.
AB  - This quantitative exploratory descriptive survey attempted to identify the needs
      of persons suffering from schizophrenia who live in the Mogoto Village, Zebediela
      District, Limpopo Province. Data obtained from 60 completed questionnaires
      indicated that these persons continued to be regarded as valued community members
      by their care-givers. Despite the apparent lack of community mental health
      services, the vast majority of the respondents reportedly took their medications
      regularly and would know when to seek help in case their symptoms deteriorated.
      Their greatest need related to a lack of employment opportunities. They could
      also benefit from counselling services for themselves and their families.

PMID- 15027272
TI  - Tertiary institutions must reflect the new SA culture.

PMID- 15027271
TI  - Rheumatoid arthritis: hand function, activities of daily living, grip strength
      and essential assistive devices.
AB  - Persons with rheumatoid arthritis use assistive devices to enable them, in spite
      of impaired hand dexterity and grip strength, to manage Activities of Daily
      Living (ADL). The aim of the research was to lay the foundation for a list of
      essential assistive devices through determining which assistive devices for ADL
      were most often used and requested, investigating whether there was a correlation
      between grip strength and the number of assistive devices, duration of disease,
      degree of difficulty in performing ADL and by investigating whether there was a
      correlation between difficulty in ADL and number of assistive devices, duration
      of the disease. STUDY SAMPLE: Fifty five persons, 42 females and 13 males, seen
      at the Pretoria Academic Hospital's Arthritis Clinic were recruited. MATERIALS
      AND METHODS: A questionnaire was used to determine the level of difficulty with
      ADL. Details about assistive devices were recorded. The modified sphygmomanometer
      was used to measure grip strength. RESULTS: Assistive devices most in use were
      the tap turner and the dagger knife with built up handle. The highest correlation
      was found between grip strength and difficulty in ADL and between difficulty in
      ADL and the number of assistive devices used. It seems therefore that loss of
      grip strength is the main indicator for assistive devices.

PMID- 15027273
TI  - Nursing students' experiences during a rural community placement programme in
      Namibia--2001.
AB  - The reviewed nursing curriculum in Namibia incorporated issues related to Primary
      Health Care and diversification in the practical field for student nurses. This
      means that the students are exposed more to their communities than before. Nurses
      identify, manage and refer, if need be, the problems at this level. The
      curriculum facilitates and strengthens problem-solving skills and enhances the
      ability of nurses to adapt a comprehensive and family centred approach. The aim
      of this article is to describe the process of the rural placement of nursing
      students and to describe the experiences of the students as derived from the
      placement programme in districts in the central health directorate. Both positive
      and negative experiences are described. It is clear that the students have gained
      self-confidence in problem management. This article further confirms that
      learning experiences in the community setting is comparable to the hospital and
      other clinical learning settings in facilitating student's personal and academic
      development.

PMID- 15027274
TI  - Health care needs of older people living permanently in a residential home
      setting in Gauteng.
AB  - This article reviews some of the prevailing health needs of elderly people living
      permanently in a residential old age home. A qualitative, exploratory and
      descriptive design was employed. Twenty-one black elderly people were purposively
      selected to participate in a focus group interview session for the purpose of
      describing their perception of their health care needs. From descriptive content
      analysis, three main data sets emerged, namely physical health needs, unmet
      psychological needs and the need for a healthy social relationship.
      Recommendations to deal with these health needs were made based on the empirical
      data supported by literature. Measures of trustworthiness were ensured as
      described by Lincoln and Guba (1985:316-327).

PMID- 15027275
TI  - Health professionals' knowledge of prevention strategies and protocol following
      percutaneous injury.
AB  - Prevention strategies and protocols for the management of percutaneous injuries
      are developed for the purpose of preventing transmission of HIV and other
      infections. However, implementation thereof requires health professionals to be
      conversant with the content of protocols and ways to prevent percutaneous
      injuries. The purpose of the study was to determine health professionals'
      knowledge of prevention strategies and protocols following percutaneous injury.
      The purpose was addressed within a quantitative survey design. Data were
      collected by means of a self-administered questionnaire. The study was conducted
      at a public-sector tertiary academic hospital in Gauteng. Seven units within the
      hospital were randomly selected for investigation. These included, trauma,
      intensive care, medical, surgical, maternity, theatre and paediatrics. A
      population of 800 health professionals worked within the sampled units. Health
      professionals were stratified according to the following three categories,
      doctors, registered and enrolled nurses and medical and nursing students. A
      sample size of 200 health professionals was purposively selected of which a
      response rate of 79.5% (n = 159) was achieved. The sample consisted of 76.7% (n =
      122) registered and enrolled nurses, 13.2% (n = 21) doctors and 8.8% (n = 14)
      medical and nursing students; 1.3% (n = 2) did not specify their health
      professional category. Awareness of the existence of a protocol for percutaneous
      injury amounted to 96.2% (n = 153). General knowledge of the contents of the
      protocol reflected a different picture; only 26.4% (n = 42) of health
      professionals could accurately quote the procedure following a percutaneous
      injury as recommended by the South African Institute of Medical Research (SAIMR)
      protocol. The lack of knowledge of the existence of a protocol was most evident
      in the medical and surgical units. A total of 16.4% (n = 26) of health
      professionals reported having sustained a percutaneous injury. A doctor (33.3%)
      was more likely to sustain a percutaneous injury than a nurse (15.6%). Intensive
      care units reported the highest incidence of percutaneous injuries (31%; n = 9).
      Health professionals were unlikely to report a percutaneous injury; as only 53.8%
      (n = 14) reported the injury. The results of this research indicate that although
      knowledge of protocol and prevention strategies was inadequate these alone are
      insufficient to reduce the incidence of percutaneous injury.

PMID- 15027277
TI  - Socio-cultural deterrents to family planning practices among Swazi women.
AB  - To investigate deterrents to family planning practices among Swazi women, 205
      structured interviews were conducted with conveniently selected women in the four
      geographical regions of Swaziland. The Statistical Package for Social Sciences
      (SPSS) was used to analyse data. These results revealed that cultural practices,
      religious beliefs, gender issues and health care practices were the main barriers
      to the use of contraceptives among Swazi women. Recommendations were suggested
      regarding the education of men, women, adolescents and the entire society about
      contraceptive practices.

PMID- 15027276
TI  - The experience of therapy by therapists and survivors after exposure to armed
      robbery.
AB  - In this article the results of research undertaken to explore the experience of
      therapy by respectively the survivor of armed robbery and the therapist of the
      survivor of armed robbery in the case where therapy is prematurely terminated by
      the survivor of armed robbery are discussed. A high percentage of therapy for the
      survivor of armed robbery is being terminated prematurely by the survivor. This
      might be the reason for failing to use all possible opportunities to recover
      within reasonable time. The research questions that arouse are: "How do survivors
      of armed robbery experience therapy after being exposed to armed robbery?" and
      "How do therapists experience therapy for the survivor of armed robbery?" A
      qualitative, exploratory, descriptive and contextual research design was
      utilised. Phenomenological, semi-structured interviews were conducted with
      survivors of armed robbery and therapists of survivors of armed robbery to
      explore and describe their experiences. It was found that therapy leads to the
      experience of anger, fear, sadness and peace. The following needs of the survivor
      of armed robbery in the course of therapy were identified: a need to be cared
      for, availability, empathy, listening, focus on the armed robbery, help with the
      handling of problems, a trustworthy relationship with the therapist, sensitivity
      by the therapist and caring by important others in the life or the survivor of
      armed robbery. These needs were identified by both groups of participants. When
      these needs are not met within therapy, therapy is terminated prematurely and
      experienced as unsuccessful. Three principles of therapy were identified, namely
      that therapy should start as soon as possible, the trend and technique should be
      explained and signs and symptoms should be explained.

PMID- 15027278
TI  - Perceptions about epilepsy in the Limpopo Province of the Republic of South
      Africa.

PMID- 15027279
TI  - Role-player expectations regarding the education of nursing research.
AB  - This article reports on role player expectations regarding the education of
      nursing research. The importance of the role player expectations are two-fold:
      firstly as a factor in the external environment influencing and guiding the
      formulation phase of the development of standards and secondly, due to the clear
      indications of problems regarding nursing research in the nursing profession in
      literature. The role player expectations were elicited using a qualitative,
      exploratory and contextual design. The role player population included nurse
      educators, nurses in managerial, clinical and research positions, students and
      the medical profession. The data was gathered using the naive sketches and
      qualitative data analysis was done using Morse & Field's approach (1996:103-107)
      in combination with Tesch's data analysis approach as cited by Creswell (1994:154
      156). Sixty initial categories were narrowed down to six final categories, which
      are the research learning programme, personnel, students, departmental policies,
      funding and support systems. The role player expectations were elicited as part
      of a research study aiming tot develop a self-evaluation system for quality
      assurance in nursing research and as such, the role player expectations plays a
      pivotal role in the development of standards for the self-evaluation system.

PMID- 15027280
TI  - DOTS for temporary workers in the agricultural sector. An exploratory study in
      tuberculosis case detection.
AB  - INTRODUCTION: This study was conducted in the Boland health district of the Cape
      Winelands of South Africa where there is a high tuberculosis incidence and
      prevalence. A survey conducted on 211 farms in the study district during 1998,
      reported that 65% (n = 9042) of all workers on these farms, were temporarily
      employed. Temporary farm workers live in communities either within or the
      outskirts of the boundaries of the Boland health district, from where they are
      transported to work daily. RESEARCH OBJECTIVE: To estimate the point prevalence
      of sputum smear-positive tuberculosis among temporary farm workers in the Boland
      health district, and to determine whether temporary farm workers diagnosed with
      tuberculosis, have access to anti-tuberculosis treatment. STUDY DESIGN: The study
      took the form of a cross-sectional active case finding survey amongst adult
      temporary farm workers (not living on farms) on the four study farms in the
      Boland health district. RESULTS: Data was analysed using the Epi Info Version 6
      computer programme. Four (4) existing (self-reported) tuberculosis cases were
      identified and six (6) previously undiagnosed new sputum smear-positive cases of
      tuberculosis were detected. The total point prevalence was 10 cases of
      tuberculosis in the cohort of temporary farm workers, resulting in a point
      prevalence rate of 2,809 cases per 100,000 temporary farm workers (95% CI 1,090
      4,527). If the four (4) self-reported cases of tuberculosis are excluded in the
      calculation, the point prevalence of new sputum smear-positive tuberculosis cases
      is six (6) and the prevalence rate 1,685 cases per (95% CI 468-2909). Of the four
      self-reported tuberculosis cases, one indicated that their supply of medication
      was depleted, whereas the other three indicated that they had the required
      treatment at home. DISCUSSION: Tuberculosis is a major health problem in this
      region of South Africa and the incidence is projected to increase in correlation
      with the increasing prevalence of HIV/AIDS. Recent legislative changes in South
      Africa have resulted in a trend where farmers decrease their permanent work force
      and increase their use of a temporary work force. The nature of temporary
      employment in the agricultural industry creates potential difficulties for farm
      workers to access tuberculosis health care. The early detection and effective
      case management of this high-risk group presents a special challenge to the South
      African health community.

PMID- 15027282
TI  - Managed care vs fee for service: is there a difference?

PMID- 15027281
TI  - Hand decontamination practices in paediatric wards.
AB  - The purpose of this study was to determine and describe hand decontamination
      practices of health care professionals in the paediatric wards of an academic
      hospital in Johannesburg. The purpose was addressed within a survey design and
      through the use of descriptive and comparative methods. Data were collected
      through direct observation conducted with the use of a researcher-administered
      checklist. A sample of sixty-six health professionals was obtained through
      convenience sampling. Results indicated that significantly fewer health
      professionals did not decontaminate their hands on entering the ward (16.6%),
      prior to making patient contact (34.8%) and prior to donning gloves (9.1%).
      Significantly more health professionals did decontaminate their hands following
      contact with the patient (63.6%) and following removal of gloves (77.8%). More
      health professional did not wash their hands after leaving the ward (51.5%). More
      than half (57.6%) of the health professionals who decontaminate their hands used
      the correct hand washing technique. Compliance with standard hand decontamination
      practices of health professionals was found to be poor with only 83.4% of health
      professionals decontaminating their hands at the start of work.

PMID- 15027283
TI  - A return to restrictive advertising.

PMID- 15027284
TI  - Dental laser identifies early stages of caries.
AB  - In conclusion, the various methods of caries detection used, including visual
      inspection, radiographs, and tactile sensation, have a significant subjective
      component. The Diagnodent allows clinicians to add a more objective test to their
      armamentarium. Should the doctor choose to "watch" a suspected lesion and treat
      with topical fluoride, the area can be monitored for the progression or
      regression of decalcification. For more information, call KaVo at (888) KaVo-USA.

PMID- 15027285
TI  - Automation: the next step for dentistry.

PMID- 15027286
TI  - Hygienists' education may be slashed.

PMID- 15027287
TI  - New directions in dentistry: an exclusive interview with Dr. Gordon Christensen.
      Interview by Phillip Bonner.

PMID- 15027288
TI  - The best advances in dentistry in the past 15 years.

PMID- 15027289
TI  - Shaping root canals, Part VI: GT File technique in abruptly curved canals.

PMID- 15027290
TI  - Technology and the new age of periodontics.

PMID- 15027291
TI  - Striving for continual improvement.

PMID- 15027292
TI  - Standardized head position and reference planes for dento-facial aesthetics.
AB  - The angulations of the anterior teeth in the sagittal view are important for
      diagnosing lip support for pleasing smiles and proper facial profiles (Figure
      19). In Figure 20, the slant of the occlusal plane (incisal-canine line), the off
      center tilted midline, and the asymmetry of the gingival line (contours) of this
      patient in the frontal view are now obvious. A diagnosis can now be made for
      possible correction using the horizontal and vertical frames of the articulator
      as a bioesthetic guide.

PMID- 15027293
TI  - Provisionalization of the anterior aesthetic case.

PMID- 15027294
TI  - Dental mythology and trends for the millennium.

PMID- 15027295
TI  - Smile improvement: the laser way.
AB  - In the beginning of this case, the "my way or the highway" approach would have
      resulted in no treatment of this patient. But by meeting her primary concern of
      aesthetics and making sure she has a pain-free experience, the patient went on to
      undergo full periodontal care with excellent results.

PMID- 15027296
TI  - Laser soft tissue therapy combined with conventional osseous surgery, Part 2.

PMID- 15027297
TI  - The business of dental hygiene, Part 1.

PMID- 15027298
TI  - What makes patients click? Marketing your practice in cyberspace.

PMID- 15027299
TI  - Decisions, decisions. Purchasing practice management software.

PMID- 15027300
TI  - [Educational method for medical students to arouse interest in learning
      physiology using the theme of eye movement].

PMID- 15027301
TI  - [Changes in muscle action potential and circulatory response due to enhanced
      physiological tremor during static muscle contraction].

PMID- 15027302
TI  - [Legislative problems concerning prediction of criminal and violent recidivism
      among mentally disordered offenders].

PMID- 15027303
TI  - [Present situation in commitment of mentally disordered offenders in a
      psychiatric hospital in Japan].

PMID- 15027305
TI  - [Legislative problems concerning recidivism among mentally disordered offenders].

PMID- 15027304
TI  - [Risk assessment for serious violence].

PMID- 15027306
TI  - [Problems in legislation on the therapy and observation of mentally disordered
      offenders].

PMID- 15027307
TI  - [Present status of consultation-liaison psychiatry].

PMID- 15027308
TI  - [Community mental health service, social work activity and clinical ethics].

PMID- 15027309
TI  - [Role of psychiatry in Diagnosis Procedure Combination and the essential
      postgraduate education].

PMID- 15027310
TI  - [Randomized controlled trial on effectiveness of the community re-entry program
      to inpatients with schizophrenia spectrum disorder, centering around acquisition
      of illness self-management knowledge].
AB  - OBJECTIVE: The objective of this study was to examine by randomized controlled
      trial the effectiveness and safety of the Japanese version of the Community Re
      Entry Program, a manualized psycho-educational program with cognitive-behavioral
      therapy techniques, in discharge preparation for inpatients with schizophrenia.
      Our hypotheses are that firstly the program is effective for patients in
      acquiring illness self-management knowledge, that secondly the program shows
      positive effects on objective behavior and symptoms, and that thirdly the program
      has no adverse effects on subjective quality of life (QOL). METHOD: The subjects
      were 32 psychiatric inpatients, 24 male and 8 female, hospitalized in psychiatric
      rehabilitation wards, who gave written informed consent to participate in this
      study. The Community Re-Entry Program consists of 16 small-group sessions of one
      hour each that teach illness self-management knowledge and related skills to
      prepare patients for discharge from hospital and re-entry to the community with
      cognitive-behavioral techniques such as demonstration, roleplay, feedback,
      behavioral modeling and homework assignments. A specialized trainer's manual,
      demonstration videotape and patient workbook are utilized in the program. The
      program content includes defining discharge readiness, identifying symptoms and
      medication effects, assisting with discharge planning, connecting with community
      care, medication self-management, monitoring relapse warning signs, and preparing
      for emergencies. Except for considerations of the sex ratio in both groups,
      subjects were randomly allocated to the program (the program group) or ordinary
      occupational therapy (the control group). Of 32 patients, 31 were diagnosed with
      schizophrenia and 1 with schizotypal disorder. For the patients in the program
      group, we administered the program of 16 sessions as well as introductory and
      closing sessions, twice a week for 9 successive weeks. Nursing staffs in the
      wards took the roles of trainers with careful fidelity to the manual and
      supervision by psychiatrists with extensive experience in cognitive-behavioral
      therapy. The subjects were assessed concerning psychopathology with PANSS by
      psychiatrists, objective behavior with REHAB by nurses, subjective QOL with
      subjects' self-reports on WHO/QOL-26 and illness self-management knowledge also
      by self-report questionnaire attached to the trainers' manual of the program,
      before and after the whole program. RESULTS: Before the program, no significant
      differences were observed between groups concerning age, illness duration,
      education, length of current hospitalization, amount of antipsychotic medication,
      psychopathology, objective behavior, subjective QOL and illness self-management
      knowledge. One patient dropped out of the program because of transient ischemic
      attack. After the program, the patients in the program group significantly
      improved in illness self-management knowledge, as well as in speech skills and
      social activity score, factors of REHAB concerned with objective behavior
      evaluation, compared with those in the control group. Positive symptoms thus
      seemed to improve in the patients in the program group compared with those in the
      control group. No significant changes were observed in other items, including
      subjective QOL, in the patients of both groups. No patients experienced psychotic
      relapse in the observation term. DISCUSSION: We consider that the results
      supported most of our hypotheses, as they showed positive effects of the program
      in learning illness self-management knowledge, objective behavior and possible
      positive effect on positive symptoms, and no adverse effects were observed in
      psychopathology, behavior or subjective QOL. Further study is necessary on
      illness self-management behavior acquisition and the effects on long-term
      clinical outcomes. Study on whether the program is effective for younger patients
      with shorter hospitalization are expected, because the subjects in this study
      were rather older (45.9 +/- 11.5 years in the program group) and hospitalized
      longer (37.8 +/- 36.7 months in the program group). CONCLUSION: The Japanese
      version of the program was effective and relatively safe for schizophrenia
      spectrum disorder inpatients for learning illness self-management knowledge in
      preparation for discharge and planning community re-entry.

PMID- 15027311
TI  - [Case of prolonged recovery from serotonin syndrome caused by paroxetine].
AB  - We report a case of serotonin syndrome in a patient being treated with paroxetine
      for depression. Despite prompt discontinuation of medication, his serotonin
      syndrome continued for 10 days before full consciousness was restored. The
      patient was a 48-year-old male with chief complaints of hypobulia and suicidal
      thoughts. He consulted as a psychiatric outpatient, and oral paroxetine 20
      mg/day, etizolam 1.0 mg/day, and brotizolam 0.25 mg/day were immediately started.
      Upsurge of feeling and disinhibition state were noted the following day, then on
      treatment day 6 his condition deteriorated to substupor state and he was admitted
      for further treatment. On admission, change of mental condition (consciousness
      disturbance), perspiration, hyperreflexia, myoclonus and tremor were seen, and
      serotonin syndrome caused by paroxetine was suspected. Paroxetine was thus
      discontinued, and under intravenous drip his condition gradually improved.
      However, it was not until the 10th hospital day that he became fully alert. In
      examinations, no infectious, metabolic or organic diseases were detected. The
      patient's condition often improves with in 24 hours of discontinuation of the
      causative medication in serotonin syndrome. Symptoms continued for 10 days in
      this patient, however, perhaps because paroxetine was administered for 6 days
      before discontinuation. In addition, interaction with other medications may have
      occurred. Therefore, when serotonin syndrome is suspected, prompt discontinuation
      of the suspected causative medication, followed by close monitoring of the
      pharmacokinetics is warranted.

PMID- 15027312
TI  - [Usefulness of immunoplatelet measurement using the flow cytometric method for
      accurate platelet counting in hematological patients with severe
      thrombocytopenia].
AB  - We measured platelet counts in 95 patients with hematological disorders
      accompanied by thrombocytopenia (platelet counts < 5.0 x 10(4)/microliter)
      including 35 patients with severe thrombocytopenia(platelet counts < 2.0 x
      10(4)/microliter). We used four methods based on different principles and
      compared the results, i.e., the flow cytometric method (BEADS method) utilizing
      platelet-specific monoclonal antibody (SZ2, antiGPIb) in conjunction with
      fluorescent reference beads (Flow-Count Fluorospheres), manual hemocytometry, and
      two automated blood cell counters, the NE-8000 (impedance method) and the
      Technicon H-2 (optical method). The BEADS method was superior to the other
      methods in linearity of serial dilutions, and the coefficient variations of the
      BEADS method(2.5-5.2%) were superior to the other methods. The platelet counts
      measured by the automated blood cell counters were higher(0.6-0.9 x
      10(4)/microliter) than those by the BEADS method and manual hemocytometry.
      Furthermore, the BEADS method was able to measure accurate platelet counts in
      samples containing red blood cell fragments. The BEADS method may be an accurate
      and useful method for measuring samples with severe thrombocytopenia, and,
      especially, samples containing red blood cell fragments.

PMID- 15027313
TI  - [Clinical significance of serum IL-18 determination in rheumatoid arthritis].
AB  - Interleukin (IL)-18 is a novel cytokine expressing at inflammatory lesion. In
      this study, to evaluate the clinical significance of IL-18 determination, we have
      examined serum IL-18, inflammation markers, sFas, and sFas-ligand concentrations
      in patients with rheumatoid arthritis(RA). Serum was obtained from 56 RA patients
      aged 35-74 years, 16 osteoarthritis (OA) patients aged 36-78 years and 178
      healthy subjects aged 20-72 years and IL-18 was measured by ELISA. Serum IL-18
      concentrations in RA (240.1 +/- 15.6 pg/ml, mean +/- SE) were significantly
      higher than OA (151.8 +/- 12.7 pg/ml, p < 0.005) and healthy controls(141.5 +/-
      26.1 pg/ml, p < 0.001). Serum IL-18 levels were significantly increased in II to
      IV stages of RA (stage II; 218.6 +/- 31.2 pg/ml, stage III; 258.7 +/- 38.4 pg/ml,
      stage IV; 231.6 +/- 13.1 pg/ml) than those in OA. Furthermore, a positive
      correlation was observed between serum IL-18 concentration and serum Fas level in
      patients with RA (r = 0.472), whereas there was no significant correlation
      between serum IL-18 and sFas-ligand or other inflammatory markers (CRP, RF, CA
      RF, IL-6, and IL-8). The present study showed that serum IL-18 level increased in
      RA, but it is unknown how IL-18 is involved in the pathogenesis of RA. Further
      study will be necessary to clarify the role of IL-18 in RA.

PMID- 15027314
TI  - [The relationship with human papilloma virus DNA in cervical adenocarcinoma].
AB  - Recently, cervical adenocarcinoma has been increasing especially among young
      women and account for 10-20% of cervical cancer. However, the detection rate of
      HPV-DNA was 35-85% and lower than that of squamous cell carcinoma. Furthermore,
      the relationship with HPV in cervical adenocarcinoma was not much investigated in
      Japan, so we studied HPV status in cervical adenocarcinoma by in situ PCR method
      using biotin-labeled DNA probes, because in situ PCR method possesses the
      advantages of both PCR and in situ hybridization in being highly sensitive and
      enabling visualization of the cellular localization of the DNA. HPV infection was
      analyzed in 60 cervical adenocarcinomas, including 1 adenocarcinoma in situ and
      15 adenosquamous carcinomas. HPV-DNA was detected in 47 of all 60 cases(78%): 35
      of 45(78%) in adenocarcinomas and 12 of 15(80%) in adenosquamous carcinomas. No
      significant correlation was found between the HPV-DNA detection rate and
      histological subtypes of adenocarcinoma. In conclusion, cervical adenocarcinoma
      demonstrates a high prevalence of HPV-DNA as well as other previous studies.
      Therefore, HPV infection plays a very important role in not only squamous cell
      carcinoma but also adenocarcinoma in uterine cervix.

PMID- 15027315
TI  - [A case of pseudothrombocytopenia during antibiotic administration].
AB  - A 70 year-old woman was prescribed of levofloxacin and ceftriaxone for acute
      bronchitis. On the seventh day of administration she was hospitalized with a dry
      cough and a decreased platelet count(2.1 x 10(4)/microliter). However, bleeding
      tendency was not seen. So, we changed anticoagulants with citric acid and heparin
      from EDTA, and measured platelet count because we suspected
      pseudothrombocytopenia(PTCP), then platelet count became elevated (respectively,
      12.5 x 10(4)/microliter and 15.0 x 10(4)/microliter). In addition, platelet
      associated IgG increased to 309.3 ng/10(7) cells. Based on drug lymphocyte
      stimulation test, she was diagnosed as having antibiotic-induced PTCP, especially
      as she had no history of thrombocytopenia. PTCP should be considered when
      thrombocytopenia occurs during antibiotic treatment.

PMID- 15027316
TI  - [Atherosclerosis and metabolic disease].
AB  - Cholesterol plays an important role in atherogenesis. Cholesterol-ester that has
      been carried by circulating low-density lipoprotein particles accumulates in the
      atherosclerotic plaque. Statins are considered the most potent and effective
      agents for reducing low-density lipoprotein cholesterol and the incidence of
      cardiovascular events. Total cholesterol and LDL cholesterol levels, however, are
      not always a useful marker for distinguishing patients with or without
      cardiovascular disease. Low levels of high-density lipoprotein cholesterol are
      the most predictive marker for cardiovascular disease. Low HDL cholesterol levels
      originate in some genetic and acquired diseases and conditions. Most cases of low
      HDL cholesterol associated with the development of atherosclerosis are of
      secondary origin, especially those associated with increasing triglyceride-rich
      lipoprotein. These conditions are present in insulin-resistant syndrome, namely
      metabolic syndrome. Type 2 diabetes mellitus and the closely related metabolic
      syndrome are associated with a significant risk for cardiovascular disease.
      Recent evidence suggests that both conditions are increasing in epidemic
      proportions. Dyslipidemia is characterized by increased triglyceride-rich
      lipoproteins; low high-density lipoprotein cholesterol; small, dense low-density
      lipoprotein particles; and increased postprandial lipemia. All these lipoprotein
      disturbances accelerate atherosclerosis. It is likely that many patients will
      need lipid-modifying therapy to help prevent cardiovascular disease.

PMID- 15027317
TI  - [Molecular targeted treatment--new treatment strategy for patients with chronic
      myeloid leukemia].
AB  - Imatinib mesylate is a new drug that can inhibit the tyrosine kinase activity of
      Bcr-Abl, the receptors for platelet-derived growth factor receptor(PDGF) and stem
      cell factor, or c-kit. Chronic myeloid leukemia (CML) is distinguished by the
      presence of a reciprocal translocation between chromosomes 9 and 22 that results
      in a shortened chromosome 22, termed the Philadelphia(Ph) chromosome. As a result
      of the translocation, a fusion gene called the Bcr-Abl gene is created from two
      normal cellular genes, encoding a chimeric Bcr-Abl protein with a deregulated
      tyrosine kinase activity. The expression of Bcr-Abl tyrosine kinase has been
      shown to be necessary and sufficient for the transformed phenotype of CML cells.
      Imatinib can block the kinase activity of Bcr-Abl, thus inhibiting the
      proliferation of Ph-positive progenitors, and has shown activity against all
      phases of CML, though responses are most substantial and durable in patients in
      the chronic phase. An international phase III study which compared the efficacy
      of imatinib with that of interferon alpha combined with low-dose cytarabine in
      newly diagnosed chronic-phase CML showed the rate of major cytogenetic response
      at 24 months was 90%, including 82% of complete cytogenetic response. These
      results indicated that imatinib was superior to interferon-containing treatment
      as a first-line therapy. More than 10,000 patients worldwide, including those in
      Japan, have been treated with imatinib in clinical trials, and a lot of
      information has been accumulated on the use of this drug. The aim of this article
      is to review the use of this drug and the practical management of patients with
      chronic myeloid leukemia.

PMID- 15027318
TI  - [Minimally invasive therapy under image guidance--emphasizing MRI-guided
      cryotherapy].
AB  - Cryotherapy may provide a method for the focal destruction of cancerous tissue
      while preserving most of the surrounding normal tissue. The mechanisms of tissue
      injury in cryotherapy are 1) intracellular ice formation, 2) dehydration of
      cells, and 3) stagnation of microcirculation. MR images were superior to CT and
      ultrasound in monitoring interstitial cryotherapy, because the very short T2
      relaxation time of ice affords excellent contrast between the ice and surrounding
      tissue, allowing an accurate depiction of the entire extent of the iceball. MR
      imaging demonstrates the iceball as sharply marginated regions of signal loss
      that expanded and engulfed the renal and hepatic masses with clear contrast
      between the iceball and surrounding tissue. Recently, a fast Joule-Thomson
      cryocycling device for MR-compatible cryotherapy application was developed and
      clinical trials under MRI-guided monitoring were performed in several sites of
      the body. In our series, cryotherapy was performed in 14 cases of renal tumor and
      4 cases of hepatic malignancy under the guidance of a horizontal open MR system.
      Fourteen of the 18 cases were discharged a day after cryotherapy. One of the
      residual tumors at the margin of a renal cancer required re-cryoablation. All
      cryoablated tumors resolved and there were no serious complications and no
      clinically significant changes-during the follow-up study.

PMID- 15027319
TI  - [Fascinated by pulmonary function].
AB  - I would like to tell you about my 35 years of research, starting when I became a
      medical doctor, titled "Fascinated by Pulmonary Function". For the first 10
      years, I studied the automation of pulmonary function tests and developed some
      automatic pulmonary function test apparatuses such as the spiro-computer,
      panspiro-computer, automatic respiratory resistant test apparatus and automatic
      respiratory central function test apparatus. For the next 15 years, I studied the
      relationships between some important pulmonary diseases and respiratory pulmonary
      functions. In particular, I studied respiratory efficiency and respiratory center
      functions. For the most recent 10 years, I have been studying the relationships
      between non-respiratory pulmonary functions and chronic respiratory diseases. I
      am studying the relationships between ATP(Adenosine Tri Phosphate) in the blood
      for the parameters of mitochondria function and pneumoconiosis and other chronic
      pulmonary diseases. I had very interesting results regarding DNA types of
      arteriosclerosis in chronic pulmonary emphysema. I thank all my research fellows
      during these 35 years from the bottom of my heart.

PMID- 15027320
TI  - [Establishment of a clinical method for evaluating flow-mediated
      vasodilation(FMD) in brachial artery].
AB  - We have established a clinical routine method for evaluating the endothelial
      function in forearm circulation in humans. Flow-mediated vasodilation(FMD) was
      used as the endothelium-dependent and the response to nitroglycerin(NTG) as the
      endothelium-independent vasodilation. Diameter of the brachial artery was
      measured by high-frequency ultrasonographic imaging before and after hyperemia
      following artery occlusion. Because vasodilation reached the maximal level when
      the artery was occluded for 5 min, this time was selected as the occlusion time.
      FMD was greater (12 vs 9%) after upper-arm occlusion than after forearm
      occlusion. The peak time to maximal vasodilation was 50 sec after forearm
      occlusion and 70 sec after upper-arm occlusion. During NO synthesis inhibitor
      infusion, vasodilation after forearm occlusion was abolished, whereas that after
      upper-arm occlusion was attenuated by half. Therefore, the mechanisms for FMD may
      differ by occlusion position. The response to NTG was attenuated by aging. FMD
      was significantly decreased by coronary artery disease and coronary risk factors
      such as hypertension, hyperlipidemia and diabetes, but the response to NTG was
      not changed by these diseases. These measurements may offer useful tools for
      assessment of endothelial function.

PMID- 15027321
TI  - [A novel cDNA array method for detecting the chimeric genes in human leukemia].
AB  - Advanced molecular diagnostics in hematological malignancy have provided us with
      a broad assortment of new assays and techniques. We have developed a simple cDNA
      microarray method for detecting the chimeric genes in human leukemia. The method,
      based on the biotin-avidine reaction, is performed with color development. The
      oligotip we have developed is indicated by simple and highly sensitive data. By
      analyzing with this method, we can obtain useful information about the subtype of
      chimeric genes in leukemia.

PMID- 15027322
TI  - [Genotyping and the quantification of hepatitis C virus by the melting curves in
      light cycler].
AB  - Detection of the HCV genome is crucial for diagnosis of HCV infection and for
      monitoring the efficacy of interferon treatment for patients with HCV. We
      developed a convenient screening test for HCV genotypes 1 and 2 based on the
      melting curve analysis with SYBER green I. Serum samples were drawn from 114
      patients with known chronic HCV infection confirmed to be antibody-positive by
      immunoblot assay. A characteristic melting profile for each genotype was obtained
      by monitoring the fluorescence as the temperature increases through the melting
      point of the PCR product. Serum samples with HCV-RNA genotype (1b, 2a and 2b)
      were analyzed every test as standard samples and the genotype of unknown samples
      was determined by the comparison with the melting point of standard samples.
      Serum samples with known HCV-RNA genotype (1b, 2a and 2b) and HCV-RNA-negative
      sample were tested using the Light cycler system. The melting curve analysis
      indicated that melting points are 93.08 +/- 0.56 degrees C for genotype 1b (n =
      63), 91.08 +/- 0.49 degrees C for genotype 2a (n = 33), and 91.77 +/- 0.28
      degrees C for genotype 2b (n = 18). The melting points for genotypes 1b, 2a, and
      2b differed by approximately 1 degree C in each other. The genotype was
      determined for all samples using Okamoto's method and Light cycler system, and
      both systems produced absolutely identical results for all the samples studied.
      Sixty-three of 114 were genotype 1b, 33 samples were genotype 2a, and 18 were
      genotype 2b. This melting curve analysis is a rapid and convenient screening test
      for differentiation of HCV genotypes 1 and 2.

PMID- 15027323
TI  - [Development of flow cytometric method to detect antisense oligonucleotides
      delivery into human platelets: the significance in thrombocytopenia].
AB  - Antisense oligonucleotides act to hybridize with RNA in a sequence-related manner
      and to modulate the selective translation in living cells. Antisense
      oligonucleotides are expected to be potential therapeutic agents toward desired
      molecular targets. However, little efforts have been made to realize the use of
      antisense oligonucleotides as powerful laboratory markers for detecting selective
      transcriptional levels. We describe here that FITC-labeled antisense for 18S
      ribosomal RNA were delivered into human platelets which were countable with flow
      cytometry. In healthy volunteers, the FITC positive platelets were 2% of PECD42b
      positive platelets. The rate was not affected by reaction time of 20 to 360 min
      and by reaction temperature at 4, 37 degrees C, or room temperature. The FITC
      positive rate was unchanged in final concentrations of both 10(-6) and 10(-5) M
      of FITC-labeled antisense. However, the rate was three times higher in patients
      with thrombocytopenia. There was a significant negative relationship between
      platelet count and FITC positive rate. FITC-labeled antisense for c-Mpl mRNA were
      more sensitive than that for 18S ribosomal RNA. These results suggest that
      fluorescence-labeled antisense oligonucleotides might be potential laboratory
      tool to reveal the distribution of RNA containing cells in the population.

PMID- 15027324
TI  - [Coagulopathy with autoantibodies to blood-clotting factors: overview and
      laboratory diagnosis].
AB  - The acquired inhibitors of blood clotting-factors are immunoglobulins that
      directly inhibit clotting factors or accelerate their clearance from circulation.
      The majority of inhibitors are directed against factor VIII, which arises
      spontaneously in healthy elderly, postpartum women, patients with autoimmune
      disorders or malignancy, and those with various underlying disorders. The most
      common initial symptom is bleeding into the skin or muscles spontaneously or
      caused by minor trauma, which sometimes extends to cause severe anemia. Those
      with acquired hemophilia may not receive a first consultation by a hematologist,
      resulting in delayed laboratory diagnosis. The activated partial thromboplastin
      time (APTT) of the hemophilia patient's plasma is prolonged, and is not corrected
      by mixing with normal plasma for 2 hours. The mixing test provides suggestive
      evidence of a factor VIII inhibitor, but can not distinguish lupus anticoagulant.
      Although the factor VIII activity of plasma is remarkably low, the activities of
      other intrinsic clotting factors can also be reduced apparently in the one-stage
      assay. A quantitative inhibitor measurement assay is required to confirm that the
      inhibitor acts specifically on factor VIII.

PMID- 15027325
TI  - [Functional role of dopamine D3 receptor in schizophrenia].
AB  - Since D3 receptors are highly localized in the limbic brain, which is closely
      linked to the positive symptoms of schizophrenia and cognition or emotional
      functions of the brain, the role of D3 receptors on schizophrenia has been
      intensively studied. Although a part of the D3 receptors acts as an autoreceptor,
      a majority of the autoreceptor function is attributed to D2 receptors, and D3
      receptors play only a modulatory role. Relatively selective D3 agonists and
      antagonists showed an opposite effect between low and high dose. This phenomenon
      is explained by the fact that these drugs act on D3 receptors at a low dose but
      also on D2 receptors at a high dose. Although most antipsychotics have moderate
      affinities to D3 receptors, no consistent results were obtained on the effects of
      chronic administration of antipsychotics on D3 receptors. No consistent findings
      were reported on the D3 receptors in the postmortem brain of the schizophrenic.
      Recent meta-analysis studies showed a weak but significant association between D3
      receptor polymorphism and schizophrenia. These studies suggest that the
      antipsychotics with some antagonistic profiles to D3 receptors can be promising
      atypical antipsychotics, which cause no prolactin secretion or extrapyramidal
      side effects.

PMID- 15027326
TI  - [Functional role of dopamine D4 receptor in schizophrenia].
AB  - D4 is the last receptor cloned among D2 receptor subtypes. Since clozapine has a
      high affinity to D4 receptors that exist abundantly in the hippocampus and
      frontal cortex, it is expected that the atypical clinical profiles of clozapine
      are associated with its blocking action to D4 receptors. Although D4 receptor
      functions have not been fully investigated, cognitive function of the brain may
      be associated with D4 receptors. D4 antagonists have only a weak inhibitory
      effect on the hyperactivity elicited by psychostimulants but induce no catalepsy
      or prolactin secretion. Previous positive studies on the elevation of the D4
      receptors in the striatum of schizophrenia as well as on the association between
      D4 receptor polymorphism and schizophrenia have been followed by negative
      findings. Two D4 antagonists (L-745,879 and fananserine) failed to show clinical
      efficacy in schizophrenia. One of the major difficulties in D4 research is that
      no selective D4 ligands are available. Although D4 receptors may not play a major
      role in schizophrenia, they are expected to have a certain effect on
      frontotemporal function, such as cognition and negative symptoms of
      schizophrenia.

PMID- 15027328
TI  - Parkinsonism induced by atypical neuroleptics in a patient with severe iron
      deficiency.
AB  - Although still controversial, iron deficiency has been indicated as one of the
      risk factors for developing neuroleptic-induced extrapyramidal symptoms (EPSs),
      including akathisia, dystonia, and neuroleptic malignant syndrome. Here we report
      our experience of iron supplementation and alternating neuroleptics for treating
      Parkinsonism in a schizophrenic female patient having severe iron deficient
      anemia.

PMID- 15027327
TI  - [Effect of concurrent treatment of SSRI on the tyrosine hydroxylase
      immunoreactivity in the rat locus coeruleus treated with chronic variable
      stress].
AB  - Locus coeruleus (LC) is the major component of noradrenergic neurons in the
      brain. corticotropine-releasing hormone (CRH) and norepinephrine (NE) are
      suggested to play significant roles in the pathophysiology of depression,
      although the involvement of the serotonergic system in the CRH-NE systems is not
      elucidated. Chronic inescapable and unpredictable stress can result in a
      sustained dysregulation of both of CRH and NE systems. In the present study we
      have investigated the TH immunoreactivity in the LC by immunohistochemical
      staining in rats treated with chronic variable stress (CVS) and concurrent
      administration with clomipramine or fluvoxamine. There was a significant decrease
      in TH levels 24 h after the last stressor of CVS, followed by a further decrease
      in that of 72 h later, whereas a marked increase was observed in TH levels
      immediately after the last stress of CVS 13 d. Concurrent clomipramine and
      fluvoxamine treatment prevented the sensitization of TH reactivity and the
      delayed decrease until 72 h later. These data suggest that an increase in
      serotonin availability would contribute to the normalization of both hypoactivity
      and sensitization of LC-NE neurons modified under "chronically stressful"
      situations.

PMID- 15027329
TI  - [The human dihydropyrimidinase-related protein 2 (DRP-2) gene on chromosome 8p21
      is associated with paranoid-type schizophrenia].
AB  - The dihydropyrimidinase-related protein (DRP) family, also called the collapsin
      response mediator protein, is implicated in the developmental process of the
      nervous system. Dysfunction of DRPs may result in neurodevelopmental
      abnormalities, which have been assumed to be a possible factor in the
      pathogenesis of schizophrenia. It has been reported that in humans, the
      expression of one member of the DRP family, DRP-2, is decreased in the brains of
      individuals with schizophrenia. In addition, the DRP-2 gene is located on
      chromosome 8p21, a region that has been implicated in schizophrenia in genetic
      linkage studies. We investigated a genetic association between five polymorphisms
      of the DRP-2 gene and schizophrenia in the Japanese population. The *2236T > C
      polymorphism in the 3' untranslated region (3'UTR) exhibited significant
      differences with respect to the distribution of the genotype and allele in
      patients compared with controls. The frequency of the *2236C allele was
      significantly higher in controls than in patients with schizophrenia (P = 0.0097)
      and patients with paranoid-type schizophrenia (P = 0.0083). These results suggest
      that the *2236C allele in the 3'UTR of the DRP-2 gene, or an unknown mutation in
      linkage disequilibrium with this allele, may reduce the susceptibility to
      schizophrenia, especially the paranoid subtype.

PMID- 15027330
TI  - [Diagnostics and clinical significance of esophageal metastasis of adenocarcinoma
      of the gastroesophageal junction].
AB  - PATIENT AND METHODS: 174 patients who had cardiac adenocarcinoma were examined in
      the endoscopic laboratory of the Surgical Department between March 1, 1994 and
      October 29, 2002. In the course of the endoscopic examinations intramural
      metastases were found in 19 patients (10.9%). Of the patients with esophageal
      metastasis, five had type 1 tumor, 10 had type 2 tumor, and 4 had type 3 tumor of
      the Siewert-Stein categorization. 16 of the patients were male, 3 were female.
      Seven patients had only one metastasis in the oesophagus, in the other patients
      the number of metastases varied between 2-5. Surgical intervention: in 4 out of
      the 19 patients no surgical intervention was performed, because they had extended
      metastases. In 4 patients a tube was inserted surgically, 1 patient had
      gastrostomy, 1 patient had explorative laparotomy, and another patient had
      diagnostical laparoscopy. Eight patients had gastric and esophageal
      resection/gastrectomy for palliative reason. RESULTS: Survival data of six
      patients out of the 19 were not evaluated, because in 1 case there was a
      postoperative complication, and in five patients the time passed since the
      diagnosis was too short. Mean survival time: 1/ patients with tube insertion:
      128.25 days; 2/ no-intervention cases: 248 days; 3/ after the gastrectomy: 164
      days; 4/ after the explorative laparotomy: 180 days; 5/ after diagnostic
      laparoscopy: 108 days. 6/ after gastric and esophageal resection/gastrectomy: 474
      days (211 days the shortest, 723 days the longest). In case of those patients,
      who underwent resection, the survival was longer and the quality of life was
      better than in the other groups. CONCLUSIONS: 1. The intramural esophageal
      metastases of the cardiac adenocarcinomas are detectable by a routine endoscopic
      examination and confirmed by histological investigation. 2. Esophageal metastases
      of cardiac adenocarcinomas occur in all the three types of the Siewert-Stein
      classification. 3. The metastasis on the oesophagus means a developed stage of
      the tumor. 4. The proper therapy--although it can only be palliative--will
      increase the survival time of acceptable quality for the patient. 5. There was no
      significant difference in the survival time of patients after the removal of
      different types of Siewert-Stein tumors.

PMID- 15027331
TI  - [Current pharmacotherapy of schizophrenia].
AB  - Second generation antipsychotics have become the standard of modern
      pharmacotherapy of schizophrenia. Amisulprid, clozapine, olanzapine, quetiapine,
      risperidone, sertindol, ziprasidone are the second generation antipsychotics
      registered in Hungary. They are more efficacious and their side effects are less
      stigmatizing than those of the first generation of antipsychotic drugs. Their use
      is limited by the availability of different formulations, by the lack of
      experience of some physicians, however the main limitation is the economic
      barrier.

PMID- 15027332
TI  - [New therapeutic possibilities for uncontrolled bleeding].
AB  - Recombinant factor VIIa (rFVIIa) enhances the haemostasis limited to the site of
      injury without systemic activation of the coagulation cascade. rFVIIa has been
      found to enhance thrombin generation in impaired coagulation and thrombocyta
      function. rFVIIa has been successfully used to treat uncontrolled nontraumatic,
      traumatic, surgical and thrombocytopenic bleeding. Authors present the cases of
      three pediatric patients, who received rFVIIa in order to reduce the uncontrolled
      traumatic, surgical, nontraumatic thrombocytopenic and coagulopathic bleeding.
      Based on the data of literature authors present the supposed, complex mechanism
      of rFVIIa and the experiences connected with clinical use.

PMID- 15027333
TI  - [Stent graft implantation for aneurysm of thoracic aorta with involvement of the
      origin of left subclavian and carotid arteries].
AB  - Development in endovascular surgery made it possible to treat thoracic and
      abdominal aortic aneurysm by using catheter techniques. In 1990, Parodi performed
      the first unilateral stentgraft implantation after which a rapid progress
      commenced in this field. Since middle nineties, bifurcated stentgrafts have been
      brought into general use. In Hungary, stentgraft implantations have been
      performed in certain centers since 1999. The authors demonstrate a case operated
      on at the Department of Vascular Surgery, University of Pecs for aneurysm of
      thoracic aorta with involvement of the origin of left subclavian and carotid
      arteries. In order to maintain the flow in left carotid artery, right to left
      carotico-carotid interposition was shaped, then stentgraft implantation was
      carried out for the thoracic aneurysm. Preoperative investigations, surgical
      technique and postoperative follow up are discussed in this case report.

PMID- 15027334
TI  - [Epidemiologic study of the psychological health and risk behaviors of medical
      students].
AB  - INTRODUCTION AND AIMS: In the present study the authors conducted a cross
      sectional study of fourth-year (eighth-semester) students at Semmelweis
      University, to assess their stress-related complaints, and also some of the more
      common forms of risk behavior, including smoking, regular alcohol consumption,
      past or current drug use and the regular use of pharmaceuticals. METHODS: A total
      of 410 students were evaluated; 263 medical students, 96 pharmaceutical students
      and 78 dentistry students. An adapted version of Anderson's questionnaire was
      used for the evaluation of the total burden of stress based on emotional,
      physical and work-related complaints. Respondents who mentioned more than three
      signs of increased stress involving any of the above three categories (emotional,
      physical and work-related) were designated "high risk" subjects. RESULTS: The
      overall prevalence of "high risk" subjects was 30.5% (29.7% in medical, 38.5% in
      pharmaceutical and 23.1% in dentistry students) with no significant gender
      differences. 55.2% of "high risk" subjects had over three complaints in only one
      category, 32.6% in two categories, and 12.2% in all three categories. 43.6% of
      the subjects experienced work-related complaints, 33.3% of them had emotional and
      23.1% had physical complaints. The overall prevalence of various forms of risk
      behavior was found to be 19.3% for smoking (25.2% in males and 15% in females),
      30.2% for regular alcohol intake (47.1 in males and 18.3% in females), 25.4% for
      the regular use of some kind of medication (14.7% in males and 33.0% in females)
      and 24.9% for those who admitted to previous drug-use (37.6% in males and 16.3%
      in females). CONCLUSION: All forms of risk behavior were more common in the "high
      risk" group, but only smoking and the regular use of medication were increased
      significantly. There were no differences in risk behavior prevalence with regards
      to a particular category of complaints.

PMID- 15027335
TI  - [Guidelines for writing biomedical articles containing statistical figures and
      analysis].
AB  - Some advices are provided in order to make statistical figures and analyses more
      correct in biomedical articles. The sample size has an outstanding significance.
      Analysing different statistical relationships the requirements of biometry should
      be fulfilled (number and distribution of data etc.) and interpretation of
      statistical findings could be done only within the domain of minimal and maximal
      values of independent variable. Extrapolation is not recommended due to the
      specific nature of the biomedical system. In some cases laboratory data should be
      transformed mathematically and the results of subsequent statistical calculations
      should be retransformed back into the biomedical system.

PMID- 15027336
TI  - [Different histological findings in two specimens from pulmonary metastasectomy
      in the same patient].
AB  - INTRODUCTION: Out of the 3310 thoracic surgical procedures performed between 1980
      and 2000 at the Department of Surgery of the National Institute of Oncology in
      Budapest, 258 were pulmonary metastasectomies involving 236 patients. Primary
      tumors were the following in order of decreasing frequency: testicular cancer,
      colorectal cancer, renal cancer, soft tissue tumor, breast cancer and others.
      METHODS: In the present study the authors report two patients with multiple
      pulmonary metastases. The primary tumor was non-seminoma testicular cancer in
      case one and endometrial cancer in case two (previously treated for thyroid
      cancer). Histological examination of resected specimens revealed unsuspected
      focal inactive tuberculosis in the first case and medullary thyroid cancer in the
      second. CONCLUSIONS: In the reported two cases the following conditions of
      metastasectomy were given: 1. satisfactory cardiopulmonary status, 2. possibility
      of surgical radicality, 3. locoregional disease control, 4. prior chemotherapy in
      chemosensitive tumor (case one). The generally accepted condition of
      metastasectomy-lack of clinically manifest disease in other distant organs--was
      not fulfilled in case two (suspected liver metastases).

PMID- 15027338
TI  - Drug-seeker lists are dangerous at best, require tight administrative controls.
AB  - It is extremely risky to keep lists of people who show up frequently in your ED
      seeking drugs, and the lists may not accomplish much anyway. If you allow staff
      or physicians to keep such lists, you should establish tight controls. Lists can
      pose confidentiality concerns. Never use a list before a patient is properly
      screened. Take a hard-line approach with obvious drug seekers to diminish repeat
      visits.

PMID- 15027337
TI  - [Treatment of celiac disease].

PMID- 15027339
TI  - Satisfaction climbs with smiles, other soft skills.
AB  - Patient satisfaction can be improved with more attention to interpersonal skills
      and catering to the concerns that most patients have about emergency care. Staff
      may resist the idea at first but can be convinced to try it. Simple things such
      as how a nurse talks to a patient have a significant effect. Managers should role
      model the changes they want. The environment of the waiting room and other areas
      also is important.

PMID- 15027340
TI  - 'Gridlock page' helps clear crowded ED.
AB  - Overcrowding in the ED starts in other areas of the hospital. Alert those areas
      and ask for help when the patient load is increasing. Page other departments to
      alert them to your patient load. Ask physicians to round earlier than usual and
      discharge patients. Seek ways to improve efficiency in other departments.

PMID- 15027341
TI  - Making the magnet commitment.
AB  - With a nursing shortage upon us, hospitals are seeking American Nurses
      Credentialing Center's Magnet designation as a way to recruit and retain staff.
      This article outlines the steps involved in achieving this prestigious award.
      Emphasis is placed on the role nursing staff development plays in fulfilling
      Magnet standards and participating in the application process.

PMID- 15027342
TI  - Evidence-based practice. The role of staff development.
AB  - Knowledge and use of evidence-based practice are essential to ensure best
      practices and safe patient outcomes. Staff development specialists must be
      leaders in this initiative to support clinical nurses toward improved practice
      outcomes. This article describes the background for understanding the historical
      evolution from research utilization to evidence-based practice, defines some key
      concepts related to evidence-based practice, and suggests essential components
      for building evidence-based practice programs in healthcare institutions.

PMID- 15027343
TI  - Refresher course for inactive RNs facilitates workforce reentry.
AB  - A refresher course developed in conjunction with a local community college has
      been successful in facilitating workforce reentry by inactive and retired RNs.
      Support of the program by the hospital and exposure to the hospital during the
      clinical practicum, has reaped benefits as the majority of participants have
      sought employment upon completion of the course.

PMID- 15027344
TI  - Beyond the classroom. Teaching staff to manage cardiac arrest situations.
AB  - Teaching staff members how to manage cardiac arrest situations effectively can be
      accomplished through a well-executed plan. An interdisciplinary task force
      researched the situation and identified educational opportunities to resolve the
      problem. Based on the task force's recommendations, a plan was developed for
      educational programs and mock code implementation. The educational programs were
      structured to meet the needs of the nursing staff, but other resuscitation team
      members were encouraged to attend. These mock codes were in all patient care
      areas, on a rotational basis, and attended by all resuscitation team members. A
      point system was created to evaluate the effectiveness of the program. A steady
      rise in points has been noted since the start of the program. This program has
      promoted staff comfort, improved patient outcomes, and strengthened the
      interdisciplinary approach to hospital resuscitations.

PMID- 15027345
TI  - New graduates in critical care. The success of one hospital.
AB  - The cycles of registered nurse (RN) shortage and surplus continues into the new
      century, and nurse executives, managers, and staff development educators are
      under extreme pressure to respond to the staffing issues. Specialty areas in
      hospitals are typically the first to experience fewer than needed RNs. The
      purpose of this article is to describe how the managers, staff development
      educators, and staff of one large public hospital created a training program for
      new graduate RNs so they could function safely and efficiently in the adult
      intensive care environment.

PMID- 15027346
TI  - Creating a cultural shift. A gerontological enrichment program for acute care.
AB  - As the number of older adults in acute care rises, acute care specialty nurses
      must gain gerontological knowledge in their nursing practice with older patients.
      A blend of two bodies of knowledge and competencies is required to care
      effectively for older adults in the hospital. To this end, a gerontological
      enrichment program was developed to improve care to hospitalized older patients
      by augmenting acute care nurses competencies with gerontological skill,
      knowledge, and abilities. This article will explain the implementation details,
      the anticipated outcomes for nurses and older acutely ill patients, the
      evaluation process, and the strategies that are in place to maintain the gains.

PMID- 15027347
TI  - Staff educator RNs. Delivering unit-based education to bedside caregivers.
AB  - In an effort to enhance educational support to nursing service personnel at the
      unit level, administrators at Central DuPage Hospital in Winfield, IL, have
      created the staff educator RN position. The staff educator RN for each nursing
      unit is charged with coordinating and implementing all unit-based educational
      activities to meet assessed educational needs. This article describes the
      development of the staff educator RN role as well as rewards and challenges
      related to this role.

PMID- 15027348
TI  - [Analysis of living motor nerve ending of a frog by endocytotic fluorescent
      marker FM 1-43].
AB  - In our experiments on motor nerve endings of the frog cutaneous pectoris muscle,
      using fluorescent marker FM 1-43, the intensity and topography of endocytosis
      were investigated after the initiation of massive exocytosis of synaptic vesicles
      by increasing the extracellular potassium concentration. Using FM 1-43,
      fluorescent spots were shown to appear, looking as accumulations of synaptic
      vesicles in the active zone region. The forms and sizes of luminous spots and the
      distances between them were analysed. Considerable variations in brightness and
      total areas of fluorescent spots per a length unit in different regions of the
      nerve ending were revealed in addition to a proximal-distal gradient of these
      parameters along the nerve terminal. Peculiarities of topography and intensities
      of luminescence in the most terminal regions of the nerve ending are described.
      The obtained data are discussed in terms of the exo- and endocytosis cycle of
      synaptic vesicles in the active zone region, and from the point of view of the
      plasticity of the motor nerve ending and active zones. The factors involved in
      the transmitter release nonuniformity are analysed.

PMID- 15027349
TI  - [Isolation and characterisation of continuous human embryonic stem cell lines].
AB  - A long-term cultivation (5-8 months) of human blastocyst-derived embryonic cells
      (hES) was performed. Several properties of hESs were examined to prove the state
      of continuous cell lines. These cells have passed through 100-175 population
      doublings with the average population doubling time equal to 37.0 +/- 1.5 h.
      Isolated hESs, referred to as HESC-1, HESC-2, HESC-3, HESC-4, cultivated on
      mitotically inactivated mouse embryonic fibroblasts (STO continuous cell line),
      formed multilayer colonies of various shape. The cells maintained stable
      proliferative activity, high activity of alkaline phosphatase and expression of
      transcription factor Oct4, and all this characterizes embryonic stem cells of
      different origin. Expression of hES specific cell surface antigens (SSEA-3, SSEA
      4, TRA-1-81 and TRA-11-81 and TRA-1-60) was confirmed by immunofluorescence
      analysis with the corresponding monoclonal antibodies. An additional prove for
      species specificity of HESC lines is the lack of expression of mouse specific
      surface antigen SSEA1. The cell cycle of HESC-1 undifferentiated cells and
      embryoid bodies was analysed cytofluorimetrically.

PMID- 15027351
TI  - [The nucleoli matrix proteins with molecular masses 40 and 27 kDa are transported
      as peripheral chromosomal material].
AB  - Using immunofluoresence method, sera M-311 and K-30 obtained from patients with
      autoimmune disease were shown to stain interphase nuclei and the periphery of
      chromosomes. Western blotting revealed a polypeptide with mol. mass 27 kDa in
      serum K-30. Both proteins were localized in the karyoplasm. One of them (27 kDa)
      has a diffuse form and contains small granules, while the other (40 kDa) is in
      the form of small clearly outlined granules. Both proteins are also revealed
      around the nucleolar periphery, making a continental ring, while the main part of
      the nucleolus remains unstained. During pro- and metaphase, these proteins were
      associated with the chromosomal periphery: 27 kDa protein formed separate groups,
      and 40 kDa protein was seen over the whole chromosomal periphery. After nuclear
      and chromosomal decondensation, induced by hypotonic treatment (15% of culture
      medium solution), both antibodies stain diffusively interphase nuclei, but in
      mitotic cells they stained the surface of the swollen chromosomes. After
      chromatin recondensation in isotonic medium these proteins were localized
      similarly as in normal cells. Thus, both proteins maintained their association
      with the periphery of chromosomes. To reveal the nuclear protein matrix, cells
      were treated with 2M NaCl, DNAase and RNAase A. After this procedure, the
      antibodies stained only the nucleolar periphery, and no fluorescence in the
      karyoplasm was seen. It shows that of all the components of the nuclear protein
      matrix (lamina, internuclear network, residual nucleoli) only 27 and 40 kDa
      proteins are contained in the nucleolar rim. The data allow to suggest that the
      nucleolar matrix proteins may be transported to new cell nuclei as part of the
      peripheral chromosomal material likely as other nucleolar (fibrillarin, B-23, and
      others) or some non-nuclear components of the nuclear protein matrix are
      transported.

PMID- 15027350
TI  - [Cytopathological effects of protein synthesis inhibitor emetine on HeLa cells
      and their nucleoli].
AB  - Eukaryotic cell nucleolus is a highly dynamic structure, which is sensitive to
      all changes within or outside cell borders. Numerous data are available on
      changes of the nucleolar structure and functions under different treatments.
      However, almost nothing is known about the action of translation inhibitors on
      the nucleolus, although these substances, together with TNF-alpha, are commonly
      used for apoptosis induction, both for scientific and therapeutic purposes.
      Emetine is one of such inhibitors. We have shown that emetine suppresses cell
      viability, decreases mitotic index, and induces apoptosis in HeLa cells. Emetine
      action is irreversible, and it sensitizes cells to unfavourable external
      conditions. The emetine action causes redistribution of UBF, one of RNA
      polymerase I factor, from the nucleolus to nucleoplasm even after a short
      exposure, i.e. when the morphology of the nucleus and chromatin still keeps its
      native pattern. It is important that other nucleolar proteins, such as
      fibrillarin and B23, are not recognized in the nucleoplasm until the very late
      stages of apoptotic process. A suggestion is made that changes in UBF
      localization may be associated with the onset of ribosomal repeat cleavage and
      migration of rDNA-"free" fragments from the nucleolus to nucleoplasm. It looks
      likely that these changes can serve as an initial morphological indication of
      apoptosis.

PMID- 15027352
TI  - [Functional specialization of the nuclei in tip-growing coenocytic algae
      Vaucheria sessilis].
AB  - The availability of numerous nuclei in coenocytic thalli creates a problem of
      their activity and division cycle coordination. An apparent random distribution
      of nuclei in tip-growing cells is regulated by some principles associated with
      physiological compartmentalization in the absence of true septae. In vegetative
      thallome of Vaucheria sessilis the nuclei are distributed equally in proximal
      parts, to be accumulated in a high density cluster in the apical zone. The
      cluster appears in the course of germination in the late phase as a result of
      nuclear migration in a forming branch. The treatment with (methyl-3H)-thymidine
      and (5-3H)-uridine revealed the functional specialization of nuclei. The most
      active accumulation of thymidine was observed at early phases of germination in
      the nuclei of aplanospore. Proportionally with the growth of the new branch, the
      nuclei migrate into it, and the most active DNA replication zone moves to the
      filament base. At the late phases of morphogenesis, when the apical cluster of
      nuclei is available, thymidine accumulation is observed only in the proximal
      parts of a vegetative branch, rather far from the apical zone. The most active
      uridine accumulation was registered in the base of a forming filament at early
      morphogenesis, and in aplanospore at late phases. The apical cluster of nuclei is
      characterized by a low transcription level and the absence of replication. The
      obtained results have demonstrated that in the course of morphogenesis the
      equipotent nuclei acquire some specialization depending on their position in the
      thallome. The nuclei migrating via the cytoplasm toward the basal part of a
      filament are able to divide and actively transcript their own genome. The nuclei
      in the aplanospore at early phases of germination may predominantly realize the
      division cycle. The nuclei in the apical cluster, with a special organization of
      the cytoskeleton net, lose their ability to divide and migrate, and lack the
      ability to transcript a proper genome. The space delimination of the growth zone
      and a zone of division, as well as a functional specialization of nuclei can be
      considered as some basic characters of the apical growth.

PMID- 15027353
TI  - [Analysis of transient G1/S arrest in E1A+E1B-19kDa transformed cells after
      ionizing radiation].
AB  - Expression of human adenovirus type 5 E1A oncogene in normal rodent cells leads
      to disruption of the G1/S cell cycle arrest realization in response to DNA
      damage. It has been shown here that rat embryo fibroblasts transformed by E1Aad5
      oncogene in complementation with E1B-19 kDa gene realize the irradiation-induced
      transient G1/S arrest, which depends on selective suppression of CyclinE-Cdk2
      activity despite functional inactivation of p21Waf1 inhibitor. Inhibitor p21Waf1
      is not revealed in complexes with cyclins E and A in E1A + E1B-19 kDa
      transformants, however, it is not due to p21Waf1 interaction with E1A
      oncoproteins, because the E1A-p21Waf1 complex formation in E1A + cHa-ras
      transformants does not prevent the high level of CycIE, A-p21Waf1 association. In
      the case of p21Waf1 inactivation, the main way of cyclin-kinase activity
      regulation in E1A + E1B-19 kDa cells may be Cdk2 phosphorylation. However,
      irradiation of E1A + E1B-19 kDa transformed cells induces no changes in CAK (Cdk7
      associated) kinase activity and in the protein level of Cdc25A phosphatase, which
      are responsible for activating Thr160 phosphoralation and Tyr15 dephosphorylation
      on Cdk2. Using phospho-Tyr15-Cdk2 specific antibodies, no increase of
      phosphorylation at Tyr15 position on immunoprecipitated Cdk2 was detected after
      irradiation. It seems likely that in the case of inactivated inhibitor p21Waf1
      the transient G1/S block after irradiation in E1A + E1B-19 kDa transformants
      depends on suppression of Cycl-E-Cdk2 activity caused by inhibition of Thr160
      Cdk2 phosphorylation, but his occurs with the involvement of other kinases rather
      than CAK.

PMID- 15027354
TI  - [Recognition of internal (TTAGGG)n repeats by telomeric protein TRF1 and its role
      in maintenance of chromosomal stability in Chinese hamster cells].
AB  - Mammalian telomeres contain long tandem (TTAGGG)n repeats, which are protected by
      a complex of different proteins. Telomeric repeat-binding factors TRF1 and TRF2
      play the key role in protection of telomeres through the formation of terminal
      loops (called T-loop). A T-loop isolates the 3' strand telomeric end and with
      this mechanism protects telomeres from the influence of enzymes of DNA reparation
      and telomere fusions and also interferes with the interaction of telomerase with
      telomeres. Many vertebrate species also contain large blocks of (TTAGGG)n
      sequences in pericentric and interstitial chromosome bands. The Chinese hamster
      genome contains a total of 18 arrays of these non-telomeric internal (TTAGGG)n
      sequences (ITs). Chromosome bands containing these arrays are unstable and should
      be protected with the help of another mechanism, rather than that using
      telomeres. In this study we analysed association of Green Fluorescent Protein
      (GFP)-tagged TRF1 in Chinese hamster V79 cells with ITs. We found that in these
      cells GFP-TRF1 associates with ITs in the interphase nucleus. We detected a
      little overlap between IT-associated GFP-TRF1 and random DSB sites visualized
      after the treatment of V79 cells with ionizing radiation. We found that the
      treatment of V79 cells with WM significantly increases the frequency of
      spontaneous chromosome aberrations. These WM effects are possible due to
      inhibiting phosphorylation of TRF1 by ATM. TRF1 is known to be eliminated from
      telomeres by overexpression of TANK1, which induces TRF1 poly(ADP-ribosyl)ation.
      We transfected V79 cells by plasmid encoding TANK1 and found that the frequency
      of chromosome rearrangements increased in these cells independently of their
      treatment by IR. Taken together, our results suggest that TRF1 may be involved in
      the sequence-specific protection of internal non-telomeric (TTAGGG)n repeats.

PMID- 15027356
TI  - Initial steps of infection of the ciliate Paramecium with bacteria Holospora sp.
AB  - New light and electron microscope data on the initial steps of endocytobiosis
      establishment between the ciliate Paramecium and specific intranuclear bacteria
      Holospora are provided. At the cytoplasmic step of infection bacteria of all
      Holospora species are found in a vesicle originating from the membrane of the
      host cell phagosome. The association between host cell microfilaments and the
      bacterium bearing vesicle may suggest a possible involvement of the ciliate
      cytoskeleton in the transportation of bacteria to the host cell nucleus. The
      authors subdivide the process of infection into 6 steps. Some strains of P.
      caudatum never take up infectious Holospora bacteria in the course of
      phagocytosis.

PMID- 15027355
TI  - [Identification of chlamydia and (or) chlamydia-like microorganisms by light
      microscopy confirmed by electron microscopy and fluorescent in situ
      hybridization].
AB  - Using light microscopy, we have shown that chlamydia and/or chlamydia-like
      microorganisms are registered in 20-25% of the healthy part of human population,
      whereas in patients of the same age with gynecological problems these were found
      in 40-50%. Commonly, the infection was slightly manifested (less than 5% of cells
      are infected). These results were confirmed in four months but only in heavily
      infected patients. The light microscope data are confirmed by observations with
      electron microscopy, and by FISH hybridization of the total chlamydial DNA on
      cytological preparations with chlamydial inclusions. In some cases, microcolonies
      revealed by FISH hybridization occupied the majority of the cytoplasm volume.
      Occasionally, the DNA material was found on the nuclear surface. It seems likely
      that in heavily infected cells chlamydia are able to penetrate into the
      perinucular space.

PMID- 15027357
TI  - [Localization of NADPH diaphorase in central nervous system of the chiton
      Leptochiton assimilis in normal conditions and during hypoxia].
AB  - By light and electron microscope histochemical and cytochemical methods, the
      localization and activity of NADPH-diaphorase (NADPH-d) were studied in the
      central nervous system (CNS) of the chiton in control and after hypoxia. After
      acute hypoxia, the enzymatic activity increased in all regions of CNS. At a
      chronic hypoxia, the activity of NADPH-d decreased to remain, however, higher
      than in control. Ultrastructural studies confirmed the availability of structural
      changes in neurons, and shifts in the activity of NADPH-d in control and in
      experimental mollusks. The elevated enzymatic activity revealed in this study may
      be due to the fact that these mollusks have been evolutionary adapted to a
      periodical oxygen deficiency.

PMID- 15027361
TI  - [Forty million persons in the world "live" with AIDS].

PMID- 15027364
TI  - [Tai Chi Chuan and personnel development].

PMID- 15027366
TI  - [From pain and suffering to the patient's quality of life].

PMID- 15027365
TI  - [Pharmaceutic information for nursing].

PMID- 15027367
TI  - [Quality of life, towards autonomy, integrity and dignity?].

PMID- 15027369
TI  - [Engagement and positioning of nursing professionals for quality of care].

PMID- 15027368
TI  - [From measurement of health to resource allocation, ambiguous quality of life
      indicators].

PMID- 15027370
TI  - [Quality of life implications in the discipline of nursing care].

PMID- 15027371
TI  - [Job satisfaction in nursing personnel].

PMID- 15027373
TI  - [Which quality of life for palliative care?].

PMID- 15027372
TI  - [Work quality of life in nursing personnel in France].

PMID- 15027374
TI  - [Last intense moments of happiness].

PMID- 15027376
TI  - [Researching the sense of nursing practices].

PMID- 15027377
TI  - [Addiction note. 10/10 Work].

PMID- 15027375
TI  - [Life projects, quality of life in two institutions].

PMID- 15027378
TI  - [Psychological care. 3/10 Loss, grief, dysfunctional sadness].

PMID- 15027379
TI  - [Nursing standard for managing patients with ulcus cruris: a manifold disease
      picture].

PMID- 15027380
TI  - [Sexuality and nursing: a taboo needs its place in routine practice].

PMID- 15027381
TI  - [Vascular access for hemodialysis: the connection for life].

PMID- 15027382
TI  - [Loss of excretory function--a psychosocial problem: more than just a body
      function].

PMID- 15027383
TI  - [Developing nursing standards for AEDL "excretion" management: not allowing daily
      practice to become routine].

PMID- 15027384
TI  - [Help for self-hel in incontinence: "not covering up problems, uncovering them
      instead" (interview by Katrin Balzer].

PMID- 15027385
TI  - [Blind spot in nursing: elderly = incontinent--an inevitable fate?].

PMID- 15027386
TI  - [Continence nursing visit: strategies to combat helplessness].

PMID- 15027388
TI  - [The Nursing Data Project in Switzerland: making nursing care visible].

PMID- 15027387
TI  - [Shame inducing situations in nursing: some times words fail.....]].

PMID- 15027389
TI  - [Presentation of statistica data 2--Circular diagrams: whatthe eye does not see].

PMID- 15027390
TI  - [Using music in postoperative nursing: between day and dream].

PMID- 15027391
TI  - [Forming questions in the hospital: totally in white? or: the dialysis unit in
      rural house design].

PMID- 15027392
TI  - [From case to case: Mrs P. alone at home].

PMID- 15027393
TI  - [Learning in ambulatory nursing: nursing in a different manner].

PMID- 15027394
TI  - [Sequelae of updating the nursing legislation from the viewpoint of targeted
      faculty].

PMID- 15027395
TI  - How involved are we in patient involvement?

PMID- 15027396
TI  - Patient safety.

PMID- 15027397
TI  - Taking sleep seriously.

PMID- 15027398
TI  - Higher level practice in nursing: the making of a profession.

PMID- 15027399
TI  - An army field hospital in Iraq.

PMID- 15027400
TI  - COPD guidelines to reflect changes.

PMID- 15027401
TI  - Gastro-oesophageal reflux disease.
AB  - Part two of this article on GORD examines investigations and treatment options
      once the initial diagnosis of the condition has been made and focuses on the role
      that nurses can play in helping patients with this condition.

PMID- 15027402
TI  - Changing manual-handling practice in a stroke rehabilitation unit.
AB  - Patients who have had a stroke are often unable to support their full weight when
      moving. Recent guidelines on patient handling stress the risk of injury to
      nurses' backs if they lift patients or support their body weight. Nurses in one
      stroke rehabilitation unit who used a 'pivot' transfer had to reconsider their
      practice and explore other options for moving patients.

PMID- 15027403
TI  - Recognising and treating the causes of chronic malodorous wounds.
AB  - Malodorous wounds are not only debilitating to patients physically, they can also
      cause them major social problems. It is therefore crucial for practitioners to
      recognise problem wounds at the earliest opportunity and to undertake a holistic
      assessment of the patient and the wound, with a view to initiating an appropriate
      management plan to resolve the underlying causes.

PMID- 15027404
TI  - Helping patients with Crohn's disease to stop smoking.
AB  - Evidence shows that Crohn's disease in cigarette smokers runs a more aggressive
      course. Two nurses worked in collaboration to identify smokers with Crohn's
      disease in order to offer pharmacological and psychological support in quitting
      the habit. This paper provides the results of a pilot study on a smoking
      cessation course targeted specifically at such patients.

PMID- 15027405
TI  - Achieving a safer health service: Part 3. Investigating root causes and
      formulating solutions.
AB  - The third paper in our series describes the National Patient Safety Agency's
      approach to investigation, root-cause analysis and significant event audit. When
      should an investigation be high level and when should it be low level? What does
      this mean, and how can lessons be translated into safety solutions in local
      areas? Central initiatives such as patient-safety alerts are also examined.

PMID- 15027406
TI  - Patients as teachers: the patient's role in improving cancer services.
AB  - The NHS Plan stipulates that health care in the 21st century should reflect the
      needs and expectations of local people, offer greater choice and involve patients
      in the planning and provision of services. This paper describes an initiative to
      involve users of cancer services in educating health-care professionals because
      patients are the experts on their condition.

PMID- 15027407
TI  - Managing the problem of pain in adolescents with sickle cell disease.
AB  - Sickle cell disease can be particularly painful during adolescence for several
      biomedical and psychosocial reasons that lead to an increase in the number of
      vaso-occlusive episodes. These can cause pain and tissue damage. Nurses must be
      aware of the range of pharmacological and psychological approaches available to
      help these patients.

PMID- 15027408
TI  - Issues relating to effective pain management in young people.
AB  - Adolescents deserve the same standards of pain management as children and adults.
      But to achieve this, health professionals need to consider additional
      psychological and philosophical issues in this age group. This paper examines how
      adolescent development impacts on pain assessment and areas such as capacity and
      consent, and concordance to treatment.

PMID- 15027409
TI  - Be prepared: how to take the fear out of giving a presentation.
AB  - A significant part of the nurse's role involves communicating with others and
      nurses need to be effective and confident communicators. Whether presenting at a
      conference to hundreds of people, or in the workplace to a dozen colleagues,
      there are several strategies that can help you prepare and deliver your message
      well, whatever the circumstances.

PMID- 15027410
TI  - Patient information: Part 5. Quality standards and evaluation.
AB  - In the final paper in this series on producing patient information, we look at
      how to ensure that the information you have created is of high quality by using
      tools designed for the purpose. Piloting your document and disseminating and
      evaluating the final product are also discussed.

PMID- 15027411
TI  - Long-term effects of prenatal morphine exposure on maternal behaviors differ from
      the effects of direct chronic morphine treatment.
AB  - Previous studies have demonstrated that chronic morphine treatment of pregnant
      rats alters maternal behavior. Other studies have shown long-term effects of
      prenatal exposure to morphine, including changes in reproductive behavior in
      adult females. The present study investigated the effects of prenatal morphine
      exposure on a variety of maternal behaviors such as nursing, maternal activities,
      nonmaternal activities, and pup retrieval. Prenatal morphine exposure increased
      active and decreased passive nursing. There were no differences in maternal
      activities such as presence in the nest, contact with pups, grooming of pups,
      and/or manipulation of nest shavings. In the retrieval test, prenatally morphine
      exposed mothers were faster in carrying the first pup, retrieving the first pup
      back to the nest, and returning all pups to the nest than prenatally saline
      exposed mothers. Maternal and nonmaternal activities also were affected by the
      light: dark cycle. All saline- and morphine-exposed mothers nursed more, were
      more often in the nest, and more often in contact with greater than half of their
      litter during the light than the dark sessions. On the other hand, nonmaternal
      activities increased during the dark sessions: Mothers cared for themselves
      (groomed, ate) more and displayed more rearing and sniffing. Mothers spent more
      time resting with their eyes closed during the light sessions regardless of
      prenatal drug exposure. The present study demonstrated that the effect of
      morphine on maternal behavior is different in adult exposed and prenatally
      exposed mothers. While direct morphine treatment impaired maternal behaviors,
      prenatal morphine exposure has the opposite effect.

PMID- 15027412
TI  - Oral compression activity on a surrogate nipple in the newborn rat: nutritive and
      nonnutritive sucking.
AB  - Newborn rats, 3 hr after birth and before any experience in suckling, were
      exposed for 10 min to a surrogate nipple providing milk. One hour later, they
      were exposed to an empty nipple for another 10-min period. The basic
      characteristics of oral behavior (oral compression activity, OCA) were assessed
      by recording intranipple pressure during the pups' first attachment to a nipple.
      The peculiarities of milk-induced changes of OCA were examined with three modes
      of milk delivery (milk infusions, and intermittent and continuous milk
      deliveries). The pattern of OCA exerted by the newborn pups on a surrogate nipple
      consisted of rhythmic oscillations within a frequency range of 0.4 to 1.0 Hz
      superimposed on slow (frequency < 0.2 Hz), irregular intranipple pressure
      fluctuations. Oral behavior during the first minute after oral capture of the
      nipple differed significantly from that during any subsequent 1-min interval in
      terms of frequency content of OCA. The pattern of OCA changes induced by milk
      infusions or intermittent milk delivery included an abrupt rise in intranipple
      pressure, accompanied or followed by a burst of fast nipple compressions (bites).
      Our data suggest that newborn rats attached to a surrogate nipple demonstrate
      patterns of oral behavior that simulate, in terms of basic frequency
      characteristics, patterns of nutritive and nonnutritive suckling observed in more
      mature pups on the maternal nipple.

PMID- 15027413
TI  - Effects of redundant and nonredundant bimodal sensory stimulation on heart rate
      in bobwhite quail embryos.
AB  - Research with both animal embryos and human infants has provided evidence that
      information presented redundantly and in temporal synchrony across sensory
      modalities (intersensory redundancy) can guide selective attention, perceptual
      learning, and memory during early development. How this facilitation is achieved
      remains relatively unexamined. This study examined the effects of redundant
      versus nonredundant bimodal stimulation on a measure of physiological arousal
      (heart rate) in bobwhite quail embryos. Results show that quail embryos exposed
      to concurrent but nonredundant auditory and visual stimulation during the late
      stages of incubation exhibit significantly elevated heart rates following
      stimulus exposure and during stimulus reexposure when compared to embryos exposed
      to redundant and synchronous audiovisual stimulation, unimodal auditory
      stimulation, or no supplemental prenatal sensory stimulation. These findings
      indicate a functional distinction between redundant and nonredundant bimodal
      stimulation during early development and suggest that nonredundant bimodal
      stimulation during the prenatal period can raise arousal levels, thereby
      potentially interfering with the attentional capacities and perceptual learning
      of bobwhite quail. In contrast, intersensory redundancy appears to foster arousal
      levels that facilitate selective attention and perceptual learning during
      prenatal development.

PMID- 15027414
TI  - Early recognition of newborn goat kids by their mother: II. Auditory recognition
      and evidence of an individual acoustic signature in the neonate.
AB  - The vocal recognition of newborn kids by their mother at 2 days postpartum and
      the possible existence of interindividual differences in the voice structure of
      newborn kids were investigated in two separate studies. The ability of goats to
      discriminate between the bleats of their own versus an alien kid was tested at 2
      days postpartum in mothers being prevented access to visual and olfactory cues
      from the young. Goats spent significantly more time on the side of the enclosure
      from which their own kid was bleating, looked in its direction for longer, and
      responded more frequently to the bleats of their own than to those of the alien
      kid (p < 0.05). In the second study, the sonograms of 13 kids, studied from Days
      1 to 5, showed significant interindividual differences for the five variables
      taken into account and on each of the 5 days (duration of bleat, fundamental
      frequency, peak frequency, and numbers of segments and of harmonics). The
      potential for individual coding ranged between 1.1 and 4.1, indicating that for
      some variables variations between individuals were greater than intraindividual
      variations. Furthermore, when considering the five parameters together, the
      discriminating scores showed an average of 95% in the 78 combinations of any 2
      kids for any given day. Finally, some significant intraindividual differences
      also were found between days, suggesting ontogenic changes in the characteristics
      of the kid's voice in early life. Therefore, mother goats are likely to recognize
      the vocalizations of their 48-hr-old kids, as they show sufficient
      interindividual variability to allow the existence of individual vocal
      signatures, even though some of the characteristics of the bleats change rapidly
      over time.

PMID- 15027415
TI  - Similarities in affiliation and aggression between cross-fostered rhesus macaque
      females and their biological mothers.
AB  - In female-bonded primate species, there is cross-generational consistency in
      female affiliative and aggressive behavior. This consistency could be the result
      of maternal effects, offspring learning, shared environment, and/or direct
      genetic inheritance of behavioral or psychological traits. In this study, I
      investigated possible similarities in affiliation and aggression between cross
      fostered rhesus macaque females and their biological mothers. Ten female infants
      were cross-fostered at birth, and selected aspects of their affiliative and
      agonistic behavior over the course of their first 3 years of life were compared
      to the behavior of their foster and biological mothers. Average offspring rates
      of social contact and aggression across the 3 years, and in particular in Years 2
      and 3, resembled those of their biological mothers whereas no clear behavioral
      similarities between offspring and foster mothers were observed at any age.
      Heritable variation in female social behavior may be maintained by natural
      selection and leads to adaptation to different socioecological niches within
      macque populations.

PMID- 15027416
TI  - Infant hand-use preferences for grasping objects contributes to the development
      of a hand-use preference for manipulating objects.
AB  - Twenty-five infants, divided into three approximately equal groups according to
      their hand-use preference for reaching for and grasping objects (right, left, or
      no-preference), were videotaped at 7 and 11 months while involved in a semiplay
      activity in which they were presented with 26 toys (20-40 s for each
      presentation). Unimanual manipulation activity was coded, and the increase or
      decrease in preferred hand use across the two ages was analyzed. Infants with a
      right preference for reaching showed an increase in right-hand use for unimanual
      manipulatory actions from 7 to 11 months. Infants with a left preference for
      reaching showed an increase in left-hand use whereas infants with no preference
      for reaching showed a modest increase in the use of the right hand. These results
      support a modified progressive lateralization theory, which posits that a hand
      use preference for reaching for and grasping objects will concatenate during
      development into a hand-use preference for manipulating objects.

PMID- 15027417
TI  - Deterministic and stochastic processes in children's isometric force variability.
AB  - This study examined the influence of deterministic and stochastic processes
      (including white Gaussian noise) on reductions in the amount of force output
      variability through childhood. The structure of the force signal produced during
      a constant isometric pinch grip task was examined as a function of age (6, 8, and
      10 years, and young adults), availability of feedback information (with and
      without vision), digit (thumb and index finger), and force level (5, 15, 25, and
      35% of maximal voluntary contraction). The amount of white Gaussian noise in the
      force signals was negligible and not age related. The availability of vision led
      increasingly over the older age groups to lower long-range correlations with more
      than a single scaling range in a 1/f-like decay process. The reductions in the
      amount of force variability from childhood to adulthood were related in large
      part to deterministic organization that increased the adaptive use of higher
      frequency components, due to the more flexible use of information feedback and
      feedforward processes.

PMID- 15027418
TI  - Peer rejection, temperament, and cortisol activity in preschoolers.
AB  - In this study, we examined a model that describes both direct and indirect
      pathways between children's temperament and activity of the hypothalamic
      pituitary-adrenal (HPA) axis when children are in peer-group settings. We
      hypothesize that in peer-group settings both shy, inhibited and exuberant,
      undercontrolled children would exhibit higher cortisol levels, but these
      associations would operate through different pathways. Sociometric measures of
      peer rejection, salivary cortisol, and teacher reports of temperament were
      collected on 82 preschoolers. Children who were rejected by classmates had higher
      cortisol levels than the other children. The combination of Surgency and Poor
      Effortful Control (Effortful Control, reverse scored) was associated with
      elevated cortisol through a pathway mediated by aggressive interactions with
      peers and peer rejection. With the indirect path explained, the combination of
      Surgency and Poor Effortful Control also was directly and negatively associated
      with classroom cortisol levels. These results help explain why temperament
      associations with HPA activity have been variable and difficult to discern when
      children are assessed in peer-group contexts. In these contexts, both direct and
      indirect pathways between temperament and cortisol need to be examined.

PMID- 15027419
TI  - A neuroimaging method for the study of threat in adolescents.
AB  - Little is understood about the brain basis of anxiety, particularly among youth.
      However, threat paradigms with animals are delineating the relationship between
      anxietylike behaviors and brain function. We adapted a threat paradigm for
      adolescents using functional magnetic resonance imaging. The aim was to examine
      amygdala activation to fear. The threat was an aversive air blast directed to the
      larynx. Participants were explicitly informed that they might receive the air
      blast when viewing one stimulus (threat condition) and would not receive the
      blast when viewing the other stimulus (safe condition). Participants provided
      fear ratings immediately after each trial. Based on the relatively mild nature of
      the air blast, we expected participants to report varying degrees of fear. Those
      who reported increased fear showed right amygdala activation during the threat
      condition and left amygdala activation in the safe condition. These procedures
      offer a promising tool for studying youth with anxiety disorders.

PMID- 15027420
TI  - Induction of maternal behavior in adult female rats following chronic morphine
      exposure during puberty.
AB  - The peripubertal period in the female rat is the time when the stimulatory
      effects of opioids on prolactin (PRL) secretion develop. In the adult rat, the
      administration of chronic high-dose morphine has been shown to attenuate the
      ability of opiates to stimulate PRL secretion. One function of PRL in adult
      virgin rats is the induction of maternal behavior. The present study examined
      whether chronic high-dose morphine exposure during the peripubertal period alters
      PRL-mediated induction of maternal behavior in adult female rats. Two groups of
      juvenile female rats were administered increasing doses of morphine or vehicle
      (s.c.) from age 30 to 50 days. As adults, these females either remained intact,
      or were ovariectomized and treated with a PRL-dependent, steroid hormone regimen
      that stimulates a rapid onset of maternal behavior. All females were then exposed
      daily to rat foster pups to determine whether peripubertal morphine exposure
      affected their latencies to induce maternal behavior. Morphine treatment resulted
      in a delay in vaginal opening and a temporary reduction in the rate of weight
      gain; however, the rate of onset of maternal behavior was unaffected by
      peripubertal morphine treatment. Thus, chronic morphine exposure in the pubertal
      female did not impact the expression of pup-induced maternal care.

PMID- 15027421
TI  - Neurochemical correlates of sparing from motor deficits in rats depleted of
      striatal dopamine as weanlings.
AB  - The behavioral and neurochemical effects of striatal DA depletions were
      investigated in rats lesioned as weanlings (Day 27) or as adults (250-300 g).
      Administration of 6-OHDA into the medial forebrain bundle resulted in comparably
      large (> or = 95%) depletions of tissue levels of DA in both age groups. As
      expected, rats depleted of DA as adults exhibited marked deficits in motoric
      behavior and body weight regulation that persisted for the 8 days of postsurgical
      observation. In contrast, rats depleted of DA as weanlings were spared from such
      deficits, and their behavior closely resembled that of age-matched controls.
      Microdialysis studies revealed dialysate levels of striatal DA that paralleled
      these age-dependent behavioral differences. At a time when age-related behavioral
      differences were still quite pronounced (5-6 days postsurgery), basal DA levels
      were reduced by 80% of control values in rats lesioned as adults whereas basal DA
      levels in rats lesioned as weanlings were unchanged relative to their controls.
      Finally, adults depleted of striatal DA as weanlings were no more sensitive to
      the movement-impairing effects of intrastriatal sulpiride (3.0 or 10.0
      micrograms/hemisphere) infusions than were control rats. These data suggest that
      weanlings compensate for large, but incomplete, denervation of striatal DA with
      markedly enhanced release and turnover from residual terminals. This
      developmental plasticity may prevent the occurrence of behavioral deficits soon
      after the lesion and also the supersensitivity to the challenging effects of DA
      antagonists as animals grow into adulthood.

PMID- 15027422
TI  - Getting what we should from doctors: rethinking patient autonomy and the doctor
      patient relationship.

PMID- 15027423
TI  - Adolescent competency and the refusal of medical treatment.

PMID- 15027424
TI  - Midwifery: strategies on the road to universal legalization.

PMID- 15027425
TI  - Telemedicine reimbursement: raising the iron triangle to a new plateau.

PMID- 15027426
TI  - Schroeder Lecture. Gaps and inequities in America's health care system.

PMID- 15027427
TI  - Cruel but not unusual punishment: the failure to provide adequate medical
      treatment to female prisoners in the United States.

PMID- 15027428
TI  - Environmental genomics, the big picture?
AB  - The enormous sequencing capabilities of our times might be reaching the point of
      overflowing the possibilities to analyse data and allow for a feedback on where
      to focus the available resources. We have now a foreseeable future in which most
      bacterial species will have an annotated genome. However, we know also that most
      prokaryotic diversity would not be included there. On the one hand, there is the
      problem of many groups not being easily amenable to culture and hence not
      represented in culture-centred microbial taxonomy. On the other hand, the gene
      pools present in one species can be orders of magnitude larger than the genome of
      one strain (selected for genome sequencing). Contrasting with eukaryotic genomes,
      the repertoire of genes present in one prokaryotic cell genome does not correlate
      stringently with its taxonomic identity. Hence gene catalogues from one
      environment might provide more meaningful information than the classical species
      catalogues. Metagenomics or microbial environmental genomics provide a different
      tool that gravitates around the habitat rather than the species. Such a tool
      could be just the right way to complement "organismal genomics". Its potential to
      advance our understanding of microbial ecology and prokaryotic diversity and
      evolution is discussed.

PMID- 15027429
TI  - HIPAA and what institutional review boards (IRBs) do not have to review.

PMID- 15027430
TI  - Interviews that do not require review by IRBs.

PMID- 15027431
TI  - Abortion and in vitro fertilization.

PMID- 15027432
TI  - Abortion as murder?: a response.

PMID- 15027434
TI  - A suggested solution to the trolley problem.

PMID- 15027433
TI  - Parenting ethics and reproductive technologies.

PMID- 15027435
TI  - Some moral issues in the correction of impairments.

PMID- 15027437
TI  - Removal of peri-gastric fat prevents acute obstruction after Lap-Band surgery.
AB  - BACKGROUND: Acute postoperative gastroesophageal obstruction is a potential
      complication after laparoscopic adjustable gastric banding (LAGB). Utilizing the
      pars flaccida technique may increase the incidence due to the incorporation of
      perigastric fat, particularly in patients with greater visceral obesity. Removal
      of peri-gastric fat pads may be necessary to avoid postoperative obstruction. We
      present our experience of 267 LAGB operations using the LapBand System and the
      incidence of postoperative obstruction, before and after incorporating routine
      removal of peri-gastric fat pads. METHODS: A retrospective review of a
      prospective database of 267 consecutive Lap-Band placements between July 2001 and
      November 2002 was conducted. RESULTS: All operations were completed
      laparoscopically using the pars flaccida technique, and all patients underwent
      esophagogram the morning after surgery. From July 2001 to May 2002, 143 Lap-Band
      placements were performed, with 11 patients (8%) having abnormal postoperative
      esophagograms. There were 43 males/100 females with mean BMI 48.3 (range 35 to
      78.9). Complete esophageal obstruction was seen in 5 of these patients, all of
      whom underwent laparoscopic revision. Significantly delayed emptying was seen in
      the 6 remaining patients, who were managed conservatively with intravenous fluids
      from 2-7 days. In these 11 patients, there were 6 males/5 females with mean BMI
      47.1 (range 37.3-57.9). Subsequently, removal of peri-gastric fat pads was
      routinely performed during Lap-Band placement. From June 2002 to November 2002,
      there were 43 males/81 females with mean BMI 48 (range 35-79); these 124 Lap-Band
      placements were performed with no abnormal postoperative esophagograms.
      CONCLUSION: Routine removal of peri-gastric fat pads when using the pars flaccida
      technique for Lap Band surgery appears to prevent postoperative esophageal
      obstruction.

PMID- 15027438
TI  - Increased body mass index and peri-operative risk in patients undergoing non
      cardiac surgery.
AB  - BACKGROUND: Increased BMI is a well known risk factor for morbidity and mortality
      in hospitalized nonsurgical patients. However, the published evidence for a
      comparable effect in surgical patients is scarce. METHODS: This retrospective
      study was designed to assess the attributable effects of increased BMI (>30
      kg/m2) on outcome (hospital mortality, admission to the intensive care unit
      (ICU), and incidence of intraoperative cardiovascular events (CVE)) in patients
      undergoing non-cardiac surgery by a computerized anesthesia record-keeping
      system. The study is based on data-sets of 28065 patients. Cases were defined as
      patients with BMI >30; controls (BMI 20-25) were automatically selected according
      to matching variables (ASA physical status, high risk and urgency of surgery, age
      and sex) in a stepwise fashion. Differences in outcome measures were assessed
      using univariate analysis. Stepwise regression models were developed to predict
      the impact of increased BMI on the different outcome measures. RESULTS: 4726
      patients (16.8%) were found with BMI >30. Matching was successful for 41.5% of
      the cases, leading to 1962 cases and controls. The crude mortality rates were
      1.1% (cases) vs 1.2% (controls); P =0.50, power=0.88). Admission to ICU was
      deemed necessary in 6.8% (cases) vs 7.5% (controls), P =0.42, power=0.65, and CVE
      were detected from the database in 22.3% (cases) vs 21.6% (controls), P =0.30,
      power=0.60. Using logistic regression analyses, no significant association
      between higher BMI and outcome measures could be verified. CONCLUSION: Increased
      BMI alone was not a factor leading to an increased perioperative risk in non
      cardiac surgery. This fact may be due to an elevated level of attention while
      caring for obese patients.

PMID- 15027439
TI  - Sex between people with "mental retardation": an ethical evaluation.
AB  - Is sex between people with "mental retardation" [1] morally permissible and, if
      at all, under what conditions? This paper tries to answer this question, but only
      with regard to sex between biologically mature individuals with mild or moderate
      mental retardation. First, the concepts of "sexual activity" and mental
      retardation" are analysed briefly, which is challenging given the widely
      divergent and sometimes rather awkward definitions of these concepts. On the
      basis of this analysis, it is argued that the liberal principle of mutual
      consent, if taken as a necessary condition of permissible sex, has unacceptable
      consequences for people with mental retardation. Many forms of sex between them
      would be morally impermissible, given the fact that their limited powers of
      practical reasoning will often make valid consent well-nigh impossible. As an
      alternative to the liberal principle of permissible sex, conditions are specified
      that include the additional consent of caretakers. If people with mental
      retardation do not have the capacities of practical deliberation required for
      valid consent, care providers with mature reasoning powers should act as their
      substitutes. Finally, some important implications for the moral education of
      future care professionals are spelled out.

PMID- 15027440
TI  - A sex police for adults with "mental retardation"? Comment on Spiecker and
      Steutel.
AB  - This article is a rebuttal of the claim by Spiecker and Steutel that sex between
      people with mild and moderate "mental retardation" is morally permissable only
      with the substitutive consent of caregivers. After a review of historical,
      empirical and practical considerations, an ethical analysis is undertaken which
      concludes that Spiecker and Steutel's arguments are deeply flawed and their
      proposed policy morally objectionable.

PMID- 15027441
TI  - Rights not restrictions for learning disabled adults: a response to Spiecker and
      Steutel.
AB  - What follows is a response to an article by Spiecker and Steutel in which they
      pose the question of whether sex between people with "mental retardation" (sic)
      is morally permissible and in which they argue that since many such people cannot
      give "valid consent", the additional consent of caretakers may be required.
      However, we argue that the term "mental retard" is offensive and that either the
      UK terminology ("the learning disabled") or the internationally accepted term
      ("intellectually disabled") are more acceptable. Moreover, we point out that
      Spiecker and Steutel are mistaken. Many "learning disabled" people can and do
      give "valid consent". In any case, their question is itself dubious. Why should
      two learning disabled people who want to have sex together need anyone else's
      consent? In addition, we briefly address the rights of the learning disabled to
      the same sexual freedom as others, on the one hand, and to freedom from sexual
      exploitation on the other hand. Finally, we consider the implications of these
      issues for moral education. We suggest that carers need to develop empathy and,
      where necessary, advocacy skills. We point to the existence of training
      programmes on sexuality and protection issues.

PMID- 15027442
TI  - Reasonable paternalism and the limits of sexual freedom: a response to Greenspan
      and Leicester and Cooke.
AB  - This response argues that Greenspan's comment is basically incoherent, and that
      the position taken by Leicester and Cooke has unacceptable practical
      consequences. Greenspan admits that many people with 'mental retardation' lack
      adult decision-making capacities, but at the same time assumes that they have
      these very capacities in assigning them freedom rights. Leicester and Cooke
      consistently argue that people with 'mental retardation' do have adult reasoning
      powers and therefore should be given freedom rights. But this point has the
      rather disquieting implication that both the practice of treating 'mental
      retardation' as an exempting condition and the practice of giving them important
      special welfare rights seem to loose their justification.

PMID- 15027443
TI  - The defining issues test and the four component model: contributions to
      professional education.
AB  - This article reviews studies examining the effect of professional education on
      ethical development. Most studies limit assessment to the measurement of moral
      judgement, observing that moral judgement plateaus during professional school
      unless an ethics intervention is present. Whereas interventions influence the
      shift to postconventional reasoning (the DIT P score), a more illuminating
      picture of change may emerge if researchers examined DIT profiles. More
      importantly, limiting assessment to measures of moral judgement ignores important
      aspects of moral functioning suggested by the Four Components Model. Assessment
      methods have been validated for sensitivity, role concept and ethical
      implementation that could be adapted to provide individuals in a particular
      profession with a more complete picture of abilities needed for real-life
      professional practice.

PMID- 15027444
TI  - Halakhic considerations.

PMID- 15027446
TI  - Past its sell-by date.

PMID- 15027447
TI  - Partners in time.

PMID- 15027445
TI  - Physicians, information technology, and health care systems: a journey, not a
      destination.

PMID- 15027448
TI  - Bovine spongiform encephalopathy: the importance of precautionary measures to
      protect the food supply.

PMID- 15027449
TI  - MAP kinase signaling in diverse effects of ethanol.
AB  - Chronic ethanol abuse is associated with liver injury, neurotoxicity,
      hypertension, cardiomyopathy, modulation of immune responses and increased risk
      for cancer, whereas moderate alcohol consumption exerts protective effect on
      coronary heart disease. However, the signal transduction mechanisms underlying
      these processes are not well understood. Emerging evidences highlight a central
      role for mitogen activated protein kinase (MAPK) family in several of these
      effects of ethanol. MAPK signaling cascade plays an essential role in the
      initiation of cellular processes such as proliferation, differentiation,
      development, apoptosis, stress and inflammatory responses. Modulation of MAPK
      signaling pathway by ethanol is distinctive, depending on the cell type; acute or
      chronic; normal or transformed cell phenotype and on the type of agonist
      stimulating the MAPK. Acute exposure to ethanol results in modest activation of
      p42/44 MAPK in hepatocytes, astrocytes, and vascular smooth muscle cells. Acute
      ethanol exposure also results in potentiation or prolonged activation of
      p42/44MAPK in an agonist selective manner. Acute ethanol treatment also inhibits
      serum stimulated p42/44 MAPK activation and DNA synthesis in vascular smooth
      muscle cells. Chronic ethanol treatment causes decreased activation of p42/44
      MAPK and inhibition of growth factor stimulated p42/44 MAPK activation and these
      effects of ethanol are correlated to suppression of DNA synthesis, impaired
      synaptic plasticity and neurotoxicity. In contrast, chronic ethanol treatment
      causes potentiation of endotoxin stimulated p42/44 MAPK and p38 MAPK signaling in
      Kupffer cells leading to increased synthesis of tumor necrosis factor. Acute
      exposure to ethanol activates pro-apoptotic JNK pathway and anti-apoptotic p42/44
      MAPK pathway. Apoptosis caused by chronic ethanol treatment may be due to ethanol
      potentiation of TNF induced activation of p38 MAPK. Ethanol induced activation of
      MAPK signaling is also involved in collagen expression in stellate cells. Ethanol
      did not potentiate serum stimulated or Gi-protein dependent activation of p42/44
      MAPK in normal hepatocytes but did so in embryonic liver cells and transformed
      hepatocytes leading to enhanced DNA synthesis. Ethanol has a 'triangular effect'
      on MAPK that involve direct effects of ethanol, its metabolically derived
      mediators and oxidative stress. Acetaldehyde, phosphatidylethanol, fatty acid
      ethyl ester and oxidative stress, mediate some of the effects seen after ethanol
      alone whereas ethanol modulation of agonist stimulated MAPK signaling appears to
      be mediated by phosphatidylethanol. Nuclear MAPKs are also affected by ethanol.
      Ethanol modulation of nuclear p42/44 MAPK occurs by both nuclear translocation of
      p42/44 MAPK and its activation in the nucleus. Of interest is the observation
      that ethanol caused selective acetylation of Lys 9 of histone 3 in the hepatocyte
      nucleus. It is plausible that ethanol modulation of cross talk between
      phosphorylation and acetylations of histone may regulate chromatin remodeling.
      Taken together, these recent developments place MAPK in a pivotal position in
      relation to cellular actions of ethanol. Furthermore, they offer promising
      insights into the specificity of ethanol effects and pharmacological modulation
      of MAPK signaling. Such molecular signaling approaches have the potential to
      provide mechanism-based therapy for the management of deleterious effects of
      ethanol or for exploiting its beneficial effects.

PMID- 15027450
TI  - Reforming European community food law: putting quality back on the agenda.

PMID- 15027451
TI  - The hang-up with HACCP: the resistance to translating science into food safety
      law.

PMID- 15027452
TI  - The Food and Drug Administration's import alerts appear to be "misbranded".

PMID- 15027453
TI  - Potential legal barriers to increasing CMS/FDA collaboration: the law of trade
      secrets and related considerations.

PMID- 15027454
TI  - Prescription drug advertising--should states regulate what is false and
      misleading?

PMID- 15027455
TI  - The final sampling regulations of the Prescription Drug Marketing Act are alive
      and well: is your sampling program compliant?

PMID- 15027456
TI  - Therapeutic orphans, pediatric victims? The Best Pharmaceuticals for Child Act
      and existing pediatric human subject protection.

PMID- 15027457
TI  - Compulsory licensing to regulated licensing: effects on the conflict between
      innovation and access in the pharmaceutical industry.

PMID- 15027458
TI  - Commentary: can we talk? About Food and Drug Regulation and the First Amendment.

PMID- 15027459
TI  - French researchers at boiling point.

PMID- 15027460
TI  - Laboratory blow for research plans.

PMID- 15027462
TI  - From biological analysis to synthetic biology.

PMID- 15027461
TI  - Geoffrey North.

PMID- 15027463
TI  - Genetic code.

PMID- 15027464
TI  - Differences in DNA methylation patterns between humans and chimpanzees.

PMID- 15027465
TI  - Morphogenesis: shroom in to close the neural tube.
AB  - A novel actin-binding protein, Shroom, localises to precisely those cells that
      will constrict during cranial neural tube closure and appears pivotal in
      regulating the apical constrictions that drive epithelial foldings in vertebrate
      embryos.

PMID- 15027466
TI  - Vertebrate organogenesis: getting the heart into shape.
AB  - Recent mutant analysis in zebrafish points to an important role for oriented cell
      division in cardiac chamber formation and reveals its molecular control by a
      novel signal from the heart's interior.

PMID- 15027467
TI  - Neuronal networks: dissection one channel at a time.
AB  - Researchers working on neuronal networks are increasingly taking advantage of the
      ability to overexpress particular molecular components such as channels. What
      hope do such studies hold for understanding neuronal phenotype and its role in
      network function?

PMID- 15027468
TI  - Muscle differentiation: a gene for slow muscle?
AB  - Skeletal muscle comes in two fundamental flavours, slow and fast, which determine
      physiological performance. Zebrafish screens have provided a handle on the
      molecular mechanism driving slow muscle formation. The transcriptional repressor
      Blimp1 has now been shown to be required in embryonic slow muscle precursor
      cells.

PMID- 15027469
TI  - Molecular motors: kinesin's interesting limp.
AB  - An ingenious new experiment used a form of kinesin with one slow head and one
      fast head to demonstrate definitively that this motor protein moves along a
      microtubule using alternating left and right steps.

PMID- 15027470
TI  - Par proteins: partners in polarization.
AB  - Proteins can be localized either by inclusion or exclusion, and the Par polarity
      proteins illustrate both mechanisms. Cdc42 recruits Par-6 to a limited region of
      the plasma membrane. Par-6 recruits Par-3, which is actively removed from other
      regions by Par-1 and Par-5. Inclusion and exclusion together ensure efficient
      segregation of the polarity proteins.

PMID- 15027471
TI  - Lipid metabolism: ceramide transfer protein adds a new dimension.
AB  - Just as non-lipidologists were becoming reconciled to the complexities of
      networks of ceramide metabolism and the diverse roles of ceramide in cell
      regulation and membrane structure, a new study reveals a new layer of regulation
      of ceramide through the actions of a ceramide binding/transfer protein.

PMID- 15027472
TI  - Neuronal development: putting motor neurons in their place.
AB  - In the developing spinal cord, motor neurons occupy discrete columns with
      different identities and axon projections. This organisation has now been shown
      to depend crucially on sequential phases of expression of Hox-c proteins,
      generated in response to fibroblast growth factor signals.

PMID- 15027473
TI  - Medicaid: 10 fixes that work. Of all the reforms states have tried, these are the
      ones that hold the most promise.

PMID- 15027474
TI  - Endoscope-based treatments for gastroesophageal reflux disease.
AB  - Endoscope-based products for the treatment of more severe forms of
      gastroesophageal reflux disease provide an alternative to the use of drugs or
      surgery. Results from case series have shown that selected patients benefit
      through relief of symptoms and reduction of medication. Reported adverse effects
      appear to be minor. Efficacy has been mostly assessed over short periods and
      there is little information on comparison with other treatments. Procedural
      skills and appropriate training in their use are required. These technologies are
      promising, but their place in health care is not established.

PMID- 15027475
TI  - Endotoxin and proinflammatory cytokines modulate Sertoli cell proliferation in
      vitro.
AB  - Sertoli cells play a key role in testicular function and their final number in
      the adult testis determines the capacity of germ cell production. Sertoli cell
      proliferation, stimulated by FSH and paracrine factors, occurs only in fetal and
      prepubertal life and may be an important target of pathogenic influences
      affecting testis development. We used a Sertoli cell proliferation assay to
      address the question whether if bacterial endotoxin (lipopolysaccharide; LPS) and
      proinflammatory cytokines could influence early postnatal Sertoli cell
      development. LPS and tumor necrosis factor-alpha (TNF-alpha) dose-dependently
      stimulated proliferation of primary cultures of isolated Sertoli cells from 8- to
      9-day-old rats, assessed by (3)H-thymidine and BrdU incorporation. LPS also
      significantly increased the number of living cells in culture, measured by
      supravital staining. Interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) had no
      direct effect on Sertoli cell growth, but were found to modulate FSH action. IL-6
      increased, while IFN-gamma inhibited, FSH-induced Sertoli cell DNA-synthesis. We
      conclude that endotoxin and TNF-alpha are potent direct stimulators of Sertoli
      cell proliferation in vitro, and that IL-6 and IFN-gamma can modulate the
      mitogenic action of FSH on immature Sertoli cells. This may contribute to the
      pathogenesis of testicular damage after infections and inflammatory diseases in
      fetal and early postnatal life, with subsequent disturbance of adult germ cell
      production.

PMID- 15027476
TI  - Primate mating systems and the evolution of immune response.
AB  - White blood cell (WBC) and red blood cell (RBC) counts were examined in a sample
      comprising 762 specimens, representing 25 genera and 38 species of captive non
      human primates. Animals suffering from illnesses exhibited higher WBC counts than
      healthy specimens sampled during routine health checks. Analysis of basal WBC
      counts in healthy animals confirmed a positive correlation between higher cell
      counts and occurrences of multiple partner mating. This finding remained
      statistically significant after use of comparative analysis of independent
      contrasts (CAIC) to control for possible phylogenetic biases in the dataset.
      These findings were confirmed when using relative testis size as an independent
      index of mating system. By contrast, RBC counts were not significantly affected
      by health or correlated with mating systems. These studies confirm a correlation
      between WBC counts and primate mating systems, and extend the findings to include
      a positive correlation between WBC counts and relative testis size. However, the
      findings do not prove that a causal relationship between these variables exists.
      Further research is required to establish the evolutionary causation of basal WBC
      counts in primates.

PMID- 15027477
TI  - Lack of association of TNFalpha gene polymorphisms and recurrent pregnancy loss
      in Caucasian women.
AB  - The tumor necrosis factor alpha (TNFalpha) gene plays an important role in
      immunology and inflammation. Variant alleles of TNFalpha are associated with
      altered RNA and serum protein levels in humans. Conflicting results have been
      obtained regarding the role of TNFalpha during pregnancy and recurrent pregnancy
      loss (RPL). This study investigated the relationship between RPL and two
      polymorphisms in the promoter of the TNFalpha gene (TNFalpha -308 and -863).
      Genotyping was performed in 168 RPL women and 212 ethnically matched healthy
      individuals. In addition, we performed analysis of TNFalpha serum protein levels.
      We demonstrate that neither the polymorphism -308 nor the polymorphism -863 of
      the TNFalpha gene is associated with RPL in Caucasian women. In addition, we did
      not find any association between TNFalpha serum levels and the occurrence of RPL
      in a subset of 36 RPL women and 36 healthy individuals. We conclude that TNFalpha
      polymorphisms and resting blood TNFalpha levels do not correlate with the
      propensity to recurrent pregnancy loss in Caucasian women.

PMID- 15027478
TI  - Sherry L. Beasley named Thelma J. Neff Award winner.

PMID- 15027479
TI  - Abstracts of the South African Heart Conference. Heart failure: prevention,
      control and repair. 24-28 October 2003.

PMID- 15027480
TI  - Cancer and inflammation. Introduction.

PMID- 15027481
TI  - Inflammation and cancer: an epidemiological perspective.
AB  - Many chronic inflammatory conditions increase the risk of cancer in affected
      tissues. Clinical conditions that involve both inflammation and increased cancer
      risk include a broad range of immunological disorders, infections (bacterial,
      helminthic, viral), and chronic chemical and mechanical irritation. For example,
      the inflammatory bowel diseases, ulcerative colitis and Crohn's disease,
      predispose to the development of cancers of the large bowel and/or terminal
      ileum; chronic infection with the bacterium Helicobacter pylori causes atrophic
      gastritis, dysplasia, adenocarcinoma and an unusual form of gastric lymphoma; and
      parasitic infection with schistosomes and other trematodes cause cancers of the
      urinary bladder and the intrahepatic and extrahepatic biliary tract. Chronic
      reflux of gastric acid and bile into the distal oesophagus causes chemical
      injury, Barrett's oesophagus and oesophageal adenocarcinoma. Chronic
      cholecystitis and gallstones predispose to cancer of the gallbladder. Besides
      these clinical syndromes, subclinical inflammation may promote the development of
      certain tumours. The expression of COX-2 and lipid mediators of inflammation
      increases during the multistage progression of these tumours. Non-steroidal anti
      inflammatory drugs (NSAIDs), which inhibit COX-2 activity and tumour development
      in many experimental and clinical settings, are inversely associated with certain
      cancers in epidemiological studies. Despite their promise, however, anti
      inflammatory drugs are not yet recommended for the prevention or treatment of any
      cancers. Numerous questions must be resolved concerning their molecular and
      cellular targets of action, efficacy, safety, treatment regimen, indications, and
      the balance of risks and benefits from treatment in designated patient
      populations.

PMID- 15027482
TI  - Chemokine-based pathogenetic mechanisms in cancer.
AB  - The chemokine system has evolved primarily to control the trafficking of
      leukocytes during immune or inflammatory responses. However, through their
      expression of chemokine ligands and receptors, cancers have commandeered various
      aspects of this host defence system in order to enhance their growth. Although
      engineered over-expression of some tumour-derived chemokines can stimulate host
      antitumour respones, this is unlikely to be the reason that tumour cells express
      them. Rather, a growing body of clinical and laboratory evidence indicates that
      cancer cells may secrete chemokines in order to attract host cells that supply
      the tumours with growth and angiogenic factors. In addition, chemokine receptor
      expression by tumour cells may permit them to use the host's pre-existing
      leukocyte trafficking system to invade target tissues during metastatic spread.
      Together, these observations suggest that therapies directed against chemokine
      ligands or receptors may be beneficial in cancer.

PMID- 15027483
TI  - Anti-TNFalpha therapy of rheumatoid arthritis: what can we learn about chronic
      disease?
AB  - The importance of tumour necrosis factor (TNF)alpha in rheumatoid arthritis (RA)
      was initially proposed on the basis of analysis of cytokine gene regulation at
      the local site of the disease, the synovium. This was then verified in animal
      models and established in an extensive series of clinical trials, culminating in
      now 250000 treated patients with either of two approved TNF inhibitors, antibody
      or fusion protein. The degree and magnitude of clinical benefit has enabled
      analyses of the mechanism by which anti-TNF benefits, and hence insights into
      important steps in the disease process. It was found that essentially all aspects
      of RA were ameliorated, and important mechanisms of benefit involved diminution
      of multiple pro-inflammatory cytokines, adhesion molecules and chemokines,
      leading to reduced cell trafficking, reduced angiogenesis and most importantly
      halting of joint destruction. What of the problems? Safety is better than prior
      drugs, but there is a small increase in severe infections, smaller than might
      have been anticipated. Cost is the major drawback limiting greater use. In view
      of the central pathological processes down-regulated, and their role in many
      diseases, the early clinical success of anti-TNF in RA led to subsequent
      successful trials and registration in Crohn's disease and juvenile rheumatoid
      arthritis, and successful trials in ankylosing spondylitis, psoriasis and
      psoriatic arthritis. The era of anti-cytokine therapeutics is just dawning.

PMID- 15027484
TI  - How do chemokine/chemokine receptor activations affect tumorigenesis?
AB  - Cells that display chemokine receptors are capable of responding to a gradient of
      chemokine with a motility response that can translate into a chemotactic
      response. This continuous response to the chemokine sometimes requires that the
      chemokine receptor be internalized and recycled back to the membrane. We have
      shown that ligand activation of the CXC chemokine receptor, CXCR2, results in
      movement of the receptor into clathrin coated pits, followed by movement into the
      early endosome, the sorting endosome, then on to the recycling endosome prior to
      trafficking back into the plasma membrane compartment. Prolonged exposure to
      saturating concentrations of the ligand results in movement of a large percentage
      of the receptor into the late endosome and on to the lysosome for degradation.
      Mutation of the receptor in a manner which impairs receptor internalization by
      altering the binding of adaptor proteins AP-2 or beta arrestin to CXCR2, results
      in a marked reduction in the chemotactic response. Chemokine receptors also
      activate multiple intracellular signals that lead to the activation of the
      transcription factor, nuclear factor kappa beta (NF-kappaB). Transformation is
      often associated with a constitutive activation of NF-kappaB, leading to
      endogenous expression of chemokines and their receptors. This creates an
      autocrine loop with NF-kappaB in the activated state, and altered cxpression of
      factors that promote tumour angiogenesis and escape from apoptosis. We have shown
      that the constitutive activation of NF-kappaB in human melanoma tumours is
      accompanied by constitutive activation of the NF-kappaB inducing kinase (NIK) as
      well as the constitutive activation of AKT. As these factors that modulate the
      expression of anti-apoptotic factors work together, the tumour cells exhibit
      enhanced survival and growth. This never ending cycle of activation of NF-kappaB,
      leading to enhanced production of chemokines, enhanced activation of AKT and NF
      kappaB, and enhanced transcription of inhibitors of apoptosis and chemokines, is
      one that has been used to foster the growth of the tumour to the disadvantage of
      the host. Thus we propose that blocking CXCR2 and/or NF-kappaB offers potential
      therapeutic promise for a number of chronic inflammatory conditions and cancers,
      including malignant melanoma.

PMID- 15027485
TI  - Proinflammatory cytokines, immune response and tumour progression.
AB  - Tumour cells naturally secrete proinflammatory cytokines and chemokines to
      interact with the microenvironment and regulate neoangiogenesis. The repertoire
      of factors thus produced shapes tumour progression. However, experiments in the
      mouse have shown that injection of a low pharmacological dose of a
      proinflammatory cytokine or chemokine into the microenvironment increases the
      inflammatory reaction so enormously that locally activated leukocytes inhibit or
      eradicate the tumour. Massive shrinkage of recurrent head and neck squamous cell
      carcinomas (SCC) and prevention of recurrences after surgical removal of a
      primary SCC follow perilymphatic administration of low doses of interleukin
      (IL)2, while low daily doses of IL12 markedly delay carcinogenesis in transgenic
      mice predestined to die of mammary carcinomas and keep them tumour-free for long
      periods. The reaction elicited by proinflammatory cytokines evidently has a great
      potential in tumour control.

PMID- 15027486
TI  - Lymphangiogenesis and tumour metastasis.
AB  - The lymphatic system serves to collect and transport interstitial fluid (lymph)
      within tissues, and plays an important role in the immune response. The lymphatic
      system also constitutes one of most important pathways of tumour dissemination.
      In several human cancers, increased expression in primary tumours of a new member
      of the vascular endothelial growth factor (VEGF) family, namely VEGF-C, is
      correlated with regional lymph node metastasis. Experimental studies using
      transgenic mice overexpressing VEGF-C or xenotransplantation of VEGF-C-expressing
      tumour cells into immunodeficient mice have demonstrated a role for VEGF-C in
      tumour lymphangiogenesis and the subsequent formation of lymph node metastasis.
      However, there is at present very little evidence for lymphangiogenesis in human
      tumours, which is at variance with the data obtained in animal models.
      Nonetheless, the striking correlation between levels of VEGF-C in primary tumours
      and lymph node metastases exists. This suggests that VEGF-C may activate pre
      existing lymphatics which then become actively involved in tumour cell
      chemotaxis, intralymphatic intravasation and distal dissemination. The role of
      VEGF-C in human tumour metastasis is therefore likely to involve
      lymphangiogenesis as well as its capacity to induce activation of pre-existing
      lymphatic endothelium.

PMID- 15027487
TI  - Infiltration of tumours by macrophages and dendritic cells: tumour-associated
      macrophages as a paradigm for polarized M2 mononuclear phagocytes.
AB  - Macrophages and dendritic cells infiltrate tumours. In the tumour
      microenvironment, mononuclear phagocytes acquire properties of polarized M2 (or
      alternatively activated) macrophages. These functionally polarized cells, and
      similarly oriented or immature dendritic cells present in tumours, play a key
      role in subversion of adaptive immunity and in inflammatory circuits which
      promote tumour growth and progression.

PMID- 15027488
TI  - The influence of CD25+ cells on the generation of immunity to tumour cell lines
      in mice.
AB  - CD25+ regulatory T cells comprise 5-10% of CD4+ T cells in naive mice and have
      been shown in several in vivo murine models to prevent the induction of
      autoimmune disease and inflammatory disease. Since T cells, which mediate
      autoimmunity, can through recognition of self-antigens also target tumour cells,
      it was postulated that CD25+ regulatory cells would also inhibit the generation
      of immune responses to rumours. Depletion of these cells using CD25-specific
      monoclonal antibodies has indeed been shown to promote rejection of several
      transplantable murine tumour cell lines including melanoma, leukaemia and
      colorectal carcinoma. Results obtained using these models indicate that in the
      absence of regulatory cells, CD4+ T cells mediate tumour immunity, although the
      precise mechanisms through which these cells result in tumour rejection have not
      yet been elucidated. The target antigens recognized by these CD4+ T cells have
      also not yet been identified. Immunization of mice with tumour cells in the
      absence of CD25+ regulatory cells does, however, induce immunity against a
      variety of different tumour cell lines indicating that the target antigen(s) are
      shared amongst tumours of distinct histological origins. Since CD25+ regulatory
      cells have been identified in humans, the possibility that the cells inhibit
      immune responses to shared rejection antigens expressed by human tumours is
      worthy of investigation.

PMID- 15027489
TI  - Macrophages: modulators of breast cancer progression.
AB  - In many solid tumour types the abundance of tumour associated macrophages (TAMs)
      is correlated with poor prognosis. Macrophages are recruited through the local
      expression of chemoattractants such as colony stimulating factor 1 (CSF-1) and
      macrophage chemoattractant protein 1. Over-expression of both of these factors is
      correlated with poor prognosis in a variety of tumours. Macrophages also play an
      important physiological role in the development and function of many tissues
      ranging from the brain to the mammary gland. Thus we hypothesized that TAMs are
      recruited to tumours through the expression of potent chemoattractants and in
      this site their normal trophic functions are subverted to promote tumour
      progression and metastasis. To test this hypothesis we crossed mice deficient in
      macrophages owing to being homozygous for a null mutation in the CSF-1 gene with
      mice pre-disposed to mammary cancer due to the epithelial restricted expression
      of the polyoma middle T oncoprotein. The absence of macrophages did not change
      the incidence or growth of the primary tumour but decreased its rate of
      progression and inhibited metastasis. These data are explicable through the known
      macrophage functions in matrix remodelling, angiogenesis and stimulation of
      tumour growth and motility through the synthesis of growth and chemotactic
      factors. Interestingly, these functions are also normally found in wound healing
      or pathologically during chronic inflammation. This supports the notion that
      tumours are 'wounds that never heal' and suggests that chronic inflammation
      through persistent infection or by other means might be an important cofactor in
      the genesis and promotion of tumours. Macrophages might therefore be important
      targets for cancer therapies.

PMID- 15027490
TI  - Chemokines: angiogenesis and metastases in lung cancer.
AB  - Non-small cell lung cancer (NSCLC) growth, angiogenesis, invasion, and metastases
      to specific organs is dependent on an orchestrated series of events that include:
      cellular transformation; establishment of a pro-angiogenic environment; tumour
      cell proliferation, invasion and entry into the circulation; and tumour cell
      trafficking and metastatic tumour growth in specific organs based on the concept
      of Paget's theory of 'seed and soil' related to homing of tumour cells to a
      specific organ. The events that destine a tumour cell to invade and metastasize
      to distant organs are analogous to leukocyte trafficking. Chemokines have had an
      increasingly important role in mediating the homing of leukocytes under both
      conditions of homeostasis and inflammatory/immunological responses. Recently, the
      biology of chemokines has extended beyond their role in mediating leukocyte
      trafficking. Specifically, CXC chemokines have been found to be important in the
      regulation of angiogenesis, and in promoting tumour cell migration and organ
      specific metastases. Data will be presented to highlight the importance of CXC
      chemokine ligands and receptors in mediating NSCLC tumour-associated
      angiogenesis, 'immunoangiostasis', and organ specific metastases. These findings
      may ultimately lead to clinical strategies to attenuate the pathobiology of CXC
      chemokines in promoting NSCLC tumour growth and metastases.

PMID- 15027491
TI  - Macrophage infiltration and angiogenesis in human malignancy.
AB  - It is well recognized that human tumours are hypoxic compared to normal adjacent
      tissues and that hypoxia is related to a poor outcome regardless of modality of
      treatment, including surgery alone, radiotherapy or chemotherapy. Hypoxia
      regulates a complex programme of gene transcription via hypoxia-inducible factors
      1 and 2 (HIF-1, -2). We have shown that in breast cancer and many other tumour
      types, tumour-associated macrophages express high levels of HIF-2alpha compared
      to normal tissue macrophages and compared to the tumour. This high macrophage HIF
      2alpha is an independent prognostic factor for poor outcome. The mechanisms up
      regulating HLF-2alpha in macrophages may include inflammatory cytokines as well
      as hypoxia. Differentiation of monocytes into macrophages increases the basal
      level of HIF-2alpha protein and changes the programme of hypoxia. Many of these
      inducible genes are involved in inflammation and angiogenesis. Thus, the
      conversion of a peripheral monocyte into a macrophage generates a complex new
      programme of hypoxia-responsive genes that may contribute to angiogenesis and the
      complex microenvironment within the tumour, and as such provides important
      targets for therapy.

PMID- 15027492
TI  - The role of inflammation in tumour growth and tumour suppression.
AB  - The relationship between inflammation and tumour growth is poorly understood. The
      quality, quantity and time point of the inflammatory response may decide whether
      inflammation supports or inhibits tumour growth. Three examples are given that
      illustrate the different role of inflammation for tumour growth. It will be shown
      that tumour infiltrating macrophages can contribute to tumour rejection, can be
      essential for tumour growth or can occur as innocent bystander cells in tumours.
      Then it will be shown that the timely arrival of T cells at the tumour site is
      critical for tumour rejection and that non-bone marrow-derived tumour stromal
      cells are important targets during tumour rejection. Finally, a protective
      inflammatory response against the chemical carcinogen methylcholanthrene (MCA)
      will be discussed. This response is related to a tissue repair response induced
      by the tissue damaging effects of the carcinogen in the course of which MCA is
      encapsulated and no longer able to induce tumours.

PMID- 15027493
TI  - Cyclooxygenase 2: from inflammation to carcinogenesis.
AB  - Cyclooxygenase (COX) is the rate-limiting enzyme in the conversion of arachidonic
      acid to prostanoids. Two COX isoforms have been cloned, of which COX-1 is
      constitutively expressed, while the expression of COX-2 is low or nondetectable
      in most tissues, but can be readily induced in response to cell activation by
      cytokines, growth factors and tumour promoters. Thus, COX-1 is considered a
      housekeeping gene and thought to be responsible for the synthesis of prostanoids
      involved in cytoprotection of the stomach and for the production of the pro
      aggregatory prostanoid thromboxane by the platelets. In contrast, COX-2 is an
      inducible, immediate-early gene, and its role has been related to inflammation,
      reproduction and carcinogenesis. Expression of COX-2 is elevated in a variety of
      human malignancies and in their precursor lesions. Furthermore, genetic deletion
      or pharmacological inhibition of COX-2 suppresses tumour growth in several animal
      models of carcinogenesis. In humans, elevated COX-2 expression is associated with
      poor prognosis in adenocarcinomas of the digestive tract and the breast, and a
      selective inhibitor of COX-2 reduced polyp burden in patients who suffer from
      familial adenomatous polyposis. Thus, COX-2 seems to be a relevant target in
      chemoprevention.

PMID- 15027494
TI  - The inflammatory cytokine network of epithelial cancer: therapeutic implications.
AB  - A network of inflammatory cytokines and chemokines is found in epithelial cancer.
      There is evidence that these mediators contribute not only to tumour cell growth
      and survival, but also to communication between the cancer cells and stromal
      elements. Tumour cell production of the inflammatory cytokine tumour necrosis
      factor alpha (TNFalpha) is one critical factor in this autocrine and paracrine
      network. TNFalpha may also initiate and sustain production of other cytokines and
      chemokines. Chemokines are key determinants of the leukocyte infiltrate in solid
      ovarian tumours and influence the extent and phenotype of the infiltrate in
      ascitic disease. Chemokines may also be involved in tumour cell spread. Thus some
      of the processes involved in chronic inflammation are also active in human
      epithelial cancers. Agents that antagonize TNFalpha or chemokines are currently
      being assessed in preclinical animal cancer models and in phase I clinical
      trials.

PMID- 15027495
TI  - In vivo manipulation of dendritic cell migration and activation to elicit
      antitumour immunity.
AB  - Two approaches have been pursued to elicit antitumour immunity: (i) induce
      recruitment of immature dendritic cells or their precursors at a site of antigen
      delivery, and (ii) induce activation of tumour-infiltrating dendritic cells
      (DCs). The recruitment of selected DC subtype conditions the class of the immune
      response. Each immature DC population displays a unique spectrum of chemokine
      responsiveness. For examples, Langerhans cells (LCs) migrate selectively in
      response to CCL20/MIP-3alpha (through CCR6), blood CD11c+ DC to MCP chemokines
      (through CCR2). All these chemokines are inducible in response to inflammatory
      stimuli. CCL20/MIP-3alpha in particular is only detected within inflamed
      epithelium, at the site of antigen entry, which is infiltrated by immature DCs.
      Furthermore, to reach the site of injury, sequential responsiveness might
      operate, blood DC precursors are recruited by a set of chemokines (MIP, MCP)
      while within the tissue other chemokines will direct their navigation (CCL20/MIP
      3alpha). Of interest, when injected in vivo together with antigen, MCP-4/CCL13,
      but not CCL20/MIP-3alpha, recruits blood monocytes or blood DC precursors that
      promptly differentiate into typical DCs and that improve antitumour immune
      responses. After antigen uptake, DCs acquire, upon maturation, responsiveness to
      CCR7 ligands (CCL21/SLC/6Ckine, CCL19/ELC/MIP-3beta) due to receptor up
      regulation. In particular, in the periphery, CCL21/SLC/6Ckine expressed by
      lymphatic vessels may direct into the lymph stream, antigen-loaded maturing DCs
      leaving the site of infection; while within lymph-node, CCL21/SLC/6Ckine plays a
      critical role in the entry of naive T cells from the blood through HEV. In regard
      to its central role, we decided to investigate whether the expression of
      CCL21/SLC/6Ckine in tumour may lead to antitumour immune responses. C26 colon
      carcinoma tumour cell line transduced with CCL21/SLC/6Ckine showed reduced
      tumorigenicity when injected in vivo into immunocompetent mice. The protection
      was CD8 dependent and associated with an important intratumoral infiltration of
      DCs. Most tumour infiltrating DCs (TIDCs) had an immature phenotype, were able to
      present TAA in the context of MHC class I, but were refractory to stimulation
      with the combination of LPS, IFNgamma and anti-CD40 antibody. TIDC paralysis
      could be reverted, however, by in vitro or in vivo stimulation with the
      combination of a CpG immunostimulatory sequence and an anti-interleukin 10
      receptor (IL10R) antibody. CpG or anti-IL10R alone were inactive in TIDC, while
      CpG triggered activation in normal DC. In particular, CpG plus anti-IL10R
      enhanced the TAA-specific immune response and triggered de novo IL-12 production.
      Subsequently, CpG plus anti-IL10R treatment showed robust antitumour therapeutic
      activity exceeding by far that of CpG alone, and elicited antitumour immune
      memory.

PMID- 15027496
TI  - Where is health-related quality-of-life assessment in oncology clinical study
      heading?

PMID- 15027497
TI  - Assessing tumor-related signs and symptoms to support cancer drug approval.
AB  - Cancer causes premature death and significant, often devastating, symptoms. While
      prolongation of survival is an obvious end point for new cancer drug approval,
      the US Food and Drug Administration (FDA) has also utilized end points that
      evaluate patient symptoms. In this article we discuss the end points, evidence,
      and analyses supporting cancer drug approvals based on evaluations of tumor
      related signs and symptoms. With advice from the Oncologic Drug Advisory
      Committee (ODAC) in the late 1970s and early 1980s, FDA determined that
      acceptable end points for cancer drug approval were survival or an improvement in
      the quality of a patient's life, e.g., an improvement in tumor-related symptoms.
      This article summarizes 15 FDA cancer drug approvals based on patient symptom
      assessments and/or physical signs (thought to represent symptomatic improvement)
      as the primary evidence of effectiveness. These include painful bone events
      (three cases), cosmetic improvement in Kaposi's sarcoma and cutaneous T-cell
      lymphoma (six cases), the consequences (decreased transfusions, etc.) of long
      duration responses in leukemias and lymphomas (two cases), relief of pulmonary or
      esophageal obstruction (two cases), and one case each of symptom benefit in
      pancreatic cancer (also associated with survival benefit) and pulmonary symptom
      benefit in lung cancer. An instructive example of an individual patient benefit
      end point is discussed, though it did not lead to a drug approval (the cisplatin
      epinephrine gel application). Improved trial designs and analysis plans may allow
      greater reliance on morbidity assessments to support future cancer drug
      approvals. Drug sponsors are encouraged to include symptom assessments in cancer
      clinical trials and to perform further research to improve symptom-assessment
      methods. The FDA routinely meets with sponsors at End of Phase 2 Meetings to
      discuss drug development plans and the design of phase 3 trials. We encourage
      sponsors to request special protocol assessments (SPA) after meeting with the FDA
      to get written confirmation of the adequacy of plans for assessing cancer
      morbidity and quality of life, including protocols, end points, statistical
      analysis plans, and draft case report forms.

PMID- 15027498
TI  - Evaluation of health-related quality-of-life measures in oncology drug product
      applications: issues and concerns.
AB  - Health-related quality-of-life outcomes as reported by patients are valuable data
      and ideally should be critical to evaluating clinical benefit. The unblinded or
      open-label designs commonly adapted in oncology trials have the potential to
      introduce selection bias, reporting bias, and analyses bias. In this paper,
      issues surrounding use of patient reported outcomes to evaluate oncology drug
      products, including definition of hypothesis, study design, analysis, and
      interpretation of patient reported outcome data, are reported.

PMID- 15027499
TI  - Planning analyses of quality-of-life studies: a case example with migraine
      prophylaxis.
AB  - Assessment of health-related quality of life (QOL) has become increasingly common
      in clinical trials. Because QOL has multiple dimensions and is assessed
      repeatedly over time, multiple comparisons and missing data must be addressed in
      the design and analysis of these trials. While the development of an analysis
      plan will be a continuous process, described here are three critical phases in
      the ideal development of a statistical analysis plan for the QOL component of a
      clinical trial: concept, initial design, and final analysis plans. A clinical
      trial designed to evaluate a new therapy for the prevention of migraines was used
      to illustrate the critical decisions that are made during the design and analysis
      phases of a trial that incorporates QOL in the assessment procedure. Specifically
      addressed are clearly defining goals and objectives, endpoints, multiple
      comparisons, analysis of longitudinal data with dropout, and estimation of power.

PMID- 15027500
TI  - The analysis, interpretation, and presentation of quality of life data.
AB  - All too often in clinical trials the assessment of quality of life is seen as a
      bolt-on study. Consequently insufficient consideration is often given to its
      design, collection, analysis and presentation, and its impact on the trial
      results and on clinical practice is minimal. In many trials quality of life is a
      key endpoint, and it is vital that quality of life expertise is involved as soon
      as possible in the design. Setting a priori quality of life hypotheses will focus
      the decisions regarding which questionnaire to use, when to administer it, the
      sample size required, and the primary analyses. Nevertheless quality of life data
      are complex, and require much skill in determining how to deal with multi
      dimensional and longitudinal data, much of which is often missing. There are no
      agreed standard ways of analysing and presenting quality of life data, but there
      are guidelines, which if followed, will add transparency to the way results have
      been calculated. Understanding the impact of treatments on their quality of life
      is vital to patients, and it is up to us, as statisticians and trialists, to
      present the data as clearly as we can.

PMID- 15027501
TI  - Issues for statisticians in conducting analyses and translating results for
      quality of life end points in clinical trials.
AB  - Quality of life (QOL) end points in pharmaceutical clinical trials are at a
      crossroads. On the one hand, much has been learned in recent years of how to
      efficiently and effectively measure patient QOL. On the other hand, investigators
      and regulatory agencies still struggle with exactly how to assess the results of
      QOL end points and other patient-reported outcomes. Statisticians are often left
      in the position of having to bridge the gap between investigators who want to
      assess patient QOL and regulatory bodies who want a sound scientific rationale
      and analysis plan for doing so. Unfortunately, little has been written
      specifically for the statistical audience to assist in this translation. The
      purpose of this paper is to attempt to bridge this gap. We will describe the
      language and methods that have been successful in translating the psychometric
      and statistical challenges into understandable findings for investigators and
      regulatory agencies. One of the most important advances is the development of a
      general guideline for assessing clinical significance, namely the "half standard
      deviation" method based on the empirical rule effect size (ERES) approach. We
      populate the paper with concrete examples of how QOL data need not be treated any
      different, in terms of statistical analysis, than tumor response or other
      clinical end points.

PMID- 15027502
TI  - Minimal important difference thresholds and the standard error of measurement: is
      there a connection?
AB  - Several recently published investigations have examined the relationship between
      the magnitude of the standard error of measurement (SEM) and established
      thresholds for a minimal clinically important difference (MCID) or a minimal
      important difference (MID) for change scores on health-related quality of life
      (HRQOL) or health status measures. These investigations, however, have resulted
      in differing SEM criteria for the MCID or MID. This study reviews and compares
      two sets of studies: (1) three investigations using a disease-specific HRQOL
      measure among patient samples with the chronic disease (heart disease, chronic
      obstructive pulmonary disease, or asthma) that have consistently demonstrated a 1
      SEM correspondence with the established MCIDs or MIDs and (2) three
      investigations among patients referred to physical therapists with back, lower
      extremity, and neck pain showing that approximately 2.3 SEMs estimated the
      established MCID standards for three different measures of health status. Chronic
      disease patients were classified to have a MCID or MID if their global change
      ratings for the better or the worse were 1, 2, or 3 on a Likert scale ranging
      from 1 (almost the same, hardly any better, or worse at all) to 7 (a very great
      deal better or worse). Back pain patients, however, needed average global
      transition scores of 5, 6, or 7 (a good, a great, or a very great deal better) on
      the same 7-point Likert scale in order to experience an MCID in their condition.
      Charting these change levels against their respective SEM-MID criteria provides
      insight and promise for linking SEM-based criteria to MCID standards for other
      HRQOL and health status measures.

PMID- 15027503
TI  - A quality-adjusted survival (Q-TWiST) model for evaluating treatments for
      advanced stage cancer.
AB  - Quality of life is an important component in the evaluation of therapies,
      especially in advanced cancer. Methods available for the analysis of longitudinal
      quality-of-life data include linear mixed models (including growth curve models),
      generalized linear models, generalized estimating equations, and joint modeling
      of quality of life and the missingness process. Quality-adjusted survival (Q
      TWiST) has also been useful to compare treatments. By weighting the durations of
      health states according to their quality of life, one arrives at a single end
      point reflecting the duration of survival and the quality of life. We propose
      methods for incorporating longitudinal quality-of-life data into quality-adjusted
      survival. We divide follow-up time into two states, "poor" and "good," based on a
      cut-off applied to observed quality-of-life scores. Disease progression is
      handled as a separate state. We then use survival analysis methods to estimate
      the mean duration of each state as well as mean quality-adjusted time. The
      analysis is repeated by varying the cut-off to illustrate the range of possible
      results. Finally a single summary analysis is achieved by averaging (possibly
      with weights) across the cut-offs used. We illustrate the methodology using data
      from a cancer clincial trial.

PMID- 15027504
TI  - Sensitivity analysis for pattern mixture models.
AB  - Incomplete series of data is a common feature in quality-of-life studies, in
      particular in chronic diseases where attrition of patients is high. Two
      alternative approaches to modeling longitudinal data with incomplete measurements
      have frequently been proposed in the literature, selection models and pattern
      mixture models. In this paper we focus on, by way of sensitivity analysis,
      extrapolating incomplete patterns using identifying restrictions. Perhaps the
      best known ones are so-called complete case missing value restrictions (CCMV),
      where for a given pattern, the conditional distribution of the missing data,
      given the observed data, is equated to its counterpart in the completers.
      Available case missing value (ACMV) restrictions equate this conditional density
      to the one calculated from the subgroup of all patterns for which all required
      components have been observed. Neighboring case missing value restrictions (NCMV)
      equate this conditional density to the one calculated from the the pattern with
      one additional measurement obtained. In this paper, these three identifying
      restriction strategies are used to multiply impute missing data in a study in
      metastatic prostate cancer. Multiple imputation is employed to reduce the
      uncertainty of single imputation. It is shown how hypothesis testing and
      sensitivity analyses are carried out in this setting.

PMID- 15027505
TI  - Frailty models for quality of life in oncology.
AB  - Quality of life (QOL) and survival data are commonly measured in clinical trials
      in oncology. Frailty models are an excellent tool to exploit the natural
      dependence between these domains. We propose a novel application of frailty
      models, providing a detailed example relating to QOL in advanced prostate cancer
      patients. We discuss model fitting, estimation, and interpretation and describe
      available software.

PMID- 15027506
TI  - Quality-of-life measurement in clinical trials--the impact of causal variables.
AB  - The theory of measurement scales, and in particular multi-item scales, has been
      extensively developed in educational testing, psychometric testing, personality
      testing, and consumer research. These scales are usually either based upon
      traditional psychometric models or modern theory using item response theory.
      However, clinical measuring instruments, including health-related quality-of-life
      questionnaires, frequently have different underlying principles and so the
      adoption of such approaches can be inappropriate. The fundamental statistical
      distinction between indicator and causal variables can be used to explain why
      psychometric methods fail. So-called clinimetric approaches may sometimes be more
      relevant, and clinimetric and psychometric ideas should be combined to yield a
      suitable measuring instrument. Recognition of the role of causal variables
      enables informed decisions to be made regarding scale development, validation,
      and scoring.

PMID- 15027507
TI  - Effect of a guarantee time on sample size determination for testing the ratio of
      means from two lifetime distributions.
AB  - This paper studies the problem of sample size determination for testing the ratio
      of means from two lifetime distributions when thresholds, or guarantee times, are
      present in the survival distributions. We consider several different approaches
      of sample size determination based on different distributional assumptions and
      discuss the role that guarantee times play in these sample size computations. We
      show that the guarantee times, if they exist, can significantly affect the sample
      size computations. The Aging Intervention Testing Program from the National
      Institute on Aging is used to demonstrate our results.

PMID- 15027508
TI  - Sample sizes based on exact unconditional tests for phase II clinical trials with
      historical controls.
AB  - Investigated in the setting of phase II clinical trials is the two-sample
      binomial problem of testing H0: pe = pc H1: pe > pc, where pe and pc are the
      unknown target population response rates for the experimental and control groups,
      respectively, using the usual Z-statistic with pooled variance estimator. The
      cornerstones that make this paper unique are as follows. First, the emphasis is
      on determining the sample size given that the control group information has
      already been collected (historical control). Second, exact unconditional
      inference, rather than an asymptotic method, is utilized. Sample size tables,
      contrasting the exact and asymptotic methods, are provided. Although asymptotic
      results were usually fairly close to the exact results, some important
      differences were observed.

PMID- 15027509
TI  - Assessing the agreement between two quantitative assays with repeated
      measurements.
AB  - We propose a statistical test in evaluating the equivalence (or agreement)
      between assay values x and y obtained using two methods in assay or instrument
      validation, where both x and y are measurements of an unobserved analyte z. Our
      method builds on the availability of repeated measurements from each sampled
      subject, which enables us to assess the agreement in terms of the conditional
      mean of the difference x - y given z as well as the conditional variance of x - y
      given z. With the help of repeated measurements and a large number of sampled
      subjects, our method does not require any distributional assumption on (x, y, z)
      or any model assumption on the conditional mean (or variance) of x - y.
      Furthermore, our test is designed so that when the null hypothesis is rejected,
      we can conclude that the two assay methods do not have practically meaningful
      difference with a high statistical assurance, which is an approach adopted in the
      assessment of bioequivalence between two drug products.

PMID- 15027510
TI  - Impact of model misspecification at design (and/or) estimation step in population
      pharmacokinetic studies.
AB  - The aim of this work is to quantitatively assess the impact of structural model
      misspecifications on the estimates of mean and interindividual variability of
      clearance in the context of population approaches. This assessment is conducted
      from simulated datasets. Our results show that impact magnitude of model
      misspecification on the estimates depends on the step at which it occurs (design
      optimization and/or estimation), on the hyperparameter of interest, and on the
      estimation method. Bias and precision might be affected differently as well as
      powers of model discrimination tests. Some practical guidelines for reducing
      impact of model misspecifications are also suggested.

PMID- 15027511
TI  - Design and analytic considerations for single-armed studies with
      misclassification of a repeated binary outcome.
AB  - Due to logistics or prohibitive costs, clinical studies often rely upon a
      potentially misclassified binary outcome variable for assessing an intervention
      effect. We consider noncomparative single-armed studies that are sometimes
      necessary for ethical reasons, and we focus on the situation in which subjects
      are selected to receive the intervention contingent upon a positive screening
      test. Both initial misclassification at screening and a regression phenomenon
      impacting the error-prone follow-up outcome measure contribute to bias in the
      typical treatment effect estimate. We propose a study design involving the
      collection of internal validation data assuming the availability of a more
      demanding gold standard outcome measure. We pursue likelihood-based analysis and
      describe efficiency considerations relevant to two different treatment effect
      definitions. We identify four possible types of validation study observations,
      and discuss finding the optimal allocation into these four types in order to
      minimize the variance of the estimated treatment effect. The optimal allocation
      can be highly dependent upon whether a ratio or a difference measure is adopted
      to evaluate the intervention. The methods are illustrated numerically, and a real
      life example motivating the proposed optimal design is provided.

PMID- 15027512
TI  - The accelerated biased coin up-and-down design in phase I trials.
AB  - The biased coin up-and-down design (BCD) is used to allocate doses in phase I
      clinical trials. The BCD requires that the treatment response or the toxicity
      evaluation is observed quickly. In trials with a long treatment evaluation, the
      BCD will lead to long trial duration because a new patient cannot be enrolled
      until the preceding patient has completed the evaluation period. We propose a
      simple method to modify the BCD that will reduce the trial duration without
      significantly affecting the estimate of the target dose. The idea is to allocate
      a dose to each patient as he or she arrives based on the toxicity information of
      the last completed subject. This allows multiple patients to be concurrently
      under evaluation. A simulation study shows that this modification does not
      adversely affect the precision of the recommended dose, as estimated by isotonic
      regression, but it does significantly reduce the total time to complete the
      study.

PMID- 15027513
TI  - Flexibility with responsibility.

PMID- 15027514
TI  - What is your diagnosis? Plummer-Vinson syndrome.

PMID- 15027515
TI  - Serious hand-and-foot syndrome in black patients treated with capecitabine:
      report of 3 cases and review of the literature.
AB  - Hand-and-foot syndrome (HFS) is one of the well-known adverse events associated
      with capecitabine, a prodrug of 5-fluorouracil (5-FU). HFS, also known as
      erythrodysesthesia, manifests as acral erythema with swelling and dysesthesia of
      the palms and plantar aspects of the feet, and, in the absence of dosage
      reduction or stoppage of the drug, progresses to moist desquamation and
      ulceration with serious infections and loss of function. In black patients, we
      observed that capecitabine given in the recommended dosage leads to
      hyperpigmentation of the palms and soles, followed by a distinct keratodermalike
      thickening not seen in white patients. Furthermore, in patients with a precarious
      peripheral vasculature, this condition evolves rapidly into grade 3 HFS, with
      ulceration and infection. We report our experience with capecitabine in 3 black
      patients and contrast it to that of 2 white patients. A brief review of the
      literature on fluoropyrimidines and HFS follows.

PMID- 15027516
TI  - Hair loss remedies--separating fact from fiction.
AB  - Hair loss is a common complaint in the outpatient setting. Frequently, patients
      conduct their own research on hair loss diagnosis and treatment and are faced
      with a number of manufacturers' claims that their products will benefit hair
      loss. This paper explores the truth behind those claims of hair regrowth. We
      intend for this information to serve as a "consumer report" for healthcare
      providers and patients and to help separate some of the valid claims for hair
      regrowth from those that are purely fiction.

PMID- 15027517
TI  - Kaposi's varicelliform eruption: a case report and review of the literature.
AB  - Disseminated herpes or vaccinia in the setting of underlying skin diseases is
      known as Kaposi's varicelliform eruption (KVE). Patients typically present with
      disseminated vesicopustules in the areas of the most severe involvement of their
      underlying skin disease. We report a case of eczema herpeticum in a woman with a
      long-standing history of atopic dermatitis (AD). This report also reviews the
      literature on eczema herpeticum and eczema vaccinatum (EV), summarizes clinical
      and histopathologic characteristics and treatment, and discusses the
      recommendations of the Centers for Disease Control and Prevention for smallpox
      vaccination.

PMID- 15027518
TI  - Phaeohyphomycosis caused by Coniothyrium.
AB  - A 49-year-old immunosuppressed heart transplant recipient developed a superficial
      and subcutaneous granulomatous infection caused by Coniothyrium. The patient
      responded to a combination of surgical excision and antifungal agents. We review
      phaeohyphomycotic infections including this second report of a Coniothyrium
      infection.

PMID- 15027519
TI  - An evaluation of the moisturizing and anti-itch effects of a lactic acid and
      pramoxine hydrochloride cream.
AB  - An open-label, single-center, observer-blinded, controlled trial was conducted
      during the winter months to evaluate the moisturizing and antipruritic effects of
      a unique formulation of lactic acid 12% neutralized with ammonium hydroxide and
      pramoxine hydrochloride (HCl) 1% in 24 women with a history of dry itchy skin.
      Baseline assessments for appearance of dryness of both lower legs of each patient
      were conducted by a blinded expert grader; skin surface hydration was measured by
      the IBS Co, Ltd, Skicon-200 (Hamamatsu, Japan) conductivity meter; and dryness
      and itch were measured through self-assessment surveys. The women stopped the use
      of all moisturizing agents 7 days prior to and throughout the study and were
      allowed to use only a nonmoisturizing soap for bathing and shaving. Patients were
      randomized as to which leg to apply the test cream; the opposite leg was used as
      a nontreated control. Patients applied the test product liberally to the assigned
      leg twice daily for 7 days and had repeat assessments for appearance and
      hydration on the morning of days 3 and 7; self-assessments of itch and dryness
      were completed on days 1, 2, 3, 6, and 7. Expert grader assessment of skin
      dryness showed significant improvement with the test cream compared with no
      treatment on day 3 (P=.0004) and on day 7 (P<.001). Patients had statistically
      significant improvement in skin surface hydration by day 3 (P<.0001), with
      further improvement by day 7 (P<.0001). Patients also reported significant
      improvements in skin dryness and itch by day 1 (P<.0001 and (P<.0001,
      respectively), which continued to improve through day 7 (P<.0001 and P<.0001,
      respectively). In conclusion, the test cream was shown to be an effective
      moisturizer and antipruritic agent in treating dry itchy skin.

PMID- 15027521
TI  - Model-independent method for fMRI analysis.
AB  - This paper presents a fast method for delineation of activated areas of the brain
      from functional magnetic resonance imaging (fMRI) time series data. The steps of
      the work accomplished are as follows. 1) It is shown that the detection
      performance evaluated by the area under the receiver operating characteristic
      curve is directly related to the signal-to-noise ratio (SNR) of the composite
      image generated in the detection process. 2) Detection and segmentation of
      activated areas are formulated in a vector space framework. In this formulation,
      a linear transformation (image combination method) is shown to be desirable to
      maximize the SNR of the activated areas subject to the constraint of removing
      inactive areas. 3) An analytical solution for the problem is found. 4) Image
      pixel vectors and expected time series pattern (signature) for inactive pixels
      are used to calculate weighting vector and identify activated regions. 5)
      Signatures of the activated regions are used to segment different activities. 6)
      Segmented images by the proposed method are compared with those generated by the
      conventional methods (correlation, t-statistic, and z statistic). Detection
      performance and SNRs of the images are compared. The proposed approach
      outperforms the conventional methods of fMRI analysis. In addition, it is model
      independent and does not require a priori knowledge of the fMRI response to the
      paradigm. Since the method is linear and most of the work is done analytically,
      numerical implementation and execution of the method are much faster than the
      conventional methods.

PMID- 15027520
TI  - Compensation for nonuniform resolution using penalized-likelihood reconstruction
      in space-variant imaging systems.
AB  - Imaging systems that form estimates using a statistical approach generally yield
      images with nonuniform resolution properties. That is, the reconstructed images
      possess resolution properties marked by space-variant and/or anisotropic
      responses. We have previously developed a space-variant penalty for penalized
      likelihood (PL) reconstruction that yields nearly uniform resolution properties.
      We demonstrated how to calculate this penalty efficiently and apply it to an
      idealized positron emission tomography (PET) system whose geometric response is
      space-invariant. In this paper, we demonstrate the efficient calculation and
      application of this penalty to space-variant systems. (The method is most
      appropriate when the system matrix has been precalculated.) We apply the penalty
      to a large field of view PET system where crystal penetration effects make the
      geometric response space-variant, and to a two-dimensional single photon emission
      computed tomography system whose detector responses are modeled by a depth
      dependent Gaussian with linearly varying full-width at half-maximum. We perform a
      simulation study comparing reconstructions using our proposed PL approach with
      other reconstruction methods and demonstrate the relative resolution uniformity,
      and discuss tradeoffs among estimators that yield nearly uniform resolution. We
      observe similar noise performance for the PL and post-smoothed maximum-likelihood
      (ML) approaches with carefully matched resolution, so choosing one estimator over
      another should be made on other factors like computational complexity and
      convergence rates of the iterative reconstruction. Additionally, because the
      postsmoothed ML and the proposed PL approach can outperform one another in terms
      of resolution uniformity depending on the desired reconstruction resolution, we
      present and discuss a hybrid approach adopting both a penalty and post-smoothing.

PMID- 15027522
TI  - "Population" approach improves parameter estimation of kinetic models from
      dynamic PET data.
AB  - Kinetic modeling is used to indirectly measure physiological parameters from
      dynamic positron emission tomography (PET) data. Usually, the unknown parameters
      of the model are estimated, in any given region of interest (ROI), by least
      squares (LS). However, when the signal-to-noise ratio (SNR) of PET data is too
      low, LS does not allow reliable parameter estimation. To overcome this problem,
      we study in this paper the applicability of approaches originally developed in
      the pharmacokinetic/pharmacodynamic literature and referred to as "population
      approaches." In particular, we consider the iterative two stage (ITS) method,
      which, given a set of M ROIs drawn on PET images of a given individual, estimates
      the unknown model parameters of each ROI by exploiting the information contained
      in all the M ROIs. After having revised the theory behind ITS, we assess its
      performance versus LS by using Monte Carlo simulations which allow us to evaluate
      the bias of the two methods in a variety of situations. Then, we compare the
      performance of LS and ITS in two case studies on [18F]FDG kinetics in human
      skeletal muscle. Both simulated and real case studies results show that a
      population approach is of potential in modeling PET images since it allows to
      reliably estimate model parameters also in those ROIs where either a bad SNR or a
      poor sampling (e.g., infrequent scanning and/or short experiment duration) make
      the use of LS unsuccessful.

PMID- 15027523
TI  - Performance of vibro-acoustography in detecting microcalcifications in excised
      human breast tissue: a study of 74 tissue samples.
AB  - X-ray mammography is the principal modality used today for detection of breast
      microcalcifications and breast lesions associated with breast cancer. X-ray
      mammography, however, is ionizing and its sensitivity is greatly reduced in dense
      breasts. Hence, alternative noninvasive and nonionizing breast imaging tools that
      can aid physicians to better diagnose early-stage breast lesions are of great
      interest. Vibro-acoustography is a novel noninvasive imaging technique that uses
      ultrasound in a fundamentally new way. This method uses the radiation force of
      ultrasound to vibrate the tissue at low (kilohertz) frequency and records the
      resulting response to produce images that are related to the mechanical
      properties of the tissue. The goal of this study is to evaluate the performance
      of vibro-acoustography in detecting breast microcalcifications by conducting
      vibro-acoustography on 74 fixed breast tissue samples with known
      microcalcifications based on their radiographs. The results indicate that in most
      cases micro-calcifications can be detected by vibro-acoustography. Further
      development of vibro-acoustography may lead to a novel-imaging tool for in vivo
      detection of microcalcifications.

PMID- 15027524
TI  - Noise equalization for detection of microcalcification clusters in direct digital
      mammogram images.
AB  - Equalizing image noise is shown to be an important step in the automatic
      detection of microcalcifications in digital mammography. This study extends a
      well established film-screen noise equalization scheme developed by Veldkamp et
      al. for application to full-field digital mammogram (FFDM) images. A simple noise
      model is determined based on the assumption that quantum noise is dominant in
      direct digital X-ray imaging. Estimation of the noise as a function of the gray
      level is improved by calculating the noise statistics using a truncated
      distribution method. Experimental support for the quantum noise assumption is
      presented for a set of step wedge phantom images. Performance of the noise
      equalization technique is also tested as a preprocessing stage to a
      microcalcification detection scheme. It is shown that the square root model based
      approach which FFDM allows leads to a robust estimation of the high frequency
      image noise. This provides better microcalcification detection performance when
      compared to the film-screen noise equalization method developed by Veldkamp.
      Substantially better results are obtained than when noise equalization is
      omitted. A database of 124 direct digital mammogram images containing 28
      microcalcification clusters was used for evaluation of the method.

PMID- 15027525
TI  - Analysis of lesion detectability in Bayesian emission reconstruction with
      nonstationary object variability.
AB  - Bayesian methods based on the maximum a posteriori principle (also called
      penalized maximum-likelihood methods) have been developed to improve image
      quality in emission tomography. To explore the full potential of Bayesian
      reconstruction for lesion detection, we derive simplified theoretical expressions
      that allow fast evaluation of the detectability of a lesion in Bayesian
      reconstruction. This work is builded on the recent progress on the theoretical
      analysis of image properties of statistical reconstructions and the development
      of numerical observers. We explicitly model the nonstationary variation of the
      lesion and background without assuming that they are locally stationary. The
      results can be used to choose the optimum prior parameters for the maximum lesion
      detectability. The theoretical results are validated using Monte Carlo
      simulations. The comparisons show good agreement between the theoretical
      predictions and the Monte Carlo results. We also demonstrate that the lesion
      detectability can be reliably estimated using one noisy data set.

PMID- 15027526
TI  - Extraction of left ventricular contours from left ventriculograms by means of a
      neural edge detector.
AB  - We propose a method for extracting the left ventricular (LV) contours from left
      ventriculograms by means of a neural edge detector (NED) in order to extract the
      contours which accord with those traced by a cardiologist. The NED is a
      supervised edge detector based on a modified multilayer neural network, and is
      trained by use of a modified back-propagation algorithm. The NED can acquire the
      function of a desired edge detector through training with a set of input images
      and the desired edges obtained from the contours traced by a cardiologist. The
      proposed contour-extraction method consists of 1) detection of "subjective edges"
      by use of the NED; 2) extraction of rough contours by use of low-pass filtering
      and edge enhancement; and 3) a contour-tracing method based on the contour
      candidates synthesized from the edges detected by the NED and the rough contours.
      Through experiments, it was shown that the proposed method was able to extract
      the contours in agreement with those traced by an experienced cardiologist, i.e.,
      we achieved an average contour error of 6.2% for left ventriculograms at end
      diastole and an average difference between the ejection fractions obtained from
      the manually traced contours and those obtained from the computer-extracted
      contours of 4.1%.

PMID- 15027527
TI  - Parametric shape modeling using deformable superellipses for prostate
      segmentation.
AB  - Automatic prostate segmentation in ultrasound images is a challenging task due to
      speckle noise, missing boundary segments, and complex prostate anatomy. One
      popular approach has been the use of deformable models. For such techniques,
      prior knowledge of the prostate shape plays an important role in automating model
      initialization and constraining model evolution. In this paper, we have modeled
      the prostate shape using deformable superellipses. This model was fitted to 594
      manual prostate contours outlined by five experts. We found that the superellipse
      with simple parametric deformations can efficiently model the prostate shape with
      the Hausdorff distance error (model versus manual outline) of 1.32 +/- 0.62 mm
      and mean absolute distance error of 0.54 +/- 0.20 mm. The variability between the
      manual outlinings and their corresponding fitted deformable superellipses was
      significantly less than the variability between human experts with p-value being
      less than 0.0001. Based on this deformable superellipse model, we have developed
      an efficient and robust Bayesian segmentation algorithm. This algorithm was
      applied to 125 prostate ultrasound images collected from 16 patients. The mean
      error between the computer-generated boundaries and the manual outlinings was
      1.36 +/- 0.58 mm, which is significantly less than the manual interobserver
      distances. The algorithm was also shown to be fairly insensitive to the choice of
      the initial curve.

PMID- 15027528
TI  - Tooth segmentation of dental study models using range images.
AB  - The accurate segmentation of the teeth from the digitized representation of a
      dental study model is an important component in computer-based algorithms for
      orthodontic feature detection and measurement and in the simulation of
      orthodontic procedures such as tooth rearrangement. This paper presents an
      automated method for tooth segmentation from the three-dimensional (3-D)
      digitized image captured by a laser scanner. We avoid the complexity of directly
      processing 3-D mesh data by proposing the innovative idea of detecting features
      on two range images computed from the 3-D image. The dental arch is first
      obtained from the plan-view range image. Using the arch as the reference, a
      panoramic range image of the dental model can be computed. The interstices
      between the teeth are detected separately in the two range images, and results
      from both views are combined for a determination of interstice locations and
      orientations. Finally, the teeth are separated from the gums by delineating the
      gum margin. The algorithm was tested on 34 dental models representing a variety
      of malocclusions and was found to be robust and accurate.

PMID- 15027529
TI  - Kinetic parameter estimation from renal measurements with a three-headed SPECT
      system: a simulation study.
AB  - We present here a direct least-squares estimation (DLSE) method for the
      determination of renal kinetic parameters from sequences of very fast
      acquisitions performed with a three-headed single photon emission computed
      tomography (SPECT) system. A simple linear model for the behavior of the
      radiopharmaceutical, as well as a spatial model for its spatial distribution are
      defined. The model enables one to estimate the kinetic parameters directly from
      the projections, once the plasma concentration function is known. A new technique
      for the accurate reconstruction of time-radioactivity curves based on the direct
      reconstruction of the region-of-interest contents from a series of data from
      three-projections is presented. The technique is used to determine the plasma
      concentration function with a sub-second time resolution. The spatially-variant
      geometrical response is also included in the model to compensate for the spatial
      resolution of the SPECT system. Results obtained from simulations are presented.
      Basic spatial and time features of the simulations are derived from a patient
      study. Noise and segmentation errors are also simulated. The DLSE method is
      compared with the conventional one of deriving kinetic parameters from the time
      series of reconstructed images. The standard deviation of results given by DLSE
      is less than 2%, whereas with the conventional method it is between 5% and 6%.
      Within the limit of statistical fluctuations, DLSE results are unbiased whereas
      those of the conventional method are overestimated by 24%.

PMID- 15027530
TI  - Denoising functional MR images: a comparison of wavelet denoising and Gaussian
      smoothing.
AB  - We present a general wavelet-based denoising scheme for functional magnetic
      resonance imaging (fMRI) data and compare it to Gaussian smoothing, the
      traditional denoising method used in fMRI analysis. One-dimensional WaveLab
      thresholding routines were adapted to two-dimensional (2-D) images, and applied
      to 2-D wavelet coefficients. To test the effect of these methods on the signal-to
      noise ratio (SNR), we compared the SNR of 2-D fMRI images before and after
      denoising, using both Gaussian smoothing and wavelet-based methods. We simulated
      a fMRI series with a time signal in an active spot, and tested the methods on
      noisy copies of it. The denoising methods were evaluated in two ways: by the
      average temporal SNR inside the original activated spot, and by the shape of the
      spot detected by thresholding the temporal SNR maps. Denoising methods that
      introduce much smoothness are better suited for low SNRs, but for images of
      reasonable quality they are not preferable, because they introduce heavy
      deformations. Wavelet-based denoising methods that introduce less smoothing
      preserve the sharpness of the images and retain the original shapes of active
      regions. We also performed statistical parametric mapping on the denoised
      simulated time series, as well as on a real fMRI data set. False discovery rate
      control was used to correct for multiple comparisons. The results show that the
      methods that produce smooth images introduce more false positives. The less
      smoothing wavelet-based methods, although generating more false negatives,
      produce a smaller total number of errors than Gaussian smoothing or wavelet-based
      methods with a large smoothing effect.

PMID- 15027531
TI  - Electrical conductivity imaging using gradient B, decomposition algorithm in
      magnetic resonance electrical impedance tomography (MREIT).
AB  - In magnetic resonance electrical impedance tomography (MREIT), we try to
      visualize cross-sectional conductivity (or resistivity) images of a subject. We
      inject electrical currents into the subject through surface electrodes and
      measure the z component Bz of the induced internal magnetic flux density using an
      MRI scanner. Here, z is the direction of the main magnetic field of the MRI
      scanner. We formulate the conductivity image reconstruction problem in MREIT from
      a careful analysis of the relationship between the injection current and the
      induced magnetic flux density Bz. Based on the novel mathematical formulation, we
      propose the gradient Bz decomposition algorithm to reconstruct conductivity
      images. This new algorithm needs to differentiate Bz only once in contrast to the
      previously developed harmonic Bz algorithm where the numerical computation of
      (inverted delta)2Bz is required. The new algorithm, therefore, has the important
      advantage of much improved noise tolerance. Numerical simulations with added
      random noise of realistic amounts show the feasibility of the algorithm in
      practical applications and also its robustness against measurement noise.

PMID- 15027532
TI  - Expert testimony and positive identification of human remains through cranial
      suture patterns.
AB  - North American forensic anthropological research should conform to the Daubert
      criteria (U.S.A.) and Mohan ruling (Canada) to ensure admissibility in a court of
      law. Positive identification through radiographic comparison of antemortem and
      postmortem cranial suture patterns was evaluated in light of these criteria. The
      technique is based on reliable principles, but problems with terminology and the
      resolution of radiographs make Sekharan's method difficult to apply. Using the
      location, length, and slope of a suture's component lines, rather than Sekharan's
      descriptions of sutural configurations, it is possible to determine the
      probability of a particular suture pattern occurring in more than one individual.
      A match of four consecutive lines is sufficient to establish positive
      identification. This approach meets the Daubert and Mohan criteria, although
      resolution of radiographs is still a major limitation. Computed tomography (CT)
      scans may prove a more useful modality for positive identification, due to better
      resolution and greater availability.

PMID- 15027533
TI  - The determination of male adult age at death by central and posterior coxal
      analysis--a preliminary study.
AB  - In forensic anthropological analysis, the pelvis is of particular interest as it
      is often a comparatively well-preserved part of the skeleton. This study in age
      determination uses the acetabulum, the central element of the pelvis, as a
      complement to the examination of the auricular surface. The test sample consisted
      of 30 individuals. First, the authors studied the auricular surface using the
      Lovejoy criteria. Second, they isolated four criteria based on chronological
      changes in the acetabulum. Third, they conducted an evaluation of each of these
      variables. The study examines the correlation between these criteria and the age
      of the individuals. A significant correlation was found between the acetabular
      criteria and age, and between the acetabular criteria and the Lovejoy criteria of
      the auricular surface. For forensic purposes, the acetabulum is an effective
      predictor in the determination of age. This newly proposed method explores the
      same criteria of ageing as the Lovejoy method. The combination of the two methods
      produces relatively consistent results in the estimation of age.

PMID- 15027534
TI  - New developments in SPME Part 2: Analysis of ammonium nitrate-based explosives.
AB  - Solid-phase microextraction (SPME) followed by gas chromatography-mass
      spectrometry (GC-MS) is a simple, reliable technique for the recovery and
      analysis of many organic explosives. However, this technique is impractical for
      the analysis of ammonium nitrate-type explosives due to the extreme polarity, low
      molecular weight, and high volatility of the amine moiety. This article describes
      an initial investigation of a derivatization process utilizing
      alkylchloroformates that converts ammonium nitrate and methylammonium nitrate
      into a form suitable for recovery by SPME and analysis by GC-MS.

PMID- 15027535
TI  - Typing of XY (male) genotype from malignant neoplastic tissue by the amelogenin
      based sex test.
AB  - DNA profiling of a cancer tissue can be problematic because of genomic
      instability. Here we have analyzed gastrointestinal cancer specimens from 46
      males, of which seven (15%) showed aberrations in determination of gender by the
      widely used amelogenin test. The X-type amelogenin allele in all cases remained
      intact. All male tumor samples showing frequent autosomal loss of heterozygosity
      had a decreased signal of the Y allele from the amelogenin marker. When tested
      with an alternate set of primers for the amelogenin locus, the Y-type allele
      showed loss of heterozygosity in the same seven cases. However, when amplified
      with 15 Y-specific STR primers, all the cancerous tissue Y chromosomes seemed to
      be intact. These results indicate when malignant neoplastic tissue specimens are
      used, that amelogenin-based gender determination should be carefully interpreted.

PMID- 15027536
TI  - Application of spectral libraries for characterization of oxidizers in post-blast
      residues by electrospray mass spectrometry.
AB  - The goal of this paper is to demonstrate that electrospray mass spectrometry when
      used with spectral libraries becomes a useful method for rapid identification of
      inorganic oxidizers commonly present in commercial and improvised explosives.
      Electrospray ionization mass spectra (ESI-MS) of oxidizers reveal a series of
      characteristic cluster ions. Such a set of cluster ions can be regarded as a
      "fingerprint" of a particular oxidizer. With the aid of a spectral library,
      tentative identification of inorganic oxidizer becomes automated and an easy-to
      implement process. The oxidizer identity may be further confirmed by using tandem
      mass spectrometry (MS/MS). Because it is not necessary to separate the components
      before analysis, results become available in real time. Little sample consumption
      and the ease of sample preparation should also be noted. The methodology can be
      readily employed on various ESI-MS systems that are already in use in analytical
      laboratories. This is another important benefit as the ESI-MS instrumentation is
      becoming increasingly common in forensic laboratories.

PMID- 15027537
TI  - Forensic identification of dyes extracted from textile fibers by liquid
      chromatography mass spectrometry (LC-MS).
AB  - LC-MS is used for the identification of dyes extracted from textile fibers and
      the utility of the method for forensic trace analysis is demonstrated. The
      technique is shown to provide a high degree of chemical structural information,
      making dye identification highly specific in comparison to optical and/or
      chromatographic methods of dye analysis. A UV-visible absorbance detector, placed
      in series before the MS detector, facilitates monitoring the elution of dyes in
      the presence of other non-dye components extracted from colored textile fibers.
      In this way, dye identification becomes practical, even when a dye standard is
      not available for comparison. A set of 22 reference dyestuffs and 10 dyes
      extracted from textile fibers were analyzed to demonstrate the utility of the
      method. Six of the extracted dyes corresponded to dyes also contained in the set
      of 22 reference dyestuffs. Reference dyestuffs were not available for four of the
      extracted dyes. Triethylamine (TEA) was shown to increase the electrospray
      ionization-mass spectrometry (ESI-MS) response of dyes containing multiple
      sulfonated groups.

PMID- 15027538
TI  - Accurate STR allele designations at the FGA and vWA loci despite primer site
      polymorphisms.
AB  - Polymerase chain reaction (PCR)-based STR DNA typing systems are used extensively
      in the field of human identification. Under optimal PCR conditions, the amplicon
      yield from both alleles of an STR locus is expected to be approximately
      equivalent. However, it is reasonable to expect that rare genomic sequence
      polymorphisms will co-localize with well-designed primer sets and induce allele
      imbalance or "dropouts". Two samples were identified in the course of genotyping
      thousands of individuals with AmpF/STR Profiler Plus that showed strong disparity
      in amplitude peak height of heterozygous peaks at the loci vWA and FGA. These
      samples were reamplified at reduced annealing temperature in an attempt to
      balance the peak heights. Nucleotide sequencing documented polymorphisms at the
      PCR primer binding sites of the affected alleles. The results indicate that
      reducing the annealing temperature to improve primer-binding efficiency at the
      mismatch and employing an alternative multiplex enhanced the data from both
      samples. Reducing annealing temperatures could provide a simple general solution
      to improving data quality for samples where polymorphisms are suspected to cause
      allele imbalance. Finally, we report on additional polymorphisms surrounding the
      vWA locus in a genetically diverse population.

PMID- 15027539
TI  - Genipin--a novel fingerprint reagent with colorimetric and fluorogenic activity.
AB  - Genipin, the hydrolytic product of geniposide, which is extracted from gardenia
      fruit, shows good potential as a fingerprint reagent. It develops latent
      fingerprints on paper as blue impressions with good contrast and resolution. Even
      very faint impressions that are barely visible in ambient light will fluoresce
      brightly upon illumination at ca. 590 nm and are best viewed with a barrier
      filter above 630 nm. Potential advantages of genipin are the combination of
      colorimetric and fluorogenic activity in one reagent as well as its being a safe
      and environmentally friendly natural product.

PMID- 15027540
TI  - Erroneous gender identification by the amelogenin sex test.
AB  - Human gender identification, based on the amelogenin gene, has important
      applications in forensic casework, prenatal diagnosis, DNA databasing, and blood
      sample storage. However, we report on the first known case, in the Israeli
      population, of an amelogenin sex test failure on a phenotypically normal male. He
      was typed as a female by both the AmpFlSTR SGM plus and GenePrint kits.
      Subsequent, karyotyping of the soldier's blood sample showed no abnormalities.
      These results suggest that the determination of sex, based on the amelogenin
      test, should be interpreted cautiously.

PMID- 15027541
TI  - Unusual association of three rare alleles and a mismatch in a case of paternity
      testing.
AB  - This study reports a paternity case analyzed by the AmpFlSTR Identifiler Kit (AB)
      in which father and daughter shared three rare alleles for D19S433, D18S51 and
      TH01 microsatellites. The case also showed an apparent exclusion, due to a
      mutation at the D3S 1358 microsatellite. Sequencing analysis was performed to
      assess the size of the rare alleles and to establish their structure, which
      revealed some molecular variations in regions flanking the motif repeats.

PMID- 15027543
TI  - Dr. Walter McCrone's contributions to microscopy workshops and the certification
      of criminalists.
AB  - Walter McCrone was not only a remarkable forensic microscopist, but also a
      skilled grants man and devoted scientific professional. This article briefly
      recounts his activities in the 1970s and 80s where he played a major role in
      securing grant funds to sponsor microscopy training around the country, and in
      using his considerable professional influence to advance the cause of
      certification.

PMID- 15027542
TI  - Remembering Walter C. McCrone--scientist, mentor, leader and friend.
AB  - Walter C. McCrone (1916-2002) was a special person. While books, journals and
      ledgers record over 400 of his technical contributions, his true legacy is his
      inspiration and leadership. In remembering "Doc" McCrone, we honor a man
      dedicated to people, to science and to education. His passion for microscopy was
      only exceeded by his love of science, people and teaching. While he ranked
      microscopy as the first step in every scientific investigation he made use of all
      technologies in formulating and testing hypotheses. Everyone who met Walter has a
      story to tell of this man's impact on his or her life; I will tell you mine.

PMID- 15027544
TI  - Dr. McCrone's teaching methods in forensic microscopy, their nature, history, and
      durability.
AB  - The microscopy teaching activities of Walter C. McCrone started long before the
      McCrone Research Institute (McRI) was incorporated as a not-for-profit research
      institute in Chicago. McCrone obtained his first microscopy training at Cornell
      University, with Emile Monnin Chamot, and was shortly thereafter appointed a full
      instructor in chemical microscopy before obtaining his Ph.D. (in 1941). After
      leaving Cornell, he had classes at the Armour Research Foundation (now Illinois
      Institute of Technology Research Institute--IITRI) from 1942-1956 and founded
      McRI in 1960. The course and student totals from McCrone's educational activities
      are impressive. As of January, 1, 2002, the cumulative for McRI (1942-2002) is
      2,130 courses for 22,557 students. There has been an average of 600 students in
      an average of 60 classes for the last several years. Nearly all of the courses
      contain one week of intensive hands-on microscopy training with usually only one
      instructor for the entire duration of the class, making it a unique teaching
      experience for both student and Instructor. Thousands of students have
      successfully completed at least one of McCrone's specialized forensic microscopy
      (trace evidence) courses and the number will steadily increase as a result of
      McRI's continued efforts to interest forensic investigators in microscopy.

PMID- 15027545
TI  - Dr. Walter C. McCrone's contribution to the characterization and identification
      of explosives.
AB  - Dr. McCrone was an amazing individual, possessing many talents and having many
      interests. He especially loved applying polarized light microscopy (PLM) to
      answering the question-at-hand and solving problems. He applied PLM to many
      different fields including the identification of air pollution particles,
      asbestos identification, art conservation, pharmaceuticals, industry problems and
      forensic sciences. A field that I believe he enjoyed the most was the
      characterization and identification of explosives. Throughout his life he worked
      on, gave presentations and published articles on the characterization and
      identification of explosives. Also, he encouraged other scientists to give
      presentations and publish on the subject by providing "behind the scene" advice
      and/or be a co-author on a paper. He unselfishly taught others how to apply PLM
      and incorporate this invaluable tool into their analytical scheme.

PMID- 15027546
TI  - Dr. Walter C. McCrone--his contributions to environmental microscopy.
AB  - This paper briefly highlights Dr. McCrone's contributions to the recently
      emerging field of forensic environmental microscopy. Few, if any, criminalists
      are not familiar with Dr. Walter C. McCrone's voluminous contributions to the
      field of forensic microscopy and the analyses of micro and ultra micro transfer
      (trace) evidence. Dr. McCrone was renowned for his life long efforts in promoting
      the application of the Polarized Light Microscope (PLM) to problem solving. It is
      therefore not surprising that Dr. McCrone would also apply his analytical and
      deductive skills employing the PLM to problems in environmental analysis. He is
      well known for his many publications dealing with the analysis of asbestos and
      asbestos like materials by PLM. His philosophy of presenting intense professional
      training courses stressing the practical applications of the PLM carried over to
      a series of courses offered to students requiring education in other areas of
      microscopical analysis. Through McCrone Research Institute, Dr. McCrone can be
      said to have been responsible for the training of a large majority of
      microscopists who literally analyzed tens of millions of samples. These analyses
      were performed utilizing methodologies developed predominately by him and adopted
      by regulatory agencies in the United States and abroad. The methods he fostered
      are a major part of the arsenal of microscopical techniques employed by forensic
      environmental microscopists in their efforts to identify a manufacturer of an
      insulation product for the purpose of litigation.

PMID- 15027548
TI  - Published works of Walter C. McCrone.

PMID- 15027547
TI  - A selection of some of Dr. McCrone's high and low profile cases in the forensic
      analysis of art.
AB  - Throughout Dr. McCrone's active professional career of over 60 years, he worked
      on many cases involving the forensic analysis of art. This is an overview of a
      small portion of these cases. Included (exposed as fakes) are the Shroud of
      Turin, the Vinland Map, Mayan pottery illustrations and Larionov pastels. Also
      included, with strong support for authentication, are three paintings attributed
      to Manet, Giorgione, and Leonardo da Vinci.

PMID- 15027549
TI  - Development of a finger printing device for use on a mobile robot.
AB  - In this paper, we describe the development of a device for fuming fingerprints
      with cyanoacrylate (Super Glue) to enable police tactical units to obtain
      fingerprint evidence from suspicious packages using a remote-controlled robot.
      Through a series of initial experiments and preliminary designs, we show that
      effective cyanoacylate fuming requires sufficient heat, humidity, and airflow.
      This work led to the development of a final working prototype, called robot
      accessory for fuming fingerprint evidence (RAFFE), which is currently being field
      tested by the Calgary Police Service.

PMID- 15027550
TI  - Attributes of specialist search dogs--a questionnaire survey of UK dog handlers
      and trainers.
AB  - The ideal and actual characteristics of specialist search dogs have been examined
      in questionnaire surveys of 244 dog handlers and trainers from the six main UK
      dog-using Government agencies. The ten most important characteristics were (ideal
      level in brackets): acuity of sense of smell (very high), incentive to find an
      object which is out of sight (very high), health (very high), tendency to hunt by
      smell alone (very high), stamina (very high), ability to learn from being
      rewarded (very high), tendency to be distracted when searching (very low);
      agility (high), consistency of behaviour from day to day (high), motivation to
      chase an object (high). Significant differences between actual and ideal levels
      were found for 22 of the 30 characteristics, predominantly in undesirable
      attributes, suggesting that there is scope for significant improvement in
      operational effectiveness.

PMID- 15027551
TI  - Crime scene ethics: souvenirs, teaching material, and artifacts.
AB  - Police and forensic specialists are ethically obliged to preserve the integrity
      of their investigations and their agencies' reputations. The American Academy of
      Forensic Sciences and the Canadian Society of Forensic Science provide no
      guidelines for crime scene ethics, or the retention of items from former crime
      scenes. Guidelines are necessary to define acceptable behavior relating to
      removing, keeping, or selling artifacts, souvenirs, or teaching specimens from
      former crime scenes, where such activities are not illegal, to prevent potential
      conflicts of interest and the appearance of impropriety. Proposed guidelines
      permit the retention of objects with educational value, provided they are not of
      significance to the case, they are not removed until the scene is released,
      permission has been obtained from the property owner and police investigator, and
      the item has no significant monetary value. Permission is necessary even if
      objects appear discarded, or are not typically regarded as property, e.g., animal
      bones.

PMID- 15027552
TI  - An example of the use of forensic palynology in assessing an alibi.
AB  - A man was found shot in the back on Mount Holdsworth in the Tararua Ranges north
      of Wellington, the capital city of New Zealand. Police investigations pinpointed
      one individual who had been seen in the area, knew, and had the means and motive
      to kill the victim. His alibi was that an eyewitness was mistaken as he never had
      been in the area and the jacket he was reported to have been wearing had been
      purchased in The Netherlands and brought to Wellington, where it never had left
      the city. Furthermore the distinctive board shorts that he was reported to have
      been wearing had been purchased in a small coastal New Zealand town after the
      victim had been murdered. Pollen of Nothofagus menziesii, a mountain plant, on
      the clothing suggested that the alibi was untrue and that the clothing had been
      in mountains in the vicinity of Mount Holdsworth or a similar mountain scene
      where Nothofagus menziesii was growing.

PMID- 15027553
TI  - Variations in pulp/tooth area ratio as an indicator of age: a preliminary study.
AB  - This paper details a method for age determination of adults from single rooted
      teeth. The sample consisted of 100 Italian white Caucasian patients (46 men, 54
      women) aged between 18 and 72 years. The single rooted maxillary right canine was
      utilized in this preliminary study. Pulp/root ration, tooth length, pulp/tooth
      length ratio, pulp/tooth area and pulp/root width ratios at three different
      levels were computed. Pearson's correlation coefficients between age and these
      variables showed that the ratio between pulp and tooth area correlated best with
      age (r2 = 0.85). Stepwise multiple regression models yielded a linear
      relationship between pulp/root width at mid-root level and chronological age and
      a linear relationship when pulp/tooth area was compared to age. Statistical
      analysis indicated that these two variables explain 84.9% of variations in
      estimated chronological age. The median of the absolute value of residual errors
      between actual and estimated ages was less than four years.

PMID- 15027554
TI  - Nutritional status of deceased illicit drug addicts in Stockholm, Sweden--a
      longitudinal medicolegal study.
AB  - Autopsy investigations, toxicological analyses, and calculation of body mass
      index were performed in 1180 deceased illicit drug addicts (IDAs) in Stockholm.
      Sweden during 1988-2000, i.e., during a period of time when the general
      population in numerous countries showed a dramatic increase in the prevalence of
      overweight. Nutritional deficit in IDAs has been pointed out as a threat to their
      health as well as to their quality of life. The prevalence of overweight in
      deceased IDAs increased from 27.4% in 1988 to 45.5% in 2000. The prevalence of
      overweight among all heroin users, heroin injectors, methadone, cocaine, and
      amphetamine users was 36.0, 38.4, 43.1, 45.0 and 50.9%, respectively, the lowest
      prevalence being among users of cannabis alone and HIV-positive IDAs (22.0 and
      16.1%, respectively). In conclusion, Stockholm's IDAs are affected by the past
      decade's dramatically increased prevalence of overweight, at least to the same
      degree as the general population. The increased body weight seems not to
      influence the danger of dying upon heroin administration.

PMID- 15027555
TI  - Pig decomposition in lotic aquatic systems: the potential use of algal growth in
      establishing a postmortem submersion interval (PMSI).
AB  - While algal community composition has been examined as a qualitative indicator of
      postmortem submersion interval (PMSI), there have been no quantitative studies on
      using algal growth rates as PMSI estimators. The present study was undertaken to
      examine pig decomposition in streams and to develop a more quantitative approach
      to estimate a PMSI. Pigs and ceramic tiles were completely submerged and
      regularly sampled for periphyton growth. Five stages of decomposition were
      identified for the submerged pig carcasses according to physical characteristics.
      Algal growth rates, measured quantitatively as a function of chlorophyll-a
      concentration, were greater on pigs compared with tiles; however, microhabitat
      (pools versus riffles) did not significantly influence algal growth.
      Additionally, there was a strong correlation between algal growth rate and time
      on pigs and tile substrates. This strong correlation was observed after
      significant rain events. Our study documents for the first time a quantitative
      technique to determine the length of time a corpse has been submerged in water.
      We suggest that algal growth rates may be a useful quantitative indicator in
      criminal investigations involving corpses that are completely submerged in stream
      or riverine habitats.

PMID- 15027556
TI  - STR typing of human DNA from fly larvae fed on decomposing bodies.
AB  - In homicides with entomological evidence, it may be important to prove the
      presumed association of fly larvae to a corpse, especially if it is in doubt
      whether all maggots used for entomological expertise developed and fed on it. The
      present study demonstrates for the first time the possibility of analyzing human
      microsatellite DNA present in the digestive tract of necrophagous larvae that fed
      on decomposed bodies with a postmortem interval up to four months. The obtained
      human STR profiles support the association of a maggot to a specific corpse. In
      addition, the identification of the host species (e.g., animal source like pig)
      can be achieved by analysis of the cytochrome b gene. Maggots were collected from
      13 corpses after various postmortem intervals and STR typing and HVR
      amplifications were performed using their crop contents. In seven cases, a
      complete STR profile was established, in two cases, an incomplete set of alleles
      was obtained, and in four cases, STR typing was not successful. HVR analysis was
      successful in all cases except one. The time of storage of the maggots and the
      length of the postmortem interval up to 16 weeks appeared to have no particular
      influence on the quality of the results.

PMID- 15027557
TI  - Mitochondrial DNA and STR analyses of maggot crop contents: effect of specimen
      preservation technique.
AB  - DNA analysis of maggot crop contents can be used to identify a missing body or
      aid entomologists with interpreting evidence used for PMI estimations.
      Entomological evidence is often collected and preserved to keep identifiable
      external features intact. The preservation methods currently in use may not be
      suitable for preserving DNA in the maggot crop for later analysis. In this study,
      carrion maggots raised on human tissue were preserved under the following 8
      preservation conditions: no fluid at -70 degrees C, no fluid at 4 degrees C, no
      fluid at 24 degrees C, 70% ethanol at 4 degrees C, 70% ethanol at 24 degrees C,
      95% ethanol at 24 degrees C, Kahle's solution at 24 degrees C and formaldehyde at
      24 degrees C. Maggots were dissected following 2 weeks, 8 weeks and 6 months of
      preservation. The maggot crops were extracted, human DNA was quantitated, and an
      attempt was made at amplifying mitochondrial DNA (mtDNA) and short tandem repeat
      (STR) loci. Both mtDNA and STRs were successfully amplified from maggots stored
      in ethanol or without any preservation fluid. Formalin-containing preservation
      solutions reduced the recovery of DNA. The best results were observed from
      maggots stored without any preservation fluid at -70 degrees C.

PMID- 15027558
TI  - Death by chainsaw: fatal kickback injuries to the neck.
AB  - Each year over 3 million new chainsaws are sold in the United States. The
      operation of these newer saws combined with the millions of older chainsaws in
      circulation results in over 28,000 chainsaw-related injures annually. The
      majority of the injuries involve the hands and lower extremities with less than
      10% involving injuries to the head and neck regions. Deaths while operating a
      chainsaw are extremely rare. The most common hazards associated with chainsaws
      are injuries caused by kickback, pushback, and pull-in. Kickback is the most
      common and poses the greatest hazard. Kickback occurs when the rotating chain is
      stopped suddenly by contact with a more solid area throwing the saw rapidly
      backward toward the operator. The cause of most injuries can be traced to
      improper use of the saw or poor judgment on part of the operator. We present two
      fatal chainsaw deaths; one with an older style saw, and the other with a modern
      type. In both cases the victims died from fatal injuries received to the neck
      region from a chainsaw kickback. The first case involved a 49-year-old white male
      operating an older style chainsaw with limited safety features. The second case
      involved a 38-year old white male who was operating a newer model chainsaw
      equipped with a low kickback chain in an unsafe manner.

PMID- 15027559
TI  - Fatal bupivacaine intoxication following unusual erotic practices.
AB  - A fatal drug overdose is described which involved unusual erotic practices. A 54
      year-old male was discovered supine on the floor surrounded by sexual
      paraphernalia, syringes, and medications including three empty bottles of
      bupivacaine. Acute and chronic injection sites of the external genitalia with
      contusions, scarring, focal necrosis, and calcification were present at autopsy.
      Toxicology revealed femoral blood, heart blood, and vitreous bupivacaine
      concentrations of 3.8, 2.8 and 1.3 mg/L, respectively. The urine bupivacaine
      concentration was 11.4 mg/L. The cause of death was attributed to bupivacaine
      intoxication and the manner of death was accidental.

PMID- 15027560
TI  - Relationships between the deinstitutionalization of healthcare for patients with
      mental disorder, substance abuse, and isolated death.
AB  - Isolated death (ID) (i.e., dying alone without anyone noticing for several days)
      has been suggested to be related to social isolation, mental disorder, and
      alcohol and/or drug abuse. A major transfer of patients with a mental disorder
      and/or alcohol and/or drug abuse from institutionalized care to treatment as
      outpatients has been enacted in Sweden during the past decade. On the basis of
      the assumption that such deinstitutionalization is likely to result in increased
      social isolation, our working hypothesis was that the incidence of ID among
      patients belonging to these categories has increased in Sweden. The present study
      involved all deaths subjected to a medicolegal examination in Stockholm County
      (with a population of approximately 1.9 million people) during the period 1992
      2000. The pattern of ID (defined as cases involving a postmortem delay between
      death and discovery of at least 1 week), as well as the incidence of fatalities
      subjected to medicolegal examination with a record of mental disorder and/or
      alcohol and/or drug abuse was evaluated. Throughout this period, the proportion
      of the deceased with a record of a mental disorder was high among all the cases
      examined and higher still among the cases of ID, especially among those younger
      than 65 years of age. There was a rather limited increase in the incidence of ID
      and a much more pronounced increase in the number of former psychiatric patients
      whose deaths were subjected to medicolegal examination, but did not satisfy the
      criteria for ID. A record of alcohol and/or drug abuse was more common than a
      diagnosis of mental disorder among both the males and females who died at an age
      of less than 65, with a clear difference between the cases of ID and non-ID in
      the case of men. There was no significant increase in incidence over the course
      of this study. Thus, this study reveals a slight increase in the number of IDs
      and a more pronounced increase in the number of medicolegal examination of non
      IDs of individuals with a record of a mental disorder.

PMID- 15027562
TI  - Differentiation of black gel inks using optical and chemical techniques.
AB  - Gel ink pens have become a common writing instrument in the United States.
      Questioned document examiners often attempt to optically differentiate gel inks
      from each other and from other non-ballpoint ink writings (e.g., those from
      roller-ball pens). Since early formulations were primarily pigment-based, they do
      not elute when analyzed by thin-layer chromatography. However, recent gel ink
      formulations (i.e., within the past five years) include dye-based inks that can
      be easily separated. This study differentiates black gel inks using optical and
      chemical techniques. The techniques include: microscopy, visible and near
      infrared reflectance, near infrared luminescence, thin-layer chromatography
      (TLC), spot tests, and gas chromatography/mass spectrometry (GC/MS). As a result
      of this study a flow chart has been developed allowing for a systematic
      determination of a questioned ink. In addition, an analysis of volatile compounds
      found in gel inks revealed that there are some unique ingredients that may be
      found in gel inks that are not typically found in other non-ballpoint inks.

PMID- 15027561
TI  - Enucleation in psychosis associated with aqueductal stenosis.
AB  - Reports of self-enucleation are frequent in medical literature, but cases of
      enucleation towards another are rare. We report the case of a man, 20 years of
      age, who suffered from psychosis with hydrocephalus and aqueductal stenosis that
      required a forensic psychiatric investigation to ascertain whether he was of
      unsound mind when he assaulted and enucleated the right eye of an officer and led
      to the surgical enucleation of the victim's left eye. Based on his clinical
      interviews and hospitalization record, we conclude that at the time of the
      assault, he was suffering from a delusional disorder with religious and demonic
      content, visual and auditory hallucinations, illusion phenomena, delusional
      interpretations, imaginative elements, a feeling of terror, and command
      hallucinations that compelled him to perform the act of aggression.

PMID- 15027563
TI  - Measurement of chemical analytes in vitreous humor: stability and precision
      studies.
AB  - The analytic accuracy and precision for measurement of chemical analytes in
      vitreous humor (VH) are critical if results are to be used in forensic pathology.
      The purpose of our study was to demonstrate the stability and the reproducibility
      of VH sodium, potassium, chloride, glucose, urea nitrogen, acetone, and beta
      hydroxybutyrate in specimens obtained from both eyes in medical examiner cases.
      We also compared with calculated VH osmolalities. Small but significant increases
      were observed in VH electrolyte concentrations in specimens refrigerated 6-12
      months: sodium pre 144 mmol/L, post 151 mmol/L; potassium pre 12.0 mmol/L, post
      12.8 mmol/L; chloride pre 121 mmol/L, post 123 mmol/L. No differences were
      observed between eyes, and within-day precision for all electrolyte measurements
      were excellent, (<1%). Frozen specimens showed significantly higher measured (439
      mOsmol/kg) as compared with calculated osmolality (305 mOsmol/kg), with 1% within
      day precision and no significance between eye variation for glucose and urea
      nitrogen. In 20 of 24 medical cases selected for possible ketoacidosis,
      measurement of beta-hydroxybutyrate concentrations appears to be a promising
      diagnostic biomarker for confirming suspected ketosis in medical examiner cases
      by means of VH analysis.

PMID- 15027564
TI  - Methadone-related deaths in Palm Beach County.
AB  - The authors reviewed cases investigated by the Palm Beach Medical Examiner's
      Office in which postmortem toxicologic studies indicated the presence of
      methadone over the period from 1998 to 2002, to examine the role of the drug in
      these deaths. There were 139 methadone-positive cases, including 75 in which the
      death was attributed to combined drug toxicity and 23 to methadone toxicity
      alone. Methadone was most frequently used in conjunction with other prescription
      or illicit drugs, most commonly benzodiazepines and/or cocaine. There was
      considerable overlap in the postmortem blood methadone concentrations among the
      groups. Concentrations ranged from 0.114 mg/L-1.939 mg/L (mean .0559 mg/L) in
      cases where death was attributed to methadone toxicity; 0.050 mg/L-1.903 mg/L
      (mean 0.411 mg/L) in cases of combined drug toxicity; 0.069 mg/L-0.644 mg/L (mean
      0.224 mg/L) in deaths attributed to other drugs; 0.062 mg/L-1.090 mg/L (mean
      0.344 mg/L) among deaths attributed to natural causes and 0.072 mg/L-2.7 mg/L
      (mean 0.605 mg/L) among deaths due to trauma. The concentrations of methadone
      detected indicate that it may not be possible to establish a lethal methadone
      range because some deaths occurred at methadone concentrations below previously
      reported lethal ranges, and because of the presence of other drugs. Determining
      the cause of death in methadone-positive cases necessitates correlation with
      autopsy results and investigative findings.

PMID- 15027565
TI  - Reliable, sensitive, rapid and quantitative enzyme-based assay for gamma
      hydroxybutyric acid (GHB).
AB  - Several assays for gamma-hydroxybutyrate (4-hydroxybutyrate, GHB) have been
      developed based on the enzyme gamma-hydroxybutyrate dehydrogenase (GHB-DH).
      Enzymatic oxidation of GHB by NAD+ is coupled to diaphorase-mediated reduction of
      pro-dye to yield colored product. GHB-DH from Ralstonia eutropha was cloned and
      expressed as a stable fusion protein easily purified by affinity chromatography.
      Quantitative initial velocity and endpoint versions of the assay in solution are
      described. Michaelis-Menten parameters for oxidation of GHB and ethanol were
      estimated. A semi-quantitative "dipstick" version of the assay on paper also is
      described. Both solution endpoint and "dipstick" assays are sensitive to about
      0.05 mg GHB/mL using 10 microL of sample. Ethanol at concentrations possible in
      urine and agents used to stabilize physiological fluids for forensics analysis do
      not interfere significantly. The "dipstick" assay also allows detection of GHB in
      alcoholic beverages after evaporation of about one-fourth drop of beverage before
      testing. The enzymatic assay for GHB is reliable, sensitive, inexpensive and
      rapid.

PMID- 15027567
TI  - Hallucinations with zolpidem and fluoxetine in an impaired driver.
AB  - A 54-year-old male was observed driving erratically. The subject displayed both
      horizontal and vertical nystagmus and poor balance on field sobriety tests
      (FST's). Further observations included slow movements, breathing, and speech,
      extremely poor coordination, lack of convergence, and pupils with slow reaction
      to light. The subject related he was seeing roadway lines doubled and felt a
      hallucinogenic effect. Breath alcohol results were negative. Blood tests found
      zolpidem and fluoxetine in addition to hydrocodone at therapeutic levels. This
      case is presented as an example of hallucinogenic effects from the combination of
      zolpidem and serotonin reuptake inhibitors.

PMID- 15027566
TI  - Hyaluronidase as a liquefying agent for chemical analysis of vitreous fluid.
AB  - Vitreous humor is a suitable specimen for postmortem clinical chemistry because
      the analytes remain relatively stable after death and they closely reflect blood
      levels immediately prior to death. The viscous nature of vitreous fluid, however,
      presents analytical problems including imprecision and inaccuracy. Various
      preanalytical treatments, such as boiling, high speed centrifugation,
      microfiltration and dilution have been used. These techniques are labor intensive
      and add to imprecision and inaccuracy. Because glycosaminoglycans contribute
      significantly to the viscosity of vitreous humor, we used hyaluronidase as a
      liquefying agent. We compared the results of analyses in 33 vitreous humor
      specimens after hyaluronidase treatment with the results after either no
      treatment or specimen dilution. Seventeen of the 33 specimens could not be
      analyzed without dilution. Even after dilution, several analytes still could not
      be measured. Hyaluronidase treatment negated the need for sample dilution and had
      no significant effect on the analyses.

PMID- 15027568
TI  - The distribution of sevoflurane in a sevoflurane induced death.
AB  - The distribution of sevoflurane (fluoromethyl 2,2,2,-trifluoro-1
      (trifluoromethyl) ethyl ether) in blood, urine, liver, kidney, vitreous humor,
      and tracheal aspirate is presented from a subject with a sevoflurane induced
      death. Sevoflurane is a nonflammable general anesthetic administered by
      inhalation of vaporized liquid. Although general inhalation anesthetics have the
      potential to be fatal if not properly administered, the incidence of abuse is
      minute in comparison to other illicit drugs. Currently, there are no citations in
      the literature defining the body distribution of sevoflurane in a sevoflurane
      induced death. The decedent was found lying in a bed with an oxygen mask
      containing a gauze pad secured to his face. Three empty bottles and one partially
      full bottle of Ultane (sevoflurane) were found with the body in addition to two
      pill boxes containing a variety of prescription and non-prescription drugs.
      Serum, urine and gastric contents from the deceased were screened for numerous
      drugs and metabolites using a combination of thin layer chromatographic,
      colorimetric and immunoassay techniques. Analysis of biological specimens from
      the deceased revealed the presence of: amphetamine, caffeine, pseudoephedrine,
      nicotine, nicotine metabolite, and valproic acid. Sevoflurane concentrations were
      determined by headspace gas chromatography with flame ionization detection and
      revealed concentrations of 26.2 microg/mL in the blood, 105 microg/mL in the
      urine, 31.9 microg/mL in the tracheal aspirate, 86.7 microg/mL in the vitreous
      humor, 30.8 mg/kg in the liver, and 12.8 mg/kg in the kidney. The decedent had
      pathologies consistent with respiratory suppression including pulmonary
      atelectasis, pulmonary edema, and neck vein distention. The official cause of
      death was respiratory suppression by sevoflurane and the manner of death was
      unclear.

PMID- 15027570
TI  - Distribution of allele frequencies for two tetranucleotide repeats (FES and
      D2S1328) among five Indian population groups.
AB  - POPULATION: The distribution of allele frequencies have been analyzed at two
      short tandem repeat (STR) loci FES and D2S1328 among five anthropologically
      distinct ethnic groups of India namely Ezhavas, Nairs, Arayas, Vishwakarma and
      Muslims. Muslims are religio-ethnic group while other populations mentioned above
      belong to distinct section of Hindu religion. All these populations are from
      Kollam district of Kerala in South India and speak Malayalam, an Indo-Dravidian
      language. A total of 264 random, healthy individuals of FES and 197 individuals
      for D2S1328 were analyzed.

PMID- 15027569
TI  - Eight short tandem repeats (STR) frequencies for descendants from Terena
      indigenous Brazilian group.
AB  - POPULATION: descendants from Terenas an indigenous group.

PMID- 15027571
TI  - Population genetics of eleven STR loci in the State of Sergipe, Northeastern
      Brazil.
AB  - POPULATION: Over 259 unrelated individuals from the State of Sergipe
      (Northeastern Brazil).

PMID- 15027572
TI  - Allele frequencies and statistical parameters for Penta E and Penta D STR loci in
      Cordoba (Argentina) population.
AB  - POPULATION: Urban and countryside population of Cordoba (Argentina).

PMID- 15027573
TI  - Minimal Y-chromosome haplotypes plus DYS287 in Jewish populations.
AB  - POPULATION: A total of 71 Jewish individuals obtained from the collection of The
      National Laboratory for the Genetics of Israeli Populations at Tel-Aviv
      University: 14 Ashkenazi, 21 Sephardic (from Turkey), 23 North African (from
      Morocco, Libya and Tunicia) and 13 Oriental (from Iraq and Iran).

PMID- 15027574
TI  - Allele frequencies of six STR loci (D3S4536, D4S2633, D5S2500, D9S925, D9S1118
      and D20S481) in Chinese Han population.
AB  - POPULATION: Over 265 unrelated individuals from Han population living in Wuhan,
      China.

PMID- 15027575
TI  - Allele frequencies for markers CSF1PO, TPOX, TH01, F13A01, FESFPS, vWA, D16S539,
      D7S820, D13S317 in the general population of Nicaragua.
AB  - POPULATION: General Hispanic-admixed individuals from Nicaragua.

PMID- 15027577
TI  - [The need for a consensus conference].

PMID- 15027578
TI  - [Definition of thrombophilia].
AB  - Thrombophilia is characterized by clinical tendency to thrombosis or molecular
      abnomalities of hemostasis that predisposes to thromboembolic disease. Hereditary
      thrombophilia may be due to antithrombin deficiency, or protein C or protein S
      deficiency. More recently, other molecular abnormalities have been described:
      activated protein C resistance due to factor V Leiden, G 20210 A polymorphism on
      the prothrombin gene, increased factor VIII plasma levels or
      hyperhomocysteinemia. Acquired thrombophilia is frequently associated with the
      antiphospholipid syndrome characterized by thrombosis and presence of lupus
      anticoagulant or phospholipid-binding antibodies. In some cases, no molecular
      abnormality is found despite recurrent thrombosis observed in patient and his/her
      family. This situation can be considered as clinical thrombophilia.

PMID- 15027576
TI  - Allele frequency distribution of two X-chromosomal STR loci in Han population in
      China.
AB  - POPULATION: 127 unrelated female and 118 unrelated male volunteer donors,
      Southwest China.

PMID- 15027579
TI  - [Epidemiology and maternal thrombosis].
AB  - The monthly incidence of deep vein thrombosis during pregnancy varies from 0.1 to
      0.8 per 1000 pregnancies, depending on the study. These figures are undoubtedly
      an underestimation because they were determined from clinical events with no
      estimation of asymptomatic forms which, in general, increase the prevalence about
      3-fold. Although the absolute figures are reliable, the consequences in terms of
      maternal mortality and post-phlebitis sequelae warrant the careful attention paid
      to this condition. Moreover, it should be recalled that the prevalence of
      superficial venous thrombosis is similar and may be associated with a risk of
      pulmonary embolism.

PMID- 15027580
TI  - [Risk factors for maternal thromboembolism: clinical predisposition].
AB  - Predisposing clinical features in pregnant women are poorly evaluated in the
      literature. Several factors are undeniable, for example extrinsic compression of
      the iliac vein (Cockett syndrome), post phlebitis disease, varicose vein disease,
      and, for most patients, unquantifiable risk factors. Careful assessment of the
      overall sensitivity to venous thrombosis, on the basis of history taking (patient
      and family), will allow better assessment of the predisposition to
      thromboembolism.

PMID- 15027581
TI  - [Risk factors for maternal thromboembolism: obstetrical circumstances].
AB  - We analyzed the statistical relationship described between the principal
      laboratory anomalies related to thrombophilia and obstetrical pathology and risk
      of maternal thromboembolism.

PMID- 15027582
TI  - [Risk factors of thromboembolism associated with pregnancy and the puerperium.
      Role of inherited and acquired thrombophilia].
AB  - Thromboembolism in pregnancy and the puerperium and inherited or acquired
      thrombophilia are associated. Thrombophilia can be revealed by pregnancy.
      Thrombotic risk during pregnancy and the puerperium is higher in asymptomatic
      women with than without thrombophilia. Antithrombin deficiency, combined
      deficiencies and homozygous or double-heterozygotes factor V Leiden and factor II
      G 20210 A mutations are associated with a higher thrombotic risk than
      heterozygote mutations or protein S and C deficiencies, whereas
      hyperhomocysteinemia does not appear as a risk factor for maternal thromboembolic
      disease. Antiphospholipid syndrome with lupus anticoagulant is strongly
      associated with thrombotic risk in pregnancy and the puerperium. Further studies
      are required to assess the thrombotic risk in women with preeclampsia as well as
      early or late recurrent pregnancy loss.

PMID- 15027583
TI  - [The risk of maternal venous thromboembolism disease. Synopsis and definition of
      high-risk groups].
AB  - Risk factors for venous thromboembolic disease, during pregnancy and post-partum,
      can be identified in as much as 75% of pregnant women, who present such an
      accident. Different risk factors are usually associated in the same women. Risk
      factors can be attribuated to the pregnant women (age over 35 years, overweight,
      varicose veins, smoking, previous deep venous thrombosis and/or pulmonary
      embolism) or to the conditions of the pregnancy (multiparity, immobilisation,
      hypertension and pre-eclampsia, cesarean delivery). Inherited or acquired
      biological thrombophilia enhance the risk of thrombosis but the magnitude of this
      effect in ante-partum, puerperium or post-partum depends on the nature of the
      abnormality. The analysis of all these risk factors and their cumulative effect
      enable classifying pregnant women into groups with very high risk, high risk or
      moderate risk for venous thromboembolism and to propose an adapted strategy to
      prevent the occurrence of such accidents.

PMID- 15027584
TI  - [Epidemiology of vascular placental disease].
AB  - Placental vascular diseases consist of obstetrical pathologies assumed to be
      linked to placental ischemia. Preeclampsia, defined as the association of
      hypertension, proteinuria and edema, occur in 3% of deliveries, in a non-selected
      population. Eclampsia, defined as the occurrence of convulsions in preeclamptic
      women, occur in 5 per 10,000 deliveries. Risk factors for preeclampsia are:
      preeclampsia in the previous pregnancy, maternal age <20 years, multiple
      pregnancies, and nulliparity. Placenta abruption, defined as premature separation
      of the placenta before delivery, occur in 5 to 15 per 1,000 deliveries. Risk
      factors are smoking, infertility, and preeclampsia or placental abruption in the
      previous pregnancy. Stillbirth, defined as fetal death between 24 weeks of
      gestation and delivery, occur in 1.5 per 1,000 deliveries, with a higher
      frequency in case of placental abruption, intrauterine growth restriction or
      preeclampsia.

PMID- 15027585
TI  - [Maternal and obstetrical risk factors of placental vascular pathology (biologic
      and epidemiological data excluded)].
AB  - The purpose is to identify maternal and prenatal risks factors for placental
      vascular disorders. We excluded biologic and epidemiological data which are
      discussed in another chapter. Maternal risks factors are pre-existing vascular
      systemic diseases. Systemic lupus erythematosus (antiphospholipid antibodies are
      studied in another chapter) is a classical disease associated with unfavorable
      outcome, particularly when the disease is not quiescent and if the patient has a
      history of previous poor outcome. Obstetricians' awareness of the influence of
      inflammatory bowel diseases on pregnancy and fetal outcome is quite poor. These
      diseases, if they are not quiescent, can induce deleterious perinatal effects.
      Type 1 or even type 2 diabetes mellitus increases the risk of preeclampsia or
      hypertension in pregnancy, particularly when there is poor glycemic control early
      in pregnancy. The duration of type 1 diabetes affects the outcome of pregnancy
      more than type 2. Smoking during pregnancy is associated with many adverse events
      including spontaneous abortion, low birth weight and placental abruption. There
      are data about the dose-response relationship between the number of cigarettes
      smoked per day and the risk of abortion. Smoking during pregnancy is also
      protective against preeclampsia and this apparent paradox suggests the complexity
      of what is called vascular placental pathology. There is a significant
      relationship between pejorative perinatal vascular outcome and the non quiescence
      of renal disease. Mid-trimester uterine artery Doppler combining bilateral
      notches and increased uterine resistance index is the best criterion to predict
      the placental vascular risk of the pregnancy. Some promising studies suggest the
      feasibility of uterine Doppler ultrasound screening early in the pregnancy during
      the first trimester. Large studies are required to confirm this practice. Uterine
      artery Doppler in combination with other tests (elevated maternal serum hCG or
      ambulatory 24-hour blood pressure monitoring at 22 weeks gestation) could be a
      more efficient predictor of vascular complications. A large-scale evaluation is
      necessary before recommendations can be made. Multiple pregnancies increase the
      risk of preeclampsia 2- or 3-fold (RR 2.62; 95% CI: 2.03-3.38). A history of
      preeclampsia is the strongest predictor of unfavorable outcome for the second
      pregnancy.

PMID- 15027586
TI  - [Is thrombophilia a risk factor for placental vascular disorders?].
AB  - First trimester recurrent fetal loss and severe second or third trimester
      placental vascular disorders are still frequently unexplained. Acquired
      biological thrombophilia (antiphospholipid syndrome, essential thrombocythemia)
      are known risk factors. Genetic thrombophilia may represent a new risk factor for
      placental vascular diseases, but reported data are conflicting. Combined
      hereditary thrombophilias are indeed a moderate risk factor, but even in these
      cases most pregnancies are normal giving healthy live birth children. Whether
      hereditary thrombophilia is associated with recurrent severe placental vascular
      disorders is unknown.

PMID- 15027587
TI  - [Vascular placental pathology in high-risk groups: definition and synopsis].
AB  - The vascular placental pathology (VPP) is associated with many etiologies. Some
      are the consequence of a maternal genetic or acquired predisposition. Others are
      associated with a chronic maternal disease (hypertension, lupus, obesity,
      diabetes, ...). Finally, some others are associated with placental implantation
      leading to fetal ischemia (multiple pregnancy, chorioangioma, primiparity, feto
      placental hydrops) or to environmental (altitude) or nutritional factors (famine
      and specific alimentary depressions). We classify these factors into three
      categories according to the risk level (moderate, significant and elevated).
      While any of these factors can increase the risk of VPP, no one is sufficiently
      sensitive or specific in predict inevitable onset of VPP. In most cases VPP
      results from a combination of two (or more) risk factors. The risk factors of VPP
      classified as moderate include age (> or = 35 years), increased blood pressure
      during the second trimester of pregnancy, a new paternity, dietetic factors or
      environmental factors, smoking and controlled diabetes (class B, C), or inactive
      systemic diseases. Risk is significantly elevated among obese (BMI > or = 25),
      primiparous women, women with a past familial history (first degree) of
      preeclampsia or eclampsia, cocaine use or association of tobacco and caffeine
      use, increased placental mass (associated with twin pregnancy, fetal hydrops or
      molar pregnancy), uncontrolled diabetes, lupus, active scleroderma. Risk is
      considered to be high among patients with chronic hypertension, women with a past
      history of preeclampsia, diabetes (class D, F, R), patients with active systemic
      disease or with antiphospholipid antibodies or women with lupus or renal lesions
      and/or proteinuria as well as chronic kidney disease resulting in proteinuria,
      hypertension and renal insufficiency. Finally, the risk of VPP is considered to
      be increased in the presence of acquired thrombophilia. It remains moderate in
      the presence of isolated genetic thrombophilia, except in forms presenting with
      multiple genetic mutations or associated with an hyperhomocysteinemia. A "high
      risk group" is defined among women with past history of deep venous
      thromboembolic events outside pregnancy, or with a past history of placental
      vascular pathology (intra-uterine death, placental abruptio, severe and
      precocious placental, intra-uterine growth retardation, early and repetitive
      fetal loss) and who, in addition, present with acquired thrombophilia
      (antiphospholipid antibodies, thrombocytemia), unique homozygous genetic
      thrombophilia, amultiple genetic thrombophilia or unique heterozygous genetic
      thrombophilia associated with hyperhomocysteinemia. Prophylactic treatment of
      acquired thrombophilia and of the multiple genetic forms or associated with
      hypercysteinemia is a logical rationale, particularly among women with a past
      history of placental vascular pathology, or with a past history of venous
      thromboembolic events. On the contrary, prophylaxis using low-molecular-weight
      heparin in the event of asymptomatic genetic thrombophilic mutations and for
      women without a past history of deep venous thromboembolism or vascular placental
      pathology remains controversial.

PMID- 15027588
TI  - [Thrombophilia and pregnancy: who should be tested? Which tests should be
      performed? The biologist point of view].
AB  - Pregnancy is associated with an increased risk of venous thromboembolism,
      especially in women with a congenital predisposition. The detection of these
      thrombophilias, with an autosomal dominant transmission, is justified if an
      appropriate prophylaxis is administered during pregnancy and/or post-partum. The
      aim of the prophylaxis is to prevent thrombotic events and possibly adverse
      pregnancy complications, such as pregnancy loss at the second or third trimester,
      intra-uterine fetal growth retardation or pre-eclampsia. The magnitude of the
      pregnancy-associated risk in the different thrombophilias is taken into account
      for the selection of the patients to be tested for the detection of
      thrombophilia. Tests to be performed are proposed and their interpretation
      depends on whether the patient is pregnant, receiving oral contraception or oral
      anticoagulants.

PMID- 15027589
TI  - [Thrombophilia and pregnancy: which tests for which patients? The clinician's
      point of view].
AB  - Venous thromboembolism is the leading cause of death in the ante-partum and post
      partum period. The role of genetic thrombophilia in venous thrombosis has been
      analyzed in several studies, but the role of genetic thrombophilia in fetal loss,
      intra-uterine growth restriction and pre-eclampsia is much more controversial.
      While we can give some recommendations on thromboprophylaxis of venous
      thromboembolism, data concerning the usefulness of antithrombotic treatment in
      obstetric complications of genetic thrombophilia are lacking. When a laboratory
      work-up of thrombophilia is required, all the known causes of thrombophilia must
      be checked as none of them is specific of a single clinical feature, but also
      because they can be associated in the same patient.

PMID- 15027590
TI  - [Prevention of deep vein thrombosis and preeclampsia. Therapeutic possibilities].
AB  - To prevent deep vein thrombosis during pregnancy and the puerperium, compression
      stockings and heparin have been proposed. These measures are safe for the mothers
      and their babies, however low molecular weight heparin (LMWH) must be preferred
      to unfractioned heparin if possible. The prevention of preeclampsia (PE) has been
      widely studied. Among nutrients, calcium supplementation is effective to prevent
      PE among women with a spontaneous low calcium intake, but fish oil
      supplementation is not. The effectiveness of folic acid is still controversial.
      Aspirin has been widely studied to prevent, and also treat, PE. The effectiveness
      of aspirin depends on an early administration during pregnancy and probably on
      the dose, while the best results have been observed with doses more than 60
      mg/day. The association of aspirin and LMWH was used among patients with systemic
      pathologies, and no hemorrhagic complications were described. Oral anticoagulants
      are used only among patients with mechanical heart valves, the use between the
      6th and the 12th week of pregnancy is controversial, because of an increased risk
      of fetal malformation, and near term because of an increased risk of neonatal
      hemorrhage.

PMID- 15027591
TI  - [Indications and monitoring of antithrombotic prophylaxis for venous
      thromboembolism during pregnancy and post-partum].
AB  - Pregnancy and puerperium are well-known risk factors for venous thromboembolism,
      but the actual incidence of the disease is low (about 1/1,500 pregnancies).
      Pregnancy-associated venous thromboembolism is rare, though it is still the
      second cause of maternal death in France. Several types of prophylaxis are
      available, mainly clinical vigilance and aggressive investigation of women with
      symptoms of venous thromboembolism, or antithrombotic prophylaxis. Given the low
      incidence of the pathology, it seems desirable to select high-risk groups of
      women for such strategies. The most studied and identified risk factors are prior
      episodes of venous thromboembolism and biological thrombophilias. Prophylaxis
      through low molecular weight heparin during pregnancy and the puerperium should
      be considered mainly in these two groups. Noteworthy, no prospective and
      randomized study is available, and treatment recommendations are grade C.

PMID- 15027592
TI  - [Preventing adverse obstetric outcome in women with thrombophilia].
AB  - Thrombophilia may represent a new risk factor for placental vascular disorders.
      Thromboprophylaxis with low doses of heparin and aspirin may be discussed in
      order to reduced adverse obstetric outcomes. No randomized controlled trials are
      currently published in the literature. Thromboprophylaxis may be unwarranted in
      asymptomatic women because of the lack for an association between thrombophilia
      and pregnancy outcome. Women with antiphospholipid syndrome are at high risk for
      pregnancy loss and maternal complications. Pregnancy in women with
      antiphospholipid syndrome appears to be improved by thromboprophylaxis, but
      adverse obstetric outcome may occur despite treatment. Thromboprophylaxis is
      recently reported in women with previous poor obstetric outcomes. These
      preliminary observational studies are still insufficient to recommend a large
      diffusion for thromboprophylaxis. Prevention for adverse outcomes with a low
      fixed dose of heparin may only be discussed in women with previous late fetal
      loss or intrauterine fetal death.

PMID- 15027593
TI  - [Therapeutic indications in placental vascular diseases (antiphospholipid
      syndrome and thrombophilia) and side effects of the different treatments used].

PMID- 15027594
TI  - [Which patients are at risk for pregnancy vascular diseases?].

PMID- 15027596
TI  - [Venous thromboembolic disease and pregnancy: therapeutic tools and indications,
      risk level assessment].

PMID- 15027595
TI  - [Iatrogenic effects of the treatment with heparin in pregnancy].

PMID- 15027597
TI  - [Thromboembolic risk factors in pregnancy and postpartum as a function of
      obstetrical and non-obstetrical clinical history].

PMID- 15027598
TI  - [Facing the risk of pregnancy vascular diseases: which tests should be carried
      out and in which patients?].

PMID- 15027599
TI  - [Which patients are at risk of pregnancy vascular diseases as a function of their
      biological status?].

PMID- 15027600
TI  - [Thrombophilia and pregnancy. Prevention of maternal thrombotic and placental
      risks].

PMID- 15027601
TI  - [What I will keep in mind of the Recommendations for my personal practice].

PMID- 15027602
TI  - Echinococcosis: disease, detection and transmission.
AB  - Echinococcosis is one of the world's most geographically widespread parasitic
      zoonoses, with transmission occurring in tropical, temperate and arctic biomes.
      Most human infections are due to Echinococcus granulosus transmitted between
      domestic dogs and livestock, but this cosmopolitan species also cycles between
      wild carnivores (principally canids) and wild ungulates. The other species with
      significant zoonotic potential is E. multilocularis that occurs naturally in fox
      definitive hosts and small mammal intermediate hosts. These two species cause
      human cystic or alveolar echinococcosis respectively, which may be considered
      serious public health problems in several regions including developed countries.
      This review provides an introductory overview to the Supplement and summarises
      the biology and epidemiology of these two related cestodes with an emphasis on
      applied aspects relating to detection, diagnosis and surveillance in animal and
      human populations, and includes aspects of transmission ecology, and also
      considers aspects of community epidemiology and potential for control.

PMID- 15027603
TI  - Application of ultrasound in diagnosis, treatment, epidemiology, public health
      and control of Echinococcus granulosus and E. multilocularis.
AB  - The last 30 years have seen an impressive use of ultrasonography (US) in many
      fields of veterinary and clinical medicine and the technique is being
      increasingly applied to a wide variety of parasitic infections including the
      cestode zoonoses Echinococcus granulosus and E. multilocularis. US provides real
      time results which are permanently recordable with a high resolution and
      diagnostic accuracy. These properties, coupled with the clinical value of the
      images obtained and the non-invasive nature of the test which is safe, require no
      special patient preparation time; it is easy to operate and this has resulted in
      the establishment of US as the diagnostic technique of choice for cystic (CE) and
      alveolar (AE) echinococcosis. The lack of ionizing radiation and side-effects
      mean that examination times are not restricted. The hand-held probes facilitate
      what amounts to a rapid, bloodless non-invasive laparotomy, enabling a search
      from an infinite number of angles for lesions producing information on their
      number, size and type of cysts, their location and clinical implications. Such
      clinical information has facilitated the development of treatment protocols for
      different cyst types. Less invasive surgical techniques, such as US guidance for
      PAIR (Puncture, Aspiration, Injection, Re-aspiration), PAIRD (PAIR plus Drainage)
      or PPDC (Percutaneous Puncture with Drainage and Curettage) are also possible.
      Longitudinal US studies have facilitated monitoring the effects of the outcome of
      treatment and chemotherapy. Portable ultrasound scanners which today weigh as
      little as a few pounds, powered by battery or generators have facilitated the use
      of the technique in mass community-based screening studies. The majority of these
      studies have been conducted in remote, low socio-economic areas where there were
      few, if any, hospitals, veterinary facilities, schools or trained personnel. The
      surveys led to the discovery of unexpectedly high prevalences of CE and AE in
      asymptomatic individuals of endemic areas and especially amongst transhumant or
      nomadic pastoralists living in various parts of the world. Screening for CE and
      AE is justified as an early diagnosis leads to a better prognosis following
      treatment. The application of US in field and clinical settings has led to a
      better understanding of the natural history of CE and AE and to the development
      of a WHO standardized classification of cyst types for CE. This classification
      can be used in helping define the treatment options for the different cysts found
      during the surveys, which in turn can also be used to calculate the public health
      cost of treating the disease in an endemic community. The case mix revealed can
      also influence the specificity (particularly proportions of cyst types CE4 and
      CE5 and cystic lesions--CL) of US as a diagnostic test in a particular setting.
      Community based US surveys have provided new insights into the public health
      importance of CE and AE in different endemic settings. By screening whole
      populations they disclose the true extent of the disease and reveal particular
      age and sex risk factors. Through the treatment and follow-up of all infected
      cases found during the mass screening surveys a drastic reduction in the public
      health impact of the disease in endemic communities can be achieved. Educational
      impacts of such surveys at the national, community and individual levels for both
      professional and lay people are beginning to be appreciated. The translation of
      the information gained into active control programmes remains to be realized. In
      areas where intermediate hosts, such as sheep and goats, are not slaughtered in
      large numbers mass US screening surveys to determine the prevalence of CE in
      livestock has proved possible. Longitudinal studies in such intermediate hosts
      would reveal changes in prevalence over time, which has been used as a marker for
      control success in other programmes. Mass US screening surveys in an ongoing
      control programme in Argentina has demonstrated the early impact of control in
      the human population and identified breakthroughs in that control programme. Mass
      US screening surveys must adhere to the highest ethical standards and the outcome
      of surveys should result in the application of appropriate WHO recommended
      treatment options for different cyst types. Follow-up strategies have to be in
      place prior to the implementation of such surveys for all infected individuals
      who do not require treatment and for all suspected, but not confirmed, cases
      found during the surveys. The use of US in community screening surveys has
      revealed the complexity of ethical issues (informed consent, confidentiality,
      follow-up, detection of lesions that are not the focus of the study etc) and also
      provided real solutions to providing the most ethical guidelines for the early
      detection and treatment of CE and AE.

PMID- 15027604
TI  - Molecular tools for studies on the transmission biology of Echinococcus
      multilocularis.
AB  - Two novel approaches for diagnosis of intestinal Echinococcus multilocularis
      infection, the detection of E. multilocularis-specific coproantigens in ELISA and
      of copro-DNA by PCR, have been successfully implemented. These methods have
      proven their value for the post mortem and the intra vitam diagnosis of E.
      multilocularis in definitive hosts. They have also made novel approaches possible
      to study the transmission biology of the parasite as they allow detection of the
      infection in faecal samples collected in the environment. Coproantigen detection
      is the diagnostic method of choice as it is sensitive, fast and cheap. Studies on
      faecal samples collected in the field revealed that coproantigen detection did
      reflect the different prevalences in fox populations as assessed from foxes at
      necropsy and also the effect of deworming efforts in foxes as achieved by long
      term distribution of praziquantel-containing baits. The use of PCR for routine
      diagnostic or large-scale purposes is hampered by the fact that DNA extraction
      from faecal material is a very laborious task. Therefore, PCR is rationally used
      for confirmatory purposes of copro-antigen-positive samples. As taeniid eggs
      cannot further be differentiated morphologically, PCR is the method of choice to
      identify E. multilocularis infections in faecal or environmental samples
      containing taeniid eggs. In intermediate rodent hosts, PCR is routinely used in
      epidemiological studies for identifying E. multilocularis from liver lesions
      which are often very small, atypical or calcified.

PMID- 15027605
TI  - Transmission ecology of Echinococcus in wild-life in Australia and Africa.
AB  - Following the introduction of E. granulosus into Australia with domestic animals
      during European settlement, the parasite quickly became established in the E.
      granulosus-naive native animals of the continent. The distribution of E.
      granulosus in wildlife in Australia is restricted by rainfall, but nevertheless
      the parasite is currently widespread and highly prevalent in many areas including
      numerous national parks and privately owned farms. The human population of Africa
      is rapidly increasing resulting in ever more pressure on wild-life populations
      and habitat. National parks, reserves and conservation areas now provide
      important tracts of preserved habitat for maintaining populations of wildlife
      that are also important in the maintenance of E. granulosus. In some parts of
      Africa, hydatid-infected humans provide a source of E. granulosus infection to
      wildlife definitive hosts. In many areas felids may also act as important
      definitive hosts for E. granulosus with the parasite being maintained in a
      prey/predator relationship between lions and a range of intermediate hosts.
      Populations of E. granulosus-infected wild-life both in Australia and Africa act
      as important reservoirs in perpetuating the transmission of E. granulosus to both
      domestic animals and humans. In Australia, E. granulosus-infected wild-life is
      infiltrating urban areas and currently represents a potentially important new
      public health problem.

PMID- 15027606
TI  - Cystic echinococcosis in the Arctic and Sub-Arctic.
AB  - The northern biotype of Echinococcus granulosus occurs throughout the holarctic
      zones of tundra and taiga, from eastern Fennoscandia to the Bering Strait in
      Eurasia and in North America from arctic Alaska approximately to the northern
      border of the United States. The cycle of the cestode is complex in taiga at
      lower latitudes, because of the greater diversity of potential hosts. In the
      Arctic and Subarctic, however, four patterns of predator/prey relationships may
      be discerned. Two natural cycles involve the wolf and wild reindeer and the wolf
      and elk (moose), respectively. Where deer of the two species coexist, both are
      prey of the wolf; the interactions of the wolf and elk are here described on the
      basis of long-term observations made on Isle Royale (in Lake Superior near the
      southern limit of taiga), where only the wolf and elk serve as hosts for E.
      granulosus. A synanthropic cycle involving herding-dogs and domesticated reindeer
      caused hyperendemicity of cystic echinococcosis in arctic Eurasia, mainly in
      northeastern Siberia. The 4th pattern, a semi-synanthropic cycle, formerly
      existed in Alaska, wherein sled-dogs of the indigenous hunters became infected by
      consuming the lungs of wild reindeer. The sequence of changes in life-style
      inherent in the process of acculturation affected the occurrence of cystic
      echinococcosis among nomadic Inupiat in arctic Alaska. When those people became
      sedentary, the environs of their early villages soon became severely contaminated
      by faeces of dogs, and cases of cystic echinococcosis occurred. Compared to
      cystic echinococcosis caused by E. granulosus adapted to synanthropic hosts (dog
      and domestic ungulates), the infection produced by the northern biotype is
      relatively benign. Nearly all diagnosed cases of cystic echinococcosis (> 300) in
      Alaska have occurred in indigenous people; only one fatality has been recorded
      (in a non-indigenous person). After sled-dogs were replaced by machines, cases
      have become rare in Alaska. A similar effect has been observed in Fennoscandia,
      in the Saami and domesticated reindeer. Recent records indicate that the
      prevalence of cystic echinococcosis is increasing in Russia, suggesting that dogs
      are used there in herding.

PMID- 15027607
TI  - Epidemiology of alveolar echinococcosis with particular reference to China and
      Europe.
AB  - Human alveolar echinococcosis (AE), caused by the metacestode of the fox tapeworm
      Echinococcus multilocularis, is the most pathogenic zoonosis in temperate and
      arctic regions of the northern hemisphere. Prospective collection of human cases
      in some areas and mass screenings using ultrasound imaging and confirmation with
      serological techniques have markedly improved our knowledge of the epidemiology
      of the disease in humans during the past two decades. Transmission occurs when
      eggs of the tapeworm, excreted by the final hosts (usually foxes but also dogs,
      wolves and cats), are ingested accidentally by humans or during normal feeding by
      a variety of rodents and small lagomorphs. However, the species of host animals
      differ according to regional changes in mammalian fauna. This review mostly
      focuses on epidemiology of alveolar echinococcosis in those parts of the world
      where new and more accurate epidemiological data are now available, i.e. China
      and Europe, as well as on new epidemiological trends that can be suspected from
      recent case reports and/or from recent changes in animal epidemiology of E.
      multilocularis infection. The People's Republic of China (PRC) is a newly
      recognized focus on AE in Asia. Human AE cases were firstly recognized in
      Xinjiang Uygur Autonomous Region and Qinghai Provinces at the end of 1950s and
      infected animals were first reported from Ningxia in central China and northeast
      of Inner Mongolia in the 1980s. E. multilocularis (and human cases of AE) appears
      to occur in three areas: (1) Northeastern China (northeast focus): including
      Inner Mongolia Autonomous region and Heliongjiang Province (2) Central China
      (central focus): including Gansu Province, Ningxia Hui Autonomous Region, Sichuan
      Province, Qinghai Province and Tibet Autonomous Region and (3) Northwestern
      China: including Xinjiang Uygur Autonomous Region, bordered with Mongolia,
      Russia, Kazakhstan and Kyrgyzstan. The highest prevalence of the disease, up to
      15 per cent of the population in some villages, is reached in China. In Europe,
      data from the European Echinococcosis Registry (EurEchinoReg: 1982-2000) show 53
      autochthonous cases of AE in Austria, 3 in Belgium, 235 in France, 126 in
      Germany, 1 in Greece, and 112 in Switzerland, and 15 'imported' cases, especially
      from central Asia; 14 cases were collected in Poland, a country not previously
      considered endemic for AE. Improved diagnostic technology, as well as a real
      increase in the infection rate and an extension to new areas, can explain that
      more than 500 cases have been reported for these 2 decades while less than 900
      cases were published for the previous 7 decades. New epidemiological trends are
      related to an unprecedented increase in the fox population in Europe, to the
      unexpected development of urban foxes in Japan and in Europe, and to changes in
      the environmental situation in many countries worldwide due to climatic or
      anthropic factors which might influence the host-predator relationship in the
      animal reservoir and/or the behavioural characteristics of the populations in the
      endemic areas.

PMID- 15027608
TI  - Echinococcosis on the Tibetan Plateau: prevalence and risk factors for cystic and
      alveolar echinococcosis in Tibetan populations in Qinghai Province, China.
AB  - Infections by larval stages of tapeworms of the genus Echinococcus
      (echinococcosis or hydatid disease) are zoonotic infections of major public
      health importance throughout much of the world. Humans become infected through
      accidental ingestion of eggs passed in faeces of canid definitive hosts. Tibetan
      populations of China have some of the highest documented levels of infections by
      both Echinococcus granulosus and E. multilocularis, the causes of cystic and
      alveolar echinococcosis, respectively. In this study we measured the prevalence
      of cystic (CE) and alveolar (AE) echinococcosis disease in Tibetan communities in
      Qinghai, Province, China, and identified putative risk factors for both
      infections in these communities. 3703 volunteers in three predominately Tibetan
      counties of Qinghai were surveyed between June 1997 and June 1998. Parasitic
      lesions were diagnosed by imaging of characteristic space-occupying lesions in
      abdominal organs (ultrasound) or the lungs (radiographs). Specific serodiagnostic
      assays (Dot-ELISA and Em2-ELISA) were performed on sera of positively imaged
      subjects to further distinguish the disease agent. All participants completed a
      questionnaire documenting age, sex, education level, occupation, lifestyle
      (nomadic or settled), slaughter practices, drinking water source, hygienic
      practice and association with dogs. Data were analyzed using SAS version 8. 6.6%
      of the volunteers had image-confirmed infection with E. granulosus (CE) and 0.8%
      had E. multilocularis (AE) infection. The significant univariate factors for
      echinococcal infection (both CE and AE) included livestock ownership, Tibetan
      ethnicity, female gender, low income, herding occupation, limited education,
      water source, age greater than 25 years old, poor hygienic practices, offal
      disposal practices and dog care. Multivariate analysis revealed that livestock
      ownership was a significant risk factor for both forms of the disease, as well as
      age greater than 25 years, female gender, herding occupation, and being nomadic
      (vs semi-nomadic or settled). No additional significant risk factors were
      identified among the 344 nomadic participants. Being female and being older than
      25 years of age were significant factors among the 1906 semi-nomadic
      participants. Among the 1445 settled participants, allowing dogs to sleep indoors
      was statistically significant. Issues such as inadequate assessment of animal
      ownership, selection bias, disease misclassification, and loss of information may
      have led to reduction in strength of some risk factor associations and need to be
      addressed in future epidemiologic analysis of echinococcosis in this population.

PMID- 15027609
TI  - Interactions between landscape changes and host communities can regulate
      Echinococcus multilocularis transmission.
AB  - An area close to the Qinghai-Tibet plateau region and subject to intensive
      deforestation contains a large focus of human alveolar echinococcosis while
      sporadic human cases occur in the Doubs region of eastern France. The current
      review analyses and compares epidemiological and ecological results obtained in
      both regions. Analysis of rodent species assemblages within quantified rural
      landscapes in central China and eastern France shows a significant association
      between host species for the pathogenic helminth Echinococcus multilocularis,
      with prevalences of human alveolar echinococcosis and with land area under
      shrubland or grassland. This suggests that at the regional scale landscape can
      affect human disease distribution through interaction with small mammal
      communities and their population dynamics. Lidicker's ROMPA hypothesis helps to
      explain this association and provides a novel explanation of how landscape
      changes may result in increased risk of a rodent-borne zoonotic disease.

PMID- 15027610
TI  - Multi-scale spatial analysis of human alveolar echinococcosis risk in China.
AB  - Risk factors for the transmission of Echinococcus multilocularis to humans
      operate at a range of spatial scales. Over a large area, such as China, regional
      scale risk is correlated with variation in climatic conditions because of its
      effect on the spatial distribution of landscapes that can support E.
      multilocularis transmission in wildlife hosts and the probability of egg
      survival. At a local scale of a few kilometres, or tens of kilometres,
      transmission risk is related to the spatial proximity of human populations and
      landscapes with active transmission. At the patch scale, when considering
      individual villages or households, human behavioural factors are important and
      for individuals genetic and immunological factors play a role. Satellite remote
      sensing can provide landscape information at a range of spatial scales and
      provide a spatial framework within which to examine transmission patterns. This
      paper reviews the application of remotely sensed data and spatial data analysis
      to develop a better understanding of disease transmission and shows how such data
      have been used to examine human alveolar echinococcosis infection patterns, at a
      range of spatial scales, in an endemic area in central China.

PMID- 15027611
TI  - Transmission dynamics and control options for Echinococcus granulosus.
AB  - Cystic echinococcosis, caused by the larval stage of Echinococcus granulosus, is
      a global public health problem. Whilst in a few localities, such as New Zealand,
      the parasite has been effectively controlled or even eradicated, in most endemic
      regions it remains a persistent problem. In some areas, such as the former Soviet
      Union, the disease incidence in humans has increased rapidly in recent years. It
      is important to have an understanding of the transmission dynamics, both between
      dogs and domestic livestock where the parasite maintains itself and from dogs to
      people. It is from this knowledge that effective control measures can be devised
      to reduce the prevalence of the parasite in animals and hence reduce the
      incidence of human disease. Mathematical models to describe the transmission of
      the parasite and the effects of different control strategies were first proposed
      over twenty years ago. Since then further information has been acquired, new
      technology has been developed and better computing technology has become
      available. In this review, we summarise these developments and put together a
      theoretical framework on the interpretation of surveillance information, how this
      affects transmission and how this information can be exploited to develop new
      intervention strategies for the control of the parasite. In particular, the
      parasite remains a persistent or re-emerging problem in countries of low economic
      output where resources for an intensive control programme, that has been
      successful in rich countries, are not available. By understanding of the
      transmission biology, including mathematical modelling, alternative and cost
      effective means of control can be developed.

PMID- 15027612
TI  - Perspective on control options for Echinococcus multilocularis with particular
      reference to Japan.
AB  - Following a brief introduction of recent advances in molecular and immunological
      technology for detection of persons and animals infected with Echinococcus
      multilocularis and an overview of the current situation of alveolar
      echinococcosis (AE) in Japan, perspectives on control options are discussed with
      reference to different epidemiological situations. AE is considered the most
      serious parasitic zoonosis in temperate and arctic regions of the northern
      hemisphere. The number of human cases differs drastically among regions. While
      high numbers of patients are apparently associated with high E. multilocularis
      prevalence in domestic dogs, e.g. in parts of Alaska and western China, the
      number of cases is moderate or low in areas where the parasite is mainly
      transmitted by wild canid species (e.g. in central Europe or temperate North
      America). However, the severity of the disease, the absence of curative treatment
      for most cases, the high cost of long-term chemotherapy and the anxiety caused
      for the population in highly endemic areas call for the development of preventive
      strategies even in regions where human AE is rare. Furthermore, in view of (1)
      drastically increasing numbers and infection rates of foxes involved in
      transmission of E. multilocularis, and (2) increasingly close contact between
      humans and foxes e.g. in Europe and Japan, there is considerable concern that AE
      incidences may in future increase in these regions. Control options depend on a
      variety of factors including the species of canid principally responsible for
      transmission and the socio-economic situation in the region. Where domestic dogs
      (stray or owned) are the principal hosts for E. multilocularis, control options
      can include those applicable to E. granulosus, i.e. reduction of the number of
      stray dogs, registration and regular preventive chemotherapy of owned dogs, and
      information campaigns for the population promoting low-risk behaviour for man and
      dogs. Where E. multilocularis is mainly transmitted by wild canids, the situation
      is far more difficult with preventive strategies still being in trial stage.
      Integrated control measures could include prevention information campaigns,
      restricting access of pet animals (dogs and cats) to rodents, chemotherapy of
      foxes on local or regional scales, and strategies to minimize contacts between
      people and foxes.

PMID- 15027613
TI  - Promises to keep (Part 2).

PMID- 15027614
TI  - Mouse models of human cancers (Part 2).

PMID- 15027616
TI  - Feasibility of a porcine adult intensive care model.
AB  - A porcine adult ICU model would be useful for several avenues of investigation
      relevant to the care of critically ill patients. The purpose of the experiments
      reported here was to test the feasibility of such a model, using healthy swine.
      Swine (n = 4; body weight, 76 +/- 5 kg) were instrumented with endotracheal,
      bladder, and central arterial and venous catheters, and were admitted to the
      intensive care unit (ICU) while undergoing mechanical ventilation under the
      continuous care of nurses. Cardiopulmonary parameters were monitored
      continuously, and serum biochemical parameters were measured intermittently.
      Survival was seven days in subject 1 and five and a half days in subject 2.
      Subjects 3 and 4 survived an abbreviated protocol (44 and 41 h, respectively).
      Care of the subjects was complicated by iatrogenic hemorrhage (n = 3), pneumonia
      (n = 2), and acute respiratory distress syndrome (n = 1). One subject was free of
      complications. Critically ill swine > or = 70 kg can survive mechanical
      ventilation in the ICU for up to seven days. When iatrogenic injury occurs, swine
      respond well to clinical care protocols. Further testing is needed to develop a
      reproducible model and determine whether healthy swine can survive the ICU
      environment for longer than 41 h.

PMID- 15027615
TI  - Transmission of enterotropic mouse hepatitis virus from immunocompetent and
      immunodeficient mice.
AB  - Mouse hepatitis virus (MHV) is the most prevalent virus that infects mice, and
      most MHV strains are enterotropic. Experiments were performed to elucidate the
      duration of enterotropic MHV-Y shedding by immunocompetent BALB/ c and C57BL/6
      mice and immunocompromised B and T cell-deficient mice. Although the use of
      molecular diagnostics to detect MHV infection is increasing, it is unclear
      whether the viral RNA detected is always infectious. The ability to detect MHV-Y
      transmission to sentinel mice exposed directly to infected mice or to soil
      bedding from infected mice was compared with reverse transcriptase-polymerase
      chain reaction-based detection of viral RNA in the feces. The BALB/c mice
      developed subclinical intestinal infection, and transmitted MHV-Y for four weeks.
      The C57BL/6 mice also developed subclinical intestinal infection, but only
      transmitted virus for two weeks. The T cell-deficient mice developed severe
      disseminated disease by two weeks and transmitted virus for four weeks. The B
      cell-deficient mice developed subclinical intestinal infection and transmitted
      virus for longer than three months, although virus RNA was not detected in feces
      late in the infection. Viral RNA detected in the feces of infected mice was
      almost always infectious. Non-infectious RNA was detected in a few mice for
      several days after transmission had ceased. In addition, constant exposure of
      naive mice to infected mice, via the use of serial sentinels, prolonged viral
      transmission.

PMID- 15027618
TI  - Rat sex differences in anesthesia.
AB  - Studies involving substantially lengthy rat surgeries require extended anesthesia
      periods and often involve use of sodium pentobarbital (PENT). Results of previous
      experiments from our laboratory and elsewhere suggest that the duration of
      anesthesia and the need for anesthetic supplementation may differ between male
      and female rats. In the study reported here, we induced anesthesia in male and
      female Sprague Dawley rats (n = 10 for each sex), using a three-step procedure:
      brief induction with 5% isoflurane inhalation, PENT (50 mg/kg of body weight,
      i.p.), combined with 50 mg of PENT/kg given intragastrically. Adequate anesthesia
      depth was confirmed by absence of a response to a toe pinch. Plasma PENT
      concentration was measured at sequential 20-min periods and was found, on
      average, to be lower (P = 0.03) in male (13.28 +/- 1.13 microg/ml) than in female
      (20.27 +/- 0.66 microg/ml) rats, and decreased more rapidly (P = 0.003) in male
      rats. Distribution to a fractionally greater lean body mass and more rapid
      metabolism in males may account for these differences and explain the need for
      anesthetic supplementation in male, but not female rats.

PMID- 15027617
TI  - Use of the P167 recombinant antigen for serodiagnosis of Helicobacter bilis.
AB  - Helicobacter bilis is widespread among research mouse colonies. Serodiagnosis of
      Helicobacter infections involves use of bacterial lysates or membrane antigen
      preparations that lack specificity, necessitating the need to identify a specific
      and sensitive antigen. A previously reported recombinant protein (P167) was
      evaluated for use as an H. bilis-specific antigen for serologic testing. Seventy
      six mice naturally infected with Helicobacter spp. were identified from
      commercially bred or sentinel mice. Infection was confirmed and speciated by use
      of cecal specimen culture and fecal polymerase chain reaction (PCR) analysis,
      followed by restriction enzyme digest of the amplicon. Forty-one mice were
      determined to be monoinfected with H. bilis, 27 mice were determined to be
      monoinfected with H. hepaticus, and eight mice were infected with another species
      of Helicobacter. Serum was diluted 1:100 to evaluate the immunoreactivity to
      enzyme-linked immunosorbent assay preparations of H. bilis membrane extract and
      the immunodominant C and D fragments of the p167 gene. The sensitivity was
      greatest for the membrane extract preparation (76%), whereas sensitivity to the
      P167C and D recombinants was lower (62 and 51%, respectively). However, the
      specificity of the membrane extract preparation was low (87%), compared with the
      much improved specificity of the recombinant P167C and D fragments (96 and 96%,
      respectively). These findings suggest that the recombinant P167C and D fragments
      of the p167 gene product from H. bilis can be used as specific reagents in the
      serodiagnosis of H. bilis infection in mice.

PMID- 15027619
TI  - Effects of nonylphenol and phytoestrogen-enriched diet on plasma vitellogenin,
      steroid hormone, hepatic cytochrome P450 1A, and glutathione-S-transferase values
      in goldfish (Carassius auratus).
AB  - The effects of nonylphenol (NP) on plasma vitellogenin (VTG) and steroid hormone
      values, as well as hepatic cytochrome P450 1A (CYP1A) and glutathione-S
      transferase (GST) activities, were measured in goldfish (Carassius auratus) fed a
      diet with a low (formulated diet, FD) or high (commercial diet, CD) content of
      phytoestrogens, including genistein and daidzein. Male goldfish with secondary
      sexual characteristics were exposed to nominal NP concentrations of 0.1, 1.0, 10,
      and 100 microg/L in the water for 28 days while being fed either the FD or CD
      diet at 1.0% of body weight daily. Plasma VTG concentration in male goldfish
      exposed to 100 microg of NP/L and fed FD was significantly higher than that in
      the FD-fed control fish at seven, 21, and 28 days. However, fish of the CD-fed
      group exposed to 100 microg of NP/ L had significantly higher plasma VTG
      concentration than did fish of the CD-fed control group at 28 days only.
      Moreover, plasma VTG concentration in fish of the CD-fed control group was about
      100-fold higher than that in fish of the FD-fed control group. Although the
      estrogenic effects of a phytoestrogen-enriched diet caused a decrease in
      testosterone and/or 11-ketotestosterone values in the CD-fed fish, there was no
      dose-response relationship between androgen and amount of NP to which the FD-fed
      fish were exposed. Nonylphenol does not have appreciable effects on hepatic CYP1A
      and GST activities in male goldfish at concentrations as low as 100 microg/L.
      These results suggest that NP has estrogenic activity in male goldfish at the
      nominal concentration of 100 microg/L, and that phytoestrogens, such as genistein
      and daidzein, in the CD inhibit an aspect(s) of steroid release and/or synthesis
      common to testosterone and 11-ketotestosterone. However, results of in vivo
      screening assays for endocrine-disrupting chemicals may be seriously affected by
      phytoestrogens in the diet, depending on content or potency of estrogenic
      activity; therefore, we recommend use in research of a standardized, open-formula
      diet in which estrogenic substances have been reduced to amounts that do not
      alter the results of studies that are influenced by exogenous estrogens.

PMID- 15027621
TI  - Assessment of retinal degeneration in outbred albino mice.
AB  - Evaluation of a pharmaceutical's safety includes assessment of the potential for
      ophthalmologic toxicity. These nonclinical studies commonly use various outbred
      stocks of mice. Pretest indirect ophthalmoscopic examinations in the commonly
      used outbred stock Hsd:ICR(CD-1) indicated that retinal degeneration was a
      problem in this particular outbred stock of mice. This prompted the authors to
      examine other stocks of outbred mice routinely used in the performance of
      nonclinical safety studies. Groups of mice were observed over a 13-week period to
      determine the progression and changing incidence of retinal degeneration. Light
      intensity in the room and caging was measured during the study, and it was
      determined that light did not play a direct role in the progression of the
      retinal degeneration observed during the study. Histomorphologic examination of
      the mouse eyes was performed at the end of the study to confirm the presence of
      retinal degeneration observed after ophthalmoscopic examination. The incidence of
      retinal atrophy in the various outbred stocks of mice was: Crl:CFW(SW)BR (98.3%),
      Tac(SW)fBR (80%), Tac:Icr:Ha(ICR)fBR (75%), Hsd:ICR(CD-1) (43.3%), and Crl:CF-1BR
      (3.0%). Retinal atrophy was not observed in the following outbred mice stocks:
      Crl:CD-1(ICR)BR, HsdWin:CFW1, and Hsd:NSA(CF-1). On the basis of these findings,
      it is highly recommended that pretest ophthalmologic screening be performed on
      mice to obviate pre-existing conditions from confounding or invalidating
      nonclinical study results.

PMID- 15027620
TI  - Effect of cage bedding on temperature regulation and metabolism of group-housed
      female mice.
AB  - Mice are generally housed in groups in cages lined with an absorbent bedding
      material at ambient temperature (Ta) of 20 to 24 degrees C, which is comfortable
      for humans, but cool for mice. Little is known about the effects of bedding on
      thermoregulation of group-housed mice. To determine whether bedding material
      affects thermoregulatory stability, core temperature (Tc) and motor activity (MA)
      were monitored by use of radiotelemetry in female CD-1 mice housed in groups of
      four in a standard plastic cage at Ta of 23.5 degrees C. Ten groups were tested
      using three types of bedding material: a deep layer of heat-treated wood shavings
      (DWS) that allowed mice to burrow, a thin layer of wood shavings (TWS) just
      covering the bottom of the cage floor, or a layer of beta chips (BC). Mice could
      not burrow in the TWS or BC. The Tc and MA were affected by bedding type and time
      of day. Mice housed with DWS maintained a significantly higher Tc (deltaTc = 1.0
      degrees C) during the day, compared with that in mice housed with TWS and BC.
      During the night, Tc and MA were high in all groups and there was no effect of
      bedding type on Tc or MA. Effect of bedding on metabolic rate (MR) was estimated
      by measuring oxygen consumption for six hours in groups of four mice at Ta of
      23.5 degrees C. The Tc was significantly reduced in mice housed on the TWS and
      BC, but MR was unaffected by bedding type. There was a trend for higher MR in
      mice on BC. Compared with use of other bedding materials, housing mice on DWS and
      comparable materials provides an environment to burrow, thus reducing heat loss.
      The effects of bedding material on temperature regulation may affect rodent
      health and well being. Moreover, bedding will affect variability in toxicologic
      and pharmacologic studies whenever an endpoint is dependent on body temperature.

PMID- 15027623
TI  - Diagnosis of tuberculosis in macaques, using whole-blood in vitro interferon
      gamma (PRIMAGAM) testing.
AB  - During the fall of 2001, a tuberculosis outbreak caused by Mycobacterium bovis
      occurred in a conditioned colony of rhesus (Macaca mulatta) and cynomolgus
      (Macaca fascicularis) macaques at Stanford University School of Medicine. During
      this outbreak, we evaluated the diagnostic performance of a new in vitro
      tuberculosis screening test (PRIMAGAM). The PRIMAGAM test measures the interferon
      gamma (IFNgamma) response to purified protein derivatives (PPDs) of M. bovis and
      M. avium. On the basis of the results of the last test administered before
      necropsy, the PRIMAGAM test had good sensitivity (68%) and excellent specificity
      (97%), compared with the disease status, as determined by the presence or absence
      of gross and/or histologic lesions indicative of tuberculosis. By contrast,
      sensitivity and specificity of the tuberculin skin test (TST) was 84 and 87%,
      respectively. Both tests suffered from intermittent positive and negative
      reactions on repeat testing. Overall, however, there was no significant
      difference (P = 0.09, McNemar's chi2-test) and moderate agreement (kappa = 0.52)
      between these two tests. Lastly, the IFNgamma response to bovine PPD was
      significantly lower in infected cynomolgus macaques. Moreover, each test failed
      to detect tuberculosis in three cynomolgus macaques. Fortunately, they were
      different animals; therefore, we recommend the parallel use of the TST and
      PRIMAGAM test for maximal overall sensitivity in a tuberculosis screening
      program, especially for cynomolgus macaques.

PMID- 15027622
TI  - Comparison of the depressive effects of four anesthetic regimens on ventilatory
      and cardiovascular variables in the guinea pig.
AB  - BACKGROUND AND PURPOSE: Guinea pigs are one of the most difficult rodents to
      anesthetize safely, and as a consequence, there is a paucity of reports regarding
      the effects of anesthesia on their cardiorespiratory variables. We used long-term
      indwelling cannulas for studying the guinea pig in the conscious state, and
      subsequently investigated the effects of four types of injectable anesthetic
      regimens on cardiorespiratory variables. METHODS: Using barometric
      plethysmography (conscious: long-term cannulated, n = 11; no cannulation, n = 28)
      or trachea-out plethysmography (anesthetized: n = 7 for each of the four groups),
      we recorded ventilatory, cardiovascular, metabolic, and arterial gas variables
      during air breathing and in response to 10 min of hypoxia (8% O2) and 10 min of
      hypercapnia (8% CO2). The four anesthetic regimens tested were: Saffan (infused
      at 9.75 mg/kg of body weight/h, i.v.); ketamine/xylazine (14.6/3.7 mg/kg/h,
      i.v.); pentobarbitone (8.3 mg/kg/h, i.v.) plus Innovar Vet (0.15 mg/kg every 1 to
      1.5 h, s.c.); or pentobarbitone alone (22 mg/kg/h, i.v.). RESULTS: The least
      depressive anesthetic with regard to ventilation (VE) was ketamine/xylazine. Air
      breathing was depressed by only 17% (cf approx 50 to 60% for all other regimes),
      and the VE responses to hypoxia and hypercapnia were attenuated the least. All
      anesthetics equally depressed mean arterial blood pressure (from 70 mmHg to 56
      mmHg) and ketamine/xylazine was the only anesthetic to reduce heart rate (from
      260 beats/min to 198 beats/min). CONCLUSION: Although all anesthetics induce
      cardiorespiratory depression to some extent, the use of ketamine/ xylazine is
      recommended for future use in respiratory studies of the guinea pig where
      anesthesia cannot be avoided.

PMID- 15027624
TI  - Outbreak of otitis media caused by Burkholderia gladioli infection in
      immunocompromised mice.
AB  - An athymic nude mouse with severe head tilt due to otitis media was identified.
      Within weeks of identification of this first case, immune-deficient mice of
      various genotypes from the same facility were similarly affected, and cases from
      other facilities were found within two months. Culture of ear exudate specimens
      from affected mice yielded bacteria that were initially identified as
      Burkholderia cepacia, a plant pathogen considered an important opportunistic
      pathogen in persons with cystic fibrosis or chronic granulomatous disease.
      Several of these isolates, however, were subsequently identified as B. gladioli
      on the basis of results of biochemical analysis and a species-specific polymerase
      chain reaction (PCR) assay. Genotyping analysis revealed clonality among the
      isolates, indicating a shared strain among affected mice. A 16S rDNA-based PCR
      assay specific for the genera Burkholderia and Ralstonia, and a selective culture
      medium were used in efforts to characterize the epidemiology of this outbreak. In
      addition to culture of specimens from the oropharyngeal cavity of affected mice,
      samples were obtained from the environment, feces, sipper tubes, drinking water,
      and soiled bedding from cages of affected individuals. Burkholderia gladioli was
      most consistently detected in oropharyngeal swab specimens from affected mice.
      The PCR assay was equivalent to selective culture in identifying mice in the
      carrier state that did not have clinical signs of infection. However, neither
      detection method had sufficient sensitivity to reliably identify all carrier
      mice, causing the organism to persist at low levels unless entire colonies of
      immune-deficient mice were removed. The organism was highly resistant to
      antibiotic therapy. The source and epidemiology of this organism remain unknown.
      This epizootic serves as an important reminder that immunocompromised rodent
      colonies may harbor important human opportunistic pathogens.

PMID- 15027625
TI  - Use of desferoxamine and S-adenosylmethionine to treat hemochromatosis in a red
      ruffed lemur (Varecia variegata ruber).
AB  - Hemochromatosis was diagnosed in a 14-year-old, male, red ruffed lemur (Varecia
      variegata ruber) on the basis of abnormal results of serum biochemical analysis,
      including high serum ferritin and transferrin saturation values, and of liver
      biopsy. Therapy included chelation, using desferoxamine to remove excess iron and
      S-adenosylmethionine to improve liver function, and monthly peripheral blood
      removal by phlebotomy to reduce total body iron content. Response to treatment
      was assessed by changes in the lemur's attitude and appetite, as well as
      variations in serum biochemical and iron panel values. Initial improvement was
      associated with the onset of therapy. After 56 days of treatment, results of
      serum biochemical analysis indicated a decrease in iron panel values. Treatment
      was temporarily discontinued from days 56 to 65, and the lemur's condition
      worsened, so therapy was re-instituted. However, the lemur died of hepatocellular
      carcinoma on day 110 of treatment.

PMID- 15027626
TI  - [100 years of the Journal for Medical Continuing Education and Quality Assurance.
      From where do we come?--Where are we?--Where are we going?].

PMID- 15027627
TI  - [Discussion. Problems and success in the battle against tuberculosis. 1904].

PMID- 15027628
TI  - [Problems and outcomes in the struggle against tuberculosis. 1904].

PMID- 15027629
TI  - [Tuberculosis--current news about the "white pestilence" in the year 2004].
AB  - Among infectious diseases tuberculosis is the second leading cause of death world
      wide, killing nearly 2 million people each year. In Africa the incidence of
      tuberculosis has increased mainly as a result of the burden of HIV infection, and
      in the former Soviet Union due to socio-economic changes and a decline of the
      healthcare system. Chemotherapeutic treatment with several drugs for 6 months or
      more can deliver cure to more than 95% of the patients. Direct observation of
      treatment (DOT) is regarded as the standard of care.

PMID- 15027630
TI  - [The technique of using extension bandages. 1904].

PMID- 15027632
TI  - [From casualty medicine to casualty surgery].
AB  - For many centuries the treatment of accident casualties -- as proven by evidence
      from prehistoric times -- has been an essential part of an empirically determined
      and crafts-oriented surgery. But though the phenomenon of accident and the
      pathophysiological complex of trauma were faced with the surgical inaccessibility
      of the human body until in the late 19th century, a kind of casualty medicine
      supported by multifaceted, scientifically founded observations was trying to
      repair or alleviate the sequelae of accidents. But only the development of
      imaging diagnostic procedures made it possible to apply pre-planned target
      oriented -- what is modernly called "outcome-oriented" -- surgical procedures.
      The change in the nature of accidents and their associated health and social
      consequences demands that the surgeons' attention be specially drawn to this
      challenge as it presents itself e.g. in the huge field of fracture management,
      the management of the general sequelae of trauma, emergency rescue and the
      prevention and control of the secondary effects of trauma (rehabilitation). There
      has never been any doubt that all this could only be achieved within the
      discipline of surgery in its entirety, though with the scientifically and
      practically acquired competence of one its specialties, i.e. casualty surgery, as
      both a prerequisite and necessary condition.

PMID- 15027631
TI  - [From continuing education to practice. Therapy of accidents. 1904].

PMID- 15027633
TI  - [On digestive glycosuria. 1904].

PMID- 15027634
TI  - [From knowledge to practice. Progress in particular diseases. 1904].

PMID- 15027635
TI  - [Diabetes: from dietary strategies to pharmacotherapy and disease management].
AB  - The first description of diabetes dates back to the 3,500-year-old Ebers papyrus.
      Until the 16th century diabetes was traditionally thought of as a disease of the
      kidney and the liver. Paracelsus was the first to suspect an association between
      diabetes and an altered blood composition. Treatment and knowledge about the
      origin of diabetes have changed. For the patients, the 20th century has been most
      important. Their chance to survive increased with the introduction of insulin.
      Today, diabetology is based on the "best practice", on evidence-based medicine
      that focuses on the diabetic patients' quality of life.

PMID- 15027636
TI  - [Chronic fibrositis. 1904].

PMID- 15027637
TI  - [Atheroma (sclerosis) of the thoracic aorta. 1904].

PMID- 15027638
TI  - [Fom knowledge and practice. Progress in particular diseases. 1904].

PMID- 15027639
TI  - [Arteriosclerosis and coronary heart disease--a hundred years later].
AB  - Within the last century, cardiovascular medicine has seen incredible progress. In
      1904 history and physical examination were the sole diagnostic tools, and only
      lifestyle changes and a few effective medications could be recommended
      therapeutically. In 2004, however, nearly every vascular region can be visualized
      and treated either medically, interventionally or surgically. And treatment is
      not only based upon expert consensus but often on evidence-based recommendations.
      In view of the demographic development, cardiovascular medicine in the following
      decades will be able to provide great benefit to the elderly population as
      regards quality of life and autonomy -- at the prize, though, of increasing
      socioeconomic challenges that society will have to face.

PMID- 15027640
TI  - [Reports in 1932. The German Medical Meeting in Rostock. 1904].

PMID- 15027641
TI  - [Report in 1932. The German Medical Meeting in Rostock].

PMID- 15027642
TI  - [A hundred years of physicians' professional organization: an overview].
AB  - The impressive advances of the natural sciences in the 19th century was in
      Germany accompanied by the formation of a medical profession that clearly
      separated itself from other healthcare providers and increasingly claimed
      autonomy from governmental agencies. But due to the opposition of the state
      governments who felt their jurisdiction over the healthcare system was
      threatened, the plan to create a legally supported Reich Physicians' Chamber
      (Reichsarztekammer) failed at the end of the 19th century. It remained the
      responsibility of teh German Physicians' Congress (Deutscher Arztetag) to
      establish consistent standards for medical professional activities in the form of
      a legally non-binding Code of Professional Conduct. During the Weimar Republic
      physicians' politics -- within a socio-political context that many felt was
      hostile towards the medial profession -- was characterized by the pursuit of the
      medical profession. By establishing the Reich Physicians' Ordinance
      (Reichsarzteordnung) in 1935 the Nazi state fulfilled a long-cherished desire of
      the German medical profession. After 1945 regional physicians' chambers and panel
      fund physicians' unions (Kassenarztliche Vereinigungen) in the form of corporate
      bodies under public law could rapidly be set up in the western zones of occupied
      Germany, while emerging structures of medical self-government in the Soviet
      occupied zone were readily smashed.

PMID- 15027643
TI  - [The Kaiserin Friedrich Foundation through the ages--100 years in the service of
      continuing medical education].

PMID- 15027644
TI  - Temperature effect on phosphate sorption by iron hydroxide.
AB  - The ion exchange sorption of phosphate on Fe(OH)3 is studied as a function of
      temperature (25-55 degrees C) and concentration (1.49-3.23 mmol l(-1)). The
      mechanism of sorption is observed to be the exchange of OH- anions from the
      adsorbent surface by those of H2PO4- and HPO4(2-) from the aqueous solution. An
      equation developed in the Langmuir formalism is used to explain the ion exchange
      sorption of phosphate on Fe(OH)3. The isosteric heat of sorption illustrates that
      the uptake of phosphate on Fe(OH)3 takes place through an anion exchange process,
      involving both the phosphate anions H2PO4- and HPO4(2-). Further, at higher
      temperature the solid prefers the HPO4(2-) anions forming a binuclear bridging
      complex.

PMID- 15027645
TI  - Influence of magnetic field on the kinetics of activated sludge.
AB  - This investigation was performed as a background study for magnetically
      stabilized fluidized bed biofilm reactors for wastewater treatment. The aim of
      this study is to show the influence of magnetic field application on microbial
      growth and to use a simplified method in batch wise study to determine this
      influence on the biological kinetic parameters. The kinetic parameters of
      mu(max), K(s), Y(x/s) and m of the activated sludge on glucose removal as a model
      substrate for wastewater treatment were determined in a simple way by using the
      data of only one batch experiment at a definite condition. At the same condition,
      instead of the difficult, expensive and time consuming several continuous steady
      state studies with different influent substrate concentrations the results of
      only one batch experiment of two identical reactors, one with and the other
      without magnetic field application, could be enough for the evaluation. It was
      found that kinetic parameters were changing with magnetic field strengths of 8.9,
      17.8, 24.4, 36.6 and 46.6 mT and 17.8 mT is the optimum strength for biological
      glucose removal under the studied conditions. While mu(max) and m are increasing
      with the application of optimum magnetic field strength of 17.8 mT, K(s) and
      Y(x/s) are decreasing implying that average affinity of microorganisms present in
      activated sludge to the substrate and their growth rates are increasing but a
      smaller amount of sludge corresponding to the amount of substrate removal was
      produced with the application of magnetic field. This result shows an improvement
      in the treatment efficiency by the application of magnetic field.

PMID- 15027646
TI  - Removal of 2-fluoro and 2-iodophenol from aqueous solutions using industrial
      wastes.
AB  - A comparative study of the adsorbents prepared from several industrial wastes for
      the removal of 2-fluorophenol and 2-iodophenol has been carried out. The results
      show that maximum adsorption on carbonaceous adsorbent prepared from fertilizer
      industry waste has been found to be 35.3 and 235.3 mg g(-1) for 2-fluorophenol
      and 2-iodophenol, respectively. Compared to carbonaceous adsorbent, the other
      three adsorbents (viz., blast furnace sludge, dust, and slag) adsorb phenols to a
      much smaller extent. This has been attributed to the carbonaceous adsorbent
      having a larger porosity and consequently higher surface area. The adsorption of
      phenols on this adsorbent has been studied as a function of contact time,
      concentration and temperature. The adsorption has been found to be endothermic,
      and the data conform to the Langmuir equation. The further analysis of data
      indicates that adsorption is a first order process and pore diffusion controlled.
      A comparative study of adsorption results with those obtained on standard
      activated charcoal sample shows that prepared adsorbent is about 45% as efficient
      as standard activated charcoal and therefore, can be fruitfully employed for the
      removal of phenolic pollutants from wastewaters.

PMID- 15027647
TI  - Treatment of slaughterhouse wastewater in a sequencing batch reactor: simulation
      vs experimental studies.
AB  - In wastewater treatment, the objective of process optimization is primarily to
      obtain a good treatment efficiency of a specific pollutant. The operational
      objective of increased productivity has also to be met. This includes a
      sufficient reduction in the duration of a batch process through batch scheduling.
      The aim of this paper is thus to find the best cycles for simultaneous carbon,
      nitrogen and phosphorus (CNP) removal from slaughterhouse wastewater in a
      sequencing batch reactor (SBR) using GPS-X software and ASM2d model. Simulations
      with different aeration strategies, residence time, sludge age and feed
      strategies were carried out to determine the best system performance. The
      simulation results showed best performance with a system comprised of two equal
      feeds operated at 48 h hydraulic retention time (HRT) and 20 d solids retention
      time (SRT). Simulation also showed that addition of metal salts was necessary to
      reduce the level of phosphorus (P) to meet the requirement (P<1 mg l(-1)). The
      addition of acetate was also necessary to complete the denitrification process.
      The simulated results were compared against the experimental results obtained
      from laboratory SBR. The simulated results of COD, nitrates/nitrites and ammonia
      removal were very close to the experimental results. A diference of 2-4% between
      the simulated COD and the experimental COD was observed and that could be
      attributed to the error in evaluation of the inert COD. For ammonia removal, the
      simulated (99.9%) and experimental (93-100%) results were practically identical.
      However, a notable difference in o-PO4 concentration was observed (38% removal by
      simulation against 78% removal through experiments). After metallic salts
      addition, P removal efficiency was 98% or 1% less than that observed through
      experimental results.

PMID- 15027648
TI  - The use of air fuel cell cathodes to remove contaminants from spent chromium
      plating solutions.
AB  - Results from experiments using an impregnation-reduction (I-R) Pt / Nafion
      membrane electrode assembly (MEA) in an air fuel cell cathode to remove
      contaminants (Cu(II), Ni(II), and Fe(III)) from spent chromium electroplating
      baths are presented in this study. A platinum-carbon (Pt-C) / Nafion MEA and a Pb
      planar cathode were also used for comparison. The average removal rates of Cu(II)
      and Ni(II) were almost the same (0.39 and 0.40 mM hr(-1) (or 0.117 and 0.12 mmol
      hr(-1)), respectively) but higher than that of Fe(III) (0.16 mM hr(-1), or 0.048
      mmol hr(-1)) in accordance with the Nernst-Planck flux equation. The removal
      rates for the same cation were independent of the cathode used. The average
      removal rate of each impurity was approximately proportional to the product of
      its initial concentration and separator area/anolyte volume ratio using Pb
      cathodes. Under constant current conditions the system using the Pt-C / Nafion
      cathode needed the highest cell voltage, about 3 V more than needed for the
      system with the Pt / Nafion cathode. The cell voltage required using the Pt /
      Nafion cathode was similar to that using the conventional planar Pb cathode.
      Analyses of cathode deposits by SEM/EDS and XPS techniques indicated they were
      minimal on the Pb and Pt / Nafion cathode and more apparent on the Pt-C / Nafion
      cathode. The primary deposits on the Pb cathode were chromium oxides (e.g.,
      Cr2O3) with minor amount of lead chromate (lead dichromate or lead trichromate)
      and other chromium solids (Cr black). As expected, the dominant deposit on the
      lead anode surface was PbO2.

PMID- 15027649
TI  - Separation of benzene, toluene, ethylbenzene, and xylenes by micellar
      electrokinetic capillary chromatography.
AB  - The use of sodium dodecyl sulfate, urea, beta-cyclodextrin, and methanol as
      additives to the electrophoretic medium containing a Na2HPO4-boric acid buffer in
      the micellar electrokinetic capillary chromatography of benzene, toluene,
      ethylbenzene, and three isomers of xylene (collectively known as BTEX) was
      investigated. The results showed that with the addition of sodium dodecyl sulfate
      only, higher selectivity and sensitivity and shorter migration time could be
      achieved, which consequently resulted in better separation of BTEX studied. For
      this buffer system, good linearity (R2>0.99) was found over the range of 5 to 500
      microg ml(-1) for individual BTEX compound and separation time of less than 5 min
      for BTEX was possible.

PMID- 15027650
TI  - Optimization of air protection expenditures on municipal scale.
AB  - The application of air protection methods and technologies involves considerable
      investment and maintenance costs. Thus, to reduce overall expenditures an
      economic calculation of air pollution control, should be applied. This problem is
      connected in special way with areas of great population of inhabitants with
      spatially uneven density, where energetic, technological and domestic emission
      sources are located. Such calculations are preferred to be used on the town and
      municipal scale. The maximized ecological effect might be calculated from
      aggregate mean annual ambient concentration and population density distribution.
      Aggregate concentration reflects concentrations of all emitted pollutants, being
      taken into account. As an example, the optimization for Bytom--an industrial town
      regarded as one of the most heavily polluted in Europe--was carried out due to
      its energy production facilities. Alternative fuels were taken into
      consideration. It demonstrates that expenditures of a relatively small percentage
      of overall energy production costs can make a substantial improvement to the
      ambient air condition.

PMID- 15027651
TI  - Precipitation of heavy metals from landfill leachates by microbially-produced
      sulphide.
AB  - Four leachates from two landfills in Sweden were treated for the removal of heavy
      metals with the aid of sulphate-reducing bacteria (SRB). Both continuous and
      batch experiments were performed. A packed-bed process was used for sulphide
      production. The metals studied were As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn. The
      continuous experiments showed that Cd and Cu were most efficiently removed and
      that Cr was the most difficult to precipitate. In a continuous experiment with
      one of the leachates, the removal of Cd, Cu and Zn depended upon the retention
      time in the system. In the batch experiments, precipitation of the metals was a
      relatively fast process. No significant differences in metal concentrations were
      found between experiments terminated after a day and those terminated after a
      week. In a batch experiment involving one of the leachates, the precipitation of
      Cd and Cu was shown to be dependent upon the metal:sulphide ratio. Removal of the
      metals increased with an increase in the sulphide:metal ratio up to 45:1. The
      process with SRB showed an interesting potential for removal of heavy metals from
      leachates. One of the two leachates for which the highest metal removals were
      obtained came from a landfill for hazardous waste.

PMID- 15027652
TI  - Comparative study of flotation techniques for the treatment of liquid effluents.
AB  - This work aimed to study the performance of three different induced air flotation
      units (flotation column, flotation tank and centrifugal flotation in
      hydrocyclone) for the treatment of a synthetic dairy effluent. Under continuous
      operation, it was possible to achieve removal efficiencies of milky material in
      suspension up to 90%, both for the flotation column and the flotation tank units.
      Using the centrifugal flotation unit in hydrocyclone, it was possible to decrease
      up to 45% of all suspended material in the effluent, with a clarified flow rate
      approximately three times greater than those found for the previous flotation
      units. In the centrifugal flotation unit, better results were obtained for air
      flow rate-feed flow rate ratios (Q(air)/Q(L)) greater than 0.15, and for
      underflow-overflow ratios (Qu/Qo) lower than 1.0.

PMID- 15027653
TI  - Detoxification of olive mill wastewater using superabsorbent polymers.
AB  - The detoxification of agro-industrial effluents using superabsorbent polymers is
      a new and innovative process. Olive mill wastewater constitutes a major
      environmental problem in Mediterranean countries due to the large volumes
      generated, the seasonality of the industry, and the high content of polyphenols
      and organic matter. The application of superabsorbent polymers allows olive mill
      wastewater to be used as a fertilizer, as it is immobilized, increasing the
      biological activity that decreases its phytotoxicity, thus making its water,
      organic matter and mineral content usable for plant nutrition. Various parameters
      that characterise olive mill wastewater were evaluated after absorption in 2
      different superabsorbent polymers (SAP1 and SAP2). The organic matter was equally
      distributed in both phases, while there was a concentration of protein and sodium
      in solution. The K:Na ratio decreased from 70:1 to 2:1. The polyphenol desorption
      from the gel into solution was found to follow Fick's law. The mass transfer
      coefficients were 0.147 min(-1) and 0.0085 min(-1) for SAP1 and SAP2,
      respectively. Phytotoxicity tests were carried out with SAP2. Olive mill
      wastewater in SAP2 with polyphenol concentrations up to 200 mg l(-1) revealed no
      phytotoxicity, and even stimulated Lepidium sativum growth, while olive mill
      wastewater without superabsorbent polymer revealed growth inhibition for all
      concentrations tested. Caffeic acid degradation by the immobilised biomass
      followed zero order kinetics. Degradation constants of 0.087 mg l(-1) min(-1)
      gSAP2(-1) and 1.156 mg l(-1) min(-1) gSAP2(-1) were found. Fungi that developed
      in the plant growth medium were identified as Aspergillus sp. and Penicillium sp.

PMID- 15027654
TI  - Chromate reduction at low sulphate concentration in hydrogen-fed bioreactors.
AB  - Aimed at developing a bioremediation process to treat Cr(VI)-bearing water at low
      sulphate concentration in order to reduce excess sulphide production, the highly
      toxic, mutagenic, and soluble Cr(VI) was reduced to the less toxic and insoluble
      Cr(III) in 2-litre fixed-bed reactors inoculated with the sulphate-reducing
      bacterium (SRB) Desulfomicrobium norvegicum, capable of performing direct
      enzymatic Cr(VI) reduction. H2 was used as the electron source. The fixed-films
      were developed on three different supports: a PVC cross-flow material, a
      pozzolana, and a ceramic granulate. The phased experiments began with a
      progressive increase of the Cr(VI) concentration in the feed to the column
      reactors, followed by a progressive decrease of the sulphate concentration.
      Inhibition by Cr(VI) was less pronounced with pozzolana than with the other
      supports; when the pozzolana column was fed with a medium containing 100 mg l(-1)
      Cr(VI) and only 250 mg l(-1) sulphate, the lowest residence time that could be
      applied for complete Cr(VI) reduction was 16 h. The molar ratio between the
      sulphate and Cr(VI) reduction rates was decreased down to 1.5, suggesting that
      indirect reaction with HS was not the sole mechanism of Cr(VI) reduction.

PMID- 15027655
TI  - Laboratory studies on recovery of N and P from human urine through struvite
      crystallisation and zeolite adsorption.
AB  - Struvite [Mg (K, NH4)(PO4) x 6H2O] crystallisation and adsorption to zeolite have
      been proposed as a method for nutrient recovery from human urine collected with
      urine separating toilets. The aim of the present study was to optimise the use of
      MgO (to precipitate struvite) and zeolite (to adsorb ammonia) in this process.
      The experiments were performed with fresh urine, to which various amounts of MgO
      and zeolite were added. After repeated stirring and settling for 3 days the
      supernatant was analysed for pH, total-N, total-P and acute toxicity for Daphnia
      magna (24- and 48-h EC50). The results show that addition of MgO reduced P and
      addition of zeolite reduced N in the supernatant, as expected. The required
      concentration of MgO added was less than expected from the stoichiometric Mg-P
      ratio for struvite. In combination with zeolite the requirement for MgO was
      reduced even further. Zeolite was effective in reducing total-N, but because of
      its interaction with MgO the effect of zeolite on N as well as P reduction was
      rather complicated. The optimal combination of MgO and zeolite for combined N and
      P recovery was found to be around 0.5 MgO per litre urine and 15 g zeolite per
      litre urine. These additions reduced supernatant P from about 1300 mg l(-1) to 10
      mg l(-1) and N from 8000 mg l(-1) to 1000 mg l(-1). The 24-h EC50 for D. magna
      was not significantly affected by these additions. The expected recovery
      potentials for P and N by addition of MgO and zeolite are, thus, about 99% for P
      and 90% for N. However, these figures need to be verified, and pilot plant
      experiments at a science centre with urine separation wastewater treatment
      (www.universeum.se) are in progress.

PMID- 15027656
TI  - A mechanistic model for m-xylene treatment with a peat-bed biofilter.
AB  - The painting of vehicles in the automobile industry generates large quantities of
      gaseous emissions which contain volatile organic compounds (VOC) like xylenes.
      This polluted air has a high moisture content and a temperature around 15-20
      degrees C. It is thus possible to consider its treatment by a biological way. In
      this paper, laboratory tests are described which led to the choice of packing
      material to make a biofilter having good removal efficiency. Moreover this
      technique is known for its simplicity and low energy cost. The maximum treatment
      capacity was obtained with peat. A mathematical model which makes it possible to
      specify the different limiting steps of the process was carried out. This
      considered both physical parameters of the biofilter and properties of the
      biofilm. By choosing a lower Henry's constant than typical air:water system, we
      obtain a better simulation of the xylenes concentration according to the
      biofilter length and applied load.

PMID- 15027657
TI  - Deconstructing clinical pathways: mapping the landscape of health care.
AB  - Grounded in a critical feminist methodology, this article undertakes a
      deconstructive discourse analysis of a newly emergent discourse within nursing
      care management, "clinical pathways." Using a Foucaultian approach to
      deconstructive discourse analysis, the power relations inherent in the "clinical
      pathways" discourse are identified and the underlying philosophical assumptions
      informing the discourse are explored. The metaphors of "map" and "landscape" are
      employed to examine the power relations within the discourse of "clinical
      pathways." Finally, an alternative, praxis-based approach to transforming the
      discourse of "clinical pathways" from a focus of social control to one of
      situated engagement and community is proposed.

PMID- 15027658
TI  - The scholarship related to nursing work environments: where do we go from here?
AB  - Nursing shortages within American hospitals are in part associated with
      problematic work environments. Scholarship related to work environments is
      multidisciplinary and has been conducted using traditional and constructivist
      approaches to science and knowledge development. Nursing research related to
      nurses' work environments in hospitals is often conceptualized around variables
      such as job satisfaction, professional practice environment, and job stress.
      Macro-level variables associated with political, economic, and social aspects of
      the work environment have received less attention. Philosophical issues are
      considered. Person-Environment Congruence Theory is proposed as a framework
      capable of addressing environmental incongruence in hospital nursing work
      environments. Implications for theory and research using the framework are
      described.

PMID- 15027659
TI  - Discourse on the transformational leader metanarrative or finding the right
      person for the job.
AB  - Changes in healthcare today have called for leadership styles that place a heavy
      demand on organizations. Shifts in markets and reimbursement strategies call for
      new leaders with vision that can guide healthcare organizations to change. In a
      postmodern era, organizations see the transformational leader as a valuable asset
      in changing times. This article addresses the foundations of the transformational
      leader metanarrative and, through a postmodern discourse, deconstructs the
      concept. The article presents a review of postmodern thought in relation to the
      metanarrative of leadership and applications to nursing administration.

PMID- 15027660
TI  - Decision-making and nurse case management: a philosophical perspective.
AB  - Decision-making related to resource allocation in home care case management
      practice is addressed from the unique perspective of nursing. The case management
      process stipulates the adherence to both client-centered and system-centered
      goals. Issues that emerge from this process include the ethical dilemma of
      deciding the equitable and fair distribution of resources related to the
      provision of appropriate levels of service; economic factors as they relate to
      limited financial resources; and the variance among case managers in their
      decision-making. Moderate realism, as compared to critical and feminist theory,
      provides a philosophical perspective that allows a practical interpretation of
      these issues.

PMID- 15027661
TI  - Empowerment of individuals with enduring mental health problems: results from
      concept analyses and qualitative investigations.
AB  - Empowerment has been proposed to enhance the well-being of individuals with
      enduring mental health problems. Despite this apparent endorsement, critics
      charge that the concept of empowerment is poorly defined, and its actualization
      within mental health care is rare. Concept analyses and findings from qualitative
      research offer helpful insights into the process of empowerment and ways to
      promote it among individuals with long-term mental health problems. An
      empowerment model is proposed based on concept analyses, which are supported by
      qualitative findings.

PMID- 15027662
TI  - The relationship between depression and emerging adulthood: theory generation.
AB  - Depression during the transition from late adolescence to young adulthood is a
      major mental health concern. Developmental theories addressing this transition,
      also called emerging adulthood, are few, and fewer yet are theories addressing
      mental health or psychopathology during this period. This article establishes the
      legitimacy of emerging adulthood as a unique developmental period and attempts to
      generate directions for theory development by merging theories of depression and
      development at the point of emerging adulthood. This article concludes with a
      theoretical discussion and application of this process in research and practice.

PMID- 15027663
TI  - Advanced practice nursing model for comprehensive care with chronic illness:
      model for promoting process engagement.
AB  - New models of providing care to chronically ill persons are needed that can
      facilitate a more integrative approach to patient care. The purposes of this
      article are to describe the utilization of a theory synthesis process for
      development of a client-focused approach for advanced practice nurse (APN)
      management of chronic illness and to present the Model for Promoting Process
      Engagement. The model was developed as a theory-driven intervention to address
      complexities of chronic illness care. This APN practice model is the direct
      result of the synthesis of a number of differing theoretical models developed by
      the authors in previous individual research endeavors.

PMID- 15027664
TI  - Preconceptional health promotion: progress in changing a prevention paradigm.
AB  - Preconceptional health promotion is a proven strategy to impact reproductive
      outcomes. Despite energy to incorporate this prevention strategy into the care of
      women in this country, little evidence exists that the paradigm shift necessary
      to reframe the clinical care of women has occurred or that public awareness about
      critical opportunities for preventing reproductive casualties is high. This
      article reviews the rationale for preconceptional counseling, discusses progress
      in moving the agenda of prepregnancy wellness forward, and reveals some of the
      lessons learned from efforts to redesign prevention emphases for reproductive
      healthcare.

PMID- 15027666
TI  - Advances in preconception genetic counseling.
AB  - Preconception counseling offers couples contemplating pregnancy the opportunity
      to identify and reduce potential pregnancy risks, plan care for known risks, and
      establish early prenatal care. The goal of preconception counseling is to promote
      physically and emotionally healthy parents in an attempt to ensure optimal
      prenatal, intrapartum, and postpartum maternal and fetal health. The advantages
      of addressing these issues prior to conception include the opportunity of giving
      recurrence or occurrence risk information for informed decision regarding
      pregnancy, the accessibility of more reproductive options such as preimplantation
      genetic diagnosis, and the opportunity to make lifestyle, medical, and behavior
      alterations for optimal maternal and fetal outcome. This article will discuss
      advances and updates in preconception genetic counseling including risk
      assessment and potential intervention for concerns identified through evaluation
      of family history, ethnicity, maternal age, medical and obstetric history, and
      associated psychosocial and nursing implications. Significant advances have
      emerged in the areas of cystic fibrosis carrier screening, first trimester
      screening, preimplantation genetic diagnosis, and detection and treatment of
      maternal thrombophilia.

PMID- 15027665
TI  - Preconception care of women with diabetes.
AB  - Preconception care in women with diabetes reduces the risk of spontaneous
      abortion and congenital malformations as a result of improved glycemic control
      before and during organogenesis. Prepregnancy planning encompasses optimizing
      glycemic control and also affording the opportunity for genetic counseling,
      contraceptive selection, management of diabetes complications, and evaluation of
      psychosocial aspects of pregnancy, childbearing, and diabetes care. The purpose
      of this article is to provide nurses with current clinical assessment and
      management strategies of women with diabetes in order to implement a
      comprehensive individualized preconception plan of care.

PMID- 15027667
TI  - Tandem mass spectrometry in newborn screening: a primer for neonatal and
      perinatal nurses.
AB  - Since 1961, newborn screening for errors of metabolism (EM) has improved the
      diagnosis, treatment and outcome of newborns with an EM. Recently, advances in
      laboratory technology with tandem mass spectrometry (MS/MS) has increased the
      identification of newborns with an EM. With a single dried filter paper blood
      spot (Guthrie R, Susi A. A simple phenylalanine method for detecting PKU in large
      populations of newborn infants. Pediatrics. 1963;32:338-343), MS/MS can identify
      more than 30 disorders of metabolism. This review will explore MS/MS to provide a
      better understanding of the development and application of this technology to
      newborn screening for perinatal and neonatal nurses.

PMID- 15027668
TI  - Surfactant protein B deficiency in infants with respiratory failure.
AB  - Surfactant Protein B (SP-B) deficiency has been recently identified as an
      uncommon, autosomal recessive lung disorder in term infants. This inability to
      produce SP-B leads to progressive, lethal, hypoxemic respiratory failure in the
      first year of life. A frameshift mutation (121 ins 2) is the predominant but not
      exclusive cause. The clue to diagnosis is to have a high suspicion of SP-B
      deficiency in any term infant with severe respiratory distress without any
      apparent cause. SP-B deficiency can be diagnosed prenatally or postnatally. The
      only current treatment options available include lung transplantation or
      compassionate care. Current developments in gene therapy offer hope for future
      treatment.

PMID- 15027669
TI  - Effects of a mock ultrasonographic procedure on cortisol concentrations during
      low-dose dexamethasone suppression testing in clinically normal adult dogs.
AB  - OBJECTIVE: To determine whether the stress of an ultrasonographic procedure would
      interfere with the suppressive effect of dexamethasone during a low-dose
      dexamethasone suppression test (LDDST) in healthy dogs. ANIMALS: 6 clinically
      normal adult dogs. PROCEDURE: In phase 1, an LDDST was performed 5 times at
      weekly intervals in each dog. Serum samples were obtained 0, 2, 4, 6, and 8 hours
      after dexamethasone injection. A mock 20-minute abdominal ultrasonographic
      examination was performed on all dogs at each time point during the LDDST on
      weeks 2 through 5. In phase 2, serum cortisol concentrations were measured before
      and immediately after a 20-minute mock abdominal ultrasonographic examination, as
      described for phase 1. RESULTS: We did not detect significant differences after
      dexamethasone injection when comparing median cortisol concentrations for weeks 2
      to 5 (mock ultrasonographic procedure) with median concentration for week 1 (no
      mock ultrasonographic procedure). For 5 of the 6 dogs, cortisol concentrations
      after dexamethasone injection decreased to < 35.9 nmol/L after each mock
      ultrasonographic procedure and remained low for the duration of the LDDST. In
      phase 2, all dogs had significant increases in cortisol concentrations
      immediately after the mock ultrasonographic procedure. CONCLUSIONS AND CLINICAL
      RELEVANCE: A 20-minute mock abdominal ultrasonographic examination performed
      during LDDST did not alter results of the LDDST in most dogs. Cortisol
      concentrations measured immediately after a mock ultrasonographic examination
      were significantly increased. Ultrasonographic procedures should be performed a
      minimum of 2 hours before collection of samples that will be used to measure
      cortisol concentrations.

PMID- 15027670
TI  - Effect of topical application of diclofenac liposomal suspension on
      experimentally induced subcutaneous inflammation in horses.
AB  - OBJECTIVE: To determine whether 1% diclofenac liposomal suspension (DLS) ointment
      would be absorbed transdermally and attenuate experimentally induced subcutaneous
      inflammation in horses. ANIMALS: 7 healthy adult horses. PROCEDURE: Inflammation
      was produced by injecting 1% sterile carrageenan into subcutaneously implanted
      tissue cages 8 hours before (time -8) and at the time of application of test
      ointment. A crossover design was used. Horses received 1 of 2 treatments
      (topically administered control or DLS ointments) during 48 hours of carrageenan
      induced subcutaneous inflammation. A single application of test ointment (7.2 g)
      was applied over each tissue cage (time 0). Samples of transudate and blood were
      collected at -8, 0, 6, 12, 18, 24, 30, 36, and 48 hours. Plasma and transudate
      diclofenac concentrations were determined by use of high-performance liquid
      chromatography. Transudate concentrations of prostaglandin E2 (PGE2) were
      determined with a competitive enzyme immunoassay. RESULTS: DLS was absorbed
      transdermally. The highest concentration (mean +/- SEM, 76.2 +/- 29 ng/mL) was
      detectable in tissue-cage fluid within 18 hours after application. Minimal
      concentrations of diclofenac were detectable in plasma. Application of DLS
      significantly decreased transudate concentrations of PGE2 at 6 and 30 hours.
      Decreases in PGE2 concentration were observed in the DLS group at all collection
      times. CONCLUSIONS AND CLINICAL RELEVANCE: A single topical application of DLS
      resulted in concentrations of diclofenac in transudate within 6 hours and
      significantly attenuated carrageenan-induced local production of PGE2. Results of
      this study suggest that DLS is readily absorbed transdermally and may be
      efficacious for reducing subcutaneous inflammation in horses.

PMID- 15027671
TI  - Effects of dermal application of 10.0% imidacloprid-0.08% ivermectin in
      ivermectin-sensitive Collies.
AB  - OBJECTIVE: To evaluate the safety of dermal application of 10.0% imidacloprid
      0.08% ivermectin in ivermectin-sensitive Collies at dose rates of 3 to 5 times
      the proposed maximum therapeutic dose. ANIMALS: 15 Collies (5 males and 10
      females) that were confirmed as ivermectin-sensitive dogs. PROCEDURE: Dogs were
      assigned to 3 treatment groups (control, 3X, or 5X group) in a randomized block
      design on the basis of the maximal ivermectin-sensitivity score obtained during
      preliminary screening. Dogs in groups 3X and 5X were treated at 3 and 5 times the
      maximum label dose, respectively. Control dogs received an application of an
      equal volume of a nonmedicated solution. Observation and scoring on all days were
      conducted to specifically include neurologic signs typical of ivermectin
      toxicosis, including lethargy, ataxia, abnormal mydriasis, and abnormal
      salivation. RESULTS: None of the dogs had clinical abnormalities during the study
      period. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of results of this study
      indicates that dermal application of 10.0% imidacloprid-0.08% ivermectin is safe
      for use in ivermectin-sensitive Collies at dose rates of 3 or 5 times the
      proposed maximum therapeutic dose.

PMID- 15027673
TI  - Urodynamic effects of a percutaneously controlled static hydraulic urethral
      sphincter in canine cadavers.
AB  - OBJECTIVE: To describe a percutaneously controlled static hydraulic urethral
      sphincter (SHUS) and evaluate urodynamic effects of the SHUS in canine cadavers.
      SAMPLE POPULATION: Cadavers of 6 adult female dogs. PROCEDURE: Cadavers were
      obtained immediately after dogs were euthanatized. Baseline maximal urethral
      closure pressure (MUCP) and cystourethral leak point pressure (CLPP) were
      measured by use of a urethral pressure profilometer. An SHUS system was
      constructed by use of a silicone vascular occluder and subcutaneous infusion
      port. The SHUS system was then placed around the pelvic urethra in each cadaver.
      Measurements of MUCP and CLPP were repeated after varying occlusion of the SHUS
      (0%, 25%, and 50% occlusion). Baseline MUCP and CLPP values were compared with
      values obtained at 0%, 25%, and 50% occlusion of the SHUS by use of repeated
      measures ANOVA. RESULTS: Mean +/- SD MUCP for canine cadavers was 7 +/- 1.3 cm
      H2O at baseline, which increased to 127 +/- 53 cm H2O after 50% occlusion of the
      SHUS. Mean CLPP was 11 +/- 8.6 cm H2O at baseline, which increased to 73 +/- 38
      cm H2O after 50% occlusion of the SHUS. Mean MUCP and CLPP were significantly
      associated with the amount of occlusion. CONCLUSIONS AND CLINICAL RELEVANCE: The
      SHUS had positive effects on MUCP and CLPP in canine cadavers. Therefore,
      additional evaluation of the SHUS in live dogs is warranted.

PMID- 15027672
TI  - Quantitative effect of tenorrhaphy on intrinsic vasculature of the equine
      superficial digital flexor tendon.
AB  - OBJECTIVE: To compare effects of the locking-loop suture pattern (LLP) and 3-loop
      pulley (3LP) suture pattern for tenorrhaphy on the intrinsic vasculature of the
      superficial digital flexor tendon (SDFT) of horses in vitro after surgery. SAMPLE
      POPULATION: 16 forelimbs obtained from 8 mature horses. PROCEDURE: Tenotomy and
      subsequent tenorrhaphy was performed in anesthetized horses. Following systemic
      administration of heparin, horses were euthanatized and the limbs were removed
      and placed under tension to load the flexor tendons. The intrinsic vasculature
      was then perfused with a mixture of barium sulfate and water. Four-millimeter
      sections of the SDFT were prepared for microangiographic analysis. Mean vessel
      density was calculated for each section by use of a grid consisting of 1.5-mm2
      vascular assessment squares (VAS). Comparisons were made among the control, LLP
      and 3LP groups. RESULTS: Mean +/- SD vessel density was 3.11 +/- 0.38, 1.47 +/-
      0.47, and 2.01 +/- 0.63 perfused vessels/1.5 mm2 for control, LLP and 3LP groups,
      respectively. Significant differences in vascular density were detected between
      the control and 3LP groups, control and LLP groups, and LLP and 3LP groups.
      CONCLUSIONS AND CLINICAL RELEVANCE: Use of the LLP and 3LP pattern has
      deleterious effects in vitro on the intrinsic vasculature of the SDFT. However,
      the 3LP pattern was less disruptive to the intrinsic vasculature, compared with
      the effects for the LLP. Use of the 3LP tenorrhaphy suture pattern in clinical
      situations may result in less damage to the intrinsic vasculature of the SDFT of
      horses during convalescence.

PMID- 15027674
TI  - Assessment of leukotriene B4 production in leukocytes from horses with recurrent
      airway obstruction.
AB  - OBJECTIVE: To determine the ex vivo leukotriene (LT) biosynthesis in peripheral
      blood neutrophils (PBNs) and inflammatory cells in bronchoalveolar lavage fluid
      (BALF) obtained from horses affected with recurrent airway obstruction (RAO).
      ANIMALS: 6 RAO-affected and 6 control horses. PROCEDURES: Before and 6, 24, and
      48 hours after stabling, disease severity was determined subjectively by clinical
      and mucus scores and measurement of the maximal change in pleural pressure
      (deltaPpl(max)); PBNs were isolated and BALF samples were examined cytologically.
      The PBN and BALF cells were activated with a calcium ionophore in the presence of
      arachidonic acid, and production of LTC4 and LTB4 was measured per 10(6) cells.
      RESULTS: Clinical and mucus scores and deltaPpl(max) increased during stabling in
      RAO-affected horses, but not in control horses. In neutrophils and BALF cells
      from both groups, production of LTB4 exceeded that of LTC4. At all times, LTB4
      production by PBNs was less in RAO-affected horses than it was in control horses.
      Before stabling, LTB4 production by cells in BALF was low in RAO-affected horses,
      but increased considerably after 6 hours of stabling. This increase coincided
      with the migration of neutrophils into the airways. In control horses, production
      of LTB4 did not change during stabling. CONCLUSIONS AND CLINICAL RELEVANCE:
      Results suggested increased production of LTB4 in airways of RAO-affected horses,
      compared with control horses, that may contribute to the infiltration of
      neutrophils into the lungs and the sustained inflammation associated with RAO.

PMID- 15027675
TI  - Assessment of the effects of age and joint disease on hydroxyproline and
      glycosaminoglycan concentrations in synovial fluid from the metacarpophalangeal
      joint of horses.
AB  - OBJECTIVE: To assess the effects of age and joint disease on hydroxyproline and
      glycosaminoglycan (GAG) concentrations in synovial fluid from the
      metacarpophalangeal joint of horses and evaluate the association of those
      concentrations with severity of osteoarthritis and general matrix
      metalloproteinase (MMP) activity. SAMPLE POPULATION: Synovial fluid was collected
      from the metacarpophalangeal joints of foals at birth (n = 10), 5-month-old foals
      (10), 11-month-old foals (5), and adult horses (73). PROCEDURE: Hydroxyproline
      and GAG concentrations were determined in synovial fluid samples. The severity of
      osteoarthritis in adult joints was quantified by use of a cartilage degeneration
      index (CDI) and assessment of general MMP-activity via a fluorogenic assay.
      RESULTS: Hydroxyproline and GAG concentrations in synovial fluid were highest in
      neonates and decreased with age. Concentrations reached a plateau in adults by 4
      years and remained constant in healthy joints. In synovial fluid from
      osteoarthritic joints, hydroxyproline and GAG concentrations were not increased,
      compared with unaffected joints, but hydroxyproline were significantly correlated
      with the CDI and general MMP activity. There was no significant correlation
      between GAG concentration and CDI value or MMP activity. CONCLUSIONS AND CLINICAL
      RELEVANCE: Changes in hydroxyproline concentration in synovial fluid appeared to
      indicate damage to collagen of the articular cartilage. In joints with
      osteoarthritis, the lack of high GAG concentration in synovial fluid and the
      absence of a significant correlation between GAG concentration and CDI values or
      MMP activity may severely limit the usefulness of this marker for monitoring
      equine joint disease.

PMID- 15027676
TI  - Evaluation of transmission of swine influenza type A subtype H1N2 virus in
      seropositive pigs.
AB  - OBJECTIVE: To examine clinical signs, virus infection and shedding, and
      transmission of swine influenza virus (SIV) subtype H1N2 among seropositive pigs.
      ANIMALS: Eighteen 3-week-old pigs with maternal antibodies against SIV subtypes
      H1N1, H3N2, and H1N2. PROCEDURE: Ten pigs (principal) were inoculated
      intranasally with subtype H1N2 and 2 groups of contact pigs (n = 4) each were
      mixed with principal pigs on day 7 (group 1) or 28 (group 2). Two principal pigs
      each were necropsied on days 4, 14, 21, 28, and 42 days after inoculation. Four
      pigs in each contact group were necropsied 35 and 14 days after contact. Virus
      excretion was evaluated after inoculation or contact. Lung lesions and the
      presence of SIV in various tissues were examined. RESULTS: Mild coughing and
      increased rectal temperature were observed in principal pigs but not in contact
      pigs. Nasal virus shedding was detected in all principal pigs from day 2 for 3 to
      5 days, in group 1 pigs from day 2 for 4 to 9 days after contact, and in group 2
      pigs from day 4 for 2 to 6 days after contact. Trachea, lung, and lymph node
      specimens from infected pigs contained virus. Antibody titers against all 3
      subtypes in all pigs gradually decreased. CONCLUSIONS AND CLINICAL RELEVANCE:
      Protection from viral infection and shedding was not observed in pigs with
      maternal antibodies, but clinical disease did not develop. Vaccination programs
      and good management practices should be considered for control of SIV subtype
      H1N2 infection on swine farms.

PMID- 15027677
TI  - Effect of nasogastric administration of sodium bicarbonate on carbon 13 isotopic
      enrichment of carbon dioxide in serum of horses.
AB  - OBJECTIVE: To determine the effect of administration of commercially available
      sodium bicarbonate (NaHCO3) on carbon 13 (13C) isotopic enrichment of carbon
      dioxide (CO2) in serum of horses. ANIMALS: 7 healthy Thoroughbreds. PROCEDURES:
      Sodium bicarbonate (450 g) was administered via nasogastric intubation to horses.
      Horses had been fed a diet obtained from the same source and had access to water
      from the same source for 3 months before the study. Blood samples were collected
      immediately before and at 2, 4, 6, and 24 hours after administration of NaHCO3.
      The concentration of total CO2 in serum was measured by use of a commercial
      analyzer. The 13C enrichment of bicarbonate in serum was estimated by measurement
      of 13C enrichment of CO2 released by acidification of the serum. The 13C
      enrichment of commercially available NaHCO3 was also determined and compared with
      that of CO2 in serum of horses before administration of NaHCO3. RESULTS:
      Commercially available NaHCO3 had a 13C enrichment significantly different from
      that of carbon dioxide in serum of horses before treatment. Administration of
      NaHCO3 increased the concentration of total CO2 from pretreatment values. The 13C
      enrichment of CO2 in serum was only transiently and minimally affected after
      administration of NaHCO3. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of
      NaHCO3 was not detected by measuring 13C enrichment of CO2 in serum of horses.

PMID- 15027678
TI  - Evaluation of the six-minute walk test in dogs.
AB  - OBJECTIVE: To determine the feasibility for use of a 6-minute walk test (6-MWT)
      in dogs with congestive heart failure (CHF) and document that the distance walked
      in 6 minutes decreases when a dog has CHF. ANIMALS: 16 young mature male hound
      crossbred dogs weighing between 25 and 37 kg. PROCEDURE: An unobstructed path
      (22.73 m) was measured in a hallway. Each dog was walked on a leash for 6
      minutes; each dog was allowed to set its own pace. At the end of 6 minutes (as
      measured by use of a stopwatch), the total distance walked was measured. Heart
      rate (HR) obtained by auscultation and mean systemic arterial pressure (MAP)
      obtained by oscillometry were recorded before and after the 6-MWT. Heart failure
      was induced by use of rapid ventricular pacing. Mean of the distance walked, HR,
      and MAP before and after the 6-MWT were compared between the control period and
      after dogs developed induced CHF. RESULTS: Dogs with CHF had a significant
      increase in resting HR, significant decrease in MAP, and a significant decrease
      in the distance walked in 6 minutes. The MAP increased slightly after exercise
      during the control period but decreased slightly after exercise during the CHF
      period. Fractional shortening decreased significantly when dogs had CHF.
      CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of these results indicated that the
      distance walked in 6 minutes decreased significantly when a dog had CHF. The 6
      MWT requires little time, space, or equipment and may replace the treadmill
      exercise test.

PMID- 15027679
TI  - Development of a reverse transcriptase-polymerase chain reaction assay to detect
      feline herpesvirus-1 latency-associated transcripts in the trigeminal ganglia and
      corneas of cats that did not have clinical signs of ocular disease.
AB  - OBJECTIVE: To develop a reverse transcriptase-polymerase chain reaction (RT-PCR)
      assay to detect feline herpesvirus-1 (FHV-1) latency-associated transcripts
      (LATs) in the corneas and trigeminal ganglia of cats that did not have clinical
      signs of ocular disease. SAMPLE POPULATION: Corneas and trigeminal ganglia
      obtained from 21 cats necropsied at the Indiana Animal Disease Diagnostic
      Laboratory and 25 cats euthanatized at a humane shelter; none of the cats had a
      recent history of respiratory tract or ocular disease, and all had normal results
      for ophthalmic examinations. PROCEDURE: Both corneas and both trigeminal ganglia
      were harvested from each cat. An initial PCR assay detected FHV-1 DNA in the
      corneas and trigeminal ganglia. The RNA was then isolated from samples positive
      for FHV-1 DNA, and an RT-PCR assay was used to detect LATs. RESULTS: FHV-1 DNA
      was detected in 45 of 92 (48.9%) corneas and 38 of 92 (41.3%) trigeminal ganglia.
      In many samples, the RNA had degraded and RT-PCR assay was not possible. Of the
      samples subjected to RT-PCR assay, none of the 39 corneas but 4 of 16 trigeminal
      ganglia had positive results when tested for LATs. CONCLUSIONS AND CLINICAL
      RELEVANCE: Analysis of the results indicated that a high percentage of cats that
      did not have clinical signs of ocular disease had detectable FHV-1 DNA in their
      corneas and trigeminal ganglia. This study documents that the RT-PCR assay can
      successfully identify LATs and may serve as a tool to better understand the
      biologic characteristics of FHV-1 and its relationship to clinical disease.

PMID- 15027680
TI  - Use of multifrequency bioelectrical impedance analysis for estimation of total
      body water and extracellular and intracellular fluid volumes in horses.
AB  - OBJECTIVE: To evaluate the use of multifrequency bioelectrical impedance analysis
      (MF-BIA) for estimating total body water (TBW), extracellular fluid volume
      (ECFV), and intracellular fluid volume (ICFV) in horses. ANIMALS: 9 healthy
      mares. PROCEDURE: TBW and ECFV were measured by use of deuterium oxide and sodium
      bromide dilution techniques, respectively. Intracellular fluid volume was
      calculated as the difference between TBW and ECFV. Concurrently, MF-BIA
      recordings were obtained by use of 4 anatomic electrode positions and 3
      measurements of length. Models for MF-BIA data were created for all combinations
      of length and anatomic electrode position. Models were evaluated to determine the
      position-length configuration that provided the most consistent estimates of TBW,
      ECFV, and ICFV, compared with values determined by use of the dilution
      techniques. RESULTS: Positioning electrodes over the ipsilateral carpus and
      tarsus and use of height at the tuber sacrale for length provided the closest
      estimate between values for TBW, ECFV, and ICFV predicted by use of MF-BIA and
      measured values obtained by dilutional techniques. This model had the narrowest
      95% limits of agreement. CONCLUSIONS AND CLINICAL RELEVANCE: MF-BIA techniques
      have been used to predict changes in TBW, ECFV, and ICFV in healthy and diseased
      humans. Results reported in this study provide an equine-specific model to serve
      as the basis for further evaluation of MF-BIA in horses with altered fluid
      states. The MF-BIA techniques have a number of potential applications for use in
      horses, including evaluation of exercise physiology, pharmacologic studies, and
      critical-care management.

PMID- 15027681
TI  - Evaluation of antiplatelet effects of ticlopidine in cats.
AB  - OBJECTIVE: To determine whether ticlopidine exerts an antiplatelet effect,
      estimate the pharmacodynamics of ticlopidine, and evaluate any acute adverse
      effects associated with administration of ticlopidine in cats. ANIMALS: 8
      domestic purpose-bred sexually intact male cats. PROCEDURE: Ticlopidine was
      administered orally (50 mg, q 24 h; 100 mg, q 24 h; 200 mg, q 24 h; and 250 mg, q
      12 h). Each treatment period consisted of 10 days of drug administration.
      Platelet aggregation studies with adenosine diphosphate (ADP) and collagen and
      evaluation of oral mucosal bleeding times (OMBTs) were performed on days 3, 7,
      and 10 during each drug administration. Serotonin was measured to evaluate
      secretion at baseline and on day 10 for cats that received the 250-mg dosage.
      RESULTS: A significant reduction in platelet aggregation was detected in response
      to ADP on days 7 and 10 at 100 mg, on day 3 at 200 mg, and on days 3, 7, and 10
      at 250 mg. A significant increase in the OMBT and decrease in serotonin release
      on day 10 at 250 mg was also detected; however, the cats had anorexia and
      vomiting at the 250-mg dosage. CONCLUSIONS AND CLINICAL RELEVANCE: Although there
      was a consistent antiplatelet effect at the 250-mg dosage, there was dose
      dependent anorexia and vomiting that we conclude precludes the clinical
      usefulness of this drug in cats.

PMID- 15027682
TI  - Alterations in thyroid hormone concentrations in healthy sled dogs before and
      after athletic conditioning.
AB  - OBJECTIVE: To determine effects of athletic conditioning on thyroid hormone
      concentrations in a population of healthy sled dogs. ANIMALS: 19 healthy adult
      sled dogs. PROCEDURE: Serum concentrations of thyroxine (T4), triiodothyronine
      (T3), thyroid-stimulating hormone (TSH), free T4 (fT4), free T3 (fT3), and
      autoantibodies directed against T3, T4, and thyroglobulin were measured in sled
      dogs that were not in training (ie, nonracing season) and again after dogs had
      been training at maximum athletic potential for 4 months. RESULTS: Analysis
      revealed significant decreases in T4 and fT4 concentrations and a significant
      increase in TSH concentration for dogs in the peak training state, compared with
      concentrations for dogs in the untrained state. Serum concentrations of T4 and
      fT4 were less than established reference ranges during the peak training state
      for 11 of 19 and 8 of 19 dogs, respectively; fT4 concentration was greater than
      the established reference range in 9 of 19 dogs in the untrained state.
      CONCLUSIONS AND CLINICAL RELEVANCE: Decreased total T4 and fT4 concentrations and
      increased serum concentrations of TSH were consistently measured during the peak
      training state in healthy sled dogs, compared with concentrations determined
      during the untrained state. Although thyroid hormone concentrations remained
      within the established reference ranges in many of the dogs, values that were
      outside the reference range in some dogs could potentially lead to an incorrect
      assessment of thyroid status. Endurance training has a profound impact on the
      thyroid hormone concentrations of competitive sled dogs.

PMID- 15027683
TI  - Effects of probiotic Lactobacillus acidophilus strain DSM13241 in healthy adult
      dogs.
AB  - OBJECTIVE: To evaluate viability of a probiotic strain of Lactobacillus
      acidophilus in a dry dog food, determine its ability to survive transit through
      the gastrointestinal tract and populate the colon, and assess its effects on
      intestinal and systemic parameters. ANIMALS: 15 adult dogs. PROCEDURE: Dogs were
      sequentially fed a dry control food for 2 weeks, the same food supplemented with
      > 10(9) L. acidophilus for 4 weeks, and the control food again for 2 weeks. Fecal
      score was assessed daily, and fecal and blood samples were collected for
      enumeration of bacterial populations and measurement of hematologic variables.
      RESULTS: Recovery of L. acidophilus from the supplemented food was 71% and 63% at
      the start and end of the study, respectively, indicating that the bacteria were
      able to survive manufacture and storage. The probiotic bacterium was detected in
      feces via ribotyping and RNA gene sequencing during the probiotic administration
      phase but not 2 weeks after cessation of administration. Administration of the
      probiotic-supplemented food was associated with increased numbers of fecal
      lactobacilli and decreased numbers of clostridial organisms. There were
      significant increases in RBCs, Hct, hemoglobin concentration, neutrophils,
      monocytes, and serum immunoglobin G concentration and reductions in RBC fragility
      and serum NO concentration. CONCLUSIONS AND CLINICAL RELEVANCE: These data
      indicate that L. acidophilus can be successfully incorporated into a dry dog
      food, survive transit through the canine gastrointestinal tract, and populate the
      colon and are associated with local and systemic changes. This probiotic
      bacterium may have the potential to enhance intestinal health and improve immune
      function in dogs.

PMID- 15027684
TI  - Inheritance of cricopharyngeal dysfunction in Golden Retrievers.
AB  - OBJECTIVE: To characterize a genetic component to cricopharyngeal dysfunction
      (CD) in Golden Retrievers. ANIMALS: 117 dogs. PROCEDURE: The CD phenotype was
      determined by videofluoroscopy, and dogs were classified as affected if the upper
      esophageal sphincter (UES) did not open, if there were morphologic abnormalities
      of the UES, or if opening of the UES was delayed for > or = 6 videofluoroscopic
      frames (0.2 seconds) after closure of the epiglottis. All survey radiographic and
      videofluoroscopic studies were reviewed by the same radiologist. RESULTS: Of the
      117 dogs (47 males and 70 females) with a CD phenotype determined via
      videofluoroscopy, 21 dogs (18.0%) had abnormalities of the UES (affected). Of
      these 21 dogs, 9 were males (19.1% of all males) and 12 were females (17.1% of
      all females). The heritability of CD in a threshold model was estimated as 0.61,
      which established that CD could be passed from parent to offspring. Results of
      complex segregation analysis suggested that a single recessive allele of large
      effect contributed to the expression of this disease in Golden Retrievers.
      CONCLUSIONS AND CLINICAL RELEVANCE: The determination that CD is inherited in
      Golden Retrievers is an important step in providing information for veterinarians
      attending dogs with this disorder. Breeders also require this information to make
      informed breeding decisions.

PMID- 15027685
TI  - Pharmacokinetics of enrofloxacin in neonatal kittens.
AB  - OBJECTIVE: To determine the pharmacokinetics of enrofloxacin in neonatal kittens
      and compare the pharmacokinetics of enrofloxacin in young and adult cats.
      ANIMALS: 7 adult cats and 111 kittens (2 to 8 weeks old). PROCEDURE: A single
      dose of 5 mg of enrofloxacin/kg was administered to adults (i.v.) and kittens
      (i.v., s.c., or p.o.). Plasma concentrations of enrofloxacin and its active
      metabolite, ciprofloxacin, were determined. RESULTS: The half-life of
      enrofloxacin administered i.v. in 2-, 6-, and 8-week-old kittens was
      significantly shorter and its elimination rate significantly greater than that
      detected in adults. The apparent volumes of distribution were lower at 2 to 4
      weeks and greater at 6 to 8 weeks. This resulted in lower peak plasma
      concentration (Cmax) at 6 to 8 weeks; however, initial plasma concentration was
      within the therapeutic range after i.v. administration at all ages. Compared with
      i.v. administration, s.c. injection of enrofloxacin in 2-week-old kittens
      resulted in similar Cmax, half-life, clearance, and area under the curve values.
      Enrofloxacin administered via s.c. injection was well absorbed in 6- and 8-week
      old kittens, but greater clearance and apparent volume of distribution resulted
      in lower plasma concentrations. Oral administration of enrofloxacin resulted in
      poor bioavailability. CONCLUSIONS AND CLINICAL RELEVANCE: In neonatal kittens,
      i.v. and s.c. administration of enrofloxacin provided an effective route of
      administration. Oral administration of enrofloxacin in kittens did not result in
      therapeutic drug concentrations. Doses may need to be increased to achieve
      therapeutic drug concentrations in 6- to 8-week-old kittens.

PMID- 15027686
TI  - Cardiovascular effects of insufflation of the abdomen with carbon dioxide in
      standing horses sedated with detomidine.
AB  - OBJECTIVE: To determine the cardiovascular effects of 60 minutes of abdominal
      insufflation with CO2 to an intra-abdominal pressure of 15 mm Hg in standing
      horses receiving a constant rate infusion of detomidine. ANIMALS: 5 horses.
      PROCEDURE: Horses were randomly allocated into treatment or control groups. A
      washout period of a minimum of 7 days separated the 2 experimental periods of the
      crossover study. Catheters were placed into the right atrium, pulmonary artery,
      jugular vein, and right transverse facial artery after lidocaine infiltration.
      All horses were sedated with detomidine (8.54 microg/kg/h, i.v.). Horses in the
      treatment group received abdominal insufflation with CO2 via a laparoscopic
      cannula to a final and constant intra-abdominal pressure of 15 mm Hg for 60
      minutes. Systemic arterial pressure, right atrial pressure, heart rate, cardiac
      output, core body temperature, and the pH and gas tensions of arterial and mixed
      venous blood were obtained. Cardiac index and systemic vascular resistance were
      calculated. Data were collected in 3 stages: preinsufflation (-10 and -5
      minutes), insufflation (0, 15, 30, 45, and 60 minutes), and postinsufflation (70
      and 80 minutes). The quality of sedation and level of analgesia were determined.
      RESULTS: The PaO2 of horses in the treatment group was significantly higher after
      60 minutes of pneumoperitoneum than in the control group. Core body temperature
      decreased significantly from baseline in both groups. CONCLUSIONS AND CLINICAL
      RELEVANCE: A 60-minute period of abdominal insufflation to an intra-abdominal
      pressure of 15 mm Hg did not induce significant cardiovascular abnormalities in
      healthy horses.

PMID- 15027687
TI  - Effects of a single intranasal dose of modified-live bovine respiratory syncytial
      virus vaccine on resistance to subsequent viral challenge in calves.
AB  - OBJECTIVE: To determine whether a single intranasal dose of modified-live bovine
      respiratory syncytial virus (BRSV) vaccine protects calves from BRSV challenge
      and characterize cell-mediated immune response in calves following BRSV
      challenge. ANIMALS: 13 conventionally reared 4- to 6-week-old Holstein calves.
      PROCEDURES: Calves received intranasal vaccination with modified live BRSV
      vaccine (VC-group calves; n = 4) or mock vaccine (MC-group calves; 6) 1 month
      before BRSV challenge; unvaccinated control-group calves (n = 3) underwent mock
      challenge. Serum virus neutralizing (VN) antibodies were measured on days -30, 
      14, 0, and 7 relative to BRSV challenge nasal swab specimens were collected for
      virus isolation on days 0 to 7. At necropsy examination on day 7, tissue
      specimens were collected for measurement of BRSV-specific interferon gamma (IFN
      gamma) production. Tissue distribution of CD3+ T and BLA.36+ B cells was
      evaluated by use of immunohistochemistry. RESULTS: The MC-group calves had
      significantly higher rectal temperatures, respiratory rates, and clinical scores
      on days 5 to 7 after BRSV challenge than VC-group calves. No difference was seen
      between distributions of BRSV in lung tissue of VC- and MC-group calves.
      Production of BRSV-specific IFN-gamma was increased in tissue specimens from VC
      group calves, compared with MC- and control-group calves. Virus-specific IFN
      gamma production was highest in the mediastinal lymph node of VC-group calves.
      Increased numbers of T cells were found in expanded bronchial-associated lymphoid
      tissue and airway epithelium of VC-group calves. CONCLUSIONS AND CLINICAL
      RELEVANCE: An intranasal dose of modified-live BRSV vaccine can protect calves
      against virulent BRSV challenge 1 month later.

PMID- 15027688
TI  - Expression of matrix metalloproteinases in feline vaccine site-associated
      sarcomas.
AB  - OBJECTIVES: To screen for expression of 9 predominant members of the matrix
      metalloproteinase (MMP) family, including membrane-type matrix metalloproteinases
      (MT-MMPs) and tissue inhibitors of metalloproteinases (TIMPs), in primary tumor
      tissue biopsy specimens of vaccine site-associated sarcomas (VSS) in cats and
      compare expression profiles of VSS with expression profiles of non-VSS and
      carcinomas. SAMPLE POPULATION: 31 primary tumor tissue biopsy specimens and 6
      nontumor (normal) tissue biopsy specimens. PROCEDURES: Tissue specimens were
      obtained from primary tumor biopsy specimens of cats. Primers for reverse
      transcriptase-polymerase chain reaction assay were designed on the basis of known
      sequences. Data were analyzed for patterns of expression of MMPs, MT-MMPs, and
      TIMPs. Differences in expression patterns were evaluated among cats of differing
      genders, ages, metastasis status, and overall survival durations, and between
      cats with VSS and cats with non-VSS tumor types. RESULTS: A total of 31 primary
      tumor tissue biopsy specimens and 6 nontumor (normal) tissue biopsy specimens
      were screened for the presence of 6 MMPs and 3 TIMPs. Matrix metalloproteinase
      and TIMP expression was found in non-VSS, carcinomas, and VSS. No significant
      differences were found in patterns of expression among tumor types. Metastasis
      was found to be the only predictive factor for overall survival duration. A
      significant correlation was found between MMP2 and MT-MMP16 expression and
      overall duration of survival. CONCLUSIONS AND CLINICAL RELEVANCE: The
      identification of MMPs in feline VSS supports an underlying inflammatory
      pathogenesis for this tumor. Expression of MMP2 and MT-MMP16 were correlated with
      survival time in our study.

PMID- 15027689
TI  - [Occupational asthma and biological damage: adequate compensation?].
AB  - The evaluation of the damage to biological and relational capacities of the
      subject is the novel approach of the Italian Insurance Regulation Decree N(o)
      38/2000 for compensating occupational asthma (OA). In this study we aimed to
      apply retrospectively the novel rating system to mild OA. From a data base of 201
      diagnosis of OA collected in the 1987-97 decade 85 eligible consecutive cases of
      mild asthma according to the criteria of NIH/WHO guidelines on asthma were
      studied. Records on compensation were documented for 41 subjects. The average
      difference between novel scales and the actual rating individually assessed by
      Italian National Agency for compensation through criteria used at that time was
      45.6 +/- 20%. The average difference between novel scales and rating calculated
      with guidelines considering the measurement of non-specific bronchial
      hyperreactivity developed by international experts and American Thoracic Society,
      endorsed by American Medical Association, was 41.5 +/- 12%. Within the actual
      rating individually assessed with previous Italian Insurance criteria no
      significant relationship (r=-0.20, p=0.2) was shown with bronchial responsiveness
      to methacoline expressed as provocative dose causing a 20% fall in FEV1 (PD20FEV1
      microg of mch). A significant (p<0.05) relationship was observed with age at the
      time of OA diagnosis (r=0.37, p=0.017) and with duration of exposure (r=0.34,
      p=0.034). This study suggests that scales of the Insurance Regulation Decree N(o)
      38/2000 grading mild OA underevaluate biological damage/impairment with reference
      both to previous practice in Italy and to international criteria guidelines.
      Among the parameters of evaluation methacoline challenge should be considered an
      adequate tool in measuring biological damage in OA for medicolegal purpose.

PMID- 15027690
TI  - [Epidemiological aspects of leishmaniosis in Italian regions].
AB  - The analysis of infectious diseases in Italy and regarding some working
      activities has pointed out several cases of leishmaniosis, in various shapes. Its
      persistent presence in some endemic areas in our country, together with
      possibility of work exposure and in assence of very sensitive or specific
      diagnostic methods, represents a problem in medical practice. It's necessary for
      physicians and veterinaries take greater attention about this illness and the
      other anthropozoonosis, always actual in some areas and increasing for AIDS's
      sicks, representing other infection sources.

PMID- 15027691
TI  - [Chemical agents and laboratory safety].
AB  - The Decree n(o) 25 of the 2nd of February 2002, according to the Directive
      98/24/CE, predetermines the general criteria that the employer, operating in
      situation of production characterized by chemical risk, must conform to. This
      risk can derive from the effects of dangerous chemical agents present in the work
      place itself or can be a result of working activities. This recent Decree is
      applied to all chemical agents--including cancerous agents--except for provisions
      of Title VII of Decree of law 626/1994; the substances and the preparations
      dangerous for the environment, chemical agents for which measures of radiological
      protection have come into force and the asbestos, for which a specific regulation
      subsists, are excluded. A particular attention, in the article, has been given to
      the activity of analysis and risk evaluation, first obligation for the employer.
      This obligation is very important in such a contest and moreover indispensable
      for the adoption of technical and procedural measures. One should emphasize that
      if the results of such an evaluation show a risk classifiable as moderate, (both
      as type and quantity of the dangerous chemical agents and as modalities and
      frequency of workers exposure), the employer is not bound either to assume
      specific measures of prevention and protection (as technical controls, measures
      of collective protection, the use of devices for individual protection, medical
      surveillance), or to comply with dispositions conceived in the case of accidents
      and emergency. In any case, if this risk is not moderate, the first intervention
      is the replacement, if possible, of dangerous chemical agent in question with
      others agents or processes showing no or less level of danger. In conclusion, it
      is important to emphasize that the recent Decree fixes that medical surveillance
      must be performed once a year, or following a different periodicity scheduled by
      the responsible physician.

PMID- 15027692
TI  - [Prevalence of primary headache related to work activity in a group of hospital
      workers undergoing periodic visits (D. Lgs. 626/94 s.s.m. ed i.)].
AB  - Since headache is one of the most frequent complaints in clinical practice, its
      burden in terms of the both social cost and individual sufference is
      considerable. Headache is a frequent cause of absence from work and decreased
      productivity; it is therefore clear that investigating its possible relationship
      with working conditions represents a topic of increasing interest for the
      scientific community. This study was aimed at identifying specific occupational
      factors able to modify the prevalence of headache in a population of hospital
      workers undergoing periodic examinations. It was indeed suspected that the
      hospital environment could be per se a predisposing factor for headache onset,
      due to the considerable impact of stress on such working environment. The results
      obtained suggest that specific occupational conditions such as shift work and
      P.C. use may play an important role in headache development even in the presence
      of a wide number of professional risk factors.

PMID- 15027693
TI  - [Airborne asbestos fibers: law references, TLV, considerations].
AB  - The ACGIH proposal of 0.1 fibers/liter as TLV for airborne asbestos fibers isn't
      a properly parameter, because it is applicable in work environments and the
      Italian legislation has forbidden every work which employs asbestos from 1993
      [Law 257/92 and Min.Dec. 6/9/94]. Actually in Italy the application of a TLV is
      only referred to two analytical results: A) 20 ff/liter by CPOM analysis, B) 2
      ff/liter by SEM analysis. We think that a CPOM 4-5 ff/liter is a no trespassing
      limit and over this concentration alarm may be notified. Waste disposal of
      asbestos materials must be properly disposed in a restricted area.

PMID- 15027694
TI  - [Peripheral neuropathy rehabilitation. Indications for a diagnostic
      rehabilitation approach].
AB  - The increased incidence of occupational neurological disorders has led, in recent
      years, to the development of new specialties in neurorehabilitation for the
      recovery of deficits of central nervous system (CNS) lesions. This same
      development has not occurred for damage to the peripheral nervous system (PNS),
      the treatment of which is still based on empirically applied rehabilitation
      techniques. This is due to the fact that the peripheral neuropathies comprise a
      vast groups of disorders caused by a huge variety of etiological agents; in order
      to identify their exact cause and thus be able to differentiate rehabilitation
      techniques it is necessary to classify them. The aim of this study is to
      summarize the main rehabilitation strategies, pharmacological treatments and
      surgical techniques used most effectively in the management of peripheral
      neuropathies in order to develop a therapeutic rehabilitation strategy for each
      of the different forms and lay the bases for the development of specific
      guidelines.

PMID- 15027695
TI  - [Influence of genetic polymorphism of CYP1A1 and GSTM1 on the levels of urinary 1
      hydroxypyrene].
AB  - In recent years scientific literature has focused the attention on the role of
      genetic polymorphisms and toxic effects of xenobiotics. Polycyclic Aromatic
      Hydrocarbons (PAHs) are widely spread xenobiotics, present both in general and
      work environment. Many papers analysed the influence of the genetic polymorphism
      of two enzymes involved in the biotransformation of PAHs, Cytochrome P450 1A1
      (CYP1A1) and Glutathione S Transferase M1 (GSTM1), on the development of cancer.
      Some papers analysed also the role of these polymorphisms on the concentration of
      the biomarker of exposure to PAHs, 1-hydroxypyrene (1OHP). The Institute of
      Occupational Health and Industrial Hygiene of the University of Brescia focused
      on this last aspect by EEC project in collaboration with Latin America. In this
      paper a thorough examination of the general topic and the synthetic project's
      results are presented.

PMID- 15027696
TI  - [Computed tomography and pneumoconioses].
AB  - In the last two decades the use of Computed Tomography (CT) has played an
      important role in the diagnosis of pneumoconioses because of its spatial
      resolution and lack of technical limitations if compared to traditional chest
      radiography, first of all in the early stages. Nevertheless the staging of these
      diseases is still based on the International Labour Office (ILO) classification
      issued in 1980, whose application is obtained comparing radiographical findings
      with a standard set of radiographs provided by ILO itself. Starting from the
      early nineties many studies attempted to propose a classification system similar
      to the ILO one, combining different symbols to describe a CT thoracic finding or
      introducing a "score system" to classify different CT patterns (fibrosis, pleural
      plaques, etc.) and their severity. Despite these efforts no classification system
      has been accepted yet. After a short description of technical and practical
      issues of using CT in the diagnosis of pneumoconioses, this article aims at
      summarizing different classification attempts.

PMID- 15027697
TI  - [Controversies in the substitute hormonal treatment of menopause].
AB  - Recent publications in magazines of the maximum impact raise serious and big
      doubts among the gynecologists. Of a side, the substitute hormonal therapy (THS)
      doesn't seem to have value like preventive of the heart attack neither of the
      osteoporosis. Of other, it can carry thrombosis in the first months of treatment,
      besides the already acquaintance increment of the mamma cancer risk starting from
      the fifth year of THS. In the present communication the systematic one is exposed
      continued so far, and the possible alternatives that we should adopt to avoid
      presumed complications, and the subsequent reclamations that the patients could
      file.

PMID- 15027698
TI  - [Bacterial adherence in pathogenesis of urinary tract infectious].
AB  - The possibility of a colonization and later urinary infection is due to a first
      contact among a series of structures of the bacterium, denominated adhesins
      (fimbrica or no-fimbrica) and some receivers or ligands of the surface of the
      urinary epitelium. The bacterial fimbriae of Escherichia coli, of those that have
      been studied up to seven different types, are protean structures coded by the
      chromosomal DNA, being the most important those of type 1, in connection with the
      colonization of the low roads, and the type P, with the cystitis and
      pyelonephritis. They are studied with detail their different protean components
      and the very complex genetic regulation of their production, made of great
      interest in the pathogeny of these infections and in the possibility of their
      prevention. The receivers of each fimbriae type are also chemically different,
      and their knowledge would explain important clinical data.

PMID- 15027699
TI  - [Genetic variability of the virus of the hepatitis C and their relationship with
      the clinic and the treatment].
AB  - The main characteristics of the genome of the virus of the hepatitis C is
      studied, especially those such parts as the IRES for its capacity of union to the
      ribosome of the cell, the HVR1 for its high capacity of viral replication, as
      well as the place of union to the PKR or the ISDR, inside the protein NS5. They
      are defined the genotype concepts, subtype and quasispecies, and their
      implications in different such aspects as: 1) pathogenicity (in the severity of
      the infectious process, in the extrahepatic manifestations and in the appearance
      of the hepatocarcinoma); 2) in the biggest or smaller sensibility in the
      diagnostic techniques; 3) in the resistance to the treatment with interferon
      (well through the road NS3 or NS5, so much through the changes in PKR or the
      mutations in ISDR), and 4) in the epidemiology (changes of geographical
      variability, use of that variability like epidemic marker and obtaining
      difficulty of vaccines).

PMID- 15027700
TI  - [Past and present perspectives of Turner Syndrome].
AB  - Herein current aspects of the Turner Syndrome are described. Clinically, it is
      emphasized the importance of phenotipically normal cases that pose difficult
      diagnosis problems. On the other side, in addition to the classical clinical
      criteria, early diagnosis is possible through prenatal sonography. However, many
      times the diagnosis is made late in excess. Therapeutically, together with former
      intervention strategies, "in vitro" fertilization is feasible today and has been
      successfully achieved, as well as GH therapy; in the presented series final
      height improved 6 cms over expected height, and in the foreseeable future, with
      increasing knowledge advances further benefits can be anticipated.

PMID- 15027701
TI  - [Sleep, learning and memory].
AB  - As a subject, "Sleep, Learning and Memory" is quite lively. Many papers have been
      published on this subject in the last 20 years. However, these papers present
      major contradictions. This is logic because it is a complex subject and,
      consquently, without simple solutions. It is important to be precise, as much on
      a basic as on a clinical experimental level, in a large number of questions. For
      a correct interpretation of the data it is necessary to sustain a unified vision
      of human nervous system function. Today we can affirm that, for correct learning
      and memory processing, a normal and harmonic sleep-wakefulness cycle, including
      the interphase transition states, is essential. Many findings demonstrate the
      special and determining role of REM sleep in the mechanisms of memory
      consolidation.

PMID- 15027702
TI  - [Does the free will exist?].
AB  - The issue of free will is a old as the history of philosophy. We all have
      subjectively the impression of being free when we carry out a voluntary act.
      Recent experiments, however, have shown that the subjective experience of a
      voluntary act and its cause can be two different events. Whilst the brain is
      approx. 800 ms active before the movement, the subjective experience of the
      conscious will occurs at approx. 200 ms before the movement. In other words:
      subjects experience a conscious will when they interpret that their own thoughts
      are the cause of their decisions, which seems to be nothing more than an
      illusion.

PMID- 15027703
TI  - [Molecular aspects of a hypothalamic glucose sensor system and their implications
      in the control of food intake].
AB  - Glucose is used mainly as an energy substrate but also as a signalling molecule
      implied in processes of primary functional concern, such as glucose sensing.
      Glucose transporter isoform GLUT-2 and especially glucokinase (GK) have been
      considered as components of a glucose sensor system controlling several key
      processes such as, glucose-dependent insulin secretion, and stimulation of
      glucose uptake by liver and skeletal muscle. In the same way this system might
      modulate feeding behavior and the release of counteregulatory hormones that
      defend against hypoglycemia. Our findings indicate that GLUT-2 and GK mRNAs and
      proteins are coexpressed mainly in the hypothalamus of human and experimental
      animals, in areas implied in the control of food intake. Also, a high Km glucose
      phosphorylating activity with kinetic properties similar to that reported
      previously in liver was observed, with a high apparent Km for glucose that
      displays no product inhibition by glucose-6-phosphate. GK activity may also be
      regulated by the presence of glucokinase regulatory protein (GKRP), which we have
      found in the brain of human and experimental animals, in the same areas than GK.
      Coexpression of GLUT-2, GK and GKRP in areas implied in feeding behavior might
      play a role in glucose sensing, in which GLUT-2 has a permissive role and the
      interactions of GK with GKRP made possible a real sensor activity. Furthermore
      the effects of anorexigenic peptides through its receptors in this system, should
      facilitate the transduction of signals required to produce a state of satiety.

PMID- 15027704
TI  - [Two surgery schools: Madrid and Barcelona. Ribera Sans and Salvador Cardenal
      (150th anniversary of their birth)].
AB  - Two eminent Spanish surgeons from the positivism period were born 150 years ago:
      Ribera Sans and Salvador Cardenal. To mark this anniversary I have studied their
      written work and their contribution to Spanish surgery as pioneers. Each school
      had its own place although they kept certain parallelism. Ribera worked in Madrid
      as a professor for 23 years and had many disciples. He initiated digestive,
      pediatric and thoracic surgery. He was a professor at San Carlos just like the
      surgeons: San Martin and Guedea. He was director of the Nino Jesus Hospital and a
      R. A. N. M. academic. Cardenal is a distinguished surgeon who carried out his
      work in Barcelona. He extended the use of the antiseptic method in Spanish
      surgery. He became Director of the Sagrado Corazon Hospital. He was also named
      Honorary professor of surgery and a member of the Royal School of Surgery in
      England, and R. A. Barcelona. His work was closely related to Dr. Ferran's. His
      son was Leon Cardenal.

PMID- 15027705
TI  - [Predictive molecular marker of distant metastasis in colorectal cancer].
AB  - Tumor development and progression is driven by the accumulation of somatic
      genetic alterations. Two major pathways have been suggested in colon
      tumorigenesis. The first one, the APC/B-catenin pathway consists of chromosomal
      imbalance (Instability) and therefore accumulation of different oncogenes and
      tumor supressor genes mutations associated with morphological changes. The second
      one is characterized by "DNA mismatch repair genes" damage with subsequent
      accumulation of somatic genetic predictive markers of distant metastasis using
      tissue microarrays in T2N0 colon cancer. In our series, we detected
      overexpression of survivin, CDK1, MIB1 and topoisomerase IIa in metastatic
      tumors.

PMID- 15027706
TI  - [Angiogenesis and heart vasculogenesis].
AB  - The first sketch of coronary arterial vascularization settles down in human
      embryos of the stadium 14 of O'Rahilly starting from endothelial islands that
      contain dense eritoblastes formations that don't present connection with the
      cavity ventricular willing subepicardial. The presence of this primitive plexus
      is in intimate dependence with the Jelly acellular of Davies and not with the
      increase and structuring of the myocardium. Each coronary artery is developed
      starting from two anlages: one distal that makes it starting from the net
      subepicardial, and another proximal coming from the evagination of the
      endocardium of the breasts Valsalva. The final period of the process of coalition
      of both anlages, and consequently the coronary vascular pattern's determination,
      it is established in the stadium 20 of O'Rahilly.

PMID- 15027707
TI  - [Mateo Orfila: a biography].
AB  - Mateo J. B. Orfila, illustrious doctor and chemical, native of Mahon, where he
      was born April 24th, 1787 and he died in Paris March 12th, 1853, buried in this
      city in the cemetery of Montmartre. He studied Medicine and Chemistry in
      Valencia, Barcelona and Paris. Chemical expert, toxicologist and medical jurist,
      Dean of the Faculty of Medicine of Paris during 18 years, in which he made the
      great Educational Reformation of Medicine that deserves to take his name, model
      for many Universities of France, Germany, Denmark, Scandinavia, etc... and in
      certain way of Spain and Italy. It carried out the Chair of Chemistry and Legal
      Medicine in the Faculty of Medicine of Paris, he projected his teaching
      internationally toward the United Kingdom, Germany, Netherlands, Spain, Italy,
      Scandinavia and North America. It diffused the toxicological knowledge and legal,
      experimental and clinical doctor, elevating his scientific range at universal
      level with methodical original, innovative constat, creator of the Toxicological
      Science. Author of countless works and publications of Chemistry, Legal Medicine
      and Intoxications in diverse countries, "doctor honoris causa" of the most noted
      universities and academies. Creator of new Chairs, Museums and Centers of
      Investigation. For their works he received honors like chemist, toxicologist and
      medical jurist. Orfila was "glory" of Spain, country where he was born, and of
      France, where it developed intense and fruitful work, in which occupied the most
      important positions, among others, Academic of the Academy of Medicine of France
      and President of it.

PMID- 15027708
TI  - [Amputations, walking and prosthesis development].
AB  - Deficiency or loss of limbs is bound to human history. From the beginning of the
      human race, prosthetics solutions have been researched for amputations. With the
      mutilation of the lower limb, walking, one of the most important functions in the
      human being is lost. The main object of surgical amputation is not only to save
      the life, but also to create a new organ, the stump, in order to adapt a
      prosthetic limb, so that the patient is able to walk again. Most prostheses in
      the past have been lost like useless objects. Some models that have been saved
      for the clinical practice, allow us to present the biggest advances in prosthetic
      technique evolution in last time.

PMID- 15027709
TI  - [In memory of his Excellency Pedro Zarco Gutierrez].

PMID- 15027710
TI  - Hepatocellular carcinoma--a model of human cancer: clinico-pathological features,
      etiology and pathogenesis.
AB  - Hepatocellular carcinoma (HCC), a unique human neoplasm, has interested many in
      several fields of biological and health sciences. This cancer is credited as the
      first that can be largely eliminated by a safe anti-viral vaccine and other
      transmission control measures. It is also the first cancer for which a reliable
      diagnostic tumour marker was identified and studies on this tumor in humans and
      animals have provided a large body of information on causation and step-wise
      evolution of cancers. Being a common and rapidly fatal tumour, mainly affecting
      males in the more populous developing countries, HCC may well be the commonest
      cancer of the human male. Clinical features are not specific for HCC but
      manifestations represent varying combinations of those due to cirrhosis which is
      a very frequently associated and pre-existent disease, those due to tumour and
      those due to malignancy. This tumour commonly takes a massive form with satellite
      nodules or a scattered multinodular form. A fibrolamellar variant is biologically
      and clinically quite different from the usual HCC and the small capsulated
      variant is seen in some geographic areas. Microscopically the trabecular variety
      is common and differentiation from metastatic cancers and benign lesions may need
      use of newly described immunohistochemical markers in addition to clinical
      evidence of cirrhosis. Hepatitis B and C viruses, dietary aflatoxin B1 and
      cirrhosis from any cause are common risk factors in that order of importance.
      Several lines of evidence including molecular biology and animal studies support
      these etiological linkages. Studies in experimental animals using chemical
      carcinogens, different hepatotropic viruses and aflatoxin have greatly helped our
      understanding of carcinogenesis in general and hepatocarcinogenesis in
      particular. Individual HCC risk factors may contribute to summation of mutations
      subsequent to repeated and continued liver cell injury act as carcinogen/co
      carcinogen or be involved in both capacities.

PMID- 15027711
TI  - Malaria still a threat to life--a postmortem study.
AB  - This study is of 25 cases of acute malaria encountered at autopsy. Cause of death
      was malaria in all the cases. The study covers a period of 6 years i.e. from
      January 1994 to December 1999. There was an upward trend in deaths due to
      malaria. P. falciparum malaria with its complications accounted for majority of
      deaths and cerebral malaria (CM) topped the list. Other complications observed
      were adult respiratory distress syndrome (ARDS), acute septicemic malaria, acute
      renal failure (ARF) and disseminated intravascular coagulation (DIC). The
      commonest presenting symptoms were fever with chills associated with central
      nervous system (CNS) complaints like altered sensorium and unconsciousness.

PMID- 15027712
TI  - Incidence of pelvic and extrapelvic endometriosis in Eastern region of Nepal.
AB  - Endometriosis is described as the presence of endometrial glands or stroma in
      abnormal locations outside the uterus. It afflicts 10% women of childbearing age.
      A 5-year retrospective analysis of histopathologically proven cases of
      endometriosis was done. Haematoxylin and Eosin stained slides were reviewed for
      type of lining epithelium, endometrial glands, stroma, fresh and old hemorrhage &
      inflammatory cells. Clinical details were analyzed. Age of the patient ranged
      from 22 - 48 years. The most common site of endometriosis was ovaries (69.23%)
      followed by scars (11.43%), cervix (7.69%), fallopian tube (3.84%), vagina
      (3.84%) and appendix (3.84%) in descending order of frequency. Most common
      symptom was pain. On ultrasound and X-ray diagnosis could not be made in any
      case. Clinically endometriosis was diagnosed in 9 (34.62%) cases. On
      histopathological examination majority of the cases (42.3%) had endometrial
      glands, stroma and hemosiderin laden macrophages. 3 cases (11.43%) had
      endometrial lining epithelium and stroma only, which on laproscopy also were
      diagnosed to have endometriosis. It was concluded that high rate of surgical
      excision of organs were done because of misdiagnosis.

PMID- 15027713
TI  - Carcinogenic effect of nicotine on normal mammary ductal epithelial cells and the
      protective role of beta-carotene.
AB  - A number of carcinogens like polycyclic hydrocarbons and aromatic amines have
      been incriminated to induce mammary carcinomas in vitro and in vivo. Studies have
      supported an inter-relationship between tobacco consumption and breast cancer.
      Because nicotine is the major alkaloid present in tobacco this study was
      conducted to find the direct in vitro effect of nicotine on normal mammary ductal
      epithelial cells. It was seen in the present work that nicotine causes a
      statistically significant increase in the proliferative rate and ER (estrogen
      receptor) expression as compared to the control group. This change was more
      pronounced with a lower concentration of nicotine (650 microg/ml). Colony
      efficiency also showed a similar trend. Beta carotene was added in the present
      work to study its anti oxidant effect on nicotine induced changes. Beta carotene
      significantly decreased the proliferation rate induced by 650 microg/ml nicotine.
      It also prevented the cytotoxic effect of higher dose of nicotine, however, it
      failed to alter significantly the ER expression induced by lower concentration of
      nicotine though it showed decreasing trend.

PMID- 15027714
TI  - Morphometric study of lymphoid cells in mycosis fungoides and its simulators.
AB  - The distinction of early stages of mycosis fungoides from benign lymphoid
      disorders of skin is difficult by conventional histological techniques. We
      studied 10 cases of mycosis fungoides, 10 cases of large plaque parapsoriasis, 10
      cases of other benign lymphoid disorders of skin and 5 cases of lymph nodes.
      Nuclear area, perimeter of the nucleus, nuclear contour index, cytoplasmic area,
      form factor and nuclear cytoplasmic ratio as well as DNA-ploidy were determined
      by image analysis. There were statistically significant difference (P value <
      0.05) between all parameters except nuclear cytoplasmic ratio of the lymphoid
      cells of Mycosis Fungoides and benign lymphoid disorders of skin. Aneuploidy was
      found in 50% cases of Mycosis Fungoides. Histopathological parameters like
      epidermotropism pautrier micro-abscess and atypical lymphocytic infiltrate in
      both epidermis and dermis were more marked in aneuploid than diploid cases. So,
      the determination of nuclear contour index and DNA-ploidy is of importance to
      differentiate between Mycosis Fungoides and benign lymphoid disorders of skin.

PMID- 15027716
TI  - Role of imprint cytology in the diagnosis of gastrointestinal tract malignancies.
AB  - Endoscopic biopsies obtained from 275 patients (180 from the upper
      gastrointestinal tract and 95 from the lower gastrointestinal tract) were studied
      to compare the accuracy of biopsy imprint cytology and histology in the diagnosis
      of gastrointestinal lesions, and also to establish the degree of reliability of
      imprint cytology alone for an early diagnosis of malignancy. Biopsy histology
      results were found to be correct in 100% cases. Imprint cytology had an overall
      accuracy of 100%, 96.7%, 95.8% and 95.8% for the diagnosis of malignancies of the
      oesophagus, stomach, duodenum and colorectum respectively. False negative results
      were obtained with lymphomas. Regenerative cellular atypia was an important cause
      for false positive results. It was concluded that imprint cytology can serve as a
      useful and simple tool for an immediate diagnosis of malignancy. This should be
      subsequently correlated with histopathology which facilitates exact tumour typing
      and assessment of tumour invasion.

PMID- 15027715
TI  - The Epstein Barr virus and gastric carcinoma.
AB  - The Epstein Barr Virus (EBV) is one of the viruses implicated in the pathogenesis
      of malignant tumors. Its association with Burkitt's Lymphoma, nasopharyngeal
      carcinoma and certain cases of Hodgkin's lymphoma is well known. More recently
      this virus has been found to be associated with gastric carcinoma. Studies on
      this association, in our country are lacking. We have studied 37 cases of
      carcinoma using immunohistochemistry for LMP1 protein. Most workers have found an
      expression of latency type I antigens in gastric adenocarcinomas, with only a few
      cases being LMP1 positive. In the 37 cases studied by us, 24.14% of cases were
      positive for LMP1. LMP1 is known to have oncogenic properties. In addition, it
      has been demonstrated earlier that the EBV particles in gastric carcinoma are
      monoclonal. These two factors support a pathogenetic role for EBV in gastric
      carcinoma.

PMID- 15027717
TI  - Semen analysis profile in male infertility: an experience with 100 cases.
AB  - In the assessment of unexplained infertility the evaluation of seminal
      characteristics is primary and paramount, as far as the male is concerned. We
      present in this article our experience with semen analyses of 100 infertile
      males. The collection and examination were according to standardized and well
      accepted methodology. We found that majority of infertile men were within the age
      interval of 26-30 years, and had been married for 1-3 years, when they first
      submitted themselves for fertility assessment. The physical parameters were found
      to be important, in that they in many patients pointed towards a specific
      physical cause; depletion in semen volume, altered colour, and pH changes were
      found especially informative. We also found the microscopic arm of semen analyses
      very useful in pin-pointing existing deficits in the male. Some significant
      correlations were also observed between abnormal microscopic parameters and
      clinical conditions. The results are discussed.

PMID- 15027718
TI  - A retrospective study of clinico-histopathological correlation in leprosy.
AB  - Leprosy is a chronic infectious disease caused by Mycobacterium Leprae and is
      characterized by well-recognized pathological changes. But there are various
      disagreement in clinical type and histological finding of leprosy. We observed
      highest parity in LL and TT group followed by histoid, BT, BL, BB, &
      indeterminate respectively. There was 10% minor disagreement (difference of one
      group) and 5% major disagreement (difference of two or more group). Non-specific
      histological finding was present in 20% cases.

PMID- 15027719
TI  - Sarcomatoid carcinoma (carcinosarcoma) of the esophagus with extensive areas of
      osseous differentiation: a case report.
AB  - A 46 year old male presented with progressively increasing dysphagia and weight
      loss. Esophagoscopy showed a large polypoidal growth involving the middle segment
      of esophagus. Histologically bulk of the tumour had a sarcoma-like appearance
      composed of spindly pleomorphic cells along with extensive areas of bone
      formation. The epithelial element was represented by a small area of squamous
      cell carcinoma. One of the draining lymph nodes also showed small islands of
      squamous cell carcinoma. A diagnosis of sarcomatoid carcinoma was made.
      Sarcomatoid carcinoma of the esophagus, also termed carcinosarcoma,
      pseudosarcoma, and spindle cell carcinoma is an unusual malignant tumour of the
      esophagus. The proportion of carcinomatous and sarcomatous component may vary
      from case to case. Rarely, the sarcomatous component may exhibit osseous
      differentiation as in our case.

PMID- 15027720
TI  - Combined primary fibrosarcoma--malignant fibrous histiocytoma of the breast: a
      case report.
AB  - Malignant mesenchymal tumours of the breast are relatively rare tumours that have
      yet to receive universal approval in terms of terminology. With classification
      based on histogenesis rapidly gaining acceptance, we present a case with
      histological features of both fibrosarcoma and malignant fibrous histiocytoma,
      with the former predominating. An unusual finding was the presence of large areas
      with haemangiopericytomatous appearance. The literature on changing concepts
      regarding classification of malignant mesenchymal tumours of the breast is
      reviewed.

PMID- 15027721
TI  - Multiple cutaneous horns of the penis: a case report.
AB  - Cutaneous horns of the penis are rare. Frequently they are unusual presentations
      of squamous cell carcinomas of the penis; therefore prompt surgical intervention
      is warranted. This is a report on a 70-year-old man with multiple cutaneous horns
      of the penis. The possible causes of cutaneous horns are reviewed.

PMID- 15027722
TI  - Reed-Sternberg-like cells in T-cell rich B-cell lymphoma: a diagnostic dilemma.
AB  - T-cell-rich B-cell lymphoma (TCRBCL) is a recently described variant of diffuse
      Non-Hodgkin's lymphoma (NHL) which requires immunohistochemical analysis for its
      recognition. Striking similarities exist between TCRBCL and lymphocyte
      predominant Hodgkin's Disease (LPHD) due to the presence of Reed-Sternberg (R-S)
      like cells. Hence, the need for distinction between the two is of utmost
      importance from a prognostic and therapeutic stand point. The present study
      describes a case of TCRBCL, misdiagnosed as Hodgkin's Disease (HD) on fine needle
      aspiration (FNA) cytology. However, immunostaining of paraffin embedded sections
      corrected the cytological diagnosis.

PMID- 15027723
TI  - Primary lymphoma of the bone.

PMID- 15027724
TI  - Primary primitive neuroectodermal tumor of the ovary: a case report.
AB  - Ovarian germ cell tumours having neuroectodermal cells, growing in patterns
      reminiscent of tumours of the central nervous system are rare. We report a case
      of primary primitive neuroectodermal tumor(PNET) of the ovary detected soon after
      pregnancy.

PMID- 15027725
TI  - Intracavitary metastatic non-Hodgkin's lymphoma simulating an atrial myxoma.
AB  - We describe a case of intracavitary metastasis of Mantle Cell Lymphoma of
      gastrointestinal tract, which mimicked an atrial myxoma. The gastrointestinal
      lymphoma led to widespread metastasis and a large metastatic tumor deposit at the
      hilum of the right lung caught up the hilar vessels. This led to infiltration
      into the pulmonary veins and intracavitary metastatis to the left side of the
      heart.

PMID- 15027726
TI  - Pernicious anemia in a young Bahraini female.
AB  - Pernicious anemia (PA) is an autoimmune disorder associated with atrophic
      gastritis, presence of antibodies to gastric parietal cells and intrinsic factor
      (IF) and vitamin B2 malabsorption leading to megaloblastic anemia. It has a
      comparatively higher prevalence in people of North European origin, is uncommon
      in Arabs and usually affects the elderly. This report, the first from Bahrain,
      describes a rare case of PA in young female. The presenting symptoms, clinical
      and laboratory features were similar to those described in classical elderly
      Caucasian patients. No association with any other autoimmune disease was
      detected.

PMID- 15027727
TI  - Primary malignant lymphoma of the breast.
AB  - Primary malignant lymphomas of the breast (PBL) are uncommon constituting only
      0.04 to 0.53% of malignant breast neoplasms. We wish to report the clinical,
      cytological and histologic findings of PBL diagnosed in a 52 years old female.

PMID- 15027729
TI  - Hemangiopericytoma of mesentery: a case report.
AB  - Mesenteric tumors are rare, most commonly encountered lesions are fibromatoses
      and leiomyoma. A case of hemangiopericytoma of mesentery in a 38 years old female
      is reported for its rarity. The classical histological findings and recticulin
      stain to demonstrate blood vessels & recticulin fibers, encircling individual
      tumor cells aids in the correct diagnosis.

PMID- 15027728
TI  - Histoplasmosis masquerading as tuberculosis: a case report.
AB  - Histoplasmosis is not reported very commonly from India. We report a patient in
      whom the presenting feature was persistent leucopenia and hepatosplenomegaly and
      was treated as a case of disseminated tuberculosis. At autopsy, this patient
      showed all features of progressive disseminated histoplasmosis.

PMID- 15027730
TI  - Malignant melanoma of the vagina: report of two cases.
AB  - Two rare cases of malignant melanoma, (one amelanotic) arising in the vagina in
      middle-aged group are being reported. Clinical, histopathological and
      immunohistochemical studies supported the diagnosis. The neoplasm is highly
      malignant & carries a poor prognosis.

PMID- 15027731
TI  - Fine needle aspiration cytology of epithelioid variant of schwannoma--a
      diagnostic dilemma.
AB  - Epithelioid variant of schwannoma is a rare type of benign nerve sheath tumor
      which has an aggressive clinical course in comparison to the conventional
      schwannoma. We report one such case in a 53 year old female with an aspirate from
      a swelling in the nape of the neck. It posed a diagnostic dilemma because of its
      cellularity numerous groups of plump epithelioid cells along with multinucleated
      cells. The cells were lying in a myxoid stroma, coming singly and in nests and
      cords thus mimicking an epithelial tumor. The initial cytologic diagnosis of
      possibly a skin adnexal tumor was rendered. This case highlights the diagnostic
      pitfall encountered in the aspiration cytology of neurogenic tumors.

PMID- 15027732
TI  - Microcystic papillary adenoma of the nose: a case report.
AB  - Microcystic papillary adenoma of nose is rarely seen in nose. This case is
      reported because of its rarity and to best our knowledge is a first case report
      from Nepal.

PMID- 15027733
TI  - Hydatidosis of female genital tract: a case report.
AB  - Hydatidosis of female genital tract mostly occurs as secondary involvement and is
      very rare. A case of primary hydatid cyst of genital tract i.e., uterine cervix
      and parametrium in a fifty five year old lady is reported, who was admitted in
      hospital in emergency with acute retention of urine.

PMID- 15027735
TI  - Primary non-Hodgkin's lymphoma of the nose and paranasal sinuses: a case report.
AB  - Non Hodgkin's Lymphomas of the sinonasal tract are uncommon neoplasms that can be
      morphologically difficult to distinguish from destructive non-neoplastic process
      or other malignant neoplasm in this site. Non-Hodgkin's Lymphomas of the
      sinonasal tract are heterogeneous diseases that can be clinically aggressive.
      Immunophenotypic pattern of Non-Hodgkin's Lymphomas shows marked variations. We
      are reporting a case of B-Cell type of Non-Hodgkin's Lymphoma of the nasal cavity
      and paranasal sinus with complete clinicopathological and immunohistochemical
      study as it is rare in Indian literature and review of the literature is done.

PMID- 15027734
TI  - Xanthogranulomatous oophoritis and salpingitis: late sequelae of inadequately
      treated staphylococcal PID.
AB  - We describe the case of a 42-year-old woman who was a follow-up case of
      incompletely treated pelvic inflammatory disease, and presented with menorrhagia
      and bilateral ovarian masses. Subtotal hysterectomy with bilateral salpingo
      oophorectomy was performed. Purulent material was obtained from the cystic
      masses, which grew Staphylococcus aureus. Histological examination of right-sided
      cystic mass revealed a simple cyst of the ovary. Left sided tuboovarian mass
      revealed the presence of lipid filled macrophages with lymphocytes, plasma cells
      and neutrophils; this established the diagnosis of xanthogranulomatous
      salpingitis and oophoritis. The case is of interest in view of the rarity of this
      condition; five cases of xanthogranulomatous salpingitis and oophoritis have been
      reported in the world literature till date.

PMID- 15027736
TI  - Odontogenic myxoma of the mandible: a case report.
AB  - A case of myxoma of mandible in a 23 years old female patient is described. The
      case was treated with enbloc resection and bone graft from iliac crest. No
      recurrence is reported after 4 years follow up.

PMID- 15027737
TI  - Massive cystic degeneration of a uterine leiomyoma presenting as an ovarian cyst:
      a case report.
AB  - An unusual case of massive cystic degeneration in an uterine leiomyoma measuring
      21 cm in diameter, in a 40 year old female is being presented. It was diagnosed
      as a cystic adnexal tumor on ultrasonogram. Interlacing bundles of smooth muscle
      were identified in the cyst wall, which was confirmed on special stains. The
      differential diagnoses considered in this case are discussed. To the best of our
      knowledge, this is the largest cystic degeneration in an uterine leiomyoma
      reported in the literature.

PMID- 15027738
TI  - Amyloid goitre: a case report.
AB  - Amyloid goitre is an exceedingly rare condition associated with a clinically
      apparent enlargement of the thyroid gland due to massive amyloid infiltration. We
      hereby report an additional case of this rare entity.

PMID- 15027739
TI  - Papillary endothelial hyperplasia in angiokeratoma.
AB  - Papillary endothelial hyperplasia (Masson's tumour) is a reactive proliferation
      of endothelium producing papillary structures with fibrovascular cores.
      Dilatation, stasis and accompanying inflammation have been incriminated as the
      inciting events, evident by the presence of this lesion in haemorrhoids, urethral
      caruncles and laryngeal polyps. We present here a case of papillary endothelial
      hyperplasia in angiokeratoma hitherto undescribed despite sharing common
      etiopathogenetic features of dilatation and stasis with other aforementioned
      lesions.

PMID- 15027740
TI  - Sertoli Leydig cell tumor with heterologous gastrointestinal epithelium: a case
      report.
AB  - Sertoli Leydig cell tumour (SLCT) of the ovary with the presence of heterologous
      elements is very unusual. A case of SLCT with virilizing symptoms and androgenic
      endocrinological profile is presented. The tumor showed presence of heterologous
      element in the form of mucinous epithelium of the gastrointestinal type.

PMID- 15027741
TI  - Clear cell adenocarcinoma of the maxillary sinus: a case report.
AB  - A variety of salivary gland tumours histologically show the presence of clear
      cells. Clear cell adenocarcinoma of salivary glands (CCASG) is a distinct clinico
      pathologic entity arising in the minor salivary glands of mainly the oral cavity
      in elderly women and having a low grade malignant potential. A case occurring in
      the maxillary sinus and extending to the nasal cavity is reported.

PMID- 15027742
TI  - Giant lobulated seborrheic keratosis at an unusual site.
AB  - Seborrheic Keratoses(SK) are common benign skin tumors of elderly occurring
      commonly on face, scalp, extremities, chest, back with genital and perianal sites
      being rare. Lesions are usually few millimeters to several centimeters, reaching
      pendulous proportions in areas of constant friction, especially in obese
      individuals. Though malignant transformation is rare, it is reported in irritated
      lesions, especially in flexures. An unusual case of giant lobulated seborrheic
      keratoses occurring in perianal area, without any evidence of malignancy on
      histopathology, in an otherwise healthy obese female is reported here.

PMID- 15027744
TI  - Squamous metaplasia in a multinodular goiter: a case report.
AB  - Squamous epithelium in thyroid is an unusual finding. It is seen in a variety of
      inflammatory and neoplastic conditions. It's presence has been attributed to
      metaplastic change of follicular epithelium by some authors and to the
      persistence of ultimobranchial body by others. We encountered a case of
      multinodular goiter with groups of squamous cells lining a cystic cavity. We
      report it because of it's rarity with a brief review of literature.

PMID- 15027743
TI  - Malignant nasal paraganglioma: a case report and review of the literature.
AB  - A rare case of malignant nasal paraganglioma is described. A 30 year old female
      patient presented with a one year history of bilateralnasal obstruction, nasal
      deformity and recurrent epistaxis. CT scan demonstrated an enhancing mass
      occupying both nasal cavities, right maxillary antrum and anterior ethmoid sinus.
      Histopathologic diagnosis was malignant paraganglioma. A total maxillectomy with
      excision of growth was performed. Post-operative radiotherapy and chemotherapy
      was given but patient expired before the completion of therapy. Nose being a rare
      site for paragangliomas, these lesions present a diagnostic challenge to
      histopathologists and clinicians alike. A review of the four previously described
      malignant nasal paragangliomas is also presented.

PMID- 15027745
TI  - Melanosis of uterine cervix: a report of two cases.
AB  - Uterine prolapse is a common gynecological problem which is associated with
      complications like keratinisation, thickening and ulceration of cervical mucosal
      epithelium. Two cases of second degree uterine prolapse are being reported here
      showing heavy melanotic pigmentation of the basal layers of ectocervical
      epithelium. It appears to be a metaplastic change in response to local trauma or
      chronic irritation.

PMID- 15027746
TI  - Multiple myeloma presenting as primary non-secretory plasma cell leukemia.
AB  - Primary plasma cell leukemia is a rare manifestation of multiple myeloma, whose
      neoplastic hierarchy in the classification of malignant hematological disorders
      is not yet very clearly defined. Morphological and immunological criteria
      indicate that the cells are at end stage of B cell maturation pathway. This
      unusual disorder is diagnosed by the presence of more than 2 x 10(9) plasma cells
      per liter of peripheral blood or more than 20% of the leucocytes being plasma
      cells on differential count. This occurs either denovo or as a terminal event in
      patients with long standing multiple myeloma. A case report of a young male
      patient with primary plasma cell leukemia is presented.

PMID- 15027747
TI  - First report in India of HIV transmission through artificial insemination.
AB  - A case of HIV-1 transmission through artificial inseminations from infertility
      clinics in Kolkata, is reported.

PMID- 15027748
TI  - Papillary cystic acinic cell carcinoma of the parotid gland diagnosed on fine
      needle aspiration cytology.
AB  - The Cytomorphological features of Papillary Cystic Acinic Cell Carcinoma a rare
      malignant tumor of the Parotid gland in a 77 years male is described. The
      differential diagnosis and prognostic features are discussed.

PMID- 15027749
TI  - Laboratory methods in the detection of herpes simplex virus (HSV) in keratitis--a
      9-year study including polymerase chain reaction (PCR) during last 4 years.
AB  - Conventional methods of fluorescent antibody test (FAT) and virus isolation (VI)
      and molecular method of polymerase chain reaction (PCR) were compared for the
      detection of HSV in keratitis during a 9-year period. Of 186 corneal scraping
      specimens, 108 were subjected to FATand VI in the pre-PCR period (initial 5
      years) while 78 to FAT, VI and PCR in the PCR period (latter 4 years). HSV was
      detected by FAT in 44/186 (23.7%), VI in 18/186 (9.7%) and PCR in 27/78 (34.6%)
      specimens. Overall, HSV was diagnosed in 56/186 (30.1%) specimens. PCR has
      increased the clinical sensitivity by 12.8%, which is statistically significant
      (McNemar test, P-0.002). VI should be replaced by PCR. FAT though less sensitive
      should always be employed as a routine to give an early diagnosis, the results of
      which could be further confirmed, if necessary, by PCR, which is a more sensitive
      and specific diagnostic tool.

PMID- 15027751
TI  - Study of enteropathogenic Escherichia coli(EPEC) diarrhoea in children.
AB  - Enteropathogenic E. coli (EPEC) are one of the predominant aetiological agents of
      diarrhoea in children. A study was undertaken to determine the incidence of EPEC
      diarrhoea in children and to assess the clinical spectrum. Faecal samples from
      300 children below 12 years of age, hospitalised with acute diarrhoea were
      processed for isolation of bacterial pathogens. EPEC were isolated from 36(12%)
      of the diarrhoeal cases. O86 was the predominant serogroup isolated. EPEC
      diarrhoea was common in children below two years of age (86.1%). Vomiting, fever
      and dehydration were the common presenting features. Faecalleucocytes were
      observed in 17(47.2%)stool samples. EPEC were found to be resistant to several
      antibiotics. Since EPEC are known to belong to restricted number of 'O'
      sergroups, serogrouping with 'O' antisera to predominant EPEC serogroups in a
      particular area remains the most convenient method for early detection of EPEC
      diarrhoea in children.

PMID- 15027750
TI  - Analysis of IgG subclasses and IgE antibodies across the clinical spectrum of
      bancroftian filariasis in an endemic area.
AB  - Analysis of immune response in individuals with different clinical manifestations
      living in filaria endemic area will be of interest to understand the
      immunological events associated with the disease development in filaria infected
      endemic population. The levels of four IgG subclasses and IgE antibodies against
      Brugia malayi microfilarial excretory-secretory (Bm mf ES) antigen as well as
      circulating filarial antigen level were evaluated in 84 individuals belonging to
      different groups in an endemic area for bancroftian filariasis. Microfilaraemics
      showed significantly elevated levels of IgG4 and IgG3 antibodies compared to
      endemic normals (P < 0.02). As many as 70% of this group were positive for IgG4 &
      IgG3 antibodies. While Acute filarial cases had pronounced IgG1 antibodies(P <
      0.001), the Grade I chronic cases showed higher levels of IgG3 and IgG4
      antibodies (P < 0.02), Occult filarial cases had higher levels of IgG4 and IgG3
      (P < 0.02) and also of IgG4 antibodies (P < 0.001). IgE antibodies were found to
      be elevated in microfilaraemics as well as other clinical filarial groups.
      Circulating filarial antigen was detected in 95% of microfilaraemics, 60% of
      acute cases, 75% to 90% of different grades of chronic filarial cases, 100% of
      occult cases and none of the endemic normals.

PMID- 15027752
TI  - Methicillin-resistant Staphylococcus aureus: need for constant
      surveillance,stringent control and vigorous treatment measures.
AB  - Staphylococcus aureus has shown a disconcerting propensity to develop resistance
      to antimicrobial agents and an increasing proportion of these have become
      resistant to methicillin as well. Regular surveillance should be carried out in
      every hospital and stringent infection control measures and vigorous treatment
      should be employed to prevent the nosocomial spread of MRSA. A total of 1056 MRSA
      were isolated from various specimens received in bacteriology division of SKIMS
      Srinagar out of which 46.32% were from inpatients and 31.87% from outpatients.
      None of these strains showed resistance to vancomycin and a good proportion were
      sensitive to amikacin (80.75%) gentamicin (69%) or ciprofloxacin (63.25%).

PMID- 15027753
TI  - Evaluation of germ tube test in various media.
AB  - One of the most valuable tests for the rapid presumptive identification of
      Candida albicans is germ tube production. Previously researchers have concluded
      superior results with serum in germ tube test. However, handling of pooled human
      serum has danger of acquisition of hepatitis and HIV infections. Therefore, in
      the present study we compared various media--pooled human serum, sterile horse
      serum, peptone water and tryptic soy broth. It was observed that human serum
      remains to be the best with 100% positivity for identification of C. albicans
      followed by horse serum (76.3%), peptone water (61.8%) and tryptic soy broth
      (61.8%).

PMID- 15027755
TI  - Prevalence of methicillin resistant Staphylococcus aureus in Karnataka.
AB  - This study was undertaken to find out the prevalence of methicillin resistant
      Staphylococcus aureus (MRSA) infection in our hospital and to compare their
      antibiotic susceptibility pattern with methicillin sensitive Staphylococcus
      aureus (MSSA). 100 strains of Staphylococcus aureus isolated from various
      clinical samples were screened for MRSA by disc diffusion method using 1 gm
      oxacillin disc. Antibiotic sensitivity testing was done by Kirby-Bauer's disc
      diffusion method. Out of these, 43% were identified as MRSA and the remaining 57%
      were MSSA. There was a marked difference in antibiotic sensitivity pattern of
      these M RSA versus the MSSA isolates. None of the MRSA isolate was found to be
      sensitive to amoxycillin while 36.8% of MSSA were sensitive to this antibiotic.
      9.3%, 18.6%, 34.9% and 95.3% of MRSA were sensitive to cotrimoxazole,
      cloxacillin, ciprofloxacin and chloramphenicol, while 75.4%, 92.9%, 91.2% and
      94.7% of MSSA were sensitive to these antibiotics respectively. Sensitivity to
      macrolide group of antibiotics like erythromycin and roxithromycin were seen in
      7% and 14% of MRSA in comparison to 85.9% and 91.2% of MSSA respectively. Amongst
      the aminoglycosides like gentamicin and amikacin, the sensitivity of MRSA was
      found to be 18.6% and 46.5% and that of MSSA was 98.2% and 94.7% respectively.
      Sensitivity to cephalosporins like cephalexin and cefotaxime was seen in 23% and
      25.5% of MRSA, whereas 100% of MSSA were sensitive to these antibiotics. All
      Staphylococcus aureus isolates were found to be uniformly sensitive to
      vancomycin. Majority of the isolates belonged to phage group III and the common
      phage types were 54, 54/75 and 54/75/85.

PMID- 15027754
TI  - Evaluation of a rapid immunochromatographic test in the diagnosis of dengue
      fever.
AB  - Serology is the mainstay of diagnosis in Dengue virus infection. Various rapid
      tests for antibody detection have been developed. They can prove to be important
      diagnostic tools especially in the field set up due to technical simplicity. We
      evaluated a Rapid immunochromatographic assay The rapid test was performed on
      acute phase sera collected from patients suspected to be suffering from Dengue
      fever/DHF. These samples were then tested by Dengue Duo Capture ELISA and
      compared The rapid test showed a good sensitivity for the detection of secondary
      dengue infection and thus can be a good screening tool.

PMID- 15027756
TI  - A study of prevalence of Chlamydia trachomatis infection in women with first
      trimester pregnancy losses.
AB  - The study included 125 patients in the first trimester of pregnancy, who were
      divided into group A (50 control subjects with normal intrauterine pregnancy),
      Group B (50 patients with spontaneous abortion), group C (25 patients with
      ectopic pregnancy). All the patients were investigated including routine blood
      and urine tests and special tests related to the cause of pregnancy loss. The
      patients were tested for IgG antibodies to Chlamydia trachomatis by ELISA
      technique and conjunctival smear were tested for presence of inclusion bodies to
      C. trachomatis. It was concluded that C. trachomatis is one of the important
      cause of spontaneous abortion and ectopic pregnancy. It is highly prevalent in
      our population, the prevalence being 10% in group A, 26% in group B, 28% in group
      C. Conjunctival smear showed presence of inclusion bodies in 0.8% patients. With
      abortions then risk of lower genital tract chlamydia infection spreading to upper
      genital tract increases. ELISA for C. trachomatis should be done when women are
      being investigated for the cause of spontaneous abortion and ectopic pregnancy.

PMID- 15027757
TI  - Detection of anti-Proteus antibodies in sera of patients with rheumatoid
      arthritis.
AB  - This study was carried out to determine increased level of antibodies to certain
      bacteria in rheumatoid arthritis (RA) patients. Fifty RA patients and 25 each of
      those suffering from osteoarthritis (OA) and healthy controls were tested for
      antibodies to somatic ('O) and flagellar ('H') antigens of Proteus mirabilis,
      Escherichia coli, and for antibodies to 'O' antigen of Klebsiella pneumoniae by
      standard tube agglutination method. Anti-Proteus antibodies against 'O' and 'H'
      antigens could be demonstrated in 70% and 64% RA cases respectively, and were
      statistically significant. Antibodies could be demonstrated against E. coli 'O'
      and 'H' antigens in 86% and 92% RA cases respectively, and were statistically
      significant. Against K. pneumoniae 'O' antigen, no antibody could be demonstrated
      in any of RA and OA cases, and healthy controls. Of the 50 RA patients, 30 had
      raised CRP levels. Antibodies against P. mirabilis and E. coli antigens appeared
      to be independent from CRP. Thus a specific elevation in the immune response to
      P. mirabilis and E. coli has been demonstrated in patients with RA from India.

PMID- 15027758
TI  - Incidence of Vibrio cholerae serogroup O139 infection with low virulence in
      Hubli, Karnataka (India).
AB  - 384 stool samples from patients with acute gastroenteritis were processed by
      standard culture techniques and antibiogram of V. cholerae was performed. Stool
      samples from 93 (24.22%) patients yielded V. cholerae, 58 (62.37%) of which were
      V. cholerae, El Tor O1 Ogawa, 31 (33.33%) V. cholerae O139 and 4 (4.30%) V.
      cholerae non O1 non O139. Of the culture proven cholera cases watery diarrhoea
      was observed in 79 (84.95%), vomiting in 57(61.29%), muscle cramps in 21 (22.58%)
      and sweating in 18 (19.35%). Majority of these patients presented with moderate
      dehydration 57 (61.29%). Mild dehydration was found in 19 (20.43%) and severe
      dehydration in 17 (18.28%). While majority of patients with O139 infection had
      mild to moderate dehydration 25 (80.65%), severe dehydration was more common with
      O1 infection 11 (64.71%). This study reflects the importance of monitoring the V.
      cholerae by serogrouping, antibiogram typing, which keep on varying constantly.

PMID- 15027759
TI  - Uropathogenic Escherichia coli--a preliminary study.
AB  - Urinary isolates of Escherichia coli were studied for presence of haemolysin,
      adhesins, serum resistance and O serotype prevalence. Of the 144 isolates
      studied, 72 exhibited hemolysin, 7 were resistant to bactericidal effect of serum
      and 50 strains showed Mannose resistant Haemagglutination (MRHA). O101,O68,O04
      and O25 were the commonest serotypes in this study.

PMID- 15027760
TI  - Rapid diagnosis of paroxysmal nocturnal haemoglobinuria by gel card test.

PMID- 15027761
TI  - Lingual cysticercosis.

PMID- 15027762
TI  - Schistosomiasis induced squamous cell carcinoma of the urinary bladder.

PMID- 15027763
TI  - Pelvic bone metastasis from transitional cell carcinoma of the urinary bladder.

PMID- 15027764
TI  - Comparison of malarial antigen detection kits with fluorescent microscopy.

PMID- 15027765
TI  - Effects of piperine on gastric acid secretion in albino rats.
AB  - Piperine, the pungent principle in Piper nigrum and Piper guinensis was studied
      for its effect on gastric acid secretion in white albino rats. Increasing the
      dose from 20 mg kg(-1) weight to 142 mg kg(-1) body weight produced dose
      dependent increases in gastric acid secretion. When compared with control basal
      acid secretion, these increases were significant (P<0.05). 20 mg kg(-1) produced
      a 22.2% (n=7) increase, while the highest dose employed in this study (142 mg kg(
      1)) produced 334.6% (n=7) increase in the gastric acid secretion. Piperine was
      however about 40 times less effective than histamine in increasing gastric acid
      secretion. The effect of piperine was significantly antagonized by cimetidine (1
      mg kg(-1), n=6) but not by atropine (1 mg kg(-1), n=6). Any involvement of
      cholinergic receptors in the observed piperine-induced increase in gastric acid
      secretion is thus excluded. There is however an indication that stimulation of
      histamine H2 receptors by piperine is likely to be involved in the increased
      acidity induced by piperine.

PMID- 15027766
TI  - Morbidity in rural southwestern Nigeria: a one year follow up of voluntary health
      worker consultations in Idere, Oyo State, Nigeria.
AB  - There is paucity of information on morbidity pattern at the community level in
      Nigeria. Available literature shows that most are based on hospital data from
      which rates cannot be generated. In addition, the low access to hospitals in the
      country especially in rural areas, coupled with inappropriate health care seeking
      behaviour in the community limits the usefulness of information derived from
      hospital data. This study was aimed at determining disease patterns in a rural
      community in Nigeria using the records of voluntary health workers. We followed
      up a well-defined rural community for one year and collated records of active
      voluntary health workers (VHWs) who provide health care to these communities.
      Results showed that Malaria, upper respiratory tract infections (URTI),
      diarrhoea, measles and accidents were the most common ailments for which the
      community members sought health care. The annual morbidity rates were malaria
      25.4%, URTI 6.0%, accidents 3.2%, and diarrhoea 2.7%. Rates generally decrease
      with increasing age, except for accidents, for which the rates were highest
      amongst school-aged children (5-14 years) and lowest amongst adults.
      Recommendations made include strengthening malaria control efforts, improving
      routine immunization coverage and providing health education regarding accident
      prevention.

PMID- 15027767
TI  - The mechano-biology of the epiphysis of the long bones as revealed by
      photoelastic models.
AB  - Stress contours have been generated in photoelastic models simulating
      cartilaginous and bony epiphyses. According to the findings, the secondary centre
      of ossification is formed in areas of the cartilaginous epiphysis shown to have
      reduced mechanical stress. The bony epiphysis appears to have been developed as a
      more mechanically efficient structure.

PMID- 15027768
TI  - Breast and cervical cancer screening activities among family physicians in
      Nigeria.
AB  - Breast and cervical cancers are the two commonest malignancies among Nigerian
      women; where they constitute about 50% of female cancers. A total of 63 out of 82
      family physicians from 4 out of the 6 health zones in Nigeria and the Federal
      Capital Territory, Abuja, Nigeria completed a self-administered questionnaire to
      determine their knowledge and screening practices for breast and cervical
      cancers. Forty nine percent (49%) of family physicians perceived cancer as one of
      the serious health problem facing women in Nigeria. Although 93.7% of responding
      physicians have heard of breast cancer screening facilities and 96.8% of cervical
      screening facilities, only 74.6% and 55.6% of these respondents offered screening
      services for breast and cervical cancers respectively. Breast examination was
      carried out monthly by 48.9% of the physicians on their regular patients. A
      comprehensive programme of continuing medical education and training in view of
      setting up facilities and offering service are recommended for family physicians.
      These stand to bridge the gap between the knowledge and the practice of breast
      and cervical cancer screening activities. The umbrella Association for Family
      Physicians and other regulating bodies should facilitate access to screening
      facilities and initiate training of willing physicians with a view to setting up
      services.

PMID- 15027769
TI  - Prevalence of hepatitis B and C viruses in pre-dialysis patients with chronic
      renal failure.
AB  - CRF affects people in their prime of life; they are often the Nation's workforces
      thereby leading to severe economic and social problems. Many patients with CRF
      who need dialysis, present for the first time in end stage renal failure. The
      commonest causes of CRF in Nigeria and other tropical countries have been
      reported to be hypertensive nephrosclerosis and chronic glomerulonephritis.
      Various studies in and outside Nigeria have documented an increased
      seroprevalence of anti-HCV and HBsAg in chronic renal failure patients on
      maintenance haemodialysis. Any association established between these viruses and
      CRF would suggest that the prevention and/or treatment of these viruses may
      likely lead to a reduction in the prevalence of CRF. Thus, forty-five (45)
      consecutive subjects with CRF and (45) age- and sex-matched control subjects who
      satisfied the eligibility criteria for the study were enrolled. Marker of HBV
      (HBsAg) was assayed using HUMAN Enzyme linked Immunosorbent Assay (ELISA) Test.
      Marker of HCV (anti-HCV) was determined using the HUMAN ELISA Test. The mean age
      of the subjects was 37 +/- 14 years (range 17 to 62 years) while the mean age of
      the control subjects was 38 +/- 14 years (range of 18 to 66 years). There were no
      statistically significant differences in the prevalence of HBsAg and anti-HCV in
      the CRF patients and controls P=0.74 and P=1.0 respectively. Although, the sample
      was small anti-HCV seropositive CRF patients were significantly younger than anti
      HCV seropositive controls P<0.027. In conclusion, this study has shown that there
      were no significant differences in the prevalences of HBsAg and anti-HCV in the
      CRF patients and controls. A larger scale study may be more desirable in defining
      the role of these viruses in patients with chronic renal failure.

PMID- 15027770
TI  - Blunt chest trauma.
AB  - A retrospective study was conducted at the cardiothoracic surgical unit of the
      University College Hospital, Ibadan on all consecutive, blunt chest injury
      patients treated between May 1975 and April 1999. The period of study was divided
      into 2 periods: May 1975-April 1987, May 1987-April 1999. The aim was to
      determine the pattern of injury, the management and complications of the injury
      among the treated. Blunt chest trauma patients were 69% (1331 patients) of all
      chest injury patients (1928 patients) treated. Mean age for the 2 periods was
      38.3 +/- 15 years and 56.4 +/- 6.2 years, the male:female ratio was 4:1 and 2:1
      respectively. The incidence of blunt chest trauma tripled in the second period.
      Blunt chest trauma was classified as involving bony chest wall or without the
      involvement of bony chest wall. Majority of the blunt chest injuries were minor
      chest wall injuries (68%, 905 patients), 7.6% (101 patients) had major but stable
      chest wall injuries, 10.8% (144 patients) had flail chest injuries. Thoracic
      injuries without fractures of bony chest wall occurred in 181 patients (13.6%).
      Seven hundred and eighty-seven patients (59.1%) had associated extra-thoracic
      injuries, in 426 patients (54.1%) two or more extra-thoracic systems were
      involved. While orthopaedic injury was the most frequent extra-thoracic injury
      (69.5%) associated with blunt chest trauma, craniospinal injury (31.9%) was more
      common injury among the patients with severe or life threatening chest trauma.
      The most common extra-thoracic operation was laparotomy (221 patients). Nine
      hundred and seventy patients (72.9%) had either closed thoracostomy drainage or
      clinical observation, 361 patients (27.1%) had major thoracic surgical
      intervention (emergent in 134 patients, late in 227 patients). Most of the severe
      lung contusion that needed ventilatory care (85 patients) featured among patients
      with bony chest wall injury, 15 were without chest wall injury. Majority of
      patients 63.2% (835 patients) had no significant complications, 486 patients
      (30.8%) of 1321 survivors had 741 complications. The commonest complications were
      atelectasis (201 patients) and pleural space complications (263 patients).
      Overall mortality was 36.2% (154 patients) among 426 patients. We conclude that
      majority of blunt chest trauma can be managed by simple procedures with minimal
      complications. Severe soft tissue chest injuries can occur without bony chest
      wall fractures.

PMID- 15027771
TI  - CT evaluation of intracranial subdural haematoma: an Accra experience.
AB  - This is a descriptive analysis of the Computed Tomographic (CT) findings in 50
      cases of intracranial subdural haematoma in Accra. The majority of patients were
      adults, though no age group was immune. The frequent aetiological factor in the
      series was trauma. Other remote causes such as meningitis and sickle cell disease
      were reported. The male to female ratio was 2.6:1, while the mean age was 32.4
      years. Subdural Haematoma (SDH) was classified into various subtypes by their CT
      densities. The commonest type, the hyperdense or acute haematoma was reported in
      56% of the patients. CT features noted in the series, include ventricular
      alteration, seen in 31 (62%) and were more often noted in the acute and isodense
      bleeds. Ipsilateral effacement of cerebral sulci was observed in only 10% of
      cases. Concave haematoma borders were reported in 76%. SDH were more often found
      on the left aspect of the cranium (52%), particularly in the frontal and
      pariental lobes. Evacuated surgery was done in only 9 of the series, where
      haematoma was demonstrated in more than 3 tomographic slices. Flake-like
      calcifications were found in three cases of long standing haematoma. Against the
      above background CT can be described as an appropriate diagnostic tool in
      clinical evaluation of SDH.

PMID- 15027772
TI  - The expression of the nuclear oncogenes c-myc and c-jun in the groove of Ranvier
      of the rabbit growth plate.
AB  - An immunohistochemical technique has been used to localise nuclear oncoproteins
      in the groove of Ranvier. The densely packed cells deep in the groove were
      immunoreactive positive for the myc protein. Cells and matrix in the same
      location were immunoreactive positive for the jun protein. These findings confirm
      the presence of proliferating cells in the groove. Injury to these cells is
      probably responsible for growth disturbances associated with trauma.

PMID- 15027773
TI  - Prevalence of active pulmonary tuberculosis in human immunodeficiency virus
      seropositive adult patients in University College Hospital, Ibadan, Nigeria.
AB  - Infection with Human Immunodeficiency Virus (HIV) has reached a pandemic
      proportion. There is a resurgence of tuberculosis (TB) Worldwide, this return of
      an old enemy has been attributed to a number of factors among which HIV infection
      has emerged as the strongest known risk factor determining the outcome of
      infection with Mycobaterium tuberculosis (M. tuberculosis). Pulmonary
      tuberculosis (PTB) accounts for more than 80% of TB cases and is the main problem
      on account of its frequency and infectivity. There have been studies determining
      prevalence of HIV in TB cases but that of prevalence of PTB in HIV infected
      patients have been limited. This study was undertaken to establish the prevalence
      of active PTB in HIV seropositive adult patients in University College Hospital
      (UCH), Ibadan. Fifty-eight confirmed HIV-seropositive adults patients were
      studied. All subjects were interviewed and examined. Subjects with positive
      respiratory symptoms and signs had their sputum examined and cultured for M.
      tuberculosis and had chest radiograph done. In this study, the prevalence of
      active PTB in HIV-seropositive subjects was 32.8% The TB prevalence shows a
      bimodal distribution at the extremes of age, while the age group 30-39 years had
      the lowest prevalence of 23.3%.

PMID- 15027774
TI  - Major limb amputation in Ibadan.
AB  - A prospective study of patients who had major limb amputation at the University
      College Hospital Ibadan over a 5-year period is presented. One hundred and one
      major limb amputations were performed within this period (71 Males, 30 Females,
      M:F = 2.3:1). Trauma accounted for 48% of the cases followed by diabetes in 26%,
      soft tissue infection in 13% and tumours also in 13%. The major post-op
      complication was wound infection. In accordance with the findings in other
      centers, a higher proportion of the amputations (69%) were carried out in the
      lower limbs. Patient's refusal to accept amputation resulted in a delay in
      amputation in 49 patients. This delay (before surgery) ranged from 1 day to 150
      days, with a mean of 15.49 (SD 9.V). From this study, we found that a reduction
      in vehicular accidents and increasing emphasis on efficient foot care (and
      glycaemic control) in the diabetic may significantly reduce the rate of
      amputations in our environment.

PMID- 15027775
TI  - Quality assessment of platelet concentrate prepared at a tertiary centre in
      Nigeria.
AB  - The need for platelet transfusion has increased at the University College
      Hospital (U.C.H.) Ibadan, Nigeria because of improved patient care and use of
      intensive therapeutic regimen associated with bone marrow aplasia. Therefore
      there is a need to assess the quality of the platelet concentrate prepared in our
      environment with a view to improving the quality of services available,
      consequently this study was carried out. Fifty platelet concentrates were
      assessed for pH, swirling index, volume, platelet count, WBC count and red cell
      count. All the concentrate preparations were within acceptable pH value of 7.25.
      The average volume was 18.52 mls/bag. The average platelet count per concentrate
      was 41.7+/-39.5 x 10(9)/L. Thirty-five percent (35%) of the platelet concentrates
      had a value > 55 x 10(9)/L. White blood cell count (WBC) < 12 x 10(9)/L was seen
      49% of the platelet concentrates prepared. Forty percent (40%) of the platelet
      concentrate had a red blood cell count (RBC count) > 12 x 10(9)/L with 30% not
      having red cell contamination. Swirling test was positive in 72% of the platelet
      concentrate units. The results from this study point to the need to improve the
      quality of the platelet concentrates being prepared in our blood bank in order to
      get maximum therapeutic values. There is also a need for regular quality control
      of the platelet concentrate being prepared in our blood bank.

PMID- 15027776
TI  - Certain red cell genetic factors and prevalence of chloroquine-induced pruritus.
AB  - The hypothesis that chloroquine-induced pruritus (CIP) may be determined by
      certain genetic factors was tested by investigating the epidemiology of CIP with
      respect to certain genetic red cell markers namely, haemoglobin genotype, glucose
      6-phosphate dehydrogenase (G6PD) deficiency and the ABO blood groups. Three
      hundred consecutive patients treated for malaria with chloroquine at the
      University College Hospital, Ibadan, Nigeria were recruited into the study. They
      were observed over 3 days for presence of CIP. ABO blood groups, G6PD and Hb
      genotypes were determined appropriately for each patient. One hundred and twenty
      four (41.3%) of the patients responded positively to CIP. There was a reduced
      frequency of the sickle cell trait (HbAS) among itchers relative to non-itchers.
      This suggests that the trait may be protective against CIP. G6PD deficiency was
      also found to be relatively more common among itchers than non-itchers. This
      indicates that G6PD deficiency may increase susceptibility to CIP. There was
      however no difference in the distribution of itchers among the different ABO
      blood groups. It was concluded that CIP may be associated with certain genetic
      red cell markers particularly Hb and G6PD types which are known malaria markers
      but not ABO blood groups.

PMID- 15027777
TI  - Radiotherapy in the management of early breast cancer in Ibadan: outcome of chest
      wall irradiation alone in clinically nodes free axilla.
AB  - The study was carried out to identify the group of patients with early breast
      cancer [stage I and II] after surgery in which chest wall irradiation alone was
      given without lymphatic irradiation thus reducing morbidity and also creating
      room for more patients on the available limited treatment facility. 92 patients
      with histologically confirmed early breast cancer that attended Radiotherapy
      clinic between June 1995 and May 1998 that satisfied selection criteria were
      studied. They all received External Radiotherapy to the chest wall, meadiasternum
      inclusive and breast if still in-situ. All also received cytotoxic chemotherapy.
      Majority of the patients 67 [84.8%] were recurrence free in 2 years while 12
      [15.2%] had recurrent disease, the recurrent sites were axilla 4 [5.06%], chest
      wall 3 [3.80%] and supraclavicular 2 [2.52%]. Average time to recurrence was 3-12
      months. In view of majority being recurrence free, chest wall irradiation alone
      in early breast cancer [stage I and II] could be encouraged, thus creating access
      to treatment for more patients in centers like ours with limited therapy
      facilities.

PMID- 15027778
TI  - Maternal and child's anxiety--effect on child's behaviour at dental appointments
      and treatments.
AB  - The objective of this study was to assess the influence of pre-existing dental
      anxiety and maternal anxiety on the behaviour of some Nigerian children during
      dental appointments. Two hundred and sixty children aged 2-15 years participated
      in this study. They were treated at the three government dental establishments in
      Ibadan, a city in South Western Nigeria, over a six-month period. The children's
      behaviour during different stages of treatment was determined by the Frankl's
      Behaviour Rating Scale. The outcome of the study revealed a high association
      between the level of pre-existing dental anxiety in the children and their
      behaviour during various phases of treatment (P<0.05). During initial stages of
      treatment, prophylaxis, administration of local anaesthesia and tooth extraction,
      children with high level of anxiety were less cooperative. In addition, a general
      tendency towards cooperative behaviour was observed among patients whose mothers
      had low anxiety levels. This study shows the importance of correct assessment of
      the pre-operative dental anxiety status in children as well as the level of
      anxiety in their mothers. The level of dental anxiety in children and their
      mothers appears to be predictive of their behaviour in the oral care setting. In
      circumstances where the level of pre-operative and maternal anxiety are high,
      efforts should first be geared toward instituting appropriate behaviour
      management skills like behaviour shaping and modelling to bring about a higher
      level of cooperation before embarking on treatment. By paying special attention
      to these children, it is possible that the dentist would succeed in improving
      acceptance of treatment in them thereby increasing cooperation at subsequent
      dental visits.

PMID- 15027779
TI  - Evaluation of auto-antibody to DNA and soluble immune complexes in children with
      urinary schistosomiasis.
AB  - Levels of serum auto-antibody to DNA and soluble immune complex (SIC) were
      determined in the sera of 40 Nigerian school children with heavy urinary
      schistosomiasis (USS), 64 school children with light USS and 36 apparently
      healthy children as controls. Haemagglutination and polyethylene glycol
      precipitation (PEG) techniques were employed respectively. 75% of USS subjects
      with heavy infection, 59% of USS subjects with light infection, and 8% of
      apparently healthy controls had auto-antibodies to DNA in the serum samples.
      Moreso, the mean concentrations of auto-antibodies to DNA and SIC were
      significantly higher in USS subjects with heavy infection compared with USS
      subjects with light infection or the controls. Significant correlation existed
      between severity of S. haematobium infection (S. haematobium egg numbers/10 ml
      urine) and SIC (r=0.21, t=2.16) or auto-anti DNA antibodies (r=0.43, t=3.86). It
      could be concluded that SIC and anti DNA antibodies are induced by antigens from
      eggs of S. haematobium and that both SIC and anti DNA antibodies may be involved
      in the pathology of USS.

PMID- 15027780
TI  - Dynamic balance and level of lesion in spinal cord injured patients.
AB  - This study investigated differences in the dynamic balance of patients with
      different levels of spinal cord injury (SCI) as well as the intraclass
      correlation coefficient (ICC) of the modified functional reach test (MFRT).
      Twenty non-standing Spinal Cord Injured patients (13 males and 7 females) with
      mean age of 43.15 years (S.D = 10.03 years) participated in the study. They were
      categorised into three groups based on the level of spinal cord lesion. Group 1
      comprised of 8 subjects with C5-T1, quadriplegia, group 2 comprised of 6 subjects
      with T6-T8 paraplegia and group 3 comprised of 6 subjects with T10-L1 paraplegia.
      The dynamic balance of all subjects was assessed using the modified functional
      reach test. The data were summarized using descriptive statistics of mean and
      standard deviation with further analysis using ANOVA and Pearson product
      correlation coefficient. The subjects with paraplegia showed higher functional
      reach (dynamic balance) than the quadriplegics but there was no significant
      difference in the functional reach values among the three groups. The ICC for
      MFRT was high and ranged from 0.981 to 0.992. The result of this study therefore
      seems to suggest that the MFRT cannot be used to classify patients with different
      levels of SCI.

PMID- 15027781
TI  - Some studies on the 5-hydroxytryptamine receptors in the isolated rat uterus.
AB  - Selective 5-hydroxytryptamine (5-HT) receptor antagonists were employed to
      further characterize the receptor subtypes mediating the contractile actions of 5
      HT on the isolated uterine preparations of the rat. Increasing concentrations
      (10(-8)-10(-6) M) of the 5-HT receptor antagonist methysergide produced rightward
      shifts of the concentration-response curves of the 5-HT-induced contractions
      (pA2=8.05, slope of A-S plot=1.12 n=7) ketanserin a 5-HT2A receptor antagonist
      (10(-8)-10(-6) M) competitively antagonized the actions of 5-HT on the
      preparation (pA2=8.81; slope=1.04; n=7). Both LY53857 (10(-8)-10(-6) M) and
      ICI169369 (10(-8)-10(-6) M) which are known 5-HT2 receptor blockers also produced
      concentration-dependent shifts of the curves LY53857 yielded a pA2 of 8.9
      (slope=0.82; n=7) while the pA2 for ICI169369 on the preparation was 7.9
      (slope=1.29; n=7). ICS205930 a potent 5-HT3 blocker (10(-12)-10(-9) M) also
      produced concentration-dependent shifts of the curves (pA2=11.3; slope=0.94;
      n=7). The presence of 5-HT1 receptors could not be established. However both 5
      HT2 and 5-HT3 receptors seem to be present on the rat uterine preparation.

PMID- 15027782
TI  - Histopathological assessment of the pattern of liver cirrhosis in a tropical
      population.
AB  - This study aims at establishing the pattern of liver cirrhosis. Histology slides
      and duplicate copies of reports were retrieved and re-examined while fresh
      sections were processed from original paraffin blocks when necessary. Cirrhosis
      was the second commonest cause of chronic liver disease after hepatocellular
      carcinoma. The commonest morphological type was macronodular cirrhosis.
      Micronodular cirrhosis is not as common in black Africans as among the
      Caucasians. This is not unexpected since alcoholic liver disease that is of
      aetiopathogenetic importance is also not as common as what is often found in
      Causasians. Biliary cirrhosis was reported in an 8 months old girl consequent
      upon congenital absence of gallbladder and biliary tree. There was male
      preponderance in the occurrence of cirrhosis with a male, female ratio of 2.5:1.
      The incidence gradually increased from early adult life but was highest in the
      middle age especially between the age group of 51-60 years and subsequently
      dropped sharply. Adequate diagnostic facilities should be provided to determine
      the incidence of hepatotropic viruses and their contribution to the incidence of
      chronic liver diseases. Case-controlled studies should be carried out to
      determine the role of local cultural practices on hepatocellular injury and the
      development of chronic liver disease.

PMID- 15027783
TI  - Anaesthesia and typhiod perforation: an anaesthetist's experience.
AB  - The acceptance of surgery as the best hope of survival in patients with typhoid
      perforation has greatly increased the role of the anaesthetist in the management
      of these patients. The purpose of this study was to review our anaesthetic
      experience in the management of patients with typhoid perforation over a period
      of 10 years (January 1988-December 1997). Ninety-five patients aged between 3 and
      70 years were anaesthetized for surgery on account of typhoid perforation within
      the study period. More than three-quarter of them (78%) were in the ASA
      classification 3 and 4. All the patients had general anaesthesia with
      endotracheal intubation. Preoperative adverse events were recorded in 30 patients
      (31.6%) and mortality rate was 18.95%. Severe dehydration and ASA=4 were
      preoperative factors of statistical prognostic importance (P=0.03 and 0.00
      respectively). We conclude that even though patients with typhoid perforation
      usually present in poor clinical state with high anaesthetic risk, a well
      conducted anaesthesia preceded by adequate resuscitation, still offers a good
      hope for fairly good surgical outcome. Anaesthetic management must ensure
      adequate oxygenation and perio-operative haemodynamic stability.

PMID- 15027784
TI  - Sirenomelia in one of Nigerian monochorionic twins.
AB  - A 1,600 gm baby with sirenomelia (caudal regression syndrome) associated with
      extensive anomalies in the internal organs occurring in one of a set of
      monochromic twins delivered at the Olabisi Onabanjo University Teaching Hospital
      (OOUTH), Shagamu, Nigeria is being reported. The baby lived for approximately
      twenty hours. The co-twin had no obvious malformation.

PMID- 15027785
TI  - Re: Audit of emergency theatre utilization by Windokun and Obideyi: Afr. J. Med.
      med. Sci. (2002) 31: 59-62.

PMID- 15027786
TI  - ["Operationalised psychodynamic diagnostics in childhood and adolescence" (OPD
      CA) in practice].
AB  - "Operationalised psychodynamic diagnostics in childhood and adolescence" (OPD-CA)
      has been completed in its first version after years of development. In a first
      interview with a 13-year-old boy, the diagnostic instruments of OPD-CA are
      presented by means of examples. The text passages of the transcribed first
      interview are evaluated in four sections by representatives of the respective
      working groups regarding the axes--relationships, conflict, structure and
      preconditions for treatment--and the diagnostic conclusions resulting from this
      are presented, thus providing a direct insight into the specific psychodynamic
      diagnostics of OPD-CA.

PMID- 15027787
TI  - Posttraumatic stress disorder and health status among female and male medical
      patients.
AB  - Posttraumatic stress disorder (PTSD) is associated with objective health problems
      in specific populations, such as Vietnam veterans. Less is known about PTSD and
      health among medical samples, especially PTSD patients with different etiologic
      traumas. This study examined PTSD and health in medical patients within the
      Department of Veterans Affairs healthcare system. A total of 134 patients
      completed an interview and questionnaires. Data on physician-diagnosed illnesses
      were gathered from medical records. PTSD diagnosis and symptoms were associated
      with a higher likelihood of circulatory and musculoskeletal disorders. In
      addition, PTSD symptoms were associated with more medical conditions. PTSD
      symptoms and diagnoses were also associated with poorer health related quality of
      life. Most of these findings remained significant after controlling for comorbid
      depressive, generalized anxiety disorder, and panic attack symptoms. Overall,
      gender did not moderate the relationship between PTSD and poorer health.

PMID- 15027788
TI  - Positive change following trauma and adversity: a review.
AB  - Empirical studies (n = 39) that documented positive change following trauma and
      adversity (e.g., posttraumatic growth, stress-related growth, perceived benefit,
      thriving; collectively described as adversarial growth) were reviewed. The review
      indicated that cognitive appraisal variables (threat, harm, and controllability),
      problem-focused, acceptance and positive reinterpretation coping, optimism,
      religion, cognitive processing, and positive affect were consistently associated
      with adversarial growth. The review revealed inconsistent associations between
      adversarial growth, sociodemographic variables (gender, age, education, and
      income), and psychological distress variables (e.g., depression, anxiety,
      posttraumatic stress disorder). However, the evidence showed that people who
      reported and maintained adversarial growth over time were less distressed
      subsequently. Methodological limitations and recommended future directions in
      adversarial growth research are discussed, and the implications of adversarial
      growth for clinical practice are briefly considered.

PMID- 15027789
TI  - Perceived coping ability mediates the relationship between PTSD severity and
      heart rate recovery in veterans.
AB  - Most psychophysiological studies of PTSD have not assessed physiological
      recovery, correlational relationships between PTSD severity and physiological
      measures within clinical populations, or mediation by cognitive appraisal.
      Relationships of PTSD severity to psychophysiological reactivity (to acoustic
      startle), habituation, and recovery were assessed in 29 combat veterans, and
      mediation by cognitive appraisal (perceived threat and coping ability) was
      assessed in a subset (n = 16) of participants. Heart rate (HR) recovery was
      linearly related to PTSD severity. Perceived ability to cope with the lab task,
      but not perceived threat inherent in the task, mediated the HR recovery-PTSD
      association. Potential implications of delayed HR recovery for functioning,
      treatment outcome, and health-risk in PTSD are presented. Cognitive appraisal may
      represent an important target for treatments.

PMID- 15027790
TI  - The accumulative effect of trauma exposure on short-term and delayed verbal
      memory in a treatment-seeking sample of female rape victims.
AB  - The accumulative effect of prior high-magnitude trauma exposure on memory was
      examined in 73 rape victims, 92% of whom had current posttraumatic stress
      disorder (PTSD). Participants were administered the Logical Memory component of
      the Wechsler Memory Scale, the Quick Test to obtain an estimate of intelligence,
      and were assessed for prior traumatic experiences. Prior exposure to high
      magnitude stressors (e.g., child rape, being kidnapped) was significantly
      correlated with poorer performance on the memory tasks. Regression analyses
      controlling for estimated IQ and psychopathology severity demonstrated that
      magnitude of prior trauma exposure predicted performance on the memory task,
      suggesting that in the current sample, deficits in verbal memory may be related
      (in part) to the degree of accumulative stress experienced over the lifetime.

PMID- 15027791
TI  - Hippocampal volume and memory performance in a community-based sample of women
      with posttraumatic stress disorder secondary to child abuse.
AB  - Childhood abuse is linked to posttraumatic stress disorder (PTSD), which follows
      abuse survivors into adulthood. This study identified the neuropsychological and
      neuromorphological sequelae of PTSD among prepubescently abused women. Right
      handed women aged 20-40 years were placed into PTSD and abuse, abuse only, and
      normal control groups (n = 17 per group). Participants were screened for trauma
      history and psychiatric symptoms, demographically matched, and given
      neuropsychological tests and a magnetic resonance scan of their brain. Women with
      PTSD did not express significant deficits in memory performance or hippocampal
      volume when compared with the abuse and normal control groups.

PMID- 15027793
TI  - Relationships of dissociation and childhood abuse and neglect with heart rate in
      delinquent adolescents.
AB  - This study examined the relationship of dissociative symptoms, abuse and neglect,
      and gender to mean heart rate (HR) in two types of interviews. Participants were
      25 female and 16 male delinquent adolescents. Dissociative symptoms and abuse and
      neglect were assessed by structured interviews. Participants were randomized to
      one of two conditions, to describe either their most stressful life experience or
      their free association thoughts. Greater dissociative symptoms were associated
      with lower mean HR, whereas abuse and neglect, being a girl, and participating in
      the free association task were associated with higher mean HR. The finding that
      high levels of dissociative symptoms may be related to a suppression of autonomic
      physiological responses to stress support Bremner's conceptualization (J. D.
      Bremner, 1999) that dissociative symptoms comprise one of two subtypes of the
      acute stress response, differing physiologically as well as subjectively from a
      predominantly hyperarousal or intrusive symptom response.

PMID- 15027792
TI  - Attention, learning, and memory in posttraumatic stress disorder.
AB  - This study compared attention and declarative memory in a sample of combat
      veterans with posttraumatic stress disorder (PTSD, n = 24) previously reported to
      have reduced concentrations of the hippocampal neuronal marker N-acetyl aspartate
      (NAA), but similar hippocampal volume compared to veteran normal comparison
      participants (n = 23). Healthy, well-educated males with combat-related PTSD
      without current depression or recent alcohol/drug abuse did not perform
      differently on tests of attention, learning, and memory compared to normal
      comparison participants. Further, hippocampal volume, NAA, or NAA/Creatine ratios
      did not significantly correlate with any of the cognitive measures when
      adjustments for multiple comparisons were made. In this study, reduced
      hippocampal NAA did not appear to be associated with impaired declarative memory.

PMID- 15027794
TI  - Mental health impact of the World Trade Center attacks on displaced Chinese
      workers.
AB  - To identify psychological sequelae of the World Trade Center attacks in immigrant
      Chinese displaced workers, we interviewed 77 displaced workers in May 2002. One
      third of the sample was classified as at least moderately depressed, and 21% met
      diagnostic criteria for posttraumatic stress disorder; however, few had utilized
      mental health services. Depression and PTSD scores were positively correlated
      with age, age at immigration to the United States, and prescription drug use
      after September 11th, among other variables. Results suggest the need for mental
      health outreach in this community. This outreach should target both displaced
      workers and their informal support networks to facilitate identification of and
      service access for those impacted by the attacks.

PMID- 15027795
TI  - Social support and depressive symptoms among displaced older adults following the
      1999 Taiwan earthquake.
AB  - This longitudinal study examines changes in depressive symptoms among displaced
      older Taiwanese adults (N = 54, M = 68 years), and the impact of various social
      supports for them at between 6 and 12 months after an earthquake. The average
      depression score between 6 and 12 months following the earthquake was unchanged
      and kept high score. Child and extended family support levels related to
      depressive symptoms after 6 months. In contrast, after 12 months, significant
      factors associated with a lessening of the depressive symptoms were social
      support from the extended family and neighbors, and social participation.
      Intervention to promote increased social networks and social participation,
      within their new environment in a temporary community, is highly recommended for
      older adults.

PMID- 15027796
TI  - Residual insomnia following cognitive behavioral therapy for PTSD.
AB  - This study examined whether insomnia persisted after completion of cognitive
      behavioral therapy (CBT) for PTSD and whether persistence of insomnia was
      associated with continuing nightmares, vigilance, depression, childhood abuse
      history, or having been traumatized in a sleep-related context. A retrospective
      analysis of posttreatment Clinician-Administered PTSD Scale (CAPS) data from 27
      patients who no longer met PTSD diagnosis following CBT for PTSD revealed that
      48% reported residual insomnia. For the large majority, insomnia persisted in the
      absence of continuing nightmares and hypervigilance. Experiencing trauma in a
      sleep-related context was associated with greater risk for residual insomnia,
      whereas childhood abuse history and depression were not. These findings suggest
      that interventions to address factors maintaining insomnia residual to PTSD
      warrant study.

PMID- 15027797
TI  - Personality disorders in veterans with posttraumatic stress disorder and
      depression.
AB  - Little is known about the frequency of the full-range of personality disorders in
      outpatients with concurrent posttraumatic stress disorder (PTSD) and depression,
      a common and oftentimes treatment-resistant combination in clinical practice. In
      a group therapy outcome study, Axis I and II diagnoses were assessed with the
      Structured Clinical Interview for DSM-IV and the Clinician-Administered PTSD
      Scale to select 115 male combat veterans with PTSD and depressive disorder.
      Within this sample, 52 (45.2%) had one or more personality disorders--most
      commonly paranoid (17.4%), obsessive-compulsive (16.5%), avoidant (12.2%), and
      borderline (8.7%)--and 19 (16.5%) had two or more. Documenting a substantial
      frequency of personality disorders is a first step in devising appropriate
      interventions for this treatment-resistant combination of disorders.

PMID- 15027798
TI  - Artificial cell bioencapsulation in macro, micro, nano, and molecular dimensions:
      keynote lecture.
AB  - Artificial cells now ranges from macro-dimensions, to micron-dimensions, to nano
      dimensions, and to molecular dimensions. Those in the macro-dimensions are
      suitable for use in the bioencapsulation of cells, tissues, microorganisms, and
      bioreactants. Those in the micron-dimensions are suitable for the
      bioencapsulation of enzymes, microorganisms, peptides, drugs, vaccine, and other
      materials. Those in the nano-dimension are being used for blood substitutes and
      carriers for enzymes, peptides, drugs, etc. Those in the molecular-dimensions are
      used as blood substitutes, crosslinked enzymes etc.

PMID- 15027799
TI  - Mechanical characterization of biocompatible microspheres and microcapsules by
      direct compression.
AB  - The mechanical properties of biocompatible microparticles including alginate
      microspheres and alginate-chitosan microcapsules with different wall thickness
      were determined using a micromanipulation technique. Single microparticles with
      diameters of 20-60 microm were compressed to a given deformation and held, and
      compressed to rupture at different speeds. The corresponding force imposed on
      them was measured simultaneously by a force transducer. Results showed that the
      force imposed on these particles increased when they were compressed, but relaxed
      significantly when they were held. For alginate microspheres, the faster the
      compression speed was, the greater the force being imposed on them at a given
      deformation. Alginate-chitosan microcapsules showed less force relaxation when
      they were held, compared with alginate microspheres. The thicker their wall was,
      the less significant force relaxation the microcapsules exhibited. The mean
      rupture force of alginate microspheres increased with the compression speed, but
      this effect in general became less for alginate-chitosan microcapsules, which
      depended on their wall thickness. However, the deformation at rupture for all
      three samples was independent of the compression speed. On average, the alginate
      chitosan microcapsules were bigger than alginate microspheres and had a greater
      rupture force.

PMID- 15027800
TI  - Influence of process conditions during impulsed electrostatic droplet formation
      on size distribution of hydrogel beads.
AB  - In the medical applications of microencapsulation of living cells there are
      strict requirements concerning the high size uniformity and the optimal diameter,
      the latter dependent on the kind of therapeutic application, of manufactured gel
      beads. The possibility of manufacturing small size gel bead samples (diameter 300
      microm and below) with a low size dispersion (less than 10%), using an impulsed
      voltage droplet generator, was examined in this work. The main topic was the
      investigation of the influence of values of electric parameters (voltage U,
      impulse time tau and impulse frequency f) on the quality of obtained droplets. It
      was concluded that, owing to the implementation of the impulse mode and
      regulation of tau and f values, it is possible to work in a controlled manner in
      the jet flow regime (U> critical voltage UC). It is also possible to obtain
      uniform bead samples with the average diameter, deff, significantly lower than
      the nozzle inner diameter dI (bead diameters 0.12-0.25 mm by dI equal to 0.3 mm,
      size dispersion 5-7%). Alterations of the physical parameters of the process
      (polymer solution physico-chemical properties, flow rate, distance between nozzle
      and gellifying bath) enable one to manufacture uniform gel beads in the wide
      range of diameters using a single nozzle.

PMID- 15027801
TI  - Encapsulated lactic acid bacteria for control of malolactic fermentation in wine.
AB  - The kinetics of both malolactic fermentation in Chardonnay wine by encapsulating
      Lactobacillus casei cells in pectate gel and lyophilized Oenococcus oeni culture
      has been carried out. The influence of acidity, sulfur dioxide content, and
      organic acid content on the malolactic activity of the bacteria has been
      controlled. Encapsulated bacteria degraded 30%, of malic acid in white wine,
      deacidifying it from pH 3.15 to 3.40, whereas the lyophilized culture degraded
      48% of malic acid, deacidifying from pH 3.15 to 3.60. The degree of conversion of
      malic acid in wine by the encapsulated cells was twice as high as that obtained
      by the free Lactobacillus casei cells. The operational stability of calcium
      pectate gel capsules was 6 months. It has been proved that the encapsulated
      biocatalyst increases the rate of fermentation, and induces the fermentation to
      take place at high ethanol concentrations. The proposed encapsulated biocatalyst
      is an attractive material for industrial applications in continuous winemaking
      processes.

PMID- 15027802
TI  - Encapsulation of enzymes in liposomes: high encapsulation efficiency and control
      of substrate permeability.
AB  - Enzyme encapsulation into liposomes is a promising technique to stabilize and
      prevent them from denaturation and proteolysis. We demonstrate this using
      acetylcholinesterase which is the main target for pesticides. In order to achieve
      a reasonable encapsulation yield, we analyzed the parameters involved in each
      step of various encapsulation procedures. The only encapsulation method which did
      not denature the protein was the lipid film hydration technique, however the
      encapsulation efficiency was usually low. The efficiency could be increased up to
      more than 40% by induction of a specific interaction between the enzyme and the
      lipid surface. Once encapsulated, the enzyme encountered another problem: the
      permeability barrier of the lipid membrane drastically diminished the activity of
      the enzyme entrapped in the liposome by reducing the entrance rate of the
      substrate molecules and then reducing the substrate concentration inside the
      liposome. To solve this problem, we controlled the permeability of the liposome
      wall by reconstituting a porin from Escherichia coli. We succeeded to recover the
      full functionality of the enzyme, while retaining the protection against
      denaturation and proteolytic enzymes.

PMID- 15027803
TI  - Flow calorimetry--a useful tool for determination of immobilized cis
      epoxysuccinate hydrolase activity from Nocardia tartaricans.
AB  - Bacterial cells Nocardia tartaricans with cis-epoxysuccinate hydrolase activity
      were entrapped in hardened calcium pectate gel by a commercial high performance
      encapsulator. This enzyme (in a single step reaction with no formation of side
      products) was used to hydrolyze disodium cis-epoxysuccinate to a pure enantiomer-
      disodium L-(+)-tartrate. Activities of this enzyme were determined using flow
      calorimetry. The validity of this method was corroborated by HPLC and
      isotachophoresis. The immobilized biocatalyst has activity (75.8 U/mgdry) able to
      convert disodium cis-epoxysuccinate to disodium tartrate at 94% yield in 5.5h.
      Immobilization of N. tartaricans in hardened calcium pectate gel beads had a
      positive effect on the activity of cis-epoxysuccinate hydrolase, storage
      stability, yield, and time of bioconversion.

PMID- 15027804
TI  - Phosphorylcholine-containing polymers for use in cell encapsulation.
AB  - A model system for encapsulation of pancreatic islets which has potential
      properties for improving biocompatibility and immunosuppression was investigated.
      In vitro and in vivo studies have shown that phosphorylcholine-containing
      polymers have high biocompatibility due to low adsorption of proteins and reduced
      thrombus formation. Encapsulation of islets isolated from rats with a compound
      membrane composed of phosphorylcholine-containing polymers and cellulose acetate
      led to rapid insulin production and diffusion across the membrane in response to
      glucose challenge. The phosphorylcholine-containing polymer had a molecular
      weight of about 1.3 x 10(4) Da. The polymer-coated membrane excluded larger
      molecules such as IgG (molecular weight 150 kDa), thereby acting as a physical
      immuno-barrier, but allowed smaller molecules such as glucose and insulin to pass
      through.

PMID- 15027805
TI  - Can magnetic resonance imaging be the key technique to visualize and investigate
      endovascular biomaterials?
AB  - OBJECTIVE: Magnetic resonance imaging (MRI) is an established modality in
      clinical use but may be potentially underutilized to visualize and investigate
      biomaterials. As its use is totally contraindicated only for ferromagnetic
      devices, it was employed to visualize deployment, biofonctionality, healing, and
      biodurability of a commercially available endovascular device, namely the
      Medtronic-AVE AneuRx. The quality of the observations coupled with the absence of
      ionizing radiations are likely to make this technique an attractive imaging
      modality in the future. METHOD: The potential benefits of the MRI technique were
      investigated in a GE Vectra-MR 0.5T MRI for the Medtronic-AVE AneuRx endovascular
      prosthesis, under different conditions: undeployed i.e., inserted in the delivery
      cartridge as received from the manufacturer (step 1), deployed in a mock glass
      aneurysm tube (step 2), and as a pathological explant harvested at the autopsy of
      a patient (step 3). The device was submitted to X-rays for examination in
      addition to MRI. At step 3, the device was further investigated with light
      microscopy and scanning electron microscopy (SEM) together with X-ray
      diffraction. RESULTS: The device which was inserted and pleated in the delivery
      cartridge did not demonstrate any significant observation either in MRI or in X
      rays. When it was deployed in the mock aneurysmal glass tube, light artefacts
      were associated with the T2 weighed FSE images around the Nitinol whereas X-rays
      gave images of indisputable interest. Similar results were noted using the
      explanted device. Very high contrasts were obtained with T1 whereas T2 images
      were almost defect free. The X-rays allowed to accurate imaging of the Nitinol
      skeleton but were poor to discriminate between the different tissues. Pathology
      observations using light microscopy were not really challenged, as the magnetic
      resonance imaging was performed using a 0.5T machine. DISCUSSION: The benefits of
      magnetic resonance imaging as a quality control technique to examine an
      endovascular device within its cartridge remains ill defined. Similarly, the role
      of conventional X-rays is unknown. The observation of devices fully deployed in a
      mock aneurysmal glass-tube under MRI are potentially useful but X-rays images
      allowed better definition. The MRI examination of the explanted device does
      permit observations related to the healing of the device that might be obtained
      in vivo and, thus offers new avenues for the follow-up of implanted devices. The
      pathological investigations brought additional informations about the tissues and
      the corrosion of the Nitinol. However, it is unlikely that MRI will permit
      detailed analysis of the biomaterials and in particular the corrosion process of
      the stents. CONCLUSION: These early observations of the follow-up of devices
      using MRI warrant further investigation. The absence of ionizing radiation with
      MRI makes this technique particularly attractive. As there is no emission of
      ionizing radiation associated with magnetic resonance, it is recommended that
      further investigation using this environment friendly technique for the follow-up
      of devices made of biomaterials that are MRI compatible.

PMID- 15027806
TI  - Effects of combined oral administration and intravenous injection on maintaining
      decreased systemic tyrosine levels in rats.
AB  - Our previous studies have indicated that encapsulated tyrosinase and crosslinked
      hemoglobin with tyrosinase (polyhemoglobin-tyrosinase) decrease systemic tyrosine
      level significantly in rats. However, we need a few days of oral administration
      of encapsulated tyrosinase before the systemic tyrosine level starts to decrease.
      Although intravenous injection of polyhemoglobin tyrosinase can lower the
      systemic tyrosine to about 10% within an hour, the level increases towards normal
      after 24 h. We therefore investigate the effects of intravenous injection of
      polyhemoglobin-tyrosinase combined with oral administration of encapsulated
      tyrosinase on lowering the systemic tyrosine level. In addition, we further
      optimize this combined method for lowering systemic tyrosine in animal studies
      and have found out that two intravenous injections of polyhemoglobin-tyrosinase
      followed by three times a day oral administration of encapsulated tyrosinase
      could immediately lower the body tyrosine and maintain this low level as long as
      the oral administration is continued.

PMID- 15027807
TI  - Hemoglobin promotes somatic embryogenesis in peanut cultures.
AB  - Critical parameters influencing somatic embryogenesis include growth regulators
      and oxygen supply. Consequently, the present investigation has focused on
      optimization of a somatic embryogenic system for peanut (Arachis hypogaea L.)
      through media supplementation with the auxin, picloram. The latter at 30 mg L(-1)
      was optimal for inducing regeneration of somatic embryos from cultured explants
      of zygotic embryos. In contrast, somatic embryogenesis did not occur in the
      absence of this growth regulator. An assessment has also been made of the
      beneficial effect on somatic embryogenesis and plant regeneration of the
      commercial hemoglobin (Hb) solution, Erythrogen. Hemoglobin at 1:50 and 1:100
      (v:v) stimulated increases in mean fresh weight (up to a maximum of 57% over
      control), mean number of explants producing somatic embryos (15%) and mean number
      of somatic embryos per explant (29%).

PMID- 15027808
TI  - Effect of gossypol in association with chromium protoporphyrin on heme metabolic
      enzymes.
AB  - Gossypol prevents the liberation of oxygen from oxyhemoglobin and exerts a
      hemolytic effect on erythrocytes. In excessive dosages of gossypol, an extreme
      burden is placed upon the respiratory and circulatory organs owing to the reduced
      oxygen carrying capacity of blood. Chromium protoporphyrin (CrPP) has been shown
      to either competitively suppress or to significantly ameliorate a variety of
      naturally occurring or experimentally induced forms of jaundice in animals and
      man. In this communication, a novel tissue dependent response to gossypol (50
      micromol/kg bw) and gossypol in association with CrPP (50 micromol/kg bw) is
      described. Our results revealed that gossypol stimulated the hepatic, splenic,
      and renal delta-aminolevulinic acid synthase (ALA-S) activity, the heme
      biosynthetic enzyme, and simultaneous administration of CrPP and gossypol
      synergized the gossypol-mediated increase of ALA-S activity. Gossypol was found
      to be a potent stimulator of heme oxygenase (HMOX) activity in rat liver and
      kidney to varying degrees. This tissue response contrasted with that of the
      spleen, where gossypol decreased the activity of the enzyme. In consonance with
      the increased hepatic and renal HMOX activity, a marked increase was observed in
      total serum bilirubin concentration in gossypol treated rats. When rats were
      given CrPP simultaneously with gossypol, the gossypol mediated increase in
      hepatic and renal HMOX activity was effectively blocked. Furthermore, the
      increase in enzymatic activity was accomplished by a decline in the total
      microsomal protein content on gossypol administration. These findings emphasize
      the toxic effect of gossypol in eliciting increased heme degradation by
      stimulating HMOX activity in the liver and the kidney and the potential
      usefulness of CrPP in experimental and perhaps clinical conditions in which
      hyperbilirubinemia occurs.

PMID- 15027809
TI  - Vascular permeability alterations induced by arsenic.
AB  - The impact of arsenic on the integrity of blood vessels in vivo via in situ
      exposure (local injection) of arsenic was investigated. Vascular permeability
      changes were evaluated by means of the Evans blue assay and the India ink tracer
      techniques. Rats were intravenously injected with Evans blue followed by
      intradermal injections of various doses of sodium arsenite on the back skins of
      the animals. Evans blue at different time points was extracted and assayed as
      indices of vascular leakage. Skin at various time point injection sites was
      sampled for arsenic measurement via graphite furnace atomic absorption
      spectroscopy. Our time course study with Evans blue technique demonstrated a
      biphasic pattern of vascular permeability change: an early phase of permeability
      reduction and a later phase of permeability promotion at all dose levels tested.
      The India ink tracer technique also demonstrated a time-correlated increase in
      vascular labelling in the tissues examined, signifying an increase in vascular
      leakage with time. Moreover, we found that despite an early increase in tissue
      arsenic content at time of injection, tissue arsenic declined rapidly and
      returned to near control levels after 30-60 min. Thus, an inverse correlation
      between tissue arsenic content and the extent of vascular permeability was
      apparent. This study provides the first demonstration that in situ exposure to
      arsenic will produce vascular dysfunction (vascular leakage) in vivo.

PMID- 15027810
TI  - The effects of diazinon on lipid peroxidation and antioxidant enzymes in
      erythrocytes in vitro.
AB  - Diazinon is one of the most widely used organophosphate insecticides (OPI) in
      agriculture and public health programs. The aim of this study was to investigate
      how an OPI, diazinon, affects lipid peroxidation (LPO) and the antioxidant
      defense system in vitro. For this purpose, two experiments were carried out. In
      experiment 1, the effects of various concentrations of diazinon on LPO and the
      activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and
      catalase (CAT) in erythrocytes were studied. Each diazinon concentration was
      incubated with a previously prepared erythrocyte samples at +4 degrees C for 0,
      60 and 180 min. After incubation, the malondialdehyde (MDA) levels and the
      activities of SOD, GSH-Px and CAT were determined. In experiment 2, in order to
      determine the direct effect of diazinon on the activities of SOD, GSH-Px and CAT,
      the erythrocytes were haemolysed and incubated with the various concentrations of
      diazinon at +4 degrees C for 0, 60 and 180 min. In experiment 1, MDA levels and
      the activities of SOD and GSH-Px increased with increasing diazinon concentration
      and incubation period, but CAT activity remained unchanged. In experiment 2, SOD
      activity was significantly decreased, and GSH-Px activity was significantly
      increased. From these results, it can be concluded that in vitro administration
      of diazinon results in the induction of erythrocyte LPO and changes the
      activities of antioxidant enzymes, suggesting that reactive oxygen species may be
      involved in the toxic effects of diazinon.

PMID- 15027811
TI  - The ability of fungal isolates from human lung aspergilloma to produce
      mycotoxins.
AB  - This study included 11 adult patients (seven men and four women) who had been
      surgically treated for pulmonary aspergilloma in the Republic of Croatia within
      two years. Mycological analysis was positive for Aspergillus genus in five
      samples of surgically removed tissue. A. fumigatus was isolated in three and A.
      versicolor in two samples. Their mycotoxigenic potency was determined by thin
      layer chromatography. A. fumigatus strains were found to produce aflatoxin B1
      (AFB), and two of them aflatoxin G1. A. versicolor strains produced AFB1 and
      sterigmatocystin. Neither isolated Aspergillus strain produced aflatoxin G2 or
      ochratoxin A. Fungal growth and production of mycotoxins are the consequences of
      interaction of fungus, host and environment. One has also to take into
      consideration that the production of mycotoxins in vitro does not reflect what
      these fungi may produce in human organisms.

PMID- 15027812
TI  - Investigation of biochemical and histopathological effects of Mentha piperita
      Labiatae and Mentha spicata Labiatae on liver tissue in rats.
AB  - The plant Mentha piperita, or peppermint, is commonly used in the treatment of
      loss of appetite, common cold, bronchitis, sinusitis, fever, nausea and vomiting,
      and indigestion as a herbal agent. In this study, we aimed to investigate
      biochemical and histological effects of M. piperita Labiatae, growing in the
      Yenisar Bademli town of Isparta city, and Mentha spicata Labiatae, growing in the
      Anamas high plateau of the Yenisar Bademli town, on the rat liver tissue. Forty
      eight male Wistar albino rats weighing 200-250 g were used for this study. Rats
      were divided into four groups of 12 animals: Group I received no herbal tea
      (control group); Group II received 20 g/L M. piperita tea; Group III received 20
      g/L M. spicata tea; and Group IV received 40 g/L M. spicata tea. Herbal teas were
      prepared daily and provided at all times to the rats during 30 days as drinking
      water. Liver function tests, including aspartate aminotransferase (AST/GOT) and
      alanine aminotransferase (ALT/GPT) activities were measured. To evaluate liver
      antioxidant defences, superoxide dismutase (SOD), glutathione peroxidase (GSH
      Px), catalase (CAT) and thiobarbituric acid reactive substance (TBARS) activities
      were determined in the homogenates of liver tissue. In addition, liver tissues
      were submitted for histopathologic examination. AST and ALT activities were
      increased in Group II, Group III and Group IV gradually when compared with the
      control group. The difference between Group II and the control group was not
      statistically significant (P > 0.016). Increases in AST and ALT activities of
      Group III and Group IV were statistically significant when compared with the
      control group. SOD, GSH-Px and CAT activities were increased in Group II when
      compared with the control group but the difference was not statistically
      significant (P > 0.016). However, SOD, GSH-Px activities and the TBARS level were
      significantly increased, and CAT activity was significantly decreased in Group
      III when compared with the control group. In Group IV, while SOD, GSH-Px and CAT
      activities were decreased, the TBARS level was increased as compared with the
      control group (P < 0.0016). Histopathological evaluation of experimental groups
      revealed a mild to severe degree of hepatic damage when compared to the control
      group. In Group II, there was only minimal hepatocytes degeneration. In Groups
      III and IV, there were granular or ballooning hepatocyte degeneration and
      necrosis, sinusoidal and central vein dilatation. It was concluded that lipid
      peroxidation and hepatic damage occurs after M. piperita and M. spicata
      administration in rat liver and the damage seems to be dose dependent.

PMID- 15027813
TI  - The effects of desferrioxamine on cisplatin-induced lipid peroxidation and the
      activities of antioxidant enzymes in rat kidneys.
AB  - Cisplatin-induced nephrotoxicity is associated with an increase in lipid
      peroxidation and oxygen free radicals in rat kidneys. In this study, the effects
      of desferrioxamine were compared to vitamin C and E on cisplatin-induced lipid
      peroxidation and antioxidant enzyme activities in rat kidneys. Rats were divided
      into five groups, with 15 Wistar rats in each group. In the control group, rats
      received 1 mL/100 g isotonic saline solution intraperitoneally (i.p.). In Group
      II, 10 mg/kg cisplatin i.p. was injected to rats. Thirty minutes before the same
      dosage of cisplatin administration, 100 mg/kg i.p. vitamin C or E was given to
      rats in groups III and IV, respectively. Rats in Group V received 250 mg/kg
      desferrioxamine i.p., before the same dose of cisplatin administration. All rats
      were killed by cervical dislocation after 72 hours. The kidneys were immediately
      removed and washed in cold saline. Spectrophotometric method was used for all
      analyses. While catalase, glutathione reductase (GR), and superoxide dismutase
      (SOD) levels were found to be significantly decreased (P < 0.001),
      malondialdehyde (MDA) (P < 0.05) and hydrogen peroxide (H2O2) (P < 0.001) levels
      were significantly increased in the cisplatin group when compared to the
      controls. MDA levels were decreased by desferrioxamine (P < 0.005) as well as
      vitamin C and E (P < 0.05 and P < 0.001, respectively). These three compounds
      induced a significant increase in SOD levels (P < 0.05), but only in the vitamin
      C group, were SOD levels not significantly different than the levels of the
      controls (P > 0.05). In the desferrioxamine (P < 0.05), vitamin C and E groups (P
      < 0.001 for both), the cisplatin elevated H2O2 levels were decreased. None of
      these drugs had any effect on GR and catalase levels (P > 0.05). Desferrioxamine
      is useful to prevent cisplatin-induced lipid peroxidation, however, vitamin C and
      E are more effective on antioxidant enzymes than desferrioxamine.

PMID- 15027814
TI  - Substitution for natural musk in Pien Tze Huang does not affect its
      hepatoprotective activities.
AB  - Previous studies showed that Pien Tze Huang, a Chinese folk medicine well known
      for its therapeutic activity in treating liver diseases, protected the liver
      against carbon tetrachloride (CCl4)-induced damage in mice. In the present study,
      natural musk, one of the important ingredients of Pien Tze Huang, was replaced by
      a formulated substitute, and the new formulation of Pien Tze Huang was shown to
      have similar chromatographic patterns to the original Pien Tze Huang in gas
      chromatography-mass spectrometry and high performance liquid chromatography. When
      used in treating mice with CCl4- or galactosamine-induced liver damage, both the
      original and new formulations of Pien Tze Huang were found to be able to suppress
      to a similar extent both the histopathological changes in the liver and the
      elevation of serum alanine aminotransferase and aspartate aminotransferase.
      Necrosis, cellular ballooning, microvesicular steatosis and lymphocytes
      infiltration were all significantly reduced in the damaged liver. In hepatoma
      cells, both formulations activated the activator protein 1 (AP1) enhancer
      sequence, indicating that both of them were able to act through the JNK signal
      transduction pathway. The results of the present study showed that the
      substitution for natural musk does not affect the hepatoprotective activities of
      Pien Tze Huang. It is also postulated that both formulations protect the liver
      through regulating signal transduction in the cell.

PMID- 15027816
TI  - Mathematical-statistical models of generated hazardous hospital solid waste.
AB  - This research work was carried out under the assumption that wastes generated
      from hospitals in Irbid, Jordan were hazardous. The hazardous and non-hazardous
      wastes generated from the different divisions in the three hospitals under
      consideration were not separated during collection process. Three hospitals,
      Princess Basma hospital (public), Princess Bade'ah hospital (teaching), and Ibn
      Al-Nafis hospital (private) in Irbid were selected for this study. The research
      work took into account the amounts of solid waste accumulated from each division
      and also determined the total amount generated from each hospital. The generation
      rates were determined (kilogram per patient, per day; kilogram per bed, per day)
      for the three hospitals. These generation rates were compared with similar
      hospitals in Europe. The evaluation suggested that the current situation
      regarding the management of these wastes in the three studied hospitals needs
      revision as these hospitals do not follow methods of waste disposals that would
      reduce risk to human health and the environment practiced in developed countries.
      Statistical analysis was carried out to develop models for the prediction of the
      quantity of waste generated at each hospital (public, teaching, private). In
      these models number of patients, beds, and type of hospital were revealed to be
      significant factors on quantity of waste generated. Multiple regressions were
      also used to estimate the quantities of wastes generated from similar divisions
      in the three hospitals (surgery, internal diseases, and maternity).

PMID- 15027815
TI  - The role of cytochrome-P450 inhibitors in the prevention of hepatotoxicity after
      paracetamol overdose in rats.
AB  - Despite the understanding that some cytochrome P450 isoforms are responsible for
      activation of paracetamol to the hepatotoxic metabolite, N-acetyl-p
      benzoquinineimine (NAPQI), the use of enzyme inhibitors for prevention and/or
      treatment of paracetamol hepatotoxicity is still not well researched. Here, a
      mixture of ketoconazole, isoniazid and caffeine (inhibitor solution), known
      inhibitors of CYP3A, CYP2E1 and CYP1A2, was investigated for prevention of
      hepatotoxicity after paracetamol over-dose in rats. The appropriate doses of
      paracetamol (1000 mg/kg/day) and the 'inhibitor solution' (ketoconazole 5 mg/kg,
      isoniazid 5 mg/kg and caffeine 10 mg/kg; =KIC-5-50), were selected in preliminary
      experiments. Thereafter, two groups of 15 male Sprague-Dawley rats each were
      treated with the toxic dose of paracetamol intraperitoneally to induce severe
      hepatotoxicity. But one of the two groups was treated with the KIC-5-50
      intraperitoneally 5 min after administration of paracetamol. Five rats were
      killed at 24, 48 and 72 hours after paracetamol administration. Plasma
      concentrations of paracetamol were determined by the polarization fluorescent
      immunoassay and a piece of liver was sent for histopathology examination. Liver
      function tests at 48 hours were higher in the 'paracetamol only' treated group
      than in the 'KIC-5-50 + paracetamol' treated group' (P < 0.05), i.e., median
      (range) AST 2025 (530-4329) i.u./L, ALT 1174 (662-2395) i.u./L versus AST 194 (81
      494) i.u./L, ALT 311 (201-945) i.u./L, respectively. The corresponding plasma
      concentrations of paracetamol were 0.26 (0.13-1.02) microg/mL for the
      'paracetamol only' treated group versus 0.17 (0.07-0.33) microg/ml for the 'KIC-5
      50 + paracetamol' treated group. Centrilobular necrosis, the pathogmonomic
      feature of paracetamol hepatotoxicity, was demonstrated only in the 'paracetamol
      only' treated group. In conclusion, coadministration of paracetamol with
      inhibitors of cytochrome P450 prevented the development of paracetamol-induced
      hepatotoxicity in rats, and this calls for research for enzyme inhibitors that
      may be of therapeutic value.

PMID- 15027818
TI  - Integrated waste management for rural development in Egypt.
AB  - Rural areas generate a large amount of plant and animal residues that can be
      recycled and utilized instead of relocation and/or burning. This will lead to
      increasing the benefits from agricultural sector in rural communities and
      ensuring a better environment. To increase the economic output and environmental
      benefits of recycling agricultural residues, integrated system should be
      considered, e.g., energy--compost-recycled water system; composting--co
      composting system; food-feed compost system, ensilage of crop residues. The
      present work was a pilot study for optimizing integrated systems for
      bioconversion agricultural residues completed by establishing a Training Center
      for Recycling Agricultural Residues (TCRAR) thereby ensuring the dissemination of
      the technical, environmental, and socioeconomic aspects to farmers, live stock
      producers, extensions service staff, and private sector. Three integrated
      subsystems for bioconversion of agricultural residues were developed. They were
      based on (i) energy--manure-recycled water system, (ii) composting and co
      composting system, and (iii) food-feed/compost system.

PMID- 15027817
TI  - Changes in the environmental parameters of treated wastewater in soils.
AB  - Available data about treated sanitary and industrial wastewater in Kuwait were
      collected and reviewed. Potential changes in the environmental parameters of
      these waters when permeated through predominantly loamy sand soil samples
      collected from three agricultural sites in Kuwait, an arid land desert area. The
      environmental parameters investigated included pH, dissolved oxygen (DO), total
      Kjeldahl nitrogen (TKN), total organic content (TOC), and total hydrocarbon
      content (THC). The results indicated these parameters have generally reflected
      marked variations. These variations were attributed to the interactions between
      soil, soil pore water, and influent wastewaters used in this study. The results
      also indicated that the above-investigated environmental parameters stayed well
      within the allowable limits set for the reuse of tertiary treated sanitary and
      industrial wastewaters in agricultural irrigation applications.

PMID- 15027819
TI  - Assessment of Kuwait's Al-Qurain landfill using remotely sensed data.
AB  - Kuwait's Al-Qurain landfill problem resulted from indiscriminate dumping of
      domestic and industrial waste in an abandoned quarry in the late 1970s and early
      1980s. The landfill and surrounding areas were set aside for a government housing
      project without an environmental assessment of the impact of the landfill on the
      project. Inhabitants of the newly constructed housing area experienced persistent
      foul odor emanating from the landfill site. Since then, the issue has generated a
      lot of public interests, and several remediation measures have been adopted. In
      this preliminary study, several remotely sensed data consisting of Landsat
      Multispectral Scanner (MSS), Landsat Thematic Mapper (TM), IKONOS, and synthetic
      aperture radar (SAR) acquired between 1972 and 2000 were processed and assessed
      for their usefulness to study and monitor the landfill site. The imagery provided
      a historical perspective of how the areas had changed over the last 30 years.
      Other useful information of the landfill obtained from the satellite imagery
      included the spatial extent, spectral reflectance, surface temperature, and
      surface roughness. The landfill site showed higher surface temperatures compared
      to the immediate surrounding areas-a process that could accelerate the
      biodegradation and the release of landfill gases. Such dataset could be
      incorporated into a GIS for the long-term monitoring of the site.

PMID- 15027820
TI  - Quality of the bottom sediment prior to dredging in the Golden Horn of Istanbul.
AB  - The Golden Horn has experienced severe pollution due to uncontrolled domestic and
      industrial wastewater discharges until recent years. A restoration project has
      been developed by our universities, upon a request from Istanbul Metropolitan
      Municipality. Two principal alternatives for the dredging and disposal of the
      bottom sediments were considered: disposing on the land and disposing in the sea.
      Both of these alternatives include several sub-alternatives. Characterization of
      the sediment quality is crucially important for selecting the best alternative
      considering the cost, environmental impact and public acceptance. However, only a
      few and rather old studies were present with which it was not possible to get a
      comprehensive information on the critical sediment characteristics. Therefore,
      the aim of this study was determination of spatial distribution of sediment
      characteristics. The project area, at which the sediment quality determined,
      covers the part of the Golden Horn remaining at the upstream of Valide Sultan
      Bridge. The number of sampling stations were thirteen and the sediment samples
      were collected from 0.0m, 5.0m and 10.0m from the bottom surface. The following
      parameters were measured on each sample: Total solids, organic matter, total
      phosphorus, TKN, oil and grease, total sulphur, and sediment oxygen demand (SOD).
      Sediment oxygen demand parameter was further divided into three fractions,
      namely, biological (SOD-B) and chemical (SOD-C). Average organic content of the
      bottom sediment was around 10% while ammonia and sulfur exhibit very high levels.
      It is found that the bottom sediment is well stabilized with very low organic
      content below 5.0m from the bottom surface. It can be said that, removing the
      upper 5m of the bottom sediment will be enough for creating a relatively stable
      bottom surface which will cause oxygen depletion in the overlaying water at
      acceptable levels. High SOD values of the bottom sediment makes the alternatives
      considering disposal in the Marmara Sea and Black Sea inapplicable. High SOD-C
      values, especially, indicate that the sediment will cause a tremendous reduction
      in the oxygen concentration in a very short time at any marine environment, and
      even it may create anaerobic conditions. Therefore, disposal of dredged sediment
      into abandoned mines 4km from the Golden Horn by a pressure pipeline has been
      chosen as the best applicable alternative.

PMID- 15027821
TI  - Landfill surface runoff and its effect on water quality on river Yamuna.
AB  - During 2000, the estimated quantity of solid waste generated in Delhi, India was
      more than 9000 tones per day. This is one of the biggest sources of environmental
      degradation in capital city of India. Since 1950's over 12 large landfill have
      been packed with all kinds of nonbiodegradable and toxic waste of Delhi. The area
      covered is at least 1% (14.83 square kilometer) of total Delhi's area. All the
      landfill sites except Tilak Nagar, Hastal, and Chattarpur are located very
      closely (0.5-6 km) to the river Yamuna. It contributes the pollution to river
      Yamuna in a significant way in a form of surface runoff from landfill site
      especially in rainy season. The chemical analysis of leachate produced by these
      landfill sites and corresponding river section (at five river points) has been
      performed for 16 selected parameter (Temperature, Odor, pH, Turbidity,
      Conductivity, COD, Total Solids, Sulphide, Chloride, Nitrate, Iron) in the first
      stage and for 8 parameters (pH, Conductivity, COD, Total Solids, Chloride,
      Nitrate, Iron) in second stage. The study was conducted between August to
      October, 2000 (rainy season). It is clear from the study that the river water
      quality is affected by the presence of landfill surface runoff. Its impact can be
      seen in the region where the drains are meeting the river. This is one of the
      causes of river pollution apart from other major municipal and industrial
      sources.

PMID- 15027822
TI  - Application of granular media filtration in wastewater reclamation and reuse.
AB  - Laboratory experiments were conducted at room temperature (20-25 degrees C) using
      four identical filter columns made of Plexiglas, each of 1 m height and 15 cm
      internal diameter, packed with granular media of 70 cm depth. Each filter was
      operated at a constant filtration rate, thus four rates were tested in the range
      of 2-15 m(3) m(-2) d(-1). Mono-media (sand) and dual-media (sand and anthracite)
      were tested and three types of municipal wastewaters, namely raw, primary and
      secondary-treated effluents were applied. The results obtained indicate that
      considerable improvements in effluent quality could be attained by tertiary sand
      filtration. Removal of solids, organics and bacteria was not significantly
      affected by the increase in filtration rate from 2 to 15 m(3) m(-2) d(-1). The
      highest removal efficiency was obtained at low filtration rate of 2 m(3) m(-2) d(
      1), but higher filtration rates achieved acceptable removal efficiencies and
      provided effluents of good quality to satisfy the irrigation water quality
      standards. Since the conventional sand filters in wastewater treatment plants
      operate at a rate in the range of 2-5 m(3) m(-2) d(-1), utilization of high rate
      filtration is advantageous and would result in significant cost savings. However,
      with high filtration rates the filters require more frequent backwashing. Dual
      media filters achieved 50% reductions in BOD suggesting that filtration could be
      used to treat primary effluents in emergency cases.

PMID- 15027823
TI  - Heavy metals content of municipal wastewater and sludges in Kuwait.
AB  - Municipal wastewater may contain heavy metals, which are hazardous to the
      environment and humans. With stringent regulations concerning water reuse and
      sludge utilization in agriculture, there is a great need to determine levels of
      heavy metals in liquid wastes, sludges and agricultural crops. The state of
      Kuwait has programs to utilize waste sludge produced at wastewater treatment
      plants as soil conditioner and fertilizer for greenery and agricultural
      development projects and to reuse treated wastewater effluents in irrigation. The
      common metals found in Kuwait's raw wastewater and sludge are Cd, Cr, Cu, Hg, Ni,
      Pb, and Zn. The effects of accumulation of heavy metals in soil are long lasting
      and even permanent. In this study, the variations in the concentration levels of
      heavy metals were measured in wastewater and sludge produced at Ardiya municipal
      wastewater treatment plant in Kuwait. A relationship was observed between the
      concentrations of heavy metals in treated wastewater and sludge used for
      agriculture and the level of accumulated heavy metals found in residual tissues
      of some crops.

PMID- 15027824
TI  - Enhancement of carbon and nitrogen transformations during composting of municipal
      solid waste.
AB  - Appropriate management of municipal solid waste (MSW) is viewed as an integrated
      system encompassing waste minimization, recycling, and resource recovery. This
      has increased the interest in the composting process, in which the biodegradable
      portion of MSW is biologically converted into a valuable product that can be
      utilized as a soil conditioner or fertilizer. Effective operation of the
      composting process can be achieved by determining the optimal conditions for the
      controlling parameters in order to enhance the biological reactions during
      composting. Information on biodegradation rates are also essential for process
      design. Therefore, this study was conducted in order to examine the factors
      affecting process performance and transformation of essential elements of MSW
      such as carbon and nitrogen. A pilot study of in-vessel aerobic composting of MSW
      was carried out and the operating parameters, which affect biodegradation of
      carbonaceous and nitrogenous matter were studied using a specially designed
      rotating drum and a carbon-rich MSW. The effects of temperature, moisture
      content, and air flow rate were examined. The performance of the composting
      process was evaluated by measuring the carbon and nitrogen content during
      experiments, each of which lasted for 30 days. The study showed that enhanced
      transformations of carbon and nitrogen occur at 55 degrees C for temperature, 60%
      for moisture content, and 10L/kgh for air flow rate using the food-rich MSW
      generated in the Gulf countries.

PMID- 15027825
TI  - Adsorption of iron and manganese using low cost materials as adsorbents.
AB  - Removal of toxic metals (iron and manganese) ions from aqueous solution by
      adsorption was studied. Batch tests were used to study the removal of each metal
      either as a single component or both metals as multicomponent. The adsorbents
      used are low cost materials namely; palm fruit bunch and maize cobs. The
      adsorption isotherms proved the favor ability of the adsorbent used. Removal of
      iron ion by adsorption on palm fruit bunch and maize cobs was in the range of 80
      57%, and for magnesium ion in the range of 79-50% for initial concentration
      ranged between 1 and 10 ppm. In case of mixture of both metals, removal of iron
      from the mixture was in the range 79-54% and for magnesium was in range of 76
      54%.

PMID- 15027826
TI  - Safety use of sewage sludge as soil conditioner.
AB  - A series of field and laboratory experiments were conducted during 1994-996 to
      study the seasonal changes in sewage sludge characteristics and to evaluate the
      effect of sludge treatment processes and their application to sandy soil on soil
      plant heavy metal contents and the numbers of some pathogenic microorganisms in
      both treated sludge and sludge provided soils. Results of seasonal production of
      sludge showed wide variation in their chemical and microbiological
      characteristics. Lime application resulted in an increase in the pH values and
      temperature degrees. The maximal values of temperature and pH were obtained when
      sludge treated with 20% lime. No big difference was observed between the sludge
      treatments received lime at rates of 10, 15, and 20% lime. The 10% limed-sludge
      treatment was the best for reducing concentrations of heavy metals and numbers of
      bacterial pathogens in sludge. Stoping addition of sludge to soil for one
      cropping season after continuous sludge addition for four seasons sharply
      decreased the soil heavy metal contents and subsequently decreased their
      accumulation in the edible parts of plants.

PMID- 15027827
TI  - Potential use of economic instruments in waste management in the Arab countries.
AB  - Changing public behavior towards the environment is considered an essential
      component in the environmental strategies of all the Arab countries. An important
      mechanism is using economic instruments (pricing, charges, taxes, and financial
      incentives) to achieve the desired changes. This article presents potential
      applications for the use of economic instruments in waste management in the Arab
      countries. Applications are suggested for implementation in several fields that
      include wastewater, solid waste, hazardous waste, and agricultural pollution.
      Examples are presented based on real data from Jordan. In addition, the
      requirements needed to implement the economic instruments are explained.

PMID- 15027828
TI  - Ion exchange extraction of heavy metals from wastewater sludges.
AB  - Heavy metals are common contaminants of some industrial wastewater. They find
      their way to municipal wastewaters due to industrial discharges into the sewerage
      system or through household chemicals. The most common heavy metals found in
      wastewaters are lead, copper, nickel, cadmium, zinc, mercury, arsenic, and
      chromium. Such metals are toxic and pose serious threats to the environment and
      public health. In recent years, the ion exchange process has been increasingly
      used for the removal of heavy metals or the recovery of precious metals. It is a
      versatile separation process with the potential for broad applications in the
      water and wastewater treatment field. This article summarizes the results
      obtained from a laboratory study on the removal of heavy metals from municipal
      wastewater sludges obtained from Ardhiya plant in Kuwait. Data on heavy metal
      content of the wastewater and sludge samples collected from the plant are
      presented. The results obtained from laboratory experiments using a commercially
      available ion exchange resin to remove heavy metals from sludge were discussed. A
      technique was developed to solubilize such heavy metals from the sludge for
      subsequent treatment by the ion exchange process. The results showed high
      efficiency of extraction, almost 99.9%, of heavy metals in the concentration
      range bound in wastewater effluents and sludges. Selective removal of heavy
      metals from a contaminated wastewater/sludge combines the benefits of being
      economically prudent and providing the possibility of reuse/recycle of the
      treated wastewater effluents and sludges.

PMID- 15027829
TI  - Removal of chromium from tannery effluents by adsorption.
AB  - Tannery effluent is characterized not only by heavy loads but also with toxic
      heavy metals especially chromium ions. Chromium is considered an important source
      of contamination due to large volume of exhaust liquid discharged and solid
      sludge produced. Details on adsorption studies were carried out using synthetic
      chromium salts (chromium chloride) as adsorbate, and cement kiln dust (a waste
      from white cement industry) as adsorbent. Equilibrium isotherms have been
      determined for the adsorption of chromium ions on cement kiln dust. Kinetic study
      provided that the adsorption process is diffusion controlled. The experimental
      results have been fitted using Freundlich, Langmuir, and Redlich Peterson
      isotherms. The maximum adsorption capacity of cement kiln dust was found to be 33
      mg/g. Industrial tannery effluent (22-mg/L chromium and COD 952 mg/L) was also
      treated by cement dust. The treated effluent (using 20 g cement dust per 1 L)
      contains only 0.6 mg/L chromium and COD 200 mg/L.

PMID- 15027830
TI  - A comparative study of sludge dewatering units for sludge management.
AB  - A comparative study of three different types of municipal sludge dewatering unit
      was performed including sludge dewatering, centrifuge, and sand drying bed. The
      purpose of that was to examine the capability of each dewatering unit for
      dewatering municipal sludge at the Jahra treatment plant. The testing program was
      performed to select the most feasible and effective unit under local conditions.
      From the experiment approach, it was clear that the application results of
      various dewatering units were different and depends entirely on the basic
      properties of each unit. It has been also found that mechanical dewatering units
      can operate and are the most feasible and effective to reduce the large
      quantities of sludge as a treatment byproduct.

PMID- 15027831
TI  - Public awareness is key to successful waste management.
AB  - A critical component in any waste management program is public awareness and
      participation, in addition to appropriate legislation, strong technical support,
      and adequate funding. Waste is the result of human activities and everyone needs
      to have a proper understanding of waste management issues, without which the
      success of even the best conceived waste management plan becomes questionable.
      The paper presents an overview of the fundamentals of waste management and, using
      examples from the United States, illustrates how public awareness and
      participation results in succcssful waste management. Examples of the methods and
      techniques that have been very effective in creating and enhancing public
      awareness of waste management problems, including the author's proven method of
      public education, are presented in the paper. The details of a course aimed at
      educating school teachers on waste management issues and a specialized curriculum
      on waste and litter control, designed for kindergarten through 8th grade students
      and developed by the author, are discussed in the paper. A case study dealing
      with remediation of one of the worst contaminated hazardous waste sites in the
      United States, that included substantial public participation, is reviewed. The
      paper concludes by emphasizing that the public must be made aware of waste
      management issues to understand the consequences of improper management of waste
      and how it may ultimately pose a serious threat to their lives and well-being.

PMID- 15027832
TI  - Computer simulation of leachate quality by recirculation in a sanitary landfill
      bioreactor.
AB  - Sanitary Landfills are the most widely used method of solid waste disposal around
      the world. Modern sanitary landfills are designed with impervious liners, and
      leachate collection, removal, and treatment systems to minimize the potential for
      groundwater contamination. Leachate recycle through the landfill is an effective
      method of leachate treatment, and to enhance solid waste stabilization. A
      mathematical model is developed to simulate the release of contaminants from
      solid wastes, and their movement into the percolating liquid. Two differential
      equations are used that express the mass balance of the contaminants in the
      percolating water and those in the solid wastes. These simultaneous linear
      differential equations are solved numerically using a fourth-order Runge-Kutta
      algorithm with many physical and process parameters. The model results are used
      to estimate the active life of landfill with and without leachate recirculation.
      Such information is valuable in the operation, maintenance, and closure plan of a
      sanitary landfill.

PMID- 15027834
TI  - Ensilage of cardboard and date palm leaves.
AB  - Eight treatments of cardboard (CB) and date palm leaves (DPL) with or without
      alkali treatments plus molasses, dates, and ammonium sulfate were ensiled in
      laboratory silos. Latobacillus plantarum and Saccharomyces cerevisiae inoculants
      were added at an application rate of 10(5) cfu/g of silage to study their
      possible influence on the fermentation process. Silos were sealed and incubated
      at 30 degrees C. The anaerobic ensiling was evaluated for chemical and
      microbiological variables by opening the silos after 30, 60, and 90 days. After
      90 days, significantly low pH values (5.2-3.5) were obtained. The percentages of
      hemicellulose, cellulose, lignin, and ash were determined. Concentrations of
      reducing sugars, ether extract, and crude protein tended to be acceptable among
      treatments. Silages showed a significantly high lactic acid concentration (up to
      4.3%) and only traces of butyric acid (below 1%). Also changes in acetic and
      propionic acids concentrations were determined. Lactobacillus populations
      remained almost static while yeast and molds populations tended to be lower after
      90 days of ensilage. Neither alkali treatment nor microbial inoculants showed a
      relationship with the ensiling process. Thus, overall, it was concluded that CB
      and DPL can be effectively ensiled and the resultant silages are acceptable to
      merit their use as ruminant feed in arid regions.

PMID- 15027833
TI  - A comparison of leachate treatment between Rhode Island and Kuwait.
AB  - The main objectives of this article were to present data on the characteristics
      of landfill leachate of Rhode Island Central landfill and those of Kuwait's
      Sulaibya landfill site, and to compare different experimental pilot plant studies
      for the treatment of sanitary landfill leachate, which was generally
      characterized by high concentration of heavy metals. The data obtained on the
      chemical analysis of leachate generated from two landfills in Rhode Island and
      Kuwait, identified variations in leachate quality due to landfill composition.
      Pilot Plant studies using physical/chemical and biological treatments (i.e.,
      rotating biological contractor) were used to examine the treatment efficiency.

PMID- 15027835
TI  - On government's role in the crossing of chasms.

PMID- 15027836
TI  - The impact of litigation on nursing home quality.
AB  - Government reports indicate that regulations have been ineffective in improving
      quality of care in many nursing homes. Some analysts feel that litigation against
      nursing homes may be the result of quality problems that are monitored during the
      inspection process, some contend litigation merely causes quality problems by
      diverting financial resources away from patient care, and some argue that
      litigation is duplicating the efforts of the inspection process. Given that the
      relationship between litigation and inspection-oriented measures of quality is
      not clear, this article explores the relationship empirically. When a significant
      relationship is found, the empirical results suggest that litigation is
      associated with a decline in inspection-oriented measured quality in the nursing
      home facing the legal claim. In contrast, litigation against a chain has a very
      different relationship to firm-level quality, where firms within a chain that is
      being sued have higher levels of inspection-oriented quality. Our results suggest
      that legal claims may result from quality problems that go unmeasured during the
      inspection process. However, more research in this area is warranted.

PMID- 15027837
TI  - State nursing home enforcement systems.
AB  - This study presents interview and statistical data from a telephone and fax
      survey of state agency officials and statistical data from the Centers for
      Medicare & Medicaid Services' Online Survey Certification and Reporting (OSCAR)
      system. State survey activities for nursing facilities were reviewed and the
      number and types of intermediate sanctions issued by states in 1999 were
      reported, along with barriers to the use of such sanctions. Using five selected
      enforcement measures to create a summary score, states were classified by
      quartiles based on the stringency of their nursing facility enforcement
      activities. Controlling for the number of complaints as a proxy for quality, the
      predictors of a summary of state enforcement actions were: percentage of
      population at age eighty-five and above. Democratic governors, higher percentages
      of chain facilities, and lower facility occupancy rates. Regional differences in
      enforcement patterns also were shown. Many federal policies and resource
      constraints were identitied as barriers to effective regulation. The findings
      identified nursing facility survey and enforcement issues that need to be
      addressed by policy makers.

PMID- 15027838
TI  - How physicians' organizations compete: protectionism and efficiency.
AB  - This article develops a framework that distinguishes four types of competitive
      strategies that physicians' organizations can adopt in their interactions with
      health plans. Two types of strategies protect physicians' incomes and autonomy
      from incursion and control by insurers; the other two enhance the efficiency of
      health care markets by controlling costs and embedding physicians' caregiving in
      a community of professionals. The mix of strategies that each organization adopts
      at any given time depends on the market conditions and regulatory policies it
      faces, as well as its organizational capacity. The article reviews recent
      developments in the field that indicate that today's markets and regulations
      create neither the pressures nor the capacity for physicians' organizations to
      adopt strategies that enhance efficiency. The managed care backlash has led to a
      relaxation of pressures to control costs, and the lack of a business case for
      quality has discouraged embedded caregiving. These developments instead have
      encouraged and enabled physicians' organizations to adopt strategies that protect
      their members from the bargaining power and micromanagement of health plans. The
      article therefore proposes changes in purchasing and regulatory policies to alter
      the pressures and improve the capacity of physicians' organizations to pursue
      efficiency and eschew protectionism.

PMID- 15027839
TI  - Monitoring the uninsured: a state policy perspective.
AB  - Because states have primary responsibility for the implementation of public
      health insurance programs, states need timely, good quality data to evaluate
      programs, monitor trends in the number and characteristics of the uninsured, and
      better understand the dynamics of health insurance coverage. This article
      provides a synthesis of the data sources available to states for monitoring rates
      of health insurance coverage. Information was collected through a comprehensive
      review of state and national health surveys and in-depth interviews with state
      analysts in all fifty states. Our findings suggest that national surveys do not
      meet states' needs for data, and in response, states have initiated their own
      household surveys. We provide information on thirty-six household surveys that
      are used to estimate state levels of health insurance coverage. We recommend that
      national and state efforts be better coordinated to facilitate efficient use of
      resources to achieve good state-level date.

PMID- 15027840
TI  - Biodegradation of amino-acid-based poly(ester amide)s: in vitro weight loss and
      preliminary in vivo studies.
AB  - A systematic in vitro biodegradation study of regular poly(ester amide)s (PEAs)
      composed of naturally occurring hydrophobic alpha-amino acids, fatty diols and
      dicarboxylic acids using gravimetric (weight loss) method was carried out in the
      presence of hydrolases like alpha-chymotrypsin, lipase and a complex of proteases
      of Papaya. The last enzyme was used for modeling the catalytic action of
      nonspecific proteases. It was found that the PEAs, in the presence of enzyme
      solutions, were biodegraded by surface chemical erosion mechanism, according to
      the first-order kinetics. Spontaneous immobilization (adsorption) of the enzymes
      onto the PEAs surfaces was observed. The surface immobilized enzyme can also
      catalyze the chemical erosion of the PEAs. The enzymes could also be impregnated
      into the PEAs to make PEAs biochemically biodegraded, i.e. 'self-destructive', at
      a target rate. A comparison of in vitro biodegradation data of the PEAs with
      polylactide (PDLLA) showed that PEAs exhibited a far more tendency toward enzyme
      catalyzed biodegradation than PDLLA. A preliminary in vivo biodegradation study
      of selected PEA films in rats with and without lipase-impregnation showed that
      those PEAs were completely absorbed within 1-2 months post-implantation (for the
      lipase-impregnated ones) and 3-6 months (for the lipase-free ones). These
      findings prompt us to suggest that these new PEAs may have a great potential for
      designing drug sustained/controlled release devices, as well as implantable
      surgical devices.

PMID- 15027841
TI  - A study on a chitosan-gelatin-hyaluronic acid scaffold as artificial skin in
      vitro and its tissue engineering applications.
AB  - Chitosan-gelatin-hyaluronic acid scaffolds for tissue regeneration were
      fabricated by freezing and lyophilizing methods. The scaffolds showed a higher
      water uptake and retention abilities than chitosan-gelatin scaffolds did.
      Fibroblasts cultured in chitosan-gelatin-hyaluronic acid scaffolds grew and
      proliferated well, and they exhibited a strong viability. Keratinocytes were co
      cultured with fibroblasts in chitosan-gelatin-hyaluronic acid scaffolds to
      construct an artificial bilayer skin in vitro. The artificial skin obtained was
      flexible and had good mechanical properties. The data from this study suggested
      that chitosan-gelatin-hyaluronic acid scaffolds are suitable for preparing a
      bilayer skin substitute.

PMID- 15027842
TI  - Effect of the fiber diameter and porosity of non-woven PET fabrics on the
      osteogenic differentiation of mesenchymal stem cells.
AB  - The proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs)
      was investigated in three-dimensional non-woven fabrics prepared from
      polyethylene terephthalate (PET) fiber with different diameters. When seeded into
      the fabrics of cell scaffold, more MSC attached in the fabric of thicker PET
      fibers than that of thinner ones, irrespective of the fabric porosity. The
      morphology of cells attached became more spreaded with an increase in the fiber
      diameter of fabrics. The rate of MSC proliferation depended on the PET fiber
      diameter and porosity of fabrics: the bigger the fiber diameter of fabrics with
      higher porosity, the higher their proliferation rate. When the alkaline
      phosphatase (ALP) activity and osteocalcin content of MSC cultured in different
      types of fabrics was measured to evaluate the ostegenic differentiation, they
      became maximum for the non-woven fabrics with a fiber diameter of 9.0 microm,
      although the values of low-porous fabrics were significantly high compared with
      those of high porous fabrics. We concluded that the attachment, proliferation and
      bone differentiation of MSC was influenced by the fiber diameter and porosity of
      non-woven fabrics as the scaffold.

PMID- 15027843
TI  - Laser surface modification of silicone rubber to reduce platelet adhesion in
      vitro.
AB  - To improve the blood compatibility, the surface of polydimethylsiloxane (PDMS)
      films were irradiated using a CO2-pulsed laser. Acrylamide (AAm) was grafted onto
      a pre-irradiated surface. The AAm-grafted and laser-treated films were
      characterized using different techniques. Platelet adhesion and activation onto
      the AAm-grafted PDMS, laser-treated (ungrafted) and unmodified PDMS film surfaces
      were compared. Data from in vitro assays indicated that the platelet adhesion was
      reduced on the AAm-grafted PDMS and laser treated PDMS films in comparison with
      the unmodified PDMS. The laser-irradiated sample showed the minimum platelet
      adhesion. It seems that laser irradiation onto a silicone rubber surface is a
      versatile technique to produce anti-thrombogenic surface for biomaterial
      applications.

PMID- 15027844
TI  - Development of a YIGSR-peptide-modified polyurethaneurea to enhance
      endothelialization.
AB  - Polyurethanes have been investigated for use as vascular grafts due to their
      excellent mechanical properties and relatively good biocompatibility. However,
      poor retention of endothelial cells and thrombogenicity in vivo remain
      problematic for vascular graft applications. The peptide YIGSR has been shown to
      increase endothelial cell adhesion but not attachment of platelets, suggesting
      its possible utility for vascular graft applications. In this study, a bioactive
      polyurethaneurea has been synthesized by incorporating GGGYIGSRGGGK peptide
      sequences into the polymer backbone. Successful incorporation of the peptides was
      confirmed by NMR, contact angle measurement and ESCA. Uniform distribution of
      peptides on the surface was observed using a fluorescent probe capable of
      reacting with tyrosine residues on the peptides. Hard segment domains were
      visualized using tapping mode AFM. Endothelial cell adhesion, spreading,
      proliferation, migration and extra-cellular matrix production were improved on
      bioactive polyurethaneurea compared to control polyurethaneurea. Competitive
      inhibition of endothelial cell attachment and spreading by soluble YIGSR peptides
      indicated that cell adhesion and spreading were specifically mediated by YIGSR
      sensitive cell adhesion receptor, not just by changed surface properties. There
      was no significant difference in the number of adherent platelets. Therefore,
      this bioactive polyurethanurea may improve vascular graft endothelialization
      without increasing thrombogenicity.

PMID- 15027845
TI  - Poly(ethylene oxide) surfactant polymers.
AB  - We report on a series of structurally well-defined surfactant polymers that
      undergo surface-induced self-assembly on hydrophobic biomaterial surfaces. The
      surfactant polymers consist of a poly(vinyl amine) backbone with poly(ethylene
      oxide) and hexanal pendant groups. The poly(vinyl amine) (PVAm) was synthesized
      by hydrolysis of poly(N-vinyl formamide) following free radical polymerization of
      N-vinyl formamide. Hexanal and aldehyde-terminated poly(ethylene oxide) (PEO)
      were simultaneously attached to PVAm via reductive amination. Surfactant polymers
      with different PEO:hexanal ratios and hydrophilic/hydrophobic balances were
      prepared, and characterized by FT-IR, 1H-NMR and XPS spectroscopies. Surface
      active properties at the air/water interface were determined by surface tension
      measurements. Surface activity at a solid surface/water interface was
      demonstrated by atomic force microscopy, showing epitaxially molecular alignment
      for surfactant polymers adsorbed on highly oriented pyrolytic graphite. The
      surfactant polymers described in this report can be adapted for simple non
      covalent surface modification of biomaterials and hydrophobic surfaces to provide
      highly hydrated interfaces.

PMID- 15027847
TI  - Pyrazolo[3,4-d]pyrimidines endowed with antiproliferative activity on ductal
      infiltrating carcinoma cells.
AB  - Novel 1,4,6-trisubstituted pyrazolo[3,4-d]pyrimidines are reported with
      preliminary in vitro activity data indicating that several of them are potent
      inhibitors (better than the reference compound) of Src phosphorylation of the
      breast cancer cells 8701-BC, known to overexpress Src. The ability of such
      compounds to significantly reduce 8701-BC cell proliferation suggests that this
      scaffold could be a promising lead for the development of antitumoral agents able
      to block Src phosphorylation of breast cancer cells.

PMID- 15027846
TI  - Cell growth on the porous sponges prepared from poly(depsipeptide-co-lactide)
      having various functional groups.
AB  - In tissue engineering, excellent biodegradable materials are desired as temporary
      scaffolds to support cell growth and disappear with the progress of tissue
      regeneration. We previously synthesized biodegradable poly(depsipeptide-co
      lactide), poly[(Glc-Asp)-co-LA] and poly[(Glc-Lys)-co-LA], having reactive side
      chain groups. Then, the effects of reactive and ionic side-chain groups on cell
      attachment and growth were investigated using co-polymer films with various
      amounts of carboxyl or amino groups. In this study, to evaluate the utility of
      these co-polymers as functional scaffolds for tissue regeneration, 3-dimensional
      porous sponges were prepared by freeze-drying method and the effects of reactive
      and ionic side-chain groups on cell growth and degradation behavior were
      investigated using co-polymer sponges with various amounts of carboxyl or amino
      groups. Good cell growth was observed on the co-polymer sponges. During cell
      culture, the co-polymer sponges exhibited various degradation rates related to
      the depsipeptide unit content. Three-dimensional biodegradable polymer matrices
      with reactive surface, controllable degradation behavior and good cell growth
      were successfully prepared using these co-polymers. Such kinds of co-polymer
      matrices are good candidate for scaffold for tissue engineering.

PMID- 15027848
TI  - 7-Alkoxy-4-phenylamino-3-quinolinecar-bonitriles as dual inhibitors of Src and
      Abl kinases.
AB  - We previously reported that several 7-alkoxy-4-phenylamino-3
      quinolinecarbonitriles were potent inhibitors of Src kinase activity. We disclose
      here a new highly efficient and versatile route to these compounds, which are
      also potent inhibitors of Abl kinase.

PMID- 15027849
TI  - Identification of 2-[2-[2-(5-bromo-2- methoxyphenyl)-ethyl]-3-fluorophenyl]-4,5
      dihydro-1H-imidazole (ML00253764), a small molecule melanocortin 4 receptor
      antagonist that effectively reduces tumor-induced weight loss in a mouse model.
AB  - The melanocortin 4 receptor (MC4R) plays an important role in body weight
      regulation and energy homeostasis. Administration of peptidic MC4R antagonists
      (usually by intracerebro ventricular injection) has been shown in the literature
      to increase body weight and/or food intake in several rodent models. We report
      here the identification of a novel nonpeptidic MC4R antagonist and its effects on
      tumor-induced weight loss in mice following peripheral administration.

PMID- 15027850
TI  - Structure-activity study on a novel series of macrocyclic inhibitors of the
      hepatitis C virus NS3 protease leading to the discovery of BILN 2061.
AB  - From the discovery of competitive hexapeptide inhibitors, potent and selective
      HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity
      relationship studies were performed focusing on optimizing the N-terminal
      carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety.
      Inhibitors meeting the potency criteria in the cell-based assay and with improved
      oral bioavailability in rats were identified. BILN 2061 was selected as the best
      compound, the first NS3 protease inhibitor reported with antiviral activity in
      man.

PMID- 15027852
TI  - Predicting the cell differentiation activity of 1 alpha,25-dihydroxyvitamin D3
      side chain analogues from docking simulations.
AB  - We present a receptor-based protocol for the prediction of the cell
      differentiation activities of a series of side chain analogues of 1 alpha,25
      dihydroxyvitamin D(3), a compound that exhibits a very large variety of
      biological functions. Our protocol is able to reproduce the activity of the
      compounds studied here. It also sheds light on the relative importance of binding
      site residues in the biological activity and on the mechanism behind it.

PMID- 15027851
TI  - Design and synthesis of a fluoroindolocarbazole series as selective topoisomerase
      I active agents. Discovery of water-soluble 3,9-difluoro-12,13-dihydro-13-[6
      amino-beta-D-glucopyranosyl]-5H,13H-benzo[b]- thienyl[2,3-a]pyrrolo[3,4
      c]carbazole- 5,7(6H)-dione (BMS-251873) with curative antitumor activity against
      prostate carcinoma xenograft tumor model.
AB  - A series of fluoroindolocarbazoles were studied with respect to their
      topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor
      activity. Emerging from this series was BMS-251873, a potential clinical
      candidate possessing a robust pharmacological profile including curative
      antitumor activity against prostate carcinoma.

PMID- 15027853
TI  - A new series of highly potent non-peptide bradykinin B2 receptor antagonists
      incorporating the 4-heteroarylquinoline framework. Improvement of aqueous
      solubility and new insights into species difference.
AB  - Introduction of nitrogen-containing heteroaromatic groups at the 4-position of
      the quinoline moiety of our non-peptide B(2) receptor antagonists resulted in
      enhancing binding affinities for the human B(2) receptor and reducing binding
      affinities for the guinea pig one, providing new structural insights into species
      difference. A CoMFA study focused on the diversity of the quinoline moiety
      afforded correlative and predictive QSAR models of binding for the human B(2)
      receptor but not for the guinea pig one. A series of 4-(1-imidazolyl)quinoline
      derivatives could be dissolved in a 5% aqueous solution of citric acid up to a
      concentration of 10 mg/mL. A representative compound 48a inhibited the specific
      binding of [(3)H]BK to the cloned human B(2) receptor expressed in Chinese
      hamster ovary cells with an IC(50) value of 0.26 nM and significantly inhibited
      BK-induced bronchoconstriction in guinea pigs even at 1 microg/kg by intravenous
      administration.

PMID- 15027854
TI  - Synthesis, structure-activity relationships, and mechanism of drug resistance of
      D- and L-beta-3'-fluoro-2',3'-unsaturated-4'-thionucleosides as anti-HIV agents.
AB  - Various D- and L-2',3'-unsaturated 3'-fluoro-4'-thionucleosides (D- and L-3'F
      4'Sd4Ns) were synthesized for the studies of structure-activity relationships.
      The synthesized D-2',3'-unsaturated 3'-fluoro-4'-thionucleosides did not show any
      significant antiviral activity against HIV-1, while unnatural L-nucleosides such
      as cytosine 34 (EC(50) = 0.13 microM; EC(90) = 1.7 microM) and 5-fluorocytosine
      35 (EC(50) = 0.031 microM; EC(90) = 0.35 microM) derivatives exhibited potent
      anti-HIV activity without significant toxicity. Molecular modeling study shows
      that the 3'-fluorine atom of the d-2',3'-unsaturated cytidine triphosphate (D-3'F
      4'Sd4CTP) experiences unfavorable electrostatic interaction with its own
      triphosphate moiety, resulting in the decreased binding affinity to wild-type HIV
      1 reverse transcriptase (RT), which may be one of the reasons for the
      insensitivity of HIV-1 RT to these compounds. On the other hand, L-3'F-4'Sd4CTP
      binds to the active site of wild-type HIV-1 RT without steric hindrance and there
      is a possible hydrogen bonding between the 3'-fluorine atom and Asp185, which
      correlates with its potent anti-HIV activity. However, L-3'F-4'Sd4C 34 and L-3'F
      4'Sd4FC 35 showed high cross-resistance to 3TC-resistant mutant (M184V) RT. Like
      other unnatural L-nucleosides, the unfavorable steric hindrance of the sugar
      moiety of L-3'F-4'Sd4CTP with the side chain of Val184 explains its significant
      cross-resistance to the M184V mutant.

PMID- 15027855
TI  - Countering cooperative effects in protease inhibitors using constrained beta
      strand-mimicking templates in focused combinatorial libraries.
AB  - A major problem in de novo design of enzyme inhibitors is the unpredictability of
      the induced fit, with the shape of both ligand and enzyme changing cooperatively
      and unpredictably in response to subtle structural changes within a ligand. We
      have investigated the possibility of dampening the induced fit by using a
      constrained template as a replacement for adjoining segments of a ligand. The
      template preorganizes the ligand structure, thereby organizing the local enzyme
      environment. To test this approach, we used templates consisting of constrained
      cyclic tripeptides, formed through side chain to main chain linkages, as
      structural mimics of the protease-bound extended beta-strand conformation of
      three adjoining amino acid residues at the N- or C-terminal sides of the scissile
      bond of substrates. The macrocyclic templates were derivatized to a range of 30
      structurally diverse molecules via focused combinatorial variation of nonpeptidic
      appendages incorporating a hydroxyethylamine transition-state isostere. Most
      compounds in the library were potent inhibitors of the test protease (HIV-1
      protease). Comparison of crystal structures for five protease-inhibitor complexes
      containing an N-terminal macrocycle and three protease-inhibitor complexes
      containing a C-terminal macrocycle establishes that the macrocycles fix their
      surrounding enzyme environment, thereby permitting independent variation of
      acyclic inhibitor components with only local disturbances to the protease. In
      this way, the location in the protease of various acyclic fragments on either
      side of the macrocyclic template can be accurately predicted. This type of
      templating strategy minimizes the problem of induced fit, reducing unpredictable
      cooperative effects in one inhibitor region caused by changes to adjacent enzyme
      inhibitor interactions. This idea might be exploited in template-based approaches
      to inhibitors of other proteases, where a beta-strand mimetic is also required
      for recognition, and also other protein-binding ligands where different templates
      may be more appropriate.

PMID- 15027856
TI  - Unraveling the active conformation of urotensin II.
AB  - Urotensin II (U-II) is a disulfide-bridged undecapeptide recently identified as
      the ligand of an orphan G-protein-coupled receptor. Human U-II (H-Glu-Thr-Pro-Asp
      cyclo[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) has been described as the most potent
      vasoconstrictor compound identified to date. With the aim of elucidating the
      active conformation of hU-II, we have performed a spectroscopic analysis of hU-II
      minimal active fragment hU-II(4-11) in different environmental conditions. The
      analysis indicated that hU-II(4-11) was highly structured in the anisotropic
      membrane mimetic SDS solution, showing a type II' beta-turn structure, which is
      almost unprecedented for L-amino acid peptides. Micelle bound structure of hU
      II(4-11) was then compared with those of four synthetic analogues recently
      synthesized in our lab, bearing modified Cys residues at position 5 and/or
      position 10 and characterized by different levels of agonist activity. The
      structures of the active compounds were found to be very similar to that of hU
      II(4-11), while a barely active compound does not show any propensity to beta
      turn formation. Furthermore, distances among putative pharmacophoric points in
      the structures of the active compounds obtained in SDS solution are in good
      agreement with those found in a recently described non-peptide agonist of the hU
      II receptor. A type II' beta-turn structure was already found for the
      somatostatin analogue octreotide. On the basis of the similarity of the primary
      and 3D structures of U-II and somatostatin analogues and on the basis of the
      sequence homology between the GPR14/UT-II receptor and members of the
      somatostatin receptor family, a common evolutionary pathway for the signal
      transmission system activated by these peptide can be hypothesized.

PMID- 15027857
TI  - 2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X
      ray crystallography, and biological activity.
AB  - Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol
      5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent
      kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims
      were to optimize potency and to evaluate the cellular mode of action of lead
      candidate molecules. Here the synthetic chemistry, the structure-guided design
      approach, and the structure-activity relationships (SARs) that led to the
      discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2
      inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore,
      X-ray crystal structures of four representative analogues from our chemical
      series in complex with CDK2 are presented, and these structures are used to
      rationalize the observed biochemical SARs. Finally results are reported that
      show, using the most potent CDK2 inhibitor compound from the current series, that
      the observed antiproliferative and proapoptotic effects are consistent with
      cellular CDK2 and CDK9 inhibition.

PMID- 15027859
TI  - Validation of molecular docking calculations involving FGF-1 and FGF-2.
AB  - A predictive relationship between calculated and observed binding affinities for
      the complexation of ligands to the fibroblast growth factors FGF-1 and FGF-2
      based on molecular docking calculations is described. The majority of the ligands
      examined in this study have high conformational flexibility, and to account for
      this, multiple conformers were generated for each and subsequently used in
      flexible docking calculations. Two scoring functions, Gscore and Emodel, were
      used to quantify the protein:ligand interaction of which the Emodel score showed
      the best correlation with experimental binding energies. Both scoring functions,
      however, predicted similar locations for the ligand sulfate groups in the binding
      site. The van der Waals radii of nonpolar atoms of both the protein and ligand,
      which modify the effective sizes of both the protein binding site and the ligand,
      were also systematically altered by factors of 1.0, 0.9, and 0.8 in order to
      optimize the conditions for predictive docking. Least squares analyses of the
      Emodel scores against experimental binding energies yielded best r(2) values of
      0.91 and 0.83 for FGF-1 and FGF-2, respectively, with slightly lower q(2) values.
      Optimized scale factor combinations in conjunction with the least squares lines
      of best fit based on the Emodel function were used to define a predictive model
      that was tested against ligands not included in the original set. Acceptable
      predictions of binding affinity were obtained for use in the initial screening of
      potential leadlike molecules for both FGF-1 and FGF-2.

PMID- 15027858
TI  - Synthesis and monoamine transporter binding of 2-(diarylmethoxymethyl)-3 beta
      aryltropane derivatives.
AB  - 3 beta-Aryltropane analogues wherein the 2-position was substituted with various
      diarylmethoxyalkyl groups were synthesized and evaluated for binding at the
      dopamine transporter (DAT), serotonin transporter (SERT), norepinephrine
      transporter (NET), and muscarinic (M(1)) receptors. The 2 beta-analogues 9a-i
      generally demonstrated high to moderate binding affinities (K(i) = 34-112 nM) at
      the DAT with good selectivity over SERT, NET, and M(1) receptors. Alternatively,
      the 2 alpha-isomers 10a-i were 10-fold less potent at the DAT with poor
      selectivity over SERT. These SAR studies provide further evidence for the varied
      binding requirements of structurally diverse tropane-based ligands and support
      future studies to elucidate DAT binding requirements in relation to cocaine-like
      behavioral endpoints.

PMID- 15027861
TI  - Discovery of a potent and novel motilin agonist.
AB  - A novel series of dihydro- and tetrahydrotriazolopyridazine-1,3-dione-based amino
      acid derivatives were identified as very potent motilin receptor agonists.
      Incorporating one additional phenylethyl glycinamide subunit to 1 (EC(50) = 660
      nM) was found to improve in vitro potency approximately 3000-fold, resulting in
      compound 10 (EC(50) = 0.22 nM). The more potent enantiomer 11A has an EC(50) of
      0.047 nM in the motilin receptor functional assay and a K(i) of 0.7 nM in the
      binding assay. In addition, compound 11A was shown to have a significantly
      reduced tendency to cause receptor desensitization as compared with the motilin
      receptor agonist ABT-229.

PMID- 15027860
TI  - Enzymatic release of antitumor ether lipids by specific phospholipase A2
      activation of liposome-forming prodrugs.
AB  - An enzymatically activated liposome-based drug-delivery concept involving masked
      antitumor ether lipids (AELs) has been investigated. This concept takes advantage
      of the cytotoxic properties of AEL drugs as well as the membrane permeability
      enhancing properties of these molecules, which can lead to enhanced drug
      diffusion into cells. Three prodrugs of AELs (proAELs) have been synthesized and
      four liposome systems, consisting of these proAELs, were investigated for
      enzymatic degradation by secretory phospholipase A(2) (sPLA(2)), resulting in the
      release of AELs. The three synthesized proAELs were (R)-1-O-hexadecyl-2-palmitoyl
      sn-glycero-3-phosphocholine (1-O-DPPC), (R)-1-O-hexadecyl-2-palmitoyl-sn-glycero
      3-phosphoethanolamine poly(ethylene glycol)(350) (1-O-DPPE-PEG(350)), and 1-O
      DPPE-PEG(2000) of which 1-O-DPPC was the main liposome component. All three
      phospholipids were synthesized from the versatile starting material (R)-O-benzyl
      glycidol. A phosphorylation method, employing methyl dichlorophosphate, was
      developed and applied in the synthesis of two analogues of (R)-1-O-hexadecyl-2
      palmitoyl-sn-glycero-3-phosphoethanolamine poly(ethylene glycol). Differential
      scanning calorimetry has been used to investigate the phase behavior of the lipid
      bilayers. A release study, employing calcein encapsulated in non-hydrolyzable 1,2
      bis-O-octadecyl-sn-glycero-3-phosphocholine (D-O-SPC) liposomes, showed that
      proAELs, activated by sPLA(2), perturb membranes because of the detergent-like
      properties of the released hydrolysis products. A hemolysis investigation was
      conducted on human red blood cells, and the results demonstrate that proAEL
      liposomes display a very low hemotoxicity, which has been a major obstacle for
      using AELs in cancer therapy. The results suggest a possible way of combining a
      drug-delivery and prodrug concept in a single liposome system. Our investigation
      of the permeability-enhancing properties of the AEL molecules imply that by
      encapsulating conventional chemotherapeutic drugs, such as doxorubicin, in
      liposomes consisting of proAELs, an increased effect of the encapsulated drug
      might be achievable due to an enhanced transmembrane drug diffusion.

PMID- 15027862
TI  - Discovery of potent inhibitors of dihydroneopterin aldolase using CrystaLEAD high
      throughput X-ray crystallographic screening and structure-directed lead
      optimization.
AB  - Potent inhibitors of 7,8-dihydroneopterin aldolase (DHNA; EC 4.1.2.25) have been
      discovered using CrystaLEAD X-ray crystallographic high-throughput screening
      followed by structure-directed optimization. Screening of a 10 000 compound
      random library provided several low affinity leads and their corresponding X-ray
      crystal structures bound to the enzyme. The presence of a common structural
      feature in each of the leads suggested a strategy for the construction of a
      directed library of approximately 1000 compounds that were screened for
      inhibitory activity in a traditional enzyme assay. Several lead compounds with
      IC(50) values of about 1 microM against DHNA were identified, and crystal
      structures of their enzyme-bound complexes were obtained by cocrystallization.
      Structure-directed optimization of one of the leads thus identified afforded
      potent inhibitors with submicromolar IC(50) values.

PMID- 15027863
TI  - N-(cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2.
      N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-
      piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor
      agent.
AB  - N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic
      amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit
      antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1
      dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS
      387032], has been identified as an ATP-competitive and CDK2-selective inhibitor
      which has been selected to enter Phase 1 human clinical trials as an antitumor
      agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was
      10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also
      highly selective over a panel of 12 unrelated kinases. Antiproliferative activity
      was established in an A2780 cellular cytotoxicity assay in which 21 showed an
      IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a
      plasma half-life of 5-7 h in three species and moderately low protein binding in
      both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21
      showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in
      mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior
      efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor
      model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.

PMID- 15027864
TI  - Synthesis of urea-based inhibitors as active site probes of glutamate
      carboxypeptidase II: efficacy as analgesic agents.
AB  - The neuropeptidase glutamate carboxypeptidase II (GCPII) hydrolyzes N-acetyl-L
      aspartyl-L-glutamate (NAAG) to liberate N-acetylaspartate and glutamate. GCPII
      was originally cloned as PSMA, an M(r) 100,000 type II transmembrane glycoprotein
      highly expressed in prostate tissues. PSMA/GCPII is located on the short arm of
      chromosome 11 and functions as both a folate hydrolase and a neuropeptidase.
      Inhibition of brain GCPII may have therapeutic potential in the treatment of
      certain disease states arising from pathologically overactivated glutamate
      receptors. Recently, we reported that certain urea-based structures act as potent
      inhibitors of GCPII (J. Med. Chem. 2001, 44, 298). However, many of the potent
      GCPII inhibitors prepared to date are highly polar compounds and therefore do not
      readily penetrate the blood-brain barrier. Herein, we elaborate on the synthesis
      of a series of potent, urea-based GCPII inhibitors from the lead compound 3 and
      provide assay data for these ligands against human GCPII. Moreover, we provide
      data revealing the ability of one of these compounds, namely, 8d, to reduce the
      perception of inflammatory pain. Within the present series, the gamma-tetrazole
      bearing glutamate isostere 7d is the most potent inhibitor with a K(i) of 0.9 nM.
      The biological evaluation of these compounds revealed that the active site of
      GCPII likely comprises two regions, namely, the pharmacophore subpocket and the
      nonpharmacophore subpocket. The pharmacophore subpocket is very sensitive to
      structural changes, and thus, it appears important to keep one of the glutamic
      acid moieties intact to maintain the potency of the GCPII inhibitors. The site
      encompassing the nonpharmacophore subpocket that binds to glutamate's alpha
      carboxyl group is sensitive to structural change, as shown by compounds 6b and
      7b. However, the other region of the nonpharmacophore subpocket can accommodate
      both hydrophobic and hydrophilic groups. Thus, an aromatic ring can be introduced
      to the inhibitor, as in 8b and 8d, thereby increasing its hydrophobicity and thus
      potentially its ability to cross the blood-brain barrier. Intrathecally
      administered 8d significantly reduced pain perception in the formalin model of
      rat sensory nerve injury. A maximal dose of morphine (10 mg) applied in the same
      experimental paradigm provided no significant increase in analgesia in comparison
      to 8d during phase 1 of this pain study and modestly greater analgesia than 8d in
      phase 2. These urea-based inhibitors of GCPII thus offer a novel approach to pain
      management.

PMID- 15027865
TI  - Glide: a new approach for rapid, accurate docking and scoring. 1. Method and
      assessment of docking accuracy.
AB  - Unlike other methods for docking ligands to the rigid 3D structure of a known
      protein receptor, Glide approximates a complete systematic search of the
      conformational, orientational, and positional space of the docked ligand. In this
      search, an initial rough positioning and scoring phase that dramatically narrows
      the search space is followed by torsionally flexible energy optimization on an
      OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The
      very best candidates are further refined via a Monte Carlo sampling of pose
      conformation; in some cases, this is crucial to obtaining an accurate docked
      pose. Selection of the best docked pose uses a model energy function that
      combines empirical and force-field-based terms. Docking accuracy is assessed by
      redocking ligands from 282 cocrystallized PDB complexes starting from
      conformationally optimized ligand geometries that bear no memory of the correctly
      docked pose. Errors in geometry for the top-ranked pose are less than 1 A in
      nearly half of the cases and are greater than 2 A in only about one-third of
      them. Comparisons to published data on rms deviations show that Glide is nearly
      twice as accurate as GOLD and more than twice as accurate as FlexX for ligands
      having up to 20 rotatable bonds. Glide is also found to be more accurate than the
      recently described Surflex method.

PMID- 15027866
TI  - Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment
      factors in database screening.
AB  - Glide's ability to identify active compounds in a database screen is
      characterized by applying Glide to a diverse set of nine protein receptors. In
      many cases, two, or even three, protein sites are employed to probe the
      sensitivity of the results to the site geometry. To make the database screens as
      realistic as possible, the screens use sets of "druglike" decoy ligands that have
      been selected to be representative of what we believe is likely to be found in
      the compound collection of a pharmaceutical or biotechnology company. Results are
      presented for releases 1.8, 2.0, and 2.5 of Glide. The comparisons show that
      average measures for both "early" and "global" enrichment for Glide 2.5 are 3
      times higher than for Glide 1.8 and more than 2 times higher than for Glide 2.0
      because of better results for the least well-handled screens. This improvement in
      enrichment stems largely from the better balance of the more widely parametrized
      GlideScore 2.5 function and the inclusion of terms that penalize ligand-protein
      interactions that violate established principles of physical chemistry,
      particularly as it concerns the exposure to solvent of charged protein and ligand
      groups. Comparisons to results for the thymidine kinase and estrogen receptors
      published by Rognan and co-workers (J. Med. Chem. 2000, 43, 4759-4767) show that
      Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.

PMID- 15027867
TI  - Inactivation of purified human recombinant monoamine oxidases A and B by
      rasagiline and its analogues.
AB  - The inactivation of purified human recombinant monoamine oxidases (MAO) A and B
      by rasagiline [N-propargyl-1(R)-aminoindan] and four of its analogues [N
      propargyl-1(S)-aminoindan (S-PAI), 6-hydroxy-N-propargyl-1(R)-aminoindan (R
      HPAI), N-methyl-N-propargyl-1(R)-aminoindan (R-MPAI), and 6-(N-methyl-N-ethyl
      carbamoyloxy)-N-propargyl-1(R)-aminoindan (R-CPAI)] has been investigated. All
      compounds tested, with the exception of R-CPAI, form stoichiometric N(5)
      flavocyanine adducts with the FAD moiety of either enzyme. No H(2)O(2) is
      produced during either MAO A or MAO B inactivation, which demonstrates that
      covalent addition occurs in a single turnover. Rasagiline has the highest
      specificity for MAO B, as demonstrated by a 100-fold higher inhibition potency
      (k(inact)/K(i)) compared to MAO A, with the remaining compounds exhibiting lower
      isozyme specificities. MAO B and MAO A are more selective for the R-enantiomer
      (rasagiline) compared to the S-enantiomer (S-PAI) by 2500-fold and 17-fold,
      respectively. Differences in UV/vis and CD spectral data of the complexes of the
      studied compounds with both MAO A and MAO B are interpreted in light of
      crystallographic data of complexes of MAO B with rasagiline and its analogues
      (Binda, C.; et al. J. Med. Chem. 2004, 47, 1767-1774.

PMID- 15027868
TI  - Crystal structures of monoamine oxidase B in complex with four inhibitors of the
      N-propargylaminoindan class.
AB  - Monoamine oxidase B (MAO B) is an outer mitochondrial membrane enzyme that
      catalyzes the oxidation of arylalkylamine neurotransmitters. The crystal
      structures of MAO B in complex with four of the N-propargylaminoindan class of
      MAO covalent inhibitors (rasagiline, N-propargyl-1(S)-aminoindan, 6-hydroxy-N
      propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan) have been
      determined at a resolution of better than 2.1 A. Rasagiline, 6-hydroxy-N
      propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan adopt
      essentially the same conformation with the extended propargyl chain covalently
      bound to the flavin and the indan ring located in the rear of the substrate
      cavity. N-Propargyl-1(S)-aminoindan binds with the indan ring in a flipped
      conformation with respect to the other inhibitors, which causes a slight movement
      of the Tyr326 side chain. Four ordered water molecules are an integral part of
      the active site and establish H-bond interactions to the inhibitor atoms. These
      structural studies may guide future drug design to improve selectivity and
      efficacy by introducing appropriate substituents on the rasagiline molecular
      scaffold.

PMID- 15027869
TI  - Antineoplastic agents. 499. Synthesis of hystatin 2 and related 1H-benzo[de][1,6]
      naphthyridinium salts from aaptamine.
AB  - The marine sponge constituent aaptamine (1) has been converted to the cancer cell
      growth inhibitor and antibiotic designated hystatin 2 (8a). Herein, we also
      report results of an initial SAR evaluation of new benzyl derivatives of
      aaptamine (1). Single benzylation was found to occur at nitrogen N-4 and led to
      the formation of the 4-benzylaaptamine derivatives 7a-c, whereas double
      benzylation gave the quaternary 1H-benzo[de][1,6]-naphthyridinium salts 8a-c. The
      anticancer and antimicrobial properties of these aaptamine derivatives are
      described. The quaternary ammonium salts 8a (hystatin 2) and 8b exhibited
      significant inhibitory activity against the murine P388 lymphocytic leukemia and
      a minipanel of human cancer cell lines. Salts 8a and 8b also had broad spectrum
      antimicrobial activities and were most potent against Mycobacterium tuberculosis,
      Neisseria gonorrhoeae, and Micrococcus luteus. Naphthyridinium chloride 8a was
      selected for further development, and results of an initial cell cycle analysis
      and a cDNA microarray study showed effects consistent with inhibition of the S
      phase of cell growth.

PMID- 15027870
TI  - Surface activity profiling of drugs applied to the prediction of blood-brain
      barrier permeability.
AB  - The present study describes a novel in vitro platform for physicochemical
      profiling of compounds, based on their impact on the air/water interfacial
      tension. Interfacial partitioning coefficient, cross-sectional area, and critical
      micelle concentration were derived from the Gibbs adsorption isotherms recorded
      for 76 structurally diverse drugs. An approximation for the membrane partitioning
      coefficient, K(memb), is introduced and calculated for the measured compounds.
      This methodology provides a fully automatic, high-throughput screening technique
      for compound characterization, yielding precise thermodynamic information on the
      partitioning behavior of molecules at air/water interfaces, which can be directly
      related to their anisotropic interaction with lipid bilayers in biological
      membranes. The latter represents the barrier for the passive entry of compounds
      into cells. The surface activity profiles are shown to correlate to the ability
      of the compounds to pass passively through the blood-brain barrier.

PMID- 15027871
TI  - Synthesis and biological evaluation in human monocyte-derived macrophages of N-(N
      acetyl-L-cysteinyl)-S-acetylcysteamine analogues with potent antioxidant and anti
      HIV activities.
AB  - We synthesized a series of N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine (10)
      analogues bearing various acyl groups on thiol cysteine or cysteamine residues,
      to investigate the structure-activity relationship for pro-GSH and anti-HIV
      properties in human macrophages. The S-substituents were ranked in the following
      order of efficacy: H > or = acetyl > isobutyryl > pivaloyl > benzoyl. We found
      that none of these derivatives had pro-GSH or antiviral activities in vitro
      higher than that of 10, but several displayed similar levels of anti-HIV
      activity, making them possible candidates for use as adjuvant therapies in
      conjunction with HAART, for treating neurological aspects of HIV infection.

PMID- 15027872
TI  - Fluorinated phenylcyclopropylamines. 1. Synthesis and effect of fluorine
      substitution at the cyclopropane ring on inhibition of microbial tyramine
      oxidase.
AB  - Two series of diastereopure phenylcyclopropylamine analogues, 2-fluoro-2
      phenylcyclopropylamines and 2-fluoro-2-phenylcyclopropylalkylamines, as well as 2
      fluoro-1-phenylcyclopropylamines and 2-fluoro-1-phenylcyclopropylmethylamines,
      were synthesized in order to study the effects of fluorine substitution on
      monoamine oxidase inhibition. Inhibitory activity was assayed using commercially
      available microbial tyramine oxidase. Characterization of tyramine oxidase,
      carried out prior to the inhibition experiments, confirmed earlier suggestions
      that this enzyme is a semicarbazide-sensitive copper-containing monoamine
      oxidase. The most potent competitive inhibitor was trans-2-fluoro-2
      phenylcyclopropylamine, which had an IC(50) value 10 times lower than that of the
      nonfluorinated compound, tranylcypromine. 2-Fluoro-1-phenylcyclopropylmethylamine
      was found to be a weak noncompetitive inhibitor of tyramine oxidase. The presence
      of a free amino group, directly bonded to the cyclopropane ring, and a fluorine
      atom in a relationship cis to the amino group were structural features that
      increased tyramine oxidase inhibition.

PMID- 15027873
TI  - 3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and analogues:
      high-affinity gamma-aminobutyric acid-A benzodiazepine receptor ligands with
      alpha 2, alpha 3, and alpha 5-subtype binding selectivity over alpha 1.
AB  - Studies with our screening lead 5 and the literature compound 6 led to the
      identification of 6-benzyloxy-3-(4-methoxy)phenyl-1,2,4-triazolo[3,4
      a]phthalazine 8 as a ligand with binding selectivity for the gamma-aminobutyric
      acid-A (GABA-A) alpha 3- and alpha 5-containing receptor subtypes over the GABA-A
      alpha 1 subtype (K(i): alpha 2 = 850 nM, alpha 3 = 170 nM, alpha 5 = 72 nM, alpha
      1 = 1400 nM). Early optimization studies identified the close analogue 10 (K(i):
      alpha 2 = 16 nM, alpha 3 = 41 nM, alpha 5 = 38 nM, alpha 1 = 280 nM) as a
      suitable lead for further study. High-affinity ligands were identified by
      replacing the 6-benzyloxy group of compound 10 with 2-pyridylmethoxy (compound
      29), but binding selectivity was not enhanced (K(i): alpha 2 = 1.7 nM, alpha 3 =
      0.71 nM, alpha 5 = 0.33 nM, alpha 1 = 2.7 nM). Furthermore, on evaluation in
      xenopus oocytes,(22) 29 was discovered to be a weak to moderate inverse agonist
      at all four receptor subtypes (alpha 1, -7%; alpha 2, -5%; alpha 3, -16%; alpha
      5, -5%). Replacement of the 3-phenyl group of 29 with alternatives led to reduced
      affinity, and smaller 3-substituents led to reduced efficacy. Methyl substitution
      of the benzo-fused ring of 29 at the 7-, 8-, and 10-positions resulted in
      increased efficacy although selectivity was abolished. Increased efficacy and
      retention of selectivity for alpha 3 over alpha 1 was achieved with the 7,8,9,10
      tetrahydro-(7,10-ethano)-phthalazine 62. Compound 62 is currently one of the most
      binding selective GABA-A alpha 3-benzodiazepine-site partial agonists known, and
      although its selectivity is limited, its good pharmacokinetic profile in the rat
      (33% oral bioavailability after a 3 mg/kg dose, reaching a peak plasma
      concentration of 179 ng/mL; half-life of 1 h) made it a useful pharmacological
      tool to explore the effect of a GABA-A alpha 2/alpha 3 agonist in vivo.

PMID- 15027874
TI  - Synthesis and antitubulin activity of N1- and N4-substituted 3,5-dinitro
      sulfanilamides against African trypanosomes and Leishmania.
AB  - Thirty analogues of N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-propylsulfanilamide
      (GB-II-5, compound 3), a new antikinetoplastid antimitotic agent, have been
      synthesized and evaluated. The addition of simple functional groups to the N1
      aromatic ring generally decreases antiparasitic and antimitotic potency, but
      placement of a dibutyl substituent at the N4 nitrogen to give N(1)-phenyl-3,5
      dinitro-N(4),N(4)-di-n-butylsulfanilamide (compound 35) augments antitrypanosomal
      and antileishmanial activity. Compound 35 possesses IC(50) values of 0.12 and 2.6
      microM against cultured T. brucei and L. donovani amastigote-like forms,
      surpassing the activity of compound 3 against these parasites by 3.4- and 1.9
      fold, respectively. Compound 35 inhibits the assembly of leishmanial tubulin with
      an IC(50) of 6.9 microM and displays antimitotic effects in cultured T. brucei as
      assessed by flow cytometry, but shows little effect on purified mammalian
      tubulin, and displays 100-fold selectivity for trypanosomes over two mammalian
      cell lines. Although 3 and 35 were not effective in initial in vivo
      antitrypanosomal assays, the in vitro potency and selectivity of these compounds
      make N(1)-aryl-3,5-dinitro-N(4),N(4)-dialkylsulfanilamides a promising new class
      of antikinetoplastid agents that act on parasite tubulin.

PMID- 15027875
TI  - Novel endoperoxide antimalarials: synthesis, heme binding, and antimalarial
      activity.
AB  - We report the synthesis of a series of novel epoxy endoperoxide compounds that
      can be prepared in high yields in one to three steps from simple starting
      materials. Some of these compounds inhibit the growth of Plasmodium falciparum in
      vitro. Structure-activity studies indicate that an endoperoxide ring
      bisubstituted with saturated cyclic moieties is the pharmacophore. To study the
      molecular basis of the action of these novel antimalarial compounds, we examined
      their ability to interact with oxidized and reduced forms of heme. Some of the
      compounds interact with oxidized heme in a fashion similar to chloroquine and
      other 4-aminoquinolines, while some of the compounds interact with reduced heme.
      However, the level of antimalarial potency is not well correlated with these
      activities, suggesting that some of the endoperoxides may exert their
      antimalarial activities by a novel mechanism of action.

PMID- 15027876
TI  - Design and synthesis of 3'- and 5'-O-(3-benzenesulfonylfuroxan-4-yl)-2'
      deoxyuridines: biological evaluation as hybrid nitric oxide donor-nucleoside
      anticancer agents.
AB  - A group of 3'-O- and 5'-O-(3-benzenesulfonylfuroxan-4-yl)-2'-deoxyuridines
      possessing a variety of substituents (H, Me, I, F, CF(3)) at the C-5 position of
      the nucleoside moiety were synthesized for evaluation as hybrid anticancer agents
      that have the ability to simultaneously release cytotoxic nitric oxide (*NO).
      Incubation of these nitric oxide donor-nucleoside conjugates in the presence of
      18 mM L-cysteine released a high percentage of *NO (21-48% at 1 h; 37-86% at 16
      h). The release of *NO in the absence of the thiol cofactor was negligible. These
      hybrid *NO donor-nucleosides exhibited high cellular toxicity (CC(50) = 10(-6)
      10(-8) M range) against a battery of tumor cell lines (143B-LTK, 143B, EMT-6,
      KBALB-STK, and KBALB) and normal human fibroblasts (Hs578Bst). No differences in
      cytotoxicity between nontransfected (143B, KBALB) and the corresponding
      transfected (143B-LTK, KBALB-STK) cancer cell lines possessing the herpes simplex
      virus type 1 (HSV-1) thymidine kinase gene (TK(+)) were observed, indicating that
      expression of the viral TK enzyme did not provide a gene therapeutic effect.

PMID- 15027877
TI  - Discovery of a new family of inhibitors of human cytomegalovirus (HCMV) based
      upon lipophilic alkyl furano pyrimidine dideoxy nucleosides: action via a novel
      non-nucleosidic mechanism.
AB  - Following our discovery of the potent anti-varicella zoster virus action of
      lipophilic alkyl furano pyrimidine 2'-deoxynucleosides, we now report that 2',3'
      dideoxy sugar analogues are devoid of anti-VZV activity but are potent and
      selective inhibitors of human cytomegalovirus (HCMV). The present compounds are
      active in vitro at ca. 1 microM with cytotoxicity only above 200 microM.
      Importantly, we have discovered that the new agents do not act as nucleoside
      analogues, despite their nucleosidic structure, and time of addition studies
      revealed that the compounds may inhibit HCMV at an event in the replication cycle
      of the virus that precedes DNA synthesis. They represent new leads in the
      discovery of improved therapies for HCMV, particularly in view of their novel
      mechanism of action.

PMID- 15027878
TI  - N,N-dialkyl-2-phenylindol-3-ylglyoxylamides. A new class of potent and selective
      ligands at the peripheral benzodiazepine receptor.
AB  - We report the synthesis and the affinity data at both the peripheral (PBR) and
      the central benzodiazepine receptors of a series of N,N-dialkyl-2-phenylindol-3
      ylglyoxylamide derivatives III, designed as conformationally constrained
      analogues of 2-phenylindole-3-acetamides II such as FGIN-1-27. Most of the new
      compounds showed a high specificity and affinity for PBR, with K(i) in the
      nanomolar to subnanomolar range. The most potent ligands (4-7, 9, 13-27)
      stimulated steroid biosynthesis in rat C6 glioma cells with a potency similar to
      or higher than that of classical ligands. The SARs of this new class of compounds
      are discussed.

PMID- 15027879
TI  - Synthesis and biological evaluation of novel chloroethylaminoanthraquinones with
      potent cytotoxic activity against cisplatin-resistant tumor cells.
AB  - Novel 1- and 1,4-substituted chloroethylaminoanthraquinones with DNA binding and
      alkylating properties along with their respective hydroxyethylaminoanthraquinone
      intermediates were synthesized. Selected chloroethylaminoanthraquinones were
      shown to cross-link DNA and alkylate guanines (at low nM concentration) with a
      preference for reaction sites containing 5'-PyG. A compound (Alchemix) with the
      bis-chloroethyl functionality confined to one side chain alkylated but did not
      cross-link DNA. All the 1,4-disubstituted chloroethylaminoanthraquinones were
      potently cytotoxic (nM IC(50)s) against cisplatin-resistant ovarian cancer cell
      lines.

PMID- 15027880
TI  - QSAR study of anticonvulsant negative allosteric modulators of the AMPA receptor.
AB  - A quantitative structure-activity relationship (QSAR) study was performed on a
      set of 49 negative allosteric modulators of AMPA receptor, acting as
      anticonvulsant agents, using multiple linear regression. The predictive ability
      of the resulting model was evaluated against a set of 12 compounds; the results
      showed good statistics in regression and revealed high correlation between
      anticonvulsant activity and some electrotopological descriptors.

PMID- 15027881
TI  - Structure-activity study of the ORL1 antagonist Ac-Arg-D-Cha-Qaa-D-Arg-D-p-ClPhe
      NH2.
AB  - The structure-activity requirements of the ORL1 antagonist Ac-Arg-D-Cha-Qaa-D-Arg
      D-p-ClPhe-NH(2) 4 were investigated by varying the position, structure, and
      charge of the Arg residues. Attempts to abridge the peptide by removal of the
      Arg, D-Cha, and D-p-ClPhe residues abolished affinity for the ORL1 receptor,
      whereas deletion of the acetamido N-terminus maintained receptor affinity and
      selectivity. This series of analogues has provided an improved potent and
      selective ORL1 receptor antagonist, Ac-Cit-D-Cha-Qaa-D-Arg-D-p-ClPhe-NH(2).

PMID- 15027882
TI  - Neuroendocrine tumours.
AB  - Neuroendocrine tumours are a heterogeneous group including, for example,
      carcinoid, gastroenteropancreatic neuroendocrine tumours, pituitary tumours,
      medullary carcinoma of the thyroid and phaeochromocytomas. They have attracted
      much attention in recent years, both because they are relatively easy to palliate
      and because they have indicated the chronic effect of the particular hormone
      elevated. As neuroendocrine phenotypes became better understood, the definition
      of neuroendocrine cells changed and is now accepted as referring to cells with
      neurotransmitter, neuromodulator or neuropeptide hormone production, dense-core
      secretory granules, and the absence of axons and synapses. Neuroendocrine
      markers, particularly chromogranin A, are invaluable diagnostically. Study of
      several neuroendocrine tumours has revealed a genetic etiology, and techniques
      such as genetic screening have allowed risk stratification and prevention of
      morbidity in patients carrying the particular mutation. Pharmacological therapy
      for these often slow-growing tumours, e.g. with somatostatin analogues, has
      dramatically improved symptom control, and radiolabelled somatostatin analogues
      offer targeted therapy for metastatic or inoperable disease. In this review, the
      diagnosis and management of patients with carcinoid, gut neuroendocrine tumours,
      multiple endocrine neoplasia types 1 and 2, and isolated phaeochromocytoma are
      evaluated.

PMID- 15027883
TI  - Considerations concerning a tailored, individualized therapeutic management of
      patients with (neuro)endocrine tumours of the gastrointestinal tract and
      pancreas.
AB  - Endocrine tumours of the gastrointestinal tract and pancreas may present at
      different disease stages with either hormonal or hormone-related
      symptoms/syndromes, or without hormonal symptoms. They may occur either
      sporadically or as part of hereditary syndromes. In the therapeutic approach to a
      patient with these tumours, excessive hormonal secretion and/or its effects
      should always be controlled first. Tumour-related deficiencies or disorders
      should also be corrected. Subsequently, control should be aimed at the tumour
      growth. Surgery is generally considered as first-line therapy for patients with
      localized disease, as it can be curative. However, in patients with metastatic
      disease the role of first-line surgery is not clearly established and other
      therapies should be considered, such as non-surgical cytoreductive therapies,
      biotherapy (with somatostatin analogues or interferon-alpha), embolization and
      chemoembolization of liver metastases, chemotherapy (with single or multiple dose
      regimens) and peptide receptor-targeted radiotherapy. The delicate balance of the
      use of the different therapeutical options in patients with endocrine tumours of
      the gastrointestinal tract and pancreas emphasizes the importance of team
      approach and team expertise.

PMID- 15027884
TI  - Inhibin/activin and ovarian cancer.
AB  - Inhibin and activin are members of the transforming growth factor beta (TGFbeta)
      family of cytokines produced by the gonads, with a recognised role in regulating
      pituitary FSH secretion. Inhibin consists of two homologous subunits, alpha and
      either betaA or betaB (inhibin A and B). Activins are hetero- or homodimers of
      the beta-subunits. Inhibin and free alpha subunit are known products of two
      ovarian tumours (granulosa cell tumours and mucinous carcinomas). This
      observation has provided the basis for the development of a serum diagnostic test
      to monitor the occurrence and treatment of these cancers. Transgenic mice with an
      inhibin alpha subunit gene deletion develop stromal/granulosa cell tumours
      suggesting that the alpha subunit is a tumour suppressor gene. The role of
      inhibin and activin is reviewed in ovarian cancer both as a measure of proven
      clinical utility in diagnosis and management and also as a factor in the
      pathogenesis of these tumours. In order to place these findings into perspective
      the biology of inhibin/activin and of other members of the TGFbeta superfamily is
      also discussed.

PMID- 15027885
TI  - Therapeutic integration of signal transduction targeting agents and conventional
      anti-cancer treatments.
AB  - The currently available treatment of cancer patients is based on the use of
      cytotoxic drugs and/or of ionizing radiations, which have potent antitumor
      activity, but also cause clinically relevant side effects, since they affect
      cellular targets that are common to both cancer cells and normal proliferating
      cells. In the past 20 years, the discoveries on the molecular mechanisms of
      cancer development and progression have prompted the search for agents which are
      more selective for cancer cell molecular targets. The possibility of combining
      conventional cytotoxic drugs with novel agents that specifically interfere with
      key pathways controlling cancer cell survival, proliferation, invasion and/or
      metastatic spreading has generated a wide interest. This could be a promising
      therapeutic approach for several reasons. First, since the cellular targets for
      these agents and their mechanism(s) of action are different from those of
      cytotoxic drugs, it is possible for their combination with chemotherapy without
      cross-resistance. Second, alterations in the expression and/or the activity of
      genes that regulate mitogenic signals not only can directly cause perturbation of
      cell growth, but also may affect the sensitivity of cancer cells to conventional
      chemotherapy and radiotherapy. In this review, we will discuss the biologic bases
      of the combination of molecular targeted drugs with conventional medical cancer
      treatments and the available results of the first series of clinical trials in
      cancer patients.

PMID- 15027886
TI  - Management of risk of breast carcinoma in postmenopausal women.
AB  - Breast carcinoma is the most frequent tumor in the female population. Many
      factors can influence the risk of breast cancer; some of them, such as old age
      and breast cancer 1/2 (BRCA1/BRCA2) gene mutations, are associated with a
      fourfold increase in risk. A previous diagnosis of atypical ductal or lobular
      hyperplasia or having a first-degree relative with a carcinoma are factors
      associated with a two- to fourfold increase in risk. A relative risk between 1
      and 2 is associated with longer exposure to endogenous hormones as a result of
      early menarche, late menopause and obesity, or with recent and prolonged use of
      hormone replacement therapy (HRT) or with behavioural factors such as high
      alcohol and fat intake. Is it possible to modify breast cancer risk in
      postmenopausal women? Risk factors related to lifestyle can be changed, even if
      it is not clear whether modifying these behavioural factors during the
      postmenopausal period will influence the overall breast cancer risk. For
      instance, the influence of exogenous hormones throughout life (both oral
      contraceptives and HRT) should be evaluated according to the individual risk
      benefit ratio. The problem is even more complex for women who carry genetic
      mutations and for those who have close relatives with breast cancer, who may be
      candidates for risk reduction strategies. Prophylactic bilateral mastectomy is
      still controversial, but is frequently offered to or requested by this group of
      women and may be indicated in BRCA1/BRCA2 carriers. Chemoprevention with
      tamoxifen and with the new selective estrogen receptor modulators, namely
      raloxifene, is very promising and deserves a thorough discussion for all high
      risk women.

PMID- 15027887
TI  - The interaction of oestrogen receptor status and pathological features with
      adjuvant treatment in relation to survival in patients with operable breast
      cancer: a retrospective study of 2660 patients.
AB  - The oestrogen receptor (ER) status of 2660 patients with primary breast cancer
      has been related to the effect of different adjuvant systemic therapies on
      survival. However, as patients in the various treatment groups also had different
      prognostic features comparison between treatments was difficult. Over 90% of
      patients receiving tamoxifen (Tam) were postmenopausal compared with <20% of
      those receiving chemotherapy (CT). The latter had more positive nodes (85% vs
      54%) and grade III tumours (54% vs 30%) than the Tam group. The combined CT and
      Tam group had similar characteristics to the CT alone group. The current reported
      increase in the proportion of women with ER+ tumours is explained by
      immunohistochemical analysis of ER and screening programmes. ER status was
      unrelated to survival in patients with small, low grade, node-negative tumours
      which was no different from that expected for age-matched women taken from the
      general population. The value of adjuvant treatment in these patients is
      therefore questionable. In those given any adjuvant treatment, survival of women
      with ER+ tumours was prolonged, with the greatest effect being seen in those
      receiving Tam. Patients with ER- tumours benefited from CT but the addition of
      Tam to CT improved survival only in those with ER+ tumours. ER status is now
      established as a major predictive factor for treatment selection in primary
      disease. Studies of prognostic and predictive markers may be invalidated by use
      of adjuvant therapy and selection criteria for different treatments. Survival
      will be influenced by both tumour biology and therapy. This important
      consideration must be remembered when analysing new markers, particularly in
      small studies.

PMID- 15027888
TI  - Controversies in the follow-up and management of well-differentiated thyroid
      cancer.
AB  - Thyroid cancer is a common malignancy with an apparent increasing incidence and a
      wide spectrum of clinical behavior and therapeutic responsiveness. Recent
      advances in diagnosis, primary treatment, and long-term monitoring have led to
      enhanced detection of primary and recurrent disease and improvements in therapy.
      Controversy still surrounds several issues: the most accurate predictive staging
      system and histological subclassification scheme, optimal preoperative assessment
      and surgical extent, appropriate use of radioiodine for remnant ablation, goal
      for thyrotropin-suppressive thyroid hormone therapy, best practices in immediate
      postoperative and long-term monitoring, and approach to the patient with
      thyroglobulin evidence of residual disease. In this paper, recent data related to
      these controversial issues are critically reviewed.

PMID- 15027889
TI  - Mechanisms of androgen receptor signalling via steroid receptor coactivator-1 in
      prostate.
AB  - The androgen receptor (AR) is a member of the nuclear receptor superfamily. These
      ligand-activated transcription factors usually contain two activation functions,
      a ligand-independent activation function 1(AF1) in the divergent N-terminal
      domain and a ligand-dependent AF2 in the more conserved C-terminal ligand-binding
      domain. To promote transcription from target promoters, DNA-bound nuclear
      receptors recruit coactivator proteins that promote transcription by modifying
      histones within nucleosomes, resulting in altered topology of chromatin to allow
      access of the basal transcriptional machinery, or stabilising the pre-initiation
      complex. It is well known that most coactivators interact with AF2 of many
      nuclear receptors via conserved, helical LxxLL motifs (where L is leucine and x
      is any amino acid). The AF2 of the AR is very weak, but we were able to
      demonstrate that its intrinsic ligand-dependent activity is potentiated by
      steroid receptor coactivator-1 (SRC1) and that this region interacts with
      coactivators via LxxLL motifs. However, a mutant SRC1 coactivator with no
      functional LxxLL motifs was still able to potentiate AR activity. We found that
      SRC1 can also be recruited to (and increase activity of) AF1 of the AR via a
      conserved, glutamine-rich region. Point mutations within this region abolish SRC1
      interaction with AF1 and also abolish or severely impair its ability to
      potentiate AR activity on all promoters tested. Thus the AR interacts with SRC1
      via two different regions and the AF1 interaction is functionally the more
      important, although the contribution of the two interactions varies in a promoter
      dependent fashion. SRC1 then potentiates receptor activity via recruitment of
      CBP/p300, a histone acetyltranferase. This is important in the context of
      prostate cancer as SRC1 and other coactivators including CBP are coexpressed with
      AR in the luminal epithelial cells of the prostate, where over 90% of prostate
      tumours arise. There is a need for effective second-line prostate cancer therapy
      aimed at blocking the AR pathway when anti-androgen therapy has failed. Since
      there is growing evidence that nuclear receptor cofactors may be implicated in
      the progression of hormone-dependent tumours to hormone-independent states, novel
      targets could include the interaction of AR with coactivator proteins. We suggest
      that the N-terminal interaction would be a more specific and effective target in
      the case of prostate cancer than the LxxLL/AF2 interaction.

PMID- 15027890
TI  - Prognostic factors of papillary and follicular thyroid cancer: differences in an
      iodine-replete endemic goiter region.
AB  - Papillary (PTC) and follicular thyroid carcinoma (FTC) are known as
      differentiated thyroid carcinoma (DTC). Nevertheless, according to the UICC/AJCC
      (TNM) classification PTC and FTC are frequently analyzed as one cancer. The aim
      of this study is to show differences in outcome and specific prognostic factors
      in an iodine-replete endemic goiter region. Six hundred and three patients with
      DTC treated within a 35-year-period were retrospectively analyzed with respect to
      carcinoma-specific survival. Prognostic factors were tested for their
      significance using univariate and multivariate analysis. The histological type
      (PTC versus FTC) was found to be a highly significant factor - carcinoma-specific
      survival both in univariate (P<0.001) and multivariate analyses (P=0.003) was
      significantly different. Univariate analysis revealed patients' age, extra
      thyroid tumor spread, lymph node and distant metastases, increasing tumor size,
      and the tall cell variant to be significant prognostic factors for PTC patients.
      Age > or =45 years, positive lymph nodes and increasing tumor size were confirmed
      as independent prognostic factors. Univariate analysis of FTC patients revealed
      age at presentation, gender, extrathyroidal tumor spread, lymph node and distant
      metastases, increasing tumor size, multifocality, widely invasive tumor growth
      and oxyphilic variant to be factors bearing prognostic significance. The presence
      of distant metastases and increasing tumor size could be identified as
      independent prognostic factors for FTC patients. This study shows distinctive
      differences in prognostic factors of PTC and FTC: independent factors predicting
      poor prognosis are age > or =45 years, positive lymph nodes and increasing tumor
      size for PTC, and distant metastases and increasing tumor size for FTC. PTC and
      FTC patients should be analyzed and reported separately.

PMID- 15027891
TI  - Detection of the differentially expressed gene IGF-binding protein-related
      protein-1 and analysis of its relationship to fasting glucose in Chinese
      colorectal cancer patients.
AB  - IGF-binding protein-related protein-1 (IGFBP-rP1) is a member of the IGF axis. In
      our previous work, we separated cDNA fragments of IGFBP-rP1 from colonic
      adenocarcinoma and normal mucosa cDNA subtraction libraries. In this study, we
      compared the expression of IGFBP-rP1 by semi-quantitative RT-PCR and
      immunohistochemistry among colorectal cancer, adenoma, normal tissue adjacent to
      cancer site, and normal tissue. Associations between IGFBP-rP1 and plasma glucose
      were further explored. We found that the mRNA level of IGFBP-rP1 was highest in
      cancer, moderate in adenoma and tissue adjacent to the cancer site and lowest in
      normal tissue (P<0.05). A significant difference was found in the
      immunoreactivity of IGFBP-rP1 between paired normal and cancer tissue (P<0.05).
      Tumor samples with upregulated expression of IGFBP-rP1 in invading tumor cells
      showed an increased frequency of metastasis to the lymph node, an increased depth
      of infiltration and stronger staining of IGFBP-rP1 compared with other samples
      (P<0.05). The fasting glucose level was significantly correlated with the
      staining of IGFBP-rP1 in cancer tissue (Spearman's rho=0.4, P<0.000). Thus, we
      concluded overexpression of IGFBP-rP1 might play an important role in the
      initiation and promotion of colorectal cancer. IGFBP-rP1 expression may also be
      associated with fasting glucose level and the presence of diabetes mellitus.

PMID- 15027892
TI  - Spontaneous enterochromaffin-like cell carcinomas in cotton rats (Sigmodon
      hispidus) are prevented by a somatostatin analogue.
AB  - Among inbred female cotton rats (Sigmodon hispidus) 25-50% of the animals develop
      spontaneous gastric carcinomas; the corresponding figure for male cotton rats is
      approximately 1%. Animals with carcinomas have hypergastrinaemia and gastric hypo
      anacidity and the tumours are derived from enterochromaffin-like (ECL) cells. The
      mechanism behind the hypo-anacidity is unknown. Carcinomas are found in all
      female cotton rats with hypergastrinaemia lasting more than 4 months and this
      represents an excellent animal model for studying gastric carcinogenesis. In this
      study, the somatostatin analogue octreotide was given to female cotton rats to
      prevent carcinoma development caused by hypergastrinaemia. Twelve female cotton
      rats were given monthly injections of long-acting octreotide (5 mg i.m.) for 6
      months. A control group of 20 animals was not given injections. Of the 20 control
      animals, 13 developed hypergastrinaemia and histologically invasive carcinomas or
      dysplasia. Of the 12 animals in the octreotide group, five developed
      hypergastrinaemia. None of these five animals developed histological cancer
      (P<0.05), whereas three had dysplasia. However, octreotide did not affect plasma
      gastrin concentration or antral gastrin mRNA abundance significantly. Dysplasia
      of the oxyntic mucosa in hypergastrinaemic animals was accompanied by a marked
      increase in chromogranin A-immunoreactive cells and cells positive for Sevier
      Munger staining. The malignant tissue also contained groups of cells with Sevier
      Munger staining. In conclusion, octreotide prevented ECL cell carcinomas in
      hypergastrinaemic cotton rats without lowering the gastrin concentration.

PMID- 15027893
TI  - Nephrocalcinosis: molecular insights into calcium precipitation within the
      kidney.
AB  - Nephrocalcinosis may be defined as a generalized increase in the calcium content
      of the kidneys. This renal calcification may occur at a molecular, microscopic or
      macroscopic level leading to progressive amounts of renal damage. The major
      causes include those associated with an increase in urinary levels of calcium,
      oxalate and phosphate. Under these conditions, urine concentration and
      supersaturation leads to calcium crystal precipitation, which may be an
      intratubular event or initiate within the renal interstitium. The focus of
      discussion concerning renal calcification is often limited to factors that lead
      to renal stones (calculi and nephrolithiasis); however, nephrocalcinosis is a
      more sinister event, and often implies a serious metabolic defect. This review
      will discuss the hypotheses concerning initiating lesions of nephrocalcinosis
      using available laboratory and clinical studies and will examine whether new
      understanding of the molecular basis of tubulopathies, that lead to
      nephrocalcinosis, has given further insights.

PMID- 15027894
TI  - Relationship between overnight neuroendocrine activity and morning haemostasis in
      working men.
AB  - Sustained effects of SNS (sympathetic nervous system) and HPAA (hypothalamic
      pituitary-adrenal axis) hyperactivity on haemostasis have not been investigated.
      In the present study, we tested for an association of overnight urinary
      catecholamine and cortisol excretion with morning plasma levels of fibrinogen,
      PAI-1 (plasminogen activator inhibitor-1) and D-dimer. Participants (639 male
      industrial employees) with a complete dataset were studied (age, 41+/-11 years;
      mean+/-S.D.). Subjects collected overnight urinary samples and had a fasting
      morning blood sample drawn. Measurement of urinary adrenaline (epinephrine),
      noradrenaline (norepinephrine) and cortisol were dichotomized to perform
      multivariate analyses of (co)variance. Haemostatic parameters were measured by
      ELISA. Fibrinogen was higher in men with high adrenaline (F(7,631)=5.68, P=0.018;
      where the subscripted value represents the degrees of freedom) and high
      noradrenaline (F(7,631)=4.19, P=0.041) compared with men with low excretion of
      the respective hormones. PAI-1 was higher in men with high cortisol than in men
      with low cortisol (F(7,631)=4.77, P=0.029). Interaction revealed that subjects
      with high cortisol/low noradrenaline had higher PAI-1 than subjects with low
      cortisol/high noradrenaline (P=0.038). Subjects with high adrenaline/high
      noradrenaline had higher D-dimer than subjects with high adrenaline/low
      noradrenaline (P=0.029), low adrenaline/high noradrenaline (P=0.022) and low
      adrenaline/low noradrenaline (not significant). When covariance for several
      confounders of haemostatic function was determined, the main effect of adrenaline
      on fibrinogen and the interaction between adrenaline and noradrenaline for D
      dimer maintained significance. Although overnight SNS hyperactivity was
      associated independently with morning hypercoagulability, the relationship
      between the activity of HPAA and haemostasis was mediated by traditional
      cardiovascular risk factors.

PMID- 15027895
TI  - Antibody probe study of Ca2+ channel regulation by interdomain interaction within
      the ryanodine receptor.
AB  - N-terminal and central domains of ryanodine receptor 1 (RyR1), where many
      reported malignant hyperthermia (MH) mutations are localized, represent putative
      channel regulatory domains. Recent domain peptide (DP) probe studies led us to
      the hypothesis that these domains interact to stabilize the closed state of
      channel (zipping), while weakening of domain-domain interactions (unzipping) by
      mutation de-stabilizes the channel, making it leaky to Ca2+ or sensitive to the
      agonists of RyR1. As shown previously, DP1 (N-terminal domain peptide) and DP4
      (central domain peptide) produced MH-like channel activation/sensitization
      effects, presumably by peptide binding to sites critical to stabilizing domain
      domain interactions and resultant loss of conformational constraints. Here we
      report that polyclonal anti-DP1 and anti-DP4 antibodies also produce MH-like
      channel activation and sensitization effects as evidenced by about 4-fold
      enhancement of high affinity [3H]ryanodine binding to RyR1 and by a significant
      left-shift of the concentration-dependence of activation of sarcoplasmic
      reticulum Ca2+ release by polylysine. Fluorescence quenching experiments
      demonstrate that the accessibility of a DP4-directed, conformationally sensitive
      fluorescence probe linked to the RyR1 N-terminal domain is increased in the
      presence of domain-specific antibodies, consistent with the view that these
      antibodies produce unzipping of interacting domains that are of hindered
      accessibility to the surrounding aqueous environment. Our results suggest that
      domain-specific antibody binding induces a conformational change resulting in
      channel activation, and are consistent with the hypothesis that interacting N
      terminal and central domains are intimately involved in the regulation of RyR1
      channel function.

PMID- 15027897
TI  - CD4+ CD25+ Treg: divide and rule?
AB  - Research on CD4+ CD25+ regulatory T cells (Treg) has gathered momentum over the
      last five years but many aspects of their fundamental biology remain elusive.
      Treg have been considered to be 'naturally anergic' based on their failure to
      proliferate in response to T-cell receptor ligation in vitro. Several recent
      studies challenge this view and demonstrate a robust proliferative capacity for
      CD25+ cells. The significance of this finding for Treg homeostasis and function
      is considered below.

PMID- 15027896
TI  - Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox
      dependent in glomerular mesangial cells.
AB  - Angiotensin II (Ang II) stimulates hypertrophy of glomerular mesangial cells. The
      signalling mechanism by which Ang II exerts this effect is not precisely known.
      Downstream potential targets of Ang II are the extracellular-signal-regulated
      kinases 1 and 2 (ERK1/ERK2). We demonstrate that Ang II activates ERK1/ERK2 via
      the AT1 receptor. Arachidonic acid (AA) mimics the action of Ang II on ERK1/ERK2
      and phospholipase A2 inhibitors blocked Ang II-induced ERK1/ERK2 activation. The
      antioxidant N-acetylcysteine as well as the NAD(P)H oxidase inhibitors
      diphenylene iodonium and phenylarsine oxide abolished both Ang II- and AA-induced
      ERK1/ERK2 activation. Moreover, dominant-negative Rac1 (N17Rac1) blocks
      activation of ERK1/ERK2 in response to Ang II and AA, whereas constitutively
      active Rac1 resulted in an increase in ERK1/ERK2 activity. Antisense
      oligonucleotides for Nox4 NAD(P)H oxidase significantly reduce activation of
      ERK1/ERK2 by Ang II and AA. We also show that protein synthesis in response to
      Ang II and AA is inhibited by N17Rac1 or MEK (mitogen-activated protein
      kinase/ERK kinase) inhibitor. These results demonstrate that Ang II stimulates
      ERK1/ERK2 by AA and Nox4-derived reactive oxygen species, suggesting that these
      molecules act as downstream signal transducers of Ang II in the signalling
      pathway linking the Ang II receptor AT1 to ERK1/ERK2 activation. This pathway
      involving AA, Rac1, Nox4, reactive oxygen species and ERK1/ERK2 may play an
      important role in Ang II-induced mesangial cell hypertrophy.

PMID- 15027899
TI  - Altered T-dependent antigen responses and development of autoimmune symptoms in
      mice lacking E2A in T lymphocytes.
AB  - E2A has been shown to be an important transcription factor downstream of the T
      cell receptor (TCR) signal during T-cell development. The TCR signal is known to
      elicit different cellular responses at different stages of T-cell development.
      Whether E2A is still required for normal TCR signalling in mature T cells is
      unknown. Here we examined T-cell function after disruption of the E2A gene
      exclusively in the T-cell lineage. The conditional E2A-deficient mice show
      enhanced humoral immunity to a T-dependent antigen. We further show that E2A is
      involved in regulating TCR-induced T-cell proliferation events. However, E2A
      seems to play opposite roles in naive and effector T cells. In the absence of
      E2A, TCR-induced proliferation is increased in naive T cells and decreased in
      effector T cells. At older ages, these mice frequently develop antinuclear
      antibodies and proteinuria. Our studies suggest that E2A regulates T-cell
      function and the loss of E2A may promote age-dependent autoimmune diseases.

PMID- 15027898
TI  - Central and peripheral autoantigen presentation in immune tolerance.
AB  - Recent studies in both humans and experimental rodent models provide new insight
      into key mechanisms regulating tolerance to self-molecules. These recent advances
      are bringing about a paradigm shift in our views about tolerance to self
      molecules with tissue-restricted expression. There is, indeed, mounting evidence
      that selected antigen-presenting cells (APCs) have the ability to synthesize and
      express self-molecules, and that such expression is critical for self-tolerance.
      Insulin is a key hormone produced exclusively by pancreatic beta-cells and a
      critical autoantigen in type 1 diabetes. It provides an excellent example of a
      molecule with tissue-restricted expression that is expressed ectopically by APCs.
      The fact that APCs expressing insulin have been demonstrated in both thymus and
      peripheral lymphoid tissues suggests that they may play a role in insulin
      presentation in both the central and peripheral immune system. Experimental mice,
      in which insulin expression was altered, provide functional data that help to
      dissect the role of insulin presentation by APCs of the immune system. This
      review addresses recent literature and emerging concepts about the expression of
      self-molecules in the thymus and peripheral lymphoid tissues and its relation to
      self-tolerance.

PMID- 15027900
TI  - gammadelta T-cell clones from intestinal intraepithelial lymphocytes inhibit
      development of CTL responses ex vivo.
AB  - Oral administration of antigen induces a state of tolerance that is associated
      with activation of CD8+ T cells that can transfer unresponsiveness to naive
      syngeneic hosts. These T cells are not lytic, but they inhibit development of
      antibody, CD4+ T helper cell, and CD8+ cytotoxic T lymphocyte (CTL) responses
      upon adoptive transfer into naive, syngeneic mice. In addition, we have shown
      that depletion of gammadelta T cells by injection of the anti-delta chain
      antibody (GL3) down modulates the expression of gammadelta T-cell receptor (TCR)
      and inhibits the induction of oral tolerance to ovalbumin. Oral administration of
      antigen also fails to induce tolerance in TCR delta-chain knockout mice
      suggesting that gammadelta T cells play a critical, active role in tolerance
      induced by orally administered antigen. To further study the contribution of
      gammadelta T cells to tolerance, murine gammadelta T cells were isolated from
      intraepithelial lymphocytes (IEL) of the small intestine by stimulation with
      splenic filler cells, concanavalin A and growth factors. gammadelta IEL lines
      demonstrated lytic activity in a redirected lysis assay. gammadelta T-cell clones
      express different gammadelta TCR genes and secrete large amounts of interleukin
      (IL)-10, but little or no IL-2, IL-4, or interferon-gamma. gammadelta IEL clones
      expressed transforming growth factor-beta1 and macrophage migration inhibitory
      factor, as well as IL-10, mRNA. Moreover, gammadelta T-cell clones potently
      inhibited the generation of CTL responses by secreted molecules rather than by
      direct cell-to-cell contact.

PMID- 15027901
TI  - Role of the major histocompatibility complex class II transmembrane region in
      antigen presentation and intracellular trafficking.
AB  - While a sorting signal in the cytoplasmic tail of the major histocompatibility
      complex (MHC) class II molecules is known to influence their endocytic transport,
      potential effects of the transmembrane (TM) domain of the MHC class II molecules
      on endocytic transport remain unclear. We have examined the role of the TM domain
      by comparing antigen-presenting functions of the wildtype (WT) I-Ab and mutant
      (MT) I-Ab molecule substituted in the beta-chain TM with alpha chain TM. A20
      cells transfected with WT I-Ab were able to present antigen (hen egg lysozyme)
      better to some hybridomas, while those transfected with MT I-Ab consistently
      outperformed WT for other hybridomas recognizing different epitopes. This
      difference in antigen processing and presentation is not caused by the
      differences in H-2M (DM) requirement or association with Ii. The time required
      for processing of specific epitopes appears to be different, suggesting
      sequential involvement of various endocytic compartments in the antigen
      processing. Although both WT and MT molecules were found in the early endocytic
      (transferrin receptor-rich) compartments, MT molecules accumulated in these
      compartments in higher quantities for longer time periods. Similarly, the MT
      molecule is retained for a longer time period than WT in late endocytic (LAMP-1
      associated) compartments. Together, our data indicate an important role of the TM
      domain of the MHC class II molecules in the intracellular trafficking and,
      consequently, antigen processing and presentation.

PMID- 15027902
TI  - Toll-like receptor 2 (TLR2) and TLR4 are present inside human dendritic cells,
      associated with microtubules and the Golgi apparatus but are not detectable on
      the cell surface: integrity of microtubules is required for interleukin-12
      production in response to internalized bacteria.
AB  - The activation of dendritic cells (DCs) by microbes is mediated by pattern
      recognition receptors including the Toll-like receptors (TLR). Bacterial
      lipopolysaccharide acts via TLR4 whereas peptidoglycan and lipoprotein responses
      are mediated by TLR2. It is generally accepted that TLR binding to microbes
      occurs at the cell surface but this has not been directly demonstrated for human
      DCs. We show here that TLR2 and TLR4 are expressed inside DCs in an abundant
      tubulovesicular pattern with a focus of intense staining adjacent to the nucleus.
      In contrast, there was no detectable expression on the cell surface. TLR2 and
      TLR4 were readily found both intracellularly and on the surface of monocytes.
      They were shown to be closely associated with the Golgi complex and colocalized
      with alpha-tubulin, displaying a high focal concentration at the microtubule
      organizing centre. Alignment of TLR2 and TLR4 with microtubules was observed,
      suggesting that microtubules serve as transport tracks for TLR vesicles.
      Depolymerization of the microtubule network disrupted the intracellular
      expression of TLR2 and TLR4 and profoundly inhibited interleukin-12 (IL-12)
      production in response to Neisseria meningitidis but did not prevent
      phagocytosis. These data are consistent with the bacterial signalling through
      TLR2 and TLR4 required for IL-12 production occurring inside DCs after
      phagocytosis.

PMID- 15027903
TI  - Limited role of the Toll-like receptor-2 in resistance to Mycobacterium avium.
AB  - The role of the Toll-like receptor (TLR)-2 in the generation of protective
      immunity to Mycobacterium avium was evaluated using gene-disrupted mice. TLR-2-/-
      mice were more susceptible than wild-type C57Bl/6 mice to M. avium strains that
      were able to proliferate in vivo before the development of protective immunity
      and mycobacteriostasis. In contrast, the elimination of non-virulent strains was
      not affected by the mutation. The generation of interferon-gamma (IFN-gamma)
      producing T cells and the expression of the interleukin-12 p40 gene were reduced
      in TLR-2-deficient mice as compared to C57Bl/6 mice early during infection with
      M. avium strain 2447. The generation of protective CD4+ T cells was also
      compromised in the mutated mice as compared with the controls. Our data show that
      TLR-2 is required for optimal immunity against certain virulent M. avium strains.

PMID- 15027904
TI  - Regulation of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)
      and TRAIL receptor expression in human neutrophils.
AB  - Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a
      member of the TNF superfamily, which is capable of inducing apoptosis in many
      cell types, including tumour and virus-infected cells, but rarely in normal
      cells. Expression of TRAIL mRNA and TRAIL receptors has previously been detected
      in neutrophils; however, the expression of TRAIL protein and the regulation of
      TRAIL and TRAIL receptor expression in these cells remain unknown. Here we
      report, for the first time, that neutrophils constitutively express TRAIL protein
      on their cell surface and that the TRAIL protein is shed during culture. TNF
      alpha is a down-regulator of TRAIL expression, whereas IFN-gamma up-regulates the
      expression of TRAIL. Neutrophils did not express a detectable level of TRAIL-R1
      or -R4, but constitutively expressed a low, but substantial, level of TRAIL-R2
      and a high level of TRAIL-R3. Although the level of TRAIL-R2 was not
      significantly altered during culture under different experimental conditions,
      approximately 30% of TNF-alpha-treated cells rapidly lost their high-level TRAIL
      R3 expression, whereas the majority of IFN-gamma-treated cells retained a high
      level of TRAIL-R3 expression. Anti-TRAIL neutralizing antibody significantly
      inhibited neutrophil apoptosis during cultures in medium alone, or in the
      presence of TNF-alpha or IFN-gamma. Thus, our study identified human neutrophils
      as a cellular source of TRAIL and suggests that neutrophil-derived TRAIL may play
      a role in immune surveillance. Our results also suggest a role for the
      TRAIL/TRAIL receptor system in neutrophil apoptosis.

PMID- 15027905
TI  - Terminal deoxynucleotidyl transferase is down-regulated by AP-1-like regulatory
      elements in human lymphoid cells.
AB  - Terminal deoxynucleotidyl transferase (TdT) is a template-independent DNA
      polymerase that catalyses the incorporation of deoxyribonucleotides into the 3'
      hydroxyl end of DNA templates and is thought to increase junctional diversity of
      antigen receptor genes. TdT is expressed only on immature lymphocytes and acute
      lymphoblastic leukaemia cells and its transcriptional expression is tightly
      regulated. We had previously found that protein kinase C (PKC) activation down
      regulates TdT expression. PKC-activation induces the synthesis of the Fos and Jun
      proteins, known as the major components of activation protein 1 (AP-1)
      transcriptional factor implicated in transcriptional control. Here we report the
      identification of several DNA-protein interactions within the TdT promoter region
      in non-TdT expressing human cells. Sequence analysis revealed the presence of a
      putative AP-1-like DNA-binding site, suggesting that AP-1 may play a relevant
      role in TdT transcriptional regulation. Using a different source of nuclear
      extracts and the AP-1-TdT motif as a probe we identified several DNA-protein
      retarded complexes in electrophoretic mobility shift assays. Super-band shifting
      analysis using an antibody against c-Jun protein confirmed that the main
      interaction is produced by a nuclear factor that belongs to the AP-1 family
      transcription factors. Our findings suggest that the TdT gene expression is down
      regulated, at least in part, through AP-1-like transcription factors.

PMID- 15027906
TI  - Cloning and characterization of an immunoglobulin A Fc receptor from cattle.
AB  - Here, we describe the cloning, sequencing and characterization of an
      immunoglobulin A (IgA) Fc receptor from cattle (bFcalphaR). By screening a
      translated EST database with the protein sequence of the human IgA Fc receptor
      (CD89) we identified a putative bovine homologue. Subsequent polymerase chain
      reaction (PCR) amplification confirmed that the identified full-length cDNA was
      expressed in bovine cells. COS-1 cells transfected with a plasmid containing the
      cloned cDNA bound to beads coated with either bovine or human IgA, but not to
      beads coated with bovine IgG2 or human IgG. The bFcalphaR cDNA is 873 nucleotides
      long and is predicted to encode a 269 amino-acid transmembrane glycoprotein
      composed of two immunoglobulin-like extracellular domains, a transmembrane region
      and a short cytoplasmic tail devoid of known signalling motifs. Genetically,
      bFcalphaR is more closely related to CD89, bFcgamma2R, NKp46, and the KIR and
      LILR gene families than to other FcRs. Moreover, the bFcalphaR gene maps to the
      bovine leucocyte receptor complex on chromosome 18. Identification of the
      bFcalphaR will aid in the understanding of IgA-FcalphaR interactions, and may
      facilitate the isolation of FcalphaR from other species.

PMID- 15027907
TI  - Non-functional immunoglobulin G transcripts in a case of hyper-immunoglobulin M
      syndrome similar to type 4.
AB  - Summary 86% of immunoglobulin G (IgG) heavy-chain gene transcripts were found to
      be non-functional in the peripheral blood B cells of a patient initially
      diagnosed with common variable immunodeficiency, who later developed raised IgM,
      whereas no non-functionally rearranged transcripts were found in the cells of
      seven healthy control subjects. All the patient's IgM heavy-chain and kappa light
      chain transcripts were functional, suggesting that either non-functional
      rearrangements were being selectively class-switched to IgG, or that receptor
      editing was rendering genes non-functional after class-switching. The functional
      gamma-chain sequences showed a normal rate of somatic hypermutation while non
      functional sequences contained few somatic mutations, suggesting that most came
      from cells that had no functional gene and therefore were not receiving signals
      for hypermutation. However, apoptosis of peripheral blood lymphocytes was not
      impaired. No defects have been found in any of the genes currently known to be
      responsible for hyper-IgM syndrome but the phenotype fits best to type 4.

PMID- 15027909
TI  - Architecture of secondary lymphoid tissue in sheep experimentally challenged with
      scrapie.
AB  - Scrapie is a transmissible spongiform encephalopathy in which there is an
      accumulation of the abnormal form of the prion protein, PrPsc, in the
      lymphoreticular system and nervous system. There is a particular accumulation of
      PrPsc on follicular dendritic cells within the germinal centre of B-cell
      follicles. Because accumulation of PrPsc in the nervous system leads to neuronal
      cell loss we have examined PrPsc accumulation in the prescapular and mesenteric
      lymph nodes in relation to lymph node architecture of scrapie-challenged sheep.
      We demonstrate that an accumulation of PrPsc in the lymph node fails to result in
      gross defects in the microanatomy and phenotype of T- and B-cell areas in the
      lymph nodes.

PMID- 15027912
TI  - Australian and New Zealand radiation oncology work practices in 2000: What do we
      want in specialty radiation oncology practice?

PMID- 15027913
TI  - Role of radiology in the treatment of malignant hilar biliary strictures 1:
      review of the literature.
AB  - Malignant strictures of the biliary tree are an uncommon cause of obstructive
      jaundice. There are a number of pathological subtypes, but tumours in this region
      tend to have similar clinical and diagnostic features and therapeutic and
      prognostic implications. We review the published literature on this topic
      discussing diagnostic modalities and treatment options with a focus on
      radiological intervention. Diagnosis currently is best achieved using a range of
      procedures. Direct cholangiography remains the gold standard in delineating
      anatomy, but the invasiveness of this procedure limits its use as a purely
      diagnostic tool. Magnetic resonance technology, in particular magnetic resonance
      cholangiopancreatography, has an increasing role as accessibility is improved.
      Treatment of these tumours is difficult. Surgical resection and palliative
      biliary enteric bypass are the most common methods used with endoscopic and
      percutaneous therapies reserved for palliating patients not fit for surgery.
      There is little firm evidence to suggest that any one palliative modality is
      superior. Interventional radiology is particularly suitable for palliative
      management of difficult and expansive lesions as the anatomy can preclude easy
      access by surgical or endoscopic techniques. Good palliative results with minimal
      mortality and morbidity can be achieved with percutaneous stenting.

PMID- 15027908
TI  - Activation of Epstein-Barr virus by saliva from Sjogren's syndrome patients.
AB  - The aim of this study was to examine the mechanism of Epstein-Barr virus (EBV)
      activation by soluble factors from the inflamed salivary glands of patients with
      Sjogren's syndrome (SS). Saliva from SS patients was used to examine the
      regulation of EBV activation by an inflammatory salivary microenvironment.
      Transient transfection of the EBV-negative salivary gland cell line (HSY) with
      BZLF1, a trans-activating EBV gene promoter-fusion construct (Zp-luc), was used
      in this study. The results showed that under conditions where the BZLF1 promoter
      is activated by potent stimuli, SS saliva (from eight of 12 patients) exerts a
      significant effect on expression of the luciferase gene. A specific inhibitor of
      protein kinase C did not affect the SS saliva-induced Zp-luc activity, whereas
      treatment with inhibitors of calmodulin, calcineurin and IP3, dose-dependently
      decreased this induction. Transforming growth factor beta1 (TGF-beta1), which is
      known to be expressed in SS salivary glands, dose-dependently induced Zp-luc
      activity. Hence, these results demonstrate the activation of EBV by SS saliva and
      suggest that EBV activation at the inflammatory site may occur in the presence of
      TGF-beta1 via triggering of the mitogen-activated protein kinase (MAPK) kinase
      signalling pathway.

PMID- 15027914
TI  - Accuracy of nasopharyngeal carcinoma staging by magnetic resonance imaging.
AB  - To audit the accuracy of magnetic resonance (MR) staging of nasopharyngeal
      carcinoma (NPC) in daily reporting, the MR images of 101 adult patients with
      newly diagnosed NPC reported between December 1996 and February 2002 were
      reviewed retrospectively. Based on the American Joint Committee on
      Cancer/International Union Against Cancer (AJCC/UICC) TNM staging criteria
      (1997), the tumour staging obtained from the MR reports and the MR films was
      compared by two experienced head and neck radiologists. The number of patients
      being upstaged, downstaged or unchanged was noted. In all stages, the NPC staging
      obtained from the MR reports revealed 18 (17.8%) understaged, eight (7.9%)
      overstaged and 75 (74.2%) the same stage when compared to the staging obtained
      from the MR films based on the AJCC/UICC criteria. The percentage of patients
      being understaged or overstaged, in decreasing order of frequency, were stages
      II, III, IV and I. Magnetic resonance of NPC should be reported by radiologists
      who are not only familiar with the pathology of this condition and its pattern of
      spread but who should also base their reports on the AICC/UICC staging criteria.
      The necessity to improve our MR staging accuracy is largely because it determines
      the type of therapy to be given and this has to be appropriate and adequate for a
      successful treatment.

PMID- 15027915
TI  - Clinical efficacy of metal stents for the treatment of focal abdominal aortic
      stenosis.
AB  - Seven patients (four women and three men) who underwent primary stenting of
      infrarenal abdominal aortic stenosis over a 4-year period are reported. The
      patients ranged between 44 and 77 years of age. All were referred for treatment
      of disabling claudication. Self-expanding stents with balloon assistance were
      used. A single complication, a retroperitoneal haematoma, requiring surgical
      intervention occurred in one patient. Patients had either complete resolution of
      symptoms (five of seven) or a substantial decrease in their claudication
      symptoms. Primary stenting is a safe and effective treatment for severe abdominal
      aortic stenosis.

PMID- 15027916
TI  - Patterns of injury in patients with radiographic occult fracture of neck of femur
      as determined by magnetic resonance imaging.
AB  - The purpose of the present study was to review retrospectively our experience
      with MRI in patients over the age of 50 who present to the emergency department
      with inability to weight bear following a fall and whose initial radiographs were
      normal. The study was designed to establish the incidence and pattern of bone and
      soft tissue injuries in these patients and to determine whether MRI could provide
      predictive information regarding length of hospital stay. The present study
      demonstrated the practicality of a protocol using MRI to obtain rapid definitive
      diagnosis in patients with occult fractures of the pelvic ring and neck of femur.
      The present study also suggests that significant prognostic information with
      regard to length of hospital stay can be obtained from an early MRI scan.

PMID- 15027917
TI  - Publication rates of abstracts presented at annual scientific meetings: how does
      the Royal Australian and New Zealand College of Radiologists compare?
AB  - The abstract to publication ratio (APR) is a measure of the quality of scientific
      meetings. The aim of the present study was to determine the publication rate of
      abstracts presented at annual Royal Australian and New Zealand College of
      Radiologists (RANZCR) conferences, and to identify the publishing journals. All
      free paper research abstracts (oral or poster) presented by RANZCR radiologists,
      radiation oncologists and trainees at the four consecutive meetings between 1996
      and 1999 were identified retrospectively from conference programmes. The PubMed
      database (http://www.ncbi.nlm.nih.gov/PubMed/) was searched to determine whether
      or not the abstract had been published as a full paper. Of the 480 free paper
      research abstracts, 168 (35%) had been published as full articles. The overall
      abstract to publication ratio for radiology was 29% and for radiation oncology
      was 41%. Papers were published in a variety of journals but Australasian
      Radiology accounted for 27%. The mean time between presentation and publication
      was 16.5 months (median 17 months). These overall abstract to publication ratios
      are lower than those reported for overseas-based meetings in each respective
      area. Guidelines to scientific committees could increase the APR by more rigorous
      selection of abstracts. Future research should look at barriers to the
      publication of research findings, and identify ways to assist the publication
      process.

PMID- 15027918
TI  - Sequential audits of unacceptable delays in radiation therapy in Australia and
      New Zealand.
AB  - Delays in accessing radiation treatment are of concern in Australia and New
      Zealand, both in terms of the proportion of patients who are actually able to
      access care, and in the timeliness of starting treatment. For those who are able
      to access treatment, one in three patients experience an unacceptable delay in
      starting treatment, and only one in four patients starts radiotherapy within
      standard good practice times. During the year 2002, more than 15 000 Australians
      who potentially could have benefited from radiotherapy, did not receive this
      treatment. For those who were able to access radiotherapy treatment, worsening
      delays were experienced in Australia, with greater than 40% of patients receiving
      curative treatment, 30% receiving palliative treatment, and 56% receiving
      emergency treatment starting outside of standard good practice times. Delays of
      up to 151 days were experienced in Australia. In Australia, delays in
      implementing recommendations to improve the infrastructure are resulting in a
      declining service for cancer patients. In New Zealand, the situation, in general,
      is improving, although there needs to be an ongoing commitment to grow the
      service according to the population needs. Urgent implementation of strategic
      planning is required.

PMID- 15027919
TI  - Intensity-modulated radiation therapy: not a dry eye in the house.
AB  - Inverse planned intensity-modulated radiation therapy (IMRT) has been applied to
      patients in a conformal fashion in order to avoid the lacrimal gland. In the
      present study, we report a patient in which a potential planned dose of 63 Gy to
      the lacrimal gland for a conventional plan was reduced to 12 Gy to the lacrimal
      gland for the IMRT plan. Dose objective inverse planning was provided using a
      Pinnacle treatment planning computer and treatment was delivered using a Varian
      dynamic multileaf collimator (MLC) on a Varian linear accelerator. Because
      multiple MLC segments are used to deliver the modulated treatment, conventional
      dose checks by manual calculation are not practical. To aid in an alternative
      dosimetric verification process, the Pinnacle planning computer has two unique
      dose tools, which provide axial and beams eye view doses on user-specified check
      phantoms. The combined field axial dose tool matched our ion chamber dose checks
      within +/- 2.4% at the isocentre. The individual beams eye view dose tool matched
      film dose maps within +/- 3% in the umbra.

PMID- 15027920
TI  - Dosimetric study of optimal beam number and arrangement for treatment of
      nasopharyngeal carcinoma with intensity-modulated radiation therapy.
AB  - The purpose of this dosimetric study was to evaluate the effect of beam number
      and arrangement on the dose distribution with intensity-modulated radiation
      therapy in patients with nasopharyngeal cancer. Computed tomography data sets of
      seven patients who were treated for nasopharyngeal carcinoma at the Peter
      MacCallum Cancer Centre were used for the present dosimetric study. The dose
      planned was 70 Gy in 7 weeks for the gross nasopharyngeal and nodal disease and
      the biological equivalents of 60 Gy in 6 weeks for the high-risk and 50 Gy in 5
      weeks for the low-risk nodal disease. A plan using seven fields was compared to
      that using nine fields in all patients. Plans were assessed on the dose to the
      planning target volume (PTV) and the degree of parotid sparing achieved by
      evaluating both dose-volume histograms (DVH) and axial slices. Seven fields
      (three anterior and four posterior) provide good PTV coverage and satisfactory
      parotid sparing in patients with localized nasopharyngeal lesions. Nine fields
      appear to be better for tumours with significant posterolateral parapharyngeal
      extension. Parotid sparing is consistently better with nine fields. Both DVH and
      axial slices need to be evaluated before accepting any plan.

PMID- 15027921
TI  - Intensity-modulated radiotherapy: examples of its utility in head and neck
      cancer.
AB  - Intensity-modulated radiotherapy (IMRT) has been available at Peter MaCallum
      Cancer Centre (PMCC) since November 2000. The present report illustrates two
      cases of our early experience with IMRT. Case 1 is a 66-year-old man with a
      T(1)N(2)M(0) nasopharyngeal carcinoma treated with chemo-radiotherapy using
      parotid-sparing IMRT. Fourteen months following treatment he remains in complete
      remission, with salivary function assessed using a xerostomia-specific quality of
      life questionnaire, having returned to near pretreatment levels by 12 months.
      Case 2 is a 70-year-old man with a T(4)N(0)M(0) base of tongue squamous cell
      carcinoma treated with chemo-radiotherapy after refusing radical surgery. He had
      received subtotal nodal irradiation to 36 Gy in 1994 for Hodgkins disease stage
      IIA. A radical dose was still achievable despite previous irradiation without
      exceeding unacceptable spinal cord dose with IMRT. He remains in complete
      remission 14 months from his initial presentation without evidence of
      neurological toxicity. Intensity-modulated radiotherapy allows sparing of
      critical normal structures in the head and neck without compromising dose to the
      tumour. It is, therefore, desirable for several clinical applications and
      essential in some, if unacceptable compromises are not to be made.

PMID- 15027922
TI  - Anterior infradiaphragmatic free gas following bronchial rupture: case report and
      literature review.
AB  - Bronchial rupture is an uncommon injury that presents clinically and
      radiologically with tension or non-tension pneumothorax, pneumomediastinum and
      subcutaneous emphysema caused by air leak and migration of free gas.
      Infradiaphragmatic gas has previously been demonstrated in mechanically
      ventilated patients with pneumomediastinum and is secondary to passage of air via
      anterior and posterior trans-diaphragmatic pathways. We present a case of
      bronchial rupture complicated by extensive infradiaphragmatic gas following
      mechanical ventilation that illustrates these pathways and some of the major
      radiographic signs associated with this injury.

PMID- 15027923
TI  - Abdominal cerebrospinal fluid pseudocyst.
AB  - A case of an abdominal cerebrospinal fluid (CSF) pseudocyst in a patient with a
      ventriculoperitoneal shunt is reported to illustrate this known but rare
      complication. In the setting of a VP shunt, the frequency of abdominal CSF
      pseudocyst formation is approximately 3.2%, often being precipitated by a recent
      inflammatory or infective process or recent surgery. Larger pseudocysts tend to
      be sterile, whereas smaller pseudocysts are more often infected. Ultrasound and
      CT each have characteristic findings.

PMID- 15027924
TI  - Haemolysis, elevated liver enzymes and low platelets syndrome: ultrasound and
      magnetic resonance imaging findings in the liver.
AB  - We describe the imaging findings of the HELLP (haemolysis, elevated liver enzymes
      and low platelets) syndrome in a gravid 36-year-old-woman who presented at 19.5
      weeks gestation with severe right upper quadrant pain. Ultrasound findings
      suggested a focal hyperechoic liver lesion suggesting pregnancy-related
      hepatopathy prior to development of biochemical signs of HELLP syndrome. Within 3
      days, the patient developed characteristic clinical and laboratory evidence of
      the HELLP syndrome. MR imaging at this time demonstrated localized hepatic
      ischaemia, further strengthening the diagnosis of HELLP syndrome.

PMID- 15027925
TI  - Communicating oesophageal duplication.
AB  - Oesophageal duplications are rare congenital abnormalities. Most of them do not
      communicate with the oesophageal lumen. We present a very uncommon finding of
      communicating oesophageal duplication in which the connection between the
      oesophagus and its duplicate portion was demonstrated by CT.

PMID- 15027926
TI  - Shocking abdominal trauma: review of an uncommon disorder of small intestine
      perfusion.
AB  - 'Shock bowel' is a rare disorder of gastrointestinal physiology with
      characteristic radiological features. It usually occurs in the setting of blunt
      abdominal trauma and hypovolaemia, with complete reversibility of these findings
      following resuscitation. We present a case demonstrating the classic features of
      this complex of imaging findings thought to be caused by end-organ hypoperfusion.

PMID- 15027927
TI  - Multiplanar reconstruction in adult intussusception: case report and literature
      review.
AB  - We describe the use of computed tomography (CT) with multiplanar reconstruction
      (MPR) in positive diagnosis of a case of enteric intussusception in an adult. To
      our knowledge, there have been no previous reports of the use of MPR in this
      setting. Intussusception in adults is an uncommon cause of bowel obstruction that
      usually presents with non-specific symptoms. An underlying lesion is found in
      most cases. Multiplanar reconstruction should be used to confirm the diagnosis of
      intussusception when suspected on axial views, and should increase the yield of
      positive diagnoses when used in the assessment of a complex abdominal mass
      involving the bowel.

PMID- 15027928
TI  - Focal nodular hyperplasia in a child with hemihypertrophy and multiple cutaneous
      vascular malformations.
AB  - A case of focal nodular hyperplasia of the liver occurring in a 9-year-old girl
      with musculoskeletal hemihypertrophy and multiple cutaneous capillary
      haemangiomata is described. The child presented because of limb length
      discrepancy and was found to have a large mass in the liver. Imaging showed a
      mass of similar characteristics to normal liver tissue. Prominent vascular supply
      to the liver was also seen. We present this case to emphasize the important
      diagnosis of focal nodular hyperplasia, which may occur in syndromic form in
      children with typical cutaneous and skeletal manifestations.

PMID- 15027929
TI  - Malignant rhabdoid tumour of the third ventricle.
AB  - A 16-year-old boy presented to the All India Institute of Medical Sciences
      hospital with signs and symptoms of raised intracranial pressure. A CT scan
      showed obstructive hydrocephalus from a large posterior third ventricle mass
      lesion. The patient underwent a subtotal resection of the tumour, followed by
      radiotherapy. Histological, ultrastructural and immunohistochemical features of
      the tumour were consistent with primary malignant rhabdoid tumour. The age of
      presentation and location of the lesion were unusual.

PMID- 15027930
TI  - Primary nasal lymphoma, NK/T-cell type: report of two cases with similar
      presentation but different outcome.
AB  - Two cases of natural killer (NK)/T-cell primary nasal lymphoma with similar
      clinical presentations are reported, for comparison and contrast, to highlight
      the clinical issues and challenges posed by this unusual disease, its
      aggressiveness being matched only by its rarity. Presenting as a lesion in the
      nasal cavity with histological features of malignant lymphoma, primary nasal
      lymphoma is an uncommon extranodal lymphoma, which poses problems in both
      diagnosis and management. In people of oriental descent, the common cell subtype
      is NK/T-cell. Although it is generally thought that combination treatment with
      chemotherapy and radiation is the best management for early stage non-Hodgkin's
      lymphoma (NHL), there is still debate as to whether combined therapy is optimal
      treatment for this particular subtype of NHL, given that it responds less well to
      conventional chemotherapy. Herein we report two patients to illustrate these
      controversies.

PMID- 15027931
TI  - Parotid gland as an initial site of metastasis.
AB  - The parotid gland is an uncommon site of metastasis from carcinomas arising
      outside the head and neck region. Involvement of the parotid gland as an initial
      site of metastasis or presentation is rare. The present case report is the first,
      to our knowledge, to describe the management and outcome of an elderly man whose
      first presentation of an asymptomatic squamous cell carcinoma of the lung was
      that of a rapidly growing fungating left parotid mass.

PMID- 15027932
TI  - Big cat scan: magnetic resonance imaging of the tiger.
AB  - In August 2002, we performed MRI scans on a female juvenile Bengal tiger. We
      present the clinical course, imaging and autopsy findings, and some comparative
      anatomy of the tiger brain and skull. Magnetic resonance images of a tiger have
      not previously been published.

PMID- 15027936
TI  - Pain management and the radiologist.

PMID- 15027937
TI  - Revised AJCC staging of breast cancer: significance of supraclavicular lymph node
      metastases.

PMID- 15027946
TI  - Anatomicohistological characteristics of the tubular genital organs of the female
      collared peccary (Tayassu tajacu) from North-eastern Amazon.
AB  - The present study examines anatomical and histological characteristics of tubular
      genital organs and its relationships with the reproductive state of 24 wild adult
      collared peccary (Tayassu tajacu) females. The tunica mucosa of the uterine tube
      presents a pseudostratified, intermittently ciliated columnar epithelium. The
      epithelial secretory cells of pregnant females and females in the luteal phase of
      the oestrous cycle became taller than the ciliated cells and showed abundant
      apical secretory blebs, whereas secretory cells of females in the follicular
      phase showed abundant mucous secretory activity (periodic acid-Schiff positive
      cells). The uterus is composed of two narrow and convoluted uterine horns,
      separated by the velum uteri, a small uterine body and a long and muscular
      cervix. The endometrial lining of both uterine horns and body is a
      monostratified, columnar ciliated epithelium. Pregnant females and females in
      luteal phase showed a more developed hyperplasia of the endometrial simple
      tubular glands than females in the follicular phase. The cervix presents
      interdigitated rows of mucosal prominences that project into the lumen,
      structures similar to pulvini cervicali, occluding the cervical canal. In
      pregnant females, the endocervical canal was filled by a viscous cervical
      secretion. Females in follicular phase presented a thicker vaginal epithelium
      than pregnant females and females in luteal phase. The present study suggests
      that the collared peccary female showed different histological features of the
      uterine tubes, uterus and vagina in accordance with the reproductive state of the
      females.

PMID- 15027947
TI  - Morphological aspects of in vivo cleavage in Myocastor coypus (coypu).
AB  - The objective of the present work was to characterize the in vivo cleavage stage
      of Myocastor coypus embryos. For this purpose a colpocytological follow-up and
      controlled mating of 18 females were performed. Specimens from the beginning of
      the first cleavage to the acquisition of a morula appearance were considered to
      be in cleavage stage. Embryos in cleavage were collected between days 3 and 6
      post-coitus. Of the collected embryos, 80% presented an even number of
      blastomeres and the remaining 20% an odd number. Embryos from 3 to 7 cells were
      blastomere associations in a spherical disposition within the zona pellucida.
      Blastomeres were spherical or ovoid, presenting slight flattening in areas
      contacting with other blastomeres. Embryos of 8 and 9 cells were as a group of
      blastomeres slightly elongated, surrounded by a spherical zona pellucida. The
      percentage of peri-vitelline space occupied by the embryonic mass ranged from
      74.1 to 95.8% for all the substages. The cleavage pattern, developed in the
      oviduct, was of a rotational holoblastic type and asynchronic.

PMID- 15027948
TI  - Basilar artery of the capybara (Hydrochaeris hydrochaeris): an ultrastructural
      study.
AB  - The present study investigated the ultrastructural features of the basilar artery
      of the largest rodent species, the capybara. The study suggests that the general
      ultrastructural morphological organization of the basilar artery of the capybara
      is similar to that of small rodents. However, there are some exceptions. The
      basilar artery of the capybara contains a subpopulation of 'granular' vascular
      smooth muscle cells resembling monocytes and/or macrophages. The possibility
      cannot be excluded that the presence of these cells reflects the remodelling
      processes of the artery due to animal maturation and the regression of the
      internal carotid artery. To clarify this issue, more systemic studies are
      required involving capybaras of various ages.

PMID- 15027949
TI  - Differentiation and developmental potential of rat post-implantation embryo
      without extra-embryonic membranes cultured in vitro or grafted in vivo.
AB  - Different experimental systems are used to study developmental processes in
      mammals. In this study, three experimental models were analysed and correlated:
      (1) cultivation of rat embryos in vitro; (2) cultivation in vitro and then
      transplantation in vivo; (3) direct transplantation in vivo. When embryos were
      cultivated in vitro and then transplanted in vivo, after the initial in vitro
      restriction, developmental potential was recovered. The in vitro restriction
      depended on medium used and duration of culture. Pre-cultivation in serum-free
      medium for 7 days restricted developmental potential for nervous tissue, and for
      14 days restricted developmental potential for skeletal muscles, adipose tissue
      and glandular epithelia. Transferrin addition improved in vitro differentiation
      of neuroblasts, cartilage and columnar epithelium. In the combined in vitro and
      in vivo method, transferrin preserved developmental potential in comparable
      extent to the addition of the serum. Even in serum-free conditions in vitro, the
      subsequent in vivo wide expression of developmental potential was possible.
      Therefore, the combination of in vitro and in vivo methods turned to be
      advantageous than the isolated approaches (in vitro or in vivo only), and enabled
      testing in more detail the influence of a single substance on developmental
      course and potential.

PMID- 15027950
TI  - A striated muscle on the hard palate of rodents and rabbits.
AB  - Summary A striated muscle of the hard palate has been previously described in
      some rodents and rabbits. It is not termed in the official veterinary anatomical
      nomenclature. The aim of this work was to verify the existence of this muscle.
      Heads of the golden hamster (Mesocricetus auratus), the guinea pig (Cavia aperea
      f. porcellus), the laboratory rat (Rattus norvegicus var. alba), the field vole
      (Microtus agrestis) and the domestic rabbit (Oryctolagus cuniculus f. domesticus)
      have been dissected. Moreover, histological sections have been prepared from
      heads of the field vole. In all species under study, we could detect a striated
      muscle of the hard palate composed of an anterior and a posterior muscle. The
      anterior muscle originated on the os incisivum and diverged in anterior, lateral
      and posterior directions. The posterior muscle originated on the processus
      palatinus maxillae and verged into the m. buccinator. Inter-species differences
      could be detected in shape and position of the muscle. The palatal muscle was
      innervated by the ramus buccalis of the facial nerve. Whether this muscle should
      be classified as an individual facial muscle or as a part of the m. buccinator
      remains to be discussed.

PMID- 15027951
TI  - Anatomical description of the muscles of the pelvic limb in the ostrich (Struthio
      camelus).
AB  - Dissections of 12 formalin-fixed ostriches were performed to give anatomical
      descriptions of the muscles and tendons of the pelvic, femoral, tibiotarsal,
      tarsometatarsal and digital regions. In the pelvic limb of the ostrich, 36
      muscles can be determined. The ostrich lacks those muscles to the first and
      second toes (with exception of the M. flexor hallucis longus), which can be found
      in birds with four toes. The Mm. iliotrochantericus medius, plantaris, extensor
      proprius digiti IV and adductor digiti IV, which are present in other birds, are
      also absent, whereas the Mm. pectineus and femorotibialis accessorius
      additionally occur in the ostrich. The Pars supramedialis is a tendineous part of
      the M. gastrocnemius, on which the Mm. flexor cruris lateralis and flexor cruris
      medialis insert by means of a fascial sheet. The caudal part of the M.
      iliofibularis terminates within the caudal aspect of the superficial fascia
      cruris. The caudal heads of the Mm. flexor perforatus digiti III and flexor
      perforatus digiti IV as well as the M. flexor hallucis longus have a common
      origin on the Fossa poplitea of the femur. The lateral head of the M. flexor
      perforatus digiti IV and the femoral head of the M. flexor perforans et
      perforatus digiti III originate on the tendon of origin of the Caput laterale of
      the M. flexor perforatus digiti III. Furthermore, the last named tendon fuses
      with the tendon of insertion of the M. ambiens. The M. extensor proprius digiti
      III originates on a plate-like fascial sheet part of the dorsal joint capsule of
      the intertarsal joint.

PMID- 15027953
TI  - Preferential expression of L-type amino acid transporter 1 in ameloblasts during
      rat tooth development.
AB  - Certain amino acid transport systems play an important role in supplying organic
      nutrients to each cell and for cell proliferation during tooth development.
      However, the mechanisms responsible for such actions are unclear. This study
      demonstrated for the first time that LAT1 and 4F2hc are expressed during tooth
      development in prenatal and postnatal rats, and that the transporters show cell
      specific expression in ameloblasts, which are the epithelium-derived dental
      cells. LAT1 and 4F2hc expression was not observed in other dental cells of the
      developing teeth such as odontoblasts and cementoblasts. Overall, these results
      suggest that LAT1 and 4F2hc might play an important role in enamel formation.

PMID- 15027952
TI  - Two cases of brachymelia in cats.
AB  - In this report, two cases of brachymelia in related neonatal cats are described.
      The malformations are described in view of normal limb development, which is
      illustrated by scanning electron microscopic images. Hypoplasia and aplasia of
      the distal limb segments were the main disorders in both kittens. Additional
      malformations in the second case included fusion of the radius and ulna,
      congenital patella luxation and a shortened tail. Brachymelia and similar cases
      of feline dysmelia are poorly documented in the existing literature. Possible
      causes and terminology of these developmental deformations are discussed.

PMID- 15027954
TI  - Expression of nestin and IGF-1 in rat pancreas after streptozotocin
      administration.
AB  - The present study examines whether centroacinar (CA) and intercalated duct (ICD)
      cells can serve as stem cells, after administration of the diabetogenic agent
      streptozotocin (STZ). Thirty rats were divided into five experimental groups: (1)
      control, (2) 1 day after STZ (STZ-1), (3) 3 days after STZ (STZ-3), (4) 7 days
      after STZ (STZ-7) and (5) 14 days after STZ (STZ-14). Many small pancreatic
      islets were observed in the STZ-7 group than in the other experimental groups,
      and many of these small islets were in close contact with ICD and CA cells. A
      higher number of nestin, insulin-like growth factor-1 (IGF-1) and IGF-1-receptor
      positive ICD and CA cells were observed at STZ-3 and STZ-7 than at the others.
      These expression patterns coincided well with the proliferating cell nuclear
      antigen pattern. The results suggest that rat pancreatic endocrine cells after
      damage by STZ administration might be recovered from newly generated cells
      derived from ICD and CA cells.

PMID- 15027955
TI  - Dynamics of mast cells in lymph node following antigenic stimulation.
AB  - Dynamics of mast cells in rat cervical lymph nodes were examined using
      conventional histological techniques after injection of Salmonella paratyphi B-H
      antigen. There was no significant change in the number of mast cells at sixth
      hour and on the first day of stimulation compared with the controls. The number
      of mast cells was increased in all lymph node compartments on the second day of
      stimulation, which continued in the following 3 days. On the eighth day of
      stimulation, although the mast cell number decreased in the subcapsular area, it
      was still high in the paracortical area and medullary sinuses of the lymph nodes.
      On the second day of stimulation, the mast cell number was apparently increased
      in the subcapsular area than those of the other compartments. In the following
      days of stimulation, the highest number of mast cells was seen in the medullary
      sinuses. The highest paracortical mast cell number was determined on the third
      day of stimulation and some mast cells were observed near the high endothelial
      venules (HEVs). The changes of mast cell number among the lymph node compartments
      after antigenic stimulation support the hypothesis that the migration of mast
      cells occurred. This migration pattern indicates that mast cells enter the lymph
      node via afferent lymphatics and migrate to the lymph node compartments following
      antigenic stimulation.

PMID- 15027956
TI  - Intestinal villus histological alterations in piglets fed dietary charcoal powder
      including wood vinegar compound liquid.
AB  - To investigate the effects of dietary charcoal powder including wood vinegar
      compound liquid (CWVC, 4 : 1) on intestinal villus histology, piglets were fed 0,
      1, 3 and 5% dietary CWVC diets for 30 days. Feed intake and body weight gain were
      measured during the experimental period. At the end of the experiments,
      intestinal villus height, epithelial cell area and cell mitosis were examined
      using light microscopy (LM), and the duodenal villus tip surface was observed
      using scanning electron microscopy (SEM). Feed efficiency tended to be improved
      in the CWVC group. The 3% CWVC group showed the highest value, followed by 1%
      CWVC group of most LM parameters in most intestinal parts, but the 5% CWVC group
      showed the almost similar value compared with the control. In addition, on the
      duodenal villus tip surface, the 3% CWVC group showed a clearer cell outline,
      larger cells and cells protuberated further into the lumen than those of the 1%
      CWVC group. However, the 5% CWVC group showed faint SEM features than the 1% CWVC
      group. The present trend of improved feed efficiency after feedings of dietary
      CWVC demonstrates that the CWVC could be incorporated into piglet diets up to 3%
      level, and that the CWVC might activate intestinal functions both at villus and
      cellular levels.

PMID- 15027957
TI  - Oxytalan fibres in the periodontal ligament of equine molar cheek teeth.
AB  - The distribution and arrangement of oxytalan fibres were examined in periodontal
      specimens of cheek teeth from seven horses. Oxidation prior to aldehyde fuchsin
      exposition permitted a selective staining of the oxytalan fibres, which are a
      distinct component of the elastic fibre system. On three horizontal levels of the
      periodontium--(a) subgingival, (b) middle third and (c) apical--two oxytalan
      fibre groups were shown histologically: 'blood vessel-related' and 'independent'
      oxytalan fibres. In levels a and b, both groups were arranged in a typical
      occluso-apical alignment along the reserve crown. Single oxytalan fibres deviated
      from their general course in order to attach to the cementum. In these cemental
      entheses the oxytalan fibres ran parallel to collagen fibre bundles. The
      interpretation of such morphological features emphasized the oxytalan fibres'
      capacity to improve the stability of periodontal blood vessel walls during
      masticatory movements. Level c, especially in regions next to the persisting
      epithelial root sheath, is the site of oxytalan fibre generation. This is a
      prerequisite for the facilitation of periodontal regeneration and reorganization
      during dental growth and eruption.

PMID- 15027958
TI  - Colocalization of DNA fragmentation and caspase-3 activation during atresia in
      pig antral follicles.
AB  - Apoptosis is the cellular mechanism of ovarian follicular atresia. The major
      downstream effector of this phenomenon in many tissues is caspase-3 but little is
      known about its role in pig ovarian apoptosis. In the present study, we detected
      the localization of caspase-3 in parallel with nuclear fragmentation (TUNEL) on
      healthy and early atretic antral follicles. In healthy antral follicles caspase-3
      and TUNEL positivity were occasionally recorded within theca layer. The incidence
      of DNA fragmentation, as indicated also by the biochemical detection, increased
      mainly in the granulosa layer of early atretic follicles. Quantitative analysis
      revealed, besides, that atresia was accompanied by a higher incidence of caspase
      3 (57.20 +/- 20.05 versus 3.64 +/- 0.61 positive cells in atretic versus healthy
      follicles, respectively; P < 0.05), of TUNEL positivity (20.13 +/- 9.33 versus
      0.42 +/- 0.12; P < 0.05) and simultaneous immunostaining for caspase-3 and TUNEL
      (15.02 +/- 6.95 versus 0.31 +/- 0.05; P < 0.05) in the granulosa layer. In
      detached granulosa cells isolated from the follicular fluid of early atretic
      follicles a further significantly increase was recorded in the percentage of
      TUNEL positivity and in the incidence of cells that showed colocalization of
      caspase-3 activity and DNA fragmentation. Granulosa cells of early atretic
      follicles exhibited a higher positivity for caspase-3 localized in the cytoplasm
      and occasionally in the nucleus area of granulosa cells. These results indicate
      that capsase-3 was involved and precociously activated during the process of
      atresia. Finally, the progressively higher incidence of TUNEL positivity and of
      double immunostaining in atretic cells collected within the follicular fluid
      seems to indicate that proteases activity leads only tardily in a detectable DNA
      fragmentation.

PMID- 15027959
TI  - Hans Spemann. One hundred years before the birth of experimental embryology.

PMID- 15027960
TI  - Ossification of the appendicular skeleton in the Spanish Ibex Capra pyrenaica
      Schinz, 1838 (Artiodactyla: Bovidae), with regard to determination of age.
AB  - We studied ossification macroscopically in 35 Spanish ibex (Capra pyrenaica)
      appendicular skeletons in order to establish the skeletochronology in both sexes
      of the species. The age of animals had been determined by means of horn segment
      counts, teeth replacement and cementum layer counts from first incisors and
      ranged from <1 to 12 years. Females showed a faster ossification process than
      males. Moreover, for each age or year class considered, regarding both sexes,
      different stages of epiphyseal fusion could be found. Therefore, if we try to use
      data from bone remains in population studies (e.g. differential mortality rates),
      determination of the ossification stage for ageing bone samples must be carried
      out with caution.

PMID- 15027961
TI  - Fine structure of the retinal pigment epithelium, Bruch's membrane and
      choriocapillaris in the ostrich (Struthio camelus).
AB  - The fine structure of the retinal pigment epithelium (RPE), Bruch's membrane and
      choriocapillaris in the ostrich (Struthio camelus) was investigated by using
      light microscopy and transmission electron microscopy. In this species, the RPE
      consisted of a single layer of low columnar cells. The epithelial cells were
      joined laterally by two type junctions, zonulae occludentes and zonulae
      adherentes located in the midregion of the cells. These cells displayed numerous
      deep basal infoldings and thick extensive apical processes, which enclosed the
      outer segments of the rods. The epithelial cell nuclei were large, vesicular and
      located basally within the epithelial cells. Smooth endoplasmic reticulum was
      very abundant, while rough endoplasmic reticulum was scarce. Mitochondria of
      various shapes were abundant basally while polysomes were plentiful and
      widespread. In the light-adapted state melanosomes were located in the apical
      region and in apical processes of the epithelial cells. Myeloid bodies were
      large, numerous and often showed ribosomes on their outer surface. Bruch's
      membrane (complexus basalis) was typical pentalaminate throughout the retina, as
      noted in the majority of other vertebrates. The endothelium of the
      choriocapillaris facing Bruch's membrane was extremely thin but only moderately
      fenestrated. Some of the fenestrations displayed a double-layered diaphragm while
      the majority showed the more typical single-layered diaphragm noted in most
      species.

PMID- 15027962
TI  - An immunohistochemical study of gastrointestinal endocrine cells in the BALB/c
      mouse.
AB  - The distributions and frequencies of some endocrine cells in the eight portions
      of the gastrointestinal tract (GIT) of BALB/c mouse were studied. Endocrine cells
      were stained using immunohistochemical method with seven types of antisera
      against bovine chromogranin (BCG), serotonin, gastrin, cholecystokinin (CCK)-8,
      somatostatin, glucagon and human pancreatic polypeptide (HPP), and the regional
      distributions and their relative frequencies were observed in the eight portions
      of the GIT of BALB/c mice. All seven types of immunoreactive (IR) cells were
      identified. Most of the IR cells in the intestinal portion were generally
      spherical or spindle in shape (open type cell) while round-shaped cells (closed
      type cell) were found in the intestinal gland and stomach regions occasionally.
      Their relative frequencies varied according to each portion of the GIT. BCG-IR
      cells were observed throughout the whole GIT except for the rectum and they were
      most predominant in the pylorus. Serotonin-IR cells were detected throughout the
      whole GIT and they showed the highest frequency in the fundus. Gastrin- and CCK
      IR cells were restricted to the pylorus and duodenum with a majority in the
      pylorus and rare or a few frequencies in the duodenum. Compared with other
      mammals, somatostatin-IR cells were restricted to the fundus and pylorus with a
      few frequencies, respectively. In addition, glucagon- and HPP-IR cells were
      restricted to the fundus and duodenum, respectively, with relative low
      frequencies. Some species-dependent unique distributions and frequencies of
      endocrine cells were observed in the GIT of BALB/c mouse compared with other
      rodents.

PMID- 15027963
TI  - Immunohistochemical study on the chicken adenohypophysis using monoclonal mouse
      anti-human FSH as a primary antibody.
AB  - This experiment was conducted to investigate the use of monoclonal mouse anti
      human FSH as a primary antibody for the immunohistochemical staining on chicken
      adenohypophysis paraffin sections. The use of monoclonal mouse anti-human primary
      antibody on chicken tissues has been developed. The protocol has been modified by
      comparing the results of the different groups. Briefly, this present protocol
      suggests modification in two areas; first, the antigen retrieval step, by placing
      the slides into the buffered citrate in microwave oven at 700 watt for 5 min, 3
      times, and antigen-antibody reactions. Secondly, the incubation with the primary
      antibody (dilution 1/100 for anti-FSH) at 37 degrees C for 90 min.

PMID- 15027964
TI  - Morphometry of the thoracic spine in German shepherd dog: a computed tomographic
      study.
AB  - Computed tomographic images of the thoracic spine of 13 German shepherd dogs were
      examined in order to determine the thoracic spine morphometry. Examinations were
      carried out in the transverse plane both intervertebral and mid-vertebral levels
      of the each thoracic vertebrae. The dorsoventral and interpedicular diameters of
      the spinal canal, the dorsoventral and transverse diameters of the vertebral
      body, the dorsoventral and transverse diameters of the spinal cord and also the
      cross-section area of the spinal canal were measured. The maximum values were
      found to be at the level of C7-T1. The shapes of the spinal canal and cord were
      circular in middle part, the shape became transverse oval in the cranial and
      caudal parts of the thoracic spine. The most significant correlation between the
      diameters was found to be in male dogs, except between dorsoventral diameters of
      the spinal canal and that of the vertebral body and between dorsoventral
      diameters of the spinal canal and transverse diameters of the vertebral body.

PMID- 15027965
TI  - Age-related change of somatostatin-immunoreactive neurones in the main olfactory
      bulb of the rat.
AB  - Somatostatin is found in the olfactory system, including the main olfactory bulb
      (MOB), and is thought to be one of the neuroactive substances for olfaction.
      However, somatostatin immunoreactivity in the olfactory system has not been
      determined during ageing. Hence, we examined the age-related changes of
      somatostatin-immunoreactive (IR) neurones in the rat MOB over a period of 2
      years, at the following various ageing stages: post-natal month 1 (PM 1), PM 3,
      PM 6, PM 12 and PM 24. In PM 1 group, a few somatostatin-IR neurones were
      detected in the granule cell layer (GCL), and had slender or oval somata and
      short processes. At PM 3, somatostatin-IR neurones were observed in the
      glomerular, external plexiform and GCL. The size of somatostatin-IR somata was
      larger than that at PM 1. In PM 6 group, the number and size of somatostatin-IR
      neurones increased, and their processes became longer while running in various
      directions. At PM 12, somatostatin-IR neurones increased in number, and their
      processes became markedly longer than those at PM 6. At this stage, somatostatin
      IR neurones had multipolar somata, and were the largest in size. In PM 24 group,
      somatostatin-IR neurones were most numerous. However, the processes of
      somatostatin-IR neurones were shorter than those at PM 12. This study suggests
      that the increased number of somatostatin-IR neurones in the MOB of aged rats may
      play a role to compensate for any decrease of olfactory function.

PMID- 15027968
TI  - Clinical practice guidelines for managing dyslipidemias in kidney transplant
      patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work
      Group of the National Kidney Foundation Kidney Disease Outcomes Quality
      Initiative.
AB  - The incidence of cardiovascular disease (CVD) is very high in patients with
      chronic kidney (CKD) disease and in kidney transplant recipients. Indeed,
      available evidence for these patients suggests that the 10-year cumulative risk
      of coronary heart disease is at least 20%, or roughly equivalent to the risk seen
      in patients with previous CVD. Recently, the National Kidney Foundation's Kidney
      Disease Outcomes Quality Initiative (K/DOQI) published guidelines for the
      diagnosis and treatment of dyslipidemias in patients with CKD, including
      transplant patients. It was the conclusion of this Work Group that the National
      Cholesterol Education Program Guidelines are generally applicable to patients
      with CKD, but that there are significant differences in the approach and
      treatment of dyslipidemias in patients with CKD compared with the general
      population. In the present document we present the guidelines generated by this
      workgroup as they apply to kidney transplant recipients. Evidence from the
      general population indicates that treatment of dyslipidemias reduces CVD, and
      evidence in kidney transplant patients suggests that judicious treatment can be
      safe and effective in improving dyslipidemias. Dyslipidemias are very common in
      CKD and in transplant patients. However, until recently there have been no
      adequately powered, randomized, controlled trials examining the effects of
      dyslipidemia treatment on CVD in patients with CKD. Since completion of the
      K/DOQI guidelines on dyslipidemia in CKD, the results of the Assessment of Lescol
      in Renal Transplantation (ALERT) Study have been presented and published. Based
      on information from randomized trials conducted in the general population and the
      single study conducted in kidney transplant patients, these guidelines, which are
      a modified version of the K/DOQI dyslipidemia guidelines, were developed to aid
      clinicians in the management of dyslipidemias in kidney transplant patients.
      These guidelines are divided into four sections. The first section (Introduction)
      provides the rationale for the guidelines, and describes the target population,
      scope, intended users, and methods. The second section presents guidelines on the
      assessment of dyslipidemias (guidelines 1-3), while the third section offers
      guidelines for the treatment of dyslipidemias (guidelines 4-5). The key guideline
      statements are supported mainly by data from studies in the general population,
      but there is an urgent need for additional studies in CKD and in transplant
      patients. Therefore, the last section outlines recommendations for research.

PMID- 15027969
TI  - Use of the scrotum as a transposition flap for closure of surgical wounds in
      three dogs.
AB  - OBJECTIVE: To describe use of the scrotum as a pedicle flap to cover defects
      created by tumor excision in the perineum or caudal and medial aspect of the
      thigh. STUDY DESIGN: Clinical study. ANIMALS: Three dogs. METHODS: After tumor
      excision and prescrotal castration, an incision was made around the base of the
      scrotum, leaving a pedicle on the side opposite the skin defect. After removal of
      the tunica dartos and abdominal fascia, the scrotal skin was stretched and shaped
      to the defect, then sutured in position with a simple interrupted pattern.
      Bandages that were changed every 48 hours compressed the flaps, and healing was
      observed until sutures were removed. RESULTS: Two dogs had first intention
      healing in 15 days, whereas 1 dog developed necrosis of 10% of the flap, and this
      area healed by second intention. CONCLUSION: In male dogs, the scrotal skin can
      be used as a pedicle flap for reconstructive surgery of wounds in the perineum
      and the proximomedial and caudal aspect of the thigh. CLINICAL RELEVANCE: The
      perineal region remains a surgical challenge because of the lack of the available
      skin for reconstruction of surgical wounds. The scrotal skin should be considered
      for use as a transposition flap to cover skin defects in this region.

PMID- 15027971
TI  - Treatment of septic common digital extensor tenosynovitis by complete resection
      in seven horses.
AB  - OBJECTIVE: To describe and evaluate a technique for radical resection of the
      entire intrathecal component of the common digital extensor tendon (CDET) in
      horses. STUDY DESIGN: Prospective clinical study. ANIMALS OR SAMPLE POPULATION:
      Seven client-owned horses. METHODS: Seven horses with wounds that resulted in
      septic tenosynovitis of the CDET sheath were treated by complete surgical
      resection of the affected tendon and ablation of the tendon sheath; 5 had
      previous surgery that was unsuccessful. Time from initial injury to complete
      resection was 1-22 weeks. In 6 horses, the wound was closed primarily using a
      closed suction (4 horses), penrose (1), or passive open drainage system (1). In 1
      horse, the surgical wound healed by second intention. All horses had
      postoperative bandaging, antibiotic administration, and physiotherapy. RESULTS:
      Surgical wounds healed primarily in 6 horses and by second intention in 1 horse.
      Follow-up (mean, 26.4 months; range, 18-38 months) was available for 6 horses;
      all returned to their athletic performance level without lameness or gait
      abnormality. CONCLUSIONS: Complete resection of the CDET was an effective
      surgical technique for management of chronic septic tenosynovitis. CLINICAL
      RELEVANCE: Horses with infection of the CDET and its sheath may be returned to
      long-term soundness without gait abnormality after radical resection.

PMID- 15027970
TI  - Effects of various anesthetic agents on laryngeal motion during laryngoscopy in
      normal dogs.
AB  - OBJECTIVE: To evaluate the effects of various drugs and drug combinations
      conventionally used for anesthesia on arytenoid cartilage motion during
      laryngoscopy in normal dogs. STUDY DESIGN: Experimental study. ANIMALS: Six large
      breed healthy dogs with no previous history of respiratory dysfunction. METHODS:
      Each dog was randomly assigned to a different injectable anesthetic protocol once
      weekly for 6 weeks, then in the 7th week all dogs were anesthetized with
      isoflurane. Videolaryngoscopy was performed and recorded starting immediately
      after induction until dogs could no longer be safely restrained for endoscopy.
      Video was digitized and 3 still images of maximal inspiration and expiration from
      the first 15 seconds (induction) and the last 15 seconds (recovery) were captured
      and imported into an image analysis software program. The height and area of the
      laryngeal ostium were measured in pixels. Normalization of the glottal gap area
      was performed using the formula (normalized glottal gap area (NGGA)=area in
      pixels/height(2)). ANOVA was performed on the NGGA of images collected at
      inspiration and expiration during induction and recovery. Fischer's exact test
      was performed when significance (P<.05) was found. RESULTS: Within each protocol,
      laryngeal motion (defined as change in NGGA) at induction was not significantly
      different from laryngeal motion measured at recovery. Additionally, no
      significant differences were found in arytenoid motion immediately after
      induction when anesthetic protocols were compared. Arytenoid motion before
      recovery was significantly greater with thiopental when compared with propofol
      (P=.046), ketamine+diazepam (P=.0098), acepromazine+thiopental (P=.0021), and
      acepromazine+propofol (P=.0065). No significant difference in arytenoid motion
      was seen immediately after induction or before recovery when
      acepromazine+butorphanol+ isoflurane and thiopental were compared. CONCLUSION: We
      concluded that intravenous thiopental given to effect is the best choice for
      assessing laryngeal function in dogs. Dogs premedicated with acepromazine with or
      without opioids that require further anesthetic restraint for laryngoscopy should
      be anesthetized with isoflurane administered by mask. CLINICAL RELEVANCE:
      Misdiagnosis of laryngeal paralysis during laryngoscopy can be avoided by
      selecting the anesthetic regimens with the least effect on arytenoid motion.

PMID- 15027973
TI  - Mandibular reconstruction of a partial hemimandibulectomy in a dog with severe
      malocclusion.
AB  - OBJECTIVE: To report treatment of severe mandibular malocclusion (after left
      partial hemimandibulectomy, approximately 7 cm gap). STUDY DESIGN: Clinical
      report. ANIMALS: A 14-month-old golden retriever. METHODS: After corrective
      osteotomy of the right horizontal mandibular ramus, normal occlusion was
      reestablished and temporarily maintained while both mandibles were stabilized by
      miniplates on the lateral alveolar surface spanning the bilateral mandibular
      defects (right=1.5 cm, left=7 cm). A fenestrated, monocortical rib graft was
      positioned beneath the left gingival surface to protect the synthetic graft,
      which was secured to the miniplate. A mandibular reconstruction plate (right) and
      a locking mandibular reconstruction plate (left) were secured to the ventral
      borders of the mandibles. Recombinant bone morphogenetic protein-2 delivered in
      collagen tricalcium phosphate sponges (rhBMP-2 collagen-TCP sponge) was inserted
      into both mandibular defects. RESULTS: New bone formation was identified at 3
      months and bony remodeling was evident at recheck examinations up to 4 years.
      Scintigraphy (6 months, 1 year) confirmed graft revascularization and viability.
      Bone collected (1 year) from the left defect site had robust new bone formation
      and evidence of continued remodeling. Only minor complications were encountered
      during the postoperative period and were easily resolved. CONCLUSIONS:
      Reconstruction of a large mandibular defect was facilitated by use of an
      osteoinductive factor (rhBMP-2 collagen-TCP sponge) as a graft substitute.
      CLINICAL RELEVANCE: One-step salvage and reconstruction facilitated by use of an
      osteoinductive factor, as a graft substitute, may be an alternative strategy for
      repair of large mandibular defects.

PMID- 15027972
TI  - Treatment of nonunions with nonglycosylated recombinant human bone morphogenetic
      protein-2 delivered from a fibrin matrix.
AB  - OBJECTIVE: To report the results of the treatment of nonunions with
      nonglycosylated recombinant human bone morphogenetic protein-2 (nglBMP-2)
      delivered from a designed fibrin matrix. STUDY DESIGN: Experimental trial in
      rodents and prospective clinical study in dogs and cats with nonunion fractures.
      ANIMALS: Twenty adult female, albino, Sprague-Dawley rats; 8 client-owned cats
      and dogs. METHODS: After development of a fibrin matrix and evaluation of nglBMP
      2 in a rodent femoral defect model, 8 consecutive long bone nonunion fractures
      (no progression in healing in > or = 3 months), were treated using 300 microg
      nglBMP-2 in a liquid fibrin precursor, injected into the defect gap after
      fracture revision and stabilization, or through a stab incision into the fracture
      site. The fibrin matrix was designed to clot in the wound after 60 seconds and to
      release the nglBMP-2 continuously over several days. RESULTS: Using only fibrin
      gel, 7% of the rat femoral defect was filled with new formed bone compared with
      79% defect filling using 2 microg nglBMP-2 (P=.006). Five and 10 microg nglBMP in
      fibrin resulted in union of all femoral defects with complete filling of the gap
      with new bone. Bony bridging and clinical healing was achieved in 7 patients
      within 24 weeks of administration of nglBMP-2. CONCLUSIONS: Application of nglBMP
      2 in a functional matrix can induce bone healing. Controlled release of nglBMP-2
      from a fibrin matrix mimics the natural fracture hematoma. CLINICAL RELEVANCE:
      nglBMP-2/fibrin can successfully replace a cancellous bone autograft in fracture
      treatment with an associated reduction in graft donor site morbidity and surgical
      time.

PMID- 15027974
TI  - The three-loop pulley suture versus two locking-loop sutures for the repair of
      canine achilles tendons.
AB  - OBJECTIVE: To compare a 3-loop pulley suture pattern with 2 locking-loop sutures
      for the repair of components of the canine Achilles mechanism. STUDY DESIGN: In
      vitro biomechanical study. ANIMALS: Forty-eight paired tendons collected from 9
      canine cadavers. METHODS: Paired tendons were repaired with either a 3-loop
      pulley suture or 2 locking-loop sutures and tensile tested to failure. To ensure
      accurate anastomosis gap measurement a direct, non-contact, method of gap
      measurement, using digital video, was devised. Load initiating gap formation
      (defined as load at a 1 mm gap) and load producing a 3 mm gap were evaluated in
      addition to maximum load, gap at failure, mode of failure, and time spent placing
      the sutures. RESULTS: Maximum load values were similar for both repairs. The mean
      1 mm gap loads were 44.0 and 18.4 N, and the mean 3 mm gap loads were 56.3 and
      34.7 N, for the 3-loop pulley pattern and the 2 locking-loops, respectively;
      these differences were statistically significant. The 3-loop pulley pattern was
      faster to place and resulted in a smaller gap at failure. All but 2 repairs
      failed by suture pull out. CONCLUSIONS: The 3-loop pulley pattern is more
      resistant to gap formation during tensile loading, and is quicker to place, than
      2 locking-loop sutures. CLINICAL RELEVANCE: Gap formation can significantly delay
      tendon healing. Tendon repairs with a gap >3 mm are reported to be at increased
      risk of rupture during the first 6 weeks postoperatively.

PMID- 15027976
TI  - Results of arthroscopic versus open arthrotomy for surgical management of cranial
      cruciate ligament deficiency in dogs.
AB  - OBJECTIVE: To evaluate postoperative morbidity in dogs after experimental cranial
      cruciate ligament transection and immediate stifle stabilization using an
      arthroscopically assisted or open arthrotomy technique. STUDY DESIGN:
      Experimental, prospective study. ANIMALS: Thirteen mature, healthy dogs. METHODS:
      Dogs were randomly assigned to 1 of 2 groups. Seven underwent open arthrotomy
      while 6 underwent arthroscopy of 1 stifle joint. Cranial cruciate ligaments were
      transected and debrided and all stifles were stabilized using 2 lateral
      extracapsular fabellar-tibial sutures. Minimally invasive suture placement was
      employed in the arthroscopy group. All animals were evaluated for 9 weeks using
      kinetic gait assessments, comfortable stifle range of motion measurements, thigh
      girth measurements, differential cell counts of synovial fluid, and subjective
      scores of behavior, limb use, and lameness. RESULTS: Significant differences in
      postoperative morbidity were observed during the 9-week postoperative period.
      Greater peak vertical force for 8 weeks (P=.015), vertical impulse for 6 weeks
      (P=.044), comfortable stifle range of motion for 9 weeks (P=.017), comfortable
      stifle flexion for 4 weeks (P=.005), and operative limb thigh circumference
      (P=.020) for 9 weeks were observed for the arthroscopy group. A trend towards a
      lower differential mean synovial polymorphonuclear cell count in the arthroscopy
      group was seen at 4 and 8 weeks postoperatively. No differences in subjective
      evaluation scores were noted. CONCLUSIONS: In this study population, significant
      differences were seen between the arthroscopy and arthrotomy groups for peak
      vertical force, vertical impulse, comfortable stifle range of motion, comfortable
      stifle flexion, and thigh circumference data. CLINICAL RELEVANCE: The results of
      this study suggest that short-term postoperative morbidity may be reduced in dogs
      receiving arthroscopic joint surgery with a limited approach for stifle
      stabilization as compared with a traditional open arthrotomy technique.

PMID- 15027975
TI  - Successful surgical treatment of mitral valve stenosis in a dog.
AB  - OBJECTIVE: To report the successful surgical management (open mitral
      commissurotomy, OMC) of mitral stenosis (MS), incorporating heart-beating
      cardiopulmonary bypass (CPB), in a 1-year-old dog. STUDY DESIGN: Clinical case.
      ANIMALS: One-year-old Cairn Terrier with MS. MATERIALS AND METHODS: Diagnosis of
      MS was confirmed by means of 2-dimensional, continuous-wave and color-flow
      Doppler echocardiography. Surgery was performed through a left intercostal
      thoracotomy. CPB was initiated and the heart was kept beating. The fused
      commissures of the mitral valve were incised to free the cusps of the valve.
      RESULTS: Left intercostal thoracotomy allowed easy observation of the mitral
      orifice during heart-beating OMC. Persistent bleeding from the atriotomy site
      required a second surgical procedure after which the dog had an uneventful
      recovery. Echocardiography at 2 weeks and 1 year postoperatively indicated
      substantial improvement in left ventricular filling (pressure half-time=187 ms
      before surgery, 105 ms [2 weeks] and 110 ms [1 year] after surgery). Enlargement
      of the left atrium resolved; however, moderate mitral valve regurgitation was
      still present. CONCLUSIONS: MS can be successfully treated by OMC, facilitated by
      use of CPB. Substantial improvement in cardiac function was evident by ultrasound
      and Doppler examination postoperatively. CLINICAL RELEVANCE: OMC under heart
      beating CPB should be considered for the treatment of MS in the dog.

PMID- 15027977
TI  - Miniplate reconstruction of severely comminuted maxillary fractures in two dogs.
AB  - OBJECTIVE: To describe the treatment of severely comminuted maxillary fractures
      that resulted in separation of the maxilla from the base of the skull in 2 dogs.
      The structural areas of support, identified by thicker areas of bones of the
      skull, were used as a guide to apply buttress plate fixation, with miniplates
      using these apparent structural buttresses. STUDY DESIGN: Case report. SAMPLE
      POPULATION: A 1-year-old Borzoi and a 5-year-old German shepherd dog. RESULTS:
      Fractures were repaired in a single procedure that resulted in excellent
      postoperative occlusion, immediate function, and cosmetic result. Healing was
      uneventful. Full function and excellent cosmetic appearance were still evident at
      5 years, and the miniplates have not been removed. CONCLUSIONS: Long-term outcome
      appeared to justify surgical reconstruction of these severely comminuted
      fractures with miniplate methods similar to those used in human maxillofacial
      surgery. Miniplates were easily contoured 3-dimensionally and placed along
      apparent lines of buttress support. Miniplate fixation provided a simple method
      to secure the bone fragments with excellent stability while maintaining both bony
      and soft tissue stability. CLINICAL RELEVANCE: Severely comminuted maxillary
      fractures in the dog may be repaired with miniplate fixation, using fixation
      principles identical to those used for similarly complex fractures in human
      maxillofacial surgery.

PMID- 15027978
TI  - Femur fractures associated with canine total hip replacement.
AB  - OBJECTIVE: To report femur fracture as a complication of canine total hip
      replacement (THR) and to report the incidence, predisposing factors, treatment
      options, and outcome. STUDY DESIGN: Prospective clinical study. ANIMALS: Twenty
      two client-owned dogs with 24 femoral fractures occurring during or after THR.
      METHODS: Cemented THR (BioMedtrix, Boonton, NJ) was performed. Medical records
      and radiographs were used to identify dogs that had femur fracture and to
      identify risk factors. Follow-up was obtained until dog death or study end.
      RESULTS: The overall incidence of femur fracture after THR was 2.9%. Femoral
      fractures occurred intraoperatively, immediately postoperatively, and up to 2196
      days after THR. In 17 dogs, fractures resulted from a traumatic event. Osteopathy
      was present at THR in 5 dogs; all developed femoral fissures during reaming.
      Three dogs had fractures associated with cortical thinning secondary to aseptic
      loosening. Fracture treatment included euthanasia (1 dog), strict confinement (3
      dogs), full cerclage wires on long oblique fractures (3 dogs), or plate and screw
      fixation (10 with, and 7 without, cerclage wires). All fractures extended near
      the distal tip of the femoral stem and all aggressively treated fractures healed.
      CONCLUSIONS: Predisposing risk factors for femur fracture after THR include
      osteopathy and iatrogenic fissures created during reaming. Trauma, excessive load
      concentration, and increased torque can lead to mid-diaphyseal fracture near the
      end of the femoral stem. Fracture did not disrupt THR implants. Cement fracture
      exposing the tip of the femoral stem did not affect fracture healing or
      rehabilitation. Immediate plate and screw fixation resulted in the most favorable
      outcome; healing occurred in 6-10 weeks. CLINICAL RELEVANCE: Femur fractures that
      occur after THR should be repaired using plate and screw fixation augmented with
      cerclage wire when needed. Forces on fissures should be neutralized to prevent
      propagation and fracture. Owners of high-risk patients (old dogs with
      osteopathies or previous hip surgery) should be counseled before THR. The
      prognosis is excellent when fractures are treated correctly.

PMID- 15027979
TI  - A mechanical comparison of 4.5 mm narrow and 3.5 mm broad plating systems for
      stabilization of gapped fracture models.
AB  - OBJECTIVE: To evaluate and compare the mechanical properties of 4.5 narrow and
      3.5 broad plating systems using their respective cortical and cancellous screws
      in unstable, central, and eccentric gap fracture models. STUDY DESIGN: Mechanical
      evaluation and comparison of 2 dynamic compression plate (DCP) systems. SAMPLE
      POPULATION: Eighteen cortical and 30 cancellous gapped fracture models. METHODS:
      DCP (4.5 mm narrow, 3.5 mm broad) with their respective cortical screws were
      applied to cortical bone density polyurethane foam blocks to construct center gap
      cortical fracture models that were tested in gap closing monotonic 4-point
      bending. DCP (4.5 mm narrow, 3.5 mm broad) with their respective cancellous
      screws were applied to cancellous bone density polyurethane foam blocks to
      construct eccentric gap cancellous fracture models. The cancellous constructs
      were tested in monotonic gap opening and gap closing cantilever bending and in
      cyclic axial loading. Univariate and multivariate repeated measures ANOVA were
      used to compare the maximum loads at failure of the 4.5 mm constructs and 3.5 mm
      constructs. RESULTS: The 4.5 mm narrow plating system withstood significantly
      higher loads at failure than the 3.5 mm broad plating system in 4-point bending
      (P<.0001) and gap opening cantilever bending (P<.0001). The 4.5 mm system failed
      in gap closing cantilever bending by plastic deformation of the plate, whereas
      the 3.5 mm system failed by screw pullout. There was no difference between the 2
      systems in cyclic axial loading. CONCLUSION: Results indicate that the 4.5 mm
      narrow plating system has a mechanical advantage over the 3.5 mm broad plating
      system for stabilization of gapped fracture models. CLINICAL RELEVANCE: The 4.5
      mm narrow plating system may be mechanically advantageous compared with the 3.5
      mm broad plating system for stabilizing unreconstructed comminuted long bone
      fractures in large dogs.

PMID- 15027980
TI  - Intraosseous gentamicin perfusion of the distal metacarpus in standing horses.
AB  - OBJECTIVE: To report tissue gentamicin concentrations after intraosseous (IO)
      perfusion in standing horses. STUDY DESIGN: In vivo study. ANIMALS OR SAMPLE
      POPULATION: Twelve horses. METHODS: Sedated horses had a cannulated cortical bone
      screw inserted into the dorsolateral aspect of the treated metacarpus and a
      tourniquet applied proximally. Gentamicin (2.2 mg/kg) diluted in sterile saline
      solution (0.1 mL/kg) was infused through the screw. Two horses were euthanatized
      at each time interval: 0, 2, 6, 12, 24, and 36 hours. Synovial fluid and bone
      samples were collected distal to the screw from both forelimbs. Gentamicin
      concentrations were measured using fluorescence polarization immunoassay.
      RESULTS: The highest synovial fluid gentamicin concentrations were 385+/-273
      microg/mL (mean+/-SD) in the metacarpophalangeal joint, 225+/-205 microg/mL in
      the proximal interphalangeal joint, 215+/-205 microg/mL in the distal
      interphalangeal joint, 382+/-195 microg/mL in the digital flexor tendon sheath,
      and 206+/-161 microg/mL in the navicular bursa. The highest bone concentrations
      of gentamicin were 55+/-30 microg/g in the distal metacarpus, 34+/-27 microg/g in
      the proximal, 16+/-15 microg/g in the middle, and 16+/-2.2 microg/g in the distal
      phalanges, and 27+/-17 microg/g in the proximal and 24+/-11 microg/g in the
      distal sesamoid bones. CONCLUSION: Standing IO perfusion of gentamicin resulted
      in local antibiotic concentrations in the synovial structures and bones of the
      distal aspect of the limb that exceed the reported minimum inhibitory
      concentration of pathogens commonly implicated in equine orthopedic infections.
      CLINICAL RELEVANCE: Standing IO perfusion of gentamicin in the distal aspect of
      the limb should be considered for treatment of orthopedic infections of this
      region in horses.

PMID- 15027981
TI  - Pre- and postoperative force plate analysis of dogs with experimentally
      transected cranial cruciate ligaments treated using tibial plateau leveling
      osteotomy.
AB  - OBJECTIVE: Quantitative and objective assessment of hindlimb kinetics after
      cranial cruciate ligament (CrCL) transection and subsequent stifle stabilization
      using the tibial plateau leveling osteotomy (TPLO) in normal dogs. STUDY DESIGN:
      In vivo experimental biomechanical evaluation. ANIMALS: Six healthy adult
      foxhounds. METHODS: Dogs were screened by orthopedic and radiographic examination
      before study entry. Force plate analysis of gait was measured before extirpation
      of the right CrCL and TPLO and again at 8 and 18 weeks after surgery. RESULTS:
      There was a significant decrease in peak vertical forces (PVFs) and vertical
      impulse (VI) of the treated hindlimb at 8 weeks when compared with preoperative
      and 18-week measurements. When compared with preoperative values, there was no
      significant difference in 18 week PVF and VI in dogs that had TPLO. CONCLUSION:
      TPLO can restore kinetic measures of limb function at 18-weeks after surgery when
      compared with preoperative values after experimental transection of the CrCL in
      dogs. CLINICAL RELEVANCE: TPLO induces lameness that returns to near normal at 18
      weeks. The severity and duration of lameness was similar to that reported for
      other experimental models of stifle instability repaired by different techniques.

PMID- 15027982
TI  - Framing the doctor-patient relationship in chronic illness: a comparative study
      of general practitioners' accounts.
AB  - How family doctors conceptualise chronic illness in the consultation has
      important implications for both the delivery of medical care, and its experience
      by patients. In this paper, we present the results of a re-analysis of
      qualitative data collected in a series of studies of British family doctors
      between 1995 and 2001, to explore the ways in which the legitimacy and authority
      of medical knowledge and practice are organised and worked out in relation to
      three kinds of chronic illness (menorrhagia; depression; and chronic low back
      pain/medically unexplained symptoms). We present a comparative analysis of (a).
      the moral evaluation of the patient (and judgements about the legitimacy of
      symptom presentation); (b). the possibilities of disposal; and (c). doctors'
      empathic responses to the patient, in each of these clinical cases. Our analysis
      defines some of the fundamental conditions through which general practitioners
      frame their relationships with patients presenting complex but sometimes diffuse
      combinations of 'social', 'psychological' and 'medical' symptoms. These are
      fundamental to, yet barely touched by, the increasingly voluminous literature on
      how doctors should interact with patients. Moving beyond the individual studies
      from which our data are drawn, we have outlined some of the highly complex and
      demanding features of what is often seen as routine and unrewarding medical work,
      and some of the key requirements for the local negotiation of patients' problems
      and their meanings (for both patients and doctors) in everyday general practice.

PMID- 15027983
TI  - Investigation of the ways in which patients' reports of their satisfaction with
      healthcare are constructed.
AB  - A characteristic feature of patient satisfaction research is the consistently
      high level of satisfaction recorded. More reliable and relevant inquiry tools are
      constantly being developed, but underlying psychological and social pressures
      that could promote such a consistent and undiscriminating response have been
      little investigated. Williams et al. (1998) explored the phenomenon and concluded
      that, by considering issues of duty and culpability, patients could make
      allowances for poor care, and avoid evaluating it negatively. Their study was in
      community mental health. This study follows up their work within elective
      orthopaedic surgery, and investigates the pressures promoting such apparent
      transformation of opinion. Using a longitudinal design, and in-depth qualitative
      interviews, the patient's process of reflection was explored. Three psycho-social
      pressures were identified that appear to work together to make the transformation
      of opinion almost the default process. They are: the relative dependency of
      patients within the healthcare system; their need to maintain constructive
      working relationships with those providing their care; and their general
      preference for holding a positive outlook. It is suggested that, while it is the
      patient's prerogative to re-interpret the quality of their care positively, it is
      not the prerogative of the inquirer to accept this re-interpretation as
      representative of the patient's experience. Methods of inquiry are needed which
      access something of patients' development of opinion, and thereby something of
      their initial, often more negative, untransformed responses to their healthcare
      experiences.

PMID- 15027984
TI  - Human growth hormone and the temptations of biomedical enhancement.
AB  - It is likely that humans have sought enhancements for themselves or their
      children for as long as they have recognised that improvements in individuals are
      a possibility. One genre of self-improvement in modern society can be called
      'biomedical enhancements'. These include drugs, surgery and other medical
      interventions aimed at improving the mind, body or performance. This paper uses
      the case of human growth hormone (hGH) to examine the social nature of
      enhancements. Synthetic hGH was developed in 1985 by the pharmaceutical industry
      and was approved by the FDA for very specific uses, particularly treatment of
      growth hormone deficiency. However, it has also been promoted for a number of
      'off label' uses, most of which can be deemed enhancements. Drugs approved for
      one treatment pave the way for use as enhancements for other problems. Claims
      have been made for hGH as a treatment for idiopathic shortness, as an anti-ageing
      agent and to improve athletic performance. Using the hGH case, we are able to
      distinguish three faces of biomedical enhancement: normalisation, repair and
      performance edge. Given deeply ingrained social and individual goals in American
      society, the temptations of biomedical enhancements provide inducement for
      individuals and groups to modify their situation. We examine the temptations of
      enhancement in terms of issues such as unnaturalness, fairness, risk and
      permanence, and shifting social meanings. In our conclusions, we outline the
      potentials and pitfalls of biomedical enhancement.

PMID- 15027985
TI  - Moving forward? Complementary and alternative practitioners seeking self
      regulation.
AB  - Complementary and alternative medicine (CAM) occupations continue to struggle
      towards achieving professional status, especially in the form of statutory
      regulation. Many consider professional status a worthwhile goal for CAM
      occupations, yet it is a process fraught with tensions. In this paper we present
      in-depth interview data from the leaders of three CAM groups (naturopaths,
      traditional Chinese medicine practitioners acupuncturists, and homeopaths) in
      Ontario, Canada that demonstrate four main strategies used by these groups to
      professionalize. The strategies discussed are related to how the knowledge base
      of each group is organised and transmitted. These strategies include: improving
      educational standards, improving practice standards, engaging in peer-reviewed
      research and increasing group cohesion. At the core of these strategies is the
      demarcation of who is qualified to practice, and a signalling to 'outsiders',
      such as medicine and the government, that practitioners are qualified and
      legitimate. Across the three groups, the leaders referred to the inclusion of
      medical science as a basis for distinguishing between 'science' and 'non-science'
      as well as who should practice and who should not. We highlight how internal
      battles over the infusion of medical science into the knowledge base are part of
      the process for establishing legitimacy for the three CAM groups in our study. We
      end with a brief discussion of the implications of these internal battles over
      medical science knowledge for the future of CAM groups.

PMID- 15027986
TI  - Sudden illness and biographical flow in narratives of stroke recovery.
AB  - The conceptual framework of biographical disruption has dominated studies into
      the everyday experience of chronic illness. Biographical disruption assumes that
      the illness presents the person with an intense crisis, regardless of other
      mitigating factors. However, our data suggests that the lives of people who have
      a particular illness that is notably marked by sudden onset are not inevitably
      disrupted. Extensive qualitative interviews were conducted with a sample of
      veteran non-Hispanic white, African-American, and Puerto Rican Hispanic stroke
      survivors, at one month, six months and twelve months after being discharged home
      from hospital. Narrative excerpts are presented to describe specific discursive
      resources these people use that offset the disrupting connotations of stroke. Our
      findings suggest a biographical flow more than a biographical disruption to
      specific chronic illnesses once certain social indicators such as age, other
      health concerns and previous knowledge of the illness experience, are taken into
      account. This difference in biographical construction of the lived self has been
      largely ignored in the literature. Treating all survivor experiences as universal
      glosses over some important aspects of the survival experience, resulting in
      poorly designed interventions, and in turn, low outcomes for particular people.

PMID- 15027988
TI  - Illness behaviour: a selective review and synthesis.
AB  - Sociologists have researched the subject of illness behaviour for more than five
      decades. Recently the discussion has taken on new importance because of changes
      in the delivery of health care and the emergence of patients' rights and
      increased patient knowledge of medicine. Through a selective review of the
      literature on illness behaviour, the paper aims to show that singular and
      segmented approaches to illness behaviour have not clearly elucidated the
      complexity of the phenomenon. A more comprehensive and structured analysis of
      illness behaviour can be accomplished with mixed qualitative and
      hierarchical/structural quantitative techniques. Following a discussion of prior
      research in social psychology, demography, economics, social networks and
      geographic systems, this paper offers a template for future analysis of illness
      behaviour.

PMID- 15027989
TI  - Self, agency and the surgical collective: detachment.
AB  - In this article, I describe the socio-technical organisation of surgical
      rehabilitation. After having gone through surgical intervention, patients are
      implicated within various types of medical work aimed at adjusting their bodies
      to post-operative social and material environments. My argument is that the
      process of re-establishment of a 'self' is mediated through a re-disposition of
      agency in the socio-technical ensemble upon which the patient depends immediately
      after surgery. Drawing on one year of ethnographic fieldwork in a neurosurgical
      clinic, and theoretical resources from science and technology studies, this paper
      is an attempt to describe how, within surgical post-operative practices, the
      relational dynamics of social and material components endorsed within those
      practices may re-institute patients' sense of themselves, and re-organise their
      relationship with the world and other people. In surgery, the outcome of this
      dynamic process is the reorganisation of forms of agency for the patient. I will
      refer to this reorganisation as 'detachment'. It is my contention that this
      research may contribute to the literature on the experience of chronic illness by
      specifying the socio-technical conditions for the local achievement of self and
      agency.

PMID- 15027990
TI  - Embodied health movements: new approaches to social movements in health.
AB  - Social movements organised around health-related issues have been studied for
      almost as long as they have existed, yet social movement theory has not yet been
      applied to these movements. Health social movements (HSMs) are centrally
      organised around health, and address: (a) access to or provision of health care
      services; (b) health inequality and inequity based on race, ethnicity, gender,
      class and/or sexuality; and/or (c) disease, illness experience, disability and
      contested illness. HSMs can be subdivided into three categories: health access
      movements seek equitable access to health care and improved provision of health
      care services; constituency-based health movements address health inequality and
      health inequity based on race, ethnicity, gender, class and/or sexuality
      differences; and embodied health movements (EHMs) address disease, disability or
      illness experience by challenging science on etiology, diagnosis, treatment and
      prevention. These groups address disproportionate outcomes and oversight by the
      scientific community and/or weak science. This article focuses on embodied health
      movements, primarily in the US. These are unique in three ways: 1) they introduce
      the biological body to social movements, especially with regard to the embodied
      experience of people with the disease; 2) they typically include challenges to
      existing medical/scientific knowledge and practice; and 3) they often involve
      activists collaborating with scientists and health professionals in pursuing
      treatment, prevention, research and expanded funding. This article employs
      various elements of social movement theory to offer an approach to understanding
      embodied health movements, and provides a capsule example of one such movement,
      the environmental breast cancer movement.

PMID- 15027991
TI  - Achieving multiple topic shifts in primary care medical consultations: a
      conversation analysis study in UK general practice.
AB  - The 'by the way' phenomenon, while commonly described in medical texts on the
      consultation, has not been systematically explored from an interactional
      perspective. Starting from a 'noticing' of an example of this phenomenon we
      studied a collection of over 200 recorded consultations in British general
      practice. New topics were introduced by both parties, but more commonly by
      patients, who used two sorts of device to change topic: an announcement, usually
      at the start of a consultation, but sometimes later, that they had multiple
      topics, which we have called a 'pre-announcement', and an apparently unexpected
      sudden change of topic, which we have called an 'in-situ announcement'. These
      phenomena occurred in about one third of our unselected collection of recorded
      consultations, drawn from nine doctors, and 27 surgery (office) sessions. We
      argue that this management of multiple topics is an important and normal part of
      the consultation, in contrast to its problematic status implied in some medical
      literature.

PMID- 15027992
TI  - Giving up on geneticization: a comment on Hedgecoe's 'Expansion and uncertainty:
      cystic fibrosis, classification and genetics'.

PMID- 15027994
TI  - Review article: the sociology of dying, death and bereavement.

PMID- 15027996
TI  - A quantitative risk assessment of waterborne cryptosporidiosis in France using
      second-order Monte Carlo simulation.
AB  - A pragmatic quantitative risk assessment (QRA) of the risks of waterborne
      Cryptosporidium parvum infection and cryptosporidiosis in immunocompetent and
      immunodeficient French populations is proposed. The model takes into account
      French specificities such as the French technique for oocyst enumeration
      performance and tap water consumption. The proportion of infective oocysts is
      based on literature review and expert knowledge. The probability of infection for
      a given number of ingested viable oocysts is modeled using the exponential dose
      response model applied on published data from experimental infections in
      immunocompetent human volunteers challenged with the IOWA strain. Second-order
      Monte Carlo simulations are used to characterize the uncertainty and variability
      of the risk estimates. Daily risk of infection and illness for the
      immunocompetent and the immunodeficient populations are estimated according to
      the number of oocysts observed in a single storage reservoir water sample. As an
      example, the mean daily risk of infection in the immunocompetent population is
      estimated to be 1.08 x 10(-4) (95% confidence interval: [0.20 x 10(-4); 6.83 x
      10(-4)]) when five oocysts are observed in a 100 L storage reservoir water
      sample. Annual risks of infection and disease are estimated from a set of oocyst
      enumeration results from distributed water samples, assuming a negative binomial
      distribution of day-to-day contamination variation. The model and various
      assumptions used in the model are fully explained and discussed. While caveats of
      this model are well recognized, this pragmatic QRA could represent a useful tool
      for the French Food Safety Agency (AFSSA) to define recommendations in case of
      water resource contamination by C. parvum whose infectivity is comparable to the
      IOWA strain.

PMID- 15027997
TI  - Combining food frequency and survey data to quantify long-term dietary exposure:
      a methyl mercury case study.
AB  - Twenty-four-hour recall data from the Continuing Survey of Food Intake by
      Individuals (CSFII) are frequently used to estimate dietary exposure for risk
      assessment. Food frequency questionnaires are traditional instruments of
      epidemiological research; however, their application in dietary exposure and risk
      assessment has been limited. This article presents a probabilistic method of
      bridging the National Health and Nutrition Examination Survey (NHANES) food
      frequency and the CSFII data to estimate longitudinal (usual) intake, using a
      case study of seafood mercury exposures for two population subgroups (females 16
      to 49 years and children 1 to 5 years). Two hundred forty-nine CSFII food codes
      were mapped into 28 NHANES fish/shellfish categories. FDA and state/local seafood
      mercury data were used. A uniform distribution with minimum and maximum blood
      diet ratios of 0.66 to 1.07 was assumed. A probabilistic assessment was conducted
      to estimate distributions of individual 30-day average daily fish/shellfish
      intakes, methyl mercury exposure, and blood levels. The upper percentile
      estimates of fish and shellfish intakes based on the 30-day daily averages were
      lower than those based on two- and three-day daily averages. These results
      support previous findings that distributions of "usual" intakes based on a small
      number of consumption days provide overestimates in the upper percentiles. About
      10% of the females (16 to 49 years) and children (1 to 5 years) may be exposed to
      mercury levels above the EPA's RfD. The predicted 75th and 90th percentile blood
      mercury levels for the females in the 16-to-49-year group were similar to those
      reported by NHANES. The predicted 90th percentile blood mercury levels for
      children in the 1-to-5-year subgroup was similar to NHANES and the 75th
      percentile estimates were slightly above the NHANES.

PMID- 15027998
TI  - A comparison of three methods for calculating confidence intervals for the
      benchmark dose.
AB  - Various methods exist to calculate confidence intervals for the benchmark dose in
      risk analysis. This study compares the performance of three such methods in
      fitting nonlinear dose-response models: the delta method, the likelihood-ratio
      method, and the bootstrap method. A data set from a developmental toxicity test
      with continuous, ordinal, and quantal dose-response data is used for the
      comparison of these methods. Nonlinear dose-response models, with various shapes,
      were fitted to these data. The results indicate that a few thousand runs are
      generally needed to get stable confidence limits when using the bootstrap method.
      Further, the bootstrap and the likelihood-ratio method were found to give fairly
      similar results. The delta method, however, resulted in some cases in different
      (usually narrower) intervals, and appears unreliable for nonlinear dose-response
      models. Since the bootstrap method is more time consuming than the likelihood
      ratio method, the latter is more attractive for routine dose-response analysis.
      In the context of a probabilistic risk assessment the bootstrap method has the
      advantage that it directly links to Monte Carlo analysis.

PMID- 15027999
TI  - Dose-response model for 13 strains of salmonella.
AB  - Data from a human feeding trial with healthy men were used to develop a dose
      response model for 13 strains of Salmonella and to determine the effects of
      strain variation on the shape of the dose-response curve. Dose-response data for
      individual strains were fit to a three-phase linear model to determine minimum,
      median, and maximum illness doses, which were used to define Pert distributions
      in a computer simulation model. Pert distributions for illness dose of individual
      strains were combined in an Excel spreadsheet using a discrete distribution to
      model strain prevalence. In addition, a discrete distribution was used to model
      dose groups and thus create a model that simulated human feeding trials. During
      simulation of the model with @Risk, an illness dose and a dose consumed were
      randomly assigned to each consumption event in the simulated feeding trial and if
      the illness dose was greater than the dose consumed then the model predicted no
      illness, otherwise the model predicted that an illness would occur. To verify the
      dose-response model predictions, the original feeding trial was simulated. The
      dose-response model predicted a median of 69 (range of 43-101) illnesses compared
      to 74 in the original trial. Thus, its predictions were in agreement with the
      data used to develop it. However, predictions of the model are only valid for
      eggnog, healthy men, and the strains and doses of Salmonella used to develop it.
      When multiple strains of Salmonella were simulated together, the predicted dose
      response curves were irregular in shape. Thus, the sigmoid shape of dose-response
      curves in feeding trials with one strain of Salmonella may not accurately reflect
      dose response in naturally contaminated food where multiple strains may be
      present.

PMID- 15028000
TI  - Children's exposure to arsenic from CCA-treated wooden decks and playground
      structures.
AB  - CCA-treated wood is widely used in the fabrication of outdoor decks and
      playground equipment. Because arsenic can be removed from the surface of CCA
      treated wood both by physical contact and by leaching, it is important to
      determine whether children who play on such structures may ingest arsenic in
      quantities sufficient to be of public health concern. Based on a review of
      existing studies, it is estimated that arsenic doses in amounts of tens of
      micrograms per day may be incurred by children having realistic levels of
      exposure to CCA-treated decks and playground structures. The most important
      exposure pathway appears to be oral ingestion of arsenic that is first dislodged
      from the wood by direct hand contact, then transferred to the mouth by children's
      hand-to-mouth activity. The next most important pathway appears to be dermal
      absorption of arsenic, while ingestion of soil that has become contaminated by
      leaching from CCA-treated structures appears to be of lesser importance, except
      possibly in the case of children with pica. Considerable uncertainty, however, is
      associated with quantitative estimates of children's arsenic exposure from CCA
      treated wood. Priorities for refining estimates of arsenic dose include detailed
      studies of the hand-to-mouth transfer of arsenic, studies of the dermal and
      gastrointestinal absorption of dislodgeable arsenic, and studies in which doses
      of arsenic to children playing in contact with CCA-treated wood are directly
      determined by measurement of arsenic in their urine, hair, and nails.

PMID- 15028001
TI  - A parametric model for detecting hormetic effects in developmental toxicity
      studies.
AB  - Hormetic effects have been observed at low exposure levels based on the dose
      response pattern of data from developmental toxicity studies. This indicates that
      there might actually be a reduced risk of exhibiting toxic effects at low
      exposure levels. Hormesis implies the existence of a threshold dose level and
      there are dose-response models that include parameters that account for the
      threshold. We propose a function that introduces a parameter to account for
      hormesis. This function is a subset of the set of all functions that could
      represent a hormetic dose-response relationship at low exposure levels to toxic
      agents. We characterize the overall dose-response relationship with a piecewise
      function that consists of a hormetic u-shape curve at low dose levels and a
      logistic curve at high dose levels. We apply our model to a data set from an
      experiment conducted at the National Toxicology Program (NTP). We also use the
      beta-binomial distribution to model the litter response data. It can be seen by
      observing the structure of these data that current experimental designs for
      developmental studies employ a limited number of dose groups. These designs may
      not be satisfactory when the goal is to illustrate the existence of hormesis. In
      particular, increasing the number of low-level doses improves the power for
      detecting hormetic effects. Therefore, we also provide the results of simulations
      that were done to characterize the power of current designs in detecting hormesis
      and to demonstrate how this power can be improved upon by altering these designs
      with the addition of only a few low exposure levels.

PMID- 15028002
TI  - Estimating contaminant dose for intermittent dermal contact: model development,
      testing, and application.
AB  - Assessments of aggregate exposure to pesticides and other surface contamination
      in residential environments are often driven by assumptions about dermal
      contacts. Accurately predicting cumulative doses from realistic skin contact
      scenarios requires characterization of exposure scenarios, skin surface loading
      and unloading rates, and contaminant movement through the epidermis. In this
      article we (1) develop and test a finite-difference model of contaminant
      transport through the epidermis; (2) develop archetypal exposure scenarios based
      on behavioral data to estimate characteristic loading and unloading rates; and
      (3) quantify 24-hour accumulation below the epidermis by applying a Monte Carlo
      simulation of these archetypal exposure scenarios. The numerical model, called
      Transient Transport through the epiDERMis (TTDERM), allows us to account for
      variable exposure times and time between exposures, temporal and spatial
      variations in skin and compound properties, and uncertainty in model parameters.
      Using TTDERM we investigate the use of a macro-activity parameter (cumulative
      contact time) for predicting daily (24-hour) integrated uptake of pesticides
      during complex exposure scenarios. For characteristic child behaviors and hand
      loading and unloading rates, we find that a power law represents the relationship
      between cumulative contact time and cumulative mass transport through the skin.
      With almost no loss of reliability, this simple relationship can be used in place
      of the more complex micro-activity simulations that require activity data on one-
      to five-minute intervals. The methods developed in this study can be used to
      guide dermal exposure model refinements and exposure measurement study design.

PMID- 15028003
TI  - Earthquake beliefs and adoption of seismic hazard adjustments.
AB  - This study investigated the prevalence of both accurate and erroneous earthquake
      related beliefs among a sample of Southern California college students and the
      relationship between their endorsement of earthquake beliefs and adoption of
      seismic hazard adjustments. In addition, the study examined the effects of an
      experimental earthquake education program and the impact of need for cognition on
      this program. The data revealed a significant degree of agreement with earthquake
      myths, a generally low level of correlation between earthquake beliefs and the
      level of hazard adjustments, and a significant effect of hazard information on
      the endorsement of accurate earthquake beliefs and increases in hazard
      adjustment. Compared with the "Earthquake Facts (Only)" format, an "Earthquake
      Myths versus Facts" format was slightly more useful for dispelling erroneous
      beliefs. Further, there was a tendency for those who were high in need for
      cognition to have higher levels of hazard adjustment. Finally, there was weak
      support for the hypothesis that those who were low in need for cognition would
      develop more accurate earthquake beliefs and higher levels of hazard adjustment
      in the "Earthquake Myths versus Facts" information condition.

PMID- 15028004
TI  - Varying risk comparison elements: effects on public reactions.
AB  - Expanding a limited empirical base on effects of risk comparisons, a pilot
      experiment explored how varying elements of such comparisons might influence
      public response. The scenario used was a hypothetical trial of an asbestos
      installing firm for putting students and staff at a junior high school at
      "unreasonable risk," first used by Slovic et al. (1990). Study participants
      played the role of jurors in the trial, asked to rate the risk, the firm's guilt,
      whether it should be made liable for future health effects, whether the school
      should be occupied in its current condition, and whether the asbestos should be
      removed at a cost of 3 million dollars. Opportunity samples of New Jersey
      residents (n= 309) received information intended to vary four comparison
      attributes: number of dimensions of comparison; single versus multiple ways of
      expressing mortality; a narrative to explain and justify the risk comparison; and
      the hypothetical role of the participant (juror vs. parent). The dependent
      variable was a hazard scale constructed from four of the five postcomparison
      judgments. ANOVA found format variations swamped in their effect by concern about
      asbestos, with the absence of a narrative and the parental role being the only
      attributes that increased negative risk reactions. Multiple regression analyses
      found that multidimensionality, narrative, role, and the presence of any risk
      comparison at all had significant effects when these (plus death formats) were
      the only independent variables. However, only multidimensionality (which
      increased negative reactions) retained significance when asbestos concern, risk
      beliefs (no safe level of exposure to a carcinogen; any exposure leads to
      cancer), and demographic variables were added to the analysis. Concern and risk
      beliefs alone explained 33% of variance in hazard scores; adding demographics and
      risk comparison variables only raised explained variance to 36% (having children
      at home and being exposed to multidimensional risk comparisons raised scores; age
      and income lowered them). The results underline the potentially small effect of
      risk comparison information on risk views (at least between subjects), but offer
      some insight into aspects of message design left unexplored in empirical
      literature to date.

PMID- 15028005
TI  - Discrimination, vulnerability, and justice in the face of risk.
AB  - Recent research finds that perceived risk is closely associated with race and
      gender. In surveys of the American public a subset of white males stand out for
      their uniformly low perceptions of environmental health risks, while most
      nonwhite and nonmale respondents reveal higher perceived risk. Such findings have
      been attributed to the advantageous position of white males in American social
      life. This article explores the linked possibility that this demographic pattern
      is driven not simply by the social advantages or disadvantages embodied in race
      or gender, but by the subjective experience of vulnerability and by
      sociopolitical evaluations pertaining to environmental injustice. Indices of
      environmental injustice and social vulnerability were developed as part of a U.S.
      National Risk Survey (n= 1,192) in order to examine their effect on perceived
      risk. It was found that those who regarded themselves as vulnerable and supported
      belief statements consistent with the environmental justice thesis offered higher
      risk ratings across a range of hazards. Multivariate analysis indicates that our
      measures of vulnerability and environmental injustice predict perceived risk but
      do not account for all of the effects of race and gender. The article closes with
      a discussion of the implications of these findings for further work on
      vulnerability and risk, risk communication, and risk management practices
      generally.

PMID- 15028006
TI  - Risk comparisons, conflict, and risk acceptability claims.
AB  - Despite many claims for and against the use of risk comparisons in risk
      communication, few empirical studies have explored their effect. Even fewer have
      examined the public's relative preferences among different kinds of risk
      comparisons. Two studies, published in this journal in 1990 and 2003, used seven
      measures of "acceptability" to examine public reaction to 14 examples of risk
      comparisons, as used by a hypothetical factory manager to explain risks of his
      ethylene oxide plant. This study examined the effect on preferences of scenarios
      involving low or high conflict between the factory manager and residents of the
      hypothetical town (as had the 2003 study), and inclusion of a claim that the
      comparison demonstrated the risks' acceptability. It also tested the Finucane et
      al. (2000) affect hypothesis that information emphasizing low risks-as in these
      risk comparisons-would raise benefits estimates without changing risk estimates.
      Using similar but revised scenarios, risk comparison examples (10 instead of 14),
      and evaluation measures, an opportunity sample of 303 New Jersey residents rated
      the comparisons, and the risks and benefits of the factory. On average, all
      comparisons received positive ratings on all evaluation measures in all
      conditions. Direct and indirect measures showed that the conflict manipulation
      worked; overall, No-Conflict and Conflict scenarios evoked scores that were not
      significantly different. The attachment to each risk comparison of a risk
      acceptability claim ("So our factory's risks should be acceptable to you.") did
      not worsen ratings relative to conditions lacking this claim. Readers who did or
      did not see this claim were equally likely to infer an attempt to persuade them
      to accept the risk from the comparison. As in the 2003 article, there was great
      individual variability in inferred rankings of the risk comparisons. However,
      exposure to the risk comparisons did not reduce risk estimates significantly
      (while raising benefit estimates), and Conflict-Claim respondents found the risk
      of the hypothetical factory less acceptable than No-Conflict respondents. Results
      suggest that neither risk comparisons nor risk acceptability claims are
      automatically anathema to audiences, but they may have tiny or unintended effects
      on audience judgments about risky situations.

PMID- 15028008
TI  - A critical look at risk assessments for global catastrophes.
AB  - Recent articles by Busza et al. (BJSW) and Dar et al. (DDH) argue that
      astrophysical data can be used to establish small bounds on the risk of a "killer
      strangelet" catastrophe scenario in the RHIC and ALICE collider experiments. The
      case for the safety of the experiments set out by BJSW does not rely solely on
      these bounds, but on theoretical arguments, which BJSW find sufficiently
      compelling to firmly exclude any possibility of catastrophe. Nonetheless, DDH and
      other commentators (initially including BJSW) suggested that these empirical
      bounds alone do give sufficient reassurance. This seems unsupportable when the
      bounds are expressed in terms of expectation value-a good measure, according to
      standard risk analysis arguments. For example, DDH's main bound, p(catastrophe) <
      2 x 10(-8), implies only that the expectation value of the number of deaths is
      bounded by 120; BJSW's most conservative bound implies the expectation value of
      the number of deaths is bounded by 60,000. This article reappraises the DDH and
      BJSW risk bounds by comparing risk policy in other areas. For example, it is
      noted that, even if highly risk-tolerant assumptions are made and no value is
      placed on the lives of future generations, a catastrophe risk no higher than
      approximately 10(-15) per year would be required for consistency with established
      policy for radiation hazard risk minimization. Allowing for risk aversion and for
      future lives, a respectable case can be made for requiring a bound many orders of
      magnitude smaller. In summary, the costs of small risks of catastrophe have been
      significantly underestimated by BJSW (initially), by DDH, and by other
      commentators. Future policy on catastrophe risks would be more rational, and more
      deserving of public trust, if acceptable risk bounds were generally agreed upon
      ahead of time and if serious research on whether those bounds could indeed be
      guaranteed was carried out well in advance of any hypothetically risky
      experiment, with the relevant debates involving experts with no stake in the
      experiments under consideration.

PMID- 15028007
TI  - Ethics and choosing appropriate means to an end: problems with coal mine and
      nuclear workplace safety.
AB  - A common problem in ethics is that people often desire an end but fail to take
      the means necessary to achieve it. Employers and employees may desire the safety
      end mandated by performance standards for pollution control, but they may fail to
      employ the means, specification standards, necessary to achieve this end. This
      article argues that current (de jure) performance standards, for lowering
      employee exposures to ionizing radiation, fail to promote de facto worker
      welfare, in part because employers and employees do not follow the necessary
      means (practices known as specification standards) to achieve the end
      (performance standards) of workplace safety. To support this conclusion, the
      article argues that (1) safety requires attention to specification, as well as
      performance, standards; (2) coal-mine specification standards may fail to promote
      performance standards; (3) nuclear workplace standards may do the same; (4)
      choosing appropriate means to the end of safety requires attention to the ways
      uncertainties and variations in exposure may mask violations of standards; and
      (5) correcting regulatory inattention to differences between de jure and de facto
      is necessary for achievement of ethical goals for safety.

PMID- 15028009
TI  - Thinking aloud about trust: a protocol analysis of trust in risk management.
AB  - There are two general theories of trust in risk management. One, derived from
      normative considerations, claims that trust is based on universally applicable
      factors such as fairness and objectivity. According to the second, social
      psychological theory, trust is based on agreement or similarity and is context
      specific. Although the first theory is normative, it also claims, along with the
      second, to be a descriptive account of how trust judgments are made. The present
      study was designed to test the adequacy of these two theories by using a think
      aloud procedure to examine the thinking associated with trust judgments in an
      experimental simulation of a typical risk management context. Contrary to the
      universalist theory, results supported two hypotheses derived from the social
      psychological theory. First, study participants--who read brief policy statements
      designed to address global climate change--based their trust judgments on
      specific forms of agreement, ranging from agreement on the importance of the
      issue to agreement on values inferred from the policy statement. Second, the
      extent and depth of participants' conscious information processing was negatively
      related to the level of trust. Disagreement and distrust generated more conscious
      consideration than agreement and trust. These results provide a more detailed
      understanding than previously available of how trust in risk management is based
      on local forms of agreement that vary across people, contexts, and time.

PMID- 15028010
TI  - GM foods and the misperception of risk perception.
AB  - Public opposition to genetically modified (GM) food and crops is widely
      interpreted as the result of the public's misperception of the risks. With
      scientific assessment pointing to no unique risks from GM crops and foods, a
      strategy of accurate risk communication from trusted sources has been advocated.
      This is based on the assumption that the benefits of GM crops and foods are self
      evident. Informed by the interpretation of some qualitative interviews with lay
      people, we use data from the Eurobarometer survey on biotechnology to explore the
      hypothesis that it is not so much the perception of risks as the absence of
      benefits that is the basis of the widespread rejection of GM foods and crops by
      the European public. Some respondents perceive both risks and benefits, and may
      be trading off these attributes along the lines of a rational choice model.
      However, for others, one attribute-benefit-appears to dominate their judgments:
      the lexicographic heuristic. For these respondents, their perception of risk is
      of limited importance in the formation of attitudes toward GM food and crops. The
      implication is that the absence of perceived benefits from GM foods and crops
      calls into question the relevance of risk communication strategies for bringing
      about change in public opinion.

PMID- 15028012
TI  - Defining susceptibility for microbial risk assessment: results of a workshop.
AB  - An interdisciplinary workshop was convened by the George Washington University in
      June 2001 to discuss how to incorporate new knowledge about susceptibility to
      microbial pathogens into risk assessment and management strategies. Experts from
      government, academic, and private sector organizations discussed definitions,
      methods, data needs, and issues related to susceptibility in microbial risk
      assessment. The participants agreed that modeling approaches need to account for
      the highly specific nature of host-pathogen relationships, and the wide
      variability of infectivity, immunity, disease transmission, and outcome rates
      within microbial species and strains. Concerns were raised about distinguishing
      between exposure and dose more clearly, interpreting experimental and outbreak
      data correctly, and using thresholds and possibly linearity at low doses.
      Recommendations were made to advance microbial risk assessment by defining
      specific terms and concepts more precisely, designing explicit conceptual
      frameworks to guide development of more complex models and data collection,
      addressing susceptibility in all steps of the model, measuring components of
      immunity to characterize susceptibility, reexamining underlying assumptions,
      applying default methods appropriately, obtaining more mechanistic data to
      improve default methods, and developing more biologically relevant and continuous
      risk estimators. The interrelated impacts of selecting specific subpopulations
      and health outcomes, and of increasing model complexity and data demands, were
      considered in the contexts of public policy goals and resources required. The
      participants stated that zero risk is unattainable, so targeted and effective
      risk reduction and communication strategies are essential not only to raise pubic
      awareness about water quality but also to protect the most susceptible members of
      the population.

PMID- 15028013
TI  - Cryptosporidiosis susceptibility and risk: a case study.
AB  - Regional estimates of cryptosporidiosis risks from drinking water exposure were
      developed and validated, accounting for AIDS status and age. We constructed a
      model with probability distributions and point estimates representing
      Cryptosporidium in tap water, tap water consumed per day (exposure
      characterization); dose response, illness given infection, prolonged illness
      given illness; and three conditional probabilities describing the likelihood of
      case detection by active surveillance (health effects characterization). The
      model predictions were combined with population data to derive expected case
      numbers and incidence rates per 100,000 population, by age and AIDS status,
      borough specific and for New York City overall in 2000 (risk characterization).
      They were compared with same-year surveillance data to evaluate predictive
      ability, assumed to represent true incidence of waterborne cryptosporidiosis. The
      predicted mean risks, similar to previously published estimates for this region,
      overpredicted observed incidence-most extensively when accounting for AIDS
      status. The results suggest that overprediction may be due to conservative
      parameters applied to both non-AIDS and AIDS populations, and that biological
      differences for children need to be incorporated. Interpretations are limited by
      the unknown accuracy of available surveillance data, in addition to variability
      and uncertainty of model predictions. The model appears sensitive to geographical
      differences in AIDS prevalence. The use of surveillance data for validation and
      model parameters pertinent to susceptibility are discussed.

PMID- 15028014
TI  - A dynamic model to assess microbial health risks associated with beneficial uses
      of biosolids.
AB  - There is increasing interest in the development of a microbial risk assessment
      methodology for regulatory and operational decision making. This document
      presents a methodology for assessing risks to human health from pathogen exposure
      using a population-based model that explicitly accounts for properties unique to
      an infectious disease process, specifically secondary transmission and immunity.
      To demonstrate the applicability of this risk-based method, numerical simulations
      were carried out for a case study example in which the route of exposure was
      direct consumption of biosolids-amended soil and the pathogen present in the soil
      was enterovirus. The output from the case study yielded a decision tree that
      differentiates between conditions in which the relative risk from biosolids
      exposure is high and those conditions in which the relative risk from biosolids
      is low. This decision tree illustrates the interaction among the important
      factors in quantifying risk. For the case study example, these factors include
      biosolids treatment processes, the pathogen shedding rate of infectious
      individuals, secondary transmission, and immunity. Further refinement in methods
      for determining biosolids exposures under field conditions would certainly
      increase the utility of these approaches.

PMID- 15028015
TI  - Scenario tree modeling to analyze the probability of classical swine fever virus
      introduction into member states of the European Union.
AB  - The introduction of classical swine fever virus (CSFV) into a country free of
      disease without vaccination may have huge consequences in terms of both disease
      spread and economic losses. More quantitative insight into the main factors
      determining the probability of CSFV introduction (PCSFV) is needed to optimally
      use resources for the prevention of CSFV introduction. For this purpose a
      spreadsheet model was constructed that calculates the annual PCSFV into member
      states of the European Union (EU). The scenario pathway approach was used as most
      probabilities in the model are very small. Probability distributions were used to
      take into account inherent variability of input parameters. The model contained
      pathways of CSFV introduction including the import of pigs and pork products,
      returning livestock trucks, and contacts with wild boar. All EU member states
      were included as possible sources of CSFV. Default results for the Netherlands
      showed a mean overall annual PCSFV of approximately 0.06, indicating that the
      Netherlands can expect CSFV introduction on average once every 18 years from the
      pathways and countries included in the model. Almost 65% of this probability
      could be attributed to the pathway of returning livestock trucks. The most likely
      sources of CSFV introduction were Germany, Belgium, and the United Kingdom.
      Although the calculated probabilities were rather low when compared with expert
      estimates and recent history, the most likely causes of CSFV introduction
      indicated by the model were considered to be realistic. It was therefore
      concluded that the model is a useful tool to structure and analyze information
      for decision making concerning the prevention of CSFV introduction.

PMID- 15028016
TI  - A Bayesian approach to quantify the contribution of animal-food sources to human
      salmonellosis.
AB  - Based on the data from the integrated Danish Salmonella surveillance in 1999, we
      developed a mathematical model for quantifying the contribution of each of the
      major animal-food sources to human salmonellosis. The model was set up to
      calculate the number of domestic and sporadic cases caused by different
      Salmonella sero and phage types as a function of the prevalence of these
      Salmonella types in the animal-food sources and the amount of food source
      consumed. A multiparameter prior accounting for the presumed but unknown
      differences between serotypes and food sources with respect to causing human
      salmonellosis was also included. The joint posterior distribution was estimated
      by fitting the model to the reported number of domestic and sporadic cases per
      Salmonella type in a Bayesian framework using Markov Chain Monte Carlo
      simulation. The number of domestic and sporadic cases was obtained by subtracting
      the estimated number of travel- and outbreak-associated cases from the total
      number of reported cases, i.e., the observed data. The most important food
      sources were found to be table eggs and domestically produced pork comprising
      47.1% (95% credibility interval, CI: 43.3-50.8%) and 9% (95% CI: 7.8-10.4%) of
      the cases, respectively. Taken together, imported foods were estimated to account
      for 11.8% (95% CI: 5.0-19.0%) of the cases. Other food sources considered had
      only a minor impact, whereas 25% of the cases could not be associated with any
      source. This approach of quantifying the contribution of the various sources to
      human salmonellosis has proved to be a valuable tool in risk management in
      Denmark and provides an example of how to integrate quantitative risk assessment
      and zoonotic disease surveillance.

PMID- 15028017
TI  - Quantifying human health risks from virginiamycin used in chickens.
AB  - The streptogramin antimicrobial combination Quinupristin-Dalfopristin (QD) has
      been used in the United States since late 1999 to treat patients with vancomycin
      resistant Enterococcus faecium (VREF) infections. Another streptogramin,
      virginiamycin (VM), is used as a growth promoter and therapeutic agent in farm
      animals in the United States and other countries. Many chickens test positive for
      QD-resistant E. faecium, raising concern that VM use in chickens might compromise
      QD effectiveness against VREF infections by promoting development of QD-resistant
      strains that can be transferred to human patients. Despite the potential
      importance of this threat to human health, quantifying the risk via traditional
      farm-to-fork modeling has proved extremely difficult. Enough key data (mainly on
      microbial loads at each stage) are lacking so that such modeling amounts to
      little more than choosing a set of assumptions to determine the answer. Yet,
      regulators cannot keep waiting for more data. Patients prescribed QD are
      typically severely ill, immunocompromised people for whom other treatment options
      have not readily been available. Thus, there is a pressing need for sound risk
      assessment methods to inform risk management decisions for VM/QD using currently
      available data. This article takes a new approach to the QD-VM risk modeling
      challenge. Recognizing that the usual farm-to-fork ("forward chaining") approach
      commonly used in antimicrobial risk assessment for food animals is unlikely to
      produce reliable results soon enough to be useful, we instead draw on ideas from
      traditional fault tree analysis ("backward chaining") to reverse the farm-to-fork
      process and start with readily available human data on VREF case loads and QD
      resistance rates. Combining these data with recent genogroup frequency data for
      humans, chickens, and other sources (Willems et al., 2000, 2001) allows us to
      quantify potential human health risks from VM in chickens in both the United
      States and Australia, two countries where regulatory action for VM is being
      considered. We present a risk simulation model, thoroughly grounded in data, that
      incorporates recent nosocomial transmission and genetic typing data. The model is
      used to estimate human QD treatment failures over the next five years with and
      without continued VM use in chickens. The quantitative estimates and probability
      distributions were implemented in a Monte Carlo simulation model for a five-year
      horizon beginning in the first quarter of 2002. In Australia, a Q1-2002 ban of
      virginiamycin would likely reduce average attributable treatment failures by 0.35
      x 10(-3) cases, expected mortalities by 5.8 x 10(-5) deaths, and life years lost
      by 1.3 x 10(-3) for the entire population over five years. In the United States,
      where the number of cases of VRE is much higher, a 1Q-2002 ban on VM is predicted
      to reduce average attributable treatment failures by 1.8 cases in the entire
      population over five years; expected mortalities by 0.29 cases; and life years
      lost by 6.3 over a five-year period. The model shows that the theoretical
      statistical human health benefits of a VM ban range from zero to less than one
      statistical life saved in both Australia and the United States over the next five
      years and are rapidly decreasing. Sensitivity analyses indicate that this
      conclusion is robust to key data gaps and uncertainties, e.g., about the extent
      of resistance transfer from chickens to people.

PMID- 15028018
TI  - Differences in perception of risk between people who have and have not
      experienced Salmonella food poisoning.
AB  - It is believed that food hygiene precautions in domestic kitchens are an
      important strategy in efforts to reduce the incidence of sporadic food poisoning,
      but recent research has shown that people who have suffered food poisoning handle
      the same types of foods and adopt similar food hygiene precautions in their
      kitchens to the rest of the population. This suggests the need to examine other
      factors. A case-control study of sporadic Salmonella food poisoning was conducted
      to investigate several domestic kitchen risk factors. Measures of perception of
      risk, knowledge, and control associated with food poisoning in case and control
      respondents are reported here. It was found that perceived personal risk from
      food poisoning in the home was less than perceived risk to other people. In
      contrast, ratings of personal knowledge about food poisoning and personal control
      over food poisoning in the home were seen to be greater than other people's
      knowledge and control. There were no differences between the cases and the
      controls in their ratings of knowledge about food poisoning or their control over
      food poisoning. However, cases perceived their personal risk from food poisoning
      to be higher than controls. Both case and control samples exhibited optimistic
      bias but this was reduced in the case sample, suggesting that experience with
      food poisoning may reduce optimistic bias.

PMID- 15028021
TI  - Prognostic value of apoptosis and apoptosis-associated proteins in salivary gland
      adenoid cystic carcinoma.
AB  - The purpose of the present study was to investigate the level of apoptosis and
      expressions of p53, mdm2 and bcl-2 proteins in salivary gland adenoid cystic
      carcinoma (ACC) to determine potential relationships among apoptosis, apoptosis
      associated proteins and clinical cumulative survival. Thirty-nine formalin-fixed,
      paraffin-embedded cases, cribriform (17), tubular (13) and solid (9), were
      studied by immunohistochemistry. Apoptosis detection and analysis were determined
      by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling
      (TUNEL). There was an inverse significance between the apoptotic index (AI) and
      bcl-2 expression (P = 0.018), whereas no correlation was found between the AI and
      either p53 or mdm2 expression (P = 0.416 and P = 0.456). Co-expression of p53 and
      mdm2 was found in 22 cases (P = 0.037). Patients with p53-positive tumors had a
      worse prognosis than those with p53-negative tumors (P = 0.014). Patients with a
      high AI had a better cumulative survival than patients with a low AI (P = 0.038).
      The present study suggests that p53 expression and AI can be useful as prognostic
      values; bcl-2 protein plays a role in the down-regulation of apoptosis and is
      also potentially useful as a prognostic parameter in salivary gland ACC.

PMID- 15028022
TI  - Characterization of expression of protein kinase C isozymes in human B-cell
      lymphoma: Relationship between its expression and prognosis.
AB  - Protein kinase C (PKC) enzymes play a major role in signal transduction and
      contribute to the regulation of cellular differentiation and proliferation.
      However, little is known about subtype-specific intracellular expression of PKC
      in human malignant lymphoma. To characterize the relationship between expression
      of PKC and B-cell lymphomas based on the different subspecies, we investigated
      the expression of four subspecies (alpha, beta II, gamma and delta) in five cases
      of reactive lymphoid tissues, 77 cases of human B-cell lymphoma and 17 human
      lymphoma cell lines. In the reactive lymphoid tissues, PKC beta II-positive cells
      were found in the mantle zones and marginal zones, and centroblasts and
      centrocytes in the germinal centers showed cytoplasmic staining with strong
      intensity against PKC delta. The present study is the first report to examine the
      expression of PKC delta in reactive lymphoid tissues. In interfollicular areas, a
      small number of T-cells were positive for PKC alpha. Protein kinase C gamma
      positive cells were not found in these lymphoid tissues. Eight cases of Burkitt
      lymphoma (BL) (8/10; 80%) showed the overexpression of PKC alpha (P < 0.01), but
      other B-cell lymphoma cases except three cases of diffuse large B-cell lymphoma
      did not express PKC alpha. In addition, six and eight out of nine BL cell lines
      expressed the protein and mRNA of PKC alpha, respectively. These results indicate
      that PKC alpha was predominantly expressed on BL in comparison with other types
      of lymphoma. The expression of PKC gamma was observed in only five cases of BL.
      The overall survival of PKC gamma-positive BL was significantly better than that
      of PKC gamma-negative BL (P < 0.05). The expression of PKC gamma seems to be
      associated with a better prognosis in the limited number of BL cases in the
      present study.

PMID- 15028023
TI  - Intravascular large B-cell lymphoma presenting with mass lesions in the central
      nervous system: a report of five cases.
AB  - We have encountered five cases of intravascular large B-cell lymphoma (IVL)
      presenting with central nervous system (CNS) mass lesions during their clinical
      course. The age of the patients ranged from 50 to 74 years and three patients
      were male. All of these cases histopathologically showed typical intravascular
      localization of the neoplastic cells in the initial biopsy specimens obtained
      from sites other than the CNS. Despite multiagent chemotherapy, patients suffered
      from single or multiple CNS mass lesions 5-44 months after the initial diagnosis
      of IVL, except for one case in which IVL and the CNS mass lesion were diagnosed
      at the same time. The subsequent biopsy and autopsy specimens obtained from the
      CNS mass lesions revealed diffuse infiltration of the tumor cells with
      perivascular spreading, but minimal or no intravascular components.
      Immunohistochemical analysis of intravascular tumor cells and CNS mass lesions
      revealed expression of CD20, CD79a, bcl-2 and negative for CD3e and Epstein-Barr
      virus encoded RNA. The overall features of the CNS mass lesions were very similar
      to or indistinguishable from those of the primary CNS lymphomas. This implies
      that CNS mass lesions in the IVL cases can be correctly diagnosed only by careful
      attention to clinical and pathological findings. Moreover, there is the
      possibility that some cases previously diagnosed as primary CNS lymphomas may
      have include IVL cases. Further investigation is needed to explore this unusual
      phenomenon.

PMID- 15028024
TI  - Significance of histological subtypes of Kikuchi's disease: comparative
      immunohistochemical and apoptotic studies.
AB  - Kikuchi's disease (KD) is a self-limiting lymphadenitis mostly affecting the
      cervical lymph nodes of young individuals. It has been classified into three
      histological subtypes and postulated to progress from the proliferative type (PT)
      to the necrotizing type (NT) and finally resolve into the xanthomatous type (XT).
      Since KD has been shown to be an apoptotic disease, the apoptotic activity was
      studied by the TUNEL method on 6, 12, and 6 cases of PT, NT, and XT,
      respectively, to see if the apoptotic activity could be shown to decrease in the
      order of the postulated sequence of evolution. Significant statistical difference
      among the three subtypes was found (P = 0.050). Further analysis revealed that PT
      versus NT was significant (P = 0.010), but NT versus XT (P = 0.385) or PT versus
      XT (P = 0.310) was not. Analysis of three stages of NT was also significant (P =
      0.019). Immunohistochemical study showed that abundant CD8+ T cells and cytotoxic
      protein positive cells were present in PT and NT, but were relatively low in XT.
      Our results showed progression of PT to NT, but not from NT to XT. Xanthomatous
      type was not the resolving stage of KD, but seemed to be a distinctive
      histological variant of KD caused by either different etiology or an unusual host
      reaction.

PMID- 15028025
TI  - Participation of the matrix metalloproteinase inhibitor in Thy-1 nephritis.
AB  - What influence would be shown in Thy-1 glomerulonephritis when the synthetic
      matrix metalloproteinase (MMP) inhibitor SI-27 is administered? Five groups of 80
      male Wistar rats were studied: healthy group; treated healthy group; nephritic
      group; pretreated nephritic group; and post-treated nephritic group. SI-27
      treatment of nephritic animals was initiated either 2 days before or 2 days after
      anti-Thy-1.1 antibody injection. On days 7, 14, 26 and 42 after disease
      induction, we examined renal histology, extracellular matrix (ECM) constituent,
      and MMP activity. SI-27 treated Thy-1 groups resulted in significant reduction of
      glomerular cells including alpha-smooth muscle actin (alpha-SMA) positive
      mesangial cells and suppressed expression of type IV collagen at 7 days.
      Moreover, type I collagen was also decreased by SI-27 at 42 days. However,
      glomerular cell numbers did not show any significant changes at 14, 26 and 42
      days. In gelatin zymography, the gelatinolytic band for MMP-9 was expressed in SI
      27 treated Thy-1 nephritis groups, although it was not expressed in the nephritic
      group at day 7. However, the expression of MMP-9 was no longer seen at 14, 26 and
      42 days. The bands for an active form of MMP-2 were expressed throughout the
      experimental period in the Thy-1 nephritic groups. These results suggest that MMP
      plays an important role in the development of Thy-1 nephritis, and even if the
      synthetic MMP inhibitor intercepts the initial increase of glomerular cells and
      matrices, it does not inhibit recovery to normal glomerular capillary structures
      in Thy-1 nephritis.

PMID- 15028026
TI  - Detection of glyceraldehyde 3-phosphate dehydrogenase messenger RNA using a
      peptide nucleic acid probe in paraffin-embedded archival specimens.
AB  - Although the human genome project has been completed, the functions of many genes
      remain undetermined. In situ hybridization (ISH) is a key method for identifying
      cells in which a given messenger RNA is transcribed. Paraffin-embedded specimens
      remain precious materials for research, but preservation of high-quality RNA in
      these specimens is not expected unless ample caution was taken during fixation.
      Peptide nucleic acid (PNA) is a recently developed hybrid molecule with genetic
      information that has high stability and high affinity to the complementary DNA or
      RNA. We applied a PNA probe to mRNA ISH of liver specimens obtained by autopsy
      and embedded in paraffin 28-48 years ago. An 18-mer PNA probe for glyceraldehyde
      3-phosphate dehydrogenase was used. Staining was then analyzed in association
      with morphology by hematoxylin and eosin staining, and with the time between
      death of the patient and tissue fixation. Notably, specimens fixed with formalin
      and embedded in paraffin 48 years ago yielded excellent results if the time
      before fixation was short enough (<8 h). There was a significant inverse
      correlation between the intensity of ISH staining and the time before fixation.
      Oligonucleotide PNA probe, albeit at high cost, would increase the value of
      paraffin-embedded specimens in storage for use in human medical research.

PMID- 15028027
TI  - Dumbbell-shaped leiomyosarcoma of the inferior vena cava with foci of rhabdoid
      changes and osteoclast-type giant cells.
AB  - An inferior vena cava (IVC) tumor was incidentally found in a 67-year-old
      Japanese man. The resected tumor was lobulated and multinodular, measuring 14.0 x
      6.5 x 7.0 cm, showing a dumbbell-shaped appearance with a central constriction.
      The tumor showed both intra- and extra-luminal growth. The tumor was primarily
      composed of well-differentiated leiomyosarcoma. Spindle tumor cells in the well
      differentiated area were positive for vimentin, muscle actin, alpha-smooth muscle
      actin, and desmin. Foci of rhabdoid cells and osteoclast-type multinucleated
      giant cells were also found. Rhabdoid cells ultrastructurally had paranuclear
      aggregates or whorls of intermediate filaments that were positive for vimentin,
      low molecular weight cytokeratin, and desmin. Osteoclast-type multinucleated
      giant cells were positive for only CD68 antigen, suggesting a reactive
      histiocytic lineage. To the best of our knowledge, this is the first case of IVC
      leiomyosarcoma accompanied by both rhabdoid tumor cells and osteoclast-type
      reactive multinucleated giant cells. These unusual features should be kept in
      mind in the diagnosis of dumbbell-shaped retroperitoneal tumors that involve the
      IVC.

PMID- 15028028
TI  - Heavily melanotic perivascular epithelioid clear cell tumor of the kidney.
AB  - A black-colored and well-circumscribed renal tumor in a 71-year-old woman is
      reported. The tumor was unique in that it was rich in vasculature and exclusively
      composed of perivascular epithelioid clear cells. Morphological features were
      reminiscent of conventional renal cell carcinoma (RCC). However,
      immunohistochemical examinations showed that the tumor cells did not express any
      epithelial markers, but diffusely and intensely expressed a melanocytic marker,
      gp-100/HMB-45. Another striking feature of the tumor was a large amount of
      cytoplasmic pigment that made the tumor wholly black. The pigment was not stained
      with Berlin-blue, completely bleached with potassium permanganate, and stained
      with Fontana-Masson staining, which suggests that the pigment was melanin.
      Morphological features and immunohistochemical findings indicated that the
      present tumor was an extreme example of a perivascular epithelioid clear cell
      tumor with a large amount of melanin, which has not been previously reported. One
      should be aware of the pure form of perivascular epithelioid clear cell tumor of
      the kidney because it is sometimes very difficult to differentiate this tumor
      from conventional RCC. Immunohistochemical examinations and the presence of
      cytoplasmic melanin can help the differentiation.

PMID- 15028029
TI  - Multicentric papillary renal cell carcinoma associated with renal adenomatosis.
AB  - A case of multicentric papillary renal cell carcinoma (RCC) associated with renal
      adenomatosis in the bilateral kidneys is reported. Bilateral multiple renal cysts
      in a 46-year-old man were pointed out incidentally by ultrasonography. Some of
      the left renal lesions were considered to be RCC, and left radical nephrectomy
      was performed accordingly. The left kidney was occupied by numerous solid
      nodules, which ranged from yellow to tan in color, and some of the large ones had
      foci of hemorrhage and necrosis. Microscopically, most of the tumors showed
      papillary RCC associated with renal adenoma, while others consisted only of
      adenomas. Ten months later, multiple lesions of the right kidney, which were
      initially considered to be multiple cysts, were found to have become enlarged and
      some of them were diagnosed as RCC. Thus, right radical nephrectomy was also
      performed, and these tumors showed the same features as the left renal tumors.
      The patient's familial history was not remarkable. The kidneys revealed various
      histological features, ranging from dysplastic to adenoma or carcinoma, including
      transitional or overlapping features between them. The findings suggest an
      adenoma-carcinoma sequence in papillary RCC. It is worth considering such
      entities.

PMID- 15028030
TI  - Cushing's syndrome due to a large adrenocortical adenoma with histological
      features simulating ACTH-independent macronodular adrenocortical hyperplasia.
AB  - A 53-year-old woman presented with Cushing's syndrome resulting from an
      adrenocortical adenoma, 6.5 cm in diameter and 75 g in weight, which is larger
      than usual. Endocrinological data of this patient showed adrenocorticotropin
      (ACTH)-independent hypercortisolemia. A computed tomography scan of the adrenal
      glands revealed a single large and well-encapsulated tumor with an irregularly
      shaped area of calcification and loss of parenchyma on the left adrenal. The
      right adrenal gland was atrophic. Laparoscopic removal of the left adrenal tumor
      was performed. The tumor was lobulated and clearly encapsulated, and the non
      neoplastic area of the left adrenal was atrophic without any nodularity. The
      histological analysis confirmed the diagnosis of adrenal adenoma. In addition,
      this adenoma displayed histopathological features in common with ACTH-independent
      macronodular adrenocortical hyperplasia (AIMAH), including clear cell
      predominance, a pattern of small compact cell nests in clear cell areas, and very
      long cord-like arrangement of small compact cells. In AIMAH, adrenals are
      extremely enlarged and are more massive than in any other subtype of Cushing's
      syndrome. The fact that the present adrenocortical adenoma was larger than those
      typical adenomas of Cushing's syndrome may reflect an AIMAH-type cellular
      composition of clear cell predominance and small compact cell nests.

PMID- 15028031
TI  - Ovarian teratoma showing a predominant hemangiomatous element with stromal
      luteinization: report of a case and review of the literature.
AB  - A solid well-circumscribed ovarian tumor in a 63-year-old Japanese woman is
      reported. Histologically, the tumor consisted predominantly of a hemangiomatous
      component with a small cyst lined by a respiratory ciliated epithelium. The
      remaining ovarian stroma showed a marked proliferation of luteinized cells that
      were strongly positive for inhibin immunohistochemically. Neither dermoid nor
      other teratomatous components were found, even in the serial sections of the
      tumor. To date, vascular tumors of the ovary are uncommon and some cases of
      ovarian hemangioma have been reported. However, their origin, whether a
      monodermal teratoma or a true neoplasm arising in the ovarian stroma, has not yet
      been elucidated. When a hemangiomatous proliferation is found in an ovarian
      tumor, a thorough microscopic search for teratomatous components is necessary
      before diagnosing the tumor as a pure hemangioma.

PMID- 15028033
TI  - Partnership research with older people - moving towards making the rhetoric a
      reality.
AB  - As nursing develops closer partnerships with older people in delivering care, it
      also needs to develop partnerships in order to create the knowledge base for
      practice in a way that challenges professional hegemony and empowers older
      people. However, the process of developing partnerships in research takes place
      against a background of academic research traditions and norms, which can present
      obstacles to collaboration. This paper is a reflection on the issues that have
      arisen in three projects where older people were involved in research at
      different levels, from sources of data to independent researchers. It points to
      some of the areas that need further exploration and development.

PMID- 15028034
TI  - Social context and outcomes for the ageing breast cancer patient: considerations
      for clinical practitioners.
AB  - Current incidence, prevalence and survival rates determine that breast cancer is
      primarily a disease of older women. This integrative essay provides an extensive
      review of the literature on (i). the social and psychological factors that
      influence adjustment to breast cancer and survival from it, (ii). the social and
      health status of older women, and (iii). the medical treatment of older breast
      cancer patients. It is concluded that while psychological orientation to the
      disease, coping strategies and functional continuities of breast cancer patients
      are important for disease outcome, adjustment to and survival from breast cancer
      by older women may be compromised by the social context - with respect to
      marriage and intimate ties, social participation, socio-economic status, and
      mental and physical health. The paper concludes with the suggestion that clinical
      practitioners need to be aware of the both the resources of, and limitations
      facing the older breast cancer patient, and with the provision of specific
      recommendations about the clinical management of this population for nurses and
      other health professionals.

PMID- 15028037
TI  - Person-centredness in gerontological nursing: an overview of the literature.
AB  - Person-centred practice is a recurring theme in gerontological nursing
      literature. While there are many descriptive accounts of attempts at developing
      person-centred practice, in reality, there are few studies that identify the
      benefits of this way of working. Thus far, systematic research into person
      centred nursing practice is poorly developed. This paper aims to explore the
      concept of person-centredness and person-centred practice in order to add clarity
      to discussions about the term in the context of gerontological nursing. This
      literature-based exploration discusses the meaning of the word 'person' and the
      way this word is translated into person-centred practice. It is argued that there
      are four concepts underpinning person-centred nursing: (i). being in relation;
      (ii). being in a social world; (iii). being in place and (iv). being with self.
      The articulation of these concepts through existing models of person-centred
      practice in nursing raises the recurring themes of knowing the person, the
      centrality of values, biography, relationships, seeing beyond the immediate needs
      and authenticity. There is a need for further research and development work in
      gerontological nursing to distinguish between person-centred practice and good
      quality care for older people.

PMID- 15028035
TI  - Dementia diagnosis and disclosure: a dilemma in practice.
AB  - BACKGROUND: Providing the individual with the correct information about their
      diagnosis can help maximize the patient's autonomy, however empirical evidence
      identifies inconsistencies in the practice of diagnosis disclosure in dementia.
      Within health care, ethical problems arise frequently and these present a
      challenge for health care professionals. This challenge can also give rise to
      conflict when professionals are torn between respecting autonomy, doing good and
      avoiding paternalism. AIM: The aim of this paper is to highlight the need for
      interprofessional collaboration when faced with ethical dilemmas such as
      diagnosis disclosure in the care of adults with dementia. The use of a dialogue
      and supplementary notes are used to explore crucial ethical points raised by
      health care professionals. RELEVANCE TO CLINICAL PRACTICE: The increasing rate of
      dementia and the need for patients to have access to timely and appropriate
      information about their diagnosis has prompted much debate about disclosing the
      diagnosis with the individual who has dementia. This paper may also be useful for
      educational purposes when used as a framework for discussion/debate in student
      nurse education. CONCLUSION: Ethical theories are of benefit in assisting the
      members of the multidisciplinary team to reach a morally defensible decision.
      Making ethical decisions in practice can cause the nurse concern. While there is
      no complete set of 'rules' that can provide an answer to each ethical dilemma, it
      is of immense value to nurses working within the multidisciplinary team to
      possess a sound knowledge of ethical positions in order to analyse the many
      complex situations that nurses encounter. The pivotal role of the health care
      professional is to work in collaboration and engage in sharing the diagnosis with
      the patient. It is hoped that this paper will stimulate and encourage further
      debate and study regarding the individual with dementia and diagnosis disclosure.
      Recommendations for practice, education, policy and research will also be
      highlighted.

PMID- 15028038
TI  - Concerns relating to the application of frameworks to promote person-centredness
      in nursing with older people.
AB  - There is an increasing need to develop a multi-dimensional discussion and
      critique around the concept of 'person-centred' in the context of the delivery of
      nursing care for older people. As the context of nursing being considered here,
      it is primarily nurses who should be leading with this discourse, although
      drawing on a broad range of ideas from outside of nursing. The person-centred
      movement, commonly believed to originate in the care of those with dementia in
      the UK, is growing, especially in the UK and Australia, with signs of it moving
      across parts of Western Europe and North America. Person-centredness has a big
      emotional appeal to many nurses working with older people, perhaps because it
      'has the right feel' for them and nurses believe it 'feels right' for older
      people. It has grabbed the attention of many practising nurses in the UK in a way
      that humanistic nursing theory and the various associated nursing models from
      previous decades, seemed to have missed. This paper contributes to the discussion
      by suggesting that there are conceptual frameworks that nurses can draw on to
      help them understand and enhance their practice. However, it is suggested that
      these frameworks are either in their infancy or incomplete and they still need to
      convince nurses of their utility for day to day practice. It is also pointed out
      that the underpinning concept of 'personhood' has not yet been fully clarified by
      nursing.

PMID- 15028039
TI  - Beyond person-centred care: a new vision for gerontological nursing.
AB  - Currently considerable emphasis is placed on the promotion of person-centred
      care, which has become a watchword for good practice. This paper takes a
      constructively critical look at some of the assumptions underpinning person
      centredness, and suggests that a relationship-centred approach to care might be
      more appropriate. A framework describing the potential dimensions of relationship
      centred care is provided, and implications for further development are
      considered.

PMID- 15028041
TI  - Concealed conduction and dual pathway physiology of the atrioventricular node.
AB  - INTRODUCTION: Both concealed conduction and dual pathway physiology are important
      electrophysiologic characteristics of the AV node. The interaction of AV nodal
      concealment and duality, however, is not clearly understood. METHODS AND RESULTS:
      The properties of AV conduction curves in the presence and absence of a
      conditioning blocked impulse were prospectively studied during premature atrial
      stimulation in 20 patients with AV nodal reentrant tachycardia before and after
      slow pathway ablation and in 14 control patients. AV nodal duality in the control
      conduction curve in the absence of a conditioning impulse was observed in 19
      (95%) of 20 patients with AV nodal reentrant tachycardia. However, AV nodal
      duality in the modulated conduction curve in the presence of a blocked impulse
      was only identified in 2 (10%) of 20 patients (2/20 vs 19/20, P < 0.0001). The
      modulated curve was characterized by a significantly longer AV nodal effective
      and functional refractory periods compared to the control curve (P < 0.0001) in
      both patients with and without AV nodal reentry and in AV nodal reentry patients
      after successful slow pathway ablation. The maximum AH interval (AH(max)) of the
      modulated curve was significantly shorter than the control curve in both patients
      with (217 +/- 74 ms vs 347 +/- 55 ms, P < 0.0001) and without AV nodal reentry
      (178 +/- 50 ms vs 214 +/- 54 ms, P = 0.02). AH(max) of the control curve was
      significantly longer in AV nodal reentry patients than in controls (P < 0.0001).
      AH(max) of the modulated curve, however, was not significantly different between
      the two groups. After slow pathway ablation, AH(max) of the control curve was
      significantly reduced (347 +/- 55 ms vs 191 +/- 40 ms, P < 0.0001). Significant
      reduction in AH(max) of the modulated curve was not observed. CONCLUSION: An
      interaction of AV nodal concealed conduction and dual pathway physiology was
      demonstrated by our data. Slow pathway conduction of the AV node was prevented by
      the concealed beat in both patients with and without AV nodal reentry.

PMID- 15028042
TI  - Anatomy and physiology of concealment in dual atrioventricular nodal pathways.

PMID- 15028043
TI  - Prospective randomized study of mode switching in a clinical trial of pacemaker
      therapy for sinus node dysfunction.
AB  - INTRODUCTION: Atrial fibrillation (AF) is common in pacemaker patients with sinus
      node dysfunction (SND) and may result in rapid ventricular pacing (RVP) in the
      DDDR mode. Mode switching (MS) reduces RVP, but its clinical benefit in patients
      with SND is unknown. METHODS AND RESULTS: Two hundred two patients in the Mode
      Selection Trial (MOST; 2,010-patient, 6-year trial of DDDR vs VVIR pacing in SND)
      randomized to DDDR pacemakers with atrial high-rate episode (AHRE) storage
      capabilities were subrandomized to MS ON (N = 96) or MS OFF (N = 106).
      Cardiovascular symptoms, quality of life (QOL), reprogramming due to RVP, death,
      stroke, and heart failure hospitalization (HFH) were compared between groups. The
      treatment groups were similar with regard to AF history (59% MS ON vs 57% MS
      OFF). AHREs occurred in 49% patients during median follow-up of 2.2 years. Median
      AHRE duration (in min; MS ON 116 vs MS OFF 58, P = 0.29), frequency AHREs/week
      (MS ON 3.5 vs MS OFF 6.4, P = 0.23), and time spent in AHRE (min/week) (MS ON
      450, MS OFF 268) were similar. Reprogramming due to any RVP during AHREs occurred
      more in MS OFF vs MS ON (13.2% vs 3.1%, P = 0.011) and marginally more for
      symptomatic RVP (8.5% vs 2.1%, P = 0.062). Cardiovascular symptoms occurred in
      93.6% MS ON vs 90.2% MS OFF (P = 0.38). Median number of symptoms reported per
      visit was similar (MS ON 1.3 vs MS OFF 1.5, P = 0.62). Median symptom
      frequency/severity, summed and averaged over visits, was similar (MS ON 4.3 vs MS
      OFF 4.5, P = 0.74). QOL was not different between groups. Death, stroke, and HFH
      were not different between groups. CONCLUSION: MS reduces pacemaker reprogramming
      due to RVP during AHREs in a small number of patients but does not improve QOL or
      cardiovascular symptoms overall among patients with SND.

PMID- 15028044
TI  - Impact of catheter ablation on pulmonary vein morphology and mechanical function.
AB  - INTRODUCTION: Previous reports have documented that radiofrequency catheter
      ablation of pulmonary veins induces a significant increase in the peak velocity
      of transvenous blood flow. Although the magnitude of the increase infers a state
      of pulmonary vein stenosis, there have been no reports of direct visualization of
      the ablation zone. METHODS AND RESULTS: In each of 23 subjects, the myocardium
      investing one or more pulmonary veins (total of 42 veins) was electrically
      isolated by applying a confluent circumferential ablation lesion to the atrial
      side of the venoatrial junction. Doppler measurements of transvenous flow
      velocity were made before and after ablation using phased-array intracardiac
      echocardiography. Direct visualization of the ablation zone was performed using
      rotating intracardiac echocardiography, permitting assessment of shape, cross
      sectional area, phasic variation in cross-sectional area, and wall thickness. In
      a subset of 5 subjects, a more detailed assessment of the ablation and contiguous
      regions was performed using three-dimensional echocardiography (rotating
      transducer). Prior to ablation, venoatrial junctions demonstrated noncircular
      shape and marked phasic variation in cross-sectional area. There was a trivial
      transvenous pressure gradient. After ablation, there was a significant increase
      in both anterograde and retrograde flow velocities and pressure gradient, the
      magnitudes of which were inversely proportional to the preablation and
      postablation areas. Direct visualization of the ablation zone revealed
      circumferential wall swelling, reduced cross-sectional area, and diminishment in
      phasic variation in cross-sectional area. Similar observations were made at
      contiguous nonablated sites, diminishing in magnitude as a function of distance.
      CONCLUSION: Pulmonary vein ablation induces significant acute changes in
      morphology and mechanical function that extend beyond the ablation zone.

PMID- 15028045
TI  - Pulmonary vein ablation: looking while cooking.

PMID- 15028046
TI  - Enhanced detection of arrhythmia vulnerability using T wave alternans, left
      ventricular ejection fraction, and programmed ventricular stimulation: a
      prospective study in subjects with chronic ischemic heart disease.
AB  - INTRODUCTION: In previous studies, the prognostic value of T wave alternans (TWA)
      was similar to that of programmed ventricular stimulation (PVS). However,
      presently it is unclear if TWA and PVS identify the same patients or provide
      complementary risk stratification information. In addition, the effects of left
      ventricular ejection fraction (LVEF) on the prognostic value of TWA are unknown.
      The aim of this study was to determine if combined assessment of TWA, LVEF, and
      PVS improves arrhythmia risk stratification. METHODS AND RESULTS: This was a
      prospective study of 144 patients with coronary artery disease and LVEF < or =40%
      who were referred for PVS for standard clinical indications. The endpoint was the
      combined incidence of death, sustained ventricular arrhythmias, and appropriate
      implantable cardioverter defibrillator (ICD) therapy. TWA (hazard ratio 2.2, P =
      0.03) and PVS (hazard ratio 1.9, P = 0.05) both were significant predictors of
      endpoint events, and TWA was the only independent predictor. LVEF markedly
      influenced the prognostic value of TWA, which was a potent predictor of events in
      subjects with LVEF between 30% and 40% (event rates: TWA+ 36%, TWA- 0%, P =
      0.001) but did not predict events in subjects with LVEF <30% (hazard ratio 1.1, P
      > 0.5). PVS successfully identified additional low-risk patients within the
      cohort with negative or indeterminate TWA results (hazard ratio 4.7, P = 0.015)
      but did not provide incremental prognostic information for TWA+ patients (hazard
      ratio 0.9, P > 0.5). CONCLUSION: The combined use of TWA, LVEF, and PVS is a
      promising new approach to arrhythmia risk stratification that permits
      identification of high-risk and very-low-risk patients.

PMID- 15028047
TI  - Electrophysiologic refinement of risk stratification: can we achieve the goal?

PMID- 15028048
TI  - Activity-responsive pacing produces long-term heart rate variability.
AB  - INTRODUCTION: Long-term heart rate variability (HRV) measures, including the
      standard deviation of means of successive 5-minute epochs of R-R interval
      intervals (SDANN) and the power law slope (beta), are important prognostic
      measures, yet their physiologic basis is unknown. We tested the hypothesis that
      long-term HRV arises from physical activity in a randomized cross-over study in
      patients with rate-responsive pacemakers. METHODS AND RESULTS: Ten patients with
      complete heart block and dual-chamber pacemakers underwent 24-hour periods of
      ambulatory ECG in each of three pacing modes: atrially tracked, fixed-rate, and
      rate-responsive pacing. SDANN, ultra low frequency (ULF; frequencies <0.0033 Hz),
      and beta slope were calculated; and high-frequency power and root mean square of
      consecutive normal R-R intervals (rMSSD) were calculated as measures of short
      term HRV, which have autonomic origins. Long-term HRV measures were similar with
      atrially tracked and rate-responsive pacing and were much greater than in fixed
      rate pacing (SDANN P = 0.0001; ULF P = 0.0001; beta slope P = 0.0002). Short-term
      HRV measures were similarly low in fixed-rate and rate-responsive pacing (P = NS)
      and were significantly lower than with atrially tracked pacing (P = 0.0034).
      CONCLUSION: Rate-responsive pacing reproduces long-term, but not short-term,
      measures of HRV, suggesting that they may be markers of heart rate responses to
      patient activity.

PMID- 15028049
TI  - Transcristal conduction during isthmus ablation of typical atrial flutter:
      influence on success criteria.

PMID- 15028050
TI  - Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form
      of long QT syndrome.
AB  - INTRODUCTION: Beta-blockers are widely used to prevent the lethal cardiac events
      associated with the long QT syndrome (LQTS), especially in KCNQ1-related LQTS
      (LQT1) patients. Some LQT1 patients, however, are refractory to this therapy.
      METHODS AND RESULTS: Eighteen symptomatic LQTS patients (12 families) were
      genetically diagnosed as having heterozygous KCNQ1 variants and received beta
      blocker therapy. Cardiac events recurred in 4 members (3 families) despite
      continued therapy during mean follow-up of 70 months. Three of these patients (2
      families) had the same mutation [A341V (KCNQ1)]; and the other had R243H (KCNQ1).
      The latter patient took aprindine, which seemed to be responsible for the event.
      By functional assay using a heterologous mammalian expression system, we found
      that A341V (KCNQ1) is a loss-of-function type mutation (not dominant negative).
      Further genetic screening revealed that one A341V (KCNQ1) family cosegregated
      with S706C (KCNH2) and another with G144S (KCNJ2). Functional assay of the S706C
      (KCNH2) mutation was found to reduce the current density of expressed
      heterozygous KCNH2 channels with a positive shift (+8 mV) of the activation
      curve. Action potential simulation study was conducted based on the KYOTO model
      to estimate the influence of additional gene modifiers. In both models mimicking
      LQT1 plus 2 and LQT1 plus 7, the incidence of early afterdepolarization was
      increased compared with the LQT1 model under the setting of beta-adrenergic
      stimulation. CONCLUSION: Multiple mutations in different LQTS-related genes may
      modify clinical characteristics. Expanded gene survey may be required in LQT1
      patients who are resistant to beta-blocker therapy.

PMID- 15028051
TI  - Ablation of focally induced atrial fibrillation: selective or extensive?
AB  - INTRODUCTION: Focally induced atrial fibrillation (AF) often is due to ectopic
      activity in the pulmonary veins (PV). Although initial approaches were aimed at
      ablating only the ectopic foci, more extensive ablation approaches have evolved
      that isolate all PVs empirically and/or create circumferential ablation lines in
      the left atrium (LA). These techniques last longer and may be associated with
      more risks. We retrospectively evaluated the outcome and risks of ablation for
      focally induced AF in a single-center patient population. METHODS AND RESULTS: We
      report on 47 patients (32 men and 15 women; age 47 +/- 10 years) in whom 52
      ablations were performed. In 19 patients (22 sessions), ablation was directed at
      the site(s) of overt ectopic activity ("selective" group), whereas in 28 patients
      (30 sessions) without sufficient ectopy to determine the culprit PV a mean of 3.5
      PVs were empirically targeted for bidirectional disconnection from the LA
      ("extensive" group). On a preprocedural Holter recording, the "selective" group
      had significantly more isolated atrial ectopy (3,276 +/- 2,933 vs 620 +/- 937
      beats/24 hours) and runs of atrial tachycardia (330 +/- 202 vs 53 +/- 87 runs/24
      hours) than the "extensive" group (P < 0.01 for both). Only 11% had persistent AF
      before ablation. Acute procedural success was 81% (elimination of all ectopy) and
      83%, respectively (bidirectional and fully circumferential isolation of all
      targeted PVs). Procedure and fluoroscopy times were significantly shorter in the
      "selective" group. There were no major complications, but 7 minor complications
      and 2 acute PV stenoses > 50% in the 30 "extensive" procedures were observed.
      Mean follow-up was 8.4 +/- 8.5 months (median 6.9). Kaplan-Meier analysis,
      excluding recurrences during only the first month ("delayed cure"), showed AF
      recurrence in 45% after 6 months and in 55% after 1 year. Outcome was not
      dependent on ablation approach ("selective" or "extensive") nor was time to first
      AF (22 +/- 64 days and 30 +/- 69 days). AF recurrence tended to be higher in
      patients with larger LA (P = 0.08), underlying heart disease or hypertension (P =
      0.08), and those "extensive" patients in whom not all 4 PVs were targeted (P =
      0.07). CONCLUSION: Trigger-directed ablation for focally induced AF is associated
      with a relatively high recurrence rate during follow-up. Apart from recurrence of
      the ectopic trigger, this may point to underlying structural changes in the
      atrial substrate not addressed by the ablation. Prospective evaluation of the
      risk-to-benefit profile of any technique (selective, extensive, including linear
      lines) is required.

PMID- 15028052
TI  - Relationship between connexins and atrial activation during human atrial
      fibrillation.
AB  - INTRODUCTION: Gap junctional connexin proteins (connexin40 [Cx40], connexin43
      [Cx43]) are a determinant of myocardial conduction and are implicated in the
      development of atrial fibrillation (AF). We hypothesized that atrial activation
      pattern during AF is related to connexin expression and that this relationship is
      altered by AF-induced remodeling in the fibrillating atria of chronic AF. METHODS
      AND RESULTS: Isochronal activation mapping was performed during cardiac surgery
      on the right atria of patients in chronic AF (n = 13) using an epicardial
      electrode array. The atrial activation pattern was categorized using a complexity
      score based on the number of propagating wavefronts of activation and by grouping
      atria into those capable of uniform planar activation (simple) and those that
      were not (complex). The activation pattern was correlated with the levels of Cx43
      and Cx40 signal measured by immunoconfocal quantification of biopsies from the
      mapped region. We studied the impact of electrical remodeling by comparing these
      findings with the unremodeled atria of patients in sinus rhythm during pacing
      induced sustained AF (n = 17). In chronic AF, atria with complex activation had
      lower Cx40 signal than atria showing simple activation (0.013 +/- 0.006
      microm(2)/microm(2) vs 0.027 +/- 0.009 microm(2)/microm(2), P < 0.02), with the
      relative connexin signal (Cx40/Cx40+Cx43) correlating with complexity score (P =
      0.01, r =-0.74). This relationship did not occur in the unremodeled atria, and
      increased heterogeneity of distribution of Cx40 labeling in chronic AF was the
      only evidence of connexin remodeling that we detected in the overall group.
      CONCLUSION: The pattern of atrial activation is related to immunoconfocal
      connexin signal only in the fully remodeled atria of chronic AF. This suggests
      that intercellular coupling and pattern of atrial activation are interrelated,
      but only in conjunction with the remodeling of atrial electrophysiology that
      occurs in chronic AF.

PMID- 15028053
TI  - Functional genomic study on atrial fibrillation using cDNA microarray and two
      dimensional protein electrophoresis techniques and identification of the myosin
      regulatory light chain isoform reprogramming in atrial fibrillation.
AB  - INTRODUCTION: Functional and structural changes of atrial tissue occur during the
      natural course of atrial fibrillation (AF), and these changes may contribute to
      further AF. We investigated the changes in AF tissue using cDNA microarray and
      two-dimensional protein electrophoresis techniques. METHODS AND RESULTS: We
      established a porcine model of AF by rapid right atrial appendage pacing at a
      rate of 600/min. Atrial tissue was obtained after rapid atrial depolarization for
      6 weeks. Microarrays containing 6,035 cDNA clones were used to evaluate the
      alterations of mRNA. Two-dimensional protein electrophoresis was performed to
      compare protein patterns. In cDNA microarray studies, we identified 387 genes
      with significant change in the left atrium and 81 genes in the right atrium.
      Among the genes, the ventricular isoform of the myosin regulatory light chain
      (MLC-2V) showed the greatest fold of change (9.4 and 7.3 in the left and right
      atrium, respectively). In protein electrophoresis, the expression levels of three
      protein spots spanning from 18 to 20 kDa in the acidic region (PI 4.5-5.0) were
      specifically elevated in the AF group. Interestingly, through tandem mass
      spectrometric analysis, these three spots were identified as MLC-2V. Thus, MLC-2V
      expression at the mRNA and protein levels corresponded well, and both indicated a
      significant increase in AF. CONCLUSION: Both cDNA microarray and two-dimensional
      polyacrylamide protein electrophoresis studies revealed characteristic changes in
      AF tissue. We demonstrated the reprogramming of myosin regulatory light chain
      isoform composition, with a significant increase of its ventricular isoform (MLC
      2V).

PMID- 15028054
TI  - Atrial fibrillation: molecular biology has yet to impact management.

PMID- 15028055
TI  - Spiral wave control by a localized stimulus: a bidomain model study.
AB  - INTRODUCTION: It has been reported that electrical stimulation can control spiral
      wave (SW) reentry. However, previous research does not account for the effects of
      stimulus-induced virtual electrode polarization (VEP) and the ensuing cathode
      break (CB) excitation. The aim of the present study was to examine the
      interaction of VEP with SW reentry in a bidomain model of electrical stimulation
      and thus provide insight into the mechanistic basis of SW control. METHODS AND
      RESULTS: We conducted 3,168 simulations of localized stimulation during SW
      reentry in an anisotropic bidomain sheet. Unipolar cathodal 2-ms stimuli of
      strengths 4, 8, 16, and 24 mA were delivered at 99 locations in the sheet. The
      interaction between stimulus-induced VEP and SW reentry resulted in 1 of 3
      possible outcomes: SW shift, SW breakup, or no effect. SW shift, which could be
      instrumental in SW termination at an anatomic or functional line of block,
      resulted from CB rather than cathode-make excitation. Stimulus timing, site, and
      strength all were important factors in VEP-mediated SW control. Furthermore, we
      found that the number of episodes of SW shift across the fibers was more
      sensitive to stimulus strength than that of SW shift along the fibers. SW shift
      can be explained by the interaction between the four VEP-induced wavebreaks and
      the wavebreak of the SW, ultimately resulting in termination of the original SW
      and the survival of one of the VEP-induced wavebreaks. This establishes a new SW
      reentry. CONCLUSION: This study provides new mechanistic insight into SW control.

PMID- 15028057
TI  - Combined epicardial-endocardial approach to ablation of inappropriate sinus
      tachycardia.
AB  - A combined epicardial-endocardial approach to ablation of inappropriate sinus
      tachycardia in a highly symptomatic patient who failed to respond to medical
      therapy and endocardial ablation is described. The anatomy and physiology of the
      sinus node is discussed, providing a basis for performing this procedure. This
      case provides an additional therapeutic option for a condition that often is
      difficult to manage.

PMID- 15028056
TI  - Left ventricular endocardial lead placement using a modified transseptal
      approach.
AB  - Coronary sinus cannulation and placement of left ventricular (LV) leads can be
      difficult. Occasionally alternative approaches are required. We report the first
      case of a modified transseptal LV endocardial lead placement via the left
      axillary vein for cardiac resynchronization.

PMID- 15028058
TI  - Unusual response to ventricular pacing during a long RP tachycardia.

PMID- 15028059
TI  - Delayed detection of stable ventricular tachycardia in a dual-chamber implantable
      cardioverter defibrillator: what is the mechanism?

PMID- 15028060
TI  - Endocardial imaging of the left atrium in patients with atrial fibrillation.

PMID- 15028061
TI  - Pronounced epsilon waves in arrhythmogenic right ventricular dysplasia.

PMID- 15028063
TI  - Cardiac surgery for arrhythmias.
AB  - Cardiac arrhythmia surgery was initiated in 1968 with the first successful
      division of an accessory AV connection for the Wolff-Parkinson-White syndrome.
      Subsequent surgical procedures included the left atrial isolation procedure and
      right atrial isolation procedure for automatic atrial tachycardias, discrete
      cryosurgery of the AV node for AV nodal reentrant tachycardia, the atrial
      transection procedure, the corridor procedure, and the maze procedure for atrial
      fibrillation, the right ventricular disconnection procedure for arrhythmogenic
      right ventricular tachycardia, and the encircling endocardial ventriculotomy,
      subendocardial resection procedure, endocardial cryoablation, the Jatene
      procedure, and the Dor procedure for ischemic ventricular tachycardia. Because of
      monumental strides in the treatment of most refractory arrhythmias by endocardial
      catheter techniques during the past decade, the only remaining viable surgical
      procedures for cardiac arrhythmias are the maze procedure for atrial fibrillation
      and the Dor procedure for ischemic ventricular tachycardia. Nevertheless, the 25
      to 30 years of intense activity in the field of cardiac arrhythmia surgery
      provided the essential foundation for the development of these catheter
      techniques and represent one of the most exciting and productive eras in the
      history of medicine. In one short professional career, we have witnessed the
      birth of arrhythmia surgery, its adolescence as an "esoteric" specialty, its
      prime as an enlightening yet exhausting period, and finally its waning years as a
      source of knowledge and wisdom upon which better methods of treatment have been
      founded. One could hardly ask for a more rewarding experience.

PMID- 15028065
TI  - Standard right atrial ablation is effective for atrioventricular nodal reentry
      with earliest activation in the coronary sinus.
AB  - INTRODUCTION: Reports suggest that coronary sinus (CS) or left atrial ablations
      may be necessary for treatment of AV nodal reentrant tachycardia (AVNRT) with
      earliest retrograde atrial activation in the CS. We assessed the efficacy of
      standard right atrial catheter ablation approaches in these tachycardias and
      determined the incidence of earliest activation in the CS in AVNRT. METHODS AND
      RESULTS: We retrospectively evaluated intracardiac recordings from 225
      consecutive patients who underwent electrophysiologic studies and radiofrequency
      (RF) ablation for AVNRT in two institutions. Atrial activation during AVNRT was
      evaluated using multiple catheters according to standard protocol used in our
      laboratories. RF ablations in the triangle of Koch were performed in all
      patients. Eighteen of 225 patients (8%) had earliest activation in one of the CS
      poles. The demographics and AVNRT characteristics of these 18 patients were
      similar to those of the other 207 patients who did not have CS as earliest
      activation site and included both typical and atypical AVNRT. Following RF
      ablation, none of the 18 patients had inducible AVNRT. CONCLUSION: Successful RF
      ablation can be performed at standard sites in the triangle of Koch regardless of
      earliest site of atrial activation. The incidence of CS as earliest retrograde
      atrial activation site in AVNRT is 8%.

PMID- 15028066
TI  - Impact of age on the outcome of pulmonary vein isolation for atrial fibrillation
      using circular mapping technique and cooled-tip ablation catheter:.
AB  - INTRODUCTION: A retrospective analysis was performed to define the impact of age
      on the outcomes and complications in patients undergoing pulmonary vein isolation
      (PVI). PVI is an evolving technique for the management of atrial fibrillation
      (AF). The impact of age on the risks, outcomes, and complications of PVI has not
      been well defined. METHODS AND RESULTS: A total of 323 patients (259 men and 64
      women; age 18-79 years) underwent PVI for treatment of drug-refractory
      symptomatic AF. An ostial isolation of the pulmonary veins was done using a
      cooled-tip ablation catheter guided by circular mapping. The patients were
      divided into three groups based on age (group I: <50 years, group II: 51-60
      years, group III: >60 years) and the results were compared. There were 106
      patients in group I, 114 patients in group II, and 103 patients in group III
      (mean age 41.3 +/- 7.8 years, 55.4 +/- 2.75 years, and 66.6 +/- 4.18 years,
      respectively) who underwent PVI for paroxysmal (53.8%), persistent (10.8%), or
      permanent (35.3%) AF. Baseline characteristics were similar except for a higher
      prevalence of hypertension and/or structural heart disease in groups II and III
      (58% and 63% vs 33% in group I, respectively). The procedural variables were
      similar in all age groups. The overall risk of complications was similar in the
      three groups, except that the risk of stroke was significantly higher in patients
      >60 years of age (3% vs 0%; P < 0.05). The recurrence rates of AF were similar in
      the three age groups (15.1%, 16.7%, and 18.4%, respectively; P > 0.05). The risk
      of severe pulmonary vein stenosis (1.8%, 2.6%, and 0.9%, respectively) was low
      and did not vary with age. CONCLUSION: PVI is a safe and effective treatment for
      patients with drug-refractory symptomatic AF, and its benefits extend to all age
      groups. The risk of procedural complications, especially thromboembolic events,
      appears to be higher in the elderly age group. This observation needs to be
      considered while assessing potential candidates for the procedure.

PMID- 15028067
TI  - Incidence of nonsustained and sustained ventricular tachyarrhythmias in patients
      with an implantable cardioverter defibrillator.
AB  - INTRODUCTION: Nonsustained ventricular tachycardia (NSVT) is a frequent
      phenomenon in some patients with heart disease, but its association with
      sustained ventricular tachycardias (ventricular tachycardia [VT]/ventricular
      fibrillation [VF]) is still not clear. The aim of this study was to determine
      whether NSVT incidence was associated with sustained VT/VF in patients with an
      implantable cardioverter defibrillator (ICD). METHODS AND RESULTS: Retrospective
      data analysis was conducted in 923 ICD patients with a mean follow-up of 4
      months. NSVT and sustained VT/VF were defined as device-detected tachycardias.
      The incidence rates of NSVT and sustained VT/VF as well as ICD therapies were
      determined as episodes per patient. The NSVT index was defined as the product of
      NSVT episodes/day times the mean number of beats per episode, i.e., total
      beats/day. The NSVT index peak was defined as the highest value on or prior to
      the day with sustained VT/VF episodes. Patients (n = 393) with NSVT experienced a
      higher incidence of sustained VT/VF (17.2 +/- 63.0 episodes/patient) and ICD
      therapies (15.2 +/- 61.4 episodes/patient) than patients (n = 530) without NSVT
      (sustained VT/VF: 0.5 +/- 6.6 and therapies: 0.5 +/- 5.6; P < 0.0001).
      Approximately 74% of NSVT index peaks occurred on the same day or <3 days prior
      to sustained VT/VF episodes. The index was higher for peaks < or =3 days prior to
      the day with sustained VT/VF (94.3 +/- 140.1 total beats/day) than for peaks >3
      days prior to the day with sustained VT/VF (32.7 +/- 55.9 total beats/day; P <
      0.0001). CONCLUSION: ICD patients with NSVT represent a population more likely to
      experience sustained VT/VF episodes with a temporal association between an NSVT
      surge and sustained VT/VF occurrence.

PMID- 15028068
TI  - Technique and results of pulmonary vein angiography in patients undergoing
      catheter ablation of atrial fibrillation.
AB  - INTRODUCTION: Delineation of pulmonary vein (PV) anatomy is an integral part of
      the PV isolation procedure. The aims of the present study were to (1) describe
      the technique of selective PV angiography, (2) show the typical fluoroscopic
      locations and appearance of the PVs, and (3) compare the ostial diameters of PVs
      measured by angiography and magnetic resonance imaging (MRI). METHODS AND
      RESULTS: Twenty consecutive patients undergoing a PV isolation procedure
      underwent selective PV angiography using a deflectable 8-French lumened catheter
      (Naviport, Cardima). The left superior PV (LSPV) runs upward and away from the
      spine in the right anterior oblique (RAO) projection and upward and toward the
      spine in the left anterior oblique (LAO) projection. The opposite is true for the
      right superior PV (RSPV). The left inferior PV (LIPV) has a bull's-eye appearance
      in the RAO projection, and the right inferior PV (RIPV) has a bull's-eye
      appearance in the LAO projection due to their end-on trajectories. The LIPV in
      the LAO projection and the RIPV in the RAO projection run horizontally toward the
      spine. An excellent correlation was noted in PV ostial size as assessed by
      angiography and MRI (r(2) < 0.90, P < 0.0001). CONCLUSION: This study describes
      the technique and results of PV angiography and fluoroscopy. The study also
      demonstrates good correlation of PV ostial diameters by contrast venography and
      MRI. PV angiography can be used as an alternate to MRI or computed tomographic
      imaging, particularly when these tests are unavailable or are contraindicated in
      the patient.

PMID- 15028069
TI  - Localization of the isthmus in reentrant circuits by analysis of electrograms
      derived from clinical noncontact mapping during sinus rhythm and ventricular
      tachycardia.
AB  - INTRODUCTION: New methods for electrogram analysis accurately estimated reentrant
      circuit isthmus location and shape in a canine model. It was hypothesized that
      these methods also would locate reentrant circuits causing clinical ventricular
      tachycardia (VT). METHODS AND RESULTS: Intracardiac electrogram recordings,
      obtained with a noncontact mapping system, were analyzed retrospectively from 14
      patients with reentrant VT who had undergone successful radiofrequency ablation
      for prevention of VT initiation. Unipolar electrograms from 256 uniformly
      distributed endocardial sites were reconstructed by mathematical transformation.
      Twenty-seven tachycardias were mapped; 15 (in 11 patients) had a complete
      endocardial reentrant circuit with a figure-of-eight conduction pattern. During
      sinus rhythm, the location and axis of the slowest and most uniform conduction in
      the region of latest endocardial activation (the primary axis), the limits of
      which were defined as boundaries with >15 ms difference in electrogram duration
      between contiguous recordings, identified the location and shape of the reentrant
      circuit isthmus with a mean sensitivity compared with activation mapping of 79.3%
      and a mean specificity of 97.6%. The midpoint of a theoretical "estimated best
      ablation line" drawn perpendicular to the primary axis of activation, spanning
      the estimated isthmus location was within 1.3 +/- 0.2 cm (mean distance +/- SD)
      of the actual ablation site that terminated tachycardia. Analysis of VT
      electrograms, based on time shifts in the far-field component of the local
      electrogram when cycle length changed (piecewise linear adaptive template
      matching [PLATM] method) in 5 of the cases, accurately estimated the time
      interval between activation at the recording site and the circuit isthmus slow
      conduction zone where the effective ablation lesion had been placed, which is
      proportional to the distance between the two locations (mean difference compared
      with activation mapping: +/-37.3 ms). CONCLUSION: In selected patients with VT
      who have a complete endocardial circuit, isthmus location and shape can be
      discerned by analysis of sinus rhythm or tachycardia electrograms, and an
      effective ablation site can be predicted without the need to construct activation
      maps of reentrant circuits.

PMID- 15028070
TI  - Long-term follow-up of right atrial ablation in patients with atrial
      fibrillation:.
AB  - INTRODUCTION: The aim of this study was to evaluate the efficacy and the impact
      on quality of life of a new ablative approach to the right atrium in patients
      with atrial fibrillation (AF). METHODS AND RESULTS: Seventy-four symptomatic
      patients with paroxysmal (n = 49) or permanent (n = 25) refractory AF underwent
      radiofrequency ablation. A nonfluoroscopic electroanatomic mapping system was
      used to perform the following lesions: (1) an isthmus line between the tricuspid
      annulus and the inferior vena cava; (2) a posterior intercaval line from the
      superior vena cava and the inferior vena cava; (3) a septal line from the
      superior vena cava to the fossa ovalis, proceeding to the coronary sinus ostium
      where a circumferential line around the ostium was performed, and then on to the
      inferior vena cava; and (4) a transversal lesion connecting the posterior
      intercaval and the septal lesions. In addition, electrical disconnection of the
      superior vena cava was performed. There were no complications. Postablation
      remapping showed the absence of discrete electrical activity inside and just
      around the ablation lines. Electrical disconnection of the superior vena cava was
      obtained in all patients. After 21 +/- 6 months, 49 patients (66%) had stable
      sinus rhythm with continuation of the previous antiarrhythmic drug therapy, 13
      patients (18%) were considered improved, and 12 (16%) received no benefit
      (unsuccessful procedure). After ablation, quality of life was significantly
      improved, reaching the levels of the general Italian population. Ejection
      fraction and the extent of the low-voltage area were found by multivariate
      analysis to be independent predictors of AF recurrence. CONCLUSION: The results
      of the present study suggest that this ablative approach in combination with
      antiarrhythmic drugs is safe and effective in treating AF, leading to a marked
      increase in quality of life in patients with refractory AF.

PMID- 15028071
TI  - Atrial tachyarrhythmia recurrence temporal patterns in bradycardia patients
      implanted with antitachycardia pacemakers.
AB  - INTRODUCTION: New-generation pacemakers allow continuous atrial tachyarrhythmia
      (AT) monitoring that provides accurate information about AT type, frequency,
      burden, and temporary evolution. METHODS AND RESULTS: We performed a prospective
      multicenter study to describe AT temporal patterns in patients with sinus
      bradycardia and AT. Two hundred forty patients (123 men; age 71 +/- 8 years) were
      implanted with a DDDRP pacemaker (model AT500, Medtronic Inc.). All patients were
      followed for 13 months. The first-month stabilization period of all patients was
      discarded from analysis. Seventy percent of patients had AT recurrences. Mean
      time to first AT recurrence (48.2 days, 95% confidence interval [CI] 37.0-59.5
      days) was significantly longer than the time between first and second AT episode
      (10.3 days, 95% CI 6.7-13.9 days, P < 0.01). A minority of patients had a uniform
      time distribution of AT recurrences: <25% of patients had AT episodes in more
      than 6 of the 12 months considered in the study. The probability density function
      of consecutive sinus rhythm days between AT episodes was calculated for each of
      40 patients who experienced >25 AT episodes and fitted by power law and
      exponential functions. The best fit was obtained by power law function in 60% of
      patients, by exponential function in 10%, and the two models gave comparable
      results in 30% of patients. CONCLUSION: In our population of patients with a
      history of sinus bradycardia and AT who were implanted with a new device equipped
      with atrial pacing therapies, 30% did not experience AT recurrences in the 12
      month study period. Analysis of interevent time showed that in 60% of patients AT
      recurrences do not follow a uniform or random distribution. These findings bring
      into question the use of cross-over design and time to first AT recurrence as a
      clinical outcome in trials for AT therapy in this patient population.

PMID- 15028072
TI  - Identification and ablation of three types of ventricular tachycardia involving
      the his-purkinje system in patients with heart disease.
AB  - INTRODUCTION: Ventricular tachycardia (VT) with involvement of the His-Purkinje
      system (HPS) can be difficult to recognize in patients with heart disease, but it
      may be particularly susceptible to ablation targeting the HPS. This study defines
      the incidence and types of HPS involvement in VT. METHODS AND RESULTS:
      Involvement of the HPS was sought during electrophysiologic study with catheter
      mapping in 234 consecutive patients referred for catheter ablation of recurrent
      VT associated with heart disease. HPS VT was observed in 20 (8.5%) patients (mean
      ejection fraction 29%+/- 17%); in 9 (11%) of 81 patients with nonischemic heart
      disease and 11 (7.1%) of 153 patients with coronary artery disease (P = NS).
      Three types of HPS VT were observed: 16 patients (group 1) had typical bundle
      branch reentry, 2 patients (group 2) had bundle branch reentry and
      interfascicular reentry, and 2 patients (group 3) had VT consistent with a focal
      origin in the distal HPS. In all three groups, the VT QRS had morphologic
      similarity to the sinus rhythm QRS. Ablation of HPS VT was successful in all
      patients in whom it was attempted but produced high-degree AV block in 6 (30%).
      In 12 patients (60%), other VTs due to reentry through scar also were inducible.
      CONCLUSION: Involvement of the HPS in VT associated with heart disease has three
      distinct clinical forms, all of which are susceptible to ablation. Ablation often
      is not sufficient as the sole therapy due to other induced VT's and conduction
      abnormalities, requiring pacemaker and/or defibrillator implantation.

PMID- 15028073
TI  - Repolarization abnormality in idiopathic ventricular fibrillation: assessment
      using 24-hour QT-RR and QaT-RR relationships.
AB  - INTRODUCTION: We evaluated the characteristics of QT-RR and QaT (apex of T wave)
      RR relationships in patients with idiopathic ventricular fibrillation (IVF)
      compared with control subjects. We hypothesized that IVF patients have unique
      repolarization dynamics related to a reduced fast Na current and a prominent
      transient outward current. METHODS AND RESULTS: The study group consisted of 9
      men (age 47 +/- 10 years) with IVF (6 with Brugada type and 3 with non-Brugada
      type) who had experienced nocturnal episodes of VF. The control group consisted
      of 28 healthy age-matched men (age 44 +/- 12 years). The relationships between QT
      and RR intervals and between QaT and RR intervals were analyzed from 24-hour
      Holter ECG data using an automatic measurement system. Both QT and QaT at RR
      intervals of 0.6, 1.0, and 1.2 seconds were determined from QT-RR and QaT-RR
      linear regression lines. Both QT-RR and QaT-RR slopes were lower in the IVF group
      than in the control group (QT-RR: 0.092 +/- 0.023 vs 0.137 +/- 0.031, P < 0.001;
      QaT-RR: 0.109 +/- 0.025 vs 0.153 +/- 0.028, P < 0.001). QT at an RR interval of
      0.6 second did not differ between two groups, but QT at RR intervals of either
      1.0 or 1.2 seconds was significantly shorter in the IVF group than in the control
      group (RR 1.0 s: 0.384 +/- 0.018 vs 0.399 +/- 0.017, P < 0.05; RR 1.2 s: 0.402 +/
      0.019 vs 0.426 +/- 0.020, P < 0.01). QaT at RR intervals of either 1.0 or 1.2
      seconds also was shorter in the IVF group (RR 1.0 s: 0.289 +/- 0.022 vs 0.312 +/-
      0.021, P < 0.01; RR 1.2 s: 0.311 +/- 0.024 vs 0.343 +/- 0.024, P < 0.01). In four
      patients, oral administration of disopyramide (300 mg/day) was effective in
      suppressing VF episodes and increased slopes of QT-RR and QaT-RR relationships.
      CONCLUSION: IVF patients had lower slopes of QT-RR and QaT-RR regression lines
      and impaired prolongation of QT and QaT at longer RR intervals compared with
      control subjects. These unique repolarization dynamics may be related to the
      frequent occurrence of VF episodes at night.

PMID- 15028074
TI  - Phenotypic characterization of a large European family with Brugada syndrome
      displaying a sudden unexpected death syndrome mutation in SCN5A:.
AB  - INTRODUCTION: Brugada syndrome is characterized by sudden death secondary to
      malignant arrhythmias and the presence of ST segment elevation in leads V(1) to
      V(3) of patients with structurally normal hearts. This ECG pattern often is
      concealed but can be unmasked using potent sodium channel blockers. Like
      congenital long QT syndrome type 3 (LQT3) and sudden unexpected death syndrome,
      Brugada syndrome has been linked to mutations in SCN5A. METHODS AND RESULTS: We
      screened a large European family with Brugada syndrome. Three members (two
      female) had suffered malignant ventricular arrhythmias. Ten members showed an ECG
      pattern characteristic of Brugada syndrome at baseline, and eight showed the
      pattern only after administration of ajmaline (total 12 female). Haplotype
      analysis revealed that all individuals with positive ECG at baseline shared the
      SCN5A locus. Sequencing of SCN5A identified a missense mutation, R367H,
      previously associated with sudden unexpected death syndrome. Two of the eight
      individuals who displayed a positive ECG after the administration of ajmaline,
      but not before, did not have the R367H mutation, and sequencing analysis failed
      to identify any other mutation in SCN5A. The R367H mutation failed to generate
      any current when heterologously expressed in HEK cells. CONCLUSION: Our results
      support the hypothesis that (1) sudden unexpected death syndrome and Brugada
      syndrome are the same disease; (2) male predominance of the phenotype observed in
      sudden unexpected death syndrome does not apply to this family, suggesting that
      factors other than the specific mutation determine the gender distinction; and
      (3) ajmaline may provide false-positive results. These findings have broad
      implications relative to the diagnosis and risk stratification of family members
      of patients with the Brugada syndrome.

PMID- 15028075
TI  - Gender difference and drug challenge in Brugada syndrome.

PMID- 15028076
TI  - Implications of implantable cardioverter defibrillator therapy in congenital
      heart disease and pediatrics.
AB  - INTRODUCTION: The incidence of appropriate and inappropriate discharges,
      indicators of system failure, and clinical implications of implantable
      cardioverter defibrillator (ICD) therapy in children and young adults with heart
      disease is poorly defined. METHODS AND RESULTS: In a retrospective study at a
      single medical center, a total of 90 ICD procedures were performed in 76 patients
      younger than age 30 years (median 16 years, range 1-30): 42% with congenital
      heart disease, 33% with primary electrical disease, 17% with hypertrophic
      cardiomyopathy, and 8% with idiopathic dilated cardiomyopathy. Indications for
      ICD included arrest or sustained ventricular tachycardia (n = 27), and
      combinations of syncope (n = 32), palpitations (n = 17), spontaneous ventricular
      arrhythmia (n = 40), inducible ventricular tachycardia (n = 36), or severe
      hypertrophic cardiomyopathy. Transvenous dual-chamber ICDs were implanted in 29
      patients. Subcutaneous arrays or epicardial patches were used in 9 patients. Over
      a median 2-year follow-up, 28% of patients received appropriate shocks for
      ventricular tachycardia (median 13 months to first shock) and 25% experienced
      inappropriate shocks for multiple causes (median 16 months). With multivariate
      analysis, growth strongly correlated with lead failure (odds ratio 73, 3.5-1530,
      P = 0.006). Complications occurred in 29 patients, including lead failure in 16
      (21%), ICD "storm" with sequential shocks in 5, and infection in 2 patients. No
      deaths were attributable to ICD placement or subsequent device failure.
      CONCLUSION: ICD therapy can effectively manage malignant arrhythmias in selected
      pediatric and congenital heart patients. Spurious shocks or ICD storm may
      increase morbidity and emphasize the need for concomitant medical and ablative
      therapy. ICD lead failure was relatively frequent in this population.

PMID- 15028077
TI  - Implantable cardioverter defibrillators in children:.

PMID- 15028078
TI  - Shock-induced epicardial and endocardial virtual electrodes leading to
      ventricular fibrillation via reentry, graded responses, and transmural
      activation.
AB  - INTRODUCTION: The mechanism of ventricular fibrillation (VF) induction by T wave
      shocks has been attributed to reentry, propagated graded responses (PGR), and
      triggered activity. The limitation of recording transmembrane potential (V(m))
      from only a single surface has hampered efforts to elucidate the relative role of
      these phenomena and their relationship to shock-induced virtual electrodes.
      METHODS AND RESULTS: V(m) patterns from epicardial and endocardial surfaces of
      isolated sheep right ventricles were recorded with two CCD cameras for monophasic
      (M) and biphasic (B) shocks delivered at various coupling intervals (CI) from a
      unipolar mesh electrode on the epicardium. VF was induced via (1) the formation
      of reentry following make or break excitation; (2) propagated graded responses
      during apparent isoelectric window; and (3) breakthrough activation patterns
      coincident with endocardial-to-epicardial gradients in V(m). M shocks depolarized
      both surfaces at long CIs and polarized epicardial and endocardial surfaces
      oppositely at short CIs. At intermediate CIs, postshock V(m) patterns could lead
      to reentry on one surface or endocardial-to-epicardial gradients resulting in
      breakthrough. B induced VF less than M for short and intermediate CIs due to more
      homogeneous end-shock V(m) patterns. However, at long CIs these homogeneous
      patterns resulted in more VF induction because B left the tissue closer to the
      V(m) threshold for propagation. CONCLUSION: Postshock activity occurred either
      immediately via epicardial or endocardial reentry, or after a delay caused by
      transmural propagation or propagated graded responses. These findings could
      explain the isoelectric window and focal activation patterns observed on the
      epicardium following VF induction shocks.

PMID- 15028079
TI  - Virtual electrode, graded responses, reentry, breakthrough, and undetermined:.

PMID- 15028080
TI  - Catheter ablation of frequently recurring ventricular fibrillation in a patient
      after aortic valve repair.
AB  - It has been demonstrated that idiopathic ventricular fibrillation (VF) can be
      triggered by ventricular premature beats (VPBs) arising from the Purkinje fibers.
      Eliminating these VPBs by radiofrequency catheter ablation prevented VF
      recurrences. Whether the same pathophysiology and the same treatment option exist
      in patients with structural heart disease is unknown. Recurrent VF was observed
      in a 17-year-old patient after aortic valve repair of a perforated noncoronary
      cusp with resulting severe aortic regurgitation. VF recurred despite therapy with
      various antiarrhythmic drugs. A maximum of 14 external defibrillations was
      necessary during a 24-hour period to stabilize the patient. Due to increasing
      hemodynamic instability as a result of this electrical storm, the patient was
      referred for invasive diagnostics. During electrophysiologic study, frequent
      short runs of VF initiated by VPB with a narrow QRS complex were observed. After
      extensive mapping of the right and left ventricles, two distinct sources of VPBs
      originating from anteroseptal and inferoseptal areas of the left ventricle could
      be successfully ablated. VPBs were preceded by distinct Purkinje potentials with
      intervals from the Purkinje potential to QRS onset of VPB of 68 ms and 30 ms at
      effective sites, respectively. During short-term follow-up of 2 months, there was
      no VF recurrence. VPB originating from the Purkinje system may be one possibility
      for VF initiation in patients with structural heart disease. Eliminating these
      sources of VPBs by catheter ablation can prevent recurrent VF in such patients.

PMID- 15028081
TI  - Optimization of cardiac resynchronization therapy by continuous hemodynamic
      monitoring:.
AB  - We report the case of a 55-year-old male patient with severe congestive heart
      failure in whom both a hemodynamic monitor and a biventricular pacemaker were
      implanted. The potential usefulness of the monitor to optimize AV delay and heart
      rate was prospectively evaluated. The AV delay associated with the lowest filling
      pressures recorded by the monitor was similar to the optimal AV delay as
      determined by standard echocardiography. Heart rates >70 beats/min acutely
      improved hemodynamics but were not tolerated when programmed chronically. This
      case illustrates that continuous hemodynamic monitoring may offer a useful tool
      for device tuning and treatment monitoring in cardiac resynchronization therapy.

PMID- 15028082
TI  - Acute coronary artery stenosis during slow pathway ablation for atrioventricular
      nodal reentrant tachycardia in a child.
AB  - Coronary injury during radiofrequency ablation is a rare but n. potentially life
      threatening complication that has been reported for attempted elimination of
      accessory pathways. This is the first report of coronary artery injury during
      slow pathway ablation for AV nodal reentrant tachycardia. Manifest signs of
      injury may be transient or nonexistent and easily missed. Controlled studies are
      needed to determine the true risk of coronary artery injury during radiofrequency
      ablation for supraventricular tachycardia, particularly in small children.

PMID- 15028084
TI  - Ablation of atrial fibrillation.

PMID- 15028083
TI  - Brief history of cardiac arrhythmias since the end of the nineteenth century:
      part II.

PMID- 15028085
TI  - Pacing during a wide complex rhythm: implantable cardioverter defibrillator
      malfunction or not?

PMID- 15028086
TI  - Apparent inappropriate shocks from an implantable cardioverter defibrillator:.

PMID- 15028087
TI  - Atriofascicular accessory pathway.

PMID- 15028088
TI  - Suppression of bidirectional ventricular tachycardia and unmasking of prolonged
      QT interval with verapamil in Andersen's syndrome.

PMID- 15028090
TI  - "Specialized" conducting cells in the pulmonary veins.

PMID- 15028093
TI  - Catheter ablation of supraventricular arrhythmias: state of the art.

PMID- 15028094
TI  - Intraoperative transesophageal echocardiography for inferior vena caval tumor
      thrombus in renal cell carcinoma.
AB  - BACKGROUND: We investigated the advantages of intraoperative transesophageal
      echocardiography (TEE) during inferior vena caval tumor thrombectomy in renal
      cell carcinoma (RCC). METHODS: Five patients with RCC that extended into the
      inferior vena cava (IVC) underwent radical nephrectomy. To remove the tumor
      thrombus in the IVC, an inflated Fogarty balloon catheter was used to pull the
      thrombus below the level of the hepatic veins with real-time TEE monitoring.
      RESULTS: In all cases, TEE monitoring during surgery provided an accurate and
      excellent view of the IVC thrombus. TEE was particularly helpful for the
      thrombectomy to minimize hepatic mobilization by using occlusion balloon catheter
      in two patients whose thrombus extended to the intrahepatic IVC. CONCLUSIONS:
      Intraoperative real-time TEE monitoring is a safe, minimally invasive technique
      that can provide accurate information regarding the presence and extent of IVC
      involvement, guidance for placement of a vena caval clamp, confirmation of
      complete removal of the IVC thrombus and intervention using catheters to assist
      in thrombectomy.

PMID- 15028095
TI  - Filarial chyluria: long-term experience of a university hospital in India.
AB  - BACKGROUND: Filariasis is an endemic problem in various Indian states. We
      evaluated the results of long-term follow up (10-20 years) of patients with
      filarial chyluria. METHODS: We conducted a retrospective analysis of 160 patients
      treated for filarial chyluria who presented to the Banaras Hindu University
      Hospital from 1982 to 1992. Eighty-four patients (52.5%) were treated using
      diethylcarbamazine (DEC) and a fat restricted diet and 76 patients (47.5%)
      underwent surgery. To examine the long-term effects of filarial chyluria we
      analysed data on post-treatment recurrence, weight gain, dietary freedom,
      chyluria free period and a number of other associated factors. RESULTS: Previous
      history of filariasis or its complication was documented in 19% of patients. In
      71% of cases, cystoscopy showed that chylous efflux was predominant in the left
      ureteric orifice. The long-term remission rate was 62% in the conservatively
      managed group (DEC + fat restricted diet), whereas 90% of patients in the
      operated group were cured. Postoperative recurrence rate was 10%. There was more
      weight gain and dietary freedom along with a longer chyluria free period in the
      operated group relative to the conservatively managed group. CONCLUSIONS:
      Definitive surgical ablation of lymphatic urinary fistula is better than
      conservative medical management because it has a higher success rate, more
      dietary freedom and, therefore, better patient acceptability.

PMID- 15028097
TI  - Intravesical resiniferatoxin for patients with neurogenic detrusor overactivity.
AB  - BACKGROUND: Resiniferatoxin (RTX), a substance isolated from some species of
      Euphobia, is a specific C-fiber neurotoxin which produces desensitization rather
      than excitation. At first, we performed intravesical RTX therapy on eight
      patients with neurogenic detrusor overactivity. After we confirmed the safety and
      efficacy, a Japanese RTX study group was organized and a new protocol made. The
      multicenter trial was performed in Japan. However, the efficacy of the treatments
      was different among the institutions. Therefore, we have compared the results
      between the first protocol and the new one at our hospital. METHODS: The first
      and second protocol involved the RTX solution (30 mL of 500 nM, and 100 mL of 1
      micro M, respectively) being instillated in the bladder for 30 min by almost the
      same procedures. Effects on bladder function were evaluated during treatment and
      at follow up. RESULTS: For the first and second protocols, six out of eight
      patients noted symptomatic improvement while two patients did not notice any
      change in the degree of incontinence for one month. The mean urodynamic bladder
      capacity had significantly increased from 138.0 +/- 64.4 mL to 227.3 +/- 112.4 mL
      and 133.1 +/- 43.3 mL to 247.0 +/- 102.3 mL 1 month after RTX treatment for the
      first and second protocols, respectively (P < 0.05). No severe side-effects were
      seen in either group. CONCLUSION: Intravesical RTX improved bladder capacity in
      patients with neurogenic detrusor overactivity in both protocols. The
      concentration of RTX did not exhibit any change in the effect and safety in our
      hospital. Intravesical RTX is a promising treatment for neurogenic detrusor
      overactivity.

PMID- 15028098
TI  - Results of the tension-free vaginal tape procedure for stress incontinence:
      patient's perspective.
AB  - BACKGROUND: To evaluate the results of the tension-free vaginal tape procedure
      (TVT) from a patient's perspective. METHODS: Between May 1999 and January 2002,
      90 patients underwent a TVT for genuine stress incontinence (GSI) and mixed
      incontinence. Prior to the procedure, GSI was confirmed by clinical examination
      and urodynamic studies. Results were then audited from patient notes and the same
      patients were sent questionnaires to examine results from a patient perspective.
      RESULTS: Overall response rate to the questionnaire was 70 (77%). The mean age of
      the patients was 50.4 years (range 31-83 years). Sixty-one patients had spinal
      anesthesia, seven had general anesthesia and two had local anesthesia. Mean
      hospital stay was 3.36 days (range 2-14 days) and mean period from the operation
      to the time of the survey and audit was 16.34 months (range 3-28; SD 6.92).
      Thirty-nine (56%) of the 70 patients who answered said that the operation had
      cured their incontinence, 16 (23%) had an improvement in their symptoms, 7 (10%)
      had worsening of their symptoms and 8 (11%) felt that the operation did not make
      any difference. The overall success rate according to the patients' perspective
      was 79%, whereas our audit showed an overall success rate of 86% (77% and 82%,
      respectively, when we compared only the 66 patients who had both notes and
      replies available for analysis). CONCLUSION: Although a patient's perception
      regarding the success of TVT tends to differ from that of a clinician, it was not
      found to be statistically significant (P = 0.22, McNemar test). The TVT is a very
      successful operation, but realistic cure rates should be offered to patients.

PMID- 15028099
TI  - Effect of vesical contraction on the non-sphincteric part of the urethra:
      recognition of vesicourethral inhibitory reflex.
AB  - OBJECTIVES: The effect of vesical contraction on the non-sphincteric part of the
      urethra has been scarcely addressed in the literature. In this study, the
      hypothesis that detrusor contraction effects dilatation of the non-sphincteric
      part of the urethra was investigated. METHODS: Non-sphincteric urethral pressure
      response to vesical balloon distension with normal saline in increments of 50 mL
      was recorded in 21 healthy volunteers (mean age 40.7 +/- 10.3 years, 13 men)
      before and after individual anesthetization of the urethra and urinary bladder.
      Vesical distension was effected by a 10F balloon-ended catheter introduced into
      bladder per urethram. Urethral and vesical pressures were measured by means of a
      two-channel microtip catheter. RESULTS: Small-volume vesical distension effected
      no significant urethral or vesical pressure changes while distension with 350 and
      400 mL of saline produced vesical pressure elevation (P < 0.01) and urethral
      pressure decrease (P < 0.01). Vesical distension after individual vesical and
      urethral anesthetization effected no change in the urethral pressure. These
      results were reproducible. CONCLUSIONS: Dilatation of the non-sphincteric part of
      the urethra upon vesical contraction is suggested to be mediated through a
      'vesicourethral inhibitory reflex' and to facilitate passage of urine through the
      urethra. The reflex may prove to be of diagnostic significance in micturition
      disorders.

PMID- 15028100
TI  - Endocrine therapy with or without radical prostatectomy for T1b-T3N0M0 prostate
      cancer.
AB  - BACKGROUND: We retrospectively compared the 5-year survival rates of T1b-T3N0M0
      prostate cancer patients treated either by endocrine therapy plus radical
      prostatectomy or endocrine therapy alone. METHODS: Clinical T1b-T3N0M0 prostate
      cancer patients were enrolled at 104 institutions in Japan. They were assigned to
      study 1 (n = 176), if they were indicated to prostatectomy, if not indicated,
      they were assigned to study 2 (n = 151). The indication of prostatectomy was
      based on the clinical judgement of physicians and/or patients. Those assigned to
      study 1 underwent prostatectomy and adjuvant endocrine therapy with or without
      preoperative androgen deprivation. Those assigned to study 2 were treated with
      leuprorelin acetate with or without chlormadinone acetate. They were followed-up
      every 3 months until death or for 5 years and over. RESULTS: Those assigned to
      study 1 were younger (mean age 67.2 vs 75.7 years), less advanced in clinical
      stage, and had lower prostate specific antigen levels (mean 43.8 vs 103.6 ng/mL).
      Death for any reason was observed less frequently in study 1 (n = 29, 16%) than
      study 2 (n = 50, 33%), and the 5-year overall survival rate was higher in study 1
      (87 vs. 68%). However, prostate cancer deaths were comparatively seldom (9% in
      study 1 and 7% in study 2), resulting in the identical 5-year cause specific
      survival rate in both study groups (91%). In both study groups the overall
      survival was almost equal to the natural survival of age-matched men.
      CONCLUSIONS: Endocrine therapy offers a reasonable survival rate in T1b-T3
      prostate cancer patients within a 5-year follow-up. Observation will be extended
      to determine 10-year outcomes.

PMID- 15028101
TI  - Clinical, biochemical and pathological features of initial and repeat transrectal
      ultrasonography prostate biopsy positive patients.
AB  - BACKGROUND: Using sextant biopsy, 16-41% of prostate cancers were diagnosed on
      repeat biopsy. The objective of the present study was to compare the differences
      in the clinical, biochemical and pathological features between patients with
      positive results on initial and repeat biopsies, with an aim to identify factors
      that can be used to improve the detection rate of transrectal ultrasound (TRUS)
      biopsy of the prostate. METHODS: Between February 2000 and April 2001, 222
      patients with a mean age of 64 years (range 38-85) underwent TRUS-guided 10-core
      prostate biopsy for either abnormal prostate specific antigen (PSA) levels (>4
      ng/mL) and/or abnormal digital rectal examination (DRE). Of this number, 165
      patients underwent their first biopsy, whereas 45 and 12 patients had had one or
      two previous biopsies, respectively. RESULTS: Prostate cancer detection rates for
      the initial biopsy group (n = 165), second biopsy group (n = 45) and third biopsy
      group (n = 12) were 29.7, 23.0 and 41.7%, respectively. Six patients who had a
      negative first 10-core biopsy underwent a second 10-core biopsy and one patient
      (16%) was found to have cancer. Apart from total prostate volume, there were no
      significant statistical differences between the patient age, mean total PSA, PSA
      density, PSA-transition zone density, DRE and TRUS findings between the initial
      and repeat biopsy groups of subjects who had cancer. Those who had cancer
      detected only on repeat biopsies had larger prostate glands (P = 0.041).
      CONCLUSION: Patients who had cancer detected only on repeat biopsies had bigger
      prostate glands, supporting the hypothesis that TRUS sextant biopsy as a
      technique suffers the error of under-sampling in a bigger prostate.

PMID- 15028102
TI  - Metanephric adenoma treated with laparoscopic nephrectomy.
AB  - A 31-year-old-female presented with a left renal mass detected incidentally
      during an abdominal ultrasound examination. Computed tomography and angiography
      revealed a hypovascular solid tumor 4.5 cm in diameter at the middle portion of
      the left kidney. Laparoscopic left nephrectomy was performed and macroscopic
      examination of the specimen revealed encapsulated tumor with grayish yellow cut
      surface. Histological examination demonstrated that the tumor cells were small
      scant cytoplasms, containing round and regular nuclei, forming a glomerular-like
      structure. There was no mitosis nor cellular atypia indicating a malignant
      structure. The histological diagnosis was metanephric adenoma.

PMID- 15028103
TI  - Nephrotic syndrome as a result of membranous nephropathy caused by renal cell
      carcinoma.
AB  - A 77-year-old woman was admitted for a renal biopsy to evaluate a case of
      nephrotic syndrome. In the course of the examination, a right renal tumor was
      incidentally found. We performed a right radical nephrectomy in advance of the
      renal biopsy. Histologically, the tumor was diagnosed as a renal cell carcinoma
      (clear cell carcinoma) and the non-neoplastic renal cell tissue showed membranous
      nephropathy (MN). After surgery, the nephrotic syndrome remitted without any
      further medical treatment and the MN was considered to be a malignancy associated
      syndrome. There have been few case reports in the literature regarding this
      association and we wish to describe another case.

PMID- 15028104
TI  - Solitary floating vena caval thrombus as a late recurrence of renal cell
      carcinoma.
AB  - We report an unusual case of solitary thrombus floating in the inferior vena cava
      (IVC) in a patient who underwent radical nephrectomy for a renal cell carcinoma
      (RCC) of the right kidney extended into the renal vein with no capsular and
      perinephric tissue invasion (pT3b). Twenty months after surgery, a routine
      computed tomography scan identified an intraluminal mass floating in the IVC.
      Cavotomy and thrombectomy with no caval resection were successfully performed. A
      review of the literature showed only three previous published cases of RCC
      recurring in the IVC only, with no local recurrence or distant metastases. We
      outline the possible etiology of these unusual and solitary recurrences in the
      IVC and we emphasize the need for a strict surveillance for all patients with RCC
      and especially for those with pT1b, pT2 and pT3 disease. An early diagnosis of
      this rare recurrence can permit an easy removal of the thrombus with no caval
      resection and graft replacement, making this disease potentially curable by
      surgery.

PMID- 15028105
TI  - Retroperitoneal lymph node dissection in patients with interaortocaval lymph node
      metastases of transitional cell carcinoma of the urinary tract.
AB  - Three patients suffered from renal pelvic, ureteral and bladder cancers that were
      treated with both standard surgical treatments and two adjuvant cycles of
      cisplatin-based combination chemotherapy. Metastases of interaortocaval lymph
      nodes were detected in all patients between 9 and 33 months from the surgery for
      primary lesions. All patients received three cycles of cisplatin-based
      combination chemotherapy and retroperitoneal lymph node dissection (RPLND). The
      chemotherapy achieved partial response (62-98%). Two patients with viable cancer
      cells died with hepatic metastases; the first 15 months and the second 25 months
      from the date of diagnosis of distant lymph node metastasis. The third patient,
      who had no viable cancer cells, remains alive and disease-free 36 months later.
      Therefore, RPLND after chemotherapy provides prognostic information that helps to
      define patients who might benefit from additional systemic chemotherapy.

PMID- 15028106
TI  - Disturbed voiding associated with von Recklinghausen's neurofibroma.
AB  - Abstract The incidence of von Recklinghausen's disease is most frequent among
      neurocutaneous syndrome. It is an intractable neurological disease. About half of
      the disease is caused by an autosomal dominant inheritance and another half by
      mutation. It is characterized by neurofibroma which arises on various parts of
      the body and gradually increases with age. We recently encountered a case where a
      growth of neurofibroma within the foreskin had disturbed voiding.

PMID- 15028107
TI  - Stromal invasion of the prostate following a complete response to bacillus
      Calmette-Guerin instillation therapy for carcinoma in situ of the ureter and the
      bladder.
AB  - Bacillus Calmette-Guerin (BCG) instillation therapy is now a standard therapy for
      high-risk superficial bladder cancer patients. Although the complete response
      rate is approximately 70%, extra-vesical progression is sometimes observed. In
      particular, those patients who present a positive urinary cytology even after
      complete response from bladder lesion should be thoroughly examined. We present
      two cases of stromal invasion of the prostate after complete remission by BCG
      therapy of carcinoma in situ of the ureter and bladder found by transrectal
      prostate biopsy.

PMID- 15028108
TI  - Primary leiomyosarcoma of the seminal vesicle.
AB  - A case of leiomyosarcoma of the seminal vesicle detected as a prerectal mass on
      routine per-rectal examination is described in a 37-year-old man. Computed
      tomography scan confirmed it to be arising from the right seminal vesicle. Per
      rectal trucut biopsy showed malignant cells. Radical cystoprostatectomy with
      bilateral pelvic lymphadenectomy with anterior resection of rectum and urinary
      diversion with ileal conduit was performed. Microscopic examination of the
      resected specimen showed moderately differentiated leiomyosarcoma from the
      seminal vesicle. The patient received adjuvant chemotherapy and sandwiched
      radiotherapy. He is well and free of tumor 20 months after surgery.

PMID- 15028109
TI  - The Knee Clinical Assessment Study--CAS(K). A prospective study of knee pain and
      knee osteoarthritis in the general population.
AB  - BACKGROUND: Knee pain affects an estimated 25% of the adult population aged 50
      years and over. Osteoarthritis is the most common diagnosis made in older adults
      consulting with knee pain in primary care. However, the relationship between this
      diagnosis and both the current disease-based definition of osteoarthritis and the
      regional pain syndrome of knee pain and disability is unclear. Expert consensus,
      based on current evidence, views the disease and the syndrome as distinct
      entities but the clinical usefulness of these two approaches to classifying knee
      pain in older adults has not been established. We plan to conduct a prospective,
      population-based, observational cohort study to investigate the relative merits
      of disease-based and regional pain syndrome-based approaches to classification
      and prognosis of knee pain in older adults. METHODS: All patients aged 50 years
      and over registered with three general practices in North Staffordshire will be
      invited to take part in a two-stage postal survey. Respondents to this survey
      phase who indicate that they have experienced knee pain within the previous 12
      months will be invited to attend a research clinic for a detailed assessment.
      This will consist of clinical interview, physical examination, digital
      photography, plain x-rays, anthropometric measurement and a brief self-complete
      questionnaire. All consenting clinic attenders will be followed up by (i) general
      practice medical record review, (ii) repeat postal questionnaire at 18-months.

PMID- 15028110
TI  - Muscle recruitment patterns during the prone leg extension.
AB  - BACKGROUND: The prone leg extension (PLE) is a clinical test used to evaluate the
      function of the lumbopelvis. It has been theorized that a normal and consistent
      pattern of muscle activation exists. Previous research has found two
      contradictory patterns of muscle activation during PLE in normal individuals. One
      study shows an almost simultaneous activation of the lower erector spinae and
      hamstring muscle group with a delayed activation of the gluteus maximus, while
      the second describes the order of activation being ipsilateral erector spinae (to
      the leg being extended), hamstrings, contralateral erector spinae and gluteus
      maximus. Due to the different conclusions from these two studies and the lack of
      quantified muscle onset times, expressed in absolute time this study attempted to
      quantify the muscle onset times (in milliseconds) during the prone leg extension,
      while noting if a consistent order of activation exists and whether a timing
      relationship also exists between the gluteus maximus and contralateral latissimus
      dorsi. METHODS: 10 asymptomatic males (Average height: 175.2 cm (SD 6.5), Average
      Weight 75.9 kg (SD 6.5), Average Age: 27.1(SD 1.28)) and 4 asymptomatic females
      (Average height 164.5 (SD 2.9), weight: 56.2 (SD 8.9), Average Age: 25 (SD 1))
      performed the prone leg extension task while the myoelectric signal was recorded
      from the bilateral lower erector spinae, gluteus maximus and hamstring muscle
      groups. Activation onsets were determined from the rectified EMG signal relative
      to the onset of the hamstrings muscle group. RESULTS: No consistent recruitment
      patterns were detected for prone leg extension among the hamstring muscle group
      and the erector spinae. However, a consistent delay in the Gluteus Maximus firing
      of approximately 370 ms after the first muscle activated was found. Five out of
      14 asymptomatic subjects showed a delay in gluteus maximus firing exceeding the
      average delay found in previous research of subjects considered to have a
      dysfunctional firing pattern. CONCLUSION: A consistent pattern of activation was
      not found. Variability was seen across subjects. These findings suggest the PLE
      is not sufficient for a diagnostic test due to the notable physiological
      variation. An overlap between normal and potentially abnormal activation patterns
      may exist.

PMID- 15028111
TI  - Prevalence, and associated risk factors, of self-reported diabetes mellitus in a
      sample of adult urban population in Greece: MEDICAL Exit Poll Research in Salamis
      (MEDICAL EXPRESS 2002).
AB  - BACKGROUND: The continuous monitoring and future prediction of the growing
      epidemic of diabetes mellitus worldwide presuppose consistent information about
      the extent of the problem. The aim of this study was to determine the prevalence
      of diagnosed diabetes and to identify associated risk factors in a sample of
      adult urban Greek population. METHODS: A cross-sectional population-based survey
      was conducted in municipality of Salamis, Greece, during an election day (2002).
      The study sample consisted of 2805 participants, aged 20-94 years. Data were
      collected using a standardized short questionnaire that was completed by a face
      to-face interview. Multiple regression analyses were performed to evaluate the
      association of diabetes with potential risk factors. RESULTS: The overall
      prevalence of diagnosed diabetes was 8.7% (95% CI 7.7-9.8%). After age adjustment
      for the current adult population (2001 census) of Greece, the projection
      prevalence was calculated to 8.2%. Multivariate logistic regression analysis
      identified as independent risk factors: increasing age (odds ratio, OR = 1.07,
      95% CI 1.06-1.08), male sex (OR = 1.43, 95% CI 1.04-1.95), overweight and obesity
      (OR = 1.97, 95% CI 1.29-3.01 and OR = 3.76, 95% CI 2.41-5.86, respectively),
      family history of diabetes (OR = 6.91, 95% CI 5.11-9.34), hypertension (OR =
      2.19, 95% CI 1.60-2.99) and, among women, lower educational level (OR = 2.62, 95%
      CI 1.22-5.63). The prevalence of overweight and obesity, based on self-reported
      BMI, were 44.2% and 18.4%, respectively. Moreover, the odds for diabetes in obese
      subjects with family history were 25-fold higher than those with normal weight
      and without family history of diabetes, while the odds in overweight subjects
      with family history of diabetes were 15-fold higher. CONCLUSIONS: Our findings
      indicated that the prevalence of diabetes is high in Greek population. It is
      suggested that the main modifiable contributing factor is obesity, whose effect
      is extremely increased upon positive heredity presence.

PMID- 15028112
TI  - A study of the average effect of the 3'APOB-VNTR polymorphism on lipidemic
      parameters could explain why the short alleles (<35 repeats) are rare in
      centenarians.
AB  - BACKGROUND: In studies on the genetics of human aging, we observed an age-related
      variation of the 3'APOB-VNTR genotypic pool (alleles: Short, S, <35 repeats;
      Medium, M, 35-39 repeats; Long, L, >39 repeats) with the homozygous SS genotype
      showing a convex frequency trajectory in a healthy aging population. This
      genotype was rare in centenarians, thus indicating that the S alleles are
      unfavorable to longevity, while common in adults, thus indicating a protective
      role at middle age. This apparent paradox could be due to possible effects
      exerted by the above polymorphism on lipidemic parameters. Aim of the work was to
      get insights into these puzzling findings METHODS: We followed a double strategy.
      Firstly, we analyzed the average effects of S (alphaS), M (alphaM), and L
      (alphaL) alleles on lipidemic parameters in a sample of healthy people (409
      subjects aged 20-102 years) recruited in Calabria (southern Italy). The (alphaS),
      (alphaM), and (alphaL) values were estimated by relating 3'APOB-VNTR genotypes to
      lipidemic parameters, after adjustment for age, sex and body mass index (multiple
      regression). Then, we analyzed the S alleles as susceptibility factors of
      Cardiovascular Atherosclerotic Disease (CD) in CD patients characterized either
      by low serum HDL-Cholesterol or by high serum LDL-Cholesterol (CD-H and CD-L
      patients, 40 and 40 subjects respectively). The Odds Ratios (OR) were computed
      for carriers of S alleles in CD-H and CD-L patients matched for origin, sex and
      age with controls extracted from the sample of healthy subjects. RESULTS: By the
      analysis of the healthy sample group we found that the S alleles lower the
      average values of serum Total Cholesterol (alphaS = -5.98 mg/dL with [-11.62/
      0.74] 95% confidence interval) and LDL-Cholesterol (alphaS = -4.41 mg/dL with [
      8.93/-0.20] 95% confidence interval) while the alleles M and L have no
      significant effect on the lipidemic phenotype. In line with these findings, the
      analysis of CD patients showed that the S alleles are protective as for CD-L
      (O.R. = 0.55 with [0.21/0.98] 95% confidence interval) while neutral as for CD-H
      (O.R. = 0.75 with [0.32/1.60] 95% confidence interval). CONCLUSION: On the whole,
      the S alleles would be advantageous in adults (by protecting from CD-L) while
      dangerous in the elderly, probably by lowering serum cholesterol below a critical
      threshold. This could explain the convex frequency trajectory of SS genotypes
      previously observed in a healthy aging population.

PMID- 15028113
TI  - Date of origin of the SARS coronavirus strains.
AB  - BACKGROUND: A new respiratory infectious epidemic, severe acute respiratory
      syndrome (SARS), broke out and spread throughout the world. By now the putative
      pathogen of SARS has been identified as a new coronavirus, a single positive
      strand RNA virus. RNA viruses commonly have a high rate of genetic mutation. It
      is therefore important to know the mutation rate of the SARS coronavirus as it
      spreads through the population. Moreover, finding a date for the last common
      ancestor of SARS coronavirus strains would be useful for understanding the
      circumstances surrounding the emergence of the SARS pandemic and the rate at
      which SARS coronavirus diverge. METHODS: We propose a mathematical model to
      estimate the evolution rate of the SARS coronavirus genome and the time of the
      last common ancestor of the sequenced SARS strains. Under some common assumptions
      and justifiable simplifications, a few simple equations incorporating the
      evolution rate (K) and time of the last common ancestor of the strains (T0) can
      be deduced. We then implemented the least square method to estimate K and T0 from
      the dataset of sequences and corresponding times. Monte Carlo stimulation was
      employed to discuss the results. RESULTS: Based on 6 strains with accurate dates
      of host death, we estimated the time of the last common ancestor to be about
      August or September 2002, and the evolution rate to be about 0.16 base/day, that
      is, the SARS coronavirus would on average change a base every seven days. We
      validated our method by dividing the strains into two groups, which coincided
      with the results from comparative genomics. CONCLUSION: The applied method is
      simple to implement and avoid the difficulty and subjectivity of choosing the
      root of phylogenetic tree. Based on 6 strains with accurate date of host death,
      we estimated a time of the last common ancestor, which is coincident with
      epidemic investigations, and an evolution rate in the same range as that reported
      for the HIV-1 virus.

PMID- 15028114
TI  - Inhibition of gastric H,K-ATPase activity and gastric epithelial cell IL-8
      secretion by the pyrrolizine derivative ML 3000.
AB  - BACKGROUND: ML 3000 ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H
      pyrrolizine-5-yl]-acetic acid) is an inhibitor of both cyclooxygenase and 5
      lipoxygenase in vitro, and shows promise as a novel non-steroidal anti
      inflammatory drug (NSAID). Unlike conventional NSAIDs which are associated with
      gastric ulcerogenic effects, ML 3000 causes little or no damage to the gastric
      mucosa, even though it significantly depresses gastric prostaglandin synthesis.
      METHODS: As part of an effort to clarify mechanisms underlying the gastric
      sparing properties of ML 3000, we studied the effects of ML 3000 on H,K-ATPase
      activity in vitro, on acid accumulation in isolated gastric parietal cells, and
      on IL-8 secretion by gastric epithelial cells in culture. RESULTS: SCH28080
      sensitive H,K-ATPase activity in highly-purified pig gastric microsomes was dose
      dependently inhibited by ML 3000 (IC50 = 16.4 microM). Inhibition was reversible,
      and insensitive to ML 3000 acidification in the pH range 2.0-8.0. In rabbit
      gastric parietal cells,ML 3000 dose-dependently inhibited histamine-stimulated
      acid accumulation (IC50 = 40 microM) and forskolin-stimulated acid accumulation
      (IC50 = 45 microM). Lastly, in human gastric adenocarcinoma (AGS) cells, ML 3000
      dose-dependently inhibited both baseline and IL-1beta-stimulated (20 ng/ml) IL-8
      secretion with IC50s of 0.46 microM and 1.1 microM respectively. CONCLUSION: The
      data indicate that ML 3000 affects acid-secretory mechanisms downstream of cAMP
      mobilization induced by histamine H2 receptor activation, that it directly
      inhibits H,K-ATPase specific activity, and that baseline gastric epithelial cell
      IL-8 secretory inhibition may be mediated by ML 3000 inhibition of 5-lipoxygenase
      activity. We conclude that these gastric function inhibitory data may underlie
      the gastric sparing properties of ML 3000.

PMID- 15028115
TI  - Effects of caloric deprivation and satiety on sensitivity of the gustatory
      system.
AB  - BACKGROUND: Sensitivity of the gustatory system could be modulated by a number of
      short-term and long-term factors such as body mass, gender, age, local and
      systemic diseases and pathological processes, excessive alcohol drinking, drug
      dependence, smoking, composition of oral fluid, state of oral hygiene,
      consumption of some foods among many others. A few studies have demonstrated the
      effects of hunger and caloric satiety on sensitivity of the gustatory system in
      obese humans and animals. The aim of the present study was to assess the effects
      of short-term caloric deprivation and satiety on recognition taste thresholds of
      healthy, non-smoking, non-drinking, non-obese young male subjects. The two
      alternative forced-choice technique was used to measure taste threshold. RESULTS:
      Recognition thresholds for sucrose and salt were significantly lower during
      fasting state than after a meal (t = 2.23, P < 0.05, and t = 2.86, P < 0.02,
      respectively) while the values of recognition thresholds for bitter substances in
      fasting state and after caloric loading did not differ significantly.
      CONCLUSIONS: Short-term caloric deprivation in our study model was associated
      with increased taste sensitivity to sweet and salty substances compared to
      satiated state while taste sensitivity to bitter substances was not affected by
      the conditions of measurements. Selective modulation of sensitivity of the
      gustatory system might reflect the different biological importance of salty,
      sweet and bitter qualities of taste.

PMID- 15028116
TI  - Identification of Bacillus anthracis specific chromosomal sequences by
      suppressive subtractive hybridization.
AB  - BACKGROUND: Bacillus anthracis, Bacillus thuringiensis and Bacillus cereus are
      closely related members of the B. cereus-group of bacilli. Suppressive
      subtractive hybridization (SSH) was used to identify specific chromosomal
      sequences unique to B. anthracis. RESULTS: Two SSH libraries were generated.
      Genomic DNA from plasmid-cured B. anthracis was used as the tester DNA in both
      libraries, while genomic DNA from either B. cereus or B. thuringiensis served as
      the driver DNA. Progressive screening of the libraries by colony filter and
      Southern blot analyses identified 29 different clones that were specific for the
      B. anthracis chromosome relative not only to the respective driver DNAs, but also
      to seven other different strains of B. cereus and B. thuringiensis included in
      the process. The nucleotide sequences of the clones were compared with those
      found in genomic databases, revealing that over half of the clones were located
      into 2 regions on the B. anthracis chromosome. CONCLUSIONS: Genes encoding
      potential cell wall synthesis proteins dominated one region, while bacteriophage
      related sequences dominated the other region. The latter supports the hypothesis
      that acquisition of these bacteriophage sequences occurred during or after
      speciation of B. anthracis relative to B. cereus and B. thuringiensis. This study
      provides insight into the chromosomal differences between B. anthracis and its
      closest phylogenetic relatives.

PMID- 15028117
TI  - VisANT: an online visualization and analysis tool for biological interaction
      data.
AB  - BACKGROUND: New techniques for determining relationships between biomolecules of
      all types--genes, proteins, noncoding DNA, metabolites and small molecules--are
      now making a substantial contribution to the widely discussed explosion of facts
      about the cell. The data generated by these techniques promote a picture of the
      cell as an interconnected information network, with molecular components linked
      with one another in topologies that can encode and represent many features of
      cellular function. This networked view of biology brings the potential for
      systematic understanding of living molecular systems. RESULTS: We present VisANT,
      an application for integrating biomolecular interaction data into a cohesive,
      graphical interface. This software features a multi-tiered architecture for data
      flexibility, separating back-end modules for data retrieval from a front-end
      visualization and analysis package. VisANT is a freely available, open-source
      tool for researchers, and offers an online interface for a large range of
      published data sets on biomolecular interactions, including those entered by
      users. This system is integrated with standard databases for organized
      annotation, including GenBank, KEGG and SwissProt. VisANT is a Java-based,
      platform-independent tool suitable for a wide range of biological applications,
      including studies of pathways, gene regulation and systems biology. CONCLUSION:
      VisANT has been developed to provide interactive visual mining of biological
      interaction data sets. The new software provides a general tool for mining and
      visualizing such data in the context of sequence, pathway, structure, and
      associated annotations. Interaction and predicted association data can be
      combined, overlaid, manipulated and analyzed using a variety of built-in
      functions. VisANT is available at http://visant.bu.edu.

PMID- 15028118
TI  - Human glutaminyl cyclase and bacterial zinc aminopeptidase share a common fold
      and active site.
AB  - BACKGROUND: Glutaminyl cyclase (QC) forms the pyroglutamyl residue at the amino
      terminus of numerous secretory peptides and proteins. We previously proposed the
      mammalian QC has some features in common with zinc aminopeptidases. We now have
      generated a structural model for human QC based on the aminopeptidase fold (pdb
      code 1AMP) and mutated the apparent active site residues to assess their role in
      QC catalysis. RESULTS: The structural model proposed here for human QC, deposited
      in the protein databank as 1MOI, is supported by a variety of fold prediction
      programs, by the circular dichroism spectrum, and by the presence of the
      disulfide. Mutagenesis of the six active site residues present in both 1AMP and
      QC reveal essential roles for the two histidines (140 and 330, QC numbering) and
      the two glutamates (201 and 202), while the two aspartates (159 and 248) appear
      to play no catalytic role. ICP-MS analysis shows less than stoichiometric zinc
      (0.3:1) in the purified enzyme. CONCLUSIONS: We conclude that human pituitary
      glutaminyl cyclase and bacterial zinc aminopeptidase share a common fold and
      active site residues. In contrast to the aminopeptidase, however, QC does not
      appear to require zinc for enzymatic activity.

PMID- 15028119
TI  - Influence of an outpatient multidisciplinary pain management program on the
      health-related quality of life and the physical fitness of chronic pain patients.
AB  - BACKGROUND: Approximately 10 to 20 percent of the population is suffering from
      chronic pain. Since this represents a major contribution to the costs of the
      health care system, more efficient measures and interventions to treat these
      patients are sought. RESULTS: The development of general health and physical
      activity of patients with chronic pain was assessed in an interdisciplinary
      outpatient pain management program (IOPP). 36 patients with an average age of 48
      years were included in the IOPP. Subjective assessment of well-being was
      performed at five time points (baseline, post intervention and 3, 6, and 12
      months thereafter) by using standardized questionnaires. The study focused on the
      quality of life survey Medical Outcomes Study Short Form-36, which is a validated
      instrument with established reliability and sensitivity. In addition, the
      patients participated in physical assessment testing strength, power, endurance,
      and mobility. Prior to therapy a substantial impairment was found on different
      levels. Marked improvements in the psychological parameters were obtained by the
      end of the program. No success was achieved with regard to the physical
      assessments. CONCLUSION: Although many different studies have evaluated similar
      programs, only few of them have attained positive results such as improvements of
      general quality of life or of physical strength. Often no difference from the
      control group could be detected only some months after the intervention. In the
      present study no significant persistent improvement of well-being occurred.
      Possible reasons are either wrong instruments, wrong selection of patients or
      wrong interventions.

PMID- 15028120
TI  - Accuracy of city postal code coordinates as a proxy for location of residence.
AB  - BACKGROUND: Health studies sometimes rely on postal code location as a proxy for
      the location of residence. This study compares the postal code location to that
      of the street address using a database from the Alberta Provincial Project for
      Outcome Assessment in Coronary Heart Disease (APPROACHCopyright ). Cardiac
      catheterization cases in an urban Canadian City were used for calendar year 1999.
      We determined location in meters for both the address (using the City of Calgary
      Street Network File in ArcView 3.2) and postal code location (using Statistic
      Canada's Postal Code Conversion File). RESULTS: The distance between the two
      estimates of location for each case were measured and it was found that 87.9% of
      the postal code locations were within 200 meters of the true address location
      (straight line distances) and 96.5% were within 500 meters of the address
      location (straight line distances). CONCLUSIONS: We conclude that postal code
      locations are a reasonably accurate proxy for address location. However, there
      may be research questions for which a more accurate description of location is
      required.

PMID- 15028122
TI  - Does managed care make a difference? Physicians' length of stay decisions under
      managed and non-managed care.
AB  - BACKGROUND: In this study we examined the influence of type of insurance and the
      influence of managed care in particular, on the length of stay decisions
      physicians make and on variation in medical practice. METHODS: We studied lengths
      of stay for comparable patients who are insured under managed or non-managed care
      plans. Seven Diagnosis Related Groups were chosen, two medical (COPD and CHF),
      one surgical (hip replacement) and four obstetrical (hysterectomy with and
      without complications and Cesarean section with and without complications). The
      1999, 2000 and 2001--data from hospitals in New York State were used and analyzed
      with multilevel analysis. RESULTS: Average length of stay does not differ between
      managed and non-managed care patients. Less variation was found for managed care
      patients. In both groups, the variation was smaller for DRGs that are easy to
      standardize than for other DRGs. CONCLUSION: Type of insurance does not affect
      length of stay. An explanation might be that hospitals have a general policy
      concerning length of stay, independent of the type of insurance of the patient.

PMID- 15028123
TI  - A Survey of the quality of nursing care in several health districts in South
      Africa.
AB  - BACKGROUND: South Africa is currently focusing strongly on human resource
      development. The purpose of this study was to describe and compare the quality of
      nursing service and care in three health districts in the KwaZulu Natal Province.
      To identify deficiencies which could be addressed by education and training, it
      might be useful to measure the quality of care given by nurses. METHODS: From
      March to August 2002 a survey was done in six hospitals and six clinics in three
      health districts of the KwaZulu-Natal province of South Africa. Five different
      aspects of care was evaluated; hand-over from one nursing shift to another,
      implementation of universal precautions, patient satisfaction, nursing records,
      management of chronic illnesses. All these aspects were evaluated using
      checklists based on record reviews or direct observation, except for patient
      satisfaction, which was evaluated by questionnaires. RESULTS: The average scores
      on the different aspects varied from 11% (for nursing records) to 73% (for
      management of chronic diseases). Specific problems became evident. In one
      district three out of four hand-overs between shifts of nurses scored less than
      50%. In all three districts the use of protective gear scored low (43%). While
      the average score for management of chronic illnesses were high at 73%, the blood
      pressures of only 23% was within the target range, and the blood sugar of only
      38% of patients were controlled. Patient satisfaction averaged 72% across the
      three districts. CONCLUSION: The quality of care measurements identified specific
      training needs, but other management strategies are probably also indicated.

PMID- 15028121
TI  - Neurohumoral stimulation in type-2-diabetes as an emerging disease concept.
AB  - Neurohumoral stimulation comprising both autonomic-nervous-system dysfunction and
      activation of hormonal systems including the renin-angiotensin-aldosterone system
      (RAAS) was found to be associated with Type-2-diabetes (T2D). Therapeutic
      strategies such as RAAS interference proved to be beneficial in both T2D
      treatment and prevention. In addition to an activated RAAS, hyperleptinemia in
      obesity, hyperinsulinemia in conditions of peripheral insulin resistance and
      overall oxidative stress in T2D represent known activators of the sympathetic
      component of the autonomic nervous system. Here, we hypothesize that sympathetic
      activation may cause peripheral insulin resistance defined as partial blocking of
      insulin effects on glucose uptake. Resulting hyperinsulinemia or hyperglycemia
      related oxidative stress may further aggravate sympatho-excitation. This notion
      leads to a secondary hypothesis: sympathetic activation worsens from obesity
      towards insulin resistance, and further towards T2D. In this review, existing
      evidence relating to neurohumoral stimulation in T2D and consequences thereof,
      such as oxidative stress and inflammation, are discussed. The aim of this review
      is to provide a rationale for therapies, which are able to intercept
      neuroendocrine pathways in T2D and precursor states such as obesity.

PMID- 15028125
TI  - In vitro mutation artifacts after formalin fixation and error prone translesion
      synthesis during PCR.
AB  - BACKGROUND: Clinical specimens are routinely fixed in 10% buffered formalin and
      paraffin embedded. Although DNA is commonly extracted from fixed tissues and
      amplified by PCR, the effects of formalin fixation are relatively unknown.
      Formalin fixation is known to impair PCR, presumably through damage that blocks
      polymerase elongation, but an insidious possibility is error prone translesion
      synthesis across sites of damage, producing in vitro artifactual mutations during
      PCR. METHODS: To better understand the consequences of fixation, DNA specimens
      extracted from fresh or fixed tissues were amplified with Taq DNA polymerase, and
      their PCR products were cloned and sequenced. RESULTS: Significantly more (3- to
      4-fold) mutations were observed with fixed DNA specimens. The majority of
      mutations were transitions, predominantly at A:T base pairs, randomly distributed
      along the template. CONCLUSIONS: Formalin fixation appears to cause random base
      damage, which can be bridged during PCR by Taq DNA polymerase through error prone
      translesion synthesis. Fixed DNA is a damaged but "readable" template.

PMID- 15028124
TI  - Occurrence and quality of anticoagulant treatment of chronic atrial fibrillation
      in primary health care in Sweden: a retrospective study on electronic patient
      records.
AB  - BACKGROUND: Chronic atrial fibrillation is a prevalent cardiac disorder. The
      literature indicates varying proportions of those treated with anticoagulants,
      and varying intensity of anticoagulation. Electronic patient records are
      providing us with clinical data concerning management of anticoagulant treatment
      in real-life practice that is useful for audits. We aimed to assess warfarin
      treatment for chronic atrial fibrillation in primary health care with regard to
      prevalence, incidence, the proportion treated and the quality of anticoagulation
      control. METHODS: Five primary health care centres in Stockholm with a registered
      population of 75146 participated in a one-year retrospective study of electronic
      patient records up until May 2000. All patients over 18 years of age with an
      encounter labelled 'Atrial fibrillation' were identified, and all records of
      patients on warfarin treatment were manually reviewed. Main outcome measures were
      number of patients with chronic atrial fibrillation, number of patients on
      wafarin treatment, and time within the therapeutic prothrombin range. RESULTS: In
      total, 419 patients had chronic atrial fibrillation, giving a prevalence of 0.60%
      (age-adjusted 0.62%), the age group 65 years or older accounted for 91.6%, and
      50.1% were women. Out of these, 50.4% (211 patients) were established on warfarin
      treatment for chronic atrial fibrillation (0.28% of the population), and there
      was a predominance of men (p = 0.02). Fifty-four patients started treatment with
      warfarin for chronic atrial fibrillation (0.07% of the population). Among 25
      randomly selected patients on established treatment, the proportion of time
      within the therapeutic range was 70.2%. Among 24 randomly selected patients
      starting treatment, the proportion of time with therapeutic values was 54.2% and
      66.9% the first and second months of treatment, respectively. CONCLUSIONS:
      Chronic atrial fibrillation is common among the elderly in primary health care,
      and about half of these patients are treated with warfarin. It appears to be
      under-diagnosed, and may also be under-treated. About two thirds of treatment
      time is spent within the therapeutic range, and further improvement of the
      quality of anticoagulation control with warfarin may therefore be hard to
      achieve.

PMID- 15028126
TI  - Surgical robotics: a review and neurosurgical prototype development.
AB  - PURPOSE: The purpose of this article is to update the neurosurgical community on
      the expanding field of surgical robotics and to present the design of a novel
      neurosurgical prototype. It is intended to mimic standard technique and deploy
      conventional microsurgical tools. The intention is to ease its integration into
      the "nervous system" of both the traditional operating room and surgeon. CONCEPT:
      To permit benefit from updated intraoperative imaging, magnetic resonance imaging
      compatible materials were incorporated into the design. Advanced haptics, optics,
      and auditory communication with the surgical site recreate the sight, sound, and
      feel of neurosurgery. RATIONALE: Magnification and advanced imaging have pushed
      surgeons to the limit of their dexterity and stamina. Robots, in contrast, are
      indefatigable and have superior spatial resolution and geometric accuracy. The
      use of tremor filters and motion scalers permits procedures requiring superior
      dexterity. DISCUSSION: Breadboard testing of the prototype components has shown
      spatial resolution of 30 microm, greatly exceeding our expectations.
      Neurosurgeons will not only be able to perform current procedures with a higher
      margin of safety but also must speculate on techniques that have hitherto not
      even been contemplated. This includes coupling the robot to intelligent tools
      that interrogate tissue before its manipulation and the potential of molecular
      imaging to transform neurosurgical research into surgical exploration of the
      cell, not the organ.

PMID- 15028127
TI  - Idiopathic intracranial hypertension.
AB  - OBJECTIVE: The history, diagnosis, and therapy of idiopathic intracranial
      hypertension (IIH) (pseudotumor cerebri) are reviewed. Theories of pathogenesis
      are considered, the clinical presentation is described, and potential diagnostic
      and therapeutic challenges are explored. METHODS: An extensive literature review
      of IIH and related conditions (secondary pseudotumor syndromes) was performed.
      The history of and rationale for the diagnosis and medical and surgical
      approaches to treatment are reviewed. Available outcome studies are presented.
      RESULTS: Diagnosis of IIH requires that the modified Dandy criteria be satisfied.
      Multiple potential contributing causes of intracranial hypertension must be
      identified or excluded. The clinical presentation most often includes headaches
      and papilledema, but many other findings have been described. The most important
      goal of therapy is to prevent or arrest progressive visual loss. Medical
      therapies include alleviation of associated systemic diseases, discontinuation of
      contributing medications, provision of carbonic anhydrase inhibitors, and weight
      loss. Surgical therapies include lumboperitoneal shunting, ventriculoperitoneal
      shunting, and optic nerve sheath fenestration. On the basis of the advantages and
      disadvantages of these treatment modalities, a suggested treatment paradigm is
      presented. CONCLUSION: Idiopathic intracranial hypertension is the term to be
      adopted instead of pseudotumor cerebri. IIH remains an enigmatic diagnosis of
      exclusion. However, prompt diagnosis and thorough evaluation and treatment are
      crucial for preventing visual loss and improving associated symptoms.

PMID- 15028128
TI  - Craniotomy for resection of pediatric brain tumors in the United States, 1988 to
      2000: effects of provider caseloads and progressive centralization and
      specialization of care.
AB  - OBJECTIVE: Large provider caseloads are associated with better patient outcomes
      after many complex surgical procedures. Mortality rates for pediatric brain tumor
      surgery in various practice settings have not been described. We used a national
      hospital discharge database to study the volume-outcome relationship for
      craniotomy performed for pediatric brain tumor resection, as well as trends
      toward centralization and specialization. METHODS: We conducted a cross sectional
      and longitudinal cohort study using Nationwide Inpatient Sample data for 1988 to
      2000 (Agency for Healthcare Research and Quality, Rockville, MD). Multivariate
      analyses adjusted for age, sex, geographic region, admission type (emergency,
      urgent, or elective), tumor location, and malignancy. RESULTS: We analyzed 4712
      admissions (329 hospitals, 480 identified surgeons) for pediatric brain tumor
      craniotomy. The in-hospital mortality rate was 1.6% and decreased from 2.7% (in
      1988-1990) to 1.2% (in 1997-2000) during the study period. On a per-patient
      basis, median annual caseloads were 11 for hospitals (range, 1-59 cases) and 6
      for surgeons (range, 1-32 cases). In multivariate analyses, the mortality rate
      was significantly lower at high-volume hospitals than at low-volume hospitals
      (odds ratio, 0.52 for 10-fold larger caseload; 95% confidence interval, 0.28
      0.94; P = 0.03). The mortality rate was 2.3% at the lowest-volume-quartile
      hospitals (4 or fewer admissions annually), compared with 1.4% at the highest
      volume-quartile hospitals (more than 20 admissions annually). There was a trend
      toward lower mortality rates after surgery performed by high-volume surgeons (P =
      0.16). Adverse hospital discharge disposition was less likely to be associated
      with high-volume hospitals (P < 0.001) and high-volume surgeons (P = 0.004).
      Length of stay and hospital charges were minimally related to hospital caseloads.
      Approximately 5% of United States hospitals performed pediatric brain tumor
      craniotomy during this period. The burden of care shifted toward large-caseload
      hospitals, teaching hospitals, and surgeons whose practices included
      predominantly pediatric patients, indicating progressive centralization and
      specialization. CONCLUSION: Mortality and adverse discharge disposition rates for
      pediatric brain tumor craniotomy were lower when the procedure was performed at
      high-volume hospitals and by high-volume surgeons in the United States, from 1988
      to 2000. There were trends toward lower mortality rates, greater centralization
      of surgery, and more specialization among surgeons during this period.

PMID- 15028130
TI  - Intraventricular thrombolysis speeds blood clot resolution: results of a pilot,
      prospective, randomized, double-blind, controlled trial.
AB  - OBJECTIVE: Animal models and clinical studies suggest that intraventricular
      thrombolysis improves clot resolution and clinical outcomes among patients with
      intraventricular hemorrhage. However, this intervention may increase the rates of
      rebleeding and infection. To assess the safety and efficacy of intraventricular
      thrombolysis, we conducted a pilot, randomized, double-blind, controlled,
      multicenter study. METHODS: Patients with intraventricular hemorrhage requiring
      ventriculostomy were randomized to receive intraventricular injections of normal
      saline solution or urokinase (25000 international units) at 12-hour intervals.
      Injections continued until ventricular drainage was discontinued according to
      prespecified clinical criteria. Head computed tomographic scans were obtained
      daily, for quantitative determinations of intraventricular hemorrhage volumes.
      The rate of clot resolution was estimated for each group. RESULTS: Twelve
      subjects were enrolled (urokinase, seven patients; placebo, five patients).
      Commercial withdrawal of urokinase precluded additional enrollment. The urokinase
      and placebo groups were similar with respect to age (49.6 versus 55.2 yr, P =
      0.43) and presenting Glasgow Coma Scale scores (7.14 versus 8.00, P = 0.72).
      Randomization to the urokinase treatment arm (P = 0.02) and female sex (P =
      0.008) favorably affected the clot resolution rate. The sex-adjusted clot half
      life for the urokinase-treated group was reduced 44.6%, compared with the value
      for the placebo group (4.69 versus 8.48 d). CONCLUSION: Intraventricular
      thrombolysis with urokinase speeds the resolution of intraventricular blood
      clots, compared with treatment with ventricular drainage alone.

PMID- 15028129
TI  - Grading of subarachnoid hemorrhage: modification of the world World Federation of
      Neurosurgical Societies scale on the basis of data for a large series of
      patients.
AB  - OBJECTIVE: The goals of this study were to use a large, prospectively collected,
      multicenter database for patients with aneurysmal subarachnoid hemorrhage (SAH)
      who were treated between 1991 and 1997 to determine the prognostic significance
      of clinical and radiological factors for outcomes and to use those factors to
      develop a grading scale to predict outcomes. METHODS: A total of 3567 patients
      with SAH who were entered into four randomized clinical trials of tirilazad were
      studied. Outcomes were assessed 3 months after SAH, with the Glasgow Outcome
      Scale. Twenty clinical and radiological factors were entered into univariate and
      multivariate analyses, to determine factors prognostic for outcomes. Grading
      scales based on the most powerful prognostic parameters were statistically
      derived and validated and were compared with the World Federation of
      Neurosurgical Societies (WFNS) grading scale. RESULTS: Factors predictive of
      outcomes included age, WFNS grade, history of hypertension, systolic blood
      pressure at admission, ruptured aneurysm location and size, blood clot thickness
      on computed tomographic scans, and angiographic vasospasm at admission. A grading
      scale using these factors could be derived; it predicted outcomes more accurately
      than did the WFNS scale, although it would be more complex to use. CONCLUSION:
      Outcome prediction after SAH can be improved by adding additional clinical and
      radiological factors to the WFNS scale, albeit with added complexity.

PMID- 15028131
TI  - Pretreatment and posttreatment evaluation of hemodynamic and metabolic parameters
      in intracranial dural arteriovenous fistulae with cortical venous reflux.
AB  - OBJECTIVE: Retrograde drainage into the cortical veins results in poor outcome in
      patients with an intracranial dural arteriovenous fistula. However, the
      pathophysiological features of dural arteriovenous fistulae remain obscure. This
      study aimed to clarify hemodynamic and metabolic conditions in these patients
      using positron emission tomography. METHODS: This study included eight patients
      with an intracranial dural arteriovenous fistula. All patients had cortical
      venous reflux, as demonstrated by angiography. Regional cerebral blood flow
      (rCBF), regional cerebral blood volume (rCBV), regional cerebral metabolic rate
      for oxygen, and regional oxygen extraction fraction (rOEF) were measured before
      and after surgical or endovascular treatment using positron emission tomography.
      RESULTS: Pretreatment positron emission tomographic studies revealed that all
      patients had abnormal hemodynamic and metabolic parameters in the area that was
      drained by the involved cortical veins. A severe increase in rCBV was noted in
      seven of the eight patients. A significant decrease in rCBF also was observed in
      all eight patients. A negative correlation was observed between rCBF and rCBV.
      Three patients had an elevated rOEF. Oxygen metabolism was impaired in seven
      patients. All patients underwent successful treatment. Follow-up studies
      demonstrated significant improvements in rCBF, rCBV, and regional cerebral
      metabolic rate for oxygen. The improvement in regional cerebral metabolic rate
      for oxygen varied among the patients. Normalization of rOEF also was confirmed in
      three patients who had increased rOEF before the treatment. CONCLUSION: The
      present results suggest that hemodynamic and metabolic characteristics vary
      widely among patients with cortical venous reflux. It is essential to precisely
      evaluate hemodynamic and metabolic conditions to predict their outcomes and
      therapeutic effects.

PMID- 15028132
TI  - Effects of head posture on cerebral hemodynamics: its influences on intracranial
      pressure, cerebral perfusion pressure, and cerebral oxygenation.
AB  - OBJECTIVE: Severely head-injured patients have traditionally been maintained in
      the head-up position to ameliorate the effects of increased intracranial pressure
      (ICP). However, it has been reported that the supine position may improve
      cerebral perfusion pressure (CPP) and outcome. We sought to determine the impact
      of supine and 30 degrees semirecumbent postures on cerebrovascular dynamics and
      global as well as regional cerebral oxygenation within 24 hours of trauma.
      METHODS: Patients with a closed head injury and a Glasgow Coma Scale score of 8
      or less were included in the study. On admission to the neurocritical care unit,
      a standardized protocol aimed at minimizing secondary insults was instituted, and
      the influences of head posture were evaluated after all acute necessary
      interventions had been performed. ICP, CPP, mean arterial pressure, global
      cerebral oxygenation, and regional cerebral oxygenation were noted at 0 and 30
      degrees of head elevation. RESULTS: We studied 38 patients with severe closed
      head injury. The median Glasgow Coma Scale score was 7.0, and the mean age was
      34.05 +/- 16.02 years. ICP was significantly lower at 30 degrees than at 0
      degrees of head elevation (P = 0.0005). Mean arterial pressure remained
      relatively unchanged. CPP was slightly but not significantly higher at 30 degrees
      than at 0 degrees (P = 0.412). However, global venous cerebral oxygenation and
      regional cerebral oxygenation were not affected significantly by head elevation.
      All global venous cerebral oxygenation values were above the critical threshold
      for ischemia at 0 and 30 degrees. CONCLUSION: Routine nursing of patients with
      severe head injury at 30 degrees of head elevation within 24 hours after trauma
      leads to a consistent reduction of ICP (statistically significant) and an
      improvement in CPP (although not statistically significant) without concomitant
      deleterious changes in cerebral oxygenation.

PMID- 15028133
TI  - Comparison of deep wound infection rates using a synthetic dural substitute
      (neuro-patch) or pericranium graft for dural closure: a clinical review of 1
      year.
AB  - OBJECTIVE: The need to repair dural defects has prompted the use of dura mater
      substitutes. Many synthetic materials have been used for dural closure. Neuro
      Patch (B. Braun Medical S.A., Boulogne, France) is a nonabsorbable microporous
      fleece composed of polyester urethane that has been approved for human use by the
      European Union since 1995. To the best of our knowledge, no clinical series with
      Neuro-Patch have been published thus far, particularly with regard to septic
      complications. The aim of our study was to compare the safety of Neuro-Patch with
      that of pericranium graft with regard to postoperative wound infections. METHODS:
      This is a retrospective study of 1 year's experience including all patients who
      underwent dural plasty with a Neuro-Patch (n = 61) or pericranium graft (n = 63).
      The follow-up period was at least 12 months after surgery. Before wound infection
      rates in the two groups were compared, factors suspected of being risks for
      neurosurgical site infection were evaluated. RESULTS: Patient characteristics
      (mean age, neurological diagnosis), surgical procedures, prophylactic
      antibiotics, and risk factors for surgical infections (including duration of
      surgery, emergency, contaminated operations, and external cerebrospinal fluid
      drainage) were similar in the Neuro-Patch and pericranium groups. Deep wound
      infection rates in the Neuro-Patch and pericranium groups were 15 and 5%,
      respectively (P = 0.06), and cerebrospinal fluid leaks were significantly more
      frequent in the Neuro-Patch group (13 versus 1.6%, P < 0.05). CONCLUSION: The
      results of our investigations show that Neuro-Patch raised the risk of wound
      infection, as do foreign materials implanted in the body. Synthetic dural grafts
      should be reserved for when autologous grafts are not sufficient or possible. An
      extensive prospective multicenter randomized trial is needed to confirm our
      results.

PMID- 15028134
TI  - Vascular endothelial growth factor is increased in cerebrospinal fluid after
      traumatic brain injury in infants and children.
AB  - OBJECTIVE: Vascular endothelial growth factor (VEGF) is an important regulator of
      angiogenesis, the formation of which is triggered by hypoxia, cytokines, and
      growth factors and is also induced by activation of the adenosine 2B receptor.
      VEGF is neuroprotective in several models of experimental brain injury and is
      increased in brain after traumatic brain injury (TBI) in humans and experimental
      animals. Adenosine is a neuroprotective purine metabolite that increases in
      cerebrospinal fluid (CSF) after clinical TBI in children. We hypothesized that
      VEGF levels would 1). be increased in CSF after TBI in infants and children, and
      2). be preceded by increases in CSF adenosine. To test this hypothesis, we
      designed a case-control study to compare the CSF of infants and children after
      severe TBI with that of uninjured children. METHODS: Using an Institutional
      Review Board-approved protocol, we compared CSF concentrations of VEGF (by enzyme
      linked immunosorbent assay) and adenosine (by high-performance liquid
      chromatography) in 73 samples from 14 infants and children with severe TBI
      (Glasgow Coma Scale score <or=8) with those in CSF from 5 noninjured control
      subjects. Patients received standard neurointensive care. RESULTS: Mean VEGF
      levels were increased after TBI versus control (39.8 +/- 6.2 versus 14.9 +/- 1.5
      ng/dl, mean +/- standard error of the mean, P = 0.0002) and peaked at 91.6 +/-
      26.4 ng/dl, approximately 6 times control (P = 0.001). Peak VEGF occurred at 22.4
      hours after injury. There was a trend toward increased adenosine concentration
      after TBI versus control (18.3 +/- 3.5 versus 11.5 +/- 2.3 nmol/L), but this did
      not reach statistical significance. A multivariate regression model showed an
      independent, significant association between the concentrations of VEGF and
      adenosine. CONCLUSION: VEGF is increased in CSF after pediatric TBI, and this
      increase is associated with an increase in CSF adenosine. These results may imply
      that a component of the vascular regenerative response of the brain is initiated
      rapidly after TBI and continues for several days after injury. Further
      investigation is warranted to determine 1). whether this association is
      causative, 2). the role of adenosine in triggering the increase in CSF VEGF
      concentration, and 3). the exact role VEGF that plays after injury.

PMID- 15028135
TI  - Primary dystonia is more responsive than secondary dystonia to pallidal
      interventions: outcome after pallidotomy or pallidal deep brain stimulation.
AB  - OBJECTIVE: The response of patients with dystonia to pallidal procedures is not
      well understood. In this study, we assessed the postoperative outcome of patients
      with primary and secondary dystonia undergoing pallidotomy or pallidal deep brain
      stimulation. METHODS: Fifteen patients with dystonia had pallidal surgery
      (lesions or deep brain stimulation). These included nine patients with primary
      dystonia (generalized and cervical dystonias) and six with secondary dystonia
      (generalized, segmental, and hemidystonias). There were nine male patients and
      six female patients. The mean age at onset was 21 years for primary dystonia and
      18 years for secondary dystonia. The primary outcome measure was a Global Outcome
      Scale score for dystonia at 6 months after surgery. Other outcome measures were
      the Burke-Fahn-Marsden Dystonia Rating Scale and Toronto Western Spasmodic
      Torticollis Rating Scale scores. RESULTS: The mean Global Outcome Scale score at
      6 months for patients with primary dystonia was 3 (improvement in both movement
      disorder and function). In contrast, patients with secondary dystonia had a mean
      score of 0.83 (mild or no improvement in movement disorder with no functional
      improvement). All patients with primary dystonia had normal brains by magnetic
      resonance imaging, whereas five of six patients with secondary dystonia had basal
      ganglia abnormalities on their magnetic resonance imaging scans. CONCLUSION: This
      study indicates that primary dystonia responds much better than secondary
      dystonia to pallidal procedures. We could not distinguish a difference in
      efficacy between pallidotomy and pallidal deep brain stimulation. The presence of
      basal ganglia abnormalities on the preoperative magnetic resonance imaging scan
      is an indicator of a lesser response to pallidal interventions for dystonia.

PMID- 15028136
TI  - Cingulotomy for psychiatric disease: microelectrode guidance, a callosal
      reference system for documenting lesion location, and clinical results.
AB  - OBJECTIVE: To evaluate magnetic resonance imaging (MRI)- and microelectrode
      recording-guided cingulotomy for patients with psychiatric disorders and to
      develop a new method of mapping lesion location in anterior cingulate cortex that
      takes into account the significant interindividual variability in callosal
      morphometry. METHODS: MRI and microelectrode recording were used to guide
      placement of radiofrequency lesions in patients with obsessive-compulsive
      disorder (n = 21) or affective disorders (n = 5). Postoperative improvement was
      evaluated with the Yale-Brown Obsessive-Compulsive Scale in 15 of the 21
      obsessive-compulsive disorder patients studied. From the postoperative MRI scans,
      we developed a coordinate system for position in the anterior cingulate cortex.
      The callosal line passes from the most anterior point of the corpus callosum (c =
      0) to the most posterior (c = 100). We reconstructed the lesions onto a sagittal
      map from the Talairach and Tournoux atlas using the distance along the callosal
      line and the distance above the upper surface of the corpus callosum. RESULTS:
      The location of neuronal activity distinguished gray and white matter and was
      useful in delineating the upper and lower cortical banks of the cingulate gyrus,
      the cingulate bundle, and the corpus callosum. This information was used to place
      the lesions. Lesions typically were 6 to 8 mm in diameter on T2-weighted MRI
      scans. The inferior margins were along the corpus callosum from c = 16 to c = 38.
      Four of 15 patients with obsessive-compulsive disorder had a documented decrease
      of more than 35% on the Yale-Brown Obsessive-Compulsive Scale, but only one
      patient had a sustained benefit for more than 1 year. CONCLUSION: Microelectrode
      recording is useful for lesion placement. Our system for reporting location in
      anterior cingulate cortex normalizes for differences in callosal morphometry.
      These techniques may aid future study.

PMID- 15028137
TI  - Stabilization of anterior cervical spine with bioabsorbable polymer in one- and
      two-level fusions.
AB  - OBJECTIVE: We present our experience using a bioabsorbable polymer in the
      surgical management of one- and two-level degenerative disc disease of the
      cervical spine with anterior cervical discectomy and fusion. Twenty-six patients
      were treated at the University of California, San Diego Medical Center or the
      Veterans Affairs Medical Center in San Diego, CA. All cases were performed under
      the direction of a single neurosurgeon (WRT). METHODS: A retrospective review of
      patients' charts and imaging was performed to determine outcomes after anterior
      cervical spine operations. Specifically, we looked at the need for additional
      surgery, local reaction to the bioabsorbable polymer, fusion rate, and
      complications. Procedures involved the C3-C4, C4-C5, C5-C6, and/or C6-C7 levels,
      and fibular allograft was used in all but one case. The anterior cervical
      discectomy and fusion procedures with internal fixation were performed in 26
      patients between March 2000 and November 2001. The patients were followed for up
      to 2 years after surgery (average, 14 mo). RESULTS: Radiographic fusion was
      achieved in 25 (96.2%) of 26 patients. Only one instance of treatment failure was
      encountered that required additional surgery and the placement of a titanium
      plate. There were no clinical signs or symptoms of reaction to the bioabsorbable
      material. CONCLUSION: The rates of fusion after single-level anterior cervical
      discectomy and fusion with internal fixation using bioabsorbable polymer and
      screws in this study match those using metallic implants, as previously reported
      in the literature, and are superior to those achieved with noninstrumented
      fusions. Preliminary results suggest that this newly available technology for
      anterior fusion is as effective in single-level disease as traditional titanium
      plating systems. The bioabsorbable material seems to be tolerated well by
      patients. A larger, randomized, controlled study is necessary to bring the
      results to statistical significance.

PMID- 15028138
TI  - Anterior lumbar interbody fusion for treatment of failed back surgery syndrome:
      an outcome analysis.
AB  - OBJECTIVE: Anterior lumbar interbody fusion (ALIF) has gained popularity for the
      treatment of degenerative disease of the lumbar spine. In this report, we present
      our experience with the ALIF procedure for treatment of failed back surgery
      syndrome (FBSS) in a noncontrolled prospective cohort. METHODS: In a 2-year
      period, we treated patients diagnosed with FBSS with ALIF. Clinical and
      radiological outcomes were recorded in a prospective, nonrandomized, longitudinal
      manner. Neurological, pain, and functional outcomes were measured preoperatively
      and 12 months after surgery. Operative data, perioperative complications, and
      radiological and clinical outcomes were recorded. RESULTS: Thirty-three patients
      with a preoperative diagnosis of FBSS, with degenerative disc disease (n = 17),
      postsurgical spondylolisthesis (n = 13), or pseudarthrosis (n = 3), underwent
      ALIF. Back pain, leg pain, and functional status improved significantly, by 76%
      (P < 0.01), 80% (P < 0.01), and 67% (P < 0.01), respectively. CONCLUSION: On the
      basis of our results, we found ALIF to be a safe and effective procedure for the
      treatment of FBSS for selected patients.

PMID- 15028139
TI  - "Tangential" resection of medial temporal lobe arteriovenous malformations with
      the orbitozygomatic approach.
AB  - OBJECTIVE: Arteriovenous malformations (AVMs) of the medial temporal lobe are
      usually resected through subtemporal-transcortical approaches that provide a
      trajectory that is perpendicular to the plane of the AVM. The pterional approach
      is sometimes used for AVMs in the uncus and amygdala, but it is not recommended
      for AVMs in the hippocampal region because it provides a "tangential" approach
      with limited access to posterior feeding arteries and draining veins. The
      orbitozygomatic approach enhances exposure along this tangential trajectory and
      was used in a consecutive series of 10 patients to determine its advantages.
      METHODS: During a 5.7-year period, 43 patients underwent resection of temporal
      lobe AVMs, 10 of which were located in the medial temporal lobe (amygdala and
      uncus [Region A] or hippocampus, parahippocampus, and fusiform gyrus [Region B]).
      AVMs were evenly distributed by region and by hemispheric dominance and included
      two Spetzler-Martin Grade IV lesions. An orbitozygomatic approach was used in all
      cases. RESULTS: Complete resection was accomplished in nine patients, and one
      patient underwent multimodality management with postoperative stereotactic
      radiosurgery. Good outcomes (Rankin outcome score <or=2) were observed in all
      patients, and six patients were improved neurologically at late follow-up (mean,
      1.3 yr). No permanent language deficits were produced by this approach.
      CONCLUSION: The orbitozygomatic approach maximizes the exposure of the tangential
      approach to medial temporal lobe AVMs and has advantages over traditional lateral
      approaches. It provides early access to critical feeding arteries from the
      anterior choroidal artery, posterior cerebral artery, and posterior communicating
      artery; it minimizes temporal lobe retraction and risk to the vein of Labbe; and
      it avoids transcortical incisions or lobectomy that might impact language and
      memory function. For these reasons, it may be the optimal approach for small- and
      medium-sized compact AVMs in the dominant medial temporal lobe.

PMID- 15028140
TI  - Subdural patch graft technique for watertight closure of large dural defects in
      extended transsphenoidal surgery.
AB  - OBJECTIVE: The most common postoperative complication of the transsphenoidal
      approach is cerebrospinal fluid (CSF) rhinorrhea. If the dura is widely opened
      beyond the sellar floor and massive intraoperative CSF leakage is encountered,
      then the conventional packing method, in which the sella turcica is filled with
      pieces of fat or muscle, demonstrates a relatively high incidence of CSF
      rhinorrhea. For more reliable prevention of postoperative CSF leakage, we
      developed a method for watertight closure of large dural defects. METHODS: For 34
      consecutive patients with suprasellar tumors, we performed tumor resection via an
      extended transsphenoidal approach, in which the surgical window in the sellar
      floor was extended to the planum sphenoidale to expose the suprasellar cistern.
      The patients were retrospectively divided into three groups according to the
      dural defect closure technique used. Group I consisted of the first two patients,
      whose large dural openings were closed with a conventional fat-packing method.
      Group II consisted of the next 10 patients, whose large dural defects were
      patched with fascia and sutured with 5-0 nylon, in a watertight manner. Group III
      consisted of the last 22 patients, who underwent watertight dural closure with a
      new knot-tying technique and a double-layer patch graft, which generously covered
      the dural defect of the cranial base with subdural placement. In Group III,
      intracranial CSF compressed the patch graft against the cranial base and sealed
      the gap between the patch graft and the cranial base in a watertight manner. The
      double-layer patch graft was composed of autologous fascial membrane and a
      commercially available, expanded polytetrafluoroethylene dural substitute.
      RESULTS: Postoperative CSF leakage was noted for 50% of the patients in Group I,
      30% of the patients in Group II, and 9% of the patients in Group III. The time
      required for dural closure for Group III was approximately 50% shorter than that
      required for Group II (45.9 +/- 12.4 min versus 93.5 +/- 19.1 min, P < 0.001).
      CONCLUSION: The subdural double-layer patch graft technique is simple and
      reliable for the prevention of CSF rhinorrhea after transsphenoidal surgery
      associated with a widely opened dura.

PMID- 15028141
TI  - Posterior surgical approach to the cervical neural foramen for intervertebral
      disc disease.
AB  - A POSTERIOR FORAMINOTOMY (hemilaminotomy and medial facetectomy) is indicated for
      the treatment of nerve root compression secondary to posterolateral disc
      herniation or spondylotic foraminal stenosis. We describe the normal and
      pathological anatomy of the cervical neural foramen as well as our surgical
      technique, which has been highly effective in cases of cervical discogenic
      radiculopathy.

PMID- 15028142
TI  - Radial artery graft for bypass of the maxillary to proximal middle cerebral
      artery: an anatomic and technical study.
AB  - OBJECTIVE: In this study, we aimed to investigate the use of a radial artery
      graft for bypass of the maxillary artery (MA) to the proximal middle cerebral
      artery (MCA) as an alternative to superficial temporal artery-to-MCA anastomosis
      or extracranial carotid-to-MCA bypass using long grafts. METHODS: Five adult
      cadavers were used bilaterally. After a frontotemporal craniotomy and a zygomatic
      arch osteotomy, the MA was found easily 1 to 2 cm inferior to the infratemporal
      crest. A hole was created with a 4-mm-tip drill in the sphenoid bone 2 to 3 mm
      lateral to the foramen rotundum extradurally, and the dura over the hole was
      opened. After the carotid and sylvian cisterns had been opened, the M2 segment of
      the MCA was exposed. The graft was passed through the hole to reach the M2
      segment. Then, the MA was freed from the surrounding tissue and was transected
      before the infraorbital artery branch. The radial artery graft was anastomosed
      end-to-end to the MA proximally and end-to-side to the M2 segment of the MCA
      distally. RESULTS: The mean thickness of the MA before the infraorbital artery
      branch was 2.6 +/- 0.3 mm. The mean thickness of the largest trunk of the MCA was
      2.3 +/- 0.3 mm. The average length of the graft was 36 +/- 5.5 mm. CONCLUSION: MA
      to-MCA bypass is as feasible as proximal MCA revascularization using long vein
      grafts. The thickness of the MA provides sufficient flow; the length of the graft
      is short, and it has a straight course. MA-to-proximal MCA bypass may be an
      alternative to superficial temporal artery-to-MCA as well as extracranial carotid
      to-MCA bypasses.

PMID- 15028143
TI  - The development of a method to measure head acceleration and motion in high
      impact crashes.
AB  - OBJECTIVE: To establish a mechanism to obtain precise measurements of the
      accelerations of the head in the high-speed racing environment and during crash
      impacts. The long-term goal is to apply this system to the assessment of head
      injury in automobile racing drivers and then in participants in other helmeted
      sports. METHODS: A multidisciplinary team conceptualized, designed, and
      successfully tested a triaxial accelerometer system capable of measuring head
      acceleration and motion in high-impact crashes. The system has been implemented
      successfully in the professional racing environment. RESULTS: Accurate and
      reproducible data have been obtained from the accelerometer system in tests on
      manikins and cadavers and in actual racing events. The system has been
      implemented in two professional racing series in 2003. Information gained from
      the accelerometer system is currently being entered into a database. Eventually,
      the data should aid in the development of improved cockpit head protection in
      racing cars. Improved helmet design not only in motor sports but also in other
      helmeted sports should benefit from the data collected. These data will also aid
      the development of improved head injury protection in military aircraft and
      passenger vehicles. CONCLUSION: Although there has been a significant decrease in
      the overall rate of injury during the past 25 years, head injury remains a
      serious safety concern in motor sports and the greatest cause of death. Sports
      related head injuries are also of great concern because repeated mild head injury
      has become an important health issue with potential long-term disability. True
      human tolerance to brain injury has yet to be established. Our scientific
      knowledge of brain injury is currently based on results derived from manikin,
      cadaver, and human volunteer testing, along with animal and computer models. The
      racing environment represents a venue to ethically measure and evaluate the
      forces involved in human brain injury.

PMID- 15028144
TI  - Microsurgical anatomy of the venous drainage of the mesencephalodiencephalic
      junction.
AB  - OBJECTIVE: The veins draining the posterior wall of the third ventricle and its
      adjacent structures and the posterior part of the midbrain have been the most
      neglected of the intracranial vascular structures in both the anatomic and
      neurosurgical literature. During our dissections of the pineal region and the
      quadrigeminal cistern, we did not always encounter topographic anatomy as
      described in previous articles. The purpose of this study is to describe the
      topographic anatomy and normal variations of the specific veins that drain the
      collicular plate and the pineal body and their adjacent structures with a view to
      better defining neurosurgical approaches to the pineal region. METHODS: The deep
      cerebral veins draining the pineal body, the collicular plate, and their
      surrounding neural structures were examined on both sides of 25 adult cadaveric
      brains. In all specimens, the carotid and vertebral arteries and the jugular
      veins were perfused with red or blue silicone, respectively, to facilitate
      dissection under x3 to x40 magnification. RESULTS: The venous plexus on the
      dorsal aspect of the collicular plate drains via collicular veins according to
      three different patterns. These types of drainage are closely related to the
      existence or absence of the basal vein on one or both sides. CONCLUSION: The
      veins draining the superior and inferior aspects of the pineal body form a
      superior and an inferior pineal vein that usually drain into the internal or
      great cerebral vein.

PMID- 15028145
TI  - Association between intravascular microthrombosis and cerebral ischemia in
      traumatic brain injury.
AB  - OBJECTIVE: To determine the association between traumatic cerebral ischemia and
      intravascular thrombosis, a common finding after traumatic brain injury (TBI).
      METHODS: We reviewed samples of the frontal cortex and hippocampus from
      individuals who had sustained a fatal TBI. Sections stained with hematoxylin and
      eosin were reviewed and rated for severity of selective neuronal necrosis (SNN).
      Because intravascular fibrin microthrombi may lyse within a few days of TBI, we
      restricted our analysis to patients who had died within 48 hours of injury.
      Medical records in all cases were reviewed to rule out severe or prolonged
      hypotension or hypoxemia. Eleven patients with severe or global SNN were compared
      with 11 patients in whom SNN was mild or absent. Slides adjacent to the
      hematoxylin and eosin sections were stained with an immunofluorescent antibody to
      antithrombin III and were reviewed for intravascular microthrombosis. The number
      of microthrombi on each slide was counted by an investigator blinded to the
      hematoxylin and eosin findings, and density of intravascular microthrombi was
      calculated. RESULTS: Intravascular microthrombi were noted in every section,
      excluding control (non-TBI) brain tissue. However, the density of microthrombi
      varied with the degree of SNN. We found a highly significant difference in the
      mean density of microthrombi between patients with severe SNN (7.74 +/-
      3.7/cm(2)) and those with little or no SNN (2.58 +/- 1.0/cm(2)). Furthermore, a
      good correlation was noted between the location of intravascular microthrombi and
      that of SNN. CONCLUSION: These data support a strong link between intravascular
      microthrombosis and neuronal death after brain trauma in humans and may have
      important implications for new therapeutic approaches.

PMID- 15028146
TI  - The cell cycle: accelerators, brakes, and checkpoints.
AB  - PROLIFERATIVE CUES TRIGGER a complex series of molecular signaling events in
      cells. Early in the cell cycle, cells are faced with an important decision that
      affects their fate. They either initiate a round of replication or they withdraw
      from cell division. Passage through the restriction point, or "point of no
      return," marks cellular commitment to a new round of division. Genetic mutations
      that predispose individuals to tumorigenesis often affect pathways that influence
      cellular proliferation. Many of the mutated genes give rise to molecules that are
      no longer able to appropriately regulate the mammalian cell cycle; the end result
      is neoplasia. In this review, the critical elements that permit cell cycle
      progression and the positive and negative regulators that affect the process are
      reviewed.

PMID- 15028147
TI  - Neurophysiological monitoring, magnetic resonance imaging, and histological
      assays confirm the beneficial effects of moderate hypothermia after epidural
      focal mass lesion development in rodents.
AB  - OBJECTIVE: To assess the effects of moderate intraischemic hypothermia on
      neurophysiological parameters in an epidural balloon compression model in rats
      and to correlate the results with magnetic resonance imaging and histological
      findings. METHODS: Neurophysiological monitoring included laser Doppler flow,
      tissue partial oxygen pressure, and intracranial pressure measurements and
      electroencephalographic assessments during balloon expansion, sustained
      inflation, and reperfusion. Moderate intraischemic cooling of animals was
      extended throughout the reperfusion period, and results were compared with those
      for normothermic animals. Moreover, histological morphometric and magnetic
      resonance imaging volumetric analyses of the lesions were performed. RESULTS:
      Laser Doppler flow decreased slightly during ischemia (P < 0.05) in animals
      treated with hypothermia, and flow values demonstrated complete reperfusion,
      compared with incomplete flow restoration in untreated animals (P < 0.05). During
      ischemia, the tissue partial oxygen pressure was less than 4.3 mm Hg in both
      groups. After reperfusion, values returned to the normal range in both groups,
      but the tissue partial oxygen pressure in hypothermic animals was significantly
      higher (P = 0.042) and demonstrated 19% higher values, compared with normothermic
      animals, before rewarming. Moderate hypothermia attenuated a secondary increase
      in intracranial pressure (P < 0.05), and electroencephalographic findings
      indicated a trend toward faster recovery (P > 0.05) after reperfusion. Lesion
      size was reduced by 35% in magnetic resonance imaging volumetric evaluations and
      by 24.5% in histological morphometric analyses. CONCLUSION: Intraischemic
      hypothermia improves cerebral microcirculation, attenuates a secondary increase
      in intracranial pressure, facilitates electroencephalographic recovery, and
      reduces the lesion size.

PMID- 15028148
TI  - Effect of mild hypothermia on brain dialysate lactate after fluid percussion
      brain injury in rodents.
AB  - OBJECTIVE: To investigate the effects of mild hypothermia on brain microdialysate
      lactate after fluid percussion traumatic brain injury (TBI) in rats. METHODS:
      Brain dialysate lactate before and after fluid percussion brain injury (2.1 +/-
      0.2 atm) was measured in rats with preinjury mild hypothermia (32 degrees C),
      postinjury mild hypothermia (32 degrees C), injury normothermia (37 degrees C),
      and the sham control group. Mild hypothermia (32 degrees C) was induced by
      partial immersion in a water bath (0 degrees C) under general anesthesia and
      maintained for 2 hours. RESULTS: In the normothermia TBI group, brain
      extracellular fluid lactate increased from 0.311 +/- 0.03 to 1.275 +/- 0.08
      mmol/L within 30 minutes after TBI (P < 0.01) and remained at a high level (0.546
      +/- 0.05 mmol/L) (P < 0.01) at 2 hours after injury. In the postinjury mild
      hypothermic group, brain extracellular fluid lactate increased from 0.303 +/-
      0.03 to 0.875 +/- 0.05 mmol/L at 15 minutes after TBI (P < 0.01) and then
      gradually decreased to 0.316 +/- 0.04 mmol/L at 2 hours after TBI (P > 0.05). In
      the preinjury mild hypothermic group, brain extracellular fluid lactate remained
      at normal levels after injury (P > 0.05). CONCLUSION: The cerebral extracellular
      fluid lactate level increases significantly after fluid percussion brain injury.
      Preinjury mild hypothermia completely inhibits the cerebral lactate accumulation,
      and early postinjury mild hypothermia significantly blunts the increase of
      cerebral lactate level after fluid percussion injury.

PMID- 15028149
TI  - Neutralizing antibody against interleukin-6 attenuates posthemorrhagic vasospasm
      in the rat femoral artery model.
AB  - OBJECTIVE: The degree to which inflammation contributes to the development of
      posthemorrhagic vasospasm is controversial. In the present study, we investigated
      the relationship between various inflammatory cytokines (tumor necrosis factor
      alpha, interleukin [IL]-1alpha, IL-1beta, and IL-6) and the development of
      experimental vasospasm. METHODS: Posthemorrhagic vasospasm was produced in the
      rat femoral artery model. A latex pouch was placed around each femoral artery,
      and one pouch was injected with autologous blood and the other with saline as an
      internal control. Animals were killed at various time points (1 h to 16 d) after
      surgery (blood exposure), and the degree of vasospasm was assessed by image
      analysis of artery cross sectional area. Levels of inflammatory cytokines were
      determined by enzyme-linked immunosorbent assay, and the ability of a polyclonal
      antibody against rat IL-6 to inhibit vasospasm was tested. RESULTS: The rat
      femoral artery model produced a biphasic vasospasm response, with maximal chronic
      delayed vasospasm occurring at 8 days after hemorrhage. Enzyme-linked
      immunosorbent assay revealed a significant increase in IL-6 concentrations in
      blood-exposed arteries relative to saline-exposed arteries at multiple time
      points (6, 12, 24, and 48 h) after hemorrhage (P < 0.0001). A relative increase
      in IL-1alpha levels was noted at 24 hours (P < 0.01). IL-1beta levels were
      similarly elevated in both blood- and saline-exposed arteries, and tumor necrosis
      factor-alpha levels were not detectable. Administration of a neutralizing
      polyclonal antibody against rat IL-6 directly into the blood-exposed periarterial
      pouch at the time of initial surgery resulted in a dose-dependent reduction in
      the degree of vasospasm compared with vehicle-treated controls at 8 days after
      hemorrhage (P < 0.05). CONCLUSIONS: These results indicate that cytokine-mediated
      inflammation is active in the setting of posthemorrhagic vasospasm produced by
      the rat femoral artery model. In particular, the profound increase in IL-6 levels
      after exposure to hemorrhage and the ability of a polyclonal antibody against IL
      6 to reduce vasospasm suggest that IL-6 may play a prominent role in the
      development of vasospasm in this model.

PMID- 15028150
TI  - Destruction of choroid plexus cells in vitro: a new concept for the treatment of
      hydrocephalus?
AB  - OBJECTIVE: The current treatment of hydrocephalus using ventriculoperitoneal
      shunts and third ventriculostomies remains problematic. We revisited the concept
      of destruction of the choroid plexus for the treatment of hydrocephalus by using
      an immunotoxin-based technique to specifically destroy this tissue. This approach
      was based on the observation that, as an epithelial tissue, choroid plexus
      expresses a number of specific cell-surface proteins that represent excellent
      potential targets for the creation of a choroid plexus-specific immunotoxin.
      METHODS: In this study, we characterized sheep and human choroid plexus cells
      (including atypical and carcinoma cell lines) using fluorescence microscopy in
      combination with histochemical staining of rat brain and confirmed the presence
      of a number of epithelium-specific proteins in choroid plexus cells. Immunotoxins
      were then manufactured by linking these antibodies to ricin A chain and ricin A-B
      chain. These immunotoxins were delivered to choroid plexus-derived cells in
      culture, and the results were compared with results of exposure to a nonspecific
      immunotoxin. RESULTS: Complete cell death of choroid plexus cells was seen after
      only a 1-hour exposure to the specific immunotoxin, as opposed to the minimal
      cell death seen with a nonspecific immunotoxin after several hours of exposure.
      CONCLUSION: These results suggest that immunotoxin-mediated ablation of choroid
      plexus may be a viable method of treating hydrocephalus and choroid plexus
      derived tumors.

PMID- 15028151
TI  - Reflections: a historical vignette.

PMID- 15028152
TI  - Fallen soldier.

PMID- 15028153
TI  - Cerebellar malignant fibrous histiocytoma: case report and literature review.
AB  - OBJECTIVE AND IMPORTANCE: Malignant fibrous histiocytoma in the central nervous
      system is uncommon. Fewer than 70 cases have been documented and, to the best of
      our knowledge, this is the first case arising from the cerebellum. CLINICAL
      PRESENTATION: A 44-year-old woman presented with headaches, vomiting, and
      dizziness. A neurological examination revealed right cerebellar syndrome. Brain
      computed tomographic scans revealed an isodense tumor in the right cerebellar
      hemisphere. The breast ultrasonographic, bone scintigraphic, and thoracoabdominal
      computed tomographic findings were normal. INTERVENTION: The patient was
      surgically treated. The tumor recurred 1.5 months later, demonstrating
      hemorrhagic characteristics on brain computed tomographic scans. The patient
      underwent a second operation, followed by radiotherapy. CONCLUSION: Malignant
      fibrous histiocytoma is still a controversial entity, and the lack of specific
      criteria means that it must be diagnosed via the process of elimination. With
      currently available therapy, our review can provide only a very poor prognosis.
      The median survival time was 27 months. In attempts to develop better therapeutic
      strategies, total excision and radiotherapy seem to represent the best treatment
      approach.

PMID- 15028155
TI  - Giant supratentorial enterogenous cyst: report of a case, literature review, and
      discussion of pathogenesis.
AB  - OBJECTIVE AND IMPORTANCE: To describe a histologically well-documented adult case
      of a giant supratentorial enterogenous cyst (EC). Fewer than 15 cases of
      supratentorial ECs are on record: 8 associated with the brain hemispheres or the
      overlying meninges, 4 with the sellar region, and 2 with the optic nerve.
      CLINICAL PRESENTATION: A 31-year-old woman complained of long-standing mild left
      brachial and crural motor deficit precipitated by headache and signs of
      intracranial hypertension. Magnetic resonance imaging revealed a huge cyst
      overlying the frontoparietal brain. INTERVENTION: Symptoms were relieved by
      evacuation of the cyst content by means of a Rickam's reservoir, and the lesion
      was subsequently removed in toto. Histological and immunohistochemical
      examination of the cyst wall clearly established the enterogenous nature of its
      epithelium. Follow-up for up to 2 years after intervention showed no sign of
      recurrence, and symptoms, including treatment-resistant seizures in the
      postoperative period, have entirely subsided. CONCLUSION: Supratentorial ECs,
      distinctly rare in adult patients, may in some cases present as giant lesions.
      Total removal seems to be curative once careful examination has eliminated the
      possibility of a metastasis from an unknown primary. A correct histological
      diagnosis is important because, in contrast to other benign cysts of similar
      location and size, ECs may be prone to intraoperative dissemination.

PMID- 15028154
TI  - Pituicytoma: report of two cases and clues regarding histogenesis.
AB  - OBJECTIVE AND IMPORTANCE: The pituicytoma is a rare primary tumor of the
      neurohypophysis. Although histologically benign, the location and vascular nature
      of these tumors can make surgical resection difficult. We present a report of two
      patients with pituicytomas and review the literature regarding treatment and
      prognosis for this unusual lesion. Possible histogenetic relationships of this
      tumor with other pituitary neoplasms are presented. CLINICAL PRESENTATION:
      Patient 1 was a 45-year-old man who presented with a 5-year history of decreased
      libido. He was found to have a 2-cm suprasellar mass on a magnetic resonance
      imaging scan. Patient 2 was a 48-year-old man who presented with multiple
      endocrine complaints. He was found to have an intrasellar mass on magnetic
      resonance imaging. INTERVENTION: Patient 1 underwent a right frontal craniotomy,
      with a subtotal resection of the suprasellar mass through the lamina terminalis.
      The residual tumor was treated with fractionated stereotactic radiotherapy. The
      intrasellar mass in Patient 2 was resected via a transsphenoidal approach. On
      surveillance magnetic resonance imaging, the tumor was found to have recurred and
      expanded into the suprasellar space. The patient underwent a right frontal
      craniotomy for decompression and a subtotal resection of the tumor. The patient
      experienced a second recurrence 7 years after the initial procedure and was
      subsequently treated with fractionated stereotactic radiotherapy. CONCLUSION:
      Pituicytomas are a distinct form of pituitary gland neoplasia that may recur if
      subtotally resected. These neurohypophysial tumors may contain a small
      subpopulation of previously unrecognized bcl-2-immunoreactive cells, whose role
      in the histogenesis of pituicytoma deserves further study.

PMID- 15028156
TI  - Headaches, shunts, and obstructive sleep apnea: report of two cases.
AB  - OBJECTIVE: This report describes two shunted patients evaluated with continuous
      intracranial pressure (ICP) monitors for worsening headaches and subsequently
      diagnosed with obstructive sleep apnea. CLINICAL PRESENTATION AND INTERVENTION:
      ICPs were monitored with strain-gauge sensors inserted into the frontal cortex.
      After the initial diagnosis of sleep apnea, 8-hour attended polysomnography was
      performed in each patient. Both patients showed apnea-hypopnea indices greater
      than 15. Consequently, a "split-night study" was performed to evaluate treatment
      with titrated nasal continuous positive airway pressure. Patient 1 was a 42-year
      old woman (body mass index, 34.1) with a 16-year history of idiopathic
      intracranial hypertension treated with lumboperitoneal and ventriculoperitoneal
      shunts. Patient 2 was a 20-year-old man (body mass index, 64.4) with the Arnold
      Chiari II malformation. The patient had had a low-pressure shunt since birth.
      Neurological examinations were normal or unchanged before evaluation.
      Neurophthalmological examinations were normal. Computed tomographic scans failed
      to show progressive ventriculomegaly. Awake ICPs were less than 15 mm Hg.
      Nighttime ICPs during rapid eye movement sleep showed multiple Lundberg A waves
      associated with obstructive sleep apnea and hypoxemia. Blood pressure did not
      change during these episodes. Polysomnography showed apnea-hypopnea indices of 31
      and 41, respectively. Continuous positive airway pressure reduced apnea-hypopnea
      indices to 17 and 0, respectively; headaches resolved with outpatient therapy.
      CONCLUSION: These observations suggest adequate shunting with reduced cerebral
      compliance in both patients. Altered respiratory mechanics associated with
      hypoxemia may have triggered cerebral vasodilation and increases in cerebral
      blood volume, particularly during rapid eye movement sleep. In noncompliant
      systems, these changes precipitated sustained elevations in ICP and intermittent
      headaches relieved by continuous positive airway pressure. The clinical patterns
      also suggest that obstructive sleep apnea should be considered in shunted
      patients with isolated symptoms of increasing headaches.

PMID- 15028157
TI  - Intramuscular thrombosed arteriovenous hemangioma of the upper right arm
      mimicking a neuroma of the ulnar nerve: case report.
AB  - OBJECTIVE AND IMPORTANCE: Soft tissue arteriovenous hemangiomas (AHs) are benign
      vascular hamartomas characterized by the presence of arteriovenous shunts. Few
      cases of soft tissue AHs have been found in the literature, and these were
      frequently described as cutaneous lesions of the limb or of the scalp.
      Intramuscular AHs are extremely rare. AHs are prevalent in children and women and
      are often associated with other types of malformations or genetic disorders. We
      present the case of an elderly woman with an intramuscular thrombosed AH on the
      volar side of the upper right arm. Owing to the close proximity of the ulnar
      nerve, this lesion was initially identified as a neuroma. CLINICAL PRESENTATION:
      A 70-year-old woman presented with a short history (a few months) of progressive
      growth of a nonpulsating, solid, palpable mass deeply localized in the distal
      third of the right upper arm. At the neurological examination, local evoked pain
      was the only sign detected. A Doppler ultrasound examination depicted a
      hyperechoic spherical lesion with widespread calcium deposits and necrosis.
      INTERVENTION: The exploration of the upper arm revealed a capsulated nodular
      lesion, 7 cm in diameter, that morphologically corresponded to a thrombosed
      vascular lesion. This lesion was removed en bloc, and an unequivocal connection
      with a muscular branch of the ulnar artery was detected. The histological
      analysis revealed AH. CONCLUSION: Intramuscular AHs are rare and may easily be
      misdiagnosed as neuromas, especially when they are contiguous to a peripheral
      nerve.

PMID- 15028189
TI  - Fall protection incentives in the construction industry: literature review and
      field study.
AB  - Safety literature confirms that incentives such as money or sunglasses seem to
      improve safety conditions over the short run. However, no studies could be found
      which tested the effect of incentives on fall protection for a period longer than
      a few days. In our research we found that after 6 months, the use of non-material
      incentives significantly improved on-time delivery and completion rates of a
      special inspection form (both p <.005). In addition, a questionnaire with
      embedded critical questions showed that even though workers said that they
      preferred material incentives, we conclude that their behavior was changed by the
      treatment (incentives). We further conclude that the use of natural reinforcers
      seems to influence worker behaviors and perception of management's commitment to
      safety over the long run, even though workers still say that they prefer tangible
      rewards. Future work should replicate these findings and explore why workers
      respond to natural incentives but express a preference for material incentives.

PMID- 15028190
TI  - Design and ergonomics. Methods for integrating ergonomics at hand tool design
      stage.
AB  - As a marked increase in the number of musculoskeletal disorders was noted in many
      industrialized countries and more specifically in companies that require the use
      of hand tools, the French National Research and Safety Institute (INRS) launched
      in 1999 a research project on the topic of integrating ergonomics into hand tool
      design, and more particularly to a design of a boning knife. After a brief recall
      of the difficulties of integrating ergonomics at the design stage, the present
      paper shows how 3 design methodological tools--Functional Analysis, Quality
      Function Deployment and TRIZ--have been applied to the design of a boning knife.
      Implementation of these tools enabled us to demonstrate the extent to which they
      are capable of responding to the difficulties of integrating ergonomics into
      product design.

PMID- 15028191
TI  - The relationship between workers' safety culture and accidents, near accidents
      and health problem.
AB  - One of the dimensions treated as part of a company's safety culture or climate is
      workers' attitudes towards risk and safety. In the present study these personal
      aspects are defined as workers' safety culture, which is understood as a way of
      acting focused on life and taking care of one's health. A questionnaire on safety
      culture was filled out by 200 employees of a metallurgical enterprise. Factor
      analysis was used to determine empirical scales of the questionnaire, whereas
      variance analysis was used to test hypotheses. The results confirmed the
      hypotheses that people who experienced accidents, dangerous situations, and--to a
      lesser extent--health problems had a lower level of safety culture. Nevertheless
      not all of the scales determined during factor analysis turned out to be
      significant as far as all kinds of those undesirable situations are concerned.
      Proposals for future studies are formulated in the conclusion.

PMID- 15028192
TI  - Is fixed-term employment a new risk for adverse physical working conditions?
AB  - Relationships between employment type and the physical work environment were
      studied among blue-collar workers (n = 1,127). Based on survey data, we set out
      to compare the evaluations of environmental load and physical strain at work
      given by fixed-term (17% of all) and permanent workers. The type of employment
      was not related to environmental load. However, working on a fixed-term basis
      increased the risk of physical strain at work. Analyses revealed that this
      connection was evident only among fixed-term construction workers. The results
      did not support the much-cited view that the disintegration of standard
      employment has given rise to a new series of work environment problems. Such
      problems are concentrated in an area with a long tradition of work environment
      problems, that is, in the construction industry.

PMID- 15028193
TI  - Isometric pull-push strengths in workspace: 1. Strength profiles.
AB  - The isometric pull and push strength profiles of males and females were
      determined in seated and standing positions in the workspace. The strongest pull
      strength location was at extreme reach vertically above the shoulder for both
      males and females. The greatest pull strength of 400 Newtons (N) for males was
      recorded in the seated and standing positions. Females' pull strengths in the
      seated and standing positions were 222 and 244 N, respectively. The strongest
      push strength was always at the maximum reach at the overhead location. Males'
      maximum push strength was 227 N in the seated position and 251 N in the standing
      position. Females' maximum push strength was 96 N in the seated position and 140
      N in the standing position. On the average the strength in the standing position
      was 79% of the seated position. The push strength was 71% of the pull strength
      and females were 56% as strong as males.

PMID- 15028194
TI  - Isometric pull-push strengths in workspace: 2. Analysis of spatial factors.
AB  - The effect of reach levels, horizontal angles and vertical angles on isometric
      pull and push strengths of males and females in standing and seated positions was
      determined. The effect of reach levels on strength varied as a consequence of
      force direction, working position and gender. Reach level has a significant
      effect on women's pull strength in the seated position and on push strength in
      the standing position. The strength value was significantly greater in the
      extreme reach than in maximum or normal reach. Vertical angle phi had a
      significant effect on strength consistently in all cases. Strength values
      increased significantly with the increase of phi angles from 0 degrees to 45
      degrees to 90 degrees. The horizontal angle theta had a significant influence
      only on the pull strength of standing and seated men and standing women (not
      seated woman). The maximum strength was significantly greater at theta = 90
      degrees.

PMID- 15028195
TI  - Major health risk factors in Iranian hand-woven carpet industry.
AB  - This paper reviews the role and importance of small-scale industries together
      with the issue of occupational health problems and their causes in Iranian hand
      woven carpet industry as a typical informal small-scale industry in an
      industrially developing country. The objective of this paper is to review health
      risk factors and related occupational health and ergonomic problems in the carpet
      industry. Since the overwhelming majority of weavers' health problems originate
      from ergonomic risk factors, it is concluded that any improvement program in this
      industry should focus on ergonomic aspects. To assess ergonomic conditions in
      weaving workshops, a checklist has been developed and an ergonomics index
      indicating the ergonomic conditions of the workshop has been proposed. To test
      and verify the checklist, 50 weaving workshops were visited and their ergonomic
      conditions were assessed. Based on the results some modifications were made and
      the checklist was shown to be an effective tool.

PMID- 15028196
TI  - The use of footwear insulation values measured on a thermal foot model.
AB  - The use of physiological data from human tests in modelling should consider
      background data, such as activity, environmental factors and clothing insulation
      on the whole body. The present paper focuses on local thermal comfort of feet
      with special attention on the effects of physical changes of footwear thermal
      properties. An alternative test method is available for footwear thermal testing
      besides the standard method. The possibility to use insulation values acquired on
      a thermal foot model in practice is shown here. The paper describes the
      correlation between cold and pain sensations, and foot skin temperatures of the
      subjects and relates these to insulation measured on a thermal foot model.
      Recommendations are made for footwear choice according to environmental
      temperature.

PMID- 15028197
TI  - Electric field prediction for a human body-electric machine system.
AB  - A system consisting of an electric machine and a human body is studied and the
      resulting electric field is predicted. A 3-phase induction machine operating at
      full load is modeled considering its geometry, windings, and materials. A human
      model is also constructed approximating its geometry and the electric properties
      of tissues. Using the finite element technique the electric field distribution in
      the human body is determined for a distance of 1 and 5 m from the machine and its
      effects are studied. Particularly, electric field potential variations are
      determined at specific points inside the human body and for these points the
      electric field intensity is computed and compared to the limit values for
      exposure according to international standards.

PMID- 15028198
TI  - The advent of laparoscopy.

PMID- 15028199
TI  - Taking the side of transperitoneal access for surgery in upper urinary tract.
AB  - Laparoscopic surgery has become a preferred treatment option for the management
      of upper urinary tract pathology. Large series of complex urologic operations
      have been published, with favorable outcomes. Although the early experience with
      urologic laparoscopy consisted almost exclusively of transperitoneal procedures,
      some surgeons prefer the retroperitoneal approach. The debate of retroperitoneal
      versus transperitoneal laparoscopy for upper tract pathology is complex because
      comparative and randomized studies are lacking. In contrast to the
      retroperitoneal approach, transperitoneal laparoscopic procedures allow for a
      larger working space, adequate maneuverability, and the presence of familiar
      anatomic landmarks. This article highlights our experiences and approaches to
      major laparoscopic upper urinary tract surgery for benign and malignant
      conditions. A summary of the published literature as it pertains to the
      transperitoneal approach also is presented.

PMID- 15028201
TI  - The advantages of hand-assisted laparoscopy.
AB  - The technical challenges of performing laparoscopic renal surgery require
      fellowship training and are associated with a steep learning curve. For the
      established urologist in practice, fellowship training is not a reality. As a
      result of these obstacles, in the late 1990s, laparoscopic renal surgery was
      entering the domain of the general surgeons who had a large number of
      laparoscopic procedures at their disposal to develop laparoscopic skills. Hand
      assisted laparoscopic renal surgery is a hybrid procedure combining the most
      salient features of open renal surgery and laparoscopic renal surgery. By
      allowing the surgeons to place their non-dominant hand into the abdominal cavity,
      palpation and spatial orientation became possible, lessening the learning curve
      for laparoscopic surgery. Moreover, hand-assisted laparoscopic surgery could be
      applied to a variety of renal surgeries, extirpative and reconstructive, with
      results similar to those already achieved by standard laparoscopy. Throughout the
      past 5 years, hand-assisted laparoscopy has allowed urologists to incorporate
      laparoscopic renal surgery into their practices to the benefit of their patients
      and of their specialty. This review article offers a historical review of the
      development of hand-assisted laparoscopy and describes the procedures commonly
      performed today using this technique.

PMID- 15028200
TI  - Justification of extraperitoneal laparoscopic access for surgery of the upper
      urinary tract.
AB  - Laparoscopic surgery was originally developed by gynecologists and general
      surgeons. Based on their experience, the first successful laparoscopic procedures
      in urology were performed transperitoneally. However, this novel technique
      transformed traditionally retroperitoneal procedures into transperitoneal
      procedures, giving free rein to distinct intraperitoneal complications.
      Retroperitoneal laparoscopy was a later development in urology. This approach has
      gained increasing popularity throughout the years and has challenged the
      transperitoneal laparoscopic route in many aspects. This review focuses on the
      advantages of retroperitoneal laparoscopic surgery of the upper urinary tract.

PMID- 15028202
TI  - Laparoscopic radical prostatectomy: the new gold standard?
AB  - Radical prostatectomy is the reference treatment for localized prostate cancer.
      The minimal invasive approach is gaining support in a large number of centers
      around the world because the laparoscopic approach seems to maintain the
      oncological control of open surgery with added benefits for the patient. In this
      paper, the main aspects of the different laparoscopic approaches, their benefits,
      difficulties, complications, and results are described and compared with the open
      radical prostatectomy. A critical review of the literature on radical
      prostatectomy comparing the open and laparoscopic techniques and the differences
      between each approach was done.

PMID- 15028203
TI  - Does the extraperitoneal laparoscopic approach improve the outcome of radical
      prostatectomy?
AB  - Laparoscopic radical prostatectomy (LRPE) became the operative procedure of
      choice for patients with clinically localized prostate cancer in selected
      urologic centers around the world. Principal advantages are the minimal invasive
      nature of the procedure, a superior visualization of the operative field because
      of the magnification of the optical system, an exact and watertight anastomosis,
      the possibility of early catheter removal, and a potentially reduced amount of
      blood loss. Recent data show that oncologic outcome is not compromised by the
      minimal invasive nature of the procedure. However, a major drawback of LRPE is
      the transperitoneal route of access to the extraperitoneal organ of the prostate.
      Therefore, principal disadvantages of LRPE are potential intraperitoneal
      complications. Endoscopic extraperitoneal radical prostatectomy is a further
      advancement of minimal invasive surgery because it overcomes the limitations of
      LRPE by the strictly extraperitoneal route of access, combining the advantages of
      minimal invasive surgery with the advantages of an extraperitoneal procedure.
      This article reviews the literature on minimally invasive (laparoscopic and
      endoscopic-extraperitoneal) radical prostatectomy.

PMID- 15028205
TI  - Cystoscopic correction of reflux.
AB  - Vesicoureteral reflux is a well-recognized cause of childhood illness and renal
      damage. In the past, surgical reimplantation had been the only procedure
      available to gain the immediate cessation of reflux. The development of an
      endoscopic injection technique as a less morbid alternative to traditional
      surgery began in the 1980s. Teflon was the first injectable agent to be
      investigated. The record of Teflon is one of efficacy and apparent patient
      tolerance. However, concerns regarding possible migration and other side effects
      led to a search for other injectable agents. The most recently investigated
      agents are polydimethylsiloxane and dextranomer polymer. These agents do not have
      the long-term follow-up of Teflon, but appear to be effective and safe. Time will
      tell which agent will become the implant of choice, but it seems clear that
      endoscopic management will play an increasingly larger role in the care of
      vesicoureteral reflux.

PMID- 15028206
TI  - Laparoscopic varicocelectomy in the adolescent male.
AB  - Laparoscopic varicocelectomy was introduced in the early 1990s as an alternative
      to the Palomo varicocelectomy. Since its introduction, the procedure has gained
      favor within the pediatric urology community. Laparoscopic varicocelectomy has
      been performed using the intraperitoneal, preperitoneal, and lumbotomy approaches
      with almost the same results as those obtained with the Palomo procedure. The
      complication rates are relatively low for this procedure except for the hydrocele
      rate, which has been similar to that encountered with the open Palomo approach.
      In this article, the results obtained with this procedure and the technique are
      explored. As more pediatric urologists become adept with laparoscopic techniques,
      we will continue to see an increase in the number of cases performed using this
      technique.

PMID- 15028207
TI  - Current management of bladder exstrophy.
AB  - Bladder exstrophy is a complex anomaly involving the urinary, genital, and
      intestinal tracts and the musculoskeletal system. The diagnosis is made typically
      at the newborn examination or on fetal ultrasonography that is performed by an
      experienced observer. Management of bladder exstrophy presents several
      challenges, beginning with initial repair using the more conventional staged
      approach or the recently re-popularized complete primary repair technique. Major
      goals in the management of bladder exstrophy are preservation of normal kidney
      function, close observation for development of adequate bladder function
      including urinary continence, and provision of acceptable cosmesis and function
      of the external genitalia. This article provides a brief overview of bladder
      exstrophy and a detailed description of modern management.

PMID- 15028208
TI  - The relationship of cryptorchidism to fertility.
AB  - Cryptorchidism is the most common genitourinary disorder of childhood, resulting
      in 27,000 surgical cases each year in the United States. Of the 3% of full-term
      infants affected, most will have testes that will descend normally within a few
      months. The remaining 1%, who have a cryptorchid condition that persists, should
      consider medical or surgical intervention. In addition, although the effect of
      cryptorchidism on testicular development and fertility has been studied
      extensively, the only fact of certainty is that untreated men with bilateral
      abdominal testes will be infertile. The remaining scenarios (unilateral,
      inguinal, gliding, and medically or surgically treated conditions) offer
      unpredictable levels of fertility. Fortunately, based on recent research, the
      correlation between testis maldescent and infertility may not be as prevalent as
      previously reported.

PMID- 15028209
TI  - The Arabidopsis thaliana chloroplast proteome reveals pathway abundance and novel
      protein functions.
AB  - BACKGROUND: Chloroplasts are plant cell organelles of cyanobacterial origin. They
      perform essential metabolic and biosynthetic functions of global significance,
      including photosynthesis and amino acid biosynthesis. Most of the proteins that
      constitute the functional chloroplast are encoded in the nuclear genome and
      imported into the chloroplast after translation in the cytosol. Since protein
      targeting is difficult to predict, many nuclear-encoded plastid proteins are
      still to be discovered. RESULTS: By tandem mass spectrometry, we identified 690
      different proteins from purified Arabidopsis chloroplasts. Most proteins could be
      assigned to known protein complexes and metabolic pathways, but more than 30% of
      the proteins have unknown functions, and many are not predicted to localize to
      the chloroplast. Novel structure and function prediction methods provided more
      informative annotations for proteins of unknown functions. While near-complete
      protein coverage was accomplished for key chloroplast pathways such as carbon
      fixation and photosynthesis, fewer proteins were identified from pathways that
      are downregulated in the light. Parallel RNA profiling revealed a pathway
      dependent correlation between transcript and relative protein abundance,
      suggesting gene regulation at different levels. CONCLUSIONS: The chloroplast
      proteome contains many proteins that are of unknown function and not predicted to
      localize to the chloroplast. Expression of nuclear-encoded chloroplast genes is
      regulated at multiple levels in a pathway-dependent context. The combined shotgun
      proteomics and RNA profiling approach is of high potential value to predict
      metabolic pathway prevalence and to define regulatory levels of gene expression
      on a pathway scale.

PMID- 15028210
TI  - MAP2c, but not tau, binds and bundles F-actin via its microtubule binding domain.
AB  - BACKGROUND: MAP2 and tau are abundant microtubule-associated proteins (MAPs) in
      neurons. The development of neuronal dendrites and axons requires a dynamic
      interaction between microtubules and actin filaments. MAPs represent good
      candidates to mediate such interactions. Although MAP2c and tau have similar,
      well-characterized microtubule binding activities, their actin interaction is
      poorly understood. RESULTS: Here, we show by using a cosedimentation assay that
      MAP2c binds F-actin. Upon actin binding, MAP2c organizes F-actin into closely
      packed actin bundles. Moreover, we show by using a deletion approach that MAP2c's
      microtubule binding domain (MTBD) is both necessary and sufficient for both F
      actin binding and bundling activities. Surprisingly, even though the MAP2 and tau
      MTBDs share high sequence homology and possess similar microtubule binding
      activities, tau is unable to bind or bundle F-actin. Furthermore, experiments
      with chimeric proteins demonstrate that the actin binding activity fully
      correlates with the ability to promote neurite initiation in neuroblastoma cells.
      CONCLUSIONS: These results provide the first demonstration that the MAP2c and tau
      MTBD domains exhibit distinct properties, diverging in actin binding and neurite
      initiation activities. These results implicate a novel actin function for MAP2c
      in neuronal morphogenesis and furthermore suggest that actin interactions could
      contribute to functional differences between MAP2 and tau in neurons.

PMID- 15028211
TI  - Integrin-dependent apposition of Drosophila extraembryonic membranes promotes
      morphogenesis and prevents anoikis.
AB  - BACKGROUND: Two extraembryonic tissues form early in Drosophila development. One,
      the amnioserosa, has been implicated in the morphogenetic processes of germ band
      retraction and dorsal closure. The developmental role of the other, the yolk sac,
      is obscure. RESULTS: By using live-imaging techniques, we report intimate
      interactions between the amnioserosa and the yolk sac during germ band retraction
      and dorsal closure. These tissue interactions fail in a subset of myospheroid
      (mys: betaPS integrin) mutant embryos, leading to failure of germ band retraction
      and dorsal closure. The Drosophila homolog of mammalian basigin (EMMPRIN, CD147)
      an integrin-associated transmembrane glycoprotein-is highly enriched in the
      extraembryonic tissues. Strong dominant genetic interactions between basigin and
      mys mutations cause severe defects in dorsal closure, consistent with basigin
      functioning together with betaPS integrin in extraembryonic membrane apposition.
      During normal development, JNK signaling is upregulated in the amnioserosa, as
      midgut closure disrupts contact with the yolk sac. Subsequently, the amnioserosal
      epithelium degenerates in a process that is independent of the reaper, hid, and
      grim cell death genes. In mys mutants that fail to establish contact between the
      extraembryonic membranes, the amnioserosa undergoes premature disintegration and
      death. CONCLUSIONS: Intimate apposition of the amnioserosa and yolk sac prevents
      anoikis of the amnioserosa. Survival of the amnioserosa is essential for germ
      band retraction and dorsal closure. We hypothesize that during normal
      development, loss of integrin-dependent contact between the extraembryonic
      tissues results in JNK-dependent amnioserosal disintegration and death, thus
      representing an example of developmentally programmed anoikis.

PMID- 15028212
TI  - Novel functions for integrins in epithelial morphogenesis.
AB  - Dorsal closure during Drosophila embryogenesis provides a valuable model for
      epithelial morphogenesis and wound healing. Previous studies have focused on two
      cell populations, the dorsal epidermis and the extraembryonic amnioserosa. Here,
      we demonstrate that there is an additional player, the large yolk cell. We find
      that integrins are expressed in the amnioserosa and yolk cell membrane and that
      they are required for three processes: (1) assembly of an intervening
      extracellular matrix, (2) attachment between these two cell layers, and (3)
      contraction of the amnioserosa cells. We also provide evidence for integrin
      extracellular matrix interactions occurring between the lateral surfaces of the
      amnioserosa cell and the leading edge epidermis that effectively mediate cell
      cell adhesion. Thus, dorsal closure shares mechanistic similarities with
      vertebrate epithelial morphogenetic events, including epiboly, that also employ
      an underlying substrate.

PMID- 15028213
TI  - Neural correlates of saccadic suppression in humans.
AB  - When you look into a mirror and move your eyes left to right, you will see that
      you cannot observe your own eye movements. This demonstrates the phenomenon of
      saccadic suppression: during saccadic eye movements, visual sensitivity is much
      reduced. Given that humans make more than 100,000 eye movements each day, it is
      clear why suppression is needed: without it, the motion on the retina would
      prevent us from seeing anything at all. Psychophysical data show that suppression
      is stimulus selective: it is strongest for the kind of stimuli that
      preferentially activate magnocellular thalamic neurons. This has led to the
      hypothesis that saccadic suppression selectively targets the magnocellular
      stream. We used fMRI to find brain areas with a stimulus-selective suppression of
      the BOLD signal that matches the psychophysical data. We found such a neural
      correlate of saccadic suppression in the dorsal stream (hMT+, V7) and in ventral
      area V4. These areas receive magnocellular input; hence our findings are
      consistent with the magnocellular hypothesis. The range of effects in our data
      and in single cell data, however, argues against a single thalamic mechanism that
      suppresses all cortical input. Instead, we speculate that saccadic suppression
      relies on multiple mechanisms operating in different cortical areas.

PMID- 15028214
TI  - Inversion leads to quantitative, not qualitative, changes in face processing.
AB  - Humans are remarkably adept at recognizing objects across a wide range of views.
      A notable exception to this general rule is that turning a face upside down makes
      it particularly difficult to recognize. This striking effect has prompted
      speculation that inversion qualitatively changes the way faces are processed.
      Researchers commonly assume that configural cues strongly influence the
      recognition of upright, but not inverted, faces. Indeed, the assumption is so
      well accepted that the inversion effect itself has been taken as a hallmark of
      qualitative processing differences. Here, we took a novel approach to understand
      the inversion effect. We used response classification to obtain a direct view of
      the perceptual strategies underlying face discrimination and to determine whether
      orientation effects can be explained by differential contributions of nonlinear
      processes. Inversion significantly impaired performance in our face
      discrimination task. However, surprisingly, observers utilized similar, local
      regions of faces for discrimination in both upright and inverted face conditions,
      and the relative contributions of nonlinear mechanisms to performance were
      similar across orientations. Our results suggest that upright and inverted face
      processing differ quantitatively, not qualitatively; information is extracted
      more efficiently from upright faces, perhaps as a by-product of orientation
      dependent expertise.

PMID- 15028215
TI  - First cleavage of the mouse embryo responds to change in egg shape at
      fertilization.
AB  - Although mouse development is regulative, the cleavage pattern of the embryo is
      not random. The first cleavage tends to relate to the site of the previous
      meiosis. Sperm entry might provide a second cue, but evidence for and against
      this is indirect and has been debated. To resolve whether sperm entry position
      relates to the first cleavage, we have followed development from fertilization by
      time-lapse imaging. This directly showed cytokinesis passes close to the site of
      the previous meiosis and to both the sperm entry site and trajectory of the male
      pronucleus in a significant majority of eggs. We detected asymmetric distribution
      of Par6 protein in relation to the site of meiosis, but not sperm entry.
      Unexpectedly, we found the egg becomes flattened upon fertilization in an actin
      mediated process. The sperm entry position tends to lie at one end of the short
      axis along which cleavage will pass. When we manipulated eggs to change their
      shape, this repositioned the cleavage plane such that eggs divided along their
      experimentally imposed short axis. Such manipulated eggs were able to develop to
      term, emphasizing the regulative nature of their development.

PMID- 15028216
TI  - A novel transport pathway for a yeast plasma membrane protein encoded by a
      localized mRNA.
AB  - Generally, plasma membrane (PM) proteins are cotranslationally inserted into the
      endoplasmic reticulum (ER) and travel in vesicles via the Golgi apparatus to the
      PM. In the yeast Saccharomyces cerevisiae, the polytopic membrane protein Ist2p
      is encoded by an mRNA that is localized to the cortex of daughter cells. It has
      been suggested that IST2 mRNA localization leads to the accumulation of the
      protein at the PM of daughter cells. Since small- and medium-sized daughter cells
      only contain cortical, but not perinuclear ER, this implies the local translation
      of Ist2p specifically at the cortical ER. Here, we show that localization of
      constitutively expressed IST2 mRNA is required for delivery of Ist2p to the PM of
      daughter, but not mother cells and that it does not result in daughter-specific
      Ist2p accumulation. In contrast to a PM-located hexose transporter (Hxt1p) that
      follows the standard secretory pathway, the trafficking of Ist2p is independent
      of myosin-mediated vesicular transport. Furthermore, colocalization experiments
      in mutants of the secretory pathway demonstrate that trafficking of Ist2p does
      not require the classical secretory machinery. These data suggest the existence
      of a novel trafficking pathway connecting specialized domains of the ER with the
      PM.

PMID- 15028217
TI  - The plant microtubule-associated protein AtMAP65-3/PLE is essential for
      cytokinetic phragmoplast function.
AB  - Directional cell expansion in interphase and nuclear and cell division in M-phase
      are mediated by four microtubule arrays, three of which are unique to plants: the
      interphase array, the preprophase band, and the phragmoplast. The plant
      microtubule-associated protein MAP65 has been identified as a key structural
      component in these arrays. The Arabidopsis genome has nine MAP65 genes, and here
      we show that one, AtMAP65-3/PLE, locates only to the mitotic arrays and is
      essential for cytokinesis. The Arabidopsis pleiade (ple) alleles are single
      recessive mutations, and we show that these mutations are in the AtMAP65-3 gene.
      Moreover, these mutations cause C-terminal truncations that abolish microtubule
      binding. In the ple mutants the anaphase spindle is normal, and the cytokinetic
      phragmoplast can form but is distorted; not only is it wider, but the midline,
      the region where oppositely oriented microtubules overlap, is unusually expanded.
      Here we present data that demonstrate an essential role for AtMAP65-3/PLE in
      cytokinesis in plant cells.

PMID- 15028218
TI  - Fusion and rivalry are dependent on the perceptual meaning of visual stimuli.
AB  - We view the world with two eyes and yet are typically only aware of a single,
      coherent image. Arguably the simplest explanation for this is that the visual
      system unites the two monocular stimuli into a common stream that eventually
      leads to a single coherent sensation. However, this notion is inconsistent with
      the well-known phenomenon of rivalry; when physically different stimuli project
      to the same retinal location, the ensuing perception alternates between the two
      monocular views in space and time. Although fundamental for understanding the
      principles of binocular vision and visual awareness, the mechanisms under-lying
      binocular rivalry remain controversial. Specifically, there is uncertainty about
      what determines whether monocular images undergo fusion or rivalry. By taking
      advantage of the perceptual phenomenon of color contrast, we show that physically
      identical monocular stimuli tend to rival-not fuse-when they signify different
      objects at the same location in visual space. Conversely, when physically
      different monocular stimuli are likely to represent the same object at the same
      location in space, fusion is more likely to result. The data suggest that what
      competes for visual awareness in the two eyes is not the physical similarity
      between images but the similarity in their perceptual/empirical meaning.

PMID- 15028219
TI  - Flies by night: Effects of changing day length on Drosophila's circadian clock.
AB  - In Drosophila, two intersecting molecular loops constitute an autoregulatory
      mechanism that oscillates with a period close to 24 hr. These loops touch when
      proteins from one loop, PERIOD (PER) and TIMELESS (TIM), repress the
      transcription of their parent genes, period (per) and timeless (tim), by blocking
      positive transcription factors from the other loop. The arrival of PER and TIM
      into the nucleus of a clock cell marks the timing of this interaction between the
      two loops; thus, control of PER:TIM nuclear accumulation is a central component
      of the molecular model of clock function. If a light pulse occurs early in the
      night as the heterodimer accumulates in the nucleus of clock cells, TIM is
      degraded, PER is destabilized, and clock time is delayed. Alternatively, if TIM
      is degraded during the later part of the night, after peak accumulation, clock
      time advances. Current models state that the effect of a light pulse depends on
      the state of the PER:TIM oscillation, which turns on the changing levels of TIM.
      However, previous studies have shown that light:dark (LD) regimes mimicking
      seasonal changes cause behavioral adjustments while altering clock gene
      expression. This should be reflected in the adjustment of PER and TIM dynamics.
      We manipulated LD cycles to assess the effects of altered day length on PER and
      TIM dynamics in clock cells within the central brain as well as light-induced
      resetting of locomotor rhythms.

PMID- 15028220
TI  - Entrainment dissociates transcription and translation of a circadian clock gene
      in neurospora.
AB  - Circadian systems coordinate the daily sequence of events in cells, tissues, and
      organisms. In constant conditions, the biological clock oscillates with its
      endogenous period, whereas it is synchronized to the 24 hr light:dark cycle in
      nature. Here, we investigate light entrainment of Neurospora crassa to
      photoperiods that mimic seasonal changes. Clock gene (frequency, or frq) RNA
      levels directly reflect the light environment in all photoperiods, whereas the
      FRQ protein follows neither RNA levels nor light transitions. Induction of frq
      RNA and protein can be dissociated by as much as 6 hr, depending on photoperiod.
      The phase of entrainment at the physiological level (e.g., asexual spore
      development) correlates with FRQ protein. Thus, a dissociation of transcription,
      translation, and protein stability is fundamental to circadian entrainment of
      Neurospora. Our findings suggest that simple feedback models are insufficient to
      explain the molecular circadian mechanisms under entrained conditions and that
      clock control of light input pathways involves posttranscriptional regulation.
      The regulators mediating the dissociation between RNA and protein levels are
      still unknown and will be the key to understanding both circadian timing at the
      molecular level and how the clock exerts control over many cellular processes.

PMID- 15028222
TI  - Chill wind over Antarctic biodiversity.

PMID- 15028226
TI  - W. Ford Doolittle.

PMID- 15028221
TI  - CNK2 couples NGF signal propagation to multiple regulatory cascades driving cell
      differentiation.
AB  - Neuronal precursor cells have the capacity to engage the Raf-MEK-ERK signal
      module to drive either of two distinctly different regulatory programs,
      proliferation and differentiation. This is, at least in part, a consequence of
      stimulus-specific shaping of the kinase cascade response. For example, the
      mitogen EGF induces a transient ERK activation, whereas the neurotrophin NGF
      induces prolonged ERK activation. Here we define a novel component of the
      regulatory machinery contributing to the selective integration of MAP kinase
      signaling with discrete biological responses. We show that the scaffold/adaptor
      protein CNK2/MAGUIN-1 is required for NGF- but not EGF-induced ERK activation. In
      addition, CNK2 makes a separate, essential contribution to the coupling of NGF
      signaling to membrane/cytoskeletal remodeling. We propose that CNK2 integrates
      multiple regulatory pathways that must function in concert to drive an
      appropriate biological response to external stimuli.

PMID- 15028227
TI  - Systems neurobiology without backbones.

PMID- 15028228
TI  - Systems biology.

PMID- 15028229
TI  - Medicago truncatula.

PMID- 15028230
TI  - 'Spalog' and 'sequelog': neutral terms for spatial and sequence similarity.

PMID- 15028231
TI  - Evidence for a Hox14 paralog group in vertebrates.

PMID- 15028232
TI  - Drug targets: turning the channel (on) for sedation.
AB  - Genetic techniques have recently implicated two different ion channels as
      critical molecular targets for the sedative action of ethanol and intravenous
      anesthetics. In each case, the target is hyperactivated by the drug.

PMID- 15028233
TI  - Membrane fusion: caught in a trap.
AB  - SNAREs are small coiled-coil proteins required for specific membrane fusion
      events in eukaryotic cells. Recent evidence points to the existence of an
      inhibitory class of SNAREs, i-SNAREs, which prevent incorrect fusions from
      occurring, adding a further layer of regulation to the process of membrane
      docking and fusion.

PMID- 15028234
TI  - Behavioral plasticity: modulation occurs across time.
AB  - Modulatory inputs alter neural network activity, which, for instance, helps
      explain why mood affects cognition. Some neurons modulate their own networks.
      This 'intrinsic' modulatory feedback implies that a network's history could
      partially determine its present activity.

PMID- 15028235
TI  - Pathogens: bacterial needles ruled to length and specificity.
AB  - The mechanisms behind length regulation of prokaryotic surface structures has
      long eluded microbiologists. The recent identification of a protein that
      functions as a 'molecular ruler' to determine the physical length of a bacterial
      extracellular needle advances our understanding of surface structure biogenesis.

PMID- 15028236
TI  - Eye movements: keeping vision stable.
AB  - A long-standing problem for vision researchers is how our perception of the world
      remains stable despite the continual motion of our eyes. Three recent studies
      begin to shed light on how the visual system suppresses the motion generated by
      these eye movements.

PMID- 15028237
TI  - Plant RNAi: How a viral silencing suppressor inactivates siRNA.
AB  - The three-dimensional structure of an siRNA bound to the tombusvirus p19 protein-
      a suppressor of gene silencing--provides a first glimpse into how plant viruses
      can defeat their host's anti-viral RNAi defenses.

PMID- 15028238
TI  - Epigenetics: imprinting in plants and mammals--the same but different?
AB  - Plants and animals both exhibit parental imprinting, but do they control it the
      same way? Recent studies show that in Arabidopsis, as in mammals, imprinted
      alleles are subject to DNA methylation--but, surprisingly, the default state is
      silence rather than activity.

PMID- 15028239
TI  - Frontal cortex: goal-relatedness and the cortical motor system.
AB  - A recent study has shown that prolonged electrical stimulation of the ventral
      premotor cortex can evoke complex defensive movements. Moreover, neurons in this
      region show activity correlated with the vigour of an induced defensive reaction.
      These results support the idea that this cortical region encodes goal-related
      actions.

PMID- 15028240
TI  - Chaperones: inserting beta barrels into membranes.
AB  - How beta-barrel proteins are inserted into cellular membranes is poorly
      understood. New work has identified a sorting and assembly machinery that
      chaperones beta-barrels into the mitochondrial outer membrane and is
      evolutionarily conserved from bacteria to man.

PMID- 15028241
TI  - Hox genes: Did the vertebrate ancestor have a Hox14?
AB  - A new group of vertebrate Hox genes, Hox14, has been discovered in two fish, the
      horn shark and the coelacanth. This reveals that ancestrally all jawed
      vertebrates may have had fourteen Hox paralogue groups rather than the thirteen
      groups of mammals and teleost fish.

PMID- 15028242
TI  - Synthesis and biological evaluation of the binding of dopamine D2/D3 receptor
      agonist, (R,S)-5-hydroxy-2-(N-propyl-N-(5'-(18)F-fluoropentyl)aminotetralin
      ((18)F-5-OH-FPPAT) in rodents and nonhuman primates.
AB  - We have synthesized a new fluorinated dopamine D2 receptor agonist, (R,S)-2-(N
      propyl-N-5'-fluoropentyl)amino-5-hydroxytetralin (5-OH-FPPAT). The radiosynthesis
      of the fluorine-18 analog, (18)F-5-OH-FPPAT was achieved in decay corrected
      yields of 10 to 15% in specific activities of approx. 1.5 to 2 Ci/micromol. In
      vitro binding and autoradiographic studies of this new radiotracer have been
      investigated. Using rat striatal homogenate binding assay, 5-OH-FPPAT exhibited
      an affinity of IC(50) = 6.95 nM. The octanol-buffer partition coefficient, Log P
      was found to be 1.60. In vitro autoradiographs in rat brain slices with (18)F-5
      OH-FPPAT revealed selective binding to the dopaminergic regions in the striata
      that was displaceable by sulpiride. This selective binding to the striata was
      also removed in the presence of the GTP analog, 5'-guanylylimidodiphosphate,
      indicative of predominant binding of (18)F-5-OH-FPPAT to the high-affinity state
      of the D2 receptor. In vivo regional distribution of (18)F-5-OH-FPPAT in rat
      brains revealed selective localization in the striata with striata/cortex ratio
      of 1.5 and striata/cerebellum ratio of 1.8 to 2.0. The binding of (18)F-5-OH
      FPPAT in the striata was reduced upon pretreatment with the antagonist,
      risperidone and the agonist, PPHT. A PET study in rhesus monkeys showed selective
      localization of (18)F-5-OH-FPPAT in the striata and the ratio between striata and
      cerebellum approached approximately 2 at 40 min post-injection.

PMID- 15028243
TI  - Comparison of the binding of the irreversible monoamine oxidase tracers,
      [(11)C]clorgyline and [(11)C]l-deprenyl in brain and peripheral organs in humans.
AB  - The monoamine oxidase A and B (MAO A and B) radiotracers [(11)C]clorgyline (CLG)
      and [(11)C]L-deprenyl (DEP) and their deuterium labeled counterparts (CLG-D and
      DEP-D) were compared to determine whether their distribution and kinetics in
      humans are consistent with their physical, chemical and pharmacological
      properties and the reported ratios of MAO A:MAO B in post-mortem human tissues.
      Irreversible binding was consistently higher for DEP in brain, heart, kidneys and
      spleen but not lung where CLG >DEP and not in thyroid where there is no DEP
      binding. The generally higher DEP binding is consistent with its higher enzyme
      affinity and larger free fraction in plasma while differences in regional
      distribution for CLG and DEP in brain, heart, thyroid and lungs are consistent
      with different relative ratios of MAO A and B in humans.

PMID- 15028244
TI  - In vivo evaluation of new carfentanil-based radioligands for the mu opiate
      receptor.
AB  - Eight derivatives of [(11)C]carfentanil were evaluated as alternative mu opioid
      receptor radioligands with the potential for lower pharmacological activity,
      faster pharmacokinetics, and/or lower non-specific binding. Derivatives with aryl
      ring substituents or alkyl group substitutions were prepared in carbon-11 labeled
      form and examined for initial brain uptake and regional brain tissue
      pharmacokinetics in mouse brain. Promising derivatives with chloro, methoxy and
      methyl substituents on one aryl ring were then evaluated for specific binding in
      an equilibrium infusion rat model of regional brain distributions. Although no
      derivatives were identified with improved pharmacokinetics or lower non-specific
      binding, several derivatives show acceptable in vivo specific binding properties
      and may deserve further evaluation as less potent and thus safer compounds for in
      vivo imaging studies.

PMID- 15028245
TI  - New alpha(1)-adrenoceptor antagonists derived from the antipsychotic sertindole -
      carbon-11 labelling and pet examination of brain uptake in the cynomolgus monkey.
AB  - Central alpha(1)-adrenergic receptors are potential targets for recently
      developed antipsychotic drugs. Two new 11C labeled potent and selective alpha(1)
      adrenoceptor antagonists, 1- [2- [4-[1-(4-fluorophenyl)-5-(2-[(11)C]methyl
      tetrazol-5-yl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-imidazolidin-2-one ([(11)C]2)
      and 1- [2- [4-[1-(4-fluorophenyl)-5-(1-[(11)C]methyl-(1,2,3-triazol-4-yl)-1H
      indol-3-yl]-1-piperidinyl]ethyl]-imidazolidin-2-one ([(11)C]3) were prepared and
      evaluated for imaging of central alpha(1)-adrenergic receptors in the cynomolgus
      monkey brain. For both compounds, the total brain radioactivity was only about
      0.6% of the radioactivity injected i.v. There was no evident binding in regions
      known to contain alpha(1)-adrenoceptors. This observation suggests that the
      affinity of the radioligands in primates in vivo is not sufficient to provide a
      signal for specific binding that can be differentiated from the background. In
      addition, active efflux by P-glycoprotein may be responsible for the low total
      brain-uptake of the two radioligands. Both compounds showed a highly polarised
      and verapamile sensitive transport across monolayers of Caco-2 cells. The total
      brain-uptake of [(3)H]2 was 6 times higher in mdr1a(-/-) knock-out mice lacking
      the gene encoding P-glycoprotein compared to wild type mice. Pretreatment of one
      monkey with Cyclosporin A (15 mg/kg) resulted in 40% higher brain uptake for
      [(11)C]3 when compared with baseline. These observations support the view that
      efflux by P-glycoprotein can be of quantitative importance for the total brain
      uptake of some PET radioligands.

PMID- 15028246
TI  - Targeting of gelatinase activity with a radiolabeled cyclic HWGF peptide.
AB  - Matrix metalloproteinases (MMPs) are a family of proteinases that play an
      important role in cancer as well as in numerous diseases. In this article, we
      describe the labeling of a phage display selected cyclic decapeptide containing
      the HWGF (histidine-tryptophane-glycine-phenylalanine) sequence to target MMP-2
      and MMP-9. To evaluate the ability of this labeled peptide to monitor non
      invasively MMP-2 and MMP-9 activity, in vitro studies, biodistribution,
      competition studies and plasma metabolites analyses in Lewis Lung cancer tumor
      bearing mice were performed.

PMID- 15028247
TI  - Human/murine chimeric 81C6 F(ab')(2) fragment: preclinical evaluation of a
      potential construct for the targeted radiotherapy of malignant glioma.
AB  - We have obtained encouraging responses in recent Phase I studies evaluating
      (131)I-labeled human/murine chimeric 81C6 anti-tenascin monoclonal antibody
      (ch81C6) administered into surgically-created tumor resection cavities in brain
      tumor patients. However, because the blood clearance is slow, hematologic
      toxicity has been higher than seen with murine 81C6 (mu81C6). In the current
      study, a series of paired-label experiments were performed in athymic mice
      bearing subcutaneous D-245 MG human glioma xenografts to compare the
      biodistribution of the fragment ch81C6 F(ab')(2) labeled using Iodogen to a)
      intact ch81C6, b) mu81C6, and c) ch81C6 F(ab')(2) labeled using N-succinimidyl 3
      [(131)I]iodobenzoate. Tumor retention of radioiodine activity for the F(ab')(2)
      fragment was comparable to that for intact ch81C6 for the first 24 h and to that
      for mu81C6 for the first 48 h; as expected, blood and other normal tissue levels
      declined faster for ch81C6 F(ab')(2.) Radiation dosimetry calculations suggest
      that (131)I-labeled ch81C6 F(ab')(2) may warrant further evaluation as a targeted
      radiotherapeutic for the treatment of brain tumors.

PMID- 15028249
TI  - Characterization of uptake of 3-[(131)I]iodo-alpha-methyl-L-tyrosine in human
      monocyte-macrophages.
AB  - The radiopharmaceutical 3-[(123)I]iodo-alpha-methyl-L-tyrosine ([(123)I]IMT) can
      be used to study amino acid transport by single-photon emission tomography
      (SPET). In order to evaluate the potential contribution of [(123)I]IMT
      accumulation in macrophages to overall uptake values measured in neoplastic
      lesions in vivo, we studied the mechanisms governing the uptake of this tracer by
      human monocyte-macrophages (HMMs). HMMs were isolated from healthy human donors
      by density gradient centrifugation using Ficoll methods. The human glioblastoma
      cell line U-138 MG (GLIOs) was obtained from American Type Culture Collection.
      Using multiwell dishes, cells were incubated in phosphate buffered saline or an
      equivalent sodium-free buffer with 50 kBq [(131)I]IMT per well. [(131)I]IMT
      uptake was quantified as % injected dose per mass of protein within each culture
      well. Several natural and artificial amino acids were used as potential transport
      inhibitors both in sodium-containing and sodium-free medium. [(131)I]IMT uptake
      was significantly lower in HMMs than in GLIOs (34 +/- 2 %/mg (40 min) vs. 507 +/-
      50 %/mg at 30 minutes of incubation, respectively; p < 0.01). Endotoxin (LPS)
      significantly increased [(131)I]IMT uptake in HMMs by a factor of approximately
      2. Transport into non-stimulated HMMs was exclusively sodium-independent and
      inhibitable by BCH, but not by MeAIB. Under LPS stimulation exclusively, there
      was in addition also a sodium-dependent inhibition of [(131)I]IMT uptake by L
      arginine and MeAIB, albeit to a minor extent. [(131)I]IMT accumulation in HMMs is
      mainly mediated via an L-like amino acid transport system and increases on HMM
      activation by LPS. LPS may induce an additional Na(+)-dependent transport system
      in HMMs. The considerably lower [(131)I]IMT uptake in HMMs than in GLIOs suggests
      that overall uptake values of this tracer measured by SPET in tumors are not
      significantly affected by [(123)I]IMT accumulation in macrophages within the
      neoplastic lesion.

PMID- 15028248
TI  - Systemic radioimmunotherapy using a monoclonal antibody, anti-Tac directed toward
      the alpha subunit of the IL-2 receptor armed with the alpha-emitting
      radionuclides (212)Bi or (211)At.
AB  - To exploit the fact that IL-2 receptors are expressed by T-cells responding to
      foreign antigens but not by resting T-cells, humanized anti-Tac (HAT) armed with
      alpha-emitting radionuclides (212)Bi and (211)At was evaluated in a cynomolgus
      cardiac allograft model. Control graft survival was 8.2+/- 0.5 days compared with
      14.0+/-1.3 days (p<0.01) survival for monkeys treated with (212)Bi labeled HAT
      and 26.7+/-2.4 days survival (p<0.001 versus controls) with (211)At labeled HAT.
      Thus, (211)At labeled HAT may have application in organ transplantation and in
      treatment of IL-2 receptor expressing T-cell leukemia.

PMID- 15028250
TI  - Biokinetics of (99m)Tc-UBI 29-41 in humans.
AB  - Antimicrobial peptides have been proposed as new agents to distinguish between
      bacterial infections and sterile inflammatory processes. (99m)Tc-UBI labeled by a
      direct method has shown high in vitro and in vivo stability, specific uptake at
      the site of infection, rapid background clearance, minimal accumulation in non
      target tissues and rapid detection of infection sites in mice. The aim of this
      study was to establish a (99m)Tc-UBI biokinetic model and evaluate its
      feasibility as an infection imaging agent in humans. Whole-body images from 6
      children with suspected bone infection were acquired at 1, 30, 120, 240 min and
      24 h after (99m)Tc-UBI administration. Regions of interest (ROIs) were drawn
      around source organs (heart, liver, kidneys and bladder) on each time frame. The
      same set of ROIs was used for all 6 scans and the cpm of each ROI were converted
      to activity using the conjugate view counting method. Counts were corrected by
      physical decay and by the background correction factor derived from preclinical
      phantom studies. The image sequence was used to extrapolate (99m)Tc-UBI time
      activity curves in each organ and calculate the cumulated activity (A). Urine
      samples were used to obtain the cumulative percent of injected activity (% I.A.)
      versus time renal elimination. The absorbed dose in organs was evaluated
      according to the general equation described in the MIRD formalism. In addition,
      (67)Ga-citrate images were obtained from all the patients and used as a control.
      Biokinetic data showed a fast blood clearance with a mean residence time of 0.52
      h. Approximately 85% of the injected activity was eliminated by renal clearance
      24 h after (99m)Tc-UBI administration. Images showed minimal accumulation in non
      target tissues with an average target/non-target ratio of 2.18 +/- 0.74 in
      positive lesions at 2 h. All infection positive(99m)Tc-UBI images were in
      agreement with those obtained with (67)Ga-citrate. The mean radiation absorbed
      dose calculated was 0.13 mGy/MBq for kidneys and the effective dose was 4.34 x
      10(-3)mSv/MBq.

PMID- 15028251
TI  - Modification of low-density lipoprotein by different radioiodination methods.
AB  - Scintigraphic imaging of radiolabeled low-density lipoproteins (LDL) is an
      interesting tool for the understanding of its role in pathomechanism of
      atherosclerosis. Metabolism of native LDL shows quite different pattern and
      kinetics as compared to that of modified LDL which is not mediated by classical
      LDL-receptor and accumulates in atherosclerotic lesions to form lipid-laden foam
      cells. Therefore we were interested whether radiolabelling of LDL induces
      structural modifications. We performed the iodine labeling of LDL for
      scintigraphic imaging of atherosclerosis by three different methods: chloramine-T
      (A), iodine monochloride (B) and iodogen (C). The highest radiolabelling yield of
      (125)I was obtained by the iodogen method (75.44+/-13.52%) and the lowest
      (49.01+/-12.74%) by iodine monochloride. Chloramine T showed a labeling yield of
      62.82+/-6.17%. The stability of the tracer was very high with all the methods,
      persisting up to 6 h (98.83+/-1.2% - 91.38+/-4.7%, 15 min vs 6 h after labeling).
      For the first time we not only investigated the influence of radiolabelling on
      relative electrophoretic mobility (REM), but also various oxidation parameters
      such as baseline dienes (BD), thiobarbituric acid reactive substances (TBARS),
      endogenous peroxides (POX) and oxidation resistance in the copper-mediated
      oxidation system (expressed as lag-time) were measured. Furthermore, oxidation-
      derived fragmentation of the lipoproteins was examined with SDS-PAGE
      electrophoresis. Data are expressed as % change compared to native LDL before
      radiolabeling. BD were reduced by 32% using the method (A), but increased by 33%
      and 47% with the monochloride (B) and iodogen method (C), respectively. The
      effect on lag-time was comparable for all the three methods, ranging from 25 to
      36% reduction in lag-time. TBARS were strongly increased 5-7 fold by all the
      methods. REM was changed by all three methods. While by methods A and C we have
      found a moderate increase in REM by 1.75 and 2.0 fold, respectively, and no
      fragmentation of Apo B was observed, in contrast by method B a dramatic 4.5 fold
      increase in REM was found. SDS-PAGE-electrophoresis showed strong fragmentation
      of the apoB only for method B. We conclude, that iodine labeling of LDL induces
      significant modification of the molecule. Once modified, LDL no longer reflects
      the native molecule, exhibiting altered functional properties. Using radiolabeled
      LDL this fact should be considered.

PMID- 15028252
TI  - Camptothecin: current perspectives.
AB  - This review provides a detailed discussion of recent advances in the medicinal
      chemistry of camptothecin, a potent antitumor antibiotic. Two camptothecin
      analogues are presently approved for use in the clinic as antitumor agents and
      several others are in clinical trials. Camptothecin possesses a novel mechanism
      of action involving the inhibition of DNA relaxation by DNA topoisomerase I, and
      more specifically the stabilization of a covalent binary complex formed between
      topoisomerase I and DNA. This review summarizes the current status of studies of
      the mechanism of action of camptothecin, including topoisomerase I inhibition and
      additional cellular responses. Modern synthetic approaches to camptothecin and
      several of the semi-synthetic methods are also discussed. Finally, a systematic
      evaluation of novel and important analogues of camptothecin and their
      contribution to the current structure-activity profile are considered.

PMID- 15028253
TI  - First pharmacophoric hypothesis for T-type calcium channel blockers.
AB  - A three-dimensional pharmacophore model was developed for T-type calcium channel
      blockers in order to map common structural features of highly active compounds by
      using CATALYST program. In the absence of three dimensional structure based
      information like binding mode and unavailability of more number of specific T
      type calcium channel blockers, this hypothesis which consists of three
      hydrophobic regions, one hydrogen bond acceptor and one positive ionizable
      regions will act as a valuable tool in designing new ligands. Further more after
      the withdrawal of mibefradil, the first marketed T-type calcium channel blocker,
      due to the drug-drug interactions, there is an urgent need for more work in this
      interest.

PMID- 15028254
TI  - 3D QSAR studies on T-type calcium channel blockers using CoMFA and CoMSIA.
AB  - Comparative molecular field analysis (CoMFA) and comparative molecular similarity
      indices analysis (CoMSIA) were performed on a series of isoxazolyl compounds as a
      potent T-type calcium channel blockers. A set of 24 structurally similar
      compounds served to establish the model. Four different conformations of the most
      active compound were used as template structures for the alignment, three of
      which were obtained from Catalyst pharmacophore modeling and one by using SYBYL
      random search option. All CoMFA and CoMSIA models gave cross-validated r(2)
      (q(2)) value of more than 0.5 and conventional r(2) value of more than 0.85. The
      predictive ability of the models was validated by an external test set of 10
      compounds, which gave satisfactory pred r(2) values ranging from 0.577 to 0.866
      for all models. Best predictions were obtained with CoMFA std model of Conformer
      no: 3 alignment (q(2)=0.756, r(2)=0.963), giving predictive r(2) value of 0.866
      for the test set. CoMFA and CoMSIA contour maps were used to analyze the
      structural features of the ligands accounting for the activity in terms of
      positively contributing physicochemical properties: steric, electrostatic,
      hydrophobic and hydrogen bonding fields.

PMID- 15028255
TI  - Synthesis and cytotoxicity evaluation of 6,11-dihydro-pyridazo- and 6,11-dihydro
      pyrido[2,3-b]phenazine-6,11-diones.
AB  - The 6,11-dihydro-pyridazo[2,3-b]phenazine-6,11-dione and 6,11-dihydro-pyrido[2,3
      b]phenazine-6,11-dione derivatives were synthesized from 6,7-dichloro-5,8
      phthalazinedione and 6,7-dichloro-5,8-quinolinedione, respectively, producing a
      series of new anticancer drugs. The cytotoxic activities of the prepared
      compounds were evaluated by a SRB (Sulforhodamine B) assay against the following
      tumor cell lines: A459 (human lung), SK-OV-3 (human ovarian), SK-MEL-2 (human
      melanoma), XF498 (human CNS), and HCT 15 (human colon). Almost all the
      derivatives of the 6,11-dihydro-pyridazo[2[,3-b]phenazine-6,11-dione and 6,11
      dihydro-pyrido[2,3-b]phenazine-6,11-dione, tetracyclic heteroquinone analogues
      with four or three nitrogen atoms, exhibited excellent cytotoxicity on almost all
      the human tumor cell lines tested. Specifically, 6,11-dihydro-pyridazo[2,3
      b]phenazine-6,11-dione (4a) exhibited potent activity against all the tumor cell
      lines, and in particular, its cytotoxic effect against HCT 15 (ED(50)=0.004
      microg/mL) was 25 times greater than that of doxorubicin (ED(50)=0.093
      microg/mL).

PMID- 15028256
TI  - Computational studies of COX-2 inhibitors: 3D-QSAR and docking.
AB  - The 3D-QSAR (three-dimensional quantitative structure-activity relationships)
      studies for 88 selective COX-2 (cyclooxygenase-2) inhibitors belonging to three
      chemical classes (triaryl rings, diaryl cycloalkanopyrazoles, and diphenyl
      hydrazides) were conducted using comparative molecular field analysis (CoMFA) and
      comparative molecular similarity indices analysis (CoMSIA). Partial least squares
      analysis produced statistically significant models with q(2) values of 0.84 and
      0.79 for CoMFA and CoMSIA, respectively. The binding energies calculated from
      flexible docking were correlated with inhibitory activities by the least-squares
      fit method. The three chemical classes of inhibitors showed reasonable internal
      predictability (r(2)=0.51, 0.49, and 0.54), but the sulfonyl-containing
      inhibitors demonstrated distinctively low binding energy compared to the others.
      The electrostatic interaction energy between the Arg513 of the COX-2 active site
      and sulfonyl group of the triaryl rings seemed to have the responsibility for
      difference in binding energy. Comparative binding energy (COMBINE) analyses gave
      q(2) values of 0.64, 0.63, and 0.50 for triaryl rings, diaryl
      cycloalkanopyrazoles, and diphenyl hydrazides, respectively. In this COMBINE
      model, some protein residues were highlighted as particularly important for
      inhibitory activity. The combination of ligand-based and structure-based models
      provided an improved understanding in the interaction between the three chemical
      classes and the COX-2.

PMID- 15028257
TI  - 3-chloropropanoic acid (UMB66): a ligand for the gamma-hydroxybutyric acid
      receptor lacking a 4-hydroxyl group.
AB  - Gamma-Hydroxybutyric acid (GHB) has gained in notoriety in recent years due to
      its association with sexual assaults. GHB is an endogenous ligand for GHB
      receptors, but its complete pharmacological mechanism of action in vivo remains
      unclear due to apparent GABAergic components. It has been proposed that the
      hydroxyl group in the 4-position acts as a hydrogen bond donor to the GHB
      receptor. Herein we show that 3-chloropropanoic acid possesses significant
      affinity for the GHB receptor, has no affinity for GABA receptors, and cannot
      undergo metabolism to GABAergic compounds. UMB66 is thus a selective agent for
      the study of GHB in vivo. These results, in combination with data from quantum
      mechanical calculations, suggest that the hydroxyl group of GHB actually acts as
      a hydrogen bond acceptor in contrast to the currently accepted model. This
      finding is anticipated to facilitate the rational design of novel agents with
      selectivity for GHB receptors that may be used to elucidate the mechanism of
      action of this common drug of abuse.

PMID- 15028258
TI  - Meta-iodobenzylguanidine derivatives containing a second guanidine moiety.
AB  - Radioiodinated meta-iodobenzylguanidine (MIBG) is used in the diagnosis and
      therapy of various neuroendocrine tumors. To investigate whether an additional
      guanidine function in the structure of MIBG will yield analogues that may
      potentially enhance tumor-to-target ratios, two derivatives-one with a guanidine
      moiety and another with a guanidinomethyl group at the 4-position of MIBG-were
      prepared. In the absence of any uptake-1 inhibiting conditions, the uptake of 4
      guanidinomethyl-3-[(131)I]iodobenzylguanidine ([(131)I]GMIBG) by SK-N-SH cells in
      vitro was 1.7+/-0.1% of input counts, compared to a value of 40.3+/-1.4% for
      [(125)I[MIBG suggesting that guanidinomethyl group at the 4-position negated the
      biological properties of MIBG. On the other hand, 4-guanidino-3
      [(131)I]iodobenzylguanidine ([(131)I]GIBG) had an uptake (5.6+/-0.3%) that was 12
      13% that of [(125)I]MIBG (46.1+/-2.7%), and the ratio of uptake by control over
      DMI-treated (nonspecific) cultures was higher for [(131)I]GIBG (20.9+/-0.3) than
      [(125)I]MIBG itself (15.0+/-2.7). The exocytosis of [(131)I]GIBG and [(125)I]MIBG
      from SK-N-SH cells was similar. The uptake of [(131)I]GIBG in the mouse target
      tissues, heart and adrenals, as well as in a number of other tissues was about
      half that of [(125)I]MIBG. These results suggest that substitution of guanidine
      functions, especially a guanidinomethyl group, in MIBG structure may not be
      advantageous.

PMID- 15028259
TI  - Determination of 3(1)-stereochemistry in synthetic bacteriochlorophyll-d
      homologues and self-aggregation of their zinc complexes.
AB  - Zinc complex of methyl 3(1)-octadecyl-bacteriopheophorbide-d was prepared from
      modification of naturally occurring chlorophyll-a. The 3(1)-epimerically pure
      samples were obtained by HPLC separation and their stereochemistry including the
      absolute configuration at the secondary alcoholic 3(1)-position was determined by
      combination of esterification to methoxy(trifluoromethyl)phenylacetate and NMR
      spectroscopy (Mosher's method). Both the epimers were monomeric in a polar
      organic solvent and self-aggregated in a non-polar solvent to give oligomers as
      well as dimers possessing red-shifted visible absorption bands. Visible spectra
      of the non-polar organic solutions were dependent upon the 3(1)-chirality and
      such a diastereoselective control on the self-aggregation led to the formation of
      self-aggregates with different supramolecular structures.

PMID- 15028260
TI  - Novel quinolinequinone antitumor agents: structure-metabolism studies with
      NAD(P)H:quinone oxidoreductase (NQO1).
AB  - A series of quinolinequinones bearing various substituents has been synthesized,
      and the effects of substituents on the metabolism of the quinones by recombinant
      human NAD(P)H:quinone oxidoreductase (hNQO1) was studied. A range of
      quinolinequinones were selected for study, and were specifically designed to
      probe the effects of aryl substituents at C-2. A range of 28 quinolinequinones 2
      29 was prepared using three general strategies: the palladium(0) catalyzed
      coupling of 2-chloroquinolines, the classical Friedlander synthesis and the
      double-Vilsmeier reaction of acetanilides. One example of an isoquinolinequinone
      30 was also prepared, and the reduction potentials of the quinones were measured
      by cyclic voltammetry. For simple substituents R(2) at the quinoline 2-position,
      the rates of quinone metabolism by hNQO1 decrease for R(2)=Cl>H approximately
      Me>Ph. For aromatic substituents, the rate of reduction decreases dramatically
      for R(2)=Ph>1-naphthyl>2-naphthyl>4-biphenyl. Compounds containing a pyridine
      substituent are the best substrates, and the rates decrease as R(2)=4-pyridyl>3
      pyridyl>2-pyridyl>4-methyl-2-pyridyl>5-methyl-2-pyridyl. The toxicity toward
      human colon carcinoma cells with either no detectable activity (H596 or BE-WT) or
      high NQO1 activity (H460 or BE-NQ) was also studied in representative quinones.
      Quinones that are good substrates for hNQO1 are more toxic to the NQO1 containing
      or expressing cell lines (H460 and BE-NQ) than the NQO1 deficient cell lines
      (H596 and BE-WT).

PMID- 15028261
TI  - Design, synthesis and in vitro antitumor activity of new trans 2-[2
      (heteroaryl)vinyl]-1,3-dimethylimidazolium iodides.
AB  - The design, the synthesis, and the in vitro antitumor activities of trans 2-[2
      (heteroaryl)vinyl]-1,3-dimethylimidazolium iodides versus MCF7 (human mammary
      carcinoma) and LNCap (prostate carcinoma) cell lines are reported. The design
      indicates trans 2-[2-[5-(2-chlorophenyl)furan-2-yl]vinyl]-1, 3
      dimethylimidazolium iodide 5 and trans 2-[2-[5-(4-bromophenyl)furan-2-yl]vinyl]
      1, 3-dimethylimidazolium iodide 6 as highly active compounds in the series. The
      synthesis of the above new derivatives and in vitro antitumor tests, confirm
      their significant antiproliferative and cytotoxic activities.

PMID- 15028263
TI  - SSR182289A, a selective and potent orally active thrombin inhibitor.
AB  - SSR182289A 1 is the result of a rational optimisation process leading to an
      orally active thrombin inhibitor. The structure incorporates an original 2
      (acetylamino)-[1,1'-biphenyl]-3-sulfonyl N-terminal motif, a central l-Arg
      surrogate carrying a weakly basic 3-amino-pyridine, and an unusual 4
      difluoropiperidine at the C-terminus. Its synthesis is convergent and palladium
      catalysis has been employed for the construction of the key C-C bonds: Suzuki
      coupling for the bis-aryl fragment and Sonogashira reaction for the delta- bond
      of the central amino-acid chain. The compound is a potent inhibitor of thrombin's
      activities in vitro and demonstrates potent oral anti-thrombotic potencies in
      three rat models of thrombosis. The observed in vitro potency could be
      rationalized through the examination of the interactions within the SSR182289A 1 
      thrombin crystal structure. SSR182289A 1, has been therefore selected for
      further development.

PMID- 15028262
TI  - Topoisomerase I-mediated DNA cleavage as a guide to the development of antitumor
      agents derived from the marine alkaloid lamellarin D: triester derivatives
      incorporating amino acid residues.
AB  - The marine alkaloid lamellarin D (LAM-D) has been recently characterized as a
      potent poison of human topoisomerase I endowed with remarkable cytotoxic
      activities against tumor cells. We report here the first structure-activity
      relationship study in the LAM-D series. Two groups of triester compounds
      incorporating various substituents on the three phenolic OH at positions 8, 14
      and 20 of 6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one pentacyclic
      planar chromophore typical of the parent alkaloid were tested as topoisomerase I
      inhibitors. The non-amino compounds in group A showed no activity against
      topoisomerase I and were essentially non cytotoxic. In sharp contrast, compounds
      in group B incorporating amino acid residues strongly promoted DNA cleavage by
      human topoisomerase I. LAM-D derivatives tri-substituted with leucine, valine,
      proline, phenylalanine or alanine residues, or a related amino side chain,
      stabilize topoisomerase I-DNA complexes. The DNA cleavage sites detected at T
      downward arrow G or C downward arrow G dinucleotides with these molecules were
      identical to that of LAM-D but slightly different from those seen with
      camptothecin which stimulates topoisomerase I-mediated cleavage at T downward
      arrow G only. In the DNA relaxation and cleavage assays, the corresponding Boc
      protected compounds and the analogues of the non-planar LAM-501 derivative
      lacking the 5-6 double bond in the quinoline B-ring showed no effect on
      topoisomerase I and were considerably less cytotoxic than the corresponding
      cationic compounds in the LAM-D series. The presence of positive charges on the
      molecules enhances DNA interaction but melting temperature studies indicate that
      DNA binding is not correlated with topoisomerase I inhibition or cytotoxicity.
      Cell growth inhibition by the 41 lamellarin derivatives was evaluated with a
      panel of tumor cells lines. With prostate (DU-145 and LN-CaP), ovarian (IGROV and
      IGROV-ET resistant to ecteinascidin-743) and colon (LoVo and LoVo-Dox cells
      resistant to doxorubicin) cancer cells (but not with HT29 colon carcinoma cells),
      the most cytotoxic compounds correspond to the most potent topoisomerase I
      poisons. The observed correlation between cytotoxicity and topoisomerase I
      inhibition strongly suggests that topoisomerase I-mediated DNA cleavage assays
      can be used as a guide to the development of superior analogues in this series.
      LAM-D is the lead compound of a new promising family of antitumor agents
      targeting topoisomerase I and the amino acid derivatives appear to be excellent
      candidates for a preclinical development.

PMID- 15028264
TI  - QSAR study on tadpole narcosis using PI index: a case of heterogenous set of
      compounds.
AB  - QSAR Study on Tadpole narcosis of heterogenous set of compounds has been carried
      out using a large set of distance-based topological indices, including logP as
      molecular descriptors. Excellent results are obtained in biparametric regression
      models. It was found that PI index, is superior to (0)chi,(2)chi and logP indices
      for modeling Tadpole narcosis.

PMID- 15028265
TI  - Inhibition of the complete set of mammalian secreted phospholipases A(2) by
      indole analogues: a structure-guided study.
AB  - Structure-guided design was employed in a search for potent and selective
      inhibitors of mammalian secreted phospholipases A(2) (sPLA(2)s). Using the X-ray
      structures of human groups IIA and X sPLA(2)s (hGIIA and hGX) as templates,
      homology structural models were made for the other human and mouse sPLA(2)s
      (hGIB, mGIB, mGIIA, mGIIC, hGIID, mGIID, hGIIE, mGIIE, hGIIF, mGIIF, hGV, mGV,
      and mGX). Me-Indoxam is a previously discovered indole analogue that binds
      tightly to many sPLA(2)s, and the X-ray structure of the hGX-Me-Indoxam complex
      was determined at a resolution of 2.0 A. Modeling suggests that the residues near
      the N(1)-substituent of Me-Indoxam vary significantly among the mammalian
      sPLA(2)s, and therefore a library of 83N(1)-variants was prepared by parallel
      synthesis. Several Me-Indoxam analogues bearing a 4-(2-oxy-ethanoic acid) side
      chain were potent inhibitors (IC(50) <0.05 microM) of hGIIA, mGIIA, mGIIC, hGIIE,
      mGIIE, hGV, and mGV, while they displayed intermediate potency (0.05-5 microM)
      against hGIB, mGIB, hGX, and mGX, and poorly inhibited (>5 microM) hGIID, mGIID,
      hGIIF, and mGIIF. Me-Indoxam analogues bearing a 5-(4-oxy-butanoic acid) side
      chain were generally less potent inhibitors. Although no compounds were found to
      be highly specific for a single human or mouse sPLA(2), combinations of Me
      Indoxam analogues were discovered that could be used to distinguish the action of
      various sPLA(2)s in cellular events. For example, Me-Indoxam and compound 5 are
      approximately 5-fold more potent on hGIIA than on hGV, and compound 21 is 10-fold
      more potent on hGV versus hGIIA.

PMID- 15028266
TI  - Mannich reaction: an approach for the synthesis of water soluble mulundocandin
      analogues.
AB  - Semisynthetic modifications at Hydroxy tyrosine (Htyr) unit of mulundocandin (1)
      were carried out to improve its aqueous solubility. A single step introduction of
      substituted aminomethyl groups at the ortho position(s) of phenolic hydroxyl of
      HTyr unit of mulundocandin has been achieved in 7-85% yield. The in vitro
      screening of Mannich products against Candida albicans and Aspergillus fumigatus,
      retained the in vivo activity of parent by oral and intraperitoneal route.
      Compound 20, showed significant improvement in activity over mulundocandin (1)
      and activity compares well with that of fluconazole.

PMID- 15028267
TI  - Synthesis and biological activity of 2-alkylated deoxyadenosine bisphosphate
      derivatives as P2Y(1) receptor antagonists.
AB  - A previous study around adenine nucleotides afforded the reference N(6)-methyl-2'
      deoxyadenosine-3',5'-bisphosphate (1a, MRS 2179) as a selective human P2Y(1)
      receptor antagonist (pA(2)=6.55+/-0.05) with antithrombotic properties. In the
      present paper, we have synthesized and tested in vitro various 2-substituted
      derivatives with the goal of exploring the 2-position binding region and
      developing more potent P2Y(1) receptor antagonists. Thus, we have adopted a novel
      and versatile chemical pathway using a palladium-catalyzed cross-coupling
      reaction with the 2-iodinated derivative 7 as a common intermediate for a very
      efficient synthesis of the 2-alkyl-N(6)-methyl-2'-deoxyadenosine-3',5'
      bisphosphate nucleotides 1e-i. The biological activity was evaluated through the
      ability of compounds to inhibit ADP-induced platelet aggregation, intracellular
      calcium rise and to displace the specific binding of [(33)P]2-MeSADP. 2-Ethyl and
      2-propyl groups appeared to be tolerated, whereas a bulky group or a C(3) linear
      substituent dramatically decreased potency of antagonists. The 2-ethynyl
      derivative 1h (pA(2)=7.54+/-0.10) was significantly more potent (10-fold) as an
      antagonist when compared to the reference 1a, revealing a potential electronic
      interaction highly favorable between triple bond orbitals and the P2Y(1) receptor
      at this position.

PMID- 15028268
TI  - Design and synthesis of DNA-intercalating 9-fluoren-beta-O-glycosides as
      potential IFN-inducers, and antiviral and cytostatic agents.
AB  - Novel 9-fluoren-beta-O-glycosides, designed as DNA-intercalating agents in
      structural correlation with antiviral tilorone and anticancer anthracyclines,
      have been prepared with yields in beta-anomers ranging between 25 and 63%. They
      have been screened for antiproliferative, immunostimulating and antiviral
      properties against HSV-1 and HSV-2 viruses. Compounds displaying significant
      antiviral activity against HSV-2 are acetylated 1 and deprotected 6 9-fluorenyl-O
      d-arabinopyranoses, whereas 9-fluorenyl-O-d-glucopyranose 3 is the most effective
      on HSV-1 replication, followed by 1 and 6. The conformational properties of these
      compounds have been evaluated by molecular modelling techniques.

PMID- 15028269
TI  - QSAR study on (13)C NMR chemical shifts on carbinol carbon atoms.
AB  - QSAR calculations of (13)C NMR chemical shifts (ppm, TMS=0) on carbinol carbon
      atoms have been attempted using a large set of distance based topological
      indices: Wiener (W)-, Szeged (Sz)-, PI (Padmakar-Ivan) and Connectivity ((m)chi,
      (m)chi(v)) indices. The regression analysis has shown that excellent results are
      obtained in multiparametric regression. The predictive power of the proposed
      models are discussed using cross-validated parameters.

PMID- 15028272
TI  - One- and two-dimensional solid-state magic angle spinning NMR studies on the
      hydration process of layered sodium disilicate SKS-6.
AB  - Three different kinds of silanols, which include isolated silanol, silanol I
      (with the hydroxyl proton bonded to an oxygen atom in the adjacent layer) and
      silanol II (with the hydroxyl proton bonded to the non-bridging oxygen at the
      same silicon atom), are generated during the hydration process of SKS-6 (delta
      Na2Si2O5). 1H-1H nuclear Overhauser enhancement spectroscopy reveals that the
      proton of silanol I has an effective chemical exchange or spin diffusion with the
      proton of hydrogen-bonded water, while the proton of silanol II is likely far
      away from the other proton-containing species. 29Si magic angle spinning, 1H-
      >29Si CP/MAS NMR and 1H-29Si phase-modulated Lee-Goldburg decoupled correlation
      experiments demonstrate that the local environments of the silicon sites in the
      final hydrated sample are mainly composed of Q2 [(SiO)2Si(OH)O(-)Na+], Q3
      [(SiO)3Si(OH) and (SiO)3SiO(-)Na+] and Q4 [Si(OSi)4] groups.

PMID- 15028270
TI  - Synthesis and biological evaluation of
      pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane derivatives as potential
      therapeutic agents in Parkinson's disease.
AB  - In previous studies, the polycyclic cage amine 8-benzylamino-8,11
      oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane (NGP1-01) and a number of its
      derivatives showed positive effects in neuroprotection studies with MPTP, in
      vivo. In view of these findings, we examined these compounds for their effects on
      [(3)H]dopamine ([(3)H]DA) release and uptake inhibition in murine striatal
      synaptosomes, as well as for inhibition of baboon liver monoamine oxidase (MAO)
      B. In order to assess specificity, initial experiments focused on compounds that
      blocked dopamine uptake without causing appreciable release (<40% at 100 microM)
      of the transmitter. NGP1-01 blocked the uptake of [(3)H]DA with an IC(50) of 57
      microM, while another compound, 8-phenylethyl-8,11
      oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane, blocked uptake at an IC(50)
      value of 23 microM. These values were comparable to that of another polycyclic
      cage amine, amantadine (IC(50); 82 micro), that is used in parkinsonian therapy.
      Structure-activity relationships of this series of compounds support the
      importance of geometric and steric, rather than electronic effects, in
      determining biological activity. MAO-B inhibition for this group was weak, with
      less than 50% inhibition at 300 microM for any of the compounds in the series.
      The present study suggests that blockage of the dopamine transporter may
      underlie, at least in part, their neuroprotective effects against MPTP-induced
      parkinsonism. These compounds may be considered as potential lead compounds for
      Parkinson's Disease therapy.

PMID- 15028273
TI  - The shape and information content of high-field solid-state proton NMR spectra of
      methyl groups.
AB  - The possible variation of the lineshape of the high-field 1H spectrum of methyl
      groups is explored by simulation and experiment. The spectrum of an isolated
      methyl group depends, apart from the orientation of the applied field B0 relative
      to the C3-axis of the group, on its rotational tunnel frequency vt and on its
      stochastic reorientation rate k. For quantitative analyses, the directional
      mobility of the C3-axis must also be taken into account. A distinct but
      frequently occurring case arises when the methyl groups come as pairs of
      magnetically equivalent close neighbours. For the experiments, single crystals of
      four compounds I-IV were grown that were isotopically substituted such that they
      contained protons only in the methyl positions. The crystal symmetry of all
      compounds I-IV allowed us to record spectra with all methyl groups being
      orientationally and otherwise equivalent. I, acetonitrile in deuterated
      hydroquinone, represents the case of a well-isolated methyl group with a "high"
      tunnel frequency vt. Its spectrum is (almost) independent of the temperature T.
      In II, monomethyl malonic acid, vt is comparable in size with the strength of the
      intramolecular dipolar H-H interaction. All seven theoretically expected lines in
      the 1H spectrum are clearly resolved in the spectra of II. vt can be inferred
      with an uncertainty of only +/- 300 Hz. vt(T) is found to possess a (flat)
      maximum near 40 K. Compound III, L-alanine, allows the study of the case of a
      methyl group with an extremely low, although nonzero tunnel frequency (vt
      approximately 3 kHz) while IV, dimethylglyoxime, represents the case of a close
      pair of equivalent methyl groups. Its spectrum reflects intriguing structural
      implications.

PMID- 15028271
TI  - Solid state and solution 43Ca NMR of calcium peroxides involved in the
      disproportionation of hydrogen peroxide by calcium hydroxide.
AB  - In order to get some insight into the mechanism of the disproportionation of
      hydrogen peroxide catalyzed by calcium hydroxide, 43Ca NMR spectra of enriched
      samples of calcium peroxides and of their precursors have been studied in both
      solution and solid state. This study demonstrates that no well-defined
      peroxidized calcium species are formed in solution, showing that the catalytic
      role of calcium is likely restricted to the solid state. Most of the calcium
      compounds that could be involved in the catalytic process have been investigated
      with solid state NMR. The shift and quadrupolar parameters of Ca(OH)2, CaO2.8H2O
      and CaO2.2H2O2 are reported for the first time. These parameters are different
      enough to allow the quantitative analysis of a complex mixture of these compounds
      by NMR.

PMID- 15028274
TI  - Electric field gradients in fluoride crystalline powders: correlation of NMR
      measurements with ab initio calculations.
AB  - Electric field gradients (EFG) of 23Na and 27Al in three model fluoride
      crystalline powders AlF3, Na3AlF6 and Na5Al3F14 were computed using the density
      functional based electronic structure code WIEN97 and compared to values derived
      from nuclear magnetic resonance (NMR). First, results of measurements of 23Na and
      27Al quadrupolar parameters in AlF3, Na3AlF6 and Na5Al3F14 were revisited by
      using high-resolution solid-state NMR. To determine chemical shifts and
      quadrupolar parameters with a high precision, the experimental procedure involved
      magic angle spinning, satellite transition spectroscopy and multi-quanta
      techniques applied to the quadrupolar nuclei together with a computed
      reconstruction of the NMR spectra. The large discrepancies which appear between
      previously published results in some cases, justify the use of ab initio
      calculations of the corresponding EFG using the WIEN97 code based on the known
      structural data of the crystalline phases. The agreement obtained between these
      calculations and the experimental results which is better than 10% in almost all
      cases supports the reliability of the present NMR investigations and of the
      crystallographic data.

PMID- 15028276
TI  - Confirming microarray data--is it really necessary?
AB  - The generation of corroborative data has become a commonly used approach for
      ensuring the veracity of microarray data. Indeed, the need to conduct
      corroborative studies has now become official editorial policy for at least 2
      journals, and several more are considering introducing such a policy. The issue
      of corroborating microarray data is a challenging one-there are good arguments
      for and against conducting such experiments. However, we believe that the
      introduction of a fixed requirement to corroborate microarray data, especially if
      adopted by more journals, is overly burdensome and may, in at least several
      applications of microarray technology, be inappropriate. We also believe that, in
      cases in which corroborative studies are deemed essential, a lack of clear
      guidance leaves researchers unclear as to what constitutes an acceptable
      corroborative study. Guidelines have already been outlined regarding the details
      of conducting microarray experiments. We propose that all stakeholders, including
      journal editorial boards, reviewers, and researchers, should undertake concerted
      and inclusive efforts to address properly and clarify the specific issue of
      corroborative data. In this article we highlight some of the thorny and vague
      areas for discussion surrounding this issue. We also report the results of a poll
      in which 76 life science journals were asked about their current or intended
      policies on the inclusion of corroborative studies in papers containing
      microarray data.

PMID- 15028275
TI  - CP dynamics of heterogeneous organic material: characterization of molecular
      domains in coals.
AB  - Simplified equations are used in common approaches to describe cross polarization
      (CP) dynamics of solids. The CP behavior may be modulated by several nuclei
      interactions and physicochemical sample properties. At high magnetic fields and
      spinning speeds, these modulations can obscure the results. To elucidate their
      impact on the CP behavior of natural organic materials variable contact time
      (VCT) experiments were acquired with a high temporal resolution for two coal
      samples. The measurements were distinctly influenced by interfering fluctuations.
      Conventional approaches showed insufficient flexibility in terms of degrees of
      freedom to calculate the CP dynamics. The use of an original fundamental equation
      as model resulted in sufficient flexibility for such heterogeneous systems. The
      best results were obtained assuming a two component system. On these conditions a
      differentiation between amorphous and crystalline domains within the coal samples
      was enabled.

PMID- 15028277
TI  - High-accuracy amplification of nanogram total RNA amounts for gene profiling.
AB  - Microarray-based gene profiling of laser-assisted microdissected tissues or
      clinical biopsies is still a challenge since the amount of total RNA in such
      samples is limited and amplification of RNA is mandatory. Representative
      amplification of mRNA is highly dependent on the reverse transcription reaction,
      which is error prone, and on the number of amplification cycles. To improve the
      accuracy of RNA amplification, we optimized, combined, and tested different
      amplification strategies for Affymetrix oligonucleotide array hybridization. We
      demonstrate that different protocols differ significantly in quality of mRNA
      amplification. To demonstrate the accuracy and reproducibility of our optimized
      protocol in a clinical setting, we analyzed total RNAs from laser-assisted,
      microdissected cells of human prostate tissues. On the basis of these results, we
      recommend a standard reverse transcription reaction for small-sample
      transcriptome profiling experiments as part of the Minimal Information about a
      Microarray Experiment (MIAME) set of standards.

PMID- 15028278
TI  - Ethnic differences in the linkage disequilibrium and distribution of single
      nucleotide polymorphisms in 35 candidate genes for cardiovascular diseases.
AB  - Single-nucleotide polymorphisms (SNPs) are commonly used to study genetics for
      common diseases and predict pharmacological response. The selection of likely
      informative SNPs in association studies depends on their allele frequencies and
      on the linkage disequilibrium (LD) between SNPs, both of which may show
      interethnic differences. Among three populations consisting of 207 Chinese, 858
      French, and 395 Spanish, we compared the allele frequency distributions of 64
      intragenic SNPs of 35 candidate genes for cardiovascular diseases. Twenty-eight
      of these SNPs from 12 genes were also examined for intragenic LD. About 20% of
      SNPs were restricted to Europeans, being monomorphic in Chinese, among them
      mostly nonsynonymous coding SNPs and noncoding SNPs. Only 1.6% of SNPs were
      specific in Chinese, commensurate with the detection of these SNPs almost
      exclusively in Caucasians. Similarly, these SNPs were more often rare (<0.1 minor
      allele frequency) in Chinese (44.3%) than in Europeans (31.1%). The variant
      allele frequencies and intermarker LDs in terms of D' and Delta(2) were highly
      correlated between French and Spanish populations (r = 0.98-0.99, p < 0.001).
      However, only moderate correlations of allele frequencies and D' were found
      between the Chinese and the European populations (r = 0.7 and 0.3, respectively)
      despite a high correlation of Delta(2) values (r = 0.8). These results suggest
      that ethnic considerations are important in the selection of SNPs for association
      studies of candidate genes, as this may affect the power of the study as well as
      the likelihood of asking relevant questions and getting medically meaningful
      answers.

PMID- 15028279
TI  - PCR isolation and cloning of novel splice variant mRNAs from known drug target
      genes.
AB  - Alternative splicing of pre-mRNAs is an important mechanism for the generation of
      vertebrate protein diversity. Unfortunately, the contribution of alternative
      splicing to protein diversity is currently not well understood because many full
      length mRNA sequences have yet to be identified. In this report, we describe the
      use of RT-PCR to identify and clone 279 novel alternatively spliced mRNAs from
      114 well-known drug target genes. Our findings demonstrate the existence of many
      novel alternatively spliced mRNA transcripts and suggest that many more genes
      undergo functionally significant alternative splicing than previously thought.

PMID- 15028281
TI  - Quantitative analysis of the cardiac fibroblast transcriptome-implications for
      NO/cGMP signaling.
AB  - Cardiac fibroblasts regulate tissue repair and remodeling in the heart. To
      quantify transcript levels in these cells we performed a comprehensive gene
      expression study using serial analysis of gene expression (SAGE). Among 110,169
      sequenced tags we could identify 30,507 unique transcripts. A comparison of SAGE
      data from cardiac fibroblasts with data derived from total mouse heart revealed a
      number of fibroblast-specific genes. Cardiac fibroblasts expressed a specific
      collection of collagens, matrix proteins and metalloproteinases, growth factors,
      and components of signaling pathways. The NO/cGMP signaling pathway was
      represented by the mRNAs for alpha(1) and beta(1) subunits of guanylyl cyclase,
      cGMP-dependent protein kinase type I (cGK I), and, interestingly, the G-kinase
      anchoring protein GKAP42. The expression of cGK I was verified by RT-PCR and
      Western blot. To establish a functional role for cGK I in cardiac fibroblasts we
      studied its effect on cell proliferation. Selective activation of cGK I with a
      cGMP analog inhibited the proliferation of serum-stimulated cardiac fibroblasts,
      which express cGK I, but not higher passage fibroblasts, which contain no
      detectable cGK I. Currently, our data suggest that cGK I mediates the inhibitory
      effects of the NO/cGMP pathway on cardiac fibroblast growth. Furthermore the SAGE
      library of transcripts expressed in cardiac fibroblasts provides a basis for
      future investigations into the pathological regulatory mechanisms underlying
      cardiac fibrosis.

PMID- 15028282
TI  - Cross-species application of cDNA microarrays to profile gene expression using UV
      induced melanoma in Monodelphis domestica as the model system.
AB  - This study established the utility of cross-species application of the cDNA
      microarray technique for investigating differential gene expression. Using both
      total RNA and mRNA samples recovered from two opossum cell lines derived from UVB
      induced melanoma, we analyzed expression of ca. 4400 genes on the human DermArray
      DNA microarrays. The signals generated on the DermArrays were clear, strong, and
      reproducible. A cDNA dot blot consisting of differentially expressed genes
      representative of different functional clusters was used to validate the
      DermArray results. We also cloned a Monodelphis gene, keratin 18 (KRT18), and
      characterized its expression patterns in tumor samples of different progression
      stages. Up-regulated expression was observed for the KRT18 gene in advanced
      melanomas, a finding consistent with the DermArray analysis. These results
      provide evidence that cross-species application of cDNA microarrays is a useful
      strategy for investigating gene expression patterns in animal models for which
      species-specific cDNA microarrays are not available.

PMID- 15028283
TI  - Ethanol-response genes and their regulation analyzed by a microarray and
      comparative genomic approach in the nematode Caenorhabditis elegans.
AB  - The nematode shows responses to acute ethanol exposure that are similar to those
      observed in humans, mice, and Drosophila, namely hyperactivity followed by
      uncoordination and sedation. We used in this report the nematode Caenorhabditis
      elegans as a model system to identify and characterize the genes that are
      affected by ethanol exposure and to link those genes functionally into an ethanol
      induced gene network. By analyzing the expression profiles of all C. elegans ORFs
      using microarrays, we identified 230 genes affected by ethanol. While the ethanol
      response of some of the identified genes was significant at early time points,
      that of the majority was at late time points, indicating that the genes in the
      latter case might represent the physiological consequence of the ethanol
      exposure. We further characterized the early response genes that may represent
      those involved directly in the ethanol response. These genes included many heat
      shock protein genes, indicating that high concentration of ethanol acts as a
      strong stress to the animal. Interestingly, we identified two non-heat-shock
      protein genes that were specifically responsive to ethanol. glr-2 was the only
      glutamate receptor gene to be induced by ethanol. T28C12.4, which encodes a
      protein with limited homology to human neuroligin, was also specific to ethanol
      stress. Finally, by analyzing the promoter regions of the early response genes,
      we identified a regulatory element, TCTGCGTCTCT, that was necessary for the
      expression of subsets of ethanol response genes.

PMID- 15028284
TI  - Atrophic macular degeneration mutations in ELOVL4 result in the intracellular
      misrouting of the protein.
AB  - Elongation of very long chain fatty acids 4 (ELOVL4) is a novel member of the ELO
      family of genes that are involved in fatty acid metabolism. ELOVL4 encodes a
      putative transmembrane protein of 314 amino acids that carries a possible
      endoplasmic reticulum (ER) retention/retrieval signal (KXKXX) at the C-terminus.
      Two distinct mutations, a 5-bp deletion and a complex mutation from the same
      region in exon 6 of this gene, have been reported so far and are associated with
      autosomal dominant atrophic macular degeneration (adMD/STGD3). Both of these
      deletions could result in C-terminal truncation and loss of the ER retention
      signal in the mutant protein. We expressed the wild-type and mutant proteins in
      COS-7 and CHO cells to study the intracellular distribution of ELOVL4 and to
      identify possible implications of the above mutations in its localization.
      Immunofluorescence analysis of these proteins along with organelle marker
      antibodies revealed predominant ER localization for wild-type ELOVL4. Targeted
      deletion of the dilysine motif at the C-terminus of the protein resulted in the
      loss of ER localization. Immunoelectron microscopy and immunofluorescence
      analysis revealed a similar ER localization pattern for the protein in human
      photoreceptors. These data indicate that ELOVL4 is an ER-resident protein, which
      supports its suggested function in fatty acid elongation. We also demonstrate
      that the localization of both mutant proteins was dramatically changed from an ER
      to a Golgi distribution. Our observations suggest that the consequences of
      defective protein trafficking could underlie the molecular mechanism associated
      with degeneration of the macula in the patients with adMD/STGD3.

PMID- 15028285
TI  - Characterization of mouse orthologue of ELOVL4: genomic organization and spatial
      and temporal expression.
AB  - Mutations in ELOVL4 are associated with dominant macular degeneration
      (adMD/STGD3). This gene is highly expressed in the retina and is conserved
      through evolution. Here we report the genomic organization of the mouse
      orthologue of ELOVL4 and its temporal and spatial expression. A significant
      amount of ELOVL4 mRNA expression is detected in the adult retina, brain, skin,
      testis, and lens. During development, expression is first noted at embryonic day
      7 (E7). A significant level of the mRNA is observed both in brain and in eyes at
      postnatal day 1 (P1), after which levels decrease in the brain and increase in
      the retina until they stabilize at P30. ELOVL4 protein is evident in the ocular
      tissues by E10.5 and becomes restricted predominantly to the photoreceptor layer
      in the mature retina. These observations suggest that ELOVL4 may play an
      important role in embryonic development and in maintaining normal physiology of
      retina and brain at later stages of development.

PMID- 15028280
TI  - Bridging expressed sequence alignments through targeted cDNA sequencing.
AB  - One of the major challenges in genome research is the identification of the
      complete set of genes in a genome. Alignments of expressed sequences (RNA and
      EST) with genomic sequences have been used to characterize genes. However, the
      number of alignments far exceeds the likely number of genes in a genome,
      suggesting that, for many genes, two or more alignments can be joined through
      overlapping sequences to yield accurate gene structures. High-throughput EST
      sequencing becomes less efficient in closing those alignment gaps due to its
      nonselective nature. We sought to bridge these alignments through a novel
      approach: targeted cDNA sequencing. Human expressed sequences from GenBank
      version 124 were aligned with the genomic sequence from NCBI build 24 using
      LEADS, Compugen's EST and RNA clustering and assembly software system. Nine
      hundred forty-eight pairs of alignments were selected based on EST clone
      information and/or their homology to the same known proteins. Reverse
      transcriptase PCR and sequencing yielded sequences for 363 of those pairs. These
      sequences helped characterize over 60 novel or otherwise incomplete genes in the
      recent UniGene build 153, which included over 1 million additional ESTs. These
      results indicate that this integrated and targeted strategy, combining
      computational prediction and experimental cDNA sequencing, can efficiently
      generate the overlapping sequences and enable the full characterization of
      genomes. Additional information about the contig pairs, the resultant overlapping
      sequences, tissue sources, and tissue profiles are available in a supplemental
      file.

PMID- 15028286
TI  - Characterization and comparative genomic analysis of intronless Adams with
      testicular gene expression.
AB  - ADAM (a disintegrin and metalloprotease) family members with testis-specific or 
      predominant gene expression are divided phylogenically into two groups: ADAMs 2,
      3, 5, 27, and 32 (the first group) and ADAMs 4, 6, 20, 21, 24, 25, 26, 29, 30,
      and 34 (the second group). We cloned and sequenced cDNAs for previously
      unidentified mouse Adams that belong to the second group. We found that all the
      Adam genes in the second phylogenic group are transcribed by both somatic and
      germ cells in mouse testis, representing a unique expression pattern different
      from that of the first-group Adams. Genomic analyses revealed that all the second
      group Adam genes lack introns interrupting protein-coding sequences and many of
      them are present as multicopy genes, resulting in total of 14 functional mouse
      genes in this phylogenic group. Comparing the mouse and human ADAM genes, we
      found that a number of these mouse Adam genes do not have human orthologues and,
      even if they exist, some orthologues are pseudogenes in human. These results
      suggest the differential expansion of the second-group Adam genes in the mouse
      genome during evolution and a relationship between these Adams and male
      reproduction unique to mouse.

PMID- 15028287
TI  - Gene structure and evolution of testicular haploid germ cell-specific genes,
      Oxct2a and Oxct2b.
AB  - OXCT/SCOT is the rate-determining enzyme in ketolysis in mitochondria of many
      extrahepatic organs. Two testicular isoforms, Oxct2a and Oxct2b, are highly
      homologous and specifically expressed in haploid spermatids of the mouse. In this
      report, we analyzed the structure and evolution of Oxct2a and Oxct2b. Both
      Oxct2's are single-copy intronless genes, of which nucleotide sequences are
      conserved with Oxct, indicating that these genes are transposons generated from
      Oxct. A CpG island was found within both Oxct2's. Oxct2a and Oxct2b are located
      in the third introns of Bmp8a and Bmp8b, and they are positioned within a 240-kb
      region in a tail-to-tail orientation on chromosome 4. This structural feature was
      also conserved in a syntenic region of human 1p34.3. Structural similarity
      between mice and humans indicated that these two sets of genes were generated by
      a segmental gene duplication, which occurred before the primate-rodent split. Dot
      matrix and phylogenetic tree analyses demonstrated that multiple rounds of
      intrachromosomal gene conversion between the two loci occurred in each species
      independently.

PMID- 15028289
TI  - Tissue-restricted expression of the Cdrap/Mia gene within a conserved multigenic
      housekeeping locus.
AB  - The mouse cartilage-derived retinoic acid-sensitive protein (Cdrap/Mia) gene is
      expressed primarily in cartilage. Various promoter motifs that participate in
      restricted gene expression have been identified. To define mechanisms of
      regulation further, we determined the DNA sequence of 12 kb flanking this gene.
      We show that two genes, Snrpa and Rab4b, that have characteristics of
      housekeeping genes, including ubiquitous expression, closely flank Cdrap/Mia. We
      found the exon/intron structure and the organization of the gene locus to be
      conserved between the mouse and the human chromosomes, suggestive of functional
      relevance. DNase I hypersensitivity assays comparing expressing and nonexpressing
      cells indicate that the chromatin structure surrounding Cdrap/Mia is not greatly
      altered for transcription. The tissue-restricted expression of Cdrap/Mia, located
      between two housekeeping genes, provides a distinctive model for restricted
      transcriptional regulation from a multigenic locus.

PMID- 15028288
TI  - Cloning and expression of a mouse member of the PLUNC protein family exclusively
      expressed in tongue epithelium.
AB  - Palate, lung, and nasal epithelium clone (Plunc, now renamed Splunc1) is a small
      secreted protein expressed in the oropharynx and upper airways of humans, mice,
      rats, and cows. This protein is structurally homologous to known mediators of
      host defense against gram-negative bacteria. We have characterized the genomic
      sequence and expression of a novel but closely related gene from rodents, which
      we call splunc5. Mouse Splunc5 sequence is 60% identical to mouse Splunc1. The
      genes also share highly conserved genomic elements including intron-exon
      structure and intronic sequence. Strikingly, splunc5 is expressed exclusively in
      the interpapillary epithelium of the tongue's dorsal surface. By comparing the
      expression profiles of splunc5, splunc1, and a third related sequence, lplunc1,
      in mice, we show that these genes are expressed in unique domains along a
      continuous corridor of oral, lingual, pharyngeal, and respiratory epithelia. This
      expression pattern is consistent with the hypothesis that these proteins protect
      epithelial surfaces colonized by potentially pathogenic microorganisms.

PMID- 15028290
TI  - A cluster of 21 keratin-associated protein genes within introns of another gene
      on human chromosome 21q22.3.
AB  - Recently, we identified multiple unique sequences in the 21q22.3 region and
      predicted them to be a cluster of genes encoding hair-specific keratin-associated
      proteins (KAPs). Detailed computer-aided analysis of these clustered genes
      revealed that the cluster spans over 165 kb and consists of 21 KAP-related
      sequences including 16 putative genes and 5 pseudogenes. These were further
      divided into two subfamilies, KRTAP12 (KRTAP12.1-12.4 and KRTAP12.5P) and KRTAP18
      (KRTAP18.1-18.12 and KRTAP18.13P-18.16P). All 16 putative genes possess several
      intragenic repeat sequences and apparently belong to the high-sulfur KAP gene
      family (16-30% cysteine content) known for nonhuman mammalian species.
      Transcripts were detected by RT-PCR analysis for all 16 putative KAP genes and
      their expression was restricted to hair root cells (radix pili cells) and not
      found in 28 other tissues, including skin. All 16 KAP genes produced unspliced
      transcripts, indicating their nature to be that of active intronless genes.
      Interestingly, all these KAP-related genes are located within introns of the
      recently identified gene TSPEAR (approved gene symbol C21orf29), 214 kb in size.
      Surprisingly, the transcriptional direction of 8 of the 16 active genes is the
      same as that of C21orf29/TSPEAR. This finding suggests a novel transcription
      mechanism in which C21orf29/TSPEAR gene transcription passes over the multiple
      transcriptional termination sites of the KAP genes.

PMID- 15028291
TI  - Striking differences between the mouse and the human alpha-fetoprotein enhancers.
AB  - The alpha-fetoprotein (AFP) gene is expressed abundantly in the fetal liver and
      transcriptionally repressed in the adult liver, but can be reactivated during
      liver regeneration and in liver tumors. Previous studies identified three
      enhancers, E1, E2, and E3, upstream of the mouse and rat Afp genes and a single
      enhancer upstream of the human gene. We have compared the sequences upstream of
      the rodent and primate AFP genes. Our analysis demonstrates that the previously
      identified human enhancer is the counterpart to mouse E2. This comparison also
      reveals that a functional primate counterpart to the rodent E1 is absent due to a
      deletion that removes the core region of this enhancer. Furthermore, our studies
      identify a novel human enhancer corresponding to rodent E3. Despite the overall
      similarity of E3 between human and mouse, we found differences in transcription
      factor binding sites between these species. A C/EBP binding site is conserved but
      two other motifs in rodent E3, one that binds orphan nuclear receptors and a
      second that binds FoxA proteins, are not conserved in humans. The human
      counterpart to the rodent FoxA site can bind COUP-TF factors. Despite the overall
      sequence similarity in E3 between mice and humans, the difference in factor
      binding sites in E3, as well as the absence of E1 in primates, indicates that
      different mechanisms regulate AFP transcription in these different species.

PMID- 15028292
TI  - The mammalian pannexin family is homologous to the invertebrate innexin gap
      junction proteins.
AB  - We have cloned the genes PANX1, PANX2 and PANX3, encoding putative gap junction
      proteins homologous to invertebrate innexins, which constitute a new family of
      mammalian proteins called pannexins. Phylogenetic analysis revealed that
      pannexins are highly conserved in worms, mollusks, insects and mammals, pointing
      to their important function. Both innexins and pannexins are predicted to have
      four transmembrane regions, two extracellular loops, one intracellular loop and
      intracellular N and C termini. Both the human and mouse genomes contain three
      pannexin-encoding genes. Mammalian pannexins PANX1 and PANX3 are closely related,
      with PANX2 more distant. The human and mouse pannexin-1 mRNAs are ubiquitously,
      although disproportionately, expressed in normal tissues. Human PANX2 is a brain
      specific gene; its mouse orthologue, Panx2, is also expressed in certain cell
      types in developing brain. In silico evaluation of Panx3 expression predicts gene
      expression in osteoblasts and synovial fibroblasts. The apparent conservation of
      pannexins between species merits further investigation.

PMID- 15028293
TI  - Genomic sequence and organization of the family of CNR/Pcdhalpha genes in rat.
AB  - CNR/Pcdhalpha family proteins are known as synaptic cadherins and Reelin
      receptors. Here we report the complete genomic sequence and organization of the
      rat CNR. The rat CNR cluster encodes 15 variable and 3 constant exons. The
      genomic organizations of the rat, mouse, and human CNR/Pcdhalpha are orthologous.
      The percentage identity of the coding regions between the rat and the mouse is
      93.6% on average at the nucleic acid level, and between rat and human it is
      82.8%. The rat CNRs (v1-v13) also contain an RGD motif in the extracellular
      cadherin 1 domains and cysteine repeats that are characteristic of the
      transmembrane and cytoplasmic domains of CNR proteins. The number of variable
      exons in the rat CNR cluster is identical to that of the human. The rat CNR
      cluster has one more variable exon than is found in laboratory mouse strains,
      because in the mouse a variable exon located between v7 and v8 is divided by the
      insertion of a retrotransposon. This exon is not disrupted in the rat, in which
      it is transcribed. By in silico analysis, CNR/Pcdhalpha was also mapped to rat
      chromosome 18, but the orientation was opposite for the mouse CNR/Pcdhalpha gene
      cluster. The relative expression profiles of the rat CNRs (v1-v13) show that all
      the CNRs are transcribed, but there are variations in the expression ratios among
      the CNRs.

PMID- 15028294
TI  - TAFA: a novel secreted family with conserved cysteine residues and restricted
      expression in the brain.
AB  - We have discovered a family of small secreted proteins in Homo sapiens and Mus
      musculus using a novel database searching strategy. The family is composed of
      five highly homologous genes referred to as TAFA-1 to -5. The TAFA genes encode
      proteins of approximately 100 amino acids that contain conserved cysteine
      residues at fixed positions. TAFA-1 to -4 are more closely related to each other
      than to TAFA-5, in which a conserved motif including CC in TAFA-1 to -4 is not
      present. In H. sapiens, TAFA-3 has two isoforms formed by alternative splicing.
      Sequence homology analyses reveal that TAFA proteins appear distantly related to
      MIP-1alpha, a member of the CC-chemokine family. TAFA mRNAs are highly expressed
      in specific brain regions, with little expression seen in other tissues.

PMID- 15028295
TI  - CCL3L1 and CCL4L1 chemokine genes are located in a segmental duplication at
      chromosome 17q12.
AB  - Sixteen CC chemokine genes localize to a 2.06-Mb interval at 17q11.2-q12 on
      genomic contig NT_010799.13. Four of these genes comprise two closely related
      paralogous pairs: CCL3-CCL3L1 and CCL4-CCL4L1. Members within each pair share 95%
      sequence identity at both the genomic and the amino acid levels. One BAC clone
      (AC131056.5) on the contig with substantial internal sequence duplication
      contains two complete copies of CCL3L1 and CCL4L1 and one truncated copy of
      CCL3L1, while a partially overlapping clone (AC003976.1) contains one copy each
      of CCL3 and CCL4. Dot-matrix comparison of the regions of AC131056.5 with those
      of AC003976.1 containing the four genes reveals 90% sequence similarity over 37
      kb. These observations support the idea that the multiple copies of CCL3L1 and
      CCL4L1 present in a single diploid genome are the result of segmental
      duplication.

PMID- 15028296
TI  - alpha-Synuclein A53T substitution associated with Parkinson disease also marks
      the divergence of Old World and New World primates.
AB  - The alpha-synuclein mutation Ala53Thr is associated with increased
      oligomerization, toxicity, and early onset Parkinson disease in humans, but 53Thr
      is the normal residue in other species. Comparative sequencing of SNCA genes
      shows that 53Ala marks the divergence of Old World and New World primates, in an
      otherwise constrained protein region. These results have implications for
      interpreting Parkinson disease models and suggest that other long-lived mammals
      have different mechanisms to forestall alpha-synucleinopathy.

PMID- 15028297
TI  - Bruton tyrosine kinase-like protein, BtkSD, is present in the marine sponge
      Suberites domuncula.
AB  - Sponges, the simplest and most ancient phylum of Metazoa, encode in their genome
      complex and highly sophisticated proteins that evolved together with
      multicellularity and are found only in metazoan animals. We report here the
      finding of a Bruton tyrosine kinase (BTK)-like protein in the marine sponge
      Suberites domuncula (Demospongiae). The nucleotide sequence of one sponge cDNA
      predicts a 700-aa-long protein, which contains all of the characteristic domains
      for the Tec family of protein tyrosine kinases (PTKs). The highest homology (38%
      identity, 55% overall similarity) was found with human BTK and TEC PTKs. Sponge
      PTK was therefore named BtkSD. Human BTK is involved in the maturation of B cells
      and mutations in the BTK gene cause X-linked agammaglobulinemia. Kinases from the
      Tec family are not present in Caenorhabditis elegans and, until now, they were
      found only in insects and higher animal taxa. Our finding implies that the
      BTK/TEC genes are of a very ancient origin.

PMID- 15028299
TI  - Sentinel node and breast cancer.

PMID- 15028300
TI  - Establishing a breast clinic in a developing country: effect of a collaborative
      project.
AB  - This paper describes a project funded by DFID (Department of International
      Development of the United Kingdom) for the establishment of breast clinic in an
      oncological center in a developing country, Sri Lanka. In Sri Lanka the commonest
      female cancer is breast cancer, with an incidence of 7.7 per 100,000. The project
      utilized a link with an existing breast clinic at the Royal Marsden UK. The
      principal methods used for establishing the clinic included, assessment of
      possible barriers by the exchange of senior staff, the development of guidelines,
      and regular review of progress by both link partners. As a result of these
      interactions, the first breast clinic in Sri Lanka was established. In has shown
      results in an increase in the pick up rate of new patients with breast cancer.

PMID- 15028301
TI  - Intraoperative margin assessment and re-excision rate in breast conserving
      surgery.
AB  - AIM: The aim of this study was to assess the efficacy of intraoperative margin
      assessment in obtaining clear margins in conserving surgery for breast cancer.
      METHODS: Two hundred and twenty patients undergoing wide local excision (WLE) for
      core biopsy proven primary invasive breast cancer, during a 30 months period,
      were included in the study. Following surgical excision the breast specimen was
      orientated with sutures, inked using India ink and coloured pigments and incised
      to identify the tumour, maintaining orientation. The distance to the individual
      radial margins were estimated macroscopically by the pathologist and conveyed
      intraoperatively to the surgeon. A macroscopic tumour-margin distance of less
      than 10 mm was considered compromised and the margin(s) in question was then
      excised if feasible. RESULTS: Eighty-one patients (37%) were judged to have
      compromised margins following intraoperative macroscopic evaluation and had at
      least one margin re-excised. Sixteen of the 81 patients (20%) in this subgroup
      had compromised margins on microscopy and required a second operation. One
      hundred and thirty-nine patients (63%) were deemed to have clear margins
      intraoperatively, subsequently confirmed on microscopic examination in 135
      patients (97%). Intraoperative macroscopic assessment of margin status was
      associated with 9.1% of patients requiring a second operation. In the absence of
      intraoperative assessment of margin status a further 47 patients (21.4%) would
      have required a second operation. CONCLUSION: Intraoperative macroscopic margin
      assessment is an effective technique in reducing the number of second operative
      procedures in patients undergoing conserving surgery for primary invasive breast
      cancer.

PMID- 15028302
TI  - Imprint cytology of the sentinel lymph node in the assessment of axillary node
      status in breast carcinoma.
AB  - BACKGROUND: Intra-operative assessment of the sentinel lymph node (SLN) status
      may allow the surgeon to complete the breast cancer surgery in most patients in
      one sitting. We have studied the role of imprint cytology in the assessment of
      SLN status. PATIENTS AND METHODS: Imprint cytology of the SLN in 132 patients
      with invasive breast carcinoma was correlated with the histopathological
      assessment of the SLN and overall axillary nodal status. In 26 patients, the
      cytology was reported intra-operatively. RESULTS: Imprint cytology reflected the
      status of the parent node well (sensitivity 86%, specificity 97%, positive
      predictive value (PPV) 92%, negative predictive value (NPV) 93%). Its ability to
      reflect the axillary status was also good (sensitivity 70%, specificity 97%, PPV
      95% and NPV 83%) but somewhat diminished by the relatively high number of false
      negative SLN in the study. Intra-operative assessment (sensitivity 86%,
      specificity 100%, PPV 100% and NPV 95%) did not reduce the accuracy of imprint
      cytology in predicting the SLN status and took a mean of 24.5 min. CONCLUSIONS:
      Imprint cytology is an accurate and relatively simple method for the assessment
      of the SLN and can be a useful intra-operative tool.

PMID- 15028303
TI  - High nuclear grade and negative estrogen receptor are significant risk factors
      for recurrence in DCIS.
AB  - INTRODUCTION: Recommendations for adjuvant treatment of DCIS after breast
      conservation are controversial. We tried to identify further risk factors in a
      retrospective study of our own practice. PATIENTS AND METHODS: Three hundred and
      thirty-two patients treated by breast conservation between 1978 and 2001 at the
      Department of General Surgery, University of Vienna were analysed. Tumour size,
      nuclear grade, hormone receptors, p53, her-2/neu, multifocality, microinvasion
      and post-operative therapy (irradiation, tamoxifen or combination) were analysed
      for their influence on breast recurrence. RESULTS: Overall recurrence rate was
      6.1% (8/132). For patients with DCIS showing high nuclear grade or negative
      estrogen receptor the risk for development of ipsilateral breast recurrence is
      significantly higher. Newer factors like p53 and her-2/neu do not have any
      prognostic significance. No recurrence was observed in patients treated by post
      operative irradiation and tamoxifen. CONCLUSION: Nuclear grade remains the most
      significant factor for breast recurrence after DCIS. Hormone receptor status
      identifies a subset of patients with more favourable prognosis.

PMID- 15028304
TI  - A simple tool for rapid access to a symptomatic breast clinic.
AB  - AIM: The introduction of a rapid referral system has led to an increase in the
      number of patients with benign disease using clinic appointments. This situation
      could delay those patients, who do have cancer but are not referred within these
      rapid referral guidelines. Existing guidelines fail to benefit those patients
      with lower risk symptoms. We reviewed prospective audit data from patients
      referred to a symptomatic breast unit with the aim of introducing a referral
      schema based upon symptoms, age and relative risk of cancer. METHOD: Demographic
      details, mode of referral, history and presenting symptoms were collected from
      each of the 2064 patients referred to the James Cook University Hospital (JCUH)
      breast unit from April 2001 to March 2002. RESULTS: Odds Ratios (OR) from eight
      dependent variables gave a 30% improvement in prediction accuracy of breast
      cancer. From these findings a breast referral schema is presented that is
      designed to expedite referral from primary care of those patients most at risk.
      CONCLUSIONS: Use of the schema within primary care could lead to an increase in
      the early referral of patients with breast cancer.

PMID- 15028306
TI  - Functional outcome after intersphincteric resection of the rectum with coloanal
      anastomosis in low rectal cancer.
AB  - OBJECTIVES: Anterior rectal resection with partial removal of the internal
      sphincter is an option for low rectal cancer. The objective of this study was to
      evaluate the functional outcome after this intersphincteric rectal resection.
      METHODS: Anal continence was evaluated by anorectal manometry and a standardized
      questionnaire (Wexner Score) in 33 patients 28+/-15 weeks and 100+/-45 weeks,
      respectively, after intersphincteric resection. Nineteen of the 33 patients were
      reconstructed with a straight anastomosis; 12 received a colonic J-pouch.
      RESULTS: Post-operatively, 25.8% of the patients were incontinent to solid stool
      and 54.8% were incontinent to liquid stool at least once a week. Mean and maximum
      resting tone (24+/-10 and 40+/-13 mmHg), maximum tolerable volume (77+/-28 ml)
      and rectal compliance (1.4+/-1.2 ml/mmHg) were reduced in anorectal manometry.
      Squeeze pressures remained unchanged. Only the maximum tolerable volume
      correlated significantly with the continence score (r=-0.45, p<0.05). The Wexner
      score and maximum tolerable volume were significantly better after colonic J
      pouch reconstruction than after straight anastomosis (9.9+/-4.5 vs 13.4+/-4.0,
      p<0.05, 65+/-20 ml vs 100+/-27 ml, p<0.01). CONCLUSION: Intersphincteric
      resection of the rectum leads to impaired post-operative continence. The
      functional outcome is improved with a colonic J-pouch.

PMID- 15028307
TI  - Expression of the p65 gene in patients with colorectal cancer: comparison with
      some histological typing, grading and clinical staging.
AB  - AIMS: P65 protein/gene is a potential, non-specific tumour marker expressed by
      different types of neoplasms. In this study p65 gene expression was estimated in
      a group of colorectal cancers and compared with some histological features,
      grading and clinical staging of the neoplasms to assess its role as a prognostic
      marker for colorectal cancer. METHODS: 109 pairs of frozen samples of colorectal
      carcinomas and adjacent normal colorectal mucosa and four samples of tissue from
      patients without neoplastic diseases were analysed by means of RT-PCR. RESULTS:
      Expression of p65 gene was found in 51 out of 109 cases of colorectal cancers.
      For 19 of them expression of examined gene was observed both in cancer and
      corresponding healthy mucosa. p65 Gene expression was associated with more
      advanced tumours (T3, T4; p=0.0003) with metastases to lymph nodes (N1, N2;
      p=0.0003) and distant metastases (p=0.0005). We did not find association between
      the age, gender, tumour localization, histological type and p65 gene expression.
      CONCLUSIONS: p65 Gene expression in primary tumour tissue is associated with poor
      prognosis for the patients with colorectal cancer in this series.

PMID- 15028308
TI  - The clinicopathological significance of inferior mesenteric lymph node metastasis
      in colorectal cancer.
AB  - AIMS: There are few studies reporting survival or recurrence patterns in
      colorectal cancer patients with inferior mesenteric lymph node metastasis
      (IMLN+). The present study evaluated the prognostic significance of patients
      being IMLN+ or IMLN- in colorectal cancer. METHODS: Survival, recurrence pattern
      and treatment protocols were compared between 63 IMLN+ patients and 108 IMLN-
      patients with stage III and IV rectal and sigmoid cancer undergoing curative
      surgery. Lymph node sampling was routinely performed prior to inferior mesenteric
      artery ligation and excision flush with aorta. Limited principal node dissection
      including IMLN was performed in cases of identified node metastasis. RESULTS: The
      5-year disease-free survival rates were 50% in IMLN- and 31% in IMLN+ patients
      (P=0.004). The 5-year disease-free survival rate was greater in the N1 group than
      the N2 group (P=0.038). Cox regression analysis showed IMLN+, lymphovascular
      tumour invasion, T4, M1, and pre-operative serum CEA level over 6 ng/ml were
      independently associated with unfavorable disease-free survival. The prognostic
      significance of M category was greater when the IMLN+ was included in the M1 as
      opposed to the N category. In patients undergoing absolute curative surgery, post
      operative recurrence rates were 34% for IMLN- and 57% for IMLN+ patients
      (P=0.009; OR, 2.611; 95% CI, 1.313-5.194). For IMLN+ patients, post-operative
      adjuvant treatment independently correlated with disease-free survival (P=0.029).
      CONCLUSIONS: IMLN+ is an independent survival factor enhancing the prognostic
      significance of the M category in the AJCC staging. Curative radical surgery and
      post-operative chemoradiotherapy appears to be warranted for IMLN+ colorectal
      cancer patients as it resulted in 5-year disease-free survival rates of up to 31%
      compared to 50% in IMLN- patients.

PMID- 15028305
TI  - Sentinel-node biopsy for axillary staging in breast cancer: results from a large
      prospective German multi-institutional trial.
AB  - PURPOSE: To analyse the reliability of sentinel-node biopsy (SNB) in a
      multicentre setting and define conditions for the routine use of the procedure.
      MATERIAL AND METHODS: SNB with consecutive axillary clearing was performed in
      1124 breast cancer patients. The detection rate of a sentinel lymph node and its
      dependence on the choice of lymphography technique, patient selection, and
      technical procedure were analysed. The diagnostic performance of the sentinel
      node method was compared to clinical, ultrasound-guided and histological staging.
      In order to study training effects all learning periods were included. RESULTS:
      Twenty-two institutions with a total of 89 surgeons participated in the trial.
      The detection rate (overall: 85.2%) was found to be related to the applied
      lymphography technique, the experience of the institution and various technical
      factors of the procedure itself. The false-negative rate (FNR, overall: 8.2%) was
      independent of patient selection and technical features. The FNR did not depend
      on experience in the application of the method, but seemed related to surgical
      accuracy to detect sentinel nodes. Compared to conventional staging procedures
      (palpation, ultrasound) SNB yielded highly reproducible results for the
      prediction of the axillary status even in a multicentre setting involving
      surgeons with different training status. CONCLUSION: SNB is suited as standard of
      care procedure. Measures of quality control appear more important than learning
      periods to minimize the FNR.

PMID- 15028309
TI  - Follow-up of patients treated by cytoreduction and chemotherapy for peritoneal
      carcinomatosis of colorectal origin.
AB  - AIM: The aim of this study was to determine the value of medical history and
      physical examination, tumour marker testing, and CT-scanning in the follow-up of
      patients treated for peritoneal carcinomatosis of colorectal origin. METHODS:
      Between November 1995 and June 2003, 107 patients were treated by cytoreduction
      and hyperthermic intra-peritoneal chemotherapy. The treatment was considered
      effective if residual tumour after cytoreduction was no thicker than 2.5 mm. The
      follow-up consisted of history, physical examination, serum CEA and CA 19.9
      testing three-monthly, and CT-scanning of the abdomen six-monthly. Location of
      the recurrence was categorized into intra-abdominal, hepatic, thoracic, and both
      intra-abdominal and systemic. The investigation that led to the detection of a
      recurrence was ranked according to its invasiveness and costs. The simplest
      investigation that could have led to the detection was marked. RESULTS: A
      recurrence developed in 63 patients of the 74 patients effective initial
      treatment during the study period. Physical examination revealed the recurrence
      in 38 patients, at least one of the markers was raised above normal value in 39
      patients and in 37 patients the CT-scan showed the recurrence. History and
      physical examination could have triggered the finding of a recurrence in 38
      patients, tumour markers in 21 patients and CT-scanning in only three of the 74
      recurrences. CONCLUSION: Physical examination and tumour marker testing detect
      most recurrences. CT-scanning is not an effective tool in the follow-up, and
      should be reserved for on-demand use.

PMID- 15028310
TI  - FDG-PET for the pre-operative evaluation of colorectal liver metastases.
AB  - INTRODUCTION: This study assesses the accuracy of routine whole body
      fluorodeoxyglucose-positron emission tomography (FDG-PET) in the pre-operative
      staging of patients with colorectal liver metastases (CLM). METHODS: A
      prospective study of patients referred for hepatic resection was undertaken.
      Patients were staged by spiral CT and FDG-PET. The results of these
      investigations were considered independently. RESULTS: Twenty-eight patients had
      confirmed CLM. Eleven patients had solitary CLM; 10 of whom were correctly
      identified by both modalities. In the remaining 17 patients, 10 had multiple CLM
      and seven had extrahepatic disease. FDG-PET detected all lesions (sensitivity
      100%, specificity 91%). CT incorrectly diagnosed solitary CLM in five patients
      and failed to detect extrahepatic disease in four patients (sensitivity 47%,
      specificity 91%). FDG-PET resulted in altered management for 12 patients of whom
      seven avoided inappropriate surgery. CONCLUSION: FDG-PET is more sensitive and
      specific for pre-operative staging of CLM. FDG-PET confers clinical benefit
      through altered patient management.

PMID- 15028311
TI  - Tumour T-lymphocyte subset infiltration and tumour recurrence following curative
      resection for colorectal cancer.
AB  - AIM: The relationship of tumour T-lymphocytic subset infiltration and recurrence
      in patients undergoing potentially curative resection for colorectal cancer has
      not been clearly defined. METHODS: Tumour sections from patients who had
      undergone potentially curative resection for colorectal cancer were stained and
      counted for CD4+ and CD8+ T-lymphocytes. RESULTS: Twenty-three patients developed
      recurrence during the follow-up period. Patients were grouped according to
      whether or not they developed recurrence. The groups were similar in age, sex,
      site of tumour, Dukes stage and the numbers of patients receiving adjuvant
      therapy. The total percentage volume of labelled CD4+ T-lymphocytes in the tumour
      was significantly lower in the patients who recurred (p<0.05). CONCLUSIONS: The
      results of the present pilot study suggest that a reduction in tumour T
      lymphocyte infiltration, in particular CD4+ T-lymphocyte infiltration, is
      associated with recurrence in patients following potentially curative resection
      for colorectal cancer.

PMID- 15028312
TI  - Platelet-derived endothelial cell growth factor expression is an independent
      prognostic factor in colorectal cancer patients after curative surgery.
AB  - AIMS: Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic
      factor that undergoes increased expression in colorectal carcinomas, but its
      prognostic value is a topic of debate. The aim of this study is to clarify the
      prognostic value of PD-ECGF expression in colorectal carcinomas. METHODS: PD-ECGF
      expression was measured by enzyme-linked immunosorbent assay in frozen materials
      from 134 colorectal cancer patients who had received curative resections.
      Patients were divided into high expression and low expression groups based upon
      selected cut-off value. Correlations among PD-ECGF expression, clinicopathologic
      features, and disease-free interval were studied by univariate and multivariate
      analysis. To evaluate the origin of PD-ECGF, serial sections of the 134 tumours
      were stained for PD-ECGF and CD68. RESULTS: PD-ECGF expression in the normal
      mucosa was 34.4+/-15.5 (Units/mg protein) and the cut-off value was 65.4
      (mean+2SD). There were no significant correlations between clinicopathological
      features and PD-ECGF expression. The disease-free interval for the high PD-ECGF
      expression group was significantly longer than that of the low expression group
      (P=0.05). A multivariate Cox's regression analysis revealed that high PD-ECGF
      expression is an independent factor for better outcome. In immunohistochemical
      study, almost all tumour cells were negative for PD-ECGF, but stromal macrophages
      were predominantly positive for PD-ECGF. CONCLUSIONS: The PD-ECGF expression
      originated from stromal macrophages was a predictor for favorable outcome after
      curative resections for colorectal cancer.

PMID- 15028313
TI  - Morbidity and mortality after D1 and D2 gastrectomy for cancer: interim analysis
      of the Italian Gastric Cancer Study Group (IGCSG) randomised surgical trial.
AB  - BACKGROUND: The disadvantages of D2 gastrectomy have been mostly related to
      splenopancreatectomy. Unlike two large European trials, we have recently showed
      the safety of D2 dissection with pancreas preservation in a one-arm phase I-II
      trial. This new randomised trial was set up to compare post-operative morbidity
      and mortality and survival after D1 and D2 gastrectomy among the same experienced
      centres that participated into the previous trial. METHODS: In a prospective
      multicenter randomised trial, D1 gastrectomy was compared to D2 gastrectomy.
      Central randomisation was performed following a staging laparotomy in 162
      patients with potentially curable gastric cancer. FINDINGS: Of 162 patients
      randomised, 76 were allocated to D1 and 86 to D2 gastrectomy. The two groups were
      comparable for age, sex, site, TNM stage of tumours, and type of resection
      performed. The overall post-operative morbidity rate was 13.6%. Complications
      developed in 10.5% of patients after D1 and in 16.3% of patients after D2
      gastrectomy. This difference was not statistically significant (p<0.29).
      Reoperation rate was 3.4% after D2 and 2.6% after D1 resection. Post-operative
      mortality rate was 0.6% (one death); it was 1.3% after D1 and 0% after D2
      gastrectomy. INTERPRETATION: Our preliminary data confirm that in very
      experienced centres morbidity and mortality after extended gastrectomy can be as
      low as those showed by Japanese authors. They also suggest that D2 gastrectomies
      with pancreas preservation are not followed by significantly higher morbidity and
      mortality than D1 resections.

PMID- 15028314
TI  - The role of staging investigations for oesophago-gastric carcinoma.
AB  - AIMS: To study the frequency with which unresectable disease was identified on
      pre-operative staging investigations in patients with oesophago-gastric
      carcinoma, and to audit whether a staging protocol had reduced the rate of
      exploratory surgery. METHODS: Ninety-eight patients with oesophageal carcinoma,
      89 patients with adenocarcinoma of the gastro-oesophageal junction (GOJ) and 68
      patients with gastric carcinoma were staged according to a protocol of
      computerised tomography, laparoscopy and endoscopic ultrasound. RESULTS: The
      frequency with which each investigation identified unresectable disease was as
      follows: (a) computerised tomography-oesophagus 12/67, GOJ 13/58, stomach 10/60;
      (b) laparoscopy-oesophagus 3/22, GOJ 5/45, stomach 8/23; and (c) endoscopic
      ultrasound-oesophagus 15/55, GOJ 3/30. By tumour location, rates of exploratory
      surgery were 1/18 for the oesophagus, 12/35 for the GOJ and 4/42 for the stomach.
      All of the staging failures in patients with GOJ carcinomas related to posterior
      tumour extension into the lesser sac. CONCLUSIONS: Staging investigations
      precluded resection in one-third of patients, the greatest yield being for
      laparoscopy in gastric carcinoma. In spite of this, 18% of patients undergoing
      surgical intervention underwent exploratory surgery alone, notably patients with
      GOJ carcinoma.

PMID- 15028315
TI  - Margin involvement and outcome in oesophageal carcinoma: a 10-year experience in
      a specialist unit.
AB  - AIMS: Positive microscopic margins after major cancer surgery adversely affect
      prognosis. We questioned whether the benefit of a multimodal approach in
      oesophageal carcinoma is due to reduced resection margin involvement and whether
      multimodal therapy alters the disease course when margins are involved. METHODS:
      Pathology specimens of 212 patients, treated with either multimodal therapy or
      surgery alone, were re-reviewed to assess margin involvement by tumour. Margin
      status was compared with recurrence and survival data. RESULTS: Margin
      involvement was decreased with multimodal therapy (16 of 103 patients) vs surgery
      (33 of 109 patients), associated with reduced tumour recurrence and a significant
      survival advantage. However, even with involved margins, multimodal therapy had
      lower recurrence vs surgery and a small survival benefit. CONCLUSIONS: Multimodal
      therapy significantly reduces margin involvement. The benefit of multimodal
      therapy remains highly significant for patients with clear margins. This study
      confirms for oesophageal carcinoma the value of an aggressive surgical approach
      in achieving negative resection margins.

PMID- 15028317
TI  - Differentiated thyroid cancer and outcome in iodine deficiency.
AB  - AIMS: Factors influencing prognosis and long-term outcome of thyroid cancer have
      been described by several groups. We wished to asses the previously described
      prognostic factors in a moderately iodine deficient region in Hungary. METHODS:
      Four hundred and fifty-four out of 492 patients who had surgery for papillary
      thyroid cancer (PTC, 386 cases) and follicular thyroid cancer (FTC, 106 cases)
      between 1971 and 1998 were analyzed. Survival curves were compared using the
      Kaplan-Meier method and Cox regression analysis. RESULTS: The 10 and 20-year
      survival rates were 87.9 and 84% for PTC, and 78.2 and 78.2% for FTC. In PTC,
      extrathyroidal invasion (p<0.0001), lymph node metastasis (p<0.0001), distant
      metastasis (p<0.0001), and age over 40 years (p=0.002) were significant adverse
      predictors. In FTC, extrathyroidal invasion (p=0.003) distant metastases
      (p<0.0001), and age over 40 years (p=0.011) were significant adverse predictors.
      CONCLUSION: Iodine intake did not appear to influence survival. The incidence of
      follicular cancer, which has less favourable prognosis, was higher in iodine
      deficient regions. This supports the importance of iodine supplementation in
      these areas.

PMID- 15028316
TI  - Significance of cytosolic hyaluronan levels in gastric cancer.
AB  - BACKGROUND: Hyaluronan a high-molecular weight glycosaminoglycan, is considered
      to be involved in the growth and progression of malignant tumours. The objective
      of this work was to evaluate the cytosolic hyaluronan content in gastric cancer
      cells, its possible relationship with clinicopathological tumour parameters and
      its potential prognostic significance. METHODS: Cytosolic hyaluronan levels were
      examined utilizing immunoenzymatic techniques in 129 patients with gastric
      cancer. The mean follow-up period for these patients was 28 months. RESULTS:
      Cytosolic hyaluronan levels ranged widely in tumours as well as in adjacent
      mucosal samples (median (range) 2822 (50-24,523) versus 3650 (507-20,782) ng/mg
      protein). Statistical analysis showed that tumour hyaluronan levels correlated
      significantly with patient's sex and the presence of lymphatic invasion. In
      addition, high tumour hyaluronan levels were significantly associated with
      shorter overall survival period (p<0.05). CONCLUSIONS: Our results suggest that
      high tumoral cytosolic hyaluronan levels are associated with lesions of
      unfavorable outcome in gastric cancer patients. Thus, hyaluronan may provide
      additional prognostic information to that given by other biochemical markers
      currently used in gastric cancer.

PMID- 15028318
TI  - Osteosarcoma of the pelvis.
AB  - AIMS: To describe the outcomes of a large number of patients with pelvic
      osteosarcoma, and to define the guidelines for appropriate treatment. METHODS: We
      reviewed 60 consecutive patients with primary pelvic high-grade osteosarcoma. The
      tumour involved the whole hemipelvis in 15 cases, while the most common location
      was the iliac wing in 29 cases (48.3%): 25 of these adjacent to or passing the
      sacroiliac joint. RESULTS: Thirty patients underwent surgery; there were 16
      hindquarter amputations and 14 internal hemipelvectomies. All the patients who
      presented with metastasis died of their disease. In 18 cases wide margins were
      achieved, however, eight patients experienced local recurrence. Of the series,
      only eight patients are still alive. CONCLUSION: The use of intense chemotherapy
      and surgical wide margin, hardly seems to achieve local control, however, tumour
      necrosis was correlated with positive prognosis. When internal hemipelvectomy it
      is not safe enough, amputation must be considered, particularly for cases with
      sacrifice of the sciatic nerve roots or for older patients where a shorter
      surgical procedure can be less risky.

PMID- 15028319
TI  - Outcomes of surgery for dermatofibrosarcoma protuberans.
AB  - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma
      usually presenting as nodular cutaneous mass on the trunk and proximal extremity.
      The tumour grows slowly, typically over years. The standard treatment is wide
      local excision with at least a 3-cm margin. The local regional recurrence is up
      to 50%, emphasizing the need for wide margins for local control. A small fraction
      of DFSP may metastasize, but on histological examination such tumours have
      features of fibrosarcomas rather than DFSP. HYPOTHESIS: This study was done to
      review our experience of the time interval to recurrence of DFSP. DESIGN: A
      retrospective review was undertaken to identify patients with DFSP in our
      university teaching hospital. METHODS: All patients received their primary
      surgical treatment in our department between February 1968 and June 2001.
      Treatment consisted of wide local excision with margins of at least 3 cm. The chi
      square test and Fisher's exact test were performed to determine the relationship
      between recurrence and clinicopathological variables. We evaluated the prognostic
      variables using the Kaplan-Meier method with log-rank comparison. RESULTS: The
      median follow-up period was 59 months. The 5 and 10-year disease-free survival
      (DFS) were 86 and 76%, respectively. The overall recurrence rate was 16.7%. The
      mean time to recurrence was 38+/-12 months (range 1-100 months). In 30% of those
      patients with recurrences, the local regional recurrence was after 5 years.
      CONCLUSION: Wide local excision with good margins decreases local regional
      recurrences in patients with DFSP. Close surveillance is necessary even beyond 5
      years because late recurrences occur.

PMID- 15028320
TI  - The quotient of number of nodes and tumour size (N/T) from primary breast cancer
      predicts the clinical course after diagnosis of distant relapse.
AB  - INTRODUCTION: Breast cancer is a disease with a very variable progression.
      Primary tumour size and metastatic lymph node involvement are the best indicators
      of the likelihood of relapse. However, their value in predicting progression
      following relapse is not clear. AIM: The aim of this study was to asses whether
      the relationship between tumour size and the number of lymph nodes involved had
      any value as predictive factors of post-relapse progression. METHOD: We
      established an index defined as the quotient between the number of diseased lymph
      nodes and the tumour size (in cm). RESULTS: Applying this index in 230
      consecutive patients with metastatic breast cancer, we observed that there was a
      significant inverse relation between the index and post-relapse progression.
      CONCLUSION: We conclude that, at the time of initial diagnosis, the quotient of
      tumour size and the number of diseased lymph nodes could be a good predictor of
      time-to-progression following the diagnosis of the metastatic disease.

PMID- 15028321
TI  - Erroneous diagnosis of pancreatic cancer after radiotherapy of testicular cancer.
AB  - BACKGROUND: After radiotherapy with or without chemotherapy radiation-induced
      normal tissue alteration may mimic cancer and may cause major morbidity. RESULTS:
      Two patients irradiated for seminoma, in one case combined with cisplatin-based
      chemotherapy, developed clinical symptoms and radiological signs comparable to
      pancreatic cancer (stenosis of the ductus choledochus). The non-malignant
      diagnosis was finally established by revision of the histological specimen (case
      1) and per-operatively (case 2). In both patients by-pass operations for biliary
      tract stenosis resulted in excellent palliation. CONCLUSION: Radiation-induced
      fibrosis within the upper retroperitoneal space is an important differential
      diagnosis versus pancreatic cancer in patients with prior radiotherapy for
      seminoma. Diagnosis based only on clinical and radiological findings may lead to
      incorrect patient information and registration errors in Cancer Registries.

PMID- 15028322
TI  - Diphenhydramine in the treatment of akathisia induced by prochlorperazine.
AB  - Dopamine D(2) antagonists are known to induce akathisia, the emergency management
      of which remains undetermined. We sought to evaluate the effectiveness of
      diphenhydramine in the treatment of akathisia induced by 10 mg intravenous
      prochlorperazine. This prospective, open-label, uncontrolled study evaluated a
      cohort of akathisic adult Emergency Department patients who were participating in
      a series of three studies of acute akathisia at an academic medical center. Each
      subject received intravenous diphenhydramine, with akathisia measurements (graded
      from 0-17 points) performed just before and 30 min after infusion. Mean scores
      were calculated using descriptive statistical analyses. The effect of treatment
      was evaluated using the paired t-test. For the 87 akathisic patients, the mean
      score before treatment was 9.8 +/- 3.6, and after treatment was 1.2 +/- 2.6, a
      mean reduction of 8.5 +/- 3.8 (95% confidence interval [CI], 7.8 to 9.4; p <
      0.0001). In conclusion, intravenous diphenhydramine rapidly reduces signs and
      symptoms of acute akathisia induced by prochlorperazine.

PMID- 15028323
TI  - A preliminary comparison of levalbuterol and albuterol in prehospital care.
AB  - Nebulized levalbuterol has been documented as more efficacious than albuterol in
      enhancing airflow in Emergency Department (ED) patients with bronchospasm. This
      work attempts to determine if nebulized levalbuterol yields similar improvements
      in peak flow measurements as those produced by albuterol in the Emergency Medical
      Services (EMS) arena. All adult EMS patients given a nebulized beta-agonist from
      January to June 2000 were included in this prospective, before-and-after, open
      label study. Data collected included demographics, initial peak expiratory flow
      (PF), and use of home inhaled or nebulized bronchodilators before EMS arrival
      (PRE-TX). Outcome variable was the change in PF after a single EMS treatment with
      one of the study agents. Statistical analysis was performed using t-test and chi
      square techniques; p was defined as 0.05. There were 298 patients enrolled;
      complete data for analysis were available for 196. Mean age was 68.0 years; 44.4%
      were male. Overall, albuterol produced a PF change of 19.7%; levalbuterol yielded
      a change of 20.4% (p = 0.9). In contrast to ED data, levalbuterol and albuterol
      produces similar changes in PF in the prehospital setting. Explanations for this
      finding may be linked to the pharmacokinetics of single vs. dual isomer
      preparations, and to the time frames of EMS care. Further efforts correlating EMS
      and ED data may better define the use of levalbuterol in prehospital care.

PMID- 15028325
TI  - The clinical presentation and impact of diagnostic delays on emergency department
      patients with spinal epidural abscess.
AB  - Previous reports have recommended the use of a "classic triad" of fever, spine
      pain, and neurologic deficits to diagnose spinal epidural abscess (SEA); however,
      the prognosis for complete recovery is poor once these deficits are present. This
      retrospective case-control study investigates the impact of diagnostic delays on
      outcome and explores the use of risk factor screening for early identification of
      SEA in a population of ED patients. Inpatients with a discharge diagnosis of SEA
      and a related ED visit before the admission were identified over a 10-year time
      period. In addition, a pool of ED patients presenting with a chief complaint of
      spine pain was generated; controls were hand-matched 2:1 to each SEA patient
      based on age and gender. Data regarding demographics, presence of risk factors,
      physical examination findings, laboratory and radiographic results, and clinical
      outcome were abstracted from medical records and entered into a database for
      further analysis. Patients with SEA were compared to matched controls with regard
      to the prevalence of risk factors and the "classic triad." We also explored the
      impact on outcome of diagnostic delays, defined as either: 1) multiple ED visits
      before diagnosis, or 2) admission without a diagnosis of SEA and >24 h to a
      definitive study. A total of 63 SEA patients were hand-matched to 126 controls
      with spine pain. Diagnostic delays were present in 75% of SEA patients. Residual
      motor weakness was present in 45% of these patients vs. only 13% of patients
      without diagnostic delays (odds ratio 5.65, 95% C.I. 1.15-27.71, p < 0.05). The
      "classic triad" of spine pain, fever, and neurologic abnormalities was present in
      13% of SEA patients and 1% of controls during the initial visit (p < 0.01); one
      or more risk factors were present in 98% of SEA patients and 21% of controls (p <
      0.01). The erythrocyte sedimentation rate (ESR) was more sensitive and specific
      than total white blood cell (WBC) count as a screen for SEA. In conclusion,
      diagnostic delays are common in patients with SEA, often leading to irreversible
      neurologic deficits. The use of risk factor assessment is more sensitive than the
      use of the classic diagnostic triad to screen ED patients with spine pain for
      SEA. The ESR may be a useful screening test before magnetic resonance imaging in
      selected patients.

PMID- 15028324
TI  - Impact of emergency medicine faculty on door to thrombolytic time.
AB  - The objective of this study was to determine the impact of Emergency Medicine
      (EM) faculty presence on timely thrombolytic therapy for acute myocardial
      infarction in the Emergency Department (ED). We performed a retrospective study
      of data regarding acute myocardial infarction patients in the ED of a large urban
      teaching hospital. Data were collected from January 1, 1998 to December 31, 1999
      when EM faculty were not present in the ED and from January 1, 2001 to December
      31, 2002 when they were. We compared median time from patient arrival to
      thrombolytics, percent of patients receiving thrombolytics within 30 min of
      arrival, and percent of patients with indications for primary revascularization
      who received it before and after EM faculty presence. The results indicate that
      EM faculty presence resulted in a decrease in median time from arrival to
      thrombolytic administration of 17 min (95% CI: 9, 28). Before EM faculty
      presence, the median time was 44 min as compared to 24 min post-EM faculty
      presence. Patients received thrombolytic therapy within 30 min 25.8% of the time
      before EM faculty presence as compared to 65.4% with EM faculty presence; an
      absolute increase of 39.6% (95% CI: 23.0%, 56.3%). Primary revascularization
      occurred in 56.9% of eligible patients pre-EM faculty presence and 81.4% post-EM
      faculty presence; an increase of 24.5% (95% CI: 13.6%, 35.4%). We conclude that
      the introduction of Emergency Medicine faculty significantly improved the quality
      of care for acute myocardial infarction patients in a large urban Emergency
      Department.

PMID- 15028326
TI  - Patient education and the Internet: do patients want us to provide them with
      medical web sites to learn more about their medical problems?
AB  - This study was performed to assess inner city Emergency Department (ED) patients'
      use of the Internet to obtain medical information, and patients' interest in
      being provided medical links by their ED physician to learn more about their
      medical condition. A convenience sample of inner city ED patients were surveyed
      regarding computer/Internet access, past searches for medical information, and
      whether they desired medical links provided with discharge paperwork. Of 328
      patients completing the survey, 178 (54%) had computers, whereas 150 (46%) had
      access to the Internet. Seventy-nine (24%) had previously used the World Wide Web
      (WWW) to obtain medical information, and 26 (33%) of these reported difficulty in
      obtaining useful information. One hundred ninety-two (59%) were interested or
      very interested in being provided links to medical sites. Patients more likely to
      want medical links were younger, college educated, and in higher salary ranges.
      There was no difference in desire to be provided links based on number of past
      medical problems or duration of symptoms. In conclusion, almost half the inner
      city ED patients in this survey have Internet access and over half were
      interested in being provided quality medical links as a part of their discharge
      paperwork.

PMID- 15028327
TI  - Fatal metabolic acidosis caused by thiamine deficiency.
AB  - Acute thiamine deficiency, an uncommon cause of hemodynamic instability in
      Western countries, may be manifested by acute heart failure and neurological
      deficits. Severe metabolic acidosis is one of its least recognized features. We
      present a report of foreign workers who complained of weakness and lower limb
      edema and were found to have acute thiamine deficiency. One died of refractory
      metabolic acidosis and shock, and the diagnosis was reached post mortem. Thiamine
      deficiency should be considered in every case of severe lactic acidosis without
      an obvious cause, especially in high-risk populations (malnourished, alcoholics,
      Far-East workers, etc). Whenever it is suspected, empiric treatment with thiamine
      should be initiated immediately. Physicians who care for populations at risk
      should be familiar with the clinical spectrum of nutritional deficits, and
      monitor the nutritional habits of these patients carefully. The treatment is
      inexpensive and devoid of adverse effects. Moreover, delaying thiamine
      administration in patients with deficiency may cause severe life-threatening
      metabolic acidosis and affect recovery. The prophylactic use of thiamine in a
      high-risk population, even before blood levels are received, may be cost
      effective.

PMID- 15028328
TI  - Cerebral infarcts in a pediatric patient secondary to phenylpropanolamine, a
      recalled medication.
AB  - Phenylpropanolamine (PPA) recently has been publicly implicated as a cause of
      stroke and other neurologic events. In November of 2000, the Food and Drug
      Administration (FDA) requested a voluntary recall of the product from all
      manufacturers. However, medications containing PPA still can be found in many
      homes of those unaware of the voluntary recall. We present a case of stroke after
      PPA ingestion that occurred 4 months after the recall in an 8-year-old boy on
      chronic peritoneal dialysis. The patient developed occipital infarcts and was
      found to have extremely elevated levels of PPA in his blood and dialysis fluid.
      Though the voluntary recall was in effect, the family already had a bottle of the
      medication at home. Physicians must be aware that the public is still ingesting
      the drug and remain rigorous in including its toxicity in the differential
      diagnosis of acute neurologic events.

PMID- 15028329
TI  - Are 1-2 tablets dangerous? Beta-blocker exposure in toddlers.
AB  - The common use and wide availability of beta-adrenergic blocking agents make them
      frequent ingestants for small children. Yet, there are no clear guidelines in the
      literature to direct the care of the toddler with the history of ingesting 1-2
      tablets. With 40 years of extensive clinical experience, not one documented case
      of death or serious cardiovascular morbidity as a direct result of a beta-blocker
      exposure is to be found in an English language review for children under 6 years
      of age. As with children on chronic beta-blocker therapy, several cases of
      symptomatic hypoglycemia associated with a single acute propranolol exposure
      suggest a vulnerability to this complication. Though the risk to the toddler
      exposed to 1-2 tablets appears to be extremely small, several factors mitigate
      the actual risk to the child and the need for triage to a health care facility.

PMID- 15028331
TI  - Ultrasound-guided suprapubic cystostomy catheter placement in the emergency
      department.
AB  - The purpose of this article is to describe a series of patients undergoing
      ultrasound-guided suprapubic cystostomy catheter placement in the Emergency
      Department. A series of 17 consecutive patients who underwent emergent real-time
      ultrasound-guided suprapubic cystostomy in the ED over a 2-year period is
      reported. The procedure was facilitated by direct ultrasound imaging of the
      bladder using a Digital Sonoace 5500 machine. Procedural notes and follow-up
      records were analyzed for efficacy, safety, and complications. The results
      demonstrated that trans-abdominal ultrasound confirmed urinary retention before
      drainage in each of the 17 cases enrolled. Each patient required emergent
      suprapubic cystostomy catheter placement for acute urinary outflow obstruction
      because urethral bladder catheterization was not possible or was contraindicated.
      Continuous real-time ultrasound-guided percutaneous suprapubic cystostomy
      placement and decompression of the bladder was successful in all 17 (100%, 90
      100% CI: 95%) cases. There were no complications reported. In conclusion, real
      time ultrasound imaging of the bladder was successful for the purpose of aiding
      the guidance of a suprapubic cystostomy catheter placement in the ED and might
      represent an improvement from the standard blind method presently used.

PMID- 15028330
TI  - CT evaluation of an anterior urethral tear.
AB  - A retrograde urethrogram is usually performed to evaluate the urethra in patients
      with suspected urethral injuries. A computed tomography (CT) scan is performed
      after the retrograde urethrogram to evaluate for further intrabdominal injuries.
      We present a case in which a CT scan performed after a retrograde urethrogram in
      a trauma patient identified a urethral tear.

PMID- 15028333
TI  - Emergency evaluation and treatment of priapism.
AB  - Priapism is a fairly uncommon presentation to the Emergency Department, but when
      it does present, it represents a true urologic emergency. Prompt treatment will
      decrease the risk of permanent sequelae including impotence. Treatment should be
      based on etiology and follow an organized approach. Various cases will arise when
      conservative management will not remedy the priapism and more aggressive measures
      will be needed, particularly if emergent urological consultation is not
      available. This article reviews the causes of priapism and systematically reviews
      techniques and procedures used to manage and treat priapism.

PMID- 15028334
TI  - Blunt renal trauma.

PMID- 15028335
TI  - Moyamoya disease: the clue from computed tomography.

PMID- 15028337
TI  - Severe infestation of cutaneous larva migrans.

PMID- 15028336
TI  - Radiologic findings in recurrent pyogenic cholangitis.

PMID- 15028338
TI  - Large osteosarcoma not apparent on conventional radiography.

PMID- 15028339
TI  - "Use of a gum elastic bougie (GEB) in a zone II penetrating neck trauma: a case
      report", by Steinfeldt J et al.

PMID- 15028341
TI  - "The history of anthrax", by Sternbach G.

PMID- 15028343
TI  - Primary spontaneous pneumothorax with clinical manifestation mimicking acute
      cholecystitis.

PMID- 15028345
TI  - Animal laboratories for procedural education of emergency medicine residents.
AB  - Many Emergency Medicine residencies incorporate animal laboratories into their
      training for procedural education because clinical opportunities to practice some
      emergency technical procedures are limited. To determine the proportion of
      Emergency Medicine residency programs utilizing animal laboratories, their
      characteristics, and the major impediments to providing animal laboratories, a
      cross-sectional descriptive survey of Emergency Medicine residency directors was
      conducted. Surveys were returned by 109/123 (89%) program directors. Ninety-four
      (87%) programs provide live animal laboratories for procedural training, an
      increase from previous studies. Although only 28% of directors knew the cost of
      the laboratories, this was the most commonly listed impediment (66%) to providing
      them. In conclusion, the use of animal laboratories for procedural training in
      Emergency Medicine residencies has increased in recent years. Cost is reported to
      be the most significant impediment to providing animal laboratories. The majority
      of program directors do not know the actual expense of providing animal
      laboratories.

PMID- 15028344
TI  - Report of two children with subacute sclerosing panencephalitis displaying an
      atypical clinical course.

PMID- 15028346
TI  - Comparing the guidelines: anticoagulation therapy to optimize stroke prevention
      in patients with atrial fibrillation.
AB  - Atrial fibrillation (AF) is an important risk factor for stroke. According to a
      pooled analysis of controlled clinical trials with warfarin, anticoagulation
      therapy reduces stroke risk by 62%. However, clinicians must decide whether the
      benefit of long-term anticoagulation therapy with available agents outweighs the
      risk of bleeding for individual patients. Guidelines issued by the American
      College of Chest Physicians and by the joint American College of Cardiology,
      American Heart Association, and the European Society of Cardiology task force
      recommend antithrombotic therapy to protect AF patients from stroke based on risk
      stratification algorithms. Risk factors for stroke AF patients include age > or
      =75 years; hypertension; thyrotoxicosis; diabetes; cardiovascular disease;
      congestive heart failure; and history of stroke, transient ischemic attack, or
      thromboembolism. Patients at high risk for stroke experience greater absolute
      benefit from anticoagulation therapy than patients at low risk. The guidelines
      are consistent in recommendations for high-risk patients (warfarin therapy,
      international normalized ratio 2.0 to 3.0) and low-risk patients (aspirin 325
      mg), but differ for intermediate-risk patients with diabetes or heart disease.
      The guidelines continue to evolve, and future guidelines are likely to
      incorporate new clinical data, including the CHADS(2) algorithm for determining
      risk and the results of the Atrial Fibrillation Follow-up Investigation of Rhythm
      Management trial, the Rate Control versus Electrical Cardioversion for Persistent
      Atrial Fibrillation study, and the Stroke Prevention Using an Oral Thrombin
      Inhibitor in Atrial Fibrillation II to V trials.

PMID- 15028347
TI  - Meta-analysis of randomized trials of percutaneous transluminal coronary
      angioplasty versus atherectomy, cutting balloon atherotomy, or laser angioplasty.
AB  - OBJECTIVES: We conducted a systematic overview (meta-analysis) of randomized
      trials of balloon angioplasty versus coronary atherectomy, laser angioplasty, or
      cutting balloon atherotomy to evaluate the effects of plaque modification during
      percutaneous coronary intervention. BACKGROUND: Several mechanical approaches
      have been developed that ablate or section atheromatous plaque during
      percutaneous coronary interventions to optimize acute results, minimize intimal
      injury, and reduce complications and restenosis. METHODS: Sixteen trials (9,222
      patients) constitute the randomized controlled experience with atherectomy,
      laser, or atherotomy versus balloon angioplasty with or without coronary
      stenting. Each trial tested the hypothesis that ablative therapy would result in
      better clinical or angiographic results than balloon dilation alone. RESULTS:
      Short-term death rates (<31 days) were not improved by the use of ablative
      procedures (0.3% vs. 0.4%, odds ratio [OR] 0.94 [95% confidence interval 0.46 to
      1.92]), but periprocedural myocardial infarctions (4.4% vs. 2.5%, OR 1.83 [95% CI
      1.43 to 2.34]) and major adverse cardiac events (5.1% vs. 3.3%, OR 1.54 [95% CI
      1.25 to 1.89]) were increased. Angiographic restenosis rates (6,958 patients)
      were not improved with the ablative devices (38.9% vs. 37.4%, OR 1.06 [95% CI
      0.97 to 1.17]). No reduction in revascularization rates (25.2% vs. 24.5%, OR 1.04
      [95% CI 0.94 to 1.14]) or cumulative adverse cardiac events rates up to one year
      after treatment were seen with ablative devices (27.8% vs. 26.1%, OR 1.09 [95% CI
      0.99 to 1.20]). CONCLUSIONS: The combined experience from randomized trials
      suggests that ablative devices failed to achieve predefined clinical and
      angiographic outcomes. This meta-analysis does not support the hypothesis that
      routine ablation or sectioning of atheromatous tissue is beneficial during
      percutaneous coronary interventions.

PMID- 15028348
TI  - Cutting balloon versus conventional balloon angioplasty for the treatment of in
      stent restenosis: results of the restenosis cutting balloon evaluation trial
      (RESCUT).
AB  - OBJECTIVES: The aim of this trial was to compare cutting balloon angioplasty
      (CBA) with conventional balloon angioplasty (i.e., percutaneous transluminal
      coronary angioplasty [PTCA]) for the treatment of patients with coronary in-stent
      restenosis (ISR). BACKGROUND: Retrospective studies suggest CBA might be superior
      to conventional PTCA in the treatment of ISR. METHODS: The Restenosis Cutting
      Balloon Evaluation Trial (RESCUT) is a multicenter, randomized, prospective
      European trial including 428 patients with all types of ISR (e.g., focal,
      multifocal, diffuse, proliferative). RESULTS: In both groups, the majority of ISR
      lesions were shorter than 20 mm. The length of restenotic stents was similar
      (CBA: 18.6 +/- 9.7 mm; PTCA: 18.3 +/- 8.7 mm). The number of balloons used to
      treat ISR was lower in the CBA group: only one balloon was used in 82.3% of CBA
      cases, compared with 75% of PTCA procedures (p = 0.03). Balloon slippage was less
      frequent in the CBA group (CBA 6.5%, PTCA 25%; p < 0.01). There was a trend
      toward a lower need for additional stenting in the CBA group (CBA 3.9%, PTCA
      8.0%; p = 0.07). At seven-month angiographic follow-up, the binary restenosis
      rate was not different between the groups (CBA 29.8%, PTCA 31.4%; p = 0.82), with
      a similar pattern of recurrent restenosis. Clinical events at seven months were
      also similar. CONCLUSIONS: Cutting balloon angioplasty did not reduce recurrent
      ISR and major adverse cardiac events, as compared with conventional PTCA.
      However, CBA was associated with some procedural advantages, such as use of fewer
      balloons, less requirement for additional stenting, and a lower incidence of
      balloon slippage.

PMID- 15028349
TI  - Heme oxygenase-1 genotype and restenosis after balloon angioplasty: a novel
      vascular protective factor.
AB  - OBJECTIVES: We investigated the association of the heme oxygenase-1 (HO-1)
      promoter genotype with the inflammatory response and restenosis after balloon
      angioplasty. BACKGROUND: Heme oxygenase-1, which is induced by balloon
      angioplasty, can inhibit neointima formation and vascular remodeling. A
      dinucleotide repeat in the HO-1 gene promoter shows a length polymorphism that
      modulates HO-1 gene transcription. Short (<25 guanosine thymidine [GT]) repeats
      are associated with a 10-fold greater up-regulation of HO-1 than are longer
      repeats. METHODS: We studied 381 consecutive patients who underwent
      femoropopliteal balloon angioplasty (n = 210) and comparison groups with
      femoropopliteal stenting (n = 68) and lower limb angiography (n = 103). C
      reactive protein (CRP) was measured at baseline, 24, and 48 h. We evaluated
      patency at six months by duplex sonography and assessed the association of the
      length of GT repeats in the HO-1 gene promoter with postintervention CRP and
      restenosis. RESULTS: Restenosis within six months was found in 74 patients (35%)
      after balloon angioplasty and in 21 patients (31%) after stenting. After balloon
      angioplasty, carriers of the short length (<25 GT) dinucleotide repeats had a
      lower postintervention CRP at 24 h (p = 0.009) and 48 h (p < 0.001) and a reduced
      risk for restenosis (adjusted relative risk 0.43, 95% confidence interval: 0.24
      to 0.71, p < 0.001) compared with patients with longer alleles. After stenting or
      angiography, we found no association between the HO-1 genotype with CRP or
      restenosis. CONCLUSIONS: The HO-1 promoter genotype that controls the degree of
      HO-1 up-regulation in response to stress stimuli is associated with the
      postintervention inflammatory response and the restenosis risk after balloon
      angioplasty.

PMID- 15028350
TI  - Implication of different cardiac troponin I levels for clinical outcomes and
      prognosis of acute chest pain patients.
AB  - OBJECTIVES: We compared outcomes in patients with non-ST-segment elevation acute
      coronary syndromes (ACS) according to the degree of cardiac troponin I (cTnI)
      elevation. BACKGROUND: Controlled trials of high-risk patients have found that
      troponin elevations identify an even higher risk subset. It is unclear whether
      outcomes are similar among a lower risk, heterogeneous patient group. Also, few
      studies have reported outcomes other than myocardial infarction (MI) or death,
      based on the peak troponin value. METHODS: Consecutively, admitted patients
      without ST-segment elevation on the initial electrocardiogram underwent serial
      marker sampling using creatine kinase (CK), CK-MB fraction, and cTnI. Patients
      were grouped according to peak cTnI: negative = no detectable cTnI; low = peak
      greater than the lower limit of detectability but less than the optimal
      diagnostic value; intermediate = peak greater than or equal to the optimal
      diagnostic value but less than the manufacturer's suggested upper reference limit
      (URL); and high = peak greater than or equal to the URL. Thirty-day outcomes
      included cardiac death, MI based on CK-MB, revascularization, significant
      disease, and a reversible defect on stress testing. Six-month mortality was also
      determined. Negative evaluations for ischemia included nonsignificant disease, no
      reversible stress defect, and negative rest perfusion imaging. RESULTS: Of the
      4,123 patients admitted, 893 (22%) had detectable cTnI values. Cardiac events and
      positive test results at 30 days and 6-month mortality increased significantly
      with increasing cTnI values. Negative evaluations for ischemia were significantly
      and inversely related to peak cTnI values. Although adverse events were
      significantly more common in patients with a low cTnI value than in those with
      negative cTnI, negative evaluations for ischemia were frequent. CONCLUSIONS:
      Increased cTnI values are associated with worse outcomes. Although low cTnI
      values are associated with adverse events, they do not have the same implication
      as higher cTnI values, and nonischemic evaluations are frequent.

PMID- 15028351
TI  - Administration of eptifibatide to acute coronary syndrome patients receiving
      enoxaparin or unfractionated heparin: effect on platelet function and thrombus
      formation.
AB  - OBJECTIVES: The goal of this study was to compare the antithrombotic effects of
      enoxaparin versus unfractionated heparin (UFH) when combined with eptifibatide in
      acute coronary syndrome (ACS) patients. BACKGROUND: An increasing number of high
      risk ACS patients are treated with low-molecular-weight heparin and a
      glycoprotein (GP) IIb/IIIa inhibitor. There is a paucity of data regarding the
      antithrombotic properties of such a combination as compared with UFH and GP
      IIb/IIIa inhibitors. METHODS: Twenty-six ACS patients scheduled to undergo
      coronary angiography were treated with subcutaneous enoxaparin (n = 13) or
      intravenous UFH (n = 13). All patients received eptifibatide just before coronary
      angiography. Antithrombotic effects were assessed as changes in platelet-thrombus
      formation using the Badimon ex vivo perfusion chamber. Perfusions were carried
      out at a high shear rate (HSR) and a low shear rate (LSR). Patients underwent two
      perfusion studies: at baseline (under enoxaparin or UFH) and 10 min after the
      eptifibatide bolus. Platelet function was evaluated by ADP-induced platelet
      aggregation and the rapid platelet function analyzer. RESULTS: Both therapeutic
      combinations achieved a marked reduction in platelet aggregation after
      eptifibatide (83% to 89.7% reduction in the enoxaparin-eptifibatide group and
      77.8% to 85.5% reduction in the UFH-eptifibatide group, inter-group differences
      not significant). Both groups also demonstrated marked reductions in thrombus
      formation, but the reductions achieved in the enoxaparin-eptifibatide group were
      significantly higher than those achieved in the UFH-eptifibatide group (HSR:
      75.6% reduction vs. 63.9%, respectively, p = 0.01; LSR: 79.7% reduction vs.
      66.1%, respectively, p = 0.0001). CONCLUSIONS: The combination of eptifibatide
      with enoxaparin appears to have a more potent antithrombotic effect than that of
      eptifibatide and UFH in the doses tested.

PMID- 15028352
TI  - Aspirin dose and six-month outcome after an acute coronary syndrome.
AB  - OBJECTIVES: This study was designed to compare the efficacy of low and
      intermediate aspirin doses in acute coronary syndromes. BACKGROUND: Little is
      known of the comparative efficacy of low and intermediate aspirin doses in this
      setting. METHODS: We compared six-month death, myocardial infarction (MI), and
      stroke in patients with unstable angina or acute MI discharged while receiving
      low (<150 mg) or intermediate (> or =150 mg) aspirin therapy in the GUSTO IIb and
      PURSUIT trials (n = 20,521). We used multivariable analysis and performed a
      propensity analysis in order to adjust for baseline imbalances between the
      groups. RESULTS: Aspirin doses <150 mg were prescribed to 29.9% (6,128) of
      patients. By six months, 6.4% of the patients (1,310 of 20,521) had a primary
      event, 6.2% of the patients receiving <150 mg and 6.6% of the patients receiving
      aspirin doses > or =150 mg (hazard ratio [HR] 1.06 [95% confidence interval (CI)
      0.94 to 1.19], p = 0.35). After adjusting for baseline imbalances and the
      propensity score for discharge aspirin dose, there was no effect of aspirin dose
      on the composite end point at six months (HR 0.92 [95% CI 0.79 to 1.07], p =
      0.28). However, the higher aspirin dose was associated with a reduction in six
      month MI (HR 0.79 [95% CI 0.64 to 0.98], p = 0.03). The outcome was similar when
      patients were matched on the basis of the propensity score for aspirin dose (HR
      for death/MI/stroke 0.94 [95% CI 0.80 to 1.12], p = 0.51), although stroke
      occurred significantly more frequently among patients receiving the higher
      aspirin dose (HR 1.74 [95% CI 1.01 to 3.02] p = 0.05) and the effect on MI was no
      longer apparent. CONCLUSIONS: Although these data are non-randomized, they
      suggest that the aspirin dose upon discharge may influence the clinical course
      after unstable angina or acute MI.

PMID- 15028353
TI  - Inhibition of platelet aggregation by aspirin progressively decreases in long
      term treated patients.
AB  - OBJECTIVES: We sought to investigate, during a two-year follow-up period, the
      effects of aspirin on platelet aggregation. BACKGROUND: The platelets of patients
      given aspirin may be less sensitive to antiplatelet treatment, although the
      extent of such phenomenon over long-term follow-up is unclear. METHODS: Adenosine
      diphosphate (ADP) and collagen-induced platelet aggregation was periodically
      monitored before and after 2, 6, 12, and 24 months of treatment with aspirin (n =
      150) or ticlopidine (n = 80) in patients matched for gender, age, and risk
      factors for atherothrombosis. RESULTS: Compared with baseline values, two months
      of aspirin treatment significantly inhibited platelet aggregation; thereafter,
      this inhibitory effect progressively decreased. At 24-month follow-up, collagen
      induced platelet aggregation was significantly higher than that observed at two
      months (p < 0.05); a more pronounced difference was observed when collagen
      induced lag phase was considered (p < 0.01). Restoration of platelet aggregation
      was less evident when ADP was used as an agonist. Conversely, the inhibition
      induced by ticlopidine was constant throughout follow-up with both agonists.
      CONCLUSIONS: The study demonstrates that a long-term treatment with aspirin is
      associated with a progressive reduction in platelet sensitivity to this drug.

PMID- 15028354
TI  - The effects of nonselective non-aspirin non-steroidal anti-inflammatory
      medications on the risk of nonfatal myocardial infarction and their interaction
      with aspirin.
AB  - OBJECTIVES: This study was designed to determine if non-aspirin non-steroidal
      anti-inflammatory drugs (NANSAIDs) are associated with lower odds of myocardial
      infarction (MI) and if NANSAIDs, particularly ibuprofen, interfere with aspirin's
      cardioprotective effect. BACKGROUND: The NANSAIDs may reduce the risk of MI but
      may also interfere with aspirin's cardioprotective effect. METHODS: A case
      control study was conducted, with cases of first, nonfatal MI identified
      prospectively and controls identified randomly from the community. RESULTS: The
      use of NANSAIDs was associated with a significant reduction in MI among those not
      using aspirin (adjusted odds ratio [OR] 0.53; 95% confidence interval [CI]: 0.42
      to 0.67). This was true for both ibuprofen (adjusted OR 0.52; 95% CI: 0.39 to
      0.69) and naproxen (adjusted OR 0.48; 95% CI: 0.28 to 0.82). Although aspirin
      itself was associated with decreased odds of MI in those not also using NANSAIDs
      (adjusted OR relative to no aspirin use 0.79; 95% CI: 0.63 to 0.98), it was not
      associated with decreased odds of MI among those who were using NANSAIDs (OR
      1.28; 95% CI: 0.85 to 1.94; p value for interaction = 0.026). The association of
      aspirin and reduced odds of MI diminished with increasing frequency of NANSAID
      use (test for interaction p = 0.006), particularly for ibuprofen (p = 0.018).
      Among frequent (4 times/week) NANSAID users, the OR for aspirin versus no aspirin
      was 2.04 (95% CI: 1.06 to 3.94). Users of prophylactic aspirin plus frequent
      ibuprofen had an OR relative to aspirin-only users of 2.03 (95% CI: 0.60 to
      6.84). CONCLUSIONS: In the absence of aspirin use, NANSAIDs are associated with
      reduced odds of MI. In those using aspirin, NANSAIDs do not provide additional
      protection. Additional study is needed to determine the clinical impact of using
      NANSAIDs along with aspirin for cardioprotection.

PMID- 15028355
TI  - The case for an adverse interaction between aspirin and non-steroidal anti
      inflammatory drugs: is it time to believe the hype?

PMID- 15028356
TI  - Preservation of the anterior fat pad paradoxically decreases the incidence of
      postoperative atrial fibrillation in humans.
AB  - OBJECTIVES: The goal of this study was to determine if parasympathetic nerves in
      the anterior fat pad (FP) can be stimulated at the time of coronary artery bypass
      surgery (CABG), and if dissection of this FP decreases the incidence of
      postoperative atrial fibrillation (AF). BACKGROUND: The human anterior epicardial
      FP contains parasympathetic ganglia and is often dissected during CABG. Changes
      in parasympathetic tone influence the incidence of AF. METHODS: Fifty-five
      patients undergoing CABG were randomized to anterior FP preservation (group A) or
      dissection (group B). Nerve stimulation was applied to the FP before and after
      surgery. Sinus cycle length (CL) was measured during stimulation. The incidence
      of postoperative AF was recorded. RESULTS: Of the 55 patients enrolled, 26
      patients were randomized to group A, and 29 patients were randomized to group B.
      In all of the 55 patients, the FP was identified before initiating
      cardiopulmonary bypass by CL prolongation with stimulation (865.5 +/- 147.9 ms
      vs. 957.9 +/- 155.1 ms, baseline vs. stimulation, p < 0.001). In group A,
      stimulation at the conclusion of surgery increased sinus CL (801.8 +/- 166.4 ms
      vs. 890.9 +/- 178.2 ms, baseline vs. stimulation, p < 0.001). In group B, repeat
      stimulation failed to increase sinus CL (853.6 +/- 201.6 ms vs. 841.4 +/- 198.4
      ms, baseline vs. stimulation, p = NS). The incidence of postoperative AF in group
      A (7%) was significantly less than that in group B (37%) (p < 0.01). CONCLUSIONS:
      This is the first study demonstrating that direct stimulation of the human
      anterior epicardial FP slows sinus CL. This parasympathetic effect is eliminated
      with FP dissection. Preservation of the human anterior epicardial FP during CABG
      decreases incidence of postoperative AF.

PMID- 15028357
TI  - Postoperative atrial fibrillation: a billion-dollar problem.

PMID- 15028358
TI  - Pulmonary vein isolation for the treatment of atrial fibrillation in patients
      with impaired systolic function.
AB  - OBJECTIVES: We aimed to determine the safety and efficacy of pulmonary vein
      isolation (PVI) in atrial fibrillation (AF) patients with impaired left
      ventricular (LV) systolic function. BACKGROUND: To date, PVI has been performed
      primarily in patients with normal LV function. Yet, many AF patients have
      impaired LV systolic function. The outcomes of PVI in patients with impaired LV
      systolic function are unknown. METHODS: We included 377 consecutive patients
      undergoing PVI between December 2000 and January 2003. Ninety-four patients had
      impaired LV function (ejection fraction [EF] <40%), and they comprised the study
      group. The control group was the remaining 283 patients who had a normal EF. End
      points included AF recurrence and changes in EF and quality of life (QoL).
      RESULTS: Mean EF was 36% in our study group, compared with 54% in controls. After
      initial PVI, 73% of patients with impaired EF and 87% of patients with normal EF
      were free of AF recurrence at 14 +/- 6 months (p = 0.03). In the study group,
      there was a nonsignificant increase in EF of 4.6% and significant improvement in
      QoL. Complication rates were low and included a 1% risk of pulmonary vein
      stenosis. CONCLUSIONS: Although the AF recurrence rate after initial PVI in
      impaired EF patients was higher than in normal EF subjects, nearly three-fourths
      of patients with impaired EF remained AF-free. Although our sample size was
      nonrandomized, our results suggest PVI may be a feasible therapeutic option in AF
      patients with impaired EF. Randomized studies with more patients and longer
      follow-up are warranted.

PMID- 15028359
TI  - Pulmonary vein isolation for atrial fibrillation in low ejection fraction
      patients: the market is growing!

PMID- 15028360
TI  - Left ventricular mechanics during right ventricular apical or left ventricular
      based pacing in patients with chronic atrial fibrillation after atrioventricular
      junction ablation.
AB  - OBJECTIVES: The aim of the study was to evaluate whether left ventricular (LV)
      mechanics are better under LV-based pacing than under right ventricular (RV)
      apical pacing in patients with permanent atrial fibrillation (AF) after
      atrioventricular junction (AVJ) ablation. BACKGROUND: "Ablate and pace" is an
      acceptable therapy for drug-refractory AF. However, the RV apical stimulation
      commonly used seems to interfere with the beneficial hemodynamic effect of
      regularization of heart rhythm. METHODS: The study included 12 patients (5 men,
      mean age 62 +/- 8.3 years), 6 with impaired and 6 with normal LV systolic
      function. All of them had a biventricular pacemaker system implanted and
      underwent atrioventricular node ablation for drug-refractory chronic AF. Using a
      conductance catheter, we analyzed LV pressure-volume loops during routine
      coronary angiography in order to evaluate short-term changes in LV mechanics
      during RV apical and LV-based (LV free wall or biventricular) pacing. RESULTS:
      Compared with RV pacing, LV-based pacing significantly improved the indexes of LV
      systolic function (i.e., end-systolic pressure and volume, cardiac index, stroke
      work, preload recruitable stroke work, maximal rate of rise of LV pressure
      [dP/dt(max)], LV ejection fraction, and end-systolic elastance). The LV diastolic
      filling indexes, end-diastolic pressure and volume, were better during LV-based
      pacing, whereas LV diastolic function indexes, -dP/dt(max), passive diastolic
      chamber stiffness, and time constant of LV isovolumic relaxation showed no clear
      change. CONCLUSIONS: In the short term, LV-based pacing is superior to RV apical
      pacing in terms of contractile function and LV filling after AVJ ablation for
      drug-refractory AF.

PMID- 15028361
TI  - Cost-effectiveness of screening with B-type natriuretic peptide to identify
      patients with reduced left ventricular ejection fraction.
AB  - OBJECTIVES: This study was designed to evaluate the cost-effectiveness of
      screening patients with a B-type natriuretic peptide (BNP) blood test to identify
      those with depressed left ventricular systolic function. BACKGROUND: Asymptomatic
      patients with depressed ejection fraction (EF) may have less progression to heart
      failure if they can be identified and treated. METHODS: We used a decision model
      to estimate economic and health outcomes for different screening strategies using
      BNP and echocardiography to detect left ventricular EF <40% for men and women age
      60 years. We used published data from community cohorts (gender-specific BNP test
      characteristics, prevalence of depressed EF) and randomized trials (benefit from
      treatment). RESULTS: Screening 1,000 asymptomatic patients with BNP followed by
      echocardiography in those with an abnormal test increased the lifetime cost of
      care (176,000 US dollars for men, 101,000 US dollars for women) and improved
      outcome (7.9 quality-adjusted life years [QALYs] for men, 1.3 QALYs for women),
      resulting in a cost per QALY of 22,300 US dollars for men and 77,700 US dollars
      for women. For populations with a prevalence of depressed EF of at least 1%,
      screening with BNP followed by echocardiography increased outcome at a cost <
      50,000 US dollars per QALY gained. Screening would not be attractive if a
      diagnosis of left ventricular dysfunction led to significant decreases in quality
      of life or income. CONCLUSIONS: Screening populations with a 1% prevalence of
      reduced EF (men at age 60 years) with BNP followed by echocardiography should
      provide a health benefit at a cost that is comparable to or less than other
      accepted health interventions.

PMID- 15028362
TI  - The effects of cardiac resynchronization therapy on left ventricular function,
      myocardial energetics, and metabolic reserve in patients with dilated
      cardiomyopathy and heart failure.
AB  - OBJECTIVES: The effects of long-term cardiac resynchronization therapy (CRT) on
      left ventricular (LV) energetics and metabolic reserve were evaluated.
      BACKGROUND: Cardiac resynchronization therapy is a new therapy for patients with
      drug-refractory severe heart failure (HF). METHODS: Ten patients with idiopathic
      dilated cardiomyopathy who had undergone implantation of biventricular pacemaker
      8 +/- 5 months earlier were studied during two conditions: CRT switched on, and
      after CRT was switched off for 24 h. Left ventricular function was measured using
      echocardiography and oxidative metabolism using [(11)C]acetate positron emission
      tomography. Both measurements were performed at rest and during dobutamine
      induced stress (5 microg/kg/min). Basal- and adenosine-stimulated (140
      microg/kg/min) myocardial blood flow were quantitated using [(15)O]water.
      RESULTS: During CRT off, LV stroke volume was significantly reduced at rest (72
      +/- 18 ml vs. 63 +/- 15 ml, p < 0.05), but LV oxidative metabolism (K(mono))
      remained unchanged (0.046 +/- 0.008 vs. 0.054 +/- 0.016 min(-1)) leading to a
      significant deterioration of myocardial efficiency of forward work (from 48.2 +/-
      16.7 to 36.6 +/- 11.7 mm Hg.l/g, p < 0.05). During dobutamine-induced stress,
      stroke volume and K(mono) values were not different whether CRT was on or off.
      However, myocardial efficiency (56.1 +/- 16.1 vs. 49.8 +/- 18.0 mm Hg.ml.g(
      1).min(-1), p = 0.099) and metabolic reserve, the response of K(mono) to
      dobutamine (0.023 +/- 0.014 vs. 0.013 +/- 0.014 min(-1), p = 0.09), tended to
      reduce when CRT was switched off. Cardiac resynchronization therapy had no
      effects on myocardial perfusion. Natriuretic peptides increased significantly
      during CRT-off period. CONCLUSIONS: Long-term CRT has beneficial effects on LV
      function and myocardial efficiency at rest in patients with HF. These effects are
      not associated with changes in myocardial perfusion or oxygen consumption. During
      dobutamine-induced stress, CRT does not affect functional parameters, but
      myocardial efficiency and metabolic reserve may be increased.

PMID- 15028363
TI  - Glucose intolerance, as reflected by hemoglobin A1c level, is associated with the
      incidence and severity of transplant coronary artery disease.
AB  - OBJECTIVES: The possible effect of plasma hemoglobin A(1c) (HbA(1c)) on the
      development of transplant coronary artery disease (TxCAD) was investigated.
      BACKGROUND: Glucose intolerance is implicated as a risk factor for TxCAD.
      However, a relationship between HbA(1c) and TxCAD has not been demonstrated.
      METHODS: Plasma HbA(1c) was measured in 151 adult patients undergoing routine
      annual coronary angiography at a mean period of 4.1 years after heart
      transplantation. Intracoronary ultrasound (ICUS) was also performed in 42
      patients. Transplant CAD was graded by angiography as none, mild (stenosis in any
      vessel < or =30%), moderate (31% to 69%), or severe (> or =70%) and was defined
      by ICUS as a mean intimal thickness (MIT) > or =0.3 mm in any coronary artery
      segment. The association between TxCAD and established risk factors was examined.
      RESULTS: Plasma HbA(1c) increased with the angiographic grade of TxCAD (5.6%,
      5.8%, 6.4%, and 6.2% for none, mild, moderate, and severe disease, respectively;
      p < 0.05 for none vs. moderate or severe) and correlated with disease severity (r
      = 0.24, p < 0.05). The HbA(1c) level was higher in patients with MIT > or =0.3 mm
      than in those with MIT <0.3 mm (6.4% vs. 5.7%, p < 0.05). Multivariate logistic
      regression analysis identified HbA(1c) as an independent predictor of TxCAD, as
      detected by angiography or ICUS (odds ratios 1.9 and 2.4, 95% confidence
      intervals 1.5 to 6.3 [p = 0.010] and 1.3 to 4.2 [p < 0.005], respectively).
      CONCLUSIONS: Persistent glucose intolerance, as reflected by plasma HbA(1c), is
      associated with the occurrence of TxCAD and may play an important role in its
      pathogenesis.

PMID- 15028364
TI  - Day-hospital treatment of acute pericarditis: a management program for outpatient
      therapy.
AB  - OBJECTIVES: We sought to investigate the safety and efficacy of a protocol for
      acute pericarditis triage and outpatient management of low-risk cases.
      BACKGROUND: Acute pericarditis has generally a brief and benign course after
      empiric treatment by non-steroidal anti-inflammatory drugs, and routine
      hospitalization of most patients may be unnecessary. METHODS: From January 1996
      to December 2001, all consecutive cases of acute pericarditis were evaluated on a
      day-hospital basis. Patients without clinical poor prognostic predictors (fever
      >38 degrees C, subacute onset, immunodepression, trauma, oral anticoagulant
      therapy, myopericarditis, severe pericardial effusion, cardiac tamponade) were
      considered low-risk cases and assigned to outpatient treatment with high-dose
      oral aspirin. Patients with poor prognostic predictors or aspirin failure were
      hospitalized for etiology search and treatment. A clinical and echocardiographic
      follow-up was performed at 48 to 72 h, 7 to 10 days, 1 month, 6 months, and 1
      year. RESULTS: Two hundred fifty-four out of 300 (84.7%) patients were selected
      as low-risk cases. Outpatient treatment was efficacious in 221 out of 254 (87%)
      cases. Thirty-three out of 254 patients were hospitalized because of aspirin
      failure. Patients treated on an out-of-hospital basis had no serious
      complications after a mean follow-up of 38 months (no cases of cardiac
      tamponade). A higher frequency of recurrences and constriction was recorded in
      aspirin-resistant cases than in aspirin responders (60.6% vs. 10.4% for
      recurrences and 9.1% vs. 0.5% for constriction, respectively; all p < 0.01).
      CONCLUSIONS: A protocol for acute pericarditis triage and outpatient therapy of
      low-risk cases is safe and efficacious and may reduce management costs.

PMID- 15028365
TI  - Cardiovascular risk reduction in hypertensive black patients with left
      ventricular hypertrophy: the LIFE study.
AB  - OBJECTIVES: We report on a subanalysis of the effects of losartan and atenolol on
      cardiovascular events in black patients in the Losartan Intervention For Endpoint
      reduction in hypertension (LIFE) study. BACKGROUND: The LIFE study compared
      losartan-based to atenolol-based therapy in 9,193 hypertensive patients with left
      ventricular hypertrophy (LVH). Overall, the risk of the primary composite end
      point (cardiovascular death, stroke, myocardial infarction) was reduced by 13% (p
      = 0.021) with losartan, with similar blood pressure (BP) reduction in both
      treatment groups. There was a suggestion of interaction between ethnic background
      and treatment (p = 0.057). METHODS: Exploratory analyses were performed that
      placed LIFE study patients into black (n = 533) and non-black (n = 8,660)
      categories, overall, and in the U.S. (African American [n = 523]; non-black [n =
      1,184]). RESULTS: A significant interaction existed between the dichotomized
      groups (black/non-black) and treatment (p = 0.005); a test for qualitative
      interaction was also significant (p = 0.016). The hazard ratio (losartan relative
      to atenolol) for the primary end point favored atenolol in black patients (1.666
      [95% confidence interval (CI) 1.043 to 2.661]; p = 0.033) and favored losartan in
      non-blacks (0.829 [95% CI 0.733 to 0.938]; p = 0.003). In black patients, BP
      reduction was similar in both groups, and regression of electrocardiographic-LVH
      was greater with losartan. CONCLUSIONS: Results of the subanalysis are sufficient
      to generate the hypothesis that black patients with hypertension and LVH might
      not respond as favorably to losartan-based treatment as non-black patients with
      respect to cardiovascular outcomes, and do not support a recommendation for
      losartan as a first-line treatment for this purpose. The subanalysis is limited
      by the relatively small number of events.

PMID- 15028366
TI  - Reduction in C-reactive protein through cardiac rehabilitation and exercise
      training.
AB  - OBJECTIVES: This study was designed to assess the effects of three-month formal
      phase II cardiac rehabilitation and exercise training programs on high
      sensitivity C-reactive protein (HSCRP) levels in patients with coronary heart
      disease (CHD). BACKGROUND: High-sensitivity C-reactive protein is associated with
      abdominal adiposity and other CHD risk factors and is a potent independent
      predictor of CHD events. Although weight reduction and statin therapy reduce
      HSCRP levels, the independent effects of cardiac rehabilitation programs on HSCRP
      are not well established. METHODS: We analyzed plasma levels of HSCRP in 277
      patients with CHD (235 consecutive patients before and after formal phase II
      cardiac rehabilitation and exercise training programs and 42 "control" patients
      who did not attend cardiac rehabilitation). Additionally, we determined the
      effects of cardiac rehabilitation on HSCRP independent of statin therapy and
      weight loss. RESULTS: Rehabilitation patients improved significantly in body fat,
      obesity indices, exercise capacity, and other cardiac risk factors. Mean (5.9 +/-
      7.7 to 3.8 +/- 5.8 mg/l; -36%; p < 0.0001) and median levels of HSCRP (-41%; p =
      0.002) decreased significantly in the rehabilitation group but not in the control
      population. Similar significant reductions in HSCRP occurred in the
      rehabilitation patients regardless of whether they received statin therapy or
      lost weight. CONCLUSIONS: Therapeutic lifestyle changes effected through a three
      month cardiac rehabilitation program significantly improved numerous cardiac risk
      factors. Through this holistic approach to secondary prevention, we observed
      significant reductions in HSCRP levels. These findings identify another clinical
      modality of reducing HSCRP beyond use of statin drugs and suggest an additional
      benefit of formal phase II cardiac rehabilitation and exercise training programs.

PMID- 15028367
TI  - Long-term outcome (up to 15 years) of balloon angioplasty of discrete native
      coarctation of the aorta in adolescents and adults.
AB  - OBJECTIVES: This study evaluated the long-term follow-up results of balloon
      angioplasty (BA) in adolescent and adult patients with discrete coarctation of
      the aorta. BACKGROUND: Although the immediate and intermediate term results of BA
      for patients with aortic coarctation (AC) have been encouraging, there is a
      paucity of data on long-term follow-up results. METHODS: This basis of this study
      was follow-up of 49 patients (mean age, 22 +/- 7 years) undergoing BA for
      discrete AC at median interval of 10.2 years, including cardiac catheterization,
      magnetic resonance imaging, and Doppler echocardiography. RESULTS: No early or
      late deaths occurred. Balloon angioplasty produced a reduction in peak AC
      gradient from 66 +/- 23 mm Hg (95% confidence interval [CI]: 59.5 to 72.7) to
      10.8 +/- 7 mm Hg (95% CI: 8.8 to 12.5) (p < 0.0001). Follow-up catheterization 12
      months later revealed a residual gradient of 6.2 +/- 6 mm Hg (95% CI: 4.4 to 7.9)
      (p < 0.001). Four patients (7.5%) with suboptimal initial outcome with peak
      gradient >20 mm Hg had successful repeat angioplasty. Aneurysm developed at the
      site of dilation in four patients (7.5%). Magnetic resonance imaging follow-up
      results revealed no new aneurysm or appreciable changes in the size of pre
      existing aneurysms, and no recoarctation was observed. Also, no appreciable
      changes in the Doppler gradient across the AC site were noted. The blood pressure
      had normalized without medication in 31 (63%) of the 49 patients. CONCLUSIONS:
      Long-term results of BA for discrete AC are excellent and should be considered as
      first option for treatment of this disease.

PMID- 15028368
TI  - Factors associated with impaired clinical status in long-term survivors of
      tetralogy of Fallot repair evaluated by magnetic resonance imaging.
AB  - OBJECTIVES: The purpose of this study was to identify independent factors
      associated with impaired clinical status in late survivors of tetralogy of Fallot
      (TOF) repair. BACKGROUND: Repair of TOF often results in chronic pulmonary
      regurgitation (PR) and right ventricular (RV) dilation, which have been linked to
      late morbidity and mortality. However, determinants of clinical status late after
      TOF repair have not been fully characterized. METHODS: The clinical and
      laboratory data of 100 consecutive patients with repaired TOF (median 21 years
      after repair) who completed a cardiac magnetic resonance imaging protocol were
      analyzed. Impaired clinical status was defined as New York Heart Association
      (NYHA) functional class > or =III. RESULTS: Of the patients, 88 were in NYHA
      functional class I or II and 12 were in NYHA functional class III. The degree of
      PR and indexed RV end-diastolic volume were not associated with impaired clinical
      status. By multivariate analysis, a lower left ventricular (LV) ejection fraction
      (EF) (odds ratio [OR] = 3.88 for 10% decrease, p = 0.002) and older age at TOF
      repair (OR = 1.70 for 5-year increase, p = 0.013) were the strongest independent
      factors associated with impaired clinical status. Among RV variables, a lower RV
      EF was the strongest independent factors associated with poor clinical status (OR
      = 2.41 for 10% decrease, p = 0.01). The LV EF correlated with RV EF (r = 0.58, p
      < 0.001). CONCLUSIONS: Moderate or severe LV or RV systolic dysfunction, but not
      PR fraction or RV diastolic dimensions, is independently associated with impaired
      clinical status in long-term survivors of TOF repair. The close relationship
      between LV EF and RV EF suggests unfavorable ventricular-ventricular interaction.

PMID- 15028369
TI  - Aortic elastic properties and left ventricular diastolic function in patients
      with Adamantiades-Behcet's disease.
AB  - OBJECTIVES: We investigated whether Adamantiades-Behcet's disease (ABD) is
      related to impaired aortic (Ao) elastic properties and left ventricular (LV)
      function. BACKGROUND: Adamantiades-Behcet's disease is an inflammatory disorder
      characterized by vasculitis leading to vascular complications and, rarely,
      myocarditis. METHODS: We studied 82 patients with ABD (age: 40 +/- 12 years) and
      24 normal control subjects by echocardiography. Abdominal Ao diameter (mm/m(2))
      and Ao elastic indexes--namely, Ao strain (%), distensibility (cm(2) x dyn(-1)x
      10(-6)), stiffness index, and pressure strain modulus (Ep) (cm(2) x dyn(-1) x 10(
      6))--were calculated from the echocardiographically derived thoracic Ao diameters
      (mm/m(2)), and the measurement of pulse pressure obtained by cuff
      sphygmomanometry. Isovolumic relaxation time (IVRT) (ms), deceleration time (DT)
      (ms), and flow propagation velocity (FPV) (cm/s) were measured by Doppler
      echocardiography to assess diastolic LV function. The duration of disease and
      presence of vascular complications were noted. RESULTS: Patients versus control
      subjects had increased Ao diameters (p < 0.01), lower mean Ao strain and
      distensibility (4 vs. 9 and 1.4 vs. 3.4, respectively, p < 0.01), higher mean
      aortic stiffness index and Ep (15.6 vs. 6 and 1.17 vs. 0.44, respectively, p <
      0.01), and impaired IVRT and FPV (p < 0.01). Aortic function indexes were related
      to the duration of disease (p < 0.01) and increased DT (p < 0.01). Deceleration
      time >190 ms predicted vascular complications with 80% sensitivity and 71%
      specificity (odds ratio 6.52 [confidence interval: 2.23 to 19.03]). CONCLUSION:
      Aortic elastic properties and diastolic LV function are impaired in patients with
      ABD and are interrelated. The link between diastolic LV dysfunction and vascular
      complications suggests the presence of a common pathophysiologic pathway and
      provides a possible marker of risk for vascular disease.

PMID- 15028370
TI  - Percutaneous pulmonary valve replacement in a large right ventricular outflow
      tract: an experimental study.
AB  - OBJECTIVES: We report our initial experience with percutaneous pulmonary valve
      replacement in animals with large pulmonary trunks, using a modified percutaneous
      approach. BACKGROUND: Percutaneous pulmonary valve replacement has recently been
      introduced, and early clinical experience has been reported. This technique is
      presently limited to patients with a right ventricular outflow tract no bigger
      than 22 mm in diameter. METHODS: In seven animals (groups 1 and 3), we implanted
      a newly designed nitinol stent in the shape of a conduit with a central
      restriction of its diameter, containing an 18-mm bovine valve, as a one-step
      procedure. The animals in groups 1 and 3 were sacrificed after valve implantation
      and after two-month follow-up, respectively. In the second group (n = 3), we
      expected to percutaneously reduce the diameter of the pulmonary artery. Eight
      weeks later, we implanted an 18-mm valve mounted in a balloon-expandable stent.
      These animals were sacrificed after valve implantation. RESULTS: Eight of 10
      devices were successfully delivered and were functioning perfectly at the initial
      evaluation and after two months. We failed to cross the tricuspid valve in two
      cases. The downsize mechanism allowed the pulmonary diameter to be reduced from
      30 to 18 mm, without an impact on right ventricular function in any of the
      animals. CONCLUSIONS: Non-surgical implantation of a pulmonary valve is possible
      in ewes with all types of pulmonary trunk, regardless of its size. A "downsize"
      stent is needed to allow valve implantation in a large trunk. Further refinements
      will make this technique feasible in humans.

PMID- 15028371
TI  - Transcatheter valve replacement: a new era of percutaneous cardiac intervention
      begins.

PMID- 15028372
TI  - Autoimmunity against the second extracellular loop of beta(1)-adrenergic
      receptors induces early afterdepolarization and decreases in K-channel density in
      rabbits.
AB  - OBJECTIVES: We sought to define the electrophysiologic property of the rabbit
      heart associated with autoimmunity against the second extracellular loop of the
      beta(1)-adrenergic receptor. BACKGROUND: Sudden death of patients with
      cardiomyopathy, probably due to lethal ventricular arrhythmias, can be predicted
      by the presence of autoantibodies against the second extracellular loop of the
      beta(1)-adrenergic receptor. METHODS: Rabbits were immunized by repetitive
      subcutaneous administration of a synthetic peptide corresponding to the second
      extracellular loop of beta(1)-adrenergic receptors (beta group; n = 30) for a
      mean of 4.2 months. Control rabbits received only vehicle (control group; n =
      30). RESULTS: One of the rabbits in the beta group died suddenly during the
      observation period, but none of the control animals died. The prevalence of
      sustained ventricular tachycardia was significantly higher in the beta group
      (beta: 4 of 27 vs. control: 0 of 30), and a standard microelectrode experiment
      revealed prolongation of the action potential duration (APD) in the right
      ventricular papillary muscle (beta: 156 +/- 5 ms vs. control: 131 +/- 4 ms; p <
      0.05). Early afterdepolarization (EAD) was observed in one rabbit in the beta
      group (1 of 26), but not in any animals in the control group (0 of 17). A dose of
      100 nmol/l of E-4031 induced EAD in the beta group (10 of 10), but not in the
      control group, except for one rabbit (1 of 10). The whole-cell, patch-clamp
      experiment on left ventricular M cells showed significant decreases in transient
      outward current (I(to1)) (-43%) and slowly activated delayed rectifier current
      (I(Ks)) densities (-33%), whereas the inward-rectifying K current (I(K1)) and
      rapidly activated delayed rectifier current (I(Kr)) densities remained unchanged.
      CONCLUSIONS: Long-term immunization against the second extracellular loop of the
      beta(1)-adrenergic receptor caused EAD and APD prolongation and decreased the K
      channel density, suggesting that an arrhythmic substrate via autoimmune
      mechanisms is present in cardiomyopathic patients who have autoantibodies
      directed against the receptors.

PMID- 15028373
TI  - The power of volunteerism.

PMID- 15028374
TI  - Highlights of the 2003 scientific sessions of the Heart Failure Society of
      America; Las Vegas, Nevada, September 21 to 24, 2003.

PMID- 15028375
TI  - The Canadian study of the sirolimus-eluting stent in the treatment of patients
      with long de novo lesions in small native coronary arteries (C-SIRIUS).
AB  - OBJECTIVES: We assessed the safety and effectiveness of the sirolimus-eluting
      stent (SES) in treating single de novo long lesions in small native coronary
      arteries compared to an identical bare metal stent (BMS). BACKGROUND: The SES was
      previously demonstrated to reduce restenosis significantly. However, patients
      with long lesions in small vessels have not been well studied and may define a
      group at very high risk. METHODS: The Canadian Study of the Sirolimus-Eluting
      Stent in the Treatment of Patients With Long De Novo Lesions in Small Native
      Coronary Arteries (C-SIRIUS) was a multicenter, randomized, double-blind trial
      comparing SES versus identical BMS. The primary end point was in-stent minimal
      lumen diameter (MLD) at eight months. Secondary end points included angiographic
      restenosis at 8 months, target lesion revascularization (TLR), and major adverse
      cardiac events (MACE) at 270 days. RESULTS: A total of 100 patients were enrolled
      at eight Canadian sites. The in-stent MLD at eight months was 2.46 +/- 0.37 mm in
      the SES compared with 1.49 +/- 0.75 mm in the BMS (a 65% increase, p < 0.001).
      Angiographic restenosis occurred in 1 of 44 SES patients (2.3%, with no in-stent
      restenosis) and in 23 of 44 BMS patients (52.3%, p < 0.001). At 270 days, there
      were two clinically driven TLRs in the SES (4%) and nine in the BMS (18%, p =
      0.05). The Kaplan-Meier estimate of freedom from MACE at 270 days was 96.0% for
      SES patients and 81.7% for BMS patients (p = 0.029). CONCLUSIONS: Patients with
      long lesions in small vessels are at very high risk of restenosis. In these
      patients, the SES dramatically reduces the risk of restenosis at eight months,
      translating into an excellent clinical outcome at nine months.

PMID- 15028376
TI  - Sirolimus-eluting stents: does a great stent still need a good interventionalist?

PMID- 15028379
TI  - Aspirin resistance: more than just a laboratory curiosity.

PMID- 15028377
TI  - First human experience with the 17-beta-estradiol-eluting stent: the Estrogen And
      Stents To Eliminate Restenosis (EASTER) trial.
AB  - OBJECTIVES: The purpose of the study was to examine the safety and efficacy of 17
      beta-estradiol-eluting stent implantation on coronary de novo lesions.
      BACKGROUND: Recent animal data indicate that local delivery of 17-beta-estradiol
      promotes re-endothelialization, inhibits cell migration and proliferation, and
      prevents restenosis. METHODS: A total of 30 consecutive patients underwent 17
      beta-estradiol-eluting BiodVysio (Biocompatibles Ltd., London, United Kingdom)
      stent implantation for the treatment of coronary de novo lesions. Clinical,
      angiographic, and intravascular ultrasound (IVUS) analysis was performed at six
      month follow-up. RESULTS: All stents were successfully deployed and patients were
      discharged home without clinical events. A total of two patients exceeded 50%
      intra-stent narrowing by angiography, whereas no patients experienced edge
      restenosis. One patient had focal intra-stent restenosis (60% diameter stenosis)
      with no symptoms and negative stress test, whereas the other patient had diffuse
      restenosis, requiring target vessel revascularization. No other patient
      experienced any major adverse cardiac event. Follow-up IVUS revealed a neointimal
      hyperplasia volume of 32.3 +/- 16.4 mm(3), whereas the stent volume was 143.7 +/-
      43.7 mm(3), resulting in a neointimal volume obstruction of 23.5 +/- 12.5%. None
      of the patients had > or =50% volume obstruction by IVUS. CONCLUSIONS:
      Implantation of 17-beta-estradiol-eluted BiodVysio stents appears feasible and
      safe, showing low rates of binary restenosis and revascularization. These results
      warrant further confirmation with a large, randomized multicenter trial.

PMID- 15028378
TI  - Aspirin resistance is associated with a high incidence of myonecrosis after non
      urgent percutaneous coronary intervention despite clopidogrel pretreatment.
AB  - OBJECTIVES: We sought to investigate the effect of aspirin resistance on the
      incidence of myonecrosis after non-urgent percutaneous coronary intervention
      (PCI) among patients pretreated with clopidogrel. BACKGROUND: Oral antiplatelet
      therapy using aspirin and a thienopyridine is the standard of care for preventing
      thrombotic complications of PCI. The effect of aspirin resistance on the outcomes
      of patients undergoing PCI is unknown. METHODS: We used the Ultegra Rapid
      Platelet Function Assay-ASA (Accumetrics Inc., San Diego, California) to
      determine aspirin responsiveness of 151 patients scheduled for non-urgent PCI.
      All patients received a 300-mg loading dose of clopidogrel >12 h before and a 75
      mg maintenance dose in the morning of the PCI. The incidence of myonecrosis was
      measured by creatine kinase-myocardial band (CK-MB) and by troponin I (TnI)
      elevations after PCI. RESULTS: A total of 29 (19.2%) patients were noted to be
      aspirin-resistant. There was a significantly higher incidence of female subjects
      in the aspirin-resistant versus aspirin-sensitive groups. The incidence of any CK
      MB elevation was 51.7% in aspirin-resistant patients and 24.6% in aspirin
      sensitive patients (p = 0.006). Elevation of TnI was observed in 65.5% of aspirin
      resistant patients and 38.5% of aspirin-sensitive patients (p = 0.012).
      Multivariate analysis revealed aspirin resistance (odds ratio [OR] 2.9; 95%
      confidence interval [CI] 1.2 to 6.9; p = 0.015) and bifurcation lesion (OR 2.8;
      95% CI 1.3 to 6.0; p = 0.007) to be independent predictors of CK-MB elevation
      after PCI. CONCLUSIONS: Despite adequate pretreatment with clopidogrel, patients
      with aspirin resistance as measured by a point-of-care assay have an increased
      risk of myonecrosis following non-urgent PCI.

PMID- 15028380
TI  - Authors, industry, and review articles.

PMID- 15028381
TI  - Statins to reduce risk of depression.

PMID- 15028383
TI  - Myocardial bridging in adult and pediatric patients with hypertrophic
      cardiomyopathy is not associated with poor outcome.

PMID- 15028385
TI  - Embolic complications in streptococcus viridans endocarditis.

PMID- 15028387
TI  - A randomized trial of aspirin on the risk of embolic events in patients with
      infective endocarditis.

PMID- 15028389
TI  - Investigation of hydrogeologic processes in a dipping layer structure: 1. The
      flow barrier effect.
AB  - Numerical simulations of a field experiment were performed in order to study the
      processes contributing to lateral diversion of water flow in the unsaturated
      zone. The experimental site is a glacial delta with dipping layers of alternating
      finer and coarser sand. Model soil physical parameters for each of the
      stratigraphic layers were estimated from soil grain size distributions.
      Anisotropy of the hydraulic conductivity within the layers was critical in order
      to reproduce the flow pattern observed in the experiment. Capillary and hydraulic
      barriers were of minor importance for the observed lateral diversion.

PMID- 15028391
TI  - Effect of cell physicochemical characteristics and motility on bacterial
      transport in groundwater.
AB  - The influence of physicochemical characteristics and motility on bacterial
      transport in groundwater were examined in flow-through columns. Four strains of
      bacteria isolated from a crystalline rock groundwater system were investigated,
      with carboxylate-modified and amidine-modified latex microspheres and bromide as
      reference tracers. The bacterial isolates included a gram-positive rod (ML1), a
      gram-negative motile rod (ML2), a nonmotile mutant of ML2 (ML2m), and a gram
      positive coccoid (ML3). Experiments were repeated at two flow velocities, in a
      glass column packed with glass beads, and in another packed with iron
      oxyhydroxide coated glass beads. Bacteria breakthrough curves were interpreted
      using a transport equation that incorporates a sorption model from microscopic
      observation of bacterial deposition in flow-cell experiments. The model predicts
      that bacterial desorption rate will decrease exponentially with the amount of
      time the cell is attached to the solid surface. Desorption kinetics appeared to
      influence transport at the lower flow rate, but were not discernable at the
      higher flow rate. Iron-oxyhydroxide coatings had a lower-than-expected effect on
      bacterial breakthrough and no effect on the microsphere recovery in the column
      experiments. Cell wall type and shape also had minor effects on breakthrough.
      Motility tended to increase the adsorption rate, and decrease the desorption
      rate. The transport model predicts that at field scale, desorption rate kinetics
      may be important to the prediction of bacteria transport rates.

PMID- 15028390
TI  - Investigation of hydrogeologic processes in a dipping layer structure: 2.
      Transport and biodegradation of organics.
AB  - Numerical simulation tools have been used to study the dominating processes
      during transport of aromatic hydrocarbons in the unsaturated soil zone.
      Simulations were based on field observations at an experimental site located on a
      glacial delta plain with pronounced layered sedimentary structures. A numerical
      model for transport in the unsaturated zone, SWMS-3D, has been extended to
      incorporate coupled multispecies transport, microbial degradation following Monod
      kinetics and gas diffusive transport of oxygen and hydrocarbons. The flow field
      parameters were derived from previous work using nonreactive tracers.
      Breakthrough curves (BTC) from the hydrocarbon field experiment were used to
      determine sorption parameters and Monod kinetic parameters using a fitting
      procedure. The numerical simulations revealed that the assumption of homogeneous
      layers resulted in deviations from the field observations. The deviations were
      more pronounced with incorporation of reactive transport, compared with earlier
      work on nonreactive transport. To be able to model reasonable BTC, sorption had
      to be reduced compared to laboratory experiments. The initial biomass and the
      maximum utilisation rate could be adjusted to capture both the initial lag phase
      and the overall degradation rate. Nevertheless, local oxygen limitation is
      predicted by the model, which was not observed in the field experiment.
      Incorporation of evaporation and diffusive gas transport of the hydrocarbons did
      not significantly change the local oxygen demand. The main cause of the observed
      discrepancies between model and field are attributed to channelling as a result
      of small-scale heterogeneities such as biopores.

PMID- 15028392
TI  - Direct-push geochemical profiling for assessment of inorganic chemical
      heterogeneity in aquifers.
AB  - Discrete-depth sampling of inorganic groundwater chemistry is essential for a
      variety of site characterization activities. Although the mobility and rapid
      sampling capabilities of direct-push techniques have led to their widespread use
      for evaluating the distribution of organic contaminants, complementary methods
      for the characterization of spatial variations in geochemical conditions have not
      been developed. In this study, a direct-push-based approach for high-resolution
      inorganic chemical profiling was developed at a site where sharp chemical
      contrasts and iron-reducing conditions had previously been observed. Existing
      multilevel samplers (MLSs) that span a fining-upward alluvial sequence were used
      for comparison with the direct-push profiling. Chemical profiles obtained with a
      conventional direct-push exposed-screen sampler differed from those obtained with
      an adjacent MLS because of sampler reactivity and mixing with water from previous
      sampling levels. The sampler was modified by replacing steel sampling components
      with stainless-steel and heat-treated parts, and adding an adapter that prevents
      mixing. Profiles obtained with the modified approach were in excellent agreement
      with those obtained from an adjacent MLS for all constituents and parameters
      monitored (Cl, NO(3), Fe, Mn, DO, ORP, specific conductance and pH).
      Interpretations of site redox conditions based on field-measured parameters were
      supported by laboratory analysis of dissolved Fe. The discrete-depth capability
      of this approach allows inorganic chemical variations to be described at a level
      of detail that has rarely been possible. When combined with the mobility afforded
      by direct-push rigs and on-site methods of chemical analysis, the new approach is
      well suited for a variety of interactive site-characterization endeavors.

PMID- 15028393
TI  - In situ sequenced bioremediation of mixed contaminants in groundwater.
AB  - A mixture of chlorinated solvents (about 0.5-10 mg/l), including
      tetrachloroethene (PCE) and carbon tetrachloride (CT), together with a petroleum
      hydrocarbon, toluene (TOL), were introduced into a 24 m long x 2 m wide x 3 m
      deep isolated section (henceforth called a gate) of the Borden aquifer and
      subjected to sequential in situ treatment. An identical section of aquifer was
      similarly contaminated and allowed to self-remediate by natural attenuation, thus
      serving as a control. The control presents a rare opportunity to critically
      assess the performance of the treatment systems, and represents the first such
      study for sequenced in situ remediation. The first treatment step was anaerobic
      bioremediation. This was accomplished using a modified nutrient injection wall
      (NIW) to pulse benzoate and a nutrient solution into the aquifer, maximizing
      mixing by dispersion and minimizing fouling near the injection wells. In the
      anaerobic bioactive zone that developed, PCE, CT and chloroform (CF), a
      degradation product of CT, degraded with a half-lives of about 59, 5.9 and 1.7
      days, respectively. The second step was aerobic bioremediation, using a biosparge
      system. TOL and cis-1,2 dichloroethene (cDCE), from PCE degradation, were found
      to degrade aerobically with half-lives of 17 and 15 days, respectively. Compared
      to natural attenuation, PCE and TOL removal rates were significantly better in
      the sequenced treatment gate. However, CT and CF were similarly and completely
      attenuated in both gates. It is believed that the presence of TOL helped sustain
      the reducing environment needed for the reduction of these two compounds.

PMID- 15028394
TI  - Hydraulic constraints on the performance of a groundwater denitrification wall
      for nitrate removal from shallow groundwater.
AB  - Denitrification walls are a practical approach for decreasing non-point source
      pollution of surface waters. They are constructed by digging a trench
      perpendicular to groundwater flow and mixing the aquifer material with organic
      matter, such as sawdust, which acts as a carbon source to stimulate
      denitrification. For efficient functioning, walls need to be permeable to
      groundwater flow. We examined the functioning of a denitrification wall
      constructed in an aquifer consisting of coarse sands. Wells were monitored for
      changes in nitrate concentration as groundwater passed through the wall and soil
      samples were taken to measure microbial parameters inside the wall. Nitrate
      concentrations upstream of the wall ranged from 21 to 39 g N m(-3), in the wall
      from 0 to 2 g N m(-3) and downstream from 19 to 44 g N m(-3). An initial
      groundwater flow investigation using a salt tracer dilution technique showed that
      the flow through the wall was less than 4% of the flow occurring in the aquifer.
      Natural gradient tracer tests using bromide and Rhodamine-WT confirmed
      groundwater bypass under the wall. Hydraulic conductivity of 0.48 m day(-1) was
      measured inside the wall, whereas the surrounding aquifer had a hydraulic
      conductivity of 65.4 m day(-1). This indicated that during construction of the
      wall, hydraulic conductivity of the aquifer had been greatly reduced, so that
      most of the groundwater flowed under rather than through the wall.
      Denitrification rates measured in the center of the wall ranged from 0.020 to
      0.13 g N m(-3) day(-1), which did not account for the rates of nitrate removal
      (0.16-0.29 g N m(-3) day(-1)) calculated from monitoring of groundwater nitrate
      concentrations. This suggested that the rate of denitrification was greater at
      the upstream face of the wall than in its center where it was limited by low
      nitrate concentrations. While denitrification walls can be an inexpensive tool
      for removing nitrate from groundwater, they may not be suitable in aquifers with
      coarse textured subsoils where simple inexpensive construction techniques result
      in major decreases in hydraulic conductivity.

PMID- 15028395
TI  - Controlled release, blind test of DNAPL remediation by ethanol flushing.
AB  - A dense nonaqueous phase liquid (DNAPL) source zone was established within a
      sheet-pile isolated cell through a controlled release of perchloroethylene (PCE)
      to evaluate DNAPL remediation by in-situ cosolvent flushing. Ethanol was used as
      the cosolvent, and the main remedial mechanism was enhanced dissolution based on
      the phase behavior of the water-ethanol-PCE system. Based on the knowledge of the
      actual PCE volume introduced into the cell, it was estimated that 83 L of PCE
      were present at the start of the test. Over a 40-day period, 64% of the PCE was
      removed by flushing the cell with an alcohol solution of approximately 70%
      ethanol and 30% water. High removal efficiencies at the end of the test indicated
      that more PCE could have been removed had it been possible to continue the
      demonstration. The ethanol solution extracted from the cell was recycled during
      the test using activated carbon and air stripping treatment. Both of these
      treatment processes were successful in removing PCE for recycling purposes, with
      minimal impact on the ethanol content in the treated fluids. Results from pre-
      and post-flushing partitioning tracer tests overestimated the treatment
      performance. However, both of these tracer tests missed significant amounts of
      the PCE present, likely due to inaccessibility of the PCE. The tracer results
      suggest that some PCE was inaccessible to the ethanol solution which led to the
      inefficient PCE removal rates observed. The flux-averaged aqueous PCE
      concentrations measured in the post-flushing tracer test were reduced by a factor
      of 3 to 4 in the extraction wells that showed the highest PCE removal compared to
      those concentrations in the pre-flushing tracer test.

PMID- 15028396
TI  - Shaping the future: training of professionals for radiotherapy in Europe.

PMID- 15028397
TI  - Updated European core curriculum for radiotherapists (radiation oncologists).
      Recommended curriculum for the specialist training of medical practitioners in
      radiotherapy (radiation oncology) within Europe.
AB  - AIM: To produce updated state-of-the-art recommendations for harmonised medical
      specialist training in radiotherapy within Europe. MATERIAL AND METHODS: The
      Minimum Curriculum for the Theoretical Education in Radiation Oncology in Europe
      from 1991 was updated under consideration of new developments in medicine in
      general, and in radiotherapy and its basic sciences in particular. Recent medical
      developments, national guidelines and training programmes from European
      countries, as well as equivalent documents from the USA and Australia were
      reviewed by an expert panel jointly appointed by the European Society of
      Therapeutic Radiology and Oncology and the European Board of Radiotherapy. A
      draft document prepared by this group was circulated among the national and
      professional societies for radiotherapy in Europe for review before a European
      consensus conference took place in Brussels in December 2002. RESULTS: The
      updated European Core Curriculum for Radiotherapists (Radiation Oncologists) was
      endorsed by representatives of 35 European nations during the Brussels consensus
      conference on December 14, 2002. Compared to the earlier version the updated
      document contains specific recommendations not only for the 5 year training
      curriculum but also for organisatoric and infrastructural aspects of teaching
      departments, and for supplementation of the training by formal teaching courses.
      CONCLUSION: The updated European core curriculum is an important step on the way
      to fully harmonise medical specialist training in Europe and to guarantee equal
      access for all European citizens to highest quality medical care. The
      responsibility for the implementation of the standards and guidelines set in the
      updated Core Curriculum for radiotherapy (radiation oncology) will lie with the
      local and/or national training bodies and authorities.

PMID- 15028398
TI  - Training logbook for radiotherapy.
AB  - AIM: To develop a structured logbook for trainees in the medical specialty of
      radiotherapy with Europe that records the increasing experience throughout their
      training period. MATERIAL AND METHODS: A working party appointed by the European
      Board of Radiotherapy developed a draft version of a European logbook for
      trainees in radiotherapy. For development, the update European Core Curriculum
      for Radiotherapists (Radiation Oncologists) was taken into consideration. The
      logbook is composed of six sections: (1) biodata of the trainee, (2) scientific
      training documentation, (3) clinical training documentation, (4) record of formal
      presentations by the trainee, (5) publications, (6) training courses. Decisions
      were made to suggest that the clinical section of the logbook should: (a) only
      collect data that was essential for the purposes of appraisal, assessment and
      regulation, (b) be as user friendly as possible, (c) concentrate on quality of
      the data and not volume. The logbook was tested by trainees in several European
      training departments and adapted according to their suggestions. A final draft of
      the logbook was circulated among the national and professional societies for
      radiotherapy in Europe for review before a European consensus conference took
      place in Brussels in December 2002. RESULTS: The European training logbook for
      radiotherapy was endorsed by representatives of 35 European nations during the
      Brussels consensus conference on December 14, 2002. CONCLUSION: Keeping a
      training logbook is an essential feature of the record of training for all EU
      trainees who wish to retain an opportunity to spend part of their training time
      in another country of the Union, important for someone who seeks an appointment
      as a specialist in another country within a few years of achieving specialist
      accreditation, and good professional practice for all other trainees. The
      European training logbook for radiotherapy is a robust instrument that allows the
      systematic collection of the information that needs to be recorded to monitor the
      professional development of European trainees in Radiation Oncology.

PMID- 15028399
TI  - Guidelines for the infrastructure of training institutes and teaching departments
      for radiotherapy in Europe.
AB  - AIM: To develop guidelines for the infrastructure of training institutes and
      teaching departments for medical specialist training in radiotherapy within
      Europe. MATERIAL AND METHODS: Guidelines for teaching departments were developed
      under consideration of the updated European Core Curriculum for Radiotherapists
      (Radiation Oncologists) by an expert panel jointly appointed by the European
      Union of Medical Specialists and the European Society of Therapeutic Radiology
      and Oncology. The group approached national professional and scientific societies
      for information on national requirements for teaching departments. Based on this
      information, a draft document was circulated among the national and professional
      societies for radiotherapy in Europe for review before a European consensus
      conference took place in Brussels in December 2002. RESULTS: The guidelines for
      the infrastructure of training institutes and teaching departments for medical
      specialist training in radiotherapy within Europe were endorsed by
      representatives of 35 European nations during the Brussels consensus conference
      on December 14, 2002. CONCLUSION: The infrastructure guidelines represent an
      important instrument that can be used by teaching departments for comparison of
      their situation with that of other departments in Europe as a basis for
      negotiations with authorities on resources provided for training.

PMID- 15028400
TI  - Guidelines for education and training of medical physicists in radiotherapy.
      Recommendations from an ESTRO/EFOMP working group.
AB  - PURPOSE: To provide a guideline curriculum covering theoretical and practical
      aspects of education and training for medical physicists in radiotherapy within
      Europe. MATERIAL AND METHODS: Guidelines have been developed for the specialist
      theoretical knowledge and practical experience required to practice as a medical
      physicist in radiotherapy. It is assumed that the typical entrant into training
      will have a good initial degree in the physical sciences, therefore these
      guidelines also require that and are additional to it. National training
      programmes of medical physics, radiation physics and radiotherapy physics from a
      range of European countries and from North America were reviewed by an expert
      panel set up by the European Society of Therapeutic Radiology and Oncology
      (ESTRO) and the European Federation of Organisations for Medical Physics (EFOMP).
      A draft document prepared by this group was circulated, via the EFOMP
      infrastructure, among national professional medical physics societies in Europe
      for review and comment and was also discussed in an education session in the May
      2003 EFOMP scientific meeting in Eindhoven. RESULTS: The resulting guideline
      curriculum for education and training of medical physicists in radiotherapy
      within Europe discusses the EFOMP terms, qualified medical physicist (QMP) and
      specialist medical physicist (SMP), and the group's view of the links to the EU
      (Directive 97/43) term, medical physics expert (MPE). The minimum level expected
      in each topic in the theoretical knowledge and practical experience sections is
      intended to bring trainees up to the requirements of a QMP. The responses from
      the circulation of the document to national societies and its discussion were
      either to agree its content, with no changes required, or to suggest changes,
      which were taken into account after consideration by the expert group. Following
      this the guidelines have been endorsed by the parent organisations. CONCLUSIONS:
      This new joint ESTRO/EFOMP European guideline curriculum is a first step to
      harmonise specialist training of medical physicists in radiotherapy within
      Europe. It provides a common framework for national medical physics societies to
      develop or benchmark their own curricula, but is also flexible enough to suit
      different situations of initial physics qualifications, medical physics training
      programmes, accreditation structures, etc. The responsibility for the
      implementation of these standards and guidelines will lie with the national
      training bodies and authorities.

PMID- 15028401
TI  - Revised European core curriculum for RTs.
AB  - AIM: To update the first version of the European core curriculum to reflect many
      developments in radiotherapy and educational philosophy that have taken place in
      the interim period. MATERIALS AND METHODS: The first version of the European core
      curriculum was reviewed by the Steering Group together with current education
      programmes from the various member states and taking into account the
      developments and changes that have taken place in radiotherapy. From these
      initial meetings, a working document and provisional timetable were prepared.
      Given the diversity of the existing programmes, the language difficulties and
      lack of national curricula it was agreed that a representative from both the
      clinical and academic areas endorsed by their national professional body would be
      identified for each country. These participants were then invited to participate
      in two workshops and the working document and timetable were circulated. Two
      workshops were held and a final draft document was circulated to the professional
      bodies and other interested groups. RESULTS: The revised European Core Curriculum
      for RTTs was endorsed by the participants of the workshops representing academic
      and clinical areas of all the member states and was welcomed by the wider
      circulation. Compared to the first version the revised curriculum describes the
      background underpinning the practice of radiation therapy and the variation
      across the member states, issues of staffing, educational philosophy,
      certification level, legislation governing recognition of qualifications and a
      core syllabus. CONCLUSION: The revised core curriculum is an important step in
      the progress of professional recognition for RTTs, towards harmonisation of
      education programmes in Europe and meeting the aim of best practice and equality
      of care for all patients receiving radiotherapy. Responsibility for developing
      education programmes from the curriculum will rest with the local and/or national
      education bodies and authorities.

PMID- 15028402
TI  - Recommendations for the future of translational radiobiology research: a Canadian
      perspective.
AB  - The use of molecular medicine is now merging into clinical practice with the
      advent of molecular targeting agents, molecular pathology and molecular imaging
      for both diagnosis and treatment response. Radiation oncologists must therefore
      gain expertise in utilizing this information to drive new treatment protocols.
      Recognizing the importance of this issue, the Canadian Association of Radiation
      Oncologists (CARO) charged a Task Force in Translational Radiobiology to: (1)
      critically assess training programs and research infrastructure in relation to
      current and future translational radiobiology requirements; and (2) make specific
      recommendations to accelerate the implementation of translational science into
      day-to-day practice. Selected Task Force recommendations included the principle
      that universities and departmental Chairs increase the opportunities for academic
      promotion, funding, and tenure track positions of radiobiologists and
      translational radiation oncologists. The dedication of 4 to 5 national centers as
      translational 'hubs', can serve as an interface between clinicians, clinical
      specimens and radiobiological sciences within the context of correlative clinical
      trials. The model of the clinician-scientist was encouraged as an important
      adjunct to good clinical care to be associated with strong enticement, training
      and mentoring programs and 75%-protected research time. Finally, an integrated
      model of radiobiological training programs and mutual continuing education
      between clinicians and basic scientists can be facilitated through a new national
      radiobiology meeting sponsored by CARO. These recommendations have been accepted
      by the national radiation oncology membership. Such a framework may serve useful
      for national programs wishing to develop rapid conduits from the lab to the
      clinic as a means of integrating molecular biology and the day-to-day practice of
      radiation oncology.

PMID- 15028403
TI  - An application of visible human database in radiotherapy: tutorial for image
      guided external radiotherapy (TIGER).
AB  - BACKGROUND AND PURPOSE: Three-dimensional conformal radiotherapy and intensity
      modulated radiotherapy allow accurate dose delivery on target volumes. Due to the
      different background among specialists involved in target volume definition, the
      contouring emerges as one of the most questionable steps in treatment planning
      procedures. A software tool devoted to contouring training, named tutorial for
      image guided external radiotherapy ('TIGER'), based on the Visible Human Project
      images data-set, is described. MATERIALS AND METHODS: TIGER is addressed to
      facilitate the learning of axial anatomical images, to promote the training and
      reproducibility in contouring process, to allow the availability of a tool to
      enhance the 'drill and practice' approach in training programs. TIGER includes
      three different environments: Anatomic tutorial devoted to facilitate a self
      learning approach to axial body sections; Contouring tutorial addressed to
      practice contouring process of anatomical structures and to undergo a test
      program prepared by tutors; Teacher's tools to offer to tutors the opportunity to
      insert new outlines in TIGER-database, according to local needs or conventions,
      and to use them in tutorial programs. TIGER-database is grouped in six main
      anatomical sections: head and neck, male thorax, female thorax, abdomen, male
      pelvis, and female pelvis. Overall 432 corresponding CT-VH images and 1189
      contours of 134 different anatomical structures and lymphatic drainage areas are
      available. The access to the TIGER software is allowed by ESTRO web site
      (http://www.estro.be). CONCLUSIONS: TIGER provides an interactive human anatomy
      cross-sectional oriented source to facilitate the interpretation of CT scan
      images usually contoured in daily practice. It offers a drill tool to facilitate
      the learning of a reproducible contouring procedure.

PMID- 15028404
TI  - Phase I study of UFT plus leucovorin with radiotherapy in patients with
      inextirpable non-rectal gastrointestinal cancer.
AB  - BACKGROUND AND PURPOSE: Chemoradiotherapy is increasingly used in the primary
      management of patients with loco-regionally advanced gastrointestinal (GI)
      cancer. Oral chemotherapy with uracil and tegafur (UFT) plus leucovorin (LV) may
      represent a convenient way of delivering protracted infusion of fluorouracil. Our
      goal was to evaluate the safety of UFT plus LV combined with radiation and
      determine the maximum-tolerated dose (MTD) and a recommended dose for further
      testing. PATIENTS AND METHODS: Patients with inextirpable GI cancer received
      escalating doses of UFT (starting at 300 mg/m(2)/d with 50 mg/m(2)/d increments
      between consecutive cohorts) and fixed doses of LV (90 mg/d). UFT and LV were
      given 5 days per week concurrently with radiation to 50 Gy (2 Gy/fraction).
      RESULTS: Twenty-five patients were treated, and 22 received the planned
      treatment. Three patients were withdrawn from treatment, two due to disease
      progression and one due to toxicity. The MTD of UFT with radiation was 400
      mg/m(2)/d with 90 mg/d of LV. Diarrhoea was the main dose limiting toxicity
      (DLT). Since some toxicity (3/12 DLTs) was seen in the expanded cohort at the
      level below, but none (0/9 DLT) at the starting level, the recommended dose
      chosen for further testing is 300-350 mg/m(2)/d depending upon the size of the
      target volume. CONCLUSION: Concomitant chemoradiation with oral UFT plus LV is
      feasible and well tolerated and should be further investigated since tumour
      responses were frequently seen.

PMID- 15028405
TI  - Treatment of T1-T2 rectal tumors by contact therapy and interstitial
      brachytherapy.
AB  - BACKGROUND AND PURPOSE: We retrospectively analysed our experience of contact
      therapy alone and/or combined with interstitial brachytherapy as exclusive
      treatment of low lying rectal tumours. PATIENTS AND METHODS: From 1971 to 2001,
      124 patients (103 adenocarcinomas, 21 villous tumours) were treated by contact
      therapy alone or combined with interstitial brachytherapy. All patients were
      staged according to the Dijon classification. The average size of the lesions was
      2.4 cm (max 7 cm), clinical aspect was polypoid in 75% of the cases, flat in 17%.
      Sixty four patients received contact therapy in three fractions and 44 patients
      received four fractions, for an average delivered dose of 95 Gy. Interstitial
      brachytherapy boost delivered 24 Gy on a reference isodose of 55 cGy/h in 10
      patients. RESULTS: The local control was 83% for T1 and 38% for T2 tumours
      (p=0.004). For mobile tumours, the local control rate is 76%, significantly
      higher than for tumours with impaired mobility (55%, P=0.03). Thirty-nine
      patients experienced a local failure (31%). For patients amenable to surgery, a
      Miles procedure was performed in 25 patients. Ultimate local control rate is 93%
      for T1, 69% for T2 (P<0.05), 15 patients failed despite treatment for local
      recurrence (15%). No significant differences were observed in a comparison of
      adenocarcinoma and villous tumours according to initial and ultimate local
      control. The mean disease free survival rate for the whole population is 66
      months. The 5-year disease free survival for T1a and T1b is, respectively, 82 and
      78%, 40 and 25% for T2a and T2b, respectively. The overall 5-year survival for
      the whole group is 62.4%. At the end of the treatment, 75% of the patients
      described a very good sphincter function. No deleterious effect on continence was
      reported during the follow-up. CONCLUSIONS: The control rate for T1 rectal cancer
      treated with contact therapy with or without brachytherapy is comparable to
      surgical series. The sphincter was preserved in 80% of the patients. Radiotherapy
      remains an efficient and cheap alternative to surgery, mainly for old and fragile
      patients, or refusing colostomy. The results of these approaches for tumors
      larger than 3 cm (T2) are not satisfactory. For patients not amenable to surgery,
      external beam radiation therapy and/or combined modality with chemoradiation
      should be discussed to increase the loco-regional control rate. A careful
      selection of patients based on rectal examination and trans-rectal ultrasound
      could select more accurately patients amenable to such an approach.

PMID- 15028406
TI  - Accelerated postoperative radiotherapy with weekly concomitant boost in patients
      with locally advanced head and neck cancer.
AB  - BACKGROUND AND PURPOSE: To assess the feasibility and efficacy of accelerated 66
      Gy postoperative radiotherapy (PORT) using a single-fraction regimen from Mondays
      to Thursdays and a concomitant boost on Friday afternoon sessions in patients
      with locally advanced head and neck cancer (LAHNC). PATIENTS AND METHODS: Between
      December 1997 and June 2002, 89 consecutive patients with pT1-pT4 and/or pN0-pN3
      LAHNC were included. PORT was indicated in patients with positive surgical
      margins, T4 tumors, or extracapsular nodal infiltration. RT consisted of 66 Gy (2
      Gy/fr) in 5 weeks and 3 days. Median follow-up was 21 months (range 2-59).
      RESULTS: Acute morbidity was acceptable: grade 3 mucositis in 20 (22%) patients,
      grade 3 dysphagia in 22 (25%) patients, and grade 3 skin erythema in 18 (20%)
      patients. Median weight loss was 2 kg (range 0-14.5). No grade 4 toxicity was
      observed. Late effects included grade 3 xerostomia in 6 (7%) patients, and grade
      3 edema in 2 (2%) patients. Median time to locoregional relapse was 10 months
      (range 2-21). Two-year overall, cause-specific, and disease-free survival rates
      were 70% (95% confidence interval (CI) 59-81), 75% (95% CI 64-86), and 63% (95%
      CI 52-74), respectively. The 2-year actuarial locoregional control rate was 80%
      (95% CI 70-90). Distant metastasis probability at 4 years was 38% (95% CI 20-56).
      Multivariate analysis revealed that pT-classification (pT1-2 vs. pT3-4) and
      extranodal extension (0, 1 vs. 2 or more) were the two factors independently
      influencing the outcome. CONCLUSIONS: We conclude that reducing the overall
      treatment time using an accelerated PORT schedule including a once-weekly
      concomitant boost (six fractions per week) is easily feasible with excellent
      local control. Acute and late RT-related morbidity is acceptable. Given the
      disease progression pattern (distant metastases), adjuvant chemotherapy should be
      considered.

PMID- 15028407
TI  - Intensity-modulated radiotherapy improves target coverage, spinal cord sparing
      and allows dose escalation in patients with locally advanced cancer of the
      larynx.
AB  - BACKGROUND AND PURPOSE: An investigation has been carried out into the potential
      of intensity-modulated radiotherapy (IMRT) to improve the coverage of the targets
      and the sparing of the spinal cord (SC) in radiotherapy treatment of the larynx
      and bilateral cervical lymph nodes, in patients with advanced larynx cancer.
      PATIENTS AND METHODS: Conventional radiotherapy (CRT) and IMRT plans were
      produced for six patients to treat the larynx (PTV1) and lymph nodes (PTV2) to 50
      Gy (phase 1). A second plan was created to treat the PTV1 to 65 Gy and PTV2 to 50
      Gy (phases 1 and 2). The potential to escalate the dose to both the larynx (to 67
      Gy) and the nodes (to 56 Gy) was investigated for the IMRT plans. RESULTS: The
      phase 1 treatment gave average minimum doses (dose received by 99% volume) of
      38.1 (+/-8.2) and 48.5 (+/-0.2)Gy for PTV1, treated by CRT and IMRT,
      respectively, and 35.9 (+/-2.9) and 46.2 (+/-1.8)Gy for PTV2. For the two phase
      treatment the average minimum doses to PTV1 were 51.6 (+/-8.2) (CRT) and 62.1 (+/
      0.7)Gy (IMRT) (p=0.028) and for PTV2 were 36.2 (+/-2.9) (CRT) and 46.8 (+/-0.5)Gy
      (IMRT) (P=0.0004). The average maximum doses (dose received by 1% volume) to the
      SC were 42.5 (+/-1.9) (CRT) and 37.9 (+/-1.4)Gy (IMRT) (P=0.01). For the dose
      escalated IMRT plans the minimum dose to PTV1 was 64.6 (+/-0.5) and 50.8 (+/
      1.8)Gy to PTV2. The average SC maximum was 41.5 (+/-1.6)Gy. CONCLUSIONS: IMRT
      offers improved target homogeneity and reduces irradiation of the SC. This
      sparing of normal tissue structures is sufficient that significant dose
      escalation of both the larynx and lymph nodes may be possible.

PMID- 15028408
TI  - Evaluation of a 2D diode array for IMRT quality assurance.
AB  - BACKGROUND AND PURPOSE: The QA of intensity modulated radiotherapy (IMRT)
      dosimetry is a laborious task. The goal of this work is to evaluate the
      dosimetric characteristics of a new 2D diode array (MapCheck from Sun Nuclear
      Corporation, Melbourne, Florida) and assess the role it can play in routine IMRT
      QA. MATERIAL AND METHODS: Fundamental properties of the MapCheck such as
      reproducibility, linearity and temperature dependence are studied for high-energy
      photon beams. The accuracy of the correction for difference of diode sensitivity
      is also assessed. The diode array is benchmarked against film and ion chambers
      for conventional and IMRT treatments. The MapCheck sensitivity to multileaf
      collimator position errors is determined. RESULTS: The diode array response is
      linear with dose up to 295 cGy. All diodes are calibrated to within +/-1% of each
      other, and mostly within +/-0.5%. The MapCheck readings are reproducible to
      within a maximum SD of +/-0.15%. A temperature dependence of 0.57%/ degrees C was
      noted and should be taken into account for absolute dosimetric measurement.
      Clinical performance of the MapCheck for relative and absolute dosimetry is
      demonstrated with seven beam (6 MV) head and neck IMRT plans, and compares well
      with film and ion chamber measurements. Comparison to calculated dose maps
      demonstrates that the planning system model underestimates the dose gradients in
      the penumbra region. CONCLUSIONS: The MapCheck offers the dosimetric
      characteristics required for performing both relative and absolute dose
      measurements. Its use in the clinic can simplify and reduce the IMRT QA workload.

PMID- 15028409
TI  - Re: Cancers of the head and neck region in developing countries. Radiother Oncol.
      2003 Apr;67(1):1-2.

PMID- 15028411
TI  - Re: Dosimetric consequences of increased seed strength for I-125 prostate
      implants. Radiother Oncol. 2003 Sep;68(3):295-7.

PMID- 15028413
TI  - Comment on 'Dieckmann K, Georg D, Zehetmayer M, Bogner J, Georgopoulos M, Potter
      R. LINAC based stereotactic radiotherapy of uveal melanoma: 4 years clinical
      experience.' [Radiother Oncol. 2003;67(2):199-206].

PMID- 15028414
TI  - Several important omissions in two recent articles concerned with radiation optic
      neuropathy.

PMID- 15028415
TI  - Regulation of matrix metalloproteinases (MMPS) and their inhibitors (TIMPS)
      during mouse peri-implantation: role of nitric oxide.
AB  - Nitric oxide (NO) is believed to play pivotal roles in embryo implantation. The
      purpose of this study was to investigate the effect of NO on matrix
      metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), as well as the
      mechanism of NO during mouse implantation. Nitric oxide synthase (NOS) inhibitor,
      L-NAME was administered with or without sodium nitroprusside (SNP), NO donor,
      into one uterine horn on day 3 of pregnancy, and the contralateral uterine horn
      served as the control. We collected the uteri on days 5, 6, and 7 of pregnancy
      and examined the mRNA expression of MMP-2, -9, and TIMP-1, -2, -3, as well as the
      activities of MMP-2 and -9 by using in situ hybridization and gelatin zymography,
      respectively. The results showed that, compared with the control, the expression
      of MMP-2 and -9 mRNAs was decreased in L-NAME-treated uteri during peri
      implantation. Treatment of mice with L-NAME had slight effect on the expression
      of TIMP-1 mRNA on day 5 of pregnancy, and no effect on TIMP-2 mRNA expression
      during peri-implantation. However, the expression of TIMP-3 mRNA was increased.
      The gelatin zymography results indicated that the activity of MMP-9 was decreased
      during peri-implantation, but the activity of MMP-2 did not change significantly
      in these time points examined. The L-NAME-mediated effect on MMPs and TIMPs were
      significantly reversed when SNP was co-administered with L-NAME. These data
      suggest that inhibition of NO production regulates the gene expression of MMP-2, 
      9, and TIMP-3, together with the activity of MMP-9 during peri-implantation,
      which may have serious consequence on embryo implantation.

PMID- 15028416
TI  - Matrix-metalloproteinase activity in first trimester placental bed biopsies in
      further complicated and uncomplicated pregnancies.
AB  - Trophoblast invasion is partly regulated by matrix-metalloproteinases (MMPs).
      Aberrations in MMP-activity in early pregnancy are thought to play a role in the
      pathophysiology of pregnancy associated conditions like pre-eclampsia and intra
      uterine growth restriction (IUGR). A direct relation however, has not been
      published. We tested the hypothesis that MMP activity in the decidua is
      compromised in the first trimester of pregnancies, which are complicated by
      hypertensive disorders or IUGR in later pregnancy. During chorionic villus
      biopsy, decidua is microscopically separated from the villi and stored. A
      selection of pregnancies complicated by pre-eclampsia or HELLP-syndrome or IUGR
      was made, with two matched controls each. Zymography was performed to identify
      the presence of MMPs, and subsequently immunohistochemistry for MMP-2 and -9 and
      cytokeratin 7 to examine differences between cases and controls. Next, a specific
      immuno-capture assay was used to determine the activity of MMP-1, -2, -3, -8, -9,
      and 13, total as well as active. Although presence of MMP-2 and MMP-9 was found,
      which corresponded with the immunohistochemistry, no significant differences
      could be demonstrated between activity of total MMP-2 and total MMP-9 in
      complicated and uncomplicated pregnancies. Activity of MMP-1, -3, -8 and -13
      could not be detected. IN CONCLUSION: our study confirms the presence of MMP-2
      and -9 in first trimester placental bed biopsies, but does not support the
      current concept of deranged MMP-activity in early pregnancy in further
      complicated pregnancies.

PMID- 15028417
TI  - Differential localization of prostaglandin E synthase isoforms in human placental
      cell types.
AB  - Increased prostaglandin E(2)(PGE(2)) synthesis involves multiple enzymes and two
      isoforms of the terminal enzyme of this biosynthetic pathway, PGE synthase
      (PGES), were recently identified. Cytosolic PGES (cPGES) is identical to the
      Hsp90 chaperone, p23, and is reportedly functionally coupled to constitutive PG
      endoperoxide H synthase-1 (PGHS-1). Microsomal PGES (mPGES), on the other hand,
      is inducible by proinflammatory cytokines such as IL-1beta. We have studied the
      cellular localization of both enzyme isoforms in human placenta at term and early
      gestation (10 weeks). Cytosolic PGES was immunolocalized to the fibroblasts and
      macrophages in villous stroma, whereas mPGES was localized in the extravillous
      trophoblasts (EVTs) as well as macrophages in both term and early gestation
      tissues. Microsomal PGES was also observed in cytotrophoblasts (CTs), but not in
      syncytiotrophoblasts (STs), in early gestation. Apoptotic early gestational STs
      were heavily stained with cPGES. We also investigated the cellular localization
      of cPLA(2)and PGHS-2 in early gestation and at term. Cytosolic PLA(2)was
      immunolocalized to the stroma and STs at term, but was only observed in CTs in
      early gestation. PGHS-2, on the other hand, was immunolocalized to both
      extravillous and STs in early gestation and at term. Our results suggest that
      mPGES could play a role in trophoblast invasion via its association with EVTs in
      the basal plate, whereas cPGES could be involved in apoptosis or repair
      mechanisms.

PMID- 15028419
TI  - Syncytiotrophoblast degradation and the pathophysiology of the malaria-infected
      placenta.
AB  - Malaria is associated with excessive parasitic infection of the placenta and a
      reduction in neonatal birthweight. This study has investigated placental cell
      death in women with active and past malarial infection. Term placentae, with and
      without malarial pathology, were obtained from women in The Gambia. Active and
      past malaria infections were identified in placental sections and histological
      examination was used to determine the number of villi, the incidence of
      apoptosis, syncytial degradation, fibrinoid deposition and the frequency of
      syncytial knots. Placentae with active malaria infection showed erythrocyte
      adhesion of infected cells to syncytiotrophoblast, syncytial degradation,
      increased syncytial knotting and, in rare cases, localized destruction of the
      villi. Past malarial infection was characterized by syncytiotrophoblast
      disruption and fibrin-type fibrinoid (FTF) deposition. Perivillous FTF deposition
      was consistent with increased syncytial lesions and both increased lesions and
      syncytial knots were associated with birthweight reductions. Active malaria
      infection produced no alteration in placental apoptosis. The numbers of chorionic
      villi remained unchanged and infiltration of inflammatory cells, although not
      measured directly, appeared to be non-pervasive within the infected tissue. These
      observations establish a direct link between malaria parasitic infection and
      syncytiotrophoblast damage. The placental rejection of parasite-affected syncytia
      may invoke structural changes to compensate for inadequate placental exchange.
      Syncytial destruction could have serious implications; impairing fetal growth and
      in some rare cases, providing a previously unrecognized pathway to congenital
      infection.

PMID- 15028418
TI  - Hydrogen peroxide induced apoptosis in amnion-derived WISH cells is not inhibited
      by vitamin C.
AB  - Increased reactive oxygen species (ROS) have been identified as a potential cause
      of remodelling and apoptotic change in fetal membrane. Vitamin C has been
      suggested as a therapeutic agent to prevent ROS induced chorio-amnion apoptosis.
      The purpose of this study was to determine whether hydrogen peroxide (HP), a ROS,
      initiates apoptosis in the WISH cell model and whether vitamin C would inhibit HP
      induced apoptosis. HP induced apoptosis in WISH cells; as assessed by cytochrome
      c release from mitochondria, Poly-(ADP-ribose)-Polymerase (PARP) cleavage,
      nuclear matrix protein (NMP) release and DNA fragmentation analysis. HP induced
      dose dependent release of cytochrome-c, PARP cleavage, NMP release, and DNA
      fragmentation. HP also increased PGE(2)release in parallel with apoptosis in WISH
      cells, in a manner similar to that reported with other apoptotic agents. Vitamin
      C pre-incubation caused cytochrome-c release earlier, and at lower HP doses, than
      HP alone. It had no effect on HP induced PARP cleavage, but enhanced DNA
      fragmentation, and induced NMP release on its own. Vitamin C partially suppressed
      dose dependent HP induced PGE(2)release. We conclude that HP causes apoptosis in
      WISH cells and vitamin C pre-incubation does not inhibit, and may accelerate and
      exacerbate, HP induced apoptosis.

PMID- 15028421
TI  - Modulation of connexin expression in sheep endometrium in response to pregnancy.
AB  - The expression pattern of two typical gap junction channel proteins, connexin 43
      and connexin 26 (Cx43 and Cx26), was identified in the endometrium of sheep, a
      species with epitheliochorial type of implantation, by indirect
      immunohistochemistry during the cyclic phases, early and late pregnancy, and
      immediately after birth. The extent of Cx43 immunoreaction bound to endometrial
      stromal cells of the early implantation stage (day 15 p.c.) was comparable to the
      situation observed in oestrus. The subsequent intensification of feto-maternal
      contact correlated with a striking increase of stromal Cx43 in the
      intercaruncular and caruncular regions of the uterus (days 18 and 21 p.c.) and
      the induction of Cx26 in the glandular epithelium of late implantation (day 21
      p.c.). In contrast, both gap junction proteins, coexpressed in the stroma of
      placentomes and interplacentomal sections on days 131 and 145 p.c., decreased
      during late pregnancy, while an intense and augmenting staining for Cx26 was
      detected at the cell borders of the glandular and luminal epithelium. The spatial
      and temporal distribution of both connexins suggests that, under embryonal and
      hormonal influences, gap junctional communication is involved in the implantation
      process and the regulation of endometrial tissue functions during sheep pregnancy
      and indicates further, that this connexin expression path resembles more the
      invasive type of implantation.

PMID- 15028420
TI  - Epidermal growth factor (EGF) in the human placental infection with Trypanosoma
      cruzi.
AB  - Maternal infection of Trypanosoma cruzi is associated with premature births,
      abortions and placentitis. A decrease in EGF levels has been suggested to occur
      in animals infected by T. cruzi, but there is no research about the levels of EGF
      in human patients with Chagas' disease. We evaluated serum EGF levels in pregnant
      women with and without the disease, and with immunological methods detected EGF
      receptors and EGF in both groups of placentae and in cultures of normal placental
      villi with and without parasites. PLAP in placentae from those women was also
      immunologically detected, since EGF can induce the release of PLAP from the
      trophoblast surface and PLAP is suggested to be a receptor allowing parasite
      invasion of the placenta. Plasma from women with Chagas' disease contained lower
      level of EGF when compared to plasma of healthy women. Placentae from women with
      Chagas' disease showed lower PLAP expression but same level of detectable EGF
      receptors and EGF when compared with placentae from women without the disease.
      Culture with parasites did not reduce EGFr level. Results suggest a lower
      availability of EGF in women with Chagas' disease, which could explain several
      malfunctions of the placenta associated with maternal Chagas' disease.

PMID- 15028422
TI  - Dynamic changes in primate endometrial leukocyte populations: differential
      distribution of macrophages and natural killer cells at the rhesus monkey
      implantation site and in early pregnancy.
AB  - The distribution of uterine leukocytes during the periimplantation period cannot
      be readily evaluated in human pregnancy. Using immunohistochemistry we examined
      the distribution of macrophages, natural killer (NK) cells, and T cells in the
      non-pregnant endometrium and in the decidua at early stages of implantation and
      pregnancy in the rhesus monkey. CD68+ macrophages, CD56+ lymphocytes and CD3+ T
      cells were present in the proliferative and secretory endometrium. The number of
      macrophages and CD56+ lymphocytes dramatically increased at implantation (day 14
      15 of pregnancy) and continued to be high in early pregnancy decidua. Macrophages
      were conspicuously more numerous in proximity to implantation site (decidua
      basalis) as compared to sites peripheral to the developing placenta (decidua
      parietalis), and were found in close association with cytotrophoblasts adjacent
      to the decidua, as well as around arteries invaded by extravillous
      cytotrophoblasts. In contrast to macrophages, CD56+ lymphocytes were more evenly
      distributed throughout the decidua. Few CD3+ T cells were seen in pregnancy,
      being scattered in the endometrial stroma with occasional aggregate formation.
      The distribution of uterine leukocytes vis-a-vis trophoblasts at the rhesus
      monkey implantation site and in early pregnancy suggests different roles for
      macrophages and uterine NK cells in the response to trophoblast invasion.

PMID- 15028423
TI  - Fetomaternal glycosylation of early placentation events in the African elephant
      Loxodonta africana.
AB  - During implantation in the African elephant (Loxodonta africana), fetal
      trophoblast displaces the surface uterine epithelium and superficially penetrates
      the uterine glands. This limited invasion is followed by the upgrowth of blunt
      fingers of endometrial stroma, covered with trophoblast and containing
      capillaries that subsequently vascularize the growing placenta. We have used
      lectin histochemistry to compare the glycosylation of maternal endothelial cells
      in the endometrium with those growing within the trophoblastic processes of a 2 g
      embryo (approximately 125 days' gestation), and also examine changes in the
      endometrial glands associated with trophoblastic invasion. Maternal vessels at
      the apices of the trophoblast-covered stromal upgrowths showed increased
      expression of terminal N-acetyl galactosamine, N-acetyl glucosamine oligomers,
      some sialic acids, and tri/tetra-antennate non-bisected complex N-linked glycan,
      as indicated by increased lectin staining. The areas of increased staining were
      also more resistant to neuraminidase digestion. Invaded glands had distended
      walls composed of flattened epithelial cells, some of which showed heavy lectin
      staining suggestive of intracellular glycan accumulation. The vascular changes
      suggest that new maternal capillary growth is accompanied by alterations in
      surface glycosylation. This may be the result of increased glycosyl transferase
      activity associated with cell proliferation and may also indicate the expression
      of significantly increased anti-adhesive molecules preventing blood stasis and
      egress of maternal immunocompetent cells into the fetal compartment.

PMID- 15028424
TI  - Placental Fas and Fas ligand expression in normal early, term and molar
      pregnancy.
AB  - To clarify the Fas and Fas-ligand status of normal and molar trophoblast, the
      expression of Fas and FasL by placental trophoblast populations in partial and
      complete hydatidiform moles was compared with that in normal first trimester and
      term pregnancies using an avidin-biotin peroxidase technique on frozen and
      formalin-fixed paraffin-embedded placental tissues with both monoclonal and
      polyclonal antibodies. The TUNEL technique was used to detect apoptotic cells in
      the same tissues. The immunoreactivity for Fas and Fas-ligand was comparable with
      both monoclonal and polyclonal antibodies on frozen as well as paraffin-embedded
      sections. In normal early and molar pregnancy there was strong FasL expression by
      villous cytotrophoblast and syncytiotrophoblast. However, there were significant
      differences in FasL expression by trophoblast subpopulations in both early and
      term normal pregnancy and between the same trophoblast subpopulation at different
      gestations, with FasL staining generally being weaker at term. Strong FasL
      staining by cytotrophoblast cells in the distal parts of cell columns contrasted
      with unstained cytotrophoblast in the proximal part of columns. Distinct
      trophoblast subpopulations in partial hydatidiform mole also differentially
      expressed FasL with reduced FasL expression in proliferating syncytiotrophoblast.
      In contrast there was no differential FasL expression in complete hydatidiform
      mole, all trophoblast subpopulations strongly expressing FasL. Unlike the
      differential expression of FasL there were no differences in Fas expression by
      trophoblast populations in normal early or term placental tissues. Fas expression
      was reduced in villous cytotrophoblast at term. Differential expression of Fas by
      different trophoblast subpopulations was noted in partial and complete
      hydatidiform mole. In complete mole villous cytotrophoblast and
      syncytiotrophoblast stained strongly compared with proliferating trophoblast.
      Using TUNEL labelling apoptosis was rarely detected in placental trophoblast.
      Differential Fas and FasL expression by trophoblast subpopulations in normal and
      pathological pregnancy does not appear to be related to apoptosis of trophoblast.

PMID- 15028425
TI  - Glutathione S-transferases and esterases in placenta after normal and pre
      eclamptic pregnancies.
AB  - Severe pre-eclampsia reduced significantly (P<0.05) by 68+/-6 per cent (mean+/
      sem, n=10) the maximal velocity (V(max)) and, consequently, reduced significantly
      by 60+/-7 per cent the catalytic efficiency (C(E)) of placental glutathione
      transferase pi, assayed with ethacrynic acid. Mild and severe pre-eclampsia
      reduced significantly by 82+/-5 per cent (mean+/-sem, n=5) and by 41+/-5 per cent
      (mean+/-sem, n=10), respectively, the V(max)and, consequently, reduced
      significantly by 72+/-7 and by 33+/-13 per cent, respectively, the C(E)of
      esterase, assayed with p-nitrophenyl acetate. Furthermore, severe pre-eclampsia
      increased significantly by 296+/-78 per cent the Michaelis-Menten constant (K(m))
      of total GST, assayed with chlorodinitrobenzene and, consequently, decreased
      significantly the C(E)by 83+/-3 per cent. On the other hand, the concentrations
      of total and non-protein thiols did not change significantly in placental
      homogenates from patients with mild or severe pre-eclampsia compared to normal
      pregnancies. These findings would indicate a decreased capacity of the
      glutathione transferases and esterase detoxification systems to protect the fetus
      from drugs prescribed to pregnant women suffering pre-eclampsia, mainly in the
      severe phase.

PMID- 15028426
TI  - Glucose metabolism in the human preterm and term placenta of IUGR fetuses.
AB  - Many fetuses suffering from intrauterine growth restriction (IUGR) are
      hypoglycaemic. However, the underlying mechanisms are not well established. An
      increased placental glucose consumption in IUGR could impair glucose transfer
      across the placenta. In this study we used two different approaches to
      investigate glucose metabolism in preterm and term placentae of IUGR fetuses. We
      determined activity and protein expression of the three rate-limiting glycolytic
      enzymes phosphofructo kinase (PFK), pyruvate kinase (PK) and hexokinase (HXK) in
      a cytoplasmic fraction of homogenates of placentae obtained from IUGR and
      appropriate for gestational age (AGA) pregnancies. Protein expression was
      assessed using Western blot and enzyme activities were determined in a
      spectrophotometer by measuring the rate of NADH oxidation (PFK and PK) or NADP
      reduction (HXK) in enzyme reactions coupled to the respective enzyme. To
      determine the distribution of the glycolytic enzymes immunocytochemistry was
      performed. We also measured glucose consumption and lactate production in fresh
      placental villous tissue using a perifusion system. The expression of PFK, PK and
      HXK as well as the activity of PK and HXK was unaltered in IUGR placentae. The
      activity of PFK on the other hand was 32 per cent lower in IUGR placentae (n=24,
      P<0.05). Immunocytochemistry confirmed the distribution of the enzymes to the
      cytoplasm of the syncytiotrophoblast. Placental glucose consumption in IUGR
      [0.06+/-0.01 micromol/(min*g), n=5] was not different from AGA [0.06+/-0.005
      micromol/(min*g), n=12], whereas lactate production was decreased by 28 per cent
      in IUGR. These results do not support the hypothesis of increased placental
      glucose consumption but suggest an altered glycolytic pathway in the IUGR
      placenta.

PMID- 15028427
TI  - Differential expression of CXCR4 receptor in early and term human placenta.
AB  - Chemokines and their receptors play a crucial role in regulation of T-cell
      migration and differentiation. Recent findings suggest that these proteins can
      also regulate cell functions such as angiogenesis and proliferation. Besides,
      CXCR4, a chemokine receptor, is one of the two major co-receptors for entry of
      the HIV virus during the late stages of HIV infection. We have studied the
      expression of CXCR4 in early (8-10 weeks) and term human placenta.
      Immunofluorescence staining and RT-PCR analysis revealed a differential
      expression of the CXCR4 receptor. Densitometric analysis revealed a two fold
      higher expression of the CXCR4 mRNA in early as compared to term placenta. This
      finding suggests that the expression of CXCR4 receptor may be developmentally
      regulated and its role in the early stages of pregnancy is implicated, when
      embryogenesis and organogenesis takes place. The fact that only 1-2 per cent of
      the placental transmission of the HIV virus takes place in the early placenta may
      also be correlated with our findings, suggesting that CXCR4 may not have a direct
      role in the transmission of HIV infection in the placenta.

PMID- 15028428
TI  - Successful patching of iatrogenic rupture of the fetal membranes.
AB  - Rupture of the fetal membranes is a common, but potentially serious complication
      of invasive fetal procedures. Quintero described a technique to seal the fetal
      membrane defect by means of a bloodpatch, usually called 'amniopatch' in this
      application. The successful use in two consecutive patients with ruptured
      membranes after a fetoscopic intervention at respectively 17 and 22 weeks'
      gestational age is described, together with a literature review of published
      experience.

PMID- 15028429
TI  - There are many approaches to the culture of human trophoblast but few that
      facilitate study of complex interactions between fetal and maternal tissues.

PMID- 15028430
TI  - Role of organ-sparing surgery in germ cell tumors of the testis.

PMID- 15028431
TI  - Use of alpha-adrenergic inhibitors in treatment of benign prostatic hyperplasia
      and implications on sexual function.

PMID- 15028432
TI  - Routine pouchograms are not necessary after continent urinary diversion.
AB  - OBJECTIVES: Pouchograms are routinely performed before catheter removal after
      continent urinary diversion at our institution. Our aim was to determine the
      necessity of pouchograms based on a review of our experience. METHODS: A
      retrospective review of patient records and radiographic studies was done for
      patients undergoing radical cystectomy and continent urinary diversions between
      1991 and 2001. RESULTS: Seventy-two patients underwent continent urinary
      diversion (orthotopic, n = 59; cutaneous, n = 13) during the study period. All
      underwent pouchogram postoperatively (median 22 days; range 20 to 27). Six
      patients (8.3%) had a demonstrable radiographic leak; in 5 of the 6 patients, the
      urine leak was suspected on clinical grounds. Three patients (4.7%) developed
      urosepsis after pouchogram. CONCLUSIONS: Our findings indicate that routine
      pouchograms before pouch activation after continent urinary diversion may not be
      necessary.

PMID- 15028434
TI  - Lower urinary tract symptoms after renal transplantation: are there changes over
      time?
AB  - OBJECTIVES: To examine the changes in bladder function after renal
      transplantation by comparing lower urinary tract symptoms in the first and third
      years after transplantation in a group of renal transplant recipients. METHODS:
      The long-term changes in bladder function after transplantation were studied
      using a longitudinal study design. The study group consisted of 53 patients who
      underwent renal transplantation in 1998 at the University Medical Centre Nijmegen
      and who returned a completed questionnaire about their micturition pattern in the
      first and third year after transplantation. The data on symptoms of lower urinary
      tract dysfunction were collected using the International Continence Society
      (male) and Bristol Female Lower Urinary Tract Symptoms questionnaires. The
      control group consisted of 74 patients who visited the Outpatient Clinic of
      Otorhinolaryngology at year 1. In our analyses, we compared the micturition
      behavior of the transplant group at year 3 with the control group and with their
      own micturition behavior at year 1. RESULTS: The results of our study showed that
      3 to 4 years after transplantation, the renal transplant group still urinated
      significantly more often during the day and during the night than did the control
      patients. Furthermore, among most (63% to 68%) of the patients who showed these
      symptoms in the first year after transplantation, the symptoms were still present
      2 to 3 years later. CONCLUSIONS: The frequency and incidence of nocturia among
      renal transplant patients are fairly persistent phenomena.

PMID- 15028433
TI  - External-internal nephro-uretero-ileal stents in patients with an ileal conduit:
      long-term results.
AB  - OBJECTIVES: To describe an improved technique for upper urinary tract drainage in
      patients with ureteroileal anastomotic stricture after radical cystectomy and
      urinary diversion to an ileal conduit, and to review our experience and long-term
      results. METHODS: From 1995 to 2002, 16 patients (18 renal units) with
      ureteroileal anastomotic stricture after radical cystectomy and urinary diversion
      to an ileal conduit underwent external-internal nephro-uretero-ileal stent
      placement. The procedure consisted of three stages: insertion of a percutaneous
      nephrostomy tube; retrograde external-internal stent placement with the help of
      an antegrade-inserted wire, leaving the stent's port in the stoma bag; and
      periodic retrograde stent exchange. The median duration of follow-up was 26.6
      months. RESULTS: The overall success rate was 94.7%. No serious complications
      occurred during the procedure or during follow-up. Patient compliance was fairly
      good. In 75% of the patients, the stent served as the definitive treatment,
      avoiding the need for surgical revision. CONCLUSIONS: External-internal nephro
      uretero-ileal stent placement can be used successfully and safely as a definitive
      treatment for anastomosis-related complications in patients after radical
      cystectomy and urinary diversion to an ileal conduit.

PMID- 15028435
TI  - Significance of thrombocytosis for determining prognosis in patients with
      localized renal cell carcinoma.
AB  - OBJECTIVES: To evaluate the significance of thrombocytosis for determining
      survival in patients with localized renal cell carcinoma (RCC) who underwent
      radical nephrectomy with curative intent. METHODS: The study population comprised
      151 patients who underwent radical nephrectomy with a diagnosis of localized RCC.
      The inclusion criteria were at least one preoperative platelet count and a tissue
      diagnosis of RCC. Thrombocytosis was defined as a platelet count greater than
      400,000/mm3. The charts of these patients were retrospectively reviewed and the
      relationship between the preoperative platelet counts and survival was evaluated
      according to the histologic variants. RESULTS: The mean follow-up was 37.1 +/-
      24.1 months (median 34, range 3 to 91). Of these 151 patients, 21 had a
      preoperative platelet count greater than 400,000/mm3. The thrombocytosis rate was
      significantly greater in those with advanced T stage (P = 0.045). Lymph node
      positivity also correlated with thrombocytosis (P = 0.028). However, no
      statistically significant correlation was found between grade and histologic
      subtypes and thrombocytosis (P = 0.053 and P = 0.354, respectively). Ten (47.6%)
      of 21 patients with thrombocytosis and 21 (16.2%) of the remaining 130 patients
      died of disease progression (P = 0.002). The Kaplan-Meier cause-specific survival
      curves showed that patients who had thrombocytosis had a mean survival of 45.2
      months compared with 76.6 months in patients without thrombocytosis (P = 0.0002).
      CONCLUSIONS: Preoperative thrombocytosis is a significant predictor for
      determining prognosis in patients with localized RCC. Thrombocytosis was found
      more frequently in patients with advanced stage RCC, and patients with
      preoperative thrombocytosis had a worse survival compared with those with normal
      platelet counts.

PMID- 15028436
TI  - Routine bladder biopsies in men with bladder outlet obstruction?
AB  - OBJECTIVES: To establish whether routine evaluation of light microscopic changes
      in bladder biopsies in men with graded bladder outlet obstruction correlates with
      urodynamic parameters and to evaluate the performance of two pathologists in
      bladder biopsy interpretation. METHODS: In 63 consecutive patients presenting
      with lower urinary tract symptoms suggestive of bladder outlet obstruction, the
      workup included bladder biopsies, which were semiquantitatively and independently
      evaluated by two pathologists for fibrosis, elastosis, muscle cell degeneration,
      inflammation, and additional remarkable findings. Furthermore, as determined by
      their general impression, the pathologists gave a diagnosis of normal or graded
      abnormality. The pathologists' performance was compared and the clinical and
      urodynamic data were correlated to the consensus histologic diagnoses. RESULTS:
      Fifty-four of 63 cases could be evaluated. The intraobserver and interobserver
      reproducibility were reasonable, with a kappa of 0.35 and 0.50, respectively. The
      consensus diagnosis of abnormal bladder biopsy correlated with impaired bladder
      compliance and capacity. However, no correlation was found between the presence
      and severity of histologic abnormalities and Schafer class, urethral resistance
      factor, instability, postvoid residual urine volume, symptom score, and prostate
      volume. CONCLUSIONS: Although abnormal bladder biopsies correlated significantly
      with impaired bladder capacity and compliance, routine evaluation of bladder
      biopsies is not indicated in the evaluation of bladder outlet obstruction.

PMID- 15028437
TI  - Antitumor activity of common antibiotics against superficial bladder cancer.
AB  - OBJECTIVES: The recurrence rate for superficial bladder tumors treated with
      complete resection averages 88%. Intravesical chemotherapy decreases the
      recurrence rate by only 14%; thus, new chemotherapeutic agents are needed.
      Antibiotics are often used to prevent infections after transurethral resection of
      bladder tumors. Oral intake of antibiotics results in significantly greater
      concentrations in the urine than in the serum. Our objective was to evaluate four
      commonly used urinary antibiotics for their cytotoxic activity against bladder
      cancer cells at clinically relevant concentrations. METHODS: Three human
      transitional cell carcinoma lines--HTB9 (grade 2), T24 (grade 3), and TccSup
      (grade 4)--were exposed to ciprofloxacin, trimethoprim-sulfamethoxazole,
      cefazolin, or nitrofurantoin at concentrations from 0 (control) to 1000, 1000,
      5000, and 2000 microg/mL, respectively, for 96 hours. Cytotoxicity was evaluated
      using the MTT colorimetric assay. Six replicates were used for each data point,
      and the results are reported as the mean +/- standard deviation. RESULTS:
      Significant cytotoxicity (P <0.001) was seen, starting at 12.5 microg/mL (HTB9,
      TccSup) and 50 microg/mL (T24) for ciprofloxacin, 31.25 microg/mL (HTB9, TccSup)
      and 62.5 microg/mL (T24) for trimethoprim-sulfamethoxazole, 19.5 microg/mL (HTB9)
      and 156.3 microg/mL (T24, TccSup) for cefazolin, and 7.8 microg/mL (HTB9, T24,
      TccSup) for nitrofurantoin. Cytotoxicity was dose dependent for all four
      antibiotics, and the maximal effect did not differ among antibiotics.
      CONCLUSIONS: Commonly used antibiotics exhibit significant dose-dependent
      cytotoxicity against bladder cancer cells at concentrations achievable in the
      urine after oral administration. The administration of antibiotics after
      transurethral resection of bladder tumors might prevent seeding of cancer cells
      and thereby decrease the recurrence rate. Preclinical data such as these must be
      considered in the design of clinical trials addressing recurrence after
      transurethral resection of bladder tumors.

PMID- 15028438
TI  - Costs of urinary incontinence and overactive bladder in the United States: a
      comparative study.
AB  - OBJECTIVES: To update the cost of urinary incontinence (UI) for year 2000 and
      compare it with the cost of overactive bladder (OAB). METHODS: Using the cost-of
      illness framework, disease epidemiologic data were combined with treatment rates,
      consequence probabilities, and average cost estimates. All costs reflect the
      costs during 2000. RESULTS: The total cost of UI and OAB was 19.5 billion dollars
      and 12.6 billion dollars, respectively (year 2000 dollars). With UI, 14.2 billion
      dollars was borne by community residents and 5.3 billion dollars by institutional
      residents. With OAB, 9.1 and 3.5 billion dollars, respectively, was incurred by
      community and institutional residents. CONCLUSIONS: OAB affected 34 million
      individuals compared with 17 million with UI. Despite the differences in
      epidemiology, the total and per-person costs of UI were higher than the OAB costs
      because OAB individuals without incontinent episodes incurred fewer costs, on
      average.

PMID- 15028439
TI  - Combined local bladder hyperthermia and intravesical chemotherapy for the
      treatment of high-grade superficial bladder cancer.
AB  - OBJECTIVES: To evaluate the effectiveness of combined local bladder hyperthermia
      and intravesical chemotherapy for the treatment of patients with high-grade (G3)
      superficial bladder cancer. METHODS: Patients with G3 bladder tumors (Stage Ta or
      T1) were treated with combined intravesical chemotherapy with mitomycin-C and
      local radiofrequency hyperthermia of the bladder wall. The patients were treated
      with either a prophylactic protocol (40 mg mitomycin-C) after complete
      transurethral resection of all tumors or with an ablative protocol (80 mg
      mitomycin-C) when visible tumor was seen on video-cystoscopy or bladder biopsies
      were positive for carcinoma in situ. RESULTS: Combined chemo-thermotherapy was
      administered to 52 patients with high-grade superficial bladder cancer (40
      patients with Stage T1 tumor, 11 with Ta, and 3 with concomitant or isolated
      carcinoma in situ). At a median follow-up of 15.2 months (mean 23, range 6 to
      90), no stage progression to T2 or disease-related mortality had occurred. The
      bladder preservation rate was 86.5%. The prophylactic protocol was administered
      to 24 patients. After a mean follow-up of 35.3 months, 15 patients (62.5%) were
      recurrence free. The bladder preservation rate was 95.8%. The ablative protocol
      was administered to 28 patients. Complete ablation of the tumor was accomplished
      in 21 patients (75%). After a mean follow-up of 20 months, 80.9% of these
      patients were recurrence free. The bladder preservation rate for the ablative
      group was 78.6%. CONCLUSIONS: Combined local bladder hyperthermia and
      intravesical chemotherapy has a beneficial prophylactic effect in patients with
      G3 superficial bladder cancer. Ablation of high-grade bladder tumors is feasible,
      achieving a complete response in about three quarters of the patients.

PMID- 15028441
TI  - Noninvasive assessment of prostatic obstruction in elderly men with lower urinary
      tract symptoms associated with benign prostatic hyperplasia.
AB  - OBJECTIVES: To investigate what combination of easily available parameters allows
      the noninvasive prediction of infravesical obstruction in optimal agreement with
      urodynamic classification. Urodynamically, men with lower urinary tract symptoms
      suggestive of benign prostatic hyperplasia are classified as nonobstructed or
      obstructed. METHODS: Mandatory and recommended tests were performed in 160
      consecutive men with lower urinary tract symptoms suggestive of benign prostatic
      hyperplasia. The classification of the International Continence Society, the
      group-specific urethral resistance factor, and Schafer's obstruction grade were
      estimated from urodynamic studies. The frequency-volume charts were analyzed. A
      separate group of 173 consecutive men was used for validation. RESULTS: The
      formula, prostate volume (in cubic centimeters) - 3 x maximal urinary free flow
      rate (in milliliters per second) - 0.2 x mean voided volume (in milliliters; as
      estimated from frequency-volume charts), was optimal in the classification
      compared with the urodynamic classification. Extension of this formula to more
      than three parameters did not result in better selection. As estimated from
      receiver operating characteristic curves, the accuracy of the formula appeared to
      be good. The method of quantifying urethral resistance minimally affected the
      classification that resulted from the combination. From the results, a diagram
      was created presenting the probability of an individual to have infravesical
      obstruction. The validation results were satisfactory. CONCLUSIONS: The
      prediction of the probability of a man with lower urinary tract symptoms
      suggestive of benign prostatic hyperplasia to have infravesical obstruction can
      be deduced from a diagram based on a formula composed of three readily available
      parameters: prostate volume, maximal urinary free flow rate, and mean voided
      volume.

PMID- 15028440
TI  - Intermediate-risk urothelial carcinoma: an unresolved problem?
AB  - OBJECTIVES: To perform a biologic characterization of the urothelial neoplasms of
      patients in the intermediate-risk group using multicolor-fluorescence in situ
      hybridization (FISH). A general consensus has not been reached with regard to the
      optimal therapy and follow-up of patients with urothelial neoplasms at
      intermediate risk of progression. On the basis of the chromosomal pattern, we
      developed a new follow-up algorithm for this group and report our preliminary
      results. METHODS: Voided urine samples of 51 consecutive patients (mean age 72.2
      years, range 52 to 93) under follow-up after complete transurethral resection of
      intermediate-risk urothelial carcinoma were evaluated by liquid-based cytology
      (ThinPrep) and uCyt+. From the residual material, Multicolor-FISH (Urovysion) was
      performed. Any cystoscopically suspicious lesion was biopsied or removed
      transurethrally. The mean follow-up time was 14.2 months (range 6 to 30, SD 5.5).
      RESULTS: Two of the 51 patients were not evaluated because of the presence of
      intense granulocytosis and insufficient urothelial cells. Of the 49 remaining
      patients, the results of the Multicolor-FISH analysis were negative (diploid
      chromosomal pattern) in 14; 20 patients showed the loss of one or both alleles of
      p16 and/or an aneuploidy of chromosome 3, and 15 patients had aneuploidy of
      chromosome 7 and/or 17. Of the 14 FISH-negative patients, 2 (14.3%) had
      histologically verified recurrence, and 3 (15.0%) of the 20 p16/3-positive
      patients had recurrence and 9 (60.0%) of the 15 7/17-positive patients had either
      recurrence or progression. CONCLUSIONS: Using the Urovysion test, it is possible
      to predict the biologic behavior of urothelial cancer with a significant impact
      on the follow-up of patients. The intermediate-risk group of urothelial cancer
      can be eliminated in the routine workup by classifying these patients according
      to their chromosomal pattern and defining those patients who can follow the low
      risk scheme and those who must be monitored according to the guidelines for high
      risk superficial lesions.

PMID- 15028442
TI  - Development and validation of a quality-of-life measure for men with nocturia.
AB  - OBJECTIVES: To develop and assess the psychometric properties of a short self
      report nocturia-specific Quality-of-Life (QOL) questionnaire. METHODS: The
      Nocturia Quality-of-Life questionnaire (N-QOL) was developed using focus group
      interviews with men experiencing nocturia. To refine it further and
      psychometrically validate the questionnaire, 107 men with nocturia (from four
      urology clinics in the United Kingdom) completed the pilot N-QOL, along with
      measures of health status and sleep quality. To assess reproducibility, men from
      one clinic completed the pilot N-QOL again at 1 week. RESULTS: After standard
      item reduction analyses, 18 items were dropped from the pilot questionnaire. The
      psychometric properties of the remaining 13-item instrument were tested in
      accordance with standard criteria. Factor analysis identified two subscales,
      sleep/energy and bother/concern, loading at 0.5 and greater. The N-QOL overall
      score and subscales proved to be internally consistent (alpha = 0.84 to 0.90) and
      reproducible (intraclass correlation coefficient = 0.74 to 0.82). N-QOL scores
      correlated with sleep quality (P <0.01) as measured by the Pittsburgh Sleep
      Quality Index and energy/vitality and social functioning (P <0.01) as measured by
      the SF-36 Health Survey, demonstrating good convergent validity. The N-QOL also
      demonstrated statistically significant differences between the scores of those
      experiencing one, two, and three or more episodes of nocturia on an average
      night, indicating excellent discriminant validity. CONCLUSIONS: These analyses
      provide support for the psychometric validity of the N-QOL for use in a male
      population with nocturia.

PMID- 15028443
TI  - Comparative analysis of lower urinary tract symptoms and bother in both sexes.
AB  - OBJECTIVES: To compare the prevalence and severity of lower urinary tract
      symptoms (LUTS) in Japanese men and women and to analyze the impact on bother in
      an age-stratified manner. METHODS: A consecutive series of 2328 men (mean age
      49.5 years) and 1735 women (mean age 48.3 years) who underwent multiphasic health
      screening at our institution completed the self-administered International
      Prostate Symptom Score (IPSS) questionnaire with quality-of-life (QOL)
      assessment. RESULTS: A significant age-related increase in the IPSSs and QOL
      scores was observed in both sexes. Age-stratified analysis showed that the total
      IPSS, voiding symptoms, and QOL score were significantly greater in men than in
      women, and the storage symptoms were not significantly different between both
      sexes. The percentage with moderate to severe symptoms (IPSS 8 or greater) among
      those younger than 40, 40 to 49, 50 to 59, 60 to 69, and 70 years old or older
      was 7.9%, 12.0%, 23.7%, 32.0%, and 48.7%, respectively, in men and 6.5%, 8.3%,
      12.1%, 13.8%, and 31.8%, respectively, in women. Within each category of the
      severity of IPSS, the distribution of the QOL score was very similar in both
      sexes, showing no sex difference in the impact of LUTS on bother. CONCLUSIONS:
      These data showed a similar age-related development of LUTS in both sexes, except
      that voiding symptoms were more prevalent among men. The impact of LUTS on bother
      was also comparable between men and women.

PMID- 15028445
TI  - Role of intraoperative biopsies during radical retropubic prostatectomy.
AB  - OBJECTIVES: To determine the value of intraoperative biopsy during radical
      retropubic prostatectomy. METHODS: Between October 2000 and August 2002, 500 men
      with clinically localized prostate cancer underwent radical retropubic
      prostatectomy by a single surgeon. A 2 to 3-mm circumferential biopsy was
      routinely obtained from the apical and bladder neck soft-tissue margin and
      submitted for frozen section examination. In selective cases suspicious for
      capsular incision, a biopsy was sent from what was believed to be the contiguous
      neurovascular bundle/lateral pedicle. RESULTS: Prostate cancer was observed in
      4.5%, 0.8%, and 1.6% of the intraoperative biopsies sent from the apical, bladder
      neck, and neurovascular bundle/lateral pedicle soft-tissue margins, respectively.
      Patient age, Gleason score, perineural invasion on diagnostic prostate biopsy,
      and clinical stage were not associated with prostate cancer at the apical soft
      tissue margin. The sensitivity, specificity, positive predictive value, negative
      predictive value, and accuracy of the surgical specimen to predict cancer in the
      apical soft-tissue margin was 57.7%, 98.2%, 62%, 97.7%, and 96%, respectively.
      Intraoperative biopsy of the apical soft-tissue margin reduced the positive
      margin rate by 3.8%. CONCLUSIONS: The yield of intraoperative biopsy of the
      bladder neck and neurovascular bundle/lateral pedicle is too low to justify it in
      routine practice. Biopsy of the apical soft tissue should be routinely performed
      to reduce the positive surgical margin rate.

PMID- 15028444
TI  - Volume-based evaluation of serum assays for new prostate-specific antigen
      isoforms in the detection of prostate cancer.
AB  - OBJECTIVES: Recently, disease-specific isoforms of the prostate-specific antigen
      (PSA) have been identified. We evaluated the efficacy of precursor isoforms of
      PSA (pPSA) and an internally cleaved form of PSA referred to as the benign
      prostatic hyperplasia-associated PSA (BPSA) for the detection of prostate cancer.
      METHODS: Serum concentrations of [-2], [-4], and [-7]pPSA, sum pPSA ([-2] + [-4]
      + [-7]pPSA), and BPSA were retrospectively measured in 43 selected men. The
      median total PSA levels in men with and without cancer were 6.5 microg/L (range
      0.4 to 12.1 microg/L) and 6.1 microg/L (range 3.7 to 21.5 microg/L),
      respectively. Of the 43 men, 15 had clinical T2 prostate cancer with an
      ultrasound-estimated prostate volume (PV) of greater than 50 mL, 13 had clinical
      T2 prostate cancer with PV less than 25 mL, and 15 were prostate cancer free with
      PV greater than 50 mL. RESULTS: The median values for BPSA, free-to-total PSA
      ratio (f/tPSA), and benign-to-total PSA ratio (B/tPSA) differed statistically
      between men with cancer and a PV less than 25 mL and men with cancer and a PV
      greater than 50 mL (P <0.05) and between the men with cancer and a PV less than
      25 mL and men without cancer and a PV greater than 50 mL (P <0.005). All
      evaluated variables had no correlation with tumor volume in 15 men who had
      undergone radical prostatectomy. CONCLUSIONS: In this preliminary study, the
      level of [-2], [-4], sum pPSA, and BPSA seemed to be PV related, but only BPSA
      and B/tPSA and f/tPSA were significantly associated with PV. Therefore, pPSA did
      not aid in better discriminating cancer from noncancer.

PMID- 15028446
TI  - Can the number of cores with high-grade prostate intraepithelial neoplasia
      predict cancer in men who undergo repeat biopsy?
AB  - OBJECTIVES: To evaluate whether the presence of, or the number of cores
      containing, high-grade prostatic intraepithelial neoplasia (PIN) found in men who
      underwent initial extended multisite biopsy could predict which men would have
      prostate cancer on subsequent repeat biopsies. METHODS: Between June 1997 and
      January 2003, 1086 men underwent initial prostate biopsy for early detection of
      prostate cancer using an extended multisite biopsy scheme. Of these, 175 men
      without cancer underwent at least one repeat biopsy (range one to three; median
      interval between biopsies, 3 months). Among these 175 patients, 47 had high-grade
      PIN on initial biopsy. RESULTS: The initial extended biopsy identified cancer in
      33.8% (367 of 1086) and high-grade PIN in 20.8% (226 of 1086). The incidence of
      high-grade PIN only in patients found to have cancer on initial biopsy was 29.7%
      (109 of 367). The presence of high-grade PIN was associated with concurrent
      prostate cancer at the initial biopsy (P <0.0001). Overall, repeat biopsy
      identified cancer in 18.3% of the 175 men. Of the 47 men with high-grade PIN, 5
      (10.6%) were found to have cancer on repeat biopsy. The number of biopsy
      specimens positive for high-grade PIN on initial biopsy was not associated with
      the likelihood of prostate cancer on repeat biopsy. Multivariate logistic
      regression analysis showed that neither the presence of high-grade PIN nor the
      number of cores containing high-grade PIN on initial biopsy were predictors for
      prostate cancer on repeat biopsy. CONCLUSIONS: The number of cores positive for
      high-grade PIN was not predictive for cancer on repeat biopsy.

PMID- 15028447
TI  - Prostate cancer diagnosed in spinal cord-injured patients is more commonly
      advanced stage than in able-bodied patients.
AB  - OBJECTIVES: To determine the incidence and characteristics of prostate cancer in
      men with spinal cord injury (SCI). Little is known about the characteristics of
      prostate cancer in men with SCI, because prostate cancer screening is not
      aggressively performed in this population. METHODS: In one fiscal year, 648 men
      with SCI older than age 50 years were actively enrolled with the SCI service,
      20,949 able-bodied men older than age 50 years were actively enrolled in the
      outpatient clinic database, and 945 patients with prostate cancer were in the
      cancer registry at our facility. These three databases were cross-referenced for
      prostate cancer diagnosis and stage and compared with the presence of SCI.
      RESULTS: Of the 648 patients with SCI, 12 patients with a prostate cancer
      diagnosis that preceded their injury were excluded. Of the remaining 636
      patients, 11 (1.7%) had been diagnosed with prostate cancer since their injury.
      In contrast, of the 20,949 able-bodied men older than age 50 years seen at our
      facility in fiscal year 1999, 919 (4.4%) had prostate cancer. Of the patients
      with SCI and prostate cancer, 7 (63.6%) had locally advanced (Stage T3) or
      metastatic prostate cancer compared with 267 (29.1%) in the able-bodied
      population (P = 0.012). CONCLUSIONS: Although the proportion of patients with a
      prostate cancer diagnosis was greater in the able-bodied patients, the prostate
      cancer detected in the patients with SCI tended to be of a more advanced stage
      and grade. The difference was likely a result of the decreased use of prostate
      cancer screening in this population.

PMID- 15028448
TI  - Safety and outcome of early catheter removal after radical retropubic
      prostatectomy.
AB  - OBJECTIVES: To assess the outcomes of patients who underwent radical retropubic
      prostatectomy (RRP) and had their indwelling urinary catheter removed on
      postoperative day 4 or later. METHODS: The medical records of 342 consecutive
      patients undergoing RRP by a single surgeon were retrospectively reviewed. None
      of these patients had received radiotherapy, transurethral resection, or simple
      prostatectomy before RRP. The 342 patients were categorized into two groups
      according to the length of catheterization. Group 1 (n = 127) had the urethral
      catheter removed on postoperative day 4, and group 2 (n = 215) had the catheter
      removed later than postoperative day 4. Removal of the urinary catheter was only
      done if control cystography failed to demonstrate anastomotic extravasation. In
      the case of acute urinary retention, home care nurses and emergency room
      personnel reinserted the urinary catheter without cystoscopic assistance.
      Incontinence was rated according to the number of protective pads used in a 24
      hour period as follow: none, mild (1 pad/day), moderate (more than 1 but 3 or
      fewer pads/day), and severe (more than 3 pads/day). RESULTS: The mean age of the
      study population was 61.5 +/- 6.1 years. Acute urinary retention after catheter
      removal occurred in 11 patients (3%), 4 from group 1 and 7 from group 2. None of
      the patients requiring catheter reinsertion presented with complications related
      to this event. The overall continence rate was 58%, 85%, and 92% at 3, 9, and 12
      months, respectively. The continence rates at 3, 9, and 12 months were higher for
      group 1 than for group 2 (P = 0.0002, P = 0.011, and P = 0.044, respectively).
      Bladder neck contracture was encountered in 14 patients (4%), 2 (2%) from group 1
      and 12 (6%) from group 2. The only factor predicting continence was the duration
      of bladder catheterization. CONCLUSIONS: Bladder catheters can be safely removed
      on postoperative day 4 in patients with normal cystograms after RRP. The
      continence and anastomotic stricture rates were improved in patients with 4 days
      of indwelling catheterization.

PMID- 15028449
TI  - Do younger men have better biochemical outcomes after radical prostatectomy?
AB  - OBJECTIVES: To examine the relationship between age and biochemical failure after
      radical prostatectomy (RP), controlling for the year of surgery. Prior studies
      have suggested that younger men have lower prostate-specific antigen recurrence
      rates after RP, although none of the prior studies had controlled for the year of
      surgery. METHODS: We examined the data from 1753 men treated with RP between 1988
      and 2002 at five equal access medical centers. We compared age, as a categorical
      variable according to decade of life (50 years old or younger, 51 to 60, 61 to
      70, and older than 70 years), with the clinical and pathologic variables at RP,
      as well as the time to biochemical recurrence, using a multivariate Cox
      proportional hazards model. RESULTS: Age was significantly related to the year of
      surgery, with the more recently treated patients being younger than less recently
      treated patients (P <0.001). After controlling for the year of surgery, the
      younger men had smaller prostates, fewer high-grade tumors on biopsy, and less
      lymph node metastasis, but a greater percentage of cores with cancer. On
      multivariate analysis, men 50 years old or younger had significantly lower
      recurrence rates than did the older men. Moreover, men older than 70 years had
      significantly greater prostate-specific antigen failure rates than men aged 51 to
      70 years or men aged 50 years or younger. CONCLUSIONS: The average age of men
      undergoing RP has decreased with time. Independent of this, young men have more
      favorable outcomes after RP than older men. Continued screening to detect
      prostate cancer among younger men when it is most curable appears warranted.

PMID- 15028450
TI  - Effect of nonsteroidal antiandrogen monotherapy versus castration therapy on
      neuroendocrine differentiation in prostate carcinoma.
AB  - OBJECTIVES: To determine whether the administration of the nonsteroidal
      antiandrogen bicalutamide reduces the risk of an increase in chromogranin A (CgA)
      levels in patients with prostate cancer who experienced biochemical failure after
      radical retropubic prostatectomy (RRP) compared with pharmacologic castration
      therapy. It has been hypothesized that continuous androgen suppression for the
      treatment of prostate cancer results in hyperactivation of neuroendocrine cells
      and an increase in CgA levels. METHODS: Forty-eight patients with pT3pN0M0
      prostate cancer and biochemical (prostate-specific antigen) progression after RRP
      were randomized to bicalutamide monotherapy or pharmacologic castration. The
      serum levels of CgA and prostate-specific antigen were measured at 1, 3, 6, 12,
      18, and 24 months of therapy. The changes in serum CgA levels were compared for
      patients who successfully responded to the first 24 months of therapy. RESULTS:
      In both treatment groups, a statistically significant trend was noted for CgA
      levels to increase from baseline to 24 months. This trend was lower in the
      bicalutamide group (slope = 0.60, 95% confidence interval 0.28 to 0.92; P =
      0.004) than in the castration group (slope = 0.29, 95% confidence interval 0.08
      to 0.50; P = 0.01). CONCLUSIONS: The results of this study provide the first
      evidence to show that in patients with prostate cancer undergoing hormonal
      therapy, nonsteroidal antiandrogen monotherapy produces a significantly lower
      increase in serum CgA compared with castration.

PMID- 15028451
TI  - No difference in six-year biochemical failure rates with or without pelvic lymph
      node dissection during radical prostatectomy in low-risk patients with localized
      prostate cancer.
AB  - OBJECTIVES: To compare differences in the actuarial biochemical relapse-free
      survival rates at 6 years in a contemporary series of patients who underwent
      radical prostatectomy with and without pelvic lymph node dissection (PLND).
      Biochemical failure was defined as a serum prostate-specific antigen level
      greater than 0.2 ng/mL confirmed at least 1 week later. METHODS: The records of
      806 consecutive radical prostatectomy cases performed between January 1995 and
      June 1999 were reviewed. A total of 336 patients with favorable tumor
      characteristics (prostate-specific antigen 10 ng/mL or less, biopsy Gleason score
      6 or less, and clinical Stage T1 or T2) not receiving adjuvant or neoadjuvant
      therapy were divided into two groups according to whether PLND was performed
      (PLND group, n = 140) or omitted (no-PLND group, n = 196). A Cox proportional
      hazards model was used to analyze the effect of age, race, family history,
      initial prostate-specific antigen level, tumor stage, biopsy Gleason score, PLND,
      extracapsular extension, and seminal vesicle invasion on the likelihood of
      biochemical failure. Biochemical relapse-free survival for each group was
      estimated by Kaplan-Meier analysis. The mean follow-up time for the entire group
      was 60.0 months, with a similar follow-up for both cohorts (mean 61.8 and 58.2
      months, respectively, P value not statistically significant). Follow-up
      information was obtained through an institutional review board-approved
      prospective patient registry. RESULTS: The 6-year biochemical relapse-free rate
      for the PLND versus no-PLND group was 86% and 88%, respectively (P = 0.28). On
      multivariate analysis, PLND was not an independent predictor of outcome (P =
      0.33). CONCLUSIONS: Our study results demonstrated that the omission of PLND in
      patients with favorable tumor characteristics does not adversely affect
      biochemical relapse rates at 6 years after surgery. Such patients can be spared
      the morbidity and cost of PLND without affecting the chance for cure.

PMID- 15028452
TI  - Long-term intracavernous therapy responders can potentially switch to sildenafil
      citrate after radical prostatectomy.
AB  - OBJECTIVES: To assess whether long-term users of intracavernous (IC) injections
      after radical prostatectomy can switch to oral therapy with sildenafil citrate.
      METHODS: Forty-nine patients (mean age 60.9 years) with erectile dysfunction
      after radical prostatectomy were identified as long-term users of IC injections
      (3.7 +/- 1.9 years). These patients received open-label treatment with sildenafil
      citrate (50 to 100 mg) for a minimum of 4 weeks or five attempts. The primary
      outcome measure of our study was assessed by the Sexual Health Inventory of Men
      (SHIM) questionnaire (International Index of Erectile Function-5 [IIEF]). A
      successful switch was prospectively defined as erection sufficient for vaginal
      penetration after sildenafil use and compliance to therapy. Patients were
      designated as responders or nonresponders on the basis of their ability to
      achieve vaginal penetration. RESULTS: Of 49 patients, only 36 agreed to receive
      oral open-label sildenafil (50 to 100 mg) for a minimum of 4 weeks or five
      attempts. Prostaglandin E1 (PGE1) was used in 70% and triple therapy (PGE1,
      papaverine, and phentolamine) in the remaining 30%. Of the 36 patients, 15 (41%)
      successfully switched to sildenafil and discontinued IC injections. When the
      results were stratified by the type of IC solution, patients with high-dose
      triple therapy had a poor success rate of switch (7%) compared with patients
      using PGE1 treatment (67%). Of the 36 patients, 14 (38%) found sildenafil
      ineffective and continued using IC injections. Patients who switched to oral
      therapy had had a greater (P <0.001) total mean SHIM (IIEF-5) score with IC
      injections than those who did not switch (12.3 +/- 7.8 versus 20.0 +/- 4.9). Of
      the 36 patients, 7 (19%) found sildenafil alone to be suboptimal but continued
      using it, enhancing the efficacy of IC injections alone. The three predictive
      factors for a successful switch were high preoperative SHIM (IIEF-5) score, high
      post-IC injection SHIM score, and type of IC medication used (PGE1 alone versus
      high-dose triple therapy). CONCLUSIONS: Long-term users of IC injection therapy
      can potentially switch to sildenafil citrate with acceptable sexual satisfaction.
      Patients will accept a lower degree of sexual satisfaction as measured by the
      IIEF-5 (SHIM) score if oral therapy is effective.

PMID- 15028454
TI  - Anatomic variations of cavernous arteries and their effect on measurement of
      hemodynamic parameters: a power Doppler study.
AB  - OBJECTIVES: To assess the cavernous arterial (CA) anatomy with power Doppler
      imaging and evaluate the effects of any anatomic variations on the measurement of
      hemodynamic parameters. METHODS: Thirty-three patients with and 26 without a
      vascular component to their erectile dysfunction were examined. The CA anatomy
      was evaluated, and hemodynamic variables were measured at multiple sites,
      including sites in each artery, if multiple CAs were present. RESULTS: The
      frequency of anatomic variation was similar between the two groups. A single CA,
      considered normal, was observed in 57.7% of 52 corpora in the nonvasculogenic
      group and in 63.6% of 66 corpora in the vasculogenic group. Seven patients
      (26.9%) in the nonvasculogenic group and 11 (33.3%) in the vasculogenic group had
      CA anatomy that was different between the right and left corpora. In both groups,
      a single CA ordinarily showed at least a 35.0% decrement in the mean peak
      systolic velocity (PSV) between the crura and the proximal shaft; double, triple,
      and bifurcated CAs also had distally decreased PSV. However, two corpora with a
      single CA showed an increased PSV distally; in 1 patient, arterial communication
      between the corpora was responsible. In 86.7% of corpora with double CAs in the
      vasculogenic group and in 52.6% in the nonvasculogenic group, the CA distant from
      the crura showed a greater PSV than that near the crura. CONCLUSIONS: CA anatomy
      is variable, and the PSV differs between sites, irrespective of the presence of a
      vascular component to erectile dysfunction. Thus, anatomic variations should be
      considered when interpreting Doppler sonography.

PMID- 15028455
TI  - Severe, but not mild, obstructive sleep apnea syndrome is associated with
      erectile dysfunction.
AB  - OBJECTIVES: To assess the association between obstructive sleep apnea syndrome
      (OSAS) and erectile dysfunction (ED). OSAS is associated with fatigue and daily
      dysfunction. We hypothesized that OSA severity will correlate with ED. We also
      sought to determine the specific features with predictive value for ED in
      patients with OSAS. METHODS: A total of 209 patients evaluated for potential OSAS
      were given a sleep questionnaire, a revised International Index of Erectile
      Function questionnaire (composed of three main topics: sexual satisfaction,
      erection during intercourse, and morning erection), and then underwent a full
      night in-laboratory polysomnography examination. The data were scored blindly.
      RESULTS: A decrease in erectile function was found in all OSAS groups compared
      with those without OSAS. However, the only group for whom this reduction was
      statistically significant (P <0.05) in all ED dimensions was the severe OSAS
      group (respiratory disturbance index [RDI] greater than 40). Furthermore, the
      patients complaining of severe ED had the greatest RDI. Stepwise multiple
      logistic regression analyses revealed that the predicting factors for ED in OSAS
      patients were age, morning tiredness, and RDI. CONCLUSIONS: Severe OSAS is
      clearly associated with ED. However, the relationship is very weak in patients
      with mild or moderate OSAS. The predictive factors for ED in patients with OSAS
      include age, morning tiredness, and RDI.

PMID- 15028456
TI  - Long-term results of laparoscopic retroperitoneal lymph node dissection: a single
      center 10-year experience.
AB  - OBJECTIVES: To evaluate the feasibility, morbidity, and long-term oncologic
      efficacy of laparoscopic retroperitoneal lymph node dissection (L-RPLND) in
      patients with nonseminomatous germ cell tumor (NSGCT). METHODS: L-RPLND was
      performed 188 times in 185 patients; 114 procedures were performed for Stage I
      NSGCT and 6 procedures for tumor marker-negative clinical Stage IIA disease. In
      the case of positive lymph nodes, adjuvant cisplatin-based chemotherapy was
      administered. After chemotherapy, L-RPLND was performed for retroperitoneal Stage
      IIA (10 patients), IIB (43 patients), and IIC lesions (15 patients). RESULTS: The
      mean operative time was 256 minutes for Stage I and 243 minutes for Stage II; the
      conversion rate was 2.6%. The mean blood loss was 159 mL in patients with Stage I
      and 78 mL in those with Stage II disease. Active tumor was found in 19.5% of
      patients with Stage I lesions and in 50% of patients with tumor marker-negative
      clinical Stage IIA disease. After chemotherapy, active tumor was found in 1
      patient with Stage IIC disease and mature teratoma in 38.2% of patients. The mean
      postoperative hospital stay for those with Stage I and II disease was 4.1 and 3.7
      days, respectively. Antegrade ejaculation was preserved in 98.4% of patients. The
      mean follow-up was 53.7 months for those with Stage I and 57.6 months for those
      with Stage II disease. All but 6 patients have remained free of relapse, and no
      patient died of tumor progression. CONCLUSIONS: The rate of tumor control after L
      RPLND and the diagnostic accuracy of L-RPLND were equal to the open procedure,
      and the morbidity was significantly lower. Therefore, L-RPLND for Stage I and low
      volume retroperitoneal Stage II disease can be performed at centers with
      experience in urologic laparoscopy and oncology.

PMID- 15028458
TI  - Children with a febrile urinary tract infection and a negative radiologic workup:
      factors predictive of recurrence.
AB  - OBJECTIVES: To determine the recurrence rate and risk factors for urinary tract
      infection (UTI) in children who present with a febrile UTI and have a negative
      radiologic evaluation. Febrile UTIs with no urinary tract abnormalities are a
      common cause of morbidity in children. METHODS: We performed a retrospective
      review of all children referred to our medical center after a febrile UTI.
      RESULTS: We reviewed 850 charts. Of 850 children, 78 had had a febrile UTI and
      normal ultrasound and voiding cystourography findings. Of the 78 children, 25 had
      had a recurrent UTI (3 boys and 22 girls). Forty-five percent of the girls with a
      febrile UTI developed a recurrent UTI and 14% of the boys had a recurrent UTI (P
      = 0.02). Three boys (two younger than 1 year of age) were uncircumcised and had
      one recurrent febrile UTI. Eleven (39%) of 28 girls who first presented at
      younger than 1 year of age and 7 (58%) of 12 girls who presented at 5 years of
      age or older had recurrent UTIs. The recurrence rate in the 2 to 5-year-old age
      group was 24% (4 of 17). Seven of the older girls exhibited symptoms of
      dysfunctional elimination syndrome. CONCLUSIONS: In children with a febrile UTI
      and a negative radiologic evaluation, recurrence was more common in girls. Boys
      who were uncircumcised may be at an increased risk of infection during the first
      year of life. In girls, the age at the time of the first infection was not
      predictive of recurrence. Although dysfunctional voiding and elimination may
      contribute to recurrent febrile UTIs in young children, an association seems to
      be present in children 5 years old and older.

PMID- 15028457
TI  - Long-term follow-up of Anglian Germ Cell Cancer Group surveillance versus
      patients with Stage 1 nonseminoma treated with adjuvant chemotherapy.
AB  - OBJECTIVES: To study survival and late events after adjuvant chemotherapy in
      Stage 1 nonseminoma. METHODS: From 1978 to 1986, all patients had surveillance.
      From 1986, adjuvant chemotherapy (initially a 3-day regimen of etoposide,
      bleomycin, and cisplatin, but, more recently, bleomycin, Oncovin, and cisplatin)
      was offered to patients at a high risk of relapse (greater than 30%). RESULTS: A
      total of 382 patients with Stage 1 nonseminoma treated between 1978 and 2000 were
      reviewed. Of the 234 patients treated by surveillance, 71 (30%) had relapses (5
      after 2 years), 6 died (2.6%) of germ cell cancer, and 3 developed second primary
      testicular cancer. Of the 148 men treated with adjuvant chemotherapy, 6 (4%) had
      relapses and 2 (1.4%) died of chemoresistant cancer. After one course of
      etoposide, bleomycin, and cisplatin, 3 (6.5%) of 46 developed a relapse; after
      two courses, 1 (3.6%) of 28 did so; and after bleomycin, Oncovin, and cisplatin
      every 10 days x2, 2 (2.7%) of 74 patients did so. Of the high-risk patients who
      were offered adjuvant treatment, 24% declined. As a consequence, the relapse rate
      of the surveillance patients only fell from 36% to 27% after the introduction of
      adjuvant therapy, although for the total cohort treated in the adjuvant era, the
      relapse rate was 16%. CONCLUSIONS: Adjuvant chemotherapy is more effective than
      retroperitoneal lymph node dissection for reducing the relapse risk in high-risk
      Stage 1 nonseminoma. However, given the uncertainty about the incidence of
      postchemotherapy late events, surveillance and retroperitoneal lymph node
      dissection remain justified alternatives. With positron emission tomography and
      laparoscopy showing increasing promise in these cases, quality-of-life studies
      and greater patient involvement in treatment selection are needed.

PMID- 15028460
TI  - Comparison of retroperitoneal laparoscopic and open nephrectomy for benign renal
      diseases in children.
AB  - OBJECTIVES: To compare the results of retroperitoneal laparoscopic versus open
      nephrectomy for benign renal diseases in children. METHODS: From January 1999 to
      February 2003, retroperitoneal nephrectomy or nephroureterectomy was performed in
      23 consecutive children (7 girls and 16 boys). The median patient age was 4 years
      (range 1 to 13). The disease was on the right side in 9 children and on the left
      side in 14. Operative and convalescence parameters, including operative time,
      blood loss, transfusion rate, resumption of oral intake, hospital stay, and
      complication rate, were evaluated in both groups. RESULTS: All laparoscopic cases
      were completed successfully without conversion to open surgery. The median
      operative time and estimated blood loss were not statistically different between
      the two groups. No major perioperative complications occurred in any child, but a
      wound site complication occurred in 1 child who had undergone open surgery. The
      median hospital stay of the open group was 4 days (range 3 to 14), significantly
      longer than that of the laparoscopic group (median 2.5 days, range 2 to 6; P =
      0.018). The cosmetic results of the laparoscopic group were excellent; the scars
      from the trocar sites were barely discernible at the initial postoperative visit.
      Convalescence was uneventful in all patients. CONCLUSIONS: Retroperitoneal
      laparoscopic nephrectomy and nephroureterectomy may be performed for benign
      disease in children with minimal morbidity, improved cosmetic results, and a
      short hospital stay. Our findings indicate that retroperitoneal laparoscopic
      nephrectomy is appropriate in children and superior, in some instances, to open
      surgery.

PMID- 15028462
TI  - Retrieval of migrated ureteral stent by intussusception of ureteral balloon
      dilator tip.
AB  - A vexing complication of ureteral stent placement is inadvertent proximal
      migration. The retrieval of a migrated ureteral stent may be performed using a
      myriad of techniques but usually requires ureteroscopic extraction. We report a
      novel, time-efficient technique to capture and reposition a migrated ureteral
      stent without ureteroscopic manipulation.

PMID- 15028463
TI  - Use of a ureteral access sheath to facilitate removal of large stone burden
      during extracorporeal shock wave lithotripsy.
AB  - Large renal stone burdens within a nondilated collecting system in patients with
      a relative contraindication to percutaneous nephrolithotomy can be a challenging
      problem. We describe a novel technique using a ureteral access sheath combined
      with extracorporeal shock wave lithotripsy to facilitate passage of stone
      fragments in such patients.

PMID- 15028464
TI  - Continent right colon reservoir using a cutaneous appendicostomy.
AB  - INTRODUCTION: Although orthotopic reconstruction has become the preferred form of
      lower urinary tract reconstruction after cystectomy there remains a select group
      of patients who are not appropriate for an orthotopic neobladder substitute. A
      continent cutaneous reservoir provides an alternative means to store urine and
      protect the upper urinary tract without the need for a urostomy appliance. We
      report our surgical technique of a continent cutaneous right colon reservoir
      using a catheterizable submucosally embedded appendicostomy. TECHNICAL
      CONSIDERATIONS: The continent cutaneous right colon reservoir with bilateral
      ureteroileal coloappendicostomy incorporates the ascending and proximal
      transverse colon, which are detubularized and folded to form the reservoir
      component of the urinary diversion. The terminal ileum acts as the afferent limb,
      with the intact native ileocecal valve providing the antireflux mechanism. The
      continence catheterizable mechanism incorporates the submucosally tunneled
      appendix with preservation of the mesentery in a flap-valve technique.
      CONCLUSIONS: The continent cutaneous right colon reservoir with bilateral
      ureteroileal coloappendicostomy is a reasonable alternative for cutaneous urinary
      diversion when an intact appendix is present, with good functional results and
      excellent continence.

PMID- 15028466
TI  - Retrovesical tuberculosis.

PMID- 15028467
TI  - Congenital seminal vesicle cyst and coexisting renal agenesis: laparoscopic
      approach.
AB  - We report a case of laparoscopic excision of a large symptomatic left seminal
      vesicle cyst and ipsilateral renal agenesis. A 26-year-old man presented with a
      15-year history of dysuria and irritative voiding symptoms. The diagnostic
      evaluation revealed a 62 x 40 x 35-mm left seminal vesicle cyst. In addition, he
      had a solitary, right, functioning kidney, with no evidence of the left renal
      unit. Transperitoneal laparoscopic excision of the cyst was performed
      successfully. The total operative time was 190 minutes, and blood loss was
      minimal. The patient was discharged from the hospital on the second postoperative
      day and did not present with any complaints or complications thereafter.

PMID- 15028468
TI  - Primary paratesticular adult ganglioneuroma.
AB  - Ganglioneuroma is a rare benign tumor, usually seen in children and young adults,
      arising in the central nervous system. Most of the noncranial ganglioneuromas are
      located in the posterior mediastinum and the retroperitoneum. We report the first
      case of a primary, adult paratesticular ganglioneuroma that presented as a
      paratesticular mass. The patient underwent surgical intervention for diagnostic
      and therapeutic purposes.

PMID- 15028469
TI  - Biochemical remission after resection of prostate cancer lung metastasis.
AB  - Once metastatic, prostate cancer was regarded as a systemic disease that is not
      amenable to surgical therapy. We present a case of a solitary pulmonary
      recurrence of prostate cancer after radical prostatectomy that was resected,
      resulting in 12 years of biochemical remission without additional therapy.

PMID- 15028470
TI  - Seminal vesicle cyst presenting as rectal obstruction.
AB  - We report an unusual case of a pelvic mass arising from the seminal vesicle. A 45
      year-old man presented with difficulty voiding and difficult bowel movements.
      Computed tomography demonstrated a large 14 x 10 x 15-cm cystic pelvic mass
      displacing the bladder anteriorly and the rectum posteriorly. Magnetic resonance
      imaging confirmed that this lesion appeared to be originating from the right
      seminal vesicle. On surgical exploration of the abdomen, a large cystic lesion in
      the posterior retroperitoneum was identified and removed. The patient improved,
      with restoration of normal bowel function.

PMID- 15028471
TI  - Granulocytic sarcoma of the testis.
AB  - Granulocytic sarcoma is a rare tumor composed of neoplastic blood cells,
      typically occurring during the course of, or before the onset of, acute
      nonlymphoblastic leukemia. We present a case of a 37-year-old man with acute
      testicular pain who was found to have a testicular mass diagnosed as granulocytic
      sarcoma (GS). Because GS virtually always progresses to leukemia, he underwent
      postoperative radiotherapy and chemotherapy. He was free of disease 6 months
      after treatment. This case highlights a rare hematologic cancer that urologists
      and pathologists should be aware of because it can present as a testicular mass.

PMID- 15028472
TI  - Renal angiomyolipoma with contrast-enhancing elements mimicking renal malignancy:
      radiographic and pathologic evaluation.
AB  - The diagnosis of angiomyolipoma can typically be made on the basis of
      characteristic computed tomography findings. Varying tissue compositions within
      an angiomyolipoma can create difficulty in pathologically differentiating benign
      from malignant lesions. Epithelioid angiomyolipoma is a variant of angiomyolipoma
      characterized by the presence of epithelioid cells. We report a case of two
      discrete contrast-enhancing lesions within an enlarging angiomyolipoma that
      radiographically mimicked malignant elements. This finding presented a diagnostic
      challenge in terms of selecting medical versus surgical intervention. Surgical
      excision of the lesions was performed and the pathologic examination revealed a
      benign angiomyolipoma with epithelioid features.

PMID- 15028473
TI  - Plasma bubble formation induced by holmium laser: an in vitro study.
AB  - OBJECTIVES: To use the elementary physical measurements of temperature and size
      to prove that the thermal effects produced by the holmium laser's pulses are due
      to the formation of a plasma bubble. The physical phenomenon related to high
      temperatures generated during procedures with the holmium laser (holmium:yttrium
      aluminum-garnet) was the object of our interest. METHODS: Using a double
      micrometric slide attached to a 550-microm optic fiber and two thermocouples
      submerged in water, a series of pulses of 0.8 J at 10 to 30 Hz was delivered from
      a holmium:yttrium-aluminum-garnet laser, and we recorded temperatures on both
      frontal and lateral planes. Subsequently, samples of prostatic tissue and small
      stones were treated with 1.5 J at 20 Hz on both frontal and lateral planes.
      RESULTS: Treatment with 1.5 J at 30 Hz (frontal plane) and with 1.5 J at 20 Hz
      (lateral plane) produced the ablation of the structure of the thermocouple at 2
      mm and 1 mm, respectively, indicating plasma formation. The dimensions of the
      bubble after the delivery of 1.5 J at 20 Hz was 2 x 1.5 mm. Coagulation of the
      prostatic tissue took place at 1 mm from the plasma bubble, on both frontal and
      lateral planes. CONCLUSIONS: The plasma bubble that forms at the tip of the fiber
      connected to the holmium:yttrium-aluminum-garnet laser makes it possible to work
      on stones and soft tissues. The coagulation of the prostatic tissue is caused by
      the hot water-vapor bubble that forms on the edge of the plasma bubble. During
      lithotripsy, guidewires and baskets within the expansion area of the plasma
      bubble risk damage.

PMID- 15028474
TI  - Abnormalities of somatic peptide-containing nerves supplying the pelvic floor of
      women with genitourinary prolapse and stress urinary incontinence.
AB  - OBJECTIVES: To test the hypothesis that genital prolapse may be related to
      peripheral nerve abnormalities, we examined the changes occurring to peptide
      containing nerve processes supplying the periurethral muscles in women with
      stress urinary incontinence associated with prolapse. METHODS: Thirty patients
      with genital prolapse and 10 age-matched control subjects entered the study. All
      patients were evaluated by urodynamic investigations. Ten of 30 patients had pure
      stress urinary incontinence; none of the control subjects was incontinent. During
      surgery, four biopsy samples were obtained from each woman from the periurethral
      and perirectal muscles. The muscle sections were processed for
      immunohistochemistry using specific antibodies to glial (S-100 protein) and
      general neuronal markers (neuron-specific enolase) and neuropeptides, including
      neuropeptide Y, vasoactive intestinal polypeptide, and substance P. The
      evaluation of immunolabeled nerves was based on a semiquantitative analysis that
      allowed for a four-point ordinate scale score. RESULTS: S-100 and neuron-specific
      enolase immunoreactive nerve fibers, running either singly or in small bundles,
      along with a dense network of neural processes containing neuropeptide Y,
      vasoactive intestinal polypeptide, and substance P, were found throughout the
      connective tissue and striated muscle of the control specimens. In contrast, in
      the muscle specimens from those with genitourinary prolapse, both the density and
      the intensity of neuropeptide Y, vasoactive intestinal polypeptide, and substance
      P immunoreactive nerves were markedly reduced compared with the control
      specimens. CONCLUSIONS: The evidence of a reduced peptide-containing nerve supply
      to the perineal muscles provides a morphologic basis suggesting that neural
      abnormalities contribute to the pathogenesis of genital prolapse and urinary
      incontinence.

PMID- 15028475
TI  - Antitumor effects of recombinant BCG and interleukin-12 DNA vaccines on
      xenografted murine bladder cancer.
AB  - OBJECTIVES: To evaluate the antitumor effects of recombinant bacille Calmette
      Guerin (BCG) DNA (multi-rBCG) and murine interleukin-12 DNA (mIL-12) vaccines on
      xenografted MBT-2 murine bladder tumors. METHODS: Treatment with combined multi
      rBCG and mIL-12 was examined in syngeneic C3H/HeN mice and athymic nude mice. The
      delivery efficiency of multi-rBCG expression was detected by flow cytometry.
      Inhibition of tumor growth was monitored, and antitumor effects were evaluated
      after one dose of electroporation immunogenetherapy, with measurement of
      cytokines and phenotyping of infiltrating lymphocytes in tumors. RESULTS: In vivo
      expression of multi-rBCG was efficient and reached a maximum on day 7 after
      electroporation. Treatment with multi-rBCG plus mIL-12 significantly inhibited
      tumor growth in C3H/HeN mice, with increased production of Th1-type cytokines,
      including interferon-gamma and IL-12. Treatment with multi-rBCG and/or mIL-12 in
      C3H/HeN mice induced infiltration of CD4+/CD8+ T cells and expansion of natural
      killer cells within tumors. By contrast, however, athymic nude mice treated in
      the same way showed no significant immune cells within tumors and died of the
      fast growing tumors. CONCLUSIONS: Electroporation using multi-rBCG plus mIL-12
      could be effective immunotherapy for existing bladder cancer. The antitumor
      effects correlated with the elicitation of Th1 lymphocytes and natural killer
      cell-mediated cytotoxic immune responses.

PMID- 15028476
TI  - Expression of metalloproteinase-2, metalloproteinase-9, and tissue inhibitor of
      metalloproteinase-1 in transitional cell carcinoma of upper urinary tract:
      correlation with tumor stage and survival.
AB  - OBJECTIVES: To investigate the relationship between the expression of matrix
      metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1,
      and TIMP-2 and pT stage or survival in patients with transitional cell carcinoma
      of the upper urinary tract. MMP-2 and MMP-9 are associated with tumor invasion in
      several malignancies. TIMPs exert an anti-invasive effect by blocking MMP
      activity. Recent studies have shown, however, that TIMPs can also stimulate cell
      proliferation and angiogenesis. METHODS: Tumor sections surgically removed from
      91 patients were examined for expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 by
      immunohistochemistry. We also determined the proliferation index and microvessel
      density in each tumor and investigated the independent roles of these factors in
      tumor stage and survival using multivariate analysis. RESULTS: Of 91 tissue
      samples, 50, 51, 45, and 39 were positive for MMP-2, MMP-9, TIMP-1, and TIMP-2
      expression, respectively. Tumors positive for MMP-2, MMP-9, and TIMP-1 exhibited
      a greater proliferation index than tumors with negative expression (P <0.001, P =
      0.013, and P <0.001, respectively). The microvessel density of tumors positive
      for MMP-2 and TIMP-1 was greater than that of negative tumors (P <0.001). The
      expression of MMP-2, MMP-9, and TIMP-1 was an independent predictor of high pT
      stage. Cox proportional hazard analysis identified TIMP-1 expression as an
      independent factor for cause-specific survival (odds ratio 5.2, P = 0.011),
      similar to microvessel density, pT4, and lymph node metastasis. CONCLUSIONS: TIMP
      1 expression correlated with pT stage and was an independent predictor of cause
      specific survival. Our results suggest that TIMP-1 expression is a potentially
      useful tool for the selection of postoperative observation strategies in patients
      with transitional cell carcinoma of the upper urinary tract.

PMID- 15028477
TI  - Expression of ezrin in prostatic intraepithelial neoplasia.
AB  - OBJECTIVES: To study the protein expression and gene copy number of ezrin in a
      set of high-grade prostatic intraepithelial neoplasia (HGPIN) samples with
      concomitant prostate cancer. Ezrin is a cytoskeleton linker protein that is
      actively involved in regulating the growth and metastatic capacity of cancer
      cells. METHODS: Nineteen HGPIN samples obtained from radical prostatectomy
      specimens were used for the study. Among them, 13 samples also contained invasive
      prostate cancer. The expression of ezrin was studied by immunohistochemistry. The
      same samples were also used for fluorescence in situ hybridization to study the
      gene copy number of ezrin. RESULTS: Immunoreactivity for ezrin was absent or weak
      in benign prostatic epithelial cells. Weak or moderate immunostaining was
      detected in 11 of 13 prostate cancer specimens. However, the immunostaining was
      moderate or strong in all HGPIN samples. In addition, whenever HGPIN and prostate
      cancer were found in the same sample, the staining was always more intense in the
      HGPIN cells than in the cancer cells. No alteration was found in the gene copy
      number detected by fluorescence in situ hybridization. CONCLUSIONS: We have shown
      that ezrin is overexpressed in HGPIN and prostate cancer compared with adjacent
      benign prostatic epithelium. In addition, HGPIN has a greater expression level of
      ezrin compared with that of prostate cancer. Our results indicate that aberrant
      expression of ezrin might be involved in the pathogenesis of prostate cancer, and
      ezrin expression may be useful for the diagnosis of HGPIN.

PMID- 15028478
TI  - Development of human chorionic gonadotropin subunit-beta promoter-based toxic
      gene therapy for testicular cancer.
AB  - OBJECTIVES: To develop a new toxic gene therapy using the tissue-specific human
      chorionic gonadotropin-beta (hCG-beta) promoter for testicular cancer. Although
      most patients presenting with disseminated testicular tumor are cured through the
      use of chemotherapy with or without surgery, those patients with relapse after
      initial therapy present a difficult clinical problem. The serum tumor marker hCG
      beta is frequently elevated in patients with testicular cancer, and the
      pretreatment and post-treatment levels of serum hCG-beta are highly predictive of
      treatment outcome. METHODS: Human testicular embryonal carcinoma cell line, NEC
      8, a human prostate cancer cell line, PC-3, and a human bladder cancer cell line,
      WH, were used in this study. A transient expression experiment was used to
      analyze the activity of a 729-bp hCG-beta promoter in all three cell lines. A
      recombinant adenovirus carrying thymidine kinase (Ad-hCG-beta-TK) under control
      of the hCG-beta promoter was generated. The tissue-specific activity of Ad-hCG
      beta-TK was tested in vitro and in vivo. RESULTS: The hCG-beta promoter had
      significantly greater activity in the hCG-beta-producing cell line (NEC 8) than
      in the non-hCG-beta-producing cell lines (PC-3 and WH). In vitro, Ad-hCG-beta-TK
      with acyclovir significantly inhibited NEC 8 growth but not PC-3 or WH cell
      growth. In vivo, Ad-hCG-beta-TK with acyclovir significantly inhibited NEC 8
      subcutaneous tumor growth in nude mice. CONCLUSIONS: In this study, we explored
      the possibility of developing a new therapeutic agent to target and induce the
      killing of testicular germ cell tumor selectively by using tissue-specific hCG
      beta promoters.

PMID- 15028479
TI  - Challenges in ocular infectious diseases and the evolution of anti-infective
      therapy.

PMID- 15028480
TI  - Reducing the risk of postoperative endophthalmitis.
AB  - Recent literature suggests that the incidence of postoperative endophthalmitis is
      variable and may be on the rise. This article reviews established perioperative
      preventative measures, and discusses some possible causes of postoperative
      endophthalmitis that may be insufficiently addressed by current risk reduction
      techniques. This article also considers future measures for reducing the risk of
      postoperative endophthalmitis.

PMID- 15028481
TI  - Dynamic morphology of sutureless cataract wounds--effect of incision angle and
      location.
AB  - OBJECTIVE: Sutureless cataract surgery has been growing in popularity over the
      last decade. These clear corneal incisions allow for rapid visual recovery after
      phacoemulsification, but may be associated with an increased risk of
      endophthalmitis. The purpose of this study was to evaluate the effect of
      intraocular pressure (IOP), location, and angle of cataract incisions on wound
      apposition and sealing in postmortem globes. METHODS: This was an ex vivo
      laboratory investigation of 20 rabbit eyes and 14 human eyes. Self-sealing clear
      corneal, limbal, and scleral incisions were created and IOP was controlled with
      an infusion cannula. Incisions were made at a variety of angles. Optical
      coherence tomography was used to image the incisions in real time as the IOP was
      varied by raising and lowering the infusion bottle, so as to simulate the
      variation in IOP occurring with blinking or squeezing of the eye. RESULTS: With
      each type of incision, optical coherence tomography demonstrated the dynamic
      nature of cataract wound morphology as IOP was varied. Higher IOPs, in general,
      were associated with more tightly sealed wounds than lower IOPs, but this varied
      according to the location and angle of the incisions. More perpendicular
      incisions, relative to the surface tangent, sealed less well than incisions
      created at smaller angles at higher levels of IOP; At lower IOPs, the reverse
      relationship was observed such that more perpendicular incisions sealed less well
      than smaller incision angles. CONCLUSION: Changes in IOP may result in variable
      and sometime poor wound apposition in sutureless cataract incisions. The type of
      incision and angle of the incision may affect the likelihood of inoculation of
      the aqueous humor with potentially pathogenic bacteria. For each type of
      incision, there may be a critical angle at which the incision is better able to
      withstand fluctuations in IOP.

PMID- 15028482
TI  - Fluoroquinolones: mechanism of action, classification, and development of
      resistance.
AB  - The fluoroquinolones represent an evolving class of broad-spectrum antimicrobial
      agents used in the prevention and treatment of a variety of ocular infections;
      however, resistance to currently available agents in the class has been emerging
      among ocular pathogens. This article reviews the mechanism of action of existing
      and new fluoroquinolones and discusses the structure-activity relationship of the
      fluoroquinolones as it relates to the classification of these compounds. This
      article also highlights the mechanism of resistance among common ocular pathogens
      and discusses the potential need for newer fluoroquinolones in ophthalmology.

PMID- 15028484
TI  - Effect of alcohol addition to the aqueous phase on the thermal effects of
      micellization of cationic benzyldimethyldodecylammonium bromide and its
      adsorption onto porous and nonporous silicas.
AB  - Titration calorimetry has been used to study the effect of the addition of two
      primary alcohols, 1-butanol and 1-heptanol, to the aqueous phase on the thermal
      effects of micellization of benzyldimethyldodecylammonium bromide (BDDAB) as well
      as its adsorption onto nonporous Spherosil XO15M and onto porous aluminosilicate
      SiAl32d22 possessing uniformly sized mesopores. A linear decrease of the critical
      micelle concentration (CMC) of the cationic surfactant with the additive content
      was inferred from the specific conductivity measurements. All adsorption and
      calorimetry experiments were carried out at 298 K and at a fixed alcohol content
      (0.01 mol kg(-1)) either in deionized water or in a 0.01 mol kg(-1) NaBr
      solution. Dilution calorimetry measurements allowed determination of the
      cumulative molar enthalpy changes and a new analysis of these data was proposed
      to calculate easily the enthalpy of micellization per mole of BDDAB, Delta(mic)h,
      and the CMC value. The alcohol addition was shown to render the micellization
      phenomenon more exothermic, the effect being larger as the chain length of
      alcohol increased. These effects were attributed to the location of alcohol
      molecules between the surfactant units, their hydroxyl groups close to the
      surfactant head-groups, in competition with the surfactant counterions. The
      individual isotherms of alcohol and surfactant adsorption onto XO15M and
      SiAl32d22 were determined. The plots of the pseudo-differential molar enthalpy of
      displacement, Delta(dpl)h, against the surface coverage by the surfactant cation,
      Theta(BDDA+), were derived from the titration calorimetry data. The formation of
      surface-bound aggregates was thought to be a prerequisite for alcohol
      coadsorption at the solid-solution interface. At least two different types of
      adsolubilization sites were postulated, one of the sites being the same as in
      micelles and the other related to the contact area between the hydrophobic
      surfactant tails and the equilibrium bulk solution. Coadsorption
      (adsolubilization) of alcohol molecules at such sites was found to increase the
      exothermic contribution to the enthalpy of displacement per mole of the BDDA+
      adsorbed.

PMID- 15028483
TI  - Fluoroquinolone resistance in ophthalmology and the potential role for newer
      ophthalmic fluoroquinolones.
AB  - The three topical ophthalmic fluoroquinolones recently introduced into the U.S.
      market--levofloxacin, gatifloxacin, and moxifloxacin--offer several advantages
      over the previously available fluoroquinolones (norfloxacin 0.3%, ciprofloxacin
      0.3%, and ofloxacin 0.3%). These include enhanced spectrum and potency for Gram
      positive cocci and possibly atypical mycobacterial species, improved penetration
      into the anterior segment, and reduced propensity to promote the development of
      resistance. Although published data and clinical experience with these agents is
      quite limited given their relatively recent entry into the U.S. market, this
      perspective will attempt to provide an understanding of the potential role of
      these newer fluorquinolones in addressing the problem of increasing
      fluoroquinolone resistance amongst bacterial ocular isolates.

PMID- 15028485
TI  - Modeling Pb(II) adsorption onto sandy loam soil.
AB  - The adsorption of Pb(II) onto hydrous sandy loam soil was investigated with batch
      equilibrium adsorption experiments. Results show that the amount of Pb(II)
      adsorbed increases with increasing pH and surface loading. It was demonstrated
      that the surface acidity of the soil could be determined using electrophoretic
      mobility measurements. The surface acidity constants, pK(a1)(int) and
      pK(a2)(int), were 1.57 and 3.43, respectively. A surface complex formation model
      (SCFM) was employed to describe the adsorption. The intrinsic stability
      constants, pK(i)(s), for the surface reaction between the Pb species and the
      ionized soil surface hydroxyl groups were determined from SCFM fitting. The
      adsorption free energy of Pb2+ and Pb(OH)+ ions ranges from -5.74 to -6.48
      kcal/mol and from -9.68 to -10.00 kcal/mol, respectively, for surface loadings
      between 1.21 x 10(-5) and 2.41 x 10(-4) mol/g. The adsorption binding calculation
      indicated that the specific chemical interaction is the major mechanism
      responsible for the adsorption process.

PMID- 15028486
TI  - Kinetics and equilibrium parameters of Hg(II) adsorption on silica-dithizone.
AB  - Silica-dithizone (Sil-dtz) was synthesized and used to adsorb Hg(II) in solution
      at pH 6.0. Increasing the temperature accelerates the mass transfer of Hg(II) to
      the silica surface. The kinetic data were evaluated using the traditional pseudo
      first-order Lagergren equation and an alternative Avrami kinetic equation. From
      the latter equation, two regions presenting distinct kinetic parameters were
      found, at 25 and 35 degrees C, and the use of the parameter n was also related to
      the determination of distinct kinetic orders. Variations of the adsorption
      kinetic rate in relation to the time and the temperature were also calculated and
      are discussed. The adsorption isotherms data were well fitted to the Freundlich
      model. Interestingly, good adsorption data correlation of the Langmuir model and
      experimental values was observed only at 45 and 50 degrees C, suggesting, for
      this temperature range, the formation of complexes with the proportion
      Hg:dithizone 1:1 on the silica surface.

PMID- 15028487
TI  - Adsorption and surface rheology of n-dodecanol at the water/air interface.
AB  - Adsorption layers of n-dodecanol at the water/air interface show phase
      transitions at low temperatures [Vollhardt, Fainerman, Emrich, J. Phys. Chem. B
      104 (2000) 8536]. Using a drop shape technique it is shown that the dilational
      elasticity disappears in the coexistence region of the adsorption layer. The
      relaxation time between the condensed and liquid-like surface states is in the
      sub-second time range.

PMID- 15028488
TI  - Heats of adsorption in the mixed polymer systems.
AB  - Adsorption of poly(butyl methacrylate) and polystyrene on aerosil from dilute,
      semidilute, and concentrated solutions has been studied. Using IR spectroscopy
      the shifts in the position of bands responsible for the vibration of free and
      bound OH-groups were found. According to the method proposed by Kiselev, the
      energies of adsorption interaction Q between OH-groups of adsorbent and polymer
      functional groups were calculated. The heats of adsorption were calculated as the
      product Q by p (p is the fraction of the bound segments). For the first time for
      the adsorption from the polymer mixtures, the adsorption heats were measured
      simultaneously separately for each polymer component and under dilute and
      concentrated regimes of solutions. It was established that the heats of
      adsorption of polymers and their mixtures from dilute, semidilute, and
      concentrated solutions are dependent on the values of adsorption and on the
      fraction of the bound segments. Increasing adsorption in the dilute solutions
      brings about the diminishing of the fraction of the bound segments which
      determine the adsorption heat. The adsorption heats from the mixed systems are
      lower as compared to adsorption heats from binary solutions.

PMID- 15028489
TI  - Effects of concentration on the partitioning of macromolecule mixtures in agarose
      gels.
AB  - To test the effects of solute concentration on the equilibrium partitioning of
      single macromolecules and macromolecule mixtures between bulk solutions and gels,
      the partition coefficient in agarose was measured for BSA and for four narrow
      fractions of Ficoll with Stokes radii of 30-59 A. Solutions of each test
      macromolecule were equilibrated with a known volume of gel, final liquid
      concentrations measured, and partition coefficients (gel concentration divided by
      bulk concentration) calculated by applying a material balance. The partition
      coefficient of each macromolecule was measured in 4 and 6% gels under dilute
      conditions and with BSA present at initial concentrations up to 13.5 g/dl. As
      expected, the partition coefficients decreased with increasing agarose
      concentration and with increasing macromolecular size. Moreover, increasing the
      BSA concentration increased the partition coefficient of BSA itself and that of
      all four Ficolls. This effect was most pronounced for the largest test solutes.
      Measurements at two ionic strengths confirmed that electrostatic interactions
      were negligible under the conditions used. The experimental results were compared
      with predictions from a previously developed excluded volume theory for the
      partitioning of mixtures of rigid, spheroidal macromolecules in fibrous media.
      Agarose was represented as a randomly oriented array of cylindrical fibers, BSA
      as a prolate spheroid, and Ficoll as a sphere. The quantitative agreement between
      the model predictions and the data was generally quite good, indicating that
      steric interactions among solute molecules and between solute molecules and gel
      fibers could explain the partitioning results. The theory is simple enough
      computationally to be applied to a variety of processes that are influenced by
      the equilibrium partitioning of macromolecules.

PMID- 15028490
TI  - Partitioning behavior of silica in the Triton X-100/dextran/water aqueous
      biphasic system.
AB  - The partitioning behavior of silica particles was investigated in the Triton X
      100/dextran/water system. It was found that both electrostatic effects and
      interactions between phase-component species and the solid surface played
      important roles in determining the distribution of solids. Silica partition was
      highly pH-dependent, which was interpreted in terms of the pH dependence of the
      Triton X-100/SiO(2) interaction and the weak acidity of dextran. The presence of
      sodium dodecyl sulfate (SDS) moved the particles from the top surfactant-rich
      phase to the interface and the bottom phase, while dodecyltrimethylammonium
      bromide (DTAB) had the opposite effect. These trends are attributable to the
      electrostatic interaction between the charged mixed micelles in the top phase and
      the particles and to the fact that the ionic surfactants modified the adsorption
      density of the nonionic surfactant on silica.

PMID- 15028491
TI  - Characteristics of manganese-coated sand using SEM and EDAX analysis.
AB  - "Manganese-coated sand" is a type of silica medium coated with manganese oxides,
      formed from the sorption of manganese oxides during long-term filtration via the
      process of rapid sand filtration, followed by aeration in a water treatment
      plant. Locally available manganese-coated sand, both for packing and as a
      byproduct of filtration processes for water treatment plants in Taiwan, was found
      to be a low-cost and promising adsorbent for removal of Mn(2+) from raw water.
      This study was conducted to build the basic data for coating hydrated manganese
      oxide on the sand surface to utilize the adsorbent properties of the coating and
      the filtration properties of the sand. In this study, gas adsorption porosimetry
      and scanning electron microscopy analyses were used to investigate the surface
      properties of the coated layer. An energy dispersive X-ray (EDAX) technique of
      analysis was used to characterize metal adsorption sites on a manganese-coated
      sand surface. Results indicated that manganese-coated sand had more micropores
      and higher specific surface area, owing to attachment of manganese sand.
      Manganese ions penetrated into the micropores and mesopores of manganese oxide on
      a sandy surface; regeneration of manganese-coated sand could be achieved by
      soaking with pH < 2.0 acid solution. Results of EDAX analysis showed that the
      interfacial layer constructed the interface of manganese-coated sand. Acid and
      alkali resistance tests interpret a wide application range of pH for manganese
      coated sand, and general temperature conditions do not affect the performance of
      this sand. Manganese-coated sand is potentially suitable for application as a
      packed bed for treatment of heavy metals from water. The results of this study
      can also benefit plant operational capacity data for engineering design.

PMID- 15028492
TI  - Preparation of silica-polystyrene core-shell particles up to micron sizes.
AB  - A method for producing silica-core composite particles with a polystyrene shell
      is proposed. Silica particles were prepared by the Stober method through
      condensation and hydrolysis of tetraethyl orthosilicate in a water-ethanol
      ammonia solution. The silica particles were the surface-modified with a coupling
      reagent, methacryloxypropyltrimethoxysilane (MPTMS), to introduce vinyl groups
      onto the particle surfaces. Polymerization of styrene was conducted with an
      initiator, potassium persulfate (KPS), and an anionic monomer, sodium p
      styrenesulfonate (NaSS), in the presence of the silica particles. In these
      coating experiments, the average size of the silica particles was varied from 339
      to 1210 nm with the concentration ranges of MPTMS (0-10 mmol/l), NaSS (0-10
      mmol/l), KPS (4-12 mmol/l), and styrene (0.12-0.4 mol/l). Selection of reaction
      conditions enabled the preparation of composite particles that contained one core
      of silica. The coefficient of variance of size distribution of the composite
      particles was less than 7%, and shell thickness was in the range 125 to 410 nm.

PMID- 15028493
TI  - Preparation of spherical nanostructured poly(methacrylic acid)/PbS composites by
      a microgel template method.
AB  - Spherical poly(methacrylic acid)/PbS (PMAA/PbS) composites with a fishnet-like
      surface and core-shell structure were prepared by a microgel template method. The
      composites were prepared in two steps. Pb(Ac)(2) was dissolved in MAA solution
      before it was polymerized into microgels in an inverse suspension system. In this
      way, Pb(2+) was trapped within the microgel network. Then, H(2)S was introduced
      slowly into the system, and the metal ions were deposited within the microgels as
      PbS. The presence of PbS was confirmed by X-ray diffraction (XRD) and
      thermogravimetric measurements, and the morphology of the composites was
      characterized by scanning electron microscopy (SEM). It was found that the
      surface structure of the microparticles depends largely on the nature of the
      continuous phase of the system. The microparticles from xylene have a fishnet
      like surface structure, and the inner structure and composition of the particles
      are different from the outer structure and composition. The surface of the
      particles from cyclohexane, however, appears smoother and denser than the surface
      of the particles from xylene. The different structure of the particle surfaces
      from the two systems has been attributed to the differences in template
      structure.

PMID- 15028494
TI  - Influence of octadecyl dihydrogen phosphate on the formation of active super-fine
      calcium carbonate.
AB  - A carbonation process for the synthesis of active super-fine calcium carbonate
      particles from Ca(OH)(2) slurry at room temperature using a CO(2)-N(2) gas
      mixture was investigated. Industrial octadecyl dihydrogen phosphate (A) was added
      as a size-controlling additive and modifier in different reaction periods
      according to the pH of the medium. Analysis of the reaction products led to the
      conclusion that the addition of A in the digestion period could inhibit the
      crystal growth of calcium carbonate, while the addition of A at pH 7 of the
      medium could modify the surface character of the calcium carbonate particle,
      which was found to exhibit hydrophobic properties. From transmission electron
      microscopy (TEM), the hydrophobic property was attributed to the deposition of
      calcium alkyl phosphates, produced in the reaction mixture, onto the surface of
      calcium carbonate particle. IR spectra and TGA analysis of the obtained products
      indicated that A was bound onto the crystalline CaCO(3).

PMID- 15028495
TI  - Rigorous calculations of linearized Poisson-Boltzmann interaction between
      dissimilar spherical colloids and osmotic pressure in concentrated dispersions.
AB  - We present computational results on the static properties of concentrated
      dispersions of bidisperse colloids. The long-range electrostatic interactions
      between dissimilar spherical colloids are determined using the singularity
      method, which provides rigorous solutions to the linearized electrostatic field.
      The NVT Monte Carlo simulation is applied to the bulk suspension to obtain the
      radial distribution function for the concentrated system. The increasing trend of
      osmotic pressure with increasing total particle concentration is reduced as the
      concentration ratio between large and small particles is increased. The increase
      of electrostatic interaction between similarly charged particles caused by the
      Debye screening effect provides an increase in the osmotic pressure. From the
      estimation of total structure factor, we observe the strong correlations
      developed between dissimilar spheres, and the small spheres are expected to tend
      to fit into the spaces between the larger ones. As the particle concentration
      increases at a given ionic strength, the magnitude of the first peak in structure
      factors increases and also moves to higher wavenumber values.

PMID- 15028497
TI  - Effect of floc structure on the rate of shear coagulation.
AB  - We derived a mathematical expression for the temporal evolution of the number of
      particles due to shear coagulation, covering the later stage by expanding the
      initial stage approximation to take into account the formation of floc structure.
      In the derivation, it is assumed that flocculation proceeds through binary
      collisions between identical fractal flocs. The capture efficiency between flocs
      is calculated on the basis of trajectory analysis, which is determined by viscous
      hydrodynamic interaction between flocs and van der Waals attractive forces
      between two primary particles located at colliding points of flocs. The validity
      of the derived equation was tested by a coagulation experiment using polystyrene
      sulfate latex particles under conditions of rapid coagulation. The experiment was
      carried out in a laminar Couette flow generated in the gap between two concentric
      cylinders. Careful and direct observation of flocculation under microscopy
      provided the data on the fractal dimension as well as the temporal evolution of
      number concentration of flocs. The measured rate of coagulation gradually
      increases in accordance with the formation of the fractal structure of flocs.
      This behavior agreed very well with the prediction based on the derived equation.

PMID- 15028496
TI  - Preparation and characterization of silver/TiO2 composite hollow spheres.
AB  - Silver-coated poly(methyl acrylic acid) (PSA) core-shell colloid particles were
      prepared by an in situ chemical reduction method. Crystalline silver/titania
      composite hollow spheres were obtained by coating the as-prepared PSA/silver
      particles with an amorphous titania layer and subsequently calcining in Ar
      atmosphere. SEM and TEM investigation indicated that the size of the as-prepared
      PSA/silver and PSA/silver/TiO(2) core-shell particles and silver/titania
      composite hollow particles was fairly uniform and the wall thickness of the
      hollow spheres was in the range of 40-80 nm. UV-vis absorption spectra were
      recorded to investigate their optical properties.

PMID- 15028498
TI  - Effect of ionic sizes on the stability ratio of a dispersion of particles with a
      charge-regulated surface.
AB  - The influence of the ionic sizes on the stability of a dispersion of particles,
      which have an amphoteric, charged-regulated surface, is discussed. A modified
      Poisson-Boltzmann equation, which takes into account the sizes of ionic species,
      is adopted to describe the electrical field. An extended DLVO theory, which takes
      into account the electrical, the van der Waals, and the hydration energies, is
      used to estimate the stability of a colloidal dispersion. The effects of the key
      parameters, including ionic strength, pH, and density of surface sites, on the
      behavior of problem under consideration are examined. The results obtained are
      qualitatively consistent with experimental findings in the literature.

PMID- 15028500
TI  - Enhanced feature analysis using wavelets for scanning probe microscopy images of
      surfaces.
AB  - In this work we develop wavelet theory for the analysis of surface topography
      images obtained by scanning probe microscopy (SPM) such as atomic force
      microscopy (AFM). Wavelet transformation is localized in space and frequency,
      which can offer an advantage for analyzing information on surface morphology and
      topography. Wavelet transformation is an ideal tool to detect trends,
      discontinuities, and short periodicities on a surface. Additionally, wavelets can
      be used to remove artifacts and noise from scanning microscopy images. In terms
      of 3-D image analysis, discrete wavelet transform can capture patterns at all
      relevant frequency scales, thus providing a level of image analysis that is not
      possible otherwise. It is also possible to use the methodology for analyzing
      surface structures at the molecular level. The results demonstrate superior
      capabilities of wavelet approach to scanning probe microscopy image analysis
      compared to traditional analysis techniques.

PMID- 15028499
TI  - A general criterion based on the implicit function theorem to model aggregation
      and adsorption in colloidal dispersions.
AB  - This paper, which may interest not only colloid scientists and physical chemists
      but also applied mathematicians, completes some previous results on aqueous
      silicon nitride dispersions. Experimental data on adsorption from liquid solution
      were first obtained by a titration method and then used to derive the number of
      solid particles from an equilibrium constraint. To discuss the complex mechanisms
      affecting simultaneous solid particle aggregation and small ion adsorption at the
      solid/liquid interface, the Dini implicit function theorem (DT) has been applied
      to the equilibrium condition for a former suspension Gibbs free energy. It was
      able to relate the average particle number to the ion concentration adsorbed, but
      not to unequivocally specify their dependence on the liquid phase pH. We attempt
      here to model aggregation both through bulk and interfacial quantities. The
      generalized DT-based criterion has first been formulated in all generality, and
      then adopted according to a wider investigation. The results obtained confirm the
      original guess, i.e., to regard solid aggregation as dominated by interfacial
      mechanisms.

PMID- 15028501
TI  - Sulfated nanozirconia: an investigation on acid-base properties and n-butane
      isomerization activity.
AB  - Hydrated zirconia was synthesized by an organo-inorganic route employing
      surfactant and was sulfated using aqueous ammonium persulfate, followed by drying
      at 110 degrees C. The sample thus obtained was calcined at 600 degrees C to
      obtain sulfated zirconia and was characterized by several physicochemical
      methods. Crystallite sizes of sulfated zirconia were calculated from X-ray line
      broadening using the Debye-Scherer equation and were found to be in the range of
      25 nm. When pretreated in air, the catalyst was found to exhibit butane
      isomerization activity at a temperature as low as 35 degrees C under atmospheric
      pressure. It showed conversion as high as 37% at 100 degrees C under normal
      pressure when pretreated in air, whereas nitrogen-pretreated catalyst showed zero
      activity under similar conditions. NH(3) and CO(2) temperature-programmed
      desorption studies on air- and helium-pretreated samples indicated that the
      catalyst surface changes appreciably during air pretreatment. Results on butane
      isomerization in conjunction with TPD studies suggest that zirconium-oxy sites
      play an important role in butane activation during the reaction.

PMID- 15028502
TI  - A study on dielectric characteristics of fluorinated polyimide thin film.
AB  - In this work, the effects of fluorination of polyimide thin films on surface and
      dielectric characteristics were studied using X-ray photoelectron spectroscopy
      (XPS) and dielectric spectrometry, respectively. The thermal and mechanical
      properties of the film were characterized by thermogravimetric analysis (TGA) and
      tensile strengths, respectively. The fluorine content of the polyimide thin film
      was increased with increasing treatment concentration, resulting in decreasing
      dielectric constant of the film. It was found that the replacement of fluorine
      led to the decrease of the local electronic polarizability of polyimide, or to
      the increase of the free volume, which can be attributed to the relatively large
      size of fluorine. Nevertheless, the fluorination did not significantly affect
      thermal or mechanical properties of the polyimide film under mild conditions in
      this system.

PMID- 15028503
TI  - Growth of layered basic zinc acetate in methanolic solutions and its pyrolytic
      transformation into porous zinc oxide films.
AB  - Layered basic zinc acetate (LBZA), Zn(5)(OH)(8)(CH(3)COO)(2).2H(2)O, was
      deposited on glass substrates by a chemical bath deposition (CBD) method using
      methanolic solutions of zinc acetate dihydrate. The substrates were put into
      bottles filled with the solutions and sealed up and were kept at 60 degrees C in
      a drying oven. Immersion time necessary for the deposition of LBZA films was
      typically more than 28 h. This was a key to inducing heterogeneous nucleation of
      LBZA through control over a degree of supersaturation in the evolution of a
      unique, nest-like morphology. Hydration water contained by zinc acetate dihydrate
      was quantitatively enough to promote hydrolysis of zinc acetate. The LBZA films
      were transformed into nanocrystalline, porous ZnO films without morphological
      deformation by heating at 150 degrees C in air. A mechanism of the formation of
      the nest-like morphology was discussed based on nonaqueous solution reactions,
      nucleation, and crystal growth during the CBD process.

PMID- 15028504
TI  - Removal of fluoride from water through ion exchange by mesoporous Ti
      oxohydroxide.
AB  - In our previous study, we found that Ti(OH)(4) exhibited fluoride ion exchange
      properties. In order to improve the ion exchange capacity, mesoporous Ti
      oxohydroxide (TiOx(OH)y) had been prepared by using dodecylamine as template.
      Zirconia and silica had been introduced into the mesoporous Ti oxohydroxide to
      enhance the ion exchange capacity. The mesoporous structure and the morphology of
      the mesoporous materials obtained were confirmed using XRD and SEM, respectively.
      A fluoride ion exchange study was done on each sample. Results showed that
      mesoporous Ti oxohydroxide containing zirconia exhibited the highest fluoride ion
      exchange capacity, as it has the smallest particle size, with high uniformity
      among the mesoporous materials prepared.

PMID- 15028505
TI  - Amperometric method for determining the degree of complexation of
      polyelectrolytes with cationic surfactants.
AB  - The complexation of sodium polystyrene sulfonate with monovalent cationic
      surfactants at a microsized liquid/liquid interface has been studied using
      electrochemistry. The method is based on measurement of surfactant ion transfer
      across the interface between two immiscible electrolyte solutions (ITIES). The
      complexation of various cationic surfactants (alkylpyridinium- and
      trimethylammonium-) with oligosized polystyrene sulfonate was measured. Binding
      isotherms were used to determine the degree of binding as a function of the
      surfactant chain length and type of head group. It was found that the
      hydrophobicity of the surfactant was the predominant factor. The effect of the
      polyelectrolyte chain length on the binding mechanism was studied using
      cetylpyridinium chloride as a complexing agent. It was found that binding
      affinity, as well as cooperativity of the binding process, decreases with
      decreasing polyelectrolyte chain length. Thermodynamics of surfactant binding was
      measured using titration microcalorimetry. The thermodynamic data obtained show
      that the enthalpy of surfactant binding is not dependent on polymer chain length,
      but an increase in chain length makes the binding process entropically more
      favorable.

PMID- 15028507
TI  - Local thermodynamic derivation of Young's equation.
AB  - A derivation of Young's equation based on the energy balance near the contact
      line is presented. Our proposal is rigorous and avoids the errors identified in
      the usual local derivation. It is valid under very general conditions (for any
      geometry, in a gravitational field and for compressive fluids). Deviations of the
      contact angle from Young's equation are discussed in several cases: surfaces of
      high curvature and line tension. Finally, the relationship between surface
      tensions and surface energies comes as an additional, natural result. Our
      derivation also provides a new physical insight into the equilibrium of forces
      acting near the contact line. Its local character makes the recourse to integral
      analysis unnecessary, which results in a great simplification when compared to
      other general treatments.

PMID- 15028506
TI  - Effect of nonionic surfactant on wetting behavior of an evaporating drop under a
      reduced pressure environment.
AB  - The evaporation of sessile drops at reduced pressure is investigated. The
      evaporation of water droplets on aluminum and PTFE surfaces at reduced pressure
      was compared. It was found that water droplets on an aluminum surface exhibit a
      'depinning jump' at subatmospheric pressures. This is when a pinned droplet
      suddenly depins, with an increase in contact angle and a simultaneous decrease in
      the base width. The evaporation of sessile water droplets with a nonionic
      surfactant (Triton X-100) added to an aluminum surface was then studied. The
      initial contact angle exhibited a minimum at 0.001 wt% Triton X-100. A maximum in
      the evaporation rate was also observed at the same concentration. Droplets with
      low surfactant concentrations are found to exhibit the 'depinning jump.' It is
      thought that the local concentration of the surfactant causes a gradient of
      surface tension. The balance at the contact angle is dictated by complex
      phenomena, including surfactant diffusion and adsorption processes at interfaces.
      Due to the strong evaporation near the triple line, an accumulation of the
      surfactant will lead to a surface tension gradient along the interface. The
      gradient of surface tension will influence the wetting behavior (Marangoni
      effect). At low surfactant concentrations the contact line depins under the
      strong effect of surface tension gradient that develops spontaneously over the
      droplet interface due to surfactant accumulation near the triple line. The
      maximum evaporation rate corresponds to a minimum contact angle for a pinned
      droplet.

PMID- 15028508
TI  - Attractive interactions in dispersions of identical charged colloidal particles:
      a Monte Carlo simulation.
AB  - Using the Debye-Huckel pair potential, the collective interactions between
      identical charged particles were examined via Monte Carlo simulations. The
      results have shown that when the number of charges per particle and the particle
      volume fraction were sufficiently large, the pair long-range electrostatic
      repulsion generated an effective attractive interaction between identical charged
      particles because of many-body effects. Disordered liquid-like structures,
      ordered crystal-like structures, ordered structures dispersed in disordered ones,
      and disordered structures dispersed in ordered ones have been found. The
      structures are dependent on the volume fraction and charge of the particles, as
      well as on the electrolyte concentration.

PMID- 15028509
TI  - Surface tension and density of mixtures of 1,3-dioxolane+alkanols at 298.15 K:
      analysis under the extended Langmuir model.
AB  - Surface tensions (sigma) for [1,3-dioxolane+methanol, ethanol, 1-propanol, 2
      propanol, 1-butanol, 2-butanol, and 1-pentanol] and excess molar volumes (v(E))
      for [1,3-dioxolane+methanol, ethanol, 1-propanol, 2-propanol, and 2-butanol] at
      the temperature 298.15 K and normal atmospheric pressure have been determined as
      a function of mole fractions. The magnitude of these experimental quantities is
      discussed in terms of the nature and type of intermolecular interactions in
      binary mixtures. In order to analyze the surface tension behavior, the extended
      Langmuir (EL) model was used and the results obtained for the systems containing
      1,3-dioxolane were compared with those of other formerly published series: [1,4
      dioxane+alkanes] and [1,4-dioxane+alcohols].

PMID- 15028510
TI  - Critical flocculation density of dilute water-in-CO2 emulsions stabilized with
      block copolymers.
AB  - The critical flocculation density (CFD), that is, the CO(2) density below which
      flocculation occurs, was studied for dilute water-in-CO(2) (W/C) miniemulsions
      stabilized with poly(1,1-dihydroperfluorooctyl methacrylate)-b-poly(ethylene
      oxide) (PFOMA-b-PEO) surfactants. The CFD, which was measured by turbidimetry,
      decreased as the PFOMA molecular weight was increased, the average droplet size
      was decreased, the surfactant loading was increased, and the temperature was
      increased. A simple model, which addressed both the van der Waals attraction
      between droplets and osmotic solvent-tail interactions, was in good qualitative
      agreement with the experimentally observed trends for the CFD and predicted a
      decrease in emulsion stability as the CO(2) density was lowered toward the theta
      density for PFOMA in bulk CO(2).

PMID- 15028511
TI  - Synthesis of ether-linked fluorocarbon surfactants and their aggregational
      properties in organic solvents.
AB  - A series of single- and double-tailed hydrocarbon-fluorocarbon (HF) surfactants
      were prepared to evaluate the effect of molecular structure on aggregate
      formation in organic solvents. The molecules were designed with ether linkages to
      permit facile syntheses of both sets of molecules. Solvent foaming studies were
      used to rapidly assess the surface-active properties of the surfactants, while
      dynamic light scattering provided quantitative critical micelle concentrations
      (CMC) and hydrodynamic radius (R(h)) measurements of the aggregates in solution.
      The single-tailed surfactants did not produce any foaming action in a number of
      hydrocarbon solvents, nor was any micellar formation observed up to 100 mM
      concentrations. Double-tailed surfactants, on the other hand, gave low CMC values
      in dodecane but with R(h) values that indicated a tight micelle structure.
      Bilayer formation was expected but not observed for these molecules, which is
      believed to be due to their unusual structural geometry, imparted by the glycerol
      backbone. No thermotropic liquid crystalline (LC) behavior was observed for any
      of the single- or double-tailed molecules. These data contrast with the known
      behavior of perfluorinated alkanes and other fluorinated surfactants, suggesting
      that the ether linkage plays an important role in the self-organizing behavior of
      these molecules.

PMID- 15028512
TI  - Experimental study of small aggregate settling.
AB  - The drag coefficient and hydrodynamic radius of particles are important
      parameters needed in crystallization science. Small aggregates of micrometric
      primary particles are mainly produced in stirred crystallizers. We present
      experimental results on the drag coefficient of macroscopic aggregates consisting
      of glass beads in the number range [2,100]. The drag coefficient is calculated
      from settling measurements in glycerol in order to preserve the Stokesian nature
      of typical flow around particles in a crystallizer. We show that the hydrodynamic
      radius of these aggregates is almost the radius based on the average projected
      area over all orientations. This result is extended to larger and more porous
      aggregates.

PMID- 15028513
TI  - Study on water evaporation through 1-alkanol monolayers by the thermogravimetry
      method.
AB  - The influence of 1-alkanol monolayers on the rate of water evaporation has been
      studied by measuring water loss per unit time using thermogravimetry. The
      evaporation rate of water from the surface covered by an insoluble monolayer for
      each of four saturated 1-alkanols (C(13)OH, C(15)OH, C(17)OH, and C(19)OH) was
      measured as a function of temperature and alkyl chain length, where the monolayer
      was under equilibrium spreading pressure. The evaporation rate decreased with
      increasing alkyl chain length or increasing molecular interaction among 1-alkanol
      molecules in the insoluble monolayer. Using the Arrhenius equation, the
      activation energy for the water evaporation was calculated from the temperature
      dependence of the evaporation rate, which showed that the activation energy
      decreased with increasing temperature. On the other hand, the activation energy
      increased with increasing alkyl chain length, which indicates that the activation
      energy includes the energy to cross the insoluble monolayer at the air/water
      interface. This energy increased almost linearly with alkyl chain length, when
      the length is longer than a dodecyl group. This means that water molecules need
      more energy to escape from the liquid to the gaseous phase across a membrane of
      longer 1-alkanols, which becomes more evident at lower temperatures. The
      temperature dependence of the activation energy was slightly larger for longer 1
      alkanols than for shorter ones.

PMID- 15028514
TI  - 3-D transient electrophoretic motion of a spherical particle in a T-shaped
      rectangular microchannel.
AB  - This paper considers the electrophoretic motion of a spherical particle in an
      aqueous electrolyte solution in a T-shaped rectangular microchannel, where the
      size of the channel is close to that of the particle. This is a complicated
      transient process where the electric field, the flow field, and the particle
      motion are coupled together. A theoretical model was developed to investigate the
      influences of the applied electric potentials, the zeta potentials of the channel
      and the particle, and the size of the particle on the particle motion. A direct
      numerical simulation method using the finite element method is employed. This
      method employs a generalized Galerkin finite element formulation that
      incorporates both equations of the fluid flow and equations of the particle
      motion into a single variational equation where the hydrodynamic interactions are
      eliminated. The ALE method is used to track the surface of the particle at each
      time step. The numerical results show that the electric field in the T-shaped
      microchannel is influenced by the presence of the particle, and that the particle
      motion is influenced by the applied electric potentials and the zeta potentials
      of the channel and the particle. The path of the particle motion is dominated by
      the local electric field and the ratio of the zeta potential of the channel to
      that of the particle. The particle's velocity is also dependent on its size in a
      small channel.

PMID- 15028515
TI  - Modeling and electrokinetic evidences on the processes of the Al(III) sorption
      continuum in SiO2(s) suspension.
AB  - Reactions of Al(III) at the interface between SiO2(s) and aqueous solution were
      characteristically and quantitatively studied using electrophoretic methods and
      applying a surface complexation/precipitation model (SCM/SPM). The surface and
      bulk properties of Al(III)/SiO2 suspensions were determined as functions of pH
      and initial Al(III) concentration. Simulated modeling results indicate that the
      SCM, accounting for the adsorption mechanism, predicts sorption data for low
      surface coverage only reasonably well. Al(III) hydrolysis and surface hydroxide
      precipitation must be invoked as the Al(III) concentration and/or pH
      progressively increase. Accordingly, the three processes in the Al(III) sorption
      continuum, from adsorption through hydrolysis to surface precipitation, could be
      identified by the divergence between the SCM/SPM predictions and the experimental
      data. SiO2(s) suspensions with low Al(III) concentrations (1 x 10(-4) and 1 x 10(
      5) M) exhibit electrophoretic behavior similar to that of a pure SiO2(s) system.
      In Al(III)/SiO2 systems with high Al concentrations of 1 x 10(-3), 5 x 10(-3) and
      1 x 10(-2) M, three charge reversals (CR) are observed, separately representing,
      in order of increasing pH, the point of zero charge (PZC) on the SiO2 substrate
      (CR1), the onset of the surface precipitation of Al hydroxide (CR2), and at a
      high pH, the PZC of the Al(OH)3 coating (CR3). Furthermore, in the 1 x 10(-3) M
      Al(III)/SiO2(s) system, CR2 is consistent with the modeling results of SCM/SPM
      and provides evidence that Al(III) forms a surface precipitate on SiO2(s) at pH
      above 4. SiO2(s) dissolution was slightly inhibited when Al(III) was adsorbed
      onto the surface of SiO2(s), as compared to the dissolution that occurs in a pure
      SiO2(s) suspension system. Al hydroxide surface precipitation dramatically
      reduced the dissolution of SiO2(s) because the Al hydroxide passive film
      inhibited the corrosion of the SiO2(s) surface by OH- ions.

PMID- 15028516
TI  - Comments on "Bubble motion in aqueous surfactant solutions".
AB  - The numerical simulations of bubble motion in dilute surfactant solutions
      reported previously by two of the authors contained a serious numerical
      inaccuracy. In agreement with experiments, single bubbles released from rest were
      predicted to reach a maximum speed before slowing to a terminal speed. However,
      subsequent experiments demonstrated that, in the simulations, the bubbles reached
      their terminal speed too quickly. The source of the discrepancy is an inaccuracy
      associated with the numerical algorithm used to solve the surfactant transport
      equation on the bubble surface. After correcting the problem, the simulations
      agree much better with the experiments.

PMID- 15028517
TI  - Changes in serum sex steroid levels throughout the reproductive cycle of Bufo
      arenarum females.
AB  - The changes in the serum levels of the sexual steroids estradiol-17beta (E(2)),
      testosterone (T), dihydrotestosterone (DHT), and progesterone (P) in Bufo
      arenarum females were determined by radioimmunoassay (RIA) during 3 consecutive
      cycles (1999-2001). The serum concentrations of T and DHT, which showed a close
      parallelism during the annual reproductive cycle, exhibited the highest levels
      during the preovulatory period, when oogenesis is advanced, while lowest serum
      levels of these hormones were found during the ovulatory period. The data
      obtained for E(2) showed a pattern contrary to that determined for androgens. The
      maximum E(2) concentrations detected in the early postovulatory period might be
      associated with vitellogenesis and follicular growth. Lowest E(2) concentrations
      were reached during the period in which B. arenarum undergoes its final
      hibernation stage. Serum P showed a peak during the preovulatoy period, related
      to the induction of nuclear maturation in full grown oocytes. A strong decrease
      in the levels of the circulating hormones was observed after ovariectomy. Our
      results showed that, out of the four hormones examined, T and DHT were the best
      indicators of ovarian and oviductal stage, as shown by the strong positive
      correlation found between androgen levels and organ weight, while E(2) showed a
      weak negative correlation with ovarian and oviductal weight.

PMID- 15028518
TI  - Deiodinase type III in the Australian lungfish, Neoceratodus forsteri.
AB  - This work presents characterisation of deiodinase type III (D3) mRNA as cDNA and
      the tissue distribution of D3 mRNA in the Australian lungfish, Neoceratodus
      forsteri. We have identified the full length of a approximately 1.4 kb D3 mRNA in
      the liver, which has a single in-frame UGA codon and a selenocysteine insertion
      sequence (SECIS) form 2 in the 3'-UTR. Lungfish D3 mRNA was expressed in all
      tested tissues (liver, lung, kidney, brain, heart, and gills) as demonstrated by
      Northern blot analyses. PCR conducted on genomic DNA indicated that the lungfish
      D3 is a single exon gene. Also, we present enzymatic characteristics of this
      exclusively IRD enzyme, have determined its substrate preference, DTT cofactor
      requirements, PTU inhibition, and kinetic properties. These results indicate that
      lungfish D3 has the typical enzymatic characteristics of vertebrate D3 enzymes.

PMID- 15028519
TI  - Cellular localization of endocrine cells in the adult pancreas of the house musk
      shrew, Suncus murinus: a comparative immunocytochemical study.
AB  - The right and left lobes of the pancreas in the house musk shrew, Suncus murinus,
      were found to be completely separated. A morphologic study of the pancreas in S.
      murinus in terms of the blood supplies and innervation of the right and left
      lobes was performed in our previous study. It revealed clearly different blood
      supply and innervation patterns in the right and left lobes, suggesting that the
      right lobe of the pancreas corresponded to the ventral pancreas, and the left
      lobe related to the dorsal pancreas. To test this perspective from the histology,
      in this study, we investigated the immunolocalization of the cells of Langerhans
      islets in the pancreas of the animal. The distribution of insulin-, glucagon-,
      somatostatin-, and pancreatic polypeptide (PP)-secreting cells of the right and
      left lobes of the pancreas was examined in 10 animals. The glucagon
      immunoreactive cells were distributed in both the right and left lobes. The PP
      immunoreactive cells were extremely abundant in the right lobe and distributed
      throughout almost all the islets of Langerhans in the right lobe. By contrast, in
      the left lobe, immunoreactive PP cells were absent in the islets of Langerhans,
      and only very few immunoreactive PP cells were scattered in the exocrine
      parenchyma in part of the specimens. Therefore, these findings support our
      previous studies, and showed that the right and left lobes of the S. murinus
      pancreas could be related to an embryological origin from the ventral and dorsal
      pancreatic primordium, respectively, and that the S. murinus pancreas is suitable
      as a new experimental model to study the development of the human pancreas.

PMID- 15028520
TI  - Temperature effects along the reproductive axis during spawning induction of
      grass carp (Ctenopharyngodon idella).
AB  - For grass carp (Ctenopharyngodon idella) raised in the Ivory Coast (with water
      temperatures of 26-31 degrees C), induced spawning is obligatory for fry
      production. However, ovulation rates following hormonal treatment are often low.
      We hypothesized that high temperatures are an inhibiting factor for the
      reproductive axis (brain-pituitary-gonad) in these conditions. By in vivo and in
      vitro experiments, we tried to determine the thermosensitive steps during
      spawning induction. We compared gonadotropin and maturation-inducing steroid
      (MIS) profiles during a spawning induction at controlled temperatures of 24 and
      28 degrees C in relation to ovulation success. We performed pituitary cell
      cultures and ovarian fragment incubations at controlled temperatures. The
      ovulation rate was lower at 28 degrees C (10%) than at 24 degrees C (36%). At the
      pituitary level, we found only minor thermal impacts on GnRH-stimulated LH
      release, but our data suggest an increase of the dopaminergic inhibition by high
      temperatures. The main effects were found at the ovary level, where ovary
      responsiveness to gonadotropin by MIS synthesis was disturbed, as well as oocyte
      responsiveness to MIS triggering final maturation, and probably ovulation. These
      results show the importance of regulating temperature during spawning induction
      to ensure a high rate of ovulation.

PMID- 15028521
TI  - Dual mode of catecholamine action on splenic macrophage phagocytosis in wall
      lizard, Hemidactylus flaviviridis.
AB  - In the present study, in vitro concentration-related effect of catecholamines,
      dopamine (DA), norepinephrine (NE), and epinephrine (E) was observed on
      phagocytic activity of splenic macrophages to understand the impact of sympatho
      adrenal-medullary (SAM) activation on innate immunity in wall lizard Hemidactylus
      flaviviridis under stress condition. Restraint stress for 1 h resulted in marked
      suppression of macrophage phagocytosis, suggesting that supra-physiological level
      of catecholamines in response to SAM activation under stress suppressed
      phagocytosis. This interpretation was reinforced since all the catecholamines
      considerably reduced phagocytosis at high concentrations ranging from 10(-7) to
      10(-5)M. On the contrary, DA, NE, and E at low concentrations considerably
      stimulated phagocytosis, which increased with the decrease of concentrations
      ranging from 10(-11) to 10(-15)M. Further, effect of NE and E was blocked by beta
      adrenergic blocker suggesting the beta-adrenoceptor-dependent regulating
      mechanism of NE and E. DA acts through both beta-adrenoceptor-dependent and D1/D2
      class receptor-dependent mechanism, since beta-adrenergic blocker could partially
      block the DA effect. beta-Adrenoceptor-linked adenylate cyclase-mediated cAMP
      action in modulation of phagocytic activity was evident as 3-isobutyl-1-methyl
      xanthine suppressed phagocytosis. Further, to delineate the mode of dual effect
      of catecholamines through beta-adrenergic receptors, in vitro concentration
      related effect of cAMP was investigated on macrophage phagocytosis. cAMP
      depending on concentration had opposite effect on phagocytosis, and its
      stimulatory effect at low concentrations was reversed by actinomycin D and
      cycloheximide, whereas these transcription and translation inhibitors,
      respectively, failed to alter the inhibitory effect of cAMP at high
      concentrations. This suggests the concentration-related two different pathways of
      catecholamine action, classical non-genomic at high concentration while genomic
      pathway at low concentration.

PMID- 15028522
TI  - Steroid receptors in the adult zebra finch syrinx: a sex difference in androgen
      receptor mRNA, minimal expression of estrogen receptor alpha and aromatase.
AB  - The zebra finch syrinx (sound production organ) is a sexually dimorphic component
      of the song system. Only male zebra finches sing, and in parallel, the overall
      mass and size of fibers in the two largest syrinx muscles are greater in males
      than females. Despite these obvious sexual dimorphisms, little is known about the
      role of steroid hormones in the maintenance of the structure and/or function of
      the syrinx. In this report, we used in situ hybridization to assess the
      expression of androgen receptor (AR), estrogen receptor alpha (ERalpha), and
      aromatase (AROM) mRNAs in the syrinx of adult male and female zebra finches.
      Increased AR mRNA expression was noted in males compared to females in two
      regions, over the ventralis muscle and in a band of connective tissue neighboring
      cartilage (perichondria). In contrast, we did not detect specific ERalpha or AROM
      mRNA expression within the syrinx. However, substantial ERalpha mRNA was present
      in oviduct, and aromatase mRNA was expressed at high levels in ovary. In
      parallel, an assay for AROM detected activity in ovary, but not in syrinx tissue
      from males or females. Taken together, these data suggest that the adult syrinx
      is sensitive to androgens; that sex differences in function and morphology of the
      syrinx may in part be due to increased expression of AR in males compared to
      females. In contrast, estrogen receptor alpha and AROM appear to have limited
      roles.

PMID- 15028523
TI  - In situ localization of preprogalanin mRNA in the goldfish brain and changes in
      its expression during feeding and starvation.
AB  - In this paper, we report (i) the in situ localization, and (ii) meal time related
      and starvation induced changes in preprogalanin mRNA expression in the goldfish
      brain. The specific brain nuclei that express galanin mRNA are the area ventralis
      telencephali pars ventralis, nucleus preopticus periventricularis, nucleus
      lateralis tuberis, and the nucleus recessus lateralis. No changes in preprandial
      preprogalanin mRNA expression were found in the brain regions studied. No changes
      in postprandial preprogalanin mRNA expression were found compared to the
      preprandial levels. However, in unfed fish, a significant increase in
      preprogalanin mRNA expression was found in the telencephalon (1 and 3 h) and
      hypothalamus (3 h) after the scheduled feeding time. The postprandial
      preprogalanin mRNA expression in the telencephalon and hypothalamus of fed fish
      at 1 and 3 h were significantly lower than the mRNA expression levels in the
      unfed fish at the same time. Preprogalanin mRNA expression levels remain
      unaltered during 7 days of starvation. The presence of preprogalanin mRNA in
      brain nuclei involved in the regulation of food intake and pituitary hormone
      secretion suggests important physiological roles for galanin in goldfish.

PMID- 15028525
TI  - Chromogranin A N-terminal fragments vasostatin-1 and the synthetic CGA 7-57
      peptide act as cardiostatins on the isolated working frog heart.
AB  - Chromogranin A (CGA) N-terminal fragments corresponding to residues 1-76 and 1
      113, named vasostatins for their inhibitory effects on vascular tension, have
      been postulated as important homeostatic regulators of the cardiovascular system.
      We have used an in vitro isolated working frog (Rana esculenta) heart as a
      bioassay to study the effects of exogenous human recombinant CGA 1-76 (VS-1) and
      human CGA 7-57 synthetic peptide on cardiac performance. Under basal conditions,
      the concentration-response curves of the two peptides exhibited a significant
      negative inotropism. This vasostatin response was unaffected by pretreatment with
      either Triton X-100 or two nitric oxide synthase inhibitors, i.e., N(G)
      monomethyl-L-arginine and L-N5 (5)(1-iminoethyl) ornithine or the soluble
      guanylate cyclase inhibitor 1H-(1,2,4) oxadiazolo-(4,3-a) quinoxalin-1-one,
      indicating an endocardial endothelium-nitric oxide-cGMP-independent mechanism.
      The negative inotropism was also unaffected by either adrenergic (i.e.,
      phentolamine and propranolol) or muscarinic (atropine) receptor or G proteins
      (pertussis toxin) inhibition. On the contrary, it was dependent from both
      extracellular Ca(2+) and K(+) channels, since it was abolished by pretreatment to
      either the Ca(2+) channel inhibitors lanthanum and diltiazem or the K(+) channel
      inhibitors Ba(2+), 4-aminopyridine, tetraethylammonium chloride, and
      glibenclamide. In conclusion, the findings that vasostatins exert an inhibitory
      modulation on basal cardiac performance and counteract, as previously reported,
      the adrenergic-mediated positive inotropism, strongly support a cardio-regulatory
      role for these peptides.

PMID- 15028524
TI  - Molecular cloning and characterization of a gonadotropin-releasing hormone
      receptor in the guinea pig, Cavia porcellus.
AB  - Guinea pig gonadotropin-releasing hormone (gpGnRH) is predicted to have a unique
      structure among all known forms of GnRH molecule [Endocrinology 138 (1997) 4123]
      and it is of great interest to determine whether the unique structure of gpGnRH
      is manifested in the characteristics of the guinea pig GnRH receptor. In the
      present study, we isolated a full-length cDNA for a GnRH receptor from the
      pituitary gland of the guinea pig. The putative guinea pig GnRH receptor protein
      has an amino acid identity of 79-87% with mammalian type I GnRH receptors. The
      amino acid residues which have been demonstrated to be important for ligand
      binding and signal transduction were conserved in the guinea pig GnRH receptor.
      However, there are several specific amino acid substitutions among mammalian type
      I GnRH receptors. Moreover, though the guinea pig has generally been classified
      as a rodent, the putative GnRH receptor protein did not have some rodent-specific
      characteristics. Total IP assays demonstrated that the cloned guinea pig GnRH
      receptor is a functional GnRH receptor and that it shows different preference of
      ligand sensitivities from the rat GnRH receptor.

PMID- 15028526
TI  - In vitro effect of FSH and testosterone on Sertoli cell nursing function in wall
      lizard Hemidactylus flaviviridis (Ruppell).
AB  - The present in vitro Sertoli cell-enriched culture study was aimed to understand
      the precise role of FSH and testosterone either alone or in combination in
      regulation of Sertoli cell nursing function such as lactate production, which in
      turn is utilized by the germ cells as an energy substrate. The stimulatory effect
      of FSH on lactate production by Sertoli cell-enriched culture was significantly
      enhanced when FSH and dihydrotestosterone were supplemented in the medium either
      simultaneously or DHT was added 12 h later to FSH (0 h FSH+12 h DHT). On the
      contrary, DHT alone or added 12 h prior to FSH (0 h DHT+12 h FSH) in the
      incubation medium, significantly reduced the lactate secretion by Sertoli cells
      as compared to control or FSH alone/FSH+DHT simultaneously/0 h FSH+12 h DHT,
      respectively. This provides the conclusive evidence that androgen has additive
      effect on nursing function of Sertoli cell-enriched clusters only when they are
      in an activated state in response to gonadotropin.

PMID- 15028527
TI  - Regulation of hepatic progesterone and estrogen receptors in the female turtle,
      Chrysemys picta: relationship to vitellogenesis.
AB  - Previous studies using the fresh water turtle Chrysemys picta have demonstrated
      the differential expression of the two progesterone receptor isoforms (PRA and
      PRB) in the liver during the turtle seasonal cycle, correlating with ER mRNA
      levels and hepatic vitellogenesis. During the inter-vitellogenic periods the
      ratio of PRB:PRA favors PRA, suggesting that the PRB:PRA ratio may be important
      in the regulation of vitellogenesis. Based on these and other studies we
      hypothesize that progesterone may have differential effects on the estrogen (E)
      induced vitellogenin response (inhibitory or stimulatory), depending on the
      PRB:PRA ratio. In this study, we determined the expression pattern and the
      hormonal regulation of progesterone receptor (PR) isoforms in the liver, during
      the estrogen-induced vitellogenin response in female C. picta. Northern blot
      analysis was used to evaluate the changes in vitellogenin mRNA, estrogen receptor
      (ER) mRNA, and PR mRNA expression; Western blot to determine changes in PR
      isoform expression and a homologous ELISA for measurement of plasma vitellogenin.
      The expression of PR isoforms in the liver of female turtles at the mRNA and
      protein levels was differentially regulated by estradiol and progesterone.
      Estradiol treatment enhanced the transcription of PR mRNA isoforms and possibly
      translation and/or increased stability of PRB protein in the female turtle liver.
      In contrast, this hormone decreased PRA protein levels. Progesterone alone down
      regulated progesterone receptor isoform A (PRA) and progesterone receptor isoform
      B (PRB) proteins equally, but did not affect PR mRNA levels. Estradiol markedly
      increased hepatic ER mRNA, vtg mRNA, and vtg in plasma, but this effect was not
      impacted significantly by progesterone. The results presented here indicate that
      in female turtles hepatic PRB:PRA ratios are markedly changed by estradiol
      treatment due primarily to a decrease in PRA. The change in the PRB:PRA ratio
      after hormonal treatment confirms that progesterone and estrogen exposure will be
      a determinant in the regulation of vitellogenesis, and, in turn, that the
      regulation of vitellogenesis will be determined by the ratio of PR isoforms and
      the physiological levels of steroid hormones.

PMID- 15028528
TI  - Maternal serum and yolk hormone concentrations in the placental viviparous
      bonnethead shark, Sphyrna tiburo.
AB  - Among vertebrates, maternal transfer of hormones to offspring has been studied
      extensively in mammals (placental transfer) and more recently in oviparous birds
      and reptiles (yolk transfer). The placental viviparous bonnethead shark, Sphyrna
      tiburo, allows the investigation of both yolk and placental hormone transfers in
      a single organism. In this species, yolk provides nutrition for the first half of
      embryonic development and placental transfer provides the second half. As sex
      determination is complete prior to development of placental connections, it was
      postulated that yolk hormones would have a prominent role in embryonic
      regulation. The goal of the current study was to determine serum and yolk hormone
      concentrations during five reproductive stages, from pre-ovulatory through pre
      implantation (pre-placental) stages. Radioimmunoassay was used to determine
      17beta-estradiol, progesterone, and testosterone concentrations in both serum and
      yolk. When yolk and serum concentrations were compared, the yolk had
      significantly higher concentrations of both estradiol and progesterone during
      post-ovulation and early pregnancy. Yolk concentrations of testosterone were
      significantly less than serum at pre-ovulation, but there were no differences
      after that stage. When yolk concentrations were compared between stages,
      significantly higher concentrations of estradiol were present in ovulatory, post
      ovulatory, and pre-implantation stages, while progesterone was significantly
      higher in post-ovulatory, early pregnancy, and pre-implantation stages and
      testosterone was higher in pre-ovulation. Most of these results are consistent
      with the published findings in birds and reptiles. Further, in the bonnethead
      shark, they suggest that yolk transfer of hormones is adequate for sexual
      differentiation in embryonic development and that estradiol probably has a
      significant developmental role.

PMID- 15028529
TI  - Growth selection in mice reveals conserved and redundant expression patterns of
      the insulin-like growth factor system.
AB  - Transgenic and knockout models have been used successfully in order to attribute
      specific functions to distinct growth factors. However, it is not clear which
      from the different IGF-components are actually altered when growth is affected.
      Furthermore it is not clear if unique or redundant patterns of IGF-component
      expression are present under conditions of elevated or reduced growth. To address
      these questions we have used a unique set of mouse models generated by divergent
      selection for high and low body growth. The set of mouse models consisted of
      eight mouse lines established in different laboratories. We have studied systemic
      and local expression of growth relevant genes in these mouse lines highly
      diverging for body and carcass weights but also for nose-rump lengths. As a
      strictly conserved pattern, serum IGF-I levels were dramatically increased in all
      H-lines if compared with the respective L-lines. By contrast serum IGFBP
      concentrations did not reveal clear patterns of expression in response to growth
      selection: IGFBP-3 was elevated in some H-lines, IGFBP-2 was increased in H- or L
      lines and IGFBP-4 was similar in H- and L-lines. The fact that IGFBP-2 was the
      only IGFBP elevated in part of the L-lines, identifies IGFBP-2 as an exclusive
      although facultative negative effector for growth in the circulation among all
      other IGFBPs. In muscle tissue from selected breeding groups characterized by
      specific increases of the carcass weights we found redundant patterns of gene
      expression indicating the absence of tissue-specific or uniquely fixed expression
      patterns during growth selection within muscle tissue. The finding that serum but
      not tissue IGF-I levels were strictly positively correlated with growth during
      growth selection argues for an important role of endocrine IGF-I for postnatal
      growth in mice.

PMID- 15028530
TI  - Changes in baseline and stress-induced glucocorticoid levels during the active
      period in free-ranging male and female little brown myotis, Myotis lucifugus
      (Chiroptera: Vespertilionidae).
AB  - Baseline and stress-responsive glucocorticoid (GC) levels were characterized
      during the active period in free-ranging male and reproductive female little
      brown myotis (Myotis lucifugus). Bats were trapped and blood was sampled within 3
      min of capture at two maternity sites during the summer and at one swarming site
      prior to hibernation in New England. Both GC hormones, cortisol and
      corticosterone, were detected, with cortisol accounting for an average of
      approximately 95% of total circulating GCs. Samples collected at the dusk
      emergence and after the first return from feeding showed significant seasonal
      differences across the active period (early pregnancy, mid-to-late pregnancy,
      lactation [and comparable mid-summer times for males], and pre-hibernation)
      within and between each sex. Elevated baseline values were found in mid-to-late
      pregnancy females at emergence, and in both males and females at the swarming
      site compared to other groups. Female GC values during mid-to-late pregnancy and
      during the pre-hibernation period were greater than those for males.
      Significantly higher GC levels following 15 min of restraint were exhibited by
      all animals in the summer and prior to hibernation. There was little variation
      between groups or sexes in the total GC levels reached following restraint. Taken
      together, these results suggest that: (1) GCs may be involved in the increased
      feeding and/or fat deposition characteristic of pregnancy and the pre-hibernation
      period, (2) GCs may be related to mating and to the generally increased levels of
      activity that occur during the pre-hibernation period, and (3) regardless of sex
      or reproductive condition, all animals maximally respond to restraint stress.

PMID- 15028531
TI  - Mechanisms of action of melanin-concentrating hormone in the teleost fish
      erythrophoroma cell line (GEM-81).
AB  - Melanin-concentrating hormone (MCH) evokes an increase of GEM-81 cell
      proliferation. This action of 10(-6)M MCH was inhibited in the presence of the
      following blockers: U-73122 (phospholipase C), Ro-31-8220 (PKC) or KN-93
      (Ca(2+)/calmodulin-dependent kinase). The more selective PKC inhibitors, HBDDE
      and Go-6983, which block, respectively, PKC alpha/gamma isoform and beta1
      isoform, were used. HBDDE was ineffective whereas Go-6983 reversed the
      proliferative response promoted by MCH. Flow cytometry assays demonstrated that
      MCH induces a slow and long-lasting rise in intracellular calcium, which can be
      blocked by U-73122. Our results also show a cAMP increase evoked by MCH. Our data
      support the assumption that MCH exerts its effect on GEM-81 erythrophoroma cells
      through activation of phosholipase C, beta1 PKC, and Ca(2+)/calmodulin-dependent
      PKC, and eliciting a slow, long-lasting rise in calcium, which may trigger the
      proliferative signal.

PMID- 15028532
TI  - 15alpha-hydroxytestosterone induction by GnRH I and GnRH III in Atlantic and
      Great Lakes sea lamprey (Petromyzon marinus L.).
AB  - The sea lamprey (Petromyzon marinus L.) represents one of the two most ancient
      classes of vertebrates and possesses a functional hypothalamus-pituitary-gonadal
      axis. However, the presence and functionality of androgens in the sea lamprey
      remain elusive. Recently, 15alpha-hydroxytestosterone (15alpha-T) has been found
      in sea lamprey gonads and blood plasma. In this study we examined changes of
      circulatory concentrations of 15alpha-T in response to gonadotropin releasing
      hormone (GnRH) treatments. Plasma concentrations of 15alpha-T in sea lamprey
      increased 2-5 times for all GnRH-injected sea lamprey compared to controls (P <
      0.001). However, there were no differences among responses: (1) to the two forms
      of GnRH (lamprey GnRH I or lamprey GnRH III), (2) to the doses delivered (50,
      100, or 200 microg/kg), or (3) between post-injection sample intervals (8 or 24
      h). Between lampreys from the Atlantic Ocean and Great Lakes sites, two of seven
      GnRH form and dosage comparisons showed between-site differences, but were not
      believed to represent an overall between-site difference. These are the first
      data to show a response of a C19 steroid to GnRH stimulation in sea lamprey.

PMID- 15028533
TI  - Activation of aggressive behavior by progesterone and testosterone in male tree
      lizards, Urosaurus ornatus.
AB  - Testosterone is usually thought to be the major sex steroid regulating adult male
      territorial aggression in vertebrates. However, recent evidence has suggested a
      role for progesterone, as well as testosterone, in the organization of the two
      male reproductive phenotypes of tree lizards (Urosaurus ornatus), which differ in
      adult levels of territorial behavior. In the present experiment we tested whether
      progesterone and testosterone could also play an activational role in the
      expression of adult aggressive behavior. We subjected post-reproductive male tree
      lizards to the following treatments: sham surgery, castration, castration with
      progesterone supplementation, and castration with testosterone supplementation.
      We measured several different dimensions of aggressive behavior. Overall in these
      post-reproductive animals, the level of aggression from lowest to highest was:
      castrates, shams, progesterone-treated, and testosterone-treated. Although
      testosterone appears to be the more potent regulator of aggressive behavior,
      progesterone enhanced several measures of aggression suggesting that it could
      play a role in natural regulation of aggressive behavior. This initial study used
      very high levels of progesterone (similar to or above those experienced by
      hatchlings) to maximize the probability of detecting an effect. Further studies
      are needed to determine if natural adult progesterone levels are sufficiently
      high to influence aggressive behavior.

PMID- 15028534
TI  - Diurnal patterns of cortisol and thyroid hormones in the Harbor seal (Phoca
      vitulina) during summer and winter seasons.
AB  - A leading hypothesis for the dramatic population decline of the Alaskan harbor
      seal over the last 2-3 decades have related environmental changes to a decrease
      in the quality or quantity of available prey. If harbor seals are experiencing
      some sort of nutritional stress, it is important to understand the physiological
      and endocrine mechanisms controlling metabolic homeostasis in this species. The
      purpose of this research project was to determine whether circadian patterns of
      cortisol and total and free thyroxine (T(4)) and triiodothyronine (T(3)) are
      present in the harbor seal during the summer and winter seasons, and identify how
      they might alter metabolic rate and maintenance of body reserves. This study was
      carried out at the Alaska SeaLife Center in Seward, Alaska in June 2000 and
      January 2001. Blood samples were obtained every 2-3 h over a 24-h period through
      in-dwelling catheters inserted the day before sampling. The presence of a diurnal
      rhythm was determined by comparing levels between ante meridian (12 am to noon)
      and post meridian (noon to 12 midnight) time periods. Mean daily cortisol
      concentrations were not significantly different between seasons, but cortisol
      displayed a circadian rhythm only during the summer. Mean concentrations of
      cortisol (51.5 ng/ml+/-20.3) in the summer hours of ante meridian differed
      significantly from levels in the hours of post meridian (28.5 ng/ml+/-17.4).
      Neither total and free T(4), nor T(3), displayed a diurnal rhythm in either
      season. However, tT(4), tT(3), and fT(3) levels were significantly higher in the
      winter than in the summer. There was no seasonal effect on fT(4) levels. The
      absence of a circadian rhythm of cortisol during the winter may have been a
      result of the limited amount of daylight as well as the continual need to produce
      metabolic heat as a by-product of gluconeogenesis. Higher levels of thyroid
      hormones in the winter indicate an adaptive mechanism to cope with the low
      temperatures of winter.

PMID- 15028535
TI  - Effects of prolactin and growth hormone on proliferation and survival of cultured
      trout leucocytes.
AB  - The in vitro effects of prolactin (PRL) and growth hormone (GH) on the
      proliferation and survival of leucocytes isolated from the blood of the rainbow
      trout (Oncorhynchus mykiss) were examined, with special reference to the
      immunosuppression by cortisol. Both PRL and GH induced a mitogenic effect in
      trout leucocytes. Contrary, the frequencies of annexin V-positive apoptotic cells
      and propidium iodide-positive dead cells were decreased by the administration of
      PRL, but were uninfluenced by GH. Administration of cortisol suppressed the
      mitotic activity and induced cell death of leucocytes. PRL inhibited the decrease
      in mitosis and the increase in cell death due to cortisol. GH significantly
      assisted recovery of cortisol-suppressed mitosis but did not influence the
      survival of leucocytes. These results suggest that PRL and GH are involved in the
      maintenance of specific immune functions in fish through a prevention of
      immunosuppression by cortisol.

PMID- 15028536
TI  - Integrating research on temperament and childhood psychopathology: its pitfalls
      and promise.
AB  - This article discusses the promise and problems associated with integrating
      research on child temperament and research on childhood psychopathology.
      Unfortunately, these 2 extensive and influential areas of psychological research
      with children have largely been conducted independently of each other. This
      article provides a summary of the disciplinary, conceptual, and methodological
      issues that have hampered an integration of these 2 important bodies of research.
      It also highlights the great promise that such an integration could have for
      advancing causal theories of childhood disorders and for eventually improving the
      treatment provided to children with serious emotional and behavioral
      disturbances.

PMID- 15028537
TI  - Temperament, anxiety, and the processing of threat-relevant stimuli.
AB  - This article discusses converging evidence from developmental, clinical, and
      cognitive psychology suggesting that there is significant overlap between
      research findings on affect, temperament, and attentional processes associated
      with pathological anxiety. We offer a proposal for the integration of these 3
      areas aimed at developing a more clear understanding of the developmental
      sequence and operative mechanisms in the dysregulation of negative affect and the
      development of symptoms of anxiety pathology. We review evidence for a model
      indicating that reactive and effortful temperamental processes, possibly mediated
      by an attentional bias toward threat-relevant information, interact to produce
      problems of dysregulated negative affect and elevated levels of pathological
      anxiety. This model may assist in understanding the development of anxiety
      disorders, identifying children at risk for such disorders, and selecting points
      of entry for both preventative and curative interventions.

PMID- 15028538
TI  - Temperament, stress reactivity, and coping:implications for depression in
      childhood and adolescence.
AB  - This article considers the role of temperament in the development of depression
      during childhood and adolescence. The features of depression in young people and
      aspects of temperament that are most relevant to depression are briefly reviewed.
      Studies that have tested the direct and indirect associations of temperament and
      depressive symptoms in young people are summarized. Evidence suggests that the
      temperamental characteristics of positive and negative emotionality, and to a
      lesser extent attentional control, are implicated in depressive symptoms. The
      role of stress, stress responses, and coping are then examined in the association
      of temperament and depression. Temperamental characteristics may moderate and be
      moderated by stress responses and coping in their effects on depression.
      Directions for future research are highlighted.

PMID- 15028539
TI  - Temperament and attachment disorders.
AB  - Reviewed in this article is research on children with reactive attachment
      disorder (RAD) who exhibit specific patterns of socially aberrant behavior
      resulting from being maltreated or having limited opportunities to form selective
      attachments. There are no data explaining why 2 different patterns of the
      disorder, an emotionally withdrawn-inhibited pattern and an indiscriminate
      disinhibited pattern, arise from similarly aberrant environments. In this
      article, we consider whether temperamental differences might contribute to the
      different manifestations of reactive attachment disorder (RAD) in the context of
      adverse environments. Although the association between attachment and temperament
      has been studied extensively and has been the subject of spirited debate within
      the field of child development, there are no extant data on the influence of
      temperament on the development of attachment disorders. We consider possible
      directions for research efforts designed to explore the biological underpinnings
      of the complex phenomenon of attachment disorders.

PMID- 15028540
TI  - Temperament and attention deficit hyperactivity disorder: the development of a
      multiple pathway model.
AB  - This article outlines the parallels between major theories of attention deficit
      hyperactivity disorder (ADHD) and relevant temperament domains, summarizing
      recent research from our laboratories on (a) child temperament and (b) adult
      personality traits related to ADHD symptoms. These data are convergent in
      suggesting a role of effortful control and regulation in the core symptoms of
      ADHD. Negative approach and anger is also associated with ADHD, but this may be
      due to the overlap of ADHD and antisocial behavior. Positive approach may be
      involved in an alternate pathway to ADHD. The involvement of effortful control is
      congruent with experimental findings of executive functioning deficits in
      children with ADHD. We hypothesize that, whereas regulation problems may occur in
      most children with ADHD, a subgroup also may be characterized by positive
      approach problems and another subgroup by negative approach problems. We conclude
      with a theorized multiple process developmental model outlining alternate
      pathways to ADHD that warrant empirical investigation to better resolve
      etiological heterogeneity in ADHD.

PMID- 15028541
TI  - Temperament and developmental pathways to conduct problems.
AB  - This article reviews research linking a number of temperamental vulnerabilities
      to the development of severe conduct problems in children. Also reviewed are 2
      areas of research that focus on important developmental processes that could
      mediate the relation between temperament and conduct problems. These processes
      are the development of emotional regulatory abilities and the development of the
      affective components of conscience. Both of these processes have been associated
      with certain temperamental vulnerabilities, and they can both place a child at
      risk for the development of conduct problems. Importantly, these 2 processes may
      designate children who develop conduct problems through distinct causal pathways
      and, as a result, could help to explain some of the subtypes of antisocial youth
      reported in past research.

PMID- 15028542
TI  - Temperament and adolescent substance use: a transactional analysis of emerging
      self-control.
AB  - Presented is a conceptual framework linking the construct of temperament with
      environmental factors that covary with the onset and escalation of substance use.
      We propose that transactions between temperament characteristics of the child in
      family and peer contexts influence the development of self-control ability, a
      mediating factor for onset and possible transition to abuse in later adolescence.
      Risk-promoting dimensions may influence the emergence of self-control by
      amplifying relationship processes that detract from competence development.
      Emergence of good self-control can serve as a resilience factor and is linked
      with health-promoting cognitions. We also suggest that temperament and self
      control moderate links between parenting, peer associations, and substance use.
      Implications of the transactional model for clinical intervention and research
      are discussed.

PMID- 15028543
TI  - Commentary: differentiated measures of temperament and multiple pathways to
      childhood disorders.
AB  - Provided is a commentary on articles written for a special section on temperament
      and childhood disorders. Temperament's contributions to the development of
      childhood disorders are considered both generally and specifically. Questions are
      raised about the use of terminology in the field, particularly the term
      difficult. Differentiation of outcomes and predictors is discussed, with a view
      to identifying multiple pathways to adaptation or disorder.

PMID- 15028544
TI  - Commentary: role of temperament in developmental models of psychopathology.
AB  - The articles in this special section provide exciting and useful perspectives on
      the role of temperament in the development of child and adolescent
      psychopathology. These articles are valuable both in summarizing what is known
      and in highlighting issues that must be addressed before further progress can be
      made. In the future, it will be essential to distinguish between the constructs
      of temperament and psychopathology in ways that are both scientifically valid and
      useful to the study of developmental psychopathology. In particular, because
      existing measures of temperament were not designed to study relations between
      temperament and psychopathology, new measures are needed that focus on relevant
      aspects of temperament and are not confounded by the inclusion of items that are
      close synonyms and antonyms of psychopathology. If circular and mentalistic
      thinking can be avoided, important advances can be expected from studies of
      temperament and psychopathology in the context of development.

PMID- 15028545
TI  - Toward effective quality assurance in evidence-based practice: links between
      expert consultation, therapist fidelity, and child outcomes.
AB  - This study validated a measure of expert clinical consultation and examined the
      association between consultation, therapist adherence, and youth outcomes in
      community-based settings. Consultant adherence to the multisystemic therapy (MST)
      consultation protocol was assessed through therapist reports, and therapist
      adherence to MST principles was assessed through caregiver reports in 2 samples
      of families (N1 = 178, N2 = 274) and therapists (N1 = 87, N2 = 162). Caregiver
      reports of youth behavior and functioning were obtained in the second sample pre-
      and posttreatment. Random effects regression models demonstrated associations
      between consultant behavior, therapist adherence, and posttreatment youth
      behavior problems and functioning. Instrumental aspects of consultation supported
      therapist adherence and improved youth outcomes; supportive aspects of
      consultation were negatively associated with adherence and outcomes. These
      findings suggest the availability to clinicians of expert consultation can impact
      clinician fidelity to a treatment model and child outcomes.

PMID- 15028546
TI  - Treating children with early-onset conduct problems: intervention outcomes for
      parent, child, and teacher training.
AB  - Families of 159, 4- to 8-year-old children with oppositional defiant disorder
      (ODD) were randomly assigned to parent training (PT); parent plus teacher
      training (PT + TT); child training (CT); child plus teacher training (CT + TT);
      parent, child, plus teacher training (PT + CT + TT); or a waiting list control.
      Reports and independent observations were collected at home and school. Following
      the 6-month intervention, all treatments resulted in significantly fewer conduct
      problems with mothers, teachers, and peers compared to controls. Children's
      negative behavior with fathers was lower in the 3 PT conditions than in control.
      Children showed more prosocial skills with peers in the CT conditions than in
      control. All PT conditions resulted in less negative and more positive parenting
      for mothers and less negative parenting for fathers than in control. Mothers and
      teachers were also less negative than controls when children received CT. Adding
      TT to PT or CT improved treatment outcome in terms of teacher behavior management
      in the classroom and in reports of behavior problems.

PMID- 15028547
TI  - Overt and relational aggression in girls with attention deficit hyperactivity
      disorder.
AB  - We employed a multi-informant approach to examine attention deficit hyperactivity
      disorder (ADHD) subtype differences, as well as ADHD versus comparison group
      differences, in overt aggression, relational aggression, and peer regard related
      to such aggression. Participants included 228 girls (ages 6 to 12 years)
      diagnosed with either ADHD-Combined (ADHD-C; n = 93), ADHD-Inattentive (ADHD-I; n
      = 47), or nondiagnosed comparisons (n = 88) who attended research-based summer
      camp programs. Girls with ADHD-C exhibited higher rates of overt and relational
      aggression than did girls with ADHD-I, who in turn exhibited higher rates than
      comparison girls. For the ADHD-C subgroup, aggressive behavior was associated
      with both negative peer regard and lack of positive peer regard; for the ADHD-I
      subgroup, aggressive behavior was related to negative peer regard but not to
      positive peer regard. Controlling for subtype, relational aggression contributed
      incremental variance in peer regard over and above overt aggression, but effects
      for the latter were stronger. We discuss the importance of overt versus
      relational aggression for girls with ADHD as well as disparities in findings
      according to informant sources.

PMID- 15028548
TI  - Risky and protective contexts and exposure to violence in urban African American
      young adolescents.
AB  - Contexts of risk for and protection from exposure to violence were identified and
      the relation of exposure to violence to delinquent behaviors and symptoms of
      trauma was examined. Using the Experience Sampling Method (ESM), the immediate
      daily experience of risky and protective contexts was examined. One hundred sixty
      seven African American 6th-, 7th-, and 8th-grade children from urban
      neighborhoods carried watches and booklets for 1 week. Structural equation
      modeling supported the hypotheses that more time in risky contexts and less time
      in protective contexts was related to more exposure to violence. Exposure to
      violence partially mediated the relation of time in protective and risky contexts
      to delinquent behaviors, assessed with the Juvenile Delinquency Scale and the
      Child Behavior Checklist, and distress levels, assessed by a posttraumatic stress
      disorder (PTSD) score.

PMID- 15028549
TI  - Assessing depression in youth: relation between the Children's Depression
      Inventory and a structured interview.
AB  - This study examined the utility of the Children's Depression Inventory (CDI) for
      predicting a diagnosis of a depressive disorder derived from the Structured
      Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (4th
      ed. [DSM-IV], American Psychiatric Association, 1994) Child Edition (KID-SCID).
      The participants were 80 referred children and adolescents with a mean age of
      12.21 years (range = 8 to 18 years). A categorical approach by means of a
      receiver-operating characteristics (ROC) analysis was used to examine the
      adequacy of cutoff scores for screening purposes. The results indicated that for
      the suggested cutoff scores of 13 and 19, the CDI has satisfactory ROCs. A cutoff
      score of 16 showed an optimal relation between sensitivity and specificity. The
      results from logistic regression indicated that the CDI total score is predictive
      of a depressive disorder. The CDI also differentiated a depressive disorder from
      an anxiety disorder and a disruptive behavior disorder. Those results provide
      support for the usefulness of the CDI as a screening tool for detecting
      depressive disorders in children and adolescents.

PMID- 15028550
TI  - The relation between parental coping styles and parent-child interactions before
      and after treatment for children with ADHD and oppositional behavior.
AB  - This study examined the relation between parental coping styles, discipline, and
      child behavior before and after participating in a parent training program for
      parents of children with Attention-Deficit/Hyperactivity Disorder (ADHD) and
      oppositional behavior. For mothers, use of more maladaptive and less adaptive
      coping styles was related to more self-reported lax and overreactive discipline,
      more observed coercive parenting, and more observed child misbehavior prior to
      parent training. No significant relations were found for mothers following parent
      training after controlling for pretreatment variables. For fathers, use of more
      maladaptive and less adaptive coping styles was related to self-reported lax
      discipline before and after parent training. Contrary to prediction, fathers who
      reported less seeking support and adaptive-focused coping showed the most
      improvement in their children's behavior. Most results remained significant after
      controlling for self-reported depression. Implications for improving parent
      training research and programs were discussed.

PMID- 15028551
TI  - Depression and anxiety in parents of children with ADHD and varying levels of
      oppositional defiant behaviors: modeling relationships with family functioning.
AB  - This study investigated the relation between parental anxiety and family
      functioning. Parental anxiety and depression, child attention deficit
      hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD) symptoms
      were all included as predictors of 3 measures of family functioning to examine
      the independent contributions of each. Using a self-report battery completed by
      45 mother-father pairs, 3 family functioning factors were derived: Parental
      Warmth and Positive Involvement, Intrusiveness and Negative Discipline, and
      Social Distress. Multilevel modeling simultaneously estimated the unique
      contributions of parental and child symptoms on family functioning. Results
      indicated that parental anxiety was negatively associated with Parental Warmth
      and Positive Involvement, Intrusiveness and Negative Discipline, and Social
      Distress; parental depression was only negatively associated with Social
      Distress. Child ODD symptoms had independent associations with all outcomes; no
      relations were found with ADHD. Sex moderated the effects of parental anxiety on
      Parental Warmth and Positive Involvement such that only for mothers did greater
      anxiety lead to less Parental Warmth and Positive Involvement.

PMID- 15028552
TI  - Empirical support for a treatment program for families of young children with
      externalizing problems.
AB  - We evaluated the efficacy of a manualized multimodal treatment program for young
      externalizing children. Families were assigned randomly to an immediate 12-week
      parent and child treatment condition (n = 24) or to a delayed-treatment condition
      (n = 23). Parents had high attendance, high satisfaction with treatment, and
      increased knowledge of behavior management principles. Relative to the waitlist
      condition, treatment parents reported statistically and clinically significant
      reductions in child behavior problems, improved parenting practices (i.e.,
      increased consistency, decreased power assertive techniques), an increased sense
      of efficacy, and reduced parenting stress. There was a trend toward parents
      improving their attitudes toward their children. In considering the process of
      change, we found evidence that improved parenting practices mediated reductions
      in child behavior problems and that child improvements mediated changes in parent
      attitudes and stress. Five months following treatment, teachers reported
      significant improvements in child behaviors, whereas parents reported that
      reductions in child behavior problems and parenting stress were maintained.

PMID- 15028553
TI  - Building relationships and combating bullying: effectiveness of a school-based
      social skills group intervention.
AB  - This study tested the efficacy of a generic social skills intervention, Social
      Skills GRoup INtervention (S.S.GRIN), for children experiencing peer dislike,
      bullying, or social anxiety. Third-grade children were randomly assigned to
      treatment (n = 187) or no-treatment control (CO; n = 194) groups. Examination of
      the direction and magnitude of change in functioning revealed that S.S.GRIN
      increased peer liking, enhanced self-esteem and self-efficacy, and decreased
      social anxiety compared to controls. S.S.GRIN was equally efficacious for all
      subtypes of peer problems targeted. Particular benefits were found for aggressive
      children who showed greater declines in aggression and bullying behavior and
      fewer antisocial affiliations than aggressive control participants. Discussion
      focuses on the benefits of heterogeneous versus homogeneous groups of
      participants and the potential value of utilizing generic social skills training
      protocols.

PMID- 15028554
TI  - A domain mimic increases DeltaF508 CFTR trafficking and restores cAMP-stimulated
      anion secretion in cystic fibrosis epithelia.
AB  - The major disease-causing mutation of the cystic fibrosis transmembrane
      conductance regulator (CFTR) is deletion of phenylalanine 508 (DeltaF508), which
      adversely affects processing and plasma membrane targeting of CFTR. Under
      conditions predicted to stabilize protein folding, DeltaF508 CFTR is capable of
      trafficking to the plasma membrane and retains cAMP-regulated anion channel
      activity. Overexpression is one factor that increases CFTR trafficking;
      therefore, we hypothesized that expression of a domain mimic of the first
      nucleotide-binding fold (NBF1) of CFTR, i.e., the site of F508, may be sufficient
      to overwhelm the quality control process or otherwise stabilize DeltaF508 CFTR
      and thereby restore cAMP-stimulated anion secretion. In epithelial cells
      expressing recombinant DeltaF508 human (h)CFTR, expression of wild-type NBF1
      increased the amount of both core-glycosylated and mature protein to a greater
      extent than expression of DeltaF508 NBF1. Expression of wild-type NBF1 in the
      DeltaF508 hCFTR cells increased whole cell Cl(-) current density to approximately
      50% of that in cells expressing wild-type hCFTR. Expression of NBF1 in polarized
      epithelial monolayers from a DeltaF508/DeltaF508 cystic fibrosis mouse (MGEF)
      restored cAMP-stimulated transepithelial anion secretion but not in monolayers
      from a CFTR-null mouse (MGEN). Restoration of anion secretion was sustained in
      NBF1-expressing MGEF for >30 passages, whereas MGEN corrected with hCFTR
      progressively lost anion secretion capability. We conclude that expression of a
      NBF1 domain mimic may be useful for correction of the DeltaF508 CFTR protein
      trafficking defect in cystic fibrosis epithelia.

PMID- 15028555
TI  - G1 cell cycle progression and the expression of G1 cyclins are regulated by
      PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells.
AB  - Ovarian cancer is one of the most common cancers among women. Recent studies
      demonstrated that the gene encoding the p110alpha catalytic subunit of
      phosphatidylinositol 3-kinase (PI3K) is frequently amplified in ovarian cancer
      cells. PI3K is involved in multiple cellular functions, including proliferation,
      differentiation, antiapoptosis, tumorigenesis, and angiogenesis. In this study,
      we demonstrate that the inhibition of PI3K activity by LY-294002 inhibited
      ovarian cancer cell proliferation and induced G(1) cell cycle arrest. This effect
      was accompanied by the decreased expression of G(1)-associated proteins,
      including cyclin D1, cyclin-dependent kinase (CDK) 4, CDC25A, and retinoblastoma
      phosphorylation at Ser(780), Ser(795), and Ser(807/811). Expression of CDK6 and
      beta-actin was not affected by LY-294002. Expression of the cyclin kinase
      inhibitor p16(INK4a) was induced by the PI3K inhibitor, whereas steady-state
      levels of p21(CIP1/WAF1) were decreased in the same experiment. The inhibition of
      PI3K activity also inhibited the phosphorylation of AKT and p70S6K1, but not
      extracellular regulated kinase 1/2. The G(1) cell cycle arrest induced by LY
      294002 was restored by the expression of active forms of AKT and p70S6K1 in the
      cells. Our study shows that PI3K transmits a mitogenic signal through AKT and
      mammalian target of rapamycin (mTOR) to p70S6K1. The mTOR inhibitor rapamycin had
      similar inhibitory effects on G(1) cell cycle progression and on the expression
      of cyclin D1, CDK4, CDC25A, and retinoblastoma phosphorylation. These results
      indicate that PI3K mediates G(1) progression and cyclin expression through
      activation of an AKT/mTOR/p70S6K1 signaling pathway in the ovarian cancer cells.

PMID- 15028556
TI  - Autoantibodies and thrombophilia in RA: TNFalpha and TNFalpha blockers.

PMID- 15028557
TI  - Serial lung function and responsiveness in cystic fibrosis during early
      childhood.
AB  - In a 4-year prospective study, we evaluated specific airway resistance (sRaw) by
      whole-body plethysmography, respiratory resistance by the interrupter technique,
      and respiratory resistance and reactance at 5 Hz by the impulse oscillation
      technique combined with measurement of responsiveness to bronchodilators and cold
      air in 30 children (mean [range] age 5.7 [2 to 8] years) with cystic fibrosis
      (CF). Spirometry was done at school age. Mean sRaw was consistently abnormal: the
      mean z score (SD) was 2.52 (2.02) (p < 0.001) at the start and was unchanged 36
      months later at 2.74 (2.02). Mean z score (SD) for FEV(1) at first satisfactory
      measurement, at a mean age (range) of 6.1 (4.9-7.5) years was -1.2 (1.2) and was
      further reduced to -1.85 (1.2) 4 years from inclusion at a mean age (range) of
      9.9 (6.8-12) years. Neither respiratory resistance by the interrupter technique
      nor the impulse oscillation technique demonstrated consistent abnormal levels.
      Patients with CF as a group did not differ from healthy subjects in
      responsiveness to bronchodilators and cold air. sRaw may be a useful tool in CF
      during early childhood. Reduced lung function was documented from consistently
      abnormal levels of sRaw and FEV1 during the study. Bronchodilator responsiveness
      and response to cold air challenge were normal.

PMID- 15028558
TI  - Progression of asthma measured by lung function in the childhood asthma
      management program.
AB  - From the Childhood Asthma Management Program cohort, which was randomly assigned
      to receive budesonide, nedocromil, or placebo for 4-6 years, we determined the
      prevalence of and factors associated with at least 1% per year loss in
      postbronchodilator FEV(1)% predicted. Participants who had a significant
      reduction in postbronchodilator FEV(1)% predicted (SRP), comprised 25.7% of the
      cohort (n = 990). Using logistic regression, predictors of SRP at baseline were
      younger age (p = 0.0005), male sex (p < 0.0001), clinic (p = 0.02), and higher
      postbronchodilator FEV(1)% predicted (p = 0.02). Examination of the SRPs
      indicated that the effect of baseline lung function was such that the higher the
      lung function, the less steep the reduction in postbronchodilator FEV(1)%
      predicted (p < 0.0001). A similar proportion of SRPs was found in each treatment
      group. Among the SRPs, the rate of reduction in postbronchodilator FEV(1)%
      predicted was similar in all treatment groups. At a single site where biomarker
      assessment was performed, SRPs also had more prominent eosinophilic inflammation
      during the washout period. The course and mechanisms of lung function reduction
      or slow lung growth velocity in children with asthma must be defined.

PMID- 15028559
TI  - Persistence of asthma symptoms during adolescence: role of obesity and age at the
      onset of puberty.
AB  - Little is known about rates and predictors of remission of childhood asthma after
      the onset of puberty. We used data collected at ages 6, 8, 11, 13, and 16 years
      from the Tucson Children's Respiratory Study, a population-based birth cohort.
      The onset of puberty was defined as the age of appearance of the first pubertal
      signs as reported by parents. Information on wheezing both before and after onset
      of puberty (mean +/- SD follow-up from onset of puberty, 4.2 +/- 1 year) was
      available for 781 children. Of these, 166 had asthma (either frequent wheezing or
      a physician-confirmed diagnosis plus any wheezing) in at least one survey before
      puberty. In this group, 58% of the children (97 of 166) reported the presence of
      wheezing after the onset of puberty (unremitting asthma). In contrast, only 30%
      (39 of 131) of the children with infrequent wheezing before puberty experienced
      wheezing episodes after the onset of puberty (unremitting wheezing). In addition
      to frequent wheezing before puberty, obesity, early onset of puberty, active
      sinusitis, and skin test sensitization were significant and independent
      predictors of unremitting asthma after the onset of puberty. Our findings from a
      population-based longitudinal cohort challenge the commonly held view that asthma
      usually remits during adolescence.

PMID- 15028560
TI  - Monocyte human leukocyte antigen-DR transcriptional downregulation by cortisol
      during septic shock.
AB  - Monocyte deactivation has been identified as a major factor of immunosuppression
      in sepsis and is associated with a loss of surface human leukocyte antigen-DR
      (HLA-DR) expression on circulating monocytes. Using flow cytometry, quantitative
      reverse transcription-polymerase chain reaction, we investigated this phenomenon
      in septic patients. We confirmed the early loss of monocyte HLA-DR expression in
      all infected patients and demonstrated that this persistent lowered expression at
      Day 6 correlated with severity scores, secondary infection, and death. This
      phenomenon occurred at a transcriptional level via a decrease in the class II
      transactivator A (CIITA) transcription. Furthermore, these abnormalities
      correlated with the high cortisol levels observed in sepsis and not with those of
      other putative factors such as catecholamines or interleukin-10. Finally, in
      vitro studies evidenced that glucocorticoids decrease HLA-DR expression at a
      transcriptional level via a decrease in CIITA mRNA levels, mainly by down
      modulating its isoforms I and III. We conclude that in human sepsis, the loss of
      HLA-DR expression on circulating monocytes is associated with a poor outcome. We
      suggest that the high endogenous cortisol level observed in septic shock may be a
      possible new factor involved in the loss of HLA-DR expression on monocytes via
      its effect on HLA-DR and CIITA transcription.

PMID- 15028561
TI  - Quality control for spirometry in preschool children with and without lung
      disease.
AB  - The reliability of spirometry is dependent on strict quality control. We examined
      whether quality control criteria recommended for adults could be applied to
      children aged 2-5 years. Forty-two children with cystic fibrosis and 37 healthy
      children attempted spirometry during their first visit to our laboratory. Whereas
      59 children (75%) were able to produce a technically satisfactory forced
      expiration lasting 0.5 second, only 46 (58%) could produce an expiration lasting
      1 second, with the youngest children having the most difficulty. Start of test
      criteria for adults were inappropriate for this age group, with only 16 of 59
      children producing a volume of back extrapolation as a proportion of forced vital
      capacity of less than 5%, whereas all but 4 could produce a volume of back
      extrapolation of 80 ml or less. More than 90% of children were able to produce a
      second forced vital capacity and a second forced expired volume in 0.75 second
      within 10% of their highest. Errors in the spirometry software resulted in
      inaccurate reporting of expiratory duration and inappropriate timed expired
      volumes in some children. We describe recommendations for modified start of test
      and repeatability criteria for this age group, and for improvements in software
      to facilitate better quality control.

PMID- 15028562
TI  - Effect of montelukast and fluticasone propionate on airway mucosal blood flow in
      asthma.
AB  - Asthma is associated with an increase in airway blood flow (Qaw), presumably as a
      manifestation of airway inflammation. We therefore determined the effect of the
      antiinflammatory agents montelukast (ML) and fluticasone propionate (FP) on Qaw
      in 12 patients with mild intermittent asthma. Using a double-blind approach, Qaw
      along with FEV(1) and Vmax(50) were determined before and after a 2-week
      treatment period with either ML (10 mg/day), FP (440 microg/day), or 10 mg of ML
      plus 440 microg of FP daily, separated by 2-week washout periods. Mean (+/- SEM)
      Qaw ranged from 68 +/- 4.2 to 71.8 +/- 5.9 microl x minute(-1) x ml(-1) anatomic
      dead space before the treatment periods. ML, FP, and ML plus FP decreased mean
      Qaw by 21.5, 20.8, and 26.9%, respectively (p < 0.05 for all). No significant
      difference was observed among the three regimens. FEV(1) and Vmax(50) were not
      changed by any of the treatments. We conclude that at the dosages used, ML and FP
      are equipotent in reducing Qaw in patients with mild asthma, and that the
      magnitude of the response is not greater if the two drugs are combined. The
      results also suggest that the vascular effects of these agents can be assessed
      independent of their effects on airway function.

PMID- 15028564
TI  - Agmatine and Imidazolines: Their Novel Receptors and Enzymes. Proceedings of the
      4th International Symposium on Agmatine and Imidazoline Systems. April 9-11,
      2003, San Diego, California, USA.

PMID- 15028565
TI  - Relevance of imidazoline receptors and agmatine to psychiatry: a decade of
      progress.
AB  - The cardiovascular relevance of imidazoline receptors (IR) has received
      tremendous attention since their discovery in 1984. However, evidence also has
      accumulated for the relevance of IR and an endogenous ligand, agmatine, to
      psychiatric disease. Emphasis has been placed on altered levels of the I(1)
      imidazoline site on human platelets and in human postmortem brain tissue from
      depressed patients. Attempts at exploring the molecular nature of the I(1)
      protein have led to the cloning of a protein, IRAS. Based on transfection
      studies, IRAS seems to be involved in neuronal plasticity events. The I(2) site
      also appears linked to psychiatric research since some of these sites are
      localized to a specific domain on monoamine oxidases. Different peptides have
      been identified by means of an imidazoline-receptor-binding-protein (IRBP)
      antiserum, and these peptides, some of which appear to be fragments derived from
      IRAS, undergo changes in platelets and brain commensurate with altered mood
      states of the subject, notably depressive symptomatology. The search for an
      endogenous ligand for imidazoline receptor(s) also has led to agmatine, a
      decarboxylated derivative of arginine. Research on agmatine has mushroomed over
      the past several years and its measurement in the blood and brain has opened new
      research opportunities. This novel neurotransmitter interacts with a variety of
      receptors and has been implicated in mediation of stress responses, analgesia,
      drug addiction and withdrawal, convulsions, and neuroprotection. Given that IR
      and agmatine appear involved in a multitude of neurophysiologic and pathologic
      functions, the potential for new drug development is intriguing.

PMID- 15028566
TI  - Regulation of inducible nitric oxide synthase and agmatine synthesis in
      macrophages and astrocytes.
AB  - Agmatine is a novel endogenous guanido amine synthesized from arginine by
      arginine decarboxylase. Among several biologic effects, the ability of agmatine
      to protect against ischemic injury and chronic neuropathic pain is particularly
      interesting. Because inflammation is a common contributor to these conditions, we
      sought to determine if agmatine acts by decreasing the production of
      proinflammatory molecules such as nitric oxide and if agmatine synthesis is
      regulated by inflammatory stimuli. We tested whether agmatine affects astroglial
      and macrophage (RAW 264.7 cell line) nitric oxide synthase-2 (NOS-2) expression.
      NOS-2 was induced in these cells by incubation with lipopolysaccharide (LPS) plus
      three cytokines for astrocytes and LPS alone for RAW 264.7 cells in the presence
      and absence of varying concentrations of agmatine. NOS-2 activity was assessed
      after 24 hours by nitrite accumulation in the culture media. Agmatine dose
      dependently inhibited nitrite accumulation, and shorter incubation with agmatine
      (1 and 4 hours) also caused significant reduction. Agmatine decreased the
      expression of NOS-2 activity and NOS-2 protein as determined by immunoblot
      analysis. Incubation of astrocytes and RAW 264.7 cells with LPS/cytokines for 2
      hours resulted in an increase in arginine decarboxylase (ADC) activity, whereas
      longer-term incubation (12-17 hours) lowered ADC activity. Agmatine levels in
      these cells are increased after 6-hour incubation with LPS/cytokines. These
      results show that agmatine inhibits the production of nitric oxide by decreasing
      the activity of NOS-2 in macrophages and astroglial cells by decreasing the
      levels of NOS-2 protein. These findings provide a molecular basis for the
      neuroprotective and anti-inflammatory actions of agmatine.

PMID- 15028567
TI  - Vertebrate agmatinases: what role do they play in agmatine catabolism?
AB  - Whereas agmatine in vertebrates may be derived from multiple sources such as the
      diet, endogenous synthesis via arginine decarboxylase, and possibly also from
      enteric bacteria, agmatinase is the only enzyme specific for agmatine catabolism.
      As it hydrolyzes a guanidino group within agmatine and also contains signature
      amino acid residues that act as ligand binding sites for the Mn(++) cofactor,
      agmatinase is classified as a member of the arginase superfamily. Very little
      information is available regarding how much agmatine in vertebrate species is
      catabolized by agmatinase versus other enzymes such as diamine and amine
      oxidases. Moreover, comparisons of primary sequences of several vertebrate
      agmatinases demonstrate that several residues essential for catalytic activity
      are not conserved in the mouse. This leads to the prediction that the agmatinase
      protein in mouse has little or no catalytic activity, not only raising questions
      about the physiologic routes of agmatine disposal in this organism, but also
      suggesting the existence of species-specific differences in mechanisms for
      regulating agmatine levels.

PMID- 15028568
TI  - Agmatine: at the crossroads of the arginine pathways.
AB  - In acute inflammatory responses, such as wound healing and glomerulonephritis,
      arginine is the precursor for production of the cytostatic molecule nitric oxide
      (NO) and the pro-proliferative polyamines. NO is an early phase response whereas
      increased generation of polyamines is requisite for the later, repair phase
      response. The temporal switch of arginine as a substrate for the inducible nitric
      oxide synthase (iNOS)/NO axis to arginase/ornithine decarboxylase (ODC)/polyamine
      axis is subject to regulation by inflammatory cytokines as well as
      interregulation by the arginine metabolites themselves. Herein we describe the
      capacity of another arginine pathway, the metabolism of arginine to agmatine by
      arginine decarboxylase (ADC), to aid in this interregulation. Agmatine is an
      antiproliferative molecule due to its suppressive effects on intracellular
      polyamine levels, whereas the aldehyde metabolite of agmatine is a potent
      inhibitor of iNOS. We propose that the catabolism of agmatine to its aldehyde
      metabolite may act as a gating mechanism at the transition from the iNOS/NO axis
      to the arginase/ODC/polyamine axis. Thus, agmatine has the potential to serve in
      the coordination of the early and repair phase pathways of arginine in
      inflammation.

PMID- 15028569
TI  - Gastrointestinal uptake of agmatine: distribution in tissues and organs and
      pathophysiologic relevance.
AB  - The authors report on (1) the absorption of agmatine from the gastrointestinal
      tract as an important source of this polycation in the organism, (2) its organ
      distribution, and (3) its putative role in liver regeneration. When rats received
      0.5 microCi [(14)C]agmatine contained in 5 grams of standard rat chow after a
      fasting period of 24 hours, radioactivity was recovered in all organs
      investigated, in blood, and in urine. In the liver 67% +/- 7% of administered
      radioactivity was found. After partial (two-thirds) hepatectomy, administration
      of 250 mg and 500 mg agmatine by gavage for 6 days reduced liver regeneration at
      day 7 by 20% and 22%, respectively, compared with animals that received no
      agmatine. Agmatine is absorbed from the gastrointestinal tract, probably by means
      of a specific transporter. It is likely that agmatine in the chyme of the gut
      represents an essential source of agmatine in the tissues of the organism. An
      increase in the availability of gastrointestinal agmatine for absorption impairs
      liver regeneration and may contribute to the development of liver diseases.

PMID- 15028570
TI  - Structure-activity analysis of guanidine group in agmatine for brain agmatinase.
AB  - To identify a selective inhibitor of mammalian agmatinase, screening was
      performed on four analogues of agmatine with modifications directly to the
      guanidine group, six analogues with modifications to the carbon-amine chain, and
      one analogue with modifications at both ends of the molecule. Control compounds
      were aminoguanidine and 7-nitroindazole, known inhibitors of the three isoforms
      (i, e, n) of nitric oxide synthase (NOS), and arcaine, a known inhibitor of the
      glutamate NMDA receptor. These compounds were compared for inhibition of rat
      agmatinase and arginine decarboxylase (ADC) activities. Results were studied by
      ab initio Hartee-Fock descriptors based on optimized geometries and van der Waals
      radii. Linear correlations were obtained using various geometric and electronic
      descriptors of the carbon (C), nitrogen (N), and hydrogen (H) atoms in the
      guanidine moiety. The best fit equation for percent activity remaining of rat
      agmatinase was = 0.3225 D + 72.76 D1916 + 64.97 D1920 - 192.58 H21 - 253.09 (r =
      0.89), where D is the calculated dipole moment, D1916 and D1920 are the N19-N16
      and N19-N20 distances, respectively, and H21 is the charge on H21. This
      agmatinase equation is distinct from the equations fit for ADC, the three NOS
      isoforms, and inhibition of NMDA receptor binding.

PMID- 15028571
TI  - Agmatine crosses the blood-brain barrier.
AB  - The question of whether agmatine crosses the blood-brain barrier has not been
      directly addressed, even though peripheral injection of this compound has
      produced behavioral responses in drug withdrawal, antidepressant, and anti
      anxiety paradigms. Two models were used in this investigation. In the first, mice
      were injected intraperitoneally (i.p.) with agmatine (10, 50, or 300 mg/kg body
      weight) or arginine (600 mg/kg). After 1 or 3 hours, the animals were killed
      under gas anesthesia by perfusing their brains with ice-cold saline, and whole
      brain agmatine was measured by HPLC. In parallel studies, a rhesus monkey was
      injected under gas anesthesia either intravenously (i.v.) with agmatine (30
      mg/kg) or arginine (150 mg/kg), or intracerebroventricularly (i.c.v.) with
      agmatine (0.3 mg/kg i.c.v.). At varying times thereafter, cisterna magna
      cerebrospinal fluid (CSF) and blood plasma were collected and analyzed for
      agmatine levels. A rise in mouse brain agmatine was apparent after doses of 50
      and 300 mg/kg i.p. Monkey CSF agmatine peaked in parallel with plasma agmatine 15
      minutes following intravenous (i.v.) agmatine injection and at one sixth the
      level of the plasma peak. Monkey CSF agmatine peaked 43 minutes after i.v.
      arginine injection. The ventricular injection of agmatine resulted in a threefold
      sustained rise in blood plasma agmatine for at least 24 hours after injection.
      Therefore, agmatine and its precursor, arginine, cross the blood-brain barrier.
      CSF agmatine may be newly synthesized from peripherally injected arginine.

PMID- 15028572
TI  - Identification and pharmacological characterization of a specific agmatine
      transport system in human tumor cell lines.
AB  - Specific accumulation of [(14C)]agmatine in six human intestinal tumor cell lines
      and in the glioma cell line SK-MG-1 was inhibited by phentolamine, idazoxan,
      clonidine, 1,3-di-(2-tolyl)guanidine, histamine, putrescine, spermine and
      spermidine. Corticosterone, desipramine, O-methylisoprenaline, cirazoline,
      moxonidine, l-arginine, l-lysine, verapamil, nifedipine, CdCl(2), ondansetron,
      and l-carnitine failed to inhibit specific [(14)C]agmatine accumulation, thus
      excluding that it is mediated by amino acid or monoamine carriers, by the
      putrescine carrier, by 5-HT(3) receptor channels, by Ca(2+) channels or by the
      organic cation transporters OCT1, OCT2, OCT3, OCTN1, or OCTN2. This conclusion is
      supported by the finding that transfection of HEK293 cells with cDNA encoding
      either hOCT1, hOCT2, or hOCT3 did not enhance specific [(14)C]agmatine
      accumulation compared to nontransfected cells. The data suggest that agmatine is
      accumulated by a specific agmatine transporter. Since incubation with exogenous
      agmatine for 24 hours increased intracellular agmatine content in all cell lines
      by a multiple of the basal endogenous content, the agmatine uptake system may be
      relevant for the regulation of the intra- and extracellular concentration of
      agmatine in humans.

PMID- 15028574
TI  - Effect of agmatine on acute and mononeuropathic pain.
AB  - Agmatine is a polycationic amine synthesized from L-arginine by arginine
      decarboxylase in brain and several tissues. It binds to N-methyl-D-aspartate
      (NMDA) subtype of glutamatergic, alpha(2)-adrenergic and imidazoline (I)
      receptors. The present study was designed to investigate effect of agmatine on
      acute and mononeuropathic pain after chronic constriction injury (CCI). CCI was
      created by four loose ligations around the right sciatic nerve. The analgesic
      threshold in rats was evaluated by using thermal hyperalgesia/allodynia (THA) at
      4 degrees C. The evaluations were made preoperatively, on postoperative day 15,
      and after drug administration. Agmatine (10, 20, 40, 80, and 100 mg/kg) was
      administered intraperitoneally for 5 days beginning on postoperative day 15.
      Agmatine significantly reduced the hyperalgesia in all doses applied. When
      agmatine was injected intraperitoneally (10, 20, 40, 80, and 100 mg/kg), it
      increased the nociceptive threshold in the tail-immersion test in a dose
      dependent manner, but it had no effect in the hot-plate test. This effect of
      agmatine in the tail-immersion test was blocked by both yohimbine (1 mg/kg) and
      idazoxan (0.5 mg/kg). When agmatine was administered intracerebroventricularly
      (25-200 microg/10 microL), it increased the nociceptive threshold in the hot
      plate but not in the tail-immersion test. We conclude that agmatine, an
      endogenous substance derived from arginine, can modulate both acute and chronic
      pain.

PMID- 15028573
TI  - Neuropharmacokinetic and dynamic studies of agmatine (decarboxylated arginine).
AB  - Agmatine has been previously proposed to represent a novel neurotransmitter. One
      of the criteria required to test that hypothesis is that the exogenously
      administered chemical produces pharmacological effects similar to the
      physiological effects of the putative neurotransmitter. Since agmatine was first
      identified in brain, approximately sixty studies of the in vivo effects of
      exogenously administered agmatine have been reported. Despite the assertion that
      agmatine functions as a neuromodulator/neurotransmitter, the vast majority of
      experiments have administered agmatine through systemic (rather than central)
      routes of administration. Systemic delivery of agmatine for studies of centrally
      mediated phenomenon (e.g., pain, spinal cord injury, cardiovascular responses)
      relies on the presumption that agmatine (a polar compound) gains appreciable
      access to the CNS. The mechanism by which agmatine crosses the blood-brain
      barrier is not well understood. A number of studies have examined the in vivo
      effects of agmatine following central administration (e.g.,
      intracerebroventricular and intrathecal). This paper summarizes and provides a
      comparison between the systemic versus central routes of administration for
      delivery of agmatine in experimental subjects.

PMID- 15028575
TI  - Spinal and supraspinal agmatine activate different receptors to enhance spinal
      morphine antinociception.
AB  - The endogenous clonidine-displacing substance, agmatine, enhances morphine
      induced antinociception and inhibits development of tolerance to morphine.
      Because agmatine binds with relatively high affinity to both alpha(2) adrenergic
      and imidazoline (I) receptors, the following studies were designed to determine
      which receptor type is involved in the morphine-enhancing activity. Mice were
      injected by various routes with agmatine, clonidine or norepinephrine as well as
      selective antagonists, and tail flick antinociception was measured. Agmatine
      administered subcutaneously (s.c.), intracerebroventricularly (i.c.v.), or
      intrathecally (i.t.) had no antinociceptive activity, but enhanced the
      antinociception produced by i.t. morphine. The morphine-enhancing activity of
      i.c.v. agmatine (and clonidine) was attenuated by coadministered yohimbine,
      idazoxan and SK and F 86466 (alpha(2) antagonists). When given i.t., agmatine,
      yohimbine and SK and F 86466 attenuated the antinociception produced by
      coadministered i.t. clonidine. In contrast, i.t. yohimbine and SK and F 86466,
      but not agmatine, attenuated antinociception produced by i.t. norepinephrine.
      These results suggested that agmatine actions were different at brain and spinal
      sites. Thus, agmatine may act at both alpha(2) and I receptors in the brain and I
      receptors in the spinal cord.

PMID- 15028576
TI  - Is agmatine an endogenous factor against stress?
AB  - Agmatine is an endogenous amine synthesized from the decarboxylation of arginine.
      A proposed intracellular role of agmatine is to balance the production of
      polyamines (a promitotic process) and nitric oxide (an inflammatory process).
      Agmatine is also released from neurons upon depolarization. We previously
      reported that agmatine concentrations are increased in rat pups' brains shortly
      after hypoxic-ischemia and in the plasma of depressed patients. Herein, male rats
      (270-290 g) were divided into four groups receiving different degrees of known
      stress: 2-hour restraint at 21 degrees C, 4-hour restraint at 21 degrees C, 4
      hour restraint at 4 degrees C, and control rats only handled at 21 degrees C.
      Cortex, cerebellum, medulla, hippocampus, hypothalamus, and blood plasma samples
      were collected for determination of endogenous agmatine levels. No changes in
      agmatine levels were detected after 2-hour and 4-hour restraint at room
      temperature, but concentrations of agmatine were increased in all brain regions
      except cerebellum after 4-hour restraint in the cold. Plasma agmatine levels
      (ng/mL) were 6.8 +/- 0.6 in controls versus 58.1 +/- 12.8 in the 4-hour restraint
      plus-cold group. Cortical agmatine levels (ng/g wet tissue) were 15.3 +/- 2.4 in
      controls versus 57.4 +/- 19.6 in the 4-hour restraint-plus-cold group. Therefore,
      endogenous agmatine was increased in response to cold-restraint stress, possibly
      as a neuroprotective agent.

PMID- 15028577
TI  - Agmatine-morphine interaction on nociception in mice.
AB  - The aim of this study was to investigate the possible participation of nitric
      oxide in the agmatine-mediated potentiation of morphine-induced analgesia in
      mice. Agmatine and L-NAME (a nitric oxide synthesis inhibitor) enhanced morphine
      induced analgesia in the tail flick test, but not in the hot plate test. L-NAME
      did not block the agmatine-induced potentiation of morphine effect. Our results
      indicate that agmatine potentiates morphine-induced spinal but not supraspinal
      analgesia, and that this effect is not mediated by a nitric oxide-dependent
      mechanism.

PMID- 15028578
TI  - Is agmatine an endogenous anxiolytic/antidepressant agent?
AB  - Agmatine, an endogenous cationic amine, exerts a wide range of biologic effects,
      but its physiologic role is still to be determined. The aim of the present
      experiments was to investigate the role of agmatine in anxiety and depression.
      The forced swim test (FST) and the elevated plus maze (EPM) were used to
      determine the antidepressant and anxiolytic effects of agmatine in comparison
      with imipramine (30 mg/kg i.p.). Agmatine (10, 20, 40, 80, or 100 mg/kg, i.p.),
      saline, or imipramine was given 30 minutes before the tests. Agmatine decreased
      immobility time in the FST and increased the time spent in the open arms in the
      EPM, as compared with the saline group. As an endogenous substance, agmatine have
      modulatory effect on anxiety and depression.

PMID- 15028579
TI  - Effect of agmatine on electrically and chemically induced seizures in mice.
AB  - Agmatine, an amine and organic cation, is formed by the decarboxylation of L
      arginine by arginine decarboxylase. It binds to alpha(2)-adrenergic and
      imidazoline receptors. It blocks N-methyl-D-aspartate (NMDA) subtype of glutamate
      receptors and inhibits nitric oxide (NO) synthase. Because the importance of NMDA
      receptors and the NO system are well known in seizure activity, this study was
      designed to investigate the effect of agmatine on electrically and chemically
      induced seizures by using maximal electroshock (MES) and pentilentetrazole (PTZ)
      models in mice. Initial studies established convulsive current 50 (CC(50)) for
      MES and effective dose 50 (ED(50)) for PTZ to produce seizures. Agmatine (20, 40,
      80, and 100 mg/kg intraperitoneally) increased the threshold of seizures in MES
      dose dependently. In PTZ-induced convulsions, the highest dose of agmatine (100
      mg/kg) increased the seizure onset time and decreased percent survival. The
      percentage of grade V seizures was found to be increased by agmatine doses
      greater than 20 mg/kg.

PMID- 15028580
TI  - Agmatine inhibits naloxone-induced contractions in morphine-dependent Guinea pig
      ileum.
AB  - This study investigates the effects of agmatine on naloxone-precipitated
      withdrawal syndrome in morphine-dependent guinea pig ileum. Male guinea pigs that
      were starved for 24 hours were decapitated after cervical dislocation, and
      terminal portions of the ilea were removed. Segments were fixed at a resting
      tension of 1 g in an organ bath containing 1 x 10(-6) M morphine in Tyrode
      solution at 37 degrees C, which was bubbled with 95% O(2) and 5% CO(2). Tissues
      were incubated in morphine containing Tyrode solution for 4 hours before agmatine
      was added. Naloxone and agmatine had no effect on naive ilea. Naloxone (1 x 10(
      6) M) contracted morphine-dependent ilea. Agmatine significantly inhibited the
      contractile response to naloxone in a dose-dependent manner (1 x 10(-7) M, 44%; 1
      x 10(-6) M, 80%; 1 x 10(-5) M, 95%). This effect of agmatine was partly abolished
      by pretreatment with yohimbine and was almost completely abolished by idazoxan.

PMID- 15028581
TI  - Effect of agmatine on the time course of brain inflammatory cytokines after
      injury in rat pups.
AB  - Pro-inflammatory cytokines play an important role in brain injury. Agmatine
      reduces brain injury. Does agmatine act by reducing cytokines? Seven-day-old rat
      pups had the right carotid artery ligated and then were subjected to 2.5 hours of
      8% oxygen. Agmatine (100 mg/kg) or vehicle was administered at 5 minutes after
      reoxygenation. Cytokines were measured in the cortex by enzyme-linked
      immunosorbent assay. Interleukin (IL)-6, IL-1b, and tumor necrosis factor-alpha
      (TNF-alpha) were significantly increased after reoxygenation. Agmatine had no
      effect.

PMID- 15028583
TI  - Comparative effects of efaroxan and beta-carbolines on the secretory activity of
      rodent and human beta cells.
AB  - The pancreatic beta-cell expresses an imidazoline-binding site that is involved
      in the regulation of insulin secretion. This site is pharmacologically atypical
      in comparison with the I(1) and I(2) sites described in other tissues, and it has
      been classified as I(3). The structural requirements for binding of ligands to
      the I(3) site have not been fully defined, although a range of synthetic I(3)
      ligands have been characterized in functional terms. Evidence has been presented
      that an endogenous I(3) ligand may exist, because extracts of brain contain an
      active principle that stimulates insulin secretion in a manner consistent with
      the involvement of I(3) sites. The active component has not been identified but
      has been equated with the long-sought clonidine displacing substance (CDS) that
      is proposed as the endogenous ligand for imidazoline-binding sites. Recent
      evidence has indicated that one active component of CDS may be a beta-carboline,
      but it is not known whether beta-carbolines can stimulate insulin secretion.
      Thus, we have studied the effects of beta-carbolines on insulin secretion and
      cytosolic Ca(2+) levels in rodent and human islet cells. The results reveal that
      harmane, pinoline, and norharmane cause a dose- and glucose-dependent increase in
      insulin secretion but show that this response differs in a number of ways from
      that elicited by the well-characterized I(3)-agonist, efaroxan. Thus, beta
      carbolines represent a new class of insulin secretagogues, although it remains
      unclear whether their action is mediated solely by I(3) sites in the beta cell.

PMID- 15028582
TI  - Endogenous beta-carbolines as clonidine-displacing substances.
AB  - Endogenous beta-carbolines, such as harmane, are known to occur in mammalian
      species including humans. Radioligand binding studies have revealed that certain
      beta-carbolines display high affinity for both I(1) and I(2) imidazoline-binding
      sites (IBS). Functional studies have shown that the beta-carboline harmane
      elicits many characteristics expected of an endogenous ligand IBS. This article
      discusses the evidence relating to beta-carbolines as endogenous ligands and
      presents a case for harmane and related compounds as endogenous ligands for IBS.

PMID- 15028584
TI  - Characterization of [(3)H]harmane binding to rat whole brain membranes.
AB  - This study investigates the binding of [(3)H]harmane to rat whole brain
      homogenates. Saturation studies revealed [(3)H]harmane labels a single,
      saturable, high-capacity population with high affinity. All the test compounds
      displaced [(3)H]harmane completely and in an apparently monophasic manner. The
      displacement profile of the test ligands indicated labeling of MAO-A. Given the
      high level of MAO-A binding, it is unlikely that a low-capacity I(2) site would
      be distinguishable from the total [(3)H]harmane population.

PMID- 15028585
TI  - Effect of harmane on mononeuropathic pain in rats.
AB  - This study was designed to investigate the effect of the endogenous beta
      carboline, harmane, on neuropathic pain produced by chronic constriction injury
      (CCI) of the sciatic nerve. Thermal allodynia evaluations were made
      preoperatively, postoperatively on the fifteenth day, and after harmane
      administration. Harmane (1, 2.5, 5, 10, or 20 mg/kg) was administered
      intraperitoneally for 5 days beginning from postoperative day 15. Treatment with
      harmane had a profound anti-allodynic effect in a dose-dependent manner. In
      conclusion, harmane might provide a new approach to treatment of neuropathic
      pain.

PMID- 15028586
TI  - Inhibitory effect of harmane on morphine-dependent Guinea pig ileum.
AB  - Studies on the occurrence and properties of b-carbolines structurally related to
      harmala alkaloids have gained attention since it was hypothesized that some of
      these compounds play a role in processes of substance abuse and dependence. This
      study investigates the effects of harmane on naloxone-precipitated withdrawal
      syndrome in morphine-dependent guinea pig ileum. Segments of ilea from starved
      male guinea pigs were obtained and fixed at a resting tension of 1 g in an organ
      bath containing 10(-6) M morphine in Tyrode solution at 37 degrees C, which was
      bubbled with 95% O(2) and 5% CO(2). Tissues were incubated in 10(-6) M morphine
      containing Tyrode solution for 4 hours before harmane was added. Naloxone and
      harmane had no effect on naive ilea. Naloxone (10(-6) M) contracted morphine
      dependent ilea. Harmane significantly inhibited the contractile response to
      naloxone in a dose-dependent manner (10(-7) M = 24%; 10(-6) M = 49.3%; 10(-5) =
      70%). These results suggest that harmane may have beneficial effects on morphine
      withdrawal syndrome.

PMID- 15028587
TI  - Effect of harmane on the convulsive threshold in epilepsy models in mice.
AB  - The study investigated the activity of harmane on maximal electroshock seizures
      (MES) and seizures induced by pentilentetrazole (PTZ) in mice. Initial studies
      established convulsive current 50 (CC(50)) values or MES and effective dose 50
      (ED(50)) for PTZ to produce seizures. Harmane (2.5, 5.0, or 10 mg/kg
      intraperitoneally) increased the threshold of seizures in MES dose-dependently.
      The convulsions produced by PTZ were decreased by the low dose of harmane (2.5
      mg/kg), but the high dose of harmane (10 mg/kg) resulted in worse grade V
      convulsions followed by more lethality compared with PTZ alone. Therefore,
      harmane seems to be protective against grand mal seizures in the MES model but
      not against a petit mal seizure model (PTZ) in mice.

PMID- 15028588
TI  - Harmane induces anxiolysis and antidepressant-like effects in rats.
AB  - A forced swim test (FST) and an elevated plus maze (EPM) were used to determine
      antidepressant and anxiolytic effects of harmane in rats in comparison with a
      known antidepressant, imipramine (30 mg/kg i.p.). Harmane (2.5, 5.0, or 10 mg/kg,
      i.p.), saline, or imipramine were given 30 minutes before the tests.
      Administration of harmane decreased the time of immobility in the FST dose
      dependently and increased the time spent in open arms in the EPM, as compared
      with the saline group. As an endogenous substance, harmane therefore has anti
      anxiety and antidepressant effects.

PMID- 15028589
TI  - No evidence for activation of alpha(2)-adrenoceptors by methanolic extracts of
      bovine brain and lung containing clonidine-displacing substance.
AB  - Methanolic extracts of bovine brain and lung are capable of displacing [(3)H]
      clonidine from alpha(2)-adrenoceptor binding sites, indicating the presence of a
      clonidine-displacing substance (CDS). We have examined alpha(2)-adrenergic
      responses and the extracts in three models: [(3)H]-cyclic AMP accumulation in
      miniprisms of guinea pig cerebral cortex, isometric tension measurements of
      isolated segments of the rat vas deferens, and porcine palmar lateral vein. The
      selective alpha(2)-adrenoceptor agonist, 5-bromo-6-2-imidazolin-2-ylamino]
      quinoxaline bitartrate (UK-14304) inhibited forskolin-stimulated [(3)H]-cyclic
      AMP accumulation in the cerebral cortex and elicited contractions of the porcine
      isolated palmar lateral vein. Clonidine (0.1-30 nM) inhibited neurogenic
      contractions of the rat vas deferens. Responses to both agonists were inhibited
      by the alpha(2)-adrenoceptor antagonists, idazoxan or rauwolscine. Brain CDS (5
      units/mL) reduced forskolin-stimulated [(3)H]-cyclic AMP accumulation in the
      guinea pig cerebral cortex, whereas lung CDS (1 unit/mL) increased the
      accumulation of the cyclic nucleotide. Neither response to the extracts was
      inhibited by 1 microM idazoxan. Low concentrations of both extracts (0.05
      unit/mL) reduced electrically evoked contractions of the rat vas deferens by
      approximately 20%, but higher concentrations enhanced neurogenic contractions by
      approximately 50%. Again, the effect of the brain extract was not altered by 1
      microM idazoxan. Lung CDS (0.02-1 unit/mL) induced contractions of the porcine
      palmar lateral vein that were also insensitive to rauwolscine. The results
      suggest that brain and lung CDS do not activate either central or peripheral
      alpha(2)-adrenoceptors.

PMID- 15028590
TI  - Complex interaction of alpha(2)-adrenoceptor binding sites with bovine brain and
      lung extracts containing clonidine-displacing substance.
AB  - Previous studies have established that methanolic extracts of bovine brain and
      lung possess CDS activity with an agonist-like profile at alpha(2)-adrenoceptor
      binding sites (i.e., greater potency against [(3)H]-clonidine sites than against
      [(3)H]-RX-821001 sites). Following prolonged reflux in ethylacetate, monovalent
      cations and histamine were removed from the lung extract, and the resulting
      extract exhibited similar potency against both radioligands, indicative of an
      antagonist-like profile. These observations help explain the absence of biologic
      activity at alpha(2)-adrenoceptors in the methanolic extracts as reported in our
      companion paper.

PMID- 15028591
TI  - Endogenous imidazoline receptor ligands relax rat aorta by an endothelium
      dependent mechanism.
AB  - Agmatine and harmane have been proposed as endogenous ligands of imidazoline
      receptors. Agmatine has been reported to activate nitric oxide synthetase (NOS)
      in endothelial cells, so we sought to determine if agmatine or harmane and an
      analogue of harmane, propyl harmane, produced vasodilatation through an
      endothelium-dependent mechanism. The experiments were performed in endothelium
      denuded and intact rat aortic rings preconstricted with phenylephrine (0.1
      microM). Agmatine (0.3-1000 microM), harmane, and propyl harmane (0.3-100 microM)
      relaxed endothelium-intact rings in a concentration-dependent manner. Removal of
      endothelium inhibited the relaxant effect of agmatine, harmane, and propyl
      harmane. The NOS inhibitor L-NIO (100 microM) inhibited the relaxant effect of
      agmatine and harmane. The I(1)-receptor antagonist AGN (100 microM) partly
      inhibited the effect of harmane but not that of agmatine. These results suggest
      that the endogenous imidazoline ligands are capable of stimulating NOS largely by
      an I(1)-receptor-independent mechanism.

PMID- 15028593
TI  - Are centrally acting imidazoline agents appropriate therapy for renovascular
      hypertension?
AB  - An increased role of the sympathetic nervous system has been suggested to be a
      major contributor to the chronic elevation of BP in renovascular hypertension. We
      assessed the effects of rilmenidine, a centrally acting antihypertensive
      imidazoline agent, on BP and renal sympathetic nerve activity (RSNA) in 2K1C
      renovascular hypertensive conscious rabbits. Rabbits were made hypertensive with
      a renal clip or were sham-operated and were studied 3 and 6 weeks later. Acute
      treatment with rilmenidine reduced BP to a greater extent in the hypertensive
      rabbits. Although rilmenidine reduced the heart rate by the same extent in all
      groups, rilmenidine produced much less inhibition of RSNA in the hypertensive
      animals. These studies suggest that the contribution of the sympathetic nervous
      system is greater in 2K1C hypertension and that imidazoline agents may be
      beneficial in treating renovascular hypertension.

PMID- 15028592
TI  - I(1) imidazoline receptors involved in cardiovascular regulation: where are we
      and where are we going?
AB  - Clonidine-like drugs (hybrid drugs) reduce blood pressure by acting centrally at
      both alpha(2)-adrenergic receptors (alpha(2)AR) and I(1) receptors (I(1)R). Some
      attempts at cloning I(1)R have failed, probably because of the lack of
      selectivity of the ligands. Recently, compounds acting exclusively at I(1)R were
      synthesized: LNP 911, LNP509, and S23515. For example, LNP911 has a K(d) value of
      1.7 nmol/L at I(1)R. LNP509 and S23515 reduce blood pressure when injected
      centrally in anesthetized animals, whereas S23757 behaves as an antagonist of
      hypotensive imidazolines. LNP509 reduces blood pressure even in genetically
      engineered mice lacking functional alpha(2)AR. An exclusive action at central
      I(1)R is therefore sufficient to modify blood pressure. With the help of drugs
      selective for I(1)R and alpha-methylnoradrenaline, selective for alpha(2)AR, we
      showed that imidazoline and alpha(2)-adrenergic mechanisms interact
      synergistically in controlling the blood pressure. Such a synergism may explain
      the very powerful hypotensive effects of hybrid drugs. The new ligands selective
      for I(1)R will be very helpful to investigate the molecular features and the
      signaling system of I(1)R.

PMID- 15028594
TI  - Cardiac effects of moxonidine in spontaneously hypertensive obese rats.
AB  - Moxonidine, an imidazoline receptor agonist that acts centrally to inhibit
      sympathetic activity, has been shown to reduce effectively blood pressure,
      fasting insulin levels, and free fatty acids. In this study, we investigated the
      long-term effects of moxonidine treatment on cardiac natriuretic peptides (ANP
      and BNP) in Spontaneously Hypertensive Obese Rats (SHROBs), a rat model that
      resembles human Syndrome X. SHROBs expressing spontaneous hypertension, insulin
      resistance, and genetic obesity (weight 590 +/- 20 g, at 30 weeks) received
      moxonidine in chow at 4 mg/kg/day for 15 days. Moxonidine significantly reduced
      not only systolic blood pressure (187 +/- 6 versus 156 +/- 5 mm Hg, P < 0.05) but
      also plasma ANP (1595 +/- 371 versus 793 +/- 131 pg/mL, P < 0.05) and BNP (22 +/-
      3 versus 14 +/- 1 pg/mL, P < 0.04), without influencing cardiac content of either
      peptide. Semi-quantitative PCR revealed that atrial ANPmRNA/GAPDHmRNA decreased
      to 39% 6 10% of pair-fed controls, P < 0.03. In left ventricles, moxonidine also
      decreased ANP mRNA to 69% +/- 7% and BNP mRNA to 74% +/- 6% of control, P < 0.02,
      but right ventricular ANP and BNP mRNA were not affected. These findings indicate
      that chronic inhibition of sympathetic activity with moxonidine in SHROB is
      associated with decreased ventricular natriuretic peptide transcription,
      consistent with the cardioprotective effects of moxonidine given the role of ANP
      and BNP as markers of cadiac disease. Moxonidine also improves the metabolic
      profile in these rats, thus it may be considered the drug of choice in treatment
      of metabolic syndrome X.

PMID- 15028595
TI  - The role of I(1)-imidazoline receptors and alpha(2)-adrenergic receptors in the
      modulation of glucose and lipid metabolism in the SHROB model of metabolic
      syndrome X.
AB  - Hypertension is commonly accompanied by obesity, hyperlipidemia, and insulin
      resistance in humans, a cluster of abnormalities known as metabolic syndrome X.
      With the notable exception of inhibitors of the renin-angiotensin system, which
      have mildly beneficial effects on insulin resistance, most antihypertensive
      agents worsen one or more components of metabolic syndrome X. Second-generation
      centrally acting antihypertensive agents such as rilmenidine and moxonidine have
      mixed effects on components of metabolic syndrome X, which might reflect in part
      actions on two different receptors: I(1)-imidazoline and alpha(2)-adrenergic.
      Using a rat model of metabolic syndrome X, we sought to separate the influence of
      these two receptors on glucose and lipid metabolism by using selective
      antagonists. Rilmenidine and moxonidine acutely raised glucose and lowered
      insulin, thereby further worsening glucose tolerance. These effects were entirely
      mediated by alpha(2)-adrenergic receptors. Rilmenidine and moxonidine also
      lowered glucagon, an effect that was mediated solely by I(1)-imidazoline
      receptors since it was potentiated by alpha(2)-blockade, but eliminated in the
      presence of I(1)-antagonists. Lowering of triglyceride and cholesterol levels
      followed the same pattern as glucagon, implicating I(1)-imidazoline receptors in
      lipid-lowering actions. Chronic treatment with moxonidine reproduced the
      beneficial effects on glucagon and lipids while the acute hyperglycemic response
      did not persist. Thus, alpha(2)-adrenergic receptors mediate an acute
      deterioration of glucose tolerance, whereas in contrast I(1)-imidazoline
      receptors appear to mediate the persistent long-term improvements in glucose
      tolerance. The therapeutic action of I(1)-imidazoline agonists may be primarily
      mediated through reduced glucagon secretion.

PMID- 15028596
TI  - Involvement of forebrain imidazoline and alpha(2)-adrenergic receptors in the
      antidipsogenic response to moxonidine.
AB  - We investigated the participation of central alpha(2)-adrenoceptors and
      imidazoline receptors in the inhibition of water deprivation-induced water intake
      in rats. The alpha(2)-adrenoceptor and imidazoline antagonist idazoxan (320
      nmol), but not the alpha(2)-adrenoceptor antagonist yohimbine, abolished the
      antidipsogenic effect of moxonidine (alpha(2)-adrenoceptor and imidazoline
      agonist, 20 nmol) microinjected into the medial septal area. Yohimbine abolished
      the antidipsogenic effect of moxonidine intracerebroventricularly. Therefore,
      central moxonidine may inhibit water intake acting independently on both
      imidazoline receptors and alpha(2)-adrenoceptors at different forebrain sites.

PMID- 15028597
TI  - Moxonidine displays a presynaptic alpha-2-adrenoceptor-dependent synergistic
      sympathoinhibitory action at imidazoline-1 receptors.
AB  - The function of presynaptic imidazoline-1 receptors (I1-R) in the heart remains
      unclear. In rat hearts, UK14.304 and moxonidine reduced norepinephrine (NE)
      release. AGN192403 had no influence on NE, whereas rilmenidine, agmatine,
      rauwolscine, and efaroxan increased NE. These effects of moxonidine and
      rilmenidine were not affected by AGN192403 adminstration. Conversely, after
      pretreatment with UK14.304, only moxonidine displayed a pronounced inhibitory
      action on NE release (sensitive to AGN192403), indicating a synergistic
      inhibitory action at I1-R under conditions of a stimulated alpha2-adrenergic
      autoinhibition.

PMID- 15028598
TI  - Norepinephrine release is reduced by I(1)-receptors in addition to alpha(2)
      adrenoceptors.
AB  - In pithed spontaneous hypertensive rats, noradrenaline overflow was diminished by
      moxonidine even when alpha(2)-adrenoceptors were blocked quantitatively using
      phenoxybenzamine, suggesting an I(1)-receptor-mediated mechanism of noradrenaline
      release. This hypothesis was confirmed, since the noradrenaline overflow was (1)
      increased under alpha(2)-adrenoceptors blockade by the mixed I(1)/alpha(2)
      antagonists efaroxan or idazoxan, (2) still reduced by moxonidine when both
      alpha(2)- and I(1)-receptors were blocked, and (3) diminished by agmatine after
      pretreatment with phenoxybenzamine, but not with AGN192403. An indirect
      ganglionic I(1)-receptor-mediated mechanism of noradrenaline release is supposed.

PMID- 15028599
TI  - Normalization of up-regulated cardiac imidazoline I(1)-receptors and natriuretic
      peptides by chronic treatment with moxonidine in spontaneously hypertensive rats.
AB  - The effect of treatment with moxonidine (120 mg/kg/h sc, 4 weeks) on cardiac I(1)
      receptors and natriuretic peptide synthesis was evaluated in spontaneously
      hypertensive rats (SHR). I(1)-receptor protein (85 kD) was up-regulated in SHR
      atria, and normalized in right and left atria by moxonidine. Similarly,
      moxonidine normalized atrial and ventricular atrial natriuretic peptide messenger
      RNA (mRNA) and brain natriuretic peptide mRNA. This study shows that cardiac I(1)
      receptors are functional, being regulated by hypertension and by chronic exposure
      to agonist, and that cardiac natriuretic peptides may be regulated by I(1)
      receptor-mediated mechanisms.

PMID- 15028601
TI  - BU98008, a highly selective imidazoline(1)-receptor ligand.
AB  - BU98008 (1-(4, 5-dihydro-1H-imidazol-2-yl)isoquinoline) is a novel isoquinoline
      derivative. Radioligand binding studies revealed it had high affinity for the
      I(1) receptor in rat kidney membranes but low affinity for the I(2) binding site
      and alpha(2)-adrenoceptor in rat brain membranes. Further evaluation of BU98008
      in vivo revealed no effect on blood pressure following peripheral administration.
      These preliminary data suggest BU98008 may be an antagonist at I(1) receptors.
      Further evaluation following central administration must be performed before a
      hypotensive action can be excluded.

PMID- 15028600
TI  - Alpha(2A)-adrenergic versus imidazoline receptor controversy in rilmenidine's
      action: alpha(2A)-antagonism in humans versus alpha(2A)-agonism in rabbits.
AB  - At the alpha(2A)-autoreceptors on the sympathetic nerve terminals of the human
      atrial appendages and rabbit pulmonary artery, rilmenidine and oxymetazoline
      exhibit different properties (antagonism and agonism, respectively). These
      opposite pharmacodynamic properties of alpha(2)-adrenoceptor ligands seem to be
      due to substantial differences in the nucleotide and amino acid sequences between
      human and rabbit alpha(2A)-adrenoceptors. Hence, the rabbit alpha(2A)
      adrenoceptor is not reliably predictive for the action of ligands at the human
      alpha(2A)-adrenoceptor.

PMID- 15028603
TI  - Atypical [(3)H]clonidine binding sites in human caudate and platelets on cryostat
      cut sections.
AB  - Pharmacological characterization is described for a human imidazoline binding
      site (I-site) labeled by [(3)H]clonidine using standard autoradiographic method.
      Under conditions that mask alpha(2)-adrenergic sites, only a single high affinity
      site was observed in human caudate and blood platelet sections. Affinity
      constants (K(i)) were highly correlated between the two tissues (r = 0.90, P =
      0.0003). This site is dissimilar to classical I(1) and I(2) sites, even though
      both tissues possess abundant I(1) and I(2) sites by filtration binding methods.
      It is suggested that the isotonic buffer conditions inherent to the procedure
      alter drug affinities to the classical I(1) site.

PMID- 15028602
TI  - Apparent absence of direct renal effect of imidazoline receptor agonists.
AB  - Imidazoline receptor agonists such as moxonidine and rilmenidine increase sodium
      excretion whether administered within the central nervous system, intravenously,
      or directly into the renal artery. To determine if this natriuresis was mediated
      by a direct renal effect and was independent of the renal sympathetic nerves, we
      used two different preparations in the pentobarbital-anesthetized rat. In the
      first series of studies, rats were unilaterally nephrectomized 7 to 10 days
      before the experiment. On the day of the experiment, the remaining kidney was
      denervated (surgical and 10% phenol/ 95% ethyl alcohol) or sham treated. The
      effect of an intravenous infusion of rilmenidine was determined. Rilmenidine (10
      nmol/kg/minute) decreased blood pressure and increased urine flow rate and sodium
      excretion in the sham- but not the denervation-treated rats. The response to
      furosemide (5.05 nmol/kg/minute) remained intact following denervation. We then
      used a two-kidney rat model that allowed for separate urine collection from each
      ureter. We used low infusion rates of moxonidine directly into the left renal
      artery. An increase in urine flow rate from the left but not the right kidney
      would suggest a direct renal action. Low infusion rates of moxonidine (10, 30
      nmol/kg/minute) increased urine flow rate similarly from both ureters. A low
      infusion rate of furosemide (9.1 nmol/kg/minute) into the left renal artery
      increased urine flow rate only from the left ureter. The failure of moxonidine to
      increase urine flow rate selectively only in the left kidney indicated the
      agonist acts at an extrarenal site to increase urine flow rate from both kidneys
      equally. The complete attenuation of the response to rilmenidine indicates the
      importance of the renal nerves and suggests that the extrarenal site is most
      probably the central nervous system. Collectively, these studies do not support a
      direct renal action of imidazoline agonists in producing natriuresis.

PMID- 15028604
TI  - Novel ligands for the investigation of imidazoline receptors and their binding
      proteins.
AB  - New ligands for imidazoline receptors are described so that these receptors can
      be more fully explored and understood. BU224, (2-(4,5-dihydroimidaz-2-yl)
      quinoline, shows high affinity and is selective for the imidazoline-2 (I(2))
      class of receptors. BU224 was tested in the rat Porsolt forced swim paradigm
      where it was found to decrease time spent immobile and increase the time spent
      swimming, consistent with an antidepressant profile. BU224 was tritiated and, in
      radioligand binding studies, was found to label a single population of saturable
      sites with high affinity. In vitro brain autoradiography with [(3)H]BU224 also
      showed a pattern of distribution similar to the known labeling of I(2) receptors.
      A new series of four 2BFI (2-(benzofuranyl)-2-imidazoline) derivatives were
      investigated as potential ligands for imaging brain I(2) receptors using positron
      emission tomography (PET). At least two, BU20012 and BU20013, retained high
      affinity and moderate selectivity and penetrated the brain when administered
      peripherally in the mouse. 2BFI has undergone the Mannich reaction to immobilized
      diaminodipropyl amine to fabricate an affinity column, which was used to isolate
      a protein from rabbit brain; this protein was sequenced and identified as the
      enzyme creatine kinase.

PMID- 15028605
TI  - The effects of chronic administration of inhibitors of flavin and quinone amine
      oxidases on imidazoline I(1) receptor density in rat whole brain.
AB  - Many imidazoline ligands have been shown to bind to the active sites of several
      amine oxidases, and endogenous ligands such as agmatine and tryptamine are amine
      oxidase substrates. In order to ascertain whether concentrations of endogenous
      imidazoline receptor agonists might be regulated by amine oxidase activities,
      rats were administered saline, clorgyline, deprenyl, MDL 72274A, aminoguanidine,
      or a combination of clorgyline, deprenyl, and aminoguanidine, for 14 days, and
      then binding parameters for [(3)H]clonidine at imidazoline I(1) receptors were
      determined in whole brain. Several EC 1.4.3.4, 1.4.3.6, and 1.5.3.11 amine
      oxidase activities were also measured ex vivo in tissues from treated animals.
      Results showed that drug treatments did not alter the affinity of clonidine for
      imidazoline I(1) receptors. There was a tendency toward a reduction in receptor
      density when monoamine oxidase (MAO)-A 1 MAO-B, MAO-B 1 semicarbazide-sensitive
      amine oxidase (SSAO), or SSAO 1 diamine oxidase (DAO) were inhibited, and a
      marked reduction in density when MAO-A 1 MAO-B 1 SSAO were inhibited. These data
      suggest that amines that are substrates both for MAO and for SSAO, such as
      tryptamine and other trace amines, may act as endogenous imidazoline I(1)
      receptor agonists, at which they may have neuromodulatory efficacy. A role for
      beta-carbolines, which can form endogenously from tryptamine, is also supported
      by the present findings.

PMID- 15028606
TI  - In vivo effects of the I(2)-alkylating agent BU99006 on the immunodensity of
      imidazoline receptor proteins in the mouse brain.
AB  - The binding sites for imidazol(ine)/guanidine drugs (identified inter alia with
      [(3)H]-clonidine and [(3)H]-idazoxan) are heterogeneous in nature, and various
      pharmacologic types of imidazoline receptors (IRs) have been characterized
      (I(1)R, I(2A)R, I(2B)R, and I(3)R). IR-receptor proteins have also been
      immunodetected using an antibody raised against an approximately 70-kD
      idazoxan/clonidine binding protein, which probably recognizes all types of IRs.
      In this study, the in vivo effects of the selective I(2)-alkylating agent BU99006
      (5-isothiocyanato-2-benzofuranyl-2-imidazoline) on immunoreactive IR proteins
      were assessed in the mouse brain to unravel the molecular nature of the I(2)R
      subtypes. In mouse tissues (cerebral cortex, liver, testis, and kidney) this
      antibody revealed the presence of 30-, 43-, 45-, 66-, and/or 85-kD IR proteins.
      Treatment with BU99006 (20 mg/kg, intraperitoneally, for 4 hours) significantly
      decreased the immunodensity of specific IR proteins in the brain (30 kD: 249%; 45
      kD: 237%; 66 kD: 218%). In contrast, the immunoreactivities of 43-kD and 85-kD IR
      proteins were not altered after I(2)R alkylation. Prolonged treatment with
      BU99006 (20 mg/kg, intraperitoneally. for 8 hours) resulted in modest but
      significant increases in the expression of all the immunodetected IR proteins in
      the mouse brain (20%-36%), suggesting compensatory increases in IR protein
      synthesis after alkylation of I(2) sites. The results indicate that the 30-kD and
      45-kD proteins, but not the 43-kD and 85-kD proteins, immunodetected in the mouse
      brain are related to the I(2)R.

PMID- 15028607
TI  - Restoration of first-phase insulin secretion by the imidazoline compound LY374284
      in pancreatic islets of diabetic db/db mice.
AB  - The effect of the imidazoline compound LY374284 has been studied in pancreatic
      islets of db/db mice, a progressive model of diabetes. In perifusion experiments,
      pancreatic islets of db/db mice showed a progressive deterioration of glucose
      induced insulin release with increasing age, whereby the first phase of insulin
      secretion was almost completely abolished and the second phase was substantially
      decreased by 15 weeks of age. LY374284 restored the first phase of glucose
      induced insulin secretion in islets of 16-week-old db/db mice to 70% of that
      observed in islets isolated from age-matched nondiabetic db/1 mice. LY374284 did
      not affect insulin secretion at a low glucose concentration (3.3 mmol/L). A
      similar restoration of first phase insulin secretion was observed after
      application of glucagon-like peptide-1, whereas a sulfonylurea agent,
      tolbutamide, was inactive. LY374284 did not affect cytosolic Ca(2+) concentration
      or cellular ATP content. Furthermore, LY374284 strongly enhanced insulin
      secretion in islets of db/db and db/1 mice maximally depolarized by 30 mmol/L
      K(+) and 250 micromol/L diazoxide. The present data suggest that the imidazoline
      compound LY374284 restores biphasic insulin secretion in islets of diabetic db/db
      mice by amplifying glucose-induced insulin secretion at a site distal to Ca(2+)
      influx.

PMID- 15028608
TI  - Effect of postmortem delay on imidazoline receptor-binding proteins in human and
      mouse brain.
AB  - Immunoreactive proteins of 45-kD and 29/30-kD doublet bands are candidate
      imidazoline receptor binding proteins (IRBP) based on associations with I(1) or
      I(2) binding sites, respectively. It was reported that the density of cortical
      membrane 29/30-kD I(2) protein is diminished whereas a 45-kD I(1) protein is
      increased in depressed suicide victims versus controls. IRBP immunoreactive bands
      of similar size have been suggested to be breakdown products of the 170-kD
      protein known as IRAS (putative full-length I(1) receptor). This study compares
      nonpathologic human brains collected and frozen after postmortem delays of 13.4
      hours +/- 1.7 (SEM) with brains of longer postmortem delays (26.1 hours +/- 1.2).
      The fresher human brains possessed more full-length IRAS (P = 0.05). In another
      study, the postmortem decay of IRBP bands in mouse brain was shown to be linear
      over time. The results are relevant to previous studies of IRBP bands in
      postmortem brains of depressed suicide victims.

PMID- 15028609
TI  - Association between I(2) binding sites and monoamine oxidase-B activity in
      platelets.
AB  - An I(2) imidazoline binding site on monoamine oxidase-B (MAO-B) is known to be
      encoded by a noncatalytic part of the enzyme, different from that which
      recognizes mechanism-based inhibitors. Herein, the relationship between I(2)
      imidazoline binding sites and MAO-B activity has been assessed using a semi
      purified source of MAO-B: platelet mitochondrial membranes. A positive
      correlation between I(2) sites and MAO-B activity was observed (r = 0.61, P =
      0.0016) among 24 human subjects. Nevertheless, the variance in MAO-B activity
      cannot be completely accounted for in relation to I(2) sites. Therefore, I(2)
      density and MAO-B activity are only weakly correlated in platelets.

PMID- 15028610
TI  - Relationship between imidazoline(2) sites and monoamine oxidase.
AB  - I(2) site-selective compounds are known to interact with and inhibit monoamine
      oxidase (MAO), but it remains unclear as to whether this interaction occurs
      through an allosteric or competitive interaction. This study used the new
      selective, irreversible I(2) ligand BU99006, to clarify the relationship between
      MAO and the I(2) binding sites (I(2)-BS). Results demonstrate that irreversible
      binding of BU99006 to rat brain membranes does not inhibit the enzyme or
      interfere with its interaction with other imidazoline enzyme inhibitors. This
      finding suggests that the I(2) sites that react with BU99006 are not those
      implicated in MAO inhibition and points to the existence of at least two distinct
      I(2) binding proteins.

PMID- 15028612
TI  - Investigation of the affinities of two new beta-carbolines for rat brain
      imidazoline(2) receptors.
AB  - The beta-carbolines are possible endogenous ligands and modulators of the
      imidazoline binding sites (I-BSs). Relatively little is known about this class of
      compound and its interaction with the I-BS. Presented here are the binding data
      for two aryl ring substituted dihydro-beta-carbolines at the imidazoline(2)
      binding site (I(2)-BS) and alpha(2)-adrenoceptor: BG-326 (5-bromo-4,9-dihydro-3H
      b-carboline) and BG-350 (5-methoxy-4,9-dihydro-3H-b-carboline). Both compounds
      show good affinity and selectivity for the I(2)-BS.

PMID- 15028611
TI  - Initial evaluation of novel selective ligands for imidazoline(2) receptors in rat
      whole brain.
AB  - Indazim, the indazole analogue of 2BFI, and four methyl-substituted analogues
      were tested for their affinity at the imidazoline(2) binding site (I(2)-BS), and
      this affinity was compared with their affinity at the alpha(2)-adrenoceptor to
      determine their structure, affinity relationship, and selectivity at the I(2)-BS.
      These studies showed that these ligands were highly selective for the I(2)-BS
      compared with 2BFI and that substitution at the 4 and 7 positions increased
      affinity without affecting selectivity.

PMID- 15028613
TI  - Identification of an I(2) binding protein from rabbit brain.
AB  - Imidazoline-2 binding proteins exist as a heterogeneous population. The aim of
      this study was to isolate and identify I(2) binding proteins from rabbit brain
      using an affinity column synthesized with a highly selective I(2) ligand, 2-(2
      benzofuranyl)2-imidazoline (2BFI). The results revealed an approximately 45-kD
      protein to be brain creatine kinase (EC 2.7.3.2). [(3)H]-2BFI (5nM) was able to
      bind specifically to the purified enzyme. This study has identified brain
      creatine kinase as a novel I(2) binding protein.

PMID- 15028614
TI  - In vivo estimation of imidazoline(2) binding site turnover.
AB  - Turnover of imidazoline(2) (I(2)) binding sites in the mouse and rat brain has
      been measured following an acute intravenous dose of BU99006. This ligand
      selectively and irreversibly knocks out I(2) sites, as defined by [(3)H]2BFI
      binding. Recovery was measured using radioligand binding and autoradiography to
      determine global and regional changes in I(2) density. The density of I(2) sites
      in brain recovered from BU99006 treatment with a half-life of 2.1 hours in mice
      and 4.3 hours in rats. Monoamine oxidase (MAO) activity and MAO binding density
      were unaltered in the brains of BU99006-treated animals. These data suggest that
      the I(2) site that reacts with BU99006 recovers rapidly and is independent of
      MAO.

PMID- 15028615
TI  - Specificity of nonadrenergic imidazoline binding sites in insulin-secreting cells
      and relation to the block of ATP-sensitive K(+) channels.
AB  - To characterize the specificity of nonadrenergic imidazoline binding sites of
      insulin-secreting HIT cells, competitive binding of insulinotropic imidazolines
      and quinine was measured and compared with the effect of these compounds on
      native K(ATP) channels and with a heterologously expressed variant of the pore
      forming subunit (Kir6.2 deltaC26). There were two nonadrenergic imidazoline
      binding sites for [(3)H]clonidine with K(d) values of 61 nM and 4.5 microM,
      respectively. Quinine reduced specific binding incompletely (73%) with K(i)
      values of 75 nM and 133 microM. Clonidine, N-allyl-clonidine (alinidine), and
      quinine inhibited native K(ATP) channels as well as Kir6.2deltaC26 channels.
      Coexpression of Kir6.2deltaC26 and SUR1 (the regulatory subunit of K(ATP)) did
      not increase the potency of quinine. There are nonadrenergic imidazoline binding
      sites in insulin-secreting HIT cells which also recognize quinine. One of these
      sites is Kir6.2, the pore-forming subunit of the K(ATP) channel.

PMID- 15028616
TI  - Moxonidine, a mixed alpha(2)-adrenergic and imidazoline receptor agonist,
      identifies a novel adrenergic target for spinal analgesia.
AB  - Moxonidine is a mixed alpha(2)-adrenergic and imidazoline receptor agonist with
      an improved side effect profile compared to clonidine. Intrathecal (i.t.)
      moxonidine has been found to possess analgesic activity that, in contrast to the
      majority of alpha(2)-adrenoceptor (alpha(2)AR) agonists, does not require
      activation of the alpha(2A)AR subtype, which mediates many of the side effects
      associated with alpha(2)AR use. In addition, moxonidine (i.t.) interacts in a
      synergistic manner with opioid agonists and this synergy is retained in
      neuropathic pain states. Moxonidine may therefore be clinically useful in the
      treatment of chronic neuropathic pain, either alone or as a coadjuvant with
      opioids.

PMID- 15028617
TI  - Evidence for nonadrenoceptor responses to imidazoline derivatives in the porcine
      isolated rectal artery.
AB  - High concentrations of phentolamine, efaroxan, and idazoxan were found to produce
      nonadrenoceptor contractions of the porcine isolated rectal artery previously
      exposed to U46619 and forskolin. These responses were insensitive to the putative
      imidazoline I(3) receptor antagonist KU-14R, unlike those previously reported in
      this preparation for oxymetazoline. The pharmacologic nature of this response and
      the obligate requirement for preconstriction suggests that these imidazoline
      derivatives modulate ion channel function through a novel nonadrenergic site.

PMID- 15028618
TI  - Cell signaling by imidazoline-1 receptor candidate, IRAS, and the nischarin
      homologue.
AB  - IRAS transfection into Chinese hamster ovary (CHO) or pheochromocytoma (PC-12)
      cell lines leads to the appearance of nonadrenergic binding sites for
      radiolabeled-clonidine. Nischarin is the mouse homologue of IRAS. IRAS seems to
      be a cytosolic protein that is anchored to the intracellular side of plasma
      membranes by a POX domain. Previous studies of IRAS-transfected HEK293 cells, and
      Nischarin-transfected 3T3 cells have shown this protein can intrinsically mediate
      cell growth and differentiation independent of imidazoline drugs through binding
      to insulin receptor substrates (HEK293 cells) and fibronectin receptors (3T3
      cells). Herein, a growth-arrested PC-12 cell line stably transfected with IRAS is
      shown to express lower basal and nerve growth factor-stimulated levels of the
      activated form of extracellular receptor kinase than found in a vector-only
      transfected control cell line treated similarly. These findings suggest that IRAS
      is a membrane-associated mediator of receptor signaling.

PMID- 15028620
TI  - Assembly of PRR-containing receptors on scaffolds: a model for imidazoline I(1)
      receptor action.
AB  - IRAS, a putative clone of the I(1)-imidazoline receptor, possesses a proline-rich
      region (PRR) motif, which might interact with SH3 regions on tyrosine kinases,
      and an integrin-binding motif. Receptors with a PRR motif can generally assemble
      onto multi-element signaling complexes (eg., the beta(3)-receptor on the EGF
      receptor) and thereby modulate signal transduction. Integrins serve as scaffolds
      for multi-element signaling complexes, similar to that assembled with the EGF
      receptor. It is therefore possible that IRAS signals through a complex with other
      receptors.

PMID- 15028619
TI  - IRAS is an anti-apoptotic protein.
AB  - Active cell death, also known as apoptosis, has been implicated in the
      pathophysiology of diseases such as cancer, heart failure and neurodegenerative
      disorders. We report the anti-apoptotic function of IRAS, which was previously
      shown to bind imidazoline ligands. The amino acid sequence of human IRAS (hIRAS)
      is unrelated to known proteins, except for rat IRAS and a mouse homologue named
      nischarin, which binds the alpha5 integrin subunit of the fibronectin receptor.
      When stably transfected into PC12 cells, hIRAS localizes to the cytosol as a 167
      kDa immunoreactive protein. Clonal PC12 cell lines expressing hIRAS displayed
      normal serum growth responses. However, hIRAS expression led to prolonged cell
      survival against known apoptotic stimuli: serum starvation or thapsigargin or
      staurosporine treatments. The apoptotic population of hIRAS-expressing cells was
      significantly reduced, and this protection was achieved by a decrease in caspase
      3 activity, phosphatidylserine translocation, and nuclear fragmentation. Similar
      protective effect was obtained in COS7 cells transiently transfected with hIRAS.
      A partial activation of the PI3 kinase pathway is possibly implicated in the anti
      apoptotic effect of IRAS. Thus, IRAS appears to represent a previously unknown
      anti-apoptotic protein involved in the regulation of cell survival.

PMID- 15028621
TI  - IRAS splice variants.
AB  - The human I(1)-imidazoline receptor candidate gene, iras, has previously been
      cloned and mapped to locus 3p21.1-9 (also known as Nischarin; accession No.
      AC006208). By comparison to a database of expressed sequence tags (ESTs), three
      alternatively spliced transcripts have been deduced. A map of 21 exons was
      constructed for the medium-length transcript (IRAS-M) containing 5,232 base pairs
      (bp) and encoding 1,504 amino acids (aas). Introns 13B and 13C are inserted into
      the two alternative transcripts, forming IRAS-S and IRAS-L mRNA (short and long
      isoforms). Northern blots confirmed the existence of these mRNA isoforms. In most
      brain regions the order of mRNA abundance was IRAS-M > IRAS-L > IRAS-S mRNA.
      Although aas 1 through 510 are theoretically identical, truncated proteins could
      be derived from IRAS-S (2,678 bp transcript yields 515 aas) and IRAS-L (9,457 bp
      transcript yields 583 aas). Because exon-16 of the iras gene has been proposed to
      encode the functional domains of imidazoline and a-5 integrin binding, only IRAS
      M is expected to possess I(1) receptor properties. Subtype-selective cDNA
      expression constructs were therefore generated and used to transfect CHO cells.
      High-affinity I(1) binding was endowed by IRAS-M and IRAS-L, but not by IRAS-S
      transfection.

PMID- 15028622
TI  - Intracellular effect of imidazoline receptor on alpha(2A)-noradrenergic receptor.
AB  - Imidazoline-1 receptors (I(1)R) and alpha(2)-noradrenergic receptors (alpha(2)AR)
      are known to coexist in many cell types and bind many of the same imidazoline
      ligands. Herein, the possibility of an interaction between these receptors was
      explored using a cloned cDNA that encodes a protein with I(1)R-like binding
      properties, designated imidazoline receptor antisera-selected (IRAS). Chinese
      hamster ovary (CHO) sublines permanently expressing the human subtype alpha(2A)AR
      cDNA were transiently cotransfected with the human IRAS cDNA (pIRAS). Saturation
      radioligand binding experiments on membranes isolated from the various sublines
      allowed distinction between I(1)R and alpha(2A)AR. Transfection of pIRAS into
      either subline led to a rise in membrane I(1)R-binding sites. Immunoblotting
      revealed that IRAS was enriched in membranes more than in cytosolic fractions.
      Transfection of pIRAS in CHO cells harboring the alpha(2A)AR cDNA resulted in a
      twofold increase in alpha(2A)AR binding sites with no change in alpha(2A)AR
      binding affinity, compared with controls. Immunoblotting also revealed increased
      expression of membranous alpha(2A)AR by IRAS. Thus, pIRAS transfection led to
      I(1) binding sites and to an increase in alpha(2A)AR binding sites in CHO cells
      expressing the human alpha(2A)AR. Although the mechanism is unclear, this
      increase in binding sites may explain previous imidazoline drug effects
      suggestive of interactions between these two receptors.

PMID- 15028623
TI  - Relationship between platelet imidazoline receptor-binding peptides and candidate
      imidazoline-1 receptor, IRAS.
AB  - A candidate human imidazoline-1 receptor, designated imidazoline receptor
      antisera-selected (IRAS) protein, was cloned based on immunoreactivity with
      antiserum against a purified imidazoline receptor binding peptide (IRBP
      antiserum). Human IRAS is 167 kD in size, different from 33- to 85-kD IRBP bands
      previously linked to the human platelet I(1) receptor. To explore the possible
      relationship between IRAS and these smaller proteins, seven different epitope
      specific antisera against IRAS were raised in rabbits for comparison with IRBP
      antiserum. Focus was on antiserum(227-241), corresponding to amino acids No. 227
      to 241 in IRAS, because this antiserum was found uniquely able to
      immunoprecipitate non-denatured 85-kD and 170-kD forms of IRAS from a human
      megakaryoblastoma cell line (MEG01), a model of platelet-producing cells. Human
      platelets lacked the 170-kD form of IRAS, but 33-kD and 85-kD bands were
      detectable and seemed to be possible fragments of full-length IRAS. The intensity
      of the 85-kD band detected by antiserum(227-241) was significantly correlated (r
      = 0.62, P = 0.04) with the intensity of the 33-kD band across 11 human platelet
      samples. A positive correlation between the intensities of the 33-kD and 85-kD
      bands is consistent with both being fragments of IRAS.

PMID- 15028624
TI  - Redox status of the oviduct and CDC2 activity in 2-cell stage embryos in heat
      stressed mice.
AB  - Mammalian preimplantation embryos are vulnerable to heat stress. However, the
      mechanisms by which maternal heat stress compromises embryonic development are
      unclear. We hypothesized that the loss of developmental competence in maternally
      heat-stressed embryos results from enhanced oxidative stress in the oviducts. In
      experiment 1, oviducts and zygotes were collected from mice that were heat
      stressed at 35 degrees C and 60% relative humidity for 12 h on the day of
      pregnancy as well as from control mice. The zygotes were cultured for 84 h to
      assess their development, and the H(2)O(2) level, glutathione concentration, and
      free radical scavenging activity (FRSA) were measured in the oviduct. In
      experiment 2, zygotes were cultured for 22 h to reach the late G(2) phase in the
      2-cell stage, and Cdc2 activity was assessed using immunoblotting. A high
      percentage (87.6%) of control embryos developed to morulae or blastocysts,
      whereas the majority (67.4%) of the heat-stressed group arrested at the 2-cell
      stage. Although heat stress did not alter the FRSA or glutathione concentration
      in the oviducts, the H(2)O(2) level (P < 0.01) and its ratio to the FRSA (P <
      0.05) significantly increased in the heat-stressed group. The Cdc2 activation at
      the 2-cell stage, as shown by the ratio of the dephosphorylated form to the
      phosphorylated form, was evident in control embryos but absent in heat-stressed
      embryos, and the level was similar to that in embryos blocked at the 2-cell stage
      (positive control). These results indicate that maternal heat stress enhances
      oxidative stress in the oviducts and that loss of developmental competence in
      maternally heat-stressed embryos correlates with a defect in Cdc2 activity at the
      2-cell stage.

PMID- 15028625
TI  - Energy substrate metabolism of mouse cumulus-oocyte complexes: response to
      follicle-stimulating hormone is mediated by the phosphatidylinositol 3-kinase
      pathway and is associated with oocyte maturation.
AB  - Successful in vitro maturation (IVM) of oocytes obtained from medium-sized antral
      follicles could avoid the need for superovulation for in vitro fertilization. The
      wide range of doses of FSH used in IVM prompted us to study the effect of varying
      concentrations of FSH on the dynamics of nutrient uptake and production by
      individual maturing mouse cumulus-oocyte complexes (COCs). COCs isolated from the
      antral follicles of unprimed, prepubertal B6CBF(1) mice were cultured
      individually in increasing concentrations of FSH (0-2000 ng/ml). Following
      culture, pyruvate, glucose, and lactate uptake or production by individual
      complexes were noninvasively assessed and compared with the stage of nuclear
      maturation of the enclosed oocyte. FSH significantly increased oocyte maturation
      and produced a two- to threefold increase in glucose uptake and lactate
      production by COCs in which the enclosed oocyte completed maturation. In these
      COCs, pyruvate was taken up under control conditions but was produced in
      progressively higher quantities in increasing concentrations of FSH. In COCs
      where the oocyte failed to complete maturation, pyruvate was taken up (rather
      than produced) and glucose uptake and lactate production were lower and
      unaffected by the presence or absence of FSH. This suggests that there is
      dialogue between cumulus cells and the maturing oocyte that influences FSH
      responsiveness and substrate metabolism of the whole COC. Finally, inhibition of
      FSH-stimulated glucose uptake by the PI3-kinase inhibitor LY294002 and the
      finding of GLUT4 protein in granulosa cells suggest that FSH increases glucose
      uptake by PI3-kinase-mediated translocation of GLUT4 to the granulosa cell
      membrane.

PMID- 15028626
TI  - Different regulatory pathways of endometrial connexin expression: preimplantation
      hormonal-mediated pathway versus embryo implantation-initiated pathway.
AB  - Transformation of the endometrium into the receptive phase is under the control
      of ovarian steroid hormones and is modulated by embryonic signals during
      implantation. We have previously shown that this differentiation process is
      accompanied by a suppression of gap junction connexins (Cx) 26 and 43 before
      implantation followed by a local induction of both connexins in the implantation
      chamber. In the present study, we demonstrate that connexin gene expression in
      the rodent endometrium is regulated via two distinct signaling pathways during
      these different stages of early pregnancy. During preimplantation, transcription
      of connexins can be induced by estrogen via an estrogen receptor (ER)-dependent
      pathway. Additionally, Cx26 and Cx43 are induced by embryonic signals during
      implantation and delayed implantation as well as during artificially induced
      decidualization. In contrast to the estrogen-induced expression, this
      embryonic/decidual-associated induction of Cx26 and Cx43 could not be blocked by
      antiestrogen, thus pointing to another regulatory pathway independent of the ER.
      Studies in ERalpha and ERbeta knockout mice confirmed these different pathways,
      demonstrating that in the endometrium, estrogen-mediated Cx26 gene induction, but
      not induction during decidualization, is dependent on functional ERalpha. To
      evaluate potential embryonic signals regulating Cx26 expression, uteri of
      pseudopregnant animals were incubated with different mediators in an organ
      culture model, showing that catechol estrogen and mediators of the inflammatory
      cascade such as prostaglandin F(2alpha) and interleukin-1beta are able to induce
      Cx26 expression through the ER-independent pathway. Thus, the present study
      demonstrates that endometrial expression of Cx26 and Cx43 is induced via estrogen
      and ERalpha during preimplantation but then utilizes an ER-independent signaling
      pathway during embryo implantation and decidualization.

PMID- 15028627
TI  - Regulation of prohibitin expression during follicular development and atresia in
      the mammalian ovary.
AB  - Prohibitin is a ubiquitous and highly conserved protein implicated as an
      important regulator in cell survival. Prohibitin content is inversely associated
      with cell proliferation, but it increases during granulosa cell differentiation
      as well as in earlier events of apoptosis in a temperature-sensitive granulosa
      cell line. In the present study, we have characterized the spatial expression
      patterns for prohibitin using established in vivo models for the induction of
      follicular development and atresia in the mammalian ovary. Comparative Western
      blot analyses of granulosa cell lysates from control ovaries and from ovaries
      primed with eCG or treated with eCG plus anti-eCG (gonadotropin withdrawal) were
      conducted. Prohibitin was immunolocalized in rat ovarian sections probed with
      antibodies against either proliferating cell nuclear antigen (PCNA) or
      cholesterol side-chain cleavage cytochrome P450 (P450(scc)) or in terminal
      deoxynucleotidyl transferase-mediated dUTP nick end labeled sections.
      Additionally, porcine oocytes, zygotes, and blastocyts were also immunolocalized
      with prohibitin antibody. Immunolocalization revealed the presence of prohibitin
      in granulosa cells, theca-interstitial cells, and the oocyte. The results
      indicate that prohibitin protein expression in the gonadotropin-treated cells was
      upregulated. Immunoreactivity of prohibitin was inversely related to PCNA
      expression during follicular maturation and colocalized with P450(scc).
      Prohibitin appeared to be translocated from the cytoplasm to the nucleus in
      atretic follicles, germinal vesicle-stage oocytes, zygotes, and blastocysts.
      These results suggest that prohibitin has several functional regulatory roles in
      granulosa and theca-interstitial cells and in the ovum during follicular
      maturation and atresia. It is likely that prohibitin may play an important role
      in determining the fate of these cells and eventual follicular destiny.

PMID- 15028628
TI  - Methylation reprogramming and chromosomal aneuploidy in in vivo fertilized and
      cloned rabbit preimplantation embryos.
AB  - Active demethylation of the paternal genome but not of the maternal genome occurs
      in fertilized mouse, rat, pig, and bovine zygotes. To study whether this early
      demethylation wave is important for embryonic development, we have analyzed the
      global methylation patterns of both in vivo-fertilized and cloned rabbit embryos.
      Anti-5-methylcytosine immunofluorescence of in vivo-fertilized rabbit embryos
      revealed that the equally high methylation levels of the paternal and maternal
      genomes are largely maintained from the zygote up to the 16-cell stage. The lack
      of detectable methylation changes in rabbit preimplantation embryos suggests that
      genome-wide demethylation is not an obligatory requirement for epigenetic
      reprogramming. The methylation patterns of embryos derived from fibroblast and
      cumulus cell nuclear transfer were similar to those of in vivo-fertilized rabbit
      embryos. Fluorescence in situ hybridization with chromosome-specific BACs
      demonstrated significantly increased chromosomal aneuploidy rates in cumulus cell
      nuclear transfer rabbit embryos and embryos derived from nuclear transfer of
      rabbit fibroblasts into bovine oocytes compared with in vivo-fertilized rabbit
      embryos. The incidence of chromosomal abnormalities was correlated with
      subsequent developmental failure. We propose that postzygotic mitotic errors are
      one important explanation of why mammalian cloning often fails.

PMID- 15028629
TI  - Tissue-specific elevated genomic cytosine methylation levels are associated with
      an overgrowth phenotype of bovine fetuses derived by in vitro techniques.
AB  - Epigenetic perturbations are assumed to be responsible for abnormalities observed
      in fetuses and offspring derived by in vitro techniques. We have designed an
      experiment with bovine Day 80 fetuses generated by somatic cell nuclear transfer
      (SCNT), in vitro fertilization (IVF), and artificial insemination (AI) to
      determine the relationship between fetal phenotype and genome-wide 5
      methylcytosine (5mC) content. When compared with AI controls, SCNT and IVF
      fetuses displayed significantly increased body weight (61% and 28%), liver weight
      (100% and 36%), and thorax circumference (20% and 11%). A reduced crown-rump
      length:thorax circumference ratio (1.175 +/- 0.017 in SCNT and 1.292 +/- 0.018 in
      IVF vs. 1.390 +/- 0.018 in AI, P < 0.001 and P < 0.002) was the external hallmark
      of this disproportionate overgrowth phenotype. The SCNT fetuses showed
      significant hypermethylation of liver DNA in comparison with AI controls (3.46%
      +/- 0.08% vs. 3.17% +/- 0.09% 5mC, P < 0.03), and the cytosine methylation levels
      for IVF fetuses (3.34% +/- 0.09%) were, as observed for phenotypic parameters,
      intermediate to the other groups. Regressions of fetal body and liver weight and
      thorax circumference on 5mC content of liver DNA were positive (P < 0.073-0.079).
      Furthermore, a significant negative regression (P < 0.021) of the crown-rump
      length:thorax circumference ratio on liver 5mC was observed. The 5mC content of
      placental cotyledon DNA was 46% lower than in liver DNA (P < 0.0001) but did not
      differ among groups. These data are in striking contrast with the recently
      reported hypomethylation of DNA from SCNT fetuses and indicate that
      hypermethylation of fetal tissue, but not placenta, is linked to the overgrowth
      phenotype in bovine SCNT and IVF fetuses.

PMID- 15028630
TI  - Cholesterol efflux alters lipid raft stability and distribution during
      capacitation of boar spermatozoa.
AB  - A reduction in plasma membrane cholesterol is one of the early events that either
      triggers or is closely associated with capacitation of mammalian spermatozoa. In
      this investigation, we have examined the effects of cholesterol efflux on
      tyrosine phosphorylation, lipid diffusion, and raft organization in boar
      spermatozoa. Results show that a low level of cholesterol efflux, mediated by 5
      mM methyl-beta-cyclodextrin (MBCD), enhances capacitation and induces
      phosphorylation of two proteins at 26 and 15 kDa without affecting sperm
      viability. Lipid diffusion rates under these conditions are largely unaffected
      except when cholesterol efflux is excessive. Low-density Triton X100-insoluble
      complexes (lipid rafts) were isolated from spermatozoa and found to have a
      restricted profile of proteins. Capacitation-associated cholesterol efflux has no
      effect on raft composition, but cholesterol depletion destabilizes them
      completely and phosphorylation is suppressed. During MBCD-mediated capacitation,
      the distribution of GM1 gangliosides on spermatozoa changes in a sequential
      manner from overlying the sperm tail to clustering on the sperm head. It is
      concluded that there is a safe window for removal of plasma membrane cholesterol
      from spermatozoa within which protein phosphorylation and polarized migration of
      lipid rafts take place. A preferential loss of cholesterol from the nonraft pool
      may be the stimulus that promotes raft clustering over the anterior sperm head.

PMID- 15028631
TI  - Interaction of cocultured decidual endothelial cells and cytotrophoblasts in
      preeclampsia.
AB  - Disturbed cell-cell communication between trophoblasts and the maternal
      endothelium may be responsible for the deficient endovascular invasion seen in
      preeclampsia. In vitro studies have been hampered by lack of suitable models to
      directly examine interactions between these cell types. Using a bilayer coculture
      model, we examined the effect of decidual endothelial cells on matrix
      metalloproteinase secretion and the migration of cytotrophoblasts from
      preeclamptic pregnancies. Cells were incubated on semipermeable membranes in 20%
      or 2% O(2) with or without the tumor promoter phorbol 12-myristate 13-acetate,
      which activates matrix metalloproteinase-2 and -9 in endothelial cells.
      Cytotrophoblasts from preeclamptic pregnancies secreted significantly less matrix
      metalloproteinase-2 and -9 than their normal counterparts. Although decidual
      endothelial cells downregulated cytotrophoblast migration in normal pregnancy,
      this was not observed in cocultures with cytotrophoblasts from preeclamptic
      pregnancies. In addition, cytotrophoblasts from preeclamptic pregnancies altered
      phorbol myristate acetate-induced activation of endothelial matrix
      metalloproteinases. Hypoxia increased cytotrophoblast migration when cells were
      incubated alone but not in coculture with decidual endothelial cells due to
      increased adhesion between the two cell types. These results suggest
      dysfunctional interactive regulation of migration and matrix metalloproteinase
      secretion in preeclampsia that could result in abnormal endovascular trophoblast
      invasion of the maternal vasculature.

PMID- 15028632
TI  - The murine testicular transcriptome: characterizing gene expression in the testis
      during the progression of spermatogenesis.
AB  - One of the most promising applications of microarrays is the study of changes in
      gene expression associated with the growth and development of mammalian tissues.
      The testis provides an excellent model to determine the ability of microarrays to
      effectively characterize the changes in gene expression as an organ develops from
      birth to adulthood. To this end, a developmental testis gene expression time
      course profiling the expression patterns of approximately 36 000 transcripts on
      the Affymetrix MGU74v2 GeneChip platform at 11 distinct time points was created
      to gain a greater understanding of the molecular changes necessary for and
      elicited by the development of the testis. Additionally, gene expression profiles
      of isolated testicular cell types were created that can aid in the further
      characterization of the specific functional actions of each cell type in the
      testis. Statistical analysis of the data revealed 11 252 transcripts (9846
      unique) expressed differentially in a significant manner. Subsequent cluster
      analysis produced five distinct expressional patterns within the time course.
      These patterns of expression are present at distinct chronological periods during
      testis development and often share similarities with cell-specific expression
      profiles. Analysis of cell-specific expression patterns produced unique and
      characteristic groups of transcripts that provide greater insight into the
      activities, biological and chronological, of testicular cell types during the
      progression of spermatogenesis. Further analysis of this time course can provide
      a distinct and more definitive view into the genes implicated, known and unknown,
      in the maturation, maintenance, and function of the testis and the integrated
      process of spermatogenesis.

PMID- 15028633
TI  - The consequences of altered somatotropic system on reproduction.
AB  - Although the primary control of gonadotropin secretion is by the hypothalamic
      GnRH and the gonadal function is controlled by the pituitary gonadotropins and
      prolactin, the emerging evidence suggests a vital role of the somatotropic axis,
      growth hormone (GH), and insulin-like growth factor-I (IGF-I) in the control of
      the pituitary and gonadal functions. It has been shown that GH deficiency, GH
      resistance, and experimental alterations in IGF-I secretion modify
      folliculogenesis, ovarian maturation, ovulation, and pregnancy, and in the male,
      GH/IGF-I plays an important role in spermatogenesis and the Leydig cell function.
      The primary focus of this review is to examine the role of GH/ IGF-I on the onset
      of puberty, fertility, pituitary, and gonadal endocrine functions. A number of
      studies have revealed that fertility is affected in GH-deficient dwarf and in IGF
      I gene-ablated mice, possibly due to subnormal function of either the pituitary
      gland or the gonads. In the female GH receptor gene knockout (GHR-KO) mice, there
      was impairment in follicular development, ovulation rate, sexual maturation,
      production of and responsiveness to pheromonal signals, and the corpus luteum
      function. In IGF-I-deficient male GHR-KO mice, puberty is delayed,
      spermatogenesis is affected, and neuroendocrine-gonadal function is attenuated.
      Similarly, in some of the human Laron syndrome patients, puberty is delayed due
      to GH resistance. These data suggest that, in addition to GnRH and gonadotropins,
      GH/IGF-I influences the pituitary and gonadal functions in animals and humans.

PMID- 15028634
TI  - Trends in prevalence of symptoms of asthma, hay fever, and eczema in 12-14 year
      olds in the British Isles, 1995-2002: questionnaire survey.

PMID- 15028636
TI  - Normal serum aminotransferase concentration and risk of mortality from liver
      diseases: prospective cohort study.
AB  - OBJECTIVE: To examine the relation between the normal range of serum
      aminotransferase concentration and mortality from liver disease. DESIGN:
      Prospective cohort study. SETTING: Korea Medical Insurance Corporation study with
      eight years' follow up. PARTICIPANTS: 94,533 men and 47,522 women aged 35-59
      years. MAIN OUTCOME MEASURE: Mortality from liver diseases according to death
      certificate. RESULTS: There was a positive association between the
      aminotransferase concentration, even within normal range (35-40 IU/l), and
      mortality from liver disease. Compared with the concentration < 20 IU/l, the
      adjusted relative risks for an aspartate aminotransferase concentration of 20-29
      IU/l and 30-39 IU/l were 2.5 (95% confidence interval 2.0 to 3.0) and 8.0 (6.6 to
      9.8) in men and 3.3 (1.7 to 6.4) and 18.2 (8.1 to 40.4) in women, respectively,
      The corresponding risks for alanine aminotransferase were 2.9 (2.4 to 3.5) and
      9.5 (7.9 to 11.5) in men and 3.8 (1.9 to 7.7) and 6.6 (1.5 to 25.6) in women,
      respectively. According to receiver operating characteristic curves the best cut
      off values for the prediction of liver disease in men were 31 IU/l for aspartate
      aminotransferase and 30 IU/l for alanine aminotransferase. CONCLUSION: People
      with slightly increased aminotransferase activity, but still within the normal
      range, should be closely observed and further investigated for liver diseases.

PMID- 15028637
TI  - Protein 14-3-3zeta binds to protein phosphatase PP1gamma2 in bovine epididymal
      spermatozoa.
AB  - The protein phosphatase PP1gamma2 is critical in the regulation of sperm motility
      and fertility. Its activity is regulated by its binding proteins and by
      phosphorylation. We have recently shown that PP1gamma2 is phosphorylated and that
      the amount of phosphorylated PP1gamma2 increases during sperm epididymal
      maturation (Huang et al., Biol Reprod 2004; 70:439-447). Microsequencing revealed
      that protein 14-3-3 coeluted with phosphorylated PP1gamma2 during column
      chromatography of bovine sperm extracts. Western blot analyses confirmed the
      presence of protein 14-3-3 not only in bovine spermatozoa but also in spermatozoa
      of diverse species-bull, hamster, horseshoe crab, monkey, rat, turkey, and
      Xenopus. The binding between PP1gamma2 and protein 14-3-3 was confirmed by
      coimmunoprecipitation experiments and in pull-down assays with recombinant GST-14
      3-3. Western blot analysis and protein 14-3-3 immunoprecipitates with antibodies
      against the consensus binding domain of protein 14-3-3 reveal that, in addition
      to PP1gamma2, at least two other protein 14-3-3 binding partners are present in
      spermatozoa. Fluorescence immunocytochemistry results indicate that
      phosphorylated PP1gamma2 and protein 14-3-3 both localize to the postacrosomal
      region of the head and principal piece of bovine spermatozoa. Together, these
      results provide conclusive evidence that protein 14-3-3 is present in mature
      spermatozoa and that PP1gamma2 is one of its binding partners.

PMID- 15028640
TI  - Search for color 'center(s)' in macaque visual cortex.
AB  - It is often stated that color is selectively processed in cortical area V4, in
      both macaques and humans. However most recent data suggests that color is instead
      processed in region(s) antero-ventral to V4. Here we tested these two hypotheses
      in macaque visual cortex, where 'V4' was originally defined, and first described
      as color selective. Activity produced by equiluminant color-varying (versus
      luminance-varying) gratings was measured using double-label deoxyglucose in awake
      fixating macaques, in multiple areas of flattened visual cortex. Much of cortex
      was activated near-equally by both color- and luminance-varying stimuli. In
      remaining cortical regions, discrete color-biased columns were found in many
      cortical visual areas, whereas luminance-biased activity was found in only a few
      specific regions (V1 layer 4B and area MT). Consistent with a recent hypothesis,
      V4 was not uniquely specialized for color processing, but areas located antero
      ventral to V4 (in/near TEO and anterior TE) showed more color-biased activity.

PMID- 15028639
TI  - Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity
      in rat hippocampal neurons: involvement of protein kinase C.
AB  - 1. Resveratrol, an active ingredient of red wine extracts, has been shown to
      exhibit neuroprotective effects in several experimental models. 2. The present
      study evaluated the neuroprotective effects of resveratrol against amyloid
      beta(Abeta)-induced toxicity in cultured rat hippocampal cells and examined the
      role of the protein kinase C (PKC) pathway in this effect. 3. Pre-, co- and post
      treatment with resveratrol significantly attenuated Abeta-induced cell death in a
      concentration-dependent manner, with a concentration of 25 microm being maximally
      effective. 4. Pretreatment (1 h) of hippocampal cells with phorbol-12-myristate
      13-acetate, a PKC activator, at increasing concentrations (1-100 ng x ml(-1)),
      resulted in a dose-dependent reduction in Abeta-induced toxicity, whereas the
      inactive 4alpha-phorbol had no effect. 5. Pretreatment (30 min) of hippocampal
      cells with GF 109203X (1 microm), a general PKC inhibitor, significantly
      attenuated the neuroprotective effect of resveratrol against Abeta-induced cell
      death. 6. Treatment of hippocampal cells with resveratrol (20 microm) also
      induced the phosphorylation of various isoforms of PKC leading to activation. 7.
      Taken together, the present results indicate that PKC is involved in the
      neuroprotective action of resveratrol against Abeta-induced toxicity.

PMID- 15028642
TI  - Self-organization model of cytochrome oxidase blobs and ocular dominance columns
      in the primary visual cortex.
AB  - There are regularly arranged blobs that contain neurons labeled by cytochrome
      oxidase (CO) in the supragranular layer of the primary visual cortex (V1) of
      monkeys and cats. This theoretical study demonstrates that CO-blob-like patterns
      can be reproduced based on the thermodynamic model for the activity-dependent
      self-organization of afferent inputs from two different groups of neurons to the
      supragranular layer of the visual cortex. Computer simulation based on the model
      shows that within a particular parameter range each blob is centered in the
      ocular dominance (OD) band, as observed in macaque monkeys and galagos.
      Furthermore, by increasing the strength of correlation in activity between inputs
      from the two eyes, nearby blobs merge across OD borders, as seen in the cat
      visual cortex. Finally, for monocular deprivation, blobs in the deprived eyes
      shrink as observed in monkeys and cats. For binocular deprivation, less intensely
      labeled blobs were reproduced, while the blob density did not change as observed
      in monkeys.

PMID- 15028641
TI  - Task-independent and task-specific age effects on brain activity during working
      memory, visual attention and episodic retrieval.
AB  - It is controversial whether the effects of aging on various cognitive functions
      have the same common cause or several different causes. To investigate this
      issue, we scanned younger and older adults with functional magnetic resonance
      imaging (fMRI) while performing three different tasks: working memory, visual
      attention and episodic retrieval. There were three main results. First, in all
      three tasks, older adults showed weaker occipital activity and stronger
      prefrontal and parietal activity than younger adults. The occipital reduction is
      consistent with the view that sensory processing decline is a common cause in
      cognitive aging, and the prefrontal increase may reflect functional compensation.
      Secondly, older adults showed more bilateral patterns of prefrontal activity than
      younger adults during working memory and visual attention tasks. These findings
      are consistent with the Hemispheric Asymmetry Reduction in Older Adults (HAROLD)
      model. Finally, compared to younger adults, older adults showed weaker
      hippocampal formation activity in all three tasks but stronger parahippocampal
      activity in the episodic retrieval task. The former finding suggests that age
      related hippocampal deficits may have a global effect in cognition, and the
      latter is consistent with an age-related increase in familiarity-based
      recognition. Taken together, the results indicate that both common and specific
      factors play an important role in cognitive aging.

PMID- 15028643
TI  - Cross-modal circuitry between auditory and somatosensory areas of the cat
      anterior ectosylvian sulcal cortex: a 'new' inhibitory form of multisensory
      convergence.
AB  - Examples of convergence of visual and auditory, or visual and somatosensory,
      inputs onto individual neurons abound throughout the brain, but substantially
      fewer incidences of auditory-somatosensory neurons have been reported. The
      present experiments sought to examine auditory-somatosensory convergence to
      assess whether there is a feature of this type of convergence that might obscure
      it from conventional methods of multisensory detection. Auditory-somatosensory
      convergence was explored in cat anterior ectosylvian sulcus (AES) cortex, where
      higher-order somatosensory area IV (SIV) and auditory field of the anterior
      ectosylvian sulcus (FAES) share a common border. While neuroanatomical tracers
      documented a projection from FAES to SIV, physiological studies failed to reveal
      the bimodal neurons expected from such cross-modal connectivity. Stimulation of
      FAES through indwelling electrodes also failed to excite any of the SIV neurons
      examined. However, when stimulation of auditory FAES was combined with
      somatosensory stimulation, a large majority (66%) of SIV neurons showed a
      significant response attenuation. FAES-induced response suppression was specific
      to SIV, could not be elicited by activating other auditory regions and was
      blocked by the microiontophoretic application of the GABAergic antagonist
      bicuculline methiodide. Based on these data, a novel, cross-modal circuit is
      proposed involving projections from auditory FAES to somatosensory SIV, where
      local inhibitory interneurons 'reverse the sign' of the cross-modal signals to
      produce auditory-somatosensory suppression. This form of excitatory-inhibitory
      multisensory convergence has not been reported before and suggests that the level
      of interaction between auditory and somatosensory modalities has been
      substantially underestimated.

PMID- 15028638
TI  - Endothelium-dependent smooth muscle hyperpolarization: do gap junctions provide a
      unifying hypothesis?
AB  - An endothelium-derived hyperpolarizing factor (EDHF) that is distinct from nitric
      oxide (NO) and prostanoids has been widely hypothesized to hyperpolarize and
      relax vascular smooth muscle following stimulation of the endothelium by
      agonists. Candidates as diverse as K(+) ions, eicosanoids, hydrogen peroxide and
      C-type natriuretic peptide have been implicated as the putative mediator, but
      none has emerged as a 'universal EDHF'. An alternative explanation for the EDHF
      phenomenon is that direct intercellular communication via gap junctions allows
      passive spread of agonist-induced endothelial hyperpolarization through the
      vessel wall. In some arteries, eicosanoids and K(+) ions may themselves initiate
      a conducted endothelial hyperpolarization, thus suggesting that electrotonic
      signalling may represent a general mechanism through which the endothelium
      participates in the regulation of vascular tone.

PMID- 15028644
TI  - Prefrontal cortex asymmetry for memory encoding of words and abstract shapes.
AB  - Previous work suggested a differential contribution of prefrontal cortex (PFC) to
      successful encoding depending on the stimulus material. Here, we tested the
      hypothesis that encoding of words preferentially involves the left PFC, while
      encoding of nonverbal items (abstract shapes) relies on the right PFC. We used an
      experimental design that evaluated encoding of both words and abstract shapes in
      the same healthy volunteers. A transient virtual lesion of the left or the right
      PFC was elicited with transcranial magnetic stimulation (TMS) while subjects
      memorized verbal and nonverbal items. We found that encoding of verbal material
      was disrupted by left PFC stimulation, whereas encoding of nonverbal material was
      disrupted by right PFC stimulation. These results demonstrate a functionally
      relevant lateralization of prefrontal contribution for verbal and nonverbal
      memory encoding.

PMID- 15028645
TI  - Differential vulnerability of anterior white matter in nondemented aging with
      minimal acceleration in dementia of the Alzheimer type: evidence from diffusion
      tensor imaging.
AB  - White matter microstructural integrity was assessed using diffusion tensor
      imaging (DTI) in 25 young adults, 25 nondemented older adults, and 25 age-matched
      older adults with dementia of the Alzheimer type (DAT). For each individual,
      measures of anisotropy and diffusivity were obtained from atlas-transformed
      images in the anterior and posterior callosum and in the frontal, parietal,
      temporal and occipital white matter. These data revealed age differences in
      anisotropy and diffusivity in all assessed regions. Age effects were greater in
      the anterior as opposed to the posterior corpus callosum and greater in the
      frontal white matter than in the temporal, parietal and occipital white matter,
      suggesting age-associated differences in white matter that exhibit a roughly
      anterior-to-posterior gradient. In contrast, individuals with early-stage
      dementia exhibited minimal, if any, additional change in anterior regions but did
      show greater deterioration of white matter in posterior lobar regions. Taken
      collectively, these results indicate that nondemented aging is characterized by
      significant changes in white matter most prominently in anterior brain regions.
      The dissociation between the regional effects of age and dementia status suggests
      that the mechanisms underlying age-associated cognitive decline are likely
      distinct from those underlying DAT.

PMID- 15028646
TI  - Individual differences in anterior cingulate/paracingulate morphology are related
      to executive functions in healthy males.
AB  - The neuropsychological correlates of inter-individual variations in cortical
      folding are poorly understood. Anterior cingulate (AC) cortex is one region
      characterized by considerable variability, particularly with respect to the
      paracingulate sulcus (PCS), which is present in only 30-60% of individuals and
      more commonly found in the left cerebral hemisphere. To investigate whether inter
      individual differences in this PCS asymmetry are related to cognitive
      performance, we classified 30 healthy right-handed males as displaying either a
      leftward, rightward or symmetric pattern of folding based on the incidence and
      extent of the PCS in each hemisphere, and compared their performance on tasks
      engaging executive cognitive processes associated with frontal lobe function. We
      found that the more common leftward PCS asymmetry was associated with better
      performance across verbal and non-verbal executive tasks, but that PCS
      variability had no effect on tasks less dependent on executive functions. These
      results suggest that the leftward pattern of folding is associated with a non
      specific performance advantage on cognitively demanding executive function tasks,
      possibly due to differences in functional interactions between AC/paracingulate
      cortex and connected frontal regions. It therefore appears that normal variations
      in brain morphology are associated with individual differences in cognitive
      abilities.

PMID- 15028647
TI  - GABAA receptors reorganize when layer 4 in ferret somatosensory cortex is
      disrupted by methylazoxymethanol (MAM).
AB  - We established a model of cortical development that arrests the birth of layer 4
      cells by injecting methylazoxymethanol (MAM) on embryonic day 33 (E33) in
      ferrets. This leads to adult somatosensory cortex with a very thin layer 4.
      Earlier, we determined the relative absence of layer 4 changed the growth and
      differentiation of the somatosensory cortex and the growth of thalamic afferents
      into the cortical plate. To identify other features of cortical organization that
      might be altered after MAM treatment, we assessed the distribution of selected
      excitatory and inhibitory receptors in area 3b of ferret somatosensory cortex.
      Initial screening revealed the distribution of several excitatory receptors
      (NMDA, AMPA, kainate) in E33 MAM-treated cortex was similar to that in normal
      adult animals. In contrast, the binding pattern of inhibitory GABAA receptors was
      altered in MAM-treated cortex. Normally, GABAA receptors densely locate in
      central layers of cortex. In E33 MAM-treated animals, GABAA receptor binding
      extended superficially, covering a broader area of cortex. Further experiments
      using antibodies directed against GABAAalpha receptors disclosed that pan alpha
      GABAA receptors strongly localize to layer 4 in normal area 3b. In E33 MAM
      treated cortex, however, GABAAalpha receptors extend outside and are located
      above and below the very thin layer 4. The redistribution of inhibitory receptors
      suggests that layer 4 plays an important role in regulating thalamic terminations
      and also in the resulting ability to refine processing of incoming stimuli.

PMID- 15028648
TI  - Concurrent tonotopic processing streams in auditory cortex.
AB  - The basis for multiple representations of equivalent frequency ranges in auditory
      cortex was studied with physiological and anatomical methods. Our goal was to
      trace the convergence of thalamic, commissural, and corticocortical information
      upon two tonotopic fields in the cat, the primary auditory cortex (AI) and the
      anterior auditory field (AAF). Both fields are among the first cortical levels of
      processing. After neurophysiological mapping of characteristic frequency, we
      injected different retrograde tracers at separate, frequency-matched loci in AI
      and AAF. We found differences in their projections that support the notion of
      largely segregated parallel processing streams in the auditory thalamus and
      cerebral cortex. In each field, ipsilateral cortical input amounts to
      approximately 70% of the number of cells projecting to an isofrequency domain,
      while commissural and thalamic sources are each approximately 15%. Labeled
      thalamic and cortical neurons were concentrated in tonotopically predicted
      regions and in smaller loci far from their spectrally predicted positions. The
      few double-labeled thalamic neurons (<2%) are consistent with the hypothesis that
      information to AI and AAF travels along independent processing streams despite
      widespread regional overlap of thalamic input sources. Double labeling is also
      sparse in both the corticocortical and commissural systems ( approximately 1%),
      confirming their independence. The segregation of frequency-specific channels
      within thalamic and cortical systems is consistent with a model of parallel
      processing in auditory cortex. The global convergence of cells outside the
      targeted frequency domain in AI and AAF could contribute to context-dependent
      processing and to intracortical plasticity and reorganization.

PMID- 15028649
TI  - Multisensory visual-auditory object recognition in humans: a high-density
      electrical mapping study.
AB  - Multisensory object-recognition processes were investigated by examining the
      combined influence of visual and auditory inputs upon object identification--in
      this case, pictures and vocalizations of animals. Behaviorally, subjects were
      significantly faster and more accurate at identifying targets when the picture
      and vocalization were matched (i.e. from the same animal), than when the target
      was represented in only one sensory modality. This behavioral enhancement was
      accompanied by a modulation of the evoked potential in the latency range and
      general topographic region of the visual evoked N1 component, which is associated
      with early feature processing in the ventral visual stream. High-density
      topographic mapping and dipole modeling of this multisensory effect were
      consistent with generators in lateral occipito-temporal cortices, suggesting that
      auditory inputs were modulating processing in regions of the lateral occipital
      cortices. Both the timing and scalp topography of this modulation suggests that
      there are multisensory effects during what is considered to be a relatively early
      stage of visual object-recognition processes, and that this modulation occurs in
      regions of the visual system that have traditionally been held to be unisensory
      processing areas. Multisensory inputs also modulated the visual 'selection
      negativity', an attention dependent component of the evoked potential this is
      usually evoked when subjects selectively attend to a particular feature of a
      visual stimulus.

PMID- 15028650
TI  - Neurotensin enhances endogenous extracellular glutamate levels in primary
      cultures of rat cortical neurons: involvement of neurotensin receptor in NMDA
      induced excitotoxicity.
AB  - Primary cultures of cortical neurons were employed to investigate the modulatory
      effects of neurotensin on glutamate excitotoxicity and the possible
      neuroprotective actions of the neurotensin receptor antagonist SR48692. NT(1-13)
      and its biologically active fragment NT(8-13) at 10 nM (30 min) increased
      endogenous glutamate levels. The inactive fragment NT(1-7) (10-100 nM; 30 min)
      was ineffective. SR48692, applied 20 min before NT and maintained in contact with
      cells during NT exposure as well as a low calcium medium (from the onset of the
      experiment) prevented the NT(1-13)-induced increase in extracellular glutamate
      levels. The addition of NMDA (0.01-10 micro M; 10 min) to the medium
      concentration-dependently increased extracellular glutamate levels. When 0.1 nM
      NT(1-13) was added in combination with 0.01 micro M NMDA, in concentrations by
      themselves ineffective, a significant increase in glutamate levels was observed.
      SR48692 at 100 nM counteracted the increase in glutamate levels induced by 0.1 nM
      NT(1-13) plus 0.01 micro M NMDA. The inhibitor of the protein kinase C (PKC)
      calphostin C (0.1 micro M; 10 min before NT) prevented the increase in glutamate
      levels induced by the combined treatments. The morphological analysis indicated
      that 10 nM NT(1-13) enhanced the glutamate (10 min)-induced apoptosis. The
      peptide was added 30 min prior to glutamate and maintained in contact with cells
      during the glutamate exposure. The presence of 100 nM SR48692 (20 min before NT)
      antagonized this effect of NT(1-13). These findings support the view of a
      pathophysiological role for NT in the cerebral cortex. Thus, under pathological
      conditions NT by enhancing glutamate outflow and by amplifying the NMDA-mediated
      glutamate signaling may be involved in increasing the degeneration of cortical
      neurons.

PMID- 15028651
TI  - Abstracts of the British Society of Gastroenterology Annual Meeting. 21-24 March
      2004, Glasgow, United Kingdom.

PMID- 15028662
TI  - BSAC standardized disc susceptibility testing method (version 3).

PMID- 15028663
TI  - Increasing resistance to antimicrobial agents of Gram-negative organisms isolated
      at a London teaching hospital, 1995-2000.
AB  - OBJECTIVES: To investigate the changes in resistance frequencies of common Gram
      negative bacteria in a London teaching hospital. METHODS: Antimicrobial
      susceptibilities were analysed for the 6 years 1995-2000. Gentamicin-resistant
      isolates from 1995 and 2000 were typed by a repetitive element sequence-based PCR
      (Rep-PCR) method. RESULTS: Resistance rates for all agents and all organisms were
      higher in isolates from inpatients than in those from outpatients or general
      practice. For most agents and most species there was a trend for a highly
      significant linear increase in resistance over the study period, and there was
      significant cross-resistance between different agents. Increases in resistance
      were especially marked in Klebsiella, Enterobacter and Acinetobacter spp.,
      organisms that tend to cause outbreaks of hospital cross-infection. For example,
      the increases in gentamicin resistance in isolates from inpatients was from 2.9%
      to 23.5% for Klebsiella spp., from 0.3% to 20.8% for Enterobacter spp. and from
      10.1% to 42.2% for Acinetobacter spp. There was much less increase in acquired
      resistance in Escherichia coli and Pseudomonas aeruginosa, organisms that tend to
      cause endogenous infections, with gentamicin resistance in isolates from
      inpatients increasing from 0.4% to 3.2% for E. coli and decreasing from 4.6% to
      3.6% for P. aeruginosa. Rep-PCR typing showed considerable diversity amongst
      gentamicin-resistant isolates of E. coli and P. aeruginosa, but dominance by a
      limited number of presumably epidemic types of gentamicin-resistant isolates of
      the other species. CONCLUSIONS: Multiple antibiotic resistance has increased
      dramatically in some hospital isolates, and appears to be associated with
      hospital cross-infection.

PMID- 15028664
TI  - Antibiotic use in animals.

PMID- 15028665
TI  - Emergence of fluoroquinolone resistance in the native Campylobacter coli
      population of pigs exposed to enrofloxacin.
AB  - OBJECTIVE: The effect of a single 5 day enrofloxacin treatment on the native
      Campylobacter coli population in conventionally weaned 5-week-old pigs was
      investigated. MATERIALS: Twelve pigs were split into two groups of six: one group
      was treated with a therapeutic dose (15 mg/pig/day) of enrofloxacin and the other
      remained untreated to act as the control. Campylobacter coli were isolated from
      faecal samples and tested for ciprofloxacin resistance by measuring MIC values.
      Mutations in the quinolone resistance-determining region (QRDR) of the gyrA gene
      of resistant isolates were identified by sequencing and denaturing HPLC. Levels
      of enrofloxacin and its primary metabolite ciprofloxacin in the pig faeces were
      also measured by HPLC. RESULTS: No quinolone-resistant C. coli (n = 867) were
      detected in any of the pigs prior to treatment, indicating <0.1% resistance in
      the group. Resistant C. coli were isolated from pigs for up to 35 days after
      treatment with a therapeutic dose. These resistant C. coli had MIC values of 128
      mg/L and 8-16 mg/L for nalidixic acid and ciprofloxacin, respectively, and the
      same single point mutation causing a Thr-86 to Ile substitution in the QRDR was
      identified in each. The concentration of enrofloxacin in the pig faeces was 2-4
      micro g/g faeces for the duration of the 5 day therapeutic treatment and was
      detected up to 10 days post-treatment. Ciprofloxacin was also measured and peaked
      at 0.6 micro g/g faeces in the treated group. CONCLUSION: This study provides
      evidence that a single course of enrofloxacin treatment contributes directly to
      the emergence and persistence of fluoroquinolone resistance in C. coli.

PMID- 15028666
TI  - Changes in in vitro susceptibility of influenza A H3N2 viruses to a neuraminidase
      inhibitor drug during evolution in the human host.
AB  - OBJECTIVES: Influenza A H3N2 viruses isolated recently have characteristic
      receptor binding properties that may decrease susceptibility to neuraminidase
      inhibitor drugs. A panel of clinical isolates and recombinant viruses generated
      by reverse genetics were characterized and tested for susceptibility to
      zanamivir. METHODS: Plaque reduction assays and neuraminidase enzyme inhibition
      assays were used to assess susceptibility to zanamivir. Receptor binding
      properties of the viruses were characterized by differential agglutination of red
      blood cells (RBCs) from different species. Sequence analysis of the
      haemagglutinin (HA) and neuraminidase (NA) genes was carried out. RESULTS:
      Characterization of a panel of H3N2 clinical isolates from 1968 to 2000 showed a
      gradual decrease in agglutination of chicken and guinea pig RBCs over time,
      although all isolates could agglutinate turkey RBCs equally. Sequence analysis of
      the HA and NA genes identified mutations in conserved residues of the HA1
      receptor binding site, in particular Leu-226 --> Ile-226/Val-226, and
      modification of potential glycosylation site motifs. This may be indicative of
      changes in virus binding to sialic acid (SA) receptors in recent years. Although
      recent isolates had reduced susceptibility to zanamivir in MDCK cell based plaque
      reduction assays, no difference was found in an NA enzyme-inhibition assay.
      Assays with recombinant isogenic viruses showed that the recent HA, but not the
      NA, conferred reduced susceptibility to zanamivir. CONCLUSION: This study
      demonstrates that recent clinical isolates of influenza A H3N2 virus no longer
      agglutinate chicken RBCs, but despite significant receptor binding changes as a
      result of changes in HA, there was little variation in sensitivity of the NA to
      zanamivir.

PMID- 15028667
TI  - Comparative in vitro activity of telavancin (TD-6424), a rapidly bactericidal,
      concentration-dependent anti-infective with multiple mechanisms of action against
      Gram-positive bacteria.
AB  - OBJECTIVE: We compared the in vitro activity of telavancin with that of
      vancomycin, teicoplanin, linezolid, quinupristin/dalfopristin, moxifloxacin and
      ampicillin, penicillin or oxacillin as appropriate, by the NCCLS/EUCAST and BSAC
      methods. METHODS: The organisms (n = 401) included in the study were patient
      isolates from St Thomas' Hospital and were selected to include representatives of
      the clinically important Gram-positive aerobic species. Susceptibility testing
      was performed by agar dilution methods on Mueller-Hinton agar according to the
      NCCLS/EUCAST guidelines, in comparison with Iso-Sensitest agar according to the
      BSAC guidelines. RESULTS: Telavancin was active against all the Gram-positive
      species tested and nearly 90% of isolates included in the study had telavancin
      MICs </= 1 mg/L. Vancomycin-resistant enterococci and lactobacilli isolates with
      vancomycin MICs > 64 mg/L had telavancin MIC ranges of 0.5-8 and 2-16 mg/L,
      respectively. There was no evidence of cross-resistance with other comparator
      drugs. The results for telavancin for the two susceptibility testing methods were
      mostly either the same or within one doubling dilution. CONCLUSION: The
      susceptibility breakpoints for telavancin have yet to be established, but it
      would appear that telavancin has superior potency to the other tested
      glycopeptides, and on a weight-for-weight basis displays activity that is
      comparable to, or better than, that of the other agents tested.

PMID- 15028668
TI  - Severely altered guanidino compound levels, disturbed body weight homeostasis and
      impaired fertility in a mouse model of guanidinoacetate N-methyltransferase
      (GAMT) deficiency.
AB  - We generated a knockout mouse model for guanidinoacetate N-methyltransferase
      (GAMT) deficiency (MIM 601240), the first discovered human creatine deficiency
      syndrome, by gene targeting in embryonic stem cells. Disruption of the open
      reading frame of the murine GAMT gene in the first exon resulted in the
      elimination of 210 of the 237 amino acids present in mGAMT. The creation of an
      mGAMT null allele was verified at the genetic, RNA and protein levels. GAMT
      knockout mice have markedly increased guanidinoacetate (GAA) and reduced creatine
      and creatinine levels in brain, serum and urine, which are key findings in human
      GAMT patients. In vivo (31)P magnetic resonance spectroscopy showed high levels
      of PGAA and reduced levels of creatine phosphate in heart, skeletal muscle and
      brain. These biochemical alterations were comparable to those found in human GAMT
      patients and can be attributed to the very similar GAMT expression patterns found
      by us in human and mouse tissues. We provide evidence that GAMT deficiency in
      mice causes biochemical adaptations in brain and skeletal muscle. It is
      associated with increased neonatal mortality, muscular hypotonia, decreased male
      fertility and a non-leptin-mediated life-long reduction in body weight due to
      reduced body fat mass. Therefore, GAMT knockout mice are a valuable creatine
      deficiency model for studying the effects of high-energy phosphate depletion in
      brain, heart, skeletal muscle and other organs.

PMID- 15028669
TI  - Polymorphisms at positions -22 and -348 in the promoter of the BAT1 gene affect
      transcription and the binding of nuclear factors.
AB  - BAT1 (D6S81E, UAP56) lies in the central MHC between TNF and HLA-B, a region
      containing genes that affect susceptibility to immunopathologic disorders. BAT1
      protein may be directly responsible for the genetic association, as antisense
      studies show it can down-regulate inflammatory cytokines. Here we investigate
      polymorphisms at positions -22 and -348 relative to the BAT1 transcription start
      site. DNA samples from healthy donors were used to confirm haplotypic
      associations with the type 1 diabetes-susceptible 8.1 ancestral haplotype (AH;
      HLA-A1,B8,BAT1-22*C,BAT1-348*C,DR3 ) and the diabetes-resistant 7.1 AH (HLA
      A3,B7,BAT1-22*G,BAT1-348*T,DR15). Alleles carried at BAT1-22 and -348 were in
      linkage disequilibrium. Electrophoretic mobility shift assays using nuclear
      proteins from T-cells (Jurkat and HT2), monocytes (THP1, U937) and epithelial
      cells (HeLa and MDA468) demonstrated DNA : protein complexes binding
      oligonucleotides spanning positions -22 and -348 on the 7.1 AH only. Competition
      assays, supershifts and molecular weight determinations suggest the complexes
      include the transcription factors YY1 (at -348) and Oct1 (at -22). Promoter
      activity was demonstrated using 520 bp and 336 bp fragments cloned from
      immediately upstream of the transcription start site and carrying all
      combinations of -22 and -348 alleles, suggesting an unidentified non-polymorphic
      sequence within 336 bp of the start site drives transcription. The 520 bp
      fragment of the BAT1 promoter cloned from the 8.1 AH was slightly less efficient
      than the equivalent from the 7.1 AH, whilst the reverse was observed with 336 bp
      fragments. This suggests BAT1 transcription on the 7.1 AH is modified by
      interactions involving DNA flanking positions -22 and -348.

PMID- 15028670
TI  - Idebenone delays the onset of cardiac functional alteration without correction of
      Fe-S enzymes deficit in a mouse model for Friedreich ataxia.
AB  - Friedreich ataxia (FRDA), a progressive neurodegenerative disorder associated
      with cardiomyopathy, is caused by severely reduced frataxin, a mitochondrial
      protein involved in Fe-S cluster assembly. We have recently generated mouse
      models that reproduce important progressive pathological and biochemical features
      of the human disease. Our frataxin-deficient mouse models initially demonstrate
      time-dependent intramitochondrial iron accumulation, which occurs after onset of
      the pathology and after inactivation of the Fe-S dependent enzymes. Here, we
      report a more detailed pathophysiological characterization of our mouse model
      with isolated cardiac disease by echocardiographic, biochemical and histological
      studies and its use for placebo-controlled therapeutic trial with Idebenone. The
      Fe-S enzyme deficiency occurs at 4 weeks of age, prior to cardiac dilatation and
      concomitant development of left ventricular hypertrophy, while the mitochondrial
      iron accumulation occurs at a terminal stage. From 7 weeks onward, Fe-S enzyme
      activities are strongly decreased and are associated with lower levels of
      oxidative stress markers, as a consequence of reduced respiratory chain activity.
      Furthermore, we demonstrate that the antioxidant Idebenone delays the cardiac
      disease onset, progression and death of frataxin deficient animals by 1 week, but
      does not correct the Fe-S enzyme deficiency. Our results support the view that
      frataxin is a necessary, albeit non-essential, component of the Fe-S cluster
      biogenesis, and indicate that Idebenone acts downstream of the primary Fe-S
      enzyme deficit. Furthermore, our results demonstrate that Idebenone is
      cardioprotective even in the context of a complete lack of frataxin, which
      further supports its utilization for the treatment of FRDA.

PMID- 15028671
TI  - Loss of the Max-interacting protein Mnt in mice results in decreased viability,
      defective embryonic growth and craniofacial defects: relevance to Miller-Dieker
      syndrome.
AB  - The Mnt gene encodes a Mad-family bHLH transcription factor located on human
      17p13.3. Mnt is one of 20 genes deleted in a heterozygous fashion in Miller
      Dieker syndrome (MDS), a contiguous gene syndrome that consists of severe
      neuronal migration defects and craniofacial dysmorphic features. Mnt can inhibit
      Myc-dependent cell transformation and is hypothesized to counterbalance the
      effects of c-Myc on growth and proliferation in vivo by competing with Myc for
      binding to Max and by repressing target genes activated by Myc : Max
      heterodimers. Unlike the related Mad family members, Mnt is expressed
      ubiquitously and Mnt/Max heterodimers are found in proliferating cells that
      contain Myc/Max heterodimers, suggesting a unique role for Mnt during
      proliferation. To examine the role of Mnt in vivo, we produced mice with null
      (Mnt(KO)) and loxP-flanked conditional knock-out (Mnt(CKO)) alleles of Mnt.
      Virtually all Mnt(KO/KO) mutants in a mixed (129S6 x NIH Black Swiss) or inbred
      (129S6) genetic background died perinatally. Mnt-deficient embryos exhibited
      small size throughout development and showed reduced levels of c-Myc and N-Myc.
      In addition, 37% of the mixed background mutants displayed cleft palate as well
      as retardation of skull development, a phenotype not observed in the inbred
      mutants. These results demonstrate an important role for Mnt in embryonic
      development and survival, and suggest that Mnt may play a role in the
      craniofacial defects displayed by MDS patients.

PMID- 15028673
TI  - A potential role for the nucleolus in L1 retrotransposition.
AB  - Determining the subcellular localization of the L1 ORF2 protein (ORF2p) has been
      impossible to date because of technical limitations in detecting either
      endogenous or overexpressed forms of the protein. Here we report visualization of
      the full-length ORF2p in cultured human cells following expression in a modified
      vaccinia virus/T7 RNA polymerase (MVA/T7RP) system. The MVA/T7RP system was used
      to ascertain subcellular localization of L1 ORF1p and ORF2p both as fusions with
      green fluorescent protein and by immunocytochemistry. Full-length ORF2p was
      predominantly cytoplasmic, while carboxy-terminal-deleted ORF2p localized
      additionally to the nucleolus. We mapped a functional nucleolar localization
      signal in ORF2p. ORF1p appeared in the cytoplasm with a speckled pattern and
      colocalized with ORF2p in nucleoli in a subset of cells. These findings help
      explain the presence of chimeras between L1s and small RNA gene sequences
      recently discovered in the human genome.

PMID- 15028672
TI  - QRX, a novel homeobox gene, modulates photoreceptor gene expression.
AB  - A novel paired-like homeobox gene, designated as Qrx, was identified by a yeast
      one-hybrid screen using the bovine Rhodopsin promoter Ret-1 DNA regulatory
      element as bait. Qrx is preferentially expressed in both the outer and inner
      nuclear layers of the retina. Its homeodomain is nearly identical to that of
      Rx/Rax, a transcription factor that is essential for eye development, but it
      shares only limited homology elsewhere. Although Qrx and Rx/Rax show similar DNA
      binding properties in vitro, the two proteins demonstrate distinct target
      selectivity and functional behavior in promoter activity assays. QRX
      synergistically increases the transactivating function of the photoreceptor
      transcription factors Crx and NRL and it physically interacts with CRX. Qrx is
      present in the bovine and human genomes, but appears to be absent from the mouse
      genome. Nonetheless, a 5.8 kb upstream region of human QRX is capable of
      directing expression in presumptive photoreceptor precursor cells in transgenic
      mice. These results indicate that Qrx may be involved in modulating photoreceptor
      gene expression. In addition, the finding of rare heterozygous QRX sequence
      changes in three individuals with retinal degeneration raises the possibility
      that QRX may be involved in disease pathogenesis.

PMID- 15028674
TI  - Spx-RNA polymerase interaction and global transcriptional control during
      oxidative stress.

PMID- 15028676
TI  - Class II 3-hydroxy-3-methylglutaryl coenzyme A reductases.

PMID- 15028675
TI  - Unveiling molecular scaffolds of the type IV secretion system.

PMID- 15028677
TI  - Complete genomic sequence of the virulent Salmonella bacteriophage SP6.
AB  - We report the complete genome sequence of enterobacteriophage SP6, which infects
      Salmonella enterica serovar Typhimurium. The genome contains 43,769 bp, including
      a 174-bp direct terminal repeat. The gene content and organization clearly place
      SP6 in the coliphage T7 group of phages, but there is approximately 5 kb at the
      right end of the genome that is not present in other members of the group, and
      the homologues of T7 genes 1.3 through 3 appear to have undergone an unusual
      reorganization. Sequence analysis identified 10 putative promoters for the SP6
      encoded RNA polymerase and seven putative rho-independent terminators. The
      terminator following the gene encoding the major capsid subunit has a termination
      efficiency of about 50% with the SP6-encoded RNA polymerase. Phylogenetic
      analysis of phages related to SP6 provided clear evidence for horizontal exchange
      of sequences in the ancestry of these phages and clearly demarcated exchange
      boundaries; one of the recombination joints lies within the coding region for a
      phage exonuclease. Bioinformatic analysis of the SP6 sequence strongly suggested
      that DNA replication occurs in large part through a bidirectional mechanism,
      possibly with circular intermediates.

PMID- 15028679
TI  - Transcriptional analysis of spo0A overexpression in Clostridium acetobutylicum
      and its effect on the cell's response to butanol stress.
AB  - Spo0A is the regulator of stationary-phase events and is required for
      transcription of solvent formation genes in Clostridium acetobutylicum. In order
      to elucidate the role of spo0A in differentiation, we performed transcriptional
      analysis of 824(pMSPOA) (a spo0A-overexpressing C. acetobutylicum strain with
      enhanced sporulation) against a plasmid control strain. DNA microarray data were
      contrasted to data from a spo0A knockout strain (SKO1) that neither sporulates
      nor produces solvents. Transcripts of fatty acid metabolism genes, motility and
      chemotaxis genes, heat shock protein genes, and genes encoding the Fts family of
      cell division proteins were differentially expressed in the two strains,
      suggesting that these genes play roles in sporulation and the solvent stress
      response. 824(pMSPOA) alone showed significant downregulation of many glycolytic
      genes in stationary phase, which is consistent with metabolic flux analysis data.
      Surprisingly, spo0A overexpression resulted in only nominal transcriptional
      changes of regulatory genes (abrB and sigF) whose expression was significantly
      altered in SKO1. Overexpression of spo0A imparted increased tolerance and
      prolonged metabolism in response to butanol stress. While most of the
      differentially expressed genes appear to be part of a general stress response
      (similar to patterns in two plasmid control strains and a groESL-overexpressing
      strain), several genes were expressed at higher levels at early time points after
      butanol challenge only in 824(pMSPOA). Most of these genes were related to
      butyryl coenzyme A and butyrate formation and/or assimilation, but they also
      included the cell division gene ftsX, the gyrase subunit-encoding genes gyrB and
      gyrA, DNA synthesis and repair genes, and fatty acid synthesis genes, all of
      which might play a role in the immediate butanol stress response, and thus in
      enhanced butanol tolerance.

PMID- 15028680
TI  - Sortase B, a new class of sortase in Listeria monocytogenes.
AB  - Sortases are transamidases that covalently link proteins to the peptidoglycan of
      gram-positive bacteria. The genome of the pathogenic bacterium Listeria
      monocytogenes encodes two sortases genes, srtA and srtB. The srtA gene product
      anchors internalin and some other LPXTG-containing proteins to the listerial
      surface. Here, we focus on the role of the second sortase, SrtB. Whereas SrtA
      acts on most of the proteins in the peptidoglycan fraction, SrtB appears to
      target minor amounts of surface polypeptides. We identified one of the SrtB
      anchored proteins as the virulence factor SvpA, a surface-exposed protein which
      does not contain the LPXTG motif. Therefore, as in Staphylococcus aureus, the
      listerial SrtB represents a second class of sortase in L. monocytogenes, involved
      in the attachment of a subset of proteins to the cell wall, most likely by
      recognizing an NXZTN sorting motif. The DeltasrtB mutant strain does not have
      defects in bacterial entry, growth, or motility in tissue-cultured cells and does
      not show attenuated virulence in mice. SrtB-mediated anchoring could therefore be
      required to anchor surface proteins involved in the adaptation of this
      microorganism to different environmental conditions.

PMID- 15028678
TI  - Crystallographic comparison of manganese- and iron-dependent homoprotocatechuate
      2,3-dioxygenases.
AB  - The X-ray crystal structures of homoprotocatechuate 2,3-dioxygenases isolated
      from Arthrobacter globiformis and Brevibacterium fuscum have been determined to
      high resolution. These enzymes exhibit 83% sequence identity, yet their
      activities depend on different transition metals, Mn2+ and Fe2+, respectively.
      The structures allow the origins of metal ion selectivity and aspects of the
      molecular mechanism to be examined in detail. The homotetrameric enzymes belong
      to the type I family of extradiol dioxygenases (vicinal oxygen chelate
      superfamily); each monomer has four betaalphabetabetabeta modules forming two
      structurally homologous N-terminal and C-terminal barrel-shaped domains. The
      active-site metal is located in the C-terminal barrel and is ligated by two
      equatorial ligands, H214NE1 and E267OE1; one axial ligand, H155NE1; and two to
      three water molecules. The first and second coordination spheres of these enzymes
      are virtually identical (root mean square difference over all atoms, 0.19 A),
      suggesting that the metal selectivity must be due to changes at a significant
      distance from the metal and/or changes that occur during folding. The substrate
      (2,3-dihydroxyphenylacetate [HPCA]) chelates the metal asymmetrically at sites
      trans to the two imidazole ligands and interacts with a unique, mobile C-terminal
      loop. The loop closes over the bound substrate, presumably to seal the active
      site as the oxygen activation process commences. An "open" coordination site
      trans to E267 is the likely binding site for O2. The geometry of the enzyme
      substrate complexes suggests that if a transiently formed metal-superoxide
      complex attacks the substrate without dissociation from the metal, it must do so
      at the C-3 position. Second-sphere active-site residues that are positioned to
      interact with the HPCA and/or bound O2 during catalysis are identified and
      discussed in the context of current mechanistic hypotheses.

PMID- 15028681
TI  - Contrasting effects of sigmaE on compartmentalization of sigmaF activity during
      sporulation of Bacillus subtilis.
AB  - Spore formation by Bacillus subtilis is a primitive form of development. In
      response to nutrient starvation and high cell density, B. subtilis divides
      asymmetrically, resulting in two cells with different sizes and cell fates.
      Immediately after division, the transcription factor sigmaF becomes active in the
      smaller prespore, which is followed by the activation of sigmaE in the larger
      mother cell. In this report, we examine the role of the mother cell-specific
      transcription factor sigmaE in maintaining the compartmentalization of gene
      expression during development. We have studied a strain with a deletion of the
      spoIIIE gene, encoding a DNA translocase, that exhibits uncompartmentalized
      sigmaF activity. We have determined that the deletion of spoIIIE alone does not
      substantially impact compartmentalization, but in the spoIIIE mutant, the
      expression of putative peptidoglycan hydrolases under the control of sigmaE in
      the mother cell destroys the integrity of the septum. As a consequence, small
      proteins can cross the septum, thereby abolishing compartmentalization. In
      addition, we have found that in a mutant with partially impaired control of
      sigmaF, the activation of sigmaE in the mother cell is important to prevent the
      activation of sigmaF in this compartment. Therefore, the activity of sigmaE can
      either maintain or abolish the compartmentalization of sigmaF, depending upon the
      genetic makeup of the strain. We conclude that sigmaE activity must be carefully
      regulated in order to maintain compartmentalization of gene expression during
      development.

PMID- 15028682
TI  - A conjugation-based system for genetic analysis of group II intron splicing in
      Lactococcus lactis.
AB  - The conjugative element pRS01 from Lactococcus lactis encodes the putative
      relaxase protein LtrB. The ltrB gene is interrupted by the functional group II
      intron Ll.ltrB. Accurate splicing of the two ltrB exons is required for synthesis
      of the mRNA encoding the LtrB conjugative relaxase and subsequent plasmid
      transfer. A conjugation-based genetic assay was developed to identify Ll.ltrB
      mutations that affect splicing. In this assay a nonsplicing, transfer-defective
      pRS01 derivative (pM1014) and a shuttle vector carrying the ltrB region,
      including the Ll.ltrB intron (pCOM9), are used. pCOM9 provides splicing-dependent
      complementation of the transfer defect of pM1014. Site-directed mutations within
      Ll.ltrB, either in the catalytic RNA or in the intron-encoded protein gene ltrA,
      were generated in the context of pCOM9. When these mutants were tested in the
      conjugation-based assay, significantly reduced mating was observed. Quantitative
      molecular analysis of in vivo splicing activity confirmed that the observed
      mating defects resulted from reduced splicing. Once the system was validated for
      the engineered mutants, random mutagenesis of the intron followed by genetic and
      molecular screening for splicing defects resulted in identification of point
      mutations that affect splicing.

PMID- 15028683
TI  - Sporulation phenotype of a Bacillus subtilis mutant expressing an unprocessable
      but active sigmaE transcription factor.
AB  - SigmaE, a sporulation-specific sigma factor of Bacillus subtilis, is formed from
      an inactive precursor (pro-sigmaE) by a developmentally regulated processing
      reaction that removes 27 amino acids from the proprotein's amino terminus. A sigE
      variant (sigE335) lacking 15 amino acids of the prosequence is not processed into
      mature sigmaE but is active without processing. In the present work, we
      investigated the sporulation defect in sigE335-expressing B. subtilis, asking
      whether it is the bypass of proprotein processing or a residual inhibition of
      sigmaE activity that is responsible. Fluorescence microscopy demonstrated that
      sigE335-expressing B. subtilis progresses further into sporulation (stage III)
      than do strains lacking sigmaE activity (stage II). Consistent with its stage III
      phenotype, and a defect in sigmaE activity rather than its timing, the sigE335
      allele did not disturb early sporulation gene expression but did inhibit the
      expression of late sporulation genes (gerE and sspE). The Spo- phenotype of
      sigE335 was found to be recessive to wild-type sigE. In vivo assays of sigmaE
      activity in sigE, sigE335, and merodiploid strains indicate that the residual
      prosequence on sigmaE335, still impairs its activity to function as a
      transcription factor. The data suggest that the 11-amino-acid extension on
      sigmaE335 allows it to bind RNA polymerase and direct the resulting holoenzyme to
      sigmaE-dependent promoters but reduces the enzyme's ability to initiate
      transcription initiation and/or exit from the promoter.

PMID- 15028684
TI  - Transcriptional analysis of butanol stress and tolerance in Clostridium
      acetobutylicum.
AB  - The effects of challenges with low (0.25%, vol/vol) and high (0.75%)
      concentrations of butanol on the growth, glucose metabolism, product formation,
      and transcriptional program of the solvent-tolerant Clostridium acetobutylicum
      strain 824(pGROE1) and the plasmid control strain 824(pSOS95del) were used to
      study solvent tolerance and stress response. Strain 824(pGROE1) was generated by
      groESL overexpression. The growth of 824(pGROE1) was less inhibited than that of
      824(pSOS95del), and 824(pGROE1) was able to metabolize glucose over the entire
      course of the culture (60 h postchallenge) while glucose metabolism in
      824(pSOS95del) lasted 24 h. A comparison of their respective DNA array-based
      transcriptional profiles identified genes with similar expression patterns (these
      genes are likely to be part of a general butanol stress response) and genes with
      opposite expression patterns (these genes are likely to be associated with
      increased tolerance to butanol). Both strains exhibited a butanol dose-dependent
      increase in expression of all major stress protein genes, including groES, dnaKJ,
      hsp18, and hsp90; all major solvent formation genes, including aad, ctfA and -B,
      adc, and bdhA and -B (an unexpected and counterintuitive finding); the butyrate
      formation genes (ptb and buk); the butyryl coenzyme A biosynthesis operon genes;
      fructose bisphosphate aldolase; and a gene with homology to Bacillus subtilis
      kinA. A dose-dependent decrease in expression was observed for the genes of the
      major fatty acid synthesis operon (also an unexpected and counterintuitive
      finding), several glycolytic genes, and a few sporulation genes. Genes with
      opposite expression kinetics included rlpA, artP, and a gene encoding a hemin
      permease. Taken together, these data suggest that stress, even when it derives
      from the solvent product itself, triggers the induction of the solvent formation
      genes.

PMID- 15028685
TI  - DNA sequence duplication in Rhodobacter sphaeroides 2.4.1: evidence of an ancient
      partnership between chromosomes I and II.
AB  - The complex genome of Rhodobacter sphaeroides 2.4.1, composed of chromosomes I
      (CI) and II (CII), has been sequenced and assembled. We present data
      demonstrating that the R. sphaeroides genome possesses an extensive amount of
      exact DNA sequence duplication, 111 kb or approximately 2.7% of the total
      chromosomal DNA. The chromosomal DNA sequence duplications were aligned to each
      other by using MUMmer. Frequency and size distribution analyses of the exact DNA
      duplications revealed that the interchromosomal duplications occurred prior to
      the intrachromosomal duplications. Most of the DNA sequence duplications in the
      R. sphaeroides genome occurred early in species history, whereas more recent
      sequence duplications are rarely found. To uncover the history of gene
      duplications in the R. sphaeroides genome, 44 gene duplications were sampled and
      then analyzed for DNA sequence similarity against orthologous DNA sequences.
      Phylogenetic analysis revealed that approximately 80% of the total gene
      duplications examined displayed type A phylogenetic relationships; i.e., one copy
      of each member of a duplicate pair was more similar to its orthologue, found in a
      species closely related to R. sphaeroides, than to its duplicate, counterpart
      allele. The data reported here demonstrate that a massive level of gene
      duplications occurred prior to the origin of the R. sphaeroides 2.4.1 lineage.
      These findings lead to the conclusion that there is an ancient partnership
      between CI and CII of R. sphaeroides 2.4.1.

PMID- 15028686
TI  - Transcriptional activation by Bacillus subtilis ResD: tandem binding to target
      elements and phosphorylation-dependent and -independent transcriptional
      activation.
AB  - The expression of genes involved in nitrate respiration in Bacillus subtilis is
      regulated by the ResD-ResE two-component signal transduction system. The membrane
      bound ResE sensor kinase perceives a redox-related signal(s) and phosphorylates
      the cognate response regulator ResD, which enables interaction of ResD with ResD
      dependent promoters to activate transcription. Hydroxyl radical footprinting
      analysis revealed that ResD tandemly binds to the -41 to -83 region of hmp and
      the -46 to -92 region of nasD. In vitro runoff transcription experiments showed
      that ResD is necessary and sufficient to activate transcription of the ResDE
      regulon. Although phosphorylation of ResD by ResE kinase greatly stimulated
      transcription, unphosphorylated ResD, as well as ResD with a phosphorylation site
      (Asp57) mutation, was able to activate transcription at a low level. The D57A
      mutant was shown to retain the activity in vivo to induce transcription of the
      ResDE regulon in response to oxygen limitation, suggesting that ResD itself, in
      addition to its activation through phosphorylation-mediated conformation change,
      senses oxygen limitation via an unknown mechanism leading to anaerobic gene
      activation.

PMID- 15028688
TI  - Hydrogen peroxide production in Streptococcus pyogenes: involvement of lactate
      oxidase and coupling with aerobic utilization of lactate.
AB  - Streptococcus pyogenes strains can be divided into two classes, one capable and
      the other incapable of producing H2O2 (M. Saito, S. Ohga, M. Endoh, H. Nakayama,
      Y. Mizunoe, T. Hara, and S. Yoshida, Microbiology 147:2469-2477, 2001). In the
      present study, this dichotomy was shown to parallel the presence or absence of
      H2O2-producing lactate oxidase activity in permeabilized cells. Both lactate
      oxidase activity and H2O2 production under aerobic conditions were detectable
      only after glucose in the medium was exhausted. Thus, the glucose-repressible
      lactate oxidase is likely responsible for H2O2 production in S. pyogenes. Of the
      other two potential H2O2-producing enzymes of this bacterium, NADH and alpha
      glycerophosphate oxidase, only the former exhibited low but significant activity
      in either class of strains. This activity was independent of the growth phase,
      suggesting that the protein may serve in vivo as a subunit of the H2O2-scavenging
      enzyme NAD(P)H-linked alkylhydroperoxide reductase. The activity of lactate
      oxidase was associated with the membrane while that of NADH oxidase was in the
      soluble fraction, findings consistent with their respective physiological roles,
      i.e., the production and scavenging of H2O2. Analyses of fermentation end
      products revealed that the concentration of lactate initially increased with time
      and decreased on glucose exhaustion, while that of acetate increased during the
      culture. These results suggest that the lactate oxidase activity of H2O2
      producing cells oxidizes lactate to pyruvate, which is in turn converted to
      acetate. This latter process proceeds presumably via acetyl coenzyme A and acetyl
      phosphate with formation of extra ATP.

PMID- 15028687
TI  - Agrobacterium-mediated transformation of Aspergillus awamori in the absence of
      full-length VirD2, VirC2, or VirE2 leads to insertion of aberrant T-DNA
      structures.
AB  - Reductions to 2, 5, and 42% of the wild-type transformation efficiency were found
      when Agrobacterium mutants carrying transposon insertions in virD2, virC2, and
      virE2, respectively, were used to transform Aspergillus awamori. The structures
      of the T-DNAs integrated into the host genome by these mutants were analyzed by
      Southern and sequence analyses. The T-DNAs of transformants obtained with the
      virE2 mutant had left-border truncations, whereas those obtained with the virD2
      mutant had truncated right ends. From this analysis, it was concluded that the
      virulence proteins VirD2 and VirE2 are required for full-length T-DNA integration
      and that these proteins play a role in protecting the right and left T-DNA
      borders, respectively. Multicopy and truncated T-DNA structures were detected in
      the majority of the transformants obtained with the virC2 mutant, indicating that
      VirC2 plays a role in correct T-DNA processing and is required for single-copy T
      DNA integration.

PMID- 15028689
TI  - The fixABCX genes in Rhodospirillum rubrum encode a putative membrane complex
      participating in electron transfer to nitrogenase.
AB  - In our efforts to identify the components participating in electron transport to
      nitrogenase in Rhodospirillum rubrum, we used mini-Tn5 mutagenesis followed by
      metronidazole selection. One of the mutants isolated, SNT-1, exhibited a
      decreased growth rate and about 25% of the in vivo nitrogenase activity compared
      to the wild-type values. The in vitro nitrogenase activity was essentially wild
      type, indicating that the mutation affects electron transport to nitrogenase.
      Sequencing showed that the Tn5 insertion is located in a region with a high level
      of similarity to fixC, and extended sequencing revealed additional putative fix
      genes, in the order fixABCX. Complementation of SNT-1 with the whole fix gene
      cluster in trans restored wild-type nitrogenase activity and growth. Using
      Western blotting, we demonstrated that expression of fixA and fixB occurs only
      under conditions under which nitrogenase also is expressed. SNT-1 was further
      shown to produce larger amounts of both ribulose 1,5-bisphosphate
      carboxylase/oxygenase and polyhydroxy alkanoates than the wild type, indicating
      that the redox status is affected in this mutant. Using Western blotting, we
      found that FixA and FixB are soluble proteins, whereas FixC most likely is a
      transmembrane protein. We propose that the fixABCX genes encode a membrane
      protein complex that plays a central role in electron transfer to nitrogenase in
      R. rubrum. Furthermore, we suggest that FixC is the link between nitrogen
      fixation and the proton motive force generated in the photosynthetic reactions.

PMID- 15028690
TI  - A DNA adenine methyltransferase of Escherichia coli that is cell cycle regulated
      and essential for viability.
AB  - DNA sequence analysis revealed that the putative yhdJ DNA methyltransferase gene
      of Escherichia coli is 55% identical to the Nostoc sp. strain PCC7120 gene
      encoding DNA methyltransferase AvaIII, which methylates adenine in the
      recognition sequence, ATGCAT. The yhdJ gene was cloned, and the enzyme was
      overexpressed and purified. Methylation and restriction analysis showed that the
      DNA methyltransferase methylates the first adenine in the sequence ATGCAT. This
      DNA methylation was found to be regulated during the cell cycle, and the DNA
      adenine methyltransferase was designated M.EcoKCcrM (for "cell cycle-regulated
      methyltransferase"). The CcrM DNA adenine methyltransferase is required for
      viability in E. coli, as a strain lacking a functional genomic copy of ccrM can
      be isolated only in the presence of an additional copy of ccrM supplied in trans.
      The cells of such a knockout strain stopped growing when expression of the
      inducible plasmid ccrM gene was shut off. Overexpression of M.EcoKCcrM slowed
      bacterial growth, and the ATGCAT sites became fully methylated throughout the
      cell cycle; a high proportion of cells with an anomalous size distribution and
      DNA content was found in this population. Thus, the temporal control of this
      methyltransferase may contribute to accurate cell cycle control of cell division
      and cellular morphology. Homologs of M.EcoKCcrM are present in other bacteria
      belonging to the gamma subdivision of the class Proteobacteria, suggesting that
      methylation at ATGCAT sites may have similar functions in other members of this
      group.

PMID- 15028691
TI  - Biochemical characterization of a dihydromethanopterin reductase involved in
      tetrahydromethanopterin biosynthesis in Methylobacterium extorquens AM1.
AB  - During growth on one-carbon (C1) compounds, the aerobic alpha-proteobacterium
      Methylobacterium extorquens AM1 synthesizes the tetrahydromethanopterin (H4MPT)
      derivative dephospho-H4MPT as a C1 carrier in addition to tetrahydrofolate. The
      enzymes involved in dephospho-H4MPT biosynthesis have not been identified in
      bacteria. In archaea, the final step in the proposed pathway of H4MPT
      biosynthesis is the reduction of dihydromethanopterin (H2MPT) to H4MPT, a
      reaction analogous to the reaction of the bacterial dihydrofolate reductase. A
      gene encoding a dihydrofolate reductase homolog has previously been reported for
      M. extorquens and assigned as the putative H2MPT reductase gene (dmrA). In the
      present work, we describe the biochemical characterization of H2MPT reductase
      (DmrA), which is encoded by dmrA. The gene was expressed with a six-histidine tag
      in Escherichia coli, and the recombinant protein was purified by nickel affinity
      chromatography and gel filtration. Purified DmrA catalyzed the NAD(P)H-dependent
      reduction of H2MPT with a specific activity of 2.8 micromol of NADPH oxidized per
      min per mg of protein at 30 degrees C and pH 5.3. Dihydrofolate was not a
      substrate for DmrA at the physiological pH of 6.8. While the existence of an
      H2MPT reductase has been proposed previously, this is the first biochemical
      evidence for such an enzyme in any organism, including archaea. Curiously, no
      DmrA homologs have been identified in the genomes of known methanogenic archaea,
      suggesting that bacteria and archaea produce two evolutionarily distinct forms of
      dihydromethanopterin reductase. This may be a consequence of different electron
      donors, NAD(P)H versus reduced F420, used, respectively, in bacteria and
      methanogenic archaea.

PMID- 15028692
TI  - Pleiotropic effects of inactivating a carboxyl-terminal protease, CtpA, in
      Borrelia burgdorferi.
AB  - A gene encoding a putative carboxyl-terminal protease (CtpA), an unusual type of
      protease, is present in the Borrelia burgdorferi B31 genome. The B. burgdorferi
      CtpA amino acid sequence exhibits similarities to the sequences of the CtpA
      enzymes of the cyanobacterium Synechocystis sp. strain PCC 6803 and higher plants
      and also exhibits similarities to the sequences of putative CtpA proteins in
      other bacterial species. Here, we studied the effect of ctpA gene inactivation on
      the B. burgdorferi protein expression profile. Total B. burgdorferi proteins were
      separated by two-dimensional gel electrophoresis, and the results revealed that
      six proteins of the wild type were not detected in the ctpA mutant and that nine
      proteins observed in the ctpA mutant were undetectable in the wild type.
      Immunoblot analysis showed that the integral outer membrane protein P13 was
      larger and had a more acidic pI in the ctpA mutant, which is consistent with the
      theoretical change in pI for P13 not processed at the carboxyl terminus. Matrix
      assisted laser desorption ionization-time of flight data indicated that in
      addition to P13, the BB0323 protein may serve as a substrate for carboxyl
      terminal processing by CtpA. Complementation analysis of the ctpA mutant provided
      strong evidence that the observed effect on proteins depended on inactivation of
      the ctpA gene alone. We show that CtpA in B. burgdorferi is involved in the
      processing of proteins such as P13 and BB0323 and that inactivation of ctpA has a
      pleiotropic effect on borrelial protein synthesis. To our knowledge, this is the
      first analysis of both a CtpA protease and different substrate proteins in a
      pathogenic bacterium.

PMID- 15028693
TI  - Effect of D-lactate on the physiological activity of the ArcB sensor kinase in
      Escherichia coli.
AB  - The Arc two-component system, comprising the ArcB sensor kinase and the ArcA
      response regulator, modulates the expression of numerous genes in response to the
      respiratory growth conditions. Under anoxic growth conditions ArcB
      autophosphorylates and transphosphorylates ArcA, which in turn represses or
      activates its target operons. The anaerobic metabolite D-lactate has been shown
      to stimulate the in vitro autophosphorylating activity of ArcB. In this study,
      the in vivo effect of D-lactate on the kinase activity of ArcB was assessed. The
      results demonstrate that D-lactate does not act as a direct signal for activation
      of ArcB, as previously proposed, but acts as a physiologically significant
      effector that amplifies ArcB kinase activity.

PMID- 15028694
TI  - Protective role for H-NS protein in IS1 transposition.
AB  - The transposase (InsAB') of the insertion element IS1 can create breaks in DNA
      that lead to induction of the SOS response. We have used the SOS response to
      InsAB' to screen for host mutations that affect InsAB' function and thus point to
      host functions that contribute to the IS1 transposition mechanism. Mutations in
      the hns gene, which codes for a DNA binding protein with wide-ranging effects on
      gene expression, abolish the InsAB'-induced SOS response. They also reduce
      transposition, whether by simple insertion or cointegrate formation, at least 100
      fold compared with the frequency seen in hns+ cells. Examination of protein
      profiles revealed that in an hns-null mutant, InsAB' is undetectable under
      conditions where it constitutes the most abundant protein in hns+ cells.
      Likewise, brief labeling of the hns cells with [35S]methionine revealed very
      small amounts of InsAB', and this was undetectable after a short chase.
      Transcription from the promoters used to express insAB' was essentially unaltered
      in hns cells, as was the level of insAB' mRNA. A mutation in lon, but not in ftsH
      or clpP, restored InsAB' synthesis in the hns strain, and a mutation in ssrA
      partially restored it, implying that the absence of H-NS leads to a problem in
      completing translation of insAB' mRNA and/or degradation of nascent InsAB'
      protein.

PMID- 15028695
TI  - Restricted distribution of the butyrate kinase pathway among butyrate-producing
      bacteria from the human colon.
AB  - The final steps in butyrate synthesis by anaerobic bacteria can occur via
      butyrate kinase and phosphotransbutyrylase or via butyryl-coenzyme A
      (CoA):acetate CoA-transferase. Degenerate PCR and enzymatic assays were used to
      assess the presence of butyrate kinase among 38 anaerobic butyrate-producing
      bacterial isolates from human feces that represent three different clostridial
      clusters (IV, XIVa, and XVI). Only four strains were found to possess detectable
      butyrate kinase activity. These were also the only strains to give PCR products
      (verifiable by sequencing) with degenerate primer pairs designed within the
      butyrate kinase gene or between the linked butyrate kinase/phosphotransbutyrylase
      genes. Further analysis of the butyrate kinase/phosphotransbutyrylase genes of
      one isolate, L2-50, revealed similar organization to that described previously
      from different groups of clostridia, along with differences in flanking sequences
      and phylogenetic relationships. Butyryl-CoA:acetate CoA-transferase activity was
      detected in all 38 strains examined, suggesting that it, rather than butyrate
      kinase, provides the dominant route for butyrate formation in the human colonic
      ecosystem that contains a constantly high concentration of acetate.

PMID- 15028696
TI  - A novel gene (narM) required for expression of nitrate reductase activity in the
      cyanobacterium Synechococcus elongatus strain PCC7942.
AB  - A new class of mutants deficient in nitrate assimilation was obtained from the
      cyanobacterium Synechococcus elongatus strain PCC7942 by means of random
      insertional mutagenesis. A 0.5-kb genomic region had been replaced by a kanamycin
      resistance gene cassette in the mutant, resulting in inactivation of two genes,
      one of which was homologous to the recently characterized cnaT gene of Anabaena
      sp. strain PCC7120 (J. E. Frias, A. Herrero, and E. Flores, J. Bacteriol.
      185:5037-5044, 2003). While insertional mutation of the cnaT homolog did not
      affect expression of the nitrate assimilation operon or the activity of the
      nitrate assimilation enzymes in S. elongatus, inactivation of the other gene,
      designated narM, resulted in specific loss of the cellular nitrate reductase
      activity. The deduced NarM protein is a hydrophilic protein consisting of 161
      amino acids. narM was expressed constitutively at a low level. The narM gene has
      its homolog only in the cyanobacterial strains that are capable of nitrate
      assimilation. In most of the cyanobacterial strains, narM is located downstream
      of narB, the structural gene of the cyanobacterial nitrate reductase, suggesting
      the functional link between the two genes. NarM is clearly not the structural
      component of the cyanobacterial nitrate reductase. The narM insertional mutant
      normally expressed narB, indicating that narM is not the transcriptional
      regulator of the structural gene of nitrate reductase. These results suggested
      that narM is required for either synthesis of the prosthetic group of nitrate
      reductase or assembly of the prosthetic groups to the NarB polypeptide to form
      functional nitrate reductase in cyanobacteria.

PMID- 15028697
TI  - Sequence polymorphism in the glycosylation island and flagellins of Pseudomonas
      aeruginosa.
AB  - A genomic island consisting of 14 open reading frames, orfA to orfN was
      previously identified in Pseudomonas aeruginosa strain PAK and shown to be
      essential for glycosylation of flagellin. DNA microarray hybridization analysis
      of a number of P. aeruginosa strains from diverse origins showed that this island
      is polymorphic. PCR and sequence analysis confirmed that many P. aeruginosa
      strains carry an abbreviated version of the island (short island) in which orfD, 
      E and -H are polymorphic and orfI, -J, -K, -L, and -M are absent. To ascertain
      whether there was a relationship between the inheritance of the short island and
      specific flagellin sequence variants, complete or partial nucleotide sequences of
      flagellin genes from 24 a-type P. aeruginosa strains were determined. Two
      distinct flagellin subtypes, designated A1 and A2, were apparent. Strains with
      the complete 14-gene island (long island) were almost exclusively of the A1 type,
      whereas strains carrying the short island were associated with both A1- and A2
      type flagellins. These findings indicate that P. aeruginosa possesses a
      relatively low number of distinct flagellin types and probably has the capacity
      to further diversify this antigenic surface protein by glycosylation.

PMID- 15028698
TI  - Plasmid evolution and interaction between the plasmid addiction stability systems
      of two related broad-host-range IncQ-like plasmids.
AB  - Plasmid pTC-F14 contains a plasmid stability system called pas (plasmid addiction
      system), which consists of two proteins, a PasA antitoxin and a PasB toxin. This
      system is closely related to the pas of plasmid pTF-FC2 (81 and 72% amino acid
      identity for PasA and PasB, respectively) except that the pas of pTF-FC2 contains
      a third protein, PasC. As both pTC-F14 and pTF-FC2 are highly promiscuous broad
      host-range plasmids isolated from bacteria that share a similar ecological niche,
      the plasmids are likely to encounter each other. We investigated the relative
      efficiencies of the two stability systems and whether they had evolved apart
      sufficiently for each pas to stabilize a plasmid in the presence of the other.
      The three-component pTF-FC2 pas was more efficient at stabilization of a
      heterologous tester plasmid than the two component pas of pTC-F14 in Escherichia
      coli host cells (+/- 92% and +/- 60% after 100 generations, respectively). The
      PasA antidote of each pas was unable to neutralize the PasB toxin of the other
      plasmid. The pas proteins of each plasmid autoregulated their own expression as
      well as that of the pas of the other plasmid. The pas of pTF-FC2 was more
      effective at repressing the pas operon of pTC-F14 than the pas of pTC-F14 was
      able to repress itself or the pas of pTF-FC2. This increased efficiency was not
      due to the PasC of pTF-FC2. The effect of this stronger repression was that pTF
      FC2 displaced pTC-F14 when the two plasmids were coresident in the same E. coli
      host cell. Plasmid curing resulted in the arrest of cell growth but did not cause
      cell death, and plasmid stability was not influenced by the E. coli mazEF genes.

PMID- 15028700
TI  - Cell death in Escherichia coli dnaE(Ts) mutants incubated at a nonpermissive
      temperature is prevented by mutation in the cydA gene.
AB  - Cells of the Escherichia coli dnaE(Ts) dnaE74 and dnaE486 mutants die after 4 h
      of incubation at 40 degrees C in Luria-Bertani medium. Cell death is preceded by
      elongation, is inhibited by chloramphenicol, tetracycline, or rifampin, and is
      dependent on cell density. Cells survive at 40 degrees C when they are incubated
      at a high population density or at a low density in conditioned medium, but they
      die when the medium is supplemented with glucose and amino acids. Deletion of
      recA or sulA has no effect. We isolated suppressors which survived for long
      periods at 40 degrees C but did not form colonies. The suppressors protected
      against hydroxyurea-induced killing. Sequence and complementation analysis
      indicated that suppression was due to mutation in the cydA gene. The DNA content
      of dnaE mutants increased about eightfold in 4 h at 40 degrees C, as did the DNA
      content of the suppressed strains. The amount of plasmid pBR322 in a dnaE74
      strain increased about fourfold, as measured on gels, and the electrophoretic
      pattern appeared to be normal even though the viability of the parent cells
      decreased 2 logs. Transformation activity also increased. 4',6'-diamidino-2
      phenylindole staining demonstrated that there were nucleoids distributed
      throughout the dnaE filaments formed at 40 degrees C, indicating that there was
      segregation of the newly formed DNA. We concluded that the DNA synthesized was
      physiologically competent, particularly since the number of viable cells of the
      suppressed strain increased during the first few hours of incubation. These
      observations support the view that E. coli senses the rate of DNA synthesis and
      inhibits septation when the rate of DNA synthesis falls below a critical level
      relative to the level of RNA and protein synthesis.

PMID- 15028699
TI  - Characterization of transcriptional regulatory genes for biphenyl degradation in
      Rhodococcus sp. strain RHA1.
AB  - Transcription of the bphA1A2A3A4C1B genes, which are responsible for the
      conversion of biphenyl and polychlorinated biphenyl to the meta-cleavage products
      in Rhodococcus sp. strain RHA1, was examined. The bphA1 promoter (P(bphA1)) was
      identified and was shown to promote transcription induction by biphenyl and
      ethylbenzene. An 8.8-kb HindIII fragment that promotes transcription induction of
      P(bphA1) in Rhodococcus erythropolis IAM1399 was isolated from the region
      downstream of bphB by using a reporter plasmid containing P(bphA1). Analysis of
      the nucleotide sequence of this fragment revealed a set of putative two-component
      regulatory system genes, which were designated bphS and bphT. Deletion analysis
      of the 8.8-kb HindIII fragment indicated that bphT is responsible for the basal
      activation of P(bphA1) and that both bphS and bphT are required for the elevated
      basal activation of and transcriptional induction by biphenyl of P(bphA1). These
      results support the notion that bphS and bphT encode a sensor kinase and a
      response regulator, respectively, of a two-component regulatory system. The bphS
      and bphT genes promote transcriptional induction by a variety of aromatic
      compounds, including biphenyl, benzene, alkylbenzenes, and chlorinated benzenes.
      A promoter activity assay and reverse transcription (RT)-PCR analysis revealed a
      weak constitutive promoter in the adjacent region upstream of bphS. RT-PCR
      analysis indicated that there is induced transcription of bphA1 through bphT, in
      which P(bphA1) is thought to take part. An insertionally inactivated bphS mutant,
      SDR1, did not grow on biphenyl. Growth was restored by introduction of an intact
      bphS gene into SDR1. These results indicate that at least bphS is indispensably
      responsible for the growth of RHA1 on biphenyl.

PMID- 15028701
TI  - Selenocysteine-containing proteins in anaerobic benzoate metabolism of
      Desulfococcus multivorans.
AB  - The sulfate-reducing bacterium Desulfococcus multivorans uses various aromatic
      compounds as sources of cell carbon and energy. In this work, we studied the
      initial steps in the aromatic metabolism of this strictly anaerobic model
      organism. An ATP-dependent benzoate coenzyme A (CoA) ligase (AMP plus PPi
      forming) composed of a single 59-kDa subunit was purified from extracts of cells
      grown on benzoate. Specific activity was highest with benzoate and some benzoate
      derivatives, whereas aliphatic carboxylic acids were virtually unconverted. The N
      terminal amino acid sequence showed high similarities with benzoate CoA ligases
      from Thauera aromatica and Azoarcus evansii. When cultivated on benzoate, cells
      strictly required selenium and molybdenum, whereas growth on nonaromatic
      compounds, such as cyclohexanecarboxylate or lactate, did not depend on the
      presence of the two trace elements. The growth rate on benzoate was half maximal
      with 1 nM selenite present in the growth medium. In molybdenum- and/or selenium
      depleted cultures, growth on benzoate could be induced by addition of the missing
      trace elements. In extracts of cells grown on benzoate in the presence of
      [75Se]selenite, three radioactively labeled proteins with molecular masses of
      approximately 100, 30, and 27 kDa were detected by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis analysis. The 100- and 30-kDa selenoproteins
      were 5- to 10-fold induced in cells grown on benzoate compared to cells grown on
      lactate. These results suggest that the dearomatization process in D. multivorans
      is not catalyzed by the ATP-dependent Fe-S enzyme benzoyl-CoA reductase as in
      facultative anaerobes but rather involves unknown molybdenum- and selenocysteine
      containing proteins.

PMID- 15028703
TI  - Multiple formaldehyde oxidation/detoxification pathways in Burkholderia fungorum
      LB400.
AB  - Burkholderia species are free-living bacteria with a versatile metabolic
      lifestyle. The genome of B. fungorum LB400 is predicted to encode three different
      pathways for formaldehyde oxidation: an NAD-linked, glutathione (GSH)-independent
      formaldehyde dehydrogenase; an NAD-linked, GSH-dependent formaldehyde oxidation
      system; and a tetrahydromethanopterin-methanofuran-dependent formaldehyde
      oxidation system. The other Burkholderia species for which genome sequences are
      available, B. mallei, B. pseudomallei, and B. cepacia, are predicted to contain
      only the first two of these pathways. The roles of the three putative
      formaldehyde oxidation pathways in B. fungorum LB400 have been assessed via
      knockout mutations in each of these pathways, as well as in all combinations of
      knockouts. The resulting mutants have the expected loss of enzyme activities and
      exhibit defects of varying degrees of severity during growth on choline, a
      formaldehyde-producing substrate. Our data suggest that all three pathways are
      involved in formaldehyde detoxification and are functionally redundant under the
      tested conditions.

PMID- 15028702
TI  - Comparative genomics of two Leptospira interrogans serovars reveals novel
      insights into physiology and pathogenesis.
AB  - Leptospira species colonize a significant proportion of rodent populations
      worldwide and produce life-threatening infections in accidental hosts, including
      humans. Complete genome sequencing of Leptospira interrogans serovar Copenhageni
      and comparative analysis with the available Leptospira interrogans serovar Lai
      genome reveal that despite overall genetic similarity there are significant
      structural differences, including a large chromosomal inversion and extensive
      variation in the number and distribution of insertion sequence elements. Genome
      sequence analysis elucidates many of the novel aspects of leptospiral physiology
      relating to energy metabolism, oxygen tolerance, two-component signal
      transduction systems, and mechanisms of pathogenesis. A broad array of
      transcriptional regulation proteins and two new families of afimbrial adhesins
      which contribute to host tissue colonization in the early steps of infection were
      identified. Differences in genes involved in the biosynthesis of
      lipopolysaccharide O side chains between the Copenhageni and Lai serovars were
      identified, offering an important starting point for the elucidation of the
      organism's complex polysaccharide surface antigens. Differences in adhesins and
      in lipopolysaccharide might be associated with the adaptation of serovars
      Copenhageni and Lai to different animal hosts. Hundreds of genes encoding surface
      exposed lipoproteins and transmembrane outer membrane proteins were identified as
      candidates for development of vaccines for the prevention of leptospirosis.

PMID- 15028704
TI  - Reconstruction of the central carbohydrate metabolism of Thermoproteus tenax by
      use of genomic and biochemical data.
AB  - The hyperthermophilic, facultatively heterotrophic crenarchaeum Thermoproteus
      tenax was analyzed using a low-coverage shotgun-sequencing approach. A total of
      1.81 Mbp (representing 98.5% of the total genome), with an average gap size of
      100 bp and 5.3-fold coverage, are reported, giving insights into the genome of T.
      tenax. Genome analysis and biochemical studies enabled us to reconstruct its
      central carbohydrate metabolism. T. tenax uses a variant of the reversible Embden
      Meyerhof-Parnas (EMP) pathway and two different variants of the Entner-Doudoroff
      (ED) pathway (a nonphosphorylative variant and a semiphosphorylative variant) for
      carbohydrate catabolism. For the EMP pathway some new, unexpected enzymes were
      identified. The semiphosphorylative ED pathway, hitherto supposed to be active
      only in halophiles, is found in T. tenax. No evidence for a functional pentose
      phosphate pathway, which is essential for the generation of pentoses and NADPH
      for anabolic purposes in bacteria and eucarya, is found in T. tenax. Most genes
      involved in the reversible citric acid cycle were identified, suggesting the
      presence of a functional oxidative cycle under heterotrophic growth conditions
      and a reductive cycle for CO2 fixation under autotrophic growth conditions.
      Almost all genes necessary for glycogen and trehalose metabolism were identified
      in the T. tenax genome.

PMID- 15028705
TI  - Bacillus anthracis and Bacillus cereus PcrA helicases can support DNA unwinding
      and in vitro rolling-circle replication of plasmid pT181 of Staphylococcus
      aureus.
AB  - Replication of rolling-circle replicating (RCR) plasmids in gram-positive
      bacteria requires the unwinding of initiator protein-nicked plasmid DNA by the
      PcrA helicase. In this report, we demonstrate that heterologous PcrA helicases
      from Bacillus anthracis and Bacillus cereus are capable of unwinding
      Staphylococcus aureus plasmid pT181 from the initiator-generated nick and
      promoting in vitro replication of the plasmid. These helicases also physically
      interact with the RepC initiator protein of pT181. The ability of PcrA helicases
      to unwind noncognate RCR plasmids may contribute to the broad-host-range
      replication and dissemination of RCR plasmids in gram-positive bacteria.

PMID- 15028706
TI  - Evidence for multiple levels of regulation of Oenococcus oeni clpP-clpL locus
      expression in response to stress.
AB  - A locus containing the clpP and clpL genes in the lactic acid bacterium
      Oenococcus oeni was studied. Real-time reverse transcription-PCR analysis
      revealed different induction factors involved in expression of these genes during
      stress. According to the conditions, clpP and clpL genes could be transcripted as
      two distinct transcripts or cotranscripted. The clpP promoter depended on the
      CtsR regulator, but surprisingly the clpL promoter did not. The amount of the
      clpL transcript depended on mRNA stability. This clp ATPase gene is at least
      controlled at the posttranscriptional level.

PMID- 15028707
TI  - A single target is sufficient to account for the biological effects of the A
      factor receptor protein of Streptomyces griseus.
AB  - In the model of the A-factor (2-isocapryloyl-3R-hydroxymethyl-gamma
      butyrolactone) regulatory cascade in Streptomyces griseus, A-factor binds ArpA,
      the A-factor receptor protein, that has bound to the adpA promoter and
      dissociates it from the DNA, thus inducing the transcription of adpA. AdpA
      switches on the transcription of a number of genes required for secondary
      metabolism and morphological differentiation, forming an AdpA regulon. Consistent
      with this model, arpA null mutants produced streptomycin and a yellow pigment in
      larger amounts and formed aerial hyphae from an earlier growth stage than the
      wild-type strain. On the other hand, mutant MK2, expressing a mutant ArpA
      (Trp119Ala), neither produced secondary metabolites nor formed aerial hyphae,
      because this A-factor-insensitive mutant ArpA always bound to and repressed the
      adpA promoter due to the amino acid replacement of Trp-119 with Ala. Introduction
      of adpA under the control of a foreign promoter into mutant MK2 restored all of
      the phenotypes that we could observe, which suggests that the only significant
      target of ArpA is adpA. In contrast to other gamma-butyrolactone regulatory
      systems, disruption of arpA had no effect on A-factor production, indicating that
      ArpA does not regulate A-factor biosynthesis. Instead, A-factor production was
      found to be repressed by AdpA in a two-step regulatory feedback loop.

PMID- 15028708
TI  - Stochastic processes influence stationary-phase decisions in Bacillus subtilis.
AB  - It has recently been proposed that phenotypic variation in clonal populations of
      bacterial species results from intracellular "noise," i.e., random fluctuations
      in levels of cellular molecules, which would be predicted to be insensitive to
      selective pressure. To test this notion, we propagated five populations of
      Bacillus subtilis for 5,000 generations with selection for one phenotype: the
      decision to sporulate. In support of the noise hypothesis, we report that none of
      the populations responded to selection by improving their efficiency of
      sporulation, indicating that intracellular noise is independent of heritable
      genotype.

PMID- 15028709
TI  - The PaaX repressor, a link between penicillin G acylase and the phenylacetyl
      coenzyme A catabolon of Escherichia coli W.
AB  - The pac gene, encoding the penicillin G acylase from Escherichia coli W, is
      regulated by the PaaX repressor of the phenylacetate catabolic pathway. pac
      expression depends on the synthesis of phenylacetyl-coenzyme A. PaaX and the
      cyclic AMP receptor protein (CRP) bind in vitro to the Ppac promoter region. A
      palindromic sequence proposed as the PaaX operator is located upstream of the -35
      box overlapping a CRP binding site, an unusual position that suggests a novel
      regulatory mechanism.

PMID- 15028710
TI  - Compartmentalization of gene expression during sporulation of Bacillus subtilis
      is compromised in mutants blocked at stage III of sporulation.
AB  - Mutations in the spoIIIA and spoIIIJ loci disrupt the compartmentalization of
      gene expression during sporulation of Bacillus subtilis. The breakdown in
      compartmentalization is not the cause of their being blocked in spore formation.
      Rather, it appears to be a consequence of the engulfed prespore's being unstable.

PMID- 15028712
TI  - A peroxisome proliferator-response element in the murine mc2-r promoter regulates
      its transcriptional activation during differentiation of 3T3-L1 adipocytes.
AB  - Adrenocorticotropic hormone can stimulate lipolysis and suppress leptin
      expression in murine adipocytes. These effects are mediated via the melanocortin
      2 receptor (MC2-R), which is expressed when 3T3-L1 cells are induced to undergo
      adipogenesis. In this study, we have characterized the mc2-r promoter in the
      murine adipocyte, one of the few extra-adrenal sites of expression and a cell
      type that lacks steroidogenic factor 1 (SF-1), a transcription factor that is
      required for mc2-r expression in adrenal cells. Transcriptional regulation of the
      mc2-r in the absence of SF-1 was investigated by 5' deletion analysis of the
      murine mc2-r promoter in both undifferentiated and differentiated 3T3-L1 cells.
      The results revealed the presence of a 59-base pair regulatory region within the
      promoter containing an adipocyte-specific enhancer. The ability of this region to
      confer enhanced activity in the adipocyte was mapped to a peroxisome proliferator
      response element (PPRE)-like sequence that bound to peroxisome proliferator
      activated receptor gamma (PPARgamma) and its heterodimeric partner retinoid X
      receptor alpha (RXRalpha) in adipocyte nuclear extracts. Co-transfection of
      PPARgamma2/RXRalpha with the pMC2-R(-112/+105)GL3 reporter resulted in
      transcriptional activation in preadipocytes, and this response required an intact
      PPRE. Mutation of the PPRE to prevent PPARgamma/RXRalpha binding resulted in a
      complete abrogation of the pMC2-R(-112/+105)GL3 reporter activity in day 3
      differentiated 3T3-L1 cells, demonstrating a key role played by this site in
      regulating MC2-R expression in the murine adipocyte. These data highlight a novel
      mechanism for mc2-r transcription, which may have significance in both adrenal
      and extra-adrenal sites of expression.

PMID- 15028711
TI  - Regulation of phospholipid synthesis in Saccharomyces cerevisiae by zinc.
AB  - Zinc is an essential nutrient required for the growth and metabolism of
      eukaryotic cells. In this work, we examined the effects of zinc depletion on the
      regulation of phospholipid synthesis in the yeast Saccharomyces cerevisiae. Zinc
      depletion resulted in a decrease in the activity levels of the CDP-diacylglycerol
      pathway enzymes phosphatidylserine synthase, phosphatidylserine decarboxylase,
      phosphatidylethanolamine methyltransferase, and phospholipid methyltransferase.
      In contrast, the activity of phosphatidylinositol synthase was elevated in
      response to zinc depletion. The level of Aut7p, a marker for the induction of
      autophagy, was also elevated in zinc-depleted cells. For the CHO1-encoded
      phosphatidylserine synthase, the reduction in activity in response to zinc
      depletion was controlled at the level of transcription. This regulation was
      mediated through the UAS(INO) element and by the transcription factors Ino2p,
      Ino4p, and Opi1p that are responsible for the inositol-mediated regulation of
      UAS(INO)-containing genes involved in phospholipid synthesis. Analysis of the
      cellular composition of the major membrane phospholipids showed that zinc
      depletion resulted in a 66% decrease in phosphatidylethanolamine and a 29%
      increase in phosphatidylinositol. A zrt1Delta zrt2Delta mutant (defective in the
      plasma membrane zinc transporters Zrt1p and Zrt2p) grown in the presence of zinc
      exhibited a phospholipid composition similar to that of wild type cells depleted
      for zinc. These results indicated that a decrease in the cytoplasmic levels of
      zinc was responsible for the alterations in phospholipid composition.

PMID- 15028713
TI  - Notch1-expressing cells are indispensable for prostatic branching morphogenesis
      during development and re-growth following castration and androgen replacement.
AB  - Notch expression is frequently associated with progenitor cells, and its function
      is crucial for development. Our recent work showing that Notch1 is selectively
      expressed in basal epithelial cells of the prostate and higher Notch1 expression
      during development suggests that Notch1-expressing cells may define progenitor
      cells in the prostate. To test this hypothesis, we have generated a transgenic
      mouse line in which the Notch1-expressing cells can be ablated in a controlled
      manner. Specific targeting was achieved by expressing the bacterial
      nitroreductase, an enzyme that catalyzes its substrate into a cytotoxin capable
      of inducing apoptosis, under the Notch1 promoter. Cell death in transgenic
      prostate was confirmed by histological analyses including terminal dUTP nick-end
      labeling and caspase 3 immunocytochemical staining. We evaluated the consequences
      of ablation of Notch1-expressing cells in two systems, organ culture of early
      postnatal prostates and re-growth of prostate in castrated mice triggered by
      hormone replacement. Our data show that elimination of Notch1-expressing cells
      inhibited the branching morphogenesis, growth, and differentiation of early
      postnatal prostate in culture and impaired prostate re-growth triggered by
      hormone replacement in castrated mice. Furthermore, we found that Notch1
      expression following castration and hormone replacement was concomitant with
      known basal cell markers p63 and cytokeratin 14 and was high in the proliferative
      human prostate epithelial cells. Taken together, these data suggest that Notch1
      expressing cells define the progenitor cells in the prostatic epithelial cell
      lineage, which are indispensable for prostatic development and re-growth.

PMID- 15028714
TI  - Regulation of Smad4 sumoylation and transforming growth factor-beta signaling by
      protein inhibitor of activated STAT1.
AB  - The tumor suppressor, Smad4/DPC4, is a common signal transducer in transforming
      growth factor-beta (TGF-beta) signaling. In this study, we demonstrated that the
      protein inhibitor of activated STAT1 (PIAS1) regulates the signaling potential of
      Smad4 through a sumoylation-dependent mechanism. PIAS1 was shown to be an E3
      ligase for Smad4 sumoylation in vitro and in vivo. PIAS1 physically interacted
      with Smad4 in a TGF-beta-inducible manner. A minimal SUMO E3 ligase domain and
      Smad4-binding domain were defined on PIAS1 protein. The RING finger domain of
      PIAS1 was essential for its E3 ligase function. Although PIAS1 enhanced the Smad4
      dependent transcriptional activation of TGF-beta signaling, a mutant lacking the
      RING domain inhibited the sumoylation of Smad4 in a dominant negative manner and,
      as a result, abolished the transcriptional response of TGF-beta. These data
      demonstrate that PIAS1 protein positively modulates TGF-beta responses as a SUMO
      E3 ligase for Smad4.

PMID- 15028715
TI  - Regulation of the circadian oscillator in Xenopus retinal photoreceptors by
      protein kinases sensitive to the stress-activated protein kinase inhibitor, SB
      203580.
AB  - Circadian rhythms are generated by transcriptional and translational feedback
      loops. Stress-activated protein kinases (SAPKs) are known to regulate
      transcription factors in response to a variety of extracellular stimuli. In the
      present study, we examined whether the SAPKs play a role in the circadian system
      in cultured Xenopus retinal photoreceptor layers. A 6-h pulse of SB 203580, an
      inhibitor of SAPKs, reset the circadian rhythm of melatonin in a phase-dependent
      manner similar to dark pulses. This phase-shifting effect was dose-dependent over
      the range of 1-100 microm. Treatment with SB 203580 also affected light-induced
      phase shifts, and light had no effect on the circadian oscillator in the presence
      of 100 microm SB 203580. In-gel kinase assays showed that SB 203580 selectively
      inhibited a small group of protein kinases in the photoreceptor cells. These SB
      203580-sensitive kinases correspond to two isoforms of phosphorylated p38 MAPK
      and three isoforms of c-Jun N-terminal kinase (JNK). Further in vitro study
      demonstrated that SB 203580 also inhibited casein kinase Iepsilon (CKIepsilon),
      which has been shown to regulate circadian rhythms in several organisms. However,
      a pharmacological inhibition of CKI reset the circadian oscillator in a phase
      dependent manner distinct from that of SB 203580. This argues against a primary
      role of CKI in the phase-shifting effects of SB 203580. These results suggest
      that SB 203580 affects the circadian system by inhibiting p38 MAPKs or JNKs and
      that these protein kinases are candidate cellular signals in the regulation of
      the circadian oscillator in the Xenopus retinal photoreceptors.

PMID- 15028716
TI  - On the mechanism and significance of ligand-induced internalization of human
      neutrophil chemokine receptors CXCR1 and CXCR2.
AB  - It is well established that leukocyte chemotactic receptors, a subset of G
      protein-coupled receptors, undergo endocytosis after stimulation by ligand.
      However, the significance of this phenomenon to cell motility and other important
      leukocyte functions induced by chemoattractants has not been clearly defined.
      Here we show that in primary human neutrophils, the threshold levels of agonist
      required for endocytosis of the chemotactic receptors CXCR1 and CXCR2 were
      approximately 10-fold or higher than those needed for maximal chemotactic and
      calcium flux responses. Moreover, when stimulated by agonists at concentrations
      that are high enough for chemotaxis but too low for receptor endocytosis,
      neutrophil CXCR1 and CXCR2 could be reactivated in response to repeated
      application of the same agonist. Both receptors were excluded from Triton X-100
      insoluble lipid rafts, and at high agonist concentrations were rapidly
      endocytosed by a clathrin/rab5/dynamin-dependent pathway. These data support the
      conclusion that neutrophil migration in response to CXCR1 or CXCR2 agonists is
      not dependent on endocytosis of CXCR1 or CXCR2. Rather than being integral to the
      process of cell migration, receptor endocytosis may be a terminal stop signal
      when cells reach the focus of inflammation where the chemoattractant
      concentrations are the highest.

PMID- 15028717
TI  - Alpha-synuclein has a high affinity for packing defects in a bilayer membrane: a
      thermodynamics study.
AB  - A number of neurodegenerative disorders, including Parkinson's disease, dementia
      with Lewy bodies, and multiple system atrophy, are characterized by the
      intracellular deposition of fibrillar aggregates that contain a high proportion
      of alpha-synuclein (alphaS). The interaction with the membrane-water interface
      strongly modulates folding and aggregation of the protein. The present study
      investigates the lipid binding and the coil-helix transition of alphaS, using
      titration calorimetry, differential scanning calorimetry, and circular dichroism
      spectroscopy. Titration of the protein with small unilamellar vesicles composed
      of zwitterionic phospholipids below the chain melting temperature of the lipids
      yielded exceptionally large exothermic heat values. The sigmoidal titration
      curves were evaluated in terms of a simple model that assumes saturable binding
      sites at the vesicle surface. The cumulative heat release and the ellipticity
      were linearly correlated as a result of simultaneous binding and helix folding.
      There was no heat release and folding of alphaS in the presence of large
      unilamellar vesicles, indicating that a small radius of curvature is necessary
      for the alphaS-membrane interaction. The heat release and the negative heat
      capacity of the protein-vesicle interaction could not be attributed to the coil
      helix transition of the protein alone. We speculate that binding and helix
      folding of alphaS depends on the presence of defect structures in the membrane
      water interface, which in turn results in lipid ordering in the highly curved
      vesicular membranes. This will be discussed with regard to a possible role of the
      protein for the stabilization of synaptic vesicle membranes.

PMID- 15028718
TI  - Direct activation of the epithelial Na(+) channel by phosphatidylinositol 3,4,5
      trisphosphate and phosphatidylinositol 3,4-bisphosphate produced by
      phosphoinositide 3-OH kinase.
AB  - The phospholipid phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)) is
      accepted to be a direct modulator of ion channel activity. The products of
      phosphoinositide 3-OH kinase (PI3K), PtdIns(3,4)P(2) and phosphatidylinositol
      3,4,5-trisphosphate (PtdIns(3,4,5)P(3)), in contrast, are not. We report here
      activation of the epithelial Na(+) channel (ENaC) reconstituted in Chinese
      hamster ovary cells by PI3K. Insulin-like growth factor-I also activated
      reconstituted ENaC and increased Na(+) reabsorption across renal A6 epithelial
      cell monolayers via PI3K. Neither IGF-I nor PI3K affected the levels of ENaC in
      the plasma membrane. The effects of PI3K and IGF-I on ENaC activity paralleled
      changes in the plasma membrane levels of the PI3K product phospholipids,
      PtdIns(3,4)P(2)/PtdIns(3,4,5)P(3), as measured by evanescent field fluorescence
      microscopy. Both PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3) activated ENaC in excised
      patches. Activation of ENaC by PI3K and its phospholipid products corresponded to
      changes in channel open probability. We conclude that PI3K directly modulates
      ENaC activity via PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3). This represents a novel
      transduction pathway whereby growth factors, such as IGF-I, rapidly modulate
      target proteins independent of signaling elicited by kinases downstream of PI3K.

PMID- 15028719
TI  - Identification of a novel PDX-1 binding site in the human insulin gene enhancer.
AB  - Islet beta cell type-specific transcription of the insulin gene is regulated by a
      number of cis-acting elements found within the proximal 5'-flanking region. The
      control sequences conserved between mammalian insulin genes are acted upon by
      transcription factors, like PDX-1 and BETA-2, that are also involved in islet
      beta cell function and formation. In the current study, we investigated the
      contribution to human insulin expression of the GG2 motif found between
      nucleotides -145 and -140 relative to the transcription start site. Site-specific
      mutants were generated within GG2 that displayed a parallel increase (i.e. -144
      base pair) or decrease (i.e. -141 base pair) in insulin enhancer-driven reporter
      and gel shift binding activity in beta cells consistent with human GG2 being
      under positive regulatory control. In contrast, the corresponding site in the
      rodent insulin gene, which only differs from the human at nucleotides -144 and 
      141, is negatively regulated by the Nkx2.2 transcription factor (Cissell, M. A.,
      Zhao, L., Sussel, L., Henderson, E., and Stein, R. (2003) J. Biol. Chem. 278, 751
      756). Human GG2 activator binding activity was present in nuclear extracts
      prepared from human islets and enriched in those from rodent beta cell lines. The
      human GG2 activator binding factor(s) was shown to be approximately 38-40 kDa and
      distinct from other size-matched islet-enriched transcription factors, including
      Nkx2.2, Pax-4, Cdx2/3, and Isl-1. Combined DNA chromatographic purification and
      mass spectrometry analysis revealed that the GG2 activator was PDX-1. These
      results demonstrate that the GG2 element, despite its divergence from the core
      homeodomain consensus binding motif, is a site for PDX-1 activation in the human
      insulin gene.

PMID- 15028720
TI  - Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in
      environmental toxicity and cancer.
AB  - The mammalian CYP1A1, CYP1A2, and CYP1B1 genes (encoding cytochromes P450 1A1,
      1A2, and 1B1, respectively) are regulated by the aromatic hydrocarbon receptor
      (AHR). The CYP1 enzymes are responsible for both metabolically activating and
      detoxifying numerous polycyclic aromatic hydrocarbons (PAHs) and aromatic amines
      present in combustion products. Many substrates for CYP1 enzymes are AHR ligands.
      Differences in AHR affinity between inbred mouse strains reflect variations in
      CYP1 inducibility and clearly have been shown to be associated with differences
      in risk of toxicity or cancer caused by PAHs and arylamines. Variability in the
      human AHR affinity exists, but differences in human risk of toxicity or cancer
      related to AHR activation remain unproven. Mouse lines having one or another of
      the Cyp1 genes disrupted have shown paradoxical effects; in the test tube or in
      cell culture these enzymes show metabolic activation of PAHs or arylamines,
      whereas in the intact animal these enzymes are sometimes more important in the
      role of detoxification than metabolic potentiation. Intact animal data contradict
      pharmaceutical company policies that routinely test drugs under development; if a
      candidate drug shows CYP1 inducibility, further testing is generally discontinued
      for fear of possible toxic or carcinogenic effects. In the future, use of
      "humanized" mouse lines, containing a human AHR or CYP1 allele in place of the
      orthologous mouse gene, is one likely approach to show that the AHR and the CYP1
      enzymes in human behave similarly to that in mouse.

PMID- 15028721
TI  - Prevention of domain swapping inhibits dimerization and amyloid fibril formation
      of cystatin C: use of engineered disulfide bridges, antibodies, and
      carboxymethylpapain to stabilize the monomeric form of cystatin C.
AB  - Amyloidogenic proteins like cystatin C and prion proteins have been shown to form
      dimers by exchange of subdomains of the monomeric proteins. This process, called
      "three-dimensional domain swapping," has also been suggested to play a part in
      the generation of amyloid fibrils. One variant of cystatin C, L68Q cystatin C, is
      highly amyloidogenic, and persons carrying the corresponding gene suffer from
      massive cerebral amyloidosis leading to brain hemorrhage and death in early adult
      life. The present work describes the production of two variants of wild type and
      L68Q cystatin C with disulfide bridges at positions selected to inhibit domain
      swapping without affecting the biological function of the four cystatin C
      variants as cysteine protease inhibitors. The capacity of the four variant
      proteins to form dimers was tested and compared with that of wild type and L68Q
      cystatin C. In contrast to the latter two proteins, all four protein variants
      stabilized by disulfide bridges were resistant toward the formation of dimers.
      The capacity of the two stabilized variants of wild type cystatin C to form
      amyloid fibrils was investigated and found to be reduced by 80% compared with
      that of wild type cystatin C. In an effort to investigate whether exogenous
      agents could also suppress the formation of dimers of wild type and L68Q cystatin
      C, a monoclonal antibody or carboxymethylpapain, an inactivated form of a
      cysteine protease, was added to systems inducing dimerization of wild type and
      L68Q cystatin C. It was observed that catalytic amounts of both the monoclonal
      antibody and carboxymethylpapain could suppress dimerization.

PMID- 15028722
TI  - Granzyme M mediates a novel form of perforin-dependent cell death.
AB  - Cell death is mediated by cytotoxic lymphocytes through various granule serine
      proteases released with perforin. The unique protease activity, restricted
      expression, and distinct gene locus of granzyme M suggested this enzyme might
      have a novel biological function or trigger a novel form of cell death. Herein,
      we demonstrate that in the presence of perforin, the protease activity of
      granzyme M rapidly and effectively induces target cell death. In contrast to
      granzyme B, cell death induced by granzyme M does not feature obvious DNA
      fragmentation, occurs independently of caspases, caspase activation, and
      perturbation of mitochondria and is not inhibited by overexpression of Bcl-2.
      These data raise the likelihood that granzyme M represents a third major and
      specialized perforin-dependent cell death pathway that plays a significant role
      in death mediated by NK cells.

PMID- 15028723
TI  - The Interactions of Allium sativum leaf agglutinin with a chaperonin group of
      unique receptor protein isolated from a bacterial endosymbiont of the mustard
      aphid.
AB  - The homopteran sucking insect, Lipaphis erysimi (mustard aphid) causes severe
      damage to various crops. This pest not only affects plants by sucking on the
      phloem, but it also transmits single-stranded RNA luteoviruses while feeding,
      which cause disease and damage in the crop. The mannose-binding Allium sativum
      (garlic) leaf lectin has been found to be a potent control agent of L. erysimi.
      The lectin receptor protein isolated from brush border membrane vesicle of insect
      gut was purified to determine the mechanism of lectin binding to the gut.
      Purified receptor was identified as an endosymbiotic chaperonin, symbionin, using
      liquid chromatography-tandem mass spectrometry. Symbionin from endosymbionts of
      other aphid species have been reported to play a significant role in virus
      transmission by binding to the read-through domain of the viral coat protein. To
      understand the molecular interactions of the said lectin and this unique
      symbionin molecule, the model structures of both molecules were generated using
      the Modeller program. The interaction was confirmed through docking of the two
      molecules forming a complex. A surface accessibility test of these molecules
      demonstrated a significant reduction in the accessibility of the complex molecule
      compared with that of the free symbionin molecule. This reduction in surface
      accessibility may have an effect on other molecular interactive processes,
      including "symbionin virion recognition", which is essential for such symbionin
      mediated virus transmission. Thus, garlic leaf lectin provides an important
      component of a crop management program by controlling, on one hand, aphid attack
      and on the other hand, symbionin-mediated luteovirus transmission.

PMID- 15028724
TI  - Crystal structure of the apo forms of psi 55 tRNA pseudouridine synthase from
      Mycobacterium tuberculosis: a hinge at the base of the catalytic cleft.
AB  - The three-dimensional structure of the RNA-modifying enzyme, psi55 tRNA
      pseudouridine synthase from Mycobacterium tuberculosis, is reported. The 1.9-A
      resolution crystal structure reveals the enzyme, free of substrate, in two
      distinct conformations. The structure depicts an interesting mode of protein
      flexibility involving a hinged bending in the central beta-sheet of the catalytic
      module. Key parts of the active site cleft are also found to be disordered in the
      substrate-free form of the enzyme. The hinge bending appears to act as a clamp to
      position the substrate. Our structural data furthers the previously proposed
      mechanism of tRNA recognition. The present crystal structure emphasizes the
      significant role that protein dynamics must play in tRNA recognition, base
      flipping, and modification.

PMID- 15028725
TI  - C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP
      activated protein kinase.
AB  - Energy homeostasis and feeding are regulated by the central nervous system. C75,
      a fatty acid synthase (FAS) inhibitor, causes weight loss and anorexia, implying
      a novel central nervous system pathway(s) for sensing energy balance. AMP
      activated protein kinase (AMPK), a sensor of peripheral energy balance, is
      phosphorylated and activated when energy sources are low. Here, we identify a
      role for hypothalamic AMPK in the regulation of feeding behavior and in mediating
      the anorexic effects of C75. 5-Aminoimidazole-4-carboxamide-1-beta-D
      ribofuranoside (AICAR), an activator of AMPK, increased food intake, whereas
      compound C, an inhibitor of AMPK, decreased food intake. C75 rapidly reduced the
      level of the phosphorylated AMPK alpha subunit (pAMPKalpha) in the hypothalamus,
      even in fasted mice that had elevated hypothalamic pAMPKalpha levels.
      Furthermore, AICAR reversed both the C75-induced anorexia and the decrease in
      hypothalamic pAMPKalpha levels. C75 elevated hypothalamic neuronal ATP levels,
      which may contribute to the mechanism by which C75 decreased AMPK activity. C75
      reduced the levels of pAMPKalpha and phosphorylated cAMP response element-binding
      protein (pCREB) in the arcuate nucleus neurons of the hypothalamus, suggesting a
      mechanism for the reduction in NPY expression seen with C75 treatment. These data
      indicate that modulation of FAS activity in the hypothalamus can alter energy
      perception via AMPK, which functions as a physiological energy sensor in the
      hypothalamus.

PMID- 15028726
TI  - Cotranslational membrane protein biogenesis at the endoplasmic reticulum.

PMID- 15028727
TI  - The function of the yeast molecular chaperone Sse1 is mechanistically distinct
      from the closely related hsp70 family.
AB  - The Sse1/Hsp110 molecular chaperones are a poorly understood subgroup of the
      Hsp70 chaperone family. Hsp70 can refold denatured polypeptides via a C-terminal
      peptide binding domain (PBD), which is regulated by nucleotide cycling in an N
      terminal ATPase domain. However, unlike Hsp70, both Sse1 and mammalian Hsp110
      bind unfolded peptide substrates but cannot refold them. To test the in vivo
      requirement for interdomain communication, SSE1 alleles carrying amino acid
      substitutions in the ATPase domain were assayed for their ability to complement
      sse1Delta yeast. Surprisingly, all mutants predicted to abolish ATP hydrolysis
      (D8N, K69Q, D174N, D203N) complemented the temperature sensitivity of sse1Delta
      and lethality of sse1Deltasse2Delta cells, whereas mutations in predicted ATP
      binding residues (G205D, G233D) were non-functional. Complementation ability
      correlated well with ATP binding assessed in vitro. The extreme C terminus of the
      Hsp70 family is required for substrate targeting and heterocomplex formation with
      other chaperones, but mutant Sse1 proteins with a truncation of up to 44 C
      terminal residues that were not included in the PBD were active. Remarkably, the
      two domains of Sse1, when expressed in trans, functionally complement the
      sse1Delta growth phenotype and interact by coimmunoprecipitation analysis. In
      addition, a functional PBD was required to stabilize the Sse1 ATPase domain, and
      stabilization also occurred in trans. These data represent the first structure
      function analysis of this abundant but ill defined chaperone, and establish
      several novel aspects of Sse1/Hsp110 function relative to Hsp70.

PMID- 15028729
TI  - Concentrative influx of functionally active cyclic ADP-ribose in dimethyl
      sulfoxide-differentiated HL-60 cells.
AB  - Native human HL-60 cells do not express CD38, a multifunctional ectoenzyme, which
      generates cyclic ADP-ribose (cADPR), a potent calcium mobilizer. However, when HL
      60 cells are induced to differentiate to granulocytes by treatment with retinoic
      acid (RA), they express CD38 and accumulate cADPR. Both processes play a causal
      role in RA-induced differentiation. Other granulocyte differentiation-inducers,
      including dimethyl sulfoxide (Me(2)SO), fail to induce CD38 expression. We
      investigated whether treatment of HL-60 cells with Me(2)SO involves any changes
      in the cADPR/intracellular calcium ([Ca(2+)](i)) signaling system and,
      specifically, whether Me(2)SO affects those nucleoside transporters (NT) (both
      equilibrative (ENT) and concentrative (CNT)) that mediate influx of extracellular
      cADPR. Semiquantitative polymerase chain reaction analysis of transcripts,
      binding of [(3)H]nitrobenzylthioinosine (NBMPR) to intact cells, and influx
      experiments of extracellular cADPR (with selective inhibitors of NT as NBMPR or
      in specific conditions) were performed in native and Me(2)SO-differentiated HL-60
      cells. The native cells showed uptake of cADPR across ENT2, whereas influx of
      cADPR into the Me(2)SO-differentiated cells occurred mostly by concentrative
      processes mediated by CNT3 and by an NBMPR-inhibitable concentrative NT
      designated cs-csg. Me(2)SO-differentiated, but not native HL-60 cells,
      accumulated cADPR and showed increased [Ca(2+)](i) levels when grown in a
      transwell co-culture setting over CD38-transfected 3T3 fibroblasts where
      nanomolar cADPR concentrations are present in the medium. NBMPR inhibited both
      responses of Me(2)SO-induced cells. Thus, concentrative influx of extracellular
      cADPR across CNT3 and cs-csg NT could substitute in the absence of CD38 in
      eliciting cADPR-dependent [Ca(2+)](i) increases in granulocyte-differentiated HL
      60 cells, as well as in other CD38(-) cells.

PMID- 15028728
TI  - Arsenite sensitizes human melanomas to apoptosis via tumor necrosis factor alpha
      mediated pathway.
AB  - Arsenic is a well established human carcinogen and is associated with a variety
      of cancers including those of the skin. Paradoxically, arsenic has also been
      used, amid at low doses, in the treatment of leukemia for over a century. Here we
      demonstrate that low to moderate concentrations of arsenite (2-10 microm) that
      has little or no effect on normal melanocytes may induce apoptosis of human
      melanomas including highly metastatic ones despite their low surface Fas levels.
      The two prerequisites that dictate apoptotic response of melanomas upon arsenite
      treatment are low nuclear NF-kappaB activity and an endogenous expression of
      tumor necrosis factor alpha. Under these conditions, melanoma cells acquired
      sensitivity to tumor necrosis factor alpha-mediated killing. On the other hand,
      signaling pathways including those of phosphatidylinositol 3-kinase-AKT, MEK-ERK,
      and JNK play a protective role against arsenite-induced oxidative stress and
      apoptosis in melanoma cells. Suppression of these pathways dramatically
      accelerates arsenite-induced apoptosis. Taken together, these data could provide
      potential approaches to sensitize melanomas to the cytotoxic effects of arsenite
      through modulating the signaling pathways.

PMID- 15028730
TI  - Topological analysis of glucosyltransferase GtrV of Shigella flexneri by a dual
      reporter system and identification of a unique reentrant loop.
AB  - Lipopolysaccharide, particularly the O-antigen component, is one of many
      virulence determinants necessary for Shigella flexneri pathogenesis. O-Antigen
      modification is mediated by glucosyltransferase genes (gtr) encoded by temperate
      serotype-converting bacteriophages. The gtrV gene encodes the GtrV
      glucosyltransferase, an integral membrane protein that catalyzes the transfer of
      a glucosyl residue via an alpha1,3 linkage to rhamnose II of the O-antigen unit.
      This mediates conversion of S. flexneri serotype Y to serotype 5a. Analysis of
      the GtrV amino acid sequence using computer prediction programs indicated that
      GtrV had 9-11 transmembrane segments. The computer prediction models were tested
      by genetically fusing C-terminal deletions of GtrV to a dual reporter system
      composed of alkaline phosphatase and beta-galactosidase. Sandwiched GtrV
      PhoA/LacZ fusions were also constructed at predetermined positions. The enzyme
      activities of cells with the GtrV-PhoA/LacZ fusions and the particular location
      of the fusions in the gtrV indicated that GtrV has nine transmembrane segments
      and one large N-terminal periplasmic loop with the N and C termini located on the
      cytoplasmic and periplasmic sides of the membrane, respectively. The existence of
      a unique reentrant loop was discovered after transmembrane segment IV, a feature
      not documented in other bacterial glycosyltransferases. Its potential role in
      mediating serotype conversion in S. flexneri is discussed.

PMID- 15028731
TI  - A novel secreted endoglycosidase from Enterococcus faecalis with activity on
      human immunoglobulin G and ribonuclease B.
AB  - The human pathogen Enterococcus faecalis can degrade the N-linked glycans of
      human RNase B to acquire nutrients, but no gene or protein has been associated
      with this activity. We identified an 88-kDa secreted protein, endoglycosidase
      (Endo) E, which is most likely responsible for this activity. EndoE, encoded by
      ndoE, consists of an alpha-domain with a family 18 glycosyl hydrolase motif and a
      beta-domain similar to family 20 glycosyl hydrolases. Phylogenetic analysis of
      EndoE indicates that the alpha-domain is related to human chitobiases, and the
      beta-domain is related to bacterial and human hexosaminidases. Recombinant
      expression of full-length EndoE or EndoEalpha, site-directed mutagenesis of the
      catalytic residues, mass spectroscopy, and homology modeling shows that
      EndoEalpha hydrolyzes the glycan on human RNase B, whereas EndoEbeta hydrolyzes
      the conserved glycan on IgG. Denaturation experiments indicate that the chitinase
      activity on RNase B is not dependent on the tertiary structure, although it is on
      IgG. The ndoE gene and secreted EndoE are present in most E. faecalis but not in
      Enterococcus faecium isolates. Correspondingly, E. faecalis, but not E. faecium,
      degrades the glycan on RNase B during growth. Thus, we have identified a secreted
      enzyme from E. faecalis, EndoE, which by two distinct activities hydrolyzes the
      glycans on RNase B and IgG. Both activities could be important for the molecular
      pathogenesis and persistence of E. faecalis during human infections.

PMID- 15028732
TI  - Both insulin signaling defects in the liver and obesity contribute to insulin
      resistance and cause diabetes in Irs2(-/-) mice.
AB  - We previously reported that insulin receptor substrate-2 (IRS-2)-deficient mice
      develop diabetes as a result of insulin resistance in the liver and failure of
      beta-cell hyperplasia. In this study we introduced the IRS-2 gene specifically
      into the liver of Irs2(-/-) mice with adenovirus vectors. Glucose tolerance tests
      revealed that the IRS-2 restoration in the liver ameliorated the hyperglycemia,
      but the improvement in hyperinsulinemia was only partial. Endogenous glucose
      production (EGP) and the rate of glucose disappearance (Rd) were measured during
      hyperinsulinemic-euglycemic clamp studies: EGP was increased 2-fold in the Irs2(
      /-) mice, while Rd decreased by 50%. Restoration of IRS-2 in the liver suppressed
      EGP to a level similar to that in wild-type mice, but Rd remained decreased in
      the Adeno-IRS-2-infected Irs2(-/-) mice. Irs2(-/-) mice also exhibit obesity and
      hyperleptinemia associated with impairment of hypothalamic phosphatidylinositol 3
      kinase activation. Continuous intracerebroventricular leptin infusion or caloric
      restriction yielded Irs2(-/-) mice whose adiposity was comparable to that of
      Irs2(+/+) mice, and both the hyperglycemia and the hyperinsulinemia of these mice
      improved with increased Rd albeit partially. Finally combination treatment
      consisting of adenovirus-mediated gene transfer of IRS-2 and continuous
      intracerebroventricular leptin infusion completely reversed the hyperglycemia and
      hyperinsulinemia in Irs2(-/-) mice. EGP and Rd also became normal in these mice
      as well as in mice treated by caloric restriction plus adenoviral gene transfer.
      We therefore concluded that a combination of increased EGP due to insulin
      signaling defects in the liver and reduced Rd due to obesity accounts for the
      systemic insulin resistance in Irs2(-/-) mice.

PMID- 15028734
TI  - Mammary epithelial-mesenchymal interaction regulates fibronectin alternative
      splicing via phosphatidylinositol 3-kinase.
AB  - The way alternative splicing is regulated within tissues is not understood. A
      relevant model of this process is provided by fibronectin, an important
      extracellular matrix protein that plays a key role in cell adhesion and migration
      and contains three alternatively spliced regions known as EDI, EDII, and IIICS.
      We used a cell culture system to simulate mammary epithelial-stromal
      communication, a process that is crucial for patterning and function of the
      mammary gland, and studied the effects of extracellular signals on the regulation
      of fibronectin pre-mRNA alternative splicing. We found that soluble factors from
      a mammary mesenchymal cell-conditioned medium, as well as the growth factors
      HGF/SF (hepatocyte growth factor/scatter factor), KGF (keratinocyte growth
      factor), and aFGF (acidic fibroblast growth factor), stimulate EDI and IIICS but
      not EDII inclusion into fibronectin mRNA in the mammary epithelial cell line
      SCp2, favoring fibronectin isoforms associated with proliferation, migration, and
      tissue remodeling. We explored the signaling pathways involved in this regulation
      and found that the mammary mesenchymal cell-conditioned medium and HGF/SF act
      through a phosphatidylinositol 3-kinase-dependent cascade to alter fibronectin
      alternative splicing. This splicing regulation is independent from promoter
      structure and de novo protein synthesis but does require two exonic elements
      within EDI. These results shed light on how extracellular stimuli are converted
      into changes in splicing patterns.

PMID- 15028733
TI  - Palmitate, but not unsaturated fatty acids, induces the expression of interleukin
      6 in human myotubes through proteasome-dependent activation of nuclear factor
      kappaB.
AB  - Circulating interleukin-6 (IL-6), insulin, and free fatty acid (FFA)
      concentrations are associated with impaired insulin action in obese and type 2
      diabetic individuals. However, a causal relationship between elevated plasma FFAs
      and IL-6 has not been shown. Because skeletal muscle represents a major target of
      impaired insulin action, we studied whether FFAs may affect IL-6 expression in
      human myotubes. We demonstrate that specifically saturated FFAs, e.g. palmitate
      (0.25 mm), induce IL-6 mRNA expression and protein secretion by a proteasome
      dependent mechanism that leads to a rapid and chronic activation of nuclear
      factor-kappaB. Insulin, high glucose concentrations, or unsaturated FFAs did not
      activate IL-6 expression. In fact, the unsaturated FFA linoleate inhibited
      palmitate-induced IL-6 production. Because inhibition of palmitate metabolism by
      the acyl-CoA synthetase inhibitor triacsin C did not abolish IL-6 expression, it
      appears that the palmitate molecule per se exerts the observed effects.
      Furthermore, we show that in human myotubes, IL-6 activates the phosphorylation
      of signal transducer and activator of transcription 3 in concentrations similar
      to hepatocytes. However, no inhibitory effect of IL-6 on insulin action,
      determined as phosphatidylinositol 3-kinase association with insulin receptor
      substrate-1, Akt phosphorylation, and glycogen synthesis, was detected. We
      conclude that IL-6 expression may be modulated by the composition of circulating
      FFA, e.g. by diet, and that skeletal muscle cells could be target cells for IL-6.

PMID- 15028735
TI  - Identification, expression, function, and localization of a novel (sixth) isoform
      of the human sarco/endoplasmic reticulum Ca2+ATPase 3 gene.
AB  - Understanding of Ca(2+) signaling requires the knowledge of proteins involved in
      this process. Among these proteins are sarco/endoplasmic reticulum Ca(2+)-ATPases
      (SERCAs) that pump Ca(2+) into the endoplasmic reticulum (ER). Recently, the
      human SERCA3 gene was shown to give rise to five isoforms (SERCA3a-e (h3a-h3e)).
      Here we demonstrate the existence of an additional new member, termed SERCA3f
      (h3f). By reverse transcriptase-PCR using monocytic U937 cell RNA, h3f mRNA was
      found to exclude the antepenultimate exon 21. h3f mRNA expression appeared as a
      human-specific splice variant. It was not found in rats or mice. h3f mRNA gave
      rise to an h3f protein differing in its C terminus from h3a-h3e. Of particular
      interest, h3f diverged in the first amino acids after the first splice site but
      presented the same last 21 amino acids as h3b. Consequently, we further
      investigated the structure-function-location relationships of the h3b and h3f
      isoforms. Comparative functional study of h3b and h3f recombinant proteins in
      intact HEK-293 cells and in fractionated membranes showed the following distinct
      characteristics: (i) resting cytosolic Ca(2+) concentration ([Ca(2+)](c)) and
      (ii) ER Ca(2+) content ([Ca(2+)](er)); similar characteristics were shown for the
      following: (i) the effects of the SERCA inhibitor, thapsigargin, on Ca(2+)
      release ([Ca(2+)](Tg)) and subsequent Ca(2+) entry ([Ca(2+)](e)) and (ii) the low
      apparent Ca(2+) affinity and the enhanced rate of dephosphorylation of the E(2)P
      phosphoenzyme intermediate. Subcellular location of h3b and h3f by
      immunofluorescence and/or confocal microscopy using the h3b- and h3f-specific
      polyclonal and the pan-h3 monoclonal (PL/IM430) antibodies suggested overlapping
      but distinct ER location. The endogenous expression of h3f protein was also
      proved in U937 cells. Altogether these data suggest that the SERCA3 isoforms have
      a more widespread role in cellular Ca(2+) signaling than previously appreciated.

PMID- 15028736
TI  - Dbp9p, a member of the DEAD box protein family, exhibits DNA helicase activity.
AB  - The yeast Dbp9p is a member of the DEAD box family of RNA helicases, which are
      thought to be involved in RNA metabolism. Dbp9p seems to function in ribosomal
      RNA biogenesis, but it has not been biochemically characterized. To analyze the
      enzymatic characteristics of the protein, we expressed a recombinant Dbp9p in
      Escherichia coli and purified it to homogeneity. The purified protein exhibited
      RNA unwinding and binding activity in the absence of NTP, and this activity was
      abolished by a mutation in the RNA-binding domain. We then characterized the
      ATPase activity of Dbp9p with respect to cofactor specificity; the activity was
      found to be severely inhibited by yeast total RNA and moderately inhibited by
      poly(U), poly(A), and poly(C) but to be stimulated by yeast genomic DNA and
      salmon sperm DNA. In addition, Dbp9p exhibited DNA-DNA and DNA-RNA helicase
      activity in the presence of ATP. These results indicate that Dbp9p has
      biochemical characteristics unique among DEAD box proteins.

PMID- 15028737
TI  - Rab27 effector granuphilin promotes the plasma membrane targeting of insulin
      granules via interaction with syntaxin 1a.
AB  - Secretory vesicle exocytosis is a highly regulated process involving vesicle
      targeting, priming, and membrane fusion. Rabs and SNAREs play a central role in
      executing these processes. We have shown recently that Rab27a and its effector,
      granuphilin, are involved in the exocytosis of insulin-containing secretory
      granules through a direct interaction with the plasma membrane syntaxin 1a in
      pancreatic beta cells. Here, we demonstrate that fluorescence-labeled insulin
      granules are peripherally accumulated in cells overexpressing granuphilin. The
      peripheral location of granules is well overlapped with both localizations of
      granuphilin and syntaxin 1a. The plasma membrane targeting of secretory granules
      is promoted by wild-type granuphilin but not by granuphilin mutants that are
      defective in binding to either Rab27a or syntaxin 1a. Granuphilin directly binds
      to the H3 domain of syntaxin 1a containing its SNARE motif. Moreover,
      introduction of the H3 domain into beta cells induces a dissociation of the
      native granuphilin-syntaxin complex and a marked reduction of newly docked
      granules. These results indicate that granuphilin plays a role in tethering
      insulin granules to the plasma membrane by an interaction with both Rab27a and
      syntaxin 1a. The complex formation of these three proteins may contribute to the
      specificity of the targeting process during the exocytosis of insulin granules.

PMID- 15028738
TI  - Cardiac-specific knock-out of lipoprotein lipase alters plasma lipoprotein
      triglyceride metabolism and cardiac gene expression.
AB  - Fatty acids are the primary energy source for the heart. The heart acquires fatty
      acids associated with albumin or derived from lipoprotein lipase (LpL)-mediated
      hydrolysis of lipoprotein triglyceride (TG). We generated heart-specific LpL
      knock-out mice (hLpL0) to determine whether cardiac LpL modulates the actions of
      peroxisome proliferator-activated receptors and affects whole body lipid
      metabolism. Male hLpL0 mice had significantly elevated plasma TG levels and
      decreased clearance of postprandial lipids despite normal postheparin plasma LpL
      activity. Very large density lipoprotein-TG uptake was decreased by 72% in hLpL0
      hearts. However, heart uptake of albumin-bound free fatty acids was not altered.
      Northern blot analysis revealed a decrease in the expression of peroxisome
      proliferator-activated receptor alpha-response genes involved in fatty acid beta
      oxidation. Surprisingly, the expression of glucose transporters 1 and 4 and
      insulin receptor substrate 2 was increased and that of pyruvate dehydrogenase
      kinase 4 and insulin receptor substrate 1 was reduced. Basal glucose uptake was
      increased markedly in hLpL0 hearts. Thus, the loss of LpL in the heart leads to
      defective plasma metabolism of TG. Moreover, fatty acids derived from lipoprotein
      TG and not just albumin-associated fatty acids are important for cardiac lipid
      metabolism and gene regulation.

PMID- 15028739
TI  - Dorsal spinal interneurons forming a primitive, cutaneous sensory pathway.
AB  - In mammals, sensory projection pathways are provided by just three classes of
      spinal interneuron that develop from the roof-plate. We asked whether similar
      sensory projection interneurons are present primitively in a developing lower
      vertebrate where function can be more readily studied. Using an immobilized
      Xenopus tadpole spinal cord preparation, we define the properties and connections
      of spinal sensory projection interneurons using whole cell patch recordings from
      single neurons or pairs, identified by dye filling. Dorsolateral interneurons lie
      in the tadpole equivalent of the spinal dorsal horn, and have dorsally located
      dendrites and an ipsilateral ascending axon that projects into the midbrain.
      These neurons receive direct, mainly AMPA receptor (AMPAR)-mediated, excitation
      from skin touch sensory neurons. They in turn produce AMPAR and N-methyl-d
      aspartate receptor (NMDAR)-mediated excitation of spinal locomotor pattern
      generator neurons rostrally on the same side of the cord. During swimming, they
      receive glycinergic modulatory inhibition from ascending interneurons in the
      spinal locomotor central pattern generator. We conclude that spinal dorsolateral
      interneurons are a primitive class of excitatory sensory projection neurons
      activated by ipsilateral cutaneous afferents and carrying excitation
      ipsilaterally and rostrally as far as the midbrain to initiate or accelerate
      swimming.

PMID- 15028740
TI  - Encoder adaptation modulates the visual responses of crayfish interneurons.
AB  - The responses of sustaining and dimming fibers were characterized by the time
      varying firing rates elicited by extrinsic current and flashes of light. These
      data were simulated by an adaptive integrate-and-fire model. A postimpulse shunt
      conductance simulated spike-frequency adaptation. The correlation between
      observed and model current-elicited impulse rates was 0.94-0.98. However, except
      for a difference in input resistance (both measured and simulated), the voltage
      to impulse encoders of the two cell groups was similar and exhibited comparable
      degrees of spike-frequency adaptation (40 to 45%). The encoder model derived from
      current-elicited responses (with fixed parameters) was used to simulate visual
      responses elicited by light flashes. These simulations included a synaptic
      current derived from the time course of the postsynaptic potential (PSP). The
      sustaining fiber visual response consisted of a large excitatory PSP and high
      frequency transient burst that adapted (by approximately 80%) to a low-frequency
      plateau discharge. The simulations indicated that spike-frequency adaptation had
      no effect on the transient discharge but reduced the plateau firing rate by
      approximately 60%. Encoder adaptation enhances the sustaining fiber response to
      the time derivative of the stimulus. In dimming fibers, the light flash elicits
      an inhibitory PSP that interrupts the "dark discharge" and an off response
      following the end of the flash. The simulations indicated that spike-frequency
      adaptation reduces the firing rate of both the dark discharge and the off
      response. Thus the model suggests that different effects of encoder adaptation on
      the two cell types arise from the same encoder mechanisms, but different actions
      are determined by differences in impulse rate and the time course of the
      discharge.

PMID- 15028741
TI  - Carbenoxolone inhibition of voltage-gated Ca channels and synaptic transmission
      in the retina.
AB  - We show that carbenoxolone, a drug used to block hemichannels in the retina to
      test the ephaptic model of horizontal cell inhibitory feedback, has strong
      inhibitory effects on voltage-gated Ca channels. Carbenoxolone (100 microM)
      reduced photoreceptor-to-horizontal cell synaptic transmission by 92%. Applied to
      patch-clamped, isolated cone photoreceptors, carbenoxolone inhibited Ca channels
      with an EC(50) of 48 microM. At 100 microM, it reduced cone Ca channel current by
      37%, reduced depolarization-evoked [Ca(2+)] signals in fluo-4 loaded retinal
      slices by 57% and inhibited Ca channels in Muller cells by 52%. A synaptic
      transfer model suggests that the degree of block of Ca channels accounts for the
      reduction in synaptic transmission. These results suggest broad inhibitory
      actions for carbenoxolone in the retina that must be considered when interpreting
      its effects on inhibitory feedback.

PMID- 15028742
TI  - Activity-driven synaptic and axonal degeneration in canine motor neuron disease.
AB  - The role of neuronal activity in the pathogenesis of neurodegenerative disease is
      largely unknown. In this study, we examined the effects of increasing motor
      neuron activity on the pathogenesis of a canine version of inherited motor neuron
      disease (hereditary canine spinal muscular atrophy). Activity of motor neurons
      innervating the ankle extensor muscle medial gastrocnemius (MG) was increased by
      denervating close synergist muscles. In affected animals, 4 wk of synergist
      denervation accelerated loss of motor-unit function relative to control muscles
      and decreased motor axon conduction velocities. Slowing of axon conduction was
      greatest in the most distal portions of motor axons. Morphological analysis of
      neuromuscular junctions (NMJs) showed that these functional changes were
      associated with increased loss of intact innervation and with the appearance of
      significant motor axon and motor terminal sprouting. These effects were not
      observed in the MG muscles of age-matched, normal animals with synergist
      denervation for 5 wk. The results indicate that motor neuron action potential
      activity is a major contributing factor to the loss of motor-unit function and
      degeneration in inherited canine motor neuron disease.

PMID- 15028743
TI  - Activation of monkey locus coeruleus neurons varies with difficulty and
      performance in a target detection task.
AB  - We previously reported that noradrenergic neurons in the monkey locus coeruleus
      (LC) are activated selectively by target stimuli in a target detection task.
      Here, we varied the discrimination difficulty in this task and recorded impulse
      activity of LC neurons to analyze LC responses on error trials and in relation to
      behavioral response times (RTs). In easy and difficult discrimination conditions,
      LC neurons responded preferentially to target stimuli with phasic activation.
      These responses consistently preceded behavioral responses regardless of task
      difficulty. Latencies for LC and behavioral responses increased similarly for
      difficult compared with easy discrimination trials. LC response latencies were
      also shorter for fast RT trials compared with slow RT trials regardless of
      difficulty, indicating a close temporal relationship between LC and behavioral
      responses. This relationship was confirmed with response-locked histograms of LC
      activity, which yielded more temporally synchronized LC responses than stimulus
      locked histograms. Population histograms of LC activity revealed that nontarget
      stimuli resulting in false alarm responses produced phasic LC activation
      (although smaller than for target-hit trials), and nontarget stimuli resulting in
      correct rejection responses yielded a small inhibition in LC activity. Population
      analyses also revealed that LC responses included an early, small excitatory
      component that was not previously detected. This early response was
      nondiscriminative because it was similar for target and nontarget stimulus
      trials. These results indicate that LC neurons exhibit early small magnitude
      responses that are closely linked to sensory stimuli. In addition, these cells
      show a later, larger magnitude response that is temporally linked to behavioral
      responses. These and other results lead us to hypothesize that LC responses are
      driven by decision processes and help facilitate subsequent behavioral responses.

PMID- 15028744
TI  - Activity of rostral superior colliculus neurons during passive and active viewing
      of motion.
AB  - The superior colliculus (SC) has long been known to be important for the control
      of saccades, and recent findings indicate that the rostral SC (rSC) plays some
      role in pursuit as well. The recent finding that the prelude activity of some SC
      neurons exhibits directional selectivity suggests that the rSC might process
      visual motion signals relevant for the control of pursuit. We have now tested the
      activity of buildup neurons in the rSC during the passive viewing of motion
      stimuli placed within their response field and also during the previewing of
      visual motion stimuli that were subsequently tracked with pursuit eye movements.
      We found that rSC buildup neurons typically responded well to motion stimuli, but
      that they exhibited essentially no selectivity for the direction or speed of
      visual motion, and that they also responded well to stationary flickering dots.
      However, during the previewing of visual motion prior to the onset of pursuit,
      many neurons did exhibit a buildup of activity similar to that exhibited before
      saccades. These results are inconsistent with the notion that the rSC mediates
      visual motion signals used to drive pursuit, but instead support the idea that
      visual motion signals can be used by rSC neurons as part of a mechanism for
      selecting targets for pursuit and saccades.

PMID- 15028745
TI  - Interlimb transfer of novel inertial dynamics is asymmetrical.
AB  - Mechanisms underlying interlimb transfer of adaptation to visuomotor rotations
      have recently been explored in depth. However, little data are available
      regarding interlimb transfer of adaptation to novel inertial dynamics. The
      present study thus investigated interlimb transfer of dynamics by examining the
      effect of initial training with one arm on subsequent performance with the other
      in adaptation to a 1.5-kg mass attached eccentrically to the forearm. Using
      inverse dynamic analysis, we examined the changes in torque strategies associated
      with adaptation to the extra mass, and with interlimb transfer of that
      adaptation. Following initial training with the dominant arm, nondominant arm
      performance improved substantially in terms of linearity and initial direction
      control as compared with naive performance. However, initial training with the
      nondominant arm had no effect on subsequent performance with the dominant arm.
      Inverse dynamic analysis revealed that improvements in kinematics were
      implemented by increasing flexor muscle torques at the elbow to counter load
      induced increases in extensor interaction torques as well as increasing flexor
      muscle torques at the shoulder to counter the extensor actions of elbow muscle
      torque. Following opposite arm adaptation, the nondominant arm adopted this
      dynamic strategy early in adaptation. These findings suggest that dominant arm
      adaptation to novel inertial dynamics leads to information that can be accessed
      and utilized by the opposite arm controller, but not vice versa. When compared
      with our previous findings on interlimb transfer of visuomotor rotations, our
      current findings suggest that adaptations to visuomotor and dynamic
      transformations are mediated by distinct neural mechanisms.

PMID- 15028746
TI  - Sleep-wake related discharge properties of basal forebrain neurons recorded with
      micropipettes in head-fixed rats.
AB  - The basal forebrain has been shown to play an important role in cortical
      activation of wake and paradoxical sleep (PS), yet has also been posited to play
      a role in slow wave sleep (SWS). In an effort to determine whether these
      different roles may be fulfilled by different cell groups, including cholinergic
      and GABAergic cells, we recorded from 123 units in waking-sleeping, head-fixed
      rats using micropipettes to allow juxtacellular labeling. Functional sets of
      intermingled cell groups emerged as units whose discharge was as follows: 1)
      maximum in active wake (aW) and positively or not correlated with EEG gamma
      activity, while positively correlated with nuchal EMG activity, and thus
      potentially facilitatory for waking and behavioral arousal (12%); 2) maximum in
      SWS or SWS-PS and positively correlated with delta EEG activity, while not or
      negatively correlated with EMG activity, and thus potentially promotive for sleep
      with cortical slow wave activity and/or accompanying behavioral changes (16%); 3)
      maximum in PS or PS and aW and positively correlated with gamma and theta EEG
      activity, while negatively or not correlated with EMG activity, and thus
      potentially promotive for cortical activation during PS or PS and W (62%); and 4)
      equivalent across all states and thus not involved in state regulation (
      approximately 10%). Units of each group also manifested different firing patterns
      typified as slow tonic (19.5%), fast tonic (32.5%), or fast phasic (48%),
      including rhythmic bursting (6%). Through these diverse cell groups, the basal
      forebrain has the capacity to modulate cortical activity, behavior, and/or
      related physiological processes across the sleep-waking cycle and thereby
      regulate the sleep-wake state of the animal.

PMID- 15028747
TI  - Rhythmic motor activity in thin transverse slice preparations of the fetal rat
      spinal cord.
AB  - Networks generating locomotor-like rhythmic motor activity are formed during the
      last week of the fetal period in the rat spinal cord. We investigated the
      coordinated rhythmic motor activity induced in transverse slice preparations of
      the lumbar spinal cord taken from fetal rats as early as embryonic day (E) 16.5.
      In slices as thin as 100 microm, bath-application of 5-hydroxytryptamine (5-HT)
      induced rhythmic [Ca(2+)](i) elevations in motoneurons labeled with Calcium Green
      1 dextran. The rhythmic [Ca(2+)](i) elevations were similar in frequency to that
      in the intact lumbar spinal cord, although there was no temporal correlation
      between the activity in the left and right sides of 100-microm slices. Such
      rhythmic [Ca(2+)](i) elevations were observed in the slices taken from all lumbar
      segments. Moreover, the rhythmic activity was abolished by simultaneous blockade
      of glutamate, glycine, and GABA(A) receptors, indicating that synaptic
      transmission mediated by these receptors is important for the generation of the
      rhythm in these slices. Synchronous rhythmic activity between the left-right
      sides was found in slices thicker than 200 microm taken from any segmental level
      of the lumbar spinal cord. In these preparations, commissural neurons were
      activated synchronously with ipsilateral motoneurons. These results indicate that
      the neuronal networks sufficient to generate coordinated rhythmic activity are
      contained in one-half of a single lumbar segment at E16.5. Such spinal cord
      slices are a promising experimental model to investigate the neuronal mechanisms
      and the development of rhythm generation in the spinal cord.

PMID- 15028748
TI  - Properties of mouse cutaneous rapidly adapting afferents: relationship to skin
      viscoelasticity.
AB  - When skin is stretched, stimuli experienced by a cutaneous mechanoreceptor neuron
      are transmitted to the nerve ending through the skin. In these experiments, we
      tested the hypothesis that the viscoelastic response of the skin influences the
      dynamic response of cutaneous rapidly adapting (RA) neurons. Cutaneous RA
      afferent neurons were recorded in 3 species of mice (Tsk, Pallid, and C57BL6)
      whose skin has different viscoelastic properties. Isolated samples of skin and
      nerve were stimulated mechanically with a dynamic stretch stimulus, which
      followed a pseudo Gaussian waveform with a bandwidth of 0-60 Hz. The mechanical
      response of the skin was measured as were responses of single RA cutaneous
      mechanoreceptor neurons. For each neuron, the strength of association between
      spike responses and the dynamic and static components of stimuli were determined
      with multiple logistic regression analysis. The viscoelastic material properties
      of each skin sample were determined indirectly, by creating a nonlinear (Wiener
      Volterra) model of the stress-strain relationship, and using the model to predict
      the complex compliance (i.e., the viscoelastic material properties). The dynamic
      sensitivity of RA mechanoreceptor neurons in mouse hairy skin was weakly related
      to the viscoelastic properties of the skin. Loss modulus and phase angle were
      lower (indicating a decreased viscous component of response) in Tsk and Pallid
      than in C57BL6 mice. However, RA mechanoreceptor neurons in Tsk and Pallid skin
      did not differ from those in C57 skin with regard to their sensitivity to the
      rate of change of stress or to the rate of change of incremental strain energy.
      They did have a decreased sensitivity to the rate of change of tensile strain.
      Thus the skin samples with lower dynamic mechanical response contained neurons
      with a somewhat lower sensitivity to dynamic stimuli.

PMID- 15028749
TI  - Molecular basis for modulation of recombinant alpha1beta2gamma2 GABAA receptors
      by protons.
AB  - We have previously shown that extracellular protons inhibit recombinant and
      native GABA(A) receptors. In this report, we studied the site(s) and mechanism by
      which protons modulate the GABA(A) receptor. Whole cell GABA-activated currents
      were recorded from human embryonic kidney (HEK) 293 cells expressing recombinant
      alpha1beta2gamma2 GABA(A) receptors. Protons competitively inhibited the response
      to GABA and bicuculline. In contrast, change in pH did not influence direct
      gating of the channel by pentobarbital, and it did not influence spontaneous
      channel openings in alpha1(L264T)beta2gamma2 receptors, suggesting pH does not
      modulate channel activity by affecting the channel gating process directly. To
      test the hypothesis that protons modulate GABA(A) receptors at the ligand binding
      site, we systemically mutated N-terminal residues known to be involved in GABA
      binding and assessed effects of pH on these mutant receptors. Site-specific
      mutation of beta2 Y205 to F or alpha1 F64 to A, both of which are known to
      influence GABA binding, significantly reduced pH sensitivity of the GABA
      response. These mutations did not affect Zn(2+) sensitivity, suggesting that H(+)
      and Zn(2+) do not share a common site of action. Additional experiments further
      tested this possibility. Treatment with the histidine-modifying reagent
      diethylpyrocarbonate (DEPC) reduced Zn(2+)-mediated inhibition of GABA(A)
      receptors but had no effect on proton-induced inhibition of GABA currents. In
      addition, mutation of residues known to be involved in Zn(2+) modulation had no
      effect on pH modulation of GABA(A) receptors. Our results support the hypothesis
      that protons inhibit GABA(A) receptor function by direct or allosteric
      interaction with the GABA binding site. In addition, the sites of action of H(+)
      and Zn(2+) in GABA(A) receptors are distinct.

PMID- 15028750
TI  - Mapping neural architectures onto acoustic features of birdsong.
AB  - The motor pathway responsible for the complex vocalizations of songbirds has been
      extensively characterized, both in terms of intrinsic and synaptic physiology in
      vitro and in terms of the spatiotemporal patterns of neural activity in vivo.
      However, the relationship between the neural architecture of the song motor
      pathway and the acoustic features of birdsong is not well understood. Using a
      computational model of the song motor pathway and the songbird vocal organ, we
      investigate the relationship between song production and the neural connectivity
      of nucleus HVc (used as a proper name) and the robust nucleus of the
      archistriatum (RA). Drawing on recent experimental observations, our neural model
      contains a population of sequentially bursting HVc neurons driving the activity
      of a population of RA neurons. An important focus of our investigations is the
      contribution of intrinsic circuitry within RA to the acoustic output of the
      model. We find that the inclusion of inhibitory interneurons in the model can
      substantially influence the features of song syllables, and we illustrate the
      potential for subharmonic behavior in RA in response to forcing by HVc neurons.
      Our results demonstrate the association of specific acoustic features with
      specific neural connectivities and support the view that intrinsic circuitry
      within RA may play a critical role in generating the features of birdsong.

PMID- 15028751
TI  - Aberrant cellular behavior of mutant torsinA implicates nuclear envelope
      dysfunction in DYT1 dystonia.
AB  - Torsion dystonia-1 (DYT1) dystonia, the most common inherited form of dystonia,
      is caused by a three base pair deletion that eliminates a single amino acid from
      the disease protein, torsinA. TorsinA is an "AAA" protein thought to reside in
      the endoplasmic reticulum (ER), yet both its cellular function and the basis for
      neuronal dysfunction in DYT1 remain unknown. A clue to disease pathogenesis is
      the fact that mutant, but not wild-type, torsinA forms membranous inclusions in
      cell culture. To explore the pathobiology of DYT1 dystonia, we generated PC12
      neural cell lines that inducibly express wild-type or mutant torsinA. Although in
      this model torsinA displays some properties consistent with ER localization,
      mutant torsinA also accumulates in the nuclear envelope (NE), a structure
      contiguous with cytoplasmic ER. Consistent with this, membranous inclusions
      formed by mutant torsinA are shown to derive not from the ER, as thought
      previously, but from the NE. We demonstrate further that torsinA forms different
      disulfide-linked complexes that may be linked functionally to subcellular
      localization in the NE versus cytoplasmic ER. Despite mutant TA accumulation in
      NE structures, nucleocytoplasmic transport of a reporter protein was unaffected.
      These findings, together with parallel studies failing to demonstrate
      perturbation of ER function, implicate the NE as a primary site of dysfunction in
      DYT1. DYT1 dystonia can be added to the growing list of inherited neurological
      disorders involving the NE.

PMID- 15028752
TI  - Enantioselectivity of projection neurons innervating identified olfactory
      glomeruli.
AB  - Projection neurons (PNs) with arborizations in the sexually dimorphic "lateral
      large female glomerulus" (latLFG) in the antennal lobe (AL) of the moth Manduca
      sexta previously were shown to respond preferentially to antennal stimulation
      with (+/-)linalool, a volatile compound commonly emitted by plants. In the
      present study, using intracellular recording and staining techniques, we examined
      the responsiveness of latLFG-PNs to the enantiomers, (+)linalool and (-)linalool
      and found that (1) latLFG-PNs are more responsive to antennal stimulation with
      (+)linalool than with (-)linalool, (2) PNs with arborizations in a glomerulus
      adjacent to the latLFG are preferentially responsive to (-)linalool, and (3) PNs
      with arborizations confined to other glomeruli near the latLFG are equally
      responsive to both enantiomers of linalool. Structure-activity studies showed
      that the hydroxyl group in this tertiary terpene alcohol is the key feature of
      the molecule determining the response of enantioselective PNs to linalool. In
      contrast, the responses of non-enantioselective PNs are less dependent on the
      alcoholic functionality of linalool. Our findings show that PNs innervating a
      uniquely identifiable glomerulus respond preferentially to a particular
      enantiomer of an odor substance. Moreover, PNs with arborizations in a glomerulus
      adjacent to the latLFG, although less sensitive than latLFG-PNs to linalool,
      respond preferentially to the opposite enantiomer, demonstrating that information
      about stimulus-absolute configuration can be encoded in different olfactory
      glomeruli.

PMID- 15028753
TI  - Origins of cortical interneuron subtypes.
AB  - Cerebral cortical functions are conducted by two general classes of neurons:
      glutamatergic projection neurons and GABAergic interneurons. Distinct interneuron
      subtypes serve distinct roles in modulating cortical activity and can be
      differentially affected in cortical diseases, but little is known about the
      mechanisms for generating their diversity. Recent evidence suggests that many
      cortical interneurons originate within the subcortical telencephalon and then
      migrate tangentially into the overlying cortex. To test the hypothesis that
      distinct interneuron subtypes are derived from distinct telencephalic
      subdivisions, we have used an in vitro assay to assess the developmental
      potential of subregions of the telencephalic proliferative zone (PZ) to give rise
      to neurochemically defined interneuron subgroups. PZ cells from GFP+ donor mouse
      embryos were transplanted onto neonatal cortical feeder cells and assessed for
      their ability to generate specific interneuron subtypes. Our results suggest that
      the parvalbumin- and the somatostatin-expressing interneuron subgroups originate
      primarily within the medial ganglionic eminence (MGE) of the subcortical
      telencephalon, whereas the calretinin-expressing interneurons appear to derive
      mainly from the caudal ganglionic eminence (CGE). These results are supported by
      findings from primary cultures of cortex from Nkx2.1 mutants, in which normal MGE
      fails to form but in which the CGE is less affected. In these cultures,
      parvalbumin- and somatostatin-expressing cells are absent, although calretinin
      expressing interneurons are present. Interestingly, calretinin-expressing bipolar
      interneurons were nearly absent from cortical cultures of Dlx1/2 mutants. By
      establishing spatial differences in the origins of interneuron subtypes, these
      studies lay the groundwork for elucidating the molecular bases for their distinct
      differentiation pathways.

PMID- 15028754
TI  - An outer segment localization signal at the C terminus of the photoreceptor
      specific retinol dehydrogenase.
AB  - Photoreceptor retinol dehydrogenase (prRDH) is a membrane-associated cytosolic
      protein that localizes to the outer segments (OS) of rods and cones. Here, we
      demonstrate that the C-terminal 16 amino acids of prRDH confer membrane
      association as well as cone and rod OS targeting on a linked green fluorescent
      protein. Membrane association in transfected 293 cells and in transgenic Xenopus
      photoreceptors is mediated by fatty acylation at one or more evolutionarily
      conserved cysteines within the prRDH C-terminal tail. In bovine OS, native prRDH
      is similarly acylated, and hydrolysis of this linkage releases the protein from
      the membrane. Efficient OS localization requires both membrane association and
      the prRDH sequence. (V/I)XPX at the extreme C terminus, which closely resembles
      the C-terminal sequence that targets opsin/rhodopsin to the OS. Taken together,
      these data imply that the C-terminal. (V/I)XPX sequence is a general OS
      localization signal that can function in the context of both integral and
      peripheral membrane proteins. This strategy for OS localization resembles those
      used for protein localization to mitochondria, peroxisomes, endosomes, and
      endoplasmic reticulum; in each case, a short N- or C-terminal sequence is shared
      among structurally diverse proteins that are targeted to the same subcellular
      destination.

PMID- 15028755
TI  - Vesicular glutamate transporter-dependent glutamate release from astrocytes.
AB  - Astrocytes exhibit excitability based on variations of their intracellular Ca2+
      concentrations, which leads to glutamate release, that in turn can signal to
      adjacent neurons. This glutamate-mediated astrocyte-neuron signaling occurs at
      physiological intracellular Ca2+ levels in astrocytes and includes modulation of
      synaptic transmission. The mechanism underlying Ca2+-dependent glutamate release
      from astrocytes is most likely exocytosis, because astrocytes express the protein
      components of the soluble N-ethyl maleimide-sensitive fusion protein attachment
      protein receptors complex, including synaptobrevin 2, syntaxin, and synaptosome
      associated protein of 23 kDa. Although these proteins mediate Ca2+-dependent
      glutamate release from astrocytes, it is not well understood whether astrocytes
      express functional vesicular glutamate transporters (VGLUTs) that are critical
      for vesicle refilling. Here, we find in cultured and freshly isolated astrocytes
      the presence of brain-specific Na+-dependent inorganic phosphate cotransporter
      and differentiation-associated Na+-dependent inorganic phosphate cotransporter
      that have recently been identified as VGLUTs 1 and 2. Indirect
      immunocytochemistry showed a punctate pattern of VGLUT immunoreactivity
      throughout the entire cell body and processes, whereas pharmacological inhibition
      of VGLUTs abolished mechanically and agonist-evoked Ca2+-dependent glutamate
      release from astrocytes. Taken together, these data indicate that VGLUTs play a
      functional role in exocytotic glutamate release from astrocytes.

PMID- 15028756
TI  - Inhibitory control at a synaptic relay.
AB  - The mammalian medial nucleus of the trapezoid body (MNTB) harbors one of the most
      powerful terminals in the CNS, the calyx of Held. The mechanisms known to
      regulate this synaptic relay are relatively ineffective. Here, we report the
      presence of a remarkably robust and fast-acting glycinergic inhibitory system
      capable of suppressing calyceal transmission. Evoked glycinergic IPSCs were
      relatively small in 2-week-old rats, an age by which calyceal maturation has
      reportedly neared completion. However, by postnatal day 25 (P25), glycinergic
      transmission had undergone a vigorous transformation, resulting in peak synaptic
      conductances as high as 280 nS. These are comparable with glutamatergic
      conductances activated by calyceal inputs. Decay kinetics for IPSCs were
      severalfold faster than for glycinergic synaptic events reported previously. At
      physiological temperatures in P25 rats, IPSCs decayed in approximately 1 msec and
      could be elicited at frequencies up to 500 Hz. Moreover, EPSPs triggered by
      glutamatergic signals derived from the calyx or simulated by conductance clamp
      were suppressed when preceded by simulated glycinergic IPSPs. The matching of
      excitatory transmission in the calyx of Held by a powerful, precision inhibitory
      system suggests that the relay function of the MNTB may be rapidly modified
      during sound localization.

PMID- 15028757
TI  - Metabotropic glutamate receptor activation regulates fragile x mental retardation
      protein and FMR1 mRNA localization differentially in dendrites and at synapses.
AB  - Fragile X syndrome is caused by the absence of the mRNA-binding protein Fragile X
      mental retardation protein (FMRP), which may play a role in activity-regulated
      localization and translation of mRNA in dendrites and at synapses. We
      investigated whether neuronal activity and glutamatergic signals regulate
      trafficking of FMRP and its encoding Fmr1 mRNA into dendrites or at synapses.
      Using high-resolution fluorescence and digital imaging microscopy in cultured
      hippocampal neurons, FMRP and Fmr1 mRNA were localized in granules throughout
      dendrites and within spines. KCl depolarization rapidly increased FMRP and Fmr1
      mRNA levels in dendrites. Metabotropic glutamate receptor (mGluR) activation, in
      particular mGluR5 activation, was necessary for localization of FMRP into
      dendrites. Blockade of either PKC or internal calcium prevented mGluR-dependent
      localization of both FMRP and Fmr1 mRNA in dendrites. The activity-dependent
      localization of FMRP was not dependent on protein synthesis. Fluorescence
      recovery after photobleaching analysis of live neurons transfected with enhanced
      green fluorescent protein-FMRP revealed increased granule trafficking in response
      to KCl depolarization. In contrast to its dendritic localization, mGluR
      activation diminished FMRP, but not Fmr1 mRNA, localization at synapses. These
      results demonstrate regulation of FMRP and Fmr1 mRNA trafficking in dendrites and
      synapses in response to specific glutamatergic signals.

PMID- 15028758
TI  - Changes in excitability of ascending and descending inputs to cerebellar climbing
      fibers during locomotion.
AB  - The inferior olive climbing fiber projection plays a central role in all major
      theories of cerebellar function. Therefore, mechanisms that control the ability
      of climbing fibers to forward information to the cerebellum are of considerable
      interest. We examined changes in transmission in cerebro-olivocerebellar pathways
      (COCPs) and spino-olivocerebellar pathways (SOCPs) during locomotion in awake
      cats (n = 4) using low-intensity electrical stimuli delivered to the
      contralateral cerebral peduncle or the ipsilateral superficial radial nerve to
      set up volleys in COCPs and SOCPs, respectively. The responses were recorded as
      evoked extracellular climbing fiber field potentials within the C1 or C3 zones in
      the paravermal cerebellar cortex (lobule Va-Vc). At most C1 and C3 zone sites,
      the largest COCP responses occurred during the stance phase, and the smallest
      responses occurred during the swing phase of the ipsilateral forelimb step cycle.
      In marked contrast, SOCP responses recorded at the same sites were usually
      largest during the swing phase and smallest during the stance phase. Because
      substantial climbing fiber responses could be evoked in all phases of the step
      cycle, the results imply that olivary neurons remain excitable throughout, and
      that the differences between SOCPs and COCPs in their pattern of step-related
      modulation are unlikely to have arisen solely through inhibition at the level of
      the inferior olive (e.g., by activity in the inhibitory cerebellar nucleo-olivary
      pathway). The different patterns of modulation also suggest that climbing fiber
      signals conveyed by COCPs and SOCPs are likely to affect information processing
      within the cerebellar cortical C1 and C3 zones at different times during
      locomotion.

PMID- 15028759
TI  - Electroconvulsive seizures regulate gene expression of distinct neurotrophic
      signaling pathways.
AB  - Electroconvulsive therapy (ECT) remains the treatment of choice for drug
      resistant patients with depressive disorders, yet the mechanism for its efficacy
      remains unknown. Gene transcription changes were measured in the frontal cortex
      and hippocampus of rats subjected to sham seizures or to 1 or 10
      electroconvulsive seizures (ECS), a model of ECT. Among the 3500-4400 RNA
      sequences detected in each sample, ECS increased by 1.5- to 11-fold or decreased
      by at least 34% the expression of 120 unique genes. The hippocampus produced more
      than three times the number of gene changes seen in the cortex, and many
      hippocampal gene changes persisted with chronic ECS, unlike in the cortex. Among
      the 120 genes, 77 have not been reported in previous studies of ECS or seizure
      responses, and 39 were confirmed among 59 studied by quantitative real time PCR.
      Another 19 genes, 10 previously unreported, changed by <1.5-fold but with very
      high significance. Multiple genes were identified within distinct pathways,
      including the BDNF-MAP kinase-cAMP-cAMP response element-binding protein pathway
      (15 genes), the arachidonic acid pathway (5 genes), and more than 10 genes in
      each of the immediate-early gene, neurogenesis, and exercise response gene
      groups. Neurogenesis, neurite outgrowth, and neuronal plasticity associated with
      BDNF, glutamate, and cAMP-protein kinase A signaling pathways may mediate the
      antidepressant effects of ECT in humans. These genes, and others that increase
      only with chronic ECS such as neuropeptide Y and thyrotropin-releasing hormone,
      may provide novel ways to select drugs for the treatment of depression and mimic
      the rapid effectiveness of ECT.

PMID- 15028760
TI  - The orexin/hypocretin system in zebrafish is connected to the aminergic and
      cholinergic systems.
AB  - The orexin/hypocretin (ORX) system is involved in physiological processes such as
      feeding, energy metabolism, and the control of sleep and wakefulness. The ORX
      system may drive the aminergic and cholinergic activities that control sleep and
      wakefulness states because of the ORX fiber projections to the aminergic and
      cholinergic cell clusters. The biological mechanisms and relevance of the
      interactions between these neurotransmitter systems are poorly understood. We
      studied these systems in zebrafish, a model organism in which it is possible to
      simultaneously study these systems and their interactions. We cloned a zebrafish
      prepro-ORX gene that encodes for the two functional neuropeptides orexin-A (ORX
      A) and orexin-B (ORX-B). The prepro-ORX gene of the zebrafish consisted of one
      exon in contrast to mammals. The sequence of the ORX-A peptide of the zebrafish
      was less conserved than the ORX-B peptide compared with other vertebrates. By
      using in situ hybridization and immunohistochemistry, we found that the
      organization of the ORX system of zebrafish was similar to the ORX system in
      mammals, including a hypothalamic cell cluster and widespread fiber projections.
      The ORX system of the zebrafish showed a unique characteristic with an additional
      putatively ORX-containing cell group. The ORX system innervated several aminergic
      nuclei, raphe, locus ceruleus, the mesopontine-like area, dopaminergic clusters,
      and histaminergic neurons. A reciprocal relationship was found between the ORX
      system and several aminergic systems. Our results suggest that the architecture
      of these neurotransmitter systems is conserved in vertebrates and that these
      neurotransmitter systems in zebrafish may be involved in regulation of states of
      wakefulness and energy homeostasis by similar mechanisms as those in mammals.

PMID- 15028761
TI  - A nonsense mutation of the sodium channel gene SCN2A in a patient with
      intractable epilepsy and mental decline.
AB  - Mutations, exclusively missense, of voltage-gated sodium channel alpha subunit
      type 1 (SCN1A) and type 2 (SCN2A) genes were reported in patients with idiopathic
      epilepsy: generalized epilepsy with febrile seizures plus. Nonsense and
      frameshift mutations of SCN1A, by contrast, were identified in intractable
      epilepsy: severe myoclonic epilepsy in infancy (SMEI). Here we describe a first
      nonsense mutation of SCN2A in a patient with intractable epilepsy and severe
      mental decline. The phenotype is similar to SMEI but distinct because of partial
      epilepsy, delayed onset (1 year 7 months), and absence of temperature
      sensitivity. A mutational analysis revealed that the patient had a heterozygous
      de novo nonsense mutation R102X of SCN2A. Patch-clamp analysis of Na(v)1.2 wild
      type channels and the R102X mutant protein coexpressed in human embryonic kidney
      293 cells showed that the truncated mutant protein shifted the voltage dependence
      of inactivation of wild-type channels in the hyperpolarizing direction. Analysis
      of the subcellular localization of R102X truncated protein suggested that its
      dominant negative effect could arise from direct or indirect cytoskeletal
      interactions of the mutant protein. Haploinsufficiency of Na(v)1.2 protein is one
      plausible explanation for the pathology of this patient; however, our biophysical
      findings suggest that the R102X truncated protein exerts a dominant negative
      effect leading to the patient's intractable epilepsy.

PMID- 15028762
TI  - Carbonic anhydrase isoform VII acts as a molecular switch in the development of
      synchronous gamma-frequency firing of hippocampal CA1 pyramidal cells.
AB  - Identification of the molecular mechanisms that enable synchronous firing of CA1
      pyramidal neurons is central to the understanding of the functional properties of
      this major hippocampal output pathway. Using microfluorescence measurements of
      intraneuronal pH, in situ hybridization, as well as intracellular, extracellular,
      and K+-sensitive microelectrode recordings, we show now that the capability for
      synchronous gamma-frequency (20-80 Hz) firing in response to high-frequency
      stimulation (HFS) emerges abruptly in the rat hippocampus at approximately
      postnatal day 12. This was attributable to a steep developmental upregulation of
      intrapyramidal carbonic anhydrase isoform VII, which acts as a key molecule in
      the generation of HFS-induced tonic GABAergic excitation. These results point to
      a crucial role for the developmental expression of intrapyramidal carbonic
      anhydrase VII activity in shaping integrative functions, long-term plasticity and
      susceptibility to epileptogenesis.

PMID- 15028763
TI  - Expression of cannabinoid CB1 receptors by vagal afferent neurons is inhibited by
      cholecystokinin.
AB  - Both inhibitory (satiety) and stimulatory (orexigenic) factors from the
      gastrointestinal tract regulate food intake. In the case of the satiety hormone
      cholecystokinin (CCK), these effects are mediated via vagal afferent neurons. We
      now report that vagal afferent neurons expressing the CCK-1 receptor also express
      cannabinoid CB1 receptors. Retrograde tracing established that these neurons
      project to the stomach and duodenum. The expression of CB1 receptors determined
      by RT-PCR, immunohistochemistry and in situ hybridization in rat nodose ganglia
      was increased by withdrawal of food for > or =12 hr. After refeeding of fasted
      rats there was a rapid loss of CB1 receptor expression identified by
      immunohistochemistry and in situ hybridization. These effects were blocked by
      administration of the CCK-1 receptor antagonist lorglumide and mimicked by
      administration of CCK to fasted rats. Because CCK is a satiety factor that acts
      via the vagus nerve and CB1 agonists stimulate food intake, the data suggest a
      new mechanism modulating the effect on food intake of satiety signals from the
      gastrointestinal tract.

PMID- 15028764
TI  - 3' untranslated region in a light neurofilament (NF-L) mRNA triggers aggregation
      of NF-L and mutant superoxide dismutase 1 proteins in neuronal cells.
AB  - The pathogenesis of neurodegenerative diseases is believed to involve abnormal
      aggregation of proteins, but the mechanisms initiating protein aggregation are
      unclear. Here we report a novel phenomenon that could be instrumental in
      triggering protein aggregation in neurodegenerative diseases. We show that the 3'
      untranslated region (3'UTR) of a light neurofilament (NF-L) transcript enhances
      the reactivity of its own translated product and leads to loss of solubility and
      aggregation of NF-L protein and to coaggregation of mutant superoxide dismutase 1
      (SOD1) protein. Full-length mouse NF-L cDNAs, with and without NF-L 3'UTR, were
      fused to the C terminus of a green fluorescent protein (GFP) reporter gene, and
      the GFP-tagged NF-L proteins were examined in transfected Neuro2a cells. The GFP
      tagged NF-L protein expressed from the transgene containing NF-L 3'UTR, but not
      from the transgene lacking NF-L 3'UTR, colocalizes with endogenous heavy
      neurofilament protein and, at high-level expression, leads to loss of solubility
      and aggregation of GFP-tagged NF-L protein. Aggregation of GFP-tagged NF-L
      protein triggers coaggregation and loss of solubility of coexpressed DsRed-tagged
      mutant (G93A) SOD1 protein but not wild-type SOD1 protein. Deletional mutagenesis
      maps the RNA sequence causing aggregation of GFP-tagged NF-L protein to the
      proximal 45 nucleotides of NF-L 3'UTR. This is the site of a major destabilizing
      element in NF-L RNA and binding site for RNA-binding proteins. Our findings
      support a working model whereby NF-L RNA, or cognate RNA-binding factors,
      enhances the reactivity of NF-L protein and provides a triggering mechanism
      leading to aggregation of NF-L and other proteins in neurodegenerative diseases.

PMID- 15028765
TI  - Constitutive spinal cyclooxygenase-2 participates in the initiation of tissue
      injury-induced hyperalgesia.
AB  - Inhibitors of the isozyme cyclooxygenase-2 (COX-2) represent an important advance
      in pain management, although where and when these inhibitors can exert their
      antihyperalgesic actions are not completely understood. Here we show that unlike
      many peripheral tissues in which COX-2 is only expressed in physiologically
      significant levels after tissue injury, in the normal rat lumbar spinal cord, the
      majority of neurons and radial glia constitutively express high levels of COX-2
      protein. Immediately after peripheral tissue injury and before any measurable
      upregulation of COX-2 protein in peripheral tissue or spinal cord, inhibition of
      constitutively expressed spinal COX-2 reduced injury-induced activation of
      primary afferent neurons, activation of spinal neurons, and the mechanical and
      thermal hyperalgesia that normally occurs after peripheral tissue injury. The
      present data demonstrate that constitutively expressed spinal COX-2 plays an
      important role in the initial hyperalgesia that follows peripheral tissue injury.
      These results suggest that blocking constitutive spinal COX-2 before tissue
      injury may reduce the initial peripheral and central sensitization that occurs
      after tissue injury.

PMID- 15028766
TI  - An arginine involved in GABA binding and unbinding but not gating of the GABA(A)
      receptor.
AB  - GABA(A) receptor function can be conceptually divided into interactions between
      ligand and receptor (binding) and the opening and closing of the ligand-bound
      channel (gating). The relationship between binding, gating, and receptor
      structure remains unclear. Studies of mutations have identified many amino acid
      residues that contribute to the GABAbinding site. Most of these studies assayed
      changes in GABA dose-response curves, which are macroscopic measures that depend
      on the interplay of many processes and cannot resolve individual microscopic
      transitions. Understanding the microscopic basis of binding and gating is
      critical, because kinetic transition rates predict how receptors will behave at
      synapses. Furthermore, microscopic rates are directly related to the molecular
      interactions underlying receptor function. Here, we focused on a residue (beta2
      R207) previously identified as lining the GABA-binding site that, when mutated to
      cysteine, greatly reduces apparent GABA affinity and was predicted to affect both
      binding and gating. To better understand the role of beta2-R207, we expressed
      alpha1beta2 and alpha1beta2-R207C receptors in human embryonic kidney 293 cells
      and studied receptor kinetics using fast solution applications. The mutation
      accelerated deactivation by 10-fold, without altering desensitization in the
      presence of saturating GABA. Maximum open probability and single-channel open
      times were also unaltered by the mutation, but the GABA-binding rate was reduced
      eightfold. Therefore, the effects of this mutation in a predicted binding site
      residue are solely attributable to changes in GABA-binding and unbinding
      kinetics, with no changes in channel gating. Because beta2-R207 stabilizes GABA
      in the binding pocket, it may directly contact the GABA molecule.

PMID- 15028767
TI  - A novel p75 neurotrophin receptor-related protein, NRH2, regulates nerve growth
      factor binding to the TrkA receptor.
AB  - Nerve growth factor (NGF) functions as a ligand for two receptors, the TrkA
      tyrosine kinase receptor and the p75 neurotrophin receptor (p75NTR). The Ig-like
      domains of Trk receptors and the cysteine-rich repeats of p75NTR are involved in
      binding to the neurotrophins. Recently, a closely related gene to p75NTR called
      neurotrophin receptor homolog-2 (NRH2) was identified; however, the function of
      NRH2 and its relevance to neurotrophin signaling are unclear. NRH2 contains a
      similar transmembrane and intracellular domain as p75NTR but lacks the
      characteristic cysteine-rich repeats in the extracellular domain. Here we show
      that NRH2 is expressed in several neuronal populations that also express p75NTR
      and Trk receptors. NRH2 does not bind to NGF; however, coimmunoprecipitation
      experiments demonstrate that NRH2 is capable of interacting with TrkA receptors.
      Coexpression of NRH2 with TrkA receptors resulted in the formation of high
      affinity binding sites for NGF. These results indicate that a transmembrane
      protein related to p75NTR is capable of modulating Trk receptor binding
      properties.

PMID- 15028768
TI  - Ischemic preconditioning: neuronal survival in the face of caspase-3 activation.
AB  - Apoptosis is an evolutionarily conserved process critical to tissue development
      and tissue homeostasis in eukaryotic organisms and, when dysregulated, causes
      inappropriate cell death. Global ischemia is a neuronal insult that induces
      delayed cell death with many features of apoptosis. Ischemic preconditioning
      affords robust protection of CA1 neurons against a subsequent severe ischemic
      challenge. The molecular mechanisms underlying ischemic tolerance are unclear.
      Here we show that ischemia induces pronounced caspase-3 activity in naive neurons
      that die and in preconditioned neurons that survive. Preconditioning intervenes
      downstream of proteolytic processing and activation of caspase-3 (a protease
      implicated in the execution of apoptosis) and upstream of the caspase-3 target
      caspase-activated DNase (CAD, a deoxyribonuclease that catalyzes DNA
      fragmentation) to arrest neuronal death. We further show that global ischemia
      promotes expression of the pro-survival inhibitor-of-apoptosis (IAP) family
      member cIAP, but unleashes Smac/DIABLO (second mitochondria-derived activator of
      caspases/direct IAP-binding protein with low pI), a factor that neutralizes the
      protective actions of IAPs and promotes neuronal death. Preconditioning blocks
      the mitochondrial release of Smac/DIABLO, but not the ischemia-induced
      upregulation of IAPs. In the absence of Smac/DIABLO, cIAP halts the caspase death
      cascade and arrests neuronal death. These findings suggest that preconditioning
      preserves the integrity of the mitochondrial membrane, enabling neurons to
      survive in the face of caspase activation.

PMID- 15028769
TI  - Evidence for gaze feedback to the cat superior colliculus: discharges reflect
      gaze trajectory perturbations.
AB  - Rapid coordinated eye-head movements, called saccadic gaze shifts, displace the
      line of sight from one location to another. A critical structure in the gaze
      control circuitry is the superior colliculus (SC) of the midbrain, which drives
      gaze saccades by relaying cortical commands to brainstem eye and head motor
      circuits. We proposed that the SC lies within a gaze feedback loop and generates
      an error signal specifying gaze position error (GPE), the distance between target
      and current gaze positions. We investigated this feedback hypothesis in cats by
      briefly stopping head motion during large ( approximately 50 degrees ) gaze
      saccades made in the dark. This maneuver interrupted intended gaze saccades and
      briefly immobilized gaze (a plateau). After brake release, a corrective gaze
      saccade brought the gaze on goal. In the caudal SC, the firing frequency of a
      cell gradually increased to a maximum that just preceded the optimal gaze saccade
      encoded by the position of the cell and then declined back to zero near gaze
      saccade end. In brake trials, the activity level just preceding a brake-induced
      plateau continued steadily during the plateau and waned to zero only near the end
      of the corrective saccade. The duration of neural activity was stretched to
      reflect the increased time to target acquisition, and firing frequency during a
      plateau was proportional to the GPE of the plateau. In comparison, in the rostral
      SC, the duration of saccade-related pauses in fixation cell activity increased as
      plateau duration increased. The data show that the cat's SC lies in a gaze
      feedback loop and that it encodes GPE.

PMID- 15028770
TI  - Presynaptic NMDA receptors modulate glutamate release from primary sensory
      neurons in rat spinal cord dorsal horn.
AB  - NMDA receptors have the potential to produce complex activity-dependent
      regulation of transmitter release when localized presynaptically. In the
      somatosensory system, NMDA receptors have been immunocytochemically detected on
      presynaptic terminals of primary afferents, and these have been proposed to drive
      release of substance P from central terminals of a subset of nociceptors in the
      spinal cord dorsal horn. Here we report that functional NMDA receptors are indeed
      present at or near the central terminals of primary afferent fibers. Furthermore,
      we show that activation of these presynaptic receptors results in an inhibition
      of glutamate release from the terminals. Some of these NMDA receptors may be
      expressed in the preterminal axon and regulate the extent to which action
      potentials invade the extensive central arborizations of primary sensory neurons.

PMID- 15028771
TI  - Anterograde transneuronal viral tracing of central viscerosensory pathways in
      rats.
AB  - Previous studies demonstrated that strain H129 of herpes simplex virus-1
      undergoes anterograde transneuronal transport in mice and primates after
      peripheral or central injection. In this study, H129 was used in rats to identify
      CNS regions that receive relayed viscero-sensory inputs from the stomach wall. We
      also examined whether transneuronal viral transport in this model is exclusively
      anterograde. H129 or an established retrograde transneuronal viral tracer,
      pseudorabies virus (PRV), was injected into the ventral stomach wall in intact
      rats or in rats with previous subdiaphragmatic vagal sensory deafferentation.
      Rats were perfused with fixative 3-5 d later, and tissues were processed for
      immunocytochemical detection of transported virus. In intact rats, H129 was
      transported transneuronally via vagal and spinal viscerosensory neurons to
      postsynaptic target cells in the medullary dorsal vagal complex and thoracic
      dorsal horn, respectively, with subsequent transport to discrete regions of the
      medullary and pontine reticular formation, cerebellum, parabrachial nucleus,
      periaqueductal gray, thalamus, hypothalamus, amygdala, bed nucleus of the stria
      terminalis, and other central sites. Comparison of labeling patterns in intact
      and vagal deafferented rats indicated that H129 also produced first-order
      retrograde infection of autonomic neurons that project directly to virus
      injection sites, similar to PRV. Unlike PRV, however, H129 was not transported
      transneuronally in the retrograde direction from infected neurons to central
      sources of presynaptic input. We conclude that transneuronal transport of H129
      occurs exclusively in the anterograde direction to reveal CNS regions that
      receive direct and relayed viscerosensory signals.

PMID- 15028772
TI  - Neurochemical and behavioral alterations in glucocorticoid receptor-impaired
      transgenic mice after chronic mild stress.
AB  - Mice (GR-i) bearing a transgene encoding a glucocorticoid receptor (GR) antisense
      RNA under the control of a neuron-specific neurofilament promoter were used to
      investigate the effects of a 4 week chronic mild stress (CMS) on the hypothalamo
      pituitary-adrenocortical (HPA) axis and the serotoninergic system in a transgenic
      model of vulnerability to affective disorders. GR-i mice showed a decrease in
      both GR-specific binding (hippocampus and cerebral cortex) and GR mRNA levels
      [hippocampus, cerebral cortex, and dorsal raphe nucleus (DRN)] as well as a
      deficit in HPA axis feedback control (dexamethasone test) compared with paired
      wild-type (WT) mice. In the latter animals, CMS exposure caused a significant
      decrease in both GR mRNA levels and the density of cytosolic GR binding sites in
      the hippocampus, whereas, in the DRN, GR mRNA levels tended to increase. In
      contrast, in stressed GR-i mice, both GR mRNA levels and the density of GR
      binding sites were significantly increased in the hippocampus, cerebral cortex,
      and DRN. Electrophysiological recordings in brainstem slices and [gamma-35S]GTP-S
      binding measurements to assess 5-HT1A receptor functioning showed that CMS
      exposure produced a desensitization of DRN 5-HT1A autoreceptors in WT, but not in
      GR-i, mice. In addition, CMS was found to facilitate choice behavior of WT, but
      not GR-i, mice in a decision-making task derived from an alternation paradigm.
      These results demonstrate that impaired GR functioning affects normal adaptive
      responses of the HPA axis and 5-HT system to CMS and alters stress-related
      consequences on decision-making behaviors.

PMID- 15028773
TI  - Formation of projection pathways from the arcuate nucleus of the hypothalamus to
      hypothalamic regions implicated in the neural control of feeding behavior in
      mice.
AB  - The arcuate nucleus of the hypothalamus (ARH) is a critical component of
      forebrain pathways that regulate a variety of neuroendocrine functions, including
      an important role in relaying leptin signals to other parts of the hypothalamus.
      However, neonatal rodents do not lose weight in response to leptin treatment in
      the same way as do adults, suggesting that certain aspects of leptin signaling
      pathways in the hypothalamus may not be mature. We tested this possibility by
      using DiI axonal labeling to examine the development of projections from the ARH
      to other parts of the hypothalamus in neonatal mice, paying particular attention
      to the innervation of the paraventricular nucleus (PVH), the dorsomedial nucleus
      (DMH), and the lateral hypothalamic area (LHA), each of which have been
      implicated in the regulation of feeding. The results indicate that ARH
      projections are quite immature at birth and appear to innervate the DMH, PVH, and
      LHA in succession, within distinct temporal domains. The projections from the ARH
      to the DMH develop rapidly and are established by the sixth postnatal day (P6),
      whereas those to the PVH develop significantly later, with the mature pattern of
      innervation first apparent between postnatal day 8 (P8)-P10. Furthermore, the
      ability of leptin to activate Fos in the PVH, DMH, and LHA appears to be age
      dependent and correlates with the arrival of ARH projections to each nucleus.
      Taken together, these findings provide new insight into development of
      hypothalamic circuits and suggest an anatomical basis for the delayed postnatal
      regulation of food intake and body weight by leptin.

PMID- 15028774
TI  - Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate
      thermal nociception and contribute to morphine analgesia.
AB  - G-protein-gated potassium (K+) channels are found throughout the CNS in which
      they contribute to the inhibitory effects of neurotransmitters and drugs of
      abuse. Recent studies have implicated G-protein-gated K+ channels in thermal
      nociception and the analgesic action of morphine and other agents. Because
      nociception is subject to complex spinal and supraspinal modulation, however, the
      relevant locations of G-protein-gated K+ channels are unknown. In this study, we
      sought to clarify the expression pattern and subunit composition of G-protein
      gated K+ channels in the spinal cord and to assess directly their contribution to
      thermal nociception and morphine analgesia. We detected GIRK1 (G-protein-gated
      inwardly rectifying K+ channel subunit 1) and GIRK2 subunits, but not GIRK3, in
      the superficial layers of the dorsal horn. Lack of either GIRK1 or GIRK2 was
      correlated with significantly lower expression of the other, suggesting that a
      functional and physical interaction occurs between these two subunits. Consistent
      with these findings, GIRK1 knock-out and GIRK2 knock-out mice exhibited
      hyperalgesia in the tail-flick test of thermal nociception. Furthermore, GIRK1
      knock-out and GIRK2 knock-out mice displayed decreased analgesic responses after
      the spinal administration of higher morphine doses, whereas responses to lower
      morphine doses were preserved. Qualitatively similar data were obtained with wild
      type mice after administration of the G-protein-gated K+ channel blocker
      tertiapin. We conclude that spinal G-protein-gated K+ channels consisting
      primarily of GIRK1/GIRK2 complexes modulate thermal nociception and mediate a
      significant component of the analgesia evoked by intrathecal administration of
      high morphine doses

PMID- 15028775
TI  - Nitric oxide inhibits the rate and strength of cardiac contractions in the
      lobster Homarus americanus by acting on the cardiac ganglion.
AB  - The lobster heart is synaptically driven by the cardiac ganglion, a spontaneously
      bursting neural network residing within the cardiac lumen. Here, we present
      evidence that nitric oxide (NO) plays an inhibitory role in lobster cardiac
      physiology. (1) NO decreases heartbeat frequency and amplitude. Decreased
      frequency is a direct consequence of a decreased ganglionic burst rate. Decreased
      amplitude is an indirect consequence of decreased burst frequency, attributable
      to the highly facilitating nature of the synapses between cardiac ganglion
      neurons and muscle fibers (although, during prolonged exposure to NO, amplitude
      recovers to the original level by a frequency-independent adaptation mechanism).
      NO does not alter burst duration, spikes per burst, heart muscle contractility,
      or amplitudes of synaptic potentials evoked by stimulating postganglionic motor
      nerves. Thus, NO acts on the ganglion, but not on heart muscle. (2) Two
      observations suggest that NO is produced within the lobster heart. First,
      immunoblot analysis shows that nitric oxide synthase (NOS) is strongly expressed
      in heart muscle relative to other muscles. Second, L-nitroarginine (L-NA), an NOS
      inhibitor, increases the rate of the heartbeat (opposite to the effects of NO).
      In contrast, the isolated ganglion is insensitive to L-NA, suggesting that heart
      muscle (but not the ganglion) produces endogenous NO. Basal heart rate varies
      from animal to animal, and L-NA has the greatest effect on the slowest hearts,
      presumably because these hearts are producing the most NO. Thus, because the
      musculature is a site of NOS expression, whereas the ganglion is the only
      intracardiac target of NO, we hypothesize that NO serves as an inhibitory
      retrograde transmitter.

PMID- 15028776
TI  - Dopamine release in response to a psychological stress in humans and its
      relationship to early life maternal care: a positron emission tomography study
      using [11C]raclopride.
AB  - Mesolimbic dopamine is thought to play a role in the processing of rewards.
      However, animal studies also demonstrate dopamine release in response to aversive
      stressful stimuli. Also, in animal studies, disruptions of the mother-infant
      relationship have been shown to have long-lasting effects on the mesolimbic
      dopamine system and the hypothalamic-pituitary adrenal axis. We therefore
      investigated dopamine release in response to stress in human subjects,
      considering the relationship to early life parental care. We screened 120 healthy
      young college students for parental care in early life using a combination of
      telephone interviews and questionnaires. Five students from the top end and five
      students from the bottom end of the parental care distribution were then invited
      for a positron emission tomography study using [11C]raclopride and a psychosocial
      stress task. The psychosocial stressor caused a significant release of dopamine
      in the ventral striatum as indicated by a reduction in [11C]raclopride binding
      potential in the stress versus resting condition in subjects reporting low
      parental care. Moreover, the magnitude of the salivary cortisol response to
      stress was significantly correlated with the reduction in [11C]raclopride binding
      in the ventral striatum (r = 0.78), consistent with a facilitating effect of
      cortisol on dopamine neuron firing. These data suggest that aversive stressful
      events can be associated with mesolimbic dopamine release in humans, and that the
      method presented here may be useful to study the effects of early life events on
      neurobiological stress systems.

PMID- 15028777
TI  - Neural stem cells show bidirectional experience-dependent plasticity in the
      perinatal mammalian brain.
AB  - Many of the effects of prenatal stress on the endocrine function, brain
      morphology, and behavior in mammals can be reversed by brief sessions of
      postnatal separation and handling. We have tested the hypothesis that the effects
      of both the prenatal and postnatal experiences are mediated by negative and
      positive regulation of neural stem cell (NSC) number during critical stages in
      neurodevelopment. We used the in vitro clonal neurosphere assay to quantify NSCs
      in hamsters that had experienced prenatal stress (maternal restraint stress for 2
      hr per day, for the last 7 d of gestation), postnatal handling (maternal
      offspring separation for 15 min per day during postnatal days 1-21), orboth.
      Prenatal stress reduced the number of NSCs derived from the subependyma of the
      lateral ventricle. The effect was already present at postnatal day 1 and
      persisted into adulthood (at least 14 months of age). Similarly, prenatal stress
      reduced in vivo proliferation in the adult subependyma of the lateral ventricle.
      Conversely, postnatal handling increased NSC number and reversed the effect of
      prenatal stress. The effects of prenatal stress on NSCs and proliferation and the
      effect of postnatal handling on NSCs did not differ between male and females. The
      findings demonstrate that environmental factors can produce changes in NSC number
      that are present at birth and endure into late adulthood. These changes may
      underlie some of the behavioral effects produced by prenatal stress and postnatal
      handling.

PMID- 15028778
TI  - Interleukin-1beta induces a reactive astroglial phenotype via deactivation of the
      Rho GTPase-Rock axis.
AB  - The cytokine interleukin-1beta (IL-1beta) is critical to the formation of an
      astrocytic scar after CNS injury, but the mechanisms by which it induces a
      reactive phenotype remain unresolved. Here, we show that IL-1beta regulates the
      phenotype of astrocytes via deactivation of the Rho GTPase-Rho kinase (ROCK)
      pathway, which governs cellular morphology and migration via effects on F-actin
      and its interactions with focal adhesions, nonmuscle myosin, and microvillar
      adapter proteins of the ezrin-radixin-moesin (ERM) family. We found that IL-1beta
      induced cortical reorganization of F-actin and dephosphorylation of focal
      adhesion kinase, myosin light chain 2, and myosin phosphatase targeting subunit 1
      in primary human astrocytes, and that all of these effects were mimicked by Rho
      ROCK pathway blockade. We also found that IL-1beta conversely potentiated ERM
      phosphorylation, and that this effect was mediated via a Rho-ROCK-independent
      mechanism. Next, we used a rhotekin pulldown assay to confirm directly that IL
      1beta deactivates Rho, and further demonstrated that a constitutively active Rho
      construct rescued astrocytes from developing an IL-1beta-induced reactive
      phenotype. These data implicate cytokine regulation of the Rho-ROCK pathway in
      the generation of a reactive astrogliosis, and we suggest that interventions
      targeted at this level may facilitate manipulation of the glial scar in
      inflammatory disorders of the human CNS.

PMID- 15028779
TI  - Organic cation transporter 3 (Slc22a3) is implicated in salt-intake regulation.
AB  - Organic cation transporters (OCTs) are carrier-type permeases known to
      participate in general detoxification functions in peripheral tissues. Previous
      in vitro studies have suggested that OCTs ensure Uptake2, a low-affinity,
      corticosteroid-sensitive catecholamine removal system, which was characterized
      initially in sympathetically innervated tissues. Although the presence of both
      Uptake(2)-like transport and most OCT subtypes has also been demonstrated in the
      brain, the physiological role of this family of transporters in CNS remained
      totally unknown. In the present work, we show that the OCT3 transporter is found
      throughout the brain and highly expressed in regions regulating fluid exchange,
      including circumventricular organs such as area postrema and subfornical organ
      (SFO), and in other structures implicated in the sensing of changes in blood
      osmolarity and regulation of salt and water ingestion. OCT3/Slc22a3-deficient
      mice show an increase in the level of ingestion of hypertonic saline under thirst
      and salt appetite conditions, as well as alterations of the neural response in
      the SFO after sodium deprivation, as monitored by Fos immunoreactivity. This work
      demonstrates that the presence of OCT3 is critical for the balanced neural and
      behavioral responses to environmentally induced variations in osmolarity and
      provides for the first time physiological evidence of the importance of OCTs for
      CNS function.

PMID- 15028780
TI  - Cloning and pharmacological characterization of CXCR1 and CXCR2 from Macaca
      fascicularis.
AB  - Two genes with high sequence homology to human CXCR1 (hCXCR1) and CXCR2 (hCXCR2)
      were cloned from blood of cynomolgus monkey (Macaca fascicularis). Comparison of
      the expression pattern of these receptors in different species demonstrated that,
      like in humans, cynomolgus CXCR1 (cCXCR1) and CXCR2 (cCXCR2) are highly expressed
      in blood. Membranes from transfected BaF3 cells expressing cCXCR1 bind
      interleukin (IL)-8 with an affinity similar to hCXCR1 (Kd values, 170 +/- 87 and
      103 +/- 37 pM, respectively) and show low binding affinity to Gro-alpha.
      Cynomolgus CXCR2 also binds hIL-8 but with somewhat higher affinity than the
      hCXCR2 (46 +/- 28 and 220 +/- 14 pM, respectively). Surprisingly, cCXCR2 has a
      reduced binding affinity to hGro-alpha (3.7 +/- 2.2 nM), a specific ligand of
      hCXCR2 (540 +/- 140 pM). Furthermore, the CXCR2-specific antagonist SB225002 [N
      (2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea] is 10-fold more potent in
      inhibiting IL-8 binding to hCXCR2 than to cCXCR2, suggesting that some of the
      observed differences in the amino acid sequences of the human and monkey receptor
      affect ligand binding sites or the conformation of the receptor. Both cynomolgus
      receptors were functionally active in inducing guanosine 5'-O-(3
      thio)triphosphate exchange on membranes in response to IL-8 and Gro-alpha and in
      mediating chemotactic activity of recombinant BA/F3 cells in response to IL-8 and
      Gro-alpha. These results identify the products of the novel cynomolgus genes as
      functional homologs of hCXCR1 and hCXCR2.

PMID- 15028781
TI  - Effects of sodium-calcium exchange inhibitors, KB-R7943 and SEA0400, on aconitine
      induced arrhythmias in guinea pigs in vivo, in vitro, and in computer simulation
      studies.
AB  - The sodium-calcium exchange (NCX) plays a pivotal role in regulating
      contractility and electrical activity in the heart. However, the effects of NCX
      blockers on ventricular arrhythmias are still controversial. We examined the
      effects of KB-R7943 (KBR) and SEA0400 (SEA), two NCX blockers, on aconitine
      induced arrhythmias in guinea pigs using the ECG recordings and the current-clamp
      method. Using Luo's and Rudy's computer model (1991 Circ Res 68:1501-1526) for
      ventricular myocytes, we simulated abnormal membrane activity produced by NCX
      inhibition. In the whole-animal model, KBR in a dose range of 1 to 30 mg/kg
      (intravenous) suppressed aconitine-induced arrhythmias dose-dependently, but 10
      mg/kg of SEA did not suppress these arrhythmias. There was a difference in
      isolated ventricular myocytes also. KBR (10 microM) suppressed abnormal
      electrical activity induced by aconitine, but SEA (100 microM) did not show such
      effects. KBR (10 microM) significantly changed the shape of the action potential
      configurations (action potential duration at 50% repolarization), but SEA (1-100
      microM) did not change these configurations. In the computer simulation study,
      the aconitine-induced abnormal electrical activity was mimicked by a negative
      shift of the kinetics of Na+ channels, and this was followed by additional
      suppression of NCX activity by 90% (mimicking the effect of NCX inhibitors),
      which enhanced abnormal membrane activity. Our results indicate that the
      inhibition of aconitine-induced arrhythmias by KBR, not by SEA, might result from
      a mechanism other than the inhibition of NCX, and thus the involvement of the NCX
      system plays an insignificant role in the aconitine-induced arrhythmias.

PMID- 15028782
TI  - Identification of caspase-independent apoptosis in epithelial and cancer cells.
AB  - We reported that 50% of cisplatin-induced apoptosis in primary cultures of rabbit
      renal proximal tubule cells (RPTC) proceeded via caspase-independent mechanisms.
      This study determined whether caspase-independent apoptosis, using multiple and
      diverse endpoints, could be produced by toxicants other than cisplatin and in
      cell models other than RPTC. Cisplatin, staurosporine, vincristine, and A23187
      induced RPTC apoptosis after 24 h as indicated by 2- to 2.5-fold increases in
      annexin V and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end
      labeling (TUNEL) staining, and 2- to 10-fold increases in cell shrinkage. All
      toxicants induced 8- to 50-fold increases in caspase-3 activities, which were
      completely inhibited by the pan caspase inhibitor ZVAD-fmk. However, ZVAD-fmk
      only decreased cisplatin- and staurosporine-induced annexin V staining and cell
      shrinkage 30 to 50%, staurosporine-induced TUNEL staining 30%, and did not affect
      vincristine- or A23187-induced RPTC apoptosis. All toxicants tested induced
      apoptotic RPTC nuclear morphology. However, similar to its effect on annexin V
      and TUNEL staining, ZVAD-fmk only partially inhibited toxicant-induced apoptotic
      nuclear morphology. Cisplatin and staurosporine also induced annexin V staining
      in the human epithelial cancer cell lines Caki-1 (kidney carcinoma), A549 (lung
      carcinoma), A172 (glioblastoma), and murine lymphocytic leukemia L1210 cells.
      Pretreatment with ZVAD-fmk inhibited cisplatin-induced annexin V staining in Caki
      1, A172, and A549 cells but had no affect in L1210 cells. Pretreatment with ZVAD
      fmk did not decrease staurosporine-induced annexin V staining in Caki-1, A549,
      L1210, and A172 cells. These results suggest that a significant fraction of
      apoptosis induced by diverse toxicants in renal epithelial cells and in four
      different cancer cell lines is caspase-independent.

PMID- 15028783
TI  - Evidence that 1,1-dichloroethylene induces apoptotic cell death in murine liver.
AB  - 1,1-Dichloroethylene (DCE) causes dysfunction of hepatic mitochondria. As
      mitochondria have been implicated in apoptosis through opening of the
      permeability transition pore (PTP), we have undertaken studies to test the
      hypothesis that DCE induces apoptosis, in addition to necrosis, in murine liver.
      Our primary objective was to identify the biochemical events associated with DCE
      induced apoptosis. Female CD-1 mice were treated with a mildly hepatotoxic dose
      of DCE (125 mg/kg, i.p.). Using the fluorescent dye JC-1 (5,5',6,6'-tetrachloro
      1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide), decreased hepatic
      mitochondrial membrane potential was detected at 2 h. Western blotting of liver
      cytosolic proteins showed greater immunoreactivity for cytochrome c in fractions
      from mice treated with DCE for 4 h than in controls. Furthermore, caspase-9
      activity was significantly increased 6 h after DCE exposure. Immunohistochemical
      studies with an antibody to activated caspase-3 and terminal deoxynucleotidyl
      transferase dUTP nick-end labeling staining were used to detect apoptotic cells.
      In both experiments, positive reactivities were observed in centrilobular
      hepatocytes 12 and 24 h after DCE. Additionally, centrilobular hepatocytes
      showing morphological criteria of apoptosis were observed at 24 h. Apoptosis and
      all apoptotic events were inhibited by pretreatment for 20 min with cyclosporine
      A (CyA) (50 mg/kg), a specific inhibitor of the mitochondrial PTP. To determine a
      major role for mitochondrial permeability transition (MPT) in DCE hepatotoxicity,
      serum alanine aminotransferase (ALT) activity was evaluated. ALT activity was
      significantly elevated 2 to 24 h after DCE, and CyA failed to inhibit this
      activity. These data suggested that DCE produces apoptosis by inducing MPT,
      causing release of cytochrome c into the cytosol and caspase activation.

PMID- 15028786
TI  - Geriatric pharmacology: safer prescribing for the elderly patient.
AB  - Adverse drug effects are common in elderly patients but can often be avoided.
      Judicious prescribing practices require the clinician to be aware of age-related
      changes in drug absorption, distribution, metabolism, and elimination. Clinicians
      may need to adjust drug dose, frequency, or the choice of drug altogether as they
      consider the physiologic changes of aging. This article reviews prescribing
      situations with elderly patients commonly encountered by the podiatric physician.
      Strategies for medication management are provided to minimize the risk of adverse
      drug events in the older patient.

PMID- 15028785
TI  - Perioperative medical assessment of the podiatric surgical patient.
AB  - Patients undergoing podiatric surgery should receive a thorough perioperative
      evaluation. Medical "clearance" is no longer sufficient; rather, formal risk
      assessment should be performed and risk-reducing strategies provided. A
      collaborative, multidisciplinary approach involving practitioners in internal
      medicine, anesthesiology, and podiatry is generally most appropriate.
      Unfortunately, expertise and training in this critical dimension of clinical
      practice are variable. Thus podiatric physicians should develop independent
      competence in perioperative evaluation in order to ensure optimal care for their
      patients. A general systematic approach is described that can be readily
      incorporated into clinical practice.

PMID- 15028787
TI  - Pharmacologic management of foot pain in the older patient.
AB  - Foot pain, if not effectively managed, can result in significant disability and
      loss of function in older patients. This article reviews treatment strategies for
      acute and persistent pain, emphasizing new pharmacologic approaches. Indications,
      guidelines, and precautions for acute-pain treatment with acetaminophen,
      nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, and opioids
      are discussed. Strategies for management of persistent pain using opioids,
      tricyclic antidepressants, gabapentin, and topical medications are reviewed.
      Common pain-management and prescribing errors are highlighted.

PMID- 15028788
TI  - Common neurologic disorders affecting the foot.
AB  - Podiatric physicians care for a wide spectrum of patients with neurologic
      illness. Often, patients with neurologic disease present to their podiatric
      physician with unrelated complaints that can be easily separated from their
      underlying neurologic condition. However, some neurologic conditions predictably
      lead to podiatric disease and, as such, are best treated in the context of the
      broader disease process. Neuropathies, spastic disorders, and cerebral palsy are
      examples of common neurologic disorders that can be associated with substantial
      podiatric manifestations; therefore, it is important for podiatric physicians to
      be familiar with these conditions. This article reviews the pathophysiology,
      clinical manifestations, and management of the common neurologic disorders
      affecting the foot.

PMID- 15028789
TI  - Changes in mental status.
AB  - Change in mental status is a common symptom in the older, hospitalized patient.
      Often referred to as delirium, it may be the first indication of a serious
      medical condition. If delirium is not identified and treated promptly, it may
      lead to severe complications. The podiatric physician can prevent many cases of
      delirium by maintaining a high level of suspicion, performing a thorough clinical
      assessment, and identifying older patients at risk in the hospital setting.

PMID- 15028790
TI  - Infection and fever in the elderly.
AB  - The elderly make more frequent use of general podiatric medical services than the
      younger population. It is therefore important for podiatric physicians to become
      familiar with the general principles of infectious disease as applied to an
      elderly population, which is susceptible to a wider spectrum of disease with more
      subtle and unusual clinical signs and symptoms. This article reviews the
      diagnosis and evaluation of suspected infection, appropriate laboratory testing,
      patterns of specific infectious disease syndromes, and antibiotic use in the
      elderly.

PMID- 15028791
TI  - Management of hyperglycemia in the hospitalized podiatric medical patient.
AB  - With the growing prevalence worldwide of diabetes mellitus and hyperglycemia,
      hospital-based health-care professionals will encounter patients with these
      conditions with increasing frequency. It is well known that long-term control of
      blood glucose reduces the rate and severity of complications in patients with
      diabetes, but there is also mounting evidence that even short-term glycemic
      control in hospitalized diabetic patients can significantly lower morbidity and
      mortality in many areas, from nosocomial infection to postoperative course. The
      results of traditional approaches to controlling blood glucose in hospitalized
      patients have been disappointing owing to a variety of factors, including the use
      of oral agents that are difficult or dangerous to use in inpatients, older
      insulin preparations with unphysiologic modes of action, and even provider
      reluctance to accept glycemic control as an essential element of the care of the
      diabetic hospitalized patient. This article provides guidelines for the effective
      management of hyperglycemia in these patients throughout the hospital stay, with
      specific recommendations for the perioperative, operative, and postoperative
      periods.

PMID- 15028792
TI  - Evaluation of common liver problems.
AB  - Diseases of the liver and abnormalities of liver enzyme levels are among the most
      common reasons for gastroenterology consultation for surgical patients. Although
      the differential diagnosis of liver disease is exceedingly broad, the majority of
      patients will have one of several common disorders. A familiarity with the major
      disorders affecting the liver and the approach to patients with liver disease is
      therefore useful for clinicians from all disciplines. This article reviews common
      liver diseases, including the viral hepatitides; the interpretation of liver
      enzyme abnormalities; and the relationship between common medications and liver
      disease. Although an exhaustive knowledge of hepatology is impractical for most
      clinicians, a practical approach to common liver diseases is a necessity for all.

PMID- 15028793
TI  - Pulmonary disease: pneumonia, chronic obstructive pulmonary disease, asthma, and
      thromboembolic disease.
AB  - Although many medical problems are generally managed in concert with a general
      medical physician, it is important for the podiatric physician to be familiar
      with some of the major diseases of the lung. Pneumonia, an infectious process
      within the lung, is the sixth-leading overall cause of death. Antibiotic
      treatment, oxygen administration, and supportive care are the mainstays of its
      therapy. Chronic obstructive pulmonary disease presents as a spectrum from
      chronic bronchitis, with a greater inflammatory component, to emphysema, with a
      more significant destructive component. Asthma, often a more episodic chronic
      obstructive disease, is characterized by inflammation of the airways leading to
      their narrowing. The work of breathing is often increased in these diseases, and
      treatment is with combination therapies with a focus on smoking cessation.
      Thromboembolic disease, the occlusion of blood vessels with consequent
      interruption of blood flow, may occur in a patient with risk factors, especially
      after surgery. Treatment is with anticoagulation agents or in some cases with
      thrombolysis. Prophylaxis is key.

PMID- 15028794
TI  - Acute and chronic renal failure.
AB  - Renal failure is defined as a deterioration of kidney function that results in
      the retention of nitrogenous waste products. It is increasingly prevalent in
      older populations, individuals with diabetes or hypertension, and postoperative
      patients. Therefore, podiatric physicians caring for these populations can expect
      to encounter this condition frequently. This article describes the epidemiology,
      causes, complications, and appropriate evaluation of renal failure relevant to a
      practicing podiatric physician. Also highlighted are treatment considerations,
      renal dosing of medications, and prevention of contrast nephropathy.

PMID- 15028795
TI  - Rheumatologic conditions of the foot.
AB  - Podiatric physicians are frequently the first clinicians with the opportunity to
      diagnose a rheumatologic disease. Awareness of the multisystem nature of the more
      common rheumatologic conditions will assist podiatrists in making the appropriate
      diagnosis. The specific joints affected, the temporal pattern of joint
      involvement, and the distribution of affected joints give clues to the diagnosis.
      Knowledge of the current treatment for rheumatic diseases as well as early
      referral for evaluation by a medical physician is essential for the appropriate
      care of patients with systemic arthritis.

PMID- 15028796
TI  - Principles of diagnosing and managing postmenopausal osteoporosis for the
      podiatric physician.
AB  - Osteoporosis is an asymptomatic disease until a fracture occurs. The prevalence
      of osteoporosis will rise with the aging of the population. Recent advances have
      led to more efficacious treatment options. Targeted screening, educating patients
      about preventive strategies, and providing appropriate treatment for those at
      high risk will allow physicians to reduce the enormous morbidity and mortality
      associated with osteoporosis.

PMID- 15028797
TI  - Laboratory medicine and diagnostic testing.
AB  - The clinical laboratory is a vital component of modern podiatric medical
      practice. In order to interpret laboratory data correctly, the practitioner must
      understand the essentials of diagnostic testing. These essentials include
      precision, accuracy, sensitivity, specificity, and prevalence-based values of a
      given test. In addition, the podiatric physician should be aware of the
      limitations, variations, and interferences that can spuriously alter test
      results.

PMID- 15028798
TI  - Informed consent and advance directives.
AB  - Contrary to popular belief, a patient's signature on a piece of paper does not
      constitute informed consent. This article describes the ethical framework of
      consent in the context of the larger process of informed decision making. The
      elements of informed consent are examined in practical terms. Common pitfalls are
      addressed, with strategies to help anticipate and resolve possible dilemmas.
      These important tools are integral to all levels of medical decision making,
      including those at the end of life.

PMID- 15028800
TI  - American Podiatric Medical Association Best Walking City Competition, 2003.
AB  - In 2003, the American Podiatric Medical Association conducted its second annual
      "Walking City Competition." The objective of the study was to update and expand
      on the results of a previous study conducted in 2002, taking into account a wider
      variety of measures of walking and walking conditions and identifying the best
      cities for walking in the United States on a regional basis.

PMID- 15028799
TI  - Primer on medical professionalism.
AB  - Medicine as a profession depends on a unique social contract between the public
      and health-care professionals. We define professionalism in medicine, provide
      examples of challenges in professionalism relevant to podiatric medicine, and
      offer resources on ethics and professionalism in medicine. "Medical
      professionalism" is the set of attitudes, values, and conduct exhibited by
      medical providers resulting from placing patients' and society's interests above
      their own. The primacy of patient welfare has been at the core of a set of values
      held by medical professionals since the drafting of the Hippocratic Oath, and it
      remains at the center of medical professionalism today.

PMID- 15028803
TI  - Microarray segmentation methods significantly influence data precision.
AB  - Little consideration has been given to the effect of different segmentation
      methods on the variability of data derived from microarray images. Previous work
      has suggested that the significant source of variability from microarray image
      analysis is from estimation of local background. In this study, we used Analysis
      of Variance (ANOVA) models to investigate the effect of methods of segmentation
      on the precision of measurements obtained from replicate microarray experiments.
      We used four different methods of spot segmentation (adaptive, fixed circle,
      histogram and GenePix) to analyse a total number of 156 172 spots from 12
      microarray experiments. Using a two-way ANOVA model and the coefficient of
      repeatability, we show that the method of segmentation significantly affects the
      precision of the microarray data. The histogram method gave the lowest
      variability across replicate spots compared to other methods, and had the lowest
      pixel-to-pixel variability within spots. This effect on precision was independent
      of background subtraction. We show that these findings have direct, practical
      implications as the variability in precision between the four methods resulted in
      different numbers of genes being identified as differentially expressed.
      Segmentation method is an important source of variability in microarray data that
      directly affects precision and the identification of differentially expressed
      genes.

PMID- 15028804
TI  - A new era for transjugular intrahepatic portosystemic shunts?

PMID- 15028805
TI  - Physician assistants in interventional radiology practice.
AB  - Interventional radiology (IR) is a clinical subspecialty; as such, there is a
      large amount of direct patient care. However, until recently, this topic has not
      been a major focus in radiology training programs. Additionally, as
      interventional radiologists develop busier and busier practices, there is less
      time to spend with individual patients. Physician extenders such as physician
      assistants (PAs) represent an excellent way to improve clinical patient care.
      This article describes what PAs are and how they work together with physicians.
      It illustrates differences between PAs and other physician extenders and
      describes the duties that may be delegated to PAs in the IR setting.

PMID- 15028807
TI  - Reteplase monotherapy and reteplase/abciximab combination therapy in peripheral
      arterial occlusive disease: results from the RELAX trial.
AB  - PURPOSE: The safety and efficacy of increasing doses of intraarterial reteplase
      monotherapy and reteplase/abciximab combination therapy were examined in patients
      with acute peripheral arterial occlusive disease (PAOD). The primary endpoint of
      this analysis was major bleeding as defined by the Thrombolysis in Myocardial
      Infarction (TIMI) investigators. MATERIALS AND METHODS: The RELAX trial was a
      prospective, dose-escalating safety trial of reteplase monotherapy (0.1, 0.2,
      0.5, or 1.0 U/h) and reteplase/abciximab combination therapy (0.25-mg/kg bolus
      and 0.125 micro g/kg/min abciximab in addition to each reteplase regimen) for
      patients with acute or subacute clinical deterioration of PAOD. Reteplase was
      administered intraarterially to 74 patients; 38 patients were also administered
      intravenous abciximab for the duration of reteplase infusion. Protocol-specified
      angiograms were obtained at 6 and 20 hours or for clinical need. Each angiogram
      was assessed for volume of thrombus dissolved and for arterial patency. The
      primary safety endpoint (TIMI major bleeding) was assessed at discharge and at
      day 7. Clinical endpoints were assessed at discharge and at days 30 and 90.
      RESULTS: Major bleeding occurred with similar frequency in patients treated with
      and without abciximab (15% of the pooled patients receiving reteplase monotherapy
      and 20% of patients receiving reteplase/abciximab combination therapy). There
      were no intracranial hemorrhagic events in the 74 patients. Reteplase doses of at
      least 0.2 U/hour were effective at dissolving thrombus and restoring patency.
      There was no clear dose-response relationship for reteplase. However, the
      addition of abciximab reduced the occurrence of distal embolic events requiring
      intervention (5% vs. 31%; P =.014). CONCLUSIONS: Over the range of reteplase
      doses studied for peripheral arterial thrombolysis, there were no significant
      differences in safety or efficacy. However, the addition of intravenous abciximab
      to reteplase was associated with a decreased rate of distal embolic events
      without a significant increase in the risk of hemorrhagic complications. Further
      investigation is needed to define the role of abciximab in catheter-directed
      thrombolysis with reteplase for PAOD.

PMID- 15028808
TI  - Transjugular intrahepatic portosystemic shunt creation with the Viatorr expanded
      polytetrafluoroethylene-covered stent-graft.
AB  - PURPOSE: To evaluate the midterm clinical results and patency of transjugular
      portosystemic shunts (TIPS) created with a commercially available expanded
      polytetrafluoroethylene (ePTFE)-covered stent-graft based on angiographic and
      ultrasonographic (US) criteria in a series of 71 patients. MATERIALS AND METHODS:
      Seventy-one patients (61 men, 10 women; mean age, 58.6 years, range, 25-78 years)
      were included in this series, which was performed in two centers. Indications for
      TIPS creation were refractory ascites (n = 44) and recurrent esophageal bleeding
      (n = 27). Ten patients had Child-Pugh class A liver cirrhosis, 43 had class B
      disease, and 18 had class C disease. Underlying liver diseases were alcoholic
      cirrhosis (n = 58), cirrhosis resulting from hepatitis (n = 9), cryptogenic
      cirrhosis (n = 3), and Budd-Chiari syndrome (n = 1). TIPS were created with
      commercially available ePTFE-covered stent-grafts in all patients. The diameters
      of the stent-grafts were 10 mm in 58 patients and 8 mm in the remaining 13
      patients. Follow-up included clinical examination and color-coded US after 5
      days, 1, 3, and 6 months, and every 6 months thereafter. Shunt angiograms were
      obtained every 6 months. Median follow-up was 16.3 months (range, 3.8-26.6
      months). RESULTS: TIPS creation was successful in all patients without
      complications, and effective portal decompression was observed with a reduction
      of the mean portal gradient from 19 mm Hg to 6 mm Hg before and after TIPS
      creation. Four shunt occlusions were observed after 5 days, 2 months, 3 months,
      and 6 months. Shunt stenosis was observed in three patients at the hepatic vein,
      which was not fully covered by the stent-graft, after 6 months (n = 2) and 12
      months, and at the portal side after 1 month in a patient who initially had
      portal vein thrombosis. The repeat intervention rate was 11.3%. The primary
      patency rates were 87.4% (95% CI, 77.7%-97.1%) after 6 months and 80.8% (95% CI,
      68.2%-93.4%) after 12 months. The rate of de novo or deteriorated hepatic
      encephalopathy was 31%. The recurrent bleeding rate was 3.7% (one of 27), and
      ascites improved or resolved in 64% of patients after 1 month. CONCLUSION: TIPS
      patency can be significantly increased if the ePTFE-covered stent-graft is used
      for shunt creation. The increased shunt patency contributes to low repeat
      intervention and recurrent bleeding rates. The rate of hepatic encephalopathy is
      within the range of previously reported rates.

PMID- 15028809
TI  - Acute iliofemoral deep vein thrombosis: evaluation of underlying anatomic
      abnormalities by spiral CT venography.
AB  - PURPOSE: To evaluate the spectrum of underlying anatomic abnormalities in
      iliofemoral deep vein thrombosis (DVT) by spiral computed tomographic (CT)
      venography. MATERIALS AND METHODS: During the past 4 years, 56 patients with
      acute iliofemoral DVT have been evaluated by CT venography at our institution.
      Forty-four patients had left-sided DVT, nine had right-sided DVT, and the
      remaining three had DVT in both extremities. CT venography was performed with use
      of 2.5-3.2-mm x-ray beam collimation and a 1.25-2.0-mm reconstruction interval.
      Spiral scans were initiated 5 minutes after intravenous contrast medium
      injection. The CT venograms were correlated with catheter venograms. In addition,
      with use of axial sections and their three-dimensional reconstructions, including
      multiplanar reformation and volume rendering, the presence or absence of central
      obstructing lesions and their causes were evaluated. RESULTS: Among 44 patients
      with left-sided DVT, 37 had significant anatomic abnormalities in their
      iliofemoral veins or inferior vena cava (IVC). The most common lesion was left
      common iliac vein compression by the right common iliac artery (n = 27;
      exaggerated by a bony spur in nine and associated with extrinsic compression by
      the left internal iliac artery in two). Of the nine patients with right-sided
      DVT, six had significant anatomic abnormalities including encasement or extrinsic
      compression of their iliac veins by various causes (n = 3) and venous stricture
      without extrinsic lesions (n = 3). Among three patients with DVT in both
      extremities, two had anatomic abnormalities in the IVC. Therefore, 45 of 56
      patients had anatomic abnormalities central to the thrombosed deep veins.
      CONCLUSION: The majority of patients with acute iliofemoral DVT had underlying
      anatomic abnormalities. The presence of central stenosis or obstruction and their
      causes can be evaluated by spiral CT venography.

PMID- 15028810
TI  - Transjugular liver biopsy in patients with end-stage renal disease.
AB  - PURPOSE: To assess the efficacy and safety of transjugular liver biopsy (TJLB) in
      patients with end-stage renal disease (ESRD) who are undergoing hemodialysis
      treatment. MATERIALS AND METHODS: Forty-six consecutive patients with liver
      disease who were undergoing hemodialysis were included in this study. An 18-gauge
      Tru-cut transjugular needle with a 20-mm throw was used to obtain liver tissue.
      All procedures were performed under fluoroscopic guidance. A single pathologist
      reviewed the biopsy specimens and assessed the size of fragments, number of
      portal tracts, and adequacy of the specimens for histologic diagnosis. All
      complications were recorded. The results were compared with the outcomes of
      percutaneous liver biopsy carried out at our institution in 32 patients with
      ESRD. RESULTS: TJLB and percutaneous biopsy techniques yielded adequate specimens
      for histologic diagnosis in all patients. The mean length of the largest
      fragments of tissue obtained via the transjugular and percutaneous routes were 16
      mm +/- 4 and 14 mm +/- 3, respectively (P = NS). There were no major
      complications among patients who underwent TJLB. Percutaneous liver biopsy was
      complicated by hemorrhage in four of 32 patients (12%), three of whom required
      blood transfusion. CONCLUSION: TJLB is an effective and safe technique to obtain
      liver tissue in patients with ESRD and is associated with a lower complication
      rate than percutaneous liver biopsy.

PMID- 15028811
TI  - Evaluation of the retrievability of the OptEase IVC filter in an animal model.
AB  - PURPOSE: A new inferior vena cava filter was evaluated in vivo to determine the
      percutaneous retrievability after an implantation period of up to 18 days.
      MATERIALS AND METHODS: The inferior venae cavae of six goats were percutaneously
      implanted with three filters, and one animal received two filters. To assess
      filter stability, a plain radiograph was obtained after 7-9 days and on the day
      of retrieval. After cavography, filter retrieval with an endovascular snare and
      retrieval catheter was performed in three animals after 12 days and in three
      others after 14 days. In one animal, retrieval of one filter was performed after
      18 days, and one filter was intended to be permanent. Twenty-eight days after
      filter retrieval, cavography was performed before inferior vena cava removal for
      gross and histologic examination. RESULTS: All filters (N = 20) were implanted
      without complications. There was no migration during the implantation period.
      Preretrieval cavography demonstrated all filters to be patent and centered.
      Filters intended for retrieval (n = 19) were all successfully extracted at 12
      (nine filters), 14 (nine filters), and 18 days (one filter). For the animal with
      the filter extracted at 18 days, one filter remained in situ intentionally.
      Postretrieval cavography showed no visible signs of vessel wall anomalies. There
      were no complications during the 28 days of follow-up after retrieval.
      Presacrifice cavography showed no evidence of caval wall abnormalities. In all
      animals, gross examination of the inner wall of the explanted vena cava showed
      only minimal macroscopic changes. The struts of the filter in situ for 46 days
      (18 days with 28 days of follow-up) were overgrown with neointima. Histological
      study of the 19 filter retrieval sites revealed no to moderate intima
      proliferation, minimal residual signs of hemorrhages, and no or only occasional
      slight inflammatory reaction. CONCLUSIONS: In this animal model, the new vena
      cava filter demonstrated event-free retrieval, without postretrieval
      complications, up to 18 days postimplantation. After implantation of 46 days, the
      filter showed neointima overgrowth of the struts.

PMID- 15028812
TI  - Radiofrequency ablation: Effect of pharmacologic modulation of hepatic and renal
      blood flow on coagulation diameter in a VX2 tumor model.
AB  - PURPOSE: To determine whether pharmacologic agents can be used to modulate blood
      flow in hepatic and renal tumors sufficiently to alter the extent of
      radiofrequency (RF)-induced coagulation. MATERIALS AND METHODS: VX2 tumors (8-15
      mm) were implanted in the liver (n = 25) or kidney (n = 8) of 33 New Zealand
      White rabbits. RF was applied to tumors for 6 minutes with use of conventional
      electrodes (125 mA +/- 35; 90 degrees C +/- 2 degrees C tip temperature). In the
      hepatic model, blood flow was modulated with use of halothane, epinephrine, or
      arsenic trioxide (2-6 mg/kg). Laser Doppler flowmetry was used to quantify
      changes in hepatic blood flow. Correlation of blood flow with induced coagulation
      diameter was performed. RF ablation was then performed in a renal model with and
      without arsenic trioxide. RESULTS: For liver tumors, halothane and arsenic
      trioxide reduced blood flow to 40.3% +/- 17.8% and 29% +/- 15% of normal,
      respectively, whereas epinephrine increased blood flow to 207.8% +/- 97.9%.
      Correlation of blood flow to coagulation diameter was demonstrated (R(2) = 0.40).
      Coagulation measured 7 mm +/- 1 with epinephrine, 10 mm +/- 1 with normal blood
      flow, 12 mm +/- 3 with halothane, and 13 mm +/- 3 with arsenic trioxide (P <.04
      compared with controls). In the renal model, arsenic trioxide decreased blood
      flow (44% +/- 16%) and increased coagulation diameter (10.9 mm +/- 1) compared
      with controls (84% +/- 11% and 7.6 mm +/- 1; P <.01, both comparisons).
      CONCLUSIONS: RF-induced coagulation necrosis in rabbit hepatic and renal tumors
      is affected by tumor blood flow. Pharmacologic modulation of tumor blood flow may
      provide a noninvasive way to decrease blood flow during thermally mediated
      ablation therapy, potentially enabling the creation of larger zones of
      coagulation necrosis.

PMID- 15028813
TI  - Maximal flow rates possible during power injection through currently available
      PICCs: an in vitro study.
AB  - PURPOSE: Currently available 4-F and 5-F peripherally inserted central catheters
      (PICCs) were investigated to evaluate their possible application for contrast
      medium injection using power injectors. The study was performed using an in vitro
      model to demonstrate the feasibility of using PICCs for contrast-enhanced
      diagnostic studies. MATERIALS AND METHODS: An evaluation of 24 catheter versions
      consisting of 4-F single-lumen and 5-F dual-lumen PICCs from 13 different
      manufacturers was conducted. Six of the catheter types were silicone and 18
      catheter types were polyurethane. Ten catheters of each type were evaluated with
      five at full length and five trimmed to 40 cm. With use of a silicone-based
      simulated SVC model, the catheters were infused with 50 mL of intravenous
      contrast medium at each flow rate increment. Catheters were tested at increasing
      flow rates from 0.5 to 5 mL/sec in 0.5-mL/sec increments using a Percupump CT
      injector. Catheters that failed to rupture were then infused at 1-mL/sec
      increments at flow rates from 5 to 17 mL/sec using a MedRad Mark V power
      injector. Tolerated and bursting pressures were recorded as well as the location
      of the catheter rupture. RESULTS: Polyurethane catheters ruptured at flow rates
      between 4 and 15.4 mL/sec, with one catheter not rupturing at the maximal flow
      rate (17 mL/sec). Silicone catheters ruptured at flow rates between 0.5 to 3.5
      mL/sec. Average rupture locations by type and length were at the extension
      leg/hub connection area on five of the PICCs, on the extension legs on 21 of the
      PICCs, on the catheter/hub connection on four PICCs, and on the proximal catheter
      on 16 of the PICCs. CONCLUSION: The low burst rates at which all silicone
      catheters ruptured suggest that those catheters are not able to withstand typical
      flow rates used for CT arteriography. Conversely, although there is a wide range
      of discrepancy in the polyurethane catheter burst pressures, many polyurethane
      catheters can tolerate relatively high flow rates without rupture. This suggests
      that they may be safely used for CT arteriography with appropriate precautions
      and protocols in place.

PMID- 15028814
TI  - Transcatheter arterial embolization for external iliac artery hemorrhage
      associated with infection in postoperative pelvic malignancy.
AB  - Transcatheter arterial embolization was attempted for external iliac artery (EIA)
      hemorrhage in five patients with wound infection after pelvic malignant tumor
      surgery. To prevent distal migration of coils and to preserve distal branches of
      the EIA, the entire weakened artery was occluded with use of coils via a
      bilateral femoral artery approach with balloon occlusion of the distal side. The
      success rate was 100%. No limb loss was observed immediately after embolization.
      This method can prevent distal migration of coils and preserve branches that can
      be collaterals to the femoral artery, and as such it can be used to embolize an
      adequate portion of the affected artery.

PMID- 15028815
TI  - Chemoembolization of liver metastasis from breast carcinoma.
AB  - Chemoembolization was performed in eight patients with liver metastasis from
      breast carcinoma. Five of eight patients had some radiographic regression of the
      liver tumors, one had stable liver disease, and two had disease progression. Two
      of four patients with pain showed clinical improvement of their symptoms. Only
      one patient with radiographic response or disease stabilization subsequently had
      intrahepatic progression (at 3 months). Five patients developed other metastasis,
      particularly brain metastasis, at a mean of 4.6 months after first
      chemoembolization (range, 2-12 months). All patients died within 13 months of
      treatment, with a mean survival of 49 months from primary diagnosis, 20 months
      from liver metastasis diagnosis, and 6 months from first chemoembolization.

PMID- 15028816
TI  - Tumor thromboembolism masquerading as bland pulmonary embolism.
AB  - Catheter-based interventions provide an important alternative to medical surgical
      management of massive central pulmonary thromboembolism. Because this option is
      increasingly being used, it is important to recognize that not all pulmonary
      thromboemboli are bland. The authors describe two cases in which tumor
      masqueraded as bland thromboembolism. Identification of tumor thromboembolism may
      help to alter future work-ups, provide useful prognostic information for a
      patient, and affect future treatment options.

PMID- 15028817
TI  - Pyosalpinx developing from a preexisting hydrosalpinx after uterine artery
      embolization.
AB  - The authors describe a case of the development of a pyosalpinx from a preexisting
      hydrosalpinx after uterine artery embolization (UAE) for leiomyomata. The
      hydrosalpinx preexisted the UAE procedure and did not cause the patient any
      symptoms or signs of infection. UAE was performed with standard technique and was
      technically as well as initially clinically successful. However, the patient
      presented 8 weeks post-UAE with a pyosalpinx and superinfection of the previously
      simple fluid collection, requiring treatment with hysterectomy and oophorectomy.
      A mechanism for the occurrence of this superinfection is proposed, and potential
      strategies to avoid this serious complication in the future are discussed.

PMID- 15028818
TI  - Modified monorail technique for insertion of tunneled hemodialysis catheters.

PMID- 15028819
TI  - Reassessing bronchial artery embolotherapy with newer spherical embolic
      materials.

PMID- 15028820
TI  - Decimal point--osteoporosis therapy at the 10-year mark.

PMID- 15028821
TI  - Earthquake relief--the U.S. medical response in Bam, Iran.

PMID- 15028822
TI  - God at the bedside.

PMID- 15028823
TI  - Ten years' experience with alendronate for osteoporosis in postmenopausal women.
AB  - BACKGROUND: Antiresorptive agents are widely used to treat osteoporosis. We
      report the results of a multinational randomized, double-blind study, in which
      postmenopausal women with osteoporosis were treated with alendronate for up to 10
      years. METHODS: The initial three-year phase of the study compared three daily
      doses of alendronate with placebo. Women in the original placebo group received
      alendronate in years 4 and 5 and then were discharged. Women in the original
      active-treatment groups continued to receive alendronate during the initial
      extension (years 4 and 5). In two further extensions (years 6 and 7, and 8
      through 10), women who had received 5 mg or 10 mg of alendronate daily continued
      on the same treatment. Women in the discontinuation group received 20 mg of
      alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by
      five years of placebo. Randomized group assignments and blinding were maintained
      throughout the 10 years. We report results for the 247 women who participated in
      all four phases of the study. RESULTS: Treatment with 10 mg of alendronate daily
      for 10 years produced mean increases in bone mineral density of 13.7 percent at
      the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3
      percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent),
      5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4
      percent), and 6.7 percent at the total proximal femur (95 percent confidence
      interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains
      occurred in the group given 5 mg daily. The discontinuation of alendronate
      resulted in a gradual loss of effect, as measured by bone density and biochemical
      markers of bone remodeling. Safety data, including fractures and stature, did not
      suggest that prolonged treatment resulted in any loss of benefit. CONCLUSIONS:
      The therapeutic effects of alendronate were sustained, and the drug was well
      tolerated over a 10-year period. The discontinuation of alendronate resulted in
      the gradual loss of its effects.

PMID- 15028824
TI  - A randomized trial of chemoradiotherapy and chemotherapy after resection of
      pancreatic cancer.
AB  - BACKGROUND: The effect of adjuvant treatment on survival in pancreatic cancer is
      unclear. We report the final results of the European Study Group for Pancreatic
      Cancer 1 Trial and update the interim results. METHODS: In a multicenter trial
      using a two-by-two factorial design, we randomly assigned 73 patients with
      resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy
      alone (20 Gy over a two-week period plus fluorouracil), 75 patients to
      chemotherapy alone (fluorouracil), 72 patients to both chemoradiotherapy and
      chemotherapy, and 69 patients to observation. RESULTS: The analysis was based on
      237 deaths among the 289 patients (82 percent) and a median follow-up of 47
      months (interquartile range, 33 to 62). The estimated five-year survival rate was
      10 percent among patients assigned to receive chemoradiotherapy and 20 percent
      among patients who did not receive chemoradiotherapy (P=0.05). The five-year
      survival rate was 21 percent among patients who received chemotherapy and 8
      percent among patients who did not receive chemotherapy (P=0.009). The benefit of
      chemotherapy persisted after adjustment for major prognostic factors.
      CONCLUSIONS: Adjuvant chemotherapy has a significant survival benefit in patients
      with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a
      deleterious effect on survival.

PMID- 15028825
TI  - Thrombocytosis.

PMID- 15028826
TI  - Acquired and inherited lipodystrophies.

PMID- 15028827
TI  - Images in clinical medicine. Eruptive xanthomas associated with
      hypertriglyceridemia and new-onset diabetes mellitus.

PMID- 15028828
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 9-2004. An 18-year-old man with respiratory symptoms and shock.

PMID- 15028829
TI  - Adjuvant therapy for pancreatic cancer--the debate continues.

PMID- 15028830
TI  - A novel BRCA2-binding protein and breast and ovarian tumorigenesis.

PMID- 15028831
TI  - Chronic allograft nephropathy.

PMID- 15028832
TI  - Surgeon volume and operative mortality.

PMID- 15028833
TI  - Dysplastic nevi.

PMID- 15028834
TI  - Chronic constipation.

PMID- 15028835
TI  - Body packing.

PMID- 15028836
TI  - Therapy for irritable bowel syndrome.

PMID- 15028837
TI  - Ribavirin-induced pure red-cell aplasia during treatment of chronic hepatitis C.

PMID- 15028838
TI  - Images in clinical medicine. Angiomatosis associated with Sneddon's syndrome.

PMID- 15028839
TI  - Order in dense hydrogen at low temperatures.
AB  - By increase in density, impelled by pressure, the electronic energy bands in
      dense hydrogen attain significant widths. Nevertheless, arguments can be advanced
      suggesting that a physically consistent description of the general consequences
      of this electronic structure can still be constructed from interacting but state
      dependent multipoles. These reflect, in fact self-consistently, a disorder
      induced localization of electron states partially manifesting the effects of
      proton dynamics; they retain very considerable spatial inhomogeneity (as they
      certainly do in the molecular limit). This description, which is valid provided
      that an overall energy gap has not closed, leads at a mean-field level to the
      expected quadrupolar coupling, but also for certain structures to the eventual
      emergence of dipolar terms and their coupling when a state of broken charge
      symmetry is developed. A simple Hamiltonian incorporating these basic features
      then leads to a high-density, low-temperature phase diagram that appears to be in
      substantial agreement with experiment. In particular, it accounts for the fact
      that whereas the phase I-II phase boundary has a significant isotope dependence,
      the phase II-III boundary has very little.

PMID- 15028840
TI  - American Pediatric Society Presidential Address 2003: the failure of Ockham's
      razor in 21st century pediatrics.

PMID- 15028841
TI  - Mitogenic activity of tracheal effluents from premature infants with chronic lung
      disease.
AB  - Lung injury alters the expression and release of growth factors that disrupt
      postnatal pulmonary development in newborns and causes chronic lung disease
      (CLD). The effect of these factors, released into the airways of newborns with
      CLD, on cell proliferation and collagen production was characterized in vitro.
      Human fetal lung fibroblast and alveolar-epithelial-like cell lines (FHs 738Lu
      and A549, respectively) were exposed to tracheal effluents from infants with CLD
      (mean gestation, 24.7 +/- 0.9 wk; birth weight, 666 +/- 85 g; postnatal age, 0-62
      d). In both cell types, proliferation was assessed by measuring [(3)H]-thymidine
      uptake; in fibroblasts, collagen production was analyzed by measuring [(3)H]
      proline incorporation. The activity of specific growth factors in effluents was
      determined using anti-growth factor antibodies and the growth factors themselves.
      Growth factors in tracheal effluents promoted proliferation in a dose-dependent
      manner and caused up to a 10.2- and 3.1-fold increase in thymidine uptake by
      fibroblasts and epithelial cells, respectively. Collagen production by
      fibroblasts increased dose dependently, peaking at 177% of baseline. Antibody
      against transforming growth factor beta-1 (TGF-beta(1)) inhibited proliferation
      and the increase in collagen production by 31% (p = 0.01) and 14% (p = 0.045),
      respectively. Antibody against hepatocyte growth factor (HGF) inhibited
      proliferation of epithelial cells (25%, p = 0.039). The effects of exogenous TGF
      beta(1) on fibroblasts and HGF on epithelial cells resembled those of tracheal
      effluents. Potent mitogenic and differentiating substances are released into the
      tracheal effluents of newborns with CLD. TGF-beta(1) may worsen CLD by inducing
      fibrosis whereas HGF may favor resolution by promoting epithelialization.

PMID- 15028843
TI  - Growth trajectory evident at birth affects age of first delivery in female
      monkeys.
AB  - Growth trajectories established early in life have proven to be important
      determinants of metabolism, health in adulthood, and ultimate mortality. The age
      of sexual maturation may also be set early in development, perhaps etched in
      utero. The following study used growth curve modeling to investigate the degree
      to which birth weight and weight gain before sexual maturation constrained the
      timing of reproduction in 147 female rhesus monkeys living under standardized
      social and nutritional conditions. Although size at birth by itself did not
      determine age of reproductive maturation, it was strongly associated with the
      subsequent developmental growth trajectory, which in turn predicted age at first
      offspring. In contrast to human studies indicating that small birth size is
      followed by a postnatal "catch-up" growth phase that accelerates menarche, growth
      trajectories remained distinctive in small and large infant monkeys. Thus, it was
      the sustained and stable disparity in size already evident at birth and amplified
      through development that accounted for variation in the age of adult sexual
      maturity.

PMID- 15028842
TI  - The R245X mutation of PCDH15 in Ashkenazi Jewish children diagnosed with
      nonsyndromic hearing loss foreshadows retinitis pigmentosa.
AB  - Usher syndrome is a frequent cause of the combination of deafness and blindness
      due to retinitis pigmentosa (RP). Five genes are known to underlie different
      forms of Usher syndrome type I (USH1). In the Ashkenazi Jewish population, the
      R245X mutation of the PCDH15 gene may be the most common cause of USH1 (Ben-Yosef
      T, Ness SL, Madeo AC, Bar-Lev A, Wolfman JH, Ahmed ZM, Desnick RK, Willner JP,
      Avraham KB, Ostrer H, Oddoux C, Griffith AJ, Friedman TB N Engl J Med 348: 1664
      1670, 2003). To estimate what percentage of Ashkenazi Jewish children born with
      profound hearing loss will develop RP due to R245X, we examined the prevalence of
      the R245X PCDH15 mutation and its carrier rate among Ashkenazi Jews in Israel.
      Among probands diagnosed with nonsyndromic hearing loss not due to mutations of
      connexin 26 (GJB2) and/or connexin 30 (GJB6), and below the age of 10, 2 of 20
      (10%) were homozygous for the R245X mutation. Among older nonsyndromic deaf
      individuals, no homozygotes were detected, although one individual was
      heterozygous for R245X. The carrier rate of the R245X mutation among the normal
      hearing Ashkenazi population in Israel was estimated at 1%. Ashkenazi Jewish
      children with profound prelingual hearing loss should be evaluated for the R245X
      PCDH15 mutation and undergo ophthalmologic evaluation to determine whether they
      will develop RP. Rehabilitation can then begin before loss of vision. Early use
      of cochlear implants in such cases may rescue these individuals from a dual
      neurosensory deficit.

PMID- 15028844
TI  - Expression of a novel cadherin in the mouse and human intestine.
AB  - Members of the cadherin superfamily mediate critical interactions in tissue
      differentiation and organogenesis, including differentiation and maintenance of
      the intestine. In this study, we report the identification and expression of a
      novel cadherin in the intestinal epithelium. We identified this cDNA by
      subtraction hybridization and obtained subsequent clones by screening a human
      cDNA library. Tissue distribution of the mRNA encoding the cadherin was assessed
      by RNA blot, reverse transcriptase PCR, and in situ hybridization. Protein
      expression was analyzed by protein blot and immunohistochemistry. The cDNA
      encodes an integral membrane protein with four consecutive cadherin binding
      domains followed by a series of mucin domains, a unique feature of this cadherin.
      Differences in the mucin domains account for four splice-forms. Multiple
      potential SH3-binding domains and a single potential PDZ-binding domain follow
      the transmembrane domain. Analysis revealed expression in the liver, kidney, and
      intestine. Three splice variants were found in the embryonic intestine as early
      as embryonic d 13 and in the adult intestine. The mRNA localizes to the mature
      enterocytes throughout the mouse small intestine and the protein, including
      several species from 90 to 100 kD, resides on the enterocyte basolateral
      membrane. We have identified intestinal expression of a novel cell cadherin with
      features suggesting the potential to transduce signals from neighboring cells to
      the cytoplasm.

PMID- 15028846
TI  - Temporal trends of cardiac and respiratory responses to ventilatory challenges in
      congenital central hypoventilation syndrome.
AB  - Congenital central hypoventilation syndrome (CCHS) patients exhibit respiratory
      deficits to ventilatory challenges, diminished breathing drive during sleep, and
      reduction of respiratory-related heart rate variation, but at least partially
      preserved peripheral chemoreception. We hypothesized that integration of afferent
      activity with respiratory motor output is deficient in CCHS, rather than
      chemoreceptor failure, and that examination of trends in heart and breathing
      rates and variabilities following ventilatory challenges may clarify the
      deficient mechanisms. Twelve children with CCHS and 12 age- and gender-matched
      control cases were subjected to hyperoxic hypercapnic, poikylocapnic hypoxic, and
      hyperoxic challenges while supine. Heart and respiratory rates and variabilities
      during 60-s baseline and 120-s challenge periods were assessed. Hypoxia and
      hypercapnia enhanced breathing rate in control subjects; in CCHS cases, the rise
      differed during hypercapnia and did not occur to hypoxia. Hyperoxia showed
      initial transient patterns in breathing rate that differed between groups. A
      heart rate increase to hypoxia and late decline to hyperoxia were muted in CCHS
      patients. In hypercapnia, heart rate followed similar rising patterns in both
      groups. Overall CCHS heart rate variability was lower in baseline and challenge
      periods, principally due to diminished respiratory-related variation, especially
      during hypercapnia. No heart rate variability group differences emerged in
      hypoxia, and only a late increase for CCHS cases developed in hyperoxia. The
      findings indicate retention of aspects of chemoreceptor sensitivity in CCHS
      cases. The heart rate alterations to ventilatory challenges suggest specific
      compensatory responses of a slower nature remain intact in CCHS, whereas other
      rapidly changing components are deficient.

PMID- 15028845
TI  - Purine and pyrimidine metabolism and electrocortical brain activity during
      hypoxemia in near-term lambs.
AB  - Insufficient cerebral O(2) supply leads to brain cell damage and loss of brain
      cell function. The relationship between the severity of hypoxemic brain cell
      damage and the loss of electrocortical brain activity (ECBA), as measure of brain
      cell function, is not yet fully elucidated in near-term newborns. We hypothesized
      that there is a strong relationship between cerebral purine and pyrimidine
      metabolism, as measures of brain cell damage, and brain cell function during
      hypoxemia. Nine near-term lambs (term, 147 d) were delivered at 131 (range, 120
      141) d of gestation. After a stabilization period, prolonged hypoxemia (fraction
      of inspired oxygen, 0.10; duration, 2.5 h) was induced. Mean values of carotid
      artery blood flow, as a measure of cerebral blood flow, and ECBA were calculated
      over the last 3 min of hypoxemia. At the end of the hypoxemic period, cerebral
      arterial and venous blood gases were determined and CSF was obtained. CSF from 11
      normoxemic siblings was used for baseline values. HPLC was used to determine
      purine and pyrimidine metabolites in CSF, as measures of brain cell damage.
      Concentrations of purine and pyrimidine metabolites were significantly higher in
      hypoxemic lambs than in their siblings, whereas ECBA was lower in hypoxemic
      lambs. Significant negative linear relationships were found between purine and
      pyrimidine metabolite concentrations and, respectively, cerebral O(2) supply,
      cerebral O(2) consumption, and ECBA. We conclude that brain cell function is
      related to concentrations of purine and pyrimidine metabolites in the CSF.
      Reduction of ECBA indeed reflects the measure of brain damage due to hypoxemia in
      near-term newborn lambs.

PMID- 15028848
TI  - Do we need additional markers of myocyte necrosis: the potential value of heart
      fatty-acid-binding protein.
AB  - Heart fatty-acid-binding protein (FABP) is a small cytosolic protein that is
      abundant in the heart and has low concentrations in the blood and in tissues
      outside the heart. It appears in the blood as early as 1.5 h after onset of
      symptoms of infarction, peaks around 6 h and returns to baseline values in 24 h.
      These features of H-FABP make it an excellent potential candidate for the
      detection of acute myocardial infarction (AMI). We review the strengths and
      weaknesses of H-FABP as a clinically applicable marker of myocyte necrosis in the
      context of acute coronary syndromes.

PMID- 15028849
TI  - Twin pairs showing discordance of phenotype in adult Gaucher's disease.
AB  - BACKGROUND: Non-neuronopathic (type 1) Gaucher's disease, a recessive disorder
      caused by glucocerebrosidase deficiency, shows marked variability in the severity
      and extent of clinical expression: many individuals who harbour two mutant
      alleles remain mildly affected or asymptomatic. Despite much effort, it is not
      possible accurately to predict disease severity from the genotype, or to identify
      those patients destined to develop severe disease and meriting early treatment.
      AIM: To determine the degree to which variance in Gaucher disease is determined
      by non-heritable factors. DESIGN: Case reports of monozygotic and dizygotic twin
      pairs. RESULTS: For the monozygotic twin pair, homozygous for the frequent N370S
      glucocerebrosidase allele, there was no evidence that significant lipid storage
      was ever initiated in the unaffected twin. In contrast, pathological storage of
      glucocerebroside has been present in the macrophages of both members of the
      dizygotic twin pair (compound heterozygotes for the N370S and L444P alleles) from
      an early age but, by the age of 57 years, only one has developed symptoms.
      DISCUSSION: Non-heritable factors influence Gaucher disease expression in
      genetically predisposed individuals. Understanding the interactions between
      heritable and non-heritable factors will be critical for an analysis of
      pathogenesis, and the treatment of individuals predisposed to Gaucher disease.

PMID- 15028850
TI  - Secondary skeletal involvement in Sanfilippo syndrome.
AB  - BACKGROUND: Sanfilippo syndrome, or mucopolysaccharidosis (MPS) type III, is a
      rare lysosomal storage disease, resulting from errors in the catabolism of
      heparan sulphate. AIM: To evaluate bone turnover and bone mineral density (BMD)
      in MPS type III patients. DESIGN: Clinical and observational study. METHODS: We
      evaluated serum markers of bone formation or resorption, and measured BMD using
      dual-energy X-ray absorptiometry (DEXA), in three patients with MPS type III.
      RESULTS: Serum vitamin D were low, and BMDs greatly reduced at lumbar and femoral
      sites, indicating the possibility of osteoporosis and osteomalacia. DISCUSSION:
      These skeletal effects probably result from nutritional deficiencies and
      inability to walk, rather than from the genetic defect itself. Secondary skeletal
      involvement in patients with MPS type III may represent a considerable cause of
      morbidity, and requires interventions to reduce the risk of pathological
      fractures.

PMID- 15028851
TI  - Microsomal triglyceride transfer protein polymorphisms and lipoprotein levels in
      type 2 diabetes.
AB  - BACKGROUND: Microsomal triglyceride transfer protein (MTP) regulates the assembly
      of chylomicrons in the intestine and very-low-density lipoprotein (VLDL) in the
      liver. Common polymorphisms have been described that do not affect lipoproteins
      in non-diabetic subjects. Their effect in diabetes has not been described in a
      Caucasian population. AIM: To investigate the association of these three common
      polymorphisms with lipoproteins in type 2 diabetes. METHODS: Eighty-two patients
      consumed a high-fat test meal. Chylomicron and VLDL apoB48, apoB100, cholesterol,
      triglycerides and phospholipids were measured fasting, and at 4 and 6 h
      postprandially. MTP genotyping was performed by PCR-RFLP. RESULTS: Thirty-three
      subjects were heterozygous for the -493 G/T substitution. These patients had
      significantly lower LDL cholesterol (3.0 +/- 0.2 vs. 3.5 +/- 0.1 mmol/l, p <
      0.02). In the postprandial period, they had higher levels of apoB48 in the VLDL
      fraction (4 h, 7.0 +/- 1.4 vs. 2.9 +/- 0.4 microg/ml plasma, p < 0.002; 6 h, 6.4
      +/- 1.0 vs. 3.5 +/- 0.5 microg/ml plasma, p < 0.05). In the VLDL fraction there
      was significantly less cholesterol at 4 and 6 h (p < 0.05). The -400 A/T
      substitution gave very similar lipoprotein results, but there was significant
      linkage dysequilibrium between the two polymorphisms. No association was found
      between the -164 T/C polymorphism and either plasma lipids or the postprandial
      lipid profile. ApoE genotype was also examined, but did not influence the above
      results. DISCUSSION: The common -493 G/T MTP polymorphism is associated with
      changes in VLDL and LDL in Type 2 diabetic patients. The importance of the
      changes in apoB48-containing small particles requires further investigation. The
      significantly lower LDL cholesterol suggests that this polymorphism may confer
      protection against atherosclerosis in type 2 diabetes.

PMID- 15028853
TI  - Severe irritability associated with statin cholesterol-lowering drugs.
AB  - BACKGROUND: As use of a drug becomes widespread, the full spectrum of its effects
      becomes clearer. Although a link has been suggested between low or lowered
      cholesterol and irritability/aggression, less is known about possible links
      between irritability and statins. AIM: To assess the possible connection of
      statin usage to severe irritability. DESIGN: Case series. METHODS: Six patients
      referred or self-referred with irritability and short temper on statin
      cholesterol-lowering drugs completed a survey providing information on character
      of behavioural effect, time-course of onset and recovery, and factors relevant to
      drug adverse effect causality. RESULTS: In each case the personality disruption,
      once evident, was sustained until statin use was discontinued; and resolved
      promptly with drug cessation. In four patients, re-challenge with statins
      occurred, and led to recrudescence of the problem. All patients experienced other
      recognized statin adverse effects while on the drug. Manifestations of severe
      irritability included homicidal impulses, threats to others, road rage,
      generation of fear in family members, and damage to property. DISCUSSION: Case
      series invariably raise more questions than they can answer. These case reports
      suggest that severe irritability may occur in some statin users. Although this
      adverse effect may be rare, potentially life-threatening adverse effects of drugs
      must be taken seriously.

PMID- 15028854
TI  - Depression and alcoholism.

PMID- 15028852
TI  - Intensified treatment of patients with type 2 diabetes mellitus and overt
      nephropathy.
AB  - BACKGROUND: Diabetic nephropathy is the single most common cause of chronic renal
      failure requiring dialysis. Effective treatment exists, but no clinical audit or
      large trial has reduced the rate of loss of renal function as effectively as in
      small groups of intensively managed patients. AIM: To determine the effect of
      intensive vs. standard medical management on the rate of progression of renal
      failure in patients with diabetic nephropathy. DESIGN: Prospective randomized
      controlled study. METHODS: Patients with type 2 diabetes and nephropathy were
      randomly allocated to an intensive group (n = 47) or control group (n = 43).
      Treatment targets were the same for both groups, but the intensive group were
      seen as often as required to meet the targets; controls were seen at their normal
      clinics. The primary end-point was the rate of progression of renal disease in
      the second year. RESULTS: The groups were well matched at baseline. During follow
      up, the intensive group had lower mean SBP, DBP and cholesterol. Median rate of
      progression of renal failure in the intensive group fell from 0.44 ml/min/month
      in the first year to 0.14 ml/min/month in the second year, compared to 0.49
      ml/min/month and 0.53 ml/min/month in the control group (p = 0.04 for second
      year). Patients in the intensive group spent significantly less time in hospital.
      DISCUSSION: Intensive treatment slowed progression of renal disease within 2
      years in patients with established diabetic nephropathy. Mean creatinine
      clearance at the start of the trial was 55 ml/min, so assuming that the rates of
      progression achieved at the end of the second year persisted, onset of dialysis
      would be delayed by 20 years in the intensive group compared with the control
      group.

PMID- 15028855
TI  - Painful arm in syringomyelia and Fabry disease.

PMID- 15028856
TI  - Junk, bricolage or 'objets de virtue'?

PMID- 15028857
TI  - Rhyming couplet.

PMID- 15028858
TI  - Throwing fat on the fire. Mice lacking supposed insulin enabler are surprisingly
      lean.

PMID- 15028859
TI  - Riddled with errors. Mutations mount in elderly sperm.

PMID- 15028860
TI  - Hop on board. Blueprint for fat-cell specialization hitches a ride from a shuttle
      protein.

PMID- 15028861
TI  - Greasing the way for bone growth. Signaling molecule steers cells toward bone and
      away from fat.

PMID- 15028864
TI  - Androgens, apoE, and Alzheimer's disease.
AB  - Increasing evidence indicates that there are reductions in estrogen and androgen
      levels in aged men and women. These hormonal reductions might be risk factors for
      cognitive impairments and the development of Alzheimer's disease (AD). Aged
      people show improved cognition after treatments with sex steroids. Therefore,
      ongoing clinical AD trials have been designed to evaluate the potential benefits
      of estrogen therapy in women and testosterone therapy in men. Apolipoprotein E
      (apoE) plays an important role in the metabolism and redistribution of
      lipoproteins and cholesterol. The three major human apoE isoforms, apoE2, apoE3,
      and apoE4, differ in their effects on AD risk and pathology. Here I review
      various mechanisms proposed to mediate the differential effects of apoE isoforms
      on brain function and highlight the potential contribution of detrimental isoform
      dependent effects of apoE on androgen- and androgen receptor (AR)-mediated
      pathways. I also discuss potential interactions of androgens with other AD
      related factors.

PMID- 15028863
TI  - Exploiting proteomics in the discovery of drugs that target mitochondrial
      oxidative damage.
AB  - To understand how oxidative stress contributes to aging and age-related diseases
      and to better evaluate the therapeutic effect of antioxidant drugs, it would be
      highly desirable to have a comprehensive and detailed readout of the types of
      oxidative damage that occur to proteins at a global or proteome level. In this
      Perspective, I examine how proteomics, defined here as the science of examining
      all proteins in an organelle, cell, or tissue in the context of biological
      phenomena, can be used to provide molecular details of mitochondrial protein
      oxidative damage. Specifically, I discuss approaches that combine knowledge of
      the mitochondrial proteome with newer mass spectrometry-based techniques that are
      capable of identifying proteins and sites of oxidative modification in a high
      throughput manner.

PMID- 15028865
TI  - Effect of body position on PaO2 and PaCO2 during pregnancy.
AB  - BACKGROUND: The body position may have an effect on gas exchange though the
      magnitude of this effect has not been studied thoroughly during the three
      trimesters of pregnancy. OBJECTIVES: This study analyzes the effect of body
      position change on arterial oxygen tension (PaO2) and arterial carbon dioxide
      tension (PaCO2) in healthy pregnant women. METHODS: We examined 21 lung healthy
      pregnant women at the end of the first, second and third trimester of pregnancy.
      Blood was drawn from the radial artery first in the sitting and subsequently in
      the supine position. Peak expiratory flow rate was determined as well. RESULTS:
      No statistically significant difference was detected between the mean values of
      PaO2 in the supine and in the sitting position at the end of the first trimester.
      On the contrary, at the end of the second trimester the mean value of PaO2 in the
      supine position was 92.39 +/- 1.95 mm Hg, while in the sitting position the mean
      PaO2 was 96.56 +/- 1.83 mm Hg (p < 0.001). At the end of the third trimester the
      mean PaO2 in the supine position was 90.48 +/- 2.91 mm Hg while in the sitting
      position the mean PaO2 was 97.48 +/- 1.46 mm Hg (p < 0.001). CONCLUSIONS:
      According to our data we conclude that the statistically significant difference
      in PaO2 in the sitting and supine positions clearly shows that the position needs
      to be considered both when attempting to establish reference values and when
      evaluating gas tensions at the end of pregnancy.

PMID- 15028862
TI  - Going Ku Ku on Bax.

PMID- 15028866
TI  - Analyses of stress resistance under laboratory conditions constitute a suitable
      criterion for wine yeast selection.
AB  - During wine production, yeast cells are affected by several conditions that are
      adverse to growth (oxidative, osmotic and ethanol stress among others) and they
      should detect and respond to these conditions, otherwise alcoholic fermentation
      can be negatively affected. In this work we have analyzed the fermentative
      behaviour of 14 commercial and non-commercial strains in several synthetic musts.
      According to the data obtained these strains have been classified into three
      groups depending on whether or not vinification was completed (and on the amount
      of residual sugar remaining in the must if it was not). Moreover, we have
      determined the resistance of these strains to several stress situations under
      laboratory growth conditions. We have been able to establish a correlation
      between the groups based on fermentative behaviour and resistance to several
      stress conditions (especially oxidative and ethanol stress), by applying
      discriminant analysis to the data obtained in these experiments. Our results
      indicate a clear relationship between stress resistance and fermentative
      behaviour and this opens up the possibility of using this information as a
      criterion for the future selection of wine yeasts.

PMID- 15028867
TI  - Pyrolysis patterns of 5 close Corynebacterium species analyzed by artificial
      neural networks.
AB  - In the present study, an artificial neural network was trained with the Stuttgart
      Neural Networks Simulator, in order to identify Corynebacterium species by
      analyzing their pyrolysis patterns. An earlier study described the combination of
      pyrolysis, gas chromatography and atomic emission detection we used on whole cell
      bacteria. Carbon, sulfur and nitrogen were detected in the pyrolysis compounds.
      Pyrolysis patterns were obtained from 52 Corynebacterium strains belonging to 5
      close species. These data were previously analyzed by Euclidean distances
      calculation followed by Unweighted Pair Group Method of Averages, a clustering
      method. With this early method, strains from 3 of the 5 species (C. xerosis, C.
      freneyi and C. amycolatum) were correctly characterized even if the 29 strains of
      C. amycolatum were grouped into 2 subgroups. Strains from the 2 remaining species
      (C. minutissimum and C. striatum) cannot be separated. To build an artificial
      neural network, able to discriminate the 5 previous species, the pyrolysis data
      of 42 selected strains were used as learning set and the 10 remaining strains as
      testing set. The chosen learning algorithm was Back-Propagation with Momentum.
      Parameters used to train a correct network are described here, and the results
      analyzed. The obtained artificial neural network has the following cone-shaped
      structure: 144 nodes in input, 25 and 9 nodes in 2 successive hidden layers, and
      then 5 outputs. It could classify all the strains in their species group. This
      network completes a chemotaxonomic method for Corynebacterium identification.

PMID- 15028868
TI  - Putative lipoproteins of Streptococcus agalactiae identified by bioinformatic
      genome analysis.
AB  - Streptococcus agalactiae is a significant pathogen causing invasive disease in
      neonates and thus an understanding of the molecular basis of the pathogenicity of
      this organism is of importance. N-terminal lipidation is a major mechanism by
      which bacteria can tether proteins to membranes. Lipidation is directed by the
      presence of a cysteine-containing 'lipobox' within specific signal peptides and
      this feature has greatly facilitated the bioinformatic identification of putative
      lipoproteins. We have designed previously a taxon-specific pattern (G+LPP) for
      the identification of Gram-positive bacterial lipoproteins, based on the signal
      peptides of experimentally verified lipoproteins (Sutcliffe I.C. and Harrington
      D.J. Microbiology 148: 2065-2077). Patterns searches with this pattern and other
      bioinformatic methods have been used to identify putative lipoproteins in the
      recently published genomes of S. agalactiae strains 2603/V and NEM316. A core of
      39 common putative lipoproteins was identified, along with 5 putative
      lipoproteins unique to strain 2603/V and 2 putative lipoproteins unique to strain
      NEM316. Thus putative lipoproteins represent ca. 2% of the S. agalactiae
      proteome. As in other Gram-positive bacteria, the largest functional category of
      S. agalactiae lipoproteins is that predicted to comprise of substrate binding
      proteins of ABC transport systems. Other roles include lipoproteins that appear
      to participate in adhesion (including the previously characterised Lmb protein),
      protein export and folding, enzymes and several species-specific proteins of
      unknown function. These data suggest lipoproteins may have significant roles that
      influence the virulence of this important pathogen.

PMID- 15028869
TI  - Identification of species of the genus Candida by analysis of the 5.8S rRNA gene
      and the two ribosomal internal transcribed spacers.
AB  - The PCR amplification and subsequent restriction analysis of the ribosomal region
      spanning the internal transcribed spacers (ITS1 and ITS2) and the 5.8S rRNA gene
      is applied to the identification of yeasts belonging to the genus Candida. This
      methodology has previously been used for the identification of some species of
      this genus, but in the present work this application has been applied to the
      identification and characterisation of a greater number of species of the genus
      Candida, with a special survey of species of clinical and biotechnological
      interest. Among the species of the genus Candida, the high variability observed,
      both in the length of the amplified region (ranging between 390 and 900 bp) and
      in their restriction patterns, allows the unequivocal identification to the
      species level, with the exception of the group of species that comprises C.
      membranifaciens, C. conglobata, C. atlantica, C. atmosphaerica, and C. oleophila,
      that required the sequencing of the D1/D2 domain of the 26S rRNA gene or the 5.8S
      ITS region for their proper differentiation. The 5.8S-ITS restriction analysis
      also failed in the differentiation of species within the pairs
      C.aaseri/C.butyri,C.fructus/C.musae,C.santamariae var. santamariae / C. beechii
      and C. zeylanoides / C. krissii. In this case, the high sequence similarities
      obtained for their 26S D1/D2 domain and the 5.8S-ITS region indicate that each
      pair of species should be considered as a single species. The main purpose of
      this work is to generate a database for a high number of yeast species, of both
      biotechnological and clinical interest, and to facilitate their easy, fast, and
      reliable identification. The present work improves the database available online
      at the IATA web page (http://motor.edinfo.es/iata/) with the patterns of 75
      species belonging to the genus Candida.

PMID- 15028870
TI  - Intra-specific variation of Lactobacillus plantarum and Lactobacillus pentosus in
      sensitivity towards various bacteriocins.
AB  - Fifty-two strains belonging to the Lactobacillus plantarum species group were
      identified and typed. They represented 32 clones of Lactobacillus plantarum and 7
      clones of Lactobacillus pentosus. Sensitivity of all strains towards bacteriocins
      of four different producer strains was investigated using a deferred inhibition
      test (DIT). Substantial intra-specific variation in sensitivity of clones was
      observed towards bacteriocinogenic lactic acid bacteria producing nisin (
      Lactococcus lactis ATCC 11454) or pediocin PA-1 ( Pediococcus acidilactici PAC
      1.0), while none of the strains were sensitive towards the two remaining
      bacteriocin producers. The minimum inhibitory concentration (MIC) of nisin
      towards selected strains confirmed the DIT results. No correlation between the
      susceptibility of fourteen selected strains towards nisin and an array of
      antibiotics was found. The present study indicates that the variation in
      bacteriocin-sensitivity within target species might be a potential limitation for
      the application of bacteriocins as biopreservatives.

PMID- 15028871
TI  - Molecular characterization of nosRZDFYLX genes coding for denitrifying nitrous
      oxide reductase of Bradyrhizobium japonicum.
AB  - The nosRZDFYLX gene cluster for the respiratory nitrous oxide reductase from
      Bradyrhizobium japonicum strain USDA110 has been cloned and sequenced. Seven
      protein coding regions corresponding to nosR, nosZ, the structural gene, nosD,
      nosF, nosY, nosL, and nosX were detected. The deduced amino acid sequence
      exhibited a high degree of similarity to other nitrous oxide reductases from
      various sources. The NosZ protein included a signal peptide for protein export.
      Mutant strains carrying either a nosZ or a nosR mutation accumulated nitrous
      oxide when cultured microaerobically in the presence of nitrate. Maximal
      expression of a P nosZ-lacZ fusion in strain USDA110 required simultaneously both
      low level oxygen conditions and the presence of nitrate. Microaerobic activation
      of the fusion required FixLJ and FixK(2).

PMID- 15028872
TI  - Mucoraceous moulds involved in the commercial fermentation of Sufu Pehtze.
AB  - Sufu is a fermented cheese-like soybean product in China and Vietnam, obtained by
      fungal solid-state fermentation of soybean curd (tofu), which results in moulded
      tofu or 'pehtze'. The final product sufu is obtained by maturing pehtze in a
      brine containing alcohol and salt during a period of several months. The present
      report deals with the identity and phylogenetic relationships of mould starter
      cultures used for the preparation ofpehtze. Starter cultures used in commercial
      pehtze fermentation were obtained from factories located in several provinces of
      China and Vietnam, isolated from their pehtze and some were obtained from culture
      collections. They were identified as Actinomucor repens, Actinomucor taiwanensis,
      Mucor circinelloides, Mocur hiemalis, Mocur racemosus, and Rhizopus microsporus
      var. microsporus. Phylogenetic relations based on sequencing of genomic DNA of
      these starters and of relevant control strains from collections indicate that the
      genera Mucor, Actinomucor and Rhizopus form distinct and homogenous clusters,
      with Mucor and Actinomucor showing a slightly closer relationship with each other
      than with Rhizopus.

PMID- 15028873
TI  - Isolation and characterization of a lipoxygenase from Pseudomonas 42A2
      responsible for the biotransformation of oleic acid into ( S )-( E )-10-hydroxy-8
      octadecenoic acid.
AB  - The isolation of a new lipoxygenase-like (LOX-like) enzyme from Pseudomonas 42A2
      and its characterization is described. The enzyme, located in the periplasm of
      the cell, which contained 0.55 mol of Fe2+ per mol of protein, is monomeric and
      has a molecular mass of 45 kDa. In the presence of oxygen, the enzyme converts
      oleic acid into (E)-10-hydroperoxy-8-octadecenoic acid (HPOD), which decomposes
      to the corresponding (E)-10-hydroxy-8-octadecenoic acid (HOD). The absolute
      configuration of this acid was determined as S on the basis of exciton-coupled CD
      data, and specific rotation and NMR analysis of the corresponding p 
      bromobenzoate derivative. The reaction in vivo leads to the dihydroxy derivative
      (E)-7,10-dihydroxy-8-octadecenoic acid (DHOD), so that the three hydroxy-fatty
      acids can be isolated from the culture medium. The activity of the enzyme was
      optimal between 25 and 30 degrees C and 44% of its activity still remained at 55
      degrees C. Its optimal pH is 8.5-9; and the presence of magnesium ions increased
      LOX activity by 1.5. The activity of the LOX is highest in unsaturated fatty
      acids containing double bonds in position 9 (oleic, linoleic and linolenic
      acids), linoleic acid being preferred (100% activity) over linolenic (60.4%) and
      oleic acids (46%). However, kinetic studies showed that the affinity of the
      enzyme is similar for the three substrates.

PMID- 15028874
TI  - The transformation of inorganic sulfur compounds and the assimilation of organic
      and inorganic carbon by the sulfur disproportionating bacterium Desulfocapsa
      sulfoexigens.
AB  - The physiology of the sulfur disproportionator Desulfocapsa sulfoexigens was
      investigated in batch cultures and in a pH-regulated continuously flushed
      fermentor system. It was shown that a sulphide scavanger in the form of ferric
      iron was not obligatory and that the control of pH allowed production of more
      biomass than was possible in carbonate buffered but unregulated batch cultures.
      Small amounts of sulphite were produced during disproportionation of elemental
      sulfur and thiosulphate. In addition, it was shown that in the presence of
      hydrogen, a respiratory type of process is favored before the disproportionation
      of sulphite, thiosulphate and elemental sulfur. Sulphate reduction was not
      observed. D. sulfoexigens assimilated inorganic carbon even in the presence of
      organic carbon sources. Inorganic carbon assimilation was probably catalyzed by
      the reverse CO-dehydrogenase pathway, which was supported by the constitutive
      expression of the gene encoding CO-dehydrogenase in cultures grown in the
      presence of acetate and by the high carbon fractionation values that are
      indicative of this pathway.

PMID- 15028875
TI  - Two ITS forms co-inhabiting a single genet of an isolate of Terfezia boudieri
      (Ascomycotina), a desert truffle.
AB  - Two fruit-bodies of Terfezia boudieri Chatin, each exhibiting a mixture of two
      ITS -RFLP profiles, were found in the Negev desert of Israel. A mycelial culture
      obtained from glebal out-growth maintained the double profile, as did
      proliferating cultures established using single hyphae isolated from the original
      cultures. The main difference between the two ITS variants lies in a 21 bp
      deletion in the smaller variant. The question whether both variants are contained
      within a single nucleus or occupy different nuclei sharing the same cytoplasm is
      discussed.

PMID- 15028876
TI  - Chemical structure, surface properties and biological activities of the
      biosurfactant produced by Pseudomonas aeruginosa LBI from soapstock.
AB  - Pseudomonas aeruginosa LBI isolated from petroleum-contaminated soil produced
      rhamnolipids (RL(LBI)) when cultivated on soapstock as the sole carbon source.
      HPLC-MS analysis of the purified culture supernatant identified 6 RL homologues
      (%): R(2) C(10) C(10) 28.9; R(2) C(10) C(12:1) 23.0; R(1) C(10) C(10) 23.4; R(2)
      C(10) C(12) 11.3; R(2) C(10) C(12) 7.9; R(2) C(10) C(12) 5.5. To assess the
      potential antimicrobial activity of the new rhamnolipid product, RL(LBI), its
      physicochemical properties were studied. RL(LBI) had a surface tension of 24 mN
      m(-1) and an interfacial tension of 1.31 mN m(-1); the cmc was 120 mg l(-1).
      RL(LBI) produced stable emulsions with hydrocarbons and vegetable oils. This
      product showed good antimicrobial behaviour against bacteria: MIC for Bacillus
      subtilis, Staphylococcus aureus and Proteus vulgaris was 8 mg l(-1), for
      Streptococcus faecalis 4 mg l(-1), and for Pseudomonas aeruginosa 32 mg l(-1).
      RL(LBI) was active against phytopathogenic fungal species, MIC values of 32 mg l(
      1) being found against Penicillium, Alternaria, Gliocadium virens and Chaetonium
      globosum. Due to its physicochemical properties and antimicrobial behaviour,
      RL(LBI) could be used in bioremediation treatment and in the food, cosmetic and
      pharmaceutical industries.

PMID- 15028878
TI  - First survey of fungi in hypersaline soil and water of Mono Lake area
      (California).
AB  - Mono Lake is a closed lake located in central California, east of the Sierra
      Nevada mountains. It contains dissolved carbonates, sulfates and chlorides at
      high concentrations. Due to its high salinity, Mono Lake was sometimes compared
      to the Dead Sea. However, it appears that Mono Lake water and vicinity abound
      with life. In this work, the fungal flora living in this extreme ecosystem was
      studied for the first time. Soil, tufa, water and sediment samples were also
      analyzed for their mineral and salt composition. Results showed that water was
      particularly rich in sodium, potassium, phosphorus and boron. Soil and sediments
      contained very high levels of calcium and magnesium, but also barium, boron and
      strontium. Sodium, phosphorus and iron levels varied in a large extent from one
      to another sample. Neutral to very alkaline pH were recorded. Water samples were
      found sterile in the conditions chosen for fungi isolation, while sediment, soil
      and tufa samples led to the isolation of a total of 67 fungal species (from 23
      samples), belonging to various taxonomic groups. From our results no clear
      effects of the chemical parameters of the samples were observed on fungal life
      apart from the pH. The methods chosen did not allow the isolation of extremely
      halotolerant species. We isolated in this work a series of ubiquitous species,
      suggesting that a selection of resistant and/or adaptable strains of some common
      species could have occurred. Depending on the medium and the temperature of
      isolation, it can be hypothesized that some species were present as dormant
      structures, while some others, isolated at pH 8 on a medium enriched in Na and
      Ca, could be in a growing form adapted to alkaline and saline conditions. This
      work contributes to a better knowledge of the mycobiota present in the Mono
      Lake's ecosystem.

PMID- 15028877
TI  - Cr(VI) reduction in a chromate-resistant strain of Candida maltosa isolated from
      the leather industry.
AB  - A Cr(VI)-resistant yeast was isolated from tanning liquors from a leather factory
      in Leon, Guanajuato, Mexico. Based on morphological and physiological analyses
      and the D1/D2 domain sequence of the 26S rDNA, the yeast was identified as
      Candida maltosa. Resistance of the strain to high Cr(VI) concentrations and its
      ability to chemically reduce chromium was studied. When compared to the three
      laboratory yeasts Candida albicans, Saccharomyces cerevisiae and Yarrowia
      lipolytica, the C. maltosa strain was found to tolerate chromate concentrations
      as high as 100 micro g/ml. In addition to this phenotypic trait, the C. maltosa
      strain showed ability to reduce Cr(VI). Chromate reduction occurred both in
      intact cells (grown in culture medium or in soil containing chromate) as well as
      in cell-free extracts. NADH-dependent chromate reductase activity was found
      associated with soluble protein and, to a lesser extent, with the membrane
      fraction.

PMID- 15028879
TI  - Modification of pharmacokinetics of cefotaxime in uranyl nitrate-induced renal
      damage in black bengal goats.
AB  - Pharmacokinetics of cefotaxime (50 mg/kg, i.m.) were studied in both healthy and
      kidney damaged female black Bengal goats. Uranyl nitrate (0.75 mg/kg) was
      administered intravenously, once daily for five consecutive days to induce kidney
      damage. The pharmacokinetic variables were calculated in both cases. Kidney
      damage caused several changes in the determined variables. The C(max) and C(min)
      of cefotaxime observed at 0.50 and 5 h in normal goats were 24.91+/-1.51 and
      1.22+/-0.07 micro g/ml, respectively, while the same in kidney damaged goats at 1
      and 72 h were 75.00+/-0.45 and 3.10+/-0.09 micro g/ml, respectively. Renal damage
      condition significantly increased t1/2,ka (0.48+/-0.01 h), t1/2,ke (20.03+/-0.16
      h), AUC (2440.10+/-24.26 micro g. h/ml) and significantly decreased Vdarea
      (0.59+/-0.007 L/kg), Vss (0.58+/-0.007 L/kg) and ClB (0.02+/-0.008 L/kg/h) values
      of cefotaxime compared to normal goats.

PMID- 15028880
TI  - Assessment of the California mastitis test usage in smallholder dairy herds and
      risk of violative antimicrobial residues.
AB  - This study evaluated how predictive the California Mastitis Test (CMT) is for sub
      clinical mastitis under tropical smallholder dairy production conditions in
      Kenya. It intended to establish whether the CMT usage could be contributing to
      misdiagnosis and consequent mistreatment with animal drugs resulting in residue
      problems. Milk samples (n = 239) were aseptically collected from lactating cows
      in the Rift Valley of Kenya and tested using the CMT, somatic cell counts (SCC)
      and bacterial culture. The samples were also screened for violative drug residues
      using the commercial delvo test and compared to the milks mastitic status for
      possible association. There was a numerical but non-significant (p > 0.05)
      difference evident in the frequencies observed using the three different mastitis
      indicators. The prevalent bacterial species isolated from mammary glands with
      subclinical mastitis were Staphylococcus aureus (45.6%), coagulase-negative
      Staphylococci (13.0%), Streptococci (11.7%) and Escherichia coli 5.9%. There was
      an overall poor but significant (p < 0.05) correlation between the CMT and the
      violative antimicrobial residues in samples from all quarters, infected and non
      infected respectively. The results suggest that the CMT use amongst the
      smallholder dairy sector as a mastitic indicator may not be a risk factor in
      violative antimicrobial residues problems in milk.

PMID- 15028882
TI  - Inherited canine copper toxicosis in Australian Bedlington Terriers.
AB  - Inherited copper toxicosis in Bedlington Terriers (CTBT) is a copper associated
      hepatopathy caused by an autosomal recessive genetic defect of gene involving
      copper metabolism. To compare clinical and histopathological findings with
      previous reports and to expand our knowledge for future genetic studies, 18
      terriers were clinically and histopathologically examined in this study. Pedigree
      information and dietary history were obtained from the owners before a thorough
      clinical examination was undertaken. Following the examination, a blood sample
      was collected for haematology, biochemistry and genetic analysis and a urine
      sample for urinalysis. Seven dogs were also liver biopsied for histopathology,
      histochemistry and electron microscopy. In this study, plasma alanine
      transaminase (ALT) activity was highly concordant with DNA marker test results
      and was the most reliable and sensitive biochemical test measured. Also clinical
      and biochemical copper toxicosisaffected states were noticed in a genotyped
      carrier dog. Histopathological and electron microscopy findings showed that the
      severity of the lesion was more closely correlated to the presence of clinical
      signs than to hepatic copper concentration. In addition, the involvement of
      apoptosis and p53 gene was observed in electron microscopy. The general findings
      related to CT-BT in this study was similar to those previously reported except
      few differences in histopathology and electron microscopy.

PMID- 15028881
TI  - Comparative study of PM2.5 - and PM10 - induced oxidative stress in rat lung
      epithelial cells.
AB  - Accurate estimation of the exposure-response relationship between ambient urban
      particulate matters (PM) and public health is important for regulatory
      perspective of ambient urban particulate matters (PM). Ambient PM contains
      various transition metals and organic compounds. PM10 (aerodynamic diameter less
      than 10 micro m) is known to induce diverse diseases such as chronic cough,
      bronchitis, chest illness, etc. However, recent evaluation of PM2.5 (aerodynamic
      diameter less than 2.5 micro m) against health outcomes has suggested that the
      fine particles may be more closely associated with adverse respiratory health
      effects than particles of larger size. This study was performed to evaluate PM2.5
      induced oxidative stress in rat lung epithelial cell in order to provide basic
      data for the risk assessment of PM2.5. PM2.5 showed higher cytotoxicity than
      PM10. Also, PM 2.5 induced more malondialdehyde (MDA) formation than PM10. In
      Hoechst 33258 dye staining and DNA fragmentation assay, apopotic changes were
      clearly detected in PM2.5 treated cells in compared to PM10. Expression of
      catalase mRNA was increased by PM2.5 rather than PM10. PM2.5 induced higher Mth1
      mRNA than PM10. In pBR322 DNA treated with PM2.5, production of single strand
      breakage of DNA was higher than that of PM10. In Western blot analysis, PM2.5
      induced more Nrf-2 protein, associated with diverse transcriptional and anti
      oxidative stress enzymes, compared to PM10. Our data suggest that PM2.5 rather
      than PM10 may be responsible for PM-induced toxicity. Additional efforts are
      needed to establish the environmental standard of PM2.5.

PMID- 15028883
TI  - Characterization of lymphocyte subpopulations and major histocompatibility
      complex haplotypes of mastitis-resistant and susceptible cows.
AB  - Bovine mastitis is an infectious disease with a major economic influence on the
      dairy industry worldwide. Many factors such as environment, pathogen, and host
      affect susceptibility or resistance of an individual cow to bovine mastitis.
      Recently, there has been considerable interest in defining genetic and
      immunological markers that could be used to select for improved disease
      resistance. In this study we have analyzed the lymphocyte subpopulations of
      mastitis-resistant and susceptible cows using monoclonal antibodies specific for
      bovine leukocyte differentiation antigens and flow cytometry. We have also used a
      microarray typing technique to define the bovine leukocyte antigen (BoLA) class I
      and class II haplotypes associated with resistance or susceptibility to bovine
      mastitis. A striking finding of the present study is that susceptibility to
      mastitis was associated with major histocompatibility complex (MHC) haplotypes
      that have only a single set of DQ genes. The study also revealed that susceptible
      cows had CD4:CD8 ratios of less than one in both their mammary gland secretions
      and peripheral blood. These results raise the possibility that the number of DQ
      genes that a cow has and/or a cow's CD4:CD8 ratio could be used as indicators of
      susceptibility to bovine mastitis.

PMID- 15028884
TI  - Immunomodulatory and antitumor effects in vivo by the cytoplasmic fraction of
      Lactobacillus casei and Bifidobacterium longum.
AB  - The immunomodulatory and antitumor effects of lactic acid bacteria (LABs) were
      investigated. Cytoplasmic fraction of Lactobacillus acidophilus, Lactobacillus
      casei and Bifidobacterium longum were tested for the antiproliferative activity
      in vitro to SNUC2A, SNU1, NIH/3T3 and Jurkat cell lines by crystal violet assay.
      All cytoplasmic fraction suppressed proliferation of tumor cells, though L. casei
      and B. longum were more effective. From these results, cytoplasmic fraction of L.
      casei and B. longum with Y400 as a control were administered as dietary
      supplements to Balb/c mice for 2, and 4 consecutive wks. Administration for 4 wks
      enhanced the number of total T cells, NK cells and MHC class II+ cells, and CD4
      CD8+ T cells in flow cytometry analysis. To determine of antitumor activity of
      LABs preparation in vivo, F9 teratocarcinoma cells were inoculated on mice at
      14th day. Body weight was decreased with increased survival rate in all groups
      with the cytoplasm of LABs. Our results showed that cytoplasmic fraction of LABs
      had direct antiproliferative effects on tumor cell lines in vitro, effects on
      immune cells in vivo, and antitumor effects on tumor-bearing mice with prolonged
      survival periods.

PMID- 15028885
TI  - The effects of cyclophosphamide treatment on the pathogenesis of subgroup J avian
      leukosis virus (ALV-J) infection in broiler chickens with Marek's disease virus
      exposure.
AB  - Studies were performed to determine the effects of Bcell suppression on the
      pathogenesis of Subgroup J avian leukosis virus (ALV-J) in broiler chickens.
      Neonatal chickens were treated with cyclophosphamide (CY) or PBS, and then
      infected with ALV-J (ADOL-7501) at 2 weeks of age. CY treatment induced B cell
      specific immunosuppression throughout the experiment confirmed by decreased
      bursal weight, intact lymphocyte mitogenetic activity stimulated by Con A and
      increased relative subpopulation of CD3-positive cells as measured by flow
      cytometry. Chickens in this experiment had Mareks disease virus exposure prior to
      three weeks of age as determined by the presence of lymphocytic infiltration and
      antibody. Virus neutralizing antibody against ALV-J was first observed at 6 weeks
      post-infection in some of the infected chickens in the PBS group. As expected,
      none of the chickens from the CY group and uninfected chickens developed virus
      neutralizing antibody. The viremic status was measured by real time RT-PCR using
      SYBR green I dye. The percentage of viremic chickens was significantly higher,
      and more chickens had high titered viremia, in the CY treated group. No
      neoplastic foci consistent with ALVJ infection were observed in any of the
      experimental chickens. The frequency and intensity of viral antigen expression
      determined by immunohistochemistry was significantly higher in tissues from CY
      treated birds than those of PBS treated chickens at 3 weeks post-infection. This
      study showed that B cell specific immunosuppression with CY treatment in chickens
      resulted in increase in viremia and viral antigen load in tissues.

PMID- 15028886
TI  - Effect of ultraviolet radiation on the hatchability and survival of eggs and
      larvae of sheep nematode.
AB  - The hatchability of sheep gastrointestinal nematode eggs exposed to ultraviolet
      (UV) radiation and the activity of the hatched larvae were examined. Hatchability
      decreased with increasing exposure to radiation. The difference in hatchability
      of eggs irradiated for 15,30 and 60 minutes were highly significant (p < 0.01
      dalpha = 3.07, 3.24 and 3.75) compared with the hatchability of the nonirradiated
      eggs. The life span of irradiated larvae was shortened, only 20% of those expose
      to UV radiation 60 minutes survive for 2 days as against 100% survival rate in
      the non-irradiated larvae. Batches of nematode larvae (L1) were irradiated with
      ultraviolet (UV) light for varying time interval to determine the influence of
      radiation on the transmission potential of the irradiated larvae. There was a
      decrease in the survival rate of the hatched free-swimming larvae that
      corresponded with the increasing radiation exposure time.

PMID- 15028887
TI  - Mutation and overexpression of p53 as a prognostic factor in canine mammary
      tumors.
AB  - We concentrated ourselves to evaluate the prognostic significance of the p53 gene
      mutations, its protein expression and MIB-1 index as a proliferative marker in
      canine mammary tumors. In the present study, a total of 20 cases were examined,
      among which there were 5 malignant mixed tumors, 4 mammary gland adenocarcinomas,
      1 papillary adenocarcinoma, 8 benign mixed tumors and 2 mammary gland adenomas.
      Positive immunostaining for p53 with PAb240 antibody was found in 2 benign (20%)
      and 3 malignant (30%) tumors. However, PAb421 antibody did not give positive
      result at all. In Western blot analysis, the p53 expression in benign and
      malignant tumors was detected in 4 and 3 cases, respectively. p53 mutations were
      found in 6 cases out of the cases with detected p53 protein expression. The MIB-1
      index in benign and malignant tumors were 17.6+/-20.8% and 29.0+/-27.2%,
      respectively and there was no significant difference between tumor types. There
      was a significant correlation between p53 mutations and p53 overexpression
      (correlation coefficient = 0.5, p < 0.05). In Kaplan-Meier survival analysis, the
      p53 index was associated with significantly shortened survival time (p < 0.01).
      In multivariate analysis, p53 overexpression was only an independent factor for
      indicator of worse prognosis in canine mammary tumors (p = 0.01). These results
      demonstrated that p53 gene mutations and protein overexpression using the PAb240
      anti-p53 antibody were useful predictors of increased malignant potential and
      poor prognosis in canine mammary tumors.

PMID- 15028888
TI  - Optimization of in situ hybridization assay using non-radioactive DNA probes for
      the detection of canine herpesvirus (CHV) in paraffin-embedded sections.
AB  - Two non-radioactive probes using digoxigenin or biotin were developed for
      detecting canine herpesvirus (CHV) and compared for their sensitivities by in
      situ hybridization (ISH) in formalin fixed, paraffin embedded sections, which has
      been used routinely in veterinary fields. Sections of the CHV-infected cell
      preparation were subjected to several different ISH protocols using digoxigenin-
      or biotin-labeled probe respectively. Results were compared for the hybridization
      and background signal intensities. The best result was obtained by the optimized
      ISH protocol using digoxigenin-labeled probe for detection of CHV DNA. The
      optimized ISH assay, which developed in this study, may be a valid tool for the
      study of pathogenesis and diagnosis of CHV infection.

PMID- 15028889
TI  - A hematogenic pleuropneumonia caused by postoperative septic thrombophlebitis in
      a Thoroughbred gelding.
AB  - A 7-year-old Thoroughbred gelding was admitted to Equine Hospital, Korea Racing
      Association for evaluation and treatment of colic. Based on the size and duration
      of the large colonic and cecal impaction, a routine ventral midline celiotomy and
      large colon enterotomy were performed to relieve the impaction. Six days
      following surgery the gelding exhibited signs of lethargy, fever, inappetence and
      diarrhea. Eleven days following surgery, the jugular veins showed a marked
      thrombophlebitis. On the sixteenth day of hospitalization the gelding died
      suddenly. Upon physical examination, the horse was febrile, tachycardic and
      tachypnoeic. Thoracic excursion appeared to be increased; however, no abnormal
      lung sounds were detected. No cough or nasal discharge was present. Hematology
      revealed neutrophilic leukocytosis. Serum biochemistry was normal but plasma
      fibrinogen increased. In necropsy, fibrinopurulent fluid was present in the
      thoracic cavity. There were firm adhesions between visceral pleura and thoracic
      wall. White, mixed and red thrombi were formed in both jugular veins from the
      insertion point of IV catheter. Histopathological examination showed
      fibrinopurulent inflammation and vascular thrombosis in the lung. The pleura
      showed edematous thickening and severe congestion. The clinicopathological and
      pathological findings suggest that septic thrombi associated with septic
      thrombophlebitis metastasized into the pulmonary circulation and were entrapped
      in the pulmonary parenchyma and provoked pleuropneumonia.

PMID- 15028890
TI  - Cholelithiasis associated with recurrent colic in a Thoroughbred mare.
AB  - A 13-year-old Thoroughbred mare, retired from race, was admitted to Equine
      Hospital, Korea Racing Association with signs of colic. One and a half months
      following the previous treatment (second time) and 11 days following her previous
      discharge (third time), the mare repeatedly exhibited signs of colic and finally
      along with icteric eyes. Routine medical treatment with intravenous fluids,
      analgesics resulted in resolution of signs of colic in the first and second
      admission. The condition of the mare did not improve in the third admission
      despite over one month supportive treatment and she was subject to euthanasia at
      the request of the owner on the thirtyeighth day of hospitalization (95 days from
      her first admission). The clinical signs (fever, icterus, mild intermittent
      colic) in conjunction with clinical laboratory findings (leukocytosis, elevations
      of serum total bilirubin, direct bilirubin, alkaline phosphatase, aspartate
      aminotransferase, gamma glutamyl transferase, creatine phosphokinase, lactic
      dehydrogenase and blood fibrinogen indicative of obstructive biliary disease) in
      this mare suggested possible chlolelithiasis. However, liver enzymes and
      bilirubin estimations are often not part of routine screening in emergency colic
      cases. At necropsy, multiple dark brown choleliths of various sizes obstructing
      hepatopancreatic ampulla were found in the hepatic duct. The choleliths were
      found as large as 3-5 cm in diameter, faceted to each other, dark brown in color
      and showed soap consistency. Histopathologic findings revealed: biliary fibrosis,
      plugging of the bile canaliculi with bile pigments, cholangiohepatitis and
      pigmentation of the hepatic lymph node with bile pigment laden macrophages.
      Although definitive diagnosis of cholelithiasis might be challenging, clinicians
      should consider this condition in the differential diagnosis of recurrent colic.

PMID- 15028891
TI  - A case of patent ductus arteriosus in a holstein calf.
AB  - This report describes a case of patent ductus arteriosus (PDA) which was found in
      a calf during an experiment on an implantable ventricular assist device. This is
      the first case report of PDA confirmed in the calf in Korea.

PMID- 15028893
TI  - Which type of observation for patients with high-risk mild head injury and
      negative computed tomography?
AB  - OBJECTIVE: Current guidelines suggest hospital admission followed by home
      monitoring for high-risk patients with mild head injury and negative computed
      tomography scan. We tested early home monitoring under the care of a competent
      observer. METHODS: A total of 1480 patients with mild head injury and negative
      computed tomography scan were prospectively studied. Based on clinical status and
      available home caretakers, patients were managed by in-hospital observation (n =
      646) or early home monitoring (n = 834). Outcome measures were: (1) the detection
      of previously undiagnosed post-traumatic intracranial injury; (2) neurosurgical
      intervention; and (3) unfavourable outcome (death, permanent vegetative state or
      severe disability). RESULTS: In the in-hospital arm, nine cases (1.4%) developed
      intracranial injuries (in three after discharge). In the early home-monitoring
      arm, six patients (0.7%) had a previously undiagnosed lesion after re-admission
      (P = 0.773 versus in-hospital arm). No patients with previously undiagnosed
      intracranial injuries had a neurosurgical intervention. After 6 months, five
      patients had died in the home monitoring arm (0.8%) versus eight (1.0%) in the in
      hospital arm (P=0.785). No permanent disability or vegetative state was observed.
      CONCLUSION: Early home monitoring may be safely proposed to selected "high-risk"
      patients, with an early negative computed tomography scan, normal clinical
      examination and feasible home monitoring.

PMID- 15028894
TI  - Out-of-hospital hypoglycaemia is safely and cost-effectively treated by
      paramedics.
AB  - OBJECTIVES: The purpose of this study was to investigate the clinical
      epidemiology of severe out-of-hospital hypoglycaemia, to evaluate the standard
      treatment protocol used, to investigate the clinical outcome during a 3-month
      follow-up period and to evaluate financial savings achieved by not transporting
      all patients to hospital. METHODS: This study was a prospective, observational
      study based on questionnaires and patient files. Two paramedic units of the
      Rescue Department filled in a study form on each hypoglycaemia patient they
      enrolled between 1 February 2001 and 31 December 2001. These patients were
      contacted by mail after 3 months and asked to fill in a questionnaire regarding
      their health. RESULTS: Sixty-nine patients were included in the study. The
      majority of the patients had diabetes mellitus for more than 5 years. The
      severity of hypoglycaemia was related to the duration of diabetes (P = 0.003) and
      insulin therapy (P = 0.021). Fifty-eight patients (84.1%) required intravenous
      glucose treatment. Sixty-two patients (89.9%) were left at the scene after
      treatment. No immediate relapses occurred. Mean patient satisfaction was 4.6 (SD
      0.8) on a scale from 1 to 5. Satisfaction was related to the duration of diabetes
      (P<0.0001) and to low haemoglobin A1c values (P<0.0001). The direct savings
      achieved by not transporting the patient to the hospital emergency department
      were estimated to be 398.5 per patient. CONCLUSION: The emergency medical
      services guideline for the treatment of hypoglycaemia and the practice of leaving
      selected patients at the scene after treatment were found to be effective, safe
      and economical. Patient satisfaction was found to be high, further supporting the
      practice of not transporting all patients to hospital.

PMID- 15028895
TI  - Effect of digital cellular phones on tachyarrhythmia analysis of automated
      external defibrillators.
AB  - OBJECTIVES: Emergency services personnel, family members, laypersons or patients
      often carry and use mobile phones on sites of emergencies. As there are reported
      effects on implanted pacemakers and cardioverter defibrillators, the influence of
      digital cellular phones on automated external defibrillators was studied.
      METHODS: Twelve automated external defibrillator models were bench tested for
      their correct decision to or not to advise a shock, while being exposed to
      electromagnetic interference from a handheld cellular phone with 2 W or a
      portable cellular phone with 8 W transmitting power. The phones were programmed
      by a special subscriber identity module card to maximum output power with a
      carrier frequency of 906.2 MHz. The tests were conducted with a burst frequency
      of 217 Hz in speech mode and 2-8 Hz in discontinuous transmitting exchange mode.
      The sensitivity and specificity of electrocardiogram analysis systems were
      tested, with shockable and non-shockable rhythms provided by an electrocardiogram
      simulator and on two human subjects with normal sinus rhythm. RESULTS: A total of
      8640 tests were recorded, each automated external defibrillator was tested a
      total of 720 times. The automated external defibrillators demonstrated a
      sensitivity of 100% and a specificity of 100%, representing a positive likelihood
      ratio of 8641 and a negative likelihood ratio of 0.000. In this setting all
      automated external defibrillators analysed correctly even under worst-case
      testing conditions, and performed excellently without any single failure. In some
      devices, voice prompts were distorted beyond comprehension, as the coil of the
      automated external defibrillator speaker received the pulsed signals. CONCLUSION:
      Shock advisory systems of automated external defibrillators are not susceptible
      to electromagnetic interference of 900 MHz cellular phones. Voice prompts,
      however, could be distorted by the operation of nearby digital mobile phones.
      During automated external defibrillator training this issue needs to be
      addressed.

PMID- 15028896
TI  - Workload and case-mix in a Greek emergency department.
AB  - The objective of the present study was to evaluate the workload and case-mix of
      the Emergency Department of a referral hospital, with the aim of determining the
      causes of overcrowding. The study was of a descriptive prospective design and was
      carried out in a 700-bed university hospital covering a population of
      approximately 200,000 inhabitants. The total number of patient visits to the
      Emergency Department and hospital admissions were recorded during one year,
      whereas the case-mix of patients visiting the department was evaluated during 11
      consecutive on-call days using a triage scale with four categories of patient
      severity. During the year of the study 81,110 patients (a mean of 443 visits per
      on-call day) visited the department, with a hospital admission rate of 14.5%. The
      case-mix analysis of 3389 patients who visited the department during the 11
      consecutive on-call days studied revealed that 5.7% were critically ill patients,
      53.8% were patients with urgent but non-critical health problems, 30% were
      patients with non-urgent problems and 10.5% were miscellaneous cases, probably
      inappropriately visiting the department. In conclusion, the Emergency Department
      studied is severely overcrowded in relation to the population that it covers. A
      great part of this overload was directly related to non-urgent cases and
      inappropriate visits.

PMID- 15028897
TI  - Hospital Accident and Emergency burden is unaffected by today's air pollution
      levels.
AB  - OBJECTIVES: Fifty years after the London smog incident, the Milan area (Italy) is
      still experiencing an air pollution emergency every winter, widely reported in
      the public media, complete with technical and political discussion, and well
      studied short-term associations between air pollution and mortality and hospital
      admissions. The influence of air pollution on the daily activity of an Accident
      and Emergency Department have rarely been investigated, other than looking at
      hospital admissions. METHODS: To assess the possible effects of high air
      pollution levels we studied 9881 residents requiring care at the hospital
      Accident and Emergency triage of Vimercate, a city north of Milan with 25 600
      inhabitants during one year. RESULTS: There was no correlation between the number
      of daily Accident and Emergency admissions and the daily mean of particulate
      matter less than 10 microm (PM), with a relative risk of 0.97 (95% confidence
      interval 0.67-1.41) for a 5th to 95th percentile variation of the PM, even after
      correcting for the day of the week, holidays and climate factors such as
      temperature and humidity. CONCLUSION: Air pollution, although still frequently
      high and relevant to the health of the population, is not easily recognizable on
      a small scale, such as a single hospital, and does not affect daily Accident and
      Emergency activities.

PMID- 15028898
TI  - Spontaneous pneumothorax outcome study (SPOT phase I): a 2-year review.
AB  - OBJECTIVE: We aim to describe the incidence of spontaneous pneumothorax
      presenting to the Emergency Department, the treatment given and the outcomes of
      treatment. METHODS: We conducted a retrospective review of patients with
      spontaneous pneumothorax presenting to the Emergency Department of the Singapore
      General Hospital from 1 January 2000 to 31 December 2001. RESULTS: Of a total of
      159 patients, with a mean age of 36.1 years (standard deviation 19.3), 94.3% were
      men, 75 (47.2%) were treated in the Emergency Department with chest-tube
      insertion, 28 (17.6%) were treated with needle aspiration, and 56 (35.2%) were
      observed. Significantly more patients had complete re-expansion with chest-tube
      (65.3%) compared with needle aspiration (17.9%) (P<0.001). Patients with needle
      aspiration or those being observed were more likely to have a second procedure
      (P<0.001), whereas patients with chest tubes were more likely to have definitive
      treatment subsequently (pleurodesis, thoracotomy). The mean duration of
      hospitalization was significantly longer for chest-tube insertion (7.4 days)
      compared with other groups (needle aspiration 4 days). There was no significant
      difference in the complication rates between treatment groups at one year.
      CONCLUSION: We found a male predominance locally. Treatment with chest-tube
      insertion is still the most popular method in the Emergency Department. Needle
      aspiration results in a shorter hospitalization, but a high proportion require a
      second procedure. Complication rates do not seem to differ from chest-tube
      insertion.

PMID- 15028899
TI  - The problems faced by three government disaster response teams of Ankara city
      during the Marmara earthquake - 1999 response.
AB  - OBJECTIVES: The objectives of this study were to determine the
      organization/system and personal problems faced by the personnel of Ankara
      greater municipality Firebrigade Department (firemen), Ankara Emergency Aid and
      Rescue Services (ambulance personnel), Civil Defence General Directorate's Ankara
      Search and Rescue Unit (rescuers), who participated in the 1999 Marmara
      earthquake. MATERIALS AND METHODS: A total of 1132 individuals were in the
      universe of the study; the total rate of participation was 95.1% (1076
      individuals). This study was a cross-sectional survey, in which self-administered
      questionnaires were used. The study was conducted in May, June and July of 2001.
      RESULTS: Overall, 33.1% of the personnel of three government disaster response
      teams (356 individuals) said that they participated in the Marmara earthquake -
      1999 response. The leading most important organization/system problem they faced
      during the Marmara earthquake was coordination (30.8%) according to the firemen,
      disaster management (31.4%) according to the rescuers, and coordination (41.6%)
      according to the ambulance personnel. The personal problems faced during the
      Marmara earthquake by the firemen were food problems (56.4%), accommodation
      problems (62.8%), safety problems (28.2%) and health problems (71.8%); according
      to the rescuers they were food problems (77.1%), accommodation problems (48.6%),
      safety problems (74.3%) and health problems (51.4%), and according to the
      ambulance personnel they were food problems (47.7%), accommodation problems
      (58.0%), safety problems (31.7%) and health problems (26.7%). CONCLUSION: Among
      the organization/system problems faced by the personnel of three government
      disaster response teams in the Marmara Earthquake of 1999, coordination problems
      were the major concern. The personnel also had some personal problems such as
      food, accommodation, safety and health.

PMID- 15028900
TI  - A complication of amiodarone infusion.
AB  - A 76-year-old man underwent an emergency laparotoray for a ruptured abdominal
      aortic ancurysm After a few days he presented ischemia of the left side of the
      colon and subsequently atrial fibrillation developed that was treated with
      Amiodarone. After an intravascular loading dose of 300 mg, he received a
      maintenance dose of 600 mg daily through a central line access. After 28 days of
      intravascular drug therapy, a chest X-ray showed a high attenuation homogeneous
      image in the right part of the mediastinum. A contrast enhanced thoracic and
      abdominal computed tomography scan showed: a high attenuation intravascular mass
      in the superior vena cava around the catheter. The catheter was substituted but
      the intravascular mass remained. The Amiodarone was then given by mouth. The mass
      spontaneously decreased its size and after three months completely disappeared
      Due to high iodine content, any deposition of Amiodarone can be detected by a
      radiological study as a high attenuation image. After reviewing all the drugs
      infused through the catheter, we did not find any other drugs that contain iodine
      or other material that could justify the chest X-ray image. We hypothesized that
      this intravascular mass was due to a deposition of the Amiodarone during the
      infusion in the central line

PMID- 15028901
TI  - Pneumomediastinum and subcutaneous emphysema after pulmonary function tests in a
      young healthy woman.

PMID- 15028902
TI  - Emergency percutaneous tracheostomy is feasable in experienced hands.
AB  - One of most stressful situations for a physician occurs when a patient is unable
      to breathe and endotracheal intubation is not possible. The establishment of an
      open airway by surgery is indicated only if the physician is unable to do so with
      an endotracheal tube. Surgical tracheostomy is not indicated in emergency
      situations because it takes a long time and can result in death if respiratory
      support cannot be provided during the procedure. Percutaneous dilatational
      tracheostomy in experienced hands takes only a few minutes. We describe six
      patients, including two trauma patients, in whom emergency percutaneous
      tracheostomy was rapidly and successfully performed under conditions of the
      imminent loss of airway and inability to intubate the patient. As this procedure
      is safe and can be performed easily by experienced personnel, we propose its
      addition to the armamentarium of emergency airway management.

PMID- 15028904
TI  - "Glass in a scalp laceration": an unusual case of penetrating head injury
      presenting to the emergency department.
AB  - A case of penetrating head injury caused by glass is reported. Rarely does this
      material cause such an injury. Other reports of this unusual type of head injury
      are reviewed. The potential for misdiagnosis, the correct management and possible
      complications of this type of injury are discussed.

PMID- 15028903
TI  - Isolated volar dislocation of distal radioulnar joint: how easy to miss!
AB  - Volar dislocation of the distal radioulnar joint without concomitant fracture of
      the radius or ulna is a very rare but a commonly missed injury in emergency
      situations. If left untreated, this injury can lead to significant functional
      disability. We report a case of a young man who sustained an acute, isolated,
      volar dislocation of the distal radioulnar joint, and highlight the important
      clinical and radiological features, which can help in diagnosing the condition in
      the Accident and Emergency Department where the patients with such injuries
      present first.

PMID- 15028905
TI  - Anticholinergic toxicity associated with lupin seed ingestion: case report.
AB  - We describe a case of acute poisoning in a 51-year-old female patient who
      presented to the Emergency Department with weakness, anxiety, dry mouth,
      bilateral mydriasis and lid drop. In differential diagnosis, botulism, Guillain
      Barre syndrome and myasthenia gravis were considered, as well as cerebral
      haematoma because of a cranial injury a week before. Symptoms, which resolved
      within 12 h without any therapy, were instead related to the ingestion of lupin
      seeds.

PMID- 15028911
TI  - Should L&D staff nurses perform amniotomies? Pro.

PMID- 15028912
TI  - Should L&D staff nurses perform amniotomies? Con.

PMID- 15028913
TI  - Cueing into infant pain.
AB  - Unfortunately the history of pain management in infant care has included decades
      of inadequate analgesia for a wide range of medical procedures, including major
      surgery. This was justified in part on fear of drug and analgesic risks to the
      infant, as well as the commonly held belief that infants do not respond to, or
      remember, painful experiences. Today we understand that infant pain is encoded
      into observable manifestations through which an infant communicates behavioral
      and physiological changes such as altered vital signs, characteristic cries, and
      facial expressions. The purposes of this article are to (1) describe infants'
      physiological and behavioral responses to pain and its adverse effects, (2)
      review pharmacologic and nonpharmacologic infant pain management modalities and
      reliable pain assessment tools for use in clinical practice, and (3) educate
      healthcare professionals about the importance of assessment and management of
      infant pain.

PMID- 15028915
TI  - Paraprofessional support for pregnant & parenting women.
AB  - PURPOSE: To review evidence regarding the role of paraprofessional support in
      improving maternal and infant outcomes in pregnant and parenting women. Although
      support provided by significant others (social support), by professionals, and by
      paraprofessionals are frequently considered together in literature reviews, this
      is inappropriate because the components of the support in each case differ. DATA
      SOURCES: Data were limited to published studies. Searches of computerized
      databases (CINAHL, Medline, PsychLit, Social sciences abstracts, Social sciences
      citation, and Social work abstracts), hand searches of journals, and backward
      searches from reference lists of studies were conducted. Nursing, medicine,
      psychology, public health, sociology, and social work literatures were searched.
      STUDY SELECTION: The studies included had statistically significant outcomes of
      paraprofessional support to pregnant and parenting women. Studies were published
      in 1985 or later, were conducted in the United States or Canada, and included
      maternal and/or infant outcomes. DATA EXTRACTION: Data were extracted from each
      study concerning the theoretical framework, design, sample, measuring
      instruments, interventions, and outcomes. CONCLUSIONS: Programs providing
      paraprofessional support to childbearing women are clearly providing an important
      service, but empirical evidence is not adequate to determine which specific
      paraprofessional program works for a specific population of women to achieve the
      best long-term outcomes for both women and children. Although proponents of
      paraprofessional support programs for pregnant and parenting women have reported
      some successes, more data are needed. Researchers should continue to conduct well
      designed and controlled studies to compare outcomes from the three types of
      support. Nurses in practice should build on services provided by
      paraprofessionals in order to meet women's need for support and to achieve
      desired outcomes.

PMID- 15028918
TI  - Home- versus hospital-laundered scrubs: a pilot study.
AB  - PURPOSE: To determine the presence of pathogens on scrub attire that had been
      either laundered at home or in the hospital. STUDY DESIGN AND METHODS: Quasi
      experimental research design with a convenience sample. The left front shoulders
      of home-laundered scrubs (n = 30) and hospital-laundered scrubs (n = 20) were
      cultured during the first 2 hours of a single workday. For the home-laundered
      scrubs, data were collected concerning home washing procedures, water
      temperature, pets in the home, and donning procedures. RESULTS: No pathogenic
      growth was found on either the hospital- or home-laundered scrubs. In addition,
      no relationships were found between home washing procedures, water temperature,
      pets in the home, and donning procedures. CLINICAL IMPLICATIONS: The results of
      this pilot study suggested that scrubs laundered both at home and in the hospital
      were free of pathogens, and that differing home washing procedures made no
      difference. Further investigation is necessary with larger numbers of subjects.

PMID- 15028917
TI  - Culture & risk taking in adolescents' behaviors.
AB  - Adolescents constitute the only segment of the population in the United States
      that has not seen a decrease in its mortality and morbidity over the last 4
      decades. The Centers for Disease Control and Prevention has identified six risk
      taking behaviors that place adolescents at risk: unintentional injuries and
      violence, tobacco use, alcohol and other drug use, sexual behaviors, unhealthy
      dietary behaviors, and physical inactivity. This list is of particular concern
      for the increasingly diverse racial and ethnic youth of America who have been
      disproportionately affected by both morbidity and mortality from risk behaviors.
      To effectively care for this segment of the population, healthcare professionals
      need to become culturally competent. In so doing, it is also important to
      recognize traditional cultural values, and to acknowledge personal attributes of
      adolescents to promote healthy lifestyle choices and deter risk-taking behaviors.

PMID- 15028919
TI  - Factors influencing pregnant women's perceptions of risk.
AB  - PURPOSE: To explore factors women consider in determining their perceptions of
      pregnancy risk, and to compare and contrast factors considered by women with
      complicated and uncomplicated pregnancies. STUDY DESIGN AND METHODS: Descriptive
      qualitative study in which women described factors they considered in making
      personal risk assessments. Of the 205 women in the study, half (n = 103) had
      pregnancy complications, while the other half (n = 102) had no known
      complications. Written responses to three open-ended questions were used to
      determine factors women considered in assessing their risks. A qualitative
      content analysis approach was used to interpret the data. RESULTS: Four major
      themes emerged that influenced perception of risk for both groups: self image,
      history, healthcare, and "the unknown." Women with complications voiced greater
      risk perceptions and identified specific risks, while women with no complications
      mentioned potential risks that were diffuse and hypothetical.

PMID- 15028920
TI  - Intimate violence in adolescent relationships: recognizing and intervening.
AB  - Women in the United States are more likely to be assaulted, injured, raped, or
      killed by an intimate partner or ex-partner than by any other perpetrator.
      Adolescents who are exposed to violence in their family of origin are at risk for
      violence in their own future relationships. This article provides an overview of
      the subject of intimate violence in adolescent relationships. The author suggests
      that it is critical for providers to advocate for patients by routinely inquiring
      about intimate violence at each healthcare visit and assisting the patient to
      resolution.

PMID- 15028921
TI  - Supporting psychosocial adaptation for the pregnant adolescent in corrections.
AB  - This article addresses an aspect of adolescent healthcare that is often
      forgotten: pregnancy in correctional detention. Young women in corrections face
      unique problems socially, personally, and with their healthcare. Stress,
      environmental and legal restrictions, unhealthy lifestyle behaviors prior to
      pregnancy, and weakened or nonexistent social support systems are common among
      pregnant adolescents who are incarcerated. Nurses who strive to deliver perinatal
      care consistent with a feminist-based, gender-sensitive framework, in which
      pregnancy is considered a health state and rights to self-determination are
      preserved, are challenged when caring for girls in correctional settings.
      Assumptions about health and freedom of choice do not always apply to minors who
      are detained in correctional settings. Ensuring safety for pregnant adolescents
      within a correctional setting requires attention to issues of security and to
      issues of timely access to healthcare. There must be a balance between
      restricting movements because of security concerns and expanding movement
      privileges necessary to support essential healthcare and other support services.
      Nurses who care for adolescents in any setting should understand more about the
      multiplicity of issues surrounding healthcare and pregnancy for these
      adolescents, for these young women will interact with the healthcare system again
      in the future.

PMID- 15028922
TI  - Infant nutrition--starting right.

PMID- 15028923
TI  - Back safety for MCH nurses.

PMID- 15028924
TI  - Cobedding twins.

PMID- 15028925
TI  - Men in obstetrical nursing.

PMID- 15028926
TI  - Analgesia for circumcision.

PMID- 15028928
TI  - Ethics of fetal monitoring.

PMID- 15028930
TI  - Management of oxytocin for labor induction and augmentation.

PMID- 15028931
TI  - HIV superinfection in the era of increased sexual risk-taking.
AB  - Recent reports have documented increases in unprotected intercourse (UI) and
      sexually transmitted diseases (STDs) among men who have sex with men (MSM) and
      other at-risk populations. A further consequence of persons living with HIV
      engaging in unprotected intercourse or shared parenteral exposures with
      seroconcordant partners is HIV recombination and superinfection, possibly with a
      drug-resistant or more pathogenic virus. The epidemiologic, clinical, and
      therapeutic implications of recent case reports confirming superinfection in
      persons living with HIV, as well as research priorities aimed at providing a more
      thorough understanding of the consequences of unprotected sex among HIV-infected
      people, are explored here.

PMID- 15028932
TI  - Associations between sexually transmitted disease diagnosis and subsequent sexual
      risk and sexually transmitted disease incidence among adolescents.
AB  - BACKGROUND: Empiric evidence is lacking in regard to the subsequent sexually
      transmitted disease (STD)-associated risk behaviors of adolescents diagnosed and
      treated for an STD. GOAL: The goal of this study was to prospectively identify
      associations between STD diagnosis and subsequent sexual risk and STD incidence
      among a sample of U.S. adolescents. STUDY DESIGN: A cohort of 455 adolescents
      (age 15-21 years) was followed for 3 months. Adolescents were recruited from
      primary care clinics and through outreach activities. RESULTS: A total of 10.8%
      were initially diagnosed with at least one STD. After adjusting for observed
      covariates, these adolescents (compared with those testing negative) were 2.8
      times (P = 0.0001) more likely to be abstinent from sex and 2.2 times more likely
      to report always using condoms (P = 0.04). However, during the ensuing 3 months,
      they were approximately 2.4 times more likely to report having sex with multiple
      partners (P = 0.01), 8.9 times more likely to test positive for trichomonas (P =
      0.009), and 3.0 times more likely to test positive for chlamydia (P = 0.04).
      CONCLUSIONS: Compared with those testing negative, adolescents diagnosed with an
      STD may subsequently adopt safer sex behaviors, including abstinence. However,
      perhaps in part as a result of having sex with multiple partners, they might fail
      to practice safer sex behaviors stringently enough to avoid subsequent STD
      acquisition.

PMID- 15028933
TI  - Gonorrhoea surveillance system in France: 1986-2000.
AB  - OBJECTIVE: The objectives of this study were to monitor epidemiologic trends in
      Neisseria gonorrhoeae (NG) infections and to assess antimicrobial resistance
      patterns of NG. METHODS: RENAGO, a voluntary-based laboratory surveillance
      system, including private and public laboratories, was set up in France in 1986.
      Every NG strain isolated by the participating laboratories was sent to the
      National Reference Center, Institut Alfred Fournier, Paris, where susceptibility
      to 6 antibiotics was tested. These laboratories reported monthly numbers of
      positive NG isolates and associated epidemiologic data. Because the number of
      laboratories varied every year, the average number of NG isolates per laboratory
      per year was computed to monitor annual trends in gonorrhea incidence. RESULTS:
      The average number of NG isolated per laboratory per year decreased steadily from
      10.6 in 1986 to 0.6 in 1997 but then yearly increased and reached 1.9 in 2000.
      Increasing gonorrhea was observed mostly in men and in the Paris area. The
      proportion of rectal strains increased significantly from 0.9% in 1986 to 9.2% in
      2000. From 1998 to 2000, 5.3% of the isolates had reduced susceptibility or were
      resistant to ciprofloxacin, 7.3% were PPNG strains and 27.4% were resistant to
      tetracycline, 18.5% had a reduced susceptibility to thiamphenicol, and 1 strain
      was resistant to the latter. Neither strain was resistant to ceftriaxone or to
      spectinomycin. CONCLUSION: From 1998 to 2000, gonorrhea markedly increased in
      France and seemed to affect mainly gay men in Paris, which suggests relapses to
      risky sexual behaviors and highlights the need for strengthening prevention.
      During the same period, NG ciprofloxacin resistance has sharply increased and
      should be carefully monitored because of the wide use of ciprofloxacin single
      dose treatment.

PMID- 15028934
TI  - Gonorrhea surveillance: estimating epidemiologic and clinical characteristics of
      reported cases using a sample survey methodology.
AB  - BACKGROUND: Little is known about the epidemiology of gonorrhea in the United
      States, except for basic demographics of reported cases. Knowing the proportion
      of reported gonorrhea cases identified through screening, the diagnostic test
      used, and patient behavioral risk factors might help to better explain changes in
      gonorrhea rates over time. GOAL: The goal of this study was to implement and
      evaluate a gonorrhea sample survey surveillance methodology in San Diego,
      California. STUDY DESIGN: Healthcare providers caring for a representative sample
      of all gonorrhea patients reported during August 16 through October 18, 2001 were
      interviewed by telephone about patient demographics, risk factors, and
      management. RESULTS: The healthcare providers of 248 gonorrhea patients were
      contacted; data were obtained on 224 (90%) patients. Major reasons for testing
      included symptoms (68%), partner referral (14%), and screening (12%). Gonococcal
      culture, DNA probe tests, and nucleic acid amplification tests were used to
      diagnose 40%, 34%, and 21% of patients, respectively. At minimum, 36% of male
      gonorrhea patients were men who have sex with men (MSM); MSM with gonorrhea were
      rarely diagnosed with rectal or pharyngeal gonorrhea outside of sexually
      transmitted disease (STD) clinics. Estimated local resources required to conduct
      this survey were $12 per completed interview. CONCLUSION: Healthcare provider
      telephone interviews regarding recently reported gonorrhea patients are feasible
      and can provide important additional information to STD programs, which could be
      used to direct intervention strategies and monitor trends. Ultimately, a national
      sampling approach could be explored and incorporated into ongoing gonorrhea
      surveillance.

PMID- 15028935
TI  - Immunophenotypes, apoptosis, and expression of Fas and Bcl-2 from peripheral
      blood lymphocytes in patients with secondary early syphilis.
AB  - OBJECTIVES: Whether syphilis influences lymphocyte apoptosis has not been
      reported so far. GOAL: The goals of this study were to determine whether syphilis
      influences lymphocyte apoptosis and to investigate the molecular mechanism of
      apoptosis. STUDY DESIGN: Peripheral blood lymphocyte (PBL) immunophenotypes,
      apoptosis, and expression of Fas (CD95) and Bcl-2 were detected by flow cytometry
      in 33 patients with secondary early syphilis and 30 healthy subjects. RESULTS:
      Compared with the control subjects, the percentage of CD4 T cells and the ratio
      of CD4:CD8 were significantly decreased, and that of CD8 T cells and the
      apoptotic rates of PBLs and CD4 T cells were obviously increased in syphilitic
      patients. Fas overexpression and Bcl-2 downexpression in the syphilitic group
      were observed in PBLs and CD4 cells but not in CD8 and CD19 cells. CONCLUSIONS:
      The increased apoptosis of PBLs and CD4 T cells by Fas-mediated death pathway and
      downexpression of Bcl-2 protein could account for immune dysfunction in secondary
      early syphilis, which is responsible for the incomplete clearance of Treponema
      pallidum from the lesions and the chronic infection.

PMID- 15028936
TI  - Risk-taking and health-seeking behavior in men with a history of urethritis: is
      there a learning curve?
AB  - BACKGROUND AND OBJECTIVES: Studies addressing how past experience with sexually
      transmitted diseases (STD) influence health-seeking behaviors among at-risk men
      are few. GOAL: The goal of this study was to determine whether health-seeking
      behaviors among men diagnosed with urethritis differ based on whether they report
      prior urethritis. STUDY DESIGN: Male STD clinic attendees answered a
      questionnaire regarding their demographic, sexual, and health-seeking
      characteristics. The men were stratified based on whether they reported prior
      urethritis. RESULTS: Of 466 men, 297 reported prior urethritis. Symptomatic men
      diagnosed with urethritis who reported prior urethritis did not recognize their
      symptoms as a possible STD earlier than those reporting no urethritis history;
      there was also no difference between the groups in their interval to presenting
      for care once symptoms were recognized as a possible STD. Furthermore, men with
      prior urethritis were as likely to engage in sex acts once they recognized their
      symptoms as a possible STD manifestation. CONCLUSION: Compared with men without
      prior urethritis, men with urethritis symptoms who reported prior urethritis did
      not recognize symptoms earlier, alter health-seeking behavior, or curtail sexual
      activity.

PMID- 15028937
TI  - The evaluation of the local tolerance of vaginal formulations, with or without
      nonoxynol-9, using the slug mucosal irritation test.
AB  - BACKGROUND: Frequent use of some vaginal formulations can induce mucosal
      irritation. Therefore, it is important to evaluate their vaginal tolerance. GOAL:
      The goal of this study was to optimize the mucosal irritation test using slugs
      for the evaluation of the local tolerance of vaginal gels and investigate the
      relevance of the test. STUDY DESIGN: The irritation potential of the gels was
      assessed by the amount of mucus produced during a repeated 30-minute contact
      period. Membrane damage was estimated from the release of proteins and enzymes.
      After optimization of the procedure, the local tolerance of several vaginal gels
      was evaluated. RESULTS: Hydroxyethyl cellulose gel induced no irritation, because
      the mucus production and the protein release were low and no enzyme release was
      detected. Replens and K-Y jelly resulted in an increased mucus production;
      however, no increased protein and no enzyme release were detected. The nonoxynol
      9-containing gels Protectaid, Advantage S, and Conceptrol caused a higher mucus
      production and an increased protein release and/or enzyme release, indicating
      severe irritation. CONCLUSION: The mucosal irritation test using slugs can be
      used for local tolerance testing of vaginal formulations.

PMID- 15028938
TI  - A randomized, double-blind clinical trial of vaginal acidification versus placebo
      for the treatment of symptomatic bacterial vaginosis.
AB  - BACKGROUND AND OBJECTIVES: Vaginal acidification has been suggested as a means of
      normalizing the vaginal flora. GOAL: The purpose of this study was to determine
      the effectiveness of an acetic acid-based vaginal gel in the treatment of
      bacterial vaginosis (BV). STUDY DESIGN: Forty-four patients with BV were enrolled
      in a randomized, double-blind clinic trial. Of these, 29 were evaluable. Patients
      were randomized to receive either 5 mL acetic acid gel (n = 14) or placebo gel (n
      = 15) intravaginally twice daily for 7 days. Clinical criteria and vaginal Gram
      stain scores were compared between the initial visit and at 2 weeks after
      initiating therapy. RESULTS: No significant differences were noted when comparing
      drug and placebo in terms of subjective or clinical improvement or improvement in
      Gram stain smears for bacterial vaginosis. CONCLUSION: Vaginal acidification with
      an acetic acid gel formulated to pH 3.9 to 4.1 was ineffective therapy for
      bacterial vaginosis.

PMID- 15028939
TI  - Comparison of sex partner meeting venues and residences of syphilis cases in
      Baltimore.
AB  - BACKGROUND: Traditional syphilis control tools could be limited in high-risk
      groups in which the disease is concentrated. Novel programmatic methods such as
      tracking and targeting sex partner meeting venues could be valuable. GOAL: The
      goals of this study were to determine if syphilis cases' sex partner meeting
      venues are geographically different than their residences and to determine the
      characteristics of identified meeting places. RESULTS: For cases diagnosed from
      September 2001 to December 2002 with geocodable data, only 9% of meetings took
      place in the same census block group as residence, and mean and median distance
      from residence to meeting place was 1.73 and 1.03 miles. The most common meeting
      location type overall was a street or corner, but differed by risk behaviors.
      CONCLUSION: Baltimore syphilis cases in general met sex partners outside their
      immediate neighborhoods. Meeting locations could provide new targets for syphilis
      control interventions.

PMID- 15028940
TI  - New estimates of herpes simplex virus type 2 seroprevalence in England: 'high'
      but stable seroprevalence over the last decade.
AB  - OBJECTIVES: There have been few recent population-based herpes simplex virus type
      2 (HSV-2) seroprevalence studies in England, but reports from the United States
      have indicated a 30% rise in HSV-2 seroprevalence between 1976 and 1994. This
      study aimed to ascertain trends in HSV-2 infection in England between 1991 and
      2000. STUDY DESIGN: Anonymized serum residues collected through public health
      laboratories across England from individuals aged 16 to 64 years seeking health
      care through the National Health Service in 1991 (n = 2259) and 2000 (n = 3646)
      were tested for anti-HSV-2 IgG using the HerpeSelect 2 enzyme-linked
      immunosorbent assay IgG (Focus). RESULTS: In 9 sites across England, the age- and
      sex-standardized HSV-2 seroprevalence was 9.7% (95% confidence interval, 8.4
      11.0%). Data from 4 sites common to both study years indicated no change in HSV-2
      seroprevalence between 1991 and 2000. CONCLUSIONS: After adjustment for age, sex,
      and geographic location, there was no evidence of a change in seroprevalence
      between 1991 and 2000.

PMID- 15028941
TI  - Gender differences in sexual biomarkers and behaviors associated with human
      papillomavirus-16, -18, and -33 seroprevalence.
AB  - BACKGROUND: The elevated risk for incident head and neck cancer among human
      papillomavirus (HPV)-16-seropositive individuals has substantiated a role for HPV
      in the etiology of head and neck cancers. The relationship between HPV
      seroreactivity and prevalent oral HPV infection in men and women without cancer
      has yet to be investigated. GOAL: The goal of this study was to evaluate a
      possible association between oral HPV infection and HPV seroreactivity after
      adjustment for gender, sexual behaviors, and sexually transmitted disease. STUDY
      DESIGN: A cross-sectional study of factors associated with HPV-16, -18, and -33
      seroreactivity was performed in a population of 586 men and women with and
      without HIV infection. Antibodies in sera were measured by use of a virus-like
      protein (VLP)-based enzyme-linked immunosorbent assay. Exfoliated cells from the
      tonsillar and oral mucosa were analyzed for the presence of 38 mucosal HPV types
      by polymerase chain reaction. RESULTS: Women had significantly greater
      seroreactivity for all HPV types investigated when compared with men (odds ratio,
      4.3; 95% confidence interval, 3.0-6.0). Seroprevalence was greatest in men and
      women aged 35 to 45 years. Tonsillar HPV infection, oral sex with men, and HIV
      infection were independently associated with HPV seroreactivity in men after
      adjustment for age and number of sexual partners. In women, HSV-2 seropositivity
      and a history of sexually transmitted diseases were similarly important. Oral and
      tonsillar HPV infection were not associated with HPV seroreactivity in women.
      CONCLUSION: HPV seropositivity is associated with sexually transmitted diseases
      among women and possibly mucosal HPV exposures in men. Tonsillar HPV infection
      could impact seroprevalence, particularly in men.

PMID- 15028942
TI  - PDX-1 and the pancreas.
AB  - Many transcription factors are critical for ensuring proper embryonic development
      of the endocrine pancreas and normal islet function. The transcription factor
      pancreatic duodenal homeobox 1 (PDX-1) is uniformly expressed in early pancreatic
      buds of embryos as well as the beta and delta cells of the islets of Langerhans.
      PDX-1 has also been found in dispersed endocrine cells of the duodenum in adults
      and plays a key role in pancreas formation. It has been reported that null
      mutation of PDX-1 in mice results in a failure of the pancreatic bud to expand;
      thus, the mice die 2-3 days after birth from hyperglycemia and dehydration.
      Heterozygous PDX-1 mice developed a pancreas but were diabetic. It has been shown
      that PDX-1 is required for maintaining the pancreatic islet functions by
      activating gene transcriptions including insulin, somatostatin (SST), islet
      amyloid polypeptide, glucose transporter type 2, and glucokinase. PDX-1 serves a
      dual role in pancreatic development. It initially contributes to pancreatic
      formation during embryogenesis and subsequently regulates the pancreatic islet
      cell physiology in mature islet cells. Understanding the underlying molecular
      mechanisms of pancreas formation, especially the function of PDX-1, may
      contribute to the enhanced treatment and prevention of debilitating diseases such
      as diabetes, insulinomas, and pancreatic carcinomas.

PMID- 15028943
TI  - Expression of the intermediate filament vimentin in proliferating duct cells as a
      marker of pancreatic precursor cells.
AB  - OBJECTIVES: The expression of the intermediate filament (IF) vimentin, usually
      considered a marker of mesenchymal cells, has been observed in the epithelial
      cells during embryogenesis, carcinogenesis, and dedifferentiation, suggesting
      that it might be useful as a marker of proliferating precursor cells in the
      pancreas. METHODS: Rat pancreata at E18 and at different time points after
      partial pancreatectomy (Px) and human and neonatal pig pancreatic tissue sections
      and monolayer cultured pancreatic duct cells were observed. All tissues were
      simultaneously immunostained with pancytokeratin and vimentin antibodies. In
      costained duct cells, PDX-1 or PCNA expression was also analyzed using confocal
      microscope images. RESULTS: In the rat embryonic pancreas at E18, all epithelial
      cells that formed ductlike structures expressed both cytokeratin and vimentin IF,
      whereas no duct cells costained for IF in the adult rat or neonatal pig pancreas.
      Such costaining reappeared in the following order: common pancreatic duct, main
      ducts, foci of regeneration and then disappeared completely at 30 days after Px.
      In humans, costaining was found in only 1 diabetic patient's pancreatic section,
      which was accompanied by massive duct cell proliferation. In monolayer culture,
      most of the duct cells of human and neonatal pigs coexpressed both IF proteins.
      Only a few costained duct cells also expressed PDX-1, and most of those cells
      were also stained with PCNA in rat embryonic pancreas and regenerating foci after
      partial Px. CONCLUSIONS: Vimentin IF expression might be a useful marker for
      pancreatic precursor cells and could be used to investigate the concept of the
      dedifferentiation of fully matured duct cells during the process of the beta-cell
      neogenesis.

PMID- 15028944
TI  - Effects of angiotensin II on rat pancreatic stellate cells.
AB  - The aim of the study was to identify pancreatic stellate cells (PSCs) as a
      potential target of angiotensin II (ATII) action because recently a local renin
      angiotensin system (RAS) has been described in the pancreas. PSCs were isolated
      from male Wistar rats and investigated for ATII receptor expression and ATII
      induced calcium transients, contractions, proliferation, and alpha-smooth muscle
      actin expression. Quiescent and activated PSCs expressed the ATII receptor
      subtype AT1 but not AT2. Addition of ATII led to a rapid elevation of
      intracellular calcium ([Ca]i). The sensitivity toward ATII with respect to
      calcium transients did not change during the transdifferentiation process. In
      activated PSCs, ATII dose dependently induced PSC cell contraction. Furthermore,
      ATII induced an activation of the c-Jun-N-terminal kinase (JNK) and extracellular
      regulated kinase (Erk), which was inhibited after intracellular calcium chelation
      by BAPTA-AM. The p38 mitogen-activated protein kinase (p38) was also activated by
      ATII. BAPTA-AM itself induced p38 activation, which was not further enhanced by
      ATII. ATII stimulated PSC proliferation, while PSC transdifferentiation, as
      indicated by alpha-smooth muscle actin expression and collagen type I secretion,
      was not enhanced. The data suggest that PSCs are targets of ATII action with
      potential pathophysiological relevance.

PMID- 15028945
TI  - Effect of GLP-1 (glucagon-like peptide 1:7-36 amide) on porcine pancreatic
      endocrine cell proliferation and insulin secretion.
AB  - INTRODUCTION: We have established a method of isolation and primary monolayer
      culture of porcine pancreatic endocrine (PE) cells using nicotinamide. Recently,
      several insulin-stimulating factors have been recognized as modifying the
      function of endocrine cells. Glucagon-like peptide 1 (GLP-1), derived from
      intestinal cells, is one of the substances that may regulate insulin secretion
      and cell proliferation. AIM: The aim of the current study was to examine the
      effect of GLP-1 on PE cell proliferation and insulin secretion in our culture
      system. METHODOLOGY: The PE cells were prepared by nonenzymatic digestion and
      cultured in media with or without 10 nmol/L GLP-1 and maintained for 15 days.
      Basal insulin secretion and the glucose stimulated-response were observed by
      enzyme assay. PE-cell proliferation was assessed using 5-bromo 2' deoxyuridine
      (BrdU). beta-Cell specificity was confirmed by double staining with anti-BrdU and
      insulin antibody. mRNA expression in PE cells for insulin and pancreatic and
      duodenal homeobox gene 1 (PDX-1), a transcription factor, was semiquantitated by
      a real-time PCR method. RESULTS: Neither baseline nor glucose-stimulated insulin
      secretion differed significantly with or without the addition of 10 nmol/L GLP-1.
      However, significant changes of insulin secretion were observed in doses up to
      100 nmol/L of GLP-1. BrdU incorporation increased with 10 nmol/L GLP-1 from
      2.35+/- 0.16% to 9.11+/- 0.53% as compared with the control (from 2.17 +/- 0.57%
      to 6.13 +/- 0.35%). This increase was observed after a 12-day culture period.
      Double staining identified well-preserved insulin-containing cells, but neither
      the number of positive cells nor staining intensity differed significantly
      between the 2 groups during the 15-day culture period. The level of mRNA
      expression for both insulin and PDX-1 increased slightly but significantly.
      CONCLUSIONS: GLP-1 has a proliferative effect on PE cells and affects gene
      expression in short-term culture.

PMID- 15028946
TI  - Amelioration of hyperglycemia in streptozotocin-induced diabetic mice with fetal
      pancreatic allografts: prevention of rejection by donor specific transfusion in
      conjunction with CTLA4Ig.
AB  - INTRODUCTION: Fetal pancreas has been considered as an alternative donor source
      for islet transplantation since it has potent capacity for beta cell
      differentiation and proliferation. However, prevention of fetal pancreatic
      allograft rejection can be hardly achieved compared with adult islet allografts.
      AIMS: The aim of the study is to determine whether donor specific transfusion
      (DST) in conjunction with CTLA4Ig has any favorable effect on prevention of fetal
      pancreatic allograft rejection in mice. METHODS: BALB/c splenocytes (SPC, 1 x 10)
      were injected iv into C57BL/6 mice in conjunction with CTLA4Ig (ip, 50 microgram,
      day 0, 2, and 4). Fourteen days later, the mice were made diabetic with
      streptozotocin (STZ, iv) and donor specific or third party pancreatic allografts
      were transplanted beneath the kidney capsule. RESULTS: Morphologically, it was
      found that rejection of fetal pancreatic allografts can be prevented at 30 days
      after transplantation only when donor specific allografts were grafted into the
      mice treated with DST in conjunction with CTLA4Ig. Functionally, 3 out of 9
      diabetic mice became normoglycemic by 120 days after transplantation of fetal
      pancreatic allografts. CONCLUSION: DST in conjunction with CTLA4Ig can have a
      favorable effect on prevention of fetal pancreatic allograft rejection resulting
      in amelioration of STZ-induced diabetes in mice.

PMID- 15028948
TI  - Onset symptoms and tumor locations as prognostic factors of pancreatic cancer.
AB  - OBJECTIVES: The prognosis of pancreatic carcinoma is generally very poor and
      difficult to predict. The aim of this study was to quantitate prognosis with the
      onset symptoms. METHODS: Survival curves and clinicopathological findings of 209
      patients with pancreatic cancer admitted to our hospital between 1992 and 1998
      were retrospectively analyzed with reference to their onset symptoms (eg,
      abdominal pain, back pain, jaundice, general fatigue, nausea) and tumor location
      (eg, head, body, tail). The interval from the onset symptoms to the patient's
      first medical treatment and laboratory data of the patients were also reviewed.
      Univariate and multivariate analyses were performed using Cox proportional
      hazards regression model. RESULTS: The patients who had initially had jaundice
      had a significantly shorter interval between onset symptoms and first medical
      treatment and a significantly better prognosis than other patients. The patients
      who initially had back pain had a significantly poorer rate survival rate. Onset
      symptoms had a significant correlation with tumor location, which is a
      significant prognostic factor, but remained a significant prognostic factor with
      multivariate analysis. CONCLUSIONS: The onset symptom of patients with pancreatic
      carcinoma closely correlates with prognosis.

PMID- 15028947
TI  - Activation and role of MAP kinases in 15d-PGJ2-induced apoptosis in the human
      pancreatic cancer cell line MIA PaCa-2.
AB  - AIM: We have previously reported that 15-deoxy-delta-prostaglandin J2 (15d-PGJ2),
      a potent ligand for peroxisome proliferator-activated receptor gamma (PPARgamma),
      induces caspase-mediated apoptosis in human pancreatic cancer cell lines. Mitogen
      activated protein kinases (MAPKs) are known to regulate apoptosis in various
      cancers. The purpose of this study was to investigate the role of MAPKs (ERK,
      JNK, and p38) in 15d-PGJ2-induced pancreatic cancer cell apoptosis. METHODOLOGY:
      The effect of 15d-PGJ2 on MAPK activity was investigated by kinase assays using
      the human pancreatic cancer cell line MIA PaCa-2. Western blot analysis was
      performed to analyze phosphorylation of MAPKs, activation of caspases and poly
      ADP-ribose polymerase (PARP) cleavage. Apoptosis was evaluated by caspase-3
      enzymatic activity and DNA fragmentation assay. RESULTS: 15d-PGJ2 activated all 3
      MAPKs in a dose- and time-dependent fashion. SB202190, an inhibitor of p38,
      prevented 15d-PGJ2-induced activation of caspase-8, -9, and -3 and significantly
      decreased apoptosis. This effect was potentiated by SP600125, an inhibitor of
      JNK, although SP600125 alone had no significant effect on 15d-PGJ2-induced
      apoptosis. In contrast, PD98059, an inhibitor of MEK, significantly increased
      sensitivity to 15d-PGJ2-induced apoptosis. CONCLUSIONS: 15d-PGJ2 stimulates
      proapoptotic and antiapoptotic MAPK pathways. Sensitivity to 15d-PGJ2-induced
      apoptosis is increased by ERK inhibition but decreased by inhibition of p38.

PMID- 15028949
TI  - ANP preconditioning does not increase protection against experimental
      pancreatitis, observed after general anesthesia and jugular vein catheterization.
AB  - It has been widely shown that preconditioning, inducing heat shock proteins, can
      protect against experimentally induced pancreatitis. Solid evidence indicates
      that HSP70 plays a central role in this context, possibly by inhibition of
      premature intracellular trypsinogen activation. Current preconditioning protocols
      such as whole body hyperthermia are, however, quite strenuous and clinically not
      applicable. There is little data on other means to induce pancreatic HSPs such as
      pharmacologic pretreatment.However, in models of ischemic liver reperfusion
      injury, it has been demonstrated that atrial natriuretic peptide (ANP) can be
      used for such pharmacologic preconditioning. Evidence indicates that ANP exerts
      its protective effects via increased cGMP levels, activation of heat shock
      transcription factor (HSF) and, increased protein levels of HSP70. Pancreatic
      acinar cells express ANP receptors and respond to ANP treatment with increased
      cGMP levels. We have, therefore, investigated whether intravenous ANP
      pretreatment could be used to protect the pancreas against experimental
      pancreatitis. When given 20 minutes prior to pancreatitis induction, ANP
      pretreatment had no effect on cerulein-induced pancreatitis. In contrast, 24
      hours after preconditioning, induction of HSP70 protein expression and protection
      against experimental pancreatitis were found. However, controls treated with NaCl
      without ANP showed a similar response. This indicates that stress caused by
      general anesthesia and jugular vein catheterization can be sufficient for
      preconditioning while ANP, in contrast to models of ischemic liver reperfusion
      injury, does not confer additional protection.

PMID- 15028950
TI  - Comparative analysis of extracellular matrix proteins in chronic pancreatitis:
      differences between pancreatic head and tail.
AB  - OBJECTIVES: In patients with chronic pancreatitis (cP) with an inflammatory mass
      in the pancreatic head, the degree of fibrosis in the pancreatic head compared
      with the tail should be determined and differences in the expression pattern of
      collagen types I, III, and IV; laminin; vitronectin; and fibronectin should be
      evaluated. METHODS: From 12 patients with alcohol-induced and idiopathic cP who
      underwent surgery due to local complications, 24 corresponding cP tissue samples
      from the pancreatic head and the resection margin were obtained. The degree of
      fibrosis was calculated using a computer-assisted method (Adobe Photo Shop). The
      expression pattern of extracellular matrix proteins (ECMPs) was investigated by
      immunostaining using the streptavidin-peroxidase technique. RESULTS: In each
      case, the degree of fibrosis was higher in the pancreatic head than in the
      resection margin. For alcohol-induced cP, the median degree of fibrosis in the
      head was 64% versus 47% in the resection margin, and for idiopathic cP, it was
      40% versus 32%. Staining intensity of collagen type IV and laminin in the head
      was higher than in the resection surface. In degenerative tissue, collagen types
      I, III, and IV and laminin were moderately expressed, fibronectin was weakly
      expressed, and vitronectin was not expressed, with no differences between the
      head and resection margin. Basement membranes in the head and the resection
      margin predominantly consisted of collagen types I, III, and IV and laminin. In
      ductal epithelia, collagen type IV staining in the head was stronger than in the
      resection margin. CONCLUSIONS: In cP with an inflammatory mass in the head, the
      degree of fibrosis in the pancreatic head is higher than in the resection margin.
      Differences in the expression pattern of ECMPs could be detected for collagen
      type IV and laminin. These results underline the hypothesis of the pancreatic
      head being the pacemaker of cP in which collagen type IV and laminin may play an
      important role.

PMID- 15028951
TI  - Disruption of paracellular sealing is an early event in acute caerulein
      pancreatitis.
AB  - Caerulein-induced pancreatitis is a widely used experimental model for studies on
      acute pancreatitis, however, the molecular mechanisms underlying pancreatitis in
      response to caerulein hyperstimulation are incompletely understood. We therefore
      studied early effects of caerulein on tight junctional integrity. Mice were
      injected with the cholecystokinin analogue caerulein (50microg/kg BW/h) to induce
      pancreatitis. In pancreatic tissue occludin, claudin 1, zonula occludens protein
      1 (ZO-1) were stained immunohistochemically and F-actin was visualized with
      phalloidin-TRITC. Stained sections and isolated acini were studied by confocal
      laser scanning microscopy. Under control conditions occludin, claudin1, ZO-1, and
      F-actin showed a linear staining pattern delineating the apical membranes of
      intralobular duct cells and of acinar cells. While in vitro caerulein
      hyperstimulation induced within 10 minutes disassembly of both occludin and ZO-1,
      in vivo caerulein hyperstimulation induced disassembly of occludin and claudin1
      but not of ZO-1 from the tight junctions. Subsequent progressive disruption of ZO
      1 was detected in a time dependent manner. Disruption of the transmembrane tight
      junction proteins occludin and claudin1 is an early event of caerulein
      hyperstimulation and may allow evasion of noxious luminal content into the
      interstitium, which may augment edema formation in acute pancreatitis.

PMID- 15028952
TI  - Effect of the antibacterial activity of pig pancreatic juice on human
      multiresistant bacteria.
AB  - INTRODUCTION: The role of the exocrine pancreas in regulating gut microflora
      colonization is unclear. The main objective in the current study was to assess
      the effect of pancreatic fluid on the growth of pathogenic bacteria and fungi.
      METHODS: The antibacterial activity of pure pig pancreatic juice collected from
      catheterized, healthy, conscious, and anesthetized pigs was investigated with
      multiresistant microbial isolates and nonpathogenic strains. Studies were
      performed on pathogenic bacterial and fungi as well as lactic acid bacteria and
      reference strains. RESULTS: Pancreatic juice was effective (P < 0.01) against
      multidrug resistant bacterial pathogens, whereas lactic acid bacteria were
      insensitive. The antibacterial action was independent of pancreatic juice
      proteolytic activity. The in vitro antibacterial properties of pancreatic juice
      last for several hours. Data suggest that broth composition may modulate the
      intensity of pancreatic juice antibacterial activity. CONCLUSIONS: Pancreatic
      juice antibacterial activity may be an important factor in limiting the
      colonization of pathogenic bacteria in the gastrointestinal tract. We postulate
      that observed antibacterial activity of the pancreatic juice could play an
      important role as one of the factors of innate immunity.

PMID- 15028953
TI  - Hereditary pancreatitis: clinical characteristics and diagnostic criteria in
      Japan.
AB  - BACKGROUND/AIM: Hereditary pancreatitis (HP) is the strongest known risk factor
      for pancreatic cancer. The aim of the present study is to establish diagnostic
      criteria for HP to predict and identify high-risk groups for pancreatic cancer.
      METHOD: We collected clinical data for 210 patients with recurrent acute or
      chronic pancreatitis, and examined mutations of the cationic trypsinogen (CT)
      gene in 57 patients with a family history of pancreatitis or with early-onset
      idiopathic recurrent acute or chronic pancreatitis (40 years of age or younger).
      DNA was extracted from peripheral blood leukocytes, and exons 2 and 3 of the CT
      gene were individually amplified by polymerase chain reaction (PCR) and
      sequenced. RESULTS: Of these 57 patients in whom mutations of the CT gene were
      examined, the R122H (20 patients) and N29I (5 patients) mutations in the CT gene
      were observed in 25 patients (43.9%). From the analysis of clinical records and
      the CT gene of these patients, we proposed the following adaptations to the
      diagnostic criteria for HP: (1) at least one of the affected members in a family
      has no known etiological factors, (2) we deleted the definition of "different
      generation", but included the upper limit of the age of onset of pancreatitis in
      the case of siblings (at least 1 of the patients in a family <40 years of age).
      According to these criteria, all patients with the CT gene mutations in the
      present study could be classified as having HP, with the exception of 2 sporadic
      cases with the R122H and N29I mutations, respectively. Based on these findings,
      we revised the criteria for the diagnosis of HP; (1) recurrent acute or chronic
      pancreatitis with R122H or N29I mutation of the CT gene, or (2) recurrent acute
      or chronic pancreatitis with a family history of 2 or more affected patients,
      irrespective of generation, with at least 1 of the patients having no known
      etiological factors, and in case of siblings only, the onset of the disease in at
      least 1 of the patients is under age 40 years. CONCLUSION: The revised criteria
      in the present study are appropriate and of clinical usefulness to diagnose
      patients with HP even in cases without the genetic testing. However, if and when
      more genes are detected, it will be important to reexamine the mutation-negative
      patients now classified as HP based on our proposed criteria.

PMID- 15028955
TI  - Successful management of severe acute pancreatitis with multiple organ failure.

PMID- 15028956
TI  - Recurrent pancreatitis and myotonic dystrophy: an unusual association.

PMID- 15028954
TI  - Spleen-preserving total pancreatectomy with conservation of the spleen vessels::
      operative technique and possible indications.
AB  - Conventional distal pancreatectomy (cDP) and total pancreatectomy (cTP) also
      involve removal of the spleen. The spleen, however, is an important organ in the
      immunologic defense of the host and is worthy of preservation if this can be
      safely achieved. We performed a spleen-preserving total pancreatectomy (SPTP),
      with good results, in a Caucasian woman, 66-year-old, affected by pancreatic
      metastases of renal clear cell carcinoma. This is the first report of a SPTP for
      pancreatic metastases to our knowledge, and we therefore wish to describe the
      surgical technique and to suggest the possible indications for this new
      technique.

PMID- 15028957
TI  - Is it necessary to suppress pancreatic exocrine secretion in acute pancreatitis?

PMID- 15028958
TI  - Nonparallel secretion of antibacterial activity and protein in porcine pancreatic
      juice.
AB  - The antimicrobial activity of exocrine pancreatic juice is an important component
      of gastrointestinal tract innate defenses, yet little is known about whether
      secretion is regulated in parallel with digestive enzymes. In this study, we used
      8 pigs with pancreatic catheters to quantify antibacterial activity and measure
      protein content (indicator of enzyme secretion) of pancreatic juice collected
      hourly from 0700 to 1900, with the animals adapted to being fed at 0800 and 1600.
      Antibacterial activity in the samples of pancreatic juice was quantified by
      comparing the growth inhibition of Staphylococcus aureus subsp. aureus strain
      ATCC 6538P relative to a known concentration of gentamicin. Antibacterial
      activity (U/mL and /min) was highest in samples collected 1 hour prior to feeding
      (equivalent to 0.6 microgram gentamicin/mL), declined as the meal was consumed,
      and was lower (P < 0.05) in samples collected while the meals were being digested
      (0.41 microgram gentamicin/mL). Protein content was negatively correlated with
      antibacterial activity, with protein secretion lower (mg/mL and /min) before
      feeding, with an increase as the pigs ate and digested the meals (P < 0.05). The
      results indicate that the antibacterial activity in pancreatic juice is not
      secreted in parallel with protein secretion, suggesting that regulation involves
      alternative signaling pathways or contrasting responses to shared signals.

PMID- 15028959
TI  - The combined inducible nitric oxide synthase inhibitor and free radical scavenger
      guanidinoethyldisulfide prevents multiple low-dose streptozotocin-induced
      diabetes in vivo and interleukin-1beta-induced suppression of islet insulin
      secretion in vitro.
AB  - Inhibition of inducible nitric oxide synthase has been shown to be
      antiinflammatory in a variety of disease states. Type I diabetes is an autoimmune
      disease resulting from the specific destruction of the insulin-producing
      pancreatic beta cells. Here we demonstrate that guanidinoethyldisulfide (GED), a
      combined inducible nitric oxide synthase inhibitor and peroxynitrite/reactive
      oxygen species scavenger reduces the hyperglycemia and incidence of type I
      diabetes induced in mice by multiple low-dose streptozotocin treatment. GED
      treatment (10 and 30 mg/kg/d) protected against the decrease in pancreatic
      insulin content as well as completely attenuating the increased pancreatic
      oxidative stress as determined by tissue levels of malondialdehyde. GED treatment
      also decreased neutrophil infiltration into the pancreas and reduced pancreatic
      levels of the chemokine MIP-1alpha and the proinflammatory cytokines IL-1 and IL
      12. We hypothesize that GED exerts these latter effects by protecting beta cells
      from destruction reducing autoantigen release and decreasing the autoimmune
      response. In vitro GED treatment of isolated rat islets of Langerhans protected
      glucose-stimulated insulin secretion from inhibition by IL-1beta. In conclusion,
      inhibiting formation and/or scavenging reactive nitrogen or oxygen species with
      GED protects against development of diabetes in vivo and isolated pancreatic
      islets of Langerhans from cytokine inhibitory effects in vitro.

PMID- 15028960
TI  - Administration of hyaluronic acid and chondroitin-4-sulfate limits endogenous
      antioxidant depletion and reduces cell damage in experimental acute pancreatitis.
AB  - Several reports have described a loss of endogenous antioxidants and molecular
      oxidative damage during acute pancreatitis. Since hyaluronic acid and chondroitin
      4-sulfate possess antioxidant properties, the effect of the administration of
      these glycosaminoglycans in a cerulein-induced acute pancreatitis in rats was
      investigated. Cerulein administration produced pancreatic edema and a marked
      increase in serum lipase and amylase activity; induced a severe depletion of
      reduced glutathione, catalase, and superoxide dismutase levels; primed lipid
      peroxidation; and promoted neutrophil intervention. Intraperitoneal pretreatment
      of rats with hyaluronic acid or chondroitin-4-sulfate or with both compounds
      ameliorated pancreatic cell conditions; restored the endogenous antioxidants
      reduced glutathione, catalase and superoxide dismutase; limited cell membrane
      peroxidation; and reduced neutrophil activation. Our data confirm the antioxidant
      activity of these 2 glycosaminoglycans.

PMID- 15028961
TI  - Suicide gene/prodrug therapy for pancreatic adenocarcinoma by E. coli purine
      nucleoside phosphorylase and 6-methylpurine 2'-deoxyriboside.
AB  - OBJECTIVE: Recent advances in diagnostics, staging, and therapy for pancreatic
      cancer have not resulted in significant improvements in long-term survival, and
      development of new approaches is particularly urgent. The use of prodrug
      activating genes is a possible approach for cancer gene therapy. The aim of this
      study was to evaluate the efficacy of Escherichia coli purine nucleoside
      phosphorylase (ePNP) on pancreatic tumors. ePNP activates the prodrug 6
      methylpurine deoxyribose (MePdR) into methyl purine (MeP), which is highly toxic
      to dividing and nondividing cells. METHODS: A recombinant pCAG-ePNP vector was
      constructed and used to establish pancreatic cancer cells expressing
      constitutively ePNP (ePNP+). The ePNP/MePdR system effects were tested in vitro
      on HA-RPC (rat) and BxPC3 (human) pancreatic cancer cell lines and then in vivo
      on tumors established in nude mice with BxPC3 ePNP+ cells. RESULTS: MePdR
      treatment of ePNP+ tumor cells induced cytotoxic and antiproliferative effects in
      a concentration-dependent manner with a 100% cell death since 5 x 10 mol/L.
      Bystander effect was strong in vitro as more than 50% of tumor cells were killed
      by MePdR with only 1%-2% of ePNP+ cells. In vivo, tumor growth was completely
      abolished with a prodrug treatment initiated 2 days after tumor cell inoculation,
      and mice remained tumor free. In addition, even if MePdR treatment was applied to
      large tumors, tumors significantly regressed. CONCLUSION: These preliminary
      results support the therapeutic potential of the MePdR/ePNP system, which induces
      a highly cytotoxic effect with a potent bystander effect on pancreatic tumors.

PMID- 15028962
TI  - Sarcoidosis or Sjogren syndrome? Clues to defining mimicry or coexistence in 59
      cases.
AB  - We present 5 new cases of coexisting sarcoidosis and Sjogren syndrome (SS) and
      review the literature for additional cases in order to analyze the clinical,
      immunologic, and histologic characteristics that may help physicians
      differentiate the mimicry of SS by sarcoidosis from a true coexistence of both
      autoimmune diseases. We considered the coexistence of sarcoidosis with SS to be
      when patients presented specific histologic patterns of both diseases,
      simultaneously or at different times.Fifty-nine patients were included in the
      analysis (54 identified in the literature search plus our 5 unpublished cases):
      49 (83%) patients were female and 10 (17%) were male, with a mean age at
      diagnosis of 50 years. According to the histopathologic examination of the
      exocrine glands performed in 53 cases, we defined coexistence of sarcoidosis and
      SS in 28 cases, while in the remaining 25 patients, sarcoidosis mimicked SS.
      Clues to identifying when sarcoidosis coexists with SS were a higher prevalence
      of systemic manifestations (arthritis and uveitis) and positive immunologic
      parameters (antinuclear antibodies, rheumatoid factor, and anti-Ro/SS-A), as well
      as the existence of a focal sialadenitis (Chisholm-Mason score grades III-IV,
      with a CD4+ lymphocytic infiltration) in the salivary gland biopsy. In patients
      first diagnosed with primary SS, the appearance of some clinical features such as
      hilar adenopathies, uveitis, or hypercalcemia leads to the diagnosis of
      coexisting sarcoidosis. A careful application of the new American-European
      consensus criteria had a sensitivity of 93% and a specificity of 92% in
      identifying when SS coexists with sarcoidosis.In conclusion, the association of
      sarcoidosis with SS leads to a true coexistence of both diseases in more than
      half the patients described in the literature, while in the remaining patients,
      sarcoidosis mimics SS. In light of these results, sarcoidosis should not be
      considered as an exclusion criterion for the diagnosis of SS, and in patients
      with a suspected overlap of the two diseases, application of the new American
      European consensus criteria for diagnosis of SS should be mandatory.

PMID- 15028963
TI  - Cutaneous vasculitis in primary Sjogren syndrome: classification and clinical
      significance of 52 patients.
AB  - To analyze the different clinical and histologic types of cutaneous vasculitis in
      patients with primary Sjogren syndrome (SS), we investigated the clinical and
      immunologic characteristics of 558 consecutive patients with primary SS from our
      units and selected those with clinical evidence of cutaneous lesions, excluding
      drug reactions and xeroderma. All patients fulfilled 4 or more of the diagnostic
      criteria for SS proposed by the European Community Study Group in 1993. A total
      of 89 (16%) patients presented with cutaneous involvement (88 female patients and
      1 male; mean age, 51.8 yr). The main cutaneous involvement was cutaneous
      vasculitis, present in 52 (58%) patients. There were 51 (98%) female patients and
      1 (2%) male, with a mean age at diagnosis of cutaneous vasculitis of 51 years
      (range, 20-80 yr). Fourteen presented with cryoglobulinemic vasculitis, 11 with
      urticarial vasculitis, and the remaining 26, with cutaneous purpura not
      associated with cryoglobulins. A skin biopsy specimen was obtained in 38 patients
      (73%). Involvement of small-sized vessels was observed in 36 (95%) patients
      (leukocytoclastic vasculitis), while the remaining 2 (5%) presented with medium
      sized vessel vasculitis (necrotizing vasculitis). Patients with cutaneous
      vasculitis had a higher prevalence of articular involvement (50% vs 29%, p =
      0.044), peripheral neuropathy (31% vs 4%, p < 0.001), Raynaud phenomenon (40% vs
      15%, p = 0.008), renal involvement (10% vs 0%, p = 0.028), antinuclear antibodies
      (88% vs 60%, p = 0.002), rheumatoid factor (78% vs 48%, p = 0.004), anti-Ro/SS-A
      antibodies (70% vs 43%, p = 0.011), and hospitalization (25% vs 4%, p = 0.005)
      compared with SS patients without vasculitis. Six (12%) patients died, all of
      whom had multisystemic cryoglobulinemia.In conclusion, cutaneous involvement was
      detected in 16% of patients with primary SS, with cutaneous vasculitis being the
      most frequent process. The main characteristics of SS-associated cutaneous
      vasculitis were the overwhelming predominance of small versus medium vessel
      vasculitis and leukocytoclastic versus mononuclear vasculitis, with a higher
      prevalence of extraglandular and immunologic SS features. Small vessel vasculitis
      manifested as palpable purpura, urticarial lesions, or erythematosus
      maculopapules, with systemic involvement in 44% of patients in association with
      cryoglobulins in 30%. Life-threatening vasculitis was closely related to
      cryoglobulinemia.

PMID- 15028964
TI  - Complex drug-drug-disease interactions between amiodarone, warfarin, and the
      thyroid gland.
AB  - Many patients with cardiac arrhythmias require concomitant therapy with warfarin
      and amiodarone. Beyond the predictable pharmacokinetic drug-drug interaction
      requiring a significant warfarin dose reduction, the iodine-rich amiodarone
      affects the thyroid gland, causing overt hypothyroidism or thyrotoxicosis in 14%
      18% of cases. In turn, thyroid disorders may affect warfarin sensitivity, with
      hypothyroidism and thyrotoxicosis resulting in increased or decreased warfarin
      requirements, respectively. We describe 3 patients on concomitant amiodarone and
      warfarin who developed amiodarone-induced thyrotoxicosis heralded by a
      significant decrease in warfarin requirements. We review the literature on the
      mechanisms of the complex drug-drug and drug-disease interactions within the
      thyroid gland, warfarin, and amiodarone triad. Given that significant thyroid
      disorders may be only mildly symptomatic and thus may escape clinical detection,
      we suggest that thyroid function should be tested in any patient with otherwise
      unexplained changes in warfarin dose requirements, particularly if concomitantly
      treated with amiodarone.

PMID- 15028965
TI  - Risk factors for cranial ischemic complications in giant cell arteritis.
AB  - Cranial ischemic complications (CICs) are among the presenting manifestations of
      giant cell arteritis (GCA). Yet patients with GCA may develop CICs at a later
      stage, despite steroid therapy. In the current report we delineate risk factors
      for CICs, both at presentation and during follow-up, and review the relevant
      literature. We reviewed charts of 175 patients with GCA. Follow-up data were
      available for 166 patients. CICs at presentation or developing within 2 weeks of
      GCA diagnosis were considered GCA related. CICs developing later were considered
      GCA related only when associated with other GCA-related manifestations or acute
      phase reactions. Associations between CICs and other variables were tested by
      multivariate analysis. At presentation, 43 patients (24.6%) had CICs. Risk
      factors were transient cerebro-ophthalmic ischemic episodes (COIEs) (odds ratio
      [OR] 4.3) and male sex (OR 2.5), while the presence of systemic symptoms was
      "protective" (OR 0.3). During follow-up 8.4% of patients with GCA developed new
      CICs. Risk factors in these cases were previous CICs at presentation (OR 5.6) and
      transient COIEs developing during follow-up (OR 14.8). The use of low-dose
      aspirin was protective (OR 0.2). These data, together with data from the
      literature review, suggest that GCA patients with transient COIEs and without
      fever or other systemic symptoms are at increased risk of presenting with CICs.
      Risk factors for late-developing CICs were CICs at presentation and late
      developing transient COIEs.

PMID- 15028966
TI  - The spectrum of cardiovascular infections due to Salmonella enterica: a review of
      clinical features and factors determining outcome.
AB  - Cardiovascular infections due to Salmonella enterica are infrequently reported,
      so their clinical features, prognosis, and optimal treatment are not completely
      known. Mortality associated with aortitis and endocarditis caused by nontyphoidal
      Salmonella remains exceedingly high. In this review of cases of cardiovascular
      infections due to Salmonella enterica studied in 2 hospitals in Madrid, we tried
      to assess the clinical manifestations and the procedures leading to diagnosis in
      addition to treatment and outcome. To complete the spectrum of infections related
      to cardiovascular surgery, cases of postoperative mediastinitis, pericarditis,
      and infections associated with cardiac devices were also included.Twenty-three
      patients were reviewed: 11 had mycotic aneurysms; 7 had endocarditis; 2 had
      device-related infections; and 3 had pericarditis, mediastinitis, and infection
      of an arteriovenous fistula, respectively. The risk of endovascular infection in
      patients older than 60 years with bacteremia due to nontyphoidal Salmonella was
      23%. Most patients with aortitis had risk factors for atherosclerosis, and 6 had
      preexisting atherosclerotic aortic aneurysms. All except 1 patient with
      endocarditis had underlying cardiac disorders. Acquired immunodeficiency disease
      (AIDS) was a major risk factor for salmonella bacteremia in 1 patient with
      aortitis and 1 with endocarditis. Fever, unremitting sepsis, "breakthrough" and
      relapsing bacteremia were the most common clinical findings. In addition,
      abdominal or thoracic pain and cardiac failure and pericarditis were common
      features in patients with aortitis and endocarditis respectively. Computed
      tomography (CT) scan, arteriography, and echocardiography were the main
      diagnostic tools. Mortality associated with mycotic aneurysms and endocarditis
      due to S. enterica was 45% and 28%, respectively. Thoracic aneurysms, rupture,
      and shock at the time of diagnosis were associated with increased mortality in
      patients with aortitis. In situ bypass grafting was successfully performed in
      most cases. After surgery, antimicrobial therapy was continued for 4-9 weeks. No
      relapses were observed after a mean follow-up of 64 months. Antimicrobial therapy
      alone or combined with valve replacement or excision of a ventricular aneurysm
      was successful treatment for most patients with salmonella endocarditis. Combined
      medical and surgical treatment was required for patients with mediastinitis and
      pericarditis, and patients with device-related infections needed removal of the
      complete device. Diagnosis of aortitis due to nontyphoidal Salmonella should be
      established as early as possible to reduce mortality. Patients older than 60
      years who have positive blood cultures for Salmonella along with fever and back,
      abdominal, or chest pain should have an extensive workup for infective aortitis.
      Immediate bactericidal antimicrobial therapy should be started and a CT scan
      should be performed on an emergency basis. If a mycotic aneurysm is found,
      surgical resection should follow as soon as possible. Resection of the aneurysm
      with in situ bypass grafting is the procedure of choice. Postoperative
      antimicrobial therapy for 6-8 weeks seems enough to avoid relapses. Optimal
      treatment of patients with endocarditis occurring on ventricular aneurysms must
      include resection of the aneurysmal sac. Salmonella endocarditis can be
      successfully treated with antimicrobials alone. Valve replacement should be
      reserved for patients with cardiac failure or persisting sepsis, and for those
      who relapse after discontinuation of antimicrobial therapy.

PMID- 15028968
TI  - A 1 year follow-up study of the consequences of Helicobacter pylori eradication
      in duodenal ulcer patients: unchanged frequency of erosive oesophagitis and
      decreased prevalence of non-erosive gastro-oesophageal reflux disease.
AB  - BACKGROUND AND AIM: Discussions concerning the increased incidence of gastro
      oesophageal reflux disease (GORD) after Helicobacter pylori eradication continue.
      In this study we aimed to evaluate the presence of co-existing GORD in (1)
      duodenal ulcer patients after successful H. pylori eradication, (2) patients with
      persistent H. pylori infection after attempts at eradication, and (3) controls in
      whom H. pylori eradication had not been attempted. METHODS: A prospective study
      of 255 patients with duodenal ulcer who were assigned to H. pylori eradication or
      to control treatment (omeprazole for 4 weeks) and followed up for 1 year or until
      peptic ulcer relapse. GORD was determined in the patients who had reflux
      oesophagitis on endoscopy at the beginning of the study and/or in patients
      without reflux oesophagitis if they experienced heartburn and/or regurgitation at
      least twice a week associated with impairment of daily activities. RESULTS: The
      study revealed a significant decrease (from 44.6% to 21.7%; P < 0.001) of
      patients with GORD at the end of the follow-up among those in whom H. pylori
      eradication had been successful. There was no significant difference in the
      frequency of reflux oesophagitis before and after the follow-up regardless of H.
      pylori status. CONCLUSIONS: H. pylori eradication did not significantly influence
      the prevalence and incidence of reflux oesophagitis in patients with duodenal
      ulcer during a 1 year follow-up period, but there was a significantly lower
      prevalence of GORD after successful H. pylori eradication, as patients with non
      erosive GORD had been cured.

PMID- 15028969
TI  - pH probe positioning for 24-hour pH-metry by manometry or pH step-up.
AB  - OBJECTIVES: Before pH measurement, manometry is recommended for precise pH probe
      positioning. We investigated whether the pH probe could be positioned accurately
      by the pH difference between the oesophagus and the stomach (pH step-up).
      METHODS: Dual-channel 24-h pH-metry with probes positioned 5 cm above either the
      manometrically determined upper lower oesophageal sphincter margin or the pH step
      up was performed in healthy volunteers and reflux patients. To determine the pH
      step-up, the pH probe was pulled back from the stomach until a sudden rise to pH
      greater than four occurred. Probe position, reflux episodes and the fraction of
      the time pH was less than four were compared using the Wilcoxon test for
      difference and the Hodges-Lehman estimate inclusive confidence interval for
      equivalence. The pH step-up method was evaluated further during proton pump
      inhibitor therapy and after drug discontinuation. RESULTS: The pH probe was
      positioned 2 cm and 1 cm closer to the stomach by the pH step-up method in the
      volunteers and reflux patients, respectively. A small increase in upright reflux
      episodes but not in supine reflux episodes was registered by the probe positioned
      by pH step-up. No significant differences in the fraction of the time pH was less
      than four were obtained between the two probes. The Hodges-Lehman calculation
      proved equivalence for both methods of probe positioning for 24-h pH-metry.
      During proton pump inhibitor therapy, no pH step-up was detectable in three
      volunteers and in one patient. On the first day after discontinuing therapy, the
      pH step-up method yielded clear-cut results again. CONCLUSION: The pH probe for
      diagnostic 24-h pH-metry and, with some limitations, also for 24-h pH-metry for
      therapy control, can be positioned accurately by the pH step-up method.

PMID- 15028971
TI  - Quality of life and outcome of ultrasound-guided laser interstitial thermo
      therapy for non-resectable liver metastases of colorectal cancer.
AB  - OBJECTIVE: Patients with non-resectable liver metastases of colorectal cancer
      have poor prognosis and are mainly treated by palliative chemotherapy. Laser
      interstitial thermo-therapy is an innovative minimal invasive procedure for local
      tumour destruction within solid organs. The aim of the study was to investigate
      quality of life and outcome of ultrasound-guided laser interstitial thermo
      therapy (US-LITT) in patients with liver metastases of colorectal cancer.
      METHODS: In this prospective non-randomized study, 45 patients with liver
      metastases of colorectal cancer were palliatively treated by US-LITT. Patient
      survival was analysed by the Kaplan-Meier method and the quality of life by
      questionnaire C30 of the European Organisation for Research and Treatment of
      Cancer before, and 1 week, 1 month, and 6 months after initiation of US-LITT.
      RESULTS: Median survival after initiation of US-LITT was 8.5 +/- 0.7 months with
      a range of 1.5-18 months. Body weight was constant 1 month after US-LITT. In the
      multivariate analyses, quality-of-life symptoms and functioning scales did not
      deteriorate in patients alive at 6 months after initiation of US-LITT. Univariate
      analyses outlined a significant increase of the pain subscale before and at 1
      week after US-LITT. CONCLUSIONS: This study first describes the quality of life
      in patients with liver metastases of colorectal cancer treated by US-LITT.
      Potential benefits of the minimal invasive procedure could be prolonged survival
      time by preserved quality of life, but this first impression needs to be verified
      in a comparative study.

PMID- 15028970
TI  - Leukotriene receptor antagonism in experimental acute pancreatitis in rats.
AB  - OBJECTIVES: Acute pancreatitis is a multifactorial disease caused by activation
      of several inflammatory mediators. Leukotrienes, beside other mediators, may be
      involved in acute pancreatitis. The aim of this study was to investigate the
      effects of 'zafirlukast', a leukotriene receptor antagonist, in acute
      pancreatitis and its relation with prostaglandin synthesis. METHODS: Eighty rats
      were randomly divided into eight groups. Acute pancreatitis was induced by
      subcutaneous injection of cerulein (20 microg/kg), four times at 1-h intervals.
      Zafirlukast (20 mg/kg) was applied intraperitoneally as a pretreatment.
      Prostaglandin synthesis was inhibited by low-dose indomethacin (5 mg/kg
      subcutaneously). Pancreatic histopathology, serum amylase activity and pancreatic
      myeloperoxidase activity were determined to assess the severity of pancreatitis.
      RESULTS: Zafirlukast pretreatment alone did not induce any inflammation and fatty
      necrosis in pancreatic tissue. However, it increased the histopathological score
      from 3.70 +/- 0.57 to 6.62 +/- 0.53 in rats with acute pancreatitis (P < 0.001).
      Fatty necrosis was especially prominent in the zafirlukast-treated acute
      pancreatitis group compared with the untreated group (2.62 +/- 0.26 versus 0.40
      +/- 0.22, respectively; P < 0.001). Inhibition of prostaglandin synthesis by
      indomethacin partially suppressed the harmful effects of zafirlukast in acute
      pancreatitis. It decreased the pathological score (4.62 +/- 0.73) and fatty
      necrosis (1.50 +/- 0.32) in that group. CONCLUSION: Interestingly, leukotriene
      receptor antagonism by zafirlukast increased the pancreatic histopathological
      score and fatty necrosis in rats with acute pancreatitis. Blocking of cysteinyl
      leukotriene receptors might cause an induction of mediator synthesis via other
      pathways. Effects of leukotriene receptor antagonism on the pancreas must be
      evaluated extensively in further studies.

PMID- 15028972
TI  - Collagenous colitis: implications for the role of vascular endothelial growth
      factor in repair mechanisms.
AB  - OBJECTIVES: Collagenous colitis is a chronic inflammatory bowel disease with a
      band-like subepithelial deposition of immature extracellular matrix. Because the
      extracellular matrix deposition is potentially reversible, an imbalance between
      fibrogenesis and fibrolysis with reduced matrix degradation has been suspected.
      Vascular endothelial growth factor plays a central role in extracellular matrix
      degradation. Therefore, we investigated the expression of vascular endothelial
      growth factor in the colonic mucosa of patients with collagenous colitis before
      and after long-term treatment with oral budesonide. METHOD: A quantitative
      immunohistochemical method was used to measure the amount of immunoreactive
      vascular endothelial growth factor, tenascin and leucocyte common antigen within
      the epithelium and the lamina propria of colonic biopsies by area morphometry.
      RESULTS: Strong immunostaining for vascular endothelial growth factor within the
      epithelium and the lamina propria, and for tenascin, was seen in patients with
      collagenous colitis compared with normal controls. The enhanced immunostaining
      for vascular endothelial growth factor within the lamina propria was accompanied
      by the accumulation of leucocytes, detected by staining for leucocyte common
      antigen. After long-term treatment with oral budesonide, the amount of
      immunostaining for leucocyte-derived vascular endothelial growth factor within
      the lamina propria decreased significantly to normal levels. In contrast,
      staining for vascular endothelial growth factor within the epithelium remained
      significantly increased. CONCLUSIONS: Our data suggest an important role of
      vascular endothelial growth factor in counteracting the local imbalance of
      fibrogenesis and fibrolysis, leading to an accumulation of immature subepithelial
      matrix in collagenous colitis.

PMID- 15028973
TI  - The role of capsule endoscopy in the work-up of obscure gastrointestinal
      bleeding.
AB  - OBJECTIVE: To evaluate the role of capsule endoscopy in the detection of causes
      of obscure gastrointestinal bleeding. METHODS: Fifteen patients, nine males and
      six females, mean age 46 years (range 20-75 years), were investigated. All
      patients had undergone upper and lower gastrointestinal endoscopy with no
      evidence of causes of bleeding. Indication for capsule endoscopy was overt
      bleeding in 10 patients (eight with melaena and two with rectal bleeding) and
      anaemia in five patients. RESULTS: Diagnosis was made in four out of 10 patients
      with overt bleeding (40%) and in four out of five (80%) in the group with
      anaemia. The overall detection rate was 53%. Of the eight patients with melaena,
      two had angiodysplasia, one showed a diffuse inflammation of the jejunum and
      ileum probably related to associated portal hypertension, and five had a normal
      examination. Of the two patients with rectal bleeding, one had a polyp in the
      terminal ileum and the other a normal examination. Of the five patients with
      anaemia, one had jejunal carcinoma, three had Crohn's disease and one had a
      normal endoscopy. CONCLUSION: Wireless capsule endoscopy is safe, effective, non
      invasive, and provides definitive diagnosis in about one-half of patients
      presenting with obscure gastrointestinal bleeding and previous negative
      endoscopic examinations.

PMID- 15028975
TI  - Multifactorial aetiology of hepatic infarction: a case report with literature
      review.
AB  - The rarity of hepatic infarction has been explained by the protection from
      ischaemia provided by the double arterial and portal inflow. Hepatic infarction
      hence should require the association of multiple factors jeopardizing
      compensatory mechanisms. We report on a case of hepatic infarction related to
      combined hepatic arterial and portal venous thrombosis after a blunt abdominal
      trauma, a previously unreported cause of hepatic infarction. Several causes of
      vascular impairment were present: shear stress injury due to the trauma, protein
      C deficiency, type II diabetes and administration of glibenclamide, a splanchnic
      vasoconstrictor agent. There was repermeation of the portal vein and hepatic
      artery following anticoagulation therapy. Because hepatic infarction is usually
      explained by the concurrence of several factors impairing the hepatic blood
      supply, an extensive search for associated conditions is necessary even when a
      conspicuous cause is present.

PMID- 15028974
TI  - Eosinophilic gastroenteritis presenting as obstructive jaundice.
AB  - Eosinophilic gastroenteritis is a rare condition of unknown aetiology, first
      described by Kaijser in 1937. It is manifest by eosinophilic infiltration of the
      gastrointestinal tract and peripheral eosinophilia. Patients have various
      clinical presentations depending on the region of the gastrointestinal tract
      involved and the depth and extent of the bowel wall involvement. Whereas
      gastrointestinal obstruction associated with this condition is not uncommon,
      isolated biliary obstruction has only been reported twice. We present a case of
      eosinophilic gastroenteritis with involvement of the biliary tract causing
      ulceration, fibrosis and obstruction. Although a rare condition, we believe the
      diagnosis of eosinophilic gastroenteritis should be entertained in patients with
      gastrointestinal symptoms and a peripheral eosinophilia who have no evidence of
      parasitic infection, vasculitis or neoplasms.

PMID- 15028976
TI  - Auto-immune haemolytic anaemia and Crohn's disease: a case report and review of
      the literature.
AB  - The association between ulcerative colitis and auto-immune haemolytic anaemia is
      well described. However, only two cases of auto-immune haemolytic anaemia
      occurring in association with Crohn's disease have been described in the
      literature. We report on a third case and discuss the importance of diagnosis and
      the therapeutic implications of this association.

PMID- 15028977
TI  - Expression of integrins in tumour tissue of a patient with cancer of the Vater's
      ampulla complicated by pancreas divisum.
AB  - We present herein a rare case where cancer of the Vater's ampulla was complicated
      with pancreas divisum. Endoscopic retrograde cholangiopancreatography
      demonstrated the pancreas divisum and stenosis of the common channel due to the
      tumorous lesion of the Vater's ampulla. Magnetic resonance
      cholangiopancreatography demonstrated that the Wirsung duct and Santorini duct
      were unconnected. The biopsy specimen at the upper gastrointestinal endoscopy
      revealed moderately differentiated tubular adenocarcinoma. The patient was
      diagnosed with cancer of the Vater's ampulla complicated with pancreas divisum,
      and underwent a pylorus-preserving pancreaticoduodenectomy. Immunohistochemical
      examination showed that the p53 protein and the alpha5beta1-integrin were
      expressed in tumour cells, and the proliferating cell nuclear antigen test was
      positive. Furthermore, the alpha5beta1-integrin was expressed in chronic
      pancreatitis tissue. We demonstrate that there is a risk that pancreas divisum
      will co-exist with malignant disease in the pancreaticobiliary area, causing a
      potential risk of complicating malignant diseases in the pancreas.

PMID- 15028978
TI  - Primary biliary cirrhosis presented as peripheral eosinophilia in asymptomatic
      women with or without elevated alkaline phosphatase.
AB  - Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease
      characterized by the destruction of biliary epithelial cells, presumably by
      autoimmune mechanism(s). Although lymphocytes play a pivotal role in the
      pathogenesis of PBC, the possible involvement of eosinophils has also been
      suggested. Recent studies have shown that eosinophilia possibly occurs in the
      peripheral blood of PBC patients. We present four cases of asymptomatic middle
      aged women with moderate-to-high eosinophilia observed during random
      investigation. Alkaline phosphatase (ALP) was increased in two of them. As a
      result of clinical and laboratory evaluations the early stages of PBC were
      diagnosed in all the patients, as attested by the detection of high titres of
      anti-mitochondrial antibodies and the characteristic lesions on liver biopsies.
      Liver function tests and eosinophils returned within normal limits after 2 months
      of treatment with ursodeoxycholic acid, suggesting that its potential
      immunomodulatory actions may extend to eosinophils. Our report further supports
      the possibility that eosinophilia may occur in PBC, especially in its early
      stages. From the clinical point of view, we believe that PBC should be considered
      in the differential diagnosis of eosinophilia with an otherwise unknown origin.
      In particular, PBC should be suspected in a patient when other causes of
      eosinophilia have been excluded, irrespective of the presence or absence of
      symptoms, or the presence or absence of elevated ALP. In such cases further
      evaluation for anti-mitochondrial antibodies should be done. These observations
      might assist the development of future therapeutic concepts in the management of
      PBC, at least for patients in early stages of the disease.

PMID- 15028979
TI  - Should routine screening for coeliac disease be considered before starting
      interferon/ribavirin treatment in patients affected by chronic hepatitis C?

PMID- 15028980
TI  - Treatment of oesophageal Crohn's disease with infliximab.

PMID- 15028981
TI  - Retrospective study of long-term treatment with sodium picosulfate.

PMID- 15028983
TI  - The importance of sleep for patients must not be forgotten.

PMID- 15028984
TI  - What lessons can we learn from conflict resolution?

PMID- 15028985
TI  - Nurse who failed to acknowledge the limitations of her practice.

PMID- 15028986
TI  - Learning about teamwork in operating room clinical placement.
AB  - The aim of nursing students' operating room (OR) clinical practice is to gain
      experience of the perioperative nursing process and to develop skills related to
      the practice within OR teams in a variety of situations. However, it has
      previously been problematic to get enough practical experience within OR teams
      because of the general urgency, e.g. rapid turnover and flow of emergency cases,
      and preceptors' multiple responsibilities related to their simultaneous need to
      work as team members. This study describes how Finnish, British and American
      nursing students (n = 30) experienced learning about teamwork during their OR
      placement period. The critical incident technique was used for data collection,
      and data were analysed using a descriptive phenomenological method. Three types
      of teamwork emerged based on the students' perceptions: functional manifestation
      of OR teamwork, gaining OR team membership and technical orientation of OR
      teamwork. The findings are discussed in relation to OR practice, education and
      research on ways to improve teamwork while maintaining a satisfactory OR learning
      context and stimulating interest in perioperative nursing.

PMID- 15028987
TI  - A case study using larval therapy in the community setting.
AB  - This article discusses the use of larval therapy by district nurses in wound bed
      preparation in the community. A case study is presented of a patient with a
      persistently necrotic and painful anterior tibial wound post-fasciotomy. The case
      study offers an insight into the practicalities involved in the use of larvae as
      effective and safe debriders of tissue for wound bed preparation. It is concluded
      that larval therapy is an underused and misunderstood resource when considering
      effective wound care and this treatment should be actively considered as an
      alternative therapy in wound care. There is a need for both qualitative and
      quantitative research in this field, enabling a more thorough discussion to be
      entered into by all practitioners with an interest in this subject.

PMID- 15028988
TI  - Using bladder instillations to manage indwelling catheters.
AB  - Indwelling urinary catheters are commonly used in both acute and primary care
      settings but patients often experience problems with blockage of the catheter as
      a result of encrustation. Bladder instillations of differing solutions are used
      in an attempt to prevent and treat this problem of encrustation. This article
      looks at some of the issues surrounding the use and methods of these solutions.
      Based on an audit performed by a group of continence clinical nurse specialists
      in five areas of the UK, results of a questionnaire sent to acute and primary
      care nursing staff in 2003 are presented and discussed. The questionnaire covered
      a variety of clinical issues involved in performing bladder instillations and the
      results show that there is a wide variation of practice across the UK. The
      authors conclude that there are issues pertaining to bladder instillations which
      warrant further work.

PMID- 15028989
TI  - Ward managers' perceptions of the role of healthcare assistants.
AB  - While unqualified nurses form an integral part of the UK's healthcare system,
      accounting for a large percentage of the workforce, there is limited evidence to
      identify the actual role of the healthcare assistant. This study explored
      hospital ward managers' views on the current and potential expansion of the
      healthcare assistant's role. A confidential survey was sent to all ward managers
      (n = 35) in one large acute hospital trust. A response rate of 94% (n = 33) was
      obtained. Data were analysed using descriptive statistics and open-ended
      questions were analysed for emerging themes. The results indicated that
      healthcare assistants are undertaking a wide diversity of procedures raging from
      general tidying to carrying out complex clinical procedures. Additionally, 82% (n
      = 27) of the managers reported that the healthcare assistant's role could be
      expanded, although concerns were raised regarding additional training and
      supervision.

PMID- 15028990
TI  - Accountability and medicinal products 3: employment.
AB  - Case Scenario: Mohammed had been trained in a previous post as an independent
      nurse prescriber. He wished to continue to use those skills in his new post as a
      clinical nurse specialist. He was notified by the trust that it was not its
      policy to introduce independent nurse prescribing. Can he lawfully refuse to obey
      these instructions?

PMID- 15028991
TI  - Nursing Record/British Journal of Nursing archives, 1888-1956.
AB  - This article centres on the experience of using a new database comprising a
      digitised historical journal - the Nursing Record/British Journal of Nursing from
      1888 to 1956, when the journal ceased publication. The project was initiated by
      the UK Centre for the History of Nursing, a collaboration between a number of
      academic bodies, including the Wellcome Trust and the Royal College of Nursing
      (RCN). The database was launched at Oxford in September 2003 and is freely
      available via the RCN website. The database was searched for material concerning
      emotion, as there has been increasing interest in this topic among service
      professionals, including nurses, during the past few decades (Hochschild, 1983;
      Smith, 1992; James et al, 2003). It seemed interesting to explore the same topic,
      as discussed in the late 19th and first half of the 20th centuries. Search terms
      used were "emotion", "feeling", "sympathy", "comfort" and "compassion". Most hits
      were achieved with "sympathy" and "feeling", but the majority of these were not
      strictly relevant to the discussion. This pilot search indicates that hand
      searching of paper copies still represents the "gold standard", in terms of
      identifying relevant material and interesting context data, not necessarily found
      when feeding specific search terms into a computer. The main advantages of the
      digitized journal are much wider access to this source and protection of fragile
      archival material.

PMID- 15028992
TI  - Problems of obesity: it is time for nurses to act.

PMID- 15028993
TI  - How to restore the public's faith in MMR?

PMID- 15028994
TI  - Chronic obstructive pulmonary disease and community-based pharmacological care.
AB  - Chronic obstructive pulmonary disease carries a high morbidity and mortality and
      is one of the few chronic diseases where the number of people affected is rising,
      a trend that looks set to continue. Unfortunately patients often present at a
      late stage of the disease when therapeutic options are more limited and many
      patients are undertreated, overtreated or misdiagnosed. While patients present
      both in primary and secondary care it is primary care where the majority of
      patients are managed and where patients are likely to be seen at an earlier stage
      of the disease process when interventions are likely to be more effective.
      Therapeutic options for patients with COPD include pharmacological approaches and
      these should be prescribed on an individual basis and both subjective and
      objective criteria used in evaluating effectiveness.

PMID- 15028995
TI  - Influencing exercise and diet to prevent osteoporosis: lessons from three
      studies.
AB  - Osteoporosis is a major public health problem, causing fractures of wrist, back
      and hip with high associated morbidity and mortality. Particularly at risk are
      postmenopausal women. Recent moves away from hormone replacement therapy as a
      preventative measure have focused attention on exercise and dietary
      supplementation with calcium for prevention and treatment. This article reports
      three studies of women screened for osteoporosis - an outpatient sample (n =
      129), a GP sample (n = 25) of women before and after bone mineral density
      screening, and a sample of women diagnosed with osteoporosis in the past 5 years
      (n = 26). Only 57% in the outpatient sample consume the recommended amount of
      calcium (1500 mg calcium daily); 65% in primary care consume 1200 mg five times
      per week, although 90% intend to do so. For bone-loading exercise, the
      recommendation is three 20-minute periods per week. Most women thought they were
      undertaking enough exercise, and diaries showed that 74% of the women undertook
      60 minutes per week, and 44% undertook 30 minutes five times per week. Women were
      more willing to change diet than exercise. Suggestions are made to help primary
      care teams to motivate women to make sustained changes in diet and exercise.

PMID- 15028997
TI  - Online information on primary care services for refugees and asylum-seekers.
AB  - Government initiatives concerning equitable services and information provision
      aim to provide for the whole community. This includes those recently arrived in
      England as refugees. This study evaluated the information provided online by 16
      London primary care trusts (PCTs) on activities under way to meet the needs of
      the local refugee population and the extent to which government initiatives are
      being met. Information published on websites of PCTs with a refugee population
      estimated to be over 2.5% of the London total refugee population was surveyed
      using a 13-item framework based on guidelines for health professionals working in
      refugee health (Burnett and Fassil, 2002). The findings show a disparity between
      different types of information provided and variations in the overall standards
      achieved by individual PCTs, indicating a need for considerable work if the
      requirements of the public and government for access to high quality information
      about services are to be met. The majority of PCTs, however, provide good
      information regarding coordination of services and evidence of a thorough health
      needs assessment. The findings are relevant to health professionals working with
      refugees and to PCT employees involved in publishing information on the internet.

PMID- 15028996
TI  - Building consensus in health care: a guide to using the nominal group technique.
AB  - The nominal group technique has been used in the health care sector in the
      development of guidelines and the identification of research priorities. The
      methodology suits research that includes both health professionals and consumers,
      since it allows for the free exchange of opinions and the generation of ideas
      within a structured and non-hierarchical discussion forum. This article describes
      the process of planning and running a nominal group and uses examples from a
      primary-care-based study to illustrate some of the advantages of using this
      method, and also the practical implications of using the technique in consensus
      development.

PMID- 15028998
TI  - Putting the record straight: the importance of documentation.
AB  - A nurse from Coventry was recently removed from the national register after
      failing to keep accurate records for patients in her care. She was found guilty
      of seven charges of misconduct. The committee heard that she failed to ensure
      care plans were prepared for several patients covering issues such as diabetes,
      pain management and dietary needs. On one occasion, she failed to notify staff of
      a patient's increased risk of haemorrhage following a drug error. The Nursing and
      Midwifery Council (NMC) found the nurse had systematically neglected a basic and
      crucial duty to keep proper records for the management of patient care.

PMID- 15028999
TI  - Children's choice of comforters and their effects on sleep.
AB  - The study aimed to explore whether the choice of comforter affected quality of
      sleep in children between the ages of 1 and 4 living in Stockport. Information
      was elicited from parents as to their child's use of comforter, and parents'
      perceptions of their child's quality of sleep. A total of 180 questionnaires were
      distributed to parents attending well-baby clinics during a 2-month period; 126
      questionnaires were returned and analysed. Data were coded, and where respondents
      were asked to construct their own comments, emerging themes were reported. Of the
      children using the comforters classified as 'easy access' (i.e. comforters they
      were more likely to find and hold) 71% were sleeping through the night at 6
      months old. The associations were incremental in that of those children who used
      both 'easy access' comforters and comforters requiring parental input, 48% were
      sleeping through the night at 6 months, and of those children using only parental
      input comforters only 38% were sleeping through the night. Implications for
      practitioners are that 'easy access' comforters could be beneficial to aid sleep
      in young children, however as the study was small, generalizations cannot be
      made.

PMID- 15029000
TI  - Widening the choice of care for patients.

PMID- 15029002
TI  - Defined and refined: criteria for identifying wound infection revisited.
AB  - Clinical criteria for the identification of wound infection are regularly based
      on a list created by Cutting and Harding (1994). This list was established from
      empirical data generated in a large, multidisciplinary clinical practice, and is
      now widely accepted as a seminal article in wound care. Both Cutting (1998) and
      Gardner et al (2001) have conducted validation exercises on these wound infection
      criteria, based on the assumption that the criteria broadly apply to most wound
      types. Although many of the original criteria do apply across the spectrum of
      wound types, the major categories of wounds should be considered separately to
      avoid the possibility of overlooking the presence of infection. The focus of this
      article is a review of the published literature on wound infection criteria for
      acute and surgical wounds, diabetic foot ulcers, venous and arterial leg ulcers,
      pressure ulcers and burns. All known criteria for each wound type are presented,
      as well as an outline of the ongoing research project to refine the criteria by
      wound type using a Delphi panel technique. No attempt has been made to correlate
      visual signs and symptoms with microbiological sampling techniques. It is clear
      that there are subtle variations between infection criteria for wound types and
      that these should be recognized if treatment is to be given appropriately and
      promptly, and morbidity avoided.

PMID- 15029003
TI  - The use of maggot therapy in the treatment of a malignant foot wound.
AB  - Mrs T presented with a necrotic wound to her right foot secondary to malignant
      adenocarcinoma. Maggot therapy was used to successfully debride the wound, which
      had failed to respond to conventional treatment. The maggot therapy removed the
      necrotic tissue and appeared to initiate the process of granulation, which
      allowed the wound to be dressed with conventional materials and progress towards
      healing.

PMID- 15029004
TI  - Evaluation of the impact of an educational initiative in diabetic foot
      management.
AB  - The diabetic foot project was an initiative designed to help develop a training
      package for community nurses and podiatrists. It also aimed to evaluate the
      impact of two days' training on the knowledge and reported practice of nurses and
      podiatrists in the management of the diabetic foot. The study used a two-group
      pre- and post-test design, which replicated the work of Luker and Kenrick (1993)
      and Nelson and Jones (1997). The Wilcoxon signed-rank test was used to determine
      if there was a difference between the experimental and control group scores. The
      results reported demonstrate the positive effect of the study days on
      practitioners' knowledge and reported practice, and the study has highlighted the
      potential to improve practitioners' knowledge and reported practice.

PMID- 15029005
TI  - [A million mistakes? Regarding the Million Women Study and the Women's Health
      Initiative].

PMID- 15029007
TI  - [Patients refusal to be treated, the problem of Jehovah's witnesses].
AB  - The principle of respecting the patient's wishes is an international medical
      principle, found in several texts. In France, it was recalled in the 1994 Civil
      Code concerning bioethical laws and has recently been included in the Public
      health Code (law concerning patient's rights dated March 4, 2002). According to
      these various texts, the patient's wishes must always be respected, even in life
      threatening cases, so long as the patient has been informed of the risk. The
      refusal by Jehovah's witnesses to receive blood transfusion is always a problem.
      When, in full consciousness, a patient refuses a blood transfusion that his life
      depends on, what should the physician do? In June 1998, the Paris Court of Appeal
      ruled on this case. The judges found that "the obligation of the physician to
      always respect the wishes of the patient.is limited by the other obligation of
      the physician (the basis of a physician's activity) which is to protect the
      health and life of that same patient". In October 2001, the State Council ruling
      on this particular case found that, given the critical conditions of this case
      and the absence of a therapeutic alternative, the physicians had not committed an
      error. But it was also clearly underlined that a physician must respect the
      wishes of the patient and that this obligation must not be superseded by the duty
      of saving a life, thus disputing the judges of the Court of Appeal. Two
      questions. Two emergency interim rulings confirmed the position of the judges:
      the non-respect of the patient's wishes is an infringement of individual freedom.
      It is only in extreme and clearly defined circumstances that the physician will
      not be punished for this offence. This raises two questions: can a physician
      treat a patient against his/her wishes? And what risks does the physician take
      when respecting the patient's wishes when his/her life is at stake?

PMID- 15029008
TI  - [Health care consumption. Empirical evidence from a survey in a regional
      university hospital].
AB  - OBJECTIVES: Emergency departments of French hospitals have been coping with
      increasing activity for ten Years. This study is aimed at describing patterns of
      health care consumption for people admitted to emergency departments and at
      linking them to their declared socio-economic status. METHODS: In May 2001, a
      survey was conducted in the emergency department of the Saint Roch Hospital in
      Nice, identifying the nature and motives of the persons admitted, health care
      consumption over the last Year and a set of socio-economic characteristics of the
      patients. RESULTS: A persisting gap in health care consumption still remains to
      the detriment of poor people. There also seems to be a threshold effect for
      patients whose income only slightly exceeds the upper limit of revenues entitling
      them to universal health insurance or other social redistribution mechanisms. For
      this category of the population, health care consumption is significantly less
      than that of the rest of the population, although visits to the emergency
      department are more often unjustified. CONCLUSION: Emergency departments are the
      major access to health care for people excluded from, or on the borderline of the
      health system. The extension of health insurance to populations excluded up till
      now, appears to induce underprivileged health traps, but at the same time making
      up for lost time (only partially in this study). Such effects merit consideration
      in order to ensure a continuum in the management of health requirements in low
      income populations.

PMID- 15029009
TI  - [Meningitis with direct negative bacteriological examination. Prospective
      assessment of a decision making tree].
AB  - OBJECTIVE: Elaboration of a decision-making tree for differential diagnosis of
      bacterial and viral meningitis, when initial Gram's staining is negative. Method
      One-Year prospective study in an adult emergency department. Comparison with the
      immediately-preceding period. RESULTS: 56 patients were included. Only 4
      bacterial meningitis, but none misdiagnosed. 86% sensitivity and 83% specificity
      for viral meningitis (n=40). Rate of patients hospitalised more than 24 hours
      decreasing from 62.5 to 41% (p=0.05). Antibiotic chemotherapy decreasing from 55
      to 16% (p<0.001). CONCLUSION: This decision-making tree safely allows emergency
      differentiation between bacterial and viral meningitis, when initial Gram's
      staining is negative. It consequently leads to decreased rates of useless
      hospitalisations and antibiotic treatments. We believe that this method can be
      helpful during outbreaks of viral meningitis.

PMID- 15029010
TI  - [Estimating the specificity of a University Hospital Centre. Example of the
      colonoscopy (EPAGE survey)].
AB  - OBJECTIVE: The specificity of a University Hospital Centre is usually assessed
      from its teaching and research capacity. The EPAGE survey, an instrument used to
      help decision making available on the Internet, permitted us to compare the
      prescription of a routine exploration, gastrointestinal endoscopy, between the
      University Hospital Center in Clermont-Ferrand and the Hospital Centre in
      Moulins. The aim was to demonstrate the differences in daily practice between
      these two geographically close hospital centres and hence to underline the
      specificity of a University Hospital Centre that is not taken into account in the
      financing systems of such hospitals. Method The data collected were taken from
      the EPAGE trial, a prospective mutlicentre study that included 21 European and
      Canadian centres. Data was collected from the University Hospital centre in
      Clermont-Ferrand over two periods: from December 2000 to March 2001, then from
      December 2001 to February 2002, and from the Hospital Centre in Moulins, from
      December 2000 to the end of November 2001. For this Article, only the patients'
      characteristics, indications for gastrointestinal endoscopy and opportunity rate
      were analysed. Comparison of patients' categories from the 2 centres was
      conducted according to their DRG (diagnostic related group) (homogeneous patient
      group) classification, thus allowing calculation of the mean of the SIA
      (synthetic index of activity) points in the two centres. RESULTS: 221 cases of
      gastrointestinal endoscopy performed in the University Hospital centre and 292 in
      the Hospital Centre were included in the survey. No statistically significant
      difference was found in the reasons motivating a gastrointestinal endoscopy, with
      regard to the indications listed on the EPAGE website. There were 18% of unlisted
      indications in the University Hospital Centre versus 4.8% in the Hospital Centre
      (p<1.10-6). Using the DRG nomenclature, calculation of the mean SIA points at the
      University Hospital Centre per patient was of 1161 versus 1147: non significant
      deviation of 1.2% in favour of the University Hospital Centre. DISCUSSION: -
      Conclusion The difference in reasons motivating a gastrointestinal endoscopy
      found between the two centres concerned rare, complex or innovating situations.
      This illustrates the role of a Regional Reference University Hospital Centre, an
      aspect clearly underestimated when measuring mixed cases according to the HPG.
      Study of the financing and/or information systems is warranted and might resolve
      the apparent underestimation of the current financing system.

PMID- 15029012
TI  - [Spontaneous rupture of the oesophagus. Two cases recently seen in an intensive
      care unit].
AB  - INTRODUCTION: Spontaneous rupture of the oesophagus, also called Boerhaave's
      syndrome, is rare. Since its clinical manifestations are non specific, it must be
      evoked when confronted the sudden onset of chest or upper abdominal pain.
      OBSERVATIONS: Two patients were admitted to the emergency department with severe
      chest pain associated with vomiting. The CT scan obtained rapidly, revealed the
      perforation of the oesophagus. Despite early surgical treatment, only one patient
      survived, the second died of infectious complications. COMMENTS: Boerhaave's
      syndrome is fatal unless promptly recognized and adequately treated. A CT scan of
      the chest is the procedure of choice demonstrating the rupture.

PMID- 15029011
TI  - [Chyloperitoneum complicated by intestinal occlusion].
AB  - INTRODUCTION: Acute chylous ascites is an affection rarely encountered among
      acute painful abdominal syndromes. OBSERVATION: An acute chylous ascites was
      observed in a 76 Year-old man without prior history. Its etiology was an acute
      pancreatitis. Intestinal occlusion on the 15th day post-surgery required
      adhesiolysis. DISCUSSION: Intestinal occlusion is exceptional after chylous
      acsites despite the potential adherence of the chyle. Regarding the pathogenesis,
      analysis of the literature and our case report suggest either a bridle,
      adherences, or a peri-intestinal sheath due to the organisation of the chyle at
      the origin of the occlusion following chyloperitonitis. CONCLUSION: Although an
      etiology of chylous ascites can be an intestinal occlusion, it can, although
      rarely, also be a more or less late complication.

PMID- 15029013
TI  - [Hyperkaliemic paralysis].

PMID- 15029014
TI  - [Characteristics of post antibiotic Clostridium difficile and Staphylococcus
      aureus diarrhoea].

PMID- 15029015
TI  - [Vitamin B12, friend or enemy of gastrectomised patients?].

PMID- 15029016
TI  - [In the beginning, there was an infection].

PMID- 15029017
TI  - [Physiopathology of severe sepsis].
AB  - Regarding the definition. Severe sepsis associates an explosive inflammatory
      reaction and organ failure. It is secondary to bacterial, fungal or viral
      infection. It can be at the origin of acute circulatory failure (state of septic
      shock). Response of the organism to infection. The presence of certain components
      of the membrane of pathogenic agents induces the release of various mediators in
      cascade, notably cytokines. Toll-like receptors (10 cloned in humans) intervene
      in the detection of microbes and in the inherent and subsequently adaptive immune
      response. Immune paralysis. The release of pro-inflammatory mediators
      characterizes the initial phase of sepsis. Persistence of the latter provokes
      acquired immunodepression, related to an anti-inflammatory profile, and hence to
      a delayed decrease in hypersensitivity, an incapacity to cope with the infection
      and the onset of nosocomial infections. The role of the mediators. During sepsis,
      the cytokines are predominantly pro-inflammatory (TNF-alpha and notably IL-1beta)
      whereas others, produced concomitantly or subsequently, are predominantly anti
      inflammatory (IL-10 in particular). In fact, the majority of the cytokines have
      multiple and intrinsic effects, they mediate immune defense but also pathological
      manifestations. Many other mediators intervene: coagulation or complement
      systems, contact system, breakdown products of the phospholipid membrane,
      arachidonic acid metabolites, free radicals and nitrous oxide. Endocrine and
      metabolic dysregulations. The concept of relative adrenal insufficiency and
      peripheral syndrome of resistance to glycocorticosteroids have led to hormone
      replacement therapy during septic shock. Acute insulin resistance has also been
      described. The role of the endothelium and coagulation. The endothelium plays a
      key part in the onset of vascular insufficiency during sepsis due to
      abnormalities in vasomotricity and thrombomodulation. The anticoagulant
      regulating system is perturbed; there is a decrease in protein C with
      inactivation of its active form, which has pro-fibrinolytic properties, and a
      decrease in antithrombin III. Regarding myocardial dysfunction During septic
      shock there is often severe left ventricular systolic dysfunction, sometimes also
      involving the right ventricle, largely under-diagnosed despite its severe
      prognosis, and associated with reduced or even collapsed heart rate.

PMID- 15029018
TI  - [Diagnosis of sepsis, severe sepsis and septic shock].
AB  - Consensual and precise definitions. Sepsis is composed of a suspected or
      documented infection associated with at least 2 SIRS criteria (systemic
      inflammatory response syndrome). Severe sepsis is sepsis with arterial
      hypotension and failure of one or several organs following the reduction in
      tIssue perfusion. Septic shock is a severe sepsis, the hypotension of which is
      refractory to volemic expansion. From an epidemiological point of view. Over the
      past two decades, its incidence is on the increase. Mortality varies from 25 to
      80% of cases and sepsis remains the first cause of death in intensive care. The
      elements of diagnosis. The initial clinical signs are those of an infection and
      the port of entry and microbiological proof must be systematically researched
      before the appearance of a drop in blood pressure with hemodynamic impact on the
      various organs and hence their possible failure. The biological abnormalities
      observed depend on the deficient organ(s); hyperlactatemia is a good marker of
      visceral hypoperfusion. The sepsis risk factors. Any situation enhancing
      immunodepression is a risk factor for sepsis. Factors of virulence of the micro
      organisms also intervene and, in cases of fungal infection, inherent risk
      factors. Genetic susceptibility probably intervenes, genetic variability playing
      either a protective or a deleterious role (the interest of Toll-like receptors).

PMID- 15029019
TI  - [Treatment of severe sepsis and septic shock].
AB  - The 3 poles of treatment. These are the hemodynamic management, early
      antibiotherapy and more specific treatments, based on improved physiopathological
      knowledge. From a hemodynamic point of view The first stage must always be to
      detect and correct the hypovolemia. The administration of vasopressive amines (or
      vasoconstricting amines) is mandatory in the case of septic shock. The choice of
      the antibiotics In the absence of microbiological proof, it is based on the germs
      most often encountered in infections of the suspected site and community or
      nosocomial nature of the infection. The antibiotherapy must be set-up as early as
      possible once the bacteriological samples have been. Treatments based on the
      physiopathology The activated protein C possesses pro-fibrinolytic, anticoagulant
      and anti-inflammatory properties; it obtained marketing Authorization in Europe
      for patients with severe sepsis and at least 2 organ failures or hypotension. Low
      dose corticosteroids should be prescribed in the case of septic shock with
      prolonged use of catecholamines, and if possible following a test with
      Synacthene(R) (relative adrenal insufficiency). Intensive insulin therapy is
      aimed at maintaining normal glycemia in the patients for as long as possible.

PMID- 15029020
TI  - [The interest of 18FDG-PET in the management of testicular cancer].
AB  - The key to prognosis. Initial staging and early recurrence diagnosis are key
      parameters in the treatment and outcome of testicular cancer. Initial staging. It
      is difficult using conventional modalities, which can miss node involvement and
      are non-specific since enlargement does not rhyme with involvement. 18FDG PET
      improves the accuracy of initial staging. Residual mass and recurrences.
      Existence of residual mass or enhancement of its Volume in the presence of an
      otherwise beneficial chemotherapy is difficult to manage. Several studies have
      demonstrated the value of 18FDG imaging in such cases. As for follow-up whole
      body 18FDG can prevent multiple diagnostic imaging and can diagnose recurrences
      with greater diagnostic accuracy than with other imaging modalities.

PMID- 15029021
TI  - [The management of acute pain in ambulatory patients. The place of nefopam].
AB  - An emergency. When treating a patient, relief of any acute pain is a priority.
      Such pain should be treated as an emergency, rapidly and effectively. Assessment
      is the first step Pain is a subjective phenomenon. Assessment of its intensity is
      the first step to its management. Regarding treatment The molecules that can be
      used for the treatment of acute pain in ambulatory patients can be classified
      into two categories, co-analgesics (antispasmodics and non-steroidal
      antiinflammatories) and pure analgesics classified by the WHO into three grades,
      although this classification presents certain limits. Nefopam is a central
      analgesic, with non-opiate action and, because of this inscribed by the WHO in
      the first grade, but with an analgesic capacity that corresponds to the
      substances of grade II analgesics. Its efficacy relies on medullar and/or
      supramedullar mechanisms. Via intramuscular injection The delay before action is
      of around 10 to 20 minutes and lasts for around 6 hours. The advantages of
      intramuscular nefopam are its analgesic capacity, its simplicity of use and its
      tolerance. The indications In ambulatory patients, Acupan is administered during
      acute arthritic pain, post-trauma and dental pain, renal colic, extremely severe
      migraine and headaches, dysmenorrhoea, and intense spasmodic colic.

PMID- 15029022
TI  - [Pre-depressive syndrome, the 7 precursor signs].

PMID- 15029023
TI  - [Pleading for a quality medical statistics training].

PMID- 15029024
TI  - [Multiple sclerosis (MS), an inflammatory or degenerative disease?].

PMID- 15029025
TI  - [To die from inflexibility].

PMID- 15029026
TI  - [Compliance and optimisation of oral antidiabetic therapy. A longitudinal study].
AB  - OBJECTIVE: To evaluate the impact of optimization of treatment and improvement in
      observance awareness in patients with type 2 diabetes on compliance with oral
      antidiabetic drug therapy and long-term glycemic control. Method Evaluation of
      compliance with oral antidiabetic therapy and of HbA1c levels in a cohort of 4
      802 patients with type 2 diabetes followed by their general practitioner, before
      and after 6 Months on optimized treatment: reduction in percentage of combination
      treatments from 69.5 to 56.8%, and increase in percentage of once-daily dosing
      regimen from 12 to 58.4%. RESULTS: Optimization of treatment led to an increase
      in the percentage of patients achieving optimal compliance with oral antidiabetic
      drug therapy from 44 to 69.5% after 6 Months (p<0.001). Metabolic control also
      improved, as evidenced by a decrease in HbA1c levels observed both in the whole
      cohort (7.5+/-1.6% to 6.9+/-1.2%; p<0.0005), as well as in individual therapeutic
      subgroups of patients (having switched from multiple-daily dosing to once-daily
      dosing schedules and from gliclazide 80 to gliclazide 30 MR once-daily
      formulation). CONCLUSION: These findings suggest that optimization of oral
      antidiabetic therapy favoring the use of oral antidiabetic agents with once-daily
      dosing administration modalities may improve metabolic control in patients with
      type 2 diabetes.

PMID- 15029027
TI  - [Quality of life assessment of type 2 diabetic patients in general medicine].
AB  - OBJECTIVE: The QUODIEM study assessed the quality of life of type II diabetic
      patients and the factors that influenced it, according to recent medical
      recommendations. Method The quality of life (QOL) of 437 type II diabetic
      patients in the Rhone-Alps area, monitored in general medicine, was assessed
      using two QOL questionaires, the SF 36, a generic, and the DQOL, a specific
      questionnaire that we adapted to type II diabetics. A third questionnaire
      assessed the wishes of the patients concerning the management of their disease.
      RESULTS: The QOL of type II diabetics is negatively influenced by age (>75
      Years), female gender, loneliness, and the absence of professional or physical
      activity. A poorly balanced diabetes, its management by a specialist, the
      presence of two complications or more related to the disease, and treatment with
      insulin were all factors reducing QOL. Self-management of glycaema was associated
      with improved QOL. Few patients wished enhanced management of their diabetes.
      CONCLUSION: The QUODIEM study underlined the fact that the QOL of type II
      diabetics must be taken into account and tools for its assessment are available
      in France.

PMID- 15029028
TI  - [Chylous ascitis revealing a non-Hodgkin lymphoma].
AB  - INTRODUCTION: Chylous ascitis is a rare form of ascitis, characterised by a
      milky, triglyceride-rich, liquid. It is due to an interruption in the lymphatic
      system due either to an obstruction or to a post-traumatic wound. We report a
      case of revealing a non-Hodgkin lymphoma. OBSERVATION: A 71 Year-old man
      consulted for abdominal distension attributed to a chylous ascitis. Peripheral
      adenopathies were palpable. The abdominal scan revealed voluminous lumbar-aortal
      adenopathies. The diagnosis of grade IV (Ann Arbor classification) centro
      follicular non-Hodgkin lymphoma was retained. The ascitis disappeared following
      chemotherapy. COMMENTS: Chylous ascitis is an uncommon complication of lymphomas,
      although representing the main cause in adults in developed countries. The
      underlying mechanism is an obstruction to sub-diaphragmatic draining lymphatic
      due to lymphomatous infiltration. Hyperalimentation, a low, dietary restriction
      of long-chain triglycerides or peritoneovenous shuntings are ineffective.
      CONCLUSION: Chylous ascitis is a rare complication of lymphomas, secondary to the
      obstruction of the abdominal draining lymphatics. Treatment is the same as that
      of a hematologic malignancy.

PMID- 15029029
TI  - [Scurvy in intensive care despite vitamin supplementation].
AB  - INTRODUCTION: Scurvy can occur in hospitalized patients despite vitamin
      supplementation. OBSERVATION: A 63 Year-old patient who had spent several weeks
      in intensive care developed an unexplained anemia and ecchymoses. Despite daily
      administration of 130 mg/day of vitamin C since his admission, his ascorbic acid
      blood levels had collapsed. Administration of 1g/day relieved the symptoms within
      four weeks. DISCUSSION: Whether a deficiency had existed prior to admission or
      not, scurvy developed during the week of intensive care despite parenteral
      nutrition supplying a daily dose of 130 mg of vitamin C. Such deficiencies
      decompensated in surgical situations remain a reality in developed countries.
      CONCLUSION: In certain pathological contexts and in all the growing number of
      cases in elderly patients and many surgical indications, the need for vitamin C
      supplementation has to be defined. The needs at that particular time must be
      taken into account and the prior nutritional status.

PMID- 15029030
TI  - [Brevundimona vesicularis bacteremia in a patient in aplasia].

PMID- 15029031
TI  - [Multiple sclerosis. New concepts and hope].

PMID- 15029032
TI  - [Can multiple sclerosis be diagnosed on a first demyelinating event?].
AB  - Progression is required. The definition of multiple sclerosis (MS) relies on the
      notion of temporo-spatial dissemination of inflammatory demyelinating
      neurological episodes. Until recently, in order to retain the diagnosis of
      definite MS, two successive neurological episodes had to be observed in two
      different territories. Since the commercialisation of new immunomodulating
      treatments, and in particular the recent demonstration of their efficacy in
      delaying the onset of a second neurological episode, it has been necessary to
      draw-up new criteria. New criteria have recently been proposed by a group of
      experts and they emphasize the fundamental role played by magnetic resonance
      imaging. New priorities. With these new criteria, certain aspects have become
      front-line. This is the case of the necessity of foreseeing more exhaustive
      differential diagnoses of MS, so as to avoid the erroneous initiation of a
      specific treatment. There is also the problem of the selection of patients at
      high risk of a potentially progressive MS, not all patients necessarily require
      such treatment at the start. Updating. We successively present the recently
      revised diagnostic criteria in order to be able to diagnose MS after the first
      demyelinising episode, we then study the clinical and paraclinical predictive
      elements that provide supplementary support for MS and, notably, progressive MS.
      We also discuss the differential diagnoses to be excluded according to the
      clinical context and, lastly, we will attempt to assess the practical
      consequences of an early diagnosis, not only with regard to its announcement, but
      also with regard to the therapeutic decisions to be made.

PMID- 15029033
TI  - [Are there arguments for initiating an etiological treatment at the onset of the
      first demyelinating episode?].
AB  - The arrival of immunomodulating treatments The pathology of multiple sclerosis
      (MS) took benefit from progresses of magnetic resonance-based and immunological
      studies, leading to the introduction of immunomodulatory agents and notably
      interferon beta (IFNbeta). The therapeutic impact of such treatments in the
      relapsing-remitting forms of the disease, and our improved knowledge on the
      natural history of the disease, raise the possibility of treating patients after
      the first demyelinating episode. This strategy may be more relevant in patients
      presenting poor prognostic criteria. Magnetic resonance imaging (MRI) data The
      clinical characteristics of the first episode do not help to predict the mean or
      long term progression. Magnetic resonance imaging has shown that the progression
      of the disease is partly infra-clinical. Other than data revealing demyelination
      involvement and inflammation, MRI has also provided arguments suggesting early
      axonal distress. In a patient, the presence of high lesion load at onset on
      weighted T2 sequences, of black holes and gadolinium enhancing lesions s on T1
      sequences, or the presence of new lesions on MRI conducted a few Months later are
      all predictive factors of clinical progression and suggest that treatment should
      be initiated early. The interest of interferon beta Two clinical trials have
      shown that treatment with IFNbeta treatment after a first demyelinating event
      significantly decreased the risk of a second episode in the short term. The aim
      of such treatment would be to limit the irreversible axonal lesions, notably in
      the form of axonal sections often associated with inflammatory lesions. An early
      reduction in the inflammatory response could lead to a lesser number of axons
      and, consequently, reduced clinical disability.

PMID- 15029034
TI  - [Aggressive multiple sclerosis. Definition and specific therapeutic indication].
AB  - Introduction. On the 29th of October 2003, mitoxantrone was approved by the
      french health agency Afssaps (Agence francaise de securite sanitaire des produits
      de sante) for its use in the aggressive forms of multiple sclerosis (MS). It is
      the first immuno-suppressor having demonstrated particular efficacy in this
      progressive form of MS. Definition of aggressive MS. Agressive multiple sclerosis
      is defined as an MS that leads to the rapid accumumation of disabilities, whether
      these latter are the result of repeated relapses (at least 2 in the past 12
      Months) or the continuous progression of a disability (increase in 2 points on
      the expanded disability status scale (EDSS) in the past 12 Months). The benefits
      of mitoxantrone. In cases of aggressive multiple sclerosis, mitoxantrone (20 mg
      IV), administered in Monthly cycles for 6 Months, clearly reduces the frequency
      of relapses, the appearance of new lesions on MRI and the progression of the
      disability. Precautions to be taken when using mitoxanthrone. The side effects
      however justify the fact that this drug is limited to the aggressive forms of MP.
      Cardiac toxicity limits the duration of the prescription and the maximum dose
      administered, requiring strict echocardiographical monitoring. Its unpredictable
      haematological toxicity can be devastating (risk of subsequent leukaemia). The
      benefit-risk ratio must be discussed with the patient and a Yearly
      echochardiography and three Monthly blood count must be continued during the 5
      Years following withdrawal of mitoxantrone. The prescription of mitoxantrone is
      limited to the neurologists of departments specialized in neurology.

PMID- 15029035
TI  - [The problematics of depression].
AB  - Doubt, one of the fundamental symptoms of depression. Patients frequently believe
      they're incurable. They are persuaded that nothing can be done for them. Most of
      the time, when they are told, they do not accept that they are going through a
      crisis, a critical period in life. The ever repeated question is: "What's the
      use?" Which shows to what extent the person is depressed and disillusioned. For
      them there is nothing that can be of any use. A frequent problem. The Yearly
      prevalence of phases of major depression in the general population in France is
      of around 10% and throughout life of more than 10% in men and 20% in women. In
      France the estimation is that more than one out of 7 inhabitants is depressed.
      The role of the general practitioner. The physician must help those who surround
      the depressed patient, but it is often necessary that the practitioner refer to a
      consulting specialist who will specify what type of depression the patient is
      suffering from, eventually make an assessment (using specific scales) of the
      intensity of the episode, and indicate which type of antidepressor is best
      adapted, the side effects that should be monitored, the associations to be
      avoided, and any control biological assays to be foreseen. The role of the
      specialist. In parallel, the specialist will schedule a psychotherapy, either
      maintenance or more structured (in such a way that the patients, if they wish,
      can work on the mechanisms that provoked the depression and hence protect
      themselves against any eventual relapse). The interest of co-therapies. It can be
      interesting that the general practitioners and specialists collaborate in the
      necessity for hospitalisation or not (with patient's consent or not), monitoring
      of a suicide risk, or the need to change treatment. The sharing of the tasks is
      always very positive for the patients. The patients, as those who surround them,
      are reassured by the fact that the family doctor and a specialist are
      collaborating in order to optimise treatment as rapidly as possible. The
      organisation of such co-therapies requires that the general practitioner also
      have good knowledge of the various types of psychotherapy available for the
      patient.

PMID- 15029036
TI  - [Magnetic resonance in osteoarticular exploration].
AB  - A major role in imaging of the locomotor apparatus. Today, magnetic resonance
      imaging (MRI) has replaced invasive explorations such as arthrography or
      saccoradiculography. However, x-rays and scans must often be performed
      beforehand. Indisputable indications. MRI is crucial in affections of the spongy
      bone (tumours, osteonecrosis, algodystrophy, fatigue fractures.) and the soft
      parts (tumours, myositis, fasciitis.). Depending on the situation. The
      indications for MRI must be weighed versus a scan or arthro-scan in many
      situations. In the case of strong suspicion of an internal articular disorder,
      the arthro-scan currently more precise must be preferred. In cases in which there
      is little clinical orientation, the MRI is justified because of its capacity for
      global articular and abarticular exploration.

PMID- 15029037
TI  - [Fever when returning from a tropical country].

PMID- 15029038
TI  - [Developing a questionnaire to evaluate pain in ocular or periocular pathologies:
      the ODEON questionnaire].
AB  - INTRODUCTION: Ophthalmologists contend with a wide range of painful acute and
      chronic diseases. However, there is no tool specific to ocular pain that aids the
      patient in describing and quantifying pain. PURPOSE: Our objective was to develop
      a tool that would allow the ophthalmologist to identify the patient's pain
      quickly and precisely in order to measure its intensity and to determine possible
      causes. METHODS: An interview guide was elaborated after a literature review.
      Structured interviews were conducted in hospitals by a clinical research
      associate with patients suffering from painful acute or chronic pathologies.
      Different types of quantification and description of pain were proposed to
      patients. A questionnaire was developed and tested. After the analysis of the
      tests, the ODEON pilot questionnaire (Objectif Douleur En Ophtalmologie et Neuro
      ophtalmologie: target: ophthalmic and neuro-ophthalmic pain) was developed.
      RESULTS: Twenty patients presenting ten different diagnoses were interviewed.
      Patients preferred to quantify pain with visual analogic or graduated scales.
      They appreciated the help of pictograms to describe their pain. Eight other
      patients presenting six different diagnoses tested the questionnaire. They judged
      the test version valid and easy to use, except for the section on emotional
      descriptors. An average of approximately 20 minutes was necessary to complete the
      questionnaire. After the tests, various questions were combined, reformulated,
      deleted or added. The ODEON pilot questionnaire contains five sections: 1.
      general health, 2. eyes and eyesight, 3. pain, 4. pain relief, 5. pictograms and
      sensorial descriptors. The closed- and open-ended questions included in these
      dimensions make it possible to measure patient pain and help the practitioner
      with patient management. CONCLUSION: The ODEON pilot questionnaire was developed
      under the supervision of a pilot committee involving clinicians and
      methodologists. Patients have indicated acceptance of this self-administered
      questionnaire during the cognitive debriefing and it is now being validated.

PMID- 15029039
TI  - [Efficacy and safety of a fluid carbomer gel versus a conventional carbomer gel
      in dry eye treatment].
AB  - AIM: To compare the risk/benefit for C974P (a 0.25% fluid carbomer gel in a vial
      allowing dropwise instillation) versus a conventional carbomer gel. MATERIAL AND
      METHODS: During this multicenter, randomized, investigator-masked trial, patients
      with dry eye syndrome were treated with C974P or C940. Control visits were
      planned on day 7, day 28 (efficacy evaluation) and day 56 (tolerance evaluation).
      The main criterion was dry eye symptoms globally assessed by a visual analog
      scale (VAS). The non-inferiority limit for the between-group difference of VAS
      changes was 10 mm. RESULTS: In the population of 169 patients (87 patients for
      C974P, 82 for C940), C974P was at least as effective as C940 on symptoms (non
      inferiority hypothesis confirmed). The mean VAS value fell by one third in the
      two groups. The objective signs improved identically in the two groups: corneal
      staining by fluorescein (p=0.96), rose Bengal score (p=0.73), and lacrimal break
      up time (p=0.73). The dosage adaptation was slightly lower than three
      instillations per day (p=0.16). The adverse events were mild or moderate.
      CONCLUSION: C974P galenic changes are able to reach the same level of efficacy on
      dry eye symptoms and ocular surface damages as the conventional tube carbomer
      gels.

PMID- 15029040
TI  - [Glaucoma screening in Martinique. Results in 813 hospital employees].
AB  - INTRODUCTION: Several US and Jamaican studies have shown that glaucoma is more
      severe in black populations than in Caucasian populations, which would lead to
      the assumption that the people of Martinique have a high glaucoma risk. METHODS:
      A prospective study was conducted in workers of Fort de France University
      Hospital with the occupational medicine unit. Intraocular pressure was measured
      with a pulse air tonometer (Topcon CT 60) and visual field abnormalities were
      detected with automated perimetry using Humphrey frequency doubling technology
      (FDT). Patients with known glaucoma or with intraocular pressure over 21 mmHg
      and/or a visual field abnormality were referred to ophthalmology examination to
      diagnose ocular hypertension, open-angle glaucoma or normal-pressure glaucoma.
      RESULTS: The occupational medicine unit examined 813 workers. The sex ratio was
      0.36, mean age was 45.35+/-8.4 years (22-64 years), and mean ocular pressure was
      12.1+/-2.62 mmHg (6-28 mmHg). Roughly 20% of workers had a family history of
      glaucoma. We found 22 patients with glaucoma (2.7%) (CI95: 1.6%-4%): 12 patients
      had open-angle glaucoma (1.5%) and 10 patients were diagnosed with normal
      pressure glaucoma (1.3%). Glaucoma prevalence increased with age, reaching 8% in
      patients over 55 years of age. Of patients with normal-pressure glaucoma, 42.9%
      had a family history of glaucoma. CONCLUSION: Our results confirm previous data
      from the literature that found higher glaucoma prevalence in black people and in
      particular in the mixed-race population of Martinique. In addition to this ethnic
      feature, the insularity of Martinique could support glaucoma expression. Easy and
      fast to use, FDT associated with the pulse air tonometer provides early detection
      of glaucoma.

PMID- 15029041
TI  - [Congenital achromatopsia: electroretinogram in early diagnosis].
AB  - PURPOSE: Achromatopsia is a hereditary disease responsible for congenital low
      vision. Patients present with nystagmus, abnormal visual behavior or photophobia.
      Only the electroretinogram (ERG) can confirm the diagnosis in infants. PATIENTS
      AND METHODS: Thirty children referred for nystagmus or low vision were included
      in this retrospective study. A complete ophthalmological examination, an ERG and
      when possible a color vision test (Ishihara, Farnsworth 15 Hue test) was done. A
      Ganzfeld ERG was performed in accordance with ISCEV standards in patients more
      than 6 years of age. In younger patients, a simplified method using
      electroluminescent diode stimulation was used and a comparative ERG in accordance
      with ISCEV standards was performed when the patients were old enough. RESULTS:
      The ERG response was identical in children and adults. It confirmed the diagnosis
      of achromatopsia: the scotopic components obtained in dark adapted conditions
      were normal, (scotopic a-wave, b2 wave). The photopic components, recorded in
      light-adapted conditions, in order to inhibit the scotopic response (photopic
      wave, b1 wave), were not recordable. The color vision tests confirmed color
      blindness; however, in some patients color denomination was correct. CONCLUSION:
      The simplified ERG procedures performed in our series were reliable in detecting
      achromatopsia. However, it may not be sufficient to discriminate complete from
      incomplete achromatopsia.

PMID- 15029042
TI  - [Intralesional corticosteroid injection in the treatment of chalazion].
AB  - OBJECTIVE: To evaluate the efficacy of intralesional corticosteroid injection in
      the treatment of chalazia in black African patients. METHODS: In a prospective
      study conducted between February 1999 and February 2000, 25 black African
      patients with chalazion (25 eyes, 29 chalazia), ranging in age from 15 to 54
      years (mean age +/- SD, 30.6+/-9 years), were treated with intralesional
      triamcinolone (injection of 0.075 - 0.5 ml triamcinolone acetate at a 5-mg/ml
      concentration). RESULTS: Success was achieved in 18 (72%) of 25 patients [20
      (74%) out of 27 eyes, 22 (76%) out of 29 chalazia)]. In 11 of 25 patients, two
      intralesional injections were necessary to obtain these results. Recurrence
      occurred in five eyes (five chalazia, 17%) after 5-6 weeks. During a mean +/- SD
      of 4.68 months (range, 3.5-12 months) of follow-up, no postinjection ocular
      complication occurred. CONCLUSION: Intralesional corticosteroid injection appears
      to be effective in managing chalazion in black African patients, as reported in
      previous studies in Caucasian patients. This treatment can be used when curettage
      is contraindicated.

PMID- 15029043
TI  - [Macular damage in Behcet's disease].
AB  - INTRODUCTION: The macular damage in Behcet's disease requires particular
      attention because of its poor prognosis. PURPOSE: The purpose of our study was to
      specify the frequency of macular alterations in Behcet's disease and discuss the
      clinical, physiopathological and therapeutic aspects. MATERIALS AND METHODS: Our
      report is based on 244 patients with Behcet's disease examined between January
      1995 and December 1997. The authors studied macular alterations in detail.
      RESULTS: Sixty-nine patients had a maculopathy affecting 108 out of 432 eyes
      (24%). The mean progression of Behcet's disease in these cases was 4 years.
      Visual acuity was<or=2/10e in 48 eyes (44.4%). Maculopathy was bilateral in 39
      cases. Macular edema was the most frequently noted form in 62% of the eyes,
      followed by cystoid macular edema (17%) and macular hole (3.4%). DISCUSSION:
      Macular edema is the most frequent sign and complication arising from the macular
      area during Behcet's disease, which can evolve into cystoid degenerescence and
      occasionally macular hole. Macular lesions are often irreversible, making
      prognosis uncertain, despite the various treatments available. CONCLUSION:
      Macular damage is the major cause of visual morbidity in patients with Behcet's
      disease and should be systematically sought.

PMID- 15029044
TI  - [Glucose tolerance of high-dose intravenous methylprednisolone therapy in
      ophthalmology].
AB  - INTRODUCTION: Short-term, high-dose intravenous methylprednisolone therapy, also
      called pulse methylprednisolone, is widely used in a variety of inflammatory eye
      diseases. Monitoring blood glucose during this therapy is recommended. We
      evaluated the clinical implications of glycemia monitoring during repeated pulse
      methylprednisolone for eye disease. PATIENTS AND METHODS: During the year 2000,
      224 patients received 120-1 000 mg daily intravenous methylprednisolone for 3
      consecutive days for acute optic neuritis (n=91), severe uveitis (n=35), ocular
      infectious diseases (n=22), corneal graft rejection (n=17) and miscellaneous
      disorders (n=59). Serial morning fasting blood glucose, i.e., before the first
      pulse and the day after each pulse, and specific hypoglycemic drug interventions
      were recorded. RESULTS: All patients showed a median 50% increase in fasting
      glucose after the first pulse with no significant difference between diabetic and
      nondiabetic patients. Thereafter, the 196 nondiabetic patients showed a
      spontaneous decrease in their fasting glucose towards baseline values despite the
      following infusions. However, none of them required hypoglycemic intervention. In
      contrast, the 28 diabetic patients demonstrated further increases in blood
      glucose levels and seven received rapid-release treatment. CONCLUSION: Glucose
      tolerance of pulse methylprednisolone was excellent in nondiabetic patients;
      close glycemia monitoring seems necessary only for patients with diabetes.

PMID- 15029045
TI  - [Branch retinal vein occlusion reveals Takayasu's arteritis].
AB  - We report a case of branch retinal vein occlusion in a 28-year-old woman that
      revealed Takayasu's arteritis. Somatic examination showed humeral blood pressure
      asymmetry and an abdominal murmur; a biological inflammatory syndrome was noted.
      Abdominal aortography showed marked stenosis of the superior mesenteric artery.
      Three of the six diagnostic criteria of Takayasu's arteritis were present in our
      patient, sufficing to make the diagnosis. This is the first case reported of
      branch retinal vein occlusion revealing Takayasu's arteritis. It is to be added
      to the List of atypical initial manifestations of Takayasu's arteritis such as
      anterior ischemic optic neuropathy. Branch retinal vein occlusion is a rare
      enough occurrence in a 28-year-old patient to warrant further clinical
      investigation.

PMID- 15029046
TI  - [Ocular metastasis of cutaneous melanoma].
AB  - We report a case of vitreal metastases from cutaneous melanoma. We describe the
      clinical findings and the histological aspects of the lesions, which allows us to
      discuss the diagnosis of masquerade syndrome and highlight the diagnostic
      importance of vitreous biopsy.

PMID- 15029047
TI  - [Anterior segment tumor imaging: advantages of ultrasound (10, 20 and 50 MHz) and
      optical coherence tomography].
AB  - PURPOSE: Detail the role of different imaging techniques for diagnosis of tumors
      of the iris. MATERIAL AND METHODS: Sixty-one tumors of the iris were explored
      using ultrasound at 10 and 20MHz (Cinescan, BVI Quantel Medical) and 50MHz (UBM,
      Paradigm) and optical coherence tomography (OCT) (Humphrey Zeiss). RESULTS:
      Ultrasound should be used at frequencies of 20MHz or greater to precisely
      characterize, localize and measure a lesion. Ultrasound biomicroscopy (UBM) is
      inadequate to measure large tumors (extending toward the back of the ciliary
      body), because of the transducer and the considerably lower image quality caused
      by the lesion. Ultrasound alone cannot characterize a solid lesion, and moreover
      cannot differentiate benign and malignant lesions. Clinical notions are also
      important in diagnosis and patient management. OCT recognizes whether a lesion is
      liquid or solid in certain cases. CONCLUSIONS: With a tumor that seems solid, a
      50MHz examination must be done rapidly, and if the entire lesion is difficult to
      see, a 20MHz ultrasound should be used. With a protruding iris, high-frequency
      ultrasound and OCT differentiate a cystic lesion from a solid mass, but only BMU
      provides a precise measurement and regular surveillance capabilities.

PMID- 15029048
TI  - [Posterior scleritis simulating acute posterior multifocal placoid pigment
      epitheliopathy].
AB  - INTRODUCTION: Posterior scleritis is a rare but probably underdiagnosed process.
      The lesions may cause diagnostic confusion with other diseases such as
      intraocular tumors and orbital or cerebral involvement. In the case presented,
      posterior scleritis simulated acute posterior multifocal placoid pigment
      epitheliopathy. CASE REPORT: A 43-year-old woman presented with a history of pain
      and eye redness with lid swelling in the left eye followed by visual
      deterioration. On fundus examination, there was disc and macular edema with
      multiple grayish-white placoid and deep chorioretinal lesions in the posterior
      pole. Fluorescein angiography was compatible with acute posterior multifocal
      placoid pigment epitheliopathy, but the inflammatory context was unusual in this
      disorder. An orbital computed tomographic scan and b-scan ultrasonography showed
      posterior scleral thickening and the diagnosis of posterior scleritis was made.
      Etiological investigations were negative. A pulse of corticosteroids was started
      and the patient's symptoms and signs improved on clinical and angiographic
      examination. DISCUSSION: Posterior scleritis may present with a range of clinical
      findings. Its clinical features may simulate many other diagnoses such as acute
      posterior multifocal placoid pigment epitheliopathy. Management is different in
      each situation: abstention in acute posterior multifocal placoid pigment
      epitheliopathy and a high dose of corticosteroids or even immunosuppressive
      therapy in posterior scleritis. CONCLUSION: This report shows that posterior
      scleritis must be evoked in patients with unilateral fundus appearance of acute
      posterior multifocal placoid pigment epitheliopathy associated with an
      inflammatory context. Ultrasonography or MRI must be carried out.

PMID- 15029049
TI  - [Cat's cratch disease and Parinaud's oculoglandular syndrome].
AB  - By presenting this case report describing Parinaud's oculoglandular syndrome, we
      review the medical literature on its most frequent etiology: catscratch disease,
      a self-limited, systemic illness caused by a Gram-negative bacillus, Bartonella
      henselae, principally affecting children under 15 years of age. Typical symptoms
      include regional lymphadenopathy, fever, malaise, and fatigue, possibly with more
      severe complications such as splenomegaly, granulomatous hepatitis, and
      encephalopathy. Ocular manifestations may include follicular conjunctivitis,
      Parinaud's oculoglandular syndrome, neuroretinitis, optic neuritis, and
      chorioretinitis. Diagnosis is based on serologic tests, and when necessary,
      antimicrobial treatment can be considered.

PMID- 15029050
TI  - [Orbital granulocytic sarcoma revealing acute myeloblastic syndrome: a case
      study].
AB  - Granulocytic sarcoma is a rare orbital complication of acute leukemia. It
      concerns primarily children under 10 years of age suffering from primitive acute
      myeloid leukemia. As this type of symptom can sometimes affect the elderly during
      the acute phase of myelodysplastic syndrome, it raises a problem with diagnosis
      and consequently with therapeutic treatments. We report the case of a 77-year-old
      female patient who had acute inflammatory proptosis during regressive right
      ethmoiditis. The diagnosis was reached by computed tomography showing an
      extraconical intraorbital tumor sprouting from the sinus, and by clinical
      examination and confirmed by the hematological investigation. Acute proptosis
      developing in an acute myeloblastic leukemia context heavily swayed diagnosis
      towards orbital granulocytic sarcoma. Chemotherapy by cytarabine and
      hydroxycarbamide associated with intravenous corticoid therapy resulted in
      complete disappearance of the proptosis within 10 days. This case report is a
      reminder of this peculiar sign of tumoral syndrome in acute myeloid leukemia. We
      also discuss different diagnostic methods and various therapeutic approaches, and
      analyze the disease course and patient follow-up.

PMID- 15029052
TI  - [Up-dated ophthalmological screening and follow-up management for long-term
      antimalarial treatment].
AB  - The early detection of macular toxicity linked to long-term antimalarial
      treatment requires regular ophthalmological screening based on
      patients'classification based on their results compared to successive controls.
      Patients are classified as "low risk" with screening every 18 months if all of
      the following criteria are met: age under 65 years, no associated renal, hepatic
      or retinal disease, treatment for less than 5 years, dose less than or equal to
      6,5mg/kg/d for hydroxychloroquine and 3mg/kg/d for chloroquine (for a lean
      patient's weight); "at risk, without fundus findings" with screening every 12
      months if one of the following criteria is met: age over 65 years (at the start
      of or during treatment), antimalarial treatment for more than 5 years, daily dose
      higher than recommended, presence of renal and/or hepatic disease; "at risk, with
      fundus findings" with screening every 6 months if a retinal dysfunction has been
      detected and even if treatment is established or followed. Screening consists of
      an in-depth clinical examination and at least two complementary tests of macular
      function: color vision (desaturated-Panel-D15 test) and/or static macular
      perimetry (central 10 degrees) and/or macular electroretinography (pattern
      ERG/multifocal ERG). If any changes or anomalies are found between two successive
      check-ups, the state of the retina can be assessed by angiography and global
      retinal function by full-field-ERG and electro-oculogram (EOG). The progression
      from one check-up to the next decides whether a course of treatment will be
      followed.

PMID- 15029051
TI  - [Extensive peripapillary myelinated nerve fibers, high ipsilateral myopia and
      refractory amblyopia].
AB  - INTRODUCTION: Extensive peripapillary myelinated nerve fibers can be associated
      with myopic anisometropia amblyopia. Despite aggressive occlusion of the good
      eye, visual results are often disappointing, probably because of structural
      anomalies of the macula, limiting visual potential. OBSERVATION: The authors
      report the case of a 5-year-old girl presenting extensive peripapillary
      myelinated nerve fibers associated with myopic anisometropia. Amblyopia did not
      respond to optical correction and continuous occlusion of the good eye for 9
      weeks. DISCUSSION: Certain authors report obtaining good results with aggressive
      treatment of amblyopia associated with extensive peripapillary myelinated nerve
      fibers and myopic anisometropia. However, the majority of the few series
      published in the literature report that amblyopia related to this pathology is
      particularly refractory to treatment, as confirmed by the case study presented
      herein. CONCLUSION: Despite a certain number of cases with a good prognosis
      reported in associated peripapillary myelinated nerve fibers and ipsilateral
      myopia, we believe that its visual prognosis remains reserved and that patients
      and/or their families should be provided with appropriate information.

PMID- 15029053
TI  - [Neurotrophic keratitis].

PMID- 15029054
TI  - [Chalazion mimicking an eyelid tumor].
AB  - A 3-year-old girl had a tumor growing for a month on the superior right eyelid,
      attached on the free margin of the eyelid and partially necrotic. A surgical
      excision was performed under general anesthesia. The histopathological study
      found an inflammatory lesion with epithelioid and giant cells, evidence of a
      granuloma, suggesting the diagnosis of chalazion. This case shows the various
      clinical presentations of this common and benign disease of the eyelid.

PMID- 15029055
TI  - The Birmingham Eye Trauma Terminology system (BETT).
AB  - PURPOSE: To evaluate the international eye injury scene and design a standardized
      terminology for mechanical eye injuries. METHODS: Surveys of practicing
      ophthalmologists and an extensive review of the international ocular trauma
      literature. Development of the Birmingham Trauma Terminology (BETT) using a logic
      based approach. RESULTS: BETT always uses the entire globe as the tissue of
      reference. Its well-defined terms encompass all types of mechanical eye injury. A
      one-to-one relationship exists between terms and clinical conditions. CONCLUSION:
      BETT provides an unambiguous, consistent, simple, and comprehensive system to
      describe any type of mechanical globe trauma. Endorsed by several societies and
      peer-reviewed journals as the standardized international language of ocular
      traumatology, BETT is expected to become the preferred terminology for
      categorizing eye injuries in daily clinical practice.

PMID- 15029056
TI  - [Digestive and visceral surgeons: an endangered species?].

PMID- 15029057
TI  - [Organizational aspects of organ harvesting in France].
AB  - Organ transplantation of kidneys, liver, heart, lungs and pancreas is a routine
      practice in numerous French surgical centers with very good long-term results.
      Tissue transplantation of cornea, blood vessels, bone, and cardiac valves has
      also shown its efficacity and these tissues should be harvested whenever
      possible. Brain death is defined as the complete and irreversible destruction of
      the brain stem and cerebral cortex. The diagnosis of brain death is largely
      clinical but must be confirmed by EEG and cerebral arteriography. The Law of
      Caillavet has established the concept of "presumed consent" and has defined the
      judicial framework to permit organ harvesting. Nevertheless, there is still a
      high level of refusal of organ donation (in a third of cases) by the family of
      the decedent. At local and regional levels, control and coordination are provided
      by trained teams in liaison with the French Establishment for Transplantation
      (Etablissement francais de greffes). The number of organ harvests grows steadily
      (18/million inhabitants in 2001) yet remains insufficient to meet the needs of
      the ever lengthening list of patients awaiting transplant. The profile of
      potential donors has also changed with time and poses increasing problems with
      regard to the quality of harvested organs.

PMID- 15029058
TI  - [Right colon diverticulitis].
AB  - Diverticulitis involving the right colon is uncommon in the Occident; only one
      case for every 300 cases of appendicitis occurs in Western countries compared to
      a ratio of 1/40-1/180 in Asia. The preferential localization of diverticula in
      the right colon among Asiatics is probably due to genetic factors. In Asia as in
      the West, a right colon diverticulum is more likely to cause hemorrhage than
      diverticulitis. The peak age of symptoms is 40-45 years and the sex ratio is 1:1.
      The patient most commonly presents with symptoms suggestive of acute
      appendicitis, acute localized peritonitis, or, more rarely, a psoas abscess.
      Clinical exam reveals an inflammatory mass in the right lower quadrant in 30% of
      cases; diffuse peritonitis, large abscesses, and fistulae are rare. Helical CT
      scan is the best tool for establishing the diagnosis and also helps to rule out
      other possible etiologies in the differential diagnosis-particularly a perforated
      right colon cancer. In noncomplicated cases with convincing evidence for the
      diagnosis by CT scan, a conservative (non-surgical) treatment with antibiotics is
      possible; a later stage colonoscopy will rule out other colonic lesions. More
      commonly, the correct diagnosis is only made after embarking on an appendectomy
      via a McBurney incision; the surgical strategy thereafter depends on the level of
      suspicion regarding the diagnosis and the extent and complexity of the
      diverticulitis. Therapeutic options may be conservative (appendectomy), limited
      (diverticulectomy, or extensive (ileocecal resection or right hemicolectomy). For
      complicated disease (abscess, localized perforation), an aggressive surgical
      approach is warranted. Surgical strategies need to be validated, particularly in
      the light of the increasing use of the laparoscopic approach for suspected
      appendicitis.

PMID- 15029059
TI  - [The technique of Trans-Jugular Porto-systemic Shunt (TIPS)].
AB  - The placement of a Trans Jugular Portosystemic Shunt (TIPS) demands a precise and
      rigorous surgical technique. The steps for insertion are: 1) Puncture of the
      right internal jugular vein with ultrasound guidance; 2) Selective
      catheterization of the right hepatic vein; 3) Transparenchymal direction of the
      catheter into a branch of the right portal vein; 4) Dilation of the parenchymal
      tract; 5) Deployment of an expanding metallic veno-venous shunt. Post-operative
      care and the most common complications are discussed.

PMID- 15029060
TI  - [How I do it: perihepatic tamponnade].

PMID- 15029061
TI  - [Endoscopic thoracic sympathectomy for hyperhidrosis of the upper extremity].

PMID- 15029062
TI  - [Techniques for extraction and biliary drainage with laparoscopy].

PMID- 15029063
TI  - [Sigmoid colon adenocarcinoma after uretero-sigmoidostomy].

PMID- 15029064
TI  - [Hepatic metastases following chemotherapy].

PMID- 15029065
TI  - [Carcinosacroma of the gallbladder].

PMID- 15029066
TI  - [105th French Congress of Surgery (Paris, October 2-4, 2003)].

PMID- 15029071
TI  - [Girls are more successful than boys at the university. Gender group differences
      in models integrating motivational and aggressive components correlated with Test
      Anxiety].
AB  - It is surprising to note the evolution of success rates in Belgian universities
      especially in the first Year. Men are less successful than women and the
      differences are escalating in an alarming way. Dropouts take the same direction
      and women now represent a majority of the students at the university. In a
      previous study, we assessed 616 students in the first Year at the university of
      Liege with Vasev, the English name of which was TASTE, a self report
      questionnaire constituted of 4 factors: anxiety, self confidence, procrastination
      and performance value; anxiety particularly concerned somatic expression of
      students before and during test evaluations; self confidence was a cognitive
      component close to self efficacy; procrastination was the behavioral component
      characterizing avoidance when students are confronted with the risk of failure;
      performance value referred to intrinsic and extrinsic motivations. French
      validation of TASTE led to an abbreviated version of 50 items (THEE) consisting
      of 5 factors, the four of TASTE and an additional one, very consistent, at first
      called depression because of its correlations with this dimension, then called
      sense of competence on account of its semantic content. Self-competence has been
      described in the literature of Achievement Motivation and corresponded to
      expectancy and ability beliefs in performance process which was also relevant to
      self-efficacy except the particularity of comparison with others, which was not
      included in the last construct. Self-competence has been considered as an
      important part of the Worry component of test anxiety. Some Authors didn't
      hesitate to view causality flowing from self-competence to test anxiety and have
      conceptualized the latter as a failure of the self where one's sense of
      competence has been undermined as a result of experienced failure. In our study,
      only that factor was equally scored in women and men whereas it was scored higher
      in failed students. In other respects anxiety and performance value were scored
      higher in women, self-confidence and procrastination higher in men. Because TASTE
      didn't discriminate the different components of motivation (performance value
      referred to intrinsic and extrinsic motivations without precise distinction) we
      decided to use the MPS (Multidimensional Perfectionism Scale) which gave the
      opportunity to distinguish SOP (Self Oriented Perfectionism) ie, the self-imposed
      unrealistic standards with inability to accept faults in order to know and master
      a subject, that corresponded to intrinsic motivation; SPP (Socially Prescribed
      Perfectionism) ie, the exaggerated expectancies of others which are subjectively
      believed as imposed and uncontrollable leading to anxiety, feelings of failure or
      helplessness, that corresponded to extrinsic motivation; POO (Perfectionism
      Oriented to Others) ie, the unrealistic demands expected from significant others,
      which especially characterized males. We assumed that women attached more
      importance to succeed and submitted more to society exigencies. That way
      extrinsic and intrinsic motivations were probably more combined unlike men who,
      dreading a loss of self esteem, tried to avoid failure responsibility in using
      self handicapping or aggressive behaviours, so separating motivation in an
      extrinsic part turned to performance value and an intrinsic one more concerned by
      self confidence and sense of competence with the result that the motivational
      balance was surely disrupted in case of high competition leading to failure or
      avoidance. In another previous study we established a structural model
      illustrating, according to gender, correlations between anxiety, sense of
      incompetence, self-oriented perfectionism and socially prescribed perfectionism.
      Self-oriented perfectionism was less correlated to socially prescribed
      perfectionism in boys than in girls; furthermore especially by those who had
      never failed, it was negatively correlated to sense of incompetence, thus leading
      to lower scores of anxiety while in girls, by contrast, such a correlation didn't
      exist, thus involving higher anxiety. That way, on the one hand, intrinsic and
      extrinsic motivations by female students complementarily operated on the sense of
      incompetence and consequently on anxiety, the emotional component of test
      anxiety; on the other hand, by male students, intrinsic motivation had a negative
      correlation with the sense of incompetence and a lower correlation with extrinsic
      motivation, thereby shedding some light on the problem of anxiety level
      differences according to gender. More, that observation corresponded well to the
      model of self-worth where test anxiety was understood as a manifestation of
      perceived incompetence and as a defensive way to ward off negative self
      evaluation; that model suited particularly well to boys and explained their
      attempts to maintain self-worth when risking academic failure. The present
      research assumes that independence or combination of motivation components is
      also correlated to different expressions of aggressiveness: hostility
      corresponding to threat and characterizing more girls while physical aggression
      is corresponding to personal challenge, a more masculine attribution. If fighting
      against the sense of incompetence actually characterizes men and consequently
      shows too the competitive aspects of performance strong enough to mobilize
      intrinsic motivation, what would be expected regarding the notion of threat
      suspected to be predominant in girls? The idea of using a questionnaire
      discriminating the specific dimensions of aggressiveness in fact the Aggression
      Questionnaire should meet the following purposes: At first establish a French
      version of that aggression questionnaire, perform the factorial analyses and
      internal consistency, compare them with other previous samples, then
      differentiate gender in general and in failure versus success situations. Finally
      include the different components of aggressiveness in the first described model
      and build a new one liable to define in boys the explicit pathways between test
      anxiety, perfectionism and aggressiveness. Statistical analyses have confirmed,
      in a 3 factor solution, the presence of emotional (anger), cognitive (hostility)
      and behavioural (physical aggression) components. Internal consistency is
      satisfactory. It is demonstrated that physical aggression characterizes boys
      (F=12.04, p=0.0001) while hostility (F=5.22, p=0.0015) and anger (F=0.49,
      p=0.0001) characterizes girls; furthermore it is noted that physical aggression
      characterizes more failed students (F=13.43, p=0.0003). Four models (see figures
      2, 3, 4, 5) have been established, at first focused on the distinction of
      correlations between motivation and cognitive and emotional components on the
      samples of boys (n=268) and girls (348), then developed on the samples of
      successful students, male (n=193) and female (n=271). They describe the
      differentiated action of intrinsic and extrinsic motivations on the different
      components of aggressiveness and test-anxiety according to gender and without
      experience of failure. The dynamic process of the organizational factors is
      different according to gender and psychopathology resulting from the combinations
      of behaviors, cognitions and emotions would be assumed, prioritizing physical
      aggression and psychopathy by boys, anxiety and depression by girls. Anyway more
      explanation about the evolution of success rates of boys and girls in Belgian
      universities is proposed.

PMID- 15029072
TI  - [Psychological and social factors predictive of loneliness: a cognitive and
      behavioral approach].
AB  - The objective of the present study was to explore the psychological and social
      mechanisms leading to loneliness. Based on cognitive and behavioral approaches
      developed in health psychology, we tested several models that might allow one to
      predict certain determinants of the feeling of loneliness. Included in the study
      were 45 individuals suffering from loneliness who had come to one of several
      Centres Therapeutiques de Lutte contre l'Isolement "Recherche et Rencontres". The
      subjects were asked to respond to four scales: the UCLA loneliness scale,
      Cattell's 16 PF 5 personality scale, Sherbourne and Stewart's social support
      scale, and Lazarus and Folkman's Ways of Coping Checklist. The present results
      confirm the previously reported deficit of social support perceived by subjects
      in this population. Concerning their personality, this population sample falls
      outside national norms in 7 dimensions: compared to the general population, the
      socially isolated individual appears essentially to be introverted and anxious,
      emotionally unstable, avoiding conflicts, timid and ill at ease in the company of
      -others, imaginative and distracted. To face up to their feeling of loneliness,
      they have a tendency to use coping styles such as "keep it to yourself" and
      "wishful thinking". On the other hand, they resort very little to social support.
      Among the pertinent variables, 5 predictive factors were recognized, and they
      could explain 51% of the variance in the feeling of loneliness: they include the
      global score of perceived social support, coping strategies focussed around
      wishful thinking, coping strategies that avoid resort to social support,
      personality traits of imaginativeness and absent-mindedness, and an introverted
      personality. Three predictors contributed independently to the model: absence of
      resort to social support, the use of wishful thinking, and the imaginative
      distracted personality trait. We likewise found evidence for a mediator role of
      the absence of resort to social support in the relation between the levels of
      perceived social support and the feeling of loneliness. Thus it is not so much
      the deficit in the subject's social relations that determines his feeling of
      loneliness as it is his difficulty of appealing to others when in distress. These
      results suggest that it would be judicious to develop specific therapeutic
      interventions for this type of person that would permit them to adjust more
      actively and to behave more realistically.

PMID- 15029073
TI  - [The alcoholic's self-image: a comparative study between men and women].
AB  - Self-image is a central problem in alcoholism. Most theories about the
      relationships between the self-image of alcoholics and their behaviour have been
      derived from -clinical observations rather than empirical research. Most
      observations have pointed out that alcoholics are prone to underevaluation of
      themselves and that low self-image is the basis of much of the problem drinker's
      behaviour. All the research on self-image has concluded that alcoholics have a
      lower self-image than non-alcoholics. Some empirical research has been conducted
      on the self-image of alcoholics; it has, however, been carried out only a few
      times, restricted to small samples, and concerned with a limited number of
      aspects of self-image. Moreover, most of these studies are not recent, and it
      seems that this area of research is not well covered. Even though the hypothesis
      of a bad self-image in alcoholics was validated by various older studies, the
      representation of alcoholism has since changed. Because of this evolution, the
      ways in which the disease has been viewed have changed. One can question to what
      extent changes in society can influence the self-image of alcoholics. This
      question seems all the more pertinent for alcoholic women, given the evolution of
      the female condition since the Seventies. The objectives of this study are to
      evaluate the self-image of alcoholics and non-alcoholics, and to compare the self
      image of male and female alcoholics. Our hypotheses are that: 1) the self-image
      of an alcoholic is more negative than that of a non-alcoholic, and that: 2)
      female alcoholics have a more negative self-image than male alcoholics. Two
      groups of 30 subjects each were made up: a group of alcoholics recruited in an
      alcohol-dependency unit and a group of non-alcoholics recruited in a public
      place. The comparison of socio-demographic data between the alcoholic group and
      the control group does not show a significant difference except for age and level
      of schooling. The average age of the control group is younger than that of the
      alcoholic group. The level of schooling of the control group is higher than that
      of the alcoholic group. These differences can be explained by the mode of
      recruitment of the participants. The significant differences between the
      alcoholic men and women are at the level of the number of Years of alcoholism,
      the age at which the disorder began and the number of detoxification episodes.
      These differences are probably due to cultural background. Indeed, the age at
      which alcoholism begins is later in women and they consult more quickly than men.
      The two groups were assessed using the Tennessee Self Concept Scale and the Self
      Esteem Inventory. Other tests were used to control factors capable of influencing
      self-image (depression, socio-demographic data). The results show that the
      alcoholics have a more negative self-image than the control group. The alcoholics
      perceived themselves significantly less favourably on the identity (what I am),
      self-satisfaction (how I feel about myself), and behaviour (what I do) scores
      than did those in the control group. The alcoholics also saw themselves in a
      significantly more negative light than did those in the control group on the
      scores relating to physical self (body, health.), moral-ethical self (moral
      worth), personal self (evaluation of personality), family self (adequacy and
      value as a family member) and social self (adequacy and worth in interaction with
      others). The self-criticism subscale provided further evidence that the
      alcoholics were more open and self-critical than were those in the control group.
      Female alcoholics had a lower self-image than male alcoholics, but not in every
      aspect. There was a significant difference between the scores of alcoholic women
      and alcoholic men, for three of the subscales measured by the Tennessee Self
      Concept Scale: "general self-image", "personal self" and "self-criticism". The
      alcoholic women perceived themselves more negatively when it came to "self
      satisfaction", "personal self" and "social self". They were however more positive
      than the men in the sectors of "identity", "behaviour", "physical self", "moral
      ethical self", and "family self". The alcoholic men were more openly self
      critical than the alcoholic women. Our results confirm the conclusions of
      empirical studies and of clinical observations. Alcoholics see themselves as
      generally inadequate and unworthy of respect. The changes in representations of
      this disease seem to have influenced the alcoholic's self-image, but it remains
      however very negative. The alcoholics'negative self-image is generalised and not
      specific to personality and behaviour. The -representation of alcoholism seems to
      have contributed to an improvement in the self-esteem and self-image of
      alcoholics, and in particular of female alcoholics. Even if the self-image of
      alcoholic women remains more negative than that of alcoholic men, it tends to
      bring back the self-image of alcoholic women to a level close to that of the men.

PMID- 15029075
TI  - [Depressive disorders among epileptic patients attending a specialised outpatient
      clinic].
AB  - The overall prevalence of psychiatric disorders in epileptic patients is
      estimated between 19 and 62%. Depressive disorders may be the most common
      psychiatric disorders and the main reason for psychiatric hospitalisation and
      taking psychotropic drugs. The underdiagnosis and undertreatment of depressive
      disorders among epileptic patients represent a problem of considerable magnitude.
      The aim of the present study was to evaluate the prevalence of depressive
      disorders among patients with primary epilepsy and to determine the risk factors
      of the occurrence of the depressive illness. The survey was conducted in a
      outpatient epilepsy clinic in the Ibn Rochd University Hospital Centre in
      Casablanca. All patients with idiopathic or cryptogenic epilepsy aged 15 Years
      and above, were eligible, except for patients with severe physical and mental
      disabilities. Neurologists diagnosed the epilepsy based on clinical criteria with
      electroencephalograms data. The depressive disorders met a psychiatrist's
      evaluation of an ICD-10 criterion. Ninety-two subjects participated in the
      survey, 57.6% were men and the mean age was 30.3 +/- 10.8 Years. The epilepsy age
      of onset was 16.3 +/- 11.4 Years with an average duration of 14.1 +/- 9.2 Years.
      The prevalence of depressive disorders among epileptic patients in our survey was
      18.5%. According to sex, the prevalence was 23.1% in women and 15.1% in men. The
      depressed patients were compared with the remaining patients without depression
      with regard to seizure variables and sociodemographic characteristics. The
      epilepsy-depression and epilepsy-control groups did not differ significantly in
      the duration of epilepsy or in the type of anticonvulsant therapy (mono versus
      polytherapy). Three variables were significantly different between the two
      groups. The mean age in the epilepsy-depression group was significantly higher
      (34.4 +/- 9.6 Years versus 29.4 +/- 10.9, p<0.03), the mean age of epilepsy age
      of onset was also higher in the epilepsy-depression group than in the epilepsy
      control group (21.8 +/- 11.9 Years versus 15.04 +/- 11.0, p<0.03) and the seizure
      frequency per week was more important among depressed epileptic patients (2.4 +
      5.2 seizures versus 0.4 + 1.5, p<0.007). The present survey confirms the findings
      of previous studies that the prevalence of the comorbidity between epilepsy and
      depression is common in specialised outpatient units. The detection and the
      treatment of depressive disorders among the epileptic patients remains a very
      great challenge in the management of the epileptic illness. It will improve the
      quality of life of these patients. A closer involvement of psychiatric and
      psychological treatment in patient management is necessary.

PMID- 15029074
TI  - [The practice of restraint in a psychiatric emergency unit].
AB  - The practice of physical restraint is relatively frequent in medical emergency
      and geriatric units. Its use in psychiatry is controversial. Although distinct,
      it is often associated with seclusion, as a response to or prevention of agitated
      mentally ill patients'behavior. A detailed review of the literature shows the
      scarceness of work defining the exclusive use of restraint without seclusion. We
      report a naturalistic study over 6 Months, covering 76 cases having required
      restraint. The study of the international literature concerns nursing care,
      geriatric, child-adolescent psychiatric and adult psychiatric reviews. The
      restraint is a usual practice in general care like emergency, intensive care or
      geriatric units in order to prevent the patients from falling or to administrate
      certain care. Legal action has been reported as a consequence of lack of
      information or agreement of the family. The psychiatric use of restraint is
      conceived as an additional measure to seclusion, which is a controversial
      procedure from a therapeutic point of view as well as because of its long
      duration of application. The practice of restraint described in French
      literature, from Pinel (in to Daumezon and from French hospital regulations to
      "transparency forms", seems to be more easily accepted for its short duration and
      its careful prescription in order to maintain relations with the patients,
      including agitated children. We made a 6 Months retrospective study in a Parisian
      psychiatric emergency unit receiving an average of 30 patients a day. The rate of
      restraint is 1.4%. The objective was to describe the main clinical,
      epidemiological and situational characteristics and to define quality criteria
      concerning restraint regarding to the existing standards. We had at our disposal
      a restraint protocol in order to avoid its prescription as a punishment or for
      the comfort or the convenience of an insufficient staff. The decision of the
      restraint is directly prescribed by a physician or decided in emergency by the
      nurses and then rapidly confirmed by medical prescription. In short, most
      restrained patients are male, the average age is 32 Years old, and the diagnoses
      associated with restraint in order of frequency are schizophrenia, personality
      disorders, acute psychotic episodes, manic episodes and toxic abuses. The main
      early-warning signs are aggressiveness, delusions, opposition, paranoiac thoughts
      and distrust. The average duration is 2 hours with continuous clinical
      supervision and a relational contact maintained. Our study confirms the notion of
      cumulate restraint days. Actually, 43% of the restraints happen on the same day
      as others do. The high rate on those days could be as Fischer hypothesized the
      result of instinctive, aggressive and sexual release of the staff, as well as the
      consequence of an increase in anxiety and agitation of the other patients. The
      legal framework is more the duty of assistance to a person in danger than
      constrained hospitalization, which is not systematically pronounced. No injury or
      somatic complication occurred during restraint. Neither complaint from the
      patient or his family nor sick leave of staff was recorded. The specific use of
      restraint can be compared to the existing standards for using the seclusion room.
      Among those standards only 1 of 23 criteria was not verified. The others was
      applicable or without object. The therapeutic use of restraint requires the
      development of specific quality standards, and the existing criteria concerning
      seclusion represent a necessary but insufficient answer. We emphasize the need to
      take into account the early warning signs, a response to the cumulative restraint
      days, as well as a satisfaction study on patients and the feasibility of such a
      study in an emergency service.

PMID- 15029076
TI  - [Pharmaco-epidemiology of antipsychotic prescription practices for schizophrenic
      patients (1995 and 1998 cross sectional surveys)].
AB  - OBJECTIVE: The two cross-sectional surveys reported here concern the field of
      pharmaco-epidemiology of prescription practices. The objective is to describe and
      understand these practices in regard to antipsychotics and their evolution in all
      indications which go beyond the field of psychotic pathology. The research
      presented here only concerns schizophrenic pathology. METHODOLOGY: These 2 cross
      sectional surveys were carried out in public psychiatric sectors in 1995 and 1998
      applying the same methodology in the same services. On a given day, in each
      sector, they concern all patients aged from 18 to 64 and receiving an
      antipsychotic prescription. A hospital unit and a consultation unit were included
      to take into account practices which could be different in these two places of
      care. A comparison was made between the 1995 stage and the 1998 one for a better
      understanding of evolution in practical terms. An unvaried analysis was carried
      out to test the differences observed between 1995 and 1998 as well as a
      correlation test to evaluate evolution according to age and duration. RESULTS:
      The main results were as follows: the number of antipsychotics slightly decreased
      significantly from 1.74 (+/- 0.02) in the 1995 survey to 1.69 (+/- 0.04) in the
      1998 one (p<0.05); the number of patients receiving antiparkinsonian medicines,
      correcting extra pyramidal effects, decreased from 60% in 1995 to 50% in 1998.
      The following associated factors were noted concerning prescription of
      antipsychotics. Women received a mean number of antipsychotics significantly
      lower than that of men. For each sex the mean number was lower in the 1998
      survey, but not significantly so. In the two surveys, there was a positive
      correlation between the mean number of antipsychotics and age; it increased as
      the patient grew older. The mean number of antipsychotics tended to increase
      significantly with length of illness, in 1995 as well as in 1998. It was for the
      shortest periods that the mean number of antipsychotics was lowest. The mean
      number of antipsychotics was significantly higher in the hospital field as
      compared to the ambulatory. The greater was the mean number of antipsychotics,
      the greater was the proportion of patients who received antiparkinsonian
      medication. Firstly, these surveys shed light on what may underlie prescription
      practices such as sex and age of the patient, length of illness and the place of
      care. Secondly, the evolution of practices in time can be followed, taking into
      account the increase of knowledge concerning this subject.

PMID- 15029077
TI  - [Loss of motivation and frontal dysfunction. Role of the white matter change].
AB  - Since the recognition of white matter changes on computed tomography, researches
      were done to investigate a possible relation with ageing and cognition. This
      study examined whether computed tomography evidence of cerebrovascular disease in
      the form of white matter changes was associated with decreased implicit
      performance of frontal tests and with a loss of motivation in a group of 10
      elderly volunteers with a mild cognitive impairment and in a group of 29 demented
      patients; 39 old patients (28 females: 82.4 +/- 7.1; 10 males: 75.5 +/- 11.3)
      cared in a psycho-geriatric day care hospital were enrolled for this essay.
      Motivation was evaluated with a specific scale: EAD. Patients were tested during
      the same period with MMSE for cognition, Cornell's scale for depression, Marin's
      scale for apathy. There were also assessed with a battery of frontal tests: BREF
      test. A brain scan was used to determinate the presence of leukoaraiosis. Table 1
      give a description of the population according to the pathology. Cognitive
      disorder, but also apathy and loss motivation, frontal evaluation significantly
      differ in the two studied groups. The presence of a leukoaraiosis is associated
      with older people, a weaker cognitive status, a more important apathy or loss of
      motivation, and weaker results with frontal evaluation (table 2). Similar results
      were obtained considering only the frontal lesions (table 3). Age related changes
      of the white matter observed on computed tomography were associated with a
      decreased cognitive status. Leukoaraiosis is associated with loss of motivation
      and related with a poor results on frontal assessment. Loss of motivation is
      associated with certain frontal dysfunctions and with brain abnormal scan
      anomalies.

PMID- 15029078
TI  - [The subjective quality of life of patients with schizophrenia: influence of
      psychopathology and patients' expectations. A comparative study].
AB  - Most studies on the quality of life (Qol) of patients with schizophrenia deal
      with objective living conditions and how they are perceived by hospitalized
      patients. The few studies that compare Qol for patients treated in part time
      services with the Qol of ambulatory patients do not show any significant
      difference in terms of subjective Qol. Some stu-dies evaluate the influence of
      psychopathology and needs (or expectations) on the subjective Qol in these groups
      of patients. Available data indicate that the general well-being is influenced by
      psychopathology (positive, negative or depressive symptoms) and unmet needs in
      ambulatory patients. They also show that subjective Qol in certain life domains
      (social relations, family relations, leisure, health, law and security) is
      influenced by negative symptoms, anxiety and depression in patients treated in
      part-time services. The aim of this study is to compare the objective and
      subjective Qol of patients with schizophrenia treated in part time services (day
      hospital and day care center) to the Qol of out-patients treated on a purely
      ambulatory basis (out patient clinic). We studied the Qol of 2 groups of 30
      patients with schizophrenia (ICD 10 criteria) treated in various centers. The
      first group was made of ambulatory patients, the second one was constituted of
      patients treated in a day hospital or a day care center. Patients were matched
      for age, duration of illness, number of hospitalizations. The instruments used
      for rating were the following: Clinical Global Impression (CGI), Global
      Assessment of Functioning (GAF), Positive And Negative Symptoms Scale (PANSS),
      Drug Attitude Inventory (DAI-10). The Qol was measured with a french version of
      the Lancashire Quality Of Life Profile (LQOLP) (Salome, Germain, Petitjean,
      Demant and Boyer, 2000). This instrument measures the objective Qol as well as
      the subjective Qol. It does possess satisfying psychometric properties and offers
      the possibility to establish Qol profiles. All Qol ratings were carried out by a
      clinician who was not involved in the treatment of the patients. When the 2
      groups are compared our results indicate that ambulatory patients are less
      symptomatic, have a better level of functioning and a better objective Qol in
      such domains as: finances, living situation, family relations and health. There
      is no significant difference in terms of anxiety and depression as measured by
      the respective items of the PANSS. Patients treated in part-time services present
      higher scores of positive symptoms. Our results indicate that there is no
      significant difference for subjective Qol variables between the two groups,
      except for general well-being, that tends to be higher in ambulatory patients.
      When exploring the influence of clinical data on the Qol in each group, we find
      negative correlations in ambulatory patients between various domains of
      subjective Qol and illness severity (law and security, family relations, social
      relations, general well-being), global functioning (family relations, social
      relation, health) and positive symptoms (living conditions, law and security,
      family relations, social relations, health). In this same group, the subjective
      Qol for family relations is significantly correlated with several expectations in
      terms of Qol improvement (leisure, social relations, family relations, transport,
      work). In these patients, the subjective Qol for social relations is also
      significantly correlated with their expectations in terms of Qol improvement
      (work, money, lodging, affective relations, transport). There is no significant
      correlation between subjective Qol and expectations in patients treated in part
      time services. Our results indicate that part time services treat schizophrenic
      patients with a lower level of global functioning and a higher level of symptom
      severity compared with ambulatory patients. These results confirm other studies
      that show no significant difference between these 2 groups in terms of subjective
      Qol. The subjective Qol in the field of relations (family and social) in
      ambulatory patients seems particularly sensitive to illness severity, positive
      symptoms and global functioning level. This has also been reported by other
      studies. In patients treated in part-time services, the subjective Qol,
      particularly for living conditions and security, seems sensitive to anxiety and
      depression. This has also been shown by other studies. Finally, our results
      underline the importance of patients' expectations in terms of subjective Qol,
      particularly in the field of relations (family and social) for ambulatory
      patients.

PMID- 15029079
TI  - [Memantine (Ebixa): a new therapeutic strategy for the treatment of moderate to
      severe forms of Alzheimer's disease].
AB  - Alzheimer's disease has definitively emerged from its ghetto and has been
      identified as a (priority) public health concern in view of the increasing age of
      the population. Considerable advances have been made in this disease over the
      last 15 Years, with progress in the following fields: knowledge of the underlying
      aetiopathogenetic, genetic and biochemical mechanisms; semiological, clinical and
      paraclinical approaches; creation of early diagnostic centres and
      multidisciplinary care networks; therapy available to patients or currently under
      development. The four existing acetylcholinesterase inhibitors having confirmed
      symptomatic action in patients with mild to moderate Alzheimer's disease have now
      been joined by memantine (Ebixa), a non-competitive agonist of N-methyl-D
      aspartate (NMDA) receptors. One pathogenic mechanism of Alzheimer's disease
      appears to be hyperactivity of the glutaminergic neurons. Various preclinical
      studies have shown that memantine (Ebixa) inhibits glutaminergic hyperactivity in
      Alzheimer's disease through modulation of NMDA receptors. Since the early 1990s,
      several controlled clinical trials in patients with moderate to severe
      Alzheimer's disease (3<MMSE< or =14) have demonstrated the efficacy of memantine
      on cognitive criteria (cognitive evaluation of severe dementia) (Severe
      Impairment Battery--SIB), functional criteria (Functional Assessment Stage--FAST)
      and global clinical criteria (Clinician's Interview-Based Impression of Change-
      CIBIC-Plus). The data from these studies together with clinical experience of
      memantine in Germany since 1982 confirm the safety of use and good tolerability
      profile of this medication at the recommended dosages (10 to 30 mg/day).
      Treatment with memantine reduces the global costs of the disease by lightening
      the burden on helpers and delaying institutionalisation of patients. These
      different studies have resulted in approval of memantine in this particular
      indication by the European Medicines Agency. The efficacy of memantine in mild to
      moderate Alzheimer's disease is currently being assessed. The preliminary results
      also appear to militate in favour of the efficacy of the drug in certain forms of
      vascular dementia. Finally, the good safety profile of combined use of this drug
      with antiacetylcholinesterases opens up a realistic perspective of bitherapy in
      Alzheimer's disease.

PMID- 15029080
TI  - [Adjunct treatments in acute mania].
AB  - When treating patients with manic states, the physician has to deal with at least
      two main Issues. First, the therapeutic decision has to be rapid because of the
      unpredictability of its immediate course. This concerns often results in
      polypharmacy with adjunct treatments. However, the therapeutic choice has to be
      cautious since part of the treatment will be maintained for prophylaxis.
      According to recent guidelines, the use of monotherapy with mood stabilisers
      during acute manic states concerns only few patients with mostly hypomania to
      moderate mania. Up to date, antipsychotics and benzodiazepines are considered as
      adjunct treatment in mania with psychotic symptoms or hostility. However, survey
      studies show that antipsychotics are widely used as adjunct treatments to mood
      stabilisers, indeed beyond the indications held by the guidelines. Our objective
      was to describe the clinical situations justifying the addition of an adjunct
      treatment during acute mania and to clear up from published data, the advantages
      and the inconveniences of combining antipsychotics and/or benzodiazepines with a
      mood stabilisers in order to define differentiated indications. Mania associated
      with either agitation, sleep disturbances or psychotic symptoms requires most of
      the time to combine mood stabiliser and respectively, sedative and/or anxiolytic,
      hypnotic or anti-psychotic treatments. Patients suffering from mania associated
      with other disorders need specific treatment adjustment and combination related
      to their medical condition. Adjunctive conventional antipsychotic remains widely
      used in first intention treatment. The conventional antipsychotic is often
      prescribed alone in the first weeks prior to the association with a mood
      stabiliser. Nevertheless there are controversies in the literature about their
      efficiency and their delay of action with regard to other treatments. When the
      conventional antipsychotic is a part of their initial treatment, manic patients
      remain taking them when discharged from hospital and are still taking them after
      6 Months in a great percentage of the cases. The adverse events with conventional
      antipsychotic are numerous and severe enough in bipolar patients to restrict
      their use in first intention mainly to psychotic mania. Moreover, there are
      evidences for higher sensitivity to adverse effects of the conventional
      antipsychotics in manic patients. When agitation in acute mania requires an
      adjunct to mood stabiliser, the conventional antipsychotic treatment could be use
      for over-excitation without catatonic features and with particular care with the
      risk of akathisia. Long term effects of conventional antipsychotics, especially
      on depressive recurrences, should argue to stop them as soon as possible. Since
      the safety of adjunctive new antipsychotics with mood stabilisers seems until now
      acceptable, its indication should be limited to acute psychotic manias.
      Adjunctive benzodiazepine, should be evaluated in the various types of mania with
      specific concerns with comorbidity frequently met in consultation-liaison
      psychiatry. Benzodiazepines plus mood stabilisers may be the treatment of choice
      for the manias in which anxious state, catatonic symptoms or sleeplessness.

PMID- 15029081
TI  - [Prodromal symptoms of schizophrenia].
AB  - The concept of prodromal symptoms of schizophrenia has frequently been subject to
      debate. Authors widely admit the existence of early specific and non-specific
      signs preceding the first psychotic episode; however, they have yet to clearly
      demonstrate their ability to predict and specify the outbreak of a psychosis.
      These prodromal symptoms consist of behavioral abnormalities, pseudo-neurotic
      signs, subtle cognitive and affective changes. All these symptoms vary from
      patient to patient. In general, it is widely believed that future patients go
      through a variety of abnormal, subjective experiences that progressively develop
      during their pre-puberty and puberty periods. However, the limit of this
      assessment is that an individual could present the same prodromal symptoms
      without necessarily developing a psychotic illness, as a result of toxic intake,
      a situational crisis, etc. Furthermore, while the prodrome is a retrospective
      concept, its value and specificity can only be prospective, given that patients'
      descriptions of pre-morbid changes may be corrupted by inefficient memory
      reconstruction. DSM III-R included prodromal symptoms; individual presenting such
      symptoms would potentially present psychopathological vulnerability to psychosis
      regardless of associated genetic risk. Several investigations have shed doubts on
      their measurement's reliability; therefore, this classification is no longer
      present in the latest version (DSM IV). Moreover, recent neurodevelopemental
      hypothesis on schizophrenia have paved the way for possible early intervention,
      especially because early treatments could well improve illness prognosis. This
      viewpoint is reinforced by the improved tolerance of new anti-psychotic
      treatment. In this report, we review the key Articles published over the last 15
      Years on this matter. We distinguish two schools of thought: on one hand, the
      German school referring to the validity of particular neuro-psychological
      symptoms: attention, perception, proprioperception which can be assessed with
      many evaluation tools: PAS, TDI, BSABS, SPI-A. The German school points to the
      fact that patients experimenting such changes could potentially be aware of their
      state. On the other hand, the Anglo-Saxon school refers to the detection of an
      "at risk" population. The Anglo-Saxons no longer refer to "prodromal symptoms"
      but rather to a "prodromal period" that extends to about one Year. This period
      would begin with the patient's first behavioral changes and extend until the
      first psychotic episode. Both schools agree that, at this stage, neither the
      recognition nor the description of the period preceding psychosis allows to
      effectively predict it. As a result, some Authors continue to refer to
      psychological changes forming a risk factor for the development of subsequent
      psychosis, rather than clear predictors of inevitable illness. As for relapses,
      prodromal signs and symptoms found in schizophrenic patients are both specific
      and non-specific. In most cases, patients experiment perceptions and behavioral
      changes before psychosis exacerbation. It is not uncommon for a substantial
      increase in prodromal symptoms to be followed by degradation in psychotic
      symptoms. On the other hand, many such increases in psychotic symptoms were not
      preceded by increases in possible prodromal symptoms; hence their importance in
      identifying the timing of an intervention, but many relapses will occur
      regardless of the detection of said symptoms.

PMID- 15029082
TI  - [Benzodiazepines and forensic aspects].
AB  - Adverse effects of benzodiazepines are well known since the first one was used in
      1958 (chlordiazepoxide). The literature collects study-cases or rarely controlled
      studies concerning side effects or paradoxical reactions to benzodiazepines. They
      mostly described drowsiness and behavioral disinhibition, including increased
      well-being feeling but also hostility, rage access with feeling of
      invulnerability, serious crimes and sometimes homicides. Delusional, manic,
      confusional or depressive states are also pointed out. Rate for aggressive
      behaviour is 0.3 to 0.7% but distinction should be done between accidental or
      "idiosyncratic" reaction and voluntary sought disinhibition, clearly more
      frequent. No benzodiazepine has any specificity for these adverse effects but
      pharmacology, doses, associated drugs (or alcohol) and psychopathology interact
      to produce hazardous psychic states. Pharmacology: GABA induces a decrease in
      serotonin compound and vigilance. Pharmacokinetic: first dose effect or over-dose
      effect, short half-life, lipophily, affinity, digestive absorption, active
      metabolites interact. Psychopathology: age, alcohol association, psychological
      status (high initial level of hostility, impulsivity, frustration, personality
      disorder and depressive status). External conditions: chronic illness, affective
      and professional frustrations, physical or psychic exhaustion contribute also.
      Some benzodiazepines (flunitrazepam, diazepam, clorazepate, triazolam,
      alprazolam, lorazepam, for example) are more often concerned for pharmacokinetics
      characteristics but also prescription habits. Forensic aspects should be
      considered in case of homicide. Especially, reality of benzodiazepines
      consumption and awareness of the potential paradoxical reaction should be
      precisely evaluated. Special focus on voluntary induced disinhibition has to be
      done for forensic considerations. Relationship but also crime facilitations are
      sometimes consciously sought. Some benzodiazepines have already been identified
      for this use: flunitrazepam, clorazepate but also triazolam and temazepam in UK,
      alprazolam in USA. Flunitrazepam is prohibited in USA and considered as narcotics
      in France. A Swedish study showed that violent acts were more frequent and
      serious in juvenile offenders taking flunitrazepam/alcohol than other young
      offenders staying in the same correctional institution. They recommended
      classification of flunitrazepam as narcotic. A study from Belgium with drug
      addicts concluded in the same way and asked for an increased information of
      professionals and a more efficient control of the delivery. Before concluding to
      idiosyncratic effect, and then possibly to penal irresponsibility, the forensic
      approach should consider: firstly the reality of the benzodiazepines absorption
      and implication in committing violence (urine test, chronology, amnesia);
      secondly, the association of unusual behaviour and converging circumstances
      (pharmacological, pharmacokinetic, psychopathology, external conditions); thirdly
      the consumer's knowledge of the disinhibition effect. In our prison practice, we
      have to be particularly cautious as population frequently associates personality
      disorder, drug addiction and high level of frustration related to penitential
      context. Special information should be given to inmates when benzodiazepines are
      prescribed, but more extensively, a preventive strategy should be adopted in
      general population.

PMID- 15029083
TI  - [Subjective well-being and self-regulation in risk taking behaviors. The case of
      scuba-diving].
AB  - Nowadays, risk-taking behaviors category is a very fast growing domain, yet not
      well known. Recent studies point out the importance of emotional phenomenons in
      subjective risk-taking behaviors. According to this axis, on scuba-diving
      empirical field, we aim to depict the size and the role of psychological process
      in the realization of the behavior; our research links personality variables and
      emotional ones. The observation of scuba-Divers behavior lead us to construct a
      fitting of conceptual positions to give an account of that behavior and its
      subjective function. The self-regulation concept has been dimensioned through
      several factors and the scales in respect of: Thrill and Adventure Seeking
      (Zuckerman, 1980), Anhedonia (Snaith-Hamilton Pleasure Scale, 1995), Subjective
      Well-being (Diener, 1992) and Differential Emotions (Izard, 1972). The population
      of this study is composed of 74 subjects. They are grouped in 2 categories
      depending of the risk-taking behavior, injured or injured less. The data have
      been statistically treated by classic methods (c2, Student t test) and logistic
      regression. It appears that Thrill and Adventure Seeking discriminate risk-taking
      in scuba-diving. The results especially support the weight of emotional
      variables. It turns out that risk-taking subjects are particularly sensitive to
      negative emotions. Negative well-being seems to be a central characteristic of
      the emotional functioning of these subjects. Moreover injured subjects tend to
      overestimate emotions linked to the behavior. Anhedonia is not a characteristic
      factor. So it introduces the notion of emotionality and sublines the interactions
      between risk-taking behavior and emotions through the self-regulation concept.

PMID- 15029084
TI  - [Translation and validation of a French version of the Young Mania Rating Scale
      (YMRS)].
AB  - Both the Young Mania Rating Scale (YMRS) and the Mania Assessment Scale (MAS)
      have been widely used during the last decade for the evaluation of severity of
      mania in clinical trials. For both scales good inter-rater reliability, validity
      and sensitivity to change have been reported. The French version of the MAS has
      been validated. To our know-ledge, the YMRS has not yet been translated into
      French and validated. The main objective of the present study was to validate a
      French version of the YMRS and to test its use in manic patients entering a study
      on the effectiveness of valproic acid and olanzapine combination. After
      translating the items in French, we tested this version of the YMRS on two
      samples of psychiatric patients recruited in a ward of adult inpatients (18 to 65
      Years old) at the Department of Psychiatry, Geneva University Hospital. The first
      sample included 18 (hypo) manic inpatients (10 males, 8 females). Mean age was
      37.0 (standard deviation 10.1). Interviews were video taped and assessed by three
      different judges on both scales (YMRS and MAS). The second sample included 20
      inpatients (5 males, 15 females) who provided written informed consent to enter a
      study on the association of valproic acid and olanzapine in the treatment of
      mania. Mean age was 40.0 (standard deviation 11.3). Patients were followed over
      four weeks and assessed on both scales (YMRS and MAS) every seven days (day 0, 7,
      14, 21 and 28). On day 7, patients were assessed during a joint interview by two
      of three judges who independently administered both scales in permuted order. On
      days 0, 14, 21 and 28, patients were evaluated by one of the same three raters.
      Inter-rater reliability was assessed by comparing item scores and total scores
      assigned by different judges with intra-class correlation coefficient ICC (2,1).
      Three judges were considered for patients in sample 1. Two judges were considered
      for patients in sample 2 (day 7 assessment). Concurrent validity with the MAS was
      analysed in sample 2 on days 0, 7, 14, 21 and 28 using Spearman rank-order
      correlation coefficient. Sensitivity to change was assessed in sample 2 by
      comparing total score at inclusion and at last observation using Wilcoxon signed
      ranks test. For both the MAS and YMRS, intraindividual change was calculated as
      the difference between total scores at inclusion and discharge (last observation
      carried forward approach). The relationship between changes on the two scales was
      analysed through Spearman correlation coefficient. Significance level was set to
      0.05 for each test. Ranges of YMRS total scores were 2 to 32 in sample 1 and 1 to
      28 in sample 2, indicating symptom severity from euthymic to moderately manic.
      Inter-rater reliability was very good for the total scores in both samples, both
      for the MAS and the YMRS (ICC>0.89). When considering YMRS individual items,
      correlation coefficient varied from 0.61 to 0.96 in the first sample. In the
      second sample, 9 of 11 items displayed values above 0.63. The remaining two
      items, increased motor activity and energy and Language-thought disorder,
      presented modest inter-rater reliability (ICC=0.54 and 0.50 respectively). This
      was largely attributable to a single patient, who was perceived very differently
      by the two judges (scores 0-2 for increased motor activity and energy; 1-4 for
      Language-thought disorder). When this patient was excluded, intra-class
      correlation coefficients were above 0.69 for both items. Overall, inter-rater
      reliability of the YMRS items was in the same range as for the MAS items (0.61
      0.96 vs 0.61-0.93 in sample 1; 0.50-0.93 vs 0.54-0.83 in sample 2). Correlation
      between the two instruments was very high and statistically significant at each
      weekly assessment (rs>0.91, p<0.001) except for day 21 which displayed a somewhat
      lower correlation (rs=0.75, p<0.01). This latter result was attributed to a
      reduced spread of values and number of patients on day 21. YMRS and MAS total
      scores as a function of time in patients receiving combined treatment with
      olanzapine and valproic acid (sample 2) show that for both at for both scales,
      total scores significantly decreased from day 0 to last observation (Wilcoxon
      signed ranks test, p<0.001), with median decrease of 18 points both on the YMRS
      (range 9-32) and MAS (range 10-33). Median relative decrease was 67% for the YMRS
      and 69% for the MAS. When analysing the relationship between intraindividual
      changes on the YMRS and MAS, highly significant correlation was observed
      (Spearman rs=0.93, p<0.001), showing that the two scales were virtually
      interchangeable in assessing treatment efficacy. In conclusion, the YMRS is a
      simple and easy-to-use instrument for measuring severity of manic symptoms The
      newly translated French version was satisfactory in terms of inter-rater
      reliability, concurrent validity with the MAS, and sensitivity to change in
      patients receiving treatment for manic symptoms. This should allow its future use
      for international comparison studies.

PMID- 15029085
TI  - [Multidimensional assessment of coping: validation of the Brief COPE among French
      population].
AB  - This Article aims to introduce the translation and the validation of a
      multidimensional measure of coping strategies: the Brief COPE, in a French
      population. The coping concept comes from psychological studies that were
      conducted on stress. In the conceptual analysis of stress by Lazarus and Folkman,
      coping works with two cognitive appraisals performed by the person concerning the
      perception of a threatening situation and his or her available resources to deal
      with it. Coping is defined as "cognitive and behavioural efforts to master,
      reduce, or tolerate the internal and/or external demands that are created by the
      stressful transaction". The Brief COPE is the abridged version of the COPE
      inventory and presents fourteen scales all assessing different coping dimensions:
      1) active coping, 2) planning, 3) using instrumental support, 4) using emotional
      support, 5) venting, 6) behavioural disengagement, 7) self-distraction, 8) self
      blame, 9) positive reframing, 10) humor, 11) denial, 12) acceptance, 13)
      religion, and 14) substance use. Each scale contains two items (28 altogether).
      This inventory has the advantage of being built from acknowledged theoretical
      models (Lazarus' transactional model of stress, 1984; behavioral self-regulation
      model, Carver and Scheier, 1981, 1998). It can be used to assess trait coping
      (the usual way people cope with stress in everyday life) and state coping (the
      particular way people cope with a specific stressful situation). As is the COPE
      inventory, the Brief COPE is a measure used for many health-relevant studies:
      drugs addiction, ageing, breast cancer, depression, AIDS. Both measures are
      widely used in Anglophone countries and translated in many Languages. Today, the
      COPE inventory has been validated among Estonian, Croatian, Chinese, and Italian
      populations and the Brief COPE is also validated among Spanish people. Thus, the
      worldwide use of this coping inventory should allow a broad comparison of medical
      and psychological research for coping strategies regarding every kind of
      pathologies. Thus, we were led to present the translation and the validation of
      this measure in a French population. Two studies are presented in this Article:
      the first one describes the validation of the inventory in a dispositional format
      (trait coping) and the second one the validation of the inventory in a
      situational format (state coping). The French version of Brief COPE, which was
      used for both studies, was back-translated and analysed by the Brief COPE Author:
      Charles S. Carver. For study 1, 834 first Year university students answered the
      Brief COPE in its dispositional format. To study the factor structure of the
      Brief COPE, we used structural equation modeling and the LISREL software. Results
      show that the expected theoretical structure and the observed one fit adequately
      (c2=606, p<0,05, RMSEA=0,04, GFI>0,95, AGFI>0,92, RMR<0,03). In order to study
      convergent and discriminant validity of Brief COPE, self-esteem (SEI, Rosenberg,
      1979), perceived stress (PSS, Cohen et al., 1983), and psychological distress
      (GHQ-12, Goldberg, 1972) measures were used. Results show that functional coping
      strategies (eg, active coping) are linked to good self-esteem, to lower perceived
      stress, and to lower psychological distress, whereas less functional strategies
      (eg, denial or self-blame) are widely linked to poor self-esteem, to a high
      perceived stress, and to psychological distress. Study 1 shows also several
      significant gender differences. Study 2 describes the Brief COPE validation in
      its situational format. 178 additional students answered this version. The method
      that was used is the same the one developed by Lazarus and his colleagues for the
      WCC validation. Participants were asked to recall and think about the most
      stressful event they had experienced during the past two Months. They were also
      to give an account of how much that situation mattered to them. They had to
      evaluate their capacity to control the situation and indicated whether they felt
      the situation was amenable to change. The study includes only peoples only people
      who labeled an event as "important" or "very important". Here again LISREL was
      used to study the factor structure of the Brief COPE. The results emphasise - as
      in study 1 - that the expected theoretical structure and the observed one fit
      adequately (c2=391, p<0,05, RMSEA<0,05, GFI=0,87, AGFI=0,80, RMR<0,06).
      Differences among means showed how the perceived control of the situation and how
      the perception of its favourable evolution influenced the coping strategies used
      (eg, humour or denial). Results in both studies indicate good psychometric
      properties for the Brief COPE in its French version, whatever the format (ie,
      dispositional or situational). Thus French searchers have a relevant tool on hand
      to measure as accurately as possible the coping strategies someone used in
      everyday life (strategies interfering on health, on a long scale), or in
      distressful situations (eg, serious illness, traumas). The fact that this easy-to
      use coping measure is worldwide spread among medical and psychological studies
      allows a better broadcast and comparison of results whatever the pathology.

PMID- 15029086
TI  - [Cannabis addiction and Telic Dominance Scale].
AB  - The research presented originates in a double set of problems: on the one hand
      the revelation of cannabis addiction and the borderline personality, and the
      other hand the link between cannabis addiction/borderline personality and the
      activity system (Telic; Paratelic). Examination of the relationship between these
      two notions makes it possible to differentiate cannabis addicts according to
      adjustments of border line personality. With this aim in mind, we hypothesized
      that "Activity System" is the type of personality adjustment of cannabis addict,
      "Character Neurosis" and "Character Psychosis". The first phase of our research
      consisted of characterization of the sample. Our population consisted of 70
      cannabis addicts selected according to precise inclusion criteria (score below 7
      on the Cannabis Dependency Questionnaire, score below 4 on the Addiction Severity
      Index and at least five criteria of borderline personality according to the DSM
      IV). The second phase investigated our hypothesis based on "Activity system". We
      expected that the cannabis addicts who had adjusted on the "Character Neurosis"
      mode would have a telic activity system unlike the cannabis addicts who had
      adjusted on the "Character Psychosis" mode. In conclusion, we can consider that
      there is a retroactive effect between cannabis addiction and borderline
      personality. The personality adjustment of cannabis addict through the
      intermediary of activity system has an influence on cannabis consumption.

PMID- 15029087
TI  - [Personality dimensions and neuropsychological performance in first-degree
      relatives of patients with schizophrenia and by affective psychosis].
AB  - Several studies have found a significant increase in the prevalence of some
      personality disorders in the first-degree relatives of patients with
      schizophrenia; other studies have found subtle neuropsychological deficits in
      these relatives. However, little is known about the specificity of the
      personality traits reported or about the relationship between these traits and
      the neuropsychological deficits. One hundred first-degree relatives of patients
      with schizophrenia (AS) and 88 first-degree relatives of affective psychotic
      (APA) patients completed the Eysenck Personality Questionnaire which measures
      extraversion, neuroticism, psychoticism. They were also administered the National
      Adult Reading Test (NART), the Trail Making Test (TMT) and a Verbal Fluency Test
      (VFT). In the AS group, the male relatives scored significantly higher on the
      psychoticism scale than the male relatives in the APA group. There were no
      significant differences in personality between female relatives of the 2 patients
      groups. In the AS group, the NART scores were superior when the psychoticism
      scores were lower and the TMT performance was better when the extraversion scores
      were higher. These results seem to indicate some specificity as well as sex
      differences of the psychoticism dimension. Moreover, the relationship between the
      personality dimensions and the neuropsychological performance could indicate that
      psychoticism increases vulnerability to schizophrenia whereas extraversion
      decreases it.

PMID- 15029088
TI  - [Secondary prevention of posttraumatic stress disorder: challenging psychological
      debriefings].
AB  - This paper examines the efficacy of secondary prevention procedures following a
      trauma (psychological debriefing). After examining psychological processes
      leading to the onset of PSTD, 3 prevention procedures are presented: the CISD of
      Mitchell, the debriefing procedure of Brom and Kleber, and a cognitive and
      behavioral debriefing procedure. Outcome studies of these procedures are
      reviewed. They suggest that CISD has no proven efficacy, while the cognitive and
      behavioral debriefing procedure significantly decreases the probability of onset
      of PTSD following a trauma. Guidelines are provided for designing optimal
      debriefing procedures.

PMID- 15029089
TI  - [Psychosurgical treatment of malignant OCD: three case-reports].
AB  - Surgery can be proposed for some patients affected by psychiatric diseases such
      as severe, disabling and refractory affective disorders (depression), OCD and
      chronic anxiety states. It can be performed after a period of evolution of
      minimum 5 Years and after all other classical treatments have failed. For the
      last Years, different stereotactic techniques have been used: capsulotomy,
      cingulotomy, subcaudate tractotomy and limbic leukotomy, performed by
      radiofrequency thermolesions or radiosurgery (g rays). In the case of OCD, these
      procedures are supposed to affect some of the neural circuits between the frontal
      lobes and different structures of the limbic system, considered as central to OCD
      symptoms. As they cause smaller cerebral lesions than earlier surgical techniques
      (mostly open surgery techniques), modern stereotactic approaches have less
      clinical side effects, primarily less deficit in emotional reactivity and
      motivation. This type of treatment offers some hope to patients seriously
      disabled by OCD. These surgeries and especially their main side effects are
      mentioned briefly in this Article. The most current indications for psychosurgery
      are severe OCD and chronic major depressive disorder. The level of stress should
      be significant and assessed by clinical and social functioning scale scores (for
      the OCD: Y-BOCS>25, GAF>50). Patients affected by demential disorders,
      sociopathic or paranoiac personality disorder, substance abuse should be excluded
      as well as patients aged 65 Years over and less than 18 Years. Several studies
      evaluating the results of the surgical treatment showed significant improvement
      in 54% of cases. and a moderate improvement in 27% of them. These results seem
      unchanged a few Years later in 56% of cases. Despite the lack of controlled
      trials of neurosurgery and several bias in published reports, evidence suggests
      that the condition of intractable OCD patients may improve after this surgery.
      Although capsulotomy and cingulotomy are mainly used, the superiority of any of
      these four surgical techniques has not been established yet. In this Article, we
      reported 3 "malignant" OCD cases treated by different psychosurgery techniques: 2
      of the cases showed a clinical improvement, whereas the third did not -benefit
      from surgery. All of them were suffering of OCD since childhood with a gradual
      clinical impairment, unless the -second patient who presented a severe impairment
      following an accident causing a ten-day coma. In all three cases social
      consequences of OCD were important: negative socio-professional and family-life
      consequences and depressive complication with suicide risk. All patients remained
      unresponsive or showed a very transient reaction to the other forms of therapy,
      including varied pharmacotherapy (potentiation pharmacotherapy strategies
      included), intensive psychotherapy, behavioural therapy and electro-convulsive
      therapy. Pre- and post-operative assessment included neurological, radiological,
      psychometric and neuropsychological examination. The free and informed consent of
      the patient was always required before surgery, notifying the nature of the
      procedure, the potential risks and outcome. The first patient benefited of a
      bilateral anterior cingulotomy by thermocoagulation in stereotactic conditions,
      followed, four years later, by a second complementary one because of a relapse
      which occurred a few months after the first intervention. A clinical improvement
      was noticed over a period of two years, though it was not sufficient according to
      the patient. The second patient benefited of a stereotactic cingulotomy
      associated with a limbic leucotomy: it was initially efficient on OCD as well as
      on thymic symptoms. Nevertheless the positive evolution on OCD is not perceived
      by the patient and has not been assessed until now by clinical rating scales.
      Anterior cingulotomy is undergone in the third case, who showed a significant
      improvement. Despite clomipramine administered secondary to the surgery, a slight
      relapse of obsessive ideas was noticed six months later. The postoperative side
      effects were transient and regressive after a few months; they were observed
      especially in the case of tractotomy (oedema and transient frontal syndrome). On
      the whole, morbidity seemed more important with extensive lesions, whereas
      recurrence rate may be higher with smaller lesions. We did not observe any
      consequences on personality or on cognitive functions of these patients. No
      additional -deficits were observed after surgery. Further research is needed in
      order to determine the optimal site and size of the lesions in terms of efficacy
      and safety. Although psychosurgery is still controversial from an ethical view
      point, this treatment appears to be an ultimate solution for these severe
      disabled patients. Psychosurgery is a safe and relatively effective treatment
      which should be carried out by an expert multidisciplinary team in these
      disorders; surgery should be considered as part of an entire treatment program
      including an appropriate psychiatric rehabilitation part. Research in this field
      is currently focused on MRI-guided basal ganglia stimulation techniques which
      would allow to target specific structures in a reversible way.

PMID- 15029090
TI  - [In utero exposure to benzodiazepine. Is there a risk for anal atresia with
      lorazepam?].
AB  - Drugs of the Benzodiazepine family are among the most frequently prescribed in
      France. Since anxiety disorders, for which these substances are mostly indicated,
      affect 10% of pregnant women, it is very likely that such a treatment could
      expose many foetuses to BZD during the first three Months of pregnancy. We know
      that the teratologic effect is not necessarily based on dose rate, but that it is
      associated with fetal drug exposure during the first 12 weeks of gestation, when
      organ formation occurs. Most epidemiologists concur that the baseline incidence
      of congenital damage is 2-2,5% in Europe. The results from a large number of stu
      dies on associations between the use of BZDs in pregnancy and congenital
      malformations are conflicting. An in-depth analysis of existing literature shows
      results that are hardly comparable, if not contradictory, due to extreme
      differences in methodological approaches. In a recent meta-analysis case-control
      studies and cohort studies were analyzed separately. Among the case-control
      studies significant associations were found between BZD exposure and both, major
      malformations and oral clefts, whereas the cohort studies showed no association
      between BZD and any kind of malformation. The purpose of our study is to search
      for a specific teratogenic effect of this class of drugs, using data collected
      (1976-1997) by the French Central-East (FCE) registry of congenital
      malformations, member of the International Clearinghouse for Birth Defects
      Monitoring Systems (ICBDMS) located in Lyon, France. This registry monitor
      malformations among 100,000 births per Year. We analyzed 13,703 cases where
      information is available on whether or not the mother took a drug during her
      first trimester of pregnancy. Among them, 3,603 (28%) actually took a drug, and
      262 (6.8%) took some sort of benzodiazepine (BDZ). BZD were divided into 9
      categories, 8 being the most frequently present, plus one broad category of
      "others". Malformations were divided into ten categories: congenital anomalies of
      heart, cleft lip and/or cleft palate, neural tube defects, other anomalies of
      central nervous system, hypospadias, urinary malformations, anal atresia, other
      digestive anomalies, limb reduction defects, and genetic anomalies, including
      chromosome aberrations and monogenic conditions. Other malformations were grouped
      in an eleventh category. The interesting aspect of this study is that it takes
      into account the BZD metabolism. It is worth noting that the hepatic catabolism
      of benzodiazepine is a very complex one, because it leads to derived molecules
      which are sometimes active and/or present in the common metabolic route of major
      commercial drugs. Our hypothesis is that if one BZD is associated specifically to
      a certain type of congenital defect, we may find this BZD to be overrepresented,
      as compared with other BZDs, in newborns exhibiting some type of congenital
      defect. The analysis was run according to a case-control approach. Odd ratios
      (OR) and their 95% confidence intervals were calculated by logistic regression
      with adjustment for maternal age and parity. When one category of defects was
      considered, infants having the corresponding malformation were considered as
      cases, while infants with other malformations were considered as controls. In a
      similar way infants having being exposed to a given drug were considered as
      exposed, while infants exposed to any other drug were considered as unexposed.
      The analysis then was run in 4 steps. Step 1: full sample. With 13,703 cases. We
      observed no increased risk for any specific malformation type associated with use
      of BZD. Step 2: further defining drug exposure as a specific BZD, and all others
      unexposed, a significant association was seen between lorazepam and anal atresia.
      OR=6.2 (95% CI2.4-15.7, p=0.01). Step 3: this finding was upheld and no other
      emerged when exposure was defined as the drug or any of its active metabolites.
      This step was performed because hepatic catabolism of BDZs leads to derived
      molecules that are sometimes active and/or present in the common metabolic route
      of major marketed BZDs. Step 4: similarly, the lorazepam/anal atresia finding was
      upheld when the analysis was restricted to the 262 malformed infants exposed to
      BZDs in utero. Six cases of anal atresia were found among all newborns exposed to
      BZD in utero, and five of them were exposed to lorazepam, representing a
      hypothesis to be tested in further. We are not aware of other reports of this
      association, and it should be regarded as preliminary until confirmed in other
      data sets.

PMID- 15029091
TI  - [Psychiatric manifestations of vitamin B12 deficiency: a case report].
AB  - Psychiatric manifestations are frequently associated with pernicious anemia
      including depression, mania, psychosis, dementia. We report a case of a patient
      with vitamin B12 deficiency, who has presented severe depression with delusion
      and Capgras' syndrome, delusion with lability of mood and hypomania successively,
      during a period of two Months. Case report - Mme V., a 64-Year-old woman, was
      admitted to the hospital because of confusion. She had no history of psychiatric
      problems. She had history of diabetes, hypertension and femoral prosthesis. The
      red blood count revealed a normocytosis with anemia (hemoglobin=11,4 g/dl). At
      admission she was uncooperative, disoriented in time and presented memory and
      attention impairment and sleep disorders. She seemed sad and older than her real
      age. Facial expression and spontaneous movements were reduced, her speech and
      movements were very slow. She had depressed mood, guilt complex, incurability and
      devaluation impressions. She had a Capgras' syndrome and delusion of persecution.
      Her neurologic examination, cerebral scanner and EEG were postponed because of
      uncooperation. Further investigations confirmed anemia (hemoglobin=11,4 g/dl) and
      revealed vitamin B12 deficiency (52 pmol/l) and normal folate level. Antibodies
      to parietal cells were positive in the serum and antibodies to intrinsic factor
      were negative. An iron deficiency was associated (serum iron=7 micromol/l; serum
      ferritin concentration=24 mg/l; serum transferrin concentration=3,16 g/l). This
      association explained normocytocis anemia. Thyroid function, hepatic and renal
      tests, glycemia, TP, TCA, VS, VDRL-TPHA were normal. Vitamin B12 replacement
      therapy was started with hydroxycobalamin 1 000 ng/day im for 10 days and iron
      replacement therapy. Her mental state improved dramatically within a few days.
      After one week of treatment the only remaining symptoms were lability of mood,
      delusion of persecution, Capgras' syndrome but disappeared totally 9 days after
      the beginning of the treatment. A neurologic examination was possible because of
      cooperation. All the tendon reflexes of inferior members were absent. The
      plantars were in flexion and there was a left inferior member hypoesthesia. The
      cerebral scan and EEG were normal. Fundic biopsy, realized by fibroscopy,
      revealed fundic atrophia and intestinal metaplasia compatible with Biermers'
      disease. The iron deficiency exploration concluded diet deficiency. Mme V.
      appeared euphoric, her speech was very rapid with play on words and overactivity.
      This hypomania state totally disappeared 3 days after. Six Months after her
      hospitalisation, she presented an hypothyroidism (TSH=3,780; T3=1,35; T4=1,08). A
      thyroid hormones replacement was started and she continued to receive Monthly B12
      replacement. Discussion - This case report illustrates psychiatric manifestations
      of Biermers' disease. The clinical arguments in favour are: white woman, more
      than 60 Years old, no history of psychiatric problems, atypical symptoms
      (confusional state with psychiatric symptoms), fluctuation of symptoms (severe
      depression with confusional state, delusion of persecution and Capgras' syndrome;
      delusion with lability of mood and hypomania), dramatic improvement after 9 days
      of vitamin B12 replacement therapy. The biological arguments are: anemia, vitamin
      B12 deficiency, normal folate level, atrophia and fundic metaplasia, positive
      antibodies to parietal cells in the serum, association between Biermers' disease
      and autoimmune disease (Haschimoto thyroidite). Psychiatric manifestations can
      occur in the presence of low serum B12 levels but in the absence of the other
      well recognized neurological and haematological abnormalities of pernicious
      anemia. Mental or psychological changes may precede haematological signs by
      Months or Years. They can be the initial symptoms or the only ones. Verbank et
      al. described the case of a patient with vitamin B12 deficiency in whom
      hypomania, paranoia and depression had been successively presented during a
      period of 5 Years before anemia have been developed. The case of Mme V. is
      similar in the succession of severe depression with delusion of persecution and
      Capgras' syndrome, delusion with lability of mood and hypomania, during a period
      of two Months. This report seems to be the first one of a sequence of several
      psychiatric states with pernicious anemia during a period of two Months with
      normocytosis anemia. To illustrate this illness we reviewed the literature
      regarding psychopathology associated with B12 deficiency. The most common
      psychiatric symptoms were depression, mania, psychotic symptoms, cognitive
      impairment and obsessive compulsive disorder. The neuropsychiatric severity by
      vitamin B12 deficiency and the therapeutic efficacy depends on the duration of
      signs and symptoms. Conclusion - We recommend consideration of B12 deficiency and
      serum B12 determinations in all the patients with organic mental disorders,
      atypical psychiatric symptoms and fluctuation of symptomatology. B12 levels
      should be evaluated with treatment resistant depressive disorders, dementia,
      psychosis or risk factors for malnutrition such as alcoholism or advancing age
      associated with neurological symptoms, anemia, malabsorption, gastrointestinal
      surgery, parasite infestation or strict vegetarian diet. In first intention, B12
      deficiency should be researched by serum B12 determination (normal 200-950
      pg/ml). Studies of methylmalonic acid and homocysteine showed that they are very
      sensitive functional indicators of cobalamin status especially when other
      evidence of cobalamin (B12) deficiency was equivocal. Measurement of
      methylmalonic acid (normal 73-271 nmol/l) and homocysteine (normal 5,4-13,9
      micromol/l) should not replace the measurement of serum cobalamin.

PMID- 15029092
TI  - Clinical interest of PPARs ligands.
AB  - Cardiovascular disease is significantly increased in patients with metabolic
      syndrome and type 2 diabetes. Several factors such as chronic hyperglycemia,
      lipId abnormalities, endothelium dysfunction, inflammation, oxIdative stress,
      increased thrombosis and decreased fibrinolysis are likely to promote
      cardiovascular events in these patients. Because of positive effects on glucose
      homeostasis, lipId metabolism, proteins involved in all stages of atherogenesis,
      endothelium function, inflammation, thrombosis and fibrinolysis, PPARS alpha
      (fibrates) and PPARs gamma (glitazones) agonists are good candIdates to reduce
      cardiovascular disease, more precisely in subjects with metabolic syndrome or
      type 2 diabetes. PPARS alpha agonists (fibrates) are potent hypolipIdemic agents
      increasing plasma HDL-cholesterol and reducing free fatty acIds, triglycerIdes,
      LDL-cholesterol and the number of small dense LDL pArticles. Moreover, they
      reduce vascular inflammation and thrombosis, promote fibrinolysis and inhibit the
      production of the vasoconstrictor factor, endothelin-1, by the endothelium. They
      have been shown, in clinical trials, to reduce cardiovascular disease, more
      particularly in patients displaying lipId abnormalities typical of metabolic
      syndrome and type 2 diabetes (high triglycerIdes, low HDL-cholesterol). PPARS
      gamma agonists (glitazones) have not only beneficial effects on glucose
      homeostasis, by increasing insulin sensitivity and reducing blood glucose level
      but also on lipId metabolism by elevating plasma HDL-cholesterol, decreasing free
      fatty acIds and the number of small dense LDL pArticles, and for pioglitazone by
      reducing plasma triglycerIdes. Furthermore, they diminish vascular inflammation
      and vasoconstriction, inhibit monocyte chemotaxis, proliferation and migration of
      smooth muscle cells, in the vascular wall and decrease the production of adhesion
      molecules and metalloproteinases. PPARs gamma agonists (glitazones) have been
      shown to reduce the development of atherosclerotic lesions in rats. The potential
      clinical benefit of PPARs gamma agonists on the reduction of cardiovascular
      disease, in type 2 diabetic patients, will be specified by the ongoing
      intervention studies.

PMID- 15029093
TI  - Adipose tissue and adipokines: for better or worse.
AB  - It is now recognized that the white adipose tIssue (WAT) produces a variety of
      bioactive peptIdes, collectively termed "adipokines". Alteration of WAT mass in
      obesity or lipoatrophy, affects the production of most adipose secreted factors.
      Since both conditions are associated with multiple metabolic disorders and
      increased risk of cardiovascular diseases, the Idea has emerged that WAT could be
      instrumental in these complications, by virtue of its secreted factors. Several
      adipokines are increased in the obese state and have been implicated in
      hypertension (angiotensinogen), impaired fibrinolysis (PAI-1) and insulin
      resistance (ASP, TNFalpha, IL-6, resistin). Conversely, leptin and adiponectin
      both exert an insulin-sensitizing effect, at least in part, by favoring tIssue
      fatty-acId oxIdation through activation of AMP-activated kinase. In obesity,
      insulin resistance has been linked to leptin resistance and decreased plasma
      adiponectin. In lipoatrophic mice, where leptin and adiponectin circulating
      levels are low, administration of the two adipokines synergistically reverses
      insulin resistance. Leptin and adiponectin also have distinct properties: leptin,
      as a long-term integrative signal of energy store and adiponectin, as a potent
      anti-atherogenic agent. The thiazolIdinedione anti-diabetic drugs increase
      endogenous adiponectin production in rodents and humans, supporting the Idea that
      the development of new drugs targeting adipokines might represent a promising
      therapeutic approach to protect obese patients from insulin resistance and
      atherosclerosis.

PMID- 15029094
TI  - Changes of fatty acid composition in incubated rat pancreatic islets.
AB  - OBJECTIVE: The hypothesis that changes in fatty acId composition of pancreatic
      islets occur during incubation was investigated. METHODS: The content and
      composition of fatty acIds (FA) from rat pancreatic islets and culture medium
      after incubation for 1 and 3 hours in the absence or in the presence of 5.6, 8.3,
      or 16.7 mM glucose were determined by HPLC analysis. RESULTS: The FA content of
      pancreatic islets was reduced after 1 hour incubation in the absence of glucose.
      However, the total FA content was restored by incubating in the presence of 5.6
      mM glucose and exceeded by incubating in the presence of 8.3 mM or 16.7 mM
      glucose. Saturated FA contributed a substantially greater proportion of the total
      FA increase in comparison to unsaturated FA, being palmitic and stearic acIds the
      most important. The total lipId content of pancreatic islets was not increased if
      the period of incubation in the presence of glucose was extended to 3 hours. A
      substantial amount of FA was found in the medium after 1 hour incubation in the
      absence of glucose: 141 ng per 80 islets for saturated and 75 ng per 80 islets
      for unsaturated. The release of FA from islets is increased in the presence of
      glucose. CONCLUSION: The release of FA from islets is a novel finding and may be
      related to modulation of B-cell function.

PMID- 15029095
TI  - The associations of endogenous testosterone and sex hormone-binding globulin with
      glycosylated hemoglobin levels, in community dwelling men. The Tromso Study.
AB  - OBJECTIVES: Low levels of endogenous testosterone have been associated with
      increased risk of cardiovascular disease and atherosclerosis in men. Long-term
      hyperglycemia, as measured by glycosylated hemoglobin (HbA1c), is related to
      cardiovascular mortality, and HbA1c across its normal range is also positively
      related to coronary heart and cardiovascular disease mortality in men. We
      therefore undertook an analysis of the cross-sectional associations of total
      testosterone and SHBG levels with HbA1c levels, in a general population of 1419
      men aged 25-84. METHODS: Total testosterone, sex hormone-binding globulin (SHBG)
      and HbA1c were measured by immuno-assay. Partial correlation and multiple
      regression analyses were used to estimate the associations between total
      testosterone and SHBG with HbA1c. Analyses of variance and covariance were used
      to compare men with or without diabetes. RESULTS: In age-adjusted partial
      correlation HbA1c was inversely associated with total testosterone (p<0.01) and
      SHBG (p<0.001). HbA1c was positively associated with body mass index (BMI) and
      waist circumference (WC) (p<0.001). In multiple regression analyses total
      testosterone, SHBG, age, number of cigarettes smoked, BMI and WC were
      independently associated with HbA1c levels. Men with a history of diabetes had
      lower levels of total testosterone in age-adjusted analyses (p<0.05) and lower
      levels of SHBG in both age- and WC-adjusted analyses (p<0.001 and p<0.01,
      respectively). CONCLUSION: Lower levels of total testosterone and SHBG were
      associated with increased HbA1c levels and diabetes independent of concomitant
      variations in obesity and body fat distribution.

PMID- 15029097
TI  - Serum triglycerides are a predictive factor for the development and the
      progression of renal and retinal complications in patients with type 1 diabetes.
AB  - OBJECTIVES: It is controversial that serum lipIds affect the development and
      progression of microvascular complications in patients with type 1 diabetes.
      METHODS: We prospectively followed 297 patients with type 1 diabetes without end
      stage renal disease for 7 Years (range: 2-10). Serum lipIds were measured at
      baseline (total and HDL-cholesterol, triglycerIdes and calculated LDL
      cholesterol, Lipoprotein (a)). The primary end-point was the occurrence of a
      renal event and the secondary end-point was the occurrence of a retinal event,
      defined as the progression to a higher stage of diabetic nephropathy or
      retinopathy, respectively. RESULTS: Serum triglycerIde (TG) levels were higher in
      patients who progressed in nephropathy than in those who dId not [median 1.21
      (range 0.41-2.96) vs 0.91 (0.31-11.07) mmol/l; p=0.0037] and in those who
      developed retinal events than in those who dId not [1.05 (0.46-8.27) vs 0.87
      mmol/l (0.31-11.07); p=0.0302], both in the whole cohort and in patients with
      normoalbuminuria at baseline. After adjustment for systolic blood pressure (SBP),
      diabetes duration, gender, stage of complications at baseline and glycohemoglobin
      (HbA1c), the relative risk for progression was 2.01 (95% CI: 1.07-3.77) for
      nephropathy and 2.30 (95% CI: 1.03-5.12) for retinopathy for patients having
      serum TG in the highest tertile, compared to the others. This result persisted
      when only patients with normoalbuminuria were consIdered. CONCLUSION: High
      triglycerIde levels are an independent predictive factor of both renal and
      retinal complications in patients with type 1 diabetes.

PMID- 15029098
TI  - Retrospective study of laparoscopic adjustable silicone gastric banding for the
      treatment of morbid obesity: results and complications in 127 patients.
AB  - OBJECTIVES: Laparoscopic gastric banding is currently the most popular surgical
      technique for morbId obesity. This wIdespread use of surgery has been evaluated
      by a number of clinical studies, particularly on weight change. METHODS: In a
      retrospective study of 127 obese patients operated between 1996 and 2000, data
      were collected for weight change, medical and surgical complications. RESULTS: Of
      127 patients, failures of gastric banding were noted during 2 surgical
      operations. The average follow-up period was 33 +/- 20 Months. Average weight
      loss in all patients was 19.9 +/- 5.3 kg (15.3 +/- 4.2%). No difference in weight
      loss was observed between diabetic and non-diabetic patients. During the follow
      up, data were collected on 53 complications (42.4% of all gastric banding
      operations). 3 main types of complication were found: access port related
      complications (22.6% of the total), band slippage (20.7% of the total) and tubing
      related complications (16.9% of the total). No prognostic factor for these
      complications could be Identified from multivariate analysis. CONCLUSIONS: Our
      results are very similar to those of other weight evolution studies. We found
      that there was a significant incIdence of surgical and medical complications
      during the follow-up because of the meticulous way all complications were
      recorded, even the most insignificant. This morbIdity must be borne in mind
      before surgery is performed.

PMID- 15029096
TI  - Management of French patients with type 2 diabetes mellitus in medical general
      practice: report of the Mediab observatory.
AB  - OBJECTIVES: The Mediab study was conducted to estimate the medical care in French
      patients with type 2 diabetes mellitus managed by general practitioners on an
      ambulatory basis, but consIdered as requiring new treatment implementation.
      METHODS: Five thousand one hundred and fourty eight diabetic patients without any
      treatment or treated with lifestyle measures either alone or combined with an
      oral antIdiabetic agent given as monotherapy were included in a cross-sectional
      study that was conducted on a nationwIde basis by using the ORP (R) methodology.
      The 4088 patients in whom HbA1c was determined with a reliable method were
      further classified into 3 categories according to whether HbA1c was<=6.5% (group
      I, n=525), ranging between 6.6 and 8% (group II, n=1699) or > 8% (group III,
      n=1864). RESULTS: A large proportion of patients (45.6%) exhibited HbA1c > 8%.
      Adherence to diet and regular physical activity were progressively decreasing
      while prevalence of diabetic complications was steadily increasing from group I
      to III, i.e. when diabetic control was worsening. The complications suffered from
      severe "underreporting". When complications were reported, the odds-ratio
      analysis showed that retinopathy is influenced by both the magnitude of glucose
      excess and the diabetes duration, while renal diseases and macroangiopathy depend
      mainly on diabetes duration. 38.1% of patients visited a diabetologist, but most
      of these patients were referred to the speciaList after the inclusion visit.
      CONCLUSIONS: Despite the development of guIdelines, a large percentage of
      patients remains poorly-controlled. Future actions should be based on: (i) better
      collaboration between general practitioners and diabetologists (ii) better
      detection of complications that suffer from severe "underreporting", (iii)
      reinforcement of lifestyle recommendations and of pharmacological treatments by
      shifting from mono- to multi-drug therapy, at earlier stages of the disease.

PMID- 15029099
TI  - Gastrointestinal tract symptoms in Maternally Inherited Diabetes and Deafness
      (MIDD).
AB  - OBJECTIVE: To evaluate the prevalence and clinical consequences of gastro
      intestinal manifestations in Maternally Inherited Diabetes and Deafness syndrome
      (MIDD). METHODS: We report the case of fatal intestinal pseudo-obstruction in a
      patient with severe MIDD. Using a standardized questionnaire, we evaluate the
      frequency of gastrointestinal tract (GIT) symptoms in 10 patients with MIDD (8
      A3243G and 2 T14709C mutations of mitochondrial DNA). The reference population
      consisted of 50 patients with type 1 diabetes matched for disease duration. In 4
      patients with digestive manifestations endoscopic examination of upper and lower
      GIT was performed allowing multiple biopsies for ultrastructural and molecular
      analysis. RESULTS: GIT symptoms were frequently reported in MIDD specially in
      patients bearing the mt 3243 mutation. The manifestations i.e. constipation,
      diarrhea or both, were more frequent in this subgroup than in type 1 diabetic
      population (88% vs 28%, p<0.05). Ileus is a rare and severe complication with a
      frequent fatal Issue. Ultrastructural analysis of the mucosa from oesophagus,
      stomach, duodenum, colon and rectum showed mild modifications such as
      accumulation of normal mitochondria and lipId droplets. Heteroplasmy levels were
      determined in 4 patients harboring the 3243 mutation. In three patients the
      percentage of mutated DNA increased from upper to lower GIT. CONCLUSIONS:
      Gastrointestinal symptoms are frequent in MIDD secondary to 3243 mutation. They
      might explain the lower body weight observed in these patients in comparison to
      reference diabetic populations. They can also lead to a severe complication
      namely the intestinal pseudo-obstruction.

PMID- 15029100
TI  - Early referral to a nephrologist is associated with better outcomes in type 2
      diabetes patients with end-stage renal disease.
AB  - OBJECTIVE: End-stage renal disease (ESRD) requiring renal replacement therapy
      (RRT) is a late complication of type 2 diabetes. The correlation between pre-ESRD
      medical care and outcome has been rarely studied in France. METHODS: Community
      based study of case-incIdent ESRD patients. Medical care practices were described
      retrospectively when starting RRT. Medical status, mortality, morbIdity, and
      quality-of-life were recorded prospectively. RESULTS: One hundred and fourty
      eight ESRD patients with type 2 diabetes were included. Factors independently
      correlated with mortality within 3 Months of RRT onset were presence of physical
      impairment of ambulation at onset of RRT [odd ratio (OR): 5, (95%CI: 1.9-13.3)],
      and starting RRT in life-threatening circumstances [OR: 3.6, (95%CI: 1.2-10.7)].
      Factors independently correlated with "poor outcome" 1 Year after the onset of
      RRT were BMI less than 20 kg/m2 [OR: 13.4, (95%CI: 1.5-120.2)] and presence of 2
      [OR: 2.7, (95%CI: 0.9-8.4)], or 3 or more comorbId conditions [OR: 4, (95% CI:
      1.4-11)]. Three Months after the first RRT session, survival was 16.4% better for
      patients who had had regular nephrological care versus none, and 9.1% better for
      those who had had late nephrological care versus none. Type 2 diabetes patients
      starting RRT in an emergency setting had had significant less regular
      nephrological care. Length of their first hospital stay was significantly longer.
      They were more likely to have lower resIdual renal function, gastrointestinal
      symptoms, lower serum albumin, lower hematocrit, lower serum calcium, and higher
      serum phosphorus. CONCLUSIONS: During the course of chronic renal failure in type
      2 diabetes patients, early implementation of nephrological well-established
      guIdelines is associated with better outcome after starting RRT.

PMID- 15029101
TI  - Anthropometric parameters and type 2 diabetes: a case-control study in a
      Guadeloupean population.
AB  - OBJECTIVE: The aim of this study was to quantify the association between three
      anthropometric parameters and type 2 diabetes in an adult population in
      Guadeloupe and to evaluate the effect of age on these associations. DESIGNS AND
      METHODS: We conducted a case-control study in a population recruited in an Health
      Center of Guadeloupe in Year 2000. A total of 309 subjects with documented type 2
      diabetes were matched on sex and age (+/- 2 Years) with controls free of any
      glycemic abnormality. Student t-test was used and conditional logistic
      regressions were performed separately for men and women to quantify the
      association between type 2 diabetes and the explanatory variables, body mass
      index (BMI), waist to hip ratio (WHR) and waist circumference (WC). RESULTS: Mean
      (SD) WC was 89.0 cm (0.9) in non diabetics men and 97.3 cm (1.1) in diabetics
      ones, p<10-4. In women, it was 87.7 (0.8) cm for non diabetics and 96.3 cm (0.9)
      for diabetics. This difference was persistent for any tertile of age in each sex.
      It was discordant for BMI and WHR at higher tertile for men and women. In the
      multivariate analysis, Odds ratio[CI95%] for WC was 9.67 [2.32-40.20] in men and
      2.97 [1.70-5.19] in women. It was 2.94 [0.99-8.74] in men and 6.15 [3.11-12.17]
      in women for WHR. Results for BMI were non significant in both sex. CONCLUSION:
      Differences between WC and WHR over age groups and sex in predicting type 2
      diabetes should be taken into account when using these parameters routinely in
      medical practice.

PMID- 15029103
TI  - Infections of the upper extremity in hospitalized diabetic patients: A
      prospective study.
AB  - OBJECTIVES: To study the clinical characteristics of a group of patients with
      diabetes and established upper extremity infections and to determine the
      causative factors of hand infections. METHODS: Prospective study of diabetic
      patients referred in to our service with infections of the upper extremity from
      January 1992 to December 2001. RESULTS: Twenty-six diabetic patients with an
      infection of the upper extremity were studied (17 F, 9 M). The admission rate
      equalled 0.7%. Twenty-one patients (80.8%) presented a Type 2 diabetes and 5 a
      Type 1 diabetes (19.2%). The diagnosis age of diabetes was 44.6 +/- 13.8 Years
      (range: 16-62). The average age at the occurrence of the lesion was 52.5 +/- 15.1
      Years (range: 21-73). The average duration of diabetes was 8.3 +/- 5.9 Years
      (range: 0-22). Diabetes was, in all the cases, poorly controlled because of an
      inadequate hypoglycaemic treatment and/or bad compliance. The patients had a high
      prevalence of peripheral neuropathy (n=17; 65.4%). The delays in presentation to
      the doctor and those related to hospitalization were respectively 9.1 +/- 10.0
      days (n=23) and 16.8 +/- 12.1 days. The hospitalization length reached 33.6 +/-
      22.6 days (range: 7-93). The final results, 6 Months after hospitalization, were
      as follows: the death rate reached 19.2% (n=5); 23.1% of the patients (n=6) had a
      minor amputation; for 53.8% of the patients (n=14), the lesions healed without
      any amputation. One patient left hospital against medical advice. Eleven out of
      20 patients (55%), amputated or not, were left with deformities and a subjective
      dysfunction of the affected limb. CONCLUSION: Infections of the upper extremity
      in diabetic patients constitute an uncommon but serious complication. They seem
      to be more frequent in housewives. They result in a high morbIdity. Prevention of
      these infections should be based on patients' education (compliance with diabetes
      treatment, hand care, prompt visit to the doctor) and General Practitioners'
      training for an adequate treatment and/or a rapId patient referral to hospital.

PMID- 15029102
TI  - Repaglinide is more efficient than glimepiride on insulin secretion and post
      prandial glucose excursions in patients with type 2 diabetes. A short term study.
AB  - OBJECTIVES: To compare the effect of Repaglinide vs Glimepiride on glucose- and
      meal-induced insulin secretion and on meal-test induced postprandial glucose
      excursions. METHODS: After 2 weeks washout period, a 3-Month randomised, cross
      over parallel group trial of R (1 mg x 2/die) vs G (2 mg/die) in 14 patients with
      type 2 diabetes "naive" in diet treatment was made. RESULTS: Both R and G
      significantly but similarly lowered fasting glucose levels and improved fasting
      plasma insulin levels vs baseline. Hyperglycemic clamp showed that both 1st
      (129.15 +/- 23.6 vs 106.90 +/- 18.6 pmol/L; p=0.01) and 2nd phase (189.42 +/-
      34.4 vs 144.21 +/- 37.3 pmol/L; p=0.003) B-cell response to glucose as well as
      area under the curve (52.07 +/- 10.86 vs 39.54 +/- 10.27 micromol/L x 120';
      p=0.005) were greater in R than G groups. Insulin action (4.0 +/- 1.1 vs 3.2 +/-
      0.9 mg x Kg x 60'/microU/mL; p=0.046) was also improved by R than G
      administration. In the meal test, R therapy produced a more rapId induction of
      insulin secretion during the first part. In fact, the mean rise in insulin
      secretion peaked at 45 min in R (p=0.001 vs G) and at 60 min in G (p=0.001 vs R).
      Consequently, glucose spike at 60 min was higher in G group compared to glucose
      spike at 45 min in R group (p=0.002). CONCLUSIONS: Our study demonstrates that R
      is more efficient that G on improving glucose- and meal- induced insulin
      secretion as well as on controlling for postprandial glucose excursion.

PMID- 15029104
TI  - Diabetes and Amoebiasis: a high risk encounter.
AB  - Amoebiasis is the second most common parasitic disease worldwIde. It occurs
      mainly in developing countries. A high percentage of people in countries where it
      is endemic are asymptomatic carriers. It results in severe disease that can be
      fatal in rare cases. Diabetics are at increased risk of exposure as travel to
      countries where it is endemic becomes more frequent, as indicated by the present
      case. This patient suffered from amoebiasis that produced an amoeboma which is
      most rare in cases of colonic amoebiasis. The clinical picture was that of an
      occluding gut tumor, but it was treated only with drugs. Retrospective studies
      show that diabetics are at increased risk of suffering severe complications after
      amoebic infection. The frequency and severity of this diabetes-amoeba association
      requires patients to take prophylactic measures, especially when travelling in
      developing countries.

PMID- 15029105
TI  - Non-invasive tests for the diagnosis of H. pylori infection.
AB  - Helicobacter pylori infection can be diagnosed by invasive techniques requiring
      endoscopy and biopsy (eg, histological examination, culture, polymerase chain
      reaction) and by non-invasive techniques such as serology, urea breath test,
      urine/blood test, or detection of H. pylori antigen in stool specimen. Some non
      invasive tests, such as the urea breath test and the stool antigen test, detect
      active infection; these are called "active tests." Non-invasive tests (eg,
      serology) are markers of exposure to H. pylori but do not indicate if active
      infection is ongoing; these are called "passive tests." Non-invasive test-and
      treat strategies are widely recommended in primary care settings. The choice of
      an appropriate test depends on the pre-test probability of infection, the
      characteristics of the test being used, and the cost-effectiveness of the test.
      This article reviews available non-invasive tests.

PMID- 15029106
TI  - Chronic hepatitis C and liver transplantation.
AB  - Chronic hepatitis C virus (HCV) is a worldwide health problem. Approximately 4
      million people in the United States are chronically infected with HCV. The
      incidence of infection peaked between 2 and 3 decades ago, and we are now
      beginning to see an increase in the complications of cirrhosis from HCV. This
      trend is expected to continue for another 2 to 3 decades. Survival is poor once
      complications of cirrhosis, such as liver failure or hepatocellular carcinoma,
      ensue, and liver transplantation is often the only option. Complications of
      chronic HCV are the most common indication for liver transplantation, accounting
      for more than 40% of transplants performed in the United States and Europe. HCV
      recurs in all patients and rapid development of hepatic fibrosis is very common.
      Several strategies have been proposed to reduce the risk of graft loss from
      recurrent HCV infection after transplantation, as the progression of the
      resulting liver disease is rapid. Although antiviral treatment is successful in
      some patients, it is extremely difficult to administer and requires dose
      reductions in the majority of cases. Retransplantation in the current era of the
      Model for End-Stage Liver Disease (MELD) system for prioritizing listing for
      transplant is associated with very low survival rates at a high cost.
      Furthermore, the system raises difficult ethical issues of utilization of limited
      resources and fairness to other transplant candidates.

PMID- 15029107
TI  - Management of chronic constipation.
AB  - Constipation is a common problem in the United States. Although most individuals
      do not seek health care for its symptoms, there are still more than 2 million
      visits to physicians annually for treatment. In this article, the author presents
      an overview of current diagnostic tools and treatment options for chronic
      constipation.

PMID- 15029108
TI  - Therapeutic equivalence of mesalamine products.
AB  - No bioequivalence studies have been conducted for mesalamine because of
      differences in formulation. Based on U.S. Food and Drug Administration
      definitions for bioequivalence, none of these drugs can be classified as
      bioequivalent or therapeutically equivalent. No adequate comparative trials have
      been conducted with equivalent mesalamine doses to determine if any of the
      current formulations are superior in the treatment of ulcerative colitis. All of
      these mesalamine formulations are effective, but they differ with regard to where
      the drug is released in the intestinal tract, which may influence the outcome in
      some patients. Therefore, the selection of a mesalamine agent should be based on
      the results of the clinical trials, individual patient response, compliance
      issues, and price, until comparative clinical trials are published.

PMID- 15029109
TI  - Pharmacological treatment and prevention of heart failure in the diabetic
      patient.
AB  - Diabetes is a strong and independent risk factor for the development of heart
      failure, and once heart failure occurs, patients with diabetes have a much poorer
      prognosis than do those without diabetes. This difference has been explained by
      the existence of a distinct diabetic cardiomyopathy characterized by morphologic
      and structural changes to the myocardium and coronary vasculature. Despite
      diabetic cardiomyopathy, the pharmacologic treatment of heart failure in diabetic
      patients is similar to that in patients without diabetes, and in general, the
      clinical response of diabetic patients to drug therapies for heart failure is
      similar, if not superior, to that of nondiabetic patients. Subgroup analyses from
      large clinical studies have shown that angiotensin-converting enzyme inhibitors
      not only reduce mortality in diabetic patients with heart failure, but also
      reduce the incidence of heart failure in at-risk diabetic patients. B-Blockers
      remain underused in the diabetic population despite overwhelming evidence of
      their efficacy in treating heart failure in patients with diabetes.

PMID- 15029110
TI  - Thrombosis and drug-eluting stents: a critical appraisal.
AB  - The clinical consequences of stent thrombosis are frequently catastrophic. This
      article reviews the factors previously implicated in the occurrence of stent
      thrombosis and analyzes recent reports of thrombosis involving a new sirolimus
      eluting stent (Cypher). Factors associated with stent thrombosis include
      intrinsic stent thrombogenicity and patient-, target lesion-, and procedure
      related issues. Stent design may influence the degree of platelet activation
      after coronary stent deployment. In drug-eluting stents, the mechanical
      properties of the bare metal stent platform might be altered by the polymer
      coating, and the propensity for thrombosis might be influenced by both the
      polymer coating and the medication with which it is impregnated. Cumulative data
      for the Cypher stent do not suggest a propensity for thrombosis, but several
      caveats should be observed to enhance the safety of the device.

PMID- 15029111
TI  - Diagnostic and therapeutic utility of B-type natriuretic peptide in patients with
      renal insufficiency and decompensated heart failure.
AB  - Chronic kidney disease (CKD) and congestive heart failure (CHF) are
      epidemiologically and pathophysiologically linked. A recent study in patients
      with severe CHF demonstrated that renal plasma flow was inversely correlated with
      pulmonary capillary wedge pressure, right atrial pressure, pulmonary pressure,
      and right ventricular ejection fraction. This article reviews the utility of B
      type natriuretic peptide (BNP) levels in assessing cardiac function and volume
      status in patients with CKD and examines the safety and efficacy of BNP therapy
      in patients with renal insufficiency and decompensated heart failure.

PMID- 15029112
TI  - Improved symptoms, physical limitation, and self-efficacy after resynchronization
      in a patient with heart failure and a prolonged QRS duration.
AB  - This report examines the impact of resynchronization therapy in a patient with
      class IV heart failure and a prolonged QRS duration on electrocardiogram. The
      Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to assess the patient's
      health status prior to, immediately after, and 2 months after placement of a
      biventricular pacemaker. B-type natriuretic peptide (BNP) values and
      electrocardiogram QRS duration were recorded to further document clinical status.
      Our patient experienced statistically significant improvements in 7 of 10 KCCQ
      domains after resynchronization. QRS duration narrowed following the procedure
      and BNP values decreased. Resynchronization therapy improved this patient's
      symptoms, physical limitations, and self-efficacy when maximal medical therapy
      failed.

PMID- 15029113
TI  - Asymmetric septal hypertrophy presenting with cardiogenic shock, complete heart
      block, and septal infarction despite normal coronaries.
AB  - A 37-year-old man, brought in following a syncopal episode, was found to be in
      cardiogenic shock with a complete infranodal heart block. A temporary transvenous
      pacemaker and an intra-aortic balloon pump were inserted emergently. Cardiac
      catheterization revealed a high left ventricular end-diastolic pressure but
      normal coronary vasculature. An echocardiogram demonstrated a hyperdynamic left
      ventricle, severe hypokinesis of the septum, and asymmetric septal hypertrophy.
      An endomyocardial biopsy showed myofibril hypertrophy and disarray. The patient
      required implantation of a permanent pacemaker for full recovery. Although
      arrhythmias are common in asymmetric septal hypertrophy, complete
      atrioventricular block is rare but can cause syncope and cardiogenic shock. This
      is the first case, reported in the literature, of asymmetric septal hypertrophy
      in which the patient presented with cardiogenic shock and complete heart block
      secondary to a septal infarction, despite normal coronaries, and in whom a
      myocardial biopsy was performed. The case report is followed by a review of the
      literature on hypertrophic cardiomyopathy associated with complete heart block.

PMID- 15029114
TI  - Trends in tuberculosis--United States, 1998-2003.
AB  - During 2003, a total of 14,871 tuberculosis (TB) cases (5.1 cases per 100,000
      population) were reported in the United States, representing a 1.4% decrease in
      cases and a 1.9% decline in the rate from 2002. This decline is the smallest
      since 1992, when TB incidence peaked after a 7-year resurgence. In addition, the
      rate remains higher than the national interim goal of 3.5 cases per 100,000
      population that was set for 2000. This report summarizes data from the national
      TB surveillance system for 2003 and describes trends during a 5-year period, with
      comparison to 1998 and 2002. Despite a decline in TB nationwide, rates have
      increased in certain states, and elevated TB rates continue to be reported in
      certain populations (e.g., foreign-born persons and racial/ethnic minorities).
      Targeted interventions for these at-risk populations, continued collaborative
      efforts toward the global fight against TB, and adequate local resources are
      essential to eliminating TB in the United States.

PMID- 15029115
TI  - Tuberculosis outbreak in a community hospital--District of Columbia, 2002.
AB  - After declining for nearly 30 years, during 1985-1992, tuberculosis (TB) rates in
      the United States experienced a resurgence, and several large nosocomial TB
      outbreaks occurred. Although data on such outbreaks are not collected
      systematically by CDC, the occurrence of nosocomial TB is believed to have
      declined sharply since the issuance and widespread implementation of infection
      control guidelines in 1994. During April 2-September 12, 2002, TB was diagnosed
      in six persons who either had been patients or had worked in a large community
      hospital (hospital A) in March or early April. This report describes the results
      of an investigation of the presumed source patient, who had spent 3 weeks on two
      general medical wards of hospital A before being placed in respiratory isolation
      and having TB diagnosed on April 2. To prevent transmission of Mycobacterium
      tuberculosis, hospital staff should remain vigilant to identify and treat
      suspected TB cases promptly.

PMID- 15029116
TI  - School-associated pertussis outbreak--Yavapai County, Arizona, September 2002
      February 2003.
AB  - On September 21, 2002, a pertussis case (confirmed by isolation of Bordetella
      pertussis) was reported to the Yavapai County Health Department (YCHD). The
      patient was a child aged 13 years in the 8th grade at a middle school in Yavapai
      County; the child had attended school during the illness. A case consistent with
      the clinical definition of pertussis had been reported in another student in the
      same classroom 2 weeks earlier. On September 22, a second culture-confirmed case
      was reported from the same classroom. Subsequent investigation identified five
      additional persons (two students in the same classroom, two 8th-grade teachers,
      and one parent of an ill student) with prolonged cough illnesses. In comparison,
      during the previous 10 years, an average of four pertussis cases were reported
      annually from this county. On September 26, YCHD, in conjunction with the Arizona
      Department of Health Services (ADHS) and school officials, notified the community
      of the pertussis outbreak in the middle school and initiated control measures.
      This report summarizes the epidemiology of the outbreak and the control measures
      used to contain it. Health-care providers should consider pertussis in persons of
      any age with acute cough illnesses and consider obtaining nasopharyngeal (NP)
      specimens for B. pertussis culture.

PMID- 15029117
TI  - Evaluation of an association between loratadine and hypospadias--United States,
      1997-2001.
AB  - Hypospadias is a birth defect that affects approximately seven in 1,000 male
      infants in the United States. In affected infants, the urethral opening is
      located along the underside of the penis, scrotum, or perineum; the condition
      usually is corrected by surgery. Hypospadias is classified in order of increasing
      severity as first, second, or third degree. In 2002, a study in Sweden noted that
      among male infants born to women who while pregnant had taken loratadine
      (Claritin), a nonsedating antihistamine commonly used for seasonal allergies,
      hypospadias prevalence was twice that of the general population. However,
      insufficient data were available to determine the severity of the hypospadias
      cases, and the study did not control for confounding variables (e.g., family
      history of hypospadias or maternal age). In 2003, a prospective study using data
      from four countries indicated that five of 142 pregnancies in women exposed to
      loratadine resulted in infants with major malformations, a prevalence consistent
      with that of the general population; none had hypospadias. To further assess any
      potential association between loratadine and hypospadias, CDC analyzed data from
      the National Birth Defects Prevention Study (NBDPS). This report summarizes the
      results of that analysis, which determined that no increased risk for second- or
      third-degree hypospadias existed among women who used loratadine in early
      pregnancy. These results might be useful for women and health-care providers to
      address concerns about loratadine use and hypospadias.

PMID- 15029118
TI  - [Pyoinflammatory ENT and upper airway diseases: the importance of the problem and
      approaches to its management].
AB  - The problem of pyoinflammatory ENT and upper airway diseases is reviewed. Some
      new approaches are proposed.

PMID- 15029119
TI  - [Effective antibacterial therapy in otorhinolaryngology: bacteriological
      rationale].
AB  - The article presents current views on etiopathogenesis of the diseases associated
      with contamination with microorganisms; reviews inflammatory ENT diseases in
      terms of current literature on clinical microbiology of these diseases;
      characterizes microorganisms more or less specific for each relevant nosological
      entity; analyses basic groups of antibacterial drugs with formulation of
      bacteriologically grounded principles of initial antibacterial therapy of ENT
      inflammation.

PMID- 15029121
TI  - [Bacterial contamination of the maxilla after radical surgical treatment].
AB  - Qualitative and quantitative examinations of the microflora in a postoperative
      cavity of 62 patients early after radical surgery on the maxilla with opening of
      the ethmoidal labyrinth have found that in spite of a noticeable antibacterial
      effect of the operation pyoinflammatory process in the wound is possible.
      Treatment basing on bacteriological findings is recommended.

PMID- 15029120
TI  - [The role of chlamydial infection in development of acute respiratory diseases in
      children].
AB  - The examination of 245 children with respiratory diseases has detected chlamydia
      in 45 (18.4%) of them. Chlamydial species were identified and clinical symptoms
      of acute respiratory diseases (ARD) of chlamydial etiology are described. Five
      serological groups of patients depending on the presence or absence of chlamydial
      infection markers were recognized. Antibacterial drug treatment showed that most
      effective were sumamed, rulid and clindamycin. Long-term outcomes in relation to
      the kind of treatment are analysed.

PMID- 15029122
TI  - [Current antibacterial therapy of acute otitis media].
AB  - General approaches to general and local therapy of acute otitis media are
      validated and schemes of antibacterial treatment of this disease are proposed.

PMID- 15029123
TI  - [Pre- and intraoperative preparation of patients with pyoinflammatory diseases of
      the ear, pharynx and paranasal sinuses].
AB  - The authors consider the problems of effective general and local antibiotic
      therapy regarding most frequently occurring now causative agents and doses of
      antibacterial drugs. Combined use of antibacterial drugs and immunostimulators is
      analysed as antibacterial drugs deteriorate nonspecific immunity.

PMID- 15029124
TI  - [Microbiological aspects of effective antibiotic therapy early after operation in
      chronic maxillary ethmoiditis and tonsillitis].
AB  - Microbiological and chromato-mass-spectrometric examinations were made in 53
      patients with chronic maxillary ethmoiditis and 52 patients with chronic
      tonsillitis. The microflora showed strong resistance to unprotected penicillines
      and cephalosporins, 100% sensitivity to amoxicilline clavulanate and mupirocine.
      The role of opportunistic microflora as pathogens of ENT inflammation is growing
      as well as the percentage of anaerobic microorganisms detected chromato-mass
      spectrometrically in chronic inflammation. Administration of mupirocine on
      polyethylenglicol base early after operation in patients with chronic maxillary
      ethmoiditis accelerated recovery of the study group patients by 2-3 days vs
      control patients.

PMID- 15029125
TI  - [Comparative efficacy and safety of amoxiclav (amoxicillin clavulanate) and
      ampicillin in the treatment of acute bacterial sinusitis].
AB  - Efficacy and safety of amoxiclav (amoxicillin clavulanate) and ampicillin were
      studied in antibacterial therapy of acute sinusitis. Antibacterial efficacy of
      amoxiclav in acute sinusitis reached 100%. Its safety was good. Antibacterial
      efficacy of ampicillin was 76%; 24% patients retained symptoms of the disease, x
      ray picture of sinusitis. Its toxicity was higher.

PMID- 15029126
TI  - [Dynamic study of antibiotic resistance of bacterial environment of the ENT
      department].
AB  - A dynamic 4-year monitoring of aerobic bacterial environment in the ENT
      department shows its relative qualitative stability with predominance of the
      coccal flora, primarily staphylococcal. Gram-negative flora was represented for
      the most part with non-fermentating microorganisms, most of them Acinetobacter. A
      wide-spectrum resistance to antibacterial drugs was found. This resistance has a
      trend to extend.

PMID- 15029127
TI  - [Middle ear mycosis].
AB  - Clinical, mycological and histological examinations of 608 patients who had
      chronic purulent otitis media (n=232) or persistent purulent discharge after
      surgery on the middle ear (n=376) detected mycosis in 22 (9%) patients with
      chronic purulent otitis media and in 77 (20%) patients after surgery on the ear.
      Aspergillus niger occurred in 52.5% patients. Specific general or local treatment
      was made basing on the species of the pathogen.

PMID- 15029128
TI  - [Microflora of the voice prostheses].
AB  - The study was made of the condition of voice prostheses Provox and Blom-Singer in
      27 patients wearing them. The prostheses were to be replaced by new ones as they
      lost impermeability for water. The prostheses were used for 6 months to 2 years.
      At the prosthesis removal from the tracheoesophageal bypass it was found that the
      esophageal flange and protective valve were contaminated with fungi and
      pathogenic bacteria. The valve was deformed, had limited motility and did not
      close tightly the esophageal opening of the prosthesis as the result of which
      liquid leaked into the airways. Bacteriological examination identified
      C.albicans, C.krusei, C.glabralis in 11 patients. Nistatin, flucostat,
      fluconasol, amphotericin were used in antifungal therapy. Prophylactic use of
      these drugs against fungi prolonged use of the prostheses 2-fold.

PMID- 15029129
TI  - [Characteristics of coronary artery lesions in patients with painless myocardial
      ischemia].
AB  - AIM: To assess extent and localization of coronary artery lesions in patients
      with painless myocardial ischemia. MATERIAL AND METHODS: Tredmill stress
      echocardiograghy, Holter ECG monitoring and coronary angiography were carried out
      in 59 male patients (age 30-72, mean 54.5 years) with either angina pectoris or
      painless ischemia. RESULTS: Among patients with painless ischemia 50% had 2
      vessel disease, mostly with right coronary artery involvement (87.5%) and there
      was no case of left main stenosis. Patients with angina were characterized by
      significantly higher index of obstruction (p<0.005) and often had multivessel
      coronary artery disease (48.8%). CONCLUSION: Patients with effort angina compared
      with those with painless ischemia had more extensive and severe coronary artery
      involvement while the latter more often had right coronary artery stenoses.

PMID- 15029130
TI  - [Automatic analysis of cardiological signals for diagnosis of ischemic heart
      disease].
AB  - A new noninvasive method for early detection of ischemic heart disease based on
      singular value decomposition is introduced. The method automatically explores
      waveforms of an ECG by making projections of individual ECG leads onto axes
      formed by the first three components of the singular value decomposition
      performed for the whole group of ECGs, including cases with and without coronary
      artery lesions (460 ECGs). Detection of the presence of lesions is performed with
      73% sensitivity and 83% specificity. Sensitivity and specificity become lower
      when specifying which coronary artery contains lesions: 69% and 77%,
      respectively, for the right coronary artery, 66% and 82%, respectively, for left
      anterior descending artery. 74% and 71%, respectively, for the left circumflex
      artery. The method is being developed so that it might be included into the
      programs of automatic ECG analysis, particularly for population studies.

PMID- 15029131
TI  - [Nebivolol in the treatment of ischemic heart disease patients with chronic heart
      failure].
AB  - AIM: To assess effectiveness of inclusion of nebivolol in complex therapy of
      patients with chronic heart failure (CHF) due to ischemic heart disease (IHD).
      MATERIAL: Patients (n=62, age 47-73 years) with NYHA class II-III CHF and left
      ventricular (LV) ejection fraction (EF) less than 45% receiving standard therapy
      +/- nebivolol (5 mg/day). The patients were followed up for 4 months. RESULTS:
      After 4 months improvement of clinical state, exercise tolerance, parameters of
      central hemodynamics and LV remodeling, lipid spectrum, rheological properties of
      blood and platelets haemostasis was more pronounced in a group of nebivolol
      treated patients. CONCLUSION: Inclusion of nebivolol in complex therapy increases
      efficacy of treatment of patients with CHF due to IHD.

PMID- 15029133
TI  - [Blood pressure dynamics and prognostication of hypertension: 20-year follow-up
      of children's cohort].
AB  - AIM: To track dynamics of blood pressure (BP) from childhood to young maturity
      and to determine predictors of hypertension. METHODS: School children (n=1082)
      were examined in a framework of an international program on juvenile hypertension
      in 1976-1977. Samples of this initial cohort were reexamined in 1988 (n=444) and
      1997 (n=505). Data on persons examined on all 3 occasions were used in this
      paper. RESULTS: BP elevation during 20 years of follow-up was more pronounced in
      men. Adulthood BP correlated with its value at the age of 12-13 and 25-26 years.
      Main predictors of adult hypertension in men and women were childhood systolic
      and diastolic BP, respectively. Body mass change from the age of 25-26 to 32-33
      years was also related to the presence of hypertension at the last examination.

PMID- 15029132
TI  - [Effect of eprosartan on microcirculation and blood rheology in patients with
      hypertensive disease].
AB  - The use of eprosartan (600-1200 mg/day for 4 weeks) in 28 patients with stage II
      hypertensive disease was associated with improvement of parameters of
      microcirculation and blood rheology.

PMID- 15029134
TI  - [Efficacy of nondrug correction of hypertension in general medical practice].
AB  - Effectiveness of nondrug correction of elevated blood pressure was assessed in a
      group of hypertensives selected from participants of a study of prevalence of
      cardiovascular risk factors conducted in one of Saint Petersburg districts.
      Patients were divided into 3 subgroups in which the following interventions were
      used: diet with decreased sodium content, aerobic physical exercise, or
      combination of these methods. Blood pressure lowering achieved with these methods
      (-11 mm Hg systolic and -6.8 mm Hg diastolic) was maintained throughout 2 years
      of observation.

PMID- 15029135
TI  - [Inflammatory-immunological cellular reaction in intima of the aorta and
      pulmonary artery and development of atherosclerosis].
AB  - AIM: To assess morphological manifestations of inflammation at initial stages of
      atherosclerosis development in intima of the aorta and pulmonary artery both in
      its intact (lipid free) zones and those with lipoidosis. METHODS: Histological,
      histochemical and immune cytochemical methods with the use of monoclonal
      antibodies to monocytes/macrophages (CD-11) and T-lymphocytes (CD-4, CD-5, CD-8)
      were applied for the study of cellular elements in membranous preparations of
      intima and transverse cross-sections of the aorta and pulmonary artery from 64
      apparently healthy persons aged 4 months-49 years who died of accidental causes.
      RESULTS: Signs of inflammatory cellular reaction (infiltration with
      monocytes/macrophages) were permanently present in aortic and pulmonary artery
      intima and progressed with age. This cellular reaction was consistently
      accompanied by infiltration of intima with mast cells. Compared with intact
      intima infiltration with lymphocytes/monocytes was more pronounced in zones with
      lipoidosis where helper-lymphocytes prevailed among T-cells and number of
      monocytes/macrophages was substantially increased. CONCLUSION: Mononuclear
      cellular infiltration with participation of mast cells was persistently present
      in aortic and pulmonary artery intima and obviously preceded its atherosclerotic
      changes. However there was no straightforward relationship between severity of
      this reaction and development of atherosclerosis in the aorta and especially in
      pulmonary artery.

PMID- 15029136
TI  - [Lowering of antiatherogenic significance of high density lipoproteins in obese
      persons].
AB  - Protein and lipid components of blood serum high density lipoproteins (HDL)
      responsible for their functional activity were studied before and after fat load
      in subjects with normal body mass and various types of obesity. Subjects with
      abdominal obesity compared with those with gluteo-femoral obesity and normal body
      mass initially had pronounced disturbances in components of HDL and their
      acceptor capacity. Fat load caused changes of HDL composition in all study
      groups. Postprandial effect in persons with normal body mass became obvious 6
      hours after load while in those with excess mass it occurred earlier - 3 hours
      after fatty meal. In subjects with gluteo-femoral obesity this effect remained on
      the same level while in those with abdominal obesity it became more pronounced by
      hour 6. Contrary to subjects with normal body mass and gluteo-femoral obesity fat
      load induced changes of HDL components in persons with abdominal obesity were not
      associated with augmented acceptor capacity of HDL what could be considered as
      proatherogenic effect.

PMID- 15029137
TI  - [QT interval shortening in families with history of sudden death at young age].
AB  - AIM: To assess frequency of short QT interval among members of families with
      history of young age sudden death. MATERIAL: Eleven children aged 3-16 years
      (mean age 11.2+/-4.2 years) from families with cases of sudden death at young age
      (<40 years) not caused by an obvious disease according to autopsy data. None of
      the probands had overt heart disease, life threatening arrhythmias, long QT
      syndrome. METHODS: Predicted QT value was estimated according to the P.
      Rautaharju formula [QT(p)=656/(1+HR/100)], and values equal to 80 and 88% of
      QT(p) (QT(p)80 and QT(p)88) were determined. Corrected QT interval duration
      (QT(c)) was calculated for all these values with the use of the Bazett formula.
      RESULTS: Values of corrected QT(c)88 370 ms and 350 ms were considered minimal
      for heart rates above and below 78 bpm, respectively. QT shortening to the level
      of QT(p)80 at heart rates above 70 bpm corresponded to QT(c) values <330 ms. Nine
      of 11 children (81.1%) had QT interval equal to or less than QT(p)88. Three
      probands with attacks of syncope had QT equal to QT(p)80, high concentration of
      sudden deaths in family (up to 30% of family members), and high prevalence of
      shortened QT <80% among family members. CONCLUSION: Shortened QT interval is
      characteristic for children with family history of sudden death at young age.
      Registration of QT duration equal to or shorter than 88% of predicted value
      requires exclusion of diseases and syndromes with increased risk of sudden death.

PMID- 15029138
TI  - [Left ventricular geometry in inhabitants of Tallinn (an echocardiographic
      population study)].
AB  - Echocardiography was performed in 325 men and 398 women in the framework of a
      population survey of inhabitants of Tallinn aged 35 to 59 years in 1999-2001.
      Left ventricular geometry was analyzed according to generally recognized four
      types. Prevalence of concentric hypertrophy was similar in men and women (7.7%
      and 9.1%, respectively). In all age groups prevalence of eccentric hypertrophy in
      women was 4-10-fold higher than in men (33.3 and 4.9%, respectively). Concentric
      remodeling was also more frequent in women than in men (9.5 and 5.5%;
      respectively, p<0.05). Regardless of sex and age, concentric hypertrophy was
      never found in participants with normal blood pressure. In hypertensives there
      was a tendency for age-related increase of prevalence of concentric hypertrophy:
      the latter was higher in women than in men (39.1% and 25.5%; respectively,
      p<0.05). In examinees with body mass index (BMI) <30 this type was rare. In obese
      persons its frequency increased with age in both sexes reaching 26.5% in men and
      21.2% in women (p<0.05). Prevalence of eccentric hypertrophy in men increased
      with age, especially in the presence of hypertension and obesity. In men the
      prevalence of concentric remodeling was not related to BMI; it was significantly
      more often found in older age groups and in hypertensives. In women the
      prevalence of eccentric hypertrophy and concentric remodeling was not related to
      age, hypertension and BMI. The frequency of normal geometry decreased with age in
      both sexes.

PMID- 15029139
TI  - [Climatic and ecological risk factors of myocardial infarction in the Far North].
AB  - Basing on analysis of 1383 hospitalizations because of myocardial infarction
      during 5 years the following climatic events were found to be associated with
      development of the disease: rapid changes of atmospheric pressure, temperature or
      humidity, and magnetic storms. Technogenic ecological factors such as levels of
      formaldehyde, phenol, nitrogen dioxide and carbon monoxide in atmospheric air
      were also related to frequency of hospitalizations due to myocardial infarction.

PMID- 15029140
TI  - [Antioxidants in complex therapy of atherosclerosis: pro et contra].
AB  - The review contains current insights into the role of free radical processes in
      formation of oxidative stress in atherosclerosis and its relevance to therapy and
      prevention. Data of epidemiological studies evidence for existence of
      correlations between blood plasma content of antioxidant vitamins and presence of
      signs of atherosclerosis. However mostly positive data on the use of antioxidants
      in various animal experimental models of atherosclerosis contrast with equivocal
      results of therapeutic application of antioxidant vitamins in humans. Possible
      causes for this controversy have been choice of suboptimal combinations of
      components, extremely high concentrations of consumed substances, lack of
      biochemical testing of baseline antioxidant status and its changes in the process
      of therapy. The authors of the review suggest novel approaches to planning of
      clinical trials of antioxidant vitamins.

PMID- 15029142
TI  - [Myocardial infarction in patients with infectious endocarditis].
AB  - Myocardial infarction (MI) developed in 9% of 230 patients with active infectious
      endocarditis. Development of MI was associated with worsened clinical course and
      poorer prognosis of infectious endocarditis. MI manifested with pain in 43 and
      was painless in 57% of these cases. In 29% of patients initial manifestations of
      MI were disturbances of cardiac rhythm and conduction, and acute left ventricular
      failure. This precluded timely electrocardiographical diagnosis. However
      repetitive ECG recordings allowed to confirm MI in all patients. Elevation of
      enzymes helped to diagnose MI in 81% of cases. Possible causes of MI were
      shutting of coronary artery ostium by vegetation from an aortic valve cusp (in
      47%) and/or lowering of perfusion pressure in coronary arteries because of severe
      aortic insufficiency (in 62% of patients). Disturbances of hemostasis with
      activation of its vascular and platelet elements and hypercoagulation found in
      all patients with infectious endocarditis also facilitated development of MI. The
      data obtained explain under investigated sides of pathogenesis of MI in
      infectious endocarditis and allow to find ways for improvement of its diagnosis
      and therapy.

PMID- 15029141
TI  - [Systolic and diastolic left ventricular dysfunction--independent types of
      cardiac failure or two sides of a single process?].
AB  - At present disturbances of systolic and diastolic myocardial function are
      subjected to intensive study. Most researches acknowledge possibility of
      development of diastolic dysfunction in the absence of systolic dysfunction.
      Meanwhile disturbances of systolic and diastolic myocardial functions have common
      pathogenetic and pathomorphological basis representing the essence of cardiac
      remodeling. Patients with instrumental signs of pure diastolic dysfunction and
      subjects with combination of disturbances of systolic and diastolic functions
      have similar clinical symptoms. This literature review deals with problems of
      relationship between systolic and diastolic dysfunction and expediency of clear
      delineation of these disturbances.

PMID- 15029143
TI  - [Comparison of eprosartan and captopril in left ventricular systolic dysfunction:
      relation of efficacy to myocardial viability].
AB  - Patients with left ventricular ejection fraction below 45% (mean 39+/-3.7%) were
      randomized either to captopril (n=33) or eprosartan after miocardial infarction
      (n=33) on days 3-7 of myocardial infarction. All patients were subjected to
      echocardiography and 40 to perfusion myocardial scintigraphy with (99m)TC
      Technetril. Myocardial viability was defined as presence of perfusion reserve in
      dysfunctional segments during test with nitroglycerin. Dysfunctional myocardium
      was found to be viable in 62.5% of patients. Fifty six patients completed 3
      months follow up and were restudied. By the time of the second study 28 patients
      continued captopril (37.5-150 mg, average dose 72+/-34.2 mg/day) and 28 -
      eprosartan (300-600 mg, average dose 471+/-151 mg/day). Captopril was stopped or
      its dose corrected in 28% of patients. In eprosartan group there were no side
      effects which required withdrawal of the drug. Similar increases of ejection
      fraction occurred on both groups (from 38+/-2.1 to 49+/-6.7%, p<0.001 and from
      39+/-4 to 51+/-6.5%, p<0.001, in eprosartan and captopril groups, respectively).
      Magnitude of left ventricular ejection fraction change did not depend on the
      presence of viable myocardium. However in both treatment groups improvement of
      myocardial perfusion and decrease of left atrial dimensions were found only in
      patients with viable myocardium at initial study.

PMID- 15029144
TI  - [Novel functional stress test (stochastic) and perspectives of its application].
AB  - AIM: To assess advantages of a stochastic functional stress test during which
      workloads change according to law of random numbers. METHOD: Results of
      stochastic tests and standard stress tests with stepwise increments of workloads
      were compared in 45 healthy subjects and 90 patients with ischemic heart disease
      (45 with angina pectoris, 45 after myocardial infarction). RESULTS: Compared with
      standard tests stochastic test was characterized by shorter times of achievement
      of ischemic threshold and higher double product. Sensitivity and specificity of
      stochastic test were significantly better than those of standard stress test. The
      difference between results of two tests can be explained by increased information
      content of the stochastic test.

PMID- 15029145
TI  - [Clinical and functional characteristics of hypertension in patients consuming
      excessive amounts of salt].
AB  - Salt sensitivity threshold was measured in 230 patients with arterial
      hypertension and clinical and functional characteristics of hypertension in
      patients consuming excessive amounts of salt were studied. Patients with high
      salt sensitivity threshold consumed more salt with food and represented a special
      group of patients. These patients suffered especially severe disease which
      developed earlier than in patients with low threshold. Patients with high salt
      sensitivity threshold more often had cardiovascular complaints, neurotic traits
      in psychological status, aggravated heredity. These patients had higher
      cholesterol level and more often smoked. Clinical course of the disease in
      patients with high salt sensitivity threshold was more often complicated by
      hypertensive crises. They also had higher blood pressure throughout 24 hours and
      impaired circadian blood pressure rhythm. Increased myocardial volume load in
      patients with high salt sensitivity threshold promoted rapid development of left
      ventricular hypertrophy and systolic dysfunction.

PMID- 15029146
TI  - [Correction of rate and structure of ventricular rhythm in permanent atrial
      fibrillation: a novel pathogenetic approach].
AB  - AIM: To analyze action of digoxin and some non-digitalis drugs (beta-blockers,
      verapamil, amiodarone, d,l-sotalol) and their combinations on electrical activity
      of atria, frequency and structure of ventricular rhythm in patients with
      permanent atrial fibrillation. MATERIAL AND METHODS: One hundred patients with
      permanent atrial fibrillation and heart rate at rest above 80 bpm were divided
      into 9 treatment groups. High-resolution orthogonal Frank lead ECG was recorded
      before and after allocated treatment. Analysis included construction of ff-waves
      periodograms, histograms of RR interval, cardiointervalograms and application of
      autocorrelation function. RESULTS: It was demonstrated that frequency and form
      (structure) of ventricular rhythm was determined not only by the state of AV
      conduction but also by value of basic period of ff-waves. The mechanisms of
      ventricular rate deceleration by investigated drugs were not identical. beta
      blockers and verapamil directly slowed AV conduction without changing parameters
      of ff-waves and differed from each other only in action on parameters of
      concealed conduction in AV node. Action of digoxin in patients with ff-waves
      period equal to or exceeding 0,15 s was biphasic. During phase I shortening of ff
      wave period (by 0.025+/-0.012 s) occurred. This was associated with increase of
      their concealed conduction through AV node. The latter phenomenon represented
      independent mechanism of ventricular rhythm deceleration. During phase II of
      digoxin action direct inhibition of AV conduction took place. Amiodarone and d,l
      sotalol increased basic ff-waves period. This facilitated their conduction
      through AV node. Greater heart rate slowing effect of d,l-sotalol was attributed
      to its ability to augment concealed conduction. Due to their antiarrhythmic
      qualities amiodarone and d,l-sotalol slowed heart rate in patients with peak RR
      duration in the region of 0.28-0.46 s. These patients often had bi- and tri-modal
      structure of interval RR histogram. Changes of ventricular rhythm structure
      during use of various drugs were different. Action of digoxin was most whilst
      that of beta-blockers least favorable. CONCLUSION: Choice of a drug for treatment
      of permanent atrial fibrillation should be conducted with consideration of ff
      waves periodicity, parameters of RR interval histogram, and characteristics of
      ventricular rhythm structure.

PMID- 15029147
TI  - [Endothelial dysfunction and risk factors of its development in subjects with
      family history of atherosclerosis].
AB  - Brachial artery blood flow reactions to hyperemia and hyperventilation
      (endothelium dependent vasodilation and vasoconstriction) were studied by doppler
      sonography in 60 persons aged 19-39 years with family history of atherosclerosis
      and risk factors of this disease. Reactivity of peripheral artery and risk
      factors of atherosclerosis development were found to be interrelated. The results
      allowed to suggest participation of atherogenic fractions of lipoproteins,
      triglycerides, proinflammatory cytokines, and monocyte derived NO in formation of
      pathological vascular reactions in persons with family history of
      atherosclerosis.

PMID- 15029148
TI  - [Protective effect of hydrophilic ubiquinone on cardiac muscle during oxidative
      stress].
AB  - AIM: To assess effects of long term administration of a natural antioxidant
      ubiquinone on isoproterenol induced myocardial injury. METHODS: Rats were given
      hydrophilic ubiquinone with water for 8 weeks. RESULTS: Long term use of
      ubiquinone did not affect myocardial ultrastructure and relative myocardial
      weight. The dose of isoproterenol used in this study exerted moderate damaging
      action evidenced by disappearance of glycogen from sarcoplasm, development of
      edema, and partial destruction of mitochondrial cristae. These effects were
      associated with lowering of maximal magnitude of contractile function of the
      isolated heart and augmentation of superoxide radicals release in perfusate.
      These changes (except disappearance of glycogen) were not present in hearts of
      ubiquinone fed rats. Compared with controls mitochondria isolated from hearts of
      ubiquinone fed rats had higher respiratory control and more than twice lower rate
      of superoxide generation. CONCLUSION: As damaging effects of isoproterenol are
      mediated by augmented generation of active forms of oxygen the results obtained
      allow to suggest that myocardium of ubiquinone fed animals is characterized by
      elevated power of the antioxidant system.

PMID- 15029150
TI  - [Clinical value of some factors of gene transcription in heart diseases].
AB  - Two families of gene transcription factors - these review deals with peroxisome
      proliferator activated receptors (PP AR) and nuclear factor kappa B (NFkappaB).
      PPAR family controls lipid metabolism, processes of inflammation and
      atherothrombosis. Activation of NFkappaB initiates transcription of genes of such
      proinflammatory factors as cytokines, chemokines and adhesion molecules. NFkappaB
      plays substantial role in processes of apoptosis, ischemic preconditioning,
      myocardial injury in ischemia and reperfusion, development of acute coronary
      syndromes and cardiac failure. Clinical perspectives of drugs affecting these
      gene transcription factors are also discussed.

PMID- 15029149
TI  - [Candesartan - a novel AT(1)-angiotensin receptor blocker: peculiarities of
      pharmacology and experience of use in arterial hypertension].
AB  - Candesartan is a novel high-affinity type 1 AT(1)-receptor blocker characterized
      by prolonged binding to and slow dissociation from the receptor. Pharmacokinetic
      properties of candesartan explain its pronounced and lengthy (24-36 hours)
      antihypertensive action which does not depend on patients sex, age and body mass.
      Long term use of candesartan has been associated with regression of left
      ventricular hypertrophy, renoprotective effect and lowered risk of stroke.
      Candesartan is well tolerated. All these features make the drug suitable for wide
      application in the management of hypertension. Preliminary results suggest that
      candesartan can be useful in the treatment of diabetic nephropathy.

PMID- 15029151
TI  - Mechanisms of action underlying the effect of repetitive transcranial magnetic
      stimulation on mood: behavioral and brain imaging studies.
AB  - In a set of experiments, we applied 10-Hz repetitive transcranial magnetic
      stimulation (rTMS) over the left mid-dorsolateral frontal cortex (MDLFC) to
      investigate rTMS-induced changes in affective state and neural activity in
      healthy volunteers. In Experiment 1, we combined 10-Hz rTMS with a speech task to
      examine rTMS-induced changes in paralinguistic aspects of speech production, an
      affect-relevant behavior strongly linked to the ACC. In Experiment 2, we combined
      10-Hz rTMS with positron emission tomography (PET) and used partial least squares
      (PLS) to identify a pattern of brain regions whose connectivity with the site of
      stimulation varied as a function of rTMS. The results of Experiment 1 revealed
      that following stimulation of the left MDLFC, subjects reported having less
      positive affect and vitality and displayed more monotonous speech. In Experiment
      2, results revealed that 10-Hz rTMS influenced the covariation between blood flow
      at the site of stimulation (ie the left MDLFC) and blood flow in a number of
      affect-relevant brain regions including the perigenual anterior cingulate gyrus,
      insula, thalamus, parahippocampal gyrus, and caudate nucleus. Taken together, our
      results suggest that changes in affect and affect-relevant behaviour following 10
      Hz rTMS applied over the left MDLFC may be related to changes in neural activity
      in brain regions widely implicated in affective states, including a
      frontocingulate circuit.

PMID- 15029153
TI  - Don't mention the 'F' word.

PMID- 15029154
TI  - Making data dreams come true.

PMID- 15029152
TI  - Modulation of anxiety-like behavior and morphine dependence in CREB-deficient
      mice.
AB  - The transcription factor cAMP-responsive element binding protein (CREB) has been
      shown to regulate different physiological responses including drug addiction and
      emotional behavior. Molecular changes including adaptive modifications of the
      transcription factor CREB are produced during drug dependence in many regions of
      the brain, including the locus coeruleus (LC), but the molecular mechanisms
      involving CREB within these regions have remained controversial. To further
      investigate the involvement of CREB in emotional behavior, drug reward and opioid
      physical dependence, we used two independently generated CREB-deficient mice. We
      employed the Cre/loxP system to generate mice with a conditional CREB mutation
      restricted to the nervous system, where all CREB isoforms are lacking in the
      brain (Crebl(NesCre)). A genetically defined cohort of the previously described
      hypomorphic Crebl(alphadelta) mice, in which the two major transcriptionally
      active isoforms (alpha and delta) are disrupted throughout the organism, were
      also used. First, we investigated the responses to stress of the CREB-deficient
      mice in several paradigms, and we found an increased anxiogenic-like response in
      the both Creb1 mutant mice in different behavioral models. We investigated the
      rewarding properties of drugs of abuse (cocaine and morphine) and natural reward
      (food) using the conditioned place-preference paradigm. No modification of
      motivational responses of morphine, cocaine, or food was observed in mutant mice.
      Finally, we evaluated opioid dependence by measuring the behavioral expression of
      morphine withdrawal and electrophysiological recordings of LC neurons. We showed
      an important attenuation of the behavioral expression of abstinence and a
      decrease in the hyperactivity of LC neurons in both Creb1 mutant mice. Our
      results emphasize the selective role played by neuronal CREB in emotional-like
      behavior and the somatic expression morphine withdrawal, without participating in
      the rewarding properties induced by morphine and cocaine.

PMID- 15029155
TI  - Battle lines are drawn as French researchers resign en masse.

PMID- 15029156
TI  - Geneticists study chimp-human divergence.

PMID- 15029157
TI  - Plague professor gets two years in bioterror case.

PMID- 15029158
TI  - Two arrested for trade in body parts from donor programme.

PMID- 15029159
TI  - Outspoken nuclear scientist 'forced out' over polygraph row.

PMID- 15029160
TI  - Varmus advises 'vow of chastity' over NIH staff consultancies.

PMID- 15029161
TI  - Health experts find obesity measures too lightweight.

PMID- 15029162
TI  - Pentagon attempts to bend light to its will.

PMID- 15029163
TI  - Biomedical institute wins reprieve from relocation.

PMID- 15029165
TI  - US science policy: mission impossible?

PMID- 15029167
TI  - Concern is more than just 'ruffled feathers'.

PMID- 15029166
TI  - Science of dieting: slim pickings.

PMID- 15029168
TI  - Health-aid efforts rely on local infrastructure.

PMID- 15029169
TI  - Confidential reports may improve peer review.

PMID- 15029174
TI  - From 'not wrong' to (maybe right).

PMID- 15029175
TI  - RNA finds a simpler way.

PMID- 15029176
TI  - Astronomy: we can see clearly now.

PMID- 15029177
TI  - Cell biology: the strain of being a prion.

PMID- 15029179
TI  - Cancer: survival pathways meet their end.

PMID- 15029180
TI  - Semiconductor physics: quick-set thin films.

PMID- 15029182
TI  - Planetary science: X-ray eyes on Saturn.

PMID- 15029181
TI  - Cancer: dangerous liaisons.

PMID- 15029184
TI  - The cultural wealth of nations.

PMID- 15029185
TI  - Opsin expression: new mechanism for modulating colour vision.
AB  - Each cone photoreceptor in the retina responds to light in a limited range of
      wavelengths, giving it a spectral phenotype. This phenotype is determined by the
      most prevalent of the photoreceptor's visual-pigment proteins (opsins) and is
      assumed to remain unchanged during an animal's lifetime. Here we show that in the
      Pacific pink salmon, Oncorhynchus gorbuscha, single cones can switch their
      spectral phenotype from ultraviolet to blue by regulating the production of the
      appropriate opsins as the fish grow older. This photoreceptor plasticity may
      operate to modulate colour vision as the salmon's lifestyle changes.

PMID- 15029186
TI  - Buckminsterfullerenes: a non-metal system for nitrogen fixation.
AB  - In all nitrogen-fixation processes known so far--including the industrial Haber
      Bosch process, biological fixation by nitrogenase enzymes and previously
      described homogeneous synthetic systems--the direct transformation of the stable,
      inert dinitrogen molecule (N2) into ammonia (NH3) relies on the powerful redox
      properties of metals. Here we show that nitrogen fixation can also be achieved by
      using a non-metallic buckminsterfullerene (C60) molecule, in the form of a water
      soluble C60:gamma-cyclodextrin (1:2) complex, and light under nitrogen at
      atmospheric pressure. This metal-free system efficiently fixes nitrogen under
      mild conditions by making use of the redox properties of the fullerene
      derivative.

PMID- 15029187
TI  - Control of gene expression by a natural metabolite-responsive ribozyme.
AB  - Most biological catalysts are made of protein; however, eight classes of natural
      ribozymes have been discovered that catalyse fundamental biochemical reactions.
      The central functions of ribozymes in modern organisms support the hypothesis
      that life passed through an 'RNA world' before the emergence of proteins and DNA.
      We have identified a new class of ribozymes that cleaves the messenger RNA of the
      glmS gene in Gram-positive bacteria. The ribozyme is activated by glucosamine-6
      phosphate (GlcN6P), which is the metabolic product of the GlmS enzyme. Additional
      data indicate that the ribozyme serves as a metabolite-responsive genetic switch
      that represses the glmS gene in response to rising GlcN6P concentrations. These
      findings demonstrate that ribozyme switches may have functioned as metabolite
      sensors in primitive organisms, and further suggest that modern cells retain some
      of these ancient genetic control systems.

PMID- 15029188
TI  - Crystal structure of spinach major light-harvesting complex at 2.72 A resolution.
AB  - The major light-harvesting complex of photosystem II (LHC-II) serves as the
      principal solar energy collector in the photosynthesis of green plants and
      presumably also functions in photoprotection under high-light conditions. Here we
      report the first X-ray structure of LHC-II in icosahedral proteoliposome assembly
      at atomic detail. One asymmetric unit of a large R32 unit cell contains ten LHC
      II monomers. The 14 chlorophylls (Chl) in each monomer can be unambiguously
      distinguished as eight Chla and six Chlb molecules. Assignment of the orientation
      of the transition dipole moment of each chlorophyll has been achieved. All Chlb
      are located around the interface between adjacent monomers, and together with
      Chla they are the basis for efficient light harvesting. Four carotenoid-binding
      sites per monomer have been observed. The xanthophyll-cycle carotenoid at the
      monomer-monomer interface may be involved in the non-radiative dissipation of
      excessive energy, one of the photoprotective strategies that have evolved in
      plants.

PMID- 15029189
TI  - Compact sources as the origin of the soft gamma-ray emission of the Milky Way.
AB  - The Milky Way is known to be an abundant source of gamma-ray photons, now
      determined to be mainly diffuse in nature and resulting from interstellar
      processes. In the soft gamma-ray domain, point sources are expected to dominate,
      but the lack of sensitive high-resolution observations did not allow for a clear
      estimate of the contribution from such sources. Even the best imaging experiment
      revealed only a few point sources, accounting for about 50% of the total Galactic
      flux. Theoretical studies were unable to explain the remaining intense diffuse
      emission. Investigating the origin of the soft gamma-rays is therefore necessary
      to determine the dominant particle acceleration processes and to gain insights
      into the physical and chemical equilibrium of the interstellar medium. Here we
      report observations in the soft gamma-ray domain that reveal numerous compact
      sources. We show that these sources account for the entirety of the Milky Way's
      emission in soft gamma-rays, leaving at most a minor role for diffuse processes.

PMID- 15029190
TI  - Structural relaxation in supercooled water by time-resolved spectroscopy.
AB  - Water has many kinetic and thermodynamic properties that exhibit an anomalous
      dependence on temperature, in particular in the supercooled phase. These
      anomalies have long been interpreted in terms of underlying structural causes,
      and their experimental characterization points to the existence of a singularity
      at a temperature of about 225 K. Further insights into the nature and origin of
      this singularity might be gained by completely characterizing the structural
      relaxation in supercooled water. But until now, such a characterization has only
      been realized in simulations that agree with the predictions of simple mode
      coupling theory; unambiguous experimental support for this surprising conclusion
      is, however, not yet available. Here we report time-resolved optical Kerr effect
      measurements that unambiguously demonstrate that the structural relaxation of
      liquid and weakly supercooled water follows the behaviour predicted by simple
      mode-coupling theory. Our findings thus support the interpretation of the
      singularity as a purely dynamical transition. That is, the anomalous behaviour of
      weakly supercooled water can be explained using a fully dynamic model and without
      needing to invoke a thermodynamic origin. In this regard, water behaves like many
      other, normal molecular liquids that are fragile glass-formers.

PMID- 15029191
TI  - High-mobility ultrathin semiconducting films prepared by spin coating.
AB  - The ability to deposit and tailor reliable semiconducting films (with a
      particular recent emphasis on ultrathin systems) is indispensable for
      contemporary solid-state electronics. The search for thin-film semiconductors
      that provide simultaneously high carrier mobility and convenient solution-based
      deposition is also an important research direction, with the resulting
      expectations of new technologies (such as flexible or wearable computers, large
      area high-resolution displays and electronic paper) and lower-cost device
      fabrication. Here we demonstrate a technique for spin coating ultrathin
      (approximately 50 A), crystalline and continuous metal chalcogenide films, based
      on the low-temperature decomposition of highly soluble hydrazinium precursors. We
      fabricate thin-film field-effect transistors (TFTs) based on semiconducting SnS(2
      x)Se(x) films, which exhibit n-type transport, large current densities (>10(5) A
      cm(-2)) and mobilities greater than 10 cm2 V(-1) s(-1)--an order of magnitude
      higher than previously reported values for spin-coated semiconductors. The spin
      coating technique is expected to be applicable to a range of metal chalcogenides,
      particularly those based on main group metals, as well as for the fabrication of
      a variety of thin-film-based devices (for example, solar cells, thermoelectrics
      and memory devices).

PMID- 15029192
TI  - A 'snowball Earth' climate triggered by continental break-up through changes in
      runoff.
AB  - Geological and palaeomagnetic studies indicate that ice sheets may have reached
      the Equator at the end of the Proterozoic eon, 800 to 550 million years ago,
      leading to the suggestion of a fully ice-covered 'snowball Earth'. Climate model
      simulations indicate that such a snowball state for the Earth depends on
      anomalously low atmospheric carbon dioxide concentrations, in addition to the Sun
      being 6 per cent fainter than it is today. However, the mechanisms producing such
      low carbon dioxide concentrations remain controversial. Here we assess the effect
      of the palaeogeographic changes preceding the Sturtian glacial period, 750
      million years ago, on the long-term evolution of atmospheric carbon dioxide
      levels using the coupled climate-geochemical model GEOCLIM. In our simulation,
      the continental break-up of Rodinia leads to an increase in runoff and hence
      consumption of carbon dioxide through continental weathering that decreases
      atmospheric carbon dioxide concentrations by 1,320 p.p.m. This indicates that
      tectonic changes could have triggered a progressive transition from a
      'greenhouse' to an 'icehouse' climate during the Neoproterozoic era. When we
      combine these results with the concomitant weathering effect of the voluminous
      basaltic traps erupted throughout the break-up of Rodinia, our simulation results
      in a snowball glaciation.

PMID- 15029193
TI  - Millennial and orbital variations of El Nino/Southern Oscillation and high
      latitude climate in the last glacial period.
AB  - The El Nino/Southern Oscillation (ENSO) phenomenon is believed to have operated
      continuously over the last glacial-interglacial cycle. ENSO variability has been
      suggested to be linked to millennial-scale oscillations in North Atlantic climate
      during that time, but the proposals disagree on whether increased frequency of El
      Nino events, the warm phase of ENSO, was linked to North Atlantic warm or cold
      periods. Here we present a high-resolution record of surface moisture, based on
      the degree of peat humification and the ratio of sedges to grass, from northern
      Queensland, Australia, covering the past 45,000 yr. We observe millennial-scale
      dry periods, indicating periods of frequent El Nino events (summer precipitation
      declines in El Nino years in northeastern Australia). We find that these dry
      periods are correlated to the Dansgaard-Oeschger events--millennial-scale warm
      events in the North Atlantic climate record--although no direct atmospheric
      connection from the North Atlantic to our site can be invoked. Additionally, we
      find climatic cycles at a semiprecessional timescale (approximately 11,900 yr).
      We suggest that climate variations in the tropical Pacific Ocean on millennial as
      well as orbital timescales, which determined precipitation in northeastern
      Australia, also exerted an influence on North Atlantic climate through
      atmospheric and oceanic teleconnections.

PMID- 15029194
TI  - Experimental evidence for apparent competition in a tropical forest food web.
AB  - The herbivorous insects of tropical forests constitute some of the most diverse
      communities of living organisms. For this reason it has been difficult to
      discover the degree to which these communities are structured, and by what
      processes. Interspecific competition for resources does occur, but its
      contemporary importance is limited because most pairs of potentially competing
      insects feed on different host plants. An alternative way in which species can
      interact is through shared natural enemies, a process called apparent
      competition. Despite extensive theoretical discussion there are few field
      demonstrations of apparent competition, and none in hyper-diverse tropical
      communities. Here, we experimentally removed two species of herbivore from a
      community of leaf-mining insects in a tropical forest. We predicted that other
      species that share natural enemies with the two removed species would experience
      lower parasitism and have higher population densities in treatment compared with
      control sites. In both cases (on removal of a dipteran and a coleopteran leaf
      miner species) we found significantly lower parasitism, and in one case (removal
      of the dipteran) we found significantly higher abundance a year after the
      manipulation. Our results suggest that apparent competition may be important in
      structuring tropical insect communities.

PMID- 15029195
TI  - Protein-only transmission of three yeast prion strains.
AB  - Key questions regarding the molecular nature of prions are how different prion
      strains can be propagated by the same protein and whether they are only protein.
      Here we demonstrate the protein-only nature of prion strains in a yeast model,
      the [PSI] genetic element that enhances the read-through of nonsense mutations in
      the yeast Saccharomyces cerevisiae. Infectious fibrous aggregates containing a
      Sup35 prion-determining amino-terminal fragment labelled with green fluorescent
      protein were purified from yeast harbouring distinctive prion strains. Using the
      infectious aggregates as 'seeds', elongated fibres were generated in vitro from
      the bacterially expressed labelled prion protein. De novo generation of strain
      specific [PSI] infectivity was demonstrated by introducing sheared fibres into
      uninfected yeast hosts. The cross-sectional morphology of the elongated fibres
      generated in vitro was indistinguishable from that of the short yeast seeds, as
      visualized by electron microscopy. Electron diffraction of the long fibres showed
      the 4.7 A spacing characteristic of the cross-beta structure of amyloids. The
      fact that the amyloid fibres nucleated in vitro propagate the strain-specific
      infectivity of the yeast seeds implies that the heritable information of distinct
      prion strains must be encoded by different, self-propagating cross-beta folding
      patterns of the same prion protein.

PMID- 15029196
TI  - Conformational variations in an infectious protein determine prion strain
      differences.
AB  - A remarkable feature of prion biology is the strain phenomenon wherein prion
      particles apparently composed of the same protein lead to phenotypically distinct
      transmissible states. To reconcile the existence of strains with the 'protein
      only' hypothesis of prion transmission, it has been proposed that a single
      protein can misfold into multiple distinct infectious forms, one for each
      different strain. Several studies have found correlations between strain
      phenotypes and conformations of prion particles; however, whether such
      differences cause or are simply a secondary manifestation of prion strains
      remains unclear, largely due to the difficulty of creating infectious material
      from pure protein. Here we report a high-efficiency protocol for infecting yeast
      with the [PSI+] prion using amyloids composed of a recombinant Sup35 fragment
      (Sup-NM). Using thermal stability and electron paramagnetic resonance
      spectroscopy, we demonstrate that Sup-NM amyloids formed at different
      temperatures adopt distinct, stably propagating conformations. Infection of yeast
      with these different amyloid conformations leads to different [PSI+] strains.
      These results establish that Sup-NM adopts an infectious conformation before
      entering the cell--fulfilling a key prediction of the prion hypothesis--and
      directly demonstrate that differences in the conformation of the infectious
      protein determine prion strain variation.

PMID- 15029197
TI  - The candidate tumour suppressor protein ING4 regulates brain tumour growth and
      angiogenesis.
AB  - Gliomas are the most common primary tumours of the central nervous system, with
      nearly 15,000 diagnosed annually in the United States and a lethality approaching
      80% within the first year of glioblastoma diagnosis. The marked induction of
      angiogenesis in glioblastomas suggests that it is a necessary part of malignant
      progression; however, the precise molecular mechanisms underlying the regulation
      of brain tumour growth and angiogenesis remain unresolved. Here we report that a
      candidate tumour suppressor gene, ING4, is involved in regulating brain tumour
      growth and angiogenesis. Expression of ING4 is significantly reduced in gliomas
      as compared with normal human brain tissue, and the extent of reduction
      correlates with the progression from lower to higher grades of tumours. In mice,
      xenografts of human glioblastoma U87MG, which has decreased expression of ING4,
      grow significantly faster and have higher vascular volume fractions than control
      tumours. We show that ING4 physically interacts with p65 (RelA) subunit of
      nuclear factor NF-kappaB, and that ING4 regulates brain tumour angiogenesis
      through transcriptional repression of NF-kappaB-responsive genes. These results
      indicate that ING4 has an important role in brain tumour pathogenesis.

PMID- 15029198
TI  - Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy.
AB  - Evading apoptosis is considered to be a hallmark of cancer, because mutations in
      apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic
      agents induce apoptosis, and so disruption of apoptosis during tumour evolution
      can promote drug resistance. For example, Akt is an apoptotic regulator that is
      activated in many cancers and may promote drug resistance in vitro. Nevertheless,
      how Akt disables apoptosis and its contribution to clinical drug resistance are
      unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis
      and drug resistance by disrupting apoptosis, and that disruption of Akt
      signalling using the mTOR inhibitor rapamycin reverses chemoresistance in
      lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a
      translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's
      action in tumorigenesis and drug resistance, but is unable to confer sensitivity
      to rapamycin and chemotherapy. These results establish Akt signalling through
      mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in
      vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity
      in a genotype-dependent manner.

PMID- 15029199
TI  - Bmi1 is essential for cerebellar development and is overexpressed in human
      medulloblastomas.
AB  - Overexpression of the polycomb group gene Bmi1 promotes cell proliferation and
      induces leukaemia through repression of Cdkn2a (also known as ink4a/Arf) tumour
      suppressors. Conversely, loss of Bmi1 leads to haematological defects and severe
      progressive neurological abnormalities in which de-repression of the ink4a/Arf
      locus is critically implicated. Here, we show that Bmi1 is strongly expressed in
      proliferating cerebellar precursor cells in mice and humans. Using Bmi1-null mice
      we demonstrate a crucial role for Bmi1 in clonal expansion of granule cell
      precursors both in vivo and in vitro. Deregulated proliferation of these
      progenitor cells, by activation of the sonic hedgehog (Shh) pathway, leads to
      medulloblastoma development. We also demonstrate linked overexpression of BMI1
      and patched (PTCH), suggestive of SHH pathway activation, in a substantial
      fraction of primary human medulloblastomas. Together with the rapid induction of
      Bmi1 expression on addition of Shh or on overexpression of the Shh target Gli1 in
      cerebellar granule cell cultures, these findings implicate BMI1 overexpression as
      an alternative or additive mechanism in the pathogenesis of medulloblastomas, and
      highlight a role for Bmi1-containing polycomb complexes in proliferation of
      cerebellar precursor cells.

PMID- 15029200
TI  - The protein kinase PKR is required for macrophage apoptosis after activation of
      Toll-like receptor 4.
AB  - Macrophages are pivotal constituents of the innate immune system, vital for
      recognition and elimination of microbial pathogens. Macrophages use Toll-like
      receptors (TLRs) to detect pathogen-associated molecular patterns--including
      bacterial cell wall components, such as lipopolysaccharide or lipoteichoic acid,
      and viral nucleic acids, such as double-stranded (ds)RNA--and in turn activate
      effector functions, including anti-apoptotic signalling pathways. Certain
      pathogens, however, such as Salmonella spp., Shigellae spp. and Yersiniae spp.,
      use specialized virulence factors to overcome these protective responses and
      induce macrophage apoptosis. We found that the anthrax bacterium, Bacillus
      anthracis, selectively induces apoptosis of activated macrophages through its
      lethal toxin, which prevents activation of the anti-apoptotic p38 mitogen
      activated protein kinase. We now demonstrate that macrophage apoptosis by three
      different bacterial pathogens depends on activation of TLR4. Dissection of anti-
      and pro-apoptotic signalling events triggered by TLR4 identified the dsRNA
      responsive protein kinase PKR as a critical mediator of pathogen-induced
      macrophage apoptosis. The pro-apoptotic actions of PKR are mediated both through
      inhibition of protein synthesis and activation of interferon response factor 3.

PMID- 15029201
TI  - Capping active volcanoes.

PMID- 15029202
TI  - Growth industry.

PMID- 15029203
TI  - Graduate journal: choosing a boss.

PMID- 15029204
TI  - Scientists and societies. An introduction to biotechnology.

PMID- 15029206
TI  - Mars: water, water everywhere.

PMID- 15029207
TI  - Prognostic impact of p27KIP1 expression in cyclin D1 positive lymphoproliferative
      disorders.
AB  - Nodal mantle cell lymphoma (MCL) is a well-defined entity, but non-nodal leukemic
      cyclin D1 positive lymphoproliferative disorders have been reported and their
      relationship with MCL remains controversial and their prognosis heterogeneous. We
      prospectively studied the expression of cyclin D1 in CD5 positive leukemic B
      lymphoproliferative disorders at diagnosis and identified 65 cases overexpressing
      cyclin D1. We did not distinguish any clinical or biological criteria allowing
      one to identify a non-MCL group. Multivariate analysis identified age, anemia and
      p27kip1 expression as independent prognostic factors of survival. By univariate
      analysis, p27kip1 high expression proved to be the strongest predictor of
      prolonged survival. The median survival of p27 low expressors was 30 months,
      while it was not reached for p27 high expressors. A high level of p27 expression
      was often found associated with the absence of nodal involvement and the presence
      of somatic mutations, but neither of them was restricted to the p27 high
      expression group. In conclusion, we hypothesize that MCL and these cyclin D1
      positive leukemic lymphoproliferative disorders represent a continuous spectrum
      of diseases. Determination of p27 expression level appears as a routine
      applicable test allowing identification of a subset of patients who could be
      considered for different therapeutic approaches.

PMID- 15029208
TI  - Effect of graft-versus-host disease on the outcome of bone marrow transplantation
      from an HLA-identical sibling donor using GVHD prophylaxis with cyclosporin A and
      methotrexate.
AB  - The effect of graft-versus-host disease (GVHD) on relapse incidence and survival
      has been analyzed in several studies, but previous studies included heterogeneous
      patients. Therefore, we analyzed the data of 2114 patients who received
      unmanipulated bone marrow graft from an HLA-identical sibling donor with a GVHD
      prophylaxis using cyclosporin A and methotrexate. Among the 1843 patients who
      survived without relapse at 60 days after transplantation, 435 (24%) developed
      grade II-IV acute GVHD. Among the 1566 patients who survived without relapse at
      150 days after transplantation, 705 (47%) developed chronic GVHD. The incidence
      of relapse was significantly lower in patients who developed acute or chronic
      GVHD, but disease-free survival (DFS) was significantly inferior in patients who
      developed acute GVHD. A benefit of 'mild' GVHD was only seen in high-risk
      patients who developed grade I acute GVHD. The strongest association between GVHD
      and a decreased incidence of relapse was observed in patients with standard-risk
      acute myelogenous leukemia/myelodysplastic syndrome. In conclusion, the
      therapeutic window between decreased relapse and increased transplant-related
      mortality due to the development of GVHD appeared to be very narrow.

PMID- 15029209
TI  - Predicting survival for myeloid leukemia after HLA-identical sibling donor
      allogeneic stem cell transplantation.

PMID- 15029210
TI  - Novel chromosomal aberrations in Philadelphia negative cells of chronic
      myelogenous leukemia patients on imatinib: report of three cases.

PMID- 15029211
TI  - Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by
      SU5402 and PD173074.
AB  - The t(4;14)(p16.3;q32), associated with 10-20% of cases of multiple myeloma (MM),
      deregulates the expression of MMSET and FGFR3. To assess the potential of FGFR3
      as a drug target, we evaluated the effects of selective inhibitors on MM and
      control cell lines. SU5402 and PD173074 specifically inhibited the growth of the
      two t(4;14)-positive MM lines, KMS-11 and OPM-2. Importantly, inhibition was
      still observed in the presence of IL-6, a growth factor known to play an
      important role in MM. Both compounds induced a dose-dependent reduction in cell
      viability and an increase in apoptosis, accompanied by a decrease in
      extracellular signal-related kinase phosphorylation. In contrast, no inhibition
      was seen with either compound against t(4;14)-negative cell lines or NCI-H929, a
      t(4;14)-positive, FGFR3-negative MM cell line. FGFR3 is thus a plausible
      candidate for targeted therapy in a subset of MM patients.

PMID- 15029212
TI  - Comparative analysis of flow cytometry and polymerase chain reaction for the
      detection of minimal residual disease in childhood acute lymphoblastic leukemia.
AB  - Minimal residual disease (MRD) is an independent prognostic factor in childhood
      acute lymphoblastic leukemia (ALL). The most widely applied MRD assays in ALL are
      flow cytometric identification of leukemia immunophenotypes and polymerase chain
      reaction (PCR) amplification of antigen-receptor genes. We measured MRD by both
      assays in 227 patients with childhood B-lineage ALL. Of 1375 samples (736 bone
      marrow and 639 peripheral blood) examined, MRD was <0.01% in 1200, and > or
      =0.01% in 129 by both assays; MRD levels measured by the two methods correlated
      well. Of the remaining 46 samples, 28 had MRD > or =0.01% by flow cytometry but
      <0.01% by PCR. However, PCR (which had a consistent sensitivity of 0.001%)
      detected leukemic gene rearrangements in 26 of these 28 samples. Conversely, in
      18 samples, MRD was > or =0.01% by PCR but <0.01% by flow cytometry. In nine of
      these samples, flow cytometry had a sensitivity of 0.001%, and detected aberrant
      immunophenotypes in eight samples. Therefore, the two most widely used methods
      for MRD detection in ALL yield concordant results in the vast majority of cases,
      although the estimated levels of MRD may vary in some. The use of the two methods
      in tandem ensures MRD monitoring in all patients.

PMID- 15029213
TI  - Expression of the adaptor protein BLNK/SLP-65 in childhood acute lymphoblastic
      leukemia.
AB  - Deficient expression of BLNK, an adaptor molecule crucial for normal B-cell
      development, is associated with increased pro-B/pre-B-cell expansion in mice. It
      has been proposed that BLNK deficiency is a primary cause of B-lineage acute
      lymphoblastic leukemia (ALL). We studied BLNK expression in the leukemic cells
      from 352 patients with childhood ALL (309 B-lineage; 43 T-lineage). By HG_U95Av2
      Affymetrix GeneChip analysis, BLNK was expressed in 275 of 284 (96.8%) B-lineage
      ALL samples but in only one of 43 (2.3%) T-lineage ALL samples. Of 118 B-lineage
      ALL samples analyzed with the HG_U133A GeneChip, 117 (99.2%) expressed BLNK. All
      30 primary B-lineage ALL samples studied by RT-PCR expressed BLNK transcripts;
      all 19 samples studied by Western blotting or flow cytometry expressed BLNK
      protein. Levels of BLNK in B-lineage ALL were as high as those of their normal
      counterparts; they were not related with genetic subgroups or differentiation
      stage. These results indicate that BLNK deficiency is a rare occurrence in
      childhood B-lineage ALL and is unlikely to be a common leukemogenic event as
      previously proposed.

PMID- 15029216
TI  - Impact of maternal age on preterm delivery and low birthweight: a hospital-based
      collaborative study of nulliparous Lebanese women in Greater Beirut.
AB  - OBJECTIVES: To analyze the impact of maternal age at first childbirth on the
      incidence of preterm delivery and low birthweight among single live births
      delivered to nulliparous Lebanese women in Greater Beirut. STUDY DESIGN: Eligible
      subjects were selected from a consecutive sample of neonatal admissions to nine
      National Collaborative Perinatal Network participating hospitals over a three
      year period (April 1, 1999 to March 31, 2002). Chi-square tests and logistic
      regression analyses were applied. RESULTS: Out of 5556 nulliparous mothers, 5.4%
      had a preterm delivery and 5.2% a low-birthweight infant. In the multivariate
      analysis, preterm delivery was not significantly affected by old maternal age.
      Mothers aged 25 years or more remained a high-risk group for low birthweight even
      after controlling for potentially confounding characteristics. CONCLUSIONS:
      Maternal age at first childbirth above 25 years is an independent risk factor for
      low birthweight, but not for preterm delivery, an outcome influenced mainly by
      obstetric complications.

PMID- 15029214
TI  - High CD33-antigen loads in peripheral blood limit the efficacy of gemtuzumab
      ozogamicin (Mylotarg) treatment in acute myeloid leukemia patients.
AB  - Gemtuzumab ozogamicin (Mylotarg) induces remission in approximately 30% of
      relapsed AML patients. We previously demonstrated that gemtuzumab infusion
      results in near-complete CD33 saturation in peripheral blood, and that saturating
      gemtuzumab levels result in continuous binding and internalization of gemtuzumab
      due to renewed CD33 expression. We now demonstrate that a high CD33-antigen load
      in peripheral blood is an independent adverse prognostic factor, likely due to
      peripheral consumption of gemtuzumab. Indeed, CD33 saturation in bone marrow is
      significantly reduced (40-90% saturation) as compared with CD33 saturation in
      corresponding peripheral blood samples (>90%). In vitro, such reduced CD33
      saturation levels were strongly related with reduced cell kill. Apparently, high
      CD33-antigen loads in blood consume gemtuzumab and thereby limit its penetration
      into bone marrow. Consequently, CD33 saturation in bone marrow is reduced, which
      hampers efficient cell kill. Therefore, gemtuzumab should be administered at
      higher or repeated doses, or, preferably, after reduction of the leukemic cell
      burden by classical chemotherapy.

PMID- 15029215
TI  - Upregulation of neutrophil surface adhesion molecules in infants of pre-eclamptic
      women.
AB  - OBJECTIVE: To evaluate evidence of neutrophil activation in infants born to pre
      eclamptic women and examine any association between degree of neutrophil
      activation and severity of pre-eclampsia. DESIGN: This study utilized
      quantitative flow cytometry to determine whether the expression of surface
      adhesion molecules: CD18, CD11a, CD11b, and CD11c on cord blood neutrophils using
      mean channel fluorescence values (MCF). A total of 20 infants of pre-eclamptic
      women were compared with a control group of 19 infants of normotensive women.
      RESULTS: MCF values were significantly higher in infants born to pre-eclamptic
      women vs controls: CD18 (432.0+/-236.3 vs 230.5+/-97.9; p=0.002), CD11a (552.9+/
      272.4 vs 326.9+/-268.6; p=0.003), CD11b (937.2+/-521.9 vs 576.6+/-352.9;
      p=0.025), and CD11c (228.5+/-130.3 vs 133.0+/-77.1; p=0.006), respectively. The
      mean MCF values appeared higher in severe vs mild pre-eclampsia. CONCLUSIONS:
      This study revealed neutrophil activation in infants born to pre-eclamptic women.
      The relationship between neutrophil activation and severity of pre-eclampsia
      warrants further study.

PMID- 15029217
TI  - Population impact of losartan use on stroke in the European Union (EU):
      projections from the Losartan Intervention For Endpoint reduction in hypertension
      (LIFE) study.
AB  - The Losartan Intervention for Endpoint reduction in hypertension (LIFE) study was
      designed to compare losartan- vs atenolol-based antihypertensive treatment on
      cardiovascular morbidity and mortality in a population of 9193 hypertensive
      patients with left ventricular hypertrophy (LVH). In LIFE, the losartan-based
      treatment further reduced the primary composite end point (cardiovascular death,
      myocardial infarction, or stroke) by 13% (risk reduction (RR) 0.87, 95%
      confidence interval (CI) 0.77-0.98, P=0.021). The further reduction in stroke
      with losartan (RR 0.75, 95% CI 0.63-0.89, P=0.001) was the major contributing
      factor to the reduction in the primary end point. Our objective was to project
      the reduction in stroke observed with a losartan- vs an atenolol-based
      antihypertensive treatment regimen in the LIFE study to the European Union (EU)
      population. The number of stroke events averted was estimated by identifying the
      number of persons in the EU expected to meet the LIFE inclusion criteria, and
      multiplying this figure by the cumulative incidence risk difference in stroke
      from LIFE at 5.5 years. The age- and gender-specific prevalence of hypertension,
      electrocardiographically (ECG)-diagnosed LVH among those with hypertension
      (inclusion criteria), and heart failure among those with LVH and hypertension
      (exclusion criteria) were applied to the EU census estimates. We conservatively
      projected that an estimated 7.8 million individuals aged 55-80 years in the EU
      are affected by hypertension and ECG-diagnosed LVH. Use of a losartan-based
      antihypertensive treatment in this population is projected to prevent
      approximately 125 000 first strokes over a 5.5-year period. A population-wide
      prevention strategy of using losartan in patients with LVH and hypertension has
      the potential to have a major public health impact by reducing the morbidity and
      mortality of stroke in the EU.

PMID- 15029218
TI  - Patient compliance in hypertension: role of illness perceptions and treatment
      beliefs.
AB  - Despite many years of study, questions remain about why patients do or do not
      take medicines and what can be done to change their behaviour. Hypertension is
      poorly controlled in the UK and poor compliance is one possible reason for this.
      Recent questionnaires based on the self-regulatory model have been successfully
      used to assess illness perceptions and beliefs about medicines. This study was
      designed to describe hypertensive patients' beliefs about their illness and
      medication using the self-regulatory model and investigate whether these beliefs
      influence compliance with antihypertensive medication. We recruited 514 patients
      from our secondary care population. These patients were asked to complete a
      questionnaire that included the Beliefs about Medicines and Illness Perception
      Questionnaires. A case note review was also undertaken. Analysis shows that
      patients who believe in the necessity of medication are more likely to be
      compliant (odds ratio (OR)) 3.06 (95% CI 1.74-5.38), P<0.001). Other important
      predictive factors in this population are age (OR 4.82 (2.85-8.15), P<0.001),
      emotional response to illness (OR 0.65 (0.47-0.90), P=0.01) and belief in
      personal ability to control illness (OR 0.59 (0.40-0.89), P=0.01). Beliefs about
      illness and about medicines are interconnected; aspects that are not directly
      related to compliance influence it indirectly. The self-regulatory model is
      useful in assessing patients health beliefs. Beliefs about specific medications
      and about hypertension are predictive of compliance. Information about health
      beliefs is important in achieving concordance and may be a target for
      intervention to improve compliance.

PMID- 15029219
TI  - Compliance with pharmacological therapy in hypertension: can we do better, and
      how?

PMID- 15029220
TI  - Hypertension screening in a salami factory: a worksite hypertension study.
AB  - The prevalence, awareness and control of hypertension are important
      epidemiological research topics worldwide. The screening of hypertension in a
      workplace has some special aspects. We have screened the employees in a Hungarian
      salami factory (Pick Salami Factory, Szeged, Hungary) for hypertensives. In a
      cross-sectional survey, the blood pressure (BP) was measured with an instrument
      meeting accepted measuring principles (BP-TRU BP) and a questionnaire was filled.
      In all, 1012 factory workers were screened (600 male and 412 female) and 25.7% of
      the workers proved to be hypertensives. Of these, 61.5% of the hypertensive
      employees were aware that their BP is high. Among the treated hypertensives,
      21.9% were controlled. These results suggest that the efficacy of the management
      of hypertension in Hungary cannot be solely responsible for the high
      cardiovascular morbidity and mortality. The improvement of the management of
      hypertension should decrease the cardiovascular risk in the hypertensive
      population. The worksite screening and follow-up of hypertension seem to be
      logical health service solutions. This has been proven to be cost-effective.

PMID- 15029222
TI  - Congruence between veno-occlusive parameters during dynamic infusion
      cavernosometry: assessing the need for cavernosography.
AB  - While dynamic infusion cavernosometry (DIC) is being performed with increasing
      rarity, some centers continue to use this investigation modality. Cavernosography
      may be utilized to identify the location of patent venous channels in men with
      venous leak. In an era when venous ligation surgery is being performed with less
      frequency, the role of cavernosography has been questioned. This study was
      conducted to define the congruence between the three parameters (flow-to-maintain
      (FTM), pressure decay (PD) and cavernosography) used in the diagnosis of venous
      leak during DIC. Established values for the three parameters were utilized and
      the diagnosis of venous leak was based upon the FTM measurement. All studies were
      performed using a vasoactive agent-redosing schedule. Cavernosography was
      conducted using a nonionic contrast agent at an intracorporal pressure of 90
      mmHg. In patients with an elevated FTM value, 24% had a normal PD recorded, all
      of whom had FTM values <10 ml/min. The Pearson correlation coefficient for the
      relationship between FTM and PD was 0.58 (P=0.025). In all, 36 patients (54%) had
      an abnormal cavernosogram (CG). All patients who had positive findings on CG had
      elevated FTM values. On the other hand, 46% of patients with abnormal FTM values
      had a normal CG. This analysis indicates that almost one-half of men with venous
      leak diagnosed at the time of DIC based on FTM measurement will fail to have any
      veins visualized on cavernosography. These data further undermine the value of
      cavernosography, particularly in men with low-grade venous leak.

PMID- 15029221
TI  - Prevalence, awareness, treatment and control of hypertension in employees of
      factories of Northern Greece: the Naoussa study.
AB  - The objective of this study was to examine the prevalence and the levels of
      awareness, control, and treatment of hypertension in workers, technicians and
      clerks of factories of the city of Naoussa. A total of 1976 employees in 19 units
      were examined. From those, 1937 (1045 men and 892 women), 15-73 years of age,
      were included in the analysis. Every employee was examined twice with 1 week's
      interval between the two examinations. Analysis was performed using the 140/90
      mmHg hypertension threshold. In every visit, three blood pressure (BP)
      measurements were taken with at least 1-min interval between them. In the
      analysis only the average BP of the second clinic visit was used. In total,
      hypertension prevalence was 30.5% (32.1% for men and 28.7% for women
      respectively, P=0.10). The levels of awareness, treatment, and control of
      hypertension in hypertensive patients were 18.6%, 11.8%, and 2.2%, respectively.
      The levels of awareness and treatment differed significantly between men and
      women (13.4 vs 25.4%, P<0.001 and 9.6 vs 14.8%, P<0.05), but there was no
      difference in the levels of control (1.5 vs 3.1%, P=0.18). Hypertension
      prevalence, awareness, and treatment differed also between patients <45 and > or
      =45 years of age (22.0 vs 53.2%, P<0.001, 9.7 vs 28.4%, P<0.001 and 6.5 vs 17.7%,
      P<0.001, respectively). In conclusion, the prevalence of hypertension in our
      study's population is high, while the levels of awareness, treatment, and control
      are disappointing and should be significantly improved. There is also a
      difference in awareness and treatment in favour of women compared to men and in
      favour of patients >/=45 years of age compared to those <45 years of age.

PMID- 15029223
TI  - Critical evaluation of the factors influencing erectile function after renal
      transplantation.
AB  - A total of 400 male renal transplant recipients (RTR) were investigated. Data on
      medical, sexual history, clinical examination and laboratory variables were
      collected. The severity of erectile dysfunction (ED) was assessed using the
      International Index of Erectile Function questionnaire. Univariate and
      multivariate logistic regression analyses were used to determine prognostic
      variables, which have independent impact on erectile function. ED was detected in
      35.8% of the whole group. Current erectile function as compared to pretransplant
      status was improved, deteriorated or remained static in 44, 12.5 and 43.5% of the
      evaluated transplant recipients, respectively. After logistic regression
      analysis, age, hemoglobin level and presence of DM and/or peripheral neuropathy
      had significant and independent negative impact on erectile function. We
      concluded that renal transplantation has varying effects on erectile function. ED
      is highly prevalent among RTR and its pathogenesis is multifactorial.

PMID- 15029224
TI  - Effects of stress on female rat sexual function.
AB  - This study was undertaken to investigate whether prolonged stress interferes with
      sexual behavior and changes biochemical and physiologic mechanisms. Experiments
      were repeated three times with different rats in each period. In all, 63 female
      Sprague-Dawley rats were employed, with 21 rats in each period, and the control
      group was maintained at room temperature with free access to food and water. The
      stress group was maintained under a scheduled stress condition for 10 days, and
      seven rats from the group were randomly selected and exposed to the control
      environment for 10 days as the recovery group. Sexual behavior, hormonal values,
      and neuronal and endothelial nitric oxide synthase (nNOS and eNOS) expressions of
      vaginal tissue were analyzed and compared. Serum testosterone levels were
      significantly elevated in the stress and recovery groups (P<0.05). Female rats in
      the stress group showed reduced receptivity to their male mates (P<0.05). Western
      blot analysis demonstrated that nNOS and eNOS expressions were significantly
      lower in the stress group (P<0.05) than in the other groups. We conclude that
      chronic physical stress modifies the sexual behavior of female rats through a
      mechanism believed to involve complex changes in sex hormones, endocrine factors,
      and neurotransmitters.

PMID- 15029225
TI  - A comparative study of sildenafil, NCX-911 and BAY41-2272 on the anococcygeus
      muscle of diabetic rats.
AB  - We compared the effects of a nitric oxide (NO)-releasing sildenafil (NCX-911), NO
      independent soluble guanylate cyclase activator (BAY41-2272) and sildenafil on
      the anococcygeus muscle from streptozotocin-induced 16-weeks diabetic rats. NCX
      911, BAY41-2272 and sildenafil reduced the phenylephrine-induced tone in the
      control group (EC50=1088.8+/-165.0, 151.6+/-9.3 and 827.1+/-167.3 nM,
      respectively). The potencies of NCX-911 and BAY41-2272 were not altered, but that
      of sildenafil was significantly reduced in the diabetic group. EC50 values for
      NCX-911, BAY41-2272 and sildenafil in the diabetic group were 1765.9+/-303.5,
      209.7+/-27.3 and 2842.2+/-640.3 nM, respectively (P<0.05 for sildenafil).
      Nitrergic relaxation responses were significantly decreased in the diabetic
      group. The remaining nitrergic relaxation responses were potentiated by BAY41
      2272 but not by sildenafil or NCX-911. These results confirm that endogenous NO
      derived from nitrergic nerves is significantly decreased in diabetes, and suggest
      that NO-releasing PDE5 inhibitors and NO-independent soluble guanylate cyclase
      activators could be more useful than PDE5 inhibitors in the treatment of ED in
      long-term diabetes.

PMID- 15029226
TI  - Insertional oncogenesis in gene therapy: how much of a risk?

PMID- 15029228
TI  - Silencing of episomal transgene expression by plasmid bacterial DNA elements in
      vivo.
AB  - We previously demonstrated that sustainable enhanced levels of transgene products
      could be expressed from a bacterial DNA-free expression cassette either formed
      from a fragmented plasmid in mouse liver or delivered as a minicircle vector.
      This suggested that bacterial DNA sequences played a role in episomal transgene
      silencing. To further understand the silencing mechanism, we systematically
      altered the DNA components in both the expression cassette and the bacterial
      backbone, and compared the gene expression profiles from mice receiving different
      DNA forms. In nine vectors tested, animals that received the purified expression
      cassette alone always expressed persistently higher levels of transgene compared
      to 2fDNA groups. In contrast, animals that received linearized DNA by a single
      cut in the bacterial backbone had similar expression profiles to that of intact
      plasmid groups. All three linear DNAs formed large concatemers and small circles
      in mouse liver, while ccDNA remained intact. In all groups, the relative amount
      of vector DNA in liver remained similar. Together, these results further
      established that the DNA silencing effect was mediated by a covalent linkage of
      the expression cassette and the bacteria DNA elements.

PMID- 15029227
TI  - Transcriptional targeting of adenoviral vector through the CXCR4 tumor-specific
      promoter.
AB  - Adenoviral vectors are considered to be good gene delivery vectors for cancer
      gene therapy due to their wide host tissue range and cell cycle-independent
      infectivity. However, the disadvantages include the lack of specificity for
      cancer cells and the high liver accumulation in vivo. The human CXCR4 gene is
      expressed at high levels in many types of cancers, but is repressed in the liver.
      We explored the CXCR4 promoter as a candidate to restrict adenoviral transgene
      expression to tumor cells with a low expression in host tissues. The luciferase
      activities in multiple cancer cell lines infected with recombinant adenovirus
      reAdGL3BCXCR4 or the control vector reAdGL3BCMV revealed that the CXCR4 promoter
      exhibited relatively high transcriptional activity in a breast cancer cell line,
      MDA-MB-361, and two ovarian cancer cell lines, OVCAR-3 and SKOV3. ip1, 65%
      (P=0.0087), 16.7% (P=0.1) and 20% (P=0.0079) compared to that of the CMV
      promoter, respectively, and low expression, 4.9 and 0.1%, respectively, in both
      normal cell lines HFBC and HMEC. In addition, CXCR4 had a low expression of
      luciferase (0.32%) compared to that of the CMV promoter in mouse liver in vivo.
      The data also revealed that the CXCR4 promoter was a stronger tumor-specific
      promoter (TSP) than the Cox-2M promoter in primary melanomas obtained from two
      patients. The CXCR4 promoter is shown to have a 'tumor-on' and 'liver-off' status
      in vitro and in vivo, and CXCR4 may prove to be a good candidate TSP for cancer
      gene therapy approaches for melanoma and breast cancers.

PMID- 15029229
TI  - Adenoviral capsid modulates secretory compartment organization and function in
      acinar epithelial cells from rabbit lacrimal gland.
AB  - Although adenovirus (Ad) exhibits tropism for epithelial cells, little is known
      about the cellular effects of adenoviral binding and internalization on
      epithelial functions. Here, we examine its effects on the secretory acinar
      epithelial cells of the lacrimal gland, responsible for stimulated release of
      tear proteins into ocular fluid. Exposure of reconstituted rabbit lacrimal acini
      to replication-defective Ad for 16-18 h under conditions that resulted in >80%
      transduction efficiency did not alter cytoskeletal filament or
      biosynthetic/endosomal membrane compartment organization. Transduction
      specifically altered the organization of the stimulated secretory pathway,
      eliciting major dispersal of rab3D immunofluorescence from apical stores normally
      associated with mature secretory vesicles. Biochemical studies revealed that this
      dispersal was not associated with altered rab3D expression nor its release from
      cellular membranes. Ultraviolet (UV)-inactivated Ad elicited similar dispersal of
      rab3D immunofluorescence. In acini exposed to replication-defective or UV
      inactivated Ad, carbachol-stimulated release of bulk protein and beta
      hexosaminidase were significantly (P< or =0.05) inhibited to an extent
      proportional to the loss of rab3D-enriched mature secretory vesicles associated
      with these treatments. We propose that the altered secretory compartment
      organization and function caused by Ad reflects changes in the normal maturation
      of secretory vesicles, and that these changes are caused by exposure to the Ad
      capsid.

PMID- 15029230
TI  - Pre-emptive gene therapy using recombinant adeno-associated virus delivery of
      extracellular superoxide dismutase protects heart against ischemic reperfusion
      injury, improves ventricular function and prolongs survival.
AB  - In high-risk patients, the ideal cardiovascular gene therapy requires a strategy
      that provides long-term protection of myocardium against episodes of
      ischemic/reperfusion injury. We report the development of an efficient, long
      lasting pre-emptive gene therapy strategy in a rat model of ischemic-reperfusion
      (I/R) injury of heart. At 6 weeks prior to myocardial injury, the human
      extracellular superoxide dismutase (Ec-SOD) gene was delivered by direct
      intramyocardial injections, using a recombinant adeno-associated virus vector.
      Significant myocardial protection was documented by the decrease in infarct size
      at 24 h post I/R, improved left ventricular function at 7 weeks postinjury, and
      enhanced long-term survival in the SOD treated group. This concept of preinjury
      delivery and 'pre-emptive' gene therapy via the expression of a secreted protein
      that renders paracrine therapeutic action can be an effective strategy for organ
      protection against future injury.

PMID- 15029231
TI  - Regulation of transgene expression in muscles by ultrasound-mediated
      hyperthermia.
AB  - Heat-sensitive transgene expression systems have been proposed recently for use
      in gene therapy to enable both spatial and temporal control of the gene activity.
      The transgene was put under the control of HSP-related promoters and could be
      turned on by external heat treatment. While the 'heat activation' phenomenon of
      the HSP-related promoters in vitro had been well documented, the detailed time
      response and temporal regulation profile in vivo were not fully understood. We
      reported here the regulation of transgene luciferase expression in vivo in
      muscles using a custom-built ultrasound-mediated hyperthermia instrument. The
      effects of different heating parameters and treatment regimens were evaluated.
      Optimal activation of gene expression was found at 39 degrees C. Significant
      tissue damage was observed at 41 degrees C and above, which directly correlated
      with the greatly reduced gene expression. The gene constructs remained stable and
      silent in muscle cells, and could be turned on at a later time without losing
      much activity. Repeated activation was also possible, but required heat treatment
      at a higher temperature to overcome thermotolerance.

PMID- 15029232
TI  - B-cell-specific transgene expression using a self-inactivating retroviral vector
      with human CD19 promoter and viral post-transcriptional regulatory element.
AB  - Retroviral gene transfer resulting in transgene expression selectively restricted
      to specific cell lineages would be desirable for many gene therapeutic
      applications. Such transcriptional targeting of retroviruses can be accomplished
      by employing eukaryotic control elements in self-inactivating (SIN) retroviral
      vectors, but use of these vectors is complicated by an accompanying reduction in
      viral titers. To overcome this restriction and address the influence of the post
      transcriptional regulatory element of the Woodchuck hepatitis virus (WPRE) on
      viral titers and transgene expression, we developed SIN-vectors with and without
      WPRE. Using the enhancer-promoter of the Spleen Focus Forming virus (SFFV) to
      direct eGFP expression to multiple hematopoietic lineages, we show that WPRE
      significantly (>10 x) increased viral titers (>10(6) per ml of unconcentrated
      supernatant) and transgene expression in NIH3T3 cells in vitro. Gene expression
      in vivo was significantly lowered in lymphoid cells, but not in myeloid cells
      when WPRE was present. Furthermore, the use of WPRE in combination with the B
      cell lineage-specific CD19 promoter significantly increased viral titers and
      allowed targeting of transgene expression by SIN-vectors specifically to B cells
      throughout their development in primary and secondary lymphoid organs.

PMID- 15029233
TI  - Efficient lentiviral transduction of Herpesvirus saimiri immortalized T cells as
      a model for gene therapy in primary immunodeficiencies.
AB  - Infection of human T lymphocytes with the Herpesvirus saimiri (HVS) yields
      immortalized T-cell lines (HVS-T) which retain all the phenotypical and
      functional characteristics of their parental cells. This represents a new
      experimental model for studying genetic disorders of T lymphocytes. In spite of
      the efforts of many laboratories, no satisfactory way has been found so far to
      modify HVS-T cells genetically. We have analyzed the capacity of oncoretroviral
      (MLV)- and lentiviral (HIV-1)-based vectors pseudotyped with vesicular stomatitis
      virus glycoprotein (VSVg) to transduce HVS-T cells. HIV-1-derived vectors
      efficiently transduced HVS-T cell lines, reaching up to 85% of cells expressing
      the transgene in a single round of infection. MLV-based vectors, on the other
      hand, were unable to transduce more than 1% of any of the HVS-T cell lines
      analyzed. Lentiviral-driven gene expression was maintained constant and stable in
      HVS-T cells for a minimum of 48 days. We also observed that although the
      lentiviral transduction efficiency achieved on HVS-T cells is lower than that
      obtained with tumor or primary endothelial cells, it is nevertheless similar to
      that found with activated primary T cells.

PMID- 15029235
TI  - Genome scan for loci linked to mite sensitivity: the Collaborative Study on the
      Genetics of Asthma (CSGA).
AB  - Mite sensitivity has been reported to be a major risk factor for asthma. As part
      of the Collaborative Study on the Genetics of Asthma (CSGA), a genome scan using
      mite reactivity (Dermatophagoides Pteronyssinus (Der p) and Dermatophagoides
      farinae (Der f)) as the phenotype was conducted. In 287 CSGA families, 122 were
      informative for linkage. Evidence supporting linkage was observed for regions on
      chromosome 19 (D19S591, lod=2.43, P=0.0008; D19S1037, lod=1.57, P=0.007) and
      chromosome 20 (D20S473/D20S604, lod=1.41, P=0.01). All three ethnic groups
      appeared to contribute to the evidence for linkage on chromosome 20. African
      American families gave strongest support for linkage on chromosomes 3 (D3S2409,
      lod=1.33, P=0.01), 12 (D12S373, lod=1.51, P=0.008) and 18 (ATA82B02, lod=1.32,
      P=0.01). Caucasian families showed strong evidence for linkage on chromosome 19
      (D19S591, lod=3.51, P=0.00006). Hispanic families supported linkage on
      chromosomes 11 (D11S1984, lod=1.56, P=0.007), 13 (D13S787, lod=1.30, P=0.01) and
      20 (D20S470, lod=1.71, P=0.005). These results suggest that multiple genes may be
      involved in controlling skin reactivity to Dermatophoigoies.

PMID- 15029236
TI  - Cost-effective analysis of candidate genes using htSNPs: a staged approach.
AB  - We have previously shown that the selection of haplotype tag single nucleotide
      polymorphisms (htSNPs) and their statistical analysis in a multi-locus
      transmission/disequilibrium test (TDT) results in a more cost-effective
      genotyping strategy in disease association studies of genes by minimising
      redundancy due to linkage disequilibrium between SNPs. Further savings can be
      achieved by the use of a two-stage genotyping strategy. This approach is
      illustrated here in conjunction with the multi-locus TDT in determining whether
      common alleles of the immune regulatory genes RANK and its ligand TRANCE (RANKL)
      are associated with type 1 diabetes (T1D). A saving of approximately 75% of
      potential genotyping reactions could be made with minimal loss of power. There
      was little evidence from our analysis for association between the TRANCE and RANK
      genes and T1D in the populations tested.

PMID- 15029234
TI  - Arginine at position 74 of the HLA-DR beta1 chain is associated with Graves'
      disease.
AB  - Graves' disease (GD) is associated with HLA-DR3 (DRB1*03) in Caucasians, but the
      exact amino-acid sequence in the DR beta1 chain conferring susceptibility to GD
      is unknown. Therefore, the aim of our study was to identify the critical sequence
      among the HLA-DRB1 amino-acid residues occupying the peptide-binding pocket,
      which conferred susceptibility to GD. We sequenced the HLA-DRB1 locus in 208
      Caucasian GD patients and 149 Caucasian controls. Sequence analysis showed an
      increased frequency of DR beta-Arg-74 in GD patients compared to controls (41.8
      and 13.4%, respectively; P=2.3 x 10(-8), OR=4.6). Moreover, subset analyses
      showed that DR beta-Arg-74 was also significantly more frequent in the HLA-DR3
      negative GD patients than in controls (7.6 vs 0.8%, P=0.02, OR=10.5), suggesting
      that the association with DR beta-Arg-74 is independent of the association with
      HLA-DR3. Structural modeling studies demonstrated that the change at position 74
      from the neutral amino acids Ala or Gln to the positively charged amino-acid Arg
      significantly modifies the three-dimensional structure of the DR peptide-binding
      pocket. Our results suggested that structural heterogeneity of the DR beta-chain
      peptide-binding pocket P4 at residue 74 predispose some at risk individuals to
      GD.

PMID- 15029237
TI  - MICA and recovery from hepatitis C virus and hepatitis B virus infections.
AB  - The polymorphic MHC class I chain-related A (MICA) gene encodes a ligand that has
      different binding affinities for the NKG2D activating receptor of CD8+ T cells
      and natural killer (NK) cells. We hypothesized that MICA heterogeneity would
      affect recovery from hepatitis C virus (HCV) and hepatitis B virus (HBV)
      infections. To test the hypothesis, we initially typed known MICA polymorphisms
      for 228 persons who cleared HCV infection and 442 persons with persistent
      hepatitis C matched on other factors affecting viral persistence. Although
      MICA(*)015 was detected more than two-fold more often in persons with viral
      clearance (odds ratio 0.36, 95% confidence interval=0.19, 0.80), it occurred in
      fewer than 5% of the study population. In a similar analysis of 442 persons with
      chronic hepatitis B and 768 matched controls who recovered, MICA(*)015 was
      detected in 2.0% of persons with chronic hepatitis B and only 0.9% of controls.
      No significant associations were detected with other MICA polymorphisms. While
      further investigation may reveal a structural basis of the MICA(*)015
      associations, these data provide little support for the hypothesis that
      differential distribution of MICA alleles substantially affects recovery from HCV
      and HBV infections.

PMID- 15029238
TI  - Phenotypic expression of pyruvate kinase deficiency and protection against
      malaria in a mouse model.
AB  - The recombinant congenic mouse strains AcB55 and AcB61 are extremely resistant to
      malaria (Plasmodium chabaudi AS) despite the presence of susceptibility alleles
      at the known Char1/Char2 resistance loci. Resistance in AcB55 and AcB61 is
      controlled by a locus on chromosome 3 (Char4) shown to be allelic with or tightly
      linked to a loss-of-function mutation in pyruvate kinase (Pklr). AcB55 and AcB61
      show important splenomegaly prior to infection caused by the expansion of the red
      pulp, and display histological signs of extramedullary erythropoiesis in the
      liver. Examination of splenic cell populations by flow cytometry demonstrates
      elevated numbers of TER119-positive erythroid precursor cells (>30% of total
      spleen cells), while RNA expression studies show elevated expression of
      erythrocyte-specific transcripts such as globin, transferrin receptor, and
      Nramp2/Slc11a2 in the spleen of both strains. Hematological profiling in both
      strains is consistent with the presence of anemia as evidenced by low total
      erythrocyte counts, decreased hemoglobin, as well as abnormally high numbers of
      circulating reticulocytes (15-20%). These results strongly suggest that the
      mutant Pklr allele (Pklr(269A)) of AcB55/61 strains causes hemolytic anemia
      compensated by constitutive erythropoiesis, which in turn protects the mice
      against P. chabaudi infection. The possible molecular basis of the Pklr
      protective effect is discussed and is under current investigation in these two
      strains.

PMID- 15029239
TI  - Ubiquitin interactions of NZF zinc fingers.
AB  - Ubiquitin (Ub) functions in many different biological pathways, where it
      typically interacts with proteins that contain modular Ub recognition domains.
      One such recognition domain is the Npl4 zinc finger (NZF), a compact zinc-binding
      module found in many proteins that function in Ub-dependent processes. We now
      report the solution structure of the NZF domain from Npl4 in complex with Ub. The
      structure reveals that three key NZF residues (13TF14/M25) surrounding the zinc
      coordination site bind the hydrophobic 'Ile44' surface of Ub. Mutations in the
      13TF14/M25 motif inhibit Ub binding, and naturally occurring NZF domains that
      lack the motif do not bind Ub. However, substitution of the 13TF14/M25 motif into
      the nonbinding NZF domain from RanBP2 creates Ub-binding activity, demonstrating
      the versatility of the NZF scaffold. Finally, NZF mutations that inhibit Ub
      binding by the NZF domain of Vps36/ESCRT-II also inhibit sorting of ubiquitylated
      proteins into the yeast vacuole. Thus, the NZF is a versatile protein recognition
      domain that is used to bind ubiquitylated proteins during vacuolar protein
      sorting, and probably many other biological processes.

PMID- 15029240
TI  - JunD regulates lymphocyte proliferation and T helper cell cytokine expression.
AB  - Transgenic mice broadly expressing JunD (Ubi-junD(m)) appear phenotypically
      normal, but have strongly reduced numbers of peripheral lymphocytes. JunD
      overexpression in lymphocytes does not protect from numerous apoptotic insults;
      however, transgenic T cells proliferate poorly and exhibit impaired activation
      due to reduced levels of IL-4, CD25 and CD69. Consistently, in the absence of
      JunD (junD(-/-)) T cells hyperproliferate following mitogen induction. Moreover,
      transgenic T helper (Th) 2 cells have decreased IL-4 and IL-10 expression,
      whereas junD(-/-) Th2 cells secrete higher amounts of both Th2 cytokines. Th1
      polarized junD(-/-) CD4(+) T cells display enhanced IFN-gamma cytokine production
      associated with upregulated T-bet expression and downregulated expression of
      suppressor of cytokine signaling-1. These novel findings demonstrate a regulatory
      role of JunD in T lymphocyte proliferation and Th cell differentiation.

PMID- 15029241
TI  - Implication of ZW10 in membrane trafficking between the endoplasmic reticulum and
      Golgi.
AB  - ZW10, a dynamitin-interacting protein associated with kinetochores, is known to
      participate directly in turning off of the spindle checkpoint. In the present
      study, we show that ZW10 is located in the endoplasmic reticulum as well as in
      the cytosol during interphase, and forms a subcomplex with RINT-1 (Rad50
      interacting protein) and p31 in a large complex comprising syntaxin 18, an
      endoplasmic reticulum-localized t-SNARE implicated in membrane trafficking. Like
      conventional syntaxin-binding proteins, ZW10, RINT-1 and p31 dissociated from
      syntaxin 18 upon Mg(2+)-ATP treatment in the presence of NSF and alpha-SNAP,
      whereas the subcomplex was not disassembled. Overexpression, microinjection and
      knockdown experiments revealed that ZW10 is involved in membrane trafficking
      between the endoplasmic reticulum and Golgi. The present results disclose an
      unexpected role for a spindle checkpoint protein, ZW10, during interphase.

PMID- 15029242
TI  - Structural basis for host recognition by the Haemophilus influenzae Hia
      autotransporter.
AB  - Haemophilus influenzae is an important human pathogen that initiates infection by
      colonizing the upper respiratory tract. The H. influenzae Hia autotransporter is
      an adhesive protein that promotes adherence to respiratory epithelial cells. Hia
      adhesive activity resides in two homologous binding domains, called HiaBD1 and
      HiaBD2. These domains interact with the same host cell receptor, but bind with
      different affinities. In this report, we describe the crystal structure of the
      high-affinity HiaBD1 binding domain, which has a novel trimeric architecture with
      three-fold symmetry and a mushroom shape. The subunit constituents of the trimer
      are extensively intertwined. The receptor-binding pocket is formed by an acidic
      patch that is present on all three faces of the trimer, providing potential for a
      multivalent interaction with the host cell surface, analogous to observations
      with the trimeric tumor necrosis factor superfamily of proteins. Hia is a novel
      example of a bacterial trimeric adhesin and may be the prototype member of a
      large family of bacterial virulence proteins with a similar architecture.

PMID- 15029243
TI  - Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for
      p53 activation.
AB  - p53 activation prevents the proliferation of genetically unstable cells.
      Conversely, p53 antagonism by its transcriptional target, the E3 ubiquitin ligase
      MDM2, is critical for the viability of unstressed, cycling cells. We demonstrate
      that MDM2 induces the degradation of p53 in both the nucleus and the cytoplasm.
      As p53 and MDM2 accumulate in the nuclei of stressed cells, we investigated
      mechanisms enabling p53 activation despite the high MDM2 levels generated during
      a DNA-damage response. We show that DNA damage destabilized MDM2 by a mechanism
      involving damage-activated kinases and MDM2 auto-ubiquitination. p53 was stable
      and transcriptionally active when MDM2 was unstable, but became unstable and
      inactive as the damage response waned and MDM2 stabilized. Importantly, blocking
      MDM2 destabilization in DNA-damaged cells prevented p53 target gene activation.
      Our data reveal that controlled MDM2 degradation is an important new step in p53
      regulation.

PMID- 15029244
TI  - Mammalian Cdh1/Fzr mediates its own degradation.
AB  - The Anaphase-Promoting Complex/Cyclosome (APC/C) ubiquitin ligase mediates
      degradation of cell cycle proteins during mitosis and G1. Cdc20/Fzy and Cdh1/Fzr
      are substrate-specific APC/C activators. The level of mammalian Cdh1 is high in
      mitosis, but it is inactive and does not bind the APC/C. We show that when Cdh1
      is active in G1 and G0, its levels are considerably lower and almost all of it is
      APC/C associated. We demonstrate that Cdh1 is subject to APC/C-specific
      degradation in G1 and G0, and that this degradation depends upon two RXXL-type
      destruction boxes. We further demonstrate that addition of Cdh1 to Xenopus
      interphase extracts, which have an inactive APC/C, activates it to degrade Cdh1.
      These observations indicate that Cdh1 mediates its own degradation by activating
      the APC/C to degrade itself. Elevated levels of Cdh1 are deleterious for cell
      cycle progression in various organisms. This auto-regulation of Cdh1 could thus
      play a role in ensuring that the level of Cdh1 is reduced during G1 and G0,
      allowing it to be switched off at the correct time.

PMID- 15029245
TI  - Developmentally regulated role for Ras-GRFs in coupling NMDA glutamate receptors
      to Ras, Erk and CREB.
AB  - p140 Ras-GRF1 and p130 Ras-GRF2 constitute a family of calcium/calmodulin
      regulated guanine-nucleotide exchange factors that activate the Ras GTPases.
      Studies on mice lacking these exchange factors revealed that both p140 Ras-GRF1
      and p130 Ras-GRF2 couple NMDA glutamate receptors (NMDARs) to the activation of
      the Ras/Erk signaling cascade and to the maintenance of CREB transcription factor
      activity in cortical neurons of adult mice. Consistent with this function for Ras
      GRFs and the known neuroprotective effect of CREB activity, ischemia-induced CREB
      activation is reduced in the brains of adult Ras-GRF knockout mice and neuronal
      damage is enhanced. Interestingly, in cortical neurons of neonatal animals NMDARs
      signal through Sos rather than Ras-GRF exchange factors, implying that Ras-GRFs
      endow NMDARs with functions unique to mature neurons.

PMID- 15029246
TI  - Structure, dynamics and interactions of p47, a major adaptor of the AAA ATPase,
      p97.
AB  - p47 is a major adaptor molecule of the cytosolic AAA ATPase p97. The principal
      role of the p97-p47 complex is in regulation of membrane fusion events. Mono
      ubiquitin recognition by p47 has also been shown to be crucial in the p97-p47
      mediated Golgi membrane fusion events. Here, we describe the high-resolution
      solution structures of the N-terminal UBA domain and the central domain (SEP)
      from p47. The p47 UBA domain has the characteristic three-helix bundle fold and
      forms a highly stable complex with ubiquitin. We report the interaction surfaces
      of the two proteins and present a structure for the p47 UBA-ubiquitin complex.
      The p47 SEP domain adopts a novel fold with a betabetabetaalphaalphabeta
      secondary structure arrangement, where beta4 pairs in a parallel fashion to
      beta1. Based on biophysical studies, we demonstrate a clear propensity for the
      self-association of p47. Furthermore, p97 N binding abolishes p47 self
      association, revealing the potential interaction surfaces for recognition of
      other domains within p97 or the substrate.

PMID- 15029247
TI  - The mitochondrial ARTS protein promotes apoptosis through targeting XIAP.
AB  - ARTS is an unusual septin-like mitochondrial protein that was originally shown to
      mediate TGF-beta-induced apoptosis. Recently, we found that ARTS is also
      important for cell killing by other pro-apoptotic factors, such as arabinoside,
      etoposide, staurosporine and Fas. In Drosophila, the IAP antagonists Reaper, Hid
      and Grim are essential for the induction of virtually all apoptotic cell death.
      We found that mutations in peanut, which encodes a Drosophila homologue of ARTS,
      can dominantly suppress cell killing by Reaper, Hid and Grim, indicating that
      peanut acts downstream or in parallel to these. In mammalian cells, ARTS is
      released from mitochondria upon pro-apoptotic stimuli and then binds to XIAP.
      Binding of ARTS to XIAP is direct, as recombinant ARTS and XIAP proteins can bind
      to each other in vitro. ARTS binding to XIAP is specific and related to its pro
      apoptotic function, as mutant forms of ARTS (or related septins) that fail to
      bind XIAP failed to induce apoptosis. ARTS leads to decreased XIAP protein levels
      and caspase activation. Our data suggest that ARTS induces apoptosis by
      antagonizing IAPs.

PMID- 15029248
TI  - A transcriptional network in polycystic kidney disease.
AB  - Mutations in cystic kidney disease genes represent a major genetic cause of end
      stage renal disease. However, the molecular cascades controlling the expression
      of these genes are still poorly understood. Hepatocyte Nuclear Factor 1beta
      (HNF1beta) is a homeoprotein predominantly expressed in renal, pancreatic and
      hepatic epithelia. We report here that mice with renal-specific inactivation of
      HNF1beta develop polycystic kidney disease. We show that renal cyst formation is
      accompanied by a drastic defect in the transcriptional activation of Umod, Pkhd1
      and Pkd2 genes, whose mutations are responsible for distinct cystic kidney
      syndromes. In vivo chromatin immunoprecipitation experiments demonstrated that
      HNF1beta binds to several DNA elements in murine Umod, Pkhd1, Pkd2 and
      Tg737/Polaris genomic sequences. Our results uncover a direct transcriptional
      hierarchy between HNF1beta and cystic disease genes. Interestingly, most of the
      identified HNF1beta target gene products colocalize to the primary cilium, a
      crucial organelle that plays an important role in controlling the proliferation
      of tubular cells. This may explain the increased proliferation of cystic cells in
      MODY5 patients carrying autosomal dominant mutations in HNF1beta.

PMID- 15029251
TI  - WORDS FROM THE EDITOR.

PMID- 15029249
TI  - Structure of a kinesin microtubule depolymerization machine.
AB  - With their ability to depolymerize microtubules (MTs), KinI kinesins are the
      rogue members of the kinesin family. Here we present the 1.6 A crystal structure
      of a KinI motor core from Plasmodium falciparum, which is sufficient for
      depolymerization in vitro. Unlike all published kinesin structures to date,
      nucleotide is not present, and there are noticeable differences in loop regions
      L6 and L10 (the plus-end tip), L2 and L8 and in switch II (L11 and helix4);
      otherwise, the pKinI structure is very similar to previous kinesin structures.
      KinI-conserved amino acids were mutated to alanine, and studied for their effects
      on depolymerization and ATP hydrolysis. Notably, mutation of three residues in L2
      appears to primarily affect depolymerization, rather than general MT binding or
      ATP hydrolysis. The results of this study confirm the suspected importance of
      loop 2 for KinI function, and provide evidence that KinI is specialized to
      hydrolyze ATP after initiating depolymerization.

PMID- 15029252
TI  - The conservation status of the herpetofauna of Honduras.
AB  - The conservation status of the members of the Honduran herpetofauna is discussed.
      Based on current and projected future human population growth, it is posited that
      the entire herpetofauna is endangered. The known herpetofauna of Honduras
      currently consists of 334 species, including 117 amphibians and 217 reptiles
      (including six marine reptiles, which are not discussed in this paper). The
      greatest number of species occur at low and moderate elevations in lowland and/or
      mesic forest formations, in the Northern and Southern Cordilleras of the
      Serrania, and the ecophysiographic areas of the Caribbean coastal plain and
      foothills. Slightly more than one-third of the herpetofauna consists of endemic
      species or those otherwise restricted to Nuclear Middle America. Honduras is an
      area severely affected by amphibian population decline, with close to one-half of
      the amphibian fauna threatened, endangered, or extinct. The principal threats to
      the survival of members of the herpetofauna are uncontrolled human population
      growth and its corollaries, habitat alteration and destruction, pollution, pest
      and predator control, overhunting, and overexploitation. No Honduran amphibians
      or reptiles are entirely free of human impact. A gauge is used to estimate
      environmental vulnerability of amphibian species, using measures of extent of
      geographic range, extent of ecological distribution, and degree of specialization
      of reproductive mode. A similar gauge is developed for reptiles, using the first
      two measures for amphibian vulnerability, and a third scale for the degree of
      human persecution. Based on these gauges, amphibians and reptiles show an actual
      range of Environmental Vulnerability Scores (EVS) almost as broad as the
      theoretical range. Based on the actual EVS, both amphibian and reptilian species
      are divided into three categories of low, medium, and high vulnerability. There
      are 24 low vulnerability amphibians and 47 reptiles, 43 medium vulnerability
      amphibians and 111 reptiles, and 50 high vulnerability amphibians and 53
      reptiles. Theoretical EVS values are assessed against available information on
      current population status of endemic and Nuclear Middle American taxa. Almost
      half (48.8%) of the endemic species of Honduran amphibians are already extinct or
      have populations that are in decline. Populations of 40.0% of the Nuclear Middle
      American amphibian species are extirpated or in decline. A little less than a
      third (27.0%) of the endemic reptiles are thought to have declining populations.
      Almost six of every ten (54.5%) of the Nuclear Middle American reptilian species
      are thought to have declining populations. EVS values provide a useful indicator
      of potential for endangerment, illustrating that the species whose populations
      are currently in decline or are extinct or extirpated have relatively high EVS.
      All high EVS species need to be monitored closely for changes in population
      status. A set of recommendations are offered, assuming that biotic reserves in
      Honduras can be safeguarded, that it is hoped will lead to a system of robust,
      healthy, and economically self-sustaining protected areas for the country's
      herpetofauna. These recommendations will have to be enacted swiftly, however, due
      to unremitting pressure from human population growth and the resulting
      deforestation.

PMID- 15029253
TI  - The herpetofauna of the cloud forests of Honduras.
AB  - The cloud forest amphibians and reptiles constitute the most important
      herpetofaunal segment in Honduras, due to the prevalence of endemic and Nuclear
      Middle American-restricted species. This segment, however, is subject to severe
      environmental threats due to the actions of humans. Of the 334 species of
      amphibians and reptiles currently known from Honduras, 122 are known to be
      distributed in cloud forest habitats. Cloud forest habitats are found throughout
      the mountainous interior of Honduras. They are subject to a Highland Wet climate,
      which features annual precipitation of >1500 mm and a mean annual temperature of
      <18 degrees C. Cloud forest vegetation falls into two Holdridge formations, the
      Lower Montane Wet Forest and Lower Montane Moist Forest. The Lower Montane Wet
      Forest formation generally occurs at elevations in excess of 1500 m, although it
      may occur as low as 1300+ m at some localities. The Lower Montane Moist Forest
      formation generally occurs at 1700+ m elevation. Of the 122 cloud forest species,
      18 are salamanders, 38 are anurans, 27 are lizards, and 39 are snakes. Ninety
      eight of these 122 species are distributed in the Lower Montane Wet Forest
      formation and 45 in the Lower Montane Moist Forest formation. Twenty species are
      distributed in both formations. The cloud forest species are distributed among
      restricted, widespread, and peripheral distributional categories. The restricted
      species range as a group in elevation from 1340 to 2700 m, the species that are
      widespread in at least one of the two cloud forest formations range as a group
      from sea level to 2744 m, and the peripheral species range as a group from sea
      level to 1980 m. The 122 cloud forest species exemplify ten broad distributional
      patterns ranging from species whose northern and southern range termini are in
      the United States (or Canada) and South America, respectively, to those species
      that are endemic to Honduras. The largest segment of the herpetofauna falls into
      the endemic category, with the next largest segment being restricted in
      distribution to Nuclear Middle America, but not endemic to Honduras. Cloud forest
      species are distributed among eight ecophysiographic areas, with the largest
      number being found in the Northwestern Highlands, followed by the North-Central
      Highlands and the Southwestern Highlands. The greatest significance of the
      Honduran herpetofauna lies in its 125 species that are either Honduran endemics
      or otherwise Nuclear Middle American-restricted species, of which 83 are
      distributed in the country's cloud forests. This segment of the herpetofauna is
      seriously endangered as a consequence of exponentially increasing habitat
      destruction resulting from deforestation, even given the existence of several
      biotic reserves established in cloud forest. Other, less clearly evident
      environmental factors also appear to be implicated. As a consequence, slightly
      over half of these 83 species (50.6%) have populations that are in decline or
      that have disappeared from Honduran cloud forests. These species possess
      biological, conservational, and economic significance, all of which appear in
      danger of being lost.

PMID- 15029250
TI  - Structural basis for differential recognition of tyrosine-phosphorylated sites in
      the linker for activation of T cells (LAT) by the adaptor Gads.
AB  - The transmembrane protein, linker for activation of T cells (LAT), is essential
      for T-cell activation and development. Phosphorylation of LAT at multiple
      tyrosines creates binding sites for the adaptors Gads and Grb2, leading to
      nucleation of multiprotein signaling complexes. Human LAT contains five potential
      binding sites for Gads, of which only those at Tyr171 and Tyr191 appear necessary
      for T-cell function. We asked whether Gads binds preferentially to these sites,
      as differential recognition could assist in assembling defined LAT-based
      complexes. Measured calorimetrically, Gads-SH2 binds LAT tyrosine phosphorylation
      sites 171 and 191 with higher affinities than the other sites, with the
      differences ranging from only several fold weaker binding to no detectable
      interaction. Crystal structures of Gads-SH2 complexed with phosphopeptides
      representing sites 171, 191 and 226 were determined to 1.8-1.9 A resolutions. The
      structures reveal the basis for preferential recognition of specific LAT sites by
      Gads, as well as for the relatively greater promiscuity of the related adaptor
      Grb2, whose binding also requires asparagine at position +2 C-terminal to the
      phosphorylated tyrosine.

PMID- 15029254
TI  - Similarities and differences in hepatitis B and C virus induced
      hepatocarcinogenesis.
AB  - Hepatocellular carcinoma (HCC), the major manifestation of primary liver cancer,
      is one of the most frequent and malignant diseases worldwide. Among other
      environmental factors, hepatitis viruses, as the hepatitis B (HBV) and hepatitis
      C (HCV) viruses, are to be listed in the etiology of HCC. Both of these viruses
      cause a wide spectrum of clinical manifestations, ranging from healthy carrier
      state to acute and chronic hepatitis, cirrhosis and HCC. HBV and HCV are
      different viruses in structure: HBV contains a DNA genome which replicates
      through an RNA intermediate and requires an active viral reverse transcriptase
      (RT) polymerase enzyme, while HCV is an RNA virus which has no RT activity and
      replicates on the cellular membrane by RNA replication. In this review we discuss
      how these two biologically diverse viruses use common pathways to induce
      hepatocarcinogenesis despite their significant structural and viral cycle
      differences. A summary is also given of several observable common and different
      features. Direct integration of HBV viral sequences into the host genome
      increases the genomic instability, which does not occur in HCV infection.
      However, viral proteins may directly play a significant role in the induction of
      carcinogenesis by both viruses.

PMID- 15029255
TI  - Clinical manifestations of genetic instability overlap one another.
AB  - Cancer syndromes are characteristic associations of specific malignancies with
      various congenital anomalies. In addition to such diseases, an increased
      prevalence in general of chromosomal instability, malformations,
      immunodeficiencies, altered growth and development, and reproductive loss has
      been observed in both childhood leukemias and solid tumors. The overlap among
      these congenital disorders suggests their common prenatal, possibly genetic
      origin and thus the existence of a nonspecific genetic instability leading to
      various clinical manifestations of disturbances in cell division. Seeking for
      related features in family members of a patient with malignancy may be of
      clinical value in detecting predisposition to cancer.

PMID- 15029256
TI  - Promoter methylation pattern of caspase-8, P16INK4A, MGMT, TIMP-3, and E-cadherin
      in medulloblastoma.
AB  - Methylation of promoter regions of CpG-rich sites is an important mechanism for
      silencing of tumor suppressor genes (TSG). To evaluate the role of tumor
      suppressor genes caspase-8 (CASP8), TIMP-3, E-cadherin (CDH1), p16INK4A, and MGMT
      in medulloblastoma tumorigenesis, 51 medulloblastomas (46 primary tumor
      specimens, 5 cell lines) were screened for methylation of promoter linked CpG
      islands. For CASP8, we examined the 5' UTR region that has been shown to be
      associated with expression of CASP8. As detected by methylation specific PCR,
      methylation rate was low for TIMP-3 (3% of tumor samples; 1/5 cell lines), for
      MGMT (0% of tumor samples; 1/5 cell lines), for p16INK4A (2% of tumor samples;
      2/5 cell lines) and for CDH1 (8% of tumor samples; 1/4 cell lines). CASP8,
      however, was methylated in 90% of tumor samples and 4/5 cell lines examined.
      Screening other tumor entities for CASP8 methylation, we found a similarly high
      level in 6 neuroblastoma cell lines in contrast to 5 osteosarcoma-, 4 Ewing's
      sarcoma- and 6 non-embryonic tumor cell lines without any increased promoter
      methylation. From our results we conclude that methylation of the CASP8 5' UTR
      region may play a role in inactivation of CASP8 in neural crest tumors.

PMID- 15029257
TI  - A WT1 expressing metastatic human Kaposi sarcoma xenograft model.
AB  - We have established a non-metastatic and a metastatic human Kaposi sarcoma (KS)
      xenograft model in SCID mice by injecting KS-Imm cells subcutaneously and
      intrasplenically, respectively. KS-Imm cells expressed endothelial markers, CD34
      and vWF in vivo. Furthermore, we have shown that these cells express all the
      splice variants of the WT1 gene and WT1wt protein in vitro and in vivo detected
      by nested PCR and immunohistochemistry. WT1 expression in the peripheral blood
      was only detectable in case of metastatic KS model suggesting it as a molecular
      marker of progression.

PMID- 15029258
TI  - Expression of Ephb2 and Ephb4 in breast carcinoma.
AB  - Eph receptor tyrosine kinases and their cell-surface-bound ligands, the ephrins,
      play key roles in diverse biological processes. Eph receptors comprise the
      largest family of receptor tyrosine kinases consisting of eight EphA receptors
      (with five corresponding ephrinA ligands) and six EphB receptors (with three
      corresponding transmembrane ephrinB ligands). Originally identified as neuronal
      pathfinding molecules, EphB receptors and ephrinB ligands are later proved to be
      crucial regulators of vasculogenesis and embryogenesis. More studies indicate
      that Eph receptors are involved in angiogenesis and tumorigenesis. This study
      aimed to investigate the expression of EphB2 and EphB4 in breast carcinomas.
      Semiquantitative RT-PCR and immunohistochemistry were used to examine the
      expression patterns of EphB2 and EphB4. Clinicopathological and survival
      correlations were statistically analyzed in a series of 94 breast carcinomas, 9
      normal specimens and 4 breast carcinoma cell lines. 1(1%), 16(17%), 29(31%),
      48(51%) of the 94 tumors were negative, weak, moderate and strong EphB2 protein
      expression, respectively. 6(6%), 27(29%), 28(30%), 33(35%) of the tumors were
      negative, weak, moderate and strong EphB4 expression, respectively. Both EphB2
      and EphB4 RTPCR products could be detected in all specimens. Increased EphB2
      protein expression was negatively associated with overall survival, and there was
      a trend that increased EphB2 protein expression was correlated with shorter
      disease free survival, while EphB4 protein expression was associated with
      histological grade and stage. EphB4 membrane staining was increased with S phase
      fraction and associated with DNA aneuploidy. These findings indicate that both
      EphB2 and EphB4 are involved in the development of breast cancer and that both
      molecules could be potential predictive markers.

PMID- 15029259
TI  - Increased angiogenesis in cutaneous T-cell lymphomas.
AB  - Primary cutaneous T-cell lymphomas (CTCL) represent a heterogeneous group of
      neoplasms derived from skin-homing T cells. CTCL behave similarly to indolent B
      cell lymphomas. There is increasing evidence that angiogenesis may be important
      in lymphoproliferative disorders. The aim of the study was to evaluate
      microvessel density (MVD) as a parameter of tumor angiogenesis measured by the
      expression of CD34 in the skin samples in CTCL patients. Formaldehyde-fixed,
      paraffin-embedded skin tumor biopsy specimens from 25 patients (16 men, 9 women)
      with CTCL (mycosis fungoides), and 8 skin samples from healthy volunteers were
      analysed. The preparations were stained with haematoxylin and eosin, and
      evaluated histopathologically. Staining for endothelial cells with monoclonal
      antibody against CD34 revealed a mean number of 134 dots per mm2 for CTCL and 106
      dots/mm2 for controls; the difference was statistically significant (p=0.0388).
      Our study shows a higher number of microvessels in primary CTCL compared with
      normal skin. Microvascular endothelial cells have become an important target in
      cancer therapy. Increased MVD in the skin of CTCL patients indicate that
      angiogenesis may play a role in the growth of CTCL, and raises the possibility of
      using angiogenesis inhibitors in CTCL therapy.

PMID- 15029260
TI  - Androgen receptor expression in relation to apoptosis and the expression of cell
      cycle related proteins in prostate cancer.
AB  - The expression of several genes involved in the regulation of cell cycle and
      apoptosis may be regulated via the androgen receptor (AR) in the prostate. AR may
      have a role in the prognosis of prostatic carcinoma. The aim was to examine AR
      expression status and its relationship with markers of proliferation, apoptosis
      and cell cycle control in prostate cancer. Expression of AR, bcl-2, bax, Ki-67
      and p53 was examined in paraffin-embedded tissues from 50 cases of prostate
      carcinoma by immunohistochemistry and evaluated using an index of staining.
      Detection of apoptotic cells was performed by TUNEL method. Correlation between
      AR expression and apoptosis, proliferation index, bcl-2, bax and p53 and also
      clinicopathological parameters including stage, pathological grade and Gleason
      score were determined. AR expression was observed in all cases with mean
      expression of 81%+/-15 and mean staining index of 141+/-65. No correlation was
      found between AR expression and apoptosis detected in patients. The mean AR
      staining index was 170+/-72 in bcl-2 positive tumors versus 120+/-53 in bcl-2
      negative tumors showing a significant association between AR and bcl-2 expression
      (p=0.015). AR expression also showed a significant association with bcl-2/bax
      ratio (r=0.321, p=0.023) and Ki-67 proliferation staining index (r=0.396,
      p=0.004). Although a significant correlation between Ki-67 and p53 with
      differentiation status of the tumors was observed (p<0.004) no correlation was
      found with AR. AR expression showed no prognostic value regarding its correlation
      with stage and differentiation status of the prostate carcinoma. However, its
      significant correlation with Ki-67 and bcl-2 that are markers of cell survival
      suggest its contribution to tumor cell progression.

PMID- 15029261
TI  - PET identifies transitional metabolic change in the spinal cord following a
      subthreshold dose of irradiation.
AB  - Positron emission tomographic (PET) investigations were performed to obtain in
      vivo information on symptomless radiation-induced pathological changes in the
      human spinal cord. PET investigations were carried out prior to radiotherapy and
      during the regular follow-up in an early hypopharyngeal cancer patient (the
      spinal cord was irradiated with a biologically effective dose of 80 Gy2), with
      [18F]fluorodeoxyglucose (FDG), [11C]methionine and [15O]butanol as tracers;
      radiosensitivity and electroneuronographic (ENG) studies were also performed. A
      very low background FDG accumulation (mean standardized uptake values, i.e. SUV:
      0.84) was observed in the spinal cord before the initiation of radiotherapy. An
      increased FDG uptake was measured 2 months after the completion of radiotherapy
      (mean SUV: 1.69), followed by a fall-off, as measured 7 months later (mean SUV:
      1.21). By 44 months after completion of irradiation, the FDG accumulation in the
      irradiated segments of the spinal cord had decreased to a level very close to the
      initial value (mean SUV: 1.11). The simultaneous [15O]butanol uptake results
      demonstrated a set of perfusion changes similar to those observed in connection
      with the FDG accumulation. The patient exhibited an extremely low [11C]methionine
      uptake within the irradiated and the nonirradiated spinal cord during the
      clinical course. She has not had any neurological symptoms, and the results of
      central ENG measurements before radiotherapy and 2 months following its
      completion proved normal. Radiobiological investigations did not reveal
      unequivocal signs of an increased radiosensitivity. A transitory increased spinal
      cord FDG uptake following radiotherapy may be related to the posttherapeutic mild
      inflammatory and regenerative processes. The normal [11C]methionine accumulation
      observed is strong evidence against intensive cell proliferation. The high degree
      of normalization of the temporarily increased FDG uptake of the irradiated spinal
      cord segments by 44 months is in good agreement with the results of monkey
      studies, which demonstrated a nearly complete recovery from radiation-induced
      spinal cord injury.

PMID- 15029262
TI  - Neuroendocrine differentiation in gastric adenocarcinomas; correlation with tumor
      stage and expression of VEGF and p53.
AB  - Studies on neuroendocrine differentiation (NED) in conventional gastric
      adenocarcinomas and its significance on tumor behavior are limited. Our aim was
      to search for the expression of neuroendocrine differentiation in conventional
      gastric adenocarcinomas and correlate it with tumor type, stage and expression of
      VEGF and p53. Forty-two gastrectomy specimens with gastric adenocarcinoma were
      stained with chromogranin A to detect neuroendocrine differentiation and 45% of
      the cases were found to be NED (+). No significant correlation was found between
      NED and tumor type. However, NED was more frequent in advanced stage cases
      independently of tumor type. VEGF expression was also considerably more frequent
      in NED (+) tumors compared to NED (-) ones (84% vs. 56%). Moreover, we found a
      significant correlation between NED and the presence of lymph node metastases.
      P53 expression in NED (+) tumors was 68%. There was no significant correlation
      between VEGF and p53 in NED (+) cases. In conclusion, neuroendocrine
      differentiation is a frequent finding in conventional gastric adenocarcinomas,
      and although it does not seem to play a specific role in tumor progression, it
      seems that neuroendocrine cells are one of the factors contributing to
      angiogenesis by expressing VEGF, especially in advanced stage cases, affecting
      the incidence of lymph node metastases. Further studies with larger series should
      be performed to confirm this observation.

PMID- 15029263
TI  - Modeling of main characteristics of bullous pemphigoid antigen-2 (BPAG2) peptide
      structure in serological recognition by autoantibodies.
AB  - The serum level of autoantibodies against autoantigens of the bullous pemphigoid
      peptides 1 and 2 (BPAG1 and BPAG2) is a relevant diagnostic marker. Twelve
      representative sera of BP were tested against the RSILPYGDSMDRIEKDRLQMAP amino
      acid sequence that is an epitope fragment of the NC16A domain of BPAG2 (AC
      Q02802; 507-528) to find the most suitable antigenic form for specific detection
      of autoantibodies of BP patients' sera by quantitative ELISA system. The
      antigenic epitope sequence was presented as an antigen in a carrier free form of
      dimeric peptide (BP22), dimeric peptide fused to glutathione S-transferase (GST
      BP22) or dimeric peptide chemically conjugated to polyLys(Ser-DL-Alam) (SAK
      BP22). The intensity of ELISA reaction was highest against the recombinant fusion
      antigen GSTBP22; the chemically conjugated SAK-BP22 performed less well than the
      free dimeric form of the peptide. In the case of the GST-BP22 antigen, the (GST
      BP22)-(GST)492nm optical density values were determined. There was no significant
      difference between the mean ODs of the GST-BP22 and the SAK-BP22 (0.888 vs.
      0.892, p= 0.9726). Conjugating the epitope peptide with the synthetic carrier SAK
      was advantageous, as it abrogated cross-reactivity with GST carrier protein.
      Consequently, the SAKBP22 conjugate appears to be the most reliable assay
      component, avoiding cross-reactivity with GST and simplifying the detection and
      evaluation of BP autoantibodies in routine ELISA diagnostic system.

PMID- 15029264
TI  - Follicular dendritic reticulum cell tumor mimicking inflammatory pseudotumor of
      the spleen.
AB  - In the course of a routine clinical check up of the 54 year old male a splenic
      well circumscribed tumor like mass of 12 cm in diameter was discovered.
      Splenectomy with removal of splenic hilar lymph nodes and liver wedge biopsy were
      performed. Four years later the patient is symptom free. In the removed spleen
      the tumor like lesion showed a pattern consistent with the diagnosis of
      inflammatory pseudotumor. However, besides lymphocytes, plasma cells,
      macrophages, eosinophils and myofibroblasts a high number of slightly
      polymorphic, frequently binucleated cells positive for CD21 and CD23 were seen.
      These cells which were scattered or formed smaller or larger groups and fascicles
      were considered to represent follicular dendritic reticulum cells (FDRCs) and the
      lesion a FDRC tumor. Flow cytometric DNA ploidy analysis showed a hyperdiploid
      cell population inside the tumor like lesion. Besides FDRC tumors of high and of
      intermediate malignancy the present case may represent a low grade type of
      moderate proliferation activity. The FDRCs of the lesion and a few smaller
      spindle cells were EBER positive indicative of the presence of EBV. No EBER
      positive cells were seen in the uninvolved spleen.

PMID- 15029265
TI  - [Acquisition of age- and sex-dependent patient data for the calculation of annual
      radiation exposure in nuclear medicine: a German pilot study].
AB  - AIM: A pilot study for estimation of radiation exposure due to diagnostic
      procedures in nuclear medicine using routine data of hospitals and practices in
      Germany. METHODS: Hospitals and practices willing to participate in the study
      supplied data of one year (1997), containing information on patients'
      identification number, age, sex, type of diagnostic procedure,
      radiopharmaceutical, administered activity, type of health insurance
      (private/public), inpatient/outpatient status, and so-called Leistungsziffer,
      which describes the type of medical performances in Germany. The effective dose
      per examination was calculated according to ICRP 80. Mean, standard deviation,
      median, 5th and 95th percentiles of the effective dose were calculated,
      stratified by type of organ system and also by sex and age, including patients of
      > or = 18 years. RESULTS: 82,039 examinations from patients of 9 hospitals and
      practices were analyzed. The median (5-95(th) percentiles) of the effective dose
      per examination for all patients was 2.9 mSv (0.4-8.5 mSv); 1.2 examinations per
      patient and year were performed on average. The three most frequent examinations
      were bone scans (median 3.4 mSv; 2.9-5.1), thyroid (0.9 mSv; 0.4-2.2) and
      cardiovascular studies (7.3 mSv; 3.8-20.2). The median effective dose for 18 to
      40 years old women was 1.0 mSv (0.4-5.8), for women between 41 and 65 years 2.2
      mSv (0.4-7.3) and for women older than 65 years 2.4 mSv (0.5-7.6). The
      corresponding values for men were 2.6 mSv (0.3-7.6); 3.3 mSv (0.4-9.1), and 3.4
      mSv (0.5-8.8). CONCLUSION: It was possible to gain an accurate determination of
      radiation exposure of diagnostic procedures in nuclear medicine by routine data.

PMID- 15029266
TI  - [Multicenter study of radiosynoviorthesis. Clinical outcome in osteoarthritis and
      other disorders with concomitant synovitis in comparison with rheumatoid
      arthritis].
AB  - AIM: Evaluation of the effectiveness of radiosynoviorthesis (RSO) in
      osteoarthritis and other disorders with concomitant synovitis versus rheumatoid
      arthritis by means of a standardized questionnaire. PATIENTS, METHODS: 803 RSO
      treatments were monitored in 691 patients by standardized questionnaires of 7
      centers in 3 countries. Patients were assigned to 3 groups according to their age
      (20-40, 41-60, 61-80 years). Additionally, the data were analyzed separately for
      patients with rheumatoid arthritis (group A) and those with osteoarthritis,
      psoriasis arthritis, pigmental villonodular synovitis or persistent effusions
      after joint replacement (group B). RESULTS: Ameliorations of joint pain,
      swelling/effusion or flexibility were found in 80% of group A and 56% of group B
      (p >0.01). Quality of life improved in 78% of group A and 59% of group B (p
      >0.01). The response rate was similar for small- and large-sized joints in group
      A, but significantly higher for large-sized joints in group B (p >0.01). The
      positive effects on joint pain, swelling/effusion or flexibility lasted longer in
      group A (p >0.01). Repeated RSOs were as effective as initial ones. The clinical
      outcome was neither influenced by age, nor gender, nor transient immobilisation
      for 48 hours after RSO. CONCLUSION: Although slightly more efficient in
      rheumatoid arthritis, RSO represents an effective treatment option also in
      osteoarthritis and other disorders with concomitant synovitis.

PMID- 15029267
TI  - [Therapy of malignant ascites in vivo by 211At-labelled microspheres].
AB  - AIM: Determination of the biological effect of the alpha emitter (211)At on
      cellular level as well as the assessment of dosimetric data in a tumour model in
      vivo. METHODS: Transplantation of malignant ascitic cells in mice
      intraperitoneally and estimation of tumour characteristics (doubling time of the
      cells, mean survival of the animals following an i.p. application of a defined
      tumour cell number). (211)At labelled human serum albumin microspheres B-20 (MSP)
      of varying activity were injected into tumour bearing mice intraperitoneally. The
      effectiveness of the therapy was evaluated by means of determination of the
      duration of cell cycle arrest as well as the microscopic analysis of the rate of
      abnormal mitotic cells due to radiation induced damage. Furthermore, dose
      dependence of survival was evaluated. RESULTS: Three days following the
      intraperitoneally application of 8 x 10(6) tumour cells, 50-600 kBq (211)At-MSP
      were applied into the abdominal cavity. Considering the volume of ascites at this
      time and the administered activity, dose calculations were performed. An activity
      of 50 kBq caused a dose of 0.84 Gy. The increase of radiation induced effect on
      ascitic tumour cells was correlated with the dose. Between the duration of the
      cell cycle arrest and the administered activity, a directly proportional
      correlation was found. The mean survival of non-treated animals was 16.9 +/- 3.7
      days. The prolongation of the survival was proportional to the activity
      administered. Using a dosage of 10 Gy, five animals out of 16 survived.
      CONCLUSION: Therapy of malignant ascitic cells using (211)At-MSP was effective in
      vivo. For tumour therapy, the (211)At represents a highly effective alternative
      to usually applied beta emitters.

PMID- 15029269
TI  - [Diagnostic standards of von Willebrand disease].
AB  - Von Willebrand disease (VWD) is caused by quantitative and/or qualitative defects
      of the von Willebrand factor (VWF), a multimeric high molecular glycoprotein.
      Typically, it affects the primary haemostatic system, which is reflected by a
      mucocutaneous bleeding tendency simulating a functional platelet defect. The VWF
      promotes its function in two ways: It promotes platelet adhesion to the injured
      vessel wall under conditions of high shear forces and it functions as carrier for
      factor VIII in plasma. Due to its complexity diagnosis of VWD is one of the most
      challenging of coagulation disorders. The stepwise diagnosis of VWD includes
      patient's and family history, orientating procedures (bleeding time, filter
      tests, platelet count, aPTT), confirmatory tests (VWF:Ag, VWF:RCo, VIII:C) and
      tests for final classification (VWF:CB, RIPA, multimeric analysis, bWF:FVIIIB,
      platelet VWF). Accumulating knowledge of the different clinical phenotypes and
      their pathophysiological basis was translated into a classification scheme that
      differentiated between quantitative and qualitative defects by means of
      quantitative and functional parameters and by analyzing the electrophoretic
      pattern of VWF multimers. The advent of molecular techniques provided the
      opportunity for genotype/phenotype studies which recently helped not only to
      elucidate or confirm important functions of VWF and the steps of its
      posttranslational processing but also many disease causing defects.

PMID- 15029268
TI  - Platelet and von Willebrand factor interactions at the vessel wall.
AB  - The process of platelet thrombus formation contributes to the haemostatic
      response that prevents excessive blood loss after tissue injury, but may become a
      life-threatening disease mechanism by causing the acute thrombotic occlusion of
      atherosclerotic arteries. The participation of platelets in the formation of
      thrombi is centered on their adhesive properties and the ability to respond to
      stimuli with rapid activation. Platelet adhesion and activation are multifaceted
      and modulated by different environmental conditions, suggesting that it should be
      possible to obtain a selective pharmacological inhibition of the pathways more
      relevant to athero-thrombosis than to haemostasis. In particular, progress in
      understanding the structure and function of von Willebrand factor and the
      mechanisms that underlie its interactions with vascular surfaces and platelets
      can elucidate important differentiating aspects of normal haemostasis and
      pathological arterial thrombosis.

PMID- 15029270
TI  - [Classification of von Willebrand disease].
AB  - Von Willebrand disease (VWD) is known for its marked heterogeneity which was
      already recognized by von Willebrand in 1926. The basis of phenotypic
      differentiation are quantitative and qualitative or functional differences
      between the different types and subtypes of VWD. One of the most important tools
      in the classification of VWD is multimer analysis that visualizes many of the
      structural abnormalities of mutant VWF. The introduction of multimer analysis was
      followed by the identification of an increasing number of different VWD
      phenotypes that were first reviewed in 1987 by Ruggeri and Zimmerman, thus
      forming a first classification of the disease. However, the detection of
      additional phenotypes required a revision of the nomenclature at a time point
      when only a few types of VWD had already been analyzed on the molecular level.
      Consequently, the molecular data only played a minor role in the revised
      classification published by Sadler in 1994. The advent of molecular techniques
      provided the opportunity for genotype/phenotype studies which recently helped not
      only to elucidate or confirm important functions of VWF and its steps of post
      translational processing but also many disease causing defects. The reproducible
      correlation between certain phenotypes and particular mutations can now be used
      for a molecular approach towards a soundly based classification of VWD, equally
      useful for the clinician and for research requirements.

PMID- 15029271
TI  - [Molecular genetics of von Willebrand disease].
AB  - Due to the multifunctional character of von Willebrand factor (VWF), its complex
      biosynthesis and structure, many different disease causing molecular mechanisms
      exist which explain the well known marked heterogeneity of clinical symptoms in
      von Willebrand disease (VWD). Identification of specific mutations that can
      either cause complete or partial absence of VWF, interfere with post-translation
      processing of VWF like dimerisation and multimerisation, impair intracellular
      transport or disturb particular functions of VWF, offered the opportunity for
      structure/function studies of VWF and genotype/phenotype analysis of VWD. Today
      the molecular tools for such studies are readily available, enabling us to
      identify the molecular defects in a reasonable time even in the case of the large
      and complex VWF gene with its 52 exons. Mutation analysis can help to find the
      correct diagnosis and to classify patients with VWD which may be crucial to
      choose the adequate therapy. It can also identify unaffected carriers of the
      disease gene among family members of patients with VWD. Furthermore, mutation
      analysis and the conclusions drawn from such data can further help to understand
      the molecular mechanisms of VWF not only in bleeding but also in arterial
      thrombotic disease.

PMID- 15029272
TI  - Women with von Willebrand disease.
AB  - The clinical presentation of VWD shows sex-related differences of symptoms. In
      women the most typical symptoms are menorrhagia, bleeding during and after
      delivery or abortion and bleeding in connection with caesarean section or
      gynaecological surgery. Menorrhagia is one of the most common symptoms presented
      to gynaecologists. In 7-20% of menorrhagia the underlying cause is VWD, in our
      cohort of 185 women with menorrhagia the prevalence of VWD was even 32%. On the
      other hand in women with VWD menorrhagia with onset at the menarche can be found
      in 60-93%, influencing substantially their morbidity and quality of life. During
      pregnancy women with mild VWD experience a decrease of bleeding tendency due to
      an increase of endogenous VWF. But as the VWF concentration drops rapidly after
      delivery, the post-partum period is often associated with significant bleeding
      complications. In severe forms of VWD the bleeding risk is high during delivery
      and postpartum period. Laboratory monitoring and therapeutical measures should be
      continued for 8-10 days after delivery. During menopause the clinical situation
      improves for most of the women with mild or moderate VWD.

PMID- 15029273
TI  - Acquired von Willebrand syndrome 2004: International Registry--diagnosis and
      management from online to bedside.
AB  - The acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with
      laboratory findings similar to those for congenital von Willebrand disease.
      Unlike the congenital form, AVWS usually occurs in individuals with no personal
      or family history of bleeding. Large studies on AVWS are not available, diagnosis
      remains difficult and treatment empirical. Acquired von Willebrand syndrome is
      especially frequent in lympho- or myeloproliferative disorders. It is associated
      with solid tumours, immunological and cardiovascular disorders as well as other
      miscellaneous conditions. Diagnosis of AVWS is based on assays measuring
      ristocetin cofactor activity or collagen binding, which are usually abnormally
      low, while factor VIII coagulant activity is some-times within the reference
      range. FVIII/VWF inhibiting activities are found in only a minority of cases.
      Bleeding episodes in patients with AVWS are mostly of the mucocutaneous type and
      can be managed with desmopressin, plasma-derived factor VIII/von Willebrand
      factor (FVIII/VWF) concentrates and intravenous immunoglobulin. Recombinant
      activated factor VII can be useful in cases unresponsive to standard therapy. In
      conclusion, the AVWS, although rare, is certainly underestimated in clinical
      practice: The actual clinical impact of AVWS should be evaluated by prospective
      studies. The authors are co-ordinating an updated version of the International
      Registry on AVWS that will allow data to be entered directly online.

PMID- 15029274
TI  - Current treatment of von Willebrand's disease.
AB  - During the last couple of decades improved pathophysiological insight, use of
      improved diagnostic tools, and improved understanding of treatment requirements,
      have converged on an improved safety of treatment and quality of life for the
      patient suffering VWD. The scientific development in this area has elucidated a
      vast heterogeneity in VWD now appreciated as a vastly heterogeneous group of
      bleeding disorders. In some subtypes, dysfunctional VWF protein characteristics
      are clarified and logically linked with the distinct site of the VWF gene
      mutation abolishing specific functions of VWF, while in other subtypes such
      relationships have not yet been established. With the most frequently occurring
      variant, designated type 1, the quantitative loss in VWF seems to correlate with
      its reduced function. However, we are only at the beginning of the era of
      molecular genetics of this specific variant. Medical evidence based guidelines by
      ordinary standards for treatment of VWD do not exist. Therefore, treatment is
      based on a mechanistic approach and empirical knowledge. The review presented
      here focuses on the management of bleeding in VWD. Its basis is a mixture of data
      reported to literature and the authors' personal clinical observations. Our
      intention is the presentation and discussion of current issues related to VWD as
      well as the various pharmaceutical treatment options available for patients
      afflicted with von Willebrand's disease, together with some theoretical thoughts
      on possible future modalities.

PMID- 15029276
TI  - [Thrombotic thrombocytopenic purpura in childhood].
AB  - Thrombotic thrombocytopenic purpura (TTP) is a micro-angiopathic disease due to
      deficiency of the specific VWF cleaving protease (VWF-CP) ADAMTS13. The acquired
      form is caused by autoantibodies against VWF-CP, whereas mutations of the
      ADAMTS13 gene are responsible for inherited TTP. In childhood both forms exist
      with predominance of inherited TTP. The phenotype of TTP in childhood can be
      rather variable. Besides the classical clinical picture, abortive forms may occur
      that can delay the identification of patients at risk. The patients are
      frequently assumed to suffer from idiopathic thrombocytopenia (ITP) or Evans
      syndrome. Further efforts are necessary to accelerate correct diagnosis and to
      establish a risk-adapted prophylactic therapy.

PMID- 15029275
TI  - [Diagnosis of thrombotic thrombocytopenic purpura].
AB  - As hallmark of TTP, generalized hyaline thrombi in the patient's microcirculation
      is known. These thrombi are composed of platelets and VWF. A severe defect of the
      VWF cleaving protease (VWF-CP) was found in all known patients with the inherited
      form of TTP. In contrary, although a severe deficiency of VWF-CP is specific for
      the acquired form, too, only a fraction of these patients is characterized by a
      severe deficiency. In most patients with a severe deficiency autoantibodies
      directed against VWF-CP is detectable in plasma. However, many patients with
      acquired TTP do not show any severe deficiency. Because treatment differs in
      inherited and acquired forms and as persistance of autoantibodies during clinical
      remission is of prognostic value, the determination of the activity of VWF-CP and
      of antibodies against VWF-CP are important parts in the workup of patients with
      TTP. In all methods for the determination of the activity of VWF-CP the first
      step is proteolysis of a specific substrate for the protease. In the second step
      the activity of the protease is measured by analysis of the residual VWF
      multimers, by the generation of specific fragments, by using the residual VWF:CB
      or VWF:RCo as marker of the loss of multimers or with help of specific monoclonal
      antibodies. In less than 30 min the cone and plate(let) aggregometer helps to
      distinguish between different forms of thrombotic microangiopathies. While
      adhesion and aggregation of platelets from a healthy person are clearly enhanced
      after addition of a small amount of plasma from a TTP patient, both
      characteristics are weakened by plasma from patients with other forms of
      thrombotic microangiopathy (dilution effect). Molecular genetics are established
      methods in the differentiation between inherited and acquired forms of TTP in
      those cases without autoantibodies against VWF-CP.

PMID- 15029277
TI  - [Thrombotic microangiopathy following stem cell transplantation].
AB  - Stem cell transplantation associated microangiopathy (TA-TMA) occurs in about 7%
      of all transplantations. While it resembles in all its features idiopathic TTP or
      HUS, response to plasma therapy is poor. The overall mortality of patients
      afflicted with TA-TMA is about 80%. Comparative studies aimed at discovering risk
      factors for the development of TA-TMA and defined different entities according to
      clinical, laboratory and outcome parameters. It is thought to be of
      multifactorial aetiology with the central event of endothelial damage. Intensive
      chemotherapy and radiation for bmt-preparation, infection in the
      immunocompromised host and graft versus host disease in conjunction with
      immunosuppressive therapy i. e. cyclosporine turn the haemostatic balance into a
      procoagulant state. Therapeutic strategies deduced from idiopathic TTP were
      disappointing with the only consensus in the withdrawal of cyclosporine from TA
      TMA patients. Future trials are directed to ameliorate endothelial dysfunction.

PMID- 15029278
TI  - Ethics and the management of terminally ill children.

PMID- 15029280
TI  - Portal hyperflow in patients with hepatosplenic mansonic schistosomiasis.
AB  - PURPOSE: The purpose of this study was to assess portal hemodynamics in patients
      with portal hypertension due to hepatosplenic schistosomiasis as well as to
      assess the contribution of splanchnic hyperflow to the pathophysiology of the
      portal hypertension. METHODS: Sixteen patients with schistosomal portal
      hypertension and previous history of upper digestive bleeding due to esophageal
      varices rupture underwent elective esophagogastric devascularization and
      splenectomy and were prospectively studied. All patients underwent intraoperative
      invasive hemodynamic portal monitoring with a 4F-thermodilution catheter. The
      intraoperative portal hemodynamic assessment was conducted after laparotomy
      (initial) and after esophagogastric devascularization (final). RESULTS: The
      initial portal pressure was elevated (mean 28.5 +/- 4.5 mm Hg), and a significant
      drop of 25% was observed at the end of the surgery (21.9 +/- 4.9 mm Hg). The
      initial portal flow was elevated (mean 1766.9 +/- 686.6 mL/min). A significant
      fall (42%) occurred at the end of the surgical procedure (1025.62 +/- 338.7
      mL/min). Fourteen patients (87.5%) presented a portal flow of more than 1200
      mL/min, and in 5 cases, values greater than 2000 mL/min were observed.
      CONCLUSIONS: Esophagogastric devascularization and splenectomy promote a
      significant reduction of the elevated portal pressure and flow in schistosomal
      portal hypertension. These data favor the hypothesis of portal hyperflow in the
      physiopathology of portal hypertension of schistosomiasis.

PMID- 15029279
TI  - Ethical aspects in the management of the terminally ill patient in the pediatric
      intensive care unit.
AB  - OBJECTIVE: To identify the prevalence of management plans and decision-making
      processes for terminal care patients in pediatric intensive care units.
      METHODOLOGY: Evidence-based medicine was done by a systematic review using an
      electronic data base (LILACS, 1982 through 2000) and (MEDLINE, 1966 through
      2000). The key words used are listed and age limits (0 to 18 years) were used.
      RESULTS: One hundred and eighty two articles were found and after selection
      according to the exclusion/inclusion criteria and objectives 17 relevant papers
      were identified. The most common decisions found were do-not-resuscitation orders
      and withdrawal or withholding life support care. The justifications for these
      were "imminent death" and "unsatisfatory quality of life". CONCLUSION: Care
      management was based on ethical principles aiming at improving benefits, avoiding
      harm, and when possible, respecting the autonomy of the terminally ill patient.

PMID- 15029281
TI  - The general practitioner and the surgeon: stereotypes and medical specialties.
AB  - OBJECTIVE: To investigate and characterize the professional stereotypes
      associated with general medicine and surgery among Brazilian medical residents.
      METHODS: A randomized sample of residents of the General Medicine and Surgery
      Residence Programs were interviewed and their perceptions and views of general
      and surgical doctors were compared. RESULTS: The general practitioner was
      characterized by the residents in general to be principally a sensitive and
      concerned doctor with a close relationship with the patient; (45%); calm,
      tranquil, and balanced (27%); with intellectual skills (25%); meticulous and
      attentive to details (23%); slow to resolve problems and make decisions (22%);
      and working more with probabilities and hypotheses (20%). The surgeon was
      considered to be practical and objective (40%); quickly resolving problems (35%);
      technical with manual skills (23%); omnipotent, arrogant, and domineering (23%);
      anxious, stressed, nervous, and temperamental (23%); and more decided, secure,
      and courageous (20%). Only the residents of general medicine attributed the
      surgeon with less knowledge of medicine and only the surgeons attributed gender
      characteristics to their own specialty. CONCLUSION: There was considerable
      similarity in the description of a typical general practitioner and surgeon among
      the residents in general, regardless of the specialty they had chosen. It was
      interesting to observe that these stereotypes persist despite the transformations
      in the history of medicine, i.e. the first physicians (especially regarding the
      valorization of knowledge) and the first surgeons, so-called "barber surgeons" in
      Brazil (associated with less knowledge and the performance of high-risk
      procedures).

PMID- 15029282
TI  - HIV-1: maternal prognosis.
AB  - Profound modifications in the profile of patients are currently being observed
      within the epidemic context of AIDS, especially with respect to pauperization and
      feminization of the disease. The population most frequently affected is in the
      reproductive age, and among adults aged 18 to 24 years, the ratio is 1 man to 1
      woman, a phenomenon occurring uniformly all over the world. One of the main
      challenges for HIV-1-infected pregnant women and their doctors is the effect of
      the interaction between HIV infection and pregnancy. The present article is a
      review of the literature; and its objective is to assess the influence of HIV-1
      infection seen from the maternal perspective, with a discussion of immunologic
      function, maternal prognosis, and the HIV-abortion interface. At present, we
      cannot conclude that pregnancy has a short-term effect on the evolution of HIV
      infection, but the concomitance of HIV and pregnancy may adversely affect the
      prognosis of gestation, especially in view of its frequent association with
      increased abortion and puerperal morbidity rates.

PMID- 15029283
TI  - Risks and benefits of hormone replacement therapy in older men.
AB  - The use of testosterone in older men, known as male hormonal replacement therapy
      or androgen replacement therapy, has become of increasing interest to both the
      medical and lay communities over the past decade. Even though the knowledge of
      the potential benefits and risks of male Androgen Replacement Therapy has
      increased dramatically, there is still much that needs to be determined. Although
      there are a number of potential benefits of male Androgen Replacement Therapy and
      data concerning clinical effects of such replacement have accumulated, as yet
      there have not been any large multicenter randomized controlled trials of this
      therapy. It is the purpose of this article to review what is currently known
      about the possible risks and benefits of male Androgen Replacement Therapy by
      discussing the clinical trials to date.

PMID- 15029284
TI  - Advances in radiochemotherapy in the treatment of head and neck cancer.
AB  - New advances are being incorporated into the radiochemotherapy treatment of
      squamous cell carcinoma of the head and neck. Although the overall prognosis is
      poor in advanced stages, the possibility of incorporating combined protocols of
      chemotherapy and radiotherapy for organ preservation or for palliation in cases
      of recurrent/locally advanced stages that are not good surgical candidates must
      not be forgotten. In this context, there is an urgent need to incorporate quality
      of life questionnaires and functional evaluation into organ-preservation studies,
      as well as to assure the importance of surgical salvage after radiotherapy and
      chemotherapy protocols. The authors provide an extensive review of the advances
      occurring in the nonsurgical treatment of head and neck cancer. Special attention
      is given to different radiotherapy protocols, new chemotherapy combinations,
      molecular markers, and molecular therapy as well as the possibility of
      incorporating re-irradiation and adjuvant therapy after surgery.

PMID- 15029285
TI  - Pulmonary hemorrhage as a manifestation of systemic lupus erythematosus.
AB  - The authors report a case of a 19-year-old woman admitted for the investigation
      of fever and hemolytic anemia for the previous 2 months. As an inpatient, she had
      convulsions and sudden loss of consciousness, developing hemoptysis, hypoxia, and
      respiratory insufficiency. Examination showed pericardial effusions on the
      echocardiogram and bilateral alveolar condensations on the thoracic radiograph. A
      hypothetical diagnosis of systemic lupus erythematosus was made, and measurement
      of the antinuclear factor was requested along with daily pulse therapy
      methylprednisolone, in spite of which the outcome was fatal. Afterwards, the
      result of the antinuclear factor test was positive, with a titer of 1:5120,
      showing a fine punctiform pattern, fulfilling the criteria for systemic lupus
      erythematosus according to the American College of Rheumatology. Secondary
      pulmonary hemorrhage in this connective tissue disease is an uncommon but serious
      complication that involves a high level of mortality in spite of intensive
      treatment, as is also reported in the literature.

PMID- 15029287
TI  - [Alcoholism: indictment or diagnosis?].
AB  - This article presents reflections on how alcohol consumption is conceived as a
      sociological object, including proscribed forms linked to the definition of
      diseases or disregard for moral norms. Through considerations on the accumulated
      investment in a research process currently under way, the author highlights the
      ethical and epistemological dilemmas faced by anthropologists who focus on this
      issue.

PMID- 15029302
TI  - [Evaluative research and epidemiology: trends and synthesis in the health
      programs evaluation process].
AB  - This article focuses on antecedents in the evaluation of health programs and
      highlights the diversity of theories and methods applied to the field. In order
      to provide support for evaluative research in HIV/AIDS, the article discusses
      several classical principles in epidemiology, particularly the theory of causal
      inference and its limits for approaching infectious diseases. The article
      contends that recent debates concerning the logic and applicability of ecological
      studies establish convergent interests between epidemiology and evaluative
      research, concerned with incorporating contextual variables into the analytical
      models. The principles and typologies of contemporary evaluative research are
      explained with a view towards defending an analytical model for health-disease
      processes from the perspective of evaluating actions and programs. The article
      concludes by highlighting common proposals and convergent trends in epidemiology
      and evaluative research, serving as the framework for discussion on the limits
      and potentialities of the proposed model.

PMID- 15029304
TI  - Risk factors for preterm births in Sao Luis, Maranhao, Brazil.
AB  - Preterm birth continues to be one of the main causes of neonatal morbidity and
      mortality. The objective of the present study was to identify risk factors for
      preterm birth in Sao Luis, Maranhao, Brazil. The sample consisted of hospital
      births at 10 public and private hospitals from March 1, 1997 to February 28,
      1998. A total of 2,443 live births were randomly selected, excluding multiple
      deliveries and stillbirths. Preterm birth rate in Sao Luis was 12.7%. Risk
      factors for preterm delivery were maternal age below 18 years, family income
      equal to or less than one minimum wage/ month, primiparity, vaginal delivery at a
      public hospital, single mothers (or living without a partner), and absence of
      prenatal care. The following factors remained associated with preterm birth after
      multivariate analysis to control for confounding: maternal age below 18 years
      (OR=1.9), primiparity (OR=1.5), and failure to appear for scheduled prenatal care
      visits (OR=1.5).

PMID- 15029303
TI  - [Prediction of aerobic fitness without stress testing and applicability to
      epidemiological studies: a systematic review].
AB  - Cardiorespiratory fitness is used as an independent factor for evaluating risk of
      all-cause mortality, but mainly from coronary heart disease. Nevertheless,
      evaluation of fitness based on stress tests poses numerous epidemiological
      difficulties. Alternative forms of evaluation have therefore been suggested using
      non-exercise-based regression models. This study aimed to analyze these models
      and their applicability to epidemiological studies. A systematic review was
      conducted of articles published from 1966 to 2002. The models were classified
      according to: (a) theoretical justification for the explanatory variables
      included in the model; (b) validation criteria (gold standard); (c) regression
      models fully reported, including standard error of estimation; and (d) cross
      validation. The search process yielded 23 studies, five of which met all
      established quality criteria. The authors conclude that cardiorespiratory
      evaluation by non-exercise-based models could be feasible in epidemiological
      studies. However, few equations appear to meet the minimum external validation
      requirements to provide data that could be generalized to large populations.

PMID- 15029305
TI  - [Breastfeeding patterns and energy adequacy].
AB  - To analyze caloric adequacy in infant feeding six months of age or under, the
      volume of breast milk consumed was estimated through a regression equation as
      proposed by Drewett. Energy adequacy was estimated according to World Health
      Organization guidelines for developing countries and the recommended daily
      allowance of the Food and Nutrition Board. A cross-sectional analysis was
      conducted on data from a cohort of 118 infants in a neighborhood around a health
      center in Campinas, Sao Paulo, Brazil, with home interviews by trained students.
      Data were gathered on social and demographic characteristics, infant feeding
      patterns, duration of breastfeeding, frequency of feedings, and age when breast
      milk substitutes were introduced. On average, weaning began early, with a 2.7
      month median duration of exclusive breastfeeding. Mean breast milk volume was
      estimated (from frequency of feeding) as 561.0 ml, 558.9 ml and 565.5 ml for
      children in exclusive, predominant, and supplemented breastfeeding, respectively.
      Mean energy consumption was adequate for all exclusively breastfed children
      regardless of age and above the recommended level for infants with supplemented
      breastfeeding and those already weaned.

PMID- 15029306
TI  - Analysis of medical prescriptions dispensed at health centers in Belo Horizonte,
      Minas Gerais, Brazil.
AB  - This article focuses on medical prescriptions dispensed at health centers under
      the Municipal Health Department in Belo Horizonte, Minas Gerais State, Brazil.
      The study analyzed 4,607 prescriptions from March to April 1999, grouped
      according to origin (internal or external). The analysis focused on information
      written on medical prescriptions. The main findings were: (a) an average of 2.4
      drugs per prescription in both groups; (b) prescriptions filled out with 4 or
      more drugs accounted for 18.0% of internal and 17.6% of external prescriptions;
      (c) 84.3% of internal and 85.5% of external prescriptions provided no
      instructions for use of medication; (d) information on dosage regimen varied from
      51.2% to 97.6% for internal and 57.9% to 96.5% for external prescriptions; (e)
      generic names were specified for 51.9% and 28.4% of all drugs on internal and
      external prescriptions, respectively; (f) prescriptions containing standard drugs
      from the Municipal Health Department accounted for 88.7% of internal and 76.4% of
      external prescriptions. Data analysis shows the need for continuing education of
      physicians and adoption of other methods to improve quality of prescriptions and
      promote rational use of drugs.

PMID- 15029307
TI  - [Demanding respect for the subjectivity of public health system clients: towards
      humanization of health care].
AB  - This paper analyzes how clients of the public health system in Natal, Rio Grande
      do Norte, Brazil, "give meaning" to their situation as "patients", basically
      focusing on three aspects: (1) evaluation of care, (2) awareness of their rights
      as citizens and role in improvement of the service, and (3) expectations
      regarding the encounter with health professionals. The results point to many
      deficiencies in the health system, besides demonstrating the population's
      passivity and resignation towards the present situation. The need to consider
      clients' subjectivity is important, as is the health professional-client
      relationship, with their encounter considered a prime moment for establishing a
      humanizing process in health practice, besides fostering the development of a
      critical awareness among clients concerning their rights and their role as agents
      of change in the health system.

PMID- 15029308
TI  - [Reliability of the Portuguese-language version of the Social Phobia Inventory
      (SPIN) among adolescent students in the city of Rio de Janeiro].
AB  - It is believed that social phobia has its onset during adolescence and precedes
      other mental disorders; it is thus important to investigate the condition among
      young people. To date there is no self-reported scale validated for the Brazilian
      population. The present study investigated the reliability of the Portuguese
      language version of the Social Phobia Inventory (SPIN) among adolescent students
      from public schools in the city of Rio de Janeiro. After SPIN was translated into
      Portuguese, a test-retest reliability study was carried out with 190 students.
      Intra-class correlation coefficient (ICC) and weighted kappa (kappaw2) were
      estimated, log-linear models were fitted, and Bland & Altman graphs were built.
      The Portuguese version showed good internal consistency (Cronbach's alpha=0.88)
      and good reliability for total score (ICC=0.78). Reliability for single items was
      not very good (kappaw2 between 0.32 and 0.65). The "semi-association" model fit
      most of the items best. Based on these findings we concluded that the Portuguese
      language version of SPIN showed good reliability results, similar to those
      obtained with the original English-language version.

PMID- 15029310
TI  - [Cesarean sections: risk perception and indication by attending obstetricians in
      a public maternity hospital in Rio de Janeiro].
AB  - The cesarean section rate in municipal public maternity hospitals in the city of
      Rio de Janeiro in the year of 2000 was 30.1%. With such a high rate, our
      hypothesis is that attending obstetricians in these units are indicating cesarean
      sections for reasons not restricted to clinical factors. The article aims to
      analyze physicians' representations of the inherent risks in cesarean sections
      that influence the medical decision for their indication. In this qualitative
      study, conducted through participant observation during ward duty and interviews
      with obstetricians, we observed that C-section indications by obstetricians are
      influenced by various non-obstetric factors, including insecurity about
      performing obstetric maneuvers, fragmented care, and fear of legal liability. The
      paper suggests that the widespread use of this intervention in private maternity
      services has fostered a practice in public obstetric services that compromises
      the quality of public health care and may jeopardize the health of women and
      infants.

PMID- 15029309
TI  - [Correspondence analysis for the evaluation of women's profile during post
      menopause and hormone replacement therapy].
AB  - This study illustrates the use of correspondence analysis to identify distinct
      profiles characterizing hormone replacement therapy (HRT) users and non-users,
      allowing the visualization of concurrent characteristics associated with this
      self-selection process. We analyzed cross-sectional information provided by 195
      women reporting natural menopause, among 2,240 participants in the Pro-Saude
      Study (Rio de Janeiro, Brazil). Non-users had an unfavorable profile, including
      greater weight gain during adult life, older age, later menopause, and less
      schooling. This analytic tool should be used more extensively in public health
      research, in exploratory analyses of the relations among a large number of
      variables in key populations.

PMID- 15029311
TI  - [Trends in dental caries rates in schoolchildren 12 and 13 years old in
      Florianopolis, Santa Catarina, Brazil, 1971-2002, in Florianopolis, Santa
      Catarina, Brazil].
AB  - The goal of this study was to identify dental caries prevalence and severity
      among all 12 and 13-year-old schoolchildren enrolled in a public school in 2002
      and to establish comparisons with the results of studies conducted previously in
      the same school in 1971 and 1997. A cross-sectional study involving 181 children
      was performed. Clinical data were collected by one examiner under World Health
      Organization (WHO) criteria. The examiner had been through calibration training.
      The project was approved by the Research Ethics Committee of the Federal
      University in Santa Catarina. The response rate was 93.8%. Intra-examiner
      agreement, on a tooth-by-tooth basis, was high (Kappa> or =0.73). The prevalence
      rates for dental caries were 98%, 93.7% or 80.0%, and 57.4% in 1971, 1997, and
      2002, respectively. The mean DMF-T index was 9.2 in 1971, 6.2 or 3.0 in 1997, and
      1.4 in 2002, taking both ages as a whole. The first value from 1997 was recorded
      under the Klein & Palmer diagnostic criterion and the second according to the WHO
      criterion. Between 1971 and 2002 there was a real reduction in caries prevalence
      and severity among the schoolchildren, even though different diagnostic criteria
      were used.

PMID- 15029313
TI  - [Prevalence of dental fluorosis in 12 and 15 years old schoolchildren in
      Salvador, Bahia, Brazil, 2001].
AB  - This study aimed to determine the prevalence of dental fluorosis in a sample of
      3,313 schoolchildren (ages 12 and 15) in a health district in Salvador, Bahia,
      Brazil. A cross-sectional study was developed, and data were collected by seven
      examiners (kappa = 0.69) according to WHO criteria (the Dean index). Additional
      information such as participation in programs, access to a dentist, place of
      residence from 0-5 years of age, sex, and ethnicity were obtained through a
      questionnaire. A descriptive analysis was performed for the municipality as a
      whole and for each district. According to the results, 31.4% of the 12-year-olds
      and 27.6% of the 15-year-olds presented fluorosis, predominantly of the "very
      mild" type. Differences were found between the districts (p<0.05). The districts
      of Pau da Lima and Brotas had the highest percentages of healthy individuals at
      12 years of age (81.8% and 81.6%). At 15 years, Suburbio Ferroviario, Pau da
      Lima, and Cajazeiras were the districts with the lowest prevalence rates (13.0%,
      14.6%, and 13.5%). The district of Liberdade had the highest prevalence (72.4%
      and 57.3%) at 12 and 15 years, respectively, attributed to differences in
      calibration. Differences were found between the health districts, thus
      emphasizing the need for health surveillance.

PMID- 15029312
TI  - [Prevalence of abnormal hemoglobins in newborns in Natal, Rio Grande do Norte,
      Brazil].
AB  - Hemoglobinopathies are among the most prevalent hereditary diseases in humans.
      Studies in different areas of Brazil have identified the prevalence of S and C
      abnormal hemoglobins. The study analyzed 1,940 cord blood samples of newborns
      from maternity hospitals in Natal, Rio Grande do Norte State, to investigate the
      prevalence of abnormal hemoglobins. All samples were submitted to cellulose
      acetate electrophoresis using a Tris-EDTA-borate buffer at pH 8.5.
      Electrophoresis in agar gel pH 6.2 was performed on samples presenting abnormal
      hemoglobin. Some 37 (1.91%) of the newborns presented hemoglobinopathies, as
      follows: 29 (1.50%) sickle cell trait (Hb FAS), 6 (0.31%) heterozygous Hb C (Hb
      FAC), one (0.05%) homozygous Hb S (Hb FS), and one (0.05%) Hb Barts suggestive of
      alpha thalassemia. The results show the need to implement screening for
      hemoglobinopathies in the neonatal population.

PMID- 15029314
TI  - [Mortality trends from uterine cervical cancer in the city of Sao Paulo from 1980
      to 1999].
AB  - Uterine cervical cancer shows a higher incidence in some Brazilian cities. It is
      a common cause of death in women from developing countries, despite the
      longstanding availability of an effective screening test, the Pap smear. This
      study aimed to evaluate the temporal trends of crude, age-adjusted, and age
      specific mortality rates from cervical cancer, endometrial cancer, and cancer of
      the uterus not otherwise specified (NOS) in the city of Sao Paulo from 1980 to
      1999. Results showed a slight reduction in cervical cancer rates, a decrease in
      NOS uterine cancer rates, and an increase in endometrial cancer mortality rates.
      The fall in mortality from NOS uterine cancer indicates an improvement in
      diagnostic accuracy and quality of information on death certificates and may
      point to an increase in coverage of cervical cancer screening using the Pap
      smear.

PMID- 15029315
TI  - [Association of the DMFT index with socioeconomic and dental services indicators
      in the state of Parana, Brazil].
AB  - This ecological study investigated the associations between dental caries,
      socioeconomic indicators, and the supply of dental services in the State of
      Parana, Brazil, for the year 1996. Two types of information were collected: (1)
      data on caries prevalence (DMFT at 12 years) for the municipalities (or counties)
      in the State; (2) data on socioeconomic conditions and the supply of dental
      services. Based on simple linear regression analysis, the study demonstrated a
      significant correlation between the caries index in municipalities and various
      social and dental services supply indicators. Results of the analysis of multiple
      linear regression showed that one indicator of income inequality remained
      significantly associated with dental caries, demonstrating that the worst oral
      health conditions cannot be dissociated from income disparities. A significant
      negative correlation was observed between DMFT and the proportion of the
      population that received fluoridated water, principally in the municipalities
      with the worst income inequality indicators. This highlights the importance of
      fluoridation for the reduction of caries rates, as well as to attenuate the
      impact of socioeconomic inequalities on the prevalence of dental caries.

PMID- 15029316
TI  - Prevalence of cervical intraepithelial neoplasia and invasive carcinoma based on
      cytological screening in the region of Campinas, Sao Paulo, Brazil.
AB  - This study aimed to estimate and analyze the prevalence of cervical
      intraepithelial neoplasia (CIN) and invasive cervical carcinoma based on
      cytological diagnosis. The study included 120,635 women undergoing cytological
      exams in public health services in the region of Campinas, Sao Paulo State,
      Brazil, between September 1998 and March 1999. Prevalence rates per 100,000 women
      were: 354 for CIN I; 255 for CIN II; 141 for CIN III; and 24 for invasive
      carcinoma. As age increased, prevalence rates and prevalence ratios decreased for
      CIN grades I and II and increased for CIN III until the 50-54 age group,
      decreasing thereafter The prevalence rate of invasive carcinoma increased with
      age. The prevalence pattern of CIN II was distinct from that of CIN III, but
      similar to that of CIN I. This would not have been observed if the Bethesda
      System had been used for cytological diagnosis. Mean age at time of CIN II
      diagnosis was about 10 years less than for CIN III diagnosis. Therefore, a high
      grade lesion diagnosed in a young woman according to the Bethesda System would
      probably be a CIN II, whereas in an older woman it would probably be a CIN III.

PMID- 15029317
TI  - Cervical cancer in Iquitos, Peru: local realities to guide prevention planning.
AB  - Cervical cancer is a major public health problem in Latin America, and in much of
      the underdeveloped world. This issue has not historically been addressed as a
      health priority, but in recent years is receiving increased attention and
      funding. This ethnographic study on the experience of cervical cancer was
      conducted in Iquitos, Peru, between August 1998 and May 1999. Research
      methodologies included: (1) observation and household interviews to obtain
      background knowledge about the region, medical systems, and local cultural
      understanding of illness; (2) cancer experience interviews; and (3) case studies
      of women in various stages of cervical cancer or diagnosis. Findings are
      presented related to local knowledge and experience of Pap smears and cervical
      cancer and the ineffectiveness of a recently initiated cervical cancer screening
      program. The findings guide recommendations for interventions in the region in
      relation to: (1) needed changes in health education, (2) screening frequency and
      age, (3) sites for screening and treatment, (4) type and availability of
      treatment, (5) payment issues, (6) documentation of care, and (7) the potential
      of herbal remedies.

PMID- 15029318
TI  - [Rapid assessment of current infant feeding practices in Sao Jose do Rio Preto,
      Sao Paulo, Brazil].
AB  - This paper describes a rapid assessment of current infant feeding practices
      conducted during a mass immunization campaign in an urban area of Sao Jose do Rio
      Preto, Sao Paulo State, Brazil. Parents or guardians of all infants (<1 year)
      attending the 8 randomly-selected health centers were interviewed. Median
      duration of breastfeeding practices was estimated by probit analysis. Of the 719
      infants, 692 (96.2%) began breastfeeding, and only 63 (8.9%) were in exclusive
      breastfeeding. Median duration of total breastfeeding (exclusive plus partial)
      was 205.93 days. Infants born by cesarean section showed a higher risk of early
      weaning: OR (95%CI)=1.51 (1.09-2.09) after adjusting for confounding variables
      (mother's educational level, gestational age, birth weight, whether breastfed).
      Median duration of total breastfeeding was higher among infants born by vaginal
      delivery (227.38 days; 95%CI=195.19-271.16) as compared to cesarean section
      (192.84 days; 95%CI=128.23-273.34). Early introduction of weaning foods such as
      water/herbal tea and cow's milk was observed with a median age at introduction of
      30 days. These findings indicate the need to improve strategies by the public
      health services to promote exclusive breastfeeding.

PMID- 15029319
TI  - [Pesticide use and poisoning among farmers from the county of Paty do Alferes,
      Rio de Janeiro, Brazil].
AB  - This survey is part of a more comprehensive study on the health consequences of
      pesticide exposure. In the county (municipality) of Paty do Alferes, Rio de
      Janeiro State, Brazil, 55 agricultural workers were interviewed on the use of
      pesticides, use of personal protective equipment, data on health status, and
      symptoms related to pesticide exposure, disposal of agrochemical containers, and
      technical assistance. The most widely used pesticides were insecticides such as
      abamectin, organophosphate compounds, and pyrethroids, and fungicides such as
      mancozeb, chlorothalonil, and copper products. As a rule, pesticides are handled
      carelessly, and 92% of workers involved in the mixing, loading, and spraying of
      insecticides and fungicides used no protective clothing or equipment whatsoever.
      Some 62% of workers reported at least one illness associated with mixing or
      spraying pesticides. The most frequently reported symptoms were headache, nausea,
      vomiting, dizziness, skin irritation, and blurred vision, and 21% of affected
      workers required medical care. In more than half (51%) of the cases, workers
      reported using organophosphate insecticides from toxicological class I when they
      felt sick.

PMID- 15029320
TI  - [Labor and health conditions of private school teachers in Vitoria da Conquista,
      Bahia, Brazil].
AB  - The scientific literature on teachers' health is scarce, recent, and focuses
      predominantly on stress and burnout. This study describes the labor conditions of
      private school teachers in Vitoria da Conquista, Bahia State, Brazil. Information
      on 250 teachers from the ten largest schools in the municipality was collected
      through a self-applied questionnaire. The most relevant characteristics of
      teachers' work, evaluated by the Job Content Questionnaire were: speed of work,
      creativity at work, and relations with colleagues. The most frequent complaints
      related to posture, mental strain, and voice problems. Prevalence of minor
      psychological disorders according to the Self Reporting Questionnaire-20 was
      41.5%, strongly associated with long periods of intense concentration on the same
      job and excessive work. Results suggest an association between the prevalence of
      minor psychological disorders and certain characteristics of teaching work,
      emphasizing teachers' exposure to stress.

PMID- 15029321
TI  - [Community health agent program: perception by patients and health service
      workers].
AB  - Two basic premises of Brazil's Community Health Agents Program (PACS) are to
      value the family and community to which the program belongs and to encourage
      their participation in health promotion and disease prevention. This study
      focused on the work developed by PACS in Bauru, Sao Paulo State, as perceived by
      the community health agents and the families served by them. As the study's point
      of departure, 22 community health agents and 22 representatives of families were
      interviewed, randomly selected according to residential micro-areas. Two focus
      groups were formed according to the PACS to which the community agents and
      families belonged. Qualitative analysis of the answers demonstrated agreement
      between the perceptions by community health agents and the community in the two
      focus groups. However, the two focus groups differed from each other. Distinct
      realities were observed in the two communities, thereby orienting new program
      actions and handling of local difficulties.

PMID- 15029322
TI  - [Knowledge and perceptions of physical exercise in an adult urban population in
      Southern Brazil].
AB  - This study evaluates perception and knowledge of physical exercise in an urban
      adult population and relates knowledge level to behavioral, demographic, and
      socioeconomic factors, using a cross-sectional, population-based approach with
      3,182 participants aged 20 or older. The questionnaire originated a score (range
      0-25 points). Mean score for the sample was 17.1 (SD=4.0). After adjustment,
      female gender, age 30 to 40 years, higher social strata, and schooling were
      strongly associated (p<0.001) with the outcome (knowledge). Weaker associations
      (p< or =0.01) were observed between the score and higher body mass index, level
      of physical activity, and white skin color. Based on the results, specific
      benefits from exercising are still unknown to some population groups. Counseling
      by teachers on the advantages of an active lifestyle is still not common
      practice.

PMID- 15029323
TI  - [Free informed consent: the experience of Brazilian researchers in the area of
      fertility regulation].
AB  - This study aimed to evaluate the experience of Brazilian researchers in relation
      to: assessment of the research protocol by a research ethics committee with the
      elaboration of a free informed term of consent (FITC) and the process of
      obtaining consent, as well as to verify whether the content and wording of the
      term of consent complies with Federal Ruling 196/96. Thirty-four researchers
      filled out a questionnaire and returned it by electronic mail. The vast majority
      of the respondents (91%) reported that the respective study protocol had been
      evaluated by a research ethics committee. More than half reported that they had
      received a previously prepared FITC; that consent from potential study subjects
      had been obtained by the researcher in charge; and that the subjects had received
      a copy of their signed FITC. Approximately one half of participants stated that
      the form of reimbursement of subjects was specified in the FITC, and 44% reported
      the same in relation to occasional damages resulting from the study. According to
      participants, in general the provisions of Ruling 196/96 had been met.

PMID- 15029324
TI  - [Environment risk prevention programs and occupational health monitoring
      programs: audits, labor inspection, and social control].
AB  - The authors analyzed environmental risk prevention programs and occupational
      health monitoring programs implemented by 30 companies from various industrial
      sectors, each with more than 100 employees, in Salvador, Bahia, Brazil. Observed
      inconsistencies were studied according to occupational risk, considering the
      different stages of development in the programs. The study suggested low
      technical quality in these programs, revealing the need to increase the range of
      government inspection and to stimulate worker and trade union participation in
      such programs. The development and improvement of inspection procedures,
      instruments, and protocols were also considered fundamentally important for
      health and safety in the workplace.

PMID- 15029325
TI  - [Prevalence of overweight and obesity in public school pupils according to three
      anthropometric diagnostic criteria].
AB  - To compare the prevalence of child obesity according to three criteria, a cross
      sectional study was performed with 6-to-11-year-old children in eight elementary
      public schools in the city of Sao Paulo. Z scores for weight-for-height (W/H) and
      body mass index (BMI) were calculated from the weight and height variables.
      Prevalence rates for overweight in males, according to Must, Cole, and WHO
      criteria, were 10.92%, 10.29%, and 11.94%, respectively, and for obesity 8.17%,
      13.67%, and 10.29%. For females, prevalence rates for overweight according to
      Must, Cole, and WHO criteria were 13.51%, 13.83%, and 13.67%, respectively, and
      for obesity 8.25%, 16.50%, and 11.73%. The study analyzes the variations in
      obesity estimates based on different criteria, highlighting the need for clinical
      and population studies to support the development of a single criterion. Such
      studies, in addition to identifying individuals with a higher probability of
      excess body fat, could also correlate body fat to risk of illness and death
      (similar to the 25 and 30 BMI cutoff points in adults).

PMID- 15029326
TI  - [Comparative analysis of cause-specific mortality for dentists in the city of Sao
      Paulo].
AB  - The present study describes cause-specific mortality among dentists living in the
      city of Sao Paulo, Brazil, from 1980 to 2000, in search of possible indications
      of work-attributable risk. Official mortality information was supplied by the
      State Data Analysis System. Comparative analysis used analogous information for
      physicians and engineers. Analysis of death distribution according to underlying
      causes indicated the absence of significant differences that might suggest
      increased risk of death for dentists as compared to physicians and engineers.
      Dentists' deaths did not present worse indications for global and specific
      categories of infectious diseases, neoplasms, suicide, or central nervous system
      or circulatory diseases. A systematic excess mortality caused by injuries was
      observed for engineers, especially in traffic-related accidents, accidental
      falls, and other accidents. We observed the absence of significant discrepancies
      indicating work-attributable risk for dentists. This observation suggests that
      dentistry can be considered a safe profession, at least regarding exposure to
      systematic risk of death.

PMID- 15029327
TI  - [Association of stressful life events and psychological distress: a community
      based study].
AB  - A cross-sectional study was conducted in 1999 to investigate the association
      between stressful psychosocial events and psychological distress. A Faces Scale
      was used to measure the outcome. Death and illness in the family, divorce,
      robbery, injury, migration, and loss of employment in the previous year were
      investigated through interviews with 3,942 individuals over 20 years. Logistic
      regression followed a hierarchical model using socio-demographic characteristics
      at the first level; psychosocial events at the second; and psychological distress
      at the third. Injury and migration were not associated with the outcome. The
      strongest effect was associated with divorce (adjusted OR=2.34). The highest
      population-attributable risks were from socioeconomic variables (education 38.2%;
      family income, 32.3%) and the occurrence of at least one event (36.4%). Public
      policies aimed at ameliorating adverse social factors such as loss of employment
      and crime, as well as social support to help individuals manage stressful life
      events are likely to improve psychological well-being.

PMID- 15029328
TI  - [Quality of diagnosis of canine visceral leishmaniasis in epidemiological
      surveys: an epidemic in Belo Horizonte, Minas Gerais, Brazil, 1993-1997].
AB  - In Brazil, visceral leishmaniasis poses a serious endemic and epidemic problem.
      In recent years the disease has spread to several States that had not previously
      reported any human or animal cases. For canine surveys, the Ministry of Health
      currently recommends use of the indirect immunofluorescence assay (IIF), with a
      sensitivity of 90-100% and specificity of 80%. Use of IIF may decrease the
      effectiveness of the Kala Azar Control Program by not detecting, and thus failing
      to sacrifice, false-negative infected animals. On the other hand, the program
      incorrectly identifies and leads to the unwarranted sacrifice of false-positive
      uninfected animals. Such uncertainties have already led to disagreement over the
      Program's objectives, such as the recommendation by some veterinarians that
      infected animals be treated. This work analyzes the quality of diagnosis of
      canine epidemic surveys against the backdrop of a visceral leishmaniasis epidemic
      in Belo Horizonte, Minas Gerais State, from 1993 to 1997.

PMID- 15029329
TI  - [Hemoglobin concentration in children from birth to one year of age].
AB  - This study aimed to describe the evolution of hemoglobin concentration
      considering the following factors: birth weight, growth rate, and food intake.
      The cross-sectional study focused on infants (<1 year of age) whose growth and
      development were monitored by public health services in cities located in the
      five geographic regions of Brazil. Some 51.7% of the children aged 6 to 12 months
      presented anemia. Estimation of [Hb] concentration by a theoretical equation
      suggested that endogenous iron is able to maintain normal Hb levels in the first
      three months of life. Prevalence of reduced Hb was higher in low birth weight
      infants. Growth rate, verified by the difference between present weight and birth
      weight in Z scores, was not the relevant factor for hemoglobin concentration. The
      relevance of breastfeeding was evident in the initial months of life. However,
      complementary foods did not influence infant Hb concentration. The high
      prevalence of low Hb levels calls attention to the need for programs to control
      anemia.

PMID- 15029331
TI  - [Sexually transmitted diseases and gender: a cross-sectional study with
      adolescents in Rio de Janeiro].
AB  - Sexually transmitted diseases (STDs) are frequent in adolescence and contribute
      to the increase in the number of AIDS cases. Early sexual initiation, multiple
      sex partners, and lack of condom use are considered risk factors and are
      influenced by a male-dominated gender system. We interviewed 356 adolescent
      patients at the Adolescent Health Research Center in Rio de Janeiro State
      University to identify possible STD risk factors in adolescence. Young men
      reported more partners and early sexual initiation. Females used condoms less
      frequently and were more subject to sexual abuse. The results confirm a model
      sustained by traditional gender values that demarcate the male and female
      spheres, with male supremacy. We conclude that to achieve more effective STD
      control, it is necessary to expand the discussion on culturally constructed
      patterns of masculinity and femininity.

PMID- 15029330
TI  - [Impact of participatory education on body mass index and blood glucose in obese
      type-2 diabetics].
AB  - Exogenous obesity increases morbidity and mortality risk and has been associated
      with nutritional habits, which in turn can be affected by health education.
      Health education aims to promote patient participation in achieving behavior
      change and healthy lifestyles. The objective of this study is to show the
      advantages of participatory education in the modification of body mass index
      (BMI) in obese type-2 diabetics. A quasi-experimental study was performed with
      random allocation of two patient groups. The educational intervention was
      organized through a reflection-action process. BMI was measured at baseline and
      then monthly for 9 months during the intervention. The groups were analyzed by
      age and sex. Statistical analysis used the Student t test, with the mean
      difference for related groups. The control group showed a mean BMI of 33.89 +
      1.96 and a final BMI of 33.2 +/- 2.15 (t:22.4; p:0.16). The experimental group
      had an initial value of 33.63 +/- 2.12 and a final BMI of 31.54 +/- 1.71;
      statistical difference: (t:11.55; p:0.003). The participatory educational
      intervention thus helped improve the BMI in obese type-2 diabetics.

PMID- 15029332
TI  - Ecology of Anopheline (Diptera, Culicidae), malaria vectors around the Serra da
      Mesa Reservoir, State of Goias, Brazil. 1--Frequency and climatic factors.
AB  - The ecology of anopheline species (Diptera, Culicidae) was studied in the
      vicinity of the Serra da Mesa Reservoir, State of Goias, Brazil. Climatic factors
      and frequency of anopheline populations were analyzed. Bimonthly human-bait and
      Shannon trap captures were conducted for 36 consecutive months (January 1997
      through December 1999). A total of 5,205 adult anophelines belonging to five
      species were collected. Anopheles darlingi was the most frequently collected
      anopheline (61.4%), followed by An. albitarsis s.l. (35.4%), An. triannulatus.
      (2.5%), An. oswaldoi (0.4%), and An. evansae (0.2%). The water level and
      vegetation along the banks of the reservoir were crucial to the frequency of the
      various anopheline species. Climatic factors had a secondary influence. The
      reservoir's water-level stability, increased frequency of An. darlingi, and the
      arrival of gold prospectors were responsible for the increase in malaria cases.

PMID- 15029334
TI  - [Air pollution and mortality in the elderly in Rio de Janeiro: a time-series
      analysis].
AB  - This study investigates the association between particulate air pollution and
      mortality from cardiovascular and respiratory diseases among the elderly in the
      city of Rio de Janeiro. Death counts, levels of total suspended particles (TSP),
      and meteorological data were obtained from secondary databases. Daily counts of
      deaths and daily TSP levels from 1990 to 1993 were analyzed in Poisson regression
      models adjusted for long-term temporal trends, seasonality, weekdays,
      temperature, and humidity. For an increase in TSP levels from the 10th to the
      90th percentile (104.7 microg/m3), the relative risks for mortality in elderly
      people from cardiovascular and respiratory diseases were 1.04 (95%CI: 0.96-1.13)
      and 1.10 (95%CI: 0.97-1.26) respectively. Although an upward trend in risk was
      observed, the associations were not statistically significant, which could be
      explained partially by the small number of pollution measures available for the
      period analyzed.

PMID- 15029333
TI  - [Waste of medical tests in preoperative evaluation for cataract surgery].
AB  - The objective of this clinical trial was to determine the frequency of medical
      tests considered unnecessary in routine preoperative evaluation for cataract
      surgery. Unnecessary costs with these tests were also evaluated. For patients
      assigned to the selective testing group, it was requested that no preoperative
      testing be performed unless the patient presented a new or worsening medical
      problem warranting medical evaluation with testing. For patients assigned to the
      routine testing group, three tests were requested: a 12-lead electrocardiogram,
      complete blood count, and serum glucose level. The costs of tests considered
      unnecessary were calculated. The sample of 1,025 patients consisted of 512
      assigned to the routine testing group and 513 to the selective testing group.
      Cumulative rate of medical events was similar in the two groups (p=0.923). The
      selective group underwent 60.7% fewer tests. The results suggest that selective
      preoperative testing in cataract surgery does not harm patients in terms of peri
      operative clinical complications and also represents a significant cost reduction
      compared to routine testing.

PMID- 15029335
TI  - Prevention of HIV infection among migrant population groups in Northeast Brazil.
AB  - HIV infection is spreading among the poor, women, and migrant communities in the
      interior of Northeast Brazil. The research focused on different configurations,
      beliefs, representations, and forms of social organization of behavior thought to
      be associated with the population's capacity to efficiently follow AIDS
      prevention measures. Participants located in neighborhoods known for having large
      migrant populations were identified by Family Health Program Workers in Fortaleza
      and Teresina. The study adopted a qualitative methodology. Several belief-system
      concepts and values, as well as the social organization of sexuality revealed in
      the study, represent obstacles both to AIDS prevention and condom use. Hunger,
      lack of prospects, and fear are associated with a social situation of poverty,
      exclusion, prejudice, and total absence of basic human rights. When examined
      together, these elements define different configurations in the migrants'
      increased vulnerability to HIV/AIDS. The groups' increased vulnerability relates
      to the socioeconomic complexity that must be considered in HIV/AIDS control and
      prevention programs.

PMID- 15029336
TI  - [Committees for the prevention of infant mortality in the State of Parana,
      Brazil: implementation and operation].
AB  - This article reports on the implementation and operation of committees for the
      prevention of infant mortality in the State of Parana, Brazil, with the
      operational strategies, formation, and relations at three levels: State,
      regional, and municipal. To implement the committees it was necessary to train
      professionals to investigate infant deaths. In two years the committees analyzed
      50% of the infant deaths occurring in the State. The goal is to increase the
      number of cases analyzed and to continue to monitor the committees' work, seeking
      improved performance, agility, and data quality.

PMID- 15029337
TI  - [Influence of anthropic habits in the dispersion of Triatoma pseudomaculata
      Correa & Espinola, 1964 through Mimosa tenuiflora (Willdenow) (Mimosaceae) in the
      State of Ceara, Brazil].
AB  - Triatoma pseudomaculata was captured in the phloem of the black acacia bush
      (Mimosa tenuiflora) in seven municipalities in the State of Ceara, Brazil. This
      bush is widespread in the caatinga (scrub forest) and is used extensively by the
      rural population for kindling. Peridomiciliary presence of triatomines in the
      Cariri region may be associated with the use of infested M. tenuiflora wood by
      the population, thus facilitating the triatomines' mobilization and dispersion.

PMID- 15029339
TI  - Gender, sexuality, and reproductive health: the establishment of a new field in
      Public Health.

PMID- 15029340
TI  - [The construction of sexual difference in medicine].
AB  - This article discusses the work of some key players in the current debate on the
      construction of the notion of sexual difference in modernity, taking as the focus
      of analysis and illustration the theses submitted at the School of Medicine in
      Rio de Janeiro, Brazil, during the 19th century. The objective is to confront the
      argument that the difference between the sexes comes to be taken for granted and
      considered immutable by science. This emphasis on a natural difference between
      the sexes is related to transformations that occurred beginning in the late 18th
      century (growing industrialization and urbanization, more extensive participation
      by women in the labor market, the emergence of women's rights movements) that
      required changes in the established gender relations. Still, it is precisely
      through the attempts to prove that the difference was natural that one perceives
      how unstable and threatening it was. Interventions such as women's education and
      labor market participation were capable of altering and even "subverting" the
      difference. Thus, "natural" was not synonymous with definitive or guaranteed.

PMID- 15029342
TI  - [Sexual partners and practices of young homosexuals in Rio de Janeiro].
AB  - This article focuses on the organization of the erotic lives of young men who
      engage in homosexual practices. The reflections presented here are based on
      ethnographic research including observation in places of homosociability and
      interviews with young men in Rio de Janeiro reporting homosexual practices. By
      presenting erotic scenes pertaining to a homoerotic circuit and recording the
      sexual trajectories of young men engaging in homosexual practices, the article
      seeks to identify the implications of the observed erotic scripts and sex-partner
      patterns for the sexual health of these individuals. The text calls special
      attention to reports concerning the emergence of different forms of erotic
      interaction in childhood, as well as cross-age and crossgenerational partnerships
      that extend into adulthood, with a growing trend toward seeking younger partners
      as the young men themselves grow older. The article suggests that such phenomena
      require a more in-depth understanding, since they have serious implications for
      planning sexual health measures for young men (and boys) who engage in homosexual
      practices.

PMID- 15029341
TI  - [Knowledge and risk perception of HIV/AIDS: a profile of the Brazilian people in
      1998].
AB  - This paper focuses on cognitive aspects related to HIV/AIDS by presenting
      distinct subgroups of the Brazilian population. Four subgroups were created
      according to their different levels of knowledge regarding HIV/AIDS and risk
      perception: subgroup 1 (no awareness and no risk perception); subgroup 2 (no
      awareness, with some risk perception); subgroup 3 (some awareness and no risk
      perception); and subgroup 4 (some awareness and some risk perception). The data
      come from the National Survey on Sexual Behavior and HIV/AIDS Risk Perception in
      the Brazilian Population, conducted by CEBRAP (the Brazilian Analysis and
      Planning Agency) together with the Ministry of Health, in 1998. The study
      highlights that in 1998, slightly over half of the Brazilian population were
      minimally aware of HIV transmission processes. Analysis of demographic and
      socioeconomic characteristics associated with protective behavior against
      HIV/AIDS showed that approximately 23% of the study population belonged to
      subgroup 1 - with no awareness and no risk perception - and were thus highly
      vulnerable to infection.

PMID- 15029343
TI  - [Kangaroo Mother Care: the role of health care services and family networks in a
      successful program].
AB  - Kangaroo Mother Care (KMC) provides many benefits to low birth-weight babies. The
      family's early and active participation in the care of these infants helps create
      and strengthen bonding. This study was intended to increase the knowledge on the
      effect of hospital and family conditions on the method's implementation. Fourteen
      women and seven men taking part in KMC in the Itapecerica da Serra General
      Hospital (Sao Paulo State) answered in-depth interviews. The respondents'
      statements are focused on the decision-making process in the method's
      implementation, which depends not only on the mother's desire and willingness,
      but also on the support provided by the family network and empathetic health care
      teams. Although mothers realize the importance of KMC for their infants'
      recovery, personal and family problems may prevent them from taking active part
      in the program. Interaction of such factors as history of perinatal death,
      presence of other children in the household, involvement of the father and other
      family members, and household management can establish patterns that may or may
      not be favorable when choosing and implementing KMC.

PMID- 15029345
TI  - [Women, family, and reproductive health: a case study on family planning on the
      outskirts of Recife, Pernambuco, Brazil].
AB  - This paper presents the results of a study on women from a low-income community
      in Recife, Pernambuco State, Brazil, focusing on how the women practice their
      family planning. The study is based on an analysis of reproductive practices by
      these women, specifically related to conception and contraception. The paper
      argues that the family planning care provided to these women involves a so-called
      "low-profile interventionist" policy, meaning that decisions concerning the
      number and spacing of children is shifted from the family domain to that of
      attending physicians, with a gradual transfer of control from the public sector
      to the health field.

PMID- 15029344
TI  - [Women's health in violent situations: municipal administrative roles and
      decision-making in the Brazilian public health system].
AB  - The aim of this study was to investigate the role of health management staff
      concerning the health of women facing violent situations and the impact these
      roles have on decisions concerning health measures targeting these women. The
      study employed a qualitative, descriptive methodology including 18 health
      management staff members from three municipalities classified as having fully
      autonomous municipal management systems under the Unified National Health System
      (SUS) in Greater Metropolitan Recife, Pernambuco State, Brazil. Staff members
      were divided into three distinct groups according to their opinions on women in
      violent situations and women's health interventions. However, the three groups
      were convergent with respect to their roles in determining decisions on health
      actions for these women. The health management staff's commitment to the feminist
      movement proved to be the most relevant factor. Common issues among staff
      members, such as the problem of public health and quality of living, or more
      technically, the cost-benefit issue, did appear as key arguments.

PMID- 15029346
TI  - [Violence against woman: clients of emergency care units in Salvador].
AB  - This article discusses research on violence against women treated at an emergency
      care hospital in Salvador, Bahia, Brazil. A total of 701 interviews were
      conducted in a cluster sample of women ages 15 to 49 years, of whom 321 reported
      some episode of physical, sexual, and/or psychological violence. Although
      violence against the women in this sample was not associated with
      social/demographic characteristics, most cases of violence occurred in the
      domestic environment. Among women reporting physical violence, there were more
      cases of mental and behavioral disorders, problems resulting from external
      causes, genitourinary tract diseases, and ill-defined causes. The article
      concludes that health services need professionals who are prepared to treat these
      women, who often come to emergency care units to relieve their pain and suffering
      but fail to find a concrete response to their real needs.

PMID- 15029347
TI  - [Pedophile, who are you? A study of pedophilia in the press].
AB  - This paper define the characteristics of pedophilia as it appears in the
      Brazilian newspaper Folha de Sao Paulo, including both the characteristics of the
      pedophile and the reasons given for such behavior. The research employs a
      technique called analysis by opposition which means that news coverage on other
      forms of sexual violence against children (sexual abuse, child pornography, rape,
      and incest) is used to help shed light on the characteristics of pedophilia
      itself. Some 384 articles were analyzed, of which 114 referred to pedophilia, all
      published between 1994 and 1999. News on sexual abuse of children was biased by
      concepts of class and violence/illness, reiterating the lay view that violence
      can be either a result of barbarianism and poverty or of psychological disorder,
      both depending on the aggressor's social class. The theoretical perspective
      adopted, that there is a correlation between media and reality, indicates that
      this bias is shared by Brazilian society as a whole.

PMID- 15029348
TI  - [Teenage contraception and pregnancy from the perspective of young low-income
      fathers in a slum area in Rio de Janeiro].
AB  - The study focuses on how teenage fatherhood affects the life histories of young
      low-income males. Field work included individual interviews of young fathers
      living in a shantytown in Rio de Janeiro city. The argument is that an approach
      from the male standpoint affords access to other levels in a web of meanings and
      relations that refer back to the logic of contraception, the formation of
      couples, and active fatherhood. The argument also highlights the links between
      type of relationship and partnership, use and non-use of contraceptive methods,
      and the meanings of fatherhood for young low-income males. It highlights that
      entering actively into fatherhood helps boys consolidate their image as "mature",
      "responsible", "adult" men.

PMID- 15029349
TI  - [Evaluation of procedures for identifying maternal deaths].
AB  - The main problems identified during maternal mortality surveillance in Pernambuco
      State, Brazil, were low coverage and poor quality of data, as well as the
      inadequacy of data-collection instruments. Based on these findings, a new
      instrument called the Confidential Form for Reporting Deaths of Reproductive-Age
      Women was developed, and later an evaluation was conducted on the available
      procedures for distinguishing maternal deaths among female deaths. The RAMOS
      method, using the new questionnaire, was applied in Camaragibe (a city in Greater
      Metropolitan Recife) based on the female deaths recorded in 2000. According to
      the results, this method, using the new form, showed improved recording of socio
      demographic and female mortality variables as compared to both the maternal
      mortality surveillance conducted by the Municipal Epidemiological Department and
      the death certificate system. This finding reinforces the need to improve
      maternal mortality surveillance in the study area, taking into account the RAMOS
      method and the new instrument.

PMID- 15029350
TI  - [Coverage and factors involved in submitting to the Papanicolaou test in the
      Municipality of Sao Paulo].
AB  - This study estimated Pap smear coverage (at least one test in the lifetime and
      one in the last three years) among women aged 15 to 49 years old. The study also
      discusses whether the women received the results of their last test, as well as
      self-reported reasons for and against submitting to the test. A population-based
      survey was conducted in the city of Sao Paulo in 2000 with a randomly selected
      representative sample of 1,172 women. Among the women who were already sexually
      active (n = 1,050), 86.1% reported having had at least one Pap smear during their
      lifetime, and 77.3% had undergone the test in the previous 3 years. Among those
      who reported having had at least one Pap smear, 87.0% had received the result of
      the last test. The main reasons reported for having had the last test were:
      spontaneous demand (55.5%), medical referral (25%), and gynecological complaints
      (18.2%). The main reasons for never having had a Pap test were: no gynecological
      problems, embarrassment or fear, and difficulties in accessing health services.
      Despite high coverage of the Pap test and the fact that the majority of the women
      had self-reported a spontaneous demand, use of the Pap test was less prevalent
      among women with the lowest socioeconomic level (and consequently at greater risk
      of cervical cancer).

PMID- 15029351
TI  - [Reproductive demands and health care for people living with HIV/AIDS: limits and
      possibilities within the context of specialized health services].
AB  - This qualitative study discusses how professionals in specialized health care
      services in the city of Sao Paulo have responded to the reproductive demands of
      people living with HIV/AIDS. Participant observation was the main methodological
      strategy; the concept of health demands was an important theoretical reference in
      the analysis. According to the health professionals, reproductive health demands
      were raised exclusively by women and related to mother-to-child HIV transmission.
      Reproductive issues were not recognized as patients  needs, nor were they
      included among the objectives of collective staff work. Distinct technical,
      ethical, and moral rationalities were observed. Among health professionals, to
      control the epidemic was the prevailing logic, while among patients, exercising
      lifestyle choice was the key issue, materialized in the "unexpected advent of
      pregnancy". In order to formulate health care strategies that respect human
      rights and reduce the risks of HIV transmission, it is necessary to recognize the
      autonomy of people living with HIV/AIDS in relation to reproductive decisions.

PMID- 15029352
TI  - [Gender and leisure-time physical activity].
AB  - This article discusses the relationship between gender and the social
      construction of the body, specifically focusing on physical exercise during
      leisure time. The Pro-Saude Project is a prospective study consisting of 4,030
      employees of a university in Rio de Janeiro, in which we analyzed the answers on
      leisure-time physical activity (LTPA) by 3,740 participants. The results show a
      prevalence of males in LTPA. Age, schooling, and per capita family income were
      directly associated with exercise among women, as compared to per capita family
      among men. Men were more frequently involved in group sports and physical
      activities that required more strength than women, including football, tennis,
      volleyball, martial arts, jogging, and weight lifting. Women performed more
      individual physical activities and those demanding less strength, like walking,
      dance, gymnastics, and hydrogym. The results suggest that LTPA is a domain of
      daily life that is organized according to certain conventions, amongst which
      gender-related conceptions concerning the ideal body, where men and women display
      distinct behaviors in relation to physical exercise.

PMID- 15029353
TI  - ["Be someone in life": a socio-anthropological analysis of adolescent pregnancy
      and motherhood in Belem, Para State, Brazil].
AB  - Focused on a group of low-income youth in Belem, Para State, Brazil, this study
      discusses the issue of adolescent pregnancy and motherhood from a socio
      anthropological perspective. Aimed at an understanding of the cultural meanings
      of this event in this context, the study suggests that for adolescent girls, it
      does not mean a break with life projects. On the contrary, pregnancy and
      motherhood are valued to the extent that they produce changes in social status
      for the girls, in terms of affirmation of projects for social mobility in the
      future, thus justifying the continuity of studies in the face of difficulties
      imposed by the situation.

PMID- 15029354
TI  - ["Sex-daring games": sexuality and gender socialization in the working-class
      children's universe].
AB  - This article focuses on the socialization of children and youth with respect to
      gender and sexuality, from a socio-anthropological perspective. The work is based
      on ethnographic research in a group of 5-14-year-old boys and girls in a
      community in Baia de Todos os Santos, Bahia, Brazil. Despite the strong influence
      of family and school in primary socialization, the children reproduced and re
      elaborated norms and practices on appropriate gender and sexual conduct,
      especially among their peers, and primarily in the context of play. The research
      analyzes the children s representations and practices in this socializing
      process, showing how gender and sexuality are socially constructed according to
      the contexts in which the different social interactions take place.

PMID- 15029355
TI  - [Breastfeeding experiences in a group of women: the limits of "the body for the
      child" and "the body for oneself"].
AB  - This study aims to understand the meanings ascribed by a group of women from
      Ribeirao Preto, Sao Paulo State, to their experiences with breastfeeding in
      relation to the sensations and manifestations in their own bodies as well as
      those they perceive in their children. The phenomenon was viewed as integrated
      with value systems related to motherhood and the body. The research methodology
      was qualitative. Participants included twenty primiparous women who had given
      birth less than 30 days previously who came to primary health care clinics due to
      various complaints. The analysis of interviews and observations was based on the
      thematic modality of content analysis. For these women, breastfeeding means to be
      a good mother and to give the best of oneself to the child. In breastfeeding
      practice, among limits and possibilities, they measure what they consider a
      "problem" based on the perceived manifestations in their own bodies and
      especially in those of their children. Their concerns are based on harm and
      danger to which they expose the child. Such experiences play out at the limits of
      being: the body for the child and the body for oneself, thereby establishing a
      sharp conflict between motherhood and individuality.

PMID- 15029356
TI  - [Female sterilization, AIDS, and medical culture in Sao Paulo and Porto Alegre,
      Brazil].
AB  - This paper explores the factors associated with reproductive choices by HIV
      positive pregnant women in two settings in Brazil, and particularly how health
      care providers and the local medical culture can affect these choices. Requesting
      and submitting to postpartum sterilization provide the focus of the analysis. The
      data come from a study conducted in prenatal care services in two cities, Sao
      Paulo and Porto Alegre. We employed two data collection strategies: collection of
      information from 427 patient records for HIV-positive women who had received
      prenatal care, and in-depth interviews with 60 women. While most women in both
      cities requested tubal ligation after delivery, a much higher proportion of women
      in Sao Paulo were actually sterilized, as compared to a tiny proportion of women
      in Porto Alegre. The local medical culture regarding sterilization and
      organization of prenatal care emerged as important factors for understanding the
      differences between the two cities.

PMID- 15029357
TI  - [Adolescence and reproduction in Brazil: the heterogeneity of social profiles].
AB  - This study aims to estimate the prevalence of adolescent pregnancy (AP) in three
      Brazilian cities Salvador, Rio de Janeiro, and Porto Alegre and to examine the
      profiles of pregnant girls and their partners in relation to pregnancy outcomes.
      Data for a retrospective assessment of AP were collected using an interview-based
      household survey applied to a stratified sample of males and females aged 18-24.
      A total of 4,634 individuals were interviewed (85.2 % of the eligible
      individuals). 21.4% of males and 29.5% of females aged 20-24 reported AP, but few
      such pregnancies had taken place before age 15 (0.6% and 1.6%). Pregnancy between
      adolescent partners was reported by 55.1% of males and 27.9% of females. 79.8% of
      the latter became pregnant while involved in a stable relationship with an older
      partner. AP levels varied inversely to schooling and income levels. 72.2% of
      females and 34.5% of males carried their first AP to completion, and more cases
      of induced abortion were reported by male partners in pregnancies (41.3%) than by
      females (15.3%). With the birth of the first child, 25.0% of women interrupted
      their studies temporarily and 17.3% definitively. However, 42.1% of primiparous
      mothers were already outside school before pregnancy.

PMID- 15029358
TI  - [Fathers' participation in childbirth at a public hospital: institutional
      difficulties and motivations of couples].
AB  - Participation by fathers in the process of childbirth, an aspect of the
      humanization of obstetric care, helps foster the fathers' involvement in raising
      their children. This participation provides psychosocial support for pregnant
      women during labor and delivery, sharing of the experience by the couple, and
      father-child bonding. The focus of this ethnographic research was the impact of
      this process on fathers participating in childbirth at a State hospital in Rio de
      Janeiro, with two stages: participant observation of labor and delivery and
      eleven interviews with fathers who had been present at delivery. Fathers'
      participation was influenced by: the motivation of mothers and fathers; social
      representations of delivery and fatherhood; and exclusion of fathers from
      reproductive health and pediatrics services. The father's participation was not
      valued by the attending staff as either a source of emotional support for the
      mother or as part of fatherhood. The following are necessary: inclusion of
      fathers in prenatal care, delivery, and pediatrics services; the training of
      staff to work with the families; social discussion of fatherhood and health
      services policies to ensure the presence of fathers during labor and childbirth.

PMID- 15029359
TI  - [Health professionals and legal abortion in Brazil: challenges, conflicts, and
      meanings].
AB  - This article discusses the roles of social workers, psychologists, nurses, and
      physicians concerning abortion and their participation in assisting legal
      abortion in Brazil for women victims of sexual violence. The working hypothesis
      was that many health professionals might oppose such programs on the grounds that
      they involve interruption of pregnancy. This qualitative study interviewed 12
      health professionals and two program managers in the State of Paraiba and the
      Federal District (Brasilia). The health professionals' representations of
      abortion ranged from a moralist and religious concept to the promotion of women's
      rights and autonomy. The health professionals faced obvious challenges in dealing
      with the abortion issue. Their experience in treating women had fostered changes
      in values and a reinterpretation of the meaning of their own practice.

PMID- 15029360
TI  - [Risk factors for hysterectomy among Brazilian women].
AB  - A case-control study was conducted to investigate risk factors for hysterectomy
      among women using the public health system in Northeast Brazil. The cases were
      373 women aged 30-54 years that had undergone elective hysterectomy for benign
      pelvic conditions. Controls were 742 women with preserved uterus selected from
      public health clinics. Data were collected through a review of medical records
      and a personal interview using a structured, pre-tested questionnaire.
      Unconditional multiple logistic regression was applied in the analysis. Women at
      greater risk for hysterectomy were those with a higher per capita family income,
      zero to three children, a history of medical consultation for menstrual problems,
      hospitalization for gynecological problems, or tubal ligation before age 30
      years. Menopause and a history of stillbirth appeared as protective factors in
      the statistical analysis.

PMID- 15029361
TI  - [The paradoxes of humanized childbirth care in a public maternity ward in
      Brazil].
AB  - The maternity ward of the University Hospital in Florianopolis, Santa Catarina,
      Brazil, attempts to follow World Health Organization guidelines for humanized
      childbirth care, including the encouragement of non-surgical delivery,
      breastfeeding, rooming-in, extended family visitation, and reduction of excessive
      technological intervention in the delivery process. The study focuses
      specifically on the choice of delivery procedure and on family presence during
      labor/childbirth, as well as women's experience with labor and breastfeeding.

PMID- 15029362
TI  - [Sexuality and STD/AIDS prevention: social representations by rural men in a
      county in the Zona da Mata region in Pernambuco, Brazil].
AB  - This study analyzes the concepts displayed by rural men in the Zona da Mata
      region in the State of Pernambuco, Brazil, concerning their sexual practices and
      STD/AIDS prevention. The study adopts a qualitative methodology, having
      interviewed 22 men According to the interviews, their first sexual intercourse is
      characterized as a learning experience and is sometimes marked by violence. They
      make a distinction between the "woman at home" and "street women"; they
      acknowledge women's sexual desire and value reciprocity in sexual relations,
      differentiating between the kinds of sex they have with different categories of
      women. Seven men report homoerotic experiences during adolescence, which they
      ascribe to immaturity, not affecting their heterosexual identity. Condom use,
      perceived in a negative light, is inconstant and irregular, inversely
      proportional to knowing the female partner. STDs in general inspire little fear,
      while AIDS is associated with death; the interviewees do not see themselves at
      risk of acquiring HIV. Ambiguities in the men's discourse, together with a
      basically ineffective approach by health services and preventive campaigns,
      reveal a high level of exposure to the risk of contracting STDs/AIDS among the
      interviewees and their female or male partners.

PMID- 15029363
TI  - [Reproductive rights of women and men in light of new legislation on voluntary
      sterilization in Brazil].
AB  - This paper aims to analyze the impacts and possible changes that the
      implementation of a new Brazilian family planning law has on reproductive
      practices, especially voluntary sterilization, and to determine whether men's and
      women's reproductive rights are being respected. The methodological approach is
      based on a six-month follow-up survey taken monthly, applied to a sample of 159
      individuals in six contextually different State capitals. Besides verifying
      whether the health sector is complying with the criteria set by the law, we
      analyze the waiting time between the request for sterilization and the surgery
      itself, utilizing survival analysis. We also conduct interviews with health
      professionals, shedding light on the procedures adopted in the practice of
      sterilization. For various reasons, the law has produced little change in the
      usual practice of sterilization, besides failing to satisfy individual
      reproductive rights.

PMID- 15029364
TI  - [Sexual culture, science, and politics: an interview with Richard Parker by
      Regina Maria Barbosa and , Estela Maria Leao de Aquino].

PMID- 15029365
TI  - [Sexual and reproductive rights: challenges for health policies].
AB  - This article discusses sexual and reproductive rights in the sense of a stance
      that assumes a perspective of transformations in social relations, the struggle
      against prejudices, the guarantee of well-being, and finally the relationship
      between sexuality, reproduction, and citizenship. The article then proceeds to
      reflect on health policy challenges in these fields, emphasizing such issues as:
      guaranteed resources, quality and quantity of health services in response to
      demands by the population, and cultural changes that produce a new view of the
      relationship between health professionals and health system clients, based on the
      principles of citizenship: recognition others as entitled to freedom and
      equality.

PMID- 15029367
TI  - Sex ratio and size structure of Micropogonias furnieri (Desmarest, 1823)
      (Perciformes, Sciaenidae) in Sepetiba Bay, Rio de Janeiro, Brazil.
AB  - Sex ratio and size structure constitute basic information in assessing
      reproductive potential and estimating stock size in fish populations. One hundred
      fifty-one individuals of Micropogonias furnieri caught by experimental otter
      trawls, in three zones (inner, central, and outer) of Sepetiba Bay between
      October 1998 and September 1999 were examined. Males outnumbered females
      (1.3:1.0) in all zones but no significant differences were detected. Only in the
      outer zone (5.0:1.0) were male/female rates significantly different according to
      the chi-square test. No temporal differences were observed in sex ratio. Fish
      size ranged from 81 to 244 mm total length (TL) with significant differences in
      155 to 185 mm TL size classes, where males predominated, and a slightly higher
      number of females were observed for the smaller size class (TL = 95-150 mm). Size
      distribution varied according to the zone, with juveniles predominating in the
      inner and adults in the outer zone. Spatial difference in size structure observed
      in this study indicates that the inner bay is a rearing ground during the first
      life-cycle period, and movement toward the sea occurs as fish increase in size.

PMID- 15029366
TI  - Ants visit nectaries of Epidendrum denticulatum (Orchidaceae) in a Brazilian
      rainforest: effects on herbivory and pollination.
AB  - Epidendrum denticulatum (Orchidaceae) produces nectar on the petioles of buds,
      flowers, and fruits (extrafloral nectaries) but no nectar is found on its
      flowers, and it is probably a deceptive species. In the Brazilian Atlantic
      rainforest, some aspects of both the ecology and behavior of Camponotus
      sericeiventris (Formicinae) and Ectatomma tuberculatum (Ponerinae), two ant
      species foraging on E. denticulatum extrafloral nectaries, were investigated.
      Both experiments, using termites as baits and field observations, suggest that
      these ant species are able to prevent reproductive organ herbivory, without
      affecting pollinator behaviour. Since a low fruit set is often cited as a
      characteristic of the family, especially for deceptive species, ants attracted to
      orchid inflorescences protect reproductive structures and increase the
      probability of pollination success. Epidendrum denticulatum flowers were visited
      and probably pollinated by Heliconius erato (Nymphalidae) and Euphyes leptosema
      (Hesperiidae).

PMID- 15029368
TI  - Age and growth of three Odontesthes species from Southern Brazil
      (Atherinopsidae), with reference to phylogenetic constraints in their life
      history.
AB  - The age and growth of three silverside species are described, and a discussion on
      possible phylogenetic constraints on life-history characteristics is presented.
      Samples were collected monthly between March 1992 and February 1993 in three
      freshwater coastal lakes. Standard length-total length (Ls-Lt) and weight-length
      (Wt-Lt) relationships studied showed interspecific differences in comparisons
      between juveniles and adults, males and females. Age was determined by scales.
      The three species presented a life-cycle duration of 4 to 5 years, with growth
      coefficients values (K) between 0.37 and 0.63, and asymptotic lengths between 211
      and 257 mm. Some interspecific differences may be useful for distinguishing
      between species (sexual and life-stage related patterns in Ls-Lt and Wt-Lt). The
      observed life-cycle ranges and maximum sizes were compared to those of other
      silversides and revealed a pattern coherent with available phylogenetic
      hypotheses at the supra-generic level, indicating that some life-history
      characteristics may be subject to phylogenetic constraints.

PMID- 15029369
TI  - Seasonal diet shifts of seven fish species in an Atlantic rainforest stream in
      Southeastern Brazil.
AB  - We analyzed the stomach contents of 116 individuals belonging to seven fishes
      species in order to investigate seasonal changes in feeding strategy and how
      trophic interactions between species affect community structure in an Atlantic
      rainforest stream in Southeastern Brazil. Oligosarcus hepsetus and Pimelodus sp.
      consumed fewer items during the winter. Phalloceros caudimaculatus switched
      feeding habits from detritus during summer to algae during winter. These examples
      are related to variations in food availability and species feeding selectivity.
      The highest diet overlap values, for most species, as measured using Schoener's
      index, were observed in summer, along with a species tendency to be more
      generalist. Feeding pattern variation may influence the fish community structure.

PMID- 15029370
TI  - Estimate of Alabama argillacea (Hubner) (Lepidoptera: Noctuidae) development with
      nonlinear models.
AB  - The objective of this work was to evaluate which nonlinear model [Davidson (1942,
      1944), Stinner et al. (1974), Sharpe & DeMichele (1977), and Lactin et al.
      (1995)] best describes the relationship between developmental rates of the
      different instars and stages of Alabama argillacea (Hubner) (Lepidoptera:
      Noctuidae), and temperature. A. argillacea larvae were fed with cotton leaves
      (Gossypium hirsutum L., race latifolium Hutch., cultivar CNPA 7H) at constant
      temperatures of 20, 23, 25, 28, 30, 33, and 35 masculine C; relative humidity of
      60 +/- 10%; and photoperiod of 14:10 L:D. Low R(2) values obtained with Davidson
      (0.0001 to 0.1179) and Stinner et al. (0.0099 to 0.8296) models indicated a poor
      fit of their data for A. argillacea. However, high R(2) values of Sharpe &
      DeMichele (0.9677 to 0.9997) and Lactin et al. (0.9684 to 0.9997) models
      indicated a better fit for estimating A. argillacea development.

PMID- 15029371
TI  - Pollen spectrum of honey produced in cerrado areas of Minas Gerais State
      (Brazil).
AB  - The pollen spectra of honey samples collected in five apiaries situated near
      cerrado areas in Minas Gerais State, Brazil, were studied from April 1996 to
      April 1998 in order to establish the contribution of different plant species in
      pollen or nectar production The honey samples were characterized by the following
      native species: Astronium sp., Alternanthera sp., Schinus sp., and Serjanea sp.
      The pollinic participation percentage of those species was related to the degree
      of preservation in the areas.

PMID- 15029373
TI  - Larval and pupal stage of Spodoptera frugiperda (J. E. Smith) (Lepidoptera:
      Noctuidae) in sweet and field corn genotypes.
AB  - Spodoptera frugiperda, the fall armyworm, is a very significant polyphagous pest
      due to the damages it causes, and control difficulties. Lack of information about
      its impact on sweet corn motivated a comparison of its biology, with respect to
      the larval and pupal stages, among the genotypes ELISA, BR 400 (sweet corns), and
      BR PAMPA (field corn). In laboratory conditions (25 +/- 1 masculine C; 70 +/- 10%
      RH; photophase 12 hours), 35 caterpillars were individualized and fed daily with
      3.14 cm(2) sections of corn leaves from the referred-to genotypes, cultivated in
      plots in the experimental area of the Departament of Fitossanidade, UFRGS, Porto
      Alegre, RS from October to November 2000. The caterpillars were weighed daily;
      after each molt, the cephalic capsules were collected and measured (in width), to
      establish growth rate; pupae were weighed and sexed when 24 hours old. The
      duration of the larval instars, the pupal sex ratio, and the mortality of larvae
      and pupae were evaluated. In the first three instars there were no differences
      registered in capsule width. In the fourth and fifth instars, capsules of
      caterpillars kept in BR 400 were smaller. The weight of caterpillars and pupae,
      instar duration and sex ratio did not differ among the genotypes. Pupal phase
      duration was less in females kept in BR 400. Mortality was greater in the larval
      phase in ELISA and in the pupal phase in BR PAMPA.

PMID- 15029372
TI  - Interaction between visiting bees (Hymenoptera, Apoidea) and flowers of Ludwigia
      elegans (Camb.) hara (Onagraceae) during the year in two different areas in Sao
      Paulo, Brazil.
AB  - This study was designed to characterize the interactions between Ludwigia elegans
      flowers and visiting bees during two years in two areas 200 km apart, at the same
      latitude (approximately 22 masculine 48'S) but at different altitudes (Aluminio,
      600 m, and Campos do Jordao, 1500 m), in the State of Sao Paulo, Brazil. As these
      flowers open simultaneously in the morning and lose their petals by sunset,
      interaction with bees occurs only during the photophase. Flowers of L. elegans
      were mainly visited by bees, the most frequent species being: Tetraglossula
      anthracina (Michener, 1989) (Colletidae), Rhophitulus sp. (Andrenidae), and
      Pseudagapostemon spp. (Halictidae), all considered specialized bees for
      collecting pollen and nectar from these flowers, as well as the generalist bee
      Apis mellifera Linnaeus, 1758 (Apidae). The specialist bees were temporally
      adjusted to the opening schedule of the flower, which occurs primarily in the
      morning, but shows a circannual variation. T. anthracina appears in both study
      areas, but only between December and April. The annual activity patterns of these
      specialist bees are synchronized to the phenology of L. elegans. Photoperiod and
      temperature cycles are suggested as the main synchronizers of both bees and
      plants.

PMID- 15029374
TI  - Ecological distribution of stream macroalgal communities from a drainage basin in
      the Serra da Canastra National Park, Minas Gerais, Southeastern Brazil.
AB  - Twelve stream segments were sampled four times in 1998-1999 (one sampling per
      season) in the drainage basin of the upper Sao Francisco River (19 masculine 45'
      21 masculine 25'S, 49 masculine 05'-51 masculine 30'W), situated in Serra da
      Canastra National Park, at altitudes ranging from 1,175 to 1,400 m. The
      macroalgae survey resulted in 30 species, with a predominance of Cyanophyta (12
      species = 40%) and Chlorophyta (11 species = 36.5%) and a lower proportion of
      Rhodophyta (seven species = 23.5%). Two species, Klebsormidium rivulare
      (Chlorophyta) and Kyliniella latvica (Rhodophyta), were new records for Brazil.
      Capsosira sp. and Stigonema sp. (Cyanophyta) and the "Chantransia" stage of
      Batrachospermum (Rhodophyta) were the most widespread macroalgae, occurring in
      six sampling sites, whereas 11 species were found at only one site. The
      proportion of macroalgal morphological types were as follows: mats (33%), free
      filaments (27%), gelatinous filaments (27%), crusts (7%), tufts (3%), and
      gelatinous colonies (3%). The flora revealed few species in common (4%-8%) with
      stream macroalgae from other Brazilian regions. The macroalgal communities proved
      to have species richness values close to the highest values reported in previous
      studies. The patterns typical for stream macroalgal communities (patchy
      distribution and dominance of few species) were also found in this basin.
      However, the stream variables most influential in macroalgal distribution in this
      study (rocky substratum, low pH, high COD, water color, and current velocity)
      were essentially the same that best describe the limnological characteristics of
      this lotic ecosystem. In addition, this combination of variables differed sharply
      from results of previous studies in other Brazilian stream ecosystems.

PMID- 15029376
TI  - Photoperiod influence on the biology and phenological characteristics of
      Dichelops melacanthus (Dallas, 1851) (Heteroptera: Pentatomidae).
AB  - The influence of the photoperiod on the biology and seasonal morphs of Dichelops
      melacanthus (Dallas, 1851) was studied in the laboratory. Four different
      photoperiods (11, 12, 13, and 14 hL = hours of light) were tested, keeping the
      temperature at 25 +/- 1 masculine C and the relative humidity at 65 +/- 5%. Nymph
      developmental time tended to be longer under shorter photophases (11 and 12 hL).
      The 14-hour photophase (long day) resulted in lower nymph mortality rates.
      Females maintained at 13 and 14 hL showed greater weight gain (1st-28th day) than
      females under 12 hL. D. melacanthus showed reproductive oligopause induced by
      short photophases, especially when exposed to 11 hL. Under 13 and 14 hL, 85% and
      65% of females oviposited, respectively, in comparison to 10% and 15% of females
      ovipositing under 11 and 12 hL, respectively. Fecundity (number of egg masses and
      number of eggs/female) was greater in the longer than under the shorter
      photophases. Seasonal dimorphism induced by photoperiod was observed in D.
      melacanthus adults. Under short-day conditions (11 and 12 hL), adults showed
      short and rounded shoulder spines, grayish brown abdomen (mainly in 11 hL), high
      lipid contents, and lower percentage of mature reproductive organs. Under long
      day conditions (13 and 14 hL), the stink bugs showed greatly developed shoulder
      spines, green abdomen, low lipid contents, and mature reproductive organs.

PMID- 15029375
TI  - Biological characteristics of Trichogramma maxacalii (Hymenoptera:
      Trichogrammatidae) on eggs of Anagasta kuehniella (Lepidoptera: Pyralidae).
AB  - Individuals of two populations of Trichogramma maxacalii (Hymenoptera:
      Trichogrammatidae) were collected from eggs of Euselasia apisaon (Lepidoptera:
      Riodinidae), a lepidopteran defoliator of Eucalyptus, in plantations in the
      states of Sao Paulo and Minas Gerais, Brazil. This study investigated the sex
      ratio, number of parasitoids per egg, and longevity of individuals of these two
      populations of T. maxacalii, when this parasitoid was reared receiving eggs of
      the factitious host Anagasta kuehniella (Lepidoptera: Pyralidae) in different
      periods after emergence, and with or without honey. Sex ratio of T. maxacalii
      varied from 0.44 to 0.60, and was affected by the interaction between
      populations, availability of food (honey), and length of time in which the
      parasitoid stayed without host eggs after their emergence. The population of T.
      maxacalii collected in Sao Paulo produced a larger number of individuals per egg
      of the host A. kuehniella and lived longer when fed.

PMID- 15029377
TI  - Ecological roles of natural products of the Brazilian red seaweed Laurencia
      obtusa.
AB  - Laboratory and field experiments were performed to assess the ecological roles of
      natural products produced by the Brazilian red seaweed Laurencia obtusa.
      Laboratory assays revealed that the natural concentration of the crude organic
      extract of L. obtusa significantly inhibited feeding by two herbivores: the crab
      Pachygrapsus transversus and the sea urchin Lytechinus variegatus. It was
      verified that this chemically defensive action was due to halogenated
      sesquiterpenoid elatol, found to be the major natural product of this red
      seaweed. In addition, it was verified that the antifouling property of the
      chemicals produced by L. obtusa could make this red alga less attractive for fish
      grazing. Direct protection against two herbivore species and indirect protection
      against herbivory by fouling inibition constitute evidence that the major natural
      product from Brazilian L. obtusa plays multiple environmental roles, thereby
      increasing the adaptive value of these metabolites. On the other hand, the
      evidence reinforces the idea that marine natural products may have different
      functions in the sea.

PMID- 15029379
TI  - Ultrastructure of the midgut endocrine cells in Melipona quadrifasciata
      anthidioides (Hymenoptera, Apidae).
AB  - In this study we describe the ultrastructure of the endocrine cells observed in
      the midgut of M. quadrifasciata anthidioides. This bee has two types of endocrine
      cells, which are numerous on the posterior midgut region. Cells of the closed
      type are smaller and have irregular secretory granules with lower electrondensity
      than those of the open cell type. The open cell type has elongated mitochondria
      mainly on the basal area, where most of the secretory granules are also found.
      Besides the secretion granules and mitochondria, endocrine cells in this species
      have well-developed autophagic vacuoles and Golgi complex elements.

PMID- 15029378
TI  - Financial comparisons of the artisanal fisheries in Urubupunga Complex in the
      middle Parana River (Brazil).
AB  - The main objective of this study was a bio-economic survey of artisanal fishing
      so as to compare average profit of the fishermen, in two different environments
      (reservoirs and river) and seasons (dry and rainy). To carry out financial
      comparisons of artisanal fisheries in Urubupunga Complex in the middle Parana
      River (Brazil), three habitats were considered: I) Ilha Solteira and Jupia
      reservoirs; II) the Parana River between the Jupia and Primavera dams; III) the
      Parana River downstream from the Primavera dam. Data collection was done through
      questionnaires addressed to a total of 187 fishersmen; just 164 of the resulting
      interviews were considered valid. They were held in July 1998 (dry season) and
      February 1999 (rainy season). The daily average profit of the resevoir fisherman
      was R$ 13.19 during the dry and R$ 19.54 during the rainy season; R$ 4.10 and R$
      12.92 for fishermen located on the Parana River between Jupia and Primavera dam;
      and R$ 1.48 and R$ 23.01 for those located on the Parana River below Primavera
      dam (R$ 1.00 = US$ 0.86 during the dry season; R$ 1.00 = US$ 0.52 during the
      rainy season). A linear model had been tried to explain the profit variable, in
      relation to those variables directly linked to fishing (e.g., as habitats;
      seasons, dry or rainy; gear used; days spent fishing) as well as several
      sociological variables (age, marital states, number of dependents, and
      education). However, due to large variability in profits, the proposed model only
      explained 48.4% of variability, and the only significant factors were education,
      type of gear, and covariant fishing days.

PMID- 15029380
TI  - The marine leech Stibarobdella loricata (Harding, 1924) (Hirudinea,
      Piscicolidae), parasitic on the angel shark Squatina spp. and sandtiger shark
      Carcharias taurus Rafinesque, 1810 (Chondrichthyes: Squatinidae, Carchariidae) in
      Southern Brazilian waters.
AB  - The presence of the marine leech, Stibarobdella loricata (Harding, 1924)
      (Hirudinea, Piscicolidae), is reported on the southern coast of Brazil, based on
      seven lots with 47 specimens, between 71 and 182 mm in total length, collected on
      the dorsal region of angel sharks, Squatina argentina (Marini, 1930); S.
      guggenheim Marini, 1936; S. punctata Marini, 1936 (Chondrichthyes, Squatinidae);
      and on the head of a sandtiger shark, Carcharias taurus Rafinesque, 1810
      (Chondrichthyes, Carchariidae). This is the first record of S. loricata in the
      western Atlantic and of its parasitic association with S. argentina, S.
      guggenheim, S. punctata, and C. taurus.

PMID- 15029381
TI  - Characterization of the imaginal reproductive diapause of Oebalus poecilus
      (Dallas) (Hemiptera: Pentatomidae).
AB  - The state of development of the internal reproductive organs of male and female
      Oebalus poecilus (Dallas) as well as the body fat amount in the abdominal cavity
      during hibernation, of individuals sampled in bamboo litter in Eldorado do Sul
      (30 masculine 02'S and 51 degrees 23'W), RS, Brazil was investigated. Females and
      males showed the abdominal cavity filled with body fat in the beginning of the
      hibernation phase. The decrease in fat reserve level occurred from August on for
      males and from October on for females. Ovaries and testis doubled in length and
      tripled in width from immature to the reproductive phase. Male sexual maturation
      occurred in the hibernation sites while for females it occurred later on outside
      of the sites. Reproductive organ immaturity and abdominal body fat hypertrophy
      characterized the diapause of O. poecilus.

PMID- 15029382
TI  - Occurrence and characterization of entomogen galls in plants from natural
      vegetation areas in Delfinopolis, MG, Brazil.
AB  - In the present work we aimed to register the occurrence of galls, inductors,
      inquilines, and parasitoids in plants of three natural vegetation areas in
      Delfinopolis, MG, Brazil. Results obtained showed 22 types of galls collected
      from leaf, vein leaf, petioles, stem, and inflorescence of nineteen species
      belonging to fifteen distinct families. Concerning gall morphology, the following
      were collected: globoid, conicle, discoidal, fusiform, shell-shape, indefinite,
      and one substituition of an ovary by an immature. As principal inducers were
      found insects of the families Cecidomyiidae (Diptera), Psyllidae, and Diaspididae
      (Sternorrhyncha/Hemiptera). As parasitoids the most common are of the
      Chalcidoidea superfamily (Hymenoptera) and, as occasional inquilines, Polyxenidae
      (Diplopoda) and Psocodea (Psocoptera). The results of this study contribute to
      existing of knowledge host-plant diversity and gall-associated insects in rocky
      fields, cerrado, and gallery forests.

PMID- 15029383
TI  - First record of Daphnia lumholtzi (SARS, 1885), exotic cladoceran, in Sao Paulo
      State (Brazil).

PMID- 15029384
TI  - Unusual shelters occupied by Brazilian hermit crabs (Crustacea: Decapoda:
      Diogenidae).

PMID- 15029385
TI  - Galls in rhizome of an aquatic macrophyte, Eichhornia azurea (Swartz) kunth
      (Pontederiaceae), in Jatai Ecological Station, Luiz Antonio, SP, Brazil.

PMID- 15029386
TI  - Coprological helminth screening in Brazilian free ranging golden lion tamarins,
      Leontopithecus rosalia (L., 1766) (Primates, Callithrichidae).

PMID- 15029387
TI  - [Barrett's esophagus: new diagnostic tools].

PMID- 15029388
TI  - [Methylene blue chromoendoscopy for Barrett's esophagus diagnosis].
AB  - BACKGROUND: Barrett's esophagus is a condition in which the normal stratified
      squamous epithelium of the esophagus is replaced by specialized intestinal
      metaplasia, that carries an increased risk for the development of adenocarcinoma
      of the esophagus. Dysplasia and initial stage carcinoma generally precede this
      neoplasm; the increased risk has led to attempts at early detection of these
      lesions through periodic upper endoscopy and biopsies. The continued rise in the
      incidence of adenocarcinoma of the esophagus has fueled resurgent interest in the
      use of a variety of endoscopic techniques, like methylene blue chromoendoscopy,
      to improve the diagnosis of Barrett's esophagus and associated complications.
      AIM: To determine if methylene blue chromoendoscopy directed biopsies offer
      advantage over the conventional technique in the detection of Barrett's
      esophagus. MATERIAL AND METHOD: Forty-five patients with previous diagnosis of
      Barrett's esophagus were enrolled in this study; all of them underwent upper
      endoscopy with random biopsies and upper endoscopy with methylene-blue directed
      biopsies within 4 weeks, in the period between April and October, 2002. RESULTS:
      Results of histologic examination of random biopsies and those of methylene blue
      directed biopsies were compared. Sensitivity, specificity, positive and negative
      predictive values were 62,5%, 15,4%, 57,7% and 18,2%, respectively. No
      significant differences were found in the total number of biopsy specimens.
      Differences were found in the total amount of time spent during each procedure
      (chromoendoscopy x conventional technique), with chromoendoscopy being
      significantly longer. CONCLUSION: We concluded that methylene blue
      chromoendoscopy offered no advantage over the conventional method in the
      diagnosis of Barrett's esophagus.

PMID- 15029389
TI  - [Barrett's esophagus associated to caustic stenosis of the esophagus].
AB  - BACKGROUND: The esophageal stenosis secondary to the ingestion of caustic
      products is frequent in Brazil, mainly due to an attempt suicide. The Barrett's
      esophagus is consequence of the chronic gastroesophageal reflux. The literature
      consulted showed that are a rare association. CASUISTIC AND METHODS: From 1981 to
      2000 were admitted and treated in the "Gastrocentro" State University of
      Campinas, SP, Brazil, 120 patients presenting caustic stenosis of the esophagus,
      and during the follow-up were found nine cases with Barrett's esophagus
      associated (7,5%). The time of caustic ingestion varied from 4 years to 54 years
      (mean 29 years), and they were four males and five females, eight whites and one
      black, with the mean age of 57,7 years (43 to 72 years). RESULTS: All the cases
      presented dysphagia and the flexible upper endoscopy showed stenotic areas and
      caustic esophagitis sequels. Three patients referred symptoms of gastroesophageal
      reflux, but hiatus hernia were found in only one case. The Barrett's esophagus
      was found in the middle third of the esophagus above the stenotic areas in three
      cases, and in the distal third in six cases. The dysphagia was treated with
      periodic esophageal dilatations. Two patients presenting severe symptoms of
      reflux were submitted to modified Nissen fundoplication by videolaparoscopy, with
      good results. CONCLUSIONS: The Barrett's esophagus in these patients could be
      associated to the caustic ingestion, because it is not situated in the distal
      third of the esophagus, as commonly found in reflux esophagitis. Its is very
      important the follow-up and biopsies of the Barrett's esophagus, due to the
      possibility of malignancy.

PMID- 15029390
TI  - Low bone mineral density in noncholestatic liver cirrhosis: prevalence, severity
      and prediction.
AB  - BACKGROUND: Metabolic bone disease has long been associated with cholestatic
      disorders. However, data in noncholestatic cirrhosis are relatively scant. AIMS:
      To determine prevalence and severity of low bone mineral density in
      noncholestatic cirrhosis and to investigate whether age, gender, etiology,
      severity of underlying liver disease, and/or laboratory tests are predictive of
      the diagnosis. PATIENTS/METHODS: Between March and September/1998, 89 patients
      with noncholestatic cirrhosis and 20 healthy controls were enrolled in a cross
      sectional study. All subjects underwent standard laboratory tests and bone
      densitometry at lumbar spine and femoral neck by dual X-ray absorptiometry.
      RESULTS: Bone mass was significantly reduced at both sites in patients compared
      to controls. The prevalence of low bone mineral density in noncholestatic
      cirrhosis, defined by the World Health Organization criteria, was 78% at lumbar
      spine and 71% at femoral neck. Bone density significantly decreased with age at
      both sites, especially in patients older than 50 years. Bone density was
      significantly lower in post-menopausal women patients compared to pre-menopausal
      and men at both sites. There was no significant difference in bone mineral
      density among noncholestatic etiologies. Lumbar spine bone density significantly
      decreased with the progression of liver dysfunction. No biochemical variable was
      significantly associated with low bone mineral density. CONCLUSIONS: Low bone
      mineral density is highly prevalent in patients with noncholestatic cirrhosis.
      Older patients, post-menopausal women and patients with severe hepatic
      dysfunction experienced more advanced bone disease. The laboratory tests
      routinely determined in patients with liver disease did not reliably predict low
      bone mineral density.

PMID- 15029391
TI  - [Prognostic factors following liver resection for hepatic metastases from
      colorectal cancer].
AB  - AIM: To determine the impact of prognostic factors on survival of patients with
      metastases from colorectal cancer that underwent liver resection. METHODS: The
      records of 28 patients that underwent liver resection for metastases from
      colorectal cancer between April 1992 and September 2001 were retrospectively
      analyzed. Thirty-eight resections were performed (more than one resection in
      eight patients and two patients underwent re-resections). The primary tumor was
      resected in all the patients. A screening protocol for liver metastases including
      clinical examinations every three months, ultrassonography and CEA level until 5
      years of follow-up and after every 6 months, was applied. The prognostic factors
      analyzed regarding the impact on survival were: Dukes C stage of primary tumor,
      size of metastasis >5 cm, a disease-free interval from primary tumor to
      metastasis < 1 year, CEA level > 100 ng/mL, resection margins < 1 cm and
      extrahepatic disease. The Kaplan-Meier curves, log rank and Cox regression were
      used for the statistical analysis. RESULTS: Perioperative morbidity and mortality
      were 39.3% and 3.6%, respectively. The 5-year survival rate was 35%. The
      independent prognostic factors were: disease-free interval from primary tumor to
      metastasis < 1 year and extrahepatic disease. CONCLUSIONS: The liver resection
      for metastases from colorectal cancer is a safe procedure with more than 30% 5
      year survival. Disease-free interval from primary tumor to metastasis < 1 year
      and extrahepatic disease were independent prognostic factors.

PMID- 15029392
TI  - Bacteremia in cirrhotic patients submitted to endoscopic band ligation of
      esophageal varices.
AB  - BACKGROUND: Endoscopic procedures can develop bacteremia. Patients with chronic
      liver disease are more predisposed to undergo bacteremia and infections because
      they are immunocompromised. AIMS: The purpose of this study was to determine the
      incidence of bacteremia in cirrhotics submitted to endoscopic variceal ligation.
      METHODS: Three groups of 40 patients each were studied. One group was made up of
      patients with cirrhosis who were submitted to ligation, a second group was
      composed of cirrhotics who underwent esophagogastroduodenoscopy only, and a third
      group was composed of patients without liver disease who underwent
      esophagogastroduodenoscopy. Blood was sampled from all patients for culture, both
      in aerobic and in anaerobic mediums, immediately before endoscopy and at 5 and 30
      minutes after its completion. RESULTS: Blood culture was positive in 6 samples.
      In 4 of these, the bacteria (Staphylococcus hominis hominis, Staphylococcus
      auricularis, Acinetobacter lwoffii, and coagulase-negative staphylococcus) were
      isolated before the endoscopic procedure and thus were considered as
      contamination. In the ligation group, a streptococcus of the viridans group was
      isolated 5 minutes after the procedure, and in the cirrhosis without ligation
      group, a Staphylococcus epidermidis was isolated at 30 minutes. None of the
      patients showed clinical evidence of infection. CONCLUSIONS: The bacteremia
      incidence in cirrhotic patients submitted to variceal ligation was 2.5%, showing
      no difference from the control groups.

PMID- 15029393
TI  - [Increased serum levels of laminin in the experimental cirrhosis induced by
      carbon tetrachloride].
AB  - BACKGROUND: Serum laminin has been correlated with portal hypertension and
      sinusoid capillarization in chronic liver diseases. Little is known about its
      dynamics in liver diseases. AIM: To investigate the levels of serum laminin in
      experimental cirrhosis induced by carbon tetrachloride, as well as to correlate
      its level with the degree of hepatic fibrosis and portal hypertension. MATERIAL
      AND METHODS: Forty-nine albino Wistar rats were studied. Twenty-three were
      treated with carbon tetrachloride solution at 8% and 16 were kept as controls.
      Between the 6th and 16th weeks, all animals were sacrificed, submitted to
      measurement of portal pressure and blood sampling of the femoral veins. Liver
      fragments were fixed for light microscopic studies. Hepatic fibrosis was
      classified as perivenular fibrosis, complete and incomplete septal fibrosis and
      cirrhosis. Determination of laminin concentration was performed by ELISA with an
      antibody against laminin isolated from Engelbreth-Holm-Swarm tumor. RESULTS: The
      portal pressure was correlated with the degree of hepatic fibrosis (rs = 0.82; n
      = 45). Its levels in septal fibrosis (10.8 +/- 1.2 cm H(2)0) and cirrhosis (13.6
      +/- 3.1 cm H(2)0) were statistically higher when compared to control (7.9 +/- 1.5
      cm H20) and perivenular fibrosis (9.1 +/- 0.8 cm H(2)0) groups. Peripheral blood
      laminin concentration in cirrhosis (40.0 +/- 18.7 mg/dL) was significantly higher
      when compared to control (13.8 +/- 12.1 mg/dL), perivenular fibrosis (19.1 +/-
      15.5 mg/dL) and septal fibrosis (22.2 +/- 27.0 mg/dL) groups. The circulating
      laminin was correlated to the degree of hepatic fibrosis (rs = 0.59; n = 49) and
      to portal pressure (r = 0.29; n = 45). CONCLUSIONS: In the chronic carbon
      tetrachloride intoxication, laminin levels are better correlated with the
      development of hepatic fibrosis than with portal hypertension.

PMID- 15029394
TI  - Protective effect of N2-mercaptopropionylglycine on rats and dogs liver during
      ischemia/reperfusion process.
AB  - BACKGROUND: N2-mercaptopropionylglycine is a powerful super oxide synthesis
      inhibitor and has been tested as a preventive agent of metabolic and structural
      hepatic damage in the ischemia/reperfusion process. AIM: To analyze some effects
      of N2-mercaptopropionylglycine administration to animals of two species submitted
      to normothermic liver ischemia/reperfusion. MATERIAL AND METHODS: Twenty-two rats
      and 22 dogs were divided into four groups: group I: rats that received
      intravenous saline 0.9%; group II: rats that received 100 mg/kg of N2
      mercaptopropionylglycine; group III: dogs that received saline intravenous 0.9%
      and group IV: dogs that received 100 mg/kg N2-mercaptopropionylglycine. RESULTS:
      Ten minutes after the saline or drug administration, each group was submitted to
      left lobe liver ischemia for 25 minutes followed by reperfusion. Biochemical
      studies 24 hours after reperfusion revealed a significantly lower elevation of
      transaminases in animals of groups II (AST = 271 +/- 182; ALT = 261 +/- 161 ) and
      IV (AST = 101 +/- 45; ALT = 123 +/- 89) when compared to the controls group: I
      (AST = 2144 +/- 966; ALT = 1869 +/- 1040 00) and III (AST = 182 +/- 76.51; ALT =
      277 +/- 219), respectively. Histology study demonstrated a significantly minor
      aggression to animals of groups II and IV when compared to groups I and III,
      respectively. CONCLUSION: These results suggest a significant release of free
      radicals of oxygen in the process and that N2-mercaptopropionylglycine may have a
      significant protective effect on liver parenchyma when submitted to
      ischemia/reperfusion.

PMID- 15029395
TI  - [Fiber and nutrients intake in children with chronic constipation].
AB  - OBJECTIVES: The aim of this case-control study was to evaluate the intake of
      fiber alimentary and macronutrients in constipated children. METHODS: Fifty-four
      children (aged 2-12 yr) with diagnosis of chronic functional constipation were
      investigated at the Pediatric Hospital, "Universidade Federal do Rio Grande do
      Norte", Natal, RN, Brazil. They were age and sex matched with 50 patients without
      constipation. A standard questionnaire was applied to both groups and a 3 day
      dietary record was analyzed by computer software. RESULTS: The mean age at onset
      of symptoms was 29,0 +/- 26,1 months. There was not sex predominance and no
      difference about nutritional condition between the groups. Constipated children
      ate less fiber, proteins, lipids, carbohydrates and less caloric and protein
      adequated percentuals. The proportion of children who ate less dietary fiber than
      recommended (age + 5 g /day) was greater in the constipated group (83,3%) than in
      controls (66,6%); odds ratio 2,6. CONCLUSION: Constipated children ate less fiber
      and macronutrients than children without constipation. Intake of dietary fiber
      below the minimum recommendation is a risk factor for chronic functional
      constipation in children.

PMID- 15029396
TI  - Upper gastrointestinal hemorrhage due to duodenal stromal tumor.
AB  - BACKGROUND: Gastrointestinal stromal tumor represents a rare neoplasm that
      originates in the muscular wall of the hollow viscera. AIM: To report
      gastrointestinal stromal tumor as a source of upper gastrointestinal bleeding,
      which required urgent surgical control. PATIENT/METHOD: A man with 61 years old
      was admitted to the emergency service sustaining hematemesis and melena.
      Endoscopy showed active bleeding from a tumor in the second portion of the
      duodenum, which was controlled by heater probe cauterization. Surgery was
      performed through a median laparotomy. A local resection of a 4 cm tumor in the
      second portion of the duodenum was carried out, together with a primary end-to
      end anastomosis and a duodenal diverticulization. No complications happened
      during the post-operative period. Morphologic examination showed gastrointestinal
      stromal tumor with no atypical mitosis and a preserved capsule. CONCLUSION:
      Albeit not being common, gastrointestinal stromal tumors can represent a source
      of substantial gastrointestinal hemorrhage.

PMID- 15029397
TI  - [Rectovaginal septum endometriosis: a disease with specific diagnosis and
      treatment].
AB  - BACKGROUND: The involvement of the rectovaginal septum, of rectum and sigmoid by
      endometriosis leads to intense symptoms as dysmenorrhea, pelvic pain, deep
      dyspareunia, tenesmus and hematochezia in young and middle aged women during
      periods. The diagnosis can be made by tipycal history and vaginal examination,
      rectal examination, barium enema, proctoscopy and so on. The indications of
      operation include severe clinic symptoms and failed conservative therapy. The
      treatment of choice for this type of endometriosis is the surgical resection of
      affected tissue, in order to relieve patient symptoms, and avoid disease
      progression. The correct assessment as to the presence and extension of the
      endometriosis-affected sites such as the rectum, uterosacral ligaments and
      rectovaginal septum is extremely important to provide better results with the
      surgical treatment of endometriosis. AIM: To describe the main aspects related to
      rectovaginal septum endometriosis and offer the general surgeon some information
      about this enigmatic disease. CONCLUSION: Rectovaginal septum endometriosis is a
      frequent disease, with specific diagnosis and treatment.

PMID- 15029399
TI  - Renal artery disease: diagnosis and management.
AB  - Renal artery stenosis (RAS) is most commonly due to either fibromuscular
      dysplasia or atherosclerosis. The former predominates in young women while
      atherosclerosis is usually encountered in individuals over the age of 55. The
      most common clinical manifestation of fibromuscular dysplasia is hypertension,
      which can frequently be cured or significantly improved with percutaneous balloon
      dilation. Atherosclerotic RAS may present with hypertension, renal failure
      (ischemic nephropathy), recurrent episodes of congestive heart failure and flash
      pulmonary edema or may be discovered incidentally during an imaging procedure for
      some other reason. Screening tests for RAS have improved considerably over the
      last decade. While captopril renography was utilized almost exclusively in the
      past, duplex ultrasound of the renal arteries or magnetic resonance angiography
      have replaced other modalities as the screening test of choice in many centers.
      Rarely does an arteriogram have to be performed for diagnostic purposes only.
      Management of RAS consists of three possible strategies: medical management,
      surgical management or percutaneous therapy with balloon angioplasty and stent
      implantation. The treatment of choice to control hypertension in patients with
      fibromuscular disease is percutaneous angioplasty. Renal artery stenting has
      replaced surgical revascularization for most patients with atherosclerotic
      disease who meet the criteria for intervention.

PMID- 15029398
TI  - [Clinical experience with the use of infliximab in 44 patients with Crohn's
      disease].
AB  - AIM: To evaluate the efficacy of infliximab in the treatment of patients with
      active Crohn's disease or with fistulas. METHODS: Forty four patients with
      Crohn's disease, resistant to conventional therapies, were treated with 5 mg/kg
      endovenous infliximab infusions. RESULTS: Thirty of them (68.2%) improved, with
      important reduction on disease activity levels, measured by the CDAI (Crohn's
      Disease Activity Index). Eight (57.1%) of 14 patients with fistulas also showed
      good results, with closure or important reduction in their flow. The drug was
      well tolerated in all cases. CONCLUSION: The use of infliximab in these cases
      seems to be a good therapeutic option, with low rates of side effects.

PMID- 15029400
TI  - Induction of immunity against human cytomegalovirus.
AB  - Most healthy individuals have been exposed to human cytomegalovirus (HCMV) and
      harbor the virus in a dormant form. However, in situations of immune compromise,
      HCMV infection is associated with high mortality rates in recipients of bone
      marrow transplants and with significant morbidity in recipients of solid organ
      transplants. Conventional vaccination with attenuated HCMV or HCMV proteins fails
      to prime protective immune responses, presumably because the antigens fail to be
      presented effectively in vivo. Dendritic cells (DC) are professional antigen
      presenting cells that can be genetically engineered to direct their ability to
      induce immune responses toward immunodominant HCMV antigens. DC are a distinct
      lineage of leukocytes whose function is most notable for their ability to form
      clusters with T cells and stimulate vigorous cytotoxic T lymphocyte responses. We
      hypothesize that in this capacity, DC engineered to express HCMV antigens are
      uniquely positioned to control immunity against HCMV.

PMID- 15029401
TI  - The multidisciplinary approach to hemodialysis vascular access at the Mount Sinai
      Hospital.
AB  - A majority of the quarter of a million end-stage renal disease patients
      nationwide are treated with hemodialysis. Important and frequent causes of
      morbidity and mortality, when they undergo this procedure, include vascular
      access infection and thrombosis associated with the use of catheters and, to a
      lesser extent, grafts. Therefore, an arteriovenous (AV) fistula is the preferred
      hemodialysis access. A multidisciplinary approach, including nephrologists,
      vascular surgeons, interventional radiologists, nurses, nephrology fellows, and
      nephrology physician assistants, meeting together weekly, should improve
      hemodialysis outcomes by promoting the use of AV fistulas. The specific roles of
      the interventional radiologist, vascular surgeon, nephrologist and other members
      of the multidisciplinary team are reviewed. Important additional components of
      this program are Doppler ultrasound for preoperative hemodialysis access vein
      mapping and screening techniques for early detection of arteriovenous graft
      stenosis. The use of arteriovenous fistulas in the Mount Sinai outpatient
      hemodialysis program has increased from 15% to 43% (p<0.001) and substantially
      limited catheter use since 1998, when the multidisciplinary program began.

PMID- 15029402
TI  - Current medical treatment of pulmonary arterial hypertension.
AB  - Primary pulmonary hypertension is a rare disease of the pulmonary vasculature
      manifested by dyspnea on exertion, syncope, and signs and symptoms of right heart
      failure. In the absence of adequate treatment, primary pulmonary hypertension has
      a grave prognosis, with a median survival of 2.8 years. Pulmonary arterial
      hypertension develops in association with known risk factors and predisposing
      clinical conditions, and shares many clinical, pathological and therapeutic
      characteristics with primary pulmonary hypertension. Therapeutic choices in
      pulmonary arterial hypertension depend on the etiology of the disease, severity
      of functional impairment and hemodynamic response following acute vasodilator
      administration during right heart catheterization. Agents currently approved for
      the specific treatment of pulmonary arterial hypertension are continuous
      intravenous epoprostenol, subcutaneous treprostinil and oral bosentan. A small
      group of patients who demonstrate true acute vasoreactivity at right heart
      catheterization may be chronically treated with oral calcium channel blockers. In
      addition, most patients with pulmonary hypertension receive conventional
      treatment, represented by anticoagulants, diuretics, inotropic medication or
      oxygen supplementation. Treatment of pulmonary arterial hypertension has
      significantly altered the natural course of the disease, with pronounced
      symptomatic, functional and survival benefit. Current clinical research focuses
      on the discovery of new targets of therapy and the use of a combination treatment
      approach, which will offer hope and valuable insight into the pathogenetic basis
      of this devastating illness.

PMID- 15029403
TI  - Neurohormonal antagonism in heart failure: what is the optimal strategy?
AB  - Pharmacologic management of chronic heart failure rests on appropriate volume
      management followed by neurohormonal antagonism. Despite the rationale for
      neurohormonal antagonists, their use remains low. Definitive studies establish
      that neurohormonal antagonists are effective across the spectrum of disease, from
      the early Stage A patient at risk of developing structural heart disease and
      symptomatic heart failure to the Stage D patient with symptoms at rest. Although
      many investigators and clinicians seem focused on the next new scientific
      breakthrough, published studies delineate strategies that will reduce death and
      disability for those at risk and those with symptomatic chronic heart failure. In
      essence, the broad use of neurohormonal antagonists, consistent with the reports
      of large-scale trials that have been reported, will markedly reduce the risk of
      disease progression and death. Overall prognosis however remains poor. We review
      the data from these trials to encourage clinicians to use these proven
      neurohormonal antagonists in optimizing therapeutic strategy.

PMID- 15029404
TI  - Intestinal metastases from renal cell carcinoma: a rare cause of intestinal
      obstruction and bleeding.
AB  - Intestinal metastases from renal cell carcinoma (RCC) are rare. Clinical
      presentation includes intestinal obstruction, bleeding, or perforation.
      Management should be aggressive, since the prognosis of RCC is unpredictable and
      metastasectomy can extend patient survival. We present a patient with intestinal
      obstruction and bleeding caused by intestinal metastases from renal cell
      carcinoma and summarize the surgical procedures employed. The relevant literature
      is briefly reviewed.

PMID- 15029405
TI  - Ectopic intrathoracic thyroid: case report.
AB  - We present a patient with ectopic intrathoracic thyroid that was removed through
      a right lateral thoracotomy. Ectopic intrathoracic thyroid is a rare presentation
      of thyroid disease and comprises about 1% of all mediastinal tumors. Its removal
      usually necessitates thoracotomy or sternotomy. The relevant literature is
      briefly reviewed.

PMID- 15029406
TI  - If I were Dean: a challenge to new medical students.
AB  - If I were Dean I would welcome new students by explaining that they will be
      trained to become humane, compassionate scientists, and that our medical sciences
      are based on classical Greek science and medicine, with its first aphorism "Life
      is short, but art and skill are long." Science involves the conception and
      construction of refutable hypotheses, and their testing by repeatable
      experiments, followed by publication of the results. Thus, science is uncertain,
      tentative, probabilistic and universal. Our students will learn compassion both
      from our bioethicists and from faculty role models. I would warn the students
      that, unfortunately, much of the general public has little understanding of
      science, does not accept our medical model, and is increasingly seeking
      alternative, pre-scientific, non-scientific and even pseudo-scientific models of
      care, not necessarily from lack of intelligence, but perhaps more from scientific
      illiteracy and innumeracy. And the public fruitlessly demands safe and effective
      drugs, free from side effects, for all ailments, but they often fail to take
      drugs when prescribed, and/or take alternative medicines instead.

PMID- 15029407
TI  - Recombinant interferon gamma lb and low dose steroid in two pediatric cases of
      nonspecific interstitial pneumonia.
AB  - We report two young girls, the first almost 18 years old and the second 12 1/2
      years old, affected with nonspecific interstitial pneumonia, both diagnosed at
      the age of 11 by open lung biopsy and both being treated with low-dose steroid.
      Due to insufficient response to conventional therapy and based on positive
      therapeutic results following the use of subcutaneous recombinant interferon
      gamma-1b in fibrosing interstitial pneumonias of adults, they were given a 1-year
      trial of subcutaneous recombinant interferon gamma-lb in association with a
      steroid. Our experience with these two young patients suggests that interferon
      gamma-lb cannot be considered as stabilizing or a curative therapy to control or
      reverse nonspecific interstitial pneumonia unresponsive to steroids alone.

PMID- 15029408
TI  - Linking up and out.

PMID- 15029410
TI  - Peritonsillar infections: local experience.
AB  - INTRODUCTION: The disease pattern and management of peritonsillar infections in
      Singapore General Hospital are studied. Other objectives are to determine if a
      seasonal variation exists and to examine the role of routine bacterial cultures
      and interval tonsillectomy. METHODS: This is a retrospective review of the
      management and outcome of patients with peritonsillar infections who were
      admitted acutely to Singapore General Hospital over a three-year period. RESULTS:
      Of 185 patients studied, 151 (81.6 percent) had peritonsillar abscess or quinsy
      and 34 (18.4 percent) had peritonsillar cellulitis. There were 139 males and 46
      females, with a racial predisposition among Malays (p value is less than 0.0005).
      There may be a seasonal variation with a bi-annual trend, though no correlation
      with upper respiration tract infections was noted. Treatment consisted mainly of
      incision and drainage (66 percent) or needle aspiration (34 percent). No
      significant difference in the length of stay was noted in patients receiving
      penicillin alone, penicillin with metronidazole, or broad-spectrum antibiotics (p
      value is equal to 0.062). Fourteen (7.6 percent) patients had recurrences, all of
      which occurred after the first month. Two patients (1 percent) had bilateral
      quinsy. CONCLUSION: Peritonsillar infections remain a common admitting diagnosis
      to the Otolaryngology department. A single episode of infection should no longer
      be an indication for tonsillectomy as the incidence of recurrence is low.

PMID- 15029409
TI  - Josef Leopold Auenbrugger (1722 - 1809): father of percussion.

PMID- 15029411
TI  - Skin paddle as an indicator of the viability of vascularised fibular graft.
AB  - INTRODUCTION: Immediate recognition of anastomotic failure is important to ensure
      the viability of the vascularised fibular graft. The problems associated with
      post-operative bone scanning and angiography for immediate detection of
      anastomotic failure have been described. METHODS: We report the effectiveness of
      using a skin paddle as an indicator of the vascularised fibular graft viability
      in 13 cases which had undergone various types of long bone reconstruction using
      fasciocutaneous free vascularised fibular graft. RESULTS: Early detection of
      anastomotic failure in 100 percent of the patients (4 out of 4) with 92 percent
      (12 out of 13 patients) success rate shows the effectiveness of this method.
      CONCLUSION: The skin paddle offers the best method of post-operative monitoring
      of fibular graft viability.

PMID- 15029412
TI  - Ruptured uterus in South Western Nigeria: a reappraisal.
AB  - INTRODUCTION: Rupture of the gravid uterus is a grave obstetric complication that
      is associated with high maternal and perinatal mortality rates. In Nigeria, the
      incidence remains high and continue to increase because of poverty, illiteracy,
      unavailability of manpower, poor supply of medical equipment and consumables, and
      dwindling health care funding. METHODS: A 10-year retrospective review of all
      cases of ruptured uterus seen at the Obafemi Awolowo University teaching hospital
      complex in Ile Ife, Nigeria was conducted. RESULTS: A total of 61 cases of
      ruptured uterus from 16,683 deliveries were recorded, giving a ratio of 1 in 273.
      Predisposing or aetiological factors for rupture were: prolonged labour (91.8
      percent), grand multiparity (50.8 percent), injudicious use of oxytocin (41.0
      percent), uterine scar (26.2 percent), obstetric manipulation (4.9 percent) and
      abnormal lie (14.8 percent). Fifty-six patients had surgery, of which 14 (25.0
      percent) had total abdominal hysterectomy, 16 (28.6 percent) had subtotal
      hysterectomy, 15 (26.8 percent) had repair of the rupture and bilateral tubal
      ligation, and 13 (19.6 percent) had repair only. Thirteen maternal deaths
      occurred with a case fatality rate of 21.3 percent. CONCLUSION: Ruptured uterus
      remains a problem in Nigeria, with primary health centres and mission houses
      being identified as major contributors to this condition. They primarily failed
      in the recognition of abnormalities in the antepartum and/or intrapartum periods,
      with delays in referral and the injudicious use of oxytocin.

PMID- 15029413
TI  - Prescription monitoring of anti-hypertensive drug utilisation at the Panjab
      University Health Centre in India.
AB  - INTRODUCTION: The present pilot study was conducted in order to establish the
      drug-prescribing trend of anti-hypertensive agents at the Panjab University
      Health Centre in India. METHODS: A pilot study of six-month duration was
      conducted at the Panjab University Health Centre. The information was collected
      from the patients attending the outpatient department through a random sample
      method. World Health Organisation-based prescription-auditing proforma was used
      for data collection. RESULTS: This study revealed that most of the male patients
      were on monotherapy (60 percent). In the monotherapy category, four classes of
      drugs were used. These were calcium channel blockers (48.1 percent), beta
      blockers (46.2 percent), ACE inhibitors (3.9 percent) and diuretics (1.9
      percent). Among monotherapy drugs, calcium channel blockers were prescribed most
      whereas diuretics were least used. Among those who were treated with drug
      combinations, 92.1% received two drugs and 7.9 percent received three drugs. In
      combination therapy, a two-drug combination consisting of beta-blockers and
      calcium channel blockers was given to the majority of the patients. Overall, 57.8
      percent patients were treated with a single anti-hypertensive drug and 42.2
      percent were treated with anti-hypertensive drug combinations. CONCLUSION: The
      present study represents the current prescribing trend for anti-hypertensive
      agents and it highlights certain shortcomings in the existing prescribing
      practice. There is a considerable scope for improvement, particularly the under
      utilisation of diuretics in the present prescribing pattern of anti-hypertensive
      drugs.

PMID- 15029415
TI  - Mucinous adenocarcinoma of the renal pelvis associated with lithiasis and chronic
      gout.
AB  - Diffusely-infiltrating mucinous adenocarcinoma of the renal pelvis associated
      with lithiasis and chronic gout is reported in a 61-year-old Malay man. The
      patient underwent left nephrectomy and vesiculo-lithotomy. This tumour is
      postulated to arise in response to chronic irritation of the urothelium.

PMID- 15029414
TI  - Recurrent abdominal pain in children: the utility of upper endoscopy and
      histopathology.
AB  - INTRODUCTION: To study the utility of upper gastrointestinal endoscopy with
      biopsy in the evaluation of children with clinically-significant recurrent
      abdominal pain. METHODS: Over a three-month period, children with three or more
      episodes of upper abdominal pain that was severe enough to impair their normal
      activity and required medical attention were included in the study. After
      complete history, physical examination and basic investigations, upper
      gastrointestinal endoscopy with biopsy was performed in all patients. RESULTS:
      Thirty-eight children were enrolled. Their average age was 10.5 years and 21 were
      female. Organic causes were identified in 44.7 percent of the cases, with
      Helicobacter pylori gastritis being the most common diagnosis (28.9 percent). No
      specific dyspeptic symptom was significantly associated with either organic cause
      of recurrent abdominal pain or Helicobacter pylori infection. Antral nodularity
      was the only endoscopic finding significantly associated with Helicobacter pylori
      infection (sensitivity 63.4 percent, specificity 85.2 percent). All patients
      improved after specific therapy was instituted. CONCLUSION: The organic causes of
      recurrent abdominal pain in children have been increasingly identified in our
      hospital, a tertiary care centre in Northern Thailand. One of the most common
      causes found in this study was Helicobacter pylori infection. Upper endoscopy was
      very helpful in identifying the underlying pathology.

PMID- 15029416
TI  - Isolated tricuspid valve vegetations and steno-insufficiency in primary
      antiphospholipid syndrome.
AB  - Although cardiac valve disease is frequent in the antiphospholipid syndrome,
      isolated tricuspid valve pathology is uncommon and tricuspid valve steno
      insufficiency with concomitant vegetations in association with primary
      antiphospholipid syndrome has very rarely been mentioned in the literature. We
      describe a 54-year-old Indian woman with newly-diagnosed antiphospholipid
      syndrome and isolated tricuspid valve disease, the nature of which was only
      discernible by transoesophageal echocardiography. This case report highlights the
      importance of being aware of antiphospholipid syndrome as the possible underlying
      diagnosis in isolated organic tricuspid valve disease and the need for
      transoesophageal echocardiography in such cases.

PMID- 15029417
TI  - Mature cystic teratoma: unusual presentation as anterior neck swelling.
AB  - The unusual presentation of a mature mediastinal cystic teratoma as an anterior
      neck swelling in a 29-year-old Malay woman is reported.

PMID- 15029418
TI  - Imaging of giant breast masses with pathological correlation.
AB  - Ultrasonography (US) and mammography are the two basic techniques for routine
      imaging in the diagnosis of breast diseases. A wide variety of breast conditions
      such as lipoma, hamartoma, cyst, fibroadenoma, phyllodes tumour, haematoma,
      abscess and carcinoma can result in solitary or multiple giant masses. These
      conditions may appear similar on physical examination. The clinical significance
      of these entities is that some lesions necessitate mastectomy but some lesions
      may require only local excision, aspiration or even conservative management.
      Imaging has enhanced our ability to characterise these lesions. The purpose of
      this pictorial review is to illustrate the causes of giant breast masses, and the
      role of US and mammography in diagnosis of these lesions.

PMID- 15029419
TI  - Clinics in diagnostic imaging (95). Os trigonum.
AB  - A 19-year-old boy presented to the Accident and Emergency Department after
      sustaining trauma to his left ankle and foot while playing soccer. The radiograph
      of his left ankle showed a well-corticated triangular fragment of bone posterior
      to the left talus, typical of an os trigonum. This accessory bone was initially
      mistaken for a fracture fragment and a plaster cast was applied. The term, do not
      touch lesion, has been coined to describe this group of benign bony entities
      which may be classified into three broad categories, namely: normal variants,
      lesions that are real but obviously benign, and lesions that are related to
      degenerative disease. The importance of recognising the characteristic
      radiographical appearances of these entities is emphasised, as the need for
      further imaging or diagnostic tests can usually be avoided.

PMID- 15029421
TI  - [Displacement of a stapes piston as a consequence of whiplash injury with head
      impact].
AB  - We report the case of a 60 year old patient suffering from a displacement of her
      stapes piston after a rear-end collision with whiplash injury. Immediately after
      the accident she complained hearing loss and tinnitus. During the following days,
      the patient developed vertigo with lateropulsion. Diagnostic tympanoscopy showed
      a piston dislocation with migration into the vestibulum as a result of the blunt
      head trauma.

PMID- 15029422
TI  - [Hearing loss following tympanic membrane injury].

PMID- 15029420
TI  - [Sinonasal hemangiopericytoma].
AB  - Hemangiopericytomas are rare perivascular tumors. The nasal cavity and paranasal
      sinuses are most often involved in the head and neck region. A case of
      hemangiopericytoma in a 63 year old patient is presented. The initial symptom was
      recurrent bleeding from the nose. The patient had a history of radiotherapy for a
      pituitary adenoma 30 years previously. Computed tomography and magnetic resonance
      imaging showed a polypoid opacification of the ethmoid, sphenoid and basal
      aspects of the frontal sinus on the right side. Histological diagnosis was
      obtained from nasal biopsy. Preoperatively, arteriography and tumor embolisation
      were performed. The tumor was completely excised using a combined endonasal and
      external approach as an osteoplastic revision of the frontal sinus via bicoronal
      incision. There was no recurrence at follow-up 1 year later.

PMID- 15029423
TI  - [Waardenburg syndrome. A heterogenic disorder with variable penetrance].
AB  - BACKGROUND: Waardenburg syndrome (WS) is an autosomal dominant disorder
      characterised by pigmentary anomalies of the skin, hairs, eyes and various
      defects of other neural crest derived tissues. It accounts for over 2% of
      congenital hearing impairment. At least four types are recognized on the basis of
      clinical and genetic criteria. PATIENTS AND METHODS: Based on a screening of
      congenitally hearing impaired children, 12 families with WS type II were
      detected. Of special interest was the phenotype of these families, in particular
      the reduced penetrance of hearing impairment within the families. RESULTS AND
      CONCLUSION: In all cases a high variability of the disease phenotype was detected
      and the penetrance of the clinical traits varied accordingly. Therefore, it is
      not possible to predict the clinical phenotype even in a single family. Based on
      these studies, we plan to identify the pathogenetic cause of the disease in order
      to perform a detailed genotype/phenotype analysis.

PMID- 15029424
TI  - [Aneurysm of the subclavian artery. An unusual cause of dysphagia].
AB  - BACKGROUND: Dysphagia may be due to oral, pharyngeal or esophageal dysfunction
      and poses a frequent problem for the otolaryngologist. Motor disturbances,
      structural disorders, functional problems, congenital lesions and malignancies
      have to be excluded in an interdisciplinary diagnostic approach. Currently,
      vascular diseases play a minor role in the diagnosis of dysphagia. CASE REPORT: A
      70-year-old female presented with constant dysphagia and a foreign body feeling
      in the throat of about 2 months duration. Palpation and ultrasound revealed a
      tumor situated in the right supraclavicular region. The lesion was identified as
      a true aneurysm of the subclavian artery by digital subtraction angiography.
      Successful resection and reconstruction was accomplished using a PTFE graft.
      DISCUSSION: Aneurysms of the subclavian artery are rare and in most cases related
      to thoracic outlet syndrome (TOS) or arteriosclerosis. It can be assumed that an
      increasingly aged population will present with an increasing incidence of
      diseases related to atherosclerosis. Moreover, the increasing incidence of
      specific infections may contribute to this phenomenon. This neglected disease
      should be included in the differential diagnosis when dealing with
      supraclavicular lesions, foreign body feeling or dysphagia.

PMID- 15029425
TI  - [Zenker's diverticulum. The endoscopic-microscopic, staple-assisted
      esophagodiverticulostomy].
AB  - BACKGROUND: The endoscopic-microscopic staple-assisted esophagodivertikulostomy
      of Zenker's diverticulum is a new modification of endoscopic operation techniques
      which minimizes complications and is able to speed up the patient's
      convalescence. PATIENTS AND METHODS: A total of 22 out of 32 patients with
      Zenker's diverticulum underwent surgery. The operation involves cutting the wall
      between the diverticular sac and the oesophagus and, at the same time, closing
      the mucosal wound edges using the "closed" surgery method. RESULTS: All
      operations were effective and uncomplicated. A total of 28 operations were
      performed on 22 patients. The operations due to relapse were predominantly
      necessary among younger patients, of whom three were operated endoscopically and
      three through the cricopharyngeal myotomy. CONCLUSIONS: The "closed" endoscopic
      microscopic staple-assisted esophagodivertikulostomy of Zenker's diverticulum
      avoids opening the retropharyngeal and retrooesophageal areas and allows a quick
      convalescence in the mostly elderly patients. This technique is effective, safe
      and has no major complications.

PMID- 15029426
TI  - [Slide-based multi-parametric cytometry in ENT. Perspectives for the clinic and
      research].
AB  - BACKGROUND: Flow cytometry is the standard method for the multi-parametric
      analysis of cells. However, for about a decade, an instrument has been available
      which analyses fluorescing cells immobilised on slides called a laser scanning
      cytometer (LSC). Its design, according to the principles of slide-based
      cytometry, promises many advantages, especially in the analysis of minimal sample
      volumes. METHODS AND PATIENTS: To date, applications for cultured cells and
      animal models have been established. Its use for clinical purposes, however,
      remains to be critically evaluated. We analysed a variety of specimens obtained
      in our clinical routine. RESULTS: First, the instrument's resolution was
      evaluated using standardised particles. This showed a very good sensitivity
      across a wide range of fluorescence intensities at various wavelengths. Next,
      diverse applications for tissue engineering, immunophenotyping, and ENT-oncology
      were tested. Considering its microanalytical capacities, LSC proved to be a
      convincing tool for clinical use. Additionally, complex structures such as bi
      layers of cultured cells were analysed. CONCLUSION: A broad spectrum of
      applications in clinical practice and research for the LSC is evident.

PMID- 15029427
TI  - [Proctologic diseases].

PMID- 15029428
TI  - [Functional anatomy of rectum and anus].
AB  - The anatomical structures of the rectum and anus are a functional unit designed
      to maintain continence mechanism. A pure anatomical description often fails to
      delineate this critical functional interaction. The topographic anatomy of the
      anorectum must be combined with an understanding of the mechanisms of anal
      continence and defecation, which can be transferred to clinical and especially
      surgical practice. The feedback-controlled reflex system of continence must be
      understood; it hinges on a complex interaction between the somatic and autonomic
      nervous systems.

PMID- 15029429
TI  - [Hemorrhoids. Differential diagnosis and therapy].
AB  - Hemorrhoidal disease results from the pathological enlargement and distal
      displacement of the upper hemorrhoidal plexus. This disorder is very widespread
      in modern industrial society. Hereditary predisposition, malnutrition with
      constipation and abnormal bowel habits seem to be the most relevant causes for
      pathogenesis. The exact classification of hemorrhoids according to the degree of
      prolapse as well as the correct evaluation of accompanying anal diseases are very
      important in order to choose the appropriate conservative or surgical treatment
      with the goal of long-term avoidance of recurrence.

PMID- 15029430
TI  - [Virus-induced anorectal diseases. Condylomata acuminata and herpes simplex].
AB  - Genital warts (condylomata acuminata) are very common sexually transmitted
      infections which may be present in perianal, anal and rarely rectal sites. Their
      incidence in the population is about 0.1%. As a rule, the diagnosis is simple and
      can be made by inspection; some variants pose a diagnostic challenge. The therapy
      is not uniform; it must be adjusted to the clinical manifestations and can be
      conservative or operative. Herpes simplex infections are also common; they too
      may be transferred by sexual intercourse and then commonly appear in the perianal
      skin and the rectal mucosa. While the clinical diagnosis is often difficult, the
      treatment is simple and effective.

PMID- 15029431
TI  - [Treatment of pilonidal sinus and acne inversa].
AB  - A pilonidal sinus is a invagination of the skin over the sacrum containing a tuft
      of hair which enlarges by repeated friction causing the hairs to penetrate the
      skin. It may become symptomatic if an infection occurs. There are similarities
      with acne inversa, which is present in about 23% of cases. Acne inversa is an
      inflammation of the sebaceous glands and terminal hair follicles, chiefly in the
      intertriginous areas. The first manifestation can occur at any time from puberty
      to advanced age. 90% of patients are smokers. Initially giant comedones and
      indolent subcutaneous nodules are found; they progress to form draining sinus
      tracts. Conservative treatment, incision and/or surgical removal of the abscesses
      and fistulas is futile. The method of choice is the early complete surgical
      excision of the involved skin extending into normal tissue both laterally and at
      the base. In most cases healing of the defects by secondary intention is
      uneventful.

PMID- 15029432
TI  - [Perianal dermatitis and its benign simulants].
AB  - Perianal dermatitis is one of the most common proctological disorders. Concerning
      the etiology, three different types of dermatitis must be distinguished-the most
      common irritative contact dermatitis, atopic dermatitis and allergic contact
      dermatitis. The correct diagnosis is essential for adequate and successful
      treatment. A variety of benign and malignant disorders must be considered in the
      differential diagnosis of anal dermatitis. Dermatitic clinical disorders which do
      not respond to therapy should always be biopsied.

PMID- 15029433
TI  - [Differential diagnosis of chronic perianal dermatitis. Premalignant and
      malignant disorders].
AB  - Several premalignant and malignant neoplasms clinically appear as chronic
      eczematous lesions of the perianal region and have to be distinguished from
      benign processes. Anal intraepithelial neoplasia (AIN) presenting as bowenoid
      papulosis and perianal Bowen disease is a precursor lesion for invasive squamous
      cell carcinoma. When AIN is widespread, persistent or progressive, an underlying
      immunosuppression should get excluded. Verrucous carcinoma of the perianal region
      is a highly differentiated variant of squamous cell carcinoma characterized as a
      slowly growing but locally invasive tumor. Extramammary Paget disease (EMP) is an
      intraepithelial adenocarcinoma of the skin with apocrine differentiation. Along
      with EMP, basal cell carcinoma, Langerhans cell histiocytosis and cutaneous T
      cell lymphoma should be included in the differential diagnosis for lesions
      simulating chronic perianal dermatitis. In such situations, biopsies and
      histopathologic examination are imperative to avoid delayed diagnosis and assure
      prompt therapy.

PMID- 15029434
TI  - [Cutaneous oxygen supply. With special consideration of skin uptake of oxygen
      from the atmosphere].
AB  - Oxygen reaches the skin from the blood as well as from the atmosphere. The
      diffusion gradient is a key factor in oxygen delivery. Measurements with puncture
      electrodes show a maximum oxygen partial pressure on the skin surface and a
      minimum in the deeper dermis. Non-invasive measures show that oxygen uptake
      depends on location. Assuming the oxygen consumption is 0.276+/-0.029 ml O(2).100
      g(-1).min(-1) (37 degrees) and no oxygen is removed by capillaries, then the skin
      can be supplied by atmospheric oxygen to a depth of 0.25 to 0.40 mm, well into
      the dermis. Only the deeper dermis receives oxygen from the blood. The stratum
      corneum is a significant barrier to diffusion from the atmosphere. When this
      barrier is damaged, the oxygen diffusion increases Keratinocytes in culture
      proliferate in response to increased oxygen pressure; the same mechanism may
      explain epidermal hyperplasia following stratum corneum damage in vivo.

PMID- 15029435
TI  - [Bacterial colonization of chronic wounds. Studies on outpatients in a university
      dermatology clinic with special consideration of ORSA].
AB  - In this retrospective investigation, we documented the bacterial colonization of
      79 patients with chronic wounds, who had been treated between January 2002 and
      May 2003 in an outpatient wound healing clinic of a university dermatology
      program. We isolated 106 facultative pathogenic bacterial strains of which 56
      were Staphylococcus aureus, 19 Pseudomonas aeruginosa, 11 Escherichia coli, 4
      Proteus mirabilis, 4 Enterobacter cloacae, 2 Serratia marcescens, 2 Streptococcus
      group G und 8 further species. 68 of these bacterial strains were gram-positive
      and 46 gram-negative. Moreover we identified one patient with Candida
      parapsilosis. Therefore, 70.8% of all patients showed Staphylococcus aureus in
      their chronic wounds. Determination of the specific resistances showed 17
      patients to be colonized with oxacillin- resistant Staphylococcus aureus (ORSA)
      strain; this corresponds to 21.5% of all patients. Consequently, 30.4% of all
      Staphylococcus aureus isolates were ORSA strains. All of the ORSA isolates were
      sensitive to vancomycin. Sensitivity to tetracycline was documented in 15, to
      amikacin in 13, to clindamycin in 7, to gentamicin and erythromycin in 6 of the
      ORSA-positive patients. In the case of trimethoprim/sulfamethoxazole, 10 were
      sensitive and 3 were intermediate in sensitivity. Beside the obligate resistance
      to oxacillin, penicillin G, ampicillin, cefuroxime and imipenem, none of the ORSA
      was sensitive to ofloxacin. The results of our investigations demonstrate the
      actual spectrum of bacterial colonization in chronic wounds of patients in an
      university dermatologic wound clinic and underline the growing problem of ORSA.

PMID- 15029436
TI  - [Facial folliculo-sebaceous cystic hamartoma. Treatment with CO2 and Er:YAG
      lasers].
AB  - Folliculo-sebaceous cystic hamartoma (FCH) is defined as an adnexal hamartoma.
      The histopathological findings of FCH are equivalent to a very late stage of
      trichofolliculoma. The clinical appearance of FCH is unspecific. For this reason
      in the majority of cases it is only the histopathological examination that leads
      to the diagnosis of FCH. Up to now FCH has been treated with surgical procedures.
      We combined the use of both CO2 and Er:YAG lasers to treat a facial FCH.

PMID- 15029437
TI  - [Sporotrichoid atypical mycobacterial infections. Antibiotic monotherapy].
AB  - Sporotrichoid forms of atypical mycobacterial infections usually do not show a
      tendency to spontaneous healing. The therapy of choice in such cases is systemic
      antibiotics. We report three cases of sporotrichoid atypical mycobacterial
      infections of the skin which healed completely under long-term monotherapy with
      modern antibiotics (levofloxacin, clarithromycin, minocycline). We recommend
      confirming the diagnosis by means of culture, followed by monotherapy with low
      side-effect antibiotics, based on sensitivity studies. If pathogen proof is
      obtained by PCR, antibiotic therapy should be based on the known sensitivity of
      the pathogen in question.

PMID- 15029438
TI  - [Treatment of recalcitrant wounds with autologous epidermal equivalents. After
      excision of multiple cylindromas of the scalp].
AB  - A 63 year old man developed non-healing ulcerations after en-bloc resection of
      multiple cylindromas of the scalp. After excision and granulation-stimulating
      local therapy, the wound was covered with mesh grafts from the thighs. He
      developed widespread tension blisters with superficial ulcerations in the
      occipital region which did not heal despite adequate topical therapy. We then
      treated him successfully with EpiDex, a tissue engineered fully differentiated
      epidermal equivalent derived from keratinocytes of the outer root sheath of
      plucked anagen hair follicles. We introduce this treatment modality as a non
      invasive effective option in treating non-healing ulcers.

PMID- 15029440
TI  - [Subtle, circumscribed plications along Langer's lines].

PMID- 15029439
TI  - [Addiction to tobacco and the consequences for the skin].
AB  - Consumption of tobacco is hazardous to the health. It leads to cardiovascular
      diseases, and increases the incidence of numerous neoplasms. The adverse effects
      on the skin are less well-known and often ignored. Changes in the rheologic
      characteristics of the blood, increased vasoconstriction and damage to the
      epithelial layer of the vessel play an important pathogenic role in impaired
      wound healing, thromboangiitis obliterans and peripheral arterial obstructive
      diseases. Interactions with collagen metabolism are of special significance in
      wound healing and skin aging. The immunological effects, such as the induction of
      an inflammation reaction play a role in palmoplantar pustulosis, psoriasis,
      atopic dermatitis, acne vulgaris, acne inversa, thromboangiitis obliterans and
      lupus erythematodes. In addition, immunosuppression caused by nicotine
      consumption may contribute to the pathogenesis of human papilloma-virus
      infections, malignant melanoma and epithelial tumors of the skin and neighboring
      mucous membranes.

PMID- 15029443
TI  - [Aspirin against cylindromatosis? Molecular functions of the CYLD tumor
      suppressor].

PMID- 15029444
TI  - [Organization model for postoperative pain management in a basic-care hospital].
AB  - Small hospitals often lack the financial and personnel resources to realize
      innovative postoperative pain management concepts. This is not-as shown here-an
      absolute contradiction. The regular measurement of pain and its documentation by
      ward nurses as well as the appropriate prescription of analgesics play a key role
      in our concept. The joint establishment of guidelines, information sessions and
      the on-going dialog between the various professional groups guarantees the
      necessary consensus of all specialists involved in postoperative pain control. If
      an anesthetist is available 24 h a day, a nurse-based acute pain service (APS)
      becomes available for managing patients with patient-controlled analgesia (PCA)
      systems. The use of PCA and the performance of pain visits at regular intervals
      increase patient comfort and satisfaction. In addition, it can contribute to
      reduced hospitalization time in the context of fast-track rehabilitation
      programs. In our opinion, embedding the measures in a quality management program
      has a valuable catalytic effect, although implementation takes at least 1-2
      years.

PMID- 15029445
TI  - Ultrastructural study of mitochondria in the spinal cord of transgenic mice with
      a G93A mutant SOD1 gene.
AB  - The purpose of this study was to examine mitochondrial changes in the spinal cord
      of transgenic mice of a relatively low transgenic copy number (gene copy 10)
      expressing a G93A mutant human Cu/Zn superoxide dismutase (SOD1) that were
      generated in our own laboratories by electron and immunoelectron microscopy from
      presymptomatic to symptomatic stages. Age-matched non-transgenic mice served as
      controls at each stage. Ultrastructurally, at the early presymptomatic stage,
      many mitochondria in large myelinated axons exhibited swelling with an increased
      number of cristae, and bore small vacuoles in the matrix, cristae or both, in the
      anterior root exit zone, anterior root, and in the neuropils of the ventral
      portion of the anterior horn. At the late presymptomatic stage, vacuoles of
      various sizes (including large ones) were observed in the same regions as in the
      previous stage. The intermembrane space of mitochondria was also vacuolated. In
      mitochondria with advanced vacuolation, the vacuolar space was filled with a
      granular or amorphous substance. At the symptomatic stage, mitochondrial
      vacuolation seen in the late presymptomatic stage persisted, although to a lesser
      extent. These vacuolated mitochondria were predominantly seen in the axons, but
      not in the somata of normal-looking neurons or dendrites at any stage, which
      differs from that described in other reports. Non-transgenic littermates
      occasionally exhibited vacuolar changes in the axons of anterior horns. However,
      they were smaller both in size and number than those in transgenic mice. By
      immunoelectron microscopy using an immunogold labeling method, at the
      presymptomatic and symptomatic stages both SOD1 and ubiquitin determinants were
      localized in vacuolated mitochondria, particularly in the granular or amorphous
      substance of large vacuoles, but were not detected in most normal-appearing
      mitochondria. The SOD1-immunoreactive mitochondria were exclusively observed in
      the axons, and not in proximal dendrites or somata. These findings suggest that
      the toxicity of mutant SOD1 directly affects mitochondria in the axons and
      increases with the disease progression. Thus, the mutant SOD1 toxicity might
      disrupt axonal transport of substrates needed for neuronal viability, leading to
      motor neuron degeneration. The localization of both ubiquitin and SOD1 in
      vacuolated mitochondria indicates that protein degradation by ubiquitin
      proteasomal system may be also disrupted by several pathomechanisms, such as
      decreased processing of ubiquitinated proteins due to impairment of mitochondrial
      function or of proteasomal function, both of which are caused by mutant SOD1.
      Moreover, giant mitochondrial vacuoles occupying almost the entire axonal caliber
      could be another contributing factor in motor neuron degeneration, in that they
      could physically block axonal transport.

PMID- 15029446
TI  - Slow component of axonal transport is impaired in the proximal axon of transgenic
      mice with a G93A mutant SOD1 gene.
AB  - The purpose of this study was to determine whether slow axonal transport of
      neurofilaments (NFs) is impaired in the spinal cord of G93A Cu/Zn superoxide
      dismutase (SOD1) mutant transgenic mice expressing a relatively low mutant
      protein (gene copy 10) and, if so, how the impairment occurs in this animal
      model. Transgenic mice were killed at the ages of 24, 28 and 32 weeks, and the
      cervical and lumbar spinal cords were examined under an electron microscope. Age
      matched non-transgenic wild-type mice served as controls. At 24 weeks (early
      presymptomatic stage), anterior horn cells were well preserved. The earliest
      morphological changes were mild vacuolar changes in the neuronal processes,
      particularly in proximal axons. At 28 weeks (late presymptomatic stage), mild
      neuronal loss of anterior horn neurons was observed. Vacuolar changes were more
      prominent in the proximal axons, including swollen axons (spheroids) and
      neuropils of the anterior horns. Vacuoles in the axons were frequently large
      enough to occupy almost the entire axonal caliber. The anterior roots were
      degenerative, showing vacuolar changes and myelin ovoids. Lewy body-like
      inclusions (LIs) consisting of filaments thicker than NFs (about 1.5 times larger
      in diameter) were frequently demonstrated in the neuronal processes including
      swollen axons (spheroids) and occasionally in the somata. At 32 weeks
      (symptomatic stage), the anterior horns showed a moderate to severe neuronal loss
      accompanied by prominent astrogliosis. Cord-like swollen axons consisting of
      accumulated NFs and many neurofilamentous accumulations were frequently observed
      in the anterior horn. Vacuolar changes were less prominent or disappeared in the
      neuropils of the anterior horns and the anterior roots, whereas LIs were
      frequently demonstrated within the neuronal processes including the cord-like
      swollen axons. In the anterior roots, degenerative changes such as marked fiber
      loss and frequent myelin ovoids were remarkable. No accumulation of NFs or
      mitochondrial vacuolation was detected in somata or proximal dendrites at any
      stage. These findings suggest that the slow component of axonal transport in the
      proximal axons is impaired at an early stage in this transgenic mouse model, and
      that the impairment is probably caused by a mechanical impediment of NFs, or by
      the accumulation of NFs in the proximal axon, as a result of the obstruction of
      the axonal flow that initially occurs by vacuolar changes, and is later
      exacerbated by accumulation of LIs.

PMID- 15029447
TI  - Aneurysmal subarachnoid hemorrhage in the first year of life: case report and
      review of the literature.
AB  - INTRODUCTION: Primary subarachnoid hemorrhage is rare in infancy. A bleeding
      arterial aneurysm as its cause is even less frequent. A review of the literature
      turned up 85 cases of cerebral aneurysm that occurred in the 1st year of life, 63
      of them presenting with subarachnoid hemorrhage (SAH). CASE REPORT: The authors
      report a case of an 8-month-old boy who presented with seizures due to ruptured
      anterior communicating (ACom) artery aneurysm with subsequent subarachnoid and
      intraventricular hemorrhage. The infant was operated successfully, without
      complications. DISCUSSION: In this report the authors highlight certain clinical
      and diagnostic features, surgical considerations, and outcomes of aneurysmal
      subarachnoid hemorrhage in the 1st year of life.

PMID- 15029448
TI  - Response properties of auditory activated cells in the occipital cortex of the
      blind mole rat: an electrophysiological study.
AB  - Previous studies have demonstrated that despite its blindness, the subterranean
      blind mole rat (Spalax ehrenbergi) possesses a noticeable lateral geniculate
      nucleus and a typical cyto-architectural occipital cortex that are reciprocally
      connected. These two areas, as revealed by the metabolic tracer 2-deoxyglucose,
      are activated by auditory stimuli. Using single unit recordings, we show that
      about 57% of 325 cells located within the occipital cortex of anesthetized mole
      rats responded to at least one of the following auditory stimuli--white noise,
      pure tones, clicks, and amplitude modulated tones--with the latter two being the
      most effective. About 85% of cells driven by either contralateral or ipsilateral
      stimulation also responded to binaural stimulation; about 13% responded only to
      binaural stimulation; and 2% were driven exclusively by contralateral
      stimulation. Comparing responsiveness and response strength to these three modes
      of stimulation revealed a contralateral predominance. Mean latency (+/-SD) of
      ipsilateral and contralateral responses were 48.5+/-32.6 ms and 33.5+/-9.4 ms,
      respectively. Characteristic frequencies could be divided into two distinct
      subgroups ranging between 80 and 125 Hz and between 2,500 and 4,400 Hz,
      corresponding to the most intensive spectral components of the vibratory
      intraspecific communication signals and airborne vocalizations.

PMID- 15029449
TI  - Cystic trigeminal schwannoma with fluid-fluid levels.

PMID- 15029451
TI  - Plastic surgery and psychomorphology: a new tool for improving communication
      between physician and dysmorphopathic patient and for perfecting appropriate
      patient selection.
AB  - The relationship between physician and patient is becoming more and more delicate
      and requires an appropriate amount of attention and balance; this holds true in
      all medical disciplines, particularly in the field of plastic surgery. In this
      research project, the author proposes the use of a psychomorphology evaluation,
      as well as, a psychomorpholinguistic approach, in the global evaluation of
      plastic surgery candidates. The aim of this project was to present a pilot study
      that evaluated plastic surgery patient/physician relationship satisfaction
      outcome using psychomorphology and psychomorpholinguistic evaluation methods. The
      research was performed by comparing, a sample group in which the psychomorphology
      evaluation method was used and a control group that was traditionally evaluated.
      All the patients in this study have been diagnosed and graded with the
      dysmorphopathy classification system. The evaluation of patient satisfaction was
      obtained using Huskisson's visual analogue scale and the SAT-P Satisfaction
      Profile. In the author's opinion this method has aided him in gathering more
      precise information and having a deeper comprehension of the patient's most
      profound psychological needs. This reduced the patient's inappropriate illusions
      and delusions, which lead to severe psychological problems in accepting
      themselves. In addition, this method also can help prevent patient
      dissatisfaction with surgical outcome, thus reducing medical-legal encounters.
      This is not a methodology for judging or categorizing a patient. It should not be
      confused with the traditional physiognomic analysis. It is a dynamic analysis
      that also integrates one's conflictual psychomorphological traits and by
      recognizing these, continually looks to arrive at a better comprehension for
      establishing a harmonious relationship between two people, in our situation,
      surgeon and patient.

PMID- 15029450
TI  - Perfusion CT in patients with advanced bronchial carcinomas: a novel chance for
      characterization and treatment monitoring?
AB  - Advanced bronchial carcinomas by means of perfusion and peak enhancement using
      dynamic contrast-enhanced multislice CT are characterized. Twenty-four patients
      with advanced bronchial carcinoma were examined. During breathhold, after
      injection of a contrast-medium (CM), 25 scans were performed (1 scan/s) at a
      fixed table position. Density-time curves were evaluated from regions of interest
      of the whole tumor and high- and low-enhancing tumor areas. Perfusion and peak
      enhancement were calculated using the maximum-slope method of Miles and compared
      with size, localization (central or peripheral) and histology. Perfusion of large
      tumors (> 50 cm3) averaged over both the whole tumor (P = 0.001) and the highest
      enhancing area (P = 0.003) was significantly lower than that of smaller ones.
      Independent of size, central carcinomas had a significantly (P = 0.04) lower
      perfusion (mean 27.9 ml/min/100 g) than peripheral ones (mean 66.5 ml/min/100 g).
      In contrast, peak enhancement of central and peripheral carcinomas was not
      significantly different. Between non-small-cell lung cancers and small-cell lung
      cancers, no significant differences were observed in both parameters. In seven
      tumors, density increase after CM administration started earlier than in the
      aorta, indicating considerable blood supply from pulmonary vessels. Tumor
      perfusion was dependent on tumor size and localization, but not on histology.
      Furthermore, perfusion CT disclosed blood supply from both pulmonary and/or
      bronchial vessels in some tumors.

PMID- 15029452
TI  - Anti-aging medicine and the aesthetic surgeon: a new perspective for our
      specialty.

PMID- 15029453
TI  - A discussion of pulsed dye laser treatment for linear scars with concave and
      erythematous appearance, by Y. Taniguchi, M. Muraoka, T. Harada, and N. Ito.

PMID- 15029454
TI  - Otoplasty: a comparison of techniques for antihelical defects treatment.
AB  - BACKGROUND: Prominauris, the most common malformative defect of the external ear,
      is dependent on a combination of elementary defects mainly affecting the
      antihelix and the concha. Transection versus cartilage weakening results in
      antihelix treatment are discussed. METHODS: In this study, 104 ears with
      antihelical defects were treated in 63 consecutive patients: the 33 patients (53
      ears) in group A, received a transection-based treatment, whereas the 30 patients
      (51 ears) in group B, underwent cartilage weakening and suture. All the patients
      were treated using a posterior access. The aesthetic results were evaluated by an
      independent well-trained plastic surgeon. RESULTS: No differences were found in
      correction degree and stability between the two methods, but cartilage weakening
      techniques provided a smoother and more natural curvature. CONCLUSIONS: Cartilage
      weakening techniques can lead to better aesthetic results, primarily because of a
      softer and more natural ear curvature.

PMID- 15029455
TI  - Risk of glove perforation in minor and major plastic surgery procedures.
AB  - BACKGROUND: Incidental needlestick injury with exposure of blood pathogens has a
      high incidence among health care workers. Because plastic surgeons make up an
      important risk group for this type of accident, this study sought to evaluate the
      incidence of glove perforation during minor and major plastic surgery procedures.
      METHODS: Evidence of glove perforation was evaluated for 390 gloves after 100
      consecutive minor surgical procedures and for 710 gloves after 100 consecutive
      major surgeries using Maffuli's test. An index based on the number of first
      assistant's glove perforation and the surgical time was created to compare these
      accidents associated with both types of procedures. RESULTS: Glove perforations
      were found in four gloves (1.02%) after minor surgery and 76 gloves (21.40%)
      after major surgery. During minor surgeries, the assistant was more likely to
      have exposure than the surgeon. During major surgery, the surgeon experienced
      more glove perforations (59.21%) than the assistant (40.79%). The most common
      location of perforations was the palmar face of the left hand in both groups. The
      surgeons did not notice these perforations at any time. The duration of the minor
      procedures varied from 10 to 30 min (average, 17.55 min), whereas the time of
      major procedures ranged from 1 to 6 h (average, 186 min). There was no
      statistical significant difference in the perforation's index between minor and
      major procedures. CONCLUSIONS: The risk of perforation to the surgeon's glove
      during minor surgery is minimal. The frequency of perforation to the first
      assistant's glove is similar between minor and major plastic surgery procedures.

PMID- 15029456
TI  - Implications for nasal recontouring: nasion position preferences as determined by
      a survey of white North Americans.
AB  - White North American men (n = 75) and women (n = 75) were surveyed to investigate
      gender specific preferences of nasion position, which may aid plastic surgeons in
      nasal shaping during rhinoplasty. The subjects were asked to rank preferences of
      various nasion positions from life-size, scaled, sketched male and female
      profiles. Nasion positions with regard to height (anterior projection) and level
      (vertical position) were altered, whereas all other facial and nasal
      anthropometric measurements were held constant. The nasion heights were drawn at
      7, 10, and 13 mm anteriorly to the corneal plane, and the nasion levels were
      drawn at the supratarsal fold (ST), upper lid ciliary margin (CM), midpupil (MP),
      and lower limbus (LL). The rank selections made by the female and male subjects
      of both gender profiles demonstrated statistical significance, as demonstrated by
      one-way analysis of variance (ANOVA) of ranks (p < 0.001). Further analysis using
      a post-Dunn test was completed to delineate significant gender specific
      preferences for the aesthetic nasion level and height. Female nasion levels were
      preferred at CM or MP over LL or ST on the basis of female ranks, and at ST, CM,
      or MP over LL on the basis of male ranks (p < 0.05 for all comparisons).
      Additionally, female nasion heights were preferred at 10 mm > 13 mm > 7 mm
      anterior to the corneal plane on the basis of both female and male ranks (p <
      0.05 for all comparisons). Male nasion levels were preferred at ST, CM, or MP
      over LL on the basis of both male and female ranks ( p < 0.05 for all
      comparisons). Male nasion heights were preferred at 10 mm > 13 mm > 7 mm anterior
      to the corneal plane by both male and female ranks (p < 0.05 for all
      comparisons). In summary, both the male and female subjects strongly disliked a
      low nasion height of 7 mm and a low nasion level placed at LL for both gender
      profiles. Both the male and female subjects were most particular concerning
      nasion height, preferring a 10-mm projection and strongly disliking a deeper 7-mm
      height for both male and female profiles. Both the male and female subjects were
      more tolerant of nasion level alterations. Whereas the male subjects tolerated
      nasion levels at ST, CM, or MP for either gender profile, the female subjects
      preferred only nasion levels at CM and MP for the female gender. Overall, these
      findings may lend support to recent trends in radix augmentation during
      rhinoplasty, especially among male patients.

PMID- 15029457
TI  - Quantitative cholescintigraphy and bile abnormalities in patients with acalculous
      biliary pain.
AB  - Acalculous biliary pain has been related to gallbladder dysfunction that produces
      a gallbladder emptying defect-a condition which favours the development of
      lithiasis. It is therefore probable that microlithiasis is present in patients
      with gallbladder dysfunction. The aims of this study were to measure gallbladder
      emptying and investigate bile abnormalities in patients with acalculous biliary
      pain. In 92 consecutive patients, gallbladder emptying was assessed by
      quantitative cholescintigraphy (abnormal ejection fraction < or =40%). In 64
      patients, a microscopic study was performed on duodenal bile, defining
      abnormality as the presence of cholesterol crystals in any amount and/or calcium
      bilirubinate granules and/or microspheroliths at a rate of >10 per slide. The
      ejection fraction was abnormal in 45 patients (49%) (median 25.1%, range 6.8
      39.3%) and normal in the remaining 47 cases (median 71.3%, range 41.0-96.1%).
      Bile was abnormal in 32 of 64 patients (50%), the most frequent finding being
      calcium bilirubinate granules. In the patients with bile abnormalities, abnormal
      ejection fraction was more frequent (20 of 32) and the median ejection fraction
      was lower (30.9%, range 12.0-94.1%) than in the patients with normal bile (16 of
      32 with an abnormal ejection fraction; median ejection fraction 50.7%, range 6.8
      96.1%). Abnormal bile was frequent (55.5%) in patients with reduced ejection
      fraction, but was not uncommon in patients with normal ejection fraction (33.3%).
      Fewer patients showed no alteration (25%). It is concluded that in most patients,
      acalculous biliary pain coexists with gallbladder dysfunction or abnormal bile,
      the combination of both alterations being common.

PMID- 15029458
TI  - Radiolabelling of glycosylated MFE-23::CPG2 fusion protein (MFECP1) with 99mTc
      for quantitation of tumour antibody-enzyme localisation in antibody-directed
      enzyme pro-drug therapy (ADEPT).
AB  - MFECP1 is a glycosylated recombinant fusion protein composed of MFE-23, a high
      affinity anti-carcinoembryonic antigen (CEA) single chain Fv (scFv), fused to the
      enzyme carboxypeptidase G2 (CPG2), and has been constructed for use in antibody
      directed enzyme pro-drug therapy (ADEPT). Radiolabelling of glycosylated MFECP1
      with technetium-99m was developed for the purpose of determining tumour
      localisation of MFECP1 in a phase I ADEPT clinical study. The method used was
      99mTc-carbonyl [99mTc(H2O)3(CO)3]+ (abbreviated to TcCO) mediated labelling of
      99mTc to the hexahistidine (His) tag of MFECP1. MFECP1 fusion protein was
      labelled with TcCO under a variety of conditions, and this was shown to be a
      relatively simple and robust method. Tissue biodistribution was assessed in a CEA
      expressing LS174T (human colon carcinoma) nude mouse xenograft model. Tissues
      were taken at 1, 4 and 6 h for assessment of distribution of radioactivity and
      for measurement of CPG2 enzyme levels. The amount of radioactivity retained by
      the tumour proved to be an accurate estimation of actual measured enzyme
      activity, indicating that this radiolabelling method does not appear to damage
      the antibody-antigen binding or the enzyme activity of MFECP1. However,
      correlation between CPG2 enzyme activity and measured radioactivity in liver,
      spleen and kidney was poor, indicating retention of radioactivity in non-tumour
      sites but loss of enzyme activity. The high retention of technetium radioisotope
      in normal tissues may limit the clinical applicability of this radiolabelling
      method for MFECP1; however, these results suggest that this technique does have
      applicability for measuring the biodistribution of His-tagged recombinant
      proteins.

PMID- 15029459
TI  - 68Ga-labelled DOTA-derivatised peptide ligands.
AB  - 68Ge/68Ga generators provide cyclotron-independent access to positron emission
      tomography (PET) radiopharmaceuticals. We describe a system which allows the safe
      and efficient handling of 68Ge/68Ga generator eluates for labelling of DOTA
      derivatised peptide ligands. The system comprises concentration and purification
      of the 68Ga eluate as well as labelling and purification steps for peptides, and
      can be used with different 68Ge/68Ga generator types. The suitability and
      efficiency were tested with two different DOTA-derivatised somatostatin
      derivatives and a DOTA-derivatised bombesin derivative. Amounts of 10-20 nmol of
      the peptides were sufficient and resulted in labelling yields of 50% for all
      peptides. The built-in safety precautions have proven to be appropriate in
      allowing use of the method for routine clinical applications. The system was set
      up and operated in a "hot lab" by personnel with no previous experience in the
      preparation of PET radiopharmaceuticals.

PMID- 15029460
TI  - Role of MIBG myocardial scintigraphy in the assessment of heart failure: the need
      to establish evidence.

PMID- 15029461
TI  - Oestrogen-mediated regulation of somatostatin receptor expression in human breast
      cancer cell lines assessed with 99mTc-depreotide.
AB  - Investigating three somatostatin receptor (SSTR)-positive (+) human breast cancer
      cell lines, Xu et al. found a time- and dose-dependent up- or down-regulation of
      SSTR2 mRNA expression by 17beta-oestradiol (E(2)) or the anti-oestrogen
      tamoxifen, respectively, in the two oestrogen receptor-positive (ER+) cell lines
      but not in the oestrogen receptor-negative (ER-) cell line. This study aimed to
      confirm the findings of Xu et al. at the protein level by means of western
      blotting and saturation binding studies using (99m)Tc-depreotide (NeoSpect). The
      ER+/SSTR+ ZR75-1 and T47D and SSTR+/ER- MDA MB231 breast cancer cell lines were
      exposed to 1 n M E(2) or a combination of 1 n M E(2) plus 100 n M tamoxifen or
      ICI 182 780 (Faslodex) for 48 h. Exposed and non-exposed controls were incubated
      with increasing concentrations of (99m)Tc-depreotide (0.5 n M-15 n M) in the
      absence and the presence of 20 micro M of octreotide. Scatchard-Rosenthal plots
      were derived using commercially available software. SSTR subtypes responsible for
      E(2)-induced changes in (99m)Tc-depreotide binding were identified by means of
      western blotting. Mean K(d) values for (99m)Tc-depreotide were 13 n M, 7 n M and
      4 n M for T47D, ZR75-1 and MDA MB231 cells, respectively. After stimulation with
      E(2), the ER+ cell line T47D demonstrated a mean increase of 81% ( P<0.05) in
      (99m)Tc-depreotide binding. Adding the partial agonist tamoxifen and full
      antagonist ICI 182 780 to E(2) blocked the induced increase in T47D cells, either
      reducing SSTR expression or restoring it to control levels. ZR75-1 cells
      stimulated with E(2) showed a mean decrease in (99m)Tc-depreotide binding of 36%
      as compared to control cells; this difference, however, proved to be not
      statistically significant. Similarly, B(max) values did not change in ZR75-1
      cells exposed to E(2) in combination with an ER antagonist as compared to control
      cells. Finally, no influence of E(2) on (99m)Tc-depreotide binding was observed
      in the ER- cell line MDA MB231. Both SSTR2 and SSTR5 were expressed at high
      levels in T47D cells and ZR75-1 cells. SSTR5 drastically increased in the absence
      of E(2) and was restored to the original detection level after E(2) treatment.
      The presented findings support an oestrogen-dependent regulation of SSTR
      expression in breast cancer cell lines.

PMID- 15029462
TI  - A new reconstruction strategy for image improvement in pinhole SPECT.
AB  - Pinhole single-photon emission computed tomography (SPECT) is able to provide
      information on the biodistribution of several radioligands in small laboratory
      animals, but has limitations associated with non-uniform spatial resolution or
      axial blurring. We have hypothesised that this blurring is due to incompleteness
      of the projection data acquired by a single circular pinhole orbit, and have
      evaluated a new strategy for accurate image reconstruction with better spatial
      resolution uniformity. A pinhole SPECT system using two circular orbits and a
      dedicated three-dimensional ordered subsets expectation maximisation (3D-OSEM)
      reconstruction method were developed. In this system, not the camera but the
      object rotates, and the two orbits are at 90 degrees and 45 degrees relative to
      the object's axis. This system satisfies Tuy's condition, and is thus able to
      provide complete data for 3D pinhole SPECT reconstruction within the whole field
      of view (FOV). To evaluate this system, a series of experiments was carried out
      using a multiple-disk phantom filled with 99mTc solution. The feasibility of the
      proposed method for small animal imaging was tested with a mouse bone study using
      99mTc-hydroxymethylene diphosphonate. Feldkamp's filtered back-projection (FBP)
      method and the 3D-OSEM method were applied to these data sets, and the visual and
      statistical properties were examined. Axial blurring, which was still visible at
      the edge of the FOV even after applying the conventional 3D-OSEM instead of FBP
      for single-orbit data, was not visible after application of 3D-OSEM using two
      orbit data. 3D-OSEM using two-orbit data dramatically reduced the resolution non
      uniformity and statistical noise, and also demonstrated considerably better image
      quality in the mouse scan. This system may be of use in quantitative assessment
      of bio-physiological functions in small animals.

PMID- 15029463
TI  - 99mTc-EDDA/HYNIC-TOC scintigraphy in the differential diagnosis of solitary
      pulmonary nodules.
AB  - Forty-three consecutive patients with solitary pulmonary nodules (SPNs) on chest
      radiographs were studied scintigraphically after administration of the
      somatostatin analogue (99m)Tc-EDDA/HYNIC-TOC. The objective of the study was to
      assess the usefulness of the procedure for differentiation of SPNs as malignant
      or benign. The administered activity was 740-925 MBq, and a single-photon
      emission computed tomography imaging technique was employed. Verification of the
      nodule aetiology was based on histology or cytology and bacteriology. A stable
      tumour size on chest radiography for at least 3 years was accepted as an
      additional criterion of benignity. In 29 patients, nodules were found to be
      malignant. The diagnoses included ten adenocarcinomas, five squamous cell
      carcinomas, two large cell carcinomas, six non-small cell lung cancers without
      specification of the more detailed morphology, two small cell lung cancers, two
      typical carcinoids and two metastatic tumours (leiomyosarcoma and malignant
      melanoma). In 14 patients the following benign tumours were diagnosed: four
      tuberculomas, one other granuloma, three hamartomas, one non-specific
      inflammatory infiltrate, one abscess, one peripheral carcinoid with the
      morphological characteristics of a benign tumour, one ectopic lesion of thyroid
      tissue and two benign tumours of unspecified aetiology with a stable size over 3
      and 5 years respectively. Positive scintigraphic results were obtained in 26 of
      the 29 patients (90%) with malignant SPNs; among these, 24 of the 25 (96%) cases
      of primary pulmonary carcinoma yielded positive results. The remaining two false
      negative cases were the metastatic tumours, liposarcoma and melanoma. Of the 14
      benign lesions, ten (71%) did not accumulate the radiopharmaceutical. The
      remaining four benign tumours that were visible on scintigrams comprised one
      tuberculoma, one hamartoma, one abscess and one case in which the diagnosis could
      not be established (the tumour had a stable size over 3 years). In conclusion,
      scintigraphy with (99m)Tc-EDDA/HYNIC-TOC appears to be an effective procedure for
      differentiation between malignant and benign SPNs. A fully credible assessment of
      the clinical efficacy of this procedure requires further study in a larger number
      of patients.

PMID- 15029465
TI  - Idiopathic arterial calcification in childhood.
AB  - Idiopathic arterial calcification in infancy is usually fatal with death in early
      life and diagnosis at post mortem. This report describes a unique, late
      presentation with hypertension and cardiac failure in a child aged 33 months,
      found to have widespread arterial calcification at radiological imaging. The
      calcium-phosphate axis was normal and there was no other demonstrable cause for
      calcification. Additionally, the histological features of arterial calcification
      at renal biopsy paralleled the findings in infants with this disorder. The late
      presentation in this case is unusual and has not been previously reported.
      Ultrasound and CT are sensitive for calcification, and the disease should be
      suspected in children presenting with cardiac or respiratory manifestations and
      features of arterial calcification, where no metabolic cause is established.

PMID- 15029464
TI  - Cerebral diffusion tensor images in children with tuberous sclerosis: a
      preliminary report.
AB  - BACKGROUND: In tuberous sclerosis (TS), tubers usually involve the white matter.
      Diffusion tensor (DT) images are used to demonstrate white-matter tracts.
      OBJECTIVE: To determine the changes in DT indices in supratentorial tubers and
      associated changes in the white-matter tracts adjacent to tubers in patients with
      TS. MATERIALS AND METHODS: The DT imaging indices, including first, second and
      third eigenvalues (EVs), apparent diffusion coefficients (ADCs), and fractional
      anisotropy (FA) in the white-matter lesions of tubers, were assessed in seven
      patients with TS exhibiting developmental delay and compared with controls.
      RESULTS: EV1, EV2, EV3, ADC and FA of the white-matter lesions of tubers were
      significantly different from contralateral unremarkable regions of the brain and
      from controls (P<0.05). The number of frontal and parietal tubers was
      significantly negatively correlated with EV1 of the superior longitudinal
      fasciculi of TS patients (r=-0.60, P =0.04). In addition, TS patients had
      significantly larger ADCs in the corona radiata and sagittal stratum than the
      control subjects. EV3s of the inferior longitudinal fasciculus and sagittal
      stratum were significantly more increased in the TS patients than in the control
      subjects. CONCLUSIONS: EV1, EV2, EV3, ADC and FA maps are potential tools for
      demonstrating cerebral white-matter changes owing to TS.

PMID- 15029466
TI  - Reduced plantar sensitivity alters postural responses to lateral perturbations of
      balance.
AB  - There is considerable evidence that lower-limb somatosensation contributes to the
      control of upright balance. In this study, we investigated the specific role of
      foot sole cutaneous afferents in the generation of balance corrections following
      lateral accelerations of the support surface. Participants were subjected to
      balance perturbations before and after targeted anesthesia of the cutaneous soles
      induced by intradermal injections of local anesthetic. Subject responses were
      quantified in terms of net joint torques at the ankles, hips and trunk. Contrary
      to the conclusions drawn in earlier studies, response torque impulses at the
      ankles and hips were clearly scaled with the perturbation impulse under both
      control and anesthetized conditions. Reduced plantar sensitivity produced a
      relative shift in compensatory torque production from the ankles and trunk to the
      hips. These findings demonstrate that plantar cutaneous afferents play an
      important role in the shaping of dynamic postural responses. Furthermore, the
      results suggest that loss of plantar sensation may be an important contributor to
      the dynamic balance deficits and increased risk of falls associated with
      peripheral neuropathies.

PMID- 15029467
TI  - Neural mechanisms of spatial stimulus-response compatibility: the effect of
      crossed-hand position.
AB  - Previous psychological experiments have indicated the existence of a visual
      proprioceptive interaction in spatial stimulus-response compatibility (SSRC)
      tasks, but there is little specific information on the neural basis of such
      interaction in humans. Using functional magnetic resonance imaging (fMRI), we
      compared the neural activity associated with two different aspects of spatial
      coding: the coding of the "internal" spatial position of motor-response effectors
      (i.e., the position of body parts) as obtained through proprioception, and the
      coding of "external" positions, i.e., the positions of visual stimuli. A 2 x 2
      factorial design was used to investigate the spatial compatibility (incompatible
      versus compatible) between a visual stimulus and hand position (crossed versus
      uncrossed). The subjects were instructed to respond to stimuli presented to the
      right or left visual field with either the ipsilateral (compatible condition) or
      the contralateral hand (incompatible condition). The incompatible condition
      produced stronger activation in the bilateral superior parietal lobule, inferior
      parietal lobule, and bilateral superior frontal gyrus than the compatible
      condition. The crossed-hand condition produced stronger activation in the
      bilateral precentral gyrus, superior frontal gyrus, superior parietal lobule, and
      superior temporal gyrus than the uncrossed-hand condition. These results suggest
      that activity in the frontal-parietal regions is related to two functions: (1)
      representation of the visual stimulus-motor response spatial configuration in an
      SSRC task, and (2) integration between external visual and internal
      proprioceptive sensory information. The activation in the superior temporal gyrus
      was not affected by the visual stimulus-motor response spatial configuration in
      an SSRC task; rather, it was affected by the crossed-hand posture. Thus, it seems
      to be related to representing internal proprioceptive sensory information
      necessary to carry out motor actions.

PMID- 15029468
TI  - On-line vs. off-line utilization of peripheral visual afferent information to
      ensure spatial accuracy of goal-directed movements.
AB  - Manual aiming movements are often initiated when one gazes at the target, while
      the hand is seen in peripheral vision. The objective of the present study was to
      determine whether vision of one's hand in peripheral vision and/or central vision
      as it progresses towards the target can be used to modulate the direction and the
      extent components of the initial movement impulse. Participants performed video
      aiming movements while vision of the cursor they were moving was permitted for
      its whole trajectory, 40 degrees to 15 degrees of visual angle, 15 degrees to 0
      degrees of visual angle, or not visible at all. Movements were to be completed
      within prescribed movement times varying between 300 ms and 900 ms. The results
      did not reveal endpoint accuracy or variability differences between the 40
      degrees -15 degrees and the 15 degrees -0 degrees visual feedback conditions.
      Both conditions yielded lower endpoint bias and variability than the no-vision
      condition from early on after movement initiation. This indicates that the visual
      afferent information available in the 40 degrees -15 degrees and the 15 degrees 
      0 degrees visual feedback conditions could be used to better plan upcoming
      movements than the no vision condition. From these data, it appears very unlikely
      that different portions of the retina are specialized for processing different
      movement attributes as has been suggested in the past (Paillard 1980; Paillard
      and Amblard 1985). Both the peripheral and central retina are apt at detecting on
      line extent and direction errors in one's movement. In addition, the data cast
      serious doubts on the widely accepted proposition that the movement initial
      impulse is essentially ballistic.

PMID- 15029469
TI  - Sleep-promoting properties of quetiapine in healthy subjects.
AB  - The aim of this study was to investigate the effects of quetiapine, an atypical
      antipsychotic, on polysomnographic sleep structure and subjective sleep quality.
      This double-blind, placebo-controlled, randomized cross-over study investigated
      the polysomnographic sleep structure and subjective sleep quality of 14 healthy
      male subjects given placebo, quetiapine 25 mg or quetiapine 100 mg. Volunteers
      were studied 3 times for 3 consecutive nights (N0, adaptation; N1, standard sleep
      conditions; N2, acoustic stress) 4 days apart. Treatment was administered orally
      1 h before bedtime on nights 1 and 2. Quetiapine 25 mg and 100 mg significantly
      improved sleep induction and continuity under standard and acoustic stress
      conditions. Increases in total sleep time, sleep efficiency, percentage sleep
      stage 2 and subjective sleep quality were seen. A significant increase in
      periodic leg movements during sleep was observed with quetiapine 100 mg. The
      sleep-improving properties of quetiapine may be important in counteracting
      different aspects of psychopathology in schizophrenia and other disorders. These
      sleep-inducing and sleep-modifying properties are probably related to
      quetiapine's receptor-binding profile, including its antihistaminergic,
      antidopaminergic and antiadrenergic properties. Other mechanisms might be
      relevant as well and further investigation is required.

PMID- 15029470
TI  - Dose-specific effects of scopolamine on canine cognition: impairment of
      visuospatial memory, but not visuospatial discrimination.
AB  - RATIONALE: The cholinergic system is linked extensively to memory, but its exact
      role remains controversial. In particular, scopolamine-induced impairment in
      rodents is not task specific, which may be due to difficulty in developing rodent
      protocols to assess deficits in recent memory, in which the remembered event is
      brief and distinct, and/or to non-specific behavioral impairment. OBJECTIVES: The
      present study sought to determine whether scopolamine-induced deficits in recent
      memory, using a working memory task, could be dose-specifically dissociated from
      deficits in associative memory in dogs. METHODS: A Latin-square design was used
      to determine the effect of scopolamine (5, 10 and 15 microg/kg; SC) on a variable
      delayed-non-matching-to-position (DNMP) task, which assesses visuospatial working
      memory. Subsequently, the minimal effective dose (15 microg/kg; SC) was
      administered prior to testing on a landmark discrimination task, which provides a
      measure of allocentric spatial ability, a black-white discrimination task, an
      oddity discrimination task and tests of exploratory behavior. We also
      investigated the effects of a 30 microg/kg dose (SC) on tests of oddity
      discrimination and behavioral activity. RESULTS: A 15 microg/kg dose produced
      significant impairment on the DNMP task, but did not affect performance of any
      discrimination task and did not alter behavior on tests of open field or
      curiosity. A 30 microg/kg dose caused disruption on discrimination performance
      and on open field measures. CONCLUSIONS: Working memory performance is most
      sensitive to scopolamine-induced impairment and can be dissociated from
      scopolamine-induced deficits in discrimination performance and non-cognitive
      behaviors. The present results indicate that scopolamine-induced impairments of
      working memory in the dog can serve as a model of age-related cholinergic
      dysfunction.

PMID- 15029471
TI  - Sigma1 receptor upregulation after chronic methamphetamine self-administration in
      rats: a study with yoked controls.
AB  - RATIONALE: Sigma(1) receptors (Sig-1R) are implicated in behavioral
      sensitization, conditioned place preference, and cellular restructuring induced
      by psychostimulants. We previously reported that rats which actively self
      administered methamphetamine for 5 weeks and were then withdrawn from
      methamphetamine for 24 h showed downregulation of dopamine D(2) autoreceptors
      (approximately 30%) in the midbrain and this was not seen in rats that passively
      received injections of methamphetamine or saline at the same time (yoked
      controls). Involvement of Sig-1R in the self-administration of psychostimulants,
      however, has never been reported. OBJECTIVES: This study examined neuroadaptive
      changes in Sig-1R in the brains of rats self-administering methamphetamine.
      METHODS: Three groups of rats were tested simultaneously 5 days per week, for 5
      weeks (25 daily sessions). Two groups served as yoked controls and passively
      received an injection of either 0.1 mg/kg methamphetamine or saline (not
      contingent on responding) each time a response-contingent injection of 0.1 mg/kg
      methamphetamine was actively self-administered by the first group of rats.
      Protein and mRNA levels of Sig-1R were then measured by Western and Northern
      blottings, respectively. RESULTS: There was a marked upregulation of Sig-1R
      proteins (50%) in the midbrain and altered levels of Sig-1R mRNA in the frontal
      cortex and hippocampus of rats that learned to actively self-administer
      methamphetamine, but not in yoked methamphetamine- or saline-control rats.
      CONCLUSIONS: Neuroadaptive increases in Sig-1R seen in this study may contribute
      to the reinforcing effects of methamphetamine. This upregulation of Sig-1R may be
      mediated by increased protein kinase A activity due to downregulation of dopamine
      D(2) autoreceptors.

PMID- 15029472
TI  - MDMA ("ecstasy"), methamphetamine and their combination: long-term changes in
      social interaction and neurochemistry in the rat.
AB  - RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) and methamphetamine (METH)
      are illicit drugs that are increasingly used in combination. The acute and long
      term effects of MDMA/METH combinations are largely uncharacterised. OBJECTIVES:
      The current study investigated the behavioural, thermal and neurotoxic effects of
      MDMA and METH when given alone or in combined low doses. METHODS: Male rats
      received four injections, one every 2 h, of vehicle, MDMA (2.5 or 5 mg/kg per
      injection), METH (2.5 or 5 mg/kg per injection) or combined MDMA/METH (1.25+1.25
      mg/kg per injection or 2+2 mg/kg per injection). Drugs were given at an ambient
      temperature of 28 degrees C to simulate hot nightclub conditions. Body
      temperature, locomotor activity and head-weaving were assessed during acute drug
      administration while social interaction, anxiety-related behavior on the
      emergence test and neurochemical parameters were assessed 4-7 weeks later.
      RESULTS: All treatments acutely increased locomotor activity, while pronounced
      head-weaving was seen with both MDMA/METH treatments and the higher dose METH
      treatment. Acute hyperthermia was greatest with the higher dose MDMA/METH
      treatment and was also seen with MDMA but not METH treatment. Several weeks after
      drug administration, both MDMA/METH groups, both METH groups and the higher dose
      MDMA group showed decreased social interaction relative to controls, while both
      MDMA/METH groups and the lower dose MDMA group showed increased anxiety-like
      behaviour on the emergence test. MDMA treatment caused 5-HT and 5-HIAA depletion
      in several brain regions, while METH treatment reduced dopamine in the prefrontal
      cortex. Combined MDMA/METH treatment caused 5-HT and 5-HIAA depletion in several
      brain regions and a unique depletion of dopamine and DOPAC in the striatum.
      CONCLUSIONS: These results suggest that MDMA and METH in combination may have
      greater adverse acute effects (head-weaving, body temperature) and long-term
      effects (decreased social interaction, increased emergence anxiety, dopamine
      depletion) than equivalent doses of either drug alone.

PMID- 15029473
TI  - What is the daily practice of mechanical ventilation in pediatric intensive care
      units? A multicenter study.
AB  - OBJECTIVE: To describe the daily practice of mechanical ventilation (MV), and
      secondarily, its outcome in pediatric intensive care units (PICUs). DESIGN:
      Prospective cohort of infants and children who received MV for at least 12 h.
      SETTING: Thirty-six medical surgical PICUs. PATIENTS: All consecutive patients
      admitted to the PICUs during 2-month period. MEASUREMENTS AND MAIN RESULTS: Of
      the 1893 patients admitted, 659 (35%) received MV for a median time of 4 days
      (25th percentile, 75%: 2, 6). Median of age was 13 months (25th percentile, 75%:
      5, 48). Common indications for MV were acute respiratory failure (ARF) in 72% of
      the patients, altered mental status in 14% of the patients, and ARF on chronic
      pulmonary disease in 10% of the patients. Median length of stay in the PICUs was
      8 days (25th percentile, 75%: 5, 13). Overall mortality rate in the PICUs was 15%
      (confidence interval 95%: 13-18) for the entire population, 50% (95% CI: 25-74)
      in patients who received MV because of acute respiratory distress syndrome, 24%
      (95% CI: 16-35) in patients who received MV for altered mental status and 16%
      (95% CI: 9-29) in patients who received MV for ARF on chronic pulmonary disease.
      CONCLUSION: One in every 3 patients admitted to the PICUs requires ventilatory
      support. The ARF was the most common reason for MV, and survival of unselected
      infants and children receiving MV for more than 12 h was 85%.

PMID- 15029476
TI  - [Prevention of nephrolithiasis. Established strategies and new concepts].
AB  - During the last 2 decades in Germany, only minor efforts were expended for the
      prevention of urinary stones. Substantial technical progress simplified the
      treatment of existing calculi; thus, it was more convenient to treat a new stone
      than to prevent its recurrence. But times change! In these days of financial
      squeeze in the medical system, prevention becomes more attractive. Nevertheless,
      strategies for kidney stone prevention developed. Established concepts for
      dietary advice were rejected due to the results of new randomized studies.
      Moreover, new pharmacological substances were introduced for metaphyalxis. The
      new concepts are feasible for the daily routine. For some treatment modalities in
      stone prevention, there is valid evidence from the literature, which should
      encourage us to adopt these modalities in the future. A number of drugs are used
      as "good common practice" without any proof from a randomized trial. Often
      prospective and valid studies are not available. The present paper intends to
      describe the status quo of nephrolithiasis prevention in Germany, focussing on
      confirmed data and unsolved problems.

PMID- 15029477
TI  - [GSTP1 CpG island hypermethylation as a molecular marker of prostate cancer].
AB  - BACKGROUND: Prostate cancer is the most commonly diagnosed cancer in men in
      Europe and North America. Despite its high prevalence, the molecular mechanism of
      its underlying development and progression is poorly understood. Many studies
      have revealed multiple molecular alterations during prostate cancer
      carcinogenesis. GSTP1 CpG island hypermethylation is one of the molecular changes
      that occur during carcinogenesis. METHODS: We evaluated the role of GSTP1 CpG
      island hypermethylation in prostatic cancers and discussed its possible role as a
      molecular biomarker of prostate cancer. RESULTS: Studies haven shown that GSTP1
      CpG island hypermethylation is present in about 90% of prostatic carcinomas. The
      DNA alteration was also detectable in body fluids such as blood, urine,
      ejaculate, or prostatic secretions. One study showed hypermethylation in
      histologically unsuspicious lymph nodes in surgical specimens in patients with
      biochemical PSA (prostate-specific antigen) recurrence. Additionally, it is
      possible to distinguish between normal prostatic tissue, benign prostatic
      hyperplasia, and prostate cancer. CONCLUSIONS: The detection of GSTP1 CpG island
      hypermethylation serves as a molecular marker in prostate cancer screening,
      detection, and diagnosis. It may even provide information on prostate cancer
      prognosis. However, prospective trials to evaluate its predictive value are
      necessary.

PMID- 15029479
TI  - [Retrocaval ureter].
AB  - A 13-year-old boy presented to our clinic with a newly found hydronephrosis,
      which was caused by a retrocaval ureter. Besides this we noticed a glandular
      hypospadia. After we made sure that the right kidney had a normal function in the
      ING, we removed the stenosed ureter segment and performed an end-to-end
      anastomosis. The DJ stent was removed without any complications 5 weeks after the
      operation.

PMID- 15029478
TI  - [Allergic contact eczema caused by lidocaine and latex gloves?].

PMID- 15029480
TI  - [Children and youths with neurogenic disturbances of bladder function. Bladder
      augmentation, substitution and the diversion of urine].
AB  - After the failure of conservative treatment in patients with neurogenic bladders,
      urinary diversion is a viable compromise between the urologist's concerns and the
      patient's desire, as the upper urinary tract can be protected in the long-term
      and high continence rates can be provided. This can be achieved with an
      acceptable complication rate. Our indications for orthotopic bladder augmentation
      or substitution involve patients with a good orthopedic condition and mobility,
      who find it easy to perform CISC through the urethra. A continent umbilical stoma
      offers a good alternative in obese, immobile or wheelchair bound patients. The
      serous lined extramural tunnel technique has proven to be superior to submucosal
      implantation in patients with fibrotic and dilated ureters.

PMID- 15029482
TI  - One-range addition theorems for derivatives of Slater-type orbitals.
AB  - Using addition theorems for STOs introduced by the author with the help of
      complete orthonormal sets of psi(alpha)-ETOs (Guseinov II (2003) J Mol Model
      9:190-194), where alpha=1, 0, -1, -2, ..., a large number of one-range addition
      theorems for first and second derivatives of STOs are established. These addition
      theorems are especially useful for computation of multicenter-multielectron
      integrals over STOs that arise in the Hartree-Fock-Roothaan approximation and
      also in the Hylleraas function method, which play a significant role for the
      study of electronic structure and electron-nuclei interaction properties of
      atoms, molecules, and solids. The relationships obtained are valid for arbitrary
      quantum numbers, screening constants and location of STOs.

PMID- 15029481
TI  - Evidence for a modifier of onset age in Huntington disease linked to the HD gene
      in 4p16.
AB  - Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal
      expansion of CAG repeats in the HD gene on chromosome 4p16.3. A recent genome
      scan for genetic modifiers of age at onset of motor symptoms (AO) in HD suggests
      that one modifier may reside in the region close to the HD gene itself. We used
      data from 535 HD participants of the New England Huntington cohort and the HD
      MAPS cohort to assess whether AO was influenced by any of the three markers in
      the 4p16 region: MSX1 (Drosophila homeo box homologue 1, formerly known as homeo
      box 7, HOX7), Delta2642 (within the HD coding sequence), and BJ56 ( D4S127).
      Suggestive evidence for an association was seen between MSX1 alleles and AO,
      after adjustment for normal CAG repeat, expanded repeat, and their product term
      (model P value 0.079). Of the variance of AO that was not accounted for by HD and
      normal CAG repeats, 0.8% could be attributed to the MSX1 genotype. Individuals
      with MSX1 genotype 3/3 tended to have younger AO. No association was found
      between Delta2642 (P=0.44) and BJ56 (P=0.73) and AO. This study supports previous
      studies suggesting that there may be a significant genetic modifier for AO in HD
      in the 4p16 region. Furthermore, the modifier may be present on both HD and
      normal chromosomes bearing the 3 allele of the MSX1 marker.

PMID- 15029483
TI  - In vitro study of a neodynium:yttrium aluminum perovskite laser on human
      nonexposed pulp after cavity preparation.
AB  - PURPOSE: The aim of this study was to investigate dental pulp reactions after a
      neodynium:yttrium aluminum perovskite laser pulse on the dentinal floor of
      occlusal cavities in an in vitro model. METHODS: A Lokki dt laser was used at 30
      Hz, 5 W, and 160 mJ for 0.5 s. The pulp reactions were analyzed in a previously
      described human tooth slice cultured model. The following markers were identified
      by immunohistochemistry: collagens I, III, and IV and HLA-DR-positive cells.
      RESULTS: After 4 days of culture, under laser pulse, a concentration of type III
      collagen beneath the odontoblast layer, a higher level of vessels and an
      accumulation of HLA-DR-positive cells were routinely observed subjacent to the
      cavity. CONCLUSION: This laser treatment leads to the first step of rapid pulp
      repair under culture conditions.

PMID- 15029484
TI  - Masticatory and nutritional aspects on fixed and removable partial dentures.
AB  - The aim of the present study was to evaluate mastication, food selection and
      nutritional aspects in two groups of persons restored with fixed (FPD, N=44) and
      removable (RPD, N=40) partial dentures respectively. The subjects were part of a
      cohort study of 67-68-year-old men living in Malmo, Sweden. The two groups were
      very similar regarding social factors and the inclusion criteria were chosen so
      that the groups were very equal regarding oral factors, apart from the difference
      in fixed and removable partial dentures. The number of natural teeth, number of
      replaced teeth and occlusal contacts did not differ significantly between the two
      groups, nor did the distribution of maxillary and mandibular dentures. A
      comprehensive examination of several general health factors included a home
      interview of dietary habits. A clinical examination included a 20-minute oral
      examination with registration of number of teeth, FPDs, RPDs, and occlusal
      contacts. It also included masticatory tests: chewing gum colour mixing, chewing
      gum bolus shaping, and swallowing threshold (number of strokes to the first
      swallow of an almond). The consumption of hard and soft foods was revealed by the
      dietary interview as well as the intake of energy and some nutrients. There was a
      significant difference between the groups regarding the capacity to mix the two
      coloured chewing gum, to shape the chewing gum bolus and in the consumption of
      hard foods. There was no difference in the swallowing threshold and the
      consumption of soft foods. The intake of energy and nutrients did not differ
      significantly between the groups. The differences in masticatory capacity found
      thus seem to have little, if any, effect on the factors of importance for general
      health. A reasonable explanation for the differences found is that artificial
      teeth that are well retained, such as FPDs, make more active chewing possible
      than do removable, and often somewhat loose-fitting partial dentures.

PMID- 15029488
TI  - Condition-specific outcome measures for low back pain. Part I: validation.
AB  - A literature review of the nine most widely used, condition-specific, self
      administered assessment questionnaires for low back pain has been undertaken.
      General and historic aspects, reliability, responsiveness and minimum clinically
      important difference, external validity, floor and ceiling effects and available
      languages were analysed for the nine most-used outcome tools. When considering
      which condition-specific measure to employ, the present overview on assessment
      tools should provide the necessary information to define the technical aspects of
      the nine questionnaires. These criteria, however, are only part of the
      consideration. In part II the construction of these scales in relationship to the
      measurement domains will be evaluated.

PMID- 15029489
TI  - Condition-specific outcome measures for low back pain. Part II: scale
      construction.
AB  - A literature review of the most widely used, condition-specific, self
      administered assessment questionnaires for low back pain has been undertaken. In
      part I, technical issues such as validity, reliability, availability and
      comparability were analyzed for the nine most widely used outcome tools. This
      second part focuses on the content and wording of questions and answers in each
      of the nine questionnaires, and an analysis of the different score results is
      performed. The issue of score bias is discussed and suggestions are given in
      order to increase the construct validity in the practical use of the individual
      questionnaires.

PMID- 15029490
TI  - Cold-stress-induced modulation of antioxidant defence: role of stressed
      conditions in tissue injury followed by protein oxidation and lipid peroxidation.
AB  - The aim of this study was to determine the effects of cold stress on antioxidant
      enzyme activities and examine protein oxidation and lipid peroxidation in various
      tissues (brain, liver, kidney, heart and stomach). Twenty male Wistar rats (3
      months old) weighing 220 +/- 20 g were used. The rats were randomly divided into
      two groups of ten: the control group and the cold stress group. Cold stress was
      applied to the animals by maintaining them in a cold room (5 degrees C) for 15
      min/day for 15 days. Blood samples were taken for measuring plasma corticosterone
      levels. Tissues were obtained from each rat for measuring the antioxidant enzyme
      activities, protein oxidation and lipid peroxidation. Corticosterone levels were
      increased in the cold stress group. Copper, zinc superoxide dismutase activities
      were increased in the brains, livers and kidneys, whereas they decreased in the
      hearts and stomachs of rats in the cold stress group. Catalase activities were
      increased in the brains, livers, kidneys and hearts, whereas they decreased in
      the stomachs of rats in the cold stress group. Selenium-dependent glutathione
      peroxidase activities were increased in the brain, liver, heart and stomach.
      Reduced glutathione levels were decreased, while levels of protein carbonyl,
      conjugated diene and thiobarbituric-acid-reactive substances were increased in
      all tissues of the cold stress group. These results lead us to conclude that cold
      stress can disrupt the balance in an oxidant/antioxidant system and cause
      oxidative damage to several tissues by altering the enzymatic and non-enzymatic
      antioxidant status, protein oxidation and lipid peroxidation.

PMID- 15029491
TI  - Microarray analysis of brassinosteroids- and gibberellin-regulated gene
      expression in rice seedlings.
AB  - In order to understand the molecular mechanisms by which two types of
      phytohormones, brassinosteroids (BRs) and gibberellins (GAs), regulate plant
      growth and development, a cDNA microarray was made containing 4000 clones
      randomly selected from a rice cDNA library constructed from RNA isolated from
      seedlings treated with GA(3) and brassinolide (BL). The array was then probed to
      identify differences in expression using labelled cDNAs prepared from treated and
      control seedlings. Nine and 29 unique cDNA clones were up-regulated, while 32 and
      42 unique cDNA clones were down-regulated by BL and GA(3), respectively. The
      predicted products of these BL- and GA-regulated genes fall into such functional
      categories as signal transduction, transcription, metabolism, cellular
      organization, and defense or anti-stress responses. Northern analysis of the
      selected BL- and GA(3)-regulated genes not only confirmed their BL or GA(3) dose
      dependent expression, but also revealed significant differences in the degree of
      expression in different organs and in response to other phytohormones. These
      results demonstrate that BR and GA influence growth and development by
      coordinately regulating the expression of specific groups of genes.

PMID- 15029492
TI  - Effects of tonicity, digestive enzymes and bile salts, and nutrient media on the
      survival of excysted metacercariae of Echinostoma caproni.
AB  - The effects of tonicity, digestive enzymes and bile salts, and various nutrients
      added to Locke's solution were studied on the chemically excysted metacercariae
      of Echinostoma caproni. Metacercariae were maintained at 37.5 degrees C in
      multiwell chambers, ten per 0.5 ml of test solution; each experiment was
      replicated five times. Most metacercariae maintained in deionized water or
      Locke's 2x solution were dead within 2 h. About 85% and 55% of the metacercariae
      were alive at 8 h in Locke's 1x and Locke's 0.5x, respectively. Metacercariae of
      this species are osmoconformers, as is the case for adult digeneans. All
      metacercariae were dead in an acid saline or acid pepsin medium by 2 h. About 50%
      of the metacercariae were alive in an alkaline trypsin-bile salts medium at 4 h.
      These results suggest that the acidic pepsin environment in the stomach of a
      definitive host would be detrimental to the survival of excysted metacercariae,
      but prolonged survival in alkaline trypsin-bile salts would facilitate
      establishment of this larval stage in the mucosa of the host small intestine.
      Studies on excysted metacercariae in Locke's 1x supplemented with various
      nutrients showed that optimal survival occurred in Locke's plus 0.1% glucose and
      in Locke's 1x plus 1% hen's egg yolk. Significant survival of excysted
      metacercariae in Locke's 1x supplemented with either 0.1% proline, 0.1%
      threonine, or 0.1% serine did not occur.

PMID- 15029493
TI  - Detection by real-time PCR of the Pfcrt T76 mutation, a molecular marker of
      chloroquine-resistant Plasmodium falciparum strains.
AB  - An efficient and fast diagnostic assay was developed to detect the point mutation
      involved in the resistance of Plasmodium falciparum to chloroquine. The test,
      based upon a real-time PCR principle and performed with the LightCycler system,
      was carried out on venous blood isolates from 221 cases of falciparum malaria.
      The assay provided a quick, sensitive and reliable detection of the T76 Pfcrt
      mutation and the chloroquine resistance. The results of this study suggest that
      this LightCycler-based technique could be used to optimise the treatment of
      imported uncomplicated falciparum malaria, and also for the molecular
      surveillance of drug resistance among imported cases of this disease.

PMID- 15029496
TI  - Confrontation of immunohistochemistry and fluorescent in situ hybridization for
      the assessment of HER-2/ neu (c-erbb-2) status in urothelial carcinoma.
AB  - Specific treatments targeted toward oncogenes expressed in cancer cells are
      currently under development. Patients with urothelial carcinomas showing HER-2/
      neu (human epidermal growth factor receptor 2) overexpression are candidates for
      such a specific treatment (trastuzumab). However, to be effective, this
      therapeutic approach requires an extremely reliable evaluation of HER-2/ neu
      status in tumors. In order to assess the status of expression of this gene and to
      optimize its assessment, we analyzed a series of 64 primary urothelial carcinomas
      using immunohistochemistry (IHC) with the CB11 monoclonal antibody coupled with
      fluorescent in situ hybridization (FISH) in 21 cases. Strong HER-2/ neu
      overexpression was detected using IHC in 15 of the 64 (23%) cases analyzed, and
      this rate rose to 33% for patients with metastases. HER-2/ neu overexpression, as
      revealed using IHC, is strongly associated (95%) with gene amplification assessed
      using FISH. Patients with urothelial carcinomas overexpressing HER-2/ neu using
      IHC are potential candidates for targeted chemotherapy.

PMID- 15029497
TI  - Identification of hypomorphic and null alleles of swallow via molecular and
      phenotypic analyses.
AB  - The swallow gene of Drosophila is required for the localization of two messenger
      RNAs, bicoid and hu-li tai shao, to the anterior pole of oocytes during the later
      stages of oogenesis. In addition, swallow appears to play a role in early
      embryogenesis, as swallow mutant embryos have defects in early nuclear cleavage
      and migration. In an effort to identify regions of the Swallow protein that are
      essential for function, we have initiated a molecular characterization of seven
      existing alleles of swallow. All seven alleles have been sequenced, and
      comparison to wild-type swallow indicates that the seven alleles include single
      amino acid substitutions that identify critical residues, as well as lesions that
      result in truncated proteins. Western blots using affinity-purified antibodies
      agree well with the DNA sequence data, and identify a probable null protein. In
      order to determine the extent to which each allele affects swallow function,
      females homozygous or hemizygous for each allele were tested for the range and
      abundance of (1) RNA localization defects, and (2) embryonic cuticular defects.
      Swallow alleles can be grouped into two categories: those that retain partial
      function, and those indistinguishable from the putative null allele. Some swallow
      mutant alleles partially rescue the dominant female sterility of mutations in the
      atypical 67C alpha-tubulin gene, supporting other studies that suggest a link
      between RNA localization and the microtubule cytoskeleton.

PMID- 15029498
TI  - snail expression during embryonic development of the coral Acropora: blurring the
      diploblast/triploblast divide?
AB  - Although corals are nominally diploblastic, the early development of Acropora
      millepora involves a process that clearly resembles gastrulation in higher
      metazoans. This similarity at the morphological level led us to search for the
      Acropora equivalents of genes whose key roles in gastrulation are conserved
      across the higher Metazoa. We here report the characterisation of one such gene,
      snail, which in both Drosophila and the mouse is expressed in cells undergoing an
      epithelial-mesenchyme transition and/or morphogenetic movements. In addition to
      an N-terminal SNAG domain, the Acropora snail protein contains four zinc fingers
      with sequences diagnostic for members of the snail protein subfamily. In situ
      hybridisation reveals expression in epithelial tissue in the central portion of
      one side of the flattened pre-gastrulation embryo, which continues to express
      snail as it is engulfed by its opposite layer. Comparison to snail expression
      during gastrulation in bilaterians such as Drosophila reveals striking
      similarities and suggests mechanistic, and possibly evolutionary, links between
      the processes of mesoderm formation in bilaterians and endoderm formation in the
      Cnidaria.

PMID- 15029499
TI  - Glaucoma and mortality.
AB  - PURPOSE: To compare mortality rates in glaucoma patients and matched controls
      from a large population screening as well as glaucoma patients diagnosed through
      routine clinical examination (self-selected patients). METHODS: A population
      based screening of 32,918 elderly citizens of Malmo was conducted between 1992
      and 1997. Individuals with newly detected, previously untreated open-angle
      glaucoma were identified. Two controls of the same age and gender were chosen
      among the screening negative participants for each patient. From the same birth
      cohorts, glaucoma patients seen in routine clinical practice (self-selected
      patients) were identified through retrospective examination of patient records
      from the Eye Department at Malmo University Hospital. The number and time of
      deaths for each group were determined based on centrally administered registers.
      RESULTS: Mean follow-up time was 7.75 years. Five-year mortality did not differ
      significantly between the groups, and was 9.2% among glaucoma patients from the
      screening (n=402), and 11.9% among the controls (n=804; p=0.7406). Self-selected
      glaucoma patients had a 5-year mortality of 8.5% (n=354), not significantly
      different from the screening-detected glaucoma patients (p=0.1361). Among
      glaucoma patients, neither IOP (p=0.1781) nor pseudoexfoliation (p=0.8882) was
      related to significantly increased mortality. CONCLUSIONS: The results of this
      study strongly suggest that the life expectancy of glaucoma patients does not
      differ from the population at large.

PMID- 15029500
TI  - Scanning laser polarimetry in myopic and hyperopic subjects.
AB  - PURPOSE: To investigate the effect of refraction error and axial length on
      retinal nerve fiber layer (RNFL) measurements as obtained by scanning laser
      polarimetry (SLP). METHODS: Besides ophthalmological standard examination
      (refractive error, keratometry, visual acuity, slit-lamp examination, applanation
      tonometry, funduscopy), perimetry, axial length measurement by means of
      ultrasound, and SLP were performed. Seventy-five myopic eyes (between -0.75 D and
      -8.5 D), 24 hyperopic eyes (0.75 D-6.5 D) and 40 emmetropic eyes were
      investigated. SLP parameters were compared in the different groups. RESULTS: The
      statistical analysis of the absolute thickness values of SLP revealed highly
      significant ( P< 0.01) reductions in average thickness, ellipse average, superior
      average, inferior average, and superior integral in both myopic and hyperopic
      eyes in comparison with the emmetropic control eyes. The amount of reduction was
      between 12.9% (inferior average; myopia) and 30.2% (superior integral;
      hyperopia). There were no significant differences between myopes and hyperopes. A
      significant linear correlation for many of the SLP parameters with the refractive
      error (spherical equivalent) but not with axial length was found in both the
      hyperopic and the myopic group. CONCLUSIONS: Despite a wide interindividual
      range, SLP measurement values decrease with increasing myopia and hyperopia. In
      clinical practice, such reduced RNFL thickness values should be viewed with the
      necessary caution and additional polarimetric signs for glaucomatous damage
      should be taken into consideration.

PMID- 15029501
TI  - Distribution of p27(KIP1), cyclin D1, and proliferating cell nuclear antigen
      after retinal detachment.
AB  - PURPOSE: To examine the expression of the p27(KIP1), cyclin D1, and proliferating
      cell nuclear antigen (PCNA) in the retina and retinal pigment epithelium (RPE)
      after retinal detachment. METHODS: Normal eyes and eyes at 2 or 4 days after
      retinal detachment with the C57B16 mouse were analyzed by immunocytochemistry
      using anti-p27(KIP1), anti-cyclin D1, and anti-proliferating cell nuclear antigen
      (PCNA) antibodies as well as anti-glutamate synthetase (GS) antibody. RESULTS:
      The p27(KIP1) positive nuclei were distributed in the inner nuclear layer (INL)
      and the RPE of the normal mice eye. In the INL, p27(KIP1) was detected in the
      middle sublayer, where the nuclei of glutamate synthetase positive Muller cells
      were situated. In contrast, cyclin D1 was not detected either in the retina or in
      the RPE. At 2 and 4 days after the retinal detachment, RPE cells under the
      detached retina were negative for p27(KIP1) and positive for cyclin D1 and PCNA.
      In the INL of the detached retina, p27(KIP1) was detected after 2 days, but was
      not detected after 4 days. In contrast, PCNA was not detected in the INL after 2
      days, but was detected after 4 days. Cyclin D1 was detected in the middle
      sublayer of the INL at both 2 and 4 days after the retinal detachment.
      CONCLUSION: These results suggested that degradation of p27(KIP1) and expression
      of cyclin D1 was involved in the proliferation of the Muller cells as well as RPE
      cells after retinal detachment.

PMID- 15029502
TI  - Induction of IL-8, MCP-1, and bFGF by TNF-alpha in retinal glial cells:
      implications for retinal neovascularization during post-ischemic inflammation.
AB  - BACKGROUND: We have demonstrated that macrophages/microglia were activated during
      post-ischemic inflammation in a mouse model of ischemic retinal
      neovascularization, and that the angiogenesis induced by tumor necrosis factor
      alpha (TNF-alpha) appeared to be modulated through such angiogenic factors as
      interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and basic
      fibroblast growth factor (bFGF) in microvascular endothelial cells. We have
      extended these studies, and investigated whether TNF-alpha is localized in
      macrophages/microglia in the mouse model of retinal neovascularization, and
      whether TNF-alpha can induce angiogenic factors in retinal glial cells. METHODS:
      C57BL/6 J pups were placed in a 75% oxygen environment on postnatal day 7 (P7)
      for 5 days and then returned to room air. The co-localization of TNF-alpha with
      macrophages/microglia in the ischemic retina was examined by fluorescent
      immunohistochemistry. Bovine retinal glial cells were isolated for Northern blot
      analysis to quantify the expression levels of monocyte chemotactic protein-1 (MCP
      1), IL-8, bFGF, and VEGF. RESULTS: Double staining of retinas revealed that the
      TNF-alpha expression level was enhanced in macrophages/microglia 4 days after the
      hypoxia. Cellular mRNA levels of MCP-1, IL-8, and bFGF, but not VEGF, were
      increased after treating retinal glial cells with TNF-alpha (100 U/ml).
      CONCLUSIONS: The results indicate that TNF-alpha is produced by activated
      macrophages/microglia and may participate in retinal neovascularization during
      post-ischemic inflammation through the induction of potent angiogenic factors in
      an autocrine or paracrine manner.

PMID- 15029503
TI  - Influence of viewing distance on vertical strabismus.
AB  - BACKGROUND: Vertical strabismus can be modulated by the viewing distance. We
      report on 19 patients with this disorder. METHODS: The following squint angles
      were measured by the alternate prism and cover test at a viewing distance of 5 m.
      At 0.3 m, measurements were taken with and without an addition of 3.0 D to the
      corrected refraction. Cases of a dissociated vertical deviation were excluded.
      Fifteen patients underwent surgery. They were reexamined 3 months later. RESULTS:
      At a viewing distance of 5 m, the vertical deviation ranged from 0 degrees to 16
      degrees (median 7 degrees ). At 0.3 m, the deviation increased by 2 degrees -15
      degrees (median 7 degrees ) in 15 patients and decreased by 3.5 degrees -8
      degrees (median 4.5 degrees ) in 4 patients. Eleven patients had a strabismus
      sursoadductorius and one had a strabismus deorsoadductorius. Eye muscle surgery
      reduced both the vertical deviation for distance fixation to 0 degrees -14
      degrees (median 2 degrees ) and the difference between the deviations for
      distance and proximal fixation to 1 degrees -6 degrees (median 3 degrees ).
      CONCLUSIONS: In certain cases, vertical strabismus can be modulated by
      convergence and accommodation. This condition is frequently associated with an
      incomitance of the vertical deviation in side gaze. The baseline deviation can be
      reduced by appropriate eye muscle surgery. In cases of vertical accommodative
      vergence, bifocal glasses can be helpful.

PMID- 15029504
TI  - Pharmacokinetics and safety of intravitreally delivered etanercept.
AB  - BACKGROUND: The anti-inflammatory drug etanercept may be an effective therapeutic
      agent in diabetic retinopathy. In order to further evaluate its potential, the
      pharmacokinetics and safety of this drug after intravitreal delivery were
      investigated. METHODS: After intravitreal administration of etanercept in
      rabbits, clinical examination, electroretinography (ERG), visually evoked
      potentials (VEP) and histology were evaluated. The pharmacokinetics and
      distribution of etanercept were analyzed using fluorescence-coupled protein at 0,
      2, 4, and 8 weeks after injection in vitreous, retina, and choroid. RESULTS: No
      adverse effects and signs of toxicity were found. Etanercept showed peak
      concentrations after 4 weeks in the retina and choroid. CONCLUSIONS:
      Intravitreally delivered etanercept is safe and results in high concentrations in
      the retina and choroid over a long period of time.

PMID- 15029506
TI  - Obstetrical and neonatal outcome in young adolescents of low socio-economic
      status: a case control study.
AB  - OBJECTIVE: The purpose of this study was to determine obstetrical and neonatal
      outcome among early adolescent pregnancies (< or =15 years). METHOD: We compared
      obstetrical and neonatal outcome of early adolescent nulliparas with outcome of
      nulliparous women aged 20-30 years. RESULTS: Two hundred and one (201) early
      adolescent nulliparous patients of low socio-economic status were enrolled at the
      Enrique C. Sotomayor Obstetrics and Gynecology Hospital, Guayaquil-Ecuador, and
      matched for gestational age with 201 low socio-economic nulliparous controls aged
      20-30. Mean maternal age of the adolescent group was 14.2+/-0.6 years. The
      incidence of cervicovaginal infections during current pregnancy was significantly
      higher among adolescents (trichomoniasis: 11.4% vs. 5% and candidiasis: 27.8% vs.
      12.4%, p<0.05). The incidence of eclampsia was higher in adolescents (2.5% vs.
      0%, p<0.05). The preterm rate in each group was 4.9%. There were no differences
      in labor characteristics and the rate of cesarean section, labor complications
      and abnormal puerperium between both studied groups. Nevertheless, mean neonatal
      weight was lower and the incidence of low birth weight infants (<2,500 g) and
      adverse neonatal outcome was significantly higher in the adolescent group
      (2,837.6+/-454 g vs. 3,017+/-547 g; 19.9% vs. 11.4% [OR=1.92, 95% CI: 1-3.5] and
      9.5% vs. 3.5% [OR=2.9, 95% CI: 1.1-7.7] respectively, p<0.05). CONCLUSION:
      Pregnancy in young adolescents (< or =15 years) of low socio-economic status did
      not impose adverse obstetrical outcome, however it did increase the risk for low
      birth weight, adverse neonatal outcome and cervicovaginal infections.

PMID- 15029505
TI  - Intraocular inflammation following endotamponade with high-density silicone oil.
AB  - BACKGROUND: The use of a mixture of silicone oil and partially fluorinated
      alkanes (high-density silicone oil) has recently been suggested as intraocular
      tamponade in complicated retinal detachment of the inferior quadrants. We
      describe a series of patients who developed a clinical picture resembling
      anterior granulomatous uveitis following endotamponade with high-density silicone
      oil. METHODS: We evaluated 19 eyes of 18 patients who underwent pars plana
      vitrectomy and intraocular tamponade with high-density silicone oil (Oxane HD).
      The indication for this type of intraocular tamponade was limited to cases with
      complicated retinal detachment of the inferior quadrants. Oxane HD was removed
      after a mean period of 3 months. RESULTS: One to eight weeks following vitrectomy
      with high-density silicone oil, an intraocular inflammation was observed in 7 of
      19 eyes (37%). These eyes presented with keratic precipitates (KP), pigmented
      clumps in the inferior part of the anterior chamber and increased anterior
      chamber cellular reaction. This inflammatory response did not react to topical
      steroids. In addition to KP a considerable amount of cellular precipitation was
      noted on the surface of the oil bubble. Strikingly, the intraocular inflammatory
      signs completely resolved following removal of the high-density silicone oil.
      CONCLUSIONS: An inflammatory response, resembling granulomatous uveitis, occurs
      in a significant number of patients after high-density silicone oil
      endotamponade. It is likely that this vitreous substitute is an immunogenic
      agent, given the complete resolution of the inflammation after removal of the
      high-density silicone oil. The routine use of this newly developed silicone oil
      should therefore await the outcome of additional controlled clinical trials.

PMID- 15029507
TI  - The role of transvaginal colour Doppler sonography in evaluation of abnormal
      uterine bleeding.
AB  - INTRODUCTION: Treatment of abnormal uterine bleeding understands a prompt
      diagnostic procedure, for the sake of defining the etiological factor of disease.
      The abnormal uterine bleeding is more common in the perimenopausal than in the
      postmenopausal women, and it is more frequent sign of an endometrial
      proliferative or hyperplastic changes. Fewer percentages of women with unexpected
      and/or acyclic and prolonged bleeding have endometrial cancer. MATERIALS AND
      METHODS: Seventy-one (71) patients with abnormal uterine bleeding, older than 40
      years, of which 10 were in post-menopause, have been tested. Prior to explorative
      curettage and histopathological analysis, ultrasonographic and hemodynamic
      studies, at the uterine blood vessels level (uterine artery bilaterally) had been
      performed by transvaginal colour Doppler method. RESULTS: Histopathological
      results indicated four types of represented changes, on the basis of how the
      patients were divided into the groups: I, proliferative endometrium--20 patients;
      II, endometrial adenocarcinoma--23 patients; III, various forms of endometrial
      hyperplasia--26 patients, IV, atrophic endometrium--2 patients. Significant
      statistical difference in the endometrial thickness was established between
      groups I and II, and endometrial cancer was not found in less than 8 mm thick
      endometrium. By analysing hemodynamic parameters, significantly lower PI values
      were obtained in the group of patients with pathologically altered endometrium,
      compared to other groups. CONCLUSION: Transvaginal colour Doppler has significant
      role in the diagnostic process for evaluation of abnormal uterine bleeding in
      perimenopausal and postmenopausal women. Doppler sonography can help in
      differentiating physiological from malignant endometrial changes and in deciding
      on the most efficient therapeutical regime.

PMID- 15029508
TI  - Automatic segmentation and plaque characterization in atherosclerotic carotid
      artery MR images.
AB  - In vivo MRI provides a means to non-invasively image and assess the morphological
      features of atherosclerotic carotid arteries. To assess quantitatively the degree
      of vulnerability and the type of plaque, the contours of the lumen, outer
      boundary of the vessel wall and plaque components, need to be traced. Currently
      this is done manually, which is time-consuming and sensitive to inter- and intra
      observer variability. The goal of this work was to develop an automated contour
      detection technique for tracing the lumen, outer boundary and plaque contours in
      carotid MR short-axis black-blood images. Seventeen patients with carotid
      atherosclerosis were imaged using high-resolution in vivo MRI, generating a total
      of 50 PD- and T1-weighted MR images. These images were automatically segmented
      using the algorithm presented in this work, which combines model-based
      segmentation and fuzzy clustering to detect the vessel wall, lumen and lipid core
      boundaries. The results demonstrate excellent correspondence between automatic
      and manual area measurements for lumen (r = 0.92) and outer (r = 0.91), and
      acceptable correspondence for fibrous cap thickness (r = 0.71). Though further
      optimization is required, our algorithm is a powerful tool for automatic
      detection of lumen and outer boundaries, and characterization of plaque in
      atherosclerotic vessels.

PMID- 15029509
TI  - Optimising the design of paramagnetic MRI contrast agents: influence of backbone
      substitution on the water exchange rate of Gd-DTPA derivatives.
AB  - Among other factors influencing the residence time of the coordinated water
      (tauM) of paramagnetic contrast agents, the steric hindrance around the
      gadolinium ion seems to play a beneficial role. Such a crowding can be achieved
      by substituting the Gd-DTPA backbone on the C4 position. Several Gd-DTPA
      complexes carrying diverse groups at this position have thus been synthesised and
      characterised: GdS-C4-Me-DTPA, GdS-C4-n-Bu-DTPA, GdS-C4-iBu-DTPA, GdS-C4-iPr
      DTPA, and Gd-C4-diMe-DTPA. TauM has been measured through the evolution of the
      water oxygen-17 transverse relaxation rate as a function of the temperature. The
      data show a reduction of tauM of GdS-C4-Me-DTPA, GdS-C4-n-Bu-DTPA, GdS-C4-iBu
      DTPA, GdS-C4-iPr-DTPA, and Gd-C4-diMe-DTPA (tauM310 = 91,82, 108,98, and 57 ns
      respectively, as compared to Gd-DTPA (tauM310 = 143 ns)). At 310 K, the nuclear
      magnetic dispersion relaxation profiles of water protons are very similar for the
      five complexes which present longitudinal relaxivities slightly higher than those
      of Gd-DTPA. Regarding zinc transmetallation, C4-monosubstituted derivatives are
      more stable than Gd-DTPA. These results confirm that a judicious substitution of
      the DTPA skeleton allows for an acceleration of the coordinated water exchange
      rate. This observation can be useful for the design of vectorised contrast agents
      for molecular imaging.

PMID- 15029510
TI  - MRI of the lung using hyperpolarized 3He at very low magnetic field (3 mT).
AB  - Optical pumping of 3He produces large (hyper) nuclear-spin polarizations
      independent of the magnetic resonance imaging (MRI) field strength. This allows
      lung MRI to be performed at reduced fields with many associated benefits, such as
      lower tissue susceptibility gradients and decreased power absorption rates. Here
      we present results of 2D imaging as well as accurate 1D gas diffusion mapping of
      the human lung using 3He at very low field (3 mT). Furthermore, measurements of
      transverse relaxation in zero applied gradient are shown to accurately track
      pulmonary O2 partial pressure, opening the way for novel imaging sequences.

PMID- 15029511
TI  - Stainless and shape memory alloy coronary stents: a computational study on the
      interaction with the vascular wall.
AB  - Balloon-expandable and self-expandable stents are the two types of coronary
      stents available. Basically, they differ in the modality of expansion. The
      present study analyses the stress state induced on the vascular wall, by the
      expansion of balloon- and self-expandable stents, using the finite element
      method. Indeed, modified mechanical stress state is in part responsible in the
      restenosis process. The balloon-expandable stents herein investigated are assumed
      to be made of stainless steel, while the self-expandable stents are made of a
      shape memory alloy. The effects of the severity of the coronary stenosis, the
      atherosclerotic plaque stiffness and the stent design are investigated. Comparing
      the self-expandable stent with the balloon-expandable one, the former induces
      fewer stresses and lower damage to the vessel, but, on the other hand, its lower
      stiffness induces a lower capability to restore vasal lumen and to contrast
      arterial elastic recoil.

PMID- 15029512
TI  - Epidemiology of candidaemia in Europe: results of 28-month European Confederation
      of Medical Mycology (ECMM) hospital-based surveillance study.
AB  - In order to update the epidemiological and mycological profile of candidaemia in
      Europe, the European Confederation of Medical Mycology conducted a prospective,
      sequential, hospital population-based study from September 1997 to December 1999.
      A total of 2,089 cases were documented by 106 institutions in seven European
      countries. Rates of candidaemia ranging from 0.20 to 0.38 per 1,000 admissions
      were reported. Candida albicans was identified in 56% of cases. Non-albicans
      Candida species were most frequently isolated from patients with haematological
      malignancies (65%). With increasing age, an increasing incidence of Candida
      glabrata was seen. The 30-day mortality rate was 37.9%. The survey results
      underline the burden of candidaemia in a wide range of patient populations,
      confirm the importance of non- albicans species, and provide baseline data for
      future surveillance studies at a European level.

PMID- 15029513
TI  - Pharmacokinetic and pharmacodynamic issues in the treatment of parasitic
      infections.
AB  - Despite increases in the incidence of many parasitic infections in recent years,
      the number of studies designed to improve the treatment of these infections has
      failed to keep pace with their huge impact on public health. Unfortunately,
      research and development in this field is not an economically attractive
      proposition for the pharmaceutical industry, and this neglect is exacerbated by
      the fact that many parasitic diseases have negligible profiles in countries that
      have the funds to research them. An absence of effective vaccines means that, for
      the foreseeable future, chemotherapy is likely to be the mainstay of disease
      management. This review describes the advances gained in our understanding of the
      relationship between pharmacokinetics and pharmacodynamics, with the aim of
      improving the way in which we use antiparasitic agents while at the same time
      highlighting those areas where there is an urgent need for further investigation.
      Unsurprisingly, much of our success has been in the chemotherapy of malaria,
      where the link between drug concentration and response is reasonably well
      characterised. For many other diseases, however, this link is poorly understood,
      in some cases because the mechanism of action of the drug has not been fully
      elucidated, or in other cases because a true pharmacodynamic endpoint may be
      unavailable. Overcoming these problems is critical if the clinician is to have
      the information necessary to enable optimal treatment of patients who may be
      severely ill and in need of immediate, life-saving attention.

PMID- 15029514
TI  - [Modification of clinical profile of stroke in atrial fibrillation patients.
      Effect of antithrombotic treatment].
AB  - BACKGROUND: Atrial fibrillation is present in 24% of the population over 60 and
      it increases the risk of stroke by 2,4% 3%/year. Antithrombotic treatment is
      considered as the treatment of choice for cardioembolic stroke prevention in this
      patients. As far as we know there are not relevant data about the influence of
      these treatments on the type of stroke that may develop in these patients. AIM:
      Analyze whether there are differences in the clinical profile and functional
      prognosis after stroke in patients with atrial fibrillation depending on the type
      of treatment they were on at the time of occurrence of the event. PATIENTS AND
      METHODS: We identified 67 patients who were admitted consecutively to our stroke
      unit with a stroke and atrial fibrillation over a period of 2 years. Patients
      were classified according to the type of antithrombotic treatment they were on.
      Functional prognosis was estimated by Rankin score at discharge. RESULTS: Treated
      patient showed a non significant tendency to suffer less severe strokes and
      present a better functional situation at discharge than those who were not on
      prophylactic treatment. Treated patients had a significant higher prevalence of
      previous TIA (44,2% vs 9,1%; p= 0,0042) and HBP (81,4% vs 52%; p= 0,041) than non
      treated patients. Embolic strokes were more frequent in non treated patients.
      CONCLUSION: Antithrombotic treatment not only prevents strokes but may also
      contribute to the development of less severe strokes with a better functional
      prognosis in patients with AF and does not contribute to increase complications
      in these group of patients.

PMID- 15029516
TI  - [The effectiveness of a correlation diagram of the echographic and haemodynamic
      patterns in the brain].
AB  - INTRODUCTION: Transcranial Doppler (TCD) constitutes a valuable method for
      managing acute/critical neurological patients and it would therefore be
      interesting to reduce, as far as possible, the complexity involved in
      interpreting its findings. AIMS: The Objective of this study was to design and
      validate a correlation diagram of the echographic patterns and acute haemodynamic
      situations in the brain that makes it easier to teach and optimises the
      effectiveness of TCD as a diagnostic aid. MATERIALS AND METHODS: A diagram that
      represents the average speed and pulsatility index on a system of coordinates.
      Five fundamental echographic patterns were identified and the most frequent acute
      cerebral haemodynamic situations are detailed for each of them. The value of the
      diagram was tested in resident doctors with varying degrees of knowledge of TCD.
      In the first phase with no diagram (evaluation A), the interpretation of the TCD
      and diagnosis of the haemodynamic situation in the brain were evaluated in nine
      clinical cases. In the second phase, with a diagram (evaluation B), they were
      asked to draw up new reports on the same cases. We compared the number of times
      they were right in the two evaluations. RESULTS: A total of 216 echographic
      reports were obtained. The mean number of correct answers in evaluation A was 2,
      interquartile range (0.25 3.75). In evaluation B the number of correct answers
      rose to 4 (3.25 6.75) (p= 0.005). Using the diagram increased the diagnostic
      capacity of all the residents, but especially so in those with less training.
      CONCLUSIONS: Use of the diagram makes it easier for people who are not experts to
      learn to interpret TCD findings in acute/critical neurological situations.

PMID- 15029515
TI  - [Episodic disseminated inflammation of the central nervous system. Case mix
      review over a 13 year period].
AB  - INTRODUCTION: Episodic disseminated inflammation of the central nervous system
      (CNS) presents in processes that are difficult to differentiate, such as acute
      disseminated encephalomyelitis (ADE) and its multiphasic variants, and multiple
      sclerosis (MS). Magnetic resonance imaging allows these problems to be identified
      more frequently than in the past. PATIENTS AND METHODS: We carried out a
      retrospective study of the cases of episodic disseminated inflammation of the
      CNS, according to clinical features and compatible neuroimaging, at the
      Neuropaediatric Unit of the Hospital Infantil Miguel Servet, between May 1990 and
      August 2003. RESULTS: Of the 6777 children evaluated over this period, 10 met the
      eligibility criteria, with a minimum age at onset of 2 years and 2 months. In
      four cases there was a history of an infectious process or vaccination. Clinical
      involvement was multisymptomatic, the most frequent being ataxia, dysmetry,
      tremor, drowsiness, paresis and cranial nerve involvement. Six of them had
      cerebrospinal fluid disorders and only two presented disorders in the fundus
      oculi. Five of them were given corticoid treatment. Progress was favourable,
      except in two cases: one due to the persistence of a corticoid dependent optical
      neuropathy and the other because of dyskinesia in the right hand. DISCUSSION:
      Diagnosis of ADE is established by signs of multifocal clinical involvement and
      neuroimaging, and depends on a compatible progression. Prognosis is generally
      good and corticoids seem to be effective, at least in shortening the time the
      clinical features last. It is not possible to completely differentiate it from
      MS, especially in recurring forms. Clinical and magnetic resonance controls must
      be carried out.

PMID- 15029517
TI  - [Clinical factors predicting the appearance of vascular events following a
      transient ischemic attack].
AB  - INTRODUCTION: Patients who have suffered a transient ischemic attack (TIA) have a
      high risk of undergoing a severe vascular event. Most of them do not receive
      early attention and cannot benefit from an adequate diagnosis and treatment.
      AIMS: The aim of this study is to identify the clinical factors that predict the
      appearance of a new vascular event in these patients. PATIENTS AND METHODS: We
      conducted a prospective study of 104 TIA patients, who had been given attention
      during the first 24 hours after the onset of symptoms, for a mean follow up time
      of 12.6 months. RESULTS: The incidence rates of strokes, ischemic heart disease,
      peripheral arteriopathy and death were 13, 6, 3 and 8%, respectively.
      Multivariate analysis identified the following aspects as independent predictors
      of new strokes: an age above 73 odds ratio (OR) 4.46 (CI 95%, 1.15 17.38) and an
      atherothrombotic aetiology OR 4.36 (CI 95%, 1.4413.18); and episodes of ischemic
      heart disease, a history of suffering from such heart disease OR 30.65 (CI 95%,
      2.94319.17) and taking oral antidiabetic drugs OR 31.23 (CI 95%, 2.65368.74).
      Leukocytosis OR 11.21 (CI 95%, 1.25100.39) is linked to the deaths caused by
      vascular disorders, whereas an atherothrombotic aetiology OR 3.83 (CI 95%, 1.31
      11.20) and being male OR 3.44 (CI 95%, 1.02 11.60) were seen to be predictors of
      the appearance of any vascular event. CONCLUSIONS: Our findings showed that the
      risk of suffering severe vascular events after a TIA becomes higher. There are a
      number of useful clinical variables (age above 73, atherothrombotic aetiology,
      being male, taking oral antidiabetic drugs and leukocytosis) for identifying the
      patients at the highest risk.

PMID- 15029518
TI  - [Spectral analysis of EEG coherence in Alzheimer's disease].
AB  - INTRODUCTION: In analysis of the electrical activity of the brain, coherence is a
      measure of the degree of synchrony between two or more regions of the brain with
      regard to their frequency values over a unit of time. AIMS: To explore the
      functional alterations caused by Alzheimer's disease (AD), by evaluating the
      behaviour of coherence over the whole spectrum of EEG frequencies. PATIENTS AND
      METHODS: We studied a group of 42 patients with AD, according to criteria of the
      NINCDS ADRDA group. Partial coherence (e.g. between two derivations each time)
      was calculated within and between hemispheres, during a state of mental rest; the
      Z statistic was also determined by comparing the coherence values with the
      standard data for age, sex and functional state of the brain. RESULTS:
      Significantly low coherence values were obtained for the frontal central regions
      of the left hemisphere (LH) and for the occipital parietal regions of the right
      hemisphere (RH) in the delta band. The same localisations were carried out for
      the theta band, in addition to the centrotemporal and temporal regions of the LH.
      The highest incoherence values were observed for the alpha and beta bands, more
      specifically in frontal central and occipital parietal derivations of the RH, and
      temporal derivations of the LH. CONCLUSIONS: Non activated partial coherence acts
      as an indicator of the degree of functional disconnection between brain regions
      in AD. Studying activated coherence in these patients could contribute new
      elements to our knowledge about the functional disorders observed in this
      disease.

PMID- 15029519
TI  - [Non neoplastic space occupying lesions mimicking central nervous system tumors].
AB  - OBJECTIVE: To establish the frequency and nature of space occupying lesions of
      the central nervous system (CNS) that mimic neoplastic growths. PATIENTS AND
      METHODS: We reviewed the clinical records, imaging and neuropathological studies
      of patients operated in different hospitals of Maracaibo, Venezuela during the
      period January 1 1996 July 31 2002. These patients had a pre operative diagnosis
      of CNS tumor, and their definitive diagnosis was non neoplastic disease. RESULTS:
      The 33 cases of expansive, non neoplastic growths represented 8% of 408 CNS
      lesions diagnosed during the study period. Approximately two thirds of the cases
      (63,36%) consisted of either inflammatory or vascular lesions, whereas the rest
      of the cases grouped miscellaneous conditions. CONCLUSIONS: Even though it is not
      frequent that non neoplastic lesions of the CNS mimic expansive growths of
      neoplastic nature, on occasions the clinical and neuroimaging features of both
      groups of entities are remarkably similar.

PMID- 15029520
TI  - [The efficacy of a formula for estimating premorbid intelligence in the Spanish
      population].
AB  - INTRODUCTION: An important aim of neuropsychological assessment is to identify
      impairment in higher cognitive or intellectual, functioning. In order to achieve
      this task the assessment of premorbid intellectual ability becomes crucial. The
      estimation of premorbid cognitive functioning will allow us to assess level of
      cognitive deterioration but also best cognitive functioning that can be expected
      in rehabilitation. Estimating premorbid cognitive ability is also crucial in
      forensic practice and for research purposes. Methods that allow the estimation of
      premorbid intelligence have been developed. Estimates derived from these methods
      are typically based on one or both of the following sources of information: (a).
      life history variables (b). measures of current cognitive functioning that are
      highly correlated with intellectual functioning and that are relatively
      unaffected by brain damage. OBJECTIVE: To present a method of estimating
      premorbid intelligence in Spanish population. SUBJECTS AND METHODS: The method we
      present has been developed applying linear regression models to the
      standardization sample of the WAIS III in Spanish population. The model is based
      exclusively on demographic and socio educational variables, allowing estimation
      free of the influence of neurological lesions squeal. CONCLUSIONS: The efficiency
      of the method we present is similar to that of other methods widely used in other
      countries.

PMID- 15029521
TI  - [Olfactory seizures and parasellar meningioma].
AB  - INTRODUCTION: Partial olfactory seizures are infrequent. They are related to the
      presence of lesions in the uncinate area of the temporal lobe. Patients describe
      smells during the ictal phase that are generally unpleasant. We report the cases
      of two patients with olfactory disorders of a paroxysmal nature caused by a
      parasellar meningioma. CASE REPORTS: Case 1: a 43 year old male who presented
      paroxysmal episodes in which he perceived a bitter smell, with dysphoria, linked
      to the presence of a left side parasellar meningioma. Case 2: a 45 year old
      female who presented paroxysmal episodes during which she could smell
      formaldehyde and this was linked to the presence of a left side parasellar
      meningioma. DISCUSSION: Olfactory seizures are related to structural alterations
      to the amygdala. The most frequent causes are associated to the presence of
      mesial temporal sclerosis and, above all, to tumours situated in the
      temporomesial structures that have diverse aetiologies.

PMID- 15029522
TI  - [Dural fistula in the craniocervical junction. A case report and review of the
      literature].
AB  - INTRODUCTION: Spinal dural fistulas consist in an artery that penetrates into the
      dura mater and drains into a perispinal vein. They are most commonly located in
      the dorsal or lumbar region; a craniocervical position is infrequent. The
      clinical features presented by these patients involve an progressive ascending
      myelopathy caused by severe venous hypertension, although they can also start
      with symptoms of a subarachnoid haemorrhage. CASE REPORT: A 62 year old male with
      symptoms of progressive myelopathy due to a dural fistula dependent on meningeal
      branches of the right PICA, which was treated surgically by fistula clipping
      performed using an extreme lateral suboccipital approach. In the literature that
      was reviewed there were 35 cases of dural fistulas located at the craniocervical
      junction. CONCLUSIONS: The existence of clinical features compatible with
      cervical myelopathy and an anodyne cervical resonance justify the need to perform
      medullar arteriography owing to a suspected vascular malformation. An early
      diagnosis of a dural fistula and its proper treatment lead to a diminished
      morbidity and mortality rate in these patients.

PMID- 15029523
TI  - [Dementia secondary to thalamic infarct: a case report].
AB  - INTRODUCTION: The term dementia refers to the deterioration of the intellectual
      or cognitive functions, with little or no alteration of consciousness, which is
      capable of interfering with the activities of daily living and the ability to
      cope by oneself. One infrequent cause of dementia is its being secondary to a
      thalamic lesion and is normally due to the involvement of both thalami. CASE
      REPORT: We report a case of sudden onset dementia caused by lesions affecting
      only the left thalamus. A 64 year old right handed female patient with chronic
      arterial hypertension for which she received regular treatment. The patient
      visited because of difficulty in speaking without any alterations to
      consciousness, and amnesia of recent anterograde and retrograde events. A CAT
      scan of the brain revealed a superlacuna in the left thalamus. From then on, the
      patient presented memory disorders, the most typical being loss of retention
      memory. CONCLUSIONS: Thalamus injuries that are accompanied by dementia are
      commonly bilateral and are preferably located in the anterior and medial nuclei.
      There have been cases of memory disorders secondary to unilateral infarcts of the
      thalamus and these are related to a thalamocortical deafferentiation. Our case is
      one of sudden onset thalamic dementia secondary to an infarct affecting only the
      left thalamus.

PMID- 15029524
TI  - [Migraine with pleocytosis: a case of atypical progression].
AB  - AIMS: Migraine with cerebrospinal fluid pleocytosis is a clinical pattern
      consisting in intermittent headaches accompanied by episodes of transient
      neurological deficit and lymphocytic pleocytosis, which last for varying lengths
      of time and have a spontaneous resolution. We describe the case of migraine with
      pleocytosis (MP) with atypical progression that responded well to corticoids.
      CASE REPORT: A 27 year old male with no familial or personal history of migraine
      who began with bouts of intense headaches that were preceded by neurological
      deficit (dysphasia and hemiparesis of the right hand side) lasting varying
      amounts of time (including hours). The serial study of cerebrospinal fluid (CSF)
      revealed a notable degree of lymphocytosis (400/mm3) with increased intracranial
      pressure (ICP) (> 30 mmHg). The other explorations that were performed
      (microbiological study of CSF and blood, humoral and cellular immunity, MR
      angiography and thyroid hormones, among others) were all normal. The neurological
      exploration carried out in the following days revealed a mild paresis of the
      right lateral rectus muscle, which was attributed to the intracranial
      hypertension and which clearly disabled the patient. As a consequence of the
      recurrence of the seizures and the long lasting increase in ICP, therapy was
      begun with 1 mg/kg/day of prednisone, at a descending rate; clinical remission
      and normalisation of the CSF was achieved within a period of two months.
      DISCUSSION: We describe this case of MP because of how atypical the progression
      was (paresis of the right abducent nerve secondary to the increase in ICP) and
      the possibility of associating corticoids in cases in which the benignity of the
      entity is in doubt.

PMID- 15029525
TI  - [The serine proteases and their function in neuronal death processes].
AB  - AIMS: In this review we analyse the role played by the serine proteases in the
      nervous system and we focus on the role they play in degenerative processes.
      DEVELOPMENT: These proteolytic enzymes, together with the caspases, play a vital
      role in the processes regulating cell functioning, both in the development stages
      and following the response to a harmful stimulus. This family of proteases
      includes the granzymes and thrombin (TR). The former, which are closely related
      to proteases I and II and cathepsin G, are situated in the cytoplasmic granules
      of the activated T lymphocytes, together with other proteins such as perforin or
      cytolysin. Granzymes A and B are linked to degenerative processes. These enter
      the target cells thanks to the action of perforin and once inside they are
      translocated to the nucleus. Granzyme A has been isolated and identified as the
      agent responsible for the immediate and complete retraction of neurites in
      different models. Its physiological substrates include fibronectin, type IV
      collagen and the proteoglycans. Granzyme B is characterised by its being a
      cysteine protease with substrates such as prointerleukin 1 beta, TR receptor and
      poly(ADP ribose) polymerase. The family of TR type proteases includes proteases
      such as TR itself, plasmin, kallikrein, urokinase plasminogen activator and
      tissue plasminogen activator. TR is considered to be an early modulator in
      damaged tissues which acts as an extracellular signal of death, leading to the
      activation of intracellular mechanisms that appear to be mediated by calcium.
      Serine protease activity is regulated by endogenous inhibitors, such as
      plasminogen activator inhibitor, protease nexin 1 and neuroserpin. CONCLUSIONS:
      Upsets in the protease inhibitor balance are crucial in the processes involved in
      the neuronal plasticity and death induced by ischemia in the brain and by
      excitotoxins.

PMID- 15029526
TI  - [Intranasal and buccal midazolam in the treatment of acute seizures].
AB  - AIMS: There are several personal and social problems involved in the
      administration of rectal diazepam that make it unsuitable for use in public
      places and by non medical workers, in children and especially in teenagers and
      adults. Intranasal and oral midazolam could be an alternative to rectal diazepam.
      We review the efficacy and safety of these ways of administering midazolam, which
      is already used in some countries as a sedative and as an anticonvulsive drug,
      despite the fact that it has not yet received authorisation. DEVELOPMENT:
      Intranasal midazolam (INM) was first used as a sedative in dental extractions,
      echocardiography, endoscopies or surgery, especially in children. After proving
      its efficacy electroencephalographically in patients with seizures, it started to
      be used to interrupt acute seizures. In three randomised trials, the efficacy of
      intranasal and oral midazolam in hospitalised patients was similar to, and even
      higher than, that of intravenous or rectal diazepam, with a similar speed of
      action and safety; no studies have been conducted, however, in the extra hospital
      milieu and its risk of respiratory depression may be like that of other
      benzodiazepines. One of the problems of using the parenteral solution for
      intranasal administration is the irritation that is produced by its acidic pH and
      the relatively large volume that has to be administered. These problems could be
      reduced by using aerosols containing a solution of midazolam in cyclodextrin,
      which accomplishes a greater concentration with a pH that is less acidic. Oral
      administration can be used in patients with nasal secretions or intense movements
      of the head. CONCLUSIONS: Intranasal or oral midazolam can improve the treatment
      of acute seizures in the hospital milieu and, more especially, in the extra
      hospital milieu when patients are attended by non medical staff. There is a need,
      however, for trials that prove its efficacy and safety in this situation.

PMID- 15029528
TI  - [The possibilities of neurocognitive rehabilitation in schizophrenia].
AB  - INTRODUCTION: Schizophrenia is a severely disability causing syndrome, what tend
      to chronically alter living project of great number of young people and its
      families. It is affected multiple cognitive functions, as executive capacity,
      explicit memory, working memory or perceptive integration. In the last years,
      neurocognitive rehabilitation techniques of this functions coming from the
      experience with brain damage patients has been applied to schizophrenia.
      DEVELOPMENT: Present work revised: a). cognitive deficits that can be considered
      as nuclear in the genesis of schizophrenia symptoms and b). recovery or
      substitution strategies of that deficits, that can be generalized to a better
      psychosocial functioning of the patient. It is proposed that attention control
      deficit (ACD), defined as the inadequate assignation of attention recourses
      during cognitive processing, results in attention processing of redundant
      information and a lack of attention recourses to process new information. Some
      explaining models are presented for subjective and perceptive symptoms, language
      disorders and executive disorders in schizophrenia. Possibilities of
      neurocognitive rehabilitation in schizophrenia are discussed, especially by the
      utilisation of implicit learning methods, that don't need attention processing.
      Some recommendations are made for the implementation of cognitive rehabilitation
      in the general framework of psychosocial and occupational rehabilitation.

PMID- 15029527
TI  - [Memory. An introduction to the study of the cognitive disorders in normal and
      pathological aging].
AB  - INTRODUCTION: As the life expectancy of the population rises, there is also an
      increase in the frequency of the diseases that appear in the elderly. Aging can
      be healthy or pathological, but the borderline between the two is still a bit
      fuzzy. DEVELOPMENT: With the increase in the longevity of the population,
      Alzheimer's Disease (AD) and other illnesses linked to the aging process have
      become more common, above all in people between 65 and 85 years of age. The
      cognitive aspects that, in clinical practice, are most frequently seen to be
      involved are memory, attention, executive functions and the speed at which
      information is processed; these are the most common in these patients but the
      most severe and insidious as well as the first to appear are problems affecting
      memory. The physiological mechanism behind memory has still not been wholly
      explained. The modulation of many of the cognitive processes given by the
      cerebellum expands the borders in the study of the different mnemonic processes.
      The prefrontal cortex plays an essential role in controlling attention and in the
      mnemonic filing system required to supervise and modulate sensory motor
      processing and the basic complex actions of cognition, emotion and human
      behaviour. CONCLUSIONS: The neuroanatomical, psychological and neurophysiological
      foundations of memory are very complex and involve the intervention of a number
      of structures that, within a single integrated context, each contribute to the
      overall functioning.

PMID- 15029529
TI  - [Attention process training application within an intervention project on
      attentional processes in children with cancer].
AB  - INTRODUCTION: Childhood cancer treatments have made a spectacular advance in
      recent years, obtaining survival rates of about 70%. These survival rates have
      permitted many children to reach adulthood, but also involve the appearance of
      previously unknown neurocognitive sequelae because of high mortality.
      DEVELOPMENT: Neuropsychological evaluation allows the detection of these deficits
      and the design of intervention. In children, rather than a loss of function there
      is a loss of the capacities that should develop in comparison with his/her peers.
      To obtain a base line to determine the affected and altered areas, it is equally
      vital to assess the acute and long term effects so as to evaluate the success of
      the intervention program. Attention Process Training (APT) is an individualized
      application program of attentional exercises of varying complexity in sustained,
      selective, alternating and divided attention. This program combines methods and
      techniques of cerebral damage rehabilitation, as well as educational and clinical
      psychology. It is completed with a self instruction training which is applied in
      situations of daily life. CONCLUSIONS: Child cancer treatment continues to carry
      long term neurocognitive sequelae. Neuropsychological evaluation is basic for its
      detection, allowing relevant information to be offered to parents and teachers,
      so as to facilitate design of individualized rehabilitation procedures. Attention
      training is basic for this type of population with generalized damage related to
      white matter, and forms part of a wider rehabilitation process that enhance the
      ecological validity of the program.

PMID- 15029531
TI  - [Vasculitis caused by toxic agents: diagnosis and follow up by magnetic resonance
      angiography].

PMID- 15029530
TI  - [Attention and executive processes in neuropsychological rehabilitation of the
      visuospatial processes].
AB  - INTRODUCTION AND OBJECTIVE: Cognitive deficits following lesions in parieto
      occipital areas tend to cause, among others, visuospatial and visuoperceptive
      alterations. The aim of this article is to examine the influence of others
      possible deficit over its rehabilitation. DEVELOPMENT: We discuss several
      patients who present visuospatial impairment after different brain injuries, not
      only those affecting the areas typically involved in these deficits, such as
      parieto occipital cortex. Rehabilitation was conducted on an individual basis in
      the brain injury unit of Beata Maria Ana hospital. Neuropsychological evaluation
      showed some difficulties not previously described together with these deficits,
      related to attention, working memory and executive functions, as well as
      topographic disorientation, lack of visuospatial coordination, distances
      perception disorders and difficulty to mentally rotate objects. The
      rehabilitation was AIMed not only at restoration but also compensation of
      visuospatial deficits, successfully achieved after treatment: patients were
      capable of returning to their daily activities, including their jobs. CONCLUSION:
      In patients with visuospatial deficits, a compressive neuropsychological
      evaluation seem to be essential to define the influence of the other cognitive
      domains over the rehabilitation of visuospatial problems. In particular, the
      reinforcement of processes related to attention control and executive functions
      could very important, give their contribution to the learning of compensatory
      strategies and assuming that those functions pay key role in the organization and
      supervision demanded for perceptual skills.

PMID- 15029532
TI  - [Postoperative intracerebral hematoma. An unusual complication of chronic
      subdural hematoma].

PMID- 15029533
TI  - [Hypothesis about the genesis of the cavum septi pellucidi in preterm infants and
      in postnatal life].

PMID- 15029538
TI  - Birth of an idea: the epidural blood patch.

PMID- 15029539
TI  - Thoracic epidural catheter placement in children: are we there yet?

PMID- 15029540
TI  - The public's perception of regional anesthesia: why don't they get "the point"?

PMID- 15029541
TI  - Author misconduct--a continuing saga.

PMID- 15029542
TI  - Thoracic epidural catheter insertion using the caudal approach assisted with an
      electrical nerve stimulator in young children.
AB  - OBJECTIVES: We evaluated whether thoracic epidural catheter placement using the
      caudal approach and assisted with an electrical stimulator could be performed in
      young children. METHODS: Ten young children (1-4 years) who underwent abdominal
      surgeries were studied. Under general anesthesia without muscle relaxants, caudal
      catheter placement was performed using an 18-gauge Crawford-type needle and a 20
      gauge radiopaque epidural catheter with a stainless-steel stylet. A metal adapter
      and a 3-way stopcock were attached to the catheter to connect to an electrical
      stimulator and to inject physiological saline. Electrical stimulation was
      performed intermittently while advancing the catheter until it reached the target
      length. The catheter position was confirmed on postoperative roentgenogram.
      RESULTS: The mean age of the subjects was 32.2 +/- 10.1 months (13-48 months),
      and the height was 85.3 +/- 6.1 cm (72-93 cm). In 9 of 10 patients, an epidural
      catheter could be placed at the first insertion. In 1 patient, the catheter could
      be placed successfully at the second insertion. The electrical current required
      for muscle contraction at the target length was 5.8 +/- 1.5 mA. CONCLUSION:
      Electrical stimulation reliably indicated the location of the catheter tip. This
      technique for thoracic epidural catheter insertion was easy to perform and could
      be used in young children.

PMID- 15029543
TI  - The public's fears about and perceptions of regional anesthesia.
AB  - BACKGROUND AND OBJECTIVES: The public is not well informed about matters relating
      to regional anesthesia. Previous studies concerning regional anesthesia have
      involved patients, surgeons, and anesthesiologists. This study is the first in
      depth survey of the attitudes of the general public toward a number of commonly
      perceived fears about regional anesthesia. METHODS: A province-wide telephone
      survey was conducted in Alberta, Canada. The sample surveyed was representative
      of the adult population of the province and included an equal balance of urban
      and rural participants. General and regional anesthesia were defined, a scenario
      involving major knee surgery was described, and participants were asked to choose
      between regional and general anesthesia. Respondents were then questioned so
      their attitudes toward commonly perceived fears associated with regional
      anesthesia could be assessed. RESULTS: A total of 1,216 people were surveyed. A
      preference for regional or general anesthesia was not expressed in this scenario.
      Approximately 27% of respondents were very concerned about permanent paralysis,
      back injury, perioperative pain, seeing the surgical procedure, and the prospect
      of a needle in the back. Only 6% of individuals were concerned about headaches.
      CONCLUSIONS: The public's fears and conceptions about regional anesthesia are
      greatly distorted. The anesthesia community has not been successful in keeping
      the public informed about regional anesthesia. Future anesthesia-related
      educational programs should address the concerns of the public about anesthesia
      matters, particularly regional anesthesia.

PMID- 15029545
TI  - Diaphragmatic excursion and respiratory function after the modified Raj technique
      of the infraclavicular plexus block.
AB  - BACKGROUND: The effects of the infraclavicular plexus block using the modified
      Raj approach on diaphragm and respiratory function have not been investigated.
      METHODS: After obtaining approval of the local ethics committee and written
      informed consent, 20 patients, scheduled for surgery of the forearm, wrist, or
      hand were prospectively included. Infraclavicular block was performed using the
      modified Raj technique with 40 to 50 mL ropivacaine 0.5%. Forced diaphragmatic
      excursion (DE), vital capacity (VC), first-second forced expiratory volume
      (FEV(1)), and peak expiratory flow rate (PEFR) were assessed the day before
      surgery and 30 and 360 minutes after blocks, respectively. RESULTS: There was no
      significant difference between pre- and postblock values, neither for DE (5.6 +/-
      1.0 cm before the block, 5.2 +/- 1.4 cm 30 minutes after the block, and 5.7 +/-
      1.4 cm 360 minutes after the block) nor for VC (3.2 +/- 0.8 L before the block,
      3.1 +/- 0.9 L 30 minutes after the block, and 3.0 +/- 0.9 L 360 minutes after the
      block), FEV(1) (2.8 +/- 0.9 L before the block, 2.8 +/- 0.9 L 30 minutes after
      the block, and 2.7 +/- 0.9 L 360 minutes after the block), or PEFR (378 +/- 116
      L/min before the block, 355 +/- 110 L/min 30 minutes after the block, and 364 +/-
      116 L/min 360 minutes after the block). CONCLUSION: Infraclavicular block using
      the modified Raj technique did not interfere with diaphragmatic excursion or
      respiratory function.

PMID- 15029544
TI  - Postoperative analgesia after total-hip arthroplasty: Comparison of intravenous
      patient-controlled analgesia with morphine and single injection of femoral nerve
      or psoas compartment block. a prospective, randomized, double-blind study.
AB  - BACKGROUND: The authors compared the analgesic effects and quality of
      rehabilitation of three analgesic techniques after total-hip arthroplasty in a
      double-blind, randomized trial. METHODS: Forty-five patients were assigned to 1
      of 3 groups, patient-controlled analgesia with morphine (PCA), femoral nerve
      block (FNB), or psoas compartment block (PCB). At the end of the procedure
      performed under general anesthesia, nerve blocks using 2 mg/kg of 0.375%
      bupivacaine and 2 microg/kg of clonidine were performed in the FNB (n = 16) and
      PCB (n = 15) groups. In the recovery room, all 3 groups received initial
      intravenous morphine titration if their pain score was higher than 30 on a 100-mm
      visual analog scale (VAS), and then a PCA device was initiated. Morphine
      consumption was the primary end point to assess postoperative analgesia. RESULTS:
      After extubation (H0), morphine titration was higher in the PCA group (P <.05).
      During the first 4 postoperative hours (H0 to H4), morphine consumption per hour
      and VAS pain score were lower in the PCB group (P <.05). After H4, there was no
      difference in morphine consumption and VAS among groups, either at rest or during
      mobilization. After H4, morphine consumption remained lower than 0.5 mg/h, and
      VAS remained lower than 30 mm in the 3 groups. In 4 patients of the PCB group, an
      epidural diffusion was noted. Hip mobility and length of stay in the
      rehabilitation center were not different among the groups. CONCLUSIONS: PCA is an
      efficient and safe analgesia technique. FNB and PCB should not be used routinely
      after total-hip arthroplasty.

PMID- 15029547
TI  - Labat Lecture 2004: Regional anesthesia risks--from Labat to tort reform.

PMID- 15029548
TI  - At the cords, the pinkie towards: Interpreting infraclavicular motor responses to
      neurostimulation.
AB  - Identification of elicited muscle twitches while performing infraclavicular block
      of the brachial plexus is often confusing but is critical for success of the
      block. An easily defined endpoint when evaluating these motor responses to
      neurostimulation is essential, as it is necessary to block the appropriate cord
      or cords. In addition to an extensive review of the motor and sensory
      neuroanatomy of the upper extremity, we describe an easy method to learn and
      remember the motor response to stimulation of each of the cords of the brachial
      plexus. If the arm is positioned in the anatomical position, the 5th digit
      (pinkie) moves laterally (pronation of the forearm) when the lateral cord is
      stimulated, posteriorly (extension) when the posterior cord is stimulated, and
      medially (flexion) when the medial cord is stimulated. The pinkie thus moves
      "toward" the cord that is stimulated.

PMID- 15029549
TI  - Ultrasound imaging for popliteal sciatic nerve block.
AB  - BACKGROUND AND OBJECTIVES: Ultrasound is a novel method of nerve localization but
      its use for lower extremity blocks appears limited with only reports for femoral
      3-in-1 blocks. We report a case series of popliteal sciatic nerve blocks using
      ultrasound guidance to illustrate the clinical usefulness of this technology.
      CASE REPORT: The sciatic nerve was localized in the popliteal fossa by ultrasound
      imaging in 10 patients using a 4- to 7-MHz probe and the Philips ATL HDI 5000
      unit. Ultrasound imaging showed the sciatic nerve anatomy, the point at which it
      divides, and the spatial relationship between the peroneal and tibial nerves
      distally. Needle contact with the nerve(s) was further confirmed with nerve
      stimulation. Circumferential local anesthetic spread within the fascial sheath
      after injection appears to correlate with rapid onset and completeness of sciatic
      nerve block. CONCLUSIONS: Our preliminary experience suggests that ultrasound
      localization of the sciatic nerve in the popliteal fossa is a simple and reliable
      procedure. It helps guide block needle placement and assess local anesthetic
      spread pattern at the time of injection.

PMID- 15029551
TI  - Postdural puncture headache and the development of the epidural blood patch.

PMID- 15029553
TI  - Conversion disorder mimicking Dejerine-Roussy syndrome (thalamic stroke) after
      spinal cord stimulation.
AB  - OBJECTIVE: Dejerine-Roussy syndrome is a complex of various signs and symptoms in
      patients suffering from central thalamic pain, usually secondary to a vascular
      etiology. We describe a patient presenting with the potentially devastating signs
      and symptoms of thalamic stroke, at least temporally related to spinal cord
      stimulator implantation. The etiology of the patient's affliction was
      subsequently revealed to be a conversion disorder. Case report A 37-year-old
      woman presented for spinal cord stimulation as treatment of her brachial
      plexopathy after failure of conservative therapy. Before implantation, she
      underwent a clinical interview with a psychologist and psychometric testing. No
      psychological pathology was detected. Trial and permanent implantation of the
      cervical stimulator lead and pulse generator were uneventful. Eleven days after
      receiving the permanent implant, the patient experienced right-sided hemicorporal
      numbness and burning dysesthesia. The patient was admitted, and a diagnosis of
      Dejerine-Roussy syndrome (thalamic stroke) was made. She was discharged, and her
      symptomatology waxed and waned over a period of weeks. The patient was
      subsequently admitted for psychiatric evaluation because of anxiety attacks.
      During her protracted admission, her psychiatrists strongly suspected a
      conversion disorder. The stimulator was removed, and the patient received
      supportive care only. Within 6 months, sensory symptoms and all motor deficits
      had completely resolved. CONCLUSIONS: Despite careful preoperative evaluation,
      latent psychosocial issues may limit the effectiveness of spinal cord
      stimulation. We present a case of conversion disorder masquerading as Dejerine
      Roussy syndrome after spinal cord stimulation. The implications of the failure of
      preoperative psychological evaluation and screening to avert implantation are
      discussed.

PMID- 15029554
TI  - An unusual case of painful phantom-limb sensations during regional anesthesia.
AB  - OBJECTIVE: The objective of this article is to describe a late-onset phantom-limb
      pain during a continuous analgesic popliteal nerve block after foot surgery and
      its alleviation and recurrence when stopping and resuming the local anesthetic
      infusion. CASE REPORT: A 29-year-old woman undergoing a left hallux valgus repair
      received a continuous popliteal sciatic nerve block for postoperative analgesia.
      Postoperatively, 6 hours after the commencement of a ropivacaine 0.2% infusion,
      she reported feelings of tingling, clenching pain, and missing-limb sensation
      below the ankle. The surgical site remained painless. Sensation elicited by touch
      and propioception were normally perceived. Only sensations for pinprick and heat
      were impaired. The ropivacaine infusion was stopped, followed 2.5 hours later by
      the complete regression of any abnormal sensation. Meanwhile, pain at the
      surgical site was scored at 50 mm on a 100-mm visual analogic scale. As the
      infusion of ropivacaine was resumed, the abnormal sensations reappeared. The
      catheter was removed, and abnormal sensations again disappeared. The patient was
      discharged from hospital without further complications. CONCLUSIONS: This
      observation suggests that phantom-limb pain can be of late-onset and might occur
      during a continuous infusion of low-concentration local anesthetic responsible
      only for an analgesic block, as shown by the fact that only thermal and pinprick
      sensations, known to depend on Adelta-fibers and C-fibers, were altered.
      Therefore, this case contradicts the usual belief that a profound block is
      necessary to elicit phantom-limb pain.

PMID- 15029556
TI  - Can we consider the psoas compartment block a reliable one?

PMID- 15029555
TI  - Assessing phantom limb sensations... and the library?

PMID- 15029558
TI  - Perineural catheter placement: another potential complication.

PMID- 15029563
TI  - Assessing the accuracy of OSHA's projections of the benefits of new safety
      standards.
AB  - BACKGROUND: In the preambles to the safety and health standards that it has
      issued since 1987, the Occupational Safety and Health Administration (OSHA)
      projected that new safety standards would prevent over 2,600 death each year. For
      six safety standards issued since 1990, we compare OSHA's projections of the
      impact of full compliance on fatalities with actual fatality changes and examine
      the reasons for the differences. METHODS: We reviewed the preambles to OSHA
      standards and the Regulatory Impact Analyses (RIAs) prepared for them to identify
      the baseline and the prevention factor that the agency used to project the number
      of deaths that would be prevented. We used three data sources to track the
      relevant categories of fatalities: the Census of Fatal Occupational Injuries
      (CFOI), the National Traumatic Occupational Fatality program, and OSHAs
      Fatality/Catastrophe investigations. RESULTS: For all six standards, OSHA
      appeared to overestimate the number of deaths prevented. The availability of CFOI
      led to better estimates of the fatality baseline, but the prevention factor was
      always overestimated, especially for standards which emphasized training.
      CONCLUSIONS: OSHA needs to develop better methods for projecting injury impacts.
      Research is needed to help OSHA predict the effects of behavioral requirements
      (e.g., training) on actual work practices and injury outcomes. For non-fatal
      injuries, new methods of data collection will be required.

PMID- 15029564
TI  - More evidence of the need for an ergonomic standard.
AB  - BACKGROUND: In 1999, the Occupational Safety and Health Administration (OSHA)
      proposed regulations designed to reduce work related inquiries by limiting worker
      exposure to "ergonomic risk factors." Congress subsequently overturned the
      regulations. We provide additional evidence on earnings losses attributable to
      musculoskeletal disorders (MSDs), and thus on the need for an ergonomic standard.
      METHODS: Regression techniques are used to analyze data from a survey of injured
      workers that has been matched to employer-reported earnings data covering pre-
      and post-injury periods, and to workers' compensation claims records. RESULTS:
      MSDs lead to large and persistent earnings losses. Cost estimates used by OSHA to
      justify the 1999 EPS are corroborated. Losses are greatest among workers who file
      workers compensation claims, but nonclaimants also have losses. CONCLUSIONS:
      Earnings losses and lost productivity associated with work-related MSDs are
      substantial and an ergonomic standard could be cost effective.

PMID- 15029565
TI  - The workers' compensation system: worker friend or foe?
AB  - BACKGROUND: The workers' compensation system was designed to help injured workers
      who have substantial medical expenses and perhaps have lost a great deal of
      income. This study determines both similarities and differences in how workers
      experience their interactions with the workers' compensation systems in Florida
      and Wisconsin. METHODS: Ethnographic open-ended interviews with 204 workers from
      Florida and 198 workers in Wisconsin were conducted. All the workers had back
      injuries in 1990 and were either paid workers' compensation temporary disability
      benefits for at least 4 weeks or received permanent disability benefits or
      compromise settlements. RESULTS: Some interactions with the workers' compensation
      system were positive. However, the majority of respondents in both states
      experienced their encounters with the workers' compensation system as cumbersome,
      frustrating, and demeaning. CONCLUSIONS: Mistrust, stigmatization, payment
      delays, and refusal of insurer personnel to pay benefits contribute to workers'
      negative experiences with the workers' compensation system. These insurer
      behaviors raise the costs to injured workers of workers' compensation benefits
      and thus may reduce the propensity of eligible workers to apply for benefits.

PMID- 15029566
TI  - Co-worker fatalities from hydrogen sulfide.
AB  - BACKGROUND: Hydrogen sulfide is a colorless, odorless gas that may cause rapid
      loss of consciousness and respiratory depression without warning. It has produced
      toxicity in workers in numerous industries and occupations. METHODS: A review of
      the United States Bureau of Labor Statistics (USBLS) Census of Fatal Occupational
      Injuries (CFOI) for occupational deaths related to hydrogen sulfide from 1993 to
      1999 was performed. RESULTS: Fifty-two workers died of hydrogen sulfide toxicity
      in this 7-year period. Deaths were most commonly reported in workers who were
      white (85%), male (98%), and in their first year of employment with the company
      (48%). Common industries included waste management, petroleum, and natural gas.
      In 21% of cases, a co-worker died simultaneously or in the attempt to save the
      workers. CONCLUSIONS: Hydrogen sulfide toxicity is uncommon, but potentially
      deadly. Toxicity is predominantly in new workers and co-worker fatalities occur
      in a significant minority of cases. Proper training and education on the warning
      signs of hydrogen sulfide toxicity may help reduce worker fatalities.

PMID- 15029567
TI  - Heat illness in the U.S. mining industry.
AB  - BACKGROUND: Heat illness is relatively common in the underground metalliferous
      mines of South Africa and Australia. Little is known about heat illness in other
      forms of mining and there have been no studies of heat illness in the US mining
      industry. METHODS: Mine Safety and Health Administration (MSHA) accident, injury,
      illness, and employment data were used to study heat illness reported by the US
      mining industry from January 1, 1983 to December 31, 2001. RESULTS: Five hundred
      thirty eight cases of heat illness were reported. None of these cases were fatal.
      Four hundred twenty seven cases (79.4%) occurred in the summer months of June,
      July, and August. Incidence rates of heat illness in underground mining ranged
      from 0.00275/10(6) person-hours for coal, to 0.168/10(6) person-hours for metal,
      rate-ratio = 61.1 (P < 0.001). Incidence rates in surface mining ranged from
      0.0265/10(6) person-hours for coal, to 0.0644/10(6) person-hours for stone, rate
      ratio = 2.43 (P < 0.001). Incidence rates in mills/preparation plants ranged from
      0.0255/10(6) person-hours for coal, to 0.417/10(6) person-hours for stone, rate
      ratio = 16.4 (P < 0.001). CONCLUSIONS: Heat illness occurs most frequently in
      stone mills, metal mills, and underground metal mines. Preventive measures should
      target the summer months of June, July, and August.

PMID- 15029568
TI  - Fatal rat bite fever in a pet shop employee.
AB  - BACKGROUND: Rat bite fever is a zoonotic disease that has been described in
      laboratory personnel as well as the general population. METHODS: A 24-year-old
      male pet shop employee contracted the disease through a minor superficial finger
      wound on a contaminated rat cage. The disease progressed from a flu-like illness
      to endocarditis involving first the aortic valve and then the mitral valve and
      septum. Despite aggressive therapy including two surgical procedures, the patient
      died from sepsis and multi-organ system failure 59 days after initial injury.
      RESULTS: This is the first reported case of rat-bite fever (RBF) in a pet shop
      work setting. CONCLUSIONS: Zoonotic infections may present a significant hazard
      to workers handling animals. Education on hazards of animal contact and other
      preventive measures are needed in small places of business like pet shops.

PMID- 15029569
TI  - Prevalence and reporting of occupational illness by company size: population
      trends and regulatory implications.
AB  - BACKGROUND: Reports of occupational disease using the Bureau of Labor Statistics
      (BLS)/OSHA survey have shown increasing rates with larger establishment size. The
      literature is divided on whether this pattern is an artifact of under-reporting
      in smaller businesses or is the result of differences in underlying risk factors.
      METHODS: A population-based survey [the Connecticut Upper-Extremity Surveillance
      Project (CUSP)] assessing prevalence of likely work related musculoskeletal
      disorders (MSD) in CT, coded by establishment size, is compared to CT MSD
      incidence rates based on the BLS/OSHA survey. RESULTS: When analyses were
      controlled for age, gender, physical risks, and occupation, there was a
      marginally significant association between business size and the rate of MSD
      [odds ratio (OR) = 0.91, CI 0.82-1.01], but in the opposite direction of the
      BLS/OSHA rates, with larger businesses having somewhat lower rates of MSD.
      Reported risk factors varied in a similar direction, though with mid-sized
      companies having the highest physical risks. CONCLUSIONS: The increased rates of
      occupational illness in larger businesses reported in the BLS/OSHA survey does
      not appear to be due to actual incidence or distribution of risk factors, but
      appears more likely to be due to under-reporting in smaller businesses. Estimates
      based on the assumption that the ORs based on size are actually similar to the
      CUSP population survey results suggest that MSD incidence is approximately 3.6
      times the reported rates.

PMID- 15029570
TI  - Assessment of occupational safety and health programs in small businesses.
AB  - BACKGROUND: Occupational safety and health (OSH) programs are a strategy for
      protecting workers' health, yet there are few peer-reviewed reports on methods
      for assessing them, or on the prevalent characteristics of OSH programs,
      especially in small businesses. METHODS: We adapted an occupational safety and
      health administration (OSHA) survey instrument to assess: management commitment
      and employee participation, workplace analysis, hazard prevention and control,
      and education and training. This was supplemented by a series of open-ended
      questions. We administered the survey in 25 small worksites. RESULTS: Scores for
      each element ranged widely, with distribution of most scores being positively
      skewed. Barriers to addressing OSH included lack of time and in-house expertise,
      and production pressures. External agents, including corporate parents, liability
      insurers, and OSHA, played an important role in motivating OSH programs.
      CONCLUSIONS: Small businesses were able to mount comprehensive programs, however,
      they may rely on outside resources for this task. Being small may not be a
      barrier to meeting the requirements of an OSHA program management rule.

PMID- 15029571
TI  - The Precautionary Principle: implications for research and policy-making.
      Statement of the Collegium Ramazzini. Approved by the fellows, 25 October, 2003.

PMID- 15029572
TI  - Implications of the Precautionary Principle in research and policy-making.
AB  - The Precautionary Principle (PP) has recently been formally introduced into
      national and international law. The key element is the justification for acting
      in the face of uncertainty. The PP is thereby a tool for avoiding possible future
      harm associated with suspected, but not conclusive, environmental risks. Under
      the PP, the burden of proof is shifted from demonstrating the presence of risk to
      demonstrating the absence of risk and it is the responsibility of the producer of
      a technology to demonstrate its safety rather than the responsibility of public
      authorities to show harm. Past experiences show the costly consequences of
      disregarding early warnings about environmental hazards. Today, the need for
      applying the PP is even greater. New research is needed to expand current insight
      into disease causation, to elucidate the full scope of potential adverse
      implications resulting from environmental pollutants, and to identify
      opportunities for prevention. Research approaches should be developed and
      strengthened to counteract innate ideological biases and to support our
      confidence in applying the PP for decision-making in the public policy arena.

PMID- 15029573
TI  - Re: Fleming et al., 2003, National Health Interview Survey mortality among US
      farmers and pesticide applicators, and Lee et al., 2002, proportionate mortality
      of crop and livestock farmers in the United States, 1984-1993.

PMID- 15029574
TI  - A benefit of reducing lung cancer incidence in women occupationally exposed to
      cotton textile dust.

PMID- 15029577
TI  - [Can a patient do heavy physical work after myocardial infarction?  Concerning
      the article in DMW 40/2003].

PMID- 15029578
TI  - Training pediatric pulmonologists for the future: academic is a state of mind not
      just a location.

PMID- 15029579
TI  - Manchester cohort.

PMID- 15029580
TI  - Exhaled breath condensate.

PMID- 15029581
TI  - Exhaled gas analysis and airway inflammation.

PMID- 15029582
TI  - Treatment options of asthma in infancy.

PMID- 15029583
TI  - HFA inhalers.

PMID- 15029585
TI  - Classification of phenotypes.

PMID- 15029584
TI  - Matching the device to the patient.
AB  - Aerosol therapy is complex, especially in young children, and can only succeed
      when the physician has detailed knowledge about: aerosol characteristics of the
      various aerosol delivery systems; the pathophysiology of the lung disease; the
      skills of the patient in various age groups. Only when this knowledge is
      available the appropriate delivery device for the child can be selected and the
      proper instructions can be given. Most aerosol delivery devices are not primarily
      developed for use in children. Particle size characteristics of most delivery
      systems are suboptimal for children since they deliver only a low mass of extra
      fine aerosol particles.

PMID- 15029586
TI  - Mechanisms of steroid resistance in asthma.

PMID- 15029587
TI  - Adherence to asthma therapy: the "blocked receptor".

PMID- 15029588
TI  - Immunotherapy should not be used for asthma.

PMID- 15029589
TI  - The biology of T-cells in allergy and asthma: beyond the TH1/TH2 concept.

PMID- 15029590
TI  - Immune effector cells: mast cells and eosinophils?

PMID- 15029591
TI  - Cytokine cross-talk.

PMID- 15029592
TI  - Asthma guidelines for children--are they useful?--no!

PMID- 15029593
TI  - Cytokine therapies.

PMID- 15029594
TI  - Antibiotics for asthma?

PMID- 15029596
TI  - TB and IUATLD.

PMID- 15029595
TI  - Tuberculosis in the developing world.

PMID- 15029597
TI  - Pulmonary complications of HIV.

PMID- 15029599
TI  - HIV and the lung in developing world.

PMID- 15029598
TI  - HIV immunology and new therapies.

PMID- 15029601
TI  - Asthma in developing worlds.

PMID- 15029600
TI  - Post-Infectious Bronchiolitis Obliterans.

PMID- 15029602
TI  - Severe acute respiratory syndrome (SARS) in children.

PMID- 15029603
TI  - Innate pulmonary immunity: cilia.

PMID- 15029604
TI  - Defensins & other peptides.

PMID- 15029605
TI  - Mucomodulator therapy in cystic fibrosis: balancing mucus clearability against
      the spread of airborne pathogens.

PMID- 15029606
TI  - Bronchoscopy in critically ill children.

PMID- 15029607
TI  - Non-genetic influences on CF lung disease: the role of sociodemographic
      characteristics, environmental exposures and healthcare interventions.

PMID- 15029608
TI  - Modifier genes in cystic fibrosis.

PMID- 15029610
TI  - The delivery of proteins and peptides to the lung.

PMID- 15029609
TI  - Early interventions in CF.

PMID- 15029611
TI  - Inhaled antibiotics.

PMID- 15029612
TI  - New treatments for pediatric sinusitis.

PMID- 15029613
TI  - Inflammation and airway remodeling.

PMID- 15029614
TI  - Airway remodeling: structure and physiology.

PMID- 15029615
TI  - Prevention strategies of chronic lung disease.

PMID- 15029617
TI  - Apparent Life Threatening Event (ALTE) assessment.

PMID- 15029616
TI  - Long-term follow-up of chronic lung disease of infancy.

PMID- 15029618
TI  - Prevention of sudden infant death syndrome.

PMID- 15029619
TI  - Optimal oxygen therapy in the newborn period.

PMID- 15029620
TI  - Living related donors.

PMID- 15029621
TI  - When should children be referred for lung or heart-lung transplantation?

PMID- 15029622
TI  - Post-transplant complications.
AB  - Lung transplantation carries the potential of great benefit to patients with
      chronic, end-stage lung disease; but it comes with significant medical, social,
      financial, and psychosocial costs that differ from those experienced prior to
      transplantation. Further understanding of its limitations, especially the
      development of acute and chronic rejection, will continue to lead to better
      immunosuppressive regimens and therapies. Success of the transplant procedure
      involves not only interventions to improve graft survival, but also those to
      improve the patient's quality of life.

PMID- 15029623
TI  - Airspace fluid clearance in the normal and edematous newborn lung: cardiogenic
      pulmonary edema fluid alters the clearance of airspace fluid.

PMID- 15029624
TI  - Monitoring and assessment of acute lung injury.

PMID- 15029625
TI  - Ventilation techniques including liquid ventilation.

PMID- 15029626
TI  - Neonatal pulmonary hypertension: a physiologic approach to treatment.

PMID- 15029627
TI  - Cath lab assessment.

PMID- 15029628
TI  - New therapies for pulmonary hypertension in neonates and children.

PMID- 15029629
TI  - Chest wall surgery for asphyxiating thoracic surgery.
AB  - Our experience to date suggests that LTE is a safe and effective treatment of
      symptomatic patients with ATD. Patients uniformly are clinically improved.
      Measured increases in thoracic volume are offset by overall increases in body
      size keeping the percent of predicted volumes low, suggesting mechanisms other
      than pure thoracic volume increase to explain the observed clinical improvement.
      Long term follow-up is mandatory.

PMID- 15029630
TI  - Pulmonary complications of neuromuscular disease.

PMID- 15029631
TI  - Deficient Na+ channel expression in newborn respiratory distress syndrome.

PMID- 15029633
TI  - Ion transport in lung disease.

PMID- 15029632
TI  - Airway proteins--surfactants.

PMID- 15029634
TI  - Assisted cough devices.

PMID- 15029635
TI  - High frequency chest compression and PEP.

PMID- 15029636
TI  - Dornase in non-CF.

PMID- 15029637
TI  - Appropriate use of palivizumb (Synagis).

PMID- 15029638
TI  - Non-invasive ventilation in preterm infants.

PMID- 15029639
TI  - Non-pulmonary therapy in the NICU.

PMID- 15029641
TI  - Snoring in children: still many questions, only a few answers.

PMID- 15029640
TI  - Consequences of snoring and sleep disordered breathing in children.

PMID- 15029642
TI  - Snoring: investigations guidelines.

PMID- 15029643
TI  - Acoustic markers of airway responses during inhalation challenge in children.

PMID- 15029644
TI  - Hemoptysis in children.

PMID- 15029645
TI  - Surfactant protein B deficiency as a prototype.

PMID- 15029646
TI  - Addressing tobacco smoke exposure: passive and active.
AB  - Many smoking parents are receptive to receiving smoking counseling messages and
      pediatric health care providers need to increase their efforts to address ETS
      exposure. Efforts to prevent smoking acquisition should continue by parents,
      doctors, schools, and the community. Start early in childhood to promote positive
      family communication and role modeling. Screen for tobacco use or intention and
      provide counseling to teen without the parent in room. Brief tobacco-dependence
      interventions are effective. Every patient/parent that uses tobacco should be
      identified, urged to quit, and offered treatment. Those willing to quit should be
      provided effective treatments using the "5 A's". Those unwilling to quit should
      be motivated using "5 R's". Quitting smoking is a major challenge but it is one
      that many people successfully achieve every day. Even a small increase in smoking
      cessation can be significant impact from a public health perspective and
      pediatric providers can play a significant role.

PMID- 15029647
TI  - Etiology of sickle cell chest.

PMID- 15029648
TI  - Sickle cell disease: pulmonary management options.

PMID- 15029649
TI  - Gastroesophageal reflux is a major cause of lung disease-pro.

PMID- 15029650
TI  - Gastroesophageal reflux disease is not a significant cause of lung disease in
      children.

PMID- 15029651
TI  - Prenatal influences on the development of allergy and asthma TH1/TH2 balance.

PMID- 15029653
TI  - The role of early infections, hygiene and intestinal microflora.

PMID- 15029652
TI  - What causes allergy and asthma? Early postnatal influences.

PMID- 15029654
TI  - The role of allergen exposure and sensitization.

PMID- 15029655
TI  - The role of passive smoking and indoor pollution.

PMID- 15029656
TI  - Outdoor air pollution and asthma.

PMID- 15029657
TI  - What causes allergy and asthma? The role of dietary factors.

PMID- 15029658
TI  - The role of allergen avoidance in primary and secondary prevention.

PMID- 15029660
TI  - Pulmonary diagnostic procedures: bronchoscopy.

PMID- 15029659
TI  - Airway inflammation and asthma treatment modalities.

PMID- 15029661
TI  - Pulmonary scintigraphy in chronic obstructive pulmonary disease.

PMID- 15029662
TI  - Tuberculosis: role of etiologic diagnosis and tuberculin skin test.

PMID- 15029663
TI  - Assessment of CFTR function in native epithelia for the diagnosis of cystic
      fibrosis.

PMID- 15029664
TI  - Sleep polygraphic studies in children: indications and techniques.

PMID- 15029665
TI  - [Committee of Nursing and Staff Education, improving education and defending the
      profession].

PMID- 15029666
TI  - [Training student nurses in nursing care in 2004. Interview by Marie-France
      Guerel].

PMID- 15029669
TI  - [Health parameters in infants and toddlers of major industrial city].
AB  - The authors studied dependence of various parameters (morbidity, physical
      development) in infants and toddlers on environmental state of major industrial
      city.

PMID- 15029668
TI  - [Human ecological genetics].

PMID- 15029667
TI  - [Pain, a major theme in education].

PMID- 15029670
TI  - [Measuring natural and artificial mineral fiber particles in air of civil
      objects].
AB  - The article deals with results of measuring natural and artificial mineral fiber
      particles in air of dwellings and public buildings, ambient air of Moscow. The
      authors evaluated the present situation in connection with nonindustrial use of
      materials containing asbestos and artificial mineral fibers. Consideration
      covered Russian MACs for asbestos fibers in ambient air of populated area.

PMID- 15029671
TI  - [Diagnostic criteria and medical examination in occupational bronchitis].
AB  - The article deals with materials comprehensively tackling a problem of
      occupational bronchitis--independent nosologic entity in occupational respiratory
      pathology.

PMID- 15029672
TI  - [On methods for unambiguous assessment of occupational environmental factors in
      occupational medicine].
AB  - Suggested system to formalize hygienic information is designed for definite and
      unambiguous assessment of varied totality of occupational environmental
      parameters in specific object of sanitary supervision; for study and analysis of
      physiologic, hygienic and clinical dependencies of workers' health state on the
      work conditions; for further specification of scientifically based prophylactic
      measures and social economic protection of workers.

PMID- 15029673
TI  - [Level of radioactive iodine intake by victims of nuclear power station accident
      could serve for early forecasting the probability of skin burns].
AB  - The authors suggested methodic approach to early individual forecasting the
      probability of skin-burns according to radioactive iodine intake by patients with
      acute lesions due to combined radiation.

PMID- 15029674
TI  - [A case of family thallium poisoning from unidentified source].
AB  - The authors described a case of thallium poisoning with thorough analysis and
      further treatment including novelty methods of hemofiltration and hemodialysis.

PMID- 15029675
TI  - [Hygienic evaluation of electromagnetic situation and vibroacoustic factors at
      workplaces for radio-technological staff of civil airports].
AB  - The authors proved electromagnetic environment for staff servicing radiolocation,
      navigation and communication systems in civil airports to be very severe:
      electromagnetic irradiation of broad frequency spectrum, in impulse and
      continuous generation mode, varying in intensity and time, with low telluric
      conditions in shielded chambers, with equivalent noise levels more than by 15 dBA
      exceeding the allowable ones.

PMID- 15029676
TI  - [Computed tomography in diagnosis and medical examination of respiratory
      occupational diseases].

PMID- 15029677
TI  - [Complex approach to hygienic evaluation and quality control or air in
      contemporary office].

PMID- 15029678
TI  - A good education. Modern Healthcare survey finds basic satisfaction with health
      management programs--and a few suggestions.
AB  - Advanced-degree programs in healthcare are adequately preparing the leaders of
      tomorrow, industry executives and other respondents indicate in a Modern
      Healthcare survey. Myron Fottler, left, a professor at the University of Central
      Florida in Orlando, says programs are becoming increasingly business-oriented to
      meet the ever-changing demands of the market.

PMID- 15029679
TI  - Raising the bar. FDA issues final regulations on bar-code adoption.

PMID- 15029680
TI  - Fuller disclosure. NQF to consider mandatory performance reporting.

PMID- 15029681
TI  - Good news, bad news on FICA. IRS tax programs will help, hurt medical residents.

PMID- 15029682
TI  - It takes a county. Tax increase proposed to save public system in Calif.

PMID- 15029683
TI  - Foiled again. Senate again fails to pass malpractice reform.

PMID- 15029684
TI  - Putting her beliefs into action. Ruth Rothstein made a career of ensuring
      healthcare to the underprivileged.

PMID- 15029685
TI  - Education first. Robert Shelton played key role in schooling HFMA members on
      Medicare.

PMID- 15029686
TI  - He helped clear the air. Former Surgeon General Luther Terry helped lead crusade
      against smoking.

PMID- 15029687
TI  - Race matters. How we can accelerate true diversity in healthcare administration.

PMID- 15029688
TI  - Flying below the radar. Small for-profit hospital companies, armed with investors
      and experienced executives, target overlooked facilities, markets.

PMID- 15029689
TI  - Not in a hurry to grow.

PMID- 15029690
TI  - Chief executive philosopher. Calif. Blue Shield's CEO sees few conflicts in
      caring for the community and caring for the bottom line.

PMID- 15029691
TI  - [Decomposition of natural aromatic structures and xenobiotics by fungi].
AB  - The review deals with transformation of natural and synthetic aromatic compounds
      by fungi (causative agents of white rot, brown rot, or soft rot, as well as soil
      filamentous fungi). Major enzyme types involved in the transformation of lignin
      and aromatic xenobiotics are discussed, with emphasis on activity regulation
      under the conditions of secondary metabolism and oxidative stress. Coupling of
      systems degrading polysaccharides/lignin and non-phenolic lignin structures
      (without the involvement of lignin peroxidase) is analyzed, together with non
      enzymatic mechanisms (involving lipoperoxide free radicals, cation-radicals,
      quinoid mediators, or transition metal ions). Metabolic pathways resulting in the
      formation of aromatic and haloaromatic compounds in fungi are described.
      Consideration is given to the mechanisms of fungal adaptation to aromatic
      xenobiotics.

PMID- 15029692
TI  - [Effect of deuteration on methanol dehydrogenase activity in Methylophilus sp. B
      7741].
AB  - We studied the effect of deuterium oxide present in the medium on the activity of
      methanol dehydrogenase (EC 1.1.99.8) from methylotrophic bacteria Methylophilus
      sp. B-7741. Methanol dehydrogenase activity in extracts of the biomass obtained
      in a highly deuterated medium (2H-enzyme) was 34-47% of enzyme activity in the
      control biomass, which depended on reaction conditions. The isotopic effects of
      substrate deuterium (methanol) for 1H-enzyme and 2H-enzyme were 1.37 +/- 0.05 and
      1.38 +/- 0.01, respectively. We revealed for the first time the reverse isotopic
      effect of solvent deuterium in the reaction catalyzed by methanol dehydrogenase
      (0.80 +/- 0.02 and 0.60 +/- 0.01 for 1H-enzyme and 2H-enzyme, respectively).

PMID- 15029693
TI  - [Isolation of conjugates of albumin and ribonuclease].
AB  - A method for separation of albumin-ribonuclease (RNase) conjugates has been
      proposed, based on the use of macroporous silicates. It was established that
      about 76% of ligand-free human serum albumin (LFHSA) formed complexes with
      enzymes. It was shown that most of the conjugates of albumin and pancreatic RNase
      contained up to 2 mol enzyme per 1 mol LFHSA. The conjugates of albumin and
      bacterial RNase, isolated from the cells of the strain Bacillus intermedius 7P,
      displayed higher specific activities, containing, on average, 2.3 mol RNase per 1
      mol LFHSA (for the conjugates with molecular weights below 92 kDa) or 3.3 mol
      RNase per 1 mol protein carrier (for the conjugates with higher molecular
      weight).

PMID- 15029694
TI  - [Isolation and properties of glucose oxidase from Penicillum funiculosum 433].
AB  - A method for isolation of extracellular glucose oxidase from Penicillium
      funiculosum 433 and its purification is proposed. The enzymatic preparation was
      produced with a yield of 56% and a specific activity of 3730 AU per 1 mg protein.
      The enzyme studied displayed a high thermostability, resistance to metal ions,
      and performance in a wide pH range and was equal in its properties to foreign
      analogues.

PMID- 15029695
TI  - [Proteinases for the gastric mucosa of the European sheatfish, Silurus glanis L].
AB  - Three proteinases named as P1, P2 and P3, were isolated from European sheatfish
      (Silurus glanis L.) gastric mucosa by salting-out of (NH4)2SO4, gel
      chromatography on Sephadex G-75 and ion-exchange chromatography on DEAE
      cellulose. Isoelectric points of isolated proteinases were determined by
      isoelectric focusing and were equal to 1.9, 3.2 and 4.75 respectively for P1, P2
      and P3. The molecular weight of P1 was 39,800 Da and proteinases P2 and P3 had a
      molecular weight of 30,200 Da. The optimum pH for three peptidases isolated from
      sheatfish gastric mucosa and maximum stability of these enzymes were found at
      acidic pH. It allowed identifying these proteinases as pepsin-type enzymes of
      fish.

PMID- 15029696
TI  - [Enzymatic hydrolysis of alpha-chitin].
AB  - It was shown that the enzymatic preparation Celloviridin G20x can be used for the
      hydrolysis of alpha-chitin of various origin. The purity of the final product of
      hydrolysis, N-acetylglucosamine, was monitored using HPLC.

PMID- 15029697
TI  - [Isolation of chitin and chitosan from honey bees].
AB  - The procedure of isolation of chitin, chitosan, and water-soluble low-molecular
      weight chitin from the corpses of bees was developed. This procedure included
      deproteinization of the corpses of bees, discoloration of the chitin-melanin
      complex, deacetylation, and enzymatic hydrolysis of chitosan.

PMID- 15029699
TI  - [Use of Panus tigrinus fungi for production of pressed materials from cotton
      plant waste].
AB  - Changes in the chemical composition of cotton plant stems used as a substrate for
      solid-phase cultivation of the fungus Panus tigrinus were studied as well as the
      effect of these changes on properties of the pressed materials made of these
      stems. During the first 3 days of growth, the fungus better consumed cellulose;
      then, the rate of cellulose consumption was comparable with that of lignin.
      Intensity and pattern of these changes depended on the age of inoculum. The rate
      of cotton plant waste biodegradation was higher when a 3-day-old incoculum was
      used. The pressed materials made of the raw stuff treated with a 3-day-old
      inoculum of P. tigrinus for 2-3 days displayed better characteristics. Annually,
      large amounts of lignocellulose stuff is lost while processing of agricultural
      waste: straw, awn, plant stems, etc. In the countries with developed cotton
      growing, the annual amount of only guza-paya (dry cotton plant stems) reaches
      several million tons. To solve this problem, bioconversion of these wastes is
      studied to manufacture useful products and materials.

PMID- 15029698
TI  - [Degradation of lignin-carbohydrate substrate by soil fungi--producers of laccase
      and cellobiose dehydrogenase].
AB  - The growth of nonsporulating mycelial fungi INBI 2-26(+), producer of laccase;
      INBI 2-26(-), producer of cellobiose dehydrogenase; and their mixed culture on
      lignin-carbohydrate substrates under conditions of submerged fermentation were
      studied. The degrees of degradation of lignin, cellulose, and hemicellulose of
      cut straw over 23 days amounted to 29.8, 51.4, and 72% for the laccase producer;
      15.8, 33.9, and 59.1% for the cellobiose dehydrogenase producer; and 15.8, 39.4,
      and 64.5% for the mixed culture, respectively. The laccase activity in the medium
      when strain 2-26(+) was cultivated individually reached its maximum on day 28;
      the activity of cellobiose dehydrogenase of strain 2-26(-), on days 14 to 28. A
      method for determining cellobiose dehydrogenase activity in the presence of
      laccase was developed. In the mixed culture, both enzymes were formed; however,
      the level of laccase synthesis was 1.5-fold lower compared to that of strain 2
      26(+), while synthesis of cellobiose dehydrogenase was similar to that of the
      corresponding producer. Cellobiose dehydrogenase failed to boost the action of
      laccase while degrading the lignin of straw.

PMID- 15029700
TI  - [Sulfur metabolism enzymes in thermoacidophilus bacteria Sulfobacillus
      sibiricus].
AB  - Sulfur oxygenase, sulfite oxidase, adenylyl sulfate reductase, rhodanase,
      sulfur:Fe(III) oxidoreductase, and sulfite:Fe(III) oxidoreductase were found in
      cells of aerobic thermoacidophilic bacteria Sulfobacillus sibiricus strains N1
      and SSO. Enzyme activity was revealed in cells grown on the medium with elemental
      sulfur or in the presence of various sulfide elements and concentrates of sulfide
      ores. The activity of sulfur-metabolizing enzymes depended little on the degree
      of aeration during bacterial growth.

PMID- 15029701
TI  - [Features of transformation of phosphates in Rhodobacter sphaeroides
      chromatophores].
AB  - We have found the ATP production in the Rhodobacter sphaeroides chromatophores
      illuminated by single short light flash, that is under conditions when the proton
      gradient formed as a result of electron transport after the second flash, is
      absent. The ATP synthesis was accompanied by the H2O2 formation. Simultaneous
      formation of H2O2 is indicative of the oxidative activation of phosphate during
      the ATP synthesis, as in the model systems with isolated chlorophyll. These data
      provide a theoretical background to the fitting of illumination parameters in
      both laboratory and industrial photobioreactors with photosynthetic bacteria used
      in biotechnological processes.

PMID- 15029703
TI  - Thermochemical characteristics of 2,4-dichlorophenol degrading strain Pseudomonas
      GT241-1 of growth metabolism by microcalorimetry.
AB  - By using LKB-2277 Bioactivity Monitor, ampoule method, the heat output of the
      growth metabolism of a 2.4-dichlorophenol degrading bacteria strain, Pseudomonas
      strain GT241-1, has been determined at 30 degrees C. From the thermogenic curves,
      it can be established that thermokinetic equation of their growth metabolism is
      Pt = Pt = 0 exp(k(m) t), dP/dt = k(m)P1, with the order of growth metabolism n =
      1. The experimental results indicate that the relationship between the metabolic
      power (P) and the cell concentration (C), and relationship between the metabolic
      power of each cell (P0) and the cell concentration can be characterized by the
      following thermal equation: C = a + kP, InC = a' + k'P0 or dC/dP0 = KC1. The
      order of the P0-C equation n is also 1. These results are very significant in
      environmental sciences, biology and thermochemistry.

PMID- 15029702
TI  - [Microorganisms--degraders of polychlorinated biphenyls].
AB  - Four strains belonging to the genus Bacillus, capable of degrading
      polychlorinated biphenyls (PCB), were isolated by screening the collection
      strains of soil bacteria, degrading a organochlorine pesticide,
      hexachlorocyclohexane (HCCH). A method for production of tritium-labeled PCB was
      developed. Consumption and degradation of PCB by the soil bacterial strains
      selected were studied using tritium-labeled PCB and GLC. It was demonstrated that
      PCB are degradable both in culture media and under in model soil samples.

PMID- 15029705
TI  - [Effect of alkylbenzenes on malting processes].
AB  - It has been shown that one of alkyl hydroxybenzenes, C7-AHB, can be used in
      malting for regulating barley growth. Depending on concentration (0.01-1.0%) and
      duration (10 min to 6 h), treatment of barley with a C7-AHB solution stimulates
      embryo development (0.01-0.02%) or suppresses the growth of vegetative organs (>
      0.5%) and modulates enzyme activities in germinating grains. Stimulation of the
      activities of the amylolytic and protein-proteinase complexes in barley depending
      on C7-AHB concentration improves malt quality by increasing both the degree of
      its saccharification and protein dissolution.

PMID- 15029704
TI  - [Effect of natural and genetically modified rhizospheric Pseudomonas aureofaciens
      bacteria on accumulation of arsenic by plants].
AB  - Gene constructions rendering bacteria resistant to arsenic and capable of
      dissolving phosphates and/or arsenates were created by cloning ars operon and the
      gene of citrate synthase from a chromosome of the strain Pseudomonas aeruginosa
      PAO1. Genetically modified variants of the strain Pseudomonas aureofaciens BS1393
      have been constructed, which are resistant to high concentrations of arsenic and
      dissolve poorly soluble phosphates and/or arsenates. Recombinant strains P.
      aureofaciens BS1393(pUCP22::arsRBC) and P. aureofaciens BS1393(pUCP22::gltA)
      exerted positive effects on the survival of sorgo (Sorghum saccharatum L.) and
      its ability to accumulate arsenic.

PMID- 15029706
TI  - [Change in activity of superoxide dismutase in callus culture of Rauwolfia
      serpentina Benth., grown in standard conditions and with temperature shock].
AB  - The rate of superoxide dismutase (SOD) accumulation in Rauwolfia serpentine
      Benth. cell culture under heat shock conditions (3 h, 45 degrees C) decreased
      insignificantly (by 4%), whereas low positive temperature (24 h, 7 degrees C)
      caused a drastic drop (by 48%). The observed decrease in the level of SOD
      activity resulted from a slowdown of the biosynthesis rate of the enzyme and
      decrease in its concentration in the cultivated cells. In addition, a
      compensatory decrease in degradation of the active protein (Kd) was observed at
      low positive temperatures and, consequently, an increase in its half-life (t1/2),
      compensating partially for a deficiency in de novo synthesized SOD molecules. The
      parameters studied restored after a 24-h adaptation of cells under standard
      temperature conditions.

PMID- 15029707
TI  - [Isolation of polysaccharides from callus culture of Lemna minor L].
AB  - Two fractions that included acid arabinogalactan and pectin were extracted from
      the callus culture of duckweed plants (Lemna minor L.) with water and ammonium
      oxalate. Residues of galactose and arabinose in the 2.0-2.5:1 ratio were the
      major constituents of acid arabinogalactan. The pectin fraction contained
      primarily residues of glucuronic acids, galactose, and arabinose. The percentage
      of arabinogalactan and pectin was similar. The yield of polysaccharide fractions
      did not depend on the method for their isolation. Extraction with water,
      treatment of the biomass with an aqueous solution of formalin and diluted
      hydrochloric acid, and extraction with an aqueous solution of ammonium oxalate
      allowed us to obtain the highest-purity pectin polysaccharide.

PMID- 15029708
TI  - [Purification and characterization of lipases from wheat germ].
AB  - A method of isolation and purification of lipase (EC 3.1.1.3) from the germ of
      wheat (Triticum aestivum) is described. Electrophoretically homogeneous
      preparation of the enzyme (specific activity, 622.5 x x 10(-3) mumol/min per mg
      protein) was obtained after purification in 61 times. The molecular weight of the
      enzyme, determined by gel chromatography, was 143 +/- 2 kDa. The optimal
      conditions for the enzyme were 37 degrees and pH 8.0. Homogeneous preparation of
      the lipase exhibited high thermal stability: over 20% of original activity was
      retained after incubation of the preparation at high temperatures (60-90 degrees)
      for 1 h at pH 8.0.

PMID- 15029709
TI  - [Role of a protein inhibitor of polygalacturonase in ripening of apples and their
      resistance of infection with Monilia fructigena, the causative agent of fruit
      rot].
AB  - We investigated the dynamics of the activity of the polygalacturonidase inhibitor
      protein (PGIP) in apple fruits of six varieties differing in ripening time and
      correlated it with the degree of damage by the causative agent of fruit rot,
      Monilia fructigena. The apple varieties studied differed significantly in PGIP
      activity and degree of damage by Monilia fructigena. The rate of dissemination
      over fruit tissues was inversely related to PGIP activity. The resistance of
      apples to M. fructigena increased with ripening. The simultaneous increase in
      PGIP activity suggests its important role in the reduction of apple damage by
      fruit rot.

PMID- 15029710
TI  - [Interaction between structure of plant steroids and their effect on
      phytonematodes].
AB  - The effects of certain plant steroids of the groups of furostanol glycosides,
      glycoalkaloids, and alpha-ecdysone on growth and development of phytoparasitic
      nematodes were studied. It was shown using an experimental system including
      tomato, Lycopersicon esculentum Mill., and root-knot nematode, Meloidogyne
      incognita Kofoid et White, that steroid molecule had significant nematicidic
      activity if it contained a carbohydrate moiety and an additional heterocycle in
      the steroid core. The maximum nematicidic activity is inherent in glycosides
      containing chacotriose as the carbohydrate moiety of the molecule. Some compounds
      tested in this work could be used for protecting plants against phytoparasitic
      nematodes.

PMID- 15029711
TI  - [Effect of heavy metals on wheat seedlings; activation of antioxidant enzymes].
AB  - Accumulation of heavy metals in wheat grain exposed to multicomponent pollutants
      (industrial waste-water) was studied. The absolute content of metals (Zn, Cd, Cu,
      Cr, Ni, Pb, and Mn) was found to be determined by the extent of purification of
      wastewater. An increase in the degree of grain contamination with heavy metals
      was accompanied by activation of antioxidant enzymes (superoxide dismutase, EC
      1.15.1; catalase, EC 1.11.1.6; and peroxidase, EC 1.11.1.7) in leaves and
      activation of superoxide dismutase and peroxidase in roots. The ratio of activity
      of membrane enzymes to activity of cytosol enzymes was demonstrated to be high.
      It was concluded that the membrane-tropic effect of multicomponent contaminants
      was due to accumulation of heavy metals capable of inducing the antioxidant
      protection in the next generation of wheat seedlings.

PMID- 15029712
TI  - [Retention of essential oil components sorbed by native cornstarch during
      storage].
AB  - Changes in the content of essential oil components sorbed by native dry
      cornstarch during storage were studied by the method of capillary gas
      chromatography. The composition of volatile substances changed insignificantly,
      and the sample retained its organoleptic characteristics over 3-month storage. We
      revealed that up to 70-80% monoterpene carbohydrates and lower sulfides
      disappeared after 6-month storage. The loss of terpene alcohols, acetates, and
      ketones did not exceed 10%. Storage was accompanied by an increase in the content
      of essential oil components bound to the surface of starch granules.

PMID- 15029713
TI  - [In memory of member-correspondent of the Academy of Sciences of the USSR Il'i
      Vasil'evich Berezin (1923-1987)].

PMID- 15029714
TI  - [Dynamics of charge transfer along an oligonucleotide at finite temperature].
AB  - The quantum-statistical approach was used to describe the charge transfer in
      nucleotide sequences. The results of numerical modeling for hole transfer in the
      GTTGGG sequence with background temperature noise are given. It was shown that,
      since guanine has an oxidation potential lower than thymine, the hole created at
      the G donor in this sequence passes through the thymine barrier into the guanine
      triplet (acceptor) at a time of approximately 10 ps at a temperature of 37
      degrees C.

PMID- 15029715
TI  - [Study of interaction of cytochrome P450 2B4 with riboflavin by fluorescence
      spectrometry].
AB  - Fluorescence quenching of riboflavin by cytochrome P450 2B4 was used to probe the
      ligand--enzyme binding interaction ((lambda ex = 385 nm, lambda em = 520 nm).
      Riboflavin is a component of a flavoprotein NADPH dependent cytochrome P450
      reductase, an essential electron carrier during cytochrome P450 catalysis.
      Fluorescence titration measurements revealed that cytochrome P450 2B4 and
      riboflavin formed a complex with an apparent Kd = 8.8 +/- 1 microM. The
      fluorescence intensity of riboflavin decreased upon the addition of cytochrome
      P450 2B4, which may be caused by the resonance excitation energy transfer from
      the fluorescent donor riboflavin to the cytochrome P450 2B4 heme acceptor. These
      data suggest that there may exist specific sites of binding of riboflavin with
      the protein globule of cytochrome P450 2B4.

PMID- 15029716
TI  - [Concentration-dependent effects of magnetic accumulation of ligand-binding
      microparticles and ferritin aggregates].
AB  - A method for measuring the magnetic susceptibility of microparticles of a
      suspension from the thickness of the layer deposited on the surface of a
      magnetized wire was developed. The magnetic accumulation was registered by means
      of a photodetector, by measuring the amplitude and spectrum of fluctuations of
      the intensity of scattered light. This was used as the basis for the development
      of a biosensor and biochips.

PMID- 15029717
TI  - [Physico-chemical properties of aqueous solutions, prepared in a membrane
      electrolyzer].
AB  - The physicochemical properties of aqueous solutions resulting from membrane
      electrolysis were studied. It was shown that the catholyte contains hydrogen
      peroxide at a concentration of 10(-7), which is formed during the reduction of
      soluble oxygen. It was found that the relaxation of the catholyte redox potential
      is caused by the transition of the reducing agent to the gaseous phase. The
      relaxation characteristics of the redox potentials of the catholyte and molecular
      hydrogen solution were compared. The similarity of the relaxation characteristics
      of the catholyte and the hydrogen solution as well as the fact that the
      catholyte, despite its low redox potential, does not reduce either potassium
      ferricyanide or 5-5'-dithiobis(2-nitrobenzoic acid) support the suggestion that
      the redox potential of the catholyte is due to molecular hydrogen. However, based
      on this suggestion, it is impossible to explain the increase in the relaxation
      time of the catholyte with increasing ionic strength and the fact that, as the
      redox potential of the catholyte decreases, the concentration of other gases
      dissolved in the catholyte remains unchanged. Thus, the question regarding the
      nature of the reducing agent remains open.

PMID- 15029719
TI  - [Interaction of amyloid beta-(1-40) peptide with model membranes].
AB  - The amyloid beta (1-40) peptide (A beta) is the main component of amyloid
      deposits found in the brain of patients afflicted with Alzheimer's disease. After
      treatment with hexafluoroisopropanol, commercial A beta is readily soluble in
      water and buffers at pH 7.4 and has an irregular secondary structure. The
      adsorption of A beta to the water-air interface and to the surface of the
      dipalmitoylphosphatidylethanolamine monolayer at a surface pressure pi close to
      zero leads to an increase in pressure up to 17 mN/m. When being adsorbed, the
      molecules of the peptide occupy a part of the monolayer surface, which leads to
      the compression of lipid molecules forming the monolayer. Further compression of
      the monolayer composed of the molecules of the lipid and peptide leads to the
      extrusion of the peptide from the monolayer. If the lipid monolayer is
      preliminarily (prior to the addition of the peptide to the liquid phase)
      compressed to pi = 30 mN/m, no adsorption of the peptide to the monolayer occurs.
      No changes in the structure of the dipalmitoylphosphatidylethanolamine monolayer
      were detected by the sliding X-ray diffraction method, indicating the absence of
      specific interactions. The method of reflection and absorption infrared
      spectroscopy makes it possible to determine the conformation of the adsorbed
      peptide and its orientation in the lipid monolayer. It was found that A beta has
      the conformation of a beta-fold oriented parallel to the interface, as it is the
      case with the adsorption of peptide molecules to the lipid monolayer at pi < 30
      mN/m and upon adsorption to the interface that is not occupied by the lipid.

PMID- 15029720
TI  - [Local coupling of respiration processes and phosphorylation in rat liver
      mitochondria].
AB  - One variant of the model of the local coupling of phosphorylation and respiration
      in intact mitochondria was experimentally verified. The model is based on the
      following postulates: (1). Upon the functioning of H+ pumps, hydrogen ions bound
      to the outer membrane surface do not enter the aqueous phase but are utilized for
      ATP synthesis in the membrane supercomplex respiratory H+ pump--ATP synthetase.
      (2). During the functioning of H+ pumps, an appreciable part of the energy of
      oxidation reactions can be stored in the form of the thermodynamic (solvation)
      potential of H+ ions bound to the outer membrane surface. According to the model,
      the hydration of hydrogen ions during the transition from the outer face of the
      inner membrane to the aqueous phase should lead to a decrease in the efficiency
      of the system of the coupling of respiration and phosphorylation. The model takes
      into account the ability of the nonpermeating buffer to catalyze the detachment
      of hydrogen ions from the membrane surface to the aqueous phase and provide their
      complete solvation. A preparation of phosphorylating mitochondria with the
      covalently bound pH probe was obtained. This made it possible to register for the
      first time the presence of a local H+ gradient on the outer side of the inner
      mitochondrial membrane during the stable functioning of the oxidative
      phosphorylation system. It was shown on these mitochondrial preparations that a
      decrease in the outer local H+ gradient by the action of increased concentrations
      of buffer is accompanied by a significant decrease in the ADP/O parameter and a
      partial dissociation of oxidative phosphorylation. Conditions were determined
      under which increased concentrations of buffer in the incubation medium cause a
      partial dissociation and a decrease in the ADP/O value from 20% to twofold
      (depending on the quality of mitochondrial preparations). The results obtained
      are in full agreement with the predictions of the model.

PMID- 15029718
TI  - [Level of hydrogen peroxide in electrochemically activated solutions and study of
      its effect on growth of Escherichia coli].
AB  - The formation of hydrogen peroxide in catholytes and anolytes of
      electrochemically activated solutions: bidistilled water and solutions of sodium
      chloride and nutrition medium M9 was studied. The concentration of hydrogen
      peroxide was determined by the method of enhanced chemiluminescence in a system
      peroxidase-luminol-p-iodophenol. It was shown that the concentration of hydrogen
      peroxide depends on the ionic content of the solution and varies from a few
      fractions of a micromole in catholytes of bidistilled water and sodium chloride
      solutions (10(-5) divided by 10(-2) M) to 20-25 microM in catholytes of medium
      M9. The concentration of H2O2 in anolytes of various solutions was 15-20 times
      lower than in the corresponding catholytes and was equal to a few nanomoles in
      bidistilled water and a few micromoles in medium M9. The biological activity of
      the catholyte of medium M9 was determined from changes in the growth of E. coli
      cells. It was found that this catholyte stimulates the cell growth. The
      stimulating effect was 20-25% and did not change after the decomposition of
      hydrogen peroxide in the catholyte by catalase. The addition of H2O2 at the
      corresponding concentration to the inactivated nutrient medium produced no
      stimulating effect. These data suggest that hydrogen peroxide formed in the
      catholyte of nutrient medium M9 does not affect its biological activity.

PMID- 15029721
TI  - [Mathematical modeling of electron and protein transport, coupled with ATP
      synthesis in chloroplasts].
AB  - A mathematical model of electron and proton transport in chloroplasts of higher
      plants was developed, which takes into account the lateral heterogeneity of the
      lamellar system. Based on the results of numerical experiments, lateral profiles
      of pH in the thylakoid lumen and in the narrow gap between grana thylakoids under
      different metabolic conditions (in the state of photosynthetic control and under
      photophosphorylation conditions) were simulated. Lateral profiles of pH in the
      thylakoid lumen and in the intrathylakoid gap were simulated for different values
      of the proton diffusion coefficient and stroma pH. The model demonstrated that
      there might be two mechanisms of regulation of electron and proton transport in
      chloroplasts: (1) the slowing down of noncyclic electron transport due to a
      decrease in the intrathylakoid pH, and (2) the retardation of plastoquinone
      reduction due to slow diffusion of protons inside the narrow gap between the
      thylakoids of grana.

PMID- 15029723
TI  - [Permeabilization of cell membrane by programmed form of electrical pulses].
AB  - The role of the shape of electric pulses of cell permeabilization and lysis was
      studied using the newly developed DPS electroporator. The effects of bipolar
      pulses, steep rising and falling edges in the pulses, delays between pulses, and
      shapes of DC signals between the edges on the lysis of bovine oocytes and the
      permeabilization of their cell membranes were investigated. Comparing the
      permeabilization rates with the lysis rates revealed a number of correlations,
      which make it possible to optimize the pulse shapes for achieving maximum
      permeabilization rates while keeping the lysis rates low. The optimization of
      pulse shape is essential for improving the procedure of electroporation in
      mammalian cloning technology.

PMID- 15029722
TI  - [Effect of mercuric chloride and methylmercury on photosynthetic activity of the
      diatom Thalassiosira weissflogii by a fluorescent method].
AB  - It was shown by the pulse-amplitude modulation fluorescent method that, at a weak
      illumination (6 microE m-2.s-1), methylmercury at a concentration of 10(-6)-10(
      7) M decreases the photochemical activity of the reaction centers of photosystem
      II in cells of microalgae Thalassiosira weissflogii after a prolonged lag phase.
      Cells resistant to methylmercury at these low concentrations were detected by the
      microfluorimetric method. Chloride mercury decreased the activity of photosystem
      II of the algae only when at higher concentrations. Both toxicants at a
      concentration of 10(-6) M decreased the rate of recovery of photoinduced damage
      of centers of photosystem II and led to an increase in the energization component
      of nonphotochemical fluorescence quenching. These results indicate that the
      complex of fluorescent methods can be used to monitor early changes in the
      photosynthetic apparatus of algae in response to the toxic action of heavy
      metals.

PMID- 15029725
TI  - [From nonequilibrium thermodynamics to nonlinear dynamics].
AB  - Differences between the thermodynamic and kinetic approaches were discussed by
      using a system with two or more different steady states as an example. It was
      shown that the behavior of such systems can be described adequately by the
      kinetic approach only.

PMID- 15029724
TI  - [A new method of identifying a systems based on the minimal quadratic discrepancy
      criterion for biophysics problems].
AB  - A wide range of biophysical systems are described by nonlinear dynamic models
      mathematically presented as a set of ordinary differential equations in the
      Cauchy explicit form: [formula: see text] Fij(X1(t),..,XN(t),t), (i = 1,...,N, j
      = 1,...,M), where Fij (X1(t), ..., XN(t), t) is a set of basis functions
      satisfying the Lipschitz condition. We investigate the problem of evaluation of
      model constants aij (the system identification) using experimental data about the
      time dependence of the dynamic parameters of the system Xi(t). A new method of
      system identification for the class of similar nonlinear dynamic models is
      proposed. It is shown that the problem of identifying an initial nonlinear model
      can be reduced to the solution of a system of linear equations for the matrix of
      the dynamic model constants [aj]i. It is proposed to determine the set of dynamic
      model constants aij using the criterion of minimal quadratic discrepancy for the
      time dependence of the set of dynamic parameters Xi(t). An important special case
      of the nonlinear model, the quadratic model, is considered. Test problems of
      identification using this method are presented for two nonlinear systems: the Van
      der Pol type multiparametric nonlinear oscillator and the strange attractor of
      Ressler, a widely known example of dynamic systems showing the stochastic
      behavior.

PMID- 15029726
TI  - [Process of adaptation in frog auditory system neurons].
AB  - The responses of single neurones located in different parts of the auditory
      system of amphibians to tone signals of a small death of amplitude modulation
      were studied. It was shown that the firing rate generally diminished during both
      the first second of sounding (short-term adaptation) and subsequent several tens
      of seconds (long-term adaptation). In a considerable proportion of neurones, a
      sharp improving of the phase-locking of the response to modulation waveform was
      observed in parallel the drop in firing rate. These effects are expressed much
      more strongly in higher nucleus of the auditory system. A sharp accentuation of
      modulation waveform could be seen also in the completely adapted regime. In some
      cases, this effect was evident only after the addition of a random noise to the
      modulating function (stochastic resonance effect). These data were compared with
      physiological results obtained on mammals and with psychophysical observations.

PMID- 15029727
TI  - [Formation of paramagnetic nitrosyl complexes of non heme iron in animals with
      participation of nitric oxide from exogenous and endogenous sources].
AB  - It was found that thiosulfate has a stabilizing effect on exogenous and
      endogenous dinitrosyl-iron complexes in mice treated with bacterial
      lipopolysaccharide. It was assumed that thiosulfate protects dinitrosyl-iron
      complexes from the destructive influence of superoxide and peroxinitrite whose
      enhanced synthesis, together with the synthesis of nitric oxide, is initiated in
      mice by the lipopolysaccharide. For the first time, the formation of dinitrosyl
      iron complexes was demonstrated, which occurs with the participation of nitric
      oxide generated enzymatically via the L-arginine-dependent pathway. The injection
      of exogenous dinitrosyl-iron complexes with thiosulfate, which, together with
      diethyldithiocarbamate, provide the formation of exogenous mononitrosyl iron
      diethyldithiocarbamate complexes, made it possible to use the ABC method, which
      markedly enhances the efficiency of scavenging of endogenous nitric oxide in mice
      treated with lipopolysaccharides.

PMID- 15029728
TI  - [Features of spatial distribution of constant electric field potential in normal
      states and in disease].
AB  - Special features of changes in human electrical field in some diseases were
      studied. Methods for the correction of the disease-induced changes in the
      intrinsic human field using an external current generator were developed.

PMID- 15029729
TI  - [Dependence of "macroscopic fluctuations" from cosmophysical factors. Spatial
      anisotropy].
AB  - It was shown in experiments with collimators that the changes with time in the
      shape of histograms constructed from the measurements of the alpha-activity of
      239Pu microsamples depend on the direction of the flow alpha-particles. If the
      flow of alpha-particles was directed to the Polar Star, the dependence of the
      probability of the realization of histograms of similar shape on time
      disappeared. The measurements of alpha-particle flows directed to the East and
      West revealed a high probability of the repeated realization of histograms of
      similar shape in 1436 min, i.e., in a sederal day. A comparison of "west" and
      "east" histograms showed a high probability of the realization of similar "west"
      histograms 718 min (half a sideral day) later than "east" histograms. The results
      suggest that the shape of histograms depends on the pattern of the starry sky and
      the space-time inhomogeneity corresponding to this pattern.

PMID- 15029730
TI  - [Possible role of iron ions in changes in composition of DNA complexes and their
      magnetic properties in cell cycle processes].
AB  - A hypothesis on the possible role of iron cations in transformations of
      nucleoprotein complexes at certain stages of the cell cycle was formulated. The
      central idea of the hypothesis is the proposition that iron ions provide changes
      in the composition of complexes formed by phosphate groups of DNA, by
      substituting effectively the cationic amino groups of organic ligands in these
      complexes by the mechanism of competitive replacement of ligands. Then iron ions
      can be removed by changing the charge of iron ions bound to DNA during redox
      reactions and their transfer to mobile complexes or by the formation and
      subsequent removal of weakly charged magnetic nanoparticles of ferric oxides.
      These magnetic nanoparticles may be responsible for the magnetic effects in
      cells, e.g., broad ESR signals inherent in ferromagnetic systems. These magnetic
      effects were discovered in DNA preparations and in cell cultures at early stages
      of cell division by L.A. Blumenfeld and coworkers.

PMID- 15029731
TI  - [In memory of Kazimierz Kaminski].

PMID- 15029733
TI  - [Prediction of fetal macrosomia using sonographically measured abdominal
      subcutaneous tissue thickness in pregnancies complicated by diabetes mellitus].
AB  - OBJECTIVE: The purpose of the study was to assess the clinical value of
      sonographically measured abdominal subcutaneous tissue thickness (SCTAd) in
      prediction of large for gestational age in pregnancy complicated by diabetes
      mellitus. MATERIAL AND METHODS: We prospectively evaluated 256 pregnant women
      with gestational and pregestational diabetes mellitus longitudinally from 24th
      week of gestation until delivery. In all cases sonography was performed, and
      abdominal subcutaneous tissue thickness was assessed. After delivery the entire
      examined group was divided into two groups. The first group comprised mothers who
      delivered newborns with birth weight above 90th percentiles, and the second group
      comprised mothers who delivered newborns with birth weight between 10th and 90th
      percentiles. RESULT: Based on statistical analyses SCTAd was bigger in Group I
      than Group II (p. < 0.01) at the beginning of the 31st week of gestation. Based
      on ROC (receiver operating characteristic) curves we estimated that 5 mm
      thickness of abdominal subcutaneous tissues differentiate AGA (appropriate for
      gestational age) and LGA groups with 71% sensitivity and 72% specificity.
      CONCLUSIONS: 1/Use of the SCTAd permitted diagnosis of asymmetric fetal
      overgrowth complicated by diabetes mellitus since 31st week of gestation 2/5 mm
      of abdominal subcutaneous tissue thickness allowed differentiate AGA and LGA with
      71% sensitivity and 72% specificity in term pregnancies complicated by diabetes
      mellitus.

PMID- 15029732
TI  - [Pregnancy duration and mode of delivery in patients with cardiac insufficiency
      on the material of Jagiellonian University OB/GYN Clinic in the years between
      1986-1999].
AB  - OBJECTIVES: Recent progress in cardiology and cardiac surgery lead many patients
      with cardiac disease in the procreative age. DESIGN: To asses the influence of
      cardiac disease on pregnancy and delivery. MATERIAL AND METHODS: 232 subjects
      with congenital and acquired cardiac anomalies, hospitalized in the Jagiellonian
      University OB/GYN Clinic between 1986-1999. Patients were divided according to
      NYHA classification depending on kind and grade of cardiovascular insufficiency.
      Acquired data were compared with data in the control group consisted of 424
      subjects without any complications during pregnancy and delivery. RESULTS: We
      proved shortening of the pregnancy duration in more advanced NYHA classes.
      Percentage shave of preterm deliveries in 3rd and 4th class was 31.15%, what
      equals to 3 times preterm delivery rate in the control group. Preterm delivery
      rate in groups of NYHA I and II was similar to the rate in the control group.
      Acquired data reveal extremely high cesarean section rate in the material of
      patients with cardiac anomalies. Cesarean section rate in the group of NYHA I and
      II was 3 times higher (30%) than in control group (rate of 10%). NYHA III and IV
      groups has a cesarean section rate of 93%. Vaginal delivery rate in the NYHA I
      and II groups equals to 58.5%, what is 10 times higher than in NYHA III and IV
      groups (equals to 6.6%). CONCLUSIONS: 1. Pregnancy duration depends on
      cardiovascular sufficiency and is significantly shorten in NYHA III and IV
      groups. 2. Extremely high cesarean section rate in the analyzed group is due to
      decreased cardiac sufficiency.

PMID- 15029734
TI  - [Disorders of glucose tolerance among women with pregnancy induced hypertension].
AB  - OBJECTIVES: Gestational diabetes is observed to coexist with pregnancy induced
      hypertension. Insulin resistance might be associated with both of these diseases.
      DESIGN: To assess the association between glucose intolerance and subsequent
      development of hypertension in pregnancy. MATERIAL AND METHODS: Glucose levels at
      the time of routine screening for gestational diabetes among 79 women with
      pregnancy induced hypertension and 79 normotensive women have been compared.
      RESULTS: Hypertensive women were statistically more often obese, their pregravid
      BMIs were greater and their pregnancy weight gain was higher. Among hypertensive
      women gestational diabetes has been more often diagnosed. As compared with
      normotensive, women developing PIH had significantly higher glucose levels after
      50 g and 75 g of glucose load. CONCLUSIONS: Women with pregnancy induced
      hypertension are at increased risk of gestational diabetes. Even within the
      normal range, levels of plasma glucose levels were higher among hypertensive
      women.

PMID- 15029735
TI  - [Immunohistochemical localisation of metallothionein in ovarian endometriosis in
      women].
AB  - OBJECTIVES: Endometriosis is an illness accompanied by invasion features, but
      malignant changes appear extremely seldom. Metallothionein (MT) is a protein and
      takes part in the detoxicating processes of the organism. MT is located, among
      others, in benign and malignant neoplasms in animals as well as humans, mainly in
      the S phase of cellular cycle, and that is why MT is considered to be both an
      index of cell proliferation and tumor progress. MATERIALS AND METHODS: 34
      specimens from 21 women with ovary endometriosis (III degree according to AFS)
      have been examined. The specimens were obtained during surgery and they were
      histopathologically verified. The material was coloured by H + E and by van
      Gieson method, and MT was determined immunohistochemically. The measurement of
      the cells number containing MT was performed with measurement system Multi-Scan
      Base V8.08, with the microscope Axiophot, Zeiss Jena in so-called measurements
      areas, with the surface 18802 microns 2. RESULTS: High MT capacity was found in
      the epithelial cells in the endometriosis focus. This high MT capacity may imply
      that there exists the proliferation process in the focuses of external
      endometriosis. Simultaneously, the lowest MT capacity was discovered in glandular
      ducts. CONCLUSIONS: Proliferating epithelial cells contain the highest capacity
      of MT, which indicates increase of number of dividing cells particularly in the S
      phase of cellular cycle and that is why MT can be considered one of the markers
      of ovary endometriosis.

PMID- 15029736
TI  - [Late results of surgical treatment of the ureteral lesions after gynecologic and
      obstetric surgery].
AB  - OBJECTIVES: The increase of the radical oncological operations in gynecology and
      caesarean section in obstetrics constantly produce urinary tracts injuries.
      DESIGN: The aim of this paper is retrospective study the results surgical
      treatment of the ureteral lesions after gynecologic and obstetrics operations.
      MATERIALS AND METHODS: 65 women in average age 44 years old were undergone to
      analyze. The follow-up was 1-39 years (mean age 7.6 y.) after ureter injury.
      Anatomical and functional status of the genitourinary tracts was estimated.
      RESULTS: Good result was obtained in 75.3%, moderate in 10.8% and bed in 13.8% of
      the operated women. CONCLUSIONS: The best time for the reconstructive surgery are
      intraoperations period and the time between 5-14 weeks after ureteral lesions.
      The multiples urinary tract injures and necessity the extravesical urinary
      diversion give worse results of the late reconstruction urinary tracts. The
      percutaneous nephrostomy and employment the Psoas Hitch procedure during ureteral
      reimplantation, significantly improve the late results in reconstructive surgery
      of ureter. The late results of reconstruction urinary tracts in last lately 20
      years are statistically better than obtained 20 years earlier.

PMID- 15029737
TI  - [Intestinal obstruction during pregnancy].
AB  - We report a rare case of intestinal obstruction during first pregnancy. 35-year
      old patient at the 16th week of her first pregnancy was admitted to the hospital
      due to hyperemesis gravidarum. After differential diagnosis the patient underwent
      successful surgical procedure followed by the intensive obstetrical care. The
      case history and a review of current literature are presented. We underline the
      importance of early diagnosis and interdisciplinary care.

PMID- 15029738
TI  - [Pregnancy and delivery in a woman after treatment for ovarian cancer].
AB  - The course of pregnancy and delivery in woman after surgical and multiagent
      chemotherapy of ovarian cancer was observed. A pregnancy complicated EPH
      gestosis. The patient delivered infant with IUGR symptom's by cesarean section at
      37 week of pregnancy. There were no clinical or macroscopic symptoms of the
      disease.

PMID- 15029739
TI  - [Vitamins supplementation in pregnancy].
AB  - An increased need for vitamins and microelements supplementation is observed in
      both pregnant and breast-feeding women. Proper vitamin supply seems to be
      essential for normal deficiency of a few vitamins may lead to congenital defects.
      It needs to be remember however, that too large doses of vitamins may act as
      toxic agents, disturb homeostasis and proper metabolism of other vitamins.

PMID- 15029740
TI  - [Thermoregulation and maintenance of appropriate temperature in newborns].
AB  - Hypothermia is one of the most important factors having an influence on morbidity
      of the newborns. Physiology of neonatal thermoregulation and thermogenesis is
      described as well as range of methods used for preventing heat loss and
      maintaining neutral temperature. An article presents the main reasons of limited
      thermogenesis in prematures, ways of heat loss and consequences resulting from
      decreased or increased newborns temperature. Special attention was put on routine
      care of infants within delivery room, intensive care units, during neonatal
      transportation and on procedures necessary to avoid hypothermia or overheating of
      preterm infants.

PMID- 15029741
TI  - [Regionalization of obstetric care in the Lublin District].
AB  - OBJECTIVES: The aim of the study was to analyse the effects of regionalization of
      perinatal care in Lublin District from 1994 to 2001. MATERIALS AND METHODS: We
      assessed the number of patients transferred to the tertiary care centres,
      mortality rate and prematurity in the hospitals in Lublin District. RESULTS: We
      found good correlation between above variables and perinatal care level.
      CONCLUSION: We concluded that perinatal regionalization in Lublin District worked
      well and it was the cause of improvement in perinatal outcome.

PMID- 15029742
TI  - [Central nervous system tumors in pregnancy].
AB  - Central nervous system tumour in pregnancy constitutes a serious complication.
      Considering frequent difficulties in diagnostics and therapy, the aim of the
      study was to present our experience in management with pregnant women with brain
      and spinal cord tumours. Between 1988-2000, in The Research Institute Polish
      Mother's Memorial Hospital in Lodzi, 4 pregnant women had been diagnosed with
      brain and spinal cord tumours. The incidence of tumours complicating pregnancy
      was 1/11460. Two patients diagnosed at 29 weeks' gestation, underwent craniotomy
      and tumour resection during pregnancy. Two other women with central nervous
      system tumours diagnosed at 39 weeks' gestation, were operated in the postpartum
      period. The analysis of the postoperative period, gestation and/or postpartum
      period in all women and well-being of their new-borns confirm undertaken medical
      decisions.

PMID- 15029744
TI  - [Importance of the vaginal ecosystem examination in the first trimester of
      pregnancy].
AB  - OBJECTIVES: Vaginal ecosystem disturbances especially bacterial vaginosis are
      strongly associated with infectious complication during the course of pregnancy.
      DESIGN: The aim of the study was the determination of the vaginal ecosystem
      examination for the diagnosis of the following infection: bacterial vaginosis,
      candidiasis and trichomoniasis in pregnant women in the first trimester of
      pregnancy. MATERIALS AND METHODS: The studies included 106 randomly selected
      asymptomatic pregnant women in I trimester of pregnancy coming for gynaecological
      examination for the first time after cessation of menstruation were divided into
      two group: 56 primiparae and 50 multiparae. The diagnosis of BV was based on
      Amsel criteria concerning vaginal secretion. Trichomonas vaginalis was determined
      in wet vaginal smear. Candida albicans was detected in vaginal smear after
      addition of 10% KOH solution. RESULTS: Out of 106 studied subjects in the first
      trimester of pregnancy, BV was detected in 17.9%, Candida albicans in 15.1%,
      Trichomonas vaginalis in 3.8%. The detectability of BV infection varied
      significantly between both groups of studied women (p < 0.001) while no
      correlation was found between the occurrence of Candida albicans and Trichomonas
      vaginalis infections. CONCLUSION: Vaginal ecosystem screening in pregnant women
      makes possible under ambulatory conditions, to detect the following infections:
      BV, candidiasis and trichomoniasis. Determination of disturbances in vaginal
      ecosystem is simple and inexpensive, not requiring laboratory facilities for the
      assessment of vaginal infections.

PMID- 15029743
TI  - [Obstetrical hysterectomy].
AB  - OBJECTIVE: Obstetrical hysterectomy still remains life saving operation. The aim
      of study was to determinate the frequency, indications and complications after
      the operation in the hospital in Zielona Gora, Poland. MATERIALS AND METHODS: A
      retrospective review based on hospital data of 36 patients undergoing obstetrical
      hysterectomy over the period of 11 years was undertaken. RESULTS: The incidence
      of obstetrical hysterectomy during 1990-2001 et the Department of Obstetrics and
      Gynaecology in the district hospital in Zielona Gora was 1: 593 deliveries. Post
      partum hysterectomy occurred in 0.021% of normal deliveries and 1.03% of cesarean
      sections. The most common indications were placenta increta and placenta accreta
      /61.1%/, followed by uterine atony /13.8%/ and rupture of the uterus /11.1%. The
      most frequent complications were shock and lesion of the urinary bladder/both
      5.6%/. The maternal mortality was 2.8%. CONCLUSIONS: 1. The most common
      indications for the obstetrical hysterectomy are: placenta's pathologies; uterine
      atony and rupture of the uterus. 2. Obstetrical hysterectomy is connected with
      high risk of complications and maternal mortality.

PMID- 15029745
TI  - [Intrauterine growth retardation--cardiologic diagnosis].
AB  - OBJECTIVES AND DESIGN: Intrauterine growth retardation (IUGR) of a fetus is one
      of the most important problem of modern perinatal medicine. It is generally known
      that low birth weight predisposes to certain disease in later life, including
      diseases of the cardiovascular system. The aim of this study is to present own
      results of cardiology diagnostics in fetuses with IUGR. MATERIALS AND METHODS: 46
      echocardiographic examinations of fetuses with IUGR were analysed. RESULTS: In
      the analysed group 21 fetuses (45.4%) presented anomalies of the cardiovascular
      system: 6 fetuses (13%)-congenital heart diseases; 5 (10.8%)-redundant foramen
      ovale; 4 (8.6%)-tricuspid regurgitation; 1 fetus (2.2%)-myocarditis. CONCLUSION:
      Fetuses with IUGR make the group of high risk of cardiovascular abnormalities.

PMID- 15029746
TI  - [Ultrasonographic morphometry of the umbilical cord during physiological and
      pathological pregnancy].
AB  - OBJECTIVES: To evaluate the relation among the ultrasonographic, morphometric
      parameters of the umbilical cord during physiological and pathological pregnancy.
      DESIGN: Ultrasonographic morphometric parameters were prospectively evaluated in
      29 consecutive cases of physiological and 42 cases of pathological pregnancies.
      MATERIALS AND METHODS: 71-ultrasonographic examinations was performed between 28
      40 weeks of gestation. The examined group consisted of 29-physiological
      pregnancies and 42-pathologic. 15-was complicated with the risk of preterm
      delivery. 27-was complicated with hypotrophy caused by Pregnancy Induced
      Hypertension (PIH) in 14 cases and by exposure to tobacco smoke in 13 cases.
      RESULTS AND CONCLUSIONS: We showed no statistically important correlation between
      the umbilical parameters and the period of pregnancy except of A/B index,
      measuring Doppler flow in umbilical artery which value was decreasing together
      with the period of gestation (r = -0.6185, p < 0.05). Hypocoiling umbilical cord
      characterised the group of patients which pregnancy was complicated with
      premature delivery. Statistically important decreasing of diameter value of
      umbilical cord and umbilical vein in cases of pregnancy complicated with
      hypotrophy was revealed. We found out the strong correlation between hypercoiling
      of umbilical cord as well as diameter of umbilical cord and degree of
      intensification of hypotrophy in smoking women (r = -0.8, p < 0.05).

PMID- 15029747
TI  - [Diagnostic value of the morphological ultrasound score system and the serum
      concentration of CA 125 in the diagnosis of malignant ovarian cancer].
AB  - OBJECTIVES: The aim of this study was to estimate the diagnostic value of the
      morphological ultrasound score system and the serum concentration of CA 125 in
      the diagnosis of malignant ovarian masses. The aim was realized by the evaluation
      of the statistical coefficients like sensitivity, specificity, positive
      predictive value and negative predictive value in three groups tested by
      different methods (A--ultrasonography, B--serum concentration of CA 125, C--both
      methods). MATERIALS AND METHODS: We have analyzed 59 patients (17-77 years old)-
      mean 46.5 +/- 14.8 with ovarian malignant masses diagnosed in years 1999-2001.
      RESULTS: Merz morphological ultrasound score system revealed its sensitivity of
      92.3%, specificity--87.9%, positive predictive value--85.7% and negative
      predictive value--93.7%. Statistical coefficients for serum Ca 125 marker
      concentration was not so attractive: sensitivity--57.7%, specificity--90.9%,
      positive predictive value--83.4% and negative predictive value--73.2%. Using both
      methods at the same time we obtained significantly different coefficients:
      sensitivity--96.2%, specificity--80.0%, positive predictive value--78.1% and
      negative predictive value--96.6%. CONCLUSIONS: Ultrasound assessment of ovarian
      morphology is very useful element in early detection of ovarian neoplasm. Serum
      CA 125 concentration assay is not a test verifying malignancy. Using both methods
      at the same time we increase its sensitivity and negative predictive value.

PMID- 15029748
TI  - [The use of magnetic resonance imaging for the evaluation of treatment outcome in
      uterine artery embolisation for fibroids].
AB  - THE AIM: Of the study was to evaluate utility of magnetic resonance (MR) in the
      assessment of the women who fulfilled inclusion criteria for uterine artery
      embolisation as a symptomatic leiomyoma treatment and outcome of procedures.
      MATERIALS AND METHODS: MR examination was performed in 220 patients. Uterine
      artery embolizations were performed in 170 patients. RESULTS: The reasons for
      disqualification were: no correlation between symptoms and size an position of
      leiomyoma--61%, adenomyosis--20%. In MR imaging dominant leiomyoma volumes were
      diminished by 59.6% (p < 0.05) over a period of 3 months. CONCLUSIONS: MR is the
      method of choice in the assessment of women referred to uterine artery
      embolisation as a symptomatic leiomyoma treatment. MR imaging is effective and
      objective method of evaluation outcomes of uterine embolisation.

PMID- 15029749
TI  - [Management of analysis in case of ectopic pregnancy--own material].
AB  - INTRODUCTION: Apart from increasing frequency of ectopic pregnancy occurrence
      during recent years there is still a need to diagnose and treat these pathology
      as early as possible. Delay in diagnosing subsequently cause severe threat to
      patients life. Recognition improvement means equally decrease in mortality
      connected to ectopic pregnancy. AIM: The aim of the study was diagnosis and
      treatment efficiency evaluation in cases of ectopic pregnancy. MATERIAL AND
      METHODS: In this paper 68 cases of women hospitalised between May 1999 and
      September 2002 in our Clinic with suspicion of ectopic pregnancy were analysed.
      Diagnostic procedures included clinical examination, biochemical assessment of
      beta HCG level, sonography and diagnostic laparoscopy. Therapeutic management
      included salpingotomy with evacuation of gestational sac, salpingectomy and
      uterine cornu excision. RESULTS: In 11 cases the presence of pregnancy was
      excluded according to non-invasive diagnostics. Laparotomy was performed in two
      cases. Laparoscopy was performed in 50 cases what equals to 73% of all subjects.
      Laparoscopy was negative in 7 cases. Misdiagnosis resulted from pathologies in
      adnexal area. The most frequent ectopic pregnancy localisation was oviduct, one
      case of cervical and one intramural localisation was diagnosed. In one case two
      salpingostomies were performed in two years apart period. CONCLUSIONS: Complex
      diagnostic management is the only diagnostic way in case of ectopic pregnancy.
      Any confusion should be solved by immediate invasive diagnostics. In our opinion
      the most efficient method in ectopic pregnancy diagnosing and treatment is early
      laparoscopy.

PMID- 15029750
TI  - [Surgical treatment of an isolated liver metastasis from endometrial cancer].
AB  - One of the principal features of the malignant process is the ability of the
      tumor to form metastases. In case of endometrial cancer pelvic and paraaortic
      lymph nodes and ovaries are the most frequent sites of metastases. In some cases
      metastases to the distant sites like the lungs and liver occur. The diagnosis of
      stage IVB disease bears a poor prognosis. Only a form of palliative treatment is
      usually offered to those unfortunate woman. The authors present a case of
      successful surgical treatment an isolated liver metastasis from endometrial
      cancer.

PMID- 15029751
TI  - [Clinical course of clarocellular ovarian cancer in 27-year old woman.
      Laparoscopy in management of malignant ovarian tumors].
AB  - A case of clarocellular ovarian cancer in 27-year old woman is reported. Authors
      present the diagnostic and management problems, their experience and the review
      of current literature. The place of laparoscopy in management of malignant
      ovarian tumors is discussed.

PMID- 15029752
TI  - [Uterine leiomyomas--risk factors].
AB  - Uterine leiomyomas are benign tumours that arise from the smooth-muscle cells of
      the human uterus. They are clinically apparent in up to 20% of women and cause
      significant morbidity, including prolonged and heavy menstrual bleeding, pelvic
      pressure or pain and reproductive dysfunction. Surgery has been the mainstay of
      fibroid treatment and various minimally invasive procedures have been developed
      in addition to hysterectomy and abdominal myomectomy, but formation of new
      leiomyomas after these conservatives therapies remains a substantial problem. The
      pathophysiology of myomas is not well understood. We present some views of
      epidemiological, reproductive and environmental factors, which may stimulate
      myomas formation. We also present a brief survey of the literature about genetic
      predisposition, mutations, steroid hormone and growth factors concentration,
      which seems to pay an important role in fibrotic processes and angiogenesis
      observed during formation and growth of these tumours. New research into the
      basic biology of these neoplasms may add new treatment options for the future as
      the role of growth factors and genetic mutations in these tumours are better
      understood.

PMID- 15029753
TI  - [Laparoscopic myomectomy: preparation for procedure and operation technique].
AB  - Uterine leiomyomata are the commonest neoplasms of the female reproductive system
      in the procreative age. In these cases operation is still a treatment of choice.
      The procedure's range depends on: number, size and localisation of the myomas,
      patient's age and possession of children. Currently uterine leiomyomata are
      removed more frequent by endoscopic operations. We present the technique of
      laparoscopic myomectomy taking into consideration very important problem-
      patients' qualification this procedure. We pay attention to necessity of precise
      closing the wound in layers after removed myoma, which seems to prevent uterine
      rupture during pregnancy and labour. We also present some controversial aspects
      of using GnRH analogues. In summary we emphasise benefits of laparoscopic
      myomectomy particularly for women in the procreative age, who are planning
      pregnancy.

PMID- 15029754
TI  - [Low birth weight infants (less than 2500g)--common problems for obstetricians
      and pediatricians].
AB  - Low birth weight infants present an increased risk of developing certain
      disorders later in life. They include a higher perinatal mortality, perinatal
      asphyxia, developmental disorders, hypertension and diabetes type 2. Low birth
      weight infants constitute about 10% of all newborn children. Nonetheless they
      necessitate special guidance. The issues presented in this article prove that
      problems arise during pregnancy and augment after birth. Therefore a close
      cooperation is needed among obstetricians and paediatricians, especially
      endocrinologists. An early assessment of LBW infants will enable to make correct
      diagnosis and initiate therapy. It will surely improve children's' development
      and health in the long run and furthermore will decrease the morbidity from
      cardiovascular diseases in later life.

PMID- 15029756
TI  - [The functions of processing on states of awareness in the Remember/Know
      paradigm: a study of using verbal materials].
AB  - The nature of recollective experience was investigated in two recognition memory
      tasks. Subjects gave "Remember" judgments to recognized items that were
      accompanied by conscious recollection and "Know" judgments to recognized items
      that were familiarity of events without recollection on recognition. High
      familiarity words that are based on conceptual and semantic information enhanced
      "Remember" judgments. In contrast, compared with high-familiarity words low
      familiarity words that are caused perceptual fluency enhanced "Know" judgments
      (Experiment 1). In Experiment 2, spacing effect, an advantage in memory for
      information repeated at separate points of time over information repeated in
      massed fashion was found for "Remember" judgments. However, spacing effect
      disappeared for "Remember" judgments when memory load was high at study. These
      findings are interpreted as providing further support for the idea that
      recognition memory entails two distinct components, one based on elaborative
      information, the other based on perceptual fluency.

PMID- 15029755
TI  - [The acquisition of schemata about location of urban facilities in public space].
AB  - The purpose of this study is to investigate acquisition of schemata about
      location of urban facilities. Materials were photos of public space, in which one
      of three urban facilities (a mailbox, a public-telephone, and a coin--operated
      locker) were removed by photo-retouching software. The task was to choose the
      most suitable urban facility for each corrected-photo and to locate it at the
      most suitable position on the photo. Among three participant groups (primary
      school 3rd grade: n = 153, primary school 5th grade: n = 118, undergraduate: n =
      250), undergraduates chose the most suitable urban facility, and their located
      position was more concentrated. The results suggest that participants acquire the
      schemata and use them for inference. Although even 3rd grade children have
      acquired the schema to some extent, the adults have more detailed schemata of
      urban facilities in public space.

PMID- 15029757
TI  - [Childbirth and changes of women's social support network and mental health].
AB  - A questionnaire surveys of women was conducted, 58 persons at one month, 73 at
      four month, and 42 at one year after childbirth, in order to investigate the
      relationship between social support and mental health. Main results concerning
      stress-buffering effects of social support were as follows. At one month after
      childbirth, marital intimacy showed stress-buffering effect. At four months,
      beneficial factors were; informational and emotional support and social
      companionship from family members other than husband or mother, and informational
      and emotional support from a friend who was the second closest. At one year were;
      instrumental, informational, and emotional support and social companionship from
      other person who was not among those already mentioned, and informational and
      emotional support and social companionship from still another who was the second
      important. These results suggested that social support network of women underwent
      successive changes after childbirth. In addition, a model of changing social
      support network was presented, and it suggested that changing support network so
      that one could obtain appropriate support was effective on stress buffer.

PMID- 15029758
TI  - [Crossmodal attention between vision and touch in temporal order judgment task].
AB  - Four experiments investigated the effects of cross-modal attention between vision
      and touch in temporal order judgment tasks combined with spatial cueing paradigm.
      In Experiment 1, two vibrotactile stimuli with simultaneous or successive onsets
      were presented bimanually to the left and right index fingers and participants
      were asked to judge the temporal order of the two stimuli. The tactile stimuli
      were preceded by a spatially uninformative visual cue. Results indicated that
      shift of spatial attention yielded by visual cueing resulted in the modulation of
      accuracy of the subsequent tactile temporal order judgment. However, this cueing
      effect disappeared when participants judged simultaneity of the two stimuli,
      instead of their temporal order (Experiment 2) or when the cue lead time between
      the visual cue and the stimuli was relatively long (Experiment 3). Experiment 4
      replicated an effect of crossmodal attention on the direction of visual illusory
      line motion induced by a somatosensory cue (Shimojo, Miyauchi, & Hikosaka, 1997).
      These results demonstrate that substantial crossmodal links exist between vision
      and touch for covert exogenous orienting of attention.

PMID- 15029759
TI  - [Anger experience and the process of calming down].
AB  - This study investigated the affects and behaviors that accompany and follow anger
      episodes, and examined the relationship among them, in hope of developing self
      regulated and effective methods of controlling anger. With an open-ended
      questionnaire, 42 anger episodes were collected and categorized. Results
      suggested that typical anger episodes were instigated by selfishness, insult,
      coercion, and trouble and a close person such as friends was often the cause and
      target of anger. Surprise and depression frequently accompanied it, and eight
      forms of response followed: rationalization, cause searching, aggression, social
      sharing, displacement to object, mood change, forgetfulness, and rumination.
      Another questionnaire examined the relationship among these variables, as well as
      trait anger, perception of malice, and sense of injury, with a sample of 118
      undergraduates. Results indicated, first, that sense of injury was heightened by
      trait anger and malice perception. Second, anger and depression were evoked only
      by a sense of injury. Finally, while anger without depression evoked aggression,
      anger with depression led to mood change and forgetfulness.

PMID- 15029760
TI  - [Spread of inhibition of return in visual search].
AB  - For conducting efficient visual search, it is important to inhibit spatial
      attention from reorienting to previously examined distractors. Several studies
      have proposed that this inhibition can be associated with object-based inhibition
      of return (IOR). The present study examined whether the spread of IOR across an
      object's surface affects the performance of visual search or not. If the spread
      of IOR occurs in visual search, unexamined targets and distractors linked with
      the previously attended items would be inhibited. We found that the spread of
      object-based IOR results in the increases of error rates in the target present
      trials and the decreases of reaction times in the target absent trials. These
      results indicate that participants made "absent" responses before examining all
      items if object-based IOR spread over unconfirmed items. We discuss the function
      of object-based IOR in visual search and also deal with how visual search is
      terminated.

PMID- 15029761
TI  - [Some observations on the functions of involuntary memory: an analysis of the
      circumstances surrounding occurrence].
AB  - The purpose of this study was to investigate the functions of involuntary memory
      in the course of daily life. The participant was the author, a 39-year-old male
      at the time when the record of involuntary memories was begun. When an
      autobiographical memory occurred spontaneously, the participant would record the
      contents of that memory and the circumstances surrounding its occurrence, such as
      the triggered cues for the remembered event and the participant's activity and
      mood at the time. Over a period of four and a half years, involuntary memories of
      184 events were collected. The results suggest four functions of involuntary
      memory: (1) confirmation of one's existence at a given time in one's life
      history; (2) confirmation of one's own psychological traits; (3) confirmation of
      one's relationship to others; and (4) the direction or regulation of one's
      behavior. One of the main functions of involuntary memory may be to provide one
      with the opportunity for recognition of the individual's stable beliefs and
      behavior, that is, the sense of self-continuity.

PMID- 15029762
TI  - [Mechanisms of cross-modal priming between visual and haptic modalities].
AB  - We explored mechanisms of cross-modal priming between visual and haptic
      modalities. Specifically, we investigated a mechanism of the visual-to-haptic
      transfer (Experiment 1) and vice versa (Experiment 2). In Experiment 1, three
      experimental groups, presented visual prime stimuli using novel three-line
      patterns, were asked to form visual images matching only with shape, haptic
      images matching only with shape, or haptic images matching with both shape and
      texture of haptic targets. Priming occurred only when induced haptic images of
      prime stimuli coincided with the actual texture of haptic targets. In Experiment
      2, two experimental groups, presented haptic prime stimuli, were asked to form
      visual images matching only with shape, or visual images matching with both shape
      and material (i.e., monochromatic contrast between foreground and background) of
      visual targets. Priming occurred regardless of experimental conditions, including
      the control group. Thus, both shape and material representations significantly
      contributed to the visual-to-haptic transfer. Contrastingly, only shape
      representation played a significant role in the haptic-to-visual transfer.

PMID- 15029763
TI  - [Reading span as an individual difference and cognitive problem solving
      performance].
AB  - This study investigated the performance on a computer game called Mastermind,
      playing of which consumes a large amount of working memory resource. First, 143
      college students took a Japanese version of reading span test (RST). They then
      played Mastermine under two conditions: with or without display of past game
      records. There were 105 participants who relied under both conditions on a
      tactical strategy that caused high memory load, and their performance data were
      analyzed. Results indicated that low-span readers (87 students) were more
      constrained than high- and medium-span readers (18 students) under the condition
      without display, and performance of the low was affected by the content of
      display. It was argued that working memory resource that RST measured was
      involved in the process of cognitive problem solving.

PMID- 15029764
TI  - [Early adult attachment styles and social adjustment].
AB  - We conducted this study in order to examine the relationships between early adult
      attachment styles and social adjustment, such as mental health and self
      perception in the context of close relationships. Questionnaires were
      administered, 460 undergraduates participated in the study, and their data were
      analyzed. Results showed that secure attachment was positively related to better
      mental health and positive self-perception in close relationships. In contrast,
      insecure attachment, especially ambivalent style, was negatively related to
      social adjustment. As for attachment dimensions, "Anxiety" was significantly
      associated with negative states in mental health, such as anxiety, insomnia, and
      sever depression, and lower self-perceived confidence in close relationships, and
      "Avoidance" with low self-perceived sociability and attractiveness in close
      relationships. These results were discussed in terms of the theoretical concepts
      of adult attachment styles.

PMID- 15029765
TI  - A switch in time.

PMID- 15029766
TI  - Puff piece: the cost of smoking.

PMID- 15029767
TI  - Weighty matters: obesity takes hold.

PMID- 15029769
TI  - Communications. This year's model.
AB  - Guy's and St Thomas' has launched its own magazine to improve community
      relations. 30,000 copies are distributed across Lambeth and Southwark. The front
      cover features local people rather than celebrities or models.

PMID- 15029768
TI  - Clinical management. Where medicine meets management. Can of worms.
AB  - There have been massive increases in the incidence of liver diseases in the UK,
      reaching epidemic levels. The development of liver services has been haphazard
      and there is no national service framework for liver disease, endangering
      patients. Specialist groups have formulated a national plan setting standards and
      guidelines.

PMID- 15029770
TI  - Communications. Geography lesson.

PMID- 15029771
TI  - Communications. What works.

PMID- 15029772
TI  - Finance. Results driven.

PMID- 15029773
TI  - HSJ people. Trail blazers.

PMID- 15029774
TI  - Are we there yet? Destinations, pitfalls mark long road for Congress in 2003.

PMID- 15029775
TI  - The vanishing supervisor.

PMID- 15029776
TI  - Managing the virtual HIM department.

PMID- 15029777
TI  - An HIM spin on the revenue cycle.

PMID- 15029778
TI  - Assessing privacy risk in outsourcing.

PMID- 15029779
TI  - Getting "hip" to other privacy laws. Part 2.

PMID- 15029780
TI  - Setting the right expectations for the EHR standard.

PMID- 15029781
TI  - A primer on network security.

PMID- 15029782
TI  - Destination 10: healthcare organization preparation for ICD-10-CM and ICD-10-PCS.

PMID- 15029783
TI  - Validating MDS and OASIS data with DAVE.

PMID- 15029784
TI  - Preparing for the ICD-10 journey.

PMID- 15029785
TI  - The three Cs for better coding. Coding Community Council takes expertise online.

PMID- 15029786
TI  - Tips for TIPS: transvenous intrahepatic portosystemic shunt.

PMID- 15029787
TI  - The expanding universe. A new manager educates herself--and upper management,
      too.

PMID- 15029788
TI  - Reclaim your job.
AB  - Ask most managers what gets in the way of their success, and you'll hear the
      familiar litany of complaints: Not enough time. Limited resources. No clear sense
      of how their work fits into the grand corporate scheme. These are, for the most
      part, excuses. What really gets in the way of managers' success is fear of making
      their own decisions and acting accordingly. Managers must overcome the
      psychological desire to be indispensable. In this article, the authors
      demonstrate how managers can become more productive by learning to manage
      demands, generate resources, and recognize and exploit alternatives. To win the
      support they want, managers must develop a long-term strategy and pursue their
      goals slowly, steadily, and strategically. To expand the range of opportunities,
      for their companies and themselves, managers must scan the environment for
      possible obstacles and search for ways around them. Fully 90% of the executives
      the authors have studied over the past few years wasted their time and frittered
      away their productivity, despite having well-defined projects, goals, and the
      necessary knowledge to get their jobs done. Such managers remain trapped in
      inefficiency because they assume they do not have enough personal discretion or
      control. They forget how to take initiative--the most essential quality of any
      truly successful manager. Effective managers, by contrast, are purposeful
      corporate entrepreneurs who take charge of their jobs by developing trust in
      their own judgment and adopting long-term, big-picture views to fulfill personal
      goals that match those of the organization.

PMID- 15029789
TI  - It's time to retire. Retirement.
AB  - Companies have been so focused on down-sizing to contain costs that they've
      largely neglected a looming threat to their competitiveness: a severe shortage of
      talented workers. The general population is aging and with it, the labor pool.
      People are living longer, healthier lives, and the birthrate is at a historical
      low. During the next 15 years, 80% of the native-born workforce growth in North
      America--and even more in much of Western Europe--is going to be in the over-50
      age cohort. When these mature workers begin to retire, there won't be nearly
      enough young people entering the workforce to compensate. The Bureau of Labor
      Statistics projects a shortfall of 10 million workers in the United States in
      2010, and in countries where the birthrate is well below the population
      replacement level (particularly in Western Europe), the shortage will hit sooner,
      be more severe, and remain chronic. The problem won't just be a lack of bodies.
      Skills, knowledge, experience, and relationships walk out the door every time
      somebody retires--and they take time and money to replace. And while the brain
      drain is beginning now, the problem is going to become much more acute in the
      next decade or so, when baby boomers--more than one-quarter of all Americans,
      amounting to 76 million people--start hitting their mid sixties. Based on the
      results of their yearlong research project, the authors of this article offer
      recommendations for gaining the loyalty of older workers and creating a more
      flexible approach to retirement that allows people to continue contributing well
      into their sixties and seventies. Companies can no longer afford to think of
      retirement as a onetime event, permanently dividing work life from leisure.

PMID- 15029790
TI  - The new rules for bringing innovations to market.
AB  - It's tough to get consumers to adopt innovations--and it's getting tougher all
      the time. That's because more and more markets are taking on the characteristics
      of networks. The interconnections among today's companies are so plentiful that
      often a new product's adoption by one player depends on its systematic adoption
      by other players. Consider the disparate companies involved with the
      popularization of digital photography: software vendors, camera manufacturers,
      broadband communications companies, printer manufacturers, and so on. By
      contrast, Kodak was pretty much the sole player involved with popularizing film
      photography. The traditional levers executives use to launch products--such as
      targeting unique customer segments or developing compelling value propositions-
      don't work as well in this new environment. Instead, innovators must orchestrate
      a change of behaviors across the market, unraveling the status quo so that a
      large number of players adopt their offerings and believe they are better off for
      having done so. In this article, Monitor Group's Bhaskar Chakravorti outlines a
      four-part framework for doing just that. The innovator must reason back from a
      target endgame, implementing only those strategies that maximize its chances of
      getting to its goal. It must complement power players, positioning its innovation
      as an enhancement to their products or services. The innovator must offer
      coordinated switching incentives to three core groups: the players that add to
      the innovation's benefits, the players that act as channels to adopters, and the
      adopters themselves. And it must preserve flexibility in case its initial
      strategy fails. Chakravorti uses Adobe's introduction of its Acrobat software as
      an example of an innovator that took into account other players in the network-
      and succeeded because of it.

PMID- 15029791
TI  - Strategy as ecology.
AB  - Microsoft's and Wal-Mart's preeminence in modern business has been attributed to
      any number of factors--from the vision and drive of their founders to the
      companies' aggressive competitive practices. But the authors maintain that the
      success realized by these two very different companies is due only partly to the
      organizations themselves; a bigger factor is the success of the networks of
      companies with which Microsoft and Wal-Mart do business. Most companies today
      inhabit ecosystems--loose networks of suppliers, distributors, and outsourcers;
      makers of related products or services; providers of relevant technology; and
      other organizations that affect, and are affected by, the creation and delivery
      of a company's own offering. Despite being increasingly central to modern
      business, ecosystems are still poorly understood and even more poorly managed.
      The analogy between business networks and biological ecosystems can aid this
      understanding by vividly highlighting certain pivotal concepts. The moves that a
      company makes will, to varying degrees, affect the health of its business
      network, which in turn will ultimately affect the organization's performance--for
      ill as well as for good. Because a company, like an individual species in a
      biological ecosystem, ultimately shares its fate with the network as a whole,
      smart firms pursue strategies that will benefit everyone. So how can you promote
      the health and the stability of your own ecosystem, determine your place in it,
      and develop a strategy to match your role, thereby helping to ensure your
      company's well-being? It depends on your role--current and potential--within the
      network. Is your company a niche player, a keystone, or a dominator? The answer
      to this question may be different for different parts of your business. It may
      also change as your ecosystem changes. Knowing what to do requires understanding
      the ecosystem and your organization's role in it.

PMID- 15029792
TI  - The geography of trust.
AB  - Leaders who rely forever on the same internal advisers, entrusting them with
      issues of ever greater sensitivity and consequence, run the risk of being sold
      short and possibly betrayed. Alternatively, lone-wolf leaders who trust no one
      may make enormous, yet preventable, mistakes when trying to sort through
      difficult decisions. A sophisticated understanding of trust can protect leaders
      from both fates. During the past decade, author and consultant Saj-nicole Joni
      studied leadership in more than 150 European and North American companies. Her
      research reveals three fundamental types of trustpersonal trust, expertise trust,
      and structural trust. Executives may persevere in relationships that are based on
      personal trust, no matter how exalted their leadership roles become. But such
      relationships are unlikely to remain static. They also probably won't provide the
      kinds of deep, often specialized knowledge leaders need. In circumstances where
      advisers' competence matters as much as their character, expertise trust-
      reliance on an adviser's ability in a specific subject--enters the picture. In
      organizations, leaders develop expertise trust by working closely with people who
      consistently demonstrate their mastery of particular subjects or processes.
      Structural trust refers to how roles and ambitions influence advisers'
      perspectives and candor. It shifts constantly as people rise through
      organizations. High-level structural trust can provide leaders with pure insight
      and information--but advisers in positions of the highest structural trust
      generally reside outside organizations. These advisers provide leaders with
      insights that their organizations cannot. High-performing leaders' most enduring-
      and most valuable--relationships are characterized by enormous levels of all
      three kinds of trust.

PMID- 15029795
TI  - Lofty missions, down-to-earth plans.
AB  - Most nonprofits make program decisions based on a mission rather than a strategy.
      They rally under the banner of a particular cause, be it "fight homelessness" or
      "end hunger." And since their causes are so worthwhile, they support any programs
      that are related--even tangentially--to their core missions. It's hard to fault
      people for trying to improve the state of the world, but that approach to making
      decisions is misguided. Acting without a clear long-term strategy can stretch an
      agency's core capabilities and push it in unintended directions. The fundamental
      problem is that many nonprofits don't have a strategy; instead, they have a
      mission and a portfolio of programs. But they hardly make deliberate decisions
      about which programs to run, which to drop, and which to turn down for funding.
      What most nonprofits call "strategy" is really just an intensive exercise in
      resource allocation and program management. This article outlines for nonprofits
      a four-step process for developing strategy. The first step is to create a broad,
      inspiring mission statement. The second step is to translate that core mission
      into a smaller, quantifiable operational mission. For instance, an agency whose
      core mission is to fight homelessness must decide if its focus is rural or urban
      and if it should concentrate on low-income housing loans or on establishing more
      shelters. The third step is to create a strategy platform; that is, the nonprofit
      decides how it will achieve its operational mission. Decisions about funding and
      about client, program, and organizational development are all made here. Once
      that platform is established, the nonprofit is ready to move to step four--making
      reasoned, strategic decisions about which programs to run and how to run them.
      The agency that follows these steps will improve its focus and its effectiveness
      at fulfilling its mission.

PMID- 15029794
TI  - How you slice it: smarter segmentation for your sales force.
AB  - Three years ago, 70-year-old Hill-Rom Incorporated was in a position familiar to
      many mature businesses: The company was strong but needed to be stronger. It was
      a top producer of hospital beds and specialty mattresses, its core product lines.
      It also had competitive complementary lines of stretchers, furniture, and
      architectural equipment. It had an extensive customer base, a respected sales
      force, and solid profit margins. But by the time Ernest Waaser took over as chief
      executive in early 2001, revenue growth had been slowing, and competition was on
      the rise. To secure Hill-Rom's place in the market, Waaser decided to focus first
      on the sales organization--partly because the cost of sales had risen gradually
      over the past five years and partly because acquisitions and other initiatives
      had made the sales organization more complex. The CEO took several steps to
      restructure the sales force. First, the company changed its customer segments to
      better reflect customers' demands and financial status, ultimately targeting two
      main groups: key and prime customers. It then changed the overall structure of
      the sales organization so it could tailor its approach to these two segments; key
      customers received more specialized service than prime customers. Finally, Hill
      Rom adjusted the sales force after the company took an in-depth look at
      historical data on products and services and sales completed. Reasons for
      staffing changes were carefully communicated to the sales force. Because of Hill
      Rom's initiatives, the cost of sales is down, short-term revenue growth is up,
      the outlook for long-term revenue growth looks bright, sales and profit margins
      are up, and customer satisfaction has increased. Best practice, indeed.

PMID- 15029796
TI  - First-dollar coverage: an idea whose time has passed.

PMID- 15029793
TI  - A real-world way to manage real options.
AB  - Each corporate growth project is an option, in the sense that managers face
      choices--push ahead or pull back--along the way. Yet many companies hesitate to
      apply options theory to initiatives such as R&D and geographic expansion, partly
      because these "real" options are highly complex. In this article, the authors
      make the case that the complexity of real options can be eased through the use of
      a binomial valuation model. Many of the problems with real-options analysis stem
      from the use of the Black-Scholes-Merton model, which isn't suited to real
      options. Binomial models, by contrast, are simpler mathematically, and you can
      tinker with a binomial model until it closely reflects the project you wish to
      value. Suppose your company is considering investing in a new plant. To use the
      binomial model, you must create an "event tree" to figure out the full range of
      possible values for the plant during the project's lifetime--next year, at the
      end of the design phase, upon completion. Then you work backward from the value
      at completion, factoring in the various investments, to determine the value of
      the project today. These calculations provide you with numbers for all the
      possible future values of the option at the various points where a decision needs
      to be made on whether to continue with the project. The authors also address
      another criticism of real options: that gaps often arise between theoretical and
      realized values of options of all types. Such gaps may be largely the result of
      managers exercising options at the wrong time. To improve the way it manages its
      real options, a company can look out for the decision trigger points that
      correspond to the nodes on a binomial decision tree. The trigger points should
      not only tell managers when they need to decide on exercise but also specify
      rules governing the exercise decisions.

PMID- 15029797
TI  - The new Medicare Advantage a disadvantage for providers?
AB  - The Medicare Advantage program, a provision of the Medicare Prescription Drug,
      Improvement, and Modernization Act of 2003, encourages providers to think about
      dealing with Medicare Advantage plans the way they now deal with commercial
      payers. Consequently, the Medicare Advantage program could either benefit or harm
      providers.

PMID- 15029798
TI  - Medicare payment for resident training in nonprovider settings.
AB  - CMS and the OIG are examining payment for residents' training in nonhospital
      settings. Over the next year, as the current moratorium on Medicare disallowances
      of GME and IME payments for these residents comes to a close, providers should
      stay up to date on the latest developments and anticipate changes that are likely
      to follow.

PMID- 15029799
TI  - How are hospitals financing the future? The future of capital spending.

PMID- 15029800
TI  - Divide and compete. A new look at service lines.

PMID- 15029801
TI  - Consumer-driven health care. Freeing providers to innovate.
AB  - Corporate entrepreneurs drive improvements in a productive economy and are
      rewarded financially. The U.S. healthcare industry, on the other hand, allows
      payers to dictate prices and punishes any providers that try to create better,
      cheaper goods and services. The result is missed opportunities for innovation.
      Consumer-driven health care (CDHC), however, allows providers to innovate and
      offers consumers choice. Basically, CDHC matches supply and demand while
      rewarding skilled entrepreneurs.

PMID- 15029802
TI  - Strategies to take hospitals off (revenue) diversion.
AB  - When a hospital goes on diversion, it not only loses potential revenue because
      new patients are not being admitted, but also relationships with physicians and
      patient satisfaction suffer. Often, diversion status is the result of emergency
      department (ED) overcrowding. A few simple steps can help hospitals resolve the
      diversion dilemma. Implement an admission and discharge center. Appoint a bed
      czar. Reduce length of stay. Enforce a hospital discharge time. Work with nursing
      on timely reporting of discharges. Work with ancillary departments to identify
      and resolve discharge delays.

PMID- 15029803
TI  - How to structure a compliant hospital-physician ASC.
AB  - Three recent advisory opinions issued by the HHS Office of Inspector General
      (OIG) provide insight into how the OIG is likely to view a proposal by a hospital
      and physicians to develop a jointly owned ambulatory surgical center (ASC). In
      assessing whether the proposed ASC meets the 13 requirements to qualify for the
      ASC safe harbor under federal fraud and abuse law, the OIG will likely insist
      that the arrangement strictly comply with some requirements, such as the one
      defining the necessary characteristics of physician owners, while allowing more
      leeway in compliance with others.

PMID- 15029804
TI  - Increasing up-front collections.
AB  - Montefiore Medical Center increased the collections of the Department of
      Obstetrics & Gynecology and Women's Health by $1.2 million without cutting costs
      or increasing its charges. Instead, the organization appointed a billing director
      to take charge of revenue-cycle performance and redesign its billing processes
      by: Implementing standard processes organizationwide Involving physicians in data
      collection to ensure accurate claims Collecting copayments at the front end.

PMID- 15029806
TI  - Using vectors to minimize the mystery of IT strategy development.

PMID- 15029805
TI  - Are you a "new-age" CFO?

PMID- 15029807
TI  - Looking for revenue? Try tapping on your keyboard.

PMID- 15029808
TI  - Tide rises on pay for performance with voluntary reporting initiative.

PMID- 15029809
TI  - Back to basics: a self-help approach to achieving financial success.

PMID- 15029810
TI  - A novel approach to mass tort class actions: the billion dollar settlement in the
      Sulzer artificial hip and knee litigation: a symposium.

PMID- 15029811
TI  - Medical errors: causes, cures, and capitalism.

PMID- 15029812
TI  - The serpent in the Garden of Eden: a look at the impact of physician financial
      incentive programs and a reconsideration of Herdrich v. Pegram.

PMID- 15029813
TI  - Lessons from Martin: the ADA and athletics don't mix.

PMID- 15029814
TI  - Reach out and touch someone: cellular phones health, safety and reasonable
      regulation.

PMID- 15029815
TI  - Tech vendors getting fiscal. General Electric Co. is leading the way with an
      array of services, from capital and equipment to consulting over quality,
      efficiency.
AB  - General Electric Co. and other technology vendors see a golden opportunity in
      cash-strapped hospital clients. By also offering financing and consulting
      services, they're helping their providers stay in the game long enough to pay
      them back for their high-tech goods, and come back for more. GE's Rick Wolfert
      says, "We have reason to believe we either are or soon will be the leading
      provider."

PMID- 15029816
TI  - Examining exemptions. House to re-evaluate tax status of not-for-profits.

PMID- 15029817
TI  - Tenet to offer discounts.

PMID- 15029818
TI  - Targeting the swindlers. Congress grapples with how to stop proliferating health
      insurance scams.

PMID- 15029819
TI  - Ending the transition.

PMID- 15029820
TI  - Looking for federal help. Healthcare leaders emphasize links between IT
      subsidies, public benefit.

PMID- 15029821
TI  - Ch-ch-ch-changes. Baptist Health announces restructuring plan.

PMID- 15029822
TI  - More beds for boomers. A top 10 list of reasons why hospitals will continue to
      expand capacity.

PMID- 15029823
TI  - Construction pace builds. Survey shows demographic shifts, other market trends
      drive healthcare projects.

PMID- 15029824
TI  - Outsiders get the call. Firms specializing in medical call centers, hospitalist
      programs see strong growth.

PMID- 15029825
TI  - Partners in prevention. Patient Safety Awareness Week aims to help consumers head
      off medical errors.

PMID- 15029826
TI  - Advances in biomolecular simulations: methodology and recent applications.
AB  - Molecular dynamics simulations are widely used today to tackle problems in
      biochemistry and molecular biology. In the 25 years since the first simulation of
      a protein computers have become faster by many orders of magnitude, algorithms
      and force fields have been improved, and simulations can now be applied to very
      large systems, such as protein-nucleic acid complexes and multimeric proteins in
      aqueous solution. In this review we give a general background about molecular
      dynamics simulations, and then focus on some recent technical advances, with
      applications to biologically relevant problems.

PMID- 15029827
TI  - Prediction of protein function from protein sequence and structure.
AB  - The sequence of a genome contains the plans of the possible life of an organism,
      but implementation of genetic information depends on the functions of the
      proteins and nucleic acids that it encodes. Many individual proteins of known
      sequence and structure present challenges to the understanding of their function.
      In particular, a number of genes responsible for diseases have been identified
      but their specific functions are unknown. Whole-genome sequencing projects are a
      major source of proteins of unknown function. Annotation of a genome involves
      assignment of functions to gene products, in most cases on the basis of amino
      acid sequence alone. 3D structure can aid the assignment of function, motivating
      the challenge of structural genomics projects to make structural information
      available for novel uncharacterized proteins. Structure-based identification of
      homologues often succeeds where sequence-alone-based methods fail, because in
      many cases evolution retains the folding pattern long after sequence similarity
      becomes undetectable. Nevertheless, prediction of protein function from sequence
      and structure is a difficult problem, because homologous proteins often have
      different functions. Many methods of function prediction rely on identifying
      similarity in sequence and/or structure between a protein of unknown function and
      one or more well-understood proteins. Alternative methods include inferring
      conservation patterns in members of a functionally uncharacterized family for
      which many sequences and structures are known. However, these inferences are
      tenuous. Such methods provide reasonable guesses at function, but are far from
      foolproof. It is therefore fortunate that the development of whole-organism
      approaches and comparative genomics permits other approaches to function
      prediction when the data are available. These include the use of protein-protein
      interaction patterns, and correlations between occurrences of related proteins in
      different organisms, as indicators of functional properties. Even if it is
      possible to ascribe a particular function to a gene product, the protein may have
      multiple functions. A fundamental problem is that function is in many cases an
      ill-defined concept. In this article we review the state of the art in function
      prediction and describe some of the underlying difficulties and successes.

PMID- 15029828
TI  - Electron tunneling through proteins.
AB  - Electron transfer processes are vital elements of energy transduction pathways in
      living cells. More than a half century of research has produced a remarkably
      detailed understanding of the factors that regulate these 'currents of life'. We
      review investigations of Ru-modified proteins that have delineated the distance-
      and driving-force dependences of intra-protein electron-transfer rates. We also
      discuss electron transfer across protein-protein interfaces that has been probed
      both in solution and in structurally characterized crystals. It is now clear that
      electrons tunnel between sites in biological redox chains, and that protein
      structures tune thermodynamic properties and electronic coupling interactions to
      facilitate these reactions. Our work has produced an experimentally validated
      timetable for electron tunneling across specified distances in proteins. Many
      electron tunneling rates in cytochrome c oxidase and photosynthetic reaction
      centers agree well with timetable predictions, indicating that the natural
      reactions are highly optimized, both in terms of thermodynamics and electronic
      coupling. The rates of some reactions, however, significantly exceed timetable
      predictions: it is likely that multistep tunneling is responsible for these
      anomalously rapid charge transfer events.

PMID- 15029829
TI  - [Current problems of epidemiology and diagnosis of trichinosis in the European
      Union and in Poland].
AB  - The paper reviews the current status of trichinellosis in Poland and in Europe.
      It aims to draw attention of Polish sanitary, veterinary and health services to
      the new threats of the disease. Additionally a revised approach to diagnosing
      trichinellosis is presented taking into account that it can be also caused by
      other then Trichinella spiralis Trichinella species.

PMID- 15029830
TI  - [Interesting aspects of immunity and immunization against toxoplasmosis].
AB  - The immunity developing in the course of infection with Toxoplasma gondii was
      discussed, pointing out its advantages and shortcomings, then the attempts at
      immunization against toxoplasmosis were presented.

PMID- 15029831
TI  - [Cystic echinococcosis (CE) in the Poznan region in the years 1990-2000].
AB  - The results of multidisciplinary studies on cystic echinococcosis (CE) in Poznan
      region, Poland carried out in 1990-2000, in co-operation with CDC, Atlanta GA,
      USA, are summarised as follows. The distinct focality of Echinococcus granulosus
      (Eg) infections has been demonstrated on some private farms rearing pigs (refs
      12, 13). A reduction in Eg prevalence rates in pigs has been achieved, from 13.0%
      in 1989 down to 0.5% in 1998. This was an effect of various factors, including
      free treatment of all dogs in the Eg foci, i.e. farms, supplying infected pigs
      (ref. 13). The experimental studies confirmed, that pig's strain of Eg has some
      distinct characteristics, in comparison with the other Eg strains (ref. 8). It
      also had a separate genotype, classified as G7 (G9) (refs 9, 10). It has been
      demonstrated, that pig's strain was the only one found in 16 patients with CE,
      hospitalised in the Clinic of Parasitic and Tropical Diseases in Poznan, Poland
      (refs 9, 10) The same genotype in pigs was found in Slovakia and Ukraine (ref.
      10). In clinical research the fine needle aspiration biopsy (FNAB) has been
      introduced in the doubtful cases and confirmed to be a safe and useful diagnostic
      technique (ref. 11). The FNAB material was examined for Eg protoscolices as well
      as for the presence of antigen 5 (ref. 24). Studies with intradermal Multiest
      suggested, that development of Eg cysts depend much on immune system, especially
      a switch between Th1 and Th2 (ref. 19). It has been observed that FNAB may have a
      beneficial effect on treatment of CE with albendazole, which can be reduced to 1
      month only in the patients treated after FNAB (refs 11, 25, 26). The studies
      carried out were a basis for one habilitation (ref. 11) and 3 MD dissertations
      (13, 19, 23).

PMID- 15029832
TI  - Clinical and epidemiological characteristic of tularemia in Kazakhstan.
AB  - From 1950 to 1977, 5049 human tularemia cases were registered that had been
      associated with a large number of non-immunized people coming to Kazakh tularemia
      endemic areas from different places of Soviet Union to harvest the grain. Since
      1978, the number of tularemia patients has considerably decreased and during 1992
      2001 thirty-one human cases were reported. Epidemiological analysis showed that
      infection was transmitted by a variety of routes, including bites of infected
      arthropod, ingestion of infected food and water, transfer to mouth by
      contaminated hands and direct contact from skinning musk-rats and hares. The
      disease presented mainly as glandular-bubonic (62.5%), bubonic (25.0%) or
      pulmonary (12.5%) forms.

PMID- 15029833
TI  - Plague in Kazakhstan at the present time.
AB  - Since 1990 to 2002, 19 human plague cases and 2 bacteria-carriers cases were
      registered in natural plague foci on the territory of the republic. For last 12
      years plague in forms of bubonic and bubonic-septic was diagnosed in Kazakhstan.
      Out of 19 patients (14 men--73.6% and 5 women--26.3%), 13 persons recovered
      (8.4%), 6 persons died (31.6%). Employment of the treatment in the new scheme
      sharply lowered lethality from plague. Live attenuated Y. pestis EV vaccine
      available for human and camel use is applied as a basic preventive measure in
      plague natural foci. Epidemiological importance of ill camels remains high. At
      the analyzed period, in 5 cases infection was a result of forced camel slaughter.
      11 people (57.8%) were infected through flea bites. Central Asian desert plague
      focus is still the most active and its potential to start epidemic increases in
      connection with rising of anthropogenic influence. All these changes occur on the
      background of epidemiological survey decreasing in natural plague foci.

PMID- 15029834
TI  - [Legionellosis in Poland in 2001-2002 and epidemiological situation in Europe].
AB  - Legionnaires' disease is an infectious disease under the internationally approved
      surveillance agreed by members of European Working Group on Legionella Infections
      EWGLI. Data over 12,000 cases of legionnaires' disease from 28 countries are
      included in European data set for years 1993-2000. The overall incidence rate for
      Europe in 2000 was evaluated as 5,4 cases per million population. The cases was
      registered as community-acquired, nosocomial or travel often foreign travel
      associated. Most 2,799 (70.7%) of the cases in 1999-2001 were confirmed by
      detection of Legionella antigens in urine of patients or by serological findings
      205 (18.1%); in them seroconversion was found in 9.5% and high titer in single
      serum specimen in 8.6% of cases. Culture proven were only 109 (9.6%) cases, and
      1.6% of cases by other methods, PCR included. In Poland in 1997 the laboratory
      examination of samples for diagnosis of Legionella infections started in National
      Institute of Hygiene. In 2001-2002 the 290 samples were examined. Five cases were
      laboratory confirmed, but the results of 16 specimen examined was only
      presumptive positive and for 8 samples equivocal. In comparison with other
      european countries the number of examined samples is still much to small to find
      legionnaires' disease cases. The minimum 220 cases by year may be expected in
      Poland. To find such number the examination of antigenuria should be performed in
      patients with pneumonia hospitalised in intensive care units because of acute
      respiratory insufficiency.

PMID- 15029835
TI  - [Pontiac fever--non-pneumonic legionellosis].
AB  - Pontiac fever is a non-pneumonic, epidemic form of legionellosis. The symptoms
      are similar to flu: fever, tiredness, myalgia, arthralgia, headache, cough, sore
      throat and nausea. The incubation period is from 30 to 90 hours, approx. 36 h.,
      the attack rate is high: 70-90%. There are no differences in sex and age of ill
      people, the same number of women and men or children were affected.
      Unfortunately, ill children symptoms might be differ: higher fever (40 C), lack
      of leukocytosis with left shift, shorten incubation period. The etiological
      agents are usually bacteria: Legionella pneumophila sg 1, sg 6 and Legionella
      micdadei. Diagnosis of Pontiac fever is after finding seroconversion or high
      titre of antibody to Legionella in serum samples or L. pneumophila antigen in
      urine sample. Pontiac fever cases are frequently found during epidemiological
      investigation of legionnaires' disease case. Detection of Pontiae fever might be
      a marker of contaminated with Legionella environment and a risk of live
      threatened pneumonia.

PMID- 15029836
TI  - [Etiology and clinical course of meningitis in children].
AB  - The aim of the paper was to pinpoint the etiological factors which caused
      meningitis, and to describe the course of the illness in the patients
      hospitalized in the years 1991-2000 at the observation ward of the Paediatrics
      Propaedeutics Clinic of the Paediatrics Institute. Etiological factors were
      determined in 42 of 80 cases included in the study: in 32 out of 62 purulent
      meningitis cases and 10 out of 18 aseptic meningitis cases. In purulent
      meningitis the most commonly isolated pathogens were N. meningitidis (16%), S.
      pneumoniae (8.1%), K. pneumoniae (4.9%) and H. influenzae type B (4.9%), where as
      in aseptic meningitis--mumps and herpes viruses. Despite appropriate treatment in
      47% of cases there were observed complications such as hydrocephalus, brain
      oedema, ependymitis as well as hearing or vision impairment and failure to
      thrive.

PMID- 15029837
TI  - [Asymptomatic HBsAg antigenemia in children referred to hospital treatment for
      various reasons].
AB  - HBsAg antigenemia still constitutes a serious clinical problem. In 852 children
      at the age of 3 months to 17 years (54.2% boys and 45.8 girls) referred in 2001
      to J. Korczak hospital in Lodz, antigen HBsAg was determined with the Axsym (V2)
      test, MEIA (Abbott) method. Asymptomatic HBsAg antigenemia was recognized in
      2.35% (20/852) children. The children were from 9 to 17 years old (0 girls and 10
      boys); they came mainly from Lodz. Among HBsAg antigenemic children, 95% (19/20)
      had not been vaccinated against Hepatitis B. The Children were hospitalized
      mainly on the surgical wards (because of accidents and injuries) as well as the
      neurological ward. Hospitalization was shown to be the mainly cause of HBV
      infection.

PMID- 15029838
TI  - [Frequency of asymptomatic C viral infections in children referred to hospital
      treatment for various reasons].
AB  - In 2221 children aged 0.468-17.580 (56% boys and 44% girls) referred to hospital
      treatment for various reasons, antibodies anti HCV were determined with 3rd
      Generation Axsym (Abbott) test. In 3% (66/221) children the result was positive.
      Significant increase in the frequency of anti HCV occurrence was observed in
      children over 6, especially in 9, 10 and 11 years old--54% (36/66). Children anti
      HCV positive came mainly from large cities: 83% (55/66). Risk factors are
      presumed to be firstly blood sampling in out-patient clinics 34.8% (23/66) and
      hospitalization 22.7% (15/66), then dental procedures 18.2 (12/66), hairdressing
      and cosmetic procedures (tattoo and ear pricking) 12.1% (8/66). The authors point
      at the necessity of control in institutions performing such procedures as well as
      the need of sanitary education among medical personnel and school children in the
      period of hepatotropic viral infections.

PMID- 15029839
TI  - [Detection of nonpoliomyelitic enteroviruses in central nervous system infections
      in Poland in 1995-2000; viral isolation data].
AB  - The aim of this study was evaluation of enterovirus diagnosis based on isolation
      of the virus in cell culture from subjects with aseptic neuroinfection conducted
      in six Provincial Sanitary-Epidemiological Stations in 1995-2000 years. Available
      data from six Sanitary-Epidemiological Stations indicated that 1429 isolation of
      enteroviruses from fecal samples of those patients were performed. The most
      frequently isolated enterovirus serotype was echovirus type 30: 138/203 isolated
      enteroviruses, but also others enterovirus serotypes were isolated in a study
      period. In the years 1995 and 1996 the percentage of positive results of
      isolation was highest with the numbers of 31% and 28.27% respectively. The
      decrease in positive isolation results has been observed from 1997 year. Negative
      results of isolation come up to 90% of investigated cases. Only 1.5% of
      enterovirus isolation attempts finished successfully in 2002 year. The situation
      when percentage of positive results of isolation is on so low level, the natural
      alterations in a profile of enterovirus serotype infected population cannot be
      observed, and serological investigations can be conducted for enterovirus
      serotypes others than really circulating and causing infections in population.

PMID- 15029840
TI  - [Viral hemorrhagic fevers--epidemiology and clinical picture].
AB  - The article presents current knowledge about viral hemorrhagic fevers (VHF),
      their epidemiology, etiological factors, pathogenesis, symptoms and clinical
      management. Since none of the diseases appear endemically in Poland, special
      attention was given to spatial distribution of VHF for the purpose to facilitate
      undertaking clinical suspicions on the basis of the patient's recent travels.
      Determining the etiological agent should lead to selection of appropriate
      management options.

PMID- 15029841
TI  - [Characteristics of bacteria isolated from body surface of German cockroaches
      caught in hospitals].
AB  - The objective of the study was to identify bacterial flora from external parts of
      German cockroaches caught in hospitals. The susceptibility of the bacteria to the
      most important groups of antimicrobial agents was also examined. 80 strains of
      bacteria were isolated, among them 34 strains of Gram-positive cocci and 31
      strains of Gram-negative rods. One of isolated strains of Citrobacter freundii
      and two strains of Serratia liquefaciens showed ESBL mechanism of resistance and
      extended level of AmpC--type beta-lactamases. Two Staphylococcus strains (S.
      epidermidis and S. equorum) were resistant to erythromycin and clindamycin (MLSB
      mechanism of resistance). Such strains, resistant to antibiotics and
      chemiotherapeutics may be reservoirs of resistance genes which can be transmitted
      into other bacteria. Presence of such pathogens on the body surface of German
      cockroaches, very mobile insects, might create conditions for easy dissemination
      of them in hospital environment.

PMID- 15029842
TI  - [Trends of hospitalization rates from asthma in children and adolescents in
      Poland].
AB  - Hospitalization rates from asthma in children and adolescents below 19 years of
      age showed a consistent rising trend over the last two decades and in the period
      1984-1996 the rates were doubled in both genders. Among boys the rates were 1.6
      times higher than in girls. On average the rates increased annually by 12.2% in
      boys and by 10.6% in girls. The fastest increase has been noted in the youngest
      children in the age 0-4 years (20.3% in boys and 18.9% in girls). In the older
      age groups (5-9 and 10-14 years) the annual increase was in the range of 10.5
      14.1%. The slowest increase was observed in children in the oldest age group
      (3.7%) and in the latter age group there was no differences in hospitalization
      rates between both genders. We found the highest rates in the southeastern and
      northern part of the country and this was not compatible with the hygienic
      hypothesis of asthma and allergic diseases.

PMID- 15029843
TI  - [Epidemiological analysis of leukemia survival in Cracow for cases registered in
      1980-1990].
AB  - The aim of the study was epidemiological analysis of survival from all types of
      leukemia occurring in Cracow in the years 1980-1990. The study was focused on
      survival times in patients according to a) cytologico-clinical type of leukemia,
      b) timeframe in which treatment was initiated (between 1980-1985 and 1986-1090).
      All patients diagnosed of leukemia between the years 1980-1990, living in Cracow
      and whose cytologico-clinical picture was determined had their survival times and
      censored survival times established. Survival until 1997 was taken into account.
      For each cytologico-clinical type of leukemia survival function according to
      Kaplan-Meier was calculated. The Cox model was implemented to analyze the risk of
      death depending on the period in which the disease appeared--two time frames were
      established 1980-1985 and 1986-1990. Other parameters considered were; age, sex
      and area in which the patient lived (suburb). Practically in all types of
      leukemia a higher probability of survival was found in patients in whom leukemia
      was diagnosed (and consequently treated) in the second period i.e., 1986-1990.
      The highest achievement was observed in acute lymphoblastic leukemia in children,
      in which the relative 5-year survival probability rose from 35% in the years 1980
      1985 to 78% in the years 1986-1990, thus achieving the level of well developed
      countries. A similar picture was seen in chronic lymphocytic leukemia where the
      relative 5 year survival probability rose from 57% to 77%, and in chronic
      granulocytic leukemia where the 5 year survival probabilities were accordingly
      23% and 39%. All cited values for the second period of analysis are at the levels
      noted in the United States and in Europe. The positive changes in the survival
      times observed in patients with leukemia seen in the second half of the 80-ies
      (in comparison to the period 1980-1985) has been interpreted as the result of
      advancements in therapy of the disease in Cracow.

PMID- 15029844
TI  - [Meta-analysis of prenatal smoking cessation interventions].
AB  - Our purpose was to assess the effect of prenatal smoking interventions on rates
      of smoking cessation. A total of 37 trials, conducted between 1976 and 2002 and
      comprising over 14000 women were identified and included in the meta-analyses.
      There was a significant increasing in the odds of women who quit smoking in late
      pregnancy in the intervention group (OR = 1.6; 95% CI 1.4-1.8). The effectiveness
      of the intervention was significantly higher in the studies that smoking
      cessation intervention included written materials for pregnant women then in the
      studies without those materials. The percentage of pregnant women who quit
      smoking was higher among American women than among women from the European
      Countries.

PMID- 15029845
TI  - [Validity and reliability of Short Form General Health Survey (SF-20) in
      population of elderly people].
AB  - Aim of this study was assessing validity and reliability of Short Form General
      Health Survey (SF-20) and it's usefulness in evaluation of health status of
      elderly people in Polish conditions. Study group consisted of 529 randomly chosen
      elderly (household residents) living in Krakow. Theoretical validity of the test
      was evaluated using exploratory factor analysis (principal components method).
      Reliability was calculated by Cronbach's alpha index and by checking if questions
      forming each sub scale fulfill Kline's criterion. Analysis showed some faults in
      theoretical validity of scales concerning mental and physical health, which
      decrease their reliability. Nevertheless, scales constituting this Survey fulfill
      Kline's and Nunnaly's criterias, which means that they have high internal
      consistency. Results confirm satisfactory value of SF-20 test as an instrument
      for evaluation of health of elderly people in Polish conditions.

PMID- 15029846
TI  - [The interest in the TV health promotion programs].
AB  - The questionnaire survey was carried out among 1000 persons to assess the
      determinants of interest in unpaid TV health programmes: present and future
      viewing. Television was found as one of the most important sources of
      information, usually accidental. Free time and air-time were among supporting
      factors. The viewers had a positive attitude toward health programmes; many
      perceived disadvantageous effects and barriers for watching. The audience
      segmentation indicated a non-representative distribution. Women, married or
      widowed persons, older, those with ill health, lower economic status and role
      models were more likely to be present and future viewers.

PMID- 15029847
TI  - [Alcohol drinking in the time of political transition in Poland. Report of the
      National Health Programme ].
AB  - The National Health Programme was adopted in Poland in the mid-1990s. It consists
      of 18 targets including target 4 that calls for diminishing alcohol consumption
      and changing its structure as well as limiting health harms associated with
      alcohol. The programme is being monitored on bi-annual basis. The monitoring
      covers a level of alcohol consumption and associated harm including trends in
      mortality and morbidity as well as in road accidents in 1990-2001 period. During
      the period in point, particularly in the beginning of the transition alcohol
      consumption increased at least by one third reaching 10-11 litres of pure ethanol
      per capita, mostly due to sudden disruption of the alcohol control system and
      high tide of unrecorded supply. Currently, the consumption is estimated to be 9.5
      10.0 litres with 30% share of the unrecorded. During last decade recorded
      morbidity due to mental disorders associated with alcohol increased by 80% and
      60% respectively in out- and in-patient system while mortality rates almost
      doubled. Male mortality due to liver diseases increased by 50% while that of
      women remained relatively flat. In last few years, alcohol related mortality
      tended to decline slightly parallel to consumption trends. Significant
      improvement has been achieved in prevention of drunken diving. The number of
      deaths in alcohol related road accidents decreased two fold while a rate of
      drunken crashes per 1000 vehicles dropped three times.

PMID- 15029848
TI  - Diabetes: blood pressure really counts.

PMID- 15029849
TI  - Doubling your odds of kicking the habit.

PMID- 15029850
TI  - New strategies for preventing vision loss.

PMID- 15029851
TI  - How knowing your family tree can save your life.

PMID- 15029852
TI  - Why has my doctor advised me not to use an over-the-counter product called
      Gugulmax to lower my cholesterol and prescribed a statin instead?

PMID- 15029853
TI  - How can I get rid of cellulite?

PMID- 15029854
TI  - Diabetes. Taking action to prevent or control this condition.

PMID- 15029855
TI  - Stem cells to your rescue.

PMID- 15029856
TI  - Preventing the most life-threatening strokes.

PMID- 15029857
TI  - Knowing when to replace a painful hip.

PMID- 15029859
TI  - Can cooking in aluminum pots cause Alzheimer's disease?

PMID- 15029858
TI  - Statins: celebrating proven benefits.

PMID- 15029860
TI  - Autism: a new treatment seems unsuccessful.

PMID- 15029862
TI  - In their own words: how children might describe an allergic reaction.

PMID- 15029861
TI  - A little exercise goes a long way.

PMID- 15029864
TI  - Product recalls. Recalls: Zutopia girl's loungewear.

PMID- 15029863
TI  - Infections/illness. It may be a "SNAP" to reduce antibiotic use.

PMID- 15029865
TI  - Potent painkillers: addictive?

PMID- 15029866
TI  - Will this drug work? Look to your genes.

PMID- 15029867
TI  - New options for soothing an irritable bowel.

PMID- 15029868
TI  - Making the right choices for radiation therapy.

PMID- 15029869
TI  - Does hemochromatosis need to be treated even if I feel fine?

PMID- 15029870
TI  - Absorption, distribution, metabolism, and excretion of CKD-732, a novel
      antiangiogenic fumagillin derivative, in rats, mice, and dogs.
AB  - The pharmacokinetics of CKD-732 (6-O-4-[dimethyl-aminoethoxy)cinnamoyl]
      fumagillol x hemioxalate) was investigated in male SD rats and beagle dogs after
      bolus intravenous administration. The parent compound and metabolites obtained
      from in vitro and in vivo samples were determined by LC/MS. The main metabolite
      was isolated and identified as an N-oxide form of CKD-732 by NMR and LC/MS/MS.
      CKD-732 was metabolized into either M11 or others by rapid hydroxylation,
      demethylation, and hydrolysis. The blood level following the intravenous route
      declined in first-order kinetics with T(1/2)beta values of 0.72 to approximately
      0.78 h for CKD-732 and 0.92 to approximately 1.09 h for M11 in rats at a dose of
      7.5 to approximately 30 mg/kg. In dogs, T(1/2)beta values of CKD-732 and M11 were
      1.54 and 1.79 h, respectively. Moreover, AUC values increased dose dependently
      for CKD-732 and M11 in rats and dogs. The CLtot and Vdss did not change
      significantly with increasing dose, indicating linear pharmacokinetic patterns.
      The excretion patterns through the urine, bile, and feces were also examined in
      the animals. The total amount excreted in urine, bile, and feces was 2.13% for
      CKD-732 and 1.29% for M11 in rats, and 1.58% for CKD-732 and 2.28% for M11 in
      dogs.

PMID- 15029872
TI  - Evidence for up-regulated central nociceptive processing in patients with
      masticatory myofascial pain.
AB  - AIMS: Previous work suggests that hyperexcitability of central nociceptive
      neurons may play a role in the pain of temporomandibular disorders (TMD). The aim
      of this study was to test this theory by assessing differences, between myalgic
      TMD patients and pain-free controls, in temporal summation of mechanically evoked
      pain and aftersensations following repetitive noxious stimulation. METHODS:
      Sixteen series of 10 repetitive, mildly noxious mechanical stimuli were applied
      to the fingers of 25 female TMD patients with masticatory myofascial pain and 25
      age-matched, pain-free female subjects. All subjects rated the pain intensity and
      unpleasantness evoked by the first, fifth, and tenth stimuli in the series and
      their aftersensations at 15 seconds and 1 minute following the last stimulus.
      Data were analyzed by 3-way repeated-measures analysis of variance. RESULTS: Pain
      and unpleasantness ratings increased with repetition of the stimulation (P <
      .0001). In addition, there was a significant trial number x group interaction for
      the pain intensity ratings, such that TMD patients provided higher ratings than
      controls for the tenth stimulus (P < .001). The increase in unpleasantness
      ratings with repetitive stimulation was also higher for the patient group (P <
      .0001). Moreover, TMD patients rated the intensity of aftersensations as higher
      (P < .005) and reported painful aftersensations at significantly greater
      frequency (P < .05). CONCLUSION: A generalized hyperexcitability of central
      nociceptive processing in this TMD patient group is indicated by their more
      pronounced temporal summation of pain and greater aftersensations following
      repetitive noxious digital stimulation versus controls. Such hyperexcitability
      may contribute to the pathophysiology of TMD pain.

PMID- 15029873
TI  - Monitoring dibutyltin and triphenyltin in fresh waters and fish in the United
      States using micro-liquid chromatography-electrospray/ion trap mass spectrometry.
AB  - There is a growing body of evidence that toxic organotins are making their way
      into terrestrial and aquatic mammals including humans. In the United States, one
      possible route of environmental exposure to organotins (specifically dibutyltin
      and triphenyltin) is via fresh surface waters and fish taken from those waters. A
      unique methodology was used for quantitative and speciation of the organotins.
      This green-chemistry method combines two extraction techniques (solid-phase
      extraction for waters; hexane/tropolone extraction for fish) with micro-liquid
      chromatography-electrospray/ion trap mass spectrometry (micro-LC-ES/ITMS) as the
      detection method. A small survey looking for organotins in fresh surface waters
      across the United States, and fish from those waters, was conducted. Various
      concentrations of dibutyltin and triphenyltin were detected in fresh water,
      ranging from nondetect to 2 ppb, and nondetect to 6 ppb, respectively. In fish
      dibutyltin and triphenyltin were detected from nondetect to 200 ppb, and
      nondetect to 400 ppb, respectively.

PMID- 15029874
TI  - Reference intervals for plasma levels of fibronectin, von Willebrand factor, free
      protein S and antithrombin during third-trimester pregnancy.
AB  - During pregnancy, significant changes occur in the hemostatic system and in the
      plasma levels for several plasma proteins, especially towards term. In this study
      changes occurring during normal pregnancy and immediately postpartum were
      investigated to establish adequate reference intervals for important hemostatic
      parameters. Blood samples were collected during pregnancy weeks 33, 36, 39 and 1
      3 h after delivery from 153 healthy pregnant women with at least one previous
      normal pregnancy. The plasma samples were analyzed for antithrombin, von
      Willebrand factor (vWf), free protein S and fibronectin. Fibronectin and vWf are
      contact-promoting proteins responsible for adhesion and aggregation during
      primary hemostasis, but are also released from thrombocytes during activation of
      the coagulation process. Antithrombin is the most important primary physiological
      inhibitor of activated serine proteases related to the coagulation cascade.
      Protein S is a co-factor to protein C and in cooperation is also an important
      inhibitor of the coagulation cascade. During third-trimester pregnancy, vWf was
      higher than in non-pregnant women, and continued to increase postpartum. The
      fibronectin plasma level was mostly unchanged in comparison with non-pregnant
      values. Within this reference interval it gradually increased during the third
      trimester, but fell slightly postpartum. Antithrombin decreased slightly during
      the third trimester and even further, postpartum. Free protein S decreased
      markedly but to a stable level from week 33 to 39, decreasing even more
      postpartum. The present results are concordant with clinical knowledge of
      increased risk of thrombosis during pregnancy and early puerperium, with
      increased levels of vWf and fibronectin and decreased levels of antithrombin and
      free protein S. Clearly, current reference values based on healthy non-pregnant
      subjects are not usable during late pregnancy and immediately postpartum.

PMID- 15029875
TI  - Evaluation of a species-specific PCR assay for the Anopheles funestus group from
      eleven African countries and Madagascar.
AB  - A newly published cocktail polymerase chain reaction (PCR) assay can identify
      five members of the Anopheles funestus group: An. funestus, An. vaneedeni, An.
      parensis, An. leesoni and An. rivulorum. The assay was evaluated on specimens
      from 11 African countries: Angola, Cote d'Ivoire, Ethiopia, Kenya, Malawi,
      Mozambique, Namibia, South Africa, Tanzania, Uganda and Zambia; and the island of
      Madagascar. The polymerase chain reaction single strand conformation polymorphism
      (PCR-SSCP) and the internal transcribed spacer PCR (ITS2-PCR) assays were used as
      a priori identification methods on 900 specimens. Of these, 96.4% were correctly
      identified using the new cocktail PCR method. The remaining 3.5% (32) from Malawi
      failed to amplify. The failure to identify these samples was not significantly
      different from the samples from the other countries (Chi-square; P > 0.05). The
      results suggest that the new species-specific PCR assay is an efficient and
      effective means of identifying 5 members of the An. funestus group in a single
      reaction. It is also less time-consuming than the molecular methods previously
      used on the group.

PMID- 15029876
TI  - Effects of healing intention on cultured cells and truly random events.
AB  - OBJECTIVE: To explore effects of healing intention and intentional space
      conditioning on the growth of cultured human brain cells and the distribution of
      truly random events. DESIGN: The experiment took place inside an
      electromagnetically and acoustically shielded chamber over a period of 3 days. On
      each day randomly selected flasks of human astrocytes in culture were exposed to
      healing treatments; an equal number of unexposed flasks served as controls.
      Intentional healing and space-conditioning mediations were repeatedly held inside
      the chamber over the course of the experiment to see if this activity would
      cumulatively enhance the efficacy of healing treatments. To monitor the
      environments for negentropic effects possibly associated with the healing
      intention, three truly random number generators were operated continuously
      throughout the duration of the experiment. OUTCOME MEASURES: For cell cultures,
      the outcome measure was the difference in mean colonies formed under healing
      intention versus control conditions, and the change in these differences over the
      3-day experiment. For the random number generators, the outcome measure was the
      variance in the distribution of random numbers generated, compared to chance
      expectation. RESULTS: There was no overall difference in growth between treated
      and control cells. A treatment by day interaction indicated that treated cells
      grew more than control cells as the experiment progressed (p=0.02). The three
      random number generators deviated from chance expectation on the morning of the
      third day of the experiment (combined peak association with p=0.00009).
      CONCLUSIONS: Results were consistent with the postulate that healing intention,
      applied repeatedly in a given location, may alter or condition that site so as to
      enhance the growth of treated cell cultures compared to untreated controls.
      Repeated intentions also appear to be associated with a general increase in
      negentropy or statistical order.

PMID- 15029879
TI  - Reliability of plantar response requires consistency of the applied stimulus.

PMID- 15029877
TI  - New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia
      related abnormalities in mice.
AB  - X-linked hypophosphatemic rickets (XLH) in humans is caused by mutation in the
      PHEX gene. Previously, three mutations in the mouse Phex gene have been reported:
      Phex(Hyp), Gy, and Phex(Ska1). Here we report analysis of two new spontaneous
      mutation in the mouse Phex gene, Phex(Hyp-2J) and Phex(Hyp-Duk). Phex(Hyp-2J) and
      Phex(Hyp-Duk) involve intragenic deletions of at least 7.3 kb containing exon 15,
      and 30 kb containing exons 13 and 14, respectively. Both mutations cause similar
      phenotypes in males, including shortened hind legs and tail, a shortened square
      trunk, hypophosphatemia, hypocalcemia, and rachitic bone disease. In addition,
      mice carrying the Phex(Hyp-Duk) mutation exhibit background-dependent variable
      expression of deafness, circling behavior, and cranial dysmorphology,
      demonstrating the influence of modifying genes on Phex-related phenotypes.
      Cochlear cross-sections from Phex(Hyp-2J)/Y and Phex(Hyp-Duk)/Y males reveal a
      thickening of the temporal bones surrounding the cochlea with the presence of a
      precipitate in the scala tympani. Evidence of the degeneration of the organ of
      Corti and spiral ganglion also are present in the hearing-impaired Phex(Hyp
      Duk)/Y mice, but not in the normal-hearing Phex(Hyp-2J)/Y mice. Analysis of the
      phenotypes noted in Phex(Hyp-Duk)/Y and Phex(Hyp-2J)/Y males, together with those
      noted in Phex(Ska1)/Y and Phex(Hyp)/Y males, now allow XLH-related phenotypes to
      be separated from non-XLH-related phenotypes, such as those noted in Gy/Y males.
      Also, identification of the genetic modifiers of hearing and craniofacial
      dysmorphology in Phex(Hyp-Duk)/Y mice could provide insight into the phenotypic
      variation of XLH in humans.

PMID- 15029880
TI  - Making the research dollar work: outcome from a small research funding body.

PMID- 15029878
TI  - Epipen use: good clinical practice.

PMID- 15029881
TI  - [Outcome-oriented retrospective analysis of open standard nucleotomy in
      comparison with microsurgical lumbar discectomy].

PMID- 15029882
TI  - ["Disease mongering" as a sign of medicalization of our society. Social Medicine
      Expert Forum 3 December 2003 in Berlin].

PMID- 15029884
TI  - [More transparence in public health service by external quality assurance? 2.
      Outcome Conference of the Federal Quality Assurance Office 4 December 2003 in
      Dusseldorf].

PMID- 15029883
TI  - [Navigation in knee prosthesis implantation--progress?].

PMID- 15029885
TI  - [Some suggestion of using the world health organization classification of the
      acute myeloid leukemia in China].

PMID- 15029886
TI  - [Prevalence of periodontal diseases among elderly and senile residents of Moscow
      and the Moscow region].

PMID- 15029887
TI  - ["Shadow economy" phenomenon in dentistry].

PMID- 15029888
TI  - [Opinion of the rural population about organization and quality of dental care].

PMID- 15029889
TI  - [Problems of medical rehabilitation of patients with fractures of the zygomatico
      orbital complex].

PMID- 15029890
TI  - [Results of treatment of patients with cancer of the facial and labial skin by
      means of LST-20/01 laser].

PMID- 15029891
TI  - Schedules of controlled substances; placement of 2,5-dimethoxy-4-(n)
      propylthiophenethylamine and N-benzylpiperazine into Schedule I of the Controlled
      Substances Act. Final rule.
AB  - This final rulemaking is issued by the Acting Deputy Administrator of the Drug
      Enforcement Administration (DEA) to place 2,5-dimethoxy-4-(n)
      propylthiophenethylamine (2C-T-7) and N-benzylpiperazine (BZP) into Schedule I of
      the Controlled Substances Act (CSA). This action by the DEA Acting Deputy
      Administrator is based on a scheduling recommendation by the Department of Health
      and Human Services (DHHS) and a DEA review indicating that 2C-T-7 and BZP meet
      the criteria for placement in Schedule I of the CSA. This final rule will
      continue to impose the regulatory controls and criminal sanctions of Schedule I
      substances on the manufacture, distribution, and possession of 2C-T-7 and BZP.

PMID- 15029892
TI  - [Validation of orthodontic use of rapid maxillary extension].

PMID- 15029893
TI  - Poliomyelitis spreads in west and central Africa.

PMID- 15029895
TI  - Earth science: an alternative origin for the 'Silverpit crater'.

PMID- 15029894
TI  - Is retinal photography useful in the measurement of stroke risk?
AB  - BACKGROUND: The retinal microcirculation can be viewed non-invasively to give a
      unique perspective of the cerebral microcirculation in vivo. Studying
      pathological changes of retinal blood vessels (microaneurysms, retinal
      haemorrhages, and retinal arteriolar narrowing) may help to understand the causes
      of various cerebrovascular disorders. Retinal photography provides such an
      opportunity. RECENT DEVELOPMENTS: Several recent studies have shown that retinal
      microvascular changes are reliably documented by retinal photographs. These
      retinopathy changes seem to be fairly common in the general population, even in
      people without hypertension or diabetes. Retinopathy is related to incident
      clinical stroke and stroke mortality and to MRI-defined subclinical cerebral
      white-matter lesions and cerebral atrophy, independent of blood pressure,
      diabetes, and other cerebrovascular risk factors. WHERE NEXT?: Retinal
      microvascular abnormalities seem to be markers of concomitant cerebral
      microangiopathy, and retinal photography may be useful for the investigation of
      microvascular disorders of the brain in clinical and epidemiological settings.
      Future research should be aimed at the development of standardised photographic
      methods for the assessment of retinal microvascular changes, the replication of
      these findings in other populations and in people with other cerebrovascular
      disorders, and the examination of the increased accuracy of stoke-risk
      stratification given by retinal photography

PMID- 15029896
TI  - Overview of artifact reduction and removal in evoked potential and event-related
      potential recordings.
AB  - Artifact in one form or another needs to be contended with in all EEG and EP
      studies. Various methods have been employed to avoid, eliminate, or minimize
      artifact. This article has described the methods that have been available for
      some time and newer methods and their advantages. It is the authors' hope that
      through the use of these methods the accuracy of all EP and ERP measurements will
      be improved and promote the validity and general acceptance of EP and ERP
      recordings. Genuine and valuable data are contained in EPs and ERPs. The
      challenge is to extract relatively small voltage signals often occurring within a
      higher voltage background of artifact. The computing power required to perform
      the artifact removal/reduction procedures now is available with basic laptop and
      desktop computers, as are the software programs that provide the artifact
      removal/reduction capabilities. It may be of interest for a prudent researcher to
      integrate the currently available artifact rejection methods before subjecting
      the ERP and EP data for further analysis and subsequent publication.

PMID- 15029898
TI  - Somatosensory evoked potentials in coma prognosis.
AB  - SEPs provide useful prognostic information regarding outcome after coma. Use of
      the summary data presented here should allow clinicians caring for these patients
      to provide families with a greater degree of certainty regarding outcome than
      previously has been available.

PMID- 15029897
TI  - Fundamental principles of somatosensory evoked potentials.
AB  - Studies of SSEP provide unique opportunities for investigating physioanatomic
      substrates of sensory pathway and cognitive functions of the sensory system.
      Progress of clinical investigation and application of SSEP have been stalled in
      more recent years, although SSEP still remain a useful tool for diagnosis of
      various neurologic disorders and for the monitoring of spinal cord function
      during surgery. Reflecting complex sensory system in human, scalp-recorded SSEP
      consists of multiple waves, having different distribution, amplitude, and
      latencies among different electrodes. The physioanatomic significance of these
      multiple waves, especially the late components, is largely unknown. These should
      be explored further, especially in relation to cognitive function.

PMID- 15029899
TI  - The use of evoked potentials in intraoperative neurophysiologic monitoring.
AB  - Although not universally adopted, the growing body of literature provides strong
      evidence of the clinical utility of IOM in a variety of cerebrovascular surgical
      and endovascular procedures. The Therapeutics and Technology Subcommittee of the
      American Academy of Neurology and Fisher et al concluded that the following are
      useful and noninvestigational: 1. EEG, compressed spectral array, and SSEP in CEA
      and brain surgeries that potentially compromise cerebral blood flow, 2. BAEP and
      cranial nerve monitoring in surgeries performed in the region of the brainstem or
      inner ear, 3. SSEP monitoring performed for surgical procedures potentially
      involving ischemia or mechanical trauma of the spinal cord. They also came to the
      conclusion that although promising, motor EPs and visual EPs are still
      investigational. Further investigation, especially in the area of outcomes
      research and cost-effectiveness, is required before IOM can become standard
      practice.

PMID- 15029900
TI  - Electrophysiologic intraoperative monitoring for spine procedures.
AB  - The advent of equipment capable of performing SEPs, MEPs, and EMG in a
      multiplexed manner and in a timely fashion brings a new level of monitoring that
      far exceeds the previous basic monitoring done with SEPs only. Whether this more
      comprehensive monitoring will result in greater protection of the nervous system
      awaits future analysis. In any event, monitoring of the spinal cord with SEPs is
      an accepted standard of care for cases that place the spinal cord at risk.
      Likewise, nerve root monitoring with EMG is a widely practiced form of monitoring
      and shows great benefit. MEPs and reflex monitoring, which address the descending
      pathways and the interneuronal connections, is efficacious in detecting
      abnormalities that may be missed by SEPs.

PMID- 15029901
TI  - The clinical use of dermatomal somatosensory evoked potentials in lumbosacral
      spinal stenosis.
AB  - DSEPs provide clinicians with a safe, noninvasive technique useful in determining
      which patients with anatomic spinal stenosis have the added component of
      neurogenic compromise. Based on physiologic principles, level-by-level
      prolongation of DSEP latencies, reduction of amplitude, asymmetry, or a complete
      absence of response is associated with dysfunction in that particular afferent
      neurologic pathway. This dysfunction does not correspond to the exact level of
      stenosis noted on MRI because the rootlets in the lumbar and sacral regions pass
      through multiple spinal segments as they course rostrally through the spinal
      canal. Given that LSSS typically develops over time, the degree of abnormality
      likely would correspond to the physiologic slowing occurring in the multiple
      rootlets of the cauda equina. These recordings are not easy to perform and
      interpret, but when done correctly, they provide the best evidence for the type
      of neurophysiologic dysfunction in LSSS that responds favorably to surgical
      decompression. Similarly, DSEPs might provide a means of neurophysiologically
      monitoring clinically significant findings in a program of conservative
      management.

PMID- 15029902
TI  - Motor evoked potentials.
AB  - Noninvasive electrical stimulation of the human brain first was attempted in the
      1950s. In the early 1980s, the first clinical application method of transcranial
      electrical stimulation was developed. Investigators in the mid-1980s showed that
      it was possible to stimulate the nerve and the brain using external magnetic
      stimulation (transcranial magnetic stimulation [TMS]), with little or no pain.
      TMS now is used commonly in clinical neurology to study central motor conduction
      time. Depending on the stimulation techniques and parameters, TMS can excite or
      inhibit brain activity, allowing functional mapping of cortical regions and
      creation of transient functional lesions. It now is used widely as a research
      tool to study aspects of human brain physiology, including motor function and the
      pathophysiology of various brain disorders.

PMID- 15029903
TI  - Clinical application of the P300 event-related brain potential.
AB  - The P300 brain potential can provide information about cognition that is
      quantitatively comparable to other clinically used biomedical assays. Causes of
      P300 variability with respect to task and biologic determinants have been well
      characterized so that refinement of ERP methods for clinical applications is
      possible. Elaboration of how P300 and other ERP components reflect
      neuropsychologic processes would help to increase their clinical relevance. In
      particular, development of reliable P3a paradigms used in conjunction with P3b
      tasks promises to augment dramatically the applicability and sensitivity of ERPs.
      Use of P300 as a clinical evaluation tool should be revisited with contemporary
      theory, methods, and analysis procedures because a reliable neuroelectric measure
      of mental function would redefine the assessment of cognitive disorders.

PMID- 15029904
TI  - Clinical applications of event-related potentials in brain injury.
AB  - ERPs may extend the battery of neurophysiologic tests currently available for
      determining the functional integrity of the central nervous system and the
      capacity of cognition in patients with brain injury. The use of stimuli relevant
      for the patient can enhance the probability to record these waves in unconscious
      patients and in patients with cognitive impairment and enhance the predictive
      value on outcome. The experimental data in these patients still are not
      sufficient, however, to standardize the indications of ERPs in clinical practice.
      Their limitations, mainly the variability also present in normal individuals and
      the limited standardization and validation, must be considered, and they must be
      judged cautiously as a prognostic index. Nevertheless, ERPs might be applied as a
      useful supplement to neuropsychologic assessment.

PMID- 15029905
TI  - Applications of the P50 evoked response to the evaluation of cognitive
      impairments after traumatic brain injury.
AB  - This article reviews the applications of the P50 evoked response to paired
      auditory stimuli (P50 ERP) in the study and evaluation of cognitive impairments
      after traumatic brain injury (TBI). The cholinergic hypothesis of cognitive
      impairment after TBI and the relationship of impaired auditory sensory gating to
      that hypothesis are presented. The neurobiology of impaired sensory gating, the
      relationship of that neurobiology to the P50 ERP, and the principles of P50 ERP
      recording are discussed. Studies of the P50 ERP among patients with persistent
      cognitive complaints after TBI are reviewed. Finally, possible clinical
      applications and limitations of the P50 ERP in the study, evaluation, and
      treatment of patients with cognitive impairments after TBI are offered.

PMID- 15029906
TI  - Clinical applications of cognitive event-related potentials in Alzheimer's
      disease.
AB  - This article has reviewed several abnormalities in the cognitive ERPs of AD
      patients. These abnormalities are prominent from latencies of approximately 200
      msec and later. In contrast, sensory-dependent evoked potentials, such as N100,
      are generally normal in AD. This finding is as one familiar with the
      neuropathology of AD would predict. Predilection sites in early AD include the
      medial temporal lobe, other limbic areas, and multimodal association cortices
      with sparing of primary sensory areas. Unimodal association cortex is involved in
      AD, but not as heavily as multimodal cortex. Particular advantages of studying a
      given ERP paradigm or component depend largely on the specific application or
      hypothesis being tested. A P300 paradigm can be useful in detecting a disorder of
      attention or in quantifying the effects of drugs that improve attention, such as
      the cholinesterase inhibitors. For the early diagnosis of AD or other memory
      disorders, a word-repetition paradigm with an explicit recognition task or one
      that fosters associative learning would be recommended. This article has
      discussed potential use of N400 in tracking disease progression. ERPs provide a
      flexible and powerful technique, with superb temporal resolution, which can be
      used as a probe into subtle "subclinical" abnormalities of cognitive processes.
      Despite being applied to AD for about 25 years since the early P300 studies, the
      full potential of ERPs in helping diagnose and treat AD patients has yet to be
      realized. In this era of rapidly evolving brain-imaging techniques,
      electrophysiologic data are important in advancing understanding of cognition.
      Brain-mapping techniques that can inform where and when key cognitive processes
      occur are finally emerging. A final example of potential clinical application of
      cognitive ERPs is in the development of rational combinational treatment of
      cognitive enhancing drugs. Along these lines, P300 investigations in epilepsy
      proved helpful in ranking the cognitive side effects of anticonvulsant drugs.
      Drug studies that use 2 x 2 combinational designs, which compare the effects of
      drug A, drug B, with A + B, are currently prohibitively expensive for full-scale
      clinical trials in AD. It is likely that precise ERP measures could hasten drug
      development in several ways. Smaller samples could be used, at lower cost, to
      test the cognitive effects of each specific drug combination. Optimal doses of
      combinational therapy perhaps could be identified by repeated within-subject ERP
      measures. Longitudinal changes in the ERP hold promise as a marker of individual
      responsivity to a particular agent, which could have diagnostic utility (eg,
      testing response to cholinergic or dopaminergic therapy). This horizon and many
      others remain wide open for well-planned explorations.

PMID- 15029907
TI  - Principles and clinical applications of auditory evoked potentials in the
      geriatric population.
AB  - Age-related changes in auditory evoked potentials are complex and complicated by
      the confounding effects of gender; concomitant high-frequency hearing sensitivity
      loss; and, in the case of event-related responses, the nature of the task used to
      elicit the response. There is a tendency for amplitude to decline and latency to
      increase, but these trends are not always clear-cut. There is also a tendency for
      activation patterns to move forward from parietal to frontal areas as age
      increases. The dichotic listening tool has revealed age-related changes in
      interaural and interhemispheric asymmetries. These asymmetries seem to be related
      to loss in the efficiency of interhemispheric transfer via the corpus callosum.

PMID- 15029908
TI  - Overview of dipole source localization.
AB  - Truly accurate dipole source localization relies on having (1) reliable, artifact
      free EP/ERP (or magnetoelectroencephalogram) data to start with; (2) landmark and
      electrode position data obtained with a three-dimensional digitizer; (3) MRI (or
      CT) data from the same subject (with a means to measure the same landmarks); (4)
      the capability to apply different dipole and volume conductor models; and (5) the
      ability to coregister the functional and anatomic data to display the final
      source solutions. Most important is to have a thorough understanding of the
      fundamental principles of the localization programs and neurophysiologic
      processes. Localization programs are simply tools. Used incorrectly, they can
      yield meaningless results. Used correctly, they can provide a window into
      neurophysiologic functioning that is not available through any other means.

PMID- 15029909
TI  - Integrated technology for evaluation of brain function and neural plasticity.
AB  - The study of neural plasticity has expanded rapidly in the past decades and has
      shown the remarkable ability of the developing, adult, and aging brain to be
      shaped by environmental inputs in health and after a lesion. Robust experimental
      evidence supports the hypothesis that neuronal aggregates adjacent to a lesion in
      the sensorimotor brain areas can take over progressively the function previously
      played by the damaged neurons. It definitely is accepted that such a
      reorganization modifies sensibly the interhemispheric differences in somatotopic
      organization of the sensorimotor cortices. This reorganization largely subtends
      clinical recovery of motor performances and sensorimotor integration after a
      stroke. Brain functional imaging studies show that recovery from hemiplegic
      strokes is associated with a marked reorganization of the activation patterns of
      specific brain structures. To regain hand motor control, the recovery process
      tends over time to bring the bilateral motor network activation toward a more
      normal intensity/extent, while overrecruiting simultaneously new areas, perhaps
      to sustain this process. Considerable intersubject variability exists in
      activation/hyperactivation pattern changes over time. Some patients display late
      appearing dorsolateral prefrontal cortex activation, suggesting the development
      of "executive" strategies to compensate for the lost function. The AH in stroke
      often undergoes a significant "remodeling" of sensory and motor hand somatotopy
      outside the "normal" areas, or enlargement of the hand representation. The UH
      also undergoes reorganization, although to a lesser degree. Although absolute
      values of the investigated parameters fluctuate across subjects, secondary to
      individual anatomic variability, variation is minimal with regards to
      interhemispheric differences, due to the fact that individual morphometric
      characters are mirrored in the two hemispheres. Excessive interhemispheric
      asymmetry of the sensorimotor hand areas seems to be the parameter with highest
      sensitivity in describing brain reorganization after a monohemispheric lesion,
      and mapping motor and somatosensory cortical areas through focal TMS, fMRI, PET,
      EEG, and MEG is useful in studying hand representation and interhemispheric
      asymmetries in normal and pathologic conditions. TMS and MEG allow the detection
      of sensorimotor areas reshaping, as a result of either neuronal reorganization or
      recovery of the previously damaged neural network. These techniques have the
      advantage of high temporal resolution but also have limitations. TMS provides
      only bidimensional scalp maps, whereas MEG, even if giving three-dimensional
      mapping of generator sources, does so by means of inverse procedures that rely on
      the choice of a mathematical model of the head and the sources. These techniques
      do not test movement execution and sensorimotor integration as used in everyday
      life. fMRI and PET may provide the ideal means to integrate the findings obtained
      with the other two techniques. This multitechnology combined approach is at
      present the best way to test the presence and amount of plasticity phenomena
      underlying partial or total recovery of several functions, sensorimotor above
      all. Dynamic patterns of recovery are emerging progressively from the relevant
      literature. Enhanced recruitment of the affected cortex, be it spared
      perilesional tissue, as in the case of cortical stroke, or intact but
      deafferented cortex, as in subcortical strokes, seems to be the rule, a mechanism
      especially important in early postinsult stages. The transfer over time of
      preferential activation toward contralesional cortices, as observed in some
      cases, seems, however, to reflect a less efficient type of plastic
      reorganization, with some aspects of maladaptive plasticity. Reinforcing the use
      of the affected side can cause activation to increase again in the affected side
      with a corresponding enhancement of clinical function. Activation of the UH MI
      may represent recruitment of direct (uncrossed) corticospinal tracts and relate
      more to mirror movements, but it more likely reflects activity redistribution
      within preexisting bilateral, large-scale motor networks. Finally, activation of
      areas not normally engaged in the dysfunctional tasks, such as the dorsolateral
      prefrontal cortex or the superior parietal cortex in motor paralysis, might
      reflect the implication of compensatory cognitive strategies. An integrated
      approach with technologies able to investigate functional brain imaging is of
      considerable value in providing information on the excitability, extension,
      localization, and functional hierarchy of cortical brain areas. Deepening
      knowledge of the mechanisms regulating the long-term recovery (even if partial),
      observed for most neurologic sequelae after neural damage, might prompt newer and
      more efficacious therapeutic and rehabilitative strategies for neurologic
      diseases.

PMID- 15029910
TI  - Open reduction of pediatric atlantoaxial rotatory fixation: long-term outcome
      study with functional measurements.
AB  - OBJECT: Atlantoaxial rotatory fixation (AARF) is an uncommon disorder of
      childhood in which resolution usually occurs spontaneously or after traction
      therapy. In a minority of children irreducible or chronic fixation develop, and
      the natural history then usually involves restriction of head on neck movement,
      abnormal head position, and progressive facial asymmetry. The conventional
      management in these cases has been a posterior fusion. METHODS: The authors
      performed an open reduction via the extreme-lateral approach without adjunctive
      fixation surgery in 13 children who ranged in age from 4 to 11 years.
      Postoperatively, halo jacket therapy was undertaken for 8 to 12 weeks. There were
      no neurological complications despite damage to one vertebral artery and one
      wound infection. Functional outcome was assessed after a minimum of 24 months
      (range 29-72 months). Facial asymmetry markedly improved. Sagittal movements were
      similar to those observed in control individuals. Axial rotation, although
      reduced compared with that in controls, was present but usually asymmetrical.
      CONCLUSIONS: In the authors' opinion, open reduction provides the best
      possibility of normal facial development and return of axial movement in cases of
      AARF.

PMID- 15029911
TI  - Retrospective study of surgery-related outcomes in patients with syringomyelia
      associated with Chiari I malformation: clinical significance of changes in the
      size and localization of syrinx on pain relief.
AB  - OBJECT: Pain is one of the major symptoms in patients with syringomyelia;
      however, its origin is not fully understood, and postoperative improvement of
      pain is difficult to predict. The objectives of this study were to assess the
      surgery-related results obtained in patients who underwent treatment for
      syringomyelia associated with Chiari I malformation, particularly related to pain
      status, and to identify factors that may influence improvement in postoperative
      pain by comparing pre- and postoperative magnetic resonance (MR) imaging
      findings. METHODS: The correlation between pre- and postoperative changes in the
      size and the location of the syrinx and pain improvement was investigated in 25
      patients. The shapes of the syringes were classified into three types: central,
      enlarged, and deviated. In most cases in which the syrinx deviated toward the
      posterolateral aspect of the spinal cord at the level corresponding to dermatomal
      distribution of preoperative pain, the lesion remained at the same position
      postoperatively, and improvement in pain was poor. On the other hand, enlarged
      type syringes were the most frequently observed prior to surgery, exhibited
      diverse changes postoperatively, and improvement in pain status was difficult to
      predict. When postoperative MR imaging revealed a transformation to the deviated
      type, poor pain improvement was noted. CONCLUSIONS: Neurons in the dorsal horn
      were thought to be involved in the development of pain as a result of the
      deafferentiation mechanism in cases of syringomyelia.

PMID- 15029912
TI  - Clinical course of patients with ossification of the posterior longitudinal
      ligament: a minimum 10-year cohort study.
AB  - OBJECT: Ossification of the posterior longitudinal ligament (OPLL) may produce
      quadriplegia. The course of future neurological deterioration in patients with
      radiographic evidence of OPLL, however, is not known. The authors conducted a
      long-term follow-up cohort study of more than 10 years to clarify the clinical
      course of this disease progression. METHODS: A total of 450 patients, including
      304 managed conservatively and 146 treated by surgery, were enrolled in the
      study. All patients underwent neurological and radiographical follow-up
      examinations for a mean of 17.6 years. Myelopathy was graded using Nurick
      classification and the Japanese Orthopaedic Association scale. Fifty-five (17%)
      of 323 patients without myelopathy evident at the first examination developed
      myelopathy during the follow-up period. Risk factors associated with the
      evolution of myelopathy included greater than 60% OPLL-induced stenotic
      compromise of the cervical canal, and increased range of motion of the cervical
      spine. Using Kaplan-Meier analysis, the myelopathy-free rate in patients without
      first-visit myelopathy was 71% after 30 years. A significant difference in final
      functional outcome was not observed between nonsurgical and surgical cases in
      which preoperative Nurick grades were 1 or 2. In patients with Nurick Grade 3 or
      4 myelopathy, however, only 12% who underwent surgery eventually became
      wheelchair bound or bedridden compared with 89% of those managed conservatively.
      Surgery proved ineffective in the management of patients with Grade 5 disease.
      CONCLUSIONS: Results of this long-term cohort study elucidated the clinical
      course of OPLL following conservative or surgical management. Surgery proved
      effective for the management of patients with Nurick Grades 3 and 4 myelopathy.

PMID- 15029914
TI  - Safety and efficacy of spinal cord stimulation for the treatment of chronic pain:
      a 20-year literature review.
AB  - OBJECT: The purpose of this report was to examine the available literature to
      determine the safety and efficacy of spinal cord stimulation (SCS) for the
      treatment of chronic pain of the trunk and limbs. METHODS: The author identified
      68 studies that fulfilled the efficacy inclusion/exclusion criteria, grouped on
      the basis of pain indication, with an overall population of 3679 patients. Fifty
      one studies fulfilled all safety inclusion/exclusion criteria. Based on the
      literature review, the author found that SCS had a positive, symptomatic, long
      term effect in cases of refractory angina pain, severe ischemic limb pain
      secondary to peripheral vascular disease, peripheral neuropathic pain, and
      chronic low-back pain, and that, in general, SCS was a safe and effective
      treatment for a variety of chronic neuropathic conditions. CONCLUSIONS: Despite
      the positive findings, there is an urgent need for randomized, controlled, long
      term studies on the efficacy of SCS involving larger patient sample sizes.

PMID- 15029913
TI  - Vascular complications related to lumbar disc surgery.
AB  - OBJECT: Vascular complications related to lumbar disc operations are rare but
      extremely fatal conditions. The authors analyzed data retrospectively obtained in
      13 patients with vascular complications that occurred during lumbar disc
      operations performed between January 1990 and January 2002. METHODS: One patient
      underwent an L5-S1 procedure and the remaining underwent L4-5 surgery. Missed
      injuries, which were found during the late postoperative period, included
      pseudoaneurysm in four cases and an arteriovenous fistula in one. In all cases
      except one in which complication occurred early in the postoperative period, the
      retroperitoneal area was reached via a transperitoneal approach. In eight
      patients with complications occurring early in the postoperative period. Dacron
      graft was placed in four with arterial injuries and saphenous vein graft in one.
      In three cases of arterial injury and five of venous injury, the lesion was
      repaired using the primer suture technique. The most commonly affected vessels
      were left common iliac arteries (76.9%) and left common iliac vein (30.8%). In
      eight early cases, shock or preshock due to hemorrhage developed during the early
      phase. During the late postoperative period, graft-related infection occurred in
      two cases in which Dacron graft was placed, and axillofemoral extraanatomical
      bypass surgery was later performed. There was no surgery-related death. During a
      mean follow-up period of 5.6 years, none of the patients suffered any problems
      related to vascular injury. CONCLUSIONS: Despite its low incidence, iatrogenic
      vascular injury related to lumbar disc surgery is a possible complication. During
      lumbar disc operations early diagnosis of vascular injuries and urgent
      transperitoneal surgery can save patients' lives.

PMID- 15029915
TI  - Biomechanical evaluation of cervical lateral mass fixation: a comparison of the
      Roy-Camille and Magerl screw techniques.
AB  - OBJECT: The purpose of this study was to assess human cervical spine pullout
      force after lateral mass fixation involving two different techniques: the Roy
      Camille and the Magerl techniques. Although such comparisons have been conducted
      previously, because of the heterogeneity of results and the importance of this
      procedure in clinical practice, it is essential to have data derived from a
      prospective and randomized biomechanical study involving a sufficient sample of
      human cervical spines. The authors also evaluated the influence of the sex, the
      vertebral level, the bone mineral density (BMD), the length of bone purchase, and
      the thickness of the anterior cortical purchase. METHODS: Twenty-one adult
      cervical spines were harvested from fresh human cadavers. Computerized tomography
      was performed before and after placing 3.5-mm titanium lateral mass screws from C
      3 to C-6. Pullout forces were evaluated using a material testing machine. The
      load was applied until the pullout of the screw was observed. A total of 152
      pullout tests were available, 76 for each type of screw fixation. The statistical
      analysis was mainly performed using the Kaplan-Meier survival method. The mean
      pullout force was 266 +/- 124 N for the Roy-Camille technique and 231 +/- 94 N
      for the Magerl technique (p < 0.025). For the C3-4 specimen group, Roy-Camille
      screws were demonstrated to exert a significantly higher resistance to pullout
      forces (299 +/- 114 N) compared with Magerl screws (242 +/- 97 N), whereas no
      difference was found between the two techniques for the C5-6 specimen group (Roy
      Camille 236 +/- 122 N and Magerl 220 +/- 86 N). Independent of the procedure,
      pullout strengths were greater at the C3-4 level (271 +/- 114 N) than the C5-6
      level (228 +/- 105 N) (p < 0.05). No significant correlation between the
      cancellous BMD, the thickness of the anterior cortical purchase, the length of
      bone purchase, and maximal pullout forces was found for either technique.
      CONCLUSIONS: The difference between pullout forces associated with the Roy
      Camille and the Magerl techniques was not as significant as has been previously
      suggested in the literature. It was interesting to note the influence of the
      vertebral level: Roy-Camille screws demonstrated greater pullout strength (23%)
      at the C34 vertebral level than Magerl screws but no significant difference
      between the techniques was observed at C5-6.

PMID- 15029916
TI  - Biomechanical comparison of anterior and posterior stabilization methods in
      atlantoaxial instability.
AB  - OBJECT: The authors compared the biomechanical stability of two anterior fixation
      procedures--anterior C1-2 Harms plate/screw (AHPS) fixation and the anterior C1-2
      transarticular screw (ATS) fixation; and two posterior fixation procedures--the
      posterior C-1 lateral mass combined with C-2 pedicle screw/rod (PLM/APSR)
      fixation and the posterior C1-2 transarticular screw (PTS) fixation after
      destabilization. METHODS: Sixteen human cervical spine specimens (Oc-C3) were
      tested in three-dimensional flexion-extension, axial rotation, and lateral
      bending motions after destabilization by using an atlantoaxial C1-2 instability
      model. In each loading mode, moments were applied to a maximum of 1.5 Nm, and the
      range of motion (ROM), neutral zone (NZ), and elastic zone (EZ) were determined
      and values compared using the intact spine, the destabilized spine, and the
      postfixation spine. The AHPS method produced inferior biomechanical results in
      flexion-extension and lateral bending modes compared with the intact spine. The
      lateral bending NZ and ROM for this method differed significantly from the other
      three fixation techniques (p < 0.05), although statistically significant
      differences were not obtained for all other values of ROM and NZ for the other
      three procedures. The remaining three methods restored biomechanical stability
      and improved it over that of the intact spine. CONCLUSIONS: The PLM/APSR fixation
      method was found to have the highest biomechanical stiffness followed by PTS,
      ATS, and AHPS fixation. The PLM/APSR fixation and AATS methods can be considered
      good procedures for stabilizing the atlantoaxial joints, although specific
      fixation methods are determined by the proper clinical and radiological
      characteristics in each patient.

PMID- 15029918
TI  - Spinal meningeal melanocytoma. Report of two cases and review of the literature.
AB  - The authors report on two patients with spinal meningeal melanocytoma and review
      the literature on this lesion. One case is particularly interesting because of
      the lesion's thoracic intramedullary localization. Meningeal melanocytoma is a
      benign but locally aggressive lesion and is very rarely associated with spinal
      localizations. This patient presented with paraparesis. Clinical and radiological
      examinations suggested the possibility of an intramedullary solid tumor. Thoracic
      laminectomy, posterior myelotomy, and tumor resection were performed; the mass
      was totally removed. The patient suffered no additional neurological deficit.
      During a 3-year follow-up period in which radiotherapy was not performed, the
      lesion did not recur. Total excision of the tumor is the best therapeutic option.

PMID- 15029917
TI  - Cervical peridural calcification in patients undergoing long-term hemodialysis.
      Report of two cases.
AB  - The authors report on two patients undergoing long-term hemodialysis in whom
      cervical myelopathy was caused by calcification related to the cervical dural
      sac. The lesions were demonstrated on plain computerized tomography (CT) scans as
      dotted curvilinear bands outlining the dural sacs in almost the whole of their
      cervical spines. During posterior decompressive surgery in both cases, the CT
      scanning--documented curvilinear bands were identified as calcified plaques
      infiltrating the fibrous membranes beneath the ligamenta flava, constricting the
      cervical dural tube. In each case, the spinal cord could not be decompressed by
      merely enlarging the osseous spinal canal; rather, it required removal of the
      calcified membrane from the posterior surface of the dura. Based on the operative
      findings, the lesion should be described as cervical peridural calcification.

PMID- 15029919
TI  - Gadolinium leakage into the surgical bed mimicking residual enhancement following
      spinal cord surgery. Case report.
AB  - Intramedullary spinal cord surgery can disrupt the blood-spinal cord barrier and
      cause intravascular contents to leak into the surgical cavity. Immediate
      postoperative Gd-enhanced magnetic resonance (MR) imaging can demonstrate leakage
      of contrast into the surgical bed and complicate the assessment of whether a
      residual enhancing tumor is present. The authors report a case in which the
      preoperative lesion was nonenhancing and not expected to enhance on postoperative
      imaging. A Gd-enhanced MR imaging study obtained less than 24 hours after surgery
      revealed that the intramedullary surgical cavity was filled with contrast
      material. Because of the time course and the lesion's preoperative appearance,
      this "enhancement" was known to be caused by the leakage of medium into the
      resection cavity rather than of pathological soft-tissue enhancement.

PMID- 15029920
TI  - Sciatic nerve entrapment in the upper thigh caused by an injury sustained during
      World War II at the battle of Anzio. Case report.
AB  - The authors present an unusual case of sciatic nerve entrapment due to a World
      War II shrapnel injury to the left thigh suffered during the battle of Anzio in
      1943. The patient presented for evaluation of left lower-extremity pain in the
      sciatic nerve distribution. Magnetic resonance imaging of the lumbosacral spine
      revealed a disc bulge at L5-S1 that would not explain severe sciatica. A positive
      Tinel sign was present in the posterior aspect of the upper thigh at the site of
      a scar resulting from a World War II shrapnel injury. The patient underwent
      exploratory external neurolysis of the area, and the sciatic nerve was released
      from fibrous adhesive entrapment. The patient improved dramatically following
      surgery. During a 3-year follow-up period, no recurrence of symptoms was noted.

PMID- 15029921
TI  - Radiation-induced malignant triton tumor associated with severe spinal cord
      compression. Case report and review of the literature.
AB  - Malignant triton tumor (MTT) is a variant of malignant peripheral nerve sheath
      tumors. The authors report a case of radiation-induced MTT in a patient with
      severe cervicothoracic cord compression and review the related literature. This
      36-year-old man presented with pain and weakness in his left arm. His medical
      history was significant for a biopsy procedure involving the sampling of an
      aneurysmal bone cyst located at T1-3 near the left lung apex; this was performed
      6 years prior to presentation and was followed by radiotherapy. Neurological
      examination demonstrated radicular findings involving the left C-8 and T-1 nerve
      roots. Neuroimaging studies revealed a large mass lesion extending from C-6 to T
      2 along the vertebral column, invading the upper thoracic cavity and the adjacent
      lung apex, and infiltrating the paravertebral muscles. A subtotal resection was
      performed, but the tumor regrew extensively within a short time. It invaded the
      spinal canal and caused significant cord compression. The patient underwent
      surgery two more times for tumor debulking and to relieve progressive airway and
      spinal canal compromise. He eventually became quadriplegic, however, and died 13
      months after diagnosis of MTT. This is the seventh case of radiation-induced MTT
      and the fifth of MTT with spinal canal involvement to be reported in the
      literature.

PMID- 15029922
TI  - High cervical disc herniation presenting with C-2 radiculopathy. Case report and
      review of the literature.
AB  - The authors report the case of a 78-year-old man with a C2-3 disc herniation that
      had migrated rostrally, causing C-2 radiculopathy. The C-2 radiculopathy
      manifested immediately after the patient underwent placement of a
      ventriculoperitoneal shunt for normal-pressure hydrocephalus. Myelography and
      computerized tomography scanning of the cervical spine revealed an extradural
      lesion anterolateral to the thecal sac eccentric to the right. The patient
      underwent a C1-3 laminectomy, C-2 nerve root decompression, and excision of the
      lesion. Postoperatively the patient's radiculopathy resolved completely. To the
      authors' knowledge, this is the first case of a C2-3 disc herniation manifesting
      as C-2 radiculopathy and treated via a posterior extradural approach.

PMID- 15029923
TI  - Recurrent atlantoaxial rotatory fixation in children: a rare complication of a
      rare condition. Report of four cases.
AB  - Atlantoaxial rotatory fixation (AARF) is an uncommon condition of childhood.
      Occasionally AARF may recur. The authors describe the cases of four patients with
      recurrent AARF (RAARF). The probable cause of the RAARF and operative procedure
      selected are discussed. In three cases, attempts were made to stabilize the
      atlantoaxial complex rather than to perform fusion to preserve the function of
      the joint complex. Joint stabilization is performed by incorporating a "check
      ligament" into the joint construct between the axial spinous process and the
      atlantal lateral mass. The authors believe this technique of joint stabilization
      augments the strength of the joint, allowing normal, but preventing excessive,
      rotation, until the joint reaches physiological maturity.

PMID- 15029924
TI  - Pseudoaneurysm of the thoracic radiculomedullary artery with subarachnoid
      hemorrhage. Case report.
AB  - The authors report a rare case of a patient with a left-sided T-5
      radiculomedullary artery pseudoaneurysm who presented with spinal subarachnoid
      hemorrhage (SAH). The patient, a 71-year-old woman, was hospitalized for
      progressive paraplegia and sensory loss with bladder and rectal dysfunction.
      Computerized tomography scanning revealed an SAH at the posterior fossa. Spinal
      T2-weighted magnetic resonance imaging demonstrated SAH and an inhomogeneous and
      slightly low signal intensity mass at T4-5. Spinal angiography revealed a tiny
      masslike staining without arteriovenous shunting. The resected specimen, which
      caused the spinal SAH, was diagnosed as a pseudoaneurysm based on operative and
      pathological findings.

PMID- 15029925
TI  - Patient advocacy: the real restraint-reduction strategy.

PMID- 15029926
TI  - Repeating the call for restraint reduction.
AB  - Over the past 2 decades, great advances have been made in reducing the use of
      physical restraints in health care facilities. In this article, misconceptions
      and facts related to restraint use are reviewed and restraint reduction
      strategies are presented. Although all those involved in health care are called
      to carefully evaluate restraint use, medical-surgical nurses can take the lead in
      changing restraint practices in the acute care workplace.

PMID- 15029927
TI  - Using a symptom-triggered approach to manage patients in acute alcohol
      withdrawal.
AB  - Nurses working in the medical-surgical setting routinely care for patients
      experiencing acute alcohol withdrawal. Symptom-triggered therapy using the
      revised Clinical Institute Withdrawal Assessment (CIWA-Ar) (Sullivan, Sykora,
      Schneiderman, Naranjo, & Sellers, 1989) is currently recommended. Scoring patient
      symptoms using the CIWA-Ar and educating staff nurses are keys to providing
      consistent management of a patient in acute alcohol withdrawal.

PMID- 15029928
TI  - Care of individuals with Alzheimer's disease in the new millennium.
AB  - The incidence of Alzheimer's disease (AD), the leading form of dementia, is
      expected to increase exponentially in the next 50 years. The nursing and medical
      care of individuals diagnosed with AD, including the health-related challenges
      faced by all aging individuals, are discussed.

PMID- 15029929
TI  - Coaching for competence.
AB  - The preceptors and leadership team on a busy acute care general medical unit
      collaborated on a temporary plan to provide clinical support for 38 nurses who
      had been hired during the year. A pilot role was created and designated "unit
      coach." Each coach questioned and prompted reflective practice in building
      confidence and critical thinking.

PMID- 15029930
TI  - Mentorship: a key to retention and recruitment.
AB  - Currently there is renewed interest in the selection of nursing as a career. As
      nursing education programs graduate more new nurses, the challenge is passed to
      the clinical agencies to provide an environment in which these novice nurses can
      flourish and remain engaged in providing quality nursing care. Mentorship
      programs are essential strategies to retain them in clinical practice as they
      begin their evolution as professional nurses.

PMID- 15029931
TI  - The role of the clinical nurse specialist in medical-surgical nursing.
AB  - A clinical nurse specialist (CNS) is an expert nurse clinician who focuses on
      improving nursing care. The CNS role is the subject of a great deal of debate and
      confusion, but clinical nurse specialists make a valuable contribution to the
      health care team.

PMID- 15029932
TI  - Update on chronic obstructive pulmonary disease.
AB  - Chronic obstructive pulmonary disease is one of the most significant chronic
      illnesses of adults. Comprehensive care of the affected patient requires the
      medical-surgical nurse to have knowledge of the disease process, collaborative
      management, and nursing care based on research and current practice guidelines.

PMID- 15029933
TI  - Women's inhibitors and facilitators associated with making behavioral changes
      after myocardial infarction.
AB  - The researchers interviewed 40 women 6 to 24 months after their first myocardial
      infarction to determine facilitators and barriers to making desired health
      behavioral changes. Nurses at the bedside are in a unique position to discuss the
      importance of attending cardiac rehabilitation with women after myocardial
      infarction, assist them to assess their individualized barriers and facilitators
      to attending, and help them develop strategies to overcome barriers to promote
      attendance.

PMID- 15029935
TI  - Basic concepts to prevent medication calculation errors.

PMID- 15029934
TI  - Nutrition and hydration.

PMID- 15029936
TI  - Earthquakes in management.

PMID- 15029937
TI  - Management of a patient with a forearm fracture and median nerve injury.
AB  - STUDY DESIGN: Case report. OBJECTIVES: Patients with peripheral nerve injury may
      demonstrate long-lasting impairments and functional limitations. In this case
      report, we describe the diagnosis of a patient with a peripheral nerve injury and
      a conventional plan of care, along with the novel intervention of neuromuscular
      electrical stimulation (NMES). We feel that the additional NMES intervention was
      instrumental in achieving more rapid functional improvements than the more
      traditional interventions that are reported in the literature. BACKGROUND: The
      patient was a 21-year-old male who sustained a forearm fracture that was
      complicated by injury to the anterior interosseous branch of the median nerve. He
      was unable to flex the interphalangeal (IP) joint of his thumb, had decreased
      strength of thenar eminence musculature, and was unable to perform fine motor
      activities with his hand. METHODS AND MEASURES: Electrophysiological tests
      revealed partial denervation of the flexor pollicis longus and pronator quadratus
      muscles. In the fifth physical therapy session, NMES to the flexor pollicis
      longus and thenar muscles was added to the patient's conventional plan of care.
      RESULTS: With a conventional ROM and strengthening plan of care, no improvement
      was seen in thumb IP joint flexion over a period of 2 weeks. After 3 sessions of
      NMES and conventional interventions, gains in active ROM were made in thumb IP
      joint flexion. After 9 sessions of NMES and conventional interventions, force of
      thumb IP flexion was registered on a pinch dynamometer. Twenty weeks after
      initial examination, strength and ROM measures had improved and the patient
      reported no functional deficits. CONCLUSIONS: The patient showed gains in
      strength of the thumb IP joint after a few NMES sessions, which suggests that
      NMES was a helpful adjunct to the plan of care, even though the precise mechanism
      underlying the functional gains are not known.

PMID- 15029938
TI  - Assessment of lumbar spine kinematics using dynamic MRI: a proposed mechanism of
      sagittal plane motion induced by manual posterior-to-anterior mobilization.
AB  - STUDY DESIGN: Descriptive study. OBJECTIVE: The purpose of this study was to
      describe the segmental motion of the lumbar spine during a posterior-to-anterior
      (PA) mobilization procedure using dynamic magnetic resonance imaging and to
      propose a mechanism of the lumbar spine's motion as a result of a PA force to a
      lumbar spinous process. BACKGROUND: Studies reporting kinematic descriptions of
      PA mobilization are in agreement that motion takes place at all lumbar vertebrae.
      However, these studies differ in the reported direction of motion. METHODS AND
      MEASURES: Twenty asymptomatic subjects (mean age +/- SD, 31.1 +/- 7.0 years)
      participated in this study. For each subject, a PA mobilization force was
      manually applied at each lumbar spinous process while sagittal plane magnetic
      resonance images were simultaneously obtained. Intervertebral motion was defined
      as the change in the intervertebral angle between the resting and end range
      vertebral positions imparted by the PA pressure. RESULTS: PA force applied at 1
      spinous process caused motion at the target vertebra and this motion was
      propagated caudally and cranially. Motion at the target segment was always into
      extension. CONCLUSIONS: A PA force applied at a single lumbar spinous process
      caused motion of the entire lumbar region. The magnitude and direction of
      intervertebral motions varied with the segment at which the PA force was applied.
      We postulated that the intervertebral motion induced by a PA force on a spinous
      process could be in part explained by the morphology of the lumbar spine.

PMID- 15029939
TI  - The effects of graded forward and backward walking on heart rate and oxygen
      consumption.
AB  - STUDY DESIGN: Single-group repeated-measures design. OBJECTIVES: To compare the
      effects of forward walking (FW) and backward walking (BW) on heart rate (HR) and
      oxygen consumption (VO2) at treadmill grades of 5%, 7.5%, and 10%. BACKGROUND:
      Previous studies of locomotion by humans on a treadmill have reported larger
      cardiovascular exertion and potential biomechanical benefits of BW as compared to
      FW for treadmill grades ranging from 0% to 5%. The present study extends these
      findings by examining the cardiovascular effects of BW and FW at treadmill grades
      greater than 5%. METHODS AND MEASURES: Twenty-nine volunteers participated in
      this study. Two subjects were excluded, leaving 27 study subjects (15 females, 12
      males; mean age +/- SD, 24.0 +/- 3.4 years). VO2 and HR were measured using open
      circuit calorimetry and electrocardiogram, respectively. For both forward and
      backward walking, subjects performed each of the 3 grades for 6 minutes, during
      which HR and VO2 were measured. Two-way repeated-measures ANOVAs were employed
      for inferential statistical analysis. RESULTS: Percent maximum heart rate
      (HR(max)) and percent maximum oxygen consumption (VO2(max)) increased
      incrementally for treadmill grades of 5% to 7.5% to 10% for both FW and BW (P <
      .00001). For each of the 3 treadmill grades, percent HR(max) and percent VO2(max)
      was 17% to 20% higher for BW than for FW (P < .00001). No statistically
      significant interactions were detected between direction of walking and treadmill
      grade. CONCLUSIONS: Backward walking on a treadmill at 67.0 m/min (2.5 mph) and
      grades of 5%, 7.5%, and 10% elicits a greater percent HR(max) and percent
      VO2(max) than does forward walking under the same conditions and, if incorporated
      into sustained training regimens, would be expected to improve aerobic endurance.

PMID- 15029940
TI  - The immediate effects of tension of counterforce forearm brace on neuromuscular
      performance of wrist extensor muscles in subjects with lateral humeral
      epicondylosis.
AB  - STUDY DESIGN: Within-subject repeated-measures study. OBJECTIVES: To examine the
      immediate effects of counterforce forearm brace on isokinetic strenght stretch
      reflex, passive stretching pain threshold of the wrist extensors, and
      proprioception of the wrist in subjects with lateral humeral epicondylosis for
      different strap tensions of a forearm brace. BACKGROUND: Counterforce forearm
      bracing has been used for treating lateral humeral epicondylosis, but the effect
      of brace tension has not been well reported. METHODS AND MEASURES: Fifteen
      subjects diagnosed with lateral humeral epicondylosis on their dominant arm were
      tested under 4 randomized conditions: (1) no brace, (2) brace with minimal
      tension, (3) brace with 25-N tension, and (4) brace with 50-N tension. The tests
      included isokinetic wrist extensors strength, passive stretching force in wrist
      flexion to elicit pain in the wrist extensors, wrist proprioception, and stretch
      reflex latency of the extensor carpi ulnari. A repeated-measures MANOVA was used
      to analyze the data and significant results were further analyzed with post hoc
      linear contrasts (alpha = .05). RESULTS: Among the 4 conditions, significant
      differences were found in wrist proprioception P = .032) and pain threshold to
      passive stretching of the wrist extensors (P = .05), but were not found in wrist
      extension isokinetic strength and stretch reflex latency of the extensor carpi
      ulnaris. CONCLUSION: A forearm counterforce brace, as applied in this study,
      affects wrist joint proprioception and increases the pain threshold to passive
      stretching of the wrist extensors in subjects with lateral humeral epicondylosis,
      but it has no effect on wrist extensor strength and stretch reflex latency of the
      extensor carpi ulnaris.

PMID- 15029941
TI  - Internet use among community college students: implications in designing
      healthcare interventions.
AB  - The Internet has become a commonly used venue for seeking healthcare information.
      Young adults search the Internet for health information more than any other
      group, yet little is known about use patterns among community college students.
      The authors surveyed a diverse community college to assess students' use of the
      Internet for health-related information. More than 80% had home Internet access,
      regardless of race or gender. Men and women searched for health information in
      almost equal numbers. Most students were interested in searching for
      diet/nutrition topics, and least interested in smoking information. Although the
      digital divide appears to be closing, varying levels of interest in a variety of
      important health topics remain. Understanding these differences could guide the
      design of more effective Web-based health interventions.

PMID- 15029942
TI  - Cigarette smoking practices among American college students: review and future
      directions.
AB  - Cigarette smoking among college students is a critical public health problem. In
      this article, the authors review available research on cigarette smoking
      practices among college students and suggest directions for future research.
      Studies show that smoking by college students is associated with being White,
      living in housing where smoking is permitted, using alcohol and other substances,
      and having a lower psychological sense of well-being. Depression, life
      satisfaction, and coping style are also related to college smoking, but the
      causal relationship remains unclear. Although a large proportion of college
      students have made an attempt to quit smoking, only a minority actually succeed.
      Most study designs examining college smoking have been cross-sectional,
      descriptive, or both. Thus, conclusions regarding predictors of smoking onset,
      maintenance, and cessation cannot be made. Future studies should use longitudinal
      designs that can identify psychological and socioenvironmental determinants of
      smoking among college students. Such information could inform the development of
      smoking prevention and cessation interventions targeted to the college student
      population.

PMID- 15029943
TI  - Tobacco, depression, and lifestyle choices in the pivotal early college years.
AB  - The author explored the correlates of tobacco use among 18- and 19-year-old
      students at a major midwestern university. A sample of 203 randomly selected
      freshmen and sophomore students completed a survey that included questions about
      tobacco use, other drug use, mental health issues, eating disorders, stress,
      smoking environment, and healthy lifestyles. The prevalence rate for tobacco use
      was 29% for the past year and 32% for the past month. Multivariate analyses
      suggested that students with a lifetime diagnosis of depression or treatment for
      depression were 7 times as likely as other students to use tobacco. In addition,
      marijuana and alcohol use and weekend exposure to smoke increased the likelihood
      of being a tobacco user. Stress and diet behaviors were found not to be
      significantly associated with tobacco use. Implications for health promotion
      among high school and college populations are drawn from the study findings.

PMID- 15029944
TI  - Occurrence of exercise dependence in a college-aged population.
AB  - Students (n = 257) were evaluated for scope and commitment to physical activity
      by use of self-reported data that assessed amount of activity per week and the
      obligatory or pathological nature of their activity patterns. Exhibiting atypical
      activity patterns, 21.8% of the students in the sample exercised 360 or more
      minutes per week and demonstrated at least one exercise "dependent" response
      pattern to queries about obligatory or pathological exercise. Although clinicians
      and educators should promote the many advantages of regular participation in
      physical activity, they should acknowledge that, for some, it may have
      undesirable consequences that occur at a frequency parallel to other age-related
      negative behaviors.

PMID- 15029945
TI  - Health belief factors and dispositional optimism as predictors of STD and HIV
      preventive behavior.
AB  - Identifying factors predictive of youth's engaging in preventive behaviors
      related to sexually transmitted diseases (STDs) and HIV remains a prominent
      public health concern. The utility of the Health Belief Model (HBM) continues to
      be suggested in identifying preventive behaviors. This study sought to examine
      the full HBM, including self-efficacy, with regard to STD and HIV preventive
      behavioral intentions in college students. Self-efficacy was identified as the
      primary predictor for each of the behavioral intentions (condom use, STD testing,
      and HIV testing), whereas response efficacy was only predictive of testing
      intentions. Inconsistent with HBM assumptions, perceived HIV severity was
      negatively related to HIV testing intentions. Students who perceived HIV as high
      in severity were less likely to intend to obtain HIV testing. Overall, the
      utility of the HBM in predicting college students' sexual preventive behavior was
      unsupported. An argument for a change in the direction of research, away from the
      continued emphasis on the study of cognitive variables, is made.

PMID- 15029946
TI  - Coronary risk assessment of university students in Crete with premature parental
      coronary heart disease.

PMID- 15029947
TI  - The Cysticercosis Working Group in Eastern and Southern Africa meets again.

PMID- 15029948
TI  - Thrombocytopaenia in canine babesiosis and its clinical usefulness.
AB  - Canine babesiosis is a common cause of thrombocytopaenia but there are few formal
      studies that have investigated this haematological finding in dogs. Thrombocyte
      counts from full blood counts were retrospectively analysed for the years 1996
      2002. Thrombocyte counts and mean platelet volumes of dogs with babesiosis were
      compared with those of dogs, seen over the same period of time, that did not have
      babesiosis. There were 1162 cases in the Babesiosis group and 10 808 in the Non
      babesiosis group. A frequency distribution of the thrombocyte counts showed a
      trimodal distribution in the Non-babesiosis group compared to a bimodal
      distribution in the Babesiosis group, with a strong positive skewness. The modes
      for the frequency distributions were 10, 40, 300 and 10, 35 x 10(9)/l
      thrombocytes, respectively. The median thrombocyte count in the Babesiosis group
      was 14 x 10(9)/l and 282 x 10(9)/l in the Non-babesiosis group. There was a
      statistically significant difference in the median thrombocyte count between the
      Babesiosis group and the Non-babesiosis group. In the Babesiosis group, 99% of
      the thrombocyte counts were below the lower reference range value (250 x 10(9)/l)
      and 62% of thrombocyte counts were below 25 x 10(9)/l. The mean platelet volume
      (11.1 fl) for the Babesiosis group was greater than the reference range (6-10 fl)
      and significantly larger than in the Non-babesiosis group (median 9.7 fl).
      Thrombocyte counts greater than 110 and 250 x 10(9)/l had a predictive value that
      the dog was not suffering from babesiosis of 99.3% and 99.8%, respectively. There
      was a statistically significant difference between the thrombocyte counts of dogs
      with babesiosis when grouped by parasitaemia scores. The mechanisms of the
      thrombocytopaenia are not fully understood, and multiple mechanisms, including
      concomitant thrombocytopaenia-inducing diseases such as ehrlichiosis, probably
      result in this haematological finding. Babesiosis in the South African canine
      population is associated with thrombocytopaenia in nearly all patients and is
      severe in the majority of them. In the absence of thrombocytopaenia, babesiosis
      is an unlikely diagnosis.

PMID- 15029949
TI  - The effects of diminazene aceturate on systemic blood pressure in clinically
      healthy adult dogs.
AB  - Diminazene aceturate is a commonly used antibabesial agent. It has been
      postulated that diminazine may induce a decrease in blood pressure and exacerbate
      the hypotension presented in dogs with babesiosis. This study was undertaken to
      assess the effect of diminazine aceturate on the blood pressure of healthy dogs.
      Six healthy German shepherd dogs between 18 and 24 months of age with a mean
      weight of 30.4 +/- 2.75 kg were used. Blood pressure was directly measured at the
      following time intervals: -5, 0, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 90 and
      120 minutes after treatment with diminazine aceturate (4.2 mg/kg)
      intramuscularly. No statistical difference (P > 0.05) was found in blood pressure
      between any of the time intervals. An increase in heart rate was seen 5 minutes
      after the administration of diminazine aceturate but no change in blood pressure
      was evident. This study concluded that diminazene aceturate in its current
      formulation with antipyrine does not alter blood pressure in healthy adult dogs.

PMID- 15029950
TI  - A survey of zoonotic diseases contracted by South African veterinarians.
AB  - A survey of 88 veterinarians employed at the Faculty of Veterinary Science,
      University of Pretoria, South Africa, was carried out to investigate the
      occurrence of zoonotic diseases among South African veterinarians. The survey
      found that 63.6% of veterinarians interviewed had suffered from a zoonotic
      disease. Veterinarians predominantly involved in farm animal practice were 3
      times more likely to have contracted a zoonotic disease than those working in
      other veterinary fields. Fifty-six percent of disease incidents were initially
      diagnosed by the veterinarians themselves. Fifty-three percent of incidents
      required treatment by a medical practitioner, but the majority (61%) of incidents
      did not require absence from work. The incidence density rate for contracting a
      zoonotic disease was 0.06 per person year of exposure. Kaplan-Meier survival
      analysis estimated that the probability of having contracted a zoonotic disease
      was 50% after 11 years in practice. The risk of contracting a zoonotic disease
      appeared to be higher early in practice. The most common mode of transmission was
      by direct contact. Approximately 46% of South Africans still live in rural areas
      and regularly come into close contact with farm animals. The implications of this
      in the light of this survey's results are discussed.

PMID- 15029951
TI  - The prevalence of subclinical gastroduodenal ulceration in Dachshunds with
      intervertebral disc prolapse.
AB  - Endoscopy was used to determine the prevalence of subclinical gastroduodenal
      ulceration in 30 Dachshunds undergoing decompressive surgery for acute
      intervertebral disc prolapse. The endoscopy was performed on the day of admission
      and on the 3rd or 4th day after surgery. Three regions of the stomach (cardia,
      corpus and pylorus) and the proximal duodenum were visually inspected and biopsy
      samples were taken for histopathology. The combination of visual and microscopic
      changes were then used to determine the prevalence of subclinical gastroduodenal
      ulceration in this population. An overall prevalence of 76% was calculated from
      these findings. Ulcerogenic medication administered prior to admission did not
      appear to influence the prevalence. This result identifies a need for
      veterinarians to be aware of this potentially severe complication and warrants
      the use of prophylactic anti-ulcer medication in spinal surgery patients.

PMID- 15029953
TI  - Ultrasonographic diagnosis of unilateral ectopic ureter in a Labrador dog.
AB  - A 3-month-old, Labrador bitch presented with urinary incontinence. A unilateral,
      ectopic ureter was diagnosed with ultrasound without the aid of additional
      contrast radiographic techniques. Ipsilateral hydroureter and mild hydronephrosis
      were also present. At the level of the bladder trigone the ectopic ureter became
      intramural and this was clearly demonstrable with ultrasound. The opening of the
      ectopic ureter into the proximal urethra was, however, not visualised owing to
      its intrapelvic location.

PMID- 15029952
TI  - Anthelmintic resistance of nematodes in communally grazed goats in a semi-arid
      area of South Africa.
AB  - A survey was conducted on the occurrence of anthelmintic resistance of nematodes
      in communally grazed goats in a semi-arid area in South Africa. In herds
      belonging to 10 small-holder goat farmers, the efficacies of fenbendazole,
      levamisole and rafoxanide were tested by faecal egg count reduction (FECR) tests.
      Efficacies of 80% were considered a threshold for anthelmintic resistance. The
      FECR tests showed that all drugs tested more than 80% effective in most
      instances, but there were notable exceptions. In 1 case, rafoxanide was only 31%
      effective and in another case fenbendazole was only 47% effective. The occurrence
      of anthelmintic resistance in this farming sector is of concern. Steps should be
      taken to prevent its further spread and to avoid the development of a situation
      as on numerous commercial sheep farms in South Africa where resistance is very
      common.

PMID- 15029954
TI  - Identification of a gene for UDP-sulfoquinovose synthase of a green alga,
      Chlamydomonas reinhardtii, and its phylogeny.
AB  - Sulfoquinovosyl diacylglycerol is responsible for the structural and functional
      integrity of the photosystem II complex of a green alga, Chlamydomonas
      reinhardtii. We cloned a cDNA of C. reinhardtii containing an open reading frame
      for a protein 36-64% identical in the primary structure to known UDP
      sulfoquinovose synthases, which are required for SQDG synthesis, in other
      organisms. Through the introduction of the cDNA, a cyanobacterial disruptant as
      to the UDP-sulfoquinovose synthase gene recovered the ability to synthesize
      sulfoquinovosyl diacylglycerol, thus confirming that the cDNA encodes the UDP
      sulfoquinovose synthase. On the genome, the cDNA was divided into 14 exons, and
      the gene designated as SQD1 was present as one copy. The molecular phylogenetic
      tree for the UDP-sulfoquinovose synthase showed grouping of C. reinhardtii
      together with species that require sulfoquinovosyl diacylglycerol for the
      functioning of the PSII complex, but not with those that do not utilize the lipid
      for photosynthesis. The role of sulfoquinovosyl diacylglycerol in the functioning
      of the photosynthetic membranes might evolve in harmony with the system of the
      membrane lipid synthesis such as UDP-sulfoquinovose synthase gene.

PMID- 15029955
TI  - Comprehensive analysis of NAC family genes in Oryza sativa and Arabidopsis
      thaliana.
AB  - The NAC domain was originally characterized from consensus sequences from petunia
      NAM and from Arabidopsis ATAF1, ATAF2, and CUC2. Genes containing the NAC domain
      (NAC family genes) are plant-specific transcriptional regulators and are
      expressed in various developmental stages and tissues. We performed a
      comprehensive analysis of NAC family genes in Oryza sativa (a monocot) and
      Arabidopsis thaliana (a dicot). We found 75 predicted NAC proteins in full-length
      cDNA data sets of O. sativa (28,469 clones) and 105 in putative genes (28,581
      sequences) from the A. thaliana genome. NAC domains from both predicted and known
      NAC family proteins were classified into two groups and 18 subgroups by sequence
      similarity. There were a few differences in amino acid sequences in the NAC
      domains between O. sativa and A. thaliana. In addition, we found 13 common
      sequence motifs from transcriptional activation regions in the C-terminal regions
      of predicted NAC proteins. These motifs probably diverged having correlations
      with NAC domain structures. We discuss the relationship between the structure and
      function of the NAC family proteins in light of our results and the published
      data. Our results will aid further functional analysis of NAC family genes.

PMID- 15029957
TI  - Differential profiles of genes expressed in neonatal brain of 129X1/SvJ and
      C57BL/6J mice: A database to aid in analyzing DNA microarrays using nonisogenic
      gene-targeted mice.
AB  - Strain-specific differences in gene expression have been observed among various
      inbred mouse strains. Two strains that are commonly used in gene-targeting
      research today are the 129 substrains, which are used to produce ES cell lines,
      and C57BL/6J, which is used for the extensive backcrosses required to produce
      isogenic knockout mice. When F2 nonisogenic littermates are assessed using DNA
      microarrays, one must determine whether the expression profiles obtained resulted
      either from specific alteration(s) induced by the targeted gene mutation or from
      gene expression differences related to the genetic background of the parent mouse
      strains. In the present study, we report the differential expression profile of
      genes expressed in neonatal brains and adult spleen and liver of 129X1/SvJ and
      C57BL/6J strains of mice. These comprehensive profiles were assessed using two
      types of Agilent Mouse Oligo Microarrays (development and standard) and were
      compiled into a publicly available database. Researchers can use this database to
      determine whether their microarray findings represent strain-specific differences
      in gene expression by comparing their data with those cataloged in our database.
      This database is useful for effectively analyzing DNA microarray data from
      nonisogenic littermates, and would help researchers avoid time-consuming
      backcrosses and confirmatory experiments requiring the use of many mice.

PMID- 15029956
TI  - Genomics approach to abscisic acid- and gibberellin-responsive genes in rice.
AB  - We used an 8987-EST collection to construct a cDNA microarray system with various
      genomics information (full-length cDNA, expression profile, high accuracy genome
      sequence, phenotype, genetic map, and physical map) in rice. This array was used
      as a probe to hybridize target RNAs prepared from normally grown callus of rice
      and from callus treated for 6 hr or 3 days with the hormones abscisic acid (ABA)
      or gibberellin (GA). We identified 509 clones, including many clones that had
      never been annotated as ABA-or GA-responsive. These genes included not only ABA-
      or GA-responsive genes but also genes responsive to other physiological
      conditions such as pathogen infection, heat shock, and metal ion stress.
      Comparison of ABA- and GA-responsive genes revealed antagonistic regulation for
      these genes by both hormones except for one defense-related gene, thionin. The
      gene for thionin was up-regulated by both hormone treatments for 3 days. The
      upstream regions of all the genes that were regulated by both hormones had cis
      elements for ABA and GA response. We performed a clustering analysis of genes
      regulated by both hormones and various expression profiles that showed three
      notable clusters (seed tissues, low temperature and sugar starvation, and thionin
      gene related). A comparison of the cis-elements for hormone response genes
      between rice and Arabidopsis thaliana, we identified cis-elements for dehydration
      stress response or for expression of amylase gene as Arabidopsis gene-specific or
      rice gene-specific, respectively.

PMID- 15029958
TI  - Structural analysis of a Lotus japonicus genome. V. Sequence features and mapping
      of sixty-four TAC clones which cover the 6.4 mb regions of the genome.
AB  - We determined the nucleotide sequences of 64 TAC (transformation-competent
      artificial chromosome) clones selected from genomic libraries of Lotus japonicus
      accession Miyakojima MG-20 based on the sequence information of expressed
      sequence tags (ESTs), cDNAs, genes and DNA markers from L. japonicus and other
      legumes. The length of the DNA regions sequenced in this study was 6,370,255 bp,
      and the total length of the L. japonicus genome sequenced so far is 32,537,698 bp
      together with the nucleotide sequences of 256 TAC clones previously reported.
      Five hundred forty-eight potential protein-encoding genes with known or predicted
      functions, 127 gene segments and 224 pseudogenes were assigned to the newly
      sequenced regions by computer prediction and similarity searches against the
      sequences in protein and EST databases. Based on the nucleotide sequences of the
      clones, simple sequence repeat length polymorphism (SSLP) or derived cleaved
      amplified polymorphic sequence (dCAPS) markers were generated, and each clone was
      genetically localized onto the linkage map of two accessions of L. japonicus, MG
      20 and Gifu B-129. The sequence data, gene information and mapping information
      are available through the World Wide Web at http://www.kazusa.or.jp/lotus/.

PMID- 15029959
TI  - Polymorphic 33-bp repeats with promoter-like activity in synaptotagmin 11 gene.
AB  - In the immediate upstream region of the transcription initiation site of human
      synaptotagmin 11 gene, we found a tandem repeat of a 33-bp unit with a promoter
      like activity. The tandem repeat is apparently polymorphic in the Japanese
      population as two DNA samples from 60 schizophrenia patients exhibited an
      increased number (three) of the unit. In a transfection assay using constructs
      with different numbers of repeats, the promoter-like activity was found to
      increase with the number of repeating unit.

PMID- 15029960
TI  - Dealing with death in man and animals.

PMID- 15029961
TI  - Current intake of veterinary students 'only just sustainable'.

PMID- 15029963
TI  - Breeding German sheep for resistance to scrapie.
AB  - Susceptibility to clinical scrapie is associated with polymorphisms in the prion
      protein (PrP) gene. The ARR allele reduces susceptibility to clinical disease
      caused by all known strains of the transmissible spongiform encephalopathy (TSE)
      agents. For the economically important German breeds of sheep the PrP allele
      frequencies are well known, but this paper presents representative genotyping
      results for 1526 sheep from two smaller milk sheep breeds and 2446 sheep from 14
      mostly indigenous land sheep breeds. The ARR allele was detected in each breed
      but the breed-specific ARR frequencies varied between 1 and 63 per cent. In small
      populations with a very low ARR frequency the ARR allele could be lost by genetic
      drift. A simulation study was therefore made to examine the effects of different
      breeding schemes in populations of different sizes on attempts to select for the
      ARR allele in an endangered population. In breeds in which no homozygous rams are
      available the breeding strategy would depend on the number of heterozygous rams,
      and the genotyping and selection of suitable breeding ewes would reduce the time
      required to achieve a highly resistant population. In general, in all the breeds
      a selection programme to achieve 99 per cent ARR homozygous genotypes would be
      feasible in six to nine generations, depending on the initial allele frequencies.
      In small populations the inbreeding rate may increase if no specific mating plans
      are developed by the breeding organisations.

PMID- 15029964
TI  - Retrospective analysis of 50 cases of guttural pouch tympany in foals.
AB  - Between 1994 and 2001, guttural pouch tympany was diagnosed in 51 foals; there
      were approximately three times as many fillies as colts, of Arabian, different
      German warmblood breeds and Western horse breeds. There were significantly more
      Arabian and paint horse foals than expected in comparison with the breed
      distribution of the foals hospitalised at the Clinic for Horses. The foals' breed
      and sex did not influence the age of onset, the type and severity of the clinical
      signs or the recurrence rate. A surgical laser technique was used on 50 of the
      foals; in 35 cases only one surgical treatment was necessary, in seven cases a
      second operation was required during the foal's initial period of
      hospitalisation, and in eight cases a second operation was performed during a
      second period of hospitalisation. Long-term follow-up information was obtained
      for 44 of the 50 treated horses; 24 of them were under two years of age and 20
      were over two years of age. In six horses, no follow-up information was
      available. Four horses were euthanased for reasons unrelated to the condition or
      its treatment. The horses over two years of age were in training or were being
      used for competitions in dressage or jumping or for breeding purposes, and in
      only one of them was an adventitious respiratory noise reported. All the horses
      up to two years of age were reported to be healthy.

PMID- 15029965
TI  - Influence of diet on the experimental infection of pigs with Brachyspira
      pilosicoli.
AB  - The effects of five different diets on the experimental infection of pigs with a
      Danish field isolate of Brachyspira pilosicoli were investigated. The diets
      tested were a pelleted and a non-pelleted standard diet based on wheat and
      barley, the standard diet supplemented with 2 per cent lactic acid, a fermented
      liquid feed and a diet based on cooked rice. Two trials were conducted, each with
      six groups of six pigs; in each, two of the groups were fed the standard diet.
      One of these groups and the other four groups were challenged after two weeks on
      the diets and euthanased four weeks later. The clinical signs of B pilosicoli
      infection varied from loose stools to watery, mucoid diarrhoea. The group fed the
      rice diet excreted B pilosicoli in their faeces for a significantly shorter
      period than the group fed the standard diet (P < 0.01), and fewer of them
      excreted the organism (P < 0.05). All the pigs fed the pelleted diet excreted B
      pilosicoli in their faeces, and significantly more of them showed clinical signs
      of disease than the pigs fed the standard diet (P < 0.05). The fermented liquid
      feed and the diet containing lactic acid had no significant effect on the
      excretion of B pilosicoli or on the numbers of pigs showing clinical signs of
      disease.

PMID- 15029966
TI  - Mastitis due to Nocardia asteroides in a UK dairy herd following restocking after
      FMD.

PMID- 15029967
TI  - Natural killer-like T cell lymphoma in a cat.

PMID- 15029968
TI  - Acute haemorrhagic leucoencephalitis in a Californian sea lion (Zalophus
      californianus).

PMID- 15029969
TI  - Ultrasonographic findings in a cow with ascites due to a mesothelioma.

PMID- 15029970
TI  - Veterinary medicines.

PMID- 15029971
TI  - Veterinary surveillance.

PMID- 15029972
TI  - Quantitative estimates of the risk of new outbreaks of foot-and-mouth disease as
      a result of burning pyres.

PMID- 15029973
TI  - Farm assurance and animal health plans in Scotland.

PMID- 15029974
TI  - Veterinary hospital or animal hospital?

PMID- 15029975
TI  - Veterinary hospital or animal hospital?

PMID- 15029976
TI  - Investigation of faecal pathogens in a flock of mute swans (Cygnus olor).

PMID- 15029978
TI  - Stolen dogs.

PMID- 15029979
TI  - Vetting spelling.

PMID- 15029980
TI  - Vetting spelling.

PMID- 15029981
TI  - Expanding role?

PMID- 15029982
TI  - Target blood pressure for patients with type 2 diabetes is difficult to achieve
      in the setting of a busy diabetes clinic.
AB  - BACKGROUND: Target blood pressure control in patients with type 2 diabetes should
      be 130/85 mmHg or less; however, it is not clear how achievable this target is in
      clinical practice. AIM: To assess the adequacy of blood pressure control in
      patients with type 2 diabetes attending a busy outpatient clinic. METHODS: One
      hundred and eight patients with type 2 diabetes were assessed for the presence of
      hypertension using a cut-off value of 130/85 mmHg. Antihypertensive treatment and
      diabetic complications were evaluated. RESULTS: Hypertension was present in 67%
      of patients, in whom 90% were receiving anti-hypertensive treatment. Forty-nine
      per cent of the treated patients achieved target blood pressure. Of the
      undertreated patients, 55% were on one antihypertensive agent, 30% were on two
      agents and 15% were on three or more agents. The corresponding figures for the
      adequately treated patients were 28%, 31% and 41%, respectively (p=0.03).
      CONCLUSION: Adequate blood pressure control was underachieved in this patient
      group underlying the difficulty in treating blood pressure to target values in
      patients with type 2 diabetes in the setting of outpatient diabetes clinics. A
      more aggressive strategy, in particular the use of multiple antihypertensive
      agents should be adopted.

PMID- 15029983
TI  - Controlled trial of maintenance treatment of intravenous buprenorphine
      dependence.
AB  - BACKGROUND: Buprenorphine dependence is a relatively novel addiction. AIMS: To
      compare the treatment outcome in three groups over 12-weeks of treatment.
      METHODS: Two hundred and four intravenous (i.v.)-buprenorphine-dependent patients
      were randomised into three groups. Subjects received 50 mg oral methadone tablet,
      or 5 mg sublingual buprenorphine tablet, or 50 mg oral naltrexone, and a weekly
      30-minute clinical counselling session. RESULTS: The majority (80%) had a history
      of opium or heroin dependency before they were introduced to i.v. buprenorphine.
      The main source of buprenorphine for misusers was street sale (91%). The mean
      duration of buprenorphine dependence was 1.9 years and the mean dose per day was
      3.9 ampoules (1 ampoule contains 0.3 mg of buprenorphine in 1 ml). Overall 59% of
      the patients completed the 12-week study. Retention in the 50 mg methadone group
      was significantly better than the 5 mg dose buprenorphine group (p=0.001) and the
      50 mg dose naltrexone group (p=0.000). Retention in the 5 mg buprenorphine group
      was significantly better than the 50 mg naltrexone dose group (p=0.000).
      CONCLUSIONS: These results support the efficacy and safety of oral methadone and
      sublingual buprenorphine tablets for injection buprenorphine-dependent patients.

PMID- 15029985
TI  - Intra-aortic balloon pump in patients with ischaemic heart disease undergoing
      oesophagogastrectomy.
AB  - BACKGROUND: Oesophagogastrectomy for carcinoma has a high operative mortality
      rate. Patients are elderly and ischaemic heart disease (IHD) is a recognised and
      frequent risk factor. AIM: To illustrate the use of the intra-aortic balloon pump
      (IABP) as prophylaxis against cardiac complications in a group of such patients.
      METHODS: Five patients aged from 63 to 78 years were presented with operable
      adenocarcinoma of the oesophagus. They had IHD of a severity thought to pose a
      risk of myocardial infarction (MI) and/or failure at the time of
      oesophagogastrectomy. With the induction of anaesthesia, the IABP was inserted
      and left in situ for up to 24 hours. RESULTS: There were no major adverse
      perioperative cardiac events. Four patients were discharged from hospital on the
      eighth and one on the tenth postoperative day. CONCLUSION: The prophylactic use
      of IABP has a potential role in the prevention of cardiac complications in
      patients with IHD undergoing high risk non-cardiac surgery.

PMID- 15029984
TI  - Management of Barrett's oesophagus in 2001 in Ireland.
AB  - BACKGROUND: Endoscopic surveillance of patients with Barrett's oesophagus is
      recommended to detect early carcinoma. The practice patterns of endoscopists
      since the publication of more recent management guidelines remain unknown.
      METHODS: All endoscopists (n=68) in the Irish Medical Directory and their
      trainees were sent a postal questionnaire on Barrett's surveillance. RESULTS:
      Fifty-five per cent (30/54) perform surveillance on all patients with Barrett's
      oesophagus and 38% on selected patients. In patients with no dysplasia, repeat
      endoscopy was more commonly practiced annually (28/54) than every two to three
      years (23/54). Surgeons were more likely to perform surveillance annually than
      gastroenterologists (75% vs 40%). Only 26% of endoscopists took four-quadrant
      biopsies every 2 cm. Intervention was recommended by a majority (28/54) of
      endoscopists in a patient with high grade dysplasia. A majority of respondents
      (47/54) would have surveillance if they were found to have Barrett's oesophagus.
      CONCLUSION: Most endoscopists in Ireland do not adhere to recent guidelines in
      their management of Barrett's oesophagus. Surgical endoscopists perform
      surveillance more frequently than their medical colleagues.

PMID- 15029986
TI  - The spectrum of urological disease in patients with spina bifida.
AB  - BACKGROUND: [corrected] Urological complications are the major cause of ill
      health during childhood and adult life of patients with spina bifida but the
      significance of urinary tract disease on the individual and the healthcare
      services is underemphasised. AIM: To assess the effects of spina bifida on the
      individual and the healthcare services. METHODS: A retrospective review was
      performed to assess the frequency and significance of urological conditions
      requiring hospital attendance in patients with spina bifida currently attending a
      specialised multidisciplinary clinic over a period of six months. RESULTS:
      Urinary sepsis accounted for the majority of admissions (62%), while 38 of 62
      patients required 60 surgical procedures. Targeting the primary urological
      abnormality (the dysfunctional and usually poorly compliant bladder) allows
      implementation of effective treatments, including regular intermittent bladder
      catherisation (52%) in order to preserve upper renal tract function. Associated
      postural abnormalities complicated both conservative and interventional
      therapies. CONCLUSION: This study highlights the surgical commitment for units
      caring for patients with spina bifida, the important considerations for the
      future healthcare services, and the range and severity of urological diseases
      encountered by these patients.

PMID- 15029988
TI  - Benzodiazepines inhibit the rate of neutrophil apoptosis.
AB  - BACKGROUND: Benzodiazepines, which are commonly administered perioperatively, can
      depress immune function. Neutrophil apoptosis plays a central role in the
      regulation of inflammation. This is particularly important during and after
      surgery. AIM: To examine the effects of benzodiazepines (midazolam and diazepam)
      on neutrophil apoptosis. METHODS: Venous blood samples were withdrawn from
      patients scheduled to undergo elective surgery, (a) immediately prior to, and 10
      minutes after administration of midazolam 0.2 mg/kg intravenously (n=11) and (b)
      immediately prior to, and 60 minutes after administration of diazepam 10 mg p.o.
      (n=10). Neutrophil apoptosis was measured by Annexin V-FITC after 1 and 12 hours
      in culture. RESULTS: The percentage of apoptotic cells was significantly less
      after midazolam at 12% (11.9) hours in culture compared to pre-midazolam 29.7%
      (13.3) (p<0.05). After diazepam, the rates of neutrophil apoptosis were also
      significantly less after 12 hours in culture (p<0.05). CONCLUSION: Administration
      of benzodiazepines in clinically relevant doses inhibits neutrophil apoptosis. In
      the perioperative period, this may influence the inflammatory response to
      surgery.

PMID- 15029987
TI  - Current concepts and recent advances in the management of age-related macular
      degeneration.
AB  - BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of visual
      impairment and blindness in the Western World in those aged 65 and older. At
      present, several treatment modalities are utilised and several more are
      undergoing investigation in an attempt to retard the occurrence and progression
      of this devastating condition. AIMS: To provide the non-ophthalmologist with an
      understanding of the current treatment options available to patients suffering
      from all variants of AMD. METHODS: Medline and Embase search. RESULTS: Several
      treatment modalities have been investigated and utilised in the treatment of all
      variants of this condition. While promising results have been reported, no
      treatment is ideal. CONCLUSION: While no curative treatment for this condition
      currently exists, early recognition and treatment, if indicated, have been shown
      to reduce the risk of severe vision loss in patients with this condition.

PMID- 15029989
TI  - Risperidone compared with olanzapine in a naturalistic clinical study in Ireland:
      a cost analysis.
AB  - BACKGROUND: Risperidone and olanzapine are thought to have similar clinical
      effects. This study was designed to compare costs of treatment. AIM: To compare
      costs of treatment with risperidone or olanzapine in a naturalistic setting.
      METHOD: The Irish Risperidone Olanzapine Drug Outcomes studies in Schizophrenia
      (RODOS) programme was a retrospective review of medical notes and prescription
      charts in 396 inpatients with schizophrenia or schizoaffective disorder. The main
      outcome measure was cost of inpatient drug treatment. RESULTS: There was no
      statistical difference in length of hospital stay between risperidone-treated and
      olanzapine-treated patients (mean duration of stay 37.8 and 40.5 days, p=0.90).
      Mean+/-SD doses of risperidone and olanzapine were 4.2+/-2.1 mg/day and 12.9+/
      5.0 mg/day, respectively. Average daily cost of all inpatient drugs was
      significantly higher for olanzapine than for risperidone (i.e. IEP5.61 [7.12] vs
      IEP3.38 [4.29]; p<0.0001), as was mean total costs of all inpatient drugs (i.e.
      IEP114.8 [145.8] vs IEP62.0 [78.7]; p<0.0001). This partly reflected the mean,
      non-significant, longer treatment duration for olanzapine compared with
      risperidone (mean 30.0 vs 26.4 days; p=0.27). Concomitant neuroleptic use was
      similar for both groups (71% risperidone, 73% olanzapine; p=0.54). CONCLUSION:
      Risperidone was associated with significantly lower drug treatment costs.

PMID- 15029990
TI  - A novel treatment for chronic pancreatitis.
AB  - BACKGROUND: Hereditary pancreatitis is an important cause of chronic
      pancreatitis, which may result in endocrine and exocrine failure. This may
      necessitate simultaneous pancreas and kidney transplant (SPK). Bladder drainage
      of the exocrine secretions may cause problems. AIM: To report one such case and
      its surgical correction. METHODS: A 20-year-old male with insulin-dependent
      diabetes mellitus secondary to idiopathic chronic pancreatitis had a SPK with
      bladder drainage. Urological and metabolic complications secondary to the
      drainage of pancreatic secretions, rich in proteolytic enzymes required
      convertion from bladder to enteric drainage. RESULTS: He was able to discontinue
      his pancreatic enzyme supplements, ceased to have steatorrhoea and gained weight.
      He was referred to the European Registry of Hereditary Pancreatitis and Familial
      Pancreatic Cancer (EUROPAC), hereditary pancreatitis was confirmed by genetic
      analysis. CONCLUSION: Enteric-drained pancreas transplantation is a successful
      treatment for exocrine as well as endocrine pancreatic failure and should be
      considered as a treatment option in patients with chronic pancreatitis.

PMID- 15029991
TI  - Pulmonary cystic hydatid disease in Ireland.
AB  - BACKGROUND: Hydatid disease is rare in Ireland and its incidence and prevalence
      are unknown. Most cases are diagnosed by a combination of clinical findings,
      morphological features on imaging and by serological testing. AIMS: We describe
      an Irish case of pulmonary hydatid disease detected at bronchoscopy by
      bronchoalveolar lavage, and discuss the diagnosis and treatment of the disorder.
      CONCLUSION: The diagnosis of this rare disease requires a high index of
      suspicion. Treatment is primarily surgical, with a role for antihelminthic
      agents.

PMID- 15029992
TI  - Arytenoid subluxation.
AB  - BACKGROUND: Disruption of the cricoarytenoid joint is uncommon and possibly
      underdiagnosed. AIM: To highlight the diagnosis of arytenoid subluxation and its
      management. METHOD: Two case reports. CONCLUSION: Arytenoid subluxation is a rare
      condition that should always be considered in patients presenting with symptoms
      following upper airway instrumentation or external trauma to the neck. Early
      diagnosis optimises the possibility of restoring normal voice and laryngeal
      function.

PMID- 15029993
TI  - Medicine in the Third World--a student's perspective.

PMID- 15029995
TI  - Bilateral quadriceps tendon rupture.

PMID- 15029994
TI  - Images from Waves--photoelastic modelling of bones. 8th Samuel Haughton Lecture,
      Bioengineering Section of Royal Academy of Medicine in Ireland. January 2002.
AB  - BACKGROUND: This paper cites the development of the principles of photoelastic
      stress analysis, contemporary to the life of Samuel Haughton. Subsequent studies
      of bone and joint replacements are discussed, with reference to hypotheses
      regarding bone, including the coincidence of trabecular structure with principal
      stresses. Issues regarding assumptions of homogeneous and isotropic properties in
      photoelastic modelling are acknowledged. AIM: Awareness of photoelastic methods
      is often through the visual appeal of the coloured fringe patterns. The aim of
      this paper is to complement this awareness by demonstration of the quantitative
      analyses that may be conducted through biomechanical examples. METHODS: Examples
      of new pseudo three-dimensional model analyses are presented together with a
      method for photoelastic study of cancellous bone, which entails novel procedures
      for preparation of replicate models and for optical evaluation of fringes.
      CONCLUSION: Photoelastic analysis offers novel solutions to studies in
      biomechanics, which are facilitated by contemporary modelling materials.

PMID- 15029996
TI  - Body piercing and endocarditis in children.

PMID- 15029997
TI  - Transient cortical blindness in impending eclampsia.

PMID- 15029998
TI  - Plasmodium chabaudi chabaudi chronic malaria and pathologies of the urogenital
      tract in male and female BALB/c mice.
AB  - BALB/c mice of both sexes were infected with a non-virulent strain of Plasmodium
      chabaudi chabaudi and any pathologies occurring in the urogenital tract and its
      accessory glands were investigated. Organs and tracts were removed from infected
      and control mice at 15, 40 and 100 days post-injection, weighed and processed for
      macroscopical and histological analyses. The relative weights of preputial,
      clitoral glands and testes were modified in infected mice during the 40 days
      following infection. The preputial glands show a marked hypotrophy at 15 days
      post-infection. The bladders of half of the infected female mice and a few
      infected male mice displayed a conspicuous haemoglobinuria and frequent
      interstitial cystitis that worsened throughout the experiment. Also, several
      chronic inflammatory reactions were detected in the prostates, preputial and
      clitoral glands up to 100 days post-infection. A probable cause of such a
      divergence in the characteristics of the infection and in the nature of the
      pathologies identified in infected male and female mice is the interaction
      between the infection and the immune and endocrine systems of the host. The cause
      of the pathologies and their consequences on the host condition are discussed.

PMID- 15029999
TI  - Natural IgM antibodies in sera from various animals but not the cat kill
      Toxoplasma gondii by activating the classical complement pathway.
AB  - Sera from swine, rabbit, and dog, that had never been exposed to Toxoplasma
      gondii, demonstrated significant killing of T. gondii tachyzoites in vitro, while
      cat serum did not. Swine and rabbit sera contained natural IgM antibody against
      the tachyzoites, and the classical complement pathway was activated by the
      binding of natural IgM antibody to the tachyzoites, leading to lysis. Anti-T.
      gondii antibodies, induced in swine or cat infected with T. gondii, had no
      killing effect by themselves but killed the tachyzoites in the presence of swine
      complement. However, the anti-T. gondii antibodies of swine or cat demonstrated a
      very low killing effect in the presence of cat complement. This suggests that T.
      gondii tachyzoites have an evasion mechanism to prevent lysis which is specific
      for cat complement.

PMID- 15030000
TI  - In vitro titration of Theileria parva tick derived stabilates.
AB  - Immunization against the protozoan Theileria parva by infection and treatment has
      proved to be very efficient for the control of East Coast fever, an acute and
      often-fatal lymphoproliferative tick-borne disease of cattle in Eastern, Central
      and Southern Africa. The immunizing dose of live T. parva sporozoites used in
      this method is usually determined by in vivo titration. An alternative in vitro
      method of quantification of sporozoites in whole tick-derived stabilates is
      proposed. The method consists of incubating serially diluted T. parva stabilates
      with bovine peripheral blood lymphocytes, the host cell that is infected
      naturally. Allowing the cultures to incubate undisturbed for the full cultivation
      period (10 days) reduced the variability among replicate titrations. Fungal
      contaminations were avoided by centrifuging stabilates at 400 g prior to the
      incubation, which did not precipitate sporozoites significantly. Fungistatics,
      Nystatin and Flucytosine, did not appear to interfere with the in vitro
      development of T. parva but their effect on fungal growth was limited. In vitro
      titration data were compared to in vivo infection data for 2 stabilates. In vitro
      titration of T. parva sporozoites should allow more ethical and efficient
      research on the preparation and storage of T. parva tick-derived stabilates.

PMID- 15030001
TI  - Molecular and immunological characterization of L14 ribosomal protein from
      Leishmania braziliensis.
AB  - The isolation and molecular characterization of the gene coding for L14 ribosomal
      protein from L. braziliensis is described. There are 2 copies of the gene per
      haploid genome, repeated in a head-to-tail tandem orientation and located in a
      single chromosome of approximately 950 kb. Northern blot analyses indicate the
      presence of a single transcript of 0.95 kb which is up-regulated when parasites
      reach the stationary growth phase. L. braziliensis L14 gene codes for a 175 amino
      acid long polypeptide showing 75-83% sequence identity with L14 proteins from
      trypanosomatids and approximately 25% with its counterparts from higher
      eukaryotic organisms. L14 ribosomal proteins from trypanosomatids and higher
      eukaryotes share along their molecules a similar distribution pattern of
      theoretically functional domains. L. braziliensis L14 recombinant protein is not
      recognized by sera from cutaneous leishmaniasis patients. Immunization of mice
      with one dose of L14 recombinant protein and a second dose of L14 protein
      covalently linked to the HSP70 from Trypanosoma cruzi induces a high antibody
      level against this L14 protein, which is mostly of the IgG2a subtype, as well as
      a strong increase in splenocyte proliferation index.

PMID- 15030002
TI  - The vertical transmission following the reactivation of a Neospora caninum
      chronic infection does not seem to be due to an alteration of the systemic immune
      response in pregnant CBA/Ca mice.
AB  - The factors responsible for the reactivation of a Neospora caninum latent
      infection are unknown, but it is postulated that the maternal immune response
      could be altered during pregnancy. The immune response was investigated in N.
      caninum chronically infected mice during successive pregnancies as well as in non
      pregnant infected mice and mice infected when pregnant. Vertical transmission was
      demonstrated in chronically infected mice after the first pregnancy but the rate
      of foetal infection fell after further pregnancies. Non-pregnant chronically
      infected mice showed a marked specific proliferative response and an IgG2a
      isotype preferential secretion. During the course of the first pregnancy, no
      significant modification of the immune response was recorded. After 2 successive
      pregnancies, the specific cellular response showed a significant fall whereas Th2
      cytokine mRNA expression was noted. At the same time, IgG1 secretion increased to
      reach the IgG2a level. At the third delivery, a partial restoration of the
      proliferative response was observed. The reactivation of N. caninum chronic
      infection during pregnancy does not seem to be consecutive to an
      immunodepression. Nevertheless, pregnancy could favour parasite multiplication in
      utero after an occasional spontaneous release of bradyzoites.

PMID- 15030003
TI  - Trypanosoma cruzi isolates from Chile are heterogeneous and composed of mixed
      populations when characterized by schizodeme and Southern analyses.
AB  - In total, 61 Chilean isolates of Trypanosoma cruzi, were analysed using
      schizodeme and Southern analysis, using as probes the highly variable regions of
      minicircles from cloned parasites. Isolates were collected and amplified from
      domestic and wild triatomines, and from infected subjects in all the endemic
      areas of Chile. Three major parasite genotypes could be detected in the domestic
      transmission cycle, whilst 1 major T. cruzi genotype is circulating in the wild
      transmission cycle. Schizodeme analysis suggested that T. cruzi isolates are
      mixed populations, whereas the Southern analyses detected only 3 mixed isolates
      using 4 selected minicircle segments as probes.

PMID- 15030004
TI  - The effect of various metals on Gyrodactylus salaris (Platyhelminthes, Monogenea)
      infections in Atlantic salmon (Salmo salar).
AB  - Atlantic salmon (Salmo salar) parr (age 0+), infected by the ectoparasite
      Gyrodactylus salaris, were exposed to aqueous aluminium (Al), copper (Cu), zinc
      (Zn), iron (Fe) and manganese (Mn), at 4 different concentrations. There was a
      negative correlation between G. salaris infections and metal concentrations in
      both Zn- and Al-exposed salmon. In the Zn-experiment, all 4 concentrations tested
      caused a decrease in the G. salaris infections, while in the Al-experiment the G.
      salaris infection did not decline at the lowest concentration. The number of G.
      salaris increased continuously during the experiments in all control groups, and
      in all groups exposed to Cu, Fe and Mn. At the highest concentration, however,
      copper seemed to impair the growth of G. salaris infection. The results show that
      aqueous Al and Zn are environmental factors of importance controlling the
      distribution and abundance of the pathogen G. salaris. Other pollutants might
      also have an influence on the occurrence of G. salaris. Finally, the results
      demonstrate that aqueous Al and Zn have a stronger effect on the parasite than on
      the salmonid host, suggesting that both metals may be used as a pesticide to
      control ectoparasites such as G. salaris.

PMID- 15030005
TI  - The impact of sexual selection on Corynosoma magdaleni (Acanthocephala)
      infrapopulations in Saimaa ringed seals (Phoca hispida saimensis).
AB  - In free-living animals sexual selection is a central force shaping the spatial
      distribution of individuals in a population as well as sexual size dimorphism. We
      studied the influence of sexual selection on spatial distribution, female-to-male
      body size ratio, and female mating success of acanthocephalans in a natural host
      population of Saimaa ringed seal (Phoca hispida saimensis) harbouring a single
      intestinal helminth species, Corynosoma magdaleni. The acanthocephalans were
      always found along the full length of the small intestine; however, the site
      selection varied among the individual seals according to the age of the
      infection. The distribution of male acanthocephalans was not random with respect
      to females, with larger males tending to aggregate around non-mated females. A
      higher proportion of C. magdaleni females had copulated in seals with relatively
      more male worms. Male-male competition for access to females can be intense in C.
      magdaleni infrapopulation and may select for large males. We found that the
      larger the infrapopulation size, the smaller the males compared to females. In
      addition, the greater the female bias in the infrapopulation, the smaller the
      testes of males. Our study shows that sexual selection may be an important
      determinant of spatial distribution, male body size and female mating success of
      C. magdaleni in Saimaa ringed seal.

PMID- 15030006
TI  - Study on the ecological distribution of alveolar Echinococcus in Hulunbeier
      Pasture of Inner Mongolia, China.
AB  - A study on the ecological distribution of alveolar Echinococcus was carried out
      in the Hulunbeier Pasture of Inner Mongolia, China during 1998 and 1999. Animals
      examined included wolves (Canis lupus), red foxes (Vulpes vulpes), sand foxes
      (Vulpes corsac), domestic dogs (Canis familiaris), Microtus brandti, Meriones
      unguiculatus, Citellus dauricus, Allactaga sibirica, Phodopus sungorus and
      Ochotona daurica. Three wolves were found to be infected with E. granulosus. Two
      sand foxes were infected with E. multilocularis. The majority of infections of
      alveolar echinococcus was found in M. brandti. Based on the structure of
      metacestodes found in the livers of naturally infected M. brandti, 3 main
      variants were observed. Type I had small alveolar cysts with thin cyst walls.
      Type II had a larger cyst with a thick cyst wall. Infection of laboratory mice
      with the gravid segments isolated from the naturally infected sand foxes led to
      the formation of mature Type I alveolar metacestodes in the lungs and Type II
      metacestodes in the livers of infected animals, respectively.

PMID- 15030007
TI  - A cathepsin F of adult Clonorchis sinensis and its phylogenetic conservation in
      trematodes.
AB  - A novel 28 kDa cysteine protease (Cs28CF) secreted by the hepatobiliary
      trematode, Clonorchis sinensis was identified. The protease was purified from the
      excretory-secretory products (ESP) of the adult worm using DEAE-ion exchange and
      Arginine-Sepharose 4B chromatography. It showed a high activity between pH 6.5
      and 7.5 in a dithiothreitol (DTT)-dependent manner. Inhibitors specific to
      cysteine proteases down-regulated the activity. Addition of Cs28CF to monkey
      cholangiocyte cultures resulted in approximately 95% cell death after 7 days. The
      full-length cDNA (1078 bp) encoded a single peptide of 328 amino acids (aa) with
      an N-terminal hydrophobic sequence, an ERFNAQ motif in the propeptide and a
      mature domain. Expression of mRNA transcripts of Cs28CF was observed in both the
      metacercaria and adult stages. Bacterially expressed recombinant protein
      exhibited a specific antibody reaction with clonorchiasis sera. Deduced aa
      exhibited 52-76% sequence identity with the cathepsin F analogues from other
      organisms. A novel E/DXGTA motif was recognized in the propeptide region.
      Phylogenetic analysis of 63 papain family members revealed that the trematode
      cysteine proteases formed 2 major clades of cathepsins F and L. The trematode
      cysteine proteases classified as cathepsin F shared higher homology among
      themselves than those classified as cathepsin L. Cathepsin F is phylogenetically
      conserved in the trematode parasites as well as in mammals.

PMID- 15030009
TI  - Parasite dose, prevalence of infection and local adaptation in a host-parasite
      system.
AB  - Parasites have been found to be more infective to sympatric hosts (local
      adaptation) in some systems but not in others. The variable nature of results
      might arise due to differences in host and/or parasite migration rates, parasite
      virulence, specificity of infection, and to differences in the dose-response
      functions. We tested this latter possibility by manipulating the dose of
      trematode (Microphallus sp.) eggs on sympatric and allopatric host populations
      (Potamopyrgus antipodarum). We found that infection rapidly increased to a high
      asymptote (0.88 +/- 0.02, 1 S.E.) in the sympatric host population, but
      infections were low and surprisingly unrelated to dose in the allopatric host. We
      also found that host survival and growth rate were not negatively affected by
      increasing parasite dose in either population. These results suggest that
      defences in the allopatric host were not overwhelmed at high parasite doses, and
      that any life-history costs of defence are not plastic responses to parasite
      dose.

PMID- 15030008
TI  - Trichinella spiralis thymidylate synthase: cDNA cloning and sequencing, and
      developmental pattern of mRNA expression.
AB  - The persistent expression of thymidylate synthase activity has previously been
      demonstrated not only in adult forms, but also in non-developing muscle larvae of
      Trichinella spiralis and T. pseudospiralis, pointing to an unusual pattern of
      cell cycle regulation, and prompting further studies on the developmental pattern
      of T. spiralis thymidylate synthase gene expression. The enzyme cDNA was cloned
      and sequenced, allowing the characterization of a single open reading frame of
      307 amino acids coding for a putative protein of 35,582 Da molecular weight. The
      amino acid sequence of the parasite enzyme was analysed, the consensus
      phylogenetic tree built and its stability assessed. The aa sequence identity with
      thymidylate synthase was confirmed by the enzymatic activity of the recombinant
      protein expressed in E. coli. As compared with the enzyme purified from muscle
      larvae, it showed apparently similar Vmax value, but higher Km(app) values
      desscribing interactions with dUMP (28.8 microM vs. 3.9 microM) and (6RS,alphaS)
      N(5,10)-methylenetetrahydrofolate (383 microM vs. 54.7 microM). With the coding
      region used as a probe, thymidylate synthase mRNA levels, relative to 18S rRNA,
      were found to be similar in muscle larvae, adult forms and newborn larvae, in
      agreement with muscle larvae cells being arrested in the cell cycle.

PMID- 15030010
TI  - Echinococcus granulosus strain typing in North Africa: comparison of eight
      nuclear and mitochondrial DNA fragments.
AB  - Recent studies of Echinococcus granulosus molecular strain typing have enabled a
      better understanding of the transmission cycle of cystic echinococcosis. There
      have been many publications in this area but there is a need for the evaluation
      of these tools. We have attempted to respond to this need in our study, which
      assessed 8 DNA fragments of 40 E. granulosus cysts from North Africa.
      Parasitological material was collected from 5 types of intermediate hosts, in 5
      different countries. The primers chosen to amplify DNA targets were defined
      either in nuclear DNA, or in mitochondrial DNA. After amplification, PCR products
      were sequenced. The sequences obtained were aligned and comparisons were made
      within the group and with GenBank sequences. Whether the target was nuclear or
      mitochondrial, the same 2 main groups of genotypes were found. The first one, the
      'sheep' strain, was found in the human, sheep and cattle samples collected in
      North Africa. The second one, the 'camel' strain, was found in the camel cysts
      and cattle and human cysts from Mauritania. These findings further confirm the
      congruence of the data given by the nuclear and the mitochondrial genome.

PMID- 15030011
TI  - The availability of socially marketed condoms in urban Tanzania, 1997-99.
AB  - The objective of this study was to evaluate trends in the availability of
      socially marketed condoms in urban Tanzania, and to assess the effect of changes
      in the social marketing programme's strategy for distributing condoms to retail
      outlets. Three retail outlet surveys conducted in urban Tanzania in 1996/97, 1998
      and 1999 were analysed. Multiple Classification Analysis (MCA) was used to
      determine changes in availability of condoms, after adjusting for differences in
      the composition of the samples. Consistent with the changes in the condom social
      marketing distribution system, the proportion of condom outlets that were
      supplied by wholesalers increased from 42% in 1997 to 60% in 1999. The increasing
      use of wholesalers allowed sales agents to devote more time to opening new
      outlets. Hence, the percentage of outlets that had been solicited to sell condoms
      by social marketing condom sales persons increased from 14% in 1997 to 25% in
      1999. Following these changes in the distribution system, the percentage of
      outlets selling socially marketed condoms increased from 25% to 32% between 1997
      and 1998, and stabilized at that level. More detailed examination showed that
      availability of socially marketed condoms increased significantly in most non
      traditional outlets, and in all regions of the country. In conclusion,
      distribution survey data indicate that changes in the distribution system
      increased the role of wholesalers, and enabled sales teams to allocate more time
      to soliciting new condom outlets. Concurrent with these changes, the availability
      of socially marketed condoms in non-traditional retail outlets increased
      significantly. Regular monitoring of condom availability can ensure that any
      emerging supply problems are identified and remedied quickly.

PMID- 15030012
TI  - Psychosocial and demographic determinants of regional differences in the
      prevalence of obesity.
AB  - Differences in the prevalence of obesity between adjacent regions are quite
      common, but usually unexplained. This study examined whether birth place,
      selective migration, intelligence or education--which are both inversely and
      possibly causally related to obesity--are determinants of such differences. This
      population-based case-control study (case-cohort design) took place in the
      greater Copenhagen area (region 1) and surrounding provincial areas of Zealand
      (region 2), Denmark. A total of 2948 men with a median age of 19 years from two
      draft board regions during 1966-1977 were examined. The odds ratio (OR) for being
      obese (defined as body mass index > or = 31 kg/m2) was investigated using
      multiple logistic regression analyses. The OR for being obese in region 2
      compared with region 1 was 1.74 (1.50-2.03). Adjustment for birth place,
      intelligence test score and educational level reduced the OR to 1.42 (1.10-1.82).
      The OR for being obese for those born in region 2 compared with region 1 was 1.71
      (1.46-2.01). Adjustments for intelligence test score, educational level and
      examination region reduced this OR to 1.13 (0.87-1.46). Irrespective of birth
      place, men examined in region 2 had a higher OR for being obese than those
      examined in region 1; this effect was most pronounced for those born in region 2
      and examined in either region 1 or 2, with an OR of 1.06 (0.71-1.57) and 1.87
      (1.58-2.22) respectively. In conclusion, the regional differences in the
      prevalence of obesity could not be explained by birth place or later selective
      migration, but educational level and intelligence test score did explain some of
      the difference.

PMID- 15030013
TI  - Pathways of the determinants of unfavourable birth outcomes in Kenya.
AB  - This paper explores the pathways of the determinants of unfavourable birth
      outcomes, such as premature birth, the size of the baby at birth, and Caesarean
      section deliveries, in Kenya using graphical log-linear chain models. The results
      show that a number of factors that do not have direct associations with
      unfavourable birth outcomes contribute to these outcomes indirectly through
      intermediate factors. Marital status, the desirability of a pregnancy, the use of
      family planning and access to health facilities have no direct associations with
      poor birth outcomes, such as premature births and the small size of the baby at
      birth, but are linked to these outcomes through antenatal care. Antenatal care is
      identified as a central link between various sociodemographic or reproductive
      factors and birth outcomes.

PMID- 15030014
TI  - Increasing pre-term and low-birth-weight rates over time and their impact on
      infant mortality in south-east Brazil.
AB  - This study investigates the possible effects of pre-term births and low birth
      weight on infant mortality rates (IMRs) over a 15-year period in Ribeirao Preto,
      Brazil, based on surveys carried out in 1978/79 and 1994. The 1978/79 survey
      included 6750 births over a 12-month period and the 1994 survey 2846 births over
      a 4-month period. Infant deaths were retrieved monthly from the city register.
      Infant mortality rate decreased from 36.6 to 16.9 deaths per 1000 over 15 years.
      The decrease in IMR was larger in the 2500-2999 g group than in any other group.
      The observed falls in IMR were attributable to decreases in birth-weight-specific
      mortality rates. Likewise, there was a general decrease in IMR in mild, moderate
      and severe pre-term births. The incidence rate ratio of infant mortality between
      surveys was 0.46 (95% CI 0.34-0.63); it increased to 0.57 (95% CI 0.35-0.75) when
      adjusted for birth weight and other factors in the model and rose to 0.69 (95% CI
      0.49-0.97) when adjusted for length of gestation and other variables. The
      increase in pre-term births and low birth weight may have had, at most, a
      marginal effect on the IMR. Progress in the care of newborns may have decreased
      the mortality risk, but even mild pre-term birth still has an impact on infant
      mortality. There is room for further improvement in IMR by tackling the high
      rates of pre-term birth.

PMID- 15030015
TI  - Husband involvement in the treatment of child illness in Guatemala.
AB  - The aim of this study is to test prevailing assumptions that Guatemalan men are
      authoritative or aloof husbands and, in turn, are either problematic or
      irrelevant to child health. Based on survey data collected in 1994-95 about 959
      children, this research examines whether, how and why husbands were involved in
      recent episodes of young children's illness and sheds light on the potential
      effect of husband involvement on treatment. A relatively high percentage of women
      reported that they asked for advice or assistance from their husbands regarding
      child illness, and, contrary to popular notions, the multivariate analyses
      suggest that husbands' involvement was not driven by their household authority.
      Rather, key determinants of whether husbands gave advice or assistance included
      characteristics of the illness and child and the availability of sources of
      social support, while key determinants of what kind of support husbands gave
      (namely whether they gave/bought medicines, recommended a provider visit, or gave
      other advice or assistance) largely related to characteristics of the illness and
      child, as well as the availability of biomedical health care providers in the
      community and ethnicity.

PMID- 15030016
TI  - Obesity and the rate of time preference: is there a connection?
AB  - It is hypothesized that recent trends in US and worldwide obesity are, in part,
      related to an increase in the marginal rate of time preference, where time
      preference refers to the rate at which people are willing to trade current
      benefit for future benefit. The higher the rate of time preference, the larger is
      the factor by which individuals discount the future health risks associated with
      current consumption. Data from the United States, as well as international
      evidence, suggest that a relationship between these two variables is plausible.
      The authors encourage researchers to explore the possible link between obesity
      and time preference, as important insights are likely to result.

PMID- 15030017
TI  - Consanguinity, caste and deaf-mutism in Punjab, 1921.
AB  - The effects of religion, population sub-division and geography on the prevalence
      of deaf-mutism were investigated using information collected in the 1921 Census
      of Punjab. The total sample size was 9.36 million, and comprised data on thirteen
      Hindu castes, seventeen Muslim biraderis and two Sikh castes. A two-way analysis
      of variance comparing males in Hindu castes in which consanguineous marriage was
      prohibited, with males in Muslim biraderis which favoured first cousin marriage,
      indicated major differences with respect to the patterns of deaf-mutism within
      each religion. In the Muslim population 9.1% of the relative variation in the
      prevalence of deaf-mutism was inter-biraderi, 36.8% between geographical regions,
      and 48.8% an interaction between biraderi and region, whereas among Hindus 46.8%
      of the observed variation was inter-caste, 12.8% inter-region and 33.6% due to
      caste region interaction. From a wider disease perspective the results obtained
      with the Hindu community indicate the significant genetic differentiation
      associated with caste endogamy. As the overwhelming majority of Hindu marriages
      continue to be within-caste, it can be predicted that similar levels of inter
      caste differences in disease frequency currently exist. By comparison, the lower
      level of inter-biraderi variation among Muslims is probably indicative of the
      dissolution of pre-existing caste boundaries and the resultant gene pool mixing
      that followed the large-scale conversion of Hindus to Islam during Muslim rule in
      North India from the 13th to the 19th centuries.

PMID- 15030018
TI  - Evidence of phenotypic and social assortative mating for anthropometric and
      physiological traits in couples from the Basque country (Spain).
AB  - This study examined 28 anthropometrical and physiological traits in 107 married
      couples living in the province of Biscay (Basque Country, Spain). The aim was to
      verify the existence of a phenotypic and/or social preference when choosing a
      mate. For this, correlations between pairs of spouses were estimated by maximum
      likelihood, and a model of familial transmission (path analysis) was applied in
      order to test if social homogamy between mates existed. The results provide
      significant evidence of phenotypic as well as social homogamy in several of the
      studied traits. Even if an assortment existed when choosing a mate for bony
      traits such as height, the effect of cohabitation cannot be discounted as the
      main causal factor for the high phenotypic resemblance observed between spouses
      for body composition traits. In addition, with the social homogeneity of the
      studied sample, significant evidence of the existence of social homogamy between
      mates was only found for 20% of the studied variables.

PMID- 15030019
TI  - The ethics of silence.

PMID- 15030020
TI  - Invisibility, moral knowledge and nursing work in the writings of Joan Liaschenko
      and Patricia Rodney.
AB  - The ethical 'eye' of nursing, that is, the particular moral vision and values
      inherent in nursing work, is constrained by the preoccupations and practices of
      the superordinate biomedical structure in which nursing as a practice discipline
      is embedded. The intimate, situated knowledge of particular persons who construct
      and attach meaning to their health experience in the presence of and with the
      active participation of the nurse, is the knowledge that provides the evidence
      for nurses' ethical decision making. It is largely invisible to all but other
      nurses. Two nurse researchers, Joan Liaschenko of the University of Minnesota and
      Patricia Rodney of the University of Victoria, have investigated the ethical
      concerns of practising nurses and noted in their separate enquiries the invisible
      nature of critical aspects of nursing work. Noting the similarities in their
      respective observations, and with the feminist ethics of Margaret Urban Walker as
      a theoretical framework, this article examines the concept of 'invisibility' as
      it relates to nursing work and nursing ethics.

PMID- 15030021
TI  - Moral professional personhood: ethical reflections during initial clinical
      encounters in nursing education.
AB  - Moral agency is an important constituent of the nursing role. We explored issues
      of ethical development in Greek nursing students during clinical practice at the
      beginning of their studies. Specifically, we aimed to explore students' lived
      experience of ethics, and their perceptions and understanding of encountered
      ethical conflicts through phenomenological analysis of written narratives. The
      process of developing an awareness of personal values through empathizing with
      patients was identified as the core theme of the students' experience. Six more
      common themes were identified. Development of the students' moral awareness was
      conceptualized as a set of stages, commencing with empathizing with patients and
      nurses, moving on to taking a moral stand and, finally, concluding by becoming
      aware of their personal values and showing evidence of an emerging professional
      moral personhood. The notions of empathy, caring and emotion were in evidence
      throughout the students' experience. Implications for practice and nurse
      education are discussed.

PMID- 15030022
TI  - 'The demolition of a man': lessons from Holocaust literature for the teaching of
      nursing ethics.
AB  - The events of the Holocaust of European Jews (and others) by the Nazi state
      between 1939 and 1945 deserve to be remembered and studied by the nursing
      profession. By approaching literary texts written by Holocaust 'survivors' from
      an interpersonal dimension, a reading of such works can develop an 'ethic of
      responsibility'. By focusing on such themes as rationality, duty, witness and the
      virtues, potential lessons for nurses working with people in a variety of
      settings can be drawn. Implications for the teaching of nursing ethics are made
      in the areas of the virtues, relationships, professional ethics and the moral
      community of nursing.

PMID- 15030023
TI  - A survey of ethical issues experienced by nurses caring for terminally ill
      elderly people.
AB  - This study examined the ethical issues experienced by nurses working in a small
      group of elderly persons' care settings in the UK, using a survey questionnaire
      previously used in other countries for examining the cultural aspects of ethical
      issues. However 'culture' relates not only to ethnicity but also the
      organizational culture in which care is delivered. Nurses working in elderly
      persons' care settings described a range of issues faced when caring for elderly
      terminally ill people, which illustrated the different needs of patients,
      relatives, professionals and society. These issues related to the unique needs of
      elderly people (such as dementia sufferers) and could have an impact on patients'
      quality of death.

PMID- 15030024
TI  - Finnish nurses' views on end-of-life discussions and a comparison with
      physicians' views.
AB  - This study investigated Finnish nurses' experiences and views on end-of-life
      decision making and compared them with physicians' views. For this purpose, a
      questionnaire was sent to 800 nurses, of which 51% responded. Most of the nurses
      had a positive attitude towards and respect for living wills, more often than
      physicians. Most also believed that a will had an effect on decision making.
      Almost all of the nurses considered it their responsibility to talk to physicians
      about respecting living wills. Do-not-resuscitate (DNR) orders were often
      interpreted to imply partial or complete palliative (symptom-orientated) care,
      which may cause confusion. Half of the nurses reported that a DNR decision was
      discussed always or often with a patient who was able to communicate; physicians
      were more positive in this respect. Surprisingly, many nurses (44%) stated that
      active treatment continued too long. Two-thirds thought that their opinions were
      taken into account sufficiently, even though only half believed that, in general,
      they had some impact.

PMID- 15030025
TI  - Meeting ethical challenges in acute care work as narrated by enrolled nurses.
AB  - Five enrolled nurses (ENs) were interviewed as part of a comprehensive
      investigation into the narratives of registered nurses, ENs and patients about
      their experiences in an acute care ward. The ward opened in 1997 and provides
      patient care for a period of up to three days, during which time a decision has
      to be made regarding further care elsewhere or a return home. The ENs were
      interviewed concerning their experience of being in ethically difficult care
      situations and of acute care work. The method of phenomenological-hermeneutic
      interpretation inspired by the French philosopher Paul Ricoeur was used. The most
      prominent feature was the focus on relationships, as expressed in concern for
      society's and administrators' responsibility for health care and the care of
      older people. Other themes focus on how nurse managers respond to the ENs' work
      as well as their relationships with fellow ENs, in both work situations and
      shared social and sports activities. Their reflections seem to show an
      expectation of care as expressed in their lived experiences and their desire for
      a particular level and quality of care for their own family members. A lack of
      time could lead to a bad conscience over the 'little bit extra' being omitted.
      This lack of time could also lead to tiredness and even burnout, but the system
      did not allow for more time.

PMID- 15030027
TI  - Nongovernmental organizations (NGOs) in Japan and the 'Hermit Crabs' Home' mental
      health project.

PMID- 15030026
TI  - A sense of life: the future of industrial-style health care.
AB  - In this article I attempt to transcend the mainstream conception of health care
      ethics, including nursing ethics, by bringing into the foreground a tension
      between a sense of life and an industrial-bureaucratic style of health care, with
      its emphasis on the systematic and procedural work culture necessary for mass
      production. I use the concept of 'a sense of life' to draw attention to the
      wisdom, sensitivity and responsibility that is necessary for the authentic care
      of others to be given a chance in the development of modern health care. I
      emphasize the mindfulness that the professional requires for genuine care, and
      how the systematic organization of modern health care, on the whole, ignores,
      obstructs and even suppresses such mindfulness.

PMID- 15030029
TI  - What is the association between Helicobacter pylori and hyperammonemia in liver
      disease?

PMID- 15030030
TI  - Gastric carcinoids--a changing trend.
AB  - OBJECTIVE: Gastric carcinoids (GC) are rare tumors. Recent studies have reported
      a higher frequency of GC, with these constituting 10%-30% of all carcinoid
      tumors. We have observed GC more frequently at our institute in recent years than
      in the past. METHODS: Endoscopy reports from January 1997 to June 2003 were
      reviewed to identify patients with GC. For these patients, biopsy specimens were
      reviewed and details of clinical features were extracted from case records.
      RESULTS: Seventeen patients with GC (aged 27 to 76 years; 11 men) were
      identified; in comparison, there had been only 8 cases in the previous 16 years.
      Of these, 14 patients had multiple tumors; these were located in the fundus (n =
      6), fundus and proximal body (4), and body (4) of the stomach. Three patients had
      solitary tumors in the antrum. The tumor size ranged from pinhead to 4 cm.
      Etiologically, 13 patients had type 1 GC (associated with chronic atrophic
      gastritis type A), one had type 2 GC (associated with Zollinger-Ellison syndrome;
      multiple endocrine neoplasia 1) and three had type 3 GC (sporadic). Treatment
      included total gastrectomy (2), distal gastrectomy (2), tumor excision (1),
      endoscopic polypectomy (3), and vitamin B12 supplementation with surveillance
      (9). CONCLUSION: Our data show an increase in diagnosis of GC, similar to reports
      from Western countries. The rise is in the proportion of GC associated with
      atrophic gastritis. Whether this reflects a higher frequency of detection due to
      more endoscopic biopsy sampling or due to some other reason needs investigation.

PMID- 15030031
TI  - Helicobacter pylori-associated gastritis and gastric cancer in Nigeria.
AB  - BACKGROUND: The etiology of gastric cancer has not been clearly delineated. There
      is some evidence of an association of gastric cancer with Helicobacter pylori
      induced chronic gastritis, atrophic gastritis and intestinal metaplasia. Previous
      studies report a high rate of H. pylori infection and chronic gastritis among
      Nigerians. METHODS: We retrospectively reviewed 84 tissue specimens with gastric
      cancer seen in our department over an 18-year period for for the presence of H.
      pylori infection, chronic gastritis, atrophic gastritis, and intestinal
      metaplasia in the adjacent non-cancerous gastric mucosa. RESULTS: H. pylori
      infection was detected in 15 (17.9%) of 84 specimens. Moderate to severe
      gastritis was found in non-cancerous areas in 77 (91.7%) specimens, and was
      equally frequent in patients with 'intestinal' and 'diffuse' types of cancer.
      Atrophic gastritis and intestinal metaplasia were observed in 22 (26.2%) and 35
      (41.7%) specimens, respectively, and were more common in 'intestinal' type of
      gastric cancer. CONCLUSION: Chronic gastritis was seen in the adjacent non
      cancerous mucosa in most specimens with gastric cancer. However, its severity did
      not correlate with the histological subtype of gastric cancer.

PMID- 15030032
TI  - Prevalence of irritable bowel syndrome in Shahrekord, Iran.
AB  - BACKGROUND: As part of a public health program, we studied the prevalence of
      irritable bowel syndrome (IBS) as per the Rome II criteria, in Shahrekord
      community in Iran. METHODS: The study was conducted between August 2002 and March
      2003. Of 5492 randomly selected subjects aged 20 years and above (from a total
      population of approximately 100,000), 4762 (86.7%) successfully completed
      interviews to fill in a questionnaire that looked into demographic data and
      various symptoms during the last one year. RESULTS: The 12-month prevalence of
      IBS was 5.8%. The female-to-male ratio among subjects with IBS was 1.17:1 and was
      similar to that among those without IBS. Pain relieved by defecation was reported
      by 427 (9%) subjects, pain associated with change in bowel habit by 340 (7.1%),
      and pain associated with change in the form of stool by 337 (7.1%) subjects.
      CONCLUSION: The prevalence of IBS in Shahrekord is lower than that reported from
      Western developed countries and is closer to that in Asian populations.

PMID- 15030033
TI  - Presentation and natural history of variceal bleeding in patients with portal
      hypertension due to extrahepatic portal venous obstruction.
AB  - BACKGROUND: The natural history of portal hypertension due to extrahepatic portal
      venous obstruction (EHPVO) in the presence of a non-cirrhotic liver is not well
      understood. AIM: To evaluate the presenting features and the natural history of
      EHPVO by assessing the bleed patterns prior to definitive management in these
      patients. METHODS: Two hundred and seven consecutive patients presenting with
      history of variceal bleeding due to EHPVO were studied prospectively. Clinical,
      hematological and biochemical features on presentation, and pattern and severity
      of bleeding prior to institution of endoscopic therapy or surgery were recorded.
      RESULTS: Ascites was observed in 16% and was invariably transient. Splenomegaly
      was present in 82%, with hypersplenism in 22%; however, hypersplenism was
      symptomatic in only 6% of patients. In 127 patients having more than one episode
      of bleeding, the frequency of bleeding episodes was 0.94/year and transfusion
      requirment was 1.47 units/year. No fixed pattern of frequency of variceal
      bleeding was identified. However, number of bleed episodes and transfusion units
      requirement correlated with each other. The maximum severity of bleeding was
      between the ages of 12 and 19 years. CONCLUSION: Hypersplenism causing symptoms
      is rare in EHPVO presenting with variceal bleed.

PMID- 15030034
TI  - Effect of Helicobacter pylori eradication on serum ammonia levels in patients
      with chronic liver disease.
AB  - BACKGROUND: Helicobacter pylori infection has been implicated in the development
      of encephalopathy in chronic liver disease (CLD); this is possibly due to
      increased production of ammonia by the action of bacterial urease on urea in the
      gastric lumen. AIM: To evaluate whether H. pylori eradication in patients with
      CLD affects arterial ammonia levels. METHODS: Forty-six patients with CLD (40
      alcoholic, 6 post hepatitis B; Child's class A 7, B 17, C 22) and 36 patients
      with symptoms of acid-peptic disease (APD) underwent gastrointestinal endoscopy
      and biopsy; gastric biopsies were evaluated for H. pylori status using rapid
      urease test and histology. H. pylori-positive subjects received quadruple-drug
      eradication therapy for 2 weeks. Fasting arterial plasma ammonia levels were
      estimated before and after eradication of H. pylori. RESULTS: H. pylori infection
      was present in 21 of 46 (45.7%) patients with CLD and 23 of 36 (63.9%) with APD.
      At baseline, mean (SD) ammonia levels were higher in the CLD group (97.4 [10.9]
      versus 81.3 [7.7] mcg/dL in the APD group; p = 0.0001), irrespective of H. pylori
      status. Amongst patients with liver disease, arterial ammonia levels were similar
      in the H. pylori-positive and -negative patients (94.1 [9.7] and 100.2 [11.3]
      mcg/dL, respectively); however, ammonia levels were higher in patients in Child's
      class C (102.7 [11.4] mcg/dL/dL) than in those in class A (88.4 [1.6] mcg/dL; p <
      0.002) or B (94.1 [9.7] mcg/dL; p < 0.002). In patients with APD, ammonia levels
      were higher in H. pylori-positive patients (85.3 [6.4] versus 74.1 [3.3] mcg/dL;
      p < 0.001). After eradication of H. pylori infection, ammonia levels decreased to
      88.4 (10.0) mcg/dL in CLD and 76.7 (4.8) mcg/dL in APD (p = 0.001 as compared to
      baseline). There was no difference in post-eradication ammonia levels between
      Child's classes. CONCLUSION: Levels of arterial blood ammonia are higher in CLD
      than in APD, and correlate with severity of liver disease. H. pylori eradication
      was associated with reduction in arterial ammonia levels in patients with CLD.

PMID- 15030036
TI  - Inadvertent choledochotomy during Frey's procedure: management options.
AB  - We report the occurrence of inadvertent injury to the intra-pancreatic common
      bile duct in 3 of 9 patients undergoing Frey's procedure for chronic pancreatitis
      with inflammatory mass in the head. In one case, the choledochotomy was extended
      and anastomosed to the cored-out parenchyma. In the other two, after lateral
      pancreatico-jejunostomy, hepatico-jejunostomy was performed using the same Roux
      loop.

PMID- 15030035
TI  - Pancreatitis in patients with primary hyperparathyroidism.
AB  - Records of patients undergoing parathyroidectomy at our institute in the period
      1991-2003 were retrospectively analyzed. Pancreatitis was associated in six of 87
      patients (6.8%) with primary hyperparathyroidism (PHPT). Pancreatitis was the
      presenting symptom in five patients, while it developed postoperatively in one
      case. All patients with a past history of pancreatitis had suffered two or more
      attacks. All patients had a history of renal stone disease. Four patients also
      had overt bone disease with multiple fractures. Parathyroid adenoma (4) or
      carcinoma (1) was the cause in all patients. All five patients who underwent
      successful parathyroidectomy had resolution of pancreatitis on conservative
      management and no further attacks during a mean follow up of 28 months (3-84
      months). Surgical exploration for parathyroid adenoma failed in one patient; this
      patient has had further attacks of pancreatitis. Repeat surgical exploration for
      parathyroidectomy has been advised. Hyperparathyroidism is a rare but treatable
      cause of pancreatitis. Parathyroidectomy has a salutary effect on the course of
      pancreatitis.

PMID- 15030037
TI  - Acute hepatitis B presenting as Guillain-Barre syndrome.
AB  - Guillain-Barre syndrome associated with acute hepatitis B virus infection is
      rare. We report a 56-year-old man who presented as Guillain-Barre syndrome in the
      absence of icterus and was subsequently shown to have acute hepatitis B. He
      improved on conservative therapy.

PMID- 15030038
TI  - Multiple squamous cell carcinomas of esophagus.
AB  - Multiple tumors of the esophagus are reported only rarely. We describe three
      patients with double carcinoma of esophagus. They developed a second squamous
      cell carcinoma of esophagus more than 4 1/2 years after external radiation for a
      primary squamous cell carcinoma at a different site in the esophagus.

PMID- 15030039
TI  - Gastric leiomyoma presenting as gastric volvulus.
AB  - We report a 45-year-old lady who presented with recurrent vomiting, retching and
      epigastric pain, and was diagnosed to have gastric volvulus. After correction of
      the volvulus by endoscopic detorsion, a tumor was seen along the greater
      curvature. This was excised surgically. Histology showed leiomyoma.

PMID- 15030040
TI  - Coloduodenal fistula: an uncommon sequel of colonic tuberculosis.
AB  - We report a 42-year-old man who developed coloduodenal fistula secondary to
      hepatic flexure tuberculosis. Initially, feeding jejunostomy and ileostomy were
      done; subsequently, after antitubercular therapy, right hemicolectomy and
      excision of the fistula with a sleeve of duodenal wall was performed.

PMID- 15030041
TI  - Gangrene of Meckel's diverticulum.
AB  - Gangrene of Meckel's diverticulum is uncommon and its pre-operative diagnosis is
      difficult. We report three cases with different presentations--simulating acute
      appendicitis, intestinal obstruction, and strangulation of the bowel.

PMID- 15030042
TI  - Reversible posterior leukoencephalopathy due to oral cyclosporine in severe
      ulcerative colitis.
AB  - We report a rare neurological complication, posterior leukoencephalopathy,
      occurring with oral cyclosporine use in a 44-year-old woman with severe
      ulcerative colitis. The condition reversed on discontinuation of the drug and
      correction of associated factors.

PMID- 15030043
TI  - Multiple spontaneous enterocutaneous fistulae in malakoplakia.
AB  - Malakoplakia is a rare chronic inflammatory disease, usually involving the
      urogenital tract. We report a patient who presented with a psoas abscess, and
      later developed colocutaneous fistula at the site of abscess drainage and
      multiple spontaneous fistulae away from the site of incision. Histology of the
      resected specimen showed Michaelis-Gutmann bodies, which are diagnostic of
      malakoplakia.

PMID- 15030044
TI  - Comparison of endoscopy with pathology in the diagnosis of esophagitis among
      children.

PMID- 15030045
TI  - Esophagogastroduodenoscopy in childhood inflammatory bowel disease.

PMID- 15030046
TI  - Prevalence of antibodies to hepatitis C virus in coastal Orissa.

PMID- 15030047
TI  - Low vitamin E level as a possible cause of complications in celiac disease.

PMID- 15030048
TI  - Adult celiac disease in northern India.

PMID- 15030049
TI  - Nimesulide-induced acute hepatotoxicity.

PMID- 15030050
TI  - Drinking glass in the rectum: a difficult therapeutic problem.

PMID- 15030051
TI  - [Medecine and chemistry in the context of the Enlightenment: the thesis of the
      Lausanne physician Marc-Louis Vullyamoz].
AB  - The chemico-medical essay "De sale lactis essentiali" is a thesis presented in
      Leyden in 1756 by a physician from Lausanne, M.-L. Vullyamoz, to obtain the
      medical degree. It shows that chemistry has become a university science connected
      with medicine and that combustion was explained at that time by G. E. Stahl's
      theory of the phlogiston. It reminds us that the hypotheses of this German
      physician, which were part of the animistic doctrine, were widely adopted in
      Europe. In chemistry they began to fade in 1789 after the publication of
      Lavoisier's work on oxydation. Nevertheless, they have contributed to establish a
      modern science. In medicine Stahl's animism evolved towards vitalism, which
      survived in several forms. Vullyamoz's thesis, which presents chemical
      experiences intended to analyse and promote a popular medicine, is a testimony of
      the spirit of Enlightenment, which rejects dogmatism and tries to understand
      facts through observation and the use of reason.

PMID- 15030052
TI  - [Which tasks for countryside physicians in 19th century France? To heal, to
      educate, to civilise the people. A country physician's report from the French
      Department of the Haut-Rhin in 1849].
AB  - This article presents a country physician's report from the French Department of
      the Haut-Rhin written for its Salubrity council in 1849. Though very simple in
      shape and content, this medical topography provides information which is rare in
      regard to its precision, its quality and its extent. It is striking how these
      physicians considered their task of healing people and organising sanitary
      prevention as a mission of civilisation.

PMID- 15030053
TI  - Health care in Greece and the Netherlands in the nineteenth century. A tale of
      two cities.
AB  - In the nineteenth century legislation concerning health care in Greece did not
      differ from that in the Netherlands, derived as it was from the French example in
      both cases. This article contains a comparison of the organisation and the
      effects of (public) health care in the Dutch city of Groningen and the Greek city
      of Piraeus, cities which in the course of the nineteenth century reached about
      the same size. It shows that on the local level, in spite of the convergence in
      national legislation, there were large differences in the way (public) health
      care was distributed and in the acceptation by the public. This was for example
      reflected in different death ratios.

PMID- 15030054
TI  - [From Basel to Bad Nassau. The fate of the psychoanalyst Arthur Muthmann (1875
      1957)].
AB  - Arthur Muthmann is known as a pioneer of psychoanalysis in German-speaking
      countries. He published on the clinical application of psychoanalysis as well as
      an article explaining the matter to laymen. His Freiburg years and later work
      have already been portrayed, while his academic failure in Switzerland and his
      directorship of a private sanatorium at the famous Hessian spa of Bad Nassau have
      hardly been looked at. Historians of psychoanalysis reported on Muthmann's
      definite split from the psychoanalytic movement after 1909 due to the fiasco
      about his professoral thesis at Basel. His contribution to the spreading of
      psychoanalytic knowledge of the time has been judged upon harshly by known
      historians. Both hypotheses will be scrutinised here.

PMID- 15030055
TI  - Insecticide resistance versus antimicrobial resistance. Biological issues in
      historical perspective.
AB  - The developments of insecticide resistance in insects and antimicrobial
      resistance in bacteria seem to have not too many aspects in common, due to the
      diverse nature of eukaryotes and prokaryotes cells and organisms. However, there
      are several approaches, both in the history of ecological systems and in the
      History of Science, that can successfully be applied to explain aspects of
      developments shared by both phenomena of resistance. Looking back to a century of
      discoveries, scientific explanations, industrial, agricultural, and medical
      practice, the historian is especially well placed for investigating the lessons
      to be learned and to be exchanged at the boundaries of research on resistant
      insects and microbes.

PMID- 15030056
TI  - [The history of the "patient": hazard, means, or object of the history of
      medicine?].

PMID- 15030057
TI  - Preventive and interceptive orthodontic demand for malocclusion.
AB  - Orthodontic unit, University College Hospital, Ibadan is young and in need of
      baseline data for effective planning. The main aim of this study was to determine
      the nature of orthodontic demands in the unit that could benefit from preventive
      and interceptive treatment so as to enhance treatment planning, teaching and
      further research. Consecutive patients who presented for treatment in the Unit
      between May 1997 and November 1999 were included in the study. The patients aged
      5-19 years with mean age of 8.8 +/- 0.82 years. One hundred and twenty-one
      (60.5%) of the orthodontic cases that presented for treatment needed one form of
      preventive and interceptive treatment or the other such as extraction of retained
      primary teeth, use of upper removable orthodontic appliances to correct teeth in
      cross bite, extraction of erupted supernumerary teeth and fabrication of oral
      habit breaking appliances such as goal post appliance. Ninety-three (76.9%) of
      these children had retained primary anterior teeth while 9.1% had proclination of
      maxillary anterior teeth with moderate spacing. Based on dental history and
      clinical examination, nine (7.4%) children were involved with oral habits, seven
      (5.8%) and one (0.8%) had anterior crossbite and supernumerary teeth,
      respectively. The remaining 39.5% needed full-blown orthodontic treatments. No
      sex predilection was found in relation to the various needs (P > 0.05). We
      suggest a need for more emphasis on preventive and interceptive orthodontic
      treatment in our environment due to the relatively high prevalence ofthese
      presenting needs.

PMID- 15030058
TI  - Emotional reactions of relatives to schizophrenic patients in Lagos, Nigeria.
AB  - Unlike what obtains in the developed countries, not much is known about the
      expressed emotions (EE) of the family to mental illness in developing nations,
      including Nigeria. Therefore, the objective of this study is to investigate the
      EE among family members to schizophrenics in Lagos, Nigeria. The Camberwell
      Family Interview was conducted with Nigerian family members of 19 schizophrenics
      whose symptoms were further ascertained using the Present State Examination.
      Sixty-three percent of the family sample showed high expressed emotions (HEE).
      The proportion of HEE families increased progressively with the number of
      previous hospitalization (r = 1, p = 0.000). The mean ratings of Critical
      Comment, Warmth and Positive Remarks were, respectively, 6.1 (+/- 3.8), 2.6 (+/-
      0.9) and 2.2 (+/- 0.9) and 2.2 (+/- 1.3). The proportions of relatives showing
      Emotional Over-Involvement and Hostility were, respectively, 26.3% and 31.6%. The
      correlation between Warmth and Critical Comment was -0.39. The findings were
      compared with those of a key cross-cultural study of EE and the implications
      highlighted.

PMID- 15030060
TI  - Some physicochemical properties of 4-amino-3,5-dinitrobenzoic acid (ADBA).
AB  - Some physicochemical properties of the aromatic amino acid 4-amino-3,5
      dinitrobenzoic acid (ADBA) were determined. This provides, for the first time,
      quantitative data about this chemical of current pharmaceutical and biomedical
      interest. The analytical reagent grade of ADBA has 100% purity, determined by
      potentiometry. The ionization constant (pKa) is 4.00 +/- 0.04. The specific
      absorbance of ADBA [A(1%, 1 cm)] was determined as 389.42 +/- 51.33 and 381.67 +/
      38.99 (p = 0.05) in water (435 nm) and octanol (415 nm), respectively. The
      lipophilicity of ADBA is described by its octanol/water partition coefficient
      (Log P) of -1.50. An analogous parameter descriptive of lipophilicity, the
      chromatographic hydrophobicity index (Rm), was determined as -0.84 on reversed
      phase thin layer chromatography (RPTLC). ADBA is more acidic thanp-amino benzoic
      acid (PABA), the prototype aromatic amino acid of which ADBA is an analogue. It
      is also about thirty-two times more water soluble than in n-octanol. These
      findings have a predictive value with respect to absorption and distribution of
      this compound in living organisms.

PMID- 15030059
TI  - Hip fractures in a tropical teaching hospital.
AB  - The pattern of hip fractures, treatment, outcome of treatment, and complications
      of forty-four consecutive patients treated over a five-year period were
      retrospectively studied. This represents 3.5% of the hospitalised patients in
      orthopaedic services. The male:female ratio was 1:1.3. Seventy percent of the
      fractures occurred in those over 65 years of age. The fractures were the result
      of low energy trauma in 81.8% of patients. Intracapsular (cervical) fractures
      accounted for 79.5% of the total cases. Only two patients had associated injuries
      on admission. Austin Moore hemiarthroplasty was the choice of hip replacement for
      intracapsular fractures, while ORIF (Open reduction and internal fixation using
      fixed angle blade plate) was done for patients with (extracapsular) trochanteric
      fractures. Anaesthesia (general or regional) was uneventful. Non-fatal pulmonary
      embolism occurred in one patient post-hemiarthroplasty while in the hospital.
      This study shows that hip fractures are not uncommon in our environment although
      far less common than what obtains in the Caucasians.

PMID- 15030061
TI  - Mesio-distal crown dimensions of permanent teeth in a Nigerian population.
AB  - This study was undertaken to establish normative values for mesio-distal crown
      dimensions of permanent teeth in some Nigerians. The mesio-distal crown
      dimensions of permanent teeth of two hundred and fifty secondary school students
      in Ibadan metropolis were measured. The sample size consisted of 125 males and
      125 females selected by modified random sampling technique. Their ages ranged
      between 12 and 15 years. The mean value for each tooth size was recorded and can
      be regarded as normal values for the study population. The largest tooth in the
      mouth was the 1st mandibular molar in males while the smallest tooth was the
      lower central incisors in females. These normal values could be used as standard
      reference table for tooth sizes which will be of great importance to the
      orthodontist for the space analysis, to the prosthodontist for correct choice of
      teeth and to other disciplines like anatomy and anthropology.

PMID- 15030062
TI  - Nonmenstrual adverse events associated with subdermal contraceptive implants
      containing normegestrel and levonorgestrel.
AB  - To improve counselling information to Nigerian family planning clients, we
      compared non-menstrual events reported by 248 Norplant users and 214 Uniplant
      users. Women using Norplant were significantly older and of higher parity and
      greater contraceptive experience than Uniplant users. Other admission
      characteristics of the two groups were similar. The total women-months of use of
      Norplant was 2,946 (mean 11.9 +/- 0.6 SE) months while that for Uniplant was
      2,315 (mean 10.8 +/- 0.2 SE) months. About 36% of Norplant users and 15% of
      Uniplant users reported non-menstrual adverse events, the commonest ones being
      pain/itching at the insertion site, unexplained low abdominal pains and
      clinically diagnosed pelvic inflammatory disease (PID). The numbers of women
      reporting drug-related adverse events were 61 (24.6%) and 23 (10.8%),
      respectively, among Norplant and Uniplant users. Drug-related serious adverse
      events were reported by 3 (1.2%) Norplant users and 5 (2%) Uniplant users. The
      adverse events leading to Uniplant removal were severe urticaria, breast lumps,
      pruritus vulvae, headache with raised blood pressure, adnexal pains and ovarian
      cysts, and static weight while those leading to Norplant removal were breast lump
      and headache with raised blood pressure. Weight gain was reported by only 7 (3%)
      of Norplant users. Although of no serious clinical consequences, drug-related
      adverse events should be added to the counselling information to prospective
      users.

PMID- 15030063
TI  - A study of psychiatric symptoms in thyrotoxic Nigerians.
AB  - Psychiatric symptoms suggesting panic, affective, and even schizophrenic
      disorders have been described in thyrotoxic patients. However, this has not been
      previously described among Nigerians. We have therefore conducted a cross
      sectional study of psychiatric symptoms among thyrotoxic Nigerians. The self
      rated General Health Questionnaire (GHQ-30) and the Hospital Anxiety and
      Depression Scale (HADS) were administered on 8 previously untreated newly
      diagnosed thyrotoxics. Eight age and sex-matched diabetics and 8 apparently
      healthy controls were also recruited as controls. 1 subject was a male while 7
      were females. Their ages ranged from 29 to 60 years, mean 44.5 +/- 11.4 years.
      Graves' disease was the cause of thyrotoxicosis in 7 subjects while the other had
      toxic multinodular goiter. Symptoms of thyroid disease had been present in them
      for a mean of 9.1 +/- 6.8 months. Based on GHQ-30 scores, 4 thyrotoxics, 4
      diabetics and 2 healthy controls had significant psychiatric symptoms. The HADS
      identified symptoms of anxiety in 3 thyrotoxics, no diabetic and 2 healthy
      controls. Symptoms of depression was however present in 2 thyrotoxics, 1 diabetic
      and no healthy control. The mean GHQ-30, Anxiety and Depression scores were
      comparable across all subject groups: P = 0.489, 0.277, and 0.125 (ANOVA),
      respectively. None of the psychiatric symptom ratings significantly correlated
      with serum T3 levels. Our result does not show prominence of psychiatric symptoms
      in our thyrotoxic patients. Further, larger studies are required to validate this
      finding.

PMID- 15030064
TI  - Transmigration of mandibular permanent canine in a Nigerian patient: presentation
      and management.
AB  - A rare dental anomaly--transmigration is presented in a 12-year-old female
      Nigerian who was referred for orthodontic assessment. A right mandibular canine
      was found completely located in the left side of the body of the mandible having
      moved ectopically and progressively from its normal developmental site through
      the symphysis of the mandible. The importance of the radiological diagnosis with
      the use of panoramic radiograph is highlighted and the management briefly
      discussed.

PMID- 15030065
TI  - Selective cholesterol deposition in the kidney tissue of rats fed palm kernel oil
      diet.
AB  - Plasma and tissue lipids were determined in twenty-four rats fed on locally
      prepared 'Ogi' diet containing palm kernel oil (PKO), red palm oil (RPO) and
      mixture of both oils. Fasting blood sample was obtained from each animal by
      cardiac puncture under light ether anesthesia after feeding on different diets
      for twelve weeks. There were significant variations in the mean liver, kidney,
      spleen (p < 0.001, p < 0.03, p < 0.002) tissue weights in the different dietary
      groups compared with the corresponding control values. The plasma total
      cholesterol, triglyceride and lipoprotein cholesterol concentrations in the
      dietary group showed no significant changes when compared with the corresponding
      control values. The liver, spleen and heart total cholesterol concentrations were
      not significantly different from the corresponding values in the control group,
      but within group analysis showed significantly elevated total cholesterol in the
      kidney tissue of rats consuming PKO diet (p < 0.001). The total cholesterol level
      in rats consuming PKO diet was significantly higher than the corresponding
      concentration in those consuming the diet containing a mixture of PKO + RPO [p <
      0.02] and control (p < 0.02) diets. There was also a significant increased in the
      kidney tissue cholesterol of rats fed RPO diet when compared with the
      corresponding control value (p < 0.05). The histological findings revealed no
      abnormality except in rats fed on PKO and RPO diets where nephrocalcinosis was
      found.

PMID- 15030066
TI  - The knowledge, attitude and practices of the reporting of notifiable diseases
      among health workers in Yobe State, Nigeria.
AB  - Effective surveillance is the key to effective disease control in the community.
      In Nigeria, it is weak with duplication of data collection and multiple reporting
      channels. There is also lack of clarity with regards to data submission
      responsibilities. However, the knowledge of reporting requirements and
      responsibilities among health personnel has not been examined adequately as a
      cause of under reporting. This study was designed to assess the knowledge of
      health workers about disease surveillance. A cross sectional study was conducted
      in six randomly selected local government areas in Yobe State, North Eastern
      Nigeria. A total of 144 health personnel from 88 health facilities were
      administered a pre-tested semi-structured questionnaire and a checklist by
      trained research assistants. The result showed that only fifty-five (38.2%) of
      the respondents were aware of the national disease surveillance system. Their
      mean score regarding immediate notifiable diseases was 0.8 +/- 1.23 SD (maximum
      of 10). Thirty nine (70.9%) reported to have ever reported, while 16 (29.1%) have
      never reported any of the notifiable conditions. Only 12 (21.8%) of the
      respondents claimed to have ever received feedback on the reports they forward to
      higher authorities and more than 92% of the health facilities lack the DSN 001
      and 002 forms. Most of the respondents 47 (85.5%) that were aware of the
      reporting requirements listed lack of training on disease surveillance as one of
      the factors affecting disease reporting. This shows that lack of knowledge of
      reporting requirement was identified as a major factor affecting disease
      surveillance among the respondents. The training and retraining of health workers
      responsible for data generation, collection and forwarding in health facilities
      on disease notification, regular feedback on diseases reported and provision of
      forms were recommended in order to improve the disease surveillance system.

PMID- 15030067
TI  - Psychosocial problems of clinical students in the University of Ibadan Medical
      School.
AB  - A cross sectional study was carried out among medical students in the University
      of Ibadan to identify their socio economic and psychological problems. Three
      hundred and sixteen students, 159 males and 157 females participated in the
      study. The questionnaire, which was self-administered, sought information about
      sources of financial support, type of accommodation, use of recreational
      facilities, smoking and drinking habits and sources of stress and insecurity on
      the campus. The GHQ-12 was used to assess their mental status. Ninety-four
      percent of students were sponsored by their parents. Average monthly income as
      pocket money ranged from N800-N15,000. Sixty-three (20%) reported that their
      pocket money was inadequate and 11 (3.5%) engage in business ventures to
      supplement their income. Two hundred and fifty-seven (81%) live on the campus, 11
      (3.5%) were current smokers and 54 (18%) were current drinkers. Stealing and lack
      of money were the commonest causes of insecurity on the campus. Lack of money,
      fear of failure of examinations, family problems and broken relationships were
      reported as causes of depression among this study population. GHQ scores ranged
      from 1 to 9 using a cut-off point of 3 scores, 38 students (12.0%) were
      categorised as having traits of poor mental health. GHQ scores were not
      associated with age, sex, smoking or drinking status or students' assessment of
      the adequacy of their pocket money. However, living off campus and poor self
      perception were associated with poor mental health (p < 0.01). Counseling
      services should be provided in the medical school to assist students to handle
      issues that constitute a source of stress in their psychosocial environment.

PMID- 15030068
TI  - Primary extranodal non-Hodgkin's lymphoma of the upper aerodigestive tract--a
      descriptive analysis of the pattern seen in the University College Hospital,
      Ibadan.
AB  - This retrospective review highlights primary extranodal non-Hodgkin's lymphoma
      (NHL), of the upper aerodigestive tract as seen in Ibadan over a ten-year period.
      There was a male preponderance (m:f ratio of 2:1), with a mean age of 42.5 years
      and a bimodal age presentation at the fourth and fifth decades. The Waldeyer's
      ring was the commonest affected site while the tonsil is the highest involved
      subsite. Sixty-eight percent of the patients had regional lymphadenopathy and
      thirty eight percent also 'B' symptom at presentation. The peculiar presentations
      of this NHL are the short duration (10 months) of symptoms, mainly
      intermediate/high grade diffuse large cell lymphoma especially in the Waldeyer's
      ring and sinonasal region with absence of low-grade small cell lymphoma. The
      majority of patients (64.3%) presented with Stage IV disease, which shows that
      the disease has an aggressive course with high mortality and generally poor
      outcome with 53.6% of the patients dead within one-year onset of symptoms. The
      overall mean survival period was 14 months. Comparison of the median survival of
      the patients that died when matched with the site, Ann Arbor staging,
      histological grade/subtype and treatment modality yielded no significant
      differences. These further confirm the aggressive nature of the disease in our
      environment.

PMID- 15030069
TI  - Blood pressure control among hypertensives managed in a specialised health care
      setting in Nigeria.
AB  - In spite of the plethora of anti-hypertensives, hypertension remains an important
      cause of morbidity and mortality among Nigerian hypertensive population. To
      determine blood pressure control rate, defined as the proportion of treated
      hypertensive population with systolic and diastolic blood pressures less than 140
      mmHg and 90 mmHg respec tively. One hundred and ten (110) treated adult Nigerian
      hypertensives aged 28-80 (mean 46.02 +/- 15.20) years with male: female ratio of
      1:1.4 who have been commenced on treatment for at least 6 months were selected by
      simple random sampling for determination of blood pressure control rate and its
      determinant factors using clinic blood pressures. Blood pressure control rate was
      42.70%. Pre-treatment mean blood pressure was significantly higher than the value
      at least 6 months post commencement of treatment: (170.09 +/- 15.20/108.98 +/-
      15.85 mmHg versus 146.10 +/- 24.50/93.8 +/- 21.90 mmHg) (t=8.73; p<0.05). In the
      group with uncontrolled blood +/- 17.91 mmHg in 42 (66.6%), rose by 10.50 +/- 1.0
      mmHg in 8 (12.70%) and was unchanged in 13 (20.66%) patients. Diastolic blood
      pressure fell by 22.22 +/- 14.58 mmHg in 32 (50.8%), rose by 7.88 +/- 6.66 mmHg
      in 16 (25.40%) and was unchanged in 15 (23.80%) patients. Clinic compliance and
      family history of hypertension were associated with satisfactory blood pressure
      control. Blood pressure control rate among the study population was low.
      Compliance and family re-enforcement should be encouraged.

PMID- 15030070
TI  - Adherence of Staphylococcus aureus isolated from urine to medical prostheses and
      glass.
AB  - The physicochemical surface property of two Staphylococcus aureus isolates
      obtained from urine (isolates B and C) and a standard strain ATCC 13709 (isolate
      A) were compared. Isolate B was the most hydrophobic while isolate A was least
      hydrophobic as determined by bacterial adherence to hydrocarbon (BATH). Isolate A
      was most adherent to silicone urinary catheter and least adherent to both glass
      and intravenous catheter placement unit. Isolate B was most adherent to glass
      while isolate C was most adherent to the intravenous catheter. The clinical
      isolates B and C were generally more adherent and more hydrophobic than the
      standard strain ATCC 13709. There was no direct correlation between
      hydrophobicity of isolates and their adherence to biomedical materials and glass
      in this work.

PMID- 15030071
TI  - Comparative effects of some local food condiments on sodium arsenite-induced
      clastogenicity.
AB  - The modulatory effects of the aqueous extracts of some locally consumed food
      condiments namely garlic (Allium sativum), ginger (Zingiber officinale), sconio
      (Pimpinella anisumm LINNE) and cloves (Syzygium aromaticum) on the clastogenic
      effects of sodium arsenite, a known inorganic clastogen were assessed in mouse
      bone marrow cells using the micronucleus assay method. Results of preliminary
      investigation of the clastogenicity of the condiments show that aqueous extracts
      of these condiments have very mild clastogenic activity in mice in the order
      garlic > ginger and sconio > cloves and that extracts of ginger and sconio seem
      to have the same degree of clastogenicity. Pre-treatment of mice for seven days
      with extracts of the condiments orally before exposure to the oral dose (2.5
      mg/kg body wt.) of sodium arsenite resulted in a remarkable reduction of the
      magnitude of formation of micronuclei in polychromatic erythrocytes of the bone
      marrow. The degree of reduction of the clastogenic effect of arsenite was of the
      order ginger > garlic > cloves > sconio. This reduction of arsenite induced
      clastogenicity by aqueous extracts of the condiments may be due in part to the
      antioxidant properties of their chemical constituents, thus suggesting that the
      condiments may be useful in the prevention of arsenite-induced toxicity in areas
      where arsenic is an environmental contaminant.

PMID- 15030072
TI  - Studies in preventive nephrology: blood pressure and proteinuria in the
      population.
AB  - The evolution of three generations of anti-hypertensive drugs has produced more
      than less effective therapy. Mild hypertension is a definite risk factor and it
      is responsible for the bulk of complications in the population and must be
      treated. Community control of high blood pressure is feasible and effective. The
      third generation drugs seem to have specific reno-protective attributes.

PMID- 15030073
TI  - Visual outcome of pressurised bottled drinks related eye injuries in Ibadan.
AB  - Records of 15 patients presenting with pressurised bottled drinks related eye
      injuries between January 1996 and 2001 were reviewed to identify factors
      contributing to accidental eye injuries from pressurised bottled drinks, reason
      for poor outcome and to make recommendations. In all, 16 eyes of 15 patients were
      studied out of which 7 were males (M:F, ratio 1:1.1). Age range, 3 years-49
      years, mean 23.6 years. The majority of those affected were students 46.7%, and
      traders 26.7%. The commonest activity leading to injury was explosion during the
      process of arranging the bottles or crates of drinks (43.8%) and accidental fall
      of bottle from hand or height (37.5%). Drinks implicated include, Coca-cola 50%,
      beer 25%, others (Fanta, Legend stout, Mirinda, Grape juice) 25%. Complications
      arising from the injury included, hyphema 43.8%, vitreous haemorrhage 12.5%, and
      retinal detachment 12.5%. The globes were retained in 12 (75%) cases, 3 defaulted
      and one eye became phthisical. The final visual acuity was 6/18 or better in 25%,
      between 6/24 and 6/60 in 12.5% and less than 6/60 in 31.3%. The final visual
      acuities of three patients who were lost to follow up were unknown. Reason for
      poor visual outcome include severity of injury with resultant serious
      complications, and delay with instituting surgical treatment. Eye injuries
      resulting from exploding bottled drinks are potentially very serious and
      therefore best prevented. It is recommended that conversion of bottled drinks to
      canned or plastic containers be considered by the manufacturers. Greater care
      should be taken with the handling of bottled drinks by the sellers, factory
      workers and consumers. High risk occupations such as bottled drink sellers and
      factory workers may need to wear protective goggles during handling. Public
      health education on need to seek prompt and proper treatment as well as need for
      Government to institute the National health insurance scheme to cater for
      indigent patients.

PMID- 15030075
TI  - Recurrent leg ulcers in a 16-year old Nigerian girl.
AB  - This is a report of a 16-year old Nigerian girl who presented with recurrent leg
      ulcers associated with gastrointestinal symptoms. The management of this patient,
      who has ulcerative colitis manifesting with pyoderma gangrenosum, underlines the
      need for thorough evaluation of cutaneous ulcers in the tropics. The medical
      treatment of ulcerative colitis in childhood, with reservation of bowel resection
      for complications is preferred.

PMID- 15030074
TI  - Traumatic vertebral artery pseudoaneurysm: a case report.
AB  - A case of traumatic vertebral artery pseudoaneurysm in a 16-year-old Nigerian
      male following a stab wound is described. Successful surgical treatment by
      proximal Subclavian artery control and excision of the lesion was achieved. The
      value of Doppler ultrasonography in the diagnosis is highlighted. This case
      illustrates and re-emphasises that this rare lesion should be considered in
      patients with neck mass following penetrating posteriorly located neck injuries.

PMID- 15030076
TI  - The diagnostic value of the triple bubble sign in proximal jejunal atresia: a
      case report.
AB  - Proximal jejunal atresia (PJA) is a common cause of intestinal obstruction in the
      newborn. Despite the need for an early surgical intervention to minimize
      morbidity and mortality, a timely identification is frequently precluded by the
      absence of specific clinical and investigative clues. Against the background of
      the limitations in making a timely diagnosis of PJA in a tropical setting, where
      opportunities for high-tech imaging tools are few, we report the diagnostic value
      of the "triple bubble" sign on the plain radiograph of a Nigerian infant. This
      radiologic finding led to an early diagnosis and ultimately a prompt surgical
      extirpation. The paper suggests that the presence of this sign should be a
      pointer to an early diagnosis of PJA.

PMID- 15030077
TI  - Exudative retinal detachment occurring in a patient with pyogenic liver abscess.
AB  - This is a report of a rare case of bilateral exudative retinal detachment
      occurring in a young Nigerian male with pyogenic liver abscess. Detailed ocular
      and clinical examination with biochemical, haematological and microbiological
      studies of the blood and liver aspirate were done. Ocular and abdominal scan plus
      surgical drainage of abscess were also done. The main features were febrile
      illness with hepatomegaly and sudden loss of eyesight. Visual acuity was light
      perception in both eyes. The cardiovascular and renal systems were normal. Ocular
      scan showed bilateral bullous retinal detachment while abdominal ultrasound
      revealed multiple liver abscess cavities. HIV and HBsAg tests were negative.
      Pyogenic liver abscess should be regarded as possible cause of exudative retinal
      detachment and has a potential blinding complication.

PMID- 15030078
TI  - Perceived susceptibility to noise induced hearing loss and attitude towards
      preventive care among metal workers at Gate, Ibadan: a pilot study.
AB  - Audiometric assessment was carried out on 26 metal workers at the spare parts
      market, Gate Ibadan to corroborate their perceived susceptibility to noise
      induced hearing loss. Of the 26 studied, 13 (50.0%) indicated non-susceptibility,
      11 (42.3%) indicated susceptibility while 2 (7.7%) did not know. Otology symptoms
      mentioned by those who indicate susceptibility were tinnitus (63.6%), hearing
      loss (36.4%), otalgia (18.2%), headache (9.1%), and post-aural pain (9.1%).
      Audiometric results showed 10 (76.9%) of non-susceptible subjects, 5 (45.5%) of
      susceptible subjects and 1 (50.0%) of undecided group had normal hearing
      bilaterally. Unilateral high frequency hearing loss was observed in 4 (36.4%) of
      the susceptible subjects. Implications of the findings for taking preventive
      action are discussed.

PMID- 15030079
TI  - Computerised tomography of intracranial subdural haematoma in Ibadan.
AB  - The high mortality and morbidity associated with intra-cranial subdural hematoma
      (SDH), has declined significantly with the introduction of Computerised
      Tomography (CT) for the evaluation of the brain in suspected cases. One hundred
      patients with CT-diagnosed SDH at the Radiology department of the University
      College Hospital, Ibadan between January 1999 and December 2000 were reviewed.
      The mean age was 47.4 years. The most frequent cause of SDH was head injury 61
      (61%). The observed CT appearances of SDH included 66 (66%) of chronic
      (hypodense), 30 (30%) of acute (hyperdense) and 4 (4%) of acute-en-chronic (mixed
      density) lesions. There were more unilateral 83 (83%) lesions than bilateral 17
      (17%). The lesions were right-sided in 45 (45%) cases and left-sided in 38 (38%).
      A total of 169 lesions were detected as some patients had multiple sites,
      however, the parietal 78 (46.2%) and frontal 64 (37.9%) lobes were mostly
      affected. We conclude that brain CT scan offers the advantage of prompt
      determination and precise anatomical localization of SDH, which significantly
      aids management.

PMID- 15030080
TI  - Haematological profile of patients with pulmonary tuberculosis in Ibadan,
      Nigeria.
AB  - The haematological indices of sixty two pre-treatment, sputum-smear-AFB positive
      pulmonary tuberculosis patients were examined. Haematocrit, white cell count and
      differentials and erythrocyte sedimentation rates (ESR) were estimated by manual
      methods. The heamatological parameters were compared with age and sex matched
      control subjects. Statistically significant heamatologic abnormalities found
      include high erythrocyte sedimentation rate (ESR), anaemia occurred in 93.6%,
      leucocytosis in 22.3%, neutrophilia in 45.2% and lymphopaenia in 4.8% of the
      patients. Thrombocytosis occurred in 12.9%,while 8% had thrombocytopaenia. None
      of the patients had leucopaenia and only 8.4% had lymphocytosis.

PMID- 15030081
TI  - Prevalence of hepatitis B virus surface antigen (HBsAg) in patients undergoing
      extraction at the University College Hospital, Ibadan.
AB  - Hepatitis B Virus (HBV) infection and its sequelae (liver chirrhosis and hepatic
      carcinoma) are endemic in Africa. The risk of transmission of the infection
      during dental treatment is real. This study was carried out to determine the rate
      of Hepatits B Surface Antigen (HBsAg) as a marker of hepatitis B virus infection
      in patients undergoing dental extraction in order to highlight the potential risk
      of nosocomial transmission among the Dental Health Workers (DHW) and their
      patients. Three hundred (143 males and 157 females) consecutive patients
      requiring dental extraction who volunteered were enrolled into this study. Their
      ages ranged from 11 years to 95 years with a mean of 37.2 years (SD = 16.725) and
      a median of 36 years. The overall HBsAg infection rate was 18.3% (55/300). A
      higher infection rate (23.1%) occurred among the male patients compared with 14%
      in females (p = 0.0086). The high rate of HBV infection found among this study
      population suggests that Dental Surgeons in this environment have a high risk of
      exposure to hepatitis B virus and should be immunized at the beginning of their
      professional life. Universal biosafety measures should be observed strictly in
      all invasive procedures.

PMID- 15030083
TI  - Human immuno-deficiency virus (HIV) infection among oral surgery patients at the
      University College Hospital, Ibadan, Nigeria.
AB  - The Human Immuno-deficiency Virus is a World-wide epidemic and evidence abound
      that the infection is spreading rapidly in sub-Saharan Africa with little or no
      control. Nosocomial transmission of HIV in the Dental Surgery has been
      documented. This study was undertaken to determine the prevalence of HIV among
      dental patients undergoing extraction at the University College Hospital, Ibadan.
      Three hundred patients requiring dental extraction at the dental clinic, UCH,
      Ibadan who consented were enrolled for the study. Blood samples from these
      individuals were tested for the presence of HIV antibodies using commercially
      available ELISA (Monolisa Sanofi, Pasteur, France). All initially reactive
      samples were confirmed by a commercial Western immunoblot assay (Bio-Rad Norapath
      HIV kit). A prevalence of 2.3% (7/300) was obtained among individuals tested for
      this study. Four (2.8%) of the 143 males and 3 (1.9%) of 157 females were
      positive for HIV antibodies. All the seropositive patients except one were within
      the age range 20-39 years and most of them (6 out of 7) do not use condom during
      intercourse. More than half (57%) of the patients had more than one sexual
      partner. This study shows that the risk of transmitting HIV to DHCW during
      treatment is also a potential hazard in this environment. Hence, adequate
      preventive measure should be observed always.

PMID- 15030082
TI  - Formulation effects on the mechanical and release properties of metronidazole
      suppositories.
AB  - A study of the effects of Tween 20 and Tween 80 non-ionic surfactants, and
      witepsol H15 and polyethylene glycol (PEG) 2850 bases, on the mechanical and
      release properties of metronidazole suppositories was made. Mechanical strength
      was assessed by breaking strength values F. The values of F increased with
      increase in concentration of surfactant. The values of F for formulations
      containing Tween 20 were higher than those obtained for formulations containing
      Tween 80. Witepsol bases gave higher values of F than corresponding PEG bases.
      Release characteristics were assessed by the time for 80% drug release (t80),
      values of dissolution rate constants, k1 and k2 and the time of intersection, t1.
      The values of t80 decreased while those of k1 and k2 increased with increase in
      surfactant concentration. The values of t80 were lower, while those of k1 and k2
      were higher, for formulations containing Tween 20 than for those formulations
      containing Tween 80. Witepsol bases gave lower t80 values and higher k1 and k2
      values than their corresponding PEG bases. The concentration of surfactant, C,
      had the largest individual effect on the mechanical and release parameters while
      the nature of surfactant, S, had the lowest. The ranking for the individual
      effects of the variables on F and k1 was C > N >> S, on t80 and k2 was C >> N
      approximately = S, was on t1 was C = N = S. The interactions between S and C were
      largest for F, t80 and k2, and lowest for k1 and t1. The ranking of the
      interaction effects of the variables on F and k2 was S-C > N-C > N-S, on t80 was
      S-C > N-S approximately = N-C, on k1 was N-C > N-S > S-C, and on t1 was N-S = N-C
      > S-C. The results suggest that the individual and interaction effects of
      formulation variables would provide useful guides in optimizing metronidazole
      suppository formulations.

PMID- 15030084
TI  - Serum micronutrient levels, nucleic acid metabolism and antioxidant defences in
      pregnant Nigerians: implications for fetal and maternal health.
AB  - Micronutrients regulate numerous metabolic processes in pregnancy but their
      possible antioxidant function and contributions of alterations in their
      metabolism to fetal and maternal morbidity and mortality have received
      insufficients attention. Serum levels of copper, manganese and zinc were
      determined in 40 pregnant Nigerian women spread across the three trimesters of
      pregnancy and compared with those of 25 non-pregnant women of similar demographic
      and anthropometric characteristics. Serum levels of uric acid were also
      determined in both groups of women. The mean serum levels of manganese and zinc
      were significantly lower in the pregnant than in the non-pregnant state (P<0.02,
      P<0.002), respectively. Unlike manganese and zinc, copper was significantly
      elevated in the pregnant than in the non-pregnant state. The endogenous anti
      oxidant, uric acid, was also significantly reduced in the pregnant than in the
      non-pregnant state (P<0.001). Copper levels increased progressively in all the
      three trimesters of pregnancy compared with controls (P<0.001). However, zinc
      levels declined steadily in all the 3 trimesters, but only the level of the third
      trimester was significantly different from the non-pregnant state (P<0.05).
      Unlike zinc, uric acid rose consistently in all the 3 trimesters compared with
      the non-pregnant state. Manganese and uric acid were significantly more elevated
      in the third than the first trimester. One way analysis of variance (ANOVA) and
      multiple comparisons (Tukey HSD) show that the differences in the antioxidant
      levels can be ascribed mainly to the second and third trimesters. The prevalence
      of zinc deficiency was 4.0% in the non-pregnant state as compared to 22.5% in the
      pregnant subjects. The implications of micronutrient deficiencies and associated
      antioxidant status in pregnancy are discussed. Considering their role in
      pregnancy, prevention of such deficiencies and attendant oxidative stress may
      contribute to a reduction in the incidence of fetal and maternal ill-health, and
      complications of pregnancy. Interventions should be aimed mainly at the second
      and third trimesters.

PMID- 15030085
TI  - The effects of ageing on the immune response to Schistosoma haematobium and
      hookworm by measuring circulating immune complexes, C3, IgG, IgA and IgM levels
      in residents of Omi dam area of Kogi State, Nigeria.
AB  - In this study, the effects of infestation (with Schistosoma haematobium or
      hookworm) during host ageing on the serum levels of circulating immune complexes
      (CIC), C3, IgG, IgA and IgM were examined in residents of Omi dam area of Kogi
      state, Nigeria. S. haematobium-infested and hookworm-infested individuals showed
      no significant alteration in the levels of CIC, C3, IgG, IgA and IgM in
      comparison with controls. These levels were the same in infested subjects and
      controls even when the patients were pooled. Infested old people had the same
      concentrations of serum CIC, C3 IgG and IgM in comparison with infested young
      people but IgA levels were higher in the aged group (t=2.100; P<0.05); and were
      significantly correlated with age (r=0.301; P<0.05). No significant increase in
      CIC levels with rising age (r=0.123; P>0.20) was observed in the overall
      population of infested subjects; and infestation in old age did not alter CIC,
      C3, IgG, IgA and IgM levels in comparison with uninfested young people. For the
      uninfested, IgG, IgA and IgM values were similar in the aged and the young but
      the levels of CIC were higher (t=2.156; P<0.05; r=0.280; P<0.05) and C3 lower
      (t=3.313; P<0.01; r=-0.236; P>0.10) in the aged. The results of this study
      suggest that the elevated CIC levels found in old people is age-related; and that
      the contribution of parasitic infestation to these raised levels is uncertain.

PMID- 15030086
TI  - Histopathological and histochemical patterns of soft tissue sarcomas in Ilorin,
      Nigeria.
AB  - This research was carried out on soft tissue sarcomas processed in the Department
      of Pathology of University of Ilorin Teaching Hospital over a period of 18 years
      (1979-1996). Tumours in which pathognomonic features necessary for diagnosis were
      present on haematoxylin and eosin sections were diagnosed accordingly while
      special stains were employed to highlight characteristic features of some other
      tumours. Also a panel of special stains was performed on the poorly
      differentiated tumours. The three commonest tumours were fibrosarcoma,
      rhabdomyosarcoma and liposarcoma in decreasing order of frequency. Fibrosarcoma
      and leiomyosarcoma were commonest in middle age while rhabdomyosarcoma was
      commonest in childhood and early adult life. There was a male preponderance of
      the tumours with a male to female ratio of 1.3:1. With the use of special stains,
      typical diagnostic histological characteristics were found in 3 out of the 13
      tumours initially diagnosed as poorly differentiated thereby reducing their
      number to 10. Plans are underway to do immunohistochemical studies and
      chromosomal analysis on the tumours through collaborative studies.

PMID- 15030087
TI  - Risk factors associated with neonatal tetanus in Ibadan, Nigeria--a revisit.
AB  - To identify major risk factors associated with recent occurrence of neonatal
      tetanus (NNT) in Ibadan Nigeria, 140 cases matched 1:1 with controls were
      recruited into the study from the major referral hospitals. Maternal age (<20
      years), low paternal education, low socio-economic status, primiparity and
      delivery outside health facilities were associated with significantly increased
      risk for NNT. Lack of trained attendant at delivery, the type of instrument used
      to cut the cord and the presence of livestock within the family compound also
      significantly increased the risk for NNT. Antenatal clinic (ANC) was attended by
      86.4% of mothers of cases but only 25.6% of these mothers received full
      immunization. Three out of four mothers of cases who attended ANC did so with a
      frequency of 5 to 20 times indicating missed opportunities for immunization. Data
      also suggest that the main reason for failure to receive full immunization was
      ignorance on the mothers' part, which reflects inadequate health education by the
      health system. The study case fatality rate was 79.4 percent. Risk factors
      observed in this population are generally known, indicating that the problem has
      not yet received adequate attention. Effort needs to be made towards providing
      the masses with formal education as well as health education, targeting the
      population at grass root level. Improving access to antenatal care services as
      well as improving the quality of these services; outreach efforts on immunization
      would contribute in no small measure to reducing the incidence of neonatal
      tetanus in this community.

PMID- 15030088
TI  - Laboratory assessment of three glucometers.
AB  - The study was designed to assess the technical performance of three common
      glucometers (Glucometer Elite, Accutrend Alpha, One Touch Basic) marketed in
      Nigeria. This is with a view to assessing their suitability for use in this
      environment and to provide an informed opinion on the selection option. Venous
      blood, capillary blood, serum and plasma were assayed during the study.
      Precision, accuracy, linearity and effect of haemolysis and haematocrit were
      carried out on each glucometer. Simultaneous analysis using the laboratory
      reference method was also carried out where necessary. Intra-assay precision was
      between 1.4% (Glucometer Elite)-11% (One Touch Basic) while the interassay
      precision was best for the Accutrend Alpha with a CV of 1.9%. All three
      glucometers correlated excellently with laboratory values and the %deviation from
      laboratory values was 0.2-10.5%. The Glucometer Elite was the most portable and
      used the least volume of blood (5 ul). One Touch Basic Glucometer was the least
      affected by haemolysis. Haematocrit values less than 50% did not have any effect
      on the three glucometer readings. The technical performance of these three
      glucometers were found to be acceptable and are recommended for use by diabetic
      patients, emergency and intensive care units and antenatal clinics, subject to
      periodic assessment and calibration.

PMID- 15030090
TI  - Hepatitis C virus (HCV) and chronic renal disease.
AB  - Recent epidemiological evidence suggests an association between HCV infections
      and immunologically mediated renal disease. A high seroprevalence of anti-HCV has
      been observed in patients with glomerulonephritis in several countries including,
      Japan, Italy, America and Spain. However, a study in France did not show such
      association but increased seroprevalence of anti-HCV has been reported in
      patients with end-stage renal disease (ESRD) on chronic haemodialysis when
      compared with normal population suggesting that dialysis patients might be at
      higher risk of acquiring this infection. Anti-HCV seroprevalence has been found
      to increase with the duration of dialysis and the number of units of blood
      transfused raising the possibility of both transfusion and nosocomial
      transmission of HCV. A greater seroprevalence of anti-HCV has also been reported
      in predialytic chronic renal failure (CRF) patients independent of blood
      transfusion when compared with patients without renal disease and the normal
      population. The mechanism underlying hepatitis C induced renal damage is not
      certain. However, most evidence suggests that glomerular injury results from the
      deposition of circulating immune complexes (CICs) containing hepatitis C
      antibodies, hepatitis C antigens and complement mainly C3 within the sub
      endothelium and mesangium. The optimal treatment strategy for hepatitis C
      associated renal diseases remains to be defined but treatment has been associated
      with improvement in the level of proteinuria and variable response in serum
      creatinine levels using some antiviral agents.

PMID- 15030089
TI  - Does screening for cervical intra-epithelial neoplasm in developing countries
      prevent invasive cervical cancer?
AB  - In a bid to evaluate the practical relevance of screening for cervical
      intraepithelial neoplasia (CIN) in reducing the incidence of invasive cancer in
      Nigeria, we performed a comparative study of CIN and invasive carcinoma in
      Ibadan, Nigeria over a period of 8 and 16 years respectively. 4.5% of patients
      with invasive cervical cancer were under the age of 30 years. It peaked at 28% in
      the age group 41-50 years. In comparison, <3% of patients with CIN were below 20
      years of age while it had the highest incidence of 37%, 34% and 36% respectively
      in age 40 years and below. The mean age for CIN was 39.6 +/- 9.6 (SD) years
      compared to 51.3 +/- 11.1 (SD) years for invasive cervical cancer (p < 0.01).
      There was a 10 year interval between the onset and peak age incidence of invasive
      cancer and CIN respectively, even though there was an overlap of cases from the
      third decade. We therefore suggest a combined approach of public education to
      encourage early presentation and provision of health service outlets for cervical
      cancer screening in Nigeria to reduce the burden of cervical cancer.

PMID- 15030091
TI  - Hepatitis B and C viral markers in patients with sickle cell disease in Ibadan,
      Nigeria.
AB  - Serum samples from 180 Sickle Cell Disease (SCD) patients attending Medical Out
      patients (MOP) clinic of the Department of Haematology, UCH, Ibadan, Nigeria were
      tested for the presence of HbsAg and anti-HCV in their blood samples. The result
      showed that HBV infection was slightly higher (not significant) than HCV
      infection among SCD patients (P>0.05). In addition, the result showed that the
      mean number of transfusion was higher among patients who were sero-positive for
      both HbsAg (5.0 +/- 6.6) and anti-HCV (4.6 +/- 6.7) when compared to patients who
      were negative for both viruses (2.7 +/- 3.0 and 2.9 +/- 3.2) for HBsAg and anti
      HCV respectively. These observations is an indication that there is an urgent
      need to screen blood units for hepatitis B and C virus infections prior to
      transfusion in order to reduce HCV infection among SCD patients in Nigeria.
      Furthermore, it suggests the need to vaccinate SCD patients against HBV in this
      environment.

PMID- 15030092
TI  - A comparative study of burnout syndrome among health professionals in a Nigerian
      teaching hospital.
AB  - Burnout as a measure of stress has generated research interest in the past two
      decades. However, there is a dearth of research on this interesting and important
      phenomenon in Nigeria. This study compared burnout and its associated factors in
      various health professionals working at the University College Hospital, Ibadan,
      Nigeria. Two hundred and sixty health care providers were sampled from 5 main
      units: Theatre/Intensive Care Unit (ICU), Accident and Emergency (A & E),
      Oncology, Dentistry and General Outpatients Department (GOP), among others.
      Included were 104 nurses (40%), 83 doctors (31.9%), 21 pharmacists/pharmacy
      technicians (8.0%), 10 medical social workers (3.8%) and 42 nursing assistants
      (16.1%). Outcome measures included the Maslach Burnout Inventory (MBI), the 30
      item General Health Questionnaire (GHQ) and the Spielberger State Trait Anxiety
      Inventory (STAI). Core findings indicated that nurses consistently reported
      higher scores on all measures of burnout: exhaustion (F = 3.60, df = 258, P <
      .05); accomplishment (F = 3.94, df = 258, P < .05) and depersonalization (F =
      4.58, df 258, P < .01) when compared with other health care providers.
      Significant differences were also noted between nurses and all other care
      providers in total scores on the General Health Questionnaire (F = 6.54, df 258,
      P < .01) and the State Trait Anxiety Inventory (F = 1.91, df 258, P < .05),
      respectively. These results are discussed in relation to the existing literature
      on burnout in Nigeria. Further empirical study is highly suggested in view of
      dearth of studies on the occupational health of health care providers in Nigeria.

PMID- 15030093
TI  - Widespread antibiotic resistance in savannah Nigeria.
AB  - There is minimal data on antibiotic resistance from savannah northern Nigeria. A
      retrospective study of 438 patients seen in 12 months (2000) with microbial
      pathogens from urinary and respiratory tracts was undertaken. Antibiotic
      susceptibilities were determined using stokes disc diffusion technique.
      Resistance in Escherichia coli (E. coli) reached 91-96% to cotrimoxazole,
      tetracycline and ampicillin but was 11%, 17% and 28% to colistin, nitrofurantoin
      and nalidixic acid. Resistance of other uropathogens (Klebsiella and Proteus spp)
      reached 83-99% to cotrimoxazole, tetracycline and ampicillin but was 14-40% to
      colistin, nitrofurantoin and nalidixic acid. Pneumococci were non-susceptible to
      penicillin (93%), cotrimoxazole (92%), tetracycline (84%), ampicillin (53%),
      chloramphenicol (21%) and cefazolin (8%). Antibiotic resistance is widespread in
      savannah northern Nigeria. Resistance is less to chloramphenicol, colistin,
      nalidixic acid, nitrofurantoin and the latter generation cephalosporins and
      quinolones than to penicillin, ampicillin, cotrimoxazole and tetracycline.

PMID- 15030094
TI  - Determination of baseline antibody titre to S. typhi/paratyphi in Ile-Ife,
      Nigeria.
AB  - The aim of the study is to determine the baseline antibody titres to Salmonella
      typhi/paratyphi in healthy individuals with a view to establishing the
      significant titre for Widal agglutination test in Ile-Ife, Western Nigeria. Three
      hundred and ten healthy volunteers were admitted into the study and forty-eight
      clinically diagnosed and culture positive cases of Enteric fever were used as
      purposeful controls. Widal test was performed on each serum. Slide agglutination
      test was first done, then positive samples were further subjected to tube
      agglutination for quantitative titration. Of the 310 healthy volunteers, 274
      (97.2%) had reciprocal antibody titre of < or = 80 to O antigen and 265 (95.0%)
      had reciprocal antibody titre of < or = 80 to H. antigen of S. typhi. On the
      other hand, in 48 control cases, 43 (89.6%) had reciprocal antibody titre of > or
      = 160 to O antigen and 38 (78.2%) had reciprocal titre of > or = 160 to H.
      antigen. The sensitivity and specificity of the test were 89.9% and 94.2% for O
      antibody, and 79.2% and 92.3% for H. antibody respectively. The baseline titre to
      S. typhi/paratyphi for both O & H antibody is 1:80 whilst the significant titre
      for O & H antibodies is 1:160 and above in Ile-Ife, Nigeria.

PMID- 15030095
TI  - Bacteraemia--a Sagamu perception.
AB  - In this study laboratory records of all positive blood cultures at Olabisi
      Onabanjo University Teaching Hospital between January 1993 and December 1998 were
      reviewed and analyzed. A total of 2057 samples of blood cultures were received in
      the laboratory during the period of study. 495 (24.1%) samples yielded
      significant growth of microorganisms. 87 (17.6%) of the positive cultures were
      from the out patients. Most of the positive blood cultures (99.6%) were mono
      microbial. A total of 497 isolates were obtained. The predominant organisms
      isolated were Klebsiella species (30.8%), Staphylococcus aureus (30.8%), atypical
      coliforms (11.9%) and Pseudomonas species (7.5%). There were more gram-negative
      organisms 309 (62.2%) than gram-positive organisms 188 (37.8%). Staphylococcus
      aureus (30.8%) and Staphylococcus epidermidis (5.0%) were the predominant gram
      positive organisms isolated. A large number (>50%) of the organisms isolated were
      resistant to Ampicillin and Gentamicin but were sensitive to third generation
      cephalosporins and quinolones. In conclusion, this study demonstrates the need
      for all hospitals to monitor the microorganisms causing septicemia so that the
      clinicians can be alerted to a suitable strategy for blind therapy.

PMID- 15030096
TI  - The anterior chamber angles in Nigerians.
AB  - The anatomic configuration of the anterior chamber angles in 240 newly diagnosed
      cases of primary glaucoma in Nigerian adults 30 years and above have been
      studied. The gonioscopic features in eyes of glaucoma patients 30 years and over
      have been compared to 250 subjects without glaucoma. Closed angles (Scheie grade
      0 or 1) was found in 15.0% of cases compared to 1.6% of controls. There was a
      statistical significant difference in the distribution of angle width between the
      2 groups (X2 = 71.47, P < 0.0001). Grade angle 0 was not found in the control
      group, subjects with closed angles in the controls had at least grade 1 angle
      width. Anterior iris insertion characterized the anterior chamber angles in eyes
      of subjects in the glaucoma group occurring in 14.2% compared to 3.2% of eyes in
      the control group. This difference was statistically significant (X2 = 18.79, P <
      0.0001). 38.8% of eyes with glaucoma were considered to have occludable angles
      compared to 10.4% of control eyes, a difference also statistically significant
      (X2 = 53.52, P < 0.0001). Trabecular meshwork pigmentation and peripheral iris
      curvature did not occur differently in the two groups. Mean central anterior
      chamber depth (CACD) was shallower in cases than in controls. This difference was
      statistically significant P = 0.002. The mean depth was shallower in female cases
      than male cases. It decreased with age in subjects with glaucoma and those
      without. The mean CACD increases with increasing angle width. Just over half of
      subjects with closed angles have mean CACD less than 2.5 mm. The other subjects
      with angle closure glaucoma with higher CACD may have plateau iris. Closed
      angles, anterior iris insertion and shallower central anterior chamber depth are
      statistically significantly associated with eyes glaucoma. Increased pigmentation
      and peripherally convex iris curvature were not significantly associated with
      eyes glaucoma.

PMID- 15030097
TI  - Lactation failure in sows--case report.
AB  - Cases of sixteen sows treated for lactation failure in piggery farms in Ibadan
      are reported. Fifteen of them had no complication of mastitis or mammary gland
      teat blockade. The fifteen uncomplicated cases responded favourably to the
      treatment with oxytocin (15-20 I. U. per sow). Only two cases needed second
      treatment with oxytocin due to poor sustenance of flow from only one treatment.
      Milk flow was achieved in less than 5 minutes in all the treated sows after the
      intramuscular injection of the drug. The only sow with accompanying acute
      mastitis responded favourably to procaine penicillin injection. Early diagnosis
      and treatment of agalactia are important in the prevention and control of baby
      pig mortality. The favourable response of these sow lactation failures to
      treatment with oxytocin, confirms the hormonal imbalance as one of the major
      factors to be considered in the unknown aetiology of lactation failure or failure
      of milk ejection reflex.

PMID- 15030099
TI  - Masking redux. I: An optimized masking method.
AB  - This is the first in a series of two papers on masking. The objective of these
      papers is to develop a masking protocol that provides valid measures of threshold
      and is, in general, faster than the plateau method. In this paper, a masking
      method is developed that can replace the traditional plateau method in most
      masking situations. This new method is optimized to require fewer masking levels
      than the plateau method. As a result, it can be significantly faster than the
      plateau method. There are some masking situations in which this optimized method
      cannot be used. This limitation will be evaluated in the second paper and an
      alternate masking strategy provided for use when the optimized method is not
      appropriate.

PMID- 15030098
TI  - The effect of mild hearing impairment on auditory processing tests.
AB  - The application of auditory processing tests to patients with sensorineural
      hearing loss is controversial. Several studies have shown that it is difficult to
      separate peripheral from central hearing processes. In the present study, a Dutch
      auditory processing test battery was administered to 24 subjects with mild,
      relatively flat, symmetrical sensorineural hearing loss. Tests were administered
      twice; the second time, the presentation level in four out of the six tests was
      adjusted according to the speech reception threshold. The scores of the hearing
      impaired subjects were significantly poorer than those of the subjects with
      normal hearing on five out of the six tests, even with the adjusted presentation
      level. Significant correlations were found between test scores and PTA (pure-tone
      average); scores on words-in-noise, filtered-speech and binaural-fusion tests
      were additionally corrected according to PTA. In contrast to previous studies in
      the literature, the present dichotic-digit and pattern-recognition tests were
      greatly influenced by mild hearing loss. Therefore, this auditory processing test
      battery cannot readily be used to diagnose central auditory processing disorders
      in patients with flat sensorineural hearing loss. At least, both adjustment of
      presentation level and additional correction are needed.

PMID- 15030100
TI  - Masking redux. II: A recommended masking protocol.
AB  - This is the second in a series of two papers on masking. The objective of these
      papers is to develop a masking protocol that provides valid measures of threshold
      and is, in general, faster than the plateau method. In the first paper, a masking
      method was presented that can replace the traditional plateau method in most
      masking situations. This new method is optimized to require fewer masking levels
      than the plateau method. As a result, this optimized method is faster, sometimes
      significantly, than the plateau method. This paper evaluates the optimized method
      and compares the optimized method to the traditional plateau method. This paper
      identifies specific masking situations in which the optimized method is not
      appropriate. A variation on the plateau method is described. When combined with
      the optimized method, these two masking methods constitute a recommended masking
      protocol that can be used in all masking situations.

PMID- 15030101
TI  - Processing of English words with fine acoustic contrasts and simple tones: a
      mismatch negativity study.
AB  - The purpose of this study was to compare the robustness of the event-related
      potential (ERP) response, called the mismatch negativity (MMN), when elicited by
      simple tone stimuli (differing in frequency, duration, or intensity) and speech
      stimuli (CV nonword contrast /de:/ vs. /ge:/ and CV word contrast /del/ vs.
      /gel/). The study was conducted using 30 young adult subjects (Groups A and B; n
      = 15 each). The speech stimuli were presented to Group A at a stimulus onset
      asynchrony (SOA) of 610 msec and to Group B at an SOA of 900 msec. The tone
      stimuli were presented to both groups at an SOA of 610 msec. MMN responses were
      elicited by the simple tone stimuli (66.7%-96.7% of subjects with MMN "present,"
      or significantly different from zero, p < 0.05) but not the speech stimuli (10%
      subjects with MMN present for nonwords, 10% for words). The length of the SOA
      (610 msec or 900 msec) had no effect on the ability to obtain consistent MMN
      responses to the speech stimuli. The results indicated a lack of robust MMN
      elicited by speech stimuli with fine acoustic contrasts under carefully
      controlled methodological conditions. The implications of these results are
      discussed in relation to conflicting reports in the literature of speech-elicited
      MMNs, and the importance of appropriate methodological design in MMN studies
      investigating speech processing in normal and pathological populations.

PMID- 15030103
TI  - Interaural cross correlation of event-related potentials and diffusion tensor
      imaging in the evaluation of auditory processing disorder: a case study.
AB  - In a previous publication (Jerger et al, 2002), we presented event-related
      potential (ERP) data on a pair of 10-year-old twin girls (Twins C and E), one of
      whom (Twin E) showed strong evidence of auditory processing disorder. For the
      present paper, we analyzed cross-correlation functions of ERP waveforms generated
      in response to the presentation of target stimuli to either the right or left
      ears in a dichotic paradigm. There were four conditions; three involved the
      processing of real words for either phonemic, semantic, or spectral targets; one
      involved the processing of a nonword acoustic signal. Marked differences in the
      cross-correlation functions were observed. In the case of Twin C, cross
      correlation functions were uniformly normal across both hemispheres. The
      functions for Twin E, however, suggest poorly correlated neural activity over the
      left parietal region during the three word processing conditions, and over the
      right parietal area in the nonword acoustic condition. Differences between the
      twins' brains were evaluated using diffusion tensor magnetic resonance imaging
      (DTI). For Twin E, results showed reduced anisotropy over the length of the
      midline corpus callosum and adjacent lateral structures, implying reduced myelin
      integrity. Taken together, these findings suggest that failure to achieve
      appropriate temporally correlated bihemispheric brain activity in response to
      auditory stimulation, perhaps as a result of faulty interhemispheric
      communication via corpus callosum, may be a factor in at least some children with
      auditory processing disorder.

PMID- 15030102
TI  - Estimating air-bone gaps using auditory steady-state responses.
AB  - Auditory steady-state responses (ASSR) were recorded using stimuli presented both
      via air conduction (AC ASSR) and bone conduction (BC ASSR) in 10 normal-hearing
      subjects with different degrees of simulated conductive hearing losses. The ASSR
      estimated ABG (air-bone gap) was compared with the ABG measured using traditional
      pure-tone audiometric procedures. Reproducibility of the BC ASSR
      electrophysiological thresholds was also assessed. Additionally, a group of five
      subjects with profound sensorineural hearing loss was used to establish
      stimulation levels in which the BC ASSR was contaminated by stimulus artifact.
      Results of this investigation showed that the ASSR and behavioral ABGs were
      strongly correlated with each other (r = .81). However, ASSR-estimated ABGs
      slightly overestimated the magnitude of the behavioral. Reproducibility of the BC
      ASSR electrophysiological thresholds was good. Data from the five subjects with
      profound hearing loss, however, demonstrated that the levels where stimulus
      artifact became problematic were relatively low. This means BC stimulation may be
      appropriate only for subjects with normal or mildly impaired cochlear
      sensitivity.

PMID- 15030104
TI  - Reception thresholds for sentences in bilingual (Spanish/English) and monolingual
      (English) listeners.
AB  - Recent evidence on the perceptual performance of bilingual listeners suggests
      that a nonaudibility-based cost exists in processing a second language. That is,
      when compared to monolingual English speakers and early bilinguals, listeners who
      acquired English as a second language after puberty show reduced performance when
      listening to the second language in background noise, despite normal auditory
      thresholds. However, past studies have not controlled for the homogeneity of the
      bilingual participants used in auditory research; therefore, it is unknown
      whether the deficit observed in bilingual function is due to a lack of control
      for language-related variables. The ability of a homogeneous group of Spanish
      English bilinguals and English monolingual listeners to perceive sentences in
      quiet and in noise at threshold levels was evaluated using the Hearing in Noise
      Test (HINT). Both groups performed similarly in quiet conditions. In the noise
      conditions, the bilingual group's performance was significantly poorer than the
      monolingual group's performance. However, both groups showed a binaural advantage
      of 7-8 dB when the signal and noise were separated by 90 degrees.

PMID- 15030105
TI  - Subgrouping in obesity based on Rorschach personality characteristics.
AB  - Conceptual (a priori) subgroups in obesity based on personality findings from the
      Rorschach Comprehensive System were suggested for 100 obese patients. The
      subgroups were further compared in terms of general anamnestic and behavioral
      data. The largest subgroup was Rorschach characterized by difficulties with
      emotions and a tendency towards depression. Demographic and behavioral data for
      this subgroup revealed intermediate or higher education, regular meals, eating
      disorders like binge eating, periodic variations in eating during the year and
      experiencing body size as having a psychological meaning. The other subgroup was
      characterized by coping liabilities and was further associated with a lower socio
      economic level and irregular or chaotic meal patterns. For the group with
      emotional difficulties, the results suggest a more complex psychological pattern,
      where eating and emotions could be closely related. The group with coping
      liabilities could have difficulties other than emotional ones concerning food and
      eating, such as finding a structure for eating and making changes in lifestyle
      and habits.

PMID- 15030106
TI  - Automatic and effortful information processing in unipolar major depression.
AB  - The present study investigated attentional dysfunction in patients with recurrent
      unipolar major depression in a visual search paradigm. The attentional aspects of
      automatic and effortful information processing were examined. The general
      hypothesis was that patients with unipolar major depression would have more
      problems with tasks that require effortful information processing than with tasks
      that require only automatic information processing. A task requiring effortful
      processing attracts attention, is more demanding, and is instruction-driven. A
      task that is automatically processed does not invoke attention, is less
      demanding, and is stimulus-driven. The results showed that the patient group
      needed significantly longer reaction times on the tasks requiring more effortful
      information processing than the control group, but there were no significant
      differences between groups on tasks requiring automatic information processing.
      Thus it seems as if the depressed patients show an impaired profile as a function
      of the degree of effort a task requires.

PMID- 15030108
TI  - A strict response criterion yields a mirror effect in the novelty paradigm.
AB  - According to the novelty/encoding hypothesis (NEH; Tulving & Kroll, 1995),
      efficacy of encoding information into long-term memory depends on the movelty of
      the information. Recognition accuracy is higher for novel than for previously
      familiarized material. This novelty effect is not a mirror effect: the
      superiority of novel over familiar items is not found in the hit rates but only
      in the false-alarm rates. The main result in the present replication study was
      that novel hit rates were higher than familiar ones when the most confident
      responses were examined separately, and thus a mirror effect could be
      demonstrated for these data, for both the low- and the high-frequency words.
      Similarly, the word-frequency effect on hits was stronger when a stricter
      response criterion was applied. It was concluded that the novelty effect and the
      word-frequency effect are more similar to one another than has hitherto been
      thought.

PMID- 15030107
TI  - Social network as a moderator in the relation between trauma exposure and trauma
      reaction: a survey among UN soldiers and relief workers.
AB  - Social network as a moderator between trauma exposure and post-trauma
      symptomatology was studied. Two samples--relief workers and UN soldiers--were
      assessed on trauma exposure, social network and three dependent measures related
      to post-trauma reactions. Regression analysis and interaction plots were used to
      determine the presence of interaction effects between trauma exposure and social
      network. All four network variables moderated the relationship between trauma
      exposure and post-trauma reactions among relief workers, while among UN soldiers
      only two such buffer effects were found. Furthermore, among UN soldiers one of
      these interaction effects was reversed, indicating social support to be important
      for those low on trauma exposure, while among relief workers support was
      important in the high-exposure condition. The results indicate a difference with
      respect to the importance of social network as a moderator between groups exposed
      to different kinds of war trauma. Differences in motivational systems may also
      exist. However, further research will have to establish this.

PMID- 15030109
TI  - Confirmatory factor analysis of the WPPSI for language-impaired children.
AB  - The present study used a maximum-likelihood confirmatory factor analysis (CFA) to
      test the hypothesis that a four-factor model is the most parsimonious explanation
      of the structure of the WPPSI for language-impaired children. Four separate
      maximum-likelihood confirmatory factor analyses were performed on a sample of 198
      Norwegian language-impaired children tested with the WPPSI, and on the Norwegian
      (n = 563) and American (n = 1200) standardization samples. A one-factor
      (general), a two-factor (verbal and performance), three-factor (parallel to the
      WISC-R) and a four-factor solution composed of "processing dependent" ("knowing
      how" and "seeing how") and "knowledge dependent" ("knowing that" and "seeing
      that") were imposed on the average intercorrelation matrices of the 11 WPPSI
      subtests. Confirmatory factor analysis indicated that the four-factor latent
      construct model was the most parsimonious explanation of the structure of the
      WPPSI for language-impaired children, as well as for normally developing
      children.

PMID- 15030110
TI  - The narcissistic personality inventory: applicability in a Swedish population
      sample.
AB  - A Swedish translation of the 40-item Narcissistic Personality Inventory (NPI) was
      mailed to 410 participants, aged 21-61 years, randomly sampled from the Swedish
      general population. The participation rate was 62%. The applicability of a
      previously published seven-factor structure (Raskin & Terry) and a four-factor
      structure (Emmons) was investigated. The factor structure found in the present in
      the Swedish sample corresponded better with Emmons's version. Therefore the four
      factor structure was chosen. Because the correspondence to Emmons's factor
      structure was not perfect, a revised NPI for Swedish use was constructed. The
      total scale score is usually used, although the Swedish NPI includes four
      subscales: Leadership/Power, Exhibitionism/Self-admiration.
      Superiority/Arrogance, and Uniqueness/Entitlement. For the total scale, the
      internal consistency (Cronbach's alpha) was 0.80 and the test-retest correlation
      was 0.93. The total scale score correlated with self-esteem as well as the
      interpersonal style and emotional aspects of psychopathy, supporting the validity
      of the scale.

PMID- 15030111
TI  - The Goteborg discotheque fire, 1998.
AB  - Findings from a study of 563 adolescents' reactions following a discotheque fire
      that killed 63 young people in Goteborg in October 1998 are presented. The group
      answered a questionnaire seven months following the disaster. The questionnaire
      included the Impact of Event Scale (IES) and the Birleson Depression Self-Rating
      Scale (DSRS). The level of trauma was found to be very high, while depression
      scores were less elevated. A little under a third of the students scored above a
      clinical cut-off point (> 35) on the IES, indicating high posttraumatic stress
      levels. Girls evidenced more depression and traumatic stress reactions than boys.
      Levels of reactions increased with more closeness (knowing victims personally)
      and if the adolescents were of non-Swedish origin.

PMID- 15030112
TI  - Differences in the justification of choices in moral dilemmas: effects of gender,
      time pressure and dilemma seriousness.
AB  - The effects on moral reasoning of gender, time pressure and seriousness of the
      issue at hand were investigated. In Experiment 1, 72 university students were
      presented with moral dilemmas and asked what actions the actors involved should
      take and to justify this. Women were found to be more care-oriented in their
      reasoning than men, supporting Gilligan's moral judgment model. Both time
      pressure and consideration of non-serious as opposed to serious moral dilemmas
      led to an increase in a justice orientation compared with a care orientation in
      moral judgments. In Experiment 2, a similar task was given to 80 persons of mixed
      age and profession, and the participants' moral reasoning was coded in terms of
      its being either duty-orientated (duty, obligations, rights) or consequence
      oriented (effects on others). Men were found to be more duty-oriented than women,
      and time pressure to lead to a greater incidence of duty orientation.

PMID- 15030113
TI  - Groups, group members and individual decision processes: the effects of decision
      strategy, social interaction style and reception of decision-threatening
      information on post-decision processes.
AB  - In two experiments, one conducted at an individual level and one at a group
      level, it was investigated how decision strategies and the reception of decision
      threatening information affect the degree of post-decision consolidation for both
      individual and group decision-makers. In Experiment 1, roughly half the 55
      participants made decisions in three-person groups and the other half
      individually. The type of decision strategies subjects employed (compensatory,
      non-compensatory, other) was assessed by questionnaire. In two post-decision
      sessions, consolidation was assessed using a memory task, either decision
      supporting or decision-threatening information being provided at the start of the
      last post-decision session. In Experiment 2, the same design and procedure were
      used at a group level. In both experiments, the groups (and the single group
      members) were analyzed with the SYMLOG instrument. The results indicated that
      individual decision-makers consolidated their own decisions more than members of
      decision-making groups. There was also greater post-decision consolidation with
      the use of non-compensatory decision strategies as well as with reception of
      decision-threatening information, this latter result being seen as providing an
      explanation for the greater consolidation that individual decision-makers showed.
      Furthermore, single task-oriented group members and groups with a task-oriented
      leader consolidated the decision made by their group.

PMID- 15030114
TI  - The use of coping strategies by Danish children classed as bullies, victims,
      bully/victims, and not involved, in response to different (hypothetical) types of
      bullying.
AB  - The coping strategies employed in response to different types of bullying, by 305
      Danish children (142 boys, 163 girls) in school years four to nine (aged 10-15
      years), were investigated. Children were classed into four bully-victim status
      types. A revised version of the Olweus Bully/Victim Questionnaire was used for
      the classification of children, and a Self-Report Coping Measure for the
      investigation of coping strategies. The coping strategy of Externalizing was used
      significantly more by children classed as bully/victims compared with victims and
      not involved children: Seeking Social Support and Internalizing were preferred
      significantly more by girls, whereas Externalizing was preferred significantly
      more by boys; Distancing, Seeking Social Support, and Internalizing were favored
      significantly more by children in years four to six compared with children in
      years seven to nine. Looking at coping strategies in response to different types
      of bullying, Seeking Social Support was used significantly more in response to
      attack on property relative to verbal bullying, social exclusion, and indirect
      bullying, and Distancing was used significantly less in response to attack on
      property compared with any of the other types of bullying. The results are
      discussed in relation to implications for educational practice.

PMID- 15030115
TI  - Smoke gets in your eyes... and in your breath!

PMID- 15030116
TI  - Breast cancer patients should not live without a HER-2/neu tissue result--but how
      safe can they live with it?

PMID- 15030117
TI  - [Levosimendan in cardiology and intensive care medicine].
AB  - Levosimendan (LS) is a new calcium sensitizer that exerts positive inotropic
      effects without increasing intracellular cAMP or Ca2+ at therapeutic doses and
      therefore may avoid major limitations of beta-adrenergic agents. LS also causes
      arteriolar and venous dilation by opening potassium channels on vascular smooth
      muscle cells. In addition, LS does not increase myocardial oxygen demand and may
      exert anti-stunning effects. LS itself has a short elimination half life but has
      shown to have active metabolites with elimination half lives up to 80 hours.
      Three hemodynamic studies show that at recommended doses LS increases cardiac
      output by 8-30% and reduces pulmonary capillary wedge pressure by 11-28% in heart
      failure patients. Systemic vascular resistance falls significantly and blood
      pressure tends to decline. The hemodynamic effects are not attenuated by
      concomitant beta-blocker medication. Two large randomized studies on patients
      with chronic and acute congestive heart failure found a decrease in mortality
      with LS. In the LIDO trial there was a 52.9% survival benefit at day 31 when
      compared with patients receiving dobutamine. In the RUSSLAN trial, the survival
      benefit approached 40% at day 14 after start of treatment compared to placebo.
      Experience in the ICU setting is limited but LS therapy in postoperative low
      output failure and cardiogenic shock seems to be feasible and LS is a promising
      agent in the inotropic armamentarium. LS has a favourable side effect profile and
      is approved for 24-hour use in congestive heart failure. It may cause hypotension
      due to vasodilation, and this effect may be aggravated by inadequate preload
      conditions. Further morbidity and mortality studies are required to confirm the
      encouraging data from the LIDO and RUSSLAN trial but already the existing data
      support LS as the inotropic agent of choice in patients with worsening heart
      failure and a systolic arterial blood pressure beyond 90 mmHg.

PMID- 15030118
TI  - [Wheezing in infants and toddlers: new insights].
AB  - Wheezing in infants and toddlers is a common symptom, and these patients are
      difficult to approach--both diagnostically and therapeutically. Congenital
      conditions causing wheezing disorders should not be missed and--not all wheezy
      bronchitis is or will become asthma. Results from longitudinal studies indicate
      that the term "asthma" includes different phenotypes: so-called transient early
      wheezing, non atopic wheezing and atopic wheezing (asthma). Transient early
      wheezing is generally accepted to define recurrent wheezing in non-atopic babies
      or toddlers and tends to disappear by the age of 3. The primary risk factor is
      reduced pulmonary function since birth. The most common cause for non-atopic
      wheezing is viral infection, most frequently caused by respiratory syncytial
      virus. Infection with respiratory syncytial virus is a risk factor for ongoing
      wheeze during childhood but resolves in most children by the age of 13. Asthma
      can start at any age and is determined by a more chronic condition, provoked by a
      number of triggers in addition to viruses, frequently associated with a family
      history of atopy, early allergic sensitization and concomitant atopic dermatitis.
      Only asthma seems to be a progressive disease; and there is evidence from long
      term studies that if anti-inflammatory interventions are started late, it might
      be too late to alter the natural course of the disease with its decline in
      pulmonary function. On the other hand, there is no evidence that small children
      with non-atopic wheezy bronchitis would benefit from long-term therapy with anti
      inflammatory treatment; in this group a therapeutic trial with bronchodilators is
      sufficient. The diagnostic and therapeutic challenges of diagnosing asthma in
      this age group are considerable and require a comprehensive approach.

PMID- 15030119
TI  - Quantification of recent smoking behaviour using proton transfer reaction-mass
      spectrometry (PTR-MS).
AB  - Smoking is the most important single risk factor in current public health.
      Surveillance of exposure to tobacco smoke may be accomplished using environmental
      monitoring or in-vivo tests for smoking biomarkers. Acetonitrile exhaled in human
      breath has been described as a potential marker mirroring recent smoking
      behavior. The aim of this study was to determine exhaled acetonitrile levels in a
      sample of 268 volunteers (48 smokers, 220 non-smokers) attending a local health
      fair. Breath specimens were collected into inert sample bags, with parallel
      collection of ambient air. Subsequently, all samples were analysed using proton
      transfer reaction-mass spectrometry (PTR-MS). Smokers had elevated levels of
      exhaled acetonitrile compared with non-smokers (p<0.001). Analysis using the
      receiver-operating-characteristic curve demonstrated that smoking can be
      predicted with a sensitivity of 79% and a specificity of 91%, using a cut-off
      concentration of 20.31 parts per billion of acetonitrile. This first field survey
      of exhaled acetonitrile in a large group of test persons demonstrates the
      feasibility of a rapid and non-invasive test for recent exposure to tobacco. We
      conclude that analysis of exhaled-breath acetonitrile may serve as a method of
      determining recent active smoking behaviour.

PMID- 15030121
TI  - Proliferative vitreoretinopathy--at what risk is the fellow eye?
AB  - PURPOSE: To find out if patients with proliferative vitreoretinopathy (PVR) due
      to complicated retinal detachment are at risk to acquire the same disease or
      other vision-threatening retinal abnormalities in the fellow eye. To furthermore
      assess in what time-period they appear and if subgroups of patients have special
      risks. METHODS: 100 consecutive PVR-patients were studied retrospectively. 21
      patients with PVR graded lower than C3, traumatic PVR, diabetic retinopathy or
      congenital vitreoretinal diseases were excluded. Age, gender, best-corrected
      visual acuity at the first and last visit, refraction, ocular disease in both
      eyes and observation-time were recorded. RESULTS: After a mean follow-up of 8.5
      years, 42 of 79 patients (53.4%) showed vision-threatening abnormalities in their
      fellow eyes: among them, 9 patients (11.4%) had PVR, 13 (16%) simple retinal
      detachments and 14 (17.3%) retinal breaks. Abnormalities in the fellow eye did
      not develop after a certain time following surgery of the primary eye; 71.4%
      appeared within 5 years. Aphakic and pseudophakic patients had retinal breaks
      significantly more often (p = 0.011) than phakic patients. Myopia did not
      increase the risk for any abnormality. Men developed retinal detachment (p =
      0.037) and PVR (p = 0.025) significantly more often than women. CONCLUSION:
      Patients with PVR have a greater than 50% risk of developing vision-threatening
      retinal abnormalities in their fellow eye. Because of this increased risk, these
      patients need regularly-scheduled long-term follow-up. SUMMARY STATEMENT:
      Patients with PVR have a greater than 50% risk of developing vision-threatening
      retinal abnormalities in their fellow eye and a 37% risk to develop PVR from
      rhegmatogenous retinal detachment. More than two thirds of abnormalities in the
      fellow eye developed within five years of surgery of the primary eye.

PMID- 15030120
TI  - Prognostic markers in breast cancer: the reliability of HER2/neu status in core
      needle biopsy of 325 patients with primary breast cancer.
AB  - INTRODUCTION: The assessment of HER2/neu overexpression in tissue provides
      information about one of the most relevant prognostic and predictive markers in
      breast cancer: overexpression of HER2/neu is associated with worse prognosis in
      primary breast cancer. Since core needle biopsy is increasingly used for the
      diagnosis of breast cancer, the purpose of this study was to assess the
      reliability of HER2/neu evaluation using this technique in patients with primary
      breast cancer. PATIENTS AND METHODS: We investigated the accuracy of
      immunohistochemical assessment of HER2/neu in core needle biopsies compared with
      surgically obtained specimens in 325 patients with primary breast cancer. In
      patients strongly positive for HER2/neu, additional fluorescence in situ
      hybridization (FISH) analysis of needle biopsies was performed. RESULTS: Using
      immunohistochemistry alone, accuracy of HER2/neu assessment in core biopsies in
      relation to surgically removed specimens was 92% and increased to 96% with
      additional FISH analysis (weighted Kappa coefficient: 0.86). DISCUSSION: As
      proven with this large series of patients, the assessment of HER2/neu status by
      core needle biopsy in breast cancer is accurate. Notwithstanding, in order to
      minimize the number of false-positive results, strongly positive core needle
      biopsies identified using immunohistochemistry should be confirmed by FISH
      analysis.

PMID- 15030122
TI  - Bone metabolism during interferon-alpha treatment of essential thrombocythemia.
AB  - In-vitro studies have demonstrated that interferon (IFN) has an inhibitory effect
      on bone formation. Changes in bone metabolism were investigated in 19 patients
      treated for essential thrombocythemia with IFN-alpha. Serum biochemical
      parameters of bone remodeling [total alkaline phosphatase, osteocalcin, type-I
      procollagen carboxy-terminal propeptide (PICP), cross-linked telopeptide type-I
      collagen (ICTP)] and mineral metabolism (total calcium, inorganic phosphate,
      parathyroid hormone, 25-hydroxyvitamin D) were measured before and after long
      term IFN-alpha treatment. The effects of the cumulative IFN-alpha dose and
      duration of therapy on biochemical markers of bone metabolism were analyzed. No
      uniform trend or pattern was observed in the measured biochemical parameters
      except for ICTP, which decreased after treatment. Correlations indicated
      modulation of bone metabolism, i.e. remodeling with suppression of resorption, as
      a consequence of therapy with IFN-alpha.

PMID- 15030123
TI  - Clinical and epidemiological features of Lyme borreliosis in Bulgaria.
AB  - INTRODUCTION: Data on disease expression and epidemiological characteristics of
      Lyme borreliosis in south-eastern Europe are scarce. PATIENTS: To reveal features
      of Lyme borreliosis in Bulgaria, clinical data and epidemiological
      characteristics of 1257 patients reported between 1999 and 2002 were analysed.
      RESULTS: The most affected age group was 5-9 years, followed by 45-49 years, 50
      54 years, and 10-14 years. Most of the patients (68%) lived in a rural area or
      were attacked by ticks during activities in a rural area. Lyme borreliosis cases
      occurred throughout the year with two peaks--one in June and second smaller one
      in September. The most common clinical manifestation was erythema migrans (EM),
      diagnosed in 868 (69.1%) of the patients. Rashes had a median diameter of 11 cm
      and were predominantly located on lower extremities. Forty-four per cent of the
      rashes consisted of homogenous erythema and 56% had central clearing. Multiple EM
      was detected in 4.3% of the EM cases. Neuroborreliosis was the second most common
      presentation of Lyme borreliosis, diagnosed in 19% of the patients. Lyme
      arthritis was found in 8% of the patients. Heart and ocular manifestations were
      recorded in 1.1% and 0.9% of the patients, respectively. Borrelial lymphocytoma
      and acrodermatitis chronica atrophicans were very rare (0.3%). Twenty-seven
      patients (2.1%) had multiple organ involvement. CONCLUSIONS: The results of the
      study show that the epidemiology and clinical manifestations of Lyme borreliosis
      in Bulgaria are similar to those in the majority European countries but possess
      some distinguishing characteristics.

PMID- 15030124
TI  - Severe thrombocytopenia as a complication of acute Epstein-Barr virus infection.
AB  - Severe thrombocytopenia is an extremely rare complication of acute Epstein-Barr
      virus (EBV) infection. EBV infection usually causes hematological abnormalities,
      mainly atypical lymphocytosis, which is a feature of infectious mononucleosis,
      and uncomplicated cases often present with mild decreases in platelet counts. Our
      otherwise healthy, 21-year-old male Caucasian patient had thrombocytopenia and
      bleeding diathesis with platelet counts of 8 x 10(9)/L without other signs and
      symptoms of infectious mononucleosis. We commenced treatment with intravenous
      methylprednisolone before the acute EBV infection was serologically confirmed.
      Platelet counts initially rose and then fell after we stopped administrating
      corticosteroids. Repeated administration of methylprednisolone was followed by
      full recovery of the platelet count and normalization of formerly elevated
      transaminases. EBV infection may happen in children, adolescents and adults and
      this differential diagnosis should be considered in every patient presenting with
      acute thrombocytopenia.

PMID- 15030125
TI  - It is not always appendicitis.
AB  - BACKGROUND: Patients who are suspected of having acute appendicitis usually
      undergo surgery in order to avoid life-threatening complications such as
      perforation and peritonitis. However, acute appendicitis is difficult to
      distinguish from other sources of right-sided abdominal pain. The clinical
      picture is almost indistinguishable from appendiceal diverticulitis, which is a
      rare entity and remains a difficult diagnostic problem. PATIENTS AND METHODS: We
      describe the case of a 39-year-old male with perforated appendiceal
      diverticulitis. The patient was admitted to our surgical unit with acute
      appendicitis-like symptoms and underwent surgery with a diagnosis of suspected
      acute appendicitis. RESULTS: The patient was found to have perforated appendiceal
      diverticulitis and standard appendectomy with abdominal lavage was carried out.
      DISCUSSION: Most patients presenting with acute right-sided peritonitic pain are
      diagnosed and managed as cases of acute appendicitis. Acute pain in the lower
      right side of the abdomen caused by appendiceal diverticulitis is very rare and
      clinically indistinguishable from acute appendicitis. Inflammatory complications
      of appendiceal diverticula mimic acute appendicitis. CONCLUSION: Every surgeon
      should be aware of the possibility of diverticulitis of the appendix in the
      operating room, even if this does not change the operative management. As
      diverticula of the cecum can be found as solitary lesions, as multiple lesions
      confined to the right colon, or as part of a generalized disease of the entire
      colon, postoperative barium enema examination may be useful.

PMID- 15030126
TI  - [The former synagogue of the old Vienna General Hospital--a sad 100 year
      anniversary].

PMID- 15030127
TI  - Social class and mortality: on the importance of psychosocial factors.

PMID- 15030128
TI  - Clinical manifestations of coronary aneurysms in the adult as possible sequelae
      of Kawasaki disease during infancy.
AB  - Coronary artery aneurysms are rare findings usually diagnosed incidentally at
      necropsy or at angiography in patients with symptoms of myocardial ischaemia.
      Even if atherosclerosis is a common cause of coronary aneurysms in the adult,
      other acquired diseases with inflammatory pathogenesis are associated with
      coronary artery aneurysms. We present three cases of patients with low
      probability of coronary artery atherosclerotic disease, due to their age, risk
      factors profile and history, complaining of chest pain suggestive of myocardial
      ischaemia and angiographic documentation of one or more coronary aneurysms. In
      all cases, although no patient had had a previous diagnosis of Kawasaki disease
      (KD), an unexplained febrile syndrome had occurred in childhood, which is
      compatible with misdiagnosed episode of KD causing the aneurysmatic lesions. The
      present reports highlight the potential clinical relevance of previously
      misdiagnosed KD in patients with ischaemic chest pain, low probability of
      atherosclerosis and coronary aneurysms.

PMID- 15030129
TI  - Electrocardiographic changes during dobutamine stress testing in patients with
      recent myocardial infarction: relation with residual infarct artery stenosis and
      contractile recovery.
AB  - OBJECTIVE: The identification of viable but jeopardized myocardium after acute
      myocardial infarction (AMI) is of great importance for selecting patients who
      could benefit from a revascularization procedure. The aim of the study was to
      determine the accuracy of the dobutamine stress electrocardiogram (ECG) 1) for
      detecting significant stenosis of the infarct-related artery and 2) for
      predicting the occurrence of contractile recovery. METHODS AND RESULTS: Ninety
      four patients underwent dobutamine stress ECG and quantitative angiography within
      the first week after AMI. A follow-up resting echocardiogram was obtained in all
      patients at 1 month. Significant stenosis of the infarct-related artery was
      detected in 76 patients and functional recovery occurred in 56 patients.
      Dobutamine stress induced ST-segment elevation in 44 patients, ST-segment
      depression in 17 and T-wave normalization in 34. Increase in QT dispersion and
      dobutamine ST elevation were more sensitive than chest pain and ST-segment
      depression (79% and 53% vs. 24% and 17%, respectively; p<0.05) for detecting
      significant infarct-related artery stenosis. Four independent variables were
      selected for predicting contractile recovery: > or = 20 ms increase in QT
      dispersion from baseline to low-dose dobutamine (p = 0.00016), dobutamine-induced
      ST-segment elevation (p = 0.0009), elective angioplasty of the infarct-related
      artery (p = 0.001) and T-wave normalization (p = 0.005). CONCLUSIONS: The
      analysis of predischarge dobutamine stress ECG is useful for predicting residual
      stenosis of the infarct-related artery and contractile recovery in the affected
      area. QT dispersion changes during the test are the most accurate parameter.

PMID- 15030130
TI  - Enhanced prognostic stratification of CAD patients with low ejection fraction by
      stress-rest Tc99m tetrofosmin gated-spect.
AB  - OBJECTIVE: This study was performed to assess whether post-stress and rest
      functional parameters, as measured by gated-SPECT, provide additional predictive
      value for long-term prognosis, over clinical and perfusion data in patients
      (pts.) with low left ventricular ejection fraction (LVEF). METHODS: 647
      consecutive pts. underwent stress/rest gated-SPECT, and 497 were followed for a
      mean period of 516 +/- 264 days. Segmental perfusion and motion/thickening (post
      stress and rest) were analysed visually, while EF and LV volumes were calculated
      using an automatic algorithm (QGS). The post-stress and rest ratio were
      determined for both end-diastolic (EDV) and end-systolic volume (ESV), while the
      post-stress LVEF change was calculated subtracting rest-EF from stress-EF.
      RESULTS: 84/497 pts. showed rest EF < 40%, and 15/84 (18%) experienced a cardiac
      event (3 cardiac deaths, 1 infarction, 3 hospitalized angina and 9 late
      revascularizations). The perfusion and functional parameters were not
      significantly more compromised in pts. with cardiac events compared with pts.
      without events. Post-stress ESV was the only index significantly higher in pts.
      with low EF and events compared with pts. with low EF without events (150 +/- 72
      ml vs. 123 +/- 53 ml, P = 0.02). Univariate Cox analysis of clinical, perfusion
      and functional data showed that the best predictor of cardiac events was stress
      ESV (score 6.5, P = 0.01), followed by rest-ESV, rest-EDV, stress-EDV and stress
      LVEF. Multivariate analysis demonstrated that the addition of stress-ESV to
      stress-EF, yielded a significant increase in the global chi2 in the prediction of
      hard events (cardiac death/infarction) (score 4.634, P = 0.03). CONCLUSION: In
      patients with depressed LVEF, stress-ESV was the only independent predictor of
      long-term outcome.

PMID- 15030131
TI  - Effect of preinfarction angina pectoris on microcirculation in patients with
      reperfused acute myocardial infarction.
AB  - Preinfarction angina pectoris has been suggested in some studies to have a
      beneficial effect on left ventricular function after acute myocardial infarction
      (AMI). The precise mechanisms of this protection have not been fully elucidated.
      The effect of preinfarction angina on myocardial tissue perfusion also needs to
      be clarified. In this study, we investigated the influence of preinfarction
      angina on microvasculatory damage by using ST-segment resolution and pressure
      derived collateral flow index (CFIp) as a marker of microcirculatory perfusion.
      METHODS: We studied 41 patients with a first AMI in whom thrombolysis in
      myocardial infarction (TIMI) grade 3 flow in the infarct-related artery was
      established by thrombolytic therapy. The percent resolution of ST-segment
      deviation (deltasigma ST) after thrombolysis was determined. All of the patients
      had TIMI grade 3 flow in IRA at the coronary angiography, which was done a mean
      of 4 days after AMI. Intracoronary pressure measurements and stent implantation
      to the IRA were performed. After angiography, CFIp was calculated as the ratio of
      simultaneously measured coronary wedge pressure-central venous pressure (Pv) to
      mean aortic pressure-Pv. RESULTS: Patients with preinfarction angina pectoris had
      greater percent deltasigma ST than those without PA (67 +/- 18% vs. 44 +/- 24%, p
      = 0.03). The mean of the coronary wedge pressure (16.4 +/- 7.4 compared with 23.2
      +/- 9.4, P < 0.03) and the pressure-derived collateral flow index (0.15 +/- 0.10
      compared with 0.22 +/- 0.08, P < 0.03) were significantly lower in patients with
      preinfarction angina compared to those without. CONCLUSION: Preinfarction angina
      is associated with a greater degree of ST-segment resolution and lower CFI-p in
      patients with TIMI-3 reflow after thrombolysis. These findings suggest that a
      protective effect of preinfarction angina against reperfusion injury may result
      in greater ST resolution and lower CFIp after AMI.

PMID- 15030132
TI  - Coexistence of prothrombic risk factors and its relation to left ventricular
      thrombus in acute myocardial infarction.
AB  - OBJECTIVE: Within the last few years a number of thrombophilic mutations have
      been identified. Pre-symptomatic testing for these established genetic risk
      factors identifies individuals predisposed to a disease and often allows to
      select suitable prophylactic interventions in time. We investigated whether or
      not the prothrombin G20210A allele, the factor V Leiden G1691A, and MTHFR C677T
      allele are risk factors for left ventricular thrombus (LV) in patients with
      myocardial infarction (AMI) or not. METHODS AND RESULTS: We analysed clinical,
      echocardiographic and biochemical data in 183 consecutive patients (aged 58 +/-
      12 years; 34 women) with a first anterior acute myocardial infarction. Two
      dimensional echocardiographic examination was performed on days 1, 3, 7, 15, and
      30. LV thrombi were detected in 42 (23%) of the 183 patients with acute
      myocardial infarction. We have used multiplex assays based on PCR and DNA
      hybridization in microtitre plates for the simultaneous analysis of three
      mutations (FV Leiden G1691A, prothrombin G20210A, and MTHFR C677T). No
      significant differences in allele frequencies of FV Leiden G1691A (9.5% vs. 8.5%,
      p = 0.75), prothrombin G20210A (9.5% vs 7.1%, p = 0.74) and MTHFR C677T (47.6%
      vs. 50.3%, p = 0.74) were found in patients with LV thrombus when compared with
      those without LV thrombus. No significant differences in haemostatic factor
      levels were found in patients with LV thrombus when compared with those without
      LV thrombus. CONCLUSION: FV Leiden, prothrombin 20210 variant, and MTHFR mutation
      are no risk factors for left ventricular thrombus in patients with myocardial
      infarction.The presence of multiple mutations did not influence the development
      and outcome of LV thrombus in patients with myocardial infarction

PMID- 15030133
TI  - Left ventricular thrombosis is associated with increased mean platelet volume in
      patients with dilated cardiomyopathy and sinus rhythm.
AB  - OBJECTIVE: Dilated cardiomyopathy has been associated with left ventricular
      thrombosis, which leads to substantial morbidity and mortality as a site for
      peripheral emboli. There are some studies on patients with dilated cardiomyopathy
      showing altered haemostasis and platelet behaviour despite sinus rhythm. Mean
      platelet volume, which is the most accurate and simple estimate of platelet
      reactivity, may be associated with the development of left ventricular
      thrombosis. METHODS AND RESULTS: We prospectively enrolled 48 consecutive
      patients with dilated cardiomyopathy and sinus rhythm with left ventricular
      thrombosis and compared them with an age-sex-matched control group having dilated
      cardiomyopathy without left ventricular thrombosis. We found that in patients
      with left ventricular thrombosis mean platelet volume is significantly higher
      than those without (9.5 +/- 0.8 vs. 8.7 +/- 0.6, p < 0.001). CONCLUSIONS: Mean
      platelet volume is increased in patients with dilated cardiomyopathy and sinus
      rhythm having left ventricular thrombosis. This might be reflecting a causal
      relationship, which in turn requires further study to establish the role of
      antiplatelet agents both in prevention and in treatment.

PMID- 15030134
TI  - Relationship between hypertensive left ventricular hypertrophy, neurohormonal
      factors and ventricular arrhythmias in very old patients.
AB  - OBJECTIVE: To study the relationship between hypertensive left ventricular
      hypertrophy (LVH) in very old patients (> or = 80 years) with neuro-hormonal
      factors and ventricular arrhythmias. METHODS: Heart rate variation, plasma renin
      (Ren), angiotensin-II (AT-II), aldosterone (Ald), insulin (Ins), Holter and
      ambulatory blood pressure monitoring were measured in 60 cases (> or = 80 years)
      which were divided into 2 groups: 30 with primary hypertension accompanied LVH in
      very old patients (group A); 30 with simple primary hypertension (group B).
      RESULTS: There was no significant difference of AT-II and Ren between group A and
      B (P > 0.05); Ins and Ald values in group A was much higher than in group B (P
      all < 0.01); the data of heart rate variability, including very low frequency
      (VLF) and low frequency (LF) and LF/HF (high frequency) in group A were
      significantly higher than in group B (P < 0.01, < 0.05, < 0.05, respectively);
      incidence of premature ventricular contractions (PVC) and myocardial ischaemia in
      group A were higher than in group B patients. CONCLUSIONS: Sympathetic nerve
      excitability in group A was greatly increased; hypertensive LVH was closely
      associated with Ald and Ins level, but not with AT-II and Ren. Group A is
      characterized by a significantly greater frequency of premature ventricular
      contractions and ischaemia.

PMID- 15030135
TI  - Drug-eluting stents: a new treatment in the prevention of restenosis. Part I:
      Experimental studies.

PMID- 15030136
TI  - Percutaneous coronary intervention for central sleep apnoea with ischaemic
      cardiomyopathy.
AB  - Central sleep apnoea is often recognized in patients with heart failure. Although
      the medical treatment to improve cardiac function is effective for sleep apnoea,
      direct evidence that improved cardiac function ameliorates sleep apnoea has not
      been reported due to the fact that a particular drug may affect a multitude of
      organs. We present a chronic heart failure patient with central sleep apnoea
      whose nocturnal desaturation was improved by percutaneous coronary intervention
      that resulted in improved cardiac function. This is the first case where
      percutaneous coronary intervention improved sleep apnoea, suggesting that the
      improved cardiac function led to amelioration of sleep apnoea.

PMID- 15030137
TI  - Percutaneous closure of a congenital coronary artery fistula complicated by an
      acute myocardial infarction.
AB  - A coronary artery fistula is not an uncommon finding on a routine coronary
      angiogram. Small fistulas need no specific treatment, but if haemodynamically
      important, elective closure is recommended. We present the case of a 69-year-old
      woman in whom a fistula originating from the right coronary artery and
      communicating with the right atrium is closed with an Amplatzer VSD occluder.
      Several hours after a successful closing procedure, the patient developed an
      acute myocardial infarction. Angiography demonstrated a thrombus that occluded a
      distal branch of the right coronary artery in the blind pouch of the closed
      fistula. Urgent bypass surgery was necessary to stabilize the patient's
      condition. The aim of this case presentation is to warn for complications related
      to uncommon interventional procedures.

PMID- 15030138
TI  - Familial hypertrophic cardiomyopathy complicated by complete atrioventricular
      block.
AB  - We described a patient with familial non-obstructive hypertrophic cardiomyopathy
      and complete atrioventricular block. A 27-year-old male was admitted to our
      institution with syncope. Electrocardiography demonstrated complete
      atrioventricular block. Two-dimensional echocardiography revealed non-obstructive
      hypertrophic cardiomyopathy. A temporary transvenous ventricular pacemaker was
      inserted urgently, and subsequently replaced by a permanent dual-chamber
      pacemaker. Meanwhile, non-obstructive hypertrophic cardiomyopathy was diagnosed
      in the mother, the aunt and one of the brothers of the patient in the screening
      of the family, but atrioventricular conduction block was not detected in them. In
      the electrophysiological study of the mother, inducible ventricular tachycardia
      was detected. The reason for diversity of the arrhythmias in the members of the
      same family with hypertrophic cardiomyopathy may be explained by penetrance. The
      phenotype of the familial hypertrophic cardiomyopathy is influenced by factors
      varying the penetrance, such as age and gender.

PMID- 15030139
TI  - Solid phase treatment of an aged soil contaminated by polycyclic aromatic
      hydrocarbons.
AB  - Laboratory scale tests were carried out in order to evaluate the removal
      efficiency of polyaromatic hydrocarbons (PAHs) during the different biological
      treatments of a Manufacturing Gas Plant site aged soil, heavily contaminated by
      high molecular weight compounds. Biodegradation studies were carried out at
      nearly 25 degrees C in solid phase reactors. Three tests were performed, over a
      period of 100 days for each test. In the first test (P1-bioaugmentated), soil was
      mixed with wood chips and urea at the start of the treatment and after six weeks
      from the beginning of the test was also periodically inoculated (at 42, 54, 69,
      82, and 96 days) with selected consortia of autochthonous PAH-degrading bacteria.
      The second test (P2-biostimulated) was performed similarly to the previous one,
      but without any inoculations. In the third test (P3-control) only soil was
      introduced. All systems were aerated daily and humidified at the occurrence. PAH
      concentration, total cultivable heterotrophs, PAH-degrading bacteria, mycetes,
      pH, ATP concentration, and enzymatic activities were monitored every two weeks
      during the treatments. Tests showed that nearly 50% of light (three rings) PAHs,
      35% of benzo-PAHs and 40% of the total PAHs could be removed in the reactor P2
      following 100 days of treatment. Lower removal efficiency could be observed for
      light PAHs (28%) in the inoculated reactor (P1) at the end of the treatment:
      comparable abatements were obtained for benzo- and total PAHs. In the reactor P3
      (control), the concentration of all polyaromatic hydrocarbons was nearly always
      constant, suggesting that the physical losses were negligible during the solid
      phase treatments. Therefore the C to N ratio balance resulted to be the key
      factor in promoting the biodegradation process of all PAHs.

PMID- 15030140
TI  - Simulation of hindered-settling column separations for soil remediation.
AB  - A phenomenological model was developed to describe the operation of a hindered
      settling column. The model is based on the convection-diffusion equation as
      applied to hindered-settling conditions. Simulation results for the size
      classifiction of soil were compared with experimental results to validate the
      model. Subsequent simulations were carried out to evaluate column performance for
      separating heavy metal or organic contaminants from soil. The simulation results
      are presented in terms of fractional recovery (partition) curves, which give the
      probability that feed particles of a given size and density will be recovered in
      the column underflow stream. The results indicate that good separations are
      possible down to approximately 75 microm in some cases. The effective size range
      of separation depends on the design and operating conditions of the hindered
      settling column and on the material being processed.

PMID- 15030141
TI  - Theoretical analysis of the influence of process parameters on the use of an
      encapsulated phosphate buffer to control pH in a soil column.
AB  - A one-dimensional mathematical model was developed to analyze the influence of
      different physical and chemical parameters on the performance of an encapsulated
      phosphate buffer for controlling pH and enhancing a pH-dependent process in a
      soil column. Three scenarios were investigated where base equivalents are
      produced through the degradation of the target compound (scenario I), through
      reactions in the matrix (scenario II), and a combination of both mechanisms
      (scenario III). In all three scenarios, the production of base equivalents is
      countered by the release of the acidic core of the encapsulated phosphate,
      resulting in an enhanced removal of the target compound. A sensitivity analysis
      on the model shows that under the conditions investigated, the removal of the
      target compound is dependent on the flowrate, porosity. dispersion coeflicient,
      reaction rate constants, mass of added capsules, and the point of addition of the
      capsules. The approach can be used to analyze scenarios where encapsulated
      buffers can control pH and optimize pH-dependent processes in a soil column.

PMID- 15030142
TI  - Biodegradation of 1,3,5-trinitro-1,3,5-triazine (RDX).
AB  - Two bacteria were isolated from 1,3,5-trinitro-1,3,5-triazine (RDX) contaminated
      soil at Picatinny Arsenal, New Jersey. These organisms were subsequently
      identified as Rhiziobium rhizogenes BL and Burkholderia sp.BL by the Deutsche
      Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ, German Collection of
      Microorganisms and Cell Cultures). In addition a fungus, identified as
      Cladosporium cladosporioides by DSMZ, was found to be growing on water wet RDX.
      All of these organisms were found to degrade RDX. The two bacteria were found to
      represent new species that have not been reported before. It was found that these
      organisms along with an added carbon source could degrade RDX to simple gaseous
      products. Data are presented that elucidate the mechanisms of RDX biodegradation
      for these organisms.

PMID- 15030143
TI  - Basic study on anaerobic biological filtration using a floating filter media.
AB  - An experiment of anaerobic filtration using a floating media was carried out in
      this study. In the present system, a bench-scale column of 50 mm in diameter and
      of 1500 mm in height and a floating media consisting of S-shaped polystyrene
      pieces were employed. The purpose of this study was to collect the basic data of
      anaerobic biological filtration using a floating media. Under the laboratory
      conditions, it was found that the start-up of an anaerobic biological filter took
      about half month at 20 degrees C and a lower BOD loading was favorable for this
      start-up. The BOD removal efficiency over 60% could be achieved at a BOD
      volumetric loading of the filter bed under 6 kg/m3/d. An effluent BOD
      concentration became high when the flow rate was high, especially with
      circulation of treated water, which afforded a large effect on an effluent BOD
      concentration. As for the mechanism of BOD removal by anaerobic filtration, it
      was evident that long retention time worked in favor for organic acid generation,
      and the circulation of treated water promoted decomposition of organic acids.

PMID- 15030144
TI  - Biological hydrogen production by enriched anaerobic cultures in the presence of
      copper and zinc.
AB  - Batch experiments were carried out to examine the productions of hydrogen and
      volatile fatty acids from glucose by enriched anaerobic culture in the presence
      of Cu and Zn. Results showed the specific hydrogen production rate was enhanced
      by the dosage of Cu at 50-100 mg/dm3 or the dosage of Zn at 10-250 mg/dm3, but
      was inhibited by Cu over 200 mg/dm3 or Zn at 500 mg/dm3. The hydrogen production
      yield was enhanced by Cu of 5-400 mg/dm3 or Zn of 5-500 mg/dm3. Productions of
      acetate and propionate were inhibited by Cu of 5-400 mg/dm3 or Zn of 5-500
      mg/dm3. On the other hand, production of butyrate was stimulated, whereas
      production of ethanol was not affected. In terms of the CI,50 values. Cu was more
      toxic than Zn. The modified Gompertz equation was able to properly describe the
      cumulative hydrogen production in the presence of Cu or Zn.

PMID- 15030145
TI  - Evaluation of bioassays for analyzing biodegradable dissolved organic carbon in
      drinking water.
AB  - Three different bioassays for analysis of biodegradable dissolved organic carbon
      (BDOC) were evaluated to identify which method is most applicable to analysis of
      drinking water. The determination of BDOC is primarily based on the differences
      between initial and final DOC levels during a certain incubation period using
      indigenous bacterial consortium as an inoculum. The assay procedures basically
      differ in the preparation method of inoculum. Inoculum was added in the form of
      suspended bacteria in one assay. In the other two assays, bacterial inoculum
      attached to either sand or inert media was used in a continuous reactor column.
      Standard solutions containing sodium acetate, sodium oxalate, or glucose at 1 mg
      C/L, and tap water were tested. The bioassay using bacteria attached to sand was
      shown to be superior to the two other methods for BDOC determination in terms of
      its incubation period, recovery, and reproducibility. Tap water samples, when
      analyzed by this assay, could not be guaranteed for biological stability due to
      their high BDOC concentrations (0.17 to 0.23 mg/L) that corresponded to 26-36% of
      the initial DOC level.

PMID- 15030146
TI  - Effects of photocatalysis on the biodegradability of Cibacron Brilliant Yellow 3G
      P (reactive yellow 2).
AB  - In this study, the biodegradability of an untreated and photocatalytically
      treated solution containing Cibacron Brilliant Yellow 3G-P was examined. Both
      untreated and partially treated dyes by photocatalysis were used in the
      biological treatment process. Respirometric measurements indicated that the
      untreated dye was not inhibitory to biological treatment at the concentration of
      100 mg/L. In addition, no significant biodegradation of both untreated and
      photocatalytically pre-treated dye occurred by either respirometric or
      conventional BOD tests using activated sludge. Respirometric measurements also
      suggested that both untreated and treated dye solutions were not biodegradable
      even with synthetic sewage. Under aerobic condition, partially treated dye
      solution showed better color removal rate than that of untreated solution.
      However, biodegradability of the 100 mg/L untreated dye solution was improved by
      50% in terms of Oxygen Uptake Rate (OUR) in respirometry by using acclimated
      sludge.

PMID- 15030147
TI  - Decolorization of dye RB-19 solution in a continuous ozone process.
AB  - This work studied the decolorization of dye C.I. Reactive Blue 19 (RB-19)
      solution in a new gas-inducing reactor under continuous process. The
      decolorization behavior, decolorization kinetic, ozone utilization rate (UO3),
      and Chemical Oxygen Demand (COD) are examined under various operation conditions,
      such as input ADMI color values (ADMIo), input liquid flow rates (QL), input
      ozone gas concentrations (CO3,i), input gas flow rates (Qg), and agitation speeds
      (N). Experimental results of decolorization behavior indicate that the American
      Dye Manufactures Institute (ADMI) removal percentage (RADMI) decreases with
      increasing ADMI color value input rate or decreasing ozone input rate. For the
      study of ozone utilization rate, UO3 increases with increasing ADMI color value
      input rate or decreasing ozone input rate. The 70% ADMI removal percentage can be
      regarded as the index of the competition of dye and its unknown intermediates for
      ozone. In addition, the increase of the agitation speed can improve the ADMI
      removal percentage as well as the ozone utilization rate. A pseudo-first order
      kinetic model is adopted to describe the decolorization behavior. At steady
      state, the overall decolorization rate constant, kADMIs.s., can be expressed as a
      function of liquid flow rate, input ADMI color value, input ozone gas
      concentration, gas flow rate, and agitation speed. This correlation can be used
      to predict the ADMI color value at steady state (ADMIs.s.) and the reactor size
      in the continuous process. The deltaO3/deltaCOD is dependent on the liquid
      composition. The higher the dye concentration in the liquid, the higher the
      deltaO3/deltaCOD. The COD removal percentage (RCOD) and the ozone utilization
      rate can be further improved by using the continuous operation with two reactors
      in series.

PMID- 15030148
TI  - Effect of UV-radiation on the migration of vinyl chloride monomer from
      unplasticized PVC pipes.
AB  - The effect of direct exposure to UV-radiation on the migration of vinyl chloride
      monomer (VCM) from unplasticized polyvinyl chloride (uPVC) pipes was investigated
      using locally manufactured pipes. Specimens 33-cm long were used throughout the
      research. The investigation was carried out, at different times of exposure to a
      UV-radiation. The VCM concentration in the water was evaluated using the gas
      chromatography (GC)/head-space technique. A VCM concentration of 2.3 microg/L
      (ppb) was detected after 14 days of exposure to the UV-radiation. The initial VCM
      concentration in the uPVC pipe was calculated and the diffusion coefficient of
      VCM was expressed as a function of time.

PMID- 15030149
TI  - Solar light induced degradation of reactive dye using photocatalysis.
AB  - Outdoors experiment with natural solar light instead of using artificial UV light
      was also conducted to investigate alternative energy source applicability on
      organics degradation. The results of this study were as follows. Degradation of
      the reactive dye, Red 120, with TiO2/solar light was enhanced by augmentation in
      TiO2 loading, and UV light intensity but was inhibited by increase in initial dye
      concentration. With both solar light illumination and TiO2 present, reactive dye
      was more effectively eliminated than with either solar light or TiO, alone.
      Photocatalytic removal efficiency of reactive dye increased with increasing TiO2
      dosage. However, over 1.5 gL(-1) of TiO2 dosage, the efficiency reached a
      plateau. The degradation rate of reactive dye, Red 120, was strongly dependent on
      initial dye concentration, and all the experimental data were fit to the first
      order rate equation. Photocatalytic degradation of reactive dye increased
      linearly with increasing UV light intensity. It is found that the presence of
      thick clouds in the sky markedly increased the time required for degradation of
      reactive dye. On the basis of these experimental observations, the photo
      oxidation degradation of reactive dye using TiO2 under solar light irradiation
      can be feasible application of the advanced oxidation process.

PMID- 15030150
TI  - An electrochemical method for decreasing the concentration of sulfate and
      molybdenum ions in industrial wastewater.
AB  - An electrochemical method is proposed for decreasing the concentration of sulfate
      and molybdenum species in industrial wastewater. The method is based on
      electromigration, electroosmosis, electrolysis, and subsequent secondary
      processes. The treatment has been carried out in electrolytic cells with graphite
      electrodes and anodic and cathodic compartments separated by a special ceramic
      membrane. Influence of the equipment design and working conditions on the
      treatment effectiveness has been studied. The concentrations of sulfate and
      molybdenum were decreased from 2000-2200 mg/L to 900-1100 mg/L and 1.9-2.2 mg/L
      to 0.8-1.2 mg/L, correspondingly. The pH of the treated water was 8.0-8.5, no
      additional chemicals were introduced and voluminous sludge was not formed. The
      method proposed is environmentally friendly and seems to be economically feasible
      for treating wastewater with large flow.

PMID- 15030151
TI  - Hardened paste of Portland cement--a new low-cost adsorbent for the removal of
      arsenic from water.
AB  - Portland cement has been used as a low-cost adsorbent for the removal of arsenic
      from the water environment. In the batch experiments conducted at an initial
      concentration of 0.2 ppm of arsenate, it was found that arsenate could be removed
      up to 95%. Kinetic profiles were developed for various conditions. Effect of
      adsorbent dose. effects of common ions such as Ca(2+), Mg(2+), Fe(3+)/Fe(2+), Cl(
      ), SO4(2-), NO3(-), PO4(3-), and the effect of pH was studied. Adsorption
      isotherm studies were performed and it was observed that the Freundlich isotherm
      was followed with a better correlation than the Langmuir isotherm. Arsenite could
      also be removed up to approximately 88% using the same material. A new detection
      method for arsenate/arsenite was developed for routine analysis of arsenic and
      used during the entire study.

PMID- 15030152
TI  - Vertical distribution and mobility of arsenic and heavy metals in and around mine
      tailings of an abandoned mine.
AB  - In the present study, the vertical distributions (0-220 cm) of arsenic and heavy
      metals in mine tailings and nearby paddy fields, and their mobility through water
      leach experiments were investigated. For the study, the area of Jingok mine
      located in Bongwha, Korea has been selected. The concentrations of arsenic and
      heavy metals in the mine tailings were extremely high compared to the paddy
      fields and control sites, i.e., up to 6675 mg/kg for As, 25 mg/kg for Cd, 22
      mg/kg for Cr, 383 mg/kg for Cu, 11,135 mg/kg for Pb, 3600 mg/kg for Zn, 5.73 wt%
      for Fe, and 3.05 wt% for Mn. The concentrations of As and heavy metals in the
      paddy fields decreased sharply with increasing distance from the mine tailings,
      with values still higher than those in the control sites, indicating the
      contamination of the paddy fields by heavy metals released from the mine
      tailings. The vertical distributions of Cd, Cu, Pb, Al, Fe, and Mn showed the
      following common pattern: the highest values in the upper part of mine tailings
      (0-20 cm), rapid decrease with increasing depth, and then nearly constant values
      below the depth of 50 cm. Significant correlations were found between total Fe
      and heavy metals (Cd, Cu, and Pb), and between total Mn and heavy metals (Cd, Cu,
      Pb, and Zn) in the mine tailings, indicating that minerals containing Fe and Mn
      play an important role in the mobility of heavy metals such as Cd, Cu, Pb, and
      Zn. The fraction of As(V) ranged from 63 to 100% of total arsenic in the samples
      of the mine tailings. The high concentrations of total As, heavy metals, sulfate.
      hydrogen ion, and As(V) in the leachates of mine tailings suggest that sulfide
      minerals containing arsenic and heavy metals in the mine tailings were actively
      oxidized.

PMID- 15030153
TI  - A combined bioprocess for integrated removal of copper and organic pollutant from
      copper-containing municipal wastewater.
AB  - Heavy metal-containing wastewater is difficult to treat by most of the bioprocess
      due to its toxicity to microorganism in activated sludge. In this study, a
      combined bioprocess consisting of biosorption section that contained magnetite
      immobilized Pseudomonas putida 5-x cell as biosorbent followed by sequence batch
      reactor (SBR) was developed to treat Cu(2+)-containing municipal wastewater. The
      production techniques of Pseudomonas putida 5-x cell as biosorbent, such as
      optimal cell harvest period and cell pretreatment techniques were studied.
      Experimental results showed, considering both cell biomass and cell adsorption
      capacity to Cu(2+), 36 h is the optimal harvest period in the course of culturing
      Pseudomonas putida 5-x cells as biosorbent, and 0.1-0.3 mol L(-1) HCl is an
      optimal cell pretreating eluant to improve Cu(2+) adsorption capacity. The
      performances of the combined bioprocess for treating Cu(2+) containing wastewater
      were assessed. Experimental results showed that after treatment by biosorption,
      the Cu(2+) level in wastewater was reduced to level that did not inhibit COD
      removal efficiency of subsequent SBR activated sludge process, although it still
      affected the COD adsorption capacity of activated sludge. In terms of COD
      removal, the biosorption section was efficient for reducing Cu(2+) concentration
      to provide biodegradable wastewater for subsequent SBR activated sludge process.

PMID- 15030154
TI  - Adsorption of copper and lead ions onto regenerated sludge from a water treatment
      plant.
AB  - In this study, water treatment sludges were sintered under various experimental
      conditions to generate Al-containing adsorbents. The adsorption of Cu2+ and Pb2+
      onto sintered oxide was examined and sorption results were further modeled using
      a surface complex model. The specific surface area of the sintered adsorbent was
      substantially reduced from 30 m2/g (dried sludge) to 2 m2/g (sinter sludge). The
      pH-adsorption-edges of both Cu2+ and Pb2+ were shifted towards a higher pH than
      the edges of the unsintered adsorbent, revealing reduced affinity of the sintered
      adsorbent for metal ions. Metal leaching was measured by the TCLP procedure, and
      the results indicated that the amount of metal leaching by the sintered adsorbent
      was negligible. The effect of background electrolytes on Cu2+ and Pb2+ sorption
      was negligible. Triple-layer model (TLM) simulation revealed that Cu2+ and Pb2+
      sorption on sintered adsorbent involves inner-sphere interactions and the
      dominant surface metal species are monodentates of Me2+ and MeOH+. The intrinsic
      adsorption constants of Cu2+ and Pb2+ on dried sludge, adsorbent sintered at 1000
      degrees C, and adsorbent sintered at 1100 degrees C were also examined.

PMID- 15030155
TI  - A study on dissolution properties of the sludges from Cr(VI) reduction
      precipitation processes.
AB  - In this article, dissolution characteristics of Cr(VI) reduction-precipitation
      sludges in the solutions containing mineral acids, organic complexing materials
      or both are examined. For this purpose, the effects of pH, concentration of
      complex forming agent and contact time on dissolution of metals from two
      different sludges obtained by using sodium sulphite and ferrous sulphate as
      reducing agents are studied. In addition, pollution potentials of the sludges are
      determined by applying the toxicity tests of TCLP, SPLP, USEPA-1979, and USEPA
      19X0. It was found that pH, contact time, concentration and type of complex
      forming substances are effective parameters on dissolution of metals from the
      sludges. In mineral acid solutions at pH 3, especially in the presence of organic
      complexing substances, chromium leached out from hydroxide sludges exceeds the
      concentration limits of USEPA for hazardous wastes. The amounts of chromium
      dissolved in the citric and ascorbic acid solutions and the amount of iron
      dissolved in the EDTA solution were found to be higher than in the other test
      solutions. Also, TCLP test shows that chromium hydroxide sludge obtained from
      sulphite reduction precipitation process of Cr(VI) is a potential hazardous
      solid. According to the results of this study, considering the probable presence
      of complexing agents in the disposal sites, toxicity test methods should be
      modified.

PMID- 15030156
TI  - Dynamic post-treatment response of olive mill effluent wastewater using activated
      carbon.
AB  - Olive mill eflluent (OME) wastewater represents a serious environmental problem
      in the Mediterranean area. It has extremely high values of COD, BOD, and phenolic
      content. A new approach of treatment steps composed of settling, centrifugation,
      and filtration is suggested to be used to condition OME wastewater. The filtrate
      is then subjected to a post-treatment process, namely adsorption on activated
      carbon. The dynamic response of phenols concentration, pH, and COD, using
      different concentrations of activated carbon, shows a peak at which maximum
      adsorption capacity is achieved. The maximum adsorption capacity for the tested
      concentrations of activated carbon is reached in less than 4 h. The maximum
      removal of phenols is about 94%, while it reaches about 83% for organic matter.

PMID- 15030157
TI  - Influences of calcium oxide content in marine fuel oil on emission
      characteristics of marine furnaces under varying humidity and temperature of the
      inlet air.
AB  - A marine furnace made of stainless steel. combined with an automatic small-size
      oil-fired burner, was used to experimentally investigate the influences of
      calcium oxide content in fuel oil on the combustion and emission characteristics
      under varying temperatures and humidity of the inlet air. Marine fuel oil
      generally contains various extents of metallic oxides such as CaO, Fe2O3, V2O5,
      etc which might affect its burning properties. In this study, an air-conditioner
      was used to adjust the humidity and temperatures of the inlet air to preset
      values prior to entering the burner. The adjusted inlet air atomized the marine
      diesel oil A containing a calcium oxide compound, to form a heterogeneous
      reactant mixture. The reactant mixture was thereafter ignited by a high-voltage
      electrode in the burner and burned within the marine furnace. The probes of a gas
      analyzer, H2S analyzer and a K-type thermocouple were inserted into the radial
      positions of the furnace through the eight rectangular slots which were cut in
      the upper side of the furnace. The experimental results showed that an increase
      of either humidity or temperature of the inlet air caused the promotion of the
      reaction rate of the fuel. The existence of calcium oxide compound in the diesel
      fuel also facilitated the oxidation reaction in the combustion chamber. The
      addition of CaO in the diesel fuel under the conditions of higher temperature or
      higher relative humidity of the inlet air produced the following: higher
      concentrations of CO2, SO2, and H2S emissions, an increased burning efficiency, a
      lowered O2 level, production of excess air and NOx emissions as well as a lower
      thermal loss and a lower burning gas temperature, as compared with the conditions
      of a lower temperature or a lower humidity of the inlet air. In addition, the
      burning of diesel fuel with added CaO compound caused a large variation in the
      burning efficiency, thermal loss, plus CO2, O2, and excess air emissions between
      the conditions of higher temperature/higher humidity and lower temperature/lower
      humidity inlet air compared with no CaO addition in the fuel. Moreover, the
      burning efficiency and the concentrations of excess air and O2 emissions
      increased, while the thermal loss, burning gas temperature and H2S, SO2, NOx, and
      CO2 emissions decreased with the increase of the axial distance from the measured
      location to the burner nozzle.

PMID- 15030158
TI  - Dynamic behavior of compost biofilters during periods of starvation and
      fluctuating hydrogen sulfide loadings.
AB  - To understand transient-state performance of biofilters and the phenomena
      occurring during changes and interruptions in their operating conditions, dynamic
      behavior of biofilters exposed to shock loadings of contaminant (H2S) and periods
      of starvation has been investigated. The initial startup and the response of the
      biofilters to step changes in the H2S concentration and air-loading rate were
      also presented and discussed. Biofilters responded very effectively to H2S
      concentration spikes at H2S mass loading rates of 19.8-48.0 g/m3h by rapidly
      recovering their original removal rates within 1.2-20.2 min. The recovery time
      after each spike showed a positive correlation to the total amount of H2S
      loadings during the spike. Biofilters showed capabilities of withstanding 11-28
      days of starvations and recovered their full performances after the starvations
      without any evident lag period.

PMID- 15030159
TI  - Herbal and vitamin/mineral supplement use by retirement community residents:
      preliminary findings.
AB  - A survey questionnaire assessed supplement use by free-living residents of a
      retirement community. Of the 318 respondents (mean age 82.2 years), 20% of women
      and 20% of men reported using herbal supplements, with 62% of these using them at
      least once per week. Most herbal supplements users (97%) also used
      vitamin/mineral supplements. Sixty-eight percent of herbal supplement users felt
      very much/somewhat informed about taking the supplements. Forty-four percent,
      however, were not sure whether there was testing before marketing; 33% were not
      sure about side effects. Half (52%) relied "very much/somewhat" on doctors/nurses
      as information sources; 40% relied on dietitians.

PMID- 15030160
TI  - Improving effectiveness of nutrition education resources for older adults.
AB  - This article discusses published reports and studies from the past decade that
      focused primarily on using written or other tangible nutrition educational
      resources with older adults, such as brief "handouts," newsletters, brochures,
      booklets, curricular lessons, board games, audiotapes and videotapes. Studies of
      health professionals' needs and desires for such materials are also reviewed.
      Thirteen articles, of which four were theory-based, were found. They are
      summarized in tables that include details regarding the educational resource(s)
      used; a description of the subjects and controls, if any; the evaluation methods
      used; and results obtained. Ten practical suggestions are offered to help
      educators select or develop more effective printed, audiotape, videotape and
      other tangible nutrition education resources appropriate for older adults. Much
      research remains to be done in this area. This article is one of a series of
      literature reviews of topics related to nutrition education for older adults.

PMID- 15030161
TI  - Using a focus group approach to determine older adults' opinions and attitudes
      toward a nutrition education program.
AB  - In order to determine older adults' (60+ years) attitudes and opinions toward a
      nutrition education program, six 45-minute focus groups were conducted. Twenty
      eight congregate meal site participants in Atlanta, Georgia, participated in the
      focus group discussions. Questions addressed opinions toward nutrition education,
      reasons for participating, outcomes following the program, and suggestions for
      future programs. Participants generally responded positively toward nutrition
      education, but viewed foods as "good" or "bad," and nutrition guidelines as
      "rules" or "orders." A predominant theme to surface was that these older adults
      were interested in receiving disease specific nutrition information, including
      handouts and goal setting activities.

PMID- 15030162
TI  - Nutrition education in six congregate meal sites improves participant's nutrition
      knowledge.
AB  - Providing relevant nutrition education at federally funded senior centers is one
      way of increasing nutrition knowledge of older adults. The purpose of this study
      was to present three nutrition education sessions on the revised Food Guide
      Pyramid, dietary protein, and dietary fiber to older adults at six senior centers
      in Atlanta, Georgia. Three 20-minute lesson plans were developed and delivered at
      six senior centers over the course of 3 weeks. Forty-eight matched pre- and post
      nutrition knowledge tests were analyzed and a significant difference (p < .01) in
      nutrition knowledge was found for the total score and three subtest scores.

PMID- 15030163
TI  - Determining gaps in a county-wide community nutrition education program for older
      adults.
AB  - This study assessed gaps in nutrition education between what was offered by
      organizations and what was wanted by older adults. In Phase I, 258 gatekeepers
      were interviewed. In Phase II, 37 non-institutionalized older adults were
      assigned to five focus groups. Study results indicated a consistency between
      gatekeepers and participants for services, topics, methods/information sources,
      and communication routes. However, a gap was found because participants wanted
      education on more topics and were interested in more specific information,
      whereas gatekeepers provided more general information. This study concluded that
      gatekeepers need to provide more topics and in greater specificity when planning
      for nutrition education programs for older adults.

PMID- 15030164
TI  - Enhancing the dining experience in long-term care: Dining with Dignity program.
AB  - Nursing home residents nationwide are at nutritional risk as the result of
      physical, social and environmental factors. The Dining with Dignity program
      integrates long-term care residents, staff, community volunteers and occupational
      therapy students to improve residents' nutritional intake. Volunteers are trained
      to provide one-on-one assistance during meals and to promote a positive dining
      experience as organized by the theory of Social Support. Resident satisfaction
      with meals and improved nutritional status are important outcomes as is volunteer
      commitment to the program.

PMID- 15030165
TI  - Reduction of palmitate-induced cardiac apoptosis by fenofibrate.
AB  - The objective of this study was to test the hypothesis that a strategy based on
      alteration of lipid metabolism would moderate the cellular toxicity of the C16:0
      saturated fatty acid-palmitate. Cardiomyocytes from neonatal mice and embryonic
      chicks were treated with palmitate and both oncotic and apoptotic death were
      observed. Fenofibrate pretreatment, 1 microM, 24 h prior to palmitate,
      significantly (p < 0.05) reduced palmitate-induced apoptosis. In contrast,
      fenofibrate had no significant effect on palmitate-induced apoptosis when
      fenofibrate treatment was concomitant with palmitate. The protective effect of
      fenofibrate was restricted to the apoptotic population. The more potent and
      specific PPARalpha agonist WY 14643, 1 microM, also reduced palmitate-induced
      apoptosis but to a smaller extent than fenofibrate. The long pretreatment time,
      24 h, was necessary to show fenofibrate's effect on apoptosis, suggesting an
      increase in gene transcription and protein expression. Indeed, fenofibrate
      increased PPARalpha expression that was mainly demonstrated in the nucleus. These
      data suggest a novel approach to the reduction of cardiac apoptosis by the
      chronic treatment with the PPARalpha agonist fenofibrate.

PMID- 15030166
TI  - Molecular analysis of signaling events mediated by the cytoplasmic domain of
      leukemia inhibitory factor receptor alpha subunit.
AB  - A chimeric receptor (130/190) containing the cytoplasmic region of leukemia
      inhibitory factor receptor alpha subunit (LIFRalpha, or gp190) and the
      extracellular transmembrane region of gp130 was generated. Expressed of the
      130/190 chimera in HL-60 cells to induced the homodimerization of the cytoplasmic
      domains (190cyt-190cyt) with whole LIFRalpha subunit on HL-60 cells in response
      to LIF. Expression and activation of the signal transducer and activator of
      transcription factor-3 (Stat3) and inhibition of leukemia cell proliferation were
      evaluated in cells transfected with this chimeric molecule. Increased tyrosyl
      phosphorylation of Stat3 at Tyr705 was detected after 10 min LIF treatment in
      cells transfected with either the 130/190 or the wild type receptor. Cell
      proliferation was decreased upon LIF treatment in both cell types. However,
      expression of the C-terminal region of the cytoplasmic region of LIFRalpha
      subunit (190CT) in HL-60 cells resulted in lower levels of Stat3 phosphorylation
      induction by LIF and cell proliferation was unaffected. Immunohistochemical
      staining indicated an inverse correlation between Cdc25B expression and the
      levels of phospho-Stat3 in 190CT and 130/190 cells. Expression of CD15, a cell
      differentiation marker, was lower in 190CT than in 130/190 cells. Together, these
      results suggest that homodimerization of the 190 cytoplasmic region promotes the
      Tyr 705 phosphorylation, which correlates with the inhibition of proliferation
      and stimulation of differentiation in HL-60 cells. Our results also suggest a
      signal link between Stat3 and Cdc25B.

PMID- 15030167
TI  - Inactivation of ERK accelerates erythroid differentiation of K562 cells induced
      by herbimycin A and STI571 while activation of MEK1 interferes with it.
AB  - K562 cells contain a Bcr-Abl chimeric gene and differentiate into various
      lineages in response to different inducers. We studied the role of the mitogen
      activated protein kinase (MAPK) kinase 1 (MEK1)/extracellular signal-regulated
      kinase (ERK) pathway during the erythroid differentiation of K562 cells induced
      by tyrosine kinase inhibitors (herbimycin A or STI571), using genetically
      modified cells (constitutively MEK1-activated K562: K562/MEK1, and inducible ERK
      inactivated K562: K562/CL100). Basal expression of glycophorin A was markedly
      reduced in K562/MEK1 cells compared with that in parental cells, while it was
      augmented in K562/CL100 cells. Herbimycin A and STI571 differentiated K562 cells
      accompanying with the transient down-regulated ERK. Moreover, the erythroid
      differentiation was markedly suppressed in K562/MEK1 cells, and early down
      regulation of ERK activity was not observed in these cells. In contrast, the
      induction of ERK-specific phosphatase in K562/CL100 cells potentiated erythroid
      differentiation. Once the phosphatase was induced, the initial ERK activity
      became repressed and its early down-regulation by the inhibition of Bcr-Abl was
      marked and prolonged. These results demonstrate that the erythroid
      differentiation of K562 cells induced by herbimycin A or STI571 requires the down
      regulation of MEK1/ ERK pathway.

PMID- 15030168
TI  - Post-translational modifications of tubulin and microtubule stability in adult
      rat ventricular myocytes and immortalized HL-1 cardiomyocytes.
AB  - Little is known about the subcellular distribution and the dynamics of tubulins
      in adult cardiac myocytes although both are modified during cardiac hypertrophy
      and heart failure. Using confocal microscopy, we examined post-translational
      modifications of tubulin in fully differentiated ventricular myocytes isolated
      from adult rat hearts, as well as in immortalized and dividing HL-1
      cardiomyocytes. Detyrosinated Glu-alpha-tubulin was the most abundant post
      translationally modified tubulin found in ventricular myocytes, while acetylated-
      and delta2-alpha-tubulins were found in lower amounts or absent. In contrast,
      dividing HL-1 cardiomyocytes exhibited high levels of tyrosinated or acetylated
      alpha-tubulins. A mild nocodazole treatment (0.1 microM, 1 h) disrupted
      microtubules in HL-1 myocytes, but not in adult ventricular myocytes. A stronger
      treatment (10 microM, 2 h) was required to disassemble tubulins in adult
      myocytes. Glu-alpha-tubulin containing microtubules were more resistant to
      nocodazole treatment in HL-1 cardiomyocytes than in ventricular myocytes.
      Endogenous activation of the cAMP pathway with the forskolin analog L858051 (20
      microM) or the beta-adrenergic agonist isoprenaline (10 microM) disrupted the
      most labile microtubules in HL-1 cardiomyocytes. In contrast, isoprenaline (10
      microM), cholera toxin (200 ng/ml, a G(S)-protein activator), L858051 (20 microM)
      or forskolin (10 microM) had no effect on the microtubule network in ventricular
      myocytes. In addition, intracellular Ca2+ accumulation induced either by
      thapsigargin (2 microM) or caffeine (10 mM) did not modify microtubule stability
      in ventricular myocytes. Our data demonstrate the unique stability of the
      microtubule network in adult cardiac myocytes. We speculate that microtubule
      stability is required to support cellular integrity during cardiac contraction.

PMID- 15030169
TI  - Inhibitory action of a new lectin from Xerocomus chrysenteron on cell-substrate
      adhesion.
AB  - Lectins are carbohydrate-binding proteins which potentially link to cell surface
      glycoconjugates and affect cell proliferation. We investigated the effect of a
      new lectin from the mushroom Xerocomus chrysenteron (XCL) on cell proliferation
      using adherent and suspension cell lines. XCL caused a dose-dependent inhibition
      of proliferation of the adherent cell lines NIH-3T3 and HeLa. Several experiments
      suggest that disruption of cell-substrate adhesion is the main factor affecting
      cell growth inhibition. (i) No antiproliferative effect was observed on the SF9
      cell line, which does not require to be attached to grow. (ii) XCL was shown to
      affect the adherence of cells following their suspension by trypsin treatment.
      (iii) XCL was localized on the cell surface where it would act as a coating
      agent. (iv) XCL induced morphological changes from well spread to rounded cells
      and disrupted the actin cytoskeleton. By contrast, flow cytometric analysis
      showed that XCL does not interfere with the cell cycle, and does not induce
      apoptosis.

PMID- 15030170
TI  - Effects of soluble TNF-alpha receptor 1 on apoptosis induced by oxidized LDL in
      endothelial cells.
AB  - Apoptosis-inducing agents have been reported to cause rapid shedding of tumor
      necrosis factor receptor 1 (TNFR1) in endothelial cells (EC). Oxidized LDL
      (oxLDL) has also been known to induce apoptosis of EC and to inhibit
      proliferation of EC. In the present study, we show that oxLDL also causes
      shedding of TNFR1 in EC and that EC transfected with soluble TNFR1 (sTNFR1 ),
      which is an extracellular domain of TNFR1, can antagonize the toxicity induced by
      oxLDL. These results suggest that transfection with the sTNFR1 gene plays a
      protective role against the injury of EC induced by oxLDL. We speculate therefore
      that sTNFR1 can be a new strategy for treatment of atherogenesis possibly by
      preventing shedding of TNFR1.

PMID- 15030171
TI  - Molecular characterization of a local sulfonylurea system in human adipose
      tissue.
AB  - ATP-sensitive potassium (KATP) channels are present in many cell types and link
      cellular metabolism to the membrane potential. These channels are heterooctamers
      composed of two subunits. The sulfonylurea receptor (SUR) subunits are targets
      for drugs that are inhibitors or openers of the KATP channels, while the inwardly
      rectifying K+ (Kir) subunits form the ion channel. Two different SUR genes (SUR1
      and SUR2) and two different Kir6.x genes (Kir6.1 and Kir6.2) have been
      identified. In addition, isoforms of SUR2, SUR2A and SUR2B, have been described.
      We have previously performed expression profiling on pooled human adipose tissue
      and found high expression of SUR2. Others have reported expression of SUR1 in
      human adipocytes. The aim of this study was to characterize the expression of the
      sulfonylurea receptor complex components in human adipose tissue. RT-PCR
      analysis, verified by restriction enzyme digestions and DNA sequencing, showed
      that SUR2B, Kir6.1 and alpha-endosulfine, but not SUR1, SUR2A or Kir6.2, are
      expressed in human adipose tissue. Real-time RT-PCR showed that SUR2B was
      expressed at higher levels in subcutaneous compared with omental adipose tissue
      in paired biopsies obtained from seven obese men (p < 0.05). Analysis of tissue
      distribution showed that SUR2B expression in adipose tissue was lower than that
      in muscle, similar to that in heart and liver, while the expression in pancreas
      was lower. The effect of caloric restriction was tested in obese men (n = 10)
      treated with very low calorie diet for 16 weeks, followed by a gradual
      reintroduction of ordinary food for 2 weeks. Biopsies were taken at week 0, 8 and
      18. There was no consistent effect of weight reduction on SUR2B or Kir6.1
      expression. We conclude that the necessary components for a local sulfonylurea
      system are expressed in human adipose tissue and that the sulfonylurea receptor
      complex in this tissue is composed of SUR2B and Kir6.1. The expression of SUR2B
      was higher in subcutaneous compared with omental adipose tissue and was not
      affected by weight loss.

PMID- 15030173
TI  - Evaluation of cellular energetics by the pasteur effect in intact cardiomyoblasts
      and isolated perfused hearts.
AB  - This work aims at exploring changes in cellular energetics by exploiting the
      Pasteur effect. We assumed that lactate overproduction arising from antimycin A
      induced inhibition of mitochondrial respiration (delta-lactate = stimulated
      [lactate] -basal [lactate]) is indicative of the energy provided aerobically by
      the cell. Rat embryonal cardiomyocytes (H9c2), incubated with 2 micromol/L
      antimycin A, increased about 6 fold their lactate production in a manner linear
      with time and cell number. Antimycin A was also delivered to Langendorff-perfused
      rat hearts under control aerobic conditions or after 20 min-ischemia and 30 min
      reperfusion. The test started at the end of each perfusion and lactate was
      measured into perfusate collected for further 25 min. A cardioplegic solution was
      also delivered during the test to exclude that lactate production was influenced
      by cardiac contraction. Control delta-lactate was 20.9 +/- 2.31 (S.E.M.)
      microg/mL and markedly decreased after reperfusion (7.66 +/- 0.51, p < 0.001),
      showing that energy production was impaired of about 70%. The determination of
      oxygen consumption by mitochondria isolated from reperfused hearts also suggested
      that the damage to the respiratory chain was similar to that evaluated by lactate
      overproduction (Respiratory Control Index: 75% lower than control, p < 0.001).
      Moreover, when delta-lactate was referred to the estimated cells which remained
      viable at the end of reperfusion (49.9%), it was 25% lower than control (p <
      0.05). Therefore, we proposed this test as a tool for quantifying both
      physiological and pathological energetic modifications in living intact
      cardiomyocytes and in isolated and perfused hearts.

PMID- 15030172
TI  - Identification, purification and characterization of matrix metalloproteinase-2
      in bovine pulmonary artery smooth muscle plasma membrane.
AB  - Bovine pulmonary artery smooth muscle tissue possesses matrix metalloproteinase-2
      (72 kDa gelatinase: MMP-2; E.C. 3.4.24.24) as revealed by immunoblot studies of
      its plasma membrane suspension with polyclonal MMP-2 antibody. In this report, we
      described the purification and partial characterization of MMP-2 in the plasma
      membrane fraction of the smooth muscle. MMP-2 has been purified from plasma
      membrane fraction of bovine pulmonary artery smooth muscle to homogeneity using a
      combination of purification steps. Heparin sepharose purified preparation of 72
      kDa progelatinase is composed of two distinct population of zymogens: a 72 kDa
      progelatinase tightly complexed with TIMP-2 (an ambient tissue inhibitor of
      metalloprotease in the smooth muscle plasma membrane), and a native 72 kDa
      progelatinase free of any detectable TIMP-2. The homogeneity of the native 72 kDa
      progelatinase form is demonstrated by SDS-PAGE under non-reducing condition, non
      denaturing native gel electrophoresis. The purified TIMP-2 free proenzyme
      electrophoresed as a single band of 72 kDa which could be activated by APMA with
      the formation of 62 and 45 kDa active species. The proenzyme is activated poorly
      by trypsin but not by plasmin. The purified 72 kDa progelatinase is stable at
      aqueous solution and does not spontaneously autoactivate. The purified 72 kDa
      gelatinase exhibited properties that are typical of MMP-2 obtained from other
      sources. These are: (i) its activity is dependent on the divalent cation, Ca+2,
      and is inhibited by EDTA, EGTA and 1:1 0-phenanthroline; (ii) it was inhibited by
      a, macroglobulin but not by the inhibitors of serine, cysteine, thiol, aspartic
      proteinases and calpains; (iii) it was found to be inhibited by TIMP-2, the
      specific inhibitor of MMP-2; (iv) like MMP-2, obtained from other sources, its
      major substrates were found to be collagens (type IV and V) and gelatins (type I,
      IV and V). Additionally, the purified MMP-2 degrades Dnp-Pro-Gln-Gly-Ile-Ala-Gly
      Gln-D-Arg-OH (dinitrophenyl labelled peptide), a well known synthetic substrate
      for the MMP-2.

PMID- 15030174
TI  - Microtubule alteration is an early cellular reaction to the metabolic challenge
      in ischemic cardiomyocytes.
AB  - Cytoskeleton damage, particularly microtubule (MT) alterations, may play an
      important role in the pathogenesis of ischemia-induced myocardial injury.
      However, this disorganization has been scarcely confirmed in the cellular
      context. We evaluated MT network disassembly in myoblast cell line H9c2 and in
      neonatal rat cardiomyocytes in an in vitro substrate-free hypoxia model of
      simulated ischemia (SI). After different duration of SI from 30 up to 180 min,
      the cells were fixed and the microtubule network was revealed by
      immunocytochemistry. The microtubule alterations were quantified using a house
      developed image analysis program. Additionally, the tubulin fraction were
      extracted and quantified by Western blotting. The cell respiration, the release
      of cellular LDH and the cell viability were evaluated at the same periods. An
      early MT disassembly was observed after 60 min of SI. The decrease in MT
      fluorescence intensity at 60 and 90 min was correlated with a microtubule
      disassembly. Conversely, SI-induced significant LDH release (35%) and decrease in
      cell viability (34%) occurred after 120 min only. These results suggest that the
      simulated ischemia-induced changes in MT network should not be considered as an
      ultrastructural hallmark of the cell injury and could rather be an early
      ultrastructural correlate of the cellular reaction to the metabolic challenge.

PMID- 15030175
TI  - Reciprocal regulation of beta-adrenergic receptor mRNA stability by mitogen
      activated protein kinase activation and inhibition.
AB  - Genes encoding numerous proto-oncogenes and cytokines, as well as a number of G
      protein coupled receptors, are regulated post-transcriptionally at the level of
      mRNA stability. A common feature of all of these genes is the presence of A + U
      rich elements (AREs) within their 3' untranslated regions. We, and others, have
      demonstrated previously that mRNAs encoding beta-adrenergic receptors (beta-ARs)
      are destabilized by agonist stimulation of the beta-AR/Galphas/adenylylcyclase
      pathway. However, in addition to PK-A, beta-ARs can also activate or inhibit
      mitogen activated kinase (MAPK) cascades, in a cell-type dependent basis. Recent
      evidence points to an important role for MAPKs in regulating the turnover of
      cytokine mRNAs, such as TNFalpha. We hypothesized that activation of MAPK's may
      also regulate beta-AR mRNA stability. The studies conducted herein demonstrate
      that generalized stimulation of MAPKs (JNK, p38) with anisomycin resulted in
      marked stabilization of beta-AR mRNA. Reciprocally, selective inhibition of JNK
      with SP600125 significantly decreased beta-AR mRNA half-life. Similarly,
      inhibition of the MEK/ERK pathway with either PD98059 or U0126 decreased beta-AR
      mRNA stability substantially. However, inhibition of p38 MAPK with SB203580
      produced destabilization of beta-AR mRNA only at higher, non pharmacologically
      selective concentrations. In contrast to their effects on several other ARE
      containing mRNAs, inhibition of tyrosine kinases by genistein or PI3K by
      wortmannin, had no detectable effect on beta-AR mRNA stability. In summary, these
      results demonstrate for the first time that modulation of MAPK pathways can bi
      directionally influence beta-AR mRNA stability.

PMID- 15030176
TI  - The protective effects of HDL and its constituents against neutrophil respiratory
      burst activation by hypochlorite-oxidized LDL.
AB  - Hypochlorite-oxidized low-density lipoprotein (oxLDL) possesses a substantial
      proinflammatory potential by modulating respiratory burst activities of
      polymorphonuclear neutrophils (PMN). As evaluated by luminol-amplified
      chemiluminescence (CL) incubation of 10(6) PMN/ml with 70 nM oxLDL was followed
      by substantial induction of neutrophil oxidant (ROS) generation. We evaluated the
      inhibitory capacity of high-density lipoprotein (HDL) and its lipid and protein
      constituents against the activating effects of oxLDL. At a HDL or apolipoprotein
      AI/LDL protein ratio of 1.0, native HDL decreased the respiratory burst
      activation by 64%, followed by trypsinized HDL (57%) and native apoAI (43%). The
      inhibitory effects of native HDL did not require prior incubation with PMN or
      with oxLDL suggesting an instantaneously acting protective mechanism in the
      minute range. OxLDL modulated ROS production not only of resting PMN but also
      that of activated PMN, as indicated by a 14-fold increase in FMLP-stimulated CL
      response and a 50% decrease in zymosan-mediated CL answer. HDL itself did not
      protect PMN from activation by FMLP and zymosan. However, it clearly reduced
      effects of oxLDL on FMLP-activation and slightly counteracted the oxLDL-mediated
      decrease in zymosan-induced ROS generation. Taken together, these findings may
      offer new insight into atheroprotective mechanisms of HDL.

PMID- 15030179
TI  - Effect of reactive oxygen species on the metabolism of tryptophan in rat brain:
      influence of age.
AB  - In an earlier study, oxidation of tryptophan hydroxylase was implicated as its
      affinity was decreased with aging in rat brain. To establish any potential link
      between its oxidative damage and aging, we have determined the activities of
      antioxidant enzymes in midbrain, pons and medulla of 2, 12 and 24 month old
      Fisher 344 BNF1 rats. The results obtained suggest that the activities of
      antioxidant enzymes varied considerably with age and brain regions studied.
      Activities of Cu/Zn superoxide dismutase and glutathione peroxidase were found to
      increase from 2 to 12 months and then decrease in 24 month old rats. However
      catalase activity decreased consistently with the age. A parallel increase in the
      carbonyl content was observed in these brain regions indicating the oxidation of
      proteins. Reactive oxygen species when included in the incubation mixture
      decreased the activity of tryptophan hydroxylase in a concentration dependent
      manner. The loss of tryptophan hydroxylase activity induced by hydrogen peroxide
      and superoxide anion was prevented by catalase. However superoxide dismutase did
      not provide such protection. Sulfhydryl agents, cysteine, glutathione and
      dithiothreitol partially prevented the loss of activity. These studies suggest an
      involvement of reactive oxygen species for sulfhydryl oxidation of tryptophan
      hydroxylase in aging.

PMID- 15030178
TI  - beta-Cryptoxanthin stimulates bone formation and inhibits bone resorption in
      tissue culture in vitro.
AB  - The effect of beta-cryptoxanthin, which is greatly present in fruits, has not
      been clarified so far on bone metabolism. The effect of beta-cryptoxanthin on
      bone formation and bone resorption was investigated in tissue culture in vitro.
      Rat femoral-diaphyseal (cortical bone) and -metaphyseal (trabecular bone) tissues
      were cultured for 48 h in Dulbecco's modified Eagle's medium (high glucose, 4.5%)
      supplemented with antibiotics and bovine serum albumin. The experimental cultures
      contained 10(-8)-10(-5) M beta-cryptoxanthin. The presence of beta-cryptoxanthin
      (10(-6) or 10(-5) M) caused a significant increase in calcium content, alkaline
      phosphatase activity and deoxyribonucleic acid (DNA) content in the diaphyseal
      and metaphyseal tissues. These increases were completely prevented in the
      presence of cycloheximide (10(-6) M), an inhibitor of protein synthesis. beta
      Carotene (10(-6) or 10(-5) M) or xantine (10(-6) or 10(-5) M) had no effect on
      the diaphyseal and metaphyseal calcium contents. The bone-resorbing factors
      parathyroid hormone (1-34) (PTH; 10(-7) M) or prostaglandin E2 (PGE2; 10(-5) M)
      caused a significant decrease in calcium content in the diaphyseal and
      metaphyseal tissues. The decrease in bone calcium content induced by PTH or PGE2
      was completely inhibited by beta-cryptoxanthin (10(-8)-10(-6) M). In addition,
      beta-cryptoxanthin (10(-8)-10(-6) M) completely inhibited the PTH (10(-7) M)- or
      PGE, (10(-5) M)-induced increase in medium glucose consumption and lactic acid
      production by diaphyseal and metaphyseal tissues. The inhibitory effect of beta
      cryptoxanthin (10(-7) M) on PTH (10(-7) M)- or PGE2 (10(-5) M)-stimulated
      decrease in the diaphyseal calcium content was significantly prevented in the
      presence of 10(-3) M vanadate, an inhibitor of protein tyrosine phosphatase.
      Vanadate (10(-3) M) did not have a significant effect on calcium content and
      lactic acid production in control bone tissues. The present study demonstrates
      that beta-cryptoxanthin has a direct stimulatory effect on bone formation and an
      inhibitory effect on bone resorption in tissue culture in vitro.

PMID- 15030177
TI  - High glucose-induced membrane translocation of PKC betaI is associated with Arf6
      in glomerular mesangial cells.
AB  - Protein kinase C (PKC)-induced changes in glomerular mesangial cell (MC)
      phenotypic behavior has been implicated in diabetes. The activity of
      diacylglycerol-sensitive PKC isoforms in MCs is altered by ambient changes in
      glucose, but the regulation of PKC activity and subsequent intracellular
      signaling events are not yet clearly defined. Small GTP-binding proteins of the
      ADP-ribosylation factor (Arfs) family, may regulate protein kinase membrane
      recruitment and hence its activity in signaling events of non-polarized cells.
      Members of the ARF family may coordinate membrane dynamics and other cellular
      functions through their interaction with PKC. We studied the activation of Arf,
      PKC betaI and phospholipase D (PLD) in MCs cultured under normal or high glucose
      conditions. MCs cultured in high glucose medium exhibited predominantly cytosolic
      localization of PKC betaI, Arf3 and Arf6. However, phorbol ester (PMA)
      stimulation of cells cultured in high glucose significantly enhanced membrane
      association of PKC betaI and Arf6, but not Arf3. Using [3H]choline chloride to
      prelabel MCs and measuring [3H]choline-containing metabolite release as PLD
      activity, PMA stimulated a significant increase of PLD activity under high
      glucose condition. Our data suggest that Arf6 plays a specific role in activation
      of PKC betaI and PLD under high glucose condition, and may be a significant
      intracellular event in the change of the mesangial cell phenotype associated with
      diabetic nephropathy.

PMID- 15030180
TI  - Heterogenic response of the liver parenchyma to ethanol studied in the
      bivascularly perfused rat liver.
AB  - Zonation of ethanol oxidation and metabolic effects along the hepatic acini were
      investigated in the bivascularly perfused liver of fed rats. Ethanol was infused
      into the hepatic artery in antegrade and retrograde perfusion. Inhibition of
      glycolysis by ethanol, expressed as micromol min(-1) (ml accessible cell space)(
      1), was more pronounced in the retrograde mode; the retrograde/antegrade ratio
      was equal to 1.63 for an ethanol infusion rate of 37.5 micromol min(-1) g(-1).
      Stimulation of oxygen uptake by ethanol was more pronounced in the retrograde
      mode; the retrograde/antegrade ratio was equal to 1.77. Diminution of the citrate
      cycle caused by ethanol was more pronounced in the retrograde mode; the
      retrograde/antegrade ratio was equal to 1.46. Transformation of arterially
      infused ethanol into acetate was more pronounced in retrograde perfusion; the
      retrograde/antegrade ratio was equal to 1.63. The increments in glucose release
      (glycogenolysis) caused by ethanol in the antegrade and retrograde modes were
      similar. It was assumed that the changes caused by arterially infused ethanol in
      retrograde and antegrade perfusion closely reflect a significant part of the
      periportal parenchyma and an average over the whole liver parenchyma,
      respectively. Under such assumptions it can be concluded that, in the perfused
      liver from fed rats, four related parameters predominate in the periportal
      region: ethanol oxidation, glycolysis inhibition, oxygen uptake stimulation and
      citrate cycle inhibition. One of the main causes for this predominance could be
      the malate/aspartate shuttle, which operates more rapidly in the periportal area
      and is essential for NADH oxidation.

PMID- 15030181
TI  - Differential prevalence of anti-heparin-PF4 immunoglobulin subtypes in patients
      treated with clivarin and heparin: implications in the HIT pathogenesis.
AB  - Heparin-induced thrombocytopenia (HIT) syndrome is a catastrophic complication of
      heparin therapy that may result in arterial/venous thromboembolic events. The
      pathophysiology of HIT is mediated by the generation of a functionally and
      molecularly heterogeneous group of anti-heparin-platelet factor 4 (AHPF4)
      antibodies that cause platelet/endothelial cell activation/destruction. These
      AHPF4 antibodies may be of various subtypes and cause differential pathogenic
      responses during HIT. This study evaluated the differential prevalence and
      functionality of AHPF4 Ig subtypes (IgA, IgG, and IgM) in plasma samples obtained
      from clinically suspected HIT patients (n = 111) and two clinical trials. In
      these trials, a low-molecular-weight heparin, clivarin and unfractionated heparin
      (UFH) were used to treat deep-vein thrombosis (CORTES) and for prophylaxis of the
      orthopedic surgery (ECHOS). In the CORTES study, three randomized groups of
      patients (n = 312-328) received prophylactic treatment with either UFH or
      clivarin (o.d. or b.i.d.). In the ECHOS study, there were approximately 600
      patients per group. Citrated plasma samples were analyzed for cumulative
      IgA/IgG/IgM and individual Ig subtypes of AHPF4 utilizing ELISA. Functionality of
      the ELISA-positive samples was ascertained by 14C-serotonin release assay. In
      clinically confirmed HIT patients (and UFH-treated CORTES and ECHOS samples), the
      Ig subtyping revealed a predominance of IgG AHPF4 antibodies in contrast to the
      asymptomatic high AHPF4 antibody titers, which were found to be mostly IgM and/or
      IgA subtypes. In the clivarin-treated patients in both trials, the prevalence of
      AHPF4 antibodies was found to be lower (2-3 fold, p < 0.01) in comparison to UFH
      group. In addition, the clivarin-treated patients with positive AHPF4 antibodies
      were found to be predominantly of the non-functional type and were found in the
      order of IgM > IgA > IgG Together, these observations demonstrate that ELISA
      detectable IgG subtype in UFH-treated patients may be more likely to cause
      functional/pathologic responses during HIT syndrome. Thus, determination of IgG
      subtype of AHPF4 antibodies during HIT syndrome may be crucial in the diagnosis;
      however, the relevance of the pathologically non-functional (IgA and/or IgM)
      antibodies and the overall mechanism(s) of these HIT-associatied antibodies need
      further investigation.

PMID- 15030183
TI  - Identification of rTid-1, the rat homologue of the drosophila tumor suppressor
      l(2)tid gene.
AB  - Active cell death ('apoptosis' or 'programmed cell death') is essential in the
      development and homeostasis of multicellular organisms and abnormal inhibition of
      apoptosis is an indicator of cancer and autoimmune diseases, whereas excessive
      cell death is implicated in neurodegenerative disorders such as Alzheimer's
      disease (AD). Here we demonstrate new isoforms of the rat homologue of the
      drosophila tumor suppressor l(2)tid gene (rTid-1). Moreover, we show that rTid-1
      interacts isoform-specifically with the heat-shock-cognate-glucose-regulated
      protein hscGRP75 and neither induces nor inhibits directly neuronal apoptosis.
      This finding points to a pivotal role of Tid-1 in the control of cellular
      survival.

PMID- 15030182
TI  - Fatty acid oxidation and related gene expression in heart depleted of carnitine
      by mildronate treatment in the rat.
AB  - The metabolic and genic effects induced by a 20-fold lowering of carnitine
      content in the heart were studied in mildronate-treated rats. In the perfused
      heart, the proportion of palmitate taken up then oxidized was 5-10% lower, while
      the triacylglycerol (TAG) formation was 100% greater than in controls. The
      treatment was shown to increase the maximal capacity of heart homogenates to
      oxidize palmitate, the mRNA level of carnitine palmitoyltransferase I (CPT-I)
      isoforms, the specific activity of CPT-I in subsarcolemmal mitochondria and the
      total carnitine content of isolated mitochondria. Concomitantly, the increased
      mRNA expression of lipoprotein lipase, fatty acid translocase and enzymes of TAG
      synthesis was associated with a 5- and 2-times increase in serum TAG and free
      fatty acid contents, respectively. The compartmentation of carnitine at its main
      functional location was expected to allow the increased CPT-I activity to ensure
      in vivo correct fatty acid oxidation rates. All the inductions related to fatty
      acid transport, oxidation and esterification most likely stem from the abundance
      of blood lipids providing cardiomyocytes with more fatty acids.

PMID- 15030185
TI  - Production and export of metabolites from liver and heart mitochondria and
      anaplerosis.
AB  - A method to study the export of citric acid cycle intermediates from rat liver
      mitochondria supplied with various individual substrates or combinations of
      substrates was designed to focus on the role of mitochondria in anaplerosis and
      cataplerosis. Under most conditions malate, citrate, and aspartate were exported
      in far higher amounts than isocitrate and alpha-ketoglutarate. In the presence of
      pyruvate alone or pyruvate in combination with most other substrates, citrate
      export equaled or was only slightly less than malate export. This contrasts with
      pancreatic islet mitochondria where citrate export is unaffected by many
      substrates. Malate and succinate potentiated pyruvate-induced citrate export and
      succinate caused massive malate export from liver mitochondria. Heart
      mitochondria, which possess very little or no pyruvate carboxylase, unlike liver
      and pancreatic islet mitochondria, did not produce malate from pyruvate. Heart
      mitochondria produced malate, but not citrate, from succinate. The results
      indicate that liver mitochondria export a larger number of metabolites from a
      wider range of substrates than do islet or heart mitochondria. This may reflect
      the multiple roles of the liver in body metabolism versus the specialized roles
      of the islet cell and heart.

PMID- 15030184
TI  - ACTH stimulates the release of alkaline phosphatase through Gi-mediated
      activation of a phospholipase C and the release of inositol-phosphoglycan.
AB  - We have previously reported that ACTH activates a phospholipase C that hydrolyzes
      glycosylphosphatidylinositol (GPI), which would release inositolphosphoglycan
      (IPG) to the extracellular medium, and that an IPG purified from Trypanosoma
      cruzi is able to inhibit ACTH-mediated steroid production in adrenocortical
      cells. In the present paper, it was found that anti-inositolphosphoglycan
      antibodies (anti-CRD) increased ACTH-mediated corticosterone production, which
      indicates that an endogenous IPG is a physiological inhibitor of ACTH response.
      On the other hand, we investigated the release to the extracellular medium of the
      GPI-anchored enzyme, alkaline phosphatase, by ACTH. We found that: (a) the
      released enzyme appeared in the aqueous phase after Triton X-114 partitioning,
      consistent with loss of the GPI, (b) the phospholipase C inhibitor, U73122,
      impaired the release of the enzyme by the hormone and (c) two inhibitors of IPG
      uptake, inositol 2-monophosphate and 2 M NaCl, increased the amount of alkaline
      phosphatase in the extracellular medium. These results suggest that ACTH releases
      alkaline phosphatase by activation of a phospholipase C. Dibutyryladenosine-3',5'
      cyclic monophosphate (db-cAMP) was able to increase the release of alkaline
      phosphatase from adrenocortical cells and this effect was inhibited by U73122,
      suggesting that cAMP is involved in the activation of phospholipase C. In
      addition, it was found that a pertussis-toxin sensitive G-protein is required for
      ACTH- and db-cAMP-mediated release of alkaline phosphatase and that incorporation
      of anti-Gi antibodies in adrenocortical cells inhibited the release of alkaline
      phosphatase by ACTH. Our results suggest that ACTH increases the release of
      alkaline phosphatase by activation of a phospholipase C through cAMP and Gi which
      would contribute to produce IPG It was also found that the two inhibitors of IPG
      uptake, inositol-2-monophosphate and 2 M NaCl, increased the amount of alkaline
      phosphatase in the extracellular medium of ACTH-treated cells more than in
      control cells, indicating that ACTH also stimulates the uptake of IPG These data
      support a role of GPI and the involvement of Gi in ACTH action.

PMID- 15030187
TI  - Cholesterol-sensor initiates M. tuberculosis entry into human macrophages.
AB  - Cholesterol-mediated mycobacteria entry into and survival within macrophages has
      added a new dimension to Tuberculosis research. The molecular mechanism through
      which cholesterol initiates this process is still poorly understood. The present
      study addressed to resolve this mechanism revealed that Mycobacterium
      tuberculosis possesses cholesterol-specific Receptor 'Ck'-like molecule
      responsible for mycobacterial entry into macrophages. Further human Receptor-Ck
      was found to regulate transcriptional expression of a gene that codes for
      Tryptophan-Aspartate containing coat (TACO) protein responsible for survival of
      mycobacteria within cells. Based upon these results, we propose that interaction
      of Receptor-Ck with cholesterol-rich membrane domains helps to create a 'Synaptic
      junction' between mycobacteria and macrophage resulting in signalling events that
      are responsible for mycobacterium entry into and survival within macrophages.

PMID- 15030186
TI  - Effect of angiotensin II type 2 receptor blockade on mitogen activated protein
      kinases during myocardial ischemia-reperfusion.
AB  - Mitogen-activated protein kinases (MAPKs) have been implicated during ischemia
      reperfusion (IR) and angiotensin II (AngII) type 2 receptor (AT2R) blockade has
      been shown to induce cardioprotection involving protein kinase Cepsilon
      (PKCepsilon) signaling after IR. We examined whether the 3 major MAPKs, p38, c
      Jun NH2-terminal kinase (JNK-1 and JNK-2), and extracellular signal regulated
      kinases (ERK-1 and ERK-2) are activated after IR and whether treatment with the
      AT2R antagonist PD123,319 (PD) alters their expression. Isolated rat hearts were
      randomized to control (aerobic perfusion, 80 min), IR (no drug; 50 min of
      perfusion, 30 min global ischemia and 30 min reperfusion; working mode), and IR +
      PD (0.3 micromol/l) and left ventricular (LV) work was measured. We measured LV
      tissue content of p38, p-p38, p-JNK-1 (54 kDa), p-JNK-2 (46 kDa), p-ERK-1 (44
      kDa), p-ERK-2 (42 kDa) and PKCepsilon proteins by immunoblotting and cGMP by
      enzyme immunoassay. IR resulted in significant LV dysfunction, increase in p-p38
      and p-JNK-1/-2, no change in p-ERK-1/-2 or PKCepsilon, and decrease in cGMP. PD
      improved LV recovery after IR, induced a slight increase in p-p38 (p < 0.01 vs.
      control), normalized p-JNK-1, did not change p-ERK-1/-2, and increased PKCepsilon
      and cGMP. The overall results suggest that p38 and JNK might play a significant
      role in acute IR injury and the cardioprotective effect of AT2R blockade
      independent of ERK. The activation of p38 and JNKs during IR may be linked, in
      part, to AT2R stimulation.

PMID- 15030188
TI  - Determination of 1-deoxynojirimycin in mulberry leaves using hydrophilic
      interaction chromatography with evaporative light scattering detection.
AB  - A simple and rapid method for determining 1-deoxynojirimycin (DNJ), a potent
      glucosidase inihibitor present in mulberry leaves (Morus alba and Morus
      bombysis), by high-performance liquid chromatography coupled to an evaporative
      light scattering detector (ELSD) has been developed. DNJ was separated from an
      extract of mulberry leaves on a TSKgel Amide-80 column, which is a representative
      column for hydrophilic interaction chromatography. During postcolumn detection,
      DNJ was detected by ELSD and concurrently identified by mass spectrometry. The
      detection limit was 100 ng. This method is sufficiently sensitive for determining
      DNJ in mulberry leaves and other related products.

PMID- 15030189
TI  - Determination of phytohormones of environmental impact by capillary zone
      electrophoresis.
AB  - A test mixture of five phytohormones [naphthaleneacetic acid (NAA),
      naphthoxyacetic acid (NOA), indoleacetic acid (IAA), indolebutyric acid (IBA),
      and indolepropionic acid (IPA)] was investigated. These compounds were cleanly
      separated with good resolution by capillary zone electrophoresis with a UV diode
      array detector using 20 mM sodium phosphate buffer (pH 7.25). The lowest
      detection limit was obtained for IPA (0.45 mg L(-)(1) or 0.005 mg kg(-)(1)) and
      the highest for NAA (1.04 mg L(-)(1) or 0.014 mg kg(-)(1)). The method has been
      applied for tomato samples fortified with the five phytohormones using a liquid
      liquid extraction procedure, obtaining recovery percentages ranging from 91 to
      109.0%.

PMID- 15030190
TI  - Accurate determination of oosporein in fungal culture broth by differential pulse
      polarography.
AB  - A simple and accurate differential pulse polarographic method has been developed
      for the determination of oosporein in the culture broth of the fungus Beauveria
      brongniartii. This hydroxybenzoquinone derivative is the only major secondary
      metabolite secreted by this entomopathogenic fungus, which is used as biological
      pest control agent (BCA) against Melolontha melolontha larvae. It can be found in
      the host organism as well as in the formulated product. The polarographic
      behavior of oosporein was examined in various buffer systems over the pH range 3
      10. In Britton-Robinson buffer/methanol solution (3:7 v/v, pH 5.5) the
      differential pulse polarograms exhibited reproducible peaks at E(p) = -0.18 V vs
      silver/silver chloride/potassium chloride (3 M). Under these conditions, a plot
      of peak height vs concentration of oosporein was found to be linear over the
      range 5.9 x 10(-)(7) to 2.5 x 10(-)(5) M (0.18-7.74 microg mL(-)(1); r = 0.9998).
      The detection limit was calculated to be 54 ng mL(-)(1). To evaluate the
      concentration of oosporein, the standard addition method was applied. The
      analysis of oosporein in the culture broth led to a mean value of 524.9 microg
      mL(-)(1) broth with a relative standard deviation (S(rel)) of +/-2.6%. The
      proposed polarographic method is accurate, not time-consuming, and it is of low
      cost because no separation steps are necessary.

PMID- 15030191
TI  - Metabolic profiling: a new tool in the study of wood formation.
AB  - In the realm of plant genomics, metabolic profiling has become a valuable tool
      with which to assess the effect of genetic and/or environmental factors on plant
      development. This paper reports the first application of metabolic profiling on
      differentiating xylem tissue of loblolly pine. A protocol is presented for the
      analysis of loblolly pine xylem tissue. The effects of sample preparation,
      extraction, and derivatization on the corresponding metabolite profiles and
      yields have been investigated and are reported. Gas chromatography-mass
      spectroscopy has been used to quantify >60 polar and lipophilic metabolites from
      wood-forming tissue. It was possible to assign chemical structures to
      approximately half of these compounds. Comparison of six loblolly pine genotypes,
      three high cellulose (50-52%) and three medium (45-48%) cellulose, showed
      distinct metabolic profiles. Principal component analysis enabled the assignment
      of metabolic phenotypes using these large data sets. Metabolic phenotype
      clustering occurred in which the three high-cellulose genotypes were segregated
      from the medium-cellulose genotypes. These results demonstrate the use of
      metabolic profiling for the study of wood-forming tissue and as a tool in
      functional genomics.

PMID- 15030192
TI  - Rapid prediction of solid wood lignin content using transmittance near-infrared
      spectroscopy.
AB  - A rapid transmittance near-infrared (NIR) spectroscopic method has been developed
      to characterize the lignin content of solid wood. Using simple, multiple
      regression, and partial least-squares statistical analysis the lignin contents of
      wood wafers, taken from increment cores, and synthetic wood, prepared by blending
      milled wood lignin and holocellulose, were compared and quantified. Strong
      correlations were obtained between the predicted NIR results and those obtained
      from traditional chemical methods. In addition to the experimental protocol and
      method development, NIR results from wood samples with different particle sizes
      and various lignin contents are discussed.

PMID- 15030193
TI  - Determination of organic acids by high-performance liquid chromatography with
      electrochemical detection during wine brewing.
AB  - Voltammetric determination of acids by means of the electrochemical reduction of
      quinone was applied to high-performance liquid chromatography (HPLC) with
      electrochemical detection (ED) for determining organic acids in fruit wines. A
      two-channel HPLC-ED system was fabricated by use of an ion-exclusion column and
      an electrochemical detector with a glassy carbon working electrode. Aqueous
      solution of 0.1 mM HClO(4) and ethanol containing 2-methyl-1,4-naphthoquinone
      served as a mobile phase and reagent solution, respectively. Determination of
      acetic, citric, lactic, malic, succinic, and tartaric acids was made by measuring
      the peak areas of the flow signals due to the reduction current of quinone caused
      by the eluted acids. The peak area was found to be linearly related to the acid
      amount ranging from 0.1 to 40 nmol per 20 microL injection. The present method
      was characterized by reproducibility with the simple and rapid procedure without
      derivatization of analytes. The method was shown as an effective means for
      following acid contents in fruit juices during fermentation with wine yeast.

PMID- 15030194
TI  - Multiresidue determination of pesticides in soil by gas chromatography-mass
      spectrometry detection.
AB  - An analytical multiresidue method for the simultaneous determination of various
      classes of pesticides in soil was developed. Pesticides were extracted from soil
      with ethyl acetate. Soil samples were placed in small columns, and the extraction
      was carried out assisted by sonication. Pesticides were determined by gas
      chromatography with electron impact mass spectrometric detection in the selected
      ion monitoring mode. Spiked blank samples were used as standards to counteract
      the matrix effect observed in the chromatographic determination. Pesticides were
      confirmed by their retention times, their qualifier and target ions, and their
      qualifier/target abundance ratios. Recovery studies were performed at 0.2, 0.1,
      and 0.05 microg/g fortification levels of each pesticide, and the recoveries
      obtained ranged from 87.0 to 106.2% with a relative standard deviation between
      2.4 and 10.6%. Good resolution of the pesticide mixture was achieved in
      approximately 41 min. The detection limits of the method ranged from 0.02 to 1.6
      microg/kg for the different pesticides studied. The developed method is linear
      over the range assayed, 25-1000 microg/L, with determination coefficients >0.999.
      The proposed method was used to determine pesticide levels in real soil samples,
      taken from different agricultural areas of Spain, where several herbicides and
      insecticides were found.

PMID- 15030195
TI  - Beta-thujaplicin: new quantitative CZE method and adsorption to goethite.
AB  - Beta-thujaplicin (beta-TH) is a toxic tropolone derivative present in the
      heartwood of western red cedar (Thuja plicata) and is used as a preservative and
      antimicrobial additive in a number of commercial goods. beta-TH released from
      western red cedar timber used outdoor and from other products containing beta-TH
      may transfer to soil and leach to groundwater and surface waters. The objective
      of this study was to quantify the adsorption of beta-TH to goethite as a typical
      model for geosorbents. Adsorption was studied using pH-adjusted goethite
      suspensions with solid:solution ratios of 1:500, 0.01 M NaNO(3) electrolyte, and
      20 degrees C. beta-TH was determined using a new capillary zone electrophoresis
      (CZE) method providing a detection limit of 0.21 microM. Near-sorption
      equilibrium was attained within 48 h. beta-TH showed maximum adsorption at low pH
      (3.8) and a 70% drop in adsorption from pH 6.2 to 8.8. The Langmuir type
      adsorption isotherm at pH 5.5 approached a maximum adsorption of 220 micromol/g
      (= 6.2 micromol/m(2)), which is more than twice the amount of phosphate adsorbed
      under similar conditions. The affinity of beta-TH for goethite is low as compared
      with organic ligands such as citrate, oxalate, and 2,4-dihydroxybenzoate. The
      adsorption data and FTIR analyses indicate that beta-TH is most likely adsorbed
      as monodentate mononuclear surface complexes at the surface of goethite.
      Hydrophobic adsorption is thought to contribute to the adsorption, in particular
      at low pH. The strong adsorption of beta-TH to goethite suggests low mobility in
      most soil environments, the risk of contamination increasing in soils with high
      pH (calcareous material), low contents of iron and aluminum oxides,
      phyllosilicates, and organic matter.

PMID- 15030196
TI  - Speciation of arsenic in different types of nuts by ion chromatography
      inductively coupled plasma mass spectrometry.
AB  - In this work the quantitative determination and analytical speciation of arsenic
      were undertaken in different types of nuts, randomly purchased from local
      markets. The hardness of the whole nuts and high lipid content made the
      preparation of this material difficult for analysis. The lack of sample
      homogeneity caused irreproducible results. To improve the precision of analysis,
      arsenic was determined separately in nut oil and in the defatted sample. The
      lipids were extracted from the ground sample with the two portions of a mixture
      of chloroform and methanol (2:1). The defatted material was dried and ground
      again, yielding a fine powder. The nut oil was obtained by combining the two
      organic extracts and by evaporating the solvents. The two nut fractions were
      microwave digested, and total arsenic was determined by inductively coupled
      plasma mass spectrometry (ICP-MS). The results obtained for oils from different
      types of nuts showed element concentration in the range 2.9-16.9 ng g(-)(1).
      Lower levels of arsenic were found in defatted material (<0.1 ng g(-)(1) with the
      exception of Brazil nuts purchased with and without shells, 3.0 and 2.8 ng g(
      )(1) respectively). For speciation analysis of arsenic in nut oils, elemental
      species were extracted from 2 g of oil with 12 mL of chloroform/methanol (2:1)
      and 8 mL of deionized water. The aqueous layer, containing polar arsenic species,
      was evaporated and the residue dissolved and analyzed by ion chromatography-ICP
      MS. The anion exchange chromatography enabled separation of As(III),
      dimethylarsinic acid (DMAs(V)), monomethylarsonic acid (MMAs(V)), and As(V)
      within 8 min. Several types of nuts were analyzed, including walnuts, Brazil
      nuts, almonds, cashews, pine nuts, peanuts, pistachio nuts, and sunflower seeds.
      The recovery for the speciation procedure was in the range 72.7-90.6%. The
      primary species found in the oil extracts were As(III) and As(V). The arsenic
      concentration levels in these two species were 0.7-12.7 and 0.5-4.3 ng g(-)(1),
      respectively. The contribution of As in DMAs(V) ranged from 0.1 +/- 0.1 ng g(
      )(1) in walnuts to 1.3 +/- 0.3 ng g(-)(1) in pine nuts. MMAs(V) was not detected
      in almonds, peanuts, pine nuts, sunflower seeds, or walnuts, and the highest
      concentration was found in pistachio nuts (0.5 +/- 0.2 ng g(-)(1)).

PMID- 15030197
TI  - Analysis of the Fusarium mycotoxins fusaproliferin and trichothecenes in grains
      using gas chromatography-mass spectrometry.
AB  - A method is described using gas chromatography-mass spectrometry (GC-MS) for the
      simultaneous detection of the Fusarium mycotoxins fusaproliferin and seven
      trichothecenes from grains. Sample purification of the raw extract was carried
      out with commercial solid phase extraction columns, and the recovery of the more
      polar analytes was increased by rinsing the column with acetonitrile. A
      significant matrix effect was found for the analysis of fusaproliferin and
      trichothecenes; thus, the calibrants should be prepared in a blank matrix. The
      response was linear in the range used. The mean recovery for fusaproliferin was
      60.4 or 62.9%, depending on the spiking level. With respect to the
      trichothecenes, the recovery was generally higher (70.2-125.3%). The method
      proved to be repeatable for the analysis of fusaproliferin and trichothecenes.
      The limit of detection for fusaproliferin in the blank matrix mixture was 50
      microg/kg, and that for trichothecenes was 5-15 microg/kg. Thirty-eight Finnish
      grain samples were analyzed for fusaproliferin and trichothecenes with the method
      developed. Fusaproliferin was not detected in any of the samples. The mean levels
      of deoxynivalenol, 3-acetyldeoxynivalenol, nivalenol, HT-2 toxin, and T-2 toxin
      in Finnish grain samples were 272, 17, 150, 40, and <20 microg/kg, respectively.

PMID- 15030199
TI  - Quantitation of mule duck in goose foie gras using TaqMan real-time Polymerase
      Chain Reaction.
AB  - A real-time quantitative Polymerase Chain Reaction (PCR) method has been
      developed for the quantitation of mule duck (Anas platyrhynchos x Cairina
      moschata) in binary duck/goose foie gras mixtures. The method combines the use of
      real-time PCR with duck-specific and endogenous control "duck + goose" primers to
      measure duck content and total foie gras content, respectively. Both PCR systems
      (duck-specific and duck + goose) were designed on the mitochondrial 12S ribosomal
      RNA gene (rRNA). The duck-specific system amplifies a 96 bp fragment from duck
      DNA, whereas the duck + goose system amplifies a 120 bp fragment from duck and
      goose DNA. The method measures PCR product accumulation through a FAM-labeled
      fluorogenic probe (TaqMan). The C(t) (threshold cycle) values obtained from the
      duck + goose system are used to normalize the ones obtained from the duck
      specific system. Analysis of experimental duck/goose foie gras binary mixtures
      demonstrated the suitability of the assay for the detection and quantitation of
      duck in the range of 1-25%. This genetic marker can be very useful to avoid
      mislabeling or fraudulent species substitution of goose by duck in foie gras.

PMID- 15030200
TI  - Using synchrotron transmission FTIR microspectroscopy as a rapid, direct, and
      nondestructive analytical technique to reveal molecular microstructural-chemical
      features within tissue in grain barley.
AB  - The objective of this study was to use synchrotron transmission FTIR
      microspectroscopy as a rapid, direct, and nondestructive analytical technique to
      reveal molecular microstructural-chemical features within tissue in grain barley.
      The results showed that synchrotron transmission FTIR microspectroscopy could
      provide spectral, chemical, and functional group characteristics of grain barley
      tissue at ultrahigh spatial resolutions. The spatially localized structural
      chemical distributions of biological components (lignin, cellulose, protein,
      lipid, and carbohydrates) and biological component ratios could be imaged. Such
      information on molecular microstructural-chemical features within the tissue can
      be used for plant breeding programs for selecting superior varieties of barley
      for special purposes and for prediction of grain barley quality and nutritive
      value for humans and animals.

PMID- 15030198
TI  - Analysis of hard-to-cook red and black common beans using Fourier transform
      infrared spectroscopy.
AB  - Extracted fractions from black and red common beans (Phaseolus vulgaris) were
      studied using Fourier transform infrared spectroscopy (FT-IR). Beans were stored
      under three conditions: control at 4 degrees C; hard-to-cook (HTC) at 29 degrees
      C, 65% RH for 3.5 months; and refrigerated at 2 degrees C, 79% RH for 3.5 months
      after a HTC period (called HTC-refrigerated). Two fractions isolated from the
      beans, the soluble pectin fraction (SPF) and the water insoluble residue of the
      cell wall (WIRCW), were analyzed using diffuse reflectance (DRIFTS) FT-IR. The
      soaking water and cooking water from the beans were also studied using attenuated
      total reflectance (ATR) FT-IR. The DRIFTS FT-IR results from the SPF and WIRCW
      fractions were consistent with previously published data for Carioca beans
      showing that in general, more phenolic compounds were associated with the SPF of
      HTC beans than in the control beans. Results also showed that HTC-refrigerated
      beans had higher concentrations of phenolic compounds than control beans in the
      SPF. The ATR FT-IR results for soaking and cooking waters from the HTC
      refrigerated and HTC beans had higher concentrations of absorbing compounds than
      the control beans, indicating that they lost more constituents to the water.
      Additionally, results indicate that the mechanism(s) for reversibility of the HTC
      defect could be different than the one(s) involved in the development of the
      defect.

PMID- 15030201
TI  - Glycosylated compounds from okra inhibit adhesion of Helicobacter pylori to human
      gastric mucosa.
AB  - In Asian medicine the fruit of the okra plant, Abelmoschus esculentus (L.)
      Moench., is used as a mucilaginous food additive against gastric irritative and
      inflammative diseases. To find a rational basis for its use against these
      diseases, several crude and purified carbohydrate-containing fractions from
      immature okra fruits were isolated and analyzed, and their effects against
      Helicobacter pylori in an in situ adhesion model on sections of human gastric
      mucosa were determined. Pretreatment of the bacteria with a fresh juice
      preparation inhibited the bacterial adhesion almost completely. Lyophilization
      and reconstitution of an extract solution led to a reduction of this effect. A
      crude polysaccharide (RPS) isolated from the fresh juice by ethanolic
      precipitation showed strong inhibitory effects. Further fractionation of RPS
      revealed a purified, highly acidic subfraction (AF III) with high antiadhesive
      qualities. Carbohydrate analysis revealed the presence of rhamnogalacturonans
      with a considerable amount of glucuronic acid, whereas other inactive
      subfractions contained little glucuronic acid or were glucuronic acid-free. After
      heat denaturation of the fresh juice or protein precipitation with 5% TCA the
      antiadhesive activity of the fresh extract was reduced, indicating that besides
      polysaccharides, protein fractions also exhibited antiadhesive properties. SDS
      PAGE analysis of the precipitate revealed several bands of glycosylated proteins
      between 25 and 37 kDa that were almost diminished in the nonactive supernatant.
      Preincubations of gastric tissue with any of the active fractions did not lead to
      reduced bacterial binding. The antiadhesive activity is therefore due to the
      blocking capacity of specific Helicobacter surface receptors that coordinate the
      interaction between host and bacterium. Neither of the active fractions showed
      inhibitory effects on bacterial growth in vitro. The antiadhesive qualities of
      okra were assumed to be due to a combination of glycoproteins and highly acidic
      sugar compounds making up a complex three-dimensional structure that is fully
      developed only in the fresh juice of the fruit.

PMID- 15030202
TI  - Angiotensin converting enzyme inhibitory activity in commercial fermented
      products. Formation of peptides under simulated gastrointestinal digestion.
AB  - The angiotensin converting enzyme (ACE)-inhibitory activity of several commercial
      fermented milks was evaluated. Most of these products showed moderate inhibitory
      activity, but a few exceptions were detected. The high ACE-inhibitory activity
      found in some cases could be related to the origin of the milk. Two of these
      products were subjected to an enzymatic hydrolysis process, which simulates
      physiological digestion, to study the influence of digestion on ACE-inhibitory
      activity. The activity did not significantly change or increase during simulated
      gastrointestinal digestion. The peptides generated from one selected product
      during simulated digestion were sequenced by tandem spectrometry. Most peptides
      found at the end of the simulated digestion were released after 30 min of
      incubation with the pancreatic extract. This suggests that physiological
      digestion promotes the formation of active peptides from the proteins present in
      these fermented products. The potential ACE-inhibitory activity of the identified
      peptides is discussed with regard to their amino acid sequences.

PMID- 15030203
TI  - In situ and in vitro antioxidant activity of sweetpotato anthocyanins.
AB  - Anthocyanins from a variety of fruits and vegetables have been shown to possess
      potent antioxidant activity in vitro, but scavenging of free radicals by
      anthocyanins has only been demonstrated in situ in the leaves of certain plants.
      We report on a new sweetpotato that exhibits mottled purple flesh attributable to
      high concentrations of anthocyanins. By perfusing transverse sweetpotato sections
      with the reactive oxygen species H(2)O(2), followed by the H(2)O(2) sensitive
      fluorochrome scopletin, we show that anthocyanins act as antioxidants in situ
      within the sweetpotato storage roots. We also demonstrate in vitro antioxidant
      activity by sweetpotato anthocyanins, where an additive effect with
      hydroxycinnamic acids is observed. Anthocyanic foods have been shown to offer
      protection against a variety of degenerative disease processes. Given that
      sweetpotato can be eaten several hundred grams at a time and as a staple, these
      data are consistent with the possibility of superior health protection by
      anthocyanic varieties of sweetpotato in comparison to most common fruits and
      vegetables.

PMID- 15030204
TI  - Relationship between antibacterial activity of (+)-catechin derivatives and their
      interaction with a model membrane.
AB  - (+)-Catechin derivatives with different alkyl chain lengths were synthesized from
      (+)-catechin and various straight chain alkylaldehydes in the presence of methyl
      mercaptan, and their antibacterial activities against Gram-positive bacteria were
      evaluated. The antibacterial activity increased markedly with elongation of the
      alkyl chain lengths of the derivatives and reached a maximum at a chain of four
      to seven carbons. Subsequently, interaction of the (+)-catechin derivatives with
      a model membrane using liposome was investigated. The derivatives with a chain of
      three carbons or more were found to have very strong affinity for the membrane.
      The injury action of the derivatives against the membrane was examined with
      liposome in which calcein was enclosed as a fluorescent indicator. The leakage
      was observed in the derivatives with chain lengths of four carbons or more.
      Particularly the derivatives with chains longer than five carbons are considered
      to destroy the liposome membrane judging from the degree of the fluorescent
      leakage. These results implied that the lipophilicity and disrupting ability of
      the (+)-catechin derivatives to the liposome membrane participate in their
      antibacterial activity.

PMID- 15030205
TI  - Effect of antioxidant flavanone, naringenin, from Citrus junoson neuroprotection.
AB  - Amyloid beta protein (Abeta)-induced free radical-mediated neurotoxicity is known
      as a leading hypothesis for a cause of Alzheimer's disease. Abeta increased free
      radical production and lipid peroxidation in PC12 nerve cells, resulting in
      apoptosis and cell death. The protective effect of naringenin, a major flavanone
      constituent isolated from Citrus junos, against Abeta-induced neurotoxicity was
      investigated using PC12 cells. Pretreatment with isolated naringenin and vitamin
      C prevented the generation of the Abeta-induced reactive oxygen species.
      Naringenin resulted in the decrease of Abeta toxicity in a manner of
      concentration dependence, which was assessed by the 3-(4,5-dimethylthiazol-2-yl)
      2,5-diphenyltetrazolium bromide assay. However, treatment with these antioxidants
      inhibited the Abeta-induced neurotoxic effect. The antiamnestic activity of
      naringenin in vivo was also evaluated using ICR mice with amnesia induced by
      scopolamine (1 mg/kg body weight). Naringenin, when administered to ICR mice at
      4.5 mg/kg body weight, significantly ameliorated scopolamine-induced amnesia as
      measured in the passive avoidance test. Therefore, these results indicate that
      micromolecular Abeta-induced in vitro oxidative cell stress is reduced by
      naringenin and naringenin may be a useful chemopreventive agent against a
      neurodegenerative disease such as Alzheimer's disease.

PMID- 15030206
TI  - Antioxidant capacity manipulation in transgenic potato tuber by changes in
      phenolic compounds content.
AB  - The main goal of this study was to generate potato tubers with increased levels
      of flavonoids and thus modified antioxidant capacities. To accomplish this, the
      vector carrying multigene construct was prepared and several transgenic plants
      were generated, all overexpressing key biosynthesis pathway enzymes. The single
      gene overexpression or simultaneous expression of genes encoding chalcone
      synthase (CHS), chalcone isomerase (CHI), and dihydroflavonol reductase (DFR)
      resulted in a significant increase of measured phenolic acids and anthocyanins.
      The increase in phenolic compounds synthesis is accompanied by decreases in
      starch and glucose levels in transgenic plants. The flavonoids-enriched plants
      showed improved antioxidant capacity; however, there is a complex relationship
      between antioxidant capacity and flavonoids content, suggesting the great
      participation of other compounds in the antioxidant potential of the plants.
      These other compounds are not yet recognized.

PMID- 15030207
TI  - Considerations on endopolygalacturonase activity and determination of comparison
      ratios with emphasis on the influence of the degree of substrate esterification.
AB  - A study on the determination and standardization of endopolygalacturonase (EPG)
      activity is reported, with emphasis on the influence of the degree of substrate
      esterification using pure yeast EPG. Differences in the results, depending on how
      the EPG activity unit was defined, are described and discussed. From a
      theoretical analysis of the expressions established, a general equation for
      expressing EPG activity in standard international units was obtained, together
      with the proportional coefficient for each of the substrates studied. It was
      observed that for a wide range of enzyme concentrations good linear correlations
      were obtained. Analysis of the comparison ratio (CR) values calculated revealed
      that these do not differ significantly, except for low-methoxyl apple pectin,
      confirming the validity of the general expression obtained for pectins with
      different degrees of esterification. The anomalous CR value found for low
      methoxyl (LM) apple pectin is discussed.

PMID- 15030208
TI  - Phytochemical composition and pigment stability of Acai (Euterpe oleracea Mart.).
AB  - Anthocyanin and polyphenolic compounds present in acai (Euterpe oleracea Mart.)
      were determined and their respective contribution to the overall antioxidant
      capacity established. Color stability of acai anthocyanins against hydrogen
      peroxide (0 and 30 mmol/L) over a range of temperatures (10-30 degrees C) was
      also determined and compared to common anthocyanin sources. Additionally,
      stability in a model beverage system was evaluated in the presence of ascorbic
      acid and naturally occurring polyphenolic cofactors. Cyanidin 3-glucoside (1040
      mg/L) was the predominant anthocyanin in acai and correlated to antioxidant
      content, while 16 other polyphenolics were detected from 4 to 212 mg/L. Red grape
      anthocyanins were most stable in the presence of hydrogen peroxide, while acai
      and pigments rich in acylated anthocyanins displayed lower color stability in a
      temperature-dependent manner. In the presence of ascorbic acid, acylated
      anthocyanin sources generally had increased color stability. Acai was recognized
      for its functional properties for use in food and nutraceutical products.

PMID- 15030209
TI  - Evaluation of the efficiency of three different solvent systems to extract
      triterpene saponins from roots of Panax quinquefolius using high-performance
      liquid chromatography.
AB  - Despite the wide availability of liquid herbal extracts using mixtures of
      alcohol, glycerin, and water, or glycerin and water as solvents, no data on the
      chemical composition of such extracts is readily available. In this study, the
      amount and the stability of the major saponins in Panax quinquefolius root
      extracts, made either with 50% (v/v) aqueous ethanol, a mixture (v/v/v) of 20%
      ethanol, 40% glycerin, and 40% water, or with 65% (v/v) aqueous glycerin, were
      evaluated by HPLC-UV analysis. The amount of total saponins was highest in the
      50% aqueous ethanol extract (61.7 +/- 0.1 mg/g dry root), although similar to the
      ethanol-glycerin-water extract (59.4 +/- 0.5 mg/g dry root). Saponins were
      significantly lower in the 65% aqueous glycerin extract (51.5 +/- 0.2 mg/g dry
      root). Interestingly, the amounts of individual saponins were quite variable
      depending on the solvent. This is in part due to enzymatic cleavage of
      ginsenosides in the glycerin containing extracts during the maceration process.
      Storage of the extracts at 25 degrees C over the period of a year led to a 13-15%
      loss of saponins with all three types of extractions.

PMID- 15030210
TI  - Matching avrami indices achieves similar hardnesses in palm oil-based fats.
AB  - This study demonstrates how chemically interesterified hydrogenated palm oil
      (IHPO) and partially hydrogenated palm oil (PHPO) can be structured to have
      similar mechanical properties. Crystallization of IHPO at 30 degrees C for 24 h
      yielded a fat with a solid fat content (SFC) of 45% and a yield force of 51.5 N.
      On the other hand, PHPO had a SFC of 50% and a yield force of 44 N when
      crystallized under the same conditions. The result was opposite from what would
      be expected from the SFC point of view, thus suggesting that the microstructure
      of the fat plays a key role in determining mechanical properties. By matching
      crystallization behavior using the Avrami index as a guide, microstructures and
      material hardness were successfully matched. These results suggest that the
      dynamics of structure formation was a key factor influencing the macroscopic
      mechanical properties of palm oil-based fats.

PMID- 15030211
TI  - White wine continuous protein stabilization by packed column.
AB  - Protein stabilization is an important stage in the production of white wine. This
      paper studies white wine protein stabilization using a continuous process with
      zirconium oxide (powder and pellets) packed in a column. The results show that
      the total proteins decrease by 50 and 70% for the pellet and powdered zirconium
      oxides, respectively. Treatment with all zirconium oxides improves wine
      stability. The effect of the heat regeneration process on both zirconium oxide
      forms is to increase the adsorption capacity. The wine treated with powdered
      zirconium oxide after the regeneration is the most effective for preventing
      protein haze. The protein profile of wine after treatment shows that the 20-50
      kDa and 50-70 kDa fractions are the ones removed preferentially, while the 15 kDa
      fraction and the ones higher than 70 kDa are removed the least. The results show
      that the protein fraction with a molecular weight of 15 kDa does not affect the
      protein instability of the wines studied. The protein fraction with a molecular
      weight higher than 70 kDa seems to influence protein instability. The
      physicochemical properties of wine after treatment were not affected, and the
      values obtained were like those of the standardized range.

PMID- 15030212
TI  - Physicochemical modifications of high-pressure-treated soybean protein isolates.
AB  - Changes induced by high pressure (HP) treatment (200-600 MPa) on soybean protein
      isolates (SPI) at pH 3 (SPI3) and pH 8 (SPI8) were analyzed. Changes in protein
      solubility, surface hydrophobicity (Ho), and free sulfhydryl content (SH(F)) were
      determined. Protein aggregation and denaturation and changes in secondary
      structure were also studied. An increase in protein Ho and aggregation, a
      reduction of free SH, and a partial unfolding of 7S and 11S fractions were
      observed in HP-treated SPI8. Changes in secondary structure were also detected,
      which led to a more disordered structure. HP-treated SPI3 was partially denatured
      and presented insoluble aggregates. A major molecular unfolding, a decrease of
      thermal stability, and an increase of protein solubility and Ho were also
      detected. At 400 and 600 MPa, a decrease of the SH(F) and a total denaturation
      were observed.

PMID- 15030213
TI  - Composition and chemical changes during storage of fish meal from Capelin
      (Mallotus villosus).
AB  - The stability of fish meal depends on processing and storage conditions, but
      habitat and seasonal variations in composition and naturally occurring anti- and
      pro-oxidants may be equally important. Capelin meal from four different seasons
      was examined by measuring chemical composition and monitoring lipid oxidation
      during storage. The results revealed that lipid content was high in the summer
      but low in the spring. It was further demonstrated that among naturally occurring
      antioxidants, astaxanthin was high during summer, whereas alpha-tocopherol was
      highest in spring. Mineral content varied, with a high copper content in the
      summer, whereas iron, selenium, and zinc were highest in the winter. Measurements
      on the stability of capelin meal indicated a decrease in peroxide values, oxygen
      uptake, and thiobarbituric acid reactive compounds with storage, whereas browning
      and CO concentration increased with time. Rancidity was highest in autumn, but
      free fatty acids were highest during spring and summer.

PMID- 15030214
TI  - Floral procyanidins of the forage legume red clover (Trifolium pratense L.).
AB  - The chemical characteristics of the purified procyanidin polymers of the flowers
      of the forage legume red clover (Trifolium pratense L.) were studied by (13)C
      NMR, acid-catalyzed degradation with benzyl mercaptan, and electrospray
      ionization mass spectrometry (ESI-MS). The (13)C NMR showed that the fraction
      consisted of predominantly procyanidin polymers. The thiolysis reaction products
      indicated a mean degree of polymerization (mDP) of 9.3 with epicatechin (81%) as
      the abundant flavan-3-ol extension unit and the terminating units dominated by
      catechin (95%). ESI-MS showed a range of oligomeric procyanidin ions (DP of 2
      11). The white clover floral prodelphinidins consist of terminal units with
      nearly equal proportions of epigallocatechin (52%) and gallocatechin (48%) and
      extender units showing epigallocatechin (56%) and gallocatechin (39%). The
      dramatic difference in the stereochemistry of the terminal and extender units
      observed for the red clover floral procyanidins contrasts with the mixture of cis
      and trans stereochemistry observed for white clover floral prodelphinidins.

PMID- 15030215
TI  - Phenolic composition of strawberry genotypes at different maturation stages.
AB  - The effects of maturation (green, pink, and ripe) on phenolic composition of
      strawberry cultivars Camarosa, Dorit, Chandler, and Osmanli and their hybrids
      were investigated using a high-pressure liquid chromatography (HPLC) method. p
      Hydroxybenzoic acid, p-coumaric acid, ellagic acid, cyanidin-3-glucoside,
      pelargonidin-3-glucoside, kaempferol, quercetin, and myricetin were individually
      quantified for each stage. The highest amounts of anthocyanins were obtained from
      ripe fruits whereas ellagic acid was found as the main phenolic in the green
      fruits. Phenolic concentrations were found statistically different in green and
      ripe fruits. One hybrid was found to have higher phenolic contents than the other
      genotypes. The p-hydroxybenzoic and p-coumaric acid levels changed during
      maturation, but no differences in contents of flavonoids in green and ripe fruit
      were detected.

PMID- 15030216
TI  - Structural characterization of imazalil/beta-cyclodextrin inclusion complex.
AB  - An equimolar inclusion complex between imazalil, a selected fungicide, and beta
      cyclodextrin using an aqueous standard solution procedure has been obtained. The
      complex has been investigated in solution by (1)H and (13)C NMR techniques in
      combination with computational methods in order to establish a valuable
      analytical protocol through which to gain insight into the interactions of the
      inclusion complex in aqueous solution. Intramolecular NMR distance constraints
      have been detected and used for three-dimensional complex structure
      determination.

PMID- 15030217
TI  - Selenate reduction in river water by Citerobacter freundii isolated from a
      selenium-contaminated sediment.
AB  - Bacterial reduction of selenate [Se(VI)] to insoluble elemental Se [Se(0)] is an
      important remedial technology to remove selenium (Se) from Se-impacted water.
      Citerobacter freundii, a Se(VI) reducer, isolated from a Se-contaminated sediment
      was assessed for its ability to reduce Se(VI) in a mineral culture medium and
      natural river water in a series of laboratory batch experiments. The results
      showed that a combination of yeast extract and glucose used in the culture medium
      was more effective than yeast extract alone, yeast extract plus sodium acetate,
      and yeast extract plus sodium lactate for reduction of Se(VI) to Se(0) by C.
      freundii. About 89-96% of the added Se(VI) (500-4500 microg/L) was reduced to
      Se(0) in the culture medium amended with 500 mg/L each of yeast extract and
      glucose. C. freundii can also survive in natural river water and reduce Se(VI).
      During an 8-day experiment in both sterile and nonsterile river water, 63-70 and
      21-22% of the added Se(VI) was reduced to Se(0) and Se(-II), respectively. These
      results suggest that C. freundii has great potential for Se(VI) reduction and may
      be used for remediating Se-impacted water.

PMID- 15030218
TI  - Volatile constituents and key odorants in leaves, buds, flowers, and fruits of
      Laurus nobilis L.
AB  - The volatiles of fresh leaves, buds, flowers, and fruits from bay (Laurus nolilis
      L.) were isolated by solvent extraction and analyzed by capillary gas
      chromatography-mass spectrometry. Their odor quality was characterized by gas
      chomatography-olfactometry-mass spectrometry (HRGC-O-MS) and aroma extract
      dilution analysis (AEDA). In fresh bay leaves 1,8-cineole was the major
      component, together with alpha-terpinyl acetate, sabinene, alpha-pinene, beta
      pinene, beta-elemene, alpha-terpineol, linalool, and eugenol. Besides 1,8-cineole
      and the pinenes, the main components in flowers were alpha-eudesmol, beta
      elemene, and beta-caryophyllene, in fruits (E)-beta-ocimene and
      biclyclogermacrene, and in buds (E)-beta-ocimene and germacrene D. The aliphatic
      ocimenes and farnesenes were absent in leaves. By using HRGC-O-MS 21 odor
      compounds were identified in fresh leaves. Application of AEDA revealed (Z)-3
      hexenal (fresh green), 1,8-cineole (eucalyptus), linalool (flowery), eugenol
      (clove), (E)-isoeugenol (flowery), and an unidentified compound (black pepper)
      with the highest flavor dilution factors. Differences between buds, flowers,
      fruits, and leaves with regard to the identified odor compounds are presented.

PMID- 15030219
TI  - Influence of temperature, modified atmosphere packaging, and heat treatment on
      aroma compounds in broccoli.
AB  - The aroma compounds in broccoli stored in different modified atmospheres were
      studied. The packaging materials used were oriented polypropylene (OPP),
      poly(vinyl chloride) (PVC), and low-density polyethylene (LDPE) containing an
      ethylene-absorbing sachet. All samples were stored for either 1 week at a
      constant temperature of 10 degrees C or for 3 days at 4 degrees C, followed by 4
      days at 10 degrees C. The atmospheres that developed inside the packaging
      materials differed significantly. The broccoli samples were analyzed raw and
      after cooking, with regard to volatile compounds, using gas-phase (headspace)
      extraction followed by gas chromatography-mass spectrometry (GC-MS) and GC
      olfactometry. Dimethyl sulfide (DMS), dimethyl disulfide (DMDS), dimethyl
      trisulfide (DMTS), hexanal, 3-cis-hexen-1-ol, nonanal, ethanol, and a group of
      thiocyanates were selected for a detailed study because these compounds cause off
      odor and can be used as indicators of stress. Significant differences were found
      in the aroma profiles of the broccoli samples relative to the packaging materials
      used for storage. Storage in OPP (14% O(2), 10.5% CO(2)) resulted in most of the
      off-odors, while storage in LDPE (6% O(2), 7% CO(2)) and PVC (17.9% O(2), 4%
      CO(2)) was found to maintain the concentration of DMS, DMDS, and DMTS during
      storage. Heat treatment of the broccoli increased the content of aroma compounds
      as well as the number of compounds containing sulfur.

PMID- 15030221
TI  - Flavor release from iota-carrageenan matrices: a kinetic approach.
AB  - Release of aroma compounds in selected iota-carrageenan systems was studied by
      static headspace analysis. By varying the sodium chloride content, different
      rheological behaviors were obtained ranging from solution to gel. From the
      release curves, mass transfer (h(D)) and partition coefficients (K(ga)) of ethyl
      butanoate, ethyl hexanoate, and linalool were extracted using a mathematical
      model based on the penetration theory. This model, previously developed for
      flavor release from stirred solutions, was found to fit well the data obtained
      from structured systems (nonstirred conditions) at the beginning and at the end
      of the release curves: this allowed the determination of h(D) and K(ga). Matrix
      effects appeared to be dependent on the chemical class of the compounds. For the
      alcohol, the main effect on both equilibrium partitioning and mass transfer
      across the interface was ascribed to a salting effect. In the opposite, for
      esters, iota-carrageenan addition induced an increase of aroma retention and also
      a slower transfer across the interface. The respective effects of an increasing
      viscosity of the medium and of the formation of a tridimensionnal network are
      discussed.

PMID- 15030220
TI  - Inhibition of acetate ester biosynthesis in banana (Musa sapientum L.) fruit pulp
      under anaerobic conditions.
AB  - The effect of anaerobic conditions on acetate ester biosynthesis in ripened
      banana pulp was investigated. Incubation of the pulp in less than 1% O(2)
      resulted in a significant reduction in the formation of ethyl acetate. Regardless
      of the presence of a large amount of endogenous ethanol and the remaining
      exogenous isobutyl alcohol after complete anaerobic incubation with the pulp, the
      production of acetate ester decreased. The effect of addition of pyruvate,
      isobutyl alcohol, acetate, and methyl hexanoate on acetate ester formation in
      100% N(2) was also investigated. The addition of pyruvate and isobutyl alcohol to
      the pulp gave lower acetate esters in N(2) than in air, whereas the pulp
      incubated with acetate and isobutyl alcohol produced more acetate ester in both
      conditions. Therefore, the lack of acetyl CoA, or more precisely acetate, in the
      tissue is the main reason for the inhibition of acetate ester formation under
      anaerobic conditions. The activity of beta-oxidation measured by incubation with
      methyl hexanoate was detected only in the samples incubated in air. The formation
      of acetyl CoA, derived from pyruvate through mitochondria and through beta
      oxidation, was inhibited by anaerobic conditions, which suggests that
      mitochondrial activity and/or beta-oxidation are essential for ester
      biosynthesis.

PMID- 15030222
TI  - Lactones. 21. Synthesis and odoriferous properties of lactones with the p
      menthane system.
AB  - Starting from (R)-(+)- and (S)-(-)-pulegone, enantiomeric pairs of esters and
      lactones with the p-menthane system were obtained. The Claisen rearrangement of
      allylic alcohols and iodolactonization of gamma,delta-unsaturated acids were the
      key steps of syntheses presented. The structures of compounds were determined by
      both spectroscopic and crystallographic methods. Some of the synthesized
      compounds are characterized by interesting odoriferous properties.

PMID- 15030223
TI  - Modeling the sensory impact of defined combinations of volatile lipid oxidation
      products on fishy and metallic off-flavors.
AB  - The volatiles (E,Z)-2,6-nonadienal, 1-penten-3-one, (Z)-4-heptenal, and (E,E)-2,4
      heptadienal were added to milk containing 1.5% fat according to a central
      composite design, to evaluate the individual and combinatory effects of these
      volatiles on sensory properties. The milk samples with added volatiles were
      subjected to sensory descriptive analysis for fishy and metallic off-flavors. The
      data were analyzed using partial least-squares regression and multiple linear
      regression to develop mathematical models. The models revealed significant main
      effects of (E,Z)-2,6-nonadienal and 1-penten-3-one and highlighted the importance
      of two-factor interactions for contribution toward off-flavors. The results
      suggest that (E,Z)-2,6-nonadienal and 1-penten-3-one could be useful markers for
      fishy and metallic off-flavors in fish oil and fish oil enriched foods. Within
      the addition levels of the volatiles there was a curvature effect of (E,Z)-2,6
      nonadienal, a compensatory effect of (Z)-4-heptenal and (E,E)-2,4-heptadienal,
      and a synergistic effect of (E,Z)-2,6-nonadienal and (Z)-4-heptenal in the
      development of fishy off-flavors.

PMID- 15030224
TI  - Determination of odor active aroma compounds in freshly cut leek (Allium
      ampeloprasum Var. bulga) and in long-term stored frozen unblanched and blanched
      leek slices by gas chromatography olfactometry analysis.
AB  - The odor active compounds in freshly cut leek slices and in blanched and
      unblanched leek slices stored for 12 months were investigated by a detection
      frequency method. Fifteen judges were evaluating the three samples randomized.
      The most important aroma compounds in the freshly cut leek slices were dipropyl
      disulfide, methyl propenyl disulfide, pentanal, decanal, and propyl propenyl
      disulfide in order of priority. When stored frozen and unblanched for 12 months,
      the aroma composition changed and the most important compounds became pentanal,
      decanal, 2,5-dimethyl furan, unknown compound I, and dipropyl disulfide.
      Blanching before freezing prevented to some degree these changes but also reduced
      the perceived intensity of the aroma compounds. The most important aroma
      compounds in the blanched sample were dipropyl disulfide, unknown compound I,
      pentanal, 2,5-dimethyl furan, and propyl propenyl disulfide.

PMID- 15030225
TI  - Comparison of isolation methods for the determination of important aroma
      compounds in black currant (Ribes nigrum L.) juice, using nasal impact frequency
      profiling.
AB  - The influence of isolation method on the determination of important aroma
      compounds in black currant juice was investigated by surface of nasal impact
      frequency (SNIF) gas chromatography-olfactometry (GC-O). The applied methods were
      solvent extraction, static headspace, and purge and trap using 15 and 60 min of
      purge time. By the four methods, a total of 59 odors were observed, and, of
      these, 44 corresponded to compounds that could be identified. For the headspace
      methods increasing purge volumes resulted in recoveries of additional, less
      volatile compounds. The main compound groups recovered by the headspace methods
      were esters and terpenes, whereas compounds recovered by solvent extraction were
      not as dominated by fruity odors. For most compounds there was agreement between
      the size of the SNIF value obtained by GC-O and the amount of the measurable
      compound found by gas chromatography-mass spectrometry.

PMID- 15030226
TI  - Gas chromatography-olfactometry and chemical quantitative study of the aroma of
      six premium quality spanish aged red wines.
AB  - The aroma of six premium quality Spanish red wines has been studied by
      quantitative gas chromatography-olfactometry (GC-O) and techniques of
      quantitative chemical analysis. The GC-O study revealed the presence of 85
      aromatic notes in which 78 odorants were identified, two of which-1-nonen-3-one
      (temptatively) and 2-acetylpyrazine-are reported in wine for the first time.
      Forty out of the 82 quantified odorants may be present at concentrations above
      their odor threshold. The components with the greatest capacity to introduce
      differences between these wines are ethyl phenols produced by Brettanomyces
      yeasts (4-ethylphenol, 4-ethyl-2-methoxyphenol, and 4-propyl-2-methoxyphenol),
      2,5-dimethyl-4-hydroxy-3(2H)-furanone (furaneol), (Z)-3-hexenol, thiols derived
      from cysteinic precursors (4-methyl-4-mercaptopentan-2-one, 3-mercaptohexyl
      acetate, and 3-mercaptohexanol), some components yielded by the wood [(E)
      isoeugenol, 4-allyl-2-methoxyphenol, vanillin, 2-methoxyphenol (guaiacol), and
      (Z)-whiskylactone], and compounds related to the metabolism (2-phenylethanol,
      ethyl esters of isoacids, 3-methylbutyl acetate) or oxidative degradation of
      amino acids [phenylacetaldehyde and 4,5-dimethyl-3-hydroxy-2(5H)-furanone
      (sotolon)]. The correlation between the olfactometric intensities and the
      quantitative data is, in general, satisfactory if olfactometric differences
      between the samples are high. However, GC-O fails in detecting quantitative
      differences in those cases in which the olfactive intensity is very high or if
      odors elute in areas in which the odor chromatogram is too complex.

PMID- 15030227
TI  - Furfuryl ethyl ether: important aging flavor and a new marker for the storage
      conditions of beer.
AB  - Recently, it was reported that furfuryl ethyl ether is an important flavor
      compound indicative of beer storage and aging conditions. A study of the reaction
      mechanism indicates that furfuryl ethyl ether is most likely formed by
      protonation of furfuryl alcohol or furfuryl acetate followed by S(N)2
      substitution of the leaving group by the nucleophilic ethanol. For the reaction
      in beer, a pseudo-first-order reaction kinetics was derived. A close correlation
      was found between the values predicted by the kinetic model and the actual
      furfuryl ethyl ether concentration evolution during storage of beer. Furthermore,
      10 commercial beers of different types, aged during 4 years in natural
      conditions, were analyzed, and it was found that the furfuryl ethyl ether flavor
      threshold was largely exceeded in each type of beer. In these natural aging
      conditions, lower pH, darker color, and higher alcohol content were factors that
      enhanced furfuryl ethyl ether formation. On the other hand, sulfite clearly
      reduced furfuryl ethyl ether formation. All results show that the furfuryl ethyl
      ether concentration is an excellent time-temperature integrator for beer storage.

PMID- 15030228
TI  - Energy from fat determined by near-infrared reflectance spectroscopy.
AB  - The amount of energy derived from fat in foods is a requirement of U.S. nutrition
      labeling legislation and a significant factor in diet development by health
      professionals. Near-infrared (NIR) spectroscopy has been used to predict total
      utilizable energy in cereal foods for nutrition labeling purposes, and in the
      current study, was investigated as a method for evaluation of the amount of
      energy derived from fat. Using NIR reflectance spectra (1104-2494 nm) of ground
      cereal samples and reference values obtained by calorimetry and by calculation,
      modified PLS regression models were developed for the prediction of percent
      energy from fat and energy from fat/g. The models were able to predict the
      percent of utilizable energy derived from fat with SECV and R(2) of 1.86-1.89% of
      kcal (n = 51, range 0-43.0) and 0.98, respectively, and SEP and r(2) of 1.74% of
      kcal (n = 55, range 0-38.0) and 0.98, respectively, when used to predict
      independent validation samples. Results indicate that NIR spectroscopy provides
      useful methods for predicting the energy derived from fat in food products.

PMID- 15030230
TI  - Characterization of the proteins from Vigna unguiculata seeds.
AB  - The proteins from Vigna unguiculata (L.) Walp. (cowpea) seeds were investigated.
      Globulins constitute over 51% of the total seed protein, with albumins composing
      approximately 45%. The globulins may be fractionated by native electrophoresis or
      anion exchange chromatography into three main components, which were termed (in
      decreasing order of anodic mobility) alpha-vignin, beta-vignin, and gamma-vignin.
      alpha-Vignin, with a sedimentation coefficient of 16.5S, is a major,
      nonglycosylated globulin, composed of a major 80 kDa subunit, which upon
      reduction, produces two polypeptides (20 and 60 kDa). beta-Vignin, with a
      sedimentation coefficient of 13S, is a major, glycosylated globulin, composed of
      two main polypeptides (55 and 60 kDa) with no disulfide bonds. Finally, gamma
      vignin, a minor globulin, is composed by one main type of subunit (22 kDa), which
      upon reduction, is converted into a single, apparently heavier polypeptide chain
      (30 kDa) due to the presence of an internal disulfide bond. Immunological
      analyses revealed structural homology between beta-vignin and beta-conglutin (the
      vicilin from Lupinus seeds) but not between alpha- or gamma-vignins and their
      Lupinus counterparts. Haemagglutination activity toward trypsinized rabbit
      erythrocytes was found exclusively in the albumin fraction and was strongly
      inhibited by N-acetylglucosamine or chitin.

PMID- 15030229
TI  - Myoglobin species with enhanced prooxidative activity is formed during mild
      proteolysis by pepsin.
AB  - Pepsin proteolysis at pH approximately 4 resulted in a lowering of the
      (pseudo)peroxidase activity of metmyoglobin both at physiological pH and at meat
      pH, as measured by a peroxidase assay with H(2)O(2) and ABTS as substrates. In
      contrast, the mildly proteolyzed myoglobin had a strongly enhanced prooxidative
      effect on lipid oxidation in an oil in water methyl linoleate emulsion compared
      to native metmyoglobin, as evidenced by rates of oxygen depletion. More severe
      proteolysis of metmyoglobin at lower pH values near the optimum for pepsin did
      not result in a similar enhancement of prooxidative activity. The mildly
      proteolyzed metmyoglobin had spectral characteristics in agreement with a
      relative stabilization of the iron(II) state. On the basis of the observed
      effects of metal chelators, of lipophilic and hydrophilic peroxides and of
      radical scavengers on oxygen depletion rates, it is suggested that the increased
      prooxidative effect is due to radicals formed by cleavage of lipid peroxides by
      iron(II)/iron(III) cycling of a heme pigment with affinity for the lipid/water
      interface.

PMID- 15030232
TI  - Changes in characters of soybean glycinin groups I, IIa, and IIb caused by
      heating.
AB  - Soybean glycinin groups I, IIa, and IIb were purified from soybeans composed of
      only glycinin groups I, IIa, and IIb, respectively. When these protein solutions
      were heated, the amount of the particulate protein formed in these solutions was
      greatest in the order of groups IIa, IIb, and I. The protein solubilities
      decreased upon the addition of magnesium chloride in the order of groups IIa,
      IIb, and I. It was determined by differential scanning calorimetry analysis that
      the denaturation temperatures of groups I, IIa, and IIb were 92.8, 96.0, and 97.9
      degrees C, and that the enthalpies of their transitions were 24.2, 27.4, and 28.1
      J g(-)(1), respectively. The alpha-helix rates of groups I, IIa, and IIb in
      aqueous solution were analyzed by circular dichroism and were 19, 16, and 15%,
      respectively. The beta-sheet rates of groups I, IIa, and IIb were 44, 38, and
      39%, respectively. In all group proteins, the alpha-helix rates were decreased by
      heating and the beta-sheet rates were increased. The surface hydrophobicity of
      these group proteins increased as a result of heating, and those of groups IIa
      and IIb were larger than that of group I. The surface hydrophobicity of these
      protein groups increased by heating, and those of groups IIa and IIb were larger
      than that of group I and beta-conglycinin. Breaking stress of curds prepared from
      these group proteins containing more than 1 of beta-conglycinin ration showed
      similar values, but the order of those containing less than 1 in strength was
      groups I, IIb and IIa. These results suggest that the increase of particulate
      contents and the curd formation are related to the increase of surface
      hydrophobicity by heating.

PMID- 15030231
TI  - Inhibitory effects of green tea polyphenols on the production of a virulence
      factor of the periodontal-disease-causing anaerobic bacterium Porphyromonas
      gingivalis.
AB  - The effect of polyphenolic compounds isolated from green tea (Camellia sinensis)
      on the production of toxic end metabolites of Porphyromonas gingivalis was
      investigated. Green tea polyphenols completely inhibited the production of n
      butyric acid and propionic acid at a concentration of 1.0-2.0 mg/mL in general
      anaerobic medium (GAM). (-)-Epigallocatechin gallate (EGCg), which is a major
      component of tea polyphenols also inhibited the production of phenylacetic acid
      at 0.5 mg/mL in GAM broth. In the experiment using resting cells of P.
      gingivalis, phenylacetic acid was produced from l-phenylalanine and phenylpyruvic
      acid, but this reaction was also inhibited by EGCg, (-)-epicatechin gallate, and
      (-)-gallocatechin gallate. However, (+)-catechin, (+)-gallocatechin, (-)
      epicatechin, and (-)-epigallocatechin did not inhibit those reactions. These
      results indicate that the inhibitory effect on the production of toxic end
      metabolites of P. gingivalis can be attributed to the presence of the galloyl
      moiety, which is ester-linked with the 3-OH of the catechin moiety in the
      polyphenolic compounds. This study shows that continuous application of tea
      polyphenols on a daily basis can be considered as a useful and practical method
      for the prevention of periodontal diseases.

PMID- 15030234
TI  - Gelation of iota-carrageenan and micellar casein mixtures under high hydrostatic
      pressure.
AB  - Effects of high-pressure treatment (HPT) on the rheological parameters and
      gelation of iota-carrageenan (iota-Car) and mixtures of micellar casein (MC) and
      iota-Car have been investigated under neutral pH conditions. It was established
      that HPT showed no significant effect, in the presence or absence of ionic
      calcium, with or without initial thermal processing, on the rheology or
      gelation/melting temperatures of the pure iota-Car solution. However, in mixed
      systems containing varying concentrations of iota-Car (up to 1 wt %) and MC (up
      to 8 wt %), considerable changes were detected. At the higher molar ratios of MC
      to iota-Car, and especially at the higher pressures, the dispersions were not
      thermoreversible in gelation, presumably due to the strong interactions of
      disrupted casein micelles with iota-Car molecules, as well as due to the
      formation of a dominant proteinaceous network at higher concentrations of MC. The
      associative protein-polysaccharide interactions in these systems are highly
      dependent on the ionic calcium content.

PMID- 15030233
TI  - In vitro and ex vivo antihydroxyl radical activity of green and roasted coffee.
AB  - The specific antiradical activity against the hydroxyl radical of the water
      soluble components in green and dark roasted Coffea arabica and Coffea robusta
      coffee samples, both in vitro by the chemical deoxiribose assay and ex vivo in a
      biological cellular system (IMR32 cells), were determined. All the tested coffee
      solutions showed remarkable antiradical activity. In the deoxiribose assay, all
      the tested solutions showed similar inhibitory activity (IA%) against the sugar
      degradation (IA values ranged from 45.2 to 46.9%). In the cell cultures, the
      survival increase (SI%) ranged from 197.0 to 394.0% with C. robusta roasted
      coffee being significantly more active than the other samples. The coffee
      solutions underwent dialysis (3500 Da cutoff membrane) to fraction their
      components. In both systems, the dialysates (MW < 3500 Da) either from green or
      roasted coffee, showed antiradical activity, while the only retentates (MW > 3500
      Da) from the roasted coffee samples were active. The preparative gel-filtration
      chromatography of roasted coffee C. robusta dialysate gave three fractions active
      in the biological system, all containing chlorogenic acid derivatives. The most
      active fraction was found to be that containing the 5-O-caffeoilquinic acid,
      which shows a linear relation dose-response ranging from 0.02 to 0.10 mM. The
      results show that both green and roasted coffee possess antiradical activity,
      that their more active component is 5-O-caffeoyl-quinic acid, and moreover that
      roasting process induces high MW components (later Maillard reaction products,
      i.e., melanoidins), also possessing antiradical activity in coffee. These results
      could explain the neuroprotective effects found for coffee consumption in recent
      epidemiological studies.

PMID- 15030235
TI  - Modulations of the Bcl-2/Bax family were involved in the chemopreventive effects
      of licorice root (Glycyrrhiza uralensis Fisch) in MCF-7 human breast cancer cell.
AB  - Recently, cancer chemoprevention with strategies using foods and medicinal herbs
      has been regarded as one of the most visible fields for cancer control. Genistein
      in soy, American ginseng, and resveratrol are well-known to have
      antiproliferative properties in human breast cancer. Licorice root is a
      botanical, a shrub native to southern Europe and Asia, which primarily has
      desirable qualities in sweetening and herbal medicine. In this study, licorice
      (Glycyrrhiza uralensis Fisch) root also inhibits cell proliferation in human
      breast cancer cell. The cell proliferation study demonstrated that licorice root
      reduced the proliferation of MCF-7 cells in a dose- and time-dependent manner.
      The extracts were fractionated in CHCl(3), EtOAc, C(6)H(14), and CH(3)OH-H(2)O
      (70:30), and these extracts of licorice root (50 microg/mL) induced DNA
      fragmentation demonstrated by Hoechst 33258 staining. Apoptosis also determined
      the sub-G1 accumulation by flow cytometry analysis. These results were consistent
      with specific cleavage of PARP and antiapoptotic protein Bcl-2 and up-regulation
      of proapoptotic protein Bax demonstrated by Western blotting. Our findings
      suggest that licorice root may have chemopreventive effects against human breast
      cancer through the modulation of the expression of the Bcl-2/Bax family of
      apoptotic regulatory factors.

PMID- 15030236
TI  - Chinese yam (Dioscorea alata cv. Tainung No. 2) feeding exhibited antioxidative
      effects in hyperhomocysteinemia rats.
AB  - Antioxidative effects of Dioscorea alata (D. alata) were investigated in
      hyperhomocysteinemia (HHcy) induced by methionine (Met) oral feeding (1 (g/kg of
      BW)/day). HHcy rats were fed a standard laboratory chow supplemented without or
      with freeze-dried D. alata powder at 1, 2.5, and 5 (g/kg of BW)/day, assigned as
      Met, Met + D1, Met + D2, and Met + D3 groups, respectively. Twelve weeks after D.
      alata feeding, plasma homocysteine levels (16.3-24.2 microM) were significantly
      decreased compared to that of the Met group (34.1 +/- 9.9 microM) (p < 0.01), and
      similar to the basal level (15.0 +/- 1.9 microM). Thrombin-induced platelet
      aggregation (PA) of the Met + D2 and Met + D3 groups was significantly lower than
      that of the Met group. Plasma malondialdehyde levels, an indicator of lipid
      peroxidation, and hepatic reactive oxygen species, an indicator of oxidative
      stress, of HHcy with D. alata feeding were significantly lower than that without
      D. alata feeding. The hepatic catalase in the Met + D2 and Met + D3 groups was
      significantly elevated compared to that in the Met group. D. alata feeding did
      not significantly change hepatic superoxide dismutase, glutathione peroxidase,
      and glutathione reductase, which were adaptively enhanced by Met feeding. The
      decreased glutathione/glutathione disulfide ratio in the Met group was increased
      after D. alata feeding. These results indicated that HHcy induced by Met could be
      reversed by D. alata feeding. D. alata feeding exhibited its antioxidative
      effects in HHcy including alleviating PA, lipid peroxidation, and oxidative
      stress, but did not induce activity of antioxidant enzymes which had already
      adaptively increased by HHcy.

PMID- 15030237
TI  - Improved fractionation of glycinin and beta-conglycinin and partitioning of
      phytochemicals.
AB  - Glycinin-rich and beta-conglycinin-rich products are prepared by soy protein
      fractionation. Physicochemical characteristics of these proteins affect their
      unique, important functionality in food systems and industrial applications.
      Soybean isoflavones and saponins are phytochemicals with potential health
      benefits. Objectives of this protein fractionation research were to (1) improve
      protein and phytochemical extraction from defatted soy flakes and recovery in
      product fractions and (2) evaluate phytochemical partitioning and profile changes
      during fractionation. Extraction environments (pH, ethanol concentration,
      temperature, and water-to-flake ratio) were each varied during bench-scale
      optimization. Optimized conditions of 45 degrees C and 10:1 water-to-flake ratio
      were compared with previous conditions of 20 degrees C and 15:1 water-to-flake
      ratio and a soy protein isolate process at pilot scale. Optimized conditions
      yielded more beta-conglycinin with higher isoflavone and saponin concentrations,
      but fraction purity was diminished by glycinin contamination. Bench-scale data
      demonstrated that increased phytochemical extraction did not translate into
      increased concentrations in product fractions.

PMID- 15030238
TI  - Automated dynamic headspace/GC-MS analyses affect the repeatability of volatiles
      in irradiated Turkey.
AB  - Although a dynamic headspace/gas chromatography-mass spectrometry (DH/GC-MS)
      method is an effective tool for determining volatiles of irradiated turkey meat,
      the profile of volatiles may be changeable depending upon the availability of
      oxygen in the sample vial and sample holding time before purge. The objective of
      this study was to evaluate the effects of helium flushing and sample holding time
      before purge on the volatiles profiles of irradiated raw and cooked turkey breast
      meat. Vacuum-packaged turkey breasts were irradiated at 2.5 kGy, and the
      volatiles of irradiated raw and cooked samples were analyzed using a DH/GC-MS
      with different holding times up to 280 min. The amounts of dimethyl disulfide and
      dimethyl trisulfide decreased as sample holding time in an autosampler (4 degrees
      C) before purge increased, whereas those of aldehdyes increased as holding time
      increased due to lipid oxidation. Helium flush of sample vials before sample
      loading on an autosampler retarded lipid oxidation and minimized the changes of
      sulfur volatiles in raw meat but was not enough to prevent oxidative changes in
      cooked meat. Although DH/GC-MS is a convenient method for automatic analysis of
      volatiles in meat samples, the number of samples that can be loaded in an
      autosampler at a time should be limited within the range that can permit
      reasonable repeatabilities for target volatile compounds.

PMID- 15030239
TI  - Chemotypical variation of tansy (Tanacetum vulgare L.) from 40 different
      locations in Norway.
AB  - Between 2001 and 2002, plant collections from wild populations of Norwegian tansy
      (Tanacetum vulgare L.) were studied with a focus on essential oil (EO) yield and
      composition in order to characterize the chemotypical EO variability. Tansy
      collections of 40 different locations from North, Mid-, and South Norway were
      transplanted to the Apelsvoll Research Centre Div. Kise in 2000 and grown for 2
      years before the aerial parts (leaves and flower buds) were harvested in June
      2002. The EO from individual plants was isolated from dried plant material by
      hydrodistillation and analyzed by gas chromatography-mass spectrometry (GC-MS) on
      a DB5 column at the Plant Biocenter. The EO yield ranged between 0.35 and 1.90%
      (v/w) (average: 0.81%); the most abundant thujone plants were especially rich in
      EO volatiles (0.95%). On the basis of GC-MS data, seven chemotypes could be
      identified as follows: A, alpha-thujone (two individuals); B, beta-thujone (22);
      C, camphor (six); D, chrysanthenyl acetate/chrysanthenol (three); E,
      chrysanthenone (two); F, artemisia ketone/artemisia alcohol (three); and G, 1,8
      cineole (two). The thujone chemotype was dominated by beta-thujone (81%)
      associated with alpha-thujone, but tansy plants rich in alpha-thujone were also
      detected (61%). The chemotypical classification of Norwegian tansy genotypes was
      underscored by preliminary studies from 2001, indicating the genetic uniformity
      and biochemical stability of the domesticated plants.

PMID- 15030240
TI  - Enrichment of conjugated linoleic acid in oats (Avena sativa L.) by microbial
      isomerization.
AB  - A method for microbial isomerization of oat linoleic acid to conjugated linoleic
      acid (CLA) was developed. The method includes hydrolysis of oat lipids in aqueous
      flour slurries by the endogenous oat lipase. Then, the flour slurry containing
      free linoleic acid is utilized as a substrate for the isomerization reaction
      carried out by resting cells of Propionibacterium freudenreichii ssp. shermanii.
      The isomerization reaction progressed most effectively when, after the lipid
      hydrolysis period, the pH of the slightly acidic oat slurry was elevated to 8.0
      8.5 and maintained at this range. With slurries containing 5% (w/v) oat flour,
      the amounts of CLA formed per dry matter were up to 10.1 mg/g corresponding to
      102 mg/g lipids or 0.44 mg/mL slurry. Increments in the flour content up to 15%
      increased the volumetric production of CLA to 0.85 mg/mL. The proportion of the
      cis-9,trans-11 isomer was 80% of the total CLA formed. CLA could be concentrated
      into the solid material of the oat slurry by acidification.

PMID- 15030241
TI  - Hydrolysis of ginger bagasse starch in subcritical water and carbon dioxide.
AB  - Ginger bagasse from supercritical extraction was hydrolyzed using subcritical
      water and CO(2) to produce reducing sugars and other low molecular mass
      substances. Response surface methodology was used to find the best hydrolysis
      conditions; the degree of hydrolysis and the yield were the two response
      variables selected for maximization. The kinetic studies of the hydrolysis were
      performed at 150 bar and temperatures of 176, 188, and 200 degrees C. The higher
      degree of hydrolysis (97.1% after 15 min of reaction) and higher reducing sugars
      yield (18.1% after 11 min of reaction) were established for the higher process
      temperature (200 degrees C). Different mixtures of oligosaccharides with
      different molecular mass distributions were obtained, depending on the
      temperature and on the reaction time. The ginger bagasse hydrolysis was treated
      as a heterogeneous reaction with a first-order global chemical kinetic, in
      relation to the starch concentration, which resulted in an activation energy of
      180.2 kJ/mol and a preexponential factor of 5.79 x 10(17)/s.

PMID- 15030242
TI  - Effect of foliar application of selenium on the antioxidant activity of aqueous
      and ethanolic extracts of selenium-enriched rice.
AB  - Selenium fertilizer was foliar applied to determine the effects of antioxidant
      activity of selenium-enriched rice assessed by alpha,alpha-diphenyl-beta
      picylhydrazyl (DPPH) radical scavenging and the ferric thiocyanate (FTC) method.
      Results showed that selenium concentration in rice was significantly enhanced
      dose dependently. Aqueous or ethanolic extracts of rice displayed significantly
      higher antioxidant activity against lipid peroxidation. The activities of aqueous
      extracts were significantly higher than those of ethanolic extracts and increased
      with the increasing selenium concentration in rice. The DPPH assay showed that
      the kinetic behaviors of aqueous extracts were complex and slow, while ethanolic
      extracts reacted quickly with DPPH radical. Aqueous extracts of rice exhibited
      higher antiradical efficiencies than ethanolic extracts, and rice (1.275 mg Se
      kg(-)(1)) presented the lowest EC(50) values of 533.46 +/- 0.58 microg mL(-)(1).
      As compared to rice extracts, all of the reference antioxidants showed more than
      4-fold antiradical efficiencies than rice extracts. This radical scavenging
      activity was significantly correlated with selenium concentrations in rice (R =
      0.862, p < 0.05), while ethanolic extracts were inversely correlated with
      selenium concentration in rice.

PMID- 15030243
TI  - Regulative actions of dietary soy isoflavone on biological antioxidative system
      and lipid metabolism in rats.
AB  - Male Sprague-Dawley rats, 4 weeks of age, were fed purified diets either with or
      without 0.2% soy isoflavones rich powder for 5 weeks to elucidate their direct
      functions such as antioxidative action and regulation of lipid metabolism.
      Dietary soy isoflavones decreased serum lipid peroxide level in rats. Levels of
      liver and serum alpha-tocopherol were higher in the rats fed isoflavone than in
      those fed isoflavones-free diet. Thus, dietary soy isoflavones exhibited mild
      antioxidative function in this animal experiment. Isoflavone metabolites from
      diet may act as scavengers of reactive oxygen species. Dietary soy isoflavones
      lowered hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity, although liver
      cholesterol level was not modulated. However, the levels of serum cholesterol and
      triglyceride decreased by consumption of soy isoflavones. Therefore, dietary soy
      isoflavones may exhibit hypocholesterolemic and hypolipidemic functions.
      Moreover, dietary soy isoflavones lowered hepatic Delta6 desaturase activity.
      Reflecting this observation, Delta6 desaturation indices ((18:2(n = 6) + 18:3(n =
      6))/20:4(n = 6)) of tissue lipids tended to be lower in rats fed isoflavones than
      in those fed isoflavones-free diet. This action may contribute to the prevention
      of inflammatory response by imbalance of eicosanoids. These observations suggest
      that the positive intake of soy isoflavones may reduce the risk of some
      cardiovasucular diseases through their radical scavenging function and
      hypocholesterolemic action.

PMID- 15030245
TI  - Contribution of water, bread, and vegetables (raw and cooked) to dietary intake
      of inorganic arsenic in a rural village of Northern Chile.
AB  - Total and inorganic As contents of cooked vegetables obtained from an arsenic
      endemic area of Chile were analyzed. Inorganic As intake from those foods, bread,
      and water was estimated. The study was performed in two different periods, in
      which the water used by the population for drinking and cooking purposes
      contained 0.572 (first period) or 0.041 microg mL(-)(1) (second period). In the
      first period, the FAO/WHO reference intake was exceeded by all of the persons
      interviewed. In the second period, the reference intake was exceeded by all of
      the persons interviewed ages 13-15. The foods studied contributed 4% (first
      period) or 25% (second period) of the inorganic As intake. The results show the
      contribution of food to inorganic As intake and the risk to which those ages 15
      or younger are exposed.

PMID- 15030244
TI  - Human exposure to polychlorinated diphenyl ethers through the diet in Catalonia,
      Spain.
AB  - Although polychlorinated diphenyl ethers (PCDEs) are recognized environmental
      pollutants, information concerning human exposure to these organic substances is
      very scarce. For the present study the concentrations of PCDEs in a number of
      foodstuffs acquired in Catalonia, Spain, were determined. The dietary intake of
      PCDEs was estimated for various age groups of the general population living in
      this Spanish region. With the exception of fish and shellfish, PCDE
      concentrations were under the limit of detection in the 10 remaining food groups
      analyzed. For an adult (20-65 years old) male of 70 kg average body weight, the
      estimated total dietary intake of PCDEs was 41 ng/day. It was assumed that if a
      PCDE congener was below the detection limit, the concentration was equal to half
      of the limit of detection. The highest exposure to PCDEs through the diet
      corresponded to the group aged 51-65 years, whereas the lowest intake
      corresponded to the youngest group (4-9 years). With the exception of the group
      aged >65 years, PCDE intake was always higher in males than in females. The
      results of this study should be of interest for future assessments of time trends
      in human exposure to PCDEs through the diet.

PMID- 15030246
TI  - Time trend investigation of PCBs, PBDEs, and organochlorine pesticides in
      selected n-3 polyunsaturated fatty acid rich dietary fish oil and vegetable oil
      supplements; nutritional relevance for human essential n-3 fatty acid
      requirements.
AB  - In addition to being used in the food and animal feed industry, fish oils have
      also been used traditionally as dietary supplements. Due to the presence of long
      chain n-3 fatty acids, fish oils have therapeutic benefits in the prevention and
      treatment of cardiovascular, immunological, and arthritic diseases, as well as
      childhood deficiency diseases such as rickets, because of a high content of
      vitamin D. However, fish oils are also susceptible to contamination with
      lipophilic organic chemicals that are now ubiquitous contaminants of marine
      ecosystems. Many vegetable oils are sources of the shorter chain precursor forms
      of n-3 fatty acids, and in recent years the specialist dietary supplement market
      has expanded to include these oils in a variety of different formulations. This
      paper reports analytical results of selected contaminants, including
      polychlorinated biphenyls, organochlorine pesticides, and polybrominated diphenyl
      ethers, for a range of commercially available n-3 fatty acid rich fish and
      vegetable oil dietary supplements. Using principal component analysis, the values
      are compared with historic samples to elucidate time trends in contamination
      profiles. Levels of contaminants are discussed in relation to the nutritional
      benefits to the consumer of long- and short-chain forms of n-3 fatty acids.

PMID- 15030247
TI  - Atheroma of the aortic arch: the missing link in the secondary prevention of
      stroke?
AB  - Atheroma of the aortic arch is an important risk factor for stroke and for
      recurrent stroke. Optimal management is not known but these patients should
      probably receive more powerful antiplatelet treatment than aspirin alone. Whether
      combination treatment with aspirin plus clopidogrel is more effective than
      warfarin alone is the subject of the ongoing ARCH study.

PMID- 15030249
TI  - Rosuvastatin: a new inhibitor of HMG-coA reductase for the treatment of
      dyslipidemia.
AB  - Rosuvastatin (Crestor, AstraZeneca) is a synthetic statin that represents an
      advance on the pharmacologic and clinical properties of other agents in this
      class. Relative to other statins, rosuvastatin possesses a greater number of
      binding interactions with HMG-CoA reductase and has a high affinity for the
      active site of the enzyme. Rosuvastatin is relatively hydrophilic and is
      selectively taken up by, and active in, hepatic cells. Rosuvastatin has the
      longest terminal half-life of the statins and is only minimally metabolized by
      the cytochrome P450 (CYP 450) enzyme system with no significant involvement of
      the 3A4 enzyme. Consistent with this finding is the absence of clinically
      significant drug interactions between rosuvastatin and other drugs known to
      inhibit CYP 450 enzymes. In patients with hypercholesterolemia, rosuvastatin 10
      40 mg has been shown to reduce low-density lipoprotein cholesterol (LDL-C) levels
      by 52-63%, as well as increase high-density lipoprotein cholesterol (HDL-C)
      levels by up to 14% and reduce triglycerides (TG) by up to 28%. Studies have
      shown that rosuvastatin is superior to atorvastatin, simvastatin and pravastatin
      in reducing LDL-C and favorably modifying other components of the atherogenic
      lipid profile. The significant decreases in LDL-C with rosuvastatin treatment
      should help to improve attainment of lipid goals and reduce the requirement for
      dose titration. In addition, the effects of rosuvastatin on HDL-C and TG levels
      will be of benefit in treating patients with abnormalities such as mixed
      dyslipidemia and the metabolic syndrome. Rosuvastatin is well tolerated, with a
      safety profile comparable with that of other currently available statins.

PMID- 15030250
TI  - Clopidogrel's role in the management of atherosclerotic disease: a focus on acute
      coronary syndromes.
AB  - Recent advances in our understanding of the role of the platelet in the
      atherosclerotic process beyond the acute formation of arterial blood clots, such
      as inflammation, have highlighted the role of antiplatelet agents as being much
      more than just 'blood thinners.' Some of the most important cardiovascular trials
      performed in the last 20 years have studied antiplatelet therapies. However,
      despite their long history, current global health implications and proven
      benefit, there remain substantial gaps in our understanding as to how to best
      utilize the limited number of antiplatelet agents available. This article will
      discuss the mechanism of action of the antiplatelet class known as
      thienopyridines, the pharmacodynamics and pharmacokinetics of the thienopyridine
      agent clopidogrel (Plavix, Bristol-Myers Squibb and Sanofi Pharmaceuticals) as
      well as the literature supporting its clinical benefits and areas of ongoing
      research that will help clarify the optimal utilization of clopidogrel for the
      treatment of cardiovascular disease.

PMID- 15030251
TI  - Etiology of valvular heart disease.
AB  - The etiology of valvular heart diseases (VHD) has changed in the last 50 years in
      the industrialized countries. A significant reduction in the incidence of
      rheumatic fever and its sequelae, increase in life expectancy, recognition of new
      causes of VHD and advancement in technology are responsible for the metamorphosis
      of the etiology of VHD. Heritable disorders of connective tissue (marfan
      syndrome, Ehlers-Danlos syndrome, adult polycystic kidney disease, floppy mitral
      valve/mitral valve prolapse); congenital heart disease (bicuspid aortic valve);
      inflammatory/immunologic disorders (rheumatic fever, AIDS, Kawasaki disease,
      syphilis, seronegative spondyloarthropathies, systemic lupus erythematosus,
      antiphospholipid syndrome); endocardial disorders (nonbacteremic thrombotic
      endocarditis, infective endocarditis, endomyocardial fibroelastosis); myocardial
      dysfunction (ischemic heart disease, dilated cardiomyopathy, hypertrophic
      cardiomyopathy); diseases and disorders of other organs (chronic renal failure,
      carcinoid heart disease); aging (calcific aortic stenosis, mitral annular
      calcification); postinterventional valvular disease; drugs and physical agents
      are all clinical entities associated with VHD. It should be emphasized that VHDs
      still constitute a major health problem which will increase with the aging
      population.

PMID- 15030252
TI  - Homografts: a review.
AB  - Since their introduction into clinical practice in 1965 homografts have become
      established in clinical routine. The storing and sterilization procedures have
      been improved over time. Long-term results showed that homografts had a superior
      durability compared to xenogenic biological prostheses. Approximately 40% were
      still in place 20 years after implantation in aortic position. Their low rate of
      thromboembolic events made a life-time anticoagulative therapy unnecessary and
      their hemodynamics were superior to all other heart valve prostheses. There exist
      two implantation techniques, subcoronary or mini-root, both technically more
      demanding compared with implantation of stented valve prostheses. When using the
      subcoronary technique, the valve is suspended into the aortic root leaving the
      coronary arteries untouched. The success of this technique, however, depends on
      the relation of the recipients aortic root and the implanted valve. The mini-root
      technique requires reimplantation of the coronary arteries but left the
      morphology of the valve and its root unchanged. Especially in patients with
      endocarditis, the mini-root technique offered the advantage of allowing for
      excision of all affected tissue with subsequent replacement by the homograft. The
      Ross-procedure uses the patient's own pulmonary valve as aortic valve substitute
      with implantation of a homograft in pulmonary position. This proved to be
      advantageous in children, since in these patients the degeneration of an aortic
      homograft was faster compared to an older population. This was explained by the
      recipient's immunologic response to the graft which was more pronounced in
      younger patients. The advantages of homografts with regards to hemodynamics and
      thromboembolic risk make them a good alternative to mechanical prostheses in
      younger, active patients. In very young patients, a Ross-procedure was shown to
      be superior to aortic homografts due to slower degeneration of the autograft. The
      decision to use a homograft must be made individually according to the patients
      demands.

PMID- 15030253
TI  - Percutaneous implantation of pulmonary valves.
AB  - Percutaneous implantation of valves is evolving as the most exciting innovation
      in transcatheter therapeutics. Valve repairs and replacements form an important
      indication of re-operations after congenital heart operations. Right ventricular
      outflow tract surgery is common after repair of conditions such as pulmonary
      atresia with Tetralogy of Fallot, common arterial trunk and Rastelli operation
      for transposition of great arteries, ventricular septal defect with pulmonary
      stenosis. Conduit survival is improving, nevertheless, re-operations are common.
      Although the re-operations can be performed at low risk, they still involve
      morbidity and mortality. Percutaneous implantation of valves is emerging as an
      alternative option for these group of patients. Our experience in percutaneous
      implantation of pulmonary valves has yielded encouraging results. For
      incompetence, the results are excellent. Evolving technology is making it
      applicable in wider clinical situations. Similar technology could also be applied
      to implantation of valves in the aortic position.

PMID- 15030255
TI  - Statistical analysis of the results of heart valve replacement.
AB  - A variety of statistical methods can be used to analyze the results of heart
      valve replacement. In this review, we illustrate the methodology and the
      application of the techniques that are most widely used. For early events,
      univariate analysis and multivariate logistic regression are illustrated. For
      late (time-related) events, nonparametric methods (Kaplan-Meier and cumulative
      incidence or 'actual' analysis), parametric methods (based on the exponential,
      Gompertz and Weibull distributions) and semiparametric methods (Cox proportional
      hazards) are illustrated.

PMID- 15030254
TI  - Imaging in mitral stenosis: assessment before, during and after percutaneous
      balloon mitral valvuloplasty.
AB  - Detailed assessment of mitral valve morphology is required to select patients for
      successful percutaneous balloon mitral valvuloplasty (PBMV). The mitral valve is
      routinely imaged using transthoracic and transesophageal echocardiography, which
      have more recently been supplemented with magnetic resonance imaging, 3D
      echocardiography and intracardiac echocardiography. The scope of PBMV is
      expanding and it is increasingly used for patients previously considered to have
      unfavorable mitral morphology. Here we review the evidence to support the
      examination of each component of the mitral valve and its surrounding structures
      and the advantages of each imaging modality. Appropriate echocardiographic views
      are recommended and periprocedural and postprocedural imaging techniques are
      discussed.

PMID- 15030257
TI  - Vascular grafts.
AB  - Autogenous vein is the conduit of choice in the surgical creation of bypasses of
      small-to-medium-caliber vessels in patients with peripheral occlusive arterial
      disease and will remain so for the near future. The success rate of bypasses
      using conduits of diameters greater than 6 mm has been excellent, whereas the
      majority of bypasses using smaller conduits fail within 5 years. In addition, due
      to a steep increase in rates of diabetes and decreasing cardiovascular mortality
      rates, increasing challenges are presented by this population. These facts have
      motivated much of the research in the cardiovascular arena over the past four
      decades, with improved techniques and new materials. Strategies to improve
      outcomes include the use of alternative materials including autologous,
      nonautologous and prosthetic grafts, utilizing different methods for their
      harvesting and preservation; tissue engineering, using either polymer- or
      biological-based scaffolds for cell seeding; endovascular methodologies; and gene
      therapy. This report presents an overview of the several options currently
      available in the management of patients with peripheral arterial occlusive
      disease, as well as the ongoing research directed towards the creation of an
      artificial engineered vessel, discussing experimental work in which endothelial
      cells have been seeded on different scaffolds and finally the potential
      application of gene therapy in the field of vascular reconstruction.

PMID- 15030256
TI  - MRI-guided therapy in acute stroke.
AB  - Stroke is the third leading cause of death after myocardial infarction and cancer
      and the leading cause of permanent disability and of disability-adjusted loss of
      independent life-years in Western countries. Thrombolysis is the treatment of
      choice for acute stroke within 3 h after onset of symptoms. Treatment beyond the
      3-h time window has not been shown to be effective in any single trial, however,
      meta-analyses suggest a somewhat less but still significant effect within 3 to 6
      h after stroke. It seems reasonable to apply improved selection criteria that
      allow the differentiation of patients with a relevant indication for thrombolytic
      therapy from those who have not. An overview of a diagnostic approach to acute
      stroke management that allows patient management individualization based on
      pathophysiological reasoning and not rigid time windows, established by
      randomized controlled trials is presented. Therefore, this review concentrates in
      the first part on giving the reader an integrated knowledge of the current status
      of thrombolytic therapy in stroke, and in the second part, develops a treatment
      algorithm based on pathophysiological information rendered by a multiparametric
      stroke magnetic resonance imaging protocol.

PMID- 15030258
TI  - Curative surgery for atrial fibrillation: current status and minimally invasive
      approaches.
AB  - Atrial fibrillation (AF) is the most common disorder of heart rhythm. Affecting
      2.2 million Americans and millions more worldwide, AF is a dangerous and costly
      epidemic. AF is associated with an increased risk of stroke, premature death and
      billions of dollars in healthcare expenditures. Traditional treatments of AF,
      which include medications aimed at rate or rhythm control have been
      disappointing, leaving most patients in AF and failing to eliminate the risk of
      stroke. In contrast, advances in surgical and catheter-based therapies offer the
      chance to cure AF. With more than a decade of experience, surgical treatment of
      AF is the most effective means of curing this arrhythmia. The classic Maze
      procedure eliminates AF in more than 90% of patients. A complex but safe
      operation, the Maze procedure is applied by relatively few surgeons. Recently,
      however, there has been a resurgence of interest in surgical treatment of AF.
      Advances in the understanding of the pathogenesis of AF and development of new
      ablation technologies enable surgeons to perform pulmonary vein ablation and
      create linear left atrial lesions rapidly and safely. Such procedures, which are
      generally applied to patients with AF and valvular heart disease, add 15 minutes
      to operative time and cure AF in approximately 80% of patients. New ablation
      technologies have been adapted to enable thoracoscopic and minimally invasive
      surgical AF ablation in patients with isolated AF, extending the possibility of
      cure to large numbers of patients.

PMID- 15030259
TI  - Endo-exuberance and abdominal aortic aneurysm management: have we gone too far?
AB  - HYPOTHESIS: new technology, such as endovascular abdominal aortic aneurysm repair
      (EVAR) may promote an 'irrational exuberance' for its application. METHODS:
      nonsuprarenal AAA repairs performed at a single institution over a 7 year period
      were retrospectively studied. Method of repair, 30-day mortality and EVAR aortic
      neck anatomy were assessed. RESULTS: 431 AAA repairs were performed between
      January 1996 and June 2002, 238 (55%) open and 193 (45%) EVAR. The percentage of
      EVAR increased steadily from approximately 20% in 1996 and 1997 to a peak of
      69.5% in 2000. However, in 2001-2002 the percentage of EVAR fell to approximately
      40% of total repairs. In this time period our selection criteria for EVAR became
      more conservative, with treatment of fewer patients with short aortic necks (12.8
      vs. 28.9% with neck length < or = 20 mm, p = 0.05; 3.8 vs. 10.8% with neck length
      < or = 15 mm, p = 0.1) or highly angulated necks (3.8 vs. 28.9% with neck
      angulation > or = 40 degrees, p = 0.04) in 2001-2002 versus 1999-2000,
      respectively. Institutional volume of AAA repairs doubled over the study period
      (p = 0.001). 30-day mortality over the study period for nonruptured EVAR and open
      AAA repair was 2.6 and 3.3%, respectively (p = NS). The complexity of open
      repairs increased significantly during the final 3 years of the review.
      CONCLUSIONS: the application of EVAR has fallen from a high of 69.5% of our AAA
      repairs in 2000 to approximately 40% in 2001-2002. More prudent patient selection
      in recent years regarding unfavorable aortic neck anatomy was felt to be a
      primary etiology of changes in overall EVAR utilization. The anticipated
      improvement in long-term results from EVAR await multi-year follow-up.

PMID- 15030260
TI  - Antiplatelet treatment for secondary prevention of acute ischemic stroke and
      transient ischemic attacks: mechanisms, choices and possible emerging patterns of
      use.

PMID- 15030262
TI  - Fixed combination therapy of hypertension: focus on valsartan/hydrochlorothiazide
      combination (Diovan/HCT).
AB  - Hypertension is a major risk factor for cardiovascular morbidity and mortality.
      Monotherapy of hypertension is often ineffective, since it controls approximately
      50% of the blood pressure of hypertensive patients. For lowering blood pressure
      to less than 140/90 mmHg (or <130/80 mmHg among people with diabetes or chronic
      renal disease) according to JNC-7 guidelines, combination therapy of two or more
      drugs is often necessary. The combination of a diuretic with an angiotensin
      converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) is
      effective and provides the additional benefit of blocking the effects of
      angiotensin II, which is responsible for cardiovascular remodeling and its
      complications. ARBs may have an advantage over the ACEIs because they block the
      action of all angiotensin II directly, whereas ACEIs are ineffective in blocking
      angiotensin II generated by nonclassical ACE pathways. Valsartan (Diovan,
      Novartis) is one of the seven currently approved ARBs in the USA for the
      treatment of hypertension, and it has been shown to be very effective in
      controlling blood pressure given once-daily in doses of 80-160 or 320 mg. Its
      fixed combination with hydrochlorothiazide (HCT) is even more effective in
      controlling blood pressure in 70% of the cases. The most commonly used
      combinations are valsartan/HCT (Diovan/HCT), 80/12.5 and 160/12.5 mg given once
      daily.

PMID- 15030263
TI  - Pharmacological profile and clinical use of moexipril.
AB  - Angiotensin-converting enzyme (ACE) inhibitors are effective and safe
      antihypertensive drugs with the exception of the rare occurrence of angioedema.
      These drugs have demonstrated additional cardiovascular protective effects to
      their blood pressure lowering and their combination with the diuretic
      hydrochlorothiazide potentiates their antihypertensive effectiveness. Moexipril
      (Univasc, Bayer) is a long-acting ACE inhibitor suitable for once-daily
      administration and, like enalapril, is a prodrug and needs to be hydrolyzed in
      the liver into its active carboxylic metabolite, moexiprilat, in order to become
      effective. Moexipril alone and in combination with low-dose hydrochlorothiazide
      has been shown in clinical trials to be effective in lowering blood pressure and
      to be well-tolerated and safe given in single daily doses. In this review, the
      pharmacological profile of this drug and its clinical usefulness will be
      discussed.

PMID- 15030264
TI  - Identification of vulnerable atherosclerotic plaques.
AB  - There has been great interest in the possibility of identifying plaques that
      might be the site of future acute coronary events. These plaques are termed
      vulnerable and the majority are lipid-rich with an abundance of inflammatory
      cells and a thin fibrous cap. Several techniques developed to identify these
      plaques are in various stages of development and in the near future, one might
      employ a strategy to potentially identify and therapeutically modify such lesions
      during percutaneous intervention to avoid future acute events. Although this
      approach of identifying the vulnerable plaque seems promising, there are
      significant potential limitations. The natural history of a vulnerable plaque is
      unknown and clinical trials utilizing this strategy of identification and
      therapeutic intervention are lacking. Moreover, in any given patient, multiple
      vulnerable plaques are likely to be present. This article reviews some of the
      techniques for identifying a vulnerable plaque and discusses the potential
      advantages and limitations of this strategy.

PMID- 15030265
TI  - Chlamydia pneumoniae and coronary artery disease: legitimized linkages?
AB  - Chlamydia pneumoniae (Cp) infection in early life may accelerate atherosclerosis
      over ensuing decades, leading to cardiovascular complications. Cp promotes
      endothelial dysfunction and may modulate inflammation underlying atherosclerosis.
      It represents a biologically plausible candidate for the causation of
      atherosclerosis. Other infections simultaneously occurring with Cp may result in
      a synergistic effect to promote atherosclerosis. Studies on the treatment of Cp
      with antibiotics indicates decreased rates of infection, modulation of
      inflammation and in some settings, fewer cardiovascular complications.

PMID- 15030266
TI  - Vascular protectants for the treatment of atherosclerosis.
AB  - AGI-1067, the monosuccinic acid ester of probucol, is a phenolic antioxidant
      member of a novel class of agents termed vascular protectants. It has strong
      antioxidant properties, equipotent to those of probucol, and anti-inflammatory
      properties. It inhibits gene expression of vascular cell adhesion molecule-1 and
      monocyte chemotactic protein-1 and has been effective at preventing
      atherosclerosis in all tested animal models. It also improved luminal dimensions
      of reference segments in the percutaneous coronary intervention (PCI) vessels in
      the CART-1 clinical trial, which suggests a direct anti-atherosclerosis effect.
      Two important trials that test the antioxidant/anti-inflammatory hypothesis are
      ongoing with AGI-1067: the Canadian Atherosclerosis and Restenosis Trial, which
      assesses its value for the reduction of both atherosclerosis progression in non
      PCI vessels and post-PCI restenosis, and the Aggressive Reduction of Inflammation
      Stops Events trial, which is evaluating the effects of AGI-1067 on hard
      cardiovascular outcomes.

PMID- 15030267
TI  - Anti-monocyte chemoattractant protein-1 gene therapy for cardiovascular diseases.
AB  - Recent studies have revealed that increased expression of monocyte
      chemoattractant protein (MCP)-1 plays a central role in the pathogenesis of
      cardiovascular diseases. 7ND is the amino-terminal deletion mutant of human MCP-1
      and works as a dominant negative inhibitor of MCP-1. We devised a new strategy of
      anti-MCP-1 gene therapy by transfecting the 7ND gene into skeletal muscles. 7ND
      gene transfection suppressed arteriosclerotic changes induced by chronic
      inhibition of nitric oxide synthesis in rats and inhibited the development,
      progression and destabilization of atherosclerosis in apolipoprotein E knockout
      mice. This strategy also reduced restenosis after balloon injury in rats, rabbits
      and monkeys, and reduced neointimal formation after stent implantation in rabbits
      and monkeys. This new strategy can be a useful and feasible gene therapy against
      MCP-1 related cardiovascular diseases.

PMID- 15030268
TI  - Genotype-specific clinical manifestation in long QT syndrome.
AB  - The congenital form of long QT syndrome (LQTS) is characterized by QT
      prolongation in the electrocardiogram (ECG) and a polymorphic ventricular
      tachycardia, Torsade de Pointes (TdP) mainly as a result of an increased
      sympathetic tone during exercise or mental stress. Recent genetic studies have so
      far identified seven forms of congenital LQTS caused by mutations in genes of the
      potassium and sodium channels or membrane adapter located on chromosomes 3, 4, 7,
      11, 17 and 21. It is of particular importance to examine the genotype-phenotype
      correlation, especially in the LQT1, LQT2 and LQT3 forms of LQTS, which make up
      more than 90% of genotyped patients with LQTS, because it would enable us to
      manage and treat genotyped patients more effectively.

PMID- 15030269
TI  - Transcatheter closure of the patent ductus arteriosus.
AB  - Patent ductus arteriosus (PDA) is one of the most common congenital heart
      defects. Although surgery is still required in symptomatic neonates, the majority
      of older infants and children can undergo safe and effective transcatheter device
      closure on an out-patient basis. First described in 1967, over the past four
      decades, numerous devices have been specifically developed for this purpose. This
      article will review the current status of transcatheter therapy. The experience
      with each device is detailed and issues and controversies are reviewed.

PMID- 15030270
TI  - Radiofrequency catheter ablation therapy in the young: current status.
AB  - Since 1989, when radiofrequency ablation was introduced into clinical practice
      for pediatric patients with supraventricular tachycardias, radiofrequency
      catheter ablation techniques have evolved as the treatment of choice for many
      forms of tachycardia in young patients. This review discusses the current status
      of ablation therapy for the four most common forms of supraventricular
      tachycardias in children, including tachycardias based on accessory
      atrioventricular pathways, atrioventricular nodal reentrant tachycardia, atrial
      ectopic tachycardia and the permanent form of junctional reciprocating
      tachycardia. In addition, the report will focus on the current status and
      limitations of ablation therapy of ventricular tachycardias and atrial reentry
      tachycardias in patients after surgical correction of congenital heart defects.

PMID- 15030271
TI  - Cardiac complications in thalassemia: noninvasive detection methods and new
      directions in the clinical management.
AB  - The natural history of thalassemia has shown substantial change during these
      years. This applies for each aspect of the pathology (for example,
      endocrinological, hepatological and psychological) and also for the pathology
      that has presented and still presents the main cause of death: myocardial
      dysfunction. In this review, the pathophysiology of cardiac complications,
      possible role of myocarditis, new knowledge on pathogenesis, and noninvasive
      detection methods for iron overload in the heart are pointed out. Prophylaxis of
      cardiomyopathy and new therapy strategies of myocardial dysfunction, including
      the impact of the new chelation treatment, are discussed.

PMID- 15030272
TI  - Cardiovascular disease: potential impact of stem cell therapy.
AB  - Atherosclerotic vascular disease becomes a clinical problem when there is
      sufficient atherosclerotic plaque burden and/or endothelial dysfunction to cause
      a limitation of nutrient blood flow to tissues. However, once myocardial
      infarction has occurred, there is little, if any, way to stimulate the growth of
      new blood vessels or cardiac muscle to replace that which has been lost. The
      potential use of hematopoietic stem cells (HSCs) to treat cardiovascular disease
      has recently been suggested from preclinical and clinical studies. HSCs are
      precursors of all the blood cells, but they may also give rise to cells of the
      vascular system, endothelial cells in the form of endothelial progenitor cells
      (EPCs). Clinical trials have been conducted in patients with either acute
      myocardial infarction or limb ischemia to determine the initial effectiveness and
      safety of this treatment approach. These studies demonstrated the potential
      clinical effectiveness of this stem cell approach to the treatment of patients
      with acute myocardial ischemia and limb ischemia. Today, more preclinical studies
      are planned to elucidate the mechanism by which transplanted stem cells can home
      and differentiate into these endothelial cells and cardiac muscle cells. At the
      same time, new clinical trials are planned to evaluate both chronic, stable as
      well as acute myocardial ischemia and limb ischemia with CD34+ and CD133+ stem
      cells, as well as with further selected EPCs and mesenchymal stem cells.

PMID- 15030273
TI  - Therapeutic potential of decoy oligonucleotides strategy in cardiovascular
      diseases.
AB  - Recent progress in molecular biology has provided several new techniques to
      inhibit target gene expression. In particular, the application of DNA technology,
      such as an antisense strategy, to regulate the transcription of disease-related
      genes in vivo has important therapeutic potential. Recently, transfer of cis
      element double-stranded oligonucleotides (ODN) (= decoy) has been reported as a
      new powerful tool in a new class of antigene strategies for gene therapy.
      Transfer of the double-stranded ODN corresponding to the cis-sequence will result
      in attenuation of the authentic cis-trans interaction, leading to removal of
      trans-factors from the endogenous cis-elements with subsequent modulation of gene
      expression.

PMID- 15030274
TI  - Intracoronary pressure and flow velocity for hemodynamic evaluation of coronary
      stenoses.
AB  - Adequate patient selection for percutaneous coronary intervention is of utmost
      importance to minimize early and late complications. Consequently, objective
      evidence for myocardial ischemia is mandatory for the management of patients with
      coronary artery disease, in particular in multivessel disease and intermediate
      lesions (40-70% diameter stenosis on angiography). The use of sensor-equipped
      guide wires for the assessment of functional coronary lesion severity has become
      widespread in the catheterization laboratory. The indices derived from pressure
      or flow measurements, fractional flow reserve, coronary flow velocity reserve and
      relative coronary flow velocity reserve show a high agreement with noninvasive
      stress testing. However, while these indices are based on either intracoronary
      pressure or flow, they do not investigate the hemodynamics of the coronary
      circulation entirely, leading to ambiguous outcomes. Only the use of
      simultaneously measured pressure and flow will avoid any possible
      misinterpretation of the data.

PMID- 15030275
TI  - Should beta-blockers form the cornerstone for the treatment of congestive heart
      failure?

PMID- 15030277
TI  - Indications and techniques of pediatric cardiac pacing.
AB  - There are special challenges associated with the use of transvenous pacemakers in
      children. For example, a child's chest cavity or vascular dimensions could be too
      small to host the generator and leads available or required. If leads are
      implanted, they may stretch as the child grows. This increases the risk that the
      leads will later dislodge or fracture. Moreover, children requiring pacemakers
      often have coexisting congenital heart defects and the structural abnormalities
      of those could hinder easy placement of the pacing system. This article will
      first review the indications for permanent pacing in children and will then
      describe the unique challenges associated with such use.

PMID- 15030278
TI  - Brugada syndrome: clinical, genetic, molecular, cellular and ionic aspects.
AB  - Brugada syndrome, first described as a new clinical entity by Pedro and Josep
      Brugada in 1992, has attracted great interest because of its high prevalence in
      many regions of the world and its association with high risk for sudden death.
      The syndrome has captured the attention of the cardiac electrophysiology
      community because it serves as a paradigm for our understanding of the role of
      spatial dispersion of repolarization in the development of cardiac arrhythmias.
      The past decade has witnessed an exponential rise in the number of reported cases
      and a striking proliferation of papers serving to define the clinical, genetic,
      cellular, ionic and molecular aspects of this disease. This brief review
      summarizes the key clinical and experimental milestones that have brought us to
      our current understanding and approach to therapy of the Brugada syndrome.

PMID- 15030279
TI  - Atrial fibrillation after cardiac surgery: evidence on prophylactic
      interventions.
AB  - Postoperative atrial fibrillation after heart surgery is frequent and may
      increase the length of hospital stay and costs of postoperative care of patients
      after heat surgery. Pharmacological and pacing interventions were evaluated in
      the large number of relatively small trials with often contradictory results.
      Conventional beta-blockers, sotalol, amiodarone and pacing were shown to be
      equally effective in the prevention of postoperative atrial fibrillation.
      Amiodarone and bi-atrial pacing were also effective in decreasing the length of
      hospital stay.

PMID- 15030280
TI  - Can antiarrhythmic drugs save lives in patients with congestive heart failure?
AB  - Although arrhythmic death is a common cause of death in patients with congestive
      heart failure (CHF), numerous trials involving prophylactic antiarrhythmic drug
      treatment have yielded few gains. To date, only beta-blockers have shown a
      distinct mortality-reducing effect and despite the antiarrythmic effect of gamma
      blockers, results point towards causes other than the antiarrhythmic effect in
      obtaining this beneficial effect. Atrial fibrillation is an often-encountered
      arrhythmia in patients with CHF and recent trials have cast doubt on the present
      treatment strategy of persistently striving to obtain sinus rhythm. This paper
      outlines the results of the large clinical trials dealing with antiarrhythmic
      drug treatment in CHF patients with or without atrial fibrillation and certain
      subgroup analysis and future treatment possibilities are discussed.

PMID- 15030281
TI  - Advanced life support therapy on out-of-hospital cardiac arrest patients: an
      engineering perspective.
AB  - In the USA alone, several hundred thousand people die of sudden cardiac arrests
      each year. Basic life support, defined as chest compressions and ventilations,
      and early defibrillation are the only factors proven to increase the survival of
      patients with out-of-hospital cardiac arrest and are key elements in the chain of
      survival defined by the American Heart Association. The current cardiopulmonary
      resuscitation guidelines treat all patients the same but studies show a need for
      more individualization of treatment. This review focusses on ideas on how to
      strengthen the weak parts of the chain of survival including the ability to
      measure the effects of therapy, improve time efficiency and optimize the sequence
      and quality of the various components of cardiopulmonary resuscitation.

PMID- 15030283
TI  - Use of GPIIb/IIIa inhibitors in cardiovascular medicine.
AB  - The GPIIb/IIIa inhibitors were the first clinically used anti-integrin
      therapeutics. They opened the gate to a rapidly developing area of anti-integrin
      targeting as a therapeutic approach to many diseases. The use of GPIIb/IIIa
      inhibitors in interventional cardiology is widespread and still increasing, as is
      the number of percutaneous coronary interventions. There seems to be a class
      effect of GPIIb/IIIa inhibitors in percutaneous coronary intervention, but there
      are major differences in the pharmacokinetics and pharmacodynamics of these
      agents. Currently clinically approved for parenteral use are the Fab fragment
      abciximab (ReoPro, Lilly) and the small-molecule GPIIb/IIIa inhibitors
      eptifibatide (Integrilin, Millennium/Schering-Plough) and tirofiban (Aggrastat,
      Merck). This review focuses on the different pharmacological properties of these
      agents and summarizes present and future therapeutic use of GPIIb/IIIa inhibitors
      in cardiovascular and other vascular diseases.

PMID- 15030282
TI  - Update on gene therapy for hereditary hematological disorders.
AB  - The past 3 years have been characterized by a number of impressive advances as
      well as setbacks in gene therapy for genetic disease. Children with X-linked
      severe combined immunodeficiency disorder (SCID-X1) have shown almost complete
      reconstitution of their immune system after receiving retrovirally transduced
      autologous CD34+ hematopoietic stem cells (HSCs). However, two of 11 treated
      patients subsequently developed a leukemia-like disease probablydue to the
      undesired activation of an oncogene. Gene transfer to HSCs resulted in
      substantial correction of immune function and multi-lineage engraftment in two
      patients with adenosine deaminase (ADA)-SCID. Several Phase I clinical trials for
      treatment of hemophilia A and B have been initiated or completed. Partial
      correction of hemophilia A, albeit transient, has been reported by ex vivo gene
      transfer to autologous fibroblasts. Intramuscular injection of adeno-associated
      viral (AAV) vector to patients with severe hemophilia B resulted in evidence of
      Factor IX gene transfer to skeletal muscle and a separate trial based on hepatic
      infusion of AAV vector is ongoing. Sustained therapeutic levels of coagulation
      factor expression have been achieved in preclinical models using retroviral,
      lentiviral, AAV and high capacity adenoviral vectors. Efficient lentiviral gene
      transfer to HSC in murine models of beta-thalassemia and sickle cell disease
      demonstrated sustained phenotypic correction.

PMID- 15030284
TI  - Deficient activity of von Willebrand factor-cleaving protease in thrombotic
      thrombocytopenic purpura.
AB  - Thrombotic thrombocytopenic purpura (TTP) is a dramatic intravascular platelet
      clumping disorder characterized by microangiopathic hemolytic anemia,
      thrombocytopenia, neurologic abnormalities, renal insufficiency and fever. TTP is
      a rare disease but is almost always fatal if untreated. More than 80% of patients
      survive with plasma therapy. In healthy individuals, the proteolytic cleavage of
      ultralarge von Willebrand factor (vWF) multimers prevents spontaneous clumping of
      platelets in the microcirculation. Patients with TIP have either severe
      congenital deficiency of von Willebrand factor-cleaving protease (vWF-cp), or
      have autoantibodies that inhibit the protease. Determination of vWF-cp levels in
      patient plasma helps to distinguish between TTP and other thrombotic
      microangiopathies with similar clinical signs and symptoms. vWF-cp is a member of
      the ADAMTS family of metalloproteases and has been designated ADAMTS13.

PMID- 15030285
TI  - Inhibition of von Willebrand factor-GPIb/IX/V interactions as a strategy to
      prevent arterial thrombosis.
AB  - Although drugs exist for the primary and secondary prevention of thrombosis, more
      potent antiplatelet drugs with sufficiently wide therapeutic windows to avoid
      bleeding complications are needed. Both academic and pharmaceutical laboratories
      are working to develop such drugs. This chapter reviews the potential of
      inhibiting interactions between von Willebrand factor (vWF) and the second most
      abundant receptor on the platelet, the glycoprotein (GP) Ib/IX/V complex,
      interactions that are essential for the activation of circulating platelets,
      contacting a vessel wall injury. Although still at the level of preclinical
      testing, this area is expected to progress quickly during the next few years,
      also in view of the three-dimensional structural information that has recently
      become available and that allows a molecular understanding of vWF binding to the
      GPIbalpha chain of the GPIb complex.

PMID- 15030286
TI  - Bleeding and thrombosis in the cancer patient.
AB  - There is an increased risk not only of bleeding but also of thrombosis in the
      cancer patient. The double jeopardy creates an additional problem in their
      management and requires special attention. This review provides information on
      pathophysiology in the regulation of hemostasis, leading to bleeding and
      thrombotic complications. The process is complex with multiple factors being
      involved. In addition to the pathogenesis, a number of clinical syndromes,
      diagnostic methods and the management of hemostatic abnormalities in the cancer
      patient are presented. Potential effects of cancer treatment on these risks
      magnify the hazards encountered by the managing team. Wherever management is
      discussed, emphasis is placed on the scientific basis for the rationale of the
      therapeutic approach.

PMID- 15030287
TI  - Antithrombotics in thrombosis and cancer.
AB  - Many cancer patients reportedly are in a hypercoaguable state, with recurrent
      thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on
      the coagulation cascade. Studies have demonstrated that unfractionated heparin
      (UFH) or low-molecular-weight heparin (LMWH) interfere with various processes
      involved in tumor growth and metastasis. These include fibrin formation, binding
      of heparin to angiogenic growth factors such as basic fibroblast growth factor
      and vascular endothelial growth factor, modulation of tissue factor and, perhaps,
      other more important modulatory mechanisms such as enhanced tissue factor pathway
      inhibitor (TFPI) release and inhibition of various matrix-degrading enzymes.
      Clinical trials have suggested a clinically relevant effect of LMWH, compared
      with UFH on the survival of cancer patients with deep vein thrombosis. Similarly,
      the impact of warfarin on the survival of cancer patients with thromboembolic
      disorders was demonstrated. Studies from our laboratory demonstrated a
      significant role for LMWH, warfarin, anti-VIIa and LMWH-releasable TFPI on the
      regulation of angiogenesis, tumor growth, and tumor metastasis. Thus, modulation
      of tissue factor/VIIa noncoagulant activities by LMWH, warfarin, anti-VIIa or
      TFPI might be a useful therapeutic option for the inhibition of angiogenesis
      associated with human tumor growth and metastasis.

PMID- 15030288
TI  - Involvement of cardiomyocyte survival-apoptosis balance in hypertensive cardiac
      remodeling.
AB  - The balance between cell death and cell survival is a tightly controlled process,
      especially in terminally differentiated cells, such as the cardiomyocyte.
      Accumulating data support a role for cardiomyocyte apoptosis in the development
      of several cardiac diseases, including the transition from hypertensive
      compensatory hypertrophy to heart failure. This review briefly summarizes the
      status of the knowledge regarding the death-survival balance of cardiomyocytes in
      the context of hypertensive heart disease. Several molecular and cellular aspects
      as well as the most relevant pathophysiological implications are presented.
      Moreover, diagnosis tools under development and the possibilities for
      pharmacological intervention are also examined.

PMID- 15030289
TI  - Renal participation in cardiovascular risk in essential hypertension.
AB  - The kidney plays a relevant role in the origin of essential hypertension in
      humans, and it suffers the consequences of sustained elevated blood pressure in
      the absence of therapy. Recently, a relevant prevalence of mild renal
      insufficiency both in general population than in hypertensive patients has been
      described. A direct relationship seems to exist between the level of
      cardiovascular risk and the prevalence of the renal disorder, whether this is
      detected as an elevation in serum creatinine or as a diminution of estimated
      creatinine clearance. This renal function impairment is a strong predictor of
      cardiovascular risk in patients with chronic heart failure and following
      myocardial infarction. Prevention of renal and cardiovascular damage in these
      patients will be one of the most relevant tasks in the future. The aim of this
      short review is to discuss the evidence in favor of a relevant prevalence of mild
      renal insufficiency in hypertensive patients, as well as the association of this
      disorder with a very significant increment in global cardiovascular risk.

PMID- 15030290
TI  - Therapeutic hypothermia after cardiopulmonary resuscitation.
AB  - Full cerebral recovery after cardiopulmonary resuscitation is still a rare event.
      Unfortunately, up to now, no specific and outcome-improving therapy was available
      after such events. From several cases it is known that low body and brain
      temperature during a cardiocirculatory arrest improves the neurological outcome
      following these events. As it is not possible in acute events to induce
      hypothermia beforehand, whether cooling after the insult could also be protective
      was evaluated. After animal studies in the 1990s and first clinical pilot trials
      of mild therapeutic and induced hypothermia, two randomized trials of hypothermic
      therapy after successful resuscitation after cardiac arrest were conducted. These
      studies demonstrated that hypothermia after cardiac arrest could improve
      neurological outcome as well as overall mortality.

PMID- 15030291
TI  - Is there HOPE for ALLHat: similarities and differences.

PMID- 15030292
TI  - Oral contraceptives, CRP levels and cardiovascular risk.

PMID- 15030294
TI  - AT1-receptor antagonism in hypertension: what has been learned with irbesartan?
AB  - Irbesartan is a long-acting angiotensin II antagonist acting specifically at the
      level of the Type 1-receptor subtype (AT1-receptor). This compound lowers blood
      pressure dose-dependently in hypertensive patients and has a placebo-like
      tolerability. The antihypertensive efficacy of irbesartan is greatly enhanced by
      the coadministration of a diuretic, and fixed-dose combinations of irbesartan and
      hydrochlorothiazide are now available. Irbesartan-based treatment appears
      especially effective for high-risk patients, such as those with diabetes, renal
      disease and cardiac hypertrophy. In patients with Type 2 diabetes, irbesartan
      delays the development of nephropathy as well as the progression of renal
      failure. Irbesartan may have antiatherosclerotic properties beyond those expected
      from blood pressure lowering per se: this AT1-blocker decreases the vascular
      oxidative stress and prevents the procoagulant as well as the pro-inflammatory
      effects of angiotensin II. Irbesartan given alone or in combination with a
      diuretic therefore represents a rational approach to treat hypertensive patients.

PMID- 15030295
TI  - Diuretics: drugs of choice for the initial management of patients with
      hypertension.
AB  - The optimal first-line treatment of hypertension has been a contentious issue.
      Despite the probable advantage of diuretics, which was demonstrated in early
      clinical trials, concern about their metabolic effects meant that therapy was
      often commenced with drugs of other types. The results of the Antihypertensive
      and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which
      compared agents of three groups of new antihypertensive drugs with a diuretic,
      demonstrated the equivalence between these drugs and chlorthalidone (Tenoretic
      AstraZeneca) in the prevention of incident fatal coronary heart disease and
      nonfatal myocardial infarction. The diuretic was superior to other drugs in
      preventing some major secondary end-points, such as cerebrovascular disease and
      heart failure. These findings, together with other very practical reasons, such
      as easy administration, few side effects and low cost, demonstrate that diuretics
      are the first option for drug management of hypertension.

PMID- 15030293
TI  - Ezetimibe: a novel option for lowering cholesterol.
AB  - Elevated low-density lipoprotein (LDL)-cholesterol is associated with a
      significantly increased risk of coronary heart disease but lowering LDL
      cholesterol to levels established in current National Cholesterol Education
      Program (NCEP) guidelines provides significant risk reduction. Nevertheless, many
      patients receiving lipid-lowering therapy, particularly those at highest coronary
      heart disease risk, do not reach LDL-cholesterol goals with their current
      medications. Ezetimibe (Zetia, Merck Schering-Plough) is the first of a new class
      of lipid-lowering drugs known as cholesterol absorption inhibitors. Ezetimibe has
      a favorable pharmacokinetic profile, which allows it to be administered once
      daily and to be given in conjunction with statins. In a series of randomized,
      controlled, multicenter studies, ezetimibe produced significant improvements in
      levels of LDL-cholesterol and other lipid parameters when used as monotherapy,
      with a safety profile comparable with that of placebo. Furthermore,
      coadministration of ezetimibe with a statin (simvastatin, atorvastatin,
      lovastatin, or pravastatin) was more effective than statin monotherapy in
      lowering LDL-cholesterol and improving other lipid parameters. Moreover,
      coadministration of ezetimibe with a statin allowed a greater percentage of
      patients to achieve treatment goals established in NCEP guidelines. The safety
      and side-effect profile of ezetimibe plus statin coadministration therapy was
      generally comparable with that of statin monotherapy. These studies establish
      ezetimibe as an effective lipid-lowering agent, which will likely be useful in
      the management of a broad range of patients with hypercholesterolemia. Ezetimibe
      can be used in conjunction with a statin at the beginning of therapy, or it can
      be added if patients do not achieve their LDL-cholesterol goal with statins
      alone.

PMID- 15030296
TI  - Combination therapy with ACE inhibitors/angiotensin II receptor antagonists and
      diuretics in hypertension.
AB  - Essential hypertension is a very heterogeneous disease and different pressor
      mechanisms might interact to increase blood pressure. It is therefore not
      surprising that antihypertensive drugs, given as monotherapy, normalize blood
      pressure in only a fraction of hypertensive patients. This is, for instance, the
      case for diuretics, angiotensin converting enzyme (ACE) inhibitors and
      angiotensin II (AT1) receptor antagonists administered as single agents. The
      rationale for combining antihypertensive agents relates in part to the concept
      that the blood pressure-lowering effect may be enhanced when two classes are
      coadministered. Also, combination therapy serves to counteract counter-regulatory
      mechanisms that are triggered whenever pharmacologic intervention is initiated
      and that act to limit the efficacy of the antihypertensive medication. For
      example, the compensatory rise in renin secretion induced by sodium depletion may
      become the predominant factor sustaining high blood pressure. Simultaneous
      blockade of the renin-angiotensin system, with either an ACE inhibitor or an AT1
      receptor blocker, makes this compensatory hyper-reninemia ineffective and allows
      maximum benefit from sodium depletion. The combination of a blocker of the renin
      angiotensin system and a low dose of a diuretic increases the effectiveness, but
      not at the expense of tolerability compared with the individual components
      administered alone. Fixed-dose combinations containing an ACE inhibitor or an AT1
      receptor blocker and a diuretic are therefore likely to become increasingly used
      not only as second-line therapy but also as first-line treatment.

PMID- 15030297
TI  - The role of renin-angiotensin-aldosterone system inhibition in chronic kidney
      disease.
AB  - Chronic kidney disease (CKD) is emerging as a new health pandemic. Underlying the
      global rise in CKD is an increase in diabetes, hypertension and other
      cardiovascular risk factors leading to progressive renal dysfunction. Emerging
      evidence strongly suggests that achieving target blood pressure goals via
      inhibition of the renin-angiotensin-aldosterone system confers significant renal
      and cardioprotection for patients with CKD. Angiotensin-converting enzyme
      inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) lower blood pressure,
      reduce proteinuria and reduce both the progression of CKD and adverse
      cardiovascular events. The role of aldosterone inhibition and combination
      therapy, such as ACEI/ARB, in CKD are under investigation. As our understanding
      of the basic mechanisms underlying CKD progression advances, novel therapies
      targeting post-translational endothelial and mesangial messengers downstream from
      angiotensin II and aldosterone may become available for clinical use.

PMID- 15030298
TI  - Antihypertensive drugs and arterial stiffness.
AB  - Arterial stiffness is recognized as an important determinant of outcome in the
      hypertensive population. Although pulse pressure is an indirect index more
      recently relatively simple non-invasive techniques to measure pulse wave
      velocity, particularly in the aorta and arterial wave analysis have been
      developed and applied to clinical trials. There are clear differences in the
      effects of antihypertensive drugs on these parameters and stiffness is becoming a
      therapeutic target in its own right.

PMID- 15030299
TI  - Ambulatory blood pressure monitoring and prognosis in the management of essential
      hypertension.
AB  - Over the past decade, several prospective outcome studies have demonstrated that
      ambulatory blood pressure measurements provide a better prediction of major
      cardiovascular events compared with clinic blood pressure measurements. This
      review summarizes the advantages of ambulatory blood pressure over clinic blood
      pressure to predict outcome in untreated and treated hypertensive subjects. Based
      on available evidence, an operational flow-chart in order to interpret results of
      ambulatory blood pressure for a better management of these subjects is suggested.

PMID- 15030300
TI  - Reactive oxygen species in vascular biology: role in arterial hypertension.
AB  - The cellular metabolism of oxygen generates potentially deleterious reactive
      oxygen species, including superoxide anion, hydrogen peroxide and hydroxyl
      radical. Under normal physiologic conditions, the rate and magnitude of oxidant
      formation is balanced by the rate of oxidant elimination. However, an imbalance
      between pro-oxidants and antioxidants results in oxidative stress, which is the
      pathogenic outcome of the overproduction of oxidants that overwhelms the cellular
      antioxidant capacity. There is growing evidence that increased oxidative stress
      and associated oxidative damage are mediators of vascular injury in
      cardiovascular pathologies, including hypertension, atherosclerosis and ischemia
      reperfusion. This development has evoked considerable interest because of the
      possibilities that therapies targeted against reactive oxygen intermediates by
      decreasing the generation of reactive oxygen species and/or by increasing
      availability of antioxidants may be useful in minimizing vascular injury. This
      review focuses on the vascular actions of reactive oxygen species, the role of
      oxidative stress in vascular damage in hypertension and the therapeutic potential
      of modulating oxygen radical bioavailability in hypertension. In particular, the
      following topics will be highlighted: chemistry and sources of reactive oxygen
      species, antioxidant defense mechanisms, signaling events mediated by reactive
      oxygen species, role of reactive oxygen species in hypertension and the putative
      therapeutic role of antioxidants in cardiovascular disease.

PMID- 15030301
TI  - Primary hypercholesterolemia: genetic causes and treatment of five monogenic
      disorders.
AB  - Coronary heart disease is a major cause of death in Europe and the USA.
      Insudation of atherogenic lipoproteins, including low-density lipoprotein (LDL),
      into the artery wall is integral to atherosclerosis. It is clear that numerous
      genetic loci contribute to increased plasma levels of LDL. However, five specific
      monogenic disorders, three of which have been reported recently, are known to
      increase LDL. These are familial hypercholesterolemia (LDL receptor gene: LDLR);
      familial ligand-defective apoB- 100 (apoB gene: APOB); autosomal recessive
      hypercholesterolemia (ARH gene); sitosterolemia (ABCG5 or ABCG8 genes) and
      cholesterol 7alpha-hydroxylase deficiency (CYP7A1 gene). This review relates the
      mechanisms underlying these five disorders with specific therapeutic
      interventions.

PMID- 15030303
TI  - Treatment of children with familial hypercholesterolemia.
AB  - Heterozygous familial hypercholesterolemia affects one in every 500 persons and
      is the most common cause of markedly elevated cholesterol levels in children.
      Some male patients experience their first coronary event before the age of 30
      years. Although dietary measures prevent atherosclerosis in adult populations,
      the effect of diet on children's lipid levels is limited and compliance is
      difficult. Trials lasting up to 2 years have shown that statins effectively lower
      low density lipoprotein (LDL)-cholesterol levels and in one study, restored
      endothelial dysfunction in children with no clinical adverse effects. To fully
      assess the effect of drugs on growth and development, especially in prepubertal
      children, longer trials are required. Gender, family history and LDL-cholesterol
      level can be used to stratify risk of coronary heart disease. Children that carry
      very high risk may benefit from starting statins after puberty.

PMID- 15030302
TI  - Dyslipidemia treatment: current considerations and unmet needs.
AB  - Monumental evidence from clinical trials indicates an approximately 30% reduction
      in atheroslcerotic cardiovascular disease (ASCVD) risk using monotherapy with
      lipid-regulating drugs in dyslipidemic patients. In order to achieve greater
      reductions in risk, other approaches are necessary, including improvements in
      technology designed to assess ASCVD risk. Recent preliminary, but encouraging
      evidence indicates that by combining drugs that have different mechanisms of
      action on lipid metabolism yields not only an additive effect on the lipoprotein
      spectrum, but also reduces ASCVD events. New studies indicate that niacin
      potently increases high-density lipoproteins (HDL) by inhibiting HDL catabolism
      and decreases hepatic production of atherogenic very-low- and low-density
      lipoproteins by inhibiting the key enzyme for triglyceride synthesis
      (diacylglycerol acyltransferase). Statins, fibrates, bile acid sequestrants and
      ezetimibe have mechanisms that are different. Combination therapy using statins
      and niacin not only safely corrects dyslipidemia, but also yields ASCVD risk
      reduction significantly in excess of the 30% seen with monotherapy. Newer drugs
      with different mechanisms of action or combinations of new formulations have
      recently become available. Drug discovery research is likely to yield additional
      agents. Clinical trials focused on combination therapies to reduce ASCVD risk
      well beyond 30% need to be conducted to establish the rationale for further
      reducing the incidence of the primary cause of death today.

PMID- 15030304
TI  - Hyperlipidemia in children with HIV infection: an emerging problem.
AB  - The introduction of highly active antiretroviral therapy (HAART) for the
      treatment of HIV infection has transformed HIV/AIDS into a chronic illness and
      the focus of clinical management has shifted from opportunistic infections to
      long-term management and toxicities of therapy. Pediatric patients with HIV
      infection perhaps pose the greatest challenge in this arena as they potentially
      face many decades of living with HIV/AIDS and its therapies. Although there are
      numerous emerging medical complications associated with chronic HIV infection and
      HAART, hyperlipidemia is increasingly recognized among HIV-infected children and
      adults and will be the focus of this review. The nature and prevalence of lipid
      abnormalities in children with HIV infection is discussed, as well as possible
      etiologies for these abnormalities and the future management of this growing
      challenge for children living with HIV disease.

PMID- 15030305
TI  - Features and functions of gamma delta T lymphocytes: focus on chemokines and
      their receptors.
AB  - gamma delta T cells are a distinct subgroup of T lymphocytes that are enriched at
      certain anatomical localizations, such as the small intestinal epithelia and
      other epithelia. gamma delta T cells recognize microbial antigens, such as heat
      shock proteins (in mice) or phosphorylated bacterial metabolites (in humans), and
      control the integrity of epithelia. At the effector cell level, they share with
      the conventional alpha beta T lymphocytes potent cytotoxic activity and the
      capacity to produce a variety of cytokines, including specific cytokines such as
      keratinocyte growth factor. Here we summarize the current knowledge on the role
      of chemokines and their receptors in the migration and function of gamma delta T
      cells. As an example, the migration of gamma delta T cells to the small intestine
      is guided by the chemokine receptor CCR9 and the local expression of the
      corresponding ligand CCL25 (also termed thymus-expressed chemokine, TECK).
      Chemokine receptor expression also correlates with the functional program of T
      cells. In this respect, the strong expression of the MIP-1 alpha/MIP-1
      beta/RANTES (CCL3/CCL4/CCL5)-receptor CCR5 correlates with a T-helper 1 phenotype
      of human V gamma 9V delta 2-expressing gamma delta T cells. The regulation of
      chemokine receptors, together with the pattern of local chemokine production,
      plays an important role in the localization of gamma delta T cells under
      physiological and pathophysiological conditions, such as infection, inflammation,
      and tumor defense.

PMID- 15030306
TI  - Shigellosis: innate mechanisms of inflammatory destruction of the intestinal
      epithelium, adaptive immune response, and vaccine development.
AB  - Acute infectious colitis remains a major pediatric issue of worldwide impact
      because it still represents a significant public health burden among the larger
      group of diarrheal diseases with the highest mortality rate. It is also a
      relevant model of inflammatory bowel diseases (IBD), such as Crohn's disease and
      ulcerative colitis. Among cases of acute colitis of infectious origin,
      shigellosis is certainly the one that has benefited the most from a significant
      research effort. Shigella, the causative agent, is a Gram-negative bacterium that
      has the capacity to invade, disrupt, and cause inflammatory destruction of the
      intestinal epithelial barrier. The molecular and cellular bases of this invasive
      phenotype essentially encompass crossing of the epithelial lining, apoptotic
      killing of macrophages, entry into epithelial cells, and escape into the
      cytoplasm, followed by cell-to-cell spread. Intracellular colonization is likely
      to protect the micro-organisms from killing by humoral and cellular effectors of
      the innate immune response. Concurrently, the capacity of Shigella to reprogram
      invaded epithelial cells to produce proinflammatory mediators plays a major role
      in the strong inflammatory profile of the disease. This profile is likely to
      impact on the nature and quality of the adaptive response, which is dominated by
      humoral protection at the mucosal level.

PMID- 15030307
TI  - Major histocompatibility lineages and immune gene function in teleost fishes: the
      road not taken.
AB  - It has become increasingly clear over the course of the past decade that the
      immune system genes of teleosts and tetrapods are plainly derived from common
      ancestral genes. The last 5 years, however, have also made it abundantly clear
      that in the teleost genome some of these genes are organized in a manner very
      different from that seen in mammals. These differences are probably the result of
      differences in life history traits, such as fecundancy, within each group of
      species when faced with an evolutionary fork in the road shortly after their
      divergence from each other. One group, the tetrapods, including mammals, chose a
      highly organized linked major histocompatibility complex, while in teleosts the
      major histocompatibility genes remained unlinked. In this review we will discuss
      the structural and functional implications of this different organization,
      particularly for major histocompatibility genes, but drawing on the current
      knowledge of some other genes for further support for the hypothesis that each
      group took a different road, one more traveled and one less taken.

PMID- 15030308
TI  - Compartmentalization gamma/delta T cells and their putative role in mucosal
      immunity.
AB  - gamma/delta T cells are an enigmatic group of cells and their functions still
      remain unknown. The epithelial-associated gamma/delta T cells, which are abundant
      at mucosal surfaces, are ideally situated to contribute to the initial stages of
      the immune response. Recent evidence suggests that they recognize stress-induced
      self-antigens which would enable a homogeneous population of gamma/delta T cells
      to monitor multiple insults to the epithelium. This could explain the observed
      oligoclonality and homogeneous distribution of cells carrying identical TCR
      within mucosal surfaces. However, the analysis of the TCR delta repertoire from
      different mucosal surfaces indicated that gamma/delta T cells are highly
      compartmentalized. Thus, gamma/delta T cells are not one homogeneous group of
      cells which recognize the same (stress-induced) self-antigens, but consist of
      different subsets that are likely to have distinct functions. It is possible that
      gamma/delta T cells interact with antigens that are specific for that organ or
      recognize foreign antigens which are limited to that site. In addition it was
      shown that gamma/delta T cells can have opposite functions and be proinflammatory
      or promote epithelial healing. This review focuses on the distribution and
      repertoire of mucosal gamma/delta T cells and discusses what is currently known
      about the functions of these cells. Furthermore, their potential role in
      inflammatory bowel disease is examined.

PMID- 15030310
TI  - A cell death pathway induced by antibody-mediated cross-linking of CD45 on
      lymphocytes.
AB  - The protein tyrosine phosphatase CD45 is a highly expressed glycoprotein present
      on all nucleated cells of hematopoietic origin. To date, all the functions
      attributed to CD45 are inherently coupled to its phosphatase activity. For
      instance, the regulation of lymphocyte antigen receptor signaling is mediated
      through the dephosphorylation, and hence activation, of Src-family kinases by
      CD45. Moreover, signaling via cytokine receptors is negatively modulated by CD45
      by dephosphorylation of Janus kinase family members. Recently, another function
      for CD45, unrelated to regulation of surface receptor signaling, has been
      unraveled. Specific engagement of CD45 by monoclonal antibodies at the surface of
      lymphocytes induced their death, through an alternative caspase-independent
      pathway. In striking contrast to all other previously reported functions for
      CD45, its phosphatase activity is completely dispensable for the induction of
      cell death. This article reviews the current knowledge on the death pathway
      triggered by CD45 ligation on lymphocytes. In an attempt to better elucidate the
      mechanism of cell death induction through CD45, we also provide original data
      regarding the susceptibility of various subsets of immature and mature T and B
      cells to death induced by CD45 engagement. The physiological significance and
      therapeutic potential of CD45-induced death are also discussed.

PMID- 15030309
TI  - CD1d-mediated antigen presentation to natural killer T (NKT) cells.
AB  - CD1d molecules are lipid antigen-presenting molecules. They are involved in
      presenting these antigens to a unique subpopulation of T cells called natural
      killer T (NKT) cells, which have the capacity to produce both T helper (Th) 1 and
      Th2 cytokines. Thus, it is possible that the antigens presented by CD1d and/or
      the level at which they are presented could have profound effects on the
      immunoregulation of autoimmune and infectious diseases, as well as cancer.
      Because of the ability of CD1d-binding ligands to modulate NKT cell responses,
      targeting CD1d-mediated antigen presentation as a novel approach for new
      therapies in these and other diseases holds great promise.

PMID- 15030311
TI  - Sympathetic overactivity in ischaemic heart disease.
AB  - The efficacy of pharmacological beta-blockade in decreasing cardiac death in
      patients after myocardial infarction suggests the existence of sympathetic
      overactivity and indicates the importance of assessing its magnitude. The paper
      by Graham and co-workers in this issue of Clinical Science has attempted to
      address this issue by measuring muscle sympathetic nerve activity (MSNA) in
      various groups of patients and control subjects. It was found that, after
      myocardial infarction, there was sympathetic overactivity, which was more marked
      and more long-lasting than after unstable angina, whereas, in the presence of
      simple coronary artery disease, sympathetic activity did not differ from that in
      control subjects. Clear signs of sympathetic overactivity lasting for months
      after an acute myocardial infarction have already been reported using quite
      different methodology, i.e. spectral analysis of heart period and systolic
      arterial pressure variability. The soundest hypothesis to explain such a
      sympathetic overactivity appears to be based on the well-demonstrated finding
      that the ischaemic heart is a powerful site of origin of both excitatory and/or
      inhibitory reflexes, which may be of paramount clinical importance.

PMID- 15030312
TI  - Mechanical stimuli regulate rapamycin-sensitive signalling by a phosphoinositide
      3-kinase-, protein kinase B- and growth factor-independent mechanism.
AB  - In response to growth factors, mTOR (mammalian target of rapamycin) has been
      identified as a central component of the signalling pathways that control the
      translational machinery and cell growth. Signalling through mTOR has also been
      shown to be necessary for the mechanical load-induced growth of cardiac and
      skeletal muscles. Although the mechanisms involved for mechanically induced
      activation of mTOR are not known, it has been suggested that activation of PI3K
      (phosphoinositide 3-kinase) and protein kinase B (Akt), via the release of
      locally acting growth factors, underlies this process. In the present study, we
      show that mechanically stimulating (passive stretch) the skeletal muscle ex vivo
      results in the activation of mTOR-dependent signalling events. The activation of
      mTOR-dependent signalling events was necessary for an increase in translational
      efficiency, demonstrating the physiological significance of this pathway. Using
      pharmacological inhibitors, we show that activation of mTOR-dependent signalling
      occurs through a PI3K-independent pathway. Consistent with these results,
      mechanically induced signalling through mTOR was not disrupted in muscles from
      Akt1-/- mice. In addition, ex vivo co-incubation experiments, along with in vitro
      conditioned-media experiments, demonstrate that a mechanically induced release of
      locally acting autocrine/paracrine growth factors was not sufficient for the
      activation of the mTOR pathway. Taken together, our results demonstrate that
      mechanical stimuli can activate the mTOR pathway independent of PI3K/Akt1 and
      locally acting growth factors. Thus mechanical stimuli and growth factors provide
      distinct inputs through which mTOR co-ordinates an increase in the translational
      efficiency.

PMID- 15030313
TI  - Actin depolymerization-induced tyrosine phosphorylation of cortactin: the role of
      Fer kinase.
AB  - The F-actin-binding protein cortactin is an important regulator of cytoskeletal
      dynamics, and a prominent target of various tyrosine kinases. Tyrosine
      phosphorylation of cortactin has been suggested to reduce its F-actin cross
      linking capability. In the present study, we investigated whether a reciprocal
      relationship exists, i.e. whether the polymerization state of actin impacts on
      the cortactin tyrosine phosphorylation. Actin depolymerization by LB (latrunculin
      B) induced robust phosphorylation of C-terminal tyrosine residues of cortactin.
      In contrast, F-actin stabilization by jasplakinolide, which redistributed
      cortactin to F-actin-containing patches, prevented cortactin phosphorylation
      triggered by hypertonic stress or LB. Using cell lines deficient in candidate
      tyrosine kinases, we found that the F-actin depolymerization-induced cortactin
      phosphorylation was mediated by the Fyn/Fer kinase pathway, independent of Src
      and c-Abl. LB caused modest Fer activation and strongly facilitated the
      association between Fer and cortactin. Interestingly, the F-actin-binding region
      within the cortactin N-terminus was essential for the efficient phosphorylation
      of C-terminal tyrosine residues. Investigating the structural requirements for
      the Fer-cortactin association, we found that (i) phosphorylation-incompetent
      cortactin still bound to Fer; (ii) the isolated N-terminus associated with Fer;
      and (iii) the C-terminus alone was insufficient for binding. Thus the cortactin N
      terminus participates in the Fer-cortactin interaction, which cannot be fully due
      to the binding of the Fer Src homology 2 domain to C-terminal tyrosine residues
      of cortactin. Taken together, F-actin stabilization prevents cortactin tyrosine
      phosphorylation, whereas depolymerization promotes it. Depolymerization-induced
      phosphorylation is mediated by Fer, and requires the actin-binding domain of
      cortactin. These results define a novel F-actin-dependent pathway that may serve
      as a feedback mechanism during cytoskeleton remodelling.

PMID- 15030314
TI  - Regulation of desmocollin gene expression in the epidermis: CCAAT/enhancer
      binding proteins modulate early and late events in keratinocyte differentiation.
AB  - Desmocollins (Dscs) are desmosomal cadherins that exhibit differentiation
      specific patterns of expression in the epidermis. Dsc3 expression is strongest in
      basal cell layers, whereas Dsc1 is largely confined to upper, terminally
      differentiating strata. To understand better the processes by which Dsc
      expression is regulated in the epidermis, we have isolated Dsc3 and Dsc1 5'
      flanking DNAs and analysed their activity in primary keratinocytes. In the
      present study, we found that transcription factors of the CCAAT/enhancer-binding
      protein family play a role in the regulation of expression of both Dscs and, in
      so doing, implicate this class of transcription factors in both early and late
      events in keratinocyte differentiation. We show that Dscs are differentially
      regulated by C/EBP (CCAAT/enhancer-binding protein) family members, with Dsc3
      expression being activated by C/EBPbeta but not C/EBPalpha, and the reverse being
      the case for Dsc1. Expression of both Dscs is activated by another family member,
      C/EBPdelta. These results show for the first time how desmosomal cadherin gene
      expression is regulated and provide a mechanism for the control of other
      differentiation-specific genes in the epidermis.

PMID- 15030315
TI  - The sulphur oxygenase reductase from Acidianus ambivalens is a multimeric protein
      containing a low-potential mononuclear non-haem iron centre.
AB  - The SOR (sulphur oxygenase reductase) is the initial enzyme in the sulphur
      oxidation pathway of Acidianus ambivalens. Expression of the sor gene in
      Escherichia coli resulted in active, soluble SOR and in inclusion bodies from
      which active SOR could be refolded as long as ferric ions were present in the
      refolding solution. Wild-type, recombinant and refolded SOR possessed
      indistinguishable properties. Conformational stability studies showed that the
      apparent unfolding free energy in water is approx. 5 kcal x mol(-1) (1 kcal=4.184
      kJ), at pH 7. The analysis of the quaternary structures showed a ball-shaped
      assembly with a central hollow core probably consisting of 24 subunits in a 432
      symmetry. The subunits form homodimers as the building blocks of the holoenzyme.
      Iron was found in the wild-type enzyme at a stoichiometry of one iron
      atom/subunit. EPR spectroscopy of the colourless SOR resulted in a single
      isotropic signal at g=4.3, characteristic of high-spin ferric iron. The signal
      disappeared upon reduction with dithionite or incubation with sulphur at elevated
      temperature. Thus both EPR and chemical analysis indicate the presence of a
      mononuclear iron centre, which has a reduction potential of -268 mV at pH 6.5.
      Protein database inspection identified four SOR protein homologues, but no other
      significant similarities. The spectroscopic data and the sequence comparison led
      to the proposal that the Acidianus ambivalens SOR typifies a new type of non-haem
      iron enzyme containing a mononuclear iron centre co-ordinated by carboxylate
      and/or histidine ligands.

PMID- 15030316
TI  - Mammalian Hsp22 is a heat-inducible small heat-shock protein with chaperone-like
      activity.
AB  - A newly identified 22 kDa protein that interacts with Hsp27 (heat-shock protein
      27) was shown to possess the characteristic alpha-crystallin domain, hence named
      Hsp22, and categorized as a member of the sHsp (small Hsp) family. Independent
      studies from different laboratories reported the protein with different names
      such as Hsp22, H11 kinase, E2IG1 and HspB8. We have identified, on the basis of
      the nucleotide sequence analysis, putative heat-shock factor 1 binding sites
      upstream of the Hsp22 translation start site. We demonstrate that indeed Hsp22 is
      heat-inducible. We show, in vitro, chaperone-like activity of Hsp22 in preventing
      dithiothreitol-induced aggregation of insulin and thermal aggregation of citrate
      synthase. We have cloned rat Hsp22, overexpressed and purified the protein to
      homogeneity and studied its structural and functional aspects. We find that Hsp22
      fragments on storage. MS analysis of fragments suggests that the fragmentation
      might be due to the presence of labile peptide bonds. We have established
      conditions to improve its stability. Far-UV CD indicates a randomly coiled
      structure for Hsp22. Quaternary structure analyses by glycerol density-gradient
      centrifugation and gel filtration chromatography show that Hsp22 exists as a
      monomer in vitro, unlike other members of the sHsp family. Hsp22 exhibits
      significantly exposed hydrophobic surfaces as reported by bis-8
      anilinonaphthalene-l-sulphonic acid fluorescence. We find that the chaperone-like
      activity is temperature dependent. Thus Hsp22 appears to be a true member of the
      sHsp family, which exists as a monomer in vitro and exhibits chaperone-like
      activity.

PMID- 15030317
TI  - p120 Ras GTPase-activating protein associates with fibroblast growth factor
      receptors in Drosophila.
AB  - Btl (breathless) and Htl (heartless), the two FGFRs (fibroblast growth factor
      receptors) in Drosophila melanogaster, control cell migration and differentiation
      in the developing embryo. These receptors signal through the conserved
      Ras/mitogen-activated protein kinase pathway, but how they regulate Ras activity
      is not known. The present study shows that there is a direct interaction between
      p120 RasGAP (Ras GTPase-activating protein), a negative regulator of Ras, and
      activated FGFRs in Drosophila. The interaction is dependent on the SH2 (Src
      homology 2) domains of RasGAP, which have been shown to interact with a
      phosphotyrosine residue within the consensus sequence (phospho)YXXPXD. A
      potential binding site that matches this consensus is found in both Btl and Htl,
      located between the transmembrane and kinase domains of each receptor. A peptide
      corresponding to this region was capable of binding RasGAP only when the tyrosine
      residue was phosphorylated. This tyrosine residue appears to be conserved in
      human FGFR-1 and mediates the association with the adapter protein CrkII, but no
      association between dCrk (Drosophila homologue of CrkII) and the activated FGFRs
      was detected. RasGAP was a substrate of the activated FGFR kinase domain, and
      mutation of the tyrosine residue within the potential binding site on the
      receptor prevented tyrosine phosphorylation of RasGAP. RasGAP attenuated FGFR
      signalling in vivo and this ability was dependent on both its SH2 domains and its
      GAP activity. On the basis of these results, we propose that RasGAP is directly
      recruited into activated FGFRs in Drosophila and plays a role in regulating the
      strength of signalling through Ras and the mitogen-activated protein kinase
      pathway.

PMID- 15030320
TI  - Effect of oxidative stress on the production of recombinant human interferon
      gamma in Escherichia coli.
AB  - To reduce the degradation pathway of rhIFN-gamma (recombinant human interferon
      gamma), the susceptibility against oxidative stress during fermentation in
      Escherichia coli cells and in purification process were investigated.
      Fermentations of recombinant E. coli were performed at 5, 30 and 60% DO
      (dissolved oxygen) concentrations. The expressed rhIFN-gamma is purified in three
      step chromatography processes with 99.9% purity under reducing and non-reducing
      conditions. Recombinant IFN-gamma production, carbonyl and dimeric contents and
      antiviral-specific activity of purified protein were monitored. The increase in
      carbonyl content was taken to be an indicator of protein oxidation. DO
      concentration did not show any noticeable effect on rhIFN-gamma production.
      During fermentation, the carbonyl-group content showed no significant increase at
      5 and 30% DO but a 10-fold increase at 60% DO concentration was observed. The
      antiviral-specific activity of purified rhIFN-gamma was decreased 35 and 69% at
      30 and 60% DO concentrations respectively. After the purification process, under
      non-reducing conditions, the activity of purified protein decreased to 30% of its
      original value. The degree of dimeric forms of protein was found to depend on the
      O2 concentration during fermentation and purification.

PMID- 15030319
TI  - Biosynthesis of UDP-GlcA, a key metabolite for capsular polysaccharide synthesis
      in the pathogenic fungus Cryptococcus neoformans.
AB  - UDP-glucose dehydrogenase catalyses the conversion of UDP-glucose into UDP-GlcA,
      a critical precursor for glycan synthesis across evolution. We have cloned the
      gene encoding this important enzyme from the opportunistic pathogen Cryptococcus
      neoformans. In this fungus, UDP-GlcA is required for the synthesis of capsule
      polysaccharides, which in turn are essential for virulence. The gene was
      expressed in Escherichia coli and the 51.3-kDa recombinant protein from wild-type
      and five mutants was purified for analysis. The cryptococcal enzyme is strongly
      inhibited by UDP-xylose and NADH, has highest activity at pH 7.5 and demonstrates
      Km (app) values of 0.1 and 1.5 mM for NAD+ and UDP-glucose respectively. Its
      activity was significantly decreased by mutations in the putative sites of NAD+
      and UDP-glucose binding. Unlike previously reported eukaryotic UDP-glucose
      dehydrogenases, which are hexamers, the cryptococcal enzyme is a dimer.

PMID- 15030318
TI  - The T-cell protein tyrosine phosphatase is phosphorylated on Ser-304 by cyclin
      dependent protein kinases in mitosis.
AB  - Two alternatively spliced forms of the human protein tyrosine phosphatase TCPTP
      (T-cell protein tyrosine phosphatase) exist: a 48 kDa form that is targeted to
      the endoplasmic reticulum (TC48) and a shorter 45 kDa form that is targeted to
      the nucleus (TC45). In this study we have identified Ser-304 (Phe301-Asp-His
      Ser304-Pro-Asn-Lys307) as a major TCPTP phosphory-lation site and demonstrate
      that TC45, but not TC48, is phosphorylated on this site in vivo. Phosphorylation
      of TC45 on Ser-304 was cell cycle-dependent, and increased as cells progressed
      from G2 into mitosis, but subsided upon mitotic exit. Ser-304 phosphorylation was
      increased when cells were arrested in mitosis by microtubule poisons such as
      nocodazole, but remained unaltered when cells were arrested at the G2/M
      checkpoint by adriamycin. Phosphorylation of Ser-304 did not alter significantly
      the phosphatase activity or the protein stability of TC45, and had no apparent
      effect on TC45 localization. Ser-304 phosphorylation was ablated when cells were
      treated with the CDK (cyclin-dependent protein kinase) inhibitors roscovitine or
      SU9516, but remained unaltered when ERK1/2 activation was inhibited with the MEK
      (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase)
      inhibitor PD98059. In addition, recombinant CDKs, but not the Polo-like kinase
      Plk1, phosphorylated Ser-304 in vitro. Our studies identify Ser-304 as a major
      phosphorylation site in human TCPTP, and the TC45 variant as a novel mitotic CDK
      substrate.

PMID- 15030321
TI  - Extracellular matrix metabolites as potential biomarkers of disease activity in
      wound fluid: lessons learned from other inflammatory diseases?
AB  - The new era of pharmacogenetics has identified a potential for individuals to
      receive customized treatments for a variety of disease states. For such
      individualized treatments to fulfil their potential, it will be essential for
      clinicians to be able to monitor disease activity, ideally in a rapid,
      noninvasive fashion. The accessibility of the skin offers much potential to
      develop noninvasive tests of metabolic and disease activity for clinical use.
      Impaired human wound healing in the skin is a chronic inflammatory disorder in
      which the development of such tests has considerable potential, aiding clinical
      decision making and monitoring responses to treatment. This review article
      discusses how studies in other human diseases have highlighted potential
      biochemical markers (biomarkers) of disease activity in secreted biofluids, as
      aids to determining disease and metabolic activity within tissues. Using, as
      examples, lessons learned in the study of disease activity and prognosis of other
      chronic inflammatory conditions, such as osteoarthritis and periodontal disease,
      this review highlights the potential of dermal extracellular matrix (ECM)
      components (collagens, proteoglycans, hyaluronan and glycoproteins) for such
      uses. The limitations of currently utilized techniques and the concept that
      analysis of ECM components in wound fluid may represent useful biomarkers of
      disease activity are also discussed.

PMID- 15030322
TI  - Terbinafine in the treatment of onychomycosis: a review of its efficacy in high
      risk populations and in patients with nondermatophyte infections.
AB  - BACKGROUND: The prevalence of onychomycosis is higher in certain high-risk
      populations, such as the immunocompromised, diabetics and human immunodeficiency
      virus (HIV)-positive patients. These patients can also develop onychomycosis due
      to nondermatophyte fungi. Although the efficacy of terbinafine is well
      demonstrated in the treatment of conventional dermatophyte nail infection, there
      are few data on the efficacy of terbinafine in high-risk patient groups or in
      nondermatophyte fungi, which can be difficult to treat. OBJECTIVES: To review
      previously published data regarding the safety and efficacy of terbinafine in
      special patient populations, such as those with diabetes mellitus or HIV
      infection, those receiving immunosuppressive therapy, and patients with
      onychomycosis due to nondermatophyte fungi. METHODS: A Medline literature search
      up to October 2002 was performed in order to identify relevant studies. Pertinent
      abstracts presented at international meetings were also included. Cure rates (per
      protocol and intention-to-treat) were extracted or calculated. All available
      safety data were also collated. RESULTS: Terbinafine was highly effective and
      well tolerated in patients with diabetes mellitus. Mycological cure rates of 62
      78% were achieved in three studies, which is comparable with the efficacy in
      nondiabetic populations. Mycological cure rates of 64-91% were achieved in
      subsets of diabetic patients with Candida-positive nail cultures. The efficacy of
      terbinafine in patients receiving immunosuppressive therapy was also similar to
      that reported in immunocompetent patients. Levels of ciclosporin in the blood
      clearly decreased, with little clinical consequence; however, consideration
      should be given to the monitoring of ciclosporin levels in patients concomitantly
      receiving immunosuppressive therapy and terbinafine. Two small studies reported
      that terbinafine was also effective in treating onychomycosis in HIV-positive
      patients. Terbinafine was also effective and well tolerated in the treatment of
      nondermatophyte onychomycosis. CONCLUSIONS: This review suggests that terbinafine
      is a safe and effective treatment for onychomycosis in high-risk populations.
      However, the majority of these studies only included small numbers of patients
      and larger clinical trials are needed, especially in patients with HIV infection.

PMID- 15030323
TI  - Proinflammatory cytokine production by human keratinocytes stimulated with
      Propionibacterium acnes and P. acnes GroEL.
AB  - BACKGROUND: Keratinocytes form the first line of defence in the skin and alert
      the host to danger by the production of a number of cytokines and chemokines.
      However, the interaction of commensal microorganisms with keratinocytes has not
      been well studied. OBJECTIVES: To investigate the effect of viable and nonviable
      cells of Propionibacterium acnes in both exponential and stationary growth
      phases, and of P. acnes GroEL on cytokine production by human primary
      keratinocytes. METHODS: Actively proliferating or contact-inhibited keratinocytes
      were cocultured with viable or formaldehyde-killed P. acnes cells in either the
      exponential or stationary phase of growth. Culture supernatants were assayed by
      enzyme-linked immunosorbent assay for the cytokines interleukin (IL)-1alpha,
      tumour necrosis factor (TNF)-alpha and granulocyte/macrophage colony-stimulating
      factor (GM-CSF). Keratinocytes were also stimulated with different concentrations
      of P. acnes GroEL and supernatants assayed for cytokines. RESULTS: Viable P.
      acnes in the stationary phase of growth stimulated keratinocyte monolayers to
      produce significantly higher amounts of IL-1alpha, TNF-alpha and GM-CSF than
      unstimulated keratinocytes. Viable exponential-phase bacteria stimulated
      production of significantly higher amounts of TNF-alpha and GM-CSF but these
      levels were significantly lower than those for stimulation with stationary-phase
      bacteria. Nonviable P. acnes from either growth phase was not able to stimulate
      cytokine production. P. acnes GroEL at concentrations in the range 0.05-1.0 micro
      g mL(-1) was able to induce increased production of cytokines by keratinocytes in
      a dose-dependent manner. This was analogous to stimulation with Escherichia coli
      GroEL. CONCLUSIONS: Stimulation of cytokine production by P. acnes and P. acnes
      GroEL may be important in the pathogenesis of inflammatory acne vulgaris and may
      have wider implications for the immunomodulation of the human immune system by
      commensal skin microorganisms.

PMID- 15030324
TI  - Gap junction development in the human fetal hair follicle and bulge region.
AB  - BACKGROUND: Gap junctions, composed of connexin (Cx) subunits, are channels that
      allow intercellular communication between adjacent cells and are thought to play
      a key role in the regulation of cell proliferation and differentiation. The Cx
      expression pattern and formation of gap junctions in human fetal hair follicles
      has yet to be clarified, including the prominent follicular bulge region that is
      believed to be a site rich in stem cells. OBJECTIVES: To study the expression of
      two major Cxs, Cx26 and Cx43, in developing hair follicles in skin samples from a
      series of human fetuses of estimated gestational age (EGA) 88-163 days, and to
      determine quantitatively the presence of gap junctions. METHODS: We used
      immunofluorescence labelling to investigate the sequential expression pattern of
      Cx26 and Cx43 in developing human hair follicles. Gap junction formation was
      observed by electron microscopy and the numbers of gap junctions were analysed
      quantitatively. Results Both Cx26 and Cx43 expression were observed at 88 days'
      EGA in the inner part of the hair peg. At 135 days' EGA, Cx26 was expressed in
      the outer root sheath (ORS) and the inner root sheath (IRS), while Cx43 was
      expressed chiefly in the IRS, hair matrix and sebaceous glands. At 163 days' EGA,
      Cx26 expression was most intense in the outermost layer of the ORS, in contrast
      to Cx43 expression which was in the inner part of the ORS. In the bulge region,
      only Cx43 was expressed in a subset of cells in the bulge. Ultrastructurally, gap
      junctions were observed at 102 days' EGA in the hair peg, and the number of gap
      junctions increased as the hair follicle matured. Gap junctions were also
      observed between the bulge cells in considerable numbers. CONCLUSIONS: The
      changing expression patterns of Cx26 and Cx43 and the increasing gap junction
      numbers suggest a close association of Cx expression and gap junction formation
      with hair follicle morphogenesis. In addition, the present ultrastructural
      observations demonstrate that considerable numbers of the bulge cells, a putative
      site rich in hair follicle stem cells, form gap junctions during human hair
      follicle development.

PMID- 15030325
TI  - Human hair greying is linked to a specific depletion of hair follicle melanocytes
      affecting both the bulb and the outer root sheath.
AB  - BACKGROUND: Although hair greying is a very common phenomenon characterized by
      loss of pigment in the hair shaft, the events that cause and control natural hair
      whitening with age in humans are still unclear. OBJECTIVES: To decipher the
      origin of natural hair whitening. METHODS: Human hair melanocytes were
      immunohistochemically characterized at different stages of whitening. RESULTS:
      Loss of hair shaft melanin was found to be associated with a decrease in both
      bulb melanin content and bulb melanocyte population. Although few melanocytes
      were present in the bulbs of grey hair, they still expressed tyrosinase and
      tyrosinase-related protein-1, synthesized and transferred melanins to cortical
      keratinocytes as seen by the presence of melanin granules. In white hair bulbs,
      no melanocytes could be detected either with pMel-17 or vimentin labelling.
      Pigmented hair follicles are known to contain inactive melanocytes in the outer
      root sheath (ORS), and grey and white hairs were also found to contain some of
      these quiescent melanocytes. However, their population was decreased compared
      with pigmented hair follicles, ranging from small to nil. This depletion of
      melanocytes in the different areas of white hairs was detected throughout the
      hair cycle, namely at telogen and early anagen stages. In contrast, the
      infundibulum and sebaceous gland of both pigmented and white hairs showed a
      similar distribution of melanocytes. Furthermore, other distinct cell populations
      located in the ORS, namely putative stem cells, Merkel cells and Langerhans cells
      were equivalently identified in pigmented and white hairs. CONCLUSIONS: Thus,
      hair greying appears to be a consequence of an overall and specific depletion of
      bulb and ORS melanocytes of human hair.

PMID- 15030326
TI  - Human adipose tissue-derived cells delay re-epithelialization in comparison with
      skin fibroblasts in organotypic skin culture.
AB  - BACKGROUND: Wound healing of deep and extensive burns can induce hypertrophic
      scar formation. During the early steps of wound healing fibroblasts migrate into
      the wounded area. Fibroblastic cells present in tissues other than dermis may
      also migrate into the wounded area and participate in the wound healing process.
      OBJECTIVES: To examine the influence of human fibroblastic cells derived from
      subcutaneous fat or dermis on epidermal morphogenesis in vitro. METHODS: We
      prepared human skin equivalents (HSEs) made of a collagen type I matrix populated
      either with dermal fibroblasts or adipose tissue-derived cells (ADCs), on top of
      which keratinocytes were seeded and subsequently grown at the air-liquid
      interface. RESULTS: A fully differentiated epidermis was formed on matrices
      populated with ADCs. However, the HSE formed differed in a number of features
      from HSE generated with dermal fibroblasts. The major differences included:
      marked contraction of the dermal matrix, low lateral migration of keratinocytes,
      high keratin 17 expression indicating increased keratinocyte activation, delayed
      deposition of collagen IV at the epidermal/matrix junction, accumulation of alpha
      smooth muscle actin-positive cells only underneath the epidermal compartment and
      positioning of these cells in a direction parallel to the epidermal compartment.
      The latter two phenomena have also been found in scar tissue. CONCLUSIONS: The
      possibility of generating HSEs with different cell types represents an attractive
      approach for in vitro studies focusing on the mechanism of wound healing.

PMID- 15030327
TI  - Assessment of the biological performance of the needle-free injector INJEX using
      the isolated porcine forelimb.
AB  - BACKGROUND: The development and utilization of novel needle-free injection
      devices in order to minimize needle stick injuries make increasing demands for
      suitable assay systems, which reflect the physiological situation in humans as
      close as possible. OBJECTIVES: It was therefore the goal of the present study to
      test the biological performance of a needle-free injector (INJEX) by the use of
      porcine skin as a model with a high predictive value for the feasibility in
      humans because of its close similarity to human skin. METHODS: In order to use
      porcine skin in the context of the underlying tissues, the isolated porcine
      forelimb was chosen as an assay model for use with the INJEX injector. Ink or the
      fluorescent dye fluorescein-isothiocyanate was injected and the penetration depth
      was determined metrically and dye distribution histologically. To assess the
      resorption of heparin, needle injection was compared with needle-free injection
      in a perfused limb model. RESULTS: Increasing amounts of ink increasingly
      penetrated into subcutaneous tissue layers in a cone-shaped manner mainly
      following lead structures. Penetration was hampered by skin thickness and by the
      deep muscle fascia, which served as a penetration barrier. Resorption of heparin
      was similar irrespective of injection by the use of a needle or the INJEX device.
      CONCLUSIONS: The isolated porcine forelimb serves as a versatile tool for the
      assessment of the biological performance of needle-free injection devices such as
      INJEX. Further studies are necessary to correlate the model for drug delivery in
      humans.

PMID- 15030329
TI  - Aberrant serum hyaluronan and hyaluronidase levels in scleroderma.
AB  - BACKGROUND: Scleroderma, or systemic sclerosis, is characterized by aberrations
      of extracellular matrix deposition. These changes parallel early stages of wound
      healing when increased deposition of hyaluronan (HA) and collagen occur. Both
      processes result ultimately in the formation of fibrotic scar tissue. Activities
      of HA synthase and hyaluronidase, the enzymes that synthesize and degrade HA, are
      critical in HA turnover. Both become elevated whenever increased matrix
      deposition occurs. HA deposition occurs early in wound healing, and increases are
      documented in the circulation of scleroderma patients. We postulated that
      elevated HA and hyaluronidase may both be indicators of early-stage disease in
      scleroderma, in parallel with early changes observed in wound healing. In an
      attempt to reduce HA accumulation and the associated fibrosis in scleroderma
      tissues, topical and intravenous hyaluronidase administrations have been used in
      the past as treatment modalities, with occasional success. This also suggested
      that hyaluronidase enzyme activity is involved in the disease process. It is now
      recognized that the hyaluronidases constitute an enzyme family. The somatic
      hyaluronidase Hyal-1 is the only activity present in human serum. OBJECTIVES: To
      determine levels of HA and Hyal-1 in the sera of scleroderma patients at various
      stages of their disease. METHODS: Levels of HA and Hyal-1 activity were
      determined in 25 scleroderma patients. Subjects were separated into two groups,
      those in the early stage with duration of disease of 2 years or less, and late
      stage patients with disease duration of more than 2 years. RESULTS: In early
      stage scleroderma, levels of HA were elevated significantly, as predicted, in
      comparison with late-stage patients and controls. Late-stage levels of HA were
      comparable with those found in control sera. By contrast, levels of Hyal-1
      activity were normal in early-stage patients, similar to those in controls, but
      were decreased in late-stage patients, falling even below those of controls.
      CONCLUSIONS: We have confirmed that circulating levels of HA are elevated in
      scleroderma, but show for the first time that such elevations occur predominantly
      in early-stage disease. Patients with late-stage disease have decreased serum
      Hyal-1 activity, perhaps reflecting decreased levels of HA turnover. This study
      also represents the first time that hyaluronidase activity levels have been
      determined in scleroderma patients.

PMID- 15030328
TI  - Expression and function of peroxisome proliferator-activated receptors in human
      melanocytes.
AB  - BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) belong to the
      superfamily of nuclear receptors that heterodimerize with the retinoic X
      receptor. Agonists of PPAR have been known to play an important role in cellular
      responses including proliferation and differentiation. The expression and
      function of PPARs have not been investigated in human melanocytes, although they
      have been widely demonstrated in keratinocytes of the skin. OBJECTIVES: To
      investigate the expression of PPARs in human melanocytes and the effects of PPAR
      activators on melanocyte growth and melanogenesis. METHODS: We used
      immunocytochemistry and Western blot analysis to determine whether PPARs are
      expressed in melanocytes. To investigate further expression of PPAR subtypes,
      reverse transcriptase-polymerase chain reaction analysis was performed using PPAR
      subtype-specific oligonucleotides. The cell proliferation was measured using the
      Coulter counter. The effects on pigmentation were investigated with measurement
      of melanin contents, tyrosinase activity and its expression. RESULTS: The mRNA of
      all three PPAR subtypes, PPAR-alpha, PPAR-beta/delta and PPAR-gamma, were
      expressed in melanocytes. Activators for PPAR-alpha (WY-14643) and PPAR-gamma
      (ciglitazone) inhibited proliferation of melanocytes in a dose-dependent manner,
      whereas bezafibrate, a preferential activator for PPAR-beta/delta, had no effect.
      This growth inhibition was accompanied by the morphological change of the
      melanocytes to an activated form with an increased number of dendrites and
      enlarged cell area compared with the control. The WY-14643 and ciglitazone also
      appeared to stimulate the melanin synthesis of melanocytes. This increase in
      pigmentation was due to stimulation of the tyrosinase activity without an
      increase in the expression of tyrosinase. CONCLUSIONS: PPARs are expressed in
      human melanocytes and PPAR-alpha and PPAR-gamma activators inhibit melanocyte
      growth and stimulate melanogenesis.

PMID- 15030330
TI  - Additional reverse transcription-polymerase chain reaction of peripheral slices
      is not superior to analysis of the central slice in sentinel lymph nodes from
      melanoma patients.
AB  - BACKGROUND: The status of the sentinel lymph node (SLN) is an important
      prognostic factor in patients with cutaneous melanoma. Reverse transcription
      polymerase chain reaction (RT-PCR) has been used as a sensitive means of
      detecting tumour cells in SLNs. OBJECTIVES: To determine whether RT-PCR analysis
      of the SLN using both the central and the peripheral slices is more sensitive
      than molecular analysis of the central slice only. METHODS: Eighty-three SLNs
      from 59 patients with primary cutaneous melanoma were identified by SLN mapping.
      All SLNs were bisected along their longitudinal axis to produce two equal halves.
      One half was used for histology and immunohistochemistry, and the other was
      analysed by RT-PCR for tyrosinase and MelanA. Parallel to the longitudinal axis,
      one central slice (approximately 2 mm in thickness) was cut manually. This
      central slice was used for our standard RT-PCR protocol. In the current study, up
      to eight additional peripheral slices (each approximately 2 mm in thickness) were
      cut parallel to the existing cut surface. These peripheral slices were analysed
      by additional RT-PCR. RESULTS: Standard RT-PCR of the central slice yielded
      positive results in 34 of 59 patients (57%). Additional RT-PCR of peripheral
      slices demonstrated positive findings in six additional patients (10%) who were
      initially negative by standard RT-PCR of the central slice. In detail, seven of
      those 34 patients positive by standard RT-PCR of the central slice had positive
      histological findings. In each of these seven patients, RT-PCR was positive both
      in the central slice as well as in the peripheral slices. The remaining 27
      patients with positive RT-PCR results of the central slice showed negative
      histological findings. Only nine (33%) of these 27 patients had a positive RT-PCR
      also in the peripheral slices. Finally, all 25 patients with negative RT-PCR
      results in the central slice showed negative histological findings. Six of these
      patients (24%) revealed positive RT-PCR results on the analysis of peripheral
      slices. However, three of these patients expressed only MelanA but not
      tyrosinase. Thirty lymph nodes from 24 nonmelanoma patients served as negative
      controls for RT-PCR. In three of these 24 patients (13%) expression of MelanA but
      not tyrosinase was detected by RT-PCR. CONCLUSIONS: Molecular analysis of
      peripheral slices yielded six additional patients (10%) positive by RT-PCR who
      were initially negative by standard RT-PCR of the central slice. However, three
      of these six patients were found to express only MelanA but not tyrosinase. As
      MelanA expression was also found in 13% of control lymph nodes, positive MelanA
      expression alone in SLNs of melanoma patients requires cautious interpretation in
      order to avoid false-positive findings. Thus, additional molecular processing of
      peripheral slices did not significantly increase the number of patients with RT
      PCR-positive SLNs.

PMID- 15030331
TI  - Impaired responses of peripheral blood mononuclear cells to nickel in patients
      with nickel-allergic contact dermatitis and concomitant atopic dermatitis.
AB  - BACKGROUND: Allergic contact dermatitis (ACD) is pathogenetically dependent on
      cell-mediated immune responses mediated by type 1 T lymphocytes. Atopic
      dermatitis (AD), in contrast, occurs as a result of sustained activation of type
      2 subsets of T cells. Although atopic patients may become sensitized to various
      contact allergens, little is known about the influence of atopy on delayed-type
      hypersensitivity. OBJECTIVES: To investigate the in vitro responses of peripheral
      blood mononuclear cells (PBMC) to nickel stimulation in groups of atopic and
      nonatopic patients with patch test-verified nickel ACD. METHODS: Ten nonatopic
      patients with nickel ACD, 10 patients with nickel ACD and concomitant AD, 10
      patients with AD but with no contact allergy, and 10 healthy persons participated
      in the study. PBMC were cultured in the presence or absence of nickel sulphate,
      phytohaemagglutinin (PHA) or tetanus toxoid (TT). [(3)H]thymidine incorporation
      was used to measure the rate of antigen-induced DNA synthesis and enzyme-linked
      immunosorbent assay was used to measure the production of interleukin (IL)-2
      (type 1 cytokine) and IL-5 (type 2 cytokine). RESULTS: Nickel-stimulated PBMC of
      nickel-allergic patients with AD proliferated significantly less and secreted
      significantly lower amounts of IL-2 than cells of nonatopic nickel-allergic
      patients. IL-5 production was also lower in the former group, although the
      difference was nonsignificant. Moreover, neither the nickel-specific DNA
      synthesis nor the cytokine production by PBMC of atopic nickel-allergic patients
      differed significantly from those of healthy control persons and AD patients
      without contact allergy. Proliferative and secretory responses of PBMC to PHA or
      TT stimulation differed nonsignificantly between the groups. Nickel-induced IL-2
      production correlated well with IL-5 production in nickel-allergic patients
      regardless of their atopic status. CONCLUSIONS: Our results indicate that PBMC of
      nickel-allergic patients with concomitant AD are characterized by impaired in
      vitro proliferative and secretory responses to the contact allergen nickel but
      not to the mitogen PHA or the recall antigen TT. The type 2 cytokine IL-5 may
      play a role in the development of ACD.

PMID- 15030332
TI  - Skin reaction and recovery: a repeated sodium lauryl sulphate patch test vs. a 24
      h patch test and tape stripping.
AB  - BACKGROUND: Little is known of the predictive value of methods to test an
      individual's susceptibility to acquiring occupational contact dermatitis.
      Recently, the recovery rate after induced irritation was suggested for this
      purpose. Although it is likely that repeated exposure to sodium lauryl sulphate
      (SLS) is preferable to a single application, there is little evidence to support
      this idea. Similarly, little is known about whether the outcome of a repeated SLS
      test can be predicted by a brief test. OBJECTIVES: We studied the relationship
      between the skin reaction after a repeated SLS test and two brief tests, devoting
      special attention to the recovery rate. METHODS: In 29 healthy volunteers, we
      measured transepidermal water loss (TEWL) and erythema after applying 0.03, 0.1
      and 0.3% SLS for 6 h, 3 days per week, over a course of 3 weeks. The data were
      compared with the effects after applying 0.1, 0.3 and 1.0% SLS for 24 h and with
      10 and 15 repetitions of tape stripping. RESULTS: A poor correlation was found
      between the repeated test and the brief SLS test, or tape stripping, when using
      an increase in TEWL (r = 0.04 and 0.26, respectively) or its recovery rate (r = -
      0.01 and 0.42, respectively). CONCLUSIONS: We presume that in a repeated test of
      sufficient duration, additional mechanisms come into play that are absent in a
      brief test, e.g. an alteration in the thickness of the epidermis, with a
      resulting change in the permeability of SLS. When such an effect differs between
      subjects it could explain the lack of agreement between the acute and the
      repeated tests. At present, a brief irritation test will, in all likelihood, be
      unable to assess an individual's susceptibility to occupational contact
      dermatitis.

PMID- 15030333
TI  - Positive patch tests to Euro coins in nickel-sensitized patients.
AB  - BACKGROUND: Many efforts have been made to prevent nickel allergy, the most
      frequent contact allergy in industrialized countries, by identifying acceptable
      limits of exposure. Even though coins are not covered by the EU Nickel Directive,
      some authors suggest that nickel release from coins during handling may elicit
      contact dermatitis in nickel-allergic people. OBJECTIVES: To evaluate sensitivity
      to nickel released from coins in nickel-allergic patients and to verify whether
      nickel release from the new Euro coins may elicit stronger cutaneous reactivity
      than from old Italian lire coins. METHODS: Twenty-five nickel-allergic patients
      were patch tested with 1- and 2-Euro coins, 1-, 2- and 50-Euro cent coins, and
      100 and 500 Italian lire coins. Ten healthy nonnickel-allergic control
      individuals were also tested. RESULTS: Nineteen patients had positive patch tests
      to 1- and 2-Euro coins. One was also positive to 1- and 2-Euro cent coins, four
      to 50-Euro cent coins, and 13 to the 500-lire coin. None had a positive patch
      test to the 100-lire coin. The number and degree of positive patch tests to coins
      were related to nickel content. CONCLUSIONS: Euro coins may be potentially more
      dangerous than old Italian coins. Coins containing little or no nickel should be
      chosen for coinage to prevent sensitization and to avoid exacerbation of contact
      dermatitis in nickel-allergic patients.

PMID- 15030334
TI  - The lupus band: do the autoantibodies target collagen VII?
AB  - BACKGROUND: Circulating autoantibodies directed against basement membrane zone
      (BMZ) components from patients with bullous pemphigoid and epidermolysis bullosa
      acquisita have been used to identify their target antigen in the skin and to
      confirm pathogenicity. Although the pattern of immunofluorescence in those
      diseases is similar to the lupus band, little is known about the origin and
      pathogenesis of the lupus band. Identifying the binding sites of the lupus band
      could provide a clue to the nature of the autoantigen that stimulates
      autoantibody formation in the skin of patients with systemic lupus erythematosus
      (SLE) and might provide valuable insight into the factors that influence the
      localization and pathogenicity of the lupus band. OBJECTIVES: To investigate the
      relation between the lupus band and the main BMZ components and to identify the
      target epitopes of autoantibodies deposited in the skin of patients with SLE.
      METHODS: Colocalization of the main components of the skin BMZ in nonlesional SLE
      skin with the lupus band was investigated using conventional immunofluorescence
      and confocal laser scanning microscopy. The effect of collagenase and pepsin on
      the expression of the lupus band was correlated with the differential sensitivity
      of these proteases on the collagenous and noncollagenous (NC) domains of collagen
      VII. Reactivity of sera from patients with SLE to a complete recombinant human
      NC1 domain of type VII collagen was then investigated by enzyme-linked
      immunosorbent assay (ELISA). RESULTS: Near complete colocalization of the lupus
      band with collagen VII was found in this study, and chemical degradation of the
      skin attenuated the expression of the lupus band. Collectively, the NC1 domain of
      collagen VII was suggested as the target antigen of the lupus band, but none of
      the sera from patients with SLE reacted with recombinant NC1 domain-coated ELISA
      plates. Alternative explanations for the results of the colocalization of the
      lupus band with collagen VII are discussed. CONCLUSIONS: The lupus band
      colocalized with collagen type VII. The findings of this study ruled out the NC1
      domain of collagen VII as a target antigen for circulating autoantibodies in SLE
      patients with no clinical evidence of blistering. Further studies are required to
      determine if other regions of collagen VII or another BMZ component is the target
      antigen for the immunoglobulins of the lupus band.

PMID- 15030335
TI  - Beta-catenin expression in benign and malignant pilomatrix neoplasms.
AB  - BACKGROUND: Beta-catenin is a 92-kDa protein, initially identified as a
      coprecipitating species with the E-cadherin cell-cell adhesive complex. It plays
      a role in signal transduction in the Wnt signalling pathway and has been
      identified as an oncogene in colon cancer and melanoma. Exon 3 beta-catenin
      activating mutations were found in 75% of cases of pilomatricoma (PM). Previous
      studies have shown that nuclear and/or cytoplasmic staining may correlate with
      beta-catenin gene mutation. OBJECTIVES: Because the immunohistochemical
      expression of beta-catenin in the nucleus or the cytoplasm correlates with beta
      catenin mutation, we studied the immunohistochemical profile of beta-catenin
      expression in normal scalp hair follicles and in PM and pilomatrix carcinoma
      (PC). METHODS: We reviewed 21 cases of PM and five cases of PC using
      immunohistochemical staining with commercially available antibody in a standard
      fashion on formalin-fixed paraffin-embedded tissue samples. RESULTS: All 26
      tumours displayed both nuclear and cytoplasmic staining in the basaloid cells
      with focal membranous staining. Shadow cells were negative in all tumours. Normal
      control sections from the scalp displayed nuclear reactivity of the matrical
      cells, mostly concentrated in the supramatrical zone of hair follicles.
      Membranous staining was present along the intercellular junctions of the
      epidermis and along the outer and inner root sheaths of hair follicles. We have
      found similar patterns of beta-catenin nuclear and cytoplasmic expression in both
      PM and PC. CONCLUSIONS: Despite the shared beta-catenin expression, the
      biological behaviour of PM and PC is markedly different. These two tumours
      probably share the activation of a common cellular pathway that could be related
      to their shared method of keratinization or a shared dysfunction of the cellular
      adhesion complex and consequently tumorigenesis. To the best of our knowledge,
      this is the first report on the beta-catenin immunohistochemical expression
      profile in PC.

PMID- 15030336
TI  - Declining mortality rates for nonmelanoma skin cancers in West Germany, 1968-99.
AB  - BACKGROUND: Mortality analyses based on routine death certification provide a
      rough guide to the magnitude of nonmelanoma skin cancer (NMSC) mortality.
      OBJECTIVES: To examine time trends in NMSC mortality over a 32-year period for
      the territory of West Germany which included a population of about 66 million
      people. METHODS: We analysed the NMSC skin cancer mortality data (1968-99) from
      the former West Germany including West Berlin. We calculated the age-specific and
      age-standardized mortality rates (World Standard Population) and used a Poisson
      regression to estimate the underlying age, cohort and period effects. RESULTS:
      The age-standardized mortality rate decreased from 0.56 per 100,000 in 1968 to
      0.24 per 100,000 in 1999 among men and from 0.42 per 100,000 in 1968 to 0.11 per
      100,000 in 1999 among women. The estimated annual percentage decrease of the age
      standardized NMSC skin cancer mortality rate was -2.3%[95% confidence interval
      (CI) -2.6 to -1.9] among men and -3.5% (95% CI -4.0 to -3.1) among women during
      the period 1968-99. This decline is mainly due to a rate decrease in people aged
      80 years or more. The change in NMSC skin cancer mortality rates was best
      explained by age, cohort and period effects. CONCLUSIONS: The NMSC mortality in
      West Germany showed a continuous decrease from 1968 to 1999. The favourable
      mortality decline by birth cohort in the most recent birth cohort is an indicator
      of a likely decline in mortality in the future.

PMID- 15030337
TI  - A retrospective observational study of primary cutaneous malignant melanoma
      patients treated with excision only compared with excision biopsy followed by
      wider local excision.
AB  - BACKGROUND: For primary cutaneous malignant melanoma the guidelines recommend an
      excision biopsy of the suspected lesion followed by wider local excision; the
      diagnosis can then be confirmed and excision margins planned. OBJECTIVES: To
      compare retrospectively the clinicopathological features, surgical margins and
      survival of patients from the Scottish Melanoma Group database whose tumour was
      removed by excision only (one-stage) or excision biopsy followed by wider local
      excision (two-stage) surgery. METHODS: The Scottish Melanoma Group database
      records the clinicopathological features, surgical treatment and follow-up
      information of all patients with malignant melanoma in Scotland. From this 1595
      patients were identified over a 19-year interval from 1979 to 1997 with follow-up
      until the end of December 1999. Overall survival, disease-free survival and
      recurrence-free interval were examined with univariate and multivariate
      statistical methods. RESULTS: The patients in the one-stage excision group (n =
      547) were statistically significantly older (P < 0.001), had thicker melanomas (P
      < 0.001), a higher proportion of lentigo maligna melanomas (P < 0.001), head and
      neck (P < 0.001), and ulcerated lesions (P < 0.003) compared with the two-stage
      group (n = 1048). The margins of excision were significantly narrower in the one
      stage compared with the two-stage group (P < 1 x 10(-5)). Fifty-two percent of
      all one-stage excisions were performed with a margin < 1 cm compared with 20% of
      the two-stage group. The excision margin was more positively correlated with the
      Breslow thickness for the two-stage over the one-stage group (Spearman rho =
      0.38, P < 0.001; and 0.27, P < 0.001, respectively). Overall survival (OS),
      disease-free survival (DFS), and recurrence-free survival (RF) were all
      statistically significantly better in the two-stage compared with the one-stage
      excision group, P < 1 x 10(-5), P < 1 x 10(-5) and P = 0.001, respectively (log
      rank test). After adjusting for the prognostic factors of age, sex, tumour
      thickness, site, histology and ulceration, OS, DFS and RF were still
      significantly better in the two-stage compared with the one-stage group [hazard
      ratio (HR) 0.75, 95% confidence interval (CI) 0.61-0.92, P = 0.006; HR 0.75, CI
      0.62-0.90, P = 0.002; and HR 0.78, CI 0.62-0.99, P = 0.04, respectively].
      CONCLUSIONS: This study showed that one-stage excisions were more common in
      patients with poorer prognostic features and that excision with margins narrower
      than those suggested by current guidelines was more likely. Patient survival was
      statistically significantly better with the two-stage procedure, although the
      reasons for this were unclear.

PMID- 15030339
TI  - Cumulative meta-analysis of systemic antifungal agents for the treatment of
      onychomycosis.
AB  - BACKGROUND: Onychomycosis is a common nail disease that is often chronic,
      difficult to eradicate, and has a tendency to recur. The most common oral
      therapies for dermatophyte toenail onychomycosis include terbinafine,
      itraconazole and fluconazole. OBJECTIVES: A cumulative meta-analysis of the
      randomized controlled trials (RCTs) for antimycotic agents was performed to
      determine whether the pooled estimate of the cure rates has remained consistent
      over the years. Furthermore, for each agent we compared the overall meta
      analytical average of both mycological and clinical response rates of RCTs vs.
      open studies. METHODS: We searched MEDLINE (1966 to November 2002) for relevant
      studies evaluating the efficacy of the oral antifungal agents terbinafine,
      itraconazole (pulse or continuous), fluconazole and griseofulvin for treating
      dermatophyte toenail onychomycosis. Studies included in this meta-analysis
      required a standard accepted dosage regimen, treatment duration and follow-up
      period. To determine the cumulative meta-analytical average, studies were
      sequentially pooled by adding one study at a time according to the date of
      publication (i.e. earliest to the most recent). RESULTS: There were 36 studies
      included in the analyses. For RCTs the change in efficacy of mycological cure
      rates from the first trial to the overall cumulative meta-average for each drug
      comparator is as follows (with 95% confidence interval): terbinafine, 78 +/- 6%
      (n = 2 studies, 79 patients) to 76 +/- 3% (n = 18 studies, 993 patients) (P =
      0.68); itraconazole pulse, 75 +/- 10% (n = 1 study, 20 patients) to 63 +/- 7% (n
      = 6 studies, 318 patients) (P = 0.25); itraconazole continuous, 63 +/- 5% (n = 1
      study, 84 patients) to 59 +/- 5% (n = 7 studies, 1131 patients) (P = 0.47);
      fluconazole, 53 +/- 6% (n = 1 study, 72 patients) to 48 +/- 5% (n = 3 studies,
      131 patients) (P = 0.50); and griseofulvin, 55 +/- 8% (n = 2 studies, 109
      patients) to 60 +/- 6% (n = 3 studies, 167 patients) (P = 0.41). The cumulative
      meta-analytical average of mycological cure rates when comparing RCTs vs. open
      studies was: terbinafine, 76 +/- 3% (n = 18 studies, 993 patients) vs. 83 +/- 12%
      (n = 2 studies, 391 patients) (P = 0.0028); itraconazole pulse, 63 +/- 7% (n = 6
      studies, 318 patients) vs. 84 +/- 9% (n = 3 studies, 194 patients) (P = 0.0001);
      and fluconazole, 48 +/- 5% (n = 3 studies, 131 patients) vs. 79 +/- 3% (n = 3
      studies, 208 patients) (P = 0.0001). CONCLUSIONS: The cumulative meta-analysis of
      cure rates for RCTs suggests that over time, as new RCTs have been conducted, the
      efficacy rates have remained consistent. The efficacy rates of open studies are
      substantially higher compared with RCTs and may therefore overestimate cure
      rates.

PMID- 15030338
TI  - Melanoma and nonmelanoma skin cancer in patients with multiple tumours--evidence
      for new syndromes in a population-based study.
AB  - BACKGROUND: The hypotheses that Swedish patients with four or more primary
      tumours [including at least one cutaneous malignant melanoma (CMM)] harbour an
      increased number of CDKN2A (formerly p16) germline mutations, and that this group
      of patients show a predisposition to other tumours, e.g. nonmelanoma skin cancer
      (NMSC), were studied descriptively. So far the mutation 113insArg explains all
      CDKN2A-associated CMM in ethnic Swedes. OBJECTIVES: All patients with four or
      more primary tumours, of which at least one was a CMM, from the Southern Swedish
      Regional Tumour Registry, between 1958 and 1999, were included in this study.
      METHODS: Forty-four patients were found and subdivided into three groups
      according to having multiple CMM (group A) or single CMM +/- NMSC (groups B and
      C). Screening for the presence of the Swedish founder mutation 113insArg in blood
      or in tissue blocks was performed. RESULTS: Patients in group A were younger at
      the time of the first CMM diagnosis than patients in group B and group C. The
      113insArg mutation was found in four of 44 patients (9%), three with multiple
      CMM. In group C (n = 14) no founder mutation was evident, while in group B (n =
      15) one mutation carrier was found. Nonmutation carriers with multiple CMM (group
      A) also had a predilection for meningiomas and neurinomas (four patients) or
      multiple NMSC (three patients). In group B CMM were especially associated with
      adenocarcinomas but in group C CMM were associated with multiple NMSC.
      CONCLUSION: The association between meningiomas and neurinomas (no acoustic
      neurinoma was seen) might indicate a new syndrome. Patients in groups B and C may
      harbour unknown genetic defects, which could interact with different
      environmental risk factors.

PMID- 15030340
TI  - Novel treatment of chronic severe hand dermatitis with bexarotene gel.
AB  - BACKGROUND: Hand dermatitis is an eczematous inflammation of the hands that is
      related to occupation or to routine activities. It often becomes chronic, and in
      some patients may become severe and disabling. Topical corticosteroids are
      effective treatment, particularly for milder forms, but they often lose
      effectiveness with time and can produce skin atrophy. OBJECTIVES: To evaluate
      bexarotene gel topical therapy for safety, tolerability and efficacy in patients
      with chronic hand dermatitis. METHODS: A phase I-II open-label randomized
      clinical study of bexarotene gel, alone and in combination with a low- and a mid
      potency steroid, was conducted in 55 patients with chronic severe hand dermatitis
      at two academic clinics. RESULTS: Patients using bexarotene gel monotherapy
      reached a 79% response rate for > or = 50% clinical improvement and a 39%
      response rate for > or = 90% clearance of hands. Adverse events possibly related
      to treatment in all patients were stinging or burning (15%), flare of dermatitis
      (16%) and irritation (29%). Thirteen patients (24%) withdrew early, including two
      for related adverse events and five for inadequate response. CONCLUSIONS:
      Bexarotene gel appears to be safe, tolerated by most patients, with useful
      therapeutic activity in chronic severe hand dermatitis.

PMID- 15030341
TI  - 0.03% Tacrolimus ointment applied once or twice daily is more efficacious than 1%
      hydrocortisone acetate in children with moderate to severe atopic dermatitis:
      results of a randomized double-blind controlled trial.
AB  - BACKGROUND: Topical corticosteroids are the usual treatment for atopic dermatitis
      (AD) in children but can have side-effects. OBJECTIVES: This study compared the
      efficacy and safety of 0.03% tacrolimus ointment applied once or twice daily over
      a 3-week period with the twice daily application of 1% hydrocortisone acetate
      (HA) ointment in children with moderate to severe AD. PATIENTS AND METHODS:
      Patients applied ointment daily to all affected body surface areas. The primary
      study endpoint was the percentage change in the modified Eczema Area and Severity
      Index (mEASI) between baseline and treatment end. RESULTS: Six hundred and twenty
      four patients, aged 2-15 years, applied 0.03% tacrolimus ointment once daily (n =
      207), twice daily (n = 210) or 1% HA twice daily (n = 207). By the end of
      treatment, application of 0.03% tacrolimus ointment both once or twice daily
      resulted in significantly greater median percentage decreases in mEASI (66.7% and
      76.7%, respectively) compared with 1% HA (47.6%; P < 0.001). Furthermore, the
      median percentage decrease in mEASI was significantly greater for patients
      applying 0.03% tacrolimus twice daily compared with once daily (P = 0.007).
      Patients with severe AD benefited especially from twice daily application of
      0.03% tacrolimus ointment compared with once daily application (P = 0.001).
      Transient mild to moderate skin burning occurred significantly more often in the
      0.03% tacrolimus groups (P = 0.028) but resolved in most cases within 3-4 days.
      Laboratory parameters showed no clinically relevant changes. CONCLUSIONS: 0.03%
      tacrolimus ointment applied once or twice daily is significantly more efficacious
      than 1% HA in treating moderate-severe AD in children. Twice daily application of
      0.03% tacrolimus ointment results in the greatest improvement in mEASI, and is
      especially effective in patients with severe baseline disease.

PMID- 15030342
TI  - Functional properties of the surface of the vermilion border of the lips are
      distinct from those of the facial skin.
AB  - BACKGROUND: The vermilion border of the lips (lip for short) is the only part on
      the face where the oral mucosa is persistently exposed to the outside. Despite
      its prominent presence on the face, constituting not only the target of cosmetics
      but also the site for various skin diseases, its functional properties remain
      almost unknown. OBJECTIVES: To elucidate the functional properties of the
      vermilion border of the lips. METHODS: We studied the biophysical properties of
      the lip by comparing them with those of the cheek skin in 303 healthy Japanese
      females aged 21-80 years, in winter. We used a closed-chamber system to measure
      transepithelial water loss (TEWL) of the lip to avoid the effect of breathing.
      Moreover, we examined the effects of oral etretinate, a drug that definitely
      produces dry, scaly lips, on the lips of seven male patients aged 49-89 (average
      67) years. RESULTS: TEWL was significantly almost three times as high on the lips
      as that on the cheek which is a site that shows far higher levels than do other
      body areas. TEWL decreased with age more remarkably on the lip than on the cheek.
      High-frequency conductance, a parameter for surface hydration state, was
      significantly lower on the lip than on the cheek. The mean values obtained were
      about one-third of those on the cheek, and no age-related changes were observed
      either on the lip or on the cheek. The superficial epithelial cells on the lip
      were parakeratotic and larger than those of the cheek skin. Furthermore, we
      detected a significant increase in TEWL on the lip as well as on the cheek of
      patients treated with oral etretinate. CONCLUSIONS: It appears that the
      incomplete corneocyte formation of the lip surface is responsible for the poor
      barrier function and water-holding capacity.

PMID- 15030343
TI  - A nail psoriasis severity index.
AB  - BACKGROUND: The Psoriasis Area and Severity Index does not take the severity of
      nail involvement into account. OBJECTIVES: To devise a system of scoring for nail
      psoriasis. METHODS: A system of scoring for nail psoriasis was devised that takes
      into account the site of the pathology, i.e. (i) the matrix, (ii) the subungual
      tissues distal to the lunula, or (iii) the whole nail unit. RESULTS: The proposed
      scoring system evaluates several signs of nail psoriasis separately, each on a 1
      3 scale: pitting, Beau's lines, subungual hyperkeratosis and onycholysis.
      CONCLUSIONS: Using this classification it will be possible to assess and grade
      nail pathology simply and accurately.

PMID- 15030344
TI  - Nitrotyrosine localization to dermal nerves in borderline leprosy.
AB  - BACKGROUND: Nerve damage is a common and disabling feature of leprosy, with
      unclear aetiology. It has been reported that the peroxidizing agents of myelin
      lipids-nitric oxide (NO) and peroxynitrite-are produced in leprosy skin lesions.
      OBJECTIVES: To investigate the localization of nitrotyrosine (NT)-a local end
      product of peroxynitrite-in leprosy lesions where dermal nerves are affected by a
      granulomatous reaction. METHODS: We investigated by immunohistochemistry and
      immunoelectron microscopy the localization of the inducible NO synthase (iNOS)
      and NT in biopsies exhibiting dermal nerves from patients with untreated leprosy.
      RESULTS: There were abundant NT-positive and iNOS-positive macrophages in the
      borderline leprosy granulomas infiltrating peripheral nerves identified by light
      microscopy, S-100 and neurofilament immunostaining. Immunoelectron microscopy
      showed NT reactivity in neurofilament aggregates and in the cell wall of
      Mycobacterium leprae. CONCLUSIONS: Our results suggest that NO and peroxynitrite
      could be involved in the nerve damage following borderline leprosy.

PMID- 15030345
TI  - Misdiagnosis of Fabry disease: importance of biochemical confirmation of clinical
      or pathological suspicion.
AB  - Generalized angiokeratoma are associated with three lysosomal storage disorders,
      one of which is Fabry disease (alpha-galactosidase A deficiency). Treatment for
      Fabry disease with supplementation of recombinant enzyme is available in the
      European Union and subsequently physicians' awareness may rise. A patient who was
      erroneously diagnosed with Fabry disease is presented.

PMID- 15030347
TI  - Toxic epidermal necrolysis-like reaction secondary to colchicine overdose.
AB  - Colchicine is a microtubule-inhibiting drug used to treat gout, familial
      Mediterranean fever and many other skin diseases. Intoxication with colchicine
      affects multiple organs, often fatally. Cutaneous sequelae of colchicine toxicity
      are rare. We describe the clinical and histological features of a toxic epidermal
      necrolysis-like exanthem in a patient who lethally overdosed on colchicine.

PMID- 15030348
TI  - Idiopathic acquired generalized anhidrosis due to occlusion of proximal coiled
      ducts.
AB  - Idiopathic acquired generalized anhidrosis is a very rare disease of unknown
      pathogenesis. We report a 25-year-old man with acquired generalized anhidrosis
      due to occlusion of the coiled ducts. He did not have sweat secretion over the
      entire surface of the body, including the palms and soles. Sweat-inducing stimuli
      provoked tingling pain on the skin. Pilocarpine iontophoresis on the forearm did
      not induce sweat secretion. Neurological examination did not reveal any
      abnormality in the central or peripheral nervous system. Skin biopsy showed that
      the coiled ducts were occluded by an amorphous eosinophilic substance. This
      amorphous eosinophilic substance was positive with periodic acid-Schiff (PAS)
      staining and was resistant to digestion by diastase. Electron microscopy
      demonstrated that the coiled ducts were completely occluded by an amorphous
      substance. The substance occluding the coiled ducts contained fibrous structures.
      These findings suggested that the acquired generalized anhidrosis in this patient
      was caused by occlusion of the coiled ducts by a PAS-positive substance probably
      derived from dark cell granules.

PMID- 15030350
TI  - Orofacial granulomatosis worsened by chocolate: results of patch testing to
      ingredients of Cadbury's chocolate.

PMID- 15030346
TI  - Childhood linear IgA disease in association with autoimmune lymphoproliferative
      syndrome.
AB  - A child is described who had the signs of autoimmune lymphoproliferative syndrome
      from an early age and later developed a blistering dermatosis that was shown to
      be childhood linear IgA disease.

PMID- 15030349
TI  - Systemic allergic contact dermatitis due to ethylenediamine following
      administration of oral aminophylline.

PMID- 15030351
TI  - Nephrogenic fibrosing dermopathy: response to high-dose intravenous
      immunoglobulin.

PMID- 15030352
TI  - Two cases of subcutaneous phaeohyphomycosis due to Exophiala jeanselmei, in
      cardiac transplant and renal transplant patients.

PMID- 15030353
TI  - Churg-Strauss syndrome: successful treatment with mycophenolate mofetil.

PMID- 15030354
TI  - 'Groveroid' Darier's disease?

PMID- 15030355
TI  - Seasonal variation in scabies.

PMID- 15030357
TI  - Keratosis follicularis squamosa (Dohi) associated with pseudoacanthosis
      nigricans.

PMID- 15030358
TI  - Multiple lesions of pyoderma gangrenosum in association with hyper-reactive
      malarial splenomegaly.

PMID- 15030359
TI  - Metastatic eccrine porocarcinoma presenting with lymphoedema.

PMID- 15030361
TI  - Neurofibromatosis 1 associated with an intracranial artery abnormality, moyamoya
      disease and bilateral congenital large hairy pigmented macules.

PMID- 15030360
TI  - The P25L mutation in the KRT5 gene in a Japanese family with epidermolysis
      bullosa simplex with mottled pigmentation.

PMID- 15030362
TI  - Tetracycline and epidermolysis bullosa simplex: a double-blind, placebo
      controlled, crossover randomized clinical trial.

PMID- 15030363
TI  - Perforating folliculitis with jaundice in an Indian male: a rare case with
      sclerosing cholangitis.

PMID- 15030364
TI  - Amyloidosis cutis dyschromica in a patient with generalized morphoea.

PMID- 15030365
TI  - Epidermal naevi associated with extrahepatic portal venous obstruction,
      hypoplastic kidney and lymphangiectasia: a new syndromic variant?

PMID- 15030366
TI  - Hourglass-like leuconychia in congenital lamellar ichthyosis.

PMID- 15030367
TI  - Successful treatment of angiokeratoma with potassium tritanyl phosphate laser.

PMID- 15030368
TI  - The application of topical tacrolimus in vesicular pemphigoid.

PMID- 15030373
TI  - Effect of angiotensin II and endothelin-1 receptor blockade on the haemodynamic
      and hormonal changes after acute blood loss and after retransfusion in conscious
      dogs.
AB  - AIM: This study investigates angiotensin II and endothelin-1 mediated mechanisms
      involved in the haemodynamic, hormonal, and renal response towards acute
      hypotensive haemorrhage. METHODS: Conscious dogs were pre-treated with
      angiotensin II type 1 (AT1) and/or endothelin-A (ETA) receptor blockers or not.
      Protocol 1: After a 60-min baseline period, 25% of the dog's blood was rapidly
      withdrawn. The blood was retransfused 60 min later and data recorded for another
      hour. Protocol 2: Likewise, but preceded by AT1 blockade with i.v. Losartan.
      Protocol 3: Likewise, but preceded by ETA blockade with i.v. ABT-627. Protocol 4:
      Likewise, but with combined AT1 plus ETA blockade. RESULTS: In controls,
      haemorrhage decreased mean arterial pressure (MAP) by approximately 25%, cardiac
      output by approximately 40%, and urine volume by approximately 60%, increased
      angiotensin II (3.1-fold), endothelin-1 (1.13-fold), vasopressin (116-fold), and
      adrenaline concentrations (3.2-fold). Glomerular filtration rate and
      noradrenaline concentrations remained unchanged. During AT1 blockade, the MAP
      decrease was exaggerated (-40%) and glomerular filtration rate fell. During ETA
      blockade, noradrenaline increased after haemorrhage instead of adrenaline, and
      the MAP recovery after retransfusion was blunted. The decrease in cardiac output
      was similar in all protocols. CONCLUSIONS: Angiotensin II is more important than
      endothelin-1 for the short-term regulation of MAP and glomerular filtration rate
      after haemorrhage, whereas endothelin-1 seems necessary for complete MAP recovery
      after retransfusion. After haemorrhage, endothelin-1 seems to facilitate
      adrenaline release and to blunt noradrenaline release. Haemorrhage-induced
      compensatory mechanisms maintain blood flow more effectively than blood pressure,
      as the decrease in cardiac output--but not MAP--was similar in all protocols.

PMID- 15030375
TI  - Global, synchronous oscillations in cytosolic calcium and adherence in bradykinin
      stimulated Madin-Darby canine kidney cells.
AB  - AIMS AND METHODS: Intercellular Ca2+ oscillations are a universal mode of
      signalling in both excitable and non-excitable cells. Here, we study the
      relationship between Ca2+ signalling and coherent changes in adhesion properties
      by measuring the transepithelial impedance across bradykinin-stimulated Madin
      Darby canine kidney (MDCK) cell layers grown on a microelectrode. During hormone
      stimulation, the impedance is found to oscillate, reflecting that the cells
      undergo morphological/adhesive alterations with high spatio-temporal
      organization. The experiments are supplemented with parallel, digital imaging
      fluorescence microscopy of bradykinin-induced single-cell Ca2+ oscillations.
      RESULTS: In agreement with previous experiments, MDCK cells are found to elicit
      synchronous, multicellular Ca2+ oscillations in response to hormone stimulus. The
      periods of the Ca2+ oscillations and the electrical fluctuations are found to
      coincide. Further, blocking of gap junctions by 18alpha-glycyrrhetinic acid
      causes a loss of synchrony in Ca2+ signals and inhibition of impedance
      oscillations, emphasizing the importance of gap junctions in the signal
      transduction process. CONCLUSION: Based on these observations it is concluded
      that the co-ordinated adhesive changes in MDCK cells are a direct consequence of
      synchronized Ca2+ oscillations. Calcium signalling represents an efficient way of
      organizing physiological responses in a tissue. A possible functional implication
      of the structural changes might be to modulate transportation of various
      substances across the cell sheet.

PMID- 15030374
TI  - Modulation of Na+,K+-ATPase activity is of importance for RVD.
AB  - AIM: This study was performed to examine the role of Na+,K+-ATPase activity for
      the adaptive response to cell swelling induced by hypoosmoticity, i.e. the
      regulatory volume decrease (RVD). METHODS: The studies were performed on COS-7
      cells transfected with rat Na+,K+-ATPase. To study changes in cell volume, cells
      were loaded with the fluorescent dye calcein and the intensity of the dye,
      following exposure to a hypoosmotic medium, was recorded with confocal
      microscopy. RESULTS: Ouabain-mediated inhibition of Na+,K+-ATPase resulted in a
      dose dependent decrease in the rate of RVD. Total 86Rb+ uptake as well as ouabain
      dependent 86Rb+ uptake, used as an index of Na+,K+-ATPase dependent K+ uptake,
      was significantly increased during the first 2 min following exposure to
      hypoosmoticity. Since protein kinase C (PKC) plays an important role in the
      modulation of RVD, a study was carried out on COS-7 cells expressing rat Na+,K+
      ATPase, where Ser23 in the catalytic alpha1 subunit of rat Na+,K+-ATPase had been
      mutated to Ala (S23A), abolishing a known PKC phosphorylation site. Cells
      expressing S23A rat Na+,K+-ATPase exhibited a significantly lower rate of RVD and
      showed no increase in 86Rb+ uptake during RVD. CONCLUSION: Taken together, these
      results suggest that a PKC-mediated transient increase in Na+,K+-ATPase activity
      plays an important role in RVD.

PMID- 15030376
TI  - Inhibition of BK channels contributes to the second phase of the response to TRH
      in clonal rat anterior pituitary cells.
AB  - AIM: Thyrotropin-releasing hormone (TRH) induces biphasic changes in the
      electrical activity, the cytosolic free Ca2+ concentration ([Ca2+]i), and
      prolactin secretion from both GH cells and native lactotrophs. It is well
      established that inhibition of erg channels contributes to the second phase of
      the TRH response. We have investigated if BK channels are also involved. RESULTS:
      The BK channels may be active at the resting membrane potential (open
      probability, Po=0.01) in clonal rat anterior pituitary cells (GH4), which makes
      it possible that inhibition of these channels may contribute to the reduced K+
      conductance during the TRH response. The specific BK channel blocker iberiotoxin
      (IbTx, 100 nm) had no effect on the resting conductance at holding potentials
      negative to -40 mV, but significantly reduced the conductance at shallower
      membrane potentials. This corresponds to the voltage dependency of the sustained
      [Ca2+]i. Furthermore, IbTx increased the action potential frequency by 36% in
      spontaneously firing cells. During the second phase of the TRH response, the
      action potential frequency increased by 34%, concomitantly with 61% reduction of
      the Po of single BK channels. The protein kinase C (PKC)-activating phorbol ester
      TPA had no significant effect on BK channel Po within the normal range of the
      resting potential. CONCLUSION: The BK channels may contribute to the resting
      membrane conductance, and they are partially inhibited by TRH during the second
      phase. This modulation seems not to depend on PKC. We propose that inhibition of
      erg and BK channels acts in concert to enhance the cell excitability during the
      second phase of the response to TRH.

PMID- 15030377
TI  - Serum insulin-like growth factor-I concentrations in late middle age: no
      association with birthweight in three UK cohorts.
AB  - BACKGROUND: Small body size at birth and during infancy is associated with an
      increased risk of adult osteoporosis and cardiovascular disease. Fetal
      programming of the growth hormone-insulin-like growth factor (GH-IGF) axis may
      provide a mechanism for these epidemiological findings. AIMS: To determine
      whether measurements of GH and IGF-I in late middle age were related to size at
      birth and in infancy. METHODS: Overnight urinary GH excretion and fasting serum
      IGF-I were measured in 309 men and 193 women from Hertfordshire (born 1920-1930)
      for whom birthweight and weight at 1 year were recorded. Serum IGF-I was measured
      in men and women from Preston (n=254, born 1935-1943) and Sheffield (n=215, born
      1939-1940) whose birthweight and other birth measurements were recorded. RESULTS:
      Urinary GH and serum IGF-I were not related to birthweight, other measurements at
      birth, or weight at 1 year. CONCLUSION: In contrast to previous studies in
      children or young adults, these data do not support the hypothesis that IGF-I
      concentrations are programmed by intra-uterine events, as assessed by
      birthweight, in late middle age.

PMID- 15030378
TI  - Interstitial glycerol concentrations in human skeletal muscle and adipose tissue
      during graded exercise.
AB  - AIM: It is not clear how lipolysis changes in skeletal muscle and adipose tissue
      during exercise of different intensities. We aimed at estimating this by
      microdialysis and muscle biopsy techniques. METHODS: Nine healthy, young men were
      kicking with both legs at 25% of maximal power (Wmax) for 45 min and then
      simultaneously with one leg at 65% and the other leg at 85% Wmax for 35 min.
      RESULTS: Glycerol concentrations in skeletal muscle and adipose tissue
      interstitial fluid and in arterial plasma increased (P<0.001) during low
      intensity exercise and increased (P<0.05) even more during moderate intensity
      exercise. The difference between interstitial muscle and arterial plasma water
      glycerol concentration, which indicates the direction of the glycerol flux, was
      positive (P<0.05) at rest (21 +/- 9 microM) and during exercise at 25% Wmax (18
      +/- 6 microM). The difference decreased (P<0.05) with increasing exercise
      intensity and was not significantly different from zero during exercise at 65% (
      11 +/- 17 microM) and 85% (-12 +/- 13 microM) Wmax. In adipose tissue, the
      difference between interstitial and arterial plasma water glycerol increased
      (P<0.001) with increasing intensity. The net triacylglycerol breakdown, measured
      chemically from the biopsy, did not differ significantly from zero at any
      exercise intensity although directional changes were similar to microdialysis
      changes. CONCLUSIONS: Skeletal muscle releases glycerol at rest and at low
      exercise intensity but not at higher intensities. This can be interpreted as
      skeletal muscle lipolysis peaking at low exercise intensities but could also
      indicate that glycerol is taken up in skeletal muscle at a rate which is
      increasing with exercise intensity.

PMID- 15030379
TI  - Decreased availability of intestinal dopamine in transmural colitis may relate to
      inhibitory effects of interferon-gamma upon L-DOPA uptake.
AB  - AIMS: The present study aimed to evaluate the relationship between intestinal
      inflammation, interferon-gamma (IFN-gamma) levels and intestinal levels of
      dopamine, its precursor l-3,4-dihydroxyphenylalanine (L-DOPA), and the activity
      of aromatic L-amino acid decarboxylase (AADC) activity along the digestive tract
      in a rat experimental model of colitis. METHODS: Colitis was induced by rectal
      administration of 2,4,6-trinitrobenzene sulphonic acid (TNBS). Catechol
      derivatives were assayed by means of HPLC-EC. RESULTS: It is shown that dopamine
      and noradrenaline levels in the distal colon (inflamed mucosa), but not in the
      ileum (non-inflamed mucosa), of TNBS-treated rats were markedly lower than in
      control animals. A slight decrease in L-DOPA tissue levels, no changes in AADC
      activity and an increase in plasma IFN-gamma levels accompanied this decrease in
      dopamine levels. Exposure of Caco-2 cells, a human intestinal epithelial cell
      line, to human IFN-gamma resulted in a concentration-dependent and long-lasting
      inhibition of L-DOPA uptake, which most likely explains the decrease in dopamine
      levels in the inflamed mucosa. CONCLUSION: Changes in tissue levels of
      noradrenaline and dopamine in experimental colitis in the rat follow a similar
      pattern to that observed in patients with Crohn's disease and ulcerative colitis.
      In this model of experimental colitis, the decrease in dopamine levels is most
      likely explained by the inhibitory effect of IFN-gamma on L-DOPA uptake by
      intestinal epithelial cells.

PMID- 15030380
TI  - Skeletal muscle HSP72 response to mechanical unloading: influence of endurance
      training.
AB  - AIMS: It has been shown that increased contractile activity results in heat shock
      protein 72 (HSP72) accumulation in various skeletal muscles. By contrast, there
      is no consensus for muscle HSP72 response to muscle disuse for short duration (5
      8 days). On the basis of a greater constitutive HSP72 expression in slow-twitch
      muscles we tested the hypothesis that mechanical unloading for a longer period (2
      weeks) would affect this phenotype to a greater extent. Secondly, we evaluated
      the effects of a physiological muscle heat shock protein (HSP) enhancer
      (endurance training) on HSP response to unloading and muscle remodelling.
      METHODS: Adult male Wistar rats were assigned randomly to four groups: (1)
      sedentary weight-bearing; (2) hindlimb-unloaded (HU) via tail suspension for 2
      week; (3) trained on a treadmill (6 week) and (4) trained 6 week and then HU for
      2 week. RESULTS: Unloading resulted in a preferential atrophy of slow muscles
      [soleus (SOL), adductor longus (AL)] and a slow-to-fast fibre transition with no
      change in HSP72 level. HSP72 levels were significantly lower in fast muscles
      [extensor digitorum longus (EDL) and plantaris (PLA)], and did not change with
      mechanical unloading. Endurance training was accompanied by a small (SOL) or a
      large (EDL, PLA) increase in HSP72 level with no change in AL. Training-induced
      accumulation of HSP72 disappeared with subsequent unloading in the SOL and PLA
      whereas HSP72 content remained elevated in EDL. CONCLUSION: The results of this
      study indicate that (1) after 2 weeks of unloading no change occurred in HSP72
      protein levels of slow-twitch muscles despite a slow-to-fast fibre transition;
      and (2) the training-induced increase of HSP72 content in skeletal muscles did
      not attenuate fibre transition.

PMID- 15030381
TI  - Human skeletal muscle cell differentiation is associated with changes in myogenic
      markers and enhanced insulin-mediated MAPK and PKB phosphorylation.
AB  - AIM: We hypothesized that myogenic differentiation of HSMC would yield a more
      insulin responsive phenotype. METHODS: We assessed expression of several proteins
      involved in insulin action or myogenesis during differentiation of primary human
      skeletal muscle cultures (HSMC). RESULTS: Differentiation increased creatine
      kinase activity and expression of desmin and myocyte enhancer factor (MEF)2C. No
      change in expression was observed for big mitogen-activated protein kinase
      (BMK1/ERK5), MEF2A, insulin receptor (IR), hexokinase II, and IR substrates 1 and
      2, while expression of glycogen synthase, extracellular signal-regulated kinase 1
      and 2 (ERK1/2 MAP kinase) and the insulin responsive aminopeptidase increased
      after differentiation. In contrast to protein kinase B (PKB)a, expression of
      (PKB)b increased, with differentiation. Both basal and insulin-stimulated PI 3
      kinase activity increased with differentiation. Insulin-mediated phosphorylation
      of PKB and ERK1/2 MAP kinase increased after differentiation. CONCLUSION:
      Components of the insulin-signalling machinery are expressed in myoblast and
      myotube HSMC; however, insulin responsiveness to PKB and ERK MAP kinase
      phosphorylation increases with differentiation.

PMID- 15030382
TI  - Mental stress inhibits pain perception and heart rate variability but not a
      nociceptive withdrawal reflex.
AB  - AIM: Do distraction from- or attention to sural nerve stimulation affect pain,
      heart rate variability, and a spinal withdrawal reflex? MATERIAL AND METHODS: In
      26 male volunteers, electrical stimulation at the distal cutaneous receptive
      field of the sural nerve elicited pain and a nociceptive withdrawal reflex.
      Intensity of pain was rated on a numeric rating scale. Electromyographic reflex
      responses were measured from biceps femoris muscle. Cardiac autonomic function
      was estimated by heart rate variability measures and was expressed in the time
      domain as mean of RR-intervals for normal heart beats (mean-RR) and standard
      deviation of all normal RR-intervals (SD-NN) and, in the frequency domain, where
      pure vagal activity was assessed by high frequency power (0.15-0.4 Hz). Low
      frequency power (0.04-0.15 Hz) reflects both parasympathetic and sympathetic
      control. Effect parameters were recorded before and during random distraction and
      attention. Distraction from sural nerve stimulation was induced by a mental
      arithmetic test, paced auditory serial addition task (PASAT), while attention was
      induced by concentrating on painful foot stimulation. RESULTS: Paced auditory
      serial addition task decreased mean-RR and SD-NN, frequency domain parameters, as
      well as pain (P<0.001). In contrast, PASAT did not change the spinal withdrawal
      reflex. Attention did not affect any effect parameter. CONCLUSION: Distraction by
      PASAT altered autonomic activity and inhibited pain but failed to affect
      withdrawal reflex responses, while attention had no effect on either parameter.
      Psychological distraction and attention may have different effects on noxious
      evoked pain perception and autonomic activity. Pain relief during PASAT probably
      involves supraspinal mechanisms.

PMID- 15030383
TI  - Specific involvement of neurotensin type 1 receptor in the neurotensin-mediated
      in vivo dopamine efflux using knock-out mice.
AB  - Abstract Neurotensin is a tridecapeptide neurotransmitter known to be involved in
      psychiatric disorders, various physiological processes and several different
      neurobiological mechanisms, including modulation of accumbal dopamine release.
      Two neurotensin extracellular binding sites, namely NT1- and NT2-receptor (NT1R
      and NT2R), have been cloned from the rat brain. These receptors are
      distinguishable by their different in vitro pharmacological properties but the
      available pharmacological tools have weak in vivo potency and specificity. The
      use of genetically engineered knock-out mice has provided a powerful alternative
      to the classical pharmacological approach to investigate their respective roles.
      In this study, using in vivo differential pulse amperometry, we show that, in
      wild-type mice, neurotensin application into the ventral tegmental area dose
      dependently evokes dopamine efflux in the nucleus accumbens. This neurotensin
      mediated efflux is dramatically decreased in mice lacking NT1R while it is
      unaffected in NT2R-deleted mice. This finding indicates that a large part of the
      dopamine efflux evoked by neurotensin in the nucleus accumbens of wild-type mice
      is mediated via NT1R present in the ventral tegmental area.

PMID- 15030384
TI  - Identification of GABAA receptor subunit variants in midbrain dopaminergic
      neurons.
AB  - Modulation of the activity of dopamine (DA)-producing neurons by GABA plays an
      important role in the control of DA-mediated brain functions. Ionotropic GABA(A)
      receptors exist as heteropentametric structures assembling different subunits
      composed of various subtypes. However, the expression pattern of these subunits
      in DA neurons in the ventral midbrain has not been fully defined. In the present
      study, we investigated the subunit composition of GABA(A) receptors in DA neurons
      in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA).
      We isolated DA neurons from the ventral midbrain of transgenic mice that express
      green fluorescent protein under the control of the tyrosine hydroxylase (TH) gene
      promoter and analyzed expression of various GABA(A) receptor subunits in single
      cells by using the reverse transcription-polymerase chain reaction. This analysis
      showed the presence of the transcripts encoding alpha2, alpha3, alpha4, beta1,
      beta3 and gamma2 subunits in the isolated DA neurons. Double fluorescence in situ
      hybridization with probes for TH and GABA(A) receptor subunit mRNAs revealed the
      expression of these six subunits in the majority of DA neurons in the SNc and the
      VTA.

PMID- 15030385
TI  - KCl and forskolin synergistically up-regulate cholecystokinin gene expression via
      coordinate activation of CREB and the co-activator CBP.
AB  - Cholecystokinin (CCK) is one of the most abundant peptide transmitters in the
      mammalian brain. Despite the physiological significance of CCK expression in long
      term memory and psychiatric disorders, little is known about the factors that
      regulate the expression of CCK peptides. Here, we report that KCl and forskolin
      synergistically increase CCK gene transcription via protein kinase A (PKA) and
      extracellular signal-regulated kinase (ERK) signalling pathways, activating cAMP
      response element-binding protein (CREB) associated with the CRE(- 80) element of
      the CCK promoter. Whereas, CREB Ser133 phosphorylation was essential for
      transcriptional activation, the synergistic stimulation was not correlated to the
      level of Ser133 phosphorylation, indicating that recruitment and/or activation of
      additional downstream factors were required for maximal stimulation.
      Transcriptional activation was reduced by co-expression of adenovirus 12S E1A,
      that inhibits binding of CREB-binding protein (CBP) to CREB. Moreover GAL4-CREB
      DIEDML, which mediates the phosphorylation-independent binding of CBP, and the C
      terminal domain of CBP was synergistically activated by forskolin and KCl. Taken
      together the results imply that neuronal CCK gene transcription is regulated by
      the cumulative action of calcium and cAMP via stimulation of the PKA and ERK
      signalling pathways and that synergy is accomplished by the coordinate activation
      of CREB and CBP.

PMID- 15030386
TI  - HMG-CoA reductase inhibition causes neurite loss by interfering with
      geranylgeranylpyrophosphate synthesis.
AB  - To determine whether neurite outgrowth depends upon the mevalonate pathway, we
      blocked mevalonate synthesis in nerve growth factor-treated PC12 cells or primary
      cortical neurones with atorvastatin, a 3-hydroxymethylglutaryl coenzyme A (HMG
      CoA) reductase inhibitor, and substituted different intermediates of the
      mevalonate pathway. We show that HMG-CoA reductase inhibition causes a profound
      reduction of neurite length, neurite loss and ultimatively cell death in
      undifferentiated and pre-differentiated PC12 cells and also in rat primary
      cortical neurones. Geranylgeranylpyrophosphate, but not farnesylpyrophosphate,
      squalene or cholesterol, completely compensated for the lack of mevalonate. Our
      data indicate that, under HMG-CoA reductase inhibition,
      geranylgeranylpyrophosphate rather than farnesylpyrophosphate or cholesterol is
      critical for neurite outgrowth and/or maintenance. Loss of neurites is an early
      manifestation of various neurodegenerative disorders, and dysfunction of
      isoprenylation might play a role in their pathogenesis.

PMID- 15030387
TI  - The neuronal SAPK/JNK pathway is altered in a murine model of
      hyperhomocysteinemia.
AB  - Deficiency in cystathionine beta synthase (CBS) leads to high plasma homocysteine
      concentrations and causes hyperhomocysteinemia, a common risk factor for vascular
      disease, stroke and possibly neurodegenerative diseases. Various neuronal
      diseases have been associated with hyperhomocysteinemia, but the molecular
      mechanisms of homocysteine toxicity are unknown. We investigated the pathways
      involved in the pathological process, by analyzing differential gene expression
      in neuronal tissues. We used a combination of differential display and cDNA
      arrays to identify genes differentially expressed during hyperhomocysteinemia in
      brain of CBS-deficient mice. In this murine model of hyperhomocysteinemia, both
      plasma and brain homocysteine concentrations were high. Several genes were found
      to be differentially expressed in the brains of CBS-deficient mice, and the
      identities of some of these genes suggested that the SAPK/JNK pathway was altered
      in the brains of CBS-deficient mice. We therefore investigated the activation of
      proteins involved in the SAPK/JNK cascade. JNK and c-Jun were activated in the
      hippocampal neurones of CBS-deficient mice, suggesting that the SAPK/JNK pathway
      may play an important role in the development of neuronal defects associated with
      hyperhomocysteinemia.

PMID- 15030388
TI  - Co-expressed presenilin 1 NTF and CTF form functional gamma-secretase complexes
      in cells devoid of full-length protein.
AB  - The enzyme gamma-secretase catalyzes the intramembrane proteolytic cleavage that
      generates the amyloid beta-peptide from the beta-amyloid precursor protein. The
      presenilin (PS) protein is one of the four integral membrane protein components
      of the mature gamma-secretase complex. The PS protein is itself subjected to
      endoproteolytic processing, generating stable N- and C-terminal fragment (NTF and
      CTF, respectively) heterodimers. Here we demonstrate that coexpression of PS1 NTF
      and CTF functionally mimics expression of the full-length PS1 protein and
      restores gamma-secretase activity in PS-deficient mammalian cells. The
      coexpressed fragments re-associate with each other inside the cell, where they
      also interact with nicastrin, another gamma-secretase complex component. Analysis
      of gamma-secretase activity following the expression of mutant forms of NTF and
      CTF, under conditions bypassing endoproteolysis, indicated that the putatively
      catalytic Asp257 and Asp385 residues have a direct effect on gamma-secretase
      activity. Moreover, we demonstrate that expression of the wild-type CTF rescues
      endoproteolytic cleavage of C-terminally truncated PS1 molecules that are
      otherwise uncleaved and inactive. Recovery of cleavage is critically dependent on
      the integrity of Asp385. Taken together, our findings indicate that ectopically
      expressed NTF and CTF restore functional gamma-secretase complexes and that the
      presence of full-length PS1 is not a requirement for proper complex assembly.

PMID- 15030389
TI  - Blockade of substance P (neurokinin 1) receptors enhances extracellular serotonin
      when combined with a selective serotonin reuptake inhibitor: an in vivo
      microdialysis study in mice.
AB  - Abstract Substance P antagonists of the neurokinin-1 receptor type (NK1) are
      gaining growing interest as new antidepressant therapies. It has been postulated
      that these drugs exert this putative therapeutic effect without direct
      interactions with serotonin (5-HT) neurones. Our recent microdialysis experiment
      performed in NK1 receptor knockout mice suggested evidence of changes in 5-HT
      neuronal function (Froger et al. 2001). The aim of the present study was to
      evaluate the effects of coadministration of the selective 5-HT reuptake inhibitor
      (SSRI) paroxetine with a NK1 receptor antagonist (GR205171 or L733060), given
      either intraperitoneally (i.p.) or locally into the dorsal raphe nucleus, on
      extracellular levels of 5-HT ([5-HT]ext) in the frontal cortex and the dorsal
      raphe nucleus using in vivo microdialysis in awake, freely moving mice. The
      systemic or intraraphe administration of a NK1 receptor antagonist did not change
      basal cortical [5-HT]ext in mice. A single systemic dose of paroxetine (4 mg/kg;
      i.p.) resulted in a statistically significant increase in [5-HT]ext with a larger
      extent in the dorsal raphe nucleus (+ 138% over basal AUC values), than in the
      frontal cortex (+ 52% over basal AUC values). Co-administration of paroxetine (4
      mg/kg; i.p.) with the NK1 receptor antagonists, GR205171 (30 mg/kg; i.p.) or
      L733060 (40 mg/kg; i.p.), potentiated the effects of paroxetine on cortical [5
      HT]ext in wild-type mice, whereas GR205171 (30 mg/kg; i.p.) had no effect on
      paroxetine-induced increase in cortical [5-HT]ext in NK1 receptor knock-out mice.
      When GR205171 (300 micro mol/L) was perfused by 'reverse microdialysis' into the
      dorsal raphe nucleus, it potentiated the effects of paroxetine on cortical [5
      HT]ext, and inhibited paroxetine-induced increase in [5-HT]ext in the dorsal
      raphe nucleus. Finally, in mice whose 5-HT transporters were first blocked by a
      local perfusion of 1 micro mol/L of citalopram into the frontal cortex, a single
      dose of paroxetine (4 mg/kg i.p.) decreased cortical 5-HT release, and GR205171
      (30 mg/kg i.p.) reversed this effect. The present findings suggest that NK1
      receptor antagonists, when combined with a SSRI, augment 5-HT release by
      modulating substance P/5-HT interactions in the dorsal raphe nucleus.

PMID- 15030390
TI  - Dorfin prevents cell death by reducing mitochondrial localizing mutant superoxide
      dismutase 1 in a neuronal cell model of familial amyotrophic lateral sclerosis.
AB  - Abstract Dorfin is a RING-finger type ubiquitin ligase for mutant superoxide
      dismutase 1 (SOD1) that enhances its degradation. Mutant SOD1s cause familial
      amyotrophic lateral sclerosis (FALS) through the gain of unelucidated toxic
      properties. We previously showed that the accumulation of mutant SOD1 in the
      mitochondria triggered the release of cytochrome c, followed by the activation of
      the caspase cascade and induction of neuronal cell death. In the present study,
      therefore, we investigated whether Dorfin can modulate the level of mutant SOD1
      in the mitochondria and subsequent caspase activation. We showed that Dorfin
      significantly reduced the amount of mutant SOD1 in the mitochondria, the release
      of cytochrome c and the activation of the following caspase cascade, thereby
      preventing eventual neuronal cell death in a neuronal cell model of FALS. These
      results suggest that reducing the accumulation of mutant SOD1 in the mitochondria
      may be a new therapeutic strategy for mutant SOD1-associated FALS, and that
      Dorfin may play a significant role in this.

PMID- 15030391
TI  - Putative endogenous mediators of preconditioning-induced ischemic tolerance in
      rat brain identified by genomic and proteomic analysis.
AB  - In brain, a brief ischemic episode induces protection against a subsequent severe
      ischemic insult. This phenomenon is known as preconditioning-induced neural
      ischemic tolerance. An understanding of the molecular mechanisms leading to
      preconditioning helps in identifying potential therapeutic targets for preventing
      the post-stroke brain damage. The present study conducted the genomic and
      proteomic analysis of adult rat brain as a function of time following
      preconditioning induced by a 10-min transient middle cerebral artery (MCA)
      occlusion. GeneChip analysis showed induction of 40 putative neuroprotective
      transcripts between 3 to 72 h after preconditioning. These included heat-shock
      proteins, heme oxygenases, metallothioneins, signal transduction mediators,
      transcription factors, ion channels and apoptosis/plasticity-related transcripts.
      Real-time PCR confirmed the GeneChip data for the transcripts up-regulated after
      preconditioning. Two-dimensional gel electrophoresis combined with MALDI-TOF
      analysis showed increased expression of HSP70, HSP27, HSP90, guanylyl cyclase,
      muskelin, platelet activating factor receptor and beta-actin at 24 h after
      preconditioning. HSP70 protein induction after preconditioning was localized in
      the cortical pyramidal neurons. The infarct volume induced by focal ischemia (1-h
      MCA occlusion) was significantly smaller (by 38 +/- 7%, p < 0.05) in rats
      subjected to preconditioning 3 days before the insult. Preconditioning also
      prevented several gene expression changes induced by focal ischemia.

PMID- 15030393
TI  - Differential modulation of NR1-NR2A and NR1-NR2B subtypes of NMDA receptor by PDZ
      domain-containing proteins.
AB  - The PSD-95/Dlg/ZO-1 (PDZ) domain-containing proteins MALS and PSD-95 localize to
      post-synaptic densities and bind the COOH-termini of NR2 subunits of the NMDA
      receptor. The effects of MALS-2 and PSD-95 on the channel activity of NMDA
      receptors were compared using the Xenopus oocyte expression system. Both MALS-2
      and PSD-95 increased the current response of the NR1-NR2B receptor to l
      glutamate. In contrast, the current response of the NR1-NR2A receptor was
      increased by PSD-95 but not by MALS-2. MALS-2 had no effect either on the
      potentiation of NR1-NR2A or NR1-NR2B channel activity by protein kinase C, or on
      Src-mediated potentiation of NR1-NR2A activity, whereas PSD-95 almost completely
      inhibited the effects of these protein kinases. Construction of chimeras of MALS
      2 and PSD-95 revealed that the first two PDZ domains and two NH(2)-terminal
      cysteine residues are essential for the inhibitory effects of PSD-95 on protein
      kinase C-mediated potentiation of NR1-NR2A and NR1-NR2B channel activity,
      respectively. The second of the three PDZ domains of PSD-95 was required for its
      inhibition of Src-mediated potentiation of NR1-NR2A activity. These results
      indicate that the NR1-NR2A and NR1-NR2B receptors are modulated differentially by
      MALS-2 and PSD-95, and that similar regulatory effects of PSD-95 on these
      receptors are achieved by distinct mechanisms.

PMID- 15030392
TI  - Protection against glucose-induced neuronal death by NAAG and GCP II inhibition
      is regulated by mGluR3.
AB  - Glutamate carboxypeptidase II (GCP II) inhibition has previously been shown to be
      protective against long-term neuropathy in diabetic animals. In the current
      study, we have determined that the GCP II inhibitor 2-(phosphonomethyl)
      pentanedioic acid (2-PMPA) is protective against glucose-induced programmed cell
      death (PCD) and neurite degeneration in dorsal root ganglion (DRG) neurons in a
      cell culture model of diabetic neuropathy. In this model, inhibition of caspase
      activation is mediated through the group II metabotropic glutamate receptor,
      mGluR3. 2-PMPA neuroprotection is completely reversed by the mGluR3 antagonist
      (S)-alpha-ethylglutamic acid (EGLU). In contrast, group I and III mGluR
      inhibitors have no effect on 2-PMPA neuroprotection. Furthermore, we show that
      two mGluR3 agonists, the direct agonist (2R,4R)-4-aminopyrrolidine-2, 4
      dicarboxylate (APDC) and N-acetyl-aspartyl-glutamate (NAAG) provide protection to
      neurons exposed to high glucose conditions, consistent with the concept that 2
      PMPA neuroprotection is mediated by increased NAAG activity. Inhibition of GCP II
      or mGluR3 may represent a novel mechanism to treat neuronal degeneration under
      high-glucose conditions.

PMID- 15030394
TI  - PIP3 is involved in neuronal polarization and axon formation.
AB  - Recent experiments in various cell types such as mammalian neutrophils and
      Dictyostelium discoideum amoebae point to a key role for the lipid product of PI
      3-kinase, PIP(3), in determining internal polarity. In neurons, as a consequence
      of the elongation of one neurite, the axon is specified and the cell acquires its
      polarity. To test the hypothesis that PI 3-kinase and PIP(3) may play a role in
      neuronal polarity, and especially in axon specification, we observed localization
      of PIP(3) visualized by Akt-PH-GFP in developing hippocampal neurons. We found
      that PIP(3) accumulates in the tip of the growing processes. This accumulation is
      inhibited by addition of PI 3-kinase inhibitors. Those inhibitors, consistently
      with a role of PIP(3) in process formation and elongation, delay the transition
      from stage 1 neurons to stage 3 neurons, and both axon formation and elongation.
      Moreover, when the immature neurite contacts a bead coated with laminin, a
      substrate known to induce axon specification, PIP(3) accumulates in its growth
      cone followed by a rapid elongation of the neurite. In such conditions, the
      addition of PI 3-kinase inhibitors inhibits both PIP(3) accumulation and future
      axon elongation. These results suggest that PIP(3) is involved in axon
      specification, possibly by stimulating neurite outgrowth. In addition, when a
      second neurite contacted the beads, this neurite rapidly elongates whereas the
      elongation of the first laminin-contacting neurite stops, consistently with the
      hypothesis of a negative feedback mechanism from the growing future axon to the
      other neurites.

PMID- 15030395
TI  - Lipid rafts identified as locations of ectodomain shedding mediated by Meltrin
      beta/ADAM19.
AB  - Meltrin beta (Mel beta, also called ADAM19) is a member of the ADAM (adisintegrin
      and metalloprotease) family, which are membrane-anchored glycoproteins that play
      crucial roles in various biological processes. Many intercellular signaling
      molecules are membrane-anchored proteins, which are proteolytically processed
      after becoming membrane-bound, to liberate their extracellular domains
      (ectodomain shedding). Genetic and biochemical studies have shown that some ADAMs
      participate in these events. We found previously that Mel beta can cleave the
      extracellular region of the membrane-anchored beta-exon-containing Neuregulin-1
      (NRG beta1) protein, which is one of the main ligands for the neural ErbB
      receptor. Mel beta-deficient mice showed developmental defects in the nervous
      system. These observations raise the possibility that the NRG ectodomain shedding
      mediated by Mel beta is closely related to the neural development. Here we show
      that Mel beta-mediated ectodomain shedding of NRG beta1 takes place in the lipid
      rafts of neurons. The lipid rafts localization of Mel beta requires its membrane
      anchoring region, and NRG beta1 ectodomain shedding is not enhanced if Mel beta
      cannot reach the lipid rafts. These results indicate that localization of Mel
      beta in lipid rafts is critical for its ectodomain shedding.

PMID- 15030396
TI  - Bcl-x L blocks mitochondrial multiple conductance channel activation and inhibits
      6-OHDA-induced death in SH-SY5Y cells.
AB  - Apoptosis is an active process that is regulated by different signalling
      pathways. One of the more important organelles involved in apoptosis regulation
      is the mitochondrion. Electron chain transport disruption increases free radical
      production leading to multiple conductance channel opening, release of cytochrome
      c and caspase activation. This death pathway can be blocked by anti-apoptotic
      members of the Bcl-2 protein family that might shift redox potential to a more
      reduced state, preventing free radical-mediated damage. 6-Hydroxydopamine (6
      OHDA) has been widely used to generate Parkinson's disease-like models. It is
      able to generate free radicals and to induce catecholaminergic cell death. In
      this paper we have used the human neuroblastoma cell line SH-SY5Y overexpressing
      Bcl-x(L) as a model to gain insights into the mechanisms through which Bcl-x(L)
      blocks 6-OHDA-induced cell death and to identify the molecular targets for this
      action. Herein, we present evidence supporting that the Bcl-x(L)-anti-apoptotic
      signal pathway seems to prevent mitochondrial multiple conductance channel
      opening, cytochrome c release and caspase-3 like activity following 6-OHDA
      treatment in the human neuroblastoma cell line SH-SY5Y.

PMID- 15030397
TI  - Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis
      sativa, on beta-amyloid-induced toxicity in PC12 cells.
AB  - Abstract Alzheimer's disease is widely held to be associated with oxidative
      stress due, in part, to the membrane action of beta-amyloid peptide aggregates.
      Here, we studied the effect of cannabidiol, a major non-psychoactive component of
      the marijuana plant (Cannabis sativa) on beta-amyloid peptide-induced toxicity in
      cultured rat pheocromocytoma PC12 cells. Following exposure of cells to beta
      amyloid peptide (1 micro g/mL), a marked reduction in cell survival was observed.
      This effect was associated with increased reactive oxygen species (ROS)
      production and lipid peroxidation, as well as caspase 3 (a key enzyme in the
      apoptosis cell-signalling cascade) appearance, DNA fragmentation and increased
      intracellular calcium. Treatment of the cells with cannabidiol (10(-7)-10(-4)m)
      prior to beta-amyloid peptide exposure significantly elevated cell survival while
      it decreased ROS production, lipid peroxidation, caspase 3 levels, DNA
      fragmentation and intracellular calcium. Our results indicate that cannabidiol
      exerts a combination of neuroprotective, anti-oxidative and anti-apoptotic
      effects against beta-amyloid peptide toxicity, and that inhibition of caspase 3
      appearance from its inactive precursor, pro-caspase 3, by cannabidiol is involved
      in the signalling pathway for this neuroprotection.

PMID- 15030398
TI  - Phospholipase D2 functions as a downstream signaling molecule of MAP kinase
      pathway in L1-stimulated neurite outgrowth of cerebellar granule neurons.
AB  - Stimulation of the neuronal cell adhesion molecule L1 in cerebellar granule
      neurons (CGNs) enhances neurite outgrowth and this response is inhibited by the
      primary alcohol ethanol. Because primary alcohols suppress the formation of the
      signaling lipid phosphatidic acid (PA) by phospholipase D (PLD), this observation
      prompted us to investigate whether PLD plays a role in the L1-mediated neurite
      outgrowth in CGNs. In the cerebellum of postnatal day 8 mice, PLD2 protein was
      abundantly expressed, while PLD1 expression was not detected. The L1-stimulated
      neurite outgrowth was inhibited by primary alcohols and by overexpression of
      lipase-deficient PLD2. Increases in cellular PA levels by direct PA application
      or overexpression of wild-type PLD2 mimicked the L1-dependent stimulation of
      neurite outgrowth. Furthermore, it was found that L1 stimulation in CGNs
      increased PLD activity concomitantly with phosphorylation of extracellular signal
      regulated kinase (ERK), both of which were inhibited by the MAP kinase-ERK kinase
      (MEK) inhibitor. These results provide evidence that PLD2 functions as a
      downstream signaling molecule of ERK to mediate the L1-dependent neurite
      outgrowth of CGNs, a mechanism that may be related to alcohol-related
      neurodevelopmental disorders.

PMID- 15030400
TI  - Hypoxia-induced ischemic tolerance in neonatal rat brain involves enhanced ERK1/2
      signaling.
AB  - Hypoxic preconditioning (HP) 24 h before hypoxic-ischemic (HI) injury confers
      significant neuroprotection in neonatal rat brain. Recent studies have shown that
      the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase
      (PI3K) intracellular signaling pathways play a role in the induction of tolerance
      to ischemic injury in heart and brain. To study the role of MAPK (ERK1/2, JNK,
      p38MAPK) and PI3K/Akt/GSK3beta signaling pathways in hypoxia-induced ischemic
      tolerance, we examined the brains of newborn rats at different time points after
      exposure to sublethal hypoxia (8% O(2) for 3 h). Immunoblot analysis showed that
      HP had no effect on the levels of phosphorylated Akt, GSK3beta, JNK and p38MAPK.
      In contrast, significantly increased levels of phosphorylated ERK1/2 were
      observed 0.5 h after HP. Double immunofluorescence staining showed that hypoxia
      induced ERK1/2 phosphorylation was found mainly in microvessels throughout the
      brain and in astrocytes in white matter tracts. Inhibition of hypoxia-induced
      ERK1/2 pathway with intracerebral administration of U0126 significantly
      attenuated the neuroprotection afforded by HP against HI injury. These findings
      suggest that activation of ERK1/2 signaling may contribute to hypoxia-induced
      tolerance in neonatal rat brain in part by preserving vascular and white matter
      integrity after HI.

PMID- 15030399
TI  - Adenosine A 2A receptor antagonists prevent the increase in striatal glutamate
      levels induced by glutamate uptake inhibitors.
AB  - Active uptake by neurons and glial cells is the main mechanism for maintaining
      extracellular glutamate at low, non-toxic concentrations. Activation of adenosine
      A(2A) receptors increases extracellular glutamate levels, while A(2A) receptor
      antagonists reduce stimulated glutamate outflow. Whether a modulation of the
      glutamate uptake system is involved in the effects elicited by A(2A) receptor
      blockers has never been investigated. This study examined the ability of
      adenosine A(2A) receptor antagonists to prevent the increase in glutamate levels
      induced by blockade of the glutamate uptake. In rats implanted with a
      microdialysis probe in the dorsal striatum, perfusion with 4 mm l-trans
      pyrrolidine-2,4-dicarboxylic acid (PDC, a transportable competitive inhibitor of
      glutamate uptake), or 10 mm dihydrokainic acid (DHK, a non-transportable
      competitive inhibitor that mainly blocks the glial glutamate transporter GLT-1),
      significantly increased extracellular glutamate levels. The effects of PDC and
      DHK were completely prevented by the adenosine A(2A) receptor antagonists SCH
      58261 (0.01 mg/kg i.p.) and/or ZM 241385 (5 nm via probe). Since an impairment in
      glutamate transporter function is thought to play a major role in
      neurodegenerative disorders, the regulation of glutamate uptake may be one of the
      mechanisms of the neuroprotective effects of A(2A) receptor antagonists.

PMID- 15030401
TI  - Lovastatin-induced up-regulation of the BH3-only protein, Bim, and cell death in
      glioblastoma cells.
AB  - The mechanism of lovastatin-induced cell death was examined in three established
      human glioblastoma cell lines; U87, U251, and U138. Changes in potential
      modifiers of apoptosis, including Bcl-2 family proteins and MAP kinase targets
      after such lovastatin treatment, were evaluated. Lovastatin (5 microm) treatment
      causes extensive cell death in two of the cell lines, U87 and U251; but only
      minimal in a third, U138. Lovastatin-induced death occurs in correlation with
      significantly increased levels of the BH3-only protein, Bim. The up-regulation of
      Bim levels was directly associated with an increased incidence of apoptosis.
      Lovastatin treatment in U87 cells results in activation of targets of three major
      mitogen-activating protein kinase cascades including Erk1/2, JNK and p38. Changes
      in levels of Bim, as well as increase phosphorylation of Erk1/2, c-jun, and p38
      are all prevented by co-incubation of lovastatin and the isoprenylation
      metabolite, geranylgeranyl pyrophosphate. Inhibition of the MAP kinase pathways
      failed to block the increased expression of Bim expression or cell death. Further
      elucidation of the mechanisms of lovastatin-induced up-regulation of Bim and
      apoptosis in glioblastoma cells are important in determining a potential role for
      lovastatin as a chemotherapy agent.

PMID- 15030402
TI  - Molecular evolution and genetics of the Saitohin gene and tau haplotype in
      Alzheimer's disease and argyrophilic grain disease.
AB  - A single nucleotide polymorphism that results in an amino acid change (Q7R) has
      been identified in the Saitohin (STH) gene and was initially found to be over
      represented in the homozygous state in subjects with late-onset Alzheimer's
      disease (AD). More extensive studies provide limited support for the association
      with AD, but confirm an association of the Q allele with progressive supranuclear
      palsy and argyrophilic grain disease. A homologous sequence was found in the
      appropriate location of the rat and mouse tau genes, but there was no open
      reading frame allowing STH expression in these species, suggesting relatively
      recent evolution of this gene. In some non-human primates, the STH gene was
      identified, and this was found to differ from the human gene at two of 128 amino
      acids. All primates in which the STH gene was identified were homozygous for the
      R allele of STH, suggesting this is the ancestral allele. This observation was
      surprising, in that the Q allele is more common in human populations, and raises
      the possibility that natural selection has operated to favor individuals carrying
      this allele. The STH polymorphism is part of the tau gene haplotype, of which two
      major variants exist in human populations, the Q being part of the H1 haplotype
      and the R part of the H2 haplotype. More detailed studies confirm the H2
      haplotype to be the ancestral tau gene. This situation is reminiscent of the
      evolution of the apolipoprotein (ApoE) gene, another locus that is potentially
      important for the risk of development of AD.

PMID- 15030403
TI  - Platelet-activating factor receptor-deficient mice are protected from
      experimental sleep apnea-induced learning deficits.
AB  - Intermittent hypoxia (IH) during sleep, a hallmark of sleep apnea, is associated
      with neurobehavioral impairments, regional neurodegeneration and increased
      oxidative stress and inflammation in rodents. Platelet-activating factor (PAF) is
      an important mediator of both normal neural plasticity and brain injury. We
      report that mice deficient in the cell surface receptor for PAF (PAFR-/-), a
      bioactive mediator of oxidative stress and inflammation, are protected from the
      spatial reference learning deficits associated with IH. Furthermore, PAFR-/-
      exhibit attenuated elevations in inflammatory signaling (cyclo-oxygenase-2 and
      inducible nitric oxide synthase activities), degradation of the ubiquitin
      proteasome pathway and apoptosis observed in wild-type littermates (PAFR+/+)
      exposed to IH. Collectively, these findings indicate that inflammatory signaling
      and neurobehavioral impairments induced by IH are mediated through PAF receptors.

PMID- 15030404
TI  - Caspase-3 and calpain activities after acute and repeated ethanol administration
      during the rat brain growth spurt.
AB  - Ethanol administration during the rat brain growth spurt triggers apoptotic
      neurodegeneration that appears to be mediated by caspase-3 activation. In order
      to gain more insight on the role of this caspase in ethanol-induced developmental
      neurotoxicity, we studied its expression and activity under different conditions
      of ethanol exposure during development. Furthermore, because of the cross-talk
      between caspase-3 and calpain we extended our study also at this protease.
      Ethanol was administered by gavage to rat pups as a single-day exposure on
      postnatal day (PN) 7 or from PN4 to PN10. Cleaved caspase-3 expression peaked in
      the cerebral cortex 12 h after ethanol treatment and returned to control values
      at 24 h. An identical pattern was found for caspase-3-like activity, that was
      increased only with the highest dose of ethanol tested (5 g/kg) and mostly in
      PN4. Repeated ethanol exposure, at a dose that was previously found to induce
      microencephaly, did not increase caspase-3 expression and activity although it
      decreased procaspase-3 expression and released mitochondrial cytochrome c.
      Repeated ethanol administration also increased calpain activity. These data show
      that acute and repeated ethanol administration differentially affect caspase-3
      and calpain activity, suggesting that calpain activation may play a role in
      developmental neurotoxicity of ethanol.

PMID- 15030405
TI  - Aging in the rat hippocampus is associated with widespread reductions in the
      number of glutamate decarboxylase-67 positive interneurons but not interneuron
      degeneration.
AB  - Increased excitability of principal excitatory neurons is one of the hallmarks of
      aging in the hippocampus, signifying a diminution in the number and/or function
      of inhibitory interneurons with aging. To elucidate this, we performed
      comprehensive GABA-ergic interneuron cell counts in all layers of the dentate
      gyrus and the CA1 and CA3 subfields, using serial sections from adult, middle
      aged and aged Fischer 344 rats. Sections were immunostained for glutamate
      decarboxylase-67 (GAD-67, a synthesizing enzyme of GABA) and GAD-67
      immunopositive interneurons were counted using an unbiased cell counting method,
      the optical fractionator. Substantial declines in the absolute number of GAD-67
      immunopositive interneurons were found in all hippocampal layers/subfields of
      middle-aged and aged animals, in comparison with the adult animals. However, the
      counts were comparable between the middle-aged and aged groups for all regions.
      Interestingly, determination of the absolute number of interneurons using neuron
      specific nuclear antigen (NeuN) expression in the strata oriens and radiatum of
      CA1 and CA3 subfields revealed an analogous number of interneurons across the
      three age groups. Furthermore, the ratio of GAD-67 immunopositive and NeuN
      positive interneurons decreased from adult age to middle age but remained
      relatively static between middle age and old age. Collectively, the results
      underscore that aging in the hippocampus is associated with wide-ranging
      decreases in the number of GAD-67 immunopositive interneurons and most of the age
      related changes in GAD-67 immunopositive interneuron numbers transpire by middle
      age. Additionally, this study provides novel evidence that age-related reductions
      in hippocampal GAD-67 immunopositive interneuron numbers are due to loss of GAD
      67 expression in interneurons rather than interneuron degeneration.

PMID- 15030406
TI  - An investigation into signal transduction mechanisms involved in insulin-induced
      long-term depression in the CA1 region of the hippocampus.
AB  - Recent work has demonstrated that brief application of insulin to hippocampal
      slices can induce a novel form of long-term depression (insulin-LTD) in the CA1
      region of the hippocampus; however, the molecular details of how insulin triggers
      LTD remain unclear. Using electrophysiological and biochemical approaches in the
      hippocampal slices, we show here that insulin-LTD (i) is specific to 3-hydroxy-5
      methylisoxazole-4-propionic acid (AMPA) receptor- but not NMDA receptor-mediated
      synaptic transmission; (ii) is induced and expressed postsynaptically but does
      not require the activation of ionotropic and metabotropic glutamate receptors;
      (iii) requires a concomitant Ca(2+) influx through l-type voltage-activated
      Ca(2+) channels (VACCs) and the release of Ca(2+) from intracellular stores; (iv)
      requires the series of protein kinases, including protein tyrosine kinase (PTK),
      phosphatidylinositol 3-kinase (PI3K), and protein kinase C (PKC); (v) is
      mechanistically distinct from low-frequency stimulation-induced LTD (LFS-LTD) and
      independent on protein phosphatase 1/2 A (PP1/2 A) and PP2B activation; (vi) is
      dependent on a rapamycin-sensitive local translation of dendritic mRNA, and (vii)
      is associated with a persistent decrease in the surface expression of GluR2
      subunit. These results suggest that a PI3K/PKC-dependent insulin signaling, which
      controls postsynaptic surface AMPA receptor numbers through PP-independent
      endocytosis, may be a major expression mechanism of insulin-LTD in hippocampal
      CA1 neurons.

PMID- 15030408
TI  - Selective loss of NMDA receptor NR1 subunit isoforms in Alzheimer's disease.
AB  - Previous work had shown that the ratio of NMDA receptor NR1 subunit mRNA
      transcripts containing an N-terminal splice cassette to those that do not is
      markedly lower in regions of the Alzheimer's disease (AD) brain that are
      susceptible to pathological damage, compared with spared regions in the same
      cases or homotropic regions in controls. To elucidate the origins of this
      difference in proportionate expression, we measured the absolute levels of each
      of the eight NR1 transcripts by quantitative internally standardized RT-PCR
      assay. Expression of transcripts with the cassette was strongly attenuated in
      susceptible regions of Alzheimer's brain, whereas expression of non-cassette
      transcripts differed little from that in controls. The expression of other NR1
      splice variants was not associated with pathology relevant to disease status,
      although some combinations of splice cassettes were well maintained in AD cases.
      The population profile of NR1 transcripts in occipital cortex differed from the
      profiles in other brain regions studied. Western analysis confirmed that the
      expression of protein isoforms containing the N-terminal peptide was very low in
      susceptible areas of the Alzheimer's brain. Cells that express NR1 subunits with
      the N-terminal cassette may be selectively vulnerable to toxicity in AD.

PMID- 15030407
TI  - Involvement of ERK MAP kinase in endoplasmic reticulum stress in SH-SY5Y human
      neuroblastoma cells.
AB  - Endoplasmic reticulum (ER) stress has increasingly come into focus as a factor
      contributing to neuronal injury. Although caspase-dependent mechanisms have been
      implicated in ER stress, the signaling pathways involved remain unclear. In this
      study, we examined the role of the extracellular signal-regulated kinase (ERK), a
      mitogen-activated protein (MAP) kinase pathway that is highly conserved in many
      systems for balancing cell survival and death. Prolonged treatment of the human
      neuroblastoma cell line SH-SY5Y with thapsigargin, an inducer of ER stress,
      increased cell death over 24-48 h, as measured by LDH release. Caspases were
      involved; increased levels of active caspase-3 and cleaved caspase substrate PARP
      were detected, and treatment with Z-VAD-FMK reduced thapsigargin-induced
      cytotoxicity. In contrast, inhibition of calpain was not protective, although
      calpain was activated following thapsigargin treatment. An early and transient
      phosphorylation of ERK1/2 occurred after thapsigargin-induced ER stress, and
      targeting this pathway with the MEK inhibitors U0126 or PD98059 significantly
      reduced cell death. Similar cytoprotection was obtained against brefeldin A,
      another ER stress agent. However, protection against ER stress via ERK inhibition
      was not accompanied by amelioration of caspase-3 activation, PARP cleavage, or
      DNA laddering. These data indicate that ERK may contribute to non-caspase
      dependent pathways of injury after ER stress.

PMID- 15030409
TI  - Mitochondrial extracellular signal-regulated kinases 1/2 (ERK1/2) are modulated
      during brain development.
AB  - Intracellular activation and trafficking of extracellular signal-regulated
      protein kinases (ERK) play a significant role in cell cycle progression,
      contributing to developmental brain activities. Additionally, mitochondria
      participate in cell signalling through energy-linked functions, redox metabolism
      and activation of pro- or anti-apoptotic proteins. The purpose of the present
      study was to analyze the presence of ERK1/2 in mitochondria during rat brain
      development. Immunoblotting, immune electron microscopy and activity assays
      demonstrated that ERK1/2 are present in fully active brain mitochondria at the
      outer membrane/intermembrane space fraction. Besides, it was observed that ERK1/2
      translocation to brain mitochondria follows a developmental pattern which is
      maximal between E19-P2 stages and afterwards declines at P3, just before maximal
      translocation to nucleus, and up to adulthood. Most of mitochondrial ERK1/2 were
      active; upstream phospho-MAPK/ERK kinases (MEK1/2) were also detected in the
      brain organelles. Mitochondrial phospho-ERK1/2 increased at 1 microm hydrogen
      peroxide (H(2)O(2)) concentration, but it decreased at higher 50-100 microm
      H(2)O(2), almost disappearing after the organelles were maximally stimulated to
      produce H(2)O(2) with antimycin. Our results suggest that developmental
      mitochondrial activation of ERK1/2 cascade contributes to its nuclear
      translocation effects, providing information about mitochondrial energetic and
      redox status to the proliferating/differentiating nuclear pathways.

PMID- 15030410
TI  - Exogenous, but not endogenous nociceptin modulates mesolimbic dopamine release in
      mice.
AB  - The effect of nociceptin (an endogenous ligand of the ORL1 receptor) on
      mesolimbic dopamine release and simultaneous horizontal locomotion was studied in
      freely moving mice undergoing microdialysis of the nucleus accumbens.
      Intracerebroventricular (i.c.v.) administration of nociceptin (7 nmol) induced a
      long-lasting suppression of mesolimbic dopamine release and horizontal locomotion
      in wild-type but not ORL1 knockout mice. I.c.v. administration of the recently
      reported peptide nociceptin antagonist [Nphe1, Arg14, Lys15] nociceptin-NH(2)
      (known also as UFP-101, 5 nmol) completely abolished the suppressive effect of
      nociceptin on mesolimbic dopamine release. However, UFP-101 administration alone
      induced a mild and lasting suppression of mesolimbic dopamine release in both
      wild-type and ORL1 knockout mice that was magnified in ORL1 knockout mice by
      coadministration of nociceptin. UFP-101 administration alone suppressed
      locomotion in both genotypes. These results confirm that the suppressive action
      of nociceptin on mesolimbic dopamine release is mediated entirely by the ORL1
      receptor, and that UFP-101 effectively antagonizes this action. However, the lack
      of a stimulatory effect of UFP-101 in wild-type mice indicates that despite being
      sensitive to exogenous nociceptin action, basal mesolimbic dopaminergic activity
      is not determined by endogenous nociceptin in mice.

PMID- 15030411
TI  - Glutamate-mediated overexpression of CD38 in astrocytes cultured with neurones.
AB  - Recently, a new system of astrocyte-neurone glutamatergic signalling has been
      identified. It is started in astrocytes by ectocellular, CD38-catalysed
      conversion of NAD(+) to the calcium mobilizer cyclic ADP-ribose (cADPR). This is
      then pumped by CD38 itself into the cytosol where the resulting free
      intracellular Ca(2+) concentration [Ca(2+)](i) transients elicit an increased
      release of glutamate, which can induce an enhanced Ca(2+) response in
      neighbouring neurones. Here, we demonstrate that co-culture of either cortical or
      hippocampal astrocytes with neurones results in a significant overexpression of
      astrocyte CD38 both on the plasma membrane and intracellularly. The causal role
      of neurone-released glutamate in inducing overexpression of astrocyte CD38 is
      demonstrated by two observations: first, in the absence of neurones, induction of
      CD38 in pure astrocyte cultures can be obtained with glutamate and second, it can
      be prevented in co-cultures by glutamate receptor antagonists. The neuronal
      glutamate-mediated effect of neurones on astrocyte CD38 expression is paralleled
      by increased intracellular cADPR and [Ca(2+)](i) levels, both findings indicating
      functionality of overexpressed CD38. These results reveal a new neurone-to
      astrocyte glutamatergic signalling based on the CD38/cADPR system, which affects
      the [Ca(2+)](i) in both cell types, adding further complexity to the bi
      directional patterns of communication between astrocytes and neurones.

PMID- 15030412
TI  - Cryoenergy catheter ablation: a new technique for treatment of permanent
      junctional reciprocating tachycardia in children.
AB  - INTRODUCTION: Permanent junctional reciprocating tachycardia (PJRT) is an
      infrequent form of reciprocating tachycardia, almost incessant from childhood and
      usually refractory to drug therapy. Radiofrequency catheter ablation currently is
      the first-line therapy for PJRT, but its application in the septal region may be
      associated with complications. In contrast, cryoenergy has several advantages,
      such as the ability to test the effects of ablation while the lesion is still
      forming, thus reducing the number of ineffective, useless, and potentially
      harmful lesions. The aim of this study was to investigate the potential clinical
      utility of percutaneous cryoenergy catheter ablation for treatment of pediatric
      patients with PJRT. METHODS AND RESULTS: Four patients (age 14 +/- 5 years; mean
      +/- SD) with a clinical diagnosis of PJRT underwent catheter cryoablation. The
      ablation was successfully accomplished in 4 (100%) of 4 patients. The mean +/- SD
      number of cryoapplications was 1.8 +/- 0.8, and from 1 to 6 cryomappings were
      performed for each permanent cryolesion. The successful site was in the mid
      septal region (2 patients), at the coronary sinus orifice (1 patient), and in the
      middle cardiac vein (1 patient). No complications with cryoablation were
      reported, nor was there prolongation of the AH interval during cryomapping or
      cryoablation. No pain was reported by patients during the cryoenergy catheter
      ablation procedure. PJRT recurrence occurred in 1 patient who underwent a second
      successful cryoablation procedure. CONCLUSION: The outcomes of cryoenergy
      catheter ablation in these 4 patients treated for PJRT suggest that cryoablation
      is a safe, effective, and pain-free technique for treating pediatric patients
      with PJRT.

PMID- 15030414
TI  - Intracardiac ultrasound catheter imaging for electrophysiologic substrate of AV
      nodal reentrant tachycardia: anatomic versus electrophysiologic evidence.

PMID- 15030413
TI  - Comparison of coronary sinus morphology in patients with and without
      atrioventricular nodal reentrant tachycardia by intracardiac echocardiography.
AB  - INTRODUCTION: Dual AV nodal physiology is the electrophysiologic substrate for AV
      nodal reentrant tachycardia (AVNRT), but the anatomic basis for this arrhythmia
      remains to be elucidated. Atrial flutter (AFL) has been shown to be more
      frequently inducible in patients with AVNRT. METHODS AND RESULTS: A 3.2-French,
      20-MHz intracardiac ultrasound (ICUS) catheter was introduced into the coronary
      sinus (CS), and two-dimensional ICUS images were recorded during transducer
      pullback in 21 patients with AVNRT and 18 control patients. Three-dimensional
      reconstruction of the CS was created using the TomTec Imaging system. The area of
      the CS lumen at 15 mm within the CS ostium (os) was not significantly different
      in patients with and without AVNRT (54.4 +/- 34.7 mm2 vs 39.1 +/- 28.5 mm2).
      However, the area of the CS os was significantly larger in patients with AVNRT
      than in those without (112.1 +/- 60.9 mm2 vs 71.7 +/- 44.4 mm2, P < 0.05). Three
      dimensional morphology of the CS os revealed flaring in patients with AVNRT,
      giving it a "windsock" appearance. Sustained AFL was induced in 10 of 21 patients
      with AVNRT, but in none of 18 control patients (P < 0.005). CONCLUSION: The CS os
      was significantly wider in patients with AVNRT than in those without. These
      findings may have important implications for arrhythmia pathogenesis in AVNRT as
      well as AFL.

PMID- 15030415
TI  - High-flow perfusion of sheaths for prevention of thromboembolic complications
      during complex catheter ablation in the left atrium.
AB  - INTRODUCTION: Mechanisms for thromboembolic complications during complex ablation
      procedures in left atrium (LA) have not been defined. The aim of this study was
      to determine the effect of the perfusion rate of the transseptal sheath on the
      incidence of thromboembolic complications during catheter ablation for atrial
      fibrillation (AF) or LA macroreentrant tachycardia. METHODS AND RESULTS: We
      analyzed clinical and procedural data from 86 consecutive patients (153
      procedures) referred for catheter ablation of AF (74 patients) or LA
      macroreentrant tachycardia (12 patients). The transseptal sheath was continuously
      perfused at a low flow rate (3 mL/hour) for the first 32 patients and at a high
      flow rate (180 mL/hour) for the subsequent 54 patients. Ablation was mainly
      performed using map-guided isolation of pulmonary veins for AF and three
      dimensional electroanatomic mapping for LA macroreentrant tachycardia. Five
      patients (6% of patients and 3.5% of procedures) developed a cerebral
      thromboembolic complication, all during procedures using low-flow perfusion.
      Sheath perfusion rate and total procedure duration were the two variables
      significantly associated with the occurrence of stroke (P = 0.013 and 0.001,
      respectively). After adjustment in a multivariable analysis, sheath perfusion
      rate remained the only risk factor for stroke. The risk was 17 times higher using
      low-flow than high-flow perfusion (odds ratio 17.26, 95% confidence interval 1.14
      260.81, P = 0.04). No other clinical or procedural parameters had any significant
      effect. CONCLUSION: Sheath perfusion rate is an important determinant of the risk
      factor for stroke during complex LA ablation procedures. Continuous high-flow
      perfusion appears to be effective in preventing this complication.

PMID- 15030416
TI  - So far, so good...

PMID- 15030417
TI  - Do patients accept implantable atrial defibrillation therapy? Results from the
      Patient Atrial Shock Survey of Acceptance and Tolerance (PASSAT) Study.
AB  - INTRODUCTION: The Medtronic Jewel AF 7250 is an implantable cardioverter
      defibrillator with atrial and ventricular therapies (ICD-AT). The ICD-AT is
      effective in managing atrial tachyarrhythmias (atrial fibrillation [AF]), but
      patient acceptance remains an issue. This aim of this study was to measure ICD-AT
      acceptance. METHODS AND RESULTS: ICD-AT acceptance was evaluated in 96 patients
      enrolled in the "Jewel AF-AF-Only Study" for > or =3 months of follow-up (mean 19
      months). Patients were mostly men (72%; age 65 +/- 12 years). Clinical data and a
      written survey (75% response rate) were used to quantify demographics, AF
      frequency and symptoms, atrial defibrillation therapy, quality of life (QOL),
      psychosocial distress, and ICD-AT therapy acceptance. From implant to survey, AF
      symptom and severity scores decreased by 18% (P < or = 0.05), and QOL (SF-36)
      scores increased by 15% to 50% (P < or = 0.05). ICD-AT therapy acceptance was
      high, with 71.3% of patients scoring in the 75th percentile on the Florida
      Patient Acceptance Survey. ICD-AT acceptance was correlated with the Physical
      Component Scale and Mental Health Component Scale scores of the SF-36 (r = 0.28
      and 0.35, respectively). ICD-AT acceptance was negatively correlated with
      depressive symptomatology (r =-0.59), trait anxiety (r =-0.48), illness
      intrusiveness (r =-0.55), and AF symptom and severity scores (r =-0.26). ICD-AT
      acceptance did not correlate with preimplant cardioversions, number of atrial
      shocks, AF episodes detected by the device, or device implant duration.
      CONCLUSION: Most patients accepted ICD-AT therapy. Patients were more likely to
      accept ICD-AT if they had less psychosocial distress, greater QOL, and lower AF
      symptom burden.

PMID- 15030418
TI  - Come see the softer side of clinical outcomes: Quality-of-life measures in
      implanted defibrillator trials.

PMID- 15030419
TI  - Linkage between mechanical and electrical alternans in patients with chronic
      heart failure.
AB  - INTRODUCTION: Progressive heart failure and ventricular fibrillation are major
      causes of death in patients with chronic heart failure. Mechanical alternans
      (pulsus alternans) has been observed in patients with severe congestive heart
      failure. Visible T wave alternans occasionally is a precursor of ventricular
      fibrillation. We investigated the occurrence of both cardiac alternans in 94
      patients with chronic heart failure. METHODS AND RESULTS: Mean left ventricular
      ejection fraction (LVEF) of the study population was 35 +/- 10%. Mechanical
      alternans was detected in left ventricular pressure during diagnostic cardiac
      catheterization. Only sustained mechanical alternans was included in the study.
      Visible T wave alternans, not microvolt alternans, was noted on standard surface
      ECG. Cardiac alternans was examined at rest, during physiologic tachycardia, and
      during stepwise dobutamine loading (2-4-8 microg/kg/min). Prevalences of
      mechanical and electrical alternans were 19.1% and 4.4% at rest, 45.5% and 8.0%
      during physiologic tachycardia, and 62.1% and 9.5% under dobutamine loading.
      Overall, 70 patients (74.5%) showed mechanical alternans and 10 patients (10.6%)
      showed T wave alternans. T wave alternans always appeared with large mechanical
      alternans. Among patients with mechanical alternans, cases with T wave alternans
      showed lower LVEF than those without (27.5 +/- 4.4 and 35.1 +/- 10.2, P < 0.002).
      CONCLUSION: Visible T wave alternans was detectable in patients with chronic
      heart failure, especially under tachycardia or catecholamine exposure.
      Investigating mechanical and mechanoelectrical alternans may bring new insights
      into the management of patients with chronic heart failure.

PMID- 15030420
TI  - Misdiagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy.
AB  - INTRODUCTION: Diagnosis of arrhythmogenic right ventricular
      dysplasia/cardiomyopathy (ARVD/C) has major implications for the management of
      patients and their first-degree relatives. Diagnosis is based on a set of
      criteria proposed by the International Task Force for Cardiomyopathies. We report
      our experience in providing a re-evaluation for patients who previously have been
      diagnosed with ARVD/C. METHODS AND RESULTS: We studied 89 patients who requested
      a re-evaluation for diagnosis of ARVD/C at our center. Each of these patients had
      been diagnosed with ARVD/C at their initial evaluation. Each patient was re
      evaluated with clinical history, physical examination, and noninvasive testing at
      our center. Invasive testing, which included electrophysiologic testing, right
      ventricular angiography, and endomyocardial biopsy, was performed when clinically
      indicated. Sixty (92%) of the 65 patients who had undergone magnetic resonance
      imaging (MRI) at an outside institution were reported to have an abnormal MRI
      consistent with ARVD/C. Among these patients, the only abnormality identified was
      the qualitative finding of intramyocardial fat/wall thinning in 46 patients. On
      re-evaluation, these qualitative findings were not confirmed. None of these 46
      patients ultimately were diagnosed with ARVD/C. Among the entire patient group,
      only 24 (27%) of the 89 patients met the Task Force criteria for ARVD/C.
      CONCLUSION: This study demonstrates that the high frequency of "misdiagnosis" of
      ARVD/C is due to over-reliance on the presence of intramyocardial fat/wall
      thinning on MRI, incomplete diagnostic testing, and lack of awareness of the Task
      Force criteria. Diagnosis of ARVD/C cannot rely solely upon qualitative features
      on MRI.

PMID- 15030421
TI  - Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: is there
      a single gold standard test?

PMID- 15030422
TI  - Electroanatomic versus fluoroscopic mapping for catheter ablation procedures: a
      prospective randomized study.
AB  - INTRODUCTION: The aim of this prospective randomized study was to compare the
      routine use of electroanatomic imaging (CARTO) with that of conventional
      fluoroscopically guided activation mapping (conventional) in an unselected
      population referred for catheter ablation. We sought to compare the two
      approaches with respect to procedure outcome and duration, radiation exposure,
      and cost. METHODS AND RESULTS: All patients undergoing catheter ablation (with
      the exception of complete AV nodal ablation) were prospectively randomized to
      either a CARTO or conventional procedure for mapping and ablation. One hundred
      two patients were randomized. Acute procedural success was similar with either
      strategy (CARTO vs conventional 43/47 vs 51/55, P > 0.5), as was procedure
      duration (144 [58] vs 125 [48] min, P = 0.07 (mean [SD]). CARTO was associated
      with a substantial reduction in fluoroscopy time (9.3 [7.6] vs 28.8 [19.5] min, P
      < 0.001) and radiation dose (6.2 [6.1] vs 20.8 [32.7] Gray, P = 0.003). CARTO
      cases used fewer catheters (2.5 [0.7] vs 4.4 [1.1], P < 0.001), but catheter
      costs were higher (13.8 vs 9.3 units, P < 0.001, where one unit is equivalent to
      the cost of a nonsteerable quadripolar catheter). CONCLUSION: For all catheter
      ablation procedures, even when a center's "learning curve" for CARTO is included,
      procedure duration and outcome are similar for CARTO and conventional procedures.
      CARTO is associated with drastically reduced fluoroscopy time and radiation dose.
      Although fewer catheters are used with CARTO, catheter costs remain higher.

PMID- 15030424
TI  - Spatial dispersion of repolarization is a key factor in the arrhythmogenicity of
      long QT syndrome.
AB  - INTRODUCTION: The occurrence of significant spatial dispersion of repolarization
      in vivo as it relates to the mechanism of arrhythmia formation in the long QT
      syndrome (LQTS) continues to be questioned. METHODS AND RESULTS: We investigated
      a guinea pig model of LQT3 using anthopleurin-A (AP-A) to study the contribution
      of rate-dependent spatial dispersion of repolarization in the intact heart to the
      arrhythmogenicity of LQTS. Optical action potentials were measured using
      potentiometric fluorescent dye di-4ANEPPS in Langendorff-perfused hearts with
      induced AV block. AP-A exacerbated the normal uniform epicardial apex-base action
      potential duration (APD) gradient, resulting in rate-dependent increased APD
      dispersion and nonuniform APD gradient. Spontaneous focal premature beats induced
      functional conduction block along boundaries where large nonuniform APD gradient
      occurred setting the stage for circulating wavefronts and ventricular
      tachyarrhythmia (VT). Endocardial ablation abolished spontaneous VT, but
      nonuniform epicardial APD gradient persisted and could be challenged by a
      stimulated premature stimulus to induce VT. CONCLUSION: The study shows that in
      LQT3, spatial variations in steady-state properties result in zones of nonuniform
      APD gradients. These provide a substrate for functional conduction block and
      reentrant excitation when challenged by subendocardial "early afterdepolarization
      triggered" premature beats. The study emphasizes the key importance of spatial
      dispersion of repolarization, whether located in epicardial or intramyocardial
      layers, in arrhythmia formation in LQTS.

PMID- 15030423
TI  - Electrophysiologic effects of salbutamol, a beta2-selective agonist.
AB  - INTRODUCTION: A positive chronotropic effect of beta2 stimulation is well known.
      Case reports of ventricular arrhythmias during beta2-inhalation therapy have been
      published. The aim of this study was to asses the overall electrophysiologic
      effects of the beta2-agonist salbutamol. METHODS AND RESULTS: Electrophysiologic
      and hemodynamic variables were measured in 10 healthy volunteers during atrial
      pacing at baseline and during infusion of salbutamol at two different rates (0.1
      and 0.2 microg/kg/min). To characterize beta2-agonist effects, a comparison was
      made with the beta1-selective agonist dobutamine. Salbutamol infusion produced
      significant changes in electrophysiologic properties in both myocardial and nodal
      tissues, with significantly greater effects on nodal properties. The proportional
      decreases in AV nodal parameters were more pronounced than in the sinus node (P <
      0.001). An interesting result was a significant increase in the duration of the
      QS interval, which in the presence of an unchanged His-Purkinje conduction (HV)
      represents slower depolarization of the ventricle. QT dispersion also increased.
      CONCLUSION: Infusion of salbutamol results in significant electrophysiologic
      effects on most heart structures, proportionally most pronounced in the AV node.
      Discordant effects on ventricular conduction, which slowed, and the
      refractoriness of the ventricular myocardium, which shortened, were seen. QT
      dispersion was increased.

PMID- 15030425
TI  - Catheter ablation of ventricular tachycardia by intramyocardial injection of
      ethanol in an animal model of chronic myocardial infarction.
AB  - INTRODUCTION: Direct injection of ethanol into myocardium has been shown to
      create large, well-demarcated lesions with transmural necrosis in normal
      ventricular myocardium and in regions of healed myocardial infarction. The aim of
      this study was to investigate the effects of direct ethanol injection on the
      inducibility of ventricular tachycardia (VT) in an animal model of chronic
      myocardial infarction. METHODS AND RESULTS: Eight sheep with reproducibly
      inducible VT underwent an electrophysiologic study 139 +/- 65 days after
      myocardial infarction. Noncontact mapping was used to analyze induced VT. Fifteen
      different VTs were targeted for catheter ablation. Ablation was achieved by
      catheter-based intramyocardial injection of a mixture of 96% ethanol, glycerine,
      and iopromide (ratio 3:1:1). Direct intramyocardial ethanol injection resulted in
      noninducibility of any VT 20 minutes after ablation in 7 of 8 animals. Four of 5
      animals with initially successful ablation remained noninducible for any VT at
      follow-up study at least 2 days after the ablation procedure. Microscopic
      examination revealed homogeneous lesions with interstitial edema, intramural
      hemorrhage, and myofibrillar degeneration at the lesion border. The lesions were
      well demarcated from the surrounding tissue by a border zone of neutrophilic
      infiltration. CONCLUSION: Catheter ablation of VT by direct intramyocardial
      injection of ethanol during the chronic phase of myocardial infarction is
      feasible. It may be a useful tool for catheter ablation when the area of interest
      is located deep intramyocardially or subepicardially or when a more regional
      approach requires ablation of larger amounts of tissue.

PMID- 15030426
TI  - Activation of the Ca(2+)-activated nonselective cation channel by diacylglycerol
      analogues in rat cardiomyocytes.
AB  - INTRODUCTION: Cardiac hypertrophy is associated with changes in
      electrophysiologic properties due to ionic channel modifications and increases in
      protein kinase C (PKC) activity and diacylglycerol (DAG) content. These changes
      may contribute to an increased propensity for arrhythmia. Similar
      electrophysiologic modifications have been reported in adult rat cardiomyocytes
      undergoing dedifferentiation in primary culture. METHODS AND RESULTS: Single
      channel measurements on such cells identified the appearance of a Ca(2+)
      activated nonselective cation channel (NSC(Ca)) during the dedifferentiation
      process. The current study investigated the sensitivity of this channel to PKC
      and DAG analogues. In the cell-attached configuration, channel conductance was
      20.2 pS under physiologic conditions. Perfusion with the DAG analogue 1-oleoyl-2
      acetyl-sn-glycerol (OAG, 0.1 mM) or the PKC activator phorbol 12-myristate 13
      acetate (PMA, 0.5 microM) increased the channel normalized open probability
      (nPo), whereas in the presence of the PKC inhibitor calphostin C (1 microM), only
      OAG retained this effect. In the inside-out configuration, perfusion of both DAG
      analogues OAG (0.1 mM) and 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG, 10 microM)
      on the inside of the membrane increased nPo. These results indicate that DAG
      regulates the NSC(Ca) channel via both the PKC pathway and by a direct
      interaction. CONCLUSION: DAG content, PKC activity, and channel expression
      increased during hypertrophy. This indicates that the NSC(Ca) channel exhibits
      high activity in this condition and, therefore, is a candidate for the genesis of
      arrhythmias in ventricular cardiomyocytes. In addition, regulation of the channel
      by DAG and PKC contributes to current understanding of the physiologic role of
      this channel, which shares properties with the cloned TRPM4b channel.

PMID- 15030427
TI  - Embryonic conduction tissue: a spatial correlation with adult arrhythmogenic
      areas.
AB  - INTRODUCTION: The occurrence of arrhythmias in adult patients may arise
      preferentially in anatomic regions derived from the specialized cardiac
      conduction system. To examine this hypothesis, we performed a detailed analysis
      of the developing cardiac conduction system using the recently described CCS-lacZ
      transgenic mouse strain. METHODS AND RESULTS: Transgenic embryos (E9.5-15.5) were
      stained for beta-galactosidase activity and co-stained with the myocardial marker
      HHF35. Results were reconstructed three dimensionally. CCS-lacZ expression was
      observed in the sinoatrial node, left and right venous valves, septum spurium,
      right and left atrioventricular ring, His bundle, bundle branches, and right
      ventricular moderator band. Furthermore, lacZ-positive cells could be
      demonstrated for the first time in the left atrium, in the posterior wall
      surrounding the pulmonary venous orifice. and, in later stages, surrounding the
      pulmonary venous wall. These cells were continuous with the left venous valve in
      the right atrium. LacZ-positive tissue also could be identified in Bachmann's
      bundle, running retro-aortically between the right atrium and left atrium.
      CONCLUSION: Known arrhythmogenic areas including Bachmann's bundle, the pulmonary
      veins, and sinus venosus derived internodal structures, demonstrate lacZ
      expression. These data support the hypothesis that areas derived from the
      developing cardiac conduction system may contribute to the arrhythmogenic
      substrate in adult hearts.

PMID- 15030428
TI  - Role of dipolar and nondipolar components of the T wave in determining the T wave
      residuum in an isolated rabbit heart model.
AB  - INTRODUCTION: Repolarization heterogeneity has been shown to constitute a
      substrate for malignant ventricular arrhythmias. Noninvasive measurement of
      abnormal repolarization through assessment of QT interval dispersion from the
      resting standard 12-lead ECG initially had shown promise in assessing arrhythmia
      risk but was challenged recently. The relative T wave residuum (TWR) has been
      proposed recently to reflect regional repolarization dispersion more accurately.
      We analyzed the role played by the dipolar and nondipolar components in
      determining TWR. METHODS AND RESULTS: Singular value decomposition was applied to
      the repolarization signals obtained from isolated rabbit hearts using a 5 x 8
      array multielectrode recording system during premature beats (N = 11) and after d
      sotalol (N = 9) exposure. Both the dipolar and nondipolar components of the T
      wave increased significantly during premature stimulation and after d-sotalol
      exposure. The relative TWR decreased significantly during premature stimulation
      but did not change after d-sotalol. Changes in the dipolar and nondipolar
      components of the second half of the T wave were significantly greater than those
      corresponding to the first half during premature stimulation, and a significant
      correlation was observed between the nondipolar components of the second half of
      the T wave and the T(peak-end) interval. CONCLUSION: Conditions exist during
      which both the dipolar and nondipolar components can change simultaneously. Under
      these conditions, the relative TWR may not reflect regional heterogeneity of
      repolarization with accuracy. The nondipolar components of the second half of the
      T wave can be linked to assessment of the transmural dispersion of
      repolarization.

PMID- 15030429
TI  - Electrical disconnection of the coronary sinus by radiofrequency catheter
      ablation to isolate a trigger of atrial fibrillation.
AB  - We report a case of radiofrequency catheter ablation for chronic atrial
      fibrillation, in which electrical disconnection of the coronary sinus was
      necessary to isolate a trigger initiating atrial fibrillation.

PMID- 15030430
TI  - Irregular narrow-QRS tachycardia: what is the mechanism?

PMID- 15030431
TI  - Arrhythmogenic right ventricular cardiomyopathy without fatty infiltration.

PMID- 15030433
TI  - Percutaneous left atrial appendage transcatheter occlusion: an effective and safe
      protection against stroke or embolism?

PMID- 15030435
TI  - Evolution of the implantable cardioverter defibrillator.

PMID- 15030437
TI  - Pedagogical underpinnings of computer-based learning.
AB  - BACKGROUND: E-learning is becoming increasingly incorporated into educational
      programmes. Digital materials usually require a lot of investment in terms of
      time, money and human resources. With advances in technology, delivery of content
      has much improved in terms of multimedia elements. However, often only low-level
      learning is achieved as a result of using these materials. AIM: The purpose of
      this article is to give a comprehensive overview of some of the most important
      issues to consider when incorporating e-learning into educational programmes.
      DISCUSSION: Computer-based learning has three components: hardware, software and
      'underware', the pedagogy that underpins its development. The latter is the most
      important, as the approach adopted will influence the creation of computer-based
      learning materials and determine the way in which students engage with subject
      matter. Teachers are responsible for the quality of their courses and have a
      vital role in helping to develop the most appropriate electronic learning
      activities that will facilitate students to acquire the knowledge and skills
      necessary for clinical practice. Therefore, they need to have an awareness of
      what contributes to educationally effective, computer-based learning materials.

PMID- 15030438
TI  - Patients with comorbidities: perceptions of acute care services.
AB  - BACKGROUND: Advances in medical science and improved lifestyles have reduced
      mortality rates in Australia and most Western countries. As a result, there is an
      ageing population with a concomitant growth in the number of people living with
      chronic illnesses. Indeed, a significant number of people will experience
      multiple chronic illnesses (comorbidities) and may require admission to hospital
      for acute care that is superimposed on their chronic illnesses. AIM: The aim of
      this study was to investigate perceptions of quality of care by patients
      experiencing comorbidities who required an acute hospital stay. METHOD: A
      qualitative descriptive design was adopted, informed by Colaizzi's
      phenomenological method. Single semi-structured interviews were conducted with 12
      patients within 14 days of being discharged home after an acute illness episode.
      FINDINGS: Data analysis revealed three themes: poor continuity of care for
      comorbidities, the inevitability of something going wrong during acute care and
      chronic conditions persisting after discharge. Combinations of chronic illnesses
      and treatments affected these patients' experiences of acute care and recovery
      postdischarge. Medicalized conceptualizations of comorbidity failed to capture
      the underlying health care needs of these patients. Limitations. No
      generalizations can be drawn because the findings and conclusions were derived
      from a purposive sample of patients who agreed to participate. CONCLUSION: These
      findings have implications for a comprehensive and co-ordinated approach to this
      group of patients, and inform the body of nursing knowledge about how patients
      with comorbidities experience nursing care.

PMID- 15030439
TI  - Older people with depression: pilot study.
AB  - BACKGROUND: Although a substantial number of studies have identified the
      prevalence of depression experienced by older adults living in the community and
      the factors that may precipitate this depression, few have focussed on depression
      in older people who attend day centres. Consequently, there is no literature
      suggesting how depression in this population may be psychologically managed.
      AIMS: The aim of this paper is to present the results of a pilot study
      investigating the incidence of depression in people attending a London Age
      Concern day centre, and its associations with perceptions of handicap,
      loneliness, social support networks, satisfaction with social support, and
      satisfaction with life. METHODS: A quasi-experimental, cross-sectional pilot
      study was conducted with attendees at a London Age Concern day centre between
      November 1998 and January 1999. The day centre manager selected a convenience
      sample of 24 of 156 participants. Inclusion criteria were that participants must
      attend the day centre regularly and be over or equal to 65 years of age. The
      exclusion criterion was known psychiatric illness. Participants were interviewed
      using the Geriatric Mental State-Automated Geriatric Examination for Computer
      Assisted Taxonomy, which identifies caseness of psychopathology and includes a
      loneliness subscale, and completed the Satisfaction with Life Scale, Social
      Support Questionnaire and London Handicap Scale. RESULTS: There was a higher
      level of depression in this day centre setting than that found in other community
      based studies. There were the expected significant associations between
      depression and loneliness, and depression and satisfaction with life. However,
      unexpectedly, there were no associations between depression and social support,
      or depression and handicap. CONCLUSIONS: The study has several limitations.
      However, the high level of depression and significant relationships between
      depression, loneliness and satisfaction with life may indicate that the social
      function of day centres is not meeting expectations. This suggests that there
      could be a role for community mental health nurses in offering psychosocial
      interventions to alleviate some of the distress experienced.

PMID- 15030440
TI  - How delivery ward staff exercise power over women in communication.
AB  - BACKGROUND: Power is a central element in all social interactions. In order to
      act appropriately in different care situations, it is important to understand the
      meaning of power. AIM: This paper reports a study whose aim was to describe
      delivery ward staff opinions about the exercise of power over women in
      communications. METHODS: Data were collected in 2000 using a questionnaire
      developed for the study with a convenience sample of 155 midwifery and nursing
      professionals in delivery wards in four Finnish hospitals. RESULTS: The results
      showed that in respondents' opinions they worked for women's good and aimed at
      relationships based on a sense of equality and individuality. Negative power was
      used in situations where women's well-being was threatened. The power used was
      verbal or non-verbal. CONCLUSIONS: The exercise of power is not only negative in
      nature. There are times, such as in life-threatening situations, when it is
      crucial that the professional takes control and makes decisions immediately, and
      in that sense exercises power.

PMID- 15030441
TI  - Socio-cultural influences on Chinese women's attendance for cervical screening.
AB  - BACKGROUND: Compared with other countries, Hong Kong has a relatively high rate
      of cervical cancer. Much of this morbidity should be avoidable with cervical
      screening, but uptake rates for screening in Hong Kong are low. In programmes to
      promote cervical screening attendance, it is essential that aspects of the socio
      cultural system be taken into account to provide appropriate preventive health
      strategies. AIM: This paper outlines an investigation of the cultural and social
      factors contributing to Chinese women's attendance for cervical screening.
      METHOD: A mixed methods design was employed, combining and comparing two data
      sets. The initial data set was drawn from 10 focus groups involving both screened
      and unscreened Chinese women (n = 54). The second data set was drawn from a total
      population of Hong Kong doctors, and involved face-to-face semi-structured
      interviews (n = 28). RESULTS: Thematic analysis of the data from women indicated
      that the social factors of cost, educational base, knowledge of risk, the social
      value of early detection and cultural issues such as modesty and embarrassment
      contributed to screening attendance. The doctors perceived a cultural tendency
      towards fatalism, as well as seeing the gender, interpersonal and
      interprofessional skills of the practitioner to be important in influencing
      levels of Chinese women's shyness and discomfort, and hence affecting attendance.
      The lay and practitioner data sets varied in the perceptions of women's pain,
      embarrassment and risk factors. CONCLUSION: Programmes providing services for
      Chinese women need to ensure that the philosophy of the staff and the approach
      and materials used are culturally relevant. Recommendations are that nurses
      equipped with relevant social and cultural knowledge of population groups should
      have a central role in health promotion and screening services.

PMID- 15030442
TI  - Reported pain after day surgery: a critical literature review.
AB  - BACKGROUND: Despite technological advancements in anaesthesia and analgesia,
      reported pain levels after day surgery remains high. Whilst it is unrealistic to
      expect no pain, the level that constitutes 'acceptable' pain remains unclear
      because of inconsistencies in reporting. These inconsistencies have resulted from
      different interpretations of what pain is and the use of different measurement
      tools. AIM: The aim of this paper is to report a study investigating any
      disparity in reported levels of pain following day surgery, within different
      specialties and in relation to specific operative procedures. METHOD: Nursing and
      health care papers published since 1983 were sought using the keywords:
      postoperative pain, postoperative complications, pain after day surgery, day
      surgery, ambulatory surgery, nursing, operation types, operative procedures,
      surgical procedures, descriptors of pain, pain intensity, verbal descriptor
      scale, numerical rating scale, visual analogue scale, validity, reliability,
      design, sample size, data collection methods and their various combinations.
      Databases searched were Medline, CINAHL, Nursing Collection, Embase, Healthstar,
      BMJ and several on-line Internet journals, specifically Ambulatory Surgery. The
      search was restricted to publications in the English language. Findings. Twenty
      four papers were identified. Inconsistencies in the reported intensity of pain
      are highlighted, in relation to different operative procedures and specialties.
      Data in the papers are based on different descriptors, measurement tools and data
      collection methods. In many cases, sample size, and validity and reliability can
      also be questioned. CONCLUSIONS: There is a disparity in reported levels of pain
      after day surgery. It is important that a unified day surgery pain measurement
      strategy is established, so that patients can be informed about the intensity of
      pain that they are likely to experience following specific procedures.

PMID- 15030444
TI  - Primary mental health workers in child and adolescent mental health services.
AB  - BACKGROUND: The interface between primary care and specialist services is
      increasingly seen as crucial in the effective management of child and adolescent
      mental health (CAMH) problems. In the United Kingdom, a new role of primary
      mental health worker (PMHW), has been established in order to achieve effective
      collaboration across the interface through the provision of clinical care in
      primary care settings and by improving the skills and confidence of primary care
      staff. However, little is known about the development of this innovative role in
      service contexts. Issues raised during the early stages of implementation may
      have important implications for the preparation and development of professionals
      who undertake the role. AIMS: The aim of this paper is to report on a study that
      examined key issues in implementation of the PMHW role in six health authorities
      in England. METHODS: Case study evaluation was conducted, using thematic analysis
      of 75 qualitative interviews with key stakeholders from different professions
      (e.g. PMHWs, general practitioners, health visitors, psychiatrists and service
      managers) and representing different sectors (primary care, specialist services
      and community child health services). FINDINGS: The study identified three models
      of organization (outreach, primary care-based and teams). Each was associated
      with different advantages and disadvantages in its effects on referral rates to
      specialist services and the development of effective working relationships with
      primary care providers. Problems associated with accommodation and effective
      integration of PMHWs with specialist services, and tensions caused by the two
      different roles that PMHWs could undertake (direct clinical care vs. consultation
      liaison) were common across all sites. CONCLUSIONS: The PMHW role is an important
      development that may go some way towards realizing the potential of primary care
      services in CAMH. The implementation of new roles and models of working in
      primary care is complex, but may be facilitated by effective planning with
      primary care providers, clear goals for staff, and a long-term perspective on
      service development.

PMID- 15030443
TI  - A systematic review to ascertain whether the standard needle is more effective
      than a longer or wider needle in reducing the incidence of local reaction in
      children receiving primary immunization.
AB  - CONTEXT: Millions of doses of vaccines are given to children within the United
      Kingdom (UK) each year, yet there is conflicting national guidance on the length
      of needle to use. Prefilled syringes come supplied with 25 Gauge 16 millimetres
      long needles. OBJECTIVES: A systematic review was completed to answer the
      clinical question of whether the standard needle is more effective than a longer
      and/or wider needle in reducing local reactions in children receiving primary
      immunizations. METHODS:  DATA SOURCES: A comprehensive search strategy, including
      searching of electronic databases, hand searching, reference/citation searching,
      contacting researchers in the field and searching for unpublished literature.
      STUDY SELECTION: Selection of studies was guided by the clinical question, the
      inclusion and exclusion criteria being applied by two people independently. Study
      quality assessment: An established quality checklist was used. Critical analysis
      of the quality of the components of the studies is included in the discussion.
      DATA EXTRACTION: Two people independently applied a data extraction form,
      designed for the study. RESULTS: (1). Rev Man (a Windows-based software package
      used by the Cochrane Collaboration) was used to perform a meta-analysis on the
      binary results of two small studies using Relative Risk as the summary statistic
      16 mm vs. 25 mm needle. (2). The pooled Relative Risk for redness was 2.52 [95%
      confidence interval (CI) fixed 1.70-3.72] P < 0.00001. (3). The pooled Relative
      Risk for swelling was 2.31 (95% CI fixed 1.55-3.43) P < 0.00003. CONCLUSION: (1).
      The results are statistically very highly significant and favour the use of the
      25 millimetre long needle. (2). No studies were identified to separate the effect
      of the gauge of the needle used, but the discussion shows that needle length is
      the most important variable. (3). The results should be incorporated into any
      future guidelines on vaccine administration in the UK.

PMID- 15030445
TI  - A community survey of loneliness.
AB  - BACKGROUND: Loneliness is associated with an increased incidence of a wide range
      of physical and mental health problems. The detection, prevention and
      amelioration of loneliness is an important public health issue for nurses.
      METHODS: This study reports findings from the 2002 Central Queensland Social
      Survey. The aims of the study were to (i). establish the extent of loneliness in
      a community sample; and (ii). to identify the factors that are predictors of
      loneliness. A random sample of 1241 subjects were interviewed by Computer
      Assisted Telephone Interviewing. This interview included the Loneliness Scale
      formulated by De Jong Gierveld and Kamphuis. FINDINGS: Loneliness is a common
      phenomenon and risk factors include experience of domestic violence in current
      relationship, not having recent paid employment, not being married/partnered, and
      the number of children under 18 years in a household. Loneliness is not
      associated with higher rates of health care professional consultations.
      CONCLUSION: Loneliness is a very common problem and should be seen as a major
      public health issue. Nurses, through a community capacity building framework,
      have a major role to play in the prevention of loneliness.

PMID- 15030446
TI  - Practical application of the Delphi technique in a bicultural mental health
      nursing study in New Zealand.
AB  - BACKGROUND: Numerous studies have employed the Delphi technique to seek expert
      opinion about aspects of clinical practice. When researching literature on the
      Delphi technique, however, we discovered discrepancies in its application, and a
      lack of detail when reporting design, administration, and analysis methods. Such
      lack of specificity hinders the replicability and assessment of the clinical and
      cultural validity and reliability of Delphi studies. AIM: The aim of this paper
      is to detail the practical application of the Delphi technique as a culturally
      and clinically valid means of accessing expert opinion on the importance of
      clinical criteria. METHODS: Reference is made to a bicultural New Zealand mental
      health nursing clinical indicator study that employed a three-round reactive
      Delphi survey. Equal proportions of Maori and non-Maori nurses (n = 20) and
      consumers (n = 10) rated the importance of 91 clinical indicator statements for
      the achievement of professional practice standards. Additional statements (n =
      21) suggested by Delphi participants in round 1 were included in subsequent
      rounds. In round 2, participants explained the rating they applied to statements
      that had not reached consensus in round 1, and summarized responses were provided
      to participants in round 3. Consensus was considered to have been achieved if 85%
      of round 3 ratings lay within a 2-point bracket on the 5-point Likert-scale
      overall, or in one of the Maori nurse, non-Maori nurse, or consumer groups. A
      mean rating of 4.5 after round 3 was set as the importance threshold. FINDINGS:
      Consensus occurred overall on 75 statements, and within groups on another 24.
      Most statements (n = 86) reached the importance benchmark. CONCLUSIONS: When
      rigorous methods of participant selection, group composition, participant
      feedback, and determination of consensus and importance are employed, the Delphi
      technique is a reliable, cost-effective means of obtaining and prioritizing
      experts judgements.

PMID- 15030447
TI  - Nurses and difficult patients: negotiating non-compliance.

PMID- 15030452
TI  - The physician scientist: an endangered breed?

PMID- 15030453
TI  - Should we think before we treat delirium?

PMID- 15030454
TI  - Systematic genome-wide approach to positional candidate cloning for
      identification of novel human disease genes.
AB  - BACKGROUND: Recent large-scale genome projects afford a unique opportunity to
      identify many novel disease genes and thereby better understand the genetic basis
      of human disease. Functional Annotation of Mouse (FANTOM) 2, the largest mouse
      transcriptome project yet, provides a wealth of data on novel genes, splice
      variants and non-coding RNA, and provides a unique opportunity to identify novel
      human disease genes. AIMS: To demonstrate the power of combining the FANTOM 2
      cDNA dataset with a positional candidate approach and bioinformatics analysis to
      identify genes underlying human genetic disease. RESULTS: By mapping all FANTOM 2
      cDNA to the human genome, we were able to identify mouse clones that co-localised
      on the human genome with mapped but uncloned human disease loci. By this method
      we identified mouse and corresponding human genes mapping within the loci of 100
      different human genetic diseases (mapped interval of <5 cM). Of particular
      interest was the elucidation through FANTOM 2 novel mouse gene data of candidate
      human genes for the following: (i) developmental -disorders: neural tube defect,
      Meckel syndrome, Wolf--Hirschhorn syndrome and keratosis follicularis spinulosa
      decalvans cum ophiasi; (ii) neurological disorders: benign familial infantile
      convulsions 3, early-onset cerebellar ataxia with retained tendon reflexes,
      infantile-onset spinocerebellar ataxia and vacuolar neuro-myopathy and (iii)
      cancer-related syndromes: tylosis with oesophageal cancer and low-grade B-cell
      chronic lymphatic leukaemia. CONCLUSIONS: The FANTOM 2 data will dramatically
      accelerate efforts to identify genes underlying human disease. It will also
      facilitate the creation of transgenic mouse models to help elucidate the function
      of potential human disease genes.

PMID- 15030455
TI  - Community-acquired pneumonia: influence of management practices on length of
      hospital stay.
AB  - AIMS: To identify variation in the management of -community-acquired pneumonia
      between two New Zealand hospitals and the factors that may account for any
      differences. METHODS: A 12-month, prospective two-centre study was conducted.
      Between July 1999 and July 2000, 474 adult patients with community-acquired
      pneumonia were enrolled: 304 in Christchurch Hospital and 170 in Waikato
      Hospital. The patients were similar in age, sex, prior antibiotic use and
      comorbidity. There was no significant difference in the clinical outcomes for the
      patients at the two centres. RESULTS: The mean duration of i.v. antibiotic
      therapy was 1.7 versus 3.0 days (P < 0.001) and length of stay (LOS) was 3.0
      versus 5.9 days (P < 0.001) for Waikato and Christchurch Hospitals, respectively.
      Using multivariate analysis, we could account for 61% of the observed variation
      in LOS. Duration of i.v. antibiotic therapy independently accounted for 16% of
      variation in LOS compared with age (2%), chronic obstructive pulmonary disease,
      duration of fever, intensive care unit admission and centre of admission (all
      <1%). For the duration of i.v. antibiotics, centre of admission, largely
      reflecting clinician practice at each centre, independently accounted for 13% of
      variation, compared with duration of fever (5%), admission to the Intensive Care
      Unit (4%), Pneumonia Severity Index score (3%) and bacteraemia (3%). CONCLUSION:
      Of the identifiable factors, variations in clinician behaviour outweighed the
      influence of patient factors on the duration of i.v. antibiotic therapy, which in
      turn was the major determinant of LOS for patients hospitalised with community
      acquired pneumonia. An early switch from i.v. to oral antibiotic therapy in
      conjunction with early discharge planning may significantly reduce LOS without
      compromising patient outcomes.

PMID- 15030456
TI  - Oral versus intravenous ganciclovir for the prophylaxis of cytomegalovirus
      disease after allogeneic bone marrow transplantation.
AB  - BACKGROUND: Prophylactic low dose i.v. ganciclovir in patients at risk after
      allogeneic bone marrow transplantation (BMT) is highly effective in the
      prevention of cytomegalovirus (CMV) disease and infection. AIM: In this study, we
      sought to assess the tolerability of oral ganciclovir in patients after
      allogeneic BMT. METHODS: CMV seropositive patients or those with CMV seropositive
      donors were randomised to be treated with i.v. ganciclovir 5 mg/kg three times
      weekly or oral ganciclovir 3 g daily from engraftment to day 84. The period of
      accrual was from May 1997 to October 1998. Patients were monitored for CMV
      infection by weekly serology. Thirty-one patients received oral ganciclovir and
      27 patients received i.v. ganciclovir, the treatment groups being balanced for
      clinical characteristics and prognostic factors. RESULTS: Renal dysfunction,
      transfusion requirements and significant nausea and vomiting were not different.
      There were no documented cases of CMV disease during the study period although
      three patients developed CMV polymerase chain reaction positivity at various
      times. One patient treated with i.v. ganciclovir developed non-fatal
      gastrointestinal CMV disease after the study period on day 108. Eight patients in
      the oral group failed to complete planned therapy, whereas two patients failed to
      complete the i.v. course. CONCLUSION: We conclude that oral ganciclovir is a
      reasonable, well-tolerated alternative to i.v. ganciclovir for the prophylaxis of
      CMV disease after allogeneic BMT.

PMID- 15030457
TI  - Prevention of falls and fall-related fractures in community-dwelling older
      adults: a meta-analysis of estimates of effectiveness based on recent guidelines.
AB  - BACKGROUND: Two recent falls prevention guidelines have been published but did
      not include quantitative estimates of effectiveness based on the published
      reports that were reviewed to support their recommendations. AIM: To produce
      quantitative estimates of effectiveness of falls prevention programs from the
      randomised controlled trials cited in the guidelines together with an updated
      search of the available published reports to August 2002. METHODS: A meta
      analysis of randomised controlled trials cited in falls guidelines and studies
      identified by an updated search of the available published reports was carried
      out. Randomised controlled trials were identified from the falls guidelines and a
      search, which met the following criteria: trials in community-dwelling older
      people; 1-year follow up; and outcome measures reported as the number of subjects
      with at least one fall or the number of subjects with a fracture. RESULTS: The
      guidelines identified four studies of 'exercise as a sole intervention', which
      when combined with one further study identified in a search of the published
      reports, gave a fixed effects odds ratio (OR) favouring this strategy of 0.81
      (95% confidence interval (CI) 0.58-1.14); the number of patients needed to be
      treated to prevent one person having a fall was 19.5. The guidelines identified
      seven studies of a 'multiple intervention' strategy that gave a random effects OR
      favouring this strategy of 0.64 (95% CI 0.47-0.88). Four further studies were
      identified by the search of the published reports. The updated OR favouring this
      intervention strategy was 0.65 (95% CI 0.52-0.81); the number of patients needed
      to be treated to prevent one person having a fall was 9.8. Only two studies had
      data for fracture and a fixed effects OR favouring falls interventions for
      fracture prevention was 0.50 (95% CI 0.18-1.40); the number of patients needed to
      be treated to prevent one person having a fracture was 45.5. CONCLUSION:
      Semiquantitative statements of evidence can both understate and overstate the
      effectiveness of falls prevention strategies. There is moderate evidence of
      efficacy for falls prevention particularly for multiple intervention strategies.

PMID- 15030458
TI  - Postmenopausal hormone therapy: the pros and cons.
AB  - The use of postmenopausal hormone therapy (HT) has recently generated much debate
      following the results of various large randomised controlled trials. This has
      challenged physicians to reassess the use of HT in each individual woman within
      the realm of her symptomatology and risk profile for long-term illnesses. There
      are several areas of definite benefit or risk and many areas of uncertainty. The
      results of recent randomised controlled trials pertain to the specific HT
      regimens used and the characteristics of the study groups, such that the
      conclusions cannot be extrapolated to the use of HT in general.

PMID- 15030459
TI  - Delirium: current trends in prevention and treatment.
AB  - Delirium is a disturbance of consciousness, cognition and perception that occurs
      frequently in medically ill patients. Although it is associated with increased
      morbidity and mortality, it is often not recognised and treated by physicians.
      Predisposing factors are believed to have multiplicative effects and include
      dementia, advanced age and male gender. Recently developed models allow for the
      estimation of the risk of developing delirium during a hospitalisation, based on
      predisposing factors and acute additional stressors. Although it has been shown
      to be efficacious, the prevention of delirium is underutilised. Prevention
      consists of aggressive management of known risk factors and early detection.
      Limited data exist to support specific pharmacological interventions for its
      treatment. In this article, the avail-able published literature regarding the
      prevention and treatment of delirium is systematically reviewed.

PMID- 15030460
TI  - Genetic testing: a round table conversation. Part II.

PMID- 15030462
TI  - Secondary prevention of fractures in older people: evaluation of a protocol for
      the investigation and treatment of osteoporosis.
AB  - It has been found previously that the investigation and treatment of osteoporosis
      following a fracture is poor, with only 9% of older people after a fracture being
      on effective osteoporosis treatment. To improve this aspect of post-fracture care
      in older people, a protocol has been instituted on an orthogeriatric
      rehabilitation ward in Christchurch, New Zealand. An audit was performed to
      assess the efficacy of this protocol in improving the investigation and treatment
      of osteoporosis (n = 193). Compliance with the investigation protocol was
      assessed and the pharmacological therapy initiated was requested from the general
      practitioner. All recommended blood-test investigations were requested in 62.8%
      of cases. Compared to a pre-protocol population, there was a marked increase in
      the measurement of bone mineral density (BMD; 93 vs 11%, P < 0.01) and vitamin D
      (95 vs 12%, P < 0.01). Vitamin D levels were low/-borderline in 95.6% of cases.
      BMD was performed in 77.7% of cases and showed osteoporosis and osteopenia to be
      present in 78.6 and 14.0%, respectively. For the 60 patients with BMD-confirmed
      osteoporosis whose therapy was obtained, 13.3% had no pharmacological therapy
      prescribed. Calcium, vitamin D or both were prescribed in 85.0%, bisphosphonates
      in 50.0% and hormone replacement therapy in 1.7% of patients. Vitamin D
      deficiency and osteoporosis on the basis of the BMD result are very common. The
      institution of a protocol has shown a significant improvement in the management
      of osteoporosis following a fracture. Some of the multifactorial barriers to full
      implementation of the guidelines are described.

PMID- 15030461
TI  - Cytokine gene polymorphisms in idiopathic pulmonary fibrosis.
AB  - Pro- and anti-fibrotic cytokine gene polymorphisms may affect expression of
      idiopathic pulmonary fibrosis (IPF). The aims of the present case-control study
      were to examine polymorphisms in the IL-6, transforming growth factor (TGF)-beta
      1, tumour necrosis factor (TNF)-alpha and interleukin-1 (IL-1)Ra genes in
      patients with IPF (n = 22) -compared to healthy controls (n = 140). Genotyping
      was performed on DNA extracted from peripheral blood lymphocytes, using
      polymerase chain reaction - restriction fragment length polymorphism with gene
      polymorphisms determined according to -published techniques. The following sites
      were examined: (i) IL-1Ra*1-5 (86 bp variable tandem repeat intron 2), (ii) IL-6
      (-174G > C), (iii) TNF-alpha (-308G > A) and (iv) TGF-beta 1 (Arg25Pro). The TNF
      alpha (-308 A) allele was over-represented in the IPF (p(corr) = 0.004) group
      compared to controls. Risk of IPF was significant for heterozygotes for: (i) the
      TNF-alpha (-308 A) allele (A/G) (odds ratio (OR) 2.9; 95% confidence interval
      (CI) 1.2-7.2; P = 0.02), (ii) homozygotes (A/A) (OR 13.9; 95%CI 1.2-160; P =
      0.04) and (iii) carriage of the allele (A/A + A/G) (OR 4; 95%CI 1.6-10.2; P =
      0.003). The distribution of alleles and genotypes for IL-6, TGF-beta 1 and IL-1Ra
      between the two groups was not significantly different. This is the third study
      to independently confirm that there is a significant association of the TNF-alpha
      (-308 A) allele with IPF. Further research is needed to assess the utility of
      cytokine gene polymorphisms as markers of disease -susceptibility.

PMID- 15030463
TI  - Recurrence of Helicobacter pylori infection in adults with intellectual
      disability.
AB  - Although Helicobacter pylori infection is very common among particular groups of
      adults with intellectual disability, the rate of recurrence (reinfection or
      recrudescence) is unknown in this population. Thirty-six months after successful
      treatment of H. pylori, 28 adults with intellectual disability were retested
      using the faecal antigen test. Six (21%) of 28 patients tested positive, giving
      an approximate yearly recurrence rate of 7%, a rate considerably higher than that
      in the general population (<1%). It is recommended that adults with intellectual
      disability who have had successful treatment of H. pylori be retested for an
      interval of 3-5 years after treatment.

PMID- 15030464
TI  - Seroquel, Serzone and seizures.

PMID- 15030466
TI  - Thoracic spinal cord compression by a rheumatoid nodule.

PMID- 15030465
TI  - Intracardiac thrombosis complicating antiphospholipid antibody syndrome.

PMID- 15030467
TI  - Giant cell arteritis, scalp necrosis and myocardial infarction.

PMID- 15030468
TI  - End-stage dementia: why treat at all?

PMID- 15030469
TI  - Highly active antiretroviral therapy: a misnomer in HIV/AIDS terminology.

PMID- 15030471
TI  - Medical graduates and scientific research in Australia: a personal reflection.

PMID- 15030472
TI  - Abstracts of the combined annual scientific meeting of the Australasian Sleep
      Association and the Australasian Sleep Technologists Association. Auckland, New
      Zealand, 10-12 October 2003.

PMID- 15030473
TI  - Collectins: players of the innate immune system.
AB  - Collectins are a family of collagenous calcium-dependent defense lectins in
      animals. Their polypeptide chains consist of four regions: a cysteine-rich N
      terminal domain, a collagen-like region, an alpha-helical coiled-coil neck domain
      and a C-terminal lectin or carbohydrate-recognition domain. These polypeptide
      chains form trimers that may assemble into larger oligomers. The best studied
      family members are the mannan-binding lectin, which is secreted into the blood by
      the liver, and the surfactant proteins A and D, which are secreted into the
      pulmonary alveolar and airway lining fluid. The collectins represent an important
      group of pattern recognition molecules, which bind to oligosaccharide structures
      and/or lipid moities on the surface of microorganisms. They bind preferentially
      to monosaccharide units of the mannose type, which present two vicinal hydroxyl
      groups in an equatorial position. High-affinity interactions between collectins
      and microorganisms depend, on the one hand, on the high density of the
      carbohydrate ligands on the microbial surface, and on the other, on the degree of
      oligomerization of the collectin. Apart from binding to microorganisms, the
      collectins can interact with receptors on host cells. Binding of collectins to
      microorganisms may facilitate microbial clearance through aggregation, complement
      activation, opsonization and activation of phagocytosis, and inhibition of
      microbial growth. In addition, the collectins can modulate inflammatory and
      allergic responses, affect apoptotic cell clearance and modulate the adaptive
      immune system.

PMID- 15030474
TI  - Point mutations associated with insecticide resistance in the Drosophila
      cytochrome P450 Cyp6a2 enable DDT metabolism.
AB  - Three point mutations R335S, L336V and V476L, distinguish the sequence of a
      cytochrome P450 CYP6A2 variant assumed to be responsible for 1,1,1-trichloro-2,2
      bis-(4'-chlorophenyl)ethane (DDT) resistance in the RDDT(R) strain of Drosophila
      melanogaster. To determine the impact of each mutation on the function of CYP6A2,
      the wild-type enzyme (CYP6A2wt) of Cyp6a2 was expressed in Escherichia coli as
      well as three variants carrying a single mutation, the double mutant CYP6A2vSV
      and the triple mutant CYP6A2vSVL. All CYP6A2 variants were less stable than the
      CYP6A2wt protein. Two activities enhanced in the RDDT(R) strain were measured
      with all recombinant proteins, namely testosterone hydroxylation and DDT
      metabolism. Testosterone was hydroxylated at the 2beta position with little
      quantitative variation among the variants. In contrast, metabolism of DDT was
      strongly affected by the mutations. The CYP6A2vSVL enzyme had an enhanced
      metabolism of DDT, producing dicofol, dichlorodiphenyldichloroethane and
      dichlorodiphenyl acetic acid. The apparent affinity of the enzymes CYP6A2wt and
      CYP6A2vSVL for DDT and testosterone was not significantly different as revealed
      by the type I difference spectra. Sequence alignments with CYP102A1 provided
      clues to the positions of the amino acids mutated in CYP6A2. These mutations were
      found spatially clustered in the vicinity of the distal end of helix I relative
      to the substrate recognition valley. Thus this area, including helix J, is
      important for the structure and activity of CYP6A2. Furthermore, we show here
      that point mutations in a cytochrome P450 can have a prominent role in
      insecticide resistance.

PMID- 15030475
TI  - The C-terminal domain of Escherichia coli Hfq increases the stability of the
      hexamer.
AB  - The Hfq (Host factor 1) polypeptide is a nucleic acid binding protein involved in
      the synthesis of many polypeptides. Hfq particularly affects the translation and
      the stability of several RNAs. In an earlier study, the use of fold recognition
      methods allowed us to detect a relationship between Escherichia coli Hfq and the
      Sm topology. This topology was further validated by a series of biophysical
      studies and the Hfq structure was modelled on an Sm protein. Hfq forms a beta
      sheet ring-shaped hexamer. As our previous study predicted a large number of
      alternative conformations for the C-terminal region, we have determined whether
      the last 19 C-terminal residues are necessary for protein function. We find that
      the C-terminal truncated protein is fully capable of binding a polyadenylated RNA
      (K(d) of 120 pm vs. 50 pm for full-length Hfq). This result shows that the
      functional core of E. coli Hfq resides in residues 1-70 and confirms previous
      genetic studies. Using equilibrium unfolding studies, however, we find that full
      length Hfq is 1.8 kcal x mol(-1) more stable than its truncated variant. Electron
      microscopy analysis of both truncated and full-length proteins indicates a
      structural rearrangement between the subunits upon truncation. This
      conformational change is coupled to a reduction in beta-strand content, as
      determined by Fourier transform infra-red. On the basis of these results, we
      propose that the C-terminal domain could protect the interface between the
      subunits and stabilize the hexameric Hfq structure. The origin of this C-terminal
      domain is also discussed.

PMID- 15030476
TI  - Heterogeneity of homologously expressed Hypocrea jecorina (Trichoderma reesei)
      Cel7B catalytic module.
AB  - The catalytic module of Hypocrea jecorina (previously Trichoderma reesei) Cel7B
      was homologously expressed by transformation of strain QM9414. Post-translational
      modifications in purified Cel7B preparations were analysed by enzymatic
      digestions, high performance chromatography, mass spectrometry and site-directed
      mutagenesis. Of the five potential sites found in the wild-type enzyme, only
      Asn56 and Asn182 were found to be N-glycosylated. GlcNAc(2)Man(5) was identified
      as the predominant N-glycan, although lesser amounts of GlcNAc(2)Man(7) and
      glycans carrying a mannophosphodiester bond were also detected. Repartition of
      neutral and charged glycan structures over the two glycosylation sites mainly
      accounts for the observed microheterogeneity of the protein. However, partial
      deamidation of Asn259 and a partially occupied O-glycosylation site give rise to
      further complexity in enzyme preparations.

PMID- 15030477
TI  - New activities of a catalytic antibody with a peroxidase activity: formation of
      Fe(II)-RNO complexes and stereoselective oxidation of sulfides.
AB  - In order to estimate the size of the cavity remaining around the heme of the 3A3
      microperoxidase 8 (MP8) hemoabzyme, the formation of 3A3-MP8-Fe(II)-nitrosoalkane
      complexes upon oxidation of N-monosubstituted hydroxylamines was examined. This
      constituted a new reaction for hemoabzymes and is the first example of fully
      characterized Fe(II)-metabolite complexes of antibody-porphyrin. Also, via a
      comparison of the reactions with N-substituted hydroxylamines of various size and
      hydrophobicity, antibody 3A3 was confirmed to bring about a partial steric
      hindrance on the distal face of MP8. Subsequently, the influence of the antibody
      on the stereoselectivity of the S-oxidation of sulfides was examined. Our results
      showed that MP8 alone and the antibody-MP8 complex catalyze the oxidation of
      thioanisole by H(2)O(2) and tert-butyl hydroperoxide, following a peroxidase-like
      two-step oxygen-transfer mechanism involving a radical-cation intermediate. The
      best system, associating H(2)O(2) as oxidant and 3A3-MP8 as a catalyst, in the
      presence of 5% tert-butyl alcohol, led to the stereoselective S-oxidation of
      thioanisole with a 45% enantiomeric excess in favour of the R isomer. This
      constitutes the highest enantiomeric excess reported to date for the oxidation of
      sulfides catalyzed by hemoabzymes.

PMID- 15030478
TI  - SUT2 is a novel multicopy suppressor of low activity of the cAMP/protein kinase A
      pathway in yeast.
AB  - SUT2 was found in a screen for multicopy suppressors of the synthetic slow growth
      phenotype of a Deltaras2Deltagpa2 double deletion mutant. It failed, however, to
      cure the lethal phenotype of a Deltaras1Deltaras2 mutant suggesting that it acts
      upstream of Ras or in a parallel pathway. By testing cAMP-dependent reactions
      including the accumulation of storage carbohydrates, pseudohyphal
      differentiation, entry of meiosis as well as the measurement of FLO11 reporter
      activity we show that Sut2p modulates the activity of protein kinase A (PKA).
      Additionally, we demonstrate that cellular levels of Ras2p are affected by Sut2p
      and that Sut2-GFPp accumulates significantly in the nucleus. Based on the
      observed influence of high SUT2 gene dosage on PKA activity as well as Sut2p's
      homology to the presumptive transcription factor Sut1p, we suggest that Sut2p
      contributes to regulation of PKA activity at the level of transcription.

PMID- 15030479
TI  - Disruption of the interaction between the Rieske iron-sulfur protein and
      cytochrome b in the yeast bc1 complex owing to a human disease-associated
      mutation within cytochrome b.
AB  - The mitochondrial cytochrome b missense mutation, G167E, has been reported in a
      patient with cardiomyopathy. The residue G167 is located in an extramembranous
      helix close to the hinge region of the iron-sulfur protein. In order to
      characterize the effects of the mutation on the structure and function of the
      bc(1) complex, we introduced G167E into the highly similar yeast cytochrome b.
      The mutation had a severe effect on the respiratory function, with the activity
      of the bc(1) complex decreased to a few per cent of the wild type. Analysis of
      the enzyme activity indicated that the mutation affected its stability, which
      could be the result of an altered binding of the iron-sulfur protein on the
      complex. G167E had no major effect on the interaction between the iron-sulfur
      protein headgroup and the quinol oxidation site, as judged by the electron
      paramagnetic resonance signal, and only a minor effect on the rate of cytochrome
      b reduction, but it severely reduced the rate of cytochrome c(1) reduction. This
      suggested that the mutation G167E could hinder the movement of the iron-sulfur
      protein, probably by distorting the structure of the hinge region. The function
      of bc(1) was partially restored by mutations (W164L and W166L) located close to
      the primary change, which reduced the steric hindrance caused by G167E. Taken
      together, these observations suggest that the protein-protein interaction between
      the n-sulfur protein hinge region and the cytochrome b extramembranous cd2 helix
      is important for maintaining the structure of the hinge region and, by
      consequence, the movement of the headgroup and the integrity of the enzyme.

PMID- 15030480
TI  - Escherichia coli thioredoxin inhibition by cadmium: two mutually exclusive
      binding sites involving Cys32 and Asp26.
AB  - Observations of thioredoxin inhibition by cadmium and of a positive role for
      thioredoxin in protection from Cd(2+) led us to investigate the thioredoxin
      cadmium interaction properties. We used calorimetric and spectroscopic methods at
      different pH values to explore the relative contribution of putative binding
      residues (Cys32, Cys35, Trp28, Trp31 and Asp26) within or near the active site.
      At pH 8 or 7.5 two binding sites were identified by isothermal titration
      calorimetry with affinity constants of 10 x 10(6) m(-1) and 1 x 10(6) m(-1). For
      both sites, a proton was released upon Cd(2+) binding. One mole of Cd(2+) per
      mole of reduced thioredoxin was measured by mass spectrometry at these pH values,
      demonstrating that the two binding sites were partially occupied and mutually
      exclusive. Cd(2+) binding at either site totally inhibited the thiol-disulfide
      transferase activity of Trx. The absence of Cd(2+) interaction detected for
      oxidized or alkylated Trx and the inhibition of the enzymatic activity of
      thioredoxin by Cd(2+) supported the role of Cys32 at the first site. The
      fluorescence profile of Cd(2+)-bound thioredoxin differed, however, from that of
      oxidized thioredoxin, indicating that Cd(2+) was not coordinated with Cys32 and
      Cys35. From FTIR spectroscopy, we inferred that the second site might involve
      Asp26, a buried residue that deprotonates at a rather high and unusual pK(a) for
      a carboxylate (7.5/9.2). The pK(a) of the two residues Cys32 and Asp26 have been
      shown to be interdependent [Chivers, T. P. (1997) Biochemistry36, 14985-14991]. A
      mechanism is proposed in which Cd(2+) binding at the solvent-accessible thiolate
      group of Cys32 induces a decrease of the pK(a) of Asp26 and its deprotonation.
      Conversely, interaction between the carboxylate group of Asp26 and Cd(2+) at a
      second binding site induces Cys32 deprotonation and thioredoxin inhibition, so
      that Cd(2+) inhibits thioredoxin activity not only by binding at the Cys32 but
      also by interacting with Asp26.

PMID- 15030481
TI  - Characterization of Mesorhizobium huakuii lipid A containing both D-galacturonic
      acid and phosphate residues.
AB  - The chemical structure of the free lipid A isolated from Mesorhizobium huakuii
      IFO 15243(T) was elucidated. Lipid A is a mixture of at least six species of
      molecules whose structures differ both in the phosphorylation of sugar backbone
      and in fatty acylation. The backbone consists of a beta (1'-->6) linked 2,3
      diamino-2,3-dideoxyglucose (DAG) disaccharide that is partly substituted by
      phosphate at position 4'. The aglycon of the DAG-disaccharide has been identified
      as alpha-D-galacturonic acid. All lipid A species carry four amide-linked 3
      hydroxyl fatty residues. Two of them have short hydrocarbon chains (i.e. 3-OH-i
      13:0) while the other two have longer ones (i.e. 3-OH-20:0). Distribution of 3
      hydroxyl fatty acids between the reducing and nonreducing DAG is symmetrical. The
      nonpolar as well as (omega-1) hydroxyl long chain fatty acids are components of
      acyloxyacyl moieties. Two acyloxyacyl residues occur exclusively in the
      nonreducing moiety of the sugar backbone but their distribution has not been
      established yet. The distal DAG amide-bound fatty acid hydroxyls are not
      stoichiometrically substituted by ester-linked acyl components.

PMID- 15030482
TI  - Chemical foundation of the attenuation of methylmercury(II) cytotoxicity by
      metallothioneins.
AB  - To elucidate the chemical interactions underlying the role of metallothioneins
      (MTs) in reducing the cytotoxicity caused by MeHg(II), we monitored in parallel
      by electronic absorption and CD spectroscopies the stepwise addition of MeHgCl
      stock solution to mammalian Zn(7)-MT1 and the isolated Zn(4)-alphaMT1 and Zn(3)
      betaMT1 fragments. The incorporation of MeHg(+) into Zn(7)-MT and Zn(3)-betaMT
      entails total displacement of Zn(II) and unfolding of the protein. However, both
      features are only partial for Zn(4)-alphaMT. The different behavior observed for
      this fragment, whether isolated or constituting one of the two domains of Zn(7)
      MT, indicates interdomain interactions in the whole protein. Overall, the binding
      properties of Zn(7)-MT, Zn(4)-alphaMT and Zn(3)-betaMT toward MeHg(+) are
      unprecedented. In addition, the sequestration of MeHg(+) by Zn(7)-MT and the
      concomitant release of Zn(II) are probably two of the main contributions in the
      detoxifying role of mammalian MT.

PMID- 15030483
TI  - Direct electrochemistry of the Desulfovibrio gigas aldehyde oxidoreductase.
AB  - This work reports on the direct electrochemistry of the Desulfovibrio gigas
      aldehyde oxidoreductase (DgAOR), a molybdenum enzyme of the xanthine oxidase
      family that contains three redox-active cofactors: two [2Fe-2S] centers and a
      molybdopterin cytosine dinucleotide cofactor. The voltammetric behavior of the
      enzyme was analyzed at gold and carbon (pyrolytic graphite and glassy carbon)
      electrodes. Two different strategies were used: one with the molecules confined
      to the electrode surface and a second with DgAOR in solution. In all of the cases
      studied, electron transfer took place, although different redox reactions were
      responsible for the voltammetric signal. From a thorough analysis of the
      voltammetric responses and the structural properties of the molecular surface of
      DgAOR, the redox reaction at the carbon electrodes could be assigned to the
      reduction of the more exposed iron cluster, [2Fe-2S] II, whereas reduction of the
      molybdopterin cofactor occurs at the gold electrode. Voltammetric results in the
      presence of aldehydes are also reported and discussed.

PMID- 15030484
TI  - Induction of endothelial apoptosis by 4-hydroxyhexenal.
AB  - Lipid peroxidation and its products such as 4-hydroxy-2-nonenal (HNE) and 4
      hydroxyhexenal (HHE) are known to affect redox balance during aging and various
      degenerative processes, including vascular dysfunction. Deterioration of the
      endothelial cells that line the vascular wall is known to be an underlying cause
      of vascular dysfunction. At present, little is known about the mechanism by which
      HHE induces endothelial cell death (i.e. apoptosis), although HNE-induced
      apoptotic cell death has been reported. The aim of this study was to determine
      whether apoptosis induced by HHE in endothelial cells involves peroxynitrite
      (ONOO(-)). Our results show that in endothelial cells HHE triggers apoptotic cell
      death by inducing apoptotic Bax coupled with a decrease in anti-apoptotic Bcl-2.
      Results show that HHE induces reactive oxygen species (ROS), nitric oxide, and
      ONOO(-) generation, leading to redox imbalance. Furthermore, the antioxidant N
      acetyl cysteine, ROS scavenger, and penicillamine, an ONOO(-) scavenger, were
      found to block HHE-mediated apoptosis. We used confocal laser microscopy to
      estimate the ability of these inhibitors to attenuate HHE-induced intracellular
      ONOO(-) levels thus confirming the oxidative mediation of apoptosis in
      endothelial cells. These findings strongly suggest that accumulated HHE triggers
      reactive species-mediated endothelial apoptosis, leading to vascular dysfunction
      as well as vascular aging. During aging, increased lipid peroxidation and its
      associated production of HHE may exacerbate the weakened redox balance, leading
      to various chronic degenerative processes including vascular dysfunction.

PMID- 15030485
TI  - Neutral N-glycans of the gastropod Arion lusitanicus.
AB  - The neutral N-glycan structures of Arion lusitanicus (gastropod) skin, viscera
      and egg glycoproteins were examined after proteolytic digestion, release of the
      glycans from the peptides, fluorescent labelling with 2-aminopyridine and
      fractionation by charge, size and hydrophobicity to obtain pure glycan
      structures. The positions and linkages of the sugars in the glycan were analysed
      by two dimensional HPLC (size and hydrophobicity) and MALDI-TOF mass spectrometry
      before and after digestion with specific exoglycosidases. The most striking
      feature in the adult tissues was the high amount of oligomannosidic and small
      paucimannosidic glycans terminated with 3-O-methylated mannoses. The truncated
      structures often contained modifications of the inner core by beta1,2-linked
      xylose to the beta-mannose residue and/or an alpha-fucosylation (mainly alpha1,6
      ) of the innermost GlcNAc residue. Skin and viscera showed predominantly the same
      glycans, however, in different amounts. Traces of large structures carrying 3-O
      methylated galactoses were also detected. The egg glycans contained mainly
      (approximately 75%) oligomannosidic structures and some paucimannosidic
      structures modified by xylose or alpha1,6-fucose, but in this case no methylation
      of any monosaccharide was detected. Thus, gastropods seem to be capable of
      producing many types of structures ranging from those typical in human to
      structures similar to those found in nematodes, and therefore will be a valuable
      model to understand the regulation of glycosylation. Furthermore, this opens the
      way for using this organism as a host for the production of recombinant proteins.
      The detailed knowledge on glycosylation also may help to identify targets for
      pest control.

PMID- 15030486
TI  - Jackbean, soybean and Bacillus pasteurii ureases: biological effects unrelated to
      ureolytic activity.
AB  - In this work we compared two plant ureases, jackbean urease (JBU) and embryo
      specific soybean urease (SBU) and a bacterial (Bacillus pasteurii) urease, for
      kinetic parameters and other biological properties described recently for ureases
      that are independent of the ureolytic activity. The insecticidal effect of
      ureases was investigated in feeding trials with the cotton sucker bug, Dysdercus
      peruvianus (Hemiptera) as an insect model. Contrasting with B. pasteurii urease
      (PBU), both plant ureases presented potent insecticidal activity, with LD(50)
      values of 0.017% (w/w) and 0.052% (w/w) for JBU and SBU, respectively. The
      insecticidal property of JBU or SBU was not affected by treatment with p
      hydroxymercuribenzoate, an irreversible inhibitor of ureolytic activity of both
      proteins. Also, contrasting with canatoxin - a urease isoform from jackbean seeds
      that displays a toxic effect in mice (LD(50) = 2 mg x kg(-1)) - no lethality was
      seen in mice injected intraperitoneally with JBU or SBU (20 mg x kg(-1)).
      Similarly to canatoxin, the three enzymes promoted aggregation of blood platelets
      (EC(50) = 400.0 micro g x mL(-1), 22.2 micro g x mL(-1), 15.8 micro g x mL(-1)
      for BPU, SBU and JBU, respectively). This platelet activating property was also
      independent of urease activity. Comparison of the kinetic properties indicated
      that SBU is fivefold less susceptible than JBU to inhibition by acetohydroxamic
      acid, a chelator of Ni(+2) and Zn(+2) ions. The ureases also showed different
      susceptibility to agents that modify cysteine residues, such as p
      hydroxymercuribenzoate and p-benzoquinone. Altogether, these data emphasize that
      biological properties that are independent of ureolytic activity are not
      restricted to jackbean ureases and that these proteins may have a role in plant
      defense against insect predators.

PMID- 15030487
TI  - Inhibition of Drosophila melanogaster acetylcholinesterase by high concentrations
      of substrate.
AB  - Acetylcholine hydrolysis by acetylcholinesterase is inhibited at high substrate
      concentrations. To determine the residues involved in this phenomenon, we have
      mutated most of the residues lining the active-site gorge but mutating these did
      not completely eliminate hydrolysis. Thus, we analyzed the effect of a
      nonhydrolysable substrate analogue on substrate hydrolysis and on reactivation of
      an analogue of the acetylenzyme. Analyses of various models led us to propose the
      following sequence of events: the substrate initially binds at the rim of the
      active-site gorge and then slides down to the bottom of the gorge where it is
      hydrolyzed. Another substrate molecule can bind to the peripheral site: (a) when
      the choline is still inside the gorge - it will thereby hinder its exit; (b)
      after choline has dissociated but before deacetylation occurs - binding at the
      peripheral site increases deacetylation rate but (c) if a substrate molecule
      bound to the peripheral site slides down to the bottom of the active-site before
      the catalytic serine is deacetylated, its new position will prevent the approach
      of water, thus blocking deacetylation.

PMID- 15030488
TI  - Possible involvement of an FKBP family member protein from a psychrotrophic
      bacterium Shewanella sp. SIB1 in cold-adaptation.
AB  - A psychrotrophic bacterium Shewanella sp. strain SIB1 was grown at 4 and 20
      degrees C, and total soluble proteins extracted from the cells were analyzed by
      two-dimensional polyacrylamide gel electrophoresis. Comparison of these patterns
      showed that the cellular content of a protein with a molecular mass of 28 kDa and
      an isoelectric point of four greatly increased at 4 degrees C compared to that at
      20 degrees C. Determination of the N-terminal amino acid sequence, followed by
      the cloning and sequencing of the gene encoding this protein, revealed that this
      protein is a member of the FKBP family of proteins with an amino acid sequence
      identity of 56% to Escherichia coli FKBP22. This protein was overproduced in E.
      coli in a His-tagged form, purified, and analyzed for peptidyl-prolyl cis-trans
      isomerase activity. When this activity was determined by the protease coupling
      assay using N-succinyl-Ala-Leu-Pro-Phe-p-nitroanilide as a substrate at various
      temperatures, the protein exhibited the highest activity at 10 degrees C with a
      k(cat)/K(m) value of 0.87 micro m(-1) x s(-1). When the peptidyl-prolyl cis-trans
      isomerase activity was determined by the RNase T(1) refolding assay at 10 and 20
      degrees C, the protein exhibited higher activity at 10 degrees C with a
      k(cat)/K(m) value of 0.50 micro m(-1) x s(-1). These k(cat)/K(m) values are lower
      but comparable to those of E. coli FKBP22. We propose that a FKBP family protein
      is involved in cold-adaptation of psychrotrophic bacteria.

PMID- 15030489
TI  - Membrane binding of SRP pathway components in the halophilic archaea Haloferax
      volcanii.
AB  - Across evolution, the signal recognition particle pathway targets extra
      cytoplasmic proteins to membranous translocation sites. Whereas the pathway has
      been extensively studied in Eukarya and Bacteria, little is known of this system
      in Archaea. In the following, membrane association of FtsY, the prokaryal signal
      recognition particle receptor, and SRP54, a central component of the signal
      recognition particle, was addressed in the halophilic archaea Haloferax volcanii.
      Purified H. volcanii FtsY, the FtsY C-terminal GTP-binding domain (NG domain) or
      SRP54, were combined separately or in different combinations with H. volcanii
      inverted membrane vesicles and examined by gradient floatation to differentiate
      between soluble and membrane-bound protein. Such studies revealed that both FtsY
      and the FtsY NG domain bound to H. volcanii vesicles in a manner unaffected by
      proteolytic pretreatment of the membranes, implying that in Archaea, FtsY
      association is mediated through the membrane lipids. Indeed, membrane association
      of FtsY was also detected in intact H. volcanii cells. The contribution of the NG
      domain to FtsY binding in halophilic archaea may be considerable, given the low
      number of basic charges found at the start of the N-terminal acidic domain of
      haloarchaeal FtsY proteins (the region of the protein thought to mediate FtsY
      membrane association in Bacteria). Moreover, FtsY, but not the NG domain, was
      shown to mediate membrane association of H. volcanii SRP54, a protein that did
      not otherwise interact with the membrane.

PMID- 15030490
TI  - Protein engineering of pyruvate carboxylase: investigation on the function of
      acetyl-CoA and the quaternary structure.
AB  - Pyruvate carboxylase (PC) from Bacillus thermodenitrificans was engineered in
      such a way that the polypeptide chain was divided into two, between the biotin
      carboxylase (BC) and carboxyl transferase (CT) domains. The two proteins thus
      formed, PC-(BC) and PC-(CT+BCCP), retained their catalytic activity as assayed by
      biotin-dependent ATPase and oxamate-dependent oxalacetate decarboxylation, for
      the former and the latter, respectively. Neither activity was dependent on acetyl
      CoA, in sharp contrast to the complete reaction of intact PC. When assessed by
      gel filtration chromatography, PC-(BC) was found to exist either in dimers or
      monomers, depending on the protein concentration, while PC-(CT + BCCP) occurred
      in dimers for the most part. The two proteins do not associate spontaneously or
      in the presence of acetyl-CoA. Based on these observations, this paper discusses
      how the tetrameric structure of PC is built up and how acetyl-CoA modulates the
      protein structure.

PMID- 15030491
TI  - Polygenic control of idiopathic generalized epilepsy phenotypes in the genetic
      absence rats from Strasbourg (GAERS).
AB  - PURPOSE: Generalized nonconvulsive absence seizures are characterized by the
      occurrence of synchronous and bilateral spike-and-wave discharges (SWDs) on
      electroencephalographic recordings, concomitant with behavioral arrest. The GAERS
      (genetic absence rats from Strasbourg) strain, a well-characterized inbred model
      for idiopathic generalized epilepsy, spontaneously develops EEG paroxysms that
      resemble those of typical absence seizures. The purpose of this study was to
      investigate the genetic control of SWD variables by using a combination of
      genetic analyses and electrophysiological measurements in an experimental cross
      derived from GAERS and Brown Norway (BN) rats. METHODS: SWD subphenotypes were
      quantified on EEG recordings performed at both 3 and 6 months in a cohort of 118
      GAERS x BN F2 animals. A genome-wide scan of the F2 progenies was carried out
      with 146 microsatellite markers that were used to test each marker locus for
      evidence of genetic linkage to the SWD quantitative traits. RESULTS: We
      identified three quantitative trait loci (QTLs) in chromosomes 4, 7, and 8
      controlling specific SWD variables in the cross, including frequency, amplitude,
      and severity of SWDs. Age was a major factor influencing the detection of genetic
      linkage to the various components of the SWDs. CONCLUSIONS: The identification of
      these QTLs demonstrates the polygenic control of SWDs in the GAERS strain.
      Genetic linkages to specific SWD features underline the complex mechanisms
      contributing to SWD development in idiopathic generalized epilepsy.

PMID- 15030492
TI  - Development of amygdaloid kindling in histidine decarboxylase-deficient and
      histamine H1 receptor-deficient mice.
AB  - PURPOSE: This study attempted to clarify the role of histamine or histamine H1
      receptors in the development of amygdaloid kindling by using histidine
      decarboxylase (HDC)-deficient and histamine H1 receptor (H1R)-deficient mice.
      METHODS: Under pentobarbital anesthesia, mice were fixed to a stereotaxic
      apparatus, and bipolar electrodes were implanted into the right amygdala.
      Electrodes were connected to a miniature receptacle, which was embedded in the
      skull with dental cement. A bipolar electroencephalogram was recorded; bipolar
      stimulation of the amygdala was applied every day with a constant-current
      stimulator and continued until a generalized convulsion was obtained. RESULTS:
      The development of amygdaloid kindling in HDC-deficient and H1R-deficient mice
      was significantly accelerated compared with that in their respective wild-type
      mice. In addition, the afterdischarge (AD) duration and generalized seizure
      duration in HDC-deficient and H1R-deficient mice were prolonged. Intraperitoneal
      injection of histidine resulted in an inhibition of amygdaloid kindled seizures
      in wild-type mice at doses that caused an increase in the histamine contents of
      the brain. However, no significant effect was observed with histidine in H1R
      deficient mice at the same dose. CONCLUSIONS: These findings suggest that
      histaminergic mechanisms through H1 receptors play a crucial role not only in
      amygdaloid kindled seizures but also in the development of amygdaloid kindling.

PMID- 15030494
TI  - Seizure, neuron loss, and mossy fiber sprouting in herpes simplex virus type 1
      infected organotypic hippocampal cultures.
AB  - PURPOSE: Epileptic seizures are frequently seen after viral encephalitis. Herpes
      simplex virus type 1 (HSV-1) encephalitis is the most common cause of acquired
      epilepsy in humans. However, little information is available about the
      neuropathogenesis of HSV-1-associated seizures. We have developed an in vitro HSV
      1-infected organotypic hippocampal slice culture to elucidate the underlying
      mechanisms of HSV-1-associated acute seizure activity. METHODS: Hippocampal slice
      cultures were prepared from postnatal day 10 to 12 rat pups. Wild-type HSV-1
      strain RE (1 x 10(5) PFU) was applied to cultures at 14 days in vitro. The
      excitability of CA3 pyramidal cells and hippocampal network properties were
      measured with electrophysiological recordings. Hematoxylin-eosin (H&E) and Timm
      stains were used. RESULTS: HSV-1 infection induces epileptiform activity, neuron
      loss, and subsequently a dramatic increase of mossy fiber sprouting in the
      supragranular area. With intracellular recordings, surviving CA3 pyramidal cells
      exhibited a more depolarizing resting membrane potential concomitant with an
      increase in membrane input resistance and had a lower threshold to generate
      synchronized bursts and a decrease in the amplitude of afterhyperpolarization
      than did controls. When the antiherpes agent acyclovir was applied with a delay
      of 1 or 24 h after HSV-1 infection, a dramatic inhibition of HSV-1 replication
      and protection of the neuron loss were observed. CONCLUSIONS: These results
      suggest that a direct change in the excitability of the hippocampal CA3 neuronal
      network and HSV-1-induced neuron loss resulting in subsequent mossy fiber
      reorganization may play an important role in the generation of epileptiform
      activity.

PMID- 15030493
TI  - Increased numbers of coassembled PSD-95 to NMDA-receptor subunits NR2B and NR1 in
      human epileptic cortical dysplasia.
AB  - PURPOSE: Glutamatergic transmission between neurons occurs at chemical synapses.
      The N-methyl-d-aspartate (NMDA)-receptor subclass of ionotropic glutamate
      receptors has been implicated in the epileptogenic mechanisms in human cortical
      dysplasia (CD). NMDA receptors are clustered at the postsynaptic membrane by
      anchoring to the postsynaptic density protein PSD-95, a putative ion channel
      clustering protein. In this study, we quantitatively investigated the coassembly
      of PSD-95 to NR2B and NR1 in human epileptogenic cortex as compared with
      nonepileptic cortex. METHODS: We used coimmunoprecipitation and immunoblotting
      techniques to quantify and compare the numbers of coassembled PSD-95 with NR2B,
      PSD-95 with NR1, and NR2B with NR1 in the membrane proteins of brain tissues
      resected from four patients (aged 3.5, 6, 14, and 18 years) with medically
      intractable neocortical epilepsy associated with CD. The resected cortical
      tissues were grouped into epileptic and nonepileptic, as determined by prolonged
      subdural electrode recordings in three patients and direct intraoperative
      electrocorticographic recording in one patient. RESULTS: In all patients, the
      amounts of immunoprecipitated complexes, which reflect the numbers of coassembled
      PSD-95 proteins to NR2B subunits, were increased in epileptic cortex as compared
      with nonepileptic cortex. CONCLUSIONS: These results suggest that increased
      coassembly of NR2B and NR1 with PSD-95 may underlie one of the cellular
      mechanisms that contribute to the in situ increased hyperexcitability, leading to
      seizure generation in focal CD.

PMID- 15030495
TI  - Daytime sleepiness in epilepsy patients receiving topiramate monotherapy.
AB  - PURPOSE: Limited research has focused to date on objective neurophysiological
      evaluation of daytime sleepiness in patients treated with newer antiepileptic
      drugs (AEDs), especially when used as monotherapy. This study was aimed at
      assessing occurrence of daytime sleepiness in newly diagnosed, drug-naive
      patients with partial epilepsy receiving initial topiramate (TPM) monotherapy.
      METHODS: Daytime vigilance was assessed in 14 consecutive, newly diagnosed and
      never medicated adult patients with focal epilepsy, receiving monotherapy with
      TPM. At baseline and 2 months after slowly titrated therapy with TPM, 200 mg/day,
      patients underwent the Multiple Sleep Latency Test (MSLT), visual simple and
      choice reaction times (VRT), and self-rated their own degree of sleepiness with
      the Epworth Sleepiness Scale. A group of 14 age- and gender-matched healthy
      volunteers served as controls. RESULTS: At baseline, mean daytime sleep latencies
      on the MSLT were comparable in patients and in controls. Two months after TPM
      monotherapy, MSLT scores did not significantly change in patients as compared
      with pretreatment values. Accordingly, subjective daytime sleepiness and VRTs,
      which were comparable in controls and in untreated patients at baseline, did not
      change in patients after TPM monotherapy. CONCLUSIONS: Study results suggest that
      an initial short-course monotherapy with TPM, 200 mg/day, does not impair daytime
      vigilance in newly diagnosed adult patients with partial seizures.

PMID- 15030496
TI  - EEG and ECG in sudden unexplained death in epilepsy.
AB  - PURPOSE: Sudden unexpected death in epilepsy (SUDEP) is a major cause of
      mortality for patients with epilepsy. Cardiac factors may be involved and were
      evaluated in this study. METHODS: EEG and ECG data for 21 patients with definite
      (n = 6) or probable (n = 15) SUDEP were compared with data from a group of 43
      patients with refractory partial epilepsy. ECG abnormalities and heart rate (HR)
      changes were correlated with clinical data. RESULTS: Fourteen patients died in
      their sleep; two were awake. Ictal maximal HR (90 seizures from 16 of 21
      patients) was significantly higher in SUDEP (mean, 149 beats/min, BPM) than in
      comparison patients (mean, 126 BPM; p < 0.001). Greater increases in HR were
      associated with seizures arising from sleep (78 BPM increase) than from
      wakefulness (47 BPM; p < 0.001) in SUDEP, as compared with the non-SUDEP group
      (52 BPM in sleep, 43 BPM in wakefulness; p = 0.27). Ictal cardiac repolarization
      and rhythm abnormalities occurred in 56% of SUDEP (including two atrial
      fibrillation, two ventricular premature depolarizations, two marked sinus
      arrhythmia, two atrial premature depolarizations, one junctional escape, one ST
      segment elevation), and 39% of comparison patients (p = 0.39). No specific
      seizure onset (laterality or lobe) was associated with SUDEP. CONCLUSIONS: This
      study reveals, for the first time, evidence of increased autonomic stimulation
      (as measured by HR) associated with seizures, particularly in sleep, in patients
      with SUDEP, as compared with a clinically similar group of patients with
      refractory epilepsy.

PMID- 15030497
TI  - Electrical stimulation of the anterior nucleus of the thalamus for the treatment
      of intractable epilepsy.
AB  - PURPOSE: Animal studies and sporadic case reports in human subjects have
      suggested that intermittent electrical stimulation of the anterior nucleus of the
      thalamus reduces seizure activity. We embarked on an open-label pilot study to
      determine initial safety and tolerability of bilateral stimulation of the
      anterior nucleus of the thalamus (ANT), to determine a range of appropriate
      stimulation parameters, and to begin to gather pilot efficacy data. METHODS: We
      report an open-label pilot study of intermittent electrical stimulation of the
      anterior nucleus of the thalamus in five patients (three men, two women; age
      range, 24-47 years), with follow-up between 6 and 36 months. All patients had
      intractable partial epilepsy. Four of the five patients also had secondarily
      generalized seizures. Stimulation was delivered by bilateral implantable,
      programmable devices by using an intermittent, relatively high-frequency
      protocol. Stimulation parameters were 100 cycles per second with charge-balanced
      alternating current; pulse width, 90 ms; and voltages ranging between 1.0 and
      10.0 V. Seizure counts were monitored and compared with preimplantation baseline.
      RESULTS: Four of the five patients showed clinically and statistically
      significant improvement with respect to the severity of their seizures,
      specifically with respect to the frequency of secondarily generalized tonic
      clonic seizures and complex partial seizures associated with falls. One patient
      showed a statistically significant reduction in total seizure frequency. No
      adverse events could clearly be attributed to stimulation. None of the patients
      could determine whether the stimulator was on or off at these parameters.
      CONCLUSIONS: Electrical stimulation of the ANT appears to be well tolerated.
      Preliminary evidence suggests clinical improvement in seizure control in this
      small group of intractable patients. Further controlled study of deep brain
      stimulation of the anterior nucleus is warranted.

PMID- 15030499
TI  - Subtraction SPECT coregistered to MRI in focal malformations of cortical
      development: localization of the epileptogenic zone in epilepsy surgery
      candidates.
AB  - PURPOSE: To determine the extent to which periictal subtraction single-photon
      emission computed tomography (SPECT) may improve detection and definition of the
      epileptogenic zone in patients with focal malformations of cortical development
      (MCDs). METHODS: Subtraction SPECT coregistered to magnetic resonance (MR) images
      (SISCOM) were constructed for 22 consecutive patients with focal MCDs who
      underwent periictal SPECT injection (18 ictal and four postictal). In the 17
      patients who had epilepsy surgery, concordance between the site of SISCOM
      localization and site of surgical resection was determined by coregistration of
      SISCOM images with postoperative MRIs. RESULTS: SISCOM images were localizing in
      19 (86%) patients, including eight of the 10 with nonlocalizing MRI. Concordance
      of SISCOM localization was 91% with MRI localization, 93% with scalp ictal EEG
      localization, and 100% with intracranial EEG localization. Eight patients whose
      SISCOM localization was concordant with the surgical resection site had lower
      postoperative seizure frequency scores (SFSs; p = 0.04) and greater postoperative
      improvement in SFSs (p = 0.05) than the nine patients whose SISCOM was either
      nonconcordant or nonlocalizing. On multiple regression analysis, a model
      combining SISCOM concordance with surgical resection site and extent of MRI
      lesion resection was predictive of postoperative SFS (R2 = 0.47; p = 0.03).
      CONCLUSIONS: Periictal subtraction SPECT using the SISCOM technique provides
      useful information for seizure localization in patients with focal MCDs, even
      when MRI is nonlocalizing.

PMID- 15030498
TI  - Identification of abnormal neuronal metabolism outside the seizure focus in
      temporal lobe epilepsy.
AB  - PURPOSE: The aim of this study was to identify metabolically abnormal
      extrahippocampal brain regions in patients with temporal lobe epilepsy with (TLE
      MTS) and without (TLE-no) magnetic resonance imaging (MRI) evidence for mesial
      temporal sclerosis (MTS) and to assess their value for focus lateralization by
      using multislice 1H magnetic resonance spectroscopic imaging (MRSI). METHODS:
      MRSI in combination with tissue segmentation was performed on 14 TLE-MTS and
      seven TLE-no and 12 age-matched controls. In controls, N
      acetylaspartate/(creatine + choline) [NAA/(Cr+Cho)] of all voxels of a given lobe
      was expressed as a function of white matter content to determine the 95%
      prediction interval for any additional voxel of a given tissue composition.
      Voxels with NAA/(Cr+Cho) below the lower limit of the 95% prediction interval
      were defined as "pathological" in patients and controls. Z-scores were used to
      identify regions with a higher percentage of pathological voxels than those in
      controls. RESULTS: Reduced NAA/(Cr+Cho) was found in ipsilateral temporal and
      parietal lobes and bilaterally in insula and frontal lobes. Temporal
      abnormalities identified the epileptogenic focus in 70% in TLE-MTS and 83% of TLE
      no. Extratemporal abnormalities identified the epileptogenic focus in 78% of TLE
      MTS but in only 17% of TLE-no. CONCLUSIONS: TLE is associated with
      extrahippocampal reductions of NAA/(Cr+Cho) in several lobes consistent with
      those brain areas involved in seizure spread. Temporal and extratemporal
      NAA/(Cr+Cho) reductions might be helpful for focus lateralization.

PMID- 15030500
TI  - A follow-up survey on seizures induced by animated cartoon TV program "Pocket
      Monster".
AB  - PURPOSE: To identify the short-term outcome of patients who had seizures while
      watching an animated cartoon TV program, "Pocket Monster," on December 16, 1997.
      METHODS: One and three years after the incident, questionnaires were sent to
      physicians of each patient about seizure recurrence, EEGs, and medication.
      RESULTS: Among 103 patients in whom epileptic seizures occurred during the TV
      program and information on the outcomes was available, 25 (24%) patients had a
      history of unprovoked seizures before the incident (Epilepsy Group), and 78 (76%)
      did not (Non-Epilepsy Group). Twenty-three (22%) patients were reported to have
      seizures after the incident, and 15 of them had visually induced seizures.
      Patients of the Epilepsy Group had more seizure recurrence than did those of the
      Non-Epilepsy Group (56% vs. 9%; p < 0.0001), either for unprovoked (44% vs. 4%; p
      < 0.0001) or visually induced seizures (28% vs. 9%; p < 0.05). Of nine patients
      of the Non-Epilepsy Group who had seizures after the incident, only three
      developed recurrent unprovoked seizures. In the Non-Epilepsy Group, no difference
      was found in seizure recurrence between patients in whom valproate (VPA) was
      prescribed immediately after the incident and in those without medication (one of
      five (20%) vs. seven of 73 (10%); p > 0.05). EEG was performed at least once in
      98 patients after the incident. Photoparoxysmal response (PPR) was present in 45
      (46%) patients, and spontaneous epileptiform discharges, in 49 (50%). PPR did not
      have any correlation with recurrence of seizures, neither spontaneous nor
      visually induced seizures, whereas spontaneous epileptiform discharges showed a
      good correlation with seizure recurrence (34% vs. 8%; p < 0.01), including
      visually induced seizures (24% vs. 2%; p < 0.01). CONCLUSIONS: Short-term
      outcomes showed that 70 (68%) of 103 patients who had a seizure during the
      incident had no seizures before and during < or = 3 years of follow-up.

PMID- 15030501
TI  - Complete loss of the cytoplasmic carboxyl terminus of the KCNQ2 potassium
      channel: a novel mutation in a large Czech pedigree with benign neonatal
      convulsions or other epileptic phenotypes.
AB  - PURPOSE: Benign neonatal familial convulsions (BNFCs) represent a rare epileptic
      disorder with autosomal dominant mode of inheritance. To date, two voltage-gated
      potassium (K+) channel genes, KCNQ2 and KCNQ3, have been identified in typical
      BNFC families. The study of new pedigrees may help detect new mutations and
      define genotype-phenotype correlations. METHODS: A large Czech family was
      detected in which BNFC was inherited together with a broad range of various
      nonneonatal epileptic phenotypes. Genetic linkage study and direct mutation
      analysis were performed to find the disease-causing mutation. RESULTS: In seven
      patients with BNFCs and no recurrence of seizures, a novel two-base-pair deletion
      (1369del2) was identified within the coding sequence of the KCNQ2 gene. The
      mutation led to a putative protein that lacked nearly all its carboxyl terminus
      part, which plays a critical role for the accurate expression of the functional
      K+ channels. Three patients with generalized tonic-clonic seizures (GTCSs), all
      without any history of BNFCs, also displayed 1369del2. Three other patients with
      other idiopathic epileptic phenotypes did not have the mutation. CONCLUSIONS: A
      novel 2-bp deletion within the coding sequence of the potassium channel KCNQ2
      gene was detected in patients from a large and heterogeneous family with BNFCs or
      non-BNFC seizures.

PMID- 15030502
TI  - Semiologic value of ictal autoscopy.
AB  - PURPOSE: Autoscopy is a pathologic perception of one's body or one's face image
      within space, either from an internal ("as in a mirror") or from an external
      ("out-of-body experience") point of view. Among various psychiatric and
      neurologic disorders, partial epilepsy is the main etiology. However, the
      significance of this rare ictal symptom remains controversial. We report this
      phenomenon in three epilepsy patients and discuss its semiologic value and
      neuropsychological significance. METHODS: Interictal EEG and/or video-EEG
      monitoring was performed, as well as neuropsychological examination and cerebral
      magnetic resonance imaging (MRI). RESULTS: The three patients had a lesion
      involving, or limited to, the right parietal region on cerebral MRI. All three
      patients experienced autoscopy associated with other ictal signs supporting a
      right parietal lobe origin of seizures. In one patient, seizure origin was
      documented with video and surface EEG ictal recordings. CONCLUSIONS: Autoscopy
      was shown to have an ictal mechanism and was associated with seizures arising
      from the nondominant parietal region. We hypothesize that ictal autoscopy may
      result from disruption of the normal integration of body representation.

PMID- 15030504
TI  - Evaluations and awards at the fifth European Congress of Epileptology, Madrid, 6
      10 October 2002.

PMID- 15030507
TI  - What does the peripheral blood tell you in SARS?

PMID- 15030506
TI  - Unravelling the genetic complexity of autoimmune thyroid disease: HLA, CTLA-4 and
      beyond.
AB  - The autoimmune thyroid diseases (AITDs) including Graves' disease (GD) and
      autoimmune hypothyroidism (AIH) are the commonest of the autoimmune conditions
      affecting 2-5% of the western population. Twin studies have clearly demonstrated
      that AITDs are caused by a combination of both environmental and genetic factors.
      Association of the HLA class II region with AITD has been documented for over 20
      years now, but the primary aetiological variant in this region remains unknown.
      More recently the CTLA-4 gene region has been identified as the second locus
      conferring susceptibility to AITD. In contrast to HLA, a polymorphism of the CTLA
      4 gene, which encodes an important negative regulator of the immune system, has
      been identified as a candidate for a primary determinant for AITD. A large number
      of candidate gene and genome wide linkage studies have been involved in the
      search for the elusive 'third' locus. The thyroglobulin (Tg) gene in humans maps
      to chromosome 8q, which has been linked in family studies to AITD. A number of
      association studies in humans and the mouse model for AITD are beginning to
      implicate the Tg gene although convincing evidence for a primary causative role
      is still needed. The establishment of large DNA disease resources along with more
      detailed genetic maps and the development of faster, more effective, high
      throughput genotyping and sequencing methods, provides some sense of optimism
      that novel loci will be identified in the near future and the complex aetiology
      of AITD will be further unraveled.

PMID- 15030508
TI  - Asthma: new developments in cytokine regulation.

PMID- 15030509
TI  - Inhibition of stem cell factor reduces pulmonary cytokine levels during allergic
      airway responses.
AB  - Stem cell factor (SCF) has a significant role in the inflammation and activation
      of allergic airway responses. When monoclonal anti-SCF was administered
      intratracheally during allergen challenge there was a significant alteration of
      eosinophil accumulation and airway hyperreactivity (AHR). Anti-SCF treatment also
      attenuated pulmonary cytokine and chemokine levels. In particular, there was an
      antibody dose-dependent decrease in interleukin (IL)-5 and tumour necrosis factor
      (TNF)-alpha. There was also a significant reduction of CCL2 and CCL5, which
      correlated with the reduction in AHR. Mice treated with anti-SCF demonstrated a
      significant decrease in pulmonary gob-5 gene expression, which has been shown to
      correlate to goblet cell hyperplasia/metaplasia relating to airway mucus
      production. Blocking SCF-mediated activation within the airway using a monoclonal
      antibody indicates that this cytokine may represent a viable target for
      therapeutic intervention that could affect multiple aspects of allergen-induced
      immunopathology.

PMID- 15030510
TI  - Blocking lymphotoxin-beta receptor activation diminishes inflammation via reduced
      mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression and leucocyte
      margination in chronic DSS-induced colitis.
AB  - The lymphotoxin-beta receptor (LTbetaR) pathway is critical for maintenance of
      organized lymphoid structures and is involved in the development of colitis. To
      investigate the mechanisms by which LTbetaR activation contributes to the
      pathology of chronic inflammation we used a soluble LTbetaR-Ig fusion protein as
      a competitive inhibitor of LTbetaR activation in the mouse model of chronic
      colitis induced by oral administration of dextran sulphate sodium. Strong
      expression of LTbeta which constitutes part of the LTalpha(1)beta(2) ligand
      complex was detected in colonic tissue of mice with chronic colitis. Treatment
      with LTbetaR-Ig significantly attenuated the development and histological
      manifestations of the chronic inflammation and reduced the production of
      inflammatory cytokines such as TNF, IL-1beta, and IL-6. Moreover, LTbetaR-Ig
      treatment significantly down-regulated mucosal addressin cell adhesion molecule-1
      (MAdCAM-1) expression, leading to reduced leucocyte rolling and sticking in
      postcapillary and collecting venules and reduced extravasation into the
      intestinal mucosa as quantified by in vivo fluorescence microscopy. Thus, LTbetaR
      pathway inhibition ameliorates DSS-induced experimental chronic colitis in mice
      by MAdCAM-1 down-regulation entailing reduced lymphocyte margination and
      extravasation into the inflamed mucosa. Therefore, a combined treatment with
      reagents blocking T cell-mediated perpetuation of chronic inflammation such as
      LTbetaR-Ig together with direct anti-inflammatory reagents such as TNF inhibitors
      could constitute a promising treatment strategy for chronic colitis.

PMID- 15030511
TI  - Reduced ratio of protective versus proinflammatory cytokine responses to
      commensal bacteria in HLA-B27 transgenic rats.
AB  - Germ-free HLA-B27 transgenic (TG) rats do not develop colitis, but colonization
      with specific pathogen-free (SPF) bacteria induces colitis accompanied by immune
      activation. To study host-dependent immune responses to commensal caecal bacteria
      we investigated cytokine profiles in mesenteric lymph node (MLN) cells from HLA
      B27 TG versus nontransgenic (non-TG) littermates after in vitro stimulation with
      caecal bacterial lysates (CBL). Supernatants from CBL-stimulated unseparated T-
      or B- cell-depleted MLN cells from HLA-B27 TG and non-TG littermates were
      analysed for IFN-gamma, IL-12, TNF, IL-10 and TGF-beta production. Our results
      show that unfractionated TG MLN cells stimulated with CBL produced more IFN
      gamma, IL-12 and TNF than did non-TG MLN cells. In contrast, CBL-stimulated non
      TG MLN cells produced more IL-10 and TGF-beta. T cell depletion abolished IFN
      gamma and decreased IL-12 production, but did not affect IL-10 and TGF-beta
      production. Conversely, neither IL-10 nor TGF-beta was produced in cultures of B
      cell-depleted MLN. In addition, CD4(+) T cells enriched from MLN of HLA-B27 TG
      but not from non-TG rats produced IFN-gamma when cocultured with CBL-pulsed
      antigen presenting cells from non-TG rats. Interestingly, IL-10 and TGF-beta, but
      not IFN-gamma, IL-12 and TNF were produced by MLN cells from germ-free TG rats.
      These results indicate that the colitis that develops in SPF HLA-B27 TG rats is
      accompanied by activation of IFN-gamma-producing CD4(+) T cells that respond to
      commensal bacteria. However, B cell cytokine production in response to components
      of commensal intestinal microorganisms occurs in the absence of intestinal
      inflammation.

PMID- 15030512
TI  - Oral administration of bovine whey proteins to mice elicits opposing
      immunoregulatory responses and is adjuvant dependent.
AB  - Most studies investigating the induction of oral tolerance (OT) use purified
      proteins such as ovalbumin (OVA), bovine serum albumin (BSA) and beta
      lactoglobulin (beta-LG). Little information is available regarding the induction
      of OT to a protein mixture, e.g. cow's milk. In this study we compared the
      regulatory mechanisms induced after the oral administration of a whey protein
      concentrate (WP) derived from cow's milk following immunization with two
      different adjuvants, complete Freund's adjuvant (CFA) and alum. OVA was used as a
      control antigen. Animals were given a single feed of these proteins at an
      equivalent dose of 1 mg/g body weight before they were immunized seven days later
      with the antigen in Freund's adjuvant or alum. Delayed type hypersensitivity
      (DTH) responses were suppressed by both a feed of WP and OVA after immunization
      with CFA. However, only OVA feeding suppressed antigen specific IgG responses. In
      an attempt to investigate whether WP would tolerize the more susceptible IgE
      responses, alum immunization replaced CFA as the adjuvant used for systemic
      immunizations. WP, after a single feed, significantly primed for DTH and IgE
      responses indicating oral sensitization to WP. In contrast, OVA suppressed DTH,
      IgE and IgG responses. Antigen specific proliferation of mononuclear cells was
      suppressed in mice fed OVA, but primed in those fed with WP. In addition cells
      taken from sensitized mice fed WP up-regulated levels of specific interleukin
      (IL) -4, -10 and -12 in vitro whereas these cytokines were suppressed in cultures
      from tolerant WP fed mice. Global suppression was obtained in cultures from
      tolerant OVA fed mice. TGF-beta was not detected in draining PLN cell cultures of
      either tolerant or sensitized mice. These data suggest that a whey protein
      mixture induces divergent responses following immunization with either CFA or
      alum despite being fed at an identical dose. We suggest that that the choice of
      the adjuvant may determine the immunoregulatory outcome and this is also
      reflected by the systemic cytokine profile.

PMID- 15030513
TI  - Induction of experimental autoimmune encephalomyelitis in Dark Agouti rats
      without adjuvant.
AB  - Experimental autoimmune encephalomyelitis (EAE) is a well-recognized model for
      multiple sclerosis (MS) in humans. However, adjuvants used with encephalitogens
      to induce EAE produce non-specific effects interfering with the mechanisms
      involved in the autoimmune response to the central nervous system (CNS) tissue.
      It is therefore important to establish a more suitable model of EAE for analysis
      of autoimmune phenomena resembling those operative in MS. Here we report that EAE
      can be induced regularly in Dark Agouti (DA) strain of rats with spinal cord
      tissue without any adjuvant, as judged by both clinical and histological
      parameters. The incidence and severity of EAE depended on the origin of the
      encephalitogen, the rat versus guinea pig spinal cord homogenate being more
      efficient. Furthermore, EAE could be reinduced in animals which had recovered
      from disease that had been induced actively with encephalitogen alone, suggesting
      the role of adjuvant-generated non-specific mechanisms in resistance to
      reinduction of EAE. Thus, EAE induced in DA rats with encephalitogen alone
      provides a reproducible model for defining pathogenically relevant events in CNS
      autoimmunity devoid of the potentially misleading effects of adjuvants.

PMID- 15030514
TI  - Maternal immunity to insulin does not affect diabetes risk in progeny of non
      obese diabetic mice.
AB  - It has been suggested that maternal environment, in particular maternal
      autoantibodies, modify the risk of developing autoimmune diabetes in offspring.
      The aim of this study was to determine whether modification of maternal
      environment and maternal diabetes risk through immunization affects autoimmune
      diabetes risk in the progeny. The risk of developing insulin antibodies and of
      developing diabetes was determined in 113 female progeny of non obese diabetic
      (NOD) dams that were immunized with insulin, control antigen or vehicle before or
      during pregnancy. Although NOD dams immunized with insulin were rendered diabetes
      resistant (40% diabetes by age 36 weeks versus 100% in control dams), diabetes
      development in their female offspring (72%, 26/36) was similar to that in female
      offspring of dams immunized with glucagon (82%, 22/27) or vehicle (76%, 19/25).
      Furthermore, no significant differences in diabetes development or insulin
      autoantibody titres were observed between female progeny of insulin autoantibody
      positive NOD dams (82% diabetes by age 36 weeks, 18/22), insulin autoantibody
      negative NOD dams (75%, 41/55), and NOD dams that had antibodies against
      exogneous insulin (71%, 22/31). The findings suggest that modification of the
      maternal risk for autoimmune diabetes via antigen-specific immunization is not
      transferred to progeny and that fetal exposure to insulin autoantibodies does not
      increase the risk for diabetes development.

PMID- 15030515
TI  - The membrane attack complex, C5b-9, up regulates collagen gene expression in
      renal tubular epithelial cells.
AB  - Evidence suggesting a direct role for proteinuria in the pathogenesis of renal
      tubulointerstitial fibrosis is accumulating. However the mechanism by which
      proteinuria leads to injury is unknown. In proteinuric states complement proteins
      are filtered through the glomerulus and could contribute to the tubular damage.
      The aim of this study was to investigate the role of complement activation in the
      progression of interstitial fibrosis. To determine whether complement activation
      may be responsible for the pro-fibrotic response that occurs in the
      tubulointerstitial compartment we stimulated primary cultures of proximal tubular
      epithelial cells with membrane attack complex, C5b-9. This led to increased mRNA
      concentrations of both collagen type IV and its intracellular chaperone, Heat
      Shock Protein 47 (HSP47). To determine whether this occurred in vivo Adriamycin
      was used to induce proteinuria in female Balb/c mice. The expression of collagen
      type IV and HSP47 was increased in proteinuric mice compared to control mice. In
      proteinuric mouse kidney, C3 was deposited at sites of tubulointerstitial injury
      and there was a relationship between C3 deposition and immunochemical staining
      for collagen type IV and HSP47. In situ hybridization suggested that the renal
      tubular epithelium was actively expressing HSP47 mRNA and, by implication, excess
      collagen. These observations support the hypothesis that complement activation on
      tubular epithelial cells can directly increase the pro-fibrotic process
      associated with tubulointerstitial damage.

PMID- 15030516
TI  - P-selectin glycoprotein ligand 1 therapy ameliorates established collagen-induced
      arthritis in DBA/1 mice partly through the suppression of tumour necrosis factor.
AB  - We investigated the therapeutic potential of P-selectin glycoprotein ligand
      (PSGL)-1 in established collagen-induced arthritis (CIA) in DBA/1 mice. PSGL-1 is
      the high-affinity specific ligand for P-selectin and is thus important in cell
      recruitment to inflammatory sites. I-316 PSGL-1 or rPSGL-1Ig fusion protein were
      administered to mice after the onset of clinical arthritis for 10 days, and the
      effect of treatment on both clinical and histopathological progression of disease
      was studied. It was found that both PSGL-1 biologicals effectively suppressed
      progression of clinical arthritis, and this was accompanied by protection against
      damage of joint tissues. We sought to investigate a mechanism underlying the
      effect of rPSGL-1Ig on the reduction of clinical arthritis. Blockade of PSGL-1/P
      selectin interaction blocks recruitment of leucocytes, thus we observed a notable
      reduction in viable cell numbers of synoviocytes from rPSGL-1Ig treated mice. In
      view of this finding we suspected an effect of treatment on the production of pro
      inflammatory mediators such as bioactive tumour necrosis factor-alpha (TNF) in
      synovial membrane ex vivo cell cultures. Production of TNF was reduced in
      arthritic mice that had been treated with rPSGL-1Ig. To further investigate the
      mechanism of rPSGL-1Ig, we explored the possibility that PSGL-1 might also have a
      direct signalling effect on TNF release from inflammatory cells. Thus synoviocyte
      cultures from arthritic mice were incubated with rPSGL-1Ig. A significant
      reduction in the spontaneous bioactive TNF release from these cultures was noted.
      We therefore confirmed these surprising findings using cultures of a mouse
      macrophage like cell line RAW 264.7, stimulated by LPS. Our results indicate that
      both forms of PSGL-1 have significant therapeutic effects in CIA murine model of
      RA. The mechanism of action involves reduced cellularity of synovium as
      anticipated, along with a reduction in TNF production from inflammatory cells in
      the synovium. The latter mechanism needs further mechanistic analysis.

PMID- 15030517
TI  - Recombination activating genes (RAG) induce secondary Ig gene rearrangement in
      and subsequent apoptosis of human peripheral blood circulating B lymphocytes.
AB  - Recombination activating gene (RAG) re-expression and secondary Ig gene
      rearrangement in mature B lymphocytes have been reported. Here, we have studied
      RAG expression of peripheral blood B lymphocytes in humans. Normal B cells did
      not express RAG1 and RAG2 spontaneously. More than a half of circulating B cells
      expressed RAG proteins, when activated with Staphylococcus aureus Cowan I (SAC) +
      IL-2. DNA binding activity of the RAG complex has been verified by a gel shift
      assay employing the recombination signal sequence (RSS). Secondary Ig light chain
      rearrangement in the RAG-expressing B cells was confirmed by linker-mediated (LM)
      PCR. Highly purified surface kappa+ B cells activated by SAC + IL-2 became RAG+,
      and thereafter they started to express lambda chain mRNA. 2 colour
      immunofluorescence analysis disclosed that a part of the RAG+ cells derived from
      the purified kappa+ B cells activated by SAC + IL-2 turned to lambda+ phenotype
      in vitro. Similarly, apoptosis induction was observed in a part of the RAG+ B
      cells. Our study suggests that a majority of peripheral blood B cells re
      expresses RAG and the RAG+ B lymphocytes could be eliminated from the B cell
      repertoire either by changing Ag receptor specificity due to secondary
      rearrangement or by apoptosis induction. Thus, RAG expression of mature B cells
      in peripheral blood would contribute to not only receptor revision for further
      diversification of B cell repertoire but in some cases (or in some B cell
      subsets) to prevention or induction of autoAb responses at this differentiation
      stage in humans.

PMID- 15030518
TI  - Regulation of complement C3 and C4 synthesis in human peritoneal mesothelial
      cells by peritoneal dialysis fluid.
AB  - Although complement is activated in the peritoneal cavity during chronic
      peritoneal dialysis (PD), little is known about its role in peritoneal defence
      and injury related to long-term PD. We examined the impact of glucose and
      commercial peritoneal dialysis solutions on complement expression in HPMCs
      obtained by primary culture from omental tissues of consented patients undergoing
      elective abdominal surgery. Constitutive expression of C3 and C4 mRNA in HPMCs
      was up-regulated upon exposure to 75 mm glucose in a time-dependent manner. C3
      and C4 protein was secreted in both apical and basolateral directions. Glucose
      doses beyond 100 mm markedly down-regulated C3 and C4 expression, and stimulated
      LDH release dose-dependently. Such cytotoxic effects were attenuated using
      equivalent doses of mannitol instead of glucose. Treatment with conventional
      lactate-buffered dialysis solution gave rise to down-regulation of C3 and C4
      expression, and heightened LDH release in HPMCs. These effects correlated with
      the glucose strength of the solution, persisted despite replacement with a
      bicarbonate-buffered solution, aggravated by glycated albumin, and were partially
      abrogated by supplementation with 10% fetal bovine serum in the culture system.
      Our findings suggest that the artificial conditions imposed by PD lead to
      alterations in local complement synthesis that have implications for the role of
      the peritoneal mesothelium in both inflammation and defence.

PMID- 15030519
TI  - Plasma inflammatory cytokines and chemokines in severe acute respiratory
      syndrome.
AB  - Severe acute respiratory syndrome (SARS) is a recently emerged infectious disease
      caused by a novel coronavirus, but its immunopathological mechanisms have not yet
      been fully elucidated. We investigated changes in plasma T helper (Th) cell
      cytokines, inflammatory cytokines and chemokines in 20 patients diagnosed with
      SARS. Cytokine profile of SARS patients showed marked elevation of Th1 cytokine
      interferon (IFN)-gamma, inflammatory cytokines interleukin (IL)-1, IL-6 and IL-12
      for at least 2 weeks after disease onset, but there was no significant elevation
      of inflammatory cytokine tumour necrosis factor (TNF)-alpha, anti-inflammatory
      cytokine IL-10, Th1 cytokine IL-2 and Th2 cytokine IL-4. The chemokine profile
      demonstrated significant elevation of neutrophil chemokine IL-8, monocyte
      chemoattractant protein-1 (MCP-1), and Th1 chemokine IFN-gamma-inducible protein
      10 (IP-10). Corticosteroid reduced significantly IL-8, MCP-1 and IP-10
      concentrations from 5 to 8 days after treatment (all P < 0.001). Together, the
      elevation of Th1 cytokine IFN-gamma, inflammatory cytokines IL-1, IL-6 and IL-12
      and chemokines IL-8, MCP-1 and IP-10 confirmed the activation of Th1 cell
      mediated immunity and hyperinnate inflammatory response in SARS through the
      accumulation of monocytes/macrophages and neutrophils.

PMID- 15030520
TI  - Early deficit of lymphocytes in Wiskott-Aldrich syndrome: possible role of WASP
      in human lymphocyte maturation.
AB  - Wiskott-Aldrich syndrome (WAS) is an X-linked platelet/immunodeficiency disease.
      The affected gene encodes WASP, a multidomain protein that regulates cytoskeletal
      assembly in blood cells. Patients have recurring infections, and their
      lymphocytes exhibit deficient proliferative responses in vitro. We report an
      evaluation of peripheral blood lymphocytes of 27 WAS patients, aged one month to
      55 years. Whereas NK cells were normal, a significant deficit of T and B
      lymphocytes was observed. The number of lymphocytes was already decreased in
      infant patients, suggesting deficient output. Both CD4 and CD8 T lymphocytes were
      affected; the decrease was most pronounced for naive T cells. Naive CD4
      lymphocytes of patients showed normal expression of Bcl-2, and Ki-67, and normal
      survival in vitro, suggesting that their in vivo survival and proliferation are
      normal. The collective data suggest that the patients' lymphocyte deficit results
      from deficient output, likely due to abnormal lymphocyte maturation in the thymus
      and bone marrow. We propose that WASP plays an important role not only in the
      function of mature T lymphocytes, but also in the maturation of human T and B
      lymphocytes and that impaired lymphocyte maturation is central to the aetiology
      of WAS immunodeficiency.

PMID- 15030521
TI  - Increased risk of adverse events when changing intravenous immunoglobulin
      preparations.
AB  - Intravenous immunoglobulin (IVIG) therapy has represented a major advance in the
      treatment of patients with primary immune deficiency disorders. In September 2000
      a new IVIG formulation, Intragam P, was introduced into clinical use. Intragam P
      is prepared by delipidation of pooled plasma followed by an ion exchange
      chromatography step to eliminate immunoglobulin aggregates. It is then
      pasteurized for 10 h at 60 degrees C for viral inactivation before storage at pH
      4.25 in 10% maltose. We report initial clinical experience with this new
      preparation. The details of adverse reactions of patients who received the new
      preparation were gathered shortly after it became apparent there was a change in
      IVIG formulation. Seven of 49 patients receiving Intragam P spontaneously
      reported adverse effects, which were temporally related to infusions.
      Subsequently, all seven patients have been able to tolerate the product with
      prophylactic use of antihistamines and paracetamol. This case series indicates
      that long-term tolerance of an older IVIG product does not necessarily equate to
      tolerance to a newer product, even if technically superior. Caution should be
      exercised when changing IVIG products, as they are not biologically equivalent.

PMID- 15030522
TI  - Serum granulysin is a marker for Th1 type immunity in pre-eclampsia.
AB  - Recent studies suggest that pre-eclampsia is associated with a Th1 predominant
      state and may be considered a failure of tolerance. Granulysin is a cytotoxic
      granule protein of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs).
      Recently, we developed an enzyme-linked immunosorbent assay (ELISA) system for
      detecting serum granulysin, and reported that serum granulysin is a useful marker
      to evaluate the cell-mediated immunity. In this study, we show that the serum
      levels of granulysin were significantly elevated in pre-eclamptic patients
      compared with those in normal pregnancy subjects. In addition, the serum
      granulysin levels in pre-eclamptic patients were well associated with mean blood
      pressure, percentage of peripheral blood Th1 cells and Th1/Th2 ratios. The
      present results suggest that the serum granulysin levels would be a useful and
      novel serum marker to evaluate the Th1/Th2 balance, especially Th1 type immunity
      in pre-eclampsia.

PMID- 15030523
TI  - GAD65 antibody isotypes and epitope recognition during the prediabetic process in
      siblings of children with type I diabetes.
AB  - We observed 42 initially non-diabetic siblings of affected children to
      characterize the humoral immune response to the 65 kDa isoform of glutamic acid
      decarboxylase (GAD65) in preclinical type I diabetes. During the observation
      period with a mean duration of 9.6 years 21 siblings progressed to type I
      diabetes. The humoral immune response to GAD65 was observed initially as a
      simultaneous response to the middle (M) and carboxy (C)-terminal regions of the
      GAD65 molecule in most cases, and if the response was restricted initially to the
      middle region, it spread rapidly to the C-terminal domain and in a few cases
      later to the amino (N)-terminal domain. There was some heterogeneity in the GAD65
      isotype response, but it was composed mainly of antibodies of immunoglobulin (Ig)
      G1 subclass. Responses of IgG2-, IgG4-, IgM- and IgA-GAD65Ab were observed
      frequently, whereas IgE- and IgG3-GAD65Ab responses were seen more rarely.
      Initially, the non-progressors tended more often to have IgG2- and IgG4-GAD65Ab
      than the progressors. As a sign of a dynamic process a significant isotype
      spreading was seen for IgG2-GAD65Ab (P < 0.05) and close to significant for IgM
      (P = 0.06) among progressors and for IgM-GAD65Ab (P < 0.05) among non-progressors
      during the observation period. This study failed to identify any GAD65 epitope-
      or isotype-specific antibody reactivity that could be used as a marker for
      progression to disease, as such progression was not associated with any specific
      changes in reactivity over time. Our findings indicate that epitope- and isotype
      specific GAD65 antibodies are hardly capable of separating progressors from non
      progressors among GAD65Ab-positive first-degree relatives of children with type I
      diabetes.

PMID- 15030524
TI  - Antibodies to TSH-receptor in thyroid autoimmune disease interact with monoclonal
      antibodies whose epitopes are broadly distributed on the receptor.
AB  - The hyperthyroidism of Graves' disease (GD) is caused by TSH-receptor (TSH-R)
      stimulating autoantibodies (TSAb), leading to overproduction of thyroid hormones.
      We present evidence for TSAb interaction with three distinct regions of the TSH
      R, one in immediate vicinity of the carboxy terminal serpentine. Three murine
      monoclonal antibodies (MoAbs 28.1, A9 and 31.7) directed to amino acids 36-40,
      147-228 and 382-415 were labelled and tested for their binding to human
      recombinant TSH-R on solid phase. All MoAbs bound to TSH-R with a K(d) of 8-12 nm
      and showed no competition among themselves. We tested 114 sera from euthyroid
      controls, 118 TBII positive sera from patients with GD (containing TSAb confirmed
      by bioassays), 16 TBII positive sera from patients with autoimmune thyroid
      disease (AIT), who were hypothyroid and had TSH blocking antibodies (TBAb), and
      20 patients with AIT, who were hypothyroid but negative for all TRAb. Mid
      regional MoAb A9 tracer achieved the highest sensitivity in the GD group (72.0%),
      whereas C-terminal MoAb 31.7 found most sera positive in the AIT group (87.5%).
      Surprisingly, the N-terminal MoAb 28.1 had the lowest sensitivity in the GD
      (10.4%) and AIT group (43.8%). Using a mixture of all three tracer MoAbs did not
      increase the sensitivity in the GD or AIT group, compared to the best single MoAb
      alone. Median inhibition of MoAb A9 was significantly (P < 0.001) higher than
      inhibition of MoAbs 28.1 or 31.7 in the group of GD patients but not in other
      groups. Almost all patient sera with positive reactivity in the MoAb tracer
      assays had TBII values in the higher range. However, there were many highly TBII
      positive sera, which did not show a displacement of the MoAb tracers. We conclude
      that, contrary to some reports, the binding of TSAb and TBAb to the TSH-R is not
      restricted to distinct and distant epitopes. The middle part of the TSH-R seems
      to be more relevant for TSAb binding than the N-terminal part, while a proportion
      of TSAb autoantibodies also binds to a C-terminal epitope of the TSH-R. The
      method described here is a TSH independent competitive assay for the detection of
      TSH-R autoantibodies.

PMID- 15030525
TI  - Evaluation of conformational epitopes on thyroid peroxidase by antipeptide
      antibody binding and mutagenesis.
AB  - Autoantibodies to thyroid peroxidase (TPO) recognize predominantly conformational
      epitopes, which are restricted to two distinct determinants, termed
      immunodominant domain region (IDR) A and B. These dominant determinants reside in
      the region with structural homology to myeloperoxidase (MPO)-like domain and may
      extend into the adjacent complement control protein (CCP) domain. We have
      explored the location of these determinants on the MPO-like domain of the
      structural model of TPO, by identifying exposed hydrophilic loops that are
      potential candidates for the autoantigenic sites, generating rabbit antipeptide
      antisera, and competing with well characterized murine monoclonal antibodies
      (mabs) specific for these two IDRs. We recently defined the location of IDR-B,
      and here report our findings on the location of IDR-A and its relationship to IDR
      B, defined with a new panel of 15 antipeptide antisera. Moreover, in combination
      with single amino acid replacements by in vitro mutagenesis, we have defined the
      limits of the IDR-B region on the TPO model. The combination of antisera to
      peptides P12 (aa 549-563), P14 (aa 599-617) and P18 (aa 210-225) inhibited the
      binding of the mab specific for IDR-A (mab 2) by 75%. The same combination
      inhibited the binding of autoantibodies to native TPO from 67 to 94% (mean 81.5%)
      at autoantibody levels of 5 IU. Fabs prepared from the antipeptide IgG and pooled
      in this combination were also effective in competition assays, thus defining the
      epitopes more precisely. IDR-A was found to lie immediately adjacent to IDR-B and
      thus the two immunodominant epitopes form an extended patch on the surface of
      TPO. Finally, by single amino acid mutagenesis, we show that IDR-B extends to
      residue N642, thus further localizing the boundary of this autoantigenic region
      on the structural model.

PMID- 15030526
TI  - Interleukin-6 production and secretion by human parathyroids.
AB  - Parathyroid hormone (PTH) stimulates osteoblasts to produce the proinflammatory
      cytokine interleukin-6 (IL-6), causing bone resorption. In patients with primary
      hyperparathyroidism, elevated serum levels of IL-6 normalize after resection of
      parathyroid tumours. Because IL-6 is also expressed in normal parathyroids and in
      other endocrine cells (adrenal and islet), we hypothesized that parathyroid
      tumours might contribute directly to the elevated serum IL-6 levels in patients
      with hyperparathyroidism. Immunohistochemistry identified IL-6, PTH, and
      chromogranin-A (an endocrine and neuroendocrine tumour marker) in normal,
      adenomatous and hyperplastic parathyroids. Using immunofluorescence and confocal
      microscopy, IL-6 co-localized with PTH and with chromogranin-A in parathyroid
      cells. All cultured parathyroid tumours secreted IL-6 at levels markedly higher
      than optimally stimulated peripheral blood mononuclear cells. Supernates from
      cultured parathyroids stimulated proliferation of an IL-6-dependent cell line,
      and anti-IL-6 MoAb abolished this stimulatory effect. IL-6 mRNA was documented in
      cultured parathyroid tumours, cultured normal parathyroids, fresh operative
      parathyroid tumours and fresh operative normal specimens. In conclusion, these
      data show that parathyroid tumours and normal parathyroids contain, produce and
      secrete IL-6. Our findings present a novel pathway by which human parathyroids
      may contribute markedly to IL-6 production and elevation of serum IL-6 levels in
      patients with hyperparathyroidism. The physiological relevance of IL-6 production
      by human parathyroids remains to be determined, but IL-6 secretion by parathyroid
      tumours may contribute to bone loss and to other multi-system complaints observed
      in these patients.

PMID- 15030527
TI  - Cathepsin D is up-regulated in inflammatory bowel disease macrophages.
AB  - Down-regulation of receptors involved in the recognition or transmission of
      inflammatory signals and a reduced responsiveness support the concept that
      macrophages are 'desensitized' during their differentiation in the intestinal
      mucosa. During inflammatory bowel disease (IBD) intestinal macrophages (IMACs)
      change to a reactive or 'aggressive' type. After having established a method of
      isolation and purification of IMACs, message for cathepsin D was one of the mRNAs
      we found to be up-regulated in a subtractive hybridization of Crohn's disease
      (CD) macrophages versus IMACs from control mucosa. The expression of cathepsin D
      in intestinal mucosa was analysed by immunohistochemistry in biopsies from IBD
      and control patients and in a mouse model of dextran sulphate sodium (DSS)
      induced acute and chronic colitis. IMACs were isolated and purified from normal
      and inflamed mucosa by immunomagnetic beads armed with a CD33 antibody. RT-PCR
      was performed for cathepsin D mRNA. Results were confirmed by Northern blot and
      flow cytometrical analysis. Immunohistochemistry revealed a significant increase
      in the cathepsin D protein expression in inflamed intestinal mucosa from IBD
      patients compared to non-inflamed mucosa. No cathepsin D polymerase chain
      reaction (PCR) product could be obtained with mRNA from CD33-positive IMACs from
      normal mucosa. Reverse transcription (RT)-PCR showed an induction of mRNA for
      cathepsin D in purified IMACs from IBD patients. Northern blot and flow cytometry
      analysis confirmed these results. Cathepsin D protein was also found in
      intestinal mucosa in acute and chronic DSS-colitis but was absent in normal
      mucosa. This study shows that expression of cathepsin D is induced in
      inflammation-associated IMACs. The presence of cathepsin D might contribute to
      the mucosal damage in IBD.

PMID- 15030532
TI  - Caffeine-withdrawal headache. The Vaga study of headache epidemiology.
AB  - In connection with the Vaga study of headache epidemiology, a search was made for
      caffeine-withdrawal headache in 1741 parishioners. Female to male ratio 1.05;
      mean age 44.2 years (range 18-65 years). A face-to-face interview technique was
      used. The mean consumption of coffee was 4.7 cups a day. Males on an average
      consumed more coffee (5.1 +/- 3.3 cups/day) than females (4.4 +/- 3.1 cups/day).
      Neither in those with a high consumption of coffee: > or =10 cups a day (n =
      134), nor in those with a considerable variation in consumption: > or =10
      cups/day (n = 31) did there seem to be a definite increase in headache resembling
      caffeine-withdrawal headache, for instance during weekends. In seven
      parishioners, however, there did seem to be such a headache, and in two of them,
      the evidence was rather convincing. This headache generally seemed to be mild and
      global and occurred mainly in the morning hours on weekends. There was no nausea,
      no throbbing quality of the pain, and no reported use of analgesics. Coffee
      seemed to abate the headache. This frequency (0.4%) should, clearly, be regarded
      as a minimum figure. Caffeine-withdrawal headache at the grassroots level may be
      a rather rare, generally vague, symptom-poor headache.

PMID- 15030529
TI  - Differential effect of calcium phosphate and calcium pyrophosphate on binding of
      matrix metalloproteinases to fibrin: comparison to a fibrin-binding protease from
      inflammatory joint fluids.
AB  - The ability of calcium phosphate (CaP) and calcium pyrophosphate (CaPPi) to
      mediate matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) binding to fibrin was
      evaluated. Substrate gel electrophoresis (gelatin zymography) revealed that CaP
      bound MMP-2 and MMP-9, forming a high molecular weight aggregate with lowered
      electrophoretic mobility. Formation of the CaP : MMP aggregate was necessary for
      fibrin binding. In contrast, CaPPi did not aggregate MMPs and did not promote
      uptake of MMPs into fibrin. Scatchard analysis (Ca/P ratio) revealed that CaPPi
      (1.96) was chemically similar to calcium pyrophosphate dihydrate (2.00) compared
      to amorphous CaP (1.50) or crystalline CaP, hydroxyapatite (1.66). MMP : CaP
      interaction appeared to be electrostatic in nature as high salt concentration
      (NaCl > 150 mm) reduced binding. In contrast, two non-ionic detergents (Brij-35
      and Tween-20) did not prevent MMP : CaP binding. MMP : CaP interaction did not
      involve the C-terminal MMP region because the specific tissue inhibitor of
      metalloproteinases (TIMPs) also did not block MMP : CaP interaction and fibrin
      binding. Although MMP : CaP binding could be decreased with albumin, this effect
      appeared non-specific due to the high albumin concentration required. High
      albumin concentration could also partially dissociate preformed MMP : CaP
      complexes. Interestingly, type I and type IV collagen substantially increased MMP
      : fibrin-binding activity, whereas denatured collagen, gelatin, did not.
      Inflammatory joint fluid from five patients also demonstrated similar MMP fibrin
      binding activity consistent with CaP mediation. The relevance of these findings
      to CaP and CaPPi in the pathogenesis of crystal arthropathies such as basic
      calcium phosphate (BCP) and calcium pyrophosphate dihydrate crystal disease
      (CPPD) is discussed.

PMID- 15030528
TI  - Binding capacity and pathophysiological effects of IgA1 from patients with IgA
      nephropathy on human glomerular mesangial cells.
AB  - IgA deposition in glomerular mesangium and the interaction with mesangial cells
      may well be the final common pathway to IgA nephropathy (IgAN). Altered hinge
      region O-glycosylation of IgA1 from patients with IgAN may predispose to
      mesangial deposition and activation of the mesangial cell (MC) by IgA1, via a
      novel IgA1 receptor, and may be a key event in the pathogensis of IgAN. The aim
      of this study was to investigate the binding capacity and biological effects of
      IgA1, from both patients with IgAN and healthy controls, on human mesangial cells
      (HMC). Serum IgA1 was isolated with jacalin affinity chromatography, heated to
      aggregated form (aIgA1) and labelled with (125)I. Binding capacity of aIgA1 in
      vitro to cultured primary HMC was evaluated by a radioligand binding assay and
      the specificity of binding was determined by a competitive inhibition assay.
      Intracellular calcium release was studied by confocal analysis and
      phosphorylation of extracellular signal-regulated kinase (ERK) was determined by
      Western blot analysis. Change of cell cycles was demonstrated by flow cytometry
      and HMC proliferation was evaluated by direct cell count. Expression of TGF-beta
      mRNA and production of supernatant fibronectin were tested by RT-PCR and indirect
      competitive ELISA, respectively. aIgA1 from both the patients with IgAN and
      normal controls bound to HMC in a dose-dependent, saturable manner, and was
      saturated at approximately 500 pmoles per 0.5 ml of aIgA1. aIgA1 from patients
      with IgAN, however, bound to HMC at a higher speed and Scatchard analysis
      revealed a Kd of (8.89 +/- 2.1) x 10(-8)m versus (4.3 +/- 1.2) x 10(-7)m for
      aIgA1 from healthy controls (P = 0.026). The binding was specific because it was
      only inhibited by unlabelled Mono-IgA1 (mIgA1) and not by serum albumin or IgG.
      aIgA1 from patients with IgAN could induce release of intracellular calcium,
      phosphorylation of ERK, DNA synthesis, proliferation of HMC, expression of TGF
      betamRNA and secretion of fibronectin in HMC in a similar time-dependent manner
      as aIgA1 from healthy controls, but the effects were much stronger and the
      durations were much longer (P < 0.05, respectively). We conclude that aIgA1 from
      patients with IgAN has a higher binding capacity to HMC and stronger biological
      effects than aIgA1 from healthy controls. This suggests that direct interaction
      between IgA1 and HMC and subsequential pathophysiological responses may play an
      important role in the pathogenesis for IgAN.

PMID- 15030533
TI  - Effects of N-, P/Q- and L-type calcium channel blockers on nociceptive neurones
      of the trigeminal nucleus with input from the dura.
AB  - In anaesthetized rats, extracellular recordings were made from neurones of the
      spinal trigeminal nucleus, involved in the processing of nociceptive input from
      the dura. Blockers of voltage-gated calcium channels (VGCCs) were administered
      topically to the exposed brainstem. Blockade of N-type (CaV2.2) channels reduced
      spontaneous activity and responses of the neurones to cold and chemical stimuli
      applied to the dura, suggesting that N-type channels regulate excitatory synaptic
      activation. Blockade of L-type (CaV1) channels enhanced spontaneous discharges of
      the neurones. Blockade of P/Q-type (CaV2.1) channels slightly decreased responses
      to chemical and cold stimuli but markedly increased spontaneous activity, an
      effect which was absent during concomitant application of GABA to the brainstem.
      The data suggest that P/Q-type VGCCs regulate a tonic synaptic inhibitory control
      of the brainstem neurones. The risk of migraine by genetic modifications of P/Q
      type channels may thus be sought in disturbed inhibition in the network that
      processes nociceptive dura input.

PMID- 15030534
TI  - Assessment of migraine severity using the MIGSEV scale: relationship to migraine
      features and quality of life.
AB  - We have recently developed an instrument to describe and categorize severity of
      migraine attacks from patient self-report, the MIGSEV questionnaire. We have now
      performed a large prospective survey using this tool to evaluate migraine
      severity in 2979 patients consulting for headache in France, included by 1164
      general practitioners, 174 neurologists and 82 gynaecologists. The objective of
      the study was to determine the prevalence of severity grades in a large
      population who consults for migraine, to test the concordance between severity
      calculated from physician-derived and patient-derived data, and to test the
      relevance of the concept of severity as applied to diagnosis, other measures of
      the burden of migraine, and to health-related quality of life. Severe attacks
      were reported in around one-fifth of the sample. Physician- and patient-derived
      data provided concordant estimates of severity in 71% of cases, the discordant
      cases representing principally an underestimate by the physician of headache
      severity. Migraine severity was associated with frequent, long-lasting and
      treatment-resistant attacks, and with poor quality of life. The MIGSEV
      questionnaire is proposed as a simple measure of severity for the diagnosis and
      management of migraineurs, suitable for use both by physicians and patients.

PMID- 15030535
TI  - Interictal daily functioning in migraine.
AB  - Migraine induces disability and an impaired quality of life, even between
      attacks. As most studies are based on subjective reports only, this study was set
      up to objectively quantify the interictal daily activities and heart rate of
      migraine patients, in relation to their subjectively reported highest realizable
      level of activity and of symptoms of mood in their habitual environment.
      Measurements were obtained during a migraine-free 2-day period of 24 patients
      (age range: 21-57 years) and 24 controls (age range: 18-59 years). Accelerometry
      was used to quantify the time spent in different postures and movements. The
      subjective parameters were documented by daily log. Whereas heart rate was
      similar for patients and controls, migraineurs were found to be significantly
      less physically active than controls and reported a significantly lower
      realizable level of activity. In addition, when active, their body motility was
      less than that of controls. Migraine patients also showed a higher level of
      sleepiness and lower level of vigour. These interictal behavioural and subjective
      phenomena objectively illustrate the individual and societal burden of migraine
      and its chronic impact on both domains.

PMID- 15030536
TI  - Circulating nociceptin levels during the cluster headache period.
AB  - The trigeminal innervation of the dura and its vessels has a prominent role in
      the mechanism of cluster headache. Nociceptin, an opioid neuropeptide, is the
      endogenous ligand of the OP-4 receptor, with both algesic and analgesic
      properties depending on the site of action. Nociceptin and its receptor are
      expressed by trigeminal ganglion cells where they co-localize with calcitonin
      gene-related peptide, a marker peptide of the trigeminovascular neurones.
      Nociceptin inhibits neurogenic dural vasodilatation, a phenomenon related to
      trigeminovascular activation. To explore its possible involvement in cluster
      headache, we studied circulating levels of nociceptin when attack-free during the
      cluster period, and also after the termination of the cluster period, using
      radioimmunoassay. In 14 cluster headache patients nociceptin levels during the
      cluster period were significantly lower than in age-, and sex-matched controls
      (4.91 +/- 1.96 vs. 9.58 +/- 2.57 pg/ml, P < 0.01). After the termination of the
      cluster period nociceptin levels (8.60 +/- 1.47 pg/ml) were not statistically
      different from controls. Nociceptin levels did not correlate with age, length of
      disease or episode length. Lower nociceptin levels during the cluster period may
      result in a defective regulation of trigeminal activity that might not protect
      sufficiently against the attacks.

PMID- 15030537
TI  - Haemodialysis-related headache.
AB  - Dialysis may induce severe headache as a result of a large amount of water and
      electrolyte shifts. It is important to recognize it because it can be a great
      problem to the patient and changing dialysis parameters or methods can prevent
      it. In this study we investigated the frequency and clinical characteristics of
      headaches occurring during haemodialysis (HD). Thirty female and 33 male patients
      with chronic renal failure on regular dialysis for at least 6 months in the HD
      unit of the Internal Medicine Department from 1996 to 2000 participated in the
      study. The dialysis solution contained acetate in 35 patients and bicarbonate in
      28 patients. In all patients capillary dialysers and Cuprophan membranes were
      used and every session of dialysis lasted 4 h. All patients received the same
      questionnaire and they were visited randomly. Dialysis headache (DH) diagnosis
      was made according to the criteria of the International Headache Society.
      Patients with primary headache and under drug treatment during HD, which can
      cause headache, were excluded from the study. The frequency of DH, its relation
      to gender, age, dialysis technique and parameters and its features were
      investigated. DH was detected in 48% (n = 30) of the study group. Compared with
      dialysis solutions, no difference was found between patients with and without DH.
      The difference in the pre- and post-dialysis value of urea in patients with DH
      was statistically significant (P < 0.05). Patients with DH showed significantly
      higher mean systolic and diastolic blood pressure predialysis values in
      comparison with patients without DH (systolic, P < 0.001; diastolic, P < 0.01),
      whereas post-treatment values did not differ between the two groups. Fronto
      temporal location, moderate severity, throbbing quality and short duration (<4 h)
      were the most prevalent features of DH in patients.

PMID- 15030538
TI  - A comparison of the pharmacokinetics and tolerability of the anti-migraine
      compound almotriptan in healthy adolescents and adults.
AB  - This study was designed to assess and compare the pharmacokinetics and
      tolerability of almotriptan, a 5-HT1B/1D agonist used to treat migraine attacks,
      in adolescents and adults. Healthy adolescents (n = 18) and adults (n = 18)
      received a single 12.5-mg dose of almotriptan after fasting overnight. Plasma and
      urinary almotriptan concentrations were measured by high-performance liquid
      chromatography. Pharmacokinetic parameters of almotriptan were determined by non
      compartment analysis. The 90% confidence interval (CI) approach was employed to
      assess age effects. Mean Cmax, tmax, area under the curve (AUC0- infinity ), half
      life, and percentage excreted in urine were nearly identical for the two
      populations. Mean oral (CLPO) and renal (CLR) clearances were similar between the
      age groups; however, weight-corrected CLPO was approximately 32% higher (90% CI
      16, 51) in adolescents compared with adults. The higher weight-corrected CLPO
      appeared to offset increases in exposure expected on the basis of lower body
      weight in adolescents. The findings were the same when a subgroup (n = 9) of 12
      14-year-old children was compared with adults. The type, incidence and severity
      of adverse events were similar between the two age groups and were consistent
      with those reported previously during adult clinical trials. Based on these
      pharmacokinetic and tolerability findings, no dose adjustment for almotriptan
      would be required when treating patients as young as 12 years old.

PMID- 15030539
TI  - Prevalence and clinical characteristics of an experimental model of 'ice-cream
      headache' in migraine and episodic tension-type headache patients.
AB  - This study was designed to compare the prevalence and clinical characteristics of
      'cold-induced headache' between migraine and episodic tension-type headache
      patients. Seventy-six migraine and 38 episodic tension-type headache patients
      were included in the study. An experimental model of an 'ice-cream headache' was
      developed for the study. The pain occurrence period, its location and quality
      were recorded for each patient who felt pain in their head during the test
      procedure. Pain in the head occurred in 74% of migraine and 32% of 'tension-type
      headache' patients. Although the most frequent pain location was the temple in
      both groups of patients, this rate was greater than twofold in migraine patients
      when compared with episodic tension-type headache patients. While headache
      quality was throbbing in 71% of migraine patients, it was so in only 8% of the
      episodic tension-type headache patients. Considering all the results, it seems
      that 'cold-stimulus headache' is not only more frequent in migraine patients, but
      also its location and quality differ from 'tension-type headache'.

PMID- 15030540
TI  - Triptans and chest symptoms: the role of pulmonary vasoconstriction.
AB  - Triptans are effective and well tolerated in the treatment of acute migraine.
      Chest symptoms are a common adverse effect unrelated to coronary vasoconstriction
      in most patients. Although the aetiology of chest symptoms remains to be fully
      defined, pulmonary vasoconstriction is a possible underlying mechanism. Pre
      clinical studies of isolated human blood vessels were used to identify the
      cerebral selectivity of triptans and ascertain if selectivity vs the pulmonary
      vasculature predicts a lower rate of chest symptoms. Controlled clinical trials
      and post-marketing surveillance studies were reviewed to document the incidence
      of chest symptoms after triptan therapy. In clinical trials, the incidence of
      chest symptoms at usual therapeutic doses ranged from 1 to 4% depending on the
      triptan and study design, whereas in post-marketing surveillance studies, up to
      41% of patients specifically asked about chest symptoms reported them. A
      comparative clinical trial showed that almotriptan was associated with lower
      incidence of chest symptoms than sumatriptan (0.3 vs 2.2%). The intrinsic
      activity of almotriptan, a second-generation triptan, on human pulmonary arteries
      and veins was lower than that of sumatriptan. Pre-clinical studies of isolated
      pulmonary blood vessels may predict the clinical likelihood of chest symptoms;
      however, additional comparisons are needed.

PMID- 15030541
TI  - The 'red ear syndrome' revisited: two cases and a review of literature.

PMID- 15030542
TI  - Did Franz Kafka suffer from cluster headache?

PMID- 15030543
TI  - Ophthalmoplegic migraine: migrainous or inflammatory?

PMID- 15030544
TI  - Controversies in headache.

PMID- 15030545
TI  - Controversies in headache.

PMID- 15030549
TI  - Cell cycle-related variation in subcellular localization of eIF3e/INT6 in human
      fibroblasts.
AB  - The Int-6 gene is a site of mouse mammary tumour virus (MMTV) integration in
      murine tumours and INT6 protein has been identified independently as a subunit
      (eIF3e) of the eukaryotic translation initiation factor eIF3. In addition, the
      protein can interact with two other multi-subunit complexes: the COP9 signalosome
      (CSN) and the proteasome. The role of INT6 in tumourigenesis is nonetheless
      currently unclear. Here, using immunofluorescence microscopy, we show that
      eIF3e/INT6 is localized in part to the nucleus, while other eIF3 components are
      cytoplasmic. Primary human fibroblasts, but not their transformed counterparts,
      showed reduced nuclear INT6 staining in some cells, and this reduction was
      maximal in early S phase. This variation in eIF3e/INT6 may indicate regulated
      shuttling between cellular compartments and would be consistent with the presence
      of a nuclear export signal as well as a nuclear localization signal in the
      protein sequence. Loss of regulation of eIF3e/INT6 redistribution may therefore
      be a significant feature of malignancy in human cells.

PMID- 15030550
TI  - Laminin-2 stimulates the proliferation of epithelial cells in a conjunctival
      epithelial cell line.
AB  - Laminin-2 (LN-2, alpha2beta1gamma1) is a basement membrane-associated laminin
      isoform usually considered in the context of muscle and nerve tissues. To test
      the hypothesis that LN-2 can additionally modulate epithelial cell biology, an
      analysis of the role of LN-2 in cell adhesion, activation of signalling
      intermediates and proliferation was undertaken. A virally transformed human
      conjunctival epithelial cell line (HC0597) was utilized in this study. Adhesion
      assays using function-inhibiting antibodies demonstrated that alpha3beta1
      integrin is essential for the rapid attachment of conjunctival epithelial cells
      to LN-2. Bromodeoxyuridine (BrdU) incorporation analyses revealed that, compared
      with LN-1 or LN-10, LN-2 significantly promotes epithelial proliferation.
      Phosphorylation of the signalling intermediates Erk1/2 and Akt-1 was observed
      within 15 min of cell adhesion to LN-2. Inhibiting alpha3beta1 integrin function
      decreased total cellular phosphotyrosine levels, specifically inhibited
      phosphorylation of Erk1/2 and Akt-1, and dampened the proliferation response of
      epithelial cells adherent to LN-2. Inhibition of Erk or Akt activation inhibited
      cell proliferation in a dose-dependent manner. However, the inhibition of Erk
      resulted in a stronger suppression of proliferation compared with Akt inhibition.
      From these results, it is concluded that human conjunctival epithelial cells
      adhere to immobilized LN-2 using alpha3beta1 integrin. alpha3beta1 integrin/LN-2
      signalling, transduced primarily through an Erk pathway, enhances epithelial cell
      proliferation. These results demonstrate that LN-2 can impact on epithelial cell
      biology in addition to nerve and muscle, and provide information regarding the
      role of this isoform in ocular surface epithelial cells.

PMID- 15030551
TI  - Activation, isolation, identification and in vitro proliferation of oval cells
      from adult rat livers.
AB  - Oval cells, putative hepatic stem cells, could potentially provide a novel
      solution to the severe shortage of donor livers, because of their ability to
      proliferate and differentiate into functional hepatocytes. We have previously
      demonstrated that oval cells can be induced to differentiate into cells with
      morphologic, phenotypic, and functional characteristics of mature hepatocytes. In
      this study, we have established a new model combining ethionine treatment with
      partial hepatectomy to activate oval cells, then developed a procedure utilizing
      selective enzymatic digestion and density gradient centrifugation to isolate and
      purify such cells from heterogeneous liver cell population. We identified oval
      cells by their morphological characteristics and phenotypic properties, thereby
      providing definitive evidence of the presence of hepatic stem-like cells in adult
      rat livers. Viewed by transmission electron microscopy, they were small cells
      with ovoid nuclei, a high nucleus/cytoplasm ratio and few organelles, including
      mitochondria and endoplasmic reticulum. Flow cytometric assay showed that these
      cells highly expressed OV-6, cytokeratin-19 (CK-19) and albumin. Reverse
      transcriptase-polymerase chain reaction (RT-PCR) analysis displayed that the
      freshly isolated cells co-expressed albumin, cytokeratin-7 (CK-7) and CK-19 mRNA,
      indicating that they were essentially bipotential hepatic stem-like cells.
      Furthermore, we set up a culture system containing growth factors and a
      fibroblast feeder layer, to provide nourishment to these cells. Thus, we were
      able to culture them in vitro for more than 3 months, with the number of cells
      doubling 100 times. Gene expressions of albumin, CK-7 and CK-19 in the cells
      derived from the expanding colonies at day 95 were confirmed by RT-PCR analysis.
      These data suggested that the hepatic oval cells derived from adult rat livers
      possess a high potential to proliferate in vitro with a large increase in number,
      while maintaining the bipotential nature of hepatic stem cells.

PMID- 15030552
TI  - Cell cycle time and rate of entry of cells into mitosis in the small intestine of
      young rats.
AB  - Cell cycle time (T(C)) and the rate of entry of cells into mitosis (r(M)) in the
      jejunum and duodenum of young rats were investigated using the stathmokinetic
      method. The cell cycle times in the jejunum were 24.3 and 28.3 h in light and
      dark periods, respectively. Cell cycle times in the duodenum were 17.1 and 21.5 h
      in light and dark periods, respectively. Rates of entry of cells into mitosis in
      the jejunum were 1.2 and 1.1 cells/cell/h in light and dark periods and rates of
      entry of cells into mitosis in the duodenum were 1.4 and 1.8 cells/cell/h in
      light and dark periods, respectively. Although these changes to cell cycle time
      values are not statistically significant, the variation between the two periods
      should be considered in relation to its possible biological effects.

PMID- 15030554
TI  - A historical perspective.

PMID- 15030553
TI  - Exposure to continuous bromodeoxyuridine (BrdU) differentially affects cell cycle
      progression of human breast and bladder cancer cell lines.
AB  - Incorporation of bromodeoxyuridine (BrdU) during DNA replication is frequently
      used for cell cycle analysis. The flow cytometric BrdU/Hoechst quenching
      technique is conducive to high-resolution assessment of cell cycle kinetics, but
      requires continuous BrdU treatment, which may have cytostatic or cytotoxic
      effects. Here, we have examined the impact of BrdU on the proliferation of BT474
      and SK-BR-3 breast cancer cell lines and compared the observed effects with cell
      proliferation of RT4 and J82 bladder carcinoma cells, previously described to be
      sensitive and insensitive to BrdU, respectively. Both uni- and bi-parametric DNA
      measurements were performed to identify BrdU-induced alterations in the S-phase
      fraction and in cell cycle progression. An annexinV/propidium iodide (PI) assay
      was used to identify potential induction of apoptosis by BrdU. Proliferative
      activity in BT474, SK-BR-3, and RT4 cultures was reduced in different cell cycle
      phases due to continuous treatment with 60, 5.0, and 3.5 micro m BrdU. This
      effect, which was not found in J82 cultures, was dependent on exposure time (96
      versus 48 h) and was also dose-dependent for RT4 and SK-BR-3. BrdU application
      does not induce apoptosis or necrosis as revealed with the annexin V/PI assay. We
      concluded that continuous BrdU treatment did not affect cell viability, but
      essentially alters cell cycle progression in three out of four cell lines tested.
      Cell-type specific validation of the feasibility of the powerful BrdU/Hoechst
      quenching technique is required and recommended.

PMID- 15030555
TI  - Cyclosporin A: a new drug in the field of canine dermatology.
AB  - In the last few years, there has been growing interest in the use of cyclosporin
      to treat canine skin diseases. Cyclosporin exhibits potent immunomodulating
      properties that reflect its ability to block the transcription of cytokines genes
      in activated T lymphocytes. Cyclosporin also inhibits a number of immune allergic
      reactions that occur after activation of mast cells, Langerhans cells,
      eosinophils and keratinocytes. In randomized controlled trials, cyclosporin has
      proven to be as effective as glucocorticoids for treatment of canine atopic
      dermatitis at the inducing dosage of 5 mg kg(-1). The drug has also proven
      beneficial for the treatment of perianal fistulas in dogs. Other potential
      applications are suggested from small pilot open trials using dogs affected with
      various immune-mediated dermatological diseases. The pharmacokinetic properties
      of cyclosporin are very similar in dogs and man, but its safety margin is much
      wider in dogs. Therefore, routine cyclosporin blood level monitoring does not
      appear necessary. Although in man renal impairment and hypertension are often
      seen, even at low doses, these effects are not observed in dogs. Adverse
      reactions consist mainly of transient emesis and diarrhoea occurring during the
      first days of treatment. Other adverse reactions, such as gingival hyperplasia,
      verruciform lesions and hypertrichosis, appear to be dose-dependent, and occur
      rarely at therapeutic doses. An increased susceptibility to infections has not
      been reported in dogs receiving this drug.

PMID- 15030556
TI  - Treatment protocols for demodicosis: an evidence-based review.
AB  - Publications discussing the treatment of demodicosis in the dog and cat are
      reviewed. Based on the evidence in the literature, amitraz rinses at 0.025-0.06%
      every 7-14 days, and oral daily ivermectin at 300 micro g kg(-1), milbemycin at 2
      mg kg(-1) and moxidectin at 400 micro g kg(-1), respectively, can all be
      recommended for the treatment of generalized canine demodicosis. Ivermectin and
      moxidectin should be initiated at lower doses and patients monitored for possible
      adverse effects during therapy. In cats, 2% lime sulfur dips and amitraz rinses
      at 0.0125-0.025% have been used successfully.

PMID- 15030557
TI  - Pemphigus: current therapy.
AB  - Pemphigus is an autoimmune skin disease that can present in a variety of forms
      and can be a challenging disease to manage and treat. An overview of the
      different forms of pemphigus and diagnostics are discussed including pemphigus
      foliaceus (PF), pemphigus erythematosus (PE), panepidermal pustular pemphigus
      (PPP), pemphigus vulgaris (PV) and paraneoplastic pemphigus (PNP). Emphasis on
      therapy is presented. Included are the most current commonly used therapeutics
      (glucocorticoids, azathioprine, chlorambucil and tetracycline and niacinamide);
      current alternative therapeutics (cyclosporin and tacrolimus and mycophenolate
      mofetil) and additional alternative therapeutics (cyclophosphamide,
      chrysotherapy, dapsone, sulfasalazine and intravenous immunoglobulin (IVIG)
      therapy).

PMID- 15030558
TI  - Treatment of dermatophytosis in dogs and cats: review of published studies.
AB  - The recent literature on the treatment of dermatophytosis in dogs and cats was
      reviewed. Based upon in vitro studies using isolated infected hairs and
      controlled or field in vivo studies, the following topical treatments were
      consistently found to be antifungal (i.e. antidermatophyte): lime sulfur (1:16),
      0.2% enilconazole rinses, and a combined 2% miconazole/chlorhexidine shampoo.
      Animals or hairs were either bathed or rinsed once or twice weekly. Itraconazole,
      griseofulvin and terbinafine were evaluated in controlled or field studies, most
      commonly involving cats. Griseofulvin (50 mg kg(-1)) was reported to cure
      infected animals in 41-70 days. Itraconazole (10 mg kg(-1) once daily or in a
      combined daily/pulse therapy 10 mg kg(-1) once daily for 28 days and then week
      on/week off) was reported to cure infected animals in 56-70 days. Low-dose
      itraconazole (1.5-3.0 mg kg(-1)) in 15-day cycles required 1-3 cycles (15-45
      days). Various doses of terbinafine (5-40 mg kg(-1)) were reportedly used to
      treat dogs or cats. The higher doses of terbinafine (> 20 mg kg(-1)) were
      required to achieve a mycological cure; the number of treatment days to cure
      varied from 21 to > 126 days. Lufenuron was reported anecdotally to be an
      effective cure, however, this was not substantiated in controlled studies.
      Finally, fungal vaccines were not found to be effective against challenge
      exposure, however, there is evidence that they may be useful in treatment
      protocols.

PMID- 15030559
TI  - Current trends in the treatment of Sarcoptes, Cheyletiella and Otodectes mite
      infestations in dogs and cats.
AB  - For a number of reasons, several of the more 'traditional' ectoparasiticides in
      the small animal veterinarian's armoury have been withdrawn over the past few
      years. New, safer products which are long-acting and easier to apply than the
      conventional dips, rinses and aerosol sprays of the past have replaced them.
      However, relatively few such novel acaricidal preparations have become
      commercially available. Consequently, practitioners and researchers frequently
      experiment with the drugs they have at their disposal to assess their efficacy
      against a variety of target acarids when used at different dosages and/or via
      different routes of administration, compared with those recommended by the
      manufacturer. This paper reviews the anecdotal and peer-reviewed reports
      describing the use of modern acaricides in dogs and cats that have recently
      appeared in the veterinary literature. It should be stressed, however, that no
      medicine should be prescribed for extra-label use without the informed consent of
      the owner.

PMID- 15030560
TI  - Immunomodulation and immunodeficiency.
AB  - This article briefly reviews the concepts of immunodeficiency and
      immunomodulation as they relate to selected skin diseases in the dog and cat.
      Immunodeficiency states are uncommon and may be associated with a subnormal or
      down-regulated immune system, including humoral deficiencies, such as IgA, and
      abnormal lymphocyte or neutrophil function. Establishing a causal relationship
      between a skin disease and presumed immunodeficient state has been difficult due
      to the rarity of such conditions, and the limited nature of the techniques used
      to characterise the immune system response. Severe combined immunodeficiency in
      dogs is a well characterised primary immunodeficiency state involving
      lymphocytes; retrovirus infection in cats may lead to an acquired immunodeficient
      state with some association with certain dermatological conditions although it
      remains unclear that infection is causally linked with disease. Immunomodulation
      usually implies stimulating the immune system along a beneficial pathway. Such a
      therapeutic approach may involve a wide variety of agents, for example
      intravenous immunoglobulin. There are few randomised controlled trials with
      veterinary patients that unequivocally demonstrate beneficial responses to
      immunomodulatory agents. Interferons are cytokines of major interest in human and
      veterinary medicine for their antiviral, anti-tumour and immunomodulatory
      effects. The advent of veterinary-licensed products containing recombinant
      interferon may enable demonstration of the efficacy of interferons for conditions
      such as canine papillomatosis and feline eosinophilic granuloma complex. Canine
      pyoderma has been treated with a number of presumed immunomodulatory agents with
      limited success. With more detailed knowledge of the pathogenesis of pyoderma it
      may be possible to develop efficacious immunomodulators.

PMID- 15030561
TI  - Ear cleaning: the UK and US perspective.
AB  - Ear cleaning helps maintain the normal otic environment and is important in the
      treatment of otitis. Over cleaning, however, may trigger otitis through
      maceration of the epidermal lining. Simple manual cleaning is useful for routine
      cleansing but doesn't remove tightly adherent debris. Bulb syringes are more
      vigorous but may damage the ear in inexperienced hands. Devices using mains water
      pressure or dental machines are also available. Thorough cleaning of the ear
      canals and middle ear cavity can only be achieved by retrograde flushing using
      specially adapted catheters, feeding tubes or video otoscopes under anaesthesia.
      Myringotomy, inspection and cleaning of the middle should be performed if the
      tympanic membrane appears abnormal. There are a wide variety of cleaning fluids
      available. Ceruminolytics soften and dissolve cerumen to facilitate cleaning.
      Surfactants emulsify debris, breaking it up and keeping it in solution.
      Astringents dry the ear canal surface, preventing maceration. Maintaining a low
      pH and incorporating antimicrobial agents can inhibit microbial proliferation and
      glucocorticoids can be used to reduce inflammation. Adverse effects and
      contraindications following ear cleaning can include maceration, contact
      reactions, otitis media, ear canal avulsion, vestibular syndrome, Horner's
      syndrome, facial nerve paralysis and deafness. Care should be exercised in
      selecting cleaning fluids if the tympanic membranes are ruptured.

PMID- 15030562
TI  - Invisible rafts at work.

PMID- 15030563
TI  - Molecular dynamics and interactions for creation of stimulation-induced
      stabilized rafts from small unstable steady-state rafts.
AB  - We have evaluated the sizes and lifetimes of rafts in the plasma membrane from
      the existing literature, with a special attention paid to their intrinsically
      broad distributions and the limited time and space scales that are covered by the
      observation methods used for these studies. Distinguishing the rafts in the
      steady state (reserve rafts) from those after stimulation or unintentional
      crosslinking of raft molecules (stabilized receptor-cluster rafts) is critically
      important. In resting cells, the rafts appear small and unstable, and the
      consensus now is that their sizes are smaller than the optical diffraction limit
      (250 nm). Upon stimulation, the raft-preferring receptors are clustered, inducing
      larger, stabilized rafts, probably by coalescing small, unstable rafts or
      cholesterol-glycosphingolipid complexes in the receptor clusters. This receptor
      cluster-induced conversion of raft types may be caused by suppression of alkyl
      chain isomerization and the lipid lateral diffusion in the cluster, with the aid
      of exclusion of cholesterol from the bulk domain and the boundary region of the
      majority of transmembrane proteins. We critically inspected the possible analogy
      to the boundary lipid concept. Finally, we propose a hypothesis for the coupling
      of GPI-anchored receptor signals with lipid-anchored signaling molecules in the
      inner-leaflet raft.

PMID- 15030564
TI  - Rafts: scale-dependent, active lipid organization at the cell surface.
AB  - Rafts have been conceptualized as lateral heterogeneities in the organization of
      cholesterol and sphingolipids, endowed with sorting and signaling functions. In
      this review we critically examine evidence for the main tenet of the 'raft
      hypothesis', namely lipid-dependent segregation of specific membrane components
      in the plasma membrane. We suggest that conventional approaches to studying raft
      organization wherein membranes are treated as passive, thermally equilibrated
      systems are unlikely to provide an adequate framework to understand the
      mechanisms of raft-organization in vivo. An emerging view of raft organization is
      that it is spatio-temporally regulated at different scales by the cell. This
      argues that rafts must be defined by simultaneous observation of components
      involved in particular functions. Recent evidence from the study of
      glycosylphosphatidyl inositol-anchored proteins, a common raft-marker, supports
      this picture in which larger scale, more stable rafts are induced from
      preexisting small-scale lipid-dependent structures actively maintained by
      cellular processes.

PMID- 15030565
TI  - Transmembrane asymmetry and lateral domains in biological membranes.
AB  - It is generally assumed that rafts exist in both the external and internal
      leaflets of the membrane, and that they overlap so that they are coupled
      functionally and structurally. However, the two monolayers of the plasma membrane
      of eukaryotic cells have different chemical compositions. This out-of-equilibrium
      situation is maintained by the activity of lipid translocases, which compensate
      for the slow spontaneous transverse diffusion of lipids. Thus rafts in the outer
      leaflet, corresponding to domains enriched in sphingomyelin and cholesterol,
      cannot be mirrored in the inner cytoplasmic leaflet. The extent to which lipids
      contribute to raft properties can be conveniently studied in giant unilamellar
      vesicles. In these, cholesterol can be seen to condense with saturated
      sphingolipids or phosphatidylcholine to form microm scale domains. However, such
      rafts fail to model biological rafts because they are symmetric, and because
      their membranes lack the mechanism that establishes this asymmetry, namely
      proteins. Biological rafts are in general of nm scale, and almost certainly
      differ in size and stability in inner and outer monolayers. Any coupling between
      rafts in the two leaflets, should it occur, is probably transient and dependent
      not upon the properties of lipids, but on transmembrane proteins within the
      rafts.

PMID- 15030566
TI  - Lipids as targeting signals: lipid rafts and intracellular trafficking.
AB  - Our view of biological membranes has evolved dramatically over the last few
      decades. In the bilayer model from Singer & Nicholson (Science 1972;175:720-731),
      both proteins and lipids freely diffuse within the plane of the membrane.
      Currently, however, membranes are viewed as a mosaic of different compartments or
      domains maintained by an active cytoskeleton network (Ritchie et al. Mol Membr
      Biol 2003; 20:13-18). Due to interactions between membrane components, several
      types of subdomains can form with different characteristics and functions. Lipids
      are likely to play an important role in the formation of so-called lipid-enriched
      microdomains or lipid rafts, adding another order of complexity to the membrane
      model. Rafts represent a type of domain wherein lipids of specific chemistry may
      dynamically associate with each other, to form platforms important for membrane
      protein sorting and construction of signaling complexes (Simons & Toomre. Nat Rev
      Mol Cell Biol 2000;1:31-39). Currently, there are several hypotheses concerning
      the nature of rafts (reviewed in (Edidin. Annu Rev Biophys Biomol Struct 2003;32:
      257-283; Zurzolo et al. EMBO Rep 2003;4:1117-1121)). The most commonly cited one,
      proposed by Kai Simons (Simons & Ikonen. Nature 1997;387:569-572; Pralle et al. J
      Cell Biol 2000;148:997-1008), suggests that rafts are relatively small structures
      ( approximately 50 nm) enriched in cholesterol and sphingolipids within which
      associated proteins are likely to be concentrated. Another proposal (Anderson &
      Jacobson. Science 2002;296:1821-1825) suggests that rafts are constructed of
      lipid shells. These are small dynamic assemblies wherein 'raft' proteins are
      preferentially associated with certain types of lipids. These 'shells' are
      thermodynamically stable mobile entities in the plane of the membrane that are
      able to target the protein they encase to preexisting rafts/caveolae domains. In
      this review we summarize the data suggesting a specific role for lipid domains in
      intracellular trafficking and sorting and present a modification of the raft
      model that may help explain the observed phenomena.

PMID- 15030568
TI  - Membrane domains in lymphocytes - from lipid rafts to protein scaffolds.
AB  - Lateral compartmentalization of the plasma membrane into domains is a key feature
      of immune cell activation and subsequent immune effector functions. Here, we will
      review the high diversity of membrane domains, ranging from elementary lipid
      rafts, envisioned as dynamic and small domains (in the tens of nm), to relatively
      stable microm-scale membrane domains, which form the immunologic synapse of T
      lymphocytes. We will discuss the relationship between these different types of
      plasma membrane domains and how raft lipid- and protein-controlled interactions
      and cell biological processes cooperate to generate functional domains that
      mediate lymphocyte activity.

PMID- 15030569
TI  - Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome
      proteins HPS3, HPS5 and HPS6.
AB  - Hermansky-Pudlak syndrome (HPS) defines a group of at least seven autosomal
      recessive disorders characterized by albinism and prolonged bleeding due to
      defects in the lysosome-related organelles, melanosomes and platelet-dense
      granules, respectively. Most HPS genes, including HPS3, HPS5 and HPS6, encode
      ubiquitously expressed novel proteins of unknown function. Here, we report the
      biochemical characterization of a stable protein complex named Biogenesis of
      Lysosome-related Organelles Complex-2 (BLOC-2), which contains the HPS3, HPS5 and
      HPS6 proteins as subunits. The endogenous HPS3, HPS5 and HPS6 proteins from human
      HeLa cells coimmunoprecipitated with each other from crude extracts as well as
      from fractions resulting from size-exclusion chromatography and density gradient
      centrifugation. The native molecular mass of BLOC-2 was estimated to be 340 +/-
      64 kDa. As inferred from the biochemical properties of the HPS6 subunit, BLOC-2
      exists in a soluble pool and associates to membranes as a peripheral membrane
      protein. Fibroblasts deficient in the BLOC-2 subunits HPS3 or HPS6 displayed
      normal basal secretion of the lysosomal enzyme beta-hexosaminidase. Our results
      suggest a common biological basis underlying the pathogenesis of HPS-3, -5 and -6
      disease.

PMID- 15030570
TI  - Golgi inheritance under a block of anterograde and retrograde traffic.
AB  - In mitosis, the Golgi complex is inherited following its dispersion, equal
      partitioning and reformation in each daughter cell. The state of Golgi membranes
      during mitosis is controversial, and the role of Golgi-intersecting traffic in
      Golgi inheritance is unclear. We have used brefeldin A (BFA) to perturb Golgi
      intersecting membrane traffic at different stages of the cell cycle and followed
      by live cell imaging the fate of Golgi membranes in those conditions. We observed
      that addition of the drug on cells in prometaphase prevents mitotic Golgi
      dispersion. Under continuous treatment, Golgi fragments persist throughout
      mitosis and accumulate in a Golgi-like structure at the end of mitosis. This
      structure localizes at microtubule minus ends and contains all classes of Golgi
      markers, but is not accessible to cargo from the endoplasmic reticulum or the
      plasma membrane because of the continuous BFA traffic block. However, it contains
      preaccumulated cargo, and intermixes with the reforming Golgi upon BFA washout.
      This structure also forms when BFA is added during metaphase, when the Golgi is
      not discernible by light microscopy. Together the data indicate that independent
      Golgi fragments that contain all classes of Golgi markers (and that can be
      isolated from other organelles by blocking anterograde and retrograde Golgi
      intersecting traffic) persist throughout mitosis.

PMID- 15030567
TI  - Lipid rafts and the regulation of exocytosis.
AB  - Exocytosis is the process whereby intracellular fluid-filled vesicles fuse with
      the plasma membrane, incorporating vesicle proteins and lipids into the plasma
      membrane and releasing vesicle contents into the extracellular milieu. Exocytosis
      can occur constitutively or can be tightly regulated, for example,
      neurotransmitter release from nerve endings. The last two decades have witnessed
      the identification of a vast array of proteins and protein complexes essential
      for exocytosis. SNARE proteins fill the spotlight as probable mediators of
      membrane fusion, whereas proteins such as munc18/nsec1, NSF and SNAPs function as
      essential SNARE regulators. A central question that remains unanswered is how
      exocytic proteins and protein complexes are spatially regulated. Recent studies
      suggest that lipid rafts, cholesterol and sphingolipid-rich microdomains,
      enriched in the plasma membrane, play an essential role in regulated exocytosis
      pathways. The association of SNAREs with lipid rafts acts to concentrate these
      proteins at defined sites of the plasma membrane. Furthermore, cholesterol
      depletion inhibits regulated exocytosis, suggesting that lipid raft domains play
      a key role in the regulation of exocytosis. This review examines the role of
      lipid rafts in regulated exocytosis, from a passive role as spatial coordinator
      of exocytic proteins to a direct role in the membrane fusion reaction.

PMID- 15030571
TI  - Recognition of lumenal prion protein aggregates by post-ER quality control
      mechanisms is mediated by the preoctarepeat region of PrP.
AB  - Prion diseases are fatal transmissible neurodegenerative disorders linked to an
      aberrant conformation of the cellular prion protein (PrP(c)). We have shown
      previously that the chemical compound suramin induced aggregation of fully
      matured PrP(c) in post-ER compartments, thereby, activating a post-ER quality
      control mechanism and preventing cell surface localization of PrP by
      intracellular re-routing of aggregated PrP from the Golgi/TGN directly to
      lysosomes. Of note, drug-induced PrP aggregates were not toxic and could easily
      be degraded by neuronal cells. Here, we focused on determining the PrP domains
      mediating these effects. Using PrP deletion mutants we show that intracellular re
      routing but not aggregation depends on the N-terminal PrP (aa 23-90) and, more
      precisely, on the preoctarepeat domain (aa 23-50). Fusion of the PrP N-terminus
      to the GPI-anchored protein Thy-1 did not cause aggregation or re-routing of the
      chimeric protein, indicating that the N-terminus is only active in re-routing
      when prion protein aggregation occurs. Insertion of a region with a comparable
      primary structure contained in the PrP paralogue prnd/doppel (aa 27-50) into N
      terminally deleted PrP re-established the re-routing phenotype. Our data reveal
      an important role for the conserved preoctarepeat region of PrP, namely
      controlling the intracellular trafficking of misfolded PrP.

PMID- 15030573
TI  - CD40 is necessary for activation of naive T cells by a dendritic cell line in
      vivo but not in vitro.
AB  - The importance of CD40-CD40L interactions during CD4(+) T-cell activation has
      been extensively investigated over the years; however, it still remains
      questionable whether the interaction is a prerequisite for dendritic cell (DC)
      mediated antigen-specific priming in vivo. Naive CD4(+) T cells require two
      signals for proper activation and induction of differentiation: signal 1 is
      provided by peptide antigens in the context of the major histocompatibility
      complex (MHC) class II, while signal 2 is delivered by costimulatory molecules
      such as CD80 or CD86 present on the antigen-presenting cell (APC). It is well
      known that the expression of CD80/CD86 is upregulated after interaction between
      CD40 on APCs and CD40L expressed by at least partly activated T cells. We used a
      DC line, JawsII, to compare the importance of CD40 expression and downstream
      signalling in vitro and in vivo. JawsII cells represent pre-immature bone marrow
      derived DCs expressing low levels of MHC molecules, low levels of B7 molecules
      and no CD40. We have previously shown that JawsII cells, despite the lack of CD40
      expression, are capable of priming naive allogeneic T cells in vitro. In
      correlation with the current literature, we present data showing that
      constitutive expression of CD40 significantly increases the priming capacity of
      JawsII cells in vitro. In addition, we show that CD40 expression is required for
      JawsII cell-dependent T-cell priming in vivo.

PMID- 15030574
TI  - A recombinant vaccinia virus encoding the interferon-inducible T-cell alpha
      chemoattractant is attenuated in vivo.
AB  - Murine interferon-inducible T-cell alpha chemoattractant (I-TAC) is a potent non
      ELR CXC chemokine that predominantly attracts activated T lymphocytes, binds to
      the receptor CXCR3 and is induced by interferon-gamma (IFN-gamma). We analysed I
      TAC expression by reverse transcriptase-polymerase chain reaction during three
      different virus-infection models in mice, respiratory syncytial virus (RSV),
      influenza A and vaccinia virus western reserve (VV-WR). In the lungs from mice
      infected with RSV or influenza A viruses, peak expression of I-TAC coincided with
      peak viraemia. Surprisingly, there was no expression in the lungs of mice
      infected with vaccinia, unlike the elevated expression shown previously for other
      interferon-regulated chemokines, such as Crg2 and Mig. To further investigate the
      importance of this difference during vaccinia infection in mice, a recombinant
      virus encoding I-TAC (rVV I-TAC) was generated. Studies in C57BL/6 and Swiss nude
      mice showed that I-TAC expression caused increased mononuclear cell infiltration
      and significantly attenuated the VV. Infection of the footpads of naive or
      already immune (with VV-WR) mice with either rVV I-TAC or VV-WR demonstrated that
      I-TAC expression reduced overall inflammation during infection and that this
      reduction was more pronounced in already immune mice. The data presented here
      show that I-TAC can have an important role during virus infections and that
      vaccinia has evolved ways to avoid inducing I-TAC expression.

PMID- 15030576
TI  - Antibodies raised against the second extracellular loop of the human muscarinic
      M3 receptor mimic functional autoantibodies in Sjogren's syndrome.
AB  - Functional antimuscarinic M3 receptor (M3R) autoantibodies have been shown to
      inhibit cholinergic neurotransmission at the postsynaptic level and appear to
      mediate parasympathetic dysfunction, including sicca symptoms in Sjogren's
      syndrome (SS). The precise epitope(s) involved in the inhibition of M3R-mediated
      cholinergic neurotransmission has not been defined. In this study, an active
      immunization approach to raise antibodies with functional activity against the
      second extracellular loop of the M3R was used and their functional properties
      were compared with those of human autoantibodies. Peptides corresponding to the
      second extracellular loop of the M3R were used as immunogens in rabbits, and
      antisera were tested for inhibition of carbachol-evoked colon smooth muscle
      contraction in parallel with immunoglobulin G from a patient with SS. Anti-M3R
      antibodies were affinity purified on a peptide representing a dominant functional
      epitope at the COOH terminus of the second extracellular loop of the M3R and
      tested for concentration-dependent inhibition. Experimentally raised anti-M3R
      antibodies, like the human autoantibodies, showed concentration-dependent and
      noncompetitive inhibition of carbachol-evoked colon contractions. Inhibitory
      activity was detected by functional assays at concentrations as low as 3 ng/ml,
      which was below the threshold of detection of antibody by peptide enzyme-linked
      immunosorbent assay. It is concluded that the experimentally raised anti-M3R
      antibodies share the functional properties of autoantibodies in patients with SS.

PMID- 15030575
TI  - Additive effects of leflunomide and tacrolimus in prevention of islet xenograft
      rejection.
AB  - Leflunomide is a low molecular weight immunosuppressive drug which inhibits the
      enzymes dehydroorotate dehydrogenase and protein tyrosine kinase, both of which
      are important components in the immune response. As the mechanisms of action of
      leflunomide and tacrolimus are different, we postulated an additive or
      synergistic effect of the two drugs and investigated the effects of leflunomide
      alone, or in combination with a suboptimal dose of tacrolimus, on xenogeneic
      islet transplantation in a rat-to-mouse model. A total of 1200-1500 rat islets
      were transplanted under the left kidney capsule of streptozotocin-induced
      diabetic BALB/c mice. The median survival time (MST) of the untreated group was 6
      days. Leflunomide at 5, 10 and 20 mg/kg/d administrated for 10 days significantly
      prolonged MST to 10, 16 and 20 days. A dose of tacrolimus (2 mg/kg/d) was
      associated with a graft survival of 9 (range 6-12) days; most grafts rejected
      during ongoing therapy. When tacrolimus (2 mg/kg/d) was combined with leflunomide
      (10 mg/kg/d), the survival time of the islet xenografts was increased further to
      22 days, significantly longer than with leflunomide or tacrolimus alone. In
      summary, our findings demonstrate that leflunomide prolonged xenogeneic islet
      graft survival, and that its immunosuppressive effect was improved when combined
      with tacrolimus.

PMID- 15030577
TI  - Regulation of mast cell migration by T and T cytokines: identification of tumour
      necrosis factor-alpha and interleukin-4 as mast cell chemotaxins.
AB  - Mast cells act as central effector and regulatory cells in many inflammatory
      disorders, including T helper 1 (T(H1))-mediated inflammations such as
      autoimmunity and T(H2)-mediated inflammations such as allergy and parasite
      infections. One characteristic for mast cell-mediated inflammations is the
      accumulation of mast cells in the inflamed tissue. The factors regulating mast
      cell recruitment in these inflammations are still not fully characterized. We
      have investigated the potency of T(H1)- and T(H2)-secreted cytokines to mediate
      mast cell migration. Supernatants from six different T(H1) and T(H2) clones were
      tested for mast cell-chemotactic activity using the human mast cell line (HMC-1)
      as a responder cell. All six clones produced factors that induced mast cell
      migration. Using blocking antibodies to a broad range of cytokines, we found that
      anti-tumour necrosis factor-alpha (anti-TNF-alpha) reduced the migration of mast
      cells to supernatants from T(H1) clones. In contrast, the main mast cell
      chemoattractants secreted by T(H2) clones were found to be interleukin-4 (IL-4)
      and IL-8. The potency of these cytokines to act as mast cell chemoattractants was
      confirmed by using recombinant IL-4, IL-8 and TNF-alpha. Our results suggest that
      TNF-alpha can be involved in the recruitment of mast cells in T(H1)-mediated
      inflammations, whereas IL-4 and IL-8 might play a similar role in T(H2)-mediated
      inflammations.

PMID- 15030578
TI  - Involvement of interleukin-1beta in systemic morphine effects on paw oedema in a
      mouse model of acute inflammation.
AB  - Recent studies suggest that peripheral morphine may represent a valuable
      treatment in acute inflammatory painful diseases through peripheral or central
      mechanisms. In the present study, anti-inflammatory effects of systemic morphine
      on carrageenan-induced hind paw oedema were examined in a model of peripheral
      acute oedema in mice. Carrageenan induced a time-dependent inflammation that was
      maximal 3 h after administration. While intraperitoneal administration of
      morphine sulfate at a low dose (1 mg/kg) increased carrageenan-induced hind paw
      oedema, intraperitoneal injection of morphine sulfate at a high dose (7 mg/kg)
      resulted in significant anti-inflammatory effects on carrageenan-induced hind paw
      oedema. These anti-inflammatory effects were blocked by pretreatment with
      naloxone. Measuring the serum levels of interleukin-1beta revealed that increases
      in serum levels of this cytokine were involved in morphine anti-inflammatory
      effects. Pretreatment with naloxone decreased interleukin-1beta serum levels near
      to those of control group. In conclusion, these data demonstrate that morphine
      produced pro- or anti-inflammatory effects in a dose-dependent manner through
      peripheral or central mechanisms. The observed anti-inflammatory effects may be
      due to an increase in the cytokine production and/or release by host immune
      systems.

PMID- 15030579
TI  - Interaction of human immunoglobulin G with CD16 on natural killer cells: ligand
      clearance, FcgammaRIIIA turnover and effects of metalloproteinases on
      FcgammaRIIIA-mediated binding, signal transduction and killing.
AB  - Human natural killer (NK) cells express low-affinity Fc immunoglobulin G (IgG)
      receptor (FcgammaRIIIA/CD16). The binding of monomeric IgG (mIgG) and F(ab')(2)
      fragments of 3G8 anti-CD16 monoclonal antibody (mAb) to FcgammaRIIIA was
      investigated by flow cytometry. Over 90% of NK cells bound endogenous IgG, and
      during incubation at 37 degrees C, the FcgammaRIIIA occupancy decreased slowly.
      Approximately 90% of NK cells bind mIgG or F(ab')(2) fragments of 3G8 anti-CD16
      mAb. The calculated half-time (T(1/2)) of in vitro mIgG dissociation from
      FcgammaRIIIA was 130 min. By cross-linking the mIgG ligand with F(ab')(2)
      fragments of anti-human IgG antibody, the T(1/2) decreases to 85 min. In kinetics
      study, it has been shown that (125)I-mIgG bound to FcgammaRIIIA is slowly
      released in the culture supernatant, maybe eluted at acid pH, or partially
      internalized and degraded. The binding of IgG to FcgammaRIIIA was increased by
      53.8% on cells cultured in the presence of RU36156, a matrix metalloproteinase
      (MMP) inhibitor. Furthermore, an increase in phosphorylation of Lyn tyrosine
      kinase, after cross-linking of mIgG-FcgammaRIIIA complex, was observed on NK
      cells treated with RU36156. When the FcgammaRIIIA was occupied by mIgG, the
      capacity of NK cells to kill K562 target cells was decreased by RU36156, because
      the MMP inhibitor protects CD16 from proteolysis. Our data demonstrate that
      binding of mIgG to human NK cells is followed by ligand dissociation and/or
      internalization, enzymatic degradation and exocytosis. The RU36156 MMP inhibitor
      protects FcgammaRIIIA from cleavage, augments NK-cell activation and may
      interfere in their killing capacity.

PMID- 15030580
TI  - Severe hypercholesterolaemia leads to strong Th2 responses to an exogenous
      antigen.
AB  - Severe hypercholesterolaemia is associated with decreased levels of
      immunoglobulin G2a (IgG2a) antibodies [T-helper 1 (Th1) response] to modified
      malondialdehyde-modified low-density lipoprotein (MDA-LDL) and increased levels
      of Th2-dependent IgG1 antibodies in apolipoprotein E-deficient (apoE(-/-)) mice.
      To investigate whether this reflects a general pattern of metabolic regulation of
      the humoral immune response, apoE(-/-) mice were fed diets resulting in different
      degrees of hypercholesterolaemia and immunized with keyhole limpet haemocyanin
      (KLH) in aluminium hydroxide. Cholesterol levels for different treatment groups
      ranged from 14 to 77 mmol/l in serum and from 10 to 39 mmol/g in liver. Mice with
      severe hypercholesterolaemia had increased IgG1 antibodies to MDA-LDL and
      decreased IgG2a anti-MDA-LDL. Importantly, titres of IgG2a antibodies to KLH were
      also decreased, while IgE anti-KLH was increased, with a corresponding induction
      of interleukin-4 (IL-4) and IL-10 and a decrease in interferon-gamma (IFN-gamma)
      in KLH-stimulated spleen cells in vitro. Thus, hypercholesterolaemia clearly
      affects antibody production both to the autoantigen MDA-LDL and to the exogenous
      antigen KLH, favouring antibody isotypes (IgG1 and IgE) that are dependent on Th2
      help to B cells. Nuclear receptors ligated by oxidized lipid derivatives modulate
      T-cell responses, and it is speculated that this mechanism may cause the switch
      to Th2 in severe hypercholesterolaemia.

PMID- 15030581
TI  - Leishmanial amastigote antigen P-2 induces major histocompatibility complex class
      II-dependent natural killer-cell reactivity in cells from healthy donors.
AB  - Innate mechanisms involving natural killer cells have been implied to play an
      important role in immunity against Leishmania infection. Previous studies have
      evaluated responses to three purified amastigote antigens, P-2, P-4 and P-8, of
      Leishmania pifanoi. The P-4 and P-8 antigens have been demonstrated to induce
      protection in mouse models, as well as to induce cellular responses in American
      cutaneous leishmaniasis patients. Cells from Leishmania aethiopica-infected
      leishmaniasis patients preferentially responded to P-8 and, to a lesser extent,
      to the cysteine proteinase, P-2. In this study, it is shown that cells from
      healthy donors, including cells from truly naive donors (cord blood), could be
      stimulated to proliferation and cytokine production by P-2. The main
      proliferating cell types in healthy adult donors were CD16/56(+) and the CD8(+)
      cells. Blocking of major histocompatibility complex (MHC) class II with alpha-MHC
      class II antibodies markedly inhibited proliferation and interferon-gamma (IFN
      gamma) production, whereas interleukin-10 production was not affected.
      Experimental evidence indicates that CD4(+) cells were not necessary for the
      proliferative and IFN-gamma responses; however, an adherent cell population was
      required. Furthermore, CD16/56(+) cells expressing MHC class II were expanded
      following P-2 stimulation. The responses to P-2 show a striking similarity to
      responses induced by the vaccine candidate Leishmania homologue of receptors for
      activated C-kinase (LACK) in healthy donors. The responses described here may not
      be desirable when aiming at inducing protective immune responses with a vaccine,
      and the implications of these results for the development of vaccines against
      leishmaniasis are discussed.

PMID- 15030583
TI  - Serum mannose-binding lectin levels and mbl2 gene polymorphisms in different age
      and gender groups of southern Chinese adults.
AB  - Mannose-binding lectin (MBL) is an acute-phase serum protein, and its inherited
      deficiency has been shown to predispose to infections. The developmental profile
      of serum MBL in preterm infants has been demonstrated previously. To determine
      the profiles of serum MBL levels and mbl2 polymorphisms over age and genders in
      an adult population, samples from 689 southern Chinese (age range 16-57 years;
      382 males and 307 females) were studied using enzyme-linked immunosorbent assay
      and high-throughput genotyping of mbl2. Serum MBL levels maintained within a
      narrow range from age groups of 16-20 years old to 31-40 years old (mean of 2050
      2160 micro g/l) and declined to a mean of 1466 micro g/l in the last age group 41
      57 years old. No significant differences were found in the distributions of mbl2
      haplotypes (YA, XA and YB) among all these age groups. Between gender groups, no
      significant imbalance of MBL profile in terms of serum MBL levels and
      distribution of mbl2 haplotypes was found. Results suggest an important role of
      circulating MBL in first-line host defence because MBL maintains at fairly
      constant levels after childhood and no gender influence on the MBL profile.

PMID- 15030582
TI  - HLA-DQB1 alleles may influence the surface expression of DQ molecules in
      lymphomononuclear cells of type 1 diabetes mellitus patients.
AB  - To evaluate the expression of human leucocyte antigen (HLA) class II (DR and DQ)
      molecules on lymphomononuclear cells involved in the pathogenesis of type 1
      diabetes, we studied 20 patients and 20 controls matched to patients for age, sex
      and HLA class II profile. The coexpression of HLA and CD3, CD4, CD8, CD19 and
      CD14 molecules was evaluated by flow cytometry. HLA-DRB1, -DQA1 and -DQB1 alleles
      were assigned using amplified DNA hybridized with sequence-specific primers. The
      fluorescence intensity of HLA-DR and -DQ molecules observed on the surface of the
      lymphomononuclear cells of patients did not differ significantly from controls.
      Patients presented decreased percentage of double-positive CD4(+)/DQ(+) cells and
      increased percentage of CD19(+)/DR(+) cells, irrespective of the HLA class II
      profile; however, the more dramatic alteration of the lymphomononuclear phenotype
      profile was observed for patients possessing the HLA-DQB1*0201 allele. These
      patients exhibited decreased percentage of CD3(+), CD4(+), CD8(+), CD19(+) and
      CD14(+) cells bearing HLA-DQ molecules and decreased fluorescence intensity for
      HLA-DQ molecules on CD19(+) cells compared to patients without the DQB1*0201
      allele. Although type 1 diabetes patients shared CD4/DQ or CD19/DR phenotype
      abnormalities, patients typed as DQB1*0201 presented additional abnormalities in
      terms of DQ expression and cell phenotypes bearing DQ molecules.

PMID- 15030584
TI  - Serum-soluble selectin levels in patients with rheumatoid arthritis and systemic
      sclerosis.
AB  - Soluble forms of selectins may play a regulatory role in inflammatory responses
      that are key to the pathophysiology of rheumatic diseases such as rheumatoid
      arthritis (RA) and systemic sclerosis (SSc). The aim of this study was to examine
      whether the elevated serum-soluble (s) selectin levels are associated with RA or
      SSc. Serum sE-, sL- and sP-selectin levels were measured by sandwich enzyme
      linked immunosorbent assay in 34 RA patients, 30 SSc patients and 16 healthy
      subjects. The levels of sE-selectin were significantly higher in RA and SSc
      patients than those in healthy subjects. The sL-selectin level was significantly
      lower in RA patients compared to healthy subjects. Serum sP-selectin levels were
      not significantly different among the study groups. The active RA patients had
      significantly higher serum sE- and sL-selectin levels compared to inactive RA
      patients. Also, some correlations were observed between the serum selectin levels
      and measures of disease activity such as erythrocyte sedimentation rate and C
      reactive protein in RA patients. The higher levels of sE-selectin were found in
      SSc patients with pulmonary fibrosis, and there was also a negative correlation
      between diffusion capacity for carbon monoxide and serum sE-selectin. Serum
      levels of selectins may provide a useful additional marker for disease activity
      in RA patients and for disease severity in SSc patients.

PMID- 15030585
TI  - Blocking CC chemokine receptor (CCR) 1 and CCR5 during herpes simplex virus type
      2 infection in vivo impairs host defence and perturbs the cytokine response.
AB  - Elimination of viral infections is dependent on rapid recruitment of leucocytes
      to infected areas. Chemokines constitute a class of cytokines that regulate
      migration of leucocytes to sites of infection. In this work, the expression and
      function of CC chemokine receptor (CCR)1 and CCR5 and their ligands during a
      generalized herpes simplex virus type 2 (HSV-2) infection in mice were studied.
      Many CCR1 and CCR5 ligands were expressed in infected organs after
      intraperitoneal infection. In particular, CC chemokine expression in the liver
      preceded the expression of CCR1 and CCR5, suggesting recruitment of cells bearing
      these receptors, which correlated with a decrease in viral titres. Administration
      of Met-RANTES, a CCR1 and CCR5 antagonist, led to impaired antiviral response
      with significantly higher viral titre in the liver on days 1 and 6 after
      infection. This observation was accompanied by a decreased and shortened
      recruitment of natural killer cells to the peritoneum of infected mice treated
      with the antagonist. Despite this reduced recruitment of antiviral leucocytes in
      mice receiving Met-RANTES, peritoneal cells from these mice produced markedly
      enhanced levels of pro-inflammatory cytokines. Altogether, the results suggest
      that CCR1 and/or CCR5 are important for both viral clearance and eventual control
      of the immune response.

PMID- 15030586
TI  - Antibodies to GAD65 epitopes at diagnosis and over the first 10 years of clinical
      type 1 diabetes mellitus.
AB  - Antibodies to glutamate decarboxylase (GAD65Ab) may persist, and their titres
      even increase after the clinical onset of type 1 diabetes. To characterize this
      phenomenon in detail, we analysed sequentially antibodies to GAD65 epitope
      clusters in a radio-binding assay in patients with type 1 diabetes. Serum samples
      were taken at diagnosis and 2, 5 and 10 years later from 50 young patients who
      had tested positive for GAD65Ab at least once during observation. The levels of
      GAD65Ab peaked in 21 patients after diagnosis. Antibodies to the middle region of
      GAD65 (GAD65-M-Ab, 88%) were more common at diagnosis than antibodies to the C
      terminal (GAD65-C-Ab, 68%, P < 0.05) or N-terminal region (4%, P < 0.001).
      Antibodies to middle and especially to C-terminal epitopes decreased in those
      with decreasing levels of GAD65Ab (P < 0.001), whereas the frequencies of GAD65-M
      Ab and GAD65-C-Ab remained quite stable among the subjects with increasing
      levels. Lower exogenous insulin dose and HbA(1) levels and stronger humoral
      immune response to islet cells were observed in those with increasing levels of
      GAD65-M-Ab than in those with decreasing levels (P < 0.05). The present
      observation supports the view that the middle region of GAD65 comprises
      immunodominant epitopes. An enhanced humoral immune response to GAD65 after
      diagnosis is related to persistent immune reactivity to the middle and C-terminal
      regions.

PMID- 15030590
TI  - Phototherapy and PUVA photochemotherapy in children.
AB  - The use of phototherapy and photochemotherapy in children has been limited due to
      concerns over their long-term carcinogenic potential. Furthermore, the method of
      administration is disconcerting to some children, particularly as phototherapy
      treatment units are seldom rendered 'child-friendly'. Despite these reservations,
      ultra-violet therapies can be useful treatment options for children with selected
      dermatological conditions provided they are used under carefully controlled
      conditions.

PMID- 15030591
TI  - Whole-body UVB (TL-01) or UVA-1 irradiation does not alter the levels of
      immunomodulatory cytokines in the serum of human volunteers.
AB  - BACKGROUND/PURPOSE: Ultraviolet (UV) exposure of mammalian skin induces local and
      systemic immunosuppression. In mice it has been proposed that systemic
      immunosuppression is mediated by an UV-induced cytokine cascade involving
      systemic interleukin (IL)-4 and IL-10 and a reduction in IL-12 activity. To
      investigate whether there was a parallel mechanism in humans we examined the
      effect of whole-body narrowband ultraviolet B (UVB) (311-313 nm; TL-01) and
      ultraviolet A (UVA)-1 (340-400 nm) on serum cytokine levels. METHODS/RESULTS: In
      a first study, five male psoriatic subjects were whole-body irradiated with three
      sessions of a standard UVB (TL-01) phototherapy regimen previously shown to cause
      downregulation of natural killer cell activity and T helper 1 (Th1) and Th2
      cytokine production by peripheral blood mononuclear cells. Enzyme-linked
      immunoabsorbent assay (ELISA) of sera taken before and after the third session
      showed no effect of phototherapy on IL-10 and tumour necrosis factor-alpha (TNF
      alpha). In a second study, five healthy subjects received three whole-body
      exposures of UVB (TL-01) and five other healthy subjects received three exposures
      of UVA-1 on alternate days (total 22 J/cm(2)). Blood samples were taken before
      the first irradiation and at 0, 4, 8, 12, 14, 24 and 48 h after the third
      irradiation. The sera were subsequently analysed for IL-10, IL-12, IL-8, IL-1beta
      and TNF-alpha, by ELISA. The levels of IL-1beta and TNF-alpha were below
      detection limits (<5 pg/ml), while no significant change in the levels of IL-10,
      IL-12 or IL-8 was detected as a result of either TL-01 or UVA-1. CONCLUSIONS: It
      seems unlikely that a modulation in these circulating cytokines assessed in this
      study accounts for systemic UV-induced immunosuppression in human subjects.

PMID- 15030592
TI  - Micronucleus evaluation in mitogen-stimulated lymphocytes of narrow-band (311 nm
      TL01) UVB-treated patients.
AB  - BACKGROUND: Narrow-band UVB (311 nm) lamps (TL01) are being increasingly used for
      phototherapy of psoriasis and other dermatoses, for their excellent effect
      compared with broad-band UVB sources and photochemotherapy. It is acknowledged
      that the TL01 lamp is probably two to three times more carcinogenic per minimum
      erythema dose than broad-band UVB, but the cumulative dose is considerably less
      than broadband UVB sources. Micronucleus (MN) test is used to detect both
      clastogenic (breaking) and aneugenic (abnormal segregation) effect of
      physical/chemical agents on chromosomes. The aim of this study is to evaluate MN
      frequencies in mitogen-stimulated lymphocytes of narrow-band UVB-treated
      patients. METHODS: Frequency of micronuclei in 72 h cultivated/mitogen-stimulated
      lymphocytes of 36 patients (age 7-73 years, mean+/-SD: 25.33+/-18.54) have been
      evaluated at pretreatment and after 20, 40, 60 sessions of narrowband UVB
      treatment. RESULTS: While the beginning MN frequency +/-SD (%) was 1.07+/-0.63,
      it increased to 1.47+/-0.92, 1.47+/- 0.77, 1.41+/-0.31 corresponding,
      respectively, to 20, 40, 60 sessions. These sessions reciprocally correspond to
      0.85+/-0.23, 2.97+/-0.72, 5.68+/-1.46 J/cm(2) doses of narrow-band UVB.
      Difference of MN frequency was statistically significant (P=0.002). Significant
      differences have been observed between the initial MN frequency and after that of
      20, 40, 60 sessions (P=0.001, 0.004, 0.002, respectively). CONCLUSIONS: The
      results of this study show that narrow-band UVB treatment causes a detectable
      chromosome damaging effect.

PMID- 15030593
TI  - Blue light inhibits melanin synthesis in B16 melanoma 4A5 cells and skin
      pigmentation induced by ultraviolet B in guinea-pigs.
AB  - BACKGROUND: Little has been known about the effects of visible light in mammalian
      cells. We recently found that blue light not only suppressed the growth of B16
      melanoma cells in a time-dependent manner but also inhibited metastasis of the
      B16 melanoma cells to the lung. These findings suggest that exposure to blue
      light modifies the functions of B16 melanoma cells. The present study
      investigated the effects of blue light on B16 melanoma 4A5 cells and Weiser-Maple
      guinea-pigs to confirm the biological effect of blue light on melanin formation.
      METHODS: The effect of red, green, and blue light on melanin synthesis in B16
      melanoma 4A5 cells was measured. The back skin of brown Weiser-Maple guinea-pigs
      was exposed to ultraviolet B (UVB; 588 mJ/cm(2) (0.7 mW/cm(2)x 14 min) three
      times a week for 2 weeks to induce melanin deposition. Thirty minutes after each
      UVB exposure, blue light was applied for 30 min. Pigmentation of the exposed
      areas of skin was checked once a week, and photographs of the skin were taken by
      digital camera. Observation was continued for 18 days after the final UVB
      exposure. RESULTS: Melanin synthesis in B16 melanoma 4A5 cells was selectively
      suppressed by blue light, but blue light did not induce decolorization of
      previously produced melanin. In the back skin of brown guinea-pigs, the
      brightness of the sites exposed to UVB began to decrease on the fifth day of the
      experiment, decreasing further from the 12th day to the 18th day after UVB
      exposure. The brightness of the sites exposed to UVB and blue light decreased in
      a manner similar during the UVB exposure, but remained relatively unchanged from
      the 12th day to the 30th day. CONCLUSIONS: These results suggest that blue light
      suppresses melanin formation following repeated UVB exposure. Further
      investigation with various light such as blue light may lead to a new approach to
      the care of ultraviolet-affected skin such as hyperpigmentation.

PMID- 15030594
TI  - Suggested mechanisms of action of UVA phototherapy in morphea: a molecular study.
AB  - BACKGROUND: Ultraviolet A (UVA) phototherapy proved to be an efficient line of
      treatment of scleroderma. The mechanism through which it acts is still not clear.
      OBJECTIVES: To detect the mechanism of action of UVA phototherapy in morphea
      through measuring its effect on the levels of different parameters related to
      collagen metabolism. METHODS: Twenty-one cases of morphea were treated with low
      dose broad-band UVA for 20 sessions. Twelve cases received 20 J/cm(2)/session
      with a cumulative dose of 400 J/cm(2) and nine cases received 10 J/cm(2)/session
      with a cumulative dose of 200 J/cm(2). The response was assessed clinically every
      week. Two skin biopsies were taken from the lesional skin of each patient before
      starting and after the end of therapy. Paraffin sections were examined for
      quantitative polymerase chain reaction measurement of collagen I, collagen III,
      collagenase, transforming growth factor-beta (TGF-beta) and interferon gamma
      (IFNgamma). RESULTS: Eighteen patients reported remarkable softening of the skin
      lesions, with variable degrees ranging from moderate in 57.1% of them good in 19%
      to very good response in 9.5%. After treatment, all the studied parameters
      revealed statistically significant changes. There was a significant decrease in
      collagen I, collagen III and TGF-beta and a significant increase in collagenase
      (MMP-1) and IFNgamma. The relative change was found to be greatest in
      collagenase, followed by IFNgamma then TGF-beta and finally collagen I. The
      changes in collagen I, collagenase, IFNgamma and TGF-beta were found to increase
      gradually with the degree of clinical response. In all the parameters studied the
      relative change was significantly higher in cases treated with 20 J/cm(2)/session
      in contrast to those treated with 10 J/cm(2)/session although no statistically
      significant difference could be detected in the clinical response to those doses.
      CONCLUSIONS: The efficacy of low-dose UVA phototherapy in the treatment of
      localized scleroderma is mainly obtained by the increased production of MMP-1 and
      IFNgamma, and to a lesser extent by decreasing TGF-beta and collagen production.
      Concerning the use of 10 or 20 J/cm(2)/session those effects are dose dependent,
      but the clinical response does not significantly differ.

PMID- 15030595
TI  - Solar urticaria in Singapore: an uncommon photodermatosis seen in a tertiary
      dermatology center over a 10-year period.
AB  - BACKGROUND: Solar urticaria is an uncommon photodermatosis, characterized by the
      appearance of pruritic wheals after sun exposure. In this study, we examine the
      photobiological characteristics of solar urticaria in the heterogeneous group of
      Singaporean patients. METHODS: The photobiological features of all patients
      treated for solar urticaria at a tertiary dermatology center in Singapore over a
      10-year period were retrospectively examined. RESULTS: A total of 19 patients
      were diagnosed to have solar urticaria from 1993 to 2002. The mean age at
      diagnosis was 26 years, with a racial distribution of 17 (90%) Chinese, one (5%)
      Malay, and one (5%) Indian. Fifteen (79%) patients were males and four (21%) were
      females. The face/neck (47%) and arms/forearms (58%) were most often affected.
      Six (32%) patients had a history of atopy and two (11%) had dermographism.
      Fifteen (79%) patients had Fitzpatrick's skin type IV, three (16%) had skin type
      III and one (5%) patient had skin type V. The mean exposure time to wheal
      formation was 23 min. The action spectra of solar urticaria were visible light
      for 12 (63%) patients, ultraviolet (UV) A for one (5%), visible light and UVA for
      five (27%), and natural sunlight for one (5%) patient. All patients reported
      partial improvement with a combination of antihistamines and sunscreens as the
      main modality of treatment. CONCLUSIONS: Our data suggest that solar urticaria is
      an uncommon photodermatosis and a rare form of urticaria. Wheals were mostly
      elicited by visible light and/or UVA. A combination of antihistamines and
      sunscreens provided a useful form of therapy for patients with solar urticaria.

PMID- 15030596
TI  - The characteristics of erythema induced by topical 5-aminolaevulinic acid
      photodynamic therapy.
AB  - BACKGROUND: Topical photodynamic therapy (PDT) is increasingly used to treat
      superficial non-melanoma skin cancers. Knowledge of the characteristics of 5
      aminolaevulinic acid (ALA)-induced phototoxicity will increase our understanding
      of PDT and may facilitate optimisation of treatment regimes. METHODS: We examined
      the characteristics of ALA-induced erythema in 10 healthy subjects and
      investigated the effect of light source and body site. RESULTS AND CONCLUSIONS:
      Maximal erythema occurred within 1-2 h of PDT and inter-individual variation in
      ALA-induced phototoxicity was seen. No detectable differences were seen in the
      phototoxicity on back or leg sites or between coherent and non-coherent light
      sources. These data provide further information to allow us to optimise topical
      PDT regimes.

PMID- 15030597
TI  - Photoinduced lichenoid reaction by thioridazine.

PMID- 15030598
TI  - Antivirals for pityriasis rosae.

PMID- 15030600
TI  - Spill-over of European bat lyssavirus type 1 into a stone marten (Martes foina)
      in Germany.
AB  - European bat lyssavirus type 1 (EBLV-1, genotype 5) is known to endemically
      circulate in insectivorous bat populations in Germany. In August 2001, a rabies
      suspect stone marten (Martes foina) was found in the city of Burg (Saxony-Anhalt,
      Germany) and was sent to the regional veterinary laboratory for routine rabies
      diagnosis. Whereas brain samples repeatedly tested negative in the fluorescent
      antibody test for classical rabies virus (genotype 1), the mouse inoculation test
      and the rabies tissue culture inoculation test yielded positive results. Rabies
      viral RNA was also detected in the stone marten brain sample both by nested and
      heminested RT-PCR specific for the nucleoprotein gene and for the nucleoprotein
      phosphoprotein junction of rabies virus. The amplification products were
      sequenced to genotype the isolate. Sequence data obtained from the first-round RT
      PCR products were analysed and the suspect stone marten isolate was confirmed as
      a rabies related virus (EBLV-1a). Phylogenetic comparison with sequences from
      recent genotype five isolates from Germany and Denmark showed that it was closely
      related to a previous isolate of EBLV-1 from a serotine bat in Saxony-Anhalt
      obtained in the same year in an area adjacent to the place where the EBLV-1
      infected stone marten was found. Both EBLV-1 isolates share a 99.5% identity.
      This is the first report of an EBLV-1a spill-over from an insectivorous bat into
      wildlife in Europe.

PMID- 15030601
TI  - Susceptibility of ferrets (Mustela putorius furo) to experimentally induced
      rabies with European Bat Lyssaviruses (EBLV).
AB  - Twenty ferrets (Mustela putorius furo) were inoculated by intramuscular (i.m.)
      injection with European Bat Lyssaviruses (EBLV) type-1 and 2 using 10(4.0) foci
      forming units (FFU) EBLV-2 (n = 6), 10(4.0) FFU EBLV-1 (n = 7) and 10(6.0) FFU
      EBLV-1 (n = 7). Furthermore, 15 mice received 10(2.5) FFU EBLV-2 (n = 5), 10(2.5)
      FFU EBLV-1 (n = 5) and 10(4.5) FFU EBLV-1 (n = 5) by i.m. inoculation. All
      ferrets and mice receiving the higher dose of EBLV-1 succumbed to infection. In
      contrast, only three of seven ferrets and two of five mice inoculated
      experimentally with the lower EBLV-1 dose died. By comparison, all of the EBLV-2
      infected ferrets and four of five mice survived infection. All 20 infected
      ferrets seroconverted. Using sensitive molecular tools, the virus was detected in
      different tissues, but it could not be found in any saliva samples taken during
      the 84-day observation period.

PMID- 15030602
TI  - An enzyme-linked immunosorbent assay (ELISA) for detection of Marek's disease
      virus-specific antibodies and its application in an experimental vaccine trial.
AB  - An enzyme-linked immunosorbent assay (ELISA) for the detection of Marek's disease
      virus (MDV)-specific antibodies was developed. Chicken embryo cells (CEC) or
      chicken kidney cells (CKC) were infected with MDV vaccine strain CVI988/Rispens,
      and infected-cell lysates were prepared at day 5 post-infection by freeze
      thawing. Uninfected-cell lysates served as negative controls. Sera were used at a
      1 : 100 dilution and were added in parallel to wells containing the infected and
      uninfected cell lysates. The optical densities at 492 nm (OD(492 nm)) were
      measured after detection of bound chicken antibodies with anti-chicken IgG
      peroxidase conjugate and colour reactions using o-phenylenediamine (OPD) as a
      substrate. The best results concerning the signal-to-noise ratio were obtained by
      using CKC cells rather than CEC for antigen preparation. The OD(492 nm) of plasma
      or serum samples with infected CKC was <0.02 when samples of unvaccinated and
      unchallenged maternal antibody-negative white leghorn chickens were tested. Sera
      and plasma samples of positive control birds exhibited OD(492 nm) of <0.01 when
      tested with uninfected CKC. The assay was used to monitor a trial that compared
      experimental BAC DNA vaccines and a commercial vaccine. Sustained seroconversion
      and antibody titers that were constantly rising until day 84 after vaccination
      (71 days after challenge) was observed only when chickens did not develop Marek's
      disease. In contrast, chickens developing the disease mounted marginal and short
      lived antibody titers only. We conclude that the developed ELISA may be a
      valuable tool for the evaluation of the efficacy of MDV vaccination under
      experimental but possibly also under field conditions.

PMID- 15030603
TI  - Severe PPR infection in gazelles kept under semi-free range conditions.
AB  - By the end of March 2002, a collection of some 200 gazelles, kept under semi
      range conditions in Saudi Arabia, was hit by a highly fatal peracute disease. The
      morbidity rate was 51% while the case mortality rate was 100%. Clinico
      pathological and virological investigations were carried out. A virus was
      isolated from the ailing gazelles which was identified as Peste des Petits
      Ruminants virus (PPRV). Epidemiology of the disease in the Arabian peninsula is
      discussed.

PMID- 15030604
TI  - Antiviral effect of Saccharomyces cerevisiae beta-glucan to swine influenza virus
      by increased production of interferon-gamma and nitric oxide.
AB  - The aim of these experiments was to investigate the potential antiviral effect of
      Saccharomyces cerevisiae beta-glucan on the pneumonia induced by swine influenza
      virus (SIV). Forty colostrum-deprived 5-day-old piglets were randomly divided
      into four groups of 10. The 20 pigs in groups 1 and 2 were administered
      Saccharomyces cerevisiae beta-glucan orally (50 mg/day/pig; En-Bio Technology
      Co., Ltd) for 3 days before SIV infection and those in groups 3 and 4 were given
      culture medium/diluent alone. Groups 1 and 3 were inoculated intranasally with 3
      ml of tissue culture fluid containing 2 x 10(6) tissue culture infective doses
      50% (TCID(50))/ml of SIV and those in groups 2 and 4 were exposed in the same
      manner to uninfected cell culture supernatant. The microscopic lung lesions
      induced by SIV infection (group 1 pigs) were significantly more severe than those
      induced by infection in animals pre-administered beta-glucan (group 3) (P <
      0.05). Significantly more SIV nucleic acid was detected in the lungs of pigs
      experimentally infected with SIV only (group 1) at 5, 7 and 10 days post
      inoculation (dpi) compared with lungs from pigs pre-administered beta-glucan and
      infected with SIV (group 3) (P < 0.05). The concentrations of interferon-gamma
      (IFN-gamma) and nitric oxide (NO) in bronchoalveolar lavage fluid from pigs pre
      administered beta-glucan and infected with SIV (group 3) were significantly
      higher than for any other group at 7 and 10 dpi for IFN-gamma, and at 5, 7 and 10
      dpi for NO (P < 0.05). Saccharomyces cerevisiae beta-glucan reduced the pulmonary
      lesion score and viral replication rate in SIV-infected pigs. These findings
      support the potential application of beta-glucan as prophylactic/treatment agent
      in influenza virus infection.

PMID- 15030605
TI  - Occurrence of Escherichia coli O157 in raw material and food in Czech Republic.
AB  - The study was carried out to investigate the incidence of Escherichia coli O157
      in raw materials, foodstuffs and the agricultural environment. Of a total of 987
      samples examined, 22 strains (2.2%) were identified as E. coli O157 and 10 of
      them as E. coli O157:H7. Cefixime-Tellurite MacConkey sorbitol agar (CT-SMAC)
      agar and Biosynth culture medium (BCM) E. coli O157:7 medium were used for the
      isolation. The virulence factors (stx1, stx2, eae, and ehxA genes) were
      identified by polymerase chain reaction (PCR). Most strains were isolated from
      the mechanically deboned poultry meat (nine), minced meat (six) and raw milk
      (four). One strain was isolated from beef carcass and two strains from waste
      water. No strains were were found in mass for sausages, refreshment salads, swabs
      of pork and poultry carcasses and faeces of cattle and pigs. Ten strains from the
      22 identified proved to be positive for all factors of virulence. They were
      isolated from minced meat (four), raw milk (four), waste water (one) and swab
      from beef carcass (one). Sensitivity to the antimicrobial drugs ampicillin (AMS),
      ampicillin-sublactam (SAM), tetracycline (TET), ofloxacine (OFL), cefuroxime
      (CRX), chloramphenicol (CPM), gentamicine (GEN), colistin (COL), cephalozine
      (CLZ), cefoxitin (CXT), aztreonam (AZT), and sulphamethoxazole + trimethoprim
      (COT) was tested using the standard dilution technique and disc diffusion test.
      Minimum inhibitory concentrations (MIC) characteristics (MIC(50), MIC(90), MIC
      range) and inhibitory zone diameter were determined for each strain. As
      determined by MICs, the resistance to tested antibiotics in E. coli O157 isolates
      was found to AMS (90.9%), CLZ (81.8%), CRX (63.6%), CXT (72.7%), CPM (72.7%), TET
      (81.8%), SAM (59.1%), COT (9.1%), COL (63.61%), AZT (9%) and GEN (4.5%). The
      similar results were obtained using the disc diffusion method. The differences
      were found relating to SAM, CXT, CMO and TET. Resistance against one or more
      antibiotics was found in 95.4% of E. coli O157. Only one strain was susceptible
      to all tested antibiotics. Most of the strains were resistant to ampicillin and
      cephalozine. Eight different resistance phenotypes were demonstrated in E. coli
      O157.

PMID- 15030606
TI  - Non-O157 Shiga toxin-producing Escherichia coli isolated from diarrhoeic calves
      in Argentina.
AB  - Faecal samples from 76 diarrhoeic calves belonging to 36 farms located in the
      Pampas plain, Argentina, were examined for Shiga toxin-producing Escherichia coli
      (STEC). A total of 15 STEC strains were isolated from 12 (15.8%) calves which
      came from six different farms. All stx positive strains assayed by PCR were also
      positives in the Vero cell cytotoxicity test. The majority (60.0%) of the STEC
      strains carried the stx(1) gene. Twelve (80.0%) of the STEC isolates which
      belonged to serotypes O5:H- (n = 4), O26:H11 (n = 4), O26:H- (n = 1), O111:H- (n
      = 2), and O123:H38 (n = 1) were also enterohaemolysin (EHly) positive and carried
      the gene encoding for intimin (eae). All the stx positive strains were negative
      for the bfpA gene. Localized adherence to HEp-2 cells were observed in 83.3% of
      the eae+ STEC strains. STEC belonging to serotype O5:H- showed atypical
      biochemical properties, including urease production. Urease was also produced by
      two strains belonging to serotypes O153:H? and non-typeable, respectively.
      Resistance to three or more antibiotics was observed in 12 (80.0%) of the STEC
      isolates. Most of the serotypes of STEC recovered in this survey carried
      virulence traits that are associated with increased human and bovine
      pathogenicity. The present study shows that highly virulent STEC strains are
      being shed by diarrhoeic calves from farms located in a high incidence area of
      human STEC infections.

PMID- 15030607
TI  - Seroprevalence of Sarcosystis spp. in cattle and buffaloes from the wet and dry
      zones of Sri Lanka: a preliminary study.
AB  - An enzyme-linked immunosorbent assay (ELISA) was developed for the detection of
      antibodies to Sarcosystis infection in cattle and buffaloes. Crude antigens
      derived from cystozoites of Sarcosystis cruzi and antibodies from the sera of
      naturally infected cattle and buffaloes were used. The assay was validated by
      determination of the specificity, sensitivity and negative and positive
      predictive values. Using ELISA, a sero-epidemiological survey for sarcosystosis
      was carried out in cattle (n = 215) and buffaloes (n = 123) from the wet and dry
      zones of Sri Lanka. The prevalence of infection in cattle was 69.3%. Prevalence
      of the infection collectively in both cattle and buffaloes in the dry zone was
      significantly higher (P < 0.001) than that in the wet zone. The number of sero
      positive cattle and buffaloes in the dry zone was significantly higher than that
      in the wet zone (P < 0.05). Buffaloes in the dry and wet zones showed a greater
      prevalence of infection (P < 0.05) than cattle.

PMID- 15030608
TI  - Monoclonal antibody characterization of rabies virus isolates from Russia,
      Finland and Estonia.
AB  - Five different rabies virus variants were identified among rabies virus-positive
      samples from Russia, Finland and Estonia, using a panel of five anti-nucleocapsid
      monoclonal antibodies. Two rabies virus isolates showed a different reaction
      pattern, suggesting the presence of a new antigenic variant. The results were
      compared with the data obtained by other research groups.

PMID- 15030609
TI  - Respiratory care in the computer age.
AB  - Computerization in health care is rapidly advancing and is improving patient
      safety (eg, computerized physician order entry decreases the frequency of medical
      errors) and practitioner effectiveness and efficiency. Computerization and other
      developing technologies raise concern about the privacy of health information. In
      1996 Congress passed the Health Insurance Portability and Accountability Act
      (HIPAA), which included privacy provisions that went into effect in April 2003.
      HIPAA has important impacts on health care providers. With the tremendous growth
      of health care information systems comes the need to standardize the storage and
      sharing of health information, so there is an initiative underway to develop a
      National Health Information Infrastructure, which will set standards for health
      information exchange among consumers, providers, and the public health sector, as
      well as consolidate the "silos" of health information that are in place today.

PMID- 15030610
TI  - Respiratory care management information systems.
AB  - Hospital-wide computerized information systems evolved from the need to capture
      patient information and perform billing and other financial functions. These
      systems, however, have fallen short of meeting the needs of respiratory care
      departments regarding work load assessment, productivity management, and the
      level of outcome reporting required to support programs such as patient-driven
      protocols. The respiratory care management information systems (RCMIS) of today
      offer many advantages over paper-based systems and hospital-wide computer
      systems. RCMIS are designed to facilitate functions specific to respiratory care,
      including assessing work demand, assigning and tracking resources, charting,
      billing, and reporting results. RCMIS incorporate mobile, point-of-care charting
      and are highly configurable to meet the specific needs of individual respiratory
      care departments. Important and substantial benefits can be realized with an
      RCMIS and mobile, wireless charting devices. The initial and ongoing costs of an
      RCMIS are justified by increased charge capture and reduced costs, by way of
      improved productivity and efficiency. It is not unusual to recover the total cost
      of an RCMIS within the first year of its operation. In addition, such systems can
      facilitate and monitor patient-care protocols and help to efficiently manage the
      vast amounts of information encountered during the practitioner's workday.
      Respiratory care departments that invest in RCMIS have an advantage in the
      provision of quality care and in reducing expenses. A centralized respiratory
      therapy department with an RCMIS is the most efficient and cost-effective way to
      monitor work demand and manage the hospital-wide allocation of respiratory care
      services.

PMID- 15030611
TI  - Computerized clinical decision-support in respiratory care.
AB  - Computers were initially used in health care for billing and administrative
      functions. More recently computers have been used to present clinical information
      such as laboratory results and pharmacy orders. Many medical informatics
      researchers believe that the ultimate goal of the "electronic health record"
      should be to advance computerized clinical decision-support. This report
      considers the challenges of developing electronic-health-record systems and
      integrating them into useful computerized decision-support systems and presents a
      "pyramid of progress" concept that involves 5 steps: (1) to gather electronic
      health data into a standardized and coded format, (2) to validate the quality of
      that electronic health data, (3) to optimize presentation of electronic health
      data and explore computerized decision-support, (4) to develop and share
      computerized knowledge bases that are based on clinical evidence as well as
      consensus, and (5) to tailor and to implement the computerized strategies so that
      they fit into the workflow process of patient care. This report discusses 3
      examples of successful computerized clinical decision-support (use of
      antibiotics, laboratory alerting, and ventilator management) and discusses
      strategies essential to making computerized clinical decision-support more widely
      available and useful.

PMID- 15030613
TI  - Respiratory system simulations and modeling.
AB  - Simulators and models of the respiratory system range from simple mechanical
      devices to complex systems that include sophisticated computers. These systems
      have considerable utility in clinician education, guiding therapies, evaluating
      new devices and techniques, and in improving our understanding of the
      cardiorespiratory system. Simulators and models are of 3 types: signs-and
      symptoms simulators, anatomic models, and physiologic models. Signs-and-symptoms
      simulators range from human actors to computer-controlled patient mannequins.
      Clinical scenarios, from minor abnormalities to catastrophic emergencies, can be
      simulated. As has been found with aircraft cockpit simulators, improved clinician
      performance in simulated emergencies should translate into improved performance
      in real patient-care situations. Anatomic modeling can simulate basic anatomy for
      training clinicians. Three-dimensional reconstruction of the airways, using real
      patient data, can help to plan therapy, understand the disease process, and warn
      of safety issues. Anatomic modeling with radiographs and magnetic resonance
      images, sometimes created using radiolabeled tracer gases, can create 3
      dimensional images of regional lung anatomy and function. Physiologic signals
      such as carbon dioxide production, oxygen consumption, and washout/washin of
      various tracer gases can be used to model ventilation-perfusion and ventilation
      volume relationships, and those models can improve understanding of disease
      processes and guide therapies.

PMID- 15030612
TI  - Information retrieval in respiratory care: tips to locate what you need to know.
AB  - We need current information to support effective practice. This information can
      be accessed relatively quickly and inexpensively, using nothing more than a
      computer and an Internet connection. This demands skills in searching and
      accessing that information. In many hospitals, computers with an Internet
      connection are readily available in the clinical wards, allowing those with
      skills in retrieving medical information to find that information near the
      bedside where it is needed. This report describes techniques to access
      information on the Internet from various sources. This information exists at high
      levels, such as PubMed, the National Guideline Clearinghouse, and the Cochrane
      Library. However, there is also much information available on the Internet that
      has not been validated or subjected to peer review. Thus, it is important not
      only to find information but also to separate useful from useless information.

PMID- 15030614
TI  - Child welfare privatization: quantitative indicators and policy issues.
AB  - The purpose of this study was to demonstrate the development of safety,
      permanency, and child well-being indicators by using administrative data sets as
      well as by using these indicators as tools for evaluating Florida's Community
      Based Care (CBC) initiative. Longitudinal data from 37 counties including 4
      counties that implemented community-based care were examined in this study. The
      results of the study indicated that the overall performance of CBC counties is at
      least as good as the performance of their comparison run by the state counties.
      The findings that emerged from this study may provide important lessons for
      developing a performance measurement system in the child welfare field.

PMID- 15030615
TI  - Modeling stability of growth between mathematics and science achievement during
      middle and high school.
AB  - In this study, the authors introduced a multivariate multilevel model to estimate
      the consistency among students and schools in the rates of growth between
      mathematics and science achievement during the entire middle and high school
      years with data from the Longitudinal Study of American Youth (LSAY). There was
      no evident consistency in the rates of growth between mathematics and science
      achievement among students, and this inconsistency was not much influenced by
      student characteristics and school characteristics. However, there was evident
      consistency in the average rates of growth between mathematics and science
      achievement among schools, and this consistency was influenced by student
      characteristics and school characteristics. Major school-level variables
      associated with parental involvement did not show any significant impacts on
      consistency among either students or schools. Results call for educational
      policies that promote collaboration between mathematics and science departments
      or teachers.

PMID- 15030616
TI  - The race gap in support group participation by breast cancer survivors: real or
      artifact?
AB  - Addressing methodological weaknesses of previous research, this study assesses
      whether African American women are, in fact, less likely to participate in breast
      cancer support groups than are White women. Of the breast cancer survivors, 958
      (26% African Americans, 73% Caucasian) completed interviews concerning
      demographic characteristics, other support networks, effects of illness on home
      and spiritual life, and support group participation. Contrary to previous
      research, no race difference was found in support group participation. This
      research suggests more effort needs to be paid to sampling techniques and other
      methodological factors to adequately reflect the experiences and needs of breast
      cancer survivors, specifically African American women.

PMID- 15030617
TI  - Picking up the challenge: developing a methodology to enumerate and assess the
      needs of the street homeless population.
AB  - This study represents the first enumeration of the street homeless population in
      Canada. Past enumeration attempts have been challenged on their significant
      methodological shortcomings. This enumeration directly addressed the lessons
      learned from previous attempts, and improvements to the methodology are presented
      and discussed. In addition, lessons learned and recommendations are discussed for
      application to future enumerations.

PMID- 15030618
TI  - The Internet's impact on policy evaluation: information compression and
      credibility.
AB  - As with all media, the Internet structures and frames information, rewarding some
      information search and decision behaviors while punishing others and, thereby,
      strongly influences evaluation research results and possibilities. Now that the
      Internet is for many evaluators the information medium of choice, the impacts of
      the medium on evaluation deserve careful attention. The objective of this article
      is to lay groundwork for a theory of the impact of the Internet on evaluation and
      policy analysis. Questions addressed include the following: (a) What is the
      impact of the Internet on the evaluator's professional role, work norms, and work
      habits? (b) Does the use of the Internet affect who is an evaluator or the
      meaning of professional evaluation? and (c) How does evaluation via Internet
      affect the technical quality and credibility of evaluation? A key thesis is that
      the Internet compresses information in the sense that it is not always easy to
      distinguish among information resources and, especially, the authority of the
      information provider and the nature of the knowledge warrant. On one hand, the
      Internet's information compression seems to hold potential for the
      democratization of evaluation. On the other hand, the diminished ability to make
      quality distinctions about evaluation-relevant information may undercut the
      legitimacy of evaluation.

PMID- 15030619
TI  - The role of collective identification in social movement participation: a panel
      study in the context of the German gay movement.
AB  - The authors conducted a panel study with two points of measurement throughout a
      12-month interval in the context of the German gay movement to test the
      predictive power of collective identification in subsequent actual social
      movement participation. Regression analyses including cross-lagged panel analyses
      clearly confirmed the hypothesized unique predictive value of identification with
      a formal social movement organization above and beyond the role the collective,
      normative, and reward motives traditionally considered in social movement
      research. Of the three motives, the normative motive was particularly predictive.
      Moreover, data from an additional telephone follow-up (3 years after the initial
      measurement) suggests that when the conflict with political opponents becomes
      particularly fierce, identification with the broader recruitment category, which
      was previously ineffective as a unique predictor, can politicize to such an
      extent that it also becomes a strong predictor of participation.

PMID- 15030620
TI  - Greed, death, and values: from terror management to transcendence management
      theory.
AB  - Research supporting terror management theory has shown that participants facing
      their death (via mortality salience) exhibit more greed than do control
      participants. The present research attempts to distinguish mortality salience
      from other forms of mortality awareness. Specifically, the authors look to
      reports of near-death experiences and posttraumatic growth which reveal that many
      people who nearly die come to view seeking wealth and possession as empty and
      meaningless. Guided by these reports, a manipulation called death reflection was
      generated. In Study 1, highly extrinsic participants who experienced death
      reflection exhibited intrinsic behavior. In Study 2, the manipulation was
      validated, and in Study 3, death reflection and mortality salience manipulations
      were compared. Results showed that mortality salience led highly extrinsic
      participants to manifest greed, whereas death reflection again generated
      intrinsic, unselfish behavior. The construct of value orientation is discussed
      along with the contrast between death reflection manipulation and mortality
      salience.

PMID- 15030621
TI  - The influence of accuracy as a function of leader's bias: the role of
      trustworthiness in the psychology of procedural justice.
AB  - The present research examined the combined effect of accuracy of procedures and
      leader's bias on fairness judgments and the experience of positive emotions. The
      results of two studies showed that the strongest positive effects on both types
      of reactions were found when procedures were accurate and the leader was
      unbiased. In addition, accuracy of procedures only revealed an impact when the
      leader was perceived as unbiased rather than biased. Moreover, this interactive
      effect was found to be mediated, at least partly, by perceptions of
      trustworthiness. These findings show that more research is needed on examining
      different types of procedural fairness, both as single and combined predictors of
      people's reactions.

PMID- 15030622
TI  - The impact of cultural internalization and integration on well-being among
      tricultural individuals.
AB  - The cultural internalization and competence of a diverse sample of tricultural
      university students was assessed. Based on recent research on the internalization
      of cultural norms, it was predicted that (a) having a heritage culture that
      embraced egalitarian values would be conducive to autonomous internalization and
      cultural competence, (b) competence and internalization would be associated with
      positive affect in heritage cultural contexts, and (c) the same positive
      relations between competence, internalization, and affect would be evident in
      English Canadian and French Canadian contexts. The study included 113
      participants representing more than 35 distinct ethnicities. Results supported
      the hypothesized relations among egalitarianism, autonomous internalization,
      competence, and affect. Furthermore, the results indicated that individuals'
      cultural adaptation in both heritage and English Canadian cultures, combined with
      the extent to which they had integrated their cultural identities in their self,
      predicted psychological wellbeing.

PMID- 15030623
TI  - Implicit/explicit motive discrepancies and volitional depletion among managers.
AB  - The compensatory model of motivation and volition is based on the assumption that
      discrepancies between implicit and explicit motives lead to psychological
      conflict, and that resolution of this conflict requires volitional regulation and
      consumes volitional strength. This suggests that implicit/explicit motive
      discrepancies (IED) are responsible for decreases in volitional strength. A
      longitudinal field study with 82 managers was conducted to test this proposition.
      Results show that IED longitudinally predicted decreases in volitional strength.
      Furthermore, structural equation modeling revealed that volitional strength
      mediated the relation between IED and impaired subjective well-being. The
      theoretical and practical implications of these results are discussed,
      particularly with respect to volitional depletion.

PMID- 15030624
TI  - Actions, intentions, and self-assessment: the road to self-enhancement is paved
      with good intentions.
AB  - Actions and intentions do not always align. Individuals often have good
      intentions that they fail to fulfill. The studies presented here suggest that
      actors and observers differ in the weight they assign to intentions when deciding
      whether an individual possesses a desirable trait. Participants were more likely
      to give themselves credit for their intentions than they were to give others
      credit for theirs (Studies 1 and 2). This caused individuals to evaluate
      themselves more favorably than they evaluated others (Studies 3-5). Discussion
      focuses on the motivational and information-processing roots of this actor
      observer difference in the weight assigned to intentions as well as the
      implications of this tendency for everyday judgment and decision making.

PMID- 15030625
TI  - Source consistency, distinctiveness, and consensus: the three dimensions of the
      Kelley ANOVA model in persuasion.
AB  - Based on a conceptual analysis and existing research, the authors propose that
      the three source dimensions specified in the ANOVA model play similar roles in
      persuasion as other source characteristics (e.g., expertise). Two studies test
      assumptions derived from this approach regarding the effects of different
      combinations of consistency and consensus (Study 1) and distinctiveness and
      consensus (Study 2). Combinations resulting in contradictory (vs. similar)
      inferences regarding message validity should affect judgmental confidence and,
      consequently, affect message scrutiny. Study 1 shows that, as predicted, high
      consistency/low consensus and low consistency/high consensus (incongruent
      combinations) lead to higher desired confidence and more extensive message
      elaboration than high consistency/high consensus and low consistency/low
      consensus (congruent combinations). Similarly, Study 2 reveals heightened message
      scrutiny given incongruent (vs. congruent) combinations of distinctiveness and
      consensus. Results are discussed with respect to majority/minority influence
      processes and multiple source characteristics.

PMID- 15030626
TI  - Criticizing groups from the inside and the outside: an identity perspective on
      the intergroup sensitivity effect.
AB  - Research on group criticism has demonstrated that criticisms are received less
      defensively when made by an ingroup member than when made by an outsider (the
      intergroup sensitivity effect). Three experiments tested the extent to which this
      effect is driven by social identity concerns or by judgments of how experienced
      the source of the criticism is. In Experiments 1 and 2, Australians who
      criticized Australia (ingroup critics) were met with less defensiveness than were
      foreigners who criticized Australia (outgroup critics), regardless of the amount
      of experience the foreigner had with Australia. Furthermore, the effects of
      speaker type on evaluations were mediated by perceptions of the extent to which
      the criticisms were intended to be constructive but not by perceptions of
      experience. Finally, Experiment 3 indicated that although experience does not
      help outgroup critics, a lack of experience can hurt ingroup critics.
      Recommendations are provided as to how people can reduce defensiveness when
      making group criticisms.

PMID- 15030627
TI  - Biased reasoning: adaptive responses to health risk feedback.
AB  - The present study examined reactions toward repeated self-relevant feedback.
      Participants in a community health screening received feedback about their
      cholesterol level on two separate occasions. Reactions to the first feedback were
      examined with regard to feedback valence and expectedness. The findings showed
      that negative feedback was devalued, but only when it was unexpected. Feedback
      consistency was incorporated into analyses of the second feedback. Again, results
      showed that negative feedback was not always devalued-only when it was
      inconsistent with the first feedback. Furthermore, positive feedback was not
      unconditionally accepted. When receiving unexpected positive feedback of low
      consistency, recipients were doubtful about its accuracy. Conversely, expected
      positive feedback was accepted regardless of its consistency. These results
      suggest that negative or unexpected positive feedbacks evoke greater sensitivity
      to feedback consistency, indicating elaborate cognitive processing. Theoretical
      accounts of these findings are discussed.

PMID- 15030628
TI  - Surviving childhood cancer: quality of life and parental regulatory focus.
AB  - Applying Regulatory Focus Theory (RFT), the authors predicted that among
      survivors of childhood cancer, quality of life (QOL) may be compromised by
      prevention-focused parenting characterized by an overly protective concern with
      possible mishaps and illness recurrence rather than promotion-focused parenting
      encouraging expectations of recovery and a normal life. Interviews with parents
      of 64 survivors (M age = 13.83 years) of acute lymphoblastic leukemia (ALL) or
      central nervous system (CNS) tumors were coded for reports of promotion or
      prevention-oriented parenting and positive and negative expectancies. Overall,
      parents expressed more promotion than prevention focus, especially in relation to
      general rather than illness-related contexts. Greater use by parents of
      prevention focus in general contexts predicted lower QOL for survivors (as rated
      both by parents and survivors themselves) and less satisfactory parental well
      being. These effects were independent of a main effect for type of cancer, with
      survivors of ALL having higher QOL.

PMID- 15030630
TI  - Optimism, pessimism, and gambling: the downside of optimism.
AB  - Three studies examined the relation between dispositional optimism and gambling.
      In Study 1, optimists were more likely than pessimists to have positive gambling
      expectations and report maintaining these expectations following losses. They
      also were more likely to indicate that winning money was a primary motivation for
      their gambling. Study 2 demonstrated that pessimists but not optimists reduce
      their betting and expectations after poor gaming performance. Study 3 replicated
      this effect using a more controlled experiment and showed that after losing,
      optimists report remembering more near wins than do pessimists. Thus, all three
      studies suggest that optimists, more than pessimists, maintain positive
      expectations and continue gambling after experiencing negative gaming outcomes.
      The authors suggest that despite optimism's many benefits, there are common
      situations in which the pessimistic tendency to disengage is beneficial.

PMID- 15030629
TI  - How does context affect intimate relationships? linking external stress and
      cognitive processes within marriage.
AB  - Stressors external to the marriage frequently affect the way spouses evaluate
      their marital quality. To date, however, understanding of the interplay between
      external stress and internal relationship processes has been limited in two ways.
      First, research has generally examined only the short-term consequences of
      stress. Second, the mechanisms through which external stressors influence
      relationship outcomes are unclear. This study addressed both limitations by
      examining relationship cognitions that may mediate the effects of external stress
      throughout 4 years of marriage. Analyses confirmed that stressful experiences
      were associated with the trajectory of marital quality overtime. Furthermore,
      both the content and the organization of spouses' specific relationship
      cognitions mediated this effect. That is, stress negatively influenced the nature
      of spouses' marital perceptions as well as the way spouses interpreted and
      processed those perceptions. These findings draw attention to ways that the
      context of relationships shapes and constrains relationship processes.

PMID- 15030631
TI  - Social desirability and self-reports: testing models of socially desirable
      responding.
AB  - The present research investigated the cognitive processes involved in responding
      to self-report items under varying conditions of social desirability.
      Participants in three experiments judged the extent to which a set of items
      (personality traits in Experiments 1 and 2; behaviors in Experiment 3) described
      them under instructions that either increased or decreased concerns with social
      desirability. Under most conditions, instructions that produced the greatest
      concern with social desirability resulted in the longest response times. This
      finding is consistent with the view that social desirability operates as an
      editing process; participants retrieve the requested information and then
      evaluate it before responding. There was also some evidence for individual
      differences in social desirability; participants scoring high on the trait of
      self-deception were generally faster at making these judgments than were
      participants scoring low on self-deception.

PMID- 15030632
TI  - Expectations about the future and the emotional consequences of perceiving
      prejudice.
AB  - Three studies tested the hypothesis that possessing a pessimistic outlook on life
      moderates the effects of perceiving sexism on emotions and self-esteem. Across
      all studies, a pessimistic outlook on life (either dispositionally held or
      experimentally induced) served as a source of emotional vulnerability among women
      (Studies 1-3) and men (Study 1) faced with evidence of sexism directed against
      their gender group. Study 3 demonstrated that one's outlook on life influences
      emotional adjustment to prejudice through the cognitive appraisal process.
      Relative to optimists, pessimists appraised sexism as more stressful and believed
      they possessed fewer resources for coping with it. This research emphasizes the
      importance of examining sources of vulnerability and resilience in understanding
      emotional responses to prejudice.

PMID- 15030633
TI  - Using partially structured attitude measures to enhance the attitude-behavior
      relationship.
AB  - This article recalls a classic scheme for categorizing attitude measures. One
      particular group of measures, those that rely on respondents' interpretations of
      partially structured stimuli, has virtually disappeared from attitude research.
      An attitude measure based on respondents' interpretation of partially structured
      stimuli is considered. Four studies employing such a measure demonstrate that it
      predicts unique variance in self-reported and actual behavior, beyond that
      predicted by explicit and contemporary implicit measures and regardless of
      whether the attitude object under consideration is wrought with social
      desirability concerns. Implications for conceptualizing attitude measurement and
      attitude-behavior relations are discussed.

PMID- 15030634
TI  - Consequences of stereotype suppression and internal suppression motivation: a
      self-regulation approach.
AB  - The present research studied the effects of suppression of stereotypes on
      subsequent stereotyping. Moreover, the moderating influence of motivation to
      suppress stereotypes was examined. The first three experiments showed that
      suppression of stereotypes leads to the experience of engaging in self-control
      (Study 1), to depleted regulatory resources as indicated by worse performance on
      an unrelated subsequent task that involves self-regulation (Study 2), and to
      hyperaccessibility of the suppressed thoughts (Study 3). However, these effects
      were moderated by internal suppression motivation: Increased self-control,
      depleted regulatory resources, and hyperaccessibility of suppressed thoughts only
      occur for people with low internal suppression motivation. Furthermore, in line
      with the argument that depletion of regulatory resources after suppression also
      should result in increased stereotyping in general, it was found that suppression
      of a specific stereotype leads to an increased use of stereotypes in general, but
      only for people with low internal suppression motivation (Study 4).

PMID- 15030635
TI  - Evolving informational credentials: the (mis)attribution of believable facts to
      credible sources.
AB  - Three studies demonstrate that individuals often rely on a "belief force equals
      credible source" heuristic to make source judgments, wherein they assume that
      statements they believe originate from credible sources. In Study 1, participants
      who were exposed to a statement many times (and hence believed it) were more
      likely to attribute it to Consumer Reports than to the National Enquirer. In
      Study 2, participants read a murder investigation article containing evidence
      against two suspects from credible and noncredible sources. When participants
      believed a particular suspect to be guilty, they misattributed evidence
      incriminating that suspect to the high-credibility source. Study 3 demonstrated
      that this phenomenon occurs because individuals assume their beliefs are true and
      that true beliefs come from credible sources; when participants were given
      feedback that their beliefs were incorrect, the relationship between beliefs and
      source inferences did not occur.

PMID- 15030637
TI  - Sticks and stones can break my bones, but ethnophaulisms can alter the portrayal
      of immigrants to children.
AB  - An archival study examined the portrayal of ethnic immigrants to children as a
      function of the prevailing cognitive representation of those ethnic immigrant
      groups in ethnophaulisms. The complexity in ethnophaulisms (and, to a lesser
      degree, the valence in ethnophaulisms) predicted the portrayal of ethnic
      immigrant groups. Overall, ethnic immigrant groups characterized in terms of
      ethnophaulisms of low complexity were less frequently present in children's
      literature, children from these ethnic groups were described more in terms of
      physical appearance than in terms of personal traits, fictional child characters
      from those ethnic groups were portrayed with smaller heads and with lower verbal
      complexity, and the folksongs attributed to these groups had a more negative
      affective tone. The implications of these results for approaches to intergroup
      relations are considered.

PMID- 15030636
TI  - Are we puppets on a string? The contextual meaning of unconscious expressive
      cues.
AB  - In three studies, the authors show that unconscious expressive cues can lead to
      opposite evaluations, depending on the context in which they occur. In Study 1,
      brow (vs. cheek) tension reduced preferences in an easy judgment context but
      increased preferences in a difficult context. In Study 2, head shaking (vs.
      nodding) either increased or decreased prosocial affect depending on the context
      in which the judged character was presented. In Study 3, a subliminal smile (vs.
      frown) led to higher self-ratings of performance when paired with one's own
      actions but to lower self-ratings of performance when paired with a competitor's
      actions. Together, these results suggest that the meaning of unconscious
      expressive cues is not fixed.

PMID- 15030638
TI  - Value correlates of ambivalent attitudes toward gender relations.
AB  - This study related measures of hostile sexism, benevolent sexism, hostility
      toward men, and benevolence toward men to value priorities. It was predicted that
      these variables would be positively related to the importance of power values for
      self and negatively related to universalism and benevolence values and that
      measures of benevolent sexism and benevolence toward men would be positively
      related to tradition values and negatively related to self-direction values.
      These predictions were supported in a study in which student participants in
      Adelaide, South Australia, completed the Glick and Fiske Ambivalent Sexism
      Inventory, the Ambivalence Toward Men Inventory, and the Schwartz Value Survey.
      The results demonstrate how values influence attitudes toward gender relations
      and provide an additional perspective on current discussions of prejudice.

PMID- 15030639
TI  - Meta-cognition about biological sex and gender-stereotypic physical appearance:
      consequences for the assessment of leadership competence.
AB  - Previous findings are inconsistent with regard to whether men are judged as being
      more or less competent leaders than women. However, masculine-relative to
      feminine-looking persons seem to be judged consistently as more competent
      leaders. Can this different impact of biological sex and physical appearance be
      due to the disparate availability of meta-cognitive knowledge about both sources?
      The results of Study 1 indicated that individuals possess meta-cognitive
      knowledge about a possible biasing influence of persons' biological sex, but not
      for their physical appearance. In Study 2, participants judged the leadership
      competence of a male versus female stimulus person with either masculine or
      feminine physical appearance. In addition, the available cognitive capacity was
      manipulated. When high capacity was available, participants corrected for the
      influence of stimulus persons' sex, but they fell prey to this influence under
      cognitive load. However, the effect of physical appearance was not moderated by
      cognitive capacity.

PMID- 15030640
TI  - Measuring self-esteem using the implicit association test: the role of the other.
AB  - In two experiments, the use of a self-other Implicit Association Test (IAT) as a
      measure of implicit self-esteem was examined. In Study 1, participants completed
      two self-other IATs: one in which the other was unspecified and one in which the
      other was specified to be a close friend. Esteem-IAT scores were significantly
      higher for the unspecified other-IAT (d = .82), indicating that the content of
      the other has a considerable influence on the over-all esteem-IAT scores. Study 2
      provided a conceptual replication of these results and provided some initial
      evidence that the valence of an unspecified other is negative. Across both
      studies, the nature of the mental representation of the self, as measured by an
      esteem-IAT, changed as a function of the mental representation of the other. The
      crucial role of the other-associations in the esteem-IAT calls into question its
      use and interpretation as a measure of self-esteem.

PMID- 15030641
TI  - What a coincidence! The effects of incidental similarity on compliance.
AB  - Four studies examined the effect of an incidental similarity on compliance to a
      request. Undergraduates who believed they shared a birthday (Study 1), a first
      name (Study 2), or fingerprint similarities (Study 3) with a requester were more
      likely to comply with a request than participants who did not perceive an
      incidental similarity with the requester. The findings are consistent with past
      research demonstrating that people often rely on heuristic processing when
      responding to requests and with Heider's description of unit relationships in
      which perceived similarities lead to positive affect. Consistent with the unit
      relation interpretation, participants did not increase compliance when hearing
      about an incidental similarity with someone other than the requester or when they
      believed the feature they shared with the requester was common.

PMID- 15030642
TI  - Masculinity-femininity guides sexual union formation in adolescents.
AB  - The authors test the idea that patterns of masculinity-femininity (MF) help sort
      adolescents into romantic couples. Using a nationally representative sample of
      adolescents in Grades 7 to 12 from a probability sample of secondary schools in
      the United States, an MF measure was constructed by selecting a set of
      questionnaire items demonstrating sex differences. For each respondent, the
      probability of being a boy was predicted. Respondents identified opposite-sex
      romantic partners within their school. When the partner identified also was
      interviewed, the authors were able to create MF for both members of the couple.
      Trichotomizing MF scores for each sex, it was determined that couples with a very
      masculine boy and very feminine girl are most likely to have sex, and to have sex
      the soonest. The couples for which both members are in the average MF range for
      their sex are the quickest to break up. The pattern of MF is a strong influence
      on the behavior of adolescent romantic couples.

PMID- 15030643
TI  - Detecting state and trait anxiety from auditory and visual cues: a meta-analysis.
AB  - Observers' ability to detect state anxiety and trait anxiety in others was
      evaluated in a meta-analysis that also included a critical moderator variable,
      communication channel. The overall effect size (r) for accuracy was .39 for the
      46 state anxiety studies and .26 for the 34 trait anxiety studies. However, the
      effect of communication channel was very substantial in magnitude and highly
      significant; it also interacted with the type of anxiety. State anxiety was
      correctly identified more often from audio-only stimuli (M r = .49) compared with
      video-only cues (r = .24), whereas the opposite was true for trait anxiety, where
      video-only cues resulted in greater accuracy (r = .31) compared with audio-only
      stimuli (r = .05). Results indicated that the moment-to-moment change in emotion
      (state anxiety) may be better communicated with vocal/verbal stimuli, whereas
      more stable features of personality (trait anxiety) may be more apparent from
      body and facial cues.

PMID- 15030644
TI  - Attachment style and the regulation of negative affect: exploring individual
      differences in mood congruency effects on memory and judgment.
AB  - Three studies examined the role that attachment style plays in moderating the
      effects of induced negative affect on memory and judgment. Israeli undergraduates
      completed an attachment style scale and were exposed to a negative or neutral
      affect induction. In Study 1, incidental recall of negative and positive
      information was assessed; in Study 2, the attribution of negative and positive
      relational events was studied; and in Study 3, findings of Study 1 were
      replicated using a different affect induction procedure. Whereas securely
      attached persons reacted to induced negative affect with an affect-incongruent
      pattern of cognitions (better recall of positive information, more
      unstable/specific attribution of negative event), anxiously attached persons
      reacted with an affect-congruent pattern (worse recall of positive information,
      more stable/global attribution of negative event). Persons scoring high on
      attachment avoidance showed no significant cognitive effect of negative affect.
      The discussion emphasizes the role that attachment strategies play in the affect
      cognition link.

PMID- 15030645
TI  - Preferences and inferences in encoding visual objects: a systematic comparison of
      semantic and affective priming.
AB  - The authors systematically compared semantic and affective priming in five
      studies involving words and pictures. In Studies 1 (lexical decision task) and 2
      (evaluation task), irrelevant short duration (200 ms) primes were briefly flashed
      before relevant targets. The authors orthogonally varied both the semantic and
      affective relations between primes and targets. In both studies, semantic priming
      but not affective priming was found. Study 3 revealed that the same stimuli can
      produce affective priming, but only when words come from a single semantic
      category. Studies 4 and 5 used pictures rather than words to examine automatic
      encoding tendencies. The results conceptually replicated those from Studies 1 and
      2. In sum, the findings suggest that affective priming may be a relatively
      fragile phenomenon, particularly when the semantic properties of objects vary in
      a salient manner.

PMID- 15030646
TI  - The power of love: mediation of rejection in roommate relationships of dependents
      and self-critics.
AB  - This research examined roommate responses to dependent and self-critical
      personality styles in the hope of finding individuals for whom rejection may be
      more likely. Interpersonal traits associated with dependency and self-criticism
      along the love and dominance axes of the Circumplex also were investigated to
      clarify patterns contributing to roommate rejection. Both dependents and self
      critics were more depressed throughout the year. Dependents, however, were
      perceived as more submissive and loving and were better accepted by roommates.
      Self-critics were seen as submissive and hostile and were more likely to be
      rejected. Structural equation modeling indicated that the personality-rejection
      effects were mediated by perceived interpersonal traits along the love axis and
      their associated affective consequences for roommates.

PMID- 15030647
TI  - Agreement in personality judgments within and between nonoverlapping social
      groups in collectivist cultures.
AB  - The social context hypothesis states that people behave differently in different
      social groups because group norms and context-specific interpersonal
      relationships uniquely affect behavior. Consequently, a person who is a member of
      different, nonoverlapping social groups (i. e., the members of different groups
      are unacquainted) should be judged consensually on personality traits within each
      group; however, between groups there should be less agreement in judgments. This
      research focused on cultural moderation of the social context effect in two
      collective cultures (China and Mexico) with different norms for interpersonal
      relationships. Among Chinese, there was greater consensus in trait judgments
      within groups than between groups, whereas in Mexico, agreement within and
      between groups was equivalent. Culturally based relationship norms that affect
      cross-context consistency of behavior and, in turn, the consistency of trait
      judgments across groups were described.

PMID- 15030651
TI  - Guanacaste, Costa Rica: a landmark for cervical cancer prevention.

PMID- 15030652
TI  - Description of a seven-year prospective study of human papillomavirus infection
      and cervical neoplasia among 10000 women in Guanacaste, Costa Rica,.
AB  - OBJECTIVE: The Guanacaste study ("Guanacaste Project," or GP), was designed to
      investigate the role of human papillomavirus (HPV) infection and its cofactors in
      the development of cervical neoplasia and to evaluate new cervical cancer
      screening technologies. The follow-up phase of the GP was designed to study why a
      small proportion of women infected with HPV develop cervical intraepithelial
      neoplasia grade 2 (CIN 2), CIN 3, or cancer (these three together are globally
      referred to as > or = CIN 2, that is, CIN 2 or worse). The purpose of this
      article is to describe this prospective study in detail and to present the
      preliminary findings regarding the incidence of cervical neoplasia. METHODS: A
      cohort of 10 049 randomly selected women from 18 to 97 years old from Guanacaste,
      a province in northwestern Costa Rica, was intensively screened in 1993-1994 and
      then followed up for seven years after being enrolled. A questionnaire for
      demographic and risk factors was administered, and a pelvic examination was
      performed on sexually active women at each follow-up visit in order to obtain
      samples for screening tests and for research purposes. The final diagnosis given
      at the end of the enrollment phase categorized women into several groups
      according to the perceived risk of their developing either high-grade precursors
      of cancer or cancer. These groups were followed up at different intervals
      according to the risk of developing > or = CIN 2. The most active follow-up
      (every 6-12 months) was concentrated on the women most likely to develop >or =
      CIN 2, based on cytology (n = 492). The remainder of the cohort was followed
      either annually (n = 2 574) or after five to seven years of passive follow-up (n
      = 3 926). All women with possibly severe lesions detected by any technique were
      referred to colposcopy for further evaluation and treatment, and they were also
      censored from the study. Lesions >or = CIN 2 served as both the censoring outcome
      and our surrogate for cancer risk. RESULTS: Participation during follow-up was
      high (near 90%). Suspected > or = CIN 2 by any screening technique censored 4.6%
      of women. Most of the women censored because of suspected > or = CIN 2 came from
      the large group perceived at entry as being at low risk of developing > or = CIN
      2, but the greatest rates of progression to > or = CIN 2 were observed among
      women perceived at entry to be at highest risk of > or = CIN 2, based on their
      cytology, virology, or sexual behavior. CONCLUSIONS: The GP is the largest
      population-based longitudinal cohort for the study of HPV and cervical neoplasia
      in the world, and its results will hopefully let us soon plan future worldwide
      prevention strategies. Research projects such as this one require the long-term
      commitment of a large multidisciplinary team and ample financial resources. The
      intensive effort and expertise applied in all aspects of this study were key
      factors in its success as a model of cooperative, interdisciplinary cancer
      research in Latin America. Quality control played an important role at all times
      during the study and made it possible to adapt new diagnostic and screening
      technology to Guanacaste. The systematic follow-up of a population-based group of
      close to 10 000 women in Guanacaste should permit careful, time-dependent
      evaluation of factors postulated to be linked to the development of cervical
      cancer as well as the evaluation of clinical markers of disease progression. The
      study results that have already been published have validated sensitive screening
      techniques and have also promoted the use of more affordable screening techniques
      in resource-poor, developing countries. The GP has also contributed to building
      knowledge for the search for vaccines against HPV as part of the effort to
      develop an effective tool to reduce the incidence and mortality of cervical
      cancer worldwide.

PMID- 15030653
TI  - Diabetes in the English-speaking Caribbean.
AB  - Rates of diabetes mellitus in the English-speaking Caribbean have been rising in
      recent years, and they are projected to continue climbing in the new millennium.
      Prevalence rates across countries of the African diaspora mirror levels of
      Western acculturation, and available data emphasize the importance of obesity as
      a modifiable risk factor. The population-based Barbados Eye Studies have provided
      new information about the burden of ocular complications of diabetes such as
      retinopathy and lens opacities. Diabetes was shown to increase the risk of lens
      opacities, and 14% of prevalent cataract was attributed to diabetes. Persons with
      type 1 diabetes were particularly at increased risk of retinopathy, as a result
      of longer durations of illness and poor glycemic control. Other Caribbean studies
      have suggested that glycemic control in patients evaluated in various clinical
      settings is suboptimal, which raises important concerns about quality of care.
      Diabetics are at increased risk of mortality compared with nondiabetics, and that
      mortality risk increases with higher baseline levels of glycosylated hemoglobin,
      even among nondiabetics. These data highlight the need for urgent attention to
      public health and clinical strategies to prevent diabetes in unaffected persons
      as well as to prevent or reduce the burden of complications among those who are
      affected. Among the measures that should be adopted to stem the flood of diabetes
      in the Caribbean region are lifestyle interventions to promote better nutrition
      and to increase exercise; patient education, particularly about the central role
      of diabetes self-management; and the multidisciplinary team approach in the
      provision of care.

PMID- 15030654
TI  - [Assessing the impact of health sector reform in Costa Rica through a quasi
      experimental study].
AB  - OBJECTIVE: To assess the impact of health sector reform in Costa Rica on that
      country's child and adult mortality rates and on the people's access to primary
      health care. METHODS: Health sector reform was initiated in Costa Rica in 1995 in
      some districts, but in others reforms were adopted later. This made it possible
      to perform a time series analysis, using a quasi-experimental study design, in
      which observations were made annually from 1985 through 2001 for each of the 420
      districts that existed in Costa Rica in 1984. The time series were divided into
      three periods that allowed all districts to be grouped into three categories
      (pioneer, intermediate, and late) according to the year when they first
      implemented health sector reform: 1995-1996; 1997-2000; and 2001 or after,
      respectively. For each of these periods, mortality rates were broken down by
      cause (communicable, socially-determined, or chronic disease), sex, and age
      group. The status of the reform process in a particular district was described by
      two indicators: (1) the presence or absence of health sector reform during a
      given period and, wherever such reforms had been adopted, (2) the number of years
      that had transpired since their adoption. Eight variables were used to control
      for confounders. Vital statistics and demographic data were obtained from the
      National Institute for Statistics and Census' [Centro Nacional de Estadistica y
      Censos] electronic database. Poisson multiple regression analysis with fixed
      effects was used to estimate the impact of reform on child and adult mortality
      from different causes. Assessment of the population's access to primary care
      before and after the reform was based on the percentage of people who lived
      within a 4 km radius of a health facility that offered patient visiting hours two
      or more days a week. This information came from a previous study that used census
      data from 2000 and geographic information systems to map health care facilities
      throughout the country. RESULTS: Multiple regression showed that the reform was
      associated with an overall 8% reduction in deaths among children and with a 2%
      reduction in deaths among adults, both statistically significant. Also noted were
      a 14% reduction in deaths from communicable diseases or from conditions brought
      on by the presence of infectious processes, a 0% reduction in deaths from
      socially-determined causes, and a 2% reduction in deaths from chronic diseases.
      An estimated 120 child lives and 350 adult lives were saved by the reform in 2001
      alone. Also, the percentage of people without equitable access to primary health
      services dropped by 15% between 1994 and 2000 in areas where health sector reform
      was implemented in 1995-1996, whereas areas that had not yet initiated health
      sector reform in 2000 experienced only a 3% reduction. CONCLUSION: Health sector
      reform significantly reduced mortality in Costa Rica and put an end to a decade
      of stagnation, as shown by certain health indicators, such as life expectancy.
      Equity in access to primary care improved considerably, perhaps because the first
      reforms were implemented in less developed areas of the country.

PMID- 15030655
TI  - [Analysis of social and environmental risk for pleural involvement in severe
      pneumonia in children younger than 5 years of age].
AB  - OBJECTIVE: To determine social and environmental risk factors associated with
      pleural involvement among children from 3 to 59 months old who were hospitalized
      with severe pneumonia in northeastern Brazil. METHODS: This was an observational
      and descriptive cross-sectional study with an analytical component. We evaluated
      154 patients hospitalized due to severe pneumonia, with or without pleural
      involvement. Pleural involvement was determined based on radiological findings.
      The following variables were analyzed: age, sex, place of residence, housing
      conditions, day care attendance, passive smoking, family income, presence of
      consumer goods in the home (e.g., television, radio, refrigerator, automobile),
      and schooling and occupation of the mother or other caregiver. The information
      was obtained by interviewing the mother or other caregiver or by consulting the
      inpatient medical chart. RESULTS: The frequency of pleural involvement among the
      154 patients evaluated was 25.3%. The following factors were associated with
      pleural involvement: living in a rural area, being in a household with two or
      fewer rooms, family income below 170 U.S. dollars per month, and birthweight < 2
      500 g. CONCLUSIONS: These findings indicate the need to improve the socioeconomic
      and living conditions of the less-privileged population, especially in rural
      areas. The health sector should emphasize primary care, focusing on a preventive
      approach beginning in the prenatal period.

PMID- 15030657
TI  - [Effects of lead exposure on the human body and health implications].
AB  - OBJECTIVE: To review the literature concerning the risks associated with exposure
      to lead and lead compounds, especially in children and in populations that are
      occupationally exposed. DATA SOURCES: Using "chumbo" [lead] and "efeitos"
      [effects] as search terms, two large databases, namely PubMed (United States
      National Library of Medicine) and LILACS (Literatura Latino-Americana e do Caribe
      em Ciencias da Saude [Latin American and Caribbean Literature in the Health
      Sciences]), were searched for studies on lead toxicity from 1988 to 2002. Other
      sources used to conduct the search include the web page of the United States
      Agency for Toxic Substances and Disease Registry, in Atlanta, Georgia, and the
      library of the Toxicology Laboratory of the Center for Workers' Health and Human
      Ecology at the National School of Public Health [Centro de Estudos da Saude de
      Trabalhador e Ecologia Humana, Escola Nacional de Saude Publica], Fundacao
      Oswaldo Cruz, Rio de Janeiro, Brazil. CONCLUSIONS: The toxic effects of lead and
      lead compounds have been extensively studied for over a century. In recent years,
      epidemiologic studies have focused primarily on the neurotoxic effects of lead on
      children, particularly in terms of impaired intellectual ability and behavioral
      problems. However, there is still insufficient information on the mechanisms of
      action that account for such toxicity. More in-depth studies are also needed on
      the effects of lead exposure on bone, the central nervous system, the
      cardiovascular system, the kidneys, the liver, the male and female reproductive
      systems, and the endocrine system. The potential teratogenicity and
      carcinogenicity of lead, as well as its effect on pregnancy outcomes and neonatal
      growth and development, also require further study.

PMID- 15030656
TI  - Smoky indoor cooking fires are associated with elevated hemoglobin concentration
      in iron-deficient women.
AB  - OBJECTIVE: Indoor air pollution from the burning of such biomass fuels as wood
      and agricultural waste is associated with a higher risk of a number of
      respiratory problems. The effect on other health outcomes, such as fetal growth,
      has not yet been adequately documented. The objective of this study was to
      determine whether, among women who burn biomass fuels for cooking indoors, the
      use of "smoky" fires is associated with elevated hemoglobin concentration in
      comparison to women using "smokeless" stoves, that is, stoves that are designed
      to reduce indoor air pollution. This research was conducted as part of a series
      of preliminary studies to determine the feasibility and potential health benefits
      of a randomized stove intervention to reduce indoor air pollution from the
      burning of biomass fuels for cooking. METHODS: A cross-sectional observational
      study was conducted in rural highland communities of Guatemala from March to
      August 1994. Venous blood samples were collected and analyzed for hemoglobin and
      ferritin. All the women studied burned biomass fuels and cooked indoors, and none
      of the women was pregnant. Eighty-nine indigenous women using smokeless stoves
      (designated as the not-exposed group) and 185 indigenous women from the same
      communities using smoky fires (the exposed group) were studied. Multiple linear
      regression analyses were used to investigate the relationship between exposure
      (smokeless stove or smoky fire) and hemoglobin concentration, with adjusting for
      potential confounding factors. RESULTS: No effect of exposure (smokeless stove or
      smoky fire) on hemoglobin concentration was found in univariate or multivariate
      analyses. In routine post hoc analysis to determine whether hemoglobin elevation
      is observed in some particular subgroup, we found that the use of a smoky fire
      was associated with a 5.2 g/L elevation in hemoglobin concentration among women
      with low ferritin stores (P < 0.10). CONCLUSIONS: The elevation of hemoglobin
      concentration through exposure to indoor air pollution resulting from the burning
      of biomass fuels in smoky fires for cooking could have important implications for
      the diagnosis of anemia. However, considering the observational nature of this
      study, further research using more rigorous measures of exposure to carbon
      monoxide as well as additional measures of iron status are needed to confirm the
      relationships among iron status, exposure to smoke from the burning of biomass
      fuels indoors, and hemoglobin concentration of women living at moderately high
      altitude. Further study of this matter could help to assure that appropriate
      adjustments to anemia cutoffs are made, if warranted, and could assist in
      clarifying potentially negative outcomes of exposure to smoke from biomass fuels
      burned indoors.

PMID- 15030659
TI  - [Risk perception and strategies for mass communication on dengue in the
      Americas].
AB  - Dengue is clearly a very serious public health problem. In the Americas the
      number of dengue cases has been increasing since the 1960s, and outbreaks of the
      disease have been occurring more frequently. Furthermore, the density of
      infestation with the disease vector, the Aedes aegypti mosquito, is high in the
      Americas. The general strategy for preventing and controlling dengue and dengue
      hemorrhagic fever is based on promoting behavior changes that lead to
      incorporating the community in controlling the disease, particularly the vector.
      In order to achieve this, mass communication programs on dengue should have two
      primary aims: converting information into practice and encouraging the community
      to take over prevention and control measures. The new generation of programs
      should be designed based on the local sanitation structure (water distribution
      and waste disposal) as well as information on community organizations and the
      roles of different family members. Furthermore, the new programs should
      incorporate all the following ten components: epidemiological surveillance,
      intersectoral actions, community participation, managing the environment and
      basic services, patient care, case reporting, education, using insecticides and
      vector control, training, and preparing for emergencies. Communication should be
      aimed at modifying the behavior of individuals and the community by empowering
      them to carry out prevention and control measures.

PMID- 15030660
TI  - [Challenges facing Caribbean countries 10 years after the International
      Conference on Population and Development in Cairo, Egypt].
AB  - At the International Conference on Population and Development (ICPD) that was
      held in Cairo, Egypt, in 1994, participants acknowledged that population,
      economic growth, and sustainable development are concepts that are closely
      linked, and important strides were made in terms of increased recognition of
      sexual and reproductive rights. The Programme of Action ratified at that
      Conference was adopted as a platform for designing national and international
      policies in the areas of population and development for a period of twenty years.
      However, in Latin America and the Caribbean all types of obstacles-financial,
      institutional, and human-still stand in the way of attaining the goals of the
      Programme of Action, and some governments have established measures that
      undermine their people's exercise of sexual and reproductive rights. The
      Caribbean Subregional Meeting to Assess the Implementation of the Programme of
      Action of the International Conference on Population and Development 10 Years
      after its Adoption was held in Port of Spain, Trinidad and Tobago, in November of
      2003. At the meeting, which was attended by representatives from 20 Caribbean
      countries and territories, a call was made for more rational use of available
      resources and for mobilization of additional funds for developing and
      implementing population and development programs and policies in the Caribbean.
      The meeting also saw the approval of the Caribbean Declaration, which lays out
      the challenges that should serve as the roadmap for taking actions to consolidate
      the progress achieved so far and come closer to attaining the goals established
      by the ICPD. In the Declaration, the countries and territories of the Caribbean
      asserted their commitment to continue legislative reforms at the national level
      while seeking to enforce these reforms in an effort to ensure implementation of
      the ICPD's Programme of Action and of the Caribbean Plan of Action for Population
      and Development that was adopted in 1996 by the Economic Community for Latin
      America and the Caribbean.

PMID- 15030661
TI  - The effect of a communal lifestyle on depressive symptoms in late life.
AB  - OBJECTIVES: This study compares depression levels among lifetime kibbutz members
      (n = 525) and old-age kibbutz residents (n = 366) with a comparable national
      sample (n = 412) and assesses the relationship between depression and individual
      differences related to lifetime in a kibbutz (e.g., health) and those related to
      current living conditions (e.g., social network). METHODS: The analysis is based
      on data from the Cross-Sectional and Longitudinal Aging Study conducted in Israel
      between 1989 and 1992 and the follow-up during 1993 and 1994. RESULTS: The
      findings indicate significantly lower depressive symptomatology among women, but
      not among men, residing in kibbutz communities. The women's lower level of
      depressive symptoms appears to be a result of better physical and mental
      functioning among kibbutz members and of such favorable lifestyle characteristics
      as frequent contact with their children among old-age kibbutz residents.
      DISCUSSION: Both lifetime and current living conditions contribute to better
      mental health of women in the kibbutz at older ages.

PMID- 15030663
TI  - A longitudinal analysis of discrete negative emotions and health-services use in
      elderly individuals.
AB  - OBJECTIVE: To test the hypothesis that everyday, discrete negative emotions
      anger, frustration, sadness, and fear-relate to health-service use in later life.
      METHOD: Community-dwelling adults (n = 345) ages 72 to 99 were interviewed about
      the frequency of recently experienced emotions. Physician visits and hospital
      admissions in the subsequent 2 years were outcomes. Covariates included prior use
      of health services, chronic illness, functional status, and demographics.
      RESULTS: Age, education, and gender moderated relations between negative emotions
      and health care use. More frustration was associated with fewer physician visits
      among older individuals. Sadness was associated with more hospital admissions for
      women. Among those with more education, frequent anger was associated with more
      physician visits. Projected effects of negative emotions resulted in increases in
      health-service use, ranging from 18% to 33%. DISCUSSION: The interactions
      indicate the importance of negative emotions and the larger social and
      developmental context in health care services use among elderly individuals.

PMID- 15030662
TI  - Pragmatic and internal validity issues in sampling in caregiver studies: a
      comparison of population-based, registry-based, and ancillary studies.
AB  - OBJECTIVES: Studies of caregivers illustrate a classic sampling dilemma:
      maximizing recruitment without compromising study validity. Because caregivers
      are defined in relation to a care recipient, sampling methods are often
      determined by pragmatic decisions such as access, efficiency, and costs. However,
      overlooking validity may result in selection bias, misclassification of caregiver
      status, and the confounding of results. Validity and pragmatic concerns were
      compared in four caregiver studies that used different sampling frames: community
      based, Alzheimer's disease registry, and ancillary studies to existing
      epidemiologic studies. METHODS: Systematic comparison of validity and of
      pragmatic aspects of sampling frames, recruitment methods, and participation
      rates, with attention to caregiver identification, inclusion criteria, and sample
      restriction. RESULTS: All studies used task-based inclusion criteria. Caregiver
      participation rates ranged from 81% to 96%, with higher rates in community-based
      and registry-based studies than in ancillary studies. The latter studies
      benefited from unbiased selection of noncaregivers. DISCUSSION: Regardless of
      sampling frame, standard task-based inclusion criteria to define caregivers may
      enhance validity.

PMID- 15030664
TI  - A profile of calls to a poison information center regarding older adults.
AB  - OBJECTIVES: The authors sought to examine the nature of calls to poison
      information centers by adults ages 50 and over. METHODS: The authors used data
      from the national Toxic Exposure Surveillance System and conducted a
      retrospective review of all cases reported to an American Association of Poison
      Control Centers Certified Regional Poison Information Center in 1998 and 1999 (N
      = 6,365). RESULTS: The results indicated that females' poison experiences were
      more likely the result of therapeutic error, adverse drug reactions, ingestions,
      and the acute-on-chronic class. The authors found that older age was inversely
      associated with acute class, suspected suicide, food poisoning, and inhalation
      and dermal exposures. DISCUSSION: Older adults are the greatest consumers of over
      the-counter drugs, take multiple medications for various medical conditions, and
      are experiencing biological changes that affect drug metabolism. Older women may
      be at especially high risk because of high drug use. Poison prevention education
      should target older adults.

PMID- 15030665
TI  - Body-weight change and physical functioning among young old adults.
AB  - OBJECTIVES: The main purpose of this study is to examine if body weight change is
      a potential risk factor for the onset of functional impairment across time among
      various functional domains. METHODS: Using longitudinal data from the Health and
      Retirement Study, logistic regression models on the onset of functional
      impairment over three time points are estimated for young old adults. RESULTS:
      Results indicate that weight gain is associated with greater risk of lower body
      mobility impairment. An increase in body mass index of greater than 5% increases
      the likelihood of the onset of lower body mobility functional impairment.
      DISCUSSION: Study findings support the promotion of healthy weight management.
      Future studies in this area may want to investigate effective interventions that
      contribute to healthy weight maintenance among this cohort.

PMID- 15030666
TI  - Factors influencing the use of mobility technology in community-based long-term
      care.
AB  - OBJECTIVES: This article adapts a framework commonly used to model personal long
      term care services to examine factors influencing the use of mobility-related
      assistive devices, both in isolation and in combination with personal care.
      METHODS: The authors analyze data from Phase 2 of the 1994-1995 National Health
      Interview Survey Disability Supplements to compare predictors of equipment use
      with those for personal care and rank the probabilities of using particular
      combinations according to health needs, access, and personal and family
      characteristics. RESULTS: The authors find that underlying health needs are the
      dominant factor related to the type of care arrangement used. The typical person
      with a mobility-related disability is most likely to use equipment alone; only at
      younger ages or at greater levels of severity are other arrangements expected to
      dominate. DISCUSSION: Research on the dynamic acquisition process, with attention
      to age and trajectories of disability severity, is needed to fully understand the
      integration of technology and personal care.

PMID- 15030679
TI  - SARS-related virus predating SARS outbreak, Hong Kong.
AB  - Using immunofluorescence and neutralization assays, we detected antibodies to
      human severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and/or
      animal SARS-CoV-like virus in 17 (1.8%) of 938 adults recruited in 2001. This
      finding suggests that a small proportion of healthy persons in Hong Kong had been
      exposed to SARS-related viruses at least 2 years before the recent SARS outbreak.

PMID- 15030680
TI  - Susceptibility of pigs and chickens to SARS coronavirus.
AB  - An outbreak of severe acute respiratory syndrome (SARS) in humans, associated
      with a new coronavirus, was reported in Southeast Asia, Europe, and North America
      in early 2003. To address speculations that the virus originated in domesticated
      animals, or that domestic species were susceptible to the virus, we inoculated 6
      week-old pigs and chickens intravenously, intranasally, ocularly, and orally with
      106 PFU of SARS-associated coronavirus (SARS-CoV). Clinical signs did not develop
      in any animal, nor were gross pathologic changes evident on postmortem
      examinations. Attempts at virus isolation were unsuccessful; however, viral RNA
      was detected by reverse transcriptase-polymerase chain reaction in blood of both
      species during the first week after inoculation, and in chicken organs at 2 weeks
      after inoculation. Virus-neutralizing antibodies developed in the pigs. Our
      results indicate that these animals do not play a role as amplifying hosts for
      SARS-CoV.

PMID- 15030681
TI  - SARS surveillance during emergency public health response, United States, March
      July 2003.
AB  - In response to the emergence of severe acute respiratory syndrome (SARS), the
      United States established national surveillance using a sensitive case definition
      incorporating clinical, epidemiologic, and laboratory criteria. Of 1,460
      unexplained respiratory illnesses reported by state and local health departments
      to the Centers for Disease Control and Prevention from March 17 to July 30, 2003,
      a total of 398 (27%) met clinical and epidemiologic SARS case criteria. Of these,
      72 (18%) were probable cases with radiographic evidence of pneumonia. Eight (2%)
      were laboratory-confirmed SARS-coronavirus (SARS-CoV) infections, 206 (52%) were
      SARS-CoV negative, and 184 (46%) had undetermined SARS-CoV status because of
      missing convalescent-phase serum specimens. Thirty-one percent (124/398) of case
      patients were hospitalized; none died. Travel was the most common epidemiologic
      link (329/398, 83%), and mainland China was the affected area most commonly
      visited. One case of possible household transmission was reported, and no
      laboratory-confirmed infections occurred among healthcare workers. Successes and
      limitations of this emergency surveillance can guide preparations for future
      outbreaks of SARS or respiratory diseases of unknown etiology.

PMID- 15030682
TI  - Introduction of SARS in France, March-April, 2003.
AB  - We describe severe acute respiratory syndrome (SARS) in France. Patients meeting
      the World Health Organization definition of a suspected case underwent a
      clinical, radiologic, and biologic assessment at the closest university
      affiliated infectious disease ward. Suspected cases were immediately reported to
      the Institut de Veille Sanitaire. Probable case-patients were isolated, their
      contacts quarantined at home, and were followed for 10 days after exposure. Five
      probable cases occurred from March through April 2003; four were confirmed as
      SARS coronavirus by reverse transcription-polymerase chain reaction, serologic
      testing, or both. The index case-patient (patient A), who had worked in the
      French hospital of Hanoi, Vietnam, was the most probable source of transmission
      for the three other confirmed cases; two had been exposed to patient A while on
      the Hanoi-Paris flight of March 22-23. Timely detection, isolation of probable
      case-patients, and quarantine of their contacts appear to have been effective in
      preventing the secondary spread of SARS in France.

PMID- 15030683
TI  - SARS outbreak, Taiwan, 2003.
AB  - We studied the severe acute respiratory syndrome (SARS) outbreak in Taiwan, using
      the daily case-reporting data from May 5 to June 4 to learn how it had spread so
      rapidly. Our results indicate that most SARS-infected persons had symptoms and
      were admitted before their infections were reclassified as probable cases. This
      finding could indicate efficient admission, slow reclassification process, or
      both. The high percentage of nosocomial infections in Taiwan suggests that
      infection from hospitalized patients with suspected, but not yet classified,
      cases is a major factor in the spread of disease. Delays in reclassification also
      contributed to the problem. Because accurate diagnostic testing for SARS is
      currently lacking, intervention measures aimed at more efficient diagnosis,
      isolation of suspected SARS patients, and reclassification procedures could
      greatly reduce the number of infections in future outbreaks.

PMID- 15030684
TI  - Multiple contact dates and SARS incubation periods.
AB  - Many severe acute respiratory syndrome (SARS) patients have multiple possible
      incubation periods due to multiple contact dates. Multiple contact dates cannot
      be used in standard statistical analytic techniques, however. I present a simple
      spreadsheet-based method that uses multiple contact dates to calculate the
      possible incubation periods of SARS.

PMID- 15030685
TI  - Risk factors for SARS among persons without known contact with SARS patients,
      Beijing, China.
AB  - Most cases of severe acute respiratory syndrome (SARS) have occurred in close
      contacts of SARS patients. However, in Beijing, a large proportion of SARS cases
      occurred in persons without such contact. We conducted a case-control study in
      Beijing that compared exposures of 94 unlinked, probable SARS patients with those
      of 281 community-based controls matched for age group and sex. Case-patients were
      more likely than controls to have chronic medical conditions or to have visited
      fever clinics (clinics at which possible SARS patients were separated from other
      patients), eaten outside the home, or taken taxis frequently. The use of masks
      was strongly protective. Among 31 case-patients for whom convalescent-phase (>21
      days) sera were available, 26% had immunoglobulin G to SARS-associated
      coronavirus. Our finding that clinical SARS was associated with visits to fever
      clinics supports Beijing's strategy of closing clinics with poor infection
      control measures. Our finding that mask use lowered the risk for disease supports
      the community's use of this strategy.

PMID- 15030687
TI  - SARS-associated coronavirus transmission, United States.
AB  - To better assess the risk for transmission of the severe acute respiratory
      syndrome-associated coronavirus (SARS-CoV), we obtained serial specimens and
      clinical and exposure data from seven confirmed U.S. SARS patients and their 10
      household contacts. SARS-CoV was detected in a day-14 sputum specimen from one
      case-patient and in five stool specimens from two case-patients. In one case
      patient, SARS-CoV persisted in stool for at least 26 days after symptom onset.
      The highest amounts of virus were in the day-14 sputum sample and a day-14 stool
      sample. Residual respiratory symptoms were still present in recovered SARS case
      patients 2 months after illness onset. Possible transmission of SARS-CoV occurred
      in one household contact, but this person had also traveled to a SARS-affected
      area. The data suggest that SARS-CoV is not always transmitted efficiently.
      Routine collection and testing of stool and sputum specimens of probable SARS
      case-patients may help the early detection of SARS-CoV infection.

PMID- 15030686
TI  - Lack of SARS transmission and U.S. SARS case-patient.
AB  - In early April 2003, severe acute respiratory syndrome (SARS) was diagnosed in a
      Pennsylvania resident after his exposure to persons with SARS in Toronto, Canada.
      To identify contacts of the case-patient and evaluate the risk for SARS
      transmission, a detailed epidemiologic investigation was performed. On the basis
      of this investigation, 26 persons (17 healthcare workers, 4 household contacts,
      and 5 others) were identified as having had close contact with this case-patient
      before infection-control practices were implemented. Laboratory evaluation of
      clinical specimens showed no evidence of transmission of SARS-associated
      coronavirus (SARS-CoV) infection to any close contact of this patient. This
      investigation documents that, under certain circumstances, SARS-CoV is not
      readily transmitted to close contacts, despite ample unprotected exposures.
      Improving the understanding of risk factors for transmission will help focus
      public health control measures.

PMID- 15030688
TI  - Secondary household transmission of SARS, Singapore.
AB  - Secondary household transmission of severe acute respiratory syndrome (SARS) was
      studied in 114 households involving 417 contacts. The attack rate was low (6.2%).
      Occupation of the index case was the factor that most influenced household
      transmission (adjusted hazard ratio for healthcare workers 0.157; 95% confidence
      interval 0.042 to 0.588).

PMID- 15030689
TI  - Probable secondary infections in households of SARS patients in Hong Kong.
AB  - Although severe acute respiratory syndrome (SARS) is highly infectious in
      clinical settings, SARS has not been well examined in household settings. The
      household and household member attack rates were calculated for 1,214 SARS case
      patients and their household members, stratified by two phases of the epidemic. A
      case-control analysis identified risk factors for secondary infection. Secondary
      infection occurred in 14.9% (22.1% versus 11% in earlier and later phases) of all
      households and 8% (11.7% versus 5.9% in the earlier and later phases) of all
      household members. Healthcare workers' households were less likely to be
      affected. Risk factors from the multivariate analysis included at-home duration
      before hospitalization, hospital visitation to the SARS patient (and mask use
      during the visit), and frequency of close contact. SARS transmission at the
      household level was not negligible in Hong Kong. Transmission rates may be
      greatly reduced with precautionary measures taken by household members of SARS
      patients.

PMID- 15030690
TI  - Lack of SARS transmission among healthcare workers, United States.
AB  - Healthcare workers accounted for a large proportion of persons with severe acute
      respiratory syndrome (SARS) during the worldwide epidemic of early 2003. We
      conducted an investigation of healthcare workers exposed to laboratory-confirmed
      SARS patients in the United States to evaluate infection-control practices and
      possible SARS-associated coronavirus (SARS-CoV) transmission. We identified 110
      healthcare workers with exposure within droplet range (i.e., 3 feet) to six SARS
      CoV-positive patients. Forty-five healthcare workers had exposure without any
      mask use, 72 had exposure without eye protection, and 40 reported direct skin-to
      skin contact. Potential droplet- and aerosol-generating procedures were
      infrequent: 5% of healthcare workers manipulated a patient's airway, and 4%
      administered aerosolized medication. Despite numerous unprotected exposures,
      there was no serologic evidence of healthcare-related SARS-CoV transmission. Lack
      of transmission in the United States may be related to the relative absence of
      high-risk procedures or patients, factors that may place healthcare workers at
      higher risk for infection.

PMID- 15030691
TI  - Healthcare worker seroconversion in SARS outbreak.
AB  - Serum samples were obtained from healthcare workers 5 weeks after exposure to an
      outbreak of severe acute respiratory syndrome (SARS). A sensitive dot blot enzyme
      linked immunosorbent assay, complemented by a specific neutralization test, shows
      that only persons in whom probable SARS was diagnosed had specific antibodies and
      suggests that subclinical SARS is not an important feature of the disease.

PMID- 15030692
TI  - SARS among critical care nurses, Toronto.
AB  - To determine factors that predispose or protect healthcare workers from severe
      acute respiratory syndrome (SARS), we conducted a retrospective cohort study
      among 43 nurses who worked in two Toronto critical care units with SARS patients.
      Eight of 32 nurses who entered a SARS patient's room were infected. The
      probability of SARS infection was 6% per shift worked. Assisting during
      intubation, suctioning before intubation, and manipulating the oxygen mask were
      high-risk activities. Consistently wearing a mask (either surgical or particulate
      respirator type N95) while caring for a SARS patient was protective for the
      nurses, and consistent use of the N95 mask was more protective than not wearing a
      mask. Risk was reduced by consistent use of a surgical mask, but not
      significantly. Risk was lower with consistent use of a N95 mask than with
      consistent use of a surgical mask. We conclude that activities related to
      intubation increase SARS risk and use of a mask (particularly a N95 mask) is
      protective.

PMID- 15030694
TI  - Atypical SARS in geriatric patient.
AB  - We describe an atypical presentation of severe acute respiratory syndrome (SARS)
      in a geriatric patient with multiple coexisting conditions. Interpretation of
      radiographic changes was confounded by cardiac failure, with resolution of fever
      causing delayed diagnosis and a cluster of cases. SARS should be considered even
      if a contact history is unavailable, during an ongoing outbreak.

PMID- 15030693
TI  - Superspreading SARS events, Beijing, 2003.
AB  - Superspreading events were pivotal in the global spread of severe acute
      respiratory syndrome (SARS). We investigated superspreading in one transmission
      chain early in Beijing's epidemic. Superspreading was defined as transmission of
      SARS to at least eight contacts. An index patient with onset of SARS 2 months
      after hospital admission was the source of four generations of transmission to 76
      case-patients, including 12 healthcare workers and several hospital visitors.
      Four (5%) case circumstances met the superspreading definition. Superspreading
      appeared to be associated with older age (mean 56 vs. 44 years), case fatality
      (75% vs. 16%, p = 0.02, Fisher exact test), number of close contacts (36 vs.
      0.37) and attack rate among close contacts (43% vs. 18.5%, p < 0.025). Delayed
      recognition of SARS in a hospitalized patient permitted transmission to patients,
      visitors, and healthcare workers. Older age and number of contacts merit
      investigation in future studies of superspreading.

PMID- 15030695
TI  - Lack of SARS transmission among public hospital workers, Vietnam.
AB  - The severe acute respiratory syndrome (SARS) outbreak in Vietnam was amplified by
      nosocomial spread within hospital A, but no transmission was reported in hospital
      B, the second of two designated SARS hospitals. Our study documents lack of SARS
      associated coronavirus transmission to hospital B workers, despite variable
      infection control measures and the use of personal protective equipment.

PMID- 15030696
TI  - Cluster of SARS among medical students exposed to single patient, Hong Kong.
AB  - We studied transmission patterns of severe acute respiratory syndrome (SARS)
      among medical students exposed exclusively to the first SARS patient in the
      Prince of Wales Hospital in Hong Kong, before his illness was recognized. We
      conducted a retrospective cohort study of 66 medical students who visited the
      index patient's ward, including 16 students with SARS and 50 healthy students.
      The risk of contracting SARS was sevenfold greater among students who definitely
      visited the index case's cubicle than in those who did not (10/27 [41%] versus
      1/20 [5%], relative risk 7.4; 95% confidence interval 1.0 to 53.3). Illness rates
      increased directly with proximity of exposure to the index case. However, four of
      eight students who were in the same cubicle, but were not within 1 m of the index
      case-patient, contracted SARS. Proximity to the index case-patient was associated
      with transmission, which is consistent with droplet spread. Transmission through
      fomites or small aerosols cannot be ruled out.

PMID- 15030697
TI  - Surgical helmets and SARS infection.
AB  - Performance testing of two brands of surgical helmets indicated that their
      efficiency at in vivo filtration of sub-micrometer-sized particles is inadequate
      for their use as respirators. These helmets are not marketed for respiratory
      protection and should not be used alone for protection against severe acute
      respiratory syndrome when performing aerosol-generating procedures.

PMID- 15030698
TI  - SARS transmission among hospital workers in Hong Kong.
AB  - Despite infection control measures, breakthrough transmission of severe acute
      respiratory syndrome (SARS) occurred for many hospital workers in Hong Kong. We
      conducted a case-control study of 72 hospital workers with SARS and 144 matched
      controls. Inconsistent use of goggles, gowns, gloves, and caps was associated
      with a higher risk for SARS infection (unadjusted odds ratio 2.42 to 20.54, p <
      0.05). The likelihood of SARS infection was strongly associated with the amount
      of personal protection equipment perceived to be inadequate, having <2 hours of
      infection control training, and not understanding infection control procedures.
      No significant differences existed between the case and control groups in the
      proportion of workers who performed high-risk procedures, reported minor
      protection equipment problems, or had social contact with SARS-infected persons.
      Perceived inadequacy of personal protection equipment supply, infection control
      training <2 hours, and inconsistent use of personal protection equipment when in
      contact with SARS patients were significant independent risk factors for SARS
      infection.

PMID- 15030699
TI  - Possible SARS coronavirus transmission during cardiopulmonary resuscitation.
AB  - Infection of healthcare workers with the severe acute respiratory syndrome
      associated coronavirus (SARS-CoV) is thought to occur primarily by either contact
      or large respiratory droplet transmission. However, infrequent healthcare worker
      infections occurred despite the use of contact and droplet precautions,
      particularly during certain aerosol-generating medical procedures. We
      investigated a possible cluster of SARS-CoV infections in healthcare workers who
      used contact and droplet precautions during attempted cardiopulmonary
      resuscitation of a SARS patient. Unlike previously reported instances of
      transmission during aerosol-generating procedures, the index case-patient was
      unresponsive, and the intubation procedure was performed quickly and without
      difficulty. However, before intubation, the patient was ventilated with a bag
      valve-mask that may have contributed to aerosolization of SARS-CoV. On the basis
      of the results of this investigation and previous reports of SARS transmission
      during aerosol-generating procedures, a systematic approach to the problem is
      outlined, including the use of the following: 1) administrative controls, 2)
      environmental engineering controls, 3) personal protective equipment, and 4)
      quality control.

PMID- 15030700
TI  - Detection of SARS coronavirus in patients with suspected SARS.
AB  - Cases of severe acute respiratory syndrome (SARS) were investigated for SARS
      coronavirus (SARS-CoV) through RNA tests, serologic response, and viral culture.
      Of 537 specimens from patients in whom SARS was clinically diagnosed, 332 (60%)
      had SARS-CoV RNA in one or more clinical specimens, compared with 1 (0.3%) of 332
      samples from controls. Of 417 patients with clinical SARS from whom paired serum
      samples were available, 92% had an antibody response. Rates of viral RNA
      positivity increased progressively and peaked at day 11 after onset of illness.
      Although viral RNA remained detectable in respiratory secretions and stool and
      urine specimens for >30 days in some patients, virus could not be cultured after
      week 3 of illness. Nasopharyngeal aspirates, throat swabs, or sputum samples were
      the most useful clinical specimens in the first 5 days of illness, but later in
      the illness viral RNA could be detected more readily in stool specimens.

PMID- 15030701
TI  - Real-time polymerase chain reaction for detecting SARS coronavirus, Beijing,
      2003.
AB  - During the 2003 severe acute respiratory syndrome (SARS) outbreak, a real-time
      quantitative polymerase chain reaction, which targets the nucleocapsid gene at
      the 3' end of the viral genome, was established to detect and identify the SARS
      associated coronavirus. We describe the use of this assay to screen >700 clinical
      samples.

PMID- 15030702
TI  - Serologic and molecular biologic methods for SARS-associated coronavirus
      infection, Taiwan.
AB  - Severe acute respiratory syndrome (SARS) has raised a global alert since March
      2003. After its causative agent, SARS-associated coronavirus (SARS-CoV), was
      confirmed, laboratory methods, including virus isolation, reverse transcriptase
      polymerase chain reaction (RT-PCR), and serologic methods, have been quickly
      developed. In this study, we evaluated four serologic tests ( neutralization
      test, enzyme-linked immunosorbent assay [ELISA], immunofluorescent assay [IFA],
      and immunochromatographic test [ICT]) for detecting antibodies to SARS-CoV in
      sera of 537 probable SARS case-patients with correlation to the RT-PCR. With the
      neutralization test as a reference method, the sensitivity, specificity, positive
      predictive value, and negative predictive value were 98.2%, 98.7%, 98.7%, and
      98.4% for ELISA; 99.1%, 87.8%, 88.1% and 99.1% for IFA; 33.6%, 98.2%, 95.7%, and
      56.1% for ICT, respectively. We also compared the recombinant-based western blot
      with the whole virus-based IFA and ELISA; the data showed a high correlation
      between these methods, with an overall agreement of >90%. Our results provide a
      systematic analysis of serologic and molecular methods for evaluating SARS-CoV
      infection.

PMID- 15030703
TI  - Real-time reverse transcription-polymerase chain reaction assay for SARS
      associated coronavirus.
AB  - A real-time reverse transcription-polymerase chain reaction (RT-PCR) assay was
      developed to rapidly detect the severe acute respiratory syndrome-associated
      coronavirus (SARS-CoV). The assay, based on multiple primer and probe sets
      located in different regions of the SARS-CoV genome, could discriminate SARS-CoV
      from other human and animal coronaviruses with a potential detection limit of <10
      genomic copies per reaction. The real-time RT-PCR assay was more sensitive than a
      conventional RT-PCR assay or culture isolation and proved suitable to detect SARS
      CoV in clinical specimens. Application of this assay will aid in diagnosing SARS
      CoV infection.

PMID- 15030704
TI  - Interferon-beta 1a and SARS coronavirus replication.
AB  - A global outbreak of severe acute respiratory syndrome (SARS) caused by a novel
      coronavirus began in March 2003. The rapid emergence of SARS and the substantial
      illness and death it caused have made it a critical public health issue. Because
      no effective treatments are available, an intensive effort is under way to
      identify and test promising antiviral drugs. Here, we report that recombinant
      human interferon-beta 1a potently inhibits SARS coronavirus replication in vitro.

PMID- 15030705
TI  - Ultrastructural characterization of SARS coronavirus.
AB  - Severe acute respiratory syndrome (SARS) was first described during a 2002-2003
      global outbreak of severe pneumonia associated with human deaths and person-to
      person disease transmission. The etiologic agent was initially identified as a
      coronavirus by thin-section electron microscopic examination of a virus isolate.
      Virions were spherical, 78 nm in mean diameter, and composed of a helical
      nucleocapsid within an envelope with surface projections. We show that infection
      with the SARS-associated coronavirus resulted in distinct ultrastructural
      features: double-membrane vesicles, nucleocapsid inclusions, and large granular
      areas of cytoplasm. These three structures and the coronavirus particles were
      shown to be positive for viral proteins and RNA by using ultrastructural
      immunogold and in situ hybridization assays. In addition, ultrastructural
      examination of a bronchiolar lavage specimen from a SARS patient showed numerous
      coronavirus-infected cells with features similar to those in infected culture
      cells. Electron microscopic studies were critical in identifying the etiologic
      agent of the SARS outbreak and in guiding subsequent laboratory and epidemiologic
      investigations.

PMID- 15030706
TI  - Combining clinical and epidemiologic features for early recognition of SARS.
AB  - Early recognition and rapid initiation of infection control precautions are
      currently the most important strategies for controlling severe acute respiratory
      syndrome (SARS). No rapid diagnostic tests currently exist that can rule out SARS
      among patients with febrile respiratory illnesses. Clinical features alone cannot
      with certainty distinguish SARS from other respiratory illnesses rapidly enough
      to inform early management decisions. A balanced approach to screening that
      allows early recognition of SARS without unnecessary isolation of patients with
      other respiratory illnesses will require clinicians not only to look for
      suggestive clinical features but also to routinely seek epidemiologic clues
      suggestive of SARS coronavirus exposure. Key epidemiologic risk factors include
      1) exposure to settings where SARS activity is suspected or documented, or 2) in
      the absence of such exposure, epidemiologic linkage to other persons with
      pneumonia (i.e., pneumonia clusters), or 3) exposure to healthcare settings. When
      combined with clinical findings, these epidemiologic features provide a possible
      strategic framework for early recognition of SARS.

PMID- 15030707
TI  - Clinical description of a completed outbreak of SARS in Vietnam, February-May
      2003.
AB  - We investigated the clinical manifestations and course of all probable severe
      acute respiratory syndrome (SARS) patients in the Vietnam outbreak. Probable SARS
      cases were defined by using the revised World Health Organization criteria. We
      systematically reviewed medical records and undertook descriptive statistical
      analyses. All 62 patients were hospitalized. On admission, the most prominent
      symptoms were malaise (82.3%) and fever (79.0%). Cough, chest pain, and shortness
      of breath were present in approximately one quarter of the patients; 79.0% had
      lymphopenia; 40.3% had thrombocytopenia; 19.4% had leukopenia; and 75.8% showed
      changes on chest radiograph. Fever developed on the first day of illness onset,
      and both respiratory symptoms and radiographic changes occurred on day 4. On
      average, maximal radiographic changes were observed on day 10, and fevers
      subsided by day 13. Symptoms on admission were nonspecific, although fever,
      malaise, and lymphopenia were common. The complications of SARS included invasive
      intubation and ventilation (11.3%) and death (9.7%).

PMID- 15030708
TI  - Index patient and SARS outbreak in Hong Kong.
AB  - During the global outbreak of severe acute respiratory syndrome (SARS) in 2003,
      treatment was empiric. We report the case history of the index patient in a
      hospital outbreak of SARS in Hong Kong. The patient recovered after conventional
      antimicrobial therapy. Further studies are needed to address treatment of SARS,
      which has high attack and death rates.

PMID- 15030709
TI  - Possible central nervous system infection by SARS coronavirus.
AB  - On day 22 of illness, generalized tonic-clonic convulsion developed in a 32-year
      old woman with severe acute respiratory syndrome (SARS). Cerebrospinal fluid
      tested positive for SARS coronavirus (SARS-CoV) by reverse transcriptase
      polymerase chain reaction. SARS-CoV may have caused an infection in the central
      nervous system in this patient.

PMID- 15030710
TI  - SARS and pregnancy: a case report.
AB  - We report a laboratory-confirmed case of severe acute respiratory syndrome (SARS)
      in a pregnant woman. Although the patient had respiratory failure, a healthy
      infant was subsequently delivered, and the mother is now well. There was no
      evidence of viral shedding at delivery. Antibodies to SARS virus were detected in
      cord blood and breast milk.

PMID- 15030711
TI  - Atypical SARS and Escherichia coli bacteremia.
AB  - We describe a patient with severe acute respiratory syndrome (SARS) whose
      clinical symptoms were masked by Escherichia coli bacteremia. SARS developed in a
      cluster of healthcare workers who had contact with this patient. SARS was
      diagnosed when a chest infiltrate developed and when the patient's brother was
      hospitalized with acute respiratory failure. We highlight problems in atypical
      cases and offer infection control suggestions.

PMID- 15030712
TI  - HHS/CDC legal response to SARS outbreak.
AB  - Before the severe acute respiratory syndrome (SARS) outbreak, the Centers for
      Disease Control and Prevention's (CDC) legal authority to apprehend, detain, or
      conditionally release persons was limited to seven listed diseases, not including
      SARS, and could only be changed using a two-step process: 1) executive order of
      the President of the United States on recommendation by the Secretary, U.S.
      Department of Health and Human Services (HHS), and 2) amendment to CDC quarantine
      regulations (42 CFR Parts 70 and 71). In April 2003, in response to the SARS
      outbreak, the federal executive branch acted rapidly to add SARS to the list of
      quarantinable communicable diseases. At the same time, HHS amended the
      regulations to streamline the process of adding future emerging infectious
      diseases. Since the emergence of SARS, CDC has increased legal preparedness for
      future public health emergencies by establishing a multistate teleconference
      program for public health lawyers and a Web-based clearinghouse of legal
      documents.

PMID- 15030713
TI  - Fear and stigma: the epidemic within the SARS outbreak.
AB  - Because of their evolving nature and inherent scientific uncertainties, outbreaks
      of emerging infectious diseases can be associated with considerable fear in the
      general public or in specific communities, especially when illness and deaths are
      substantial. Mitigating fear and discrimination directed toward persons infected
      with, and affected by, infectious disease can be important in controlling
      transmission. Persons who are feared and stigmatized may delay seeking care and
      remain in the community undetected. This article outlines efforts to rapidly
      assess, monitor, and address fears associated with the 2003 severe acute
      respiratory syndrome (SARS) epidemic in the United States. Although fear,
      stigmatization, and discrimination were not widespread in the general public,
      Asian-American communities were particularly affected.

PMID- 15030715
TI  - SARS preparedness checklist for state and local health officials.
AB  - A planning checklist for widespread severe acute respiratory syndrome, modeled on
      an Association of State and Territorial Health Officials (ASTHO) pandemic
      influenza planning checklist, was developed jointly by ASTHO, the National
      Association of County and City Health Officials, and the Centers for Disease
      Control and Prevention. This checklist, distributed May 2003, has been widely
      used.

PMID- 15030714
TI  - Crisis prevention and management during SARS outbreak, Singapore.
AB  - We discuss crisis prevention and management during the first 3 months of the
      severe acute respiratory syndrome (SARS) outbreak in Singapore. Four public
      health issues were considered: prevention measures, self-health evaluation, SARS
      knowledge, and appraisal of crisis management. We conducted telephone interviews
      with a representative sample of 1,201 adults, > or = 21 years of age. We found
      that sex, age, and attitude (anxiety and perception of open communication with
      authorities) were associated with practicing preventive measures. Analysis of
      Singapore's outbreak improves our understanding of the social dimensions of
      infectious disease outbreaks.

PMID- 15030716
TI  - Body temperature monitoring and SARS fever hotline, Taiwan.
AB  - In Taiwan, a temperature-monitoring campaign and hotline for severe acute
      respiratory syndrome (SARS) fever were implemented in June 2003. Among 1,966
      calls, fever was recorded in 19% (n = 378); 18 persons at high risk for SARS were
      identified. In a cross-sectional telephone survey, 95% (n = 1,060) of households
      knew about the campaign and 7 households reported fever.

PMID- 15030717
TI  - Health communication during SARS.
AB  - During the severe acute respiratory syndrome (SARS) outbreak, electronic media
      made it possible to disseminate prevention messages rapidly. The Centers for
      Disease Control and Prevention's Travelers' Health Web site was frequently
      visited in the first half of 2003; more than 2.6 million visits were made to
      travel alerts, advisories, and other SARS-related documents.

PMID- 15030727
TI  - [Continuous positive airway pressure titration: manual, automatic, or
      empirical?].

PMID- 15030728
TI  - [How can we assess the perception of induced dyspnea in chronic obstructive
      pulmonary disease?].
AB  - OBJECTIVE: To evaluate various methods for studying the perception of dyspnea in
      chronic obstructive pulmonary disease (COPD) using a new parameter, the change in
      Borg scale rating, and others already in use: the linear regression slope and the
      application of Stevens' law to the response perception curve--ie change in forced
      expiratory volume in 1 second (delta FEV1)--change in dyspnea (delta dyspnea).
      PATIENTS AND METHODS: A bronchial challenge test was performed on 70 patients
      with stable COPD and no contraindications for performing the test (European
      Respiratory Society criteria), during which dyspnea was measured (Borg scale)
      after each nebulization. Perception was analyzed using: a) the linear regression
      slope of delta FEV1 plotted against (delta dyspnea); b) the exponent n of
      Stevens' law (psi=k phi n, in which psi is delta dyspnea and phi is delta FEV1,
      with perception being poor when n<1 and good when n>1), and c) change in Borg:
      difference between dyspnea when FEV1 has fallen 20% and dyspnea after saline
      inhalation. Subjects were classified according to the slope and change in Borg as
      hypoperceivers, normal perceivers, or hyperperceivers. These 2 methods of
      classification were compared using the kappa statistic. RESULTS: According to the
      exponent n, all patients were hypoperceivers (n<1). According to the slope, there
      were 33 hypoperceivers, 28 normal perceivers, and 9 hyperperceivers. The change
      in Borg classified 37 subjects as hypoperceivers, 23 as normal perceivers, and 10
      as hyperperceivers. All except 5 subjects were classified in the same way by the
      slope and the change in Borg (kappa=0.88). In most of the 5 cases of discrepancy,
      the slope classified subjects as better perceivers. CONCLUSIONS: The n exponent
      is not valid for evaluating the perception of dyspnea induced by a bronchial
      challenge test in COPD. Change in Borg is at least as useful as the slope for
      evaluating perception of dyspnea. The percentage of patients with this disease
      who are hyperperceivers is high.

PMID- 15030729
TI  - [Spirometry is a good method for detecting and monitoring chronic obstructive
      pulmonary disease in high-risk smokers in primary health care].
AB  - OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a common disease, the
      early diagnosis of which allows effective management and treatment. The aim of
      the present study is to show the effectiveness of a screening and monitoring plan
      for COPD in high-risk patients in primary health care. PATIENTS AND METHODS: The
      subjects in this prospective observational longitudinal study comprised 164 high
      risk smokers aged between 40 and 76 years. Age, sex, weight, height, and smoking
      habit (pack-years) were recorded and spirometry was performed according to the
      guidelines of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR).
      Patients were informed of their results and given brief advice on how to stop
      smoking. After 3 years, the patients underwent the same evaluation. RESULTS: In
      1999, 22% of the smokers were diagnosed with COPD. Three years later, an
      additional 16.3% were diagnosed as having COPD, and the disease had worsened in
      38.8% of those already diagnosed. Of the patients with a forced expiratory volume
      in one second (FEV1) less than 90%, 44.8% developed COPD (relative risk: 10.54).
      An accelerated decrease in FEV1 was found in 18.1% of the patients (20.7% with
      COPD and 9.0% without COPD). Mean tobacco consumption in 1999 was 28.1 pack-years
      in subjects without COPD and 31.7 pack-years in those with COPD, whereas in 2002,
      consumption was 30.6 pack-years in patients with COPD and 31.9 pack-years in
      those without. In 3 years, 22.8% had stopped smoking (20.5% without COPD and
      30.3% with COPD). CONCLUSIONS: Many smokers managed to give up smoking after
      learning their spirometric results. FEV1 can identify smokers at greatest risk of
      developing COPD. Spirometric screening and monitoring of smokers at high risk in
      primary health care can identify those most susceptible to developing COPD while
      the disease is in an early phase. Therefore the most appropriate strategy can be
      adopted for each patient.

PMID- 15030730
TI  - [Demographic study of tobacco addiction in Health District 5, Valencia, Spain].
AB  - OBJECTIVES: To determine the number of smokers, their demographic
      characteristics, and the stages of change among patients visiting health care
      centers. PATIENTS AND METHODS: Descriptive cross-sectional study carried out at 7
      primary health care centers in Health District 5 of the Autonomous Community of
      Valencia. RESULTS: An interview was given to 3633 people with a mean (SD) age of
      55 (19) years, (range: 14-96 years). Women made up 61.7%, and 65% were seeking
      medical attention. Twenty-three per cent were current smokers (mean age 41.8
      [15.2] years), 17.2% ex-smokers (60.6 [16.2] years), and 59.8% never smokers
      (58.4 [18.8] years). The stages of change were pre-contemplation for 32.1%,
      contemplation for 4.9%, chronic contemplation for 12.2%, preparation to quit for
      6.8%, action for 2.3%, maintenance for 15.1%, and termination for 26.7%.
      According to current recommendations, it seems that between 23.6% and 44.7%,
      depending on category definitions, needed specific attention concerning tobacco
      dependence. CONCLUSIONS: Twenty-three per cent of the patients attended by the
      primary care physician were smokers. More than half did not want to quit smoking
      and 1 in 10 were prepared to do so. Between 23.6% and 44.7% of the people who
      came to the primary care center needed specific attention concerning tobacco
      dependence.

PMID- 15030732
TI  - [The travels of a pulmonologist through the upper airway].

PMID- 15030731
TI  - [Emerging pleuropulmonary diseases associated with asbestos inhalation].

PMID- 15030733
TI  - [Giant solitary fibrous tumor of the pleura treated by video-assisted surgery: a
      case report].
AB  - Solitary fibrous tumors of the pleura are rare, with unpredictable clinical
      manifestations. By the time of diagnosis, the size and consistency of the tumor
      usually preclude the use of minimally invasive surgical techniques. We present a
      case of a 34-year-old male with a solitary fibrous tumor of the visceral pleura
      masquerading as a mediastinal tumor. The tumor was removed by video-assisted
      thoracic surgery.

PMID- 15030734
TI  - [Mediastinal enteric cyst: unusual clinical presentation and histopathology].
AB  - A mediastinal enteric cyst is an uncommon entity which is rare in adults and
      usually found incidentally. In most cases the lesion is lined by gastrointestinal
      mucosa, and theories as to the origin of such lesions are diverse. We report an
      adult case of thoracic enteric cyst that presented with cardiac tamponade and for
      which histopathological examination revealed the presence of pancreatic tissue.
      Review of the literature yielded only 1 case of mediastinal enteric cyst with
      pancreatic tissue.

PMID- 15030735
TI  - [Persistent hemoptysis secondary to extensive epithelioid angiosarcoma].
AB  - Pulmonary angiosarcoma is an unusual cause of diffuse pulmonary hemorrhage.
      Angiosarcomas are rare malignant vascular tumors accounting for 1% to 2% of all
      sarcomas. Angiosarcomas have been detected in nearly all organs, but lung
      involvement is unusual, accounting for less than 7%. The literature describes
      approximately 10 isolated cases of primary pulmonary angiosarcoma as opposed to
      the more common metastatic type. Given that primary and metastatic types are
      clinicopathologically similar, the presence of a distant primary sarcoma must be
      ruled out before a diagnosis of primary pulmonary angiosarcoma can be made. A
      pathological diagnosis requires a finding of polygonal or oval cells with
      atypical irregular nuclei and vascular spaces lined with such cells surrounded by
      hemorrhagic phenomena. Immunohistochemical analysis is positive for specific
      endothelial cell markers such as CD31 and factor VIII, and coexpression of
      keratin is a frequent finding.

PMID- 15030736
TI  - [Bronchial inflammation in smokers: clarifying terms].

PMID- 15030737
TI  - [Lymphoma of bronchus-associated lymphoid tissue].

PMID- 15030738
TI  - [Docetaxel in combination with cisplatin for first-line treatment of locally
      advanced or metastatic non-small cell lung cancer: meta-analysis of randomized
      and controlled clinical trials].
AB  - BACKGROUND AND OBJECTIVE: Recent approval of docetaxel in combination with
      cisplatin (DP) for non-small cell lung cancer (NSCLC) treatment means that an
      assessment of its effectiveness and toxicity is necessary. The aim of this study
      was to evaluate docetaxel/cisplatin combination versus other cisplatin-based
      regimens as the front-line treatment of metastatic or locally advanced NSCLC.
      MATERIAL AND METHOD: We searched randomized and controlled phase III clinical
      trials comparing DP versus other cisplatin combinations. Patients had to be
      diagnosed of advanced NSCLC and had not previously received chemotherapy.A meta
      analysis was performed using the Mantel-Haenzel method. Antitumoral activity and
      adverse events were both evaluated. We also made a heterogeneity test and
      determined the NNT Index (Number Needed to Treat) for two-year survival. RESULTS:
      We found three clinical trials that fulfilled our criteria. Results showed
      significant enhanced two-year survival for DP (11-47% higher than others), but a
      greater incidence of diarrhea (odds ratio [OR] = 2.525; confidence interval 95%
      [CI], 1.697-3.756]). Heterogeneity was significant for response, anemia and
      thrombopenia. NNT was 17 patients for two-year survival. CONCLUSIONS: DP is a
      good option in first-line therapy of advanced NSCLC. The two-year survival is
      significantly longer and its toxic profile similar to other treatments, except
      for diarrhea.

PMID- 15030739
TI  - [Validation of the Spanish version of the International Consultation on
      Incontinence Questionnaire-Short Form. A questionnaire for assessing the urinary
      incontinence].
AB  - BACKGROUND AND OBJECTIVE: A big proportion (40-70%) of patients with urinary
      incontinence (UI) do not ask for medical advice. Self-administered questionnaires
      may help in detecting UI. The objective of the present study was to validate the
      Spanish version of the questionnaire ICIQ-SF. PATIENTS AND METHOD: 500 women who
      consulted at a UI-specialized unit responded to the questionnaire. A urodynamic
      study was carried out and sociodemographic and clinical data were collected.
      Feasibility, validity and reliability were assessed. Sensitivity (Se),
      specificity (Sp) and positive (PPV) and negative (NPV) predictive values of the
      clinical and urodynamic study were also calculated. RESULTS: The mean time of
      administration was 3.5 (1.5) minutes. All patients answered all the items of the
      ICIQ-SF. According to the clinical diagnosis, patients with UI scored 11.6 (5.9)
      and patients without UI scored 4.5 (6.3) (p < 0.001). According to the urodynamic
      diagnosis, UI patients scored 11.1 (6.3) vs 6.2 (6.5) (p < 0.001). In patients
      with an urodynamic diagnosis of stress UI, a higher severity degree was
      associated with a higher score on the ICIQ-SF. The values of Se, Sp, PPV and NPV
      were 92.1%, 55.6%, 88.3% and 65.9%, respectively, regarding clinical diagnosis,
      and 87.7%, 40.8%, 85.1% and 46.2%, respectively, regarding the urodynamic study.
      CONCLUSIONS: This is the first questionnaire designed for diagnosing UI validated
      in Spain. The psychometric properties of the ICIQ-SF are satisfactory and allow
      to recommend the use of the questionnaire in the clinical practice.

PMID- 15030740
TI  - [Assessing COPD-associated morbidity: factors of prognosis].
AB  - BACKGROUND AND OBJECTIVE: Forced respiratory volume in first second spirometry is
      currently used to diagnose chronic obstructive pulmonary disease. However, this
      technique does not always provide a reliable short-term prognosis, especially in
      patients with associated morbidity. We propose that specific health-related
      quality of life questionnaires are a better tool to estimate the prognosis of
      chronic obstructive pulmonary disease. PATIENTS AND METHOD: A total of 93
      patients who had been admitted to Unit 1 of the Department of Internal Medicine
      at the Reina Sofia Hospital for chronic obstructive pulmonary disease
      exacerbation were followed up for one year after discharge. The number of
      hospital readmissions were recorded. A prospective cohort design and logistic
      regression analysis were used. RESULTS: Mean age was 70.8, 83% were males, 89.2%
      presented with an associated illness, and 59.1% had been hospitalized previously.
      The mean forced respiratory volume in first second was 34% and the overall score
      for the St George's Respiratory Questionnaire was 58.2. After one year, 40.4% of
      patients were readmitted to hospital. The regression model included scores for
      the St George's Respiratory Questionnaire activity scale (OR 1.05) and long-term
      home oxygen therapy (OR 5.18). CONCLUSIONS: The St George's Respiratory
      Questionnaire score better predicts hospital readmission after one year than the
      forced respiratory volume in first second. The activity scale is the best
      predictor of readmission. Long-term home oxygen therapy is associated with an
      increase in the number of hospitalizations.

PMID- 15030741
TI  - [Cardiovascular disease in HIV-infected patients on highly active antiretroviral
      therapy].
AB  - BACKGROUND AND OBJECTIVE: Our goal was to assess the main characteristics of
      cardiovascular disease in HIV-infected patients on highly active antiretroviral
      therapy (HAART). PATIENTS AND METHOD: Retrospective analysis of the clinico
      epidemiological characteristics of 16 HIV-infected patients treated with HAART
      who had suffered a cardiovascular event from a 1,459 patients' cohort. RESULTS:
      Clinical presentation of cardiovascular disease was an acute coronary syndrome in
      12 cases, ischemic stroke in 2 and peripheral vascular disease in 2. Patients
      included in the study had a mean of 3.2 cardiovascular risk factors, smoking and
      low HDL levels being the more prevalent risk factors. Eight (50%, 95% CI, 25-75%)
      patients fulfilled the criteria of metabolic syndrome. The mean CD4 count was 548
      x 10(6)/l. CONCLUSIONS: HIV-infected patients on HAART ha-ve a high
      cardiovascular risk. A strict management of modifiable risk factors must be
      warranted in these patients.

PMID- 15030742
TI  - [Cardiovascular risk and HIV type 1 infection].

PMID- 15030743
TI  - [Biphosphonates for the prevention of osteoporosis in postmenopausal women with a
      low bone mass].

PMID- 15030745
TI  - [Assessment of nevirapine liver toxicity in patients with HIV and HVC
      coinfection].

PMID- 15030744
TI  - [Azithromycin therapy in cystic fibrosis].
AB  - Progressive lung disease, caused by chronic endobronchial colonization, is the
      major cause of morbidity and mortality in patients with cystic fibrosis (CF).
      Several pathogens, including Staphylococcus aureus and Pseudomonas aeruginosa are
      responsible for this effect. The steadily improving prognosis of CF has been
      attributed to the use of antibiotics with activity against these organisms.
      Despite a significant increase in the amount of published material demonstrating
      the potential role of macrolide antibiotics as antiinflammatory agents and their
      effects on bacterial virulence, their mechanism of action in CF patients is still
      unknown. Although there is a limited number of clinical trials assessing the
      efficacy and safety of azithromycin (AZM) in CF, increasing evidence suggests
      that 3 to 6-month AZM treatment in CF patients is safe and well tolerated. This
      treatment results in clinical improvement, decreasing the number of pulmonary
      exacerbations and increasing pulmonary function. Therefore, chronic treatment
      with AZM should be considered in CF patients added to conventional therapy.
      Clinical experience with macrolides other than AZM in CF patients is very
      limited.

PMID- 15030746
TI  - [Spontaneous dissection of vertebral arteries].

PMID- 15030747
TI  - [Fatal acute pancreatitis in a patient who received an homeopathic treatment].

PMID- 15030748
TI  - ["Cognitive": a term in discussion. "Non ethic", an homeric solution].

PMID- 15030750
TI  - Coordinating morphogenesis: epithelial integrity during heart tube assembly.
AB  - Formation of the embryonic heart tube requires the medial migration and merger of
      bilateral precursor populations. A new study of zebrafish cardiogenesis published
      in this issue of Developmental Cell indicates that precursor migration involves
      formation of a coherent epithelium and that fibronectin plays an important role
      in maintaining cardiac epithelial integrity.

PMID- 15030751
TI  - Formins coming into focus.
AB  - Two new crystal structures published in Cell and Molecular Cell provide the first
      clues about how fascinating proteins called formins interact with actin
      filaments.

PMID- 15030752
TI  - Bacterial invasion: a new strategy to dominate cytoskeleton plasticity.
AB  - Some bacterial pathogens enter mammalian cells by injecting, directly into the
      host cytosol, proteins that trigger cytoskeletal rearrangements necessary for
      internalization. In the February 27 issue of Molecular Cell, McGhie et al.
      identify mechanisms by which the Salmonella protein SipA interferes with
      ADF/cofilin and gelsolin function. Thus Salmonella not only triggers actin
      polymerization but also counteracts the major F-actin destabilizing proteins.

PMID- 15030753
TI  - Tipping the balance toward longevity.
AB  - Genetic experiments in C. elegans suggested that SIR2, an NAD-dependent protein
      deacetylase, acts through FOXO/DAF-16 transcription factor to prolong life.
      Recent studies show that mammalian SIR2 deacetylates FOXO, and may maximize
      survival by tempering cell death and increasing stress resistance.

PMID- 15030754
TI  - Twist genes regulate Runx2 and bone formation.
AB  - Runx2, a master regulator of osteoblast differentiation, is expressed several
      days before osteoblast genes in bone anlage. In this issue of Developmental Cell,
      show that Twist-1 and Twist-2 suppress the activity of Runx2 and thereby regulate
      bone formation.

PMID- 15030755
TI  - Cryptic bracts exposed: insights into the regulation of leaf expansion.
AB  - Arabidopsis is unusual in producing flowers that are not subtended by specialized
      leaves, called floral bracts. Writing in Development, Dinneny et al. and Ohno et
      al. show that gain-of-function mutations of the JAGGED transcription factor
      produce bracts, and provide evidence that this gene plays a key role in a
      developmental program that regulates the size and shape of all leaves and leaf
      homologs.

PMID- 15030756
TI  - Cell cycle development.
AB  - The Keystone Symposium on the Cell Cycle and Development brought together
      biologists with an interest in how cell cycle control is integrated into the
      ontogenetic program of multicellular organisms, and showcased research using a
      wide variety of systems from both animals and plants. A clear indication from the
      meeting is that this research is changing the conventional wisdom on both cell
      cycle control and development.

PMID- 15030757
TI  - Dynamics of homologous chromosome pairing during meiotic prophase in fission
      yeast.
AB  - Pairing of homologous chromosomes is important for homologous recombination and
      correct chromosome segregation during meiosis. It has been proposed that telomere
      clustering, nuclear oscillation, and recombination during meiotic prophase
      facilitate homologous chromosome pairing in fission yeast. Here we examined the
      contributions of these chromosomal events to homologous chromosome pairing, by
      directly observing the dynamics of chromosomal loci in living cells of fission
      yeast. Homologous loci exhibited a dynamic process of association and
      dissociation during the time course of meiotic prophase. Lack of nuclear
      oscillation reduced association frequency for both centromeric and arm regions of
      the chromosome. Lack of telomere clustering or recombination reduced association
      frequency at arm regions, but not significantly at centromeric regions. Our
      results indicate that homologous chromosomes are spatially aligned by oscillation
      of telomere-bundled chromosomes and physically linked by recombination at
      chromosome arm regions; this recombination is not required for association of
      homologous centromeres.

PMID- 15030758
TI  - Patterned gene expression directs bipolar planar polarity in Drosophila.
AB  - During convergent extension in Drosophila, polarized cell movements cause the
      germband to narrow along the dorsal-ventral (D-V) axis and more than double in
      length along the anterior-posterior (A-P) axis. This tissue remodeling requires
      the correct patterning of gene expression along the A-P axis, perpendicular to
      the direction of cell movement. Here, we demonstrate that A-P patterning
      information results in the polarized localization of cortical proteins in
      intercalating cells. In particular, cell fate differences conferred by striped
      expression of the even-skipped and runt pair-rule genes are both necessary and
      sufficient to orient planar polarity. This polarity consists of an enrichment of
      nonmuscle myosin II at A-P cell borders and Bazooka/PAR-3 protein at the
      reciprocal D-V cell borders. Moreover, bazooka mutants are defective for germband
      extension. These results indicate that spatial patterns of gene expression
      coordinate planar polarity across a multicellular population through the
      localized distribution of proteins required for cell movement.

PMID- 15030759
TI  - Tensin stabilizes integrin adhesive contacts in Drosophila.
AB  - We report the functional characterization of the Drosophila ortholog of tensin, a
      protein implicated in linking integrins to the cytoskeleton and signaling
      pathways. A tensin null was generated and is viable with wing blisters, a
      phenotype characteristic of loss of integrin adhesion. In tensin mutants,
      mechanical abrasion is required during wing expansion to cause wing blisters,
      suggesting that tensin strengthens integrin adhesion. The localization of tensin
      requires integrins, talin, and integrin-linked kinase. The N-terminal domain and
      C-terminal PTB domain of tensin provide essential recruitment signals. The
      intervening SH2 domain is not localized on its own. We suggest a model where
      tensin is recruited to sites of integrin adhesion via its PTB and N-terminal
      domains, localizing the SH2 domain so that it can interact with phosphotyrosine
      containing proteins, which stabilize the integrin link to the cytoskeleton.

PMID- 15030760
TI  - Fibronectin regulates epithelial organization during myocardial migration in
      zebrafish.
AB  - Several genes have been implicated in heart tube formation, yet we know little
      about underlying cellular mechanisms. We analyzed the cellular architecture of
      the migrating myocardial precursors, and find that they form coherent epithelia
      that mature as they move medially. Mutant analyses indicate that the cardia
      bifida locus natter (nat) is required for the integrity of the myocardial
      epithelia. We positionally cloned nat and show that it encodes Fibronectin.
      During myocardial migration, Fibronectin is deposited at the midline between the
      endoderm and endocardial precursors, and laterally around the myocardial
      precursors. Further analyses show that Fibronectin deposition at the midline is
      required for the timely migration of myocardial precursors, but dispensable for
      the migration process itself. In the complete absence of Fibronectin, adherens
      junctions between myocardial precursors do not form properly, suggesting that
      cell-substratum interactions are required for epithelial organization. These data
      suggest that myocardial migration is dependent on epithelial integrity.

PMID- 15030761
TI  - Integration of semaphorin-2A/MAB-20, ephrin-4, and UNC-129 TGF-beta signaling
      pathways regulates sorting of distinct sensory rays in C. elegans.
AB  - Semaphorins and ephrins are axon guidance cues. In C. elegans, semaphorin-2a/mab
      20 and ephrin-4/efn-4/mab-26 also regulate cell sorting to form distinct rays in
      the male tail. Several erf (enhancer of ray fusion) mutations were identified in
      a mab-20 enhancer screen. Mutants of plexin-2 (plx-2) and unc-129, which encodes
      an axon guiding TGF-beta, were also found to be erfs. Genetic analyses show that
      plx-2 and mab-20 function in the same pathway, as expected if PLX-2 is a receptor
      for MAB-20. Surprisingly, MAB-20 also signals in a parallel pathway that requires
      efn-4. This signal utilizes a non-plexin receptor. The expression of plx-2, efn
      4, and unc-129 in subsets of 3-cell sensory ray clusters likely mediates the ray
      specific cell sorting functions of the ubiquitously expressed mab-20. We present
      a model for the integrated control of TGF-beta, semaphorin, and ephrin signaling
      in the sorting of cell clusters into distinct rays in the developing male tail.

PMID- 15030762
TI  - Nodal and BMP2/4 signaling organizes the oral-aboral axis of the sea urchin
      embryo.
AB  - In the sea urchin embryo, the oral-aboral axis is specified after fertilization
      by mechanisms that are largely unknown. We report that early sea urchin embryos
      express Nodal and Antivin in the presumptive oral ectoderm and demonstrate that
      these genes control formation of the oral-aboral axis. Overexpression of nodal
      converted the whole ectoderm into oral ectoderm and induced ectopic expression of
      the orally expressed genes goosecoid, brachyury, BMP2/4, and antivin. Conversely,
      when the function of Nodal was blocked, by injection of an antisense Morpholino
      oligonucleotide or by injection of antivin mRNA, neither the oral nor the aboral
      ectoderm were specified. Injection of nodal mRNA into Nodal-deficient embryos
      induced an oral-aboral axis in a largely non-cell-autonomous manner. These
      observations suggest that the mechanisms responsible for patterning the oral
      aboral axis of the sea urchin embryo may share similarities with mechanisms that
      pattern the dorsoventral axis of other deuterostomes.

PMID- 15030763
TI  - Regulation of retinoic acid distribution is required for proximodistal patterning
      and outgrowth of the developing mouse limb.
AB  - Exogenous retinoic acid (RA) induces marked effects on limb patterning, but the
      precise role of endogenous RA in this process has remained unknown. We have
      studied the role of RA in mouse limb development by focusing on CYP26B1, a
      cytochrome P450 enzyme that inactivates RA. Cyp26b1 was shown to be expressed in
      the distal region of the developing limb bud, and mice that lack CYP26B1
      exhibited severe limb malformation (meromelia). The lack of CYP26B1 resulted in
      spreading of the RA signal toward the distal end of the developing limb and
      induced proximodistal patterning defects characterized by expansion of proximal
      identity and restriction of distal identity. CYP26B1 deficiency also induced
      pronounced apoptosis in the developing limb and delayed chondrocyte maturation.
      Wild-type embryos exposed to excess RA phenocopied the limb defects of Cyp26b1(-/
      ) mice. These observations suggest that RA acts as a morphogen to determine
      proximodistal identity, and that CYP26B1 prevents apoptosis and promotes
      chondrocyte maturation, in the developing limb.

PMID- 15030764
TI  - A twist code determines the onset of osteoblast differentiation.
AB  - Runx2 is necessary and sufficient for osteoblast differentiation, yet its
      expression precedes the appearance of osteoblasts by 4 days. Here we show that
      Twist proteins transiently inhibit Runx2 function during skeletogenesis. Twist-1
      and -2 are expressed in Runx2-expressing cells throughout the skeleton early
      during development, and osteoblast-specific gene expression occurs only after
      their expression decreases. Double heterozygotes for Twist-1 and Runx2 deletion
      have none of the skull abnormalities observed in Runx2(+/-) mice, a Twist-2 null
      background rescues the clavicle phenotype of Runx2(+/-) mice, and Twist-1 or -2
      deficiency leads to premature osteoblast differentiation. Furthermore, Twist-1
      overexpression inhibits osteoblast differentiation without affecting Runx2
      expression. Twist proteins' antiosteogenic function is mediated by a novel
      domain, the Twist box, which interacts with the Runx2 DNA binding domain to
      inhibit its function. In vivo mutagenesis confirms the antiosteogenic function of
      the Twist box. Thus, relief of inhibition by Twist proteins is a mandatory event
      precluding osteoblast differentiation.

PMID- 15030766
TI  - An aurora kinase is essential for flagellar disassembly in Chlamydomonas.
AB  - Cilia and flagella play key roles in development and sensory transduction, and
      several human disorders, including polycystic kidney disease, are associated with
      the failure to assemble cilia. Here, we show that the aurora protein kinase CALK
      in the biflagellated alga Chlamydomonas has a central role in two pathways for
      eliminating flagella. Cells rendered deficient in CALK were defective in
      regulated flagellar excision and regulated flagellar disassembly. Exposure of
      cells to altered ionic conditions, the absence of a centriole/basal body for
      nucleating flagellar assembly, cessation of delivery of flagellar components to
      their tip assembly site, and formation of zygotes all led to activation of the
      regulated disassembly pathway as indicated by phosphorylation of CALK and the
      absence of flagella. We propose that cells have a sensory pathway that detects
      conditions that are inappropriate for possession of a flagellum, and that CALK is
      a key effector of flagellar disassembly in that pathway.

PMID- 15030767
TI  - Unraveling the NALP-3/IL-1beta inflammasome: a big lesson from a small mutation.
AB  - Cytokine-mediated inflammation is a target for novel therapies as well as for
      fundamental research. A single amino acid mutation in the NALP-3 gene controlling
      the activation of caspase-1 results in increased processing of the inactive IL
      1beta precursor and release of the active cytokine. Blocking IL-1 receptors
      arrests inflammation in humans with the mutation.

PMID- 15030765
TI  - Definitive hematopoiesis requires the mixed-lineage leukemia gene.
AB  - The Mixed-Lineage Leukemia (MLL) gene encodes a Trithorax-related chromatin
      modifying protooncogene that positively regulates Hox genes. In addition to their
      well-characterized roles in axial patterning, Trithorax and Polycomb family
      proteins perform less-understood functions in vertebrate hematopoiesis. To define
      the role of MLL in the development of the hematopoietic system, we examined the
      potential of cells lacking MLL. Mll-deficient cells could not develop into
      lymphocytes in adult RAG-2 chimeric animals. Similarly, in vitro differentiation
      of B cells required MLL. In chimeric embryos, Mll-deficient cells failed to
      contribute to fetal liver hematopoietic stem cell/progenitor populations.
      Moreover, we show that aorta-gonad-mesonephros (AGM) cells from Mll-deficient
      embryos lacked hematopoietic stem cell (HSC) activity despite their ability to
      generate hematopoietic progeny in vitro. These results demonstrate an intrinsic
      requirement for MLL in definitive hematopoiesis, where it is essential for the
      generation of HSCs in the embryo.

PMID- 15030768
TI  - All roads lead to Rome: triggering dendritic cell migration.
AB  - Migration of dendritic cells to secondary lymphatic organs is a key event in
      acquired immunity. The role of the multifunctional ectoenzyme CD38 in humoral
      immune responses has now been revisited, suggesting that CD38 links innate and
      adaptive immunity by triggering chemokine-mediated dendritic cell chemotaxis.

PMID- 15030769
TI  - Immunobiology of mucosal HIV infection and the basis for development of a new
      generation of mucosal AIDS vaccines.
AB  - Mucosal tissues are the primary site of natural HIV transmission and a major
      reservoir for HIV replication. Targeting immune responses to the mucosal entry
      site before viral dissemination could protect and also clear viral reservoirs.
      Recent understanding of mucosal HIV transmission and of chemokines and integrins
      in mucosal trafficking can aid design of new strategies to enhance AIDS vaccine
      efficacy.

PMID- 15030770
TI  - Calcineurin B1 is essential for positive but not negative selection during
      thymocyte development.
AB  - During development, discrete cell fates often result from variation in the
      intensity of a particular signal. The mechanisms underlying these seemingly
      analog-to-digital switches are not understood. In developing T lymphocytes, low
      intensity signals through the antigen receptor result in positive selection while
      more intense signals give rise to negative selection. By deleting the genetic
      locus encoding the regulatory B1 subunit of calcineurin specifically in
      thymocytes, we found an absolute requirement for calcineurin in positive
      selection. In contrast, calcineurin activity was dispensable in several models of
      negative selection. Unexpectedly, we found that removal of calcineurin activity
      from thymocytes results in inefficient ERK activation at the double-positive
      stage of thymocyte development, when selection occurs. These studies clarify the
      mechanism by which graded signals are converted to discrete outcomes in T cell
      development and further indicate that the developmental roles of calcineurin
      likely contribute to immunosuppression by calcineurin inhibitors.

PMID- 15030771
TI  - Type 2 immunity reflects orchestrated recruitment of cells committed to IL-4
      production.
AB  - Using IL-4 reporter mice we identified eosinophils, basophils, and Th2 cells as
      the three IL-4-producing cell types that appear in the lungs of mice infected
      with the migrating intestinal helminth, Nippostrongylus brasiliensis. Eosinophils
      were most prevalent, peaking by approximately 1000-fold on day 9 after infection,
      with Th2 cells and basophils at 3- and 10-fold lower numbers, respectively.
      Eosinophil and basophil expansion in blood in response to parasites and their
      capacity for IL-4 expression required neither Stat6 nor T cells. Th2 induction
      and expansion in draining lymph nodes was also Stat6 independent. In contrast,
      eosinophil (and Th2 cell) recruitment to the lung was dependent on Stat6
      expression by a bone marrow-derived tissue resident cell, whereas basophil
      recruitment was Stat6 and IL-4/IL-13 independent but T cell dependent. Primary
      type 2 immune responses in the lung represent the focal recruitment and
      activation of discrete cell populations from the blood that have previously
      committed to express IL-4.

PMID- 15030772
TI  - Regulation of dendritic cell trafficking by the ADP-ribosyl cyclase CD38: impact
      on the development of humoral immunity.
AB  - Mice lacking CD38, an ectoenzyme that generates the calcium-mobilizing metabolite
      cADPR, make reduced T cell-dependent antibody responses. Despite the predicted
      role for CD38 in B cell activation, we find that CD38 regulates the migration of
      dendritic cell (DC) precursors from the blood to peripheral sites and controls
      the migration of mature DCs from sites of inflammation to lymph nodes. Thus, T
      cells are inefficiently primed in Cd38(-/-) mice, leading to poor humoral immune
      responses. We also show that CD38 and cADPR modulate calcium mobilization in
      chemokine-stimulated DCs and are required for the chemotaxis of immature and
      mature DCs to CCL2, CCL19, CCL21, and CXCL12. Therefore, CD38 regulates adaptive
      immunity by controlling chemokine receptor signaling in DCs.

PMID- 15030773
TI  - Functional impairment of CD8(+) T cells by regulatory T cells during persistent
      retroviral infection.
AB  - The establishment of viral persistence generally requires evasion of the host
      CD8(+) T cell response. Here we describe a form of evasion wherein the CD8(+) T
      cells are fully capable of recognizing their cognate antigen but their effector
      functions are suppressed by regulatory T cells. Virus-specific CD8(+) T cells
      adoptively transferred into mice persistently infected with Friend virus
      proliferated and appeared activated, but failed to produce IFNgamma or reduce
      virus loads. Cotransfer experiments revealed that a subpopulation of CD4(+) T
      cells from persistently infected mice suppressed IFNgamma production by the
      CD8(+) T cells. Treatment of persistently infected mice with anti-GITR antibody
      to ameliorate suppression by regulatory T cells significantly improved IFNgamma
      production by transferred CD8(+) T cells and allowed a significant reduction in
      viral loads. The results indicate that CD4(+) regulatory T cells contribute to
      viral persistence and demonstrate an immunotherapy for treating chronic
      retroviral infections.

PMID- 15030774
TI  - Viral degradation of the MHC class I peptide loading complex.
AB  - The murine gamma-herpesvirus-68 MK3 protein inhibits CD8(+) T cell recognition by
      ubiquitinating the cytoplasmic tails of classical MHC class I heavy chains. Here
      we show that MK3 also provides the first example of a protein that degrades
      tapasin and TAP. The degradation was MK3 RING finger dependent and primarily
      affected TAP. MK3 associated with TAP1 in the absence of tapasin or TAP2,
      suggesting that TAP1 was a primary binding partner in the peptide loading
      complex. TAP2 also played a major role in MK3 stability and function. By
      degrading TAP, therefore, MK3 limited its own expression. However, TAP
      degradation also broadened the MK3 inhibitory repertoire and achieved a
      remarkable resistance to MHC class I upregulation by interferon-gamma, suggesting
      that it represents a specific adaptation to immune evasion in lymphoid tissue.

PMID- 15030775
TI  - NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle
      Wells autoinflammatory disorder.
AB  - Mutations within the NALP3/cryopyrin/CIAS1 gene are responsible for three
      autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory
      syndrome, and CINCA. The NALP3 protein is homologous to NALP1, which is a
      component of the inflammasome, a molecular platform that activates the
      proinflammatory caspases-1 and -5. NALP3 (and other members of the NALP family)
      lacks the C-terminal, CARD-containing sequence of NALP1, and its role in caspase
      activation is unclear. Here, we report that NALP2 and NALP3 associate with ASC,
      the CARD-containing protein Cardinal, and caspase-1 (but not caspase-5), thereby
      forming an inflammasome with high proIL-1beta-processing activity. Macrophages
      from Muckle-Wells patients spontaneously secrete active IL-1beta. Increased
      inflammasome activity is therefore likely to be the molecular basis of the
      symptoms associated with NALP3-dependent autoinflammatory disorders.

PMID- 15030776
TI  - B7-H1 determines accumulation and deletion of intrahepatic CD8(+) T lymphocytes.
AB  - Upon systemic activation by antigens, CD8(+), but not CD4(+), T cells selectively
      accumulate and undergo apoptosis in the liver, a mechanism associated with the
      induction of hepatic tolerance and chronic infection. The molecular basis for
      CD8(+) T cell preference in this process is unknown. We prepared B7-H1-deficient
      mice by gene targeting and found spontaneous accumulation of CD8(+) T cells in
      the liver while CD4(+) T cell levels remained normal. Moreover, antigen-driven
      CD8(+) T cells proliferated normally while apoptotic levels during the
      contraction phase was selectively impaired in the liver, leading to accelerated
      hepatocyte damage in experimental autoimmune hepatitis. Therefore, B7-H1 is a key
      protein selectively regulating the accumulation and deletion of intrahepatic
      CD8(+) T cells and may also contribute to inflammation, autoimmune diseases, and
      tolerance in the liver.

PMID- 15030779
TI  - Using sonochemistry for the fabrication of nanomaterials.
AB  - One of the reasons for the huge interest in nanomaterials originated because of
      the prohibitive price that commercial companies have to pay for introducing new
      materials into the market. Nanotechnology enables these companies to obtain new
      properties using old and recognized materials by just reducing their particle
      size. For these known materials no government approval has to be obtained. Thus,
      the interest in nanomaterials has led to the development of many synthetic
      methods for their fabrication. Sonochemistry is one of the earliest techniques
      used to prepare nanosized compounds. Suslick, in his original work, sonicated
      Fe(CO)5 either as a neat liquid or in a decalin solution and obtained 10-20 nm
      size amorphous iron nanoparticles. A literature search that was conducted by
      crossing Sono* and Nanop* has found that this area is expanding almost
      exponentially. It started with two papers published in 1994, two in 1995, and
      increased to 59 papers in 2002. A few authors have already reviewed the fields of
      Sono and Nano. It should be mentioned that in 1996, Suslick et al. published an
      early review on the nanostructured materials generated by ultrasound radiation.
      Suslick and Price have also reviewed the application of ultrasound to materials
      science. This review dealt with nanomaterials, but was not directed specifically
      to this topic. The review concentrated only on the sonochemistry of transition
      metal carbonyls and catalytic reactions that involve the nanoparticles resulting
      from their sonochemical decomposition. Grieser and Ashokkumar have also written a
      review on a similar topic. A former coworker, Zhu, has recently submitted for
      publication a review article entitled "Novel Methods for Chemical Preparation of
      Metal Chalcogenide Nanoparticles" in which he reviews three synthetic methods
      (sonochemistry, sonoelectrochemistry, and microwave heating) and their
      application in the synthesis of nanosized metal chalcogenides. Although still
      unpublished, I myself have recently written a review discussing novel methods
      (sonochemistry, microwave heating, and sonoelectrochemistry) for making nanosized
      materials. The current review will: (1) Present the four main advantages that
      sonochemistry has over other methods related to materials science and
      nanochemistry; (2) concentrate on the more recent (2003) literature that was not
      reviewed in the previously-mentioned reviews, and (3) focus on a specific
      question, such as what is the typical shape of products obtained in
      sonochemistry? This review will not survey the literature related to
      sonoelectrochemistry.

PMID- 15030778
TI  - Long-term cultured E2A-deficient hematopoietic progenitor cells are pluripotent.
AB  - E2A proteins are essential for the development of B cells beyond the progenitor
      cell stage. Here we have isolated E2A-deficient bone marrow-derived cells that
      have the ability to grow long-term in vitro and coexpress, at low levels,
      regulators of different hematopoietic cell lineages. When transferred into
      lethally irradiated hosts, E2A-deficient hematopoietic progenitor cells
      reconstitute the T, NK, myeloid, dendritic, and erythroid lineages but fail to
      develop into mature B lineage cells. Enforced expression of E47 in E2A-deficient
      hematopoietic progenitor cells directly activates the transcription of a subset
      of B lineage-specific genes, including lambda5, mb-1, and Pax5. In contrast, E47
      inhibits the expression of regulators of other hematopoietic lineages, including
      TCF-1 and GATA-1. These observations indicate that E2A-deficient hematopoietic
      progenitor cells remain pluripotent after long-term culture in vitro and that E2A
      proteins play a critical role in B cell commitment.

PMID- 15030777
TI  - Structural and functional analysis of the costimulatory receptor programmed death
      1.
AB  - PD-1, a member of the CD28/CTLA-4/ICOS costimulatory receptor family, delivers
      negative signals that have profound effects on T and B cell immunity. The 2.0 A
      crystal structure of the extracellular domain of murine PD-1 reveals an Ig V-type
      topology with overall similarity to the CTLA-4 monomer; however, there are
      notable differences in regions relevant to function. Our structural and
      biophysical data show that PD-1 is monomeric both in solution as well as on cell
      surface, in contrast to CTLA-4 and other family members that are all disulfide
      linked homodimers. Furthermore, our structure-based mutagenesis studies identify
      the ligand binding surface of PD-1, which displays significant differences
      compared to those present in the other members of the family.

PMID- 15030780
TI  - Inactivation of Escherichia coli by ultrasonic irradiation.
AB  - Ultrasonic inactivation of Escherichia coli XL1-Blue has been investigated by
      high-intensity ultrasonic waves from horn type sonicator (27.5 kHz) utilizing the
      "squeeze-film effect". The amplitude of the vibration face contacting the sample
      solution was used as an indication of the ultrasonic power intensity. The
      inactivation of the E. coli cells by ultrasonic irradiation shows pseudo first
      order behavior. The inactivation rate constant gradually increased with
      increasing amplitude of the vibration face and showed rapid increase above 3
      microm (p-p). In contrast, the H2O2 formation was not observed below 3 microm (p
      p), indicating that the ultrasonic shock wave might be more important than
      indirect effect of OH radicals formed by ultrasonic cavitation in this system.
      The optimal thickness of the squeeze film was determined as 2 mm for the E. coli
      inactivation. More than 99% of E. coli cells was inactivated within 180-s
      sonication at the amplitude of 3 microm (p-p) and 2 mm of the thickness of the
      squeeze film.

PMID- 15030781
TI  - Inactivation of Saccharomyces cerevisiae by ultrasonic irradiation.
AB  - We have investigated the inactivation of Saccharomyces cerevisiae (yeast cells)
      by ultrasonic irradiation. The amplitude on the vibration face contacting the
      sample solution was used as an indication of the ultrasonic power intensity. The
      effects of the amplitude on the vibration face and the initial cell numbers on
      the sonolytic inactivation of yeast cells have been investigated using a horn
      type sonicator (27.5 kHz). The inactivation of the yeast cells by ultrasonic
      irradiation shows pseudo first-order behavior. The inactivation rate constant
      varied from 0.0007 to 0.145 s(-1) when the amplitude on the vibration face was in
      the range of 1-7 microm(p-p). The change in the inactivation rate constant as a
      function of the amplitude on the vibration face was similar to that of the OH
      radical formation rate under the same conditions. The threshold of this sonicator
      was 3 microm(p-p) with the amplitude on the vibration face. The initial cell
      numbers (from 10(2) to 10(5) mL(-1)) had an influence on the inactivation of the
      yeast cells by ultrasonic irradiation. The inactivation rate constants varied
      from 0.023 to 6.4 x 10(-3) s(-1), and the inactivation by ultrasonic irradiation
      was fastest at the lowest initial cell numbers. In a squeeze-film-type sonicator
      (26.6 kHz), 90% inactivation of the yeast cells was achieved by ultrasonic
      irradiation for 60 min.

PMID- 15030782
TI  - Static foam destruction: role of ultrasound.
AB  - High intensity ultrasonic vibrations were used for destabilizing the static foam
      structure. Ultrasonic horn as a source of ultrasonic vibration was used for the
      destruction of the foam. The effect of the ratio of the horn to the column
      diameter on the drainage and collapse rate of foam has been analyzed. Further, an
      empirical correlation for the initial foam collapse rate in the presence of
      ultrasonic horn has been developed in terms of the initial liquid hold-up,
      surface tension of the surfactant solution and the ratio of horn diameter to the
      column diameter. Efficiency of the ultrasonic horn is related to the position of
      the tip of the horn. Periodic supply of ultrasonic vibrations was found to be a
      more viable option than the continuous supply in terms of saving in energy and
      operating cost for defoaming using ultrasound.

PMID- 15030783
TI  - Studies on solution and solution-cast film of polyaniline colloids prepared in
      the absence and presence of ultrasonic irradiation.
AB  - Spectroscopic and voltammetric features for the solution and solution-cast film
      of polyaniline (PANI) colloids prepared in the absence and presence of ultrasonic
      irradiation were examined. Significant differences in the color and absorption
      spectra between the solution of colloids prepared in the absence and presence of
      irradiation were observed. Effects of ambient atmosphere on the solution of
      colloids were also studied. A gradual decay in the absorption at approximately
      365 nm was occurred upon ageing the solution in air for the colloid prepared
      under ultrasonic irradiation. PANI film, cast from its colloidal solution,
      exhibited excellent electroactivity. The films thus cast were applied to
      electrode modification to control electrochemical reaction. Clear voltammetric
      response was observed on the electrode modified with the colloid prepared in the
      presence of ultrasonic irradiation.

PMID- 15030784
TI  - Ultrasound-assisted cracking process to prepare MoS2 nanorods.
AB  - A simple ultrasound-assisted cracking process was applied to prepare high
      crystallinity MoS2 nanorods using MoS2 micron particles as raw materials. The
      products were characterized by various techniques, including XRD, SEM, TEM and
      HRTEM. Systematic studies showed that acid treatment and ultrasound irradiation
      are both prerequisites for the preparation of ideal MoS2 nanorods. TEM images
      indicate that these nanorods have uniform morphology, with an average diameter of
      approximately 150 nm and length up to several microm. Based on the controlled
      experiments and observation on morphological changes, it is proposed that the
      activated layered MoS2 first exfoliate into sheets and further crack into smaller
      nanorods due to the strong mechanical agitation, shear forces, and micro-jets
      created by the ultrasound irradiation.

PMID- 15030785
TI  - Biological effects of ultrasound exposure on adriamycin-resistant and cisplatin
      resistant human ovarian carcinoma cell lines in vitro.
AB  - Human ovarian cancer cell lines, SKOV3 and its adriamycin-resistant substrain
      SKOV3/ADR and COC1 and its cisplatin-resistant substrain COC1/DDP, were subjected
      to acoustic exposure. The critical levels (LC), which resulted in no immediate
      cell killing, were determined in four cell lines, respectively. LC were the same
      in four cell lines. After being insonated by LC, cell proliferation and clone
      forming of SKOV3/ADR were suppressed but those of SKOV3 were not affected (1);
      cell reproduction of COC1 was triggered but that of COC1/DDP was not influenced
      (2); flow cytometry detected sub-G1 peaks in SKOV3/ADR and COC1/DDP (3). These
      findings suggested that there were differences in the responses to ultrasound
      exposure between chemosensitive and chemoresistant human ovarian cancer cells.

PMID- 15030786
TI  - A review of research into the uses of low level ultrasound in cancer therapy.
AB  - The use of low power ultrasound in therapeutic medicine is a developing field and
      this review will concentrate on the applications of this technology in cancer
      therapy. The effects of low power ultrasound have been evaluated in terms of the
      biological changes induced in the structure and function of tissue. The main
      fields of study have been in sonodynamic therapy, improving chemotherapy, gene
      therapy and apoptosis therapy. The range of ultrasonic power levels that can be
      effectively employed in therapy appears to be narrow and this may have hindered
      past research in the applications in cancer treatment.

PMID- 15030787
TI  - Localization of ion channels to lipid Raft domains within the cardiovascular
      system.
AB  - The subcellular localization of ion channels to discrete microdomains is critical
      for proper electrical signaling in the cardiovascular system. Ion channels are
      important components of many signal transduction pathways; therefore, this
      localization ensures that the channels are located in proximity to the signaling
      molecules that modulate them, permitting dynamic regulation of cardiovascular
      function. However, little is known about the mechanisms governing the subcellular
      localization of ion channels. Whereas protein-protein interactions play an
      important role in ion channel localization, the recent discovery of ion channels
      in sphingolipid- and cholesterol-rich lipid rafts presents a novel mechanism for
      ion channel localization. Furthermore, many signaling proteins are localized to
      lipid rafts, including several that play an important role in cardiovascular
      function. This review focuses on the localization of cardiovascular ion channels
      to lipid rafts and its impact on channel function.

PMID- 15030788
TI  - A southpaw joins the roster: the role of the zebrafish nodal-related gene
      southpaw in cardiac LR asymmetry.
AB  - The establishment of the left-right (LR) asymmetry of the zebrafish heart
      involves at least two discrete events: cardiac jogging and cardiac looping. The
      nodal-related gene southpaw is required for both aspects of heart LR asymmetry as
      well as for LR patterning of other visceral organs. Reductions in southpaw
      activity abolish the normal LR biases of jogging and looping and uncouple the
      normal correlation between jogging and looping polarities. These loss-of-function
      experiments also reveal that southpaw is required for organizing at least the
      initial phase of diencephalic LR asymmetry and suggest that heart and brain LR
      patterning may be coordinated by southpaw signaling originating within the
      anterior, left lateral plate mesoderm.

PMID- 15030789
TI  - Stress-activated MAP kinases in cardiac remodeling and heart failure; new
      insights from transgenic studies.
AB  - Activation of stress-activated mitogen-activated protein kinases (SAPKs), mainly
      c-Jun N-terminal kinase (JNK) and p38, have long been associated with different
      forms of cardiac pathology across a wide spectrum of species. However, their
      specific roles in the development of heart failure are still unclear. Previous
      studies in neonatal myocytes in culture suggest a critical role for both JNK and
      p38 in hypertrophy and apoptosis. A far more complex picture has been provided by
      recent observations from both cellular and transgenic models that have not only
      challenged their role in hypertrophy and cell death but have also pointed out
      novel functions of SAPKs in different aspects of cardiac pathology, including
      contractile function, extracellular matrix remodeling, intercellular
      communication, and metabolic regulation.

PMID- 15030790
TI  - LRP and PDGF signaling: a pathway to atherosclerosis.
AB  - The low-density lipoprotein (LDL) receptor-related protein (LRP) is a member of
      the LDL receptor family. In addition to its role in endocytosis and uptake of
      multiple ligands, it is now apparent that LRP, like some other members of the
      family, is also involved in signal transduction. Through LRP, both endocytosis
      and signaling coexist at the surface of the plasma membrane and regulate critical
      cellular physiology and signal transduction events. This article focuses on the
      recently uncovered molecular mechanisms by which LRP, its ligand apolipoprotein
      E, and the platelet-derived growth factor receptor cooperate in the remodeling of
      the vascular wall and protect against atherosclerosis.

PMID- 15030791
TI  - Cellular basis of triggered arrhythmias in heart failure.
AB  - Ventricular tachycardia in nonischemic heart failure (HF) initiates by a
      nonreentrant mechanism that appears to be due to triggered activity primarily
      from delayed afterdepolarizations that arise from altered cellular Ca handling
      and ionic currents. In HF, factors that conspire to enhance triggered arrhythmias
      include upregulated Na/Ca exchange, preserved beta-adrenergic responsiveness, and
      decreased I(K1). Overall, the further delineation of key factors that underlie
      triggered arrhythmias in HF will provide the basis for new therapeutic strategies
      directed toward novel targets that can reduce the high incidence of sudden death
      in patients with HF.

PMID- 15030792
TI  - The niemann-pick disease genes; regulators of cellular cholesterol homeostasis.
AB  - Cellular cholesterol homeostasis is maintained through activation of the
      designated sterol regulatory element binding proteins and liver X receptor
      transcriptional pathways. Insight into the molecular mechanisms that regulate
      these pathways has come from the study of Niemann-Pick C (NPC) disease. Mutations
      in the NPC1 and NPC2 disease genes lead to lysosomal accumulation of cholesterol
      and defects in regulation of sterol homeostatic responses. NPC1 and NPC2 are key
      participants in intracellular cholesterol trafficking and are required for
      production of low-density lipoprotein cholesterol-derived oxysterols. In this
      review, the function of NPC1 and NPC2 in sterol trafficking and regulation of
      cholesterol homeostasis is examined. Study of the NPC proteins will further
      understanding of the mechanisms involved in atherogenesis.

PMID- 15030793
TI  - Fatty acid metabolism and vascular disease.
AB  - Fatty acid metabolism is abnormal in insulin-resistant states that increase the
      risk of atherosclerosis such as type 2 diabetes and the metabolic syndrome. How
      fatty acids promote vascular disease is poorly understood, but lipoprotein lipase
      and peroxisome proliferator-activated receptor alpha (PPARalpha)-physiologically
      related proteins involved in fatty acid metabolism-may be involved.
      Glucocorticoid metabolism is also abnormal in insulin-resistant states and may
      promote several components of the metabolic syndrome. Recent studies have shown
      that hepatic fatty acid metabolism is required for the development of insulin
      resistance and hypertension caused by glucocorticoid excess, suggesting that
      crosstalk between glucocorticoid receptor-and PPARalpha-dependent pathways may
      contribute to vascular disease.

PMID- 15030794
TI  - The role of stearoyl-CoA desaturase in body weight regulation.
AB  - Obesity is a significant health problem due to its serious medical complications
      that include hypertension, insulin resistance, diabetes, coronary artery disease,
      and heart failure. This review addresses the hypothesis that stearoyl-CoA
      desaturase (SCD) is an important metabolic control point in body weight
      regulation. SCD is the rate-limiting enzyme in the biosynthesis of
      monounsaturated fatty acids. These products are the most abundant fatty acids
      found in triglycerides, cholesterol esters, wax esters, and phospholipids. Mice
      with a disruption in the scd1 gene (scd1(-/-)) have increased energy expenditure,
      reduced body adiposity, and increased insulin sensitivity, and are resistant to
      diet-induced obesity. The expression of several genes encoding enzymes of lipid
      oxidation is upregulated, whereas genes encoding enzymes of lipid synthesis are
      down regulated in the scd1-deficient mice. scd1 is also a component of the novel
      metabolic response to the hormone leptin. SCD therefore appears to be an
      important metabolic control point, and inhibition of its expression could be of
      benefit in the treatment of obesity, diabetes, cardiovascular disease, and other
      metabolic diseases.

PMID- 15030796
TI  - Eyelid movements in health and disease. The supranuclear impairment of the
      palpebral motility.
AB  - The eyelid movements are mediated mainly by the orbicularis oculi (OO) and the
      levator palpebrae superioris (LPS) muscles. Dissociated upper lid functions
      exhibit different counterbalanced action of these muscles, and in blinking they
      show a strictly reciprocal innervation. The disturbance of this close LPS-OO
      relationship likely leads to many of the central lid movement disorders. Three
      groups of supranuclear motor impairment of lid movements are considered: the
      disorders of the lid-eye movements' coordination, the disturbances of blinking
      and lid "postural" maintenance, and the alteration of voluntary lid movements.
      Nuclei of the posterior commissure control the inhibitory modulation of LPS motor
      neuronal activity and they are involved in the lid-eye coordination disorders
      such as lid retraction, which is observed in the Parinaud's syndrome and also in
      parkinsonism and progressive supranuclear palsy. Spontaneous (SB) and reflex
      blinking consist of two components: the inhibition of the basal tonic LPS
      activity, which keeps the eyes open, and the concurrent activation of the OO
      muscles. LPS inhibition precedes and outlasts the OO activation. This normal
      configuration is impaired in parkinsonism and blepharospasm (BSP). SB shows a
      highly interindividual rate variation (among 10-20 per minute in adults) and
      abnormal blink rates occur in neurological diseases related to dopaminergic
      transmission impairments. Lid postural abnormalities include involuntary eyelid
      closure, which is usually associated with inability to open the eyes. Two major
      disorders share these two aspects: BSP and blepharocolysis (BCO). BSP consists of
      an involuntary overactivity of the OO, with LPS co-contraction activity, and is
      expressed as frequent and prolonged blinks, clonic bursts, prolonged tonic
      contraction or a blend of all of them. BCO (commonly named "so-called lid opening
      apraxia") is an overinhibition of the LPS with no evidence of ongoing OO
      activity. BSP and BCO occur in many instances of idiopathic dystonias and basal
      ganglia diseases and, less frequently, in rostral brainstem lesions. Both may
      coincide in the same patient. Voluntary lid movement disorders comprise the
      impairment of Bell's phenomenon, the voluntary eyelid closure palsy and the so
      called cerebral ptosis, all related to lesions of frontal cortical areas and/or
      the corticospinal system.

PMID- 15030797
TI  - Electroencephalography (EEG) and somatosensory evoked potentials (SEP) to prevent
      cerebral ischaemia in the operating room.
AB  - We review the principal aspects of EEG and SEP to detect and prevent cerebral
      ischaemia in the operating room during interventions at risk. EEG and SEP are
      variables that indirectly reflect cerebral blood flow (CBF) provided that
      anaesthetic regimen, body temperature, and arterial blood pressure of the patient
      are stable. When CBF decreases and reaches the functional threshold, slowing
      and/or attenuation of EEG occurs while the amplitude and the latency of cortical
      SEP are, respectively decreased and lengthened. Based on these changes, numerous
      criteria corresponding to critical thresholds have been defined. A decrease in
      EEG amplitude greater than 30% or EEG changes lasting more than 30 s have been
      considered as significant by clinicians. The main criteria resulting from
      computerized EEG analysis were a reduction in total power and/or in spectral edge
      frequency. Regarding SEP, a more than 50% decrease in N20 amplitude and/or a more
      than 1 ms increase in central conduction time were the most frequently used
      criteria. According to the bulk of literature, it may be concluded that processed
      EEG analysis is more sensitive than visual EEG analysis to detect cerebral
      ischaemia, and that SEP are not less sensitive than conventional EEG. Moreover,
      literature shows that SEP are as specific as computerized EEG analysis to
      disclose ischaemia during carotid endarterectomy.

PMID- 15030798
TI  - Fear-conditioned cues of impending pain facilitate attentional engagement.
AB  - AIMS OF STUDY: Selective attention to signals of impending pain allows the
      avoidance of bodily harm. In order to identify the attentional components
      involved in the selection of pain signals over competing demands, we used an
      emotional modification of an exogenous cueing task. METHODS: Fifty-two pain-free
      volunteers detected visual targets of which the location was correctly or
      incorrectly predicted by a spatial cue. Cues were emotionally modulated using
      differential classical conditioning. The conditioned cue (CS+) was sometimes
      followed by an electrocutaneous stimulus (UCS), thus becoming a pain signal,
      whereas the UCS never followed the other cue (CS-), referred to as safety signal.
      RESULTS: Analyses of response times showed that pain signals facilitated the
      directing of attention to their location in comparison to safety signals. In
      contrast, pain signals did not impair disengagement of attention from their
      location in comparison to safety signals. CONCLUSION: It is concluded that
      attention is more strongly engaged to a signal of impending pain compared with a
      cue signalling its absence. We explore why disengagement from the pain signal is
      not impaired compared to the safety signal. The findings are discussed in terms
      of the defensive importance of pain anticipation.

PMID- 15030799
TI  - [Lombosacral radiculopathy (L3-S1) and specificity of multifidus EMG].
AB  - AIMS OF THE STUDY: This prospective study tried to establish, in a group of
      patients with lombosacral radiculopathy, whether the electromyography of the
      multifidus muscles following the "Paraspinal Mapping" described by Haig and
      colleagues (1991, 1993, 1995, 1997) allows to specify the exact level of the
      radiculopathy. MATERIAL AND METHODS: Twenty-three patients with symptoms of mono
      or pluriradiculopathy were submitted to an EMG of the lower limbs and multifidus
      muscles at different levels in accordance to the "Paraspinal Mapping"
      cartography. RESULTS AND CONCLUSION: No patient had signs of acute denervation in
      the multifidus muscles that corresponded exclusively to the suspected levels as
      determined by clinical and radiological examinations. No patient had signs of
      acute denervation in the multifidus muscles without associated signs in the lower
      limb muscles. Conversely, four patients had signs of acute denervation in the
      lower limb muscles without any signs in the multifidus muscles. In our small
      series, the EMG of the multifidus muscles was neither sensitive nor specific and
      did not allow by itself topographical diagnosis.

PMID- 15030800
TI  - Rett syndrome: a case presenting with atypical seizures. Neurophysiological and
      clinical aspects.
AB  - OBJECTIVE: To describe a specific electroclinical type of epileptic seizure in a
      patient with Rett syndrome. PATIENT AND METHODS: We present the case of a girl
      with Rett syndrome and epilepsy, whose seizures followed two differentiated
      phases, namely (a) a brief hypertonic onset with tonic-axial predominance,
      followed by (b) a posterior prolonged clinical absence. These two phases were
      associated, respectively, to a paroxystic desynchronisation or generalised rapid
      spikes discharges, followed by a critical slow activity. CONCLUSIONS: The
      epileptic seizures described in this report have not been previously documented
      in Rett syndrome. We review and discuss pathophysiological hypotheses in the
      light of this and previously reported cases of the syndrome.

PMID- 15030801
TI  - Combining wavefront and topography data for excimer laser surgery: the future of
      customized ablation?

PMID- 15030802
TI  - Visual acuity measurements.

PMID- 15030803
TI  - Analyzing refractive data.

PMID- 15030805
TI  - Intraocular ointment causing uveitis and glaucoma.

PMID- 15030806
TI  - Orbscan versus ultrasound.

PMID- 15030807
TI  - Consultation section. Cataract surgical problem.

PMID- 15030816
TI  - Pars plana suture fixation for intraocular lenses dislocated into the vitreous
      cavity using a closed-eye cow-hitch technique.
AB  - We describe a modified intraocular cow-hitch technique for pars plana suture
      fixation of intraocular lenses (IOLs) that dislocated into the vitreous cavity in
      3 patients who had a 3-port vitrectomy and IOL implantation because of retinal
      disease. To reposition the dislocated IOL after the residual vitreous was
      removed, 2 additional sclerotomies for suture fixation were made 3.0 mm posterior
      to the limbus. A loop (cow-hitch knot) was made with 10-0 polypropylene for
      suture fixation. After the neck of the cow-hitch loop was grasped with an
      intraocular forceps, the loop was used to lasso a haptic of the dislocated IOL,
      which was then pulled forward to the sclerotomy. The same procedure was used for
      the other haptic, and both sutures were secured to the sclera under scleral
      flaps. In all patients, the dislocated IOLs were repositioned without the need
      for extraction. The procedures were uneventful. Pars plana suture fixation with
      the intraocular cow-hitch technique can be used to reposition an IOL that has
      dislocated into the vitreous cavity.

PMID- 15030817
TI  - Effect of prophylactic antibiotics on antimicrobial resistance of viridans
      streptococci in the normal flora of cataract surgery patients.
AB  - PURPOSE: To evaluate the effect of prophylactic treatment including vancomycin in
      the irrigating solution and topical chloramphenicol on antimicrobial resistance
      in viridans-group streptococci in the normal flora of patients having cataract
      surgery. SETTING: Department of Ophthalmology, Turku University Central Hospital
      and Antimicrobial Research Laboratory, National Public Health Institute, Turku,
      Finland. METHODS: Minimal inhibitory concentrations (MICs) of 15 antimicrobials
      were determined for 529 viridans streptococci isolated from throat,
      nasopharyngeal, and conjunctival swabs of 23 patients on 4 sampling occasions:
      before cataract surgery and 1 day, 1 month, and 3 months after surgery.
      Resistance mechanisms of erythromycin-resistant isolates were studied by the
      double-disk test and polymerase chain reaction of resistance genes. RESULTS: No
      statistically significant changes occurred in the proportions of isolates with
      elevated MICs between different sampling occasions. Resistance to vancomycin or
      chloramphenicol was not found. Resistance to tetracycline, erythromycin,
      penicillin, quinupristin-dalfopristin, clindamycin, levofloxacin, and
      moxifloxacin was found on different sampling occasions in 27.9% to 38.7%, 13.1%
      to 21.8%, 11.5% to 19.4%, 8.9% to 16.9%, 2.3% to 5.6%, 0% to 2.4%, and 0% to 2.2%
      of the isolates, respectively. Of the erythromycin-resistant isolates, 80.8% had
      the M phenotype and mefA gene and 19.2% has the macrolide-lincosamide
      streptogramin B phenotype and ermB gene. CONCLUSIONS: Development of resistance
      of viridans streptococci in the normal flora to vancomycin and chloramphenicol
      during prophylactic use with uneventful cataract surgery is unlikely; the effect
      on resistance patterns of other antimicrobials is minor. Routine use of
      prophylactic vancomycin is discouraged, however, because of the lack of
      scientific proof of its efficacy in preventing postoperative endophthalmitis.

PMID- 15030818
TI  - Posterior capsule opacification after phacoemulsification in patients with
      postoperative steroidal and nonsteroidal treatment.
AB  - PURPOSE: To evaluate the effect of dexamethasone, diclofenac, and a placebo given
      for 3 weeks after phacoemulsification and intraocular lens (IOL) implantation on
      the formation of posterior capsule opacification (PCO). SETTING: St. Erik's Eye
      Hospital, Stockholm, Sweden. METHODS: In a 2-year prospective randomized double
      blind study, a laser flare meter was used to measure aqueous flare intensity
      preoperatively and 3 days, 2 weeks, and 2 years after phacoemulsification and IOL
      implantation. Posterior capsule opacification was evaluated 2 years
      postoperatively using retroillumination images taken with a Scheimpflug camera.
      The Evaluation of Posterior Capsule Opacification system was used to score the
      areas of PCO density. RESULTS: The median rate of PCO 2 years after
      phacoemulsification was 0.72 (range 0.32 to 1.57) in the dexamethasone group,
      0.78 (range 0.19 to 2.14) in the diclofenac group, and 0.70 (range 0.35 to 1.70)
      in the placebo group. The differences were not statistically significant (P>.05;
      Kruskal-Wallis analysis of variance, multiple comparisons). The rate of
      neodymium:YAG laser posterior capsulotomy during the 2 years after surgery was
      not statistically different between groups (P>.05, chi-square test). There was no
      correlation (Spearman rank coefficient) between laser flare measurements and PCO
      formation in any group during the study (P>.05). CONCLUSION: Topical instillation
      of diclofenac, dexamethasone, or a placebo in the immediate period after
      phacoemulsification and IOL implantation did not seem to influence the formation
      of PCO 2 years after cataract surgery.

PMID- 15030819
TI  - Confocal microscopy evaluation of stromal ablation depth after myopic laser in
      situ keratomileusis and photorefractive keratectomy.
AB  - PURPOSE: To compare the measured ablation depth after myopic laser in situ
      keratomileusis (LASIK) and photorefractive keratectomy (PRK) with the predicted
      ablation depth. SETTING: Mayo Clinic, Rochester, Minnesota, USA. METHODS: Twenty
      five eyes of 15 patients had PRK and 25 eyes of 15 patients had LASIK to correct
      refractive errors between -1.50 diopters (D) and -11.00 D. The corneas were
      examined by in vivo confocal microscopy before and 1 month after both procedures.
      Thickness measurements were obtained from digital-image analysis of confocal
      scans. The measured ablation depth, an estimate of the actual photoablation
      depth, was obtained as the surgically induced stromal thinning between the
      preoperative and the 1-month post-PRK or post-LASIK central stromal thickness.
      The predicted ablation depth was recorded from the laser's software program.
      RESULTS: In LASIK, the measured ablation depth (81 microm +/- 34 [SD]) was 25%
      greater than the predicted ablation depth (65 +/- 13 microm, P =.007) and the
      difference between the measured and predicted ablation depths was positively
      associated with the mean ablation depth (r = 0.81, P<.001). In PRK, there was no
      difference between the measured ablation depth (48 +/- 19 microm) and the
      predicted ablation depth (47 +/- 18 microm, P =.84). CONCLUSION: Significantly
      more tissue than predicted was removed by LASIK than by PRK excimer photoablation
      with the laser system used in this study.

PMID- 15030820
TI  - Anterior capsule staining for capsulorhexis in cases of white cataract:
      comparative clinical study.
AB  - PURPOSE: To compare the safety and efficacy of trypan blue 0.1%, gentian violet
      0.001%, indocyanine green 0.5% (ICG), fluorescein 2%, and the patient's
      autologous blood for anterior capsule staining in cases of white cataract.
      SETTING: Rajendra Prasad Center for Ophthalmic Sciences, All India Institute of
      Medical Sciences, New Delhi, India. METHODS: Fifty eyes of 50 patients with age
      related white cataract had anterior capsule staining with trypan blue, ICG, or
      gentian violet under an air bubble or subcapsularly with fluorescein or
      autologous blood followed by phacoemulsification with foldable intraocular lens
      implantation. Each stain was used in 10 eyes. The ease of creating a continuous
      curvilinear capsulorhexis (CCC) and the complications during the surgery were
      noted. Postoperative examinations at 6 hours, 1 day, 1 week, and 1 month included
      slitlamp microscopy, uncorrected visual acuity, and best corrected visual acuity
      (BCVA). The staining patterns on the anterior capsule, side port, corneal tunnel,
      and anterior cortex were assessed intraoperatively and within 6 hours and at 1
      day. The intraocular pressure (IOP) was assessed at 1 day; pachymetry, at 1 day
      and 1 month; and the endothelial cell count, at 1 month. RESULTS: The surgeon had
      best visualization during the anterior capsulorhexis with trypan blue, ICG, and
      gentian violet, and a complete CCC was achieved in all eyes in the 3 groups. Two
      eyes each in the fluorescein and autologous blood groups had extension of the CCC
      so that the capsulorhexis was complete but not curvilinear. Anterior capsule
      fibrosis was detected with trypan blue (1 eye) and ICG (2 eyes). The anterior
      vitreous was stained with fluorescein in 2 eyes. All eyes achieved a BCVA of
      20/30 or better from 1 week postoperatively to the last follow-up. The side port
      and corneal tunnel were stained most intensely with gentian violet followed by
      trypan blue and ICG and less intensely with fluorescein and autologous blood. The
      IOP, pachymetry, and endothelial cell loss were comparable between the stains.
      CONCLUSION: Although trypan blue, ICG, gentian violet, fluorescein, and
      autologous blood were safely used to stain the anterior capsule for
      phacoemulsification in eyes with white cataract, trypan blue, ICG, and gentian
      violet were more effective in staining the capsule.

PMID- 15030821
TI  - Effect of amniotic membrane after laser-assisted subepithelial keratectomy on
      epithelial healing: clinical and refractive outcomes.
AB  - PURPOSE: To evaluate the effect of an amniotic membrane (AM) on
      reepithelialization time, corneal haze, and postoperative visual and refractive
      outcomes after laser-assisted subepithelial keratectomy (LASEK) for myopia and
      myopic astigmatism. SETTING: Department of Ophthalmology, Yonsei University
      College of Medicine, and Balgeunsesang Ophthalmology Clinic, Seoul, Korea.
      METHODS: One hundred fifty-two eyes of 84 patients with myopia or myopic
      astigmatism were prospectively evaluated for 6 months after LASEK. An AM was
      placed as a strip on the inferior limbus in 94 eyes of 54 patients after LASEK;
      58 eyes of 30 patients served as the control group. Postoperative epithelial
      healing time, uncorrected visual acuity (UCVA), best corrected visual acuity,
      remaining refractive error, and corneal haze were examined. RESULTS: The
      reepithelialization time was shorter in the AM group (2.40 days +/- 0.94 [SD])
      than in the control group (3.90 +/- 0.97 days) (P<.001). At 6 months, 86 eyes
      (91.5%) in the AM group had a UCVA of 20/25 or better and 90 eyes (95.7%) had a
      UCVA of 20/40 or better; 48 eyes (82.8%) and 53 eyes (91.4%) in the control group
      had a UCVA of 20/25 or better and 20/40 or better, respectively. The mean
      spherical equivalent in the AM group was -0.48 +/- 0.54 diopter (D) and in the
      control group, -0.94 +/- 0.60 D (P<.001). The corneal haze was significantly less
      in the AM group than in the control group (P<.001). CONCLUSION: Amniotic membrane
      use after LASEK induced rapid epithelial healing with more favorable visual and
      refractive outcomes and lower corneal haze scores than conventional LASEK.

PMID- 15030822
TI  - Keratocyte activation and inflammation in diffuse lamellar keratitis after
      formation of an epithelial defect.
AB  - PURPOSE: To examine the inflammatory reaction in acute or late-onset post-laser
      in situ keratomileusis (LASIK) diffuse lamellar keratitis (DLK) associated with
      an epithelial defect. SETTING: Department of Ophthalmology, Helsinki University
      Central Hospital, Helsinki, Finland. METHODS: Six consecutive LASIK patients
      presented with stage 2 to 3 unilateral DLK 1 to 4 days after formation of an
      epithelial detachment (intraoperatively or up to 19 months postoperatively). Five
      corneas of 5 DLK patients, 1 eye twice, were examined by corneal in vivo confocal
      microscopy 1 to 8 days after the appearance of the epithelial defect. Confocal
      microscopy of conjunctival venules was performed in 2 of 6 DLK patients to
      quantify leukocyte rolling and extravasation. Corneas of 5 patients and
      conjunctival venules of 4 patients who had uneventful LASIK served as controls.
      RESULTS: Two of the 4 patients examined 0 to 1 day after the onset of DLK
      presented with small objects, presumably inflammatory cells (diameter 6.0 to 10.0
      microm), in the LASIK flap interface. A third patient examined 1 day after the
      onset of DLK had larger objects (approximately 13.0 microm in diameter) in the
      interface. Three other cases (1 to 7 days after the onset of DLK) showed changes
      typical of keratocyte activation and altered extracellular matrix. All cases
      healed completely following treatment with steroids. Control LASIK subjects
      showed some keratocyte activation on day 5. CONCLUSIONS: Neither uneventful LASIK
      nor DLK induced an inflammatory reaction displaying leukocyte rolling in
      conjunctival venules or extravasation into the conjunctival stroma. Diffuse
      lamellar keratitis related to an epithelial defect does not always lead to the
      appearance of inflammatory cells in the flap interface. The corneal
      manifestations of epithelial defect-related DLK may originate from sterile
      epithelial-stromal or inflammatory cell-stromal cell interactions, leading to
      alteration of the keratocyte phenotype.

PMID- 15030823
TI  - Effect of retrobulbar injection of lidocaine on saccadic velocities.
AB  - PURPOSE: To determine whether exposing the extraocular muscles (EOMs) to
      lidocaine via retrobulbar injection for cataract surgery has a demonstrable
      negative effect on subsequent function of the muscle. SETTING: York Finch Eye
      Associates, Humber River Regional Hospital, and Toronto Western Hospital Research
      Institute, Toronto, Ontario, Canada. METHODS: This study comprised 37 eyes that
      had phacoemulsification and posterior chamber intraocular lens implantation; 13
      eyes had retrobulbar lidocaine with hyaluronidase and 24 eyes, topical
      anesthesia. The postoperative saccadic velocities were compared with the
      preoperative velocities using a sensitive recording device. The results were
      compared within and between the retrobulbar lidocaine and topical anesthesia
      groups. RESULTS: No detectable decrement in postoperative saccadic velocities was
      detected in any patient, and no difference was found between the groups.
      CONCLUSIONS: Exposing EOMs to lidocaine for cataract surgery had no detectable
      negative effect on saccadic velocities 1 week after surgery.

PMID- 15030824
TI  - Clinical comparison of Healon5 and Healon in phacoemulsification and intraocular
      lens implantation; Randomized multicenter study.
AB  - PURPOSE: To compare the overall clinical performance during phacoemulsification
      and intraocular lens (IOL) implantation, the effect on intraocular pressure
      (IOP), and the effect on corneal endothelium of Healon5 (sodium hyaluronate 2.3%)
      and Healon (sodium hyaluronate 1.0%) ophthalmic viscosurgical devices (OVDs).
      SETTING: Multicenter study. METHODS: In this randomized prospective clinical
      study, the performance of Healon5 (viscoadaptive; dispersive and cohesive) and
      Healon (cohesive) during cataract surgery was evaluated in 157 patients, 79 with
      Healon5 and 78 with Healon. Surgeons evaluated the following on a 5-point scale:
      retention during phacoemulsification (primary endpoint), ease of injection,
      anterior chamber maintenance during continuous curvilinear capsulorhexis (CCC),
      facilitation of IOL implantation, and ease of removal from the eye. Masked
      examiners other than the surgeon performed the following measurements: IOP
      preoperatively and 5 and 24 hours, 7 days, and 3 months postoperatively; corneal
      thickness before and 24 hours, 7 days, and 3 months postoperatively; and corneal
      endothelial cell count preoperatively and 3 months postoperatively. RESULTS:
      Intraocular retention during phacoemulsification was assessed as good or very
      good in 77% in the Healon5 group and 8% in the Healon group; the difference was
      statistically significant (P<.0001, Wilcoxon rank sum test). The Healon5 group
      had significantly better scores for anterior chamber maintenance during CCC
      (P<.0001) and facilitation of IOL implantation (P =.032), and the Healon group
      had significantly better scores for ease of injection (P<.0001) and ease of
      removal (P<.0001). There were no statistically significant between-group
      differences in IOP, corneal endothelial cell count, or corneal thickness.
      CONCLUSIONS: Surgeons rated Healon5 better than Healon in retention during
      phacoemulsification, anterior chamber maintenance during CCC, and facilitation of
      IOL implantation. They assessed Healon as easier to inject and remove. There was
      no difference in safety-related parameters between the 2 OVDs. These findings
      indicate that Healon5 is effective in cataract surgery.

PMID- 15030825
TI  - Predictive formula for calculating the probability of LASIK enhancement.
AB  - PURPOSE: To develop a formula to predict a patient's need for laser in situ
      keratomileusis (LASIK) enhancement. SETTING: Northwestern Laser Vision Center,
      Department of Ophthalmology, Northwestern University, Feinberg School of
      Medicine, Chicago, Illinois, USA. METHODS: In this retrospective study, charts of
      patients who received LASIK with the Visx Star excimer laser for myopia and
      myopic astigmatism were reviewed. Laser in situ keratomileusis enhancement was
      performed in 130 of 720 eyes. Variables such as age, keratometry, spherical
      power, power and axis of astigmatism, and surgeon factor were compared in
      patients who required retreatment and those who did not. Multivariate logistic
      regression analysis was used to determine a formula for the probability of
      enhancement surgery. RESULTS: Age (P<.0001), preoperative cycloplegic sphere
      (P<.0001), and surgeon (P<.0001) were the statistically significant factors for
      predicting retreatment. The predictive formula derived from these factors had a
      sensitivity of 79%, a specificity of 61%, and positive and negative predictive
      values of 31% and 93%, respectively. CONCLUSIONS: Older age, higher preoperative
      cycloplegic sphere, and surgeon significantly influenced a patient's likelihood
      for LASIK retreatment. A formula based on these predisposing factors helps to
      more accurately predict the need for retreatment.

PMID- 15030826
TI  - Therapeutic flap massage for microstriae after laser in situ keratomileusis:
      treatment technique and implications.
AB  - PURPOSE: To study the effect of a technique of external flap massage for the
      treatment of clinically significant flap microstriation after uneventful laser in
      situ keratomileusis (LASIK). SETTING: TLC Laser Eye Center, Elmwood Park, New
      Jersey, USA. METHODS: Twenty-five consecutive eyes with loss of best corrected
      visual acuity (BCVA) due to flap microstriation were treated using therapeutic
      external flap massage with a Caro flap manipulator (Moria) at the slitlamp. After
      topical anesthesia and carboxymethylcellulose drops (Celluvisc) were instilled in
      the eye, gentle pressure was applied to the flap centrally over the pupil area
      and then in enlarging concentric circles over the entire microstriation zone for
      30 seconds with 3 repetitions at each treatment session. After the massage,
      collagen intracanalicular plugs were placed and patients were instructed to
      lubricate aggressively for 48 to 72 hours before reassessment. Patients were
      evaluated for improvement in uncorrected visual acuity, BCVA, and flap appearance
      as well as with serial axial topography. If a minimum of 3 massage cycles failed
      to improve the clinical status, patients were advised to have standard "lift and
      smooth" flap stretching procedures. RESULTS: In 24 (96%) of the 25 treated eyes,
      the BCVA returned to the preoperative level; 1 patient required a flap lift.
      Twenty eyes obtained a BCVA of 20/20 without laser enhancement [correction]. One
      eye had a persistent loss of BCVA limited to 1 line. In no eye did the acuity
      deteriorate after massage. CONCLUSION: External flap massage was an effective
      treatment of symptomatic flap microstriation after LASIK.

PMID- 15030827
TI  - Comparison of manual and automated methods to determine horizontal corneal
      diameter.
AB  - PURPOSE: To compare 2 manual methods and 2 automated devices for measuring the
      horizontal corneal diameter (white-to-white [WTW] distance). SETTING: Department
      of Ophthalmology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
      METHODS: In 100 eyes of 61 patients, the WTW distance was measured independently
      by 2 examiners using the following techniques: the Holladay-Godwin gauge, a
      measuring caliper, Zeiss IOLMaster, and Orbscan II topography system (Bausch &
      Lomb). The results were compared with measurements on magnified slitlamp
      photographs of the anterior eye segment. Statistical evaluation was performed
      using the Bland-Altman method for comparison of measurement techniques. RESULTS:
      The mean horizontal corneal diameter was 11.91 mm +/- 0.71 (SD) with the
      measuring caliper, 11.8 +/- 0.60 mm with the Holladay-Godwin gauge, 11.78 +/-
      0.43 mm with the Orbscan II, and 12.02 +/- 0.38 mm with the IOLMaster. The
      coefficient of inter-rater repeatability was 1.30 for the caliper, 0.92 for the
      Holladay-Godwin gauge, 0.76 for the Orbscan II, 0.50 for the IOLMaster, and 1.16
      for the manual measurement in anterior segment images. The results obtained with
      the caliper were statistically significantly different between the 2 examiners
      (P<.001). The measurements of examiner 2 using the caliper were significantly
      different from the measurements of the same examiner using the Holladay-Godwin
      gauge. This was not the case with the 2 automated devices. CONCLUSIONS: Automated
      measurement of the WTW distance provides more precise results than measurements
      using manual methods. The Zeiss IOLMaster had the highest reliability in
      measuring corneal diameter.

PMID- 15030828
TI  - Estimation of pupil size by digital photography.
AB  - PURPOSE: To evaluate a digital photography method of pupil size estimation over a
      broad range of illumination conditions and to compare this method with common
      clinical techniques. SETTING: College of Optometry, Ohio State University,
      Columbus, Ohio, USA. METHODS: Two examiners measured the pupil diameter in 45
      right eyes at 3 illumination levels: <0.63 lux (dark), 5 lux (dim), and 1000 lux
      (bright). Estimation by infrared video recording, the reference standard, was
      compared with measurements by digital photography, ruler, semicircular templates,
      and the Colvard pupillometer. Masked graders measured pupil size from infrared
      video recordings and digital photographs. RESULTS: The repeatability of the
      measurement method determined by the mean intraclass correlation coefficients was
      highest for video recording across conditions (0.86-0.97), followed by digital
      photography (0.76-0.94), Colvard pupillometry (0.63-0.82), ruler (0.71-0.85), and
      templates (0.70-0.83). An analysis of variance showed a significant difference in
      pupil size by method (P<.001). All methods except digital photography estimated
      smaller pupil sizes under dark and dim illumination than infrared video
      measurements (all P<.01). Under bright illumination, the ruler measurements were
      significantly smaller (-0.15 mm) and the Colvard pupillometer measurements were
      greater (+0.30 mm) than the reference (P<.01). The 95% limits of agreement (LoA)
      between examiners were smallest for video measurements at all light levels. The
      remaining measures ranked from best to worst by 95% LoA were digital photography,
      Colvard pupillometry, ruler, and templates. CONCLUSIONS: Estimation of pupil size
      by digital photography was more repeatable and accurate than estimates by common
      clinical techniques over a wide range of illumination. Although not as quick as
      other methods, digital photography is relatively inexpensive, permits lasting
      documentation, and allows independent grading suitable for clinical research
      purposes.

PMID- 15030829
TI  - Evaluation of intraocular pressure change after laser in situ keratomileusis
      using the pressure phosphene tonometer.
AB  - PURPOSE: To evaluate the applicability of pressure phosphene tonometry in
      measuring intraocular pressure (IOP) after laser in situ keratomileusis (LASIK).
      SETTING: Baptist Eye Clinic, Kyoto, Japan. METHODS: Thirty-six eyes of 22
      consecutive patients who had had LASIK for myopia were enrolled in this
      prospective comparative study. The mean age of the patients was 32.6 years +/-
      9.0 (SD). The IOP was measured using the pressure phosphene tonometer (FPT),
      Goldmann applanation tonometry (GAT), and noncontact tonometry (NCT). The
      patients themselves took measurements with the FPT before and 1 week after
      surgery. One-way analysis of variance followed by a Bonferroni/Dunn multiple
      comparison post hoc test was administered to compare the preoperative and
      postoperative measurements with each tonometer. These data were represented
      graphically using a method described by Bland and Altman. The relationship
      between each tonometric change and the central corneal thickness (CCT) or
      keratometry (K) changes after LASIK were evaluated with by Pearson correlation
      coefficient. RESULTS: Statistically significant differences were found between
      preoperative and postoperative measurements with GAT and NCT but not with FPT.
      Preoperative and postoperative FPT readings conformed to the British Standard for
      reproducibility of a standard test method for IOP estimation. No significant
      correlation between FPT changes and CCT or K changes was found. CONCLUSIONS:
      Pressure phosphene tonometry measures IOP through the upper eyelid, and changes
      in corneal shape do not appear to have an effect on the IOP. The IOP measurements
      with FPT were constant before and after LASIK.

PMID- 15030831
TI  - Diagnosis and management of congenital cataract with preexisting posterior
      capsule defect.
AB  - PURPOSE: To establish and evaluate the diagnostic signs, intraoperative
      performance, and postoperative outcomes in children with congenital cataract with
      a preexisting posterior capsule defect (PCD). SETTING: Iladevi Cataract & IOL
      Research Centre, Ahmedabad, India. METHODS: This study evaluated 400 consecutive
      eyes that had congenital cataract surgery, of which 27 (20 children) had a
      confirmed preexisting PCD. Seven children had bilateral defects. The preoperative
      diagnostic signs of PCD under maximum pupil dilation included well-demarcated,
      thick defect margins; white dots on the posterior capsule; and white dots in the
      anterior vitreous that moved with the degenerated vitreous like a fish tail (fish
      tail sign). Hydrodissection was not attempted. Bimanual irrigation/aspiration and
      2-port anterior vitrectomy were performed. The mean follow-up was 17.9 months +/-
      16.96 (SD). RESULTS: The mean age of the 16 boys and 4 girls with a PCD was 21.98
      +/- 33.33 months. Nineteen eyes (70.3%) had total white mature cataract. In 7
      eyes (25.92%), the preexisting PCD was converted into a posterior capsulorhexis.
      Twenty eyes (74.07%) had an AcrySof MA30BA intraocular lens (IOL) implanted in
      the bag and 4 eyes (14.81%), in the sulcus. Three eyes (11.11%) were left
      aphakic. The visual axis remained clear in all eyes, and the IOL was well
      centered in 24 eyes (88.88%). CONCLUSION: Establishing the diagnostic signs of
      PCD with the eye fully dilated and carefully planning the surgery produced
      satisfactory technical and visual outcomes.

PMID- 15030832
TI  - Reliability of the IOLMaster in measuring corneal power changes after
      photorefractive keratectomy.
AB  - PURPOSE: To test the accuracy of the IOLMaster (Carl Zeiss) in detecting corneal
      power changes after photorefractive keratectomy (PRK). SETTING: Department of
      Ophthalmology, 2nd University of Naples, Naples, Italy. METHODS: Two hundred
      twenty-five consecutive eyes that had PRK (mean -5.13 diopters [D] +/- 2.98 [SD]
      [range +0.25 to -16.25 D]) were analyzed. The data included preoperative and
      postoperative (1, 3, and 6 months) subjective refraction and computerized
      keratometry. Statistical analysis was performed to determine the correlation
      between the changes in the subjective refraction at the corneal plane and the
      changes in keratometry. RESULTS: The mean difference between the changes in
      refraction and the measured corneal changes was 0.75 +/- 1.13 D (range -3.84 to
      +7.68 D) at 1 month, 0.92 +/- 1.10 D (range -0.87 to +7.93 D) at 3 months, and
      0.75 +/- 0.98 D (range -1.70 to +3.85 D) at 6 months. The difference was
      significant (P<.001). CONCLUSION: Automated keratometry provided by the IOLMaster
      did not accurately reflect the effective refractive changes after PRK,
      particularly in eyes that had a high dioptric treatment.

PMID- 15030830
TI  - Wavefront- and topography-guided ablation in myopic eyes using Zyoptix.
AB  - PURPOSE: To evaluate the results of wavefront- and topography-guided ablation in
      myopic eyes using Zyoptix (Bausch & Lomb). SETTING: Eye Research Center and Dr.
      Agarwal's Eye Hospital, Chennai, India. METHODS: This observational case study
      comprised 150 eyes with myopia and compound myopic astigmatism. Preoperatively,
      the patients had corneal topography with Orbscan IIz (Bausch & Lomb) and
      wavefront analysis with the Zywave aberrometer (Bausch & Lomb) in addition to the
      routine workup before laser in situ keratomileusis (LASIK). The results were
      assimilated using Zylink software (Bausch & Lomb), and a customized treatment
      plan was formulated. Laser in situ keratomileusis was performed with the
      Technolas 217 system (Bausch & Lomb). The patients were followed for at least 6
      months. RESULTS: The mean preoperative best corrected visual acuity (BCVA) (in
      decimal equivalent) was 0.83 (20/25) +/- 0.18 (SD) (range 0.33 to 1.00) and the
      mean postoperative (6 months) BCVA, 1.00 (20/20) +/- 0.23 (range 0.33 to 1.50).
      Three eyes (2%) lost 2 or more lines of best spectacle-corrected visual acuity.
      The safety index was 1.20. The mean preoperative uncorrected visual acuity (UCVA)
      was 0.06 (20/350) +/- 0.02 (range 0.01 to 0.50) and the mean postoperative UCVA,
      0.88 (20/25) +/- 0.36 (range 0.08 to 1.50). The efficacy index was 14.66. The
      mean preoperative spherical equivalent (SE) was -5.25 +/- 1.68 diopters (D)
      (range -0.87 to -15.00 D) and the mean postoperative SE (6 months), -0.36 +/-
      0.931 D (range -4.25 to +1.25 D). At 6 months, the UCVA was 1.00 (6/6) or better
      in 105 eyes (69.93%) and 0.5 (6/12) or better in 126 eyes (83.91%). The
      postoperative aberrations were decreased compared with the preoperative
      aberrations. One eye (0.66%) had a free cap during LASIK with subsequent loss of
      2 lines of BCVA and induced higher-order aberrations (HOAs). Nine patients
      (11.2%) complained of halos at night. CONCLUSIONS: Wavefront- and topography
      guided LASIK leads to improve visual performance by decreasing HOAs. Scotopic
      visual complaints may be reduced with this method.

PMID- 15030833
TI  - Opposite clear corneal incisions on the steep meridian in phacoemulsification:
      early effects on the cornea.
AB  - PURPOSE: To evaluate the effect of on-axis opposite clear corneal incisions
      (OCCIs) in phacoemulsification on reducing preoperative corneal astigmatism and
      to predict the astigmatic outcome of the incisions. SETTING: Royal Eye Infirmary,
      Dorset County Hospital, and Winterbourne Hospital, Dorchester, Dorset, and the
      Department of Ophthalmology, East Somerset Hospital, Yeovil, Somerset, United
      Kingdom. METHODS: This prospective study included all patients (n = 103) who had
      on-axis OCCIs as a part of routine phacoemulsification with foldable intraocular
      lens (IOL) implantation performed by 1 surgeon during 2000. Keratometry was done
      6 to 8 weeks postoperatively. The differences in the preoperative and
      postoperative corneal astigmatism and corneal spherical equivalent (SE) were
      recorded. Surgically induced astigmatism (SIA) was calculated using vector
      analysis. RESULTS: The mean reduction in corneal astigmatism was 0.50 diopter (D)
      (P<.001). The mean SIA was 1.57 D (95% confidence interval [CI], 1.42 to 1.71).
      There was a weak association between the SIA and the patient's age and axis of
      preoperative astigmatism. The mean change in SE was +0.02 D (95% CI, -0.08 to
      +0.12). CONCLUSIONS: Results indicate that on-axis OCCIs are a reliable and
      practical way of reducing preexisting corneal astigmatism. The change in SE was
      negligible and thus can be ignored during biometry.

PMID- 15030834
TI  - Astigmatism outcomes of horizontal temporal versus nasal clear corneal incision
      cataract surgery.
AB  - PURPOSE: To compare the short- and long-term astigmatism outcomes after cataract
      surgery using temporal clear horizontal corneal incisions and nasal horizontal
      clear corneal incisions. SETTING: Wilmer Eye Institute, Johns Hopkins Hospital,
      Baltimore, Maryland, USA. METHODS: This retrospective study included a
      consecutive series of eyes having phacoemulsification with implantation of a 6.0
      mm foldable acrylic intraocular lens through a 3.5 mm horizontal clear corneal
      incision at 180 degrees (temporal incision in right eyes, nasal incision in left
      eyes). Astigmatism was measured by keratometry readings before surgery and 6
      weeks and 12 months postoperatively. RESULTS: The mean preoperative astigmatism
      in the 178 eyes (94 right, 84 left) of 161 patients was 0.78 diopter (D); 54.5%
      of eyes had against-the-rule (ATR) astigmatism, 22.5% had with-the-rule (WTR)
      astigmatism, and 14.0% were astigmatically neutral. A significant shift toward
      WTR astigmatism occurred postoperatively. At 6 weeks, 48.3% of eyes had WTR
      astigmatism and 23.0% had ATR astigmatism. At 12 months, 43.8% had WTR
      astigmatism and 25.8% had ATR astigmatism. Vector analysis revealed a mean
      surgically induced astigmatism (SIA) of 1.17 D at 6 weeks and 1.04 D at 12
      months. The side of the incision significantly affected SIA. At 6 weeks, temporal
      incisions yielded a mean SIA of 0.74 D and the nasal incisions, of 1.65 D. This
      trend in SIA persisted at 12 months: 0.71 D for temporal incisions and 1.41 D for
      nasal incisions. CONCLUSIONS: Cataract surgery using a horizontal clear corneal
      incision induced WTR astigmatism 6 weeks and 12 months postoperatively. Temporal
      incisions induced significantly less astigmatism than nasal incisions.

PMID- 15030835
TI  - Oxidative tissue damage after phacoemulsification: influence of ophthalmic
      viscosurgical devices.
AB  - PURPOSE: To quantify the oxidative tissue damage after phacoemulsification,
      correlate the damage to the energy applied, and investigate the influence of
      ophthalmic viscosurgical devices (OVDs). SETTING: Department of Ophthalmology,
      University of Mainz, Mainz, Germany. METHODS: The study comprised 130 eyes
      operated on by 1 surgeon using the same phacoemulsification machine. Some eyes
      received an OVD before phacoemulsification and some did not. Energy values were
      expressed as phaco time; that is, ultrasound (US) time (seconds) after conversion
      to 100% phaco power. Patients were grouped as follows: Group 1, phaco time less
      than 20 seconds and no OVD; Group 2, phaco time 20 to 40 seconds and no OVD;
      Group 3, phaco time more than 40 seconds and no OVD; Group 4, phaco time 20 to 40
      seconds and hydroxypropyl methylcellulose 2% (HPMC); Group 5, phaco time 20 to 40
      seconds and sodium hyaluronate 1%. Aqueous humor from pseudophakic eyes served as
      a control. At the end of surgery, anterior chamber fluid was analyzed for lipid
      peroxides using the thiobarbituric acid method. RESULTS: Lipid peroxides were
      detected in all groups. The values were significantly higher in Group 2 than in
      Group 1 (P<.01) and in Group 3 than in Groups 1 and 2 (P<.01). The differences in
      lipid peroxide values between all phaco groups and the control group were
      statistically significant. Sodium hyaluronate 1% and HPMC 2% produced
      significantly lower lipid peroxide values than in the respective phaco groups
      that did not receive an OVD (both P<.01). CONCLUSIONS: Oxidative tissue damage
      occurred during phacoemulsification. The damage, which correlated with the US
      energy applied, can be reduced by the use of OVDs.

PMID- 15030836
TI  - Occurrence and progression of diabetic retinopathy after phacoemulsification
      cataract surgery.
AB  - PURPOSE: To evaluate the risk factors associated with the occurrence and
      progression of diabetic retinopathy (DR) after phacoemulsification cataract
      surgery. SETTING: Department of Ophthalmology, Kaplan Medical Center, Rehovot,
      Israel. METHODS: The medical charts of 52 eyes of 48 consecutive patients who had
      phacoemulsification were retrospectively reviewed. The occurrence of DR (new
      development of any DR) and progression (DR requiring laser treatment) were
      correlated with patients' age, sex, duration of diabetes, control of diabetes,
      hypertension, ischemic heart disease, and surgical technique. Exclusion criteria
      were significant ocular conditions and a follow-up shorter than 6 months.
      RESULTS: The occurrence of DR was associated with male sex, and among males, with
      the duration of the disease. An analysis including all patients showed that
      postoperative progression of preexisting DR was not associated with any factor
      except poor blood sugar control. Neither the occurrence nor progression of DR was
      associated with reduced visual acuity CONCLUSIONS: The occurrence and progression
      of DR after phacoemulsification were associated with different factors. Poor
      systemic control of diabetes increases the risk.

PMID- 15030837
TI  - Effect of the Honan intraocular pressure reducer in sub-Tenon's anesthesia.
AB  - PURPOSE: To ascertain whether the Honan intraocular pressure reducer (HIPR) has
      an effect on the preoperative intraocular pressure (IOP), surgeon's assessment of
      anesthesia, and patients' analgesic experience when sub-Tenon's anesthesia is
      used for routine cataract surgery. SETTING: Princess Alexandra Eye Pavilion,
      Edinburgh, Scotland. METHOD: Forty-five eyes of 45 patients having routine
      phacoemulsification cataract surgery were randomized to receive 10 minutes of
      ocular compression using the HIPR or no compression after administration of sub
      Tenon's anesthesia. The IOP was measured immediately before and immediately and
      10 minutes after sub-Tenon's anesthesia administration using a standard
      technique. One surgeon who was masked to the randomization process performed all
      injections and completed a questionnaire on aspects of the anesthetic block.
      Patients scored their level of analgesia during surgery. RESULTS: The mean rise
      in IOP immediately after administration of sub-Tenon's anesthesia was 1.39 mm Hg
      +/- 3.91 (SD) (95% confidence interval +0.22 to 2.57; P =.021). In the 22
      patients who received compression, there was a mean IOP reduction of 4.20 +/-
      2.74 mm Hg at 10 minutes. The mean difference between the compression and no
      compression groups at 10 minutes was 4.99 mm Hg (P<.0001). There was no
      difference in the surgeon's scores for any aspect of the sub-Tenon's anesthesia
      (P>.05). All patients reported good levels of analgesia. CONCLUSIONS: There was a
      significant reduction in IOP after compression using the HIPR. However, the rise
      in IOP after administration of sub-Tenon's anesthesia was small and the use of
      the HIPR did not make a significant difference in the effectiveness of the
      anesthesia to the surgeon or patients.

PMID- 15030838
TI  - Effect of midazolam on anxiety level and pain perception in cataract surgery with
      topical anesthesia.
AB  - PURPOSE: To study the effect of sedation on patients' anxiety level and
      perception of pain during cataract surgery under topical anesthesia. SETTING:
      Royal Eye Infirmary, Plymouth, England. METHODS: This prospective controlled
      double-blind clinical trial comprised 100 consecutive patients having routine
      phacoemulsification with posterior chamber intraocular lens implantation under
      topical anesthesia by a single experienced surgeon. Patients were randomized to
      receive intravenous midazolam (0.015 mg/kg body weight) 15 minutes before surgery
      or no sedation. The main evaluation criteria were the anxiety based on the 6
      item, short form of the State-Trait Anxiety Inventory, the pain score using a
      visual analog scale, and overall patient satisfaction. RESULTS: All operations
      were uneventful, and no side effects were noted from the use of midazolam.
      Anxiety scores were significantly higher on arrival at the hospital than just
      before the commencement and after the conclusion of the surgery in both groups
      (P<.05). Patients were less anxious after administration of midazolam, but this
      did not achieve statistical significance. The mean pain score was 0.29 (range 0
      to 4) in the sedation group and 0.38 (range 0 to 4) in the control group; the
      difference between groups was not statistically significant. The patients were
      equally satisfied in both groups, with mean scores of 3.84 (range 0 to 4) and
      3.88 (range 2 to 4), respectively. CONCLUSIONS: Patients who had cataract surgery
      under topical anesthesia were highly satisfied with their operative experience
      and reported minimal pain during surgery. Anxiety levels diminished after arrival
      at the hospital, possibly because of reassurance by experienced staff.
      Intravenous midazolam did not seem to significantly reduce pain or anxiety.

PMID- 15030839
TI  - Visual sensation during phacoemulsification and intraocular lens implantation
      using topical and regional anesthesia.
AB  - PURPOSE: To evaluate patients' visual sensations at different stages of
      phacoemulsification and posterior chamber intraocular lens (PC IOL) implantation
      under topical and regional anesthesia. SETTING: Department of Ophthalmology,
      United Christian Hospital and Tseung Kwan O Hospital, Kowloon, Hong Kong, China.
      METHODS: Seventy-six consecutive patients having phacoemulsification were
      randomized to a topical anesthesia group (n = 35) or regional anesthesia group (n
      = 41). The topical anesthesia group received lidocaine hydrochloride 2% gel
      (Xylocaine) and the regional anesthesia group, a peribulbar or retrobulbar
      injection of lignocaine 2%. The patients' visual sensations, including light and
      color sensations, shape of objects, and visual patterns, were evaluated at
      different stages of surgery. RESULTS: Two patients (4.9%) in the regional
      anesthesia group and none in the topical anesthesia group experienced total loss
      of light sensation throughout surgery (P =.50). There was a significant
      association between color perception and the type of anesthesia at stages 1 and 2
      (P<.05) but not at stages 3, 4, and 5 (P>.05). The perception of objects and
      visual patterns had no association with the type of anesthesia at any stage
      (P>.05). Of all patients in the study, 56 (73.7%) reported color changes as
      surgery proceeded. Both groups saw waves, defined as curves with periodic
      fluctuations in amplitude, at all stages. The perception of some colors and a
      rectangular moving object was significantly associated with the type of
      anesthesia at some or all stages (P<.05). CONCLUSIONS: Patients having
      phacoemulsification and PC IOL implantation under topical or regional anesthesia
      had a wide spectrum of visual sensations that were similar at most stages of
      surgery. Patients in the topical anesthesia group perceived more colors at the
      early stages and more blue throughout surgery than patients in the regional
      anesthesia group.

PMID- 15030840
TI  - Posterior capsule rupture and vitreous loss during phacoemulsification with or
      without the use of an anterior chamber maintainer.
AB  - PURPOSE: To compare the incidence of posterior capsule rupture and vitreous loss
      during phacoemulsification with and without the use of an anterior chamber
      maintainer (ACM) SETTING: Aristotle University Eye Clinic, Thessaloniki, Greece.
      METHODS: The surgical records of patients who had phacoemulsification by
      experienced surgeons over a 2-year period were reviewed. The cases were divided
      into 2 groups: surgery performed without the use of an ACM (no-ACM group) and
      surgery performed with the use of an ACM (ACM group). RESULTS: The no-ACM group
      comprised 231 cases and the ACM group, 312 cases. Posterior capsule rupture
      occurred in 19 cases (8.22%) and 22 cases (7.05%), respectively. Of the patients
      with posterior capsule rupture, 6 (31.57%) in the no-ACM group and 16 (72.72%) in
      the ACM group had vitreous loss and required an anterior vitrectomy; the
      difference between the 2 groups was statistically significant (P =.03).
      CONCLUSIONS: The use of an ACM in phacoemulsification provided a consistently
      deep anterior chamber and approximately the same rate of complications as with a
      standard technique in the hands of experienced surgeons. However, when posterior
      capsule rupture occurred, the incidence of vitreous loss was significantly higher
      in eyes with an ACM.

PMID- 15030841
TI  - Empty-bag technique for acrylic intraocular lens implantation using Healon5.
AB  - PURPOSE: To determine how often the empty-bag technique (EBT) for injecting an
      acrylic foldable intraocular lens (IOL) into the capsular bag using Healon5
      (sodium hyaluronate 2.3%) will require a 2-compartment technique to remove the
      ophthalmic viscosurgical device (OVD) and compare this with that of a standard
      injection method using Healon5. SETTING: Cincinnati Eye Institute and Ambulatory
      Surgical Center, Cincinnati, Ohio, USA. METHODS: Forty-one eyes of 40 patients
      were randomly assigned to 1 of 2 groups. In Group A, standard capsular bag
      expansion was performed with Healon5 before implantation of an acrylic posterior
      chamber (PC) IOL. In Group B, Healon5 was placed in the anterior chamber followed
      by balanced salt solution expansion of the capsular bag before acrylic PC IOL
      implantation. In all patients, complete OVD removal was attempted with the
      automated aspiration tip anterior to the optic (rock 'n roll technique). The
      number of patients in each group who required placement of the aspiration tip
      posterior to the optic for complete removal was compared. Early postoperative
      intraocular pressure (IOP) was also compared. RESULTS: In Group A, 15 (75%) of 20
      eyes required placement of the aspiration tip posterior to the optic for complete
      OVD removal and in Group B, 1 (0.05%) of 20 eyes. The postoperative IOP was
      similar in both groups. CONCLUSIONS: The EBT decreased the likelihood that a 2
      compartment OVD removal method would be necessary when using Healon5 for acrylic
      PC IOL implantation. The limitations of this new technique must be fully
      understood before it is used.

PMID- 15030842
TI  - Folding procedure for acrylic intraocular lenses.
AB  - PURPOSE: To compare in vitro the effect of 2 standard methods of folding acrylic
      intraocular lenses (IOLs) on surface characteristics and bacterial adhesion.
      SETTING: Eye Clinic and Department of Health-Microbiology Unit, University of
      Florence, Florence, Italy. METHODS: To evaluate the effect of folding, 2 types of
      acrylic IOLs were not folded or folded with a forceps or an injector and then
      processed for scanning electron microscopy (SEM) examination. Bacterial adhesion
      was assessed using an ocular isolate of Pseudomonas aeruginosa. Nonfolded and
      folded IOLs were placed in test tubes containing the bacterial suspension for
      direct counting of viable adherent bacteria and for SEM. RESULTS: The injector
      folded IOLs did not show major alterations on the surface; 5 of the 9 forceps
      folded IOLs showed marks or scratches in the profile of the optic. The mean
      number of viable adherent bacteria per area of IOL optic was 1082 (95% confidence
      interval [CI], 835-1330) in forceps-folded IOLs, 366 (95% CI, 192-359) in
      injector-folded IOLs, and 206 (95% CI, 123-289) in nonfolded IOLs. Scanning
      electron microscopy confirmed more surface irregularities on forceps-folded IOLs,
      with bacteria adherent preferentially on the surface scratches. CONCLUSION:
      Forceps-folding provoked more surface irregularities, which probably make IOLs
      more susceptible to bacterial adhesion.

PMID- 15030843
TI  - Effect of excimer laser beam delivery and beam shaping on corneal sphericity in
      photorefractive keratectomy.
AB  - PURPOSE: To evaluate the impact of beam delivery and beam shaping on corneal
      profiles after myopic excimer laser photorefractive keratectomy (PRK). SETTING:
      Department of Ophthalmology, Charite-Campus Virchow Hospital, Humboldt University
      of Berlin, Berlin, Germany. METHODS: Standard myopic 193 nm excimer laser PRK of 
      3.0 diopters (D) and -6.0 D was performed in porcine eyes using 2 commercially
      available broad-beam lasers with band-mask and fractal-mask beam shaping, 2
      flying-spot lasers, and a scanning-slit laser. A silicone replica was obtained to
      preserve the corneal profile and was measured with a dynamic focusing topometry
      system. RESULTS: The scanning-slit and flying-spot lasers created uniform
      profiles comparable to those in an untreated control group. Both broad-beam
      lasers with band-mask and fractal-mask beam shaping created central islands and
      paracentral profile valleys of 15.10 microm and 17.00 microm maximum height after
      -3.0 D PRK and 26.45 microm and 24.31 microm after -6.0 D PRK. An anti-central
      island program, which applied a series of laser pulses centrally to compensate
      for the central profile elevations, did not eliminate the islands. Stromal
      surface roughness increased with ablation depth and was significantly worse after
      scanning-slit ablation than after broad-beam ablation. CONCLUSIONS: Laser-induced
      deviations from the intended uniform corneal profiles were associated with broad
      beam ablation and increased ablation depth and therefore lessened the
      predictability of the refractive outcomes. Scanning-slit and flying-spot systems
      produced predictably uniform corneal profiles.

PMID- 15030844
TI  - Optical characteristics of oblique incident rays in pseudophakic eyes.
AB  - PURPOSE: To demonstrate visually the change in the optical path of oblique
      incident rays in pseudophakic eyes with intraocular lenses (IOLs) of different
      shapes using a 3-dimensional, computer-simulated model eye with an aspherical
      corneal surface. SETTING: Department of Ophthalmology, Hamamatsu Red Cross
      Hospital, Hamamatsu, Japan. METHODS: A Gullstrand schematic eye was created using
      an optical design program (Zemax), and the anterior and posterior surfaces of the
      cornea were replaced by rotationally symmetrical, aspherical surfaces expressed
      as polynomial equations based on the corneal topography (Orbscan II, Bausch &
      Lomb). The lens was replaced by an IOL (anterior convex or posterior convex). The
      model eye was displayed 3-dimensionally, and an incident ray 45 degrees from the
      visual axis was projected. The astigmatic difference was compared by visually
      confirming the convergence profile of tangential and sagittal rays. Coma
      aberration was also compared by the shape of the spot diagram. RESULTS: The
      distance between the tangential and sagittal foci was larger with an anterior
      convex IOL than with a posterior-convex IOL. Coma aberration markedly deformed
      the spot diagram at the retinal surface in the eye with an anterior-convex IOL.
      CONCLUSIONS: The optical characteristics of the oblique incident rays in a
      pseudophakic eye were visually represented with sufficient clarity. Aberrations
      in the oblique incident rays were larger in the eye with an anterior-convex IOL
      than in the eye with a posterior-convex IOL, making examination and retinal
      photocoagulation of the peripheral fundus difficult.

PMID- 15030845
TI  - Endothelial cell integrity after phacoemulsification with 2 different handpieces.
AB  - PURPOSE: To investigate corneal endothelial cell loss in fresh phakic human
      autopsy cadaver eyes after phacoemulsification (PE) with a conventional handpiece
      or a new oscillatory handpiece. SETTING: Department of Ophthalmology, Storm Eye
      Institute, Medical University of South Carolina, Charleston, South Carolina, USA.
      METHODS: Twenty fresh phakic human autopsy globes were randomized to PE with a
      conventional handpiece (n = 10) or an oscillatory handpiece (n = 10). The main
      parameters evaluated were age, nucleus density, amount of ophthalmic
      viscosurgical device (OVD) used, and mean PE time and ultrasound (US) power.
      After surgery, the corneas were excised and the endothelia were vitally stained
      with trypan blue and alizarin red. Light microscopy was used to assess the
      endothelial cell loss. RESULTS: The mean age, density of the nucleus, OVD used,
      and US power were similar between the groups. The mean PE time was less with the
      NeoSoniX handpiece (0.71 minutes +/- 0.39 [SD]) than with the conventional
      handpiece (1.05 +/- 0.53 minutes). The mean number of dead endothelial cells was
      significantly lower in the oscillatory handpiece group (31.3 +/- 24.2
      cells/mm(2)) than in the conventional handpiece group (60.4 +/- 46.8 cells/mm(2))
      (P<.001, Mann-Whitney rank sum test). CONCLUSIONS: Less corneal endothelial cell
      loss occurred after PE with an oscillatory handpiece than with a conventional
      handpiece. Further randomized clinical trials are recommended to validate this
      study.

PMID- 15030846
TI  - Simulation of air-bag impact on an eye with transsclerally fixated posterior
      chamber intraocular lens using finite element analysis.
AB  - PURPOSE: To determine the physical and mechanical conditions of an impacting air
      bag that would rupture an eye with a transsclerally fixated posterior chamber
      intraocular lens (IOL). SETTING: Numerical simulation study on a computer.
      METHODS: Simulations in a model human eye were performed with a computer using
      the finite element analysis program PAM-CRASH (Nihon ESI). The air bag was set to
      impact the surface of an eye with a transsclerally fixated posterior chamber IOL
      at various velocities. The tensile force limit of a 10-1 polypropylene suture was
      assumed to be 0.16 N, which is specified in the U.S. Pharmacopeia XXII. RESULTS:
      At the lowest velocity of 20.0 m/s, 10-0 polypropylene sutures were not likely to
      break. Sutures fixating the IOL might break and a corneoscleral incision was
      likely to open after 0.3 second at the medium impacting velocity (30 m/s). Suture
      rupture was very likely at the highest velocity (40 m/s) since the tensile force
      on the sutures continuously exceeded the breaking force after the impact.
      CONCLUSIONS: In an eye with a transsclerally fixated posterior chamber IOL,
      severe ocular trauma can be caused by an air bag at high velocity. Small
      individuals such as elderly women are at greater risk for air-bag ocular injury.
      Further research on modifying air-bag design and deployment is important to
      minimize the risk for ocular injury.

PMID- 15030847
TI  - Detection of laser in situ keratomileusis in a postmortem eye using optical
      coherence tomography.
AB  - With more individuals having laser in situ keratomileusis (LASIK), eye banks are
      challenged to detect prior refractive surgery in donor tissue. We report the case
      of a donor who had LASIK 9 months before his death. Slitlamp biomicroscopy,
      corneal topography, and optical coherence tomography (OCT) were performed to
      evaluate the corneas. Few changes were detected under slitlamp examination and
      corneal topography. We demonstrate that OCT is capable of detecting LASIK-induced
      structural changes in the immediate postmortem evaluation and during the early
      and late period of organ culture. We recommend OCT screening of potential donor
      corneas before organ culture and between days 9 and 12 of organ culture.

PMID- 15030848
TI  - Anterior stromal puncture for recurrent corneal erosion after laser in situ
      keratomileusis.
AB  - A 55-year-old woman had bilateral laser in situ keratomileusis (LASIK). An
      epithelial defect was observed in the left eye after the flap was cut.
      Postoperatively, the patient developed recurrent corneal erosion in the left eye
      related to the traumatic epithelial defect sustained during LASIK. The erosion
      led to secondary diffuse lamellar keratitis (DLK). Anterior stromal puncture was
      required to treat the erosion after conventional treatment failed. The secondary
      DLK resolved quickly after the erosion healed, without the need for topical
      corticosteroids. Anterior stromal puncture may be a useful treatment for
      recurrent corneal erosions that do not respond to conventional therapy.

PMID- 15030849
TI  - Implantation of a toric phakic intraocular lens to correct high corneal
      astigmatism in a patient with bilateral marginal corneal degeneration.
AB  - We present a patient with marginal corneal degeneration and corneal astigmatism
      of more than 10.0 diopters (D). A toric phakic intraocular lens (IOL) of 7.0 D
      cylindrical power was implanted in both eyes to correct the high astigmatism. An
      uncorrected visual acuity of 20/40 was achieved in both eyes, and the best
      corrected visual acuity improved by 4 Snellen lines to 20/20 in both eyes.
      Refraction and visual acuity remained stable at 1.5 years postoperatively.
      Implantation of a toric phakic IOL can be an option to correct high corneal
      astigmatism even when the full corneal astigmatism cannot be treated.

PMID- 15030850
TI  - Capsular tension ring use in a patient with congenital coloboma of the lens.
AB  - Cataract surgery was performed in a 63-year-old man with bilateral coloboma of
      the lens. There was no traumatic history, but the patient had lower zonule
      deficiency and zonular weakness in both eyes, leading us to suspect congenital
      coloboma of the lens. In the first eye having cataract surgery, it was impossible
      to rotate the cataractous lens and place the intraocular lens (IOL) centrally in
      the capsular bag because the lens capsule was not round. The second eye had
      similar problems, and capsular tension ring implantation improved cataract lens
      rotation and phacodonesis, enabling central IOL implantation in the capsular bag.
      The visual acuity recovered to 20/20 in both eyes. Capsular tension ring
      implantation can facilitate cataract surgery in coloboma of the lens, even in
      long-term and continuous lens capsule deformity.

PMID- 15030851
TI  - Ulcerative keratitis caused by Serratia marcescens after laser in situ
      keratomileusis.
AB  - We report 2 cases of severe corneal infections caused by Serratia marcescens
      after laser in situ keratomileusis (LASIK). Twenty-four hours after LASIK, 2
      patients developed infectious keratitis, 1 bilaterally. In each eye, the corneal
      flap was edematous, ulcerated, and detached from the stromal bed. Treatment
      included removal of the necrotic flap and aggressive antibiotic therapy. Cultures
      from corneal exudates were positive for S marcescens. After 1 year, both patients
      had a loss of best corrected visual acuity (BCVA) ranging from 20/40 to 20/22
      because of irregular astigmatism. Overrefraction with a hard contact lens
      resulted in a BCVA of 20/20 in the 3 affected eyes. Slitlamp examination showed
      trace subepithelial haze without severe corneal scarring. Videokeratography
      disclosed areas of paracentral inferior steepening resembling keratoconus.
      Refraction and videokeratography remained stable after 6 months of follow-up.
      Ulcerative keratitis caused by S marcescens is a potential complication of LASIK.
      Bilateral involvement may occur if bilateral simultaneous surgery is performed.

PMID- 15030852
TI  - Goniosynechialysis with lens aspiration and posterior chamber intraocular lens
      implantation for glaucoma in spherophakia.
AB  - A 17-year-old girl presented with bilateral angle-closure glaucoma associated
      with spherophakia. A previous bilateral laser iridotomy failed to control
      intraocular pressure (IOP). Goniosynechialysis with lens aspiration and posterior
      chamber intraocular lens implantation were performed in both eyes. Peripheral
      iridoplasty was performed 3 days later. The postoperative IOP was controlled
      without medication for 12 months in the right eye and 24 months in the left eye.
      By restructuring the physiologic aqueous outflow route, goniosynechialysis safely
      and effectively treated secondary glaucoma from spherophakia.

PMID- 15030854
TI  - Retained anterior chamber cilium causing endophthalmitis after
      phacoemulsification.
AB  - An 81-year-old white man had uneventful cataract surgery by an experienced
      surgeon. Three days postoperatively, he presented with endophthalmitis and was
      treated in accordance with the standard departmental protocol. During the
      recovery, a curvilinear foreign body was identified and subsequently removed from
      the interior anterior chamber. Histological examination confirmed the foreign
      body as an eyelash. The patient improved to a final corrected visual acuity of
      6/9. The relevant literature is reviewed, and ways to prevent this potentially
      blinding but avoidable complication of intraocular surgery are presented.

PMID- 15030853
TI  - Opacification of a silicone intraocular lens caused by calcium deposits on the
      optic.
AB  - We describe opacification of a plate-haptic silicone intraocular lens (IOL)
      caused by calcification in a diabetic patient with asteroid hyalosis. The IOL was
      explanted 48 months after uneventful phacoemulsification because opacification of
      the posterior surface was causing significant visual disturbance. Light and
      scanning electron microscopy and x-ray spectrometry of the explanted IOL showed
      the opacification consisted mainly of calcium and phosphate, presumably
      hydroxyapatite, in the form of precipitations on the posterior surface of the
      optic.

PMID- 15030855
TI  - Histology and immunohistochemistry of fibrous posterior capsule opacification in
      an infant.
AB  - We report the histological findings in posterior capsule opacification (PCO) in 2
      eyes of a 10-month-old infant 8 months after cataract extraction and intraocular
      lens (IOL) implantation. The PCO in the right eye had a regenerated lenticular
      structure; in the left eye, it was fibrotic. The PCO in the right eye was soft
      and aspirated with Simcoe's irrigation/aspiration cannula; in the left eye, it
      was excised surgically. Paraffin sections of the fibrous PCO tissue from the left
      eye were examined histologically. Hematoxylin-eosin staining showed extracellular
      matrix (ECM) accumulation and the presence of elongated fibroblastic cells,
      presumed to be lens epithelial cells (LECs). Immunohistochemistry revealed the
      presence of fibrous collagen types and cellular fibronectin. The presumed LECs
      amid the ECM were positive for vimentin and alpha-smooth muscle actin. Histology
      of the fibrous PCO tissue from this infant was similar to that in adult patients.

PMID- 15030856
TI  - Surgery for 4 refractive errors in 1 patient.
AB  - We report a case of cataract extraction with implantation of a multifocal
      intraocular lens (IOL) after photorefractive keratectomy for myopia and
      astigmatism and subsequent laser thermal keratoplasty for surgically induced
      hyperopia. Good refractive results were obtained using standard biometry
      techniques for calculation of the IOL power.

PMID- 15030857
TI  - [Prognostic contribution for potentials evoked in unit of intensive care].

PMID- 15030858
TI  - [Auditive and somato-sensory event-related potentials in comas: prognostic value
      for awakening, social and professional reinstatement].
AB  - OBJECTIVE: To appreciate prognostical value of event-related potentials in
      comatose states and the influence of the stimulation's modality. PATIENTS AND
      METHODS: Thirty-five patients were recorded with the auditory modality whose
      thirteen were also recorded with the somesthetic modality. They were free of
      sedation except for five. For 21 patients out of coma, it was possible to get
      information about their social readaptation 14 months later. RESULTS: When
      present, cognitive components predict awakening in 100 % of the cases, but only
      50 % of the patients who awake had these components. The somesthetic modality
      seemed to enlarge their detection, but did not improve short-term forecasts. We
      could not confirm their absence could hamper social reinstatement. CONCLUSION:
      Event-related potentials are strengthened as having excellent positive prognostic
      value. Further studies should clarify the interest of the somesthetic modality,
      and the possibility to get remote prognostic.

PMID- 15030859
TI  - [Protocol for advanced prehospital emergency care of severe head injury].
AB  - OBJECTIVES: To analyze the frequency of systemic factors leading to secondary
      brain insults in victims of serious head trauma in a prehospital setting and to
      evaluate a protocol for the advanced prehospital emergency care by mobile
      intensive care unit (i.e., the French Samu-Smur system). STUDY DESIGN:
      Prospective study, over a period of 24 months. PATIENTS AND METHODS: This
      prospective study involved 60 victims of severe head injuries (with the exception
      of polytrauma patients). Tracheal intubation was performed on each patient under
      direct laryngoscopy and after induction of anaesthesia (fentanyl-etomidate
      rocuronium). Controlled ventilation and vascular loading (objectives: SpO(2) >or=
      97%, PETCO(2) between 30 and 35 mmHg, SAP >or= 90 mmHg) were administered.
      RESULTS: Hypoxaemia was found to be the most frequent cause of secondary insults
      (57% of patients with SpO(2) < 97%). In the case involving an accident that
      occurred 17 km from the hospital (with extremes of 6-65 km), the speed of medical
      intervention was note-worthy: tracheal intubation was performed 50 min after the
      accident, and the patient was admitted into a trauma centre 101 min after impact
      (median). However, faster intervention could be obtained if the transmission of
      the alert was improved. The conditions under which the tracheal intubation was
      performed were found to be satisfactory (difficult intubation 1.6%) without
      deteriorating the haemodynamic status. This is probably related to the use of
      muscle relaxants and the choice of etomidate as the first line hypnotic in the
      prehospital emergency care.

PMID- 15030860
TI  - [Antimicrobial prophylaxis in surgical procedures: assessment of the guidelines
      application and validation of antibiotic prophylaxis kits].
AB  - INTRODUCTION: Surgical wounds infections represent a major cause of morbidity and
      are at the origin of an increase in the postoperative mortality rate. Those
      infections represent in France one-fourth of the nosocomial infections. Combine
      with the elementary hygiene rules and the surgical "good practices",
      antimicrobial prophylaxis with antibiotics is an essential tool for the reduction
      of the surgical wound infections rate. In the French hospitals, antimicrobial
      prophylaxis represents one-third of the antibiotic prescriptions. The rules for
      the application of surgical prophylaxis are based on current guidelines for
      antibiotic prophylaxis, however, guidelines are not totally respected. MATERIALS
      AND METHODS: Study 1: assessment of the guidelines application (practical audit)
      of the antibiotic antimicrobial prophylaxis in surgery, and of their impact on
      the established prescriptions: three audits were realized with four years
      interval (1994, 1998 and 2002), in order to estimate the evolution in the
      application of the current guidelines, which indirectly estimate the evolution of
      the guidelines impact. Study 2: assessment of the use of an antibiotic kit
      through a prospective comparative study of two groups: exposed patients vs non
      exposed patients. Nominatives kits contained the recommended antibiotics with
      recommended posology and the instructions for each surgical procedure. RESULTS:
      Study 1: this study showed a significant increase in the antibiotics prescription
      volume since 1994 (+23%). After a temporary increase from 1994 to 1998, the
      conformity of the effective prescriptions with the current guidelines for the
      indication to realize or not to realize an antibiotic surgical prophylaxis
      decreases of 7% between 1998 and 2002. Nevertheless, we noticed an overall
      improvement in the guidelines application for the modalities of the antimicrobial
      prophylaxis when it was prescribed in a valid indication. Persistent weak points
      were in 2002 the antibiotic molecule choice (error rate of 25%), the duration of
      prescription (rate of abnormal prolonged antibiotic prophylaxis of 19%), and the
      timing of administration (error rate of 31%). Study 2: antibiotic kits have
      permitted to increase the accordance of the antimicrobial prophylaxis
      prescriptions with the guidelines. Antibiotic prophylaxis was in total agreement
      with guidelines for 82% of exposed patients vs 41 for non-exposed patients.
      Choice of the antibiotic molecule, timing of administration and duration of
      prescription were the parameters particularly well rectified by this new
      antibiotic prophylaxis technical. CONCLUSION: In this study, guidelines diffusion
      seems to be an essential but also an insufficient point for the improvement of
      the quality prescriptions in surgical antimicrobial prophylaxis. The "day by day"
      nominative antibiotic prophylaxis deliverance in the shape of a << ready to use
      >> antibiotic kit went with an increase in the respect of the recommendations, by
      correcting in a significant way the persistent weak points identified during the
      first part of our study. The antibiotic prescriptions control is an imperative
      goal in individual health (the patient himself), but also in public health (the
      community). This radical change in habits is listed in a policy of antimicrobial
      agent prescription improvement (best efficacy with less cost).

PMID- 15030861
TI  - [Assessment of teaching methods of anaesthesiology and intensive care medicine in
      France: opinions of teacher and residents].
AB  - OBJECTIVE: The objective of this study was to provide informations about French
      practice of anaesthesiology and intensive care graduation. STUDY DESIGN:
      Prospective study. MATERIAL AND METHODS: [corrected] Surveys relative to
      evaluation tools were sent to professors, and students in anaesthesiology and
      intensive care in France. RESULT: About 95% of French students in anaesthesiology
      and intensive care want to be evaluated all over their cursus, by using "Carnet
      de stage", tutor-student agreement or written examinations. Pedagogical
      evaluation is hardly wished by students and professors despite that "Carnet de
      stage" and written examinations are frequently used before professional
      certification. In order to improve the professional competence, the patronage and
      use of simulator are frequently quoted by professors. CONCLUSION: Despite the
      fact that "Carnet de stage" and written examinations are frequently used,
      pedagogic dimension of evaluation need to be improved.

PMID- 15030862
TI  - [Uncommon cause of respiratory distress in the post-anaesthesia care unit].
AB  - We report a case of respiratory distress in the post anesthesia care unit
      following general anaesthesia for a dilatation and curettage related to
      miscarriage in a 32-year-old woman. The preoperative physical examination showed
      no abnormalities except for the presence of dry cough during the preceding two or
      three days. A few minutes after her arrival in the PACU, the patient developed
      hyperthermia till 40.6 degrees C, cough, polypnea and oxygen desaturation
      (SpO(2): 82% on FiO(2): 40%). A thoraco-abdominal angioscanner showed pulmonary
      basal condensations and a thrombosis of the right ovarian vein. The patient had
      to be transferred to the intensive care unit where she remained intubated and
      ventilated during 13 days because of a Haemophilus influenzae pneumonia.

PMID- 15030863
TI  - [Mediastinal and abdominal lymphoedema: consequence of massive pulmonary embolism
      with shock?].
AB  - We report a case of severe pulmonary embolism diagnosed using spiral CT-scan in a
      patient admitted for shock associated with acute abdominal symptoms. Intraluminal
      clots images were visualized associated with an infiltration of mediastinal fat.
      Abdominal CT showed infiltration of the hepatobiliary hilum. After thrombolysis,
      the clinical thoracic and abdominal symptoms improved. A CT-scan at the 48(th)
      hour showed that the thoracic and abdominal features had disappeared. We
      emphasize the misleading aspect of the CT-scan images and we speculated that this
      infiltration could reflect the abdominal and mediastinal lymphoedema.

PMID- 15030864
TI  - [Stomach rupture after nasal oxygen administration].
AB  - We report a case of a spontaneous rupture of a normal stomach after therapeutic
      oxygen administration. In this case, early treatment precluded the need for a
      laparotomy. This rare complication highlights the importance of the right
      positioning of a nasal catheter and leads us to question its role compared to
      other means of oxygen delivery (nasal cannulae, Hudson mask, Venturi mask).

PMID- 15030865
TI  - [Amniotic fluid embolism suspected in a case of seizure and mild uterine
      haemorrhage with activation of coagulation and fibrinolysis].
AB  - After a normal pregnancy and labour in a 29-year-old parturient, a single seizure
      followed by a transient headache was observed during the uterine revision for
      placental retention. Mild uterine haemorrhage of 150 ml per hour without any
      uterine atony was associated with activation of clotting and fibrinolysis
      (decrease of fibrinogen, elevated fibrin soluble complexes and D-dimers). A ten
      fold value of foetal blood cells in maternal serum suggested the diagnosis of
      amniotic fluid embolism. Atypical forms of amniotic fluid embolism and their
      diagnosis are discussed.

PMID- 15030866
TI  - [Oxygenator thrombosis without heparin resistance].
AB  - A 55-year-old male with a history of positive HIV serology and Polycytemia vera
      underwent coronary artery bypass graft surgery with normothermic extracorporeal
      circulation. Following heparin administration the activated clotting time (ACT)
      was 633 seconds (Hemocron) with kaolin). Lower than expected arterial and venous
      oxygen partial pressures together with high pressure (350 mmHg) in the arterial
      line upstream of the oxygenator were observed. Because of these signs the
      oxygenator was changed during the procedure. The outcome was uneventful.
      Electronic microscopic examination of the oxygenator membrane and thermic
      exchanger revealed fibrin and platelet deposits.

PMID- 15030867
TI  - [Pregnancy-induced hypertension complicated by acute pancreatitis].
AB  - The acute pancreatitis is a rare complication during the pregnancy. Causes are
      dominated by the gallstones and hyperlipidemia. This case report describes a 35
      year-old pregnant woman who developed acute pancreatitis while suffering from a
      severe pre-eclampsia syndrome. Since she had no gallstones or other known
      aetiological factors of acute pancreatitis, the possibility of an etiologic role
      of pancreatic ischaemic changes associated with eclampsia is discussed. Evolution
      was marked with multi-organ system failure and poor outcome. Our experience and
      the previously reported case suggest that pre-eclampsia could be added to the
      list of causes of the acute pancreatitis.

PMID- 15030868
TI  - [Seizure-like movements following sevoflurane induction in paediatric
      anaesthesia].

PMID- 15030869
TI  - [Diuretics use in the intensive care unit: results of a prevalence study].

PMID- 15030870
TI  - [Uncontrollable pain in intensive care unit: ketamine contribution].

PMID- 15030871
TI  - [Critical review of the literature concerning the comparative use of two
      antiseptic solutions before intravascular or epidural catheterization].

PMID- 15030872
TI  - [Cellulitis of the meso of the rectosigmoid due to primary group A streptococcal
      peritonitis].

PMID- 15030873
TI  - [Use of local and locoregional anesthesia by physicians not specialized in
      anesthesia-reanimation, within the frame of emergencies].

PMID- 15030874
TI  - Flow-injection inhibition chemiluminescence determination of indapamide based on
      luminol-ferricyanide reaction.
AB  - A novel and sensitive chemiluminescence (CL) method for the determination of
      indapamide coupled with flow-injection analysis (FIA) technique is developed in
      this paper. It is based on the inhibition effect of the studied drug on the
      chemiluminescence emission of luminol-potassium ferricyanide system. Under the
      optimum conditions, the decreased CL intensity is proportional with the
      concentration of indapamide in the range of 1 x 10(-8) to 1.0 x 10(-6) g ml(-1).
      The detection limit is 3.4 x 10(-9) g ml(-1) (3sigma). A complete analysis could
      be performed in 45 s including washing and sampling, giving a throughout of about
      90 h(-1). The relative standard deviation (R.S.D.) for 11 parallel measurements
      of 1.0 x 10(-7) g ml(-1) indapamide is 3.0%. The proposed method has been applied
      for the determination of indapamide in its pharmaceutical formulations. The
      results obtained compared well with those by an official method. The possible
      inhibition mechanism of indapamide on luminol-potassium ferricyanide CL system
      was discussed briefly.

PMID- 15030875
TI  - The photocatalytic process as a tool to identify metabolitic products formed from
      dopant substances: the case of buspirone.
AB  - The photocatalytic transformation of buspirone, an analgesic anxiolytic drug, and
      the formation of intermediates products have been evaluated by adopting titanium
      dioxide as a photocatalyst. Several molecules resulting from buspirone
      degradation have been identified and characterized by using HPLC/MS/MS technique.
      The main intermediates formed in these experimental conditions agree with the
      major buspirone metabolites found "in vivo" on rats and horses: hydroxy and
      dihydroxy-buspirone, despyrimidinyl buspirone and 1-pyrimidinyl piperazine. This
      shows that the photocatalytic system could provide in the present case a useful
      simulation of the metabolic transformation of dopant substances. Moreover, some
      more oxidized species have been recognized with the photocatalytic process, and
      this could offer a suggestion for yet to come metabolism studies.

PMID- 15030876
TI  - Stable isotopic characterization of active pharmaceutical ingredients.
AB  - Stable isotopic characterization or "fingerprinting" of active pharmaceutical
      ingredients (APIs) is a highly-specific means of defining the provenance of these
      pharmaceutical materials. The isotopic analysts in this study were provided with
      20 blind samples of four APIs (tropicamide, hydrocortisone, quinine HCL, and
      tryptophan) from one-to-five production batch(es) from one-to-five
      manufacturer(s). Only the chemical identity of the APIs was initially provided to
      the isotopic analysts. Depending on the API chemical composition, isotopic ratios
      of either three or four elements (13C/12C, 15N/14N, 18O/16O, and/or D/H) were
      measured by either elemental analyzer/isotope ratio mass spectrometry (EA/IRMS:
      carbon (delta13C) and nitrogen (delta15N)) or by thermal conversion-EA/IRMS
      (TCEA/IRMS; hydrogen (deltaD) and oxygen (delta15N)); in all cases, the isotopic
      results are reported in the standard delta-notation which represents part-per
      thousand () variations from the isotopic ratios of international standards. The
      stable isotopic analyses of the four suites of APIs spanned broad ranges in
      absolute value (deltadelta) and in estimated specificity (a product of dynamic
      ranges (DR, unitless)--note that these are upper limits of specificity because
      some of these isotope values may be partially interdependent). The five samples
      of tropicamide from one production batch and one manufacturer demonstrated the
      narrowest ranges (deltadelta13C=0.13 ; deltadelta15N=0.52 ; deltadelta18O=0.24 ;
      deltadeltaD=2.8 ) and the smallest specificity of 1:30.9. By contrast, the five
      samples of tryptophan that came from five separate manufacturers had some of the
      widest isotopic ranges observed (deltadelta13C=21.32 ; deltadelta15N=5.26 ;
      deltadelta18O=22.07 ; deltadeltaD=55.3 ) and had the largest specificity of
      1:19.6 x 10(6). The isotopic provenance of the four suites of APIs readily
      emerged from bivariate plots of selected isotope ratios, particularly deltaD
      versus delta18O.

PMID- 15030877
TI  - Quantitative determination of Piroxicam by TLC-MALDI TOF MS.
AB  - A quantitative thin-layer chromatography (TLC)-matrix-assisted laser desorption
      (MALDI) TOF mass spectrometry (MS) method for the determination of Piroxicam has
      been developed. Following preliminary experiments three different approaches to
      the incorporation of the internal standard (Tenoxicam) into the TLC plates were
      investigated. These were: (a) adding the internal standard to the mobile phase
      and pre-developing the plate, (b) coating the plate with internal standard by
      electrospraying prior to matrix application and finally, (c) mixing the internal
      standard into the matrix solution and electrospraying both. The most successful
      method was that where the internal standard was pre-developed over the plate. For
      this method linearity was observed over the range between 400 and 800ng of
      Piroxicam. The precision was found to be in the range of 1-9% R.S.D. from the
      average detected value (n = 5), dependent on the amount of analyte on the TLC
      plate. The proposed method was accurate with +/-2% deviation from the known
      amount of Piroxicam in the sample spot.

PMID- 15030878
TI  - Development and validation of a high-performance liquid chromatographic method
      for the determination of buspirone in pharmaceutical preparations.
AB  - A stability indicating, reversed-phase high-performance liquid chromatographic
      method was developed and validated for the determination of buspirone (Bsp) in
      pharmaceutical dosage forms. The use of a semi-micro XTerra MS C18 (150 mm x 3.0
      mm i.d., 5 microm particle size) analytical column, results in substantial
      reduction in solvent consumption and increased sensitivity. The mobile phase
      consisted of a mixture of 0.010 M ammonium acetate (pH 4.0) and methanol (55:45,
      v/v), pumped at a flow rate 0.30 ml min-1. The UV detector was operated at 245
      nm. The retention times for lidocaine (Ldc), which was used as internal standard,
      and buspirone were 4.57 and 7.72 min, respectively. The calibration graph was
      ranged from 1.00 to 5.00 microg ml-1, while detection and quantitation limits
      were found to be 0.22 and 0.67 microg ml-1, respectively. The intra- and inter
      day relative standard deviation (% R.S.D.) values were less than 1.94%, while the
      relative percentage error (% Er) was less than 4.0% (n = 5). The method was
      applied to the quality control of commercial tablets and content uniformity test
      and proved to be suitable for rapid and reliable quality control.

PMID- 15030879
TI  - Spectrophotometric and electrochemical study of the inclusion complex between
      beta-cyclodextrin and furnidipine.
AB  - Inclusion complexation between furnidipine (2,6-dimethyl-4-(2-nitrophenyl)-1,4
      dihydropyridine-3,5-dicarboxylic acid 3-tetrahydrofurfuryl 5-methyl diester), a
      calcium-channel antagonist, and beta-cyclodextrin (beta-CyD) was studied in
      aqueous solution by using both spectrophotometric and electrochemical
      measurements. The phase solubility profile was classified as A(L)-type,
      indicating the formation of 1:1 stoichiometric inclusion complex of furnidipine
      with beta-CyD. Based on the spectrophotometric absorbance's variations, a
      formation constant value, K(f), of 156 M(-1) was determined. Electrochemical
      measurements using chronocoulometric experiments were used for the determination
      of the diffusion coefficients. In absence of beta-CyD, a diffusion coefficient
      value of 4.32 x 10(-6) cm2 s(-1) was obtained for furnidipine. The addition of
      beta-CyD produced a decrease of 30% for the diffusion coefficient. Formation of
      inclusion complexes of furnidipine with beta-CyD was proved to increase more than
      three times the solubility of furnidipine.

PMID- 15030880
TI  - Analysis by liquid chromatography and infrared spectrometry of di(2
      ethylhexyl)phthalate released by multilayer infusion tubing.
AB  - Di(2-ethylhexyl)phthalate (DEHP), a plasticiser present in infusion equipment, is
      known to be harmful to human health. Various studies have shown that DEHP is
      released into drug solutions from polyvinyl chloride (PVC) infusion lines. New
      multi-layer tubing has therefore been marketed to overcome this problem. We
      assessed the inertness of this tubing when placed in contact with a solution of
      CELLTOP. Chromatographic assay of DEHP showed no significant difference in DEHP
      levels in the solution when placed in contact with PVC and with multi-layer
      tubing. Analysis by infrared spectrometry showed that DEHP was initially present
      in the polyethylene layer of the multi-layer tubing even before contact with the
      drug solution. Contact with the solution results in release of DEHP from the
      container into the contents. The substance responsible for this release is in
      fact an excipient of CELLTOP, polysorbate. This release of DEHP further proves to
      depend on parameters such as temperature, time of contact between solution and
      tubing, and the concentration of polysorbate in the infused drug solution.

PMID- 15030881
TI  - Rapid estimation of kinetic parameters for thermal decomposition of penicillins
      by modulated thermogravimetric analysis.
AB  - Modulated thermogravimetic analysis (MTGA) is evaluated for the rapid estimation
      of thermal stability using several penicillin antibiotics as model compounds. The
      MTGA technique utilizes an oscillatory temperature program to obtain Arrhenius
      kinetic parameters through a mass loss during thermal degradation. To evaluate
      the reliability of this technique, activation energies (E(a)), log pre
      exponential factor (logZ), and log first order rate constants (logk) obtained by
      MTGA for the thermal decomposition of ampicillin anhydrous, ampicillin
      trihydrate, ampicillin sodium salt, and penicillin G potassium salt are compared
      to existing literature values. The logk values estimated by MTGA agreed well with
      literature values when the weight loss observed by MTGA was shown to be due to
      the first decomposition step of the compound. The E(a) and logZ values determined
      by MTGA did not consistently agree with literature values as these parameters
      increased with decreasing heating rate (beta). The increase in E(a) and logZ
      values with decreasing beta seemed to offset each other to some extent to yield a
      relatively consistent logk estimate regardless of beta.

PMID- 15030882
TI  - Physicochemical characterization and dissolution properties of meloxicam
      cyclodextrin binary systems.
AB  - The objective of the work is physicochemical characterization of meloxicam (ME)
      cyclodextrin (CD) binary systems both in solution and solid states and to improve
      the dissolution properties of meloxicam via complexation with alpha-, beta- and
      gamma-cyclodextrins. Detection of inclusion complexation was done in solution
      state by means of phase solubility analysis, mass spectrometry and 1H nuclear
      magnetic resonance (NMR) studies, and in solid state using differential scanning
      calorimetry (DSC), powder X-ray diffractometry, and in vitro dissolution studies.
      Phase solubility, mass spectrometry and 1H NMR studies in solution state revealed
      1:1M complexation of meloxicam with all CDs. A true inclusion of ME with gamma-CD
      at 1:1 and 1:2M in solid state was confirmed by DSC, powder XRD and scanning
      electron microscopy (SEM) studies. Dissolution properties of ME-CDs binary
      systems were superior when compared to pure ME.

PMID- 15030885
TI  - Determination of xylazine and its metabolites by GC-MS in equine urine for doping
      analysis.
AB  - Xylazine and its main metabolites were detected in equine urine after a single
      dose intravenous administration of 0.98 and 1.01 mg/kg body weight xylazine,
      respectively, in two horses, in order to be used for equine doping control
      routine analysis. The urine levels of the parent drug and its metabolites were
      determined using gas chromatography-mass spectrometry (GC-MS). Xylazine is
      metabolised rapidly, down to a concentration level of about 1.0 microg/ml after 1
      3h administration. Seven metabolites were identified in urine. 4-Hydroxy
      xylazine, the major metabolite, could be traced for 25 h and it is regarded as
      the long-term metabolite of xylazine in horse. 2,6-Dimethylaniline was, for the
      first time, reported as metabolite in equine.

PMID- 15030884
TI  - Integrated application of transcriptomics and metabonomics yields new insight
      into the toxicity due to paracetamol in the mouse.
AB  - Gene chip array (Affymetrix) data from liver tissue and high resolution 1H NMR
      spectra from intact liver tissue, tissue extracts and plasma have been analyzed
      to identify biochemical changes arising from hepatotoxicity in mice dosed with
      acetaminophen. These data sets have been co-interpreted in terms of common
      metabolic pathways. The principal metabolic changes comprised a decrease in
      hepatic glucose and glycogen in intact tissue, coupled with an increase in lipid
      content, with increases in the levels of glucose, pyruvate, acetate and lactate
      in plasma, and increases in alanine and lactate in the aqueous tissue extracts.
      Collectively these data provide evidence for an increased rate of hepatic
      glycolysis. The metabolic observations were consistent with the altered levels of
      gene expression relating to lipid and energy metabolism in liver which both
      preceded and were concurrent with the metabolic perturbations. The results show
      that these two technology platforms together offer a complementary view into
      cellular responses to toxic processes, providing new insight into the toxic
      consequences, even for well-studied therapeutic agents such as acetaminophen.

PMID- 15030883
TI  - Development of a high pressure liquid chromatography method for the determination
      of mycophenolic acid and its glucuronide metabolite in small volumes of plasma
      from paediatric patients.
AB  - In order to facilitate the simultaneous determination of the levels of
      mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG) in plasma
      samples a step wise gradient high performance liquid chromatography (HPLC) method
      was developed using UV detection system and naproxen as an internal standard. The
      analytes were extracted from plasma using Strata-X polymeric solid phase
      extraction (SPE) cartridges. Separation was achieved within a total
      chromatographic run time of 18 min at 1.0 ml/min flow rate using a Hv PURITY C18
      column. The method was found to be linear over the concentration range
      investigated, 1.0-16 microg/ml (r > 0.99) for MPA and 10-160 microg/ml (r > 0.99)
      for MPAG. The limit of detection was 0.1 microg/ml for both MPAG and MPA. The
      intra- and inter-day imprecisions expressed as R.S.D. were 7.8 and 6.6%,
      respectively, for MPA (1 microg/ml) and 6.2% and 5.6%, respectively, for MPAG (20
      microg/ml). The average extraction recovery from plasma was 93.06%, for MPA and
      92.41% for MPAG. The method developed was found to be accurate and precise in
      quantifying the level of MPA and MPAG over a their therapeutic range of
      concentrations in small volumes of plasma and thus can be effectively used in the
      routine drug monitoring procedures and pharmacokinetic studies. It was also
      developed in such a way that it should be easily coupled to an electro-spray
      ionization mass spectrometer should greater sensitivity be required.

PMID- 15030886
TI  - Prediction of anti-plasmodial activity of Artemisia annua extracts: application
      of 1H NMR spectroscopy and chemometrics.
AB  - We describe the application of 1H NMR spectroscopy and chemometrics to the
      analysis of extracts of Artemisia annua. This approach allowed the discrimination
      of samples from different sources, and to classify them according to anti
      plasmodial activity without prior knowledge of this activity. The use of partial
      least squares analysis allowed the prediction of actual values for anti
      plasmodial activities for independent samples not used in producing the models.
      The models were constructed using approximately 70% of the samples, with 30% used
      as a validation set for which predictions were made. Models generally explained
      >90% of the variance, R(2) in the model, and had a predictive ability, Q(2) of
      >0.8. This approach was also able to correlate 1H NMR spectra with cytotoxicity
      (R2=0.9, Q2=0.8). This work demonstrates the potential of NMR spectroscopy and
      chemometrics for the development of predictive models of anti-plasmodial
      activity.

PMID- 15030887
TI  - A sensitive HPLC-MS-MS assay for quantitative determination of midazolam in dog
      plasma.
AB  - The clinical pharmacokinetics of midazolam have been extensively studied, due to
      its high clearance by CYP3A4 and sensitivity to drug-drug interactions. In order
      to investigate the potential to model drug-drug interactions with midazolam in
      the dog, a selective and sensitive high performance liquid chromatography-tandem
      mass spectroscopy (HPLC-MS-MS) method has been developed, with sufficient
      sensitivity to allow analysis of dog plasma samples generated following
      administration of a clinically relevant dose. The method involves extraction of
      midazolam and internal standard (flunitrazepam) from dog plasma, using 96-well
      Oasis MCX solid phase extraction plates. The assay has been validated over a
      concentration range of 0.1-10 ng/ml and its specificity, accuracy and precision
      demonstrated. The relative bias of the assay was within +/-15% for all standards
      with intra- and inter-assay precision (coefficient of variation-%CV) of less than
      15%. The assay was applied to the analysis of plasma samples (0.2 ml), generated
      following intravenous or oral administration of midazolam to male beagle dogs, at
      a dose level of 0.05 mg/kg, and pharmacokinetic parameters were derived from the
      resulting data.

PMID- 15030888
TI  - HPLC assay with UV spectrometric detection for the evaluation of inhibitors of
      cytosolic phospholipase A2.
AB  - A non-radioactive spectrometric assay for the evaluation of inhibitors of
      cytosolic phospholipase A(2) (cPLA(2)) is described. The enzyme was isolated from
      human platelets applying anion exchange chromatography. Sonicated covesicles
      consisting of 0.2mM 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine and
      0.1mM 1,2-dioleoyl-sn-glycerol were used as enzyme substrate. The cPLA(2)
      activity was determined by measuring the arachidonic acid released by the enzyme
      with reversed-phase HPLC and UV detection at 200 nm after cleaning up the samples
      by solid phase extraction. Two known cPLA(2) inhibitors were used to validate the
      test assay.

PMID- 15030889
TI  - Simple, rapid determination of enrofloxacin and ciprofloxacin in bovine milk and
      plasma by high-performance liquid chromatography with fluorescence detection.
AB  - A rapid and simple procedure for determination of enrofloxacin and ciprofloxacin
      in bovine milk and plasma is described. Protein precipitation from both milk and
      plasma samples was achieved by addition of acetonitrile and phosphoric acid.
      Acetonitrile was removed with methylene chloride, leaving enrofloxacin and
      ciprofloxacin in the acidic aqueous extract. The aqueous extract was analyzed by
      high-performance liquid chromatography (HPLC) with fluorescence detection. The
      limit of quantitation (LOQ) for enrofloxacin and ciprofloxacin in milk was found
      to be 2ng/ml. LOQ for enrofloxacin and ciprofloxacin in plasma was found to be
      1ng/ml. Linear calibration curves were obtained with correlation coefficient
      (r(2)) >/=0.99. Analysis of quality control (QC) samples gave results within +/
      10% of the nominal values. Inter-assay precision for the analysis of milk QC
      samples were in the ranges: 4.63-12.49% (for enrofloxacin) and 4.67-9.86% (for
      ciprofloxacin). Inter-assay precision for the analysis of plasma QC samples were
      in the ranges: 6.60-17.31% (for enrofloxacin) and 6.14-13.87% (for
      ciprofloxacin). Intra-assay precision for the analysis of milk QC samples were in
      the following ranges: 3.65-7.21% (for enrofloxacin) and 1.58-14.28% (for
      ciprofloxacin). Intra-assay precision for the analysis of plasma QC samples were
      in the following ranges: 2.17-16.95% (for enrofloxacin) and 3.31-16.31% (for
      ciprofloxacin). The effectiveness of protein precipitants other than phosphoric
      acid was investigated. The method described has been applied to a study of the
      pharmacokinetics of enrofloxacin and ciprofloxacin in lactating dairy cows and
      beef steers.

PMID- 15030890
TI  - Measuring tobacco smoke exposure: quantifying nicotine/cotinine concentration in
      biological samples by colorimetry, chromatography and immunoassay methods.
AB  - Procedures to assess tobacco smoke exposure are reviewed and biomarkers used for
      determining the smoking status of an individual are compared. Methods used to
      extract these biomarkers from saliva, urine, and blood and the advantages and
      disadvantages of the assays are discussed. Finally, the procedures used to
      measure the levels of cortisol, a stress hormone speculated to be linked to
      nicotine metabolism, are discussed.

PMID- 15030891
TI  - Determination of naltrexone and 6-beta-naltrexol in human plasma following
      implantation of naltrexone pellets using gas chromatography-mass spectrometry.
AB  - An alternative to detoxification by oral therapy with the narcotic antagonist
      naltrexone is the subcutaneous implantation of naltrexone pellets. From
      detoxified patients with naltrexone implants (1g) 26 blood samples were collected
      up to 73 days after implantation. The assay for naltrexone and 6-beta-naltrexol
      in plasma was developed using automated mixed-mode solid-phase extraction,
      catalysed trimethylsilylation and gas chromatography-mass spectrometry in single
      ion monitoring mode with naloxone as internal standard. The analytical method was
      very sensitive with limits of detection of 0.1 ng/ml and was linear up to 60
      ng/ml for naltrexone and 200 ng/ml for naltrexol. Intra-day precision for
      naltrexone and naltrexol were 24.3 and 22.9%, respectively, at the LLOQ (accuracy
      1.4 and 0.4%, respectively) and less than 10% (2.0, 6.0 and 20.0 ng/ml, n = 6
      each) above. Inter-day precision was 7.9% (accuracy -0.6%) for naltrexone and
      10.9% (accuracy 1.6%) for naltrexol (20 ng/ml, n = 10). Extraction recoveries
      were 83% for both analytes (10 ng/ml, n = 6). The concentrations of naltrexone
      and naltrexol in the plasma samples were in the range of 0.7-13.7 and 0.9-17.0
      ng/ml, respectively. The simple analytical procedure described provided good
      sensitivity for the assay of naltrexone and naltrexol in plasma after naltrexone
      pellet implantation.

PMID- 15030892
TI  - HPLC-radiometric determination of quinlukast in biological fluids.
AB  - An analytical method for the analysis of a novel antiasthmatic drug quinlukast
      and its metabolites in the plasma, bile and urine was developed. For the
      analysis, the solid phase extraction method and the C(8) RP-HPLC with radiometric
      detection of the drug were used. This method enables a quantitative determination
      of the agent and all of its metabolites (even of those with an unknown structure)
      in a biological system. The procedure is, therefore, suitable both for the
      pharmacokinetic analysis of quinlukast and the determination of its elimination
      pathways.

PMID- 15030893
TI  - A selective and sensitive assay of berberine using total internal reflected
      resonance light scattering technique with fluorescein at the water/1,2
      dichloroethane interface.
AB  - An assay of berberine (BE) was developed with good selectivity and sensitivity
      based on the total internal reflected resonance light scattering (TIR-RLS)
      signals from water/1,2-dichloroethane (H(2)O/DCE) interface. Under optimal
      conditions, amphiphilic complex formed by BE and fluorescein (Flu) was adsorbed
      to H(2)O/DCE interface, resulting in good separation of BE from the coexisting
      foreign substances in aqueous phase and significant enrichment of BE at the
      interface. This enriched species at the interface was found corresponding to
      enhanced TIR-RLS signals located at 370.0 nm. Proportional relationships were
      established between the enhanced TIR-RLS intensity and the BE in the range of 3.2
      x 10(-9) to 3.2 x 10(-6) mol l(-1) with the limit of detections (3sigma) being
      1.3 ng ml(-1). Favorable sensitivity of TIR-RLS technique was demonstrated
      superior to that of high-performance liquid-chromatography (HPLC) method. The
      feasibility of the proposed technique was validated by the satisfactory
      performance of intra-assay and inter-assay BE in tablets.

PMID- 15030894
TI  - Fragmentation pathway of dopamine transporter ligands: N-substituted-2beta
      carbomethoxy-3beta-phenylnortropane derivatives.
AB  - Electron impact mass spectra of iodinated tropane derivatives which are of
      clinical importance are described. The major fragment ions were found to come
      from the cleavage of the Calpha-Cbeta bond of the bridgehead nitrogen, affording
      to hydrogenopyrrolidine derivatives ions. The fragment ions generated from the EI
      mass spectra were assigned and fragmentation mechanisms were proposed.

PMID- 15030895
TI  - Analysis of the phospholipid composition of bronchoalveolar lavage (BAL) fluid
      from man and minipig by MALDI-TOF mass spectrometry in combination with TLC.
AB  - Surfaces of lungs are covered by the surfactant, an aqueous mixture of different
      phospholipids (PL) and proteins. Although the surfactant represents a relatively
      simple mixture of only a few PL (primarily phosphatidylcholine (PC) and
      phosphatidylglycerol (PG)), reliable methods of routine lipid analysis of the
      surfactant are still lacking. It will be shown that matrix-assisted laser
      desorption and ionisation time-of-flight mass spectrometry (MALDI-TOF MS)
      represents a suitable technique for the differentiation of the apolar components
      of the surfactant of different species. Samples of man and minipig are used in
      this study since both are known to vary in their PL composition. PL of surfactant
      were separated by thin-layer chromatography (TLC) and the obtained subfractions
      subjected to MALDI-TOF MS analysis in order to monitor the presence of even minor
      PL species. It will be shown that besides PG and PC, also
      phosphatidylethanolamine, -inositol and sphingomyelin can be detected in
      surfactant of man, whereas only sphingomyelin could be detected in the minipig
      sample.

PMID- 15030896
TI  - Simultaneous determination of ginsenoside Rb(1) and Rg(1) in human plasma by
      liquid chromatography-mass spectrometry.
AB  - A liquid chromatographic-mass spectrometric (LC/MS) method for the simultaneous
      determination of ginsenoside Rb(1) and Rg(1) in human plasma was developed. The
      method involved the protein precipitation followed by analysis of ginsenoside
      Rb(1) and Rg(1) in an Atlantis C(18) column with the gradient elution of
      acetonitrile and ammonium formate (10mM, pH 3.0) at a flow rate of 0.2 ml/min.
      The analytes were determined using electrospray negative ionization mass
      spectrometry in the selected ion monitoring mode. The standard curves for
      ginsenoside Rb(1) and Rg(1) were linear over the concentration range of 10.0-1000
      ng/ml. The lower limit of quantification was 10.0 ng/ml using 100 microl plasma
      sample. The coefficient of variation of intra- and inter-day assays for
      ginsenoside Rb(1) and Rg(1) at three quality control levels ranged from 1.0 to
      6.8% and 5.4 to 9.8%, respectively. Ginsenoside Rb(1) and Rg(1) were stable in
      blank human plasma at room temperature for 24h and following three freeze-thaw
      cycles.

PMID- 15030897
TI  - Quantitative structure-retention and retention-activity relationships of some 1,3
      oxazolidine systems by RP-HPTLC and PCA.
AB  - A quantitative structure-retention and retention-activity relationships
      investigations were performed on the lipophilicities of some 1,3-oxazolidine
      systems as estimated by RP-HPTLC retention parameters. The classical R(Mo) values
      were compared with the factors scores obtained by principal component analysis
      based also onto the TLC retention data. The lipophilicities (R(Mo) and factor
      scores) were correlated with the theoretical molecular descriptors of 1,3
      oxazolidine derivatives providing by the ALCHEMY 2000 software package. The
      reliability of the factor scores values as lipophilic indices are shown by their
      significant correlation with the classical R(Mo) values and other molecular
      descriptors. In addition, the "lipophilicity chart" described by the first two
      components, and/or the "lipophilicity space" described by the first three
      components have the effect of separating compounds from each other most
      effectively from the congeneric (similarity) aspect point of view. Finally, these
      findings support the idea that the chromatographic process of the investigated
      compounds in this paper and consequently their partitioning over a bio-membrane
      are controlled mainly by lipophilicity.

PMID- 15030899
TI  - A capillary zone electrophoresis (CZE) method for the determination of cyclizine
      hydrochloride in tablets and suppositories.
AB  - Current compendial methods of assay for the analysis of cyclizine tablets involve
      the use of UV spectrophotometry. Since this is a non-selective technique its
      application to more complex dosage forms, such as suppositories, is unlikely to
      be appropriate. There is therefore a need for the development of a highly
      specific quantitative analytical method, such as high performance liquid
      chromatography (HPLC) or capillary electrophoresis (CE). The latter technique was
      chosen in view of some specific advantages over HPLC, such as the use of
      relatively non-toxic aqueous buffers, as opposed to organic solvents, which
      obviates the use of expensive HPLC grade solvents making CE more cost effective.
      Cyclizine was analyzed in 50mM phosphate buffer (pH 2.3) and run at an applied
      voltage 25 kV. Detection sensitivity was enhanced by using a wavelength of 200 nm
      and samples were loaded hydrodynamically onto an uncoated fused-silica capillary
      (60 cm x 50 mm i.d.). Chlorcyclizine was used as the internal standard and
      resolution of both compounds was achieved in less than 7 min. Stress testing was
      undertaken in order to investigate the appearance of breakdown products. The
      method has the requisite accuracy, selectivity, sensitivity and precision to
      assay cyclizine in tablets and suppositories. Degradation products resulting from
      the stress studies did not interfere with the detection of cyclizine and the
      assay is thus stability-indicating.

PMID- 15030898
TI  - Simultaneous determination of cefatrizine and clavulanic acid in dog plasma by
      HPLC.
AB  - A rapid and specific high-performance liquid chromatographic method was developed
      and validated for the simultaneous determination of cefatrizine and clavulanic
      acid in the plasma of beagle dog. The sample pretreatment procedure involved
      reaction of clavulanic acid with 1,2,4-triazole, which readily produced a
      derivative with its maximum UV absorption at 314 nm. This derivative was
      separated in a reverse-phase C-18 column without being interfered by other
      components present in plasma. Cefatrizine, however, was not derivatized and,
      therefore determined directly at 269 nm. Sulfanilamide was used as an internal
      standard. The retention times of sulfanilamide, the derivative, and cefatrizine
      were, 3.5, 4.9, and 6.0 min, respectively. The assay showed linearity from 2 to
      100 microg/ml for cefatrizine and from 1 to 50 microg/ml for clavulanic acid.
      Precision expressed as R.S.D. ranged from 4.2 to 18.2% for cefatrizine and 5.5 to
      15.8% for clavulanic acid. Accuracy ranged from 97.9 to 120% (lower limit of
      quantitation) for cefatrizine and from 97.7 to 119.2% for clavulanic acid.
      Extraction efficiencies for cefatrizine, clavulanic acid, and internal standard
      from dog plasma averaged 79.8+/-5.8%, 84.8+/-6.2%, and 89.0+/-3.8%, respectively.
      This method was employed successfully to follow the time course of the
      concentration of cefatrizine and clavulanic acid in beagle dogs following oral
      administration of cefatrizine and clavulanic acid.

PMID- 15030900
TI  - Founders of child neurology in Japan - Keiya Tada.

PMID- 15030901
TI  - The neurology of sign language.
AB  - Forms of sign language have developed in a number of countries. American Sign
      Language, which originated from French signing, has been most extensively
      researched. As sign language is based on gestures executed in space and perceived
      visually it might be thought that it would mainly be a function of the right
      cerebral hemisphere when this is the non-dominant one. A number of studies are
      reviewed showing that sign language is a language in its own right and therefore,
      as with spoken language, its primary site of organization is in the dominant
      hemisphere. This does not mean that there is not a significant contribution from
      the other hemisphere with an interplay between the two. Each research project
      usually contributes some facet of knowledge apart from the main conclusions.
      These included the importance of distinguishing signs from gestures, the
      localization of different types of signing within the left dominant cerebral
      hemisphere, the fact that lesions of the right non-dominant hemisphere, although
      not causing a loss of signing will result in dyspraxia, and that aphasic symptoms
      of signing and speech are not modality dependant but reflected a disruption of
      language processes common to all languages. Examples are given of discoveries
      made by the use of the newer neuroradiological techniques such as functional
      magnetic resonance imaging and positron emission tomography, and no doubt these
      will lead to further advances in knowledge. The use of sign language in the
      treatment of patients with verbal aphasia is considered, especially of children
      with the Landau-Kleffner syndrome, but therapy of this kind can be used in
      children with delayed language development, and in other types of acquired
      aphasia at any age. Other methods of treatment than signing, such as cochlear
      implants may be increasingly used in the future, but it seems likely that sign
      language will continue to be a dominant feature in the deaf culture.

PMID- 15030902
TI  - Unilateral closed-lip schizencephaly and epilepsy: a comparison with cases of
      unilateral polymicrogyria.
AB  - We compared the electroclinical features and evolution of patients with two
      different types of abnormal cortical organization: unilateral closed-lip
      schizencephaly (SCHZ) and unilateral polymicrogyria (PMG). Between February 1990
      and June 2002, 51 children with either unilateral PMG or closed-lip SCHZ were
      selected through neuroradiological analysis for investigation at our service. We
      evaluated the frequency of epilepsy, electroclinical features and evolution. The
      mean time of follow-up was 7 years (range 1-12 years). All patients underwent
      neurological examination, computed tomography scan and magnetic resonance
      imaging, serial electroencephalographic (EEG) recordings and neuropsychological
      assessment. Thirty-six of the 51 patients had unilateral PMG. All patients had
      hemiparesis with mild spasticity. Mental retardation was mild in 20 and moderate
      in 14. In two patients IQ was normal. Partial motor seizures were recorded in 28
      patients, with secondary generalization in 20. The median age at onset of
      seizures was 2 years (range 4 months-7 years). Interictal EEGs showed unilateral
      spikes in all patients. In 21 patients epilepsy worsened between the ages of 4
      and 8 (mean 5.6 years) with frequent atonic seizures, atypical absences,
      epileptic negative myoclonus and gait difficulties. EEGs showed continuous spike
      wave activity or bilateral high-frequency spike discharges during slow-wave
      sleep. Frequent relapses of atonic and myoclonic seizures were seen in nine
      patients. At present, 16 patients are seizure-free. Fifteen patients with
      unilateral SCHZ were included in the study. Focal motor seizures were registered
      in seven cases, in three of them with secondary generalization. The median age at
      onset of epilepsy was 2.5 years (range 1-4 years). Interictal EEGs showed
      unilateral spikes in these seven cases. All patients except one presented mild
      spastic hemiparesis. Mental retardation was mild in ten children, moderate in two
      and IQ was normal in three. Although the underlying mechanisms leading to PMG and
      SCHZ are probably similar, the electroclinical phenomenon of secondary bilateral
      synchrony with frequent negative myoclonus was not present in our cases with
      unilateral closed-lip SCHZ.

PMID- 15030903
TI  - Vagus nerve stimulation for drug-resistant epilepsy in children and young adults.
AB  - We present our experience with the use of intermittent vagal nerve stimulation in
      13 patients with medically intractable epilepsy. A surgical approach, with the
      exception of callosotomy, was impossible. The age range was 6-28 years (median 17
      years). In all patients the epilepsy was severe and in six of them was
      symptomatic. Seven patients had Lennox-Gastaut syndrome, one epilepsy with
      myoclonic-astatic seizures, four localization-related and one symptomatic
      generalized epilepsy. The length of the follow-up averaged 22 months (range 8
      months-3 years). Of the 13 patients, five (38.4%) had a 50% or more reduction in
      the number of seizures compared with preimplantation. Of these patients, one with
      a localization-related epilepsy had a 90% reduction as well as a significant
      improvement in alertness. Three patients showed no improvement with regard to the
      number of seizures but there was an improvement in alertness and, in one case in
      hyperactivity. Some seizure types responded better than others did: complex
      partial seizures with secondary generalization and atonic seizures. All our
      responsive patients improved in the first 2 months of VNS activation and only one
      case with further improvement was observed after this period. Considering the
      severity of the epilepsy the results can be considered satisfactory. We think
      that this treatment appears to be a safe adjunctive therapy for children and
      adults with medically and surgically intractable epilepsy.

PMID- 15030904
TI  - Efficacy of antiepileptic drugs in patients with benign convulsions with mild
      gastroenteritis.
AB  - The aim of this study was to clarify the efficacy of antiepileptic drugs during a
      cluster of seizures in patients with convulsions with mild gastroenteritis (CwG).
      We retrospectively investigated the details of antiepileptic treatment in 110
      consecutive episodes in 103 patients with CwG. The temporal course of the
      seizures and the use of antiepileptic drugs were investigated in each episode.
      Drugs were judged as effective when seizure cessation was achieved after
      administration of the drug. As the first drug, diazepam (DZP)/bromazepam (BZP)
      was effective in 38%, phenobarbital (PB) in 40%, and lidocaine (LD) in 100%. As
      the second drug, DZP/BZP was effective in 42%, PB in 69%, and LD in 100%. As the
      third drug, PB was effective in 70%. When the efficacy of the first doses of PB
      and LD were compared, the efficacy rate was significantly higher for LD than for
      PB (P = 0.047). In conclusion, LD was effective for the cessation of seizures in
      patients with CwG.

PMID- 15030905
TI  - Bacterial meningitis in infants: the epidemiology, clinical features, and
      prognostic factors.
AB  - This 16-year (1986-2001) retrospective study enrolled 80 infantile patients
      (aged, 30-365 days old) with culture-proven bacterial meningitis. The most
      prevalent pathogens were Salmonellaspecies, Streptococcus (S.) agalactiae,
      Escherichia (E.) coli, and Haemophilus (H.) influenzae, accounting for about 59%
      of the episodes. Meningitis caused by Salmonella species, E. coli and H.
      influenzae occurs more often in the older infants, while that caused by S.
      agalactiae occurs more often in young infants. Our study revealed a decrease in
      the proportion of Salmonella meningitis from 27% in the first 8 years to 9% in
      the second 8 years with E. coli replacing Salmonella species as the leading
      pathogen of this disease during the second period. Overall mortality rate for
      both periods of time was 11%. However, if we take those with undesirable poor
      outcomes into account, 43% of patients could be considered treatment failures.
      The study also reveals a high prevalence of neurological complications when this
      disease is caused by H. influenzae, S. pneumoniae, and Salmonella species.
      Stepwise logistic regression analysis revealed that only initial changing levels
      of consciousness (P = 0.006) were independently associated with treatment
      failure. The most frequent neurological complications associated with this
      disease included subdural empyema, hydrocephalus, cerebral infarctions, and
      seizures. Because therapeutic regimens may require attention to the eradication
      of bacterial pathogen but also the neurological complications, early diagnosis
      and choice of appropriate antibiotics are essential to increasing the possibility
      of survival.

PMID- 15030906
TI  - Hypothermia during kainic acid-induced seizures reduces hippocampal lesions and
      cerebral nitric oxide production in immature rabbits.
AB  - We investigated (1) whether cerebral hypothermia during kainic acid (KA)-induced
      seizures was neuroprotective; and (2) whether nitric oxide (NO) production in the
      brain during seizures was altered by cerebral hypothermia in immature rabbits.
      Twelve female rabbits, aged 2 weeks, were anesthetized, paralyzed and
      mechanically ventilated. We continuously measured NO production in the brain by
      NO-selective electrode, cortical electroencephalogram (EEG), regional cerebral
      blood flow (rCBF) by laser Doppler flowmetry, rectal and cerebral temperatures
      and mean arterial blood pressure (MABP) during KA (12 mg/kg, i.v.)-induced
      seizures in the hypothermic group (n = 6; rectal temperature, 33 degrees C), and
      in the normothermic group (n = 6; rectal temperature, 37 degrees C). The
      normothermic group showed a gradual increase in NO generation in the brain, which
      was significantly inhibited in the hypothermic group. There were no significant
      differences in the increases in rCBF, MABP, arterial blood gases, blood glucose,
      or EEG abnormalities between the two groups. Neuronal damages in the hippocampus
      (CA3) were significantly lower in hypothermia than in normothermia. These results
      suggest that hypothermia attenuates NO production during drug-induced seizures
      and decreases hippocampal brain lesions in the immature rabbit brain. These
      results may help to explain the neuroprotective effects of hypothermia.

PMID- 15030907
TI  - Clinical investigation of genetic contributions to childhood-onset epilepsies and
      epileptic syndromes.
AB  - Although there have been major advances in the understanding of the molecular
      bases of certain inherited epilepsy syndromes, clinical studies are still needed
      to verify the possible genetic contributions to common epilepsies. We examined
      the proportions of positive family histories of epilepsy (within second-degree
      relatives) and consanguinity (within first-degree relatives) in 311 probands with
      childhood-onset epilepsy, and found that they had high family history rates of
      epilepsy (19.3%) and consanguinity (6.1%). A positive family history of epilepsy
      was found more in probands with generalized epilepsy than in ones with
      localization-related epilepsy, and more in probands with idiopathic/cryptogenic
      epilepsy than in ones with symptomatic epilepsy. However, on analysis after the
      symptomatic epilepsies had been divided into two categories, probands with pre-
      or perinatal symptomatic generalized epilepsy and ones with postnatal symptomatic
      localization-related epilepsy showed high positive family history rates, similar
      to ones with idiopathic/cryptogenic epilepsy. On the other hand, a positive
      family history of consanguinity was noted more in probands with generalized
      epilepsy than in ones with localization-related epilepsy, but there was no
      significant difference between probands with idiopathic/cryptogenic epilepsy and
      ones with symptomatic epilepsy. These findings suggest that in addition to the
      hereditary effect on idiopathic/cryptogenic epilepsy, a genetic susceptibility
      may contribute to the development of pre- or perinatal symptomatic generalized
      epilepsy, and to that of postnatal symptomatic localization-related epilepsy.
      Furthermore, a genetic predisposition seems to have an influence through
      consanguinity on the etiologies of both idiopathic/cryptogenic and symptomatic
      generalized epilepsies.

PMID- 15030909
TI  - Influence of the state of alertness on the pattern visual evoked potentials
      (PVEP) in very young infant.
AB  - The aim of the study was to evaluate the pattern visual evoked potentials (PVEP)
      combined with an optimal state of vigilance, called liberated state (LS), in
      order to improve testing in very young infants. Transient PVEP were recorded in
      response to a checkerboard pattern of 120, 60 and 30 min of arc. in 56 fullterm
      newborns and 79 preterm infants from birth to 4 months of age. In the fullterms,
      28 infants in each group were tested in LS or spontaneous alertness (SA) while in
      the preterms, 48 infants in each group were tested in LS or SA. No significant
      difference was found in the amplitude and/or peak time of the PVEP responses
      between subjects tested in LS compared to SA groups. However, the LS condition
      improved by approximately 25% the feasibility of prolonged PVEP testing in
      preterms aged less than 2 months (corrected age). This suggest that the LS
      condition enhances the clinical feasibility of PVEP testing in very young infants
      and should be used to optimize the evaluation of visual development in high risk
      infants in this age group.

PMID- 15030908
TI  - Over-expression of S100B protein in children with cerebral palsy or delayed
      development.
AB  - S100B protein plays a role in promoting the maturation of a variety of neurons in
      many different CNS regions. Behavioral dysfunction in S100B over-expressed
      transgenic mice and the chronic elevation of S100B in Down's syndrome and in
      schizophrenia suggest that S100B over-expression is related to abnormal brain
      function. Therefore, we believed that the over-expression of S100B protein might
      be implicated in developmental brain dysfunction. The purpose of this study was
      to evaluate the serum S100B protein levels in patients with developmental brain
      dysfunction, such as cerebral palsy and delayed development, and to determine the
      clinical relevance of serum S100B protein in these patients. The mean values of
      serum S100B protein were significantly increased in both conditions. Patients
      with cerebral palsy had a S100B protein level of 3455.8 +/- 5004.6 ng/L and those
      with delayed development of 2557.0 +/- 2321.0 ng/L, compared with a normal
      control level of 583.8 +/- 483.0 ng/L (P < 0.05). The over-expression of S100B
      (defined as the normal mean plus three standard deviations) was found in 47.1% of
      the total patient group (delayed development (47.5%) and cerebral palsy (47.0%)).
      The frequency of over-expression was not significantly related to clinical
      diagnosis, disease severity or to brain MRI findings. However, patients who had
      periventricular leukomalacia by brain MRI showed a wide range and very high
      levels of S100B exceeding 10,000 ng/L in some cases. These findings suggest that
      the pathogenesis implied by the over-expression of S100B protein during brain
      development may play a role in developmental brain dysfunction.

PMID- 15030910
TI  - Wolf-Hirschhorn syndrome with posterior intraorbital coloboma cyst: an unusual
      case.
AB  - Wolf-Hirschhorn syndrome (WHS) is associated with partial deletion of short arm
      of chromosome 4, and characterized by severe growth retardation. Other
      characteristic features are microcephaly, intellectual handicap, Greek helmet
      facies and closure deficits such as cleft lip or cleft palate, coloboma of the
      eye, and cardiac septal defect. We herein present a new case of WHS with
      bilateral iris colobomata and a left intraorbital large coloboma cyst causing
      exophthalmos.

PMID- 15030911
TI  - A case of infantile Alexander disease with a milder phenotype and a novel GFAP
      mutation, L90P.
AB  - Alexander disease is a leukoencephalopathy that usually presents during infancy
      with developmental delay, macrocephaly and seizures. Several sequencing analyses
      have identified mutations in the gene encoding glial fibrillary acidic protein
      (GFAP) of patients with Alexander disease. We described a girl who developed
      seizures in infancy with atypical CT findings and in whom a novel heterozygous
      mutation, L90P (283T --> C), was detected in exon 1 of the GFAP gene. The
      neurological deterioration was mild and appeared relatively late for infantile
      onset.

PMID- 15030912
TI  - Another case of cerebro-facio-thoracic dysplasia (Pascual-Castroviejo syndrome).
AB  - We report another case of cerebro-facio-thoracic dysplasia (Pascual-Castroviejo
      syndrome) characterized by mental retardation and characteristic facies: narrow
      forehead, synophris, hypertelorism, broad nasal bridge, long philtrum,
      micrognathia, triangular-shaped mouth and low posterior hairline, and also
      brachycephaly, calcified clinoid ligaments, and upper rib deformities. Although
      the severity of mental retardation within the syndrome varies, the reported case
      shows not only a severe degree, but also cerebral malformations not reported in
      any of the previous cases of cerebro-facio-thoracic syndrome. These include
      cortical-subcortical atrophy with hypoplasia of the corpus callosum, and of the
      cerebellar vermis. We also discuss the inheritance pattern and differential
      diagnosis, comparing this phenotype to other similar dysmorphic syndromes.

PMID- 15030913
TI  - The new European legislation on traditional herbal medicines: main features and
      perspectives.
AB  - Under the Italian Presidency of the Council of the European Union (July 2003
      December 2003) an agreement has been reached by the European Parliament and the
      Council on the approval of the proposal of Directive of the European Parliament
      and the Council amending the Directive 2001/83/EC as regards traditional herbal
      medicinal products. Once implemented in the E.U. Member States, this new
      Directive will remove the constraints that have made it difficult granting
      marketing authorisations of herbal substances and preparations as traditional
      medicinal products under the pre-existing Community legislation. The main
      features (i.e. traditional herbal medicine definition, simplified registration
      procedure, provisions for Community herbal monographs and Community list of
      herbal substances and preparations and establishment of the Committee for Herbal
      Medicinal Products) of this new Community legislation are analysed and discussed
      in the present paper together with some expected positive public health impacts.

PMID- 15030914
TI  - A novel furostanol saponin from Tribulus terrestris of Bulgarian origin.
AB  - The phytochemical investigation of the aerial parts of Tribulus terrestris of
      Bulgarian origin has resulted in the isolation of the novel furostanol saponin 1,
      named tribol, together with the known spirostanol saponins 2 and 3 and sitosterol
      glucoside. The structure of tribol was determined as (25R)-furost-5(6)-ene
      3beta,16,26-triol-3-O-alpha-rhamnopyranosyl-(1-->2)-[alpha-rhamnopyranosyl-(1-
      >4)]-beta-glucopyranoside (1) by spectral analysis, including extensive 1D and 2D
      NMR experiments.

PMID- 15030915
TI  - Anti-inflammatory and analgesic activity of the topical preparation of Glaucium
      grandiflorum.
AB  - The species of Glaucium have been used in Iranian herbal medicine in the
      treatment of dermatitis. Due to anti-inflammatory and analgesic activity of
      Glaucium grandiflorum methanolic extract in i.p. administration, these effects in
      topical administration were studied using carrageenan-induced edema and formalin
      test. Several formulations were prepared and the best cream was chosen as
      vehicle. Piroxicam gel and methyl salicylate ointment were studied as positive
      control for anti-inflammatory and analgesic activity, respectively. The edema
      inhibition of preparations containing extract at the doses of 1-5% w/w were
      significantly different from control group. The anti-inflammatory effect of MS4
      5% was similar to the effect of piroxicam gel at 3 h after carrageenan injection.
      Topical preparation containing G. grandiflorum methanolic extract showed
      analgesic effect in concentrations more than 4% w/w in early phase in formalin
      test. This activity was observed in concentrations more than 3% w/w in late
      phase. The topical analgesic activity of extract was less than the analgesic
      activity of methyl salicylate ointment.

PMID- 15030916
TI  - E-octadec-7-en-5-ynoic acid from the roots of Capparis zeylanica.
AB  - A new fatty acid, E-octadec-7-en-5-ynoic acid (1), has been isolated from
      chloroform extract of the roots of Capparis zeylanica. The structure of this
      compound was established primarily by 1D and 2D-NMR spectroscopy.

PMID- 15030917
TI  - Two new cytotoxic isoprenylated flavones, artoindonesianins U and V, from the
      heartwood of Artocarpus champeden.
AB  - Two new isoprenylated flavones, artoindonesianins U (1) and V (2), have been
      isolated from the heartwood of Artocarpus champeden together with three known
      isoprenylated flavonoids, 5'-hydroxycudraflavone A, cyclocommunin and artonin B.
      The structures of the new flavones were elucidated on the basis of spectroscopic
      evidence. Both compounds 1 and 2 showed strong cytotoxic activity against P-388
      cell lines.

PMID- 15030918
TI  - Effects of methanolic extract and fractions from Litsea cubeba bark on the
      production of inflammatory mediators in RAW264.7 cells.
AB  - Both the methanolic extract and its fractions (0.01 mg/ml) from Litsea cubeba
      bark were found to inhibit NO and PGE2 production in LPS-activated RAW264.7
      macrophages without significant cytotoxicity at less than 0.01 mg/ml
      concentration. Moreover, L. cubeba bark extract and its fractions significantly
      decreased the activity of myeloperoxidase catalyzing oxidation of chloride to
      HOCl and O2- production was reduced by methanol extract (0.05 mg/ml), chloroform
      fraction (0.025-0.05 mg/ml) and butanol fraction (0.005 mg/ml). These findings
      suggest that L. cubeba is beneficial for inflammatory conditions and may contain
      compound(s) with anti-inflammatory properties.

PMID- 15030919
TI  - Medicinal plant diversity in the flora of Saudi Arabia 1: a report on seven plant
      families.
AB  - A preliminary survey on the medicinal plant diversity in the flora of the Kingdom
      of Saudi Arabia has been made with seven families: Amaranthaceae, Apocynaceae,
      Capparidaceae, Euphorbiaceae, Labiatae, Polygonaceae and Solanaceae, as an
      initial study. These families are represented in the flora with 254 species (i.e.
      12% of the total species), and individually with 21, 7, 29, 66, 76, 22 and 33
      species, respectively. Of these, 86 species, so far investigated, are medicinal,
      distributed in these seven families as follows: 7, 5, 12, 20, 23, 7 and 12,
      respectively. The Labiatae have the highest number (23) of medicinal plants among
      them while maximum medicinal plant diversity within the family has been observed
      with the Apocynaceae. An enumeration of these 86 medicinal species is presented
      with the current nomenclature, Arabic names and medicinal uses. This
      communication aims at emphasizing the importance of setting up conservation
      priorities, and sustained development of various medicinal plants of Saudi
      Arabia.

PMID- 15030920
TI  - Monitoring the antioxidant activity of extracts originated from various Serratula
      species and isolation of flavonoids from Serratula coronata.
AB  - The antioxidant effect of aqueous methanolic herb extracts of Serratula coronata,
      S. wolffii and S. tinctoria was investigated using both enzyme-dependent and
      enzyme-independent systems. The extracts displayed concentration-dependent
      inhibition of lipid peroxidation. Flavonoids and ecdysteroids present in the
      extracts were evaluated as antioxidant components. The flavonoid-containing
      fraction of the herb extract of S. coronata was more effective in lipid
      peroxidation than the ecdysteroid-containing fraction. This paper also reports
      the isolation of quercetin 3-O-methyl ether, apigenin, luteolin, quercetin,
      luteolin 4'beta-D-glucoside and quercetin 4'beta-D-glucoside from S. coronata.

PMID- 15030921
TI  - Extraction and characterization of volatile compounds in Maytenus ilicifolia,
      using high-pressure CO2.
AB  - This work is focused on the chemical characterization of Maytenus ilicifolia
      extracts obtained from high-pressure CO2 extraction. The experiments were
      performed in a laboratory-scale unit, where the effect of particle size (35-200
      mesh), CO2 mass flow rate (1-3 g/min), temperature (293-323 K), pressure (100-250
      bar), and extraction time was investigated in terms of liquid yield and chemical
      composition of the extracts. Results show that the particle size and CO2 mass
      flow rate did not affect the liquid yield, whereas the extraction temperature and
      solvent density exerted a pronounced effect on both liquid yield and chemical
      distribution of volatile compounds. The extracts were chemically analyzed with
      regard to phytol, squalene, vitamin E, stigmasterol, friedelan-3-ol, friedelin,
      dodecanoic acid and geranyl acetate in a GC/MSD.

PMID- 15030922
TI  - Dual inhibition of cyclooxygenase-1 and 5-lipoxygenase by aerial part of
      Bupleurum fruticescens methanol extract.
AB  - The effect of the methanol extract from aerial parts of Bupleurum fruticescens on
      the release of eicosanoids and hydrolytic enzymes was determined on in vitro cell
      systems. The extract had a significant effect on 5-lipoxygenase (5-LOX) activity,
      inhibiting both LTB4 and 5(S)-HETE production with IC50 values of 112 microg/ml
      and 95 microg/ml, respectively. At concentrations of 200 microg/ml, the extract
      also inhibited cyclooxygenase-1 (90%) and elastase activities (54%). The 12-LOX
      activity in intact platelets was not affected; a fact, which suggests that
      phospholipase A2 (PLA2) activity, is not modified by the extract.

PMID- 15030923
TI  - Effect of an integral suspension of Lepidium latifolium on prostate hyperplasia
      in rats.
AB  - This paper studies the effect of an integral suspension of Lepidium latifolium on
      experimental induced prostate hyperplasia, in rats. Oral treatment with 0.86 mg
      kg(-1) day(-1) for 6 months, significantly reduced prostate size and volume in
      castrated rats where the hyperplasia were induced by steroid treatment.

PMID- 15030924
TI  - Antimicrobial activity of Artemisia douglasiana leaf essential oil.
AB  - Artemisia douglasiana leaf has been shown to be efficacious complementary herbal
      treatment for chronic bladder infection in a paraplegic youth. The leaf oil has
      been analyzed by GC-MS and the major components found to be camphor (29%),
      artemisia ketone (26%), artemisia alcohol (13%), alpha-thujone (10%), 1,8-cineole
      (8%), and hexanal (5%). The leaf oil and the major components have been tested
      for antimicrobial activity against Bacillus cereus, Staphylococcus aureus,
      Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Aspergillus
      niger. The essential oil shows limited antimicrobial activity in vitro, so it is
      unclear if the oil exerts a direct antimicrobial effect in vivo, or plays some
      role in stimulation of host defenses.

PMID- 15030925
TI  - Antimicrobial activity of four Artemisia species of Iran.
AB  - The antimicrobial activities of methanol extracts of four species of Artemisia
      species of Iran are reported.

PMID- 15030926
TI  - Antibacterial activities of some constituents from oleo-gum-resin of Commiphora
      mukul.
AB  - The essential oil, chloroform extract and seven sesquiterpenoids compounds newly
      isolated from the oleo-gum-resin of Commiphora mukul showed a wide range of
      inhibiting activity against both Gram (+) and Gram (-) bacteria.

PMID- 15030927
TI  - Antioxidative and EROD activities of osajin and pomiferin.
AB  - The major constituents of fruits of Maclura pomifera are the prenylated
      isoflavones, osajin (1) and pomiferin (2). Since significant biological
      activities of extracts from the wood of M. pomifera were previously reported, the
      peroxynitrite scavenging activity, inhibition of lipid peroxidation, scavenging
      of DPPH and EROD activity of these two major substances were studied.

PMID- 15030929
TI  - Antinociceptive effects of hydroalcoholic extract and essential oil of Zataria
      multiflora.
AB  - Antinociceptive effect of hydroalcoholic extract and essential oil of Zataria
      multiflora was studied using writhing, tail flick and formalin tests. In tail
      flick test, the hydroalcholic extract (500 mg/kg, i.p.) and the essential oil
      (0.3 ml/kg, i.p.) of the plant showed antinociceptive activity (P<0.05).
      Moreover, they showed antinociceptive activity in writhing and formalin tests.

PMID- 15030928
TI  - Chemical and biological diversity of Bergamot (Citrus bergamia) in relation to
      environmental factors.
AB  - Oil of bergamot is receiving renewed popularity in aromatherapy. The
      biovariability of Citrus bergamia grown wild in Calabria (Italy) was investigated
      as far as chemical markers (linalool, linalyl acetate and bergapten) content and
      antioxidant and antifungal activities of the methanolic extracts. The average
      content in the markers presents slight variations with the altitude and more
      evident changes with the latitude of the areas of plant collection.

PMID- 15030930
TI  - Antioxidant activity of Citrus paradisi seeds glyceric extract.
AB  - The antioxidant activity of Citrus paradisi (grapefruit) seeds glyceric extract
      dissolved in ethanol and in aqueous media was evaluated using three different
      methods: evaluation by DPPH assay, by 5-lipoxygenase assay and by
      luminol/xanthine/xanthine oxidase chemiluminescence assay. The total phenolic
      content was determined by the Prussian Blue method opportunely modified. The
      grapefruit seeds glyceric extract utilized as aqueous solutions demonstrated
      antioxidant properties better than those displayed by alcoholic solutions.

PMID- 15030931
TI  - Cytotoxic activity of five compounds isolated from Colombian plants.
AB  - Cytotoxic effect of five known compounds, khellin, berberine, lupeol, scopolin,
      rapanone, obtained from Colombian plants, were determined against human tumor
      cell lines as an indicator of the potential anticancer activity of these
      compounds. Berberine and rapanone presented interesting cytotoxicity.

PMID- 15030932
TI  - Antibacterial compounds from the seeds of Psoralea corylifolia.
AB  - Psoralidin, bakuchicin, psoralin and angelicin, isolated from the seeds of
      Psoralea corylifolia, showed significant antibacterial activities against a
      number of Gram (+) and Gram (-) bacteria.

PMID- 15030933
TI  - Antibacterial screening of plants used in Iranian folkloric medicine.
AB  - Fifty methanolic plant extracts belonging to 44 plant species of 33 families
      finding use in Iranian folkloric medicine were screened for antibacterial
      activity. Thirty samples, including 28 species in 20 families, had antibacterial
      activity against at least on one of the bacteria. Among the active plants, 32.6%
      were active against G(-), 62% against G(+), and 47.3% against both G(-) and G(+)
      bacteria. Dianthus coryophyllus was active against all tested G(-) and G(+)
      bacteria except Micrococcus luteus. Most susceptible G(-) bacteria were
      Klebsiella pneumoniae and Bordetella bronchiseptica and least susceptible G(-)
      bacterium was Escherichia coli. In G(+) bacteria, most and least susceptible were
      Staphylococcus aureus and M. luteus, respectively. The least MIC, as 0.62 mg/ml,
      belonged to Myrtus communis seeds against S. aureus, Bacillus cereus and B.
      bronchiseptica, and to Terminalia chebula ripe seeds against S. aureus.

PMID- 15030934
TI  - Eudesmane sesquiterpene glycosides from Parepigynum funingense.
AB  - A new eudesmane sesquiterpene glycoside, pterodontriol D-6-O-beta-D
      glucopyranoside (1), together with a known compound, ainsliaside E (2), was
      isolated from the roots of Parepigynum funingense. The structure of 1 was
      determined by 1D and 2D-NMR spectroscopy. Compound 2 was isolated from this plant
      for the first time.

PMID- 15030935
TI  - A new oxoaporphine alkaloid from Sinofranchetia chinensis.
AB  - A new oxoaporphine alkaloid, sinofranine, was isolated from the stem of
      Sinofranchetia chinensis. The structure of the new alkaloid was elucidated by a
      combination of spectral methods (IR, MS, 1H and 13C-NMR, NOED and COSY).

PMID- 15030936
TI  - A new coumarin glucoside, coumarins and alkaloids from Ruta corsica roots.
AB  - A new coumarin glucoside, 3'(S)-hydroxy-2',2'-dimethyl-dihydropyranocoumarin-8
      beta-d-glucopyranosyl, one coumarin, five furanocoumarins, three bicoumarins,
      three quinoline alkaloids and one sinapoyl sucrose derivative have been isolated
      from the roots of Ruta corsica.

PMID- 15030937
TI  - Central pain: distributed effects of focal lesionsSee related article, by Willoch
      et al., in this issue.

PMID- 15030938
TI  - Toward an integrated model of pain over the life course.

PMID- 15030939
TI  - Communicating the experience of pain: the role of analogy.

PMID- 15030940
TI  - Central poststroke pain and reduced opioid receptor binding within pain
      processing circuitries: a [11C]diprenorphine PET study.
AB  - Based on concepts that endogenous opioids participate in neural transmission of
      pain, the present study in central poststroke pain (CPSP) patients investigated
      changes in opioid receptor (OR) binding in neural structures centrally involved
      in the processing of pain. Five patients with central pain after lesions in the
      brain stem, thalamus or parietal cortex and twelve healthy volunteers underwent a
      [11C]diprenorphine positron emission tomography study. Binding potentials were
      calculated using a reference region model in all subjects. Statistical parametric
      mapping was applied for t-statistical analysis on voxel-basis. Binding potential
      values for each individual were extracted from a volume of interest at each
      identified significant peak. Spectral analysis was applied for quantification of
      global values. Significant regional reduced 11C-diprenorphine binding (corrected
      for multiple tests) was detected in contralateral thalamus, parietal, secondary
      somatosensory, insular and lateral prefrontal cortices, and along the midline in
      anterior cingulate, posterior cingulate and midbrain gray matter. Individual
      extracted binding values disclosed a reduced binding in these regions in all
      patients independent from the particular lesion site. The poststroke pain
      syndrome is associated with a characteristic pattern of reduced OR binding within
      the neural circuitry processing pain. It is suggested that an imbalance of
      excitatory-inhibitory mechanisms in certain brain structures, as evidenced in
      decreased [11C]diprenorphine binding, is one of the causes or the consequences of
      poststroke pain.

PMID- 15030941
TI  - Adolescent chronic pain: patterns and predictors of emotional distress in
      adolescents with chronic pain and their parents.
AB  - Adolescents with chronic pain also report severe disability and emotional
      distress. A clinical sample of 80 adolescents and accompanying parents were
      investigated to first measure the extent of distress, and second to investigate
      the relationships between adolescent distress, parental distress and adolescent
      coping. Measures of pain intensity, anxiety, depression, disability and coping
      were obtained from adolescents. Parents completed measures including their own
      anxiety, depression and parenting stress. Overall, adolescents reported high
      levels of disability, depression and anxiety, and parents reported high levels of
      depression, anxiety and parenting stress. Multiple regression analyses revealed
      that the best predictors of adolescent emotional distress were the extent to
      which the adolescents catastrophize and seek social support to cope with the
      pain. There were no clear predictors of parental anxiety or depression but the
      specific pattern of parenting stress was best predicted by the younger age of the
      adolescent, the greater the chronicity of the problem, and the greater the extent
      of adolescent depression. These findings suggest that emotional coping is a
      critical variable in the distress associated with adolescent chronic pain. It is
      argued that adolescent emotional coping may best be understood within a
      relational context of seeking emotional support.

PMID- 15030942
TI  - Sex differences in pain perception and anxiety. A psychophysical study with
      topical capsaicin.
AB  - Much evidence indicates that women experience painful stimuli as more intense
      than men do. Nevertheless, some data suggest that sustained low-level pain may be
      more disturbing to men than to women. The current experiment evaluated the
      hypothesis that pain is more disturbing for men than for women by comparing
      across genders sensory and emotional aspects of pain evoked by capsaicin. Ten men
      and 10 women (aged 20-46 years) received topical capsaicin for 30 min on the face
      in one session and on the ankle in another. The subjects rated on visual analog
      scales pain intensity, unpleasantness and anxiety each minute during capsaicin
      application and for 30 min after its removal. During capsaicin application,
      females rated both pain intensity (P = 0.04) and unpleasantness (P = 0.05) higher
      than did males. Further, subjects rated pain intensity and unpleasantness higher
      on the face than on the ankle, although the physical stimulus was the same.
      Despite their lower pain ratings, men reported more pain-related anxiety than
      women (P = 0.02) Moreover, men showed a significant positive correlation between
      anxiety and pain intensity and unpleasantness, whereas women did not. After
      removing the capsaicin, there was no overall effect of sex on either intensity (P
      = 0.18) or unpleasantness (P = 0.37) of the residual sensation. However, men
      still showed a positive correlation between anxiety and the intensity and
      unpleasantness of the sensation. Our data confirm with the topical capsaicin
      model that women rate pain higher than men, but despite their lower pain ratings,
      males have more anxiety related to pain.

PMID- 15030943
TI  - Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal
      root ganglia neurons in inflammatory pain.
AB  - Nociceptive neurons within dorsal root ganglia (DRG) express multiple voltage
      gated sodium channels, of which the tetrodotoxin-resistant (TTX-R) channel
      Na(v)1.8 has been suggested to play a major role in inflammatory pain. Previous
      work has shown that acute administration of inflammatory mediators, including
      prostaglandin E2 (PGE2), serotonin, and adenosine, modulates TTX-R current in DRG
      neurons, producing increased current amplitude and a hyperpolarizing shift of its
      activation curve. In addition, 4 days following injection of carrageenan into the
      hind paw, an established model of inflammatory pain, Na(v)1.8 mRNA and slowly
      inactivating TTX-R current are increased in DRG neurons projecting to the
      affected paw. In the present study, the expression of sodium channels Na(v)1.1
      Na(v)1.9 in small (< or = 25 micromdiameter) DRG neurons was examined with in
      situ hybridization, immunocytochemistry, Western blot and whole-cell patch-clamp
      methods following carrageenan injection into the peripheral projection fields of
      these cells. The results demonstrate that, following carrageenan injection, there
      is increased expression of TTX-S channels Na(v)1.3 and Na(v)1.7 and a parallel
      increase in TTX-S currents. The previously reported upregulation of Na(v)1.8 and
      slowly-inactivating TTX-R current is not accompanied by upregulation of mRNA or
      protein for Na(v)1.9, an additional TTX-R channel that is expressed in some DRG
      neurons. These observations demonstrate that chronic inflammation results in an
      upregulation in the expression of both TTX-S and TTX-R sodium channels, and
      suggest that TTX-S sodium channels may also contribute, at least in part, to pain
      associated with inflammation.

PMID- 15030944
TI  - Development and validation of the Neuropathic Pain Symptom Inventory.
AB  - This study describes the development and validation of the Neuropathic Pain
      Symptom Inventory (NPSI), a new self-questionnaire specifically designed to
      evaluate the different symptoms of neuropathic pain. Following a development
      phase and a pilot study, we generated a list of descriptors reflecting
      spontaneous ongoing or paroxysmal pain, evoked pain (i.e. mechanical and thermal
      allodynia/hyperalgesia) and dysesthesia/paresthesia. Each of these items was
      quantified on a (0-10) numerical scale. The validation procedure was performed in
      176 consecutive patients with neuropathic pain of peripheral (n = 120) or central
      (n = 56) origin, recruited in five pain centers in France and Belgium. It
      included: (i) assessment of the test-retest reliability of each item, (ii)
      determination of the factorial structure of the questionnaire and analysis of
      convergent and divergent validities (i.e. construct validity), and (iii)
      evaluation of the ability of the NPSI to detect the effects of treatment (i.e.
      sensitivity to change). The final version of the NPSI includes 10 descriptors
      (plus two temporal items) that allow discrimination and quantification of five
      distinct clinically relevant dimensions of neuropathic pain syndromes and that
      are sensitive to treatment. The psychometric properties of the NPSI suggest that
      it might be used to characterize subgroups of neuropathic pain patients and
      verify whether they respond differentially to various pharmacological agents or
      other therapeutic interventions.

PMID- 15030945
TI  - Contribution of sensitized P2X receptors in inflamed tissue to the mechanical
      hypersensitivity revealed by phosphorylated ERK in DRG neurons.
AB  - The mechanism of mechanical hyperalgesia in inflammation might involve a
      'mechanochemical' process whereby stretch evokes the release of adenosine 5'
      triphosphate (ATP) from the damaged tissue that then excites nearby primary
      sensory nerve terminals. In the present study, phosphorylated extracellular
      signal-regulated protein kinase (pERK) immunoreactivity was used as a marker
      indicating functional activation of primary afferent neurons to examine the P2X
      receptor-mediated noxious response in DRG neurons in a rat model of peripheral
      inflammation. We found that very few pERK-labeled DRG neurons were detected in
      normal rats after alpha, beta methylene-ATP (alphabetame-ATP) intraplantar
      injection. However, a number of DRG neurons were labeled for pERK after
      alphabetame-ATP injection to the complete Freund's adjuvant (CFA) induced
      inflamed paw. Seventy-three percent of pERK-labeled DRG neurons co-expressed the
      P2X3 receptor. After mechanical noxious stimulation to the hind paw of CFA
      inflamed rats, we found many more pERK-labeled neurons compared to those in the
      normal rats. Administration of the P2X3 receptor antagonists, pyridoxalphosphate
      6-azophenyl-2',4'-disulfonic acid or 2'- (or 3')-O-(trinitrophenyl)adenosine 5'
      triphosphate (TNP-ATP), significantly decreased the mechanical stimulation-evoked
      pERK labeling in CFA-inflamed rats, but not in normal rats. We also found the
      recruitment of neurons with myelinated A fibers labeled for pERK in CFA-inflamed
      rats, which was reversed by P2X3 receptor antagonists. Moreover, TNP-ATP dose
      dependently reduced the mechanical hypersensitivity of CFA rats. These data
      suggest that the P2X receptors in primary afferent neurons increase their
      activity with enhanced sensitivity of the intracellular ERK signaling pathway
      during inflammation and then contribute to the hypersensitivity to mechanical
      noxious stimulation in the inflammatory state.

PMID- 15030946
TI  - Pattern-reversal visual-evoked potentials in children with migraine and other
      primary headache: evidence for maturation disorder?
AB  - Recently, evidence for a disturbed maturation of cerebral information processing
      in migraine came from studies investigating the auditory-evoked contingent
      negative variation and the auditory-evoked potential from childhood to adulthood.
      This study is to clarify whether age-dependent development is altered also for
      the processing of visual stimuli in migraine. Components of pattern-reversal
      visual-evoked potentials at four different spatial frequencies (which can
      preferentially activate the magno- and the parvocellular visual system) were
      compared between children aged 6 and 18 years with primary headache (N = 123; 67
      migraine without aura, MO; 32 migraine with aura, MA; 24 tension-type headache,
      TH) in the headache-free interval and healthy controls (N = 82). Children were
      divided into two age groups: 6-11 years (pre- and early puberty) and 12-18 years
      (late and post-puberty). Age-dependent development was normal for N80 and P100
      latency in children with primary headache, but altered for N135 latency as
      indicated by a significant interaction among the factors diagnosis, spatial
      frequency and age group (P < 0.01). In headache-free controls, N135 latency
      reduction between pre- and post-puberty age was most pronounced at high spatial
      frequency. The main 'decline' of N135 latency with increasing age was shifted to
      lower spatial frequencies in the headache subgroups. The results give evidence
      that maturation of visual processing is partly disturbed in migraineurs.

PMID- 15030947
TI  - Using the self-regulatory model to cluster chronic pain patients: the first step
      towards identifying relevant treatments?
AB  - The pain literature indicates that, despite extensive investigations and
      recommendations, treatment outcomes can be poor. This study assesses whether a
      theoretical approach using the self-regulatory model (SRM) could usefully
      categorise chronic pain patients on the basis of their illness representations,
      since these have been shown to influence outcomes for other health-related
      conditions. One hundred and thirty newly referred patients of a pain relief
      clinic completed the revised Illness Perceptions Questionnaire and other
      measures. Cluster analysis supported the utility of a theoretical model of
      illness representations to identify pain groups, with the groups so identified
      differing in measures of pain, mood, and functioning. This study can be viewed as
      a preliminary step for future research employing stronger design methodologies to
      explore the validity of the SRM for classifying chronic pain patients, and to
      compare efficacy of treatment choice and outcome for this population based on
      illness representations.

PMID- 15030948
TI  - Central representation of muscle pain and mechanical hyperesthesia in the
      orofacial region: a positron emission tomography study.
AB  - Functional neuroimaging studies of the human brain have revealed a network of
      brain regions involved in the processing of nociceptive information. However,
      little is known of the cerebral processing of pain originating from muscles. The
      aim of this study was to investigate the cerebral activation pattern evoked by
      experimental jaw-muscle pain and its interference by simultaneous mechanical
      stimuli, which has been shown to evoke hyperesthesia. Ten healthy subjects
      participated in a PET study and jaw-muscle pain was induced by bolus injections
      of 5% hypertonic saline into the right masseter muscle. Repeated von Frey hair
      stimulation (0.5 Hz) of the skin above the masseter muscle was used as the
      mechanical stimulus. Hypertonic saline injections caused strong muscle pain
      spreading to adjacent areas. von Frey stimulation was rated as non-painful but
      produced hyperesthesia during jaw-muscle pain. Jaw-muscle pain was associated
      with significant increases in regional cerebral blood flow (rCBF) in the dorsal
      posterior insula (bilaterally), anterior cingulate and prefrontal cortices, right
      posterior parietal cortex, brainstem, cavernous sinus and cerebellum. No rCBF
      changes occurred in primary or secondary somatosensory cortices. In contrast, von
      Frey stimulation produced a significant rCBF increase in the contralateral SI
      face representation. Mechanical hyperesthesia was associated with significant
      rCBF increases in the subgenual cingulate and the ventroposteromedial and
      dorsomedial thalamus. These results suggest that the cerebral processing of jaw
      muscle pain may differ from the processing of cutaneous pain and that mechanical
      hyperesthesia, which often is encountered in clinical cases, has a unique
      representation in the brain.

PMID- 15030949
TI  - Some cases of severe post-mastectomy pain syndrome may be caused by an axillary
      haematoma.
AB  - Post-mastectomy pain syndrome (PMPS) is experienced by 20-65% of patients who
      undergo breast surgery for cancer. The etiology of this chronic neuropathic pain
      syndrome is unclear and most likely multi-factorial. Symptoms may be mild, not
      requiring treatment, or severe, considerably restricting quality of life. The
      effectiveness of available pharmacological and pain management therapies is
      unknown. Certainly, some women remain under-treated with poor pain control. We
      report three women undergoing wide local excision for cancer of the breast and
      block dissection of axillary lymph nodes who subsequently developed severe PMPS.
      In these cases the symptoms were completely relieved by the aspiration or formal
      drainage of an encapsulated haematoma in the axilla. The removal of a minimal
      amount of blood brought instant improvement suggesting that pressure within the
      haematoma could be an etiological factor. An axillary haematoma, which may not be
      clinically obvious, should be considered as a possible cause of PMPS.

PMID- 15030950
TI  - Pulsed percutaneous radiofrequency treatment of the Gasserian ganglion for
      therapy of trigeminal neuralgia: technical notes, validity of the method and
      selection of the patients.

PMID- 15030952
TI  - Proper hospital nutrition as a human right.

PMID- 15030953
TI  - n-3 polyunsaturated fatty acids and colon cancer prevention.
AB  - The incidence of colon cancer in industrialised countries has increased since the
      early 1970s. It is estimated that more than one-third of cases are associated
      with factors related to a Western diet. Both the type and amount of dietary fats
      consumed have been implicated in colon cancer aetiology. Recent studies have
      demonstrated that n-3 polyunsaturated fatty acids (PUFAs), commonly found in fish
      oil (FO), could prevent colon cancer development. Evidences show that n-3 PUFAs
      act at different stages of cancer development and through several mechanisms
      including the modulation of arachidonic acid-derived prostaglandin synthesis, and
      Ras protein and protein kinase C expression and activity. As a result, n-3 PUFAs
      limit tumour cell proliferation, increase apoptotic potential along the crypt
      axis, promote cell differentiation and possibly limit angiogenesis. The
      modulatory actions of n-3 PUFAs on the immune system and their anti-inflammatory
      effects might also play a role in reducing colon carcinogenesis. There remains,
      nevertheless, some ambiguity over the safety of n-3 PUFAs with respect to
      secondary tumour formation. However, it appears that n-3 PUFAs may be of use in
      colon cancer prevention.

PMID- 15030954
TI  - Assessment of whole body protein metabolism in critically ill children: can we
      use the [15N]glycine single oral dose method?
AB  - BACKGROUND & AIMS: Most stable-isotope methods to evaluate whole body protein
      metabolism in patients are invasive and difficult to use in children. In this
      study protein metabolism was evaluated with the non-invasive [15N]glycine single
      oral dose method in critically ill children and the value of the method is
      discussed. METHODS: [15N]glycine (100mg) was given orally to children (mean age
      5.5 years; range 0.6-15.5 years) with meningococcal septic shock (MSS, n = 8),
      pneumonia (n = 5), and to healthy, fed and post-absorptive children (n = 10).
      Urine was collected during 9h, total amount of NH(3), labelled NH(3) and nitrogen
      were measured, and protein turnover, synthesis and breakdown were calculated
      using urinary NH(3) as end-product. RESULTS: Mean protein turnover in children
      with MSS, pneumonia and fed and post-absorptive healthy children was 0.63+/-0.13,
      0.38+/-0.10, 0.28+/-0.03 and 0.28+/-0.02g N/kg/9h, respectively. Mean protein
      synthesis was 0.55+/-0.12, 0.29+/-0.09, 0.18+/-0.02, 0.20+/-0.02g N/kg/9h,
      respectively. Mean protein breakdown was 0.56+/-0.14, 0.28+/-0.12, 0.08+/-0.03,
      0.28+/-0.02g N/kg/9h, respectively. Protein turnover, synthesis and breakdown
      were significantly increased in MSS patients compared to fed healthy children (P
      <0.01) and post-absorptive children (P <0.05). Protein turnover, protein
      synthesis, protein breakdown were significantly correlated with disease severity
      and body temperature (P <0.05). CONCLUSION: Results of whole body protein
      metabolism measured with the [15N]glycine single oral dose method in children
      with MSS and in healthy children were in line with expectations based on results
      obtained in earlier reports and with different methods.

PMID- 15030955
TI  - Dietary beliefs of people with ulcerative colitis and their effect on relapse and
      nutrient intake.
AB  - BACKGROUND & AIMS: Ulcerative colitis usually follows a relapsing and remitting
      course. Patients believe that dietary factors are important. We wished to
      determine the nature of and reasons for patients' dietary beliefs and their
      effect on relapse and nutrient intake. METHODS: In a 1-year prospective cohort
      study, patients' nutrient intake and disease activity were measured with a
      validated food frequency questionnaire and disease activity index. Food beliefs,
      demographics and disease characteristics were recorded. The influence of beliefs
      on the risk of relapse and nutrient intake were examined using chi-squared and
      Mann-Whitney U-tests. RESULTS: One hundred and eighty-three patients were studied
      and 52% relapsed. Sixty-eight per cent held dietary beliefs and reported
      modifying their intake accordingly. The most common reported behaviour was the
      avoidance of milk and dairy products. Food beliefs were more common amongst those
      who had received dietary advice. No reported behaviour reduced the risk of
      relapse, but patients who avoided dairy products had a significantly lower intake
      of calcium. Folate intake was below UK recommended levels in 13% of patients.
      CONCLUSIONS: Patients with ulcerative colitis believe that many foods are harmful
      or helpful to their disease activity. Commonly held beliefs do not modify the
      risk of relapse, but do adversely affect nutrient intake.

PMID- 15030956
TI  - The routine microbiological screening of central venous catheters in home
      parenteral nutrition patients.
AB  - BACKGROUND & AIMS: Catheter-related bloodstream infection (CRBSI) is a major
      complication for patients receiving home parenteral nutrition (HTPN). Endoluminal
      sampling techniques allow the diagnosis of CRBSI without catheter removal and may
      allow the screening of asymptomatic patients. METHODS: Over a 5-year period,
      patients receiving HTPN were offered screening on a 3 monthly basis. All patients
      had tunnelled cuffed Hickman lines. All were asymptomatic at the time of
      screening, which took the form of either endoluminal brushing or quantitative
      cultures on through-line blood. RESULTS: Thirty-two patients were suitable for
      inclusion within the study period (10 male, median age 51 (iqr 46-61)) years with
      30 of these having a least one screening performed. Four had positive screening
      results and underwent appropriate treatment. Of the remainder, 12 presented with
      at least one clinical episode of CRBSI and 14 had neither clinical CRBSI nor a
      positive screening result. The combined clinical and screening CRBSI rate was
      0.39 episodes per catheter year. CONCLUSION: Although routine microbiological
      catheter screening can detect subclinical infections in HTPN patients the
      positive rate is low with the majority of patients still presenting clinical.
      Identification of higher risk patients and appropriate alterations to screening
      frequency may improve its value further.

PMID- 15030957
TI  - Decreased peritoneal macrophage NF-kappaB translocation to the nucleus in protein
      energy malnutrition--a role for the glucocorticoid response?
AB  - BACKGROUND & AIMS: Protein energy malnutrition (PEM) induces immune suppression
      leading to increased morbidity and mortality. The mechanism(s) underlying PEM
      mediated immune suppression remain unclear. Plasma glucocorticoid levels are
      elevated in PEM and it has been postulated that these increased levels may
      mediate macrophage (MO) dysfunction in PEM. We have previously shown that nuclear
      factor kappa B (NF-kappaB) activation in response to LPS stimulation is
      diminished in peritoneal macrophages (PMOs) from PEM mice. We hypothesized that
      decreased NF-kappaB activation in lipopolysaccharide (LPS)-stimulated PMOs in PEM
      is mediated through increased circulating glucocorticoid levels. METHODS: Mice
      were randomized to six groups of n = 15 each as follows: (1) control diet (24%
      casein) (C); (2) protein-free diet (PF); (3) mice with subcutaneously implanted
      corticosterone pellet on the control diet; (4) mice with subcutaneously implanted
      placebo pellet on the control diet; (5) adrenalectomized mice on the control
      diet; (6) adrenalectomized mice on the PF diet. Within each group, the mice were
      pair-fed for 7 days. At the end of the experimental time period, PMOs were
      harvested and NF-kappaB activation determined by electrophoretic mobility shift
      assay (EMSA). RESULTS: Elevated circulating glucocorticoids diminished NF-kappaB
      activation but adrenalectomy failed to restore this diminution in a murine model
      of PEM. CONCLUSION: NF-kappaB translocation to the nucleus in PEM is independent
      of elevated circulating glucocorticoid levels.

PMID- 15030959
TI  - A prospective randomised controlled trial of nutritional supplementation in
      malnourished elderly in the community: clinical and health economic outcomes.
AB  - BACKGROUND & AIMS: Malnutrition is common in sick elderly people on admission to
      hospital and in the community. We conducted a randomised controlled trial to
      determine if nutritional supplementation after discharge from hospital improved
      nutritional status and functional outcomes, or reduced health-care costs.
      METHODS: Elderly malnourished subjects were randomised to 8 weeks of
      supplementation or no supplementation post discharge, and followed up for 24
      weeks. Weight, body mass index, anthropometrics, handgrip strength, quality of
      life and requirements for health-care professionals' services and social services
      were measured throughout the study. RESULTS: Nutritional status improved
      significantly from baseline to week 24 in the intervention group (P<0.05), but
      not in the control group. There was no significant difference in nutritional
      status between groups at week 24. Handgrip strength improved significantly in the
      intervention group during supplementation, and was significantly different from
      that of the control group at week 8, but decreased thereafter. There was no
      significant difference in quality of life or health economic outcomes between
      groups at week 24. CONCLUSIONS: In already malnourished elderly subjects, it may
      be too late to expect to improve function or quality of life or to reduce health
      care costs simply by providing nutritional supplements after hospitalisation.
      Prevention is key. All elderly patients should be nutritionally assessed as part
      of their routine care, and appropriate intervention initiated early.

PMID- 15030958
TI  - L-ergothioneine modulates oxidative damage in the kidney and liver of rats in
      vivo: studies upon the profile of polyunsaturated fatty acids.
AB  - BACKGROUND & AIMS: L-ergothioneine is a fungal metabolite exhibiting antioxidant
      functions in cells. The aim of this study was to assess the effect of oral
      administration of L-ergothioneine on the oxidative damage in vivo caused by the
      Fenton reagent ferric-nitrilotriacetate. METHODS: Rats were supplemented with L
      ergo prior to the administration of acute dose of ferric-nitrilotriacetate.
      Kidney and liver levels of L-ergothioneine, glutathione, alpha-tocopherol,
      polyunsaturated fatty acids and conjugated dienes were assessed. RESULTS: Oral
      administration of 70 mg L-ergo/kg body weight of rats for 7 days prior to the
      injection of ferric-nitrilotriacetate protected the fatty acids against
      oxidation, with notable protections directed to: 20:5 (eicosapentaenoic acid)
      (23%), 22:6 (docosahexaenoinic acid) (30%), 20:3 n6 (eicosatrienoic acid) (22%),
      20:4 (arachidonic acid) (25%), 18:2 linoleic acid (25%) and 18:1 oleic acid (14%)
      in the kidney. The protection of 20:5, 20:3 n6 and 18:1 in the liver by 32%, 20%
      and 11%, respectively, were statistically significant. L-ergothioneine
      significantly reduced kidney and liver levels of conjugated dienes and conserved
      the concentrations of alpha-tocopherol and glutathione in the kidney and liver in
      the ferric-nitrilotriacetate/L-ergothioneine treated rats. CONCLUSION:
      Supplementation with L-ergothioneine not only protects the organs against the
      lipid peroxidation but conserves the consumption of endogenous glutathione and
      alpha-tocopherol. However consumption of mushrooms may have better promise as
      dietary sources of L-ergothioneine to humans.

PMID- 15030960
TI  - Accumulation of vitamin E metabolites in the blood of renal failure patients.
AB  - BACKGROUND & AIMS: Carboxyethyl-hydroxychromans (CEHC) are hydrosoluble vitamin E
      metabolites excreted through the renal filter. In this study we investigated the
      effect of the kidney damage on the blood levels of CEHC. METHODS: Plasma levels
      of alpha-CEHC, gamma-CEHC and their precursors (namely, alpha-tocopherol and
      gamma-tocopherol) were measured by HPLC with electrochemical detection in chronic
      (CRF) and end-stage renal failure patients on regular hemodialysis (HD) before
      and after dialysis. CRF patients (n = 26) were divided into three subgroups with
      different extent of kidney damage as measured by the intervals of creatinine
      clearance (CrCl, in ml/min): (a) 2-10, (b) 10-20, and (c) 20-45. HD patients (n =
      8) did not show residual renal function. In all the subjects the intake of
      vitamin E (as alpha-tocopherol) was assessed using a food frequency
      questionnaire. In the HD group, the plasma concentrations of ascorbic and uric
      acid (AA and UA, respectively), total thiols, the total antioxidant status (TAS)
      and reactive carbonyls were also measured. RESULTS: The progressive deterioration
      of the kidney function in the different groups of patients produced an
      exponential increase of both alpha-CEHC and gamma-CEHC in plasma. Compared with
      healthy controls (alpha-CEHC = 20.1+/-13.4 and gamma-CEHC = 230.6+/-83.0 nmol/l)
      the levels of CEHC approximately doubled in patients with CrCl < or = 20ml/min
      (42.4+/-20.2 and 424.5.5+/-174.4; P <0.05 or higher in both) and reached a 3-fold
      maximum increase in HD patients (77.3+/-45.7 and 636.6+/-219.3). The hemodialysis
      provided a significant, but only a transient, correction of CEHC accumulation
      (44.8+/-23.5, 364.2+/-189.9). The HD patients showed lower intake and levels of
      vitamin E (alpha-tocopherol = 5.1+/-1.0 and gamma-tocopherol =0.32+/-0.11
      micromol/mmol cholesterol; P <0.05) compared to healthy controls (5.8+/-0.8 and
      0.43+/-0.14), but in the CRF patients tocopherol levels were normal or only
      slightly decreased even though approximately half of the subject had lowered
      vitamin E intake. When the entire patient population was considered, the blood
      concentrations of parental tocopherols and CEHC did not correlate. The HD
      patients before dialysis showed a marked decrease of TAS/UA, AA and thiols
      levels, while UA and free carbonyls significantly increased. After dialysis, the
      depletion of AA and thiols further worsened and also UA and TAS/UA decreased, but
      free carbonyls slightly increased. CONCLUSIONS: The results other than to confirm
      the key importance of the renal route for the excretion of CEHC, demonstrate that
      CEHC cannot be reliably used to investigate vitamin E biokinetics and
      transformation without a careful examination of the renal function. CEHC
      accumulation does not seem to influence the antioxidant status in the plasma of
      HD patients. Further studies are requested to establish whether such an increase
      in blood CEHC concentrations might be harmful or could contribute to the
      biological functions of the vitamin E in uremia and dialysis patients.

PMID- 15030961
TI  - An investigation into the relationships between quality of life, nutritional
      status and physical function.
AB  - BACKGROUND & AIMS: The measurement of quality of life adds a holistic dimension
      to the assessment of a clinical state or the response to an intervention. The
      relationship between quality of life and nutritional status is not well studied.
      This study aimed to investigate this relationship in a group of sick elderly in
      patients. METHODS: We used data from a RCT investigating the benefits of
      intensive feeding support on acute medicine for the elderly wards. The EuroQol EQ
      5D questionnaire was administered to patients on admission and the results were
      then related to parameters of nutritional status, physical function, depression
      and serum albumin collected at the same time. RESULTS: Two hundred and thirty
      three patients completed the EQ-5D questionnaire. Comparisons with UK norms for
      community living elderly showed significantly lower scores. No direct
      relationship was found between the EQ-5D scores and markers of nutritional
      status. However, clear differences were observed between patients with and
      without swallowing problems, those with good and poor appetite and those with
      good and poor physical function. Increasing risk of depression had a profound
      effect on quality of life scores. CONCLUSIONS: Nutritional status does not appear
      to directly influence quality of life, as measured by the EQ-5D, but may affect
      it through the consequences of reduced physical function. Additionally, factors
      that directly affect a persons food intake seem to have a greater impact on
      quality of life, which underlines the importance of food and eating as an aspect
      of life quality.

PMID- 15030962
TI  - Malnutrition in critically ill children: from admission to 6 months after
      discharge.
AB  - BACKGROUND & AIMS: Little is known about the nutritional status of critically ill
      children during hospitalisation in and after discharge from an intensive care
      unit. We set up a prospective, observational study to evaluate the nutritional
      status of children in an intensive care unit from admission up to 6 months after
      discharge. A secondary aim was identifying patient characteristics that influence
      the course of the various anthropometric parameters. METHODS: The nutritional
      status of 293 children--104 preterm neonates, 96 term neonates and 93 older
      children--admitted to our multidisciplinary tertiary pediatric and neonatal
      intensive care unit was evaluated by anthropometry upon and during admission, at
      discharge and 6 weeks and 6 months following discharge. RESULTS: Upon admission,
      24% of all children appeared to be undernourished. Preterm and term neonates, but
      not older children, showed a decline in nutritional status during admission. At 6
      months after discharge almost all children showed complete recovery of
      nutritional status. Length of stay and history of disease were the parameters
      that most adversely affected the nutritional status of preterm and term neonates
      at discharge and during follow-up. CONCLUSION: While malnutrition is a major
      problem in pediatric intensive care units, most children have good long-term
      outcome in terms of nutritional status after discharge.

PMID- 15030964
TI  - Weight stabilisation is associated with improved survival duration and quality of
      life in unresectable pancreatic cancer.
AB  - BACKGROUND & AIMS: Cancer-induced weight loss is associated with poor outcomes
      and is common in pancreatic cancer. The aims were to determine whether
      stabilising weight loss for patients with unresectable pancreatic cancer was
      associated with improved survival and quality of life (QoL) and to identify
      determinants of weight stabilisation. METHODS: A post hoc analysis was performed
      using data from 107 patients in a multicentre trial. Patients were categorised as
      weight losing (> 1 kg lost) or weight stable (< or = 1 kg lost) after an 8 week
      nutrition intervention period. Group survival duration (Kaplan Meier) and QoL
      (EORTC QLQ-C30) were compared. Predictors of weight stability were determined
      using logistic regression analysis. RESULTS: Patients with weight stabilisation
      survived longer from baseline (log rank test 5.53, P = 0.019). They also reported
      higher QoL scores (P = 0.037) and a greater mean energy intake (P <0.001) at Week
      8 than those who continued to lose weight. The absence of nausea and vomiting (OR
      6.5, P =0.010) and female gender (OR 5.2, P = 0.020) were independent
      determinants of weight stabilisation. CONCLUSIONS: Weight stabilisation over an 8
      week period in weight-losing patients with unresectable pancreatic cancer was
      associated with improved survival duration and QoL.

PMID- 15030963
TI  - The relationship between leptin concentrations, the systemic inflammatory
      response and illness severity in surgical patients admitted to ITU.
AB  - BACKGROUND & AIMS: The relationship between circulation leptin concentrations,
      mediators of the systemic inflammatory response and illness severity in
      critically ill patients remains unclear. The aim of the present study was to
      examine these relationships in critically ill surgical patients admitted to the
      intensive therapy unit (ITU). PATIENTS AND METHODS: Patients (n = 38) who had
      undergone surgery and subsequently admitted to ITU were prospectively entered
      into a cross-sectional study. Circulating concentrations of leptin, cortisol,
      growth hormone, interleukin-6, C-reactive protein and albumin were measured. Sex
      and age matched controls (n = 14) were also studied. RESULTS: On day 1, the
      critically ill group had lower BMI and leptin concentrations and a pronounced
      systemic inflammatory response compared with controls. There was a weak positive
      correlation between leptin concentrations and BMI in the critically ill patients
      (r = 0.42, P<0.10). In contrast, leptin was inversely correlated with C-reactive
      protein (r = -0.59, P<0.05) but not with cortisol, growth hormone, interleukin-6,
      APACHE II or predicted mortality. Leptin concentrations did not alter with the
      day of admission to ITU. CONCLUSIONS: On ITU admission, leptin concentrations
      appeared to be low for BMI, related to the magnitude of the systemic inflammatory
      response but did not appear to be regulated by proposed mediators in critically
      ill surgical patients.

PMID- 15030965
TI  - Changes in circulating concentrations of vitamins and trace elements after
      cessation of nocturnal enteral tube feeding.
AB  - BACKGROUND: This study aimed to examine whether circulating concentrations of a
      range of vitamins and trace elements in patients receiving long-term cyclic
      enteral tube feeding vary during the day, and whether standardised time points
      for blood sampling are required for assessment of nutrient status. METHODS:
      Circulating concentrations or activities of water-soluble vitamins (thiamine,
      riboflavin, and vitamins B6, B12, folate and C), fat-soluble vitamins (A, D, E)
      and trace elements (iron, zinc, copper and selenium (assessed by glutathione
      peroxidase activity), were measured at 0,3,6 and 9-12h after cessation of
      nocturnal feeding (fasting), in eight clinically stable patients receiving cyclic
      nocturnal enteral nutrition. RESULTS: The circulating concentrations of the
      nutrients did not change between the fed and fasted state (repeated-measures
      ANOVA) except the following: plasma folate increased progressively from 10.9 (SD
      4.6)nmol/l in the fed state to 14.0 (SD 4.4)nmol/l at 9-12 h after cessation of
      feeding (P<0.05); plasma zinc increased progressively throughout the fasting
      period by 33.5% (8.57, SD 0.68 vs. 11.44, SD 1.85 micromol/l, in fed state vs. 9
      12h fast respectively, P<0.05); and total tocopherol/cholesterol ratio decreased
      by 9.6% during the study period (P<0.02), while gamma-tocopherol increased by
      59.2% (P<0.05). For all analytes, the concentrations in blood samples taken at 3
      and 6h after cessation of feeding were not significantly different from those at
      9-12h. CONCLUSIONS: Although cessation of nocturnal tube feeding had no
      significant effect on the circulating concentrations of most micronutrients, it
      increased plasma folate and zinc concentrations, and decreased the
      tocopherol/cholesterol ratio. The timing for blood sampling should be
      standardised when the status of these nutrients is assessed in patients receiving
      cyclic tube feeding.

PMID- 15030966
TI  - The effects of standard and branched chain amino acid enriched solutions on
      thermogenesis and energy expenditure in unconscious intensive care patients.
AB  - BACKGROUND & AIMS: This study aims to compare the effects of standard and
      branched chain amino acid enriched solutions on thermogenesis and energy
      expenditure in unconscious and mechanically ventilated intensive care patients.
      DESIGNS: The study was carried out at multidisciplinary intensive care unit.
      Twenty unconscious and mechanically ventilated patients (18-65 years of age) were
      included in the study. Patients were hemodynamically stable and all received
      continuous enteral nutrition. Energy expenditure was calculated using the Harris
      Benedict Equation for all of the patients. Patients were randomly assigned to
      receive a 4h infusion of 0.4 g/kg protein as amino acid solution. Group I (n =
      10) received standard amino acid solution and group II (n = 10) received branched
      chain amino acid enriched solution. Energy expenditure, oxygen consumption and
      carbon dioxide production were measured by indirect calorimetric method every 30
      min during the 4h infusion period and 3h thereafter. Rectal temperature was
      recorded concomitantly with the metabolic measurements throughout the study.
      RESULTS: There was a statistically significant increase in body temperature
      during the infusion of amino acid solution between 30 and 210 min in group I and
      between 30 and 120 min in group II (P <0.05). We observed a significant increase
      in energy expenditure at 30, 150, 180 and 210 min in group I and at 30-240 min in
      group II (P <0.05). There were no differences between the two groups in terms of
      thermogenesis or energy expenditure values during the study (P >0.05).
      CONCLUSION: Thermogenesis and energy expenditure values were increased during the
      parenteral infusion of both standard amino acid and branched chain amino acid
      enriched solutions in unconscious intensive care patients without any
      significance in between.

PMID- 15030967
TI  - Micronutrient supplementation in mild Alzheimer disease patients.
AB  - OBJECTIVE: To evaluate if nutritional supplementation with or without
      micronutrient enhancement prevent weight loss and the progression of the disease
      in mild Alzheimer's Disease (AD) patients. DESIGN: Mild AD patients were
      recruited from an Alzheimer Day Centre. Subjects received oral liquid supplements
      with (Study-group: S) or without (Control-group: C) micronutrient enhancement.
      Intake assessment, nutritional status, biochemical parameters, cognitive
      function, and eating behaviour disorders were determined at baseline and at 6
      months of treatment. RESULTS: At baseline both groups were not different in any
      variable measured. They were norm nourished, with normal biochemical parameters.
      Blandford scale demonstrated a mild alteration of feeding behaviour, the
      cognitive scale classified the patients as impaired and there was presence of
      memory complaints. After 6 months of nutritional supplements, a similar increase
      in energy consumption was observed in both groups of patients (P<0.05). In the
      within-group analysis, we found a trend (P=0.05) to increase body mass index; a
      significant increase in triceps skin fold thickness, mid-upper-arm circumference
      and serum magnesium, zinc and selenium, and a significant reduction in serum
      vitamin E (P<0.001, each). Serum cholesterol decreased substantially only in the
      S-group (P=0.025). No significant differences at baseline, within-group, neither
      between-group analysis in feeding behaviour nor in cognitive function were
      observed. CONCLUSIONS: According to our results no benefits in the progression of
      the disease was observed with micronutrient enhancement supplements.
      Effectiveness of nutritional supplements in preventing weight loss in mild AD
      patients showed a similar behaviour as observed in other populations. Due to the
      beneficial evolution of serum cholesterol in the S-group, this intervention
      deserves further investigation.

PMID- 15030968
TI  - Muscle wasting and energy balance in critical illness.
AB  - BACKGROUND: In nine patients with multiple organ failure ultrasound was able to
      identify muscle wasting despite the presence of oedema (Campbell et al., J Clin
      Nutr 62 (1995) 533). AIMS: The purpose of the present study was twofold: one was
      to determine whether this technique was applicable to a much larger ICU
      population, many of whom were not as ill as the original subjects. The second
      reason was to determine whether a relationship could be identified between rates
      of wasting and energy balance. METHODS: Serial measurements of both mid-upper arm
      circumference (MAC) and muscle thickness, using ultrasound, were made at 1-3 day
      intervals between 5 and 39 (median 7) days in 50 critically ill patients.
      RESULTS: Muscle thickness decreased in 48 of the 50 patients at a median rate of
      1.6%/day with a range of 0.2-5.7%/day. In 33 patients, in whom MAC did not change
      significantly with time, muscle thickness decreased by between 0.3 and 4.2
      (median 1.6)%/day. In three patients MAC increased significantly with time but
      muscle thickness decreased by between 1.3 and 5.7 (median 2.6)%/day. Twelve
      patients showed a significant decrease in MAC with time and muscle thickness in
      this group decreased by between 0.2 and 4.0 (median 1.3)%/day. The percentage
      decrease in muscle thickness between the groups, in whom MAC decreased or did not
      change, was not significantly different (P = 0.475). CONCLUSION: We have
      demonstrated that an ultrasound technique devised to identify muscle wasting in
      the presence of severe fluid retention works in the majority (48/50) of patients
      when applied to a wider ICU population. Energy balance made no difference to the
      rate of wasting.

PMID- 15030969
TI  - Diabetic children with asymptomatic celiac disease: is it necessary to stress
      gluten-free diet?

PMID- 15030971
TI  - Liver transplantation for primary sclerosing cholangitis.

PMID- 15030972
TI  - The spectrum expanded: cryptogenic cirrhosis and the natural history of non
      alcoholic fatty liver disease.

PMID- 15030973
TI  - Multidrug resistance-associated protein 4 is up-regulated in liver but down
      regulated in kidney in obstructive cholestasis in the rat.
AB  - BACKGROUND/AIMS: Multidrug resistance-associated protein 4 (Mrp4, ABCC4)
      transports cyclic nucleotides, anti-retroviral compounds, and sulfated bile
      acids. Mrp4 expression is increased in farnesyl/bile acid receptor knockout mice.
      Our aim was to investigate Mrp4 expression and function in rat liver and kidney
      in obstructive cholestasis. METHODS: Male Sprague-Dawley rats were subjected to
      bile duct ligation (BDL) or sham-surgery. Animals were sacrificed after 3, 7, and
      14 days and tissues were harvested for Western blot analysis, real-time reverse
      transcriptase-mediated polymerase chain reaction (RT-PCR), and
      immunohistochemistry. RESULTS: Western blot analysis revealed a progressive, more
      than seven-fold increase (P < 0.05) of Mrp4 expression in cholestatic livers, 14
      days after BDL. In contrast, Mrp4 in 14-day BDL kidneys decreased to 26+/-4% of
      controls (P < 0.005). Immunohistochemistry localized Mrp4 to the basolateral
      hepatocyte membrane and corroborated its hepatic up-regulation after BDL. Real
      time RT-PCR demonstrated no major changes of Mrp4 mRNA levels in liver and kidney
      after BDL. Cyclic adenosine monophosphate, an MRP4 substrate, was increased in
      plasma and urine, consistent with these findings. CONCLUSIONS: Obstructive
      cholestasis in rats results in progressive up-regulation of Mrp4 protein in liver
      but down-regulation in kidney. The absence of corresponding changes in Mrp4 mRNA
      suggests posttranscriptional mechanisms as predominant regulators of Mrp4
      expression in BDL rats.

PMID- 15030974
TI  - Isolated idiopathic bile ductular hyperplasia in patients with persistently
      abnormal liver function tests.
AB  - BACKGROUND/AIMS: In routine examination of liver biopsies isolated ductular
      hyperplasia (IDH) may be the only histopathological change. Here we describe the
      clinical and immunophenotypic features of a number of cases retrospectively
      identified reviewing consecutive liver biopsies from five Italian centers over 4
      years. METHODS: We reviewed 1235 cases biopsied for chronic liver disease (1078
      for viral hepatitis). Records of cases fulfilling the inclusion criteria for IDH
      were reviewed to identify possible aetiologies. Biopsies showing IDH and control
      biopsies were studied by immunohistochemistry for cytokeratin-7, epithelial
      membrane-antigen (EMA), neural-cell-adhesion-molecule (NCAM), Ki-67. RESULTS: Out
      of 70 biopsies fulfilling IDH criteria, 16 (22.8%) were of unknown aetiology.
      Patients with idiopathic IDH (age 38.2+/-11 years) were asymptomatic with mild,
      long-lasting ALT and/or gammaGT increases. A significant increase of well
      differentiated (EMA-positive; NCAM-negative) bile ductules localized at the
      portal interface and inside the lobule was found in idiopathic IDH. CONCLUSIONS:
      Idiopathic IDH was present in 10% of adults biopsied for persistent mild liver
      function test abnormalities unrelated to viral hepatitis. In contrast with the
      ductular reaction seen in many forms of liver disease, it is characterized by
      well-differentiated hyperplastic ductules in absence of significant inflammation,
      and may represent a non-specific pattern of reaction to mild liver damages.

PMID- 15030975
TI  - The transport of triglycerides through the secretory pathway of hepatocytes is
      impaired in apolipoprotein E deficient mice.
AB  - BACKGROUND/AIMS: Apolipoprotein E (apoE)-deficient mice develop hepatic steatosis
      and secrete reduced levels of VLDL-TG. METHODS AND RESULTS: We examined the
      effects of apoE-deficiency on intracellular lipid homeostasis and secretion of
      triglycerides (TG). We show that intracellular TG turnover and activities of
      diacylglycerol acyltransferase (DGAT) and microsomal triglyceride transfer
      protein (MTP) are similar in Apoe(-/-) and wild type mice. In addition, apoB
      synthesis was not decreased in Apoe(-/-) cells. Thus, the accumulation of lipid
      in these cells is not attributable to perturbed TG turnover, apoB synthesis, and
      the activities of DGAT and MTP. Inhibition of MTP had a more profound impact on
      the secretion of VLDL-TG from wild type hepatocytes than Apoe(-/-) hepatocytes,
      indicating that MTP was more limiting for the production of VLDL-TG from wild
      type cells. In marked contrast to the MTP-deficient model of fatty liver,
      electron microscopy of lipid-stained liver sections of Apoe(-/-) mice revealed an
      accumulation of lipid in numerous small, putative ER-derived vesicles and in the
      cytosol. No abnormalities were observed in the Golgi of Apoe(-/-) mice.
      CONCLUSIONS: These results suggest that the removal of lipids from the early or
      intermediary compartments of the secretory pathway of hepatocytes is impaired in
      Apoe(-/-) mice.

PMID- 15030976
TI  - Iron-induced mitochondrial permeability transition in cultured hepatocytes.
AB  - BACKGROUND/AIMS: We previously described that the cold-induced apoptosis of
      cultured hepatocytes and liver endothelial cells is mediated by an increase in
      the cellular chelatable iron pool-in the absence of any increase in O(2)(.
      )/H(2)O(2) formation. As this is an unusual mechanism, we here set out to assess
      whether an increase in cellular chelatable iron per se is sufficient to trigger
      cell injury/apoptosis. METHODS: Cultured rat hepatocytes were acutely loaded with
      iron using the membrane-permeable complex Fe(III)/8-hydroxyquinoline and
      incubated under otherwise 'physiological' conditions. RESULTS: Incubation with
      Fe(III)/8-hydroxyquinoline (15 microM/30 microM) increased the cellular
      chelatable iron and induced strong hepatocellular injury with morphological
      features of apoptosis, but also of necrosis. The iron-induced cell injury was
      oxygen-dependent, and although it was not inhibitable by extracellular catalase,
      it was strongly inhibited by the novel membrane-permeable catalase mimic TAA
      1/Fe. The experimentally induced increase in cellular chelatable iron triggered a
      mitochondrial permeability transition (MPT) as assessed using double-staining
      with calcein and tetramethylrhodamine methyl ester. The MPT inhibitor
      cyclosporine A partially and the well-known inhibitor combination
      trifluoperazine+fructose completely inhibited the iron-induced cell
      injury/apoptosis. CONCLUSIONS: These results show that iron per se can induce
      cell injury/apoptosis and that this injury is mediated via an MPT.

PMID- 15030978
TI  - Tumour necrosis factor-alpha expression by activated monocytes and altered T-cell
      homeostasis in ascitic alcoholic cirrhosis: amelioration with norfloxacin.
AB  - BACKGROUND/AIMS: To investigate the distribution and activation state of
      circulating monocytes and T-cell subsets, their contribution to tumour necrosis
      factor-alpha (TNFalpha) production, and their potential relationship with
      bacterial products of enteric origin in alcoholic cirrhosis. METHODS: Peripheral
      blood monocytes and T-lymphocytes from 60 cirrhotic patients and 24 controls were
      characterized by four-color flow-cytometry after labelling of differentiation
      antigens and cytokines, before and after a 4-week course of norfloxacin or
      placebo. RESULTS: Monocytes from ascitic patients showed increased number,
      enhanced CD80 and HLA-DR surface levels, and spontaneous intracytoplasmic
      TNFalpha expression, when compared to non-ascitic patients and controls. Blood
      TNFalpha levels directly correlated with the amount of TNFalpha expressed by
      monocytes. In ascitic patients, there was a collapse of virgin CD4(+) and CD8(+)
      T-cell subsets; and, an expansion of activated CD4(+) T-cells. The above
      abnormalities were mainly restricted to ascitic patients with high serum levels
      of lypolysaccharide-binding-protein. Norfloxacin normalized the number of
      monocytes, reduced their activated phenotype and ability to produce TNFalpha and
      improved the abnormal T-cell homeostasis. CONCLUSIONS: In ascitic cirrhosis with
      high lipolysaccharide-binding-protein, monocytes are spontaneously activated to
      produce TNFalpha and are major contributors to the elevated serum TNFalpha. The T
      cell compartment is profoundly depleted. Enteric bacterial products play a
      relevant role in these immune cellular abnormalities.

PMID- 15030977
TI  - Up-regulation of IL-1 receptor through PI3K/Akt is essential for the induction of
      iNOS gene expression in hepatocytes.
AB  - BACKGROUND/AIMS: Nuclear translocation and DNA binding of NF-kappaB is essential,
      as interleukin-1beta (IL-1beta) stimulates the induction of inducible nitric
      oxide synthase (iNOS) gene expression in hepatocytes. However, recent evidence
      indicates that the activation of NF-kappaB is not sufficient to induce the NF
      kappaB-dependent transcription, and the existence of a second signaling is
      postulated. METHODS: Primary cultured hepatocytes were treated with IL-1beta, and
      the expression of iNOS and type 1 IL-1 receptor (IL-1R1) was analyzed in the
      presence of antisense of IL-1R1, phosphatidylinositol 3-kinase (PI3K) inhibitor,
      proteasome inhibitor and hypoxia. Moreover, the activities of Akt and NF-kappaB
      were recorded and the cotransfection was carried out. RESULTS: Antisense
      experiment revealed that IL-1R1 was required for iNOS transcription. IL-1beta
      markedly stimulated the induction of IL-1R1, which preceded the induction of
      iNOS. The IL-1R1 induction was found to be PI3K/Akt-dependent but NF-kappaB
      independent. The up-regulation of IL-1R1 was associated with the second
      activation of Akt, which accelerated the phosphorylation of NF-kappaB p65
      subunit. Cotransfection experiments revealed that Akt increased the
      transcriptional activity of iNOS gene promoter. CONCLUSIONS: These results
      indicate that the up-regulation of IL-1R1 in concert with the activation of NF
      kappaB is required for the transcriptional activation of iNOS gene.

PMID- 15030979
TI  - N-Acetyl-cysteine modulates inducible nitric oxide synthase gene expression in
      human hepatocytes.
AB  - BACKGROUND/AIMS: A major role has been described for inducible nitric oxide (NO)
      synthase in several chronic inflammatory liver diseases. N-Acetyl-cysteine (NAC)
      is a sulfhydryl donor molecule with antioxidant and antiinflammatory effects. It
      attenuates NO generation following lipopolysaccharide injection in rats. Our goal
      was to study the effect of NAC on NO synthase induction in hepatocytes in
      response to proinflammatory cytokines. METHODS: The effect of NAC on NO synthase
      induction was studied in the human hepatocyte cell lines HepG2 and 2.2.15 treated
      with a mixture of proinflammatory cytokines. Interactions between NAC and
      cytokines on nuclear factor-kappaB (NF-kappaB) activation and NO synthase
      promoter transactivation were investigated. RESULTS: NAC dose-dependently
      modulated the induction of NO synthase mRNA expression, the release of nitrites
      and the formation of NF-kappaB binding complexes in cytokine-treated hepatocytes.
      NAC also reduced the transactivation of the NO synthase promoter. CONCLUSIONS:
      Our data show that exposure of hepatocytes to NAC modulated NO synthase
      expression and NF-kappaB activity, the key responses of the hepatocyte to
      inflammatory mediators. These data constitute preliminary evidence that NAC might
      have hepatoprotective actions of potential relevance in chronic inflammatory
      liver diseases, mediated partially through the modulation of NO production.

PMID- 15030980
TI  - Modulation of fibronectin gene expression in inflammatory mononuclear phagocytes
      of rat liver after acute liver injury.
AB  - BACKGROUND/AIMS: In acute liver injury, fibronectin (FN) is deposited at the site
      of hepatocellular necrosis. We have previously shown that liver inflammatory
      mononuclear phagocytes (MNP), in contrast to quiescent hepatic macrophages,
      synthesize abundant amounts of FN. We now analyzed effects of agents known to
      influence macrophage functions to better understand liver damage and repair.
      METHODS: Acute rat liver injury was induced by CCl(4). Liver cellular FN (cFN)
      expression was analyzed by in situ-hybridization. Liver MNP were isolated and
      characterized immunocytochemically. Protein synthesis was studied by biosynthetic
      labeling, immunoprecipitation, and SDS-PAGE. RNA was analyzed by Northern
      Blotting. RESULTS: cFN gene expression was localized by in situ-hybridization and
      immunohistochemistry within the pericentral inflammatory infiltrate. Treatment of
      inflammatory MNP with dexamethasone, or interferon-gamma, or lipopolysaccharide
      induced a dose-dependent decrease in cFN gene expression, whereas transforming
      growth factor-beta increased cFN gene expression. CONCLUSIONS: 1. Inflammatory
      MNP express cFN. 2. Downregulation of cFN expression by dexamethasone in
      inflammatory MNP may explain delayed wound healing after corticosteroid therapy.
      Interferon-gamma and lipopolysaccharide could also delay the repair process in
      the liver. Transforming growth factor-beta may promote liver wound healing after
      acute liver injury by increasing local cFN synthesis in inflammatory mononuclear
      phagocytes of the inflammatory infiltrate.

PMID- 15030981
TI  - Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis.
AB  - BACKGROUND/AIMS: Reduction in hepatic fibrosis and reversibility of cirrhosis has
      been described in chronic liver disease. Our goal was to determine changes in
      fibrosis and the frequency of histological cirrhosis in corticosteroid-treated
      autoimmune hepatitis (AIH). METHODS: Three hundred twenty-five liver specimens
      from 87 treated patients were reviewed in batch under code by one pathologist and
      graded by the Ishak method. RESULTS: Fibrosis scores improved (3.4+/-0.2 versus
      2.6+/-0.2, P=0.0002) during 63+/-6 months, and histological activity indices
      decreased concurrently (6.8+/-0.5 versus 2.1+/-0.2, P<0.0001). Fibrosis scores
      improved in 46 patients (53%) during 57+/-7 months and did not progress in 23
      patients during 62+/-12 months. The fibrosis score improved more commonly in
      patients who had improvement in the histological activity indices than in others
      (61 versus 32%, P=0.02), and the frequency of histological cirrhosis decreased
      from 16% (14 patients) to 11% (10 patients). CONCLUSIONS: Fibrosis commonly
      improves or does not progress during corticosteroid therapy of AIH, and
      histological cirrhosis may disappear. Improvements in fibrosis are associated
      with suppression of inflammatory activity. Improvement or prevention of fibrosis
      may be a common but unheralded advantage of corticosteroid therapy.

PMID- 15030982
TI  - Hepatitis B virus transmission and hepatocarcinogenesis: a 9 year retrospective
      cohort of 13676 relatives with hepatocellular carcinoma.
AB  - BACKGROUND/AIMS: Familial clustering of hepatitis B virus (HBV) infection is
      related to perinatal transmission, and is the main cause of familial-type
      hepatocellular carcinoma (HCC). The route of HBV transmission differs between the
      children and siblings of patients with HCC. This study examined the differences
      in HBV carrier rates and HCC-related mortality between two generations in HCC
      families. METHODS: From 1992 to 1997, relatives of individuals with HCC were
      screened prospectively with ultrasonography, alpha-fetoprotein, liver
      biochemistry tests and viral markers. Total HCC-related deaths during a 9-year
      period were compared between the generations of index patients and their
      children. RESULTS: The study included a total of 13676 relatives in two
      generations. More HCC-related deaths occurred in the index patient generation
      than in the child generation. Furthermore, children of female index patients had
      higher rates of liver cancer related mortality than children of male index
      patients. The same was true when the analysis was limited to male HBV carriers.
      The prevalence of HBsAg in the offspring of HBsAg positive mothers was 66% in the
      child generation and 72% in the index patient generation. These high prevalences
      indicated high maternal HBV replication status. CONCLUSIONS: Perinatal
      transmission and maternal viral load are important risk factors in
      hepatocarcinogenesis.

PMID- 15030983
TI  - Multiple chromosomal abnormalities in human liver (pre)neoplasia.
AB  - BACKGROUND/AIMS: In human hepatocarcinogenesis the tumor precursor lesions and
      the sequence of genetic aberrations are not known. We therefore compared genetic
      alterations of different types of benign liver lesions to those of hepatocellular
      carcinoma. METHODS: By comparative genomic hybridisation (CGH) 40 cases,
      including cirrhotic liver (CL), focal nodular hyperplasia (FNHs), hepatocellular
      adenoma (HCAs), dysplastic nodules (DNs), primary hepatocellular carcinoma
      (HCCs), and hepatocellular metastases to the lung were studied. RESULTS: FNHs and
      HCAs exhibited few chromosomal abnormalities. Frequency and pattern of genetic
      alterations in DNs highly resembled those in HCCs: gains of DNA clustered in
      chromosome arms 1p/q, 7q, 15q, 16p, 17q, and 20q and losses were often found at
      3p, 4q, 9p, and 11q. Aberrations on 1p, 6q, 8p/q, and 13q occurred almost
      exclusively in HCCs; the gain at 8q encompassed amplification of c-myc, as
      verified by fluorescence in situ hybridisation. CONCLUSIONS: The pattern of
      genetic alterations in HCCs resembled more the alterations found in DNs than in
      FNHs and HCAs, suggesting that DNs may be the actual tumor precursors.
      Furthermore, alterations at 4q, 9p, 11q, 16p, and 17q appear as early genetic
      events being crucial for hepatocarcinogenesis.

PMID- 15030984
TI  - Treatment of recurrent hepatitis C after liver transplantation: a pilot study of
      peginterferon alfa-2b and ribavirin combination.
AB  - BACKGROUND/AIMS: After liver transplantation (LT) for HCV-related cirrhosis,
      recurrence of HCV infection is universal and the risk of progression to cirrhosis
      is high. The modalities and efficacy of antiviral therapy in this indication are
      still controversial. We present here the results of a pilot study of a 12-month
      combination therapy by pegylated alfa 2b-interferon (PEG-IFN) and ribavirin in 20
      patients. METHODS: Twenty patients entered the study (13 male and 7 female,
      median age 53.8 years). In 80% of patients, HCV infection was of genotype 1. The
      delay between LT and antiviral therapy was 28 months. The doses were
      progressively increased from 0.5 to 1 micro g/kg/week for PEG-IFN and from 400 to
      1000-1200 mg/d for ribavirin. Follow-up was based on biochemical (ALT),
      virological (HCV-RNA) and histological (liver biopsy) examinations. RESULTS: Four
      patients (20%) were withdrawn due to adverse effects. In 6 patients the dose of
      PEG-IFN had to be reduced to 0.5 micro g/kg/week. A reduction in the dose of
      ribavirin in 13/16 cases was due to the onset of anemia. Histological evidence of
      mild acute rejection increased the immunosuppressive regimen in 5/20 patients. At
      the end of the treatment, 75% of the patients had a biochemical response and 55%
      a virological response. The mean METAVIR score, according to activity and
      fibrosis, was A1.8 F2.2 before treatment and A0.3 F1.6 at the end of treatment.
      In 9/20 patients, virological response persisted 6 months after the end of the
      treatment. CONCLUSIONS: Our results suggest that combination therapy by PEG-IFN
      and ribavirin may be well tolerated and beneficial during recurrent hepatitis C
      in liver transplant recipients.

PMID- 15030985
TI  - The impact of peginterferon alfa-2a plus ribavirin combination therapy on health
      related quality of life in chronic hepatitis C.
AB  - BACKGROUND/AIMS: Peginterferon alfa-2a plus ribavirin improves sustained
      virological responses compared with interferon alfa-2b and ribavirin, or
      peginterferon alfa-2a alone in chronic hepatitis C. We examined the impact of
      these treatments on health related quality of life (HRQOL). METHODS: Patients
      (n=1121) were randomized to peginterferon alfa-2a weekly plus ribavirin or
      placebo, or interferon alfa-2b thrice weekly plus ribavirin. HRQOL was assessed
      with the SF-36 Health Survey and Fatigue Severity Scale (FSS). RESULTS: Patients
      receiving peginterferon alfa-2a plus ribavirin reported better HRQOL than those
      receiving interferon alfa-2b plus ribavirin. These differences were statistically
      significant for three SF-36 domains and both FSS scores (p<=0.05). Patients
      receiving peginterferon alfa-2a plus placebo had the least impairment; adding
      ribavirin significantly decreased five domains of the SF-36 and both FSS scores.
      Sustained virological response was associated with improvement at follow-up on
      all SF-36 and FSS scores. CONCLUSIONS: The effects of combination therapy on
      HRQOL and fatigue are less with peginterferon alfa-2a plus ribavirin than
      interferon alfa-2b plus ribavirin. Each medication in combination therapy with
      interferon and ribavirin, affects patients' quality of life differently.
      Understanding the relationship of specific therapeutic options to HRQOL may help
      physicians minimize the impact of therapy on HRQOL.

PMID- 15030986
TI  - Intrahepatic hepatitis C virus RNA quantification in microdissected hepatocytes.
AB  - BACKGROUND/AIMS: Debate continues on whether serum and intrahepatic HCV viral
      loads are correlated and if HCV viral load correlates with the severity of liver
      disease. These difficulties may at least in part be linked to liver cell
      heterogeneity, when total liver extracts from HCV-infected individuals are tested
      for HCV RNA quantification. We have therefore investigated the feasibility of
      quantifying HCV replication using a laser-based microdissection technique.
      METHODS: We compared the results with those obtained for serum HCV RNA
      quantification and immunochemistry in the case of HCV antigen detection in the
      liver. Twenty-one HCV-positive patients with chronic active hepatitis (n=10) or
      cirrhosis (n=11) were analyzed. RESULTS: A positive correlation (P=0.0019) was
      observed between HCV RNA quantifications in sera and microdissected cells.
      Immunohistochemistry demonstrated that HCV antigen hepatocytes were randomly
      distributed within liver lobules. Their percentage varied in different patients
      (0-40%), but did not correlate with the HCV viral load. CONCLUSIONS: We have
      designed a sensitive methodology to evaluate the intrahepatic HCV viral load by
      combining a standardized RNA quantification method with microdissected
      hepatocytes from frozen liver needle biopsies. Our results directly demonstrate a
      positive correlation between serum and intrahepatic viral loads, which therefore
      provides a reliable reflection of intrahepatic HCV replication.

PMID- 15030987
TI  - Reduction of relapse rates by 18-month treatment in chronic hepatitis C. A
      Benelux randomized trial in 300 patients.
AB  - BACKGROUND/AIMS: Treatment of chronic hepatitis C with interferon can be
      ineffective due to relapse. We aimed to reduce the 40% relapse rate of 6 months
      interferon-ribavirin combination therapy by prolonging treatment to 18 months.
      METHODS: Three hundred patients with treatment-naive hepatitis C, were randomized
      to 18 months combination therapy with interferon (3MU tiw) and ribavirin (1000
      1200 mg/day), 18 months interferon combined with placebo, or 6 months combination
      therapy with interferon and ribavirin, in a double blinded manner. All 295
      patients who received at least one dose of treatment were included in the
      intention to treat analysis. RESULTS: At the end of treatment, HCV RNA was
      undetectable in 55 and 49% of those on 6 and 18 months combination therapy,
      respectively, versus 26% of those on monotherapy (P<0.001). The relapse rate was
      38% for 6 months combination therapy, 38% for 18 months monotherapy, and only 13%
      for 18 months combination treatment (P=0.002). The sustained response rates were
      34% for 6 months combination therapy, 16% for 18 months monotherapy and 43% for
      18 months combination therapy (P<0.05). CONCLUSIONS: Reduction of relapse rates
      to 15% or less is feasible by prolongation of interferon-ribavirin treatment to
      18 months.

PMID- 15030988
TI  - Rusty notions of cell injury.

PMID- 15030989
TI  - Changing faces-natural course and treatment of hepatitis C after liver
      transplantation.

PMID- 15030990
TI  - Intestinal absorption of iron in HFE-1 hemochromatosis: local or systemic
      process?

PMID- 15030992
TI  - Severe blunt liver injury treated by angiographic embolization.

PMID- 15030991
TI  - Autosomal dominant iron overload due to a novel mutation of ferroportin1
      associated with parenchymal iron loading and cirrhosis.
AB  - We report the identification of a novel mutation in ferroportin1 in an Australian
      family with autosomal dominant iron overload. The phenotype of iron overload in
      one member of this family is associated with high serum ferritin concentration
      and elevated transferrin saturation. The pattern of iron overload in the liver
      shows accumulation predominantly in parenchymal cells with some Kupffer cell iron
      loading. Although some cases of type 4 haemochromatosis have been associated with
      the development of liver fibrosis this is the first report of a patient with
      fully established cirrhosis at a relatively young age (32 years). The coexistence
      of sarcoidosis in this patient may contribute to the more severe phenotype. This
      report highlights the phenotypic variability that can occur in type 4
      haemochromatosis. Some patients have predominant reticuloendothelial iron loading
      and normal transferrin saturation whereas others have predominant parenchymal
      iron loading and elevated transferrin saturation. The reasons for this
      variability remain to be determined. Interestingly this is the third mutation to
      affect asparagine 144, reinforcing the important role for this amino acid in the
      function of ferroportin1.

PMID- 15030993
TI  - A prospective study of the prevalence of hepatitis B and C virus co-infection
      among patients with chronic renal disease under hemodialysis.

PMID- 15030994
TI  - Atorvastatin as a trigger of autoimmune hepatitis.

PMID- 15030995
TI  - SRD5B1 (AKR1D1) gene analysis in delta(4)-3-oxosteroid 5beta-reductase
      deficiency: evidence for primary genetic defect.

PMID- 15030997
TI  - Calcium is good for the nucleus.

PMID- 15030996
TI  - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) during liver
      regeneration.

PMID- 15030998
TI  - Hepatitis B vaccination after liver transplantation as a strategy to discontinue
      prophylaxis with hepatitis B immune globulin.

PMID- 15030999
TI  - Role of atypical bacterial infection of the lung in predisposition/protection of
      asthma.
AB  - Asthma is a common inflammatory disease of the airways that results in airway
      narrowing and wheezing. Allergic asthma is characterised by a T-helper cell-type
      (Th) 2 response, immunoglobulin (Ig) E production, and eosinophilic influx into
      the airways. Recently, many clinical studies have implicated Mycoplasma
      pneumoniae and Chlamydia pneumoniae in the development and exacerbation of both
      chronic and acute asthma. It is widely accepted that M. pneumoniae and C.
      pneumoniae infections require Th1 immunity for clearance; therefore, according to
      the hygiene hypothesis, these infections should be protective against asthma.
      Here, we review the clinical evidence for the association and mechanisms of
      predisposition to and protection against asthma by these infections. We will
      examine the following question: Is it the absence of infection or the age of the
      individual on infection that confers susceptibility or resistance to asthma and
      does this vary between normal and predisposed individuals? We put forward a
      hypothesis of the effects of these infections on the development and prevention
      of asthma and how novel preventative and treatment strategies involving these
      microbes may be targeted against asthma.

PMID- 15031000
TI  - Ethanol regulation of gamma-aminobutyric acid A receptors: genomic and nongenomic
      mechanisms.
AB  - gamma-Aminobutyric acid(A) (GABA(A)) receptors are ligand-gated ion channels
      that, predominantly, mediate inhibitory synaptic transmission in the CNS. These
      receptors are pentameric complexes that are comprised of subunits from several
      classes (alpha, beta, gamma, delta, ), with each class consisting of several
      isoforms. Chronic ethanol consumption alters GABA(A) receptor function producing
      cellular tolerance to GABA and ethanol, cross-tolerance to benzodiazepines and
      barbiturates, and sensitization to inverse agonists. Recent studies have clearly
      demonstrated that GABA(A) receptors play an important role in ethanol dependence
      and functional properties of GABA(A) receptor are altered following chronic
      ethanol administration. However, the exact mechanisms that account for
      alterations in GABA(A) receptor function following chronic ethanol administration
      have not been resolved. The mechanisms responsible for adaptation of GABA(A)
      receptors to chronic ethanol exposure may involve ethanol-induced changes in cell
      surface expression, subcellular localization, synaptic localization, receptor
      phosphorylation, neurosteroids, and/or changes in GABA(A) receptor subunit
      composition. In this review, we provide an overview of recent data pertaining to
      mechanisms that could be responsible for altered properties and expression of
      GABA(A) receptors following chronic ethanol administration.

PMID- 15031001
TI  - Heat shock proteins in the regulation of apoptosis: new strategies in tumor
      therapy: a comprehensive review.
AB  - Heat shock proteins (Hsp) form the most ancient defense system in all living
      organisms on earth. These proteins act as molecular chaperones by helping in the
      refolding of misfolded proteins and assisting in their elimination if they become
      irreversibly damaged. Hsp interact with a number of cellular systems and form
      efficient cytoprotective mechanisms. However, in some cases, wherein it is better
      if the cell dies, there is no reason for any further defense. Programmed cell
      death is a widely conserved general phenomenon helping in many processes
      involving the reconstruction of multicellular organisms, as well as in the
      elimination of old or damaged cells. Here, we review some novel elements of the
      apoptotic process, such as its interrelationship with cellular senescence and
      necrosis, as well as bacterial apoptosis. We also give a survey of the most
      important elements of the apoptotic machinery and show the various modes of how
      Hsp interact with the apoptotic events in detail. We review caspase-independent
      apoptotic pathways and anoikis as well. Finally, we show the emerging variety of
      pharmacological interventions inhibiting or, just conversely, inducing Hsp and
      review the emergence of Hsp as novel therapeutic targets in anticancer protocols.

PMID- 15031002
TI  - GABAA receptors: building the bridge between subunit mRNAs, their promoters, and
      cognate transcription factors.
AB  - The type A gamma-aminobutyric acid (GABA(A)) receptors mediate the majority of
      fast inhibitory neurotransmission in the CNS, and alterations in GABA(A) receptor
      function is believed to be involved in the pathology of several neurological and
      psychiatric illnesses, such as epilepsy, anxiety, Alzheimer's disease, and
      schizophrenia. GABA(A) receptors can be assembled from eight distinct subunit
      families defined by sequence similarity: alpha(1-6), beta(1-3), gamma(1-3),
      delta, pi, theta, and rho(1-3). The regulation of GABA(A) receptor function in
      the brain is a highly compensating system, influencing both the number and the
      composition of receptors at the cell surface. While transcriptional and
      translational points of control operate in parallel, it is becoming increasingly
      evident that many functional changes in GABA(A) receptors reflect the
      differential gene regulation of its subunits. The fact that certain GABA(A)
      receptor subunit genes are transcribed in distinct cell types during specific
      periods of development strongly suggests that genetic control plays a major role
      in the choice of subunit variants available for receptor assembly. This review
      focuses on the physiological conditions that alter subunit mRNA levels, the
      promoters that may control such levels, and the use of a conceptual framework
      created by bioinformatics to study coordinate and independent GABA(A) receptor
      subunit gene regulation. As this exciting field moves closer to identifying the
      language hidden inside the chromatin of GABA(A) receptor subunit gene clusters,
      future experiments will be aimed at testing models generated by computational
      analysis with biologically relevant in vivo and in vitro assays. It is hoped that
      through this functional genomic approach there will be the identification of new
      targets for therapeutic intervention.

PMID- 15031003
TI  - Simultaneous biological removal of endosulfan (alpha+beta) and nitrates from
      drinking waters using wheat straw as substrate.
AB  - Nitrate and endosulfan (alpha+beta) removal was studied in an upflow biological
      denitrification reactor packed with wheat straw as carbon source and support
      particles for microorganisms. While almost complete nitrate elimination and
      between 65% and 70% endosulfan (alpha+beta) elimination occurred when the
      temperature was higher than 20 degrees C; below that value, nitrate removal
      efficiency decreased to about 10%. Nitrate, dissolved organic carbon (DOC), and
      endosulfan (alpha+beta) removal efficiencies decreased considerably at 1500
      microg/l endosulfan concentration in the batch experiments. Although a high
      removal efficiency was observed for endosulfan (alpha+beta) and nitrate in the
      biological denitrification continuous reactor, the effluent water could not be
      used for drinking purpose because of the unacceptable levels of endosulfan
      (alpha+beta), colour and dissolved organic content. During the continuous study,
      23.4% of the initial weight of wheat straw was lost and 24 g was consumed per
      gram of nitrogen removed. The results of the continuous study showed that 21.3%
      of the endosulfan removal was achieved by adsorption onto the wheat straw and
      68.2% of the endosulfan removal occurred by biological activity and the remaining
      portion was detected in the effluent water.

PMID- 15031004
TI  - Possible influence of lipid content on levels of organochlorine compounds in
      mussels from Galicia coast (Northwestern, Spain). Spatial and temporal
      distribution patterns.
AB  - Influence of lipid content of mussel on levels of organochlorine compounds
      (polychlorinated biphenyls [PCBs] and OC pesticides) has been studied. Mussel
      samples coming from three sites in Galicia coast (Northwestern, Spain), Moana and
      Cangas C from Ria de Vigo and Barallobre from Ria de Ferrol, collected monthly in
      the period from November 2000 to October 2001, have been analysed. Organochlorine
      compounds, PCBs (IUPAC nos. 31, 28, 52, 101, 118, 153, 105, 138, 156 and 180) and
      OC pesticides (pp'-DDE, op'-DDT, pp'-DDT, aldrin, isodrin and endrin) have been
      extracted by means of Soxhlet and determined by using gas chromatography
      (electron capture detector [ECD]) and gas chromatography-mass spectrometry.
      Statistical analysis has been performed using the SPSS statistical package. Few
      compounds were correlated with lipid content (Pearson product-moment
      correlation); for samples coming from Barallobre, only the individual PCBs 31,
      28, 52 (tri- and tetrachlorinated biphenyls) and 180 (heptachlorinated biphenyl)
      presented a significant correlation; for Moana samples, two cyclodiene
      pesticides, endrin and isodrin, presented a slight significant correlation with
      lipid content. From these results, it is deduced that the normalization of the
      concentration of organochlorine compounds to the lipid content is not necessary,
      in this way, avoiding possible error sources associated to the analytical
      determination of the lipid contentor reproductive status of mussel. Multivariate
      techniques (PCA) have been employed in order to study spatial and temporal
      distribution patterns of organochlorine compounds. The great differences found in
      studied samples are mainly related to spatial distribution: separations between
      estuarine bays (samples coming from Ria de Vigo and Ria de Ferrol) and between
      rural and urban zones (samples coming from Moana and Cangas C and samples from
      Barallobre, respectively).

PMID- 15031005
TI  - Distributions of zinc, copper, cadmium and lead in a tropical ultisol after long
      term disposal of sewage sludge.
AB  - Heavy metals present in soils constitute serious environmental hazards from the
      point of view of polluting the soils and adjoining streams and rivers. The
      distribution of heavy metals in a sandy Ultisol (Arenic Kandiustult) in south
      eastern Nigeria subjected to 40 years disposal of sewage wastes (sludge and
      effluents) was studied using two profile pits (S/NSK/1 and S/NSK/2) sited in the
      sewage disposal area and one profile pit (NS/NSK) sited in the non-sewage
      disposal area. Soil samples were collected in duplicate from these soil horizons
      and analyzed for their heavy metal contents. The mean concentrations of Zn, Cu,
      Cd and Pb in the top- and sub-soil horizons of sewage soil were 79.3, 32, 0.29
      and 1.15 mg/kg, respectively. These levels were high enough to constitute health
      and phytotoxic risks. All the metal levels were much higher in the AB horizon in
      the sewage than in the non-sewage soil profile, but Pb and Cu contents were also
      high down to the Bt1 horizon, indicating their apparent relatively high mobility
      in this soil. There was a significant correlation between organic matter (OM) and
      Zn (r=0.818**), and between OM and Cd (0.864**) in the sewage soil. The high OM
      status of the sewage sludge, together with its corresponding low pH, might have
      favoured metal-OM complexation that could reduce heavy metal mobility and
      phytotoxicity in this soil.

PMID- 15031006
TI  - Pesticides in shallow groundwater of Bahawalnagar, Muzafargarh, D.G. Khan and
      Rajan Pur districts of Punjab, Pakistan.
AB  - In Pakistan there is little data on environmental contamination of rural water
      sources by pesticides. This study evaluated pesticide contamination of
      groundwater in four intensive cotton growing districts. Water samples were
      collected from 37 rural open wells in the areas of Bahwalnagar, Muzafargarh, D.G.
      Khan and Rajan Pur districts of Punjab and analysed for eight pesticides which
      are mostly used. Information on types of pesticide used and distance to nearest
      pesticide mixing area and application areas was obtained for each site. From the
      eight pesticides analysed, six pesticides were detected in the water samples.
      Only cypermethrin and cabosulfan were not detected. The percentage of detection
      of bifenthrin, lambda-cyhalothrin, carbofuran, endosulfan, methyl parathion and
      monocrotophos was, respectively 13.5%, 5.4%, 59.4%, 8%, 5.4% and 35.1% in July;
      16.2%, 13.55%, 43.2%, 8%, N.D. (not detected) and 24.3% in October. Maximum
      contamination levels (MCLs) established by the U.S. Environmental Protection
      Agency for drinking water were not exceeded. The study has shown the need for
      monitoring pesticide contamination in rural water resources, and the development
      of drinking water quality standards for specific pesticides in Pakistan. The
      conclusions and recommendations will be disseminated to senior decision makers in
      central and local governments, extension agents and farmers.

PMID- 15031007
TI  - Health risk assessment of emissions of dioxins and furans from a municipal waste
      incinerator: comparison with other emission sources.
AB  - The aim of this study was to calculate the incremental lifetime-risk to dioxins
      and furans (PCDD/Fs) for the population living in the surroundings of a municipal
      solid waste incinerator (MSWI), as well as to establish the potential reduction
      on human health risks as a consequence of the adaptation to the EU legislation on
      pollutant emissions from the MSWI stack. Analytical and modelled results were
      obtained. PCDD/F concentrations in environmental media were determined by means
      of a simple-compartment-multimedia model (air-soil-vegetation model). Predicted
      and measured PCDD/F concentrations in soils and vegetation were compared, and the
      effects of MSWI emissions in the environmental media were determined. Human
      health risks due to PCDD/F emissions from the MSWI were also estimated based on I
      TEQ measured and modelled in various environmental media. Cancer risks due to
      PCDD/F emissions of the plant were 1.07E-07 and 3.08E-09, before and after
      installation of the clean air system, respectively. On the other hand, cancer
      risks due to other PCDD/F emission sources in the area were 5.54E-06 and 1.86E
      06. Total PCDD/F cancer risks (including those from diet) for the population
      living in the vicinity of the MSWI were 1.3E-04 and 4.25E-05, respectively (67.6%
      of reduction). Hazard ratio for total PCDD/F exposure (including diet) decreased
      during the last 5 years from 1.16 to 0.38. The above data show that other
      emission sources of PCDD/Fs also have a notable environmental impact on the area
      under direct influence of the MSWI.

PMID- 15031008
TI  - Effect of arsenic contamination on microbial biomass and its activities in
      arsenic contaminated soils of Gangetic West Bengal, India.
AB  - A study was conducted to see the effect of arsenic contamination on soil quality
      indicators, viz., microbial biomass, soil respiration, fluorescein diacetate and
      dehydrogenase (DHG) activity in arsenic contaminated soils of West Bengal. All
      the parameters were significantly and negatively correlated with all the form of
      arsenic (bioavailable and total) but the microbial metabolic quotient was
      significantly and positively correlated with all forms of arsenic, indicating
      arsenic induced stress to the soil microbial community. This may be due to part
      of the microbial biomass, which is located in the inner parts of the micro
      aggregates of soil, which is affected by arsenic accumulates present in soil
      particles. Linear regression analysis revealed that the bioavailable arsenic
      exerted greater inhibitory effect on the soil microbial population than the total
      arsenic content of soils. Water-soluble arsenic showed more inhibitory effect
      than NaHCO(3) extractable form, in their association with biological properties
      of the contaminated soils. Water-soluble form of arsenic was much more toxic than
      insoluble forms. This signified that with increase in bioavailability, the
      arsenic exerted more inhibitory effect on these parameters. It is thus suggested
      that the microbial biomass, fluorescein diacetate and dehydrogenase activity
      alone and expressed on a soil organic matter basis along with the soil
      respiration parameters can be helpful in assessing the effects of arsenic on the
      size and activity of microbial biomass in soils.

PMID- 15031009
TI  - Naturally occurring thallium: a hidden geoenvironmental health hazard?
AB  - This paper illustrates a real environmental concern and draws attention to the
      fact that natural processes can mobilize thallium (Tl), a highly toxic metal,
      which may enter the food chain as a "hidden health killer" with severe health
      impacts on local human population. Natural processes may be exacerbated by human
      activities such as mining and farming, and may cause enrichment of Tl in the
      environment. In geochemically anomalous areas with concentrated levels of Tl in
      the surface environment (bedrocks, waters, soils, and crops), such as the
      Lanmuchang area in southwestern Guizhou Province, China, it is essential to
      establish base-level values and to pay heed to the geological context of "natural
      contamination," as high concentrations of Tl in bedrocks/ores (6-35,000 mg/kg)
      can lead to enrichment of Tl in the aquatic system (0.005-1100 microg/l in
      groundwaters and 0.07-31 microg/l in surface waters) and soil layers (1.5-124
      mg/kg). In sensitive areas such as the Yanshang area of southwestern Guizhou,
      elevated natural levels of Tl from bedrocks may also cause higher concentrations
      of Tl in the surface environment, and thus more attention must be paid to
      geoenvironmental management of human activities if socio-economic catastrophes
      are to be avoided. Due to high uptake of Tl by crops, Tl can be transferred from
      soils to crops and remarkably concentrated in food crops. Concentrations of 1-500
      mg/kg Tl based on dry weight (DW) were determined in many food crops growing on
      Tl-contaminated arable soils from the Lanmuchang area. The daily intake of 1.9 mg
      of Tl from consumed food crops was estimated for the local adult inhabitant of
      Lanmuchang. Thus, Tl is regarded as a latent health hazard with potential risk of
      toxicity in humans within areas of "natural" contamination by Tl.

PMID- 15031010
TI  - Phytodegradation of extra heavy oil-based drill cuttings using mature reed
      wetland: an in situ pilot study.
AB  - Environmental contamination caused by extra heavy oil-based drill cuttings (DCs)
      is a major problem in the Liaohe Oilfield, northeastern China. To study the
      potential effectiveness of the mature reed wetland in removing extra heavy oil
      contained in drill cuttings, biodegradation of extra heavy oils and study of the
      effects on soil property and ecophysiological and quality indices of reeds were
      carried out in a 2-year in situ pilot experiment. In the wetland, four reed beds
      were used to treat drill cuttings in various loadings: 0 (control), 5, 20, and 40
      kg/m(2), corresponding to 150, 600, and 1200 g/m(2) extra heavy oil hydrocarbons
      (HCs). The obtained results demonstrate that the mature reed wetland was
      effective at degrading extra heavy oils without extra fertilization. Removal
      efficiencies of reed bed 2 in the 0- to 80-cm soil profile increased with time,
      from 90.1% (first harvest season) to 95.8% (second harvest season). After 2
      years, only 4.2% of the initial hydrocarbons residual was retained in the surface
      soil. There was no apparent adverse effects on the surface soil property during
      degradation of extra heavy oils and, actually, the deeper soil property and reed
      quality indices were improved at the end of the experiment. Phytotoxicity,
      resulting in reduction of reed yield, was observed in the most heavily treated
      beds in the first year. However, long-term reed yield recovered robustly. During
      the 2-year period, reed height and leaf number were slightly inhibited.

PMID- 15031011
TI  - Relationship between air pollution and daily mortality in a subtropical city:
      Taipei, Taiwan.
AB  - Air pollution has been associated with daily mortality in numerous studies over
      the past decade. However most of these studies were conducted in the United
      States and Europe with relatively few done in Asia. In the current study, the
      association between ambient air pollution and daily mortality in Taipei, Taiwan's
      largest city which has a subtropical climate was undertaken, for the period 1994
      1998 using a case-crossover analysis. This design is an alternative to Poisson
      time series regression for studying the short-term adverse health effects of air
      pollution. The air pollutants examined included particulate matter (PM(10)),
      sulfur dioxide (SO(2)), ozone (O(3)), nitrogen dioxide (NO(2)), and carbon
      monoxide (CO). The largest observed effect, which was without statistical
      significance, was seen for NO(2) and CO levels on deaths due to respiratory
      diseases (ORs=1.013 and 1.014, respectively). The well established link between
      air pollution levels and daily mortality may not be as strong in cities in
      subtropical areas, although other factors such as differences in pollutant mix or
      the underlying health of the population may explain the lack of a strong
      association in this study. Further studies of this type in cities with varying
      climates and cultures are needed.

PMID- 15031012
TI  - Adsorption and desorption of iodine by various Chinese soils: I. Iodate.
AB  - In order to assess the adsorption of iodate by different soils from China, a
      series of batch experiments were conducted. It was found that soils rich in iron
      oxide had high affinity for iodate. Iodate adsorption isotherms could be well
      fitted with both Langmuir and Freundlich equations. Iodate adsorption by 20
      different soils from China revealed that iodate adsorption was significantly
      correlated with soil organic matter negatively and positively with free iron
      oxide contents. At initial concentration of 4 mg I L(-1), iodate adsorption
      ranged between 9 and 34 mg kg(-1) soil. No correlation between iodate adsorption
      and cation exchange capacity and soil pH was found. For a single soil, there was
      a significant linear relationship between the amounts of iodate adsorbed and
      desorbed, but for a group of different soils, the relationship between the
      amounts of iodate adsorption and desorption followed a nonlinear relationship,
      the deviation mainly occurred at high adsorption side. The relationship between
      K(d) and free aluminum oxide and free iron oxide contents showed an exponential
      relationship for various soils with exception of the soil from Hetian in
      Xinjiang.

PMID- 15031013
TI  - Assessment of the effectiveness of different phosphorus fertilizers to remediate
      Pb-contaminated soil using in vitro test.
AB  - The addition of P-containing amendments was found to effectively reduce the
      bioaccessibility of Pb in soils to the human, using an in vitro test. For all
      treatments with P additions, the removal of soluble Pb in the small intestinal
      phase was observed. The effectiveness of various P treatments in the small
      intestinal phase generally followed this order at the equivalent P addition
      level: hydroxyapatite (HA)>phosphate rock (PR)>HA+single super-phosphate
      (SSP)>SSP. The relatively low effectiveness of P amendments at the gastric phase
      may be explained by the high solubility of pyromorphite at relatively low pH of
      1.7, compared with that at the neutral small intestinal pH. Single super
      phosphate showed the best performance in minimizing the bioaccessibility of Pb in
      the gastric phase, possibly due to its highest solubility at pH 1.7. Single super
      phosphate showed the best performance in minimizing the bioaccessibility of Pb in
      gastric phase, possibly due its highest solubility at pH 1.7. However, in the
      small intestinal phase, SSP appears to be the least effective amendment, possibly
      due to its lowest Ca supply level to replace Pb form exchangeable sites, as
      reflected by its lowest molar Ca/P ratio of 1:2. The disagreement of the
      sequential extraction results with that of the in vitro test results indicated
      that the sequential extraction was not suitable for the assessment of the effect
      of P addition on minimizing the bioaccessibility of Pb to human due to the
      formation of pyromorphite during the extraction procedure. Results from this
      study also suggested that the time required for the in vitro test might be
      shortened for fast screening.

PMID- 15031014
TI  - New regulations to minimize water impairment from animals rely on management
      practices.
AB  - Water pollution from concentrated animal feeding operations (CAFOs) led to
      revised federal regulations in the United States. The regulations provide for the
      greater management of potential sources of agricultural contamination and impose
      additional financial costs on producers. Along with a duty to secure a permit,
      significant changes address coverage of pollutants, separation of production and
      land application areas, effluent limitation guidelines, and differentiating
      agricultural storm water discharges from other discharges. The revised provisions
      require more producers to secure National Pollutant Discharge Elimination System
      permits and mandate that large CAFOs develop technology-based effluent discharge
      limitations involving best management practices. Medium- and small-sized CAFOs
      need to adopt technology-based effluent discharge requirements employing best
      professional judgment. For farms raising animals that are not CAFOs, voluntary
      management practices may be employed to intercept pollutants before they enter
      waterbodies. Additional educational efforts promoting the implementation of
      further management practices that address the agricultural impairment of water
      resources may be needed.

PMID- 15031015
TI  - Modeling soil organic matter dynamics as affected by soil water erosion.
AB  - Soil organic carbon (SOC) stock is an important component of the global carbon
      (C) cycle, which has the potential to influence global climate. In this paper we
      presented an overview of soil organic matter (SOM) models in the context of soil
      erosion and discussed basic processes driving erosion-induced SOC loss. Although
      the mechanism of this loss is poorly understood, erosion influences SOC in two
      ways: redistribution of C within the watershed or ecosystem, and loss of C to the
      atmosphere. Erosion disperses soil, altering its microbiological activity as well
      as water, air and nutrient regimes. This, along with sediment enrichment, has an
      impact on greenhouse gas emission from soil. For most of agricultural settings,
      field studies suggest that cultivation along with soil erosion are the primary
      reasons for SOC loss. Tracing the fate of eroded C is a challenging task.
      Modeling is the approach taken most often. In this paper we discuss approaches
      used in various SOC models to assess erosion-induced C loss from soil in
      agricultural ecosystems. An example with Century model applied to meadow and corn
      soybean rotation under chisel-till demonstrated the model's ability to respond
      well to different erosion scenarios. It was estimated that at soil loss rate of
      10 t ha(-1) year(-1) (value often considered a threshold for maintaining
      productivity) 19% of the total SOC loss would be attributed to erosion after 90
      years of cultivation.

PMID- 15031016
TI  - Characterisation of heavy metal discharge into the Ria of Huelva.
AB  - The Ria of Huelva estuary, in SW Spain, is known to be one of the most heavy
      metal contaminated estuaries in the world. River contribution to the estuary of
      dissolved Cu, Zn, Mn, Cr, Ni, Cd, and As were analysed for the period 1988-2001.
      The obtained mean values show that this contribution, both because of the
      magnitude of total metals (895.1 kg/h), composition, toxicity (8.7 kg/h of
      As+Cd+Pb) and persistence, is an incomparable case in heavy metal contamination
      of estuaries. The amount and typology of heavy metal discharge to the Ria of
      Huelva are related to freshwater flow (and, consequently, to rainfall); as a
      result, two different types of heavy metal discharge can be distinguished in the
      estuary: during low water (50% of the days), with only 19.3 kg/h of heavy metals,
      and during high water or flood (17% of the days), where daily maximum discharge
      of 72,475 kg of heavy metals were recorded, from which 1481 kg were of As, 470 kg
      of Pb, and 170 kg of Cd. In the most frequent situation (77% of the days), the
      Odiel River discharges from 90% to 100% of the freshwater received by the
      estuary. Despite this, the high concentration of heavy metals in the Tinto River
      water causes this river to discharge into the Ria of Huelva 12.5% of fluvial
      total dissolved metal load received by the estuary.

PMID- 15031017
TI  - Accumulation of Pb, Cd, Cu and Zn in plants and hyperaccumulator choice in
      Lanping lead-zinc mine area, China.
AB  - A field survey of higher terrestrial plants growing on Lanping lead-zinc mine,
      China were conducted to identify species accumulating exceptionally large
      concentrations of Pb, Cd, Cu and Zn of 20 samples of 17 plant species.
      Concentrations of Pb and Zn in soil and in plant were higher than that of Cu and
      Cd. Significant difference was observed among the average concentrations of four
      heavy metals in plants (except Cd and Cu) and in soil (except Pb and Zn)
      (P<0.05). For the enrichment coefficient of the four heavy metals in plant, the
      order of average was Pb<Cu<Cd<Zn. Between four heavy metals, only significant
      difference was observed between the enrichment coefficient average of Cd and Cu
      (P<0.05). The enrichment coefficients were higher than 1 in Llex plyneura and
      Rhododendron annae in Paomaping for Pb, Salix cathayana, L. plyneura and R. annae
      in Paomaping for Cd, and R. annae in Paomaping for Zn, respectively.
      Concentrations and enrichment coefficient of Pb, Cd and Zn of Rhododendron were
      higher than that of Gramimeae. Enrichment coefficient of Pb, Cd and Zn were
      bush>tree>herbaceous, and herbaceous grew in soil with the highest concentrations
      of four heavy metals. In different areas, the concentrations of Pb, Cd, Cu and Zn
      in plants and soils and enrichment coefficient were different. Plants in
      Paomaping had more accumulating ability to Pb, Cd and Zn, and plants in Jinfeng
      River had more accumulating ability to Cu. Six plant species, i.e. S. cathayana,
      Lithocarpus dealbatus, L. plyneura, Fargesia dura, Arundinella yunnanensis and R.
      annae in Paomaping, had high accumulation capacity. R. annae in Paomaping had
      hyperaccumulating capacity to Pb, Cd and Zn, L. plyneura to Pb and Cd, and S.
      cathayana to Cd, respectively.

PMID- 15031018
TI  - Tsunami hazards in Europe.
AB  - Tsunami represents one of the most potentially serious forms of coastal flood
      risk. Although much is known on the recorded history of tsunamis for given areas
      of the world, very little information is available on the occurrence of
      palaeotsunamis during prehistory. This is of fundamental importance in
      calculating tsunami flood risk for any given coastal area. Given sufficient
      information on past tsunami activity for a particular coastal area, the numerical
      calculation of aggregate coastal flood risk (including tsunami) for a coastal
      area is very difficult to estimate since one needs also to take into account the
      risk of a tsunami and a storm surge taking place simultaneously during a high
      tide. Estimates of coastal flood risk also need to consider future changes in
      relative sea level caused by the combined effects of global climate change and
      vertical movements of the lithosphere.

PMID- 15031019
TI  - Natural attenuation of contaminated soils.
AB  - Natural attenuation is increasing in use as a low cost means of remediating
      contaminated soil and groundwater. Modelling of contaminant migration plays a key
      role in evaluating natural attenuation as a remediation option and in ensuring
      that there will be no adverse impact on humans and the environment. During
      natural attenuation, the contamination must be characterized thoroughly and
      monitored through the process. In this paper, attenuation mechanisms for both
      organic and inorganic contaminants, use of models and protocols, role of
      monitoring and field case studies will be reviewed.

PMID- 15031020
TI  - The hidden health trauma of child soldiers.

PMID- 15031021
TI  - Oocyte developmental competence after heterotopic transplantation of
      cryopreserved ovarian tissue.

PMID- 15031022
TI  - HIV-1 and immune control: can we change the course of HIV-1?

PMID- 15031023
TI  - Stroke units: the next 10 years.

PMID- 15031026
TI  - Embryo development after heterotopic transplantation of cryopreserved ovarian
      tissue.
AB  - BACKGROUND: Cancer treatments, including chemotherapy, radiotherapy, and radical
      surgery, can induce premature menopause and infertility in hundreds of thousands
      of women of reproductive age every year. One of the ways to possibly preserve
      fertility before these treatments is to cryopreserve ovarian tissue for later
      transplantation. We aimed to restore fertility by cryopreservation and
      transplantation of ovarian tissue. METHODS: Ovarian tissue was cryopreserved from
      a 30-year-old woman with breast cancer before chemotherapy-induced menopause, and
      this tissue was transplanted beneath the skin of her abdomen 6 years later.
      FINDINGS: Ovarian function returned in the patient 3 months after
      transplantation, as shown by follicle development and oestrogen production. The
      patient underwent eight oocyte retrievals percutaneously and 20 oocytes were
      retrieved. Of the eight oocytes suitable for in-vitro fertilisation, one
      fertilised normally and developed into a four-cell embryo. INTERPRETATION:
      Fertility and ovarian endocrine function can be preserved in women by long-term
      ovarian tissue banking.

PMID- 15031028
TI  - Frequency and natural history of subdural haemorrhages in babies and relation to
      obstetric factors.
AB  - BACKGROUND: Subdural haematomas are thought to be uncommon in babies born at
      term. This view is mainly based on findings in symptomatic neonates and babies in
      whom subdural haemorrhages are detected fortuitously. We aimed to establish the
      frequency of subdural haemorrhages in asymptomatic term neonates; to study the
      natural history of such subdural haematomas; and to ascertain which obstetric
      factors, if any, are associated with presence of subdural haematoma. METHODS: We
      did a prospective study in babies who were born in the Jessop wing of the Central
      Sheffield University Hospitals between March, 2001, and November, 2002. We
      scanned neonates with a 0.2 T magnetic resonance machine. FINDINGS: 111 babies
      underwent MRI in this study. 49 were born by normal vertex delivery without
      instrumentation, 25 by caesarean section, four with forceps, 13 ventouse, 18
      failed ventouse leading to forceps, one failed ventouse leading to caesarean
      section, and one failed forceps leading to caesarean section. Nine babies had
      subdural haemorrhages: three were normal vaginal deliveries (risk 6.1%), five
      were delivered by forceps after an attempted ventouse delivery (27.8%), and one
      had a traumatic ventouse delivery (7.7%). All babies with subdural haemorrhage
      were assessed clinically but no intervention was needed. All were rescanned at 4
      weeks and haematomas had completely resolved. INTERPRETATION: Presence of
      unilateral and bilateral subdural haemorrhage is not necessarily indicative of
      excessive birth trauma.

PMID- 15031027
TI  - Relative rates of non-pneumonic SARS coronavirus infection and SARS coronavirus
      pneumonia.
AB  - BACKGROUND: Although the genome of severe acute respiratory syndrome coronavirus
      (SARS-CoV) has been sequenced and a possible animal reservoir identified,
      seroprevalence studies and mass screening for detection of subclinical and non
      pneumonic infections are still lacking. METHODS: We cloned and purified the
      nucleocapsid protein and spike polypeptide of SARS-CoV and examined their
      immunogenicity with serum from patients with SARS-CoV pneumonia. An ELISA based
      on recombinant nucleocapsid protein for IgG detection was tested with serum from
      149 healthy blood donors who donated 3 years previously and with serum positive
      for antibodies against SARS-CoV (by indirect immunofluorescence assay) from 106
      patients with SARS-CoV pneumonia. The seroprevalence of SARS-CoV was studied with
      the ELISA in healthy blood donors who donated during the SARS outbreak in Hong
      Kong, non-pneumonic hospital inpatients, and symptom-free health-care workers.
      All positive samples were confirmed by two separate western-blot assays (with
      recombinant nucleocapsid protein and recombinant spike polypeptide). FINDINGS:
      Western-blot analysis showed that the nucleocapsid protein and spike polypeptide
      of SARS-CoV are highly immunogenic. The specificity of the IgG antibody test
      (ELISA with positive samples confirmed by the two western-blot assays) was 100%,
      and the sensitivity was 94.3%. Three of 400 healthy blood donors who donated
      during the SARS outbreak and one of 131 non-pneumonic paediatric inpatients were
      positive for IgG antibodies, confirmed by the two western-blot assays (total,
      0.48% of our study population). INTERPRETATION: Our findings support the
      existence of subclinical or non-pneumonic SARS-CoV infections. Such infections
      are more common than SARS-CoV pneumonia in our locality.

PMID- 15031029
TI  - Bone tumour and haemodialysis.

PMID- 15031030
TI  - A combined syndrome of juvenile polyposis and hereditary haemorrhagic
      telangiectasia associated with mutations in MADH4 (SMAD4).
AB  - BACKGROUND: Juvenile polyposis and hereditary haemorrhagic telangiectasia are
      autosomal dominant disorders with distinct and non-overlapping clinical features.
      The former, an inherited gastrointestinal malignancy predisposition, is caused by
      mutations in MADH4 (encoding SMAD4) or BMPR1A, and the latter is a vascular
      malformation disorder caused by mutations in ENG (endoglin) or ACVRL1 (ALK1). All
      four genes encode proteins involved in the transforming-growth-factor-beta
      signalling pathway. Although there are reports of patients and families with
      phenotypes of both disorders combined, the genetic aetiology of this association
      is unknown. METHODS: Blood samples were collected from seven unrelated families
      segregating both phenotypes. DNA from the proband of each family was sequenced
      for the ACVRL1, ENG, and MADH4 genes. Mutations were examined for familial
      cosegregation with phenotype and presence or absence in population controls.
      Findings No patient had mutations in the ENG or ACVRL1 genes; all had MADH4
      mutations. Three cases of de-novo MADH4 mutations were found. In one, the
      mutation was passed on to a similarly affected child. Each mutation cosegregated
      with the syndromic phenotype in other affected family members. INTERPRETATION:
      Mutations in MADH4 can cause a syndrome consisting of both juvenile polyposis and
      hereditary haemorrhagic telangiectasia phenotypes. Since patients with these
      disorders are generally ascertained through distinct medical specialties, genetic
      testing is recommended for patients presenting with either phenotype to identify
      those at risk of this syndrome. Patients with juvenile polyposis who have an
      MADH4 mutation should be screened for the vascular lesions associated with
      hereditary haemorrhagic telangiectasia, especially occult arteriovenous
      malformations in visceral organs that may otherwise present suddenly with serious
      medical consequences.

PMID- 15031031
TI  - "African medicine" and Reye's syndrome.

PMID- 15031032
TI  - Post-traumatic stress in former Ugandan child soldiers.
AB  - Worldwide, 300?000 children are currently used as child soldiers in armed
      conflicts. We interviewed 301 former child soldiers who had been abducted by the
      northern Ugandan rebellion movement Lord's Resistance Army. All the children were
      abducted at a young age (mean 12.9 years) and for a long time (mean 744 days).
      Almost all the children experienced several traumatic events (mean six events);
      233 (77%) saw someone being killed, and 118 (39%) had to kill someone themselves.
      71 children also filled in the impact of event scale--revised to assess their
      post-trauma stress reactions. 69 (97%) reported post-traumatic stress reactions
      of clinical importance. The death of a parent, especially of the mother, led to
      an important increase in score for avoidance symptoms (mother alive 16.4, mother
      not alive 21.6; p=0.04), with a high increase for girls (from 15.1 to 25.8), but
      almost no change for boys (from 17.7 to 17.4; p=0.02). Our findings shed light on
      the nature of severe trauma experienced by this group of children, and show a
      high rate of post-traumatic stress reactions.

PMID- 15031033
TI  - HIV-1 specific CD8+ T cells with an effector phenotype and control of viral
      replication.
AB  - Most people infected with HIV-1 cannot control viral replication despite the
      presence of virus-specific CD8+ T cells. It has been postulated that this
      inability is related to the failure of these cells to mature into fully
      differentiated effector cells. We tested this hypothesis by comparing the
      maturation phenotype of virus-specific CD8+ T cells in people who could control
      viral replication off anti-retroviral therapy with those who could not. In five
      patients with treated acute HIV-1-infection, structured treatment interruption
      (STI) induced control of viral replication was associated with expansion of virus
      specific CD8+ T cells with a fully differentiated effector phenotype. These
      effector cells were also expanded in treatment-naive chronically infected
      individuals who spontaneously controlled viral replication, and augmented
      expression of perforin was noted in both settings. Our data show that full
      maturation of virus-specific CD8+ T cells is possible in the context of HIV-1
      infection, and suggest that such maturation might be important in viral control.

PMID- 15031034
TI  - Multiple myeloma.
AB  - Multiple myeloma is a malignant disease of plasma cells that manifests as one or
      more of lytic bone lesions, monoclonal protein in the blood or urine, and disease
      in the bone marrow. Treatment for myeloma has changed beyond recognition in the
      past decade, and now includes state of the art supportive treatment and
      infusional chemotherapy courses, followed for younger patients by high-dose
      melphalan and an autologous transplant. Patients younger than 70 years can now
      expect a doubling of median survival to 5 years, a 20% chance of surviving longer
      than 10 years, and a 50% chance of attaining complete morphological and
      biochemical remission. Bisphosphonate control of bone disease is essential.
      Exploitation of the understanding of the biology of myeloma has led to the
      development of biological treatments, such as thalidomide, CC-5013, and
      bortezomib, which target the myeloma cell and the bone-marrow microenvironment,
      which plays a crucial part in the disease's pathogenesis. These treatments will
      hold the key to future success.

PMID- 15031035
TI  - Multiple myeloma.

PMID- 15031036
TI  - Selenoprotein synthesis and side-effects of statins.
AB  - Statins are possibly the most effective drugs for the prevention and treatment of
      hypercholesterolaemia and coronary heart disease. They are generally well
      tolerated, however, they do cause some unusual side-effects with potentially
      severe consequences, most prominently myopathy or rhabdomyolysis and
      polyneuropathy. We noted that the pattern of side-effects associated with statins
      resembles the pathology of selenium deficiency, and postulated that the mechanism
      lay in a well established, but often overlooked, biochemical pathway--the
      isopentenylation of selenocysteine-tRNA([Ser]Sec). A negative effect of statins
      on selenoprotein synthesis does seem to explain many of the enigmatic effects and
      side-effects of statins, in particular, statin-induced myopathy.

PMID- 15031037
TI  - Ambulances and curfews: delivering health care in Palestine.

PMID- 15031039
TI  - Ambulances and curfews: delivering health care in Palestine.

PMID- 15031040
TI  - Venous thromboembolism in long-distance air travellers.

PMID- 15031041
TI  - Venous thromboembolism in long-distance air travellers.

PMID- 15031044
TI  - Rosuvastatin-warfarin drug interaction.

PMID- 15031042
TI  - Venous thromboembolism in long-distance air travellers.

PMID- 15031045
TI  - Prevention of cholera.

PMID- 15031046
TI  - Prevention of cholera.

PMID- 15031047
TI  - Hepatocellular carcinoma.

PMID- 15031048
TI  - Improvement of water and sanitation for developing countries.

PMID- 15031049
TI  - Hepatocellular carcinoma.

PMID- 15031050
TI  - Long-term effects of protease-inhibitor-based combination therapy.

PMID- 15031053
TI  - Prevalence of Lyme borreliosis.

PMID- 15031052
TI  - Prevalence of iodine deficiency worldwide.

PMID- 15031055
TI  - Prescient description of frontal lobe syndrome in an Edgar Allan Poe tale.

PMID- 15031057
TI  - Amin J Barakat. Interview.

PMID- 15031061
TI  - I told you it was going to happen...

PMID- 15031062
TI  - The death of spine surgery as we know it today.

PMID- 15031063
TI  - Lumbar fusion or no fusion: what is the evidence?

PMID- 15031064
TI  - Instrumented fusions: a need for guidelines and research.

PMID- 15031065
TI  - Pain treatment and spine surgery.

PMID- 15031066
TI  - Wrong disc space level surgery: medicolegal implications.
AB  - BACKGROUND: Operating the wrong disc level for herniated disc disease is a rarely
      reported complication. However, it is considered by many a breach in the standard
      of care. It is not unusual for litigation to result. Sixty-nine cases of wrong
      disc space level surgery were identified; 68 cases were the subject of lawsuits.
      METHODS: Sixty-five lawsuit outcomes were published in a national monthly
      newsletter of malpractice cases, Medical Malpractice Verdicts, Settlements and
      Experts. Two cases came from medicolegal review, one case from a news article,
      and one case for which no claim was made. RESULTS: Thirty-seven cases were
      settled. A plaintiff verdict was rendered in 18 cases and a defense verdict in 13
      cases (42% of the cases that were decided by a jury). CONCLUSIONS: The authors
      summarize steps to reduce the incidence of this misadventure. The authors
      recommend that the patient be advised of this potential and the patient be
      informed of the risk factors when special circumstances exist.

PMID- 15031070
TI  - Posttraumatic total dislocation of the upper thoracic spine.
AB  - BACKGROUND: Difficulty in proper visualization of the upper thoracic spine in
      plain radiographs allows for injuries at this level to be missed, especially in a
      busy trauma center. This window of error is increased when the patient presents
      with no symptoms or signs of neurologic or spinal involvement, as upper thoracic
      dislocations commonly present early. CASE DESCRIPTION: The authors report a 19
      year-old girl who developed progressive paraparesis 18 hours following initial
      presentation with a scalp avulsion injury. Imaging revealed a complete
      dislocation at T1-T2, with cord compression. Emergency surgical decompression and
      reconstruction of her spinal column was performed with a 360-degree
      stabilization. There was immediate neurologic improvement and on follow-up the
      patient is neurologically normal. CONCLUSIONS: The case highlights the difficulty
      in visualization of the upper thoracic spine in routine radiographs taken in a
      casualty setting. Treating physicians should have a low threshold for
      investigation of cervico-thoracic dislocations. The possibility of a delayed
      progressive dislocation should be kept in mind when dealing with injuries with a
      potential for spinal injury.

PMID- 15031071
TI  - Recurrent spinal fistula as result of a rare combination of a perimedullary and
      peridural spinal fistula: case report.
AB  - OBJECTIVES: We report on a patient with the combination of a peridural and a
      perimedullary spinal fistula, which manifested consecutively. The clinical course
      and diagnostic steps reveal important observations helpful in the management of
      this pathology. CASE PRESENTATION: A 61-year-old male patient presented with a
      six-month history of progressive weakness of the lower limbs. Magnetic resonance
      imaging revealed edema and dilated spinal veins of the lower thoracic spinal
      cord. Spinal angiography confirmed the diagnosis of spinal dural fistula at level
      T9 on the left. The patient underwent surgery and the fistula was surgically
      excised. Two months after initial improvement, the clinical symptoms of lower
      limb weakness recurred. On re-angiography a spinal perimedullary fistula was
      found at level T7 that was not apparent on the previous angiogram and on the
      postoperative control angiogram. The patient underwent surgery again, and the
      second fistula was also excised. The clinical symptoms subsequently improved.
      CONCLUSION: The interesting point in this case was the rare combination of a
      peridural and a perimedullary spinal fistula. They presented consecutively and
      could not be identified simultaneously on the first angiogram. Only after closure
      of the first fistula did the second become apparent. We believe that this may be
      a result of a postoperative pressure change in the venous system of the cord.
      After closure of the first fistula, the arterio-venous (AV) shunt of the second
      fistula developed gradually. The possibility of a second fistula should be
      considered in the presence of persistent edema of the cord on magnetic resonance
      imaging (MRI) and subsequent clinical deterioration.

PMID- 15031072
TI  - Rendu-Osler-Weber disease with a giant intracerebral varix secondary to a high
      flow pial AVF: case report.
AB  - BACKGROUND: Intracranial varices are rare and most are associated with vein of
      Galen arteriovenous malformations (AVM) or fistulas (AVF). DESCRIPTION: A 43-year
      old left-handed man presented with right hemihypesthesia and spastic gait.
      Neuroradiological examination revealed a spinal AVF and a giant intracerebral
      varix associated with a high-flow pial AVF. He had recurrent episodes of nasal
      bleeding, which were also confirmed in his mother's medical history, and
      telangiectases in the tip of his tongue and fingers. He was diagnosed with Rendu
      Osler-Weber disease. After resection of the spinal AVF that produced his
      symptoms, we surgically exposed and obliterated the giant varix and AVF under
      intra- and postoperative hypotension and mild barbiturate therapy. The
      arteriovenous shunt was completely obliterated without hyperperfusion of the
      surrounding brain. CONCLUSION: This is an extremely rare case of Rendu-Osler
      Weber disease with a giant intracerebral varix secondary to a high-flow pial AVF
      that did not involve the vein of Galen.

PMID- 15031073
TI  - Preoperative evaluation of the venous system for potential interference in the
      clipping of cerebral aneurysm.
AB  - BACKGROUND: Variations of the venous system affecting the surgical treatment of
      cerebral aneurysm were evaluated using three-dimensional computed tomography
      angiography (3D-CTA) to evaluate the essential aspects of preoperative diagnosis.
      METHODS: This study included 50 patients who underwent clipping of cerebral
      aneurysm through the pterional and trans-sylvan approaches. The 3D-CTA and
      operative findings were compared to assess the characteristics of cases in which
      the veins restrict brain retraction, hinder operative manipulations or require
      sacrifice because of the position in the operative field. RESULTS: Superficial
      sylvian veins that restricted brain retraction were identified in 8 cases. The
      veins entered the cavernous sinus in a relatively high position just below either
      the sphenoid ridge (superior lateral type) or the anterior clinoid process
      (superior medial type), and the veins entering at a more medial position were
      closer to the spatula and tended to be compressed or directly excluded (superior
      medial type). The inferior medial type did not tend to become tense and so did
      not restrict brain retraction. The inferior lateral type hardly affected the
      operative manipulation. The first segment of the basal vein of Rosenthal, the
      uncal vein entering the cavernous sinus, or the sphenoparietal sinus were located
      in the operative field in six cases, and affected the manipulation of dissecting
      arteries, and exposure and clipping of the aneurysm. CONCLUSIONS: 3D-CTA provides
      essential information for operative planning to protect the venous system during
      the pterional and trans-sylvian approaches.

PMID- 15031077
TI  - Cerebrovascular disease in 2025.

PMID- 15031075
TI  - Rebleeding of a vertebral artery dissecting aneurysm during stent-assisted coil
      embolization: a pitfall of the "stent and coil" technique.
AB  - BACKGROUND: A stent-assisted coil embolization has been applied as a novel choice
      of treatment for vertebral artery dissecting aneurysms (VADAs). CLINICAL
      PRESENTATION: A 45-year-old man suffered from subarachnoid hemorrhage three times
      within 2 hours. The left vertebral angiogram showed a VADA at the distal origin
      of the posterior inferior cerebellar artery. The right vertebral artery was
      hypoplastic, and collateral circulation to the posterior fossa was poor.
      INTERVENTION: Stent-assisted coil embolization was performed under general
      anesthesia. The aneurysm was excluded from the circulation with good patency of
      the vertebral artery, although the fourth coil caused rebleeding from the
      aneurysmal dome during the procedure. CONCLUSION: This is the first case report
      that demonstrates rebleeding from VADA during stent-assisted coil embolization in
      the acute stage of its rupture. We have to be aware of the risks and be ready to
      prevent fatal complications with this novel technique.

PMID- 15031078
TI  - Surgical management of brachial plexus region tumors.
AB  - BACKGROUND: Brachial plexus region tumors are uncommon and often present a
      challenge to neurosurgeons. METHODS: Provide a brief historical overview, a
      description of the anatomy, and contribute information that provides management
      guidelines and improves surgical outcomes for tumors of the brachial plexus
      region. We also review different surgical approaches followed by surgical outcome
      from recent studies, as well as our own experience of treating 42 patients with
      tumors of the brachial plexus region at the University of Pennsylvania Medical
      Center between 1990 and 2001. RESULTS: A thorough understanding of the anatomy,
      the clinical presentation, imaging techniques, and the various surgical
      approaches for brachial plexus tumor resection is necessary to ensure the best
      possible treatment outcome. CONCLUSION: We conclude that with proper patient
      selection and appropriate perioperative and intraoperative management, neurologic
      deficits from brachial plexus tumor surgery can be minimized.

PMID- 15031079
TI  - Common peroneal nerve palsy as a complication of anterior cervical operation: a
      case report.
AB  - BACKGROUND: Common peroneal nerve palsy is a well-recognized complication
      following orthopedic procedure in and around the knee region. In neurosurgical
      practice, however, this kind of injury with regard to the patients' position is
      seldom reported. CASE DESCRIPTION: We describe an immediately developed common
      peroneal nerve palsy in a 53-year-old slender man who underwent anterior cervical
      operative procedure. He suffered incomplete common peroneal nerve injury for
      about 8 months and during this period, he underwent 2 electromyographic
      examinations suggesting demyelinating injury. He received conservative treatment
      including physiotherapy and rigid foot orthosis and finally made a favorable but
      incomplete recovery. CONCLUSION: We propose that such palsy may result from
      immobilization in a certain position instead of direct compression or traction of
      the corresponding nerve, although this is not proven. In this report, we suggest
      the possible risk factors, preventive measures, therapeutic options, and relevant
      outcome of this unwanted result.

PMID- 15031081
TI  - Intracavernous granular cell tumor.
AB  - BACKGROUND: Granular cell tumors in the central nervous system are quite rare. To
      date, only 6 cases of granular cell tumor arising from cranial nerves have been
      reported in the literature. To the best of our knowledge, we present the first
      case of a predominant intracavernous granular-cell tumor arising from oculomotor
      nerve. CASE PRESENTATION: A 42-year-old man presented with third-nerve paresis
      and decreased visual acuity on the left side. Magnetic resonance imaging showed a
      mainly intracavernous mass partially extending to the superior orbital fissure
      and entrance of the optic canal. Using a pterional craniotomy, the tumor was
      removed from within the cavernous sinus via combined superior and lateral
      intradural approach, and optic nerve was also decompressed. Histologically, the
      tumor was diagnosed as a granular cell tumor. CONCLUSIONS: Although it is quite
      rare, granular cell tumor should be included into the differential diagnosis of
      intracavernous masses because surgical treatment is curative.

PMID- 15031083
TI  - Benign fronto-orbital osteoblastoma arising from the orbital roof: case report
      and literature review.
AB  - BACKGROUND: Osteoblastoma is an uncommon benign osteogenic neoplasm that rarely
      involves the orbit. Intracranial and intraorbital extension causing neurologic
      and ophthalmologic symptoms and signs is very unusual. We report the case of an
      osteoblastoma of the orbital cavity with ethmoidal and anterior cranial fossa
      extension presenting as unilateral proptosis. Manifestations and management of
      this rare fronto-orbital lesion are discussed, and the relevant literature is
      reviewed. CASE DESCRIPTION: This 22-year-old man experienced a 3-month history of
      progressive left proptosis without neurologic symptoms. Computed tomography and
      magnetic resonance imaging scans demonstrated a bony mass involving the roof of
      the left orbit and extending laterally to the adjacent ethmoid cells and upward
      to the lower part of the homolateral frontal convexity without parenchymal
      abnormality. A presumptive diagnosis of osteoma was considered. A left fronto
      orbital craniotomy was performed. At surgery, the tumor was well circumscribed by
      a sclerotic margin. It was granular with bony spicules, destroying the orbital
      roof and involving the orbital cavity, ethmoidal cells, and anterior cranial
      fossa. The lesion was totally removed, and the anterior cranial base
      reconstructed. The histologic features were typical of benign osteoblastoma.
      After a follow-up period of 12 months, the patient has remained well without
      evidence of recurrence. CONCLUSION: Osteoblastoma should be considered in the
      differential diagnosis with other fronto-orbital bone-forming lesions. Although
      generally regarded as benign, a complete resection is recommended to prevent the
      possibility of postoperative recurrence and malignant transformation. Twelve
      previously reported cases were also reviewed.

PMID- 15031085
TI  - Microvascular decompression for hemifacial spasm caused by the vertebral artery:
      a simple and effective transposition method using surgical glue.
AB  - BACKGROUND: Microvascular decompression for the treatment of trigeminal neuralgia
      and hemifacial spasm (HFS) has been established and has brought about excellent
      results. However, recurrence or lack of relief from the symptoms was experienced
      in some cases in which the nerve root or root exit zone were compressed by the
      vertebral (VA) and basilar arteries. We experienced a severe HFS case, mainly
      caused by a compression with the tortuous VA. A more simple transposition
      technique of the offending VA using surgical glue is reported. METHODS: A 64-year
      old male had been suffering from HFS for six years. The tortuous right VA with
      anterior inferior cerebellar arteries (AICA) was considered to be responsible for
      his vascular compression syndrome. The VA was carefully and slowly dislocated
      away from the pontomedullary junction toward the cranial base. Then the
      arteriosclerotic portion of the VA wall was chosen, where a small piece of
      Surgicel (ETHICON, Inc., Somerville, NJ) is placed beforehand so as to use a
      minimum amount of glue (Biobond; Mitsubishi Pharma Corp., Osaka, Japan). Until
      the glue is hardened, the VA is held away from the brain stem. After this
      procedure, the ordinary transposition of AICA branches was added. RESULTS: The
      annoying HFS completely disappeared immediately after the operation. CONCLUSION:
      The advantage of our method is the simplicity of the procedure. It requires less
      space and time while the other methods using tapes, strips, and clips need a
      greater working space and more time.

PMID- 15031087
TI  - Characteristics of an entrepreneur.

PMID- 15031086
TI  - Concerns of the young neurosurgeon.

PMID- 15031088
TI  - Motion repulsion is monocular.
AB  - Motion repulsion is the illusory enlargement of the angle between objects moving
      in two different directions of motion. Previous work suggests that motion
      repulsion occurs under dichoptic conditions, and therefore is binocular. In
      reference repulsion the direction of motion is misperceived even if only a single
      direction of motion is presented. In an experiment I show that repulsion under
      dichoptic conditions is correlated with reference repulsion, but not with
      binocular motion repulsion. This suggests that motion repulsion proper, which
      occurs over and beyond reference repulsion, does not occur under dichoptic
      conditions, implying that motion repulsion is monocular.

PMID- 15031089
TI  - Crowding under scotopic conditions.
AB  - Under certain circumstances, a subject's ability to discriminate spatial features
      of a target may be hampered by neighbouring contours. This phenomenon is
      popularly known as the "crowding effect", and it has been intensely studied for
      photopic vision: little attention has been paid to the effect at lower light
      levels. The underlying basis of the crowding effect has recently provoked some
      conjecture, with Hess and colleagues claiming that a passive "physical"
      phenomenon may either wholly [Vis. Res. 40 (2000) 365], or partially [J. Opt.
      Soc. Am. A--Opt. Image Sci. Vis. 17 (2000) 1516], account for the effect. In
      order to investigate the crowding effect under scotopic conditions, we conducted
      scotopic frequency of seeing experiments for Landolt C targets presented both
      with, and without, flanking bars; the size of the targets was varied so that
      frequency of seeing curves could be derived for each stimulus condition. Our
      results suggest that the spatial extent of crowding is significantly less for
      scotopic vision than for photopic vision at the same eccentricity--furthermore
      the effect does not seem to scale in proportion to target size. We also compared
      the resulting empirical curves to those that would be predicted by the hypothesis
      of Hess and colleagues. Our results do not support the hypothesis that the
      scotopic crowding effect is caused by a passive physical process.

PMID- 15031090
TI  - Quantitative properties of achromatic color induction: an edge integration
      analysis.
AB  - Edge integration refers to a hypothetical process by which the visual system
      combines information about the local contrast, or luminance ratios, at luminance
      borders within an image to compute a scale of relative reflectances for the
      regions between the borders. The results of three achromatic color matching
      experiments, in which a test and matching ring were surrounded by one or more
      rings of varying luminance, were analyzed in terms of three alternative
      quantitative edge integration models: (1) a generalized Retinex algorithm, in
      which achromatic color is computed from a weighted sum of log luminance ratios,
      with weights free to vary as a function of distance from the test (Weighted Log
      Luminance Ratio model); (2) an elaboration of the first model, in which the
      weights given to distant edges are reduced by a percentage that depends on the
      log luminance ratios of borders lying between the distant edges and the target
      (Weighted Log Luminance Ratio model with Blockage); and (3) an alternative
      modification of the first model, in which Michelson contrasts are substituted for
      log luminance ratios in the achromatic color computation (Weighted Michelson
      Contrast model). The experimental results support the Weighted Log Luminance
      Ratio model over the other two edge integration models. The Weighted Log
      Luminance Ratio model is also shown to provide a better fit to the achromatic
      color matching data than does Wallach's Ratio Rule, which states that the two
      disks will match in achromatic color when their respective disk/ring luminance
      ratios are equal.

PMID- 15031092
TI  - The blanking phenomenon: a novel form of visual disappearance.
AB  - We describe a novel illusion produced by the scintillating grid. Under specific
      conditions, a light disk presented at an intersection of black squares is
      undetectable. We term this disappearance "blanking;" conditions yielding the
      blanking phenomenon were examined. Results indicate the light disk must be
      presented peripherally, surrounded by at least four black squares for effective
      blanking to occur. Additionally, the grid and disk must be presented
      simultaneously. Dark disks presented in the same configuration remained visible.
      The blanking phenomenon is a unique form of visual disappearance, not dependent
      on adaptation, motion, or masking.

PMID- 15031091
TI  - A fresh look at interocular grouping during binocular rivalry.
AB  - During binocular rivalry, observers sometimes perceive one complete visual object
      even though component features of that perceptually dominant object are
      distributed between the two eyes and are in rivalry against other, dissimilar
      features. This interocular grouping cannot be explained by models of rivalry in
      which one eye or the other is completely dominant at any given moment. But
      perhaps global interocular grouping is achieved by simultaneous local eye
      dominance, wherein portions of one eye's view and complementary portions of the
      other eye's view become dominant simultaneously. To test this possibility, we
      performed two experiments using relatively large, complex figures as rival
      targets. In one experiment we used an "eye-swap" technique to confirm that within
      given, local spatial regions of rivalry it was the region of an eye--not a given
      stimulus feature--that was usually dominant. In a second experiment, we measured
      dominance durations for multiple, local zones of rivalry and then created 1-min
      animations of a global "montage" in which dominance within local regions was
      governed by the distributions of dominance measured empirically. These animations
      included significant periods of time during which global interocular grouping was
      evident; observers viewed these animations intermixed with actual rivalry
      displays, and the resulting tracking data confirmed the similarity in global
      dominance of the two display types. Thus interocular grouping during rivalry does
      not rule out local, eye-based rivalry, although synergistic and top-down
      influences almost certainly provide additional force in the promotion of
      interocular grouping.

PMID- 15031093
TI  - Asymmetry in the perception of motion-in-depth.
AB  - We investigated the anisotropic responses between the detection of motion toward
      and motion away from the observers with expanding/contracting shaded circles. Our
      experiments followed visual search paradigm with two exceptions: (1) the stimulus
      presentation time was fixed for 300 ms and (2) the mean error rates were adopted
      as a dependent variable. In Experiment 1, targets and distractors were defined by
      expanding (or contracting) convex/concave circles. Results of Experiment 1
      suggested that the human visual system is more sensitive to expanding convex
      circles (which create the impression of approaching objects) than others. In
      Experiment 2, the targets and distractors were defined by expanding (or
      contracting) step gradient (top-lighting/bottom-lighting) circles. The results of
      Experiment 2 suggest that the anisotropy for the perception of motion-in-depth
      should not be caused by change of luminance polarity but by change of shading
      cue.

PMID- 15031094
TI  - Eye movements when reading disappearing text: is there a gap effect in reading?
AB  - Readers' eye movements were monitored when they read either normal sentences or
      sentences with masked or disappearing text (in which the fixated word disappeared
      or was masked after 60 ms). The goals of the research were to investigate (1)
      whether a gap effect occurred in reading and (2) the influence of linguistic and
      visual factors on oculomotor control. The results of a number of global analyses
      of eye movements under disappearing text conditions clearly demonstrated that
      there is no gap effect in reading. However, comparative analyses across a number
      of local measures in the experiments indicated that cognitive/lexical processes,
      as well as the continual uptake of visual information, influence eye movement
      control during reading. A persistent visual object throughout fixation caused
      refixations and even when a fixated word had disappeared (or been masked), there
      were significant effects of word frequency and word length.

PMID- 15031095
TI  - Are the original Roelofs effect and the induced Roelofs effect confounded by the
      same expansion of remembered space?

PMID- 15031097
TI  - New method for detecting misrouted retinofugal fibers in humans with albinism by
      magnetoencephalography.
AB  - In humans with albinism, a large percentage of the ganglion cell axons from the
      temporal retina decussate abnormally in the chiasm and synapse in the
      contralateral LGN. The aim of this study was to determine whether the misrouting
      of the optic fibers can be detected by magnetoencephalography (MEG). Visually
      evoked magnetic fields (VEFs) were recorded from three patients with albinism.
      After monocular stimulation, the isofield contour maps of the VEFs showed a
      single current dipole pattern over the contralateral hemisphere in patients with
      albinism. These results clearly illustrated the reduced uncrossed retinofugal
      pathway of patients with albinism.

PMID- 15031098
TI  - A comparison of the effects of ageing upon vernier and bisection acuity.
AB  - While most positional acuity tasks exhibit an age-related decline in performance,
      the effect of ageing upon vernier acuity continues to be the subject of some
      debate. In the present study we employed a stimulus design that enabled the
      simultaneous determination of bisection and vernier acuities in 36 subjects, aged
      between 22 and 84 years. This approach provided a means for directly testing the
      hypothesis that ageing affects bisection acuity but not vernier acuity by
      ensuring that differences in stimulus configuration and in the subject's task
      were kept to an absolute minimum. Optimum thresholds increased as a function of
      age for both bisection and vernier tasks. Inter-subject threshold variability
      also increased with age. Issues surrounding the comparison of absolute vernier
      thresholds across different studies are discussed and two important
      methodological factors are identified: the precise statistical method used to
      estimate thresholds, and the magnitude, in angular terms, of the smallest spatial
      offset of the elements of the vernier stimulus which can be displayed. Comparison
      with previously published data indicates that the discrepancy between this study
      and most previous investigations with respect to the effect of age upon vernier
      performance can be at least partly accounted for by differences in the minimum
      displayable vernier offset. Vernier thresholds do increase with age. The
      increased variability of vernier thresholds in older subjects would appear to
      limit the diagnostic value of the test as a means of enabling normal ageing to be
      distinguished from visual loss due to pathology of the eye or visual system.

PMID- 15031099
TI  - Sequential spatial frequency discrimination is consistently impaired among adult
      dyslexics.
AB  - The degree and nature of dyslexics' difficulties in performing basic visual tasks
      have been debated for more than thirty years. We recently found that dyslexics'
      difficulties in detecting temporally modulated gratings are specific to
      conditions that require accurate comparisons between sequentially presented
      stimuli [Brain 124 (2001) 1381]. We now examine dyslexics' spatial frequency
      discrimination (rather than detection), under simultaneous (spatial forced
      choice) and sequential (temporal forced choice) presentations. Sequential
      presentation (at SOAs of 0.5, 0.75 and 2.25 s) yielded better discrimination
      thresholds among the majority of controls (around 0.5 c/ degrees reference), but
      not among dyslexics. Consequently, there was a (large and significant) group
      effect only for the sequential conditions. Within the same dyslexic group,
      performance on a sequential auditory task, two-tone frequency discrimination, was
      impaired in a smaller proportion of the participants. Taken together, our
      findings indicate that visual paradigms requiring sequential comparisons are
      difficult for the majority of dyslexic individuals, perhaps because deficits
      either in visual perception or in visual memory could both lead to difficulties
      on these paradigms.

PMID- 15031100
TI  - How cells dedifferentiate: a lesson from plants.
AB  - The remarkable regenerative capacity displayed by plants and various vertebrates,
      such as amphibians, is largely based on the capability of somatic cells to
      undergo dedifferentiation. In this process, mature cells reverse their state of
      differentiation and acquire pluripotentiality--a process preceding not only
      reentry into the cell cycle but also a commitment for cell death or trans- or
      redifferentiation. Recent studies provide a new perspective on cellular
      dedifferentiation, establishing chromatin reorganization as its fundamental
      theme.

PMID- 15031101
TI  - Analysis of genes from inner ear developmental-stage cDNA subtraction reveals
      molecular regionalization of the otic capsule.
AB  - Although the gross embryology of inner ear development has been documented for
      several different vertebrate species at a descriptive level, our understanding of
      the molecular mechanisms involved remains rudimentary. Therefore, we have used
      cDNA subtraction and normalization procedures to define genes upregulated in the
      13.5dpc mouse inner ear, a developmental stage where inner ear morphogenesis and
      tissue remodeling is active and differentiation of future hair cells is being
      initiated. We recovered 33 different genes from this subtraction and using gene
      specific primers have confirmed the transcriptional upregulation of 26 of these
      in the 13.5dpc inner ear. Northern analyses were used to investigate splicing
      differences between the inner ear and the whole embryo at 13.5dpc. Spatial
      localization of expression was determined through whole-ear in situ hybridization
      analysis, and selected genes were analyzed in more detail through in situ
      hybridization of tissue sections. These data illustrate that the genes isolated
      in this study are expressed in the developing otic capsule and/or
      neuroepithelium. Furthermore, the expression patterns also reveal molecular
      heterogeneity in the developing capsule and indicate that for some genes, the
      chondrogenic otic capsule is composed of distinct domains of gene expression.

PMID- 15031102
TI  - Identification and analysis of genes from the mouse otic vesicle and their
      association with developmental subprocesses through in situ hybridization.
AB  - The otic vesicle (otocyst) occupies a pivotal position in inner ear development,
      bridging the gap between otic placode determination, and morphogenesis of
      vestibular and auditory compartments. The molecular mechanisms underlying the
      progressive subdivision of the developing inner ear into different compartments,
      and the molecular control and execution of the different developmental processes
      involved, are largely unknown. Since relatively few genes have been implicated in
      these processes, we have undertaken this study to identify genes involved in
      these early embryonic stages. We have used cDNA subtractions of mouse otic
      vesicle against adult liver cDNA, and describe a set of 280 candidate genes. We
      have also performed otic vesicle RNA hybridizations against DNA chips to not only
      confirm the efficacy of the library approach, but also to investigate the utility
      of DNA array alternatives. To begin to dissect potential developmental roles, we
      investigated the spatial pattern of gene expression for a selected set of 80
      genes in developing mouse embryos at mid-gestation by whole-mount in situ
      hybridization. These data illustrate the compartmentalisation of gene expression
      in the otic vesicle for the majority of genes tested, and furthermore, implicate
      many of the genes tested with distinct developmental subprocesses.

PMID- 15031103
TI  - Testis-like development of gonads in female moles. New insights on mammalian
      gonad organogenesis.
AB  - Moles are unique among mammals because all females of several species of genus
      Talpa have bilateral ovotestes (gonads with both ovarian and testicular tissue).
      Based on the analysis of a large sample of embryos, foetuses and infants over a
      13-year period, we have studied the development of the gonads in male and female
      moles of the species Talpa occidentalis. Several new field and laboratory
      procedures were developed specifically to obtain and manage this singular
      material. Our results reveal that gonads of female moles develop according to a
      testis-like pattern, which includes cord formation and mesonephric cell
      migration, and begins at the same time as testis differentiation in males. The
      first signs of sex differentiation do not appear in males but in females. Female
      (but not male) gonads are regionalised with a cortex (precursor of the ovarian
      tissue) and a medulla (precursor of the testicular tissue). Germ cells
      concentrate only in the cortex, so that the medulla soon becomes sterile.
      Testicular tissue development is transiently retarded in females for about a week
      before birth, and resumes afterwards. Development of the ovarian tissue in
      females is considerably delayed with respect to that of testicular tissue in both
      males and females. The molecular characterisation of peritubular myoid cells,
      which are exclusive of testes, evidences the presence of testicular tissue in the
      gonads of female moles, which also contain Leydig cells. However, the absence of
      fully differentiated Sertoli cells indicates that these cells are not responsible
      for triggering the differentiation of such a testicular tissue. Our results are
      also discussed regarding the definition of Sertoli cell morphology and function,
      and the possible role of germ cells in the sex-reversal process. Differences
      observed between XX and XY gonad development in moles suggest that the mammalian
      testis-determining gene, SRY, has an "anti-regionalisation" role during gonadal
      development, at least in those mammalian species in which regionalisation of the
      female gonad occurs.

PMID- 15031104
TI  - The development of signal transduction pathways during epididymal maturation is
      calcium dependent.
AB  - Capacitation has been correlated with the activation of a cAMP-PKA-dependent
      signaling pathway leading to protein tyrosine phosphorylation. The ability to
      exhibit this response to cAMP matures during epididymal maturation in concert
      with the ability of the spermatozoa to capacitate. In this study, we have
      addressed the mechanisms by which spermatozoa gain the potential to activate this
      signaling pathway during epididymal maturation. In a modified Tyrode's medium
      containing 1.7 mM calcium, caput spermatozoa had significantly higher [Ca2+]i
      than caudal cells and could not tyrosine phosphorylate in response to cAMP.
      However, in calcium-depleted medium both caput and caudal cells could exhibit a
      cAMP-dependent phosphorylation response. The inhibitory effect of calcium on
      tyrosine phosphorylation was also observed in caudal spermatozoa using
      thapsigargin, a Ca(2+)-ATPase inhibitor that increased [Ca2+]i and precipitated a
      corresponding decrease in phosphotyrosine expression. We also demonstrate that
      despite the activation of tyrosine phosphorylation in caput spermatozoa, these
      cells remain nonfunctional in terms of motility, sperm-egg recognition and
      acrosomal exocytosis. These results demonstrate that the signaling pathway
      leading to tyrosine phosphorylation in mouse spermatozoa is negatively regulated
      by [Ca2+]i, and that maturation mechanisms that control [Ca2+]i within the
      spermatozoon are critically important during epididymal transit.

PMID- 15031105
TI  - Kruppel-homolog is essential for the coordination of regulatory gene hierarchies
      in early Drosophila development.
AB  - Drosophila development is marked by two major morphogenetic processes:
      embryogenesis and metamorphosis. While insect metamorphosis is known to be
      controlled by the steroid hormone ecdysone, relatively little is known concerning
      the hormonal control of embryogenesis. Here we show that many ecdysone-regulated
      transcripts of metamorphosis are also expressed in a wavelike manner during
      embryogenesis, suggesting that these genes also participate in an embryonic
      ecdysone response. At metamorphosis, the Kruppel-homolog (Kr-h) gene, coding for
      a zinc finger protein, is required during the prepupal ecdysone response. Kr-h
      mutants die at the prepupal-pupal transition. In these mutants, the expression of
      several ecdysone-regulated genes is disrupted and we concluded that Kr-h was a
      key modulator of the hormonal response [Dev. Biol. 221 (2000) 53]. While Kr-h is
      expressed in many tissues at metamorphosis, in embryos expression is restricted
      to neurons. Here, we investigate its role during early Drosophila development
      using new alleles with an earlier lethality than those previously described.
      Although we detect only minor morphological defects in these mutants, we show
      that Kr-h expression is necessary for the early development of Drosophila and
      that, during metamorphosis, Kr-h acts as a modulator of the expression of many of
      these ecdysone-regulated genes.

PMID- 15031106
TI  - p38 MAPK signaling during murine preimplantation development.
AB  - Mitogen-activated protein kinase (MAPK) pathways mediate some important cellular
      processes and are likely to also regulate preimplantation development. The role
      of p38 MAP kinase signaling during murine preimplantation development was
      investigated in the present study. p38 MAPK, p38-regulated or -activated kinase
      (PRAK; MK5), map kinase-activated protein kinase 2 (MK2), and heat shock protein
      25 (hsp25) mRNAs and proteins were detected throughout preimplantation
      development. Two-cell stage embryos cultured in the presence of SB220025 and
      SB203580 (specific inhibitors of p38 MAPK alpha/beta), progressed to the eight
      cell stage with the same frequency as controls; however, treated embryos halted
      their development at the 8- to 16-cell stage. In addition, embryos treated with
      p38 MAPK inhibitors displayed a complete loss of MK2 and hsp25 phosphorylation
      and also a complete loss of filamentous actin as indicated by the absence of
      rhodamine-phalloidin staining. In these inhibitor-treated groups, the embryos
      were composed of a mixture of compacting and noncompacting cells, and the embryos
      were one to two cell divisions behind controls. Treated embryos remained viable
      as the developmental blockade was rescued by removing embryos from the drug
      treatment and placing them in drug-free medium until they progressed to the
      blastocyst stage. This study demonstrates that p38 MAPK activity is required to
      support development through the murine preimplantation interval.

PMID- 15031107
TI  - Gene expression suggests decoupled dorsal and ventral segmentation in the
      millipede Glomeris marginata (Myriapoda: Diplopoda).
AB  - Diplopods (millipedes) are known for their irregular body segmentation. Most
      importantly, the number of dorsal segmental cuticular plates (tergites) does not
      match the number of ventral structures (e.g., sternites). Controversial theories
      exist to explain the origin of this so-called diplosegmentation. We have studied
      the embryology of a representative diplopod, Glomeris marginata, and have
      analyzed the segmentation genes engrailed (en), hedgehog (hh), cubitus
      interruptus (ci), and wingless (wg). We show that dorsal segments can be
      distinguished from ventral segments. They differ not only in number and
      developmental history, but also in gene expression patterns. engrailed, hedgehog,
      and cubitus-interruptus are expressed in both ventral and dorsal segments, but at
      different intrasegmental locations, whereas wingless is expressed only in the
      ventral segments, but not in the dorsal segments. Ventrally, the patterns are
      similar to what has been described from Drosophila and other arthropods,
      consistent with a conserved role of these genes in establishing parasegment
      boundaries. On the dorsal side, however, the gene expression patterns are
      different and inconsistent with a role in boundary formation between segments,
      but they suggest that these genes might function to establish the tergite
      borders. Our data suggest a profound and rather complete decoupling of dorsal and
      ventral segmentation leading to the dorsoventral discrepancies in the number of
      segmental elements. Based on gene expression, we propose a model that may resolve
      the hitherto controversial issue of the correlation between dorsal tergites and
      ventral leg pairs in basal diplopods (e.g., Glomeris) and is suggestive also for
      derived, ring-forming diplopods (e.g., Juliformia).

PMID- 15031108
TI  - Analysis of sex differences in EGC imprinting.
AB  - Sex-specific differences are apparent in the methylation patterns of H19 and Igf2
      imprinted genes in embryonic germ cells (EGCs) derived from 11.5 or 12.5 days
      post coitum (dpc) primordial germ cells (PGCs). Here we studied whether these
      differences are associated either with the sex chromosome constitution of the
      EGCs or with the sex of the genital ridge (testis versus ovary) from which the
      PGCs were isolated. For this purpose we derived pluripotent EGC lines from sex
      reversed embryos, either XY embryos deleted for Sry (XY(Tdym1)) or XX embryos
      carrying an Sry transgene. Southern blotting of the EGC DNA was used to analyze
      the differentially methylated regions of Igf2 and H19. The analysis revealed that
      both genes were more methylated in EGCs with an XY sex chromosome constitution
      than in those with an XX sex chromosome constitution, irrespective of the
      phenotypic sex of the genital ridge from which the EGCs had been derived. We
      conclude that the sex-specific methylation is intrinsic and cell-autonomous, and
      is not due to any influence of the genital ridge somatic cells upon the PGCs.

PMID- 15031109
TI  - Extracellular matrix dynamics during vertebrate axis formation.
AB  - The first evidence for the dynamics of in vivo extracellular matrix (ECM) pattern
      formation during embryogenesis is presented below. Fibrillin 2 filaments were
      tracked for 12 h throughout the avian intraembryonic mesoderm using automated
      light microscopy and algorithms of our design. The data show that these ECM
      filaments have a reproducible morphogenic destiny that is characterized by
      directed transport. Fibrillin 2 particles initially deposited in the segmental
      plate mesoderm are translocated along an unexpected trajectory where they
      eventually polymerize into an intricate scaffold of cables parallel to the
      anterior-posterior axis. The cables coalesce near the midline before the
      appearance of the next-formed somite. Moreover, the ECM filaments define global
      tissue movements with high precision because the filaments act as passive motion
      tracers. Quantification of individual and collective filament "behaviors"
      establish fate maps, trajectories, and velocities. These data reveal a caudally
      propagating traveling wave pattern in the morphogenetic movements of early axis
      formation. We conjecture that within vertebrate embryos, long-range mechanical
      tension fields are coupled to both large-scale patterning and local organization
      of the ECM. Thus, physical forces or stress fields are essential requirements for
      executing an emergent developmental pattern-in this case, paraxial fibrillin
      cable assembly.

PMID- 15031110
TI  - The role of Brn4/Pou3f4 and Pax6 in forming the pancreatic glucagon cell
      identity.
AB  - Brain 4 (Brn4/Pou3f4) and Pax6 are POU-homeodomain and paired-homeodomain
      transcription factors, respectively, that are expressed in the brain and the
      glucagon-expressing cells in the pancreas. Brn4 expression begins at embryonic
      day 10 in the pancreas, just before pax6 and both appear in the glucagon
      immunoreactive cells. At a later time point, E19, no Brn4 co-localization is
      observed with insulin or somatostatin but a rare pancreatic polypeptide (PP)
      producing cell can be found, while Pax6 is found in all endocrine cells. These
      data suggest that brn4 is the only alpha-cell specific transcription factor yet
      identified; therefore, we sought to analyze alpha-cell development and function
      in mice with a targeted disruption of the brn4 gene. In homozygous brn4(-/-)
      mice, pancreatic bud formation, glucagon cell numbers and physiological
      measurements all appear normal. Examination of other transcription factors found
      in the glucagon cells showed normal Pax6 and Nkx2.2 immunoreactivity, suggesting
      that Brn4 does not regulate these transcription factors. Pax6 mutant mice
      (pax6(Sey/Sey)), with a natural inactivating mutation in pax6, have few endocrine
      cells but normal numbers of Brn4 and Nkx2.2 cells. The pancreatic phenotype of
      the pax6 mutants can be rescued with a YAC clone containing the human Pax6 gene.

PMID- 15031111
TI  - Alpha5beta1, alphaVbeta3 and the platelet-associated integrin alphaIIbbeta3
      coordinately regulate adhesion and migration of differentiating mouse trophoblast
      cells.
AB  - During blastocyst implantation, interaction between integrins on the apical
      surface of the trophoblast and extracellular matrix (ECM) in the endometrium
      anchors the embryo to the uterine wall. Strong adhesion of the blastocyst to
      fibronectin (FN) requires integrin signaling initiated by exogenous fibronectin.
      However, it is not known how integrin signaling enhances blastocyst adhesion. We
      present new evidence that the integrin, alphaIIbbeta3, plays a key role in
      trophoblast adhesion to fibronectin during mouse peri-implantation development.
      Trafficking of alphaIIb to the apical surface of the trophoblast increased
      dramatically after blastocysts were exposed to fibronectin, whereas other
      fibronectin-binding integrins, alpha5beta1 and alphaVbeta3, were resident at the
      apical surface before ligand exposure. Functional comparisons among the three
      integrins revealed that ligation of alpha5beta1 most efficiently strengthened
      blastocyst fibronectin-binding activity, while subsequent trophoblast cell
      migration was dependent primarily on the beta3-class integrins. In vivo, alphaIIb
      was highly expressed by invasive trophoblast cells in the ectoplacental cone and
      trophoblast giant cells of the parietal yolk sac. These data demonstrate that
      trafficking of alphaIIb regulates adhesion between trophoblast cells and
      fibronectin as invasion of the endometrium commences.

PMID- 15031112
TI  - Localized maternal factors are required for zebrafish germ cell formation.
AB  - Maternally supplied factors in fertilized eggs play essential roles in the
      establishment of primordial germ cells. In zebrafish, cytoplasm at the distal
      ends of the first and second cleavage furrows has been assumed to contain germ
      lineage determinants, since maternal transcripts of germ lineage-specific genes
      are localized to ends of the cleavage furrows. To investigate whether these parts
      of cytoplasm are required for germ cell formation, we removed all four regions of
      the cytoplasm by glass capillary at the 4-cell stage. Histological analysis
      revealed that the ablation of cytoplasm at the ends of the cleavage planes
      resulted in a severe reduction in the number of germ cells. In addition, the
      expression of germ lineage markers was eliminated by cytoplasmic ablation. These
      results demonstrated that cytoplasm at the distal ends of cleavage furrows is
      essential for germ cell formation. We also found novel localization patterns for
      zDazl and brul mRNAs along the cleavage planes. Our findings provide the first
      direct evidence that localized cytoplasmic factors are indispensable for germ
      cell establishment in zebrafish.

PMID- 15031113
TI  - Expression of a novel secreted factor, Seraf indicates an early segregation of
      Schwann cell precursors from neural crest during avian development.
AB  - The neural crest gives rise to glial cells in the peripheral nervous system.
      Among the peripheral glia, Schwann cells form the myelin often wrapping the
      peripheral axons. Compared to other crest-derived cell lineages such as neurons,
      the analysis of fate determination and subsequent differentiation of Schwann
      cells is not well advanced, partly due to the lack of early markers of this
      phenotype. In this study, we have identified a gene, uniquely expressed in avian
      embryo Schwann cell precursors, which encodes a novel secreted factor, designated
      Seraf (Schwann cell-specific EGF-like repeat autocrine factor). Expression of
      Seraf and P0 delineates the earliest phase of Schwann cell differentiation. Seraf
      binds to neural crest cells and Schwann cells, and affects the distribution of
      Schwann cells, when introduced to chicken embryos during neural crest migration.
      Our results suggest an autocrine function of Seraf and provide a significant step
      to understand the developmental processes of Schwann cell lineage.

PMID- 15031115
TI  - The activation level of the TNF family receptor, Edar, determines cusp number and
      tooth number during tooth development.
AB  - Mutations in members of the ectodysplasin (TNF-related) signalling pathway, EDA,
      EDAR, and EDARADD in mice and humans produce an ectodermal dysplasia phenotype
      that includes missing teeth and smaller teeth with reduced cusps. Using the
      keratin 14 promoter to target expression of an activated form of Edar in
      transgenic mice, we show that expression of this transgene is able to rescue the
      tooth phenotype in Tabby (Eda) and Sleek (Edar) mutant mice. High levels of
      expression of the transgene in wild-type mice result in molar teeth with extra
      cusps, and in some cases supernumerary teeth, the opposite of the mutant
      phenotype. The level of activation of Edar thus determines cusp number and tooth
      number during tooth development.

PMID- 15031114
TI  - Evolutionary conserved role of ptf1a in the specification of exocrine pancreatic
      fates.
AB  - We have characterized and mapped the zebrafish ptf1a gene, analyzed its embryonic
      expression, and studied its role in pancreas development. In situ hybridization
      experiments show that from the 12-somite stage to 48 hpf, ptf1a is dynamically
      expressed in the spinal cord, hindbrain, cerebellum, retina, and pancreas of
      zebrafish embryos. Within the endoderm, ptf1a is initially expressed at 32 hpf in
      the ventral portion of the pdx1 expression domain; ptf1a is expressed in a subset
      of cells located on the left side of the embryo posteriorly to the liver
      primordium and anteriorly to the endocrine islet that arises from the
      posterodorsal pancreatic anlage. Then the ptf1a expression domain buds giving
      rise to the anteroventral pancreatic anlage that grows posteriorly to eventually
      engulf the endocrine islet. By 72 hpf, ptf1a continues to be expressed in the
      exocrine compartment derived from the anteroventral anlage. Morpholino-induced
      ptf1a loss of function suppresses the expression of the exocrine markers, while
      the endocrine markers in the islet are unaffected. In mind bomb (mib) mutants, in
      which delta-mediated notch signalling is defective [Dev. Cell 4 (2003) 67], ptf1a
      is normally expressed. In addition, the slow-muscle-omitted (smu) mutants that
      lack expression of endocrine markers because of a defective hedgehog signalling
      [Curr. Biol. 11(2001) 1358] exhibit normal levels of ptf1a. This indicates that
      hedgehog signaling plays a different genetic role in the specification of the
      anteroventral (mostly exocrine) and posterodorsal (endocrine) pancreatic anlagen.

PMID- 15031116
TI  - Transgenic RNAi-mediated reduction of MSY2 in mouse oocytes results in reduced
      fertility.
AB  - MSY2 is implicated in regulating the stability and translation of maternal mRNAs
      during mouse oogenesis. We report here that by driving the expression of a
      transgene encoding an Msy2 hairpin dsRNA in growing oocytes using the oocyte
      specific Zp3 promoter, the amount of MSY2 protein was reduced by at least 60% in
      fully grown oocytes. The decrease appeared specific because no decrease was
      observed in either non-targeted mRNAs or proteins. Fertility of transgenic
      females was severely reduced. Although transgenic eggs could be inseminated, the
      eggs did not exhibit the normal series of oscillations in intracellular Ca2+,
      resume meiosis, undergo cortical granule exocytosis, or ZP2 cleavage to ZP2f.
      Transgenic oocytes also displayed a higher incidence of both the non-surrounded
      nucleolus chromatin morphology, and abnormal meiotic spindle formation was
      observed following oocyte maturation. Transgenic oocytes contained less total
      mRNA (approximately 75-80% that of non-transgenic oocytes) and displayed a
      reduced level of protein synthesis. Moreover, several of the maturation
      associated changes in protein synthesis failed to occur in the transgenic
      oocytes. These results support a role for MSY2 in stabilizing maternal mRNAs in
      growing oocytes, a process essential to generate meiotically and developmentally
      competent oocytes.

PMID- 15031117
TI  - Timed interactions between the Hox expressing non-organiser mesoderm and the
      Spemann organiser generate positional information during vertebrate gastrulation.
AB  - We report a novel developmental mechanism. Anterior-posterior positional
      information for the vertebrate trunk is generated by sequential interactions
      between a timer in the early non-organiser mesoderm and the organiser. The timer
      is characterised by temporally colinear activation of a series of Hox genes in
      the early ventral and lateral mesoderm (i.e., the non-organiser mesoderm) of the
      Xenopus gastrula. This early Hox gene expression is transient, unless it is
      stabilised by signals from the Spemann organiser. The non-organiser mesoderm and
      the Spemann organiser undergo timed interactions during gastrulation which lead
      to the formation of an anterior-posterior axis and stable Hox gene expression.
      When separated from each other, neither non-organiser mesoderm nor the Spemann
      organiser is able to induce anterior-posterior pattern formation of the trunk. We
      present a model describing that convergence and extension continually bring new
      cells from the non-organiser mesoderm within the range of organiser signals and
      thereby create patterned axial structures. In doing so, the age of the non
      organiser mesoderm, but not the age of the organiser, defines positional values
      along the anterior-posterior axis. We postulate that the temporal information
      from the non-organiser mesoderm is linked to mesodermal Hox expression.

PMID- 15031118
TI  - The presence of FGF2 signaling determines whether beta-catenin exerts effects on
      proliferation or neuronal differentiation of neural stem cells.
AB  - Neural stem cells proliferate and maintain multipotency when cultured in the
      presence of FGF2, but subsequent lineage commitment by the cells is nevertheless
      influenced by the exposure to FGF2. Here we show that FGF2 effects on neural stem
      cells are mediated, in part, by beta-catenin. Conversely, the effects of beta
      catenin in neural stem cells depend in part upon whether there is concurrent
      fibroblast growth factor (FGF) signaling. FGF2 increases beta-catenin signaling
      through several different mechanisms including increased expression of beta
      catenin mRNA, increased nuclear translocation of beta-catenin, increased
      phosphorylation of GSK-3beta, and tyrosine phosphorylation of beta-catenin.
      Overexpression of beta-catenin in the presence of FGF2 helps to maintain neural
      progenitor cells in a proliferative state. However, overexpression of beta
      catenin in the absence of FGF2 enhances neuronal differentiation. Further,
      chromatin immunoprecipitation (ChIP) assays demonstrate that both beta-catenin
      and Lef1 bind directly to the neurogenin promoter, and luciferase reporter assays
      demonstrate that beta-catenin is directly involved in the regulation of
      neurogenin 1 and possibly other proneural genes when neural stem cells are
      cultured in the presence of FGF2. We suggest that the balance between the
      mitogenic effects and the proneural effects of beta-catenin is determined by the
      presence of FGF signaling.

PMID- 15031119
TI  - The mitochondrial-apoptotic pathway is triggered in Xenopus mesoderm cells
      deprived of PDGF receptor signaling during gastrulation.
AB  - Platelet-derived growth factor receptor (PDGFR) signaling is required for normal
      gastrulation in Xenopus laevis. Embryos deprived of PDGFR signaling develop with
      a range of gastrulation-specific defects including spina bifida, shortened
      anteroposterior axis, and reduced anterior structures. These defects arise
      because the involuting mesoderm fails to move appropriately. In this study, we
      determine that inhibition of PDGFR signaling causes prospective head mesoderm
      cells to appear in the blastocoel cavity at the onset of gastrulation, stage 10.
      These aberrant cells undergo apoptosis via the caspase 3 pathway at an embryonic
      checkpoint called the early gastrula transition (EGT). They are TUNEL-positive
      and have increased levels of caspase 3 activity compared to control embryos.
      Apoptotic death of these mesoderm cells can be prevented by co-injection of mRNA
      encoding Bcl-2 or by injection of either a general caspase inhibitor or a caspase
      3-specific inhibitor. Prevention of cell death, however, is not sufficient to
      rescue gastrulation defects in these embryos. Based on these data, we propose
      that PDGFR signaling is necessary for survival of prospective head mesoderm
      cells, and also plays an essential role in the control of their cell movement
      during gastrulation.

PMID- 15031121
TI  - Blood flow conditions in the proximal pulmonary arteries and vena cavae: healthy
      children during upright cycling exercise.
AB  - Diagnostic testing in patients with congenital heart disease is usually performed
      supine and at rest, conditions not representative of their typical hemodynamics.
      Upright exercise measurements of blood flow may prove valuable in the assessment
      of these patients, but data in normal subjects are first required. With the use
      of a 0.5-T open magnet, a magnetic resonance-compatible exercise cycle, and cine
      phase-contrast techniques, time-dependent blood flow velocities were measured in
      the right (RPA), left (LPA), and main (MPA) pulmonary arteries and superior (SVC)
      and inferior (IVC) vena cavae of 10 healthy 10- to 14-yr-old subjects.
      Measurements were made at seated rest and during upright cycling exercise (150%
      resting heart rate). Mean blood flow (l/min) and reverse flow index were computed
      from the velocity data. With exercise, RPA and LPA mean flow increased 2.0 +/-
      0.5 to 3.7 +/- 0.7 (P < 0.05) and 1.6 +/- 0.4 to 2.9 +/- 0.8 (P < 0.05),
      respectively. Pulmonary reverse flow index (rest vs. exercise) decreased with
      exercise as follows: MPA: 0.014 +/- 0.012 vs. 0.006 +/- 0.006 [P = not
      significant (NS)], RPA: 0.005 +/- 0.004 vs. 0.000 +/- 0.000 (P < 0.05), and LPA:
      0.041 +/- 0.019 vs. 0.014 +/- 0.016 (P < 0.05). SVC and IVC flow increased from
      1.5 +/- 0.2 to 1.9 +/- 0.6 (P = NS) and 1.6 +/- 0.4 to 4.9 +/- 1.3 (P < 0.05),
      respectively. A 56/44% RPA/LPA flow distribution at both rest and during exercise
      suggests blood flow distribution is dominated by distal pulmonary resistance.
      Reverse flow in the MPA appears to originate solely from the LPA while the RPA is
      in relative isolation. During seated rest, the SVC-to-IVC venous return ratio is
      50/50%. With light/moderate cycling exercise, IVC flow increases by threefold,
      whereas SVC remains essentially constant.

PMID- 15031120
TI  - Direction-dependent conduction abnormalities in a canine model of atrial
      fibrillation due to chronic atrial dilatation.
AB  - Chronic rapid atrial pacing (RAP) leads to changes that perpetuate atrial
      fibrillation (AF). Chronic atrial dilatation due to mitral regurgitation (MR)
      also increases AF inducibility, but it is not clear whether the underlying
      mechanism is similar. Therefore, we have investigated atrial electrophysiology in
      a canine MR model (mitral valve avulsion, 1 mo) using high-resolution optical
      mapping and compared it with control dogs and with the canine RAP model (6-8 wk
      of atrial pacing at 600 beats/min, atrioventricular block, and ventricular pacing
      at 100 beats/min). At followup, optical action potentials were recorded using a
      16 x 16 photodiode array from 2 x 2-cm left atrial (LA) and right atrial (RA)
      areas in perfused preparations, with pacing electrodes around the field of view
      to study direction dependency of conduction. Action potential duration at 80%
      repolarization (APD(80)) was not different between control and MR but was reduced
      in RAP atria. Conduction velocities during normal pacing were not different
      between groups. However, the MR LA showed increased conduction heterogeneity
      during pacing at short cycle lengths and during premature extrastimuli, which
      frequently caused pronounced regional conduction slowing. Conduction in the MR LA
      during extrastimulation also displayed a marked dependence on propagation
      direction. These phenomena were not observed in the MR RA and in control and RAP
      atria. Thus both models form distinctly different AF substrates; in RAP dogs, the
      decrease in APD(80) may stabilize reentry. In MR dogs, regional LA conduction
      slowing and increased directional dependency, allowing unidirectional conduction
      block and preferential paths of conduction, may account for increased AF
      inducibility.

PMID- 15031122
TI  - Contribution of myocardium hydraulic skeleton to left ventricular wall
      interaction and synergy in dogs.
AB  - The most premature motion change after coronary occlusion is early diastolic
      thinning of the ischemic left ventricular (LV) wall, with concomitant thickening
      of the normoperfused wall. We aimed 1). to demonstrate that these early changes
      are the result of the absence of fluid within the ischemic myocardium (hydraulic
      skeleton) rather than to cell anoxia and 2). to quantitate the contribution of
      the lack of hydraulic skeleton to left ventricular asynergy of contraction in
      seven anesthetized dogs submitted to acute, short-lasting circumflex artery (Cx)
      occlusion (ischemia) and to perfusion of the Cx with an oxygen-free solution
      (anoxia). We analyzed the time course of regional work index (WI, area of the LV
      pressure-wall thickness loop) and regional efficiency (defined as the ratio of WI
      to the maximum possible work). Interwall asynergy was defined as the difference
      between the regional efficiency of the anterior and posterior walls. After 9-10
      s, posterior wall efficiency decreased 37 +/- 6% with anoxia and 72 +/- 3% with
      ischemia (P < 0.025), and interwall asynergy was 0 +/- 6% with anoxia and 32 +/-
      5% with ischemia (P < 0.05). The contribution of absent hydraulic skeleton to
      interwall asynergy (calculated as the difference between %asynergy in anoxia and
      %asynergy in ischemia) was 30 +/- 8% (P < 0.05). In conclusion, the earliest wall
      motion change observed after acute coronary occlusion, namely ischemic wall
      thinning concomitant with normoperfused wall thickening during isovolumic
      relaxation, is the result of the absence of intracoronary fluid. The lack of
      hydraulic skeleton within the myocardium contributes approximately 30% to
      interwall asynergy.

PMID- 15031123
TI  - Saturated glucose uptake capacity and impaired fatty acid oxidation in
      hypertensive hearts before development of heart failure.
AB  - Abnormalities in energy metabolism may play an important role in the development
      of hypertensive heart failure. However, the transition from compensated
      hypertrophy to heart failure is not fully understood in terms of energy
      metabolism. In Dahl salt-sensitive (DS) and salt-resistant (DR) rats, myocardial
      fatty acid and glucose uptake values were determined using (131)I- or (125)I
      labeled 9-methylpentadecanoic acid ((131)I- or (125)I-9MPA), and
      [(14)C]deoxyglucose ([(14)C]DG), fatty acid beta-oxidation was identified using
      thin-layer chromatography, and insulin-stimulated glucose-uptake was observed
      using a euglycemic hyperinsulinemic glucose clamp. Six-week-old rats were fed a
      diet that contained 8% NaCl, which resulted in development of compensated
      hypertrophy in DS rats at 12 wk of age and ultimately led to heart failure by 18
      wk of age. Uptake of [(14)C]DG increased markedly with age in the DS rats,
      whereas (131)I-9MPA uptake was marginally but significantly increased only in
      animals aged 12 wk. The ratio of (125)I-9MPA beta-oxidation metabolites to total
      uptake in the DS rats was significantly lower (P < 0.05) at 12 (37%) and 18 (34%)
      wk compared with at 6 (45%) wk. Insulin increased [(14)C]DG uptake more than
      twofold in the DS rats at 6 wk, although this increase was markedly attenuated at
      12 and 18 wk (11 and 8%, respectively). Our data suggest that in a hypertrophied
      heart before heart failure, fatty acid oxidation is impaired and the capacity to
      increase glucose uptake during insulin stimulation is markedly reduced. These
      changes in both glucose and fatty acid metabolism that occur in association with
      myocardial hypertrophy may have a pathogenic role in the subsequent development
      of heart failure.

PMID- 15031124
TI  - Thrombin inhibitor reduces myocardial infarction in apoE-/- x LDLR-/- mice.
AB  - We have previously shown that atherosclerotic apolipoprotein E-deficient (apoE(-/
      )) x LDL receptor-deficient (LDLR(-/-)) mice develop myocardial infarction when
      exposed to hypoxic stress. This study was performed to assess the role of
      thrombin and thrombosis in this process. ApoE(-/-) x LDLR(-/-) mice were fed a
      cholesterol-rich diet for 8 mo and were then subjected to hypoxic stress while
      receiving isoflurane anesthesia. One group received a bolus dose (5.6
      micromol/kg) of the thrombin inhibitor melagatran, and control animals received
      PBS 10 min before the hypoxic stress. The mice were exposed to 10 min of hypoxia
      followed by normoxia. Ten minutes after the stress, Alzet pumps delivering
      melagatran (20 nmol x kg x (-1)min(-1)) or PBS were implanted, and the mice were
      allowed to recover for 48 h. The cardiac response was analyzed by histology,
      immunohistochemistry, and serum troponin T assay. All animals showed reversible
      ECG changes as a sign of ischemia during hypoxic stress, and 50% developed
      infarctions afterward as judged by troponin T levels. The group that received
      thrombin inhibitor had significantly lower troponin T and smaller myocardial
      infarctions than the PBS-treated group. These data show that thrombin generation
      is an important pathogenetic factor and suggest that coronary thrombosis is
      involved in myocardial infarction in atherosclerotic mice. Exposure of
      atherosclerotic mice to hypoxia leads to myocardial infarction through a two
      phase pathway in which acute transient ischemia is followed by thrombin
      dependent, irreversible, myocardial ischemia and myocardial cell death.

PMID- 15031125
TI  - Introgression of chromosome 13 in Dahl salt-sensitive genetic background restores
      cerebral vascular relaxation.
AB  - To evaluate the potential role of impaired renin-angiotensin system (RAS)
      function in contributing to reduced vascular relaxation in Dahl salt-sensitive
      (S) rats, responses to ACh (10(-6) mol/l) and hypoxia (Po(2) reduction to 40-45
      mmHg) were determined in isolated middle cerebral arteries of Dahl S rats, Brown
      Norway (BN) rats, and consomic rats having chromosome 13 (containing the renin
      gene) or chromosome 16 of the BN rat substituted into the Dahl S genetic
      background (SS-13(BN) and SS-16(BN), respectively). Arteries of BN rats on a low
      salt (LS) diet (0.4% NaCl) dilated in response to ACh and hypoxia, whereas
      dilation in response to these stimuli was absent in Dahl S rats on LS diet.
      Vasodilation to ACh and hypoxia was restored in SS-13(BN) rats on an LS diet but
      not in SS-16(BN) rats. High-salt diet (4% NaCl), to suppress ANG II, eliminated
      vasodilation to hypoxia and ACh in BN and in SS-13(BN) rats. Treatment of SS
      13(BN) rats with the AT(1) receptor antagonist losartan also eliminated the
      restored vasodilation in response to ACh and hypoxia. These studies suggest that
      restoration of normal RAS regulation in SS-13(BN) consomic rats restores vascular
      relaxation mechanisms that are impaired in Dahl S rats.

PMID- 15031126
TI  - Elevated MnSOD is not required for exercise-induced cardioprotection against
      myocardial stunning.
AB  - Endurance exercise provides cardioprotection against ischemia-reperfusion-induced
      myocardial stunning and infarction. A recent study demonstrates that an exercise
      induced increase in myocardial manganese superoxide dismutase (MnSOD) activity is
      essential to protect the heart against infarction. It is unknown if an elevation
      in cardiac MnSOD is also a prerequisite to achieve exercise-induced protection
      against myocardial stunning. Therefore, this study determined if an exercise
      induced increase in myocardial MnSOD activity is a requirement to achieve
      protection against myocardial stunning. Adult male rats remained sedentary or
      performed successive bouts of endurance exercise. Hearts were exposed to 25 min
      of global ischemia followed by reperfusion in an isolated working heart
      preparation. Postischemic recovery of cardiac external work during reperfusion
      was significantly higher (84 +/- 3 vs. 67 +/- 4%) in exercised animals compared
      with sedentary controls. Furthermore, prevention of exercise-induced expression
      of myocardial MnSOD via antisense oligonucleotides did not retard this exercise
      induced protection against myocardial stunning. These data demonstrate that
      exercise-induced increases in cardiac MnSOD activity are not essential to achieve
      exercise-mediated protection against myocardial stunning. Therefore, we conclude
      that different mediators are responsible for exercise-induced cardioprotection
      against myocardial stunning and infarction.

PMID- 15031128
TI  - Vascular endothelial zinc finger 1 is involved in the regulation of angiogenesis:
      possible contribution of stathmin/OP18 as a downstream target gene.
AB  - OBJECTIVE: Vascular endothelial zinc finger 1 (Vezf1) is a recently identified
      zinc finger transcription factor that is expressed in endothelial cells (ECs)
      during vascular development in mouse embryo. Here, we present that Vezf1 was
      expressed in ECs at the site of postnatal angiogenesis. We therefore examined
      whether Vezf1 was involved in the regulation of angiogenesis. METHODS AND
      RESULTS: The specific downregulation of Vezf1 by antisense oligodeoxynucleotide
      (AS-ODN) significantly inhibited the proliferation, migration, and network
      formation of cultured ECs as well as angiogenesis in vivo. Vezf1 AS-ODN
      downregulated the expression of stathmin/oncoprotein18 (OP18), a microtubule
      destabilizing protein, in ECs, whereas transient transfection of Vezf1 cDNA
      increased the expression of stathmin/OP18 in ECs. To explore the relationship
      between Vezf1 and stathmin/OP18, we specifically downregulated stathmin/OP18. We
      found that stathmin/OP18 AS-ODN inhibited the proliferation, migration, and
      network formation of ECs as Vezf1 AS-ODN did. Moreover, Vezf1 AS-ODN decreased
      G2/M population of ECs and increased apoptosis, which reproduced the
      characteristic feature of stathmin/OP18 inhibition. CONCLUSIONS: These results
      suggest that Vezf1 is involved in the regulation of angiogenesis, at least in
      part, through the expression of stathmin/OP18 in ECs.

PMID- 15031127
TI  - Prevention of coronary hyperreactivity in preatherogenic menopausal rhesus
      monkeys by transdermal progesterone.
AB  - OBJECTIVE: To test if transdermal progesterone (P) confers coronary vascular
      protection in surgically menopausal preatherosclerotic rhesus monkeys. METHODS
      AND RESULTS: Ovariectomized rhesus monkeys fed an atherogenic diet (AD) for 19
      months were treated with an investigational transdermal P cream (n=7) or
      identical placebo cream (n=5) for 4 weeks. Aorta and carotids showed fatty
      streaks and Oil Red O staining demonstrated lipid deposition. Serum P levels in P
      treated rhesus monkeys (0.6 ng/mL) were significantly greater than placebo (0.2
      ng/mL). Significant elevation of cholesterol, LDL cholesterol, and HDL
      cholesterol, was noted in all animals. Lp(a) was significantly attenuated in the
      AD-fed P-treated monkeys. Coronary angiographic experiments stimulating
      vasoconstriction by intracoronary injections of serotonin plus U46619 showed
      exaggerated prolonged actions amplified by AD, but significant protection against
      severe prolonged vasoconstriction in P-treated monkeys. Immunocytochemistry
      confirmed co-expression of P and thromboxane prostanoid (TP) receptors in
      coronaries and aorta. Western blotting demonstrated TP receptor attenuation in
      vascular muscle after P treatment. CONCLUSIONS: Coronary hyperreactivity, a
      putative component of coronary artery disease mediated via increased vascular
      muscle thromboxane prostanoid receptors, can be prevented by subphysiological
      levels of P, not only in nonatherosclerotic (previously shown) but also in
      preatherosclerotic primates.

PMID- 15031129
TI  - Tissue angiotensin-converting enzyme in imposed and physiological flow-related
      arterial remodeling in mice.
AB  - OBJECTIVE: To test whether membrane-bound angiotensin I-converting enzyme (t-ACE)
      is involved in arterial remodeling, we applied unilateral carotid artery (CA)
      ligation and studied uterine arteries (UA) before, during, and after pregnancy in
      t-ACE-/- and t-ACE+/+ mice. RESULTS- In CA of t-ACE-/- mice, blood pressure,
      outer diameter (D), and medial cross-sectional area (mCSA) were reduced, whereas
      blood flow (BF) and the number of medial cells (mC) were not modified. In the
      ligated CA, mCSA and number of mC were increased while outer D and distensibility
      were reduced. These changes were significantly less pronounced in t-ACE-/- than t
      ACE+/+ mice. In UA of t-ACE-/- mice, D was larger and mCSA was unaltered. At term
      pregnancy, D and mCSA of the UA were reversibly increased. Structural changes of
      UA during and after pregnancy were comparable in both strains. CONCLUSIONS: t-ACE
      contributes to arterial structure and remodeling. It plays a major role in
      hyperplastic inward remodeling of the CA imposed by blood flow cessation, but it
      is not essential for outward hypertrophic and subsequent inward hypotrophic
      remodeling of the UA during and after pregnancy.

PMID- 15031130
TI  - High glucose-induced alterations in subendothelial matrix perlecan leads to
      increased monocyte binding.
AB  - OBJECTIVE: Hyperglycemia is an independent risk factor for cardiovascular disease
      in diabetic patients, although the link between the two is unknown. These studies
      were designed to model effects of high glucose on an early event in
      atherogenesis: the binding of monocytes to subendothelial matrix (SEM). METHODS
      AND RESULTS: SEM was prepared from human aortic endothelial cells (HAECs) and
      bovine aortic endothelial cells (BAECs) cultured in the presence of low (5
      mmol/L) or high (30 mmol/L) glucose for 3 to 5 days. Monocyte binding was
      significantly higher (P<0.05) to the SEM of both HAEC and BAEC exposed to high
      glucose. This increase was a result of changes in SEM heparan sulfate
      proteoglycans (HSPGs). Metabolic radiolabeling of BAEC demonstrated a 24%
      decrease in [35S]sulfate incorporation into SEM HSPG produced by cells incubated
      in 30 mmol/L versus 5 mmol/L glucose, whereas no glucose-associated differences
      were measured in [35S]methionine incorporation into proteoglycans (PGs) or non-PG
      proteins. Autoradiography revealed 2 high-molecular weight SEM HSPGs. One was a
      hybrid PG that contained both heparan sulfate and chondroitin sulfate/dermatan
      sulfate chains. Both PGs were identified by Western blotting as perlecan.
      CONCLUSIONS: These results illustrate that hyperglycemia-induced structural
      changes in perlecan may result in a SEM that is more favorable to retention of
      monocytes.

PMID- 15031131
TI  - Large artery stiffness is not related to plasma cholesterol in older subjects
      with hypertension.
AB  - OBJECTIVE: Previous studies have demonstrated a prognostic role of large artery
      stiffness in hypertensive subjects and increased stiffness in subjects with
      coronary artery disease. Although plasma cholesterol is an established risk
      factor for cardiovascular disease, its relationship with large artery properties
      in a hypertensive population is unclear. METHODS AND RESULTS: Plasma cholesterol
      and large artery properties were measured at baseline in a subset of participants
      of a randomized controlled trial (ANBP2) evaluating hypertension treatment in
      older (65 to 84 years) subjects. Noninvasive measures of large artery behavior
      were central augmentation index (AI), systemic arterial compliance (SAC), and
      transverse expansion of the aortic arch (aortic distensibility). Arterial
      waveforms acceptable for analysis were obtained in approximately 80% of cases
      yielding valid measurements of AI in 868, SAC in 846, and aortic distensibility
      in 680 subjects. Mean total and high-density lipoprotein (HDL) concentrations
      were 5.5+/-1.0 and 1.4+/-0.5 mmol L(-1). Total and HDL cholesterol and AI were
      greater in females than males, whereas SAC and aortic distensibility were greater
      in males. In multiple regression analyses there were no significant associations
      between stiffness parameters and total or HDL cholesterol. Significant
      independent associations in such analyses were found for mean arterial blood
      pressure, gender, age, height, and heart rate, in keeping with previous findings.
      CONCLUSIONS: In the largest cohort of elderly hypertensive subjects studied to
      date, plasma cholesterol per se was not associated with large artery stiffness.
      Such independence from cholesterol increases the potential for artery stiffness
      measurements to additionally contribute to cardiovascular risk assessment in this
      population.

PMID- 15031132
TI  - Cold-induced thermogenesis mediated by GABA in the preoptic area of anesthetized
      rats.
AB  - Bilateral microinjections of GABA (300 mM, 100 nl) or the GABA(A) receptor
      agonist muscimol (100 microM, 100 nl) into the preoptic area (POA) of the
      hypothalamus increased the rate of whole body O(2) consumption (VO(2)) and the
      body core (colonic) temperature of urethane-chloralose-anesthetized, artificially
      ventilated rats. The most sensitive site was the dorsomedial POA at the level of
      the anterior commissure. The GABA-induced thermogenesis was accompanied by a
      tachycardic response and electromyographic (EMG) activity recorded from the
      femoral or neck muscles. Pretreatment with muscle relaxants (1 mg/kg pancuronium
      bromide + 4 mg/kg vecuronium bromide i.v.) prevented GABA-induced EMG activity
      but had no significant effect on GABA-induced thermogenesis. However,
      pretreatment with the beta-adrenoceptor propranolol (5 mg/kg i.v.) greatly
      attenuated the GABA-induced increase in VO(2) and tachycardic responses.
      Accordingly, the GABA-induced increase in VO(2) reflected mainly nonshivering
      thermogenesis. On the other hand, cooling of the shaved back of the rat by
      contact with a plastic bag containing 28 degrees C water also elicited
      thermogenic, tachycardic, and EMG responses. Bilateral microinjections of the
      GABA(A) receptor antagonist bicuculline (500 microM, 100 nl), but not the vehicle
      saline, into the POA blocked these skin cooling-induced responses. These results
      suggest that GABA and GABA(A) receptors in the POA mediate cold information
      arising from the skin for eliciting cold-induced thermogenesis.

PMID- 15031133
TI  - A mapping study of cardiorespiratory responses to chemical stimulation of the
      midline medulla oblongata in ventilated and freely breathing rats.
AB  - The aim of this study was to examine the cardiorespiratory effects of chemically
      stimulating neurons in the midline medulla oblongata (MM) of artificially
      ventilated and freely breathing anesthetized rats. Earlier studies reported that
      stimulation of the MM elicits increases or decreases in mean arterial pressure
      (MAP) and phrenic nerve activity, depending on the mode and site of stimulation,
      anesthetic, and species. In the first series of experiments, rats were
      anesthetized with urethane, artificially ventilated, paralyzed, and bilaterally
      vagotomized. The rostrocaudal extent of the MM was mapped by microinjections of
      DL-homocysteic acid or L-glutamate (both 100 mM, 100 nl), and, in line with
      previous studies, most injections produced only small responses in MAP, heart
      rate, and splanchnic sympathetic nerve activity. Increases in respiratory
      parameters were evoked in caudal regions. However, activation of a discrete
      region of the MM at the level of the caudal pole of the facial nucleus (CP7)
      consistently caused a dramatic reduction in phrenic nerve amplitude and/or
      frequency and, in six rats, produced a prolonged apnea. The second series of
      experiments was carried out on freely breathing pentobarbitone sodium
      anesthetized rats, with a diaphragmatic electromyogram used to monitor
      respiratory activity. Respiratory activity could again be abolished at CP7 after
      microinjections of glutamate (100 mM, 50 nl); however, these responses were
      accompanied by large decreases in MAP and moderate reductions in heart rate. This
      depression of respiratory activity may be due to activation of propriobulbar
      inhibitory neurons that project to known respiratory centers in the brain stem.

PMID- 15031134
TI  - Mice with deletion of the mitochondrial glycerol-3-phosphate dehydrogenase gene
      exhibit a thrifty phenotype: effect of gender.
AB  - To define the role of mitochondrial glycerol-3-phosphate dehydrogenase (mGPD; EC
      1.1.99.5) in energy balance and intermediary metabolism, we studied transgenic
      mice not expressing mGPD (mGPD-/-). These mice had approximately 14% lower blood
      glucose; approximately 50% higher serum glycerol; approximately 80% higher serum
      triglycerides; and at thermoneutrality, their energy expenditure (Qo(2)) was 15%
      lower than in wild-type (WT) mice. Glycerol-3-phosphate levels and lactate-to
      pyruvate ratios were threefold elevated in muscle, but not in liver, of mGPD-/-
      mice. WT and mGPD-/- mice were then challenged with a high-fat diet, fasting, or
      food restriction. The high-fat diet caused more weight gain and adiposity in mGPD
      /- than in WT female mice, without the genotype differentially affecting Qo(2) or
      energy intake. After a 30-h fast, WT female lost 60% more weight than mGPD-/-
      mice but these latter became more hypothermic. When energy intake was restricted
      to 50-70% of the ad libitum intake for 10 days, mGPD-/- female mice lost less
      weight than WT controls, but they had lower Qo(2) and body temperature. WT and
      mGPD-/- male mice did not differ significantly in their responses to these
      challenges. These results show that the lack of mGPD causes significant
      alterations of intermediary metabolism, which are more pronounced in muscle than
      liver and lead to a thrifty phenotype that is more marked in females than males.
      Lower T(4)-to-T(3) conversion in mGPD-/- females and a greater reliance of normal
      females on mGPD to respond to high-fat diets make the lack of the enzyme more
      consequential in the female gender.

PMID- 15031135
TI  - Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod
      genes.
AB  - In mammals, sleep is regulated by circadian and homeostatic mechanisms. The
      circadian component, residing in the suprachiasmatic nucleus (SCN), regulates the
      timing of sleep, whereas homeostatic factors determine the amount of sleep. It is
      believed that these two processes regulating sleep are independent because sleep
      amount is unchanged after SCN lesions. However, because such lesions necessarily
      damage neuronal connectivity, it is preferable to investigate this question in a
      genetic model that overcomes the confounding influence of circadian rhythmicity.
      Mice with disruption of both mouse Period genes (mPer)1 and mPer2 have a robust
      diurnal sleep-wake rhythm in an entrained light-dark cycle but lose rhythmicity
      in a free-run condition. Here, we examine the role of the mPer genes on the
      rhythmic and homeostatic regulation of sleep. In entrained conditions, when
      averaged over the 24-h period, there were no significant differences in waking,
      slow-wave sleep (SWS), or rapid eye movement (REM) sleep between mPer1, mPer2,
      mPer3, mPer1-mPer2 double-mutant, and wild-type mice. The mice were then kept
      awake for 6 h (light period 6-12), and the mPer mutants exhibited increased sleep
      drive, indicating an intact sleep homeostatic response in the absence of the mPer
      genes. In free-run conditions (constant darkness), the mPer1-mPer2 double mutants
      became arrhythmic, but they continued to maintain their sleep levels even after
      36 days in free-running conditions. Although mPer1 and mPer2 represent key
      elements of the molecular clock in the SCN, they are not required for homeostatic
      regulation of the daily amounts of waking, SWS, or REM sleep.

PMID- 15031136
TI  - Daily exercise facilitates phase delays of circadian melatonin rhythm in very dim
      light.
AB  - Shift workers and transmeridian travelers are exposed to abnormal work-rest
      cycles, inducing a change in the phase relationship between the sleep-wake cycle
      and the endogenous circadian timing system. Misalignment of circadian phase is
      associated with sleep disruption and deterioration of alertness and cognitive
      performance. Exercise has been investigated as a behavioral countermeasure to
      facilitate circadian adaptation. In contrast to previous studies where results
      might have been confounded by ambient light exposure, this investigation was
      conducted under strictly controlled very dim light (standing approximately 0.65
      lux; angle of gaze) conditions to minimize the phase-resetting effects of light.
      Eighteen young, fit males completed a 15-day randomized clinical trial in which
      circadian phase was measured in a constant routine before and after exposure to a
      week of nightly bouts of exercise or a nonexercise control condition after a 9-h
      delay in the sleep-wake schedule. Plasma samples collected every 30-60 min were
      analyzed for melatonin to determine circadian phase. Subjects who completed three
      45-min bouts of cycle ergometry each night showed a significantly greater shift
      in the dim light melatonin onset (DLMO(25%)), dim light melatonin offset, and
      midpoint of the melatonin profile compared with nonexercising controls (Student t
      test; P < 0.05). The magnitude of phase delay induced by the exercise
      intervention was significantly dependent on the relative timing of the exercise
      after the preintervention DLMO(25%) (r = -0.73, P < 0.05) such that the closer to
      the DLMO(25%), the greater the phase shift. These data suggest that exercise may
      help to facilitate circadian adaptation to schedules requiring a delay in the
      sleep-wake cycle.

PMID- 15031137
TI  - Effects of Ca2+ channel antagonists on acetylcholine and catecholamine releases
      in the in vivo rat adrenal medulla.
AB  - To elucidate the types of voltage-dependent Ca(2+) channels controlling ACh and
      catecholamine releases in the in vivo adrenal medulla, we implanted microdialysis
      probes in the left adrenal medulla of anesthetized rats and investigated the
      effects of Ca(2+) channel antagonists on ACh, norepinephrine, and epinephrine
      releases induced by nerve stimulation. The dialysis probes were perfused with
      Ringer solution containing a cholinesterase inhibitor, neostigmine. The left
      splanchnic nerves were electrically stimulated at 2 and 4 Hz before and after
      intravenous administration of Ca(2+) channel antagonists. omega-Conotoxin GVIA
      (an N-type Ca(2+) channel antagonist, 10 microg/kg) inhibited ACh release at 2
      and 4 Hz by approximately 40%, norepinephrine release at 4 Hz by approximately
      50%, and epinephrine release at 2 and 4 Hz by approximately 45%. A fivefold
      higher dose of omega-conotoxin GVIA (50 microg/kg) did not further inhibit these
      releases. omega-Conotoxin MVIIC (a P/Q-type Ca(2+) channel antagonist, 50
      microg/kg) inhibited ACh and epinephrine releases at 4 Hz by approximately 30%.
      Combined omega-conotoxin GVIA (50 microg/kg) and MVIIC (250 microg/kg) inhibited
      ACh release at 2 and 4 Hz by approximately 70% and norepinephrine and epinephrine
      releases at 2 and 4 Hz by approximately 80%. Nifedipine (an L-type Ca(2+) channel
      antagonist, 300 and 900 microg/kg) did not change ACh release at 2 and 4 Hz;
      however, nifedipine (300 microg/kg) inhibited epinephrine release at 4 Hz by 20%,
      and nifedipine (900 microg/kg) inhibited norepinephrine and epinephrine releases
      at 4 Hz by 30%. In conclusion, both N- and P/Q-type Ca(2+) channels control ACh
      release on preganglionic splanchnic nerve endings while L-type Ca(2+) channels do
      not. L-type Ca(2+) channels are involved in norepinephrine and epinephrine
      releases on chromaffin cells.

PMID- 15031138
TI  - alpha-Tropomyosin mutations Asp(175)Asn and Glu(180)Gly affect cardiac function
      in transgenic rats in different ways.
AB  - To study the mechanisms by which missense mutations in alpha-tropomyosin cause
      familial hypertrophic cardiomyopathy, we generated transgenic rats overexpressing
      alpha-tropomyosin with one of two disease-causing mutations, Asp(175)Asn or
      Glu(180)Gly, and analyzed phenotypic changes at molecular, morphological, and
      physiological levels. The transgenic proteins were stably integrated into the
      sarcomere, as shown by immunohistochemistry using a human-specific anti-alpha
      tropomyosin antibody, ARG1. In transgenic rats with either alpha-tropomyosin
      mutation, molecular markers of cardiac hypertrophy were induced. Ca(2+)
      sensitivity of cardiac skinned-fiber preparations from animals with mutation
      Asp(175)Asn, but not Glu(180)Gly, was decreased. Furthermore, elevated frequency
      and amplitude of spontaneous Ca(2+) waves were detected only in cardiomyocytes
      from animals with mutation Asp(175)Asn, suggesting an increase in intracellular
      Ca(2+) concentration compensating for the reduced Ca(2+) sensitivity of isometric
      force generation. Accordingly, in Langendorff-perfused heart preparations,
      myocardial contraction and relaxation were accelerated in animals with mutation
      Asp(175)Asn. The results allow us to propose a hypothesis of the pathogenetic
      changes caused by alpha-tropomyosin mutation Asp(175)Asn in familial hypertrophic
      cardiomyopathy on the basis of changes in Ca(2+) handling as a sensitive
      mechanism to compensate for alterations in sarcomeric structure.

PMID- 15031139
TI  - Tension- and afferent input-associated responses of neuromuscular system of rats
      to hindlimb unloading and/or tenotomy.
AB  - Responses of electromyogram (EMG) in soleus muscle and both afferent and efferent
      neurograms at the fifth lumbar (L(5)) segmental level of spinal cord were
      investigated during acute and chronic unloading induced by hindlimb suspension
      and/or tenotomy in adult rats. The soleus EMG and afferent neurogram decreased 88
      and 37%, respectively, relative to those at quadrupedal posture on the floor
      after acute hindlimb suspension that causes passive shortening of soleus due to
      ankle plantarflexion. However, the afferent neurogram (P < 0.05) and soleus EMG
      (P > 0.05) recorded on the floor increased after tenotomy of synergists.
      Furthermore, the afferent input was inhibited when the soleus EMG disappeared
      after tenotomy of soleus. The afferent neurogram and EMG of the soleus showed
      correlated responses to a variety of treatments, suggesting that the afferent
      neurogram recorded at the L(5) segmental level reflects the neural input
      associated with the activity level of the soleus predominantly. The level of
      efferent neurogram decreased after acute hindlimb suspension but was not
      influenced significantly by tenotomy of synergists and/or soleus itself. The EMG
      and afferent neurograms remained low up to the 4th day but recovered to the
      preexperimental levels within 14 days, due to reorganization of sarcomere number
      and length, as well as the shortening of muscle fiber length and recovery of
      tension development. It is suggested that the levels of EMG and afferent
      neurogram associated with antigravity muscle are closely related to the tension
      development of the muscle.

PMID- 15031140
TI  - Effect of photoperiod on the mechanical response of the pregnant rabbit uterus to
      oxytocin.
AB  - We present findings suggesting that photoperiod is important in determining the
      sensitivity of the late-pregnant rabbit uterus to oxytocin (OT). Longitudinal
      myometrial strips were taken from term-pregnant and estrous rabbits and mounted
      in an organ bath for isometric myographic recording at different times during a
      16:8-h light-dark cycle (lights on 0600-2200; n = 5/group), and the strength of
      contractions was registered in response to the application of OT or KCl. Strength
      of contractions was dose dependent and was up to 200 times greater at doses three
      to four orders of magnitude lower in tissue taken from pregnant animals during
      the light phase (0700 and 1300) than during the dark phase (2400 and 0400).
      Strips from nonpregnant estrous females also showed greater sensitivity and
      contractile force when taken in the light (0700) than in the dark (0400),
      although the differences were not significant. Consistent with the influence of
      photoperiod on uterine sensitivity to OT, strips taken from two groups of
      pregnant females (n = 5/group) maintained on a light-dark cycle advanced 12 h
      showed significantly greater sensitivity and force in response to OT during the
      new subjective light than during the new subjective dark phase. The photoperiod
      dependent contractile response to OT was specific and not simply the result of a
      change in general mechanical properties of the muscle, because administration of
      KCl resulted in dose-dependent contractions of similar magnitude in both the
      light and dark phase. These results are consistent with the fact that rabbits,
      like other nocturnal mammals, typically give birth during the day.

PMID- 15031141
TI  - Inhibition of the formation of EETs and 20-HETE with 1-aminobenzotriazole
      attenuates pressure natriuresis.
AB  - This study examined the effects of chronic blockade of the renal formation of
      epoxyeicosatrienoic acids and 20-hydroxyeicosatetraenoic acid with 1
      aminobenzotriazole (ABT; 50 mg.kg(-1). day(-1) ip for 5 days) on pressure
      natriuresis and the inhibitory effects of elevations in renal perfusion pressure
      (RPP) on Na(+)-K(+)-ATPase activity and the distribution of the sodium/hydrogen
      exchanger (NHE)-3 in the proximal tubule of rats. In control rats (n = 15),
      sodium excretion rose from 2.3 +/- 0.4 to 19.4 +/- 1.8 microeq.min(-1).g kidney
      weight(-1) when RPP was increased from 114 +/- 1 to 156 +/- 2 mmHg. Fractional
      excretion of lithium rose from 28 +/- 3 to 43 +/- 3% of the filtered load.
      Chronic treatment of the rats with ABT for 5 days (n = 8) blunted the natriuretic
      response to elevations in RPP by 75% and attenuated the increase in fractional
      excretion of lithium by 45%. In vehicle-treated rats, renal Na(+)-K(+)-ATPase
      activity fell from 31 +/- 5 to 19 +/- 2 micromol P(i).mg protein(-1).h(-1) and
      NHE-3 protein was internalized from the brush border of the proximal tubule after
      an elevation in RPP. In contrast, Na(+)-K(+)-ATPase activity and the distribution
      of NHE-3 protein remained unaltered in rats treated with ABT. These results
      suggest that cytochrome P-450 metabolites of arachidonic acid contribute to
      pressure natriuresis by inhibiting Na(+)-K(+)-ATPase activity and promoting
      internalization of NHE-3 protein from the brush border of the proximal tubule.

PMID- 15031143
TI  - Identification of cytochrome P450-reductase as the enzyme responsible for NADPH
      dependent lucigenin and tetrazolium salt reduction in rat epididymal sperm
      preparations.
AB  - Lucigenin-dependent chemiluminescence and WST-1 reduction can be detected
      following addition of NADPH to many cell types, including rat epididymal sperm
      suspensions. Although many reports suggest that such a phenomenon is due to
      reactive oxygen species production, other probes-such as MCLA and luminol-that
      are capable of detecting reactive oxygen metabolites do not produce a
      chemiluminescent signal in this model system. Our aim was to purify and identify
      the enzyme catalyzing the NADPH-dependent lucigenin and WST-1 reduction from rat
      epididymal spermatozoa preparations. Here, we show the identity of this enzyme as
      cytochrome P450-reductase. In support of this, a homogenous preparation of this
      protein was capable of reducing lucigenin and WST-1 in the presence of NADPH.
      Moreover, COS-7 cells overexpressing cytochrome P450-reductase displayed a 3-fold
      increase in the aforementioned activity compared with mock-transfected cells.
      Immunolocalization studies and biochemical analysis suggest that the majority of
      the NADPH-lucigenin activity is localized to the epithelial cells present within
      the epididymis. These results emphasize the importance of the direct NADPH
      dependent reduction of superoxide-sensitive probes by cytochrome P450-reductase
      even though this enzyme does not, on its own accord, produce reactive oxygen
      species.

PMID- 15031142
TI  - No evidence for pituitary priming to gonadotropin-releasing hormone in relation
      to luteinizing hormone (LH) secretion prior to the preovulatory LH surge in ewes.
AB  - The purpose of this study was to determine the occurrence of and the regulatory
      mechanisms involved in priming of the pituitary to GnRH before the preovulatory
      LH surge in sheep. Experiment 1: Forty-two ewes had progestagen devices removed
      after 14 days and were assigned to luteal (Lut) or follicular (Foll) groups.
      Fifteen days later, blood sampling was initiated either immediately or 36 h after
      induced luteolysis in groups Lut and Foll, respectively. After 4 h, ewes were
      administered either saline (n = 5) or 250 ng (n = 8) or 10 microg (n = 8) of
      GnRH. Five ewes per treatment group were killed 1 h later, while remaining
      animals were blood sampled for a further 7 h. Experiment 2: Eighteen ewes were
      allocated to Lut and Foll groups (described above). Blood samples were collected
      from 2 h before GnRH (10 microg) treatment until 7 h after. Despite up-regulated
      GnRH-R mRNA levels in Foll ewes, pituitary content and plasma levels of LH and
      LHbeta mRNA levels were similar between groups. Mean FSHbeta mRNA and plasma FSH
      levels were elevated in Lut ewes but declined after GnRH treatment. Inversely,
      plasma estradiol and inhibin-A concentrations were higher in Foll ewes and
      declined after GnRH treatment. Fewer LH(+ve)/secretogranin II(-ve) (SgII(-ve))
      granules were present in gonadotropes of Foll ewes, coincident with increased
      basal LH levels. Fewer smaller sized granules were present after GnRH treatment.
      In conclusion, there was no evidence of self-priming before onset of the
      preovulatory LH surge. Constitutive release of LH(+ve)/SgII(-ve) granules may
      maintain basal LH levels while smaller sized, presumably mature granules may be
      preferentially released after GnRH stimulation.

PMID- 15031144
TI  - A new alternative method for superovulation using passive immunization against
      inhibin in adult rats.
AB  - The present study was undertaken to investigate the effects of passive
      immunoneutralization of endogenous inhibin on ovulation rate and embryo
      development in vivo and in vitro to establish a new alternative superovulation
      method in the adult rat. Female adult rats of Wistar strain were superovulated
      with a single injection of inhibin antiserum (inhibin-AS; 100 or 400 microl) or
      an injection of 20 IU eCG followed by an injection of 10 IU hCG. Untreated
      animals served as controls. Embryos were collected from oviducts or uteri on Days
      1-5 of pregnancy, and the number of embryos and implantation sites were observed.
      On Day 1 of pregnancy, the two-cell-stage embryos were cultured and embryos from
      the 100-microl inhibin-AS group and the control group were transferred to
      recipient females to determine developmental competence. There were no
      significant differences between groups in fertilization rate. The numbers of
      normal embryos in the inhibin-AS-treated groups were significantly higher than
      the control and the eCG-hCG-treated groups throughout Days 1-4 of pregnancy. The
      number of implantation sites observed on Day 5 of pregnancy in the inhibin-AS
      treated groups was significantly higher than both the control and the eCG-hCG
      treated groups. Furthermore, the rate of blastocyst development in vitro in the
      inhibin-AS-treated groups and posttransfer viability in the 100-microl-inhibin-AS
      group were comparable with those of the control group. These results indicate
      that immunoneutralization of endogenous inhibin is a new practical alternative
      for induction of superovulation as a substitution for eCG-hCG method in the adult
      rat.

PMID- 15031145
TI  - A dominant-negative isoform of hypoxia-inducible factor-1 alpha specifically
      expressed in human testis.
AB  - Spermatogenesis in the seminiferous tubuli of the testis occurs under a high
      proliferation rate, suggesting considerable oxygen consumption. Because of the
      lack of blood vessels, the oxygen partial pressure in the lumen of these tubuli
      is very low. We previously identified a testis isoform of the hypoxia-inducible
      factor (HIF)-1alpha in the mouse, termed mHIF-1alphaI.1. Here, we demonstrate
      that expression of mHIF-1alphaI.1 increases during puberty, further demonstrating
      its gene induction in postmeiotic germ cells. Using 5'-rapid amplification of
      cDNA ends, we identified a novel HIF-1alpha isoform in the human testis, called
      hHIF-1alphaTe. Like mHIF-1alphaI.1, hHIF-1alphaTe mRNA is derived from an
      alternative promoter-first exon combination, but with a different genomic
      organization and a different nucleotide sequence. Reverse transcription
      polymerase chain reaction analysis confirmed that hHIF-1alphaTe is exclusively
      expressed in the testis. As determined by immunofluorescence of ejaculated sperm
      cells, HIF-1alpha protein is mainly localized in the postacrosomal head and in
      the midpiece of spermatozoa. Though overlapping with mitochondrial localization
      in human and mouse spermatozoa, neither hHIF-1alphaTe nor hHIF-1alpha associated
      with mitochondria. In contrast with the ubiquitously expressed HIF-1alpha protein
      and the mouse testis-specific mHIF-1alphaI.1 isoform, the hHIF-1alphaTe mRNA
      sequence predicts a protein with an N-terminal truncation of the DNA-binding
      domain. As shown by yeast two-hybrid assays, hHIF-1alphaTe still formed
      heterodimeric complexes with HIF-1beta. However, hHIF-1alphaTe was incapable of
      forming a DNA-binding HIF-1 complex. Overexpression of exogenous hHIF-1alphaTe
      resulted in the inhibition of the endogenous HIF-1 transcriptional activity,
      demonstrating that the testis-specific hHIF-1alphaTe isoform is a dominant
      negative regulator of normal HIF-1 activity.

PMID- 15031148
TI  - What we don't know about eccentric viewing.

PMID- 15031147
TI  - Myopia in Asia.

PMID- 15031149
TI  - The pathogenesis of diabetic retinopathy.

PMID- 15031150
TI  - Ophthalmic surgery and Creutzfeldt-Jakob disease.

PMID- 15031152
TI  - Cost utility of screening and treatment for early age related macular
      degeneration with zinc and antioxidants.
AB  - AIM: To assess the cost effectiveness of high dose zinc and antioxidants for
      delaying and reducing the progression of early age related macular degeneration
      (AMD). BACKGROUND: AMD is the leading cause of severe vision impairment and
      blindness in older people throughout the developed world. It currently affects
      around 420 000 people in the United Kingdom. METHODS: A cost utility analysis
      (CUA) was conducted to estimate the cost per quality adjusted life year (QALY)
      for screening a cohort of men and women, aged 55 years and over, for early AMD
      and then treating them with zinc and antioxidants. The incremental CUA was based
      on a decision analytic model, comparing screening with a no screening comparator
      (current practice). Extensive one way sensitivity analysis of parameters was
      conducted to determine the robustness of the model. RESULTS: In this model the
      cost effectiveness of screening for early AMD was pound 22 722 per quality
      adjusted life year (QALY) saved. The cost per QALY decreased to pound 18 948 if
      photodynamic therapy with verteporfin savings were included. CONCLUSIONS:
      Screening for, and prophylactic treatment of, early AMD is estimated to cost
      around pound 22 700 per QALY saved. This cost falls within accepted levels to
      warrant further investigation. These findings have implications for ophthalmic
      practice and healthcare planning.

PMID- 15031153
TI  - The epidemiology of ocular trauma in rural Nepal.
AB  - AIMS: To estimate the incidence of ocular injury in rural Nepal and identify
      details about these injuries that predict poor visual outcome. METHODS: Reports
      of ocular trauma were collected from 1995 through 2000 from patients presenting
      to the only eye care clinic in Sarlahi district, Nepal. Patients were given a
      standard free eye examination and interviewed about the context of their injury.
      Follow up examination was performed 2-4 months after the initial injury. RESULTS:
      525 cases of incident ocular injury were reported, with a mean age of 28 years.
      Using census data, the incidence was 0.65 per 1000 males per year, and 0.38 per
      1000 females per year. The most common types of injury were lacerating and blunt,
      with the majority occurring at home or in the fields. Upon presentation to the
      clinic, 26.4% of patients had a best corrected visual acuity worse than 20/60 in
      the injured eye, while 9.6% had visual acuity worse than 20/400. 82% were
      examined at follow up: 11.2% of patients had visual acuity worse than 20/60 and
      4.6% had vision worse than 20/400. A poor visual outcome was associated with
      increased age, care sought at a site other than the eye clinic, and severe
      injury. 3% of patients were referred for further care at an eye hospital at the
      initial visit; 7% had sought additional care in the interim between visits, with
      this subset representing a more severe spectrum of injuries. CONCLUSIONS: The
      detrimental effects of delayed care or care outside of the specialty eye clinic
      may reflect geographic or economic barriers to care. For optimal visual outcomes,
      patients who are injured in a rural setting should recognise the injury and seek
      early care at a specialty eye care facility. Findings from our study suggest that
      trained non-ophthalmologists may be able to clinically manage many eye injuries
      encountered in a rural setting in the "developing" world, reducing the demand for
      acute services of ophthalmologists in remote locations of this highly
      agricultural country.

PMID- 15031154
TI  - Can fixation instability improve text perception during eccentric fixation in
      patients with central scotomas?
AB  - BACKGROUND: Oculomotor behaviour was investigated in 14 patients with central
      scotomas from age related macular degeneration (AMD) or Stargardt's disease. A
      scanning laser ophthalmoscope (SLO) was used to project letters and words onto
      the retina and to assess fixation behaviour. Five patients reported while
      deciphering letters that they needed to "move their eye" to prevent the image
      from vanishing. The observation of the SLO fundus images revealed that the
      gradual disappearance of the stimulus did not result from a transient projection
      of the word in the lesion. This prompted the authors to investigate, in an
      experimental setting, whether purposeful changes in fixation position could
      improve the perception of an eccentrically fixated text stimulus. METHODS: Twenty
      normal subjects were asked to alternate fixation, every three to four seconds,
      between two vertically aligned dots, spaced 10 degrees apart, and to report any
      changes in the perception of a laterally located letter, 1.5 degrees in height, 7
      degrees apart and equidistant between the two fixation spots. RESULTS: Nineteen
      subjects reported a transient refreshment of the letter image immediately after
      the realisation of a saccade. Improved perception lasted approximately a second.
      With persistent fixation, they noted a rapid fading effect that reduced letter
      recognition. CONCLUSION: These observations suggest that ocular instability
      during eccentric viewing can have a functional advantage, probably related to
      counteracting Troxler's phenomenon. In addition to alternating between PRLs, it
      appears that saccades related to fixation instability might be valuable and
      improve text perception in individuals with a central scotoma and eccentric
      fixation. This possibility should be taken into consideration when conducting
      visual rehabilitation procedures.

PMID- 15031155
TI  - A protocol for low contamination risk of autologous serum drops in the management
      of ocular surface disorders.
AB  - AIM: To assess microbial contamination of 20% autologous serum (AS) eye drops
      used in a hospital inpatient setting. METHOD: 14 patients received autologous
      serum drops from 4 to 14 days with a cumulative total of 67 days. For each day
      the first and last drop (total 134 samples) was cultured on broth and blood agar.
      RESULTS: Four patients (9 samples) grew Staphylococcus epidermidis only. One
      patient (1 sample) showed Staphylococcus epidermidis and a scanty growth of
      viridans streptococci in the same sample, and on different days the same patient
      grew Staphylococcus aureus in one sample and Staphylococcus epidermidis in
      another sample. One patient (1 sample) grew micrococcus. There was no clinical or
      microbial evidence of infection in any of these six patients. CONCLUSION: This
      study shows that autologous serum drops can be safely used in an inpatient
      setting, under a strict protocol of preparation and storage, without significant
      risk of bacterial contamination and consequent infection.

PMID- 15031156
TI  - Comparison of corneal thickness measurements using Orbscan II, non-contact
      specular microscopy, and ultrasonic pachymetry in eyes after laser in situ
      keratomileusis.
AB  - AIMS: To compare central corneal thickness measurements of three pachymetry
      devices in eyes after laser in situ keratomileusis (LASIK). METHODS: Central
      corneal thickness was measured in 203 eyes after myopic LASIK. Orbscan II
      scanning slit topography (Bausch & Lomb), SP-2000P non-contact specular
      microscopy (Topcon), and ultrasonic pachymetry (Tomey) were used in this
      sequence. RESULTS: Three devices gave significantly different corneal thickness
      readings (p<0.0001, repeated measure analysis of variance). The measurements of
      Orbscan II (445.6 (SD 60.0) microm) were significantly smaller than those of
      noncontact specular microscopy (467.9 (SD 40.2) micro m; p<0.0001, Tukey multiple
      comparison) and ultrasonic pachymetry (478.8 (SD 41.9) microm; p<0.0001). The
      value obtained with SP-2000P non-contact specular microscopy was significantly
      smaller than that taken with ultrasonic pachymetry (p<0.001). There were
      significant linear correlations between scanning slit topography and non-contact
      specular microscopy (Pearson's correlation coefficient r = 0.912, p<0.0001), non
      contact specular microscopy and ultrasonic pachymetry (r = 0.968, p<0.0001), and
      ultrasonic pachymetry and scanning slit topography (r = 0.933, p<0.0001).
      CONCLUSION: In post-LASIK eyes, Orbscan II scanning slit topography significantly
      underestimated corneal thickness. Non-contact specular microscopy gave smaller
      thickness readings than ultrasonic pachymetry, but these two units showed an
      excellent linear correlation.

PMID- 15031157
TI  - Genotypic and phenotypic heterogeneity in familial microcoria.
AB  - AIMS: To describe the clinical features and genetic findings in two families
      presenting with microcoria inherited as an autosomal dominant trait. METHODS:
      Both affected and unaffected members of two families displaying familial
      microcoria were examined. Flash photography or infrared pupillography were used
      to assess pupils, and a full ophthalmic examination including visual acuity and
      field testing, refraction, biomicroscopy of anterior and posterior segments, and
      measurement of intraocular pressure were performed. DNA from the blood of
      affected and unaffected family members was investigated using standard markers to
      look for a possible gene defect in the chromosome 13q31-q32 region. RESULTS: All
      affected members of both families had pinpoint pupils which responded normally to
      light and accommodation. None of these subjects exhibited any other ocular
      abnormality. The iris of affected members showed stromal thinning and apparent
      absence of the iris dilator muscle in the first family, but was smooth and lacked
      all trabecular structure in the second family. The microcoria was present at
      birth in the first family but developed progressively at a later age in the
      second family. Haplotype analysis suggested the gene defect is not located in the
      chromosome 13q31-q32 region in the first family but the evidence was not
      conclusive in the second family. CONCLUSION: Although both families presented
      with similar pupil abnormalities inherited as an autosomal dominant trait, they
      show important phenotypic and genotypic differences suggesting that this is a
      heterogeneous condition. The possible mechanisms underlying the microcoria are
      discussed.

PMID- 15031158
TI  - Suprachoroidal haemorrhage complicating cataract surgery in the UK: a case
      control study of risk factors.
AB  - AIMS: To study the risk factors for suprachoroidal haemorrhage (SCH) complicating
      cataract surgery in the United Kingdom. METHODS: 109 cases of SCH complicating
      cataract surgery prospectively collected through the British Ophthalmological
      Surveillance Unit were compared with 449 controls that underwent cataract
      extraction from 13 "control centres" throughout UK in a case control study. 40
      systemic, ophthalmic, and operative variables were examined. RESULTS:
      Statistically significant risk factors for SCH in univariate analysis included:
      older age (p<0.001), taking at least one cardiovascular medication (p<0.001),
      peripheral vascular disease (p = 0.014), hyperlipidaemia (p = 0.005), glaucoma
      (p<0.001), elevated preoperative intraocular pressure (p<0.001), sub-Tenon's
      local anaesthesia (LA) (p<0.001), topical LA (p<0.001), the lack of orbital
      compression following LA (p<0.001), posterior capsule (PC) rupture before SCH
      (p<0.001), elective extracapsular cataract extraction (ECCE) (p = 0.038), and
      phacoemulsification conversion (p<0.001). Logistic regression analysis identified
      the following significant independent risk factors: older age, taking at least
      one cardiovascular medication, glaucoma, elevated preoperative intraocular
      pressure, the lack of orbital compression, PC rupture before SCH, elective ECCE,
      and phacoemulsification conversion. CONCLUSION: The results allow identification
      of patients at risk of SCH. Attention to the various modifiable preoperative and
      intraoperative risk factors is recommended in order to minimise the risk of SCH.

PMID- 15031159
TI  - Suprachoroidal haemorrhage complicating cataract surgery in the UK: epidemiology,
      clinical features, management, and outcomes.
AB  - AIMS: To study the incidence, management, and outcomes of suprachoroidal
      haemorrhage (SCH) complicating cataract surgery in the United Kingdom. METHODS:
      Cases were prospectively collected by active surveillance through the British
      Ophthalmological Surveillance Unit. Details were obtained using an incident
      questionnaire with follow up at 6 months. RESULTS: 118 cases were reported in 1
      year. The estimated incidence of SCH was 0.04% (95% confidence interval 0.034% to
      0.050%). Cataract extractions were by phacoemulsification in 76.2%, extracapsular
      cataract extraction (ECCE) in 11.0%, and phacoemulsification conversion in 12.8%.
      SCH was "limited" (1 to 2 quadrants) in 48.7%, "full blown" (3 to 4 quadrants) in
      43.1%. SCH in phacoemulsification was more likely to be limited (63.2%), compared
      with ECCE (11.1%) and phacoemulsification conversion (23.1%) (p<0.001, chi(2)
      test). Visual acuity (VA) was better than 6/60 in 57 of 95 (60%) cases after a
      median follow up interval of 185 days. 33 of 34 cases (97.1%) with secondary
      anterior segment revision had VA better than 6/60. VA was worse than 6/60 in 7 of
      8 (87.5%) cases that had intraoperative sclerostomy, and in all 6 (100%) cases
      that had secondary posterior segment intervention. CONCLUSION: SCH is a rare but
      serious complication of cataract surgery. Poor prognostic factors included full
      blown SCH, ECCE, phacoemulsification conversion, retinal apposition, and retinal
      detachment.

PMID- 15031160
TI  - Primary IOL implantation in children: a risk analysis of foldable acrylic v PMMA
      lenses.
AB  - BACKGROUND: /aims: To compare the relative risks of poly (methylmethacrylate)
      (PMMA) and soft acrylic (AcrySof) primary intraocular lens (IOL) implantation in
      paediatric cataract surgery. METHODS: A retrospective analysis of clinical data
      was performed on eyes of 61 infants and children who underwent cataract surgery
      with primary IOL implantation. Age at operation ranged from 3 weeks to 15 years.
      Mean follow up duration was 24.5 months (range 0.5-68 months). Factors examined
      included type of IOL (PMMA, acrylic), performance of a primary posterior
      continuous curvilinear capsulorhexis (PCCC) or capsulotomy with limited anterior
      vitrectomy, perioperative complications, and subsequent intervention for
      posterior capsule opacification (PCO). Risk factors for perioperative
      complications were examined with 2x2 tables to give odds ratios (OR) as measures
      of association. A survival analysis was performed to assess risk of subsequent
      intervention for PCO with different IOL types. Relative risks (hazards) and
      confidence intervals (CI) were calculated with Cox regression to adjust for
      potential confounding. RESULTS: Compared to acrylic, PMMA IOLs were significantly
      associated with perioperative complications (OR 5.2, 95% CI 1.4 to 19, p = 0.01).
      However, IOL and type of section were highly correlated factors, and this finding
      may reflect risks associated with larger scleral wounds used for PMMA IOLs. No
      statistically significant difference in risk of subsequent intervention for PCO
      was found between different IOL types. Mean times till intervention for PMMA and
      acrylic IOLs were 30.1 months (95% CI 22 to 38) and 19.8 months (95% CI 12 to 27)
      respectively (log rank test statistic 1.53, one degree of freedom, p = 0.22). At
      12 months post-implant surgery, 76% (95% CI 59 to 93) of PMMA cases and 54% (95%
      CI 35 to 72) of acrylic cases had not required intervention for PCO; these
      proportions fell to 55% (95% CI 35 to 75) and 38% (95% CI 14 to 61) for PMMA and
      acrylic cases respectively at 2 years post-surgery. After adjustment for age at
      surgery, primary posterior capsulorhexis, and perioperative complications
      relative risk of intervention after acrylic IOL implantation was 1.6 (95% CI 0.66
      to 3.9, p = 0.29). CONCLUSION: Primary implantation of foldable soft acrylic IOLs
      in paediatric eyes may allow fewer perioperative complications than rigid PMMA
      IOLs. Short term safety profiles of primary implantation in paediatric cataract
      surgery are otherwise comparable for PMMA and soft acrylic IOLs.

PMID- 15031161
TI  - Defining "occludable" angles in population surveys: drainage angle width,
      peripheral anterior synechiae, and glaucomatous optic neuropathy in east Asian
      people.
AB  - BACKGROUND: /aim: A current consensus in epidemiological studies of primary angle
      closure (PAC) is to diagnose the condition only if the posterior (usually
      pigmented) trabecular meshwork is seen for less than 90 degrees of the angle
      circumference, termed an "occludable angle." The authors sought to assess the
      validity of this epidemiological classification by exploring the relation between
      drainage angle width, peripheral anterior synechiae (PAS) and glaucomatous optic
      neuropathy (GON). METHODS: 918 Mongolians and 995 Chinese Singaporeans, both
      groups aged 40 years and older were examined in two population based surveys.
      Gonioscopic angle width was graded in five categories (0 = closed to 4 = wide
      open) according the scheme described by Shaffer. Cases with secondary PAS were
      excluded. RESULTS: The rate of PAS was between 0.3% and 1.7% in people with wide
      angles (grades 3 and 4). In those with grade 2 angles, PAS were seen in between
      8% of eyes. In eyes with grade 1 angles, the rate rose to 17% in Chinese
      Singaporeans, and 31% in Mongolians. The odds of PAS were higher in people with
      narrower angles. However, there was a greater absolute number of people with PAS
      whose drainage angles were classified as "not occludable" than those classified
      "occludable." CONCLUSIONS: The traditional view that primary angle closure
      becomes a significant possibility in drainage angles of < or = grade 2
      (approximately 20 degrees ) is valid in east Asians. The definition of an
      "occludable" angle examined here excludes many people with PAS. This probably
      serves to underemphasise the role of PAC in population surveys of glaucoma
      prevalence in Asian people.

PMID- 15031163
TI  - A new form of retinopathy associated with myocardial infarction treated with
      percutaneous coronary intervention.
AB  - AIM: To report a new form of retinopathy that was observed in patients who had
      undergone percutaneous coronary intervention (PCI) following acute myocardial
      infarction (AMI). METHODS: Serial ophthalmological examinations were conducted in
      40 patients who underwent PCI. Thirty patients were diagnosed with AMI, and
      another 10 had stable angina pectoris. RESULTS: Cotton wool spots developed in 17
      (57%) patients from the group with AMI undergoing PCI (n = 30) within 2 months.
      Of these, 41% (seven patients) also developed superficial haemorrhages.
      Retinopathy was most prominent 1-2 months after AMI and then tended to become
      quiescent afterwards, without treatment. CONCLUSION: We have identified a new
      form of retinopathy in patients with AMI that spontaneously subsides without
      treatment.

PMID- 15031162
TI  - Normal tension glaucoma is not associated with the common apolipoprotein E gene
      polymorphisms.
AB  - BACKGROUND: /aims: In normal tension glaucoma (NTG) factors other than raised
      intraocular pressure have a role in the pathogenesis of the optic neuropathy.
      Because particular apolipoprotein E (ApoE) gene polymorphisms have been
      associated with cell death and survival in neurological degenerative diseases,
      the purpose of this study was to determine the ApoE allele frequencies in
      patients with normal tension glaucoma. METHODS: The apolipoprotein E genotype of
      155 patients with normal tension glaucoma was compared to that of 349 non
      affected, control subjects from the same geographical area. A similar comparison
      was made between 53 patients with normal tension glaucoma who demonstrated
      progressive visual field loss, and control subjects. The frequencies of genotypes
      was compared with the chi(2) test and Mantel-Haenszel coefficent. RESULTS: There
      was no significant difference in the frequency of ApoE alleles or genotypes in
      the normal tension glaucoma population compared to the control group. The ApoE
      alleles and genotypes in NTG patients with progressive disease were not different
      from the control group. CONCLUSION: ApoE gene polymorphisms are not linked to
      normal tension glaucoma, suggesting that this gene does not have a role in the
      pathogenesis of optic neuropathy in this disease.

PMID- 15031165
TI  - Ophthalmodynamometric determination of the central retinal vessel collapse
      pressure correlated with systemic blood pressure.
AB  - AIMS: To evaluate whether determination of the central retinal artery and vein
      collapse pressure correlate with systemic blood pressure measurements, using a
      new Goldmann contact lens associated ophthalmodynamometric device METHODS: The
      prospective clinical study included 92 eyes of 92 patients presenting with
      cataract or refractive problems (n = 40; control study group) or with retinal and
      orbital pathologies (n = 52). With topical anaesthesia, a Goldmann contact lens
      fitted with a pressure sensor in its holding ring was placed onto the cornea.
      Pressure was asserted onto the globe by pressing the contact lens, and the
      pressure value at the time when the central retinal artery and vein started
      pulsating were noted as central retinal artery and vein collapse pressure.
      Additionally, the brachial arterial blood pressure was measured. RESULTS: In the
      control study group, central retinal artery collapse pressure was highly
      significantly correlated with diastolic blood pressure (correlation coefficient r
      = 0.77; p<0.001) and systolic blood pressure (r = 0.35; p = 0.03). Central
      retinal vein collapse pressure was statistically independent of diastolic blood
      pressure (p = 0.11). In eyes with retinal or orbital diseases, the correlation
      coefficients were lower than in the control study group. In eyes with retinal
      arterial occlusions, central retinal vessel collapse pressure measurements were
      not correlated with arterial blood pressure measurements. CONCLUSIONS: Depending
      on coexisting retinal or orbital diseases, ophthalmodynamometric estimation of
      the central retinal artery collapse pressure, performed during a routine Goldmann
      contact lens ophthalmoscopy, correlates with systemic blood pressure
      measurements.

PMID- 15031164
TI  - Oligocone trichromacy: a rare and unusual cone dysfunction syndrome.
AB  - AIM: To describe the phenotype of a case series of six patients with oligocone
      trichromacy. METHODS: The six affected individuals underwent an ophthalmological
      examination, electrophysiological testing and detailed psychophysical assessment.
      RESULTS: All six affected patients had a history of moderately reduced visual
      acuity (6/12 to 6/24) from infancy, not improved by full spectacle correction.
      They complained of mild photophobia and they were not aware of any colour vision
      deficiency. They had no nystagmus and fundi were normal. Electrophysiological
      testing revealed either absent/profoundly reduced cone flicker responses or
      preserved but delayed and mildly reduced flicker responses. Colour vision was
      found to be within normal limits, but some patients showed mildly elevated
      discrimination thresholds along all axes. CONCLUSION: The largest case series to
      date of patients with oligocone trichromacy is presented. The
      electrophysiological findings suggest that there may be more than one disease
      mechanism. The mode of inheritance is likely to be autosomal recessive, and while
      previous reports have suggested that this disorder is stationary, in one of these
      families there is clinical evidence of progression.

PMID- 15031166
TI  - Ophthalmic artery blood flow in patients with internal carotid artery occlusion.
AB  - AIM: To evaluate the risk factors for rubeosis iridis by colour Doppler imaging
      (CDI) in patients with complete internal carotid artery occlusion (ICAO).
      METHODS: 34 eyes of 32 consecutive patients with complete ICAO were enrolled.
      Using CDI, blood flow direction (forward, reverse, undetectable) in the
      ophthalmic artery (OA), central retinal artery (CRA), and short posterior ciliary
      artery (SPCA) were determined. Arterial mean blood velocity (Vmean) and resistive
      index (RI) were calculated and correlations between the rubeosis iridis incidence
      and CDI parameters analysed. RESULTS: The eyes were classified into four types
      according to blood flow direction: forward flow in OA, CRA, and SPCA (type 1; n =
      11); reverse OA and forward CRA and SPCA flow (type 2a; n = 12); reverse OA and
      undetectable CRA and SPCA flow (type 2b; n = 8); undetectable flow in all three
      arteries (type 3; n = 3). Rubeosis iridis was seen only in type 2b and 3 eyes.
      Type 2b showed significantly (p<0.01) higher Vmean and lower RI values in the OA,
      indicating more rapid reverse flow than in type 2a eyes. Although in type 1 and
      2a eyes OA flow was in opposite directions, they manifested no rubeosis iridis
      and no difference in the Vmean and RI values of the CRA and SPCA. CONCLUSIONS:
      The classification of eyes from patients with ICAO into four types by CDI may
      facilitate the identification of the eyes at high risk for rubeosis iridis.
      Markedly diminished flow in both the CRA and SPCA may result in rubeosis iridis,
      regardless of OA flow direction.

PMID- 15031167
TI  - Why is squint surgery in children in decline?
AB  - BACKGROUND: /aims: Paediatric squint surgery appears to be declining. This study
      aims to identify if this is so and, if so, why. METHODS: Retrospective review of
      (1) episodes of paediatric squint surgery in Scotland and Tayside, 1986-2001, (2)
      presentations to orthoptists (Tayside) during 1986 and 1996. RESULTS: (1)
      Overall, a 58% fall in surgery in Scotland and 59% in Tayside. For esotropia, a
      reduction of 63% (Scotland) and 69% (Tayside). (2) Incidence of esotropia was
      unchanged; surgery for these esotropes fell (from 55% to 30%) (p = 0.013). More
      children received maximum hypermetropic correction (p <0.001) and more developed
      stereopsis (p = 0.003). CONCLUSION: Childhood strabismus surgery, particularly
      for esotropia, is declining. The maximum hypermetropic correction has improved
      the functional results.

PMID- 15031168
TI  - The risk of complications of uveitis in a district hospital cohort.
AB  - AIMS: To establish the frequency and risk factors for visual loss in a primary
      referral cohort of hospital patients with uveitis. METHODS: 561 consecutive
      uveitis patients attending three district hospitals were recruited and the acuity
      at the end of the study period recorded. A retrospective case-control study of
      risk factors for visual loss (permanent loss of acuity <6/9) was performed. Risk
      factors examined included type of uveitis, age at onset of uveitis, race, type of
      systemic inflammatory disease, length of follow up, and treatment variables.
      RESULTS: Visual loss of at least 6/12 in one eye was found in 111 patients
      (19.9%). Only four patients (0.7%) suffered severe bilateral visual loss (6/36 or
      less). Visual loss was associated with age at onset >60 years (odds ratio 3.9,
      95% confidence interval (CI) 2.2 to 7.0, long follow up 2.0 (1.2 to 3.3) and a
      history of cataract surgery 3.9 (2.1 to 7.2). It was less likely in patients with
      acute anterior uveitis 0.2 (0.1 to 0.3). CONCLUSION: The frequency of visual loss
      associated with uveitis in a district hospital cohort is less than that found in
      referral centres and levels of legal blindness are low. Although acute anterior
      uveitis has a low frequency of visual loss it contributes significantly to the
      total burden. The ocular co-morbidity of the elderly may contribute to the
      increased visual loss of late onset uveitis.

PMID- 15031169
TI  - Effect of corneal parameters on measurements using the pulsatile ocular blood
      flow tonograph and Goldmann applanation tonometer.
AB  - AIMS: To investigate the effect of central corneal thickness and corneal
      curvature on intraocular pressure measurements using the pulsatile ocular blood
      flow tonograph and the Goldmann applanation tonometer, and to assess the
      agreement between the pulsatile ocular blood flow tonograph and the Goldmann
      applanation tonometer in intraocular pressure measurement. METHODS: 479 subjects
      underwent intraocular pressure measurements with the Goldmann applanation
      tonometer and the pulsatile ocular blood flow tonograph. Of these, 334 patients
      underwent additional measurement of central corneal thickness with an ultrasonic
      pachymeter and corneal curvature measurement with a keratometer. RESULTS: The
      intraocular pressure measurements obtained with both the Goldmann applanation
      tonometer and the pulsatile ocular blood flow tonograph varied with central
      corneal thickness and mean keratometric reading. Intraocular pressure measured
      using the Goldmann applanation tonometer increased by 0.027 mm Hg per micro m
      increase in central corneal thickness. Intraocular pressure measured using the
      pulsatile ocular blood flow tonograph increased by 0.048 mm Hg per micro m
      increase in central corneal thickness. For an increase of 1 mm of mean corneal
      curvature there was rise in intraocular pressure of 1.14 mm Hg measured by the
      Goldmann applanation tonometer and of 2.6 mm Hg measured by the pulsatile ocular
      blood flow tonograph. When compared to the Goldmann applanation tonometer, the
      pulsatile ocular blood flow tonograph underestimated at low intraocular pressure
      and overestimated at higher intraocular pressure. CONCLUSION: Central corneal
      thickness and corneal curvature affected measurements obtained with the pulsatile
      ocular blood flow tonograph more than they affected measurements obtained with
      the Goldmann applanation tonometer.

PMID- 15031171
TI  - An atypical phenotype of macular and peripapillary retinal atrophy caused by a
      mutation in the RP2 gene.
AB  - AIMS: To determine the molecular basis and describe the phenotype of an atypical
      retinal dystrophy in a family presenting with bilateral, progressive central
      visual loss. METHODS: Family members were examined. Investigations included
      Goldman perimetry, electrophysiology, and autofluorescence imaging. Candidate
      gene screening was performed using SSCP and sequence analysis. The proband's
      lymphoblastoid cells were examined for protein expression. RESULTS: Fundal
      examination of the proband, his mother, and brother revealed peripapillary and
      macular atrophy. Autosomal dominant retinal dystrophy was suspected, but less
      severe disease in the mother led to screening for mutations in X linked genes. A
      4 bp microdeletion in exon 3 of the RP2 gene, segregating with disease, was
      identified. No RP2 protein expression was detected. CONCLUSION: The distinct
      phenotype in this family, caused by this frameshifting mutation in RP2, broadens
      the phenotypic spectrum of X linked retinitis pigmentosa. The absence of RP2
      protein suggests that loss of protein function and not novel gain of function
      could account for the atypical phenotype. A definitive diagnosis of X linked
      retinitis pigmentosa permits appropriate genetic counselling with important
      implications for other family members. Clinicians should have a low threshold for
      screening RP2 in families with retinal dystrophy, including posterior retinal
      disease, not immediately suggestive of X linked inheritance.

PMID- 15031170
TI  - Endothelin-1 concentration is increased in the aqueous humour of patients with
      exfoliation syndrome.
AB  - BACKGROUND: /aim: Endothelin 1 (ET-1) is considered the most potent
      vasoconstrictor in the body and the eye. This molecule may play a significant
      role in the pathobiology of exfoliation syndrome (XFS), a disorder characterised
      by a progressive iris vasculopathy. The purpose of this study was to investigate
      the concentration of ET-1 in the aqueous humour of cataract patients with and
      without XFS. METHODS: Aqueous humour samples were obtained from 25 consecutive
      eyes of 25 cataract patients with XFS and an equal number of age matched controls
      during phacoemulsification cataract surgery. None of the subjects had elevated
      intraocular pressure or glaucoma. ET-1 concentration in the aqueous was measured
      using a specific immunoassay with 100% immunoreactivity for ET-1. Total aqueous
      humour protein concentration was measured with a microplate Coomassie blue based
      method and was correlated with ET-1 concentration. RESULTS: Mean ET-1
      concentration in the XFS aqueous samples (4.6 (SD 2.3) pg/ml) was significantly
      higher than that measured in the age matched control samples (2.8 (SD 1.71)
      pg/ml); (p = 0.006). Although total protein concentration was significantly
      elevated in the XFS samples (0.380 (SD 0.159) v 0.279 (SD 0.144) mg/ml in the
      controls); (p = 0.023), no correlation was found between aqueous ET-1 and total
      protein concentration (p = 0.730). CONCLUSION: The increased concentration of ET
      1 in the aqueous humour of XFS patients suggests that ET-1 may play a role in the
      pathobiology of XFS.

PMID- 15031172
TI  - Twelve hour reproducibility of choroidal blood flow parameters in healthy
      subjects.
AB  - AIMS/BACKGROUND: To investigate the reproducibility and potential diurnal
      variation of choroidal blood flow parameters in healthy subjects over a period of
      12 hours. METHODS: The choroidal blood flow parameters of 16 healthy non-smoking
      subjects were measured at five time points during the day (8:00, 11:00, 14:00,
      17:00, and 20:00). Outcome parameters were pulsatile ocular blood flow as
      assessed by pneumotonometry, fundus pulsation amplitude as assessed by laser
      interferometry, blood velocities in the opthalmic and posterior ciliary arteries
      as assessed by colour Doppler imaging, and choroidal blood flow, volume, and
      velocity as assessed by fundus camera based laser Doppler flowmetry. The
      coefficient of variation and the maximum change from baseline in an individual
      were calculated for each outcome parameter. RESULTS: None of the techniques used
      found a diurnal variation in choroidal blood flow. Coefficients of variation were
      within 2.9% and 13.6% for all outcome parameters. The maximum change from
      baseline in an individual was much higher, ranging from 11.2% to 58.8%.
      CONCLUSIONS: These data indicate that in healthy subjects the selected techniques
      provide adequate reproducibility to be used in clinical studies. Variability may,
      however, be considerably higher in older subjects or subjects with ocular
      disease. The higher individual differences in flow parameter readings limit the
      use of the techniques in clinical practice. To overcome problems with measurement
      validity, a clinical trial should include as many choroidal blood flow outcome
      parameters as possible to check for consistency.

PMID- 15031173
TI  - The relation between birth size and the results of refractive error and biometry
      measurements in children.
AB  - AIM: To examine the association of birth parameters with biometry and refraction
      in Singapore Chinese schoolchildren. METHODS: Chinese children aged 7-9 years (n
      = 1413) from three schools in Singapore were recruited. Birth parameter
      information on birth weight, head circumference, length at birth, and gestational
      age were obtained from standard hospital records. Cycloplegic autorefraction,
      keratometry and biometry measures (axial length, vitreous chamber depth, lens
      thickness, and anterior chamber depth) were obtained. RESULTS: Across the normal
      birthweight range (2.0-4.9 kg), children with birth weights > or =4.0 kg had
      longer axial lengths (adjusted mean 23.65 mm versus 23.16 mm), compared with
      children with birth weights <2.5 kg, after controlling for age, sex, school,
      height, parental myopia, and gestational age. For every 1 cm increment in head
      circumference at birth, the axial length was longer by 0.05 mm. For every 1 cm
      increment in birth length, the axial length was longer by 0.02 mm in multivariate
      analysis. Additional week increases in gestational age till 46 weeks resulted in
      axial lengths that were longer by 0.04 mm, controlling for age, sex, school,
      parental myopia, and height. Children with larger birth weights, head
      circumferences, birth lengths, or gestational ages had deeper vitreous chambers
      and larger corneal curvature radii; however, there were no significant
      associations with refraction. CONCLUSIONS: Children who were born heavier, had
      larger head sizes or lengths at birth, or who were born more mature had longer
      axial lengths, and deeper vitreous chambers; but there were no differences in
      refraction at ages 7-9 years, possibly because of the observed compensatory
      flattening of the cornea.

PMID- 15031175
TI  - A comparison of 10 MHz and 20 MHz ultrasound probes in imaging the eye and orbit.
AB  - BACKGROUND: /aims: B-scan ultrasonography is an invaluable, versatile, non
      invasive tool in ophthalmology. Recently, a "high frequency" contact 20 MHz probe
      has been introduced. B-scanning ultrasonography of orbital and ocular structures
      was performed with both a 10 MHz and the new 20 MHz probe, to evaluate what
      information was best obtained from each probe, and provide recommendations for
      the use of each. METHODS: Patients were selected from routine ultrasound clinics
      at Aberdeen Royal Infirmary between 1 January 2002 and 1 August 2002. The
      vitreous, retina, choroid, sclera and, in the orbit, the extraocular muscles,
      optic nerve, and orbital fat were assessed with both the 10 MHz and 20 MHz
      probes. In the laboratory, using a "point target," the characteristics of the
      ultrasound beam at different distances from the probe were also assessed.
      RESULTS: The point target showed that focus was deeper and that the lateral, and
      to a lesser degree the axial, resolution are sharper with the 20 MHz probe,
      compared with the 10 MHz probe. In patients' eyes, highly reflective structures
      are seen at higher resolution with the 20 MHz probe. Imaging of lower intensity
      reflectors such as the vitreous and particles within it are seen better with the
      10 MHz probe. Increased tissue attenuation was evident with the 20 MHz probe.
      CONCLUSION: The 20 MHz probe has a superior resolution and can be used to better
      detect details at the posterior pole and in the orbit. The 10 MHz probe can be
      used to examine low intensity scatterers, such as the vitreous humour, that
      cannot be seen using a higher frequency probe.

PMID- 15031174
TI  - Towards optimal filtering of "standard" multifocal electroretinogram (mfERG)
      recordings: findings in normal and diabetic subjects.
AB  - AIMS: To study the effects of two commonly used pre-amplifier filtering
      bandwidths on normal multifocal electroretinogram (mfERG) responses and their
      comparative abilities to detect retinal disease. METHODS: 103 standard mfERGs
      were recorded simultaneously in two channels with different pre-amplifier
      settings (10-100 Hz and 10-300 Hz) from one eye of each of 20 normal subjects, 17
      diabetics with non-proliferative diabetic retinopathy (NPDR), and 12 diabetics
      without retinopathy. Signal to noise ratios (SNR) of the normal subjects' first
      order mfERGs were compared between channels. All subjects' amplitudes and
      implicit times were derived using a "template stretching" method. For comparison,
      implicit time was also measured using a "template sliding" method. mfERG
      amplitudes and implicit times were compared between the channels and among
      subject groups. RESULTS: Normal mean amplitudes and implicit times were similar
      for the two channels. However, normal 10-100 Hz recordings had significantly
      higher SNR and lower intersubject variability than 10-300 Hz recordings. In NPDR,
      the 10-100 Hz channel identified significantly more implicit time and amplitude
      abnormalities. In the diabetics without retinopathy, 10-100 Hz filtering
      identified significantly more implicit time abnormalities than 10-300 Hz
      filtering. For both filter settings, diabetic implicit times were more often
      abnormal than amplitudes. The 10-100 Hz channel was superior for both implicit
      time measurements. CONCLUSION: Standard mfERGs recorded from normal eyes and
      filtered 10-100 Hz contain less noise, higher SNR, and less intersubject
      variability than those filtered at 10-300 Hz. This underlies the finding that the
      10-100 Hz filter setting identifies more retinal dysfunction than the 10-300 Hz
      setting.

PMID- 15031176
TI  - Removal of sodium from the solvent reduces retinal pigment epithelium toxicity
      caused by indocyanine green: implications for macular hole surgery.
AB  - BACKGROUND: s/aims: Staining of internal limiting membrane with indocyanine green
      (ICG) has been reported to be associated with postoperative atrophic retinal
      pigment epithelium (RPE) change. Here the authors examined whether removing
      sodium from the solvent reduces ICG induced RPE cytotoxicity. METHODS: Human RPE
      cells were exposed to ICG (0.25 and 0.025 mg/ml) reconstituted with balanced salt
      solution (BSS) or Na(+) free BSS. Light microscopy, trypan blue dye exclusion,
      acridine orange/ethidium bromide staining, and DNA electrophoresis were used to
      evaluate the cytotoxic effects of ICG. ICG uptake was measured by optical
      absorption at 790 nm. RESULTS: Sodium removal reduced the ICG induced changes in
      cell morphology and improved the RPE cell viability. When RPE cells were
      incubated for 4 hours in 0.25 mg/ml ICG dissolved in BSS and sodium free BSS,
      86.3% (SD 6.7%) and 2.4% (1.1%) of the cells were stained with trypan blue,
      respectively. After ICG treatment, RPE dies mainly through a necrotic mechanism.
      ICG uptake by RPE was also reduced with sodium removal. CONCLUSIONS: ICG induced
      cytotoxicity in cultured human RPE was reduced with removal of sodium from the
      solvent. This reconstitution method may provide a safer intravitreal use of ICG
      in macular hole surgery.

PMID- 15031177
TI  - Human corneal equivalent as cell culture model for in vitro drug permeation
      studies.
AB  - AIMS: For the study of transcorneal in vitro permeation of ophthalmic drugs,
      excised animal cornea or corneal epithelial cell culture are frequently used as a
      replacement for the human cornea. The main purposes of this study were to
      reconstruct a complete human organotypic cornea equivalent, consisting of all
      three different cell types (epithelial, stromal, and endothelial); to test the
      barrier function of this bio-engineered human cornea using three different model
      drugs (pilocarpine hydrochloride (PHCl), befunolol hydrochloride (BHCl), and
      hydrocortisone (HC)); and to determine its usefulness as an in vitro model for
      prediction of ocular drug absorption into the human eye. METHODS: A multilayer
      tissue construct was created step by step in Transwell cell culture insert using
      SV-40 immortalised human endothelial and epithelial cells and native stromal
      cells (fibroblasts). Morphology was characterised by light microscopy using
      routine H&E staining. Scanning electron microscopy was used to evaluate
      ultrastructural features. Ocular permeation of drugs across the human cornea
      construct was tested using modified Franz cells and compared with data obtained
      from excised porcine cornea and previously described porcine cornea constructs.
      RESULTS: and conclusion: The cornea construct exhibited typical corneal
      structures such as a monolayer of hexagonally shaped endothelial cells and a
      multilayered epithelium consisting of seven to nine cell layers with flat
      superficial cells. The formation of microplicae and microvilli was also
      confirmed. The human cornea construct showed similar permeation behaviour for all
      substances compared with excised porcine cornea. However, permeability
      (permeation coefficients K(p)) of the human cornea equivalent (PHCl 13.4*10(-6)
      (SD 3.01*10(-6)); BHCl 9.88*10(-6) (SD 1.79*10(-6)); HC 5.41*10(-6) (SD 0.40*10(
      6)) cm/s) was about 1.6-1.8 fold higher than excised porcine cornea. Compared
      with data from the porcine cornea construct the cultivated human equivalent
      showed a decreased permeability. The reconstructed human cornea could be
      appropriate to predict drug absorption into the human eye.

PMID- 15031179
TI  - Retinal toxicity of intravitreal tenecteplase in the rabbit.
AB  - AIM: To investigate the retinal toxicity of intravitreal injection of a novel
      fibrinolytic tenecteplase in rabbit eyes. METHODS: Tenecteplase (25-350 micro g
      in 0.1 ml BSS) was injected into the vitreous cavity of normal rabbit eyes.
      Control (fellow) eyes received 0.1 ml of BSS. One day, 1 week, and 2 months post
      injection, the eyes were examined by slit lamp biomicroscopy, indirect
      ophthalmoscopy, and electroretinography, and then harvested for histopathological
      examination. RESULTS: No evidence of retinal toxicity was seen with tenecteplase
      doses up to and including 50 micro g. At a dose of 150 micro g ophthalmoscopy was
      normal, but histology showed mild retinal damage in the inner nuclear layer and
      electroretinography showed a temporary reduction in B-wave amplitude. At doses of
      200 micro g and above, there was evidence of retinal toxicity on
      electroretinography, ophthalmoscopy, and histology. Ophthalmoscopic findings
      included vitreal fibrosis, retinal necrosis and tractional retinal detachment and
      light microscopy revealed necrosis of retinal pigment epithelium and other
      retinal layers. Damage was centred around the injection site but was more
      widespread with the higher doses. CONCLUSION: A dose of 50 micro g tenecteplase
      appears safe for intravitreal injection in the rabbit. Tenecteplase could have
      potential applications in the treatment of submacular haemorrhage and retinal
      vein occlusion.

PMID- 15031178
TI  - Vascular leucocyte adhesion molecules unaltered in the human retina in diabetes.
AB  - BACKGROUND/AIMS: Capillary occlusion is believed to have a critical role in the
      development of diabetic retinopathy (DR). The exact mechanism by which it occurs,
      however, remains unclear. Several in vitro and animal model studies have
      suggested increased adhesion of leucocytes to the endothelium via upregulated
      ICAM-1 on the retinal microvasculature as a possible mechanism. In this
      comparative immunohistochemical study the expression of ICAM-1 was compared in
      the retinal vasculature of 41 eyes obtained from 37 diabetic people with 19 eyes
      from 19 non-diabetic controls. METHODS: Serial cryosections of postmortem
      posterior tissue from 41 diabetic eyes and 19 non-diabetic eyes were stained with
      the monoclonal antibodies ICAM-1 (two clones), CD31(panendothelial marker), and
      PAL-E (vascular leakage marker). RESULTS: A similar pattern of vascular ICAM-1
      staining was observed between diabetic and non-diabetic eyes. A diffuse ICAM-1
      staining of the retina was also observed that was significantly more intense in
      the diabetic subjects (p = 0.001). CONCLUSION: These results indicate that ICAM-1
      is constitutively expressed on retinal and choroidal vasculature of non-diabetic,
      control subjects and that this level of expression is not significantly altered
      by the diabetic environment. Taken together, these results do not support the
      prevalent paradigm of increased adhesion molecule expression as a primary
      mechanism responsible for capillary occlusion reported in diabetic individuals.

PMID- 15031180
TI  - Controlled study of the influence of storage medium type on endothelial
      assessment during corneal organ culture.

PMID- 15031181
TI  - Mixed infection (Pseudomonas and coagulase negative staphylococci) microbial
      keratitis associated with extended wear silicone hydrogel contact lens.

PMID- 15031182
TI  - Prospective case control study on genetic assocation of apolipoprotein epsilon2
      with intraocular pressure.

PMID- 15031183
TI  - The safety of anterior chamber paracentesis in patients with uveitis.

PMID- 15031184
TI  - Rapid recovery of night blindness due to obesity surgery after vitamin A
      repletion therapy.

PMID- 15031186
TI  - Spontaneous resolution of sixth nerve palsy with ipsilateral cavernous carotid
      dolichoectasia.

PMID- 15031185
TI  - Incision-less frontalis suspension.

PMID- 15031187
TI  - Intravitreal triamcinolone acetonide as treatment for extensive exudative retinal
      detachment.

PMID- 15031189
TI  - Retinal arterial collapse pressure in eyes with retinal arterial occlusive
      diseases.

PMID- 15031188
TI  - Long term efficacy and safety of botulinum toxin A injection for crocodile tears
      syndrome.

PMID- 15031190
TI  - Modified self sealing sclerotomy for drainage of subretinal fluid during scleral
      buckling surgery.

PMID- 15031191
TI  - Conjunctival dendrite in a case of primary herpes simplex infection.

PMID- 15031192
TI  - Swollen optic discs in a patient with the chromosome 22q11.2 deletion syndrome.

PMID- 15031193
TI  - Severe ocular trauma caused by an ostrich.

PMID- 15031194
TI  - The correlation of phenylephrine 1% with hydroxyamphetamine 1% in Horner's
      syndrome.

PMID- 15031195
TI  - Tetraspanin protein KAI1 expression in retinoblastoma.

PMID- 15031196
TI  - Bilateral ocular surface squamous neoplasia: a clinicopathological case report.

PMID- 15031197
TI  - Employing endoscopic guidance for placement of a black diaphragm aniridia
      intraocular lens following destructive Acanthamoeba sclerokeratitis.

PMID- 15031198
TI  - Variant CJD and tonometry.

PMID- 15031199
TI  - Viscosurgery in diabetic vitrectomy.

PMID- 15031200
TI  - Intravitreal triamcinolone acetonide for exudative age related macular
      degeneration.

PMID- 15031203
TI  - Artificial antigen-presenting constructs efficiently stimulate minor
      histocompatibility antigen-specific cytotoxic T lymphocytes.
AB  - Cytotoxic T lymphocytes (CTLs) specific for hematopoietic-restricted minor
      histocompatibility antigens (mHags) are important reagents for adoptive
      immunotherapy of relapsed leukemia after allogeneic stem cell transplantation.
      However, expansion of these CTLs to therapeutic numbers is often hampered by the
      limited supply of antigen-presenting cells (APCs). Therefore, we evaluated
      whether cell-sized latex beads coated with HLA/mHag complexes HLA-A2/HA-1 or HLA
      A2/HA-2 and recombinant CD80 and CD54 molecules can replace professional APCs.
      The artificial antigen-presenting constructs (aAPCs) effectively stimulated HA-1-
      and HA-2-specific CTL clones as shown by ligand-specific expansion, cytokine
      production, and maintenance of cytotoxic activity, without alteration of CTL
      phenotype. Furthermore, HA-1-specific polyclonal CTL lines were enriched as
      efficiently by aAPCs as by autologous HA-1 peptide-pulsed dendritic cells. Thus,
      aAPCs coated with HLA/mHag complexes, CD80, and CD54 may serve as tools for in
      vitro enrichment of immunotherapeutic mHag-specific CTL lines.

PMID- 15031204
TI  - MAPK and JNK transduction pathways can phosphorylate Sp1 to activate the uPA
      minimal promoter element and endogenous gene transcription.
AB  - Two upstream regions of the human urokinase (uPA) gene regulate its
      transcription: the minimal promoter (MP) and the enhancer element. The activity
      of the minimal promoter is essential for basal uPA transcription in prostate
      adenocarcinoma PC3 cells. Binding of a phosphorylated Sp1 transcription factor
      is, in turn, essential for the activity of the MP. Here we report that the Jun
      kinase (JNK) pathway is required for the basal activity of the MP and for the
      expression of the endogenous uPA gene in PC3 cells and for activated
      transcription in LNCaP cells. On the other hand, the p42/p44 mitogen-activated
      protein kinase (MAPK) pathway activates uPA gene expression through Sp1
      phosphorylation in HeLa, LNCaP, and CCL39-derivative cells that do not typically
      express uPA in basal conditions. In HeLa cells the dominant-negative form of JNK
      interferes with the p42/p44 MAPK activation of the uPA-MP. The results suggest
      that the stress-activated protein kinase (SAPK)/JNK pathway plays an important
      role in the phosphorylation of Sp1, which, in turn, leads to basal or activated
      transcription from the uPA-MP element.

PMID- 15031205
TI  - Treatment with arsenic trioxide (ATO) and MEK1 inhibitor activates the p73
      p53AIP1 apoptotic pathway in leukemia cells.
AB  - Arsenic trioxide (ATO) induces differentiation and apoptosis of malignant cells
      in vitro and in vivo and has been used in the treatment of a variety of
      hematologic malignancies. We found that in NB4 acute promyelocytic and in K562
      erythroleukemia cell lines treatment with the MEK1 inhibitors PD98059 and
      PD184352 greatly enhances apoptotic cell death induced by ATO alone. Combined
      treatment results in the induction of the p53AIP1 (p53-regulated apoptosis
      inducing protein 1) gene in both cell lines. Because NB4 and K562 cell lines
      carry an inactive p53, we investigated the possible role of p73, a p53 paralogue
      that has been shown to regulate several p53 target genes including p21, Bax, and
      p53AIP1. We found that MEK1 inhibitors reduce the levels of dominant-negative
      (DeltaN) p73 proteins and promote the accumulation of endogenous p73alpha through
      its transcriptional activation and its tyrosine phosphorylation, resulting in p21
      up-regulation and significant inhibition of cell growth. ATO reduces DeltaNp73
      levels and promotes a p300-mediated acetylation of endogenous p73, thus favoring
      cell cycle arrest and apoptosis. Finally, the combined treatment with MEK1
      inhibitors and ATO enhances the affinity of phosphoacetylated p73 for the p53AIP1
      promoter in vivo, as determined by chromatin immunoprecipitation experiments,
      leading to p53AIP1 up-regulation and increased apoptosis.

PMID- 15031206
TI  - Blood mononuclear cell gene expression profiles characterize the oxidant,
      hemolytic, and inflammatory stress of sickle cell disease.
AB  - In sickle cell disease, deoxygenation of intra-erythrocytic hemoglobin S leads to
      hemoglobin polymerization, erythrocyte rigidity, hemolysis, and microvascular
      occlusion. Ischemia-reperfusion injury, plasma hemoglobin-mediated nitric oxide
      consumption, and free radical generation activate systemic inflammatory
      responses. To characterize the role of circulating leukocytes in sickle cell
      pathogenesis we performed global transcriptional analysis of blood mononuclear
      cells from 27 patients in steady-state sickle cell disease (10 patients treated
      and 17 patients untreated with hydroxyurea) compared with 13 control subjects. We
      used gender-specific gene expression to validate human microarray experiments.
      Patients with sickle cell disease demonstrated differential gene expression of
      112 genes involved in heme metabolism, cell-cycle regulation, antioxidant and
      stress responses, inflammation, and angiogenesis. Inducible heme oxygenase-1 and
      downstream proteins biliverdin reductase and p21, a cyclin-dependent kinase, were
      up-regulated, potentially contributing to phenotypic heterogeneity and absence of
      atherosclerosis in patients with sickle cell disease despite endothelial
      dysfunction and vascular inflammation. Hydroxyurea therapy did not significantly
      affect leukocyte gene expression, suggesting that such therapy has limited direct
      anti-inflammatory activity beyond leukoreduction. Global transcriptional analysis
      of circulating leukocytes highlights the intense oxidant and inflammatory nature
      of steady-state sickle cell disease and provides insight into the broad
      compensatory responses to vascular injury.

PMID- 15031207
TI  - Selective recognition of fibroblast growth factor-2 by the long pentraxin PTX3
      inhibits angiogenesis.
AB  - The long pentraxin PTX3 is a soluble pattern recognition receptor produced by
      monocytes and endothelial cells that plays a nonredundant role in inflammation.
      Several pathologic conditions are characterized by local production of both PTX3
      and the angiogenic fibroblast growth factor-2 (FGF2). Here, solid-phase binding
      assays demonstrated that PTX3 binds with high affinity to FGF2 but not to a panel
      of cytokines and growth factors, including FGF1, FGF4, and FGF8. Accordingly,
      PTX3 prevented (125)I-FGF2 binding to endothelial cell receptors, leading to
      specific inhibition of FGF2-induced proliferation. PTX3 hampered also the
      motogenic activity exerted by endogenous FGF2 on a wounded endothelial cell
      monolayer. Moreover, PTX3 cDNA transduction in FGF2-transformed endothelial cells
      inhibited their autocrine FGF2-dependent proliferation and morphogenesis in vitro
      and their capacity to generate vascular lesions when injected in nude mice.
      Finally, PTX3 suppressed neovascularization triggered by FGF2 in the chick embryo
      chorioallantoic membrane with no effect on physiologic angiogenesis. In contrast,
      the short pentraxin C-reactive protein was a poor FGF2 ligand/antagonist. These
      results establish the selective binding of a member of the pentraxin superfamily
      to a growth factor. PTX3/FGF2 interaction may modulate angiogenesis in various
      physiopathologic conditions driven by inflammation, innate immunity, and/or
      neoplastic transformation.

PMID- 15031208
TI  - Yolk sac-derived primitive erythroblasts enucleate during mammalian
      embryogenesis.
AB  - The enucleated definitive erythrocytes of mammals are unique in the animal
      kingdom. The observation that yolk sac-derived primitive erythroid cells in
      mammals circulate as nucleated cells has led to the conjecture that they are
      related to the red cells of fish, amphibians, and birds that remain nucleated
      throughout their life span. In mice, primitive red cells express both embryonic
      and adult hemoglobins, whereas definitive erythroblasts accumulate only adult
      hemoglobins. We investigated the terminal differentiation of murine primitive red
      cells with use of antibodies raised to embryonic beta H1-globin. Primitive
      erythroblasts progressively enucleate between embryonic days 12.5 and 16.5,
      generating mature primitive erythrocytes that are similar in size to their
      nucleated counterparts. These enucleated primitive erythrocytes circulate as late
      as 5 days after birth. The enucleation of primitive red cells in the mouse embryo
      has not previously been well recognized because it coincides with the emergence
      of exponentially expanding numbers of definitive erythrocytes from the fetal
      liver. Our studies establish a new paradigm in the understanding of primitive
      erythropoiesis and support the concept that primitive erythropoiesis in mice
      shares many similarities with definitive erythropoiesis of mammals.

PMID- 15031209
TI  - Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and
      monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent
      patients.
AB  - In Epstein-Barr-virus (EBV)-positive lymphomas in immunocompetent patients,
      release of EBV DNA from tumor cells into the plasma might be useful for disease
      monitoring and prognostication. To test this hypothesis, we quantified serially
      plasma EBV DNA by quantitative polymerase chain reaction in 39 cases of EBV
      positive (natural killer [NK] cell, n = 23; T cell, n = 8; B cell, n = 4;
      Hodgkin, n = 4) lymphomas. As control, EBV DNA was undetectable in 34 cases of
      EBV-negative lymphomas at diagnosis and during chemotherapy. In all cases of EBV
      positive lymphomas, EBV DNA was detectable (10(5)-10(10) copies/mL) at diagnosis.
      It paralleled the clinical course, with EBV DNA becoming undetectable at
      remission and remaining elevated in refractory disease. On multivariate analysis,
      high-presentation EBV DNA (> 7.3 x 10(7) copies/mL) was significantly associated
      with an inferior overall survival (OS). Subgroup analysis of NK cell lymphomas,
      the largest cohort in this study, showed that presentation EBV DNA was correlated
      with disease stage and lactate dehydrogenase. On multivariate analysis, high
      presentation EBV DNA (> 6.1 x 10(7) copies/mL) was significantly associated with
      an inferior disease-free survival. During treatment, patients with EBV DNA that
      showed further increases or failed to become undetectable had significantly
      inferior OS. In EBV-positive lymphomas, plasma EBV DNA is valuable as a tumor
      biomarker and for prognostication.

PMID- 15031210
TI  - GILZ, a new target for the transcription factor FoxO3, protects T lymphocytes
      from interleukin-2 withdrawal-induced apoptosis.
AB  - Interleukin-2 (IL-2) withdrawal is a physiologic process inducing cell death in
      activated T lymphocytes. Glucocorticoid-induced leucine zipper (GILZ) has
      recently been identified as a protein modulating T-cell receptor activation by
      repressing various signaling pathways. We report here that IL-2 deprivation leads
      to expression of GILZ in T lymphocytes. We then characterized the human gilz
      promoter and showed that FoxO3 (Forkhead box class O3) binding to the Forkhead
      responsive elements identified in the promoter is necessary for induction of gilz
      expression upon IL-2 withdrawal. To assess the functional consequences of this
      induction, we used 2 strategies, GILZ overexpression and GILZ silencing in murine
      IL-2-dependent CTLL-2 cells. GILZ overexpression protects CTLL-2 cells from IL-2
      withdrawal-induced apoptosis, whereas cell death is accelerated in cells unable
      to express GILZ. Concomitantly, the expression of Bim is inhibited in GILZ
      overexpressing cells and enhanced when GILZ expression is impaired. Furthermore,
      GILZ inhibits FoxO3 transcriptional activity that leads to inhibition of Bim
      expression but also to down-regulation of GILZ itself. Therefore, GILZ is a
      transiently expressed protein induced upon IL-2 withdrawal that protects T cells
      from the onset of apoptosis.

PMID- 15031211
TI  - In vitro-expanded human CD4(+)CD25(+) T-regulatory cells can markedly inhibit
      allogeneic dendritic cell-stimulated MLR cultures.
AB  - CD4(+)CD25(+) T-regulatory (Treg) cells have been shown to critically regulate
      self- and allograft tolerance in several model systems. Studies of human Treg
      cells have been restricted by the small number present in peripheral blood and
      their naturally hypoproliferative state. To better characterize Treg suppressor
      cell function, we determined methods for the isolation and expansion of these
      cells. Stringent magnetic microbead-based purification was required for potent
      suppressor cell line generation. Culture stimulation with cell-sized Dynabeads
      coated with anti-CD3 and anti-CD28 monoclonal antibodies, CD4(+) feeder cells,
      and interleukin 2, provided for marked expansion in cell number (100-fold), with
      retention and enhancement of suppressor function. The potent Treg cell lines
      suppressed proliferation in dendritic cell-driven allo-mixed lymphocyte reaction
      (MLR) cultures by more than 90%. The Treg-derived suppressor cells functioned
      early in allo-MLR because expression of activation antigens and accumulation of
      cytokines was nearly completely prevented. Importantly, cultured Treg cells also
      suppressed activated and matured dendritic cell-driven responses. These results
      demonstrate that short-term suppressor cell lines can be generated, and they can
      express a very potent suppressive activity. This approach will enable more
      detailed biologic studies of Treg cells and facilitate the evaluation of cultured
      Treg cells as a novel form of immunosuppressive therapy.

PMID- 15031212
TI  - Platelets, protease-activated receptors, and fibrinogen in hematogenous
      metastasis.
AB  - Procoagulant activity on tumor cells can enhance their ability to spread via the
      circulation to colonize distant organs. Toward defining the relative importance
      of the main host responses to coagulation for hematogenous metastasis, we
      examined lung metastases after intravenous injection of melanoma cells in Nf-E2(
      /-) mice, which have virtually no circulating platelets; Par4(-/-) mice, which
      have platelets that fail to respond to thrombin; Par1 and Par2(-/-) mice, which
      have markedly attenuated endothelial responses to coagulation proteases; and Fib(
      /-) mice, which lack fibrinogen. In a severe combined immunodeficiency (SCID)
      background, median lung tumor count in Nf-E2(-/-), Par4(-/-), and Fib(-/-) mice
      was 6%, 14%, and 24% of wild type, respectively; total tumor burden was only 4%,
      9%, and 3% of wild type, respectively. Similar results were seen in a syngeneic
      C57BL6 background. By contrast, deficiencies of protease-activated receptor 1
      (PAR1) or PAR2 did not provide protection. These results provide strong genetic
      evidence that platelets play a key role in hematogenous metastasis and contribute
      to this process by both thrombin-dependent and -independent mechanisms.
      Importantly, PAR4 heterozygosity conferred some protection against metastasis in
      this model. Thus even partial attenuation of platelet function may be sufficient
      to provide benefit.

PMID- 15031213
TI  - Preventing falls in elderly people.

PMID- 15031214
TI  - Extending CONSORT to include cluster trials.

PMID- 15031215
TI  - Diagnosis of stroke on neuroimaging.

PMID- 15031216
TI  - Improving peer review: who's responsible?

PMID- 15031218
TI  - UK government announces plan to tackle alcohol.

PMID- 15031219
TI  - GPs need help in spotting cancer symptoms, report says.

PMID- 15031220
TI  - Women sue over delays in treatment for breast cancer.

PMID- 15031224
TI  - Infectious diseases expert sentenced to prison and fined.

PMID- 15031222
TI  - Hospital breached boy's human rights by treating him against his mother's wishes.

PMID- 15031225
TI  - Roma woman goes to UN claiming sterlisation without consent.

PMID- 15031229
TI  - Drug resistant tuberculosis soars in eastern Europe.

PMID- 15031232
TI  - Requiring doctors to take part in continuing medical education doesn't improve
      heart attack care.

PMID- 15031233
TI  - Benefits of implantable cardiac defibrillators in heart failure are confirmed.

PMID- 15031234
TI  - Hospitals that follow heart attack guidelines save lives.

PMID- 15031235
TI  - Malnutrition reaches alarming level in Darfur, Sudan.

PMID- 15031236
TI  - WHO report calls for new approach to substance dependence.

PMID- 15031238
TI  - Effectiveness of targeted falls prevention programme in subacute hospital
      setting: randomised controlled trial.
AB  - OBJECTIVE: To assess the effectiveness of a targeted, multiple intervention falls
      prevention programme in reducing falls and injuries related to falls in a
      subacute hospital. DESIGN: Randomised controlled trial of a targeted multiple
      intervention programme implemented in addition to usual care compared with usual
      care alone. SETTING: Three subacute wards in a metropolitan hospital specialising
      in rehabilitation and care of elderly patients. PARTICIPANTS: 626 men and women
      aged 38 to 99 years (average 80 years) were recruited from consecutive admissions
      to subacute hospital wards. INTERVENTION: Falls risk alert card with information
      brochure, exercise programme, education programme, and hip protectors. MAIN
      OUTCOME MEASURES: Incidence rate of falls, injuries related to falls, and
      proportion of participants who experienced one or more falls during their stay in
      hospital. RESULTS: Participants in the intervention group (n = 310) experienced
      30% fewer falls than participants in the control group (n = 316). This difference
      was significant (Peto log rank test P = 0.045) and was most obvious after 45 days
      of observation. In the intervention group there was a trend for a reduction in
      the proportion of participants who experienced falls (relative risk 0.78, 95%
      confidence interval 0.56 to 1.06) and 28% fewer falls resulted in injury (log
      rank test P = 0.20). CONCLUSIONS: A targeted multiple intervention falls
      prevention programme reduces the incidence of falls in the subacute hospital
      setting.

PMID- 15031240
TI  - Revalidation: the purpose needs to be clear.

PMID- 15031239
TI  - Interventions for the prevention of falls in older adults: systematic review and
      meta-analysis of randomised clinical trials.
AB  - OBJECTIVE: To assess the relative effectiveness of interventions to prevent falls
      in older adults to either a usual care group or control group. DESIGN: Systematic
      review and meta-analyses. DATA SOURCES: Medline, HealthSTAR, Embase, the Cochrane
      Library, other health related databases, and the reference lists from review
      articles and systematic reviews. DATA EXTRACTION: Components of falls
      intervention: multifactorial falls risk assessment with management programme,
      exercise, environmental modifications, or education. RESULTS: 40 trials were
      identified. A random effects analysis combining trials with risk ratio data
      showed a reduction in the risk of falling (risk ratio 0.88, 95% confidence
      interval 0.82 to 0.95), whereas combining trials with incidence rate data showed
      a reduction in the monthly rate of falling (incidence rate ratio 0.80, 0.72 to
      0.88). The effect of individual components was assessed by meta-regression. A
      multifactorial falls risk assessment and management programme was the most
      effective component on risk of falling (0.82, 0.72 to 0.94, number needed to
      treat 11) and monthly fall rate (0.63, 0.49 to 0.83; 11.8 fewer falls in
      treatment group per 100 patients per month). Exercise interventions also had a
      beneficial effect on the risk of falling (0.86, 0.75 to 0.99, number needed to
      treat 16) and monthly fall rate (0.86, 0.73 to 1.01; 2.7). CONCLUSIONS:
      Interventions to prevent falls in older adults are effective in reducing both the
      risk of falling and the monthly rate of falling. The most effective intervention
      was a multifactorial falls risk assessment and management programme. Exercise
      programmes were also effective in reducing the risk of falling.

PMID- 15031241
TI  - Revalidation for general practitioners: randomised comparison of two revalidation
      models.
AB  - OBJECTIVE: To compare two models of revalidation for general practitioners.
      DESIGN: Randomised comparison of two revalidation models. SETTING: Primary care
      in Tayside, Scotland. PARTICIPANTS: 66 Tayside general practitioners (principals
      and non-principals), 53 of whom completed the revalidation folders. Interventions
      Two revalidation models: a minimum criterion based model with revalidation as the
      primary purpose, and an educational outcome model with emphasis on combining
      revalidation with continuing professional development. MAIN OUTCOME MEASURES:
      Feasibility and acceptability of each approach and effect on the doctor's
      continuing professional development. The ability to make a summative judgment on
      completed models and whether either model would allow patient groups to have
      confidence in the revalidation process. RESULTS: The criterion model was
      preferred by general practitioners. For both models doctors reported making
      changes to their practice and felt a positive effect on their continuing
      professional development. Summative assessment of the folders showed reasonable
      inter-rater reliability. CONCLUSIONS: The criterion model provides a practical
      and acceptable model for general practitioners to use when preparing for
      revalidation.

PMID- 15031243
TI  - Recent developments in secondary prevention and cardiac rehabilitation after
      acute myocardial infarction.

PMID- 15031245
TI  - Setting up a cessation service.

PMID- 15031246
TI  - CONSORT statement: extension to cluster randomised trials.

PMID- 15031247
TI  - Suspension of doctors: medical suspensions may have ideological nature.

PMID- 15031248
TI  - Suspension of doctors: GMC may be ultimate sacrifice.

PMID- 15031249
TI  - Suspension of doctors: reports highlight lack of human resources and legal
      expertise in NHS trusts.

PMID- 15031250
TI  - Suspension of doctors: be careful with suspensions.

PMID- 15031251
TI  - Ethics review in research: research governance also delays research.

PMID- 15031252
TI  - Ethics review in research: role of ethics committee review is interpreted widely.

PMID- 15031253
TI  - Ethics review in research: ethics committees are risk averse.

PMID- 15031254
TI  - Ethics review in research: time has come for reassessment.

PMID- 15031255
TI  - Exercise training in patients with chronic heart failure: more information is
      needed on outcomes in individual studies.

PMID- 15031256
TI  - Increase in non-evidence based use of antidepressants in children is cause for
      concern.

PMID- 15031257
TI  - Top up fees and medicine: waive repayments completely if working life is spent in
      the NHS.

PMID- 15031258
TI  - Top up fees and medicine: ability to commit to unspecified debt may take
      precedence over ability.

PMID- 15031259
TI  - Regularly imbibing Dickens may inspire healthfulness.

PMID- 15031260
TI  - Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII
      gene in smooth muscle.
AB  - Bone morphogenetic peptides (BMPs), a family of cytokines critical to normal
      development, were recently implicated in the pathogenesis of familial pulmonary
      arterial hypertension. The type-II receptor (BMPRII) is required for recognition
      of all BMPs, and targeted deletion of BMPRII in mice results in fetal lethality
      before gastrulation. To overcome this limitation and study the role of BMP
      signaling in postnatal vascular disease, we constructed a smooth muscle-specific
      transgenic mouse expressing a dominant-negative BMPRII under control of the
      tetracycline gene switch (SM22-tet-BMPRII(delx4+) mice). When the mutation was
      activated after birth, mice developed increased pulmonary artery pressure,
      RV/LV+S ratio, and pulmonary arterial muscularization with no increase in
      systemic arterial pressure. Studies with SM22-tet-BMPRII(delx4+) mice support the
      hypothesis that loss of BMPRII signaling in smooth muscle is sufficient to
      produce the pulmonary hypertensive phenotype.

PMID- 15031261
TI  - G protein-coupled receptor internalization signaling is required for
      cardioprotection in ischemic preconditioning.
AB  - The present study is designed to explore the role of G protein-coupled receptors
      (GPCRs) in the protection afforded by ischemic preconditioning (PC). We used TG
      mice with cardiac-specific overexpression of a Gbetagamma-sequestering peptide,
      betaARKct (TG betaARKct mice), to test whether the protection of PC is Gbetagamma
      dependent. To test the role of G(i) protein, we used wild-type mice pretreated
      with the G(i) inhibitor pertussis toxin. Recovery of left ventricular developed
      pressure and infarct size were measured as indices of protection. PC induced
      protection in wild-type mice, but this protection was blocked by pertussis toxin
      treatment and was also blocked in TG betaARKct mice. To determine the mechanism
      of Gbetagamma-induced protection in PC, we investigated one of the downstream
      targets of Gbetagamma, the PI3K/p70S6K pathway. PC-induced phosphorylation of
      p70S6K was not blocked in TG betaARKct hearts; therefore, we investigated other
      targets of Gbetagamma. Recent studies suggest a role for Gbetagamma in GPCR
      internalization. We found that betaARKct, a specific PI3K inhibitor wortmannin,
      and bafilomycin A1, which all block receptor recycling, all blocked the
      protective effect of PC. To additionally test whether PI3K is involved in PC
      activated receptor internalization and endosomal signaling, we used TG mice with
      cardiac-specific overexpression of a catalytically inactive mutant PI3Kgamma,
      which disrupts the recruitment of functional PI3K to agonist-activated GPCRs in
      vivo. We found that the catalytically inactive mutant of PI3Kgamma blocks the
      protection of PC. In summary, these data suggest the novel finding that the
      cardioprotective effect of PC requires receptor internalization.

PMID- 15031262
TI  - Extracellular matrix glycoprotein biglycan enhances vascular smooth muscle cell
      proliferation and migration.
AB  - Proteoglycans are produced and secreted by vascular smooth muscle cells, but the
      pathophysiological role of these glycoproteins in the vasculature is an enigma.
      Because the small leucine-rich proteoglycan (SLRP) biglycan is overexpressed in
      arteriosclerotic lesions, we produced mice constitutively overexpressing biglycan
      in the vascular smooth muscle, in order to examine the effects on vascular
      pathology. In the aorta and renal vasculature, increased vascular proliferation
      was seen both in the basal state and after infusion of angiotensin II (Ang II) in
      the transgenic mice compared with wild-type controls. In addition, the
      combination of biglycan overexpression and Ang II infusion resulted in marked
      increases in vascular smooth muscle cell proliferation and migration in the
      coronary arteries, as well as increases in fibrosis surrounding the vessels. In
      vitro, biglycan caused an increase in thymidine incorporation and migration of
      vascular smooth muscle cells, whereas these parameters were unchanged or reduced
      in endothelial cells. Moreover, addition of biglycan resulted in an increase in
      cdk2 expression and decrease in p27 levels in the vascular smooth muscle cells.
      These results suggest that this extracellular matrix SLRP may be involved in the
      regulation of vascular smooth muscle growth and migration through cdk2- and p27
      dependent pathways. Furthermore, changes in biglycan expression could be a factor
      influencing the susceptibility of arteries to vascular injury, and may play a
      direct role in the pathogenesis of vascular lesions.

PMID- 15031263
TI  - Antiremodeling effects of iloprost and the dual-selective phosphodiesterase 3/4
      inhibitor tolafentrine in chronic experimental pulmonary hypertension.
AB  - Severe pulmonary hypertension is a disabling disease with high mortality. We
      investigated acute and chronic effects of iloprost, a long-acting prostacyclin
      analogue, and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in
      monocrotaline-induced pulmonary hypertension in rats. Twenty-eight and 42 days
      after administration of the alkaloid, right ventricular systolic pressure
      increased from 25.8+/-2.0 to 62.9+/-3.4 and 70.5+/-7.4 mm Hg, with concomitant
      decline in cardiac index, central venous oxygen saturation, and arterial
      oxygenation. Marked right heart hypertrophy was demonstrated by the strongly
      elevated ratio of right ventricle/left ventricle plus septum weight, and massive
      thickening of the precapillary artery smooth muscle layer was shown
      histologically. Western blot analysis demonstrated increased levels of matrix
      metalloproteinases (MMPs) -2 and -9 and increased gelatinolytic activities in
      isolated pulmonary arteries. In these animals, both intravenous iloprost and
      tolafentrine displayed characteristic features of pulmonary vasodilators. When
      chronically infused from days 14 to 28, both agents significantly attenuated all
      monocrotaline-induced hemodynamic and gas exchange abnormalities as well as right
      heart hypertrophy. Full normalization of all variables including right ventricle
      size was achieved on combined administration of both agents during this period.
      This was also true for MMP-2 and MMP-9 expression and activity. Moreover, when
      iloprost plus tolafentrine was used for late therapeutic intervention, with
      infusion from days 28 to 42 after full establishment of severe pulmonary
      hypertension and cor pulmonale, hemodynamic, gas exchange, and cardiac and
      pulmonary vascular remodeling changes were significantly reversed. We conclude
      that the combined administration of iloprost and a dual-selective
      phosphodiesterase 3/4 inhibitor prevents and reverses the development of
      pulmonary hypertension and cor pulmonale in response to monocrotaline in rats.
      This regimen may therefore offer a possible antiremodeling therapy in severe
      pulmonary hypertension.

PMID- 15031264
TI  - Photoreceptor ubiquitination by COP1 E3 ligase desensitizes phytochrome A
      signaling.
AB  - Desensitization of activated receptors is an important mechanism for terminating
      signal transduction. Here we show that phytochrome (phy) A, a predominant
      photoreceptor for seedling deetiolation, colocalizes in nuclear bodies with
      CONSTITUTIVELY PHOTOMORPHOGENIC (COP) 1, a RING motif-containing E3 ligase. The
      phyA PAS domain interacts with the COP1 WD40 domain. Both the Pr and the Pfr
      forms of phyA, as well as the PHYA apoprotein, are ubiquitinated by COP1 in
      vitro. The phyA destruction rate is decreased in cop1 mutants and by expression
      of a COP1 RING motif mutant. Our results indicate that COP1 acts as an E3 ligase
      to regulate phyA signaling by targeting elimination of the phyA photoreceptor
      itself.

PMID- 15031266
TI  - Assessing the clinical impact of prostate-specific antigen assay variability and
      nonequimolarity: a simulation study based on the population of the United
      Kingdom.
AB  - BACKGROUND: Prostate-specific antigen (PSA) is the most widely used serum
      biomarker to differentiate between malignant and benign prostate disease. Assays
      that measure PSA can be biased and/or nonequimolar and hence report significantly
      different PSA values for samples with the same nominal amount. This report
      investigates the effects of biased and nonequimolar assays on the decision to
      recommend a patient for a prostate biopsy based on age-specific PSA values.
      METHODS: A simulation model, calibrated to the distribution of PSA values in the
      United Kingdom, was developed to estimate the effects of bias, nonequimolarity,
      and analytical imprecision in terms of the rates of men who are recommended to
      have a biopsy on the basis of their assay-reported PSA values when their true PSA
      values are below the threshold (false positives) or vice versa (false negatives).
      RESULTS: False recommendation rates for a calibrated equimolar assay are 0.5-0.9%
      for analytical imprecision between 5% and 10%. Positive bias leads to significant
      increases in false positives and significant decreases in false negatives,
      whereas negative bias has the opposite effect. False-positive rates for
      nonequimolar assays increase from 0.5% to 13% in the worst-case scenario, whereas
      false-negative rates are almost always 0%. CONCLUSIONS: Biased and nonequimolar
      assays can have major detrimental effects on both false-negative and false
      positive rates for recommending biopsy. PSA assays should therefore be calibrated
      to the International Standards and be unbiased and equimolar in response to
      minimize the likelihood of incorrect clinical decisions, which are potentially
      detrimental for both patient and healthcare provider.

PMID- 15031265
TI  - Natural genetic variation in Arabidopsis identifies BREVIS RADIX, a novel
      regulator of cell proliferation and elongation in the root.
AB  - Mutant analysis has been tremendously successful in deciphering the genetics of
      plant development. However, less is known about the molecular basis of
      morphological variation within species, which is caused by naturally occurring
      alleles. In this study, we succeeded in isolating a novel regulator of root
      growth by exploiting natural genetic variation in the model plant Arabidopsis.
      Quantitative trait locus analysis of a cross between isogenized accessions
      revealed that a single locus is responsible for approximately 80% of the variance
      of the observed difference in root length. This gene, named BREVIS RADIX (BRX),
      controls the extent of cell proliferation and elongation in the growth zone of
      the root tip. We isolated BRX by positional cloning. BRX is a member of a small
      group of highly conserved genes, the BRX gene family, which is only found in
      multicellular plants. Analyses of Arabidopsis single and double mutants suggest
      that BRX is the only gene of this family with a role in root development. The BRX
      protein is nuclear localized and activates transcription in a heterologous yeast
      system, indicating that BRX family proteins represent a novel class of
      transcription factors. Thus, we have identified a novel regulatory factor
      controlling quantitative aspects of root growth.

PMID- 15031267
TI  - Electrical restitution hysteresis: good memory or delayed response?

PMID- 15031268
TI  - Understanding cardiac alternans: the answer lies in the Ca2+ store.

PMID- 15031269
TI  - A different outlook on the role of bone marrow stem cells in vascular growth:
      bone marrow delivers software not hardware.

PMID- 15031270
TI  - Telomeres and cardiovascular disease: does size matter?
AB  - Telomeres-the specialized DNA-protein structures at the ends of eukaryotic
      chromosomes-are essential for maintaining genome stability and integrity and for
      extended proliferative life span in both cultured cells and in the whole
      organism. Telomerase and additional telomere-associated proteins are necessary
      for preserving telomeric DNA length. Age-dependent telomere shortening in most
      somatic cells, including vascular endothelial cells, smooth muscle cells, and
      cardiomyocytes, is thought to impair cellular function and viability of the aged
      organism. Telomere dysfunction is emerging as an important factor in the
      pathogenesis of hypertension, atherosclerosis, and heart failure. In this Review,
      we discuss present studies on telomeres and telomere-associated proteins in
      cardiovascular pathobiology and their implications for therapeutics.

PMID- 15031271
TI  - Effects of mechanical forces and mediators of hypertrophy on remodeling of gap
      junctions in the heart.
AB  - This review article focuses on remodeling of gap junctions in response to
      chemical mediators of ventricular hypertrophy, mechanical forces, and alterations
      in cell-to-cell adhesion. Signaling mediated by mechanical forces is likely to be
      involved in the upregulation of cardiac gap junctions during the early phase of
      cardiac hypertrophy and the subsequent downregulation in cardiac failure. Several
      signaling pathways involving cAMP, angiotensin II, transforming growth factor
      beta, vascular endothelial growth factor, and integrin-mediated regulators have
      been shown to affect expression of gap junction proteins. However, a
      comprehensive view of regulation of gap junction trafficking, synthesis, and
      degradation is still lacking. In addition to gap junction regulation by
      extracellular mechanical forces, there is a close relation between gap junctions
      and adhesion junctions and their linkage to the cytoskeleton. This can be
      inferred from experiments on neoformation of cell-to-cell coupling, concomitant
      upregulation of adherens and gap junctions after mechanical stretch, and human
      cardiomyopathies caused by genetic defects in cell-cell adhesion junction
      proteins. The molecular mechanisms responsible for the interaction between
      mechanical and functional cell-to-cell coupling remain to be elucidated.

PMID- 15031272
TI  - Fifteen-month follow-up results of a school-based life-skills approach to smoking
      prevention.
AB  - The life-skills approach to smoking prevention was tested in this study. In
      total, 1024 pupils (mean age 11.4 years, SD = 0.90) from Austria, Denmark,
      Luxembourg and Germany were recruited as an experimental group, and a sample of
      834 matched pupils served as a control group. While the pupils from the control
      group received no specific intervention, the pupils in the experimental group
      participated in an intervention programme which was based on the life-skills
      approach and consisted of 21 sessions. The aims of the programme were to promote
      fundamental social competencies and coping skills. In addition, specific
      information on cigarette smoking was given and skills for resisting social
      influences to smoke were rehearsed. The programme was conducted by trained school
      teachers during a course of 4 months. Anonymous questionnaires were administrated
      (1) before the programme was implemented and (2) 15 months after the programme
      had started. Teachers as well as pupils showed a high level of satisfaction with
      the programme idea and the materials. With regard to the outcome variables, the
      programme had no differential effect on current smoking (4-week prevalence). The
      programme showed a weak effect (P < 0.1) on lifetime smoking prevalence and
      experimental smoking. There was also an effect of the programme on smoking
      knowledge, on the social competences of the pupils as well as on the classroom
      climate. No effects were found on susceptibility to smoking among never-smokers,
      attitudes towards smoking and the perceived positive consequences of smoking. The
      results indicate that prevention programmes that are run for only a few months
      can have a positive impact on variables considered to be protective with regard
      to smoking uptake.

PMID- 15031273
TI  - Differences in physical activity levels between urban and rural school children
      in Cyprus.
AB  - This study attempted to examine differences in physical activity levels between
      urban and rural primary school children. The sample consisted of 256 Greek
      Cypriot children and their parents from two schools representing urban areas and
      three schools representing rural areas. Children's activity levels were assessed
      for 4 weekdays in the winter and for 4 weekdays in the summer using a pedometer
      (DW-200; Yamax, Tokyo, Japan). Daily step counts were used to describe children's
      activity levels. Parents completed a questionnaire assessing environmental
      variables in both seasons. Two-way ANOVAs indicated that urban school children
      were significantly more active in winter than rural school children (means =
      13,583 +/- 4,313 versus 12 436 +/- 3610, P < 0.001) and that rural school
      children were significantly more active in the summer (means = 16,450 +/- 5134
      versus 14,531 +/- 4,901, P < 0.001). Parents of children in rural schools
      reported more space available in the garden and in the neighbourhoods, and safer
      neighbourhoods than parents of children in urban schools, whereas children in
      urban schools had more exercise equipment available at home and were transported
      more frequently to places where they could be physically active. Results of this
      study suggest that intervention programmes to promote physical activity need to
      consider seasonal and geographical location differences in physical activity
      levels.

PMID- 15031275
TI  - Introductory postcards: do they increase response rate in a telephone survey of
      older persons?
AB  - The purpose of this study was to assess whether contact by mail via an
      introductory postcard would increase the response rate to a telephone survey in a
      selected population of 348 people 60 years and older. Of this group, 208 were
      sent a postcard introducing the study and informing them that someone would call
      in the next 1-2 weeks to conduct a telephone interview. The remaining sample of
      140 did not receive the introductory postcard. Amongst the potential participants
      who were contacted and able to participate (n = 240), the response rate for
      completed interview was 58.0% for those sent a postcard and 42.3% for those who
      were not. The refusal rate was 25.3% (postcard sent) and 37.2% (not sent a
      postcard). When the outcome of contact is collapsed to two categories, 'agreed to
      participate' and 'refusal', the response rate to participate was 73.5% (sent a
      postcard) and 59.0% (not sent a postcard) (chi(2) 5.14, d.f. 1, sign. 0.023). The
      response rate amongst those who recall being sent a postcard rose to 86.0%.
      Whether agreeing to participate or refusing to be involved in the survey was
      dependent on being sent an introductory postcard. The conclusion is that mailing
      a postcard prior to the first telephone contact increases the participation rates
      of older persons in a telephone survey at very little extra cost (A$0.60 per
      person).

PMID- 15031274
TI  - A fresh perspective on a rank issue: pupils' accounts of staff enforcement of
      smoking restrictions.
AB  - Evidence on the effectiveness of school-based smoking restrictions on reducing
      pupil smoking rates is mixed. So far, the effect of such policies has only been
      considered using quantitative methods and 'level of enforcement' has primarily
      been measured according to data collected from staff. This qualitative study is
      based on data collected during 25 discussion groups held with 13-year-old pupils
      concerning whether and how staff in their school addressed pupil smoking. Groups
      were conducted in two schools. Both served relatively deprived communities but
      varied in their pupil smoking rates. Pupils made reference to members of the
      Senior Management Team, teaching and non-teaching staff. They mentioned a range
      of possible staff reactions and discussed what factors they felt influenced how
      staff responded. It appeared that a more proactive, firm line was being taken in
      the 'high' than in the 'low' smoking school.

PMID- 15031276
TI  - Reported barriers to eating more fruit and vegetables before and after
      participation in a randomized controlled trial: a qualitative study.
AB  - This qualitative study compares the barriers to eating more fruit and vegetables
      reported before and after participation in a 6-month randomized controlled trial
      in primary care. At the initial intervention appointment of a primary care
      intervention to promote eating five or more portions of fruit and vegetables a
      day, participants were asked to identify the barriers that they thought they
      might encounter. Barriers were discussed again at the final appointment 6 months
      later. At the end of the study, a purposive sample of 40 of the trial
      participants was interviewed to explore their experiences in greater detail.
      Transcripts of tape recordings of the intervention appointments and the semi
      structured interview were analysed using qualitative methods. This paper presents
      the results of a qualitative analysis of these appointment and interview
      transcripts (results of the trial are published elsewhere). Women reported that
      children and male partners were obstructive to their attempts to eat more fruit
      and vegetables, whilst men reported that their partners were supportive of the
      change. The perception that fruit and vegetables were expensive was a relatively
      intractable barrier for those with inflexible food budgets. Some barriers,
      including the problem of getting fruit and vegetables when travelling or when the
      daily routine is disrupted such as at weekends, were not anticipated and only
      encountered when participants tried to make changes. However, while all but three
      of the interview respondents described experiencing at least one barrier to
      eating more fruit and vegetables, three quarters (29 of 40) reported an increase
      in intake of between one and five daily portions. This study adds to the existing
      literature in that it investigates those barriers that were reported at the end
      of, as well as before, a 6-month trial of a dietary intervention. The findings
      show that trial participants were not always able to anticipate what might be a
      barrier to change at the initial intervention appointment. The flexible action
      plan meant that if participants found their initial plan hard to maintain, they
      were able to adapt it rather than give up. This suggests that health behaviour
      interventions that are negotiated and non-prescriptive may be more successful
      than those that are relatively inflexible.

PMID- 15031277
TI  - The social distribution of reports of health-related concerns among adolescents
      in Sao Paulo, Brazil.
AB  - This study investigated the health-related concerns of adolescents living on
      streets as compared to poor and privileged adolescents living with their families
      in Sao Paulo, Brazil. The different groups of respondents were similar in terms
      of individuals' fear of disease and lack of concern about health in old age. AIDS
      and cancer were feared by most of the respondents in the different groups,
      particularly because of their severity and people's vulnerability to these
      conditions. Health in old age was not a major concern in any of the study groups.
      It is suggested that health educators take into account the wide range of
      concerns among adolescents on the streets in order to design interventions that
      cater for different levels of interest and motivation. It is also argued that
      there is a need for health education in order to clarify misperceptions about
      disease transmission, prevention and treatment among adolescents from different
      socioeconomic backgrounds.

PMID- 15031278
TI  - Evaluation of a theoretically based AIDS/STD peer education program on postponing
      sexual intercourse and on condom use among adolescents attending high school.
AB  - The effectiveness of an intervention based upon the theories of Ajzen and
      Triandis was evaluated among 698 junior and 306 senior high school students. The
      intervention to juniors was offered by senior students who were trained during a
      course integrated into the school curriculum. Respondents in the control and
      experimental groups completed a questionnaire at baseline and 9 months after the
      program. Compared to junior respondents in the control group, those in the
      experimental group positively modified their attitude, perceived behavioral
      control, personal normative beliefs, perceived role beliefs, anticipated regret
      and intention with respect to postponing sexual intercourse and with respect to
      condom use, as well as perceived self-efficacy to negotiate both behaviors.
      Compared to senior respondents in the control group, those in the experimental
      group showed a significant positive modification of all the above variables
      except perceived behavioral control (indirect measure), anticipated regret and
      intention with respect to postponing sexual intercourse. At post-test, seniors in
      the experimental group were more likely to use condoms on a regular basis than
      those in the control group. Program effects occurred among both sexes, but a few
      differences in response were observed among males and females. Results suggest
      this type of theory-based program is effective in modifying psychosocial
      variables related to postponing sexual intercourse and related to condom use
      among adolescents. Personal involvement in designing intervention appears to be
      effective in modifying the behavior of peer educators.

PMID- 15031279
TI  - Student participation: a democratic education perspective--experience from the
      health-promoting schools in Macedonia.
AB  - The paper addresses the issue of student participation from the perspective of
      the health-promoting schools initiative. It draws on experience from the
      Macedonian Network of Health-Promoting Schools and its collaboration with the
      Danish as well as other country networks within the European Network of Health
      Promoting Schools. Student participation is viewed as one of the main focal
      points of the conceptual framework and model of a health-promoting school
      developed within the Macedonian context. This model and the model distinguishing
      between two different qualities of participation-genuine and token participation
      are presented and discussed in the paper. Underpinning values that these models
      endorse as important for the processes of health promotion in schools include
      self-determination, participation, democracy, diversity and equity.

PMID- 15031281
TI  - A repeated GGA motif is critical for the activity and stability of the
      riboregulator RsmY of Pseudomonas fluorescens.
AB  - The riboregulator RsmY of Pseudomonas fluorescens strain CHA0 is an example of
      small regulatory RNAs belonging to the global Rsm/Csr regulatory systems
      controlling diverse cellular processes such as glycogen accumulation, motility,
      or formation of extracellular products in various bacteria. By binding multiple
      molecules of the small regulatory protein RsmA, RsmY relieves the negative effect
      of RsmA on the translation of several target genes involved in the biocontrol
      properties of strain CHA0. RsmY and functionally related riboregulators have
      repeated GGA motifs predicted to be exposed in single-stranded regions, notably
      in the loops of hairpins. The secondary structure of RsmY was corroborated by in
      vivo cleavage with lead acetate. RsmY mutants lacking three or five (out of six)
      of the GGA motifs showed reduced ability to derepress the expression of target
      genes in vivo and failed to bind the RsmA protein efficiently in vitro. The
      absence of GGA motifs in RsmY mutants resulted in reduced abundance of these
      transcripts and in a shorter half-life (< or = 6 min as compared with 27 min for
      wild type RsmY). These results suggest that both the interaction of RsmY with
      RsmA and the stability of RsmY strongly depend on the GGA repeats and that the
      ability of RsmY to interact with small regulatory proteins such as RsmA may
      protect this RNA from degradation.

PMID- 15031283
TI  - Oxidative inhibition of human soluble catechol-O-methyltransferase.
AB  - A common polymorphism in the human gene for catechol-O-methyltransferase results
      in replacement of Val-108 by Met in the soluble form of the protein (s-COMT) and
      has been linked to breast cancer and neuropsychiatric disorders. The 108M and
      108V variants are reported to differ in their thermal stability, with 108M COMT
      losing catalytic activity more rapidly. Because human s-COMT contains seven
      cysteine residues and includes CXXC and CXXS motifs that are associated with
      thiol-disulfide redox reactions, we examined the effects of reducing and
      oxidizing conditions on the enzyme. In the absence of a reductant 108M s-COMT
      lost activity more rapidly than 108V, whereas in the presence of 4 mm
      dithiothreitol (DTT) we found no significant differences in the stability of the
      two variants at 37 degrees C. DTT also restored most of the activity that was
      lost upon incubation at 37 degrees C in the absence of DTT. Mass spectrometry
      showed that cysteines 188 and 191 formed an intramolecular disulfide bond when s
      COMT was incubated with oxidized glutathione, whereas cysteines 69, 95, 157, and
      173 formed protein-glutathione adducts. Replacing Cys-95 by serine protected 108M
      s-COMT against inactivation in the absence of a reductant; C33S and Cys-188
      mutations had little effect, and C69S was destabilizing. The sequences
      surrounding the reactive cysteine residues of human s-COMT and other proteins
      that form glutathione adducts at identified sites all include Pro and/or Gly and
      most include a hydrogen-bonding residue, suggesting that glutathiolation at
      conserved sites plays a physiologically important role.

PMID- 15031282
TI  - The Kruppel-like KLF4 transcription factor, a novel regulator of urokinase
      receptor expression, drives synthesis of this binding site in colonic crypt
      luminal surface epithelial cells.
AB  - The urokinase-type plasminogen activator receptor (u-PAR) plays a central role in
      cell migration, growth, and invasion and is regulated, in part,
      transcriptionally. In mice, u-PAR expression is restricted to a few tissues, one
      of which is the colon. We therefore screened a colon expression library for
      regulators of u-PAR promoter activity and identified a zinc finger protein
      bearing consensus sequences to the Kruppel-like family of transcription factors
      and showing partial homology with one of the members, KLF4. Like u-PAR, KLF4
      expression is predominant in the luminal surface epithelial cells of the colonic
      crypt, and we hypothesized that u-PAR synthesis in these cells is directed by
      this transcription factor. Colon cells from KLF4 null mice showed a dramatic
      reduction in u-PAR protein compared with wild-type mice. Conversely, KLF4
      expression in HCT116 colon cancer cells increased the amount of u-PAR
      protein/mRNA. Transient transfection of KLF4 with a reporter driven by 5'-deleted
      u-PAR promoter fragments indicated the requirement of the proximal 200 base pairs
      for optimal expression. Mobility-shifting experiments demonstrated binding of
      KLF4 to multiple regions of the u-PAR promoter (-154/-128, -105/-71, and -51/
      24), and chromatin immunoprecipitation assays confirmed the binding of KLF4 to
      the endogenous promoter. Deletion of the -144/-123 promoter region diminished but
      did not eliminate the ability of KLF4 to transactivate the u-PAR promoter,
      suggesting cooperativity of these binding sites with respect to activation of
      gene expression. In conclusion, we have identified KLF4 as a novel regulator of u
      PAR expression that drives the synthesis of u-PAR in the luminal surface
      epithelial cells of the colon.

PMID- 15031284
TI  - Characterization of recombinant, membrane-attached full-length prion protein.
AB  - An abnormal isoform, PrP(Sc), of the normal cellular prion protein (PrP(C)) is
      the major component of the causative agent of prion diseases. Both isoforms were
      found to possess the same covalent structures, including a C-terminal
      glycosylphosphatidylinositol anchor, but different secondary and tertiary
      structures. In this study, a variant of full-length PrP with an unpaired cysteine
      at the C terminus was recombinantly produced in Escherichia coli, covalently
      coupled to a thiol-reactive phospholipid, and incorporated into liposomes to
      serve as a model for studying possible changes in structure and stability of
      recombinant PrP upon membrane attachment. Covalent coupling of PrP to liposomes
      did not result in significant structural changes observable by far-UV circular
      dichroism. Moreover, limited proteolysis experiments failed to detect changes in
      the stability of liposome-bound PrP relative to soluble PrP. These data suggest
      that the requirement of raft localization for the PrP(C) to PrP(Sc) conversion,
      observed previously in cell culture models, is not because of a direct influence
      of raft lipids on the structure and stability of membranebound PrP(C) but caused
      by other factors, e.g. increased local PrP concentrations or high effective
      concentrations of membrane-associated conversion factors. The availability of
      recombinant PrP covalently attached to liposomes provides the basis for
      systematic in vitro conversion assays with recombinant PrP on the surface of
      membranes. In addition, our results indicate that the three-dimensional structure
      of mammalian PrP(C) in membranes is identical to that of recombinant PrP in
      solution.

PMID- 15031285
TI  - A pitfall in diagnosis of human prion diseases using detection of protease
      resistant prion protein in urine. Contamination with bacterial outer membrane
      proteins.
AB  - Because a definite diagnosis of prion diseases relies on the detection of the
      abnormal isoform of prion protein (PrPSc), it has been urgently necessary to
      establish a non-invasive diagnostic test to detect PrPSc in human prion diseases.
      To evaluate diagnostic usefulness and reliability of the detection of protease
      resistant prion protein in urine, we extensively analyzed proteinase K (PK)
      resistant proteins in patients affected with prion diseases and control subjects
      by Western blot, a coupled liquid chromatography and mass spectrometry analysis,
      and N-terminal sequence analysis. The PK-resistant signal migrating around 32 kDa
      previously reported by Shaked et al. (Shaked, G. M., Shaked, Y., Kariv-Inbal, Z.,
      Halimi, M., Avraham, I., and Gabizon, R. (2001) J. Biol. Chem. 276, 31479-31482)
      was not observed in this study. Instead, discrete protein bands with an apparent
      molecular mass of approximately 37 kDa were detected in the urine of many
      patients affected with prion diseases and two diseased controls. Although these
      proteins also gave strong signals in the Western blot using a variety of anti-PrP
      antibodies as a primary antibody, we found that the signals were still detectable
      by incubation of secondary antibodies alone, i.e. in the absence of the primary
      anti-PrP antibodies. Mass spectrometry and N-terminal protein sequencing analysis
      revealed that the majority of the PK-resistant 37-kDa proteins in the urine of
      patients were outer membrane proteins (OMPs) of the Enterobacterial species. OMPs
      isolated from these bacteria were resistant to PK and the PK-resistant OMPs from
      the Enterobacterial species migrated around 37 kDa on SDS-PAGE. Furthermore,
      nonspecific binding of OMPs to antibodies could be mistaken for PrPSc. These
      findings caution that bacterial contamination can affect the immunological
      detection of prion protein. Therefore, the presence of Enterobacterial species
      should be excluded in the immunological tests for PrPSc in clinical samples, in
      particular, urine.

PMID- 15031286
TI  - Tip110, the human immunodeficiency virus type 1 (HIV-1) Tat-interacting protein
      of 110 kDa as a negative regulator of androgen receptor (AR) transcriptional
      activation.
AB  - Upon binding to androgen, androgen receptor (AR) can activate expression of
      target genes through its direct binding to the androgen-responsive elements
      (AREs), which are located within the target gene promoters and/or enhancers. A
      number of cellular proteins have been identified as co-regulators to regulate
      this transactivation process. One common structural feature among these co
      regulators is the presence of the LXXLL motif (X, any amino acid), the so-called
      nuclear receptor (NR) box, through which binding of these regulatory proteins to
      AR occurs. We have recently shown that Tip110 functions to potentiate the
      transactivation activity of human immunodeficiency virus type I (HIV-1) Tat
      protein. In this study, we report that Tip110 is a potent AR-binding protein that
      can suppress AR activity. Tip110 bound to AR in an NR box-dependent manner and
      inhibited AREs-mediated reporter gene expression. The inhibitory effects were
      abolished by removal of the NR box. Moreover, knock-down of the constitutive
      Tip110 expression significantly augmented AR transcriptional activation. In
      agreement with these findings, Tip110 overexpression blocked the prostate
      specific antigen (PSA) gene, a well characterized target gene of AR from
      expression in LNCaP cells. Further analysis revealed that Tip110 prevented the
      complex formation between AR and AREs. Taken together, these results indicate
      that Tip110 is a negative regulator of AR transcriptional activation, and may be
      directly involved in AR-related developmental, physiological, and pathological
      processes.

PMID- 15031287
TI  - Non-fibrillar components of amyloid deposits mediate the self-association and
      tangling of amyloid fibrils.
AB  - Amyloid deposits are proteinaceous extra-cellular aggregates associated with a
      diverse range of disease states. These deposits are composed predominantly of
      amyloid fibrils, the unbranched, beta-sheet rich structures that result from the
      misfolding and subsequent aggregation of many proteins. In addition, amyloid
      deposits contain a number of non-fibrillar components that interact with amyloid
      fibrils and are incorporated into the deposits in their native folded state. The
      influence of a number of the non-fibrillar components in amyloid-related diseases
      is well established; however, the mechanisms underlying these effects are poorly
      understood. Here we describe the effect of two of the most important non
      fibrillar components, serum amyloid P component and apolipoprotein E, upon the
      solution behavior of amyloid fibrils in an in vitro model system. Using
      analytical ultracentrifugation, electron microscopy, and rheological
      measurements, we demonstrate that these non-fibrillar components cause soluble
      fibrils to condense into localized fibrillar aggregates with a greatly enhanced
      local density of fibril entanglements. These results suggest a possible mechanism
      for the observed role of non-fibrillar components as mediators of amyloid
      deposition and deposit stability.

PMID- 15031288
TI  - Identification and characterization of rain, a novel Ras-interacting protein with
      a unique subcellular localization.
AB  - The Ras small GTPase functions as a signaling node and is activated by
      extracellular stimuli. Upon activation, Ras interacts with a spectrum of
      functionally diverse downstream effectors and stimulates multiple cytoplasmic
      signaling cascades that regulate cellular proliferation, differentiation, and
      apoptosis. In addition to the association of Ras with the plasma membrane, recent
      studies have established an association of Ras with Golgi membranes. Whereas the
      effectors of signal transduction by activated, plasma membrane-localized Ras are
      well characterized, very little is known about the effectors used by Golgi
      localized Ras. In this study, we report the identification of a novel Ras
      interacting protein, Rain, that may serve as an effector for endomembrane
      associated Ras. Rain does not share significant sequence similarity with any
      known mammalian proteins, but contains a Ras-associating domain that is found in
      RalGDS, AF-6, and other characterized Ras effectors. Rain interacts with Ras in a
      GTP-dependent manner in vitro and in vivo, requires an intact Ras core effector
      binding domain for this interaction, and thus fits the definition of a Ras
      effector. Unlike other Ras effectors, however, Rain is localized to perinuclear,
      juxta-Golgi vesicles in intact cells and is recruited to the Golgi by activated
      Ras. Finally, we found that Rain cooperates with activated Raf and causes
      synergistic transformation of NIH3T3 cells. Taken together, these observations
      support a role for Rain as a novel protein that can serve as an effector of
      endomembrane-localized Ras.

PMID- 15031289
TI  - Shp2, an SH2-containing protein-tyrosine phosphatase, positively regulates
      receptor tyrosine kinase signaling by dephosphorylating and inactivating the
      inhibitor Sprouty.
AB  - Src homology 2-containing phosphotyrosine phosphatase (Shp2) functions as a
      positive effector in receptor tyrosine kinase (RTK) signaling immediately
      proximal to activated receptors. However, neither its physiological substrate(s)
      nor its mechanism of action in RTK signaling has been defined. In this study, we
      demonstrate that Sprouty (Spry) is a possible target of Shp2. Spry acts as a
      conserved inhibitor of RTK signaling, and tyrosine phosphorylation of Spry is
      indispensable for its inhibitory activity. Shp2 was able to dephosphorylate
      fibroblast growth factor receptor-induced phosphotyrosines on Spry both in vivo
      and in vitro. Shp2-mediated dephosphorylation of Spry resulted in dissociation of
      Spry from Grb2. Furthermore, Shp2 could reverse the inhibitory effect of Spry on
      FGF-induced neurite outgrowth and MAP kinase activation. These findings suggest
      that Shp2 acts as a positive regulator in RTK signaling by dephosphorylating and
      inactivating Spry.

PMID- 15031290
TI  - Zn2+ inhibits glycine transport by glycine transporter subtype 1b.
AB  - In the central nervous system, glycine is a co-agonist with glutamate at the N
      methyl-D-aspartate subtype of glutamate receptors and also an agonist at
      inhibitory, strychnine-sensitive glycine receptors. The GLYT1 subtypes of glycine
      transporters (GLYTs) are responsible for regulation of glycine at excitatory
      synapses, whereas a combination of GLYT1 and GLYT2 subtypes of glycine
      transporters are used at inhibitory glycinergic synapses. Zn2+ is stored in
      synaptic vesicles with glutamate in a number of regions of the brain and is
      believed to play a role in modulation of excitatory neurotransmission. In this
      study we have investigated the actions of Zn2+ on the glycine transporters,
      GLYT1b and GLYT2a, expressed in Xenopus laevis oocytes and we demonstrate that
      Zn2+ is a noncompetitive inhibitor of GLYT1 but has no effect on GLYT2. We have
      also investigated the molecular basis for these differences and the relationship
      between the Zn2+ and proton binding sites on GLYT1. Using site-directed
      mutagenesis, we identified 2 histidine residues, His-243 in the large second
      extracellular loop (ECL2) and His-410 in the fourth extracellular loop (ECL4), as
      two coordinates in the Zn2+ binding site of GLYT1b. In addition, our study
      suggests that the molecular determinants of proton regulation of GLYT1b are
      localized to the 2 histidine residues (His-410 and His-421) of ECL4. The ability
      of Zn2+ and protons to regulate the rate of glycine transport by interacting with
      residues situated in ECL4 of GLYT1b suggests that this region may influence the
      substrate translocation mechanism.

PMID- 15031291
TI  - The C terminus of c-Src inhibits breast tumor cell growth by a kinase-independent
      mechanism.
AB  - Overexpression or increased activity of cellular Src (c-Src) is frequently
      detected in human breast cancer, implicating involvement of c-Src in the etiology
      of breast carcinomas. Curiously, overexpression of c-Src in tissue culture cells
      results in a weakly or non-transforming phenotype, indicating that it alone is
      not sufficient for oncogenesis. However, the protein has been demonstrated to
      potentiate mitogenic signals from transmembrane receptors. This report
      investigates the requirement for c-Src in breast cancer as a transducer and
      integrator of anchorage-dependent and -independent growth signals by utilizing
      the Src family pharmacological inhibitors, PP1 and PP2, or stable overexpression
      of the catalytically inactive c-Src mutant (K- c-Src). Both methods of inhibiting
      endogenous c-Src diminished formation of soft agar colonies and tumors in nude
      mice. The majority of the dominant-negative activity of K- c-Src was mapped to
      the Src homology 2 (SH2) domain and C-terminal half of the molecule, but not to
      the Unique domain, Src homology 3 (SH3) domain, or the N-terminal half of K- c
      Src. Further analysis of the C terminus revealed that its ability to inhibit
      growth localized to the N-terminal lobe (N-lobe) of the catalytic region. These
      results underscore the requirement for c-Src to maintain the oncogenic phenotype
      of breast cancer cells and suggest that c-Src may be manipulated to inhibit cell
      growth by the direct disruption of its catalytic activity or the introduction of
      either the SH2 domain or the N-lobe of K- c-Src.

PMID- 15031292
TI  - The c-Abl tyrosine kinase phosphorylates the Fe65 adaptor protein to stimulate
      Fe65/amyloid precursor protein nuclear signaling.
AB  - The amyloid precursor protein (APP) is proteolytically processed to release a C
      terminal domain that signals to the nucleus to regulate transcription of
      responsive genes. The APP C terminus binds to a number of phosphotyrosine binding
      (PTB) domain proteins and one of these, Fe65, stimulates APP nuclear signaling.
      Fe65 is an adaptor protein that contains a number of protein-protein interaction
      domains. These include two PTB domains, the second of which binds APP, and a WW
      domain that binds proline-rich ligands. One ligand for the Fe65WW domain is the
      tyrosine kinase c-Abl. Here, we show that active c-Abl stimulates APP/Fe65
      mediated gene transcription and that this effect is mediated by phosphorylation
      of Fe65 on tyrosine 547 within its second PTB domain. The homologous tyrosine
      within the motif Tyr-(Leu/Met)-Gly is conserved in a variety of PTB domains, and
      this suggests that PTB tyrosine phosphorylation occurs in other proteins. As
      such, PTB domain phosphorylation may represent a novel mechanism for regulating
      the function of this class of protein.

PMID- 15031293
TI  - Regulation of phospholipase D2 activity by protein kinase C alpha.
AB  - It has been well documented that protein kinase C (PKC) plays an important role
      in regulation of phospholipase D (PLD) activity. Although PKC regulation of PLD1
      activity has been studied extensively, the role of PKC in PLD2 regulation remains
      to be established. In the present study it was demonstrated that phorbol 12
      myristate 13-acetate (PMA) induced PLD2 activation in COS-7 cells. PLD2 was also
      phosphorylated on both serine and threonine residues after PMA treatment. PKC
      inhibitors Ro-31-8220 and bisindolylmaleimide I inhibited both PMA-induced PLD2
      phosphorylation and activation. However, Go 6976, a PKC inhibitor relatively
      specific for conventional PKC isoforms, almost completely abolished PLD2
      phosphorylation by PMA but only slightly inhibited PLD2 activation. Furthermore,
      time course studies showed that phosphorylation of PLD2 lagged behind its
      activation by PMA. Concentration curves for PMA action on PLD2 phosphorylation
      and activation also showed that PLD2 was activated by PMA at concentrations at
      which PMA didn't induce phosphorylation. A kinase-deficient mutant of PKCalpha
      stimulated PLD2 activity to an even higher level than wild type PKCalpha. Co
      expression of wild type PKCalpha, but not PKCdelta, greatly enhanced both basal
      and PMA-induced PLD2 phosphorylation. A PKCdelta-specific inhibitor, rottlerin,
      failed to inhibit PMA-induced PLD2 phosphorylation and activation. Co
      immunoprecipitation studies indicated an association between PLD2 and PKCalpha
      under basal conditions that was further enhanced by PMA. Time course studies of
      the effects of PKCalpha on PLD2 showed that as the phosphorylation of PLD2
      increased, its activity declined. In summary, the data demonstrated that PLD2 is
      activated and phosphorylated by PMA and PKCalpha in COS-7 cells. However, the
      phosphorylation is not required for PKCalpha to activate PLD2. It is suggested
      that interaction rather than phosphorylation underscores the activation of PLD2
      by PKC in vivo and that phosphorylation may contribute to the inactivation of the
      enzyme.

PMID- 15031294
TI  - Transgenic overexpression of protein-tyrosine phosphatase 1B in muscle causes
      insulin resistance, but overexpression with leukocyte antigen-related phosphatase
      does not additively impair insulin action.
AB  - Previous studies implicate protein-tyrosine phosphatase 1B (PTP1B) and leukocyte
      antigen-related phosphatase (LAR) as negative regulators of insulin signaling.
      The expression and/or activity of PTP1B and LAR are increased in muscle of
      insulin-resistant rodents and humans. Overexpression of LAR selectively in muscle
      of transgenic mice causes whole body insulin resistance. To determine whether
      overexpression of PTP1B also causes insulin resistance, we generated transgenic
      mice overexpressing human PTP1B selectively in muscle at levels similar to those
      observed in insulin-resistant humans. Insulin-stimulated insulin receptor (IR)
      tyrosyl phosphorylation and phosphatidylinositol 3'-kinase activity were impaired
      by 35% and 40-60% in muscle of PTP1B-overexpressing mice compared with controls.
      Insulin stimulation of protein kinase C (PKC)lambda/zeta activity, which is
      required for glucose transport, was impaired in muscle of PTP1B-overexpressing
      mice compared with controls, showing that PTP1B overexpression impairs activation
      of these PKC isoforms. Furthermore, hyperinsulinemic-euglycemic clamp studies
      revealed that whole body glucose disposal and muscle glucose uptake were
      decreased by 40-50% in PTP1B-overexpressing mice. Overexpression of PTP1B or LAR
      alone in muscle caused similar impairments in insulin action; however, compound
      overexpression achieved by crossing PTP1B- and LAR-overexpressing mice was not
      additive. Antibodies against specific IR phosphotyrosines indicated overlapping
      sites of action of PTP1B and LAR. Thus, overexpression of PTP1B in vivo impairs
      insulin sensitivity, suggesting that overexpression of PTP1B in muscle of obese
      humans and rodents may contribute to their insulin resistance. Lack of additive
      impairment of insulin signaling by PTP1B and LAR suggests that these PTPs have
      overlapping actions in causing insulin resistance in vivo.

PMID- 15031295
TI  - Primary and essential role of the adaptor protein APS for recruitment of both c
      Cbl and its associated protein CAP in insulin signaling.
AB  - APS (adapter protein with Pleckstrin homology and Src homology 2 domains) is
      recruited by the autophosphorylated insulin receptor and is essential for Glut4
      translocation. Although both APS and CAP (c-Cbl-associated protein) interact with
      c-Cbl during insulin signaling, the relative importance of each protein in
      recruiting c-Cbl has not been clear. We performed a side-by-side comparison by
      ectopic expression of APS or Src homology 2-Balpha (SH2-Balpha) and CAP in
      Chinese hamster ovary (CHO) cells. In cells co-expressing insulin receptor and
      CAP, without APS, no association of the insulin receptor and CAP could be
      detected and no insulin-stimulated phosphorylation of Cbl was observed. Insulin
      stimulated Cbl phosphorylation was reconstituted when APS was co-expressed with
      insulin receptor, with or without CAP. APS or SH2-Balpha and CAP interacted in
      the basal state, and in the case of APS this interaction was mediated by the C
      terminus of APS. Insulin stimulation resulted in the dissociation of APS and CAP.
      Similarly, insulin stimulation also resulted in the dissociation of SH2-Balpha
      and CAP in CHO cells. CAP was localized to the membrane in the presence of APS.
      Insulin stimulation resulted in the re-localization of CAP to the cytosol only
      when APS was co-expressed. In 3T3-L1 adipocytes, small interfering RNA-mediated
      knockdown of the mouse APS gene abolished the insulin-stimulated phosphorylation
      of c-Cbl. Taken together, these results indicate that APS plays a central role in
      recruiting both CAP and c-Cbl to the insulin receptor after insulin stimulation
      and is necessary and sufficient for the insulin-stimulated phosphorylation of c
      Cbl, whereas SH2-Balpha may provide an alternative pathway for the recruitment of
      CAP.

PMID- 15031296
TI  - A fluorescence cell biology approach to map the second integrin-binding site of
      talin to a 130-amino acid sequence within the rod domain.
AB  - The cytoskeletal protein talin, which provides a direct link between integrins
      and actin filaments, has been shown to contain two distinct binding sites for
      integrin beta subunits. Here, we report the precise delimitation and a first
      functional analysis of the talin rod domain integrin-binding site. Partially
      overlapping cDNAs covering the entire human talin gene were transiently expressed
      as DsRed fusion proteins in Chinese hamster ovary cells expressing
      alpha(IIb)beta(3), linked to green fluorescent protein (GFP). Two-color
      fluorescence analysis of the transfected cells, spread on fibrinogen, revealed
      distinct subcellular staining patterns including focal adhesion, actin filament,
      and granular labeling for different talin fragments. The rod domain fragment G
      (residues 1984-2344), devoid of any known actin- or vinculin-binding sites,
      colocalized with beta(3)-GFP in focal adhesions. Direct in vitro interaction of
      fragment G with native platelet integrin alpha(IIb)beta(3) or with the
      recombinant wild type, but not the Y747A mutant beta(3) cytoplasmic tail, linked
      to glutathione S-transferase, was demonstrated by surface plasmon resonance
      analysis and pull-down assays, respectively. Here, we demonstrate for the first
      time the in vivo relevance of this interaction by fluorescence resonance energy
      transfer between beta(3)-GFP and DsRed-talin fragment G. Further in vitro pull
      down studies allowed us to map out the integrin-binding site within fragment G to
      a stretch of 130 residues (fragment J, residues 1984-2113) that also localized to
      focal adhesions. Finally, we show by a cell biology approach that this integrin
      binding site within the talin rod domain is important for beta(3)-cytoskeletal
      interactions but does not participate in alpha(IIb)beta(3) activation.

PMID- 15031297
TI  - Identification of a novel domain of Ras and Rap1 that directs their differential
      subcellular localizations.
AB  - The small GTPase Ha-Ras and Rap1A exhibit high mutual sequence homology and share
      various target proteins. However, they exert distinct biological functions and
      exhibit differential subcellular localizations; Rap1A is predominantly localized
      in the perinuclear region including the Golgi apparatus and endosomes, whereas Ha
      Ras is predominantly localized in the plasma membrane. Here, we have identified a
      small region in Rap1A that is crucial for its perinuclear localization. Analysis
      of a series of Ha-Ras-Rap1A chimeras shows that Ha-Ras carrying a replacement of
      amino acids 46-101 with that of Rap1 exhibits the perinuclear localization.
      Subsequent mutational studies indicate that Rap1A-type substitutions within five
      amino acids at positions 85-89 of Ha-Ras, such as NNTKS85-89TAQST, NN85-86TA, and
      TKS87-89QST, are sufficient to induce the perinuclear localization of Ha-Ras. In
      contrast, substitutions of residues surrounding this region, such as FAI82-84YSI
      and FEDI90-93FNDL, have no effect on the plasma membrane localization of Ha-Ras.
      A chimeric construct consisting of amino acids 1-134 of Rap1A and 134-189 of Ha
      Ras, which harbors both the palmitoylation and farnesylation sites of Ha-Ras,
      exhibits the perinuclear localization like Rap1A. Introduction of a Ha-Ras-type
      substitution into amino acids 85-89 (TAQST85-89NNTKS) of this chimeric construct
      causes alteration of its predominant subcellular localization site from the
      perinuclear region to the plasma membrane. These results indicate that a
      previously uncharacterized domain spanning amino acids 85-89 of Rap1A plays a
      pivotal role in its perinuclear localization. Moreover, this domain acts
      dominantly over COOH-terminal lipid modification of Ha-Ras, which has been
      considered to be essential and sufficient for the plasma membrane localization.

PMID- 15031298
TI  - Protein disulfide bond formation in the cytoplasm during oxidative stress.
AB  - The majority of disulfide-linked cytosolic proteins are thought to be enzymes
      that transiently form disulfide bonds while catalyzing oxidation-reduction
      (redox) processes. Recent evidence indicates that reactive oxygen species can act
      as signaling molecules by promoting the formation of disulfide bonds within or
      between select redox-sensitive proteins. However, few studies have attempted to
      examine global changes in disulfide bond formation following reactive oxygen
      species exposure. Here we isolate and identify disulfide-bonded proteins (DSBP)
      in a mammalian neuronal cell line (HT22) exposed to various oxidative insults by
      sequential nonreducing/reducing two-dimensional SDS-PAGE combined with mass
      spectrometry. By using this strategy, several known cytosolic DSBP, such as
      peroxiredoxins, thioredoxin reductase, nucleoside-diphosphate kinase, and
      ribonucleotide-diphosphate reductase, were identified. Unexpectedly, a large
      number of previously unknown DSBP were also found, including those involved in
      molecular chaperoning, translation, glycolysis, cytoskeletal structure, cell
      growth, and signal transduction. Treatment of cells with a wide range of hydrogen
      peroxide concentrations either promoted or inhibited disulfide bonding of select
      DSBP in a concentration-dependent manner. Decreasing the ratio of reduced to
      oxidized glutathione also promoted select disulfide bond formation within
      proteins from cytoplasmic extracts. In addition, an epitope-tagged version of the
      molecular chaperone HSP70 forms mixed disulfides with both beta4-spectrin and
      adenomatous polyposis coli protein in the cytosol. Our findings indicate that
      disulfide bond formation within families of cytoplasmic proteins is dependent on
      the nature of the oxidative insult and may provide a common mechanism used to
      control multiple physiological processes.

PMID- 15031299
TI  - Tsukamurella paurometabola lipoglycan, a new lipoarabinomannan variant with pro
      inflammatory activity.
AB  - The genus Tsukamurella is a member of the phylogenetic group nocardioform
      actinomycetes and is closely related to the genus Mycobacterium. The
      mycobacterial cell envelope contains lipoglycans, and of particular interest is
      lipoarabinomannan, one of the most potent mycobacterial immunomodulatory
      molecules. We have investigated the presence of lipoglycans in Tsukamurella
      paurometabola and report here the isolation and structural characterization of a
      new lipoarabinomannan variant, designated TpaLAM. Matrix-assisted laser
      desorption ionization-mass spectrometric analysis revealed that TpaLAM had an
      average molecular mass of 12.5 kDa and consequently was slightly smaller than
      Mycobacterium tuberculosis lipoarabinomannan. Using a range of chemical
      degradations, NMR experiments, capillary electrophoresis, and mass spectrometry
      analyses, TpaLAM revealed an original carbohydrate structure. Indeed, TpaLAM
      contained a mannosylphosphatidyl-myo-inositol (MPI) anchor glycosylated by a
      linear (alpha1-->6)-Manp mannan domain, which is further substituted by an
      (alpha1-->5)-Araf chain. Half of the Araf units are further substituted at the O
      2 position by a Manp-(alpha1-->2)-Manp-(alpha1--> dimannoside motif. Altogether,
      TpaLAM appears to be the most elaborated non-mycobacterial LAM molecule
      identified to date. TpaLAM was found to induce the pro-inflammatory cytokine
      tumor necrosis factor (TNF)-alpha when tested with either human or murine
      monocyte/macrophage cell lines. This induction was completely abrogated in the
      presence of an anti-toll-like receptor-2 (TLR-2) antibody, suggesting that TLR-2
      participates in the mediation of TNF-alpha production in response to TpaLAM.
      Moreover, we established that the lipomannan core of TpaLAM is the primary moiety
      responsible for the observed TNF-alpha-inducing activity. This conclusively
      demonstrates that a linear (alpha1-->6)-Manp chain, linked to the MPI anchor, is
      sufficient in providing pro-inflammatory activity.

PMID- 15031300
TI  - Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT
      syndrome.
AB  - Prolongation of the QT interval of the ECG is associated with increased risk of
      torsades de pointes ventricular tachycardia. Ranolazine, a novel antianginal
      agent, is reported to decrease the delayed rectifier potassium current, I(Kr),
      and to increase action potential duration (APD) and the QT interval. However,
      ranolazine is also reported to reduce late sodium current (late I(Na)), a
      depolarizing current that contributes to prolongation of the plateau of the
      ventricular action potential. We hypothesized that ranolazine would decrease APD
      and the occurrence of arrhythmias when late I(Na) is increased. Therefore, we
      measured the effects of ranolazine alone and in the presence of anemone toxin
      (ATX)-II, whose action mimics the sodium channelopathy associated with long-QT3
      syndrome, on epicardial monophasic action potentials and ECGs recorded from
      guinea pig isolated hearts. Ranolazine (0.1-50 microM) prolonged monophasic APD
      at 90% repolarization (MAPD(90)) by up to 22% but did not cause either early
      afterdepolarizations (EADs) or ventricular tachycardia (VT). ATX-II (1-20 nM)
      markedly increased APD and caused EADs and VT. Ranolazine (5-30 microM)
      significantly attenuated increases in MAPD(90) and reduced episodes of EADs and
      VT produced by ATX-II. Ranolazine also attenuated the synergistic effect of
      MAPD(90) increase caused by combinations of ATX-II and blockers of I(K) [E-4031;
      1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)piperidine]. Thus,
      although ranolazine alone prolonged APD, it reduced APD and ventricular
      arrhythmias caused by agents that increased late I(Na) and decreased I(K).

PMID- 15031302
TI  - A guinea pig hippocampal slice model of organophosphate-induced seizure activity.
AB  - Extracellular recording techniques have been used in the guinea pig hippocampal
      slice preparation to investigate the electrophysiological actions of the
      organophosphate (OP) anticholinesterase soman. When applied at a concentration of
      100 nM, soman induced epileptiform activity in the CA1 region in approximately
      75% of slices. This effect was mimicked by the anticholinesterases paraoxon (1
      and 3 microM), physostigmine (30 microM), and neostigmine (30 microM), thus
      providing indirect evidence that the epileptiform response was mediated by
      elevated acetylcholine levels. Soman-induced bursting was inhibited by the
      muscarinic receptor antagonists atropine (concentrations tested, 0.1-10 microM),
      telenzepine (0.03-3 microM), AF-DX116 [11-(2-[(diethylamino)methyl]-1-piperidinyl
      acetyl)-5,11-dihydro-6H-pyrido 92.b-b) (1,4)-benzodiazepin-6-one] (0.3-300
      microM), and biperiden (0.1-10 microM) and by the benzodiazepine anticonvulsants
      diazepam (3-30 microM) and midazolam (3-30 microM), but it was not inhibited by
      the nicotinic antagonists mecamylamine (30 microM) and methyllycaconitine (300
      nM). In contrast to soman-induced epileptiform activity, bursting induced by the
      K(+) channel blocker 4-aminopyridine (30 microM), the adenosine A1 receptor
      antagonist 8-cyclopentyl-1,3-dipropylxanthine (30 nM) or perfusion with low
      Mg(2+) buffer was insensitive to atropine (10 microM). The ability of muscarinic
      antagonists and benzodiazepines to inhibit soman-induced epileptiform activity is
      in accordance with the in vivo pharmacology of soman-induced seizures and
      suggests that the guinea pig hippocampal slice preparation may provide a useful
      tool for the evaluation of novel anticonvulsant therapies for the treatment of
      seizures related to OP poisoning.

PMID- 15031301
TI  - Blood-brain barrier permeability of novel [D-arg2]dermorphin (1-4) analogs:
      transport property is related to the slow onset of antinociceptive activity in
      the central nervous system.
AB  - To clarify the pharmacological characteristics of Nalpha-amidino-Tyr-D-Arg-Phe
      betaAla-OH (ADAB) and Nalpha-amidino-Tyr-D-Arg-Phe-MebetaAla-OH (ADAMB), mu1
      opioid receptor-selective [D-Arg2]dermorphin tetrapeptide analogs, the plasma
      pharmacokinetics, and the in vivo blood-brain barrier (BBB) transport of these
      peptides were quantitatively evaluated. The mechanism responsible for the BBB
      transport of these peptides was also examined. The in vivo BBB permeation influx
      rates of 125I-ADAB and 125I-ADAMB after an i.v. bolus injection into mice were
      determined to be 0.0515 +/- 0.0284 microl/(min.g of brain) and 0.0290 +/- 0.0059
      microl/(min.g of brain), respectively, both rates being slower than that of 125I
      Tyr-D-Arg-Phe-betaAla-OH (125I-TAPA), a [D-Arg2]dermorphin tetrapeptide analog.
      To elucidate the BBB transport mechanism of ADAB and ADAMB, a conditionally
      immortalized mouse brain capillary endothelial cell line (TM-BBB4) was used as an
      in vitro model of the BBB. The internalization of both 125I-ADAB and 125I-ADAMB
      into cells was concentration-dependent with half-saturation constant (Kd) values
      of 3.76 +/- 0.83 and 5.68 +/- 1.75 microM, respectively. The acid-resistant
      binding of both ADAB and ADAMB was significantly inhibited by dansylcadaverine
      (an endocytosis inhibitor) and poly-l-lysine and protamine (polycations), but it
      was not inhibited by 2,4-dinitrophenol, or at 4 degrees C. These results suggest
      that ADAB and ADAMB are transported through the BBB with slower permeation rates
      than that of TAPA, and this is likely to be a factor in the slow onset of their
      antinociceptive activity in the central nervous system. The mechanism of the BBB
      transport of these drugs is considered to be adsorptive-mediated endocytosis.

PMID- 15031303
TI  - Biomarkers of bone turnover can be assayed from human saliva.
AB  - The purpose of this study was to determine if biomarkers of bone turnover
      [deoxypyridinium (D-PYR) or osteocalcin (OC)] could be detected in human saliva.
      These biomarkers have been measured in ovariectomized sheep saliva, but not in
      human saliva. Saliva was collected from 37 women. The bone mineral density of the
      calcaneus was assessed by quantitative ultrasound and expressed as a T score.
      Salivary D-PYR and OC concentrations were determined by enzyme-linked
      immunosorbent assay. Data were analyzed by a Spearman's rho correlation test and
      factorial analysis of variance was followed by a post hoc Tukey's test. There
      were significant correlations between age, body mass index, D-PYR, or OC
      concentration and calcaneus T scores (p<.05), suggesting that saliva could be
      used as a fluid for assay of human biomarkers of bone turnover. Our data suggest
      a beneficial use of saliva in situations where a large number of patients are to
      be screened for metabolic bone diseases.

PMID- 15031304
TI  - How are biomarkers related to physical and mental well-being?
AB  - We investigate how biological markers of individual responses to stressful
      experiences are associated with profiles of physical and mental functioning in a
      national sample of middle-aged and elderly Taiwanese. Data come from a population
      based sample of middle-aged and elderly Taiwanese in 2000. The data combine rich
      biological measures with self-reported information on physical and mental health.
      Grade of membership methods are used to summarize functional status, and
      multinomial logit models provide information on the association between
      biological measures and function. The analysis identifies significant
      associations between biomarkers of stressful experience and profiles of physical
      and mental functioning. The estimates reveal the potential importance for health
      of both low and high values of biological parameters. The findings point to
      directions for future research regarding development of aggregate measures of
      cumulative dysregulation across multiple physiological systems.

PMID- 15031306
TI  - Genome-wide scan for a healthy aging phenotype provides support for a locus near
      D4S1564 promoting healthy aging.
AB  - Living to a late age without suffering any major health problems is a genetically
      influenced trait. To identify the genes contributing to this important phenotype,
      a 10 cM genome screen was performed in 95 pairs of male fraternal twins
      concordant for healthy aging. Individuals meeting these criteria were defined as
      those attaining the age of 70 free of cardiovascular disease (coronary surgery,
      diabetes, heart attack, and stroke) and prostate cancer. Six chromosomal regions
      were identified with logarithm of odds (LOD) scores greater than 1.2 (p<.01). A
      region on chromosome 4 at marker D4S1564 produced a LOD score of 1.67; this was
      the same marker previously linked to extreme longevity segregating as an
      autosomal dominant trait in centenarian families. Our results provide independent
      evidence that a locus on the long arm of chromosome 4 is associated with better
      physical aging and/or longevity.

PMID- 15031305
TI  - Genetic contribution to biological aging: the Framingham Study.
AB  - This study assessed the contribution of genetic and nongenetic factors to
      biological aging in American Caucasians. The studied sample included 1402 members
      of 288 pedigrees from the Framingham Heart Study. The original cohort
      participants received hand radiography in 1967-1969 (mean age, 58.7 years) and
      their offspring in 1992-1993 (mean age, 51.6 years). An osseographic score was
      applied to hand radiographs. Standardized residuals between Osseographic Scoring
      System-predicted age and actual age were used as a measure of biological age
      (BA). In variance component genetic analysis, sex, cohort, height, body mass
      index, and, in women, menopausal status and estrogen use, jointly explained
      approximately 6% of the total variance of BA. Genetic factors explained an
      additional 57%. Linkage analysis of covariate-adjusted BA suggested the presence
      of quantitative trait loci on chromosomes 3p, 7q, 11p, 16q, and 21q. In
      conclusion, the variation in BA measured by radiography was strongly governed by
      genetic factors in a sample of American adults.

PMID- 15031307
TI  - Anemia and quality of life: unrecognized and undertreated.

PMID- 15031308
TI  - Inflammatory markers and physical performance in older persons: the InCHIANTI
      study.
AB  - BACKGROUND: Some studies have proposed chronic inflammation as an underlying
      biological mechanism responsible for physical function decline in elderly people.
      The aim of this study is to evaluate the relationship between several
      inflammatory markers and physical performance in an older population. METHODS:
      This study is part of the "Invecchiare in Chianti" (InCHIANTI) study, a
      prospective population-based study of older people, aimed at identifying risk
      factors for late-life disability. The study sample consisted of 1020 participants
      aged 65 years and older living in the Chianti area of Italy. Physical performance
      was assessed using walking speed, the chair-stand test, and the standing balance
      test. Hand-grip strength was assessed using a hand-held dynamometer. Serum levels
      of C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-alpha (TNF
      alpha), IL-10, IL-1beta, IL-6sR, and IL-1RA were determined. Linear regression
      analyses were used to assess the multivariate relationship of inflammatory marker
      levels with physical performance, scored as a continuous variable from 0 to 3,
      and hand-grip strength after adjustment for demographics, chronic conditions,
      medication use, and other biological variables. RESULTS: CRP, IL-6, and IL1RA
      were significantly correlated with physical performance (r=-0.162, r=-0.251, and
      r=-0.127, respectively). Significant correlations with hand-grip strength were
      found for CRP and IL-6 (r=-0.081 and r=-0.089, respectively). After adjustment
      for covariates, high levels of IL-6 and IL-1RA continued to be strongly
      associated with worse physical performance (p<.001 and p=0.004, respectively).
      High levels of CRP (p<.001) and IL-6 (p<.001) were associated with low hand-grip
      strength. Mean adjusted physical performance scores ranged from 2.21 in the
      CRP<0.59 mg/dl group to 2.07 in the CRP>0.60 mg/dl group (p for trend=.004), and
      from 2.25 in the lowest IL-6 quartile to 2.08 in the highest IL-6 quartile (p for
      trend<.001). This trend was also reflected in mean adjusted hand-grip strength,
      with a range from 28.8 kg for the CRP<0.59 mg/dl group to 26.0 kg for the
      CRP>0.60 mg/dl group (p for trend=.001), and from 27.4 kg for the lowest IL-6
      quartile to 25.1 kg for the highest IL-6 quartile (p for trend=.001).
      CONCLUSIONS: Inflammation, measured as high levels of IL-6, CRP, and IL-1RA, is
      significantly associated with poor physical performance and muscle strength in
      older persons. These data also support the biological face validity of physical
      performance measures. The assessment of inflammatory markers may represent a
      useful screening test and perhaps a potential target of intervention.

PMID- 15031309
TI  - Hemoglobin levels and skeletal muscle: results from the InCHIANTI study.
AB  - BACKGROUND: Anemia is associated with reduced physical performance and muscle
      strength. The aim of the study was to explore whether anemia and hemoglobin
      levels are associated with differences in quantitative and qualitative measures
      of muscle and fat. METHODS: The study sample consisted of 909 participants 65
      years and older enrolled in the "Invecchiare in Chianti" (InCHIANTI) study, a
      prospective population-based study of older people aimed at identifying risk
      factors for late-life disability. All the analyses were performed considering
      continuous hemoglobin levels as well as the dichotomous anemia variable (defined
      according to World Health Organization criteria as hemoglobin <12 g/dL in women
      and <13 g/dL in men). A peripheral quantitative computed tomography (pQCT) scan
      was performed in all participants to evaluate total, muscular, and fat cross
      sectional areas of the calf and relative muscle density. Ankle extension strength
      was measured using a hand-held dynamometer. Linear regression analyses were used
      to assess the multivariate relationship of pQCT and skeletal muscle strength
      measures with hemoglobin levels and anemia after adjustment for demographics,
      chronic conditions, medication use, and other biological variables. RESULTS:
      Participants were aged 74.8 +/- 6.8 years. In our sample, 94 participants (10.3%)
      were anemic. Hemoglobin levels were significantly associated with muscle density
      (beta = 0.225 [SE, standard error 0.098], p=.02), muscle area/total area ratio
      (beta=0.778 [SE 0.262], p=.003), fat area/total area ratio (beta=-0.869 [SE
      0.225]; p<.001). Skeletal muscle strength and muscle density were highly
      associated with anemia (beta=-3.266 [SE 1.173], p=.005 and beta=-0.816 [SE
      0.374], p=.03, respectively). Results did not change when analyses were rerun in
      a restricted sample of participants not affected by major medical conditions.
      CONCLUSION: The present study shows that hemoglobin levels are associated with
      the parameters of body composition obtained by pQCT, and that decreases in
      muscular strength measures occur in the presence of anemia.

PMID- 15031310
TI  - Untangling the concepts of disability, frailty, and comorbidity: implications for
      improved targeting and care.
AB  - Three terms are commonly used interchangeably to identify vulnerable older
      adults: comorbidity, or multiple chronic conditions, frailty, and disability.
      However, in geriatric medicine, there is a growing consensus that these are
      distinct clinical entities that are causally related. Each, individually, occurs
      frequently and has high import clinically. This article provides a narrative
      review of current understanding of the definitions and distinguishing
      characteristics of each of these conditions, including their clinical relevance
      and distinct prevention and therapeutic issues, and how they are related. Review
      of the current state of published knowledge is supplemented by targeted analyses
      in selected areas where no current published data exists. Overall, the goal of
      this article is to provide a basis for distinguishing between these three
      important clinical conditions in older adults and showing how use of separate,
      distinct definitions of each can improve our understanding of the problems
      affecting older patients and lead to development of improved strategies for
      diagnosis, care, research, and medical education in this area.

PMID- 15031311
TI  - Daily ambulation activity and task performance in community-dwelling older adults
      aged 63-71 years with preclinical disability.
AB  - BACKGROUND: The purpose of this study was to examine differences in daily
      ambulation activity and task modification between community-dwelling older adults
      above and below an empirically derived physical threshold that has been linked to
      independence. METHODS: 20 community-dwelling older adults (72.8 +/- 6 years) were
      categorized into groups based on functional performance using the Continuous
      scale Physical Functional Performance Test total score (Cs-PFP). Individuals with
      Cs-PFP > or =57 were assigned to the high functioning group (HIGH; n=10) with all
      others assigned to the lower functioning group (LOW; Cs-PFP<57; n=10). Dependent
      variables included steps/day, number of tasks reported with difficulty, and
      number of tasks reported with modification. RESULTS: HIGH took significantly more
      steps/day (HIGH: 9503 +/- 4623; LOW: 5048 +/- 2917, p=.019) compared to LOW.
      Groups reported having difficulty with a similar number of tasks (HIGH: 0.4 +/-
      1; LOW: 1.0 +/- 1, p=.092) but LOW reported modifying a significantly larger
      number of tasks (HIGH: 0.3 +/- 1; LOW 1.4 +/- 1, p=.049). CONCLUSIONS: Older
      adults with preclinical disability have reduced daily ambulatory activity
      compared to older adults with high function despite a similar independent living
      status. Individuals compensate for reduced physical reserves by modifying the
      method of performing a task. Identifying early declines in physical ability
      through task modification and daily ambulation will provide the opportunity for
      timely intervention to older adults desiring to remain independent within a
      community-dwelling environment.

PMID- 15031312
TI  - Predictors of cognitive decline and mortality of aged people over a 10-year
      period.
AB  - BACKGROUND: The search for preventable and remediable risk conditions of
      cognitive decline is ongoing, but results have thus far been inconsistent.
      According to the hypothesis of our 10-year prospective study, the predictive
      values of different risk indicators change over time in a general 75+ population.
      METHODS: A population-based sample of 75-, 80-, and 85-year-old individuals
      (n=650) underwent comprehensive clinical examinations in 1990 in Helsinki,
      Finland. Cognitive function was assessed by the Mini-Mental State Examination
      (MMSE) and/or Clinical Dementia Rating (CDR) at baseline and after 1, 5, and 10
      years. RESULTS: At baseline, a low MMSE score was associated with age, history of
      stroke, apolipoprotein E allele epsilon4 (APOE4), and intermittent claudication.
      After 1 year, cognitive decline was typical of participants suffering from
      vascular diseases, e.g., heart failure and intermittent claudication. Five-year
      decline was predicted by the presence of atrial fibrillation (RR [relative risk]
      2.8), APOE4 (RR 2.4), elevated C-reactive protein (CRP) (RR 2.3), diabetes
      mellitus (RR 2.2), and heart failure (RR 1.8). They also tended to increase 5
      year all-cause mortality. At 10 years, the decline associated with APOE4 (RR
      3.3), slightly elevated serum ionized calcium (RR 3.3), and feelings of
      loneliness (RR 3.0). CONCLUSIONS: Long follow-up of a general aged population
      explains several inconsistencies of earlier reports. In 75+ individuals, general
      ill health is a strong associate of cognitive deficits. The strongest predictors
      of both cognitive decline and mortality are age, APOE4, manifest vascular
      diseases, and diabetes. The role of new potential predictors, feelings of
      loneliness and hypercalcemia, needs clinical testing.

PMID- 15031313
TI  - Frequency of going outdoors: a predictor of functional and psychosocial change
      among ambulatory frail elders living at home.
AB  - BACKGROUND: This study investigated the relationship between the frequency of
      going outdoors among ambulatory frail elders living at home and subsequent
      functional and psychosocial changes. METHODS: In this 9-month prospective cohort
      study, data were collected via questionnaire from 112 frail elderly persons
      living at home and their families. Functional and psychosocial status at baseline
      and follow-up regarding activities of daily living, functional capacity,
      depression, self-efficacy for daily activities, self-efficacy for health
      promotion, and social support, were compared among 3 groups defined by the
      frequency of going outdoors: 1) more than 4 times a week, 2) 1-3 times a week, 3)
      less than once a week. At baseline, elders going outdoors more often were less
      functionally impaired, more socially active, and scored less depressed than
      elders going outdoors less often. RESULTS: There were significant differences in
      functional capacity (p=.0201) and intellectual activities (p=.0026) over time
      according to the frequency of going outdoors, even when controlling for baseline
      differences, and the scores of those who seldom went outdoors decreased rapidly.
      There were similar relationships between frequency of going outdoors and changes
      in self-efficacy for both daily activities (p=.0067) and for health promotion
      (p=.0245), with participants going outdoors most frequently improving
      significantly more. CONCLUSIONS: These results suggest that the frequency of
      going outdoors may be a useful and simple indicator to predict changes in
      functional capacity, intellectual activity and self-efficacy.

PMID- 15031314
TI  - A minimum data set prevalence of pain quality indicator: is it accurate and does
      it reflect differences in care processes?
AB  - BACKGROUND: A new prevalence of pain quality indicator based on the Minimum Data
      Set (MDS) has been developed for the purpose of providing nursing home (NH)
      consumers with information that would allow them to compare the quality of pain
      care between facilities. The purpose of this study was to compare pain-related
      care processes between NHs that scored in the lower 25th percentile (low pain
      prevalence) or upper 75th percentile (high pain prevalence) based on this
      indicator. METHODS: Care processes related to pain assessment, documentation, and
      treatment were independently evaluated using standardized resident interview and
      medical record review protocols for 255 residents in 16 NHs that reported MDS
      pain prevalence of less than 15% (8 NHs in lower 25th percentile) or greater than
      30% (8 NHs in upper 75th percentile). RESULTS: A significantly greater proportion
      of participants in the high pain prevalence NHs reported symptoms indicative of
      chronic pain during interview. The standardized pain interview revealed a
      significantly higher prevalence of pain among participants in the lowest quartile
      NH group compared to the MDS pain prevalence quality indicator, but the pain
      prevalence according to both MDS and interview were comparable in the higher
      quartile NHs. Medical record review showed that a significantly greater
      proportion of participants in upper quartile NHs had pain assessments documented
      by licensed nurses and physicians, received pain medication, and had
      documentation of treatment response. CONCLUSIONS: An MDS pain quality indicator
      accurately discriminates prevalence of pain between facilities. However,
      interpretation of the pain indicator requires caution. Rather than reflecting
      poor quality, a high prevalence of pain according to the MDS was associated with
      better pain assessment and treatment care processes.

PMID- 15031315
TI  - Age-related changes in maximal hip strength and movement speed.
AB  - BACKGROUND: We quantified age-related decreases in the ability of female
      participants to generate whole leg movements about the hip. METHODS: We measured
      maximum hip strength and hip velocity in 12 young and 12 older healthy women.
      Both capabilities could help fall prevention by contributing to fast leg
      movements. We also measured maximum velocities as a function of isotonic load.
      RESULTS: Young participants produced 107.6 +/- 25.4 N-m (mean +/- SD) isometric
      torque in flexion and 109.3 +/- 22.3 N-m in extension. Older participants
      produced 22% and 31% lower torques, respectively (p<.001). Young participants
      generated maximum velocities of 362.8 +/- 51.5 degrees/s in flexion and 371.5 +/-
      54.2 degrees/s in extension. Older participants produced 16% lower velocities in
      both directions (p<.001). Older participants also produced lower velocities as a
      function of load (p<.001), and lower maximum power (p<.001). CONCLUSION: Both
      maximum strength and velocity contribute to reduced ability to move the leg
      quickly with age.

PMID- 15031316
TI  - Low cholesterol levels are associated with short-term mortality in older patients
      with ischemic stroke.
AB  - BACKGROUND: The possible relationship between serum total cholesterol (TC) levels
      and outcome following ischemic stroke is still controversial. We evaluated the
      association between TC levels and 30-day mortality in a sample of older patients
      with acute ischemic stroke. METHODS: We enrolled 490 older patients with severe
      ischemic stroke consecutively admitted to University Hospital's Internal Medicine
      or Geriatrics Department. Stroke type was classified according to the Oxfordshire
      Community Stroke Project. The data recorded included clinical features, medical
      history, electrocardiogram, and blood analyses. Patients were divided into three
      groups by TC levels: group I (TC<4.1 mmol/L), group II (TC 4.1-5.2 mmol/L), and
      group III (TC>5.2 mmol/L). RESULTS: The overall mortality was 27.7%. Mortality
      was higher in patients with low TC levels (47.4%) compared with those with normal
      and high TC levels (23.0% and 24.1%, respectively). The odds ratio (OR) for short
      term death was 2.17 (95% confidence interval [CI] 1.22-3.85) in group I compared
      with group III, after adjustment for age and gender. This result did not change
      after adjustment for possible confounders (OR 2.87; 95% CI 1.23-6.68). A similar
      trend was observed after adjustment for the Oxfordshire classification, age, and
      gender (OR 1.67; 95% CI 0.83-3.33). CONCLUSIONS: Short-term mortality following
      ischemic stroke is higher in older participants with low TC levels, independent
      of a large number of factors. Low TC levels might be useful in identifying frail
      older participants at high risk of stroke short-term mortality.

PMID- 15031317
TI  - Comparative analysis of orthologous eukaryotic mRNAs: potential hidden functional
      signals.
AB  - Sequencing of multiple, nearly complete eukaryotic genomes creates opportunities
      for detecting previously unnoticed, subtle functional signals in non-coding
      regions. A genome-wide comparative analysis of orthologous sets of mammalian and
      yeast mRNAs revealed distinct patterns of evolutionary conservation at the
      boundaries of the untranslated regions (UTRs) and the coding region (CDS).
      Elevated sequence conservation was detected in approximately 30 nt regions around
      the start codon. There seems to be a complementary relationship between sequence
      conservation in the approximately 30 nt regions of the 5'-UTR immediately
      upstream of the start codon and that in the synonymous positions of the 5'
      terminal 30 nt of the CDS: in mammalian mRNAs, the 5'-UTR shows a greater
      conservation than the CDS, whereas the opposite trend holds for yeast mRNAs.
      Unexpectedly, a approximately 30 nt region downstream of the stop codon shows a
      substantially lower level of sequence conservation than the downstream portions
      of the 3'-UTRs. However, the sequence in this poorly conserved 30 nt portion of
      the 3'-UTR is non-random in that it has a higher GC content than the rest of the
      UTR. It is hypothesized that the elevated sequence conservation in the region
      immediately upstream of the start codon is related to the requirement for
      initiation factor binding during pre-initiation ribosomal scanning. In contrast,
      the poorly conserved region downstream of the stop codon could be involved in the
      post- termination scanning and dissociation of the ribosomes from the mRNA, which
      requires only the mRNA-ribosome interaction. Additionally, it was found that the
      choice of the stop codon in mammals, but not in yeasts, and the context in the
      immediate vicinity of the stop codons in both mammals and yeasts are subject to
      strong selection. Thus, genome-wide analysis of orthologous gene sets allows
      detection of previously unrecognized patterns of sequence conservation, which are
      likely to reflect hidden functional signals, such as ribosomal filters that could
      regulate translation by modulating the interaction between the mRNA and
      ribosomes.

PMID- 15031319
TI  - Inactivation of the glucocorticoid receptor in hepatocytes leads to fasting
      hypoglycemia and ameliorates hyperglycemia in streptozotocin-induced diabetes
      mellitus.
AB  - Hepatic glucose production by gluconeogenesis is the main source of glucose
      during fasting and contributes significantly to hyperglycemia in diabetes
      mellitus. Accordingly, glucose metabolism is tightly controlled by a variety of
      hormones including insulin, epinephrine, glucagon, and glucocorticoids (GCs)
      acting on various cell types. GC effects are mediated by the GC receptor (GR), a
      ligand-dependent transcription factor, which in the liver and kidney controls
      gluconeogenesis by induction of gluconeogenic enzymes. To specifically study the
      contribution of GC on liver carbohydrate metabolism, we generated mice with an
      inactivation of the GR gene exclusively in hepatocytes using the Cre/loxP
      technology. Half of the mutant mice die within the first 2 d after birth most
      likely due to hypoglycemia. Adult mice have normal blood sugar under basal
      conditions but show hypoglycemia after prolonged starvation due to reduced
      expression of genes involved in gluconeogenesis. We further demonstrate that
      absence of GR in hepatocytes limits the development of hyperglycemia in
      streptozotocin-induced diabetes mellitus probably due to impaired induction of
      gluconeogenesis. These findings show the essential role of GR function in liver
      glucose metabolism during fasting and in diabetic mice and indicate that liver
      specific GC antagonists could be beneficial in control of diabetic hyperglycemia.

PMID- 15031318
TI  - Improving the sensitivity and specificity of gene expression analysis in highly
      related organisms through the use of electronic masks.
AB  - DNA microarrays are powerful tools for comparing gene expression profiles from
      closely related organisms. However, a single microarray design is frequently used
      in these studies. Therefore, the levels of certain transcripts can be grossly
      underestimated due to sequence differences between the transcripts and the
      arrayed DNA probes. Here, we seek to improve the sensitivity and specificity of
      oligonucleotide microarray-based gene expression analysis by using genomic
      sequence information to predict the hybridization efficiency of orthologous
      transcripts to a given microarray. To test our approach, we examine hybridization
      patterns from three Escherichia coli strains on E.coli K-12 MG1655 gene
      expression microarrays. We create electronic mask files to discard data from
      probes predicted to have poor hybridization sensitivity and specificity to cDNA
      targets from each strain. We increased the accuracy of gene expression analysis
      and identified genes that cannot be accurately interrogated in each strain using
      these microarrays. Overall, these studies provide guidelines for designing
      effective electronic masks for gene expression analysis in organisms where
      substantial genome sequence information is available.

PMID- 15031320
TI  - Differential effect of small ubiquitin-like modifier (SUMO)-ylation of the
      androgen receptor in the control of cooperativity on selective versus canonical
      response elements.
AB  - The androgen receptor (AR) can be small ubiquitin-like modifier (SUMO)-ylated in
      its amino-terminal domain at lysines 385 and 511. This SUMO-ylation is responsive
      to several agonists, but is not induced by the pure antagonist hydroxyflutamide.
      We show that the main site of interaction of Ubc9, the SUMO-1 conjugating enzyme,
      resides in transcription activation unit 5. Overexpression of SUMO-1 represses
      the AR-mediated transcription, and this effect is abolished after mutating both
      SUMO-1 acceptor sites. On the other hand, the mutation of lysine 385 clearly
      affects the cooperativity of the receptor on multiple hormone response elements.
      Lysine 511 is not implicated in this function. Surprisingly, these effects on
      cooperativity clearly depend on the nature of the response elements. When
      selective androgen response elements, which are organized as direct repeats of 5'
      TGTTCT-3'-like sequences, were tested, the lysine 385 mutation did not increase
      the androgen response. Point mutations changing the direct-repeat elements into
      inverted-repeat elements restored the effects of the lysine 385 mutation on
      cooperativity. In conclusion, SUMO-ylation of the AR might have a differential
      function in the control of cooperativity, depending on the conformation of the AR
      dimer bound to DNA.

PMID- 15031321
TI  - Activin inhibits pituitary prolactin expression and cell growth through Smads,
      Pit-1 and menin.
AB  - Activin, a member of the TGFbeta superfamily, is a negative regulator of cell
      growth and prolactin (PRL) production in pituitary lactotrope cells. However, the
      mechanisms by which this growth factor exerts its growth-inhibitory and 
      repressive effect on PRL remain unclear. In this study, we show that activin
      negatively regulates PRL expression at the transcriptional level through the Smad
      pathway and the multiple endocrine neoplasia type 1 gene product, menin. Our
      results also demonstrate that the tumor suppressor menin is required for activin
      induced growth arrest of somatolactotrope cells. Moreover, we show that activin
      represses transcription and expression of Pit-1, a pituitary transcription factor
      that is essential for maintenance and development of lactotrope cells. We defined
      two Pit-1 DNA-binding sites in the proximal region of the PRL promoter as
      critical for the activin-mediated inhibition. Together, our results highlight the
      Smad pathway and the tumor suppressor menin as key regulators of activin effects
      on PRL and Pit-1 expression, as well as on cell growth inhibition, and emphasize
      the critical role of activin in the regulation of pituitary function.

PMID- 15031322
TI  - A splice variant of the human luteinizing hormone (LH) receptor modulates the
      expression of wild-type human LH receptor.
AB  - We previously reported a splice variant form of human LH receptor [hLHR(exon 9)]
      that lacks exon 9, coding the N-terminal extracellular region close to the first
      transmembrane domain. Several recent studies suggest that G protein-coupled
      receptors are able to form dimerization or oligomerization of the receptor,
      suggesting an intermolecular interaction between hLHR(exon 9) and the wild-type
      LH receptor (hLHR). The aim of this study, using coimmunoprecipitation, is to
      examine whether hLHR forms an association with hLHR(exon 9). An interaction
      between hLHR(exon 9) with the immature band (68 kDa) of hLHR and not with the
      mature band (85 kDa) was seen. When hLHR and hLHR(exon 9) were coexpressed, the
      density of hLHR expression was significantly reduced, compared with hLHR
      expressed alone. The human chorionic gonadotropin-stimulated cAMP accumulation in
      the cells expressing hLHR(exon 9) was also impaired, compared with the cells
      expressing hLHR. In this study, we demonstrated that hLHR is capable of forming
      receptor complexes. Our findings may expand the possibility of a splice variant
      of hLHR specifically modulating the functional property of the wild-type hLHR.

PMID- 15031323
TI  - Genomic targets of nuclear estrogen receptors.
AB  - Estrogen influences the physiology of many target tissues in both women and men.
      The long-term effects of estrogen are mediated predominantly by nuclear estrogen
      receptors (ERs) functioning as DNA-binding transcription factors. Tissue-specific
      responses to estrogen therefore result from regulation of different sets of
      genes. However, it remains perplexing as to what regulatory sequence contexts
      specify distinct genomic responses. First, this review classifies estrogen
      response sequences in mammalian target genes. Of note, around one third of known
      human target genes associate only indirectly with ER, through intermediary
      transcription factor(s). Then, computational approaches are presented both for
      refining direct ER-binding sites and for formulating hypotheses regarding the
      overall genomic expression pattern. Surprisingly, limited evolutionary
      conservation of specific estrogen-responsive sites is observed between human and
      mouse. Finally, consideration of the cellular functions of regulated human genes
      suggests links between particular biological roles and specific types of estrogen
      response elements, although with the important caveat that only a restricted set
      of target genes is available. These analyses support the view that specific,
      hormone-driven gene expression programs can result from the interplay of
      environmental and cellular cues with the distinct types of estrogen-response
      sequences.

PMID- 15031324
TI  - Are there endogenous molecules that protect kidneys from injury? The case for
      bone morphogenic protein-7 (BMP-7).

PMID- 15031325
TI  - Is there a need for novel cardiovascular risk factors?

PMID- 15031326
TI  - Measuring blood pressure: pitfalls and recommendations.

PMID- 15031327
TI  - Renin-angiotensin system and atherosclerosis.

PMID- 15031328
TI  - Trends in the prevalence of primary aldosteronism, aldosterone-producing
      adenomas, and surgically correctable aldosterone-dependent hypertension.

PMID- 15031329
TI  - Endothelial dysfunction in diabetic nephropathy: state of the art and potential
      significance for non-diabetic renal disease.

PMID- 15031330
TI  - Optimal peritoneal dialysis: choice of volume and solution.

PMID- 15031331
TI  - Optimal composition of the dialysate, with emphasis on its influence on blood
      pressure.
AB  - Introduction. From the beginning of the dialysis era, the most appropriate
      composition of the dialysate has been one of the central topics in the delivery
      of dialysis treatment. METHODS: A discussion is employed to achieve a consensus
      on key points relating to the composition of the dialysate, focusing on the
      relationships with blood pressure behaviour. RESULTS: Sodium balance is the
      cornerstone of intra-dialysis cardiovascular stability and good inter-dialysis
      blood pressure control. Hypernatric dialysis carries the risk of positive sodium
      balance, with the consequent possibility of the worsening sense of thirst and
      hypertension. Conversely, hyponatric dialysis may lead to negative sodium
      balance, with the possibility of intra-dialysis cardiovascular instability and
      'disequilibrium' symptoms including fatigue, muscle cramps and headache. The goal
      is to remove with dialysis the exact amount of sodium that has accumulated in the
      inter-dialysis interval. The conductivity kinetic model is applicable on-line at
      each dialysis session and has been proved to be able to improve intra-dialytic
      cardiovascular stability in hypotension-prone patients. Therefore, it should be
      regarded as a promising tool to be implemented in everyday clinical practice.
      Serum potassium concentration and variations during dialysis treatment certainly
      play a role in the genesis of cardiac arrhythmia. Potassium profiling, with a
      constant gradient between plasma and dialysate, should be implemented in clinical
      practice to minimize the arrhythmogenic potential of dialysis. Calcium plays a
      role both in myocardial contractility and in peripheral vascular resistance.
      Therefore, an increase in dialysate calcium concentration may be useful in
      cardiac compromised hypotension-prone patients. Acid-buffering by means of base
      supplementation is one of the major roles of dialysis. Bicarbonate concentration
      in the dialysate should be personalized in order to reach a midweek pre-dialysis
      serum bicarbonate concentration of 22 mmol/l. The role of convective dialysis
      techniques in cardiovascular stability is still under debate. It has been
      demonstrated that dialysate temperature and sodium balance play a role and this
      should be taken into account. Whether removal of vasoactive, middle-sized
      compounds by convection plays an independent role in improving cardiovascular
      stability is still uncertain. CONCLUSIONS: The prescription of dialysis fluid is
      moving from a pre-fixed, standard dialysate solution to individualization of
      electrolyte and buffer composition, not only during the dialysis session, but
      also within the same session (profiling) in order to provide patients with an
      optimal blood purification coupled with a high degree of tolerability.

PMID- 15031332
TI  - Counter-regulatory effects of procalcitonin and indoxyl sulphate on net albumin
      secretion by cultured rat hepatocytes.
AB  - BACKGROUND: Although hypoalbuminaemia is a significant predictor of mortality in
      haemodialysis (HD) patients, the pathophysiological mechanisms involved remain to
      be determined. Albumin is a negative acute-phase reactant and many
      proinflammatory substances are elevated in HD patients. We investigated factors
      that may affect liver albumin synthesis. METHODS: Hepatocytes were isolated from
      rat livers and were cultured with interleukin (IL)-4, IL-6, IL-12, tumor necrosis
      factor (TNF)-alpha, procalcitonin (PCT), a sensitive marker of infection, and
      indoxyl sulphate (IS), a uraemic toxin. Albumin levels in the supernatant were
      measured by enzyme-linked immunosorbent assay. Albumin mRNA expression was
      determined by reverse transcriptase polymerase chain reaction. RESULTS: IL-6 and
      TNF-alpha significantly decreased albumin levels in a dose-dependent manner
      (P<0.01 and P<0.05, respectively). In contrast, IL-4 and IL-12 did not modulate
      albumin production. PCT and IS significantly and dose-dependently increased
      albumin levels (both P<0.01). PCT increased albumin mRNA expression in the
      hepatocytes (P = 0.05) and dose-dependently abrogated IL-6-induced suppression of
      albumin synthesis (P<0.01). IS also blocked the IL-6-induced decrease in net
      albumin secretion (P<0.01). CONCLUSION: Our findings indicate that PCT and IS
      protect against suppression of hepatic albumin synthesis caused by
      proinflammatory cytokines, suggesting their potential role in preventing
      hypoalbuminaemia in HD patients.

PMID- 15031333
TI  - Age-dependent thickening of glomerular basement membrane has no major effect on
      glomerular hydraulic conductivity.
AB  - BACKGROUND: The effect of the increasing thickness of the glomerular basement
      membrane (GBM), which is seen in ageing rats, on the effective hydraulic
      conductivity (k) of the glomerular capillary wall was studied in Wistar rats aged
      2 and 18 months. METHODS: With the use of micropuncture techniques,
      ultrafiltration characteristics of cortical glomeruli were determined in isolated
      cell-free perfused kidneys. Because the filtration fraction in this preparation
      is low (3%) as a consequence of high perfusion rates at glomerular filtration
      rates comparable with in vivo conditions, uniform ultrafiltration conditions are
      provided over the whole filtering surface. After fixation at a defined perfusion
      pressure, the surface of glomerular capillaries (S) was obtained morphometrically
      on light microscopic sections of the glomeruli studied previously. RESULTS: The
      glomerular ultrafiltration coefficient (K(f)) was 0.025 nl/s.mmHg in young rats
      and 0.038 nl/s.mmHg in old rats (P<0.0005) and S was 0.140 mm(2) in young and
      0.244 mm(2) in old rats (P<0.0005). However, k was not significantly different
      (18.0 nl/s.mmHg.cm(2) in young and 15.8 nl/s.mmHg.cm(2) in old rats) despite a
      2.4-fold increase of GBM thickness as estimated from electron microscopic
      sections. CONCLUSIONS: These findings indicate that the age-dependent increase of
      GBM thickness in rat kidneys did not substantially increase hydraulic resistance
      of the glomerular capillary wall.

PMID- 15031334
TI  - Direct transfer of hepatocyte growth factor gene into kidney suppresses
      cyclosporin A nephrotoxicity in rats.
AB  - BACKGROUND: The clinical utility of cyclosporin A (CsA) has been limited by its
      nephrotoxicity, which is characterized by tubular atrophy, interstitial fibrosis
      and progressive renal impairment. Hepatocyte growth factor (HGF), which plays
      diverse roles in the regeneration of the kidney following acute renal failure,
      has been reported to protect against and salvage renal injury by acting as a
      renotropic and anti-fibrotic factor. Here, we investigated protective effects of
      HGF gene therapy on CsA-induced nephrotoxicity by using an electroporation
      mediated gene transfer method. METHODS: CsA was orally administered as a daily
      dose of 30 mg/kg in male Sprague-Dawley rats receiving a low sodium diet (0.03%
      sodium). Plasmid vector encoding HGF (200 micro g) was transferred into the
      kidney by electroporation. RESULTS: HGF gene transfer resulted in significant
      increases in plasma HGF levels. Morphological assessment revealed that HGF gene
      transfer reduced CsA-induced initial tubular injury and inhibited interstitial
      infiltration of ED-1-positive macrophages. In addition, northern blot analysis
      demonstrated that cortical mRNA levels of TGF-beta and type I collagen were
      suppressed in the HGF group. Finally, HGF gene transfer significantly reduced
      striped interstitial phenotypic alterations and fibrosis in CsA-treated rats, as
      assessed by alpha-smooth muscle actin expression and Masson's trichrome staining.
      CONCLUSIONS: These results suggest that HGF may prevent CsA-induced
      tubulointerstitial fibrosis, indicating that HGF gene transfer may provide a
      potential strategy for preventing renal fibrosis.

PMID- 15031336
TI  - Renal hyaluronan accumulation and hyaluronan synthase expression after ischaemia
      reperfusion injury in the rat.
AB  - BACKGROUND: Hyaluronan (HA) is a connective tissue component with unique water
      binding and pro-inflammatory properties. It has been suggested that HA is
      involved in normal renal water handling but also in several pathological
      conditions such as organ rejection and ischaemia-reperfusion (IR) injury.
      METHODS: In anaesthetized normal rats we investigated if renal cortical HA
      accumulation and the intrarenal distribution and expression of HA synthases (Has
      1, 2 and 3) correlate with renal dysfunction after renal IR injury. After 20, 30
      or 45 min of unilateral renal ischaemia and 72 h of reperfusion, renal function
      and cortical HA content were measured. Has 1, 2 and 3 mRNA were determined in
      control and IR kidneys subjected to 45 min ischaemia and 72 h reperfusion.
      RESULTS: IR kidneys had reduced urine concentrating ability, potassium excretion,
      glomerular filtration rate (GFR) and renal blood flow. On average, IR kidneys had
      more than 10 times higher amounts of cortical HA than the contralateral control
      kidney and their water content was elevated while medullary HA was largely
      unaffected. Has 2 expression in the cortex was heavily up-regulated in IR kidneys
      while Has 3 remained at control levels. Has 1 could never be detected. There was
      a direct correlation between the amount of cortical HA and the time period of
      ischaemia and also between the cortical amount of HA and depression of functional
      parameters. CONCLUSIONS: IR injury depresses parameters of renal function, which
      coincides with an elevated cortical HA content and Has 2 expression. The enhanced
      Has 2 expression indicates that the cortical HA accumulation is primarily
      dependent on increased HA synthesis and not impaired degradation/elimination. The
      water binding and pro-inflammatory properties of HA may contribute to renal
      dysfunction after IR.

PMID- 15031335
TI  - Novel expression of sodium/myo-inositol co-transporter in podocytes in puromycin
      aminonucleoside nephrosis.
AB  - BACKGROUND: How podocytes respond to injury is poorly understood, although
      podocyte injury in the glomerulus has been proposed as the crucial mechanism in
      the pathogenesis of proteinuria and focal segmental glomerulosclerosis. An
      increase in sodium/myo-inositol co-transporter (SMIT) transcripts, an
      osmoprotective gene, has been demonstrated in a variety of brain injury models.
      In the present study, we investigated SMIT expression in podocytes in
      experimental nephrosis. METHODS: Two types of nephrosis were induced in rats:
      puromycin aminonucleoside (PAN) nephrosis and monoclonal antibody (mAb) 5-1-6
      nephropathy. Podocyte injury was morphologically distinct in the former type of
      nephrosis and limited to a minimum in the latter. SMIT expression in isolated
      glomeruli was estimated by ribonuclease protection assay. Localization of SMIT
      expressing cells in glomeruli was examined by in situ hybridization. RESULTS:
      SMIT transcripts in glomeruli increased conspicuously in the nephrotic stage of
      PAN nephrosis, whereas the transcripts in cortices and medullae did not show
      significant changes. In situ hybridization revealed that podocytes were
      predominant cells expressing SMIT in the glomerulus. Significant increase of SMIT
      mRNA in the glomeruli was detected before the onset of massive proteinuria. In
      contrast, up-regulation of SMIT expression was not observed in mAb 5-1-6
      nephropathy, whose urinary protein levels were comparable with those in the
      nephrotic stage of PAN nephrosis. CONCLUSIONS: These findings suggest that SMIT
      expression in podocytes is not provoked by an effect of massive proteinuria but
      by extensive cellular injury.

PMID- 15031337
TI  - In vitro and in vivo models for peritonitis demonstrate unchanged neutrophil
      migration after exposure to dialysis fluids.
AB  - BACKGROUND: Recurrent infections in peritoneal dialysis (PD) patients may alter
      the abdominal wall resulting in an impairment of its dialysis capacity. In this
      study we investigated both in vitro and in vivo the effects of mesothelial
      exposure to dialysis fluids on the migration of neutrophils and their capacity to
      clear a bacterial infection. METHODS: First, we evaluated neutrophil migration in
      an in vitro transwell model for the peritoneal membrane with monolayers of
      primary human mesothelial cells (MC) on the lower side and primary human
      endothelial cells (EC) on top of the same transwell membrane, upon exposure of MC
      to PD fluid (PDF)-derived components. In addition to this in vitro model, we
      combined chronic peritoneal exposure to PDF with a peritoneal infection model in
      the rat. We investigated the kinetics of the chemokine response, neutrophil
      recruitment and bacterial clearance. RESULTS: Known chemoattractants, such as
      fMLP and IL-8, strongly increased neutrophil migration across both cell layers in
      the in vitro model of the peritoneal membrane. Pre-incubation of the MC layer for
      48 h with 55 mM glucose, a combination of two glucose degradation products,
      methylglyoxal and 3-deoxyglucosone, or conventional dialysis fluid (1:4
      dilution), however, did not change the IL-8-induced migration of neutrophils. In
      concert with this finding we demonstrated an unchanged MC expression of ICAM-1
      and VCAM-1 after these pre-treatments. Unexpectedly, chronic i.p. exposure to
      conventional PDF or a recently developed lactate/bicarbonate-buffered PDF in a
      rat peritoneal exposure model strongly hampered the chemokine response upon
      bacterial challenge. Nevertheless, neutrophil recruitment and bacterial clearance
      were effective and did not differ from rats not pre-exposed to PDF. CONCLUSIONS:
      We conclude that exposure of MC to PDF does not hamper the recruitment of
      functional neutrophils upon challenge.

PMID- 15031338
TI  - Analgesic nephropathy in Hungary: the HANS study.
AB  - BACKGROUND: The diagnosis of analgesic nephropathy has improved significantly
      with modern imaging techniques. We reviewed a large portion of the Hungarian
      dialysis population to obtain additional insight into the problem. METHODS:
      Twenty-two participating dialysis units enrolled 1400 patients on renal
      replacement therapy between 1 January 1995 and 1 January 1998. Patients with no
      known aetiology (n = 284) were interviewed and studied with renal imaging. We
      assessed the presence of decreased renal mass combined with either bumpy
      contours, papillary calcification, or both. The subjects studied were
      interrogated extensively. RESULTS: Our survey suggested analgesic nephropathy in
      47 of 1400 patients (3.3%), 3-fold higher than the EDTA database estimate for
      Hungary. The analgesics most commonly abused were phenacetin-containing mixtures.
      The driving symptoms were mainly headache and joint pain. Cardiovascular
      complications were more common than in the rest of the dialysis population,
      independent of smoking and lipid values (P<0.01). CONCLUSIONS: Phenacetin should
      be banned. Our study results support the need for longitudinal cohort and case
      control studies in Hungary.

PMID- 15031339
TI  - Expression of alpha-actinin-4 in acquired human nephrotic syndrome: a
      quantitative immunoelectron microscopy study.
AB  - BACKGROUND: The molecular basis for the alteration of glomerular podocyte
      phenotype in nephrotic syndrome probably involves adaptive changes of the actin
      cytoskeleton. alpha-Actinin-4 is an actin cross-linking protein that also
      interacts with intra- and intercellular adhesion molecules and elements of the
      transmembrane signal transduction pathway and is implicated in nephrotic syndrome
      by animal models and human genetic studies. METHODS: We have performed the first
      quantitative immunoelectron microscopy study of alpha-actinin-4 expression in
      humans, analysing 12 cases of minimal change nephrosis (MCNS) and 16 cases of
      idiopathic membranous nephropathy (MGN), and comparing this with expression in
      normal tissue from seven nephrectomies (Nx). alpha-Actinin-4 was visualized by
      immunogold labelling of plastic-embedded whole glomerular cross-sections, and
      analysed using LUCIA software. RESULTS: Despite podocyte effacement, alpha
      actinin-4 expression (group mean+/-1 SD) in MCNS was similar to that seen in
      normal Nx podocytes. In contrast, alpha-actinin-4 expression in MGN was
      significantly higher than in MCNS or Nx (P<0.001). Furthermore, in MGN cases
      showing a segmental deposition, expression of alpha-actinin-4 was significantly
      higher only in those capillary loop segments containing deposits, whereas in
      those segments without deposits expression was unchanged compared with that seen
      in Nx (P<0.001). alpha-Actinin-4 expression was higher in MGN cases where
      subepithelial deposits abutted podocyte cytoplasm, and lower in disease stages
      where deposits were contained within the glomerular basement membrane or were
      being reabsorbed. CONCLUSIONS: Elevated alpha-actinin-4 expression is observed
      only in MGN, and only in areas of subepithelial deposits. Further investigation
      into the cause of this may reveal insights into the pathogenesis of acquired
      nephrosis.

PMID- 15031340
TI  - Effects of co-administration of urokinase and benazepril on severe IgA
      nephropathy.
AB  - BACKGROUND: The availability of treatment for IgA nephropathy (IgAN) is limited.
      Method. A prospective randomized controlled clinical trial was performed to
      evaluate the effects of therapy with urokinase (UK) and benazepril (BZ, an
      angiotensin-converting enzyme inhibitor) or BZ alone on severe IgAN. We divided
      71 cases of IgAN, Lee's grade >/=III and with fibrinogen deposits, into two
      groups to be treated for 12 months with either UK + BZ or BZ alone. RESULTS:
      There was no significant difference between the two groups in baseline clinical
      and histopathological data. After 12 months of treatment, 25 of 35 patients
      (71.4%) in the UK + BZ group and 16 of 36 (44.4%) in the BZ-alone group had a
      >/=50% decrease in 24-h urinary protein excretion compared with the baseline
      (chi(2) test, P<0.05). Proteinuria significantly decreased at 6 and 12 months of
      treatment in both groups compared with baseline (P<0.01 in the UK + BZ group,
      P<0.05 in the BZ group), and the therapeutic efficiency of UK + BZ was better
      than that of BZ alone (P<0.05 at 6 and 12 months). The endogenous creatinine
      clearance rate (Ccr) was stable in the UK + BZ group, while Ccr declined
      significantly at 6 and 12 months in the BZ-alone group compared with baseline
      (P<0.05, respectively). The Ccrs of the two groups at 12 months of treatment were
      statistically different (P<0.05). CONCLUSIONS: Combined therapy with UK and BZ
      was more effective than with BZ alone in reducing proteinuria and protecting
      renal function in patients with severe IgAN.

PMID- 15031341
TI  - Efficacy of methylprednisolone and urokinase pulse therapy combined with or
      without cyclophosphamide in severe Henoch-Schoenlein nephritis: a clinical and
      histopathological study.
AB  - BACKGROUND: There have been few controlled studies of combined therapy with
      multiple drugs, including immunosuppressives, for severe Henoch-Schoenlein
      nephritis (HSPN). We evaluated the efficacy of methylprednisolone and urokinase
      pulse therapy combined with cyclophosphamide for patients with HSPN of at least
      grade IVb. METHODS: We studied 37 patients who had been diagnosed with HSPN of at
      least grade IVb. Of them, 20 (Group A) were treated with methylprednisolone and
      urokinase pulse therapy, and 17 (Group B) were treated with methylprednisolone
      and urokinase pulse therapy combined with cyclophophamide. We analysed the
      clinical features, laboratory and pathological findings of the two groups
      retrospectively. RESULTS: After 6 months of treatment, mean urinary protein
      excretion in Group B had significantly decreased compared with Group A, and the
      activity index of both groups at the second biopsy was lower than that at the
      first. Furthermore, at the second biopsy, the chronicity index of Group B was
      lower than that of Group A. Four patients of Group A but none of Group B had
      persistent nephropathy (P<0.05). CONCLUSIONS: Our study suggests that
      methylprednisolone and urokinase pulse therapy combined with cyclophosphamide is
      useful for patients with severe HSPN.

PMID- 15031342
TI  - Plasma and urinary free 3-nitrotyrosine following cardiac angiography procedures
      with non-ionic radiocontrast media.
AB  - BACKGROUND: Radiocontrast media (RCM) administration is a common cause of
      hospital-acquired acute renal failure, especially in high-risk patients, but
      mechanisms of nephrotoxicity have not been fully elucidated. Reactive oxidant
      species recently have been shown to play a role in experimental RCM nephropathy,
      while there is clinical evidence that acetylcysteine, an antioxidant drug, has a
      protective effect against RCM nephropathy in humans. However, no study has been
      published showing that RCM administration elicits oxidative stress in humans.
      METHODS: In an unselected series of patients undergoing elective cardiac
      catheterization for coronary artery angiography and/or angioplasty, we monitored
      the time course of plasma and urinary levels of free 3-nitrotyrosine (3-NT), a
      stable marker of peroxynitrite generation resulting from the in vivo reaction of
      superoxide and nitric oxide. Urinary 3-NT levels were measured as the ratio of
      urinary 3-NT to urinary creatinine. Measurements were taken at baseline,
      immediately after the procedure and at 24, 48 and 72 h. RESULTS: Twenty-six
      patients were studied (median age 67.5 years, range 42-86; baseline serum
      creatinine 1.0 mg/dl, 0.6-1.5; RCM dose 215 ml, 100-580). Plasma 3-NT levels
      slightly increased over the 72 h following the procedure (P<0.001), while urinary
      3-NT levels peaked at the end of the procedure (P<0.001). Urinary 3-NT levels
      reached at the end of the procedure were proportional to the RCM dose
      administered (P = 0.017). CONCLUSIONS: The present study provides indirect
      evidence that RCM administration in humans is associated with an increased
      production of 3-NT. Further studies are needed to ascertain whether oxygen- and
      nitrogen-derived radical species play a major role in the pathogenesis of RCM
      associated nephrotoxicity in the clinical setting.

PMID- 15031343
TI  - Effect of 18 months of treatment with alfacalcidol on bone in patients with mild
      to moderate chronic renal failure.
AB  - BACKGROUND: The bone abnormalities that lead to symptomatic renal osteodystrophy
      commence early in the course of renal failure, but the optimal time to start
      treatment needs clarifying. The present study examined the effect of alfacalcidol
      treatment on bone metabolism and bone density in patients with pre-dialysis
      chronic renal failure (CRF) in a prospective, randomized, placebo-controlled
      double blind design. METHODS: Repetitive measures of bone mineral density (BMD)
      estimated by dual energy X-ray absorptiometry and plasma levels of biochemical
      markers of bone turnover [osteocalcin, bone alkaline phosphatase, propeptide of
      type-I collagen (PICP) and telopeptide of type-I collagen] and parameters of
      calcium homeostasis were performed in 36 patients with a glomerular filtration
      rate (GFR) of 6-60 ml/min. RESULTS: A significant difference in BMD between the
      treatment groups in favour of the alfacalcidol-treated patients was found in the
      spine (4.2%), the femoral neck (4.9%) and the total femur (3.0%) (P<0.05). In the
      alfacalcidol group, plasma levels of parathyroid hormone 1-84 decreased from
      baseline values by 47+/-9%, and p-osteocalcin and bone alkaline phosphatase
      decreased by 24+/-9% and 48+/-8%, respectively (P<0.05). In the placebo group,
      PICP increased by 32+/-26% (P<0.05). No significant changes were found in plasma
      levels of vitamin D metabolites. GFR decreased significantly from baseline values
      in the alfacalcidol group (by 28+/-4 ml/min) and in the placebo group (by 26+/-5
      ml/min) (P<0.05), with no difference being detected between the groups.
      CONCLUSIONS: Long-term treatment with alfacalcidol is safe and might be
      beneficial for the preservation of bone mass in the pre-dialysis stages of CRF,
      most likely through a reduction in bone turnover as estimated from the changes of
      the biochemical bone markers.

PMID- 15031344
TI  - Sustained low-efficiency daily diafiltration (SLEDD-f) for critically ill
      patients requiring renal replacement therapy: towards an adequate therapy.
AB  - BACKGROUND: Sustained low-efficiency daily dialysis (SLEDD) is an increasingly
      popular renal replacement therapy for intensive care unit (ICU) patients. SLEDD
      has been previously reported to provide good solute control and haemodynamic
      stability. However, continuous renal replacement therapy (CRRT) is considered
      superior by many ICU practitioners, due first to the large amounts of convective
      clearance achieved and second to the ability to deliver treatment independently
      of nephrology services. We report on a program of sustained low-efficiency daily
      diafiltration (SLEDD-f) delivered autonomously by ICU nursing personnel, and
      benchmark solute clearance data with recently published reports that have
      provided dose-outcome relationships for renal replacement therapy in this
      population. METHODS: SLEDD-f treatments were delivered using countercurrent
      dialysate flow at 200 ml/min and on-line haemofiltration at 100 ml/min for 8 h on
      a daily or at least alternate day basis. All aspects of SLEDD-f were managed by
      ICU nursing personnel. Clinical parameters, patient outcomes and solute levels
      were monitored. Kt/V, corrected equivalent renal urea clearance (EKRc) and
      theoretical Kt/V(B12) were calculated. RESULTS: Fifty-six SLEDD-f treatments in
      24 critically ill acute renal failure patients were studied. There were no
      episodes of intradialytic hypotension or other complications. Observed hospital
      mortality was 46%, not significantly different from the expected mortality as
      determined from the APACHE II illness severity scoring system. Electrolyte
      control was excellent. Kt/V per completed treatment was 1.43+/-0.28 (0.96-2.0).
      Kt/V(B12) per completed treatment was 1.02+/-0.21 (0.6-1.38). EKRc for patients
      was 35.7+/-6.4 ml/min (25.0-48.2). CONCLUSION: SLEDD-f provides stable renal
      replacement therapy and good clinical outcomes. Logistic elements of SLEDD-f
      delivery by ICU nursing personnel are satisfactory. Small solute clearance is
      adequate by available standards for CRRT and intermittent haemodialysis, and
      larger solute clearance considerable. SLEDD-f is a viable alternative to CRRT in
      this setting.

PMID- 15031345
TI  - Carotid atherosclerosis is a predictor of coronary calcification in chronic
      haemodialysis patients.
AB  - BACKGROUND: Coronary artery calcification scores (CACS) calculated by electron
      beam computed tomography (EBCT) have been correlated with atherosclerotic burden
      in the non-uraemic population. However, the validity of this test in chronic
      haemodialysis patients (HD) is currently uncertain. In the present cross
      sectional study, associations between carotid atherosclerosis and coronary
      calcification in HD patients are investigated. METHODS: We studied 79 chronic HD
      patients (39 male, 40 female; mean age, 45+/-12 years). The mean time on HD was
      68+/-54 months (range, 6-187 months). In these patients, we measured serum
      calcium, phosphorus, total cholesterol, cholesterol subgroups and iPTH levels.
      EBCT, echocardiography, and high-resolution B-mode carotid Doppler
      ultrasonography were also performed. RESULTS: Plaque-positive HD patients had
      significantly higher CACS than plaque-negative patients (851+/-199 vs 428+/-185,
      mean+/-SE, P = 0.006). Coronary calcification scores were correlated with serum
      phosphorus (r = 0.37; P = 0.001). Only 8 of the 24 HD patients without coronary
      calcification had carotid plaques (33%), whereas 34 of the 53 patients with
      coronary calcification had carotid plaques (64%) (P = 0.015). Carotid plaque
      scores were correlated with CACS (r = 0.40; P = 0.001). A stepwise linear
      regression (model r = 0.72; P<0.001) revealed that CACS (log-transformed data of
      CACS) was associated with age (P<0.001), time on dialysis (P = 0.004), serum
      phosphorus level (P = 0.016) and carotid plaque scores (P = 0.037). CONCLUSIONS:
      Atherosclerosis is independently associated with coronary artery calcification
      and with hyperphosphataemia in chronic HD patients. CACS appeared to be
      predictive of both coronary atherosclerosis and carotid atherosclerosis.

PMID- 15031346
TI  - Intact PTH assay overestimates true 1-84 PTH levels after maxacalcitol therapy in
      dialysis patients with secondary hyperparathyroidism.
AB  - BACKGROUND: Although the so-called intact parathyroid hormone (iPTH) assay
      detects not only true 1-84 PTH (1-84PTH) but also large C-terminal PTH fragments,
      it remains inconclusive whether the 1-84PTH assay is more useful in clinical
      practice. Previous studies have shown that the results of these two PTH assays in
      dialysis patients are closely correlated. METHODS: Chronic dialysis patients
      whose plasma iPTH levels were >400 pg/ml were selected for inclusion in the
      present study. Following a 4 week wash-out time during which all vitamin D
      administration was halted, maxacalcitol was intravenously injected at the end of
      dialysis sessions three times per week for 24 weeks, at an initial dosage of 10
      micro g. RESULTS: Ninety-seven patients with secondary hyperparathyroidism were
      included in our analysis. Their serum calcium levels were elevated from the start
      levels while phosphate levels remained unchanged. The plasma 1-84PTH levels
      constantly declined throughout the 24 weeks. Although the patients' plasma 1
      84PTH and iPTH levels were closely correlated with each other both at the
      beginning of the study and after 24 weeks of maxacalcitol therapy, the ratio of 1
      84PTH/iPTH consistently decreased throughout the study period (P<0.01). The
      changes in the ratio were significantly correlated with changes in serum calcium
      levels. CONCLUSIONS: Twenty-four weeks of intravenous maxacalcitol injection
      therapy significantly reduced the 1-84PTH/iPTH ratio. Estimated 1-84PTH levels
      from iPTH levels using a conversion formula obtained before the treatment were
      21.0+/-20.4% higher than measured 1-84PTH levels after the therapy. Thus, iPTH
      measurement has a potential risk to overestimate 1-84PTH levels when evaluating
      the efficacy of maxacalcitol therapy in dialysis patients with secondary
      hyperparathyroidism.

PMID- 15031347
TI  - Darbepoetin alfa administered once monthly maintains haemoglobin levels in stable
      dialysis patients.
AB  - BACKGROUND: Darbepoetin alfa, a glycoprotein that stimulates erythropoiesis by
      the same mechanism as endogenous erythropoietin, has a 3-fold longer terminal
      half-life than recombinant human erythropoietin, allowing for an extended dosing
      interval. Darbepoetin alfa is currently recommended for once-weekly and once
      every 2 weeks administration in patients with chronic renal failure (CRF). The
      objective of this study was to explore once-monthly administration in this
      patient population. METHODS: Clinically stable dialysis patients (mean
      haemoglobin concentration, 10.0-13.0 g/dl) receiving stable darbepoetin alfa
      therapy administered once every 2 weeks in a long-term treatment study were
      converted to darbepoetin alfa once every 3 weeks for 20 weeks and then, if
      haemoglobin concentrations were successfully maintained between 10.0 and 13.0
      g/dl, were converted to darbepoetin alfa once every 4 weeks for 20 weeks. The
      darbepoetin alfa dose was titrated to maintain haemoglobin within a target range
      (-1.0 to +1.5 g/dl of baseline haemoglobin, and between 10.0 and 13.0 g/dl).
      Success with the extended dosing interval was defined as maintenance of mean
      haemoglobin >/=10.0 g/dl during a 4-week evaluation at the end of the dosing
      period. RESULTS: Of the 54 patients who entered the study, 38 patients were
      converted to darbepoetin alfa administered once every 4 weeks. Of these, 36
      patients were considered evaluable and 30 (83%) of those evaluable patients
      successfully maintained the target haemoglobin. For successful patients the mean
      (SD) haemoglobin during evaluation was 11.16 (0.60) g/dl, and the mean change in
      haemoglobin from baseline to evaluation was -0.26 g/dl (95% CI: -0.51, -0.01).
      The median change from baseline in average weekly darbepoetin alfa dose was 1.61
      microg (95% CI: 0.00, 4.75). Adverse events were consistent with those expected
      for this patient population. CONCLUSIONS: Darbepoetin alfa, administered once
      monthly, maintained haemoglobin effectively and safely in most dialysis patients
      stabilized previously on once every 2 weeks dosing. Once-monthly dosing may
      optimize anaemia management for patients with CRF and for health care providers.

PMID- 15031348
TI  - The changing epidemiology of hepatitis C virus (HCV) infection in haemodialysis:
      European multicentre study.
AB  - BACKGROUND: The high prevalence of anti-hepatitis C virus (HCV) antibodies in HD
      patients has been known since the early 1990s but its evolution over the last
      decade is poorly documented. METHODS: All chronic HD patients from 15 Belgian
      units were tested at (re)start of HD and every 18 months for anti-HCV antibodies
      (ELISA 2 in May 1991 and November 1992, then ELISA 3 until May 2000). All chronic
      HD patients from HD units from eight other European countries, whose prevalence
      of anti-HCV (+) patients had been studied in 1991-1994 (and published except in
      one country), were tested for anti-HCV antibodies in 1999. RESULTS: Anti-HCV (+)
      prevalence decreased (P<0.001) from 13.5 (1991) to 6.8% (2000) in the Belgian
      cohort (n = 1710). Prevalence also decreased (P<0.05) in the participating units
      from France (42-30%), Sweden (16-9%) and Italy (28-16%), tended to decrease in
      the participating units from UK (7-3%, P = 0.058) and Hungary (26-15%, P = 0.057)
      but did not change (NS) in the participating units from Germany (7 to 6%), Spain
      (5 to 12%) and Poland (42 to 44%). In the Belgian cohort, the prevalence of anti
      HCV(+) at (re)start of HD did not change significantly over 1991-2000.
      CONCLUSION: The prevalence of anti-HCV(+) in HD has decreased markedly over the
      last decade in the participating units from most European countries. This
      decrease should reduce further the risk of nosocomial and occupational HCV
      infection in HD and ultimately contribute to improved long-term prognosis of HD
      patients and kidney graft recipients.

PMID- 15031349
TI  - Nepsilon-(carboxymethyl)lysine, Nepsilon-(carboxyethyl)lysine and vascular cell
      adhesion molecule-1 (VCAM-1) in relation to peritoneal glucose prescription and
      residual renal function; a study in peritoneal dialysis patients.
AB  - BACKGROUND: Advanced glycation end products (AGEs) may contribute to peritoneal
      and cardiovascular damage in peritoneal dialysis (PD) patients, possibly in part
      by over-expression of vascular cell adhesion molecule-1 (VCAM-1). It has been
      suggested that peritoneal glucose load, oxidative stress, as well as the uraemic
      state itself may lead to an increased formation of AGEs. Aims of the present
      study were first to investigate the relation between residual glomerular
      filtration rate (rGFR), malondialdehyde (MDA) as a marker of lipid peroxidation,
      and peritoneal glucose prescription and absorption with serum levels of VCAM-1
      and with the well characterized AGEs N(epsilon)-(carboxymethyl)lysine (CML) and
      N(epsilon)-(carboxyethyl)lysine (CEL), as well as with CML and CEL in peritoneal
      effluent. METHODS: CML and CEL were measured by tandem mass spectroscopy, MDA by
      HPLC, and VCAM-1 by ELISA in 37 stable PD patients (age 54 +/- 12 years; time on
      PD 25 +/- 18 months). CML and CEL were also measured after a 4-month interval.
      RESULTS: rGFR was independently related to CML both in serum (r = -0.66; P<0.001)
      and effluent (r = -0.62; P<0.001), whereas peritoneal glucose prescription and
      absorption were, respectively, related to CML in serum and effluent (r = 0.49;
      P<0.001 and r = 0.44; P<0.01). Relationships were comparable when assessed after
      the follow-up period. Peritoneal glucose absorption (r = 0.37; P<0.05), but not
      rGFR, was related to CEL in serum. The relation between peritoneal glucose
      prescription and CML in effluent lost significance when rGFR was added to the
      multi-regression model. Both rGFR (r = -0.40; P<0.05) and peritoneal glucose
      absorption (r = 0.37; P<0.05) were associated with VCAM-1 expression, which was
      itself weakly related only to CML in effluent (r = 0.38; P<0.05). MDA was not
      related to any parameter. CONCLUSION: Peritoneal glucose prescription and
      absorption, as well as rGFR are related to serum and effluent levels of CML and
      to VCAM-1 expression in serum, whereas peritoneal glucose absorption was related
      to serum levels of CEL. Still, the effect of rGFR, which does not appear to be
      mediated through lipid peroxidation pathways, on effluent levels of CML appears
      to outweigh the effect of the PD treatment. Even small differences in residual
      renal function in patients already on dialysis therapy are related to large
      variations of CML in serum and the peritoneal cavity.

PMID- 15031350
TI  - Peritoneal dialysis with solutions low in glucose degradation products is
      associated with improved biocompatibility profile towards peritoneal mesothelial
      cells.
AB  - BACKGROUND: In vitro experiments point to a better biocompatibility profile of
      new pH-neutral peritoneal dialysis fluids (PDFs) containing low levels of glucose
      degradation products (GDPs). The present study examines the impact on human
      peritoneal mesothelial cells (HPMCs) of equilibrated dialysates obtained during
      dialysis with either conventional or new PDFs. METHODS: Peritoneal dialysate was
      collected from 17 patients participating in a randomized, controlled, cross-over
      trial comparing a pH-neutral low-GDP solution (Balance) to a conventional
      solution (S-PDF). All patients were treated sequentially for 3 months with both
      PDFs. At the end of each treatment phase, peritoneal effluent was drained after a
      timed 10 h dwell. Samples of dialysate were then mixed with standard culture
      medium and added to in vitro cultures of HPMCs from healthy donors. Cells were
      assessed for proliferation, viability and cytokine release. RESULTS:
      Proliferation and viability of HPMCs were better preserved in the presence of
      effluent obtained during dialysis with Balance (P<0.046 and P<0.035,
      respectively). The proliferative response of HPMCs correlated with the
      concentration of fibronectin in dialysates (P = 0.0024). Effluent drained
      following a 3 month dialysis with Balance contained significantly increased
      levels of fibronectin (P = 0.004) and CA125 antigen (P = 0.0004) compared with S
      PDF. There was no significant difference in constitutive and stimulated cytokine
      (IL-6, MCP-1, VEGF) synthesis by HPMCs treated with either Balance- or S-PDF
      derived effluents. CONCLUSIONS: These results suggest that therapy with new pH
      neutral low-GDP solutions contribute to an intraperitoneal milieu that improves
      mesothelial cell proliferation and viability. It may positively impact on the
      preservation of the peritoneal membrane integrity during long-term dialysis.

PMID- 15031351
TI  - Effect of peritoneal dialysis fluid composition on peritoneal area available for
      exchange in children.
AB  - BACKGROUND: Although conventional peritoneal dialysis fluids (PDFs), such as
      Dianeal, are non-physiological in composition, new PDFs including Physioneal have
      a more neutral pH, are at least partially buffered with bicarbonate and, most
      importantly, contain low concentrations of glucose degradation products (GDPs).
      METHODS: To evaluate the impact of new PDFs in childcare, we performed a
      comparative crossover study with Dianeal and Physioneal. We examined both
      intraperitoneal pressure (IPP), which partly reflects pain induction, and the
      total pore area available for exchange, which indicates the number of capillaries
      perfused in the peritoneal membrane at any given moment and therefore partly
      reflects peritoneal dialysis capacity. The IPP was determined after inflow of
      1000 ml/m(2) body surface area (BSA) of dialysate (intraperitoneal volume; IPV).
      The steady-state unrestricted area over diffusion distance (A(0)/ triangle up x,
      in cm(2)/cm per 1.73 m(2) BSA) was calculated from the three-pore theory. Six
      children were enrolled in the study. On the first day, two consecutive peritoneal
      equilibration tests of 90 min each were performed using first Dianeal and then
      Physioneal. On the second study day, the procedure was repeated with the fluids
      given in the opposite order. RESULTS: The mean IPP normalized to IPV (ml/m(2))
      was significantly higher for Dianeal (9.5 +/- 0.9 cm/1000 ml/m(2)) than for
      Physioneal (7.9 +/- 1.2 cm/1000 ml/m(2), P < 0.01). The mean A(0)/ triangle up x
      was 17 +/- 4% larger with Dianeal (36 095 +/- 2009 cm(2)/cm per 1.73 m(2)) than
      with Physioneal (31 780 +/- 2185 cm(2)/cm per 1.73 m(2), P < 0.001; based on 24
      data pairs). CONCLUSIONS: These pilot study results suggest a higher
      biocompatibility for Physioneal than for Dianeal. Less inflow pain associated
      with Physioneal induced a lower IPP reflecting enhanced fill volume tolerance,
      and the lower A(0)/ triangle up x reflected less capillary recruitment. Taken
      together, these results suggest that the new more biocompatible PDFs will improve
      peritoneal dialysis therapy, although this conclusion will require verification
      in extended clinical trials.

PMID- 15031352
TI  - Acute renal allograft rejections with major interstitial oedema and plasma cell
      rich infiltrates: high gamma-interferon expression and poor clinical outcome.
AB  - BACKGROUND: Acute rejections are scored according to three main criteria:
      vasculitis, tubulitis and interstitial infiltration as defined in the Banff
      classification. Typically, B cells account for <8% of the infiltrates and oedema
      is limited. The clinical significance of severe interstitial oedema and plasma
      cell-rich infiltrates (OPcR) are still a matter of debate. METHODS: Kidney graft
      biopsies performed between 1991 and 1998 were retrospectively evaluated for these
      two criteria. RESULTS: Among the 826 biopsies performed during the study period,
      14 samples in 12 patients met these criteria; 11 were of Banff type I acute
      rejection and three were borderline. Based on clinical data, all were treated as
      acute rejections. OPcR occurred at a median of 187 days post-transplantation. All
      episodes were steroid resistant. Graft survival was 40% at 1 year following the
      rejection. Circulating antibodies reactive either to donor HLA or to endothelial
      cells were present in eight of 12 patients and widespread C4d deposit in
      peritubular capillary were present in three out of five patients studied. Level
      of gamma-interferon mRNA within the graft was significantly higher than in
      standard acute cellular rejection (ACR). CONCLUSION: This study showed that OPcR
      rejections portend a poor outcome irrespective of the Banff score. Our data
      strongly support the hypothesis that a humoral component participated in the
      graft injuries. Altogether, the data suggest that OPcR rejection might represent
      a late and attenuated variant of acute humoral rejection that should be
      classified separately from ACR.

PMID- 15031353
TI  - The benefits of renin-angiotensin blockade in renal transplant recipients with
      biopsy-proven allograft nephropathy.
AB  - BACKGROUND: Allograft nephropathy, regardless of aetiology, leads to progressive
      renal injury and eventual graft loss. In native kidney disease, treatment of
      hypertension, in particular with angiotensin-converting enzyme inhibitors (ACEi)
      or angiotensin receptor blockers (ARB), has proven beneficial in retarding renal
      function decline. In the present study, we reviewed the clinical course of a
      renal transplant recipient cohort that was prescribed either an ACEi or ARB for
      biopsy-proven allograft nephropathy. METHODS: Patients were followed from the
      time of post-biopsy initiation of ACEi/ARB and were stratified based on biopsy
      findings. Outcomes of interest included safety, allograft survival, renal
      function and change in slope of renal function pre- and post-ACEi/ARB. RESULTS:
      The 5 year allograft survival after biopsy diagnosis of allograft nephropathy was
      83%. Serum creatinine was 191+/-97 (86-377) micromol/l at the time of biopsy and
      228+/-102 (102-575) micromol/l at last follow-up. The slopes of reciprocal
      creatinine vs time were used to calculate the decline in renal function and were
      compared pre- and post-ACEi/ARB. The mean slope+/-SD was -0.06+/-0.21 l/micromol
      x 10(-3) per month in the 12 months prior to therapy and -0.03+/-0.09 l/micromol
      x 10(-3) per month following therapy. The absolute difference in slopes was 0.03
      (P =<0.0001). CONCLUSIONS: Treatment with ACEi/ARB may be beneficial in the
      management of allograft nephropathy.

PMID- 15031354
TI  - How great is the survival advantage of transplantation over dialysis in elderly
      patients?
AB  - BACKGROUND: Patients >60 years old represent 66% of all new patients starting
      renal replacement therapy in Scotland. The aim of this study was to investigate
      whether or not transplantation provides any survival benefit in this group of
      patients. METHODS: 325 patients >60 years old listed for transplantation in
      Scotland between 1 January 1989 and 31 December 1999 were followed up until 31
      December 2000. Sociodemographic, comorbidity, listing and transplant data were
      obtained from the national renal and transplant databases and case-notes review.
      Survival was compared between those who received a transplant and those who were
      listed but did not receive a transplant by the end of the follow-up period. Mann
      Whitney, chi(2), Fisher's exact and log-rank tests were used where appropriate.
      RESULTS: Of the 325 patients listed, 128 (39.4%) received a first transplant
      within the study period and the remaining 197 (60.6%) continued to undergo
      dialysis. The transplant recipients were younger at listing (P<0.0001), lived
      closer to the transplant centre (P = 0.043) and spent less time on the active
      waiting list (P<0.0001) than patients who remained on dialysis. They had less
      ischaemic heart disease (P = 0.024), cerebrovascular disease (P = 0.03) and
      arrhythmias (P = 0.016). The overall mortality rate was 0.16 per patient-year for
      dialysis and 0.10 for transplantation. There was a significantly lower risk of
      death (RR = 0.35, 95% CI 0.22--0.54; P<0.0001, log-rank) and a longer life
      expectancy after listing with a transplant (8.17 vs 4.32 years). CONCLUSIONS:
      Renal transplantation offers a significant survival advantage over dialysis in
      elderly patients with end-stage renal failure who are considered suitable for
      transplantation.

PMID- 15031355
TI  - Strategies for compensating for the declining numbers of cadaver donor kidney
      transplants.
AB  - BACKGROUND: The living-donor and dual kidney transplantation programmes were
      initiated in the transplantation centre of Munster (TCM) as two approaches to
      compensate for the declining numbers of cadaver donor kidney transplants after
      the implementation of the new Eurotransplant Kidney Allocation System (ETKAS). We
      analysed the outcome of cadaver, living-donor and dual kidney transplantation and
      their effects on the waiting list in the TCM. METHODS: Between January 1990 and
      December 2000, 1184 kidney transplants were performed in the TCM. They were
      subdivided into cadaver, living-donor and dual kidney transplants and
      retrospectively analysed in terms of the number of kidney transplants performed,
      waiting time and waiting coefficient. In addition four representative groups were
      formed to reflect donor origin (I: cadaver kidney transplants allocated by the
      old ETKAS, n = 180; II: cadaver kidney transplants allocated by the new ETKAS, n
      = 139; III: living-donor kidney transplantation, n = 59; IV: dual kidney
      transplantation, n = 31) and compared according to graft function (initial
      diuresis, creatinine, 3-year graft function), patient survival and median waiting
      time. RESULTS: After the implementation of the new ETKAS, the number of cadaver
      donor kidney transplants at the TCM almost halved, but the proportion of living
      donor kidney transplantations increased significantly by 12.8% and of dual kidney
      transplantations by 8.5%. Patients who had received kidneys from cadaver donors
      allocated by the new ETKAS (group II) had a better survival rate, short- and long
      term function but a longer waiting time than in group I (old ETKAS). Patients
      with dual kidney transplants (group IV) showed the lowest survival and short-term
      function rate, but had long-term function equivalent to that of cadaver kidney
      transplants (groups I and II). Patients who had received kidneys from living
      donors (group III) had the best survival, and short- and long-term function rate
      as well as the shortest mean waiting time. CONCLUSIONS: Living-donor and dual
      kidney transplantation proved to be functionally equivalent alternatives and
      successful strategies for compensating the declining numbers of cadaver donor
      kidney transplants.

PMID- 15031356
TI  - Variation in cadaveric organ donor rates in the UK.
AB  - BACKGROUND: Considerable variation exists in the organ donation rate between
      kidney retrieval areas (KRAs) within the UK. The causes for this are unknown.
      This study examines whether or not observed variations are correlated with
      various possible explanatory factors. METHODS: A geographical study involving
      Poisson regression analysis was carried out of all 21 KRAs in the UK in 1999 and
      2000, with donor rate as dependent variable, and the following independent
      variables: road traffic accident, intracerebral haemorrhage and other trauma
      death rates; intensive care unit (ICU) bed numbers; co-location of transplant and
      neurosurgical units; population ethnicity; proportion of the population on the
      organ donor register; transplant coordinator numbers; and transplant unit
      numbers. Main outcome measures were: donor rate in each KRA; strength of
      association between independent and dependent variables; and magnitude of changes
      in the donor rate associated with changes in independent variables. RESULTS: The
      donor rate varied between eight and 27.4 donors per million population per year.
      There was an association between donor rate and general ICU bed numbers (more
      beds associated with a higher donor rate), but this was of borderline statistical
      significance (P = 0.065). However, the donor rate was negatively associated (P =
      0.02) with neurosurgical ICU bed numbers (more beds, fewer donors) and the
      proportion of the population from minority ethnic communities. There was no
      statistically significant association with the other independent variables.
      CONCLUSIONS: There is significant variation in the organ donor rate between
      different parts of the UK. More research is needed to explore the counter
      intuitive association between neurosurgical ICU beds and donations, and to
      determine the remaining causes of the observed variation.

PMID- 15031357
TI  - No association of G-463A myeloperoxidase gene polymorphism with MPO-ANCA
      associated vasculitis.
AB  - BACKGROUND: The activation of neutrophils and monocytes by ANCA, resulting in the
      release of reactive oxygen species and proteases like myeloperoxidase (MPO), is
      essential to the pathogenesis of ANCA-associated vasculitis. As the A allele of
      the G-463A MPO gene polymorphism is associated with diminished activity of MPO,
      it is conceivable that the presence of this allele protects against MPO-ANCA
      associated vasculitis. METHODS: Allelic frequencies of the G-463A polymorphism
      were studied in 119 ANCA-associated vasculitis patients, 48 with MPO-ANCA and 71
      with proteinase 3 (PR3)-ANCA. RESULTS: Allelic frequencies of MPO G-463A promoter
      polymorphism did not differ between MPO-ANCA- and PR3-ANCA-associated vasculitis
      patients. Moreover, allelic distribution was similar to that of the normal
      population. CONCLUSIONS: The data suggest that G-463A polymorphism does not seem
      to contribute to either MPO-ANCA- or PR3-ANCA-associated vasculitis formation.

PMID- 15031358
TI  - Phospholipid plasmalogen, a surrogate marker of oxidative stress, is associated
      with increased cardiovascular mortality in patients on renal replacement therapy.
AB  - BACKGROUND: There is a high incidence of premature cardiovascular disease (CVD)
      in patients with end-stage renal disease (ESRD). Free radical-induced tissue
      damage is thought to play a major role in the pathogenesis of atherosclerosis,
      and there are several reports indicating an increased oxidative stress in ESRD.
      However, it is not well established that increased oxidative stress predicts
      cardiovascular mortality in ESRD. Plasmalogens, a group of phospholipids with a
      vinyl ether bond in the sn-1 position, are considered to be sensitive markers of
      oxidative stress. METHODS: Cardiovascular and non-cardiovascular mortality was
      recorded (follow-up time 1860+/-94 days) in 105 ESRD patients (mean age 51+/-2
      years) in whom the fasting ratio of the erythrocyte levels of plasmalogens (DMA
      16/C16:0 and DMA 18/C18:0) had been determined at the start of renal replacement
      therapy (RRT). The prevalence of malnutrition (subjective global assessment),
      diabetes mellitus (DM), smoking habits and CVD was also determined. RESULTS:
      Thirty-eight patients who died of CVD (0.066+/-0.003) had a significantly lower
      DMA 16/C16:0 ratio than 15 patients who died of non-cardiovascular causes
      (0.078+/-0.005; P<0.05) and 52 patients alive at follow-up (0.075+/-0.003;
      P<0.05). A Cox proportional hazard model analysis showed that a low (<median) DMA
      16/C16:0 ratio at the start of RRT was associated (relative risk 1.50; confidence
      interval 1.07-2.16; P<0.05) with CVD mortality independently of age, gender, DM
      and CVD. CONCLUSION: These results suggest that increased oxidative stress may be
      a risk factor for cardiovascular mortality in ESRD.

PMID- 15031359
TI  - Renal magnesium loss causing hypomagnesaemia and autonomous hyperparathyroidism.

PMID- 15031360
TI  - Inferior vena cava thrombosis due to acute pyelonephritis.

PMID- 15031361
TI  - Wegener's granulomatosis presenting as multiple bilateral renal masses.

PMID- 15031362
TI  - Membranoproliferative glomerulonephritis associated with type 1 diabetes mellitus
      and Hashimoto's thyroiditis.

PMID- 15031363
TI  - Membranous nephropathy in a patient with hereditary complete complement C4
      deficiency.

PMID- 15031364
TI  - Successful triplet pregnancy in a patient on chronic haemodialysis.

PMID- 15031365
TI  - The axillary artery-popliteal vein extended polytetrafluoroethylene graft: a new
      technique for the complicated dialysis access patient.

PMID- 15031366
TI  - Post-transplantation swelling of the lower eyelid.

PMID- 15031368
TI  - Incidental detection of renomedullary interstitial cell tumour in a renal biopsy
      specimen.

PMID- 15031367
TI  - Labile hypertension, increased metanephrines and imaging misadventures.

PMID- 15031369
TI  - Early initiation of dialysis fails to prolong survival in patients with end-stage
      renal failure.

PMID- 15031370
TI  - Characteristics of hypotension-prone haemodialysis patients: is there a critical
      relative blood volume?

PMID- 15031371
TI  - Bone mineral density in the distal radius and increased risk of fractures in
      haemodialysis.

PMID- 15031372
TI  - Could proteinuria evaluation be helpful in predicting renal progression in
      apolipoprotein E-deficient (E-/-) mice with chronic renal failure?

PMID- 15031373
TI  - Stopping a medical research project for financial reasons.

PMID- 15031374
TI  - Detecting 'decoy cells' by phase-contrast microscopy.

PMID- 15031376
TI  - Acute tubulointerstitial nephritis associated with celecoxib.

PMID- 15031375
TI  - Immunotactoid glomerulonephritis as a cause of acute renal failure.

PMID- 15031377
TI  - Extracellular fluid volume and EPO dose in haemodialysis.

PMID- 15031378
TI  - Enzyme replacement in the treatment of Fabry's disease. Is there a point-of-no
      return?

PMID- 15031379
TI  - Hypothyroidism and resistance to human recombinant erythropoietin.

PMID- 15031381
TI  - Severe anaphylactic reaction in a haemodialysis patient after administration of
      reviparin.

PMID- 15031380
TI  - The use of androgens in anaemia resistant to erythropoietin and i.v. iron in
      patients with heart and renal failure.

PMID- 15031382
TI  - Dialysis: when to start or when to stop?

PMID- 15031383
TI  - Severe ascites following renal transplant biopsy caused by a rupture of a
      subcapsular lymphocele: treated successfully by retroperitonealization.

PMID- 15031384
TI  - Workplace interventions.

PMID- 15031385
TI  - The effectiveness of ergonomic interventions on return-to-work after low back
      pain; a prospective two year cohort study in six countries on low back pain
      patients sicklisted for 3-4 months.
AB  - AIMS: To study occurrence and effectiveness of ergonomic interventions on return
      to-work applied for workers with low back pain (LBP). METHODS: A multinational
      cohort of 1631 workers fully sicklisted 3-4 months due to LBP (ICD-9 codes 721,
      722, 724) was recruited from sickness benefit claimants databases in Denmark,
      Germany, Israel, Sweden, the Netherlands, and the United States. Medical,
      ergonomic, and other interventions, working status, and return-to-work were
      measured using questionnaires and interviews at three months, one and two years
      after the start of sickleave. Main outcome measure was time to return-to-work.
      Cox's proportional hazards model was used to calculate hazard ratios regarding
      the time to return-to-work, adjusted for prognostic factors. RESULTS: Ergonomic
      interventions varied considerably in occurrence between the national cohorts:
      23.4% (mean) of the participants reported adaptation of the workplace, ranging
      from 15.0% to 30.5%. Adaptation of job tasks and adaptation of working hours was
      applied for 44.8% (range 41.0-59.2%) and 46.0% (range 19.9-62.9%) of the
      participants, respectively. Adaptation of the workplace was effective on return
      to-work rate with an adjusted hazard ratio (HR) of 1.47 (95% CI 1.25 to 1.72; p <
      0.0001). Adaptation of job tasks and adaptation of working hours were effective
      on return-to-work after a period of more than 200 days of sickleave with an
      adjusted HR of 1.78 (95% CI 1.42 to 2.23; p < 0.0001) and 1.41 (95% CI 1.13 to
      1.76; p = 0.002), respectively. CONCLUSIONS: Results suggest that ergonomic
      interventions are effective on return-to-work of workers long term sicklisted due
      to LBP.

PMID- 15031386
TI  - Mortality patterns among residents in Louisiana's industrial corridor, USA, 1970
      99.
AB  - BACKGROUND: Because of the high concentration of oil refining and petrochemical
      facilities, the industrial area of the lower Mississippi River of South Louisiana
      has been termed the Industrial Corridor and has frequently been referred to as
      the "Cancer Corridor". AIMS: To quantitatively assess the "Cancer Corridor"
      controversy based on mortality data available in the public domain, and to
      identify potential contributing factors to the observed differences in mortality.
      METHODS: Age adjusted mortality rates were calculated for white and non-white
      males and females in the Industrial Corridor, Louisiana, and the United States
      for the time periods 1970-79, 1980-89, and 1990-99. RESULTS: All-cause mortality
      and all cancer combined for white males in the Industrial Corridor were
      significantly lower than the corresponding Louisiana population while Louisiana
      had significantly higher rates than the US population for all three time periods.
      Cancer of the lung was consistently higher in the Industrial Corridor region
      relative to national rates but lower than or similar to Louisiana. Non
      respiratory disease and cerebrovascular disease mortality for white males in the
      Industrial Corridor were consistently lower than either Louisiana or the USA.
      However, mortality due to diabetes and heart disease, particularly during the
      1990s, was significantly higher in the Industrial Corridor and Louisiana when
      compared to the USA. Similar mortality patterns were observed for white females.
      The mortality for non-white males and females in the Industrial Corridor was
      generally similar to the corresponding populations in Louisiana. There were no
      consistent patterns for all cancer mortality combined. Stomach cancer was
      increased among non-whites in both the Industrial Corridor and Louisiana when
      compared to the corresponding US data. Mortality from diabetes and heart disease
      among non-whites was significantly higher in the Industrial Corridor and
      Louisiana than in the USA. CONCLUSIONS: Mortality rates in the Industrial
      Corridor area were generally similar to or lower than the State of Louisiana,
      which were increased compared to the United States. Contrary to prior public
      perceptions, mortality due to cancer in the Industrial Corridor does not exceed
      that for the State of Louisiana.

PMID- 15031387
TI  - A case-crossover study of transient risk factors for occupational acute hand
      injury.
AB  - BACKGROUND: Workers with acute hand injuries account for over 1 000 000 emergency
      department visits annually in the United States. AIMS: To determine potential
      transient risk factors for occupational acute hand injury. METHODS: Subjects were
      recruited from 23 occupational health clinics in five northeastern states in the
      USA. In a telephone interview, subjects were asked to report the occurrence of
      seven potential risk factors within a 90-minute time period before an acute hand
      injury. Each case also provided control information on exposures during the month
      before the injury. The self-matched feature of the study design controlled for
      stable between-person confounders. RESULTS: A total of 1166 subjects were
      interviewed (891 men, 275 women), with a mean age (SD) of 37.2 years (11.4). The
      median time interval between injury and interview was 1.3 days. Sixty three per
      cent of subjects had a laceration. The relative risk of a hand injury was
      increased when working with equipment, tools, or work pieces not performing as
      expected (11.0, 95% CI 9.4 to 12.8), or when using a different work method to do
      a task (10.5, 95% CI 8.7 to 12.7). Other transient factors in decreasing order of
      relative risk were doing an unusual task, being distracted, and being rushed.
      Wearing gloves reduced the relative risk by 60% (0.4, 95% CI 0.3 to 0.5).
      Occupational category, job experience, and safety training were found to alter
      several of these effects. CONCLUSION: The results suggest the importance of these
      transient, potentially modifiable factors in the aetiology of acute hand injury
      at work. Attempts to modify these exposures by various strategies may reduce the
      incidence of acute hand injury at work.

PMID- 15031388
TI  - Biological monitoring of kidney function among workers occupationally exposed to
      trichloroethylene.
AB  - AIMS: To investigate the nephrotoxic potential of trichloroethylene in a
      currently exposed population using sensitive urinary markers of kidney toxicity.
      METHODS: Renal dysfunction was monitored in a cross-sectional study of 70 workers
      currently exposed to trichloroethylene. An age and sex matched control population
      of 54 individuals was drawn from hospital and administrative staff. RESULTS: The
      mean exposure to trichloroethylene, estimated from urinary trichloroacetic acid
      concentrations, was 32 ppm (range 0.5-252 ppm) with an average duration of
      exposure of 4.1 years (range 1-20 years). Significant differences between the
      exposed and control populations were found for nephrotoxicity markers N
      acetylglucosaminidase (NAG) and albumin, and for the mode of action marker,
      formic acid. However, neither NAG nor albumin showed a significant correlation
      with either the magnitude or duration of exposure to trichloroethylene. There was
      a significant correlation between urinary formic acid and trichloroacetic acid
      concentrations. Within the exposed population there were dose dependent increases
      in urinary methylmalonic acid concentrations and urinary glutathione S
      transferase alpha activity. Although still within the control range, these
      changes were clearly dose dependent and consistent with one of the proposed
      mechanisms of trichloroethylene induced kidney toxicity. CONCLUSION: Although
      there was no evidence of kidney toxicity within the population studied, the
      results suggest that kidney damage could occur at exposure concentrations higher
      (>250 ppm) than those encountered in this study.

PMID- 15031389
TI  - Pre-employment urine drug testing of hospital employees: future questions and
      review of current literature.
AB  - BACKGROUND: Patient safety and optimisation of worker performance are high
      current priorities. Arguments over employee drug testing have been debated over
      the past two decades. AIMS: To review prior information to reveal how current
      principles and practices regarding pre-employment drug testing of health care
      workers evolved, and to explore pressing current and future issues. METHODS: A
      literature search of Medline from 1980 to 1999 was performed. This yielded seven
      citations that reported results of pre-employment drug testing of health care
      workers, which we critically reviewed. RESULTS: The process by which a rational
      testing process was developed for pre-employment urine drug screening in the
      health care field is illustrated. Also depicted are some important principles,
      inequities, and shortcomings of the system. The range of positive tests was wide,
      from 0.25% to 12%. Testing was not always applied uniformly to all health care
      workers. It became apparent that positive tests also require medical review to
      determine if they were truly due to illicit substance use. CONCLUSIONS: Although
      pre-employment drug testing programmes in the health care industry have been
      firmly in place for many years, it is unclear whether such strategies have
      achieved their stated purposes. The next step is to study whether such programmes
      are effective at accomplishing specific goals, such as decreasing absenteeism,
      turnover, accidents, and medical errors, in order to justify continuing pre
      employment testing versus changing to an alternative testing strategy.

PMID- 15031390
TI  - Temporal association between serum prolactin concentration and exposure to
      styrene.
AB  - BACKGROUND: Previous studies have suggested that occupational exposure to styrene
      is associated with increased serum levels of the anterior pituitary hormone
      prolactin (PRL). AIMS: To test the hypotheses that: (1) the effect of styrene
      exposure on PRL secretion is an acute effect, not a subchronic or chronic effect;
      (2) blood styrene, as a measure of absorbed dose, is a stronger predictor of
      serum PRL level than personal breathing zone air styrene concentration. METHODS:
      Subjects were recruited from 17 workplaces in the reinforced plastics industry.
      Personal breathing zone air styrene, whole blood styrene, and serum PRL were
      measured during one to three sessions, approximately one year apart. Linear
      multiple regression was used to model the relations between acute (air styrene or
      blood styrene obtained at same time as PRL), subchronic (average air or blood
      styrene over two or three sessions), and chronic (years of work in industry or
      facility times average air styrene over all sessions) indices of styrene exposure
      and serum PRL. RESULTS: Acute blood styrene concentration was the strongest
      predictor of serum PRL concentration, with the model predicting a 2.06-fold
      increase in PRL (95% CI 1.11 to 3.84) for every 10-fold increase in blood
      styrene. Serum PRL tended to increase with increasing styrene exposure in both
      men and women; however, women tended to have higher PRL levels. For women, the
      change in blood styrene between sessions 1 and 2 was a significant predictor of
      the change in serum PRL between sessions. CONCLUSIONS: Results confirm that
      styrene exposure enhances serum PRL concentrations and support an acute effect of
      styrene on PRL secretion.

PMID- 15031391
TI  - Paternal exposure to agricultural pesticides and cause specific fetal death.
AB  - AIMS: To study the association between fetal death and paternal agricultural
      occupation in areas and time periods with different levels of use of agricultural
      pesticides. METHODS: A total of 1 473 146 stillbirths and births occurring in
      Spain between 1995 and 1999 were analysed. RESULTS: The offspring of agricultural
      workers had the highest risk of fetal death from congenital anomalies in the
      southern and eastern area (where pesticide use is greatest) and the lowest risk
      in the rest of Spain. In both areas the offspring of agricultural workers had a
      similar excess risk of fetal death from the remaining causes of death. The
      relative risk of fetal death from congenital anomalies in infants conceived
      between April and September (the months of greater use of pesticides) in the
      southern and eastern area was 0.90 in manual workers and 1.62 in agricultural
      workers, compared to non-manual workers; in individuals who were conceived during
      the rest of the year, the relative risk was 0.87 and 0.85, respectively. In both
      periods the offspring of agricultural workers had an excess risk of fetal death
      from the remaining causes of death. CONCLUSIONS: Paternal agricultural work in
      the areas where pesticides are massively used increases the risk of fetal death
      from congenital anomalies. The risk is also increased for fetuses conceived
      during the time periods of maximum use of pesticides The higher risk of fetal
      death from the remaining causes of death in the offspring of agricultural workers
      seems unrelated to pesticide exposure.

PMID- 15031393
TI  - Reducing absenteeism in hospital cleaning staff: pilot of a theory based
      intervention.
AB  - AIMS: To develop, pilot, and evaluate a workplace intervention to reduce sickness
      absence, based on a demand-control-support model of job strain. METHODS: Changes
      in the working arrangements of hospital cleaning staff were introduced with the
      aim of increasing their control over work and the support received at work. The
      study design was quasi-experimental, with 221 cleaning staff in the intervention
      group and 91 catering staff in the control group. The dependent variable was the
      difference in percentage monthly sickness absence between the 12 months preceding
      and following the intervention. Differences in sickness absence between staff
      groups for each month after the intervention were compared with differences
      between staff groups for the equivalent month one year prior to it. RESULTS:
      There was a significant reduction in the difference in sickness absence rates
      between the intervention and control group of 2.3% in the six months after the
      intervention, compared to the six months before. The difference was not
      maintained at 12 months. CONCLUSIONS: These results suggest that a workplace
      intervention aimed at increasing control and support at work has a small effect
      on reducing sickness absence among hospital cleaning staff in the short term.
      Future research should seek to replicate this effect in larger, experimental
      studies, analyse postulated mediators of such theory based interventions, and
      develop interventions that maintain improvement.

PMID- 15031392
TI  - Cigarette smoking, occupational exposure to noise, and self reported hearing
      difficulties.
AB  - AIMS: To explore the interaction of smoking and occupational exposure to noise as
      risk factors for hearing difficulty in the general population. METHODS: A
      questionnaire was mailed to 21 201 adults of working age, selected at random from
      the age-sex registers of 34 British general practices, and to 993 members of the
      armed services, randomly selected from pay records. Questions were asked about
      smoking habits, years spent in a noisy occupation, difficulty in hearing
      conversation, and wearing of a hearing aid. Associations of hearing difficulty
      with smoking habit were examined by logistic regression and compared across
      strata of noise exposure, with adjustment for potential confounders. RESULTS:
      Around half of the respondents had ever smoked, and half of these still smoked.
      Among 10 418 who provided details on hearing, 348 were classed as having moderate
      and 311 as having severe hearing difficulty. Risk of hearing difficulty was 3-5
      fold higher in those employed for >5 years in noisy work compared with those
      never employed in a noisy job. Within strata of noise exposure (including those
      who had never worked in a noisy job), ex- and current smokers had a higher risk
      of hearing difficulty than lifetime non-smokers. The additional risks were small
      compared with those of long term noise exposure, and the combination of effects
      was more consistent with an additive than a multiplicative interaction.
      CONCLUSIONS: Smoking may adversely affect hearing, and workers should be
      encouraged to refrain from both smoking and exposure to noise. However, the extra
      risk to hearing incurred by smoking in high ambient noise levels is small
      relative to that from the noise itself, which should be the main target for
      preventive measures.

PMID- 15031394
TI  - Long term effects of exposure to automobile exhaust on the pulmonary function of
      female adults in Tokyo, Japan.
AB  - AIMS: To investigate the chronic effects of air pollution caused mainly by
      automobiles in healthy adult females. METHODS: Respiratory symptoms were
      investigated in 5682 adult females who had lived in the Tokyo metropolitan area
      for three years or more in 1987; 733 of them were subjected to pulmonary function
      tests over eight years from 1987 to 1994. The subjects were divided into three
      groups by the level of air pollution they were exposed to during the study
      period. The concentrations of nitrogen dioxide and suspended particulate matter
      were the highest in group 1, and the lowest in group 3. RESULTS: The prevalence
      rates of respiratory symptoms in group 1 were higher than those in groups 2 and
      3, except for wheezing. Multiple logistic regression analysis showed significant
      differences in persistent phlegm and breathlessness. The subjects selected for
      the analysis of pulmonary function were 94, 210, and 102 females in groups 1, 2,
      and 3, respectively. The annual mean change of FEV(1) in group 1 was the largest
      (-0.020 l/y), followed by that in group 2 (-0.015 l/y), and that in group 3 (
      0.009 l/y). Testing for trends showed a significant larger decrease of FEV(1)
      with the increase in the level of air pollution. CONCLUSIONS: The subjects living
      in areas with high levels of air pollution showed higher prevalence rates of
      respiratory symptoms and a larger decrease of FEV(1) compared with those living
      in areas with low levels of air pollution. Since the traffic density is larger in
      areas with high air pollution, the differences among the groups may reflect the
      effect of air pollution attributable to particulate matter found in automobile
      exhaust.

PMID- 15031395
TI  - Mortality of workers exposed to ethylene oxide: extended follow up of a British
      cohort.
AB  - AIMS: To obtain further information about the risks of cancer associated with
      occupational exposure to ethylene oxide METHODS: Follow up was extended by 13
      years for a cohort of 2876 men and women with definite or potential exposure to
      ethylene oxide in the chemical industry or in hospital sterilising units.
      Subjects were traced through National Health Service and social security records,
      and their mortality was compared with that expected from rates in the national
      population by the person-years method. RESULTS: Analysis was based on 565 deaths,
      of which 339 had occurred during the additional period of follow up. Mortality
      was close to or below expectation for all causes (565 deaths v 607.6 expected),
      all cancers (188 v 184.2), and for all specific categories of malignancy
      including stomach cancer (10 v 11.6), breast cancer (11 v 13.2), non-Hodgkin's
      lymphoma (7 v 4.8), and leukaemia (5 v 4.6). All five deaths from leukaemia
      occurred in the subset of subjects with greatest potential for exposure to
      ethylene oxide, but even in this group the excess of deaths was small (2.6
      expected). CONCLUSIONS: The balance of evidence from this and other
      epidemiological investigations indicates that any risk of human cancer from
      ethylene oxide is low, particularly at the levels of occupational exposure that
      have occurred in Britain over recent decades. This may reflect the capacity of
      human cells to repair DNA damage caused by the chemical, which is a potent
      genotoxin and animal carcinogen.

PMID- 15031398
TI  - Building camps and work related injuries.
AB  - AIMS: To focus on one possible predictor of reported work related injuries--the
      role of living in building-site camps versus daily commuting from home to
      construction sites. METHODS: A cohort of construction workers was collected,
      based on personnel files from contractors involved in the building of the Great
      Belt Bridge. The files included information on employment periods and whether or
      not the employees lived in building-site camps. The cohort was followed up for
      injuries reported to the National Work Environment Authority. RESULTS:
      Construction workers living in camps reported 217 accidents, of which 24 were
      serious or fatal. Among those not living in camps we found 262 accidents, of
      which 29 were serious or fatal. The relative risk for all accidents for camp
      versus non-camp was 0.84 (95% CI 0.69 to 1.00). The respective figure for serious
      or fatal accidents was RR = 0.85 (95% CI 0.47 to 1.52). CONCLUSION: Results
      suggest that high accident rates at large construction sites may be reduced, if
      commuting is replaced by living on-site.

PMID- 15031396
TI  - Mortality in a cohort of vermiculite miners exposed to fibrous amphibole in
      Libby, Montana.
AB  - BACKGROUND: Fibrous tremolite is a widespread amphibole asbestiform mineral,
      airborne fibres of which constitute an environmental hazard in Libby, Montana,
      northern California, and elsewhere. AIMS: To determine excess risk from lung
      cancer, mesothelioma, and all-cause mortality in a cohort of men exposed to
      tremolite, but no other form of asbestos. METHODS: Mortality by certified cause
      and various measures of exposure to tremolite and related amphibole fibres was
      assessed in a cohort of 406 vermiculite mineworkers in Libby, Montana, employed
      before 1963 and followed until 1999. RESULTS: Total deaths were: lung cancer 44
      (SMR 2.40), non-malignant respiratory disease (NMRD) 51 (SMR 3.09), all causes
      285 (SMR 1.27); included among the total were 12 deaths ascribed to mesothelioma
      (4.21% of all deaths). Adjusted linear increments in relative risks (per 100
      f/ml.y), estimated by Poisson regression, were: lung cancer (0.36, 95% CI 0.03 to
      1.20), NMRD (0.38, 95% CI 0.12 to 0.96), and all deaths (0.14, 95% CI 0.05 to
      0.26). CONCLUSIONS: The all-cause linear model would imply a 14% increase in
      mortality for mine workers exposed occupationally to 100 f/ml.y or about 3.2% for
      a general population exposed for 50 years to an ambient concentration of 0.1
      f/ml. Amphibole fibres, tremolite in particular, are likely to be
      disproportionately responsible for cancer mortality in persons exposed to
      commercial chrysotile, but to what extent cannot be readily assessed.

PMID- 15031397
TI  - Respiratory symptoms and airflow limitation in asphalt workers.
AB  - BACKGROUND: Asphalt workers are exposed to bitumen fume and vapour, and to
      exhaust from engines and passing traffic. AIMS: To assess the occurrence of
      respiratory symptoms and signs of airflow limitations in a group of asphalt
      workers. METHODS: All 64 asphalt workers and a reference group of 195 outdoor
      construction workers from the same company participated in a cross-sectional
      study. Spirometric tests and a questionnaire on respiratory symptoms and smoking
      habits were administered. Respiratory symptoms and lung function were adjusted
      for age and smoking. RESULTS: The FEV1/FVC% ratio was significantly lower in the
      asphalt workers than in the referents. Symptoms of eye irritation, chest
      tightness, shortness of breath on exertion, chest wheezing, physician diagnosed
      asthma, and chronic obstructive pulmonary disease (COPD) were all significantly
      more prevalent among the asphalt workers. CONCLUSION: In asphalt workers there is
      an increased risk of respiratory symptoms, lung function decline, and COPD
      compared to other construction workers.

PMID- 15031399
TI  - World at work: manufacturing "tatami" mats in China.

PMID- 15031400
TI  - Lifetime risk of silicosis death for quartz exposed workers among German
      population.

PMID- 15031401
TI  - Personal and static sample measurements are related.

PMID- 15031402
TI  - Dermal exposure to chemicals in the workplace: just how important is skin
      absorption?

PMID- 15031404
TI  - Particulate air pollution and panel studies in children: a systematic review.
AB  - BACKGROUND: Panel studies have been used to investigate the short term effects of
      outdoor particulate air pollution across a wide range of environmental settings.
      AIMS: To systematically review the results of such studies in children, estimate
      summary measures of effect, and investigate potential sources of heterogeneity.
      METHODS: Studies were identified by searching electronic databases to June 2002,
      including those where outcomes and particulate level measurements were made at
      least daily for > or =8 weeks, and analysed using an appropriate regression
      model. Study results were compared using forest plots, and fixed and random
      effects summary effect estimates obtained. Publication bias was considered using
      a funnel plot. RESULTS: Twenty two studies were identified, all except two
      reporting PM10 (24 hour mean) >50 microg x m(-3). Reported effects of PM10 on PEF
      were widely spread and smaller than those for PM2.5 (fixed effects summary: 
      0.012 v -0.063 l x min(-1) per microg x m(-3) rise). A similar pattern was
      evident for symptoms. Random effects models produced larger estimates. Overall,
      in between-study comparisons, panels of children with diagnosed asthma or pre
      existing respiratory symptoms appeared less affected by PM10 levels than those
      without, and effect estimates were larger where studies were conducted in higher
      ozone conditions. Larger PM10 effect estimates were obtained from studies using
      generalised estimating equations to model autocorrelation and where results were
      derived by pooling subject specific regression coefficients. A funnel plot of
      PM10 results for PEF was markedly asymmetrical. CONCLUSIONS: The majority of
      identified studies indicate an adverse effect of particulate air pollution that
      is greater for PM2.5 than PM10. However, results show considerable heterogeneity
      and there is evidence consistent with publication bias, so limited confidence may
      be placed on summary estimates of effect. The possibility of interaction between
      particle and ozone effects merits further investigation, as does variability due
      to analytical differences that alter the interpretation of final estimates.

PMID- 15031403
TI  - Biomarkers of exposure to polycyclic aromatic hydrocarbons from environmental air
      pollution.
AB  - Metabolites of pyrene and DNA adducts have been used as biomarkers of high level
      exposure to polycyclic aromatic hydrocarbons (PAHs). A systematic review was
      performed to evaluate whether these biomarkers are also valid markers of low
      level environmental exposure to PAHs. Thirty five studies were identified with
      more than 10 subjects that evaluated environmental air pollution to PAHs in
      relation to metabolites of PAHs, mainly hydroxypyrene (1-OHP), PAH-DNA adducts,
      or protein adducts. PAH metabolites and, to a less extent, PAH-DNA adducts
      correlated well at the group level with exposure to B(a)P even at low levels of
      air pollution. The use of these biomarkers should be more widely implemented in
      combination with more traditional techniques for the assessment of general
      population exposure to PAHs from ambient air pollution.

PMID- 15031405
TI  - Malignant pleural and peritoneal mesotheliomas in former miners and millers of
      crocidolite at Wittenoom, Western Australia.
AB  - AIMS: To report the number of malignant pleural and peritoneal mesotheliomas that
      have occurred in former Wittenoom crocidolite workers to the end of 2000, and to
      compare this with earlier predictions. METHODS: A group of 6493 men and 415 women
      who had worked at the former Wittenoom crocidolite mine and mill at some time
      between 1943 and 1966 have been followed up throughout Australia and Italy to the
      end of 2000. RESULTS: The cumulative number of mesotheliomas up to 2000 was 235
      in men (202 pleural, 33 peritoneal) and seven (all pleural) in women. There had
      been 231 deaths with mesothelioma (9% of known deaths). CONCLUSIONS: The number
      of deaths in men with mesothelioma between 1987 and 2000 was at the low end of
      the predictions made earlier based on the number of cases to 1986. If this trend
      continues, it is predicted that about another 110 deaths with mesothelioma will
      occur in men by 2020.

PMID- 15031406
TI  - Arabidopsis peptide methionine sulfoxide reductase2 prevents cellular oxidative
      damage in long nights.
AB  - Peptide methionine sulfoxide reductase (PMSR) is a ubiquitous enzyme that repairs
      oxidatively damaged proteins. In Arabidopsis (Arabidopsis thaliana), a null
      mutation in PMSR2 (pmsr2-1), encoding a cytosolic isoform of the enzyme,
      exhibited reduced growth in short-day conditions. In wild-type plants, a
      diurnally regulated peak of total PMSR activity occurred at the end of the 16-h
      dark period that was absent in pmsr2-1 plants. This PMSR activity peak in the
      wild-type plant coincided with increased oxidative stress late in the dark period
      in the mutant. In pmsr2-1, the inability to repair proteins resulted in higher
      levels of their turnover, which in turn placed an increased burden on cellular
      metabolism. This caused increased respiration rates, leading to the observed
      higher levels of oxidative stress. In wild-type plants, the repair of damaged
      proteins by PMSR2 at the end of the night in a short-day diurnal cycle alleviates
      this potential burden on metabolism. Although PMSR2 is not absolutely required
      for viability of plants, the observation of increased damage to proteins in these
      long nights suggests the timing of expression of PMSR2 is an important adaptation
      for conservation of their resources.

PMID- 15031407
TI  - A nonsymbiotic root hair tip growth phenotype in NORK-mutated legumes:
      implications for nodulation factor-induced signaling and formation of a
      multifaceted root hair pocket for bacteria.
AB  - The Medicago truncatula Does not Make Infections (DMI2) mutant is mutated in the
      nodulation receptor-like kinase, NORK. Here, we report that NORK-mutated legumes
      of three species show an enhanced touch response to experimental handling, which
      results in a nonsymbiotic root hair phenotype. When care is taken not to induce
      this response, DMI2 root hairs respond morphologically like the wild type to
      nodulation factor (NF). Global NF application results in root hair deformation,
      and NF spot application induces root hair reorientation or branching, depending
      on the position of application. In the presence of Sinorhizobium meliloti, DMI2
      root hairs make two-dimensional 180 degrees curls but do not entrap bacteria in a
      three-dimensional pocket because curling stops when the root hair tip touches its
      own shank. Because DMI2 does not express the promoter of M. truncatula Early
      Nodulin11 (ENOD11) coupled to beta-glucuronidase upon NF application, we propose
      a split in NF-induced signaling, with one branch to root hair curling and the
      other to ENOD11 expression.

PMID- 15031408
TI  - RPT2 is a signal transducer involved in phototropic response and stomatal opening
      by association with phototropin 1 in Arabidopsis thaliana.
AB  - Phototropin 1 (phot1) and phot2, which are blue light receptor kinases, function
      in blue light-induced hypocotyl phototropism, chloroplast relocation, and
      stomatal opening in Arabidopsis (Arabidopsis thaliana). Previous studies have
      shown that the proteins RPT2 (for ROOT PHOTOTROPISM2) and NPH3 (for
      NONPHOTOTROPIC HYPOCOTYL3) transduce signals downstream of phototropins to induce
      the phototropic response. However, the involvement of RPT2 and NPH3 in stomatal
      opening and in chloroplast relocation mediated by phot1 and phot2 was unknown.
      Genetic analysis of the rpt2 mutant and of a series of double mutants indicates
      that RPT2 is involved in the phot1-induced phototropic response and stomatal
      opening but not in chloroplast relocation or phot2-induced movements. Biochemical
      analyses indicate that RPT2 is purified in the crude microsomal fraction, as well
      as phot1 and NPH3, and that RPT2 makes a complex with phot1 in vivo. On the other
      hand, NPH3 is not necessary for stomatal opening or chloroplast relocation. Thus,
      these results suggest that phot1 and phot2 choose different signal transducers to
      induce three responses: phototropic response of hypocotyl, stomatal opening, and
      chloroplast relocation.

PMID- 15031409
TI  - Formation of monoterpenes in Antirrhinum majus and Clarkia breweri flowers
      involves heterodimeric geranyl diphosphate synthases.
AB  - The precursor of all monoterpenes is the C10 acyclic intermediate geranyl
      diphosphate (GPP), which is formed from the C5 compounds isopentenyl diphosphate
      and dimethylallyl diphosphate by GPP synthase (GPPS). We have discovered that
      Antirrhinum majus (snapdragon) and Clarkia breweri, two species whose floral
      scent is rich in monoterpenes, both possess a heterodimeric GPPS like that
      previously reported from Mentha piperita (peppermint). The A. majus and C.
      breweri cDNAs encode proteins with 53% and 45% amino acid sequence identity,
      respectively, to the M. piperita GPPS small subunit (GPPS.SSU). Expression of
      these cDNAs in Escherichia coli yielded no detectable prenyltransferase activity.
      However, when each of these cDNAs was coexpressed with the M. piperita GPPS large
      subunit (GPPS.LSU), which shares functional motifs and a high level of amino acid
      sequence identity with geranylgeranyl diphosphate synthases (GGPPS), active GPPS
      was obtained. Using a homology-based cloning strategy, a GPPS.LSU cDNA also was
      isolated from A. majus. Its coexpression in E. coli with A. majus GPPS.SSU
      yielded a functional heterodimer that catalyzed the synthesis of GPP as a main
      product. The expression in E. coli of A. majus GPPS.LSU by itself yielded active
      GGPPS, indicating that in contrast with M. piperita GPPS.LSU, A. majus GPPS.LSU
      is a functional GGPPS on its own. Analyses of tissue-specific, developmental, and
      rhythmic changes in the mRNA and protein levels of GPPS.SSU in A. majus flowers
      revealed that these levels correlate closely with monoterpene emission, whereas
      GPPS.LSU mRNA levels did not, indicating that the levels of GPPS.SSU, but not
      GPPS.LSU, might play a key role in regulating the formation of GPPS and, thus,
      monoterpene biosynthesis.

PMID- 15031410
TI  - Circadian and diurnal calcium oscillations encode photoperiodic information in
      Arabidopsis.
AB  - We have tested the hypothesis that circadian oscillations in the concentration of
      cytosolic free calcium ([Ca2+]cyt) can encode information. We imaged oscillations
      of [Ca2+]cyt in the cotyledons and leaves of Arabidopsis (Arabidopsis thaliana)
      that have a 24-h period in light/dark cycles and also constant light. The
      amplitude, phase, and shape of the oscillations of [Ca2+]cyt and [Ca2+]cyt at
      critical daily time points were controlled by the light/dark regimes in which the
      plants were grown. These data provide evidence that 24-h oscillations in
      [Ca2+]cyt encode information concerning daylength and light intensity, which are
      two major regulators of plant growth and development.

PMID- 15031411
TI  - A haplotype-specific Resistance gene regulated by BONZAI1 mediates temperature
      dependent growth control in Arabidopsis.
AB  - Plant growth homeostasis and defense responses are regulated by BONZAI1 (BON1),
      an evolutionarily conserved gene. Here, we show that growth regulation by BON1 is
      mediated through defense responses. BON1 is a negative regulator of a haplotype
      specific Resistance (R) gene SNC1. The bon1-1 loss-of-function mutation activates
      SNC1, leading to constitutive defense responses and, consequently, reduced cell
      growth. In addition, a feedback amplification of the SNC1 gene involving
      salicylic acid is subject to temperature control, accounting for the regulation
      of growth and defense by temperature in bon1-1 and many other mutants. Thus,
      plant growth homeostasis involves the regulation of an R gene by BON1 and the
      intricate interplay between defense responses and temperature responses.

PMID- 15031412
TI  - The Arabidopsis chloroplastic NifU-like protein CnfU, which can act as an iron
      sulfur cluster scaffold protein, is required for biogenesis of ferredoxin and
      photosystem I.
AB  - The biosynthesis of iron-sulfur clusters is a highly regulated process involving
      several proteins. Among them, so-called scaffold proteins play pivotal roles in
      both the assembly and delivery of iron-sulfur clusters. Here, we report the
      identification of two chloroplast-localized NifU-like proteins, AtCnfU-V and
      AtCnfU-IVb, from Arabidopsis (Arabidopsis thaliana) with high sequence similarity
      to a cyanobacterial NifU-like protein that was proposed to serve as a molecular
      scaffold. AtCnfU-V is constitutively expressed in several tissues of Arabidopsis,
      whereas the expression of AtCnfU-IVb is prominent in the aerial parts. Mutant
      Arabidopsis lacking AtCnfU-V exhibited a dwarf phenotype with faint pale-green
      leaves and had drastically impaired photosystem I accumulation. Chloroplasts in
      the mutants also showed a decrease in both the amount of ferredoxin, a major
      electron carrier of the stroma that contains a [2Fe-2S] cluster, and in the in
      vitro activity of iron-sulfur cluster insertion into apo-ferredoxin. When
      expressed in Escherichia coli cells, AtCnfU-V formed a homodimer carrying a [2Fe
      2S]-like cluster, and this cluster could be transferred to apo-ferredoxin in
      vitro to form holo-ferredoxin. We propose that AtCnfU has an important function
      as a molecular scaffold for iron-sulfur cluster biosynthesis in chloroplasts and
      thereby is required for biogenesis of ferredoxin and photosystem I.

PMID- 15031413
TI  - The novel gene HOMOLOGOUS PAIRING ABERRATION IN RICE MEIOSIS1 of rice encodes a
      putative coiled-coil protein required for homologous chromosome pairing in
      meiosis.
AB  - We have identified and characterized a novel gene, PAIR1 (HOMOLOGOUS PAIRING
      ABERRATION IN RICE MEIOSIS1), required for homologous chromosome pairing and
      cytokinesis in male and female meiocytes of rice (Oryza sativa). The pair1
      mutation, tagged by the endogenous retrotransposon Tos17, exhibited meiosis
      specific defects and resulted in complete sterility in male and female gametes.
      The PAIR1 gene encodes a 492-amino acid protein, which contains putative coiled
      coil motifs in the middle, two basic regions at both termini, and a potential
      nuclear localization signal at the C terminus. Expression of the PAIR1 gene was
      detected in the early stages of flower development, in which the majority of the
      sporocytes had not entered meiosis. During prophase I of the pair1 meiocyte, all
      the chromosomes became entangled to form a compact sphere adhered to a nucleolus,
      and homologous pairing failed. At anaphase I and telophase I, chromosome
      nondisjunction and degenerated spindle formation resulted in multiple uneven
      spore production. However, chromosomal fragmentation frequent in plant meiotic
      mutants was never observed in all of the pair1 meiocytes. These observations
      clarify that the PAIR1 protein plays an essential role in establishment of
      homologous chromosome pairing in rice meiosis.

PMID- 15031415
TI  - Toxic effects from metformin exposure.
AB  - BACKGROUND: The major risk associated with metformin is lactic acidosis. The
      incidence of lactic acidosis is not clear. Hypoglycemia is not expected to be a
      major concern after metformin exposure. OBJECTIVE: This study assessed the
      demographics, toxic effects, and clinical syndromes of metformin exposures
      reported to poison centers nationally. METHODS: The Toxic Exposure Surveillance
      System (TESS) of the American Association of Poison Control Centers was searched
      for all metformin-only exposures occurring from January 1, 1996, through December
      31, 2000. RESULTS: There were 10,958,526 total poisoning exposures reported to
      TESS during the study period. Of those, 4072 cases met the study criteria.
      Exposures occurred in 2421 (59%) women and were categorized in all patients as
      acute (3074; 75%), acute-on-chronic (767; 19%), chronic (200; 5%), and chronicity
      unknown (31; 1%). Children < or =12 years old experienced few adverse outcomes
      and no deaths. There were 20 moderate-effect outcomes (1.8%) and 2 major-effect
      outcomes (0.2%) in children <6 years old and 4 moderate-effect outcomes (2.3%)
      and no major-effect outcomes in children 6-12 years old. In the adult population,
      the adverse outcomes were distributed evenly across the age span, with a trend
      toward more serious outcomes in the elderly. There were 9 deaths (0.2%), 32 major
      effect cases (0.8%), and 187 moderate-effect cases (4.6%). In all age groups,
      acidosis was rare (n = 68; 1.6%). Hypoglycemia is more common than previously
      reported (n = 112; 2.8%). Clinical effects associated with a major outcome or
      death were hyperglycemia, acidosis, elevated anion gap, elevated creatinine,
      hypotension, and coma. CONCLUSIONS: Severe adverse events after exposure to
      metformin are not common, occurring in approximately 1% of cases; this is in
      agreement with previous reports. The presence of hypotension, acidosis, elevated
      anion gap, hyperglycemia, and coma may be prognostic of severe or fatal outcome.

PMID- 15031414
TI  - B1-type cyclin-dependent kinases are essential for the formation of stomatal
      complexes in Arabidopsis thaliana.
AB  - Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle. In yeasts,
      only one CDK is sufficient to drive cells through the cell cycle, whereas higher
      eukaryotes developed a family of related CDKs. Curiously, plants contain a unique
      class of CDKs (B-type CDKs), whose function is still unclear. We show that the
      CDKB1;1 gene of Arabidopsis (Arabidopsis thaliana) is highly expressed in guard
      cells and stomatal precursor cells of cotyledons, suggesting a prominent role for
      B-type CDKs in stomatal development. In accordance, transgenic Arabidopsis plants
      with reduced B-type CDK activity had a decreased stomatal index because of an
      early block of meristemoid division and inhibition of satellite meristemoid
      formation. Many aberrant stomatal cells were observed, all of them blocked in the
      G2 phase of the cell cycle. Although division of stomatal precursors was
      inhibited, cells still acquired stomatal identity, illustrating that stomatal
      cell differentiation is independent of cellular and nuclear division.

PMID- 15031416
TI  - Inadequate prevention of NSAID-induced gastrointestinal events.
AB  - BACKGROUND: Use of nonsteroidal antiinflammatory drugs (NSAIDs) is a well-known
      cause of gastrointestinal (GI) adverse events. To protect patients at risk,
      several strategies are advised, including concomitant treatment with proton-pump
      inhibitors or switching to cyclooxygenase (COX)-2 selective NSAIDs. It is as yet
      unknown how many patients at risk for NSAID-induced events are protected.
      OBJECTIVE: To estimate the number of patients using GI preventive treatment while
      at risk for NSAID-induced GI events. METHODS: Records of patients using NSAIDs
      consecutively for at least 100 days (from 2001 to 2002) were obtained from the
      PHARMO system in the Netherlands (N = 1,000,000). GI preventive treatments were
      classified as adequate or inadequate based on evidence-based criteria. Adequate
      treatment was defined as concomitant use of misoprostol (>400 microg daily),
      histamine2-antagonists (> or =2 times recommended dose) or proton-pump inhibitors
      (> or =1 recommended dose), or alternative treatment with COX-2 selective
      inhibitors. RESULTS: A total of 10,121 patients met the study inclusion criteria;
      70% were women. One or more preventive strategies were prescribed in 4340
      patients (42.9%), of which 2799 (64.5%) were adequate and 1541 (35.5%)
      inadequate. Prescribing of adequate preventive treatments increased with the
      number of risk factors, from 13.3% among those with no additional risk factors to
      61.9% for those with > or =4 risk factors. CONCLUSIONS: Although risk factors for
      GI damage were recognized, a large number of patients in the Netherlands were not
      or were inadequately protected against potential NSAID-associated GI damage.
      Despite recommendations, and even in the presence of > or =4 risk factors, almost
      40% of these patients were not prescribed adequate GI preventive treatment.

PMID- 15031417
TI  - Glycosylated hemoglobin, cardiovascular, and renal outcomes in a pharmacist
      managed clinic.
AB  - BACKGROUND: Pharmacists' responsibilities in caring for patients with diabetes
      mellitus are expanding. However, few data are available to support pharmacists
      optimizing therapy and improving outcomes in these patients. OBJECTIVE: To
      determine the effect of a clinical pharmacist-directed diabetes management clinic
      on glycemic control and cardiovascular and renal parameters in patients with type
      2 diabetes. METHODS: A nonrandomized, prospective study was conducted in 70
      Veterans Affairs patients. Patients met with the pharmacist every 6-8 weeks for
      approximately 30 minutes for education, medication counseling, monitoring, and
      management. The primary endpoint was the impact of 9-12 months of participation
      in the clinic on glycosylated hemoglobin (HbA1C). Secondarily, we evaluated body
      weight, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high
      density lipoprotein cholesterol, triglycerides, systolic and diastolic blood
      pressure, and level of microalbuminuria. All comparisons were made using a paired
      t-test at a significance level of p < or = 0.05. RESULTS: HbA1C significantly
      decreased from 10.3% +/- 2.2% at baseline to 6.9% +/- 1.1% (mean +/- SD) during
      the 9- to 12-month evaluation period (p < 0.001). The secondary endpoints
      including systolic (p < 0.001) and diastolic (p < 0.001) blood pressure, total
      cholesterol (p < 0.001), LDL-C (p < 0.001), triglycerides (p = 0.006), and level
      of microalbuminuria (p < 0.001) also were reduced at 9-12 months. CONCLUSIONS:
      This study demonstrated that a clinical pharmacist can effectively care for
      patients with diabetes referred by their primary care provider because of poor
      glycemic control.

PMID- 15031418
TI  - Influential characteristics of physician/pharmacist collaborative relationships.
AB  - BACKGROUND: A theoretical model of physician/pharmacist collaborative
      relationships, driven by 3 groups of relationship characteristics termed
      participant, context, and exchange, has been developed. There are no studies that
      have examined the types of characteristics which most influence development of
      collaborative relationships between physicians and pharmacists. OBJECTIVE: To
      test the model and determine which drivers most influence physician/pharmacist
      collaboration. METHODS: Data on the relationship drivers and collaborative
      practice were collected via a mailed survey of a random sample of 1000 primary
      care physicians in Iowa. Participant variables include demographics; context
      drivers refer to the practice environment and professional interactions between
      physicians and pharmacists. Exchange characteristics describe the nature of
      social exchange and were elicited using scores from 3 domains (relationship
      initiation, trustworthiness, role specification) of the Physician/Pharmacist
      Collaboration Instrument (PPCI). Five additional questions asked about the
      physician's collaborative practice with a pharmacist. Hierarchical linear
      regression analysis was performed with collaborative practice as the dependent
      variable and measures of participant, context, and exchange drivers as
      independent variables. RESULTS: Three hundred forty usable surveys (34%) were
      returned. Almost 70% of the respondents were male and aged 45.8 +/- 9.9 years
      (mean +/- SD). The majority were family practice physicians (72.1%) in private
      practice (67.3%). Regression analyses produced an R2 = 0.804 (p < 0.001).
      Significant predictors in the model were internal medicine physicians,
      professional interaction with a pharmacist, and the 3 domains of exchange drivers
      from the PPCI (p < 0.05). CONCLUSIONS: Although participant and context factors
      influenced physician/pharmacist collaborative relationships, exchange
      characteristics were the most influential relationship drivers. Role
      specification, trustworthiness, and relationship initiation were positively
      associated with physician/pharmacist collaborative practice. Recognition of these
      drivers may help pharmacists who are developing collaborative working
      relationships with physicians. But, studies are needed to delineate other factors
      that may influence physician/pharmacist relationships.

PMID- 15031423
TI  - Chiral biphenyl diphosphines for asymmetric catalysis: stereoelectronic design
      and industrial perspectives.
AB  - Two original chiral diphosphines, SYNPHOS and DIFLUORPHOS, have been synthesized
      on multigram scales. Their steric and electronic profiles have been established
      in comparison with the commonly used 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
      and 6,6'-dimethoxy-2,2'-bis(diphenylphosphino)-1,1'-biphenyl ligands. A screening
      study of the four ligands in Ru(II)-catalyzed asymmetric hydrogenation of
      prochiral ketones and olefins has been performed. It revealed that the
      stereoelectronic features of the ligand and the substrate deeply influenced the
      enantioselectivities obtained in asymmetric hydrogenation, SYNPHOS and
      DIFLUORPHOS being fully complementary in terms of enantioselectivity for this
      reaction.

PMID- 15031428
TI  - Suppression of nuclear oscillations in Saccharomyces cerevisiae expressing Glu
      tubulin.
AB  - In most eukaryotic cells, the C-terminal amino acid of alpha-tubulin is aromatic
      (Tyr in mammals and Phe in Saccharomyces cerevisiae) and is preceded by two
      glutamate residues. In mammals, the C-terminal Tyr of alpha-tubulin is subject to
      cyclic removal from the peptide chain by a carboxypeptidase and readdition to the
      chain by a tubulin-Tyr ligase. There is evidence that tubulin-Tyr ligase
      suppression and the resulting accumulation of detyrosinated (Glu) tubulin favor
      tumor growth, both in animal models and in human cancers. However, the molecular
      basis for this apparent stimulatory effect of Glu tubulin accumulation on tumor
      progression is unknown. Here we have developed S. cerevisiae strains expressing
      only Glu tubulin and used them as a model to assess the consequences of Glu
      tubulin accumulation in cells. We find that Glu tubulin strains show defects in
      nuclear oscillations. These defects are linked to a markedly decreased
      association of the yeast ortholog of CLIP170, Bik1p, with microtubule plus-ends.
      These results indicate that the accumulation of Glu tubulin in cells affects
      microtubule tip complexes that are important for microtubule interactions with
      the cell cortex.

PMID- 15031430
TI  - Low back pain: influence of early MR imaging or CT on treatment and outcome-
      multicenter randomized trial.
AB  - PURPOSE: To establish whether early use of magnetic resonance (MR) imaging or
      computed tomography (CT) influences treatment and outcome of patients with low
      back pain (LBP) and whether it is cost-effective. MATERIALS AND METHODS: In a
      multicenter randomized study, two imaging policies for LBP were compared in 782
      participants with symptomatic lumbar spine disorders who were referred to
      orthopedists or neurosurgeons. Participants were randomly allocated to early (393
      participants; mean age, 43.9 years; range, 16-82 years) or delayed selective (389
      participants; mean age, 42.8 years; range, 14-82 years) imaging groups. Delayed
      selective imaging referred to imaging restricted to patients in whom a clear
      clinical need subsequently developed. Main outcome measures were Aberdeen Low
      Back Pain (ALBP) score, Short Form 36 (SF-36) score (for multidimensional health
      status), EuroQol (EQ-5D) score (for quality-adjusted life-year [QALY] estimates),
      and healthcare resource use at 8 and 24 months after randomization. Data were
      evaluated with analysis of covariance, ordinal logistic regression analysis, and
      chi(2) and Mann-Whitney tests. RESULTS: Both groups showed improvement in ALBP
      score, but this was greater in the early group (adjusted mean difference between
      groups, -3.05 points [95% CI: -5.16, -0.95; P =.005] and -3.62 points [95% CI: 
      5.92, -1.32; P =.002] at 8 and 24 months, respectively). Scores for SF-36 (bodily
      pain domain) and EQ-5D were also significantly better at 24 months. Clinical
      treatment was similar in both groups. Differences in total costs reflected cost
      of imaging. Imaging provided an adjusted mean additional QALY of 0.041 during 24
      months at a mean incremental cost per QALY of $2,124. CONCLUSION: Early use of
      imaging does not appear to affect treatment overall. Decisions about the use of
      imaging depend on judgments concerning whether the small observed improvement in
      outcome justifies additional cost.

PMID- 15031431
TI  - Diagnostic CT scans: assessment of patient, physician, and radiologist awareness
      of radiation dose and possible risks.
AB  - PURPOSE: To determine the awareness level concerning radiation dose and possible
      risks associated with computed tomographic (CT) scans among patients, emergency
      department (ED) physicians, and radiologists. MATERIALS AND METHODS: Adult
      patients seen in the ED of a U.S. academic medical center during a 2-week period
      with mild to moderate abdominopelvic or flank pain and who underwent CT were
      surveyed after acquisition of the CT scan. Patients were asked whether or not
      they were informed about the risks, benefits, and radiation dose of the CT scan
      and if they believed that the scan increased their lifetime cancer risk. Patients
      were also asked to estimate the radiation dose for the CT scan compared with that
      for one chest radiograph. ED physicians who requested CT scans and radiologists
      who reviewed the CT scans were surveyed with similar questions and an additional
      question regarding the number of years in practice. The chi(2) test of
      independence was used to compare the three respondent groups regarding perceived
      increased cancer risk from one abdominopelvic CT scan. RESULTS: Seven percent
      (five of 76) of patients reported that they were told about risks and benefits of
      their CT scan, while 22% (10 of 45) of ED physicians reported that they had
      provided such information. Forty-seven percent (18 of 38) of radiologists
      believed that there was increased cancer risk, whereas only 9% (four of 45) of ED
      physicians and 3% (two of 76) of patients believed that there was increased risk
      (chi(2)(2) = 41.45, P <.001). All patients and most ED physicians and
      radiologists were unable to accurately estimate the dose for one CT scan compared
      with that for one chest radiograph. CONCLUSION: Patients are not given
      information about the risks, benefits, and radiation dose for a CT scan.
      Patients, ED physicians, and radiologists alike are unable to provide accurate
      estimates of CT doses regardless of their experience level.

PMID- 15031432
TI  - Liver tumors: MR imaging of radioactive holmium microspheres--phantom and rabbit
      study.
AB  - PURPOSE: To investigate the use of magnetic resonance (MR) imaging in the
      administration and biodistribution of holmium-loaded poly(L-lactic acid)
      microspheres (Ho-PLLA-MS) in liver tumors. MATERIALS AND METHODS: MR imaging
      measurements were obtained in phantoms, three ex vivo rabbit livers, and four
      livers in living rabbits. When applicable, measurements were compared with those
      on scintigraphic images. The transverse relaxivity R2* of the Ho-PLLA-MS was
      determined in a phantom study. The in vivo animal experiments were performed by
      using rabbits with an implanted VX2 tumor. Detection of passing Ho-PLLA-MS to
      estimate lung shunting was performed in a scaled model of the vena cava. RESULTS:
      In the ex vivo liver experiments, the feasibility of real-time MR imaging during
      administration of microspheres was demonstrated. The in vivo rabbit experiments
      demonstrated that MR imaging can depict radioactive, nonradioactive, and decayed
      Ho-PLLA-MS after treatment for as long as they remain in the body. Furthermore,
      this study showed the ability of dynamic MR imaging to detect single doses of
      passing Ho-PLLA-MS. CONCLUSION: Ho-PLLA-MS used for internal radionuclide therapy
      can be imaged clearly in vivo with MR imaging.

PMID- 15031433
TI  - Suspected appendicitis in children: diagnosis with contrast-enhanced versus
      nonenhanced Helical CT.
AB  - PURPOSE: To compare the diagnostic accuracy of limited-area (lower abdominal)
      nonenhanced helical computed tomography (CT), intravenous contrast material
      enhanced helical CT of the entire abdomen, and the combination of both. MATERIALS
      AND METHODS: Three hundred six children suspected of having appendicitis, who
      were previously included in a prospective study, underwent limited-area
      nonenhanced helical CT of the lower abdomen and contrast-enhanced CT of the
      entire abdomen. No oral or rectal contrast material was administered. The CT
      scans were retrospectively reviewed by three independent readers both separately
      and together. The readers were blinded to all clinical information and to the
      results of previous ultrasonographic and CT examinations. Final diagnoses were
      established on the basis of surgical, histopathologic, or clinical follow-up
      findings. The Pearson chi(2) test was performed to compare values between groups.
      The Student two-sample t test was performed to determine statistically
      significant differences in age and sex. RESULTS: One hundred twenty-nine patients
      (42%) had appendicitis. Readers diagnosed appendicitis with 66% pooled
      sensitivity and 96% pooled specificity with limited-area nonenhanced CT. With
      contrast-enhanced CT of the entire abdomen, appendicitis was diagnosed with 90%
      pooled sensitivity and 94% pooled specificity. With both sequences together,
      readers diagnosed appendicitis with 90% pooled sensitivity and 94% pooled
      specificity. The difference between the sensitivity of limited-area nonenhanced
      CT and that of contrast-enhanced CT was statistically significant (P <.001).
      CONCLUSION: Sensitivity of helical CT for suspected appendicitis in children
      improved significantly with abdominal contrast-enhanced CT compared with limited
      area nonenhanced CT. No further improvement in sensitivity was achieved with the
      combination of both sequences in comparison to that with contrast-enhanced CT
      alone.

PMID- 15031434
TI  - Local-regional staging of endometrial carcinoma: role of MR imaging in surgical
      planning.
AB  - PURPOSE: To assess magnetic resonance (MR) imaging in depicting the depth of
      myometrial infiltration, cervical invasion, and presence of enlarged lymph nodes
      in patients with endometrial adenocarcinoma compared with surgicopathologic
      findings. MATERIALS AND METHODS: Thirty-seven consecutive patients with
      endometrial carcinoma were included in this prospective study. All patients
      underwent MR imaging and surgery. Qualitative image analysis included the depth
      of myometrial infiltration, infiltration of the uterine cervix, and presence of
      enlarged lymph nodes. Quantitative image analysis included tumor and myometrium
      contrast-to-noise ratios during different phases of dynamic imaging. MR imaging
      findings were compared with surgicopathologic findings. Sensitivity, specificity,
      diagnostic accuracy, and positive and negative predictive values of MR imaging in
      depicting myometrial and cervical infiltration and in lymph node assessment were
      calculated. RESULTS: Respective sensitivity, specificity, diagnostic accuracy,
      and positive and negative predictive values in assessing myometrial infiltration
      were 87%, 91%, 89%, 87%, and 91%; those for cervical infiltration, 80%, 96%, 92%,
      89%, and 93%; and those for lymph node assessment, 50%, 95%, 90%, 50%, and 95%.
      There was significant agreement between MR imaging and surgicopathologic findings
      in assessment of myometrial invasion (P <.001). Myometrial and cervical invasion
      and lymph node enlargement were correctly assessed with MR imaging in 28 (76%) of
      37 patients. Quantitative analysis showed a significant improvement in tumor and
      myometrium contrast-to-noise ratios during the equilibrium phase compared with
      the arterial and precontrast phases (P <.001). CONCLUSION: MR imaging coupled
      with contrast material-enhanced dynamic MR imaging is highly accurate in local
      regional staging of endometrial carcinoma; more challenging is the assessment of
      pelvic and lumboaortic lymph nodes.

PMID- 15031435
TI  - Ultrahigh strength and high electrical conductivity in copper.
AB  - Methods used to strengthen metals generally also cause a pronounced decrease in
      electrical conductivity, so that a tradeoff must be made between conductivity and
      mechanical strength. We synthesized pure copper samples with a high density of
      nanoscale growth twins. They showed a tensile strength about 10 times higher than
      that of conventional coarse-grained copper, while retaining an electrical
      conductivity comparable to that of pure copper. The ultrahigh strength originates
      from the effective blockage of dislocation motion by numerous coherent twin
      boundaries that possess an extremely low electrical resistivity, which is not the
      case for other types of grain boundaries.

PMID- 15031436
TI  - Genetic dissection of complex traits with chromosome substitution strains of
      mice.
AB  - Chromosome substitution strains (CSSs) have been proposed as a simple and
      powerful way to identify quantitative trait loci (QTLs) affecting developmental,
      physiological, and behavioral processes. Here, we report the construction of a
      complete CSS panel for a vertebrate species. The CSS panel consists of 22 mouse
      strains, each of which carries a single chromosome substituted from a donor
      strain (A/J) onto a common host background (C57BL/6J). A survey of 53 traits
      revealed evidence for 150 QTLs affecting serum levels of sterols and amino acids,
      diet-induced obesity, and anxiety. These results demonstrate that CSSs greatly
      facilitate the detection and identification of genes that control the wide
      diversity of naturally occurring phenotypic variation in the A/J and C57BL/6J
      inbred strains.

PMID- 15031437
TI  - Functional conversion between A-type and delayed rectifier K+ channels by
      membrane lipids.
AB  - Voltage-gated potassium (Kv) channels control action potential repolarization,
      interspike membrane potential, and action potential frequency in excitable cells.
      It is thought that the combinatorial association between distinct alpha and beta
      subunits determines whether Kv channels function as non-inactivating delayed
      rectifiers or as rapidly inactivating A-type channels. We show that membrane
      lipids can convert A-type channels into delayed rectifiers and vice versa.
      Phosphoinositides remove N-type inactivation from A-type channels by immobilizing
      the inactivation domains. Conversely, arachidonic acid and its amide anandamide
      endow delayed rectifiers with rapid voltage-dependent inactivation. The
      bidirectional control of Kv channel gating by lipids may provide a mechanism for
      the dynamic regulation of electrical signaling in the nervous system.

PMID- 15031438
TI  - Integration of word meaning and world knowledge in language comprehension.
AB  - Although the sentences that we hear or read have meaning, this does not
      necessarily mean that they are also true. Relatively little is known about the
      critical brain structures for, and the relative time course of, establishing the
      meaning and truth of linguistic expressions. We present electroencephalogram data
      that show the rapid parallel integration of both semantic and world knowledge
      during the interpretation of a sentence. Data from functional magnetic resonance
      imaging revealed that the left inferior prefrontal cortex is involved in the
      integration of both meaning and world knowledge. Finally, oscillatory brain
      responses indicate that the brain keeps a record of what makes a sentence hard to
      interpret.

PMID- 15031440
TI  - Name those quantities.

PMID- 15031439
TI  - Biochemistry. Oily barbarians breach ion channel gates.

PMID- 15031441
TI  - Biokinetic models for the behaviour of carbon-14 from labelled compounds in the
      human body: can a single generic model be justified?
AB  - The published data on the biokinetic behaviour of 27 14C-labelled compounds in
      humans or animals have been reviewed. Effective doses have been calculated for
      those compounds for which this information had not been published and doses have
      been compared to that calculated with the International Commission on
      Radiological Protection (ICRP) default model for carbon compounds of unknown
      composition. The compound-specific effective doses for a few natural human
      biochemical substrates are quite close to the ICRP default dose coefficient, but
      for the remainder of the compounds considered the doses are smaller by factors
      ranging from about 5 to 200. Comparison of the dosimetric data suggests that
      although the ICRP default model will overestimate the dose for very many
      compounds it could remain useful as a guide for general prospective radiological
      protection purposes. However, a comparison of the biokinetic information
      indicates that the ICRP default model would not be reliable for the
      interpretation of bioassay data.

PMID- 15031442
TI  - A biokinetic model for carbon dioxide and bicarbonate.
AB  - A systemic biokinetic model is presented for radiocarbon taken into the body as
      carbon dioxide or bicarbonate. Parameter values describing retention and
      excretion of carbon during the first few weeks after administration are based on
      studies of the fate of radiocarbon in human subjects after injection of labelled
      bicarbonate or inhalation of carbon dioxide. Data on laboratory animals
      administered labelled bicarbonate, carbonate or carbon dioxide provide
      information on the tissue distribution and long-term retention of carbon. Model
      predictions of the time-dependent distribution and retention of carbon differ
      considerably from those of models recommended by the International Commission on
      Radiological Protection.

PMID- 15031443
TI  - The annual effective dose from natural sources of ionising radiation in Canada.
AB  - A review and analysis of published information combined with the results of
      recent gamma ray surveys were used to determine the annual effective dose to
      Canadians from natural sources of radiation. The dose due to external radiation
      was determined from ground gamma ray surveys carried out in the cities of
      Toronto, Ottawa, Montreal and Winnipeg and was calculated to be 219 microSv. A
      compilation of airborne gamma ray data from Canada and the United States shows
      that there are large variations in external radiation with the highest annual
      outdoor level of 1424 microSv being found in northern Canada. The annual
      effective inhalation dose of 926 microSv from 222Rn and 220Rn was calculated from
      approximately 14,000 measurements across Canada. This value includes a
      contribution of 128 microSv from 222Rn in the outdoor air together with 6 microSv
      from long-lived uranium and thorium series radionuclides in dust particles. Based
      on published information, the annual effective dose due to internal radioactivity
      is 306 microSv. A program developed by the Federal Aviation Administration was
      used to calculate a population-weighted annual effective dose from cosmic
      radiation of 318 microSv. The total population-weighted average annual effective
      dose to Canadians from all sources of natural background radiation was calculated
      to be 1769 microSv but varies significantly from city to city, largely due to
      differences in the inhalation dose from 222Rn.

PMID- 15031444
TI  - Assessing occupational and domestic ELF magnetic field exposure in the uk adult
      brain tumour study: results of a feasibility study.
AB  - The feasibility of measuring exposure to extremely low frequency magnetic fields
      (ELF MF) in the UK Adult Brain Tumour Study (UKABTS) was examined. During the
      study, 81 individuals and 30 companies were approached with 79 individuals and 25
      companies agreeing to participate. Exposure data were collected using EMDEX II
      dosemeters worn by the participants for 3-4 consecutive days. Data were collected
      over a total of 321 d, including non-occupational periods. The results showed
      occupational exposure to be the main determinant of overall exposure. Moderate to
      strong correlations were found between arithmetic mean exposure and all other
      metrics with the possible exception of maximum exposure. Significant differences
      in exposure were found between job categories with large variability in certain
      categories. Highest average exposures were found for security officers
      (arithmetic mean, AM: 0.78 micro T), secretaries (AM: 0.48 micro T) and dentists
      (AM: 0.42 micro T). Welding and working near high-voltage power lines were
      associated with elevated exposure. In summary, acceptably precise measures of ELF
      MF exposure are feasible at relatively moderate cost. The results were used to
      develop a protocol for data collection from subjects in the UKABTS.

PMID- 15031445
TI  - Estimation of doses to personnel and patients during endovascular brachytherapy
      applications.
AB  - In the last few years coronary endovascular brachytherapy using gamma- and beta
      emitting radionuclides has been established as a standard treatment procedure to
      prevent restenosis after percutaneous coronary interventions. Direct measurements
      and calculations were made to determine personnel doses and organ doses of
      patients due to gamma rays of 192Ir and beta rays of 90Sr/90Y and 32P sources. In
      general, our results show that the dose levels are low compared with the X-ray
      exposure from angiography. The dose rate from bremsstrahlung at 1 m distance from
      a device containing a 90Sr/90Y source of 2.3 GBq is 4 micro Sv h(-1). The skin
      dose from beta rays during source transfer into and from the patient was
      estimated with the directional dose equivalent H'(0.07) of 10 micro Sv at 1 m
      distance from the catheter. By maintaining safe distances, the dose levels can be
      kept well within annual dose limits.

PMID- 15031446
TI  - Performance of three different unfolding procedures connected to Bonner sphere
      data.
AB  - This paper presents the results obtained in a comparison of three neutron
      spectrum unfolding procedures based on the SAND, MINCHI and UNFANA computer
      programs. The calculations were performed with data obtained previously from
      measurements using the PTB Bonner sphere spectrometer and taken from the
      literature; the neutron dosimetry was done with the Leake rem-meter. The
      evaluation of some spectrum hardness quantifiers is also reported. The codes give
      comparable neutron spectrum results. Relative to ambient dose equivalent derived
      from the Bonner sphere system, as a function of the unfolding code used, the
      Leake calculated readings were typically 1.16 to 1.91 and 1.58 to 2.69 times
      larger for the environment of a transport cask with spent fuel elements (Clab)
      and inside the containment building of a pressurised water reactor (Ring-G),
      respectively, depending on the calibration fields.

PMID- 15031447
TI  - Neutron measurements in the vicinity of a self-shielded PET cyclotron.
AB  - The radionuclides used in positron emission tomography (PET) are short-lived and
      generally must be produced on site using a cyclotron. A common end product of the
      nuclear reactions used to produce the PET radionuclides is neutron radiation.
      These neutrons could potentially contribute to the annual effective dose received
      by hospital personnel. A Bonner sphere spectrometer was used to measure neutron
      energy spectra at three locations near a self-shielded PET cyclotron. This
      cyclotron accelerates protons to 11 MeV. The neutron measurements reported were
      made during the production of 18F via the 18O(p,n)18F reaction (Q = -2.4 MeV).
      Neutron spectra were obtained with the BUMS unfolding code and converted to dose
      equivalent rates.

PMID- 15031448
TI  - Increasing film-focus distance (FFD) reduces radiation dose for x-ray
      examinations.
AB  - Increasing film-focus distance (FFD) from the traditional 100 cm has been shown
      to be an effective method of reducing dose whilst maintaining image quality. In
      particular, previous work increasing the FFD from 100 to 130 cm for lumbar spine
      examinations demonstrated an effective dose reduction of 44%. Objective. The
      current study continues on from this work by investigating the dose-reducing
      efficacy of this FFD change for pelvis X-ray examinations. Materials and methods.
      Dose measurements at 100 and 130 cm using thermoluminescent dosemeters were
      undertaken using an anthropomorphic phantom and patients. Image quality was
      assessed using CEC anatomical criteria and psychophysical tests. Results. The
      results showed that increasing the FFD results in a reduction in effective dose
      of 33%, with no change in image quality. The data provided in this and previous
      studies demonstrate the need for rapid implementation of this simple cost
      effective procedure across imaging departments, leading to an important reduction
      in collective dose. Conclusion. The CEC recommendation of using 115 cm FFD for a
      number of procedures, although useful compared with 100 cm, undervalues by a
      factor between 2 and 3 the potential of this dose-reducing tool.

PMID- 15031453
TI  - Tissue plasminogen activator -7351C/T enhancer polymorphism is a risk factor for
      lacunar stroke.
AB  - BACKGROUND AND PURPOSE: Occlusive thrombosis is an important component of small-
      and large-vessel ischemic stroke. Endogenous tissue plasminogen activator (TPA)
      is the primary mediator of intravascular fibrinolysis and is predominantly
      expressed by the endothelium of small vessels. The acute release of TPA is
      influenced by the TPA -7351C/T polymorphism and therefore may play an important
      role in the pathogenesis of lacunar stroke. In this study, we investigated the
      risk of lacunar and nonlacunar ischemic stroke associated with the TPA -7351C/T
      polymorphism. METHODS: We conducted a case-control study of 182 cases of ischemic
      stroke and 301 community controls. Participants were evaluated for known
      cerebrovascular risk factors, and the TPA -7351C/T genotype was established by a
      polymerase chain reaction (PCR) method. Logistic regression was used to determine
      the risk of lacunar and nonlacunar ischemic stroke associated with the TPA 
      7351C/T polymorphism. RESULTS: The prevalence of the TPA -7351 CC, CT, and TT
      genotypes were 46%, 45%, and 9% for controls and 41%, 46%, and 13% for stroke
      patients, respectively. After adjustment for known cerebrovascular risk factors,
      the TT genotype was significantly associated with ischemic stroke (OR: 1.9; 95%
      CI: 1.01 to 3.6). Stratification for stroke subtype showed a significant
      association between the TT genotype and lacunar stroke but not nonlacunar stroke
      (OR: 2.7; 95% CI: 1.1 to 6.7). CONCLUSIONS: The TPA -7351C/T polymorphism is an
      independent risk factor for lacunar stroke. The findings suggest that impaired
      fibrinolysis may play a role in the pathogenesis of lacunar stroke.

PMID- 15031454
TI  - Ultrasound perfusion imaging in acute middle cerebral artery infarction predicts
      outcome.
AB  - BACKGROUND AND PURPOSE: Initial reports indicate that transcranial harmonic
      imaging after ultrasound contrast agent bolus injection (BHI) can detect cerebral
      perfusion deficits in acute ischemic stroke. We evaluated parametric images of
      the bolus washout kinetics. METHODS: Twenty-three patients with acute internal
      carotid artery infarction were investigated with perfusion harmonic imaging after
      SonoVue bolus injection < or =40 hour after the onset of symptoms. The findings
      were compared with those of cranial computed tomography (CCT) and clinical course
      4 months after stroke. RESULTS: Images of pixel-wise peak intensity (PPI) and
      time to peak intensity could be calculated for all patients. Spearman rank
      correlations of r=0.772 (P<0.001) and r=0.572 (P=0.008) between area of PPI
      signal decrease and area of infarction in the follow-up CCT as well as outcome
      after 4 months were obtained, respectively. CONCLUSIONS: In the early phase of
      acute ischemic stroke, BHI after SonoVue bolus injection is a useful ultrasound
      tool for analyzing cerebral perfusion deficits at the patient's bedside. BHI data
      correlate with the definite area of infarction and outcome after 4 months.

PMID- 15031455
TI  - Sample size calculations in acute stroke trials: a systematic review of their
      reporting, characteristics, and relationship with outcome.
AB  - BACKGROUND AND PURPOSE: Only a few randomized controlled trials in acute stroke
      have shown a treatment-related benefit. Inadequate trial design, especially low
      sample size, may partly explain this failure. We investigated sample size
      calculations (SSCs) in a systematic review of acute stroke trials. METHODS: Full
      reports of nonconfounded randomized controlled trials that recruited patients
      within 1 week of stroke onset and were published before the end of 2001 were
      identified from the Cochrane Library and other bibliographic databases.
      Information on the SSC and outcome event rates was collected for each trial.
      RESULTS: Of 189 identified trial reports, 57 (30%) reported > or =1 components of
      the SSC, phase II 14/129 (11%) versus phase III 43/60 (72%) (P<0.001), with 32
      (56%) giving all the required parameters. Significance (alpha) was mentioned in
      54 (96%) reports; 53 used a significance level of alpha=0.05. And 55 (98%)
      reports gave the power (1-beta) of the study (median [25th and 75th percentile]
      0.80 [0.80, 0.90]). The anticipated percentage of control subjects having a
      primary outcome event was given in 24 (42%) articles: case fatality 21.8% (11.8%,
      23.5%, n=4) and combined death or disability/dependency 55.5% (44.5%, 66.3%,
      n=20); 25 studies used other outcomes and 8 studies gave insufficient
      information. Four of the 22 trials achieved a control rate within 5% of their
      prediction. 49 (86%) reports gave the anticipated treatment effect; case
      fatality: anticipated 9.5% (1.1%, 12.5%, n=6), achieved -0.3% (-4.1%, +2.4%);
      combined death or disability/dependency: anticipated 13.0% (10.0%, 16.0%, n=25),
      achieved 1.8% (-0.5%, +5.4%). The median calculated sample size was 600 (198,
      995, n=54). CONCLUSIONS: Too few trial publications report the assumptions
      underlying their SSC. Most trials were underpowered, ie, power <0.90, used
      inappropriate assumptions for event rates, and were grossly overoptimistic in
      their expectation of treatment effect. These deficiencies will together have
      resulted in trials being far too small and reduced their chance of being able to
      detect real treatment effects.

PMID- 15031456
TI  - Prolonged opportunity for ischemic neuroprotection with selective kappa-opioid
      receptor agonist in rats.
AB  - BACKGROUND AND PURPOSE: We have previously demonstrated that pretreatment with
      selective kappa-opioid agonist BRL 52537 hydrochloride [(+/-)-1-(3,4
      dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine], provides ischemic
      neuroprotection following transient focal ischemia in rats. The present study was
      undertaken to a) define "therapeutic opportunity" for ischemic neuroprotection
      with BRL 52537, and b) determine if BRL 52537 attenuates ischemia-evoked efflux
      of dopamine and its metabolites in the striatum in vivo following transient focal
      ischemia. METHODS: Using the intraluminal filament technique, halothane
      anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery
      occlusion (MCAO). In a blinded, randomized fashion, rats were treated with saline
      (vehicle) or 1 mg/Kg/hr BRL 52537 infusion for 22 hours, initiated at onset, 2,
      4, or 6 hours of reperfusion (Rep). In a separate set of experiments utilizing in
      vivo microdialysis, extracellular levels of dopamine and its metabolites were
      determined in the striatum during 2 hours of MCAO and 3 hours of reperfusion.
      RESULTS: Infarct volume (% of contralateral structure; mean +/-SEM) in cortex was
      significantly attenuated when BRL 52537 was administered at reperfusion (22+/
      6%), 2 hours (21+/-6%), and 4 hours (18+/-5%) compared with controls (39+/-5%).
      In striatum, infarct volume was significantly attenuated when BRL 52537 was
      administered at reperfusion (38+/-9%), 2 hours (40+/-8%), 4 hours (50+/-8%), and
      6 hours (46+/-9%) as compared with controls (70+/-4%). A 6- to 8-fold increase in
      dopamine in microdialysates occurred within 40 minutes of MCAO. Pretreatment with
      BRL 52537 did not alter microdialysate levels of dopamine or its metabolites in
      the striatum during MCAO and early reperfusion, as compared with saline controls.
      CONCLUSIONS: These data demonstrate that BRL 52537 provides robust ischemic
      neurprotection with a long therapeutic opportunity (at least 6 hours) without
      altering ischemia-evoked efflux of dopamine (DA) and its metabolites in striatum
      during ischemia and early reperfusion.

PMID- 15031458
TI  - In vivo regional neurochemistry in stroke: clinical applications, limitations,
      and future directions.

PMID- 15031457
TI  - Trial application of a Model of Resource Utilization, Costs, and Outcomes for
      Stroke (MORUCOS) to assist priority setting in stroke.
AB  - BACKGROUND AND PURPOSE: Cost-effectiveness data for stroke interventions are
      limited, and comparisons between studies are confounded by methodological
      inconsistencies. The aim of this study was to trial the use of the intervention
      module of the economic model, a Model of Resource Utilization, Costs, and
      Outcomes for Stroke (MORUCOS) to facilitate evaluation and ranking of the
      options. METHODS: The approach involves using an economic model together with
      added secondary considerations. A consistent approach was taken using standard
      economic evaluation methods. Data from the North East Melbourne Stroke Incidence
      Study (NEMESIS) were used to model "current practice" (base case), against which
      2 interventions were compared. A 2-stage process was used to measure benefit:
      health gains (expressed in disability-adjusted life years [DALYs]) and filter
      analysis. Incremental cost-effectiveness ratios (ICERs) were calculated, and
      probabilistic uncertainty analysis was undertaken. RESULTS: Aspirin, a low-cost
      intervention applicable to a large number of stroke patients (9153 first-ever
      cases), resulted in modest health benefits (946 DALYs saved) and a mean ICER
      (based on incidence costs) of US 1421 dollars per DALY saved. Although the health
      gains from recombinant tissue-type plasminogen activator (rtPA) were less (155
      DALYs saved), these results were impressive given the small number of persons
      (256) eligible for treatment. rtPA dominates current practice because it is more
      effective and cost-saving. CONCLUSIONS: If used to assess interventions across
      the stroke care continuum, MORUCOS offers enormous capacity to support decision
      making in the prioritising of stroke services.

PMID- 15031460
TI  - Symptomatic and asymptomatic retinal embolism have different mechanisms.
AB  - PURPOSE: To investigate differences between symptomatic and asymptomatic retinal
      embolism regarding the frequency and source of cerebral microemboli. METHODS:
      Thirty-seven patients with transient monocular blindness or retinal infarction
      and 27 patients (29 eyes) with asymptomatic retinal embolism were prospectively
      enrolled. Patients underwent a transcranial Doppler study and noninvasive imaging
      of the cervical internal carotid arteries (ICA). The middle cerebral artery (MCA)
      ipsilateral to the affected eye was monitored for 30 minutes for microembolic
      signals (MES), which were saved and analyzed offline. Age-matched controls (n=15)
      had no history of retinal or brain ischemia, <50% ICA stenosis, and normal
      ophthalmologic examinations. RESULTS: MES were detected in 0/15 (0%) controls,
      11/37 (30%) MCAs in the symptomatic group (P=0.02), and 3/29 (10%) MCAs in the
      asymptomatic group (P=0.54). Nine of 11 (82%) symptomatic eyes with MES had
      ipsilateral ICA stenosis of > or =50%, as compared with 0/3 (0%) eyes in the
      asymptomatic group with MES (P=0.03). Both MES and ICA stenosis of >50% were
      present in 9/37 (24%) cases in the symptomatic and in 0/29 (0%) cases of the
      asymptomatic group (P=0.0036). CONCLUSIONS: The frequency and potential source of
      cerebral microemboli in symptomatic and asymptomatic retinal embolism are
      different. Cerebral microemboli are more frequent in symptomatic patients and are
      associated with ICA stenosis.

PMID- 15031461
TI  - Drug discovery.

PMID- 15031462
TI  - U.S. trade policy. Editing ban to be eased, but Cuban travel blocked.

PMID- 15031464
TI  - Planetary science. Far-out ice world.

PMID- 15031463
TI  - Texas bioterror case. Butler gets 2 years for mishandling plague samples.

PMID- 15031465
TI  - Astronomy. Academy, GAO to study possible robotic Hubble mission.

PMID- 15031466
TI  - Japan. Older scientists win majority of funding.

PMID- 15031467
TI  - Particle physics. Gamma rays spotlight a dark horse for dark matter.

PMID- 15031468
TI  - Ecology. Naturalists' surveys show that British butterflies are going, going.

PMID- 15031469
TI  - Conflict of interest. Varmus backs some limits on NIH's consulting policy.

PMID- 15031471
TI  - Astronomy. Surveys scour the cosmic deep.

PMID- 15031470
TI  - French protests. Government dangles fresh carrots to dispirited scientific
      community.

PMID- 15031472
TI  - Ecology. A bid to save the 'Galapagos of the Indian Ocean'.

PMID- 15031473
TI  - Genomic medicine. Gene expression tests foretell breast cancer's future.

PMID- 15031474
TI  - Intellectual property. NIH roils academe with advice on licensing DNA patents.

PMID- 15031475
TI  - Intellectual property. Most academics eschewing patents?

PMID- 15031476
TI  - Scientific lives. Reflected glory: life with a Nobelist parent.

PMID- 15031477
TI  - The difficulties of defining the term "GM".

PMID- 15031478
TI  - "Physics first" and high school teachers.

PMID- 15031479
TI  - Research on contraceptives.

PMID- 15031480
TI  - Comment on "Contributions of anthropogenic and natural forcing to recent
      tropopause height changes".

PMID- 15031483
TI  - Evolution. Parallel evolution is in the genes.

PMID- 15031482
TI  - Science and government. An international framework to promote access to data.

PMID- 15031484
TI  - Climate. Society and sea level rise.

PMID- 15031485
TI  - Biochemistry. Water photolysis in biology.

PMID- 15031486
TI  - Computers and mathematics. Quantum channel capacities.

PMID- 15031488
TI  - Geophysics. Rupture in the laboratory.

PMID- 15031487
TI  - Virology. 1918 and all that.

PMID- 15031490
TI  - Surviving the blockbuster syndrome.

PMID- 15031491
TI  - Orphan drugs of the future?

PMID- 15031492
TI  - Protein kinase inhibitors: insights into drug design from structure.
AB  - Protein kinases are targets for treatment of a number of diseases. This review
      focuses on kinase inhibitors that are in the clinic or in clinical trials and for
      which structural information is available. Structures have informed drug design
      and have illuminated the mechanism of inhibition. We review progress with the
      receptor tyrosine kinases (growth factor receptors EGFR, VEGFR, and FGFR) and
      nonreceptor tyrosine kinases (Bcr-Abl), where advances have been made with cancer
      therapeutic agents such as Herceptin and Gleevec. Among the serine-threonine
      kinases, p38, Rho-kinase, cyclin-dependent kinases, and Chk1 have been targeted
      with productive results for inflammation and cancer. Structures have provided
      insights into targeting the inactive or active form of the kinase, for targeting
      the global constellation of residues at the ATP site or less conserved additional
      pockets or single residues, and into targeting noncatalytic domains.

PMID- 15031493
TI  - Polyketide and nonribosomal peptide antibiotics: modularity and versatility.
AB  - Polyketide (PK) and nonribosomal peptides (NRP), constructed on multimodular
      enzymatic assembly lines, often attain the conformations that establish
      biological activity by cyclization constraints introduced by tailoring enzymes.
      The dedicated tailoring enzymes are encoded by genes clustered with the assembly
      line genes for coordinated regulation. NRP heterocyclizations to thiazoles and
      oxazoles can occur on the elongating framework of acyl-S enzyme intermediates,
      whereas tandem cyclic PK polyether formation of furans and pyrans can be
      initiated by post-assembly line epoxidases. Macrocyclizations of NRP, PK, and
      hybrid NRP-PK scaffolds occur in assembly line chain termination steps. Post
      assembly line cascades of enzymatic oxidations also create cross-linked and
      cyclized architectures that generate the mature scaffolds of natural product
      antibiotics. The modularity of the natural product assembly lines and
      permissivity of tailoring enzymes offer prospects for reprogramming to create
      novel antibiotics with optimized properties.

PMID- 15031494
TI  - Organic chemistry in drug discovery.
AB  - The role played by organic chemistry in the pharmaceutical industry continues to
      be one of the main drivers in the drug discovery process. However, the precise
      nature of that role is undergoing a visible change, not only because of the new
      synthetic methods and technologies now available to the synthetic and medicinal
      chemist, but also in several key areas, particularly in drug metabolism and
      chemical toxicology, as chemists deal with the ever more rapid turnaround of
      testing data that influences their day-to-day decisions.

PMID- 15031495
TI  - The many roles of computation in drug discovery.
AB  - An overview is given on the diverse uses of computational chemistry in drug
      discovery. Particular emphasis is placed on virtual screening, de novo design,
      evaluation of drug-likeness, and advanced methods for determining protein-ligand
      binding.

PMID- 15031496
TI  - Drug delivery systems: entering the mainstream.
AB  - Drug delivery systems (DDS) such as lipid- or polymer-based nanoparticles can be
      designed to improve the pharmacological and therapeutic properties of drugs
      administered parenterally. Many of the early problems that hindered the clinical
      applications of particulate DDS have been overcome, with several DDS formulations
      of anticancer and antifungal drugs now approved for clinical use. Furthermore,
      there is considerable interest in exploiting the advantages of DDS for in vivo
      delivery of new drugs derived from proteomics or genomics research and for their
      use in ligand-targeted therapeutics.

PMID- 15031497
TI  - Inhibition of hepatitis B virus replication by APOBEC3G.

PMID- 15031498
TI  - Optical frequency synthesis and comparison with uncertainty at the 10(-19) level.
AB  - A femtosecond laser-based optical frequency synthesizer is referenced to an
      optical standard, and we use it to demonstrate the generation and control of the
      frequency of electromagnetic fields over 100 terahertz of bandwidth with
      fractional uncertainties approaching 1 part in 10(19). The reproducibility of
      this performance is verified by comparison of different types of femtosecond
      laser-based frequency synthesizers from three laboratories.

PMID- 15031499
TI  - A molecular elevator.
AB  - We report the incrementally staged design, synthesis, characterization, and
      operation of a molecular machine that behaves like a nanoscale elevator. The
      operation of this device, which is made of a platformlike component interlocked
      with a trifurcated riglike component and is only 3.5 nanometers by 2.5 nanometers
      in size, relies on the integration of several structural and functional molecular
      subunits. This molecular elevator is considerably more complex and better
      organized than previously reported artificial molecular machines. It exhibits a
      clear-cut on-off reversible behavior, and it could develop forces up to around
      200 piconewtons.

PMID- 15031500
TI  - Electrical or photocontrol of the rotary motion of a metallacarborane.
AB  - Rotary motion around a molecular axis has been controlled by simple electron
      transfer processes and by photoexcitation. The basis of the motion is
      intramolecular rotation of a carborane cage ligand (7,8-dicarbollide) around a
      nickel axle. The Ni(III) metallacarborane structure is a transoid sandwich with
      two pairs of carbon vertices reflected through a center of symmetry, but that of
      the Ni(IV) species is cisoid. The interconversion of the two provides the basis
      for controlled, rotational, oscillatory motion. The energies of the Ni(III) and
      Ni(IV) species are calculated as a function of the rotation angle.

PMID- 15031501
TI  - Directional dynamics in the photodissociation of oriented molecules.
AB  - We observed directional dynamics in the photodissociation of an oriented
      molecule. When a laser dissociated hexapole-oriented carbonyl sulfide molecules,
      the three-dimensional recoil of carbon monoxide fragments, which we measured with
      ion imaging, was strongly asymmetric. We obtained a microscopic view of molecular
      bond breaking that revealed both the sign and the magnitude of the deflection
      angle of the fragment in the molecular frame. This experimental approach can be
      applied to study and control the three-dimensional dynamics of photoinitiated
      reactions of fixed molecules or molecules oriented by emerging techniques.

PMID- 15031502
TI  - On the cause of the 1930s Dust Bowl.
AB  - During the 1930s, the United States experienced one of the most devastating
      droughts of the past century. The drought affected almost two-thirds of the
      country and parts of Mexico and Canada and was infamous for the numerous dust
      storms that occurred in the southern Great Plains. In this study, we present
      model results that indicate that the drought was caused by anomalous tropical sea
      surface temperatures during that decade and that interactions between the
      atmosphere and the land surface increased its severity. We also contrast the
      1930s drought with other North American droughts of the 20th century.

PMID- 15031503
TI  - Laboratory earthquakes: the sub-Rayleigh-to-supershear rupture transition.
AB  - We report on the experimental observation of spontaneously nucleated supershear
      rupture and on the visualization of sub-Rayleigh-to-supershear rupture
      transitions in frictionally held interfaces. The laboratory experiments mimic
      natural earthquakes. The results suggest that under certain conditions supershear
      rupture propagation can be facilitated during large earthquake events.

PMID- 15031504
TI  - Stathmin-tubulin interaction gradients in motile and mitotic cells.
AB  - The spatial organization of the microtubule cytoskeleton is thought to be
      directed by steady-state activity gradients of diffusible regulatory molecules.
      We visualized such intracellular gradients by monitoring the interaction between
      tubulin and a regulator of microtubule dynamics, stathmin, using a fluorescence
      resonance energy transfer (FRET) biosensor. These gradients were observed both
      during interphase in motile membrane protrusions and during mitosis around
      chromosomes, which suggests that a similar mechanism may contribute to the
      creation of polarized microtubule structures. These interaction patterns are
      likely to reflect phosphorylation of stathmin in these areas.

PMID- 15031505
TI  - Conserved genetic basis of a quantitative plumage trait involved in mate choice.
AB  - A key question in evolutionary genetics is whether shared genetic mechanisms
      underlie the independent evolution of similar phenotypes across phylogenetically
      divergent lineages. Here we show that in two classic examples of melanic plumage
      polymorphisms in birds, lesser snow geese (Anser c. caerulescens) and arctic
      skuas (Stercorarius parasiticus), melanism is perfectly associated with variation
      in the melanocortin-1 receptor (MC1R) gene. In both species, the degree of
      melanism correlates with the number of copies of variant MC1R alleles.
      Phylogenetic reconstructions of variant MC1R alleles in geese and skuas show that
      melanism is a derived trait that evolved in the Pleistocene.

PMID- 15031506
TI  - Genetic basis of natural variation in D. melanogaster antibacterial immunity.
AB  - Many genes involved in Drosophila melanogaster innate immune processes have been
      identified, but whether naturally occurring polymorphism in these genes leads to
      variation in immune competence among wild flies has not been tested. We report
      here substantial variability among wild-derived D. melanogaster in the ability to
      suppress infection by a Gram-negative entomopathogen, Serratia marcescens.
      Variability in immune competence was significantly associated with nucleotide
      polymorphism in 16 innate immunity genes, corresponding primarily to pathogen
      recognition and intracellular signaling loci, and substantial epistasis was
      detected between intracellular signaling and antimicrobial peptide genes.
      Variation in these genes, therefore, seems to drive variability in
      immunocompetence among wild Drosophila.

PMID- 15031507
TI  - Impact of nitrogen deposition on the species richness of grasslands.
AB  - A transect of 68 acid grasslands across Great Britain, covering the lower range
      of ambient annual nitrogen deposition in the industrialized world (5 to 35 kg Nha
      1 year-1), indicates that long-term, chronic nitrogen deposition has
      significantly reduced plant species richness. Species richness declines as a
      linear function of the rate of inorganic nitrogen deposition, with a reduction of
      one species per 4-m2 quadrat for every 2.5 kg Nha-1 year-1 of chronic nitrogen
      deposition. Species adapted to infertile conditions are systematically reduced at
      high nitrogen deposition. At the mean chronic nitrogen deposition rate of central
      Europe (17 kg Nha-1 year-1), there is a 23% species reduction compared with
      grasslands receiving the lowest levels of nitrogen deposition.

PMID- 15031508
TI  - Comparative losses of British butterflies, birds, and plants and the global
      extinction crisis.
AB  - There is growing concern about increased population, regional, and global
      extinctions of species. A key question is whether extinction rates for one group
      of organisms are representative of other taxa. We present a comparison at the
      national scale of population and regional extinctions of birds, butterflies, and
      vascular plants from Britain in recent decades. Butterflies experienced the
      greatest net losses, disappearing on average from 13% of their previously
      occupied 10-kilometer squares. If insects elsewhere in the world are similarly
      sensitive, the known global extinction rates of vertebrate and plant species have
      an unrecorded parallel among the invertebrates, strengthening the hypothesis that
      the natural world is experiencing the sixth major extinction event in its
      history.

PMID- 15031509
TI  - Epidemiology of malaria in a hypoendemic Brazilian Amazon migrant population: a
      cohort study.
AB  - The present study describes aspects of the epidemiology of malaria in a migrant
      population living in a hypoendemic area in Brazil using an open cohort study
      design. Rural settlement residents in Leonislandia, Peixoto de Azevedo, Mato
      Grosso, Brazil were followed from September 1996 to April 1997. At baseline, an
      interview and malaria diagnoses were carried out and spleen size was measured.
      Incident cases were detected through follow-up visits and laboratory records. Cox
      regression was used to assess risk factors for time to malaria onset. Eighty
      percent (n = 414) of the study population (n = 521) contributed follow-up data.
      Overall, malaria prevalence during any study visit ranged from 0.3% to 5.4% and
      the malaria incidence rate (IR) was 4.49 (95% confidence interval = 3.66, 5.46)
      per 100 person-months. The IR of Plasmodium vivax malaria was approximately four
      times higher than the IR for P. falciparum malaria during follow-up. Among
      individuals who had had malaria during his or her lifetime, 14.03% reported
      hospitalization (median duration = 3 days) and 70.1% reported days of work lost
      (median duration = 4 days for P. falciparum malaria and 3 days for P. vivax
      malaria) related to the last malaria episode. No important risk factor was
      associated with the malaria IR. The fact that neither work-related factors nor
      age was associated with the risk of malaria indicates that indoor/peri
      domiciliary transmission by the local vector is more important or as important as
      workplace-related transmission.

PMID- 15031510
TI  - Molecular epidemiology of malaria in Cameroon. XVIII. Polymorphisms of the
      Plasmodium falciparum merozoite surface antigen-2 gene in isolates from
      symptomatic patients.
AB  - Merozoite surface antigen-2 (MSA-2) is a polymorphic genetic marker that is
      highly discriminatory for characterizing Plasmodium falciparum field isolates.
      Genetic diversity of isolates obtained from symptomatic patients residing in
      Yaounde, Cameroon was analyzed by an allele-specific polymerase chain reaction
      and direct sequencing of amplification products. Of 137 isolates, 25 (18%) had
      only FC27-type alleles, 40 (29%) had only 3D7-type alleles, and 72 (53%) had
      multiple parasite populations with both alleles. Of 295 fragments, 145 (49.2%)
      and 150 (50.8%) belonged to FC27 and 3D7 alleles, respectively. There were 23
      different MSA-2 alleles (10 FC27-type and 13 3D7-type that yielded 44 different
      combinations in multiple infections). DNA sequencing showed distinct individual
      sequences. Sequences belonging to the FC27 allelic family were relatively
      conserved, with most of the polymorphism arising from differences in the number
      of repeat units. In contrast, the sequences within the GSA-rich region in 3D7
      allelic family were less conserved, but many of the sequences in Cameroonian
      isolates have been identified in other isolates from geographically distant
      origins. Our results show an extensive diversity of the central region of MSA-2
      in size, allelic family, combinations of these two features in multiple
      infections, and sequence variations underlying the complex population structure
      of P. falciparum clinical isolates in Yaounde, Cameroon.

PMID- 15031511
TI  - Molecular epidemiology of malaria in Cameroon. XIX. Quality of antimalarial drugs
      used for self-medication.
AB  - Substandard and counterfeit pharmaceutical products are increasingly circulating
      and distributed around the world, in particular in less developed countries.
      These low-quality or counterfeit products often involve drugs that are in high
      demand for the prevention and treatment of highly prevalent diseases, such as
      antimalarial drugs in endemic countries. Self-medication for presumed malarial
      infections with drugs purchased from unofficial drug vendors is a common practice
      in Africa. The aim of the study was to investigate the quality of chloroquine,
      quinine, and sulfadoxine-pyrimethamine obtained from illegitimate sector in urban
      and rural areas in Cameroon and analyze the impact of these drugs on patients. We
      collected 284 samples of three antimalarial drugs from 132 different sources in
      16 villages and cities throughout the country. We also collected antimalarial
      drugs that were used for self-medication by malaria-infected patients. Drug
      quality was assessed by a simple color reaction test and semi-quantitative thin
      layer chromatography. Fifty (38%) of 133 chloroquine, 52 (74%) of 70 quinine, and
      10 (12%) of 81 antifolates had either no active ingredient, an insufficient
      active ingredient, the wrong ingredient, or unknown ingredient(s). Self
      medication with antimalarial drugs purchased from unofficial vendors is not a
      reliable strategy to diminish morbidity and mortality. These counterfeit drugs
      contribute to the spread of drug-resistant malaria parasites and may lead to
      increasing therapeutic failure and medical expense.

PMID- 15031512
TI  - Molecular analysis of Plasmodium falciparum from drug treatment failure patients
      in Papua New Guinea.
AB  - A study was conducted in Papua New Guinea to analyze Plasmodium falciparum drug
      resistance polymorphisms in patients presenting with resistant malaria. One
      hundred ninety-nine P. falciparum-positive patients were recruited at two sites,
      Madang and Maprik. Exposure to the 4-aminoquinolines chloroquine and amodiaquine
      was uniformly high, at 84% overall. However, 59% of these were taken in various
      combinations of sulfadoxine/pyrimethamine and/or primaquine and/or quinine. Two
      markers for 4-aminoquinoline resistance, P. falciparum chloroquine resistance
      transporter 76T and P. falciparum multidrug resistance 1, were fixed in the
      population and two markers for pyrimethamine resistance, dihydrofolate reductase
      (dhps) 59R and 108N, were found at moderate to high levels, overall 60% and 75%,
      respectively. No polymorphisms in dhps associated with sulfadoxine resistance
      were present. Differences between the two sites are analyzed. The study period
      encompasses a change in standard malaria treatment policy. These findings stress
      the need for regular monitoring of the effects of standard drug treatment of
      uncomplicated malaria in Papua New Guinea.

PMID- 15031513
TI  - Widespread occurrence of the Plasmodium falciparum chloroquine resistance
      transporter (Pfcrt) gene haplotype SVMNT in P. falciparum malaria in India.
AB  - The Plasmodium falciparum chloroquine resistance transporter (Pfcrt) K76T
      mutation and haplotype (amino acids 72-76) and the P. falciparum multidrug
      resistance 1 (Pfmdr1) mutation (N86Y) were analyzed as markers of chloroquine
      resistance in the DNAs of 73 blood samples from patients with P. falciparum
      malaria in India. Seventy of the 73 DNAs had the Pfcrt K76T mutation. Of these,
      66 had the SVMNT haplotype and four had CVIET, the African/Southeast Asian
      haplotype. Only 20 of 69 DNAs had the Pfmdr1 N86Y mutation. It is surprising that
      the Pfcrt haplotype in India is predominantly SVMNT, rather than that seen in
      Southeast Asia. The widespread prevalence of the Pfcrt K76T mutation is a cause
      for concern.

PMID- 15031514
TI  - Restriction fragment length polymorphism method for the identification of major
      African and Asian malaria vectors within the Anopheles funestus and An. minimus
      groups.
AB  - The African Anopheles funestus and the Asian An. minimus groups are closely
      related and are probably considered distinct only because of their geographic
      separation. This study aimed at improving two identification methods based on
      polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)
      already developed for either group. Each PCR-RFLP, either on the internal
      transcribed spacer 2 (ITS2) for the An. minimus group, and domain 3 (D3) for the
      An. funestus group, was applied to the other group for the standardization of one
      identification method applicable on both continents. The ITS2 fragment digested
      by Bsi ZI showed the highest diagnostic power. This assay allowed the
      discrimination of at least 13 Anopheles species within the subgenus Cellia from
      two continents (Africa and Asia), among which are five major malaria vectors.
      Moreover, digestion of the D(3) with Msp I showed intragenomic variations within
      An. funestus populations. Two types of D3 copies (M and W) occurred in specimens
      from southern Africa. The populations from West-Central Africa presented only
      type W and East-Malagasy populations exhibited type M. Since An. funestus shows a
      great capacity of adaptation, these molecular variations, along with behavioral
      and ecologic ones, reinforce the hypothesis of a species complex that will need
      to be further investigated.

PMID- 15031515
TI  - Community- and individual-level determinants of Wuchereria bancrofti infection in
      Leogane Commune, Haiti.
AB  - We conducted a school-based assessment of the geographic distribution of
      Wuchereria bancrofti infection in Leogane Commune, Haiti, using the
      immunochromatographic test. In multivariate analyses performed using generalized
      linear mixed models, children attending schools in the foothills and plains were
      3.95 (95% confidence interval [CI] = 1.28-12.23) and 23.56 (95% CI = 8.99-61.79)
      times as likely to be infected, respectively, as children attending mountain
      schools. Infection prevalence decreased with increasing altitude, but some local
      foci of infection were detected at higher altitudes. Higher school tuition, a
      marker of socioeconomic status (SES), was not associated with decreased infection
      prevalence. Our results indicate that although the force of infection in Leogane
      Commune is greatest below 70 meters above sea level, higher altitude communities
      are not exempt from infection. Lymphatic filariasis (LF) elimination programs
      should consider extending infection mapping activities to presumed non-LF
      altitudes. In addition, higher SES does not confer protection against W.
      bancrofti infection.

PMID- 15031516
TI  - Immunogenicity and safety of a varicella vaccine (Okavax) and a trivalent
      measles, mumps, and rubella vaccine (Trimovax) administered concomitantly in
      healthy Filipino children 12-24 months old.
AB  - The immunogenicity and safety of Okavax trade mark varicella vaccine, when
      administered concomitantly with Trimovax trade mark measles, mumps, and rubella
      (MMR) vaccine, were assessed in 300 Filipino children 12-24 months old. Three
      groups received Okavax only, Trimovax only, or both vaccines concomitantly. In
      sera obtained six weeks after vaccination, high varicella antibody geometric mean
      titers (GMTs) (115 and 79.8 mIU/mL, respectively) and seroconversion rates (>or=
      91.9%) were similar for Okavax given alone or concomitantly with Trimovax. High
      MMR GMTs and seroconversion rates (mumps >or= 94.6%, measles and rubella >or=
      98.6%) were not affected by concomitant administration of Trimovax with Okavax.
      Solicited local and systemic reactions recorded by parents were slightly more
      numerous after concomitant administration, but the majority of all reactions were
      mild and transient. The good tolerance and high immunogenicity observed supports
      the concomitant administration of Okavax and Trimovax to children in their second
      year of life to protect against four life-threatening diseases while simplifying
      childhood immunization programs.

PMID- 15031517
TI  - Negative effect of antibodies against maxadilan on the fitness of the sand fly
      vector of American visceral leishmaniasis.
AB  - Lutzomyia longipalpis expresses a salivary protein called maxadilan (MAX) that
      functions to dilate vertebrate blood vessels and thereby to facilitate the sand
      fly's acquisition of blood. We hypothesized that antibodies specific for one of
      many MAX variants would inhibit vasodilatory function of that variant. In vitro
      and in vivo experiments showed that antibodies against a specific MAX variant
      decreased vasodilatory function. More specifically, antibodies against MAX
      blocked vasodilation of a constricted rabbit aorta. Additionally, a strain of Lu.
      longipalpis, with a nearly uniform MAX genotype, obtained a larger blood meal
      from naive BALB/c mice compared with mice that were either immunized with a
      homologous MAX genotype or sensitized to bites of flies from the same strain.
      Those flies taking blood from mice sensitized by sand fly bites also laid
      significantly fewer eggs than when they took blood from naive mice. These results
      have potential epidemiologic importance in light of the potential use of MAX in a
      vaccine or as part of a diagnostic test because they imply that a uniform MAX
      genotype is selected against by the vertebrate host immune response and that
      antigenic diversity is selected for.

PMID- 15031518
TI  - Antigenic diversity in maxadilan, a salivary protein from the sand fly vector of
      American visceral leishmaniasis.
AB  - The salivary protein maxadilan (MAX) is a vasodilator and immunomodulator from
      the sand fly vector of the protozoan parasite Leishmania chagasi. Vaccinating
      BALB/c mice with sand fly salivary gland extracts or with MAX protects the host
      against L. major infection. Because of the potential use of MAX in an anti
      Leishmania vaccine, we characterized the vertebrate host IgG response to MAX in
      the present study. Our immunochemical analysis indicated that antibodies to MAX
      were detected in BALB/c mice, as well as in pigs and humans, from a area in
      Nicaragua endemic for Lutzomyia longipalpis. Previous studies demonstrate that
      the MAX protein is polymorphic on the amino acid level. Our findings suggested
      that naturally occurring MAX variants were recognized specifically by the host
      immune system and antigenicity appeared to be associated with amino-acid sequence
      variability. Thus, antigenic diversity of MAX and possibly of other arthropod
      salivary proteins may dictate the development of vector-based vaccines(s).

PMID- 15031519
TI  - A sensitive new microculture method for diagnosis of cutaneous leishmaniasis.
AB  - A sensitive microcapillary culture method (MCM) was developed for rapid diagnosis
      of cutaneous leishmaniasis (CL). The MCM is superior to the traditional culture
      method (TCM) as determined by the smaller inoculum size, the higher sensitivity
      for detection of promastigotes, and the more rapid time for emergence of
      promastigotes. With lesion amastigote loads from grade III to 0, the positive
      rates and the periods for promastigote emergence were 3-4-fold higher and faster
      with the MCM than with the TCM, e.g., 83-97% positive in 4-7 days versus 20-40%
      positive in 15-30 days (P = 0.0001). The higher Pco(2) and lower Po(2) and pH
      presumably encourage a rapid amastigote-to-promastigote differentiation and/or
      the survival or growth of the latter. This MCM has the advantage of simplicity,
      and may be suitable for diagnostic use and for parasite retrieval in many other
      endemic sites where parasites are known to be difficult to grow.

PMID- 15031520
TI  - Frequency of visceral leishmaniasis relapses in human immunodeficiency virus
      infected patients receiving highly active antiretroviral therapy.
AB  - There are contradictory data about whether highly active antiretroviral therapy
      (HAART) prevents visceral leishmaniasis (VL) relapses in human immunodeficiency
      virus type 1 (HIV-1)-infected patients. The aim of this study was to assess the
      frequency of VL relapses in individuals receiving HAART. Thirty-one patients who
      received HAART after developing VL were included in a retrospective cohort study.
      Ten of them received secondary chemoprophylaxis and the rest did not. Eight (38%)
      patients without secondary chemoprophylaxis showed a VL relapse. None of the
      seven subjects with VL relapses and 6 of 11 without recurrence (P = 0.038), in
      whom all scheduled data were available, showed an increase of more than 100 CD4+
      cells/mm(3) during the follow-up. Patients with relapse showed higher levels of
      HIV RNA viral load at their last visit (P = 0.047). The frequency of VL relapses
      in patients receiving HAART is high. Relapses of VL are observed only in
      individuals with uncontrolled HIV replication and/or poor immunologic responses.

PMID- 15031521
TI  - Prevalence of antibodies to hantavirus among family and health care worker
      contacts of persons with hantavirus cardiopulmonary syndrome: lack of evidence
      for nosocomial transmission of Andes virus to health care workers in Chile.
AB  - Nosocomial transmission of Andes virus has been documented in Argentina, but has
      not yet been proven in Chile. We studied 215 contacts (106 family member contacts
      and 109 health care worker contacts) of 20 index cases of hantavirus
      cardiopulmonary syndrome (HCPS) in Chile. The seroprevalence of IgG antibodies
      against Andes virus was 1.9% (95% confidence interval [CI] = 0.34-6.3%) among the
      family members and 0.0% (95% CI = 0-3.2%) among the health care workers. Our data
      suggest that there is no evidence for nosocomial transmission of Andes virus in
      region IX of Chile.

PMID- 15031522
TI  - Peridomestic small mammals associated with confirmed cases of human hantavirus
      disease in southcentral Chile.
AB  - Cases of human hantavirus disease have been reported in Chile since 1995, most of
      them in people living in rural and periurban areas. We conducted a peridomestic
      study of small mammals to evaluate the relationships between the presence of
      rodents with antibodies to Andes virus confirmed human cases of hantavirus
      pulmonary syndrome in southcentral Chile. The results of 20 sampled sites, which
      involved the capture of 272 mice over an 18-month period, showed the occurrence
      of 10 small mammal species, of which Oligoryzomys longicaudatus was the only
      seropositive species for hantavirus, with an intra-specific serologic rate of
      10.4%.

PMID- 15031523
TI  - Wounding: the primary mode of Seoul virus transmission among male Norway rats.
AB  - In rodent populations, males are more likely to be infected with hantaviruses and
      to engage in aggression than are females. To assess the relationship between
      aggression and Seoul virus infection, Norway rats were trapped in Baltimore,
      Maryland and wounding, infection status, and steroid hormone concentrations were
      examined. Older males and males with high-grade wounds were more likely to have
      IgG antibody to Seoul, to shed virus in saliva, urine, and feces, and to have
      viral RNA in organs than either juveniles or adult males with less severe wounds.
      In contrast, neither age nor wounding predicted virus shedding among females.
      Although viral antigen was not identified in the brain, viral protein was
      detected in the gonads and adrenal glands of adult males. Males with more severe
      wounds had higher testosterone concentrations than males with no or low-grade
      wounds. Because wounding, testosterone, and virus shedding are associated among
      males, aggression may be the primary mode of Seoul virus transmission among male,
      but not female, Norway rats.

PMID- 15031524
TI  - Development of a questionnaire assessing Buruli ulcer-induced functional
      limitation.
AB  - Buruli ulcer, a disease with long-term consequences, is emerging in west Africa.
      Thus, a functional limitation scoring system is needed to assess its nature and
      severity. A list of daily activities was developed for this disease. Following
      treatment of Buruli ulcer, persons in Benin (n = 47) and Ghana (n = 41) were
      investigated. Nineteen items were identified with good internal consistency.
      Participants (median age = 14 years) could not perform 23% of their daily
      activities. Twenty-nine participants did not have any functional limitation. The
      average limitation score was 31% in Benin and 15% in Ghana (P = 0.006). The mean
      limitation score in participants without visible contractures (n = 65) was 13%,
      whereas patients with visible contractures (n = 20) or an amputation (n = 3) had
      a score of more than 50%. Validity and reliability should be further analyzed to
      optimize the scale for use in individual evaluation, as an end point in
      intervention trials, and in planning of resources needed for the care of patients
      with functional limitations.

PMID- 15031525
TI  - Rapid diagnosis of typhoid fever by enzyme-linked immunosorbent assay detection
      of Salmonella serotype typhi antigens in urine.
AB  - We developed and evaluated an enzyme-linked immunosorbent assay (ELISA) using
      monoclonal antibodies to capture somatic antigen 9 (O9), flagellar antigen d
      (Hd), and the Vi capsular polysaccharide antigen (Vi) from the urine of persons
      with and without typhoid fever. Sequential urine samples were collected from 44
      patients with blood culture-confirmed typhoid fever and from two control groups.
      The first control group included patients with brucellosis (n = 12) and those
      with clinically diagnosed, non-typhoid, acute, febrile illness (n = 27). The
      second control group was a sample of healthy volunteer laboratory workers (n =
      11). When assessed relative to date of fever onset, sensitivity was highest
      during the first week for all three antigens: Vi was detected in the urine of
      nine (100%) patients, O9 in 4 (44%) patients, and Hd in 4 (44%) patients.
      Sequential testing of two urine samples from the same patient improved test
      sensitivity. Combined testing for Vi with O9 and Hd produced a trend towards
      increased sensitivity without compromising specificity. The specificity for Vi
      exceeded 90% when assessed among both febrile and healthy control subjects, but
      was only 25% when assessed among patients with brucellosis. Detection of urinary
      Vi antigen with this ELISA shows promise for the diagnosis of typhoid fever,
      particularly when used within the first week after fever onset. However, positive
      reactions for Vi antigen in patients with brucellosis must be understood before
      urinary Vi antigen detection can be developed further as a useful rapid
      diagnostic test.

PMID- 15031526
TI  - Human cystic echinococcosis: evaluation of post-treatment serologic follow-up by
      IgG subclass antibody detection.
AB  - Assessment of post-treatment disease activity among patients with cystic
      echinococcosis (CE) is insensitive using detection of CE-specific total IgG
      antibody. This study investigated whether serum concentrations of CE-specific IgG
      subclasses 1-4 correlate better with disease activity than total IgG. We studied
      a cohort of patients (n = 28) with symptomatic CE treated with anthelminthic
      drugs and surgery and who were followed up clinically and radiologically for a
      mean of 5.6 years (range = 3-12 years). Serial archived sera collected during
      follow-up were retrospectively analyzed by enzyme-linked immunosorbent assays
      using crude horse hydatid cyst fluid as antigen. Changes in concentrations of
      antibodies were correlated with clinical and radiologic outcome. At diagnosis,
      concentrations of CE-specific total IgG, IgG1, and IgG2 antibodies were
      significantly elevated in a greater proportion of patients compared with IgG3 and
      IgG4 antibodies. During post-treatment follow up, the IgG2 antibody response
      provided the best correlate of disease activity.

PMID- 15031527
TI  - Toll-like receptor 3: a link between toll-like receptor, interferon and viruses.
AB  - Production of type I interferon (IFN-alpha/beta) by virus-infected cells is the
      central event in their antiviral immune responses. In mammalian cells, IFN
      alpha/beta gene transcription is induced through distinct signaling pathways by
      viral infection or by treatment with double-stranded (ds) RNA, which is an
      intermediate of virus replication. Toll-like receptor 3 (TLR3) was found to
      recognize dsRNA and transmit signals to activate NF-kappaB and the IFN-beta
      promoter. Recent identification of the TLR3-adaptor protein and its downstream
      signaling molecules, which are involved in IFN-alpha/beta production, revealed a
      novel IFN-inducing pathway for an anti-viral immune response. Here, we summarize
      the current knowledge of TLR3-mediated immune responses.

PMID- 15031528
TI  - Molecular characterization of dextranase from Streptococcus rattus.
AB  - The complete nucleotide sequence of the dextranase gene of Streptococcus rattus
      ATCC19645 was determined. An open reading frame of the dextranase gene was 2,760
      bp long and encoded a dextranase protein consisting of 920 amino acids with a
      molecular weight of 100,163 Da and an isoelectric point of 4.67. The S. rattus
      dextranase purified from recombinant Escherichia coli cells showed dextran
      hydrolyzing activity with optimal pH (5.0) and temperature (40 C) similar to
      those of dextranases from Streptococcus mutans and Streptococcus sobrinus. The
      deduced amino acid sequence of the S. rattus dextranase revealed that the
      dextranase molecule consists of two variable regions and a conserved region. The
      variable regions contained an N-terminal signal peptide and a C-terminal cell
      wall sorting signal; the conserved region contained two functional domains,
      catalytic and dextran-binding sites. This structural feature of the S. rattus
      dextranase is quite similar to that of other cariogenic species such as S.
      mutans, S. sobrinus, and Streptococcus downei.

PMID- 15031529
TI  - Preparation of virosomes coated with the vesicular stomatitis virus glycoprotein
      as efficient gene transfer vehicles for animal cells.
AB  - The vesicular stomatitis virus (VSV) glycoprotein (G) was used to prepare
      virosomes as a model vehicle of gene transfer to animal cells, for which viral
      envelope functions (receptor recognition and binding and the pH-dependent
      membrane-fusion) were expected to work. Plasmid DNA (pEGFP-N1; Clontech) was
      first encapsulated into liposomes by a method of repeated freezing and thawing of
      the mixture of DNA and lipids (phosphatidylcholine, phosphatidylserine and
      cholesterol mixed at a molar ratio of 5: 1: 4). Then, particle size of the
      liposomes was stepwise reduced to 200 nm or less in diameter by successive
      filtrations through a series of plastic filters of various pore sizes (10 micro
      m, 2 micro m, 0.65 micro m, and then 0.45 micro m). Assembly of the VSV G protein
      coated liposomes (VSV G-virosomes) was performed by mixing the DNA-encapsulated
      liposome suspensions with the purified VSV G proteins at pH 5.5, followed by
      ultracentrifugation in a discontinuous sucrose gradient. The highest gene
      transducing activity was detected in a single band formed between 20% and 45%
      sucrose layers. Negatively stained electron microscopic images showed that the
      band contained spherical particles of various sizes, ranging from 40 to 140 nm in
      diameter, that were covered with viral spike projections. The VSV G-virosomes
      displayed a roughly similar level of gene-transducing activity to that mediated
      by cationic liposomes (e.g., Lipofectamine), which was blocked either by
      pretreatment with anti-VSV G antiserum or by addition of 20 m M NH(4) Cl to
      transfected cultures. From these results, we assume that the virosome-mediated
      gene-transduction was first achieved by using the whole functions of VSV G
      protein, and can also be used for further studies of the protein.

PMID- 15031530
TI  - WT1 peptide-based immunotherapy for patients with lung cancer: report of two
      cases.
AB  - The Wilms' tumor gene WT1 is overexpressed in various types of solid tumors,
      including lung and breast cancer and WT1 protein is a tumor antigen for these
      malignancies. In phase I clinical trials of WT1 peptide-based cancer
      immunotherapy, two patients with advanced lung cancer were intradermally injected
      with 0.3 mg of an HLA-A*2402-restricted, 9-mer WT1 peptide emulsified with
      Montanide ISA51 adjuvant. Consecutive WT1 vaccination at 2-week intervals
      resulted in a reduction in tumor markers such as chorio-embryonic antigen (CEA)
      and sialyl Lewis (x) (SLX) and by a transient decrease in tumor size. No adverse
      effects except for local erythema at the injection sites of WT1 vaccine were
      observed. These results provided us with the first clinical evidence
      demonstrating that WT1 peptide-based immunotherapy should be a promising
      treatment for patients with lung cancer.

PMID- 15031531
TI  - Evaluation of the effects of sulfamethoxazole on Toxoplasma gondii loads and
      stage conversion in IFN-gamma knockout mice using QC-PCR.
AB  - Toxoplasma gondii abundance with or without sulfamethoxazole treatment was
      evaluated by quantitative competitive polymerase chain reaction (QC-PCR) assay in
      various organs of IFN-gamma knockout BALB/c (B/c) mice after peroral infection
      with the cyst-forming Fukaya strain. T. gondii infection was observed in the
      brain, skin, tongue, heart, and skeletal muscle of the mice treated with
      sulfamethoxazole, although the parasite was not observed during the treatment in
      the mesenteric lymph node, spleen, small intestine or kidney. After discontinuing
      the therapy, T. gondii reappeared within five days in all organs. Reverse
      transcriptase (RT)-PCR showed that sulfamethoxazole treatment accelerated the
      stage conversion of T. gondii from tachyzoites into bradyzoites in the brain,
      lung, and heart. In contrast, after discontinuing sulfamethoxazole treatment, T.
      gondii underwent stage conversion from bradyzoites into tachyzoites in these
      organs. These results indicate that we successfully established an animal model
      for evaluating chemotherapy regimens in immunocompromised hosts infected with T.
      gondii.

PMID- 15031532
TI  - Human cytomegalovirus (HCMV) infection in osteosarcoma cell line suppresses GM
      CSF production by induction of TGF-beta.
AB  - This study was performed to elucidate the possible mechanism of the disturbance
      of hemopoiesis by HCMV infection. Saos-2 cells constitutively express mRNA of GM
      CSF, and its expression was profoundly decreased by HCMV infection, which
      required full replication of the virus and was mediated by soluble factors
      released from the HCMV-infected Saos-2 cells. TGF-beta1 production was
      statistically and significantly increased from one day after HCMV infection.
      Expression and production of GM-CSF in Saos-2 cells were restored when a culture
      supernatant of HCMV-infected Saos-2 cells was reacted with neutralizing anti-TGF
      beta antibody. Conclusively, HCMV inhibits GM-CSF expression in Saos-2 cells
      partly by the increased production of TGF-beta1.

PMID- 15031533
TI  - Immunomagnetic capture rt-PCR for detection of norovirus from foods implicated in
      a foodborne outbreak.
AB  - In February 2001, an outbreak of acute gastroenteritis due to Norovirus (NV)
      occurred among employees of 11 companies in Aichi Prefecture. The illness was
      strongly associated with eating a delivered box-lunch. The use of magnetic beads
      coated with the antibody to the baculovirus-expressed recombinant capsid proteins
      of the Chiba virus (rCV) facilitated capture of NV from the food items implicated
      in the outbreak. Following immunomagnetic capture, NV bound to the beads was
      detected by reverse transcriptionpolymerase chain reaction (RT-PCR). Of the nine
      food items tested, two were positive for a genogroup 1 NV. Sequence analysis of
      RT-PCR products indicated that the nucleotide sequences of NV strains from foods
      were almost identical to those of NV strains detected in stool samples of ill
      patients. As the immunocapture RTPCR method is simple and easy to perform, this
      technique should be useful for the detection of NV from outbreak-implicated
      foods.

PMID- 15031534
TI  - Human herpesvirus 6 immediate-early 2 protein interacts with heterogeneous
      ribonucleoprotein K and casein kinase 2.
AB  - Human herpesvirus 6 (HHV-6) immediate-early (IE) 2 protein (IE2) may play
      important but incompletely defined roles during infection. We used yeast two
      hybrid screening to detect proteins interacting with HHV-6 IE2, and found
      heterogeneous nuclear ribonucleoprotein K (hnRNP K) and the beta subunit of
      casein kinase 2 (CK2beta) specifically interacted with HHV-6 IE2. The
      interactions were confirmed by GST pull-down assay, coimmunoprecipitation, and
      colocalization studies. These findings indicate that the HHV-6 IE2 protein
      interacts with hnRNP K and CK2, and these interactions may affect viral and
      cellular RNA transcription and translation in viral replication.

PMID- 15031535
TI  - Phenotypic stability of mature dendritic cells tuned by TLR or CD40 to control
      the efficiency of cytotoxic T cell priming.
AB  - It is generally accepted that after stimulation immature DCs turn into mature
      DCs, which present exogenous antigens together with their MHC class I molecules
      and then activate the antigen-specific CTLs. Although both TLR and CD40
      stimulation appeared to provide the same effects on DC maturation, CD40-dependent
      CTL activation is much more potent than CTL activation through LPS stimulation.
      Despite their different outcomes, the factors that lead mature DCs to different
      functions remain largely undefined. In this study, we defined the transient
      maturation and subsequent deactivation of DCs by TLR stimuli, including those by
      LPS and CpG-ODN. In contrast, CD40 stimulation induced stable mature DCs that
      elicited sufficient CTL proliferation. The deactivated DCs, which we defined as
      "expired DCs," were phenotypically similar to immature DCs, except for their
      phenotype stability, MHC class I expression level and IL-10 production. Moreover,
      the functions of expired DCs were comparable to those of immature DCs in terms of
      CTL induction and tolerogenicity. These results may provide an explanation for
      the role of CD40 stimulation in antigen-specific CTL induction.

PMID- 15031536
TI  - Effect of capsaicin on cholecystokinin and neuropeptide Y expressions in the
      brain of high-fat diet fed rats.
AB  - Capsaicin, one of the pungent principles of hot pepper, has been reported to
      cause a cessation of increases in body weight and fat gain induced by high-fat
      feeding. Especially, in body weight and feeding control, cholecystokinin (CCK)
      has been well known as a satiety signal and neuropeptide Y (NPY) has been
      described as one of the most potent orexigenic signals. This study was carried
      out to investigate the effect of capsaicin on CCK- and NPY- immunoreactivities
      (IR) in the brain of high-fat fed rats. The animals were divided into normal-fat
      diet (NF), high-fat diet (HF) and high-fat diet containing capsaicin (HF-CAP)
      groups. Mean body weight gain (MBWG) of HF group was higher than that of NF
      group. However, in HF-CAP group, MBWG was lower than that of HF group. CCK-IR in
      suprachiasmatic nucleus (SCN), paraventricular nucleus (PVN), median eminence
      (ME), arcuate nucleus (ARC) and amygdala was not prominent in all the groups. In
      cerebral cortex, CCK-IR was more reduced in HF-CAP group than in the other
      groups. In the HF-CAP group, NPY-IR in the hypothalamic nuclei, amygdala and
      cerebral cortex was more poorly found than in the NF and HF groups. It is
      concluded that (1) NPY-IR may react more sensitively on capsaicin than CCK-IR,
      (2) no rapid increase of body weight in capsaicin treated rats may result from
      the diminished food intake through the low expression of NPY in hypothalamus in
      HF-CAP group.

PMID- 15031538
TI  - Changes in the localization of type I, III and IV collagen mRNAs in the kidneys
      of hereditary nephritic (ICGN) mice with renal fibrosis.
AB  - Renal fibrotic change, extreme accumulation of extracellular matrix (ECM)
      components in glomeruli and tubulointerstitum, is one of the characteristic
      features of ICR-derived glomerulonephritis (ICGN) mice. Decreased degradation of
      ECMs by matrixmetalloproteinases was demonstrated in kidneys of ICGN mice. To
      determine the balance between production and degradation of ECMs in kidneys of
      ICGN mice, we examined expression of mRNAs of ECMs in those. To demonstrate the
      localization of type I, III and IV collagen mRNAs in kidney sections of ICGN and
      control ICR mice, in situ hybridization using digoxigenin-labeled oligonucleotide
      antisense probes for procollagen-alpha(1) (I), -alpha(1) (III) and -alpha(1) (IV)
      mRNAs, respectively, was performed. Negative or trace expressions of type I and
      III collagen mRNAs were observed in the kidneys of control mice, but stronger
      expressions of those were seen in glomeruli and injured renal tubules of the
      kidneys of ICGN mice. Moderate expression of type IV collagen mRNA was
      demonstrated in a part of glomeruli and renal tubules of both control and ICGN
      mice, and no remarkable difference was seen between them. Severe renal fibrosis,
      extreme accumulation of interstitial type I and III collagens is caused by
      increased production and decreased degradation in the kidneys of ICGN mice. Thus,
      the profiles of metabolism between interstitial and membranous collagens may be
      different in the kidneys of ICGN mice, and excessive production of interstitial
      collagens may be the dominant cause of renal disease in them.

PMID- 15031539
TI  - Prevalence of porcine endogenous retrovirus in domestic pigs in Japan and its
      potential infection in dogs xenotransplanted with porcine pancreatic islet cells.
AB  - The prevalence of porcine endogenous retrovirus (PERV) proviral DNA among various
      pig breeds raised in Japan was investigated by polymerase chain reaction (PCR).
      Moreover, potential infection of PERV was investigated by PCR and reverse
      transcriptase-polymerase chain reaction (RT-PCR) in experimentally induced
      diabetic dogs (n=5) implanted with the diffusion chamber type bio-artificial
      endocrine pancreas (Bio-AEP) containing porcine pancreatic endocrine (PE) cells.
      No immunosuppressant was used after the transplantation. PERV gag, pol, env-A and
      env-B genes were detected in any pigs examined. In two of three Landrace breeds,
      env-C gene was absent. PERV proviral DNAs and viral RNAs were also detected from
      the cultured porcine PE-cells. In the peripheral blood mononuclear cells and the
      spleen obtained at 6, 30, 32, 36, 79 weeks of xenotransplantation in dogs,
      however, no evidence of microchimerism, infection and viremia were confirmed.
      These results suggested that the risk of PERV infection through
      xenotransplantation of Bio-AEP containing porcine islet cells without
      immunosuppressants may be quite low.

PMID- 15031537
TI  - A potential live vector, foamy virus, directed intra-cellular expression of ovine
      interferon-tau exhibited the resistance to HIV infection.
AB  - Interferon-tau (IFN-tau), produced by the embryonic trophectoderm, is a member of
      type I IFNs required for the establishment of pregnancy in the ruminant
      ungulates. Although this IFN possesses antiviral activity similar to other type I
      IFNs, the effectiveness of IFN-tau as an antiviral agent has not been well
      characterized. To investigate possible antiviral effects of ovine IFN-tau (oIFN
      tau), oIFN-tau-GST fusion protein was expressed in E. coli BL21, from which the
      purified protein isolated possessed anti-viral activity. An apathogenic human
      foamy virus (hFV) was then used to establish a potential recombinant live vector
      consisting of oIFN-tau cDNA sense (+) or antisense (-) sequence, oIFN-tau(+)/hFV
      or oIFN-tau(-)/hFV, respectively. Human hematopoietic and other mammalian cell
      lines that had been transduced with hFV vector consisting of no oIFN-tau, oIFN
      tau(+)/hFV or oIFN-tau(-)/hFV construct were cultured initially for 12 days, and
      three of cell lines were then maintained for up to 90 days. These cells with oIFN
      tau expression directed by hFV exhibited the in vitro cytopathic effect
      minimally. Transduced cell lines that had been cultured for 90 days were
      subjected to studies on human immunodeficiency virus type-1 (HIV-1) infection,
      which was measured with infectivity of viral particles resulted from the GFP
      inserted T-cell tropic HIV SF2 or macrophage tropic HIV SF162: the number of HIV
      1 positive cells was reduced by the hFV driven-intra-cellular oIFN-tau
      expression. Since oIFN-tau/hFV transduced cells exhibited the resistance to HIV-1
      infection and/or replication, oIFN-tau could be considered as one of effective
      antiviral agents against HIV-1. These results suggest that the hFV genome could
      be an effective recombinant live vector for the expression of a targeted gene in
      various cell types.

PMID- 15031540
TI  - Effect of modified oligopeptides from the beetle Allomyrina dichotoma on
      Escherichia coli infection in mice.
AB  - The novel peptides based on a putative active site of defensin, an anti-bacterial
      peptide from the beetle Allomyrina dichotoma, were synthesized. These synthetic
      oligopeptides exhibited strong anti-bacterial activity in vitro, even against
      antibiotic-resistant pathogenic bacteria. Then, anti-bacterial activity of two
      newly synthesized peptides, RLYLRIGRR-NH(2) (peptide A) and RLRLRIGRR-NH(2)
      (peptide B) was also examined by macroscopic and histopathologic assessment
      during the course of infection in mice inoculated with antibiotic-resistant
      pathogenic Escherichia coli (E. coli) in vivo. Peptide B decreased the mortality
      of mice inoculated with antibiotic-resistant pathogenic E. coli. The results of
      macroscopic and histopathologic examinations revealed that peptide B could
      protect the mice from infection. In contrast, peptide A failed to protect mice
      from infection with antibiotic-resistant pathogenic E. coli. Also, modified
      peptides A and B produced no toxicity or side effects in mice. These results
      suggest that peptide B is useful for developing novel antibiotics against
      antibiotic-resistant pathogenic bacteria.

PMID- 15031541
TI  - Chicken peripheral blood CD3+CD4-CD8- cells are regulated by endocrine and nerve
      systems.
AB  - The existence of CD3(+)CD4(-)CD8(-) T cells in thymus and spleen has already been
      known. However, because of the presence of large amounts of thrombocytes in
      peripheral blood (PB), the proportion of CD3(+)CD4(-)CD8(-) T cells in PB has yet
      to be investigated. Therefore, the proportion of peripheral T cell-subsets was
      investigated in 6-week-old chickens. The percentage of CD3(+) cells, CD4(+)
      cells, CD8 alpha(+) cells, CD8 beta(+), and CD3(+)CD4(-)CD8(-) cells was 76%,
      41%, 14%, 5%, and 15%, respectively. The proportion of CD3(+)CD4(-)CD8(-) cells
      in PB increased during egg-laying periods and in chickens treated with an analog
      of estrogen, while it decreased with age and in response to restraint stress. All
      of the CD3(+)CD4(-)CD8(-) cells expressed TCR1, and did not have NK activity.
      CD3(+)CD4(-)CD8(-) cells represent about 60% of peripheral TCR1(+) cells. These
      findings indicate that the proportion of CD3(+)CD4(-)CD8(-) cells is regulated by
      the endocrine and nerve systems.

PMID- 15031542
TI  - Oral administration of lactoferrin inhibits inflammation and nociception in rat
      adjuvant-induced arthritis.
AB  - Lactoferrin (LF) is a ubiquitous protein which exists in milk, plasma, synovial
      fluids, cerebrospinal fluid and other biological fluids. LF is also well known as
      a natural immunomodulator. Recently, we found that bovine milk-derived LF (BLF)
      produced micro-opioid receptor-mediated analgesia. In this study, we examined
      whether oral administration of BLF causes anti-nociceptive and anti-inflammatory
      effects, and also whether it modulates LPS-induced TNF-alpha and IL-10 production
      in rat model of rheumatoid arthritis (RA), rat adjuvant arthritis. BLF was
      administrated once daily, starting 3 hr before (preventive experiment) or 19 days
      after (therapeutic experiment) adjuvant injection. In both experiments, BLF
      suppressed the development of arthritis and the hyperalgesia in the adjuvant
      injected paw. The single-administered BLF produced a dose-dependent analgesia,
      which was reversed by naloxone, in the adjuvant arthritis rats. Both repeated and
      single administration of BLF suppressed TNF-alpha production and increased IL-10
      production in the LPS-stimulated adjuvant arthritis rats. These results suggest
      that orally administered BLF has both preventive and therapeutic effects on the
      development of adjuvant-induced inflammation and pain. Moreover, the
      immunomodulatory properties of BLF, such as down-regulation of TNF-alpha and up
      regulation of IL-10, could be beneficial in the treatment of RA. Thus, we
      concluded that LF can be safely used as a natural drug for RA patients suffering
      from joint pain.

PMID- 15031543
TI  - Acquisition of quinolone resistance and point mutation of the gyrA gene in
      Campylobacter jejuni isolated from broilers and in vitro-induced resistant
      strains.
AB  - A dramatic rise in the number of resistant Campylobacter to quinolones has been
      documented in human patients and domestic animals. In this study, the mechanism
      of acquisition of quinolone resistance was studied by detecting point mutations
      in the gyrA gene of Campylobacter strains obtained from broilers and strains with
      in vitro-induced resistance. The minimal inhibitory concentrations (MICs) of
      norfloxacin (NFLX) and ofloxacin (OFLX) for the strains that had no point
      mutation were slightly increased from the source strain (Campylobacter jejuni
      ATCC 33560). The MICs of nalidixic acid (NA), NFLX, and OFLX for the strains that
      had the point mutation at Thr-86 were 100 or 200 microg/ml, 50 microg/ml, and 25
      microg/ml, respectively. The MIC of NA for the strain that had a point mutation
      at Asp-90 higher than those for the strains that had the point mutation at Thr
      86, but the MICs of NFLX and OFLX were relatively lower than those for the
      strains that had point mutation at Thr-86. These findings suggest that the degree
      of antimicrobial resistance against NA, NFLX, and OFLX in the in vitro-induced C.
      jejuni strains was associated with the location of the point mutation in gyrA. On
      the other hand, a point mutation in all seven resistant strains isolated from
      broilers was located only at Thr-86, while the MICs of the three quinolones
      varied in each wild strain. This suggests that another mechanism might also be
      involved in the acquisition of quinolone resistance in C. jejuni wild strains.

PMID- 15031544
TI  - Cytopathogenicity of classical swine fever viruses that do not show the
      exaltation of Newcastle disease virus is associated with accumulation of NS3 in
      serum-free cultured cell lines.
AB  - Pestiviruses can be distinguished as two biotypes, cytopathogenic (cp) and
      noncytopathogenic (noncp), by the morphological changes that they induce during
      growth in cultured cells. In this study, the cp phenotype of several classical
      swine fever viruses (CSFV) was evaluated by the detections of the nonstructural
      proteins NS2-3 and NS3 using immunoprecipitation and Western blotting in
      different porcine cell lines. Most CSFVs that showed the exaltation of Newcastle
      disease virus (END) phenomenon (END(+) viruses) did not induce cytopathic effect
      (CPE) in any cell line, and detections of NS2-3 and NS3 showed a strong signal
      for NS2-3 in the END(+) virus-infected cells. However, clear CPE was observed in
      serum-free cultured cells (FS-L3 and CPK-NS) infected with viruses that induce
      intrinsic interference but did not show the END phenomenon (END(-) viruses), and
      signal of NS3 was strongly detected than that of NS2-3 in these cells at 72 hr
      after infection. As the results of the analysis of FS-L3 cells infected with ALD
      (END(+) virus) and ALD-END(-) virus (END(-) virus) at several incubations, the
      signal of NS3 detected was strengthened with CPE that become evident
      progressively. These results suggest that CPE is associated with the accumulation
      of NS3, which is promoted in serum-free cell lines infected with END(-) viruses.
      Thus, indicating there is a close relationship between CPE and the quantity of
      NS3 produced in END(-) CSFV infection.

PMID- 15031545
TI  - Development of canine nephrotic syndrome model.
AB  - To develop an experimental animal model for immune-mediated glomerulonephritis
      and nephrotic syndrome, nine healthy dogs were sensitized by intravenous
      injection with 1 microg of endotoxin and 5 mg of native bovine serum albumin.
      After 1 week, 120 mg of cationized bovine serum albumin was injected
      intravenously 5 times a week. Among nine dogs, five dogs were confirmed as having
      developed glomerulonephritis and nephrotic syndrome by increase of urine protein
      to-creatinine ratio (>1.0), hypoalbuminemia (<1.5 g/dl), hypercholesterolemia
      (>240 mg/dl), and edema. This model should be useful for studying immune-mediated
      glomerulonephritis and nephrotic syndrome.

PMID- 15031546
TI  - Lymphoid apoptosis in acute canine distemper.
AB  - The relationship between the canine distemper virus (CDV) infection and apoptosis
      in the canine lymphoid tissues was investigated using immunostaining for single
      stranded DNA (ssDNA), TdT-mediated dUTP-biotin nick end-labeling (TUNEL) method,
      and electron microscopy. Twenty-six lymphoid tissues from 8 spontaneously CDV
      infected dogs and 1 non-infected dog were used, and lesions were classified into
      4 groups according to frequency of the CDV-antigen. Histologically, the degree of
      lymphoid depletion tended to depend on amount of CDV antigen. The numbers of
      ssDNA- and TUNEL-labeling cells were significantly high in the lymphoid tissues
      with abundant viral antigen. However, ssDNA- and TUNEL-positive lymphocytes were
      also frequently found even in the lymphoid tissues where there was only a small
      amount of CDV-antigen in sinus histiocytes. The incidence and distribution of
      apoptotic cells in the CDV-antigens-negative lymphoid tissues from infected dogs
      were equal to those from a non-infected dog. Double labeling immunostaining using
      a ssDNA and a CDV nucleocapsid protein (CDV-NP) antibody revealed that there were
      ssDNA positive but CDV-NP negative cells besides those stained doubly positive.
      Ultrastructurally, lymphocytes in the CDV-infected lymphoid tissues frequently
      had characteristic morphological features of apoptosis such as apoptotic bodies.
      All these results suggest that CDV leads to lymphocytic apoptosis directly or
      indirectly, resulting in severe lymphoid depletion and immunosuppression in acute
      or subacute phase of CDV infection.

PMID- 15031547
TI  - Breed differences in genotype and allele frequency of catechol O
      methyltransferase gene polymorphic regions in dogs.
AB  - Catechol O-methyltransferase (COMT) inactivates catecholamines and catechol
      containing drugs such as L-DOPA. The common genetic polymorphism Val158Met in the
      human COMT gene is suspected to be associated with "persistence" or risk for
      schizophrenia. In this study, we attempted to identify the canine COMT gene
      fragment and to find a similar polymorphism and to reveal its genetic
      distribution among five representative canine breeds. We found that the amplified
      gene consisted of 663 bp nucleotides and was 84% homologous with the human COMT
      gene. The single nucleotide polymorphisms, guanine adenine substitution, were
      observed at the 39th, 216th and 482nd nucleotides. From the genotyping of the
      216th polymorphism among 266 dogs by the polymerase chain reaction-restriction
      fragment length polymorphism method with restriction enzyme EagI, and that of the
      482nd polymorphism with restriction enzyme SfcI, we found inter-breed variations
      of genotypes as well as of allelic frequencies for both of these polymorphic
      regions. These results suggest that the identified polymorphisms will be useful
      tools in elucidating the genetic background of canine behavioral traits.

PMID- 15031549
TI  - The effect of Korean red ginseng on liver regeneration after 70% hepatectomy in
      rats.
AB  - The effect of Korean red ginseng (KRG) on morphologic change and function of the
      liver was investigated after 70% hepatectomy in rats. The liver weight and
      hepatocyte proliferation of the KRG treated groups significantly increased
      compared to those of the control group. KRG inhibited the increase of aspartate
      aminotransferase (AST) and alanine aminotransferase (ALT) levels, and the number
      and area of lipid droplets. On the basis of these results, it could be concluded
      that KRG accelerated the liver regeneration and ameliorated liver injury after
      hepatectomy in rats.

PMID- 15031548
TI  - B-cell immunoblastic lymphoma with multinucleated giant cells in a cat.
AB  - A 10-year-old male mixed breed cat died after six months history of intermittent
      vomiting and weight loss. At necropsy, large white-colored foci were found in
      both kidneys, and whitish thickening of the gastric wall was present at the
      pyloric part of the stomach. Histopathological examination revealed that both
      lesions consisted of proliferation of large-sized neoplastic lymphocytes
      intermingled with multinucleated giant cells. Immunohistochemically, the
      neoplastic cells were positive for both B-cell antigen receptor complex (CD 79
      alpha cy) and MHC class II, although multinucleated giant cells were negative.
      The present case was diagnosed as B-cell immunoblastic lymphoma with
      multinucleated giant cells.

PMID- 15031550
TI  - Lymphangiosarcoma in a dog treated with surgery and chemotherapy.
AB  - A large subcutaneous mass at the left cervical site in a 9-year-old male Siberian
      husky was removed surgically. Histopathologically, the mass was mainly consisted
      of a proliferation of spindle-shaped neoplastic cells arranging in solid sheath
      and partially vascular channels containing few blood cells. The tumor cells
      exhibited highly invasive activity to the surrounding tissues. In addition, the
      tumor cells were immunopositive for Factor VIII-related antigen. On the basis of
      these findings, the tumor was diagnosed as lymphangiosarcoma. Recurrent mass was
      noticed 3 weeks after surgery but completely disappeared after the doxorubicin
      treatment. Neither recurrence nor metastasis was observed for 9 months after the
      remission.

PMID- 15031551
TI  - Aspergillus fumigatus infection in an ostrich (Struthio camelus).
AB  - An 11-month-old female ostrich (Struthio camelus) had become gradually emaciated
      over a 2-week period and subsequently died. Necropsy revealed white to green mold
      growth on the walls of caseous thickened air sac membranes and multiple white
      necrotic foci in the lungs and liver. Histologically, the multiple exudative,
      necrotic and granulomatous lesions were compatible with mycotic infection in the
      air sacs and lungs, and hyphae positively reacted with a monoclonal antibody (Mab
      WF-AF-1) to Aspergillus fumigatus wall fractions. Multifocal hepatic necrosis was
      also found, and several spores were observed in the blood vessels. Fungal culture
      of these lesions yielded pure growth of A. fumigatus. This is an established case
      of fatal A. fumigatus infection in an ostrich reared in Japan.

PMID- 15031552
TI  - Binding of Vibrio anguillarum to neutral glycosphingolipids from intestinal
      mucosa of rainbow trout (Oncorhynchus mykiss).
AB  - To test whether glycosphingolipids (GSLs) on the intestinal mucosa of rainbow
      trout (Oncorhynchus mykiss) serve as a binding receptor for Vibrio anguillarum,
      we analyzed neutral GSLs from rainbow trout intestinal mucosa and investigated
      the binding of bacteria to neutral GSLs. Two kinds of neutral GSLs, designated N
      1 and N-2, were identified on high-performance thin-layer chromatography (TLC)
      plates. In TLC immunostaining tests, V. anguillarum bound only to
      galactosylceramide (GalCer), lactosylceramide and N-1 having the same TLC
      mobility as GalCer, but neither to glucosylceramide nor to N-2. These results
      suggest that N-1 is GalCer (Gal beta 1-1Cer) and also that N-1 (GalCer) on
      rainbow trout intestinal mucosa act as a receptor for V. anguillarum.

PMID- 15031553
TI  - Rumen ciliate protozoal fauna of reindeer in Inner Mongolia, China.
AB  - Rumen ciliate species and composition were surveyed on the reindeer kept in Inner
      Mongolia, China. As a result of survey, all the reindeer had the same 18 species
      of 8 genera of the ciliates in their rumen. Appearance of Entodinium parvum is
      the first record in this host species. Of the species detected, 15 species
      including Entodinium anteronucleatum, E. bicornutum, Enoploplastron confluens and
      Epidinium gigas which have been detected only from reindeer were common with
      those in the reindeer kept in the other areas, such as Alaska, Russia and
      Finland, indicating that every rumen ciliate faunae in reindeer has high
      similarity to each other, and suggesting that these hosts have been isolated from
      the other ruminants for long time and established characteristic ciliate fauna.
      The ciliate density was estimated as 1.1-2.5 x 10 (6)/ml, which value was fairly
      higher than those in domestic ruminants. Surface structures of characteristic
      species were observed by SEM.

PMID- 15031554
TI  - Passive transfer of antibodies to Shiga toxin-producing Escherichia coli O26,
      O111 and O157 antigens in neonatal calves by feeding colostrum.
AB  - To study whether or not passive immunity of neonatal calves against Shiga toxin
      producing Escherichia coli (STEC) O26, O111, and O157 was obtained by colostrum
      administration, serum antibodies in calves after the feeding were determined by
      enzyme-linked immunosorbent assay (ELISA) in comparison with antibodies in
      colostrum and sera from donor dams. The highest antibody titers to STEC in
      colostrum from dams were detected soon after parturition. The antibody titers
      were found to be elevated in sera of neonatal calves (4-9 hr after birth) orally
      administered with colostrum with high antibody titers, suggesting that passive
      immunity of neonatal calves to STEC infection may be obtained by feeding
      colostrum. These results suggest that colostrum administration to neonatal calves
      may play an important role in elevating serum antibodies against STEC in neonatal
      calves.

PMID- 15031555
TI  - Surgical correction of congenital lobar emphysema in a dog.
AB  - Massive lobar emphysema in the middle lobe of the right lung was observed in a
      dog brought to our clinic with sudden onset of tension pneumothorax, and
      lobectomy was performed to excise it. Pathological examination resulted in a
      diagnosis of congenital bronchiectasis associated with bronchial cartilage
      hypoplasia. Two cases of diagnosis and successful treatment of congenital lobar
      emphysema have been reported in dogs.

PMID- 15031556
TI  - Temperature and metal ions-dependent activity of the family I inorganic
      pyrophosphatase from the swine roundworm Ascaris suum.
AB  - Temperature dependence, heat stability and metal ions-dependent activity were
      examined on the Family I inorganic pyrophosphatase (PPase) recently identified
      from Ascaris suum. Recombinant A. suum PPase (rAsPPase) showed an optimal
      activity at 55 degrees C. The rAsPPase was heat stable at 40 degrees C in the
      absence of added Mg(2+) and at 50 degrees C in its presence. The enzyme required
      divalent metal ions for its activity. The preferences for the metal ions (5 mM
      concentration) were in the order: Mg(2+)> Co(2+)> Cu(2+)> Fe(2+)> Zn(2+)> Mn(2+).
      On the contrary, enzyme activity was inhibited by Ca(2+). These findings suggest
      that catalytic features of AsPPase are consistent with the Family I PPases
      reported from a wide range of organisms.

PMID- 15031557
TI  - Comprehensive search for X-ray-responsive elements and binding factors in the
      regulatory region of the GADD45a gene.
AB  - The growth arrest and DNA damage-inducible protein 45alpha (GADD45a) gene is
      responsive to a variety of DNA-damaging agents. It is known that induction of the
      GADD45a gene is regulated in a p53-dependent manner after ionizing irradiation.
      Our previous study showed that X-ray irradiation increased the transcription rate
      of the GADD45a gene much earlier than the maximum accumulation of stabilized p53
      protein in human myeloblastic leukemia ML-1 cells. We hypothesized that some
      transcription factor(s) may cooperate with p53 in regulating the GADD45a gene
      early after the irradiation of ML-1 cells. This idea is supported by recent
      studies showing that the p53-dependent activation of several genes in human and
      mouse cells requires some additional transcription factors, such as Sp1, GKLF,
      Ets1, and IRF-1. To examine the possible involvement of cooperating factors in
      transcriptional regulation of the GADD45a gene by ionizing radiation, we
      comprehensively searched for the X-ray-inducible binding locus of the nuclear
      factor throughout the upstream region (-2244 bp/+89 bp) and the third intron
      (+1389 bp/+2488 bp) of the GADD45a gene by EMSA using 136 probes. The X-ray
      responsive binding of nuclear factors was detected at eight loci. Oct, NF-kappaB,
      HNF, NF-AT, and KLF family transcription factors were identified by a competition
      assay. It is possible that some of these factors cooperate with p53 to mediate
      transcriptional regulation of the GADD45a gene after ionizing irradiation.

PMID- 15031558
TI  - Resuspension: decadal monitoring time series of the anthropogenic radioactivity
      deposition in Japan.
AB  - Monthly atmospheric depositions of (90)Sr and (137)Cs have been observed at the
      Meteorological Research Institute (MRI), Tsukuba, Japan. This study reports
      temporal trends and levels of (90)Sr and (137)Cs depositions in the 1990s.
      Although the current (90)Sr and (137)Cs concentrations declined dramatically,
      they have been found continuously in the deposition samples throughout the 1990s.
      During this period, the annual (90)Sr ((137)Cs) deposits at MRI ranged from 70
      180 (140-350) mBq/m(2)/year. With a sufficiently long time series, the decreasing
      trend of the deposition evidently differs from the past stratospheric fallout; it
      is far slower. Thus, reservoirs other than the stratosphere provide small amounts
      of (90)Sr and (137)Cs to the atmosphere. A simple calculation clearly refutes the
      significance of the ocean as a potential source of airborne anthropogenic
      radioactivity. We will demonstrate that these radionuclides in the deposited
      materials originate from resuspension processes (soil dust suspension processes).
      The temporal trends of the time series monitoring reveal differences from those
      in the UNSCEAR Report 2000, which were predicted by a model that disregarded
      resuspension. The specific activity of (90)Sr ((137)Cs) in the annual depositions
      exhibited a 10-year (20-year) half-life. Those data were comparable with values
      reported in the literature for the half-residence time (HRT) of (90)Sr and
      (137)Cs in Japanese surface soils. They were also comparable to those calculated
      from nationwide data of (90)Sr and (137)Cs concentrations in the surface soil (0
      10 cm) obtained from the Ministry of Education, Culture, Sports, Science and
      Technology Environmental Radiation Database (the MEXT Database). Regarding the
      activity ratio of (137)Cs/(90)Sr, the Japanese nationwide surface soil data
      collected during the 1990s in the MEXT Database (median: 5.3, n = 584) did not
      accord with that in the deposition samples (average: 2.1, n = 82) at MRI. This
      supports our previous hypothesis that Asian dust may transport a large fraction
      of anthropogenic radioactivity into the Japanese atmosphere. We need to study the
      fate of long-lived anthropogenic radioactivity dispersed in the environment over
      greater spatial and temporal scales.

PMID- 15031559
TI  - Radiosensitization of normal human cells by LY294002: cell killing and the
      rejoining of DNA and interphase chromosome breaks.
AB  - The radiosensitizing effect of a phosphoinositide-3 kinase (PI3K) inhibitor,
      wortmannin, has been studied rather extensively, but there have been few studies
      on the radiosensitizing effect of another PI3K inhibitor, LY294002. In this
      report, we present the radiosensitizing effect of LY294002 using normal human
      cells. Clonogenic cell survival indicated that LY294002 enhanced the killing
      effect of gamma-rays in a dose-dependent manner, although this drug by itself did
      not affect the cell killing. To obtain a 10% cell survival, about one half of the
      radiation dose was needed when cells were treated with 50 microM LY294002 as
      compared to cells without the drug. A mild inhibition of repair of DNA double
      strand breaks (DSBs) was observed in irradiated normal human cells pre-treated
      with LY294002 (50 microM). At the interphase chromosome level, we also observed
      an increase in the number of residual breaks when irradiated cells were pre
      treated with this drug (about 2-fold at 5 Gy). These results suggest that the
      inhibition of DSB repair mediated the radiosensitizing effect of LY294002 at the
      dose level that we used.

PMID- 15031560
TI  - Radiation chemical studies on thermosensitive N-isopropylacrylamide and its
      polymer in aqueous solutions.
AB  - The pulse radiolysis technique has been employed to determine the initiation and
      propagation rates of different transient species involved in the polymerization
      of N-isopropylacrylamide (NIPA) in aqueous solutions. Polymerization by anionic
      mechanism has been observed to be faster than by the free-radical mechanism. The
      kinetic, spectroscopic and redox properties of the transient species formed upon
      reaction of primary radiolytic species of water radiolysis with NIPA have been
      evaluated. The one-electron oxidation potential for the formation of a radical
      cation is quite high (>2 V), but the one-electron reduction potential is low (in
      the range of -0.3 to -0.7 V). The radical anion of NIPA is able to undergo an
      electron-transfer reaction with MV(2+), and has a pK(a) value of 3.2. The tert
      butyl alcohol radical was also able to initiate polymerization. Gamma radiation
      induced polymerization studies showed that the reaction of H(.)/(.)OH/e(aq)(
      )/tert-butyl alcohol radicals with NIPA results in a nearly equal yield of the
      gel fraction. The hydrogel is observed to have very little swelling below pH 3
      and above pH 10. The linear polymer of NIPA formed by irradiating dilute aqueous
      solution is found to be a thermosensitive polymer with lower a critical solution
      temperature (LCST) of ~33 degrees C. The diameters of polymer molecules were 290
      and 20 nm at temperature below and above LCST, respectively.

PMID- 15031561
TI  - Neuropathology of delayed encephalopathy in cats induced by heavy-ion
      irradiation.
AB  - AIM: The pathogenesis of delayed encephalopathy induced by heavy-ion irradiation
      was investigated experimentally in cats. The left cerebral hemispheres were
      irradiated with 15-40 Gy of heavy ions (carbon), and histologically and
      morphometrically examined 12 months later. RESULTS: In the irradiated cerebral
      white matter the following occurred as the dose increased: astrocytic swelling,
      then the dilatation of small blood vessels with a fibrous thickening of the wall,
      and then loosening of the white matter with cavity formation and diffuse albumin
      deposition. Pathological features of these cavities suggested that they are
      induced by long-standing edema. Although the dilated vessels were arteries,
      veins, and capillaries, arteriovenous shunt and damage of the smooth muscle cells
      of the arterial media were absent. Changes of the cerebral cortex were scarce.
      Morphometrically, the irradiated cerebral white matter was swollen, and the
      capillary density tended to be reduced in the deep cortex and subcortical white
      matter, but this effect was not dose dependent. CONCLUSION: Heavy-ion irradiation
      induces delayed encephalopathy in cats, preferentially involving the white
      matter. The cardinal pathogenesis was long-standing edema of the white matter due
      to vascular hyperpermeability, and the vascular dilatation seemed to be caused by
      a reduction in the vascular bed and/or hemoconcentration due to
      hyperpermeability.

PMID- 15031562
TI  - Identification of a new G-to-A transition mutation at nucleotide position 129 of
      the Xrcc4 gene in ionizing radiation-hypersensitive mutant LX830 cells.
AB  - The mouse lymphoma cell line LX830 is an X-ray-hypersensitive mutant.
      Complementation tests between LX830 cells and radiation-sensitive mutants of M10
      (Xrcc4 deficient cells) or SX10 (DNA ligase IV deficient cells) cells showed that
      M10 cells did not complement LX830 cells, but SX10 cells did, suggesting that
      LX830 cells would belong to the X-ray-cross complementation group (XRCC4). A
      sequence analysis of Xrcc4 cDNA in LX830 cells disclosed a transition of G to A
      at nucleotide position 129, which resulted in a change of tryptophan (43) to a
      termination codon. Transfection of the mouse Xrcc4 cDNA rescued the X-ray
      sensitivity of the mutant cells. LX830 is an Xrcc4-deficient cell line bearing a
      termination codon in exon 2 of the Xrcc4 gene and no wild-type Xrcc4 gene.

PMID- 15031563
TI  - Radiosensitizer sanazole (AK-2123) enhances gamma-radiation-induced apoptosis in
      murine fibrosarcoma.
AB  - Sanazole (AK-2123) (N-2'-methoxy ethyl)-2-(3"-nitro-1"-triazolyl)acetamide, which
      has completed phase III clinical trials as a radiosensitizer, enhanced gamma
      radiation induced apoptosis in murine fibrosarcoma upon i.p. administration at 40
      mg/kg body weight one hour prior to irradiation. A microscopic examination of
      Giemsa-May-Grunwald stained cells has shown a higher frequency of condensed
      nuclei and fragmented nuclei in the tumor cells. The administration of sanazole
      to tumor-bearing animals enhanced the radiation-induced internucleosomal
      fragmentation in the nuclear genome of tumor cells. Higher levels of caspase-3
      activity were also observed in the cell extracts of tumours from AK-2123
      administered mice. Exposure to gamma-radiation of AK-2123-treated mouse further
      enhanced the caspase-3 activity, indicating the induction of apoptosis. The
      radiation sensitization property of sanazole was discernible by comparing the
      relative tumor diameter following irradiation after i.p. administration of AK
      2123 and irradiation alone; it was higher during the first few days followed by
      the treatment.

PMID- 15031564
TI  - Diagnostic invasive procedures in diffuse infiltrative lung diseases.
AB  - The diagnosis of infiltrative diffuse lung disease may require invasive
      procedures after all noninvasive tools have failed. The clinical context in which
      these diseases develop and the radiological patterns are crucial for defining the
      timing and the methods to be used. Immunocompromised hosts are usually acutely
      ill with fever, cough, shortness of breath, and often with progressive hypoxemia.
      In this context a prompt diagnosis is necessary to decrease mortality.
      Bronchoalveolar lavage [especially in cases that show ground-glass attenuation or
      alveolar opacification in high-resolution CT scan (HRCT)] is the most important
      invasive procedure allowing the identification of infectious agents, neoplastic
      elements and characteristic cytological and phenotypical profiles (for drug
      injury) in the majority of cases. Less frequently transbronchial lung biopsy,
      transbronchial needle aspiration and biopsy or surgical lung biopsy are
      necessary. In immunocompetent patients the clinical spectrum of diffuse lung
      disease is quite broad. Furthermore, in the last two decades HRCT, used in
      conjunction with clinical and other noninvasive investigative modalities, has
      increased the accuracy of diagnosis for some diseases without the need of
      surgical biopsy. Also in these patients bronchoalveolar lavage, frequently in
      combination with transbronchial lung biopsy, is sufficient to achieve a
      definitive diagnosis in the majority of cases. Surgical lung biopsy is, however,
      still relevant in cases with idiopathic interstitial pneumonias. In this article
      invasive diagnostic procedures in patients with diffuse lung infiltrates are
      discussed from the perspective of their clinical context and their imaging
      characteristics.

PMID- 15031565
TI  - Chlamydia pneumoniae infection and inflammation in adults with asthma.
AB  - BACKGROUND: Chlamydia pneumoniae infection and immune response to the C.
      pneumoniae heat shock protein 60 (CpHsp60) have been suggested to be associated
      with asthma. OBJECTIVES: To study whether a slightly elevated C-reactive protein
      (CRP) level as a marker of low-grade systemic inflammation has a role in this
      association, we collected serum and sputum samples from 103 asthma patients with
      disease severity ranging from mild to moderate and from 30 healthy volunteers.
      METHODS: IgA and IgG antibodies to C. pneumoniae elementary bodies (CpEB) and
      CpHsp60 were measured by enzyme immunoassay. Serum CRP levels were measured with
      a rapid two-site ultra-sensitive assay based on time-resolved immunofluorometry.
      RESULTS: The asthma patients, especially those with moderate asthma, had higher
      serum IgA antibody levels to CpHsp60 than the healthy controls (test for trend, p
      = 0.05), whereas antibody levels to CpEB antigen did not differ between the study
      groups. CRP levels were higher in both asthma groups compared to the control
      group and moreover, the patients with moderate asthma had higher CRP levels than
      those with mild asthma (test for trend, p < 0.01). The subjects with a slightly
      elevated CRP level, defined as > or =1.8 mg/l, had higher CpEB IgA (p = 0.001),
      CpEB IgG (p = 0.008) and CpHsp60 IgA (p = 0.023) antibody levels in serum
      compared to the subjects with lower CRP levels. CONCLUSIONS: Slightly elevated
      CRP levels as a marker of low-grade systemic inflammation may be associated with
      C. pneumoniae infection in asthma patients.

PMID- 15031567
TI  - Visits to the emergency room for asthma attacks and short-term variations in air
      pollution. A case-crossover study.
AB  - BACKGROUND: The 'case-crossover' design is a strategy fitted to studying
      transient effects of intermittent exposure on acute-onset disease occurring
      shortly after exposure. It has the important advantage of eliminating most
      confounding variables, allowing a stronger causality inference. OBJECTIVES: The
      objective of the study was to evaluate the relationships between emergency room
      (ER) visits for asthma attacks and gaseous air pollution changes. METHODS: The
      study included 549 individuals, 3-49 years old, visiting the ER during 1 year.
      Exposure to gaseous air pollutants (SO2, NO2, O3) on the same day and up to 4
      days before was computed according to the patient's address. The statistical
      analysis included meteorological data as potential confounding variables.
      RESULTS: No association could be shown between ER visits and SO2 or NO2 levels.
      In contrast, there was a statistically significant association between ER visits
      and mean O3 levels, on the day of admission and also on D -2 and D -3. For an
      increase of 10 microg/m3, the risk of requiring an ER admission increased by 6
      10%. CONCLUSIONS: Using this new strategy, we confirmed that ozone changes lead
      to a moderate increase in risk of requiring an ER admission in asthmatic
      subjects.

PMID- 15031566
TI  - Comparable efficacy and tolerability of formoterol (Foradil) administered via a
      novel multi-dose dry powder inhaler (Certihaler) or the Aerolizer dry powder
      inhaler in patients with persistent asthma.
AB  - BACKGROUND: For maximum treatment compliance there is a need to provide asthma
      patients with devices that suit their particular preferences. The Foradil
      Certihaler is a novel multi-dose dry powder inhaler developed to increase the
      choice of devices available. OBJECTIVES: To evaluate the safety and efficacy of
      formoterol administered via the Foradil Certihaler, or via the single-dose
      inhaler Foradil Aerolizer. METHODS: This was a randomized, placebo-controlled,
      double-dummy, incomplete block crossover, dose-ranging and pharmacokinetic study
      in patients with persistent asthma. Sixty-seven patients (mean 48.0 years) were
      randomized to formoterol 5, 10, 15 and 30 microg twice daily via the Certihaler,
      12 microg formoterol b.i.d. via the Aerolizer, or placebo in four 1-week double
      blind treatment periods separated by 1-week single-blind washouts. RESULTS All
      formoterol doses delivered via the Certihaler or the Aerolizer significantly
      increased FEV(1) compared with placebo (p < 0.0001). Formoterol demonstrated an
      onset of action of <3 min. All active treatments were well tolerated. Tremor was
      the most common adverse event and was more pronounced at high doses. At lower
      doses the incidence of tremor with the Certihaler was similar to that observed
      with placebo or the Aerolizer. The pharmacokinetic evaluation comprised 41
      patients (mean 45.9 years). Urinary excretion of unchanged formoterol and total
      formoterol increased with dose delivered via the Certihaler. The optimum dose of
      formoterol via the Certihaler was 10 microg. CONCLUSION: Delivery of formoterol
      via the Certihaler or Aerolizer combines rapid relief with enduring control and
      provides convenient bronchodilation in patients with persistent asthma.

PMID- 15031568
TI  - Increased prevalence of perennial allergic rhinitis in patients with obstructive
      sleep apnea.
AB  - BACKGROUND: Impaired nasal breathing is a risk factor for obstructive sleep apnea
      syndrome (OSAS). OBJECTIVES: The aim of this study was to determine whether atopy
      to perennial allergens and existence of perennial allergic rhinitis was a risk
      factor for OSAS. METHODS: In a case-control study, we compared the proportions of
      OSAS patients with atopy to perennial allergens and perennial allergic rhinitis
      to the proportions in patients with chronic obstructive pulmonary disease (COPD).
      Seventy-two OSAS patients (mean age 60.7 years; 79.4% male) and 44 COPD patients
      (mean age 63.6 years; 88.6% male) were selected from a hospital outpatients'
      clinic in Switzerland. All patients completed a respiratory symptom
      questionnaire, performed spirometry and had a skin prick test for atopy. RESULTS:
      OSAS patients were significantly heavier than COPD patients (BMI 32.4 +/- (SD)
      6.6 vs. 29.2 +/- 6.6 kg/m2, p = 0.04) and had a better lung function than COPD
      patients (FEV1% predicted 91.3 +/- 19.2 vs. 51.6 +/- 18.9%, p < 0.001). Patients
      with OSAS were more likely to be sensitized to perennial allergens such as house
      dust mite (23.6 vs. 4.5%, p = 0.009) and dog (18 vs. 4.5%, p = 0.04) than the
      COPD patients. Perennial allergic rhinitis (having nose problems [nasal
      obstruction and/or runny nose and/or sneezing] all year and being atopic to at
      least one perennial allergen) was reported in 11% of OSAS patients but in only
      2.3% of COPD patients (p = 0.15). CONCLUSION: We conclude that subjects with OSAS
      may have an increased risk of being allergic to perennial allergens and suffer
      from perennial rhinitis. Awareness of this risk may have important consideration
      in the clinical situation.

PMID- 15031569
TI  - Non-invasive pressure support ventilation in patients with respiratory failure
      due to severe acute cardiogenic pulmonary edema.
AB  - BACKGROUND: Recent studies suggest the use of non-invasive pressure support
      ventilation (NIPSV) in patients with acute cardiogenic pulmonary edema (ACPE).
      However, it remains unclear whether all patients with ACPE benefit from NIPSV.
      OBJECTIVES: To investigate short-term effects of NIPSV on respiratory,
      hemodynamic and oxygenation parameters in patients with respiratory failure due
      to severe ACPE and to identify factors predicting the need for intubation and in
      hospital mortality. METHODS: In a prospective, uncontrolled, open study, 28
      patients admitted with signs and symptoms of severe respiratory distress due to
      ACPE were given NIPSV in addition to standardized pharmacological treatment.
      Physiological parameters were obtained before and after NIPSV, and intubation
      rate and in-hospital mortality were recorded. RESULTS: NIPSV increased arterial
      oxygenation from paO2 54.2 +/- 12.4 to 76.9 +/- 12.6 mm Hg (p = 0.0001) and
      decreased respiratory frequency from 40.1 +/- 8.2 to 22.4 +/- 4.9 breaths/min (p
      = 0.0001). Significant improvements were also noted for heart rate, blood
      pressure and the paO2/FiO2 ratio. Four patients (14%) required intubation despite
      NIPSV. Patients who required intubation had lower paCO2 levels (p = 0.0002),
      lower serum bicarbonate concentrations (p = 0.04) and lower systolic blood
      pressure (p = 0.045) than patients who were successfully treated with NIPSV.
      Eight patients (28.5%) died during hospitalization. In patients with a paCO2 < or
      =35 mm Hg on admission, the in-hospital mortality was 87%, but in patients with a
      paCO2 >35 mm Hg the in-hospital mortality was 6%. CONCLUSIONS: NIPSV improves
      oxygenation and alleviates respiratory distress in patients with respiratory
      failure due to severe ACPE. However, a subgroup of patients with hypocapnia on
      admission might have a poor prognosis, with a higher risk of intubation and in
      hospital mortality.

PMID- 15031570
TI  - Acute antiarrhythmic effects of bi-level positive airway pressure ventilation in
      patients with acute respiratory failure caused by chronic obstructive pulmonary
      disease: a randomized clinical trial.
AB  - BACKGROUND: Cardiac arrhythmias are common in patients with chronic obstructive
      pulmonary disease (COPD) and acute respiratory failure (ARF) and may be life
      threatening. Recently, non-invasive positive pressure ventilation has been
      advanced as a useful tool in COPD patients with ARF. This method can affect
      global cardiac performance through its effects on many determinants of cardiac
      function and may be helpful in reducing arrhythmias. OBJECTIVE: To assess the
      role of bi-level positive pressure ventilation (BiPAP) in the management of
      cardiac arrhythmias in patients with ARF caused by COPD. METHODS: We studied 30
      consecutive patients with ARF related to COPD diagnosed according to American
      Thoracic Society criteria. All subjects were smokers; the mean age was 68 +/- 7
      years. They were randomly assigned to receive BiPAP plus standard therapy (group
      1) or standard therapy alone (group 2). Patients randomized to receive BiPAP were
      first fitted with a nasal mask, and BiPAP was administered after 12 h of standard
      therapy. All subjects were studied using a computerized 24-hour Holter ECG. Blood
      gases, plasma electrolytes, respiratory rate and blood pressure were measured at
      study entry, at 30, 60 and 120 min and then every 3 h. RESULTS: Heart rate
      decreased from 86.08 +/- 7.86 to 74.92 +/- 5.39 in group 1 (p < 0.001) versus
      82.77 +/- 8.78 to 75.82 +/- 6.76 in group 2 (p = 0.033). Ventricular premature
      complexes decreased from 564.38 +/- 737.36 to 166.15 +/- 266.26 in group 1 (p <
      0.001) versus 523.38 +/- 685.75 to 353.54 +/- 469.93 in group 2 (p = 0.021).
      Atrial premature complexes decreased from 570.00 +/- 630.36 to 152.31 +/- 168.88
      in group 1 (p < 0.001) versus 513.77 +/- 553.81 to 328.62 +/- 400.81 in group 2
      (p = 0.021). CONCLUSIONS: Cardiac arrhythmias decreased significantly in both
      groups after the start of both treatments, although data obtained from group 1
      revealed a more important statistical significance. Our data seem to support the
      hypothesis that BiPAP may be a useful tool in managing COPD patients with ARF and
      mild arrhythmias.

PMID- 15031571
TI  - Comparative effects of a two-week treatment with nebivolol and nifedipine in
      hypertensive patients suffering from COPD.
AB  - BACKGROUND: It has been suggested that the antihypertensive agent nebivolol, a
      beta1-adrenoceptor-blocking agent that modulates the endogenous production of
      nitric oxide, is preferable to 'conventional' beta1-blockers in hypertensive
      patients with airway dysfunction. OBJECTIVES: Since beta1-blockade by nebivolol
      is larger after repeated dosing than after a single oral intake, we have explored
      its effect on pulmonary function after a 2-week treatment in hypertensive
      patients with mild to moderate COPD. METHODS: A single-blind crossover design was
      used. Twenty patients with COPD as selected above and with a diastolic blood
      pressure of 95-110 mm Hg after 1 week of placebo run-in were entered into the two
      2-week active treatment periods with either 5 mg nebivolol (n = 10) or 30 mg
      nifedipine gastrointestinal-transport-system (GITS) (n = 10) taken for a period
      of 2 weeks. After a further 1-week washout, subjects were crossed-over to receive
      the other drug for 2 additional weeks. At each visit, changes in spirometric
      indexes and the interaction with the bronchodilator effect of salbutamol were
      investigated. Moreover, systolic and diastolic blood pressure (BP) together with
      heart rate were manually measured in order to evaluate the cardiovascular effects
      of the different treatments. Throughout the study, patients recorded symptoms.
      RESULTS: Similar and significant reductions in systolic and diastolic BP were
      observed with both treatments. The impact of nifedipine on FEV1 was not
      significant (p > 0.05), while that of nebivolol was slight. The maximum response
      to salbutamol was slightly decreased with either nebivolol or nifedipine GITS.
      Day-to-day airway obstruction control, interpreted from patient recordings of
      symptom scores and inhaler use, was similar with both treatments. CONCLUSIONS:
      Our pilot study suggests that the use of nebivolol in hypertensive patients with
      stable mild to moderate COPD was safe during a 2-week trial. Evaluation of longer
      time periods, larger patient numbers with more severe COPD or during
      exacerbations is warranted.

PMID- 15031572
TI  - Potential limitations of clinical criteria for the diagnosis of idiopathic
      pulmonary fibrosis/cryptogenic fibrosing alveolitis.
AB  - BACKGROUND: The need to perform surgical lung biopsy (SLB) in all cases of
      suspected idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis
      (IPF/CFA) is controversial. The American Thoracic Society (ATS) and the European
      Respiratory Society (ERS) recently endorsed explicit clinical criteria for the
      diagnosis of IPF/CFA in the absence of SLB. Prior studies evaluating clinical
      criteria for the diagnosis of IPF/CFA have been limited in that either they were
      performed by clinicians with expertise in the diagnosis of IPF/CFA or they did
      not utilize explicit diagnostic criteria. We investigated the accuracy of the
      ATS/ERS criteria when applied in a general pulmonary medicine setting.
      OBJECTIVES: To determine the interobserver variability of clinical criteria for
      the diagnosis of IPF/CFA. METHODS: This was a retrospective, blinded evaluation
      by three board certified pulmonary physicians without extensive experience in the
      evaluation of IPF/CFA performed at a United States Army tertiary care academic
      medical center. Patients referred for surgical lung biopsy as part of a
      diagnostic evaluation of interstitial lung disease (ILD) were evaluated. The
      physicians reviewed high-resolution computed tomography scans of the chest (HRCT)
      and clinical data for each patient. The physicians were blinded to all other data
      and to the opinions of other study participants. Employing the histologic
      presence of usual interstitial pneumonia (UIP) coupled with appropriate clinical
      findings as the gold standard for a diagnosis of IPF/CFA we determined the
      accuracy and interobserver variability for a diagnosis of IPF/CFA based on HRCT
      alone and based on the ATS/ERS clinical criteria. RESULTS: The sensitivity and
      positive predictive value for a HRCT diagnosis of IPF/CFA were 71% each while
      specificity and negative predictive value were 67% each. For the ATS/ERS criteria
      sensitivity, specificity, positive predictive value and negative predictive value
      were 71, 75, 77 and 69%, respectively. The interobserver variability, expressed
      as a kappa coefficient, for HRCT and the ATS/ERS criteria were 0.59 and 0.53,
      respectively. CONCLUSIONS: Both HRCT and the ATS/ERS clinical criteria may lead
      to misdiagnosis of patients with ILD. Further studies are needed to fully
      characterize the accuracy of these tests when applied in a routine pulmonary
      medicine practice setting.

PMID- 15031573
TI  - Thrombocytosis as a useful prognostic indicator in patients with lung cancer.
AB  - BACKGROUND: Thrombocytosis can accompany various cancers including lung cancer.
      This finding has recently been suggested to indicate poor prognosis. OBJECTIVES
      AND METHODS: We retrospectively examined the clinical records of 611 patients
      with lung cancer to investigate whether there is a correlation between
      thrombocytosis, other clinicopathologic factors, and survival. RESULTS: Ninety
      eight of the patients (16%) manifested thrombocytosis at the time of their first
      evaluation at our hospital. Thrombocytosis and age (p = 0.0006) and
      thrombocytosis and performance status (p = 0.0002) are significantly correlated,
      but thrombocytosis is not related to gender, tumor histology, clinical stage, or
      serum lactate dehydrogenase concentrations. Survival is significantly shorter in
      patients with thrombocytosis: [median survival time (MST) 7.5 months; n = 98]
      than without thrombocytosis (MST 10.1 months; n = 513; p = 0.0029). Multivariate
      analysis of prognostic factors using the Cox proportional hazards model indicated
      that thrombocytosis had independent prognostic significance. CONCLUSION:
      Thrombocytosis at the first patient evaluation is an independent prognostic
      factor in lung cancer.

PMID- 15031574
TI  - Bronchoscopy with the Vision Sciences BF100 disposable-sheath device: French
      experience after 328 procedures.
AB  - BACKGROUND: In spite of adhesion to recommended disinfection procedures, the
      transmission of infections by bronchoscopes is a permanent problem. OBJECTIVE:
      The new device may prevent nosocomial infections because it consists of two
      parts: a specific bronchoscope Vision Sciences BF100 and a single-use protective
      sheath for each procedure. The aim of this paper is to report our practice and
      the difficulties encountered when using this system. METHODS: We report our
      experience from 1997 to 2002 after 328 elective and emergency endoscopic
      procedures with the BF100 device. In a retrospective study, we describe the
      population and the incidents during procedure. We discuss the impact of the use
      of BF100 on the cost of bronchoscopies. RESULTS: The major constraint is the care
      required in assembling the optical device and disposable sheath. The intrinsic
      qualities of the optics are confirmed; any sample may be taken although image
      quality and suction capacity are inferior to videoscopes. Maneuverability is
      inferior to videoscopes, but improves with a short experience. In addition, this
      device is expensive. CONCLUSIONS: The technical performances of the BF100 device
      are inferior to those of videoscopes but the concept of sterile single-use
      sheaths is able to prevent the nosocomial infections related to bronchoscopes.
      Because of the cost, examination with the BF100 should be reserved to patients
      with proved or suspected infection (multiresistant bacteria, tuberculosis,
      hepatitis C and B virus, HIV, prions) and immunosuppression (hematologic
      diseases).

PMID- 15031576
TI  - Differences in the distribution of CD4+ and CD8+ T cells in emphysematous lungs.
AB  - BACKGROUND: Recent studies have shown that T cells are the predominant cells
      infiltrating the alveolar wall of patients with emphysema. Since CD4+ and CD8+
      cells have dissimilar function, they may have different distributions in
      emphysematous lungs. OBJECTIVES: The aim of this study was to investigate whether
      CD4+ and CD8+ are differently distributed in the lungs of patients with
      emphysema. METHODS: We evaluated CD4+ and CD8+ cell infiltration in lung tissue
      sections obtained from smokers with pulmonary emphysema who had undergone lung
      volume reduction surgery (n = 10). Paraffin-embedded lung tissue sections were
      immunostained using antibodies against CD4+ or CD8+, and distributions of CD4+
      and CD8+ cells were evaluated using a morphometric analysis. We determined the
      degree of emphysema using the area fraction of the alveolar wall (A(A,aw)) and
      examined its relation to the number of cells per unit area of the alveolar wall
      (NA). RESULTS: The majority of CD4+ cells were located in the lung parenchyma of
      severe emphysematous lesions characterized by the lowest alveolar wall fraction
      (A(A,aw)). In contrast, more CD8+ cells were located in mild emphysematous
      lesions than in severe lesions. CONCLUSIONS: These results suggest that CD4+ and
      CD8+ cells are differently distributed according to the severity of emphysema.
      CD4+ T cells are located preferentially in severe emphysematous lesions whereas
      CD8+ T cells occur preferentially in mild emphysematous lesions.

PMID- 15031575
TI  - Vascular stenting for palliation of superior vena cava obstruction in non-small
      cell lung cancer patients: a future 'standard' procedure?
AB  - BACKGROUND: Stenting is a relatively new option in the management of superior
      vena cava obstruction (SVCO), but available data often concern non-malignant
      and/or various malignant diseases. OBJECTIVE: The aim of this study was to assess
      the efficacy of vascular stenting as a first-choice treatment in SVCO in the
      exclusive setting of NSCLC. PATIENTS AND METHODS: Retrospective study of NSCLC
      patients with SVCO treated in the past year. Demographic data, disease
      characteristics, etiologic and palliative treatment (use of vascular stenting)
      were recorded as well as treatment outcome and survival. RESULTS: 17 patients
      were recruited. Eight had vascular stenting while 9 did not. Except for stenting,
      there was no difference between the two groups (median age 54 years; 80% men; 53%
      stage IIIB and 47% stage IV). Stenting (median length 60 mm) achieved complete
      resolution of SVCO more frequently (75 vs. 25%, p = 0.05) and faster (2 vs. 21
      days, p = 0.002) without immediate or delayed complication. All patients with
      stents received anticoagulation therapy. Relapse rate after complete response (33
      g, 50%, p = 0.6) was lower and time to relapse (6.5 g, 2 months) was longer for
      patients undergoing stenting, without reaching statistical significance. Median
      overall survival was not statistically different (8 and 5 months, p = 0.06).
      CONCLUSIONS: This study demonstrated the effectiveness of vascular stenting for
      SVCO in NSCLC patients. The high response rate, quick effect and safety of
      vascular stenting make this palliative treatment a candidate as a potential
      standard procedure. The results, however, must be confirmed in a prospective
      randomized trial including quality of life assessment.

PMID- 15031577
TI  - Tuberculous empyema necessitatis.

PMID- 15031578
TI  - Treatment of primary pulmonary hypertension with oral sildenafil.
AB  - Sildenafil, a selective phosphodiesterase-5 inhibitor, was administered orally to
      a 14-year-old girl with primary pulmonary hypertension (PPH) at a dose of 0.5
      mg/kg/4 h on a daily basis, increased to doses of 1 and 2 mg/kg at monthly
      intervals. Following therapy, oxygen saturation increased and exercise capacity
      improved significantly, but with no change in pulmonary haemodynamics. No side
      effects were noted. Sildenafil may be beneficial in children with PPH, but the
      mechanism of benefit is unclear.

PMID- 15031579
TI  - Long-term survival of a patient with congenital central hypoventilation syndrome
      despite the lack of continuous ventilatory support.
AB  - Untreated idiopathic congenital central hypoventilation syndrome (CCHS) is
      thought to cause infant death within 1-2 months. Here we present an adult patient
      with CCHS who survived without continuous ventilatory support, despite
      hypoventilation from early childhood onward. The diagnosis was confirmed at the
      age of 22 years, when the patient presented with hypoventilation during the night
      (PaCO2 60 mm Hg, PaO2 56 mm Hg, pH 7.32 HCO3- 30 mmol/l) but hyperventilation
      when awake (PaCO2 26 mm Hg, PaO2 81 mm Hg, pH 7.56, HCO3- 23 mmol/l). The maximal
      hematocrit was 77%. Despite mental retardation, noninvasive positive pressure
      ventilation (NPPV) could be successfully established. NPPV-supported ventilation
      during the night (PaCO2 36, PaO2 84 mm Hg, pH 7.47, HCO3- 25 mmol/l) reduced
      hematocrit values (40.6 to 36.8%) over a period of 4 years. In conclusion, long
      term survival with CCHS is possible without continuous ventilatory support.
      Spontaneous improvement of hypoventilation during sleep throughout childhood is
      possible and hyperventilation during wakefulness may occur in patients with CCHS.
      CCHS can be managed with NPPV despite mental retardation, even over a long-term
      period.

PMID- 15031580
TI  - Shewanella putrefaciens isolated in a case of ventilator-associated pneumonia.
AB  - We report the isolation of the aquatic gram-negative bacterium Shewanella
      putrefaciens from the bronchoalveolar lavage in a case of ventilator-associated
      pneumonia. To our knowledge, this species has never been isolated from the lower
      respiratory tract before as a potential pathogen.

PMID- 15031581
TI  - An unusual case of non-specific interstitial pneumonitis.

PMID- 15031582
TI  - From clinical observations to clinimetrics: a tribute to Alvan R. Feinstein, MD.

PMID- 15031583
TI  - Modern psychometrics in clinimetrics: impact on clinical trials of
      antidepressants.

PMID- 15031584
TI  - Assessment of psychopathology.

PMID- 15031585
TI  - The additional value of clinimetrics needs to be established rather than assumed.

PMID- 15031586
TI  - Psychometric theory is an obstacle to the progress of clinical research.
AB  - Psychometric theory is the basis for the development of assessment instruments in
      psychiatric research. However, the psychometric model appears to be largely
      inadequate in the clinical setting because of its lack of sensitivity to change
      and its quest for homogeneous components. Clinimetrics offers a viable
      alternative to psychometrics, both from a conceptual and a methodological
      viewpoint. Current diagnostic entities (DSM) are based on clinimetric principles,
      but their use is still influenced by psychometric models. Suggestions for
      switching gears in assessment research are offered.

PMID- 15031587
TI  - Management of obsessive compulsive disorder.

PMID- 15031588
TI  - Panic attacks and the risk of depression among young adults in the community.
AB  - OBJECTIVES: To determine the association between panic attacks and the risk of
      major depression among young adults in the community. METHODS: Data were drawn
      from a 21-year longitudinal birth cohort study (n = 1, 265). Multiple logistic
      regression analyses were used to determine the association between panic attacks
      in adolescence (age 15-21 years) and the risk of current major depression (past
      month). RESULTS: Having a panic attack in the preceding 3 years was significantly
      associated with elevated risk of current major depression (past month) at the
      ages of 18 and 21. This association persisted after adjusting for a range of
      fixed social, family and individual risk factors for psychopathology, history of
      major depression, comorbid psychiatric disorder and life adversity among both
      males (OR = 8.9; 95% CI = 3.9-20.4) and females (OR = 2.3; 95% CI = 1.2-4.2).
      CONCLUSIONS: These data are consistent with and extend previous work by showing
      that panic attack increases the risk of current major depression, independent of
      the effects of psychiatric comorbidity and other early risk factors for
      psychopathology, though much of this relationship appears to be explained by
      common risk factors and comorbidity. These data show new evidence of interaction
      between gender and panic attacks in the risk of depression among young persons.
      Replication of these findings is needed, as are future studies that further
      investigate the underlying mechanism of this association.

PMID- 15031589
TI  - Prediction of treatment outcome of patients with functional gastrointestinal
      disorders by the diagnostic criteria for psychosomatic research.
AB  - BACKGROUND: The Diagnostic Criteria for Psychosomatic Research (DCPR) have been
      demonstrated to be useful in identifying specific psychological conditions of
      medical patients. The aim of this study was to evaluate the clinical utility of
      the DCPR in predicting the treatment outcome of patients with functional
      gastrointestinal disorders (FGID). METHODS: FGID outpatients were allocated to
      improved (n = 65) and unimproved (n = 40) groups on the basis of preestablished
      criteria following 6 months of treatment. Patients were administered the
      structured interview for DCPR at baseline and the Gastrointestinal Symptom Rating
      Scale both at baseline and follow-up. RESULTS: In the unimproved patients, the
      prevalence of the DCPR categories of alexithymia (82.2%) and persistent
      somatization (72.5%) was significantly higher while health anxiety was more
      prevalent in improved patients (21.5%). No unimproved patient lacked a DCPR
      diagnosis while multiple DCPR diagnoses were significantly higher in the
      unimproved group (90%). In the regression analysis, alexithymia, persistent
      somatization, a higher number of DCPR diagnoses for each patient and, to a lesser
      extent, greater symptom severity at baseline were significant predictors of
      unimprovement. Health anxiety, even after controlling for gastrointestinal
      symptoms, was a significant predictor of improvement. CONCLUSIONS: The ability to
      predict treatment outcome indicates the clinical utility of the DCPR. Clinicians
      may improve treatment outcome for FGID patients by identifying particular
      psychosomatic syndromes (alexithymia, persistent somatization, and health
      anxiety) and patients with multiple DCPR clusters, and attempting to address
      specific therapeutic interventions.

PMID- 15031590
TI  - Social support and the persistence of complaints in chronic fatigue syndrome.
AB  - BACKGROUND: Several studies suggested that the surroundings of chronic fatigue
      syndrome (CFS) patients are of importance in the persistence of complaints.
      Contrary to what was expected, participation in support groups has not led to
      clinical improvement. The purpose of the present study was to describe social
      support in CFS patients as compared with other fatigued and non-fatigued groups.
      Further, changes in social support and the influence of social support on the
      course of CFS over a period of more than 1 year were studied in patients with and
      without treatment. METHODS: Baseline data were assessed in 270 CFS patients, 150
      disease-free breast cancer patients, 151 fatigued employees on sick-leave and 108
      healthy subjects using the Social Support List and Significant Others Scale. CFS
      patients were followed in cognitive behaviour therapy (CBT), guided support
      groups and natural course at 8 and 14 months. RESULTS: CFS patients and fatigued
      employees reported more negative interactions and insufficiency of supporting
      interactions than cancer patients and healthy controls. No differences in
      frequency of supporting interactions were found. Negative interactions decreased
      significantly after treatment with CBT, but did not change in support groups or
      natural course. In the natural course, higher fatigue severity at 8 months was
      predicted by more negative interactions at baseline. CONCLUSIONS: In CFS patients
      and fatigued employees, social support is worse than in disease-free cancer
      patients and healthy controls. Lack of social support was identified as a new
      factor in the model of perpetuating factors of fatigue severity and functional
      impairment in CFS.

PMID- 15031591
TI  - Does meeting needs improve quality of life?
AB  - BACKGROUND: This study investigated the relationship between patient-rated unmet
      needs and subjective quality of life using routine outcome data. METHODS: 265
      mental health service patients from South Verona were assessed using the
      Camberwell Assessment of Need, the Lancashire Quality of Life Profile, and other
      standardised assessments of symptoms, disability, function and service
      satisfaction. At 1-year follow-up, 166 patients were still in contact, of whom
      121 patients (73%) were re-assessed. RESULTS: Higher baseline quality of life was
      associated with being male, a diagnosis of psychosis, higher disability, higher
      satisfaction with care, fewer staff-rated or patient-rated unmet needs, and fewer
      patient-rated met needs (accounting for 40% of the variance). Specifically, fewer
      baseline patient-rated unmet needs were cross-sectionally associated with a
      higher quality of life (B = -0.08, 95% CI -0.12 to -0.04). Apart from its
      baseline value, the only baseline predictor of follow-up QoL was patient-rated
      unmet need (B = -0.08, 95% CI -0.21 to -0.09), accounting for 58% of the variance
      in follow-up quality of life. Graphical chain modelling confirmed this
      association. CONCLUSIONS: The association between high numbers of unmet needs and
      low subjective quality of life appears increasingly robust across several
      studies. Future research will need to investigate whether changes in needs
      precede changes in quality of life. This study provides further evidence that a
      policy of actively assessing and addressing patient-rated unmet needs may lead to
      improved quality of life.

PMID- 15031592
TI  - Convergent and discriminant validity of the Yale-Brown Obsessive-Compulsive Scale
      Symptom Checklist.
AB  - BACKGROUND: The factor structure of the Yale-Brown Obsessive-Compulsive Scale
      Symptom Checklist (Y-BOCS-SC) has been well established, but its convergent and
      divergent reliability have yet to be studied. METHODS: Fifty-six obsessive
      compulsive disorder (OCD) patients were administered the clinician-administered Y
      BOCS-SC and Hamilton Rating Scale for Depression (HRSD), together with the self
      administered Maudsley Obsessive Compulsive Inventory (MOCI), Padua Inventory
      (PI), State-Trait Anxiety Inventory (STAI), and Beck Depression Inventory (BDI).
      RESULTS: Overall, the correspondence between the Y-BOCS-SC and self-administered
      measures of OCD symptoms was poor to moderate. Its convergent validity was
      adequate for its washing dimension but poor for its other dimensions. The
      discriminant validity of the Y-BOCS-SC was adequate, showing little overlap with
      overall illness severity (total Y-BOCS) and state measures (BDI, STAI, HRSD). In
      contrast, self-administered OCD measures were significantly correlated with
      overall illness severity and state measures. CONCLUSIONS: The convergent validity
      of the Y-BOCS-SC was generally poor and this could only be partially explained by
      the incomplete coverage of some OCD symptoms in the self-administered scales. Its
      discriminant validity was good. Both self- and clinician-administered measures
      should be used in OCD research, as they seem to measure relatively non
      overlapping constructs. Further research on the psychometric properties of the Y
      BOCS-SC is needed.

PMID- 15031593
TI  - The role of new agents in the treatment of colorectal cancer.
AB  - New drugs improved efficacy or convenience of treatment in metastatic colorectal
      cancer. The oral fluoropyrimidines capecitabine and UFT are less toxic but
      equally efficacious relative to intravenous bolus 5-fluorouracil (5-FU)/folinic
      acid (FA). These agents might be beneficial for patients who unlikely benefit
      from the more intensive combination therapy with infusional 5-FU/FA and
      irinotecan or oxaliplatin. First-line therapy with irinotecan or oxaliplatin and
      5-FU/FA induces an objective response in up to 50% of the patients and may allow
      neoadjuvant concepts in unresectable liver metastasis. The combination therapy
      increased progression-free survival and in the case of irinotecan/5-FU/FA also
      overall survival when compared to 5-FU/FA. Sequential treatment with infusional 5
      FU/FA plus oxaliplatin followed by 5-FU/FA plus irinotecan or vice versa results
      in a median survival exceeding 20 months. Thus, patients in a good performance
      status and with favorable prognostic parameters should be offered first-line
      combination treatment of irinotecan or oxaliplatin with 5-FU/FA, whereby 5-FU is
      preferably administered as an infusion for combination therapy. New targets in
      the treatment of colorectal cancer are the EGF and VEGF receptor. The monoclonal
      EGF receptor antibody cetuximab alone and in combination with irinotecan is
      active in second-line treatment. The VEGF antibody bevacizumab prolongs survival
      when given in combination with 5-FU/FA and irinotecan.

PMID- 15031594
TI  - Gemcitabine plus paclitaxel as first-line chemotherapy for patients with advanced
      breast cancer.
AB  - OBJECTIVES: To assess the efficacy and tolerability of gemcitabine and paclitaxel
      as first-line treatment in advanced breast cancer. METHODS: Patients with
      histologically confirmed metastatic or metastatic plus locally advanced breast
      cancer received gemcitabine 1,200 mg/m(2) on days 1 and 8 and paclitaxel 175
      mg/m(2) on day 1 every 21 days for 8 cycles. RESULTS: From December 1999 to
      August 2001, 45 patients, with a median age of 53.5 years (range, 22-77),
      received a total of 260 cycles. All were assessable for response and toxicity.
      Twenty-seven patients had prior adjuvant therapy. Hormonal receptor status was
      positive in 31.1% and negative in 40.0% of patients. Main metastatic sites
      included soft tissue (62.2%) and lung (53.3%). The objective response rate was
      66.7%; complete response, 22.2%; partial response, 44.4%; stable disease, 15.6%;
      progressive disease, 17.8%. Median duration of response was 18 months and median
      time to tumor progression was 11 months. Grade 3/4 leukopenia, neutropenia, and
      thrombocytopenia developed in 13.3% of patients, and 15.5% developed grade 3/4
      mucositis. No treatment-related deaths occurred. Median overall survival was 19
      months. CONCLUSIONS: Gemcitabine plus paclitaxel is an active combination with a
      favorable toxicity profile as first-line treatment for patients with advanced
      breast cancer.

PMID- 15031595
TI  - Transcatheter arterial chemotherapy with and without embolization in patients
      with hepatocellular carcinoma.
AB  - OBJECTIVE: This study compared the antitumor effect, adverse effects and survival
      between transcatheter arterial embolization (TAE) and transcatheter arterial
      infusion chemotherapy (TAI) in patients with hepatocellular carcinoma (HCC).
      METHODS: The study population consisted of 168 consecutive patients with advanced
      HCC treated with transcatheter arterial treatments using cisplatin suspended in
      lipiodol. Among these, 74 patients were treated with TAE, and the remaining 94
      patients were treated with TAI. RESULTS: There were no significant differences in
      any baseline characteristics except hemoglobin, platelets, albumin, and glutamic
      pyruvic transaminase. Complete or partial tumor response was achieved in 54
      patients (73%) in the TAE group and in 48 patients (51%) in the TAI group (p <
      0.01). There were two treatment-related deaths caused by acute hepatic failure
      and acute renal failure in the TAE group. Nausea and deterioration of serum
      transaminase after TAE were significantly more severe than after TAI. Median
      survival time and survival rates at 5 years were 3.1 years and 25% in the TAE
      group, and 2.5 years and 18% in the TAI group (p = 0.37). CONCLUSION: TAE has a
      higher antitumor effect than TAI, but does not significantly improve the survival
      of patients with HCC.

PMID- 15031596
TI  - Phase II study of gemcitabine combined with uracil-tegafur in metastatic
      pancreatic cancer.
AB  - OBJECTIVE: The single agent gemcitabine is the standard first-line treatment for
      advanced pancreatic cancer. Recent studies of a combination of gemcitabine and 5
      fluorouracil (5-FU) revealed that survival data were superior to those with
      gemcitabine or 5-FU alone. The administration of oral uracil-tegafur (UFT) is
      more convenient and simulates the effect of a continuous or protracted infusion
      of 5-FU. Therefore, we conducted a phase II study of gemcitabine combined with
      UFT in metastatic pancreatic cancer patients and assessed the efficacy and the
      toxicity of the regimen. METHODS: Twenty-two pancreatic adenocarcinoma patients
      (18 males, 4 females) were enrolled from December 2000 to September 2002. The
      regimen consisted of gemcitabine 1,000 mg/m(2) once weekly for 3 consecutive
      weeks, and oral UFT 390 mg/m(2)/day (in 3 divided doses) on days 1-14. The cycle
      was repeated every 28 days. The objective tumor response was evaluated after 2
      courses of chemotherapy. RESULTS: 82 cycles were administered in total, with a
      median of 3 cycles per patient (range 1-6 cycles). The median age was 52 years
      (range 28-69 years). Response to treatment could be assessed in all patients. The
      objective response rate was 22.7% (95% CI, 7.8-45.4) with no complete response
      and 5 partial responses. Four patients (18.2%) had stable disease and 13 patients
      (59.1%) had a progression. The median time to progression was 4.2 months (range
      0.9-13.6). The median overall survival was 5.8 months (range 0.5-13.6). Of 10
      patients eligible for the assessment of clinical benefit response, 4 (40%, 95% CI
      12.2-73.8) showed clinical benefit. Among 21 patients with baseline CA 19-9
      levels, CA 19-9 was reduced by 50% or more in 12 patients (57.1%). The
      chemotherapy was generally well tolerated and the most common grade 3-4 toxic
      side effects were neutropenia (18.2%), anemia (4.5%), and diarrhea (4.5%).
      CONCLUSIONS: The combination chemotherapy with gemcitabine and UFT in metastatic
      pancreatic cancer was tolerable for most patients but showed modest response
      rates and clinical benefit. However, a randomized phase III study should be
      conducted in order to further test the efficacy of the regimen.

PMID- 15031598
TI  - Response to chemotherapy (irinotecan plus 5-fluorouracil) in colorectal carcinoma
      can be predicted by tumour DNA content.
AB  - OBJECTIVE: The aim of this study was to identify markers that might predict
      response to chemotherapy. Postoperative chemotherapy improves the outcome in
      stage III colon cancer and is widely accepted as a standard therapy, but there
      are currently no reliable predictors to identify and select patients that will
      benefit. METHODS: Using DNA image cytometry, the DNA content was determined from
      the isolated nuclei of 56 primary colorectal carcinomas of patients who received
      chemotherapy (either irinotecan or irinotecan plus 5-fluorouracil and folinic
      acid) for advanced disease. Response to chemotherapy could be reliably evaluated
      in 53 patients. RESULTS: The modal DNA content (ploidy status) of the tumour
      correlated with the observed response to chemotherapy (p = 0.01). An objective
      response was observed in 56% of patients whose tumour histograms displayed
      tetraploid, peri-tetraploid or multiploid patterns of peaks, compared with 19% in
      patients with diploid, peri-diploid or aneuploid peaks. Notably, 86% (6/7) of
      patients whose tumours displayed a multiploid peak pattern showed an objective
      response and 1 patient had stable disease. CONCLUSIONS: This study suggests that
      modal DNA content can be used to predict a patient's response to chemotherapy in
      advanced colorectal carcinoma. This may help in identifying patients who will
      benefit most from therapy for advanced colorectal cancer.

PMID- 15031597
TI  - A phase II study of three-weekly docetaxel and weekly trastuzumab in HER2
      overexpressing advanced breast cancer.
AB  - BACKGROUND: To test safety and activity of 3-weekly doses of docetaxel and a
      weekly dose of trastuzumab in women with HER2-overexpressing advanced breast
      cancer. PATIENTS AND METHODS: Forty-two women, median age 53 years (range 36-73
      years), with HER2-overexpressing advanced breast cancer were enrolled in a study
      of docetaxel, 75 mg/m(2) q3w for 6 cycles, and trastuzumab, 4 mg/kg loading dose,
      2 mg/kg weekly thereafter. Thirty-four patients (81%) had visceral metastatic
      involvement. Thirty-five patients had received prior chemotherapy as part of
      their treatment: adjuvant/neoadjuvant (26), metastatic (2) and both (7). Thirty
      one patients had been previously exposed to an anthracycline and 11 to
      paclitaxel. Four patients had previously received high-dose chemotherapy followed
      by autologous stem cell transplant. RESULTS: 226 cycles (median 6, range 1-6)
      were administered. The median delivered dose intensity for docetaxel was 24
      mg/m(2)/week (range 16-25 mg/m(2)/week). The intent to treat overall response
      rate was 67% (95% confidence interval, 52-79%). Median progression-free survival,
      time to treatment failure, and duration of response were 9, 8 and 12 months,
      respectively. Symptomatic cardiotoxicity (grade 3) occurred in 1 patient. The
      most common grade 3/4 toxicity was neutropenia (76% of the patients), although
      febrile neutropenia did not occur. CONCLUSIONS: Three-weekly doses of docetaxel
      and a weekly dose of trastuzumab is an active and safe combination in patients
      with HER2-overexpressing advanced breast cancer.

PMID- 15031599
TI  - Mechanisms of paclitaxel-induced apoptosis in an ovarian cancer cell line and its
      paclitaxel-resistant clone.
AB  - BACKGROUND: To understand the complicated network of paclitaxel (PTX)-induced
      apoptosis pathways and to elucidate mechanisms of drug resistance in ovarian
      cancer, we looked at PTX-induced apoptosis by using cDNA microarray. We also
      quantitated the changes in apoptosis-related proteins in the process of
      apoptosis. METHODS: An ovarian cancer cell line KF, and its PTX-resistant clone
      KFTX, were treated with PTX or carboplatin (CBDCA). After exposure to PTX or
      CBDCA, the induction of apoptosis was examined by internucleosomal DNA
      fragmentation. Changes in mRNA expression after 12 h of exposure to PTX were
      studied using cDNA microarray and RT-PCR. Changes in P53 and Bcl-2 levels were
      also measured over 24 h by ELISA. RESULTS: With increased doses of PTX or CBDCA,
      an increase in apoptosis was noted in both cell lines. cDNA microarray revealed
      that PTX treatment upregulated expression of caspase 1, 2, 3, 4, 6, 9, 10, their
      activator apaf-1, and stress reaction-related genes, gadd34, gadd153 in KF,
      although most of them were unchanged or downregulated in KFTX. bag-1 and hsc70
      were markedly upregulated in KFTX. p53 and bcl-2 were not upregulated in either
      cell line. Results from protein studies also supported the cDNA microarray data.
      CONCLUSIONS: p53-independent mitochondrial pathways and stress-reaction-induced
      pathways play critical roles in PTX-induced apoptosis in ovarian cancer cells.
      Suppression of those pathways and upregulation of bag-1 and hsp-70 played an
      important role in acquiring resistance to PTX.

PMID- 15031600
TI  - Pharmacokinetics of 1alpha,25-dihydroxyvitamin D3 in normal mice after systemic
      exposure to effective and safe antitumor doses.
AB  - OBJECTIVES: Calcitriol, 1alpha,25-dihydroxyvitamin D(3) (1,25-D(3)) has potent
      antiproliferative effects and potentiates the antitumor activity of many other
      cytotoxic drugs. 1,25-D(3) plasma pharmacokinetic (PK) parameters associated with
      antitumor activity in experimental animal models are unknown. The objective of
      this study was to determine plasma calcitriol PK in normal mice at doses of
      calcitriol which are active in suppressing tumor growth. METHODS: Plasma 1,25
      D(3) PK were examined in normal C3H/HeJ mice after a single intraperitoneal dose
      of 0.125 or 0.5 microg 1,25-D(3)/mouse. PK blood samples were collected from
      groups of 5-9 mice at each time point up to 24 h after 1,25-D(3) administration.
      Plasma 1,25-D(3) concentrations were measured by radioimmunoassay. Plasma 1,25
      D(3) concentration diurnal variation was determined in blood samples from
      untreated animals collected in the morning (9:00-11:00 a.m.) and in the evening
      (4:00-9:00 p.m.). RESULTS: Median baseline plasma 1,25-D(3) concentration
      measured in the morning and in the evening were 0.082 ng/ml (CI 95%, 0.076-0.099)
      and 0.067 ng/ml (CI 95%, 0.058-0.075), respectively (p = 0.004). After 0.125 and
      0.5 microg dosing, peak plasma 1,25-D(3) concentrations (Cp(max)) were 12.0 ng/ml
      (CI 95%, 10.8-12.6) and 41.6 ng/ml (CI 95%, 40.8-53.6), respectively. The
      corresponding areas under the curve (AUC(0->24 h)) were 47.0 (CI 95%, 43.2-51.1)
      and 128.0 (CI 95%, 127.0-130.0) ng.h/ml. No dose-related changes in time to
      Cp(max) and apparent total plasma clearance were observed. CONCLUSIONS: These
      results demonstrate diurnal variation in baseline plasma 1,25-D(3) concentrations
      in mice. Plasma 1,25-D(3) PK in mice receiving doses that are effective in
      slowing tumor growth, inducing cell cycle arrest and apoptosis, and potentiating
      taxanes and platinum analogue antitumor activity are at least 5-10 times higher
      than those easily achieved and nontoxic in patients receiving high-dose
      intermittent oral therapy.

PMID- 15031601
TI  - Beta-hydroxyisovalerylshikonin and cisplatin act synergistically to inhibit
      growth and to induce apoptosis of human lung cancer DMS114 cells via a tyrosine
      kinase-dependent pathway.
AB  - beta-Hydroxyisovalerylshikonin (beta-HIVS) and cisplatin (CDDP) had a synergistic
      growth-inhibitory effect on cultured human small-cell lung carcinoma DMS114
      cells, as well as on human leukemia U937 and epidermoid carcinoma A431 cells,
      while beta-HIVS and CDDP alone at the same respective concentrations had little
      effect. Growth inhibition was accompanied by induction of apoptosis, as
      determined by an ELISA for the detection of cell death and the TUNEL assay. Using
      phosphotyrosine-specific antibodies (PY20), we observed that tyrosine kinase
      activity in DMS114 cells was inhibited by treatment with beta-HIVS and CDDP
      together. The tyrosine kinase activity of isolated Src and that of isolated
      receptors for epidermal growth factor were also inhibited by the two agents
      together. The synergistic effects of the growth of DMS114 cells of beta-HIVS and
      CDDP were not due simply to the intracellular accumulation of CDDP or to levels
      of DNA adducts. Our data suggest that the synergistic effect on the growth of
      DMS114 cells of beta-HIVS and CDDP might be a result of the inhibition of a
      tyrosine kinase-dependent pathway.

PMID- 15031602
TI  - Effects of histamine and the h2 receptor antagonist ranitidine on ischemia
      induced acute renal failure: involvement of IL-6 and vascular endothelial growth
      factor.
AB  - BACKGROUND: Vascular endothelial growth factor (VEGF) exerts cytoprotective,
      antiapoptotic and proangiogenic effects; its synthesis is induced by hypoxia,
      several cytokines and histamine. The effects of histamine and the H2 receptor
      antagonist ranitidine on renal VEGF and IL-6 synthesis were investigated in a
      well-established rat model of renal ischemia/reperfusion injury. METHODS:
      Following 7 days of pretreatment with histamine (H group; n = 12), ranitidine (R
      group; n = 10) or vehicle (controls; n = 13), the left vascular pedicle was
      clamped for 50 min in uninephrectomized male rats and survival assessed in the
      different treatment groups. Additionally, renal IL-6 mRNA expression, as well as
      VEGF mRNA and protein abundance were measured in the three treatment groups
      following pretreatment only, 2 and 16 h after 50 min of renal ischemia (n =
      6/group/timepoint). RESULTS: Ranitidine significantly increased, while histamine
      significantly decreased survival following renal ischemia. Renal IL-6 mRNA
      expression increased 2 h after reperfusion in all groups and decreased
      thereafter, with the lowest level observed in the R group. While VEGF mRNA did
      not change in controls, histamine increased, whereas ranitidine decreased its
      expression during the follow-up. Two hours after ischemia a twofold increase in
      renal VEGF protein abundance was observed in controls and the H group and
      significantly higher values were noted in the R group at this time point. A
      further increase in VEGF protein was only present in the H group 16 h after
      reperfusion. CONCLUSION: These results indicate an important role of histamine in
      kidney damage following renal ischemia. The beneficial effects of ranitidine were
      partly mediated by decreased IL-6 and VEGF mRNA expression and significant early
      increase in renal VEGF abundance.

PMID- 15031603
TI  - Endothelial cells modulate osteogenesis in calcifying vascular cells.
AB  - The potential role of vascular endothelium in atherosclerotic calcification is
      unknown. Endothelial cells (EC) express bone morphogenetic proteins (BMP), and EC
      conditioned medium is osteoinductive in marrow stromal cells. To test whether EC
      are osteoinductive in vascular cells, we used calcifying vascular cells (CVC)
      that form nodules and mineralize in vitro. We established a coculture model with
      EC grown opposite CVC on membranes coated with collagen I or collagen IV, both of
      which are expressed in atherosclerotic lesions. On collagen I, EC did not alter
      CVC nodule formation, calcification or expression of the osteogenic marker Cbfa1,
      the chondrogenic marker collagen IX or smooth muscle cell alpha-actin. However,
      on collagen IV, EC abolished nodule formation and calcification, and expression
      of cell markers decreased, suggesting dedifferentiation. Matrix GLA protein
      (MGP), also expressed in atherosclerotic lesions, was added to CVC in coculture.
      Unexpectedly, MGP enhanced Cbfa1 expression in CVC on both collagen I and IV. The
      enhancement was most apparent on collagen IV, where calcification also increased.
      However, MGP did not restore nodule formation on collagen IV, suggesting that
      nodule formation and cell differentiation are separate processes. The effect of
      EC on CVC calcification was suppressed by noggin, an inhibitor of BMP activity,
      and in part mimicked by replacement of EC by BMP-2. Our results support a role
      for endothelium in vascular calcification, modulated by collagens and MGP.

PMID- 15031604
TI  - Exogenous BH4/Bcl-2 peptide reverts coronary endothelial cell apoptosis induced
      by oxidative stress.
AB  - BACKGROUND: Vascular endothelium undergoes apoptosis when exposed to reactive
      oxygen species (ROS), including hydrogen peroxide and superoxide radicals. ROS
      are believed to be the cause of damage to small vessels during ischemia
      reperfusion injury and of arterial damage during atherosclerosis. Hydrogen
      peroxide-induced apoptosis is mediated through the inhibition of Bcl-xl activity
      and caspase-3 and caspase-9 activation. The BH4 domain of the Bcl-2 family
      members is responsible for their antiapoptotic activity. The BH4 domains of Bcl-2
      and Bcl-xl inhibit cytochrome c release and the loss of mitochondrial membrane
      potential. METHODS AND RESULTS: The purpose of this project was to study the
      antiapoptotic effect of cell-permeant derivative of Bcl-2 (BH4 peptide) on
      endothelial cells exposed to stress conditions. BH4 peptide was conjugated to the
      cell-permeable peptide TAT and was applied to endothelial cells under conditions
      of serum starvation and hydrogen peroxide treatment. TAT-BH4 reduced caspase-3
      activity and prevented apoptotic cell death. CONCLUSION: Our results indicate
      that TAT-BH4 peptide can protect endothelial cells from ROS-induced apoptosis.

PMID- 15031605
TI  - The basophil-specific ectoenzyme E-NPP3 (CD203c) as a marker for cell activation
      and allergy diagnosis.
AB  - Basophils are effector cells of allergic reactions. These cells produce and store
      a number of vasoactive and immunomodulatory mediators. During an allergic
      reaction, basophils can release their mediator substances into the extracellular
      space and thus contribute to the clinical picture and symptoms in allergy. The
      phenotypic hallmark of basophils is expression of high-affinity IgE receptors (Fc
      epsilon RI) on their cell surface together with expression of the activation
      linked molecule CD203c. This ectoenzyme is located both on the plasma membrane
      and in the cytoplasmic compartment of basophils. Cross-linking of the Fc epsilon
      RI by an allergen or anti-IgE antibody results in a rapid upregulation of
      intracellular CD203c molecules to the cell surface and is accompanied by mediator
      release. CD203c is therefore a promising target molecule for a flow cytometry
      based test to analyze sensitized individuals and patients with type I allergy. In
      the present article, we review the current knowledge of CD203c with special
      regard to its tissue distribution and regulation in basophil activation. In
      addition, we discuss the application of CD203c in allergy diagnosis.

PMID- 15031606
TI  - What is going on with natural killer cells in HIV infection?
AB  - Natural killer (NK) cells represent 10-15% of circulating lymphocytes and are
      important mediators of both natural and adaptive immunity. They participate in
      immune surveillance against malignancies and virus infection and are involved in
      the complex immune responses of transplantation, autoimmune diseases and
      immunosuppression. They can also mediate physiological regulation of
      hematopoiesis, homeostasis of reproduction and placentation. In recent years new
      advances have been achieved in understanding the mechanisms whereby NK cells
      exert their cytotoxic and regulatory roles. Here, we review the physiology of NK
      cells with special attention to its role in HIV infection.

PMID- 15031607
TI  - Expression of actin and tubulins in purified human basophil leukocytes upon
      stimulation with IL-3.
AB  - BACKGROUND: Pharmacological and morphological results indicate that the
      cytoskeleton proteins tubulins and actin play a role in the histamine release
      process in basophil leukocytes and mast cells. In this report, we investigate the
      expression of these cytoskeleton proteins in purified human basophils upon
      stimulation with anti-IgE and IL-3. METHODS: Human basophils were purified using
      a negative selection procedure. They were incubated for 6 h with anti-IgE and/or
      IL-3 in radiolabeling media. Proteins in the cells were analyzed by two
      dimensional gel electrophoresis and autoradiography. Actin and alpha- and beta
      tubulin were identified by amino acid sequence analysis or matrix assisted laser
      desorption/ionisation time-of-flight mass spectrometry. The synthesis of these
      proteins under different experimental conditions was evaluated by densitometry.
      RESULTS: Actin is regulated dose dependently by IL-3 with an optimum
      concentration of 100 ng/ml, corresponding to the optimal IL-3 concentration for
      enhancement of histamine release. The synthesis of tubulins was not significantly
      upregulated by IL-3 or anti-IgE alone, but there was a slight and significant
      upregulation of tubulins upon stimulation with both IL-3 and anti-IgE in doses
      optimal for maximal histamine release. CONCLUSIONS: The de novo synthesis of
      actin is regulated dose dependently by IL-3 in purified human basophils in short
      term culture. The optimum IL-3 concentration is the same as for enhancement of
      histamine release, suggesting that the same processes that regulate IL-3-induced
      enhancement of histamine release also regulate the expression of actin. The
      finding that the expression of the tubulins is not upregulated by IL-3 alone
      suggests that regulation of tubulin synthesis is not a pathway by which IL-3 in
      itself primes basophil histamine release.

PMID- 15031609
TI  - Caspase-3-mediated apoptosis of human eosinophils by the tissue-invading helminth
      Paragonimus westermani.
AB  - BACKGROUND: Eosinophils are important cells in host immunity to infections by
      parasitic worms. Tissue-invasive helminthic parasites have been known to induce
      apoptosis of immune cells for their successful establishment in vivo. We have
      previously found that high doses of excretory-secreted products (ESP) secreted by
      lung fluke Paragonimus westermani newly excysted metacercariae (PwNEM), which
      cause pulmonary or extrapulmonary paragonimiasis in human beings, accelerate
      eosinophil cell death. However, little is known about the mechanism of eosinophil
      apoptosis induced by the Paragonimus-derived products. OBJECTIVE: We examined
      involvement of caspase 3 activation in eosinophil cell death induced by ESP
      produced by PwNEM. METHODS: Eosinophils were isolated from the peripheral blood
      of healthy donors by CD16-negative immunomagnetic selection. We examined the
      inhibitory effect of pan-caspase inhibitor on ESP-triggered phosphatidylserine
      (PS) externalization on the outer surface of eosinophils and intracellular
      activation of caspase 3 in cell lysates treated with the ESP. RESULTS: When ESP
      secreted by PwNEM were incubated for up to 3 h with eosinophils, they increased
      surface exposure of PS on eosinophils in a time- and dose-dependent manner. This
      proapoptotic effect of the ESP on eosinophils was significantly inhibited by
      pretreatment of cells with pan-caspase inhibitor z-VAD-fmk, and was completely
      abolished by heat inactivation of ESP at 56 degrees C. The activated forms of
      caspase 3 were also clearly detected in eosinophils incubated with ESP. Moreover,
      ESP potently inhibited prolonged survival of eosinophils induced by cytokines
      such as IL-5, IL-3, and GM-CSF. CONCLUSION: These results suggest that ESP
      secreted by PwNEM contain biological active factors causing caspase-3-mediated
      apoptosis of human eosinophils, thereby enabling the larvae to evade and to
      subvert the tackle by eosinophils during the early phase of the infection.

PMID- 15031610
TI  - Exposure to indoor allergens in homes of patients with asthma and/or rhinitis in
      southeast Brazil: effect of mattress and pillow covers on mite allergen levels.
AB  - BACKGROUND: Exposure and sensitization to indoor allergens have been associated
      with the development of asthma and other allergic diseases in many parts of the
      world. It is important to establish the degree of exposure, and to evaluate
      whether allergen control measures are effective in a particular area. METHODS:
      Concentrations of major allergens of mites, cockroach, cat and dog were measured
      in dust samples from homes of 24 mite-allergic patients living in Ribeirao Preto,
      Brazil. Allergen concentrations were quantitated by monoclonal antibody-based
      ELISA. Mite-impermeable mattress and pillow covers were applied to beds in the
      homes of 19 of the 24 patients, and group 1 mite allergen levels were measured 1
      and 6 months following intervention. RESULTS: Patients were exposed to high
      concentrations of mite allergens in their homes. 87.5% of the homes presented
      concentrations of group 1 allergens >10 microg/g of dust in at least one site.
      Cockroach allergen concentrations were low in most samples. Dog allergen
      concentrations were significantly higher in homes with dogs as compared to those
      without dogs. Mean concentrations of cat allergen were 0.1 microg/g. Mite
      allergen concentrations in bedding samples dropped from 24 microg/g at baseline
      to 0.9 and 1.0 microg/g, respectively, 1 and 6 months following encasement of
      mattresses and pillows. CONCLUSIONS: Significant mite allergen reduction can be
      achieved in an area of high degree of exposure to mite allergens. Further studies
      evaluating the effect of this reduction on symptoms and airway inflammation will
      be necessary to establish the effectiveness of mite avoidance measures in our
      area.

PMID- 15031611
TI  - Efficacy and safety of ebastine 20 mg compared to loratadine 10 mg once daily in
      the treatment of seasonal allergic rhinitis: a randomized, double-blind, placebo
      controlled study.
AB  - BACKGROUND: Few randomized studies have compared loratadine to ebastine in the
      symptomatic treatment of seasonal allergic rhinitis (SAR) patients. METHODS: This
      double-blind, placebo-controlled, randomized, parallel-group, comparative trial
      compared the efficacy and safety of ebastine 20 mg (E20), loratadine 10 mg (L10)
      and placebo (P), administered once daily, in the control of SAR symptoms over a 2
      week period. An additional 2-week treatment period was included in order to check
      sustained efficacy and tolerability. RESULTS: A total of 703 patients were
      enrolled: 282 patients in the E20 group, 279 in the L10 group and 142 in the P
      group. E20 showed a greater decrease from baseline in the main efficacy variable
      (mean daily reflective total symptom score) than L10 (p = 0.0018) or P (p =
      0.0024), whereas the difference between L10 and P was not significant. Moreover,
      reductions from baseline in all composite/individual daily reflective rhinitis
      symptom scores were significantly larger in patients receiving E20 than in
      patients receiving L10 or P. Most significant differences between E20 and L10 or
      P were maintained after 4 weeks of treatment. Overall, all treatments were safe
      and well tolerated. There was no significant difference in the percentage of
      patients who reported one or more adverse events (AEs) between the groups, and
      most AEs were mild to moderate (89.9%). CONCLUSIONS: E20 given once daily for 2
      weeks was more effective in the treatment of SAR symptoms than L10 or P. E20 also
      showed a sustained efficacy after 4 weeks of treatment, and overall was well
      tolerated and proved safe.

PMID- 15031608
TI  - Novel protein kinase C and matrix metalloproteinase inhibitors of vegetable
      origin as potential modulators of Langerhans cell migration following hapten
      induced sensitization.
AB  - BACKGROUND: Migration and maturation of epidermal dendritic cells, the Langerhans
      cells (LC), are central events in the initiation of the cutaneous immune
      response. LC migration from skin to draining lymph nodes is regarded as an
      indispensable step for the early phase of antigen-specific sensitization. Among
      the several agents which influence the ability of LC to migrate, previous studies
      have revealed that matrix metalloproteinases (MMPs) and protein kinase C (PKC)
      contribute to promoting LC migration. In this work, we studied the effect of two
      recently developed PKC and MMPs inhibitors of vegetable origin on the migration
      of in vitro activated LC. METHODS: The migratory capacity of epidermal and in
      vitro generated LC was assessed using a reconstituted basement membrane assay
      (Matrigel), mimicking the prerequisite passage through the dermal-epidermal
      basement membrane on the way to the lymph nodes. RESULTS: Contact with chemical
      allergens, Bandrowski's base or 2,4-dinitrobenzenesulfonic acid (DNBS), triggered
      migration. In the presence of PKC inhibitors, D-erythro-sphingosine and OX100, or
      an inhibitor of MMPs, LU105, allergen-induced migration of LC was strongly
      decreased. The association between OX100 and LU105 was more efficient in
      modulating the migration of activated LC compared to each molecule tested
      separately. CONCLUSIONS: These results showed that PKC and MMPs inhibitors act in
      synergy to inhibit the migration of activated epidermal dendritic cells in vitro.
      They underscore the role of PKC and MMPs inhibitors and suggest they may be of
      relevance for therapeutically regulating epidermal dendritic cell migration in
      inflammatory dermatoses.

PMID- 15031612
TI  - (S,S)-formoterol increases the production of IL-4 in mast cells and the airways
      of a murine asthma model.
AB  - BACKGROUND: Racemic formoterol is an equimolar mixture of (R,R)- and (S,S)
      formoterol. Several studies have shown (S,S)-formoterol to have proinflammatory
      effects. We previously reported that (S)-albuterol increased the secretion of
      histamine and interleukin (IL)-4 in murine mast cells. We thus hypothesized that
      (S,S)-formoterol promotes asthma by enhancing IL-4 production in mast cells of
      the asthmatic airway. METHODS: Murine and human mast cells were stimulated by
      high affinity IgE receptor (Fc epsilon RI) cross-linking or with phorbol
      myristate acetate/calcium ionophore A23187 (PMA/A23187). Jurkat T cells were
      stimulated with PMA. Cells were pretreated with either (R,R)- or (S,S)
      formoterol. Ovalbumin (OVA)-sensitized BALB/c mice were pretreated with (R,R)- or
      (S,S)-formoterol before each intranasal OVA challenge for 10 days.
      Bronchoalveolar lavage fluid was obtained from the mice. The levels of IL-4,
      histamine and PGD(2) were measured. Early and late allergic responses (EAR and
      LAR, respectively) to OVA challenge and airway hyperresponsiveness (AHR) were
      measured. RESULTS: (S,S)-formoterol enhanced the production of IL-4, histamine,
      and PGD(2) in mast cells, whereas (R,R)-formoterol had no effect. Neither (S,S)-
      nor (R,R)-formoterol had effect on IL-4 production in Jurkat T cells. In OVA
      challenged mice, (S,S)-formoterol increased IL-4 secretion, whereas (R,R)
      formoterol had no effect. Finally, (S,S)-formoterol enhanced the inflammatory
      changes in the peribronchial and perivascular areas without affecting EAR, LAR or
      AHR, whereas (R,R)-formoterol reduced EAR, LAR and AHR as well as cellular
      infiltration in the lung tissue of these mice. CONCLUSION: (S,S)-formoterol may
      exert adverse effects in asthma control by activating mast cells to produce
      proinflammatory mediators such as IL-4.

PMID- 15031613
TI  - Role of substance P in an NC/Nga mouse model of atopic dermatitis-like disease.
AB  - BACKGROUND: Atopic dermatitis (AD) can be exacerbated or induced in genetically
      predisposed individuals by psychological stress, which causes the release of
      substance P (SP). Therefore, SP may play an etiological role in the mechanisms
      underlying AD. METHODS: Changes in the number of mast cells and SP-containing
      mast cells in lesional skin, and the serum concentrations of SP and IgE during
      the development of AD-like disease up to 8 weeks after the start of picryl
      chloride (PiCl) induction in NC/Nga mice were examined. RESULTS: Clinical signs
      and symptoms seen in PiCl-treated NC/Nga mice as a model of AD-like disease began
      with erythema and haemorrhage, followed by oedema, superficial erosion, deep
      excoriation, scaling and dryness of the skin, as well as retarded growth, and the
      changes were exacerbated with an increase in the number of PiCl applications. An
      increase in the number of mast cells and eosinophil infiltration was observed in
      the lesional skin. The increase in SP-positive mast cells in the dermis in this
      model was significant from 1 week after the start of induction treatment,
      compared with intact mice, and SP-positive nerve fibres were observed in the
      dermis. CONCLUSION: SP is a crucial mediator of both dermatitis and scratching
      behaviour in this model.

PMID- 15031614
TI  - Effects of conjugated equine estrogen and medroxyprogesterone acetate on
      lipoprotein(a) and other lipoproteins in japanese postmenopausal women with and
      without dyslipidemia.
AB  - BACKGROUND/AIM: The cardiovascular effects of postmenopausal hormone replacement
      are controversially discussed. We investigated the effects of 12 months of
      treatment with conjugated equine estrogen and medroxyprogesterone acetate on
      lipoprotein(a) [Lp(a)] and other lipoproteins in Japanese postmenopausal women
      (PMW) with and without dyslipidemia. METHODS: Forty-three normolipidemic and 17
      dyslipidemic PMW [total cholesterol (TC) >/=220 mg/dl or triglyceride (TG) >/=150
      mg/dl] received conjugated equine estrogen (0.625 mg) plus medroxyprogesterone
      acetate (2.5 mg) daily for 12 months, and the results were compared with those of
      26 normolipidemic and 14 dyslipidemic subjects declining this treatment as
      controls. The fasting serum levels of Lp(a), TC, TG, high-density lipoprotein
      cholesterol, low- density lipoprotein cholesterol, apolipoprotein (Apo) AI, Apo
      AII, Apo B, Apo CII, and Apo E were measured in each subject at baseline and 12
      months after this treatment initiation. RESULTS: The treatment decreased Lp(a)
      similarly in normolipidemic and dyslipidemic PMW and decreased TC, low-density
      lipoprotein cholesterol, Apo CII, and Apo E and increased high-density
      lipoprotein cholesterol, Apo AI, and Apo AII in both groups. The therapy also
      significantly increased TG in normolipidemic but not dyslipidemic subjects. In
      controls, the levels of Lp(a) and other lipoproteins were unaltered. CONCLUSIONS:
      In PMW with or without dyslipidemia, improvement in Lp(a) and other lipoproteins
      may represent cardiovascular benefits of hormone replacement therapy. However, an
      elevation of the TG levels seen with the therapy warrants caution, especially in
      PMW without dyslipidemia.

PMID- 15031615
TI  - Effects of vitamin D supplementation on calcium balance and bone growth in young
      rats fed normal or low calcium diet.
AB  - OBJECTIVE: We examined the effect of vitamin D supplementation on bone growth in
      young rats fed a normal or low calcium diet. METHODS: Fifty female Sprague-Dawley
      rats, 6 weeks of age, were randomized by stratified weight method into five
      groups with 10 rats in each group: baseline control, 0.5% (normal) or 0.1% (low)
      calcium diet, and 0.5 or 0.1% calcium diet + vitamin D (25 microg/100 g, food
      intake). Duration of the experiment was 10 weeks. RESULTS: Vitamin D
      supplementation stimulated intestinal calcium absorption and increased urinary
      calcium excretion in rats fed a low or normal calcium diet. Vitamin D
      supplementation prevented the reduction in periosteal bone gain but enhanced
      enlargement of the marrow cavity and reduced the maturation-related cancellous
      bone gain in rats fed a low calcium diet, and increased the maturation-related
      cancellous and cortical bone gains in rats fed a normal calcium diet. CONCLUSION:
      This study shows the differential effects of vitamin D supplementation on born
      growth in young rats fed a normal or low calcium diet.

PMID- 15031616
TI  - Growth and metabolic control during puberty in girls with X-linked
      hypophosphataemic rickets.
AB  - OBJECTIVE: X-linked hypophosphataemic rickets (XLH) results in defective bone
      mineralization and impaired growth. Treatment with oral phosphate (Pi) and
      calcitriol improves but does not normalize growth. This study assessed whether
      pubertal growth and metabolic control contribute to the height deficit. METHODS:
      Study included patients with XLH who were treated with Pi-calcitriol from
      diagnosis to adult height; their hospital records, biochemistry and radiographs
      were reviewed. RESULTS: Six females with XLH were included. Their mean peak
      height velocity and total height gain during puberty were nearly normal despite
      deteriorating metabolic control. CONCLUSIONS: In treated girls with XLH, the
      pubertal growth is nearly normal despite suboptimal metabolic control. The major
      height loss occurs prior to puberty and is not recovered during the pubertal
      growth spurt.

PMID- 15031617
TI  - Association studies in candidate genes: strategies to select SNPs to be tested.
AB  - OBJECTIVE: When numerous single nucleotide polymorphisms (SNPs) have been
      identified in a candidate gene, a relevant and still unanswered question is to
      determine how many and which of these SNPs should be optimally tested to detect
      an association with the disease. Testing them all is expensive and often
      unnecessary. Alleles at different SNPs may be associated in the population
      because of the existence of linkage disequilibrium, so that knowing the alleles
      carried at one SNP could provide exact or partial knowledge of alleles carried at
      a second SNP. We present here a method to select the most appropriate subset of
      SNPs in a candidate gene based on the pairwise linkage disequilibrium between the
      different SNPs. METHOD: The best subset is identified through power computations
      performed under different genetic models, assuming that one of the SNPs
      identified is the disease susceptibility variant. RESULTS: We applied the method
      on two data sets, an empirical study of the APOE gene region and a simulated
      study concerning one of the major genes (MG1) from the Genetic Analysis Workshop
      12. For these two genes, the sets of SNPs selected were compared to the ones
      obtained using two other methods that need the reconstruction of multilocus
      haplotypes in order to identify haplotype-tag SNPs (htSNPs). We showed that with
      both data sets, our method performed better than the other selection methods.

PMID- 15031619
TI  - High-resolution joint linkage disequilibrium and linkage mapping of quantitative
      trait loci based on sibship data.
AB  - This paper proposes variance component models for high resolution joint linkage
      disequilibrium (LD) and linkage mapping of quantitative trait loci (QTL) based on
      sibship data; this can include population data if independent individuals are
      treated as single sibships. One application of these models is late onset complex
      disease gene mapping, when parental data are not available. The models
      simultaneously incorporate both LD and linkage information. The LD information is
      contained in mean coefficients of sibship data. The linkage information is
      contained in the variance-covariance matrices of trait values for sibships with
      at least two siblings. We derive formulas for calculating the probability of
      sharing two trait alleles identical by descent (IBD) for sibpairs in interval
      mapping of QTL; this is the coefficient of dominant variance of the trait
      covariance of sibpairs on major QTL. To investigate the performance of the
      formulas, we calculate the numerical values via the formulas and get satisfactory
      approximations. We compare the power and sample sizes for both LD and linkage
      mapping. By simulation and theoretical analysis, we compare the results with
      those of Fulker and Abecasis "AbAw" approach. It is well known that the
      resolution of linkage analysis can be low for complex disease gene mapping. LD
      mapping, on the other hand, can increase mapping precision and is useful in high
      resolution mapping. Linkage analysis is less sensitive to population subdivisions
      and admixtures. The level of LD is sensitive to population stratification which
      may easily lead to spurious association. Performing a joint analysis of LD and
      linkage mapping can help to overcome the limits of both approaches. Moreover, the
      advantages of the two complementary strategies can be utilized maximally. In
      practice, linkage analysis may be performed using pedigree data to identify
      suggestive linkage between markers and trait loci based on a sparse marker map.
      In the presence of linkage, joint LD and linkage mapping can be carried out to do
      fine gene mapping based on a dense genetic map using both pedigree and population
      data. Population and pedigree data of any type can be combined to perform a joint
      analysis of high resolution LD and linkage mapping of QTL by generalizing the
      method.

PMID- 15031618
TI  - Robust indices of Hardy-Weinberg disequilibrium for QTL fine mapping.
AB  - Hardy-Weinberg disequilibrium (HWD) measures have been proposed using dense
      markers to fine map a quantitative trait locus (QTL) to regions < approximately 1
      cM. Earlier HWD measures may introduce bias in the fine mapping because they are
      dependent on marker allele frequencies across loci. Hence, HWD indices that do
      not depend on marker allele frequencies are desired for fine mapping. Based on
      our earlier work, here we present four new HWD indices that do not depend on
      marker allele frequencies. Two are for use when marker allele frequencies in a
      study population are known, and two are for use when marker allele frequencies in
      a study population are not known and are only known in the extreme samples. The
      new measures are a function of the genetic distance between the marker locus and
      a QTL. Through simulations, we investigated and compared the fine mapping
      performance of the new HWD measures with that of the earlier ones. Our results
      show that when marker allele frequencies vary across loci, the new measures
      presented here are more robust and powerful.

PMID- 15031621
TI  - How to model a complex trait. 2. Analysis with two disease loci.
AB  - Complex traits are often governed by more than one trait locus. The first step
      towards an adequate model for such diseases is a linkage analysis with two trait
      loci. Such an analysis can be expected to have higher power to detect linkage
      than a standard single-trait-locus linkage analysis. However, it is crucial to
      accurately specify the parameters of the two-locus model. Here, we recapitulate
      the general two-locus model with and without genomic imprinting. We relate
      heterogeneity, multiplicative, and additive two-locus models to biological or
      pathophysiological mechanisms, and give the corresponding averaged ("best
      fitting") single-trait-locus models for each of the two loci. Furthermore, we
      derive the two-locus penetrances from the averaged single-locus models, under the
      assumption of one of the three model classes mentioned above. Using these
      formulae, if the best-fitting single-locus models are available, investigators
      may perform a two-trait-locus linkage analysis under a realistic model. This
      procedure will maximize the power to detect linkage for traits which are governed
      by two or more loci, and lead to more accurate estimates of the disease-locus
      positions.

PMID- 15031620
TI  - A framework for controlling false discovery rates and minimizing the amount of
      genotyping in the search for disease mutations.
AB  - OBJECTIVES: To develop a method for designing studies to find disease mutations
      that can achieve a set of goals with respect to proportions of false and true
      discoveries with the minimum amount of genotyping. METHODS: Derivation of an
      analytical framework supplemented with simulation techniques. The approach is
      illustrated for a fine mapping study and a whole-genome linkage disequilibrium
      scan. RESULTS: The use of multiple stages where earlier stages are characterized
      by very high false discovery rates (FDR) followed by an abrupt change to the
      required FDR in the final stage results in a 50-75% reduction in genotyping. The
      proportion of true discoveries is a much more important determinant of the
      genotyping burden than the FDR. Neither sample size nor controlling the false
      discoveries will present major problems in whole-genome LD scans but the amount
      of genotyping will be extremely large even if the study is completely designed to
      minimize genotyping. CONCLUSIONS: The proposed statistical framework presents a
      simple and flexible approach to determine the design parameters (e.g. sample
      size, p values at which tests need to be performed at each stage) that minimize
      the genotyping burden given a set of goals for the percentage of true and false
      discoveries.

PMID- 15031622
TI  - Sono-guided endometrial biopsy: comparison with hysteroscopy biopsy. Sono-guided
      endometrial biopsy using the Bernard catheter had no impact on endometrial
      assessment by sonohysterography.
AB  - OBJECTIVE: To assess the feasibility, tolerance and diagnostic accuracy of
      endometrial biopsy (EB) during sonohysterography (SH) compared to EB after
      hysteroscopy (HSC) in endometrial disorders. METHODS: 105 consecutive patients
      with irregular uterine bleeding were included prospectively in the calendar year
      2001. SH and flexible HSC were performed in an office setting, subsequently and
      in a random order, by two different practitioners blind to the former experiment.
      SH-EB was performed using a 3.1-mm ultrasound-guided Bernard catheter in the
      uterine cavity still partly distended and with a gentle 20-ml syringe vacuum
      aspiration. The biopsy was directed on focal lesions or else randomly when no
      targets had previously been found. A Cornier Pipelle was used to perform EB after
      HSC. We investigated all patients by biopsy, independent of the endometrial
      thickness. HSC-EB was the gold standard. RESULTS: For both methods, cervical
      catheterism was impossible in 20 patients, 75 of them successfully underwent both
      exams. Duration and tolerance were similar. SH was effective in the distinction
      between normal and pathologic cavities, as well as in the diagnosis of polyps.
      Endometrium appeared significantly thinner with HSC (1.8 mm) when compared to SH
      (2.9 mm, p < 0.05). Histological endometrial assessment failed in 30 cases of SH
      EB and in 22 cases in HSC-EB (NS). There was a poor correlation of the
      histological results of both techniques. Hyperplasia has never been diagnosed by
      SH-EB, whereas 3 EB issued from HSC-EB brought up this diagnosis. CONCLUSION: SH
      EB with our technique did not improve the diagnostic potential of SH and severe
      diagnosis was missed. Histological assessment should fail less when we exclude
      endometrial atrophy. The diameter of the catheter and the aspiration technique
      must be revised and the learning curve must be considered. Our technique cannot
      replace EB by HSC.

PMID- 15031623
TI  - Anti-dysrhythmic effects of long-pulse gastric electrical stimulation in dogs.
AB  - BACKGROUND/AIM: The aim of this study was to investigate the anti-dysrhythmic
      effect of long-pulse gastric electrical stimulation (GES) in dogs. METHODS: The
      study was performed in 7 healthy dogs implanted with 4 pairs of serosal gastric
      electrodes. Each dog was studied in three sessions on 3 separate days in a
      randomized order with recordings of gastric slow waves. In session 1 or 2,
      infusion of either saline or glucagon (0.1 U/kg in 20 ml saline instilled in 40
      min) was given during the 2nd and 3rd 20-min periods. The protocol of session 3
      was the same as that of session 2 except that GES was performed during the 2nd 20
      min period. RESULTS: (1) Glucagon induced gastric dysrhythmia and decreased
      gastric slow-wave coupling (ANOVA, p < 0.001). The long-pulse GES normalized
      glucagon-induced gastric dysrhythmia and the uncoupling of slow waves. (2)
      Glucagon induced symptoms and behaviors suggestive of nausea and the symptoms
      were not improved by long-pulse GES. CONCLUSION: (1) Glucagon induces gastric
      dysrhythmias, slow-wave uncoupling and symptoms, and (2) long-pulse GES
      normalizes glucagon-induced gastric dysrhythmia and slow-wave uncoupling with no
      improvement in symptoms.

PMID- 15031624
TI  - The Wagner-Nelson method can generate an accurate gastric emptying flow curve
      from CO2 data obtained by a 13C-labeled substrate breath test.
AB  - BACKGROUND: In pharmacokinetics, the Wagner-Nelson (W-N) method can accurately
      estimate the rate of drug absorption from its urinary elimination rate. A stable
      isotope (13C) breath test attempts to estimate the rate of absorption of 13C, as
      an index of gastric emptying rate, from the rate of pulmonary elimination of
      13CO2. The time-gastric emptying curve determined by the breath test is quite
      different from that determined by scintigraphy or ultrasonography. In this
      report, we have shown that the W-N method can adjust the difference. METHODS: The
      W-N equation to estimate gastric emptying from breath data is as follows: the
      fractional cumulative amount of gastric contents emptied by time t = Abreath
      (t)/Abreath (infinity) + (1/0.65).d[Abreath (t)/Abreath (infinity) ]/dt, where
      Abreath (t) = the cumulative recovery of 13CO2 in breath by time t and Abreath (
      infinity ) = the ultimate cumulative 13CO2 recovery. The emptying flow curve
      generated by ultrasonography was compared with that generated by the W-N method
      adjusted breath test in 6 volunteers. RESULTS: The emptying curves by the W-N
      method were almost identical to those by ultrasound. CONCLUSIONS: The W-N method
      can generate an accurate emptying flow curve from 13CO2 data, and it can adjust
      the difference between ultrasonography and the breath test.

PMID- 15031625
TI  - A solitary Peutz-Jeghers-type hamartomatous polyp in the duodenum. A case report
      including results of mutation analysis.
AB  - BACKGROUND/AIMS: We report a case of solitary Peutz-Jeghers-type hamartomatous
      polyp of the duodenum in a 22-year-old Japanese woman along with the results of
      genomic analysis. METHODS/RESULTS: The patient was almost asymptomatic, though
      endoscopic examination revealed a solitary lobular polypoid lesion measuring 3 cm
      in diameter in the first portion of the duodenum. The lesion was resected
      endoscopically. Histopathological examination showed hyperplasia with a tree
      branch-like extension of the lamina propria derived from the muscularis mucosae,
      consistent with histological features of polyps of Peutz-Jeghers syndrome (PJS).
      No mucocutaneous pigmentation of the skin was evident and family history was
      negative. Analysis of the loss of heterozygosity at the locus of 19p 13.3 and
      mutation analysis of the STK11/LKB1 gene, which has recently been recognized as a
      susceptible gene in PJS, were performed. However, no evidence of genomic
      abnormality was found. CONCLUSION: The clinical and investigative findings in our
      case suggest that the solitary Peutz- Jeghers-type hamartomatous polyp can be
      regarded as a clinical entity separate from PJS.

PMID- 15031627
TI  - Aldosterone antagonism ameliorates proteinuria and nephrosclerosis independent of
      glomerular dynamics in L-NAME/SHR model.
AB  - BACKGROUND: The renin-angiotensin-aldosterone system participates importantly in
      the progression of hypertensive renal disease. Angiotensin-converting enzyme
      inhibitors or angiotensin II receptor antagonists have been demonstrated to
      afford renoprotection in L-NAME-exacerbated nephrosclerosis in SHR rats. This
      study was designed to examine the effects of the aldosterone antagonist
      eplerenone on systemic and renal hemodynamics, glomerular dynamics, renal
      function and histopathology in L-NAME/SHR, and determine whether aldosterone
      antagonism would enhance the effectiveness of ACE inhibition. METHODS: Six groups
      of 20-week-old SHR were studied using renal micropuncture and histopathological
      techniques after 3 weeks of treatment: SHR control (tapwater, n = 10); SHR +
      eplerenone (101 +/- 8.3 mg/kg/day, n = 10); SHR + L-NAME (5.0 +/- 0.12 mg/kg/day,
      n = 9); SHR + L-NAME + eplerenone (n = 8); SHR + L-NAME + lisinopril (3
      mg/kg/day, n = 9), and SHR + L-NAME + eplerenone + lisinopril (n = 9). RESULTS: L
      NAME-treated SHR developed massive proteinuria, severe hypertensive
      nephrosclerosis, and tubulointerstitial damage. Eplerenone significantly reduced
      proteinuria (127.4 +/- 26.5 vs. 51.9 +/- 16.7 mg/24 h, p < 0.01), improved
      glomerular and arteriolar injuries (65 +/- 9 vs. 29 +/- 9 score/100 glomeruli, p
      < 0.01; 116 +/- 18 vs. 41 +/- 13 score/100 arterioles, p < 0.01, respectively),
      and decreased tubulointerstitial damage index (1.43 +/- 0.07 vs. 0.39 +/- 0.07, p
      < 0.01) without altering mean arterial pressure or glomerular dynamics. Combined
      therapy of eplerenone with lisinopril produced no further benefits than
      lisinopril alone. CONCLUSION: The aldosterone antagonist eplerenone significantly
      ameliorated proteinuria and nephrosclerosis in the L-NAME/SHR model, independent
      of hemodynamic effects.

PMID- 15031626
TI  - Biocompatibility of cellulosic and synthetic membranes assessed by leukocyte
      activation.
AB  - BACKGROUND/AIMS: The contact of blood with artificial surfaces may activate blood
      leukocytes and platelets and initiate the leukocyte inflammatory response. We
      have investigated the effect of a hemodialysis (HD) with a cellulosic- and a
      synthetic-based membrane on circulating leukocyte activation. METHODS: Samples
      were obtained from patients with ESRD at baseline, and at 15 and 120 min of a
      hemodialysis session from both the arterial and venous lines. Leukocyte
      respiratory burst was analyzed by luminol chemiluminescence. Actin
      polymerization, expression of CD11b, and heterotypic aggregation were studied by
      flow cytometry, leukocyte labeling with NBD phallacidin and monoclonal
      antibodies, respectively. RESULTS: HD with a cellulosic membrane induced a
      transient fall in neutrophil (1.2 +/- 0.5 x 10(9) vs. 3.6 +/- 0.6 x 10(9)
      cells/l; p < 0.05) and monocyte counts (0.2 +/- 0.1 x 10(9) vs. 0.7 +/- 0.1 x
      10(9) cells/l; p < 0.05). There was also an increase in respiratory burst in the
      venous line during a HD with a cellulosic membrane, at 15 and 120 min (100 +/- 41
      and 143.2 +/- 45.3 vs. 23.8 +/- 15.7; p < 0.05). Polymerized actin, expressed as
      fluorescence arbitrary units, was increased in baseline samples from uremic
      patients versus control subjects (327.8 +/- 60.8 for a cellulosic membrane, p <
      0.005, and 205 +/- 26.5 for a synthetic one, p < 0.05 vs. 97.8 +/- 27.6 in
      controls). The percentage of CD11b+ cells increased in samples during a HD with a
      cellulosic membrane at the venous line at 15 and 120 min (9.6 +/- 4.5 and 18.4 +/
      7.1% vs. 3.3 +/- 1.9%; p < 0.05%). Changes in heterotypic aggregation during HD
      did not reach statistical significance, but levels were higher in patients
      treated with a cellulosic membrane at all points than in patients dialyzed with a
      synthetic one. CONCLUSION: There is evidence of a priming state of leukocytes
      from uremic patients, which is more evident in patients dialyzed with a
      cellulosic membrane. Cellulosic membranes also induce greater leukocyte
      activation than synthetic membranes during hemodialysis.

PMID- 15031628
TI  - Human PRMT5 expression is enhanced during in vitro tubule formation and after in
      vivo ischemic injury in renal epithelial cells.
AB  - BACKGROUND: The interactions between cells and the extracellular matrix (ECM) are
      important in the regulation of cell growth and differentiation. Cells cultured in
      ECM differentiate and develop tubular structures. The kidney has the ability to
      partially recover function after an ischemic insult through repairing its tubular
      epithelium. The factors that contribute to tubule formation in vitro may mediate
      tubule regeneration in the recovery stage of acute tubular necrosis. METHODS: RNA
      purified from cells grown on plastic, on Matrigel and in Matrigel matrix were
      subjected to differential display analysis to identify the transcripts that are
      differentially expressed during in vitro tubulogenesis. RESULTS: Protein arginine
      methyltransferase 5 (PRMT5) expression increased in renal epithelial cells
      undergoing tubule formation. PRMT5 expression is developmentally regulated and
      ubiquitously expressed in a variety of adult tissues. We also demonstrated that
      expression of PRMT5 is enhanced in the renal tubular epithelium of animals
      subjected to ischemic reperfusion injury (IRI). CONCLUSION: The role of PRMT5 in
      the regulation of mitosis, its induction in renal epithelial cells undergoing
      tubule formation in vitro and its expression in the tubules of the kidneys
      subjected to IRI suggest that it functions in the regulation of cell growth and
      differentiation during tubule formation and regeneration.

PMID- 15031629
TI  - Influence of genetic polymorphisms of the renin-angiotensin system on IgA
      nephropathy.
AB  - BACKGROUND: We evaluated the impact of the three major genetic polymorphisms of
      the renin-angiotensin system [angiotensinogen (AGT) gene M235T, angiotensin
      converting enzyme (ACE) gene-I/D and angiotensin II-type 1 receptor (AT1R) gene
      A1166C polymorphisms] as risk factors in IgA nephropathy. METHODS: The clinical
      course of 107 patients with biopsy proven IgA nephropathy followed up for 6.6 +/-
      5.8 years was examined. The genetic polymorphisms were determined by PCR
      amplification. RESULTS: The allele frequencies of the polymorphisms studied were
      similar in patients and control subjects. AGT-M235T genotype was associated with
      the presence of nephrotic syndrome (p < 0.05), correlated to the number of
      antihypertensive drugs agents taken (p < 0.01) and influenced the rate of
      deterioration of renal function (p < 0.05). Combined analysis of AGT-M235T and
      ACE-I/D polymorphisms detected an interaction on affecting progression (p <
      0.05). ACE-inhibition had a more pronounced effect in certain AGT-M235T and ACE
      I/D genotypes (p < 0.05) and their combined analysis showed a synergistic effect
      (p < 0.01). No association between AT(1)R-A1166C polymorphism and any of the
      parameters studied was observed. CONCLUSIONS: Our results suggest that
      angiotensinogen-M235T polymorphism is an important marker of progression in IgA
      nephropathy in Caucasian patients, especially when analyzed in combination with
      ACE-I/D polymorphism.

PMID- 15031630
TI  - Serum protein profile alterations in hemodialysis patients.
AB  - BACKGROUND: Serum protein profiling patterns can reflect the pathological state
      of a patient and therefore may be useful for clinical diagnostics. Here, we
      present results from a pilot study of proteomic expression patterns in
      hemodialysis patients designed to evaluate the range of serum proteomic
      alterations in this population. METHODS: Surface-enhanced laser
      desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was used to
      analyze serum obtained from patients on periodic hemodialysis treatment and
      healthy controls. Serum samples from patients and controls were first
      fractionated into six eluants on a strong anion exchange column, followed by
      application to four array chemistries representing cation exchange, anion
      exchange, metal affinity and hydrophobic surfaces. A total of 144 SELDI-TOF-MS
      spectra were obtained from each serum sample. RESULTS: The overall profiles of
      the patient and control samples were consistent and reproducible. However, 30
      well-defined protein differences were observed; 15 proteins were elevated and 15
      were decreased in patients compared to controls. Serum from 1 patient exhibited
      novel protein peaks suggesting possible additional changes due to a secondary
      disease process. CONCLUSION: SELDI-TOF-MS demonstrated consistent serum protein
      profile differences between patients and controls. Similarity in protein profiles
      among dialysis patients suggests that patient physiological responses to end
      stage renal disease and/or dialysis therapy have a major effect on serum protein
      profiles.

PMID- 15031631
TI  - Fas ligand-mediated apoptosis in degenerative disorders of the brain.
AB  - While defective apoptosis predisposes to neoplasia, inappropriate apoptosis in
      the brain leads to permanent neurological deficits. Disregulated apoptosis has
      been implicated in several neurodegenerative disorders including Alzheimer's,
      Parkinson's, and Huntington's diseases. Recent reports have suggested that the
      key apoptosis regulator Fas ligand (FasL) may participate in both neuronal and
      immune cell apoptosis in Alzheimer's disease. FasL has also been implicated as a
      negative regulator for the inflammatory component of the demyelinating brain
      disorder multiple sclerosis (MS). Here we discuss how FasL-mediated apoptosis may
      balance immune cell access to the brain with Alzheimer's disease and MS
      representing extremes of too little and too much immune access, respectively.

PMID- 15031633
TI  - Diversity of PR3-ANCA epitope specificity in Wegener's granulomatosis. Analysis
      using the biosensor technology.
AB  - Wegener's granulomatosis is a systemic disease characterized by the presence of
      antineutrophil cytoplasm autoantibodies specific for proteinase 3 (PR3-ANCA). The
      functional characteristics of PR3-ANCA differ between quiescent and active
      disease, suggesting changes in the properties of the autoantibodies in time.
      Using biosensor technology, we found that PR3-ANCA of different patients (n = 8)
      recognize a limited number of overlapping regions on PR3 at the time of diagnosis
      of Wegener's granulomatosis. This area might cover an immunodominant epitope,
      common for PR3-ANCA from all patients, irrespective of the size of the total area
      recognized by an individual autoantibody. Experiments with sera (n = 4) collected
      at the moment of diagnosis and at the time of relapse showed that the individual
      epitope specificities of PR3-ANCA change during the course of the disease. These
      changes in epitope specificity of PR3-ANCA may be responsible for the differences
      in functional properties of these autoantibodies between various stages of the
      disease.

PMID- 15031634
TI  - Relationships of differential leukocyte and lymphocyte subpopulations with
      carotid atherosclerosis in elderly men.
AB  - To examine the relationship between systemic immune status and carotid
      atherosclerosis in elderly men, differential leukocyte counts and lymphocyte
      subpopulations were measured in 557 apparently healthy Japanese men aged 60-75
      years. Each individual also underwent high-resolution ultrasonography for
      measurement of intima-media thickness (IMT) of the common carotid arteries. The
      increased numbers of circulating lymphocyte subpopulations, including memory T
      cells (CD4+CD45RO+T cells) and late-phase activated B cells (CD19+CD80+B cells)
      correlated significantly and positively with the mean IMT of the common carotid
      artery after adjustment for age, smoking, and other cardiovascular risk factors.
      The positive associations of CD19+CD80+B and CD4+CD45RO+ T cell counts with mean
      IMT were more evident among nonsmokers, hypertensives, and men with lower HDL
      cholesterol levels. The present epidemiological study provided the evidence that
      alterations in lymphocyte subpopulations, in particular memory T cells and late
      phase activated B cells concur with carotid atherosclerosis among free-living
      elderly men.

PMID- 15031632
TI  - Mechanisms of apoptosis in the heart.
AB  - Apoptosis is a complex and highly regulated form of cell death, and believed to
      contribute to the continuous decline of ventricular function in heart failure.
      Apoptotic cell death is observed in a variety of cardiovascular diseases,
      including myocardial infarction, ischemia-reperfusion injury, end-stage heart
      failure, arrhythmias, and adriamycin cardiomyopathy. There are several pathways
      leading to programmed cell death. Apoptosis can be initiated by extracellular or
      intracellular stimuli, leading to the activation of caspases and subsequent cell
      death. A better understanding of the process of apoptosis in the heart is clearly
      important as it may lead to the identification of novel therapies for
      cardiovascular disease. This review is focused on the basic cellular mechanisms
      of apoptosis, as well as our current understanding of this process in the heart.

PMID- 15031635
TI  - Gold sodium thiomalate and chloroquine inhibit cytokine production in monocytic
      THP-1 cells through distinct transcriptional and posttranslational mechanisms.
AB  - Gold sodium thiomalate (GST), chloroquine (CQ), and methotrexate have been widely
      used in the therapy of rheumatoid arthritis and other inflammatory conditions.
      Using the human monocytic cell line THP-1 we have analyzed effects of these drugs
      on cytokine production and intracellular signaling. GST and CQ were equally
      effective in reducing lipopolysaccharide (LPS)-induced IL-1 beta release while CQ
      was a more effective inhibitor of TNF-alpha production than GST. Methotrexate did
      not affect production of these cytokines. CQ reduced IL-1 beta mRNA expression
      and strongly inhibited phosphorylation of mitogen-activated protein kinase (MAPK)
      p38, and to a lesser extent c-Jun N-terminal kinase and extracellular signal
      regulated kinase 1/2. In contrast, GST did not affect cytokine mRNA expression or
      MAPK activation. However, GST selectively inhibited the activity of the
      interleukin-1 converting enzyme (ICE)/caspase-1. These data demonstrate that CQ
      inhibits IL-1 beta release from monocytes by interfering with pretranscriptional
      signaling and TNF-alpha release by posttranslational events whereas GST
      downregulates IL-1 beta secretion by interfering with posttranslational IL-1 beta
      processing.

PMID- 15031636
TI  - Deficient IFN-gamma expression in umbilical cord blood (UCB) T cells can be
      rescued by IFN-gamma-mediated increase in NFATc2 expression.
AB  - Regulation of nuclear factor of activated T cells-c2 (NFATc2) gene expression is
      not clearly defined. We previously reported reduced NFATc2 protein expression in
      cord blood T lymphocytes. Here we show that NFATc2 expression in T cells is
      dependent in part on the presence of IFN-gamma during primary stimulation, as
      blocking of IFN-gamma blunted NFATc2 protein and mRNA upregulation. Conversely,
      addition of exogenous IFN-gamma during stimulation resulted in increased
      expression of NFATc2 in cord blood T lymphocytes. This correlated with rescue of
      deficient IFN-gamma expression by cord blood T cells. Rescue of IFN-gamma
      expression in cord blood T cells was dependent on the presence of antigen
      presenting cells, as addition of IFN-gamma during stimulation of purified cord
      blood T cells did not result in an increase of IFN-gamma expression, and
      depletion of monocytes ablated the rescue of IFN-gamma expression. Our results
      point to impaired function in the antigen-presenting cell population of cord
      blood, playing a role in the hyporesponsiveness of T cells.

PMID- 15031637
TI  - Analysis of the expression of MICA in small intestinal mucosa of patients with
      celiac disease.
AB  - The MHC class I chain-related A gene (MICA) is expressed in gastrointestinal
      epithelium and functions as an immune activation signal under stress conditions.
      MICA protein binds to NKG2D, a receptor of gamma delta T cells containing the TCR
      variable region V(delta)1, which are the most abundant subset of T cells in the
      intestinal epithelium. Ingested gluten in patients with celiac disease (CD) may
      function as a stress signal for the epithelial cells, and could enhance MICA
      expression on their surface. In this study, we have analyzed MICA expression in
      intestinal biopsy specimens from newly diagnosed and treated CD patients and
      controls. Quantitative RT-PCR analysis did not show differences in MICA
      expression among the three groups. With these results, we conclude that
      overexpression of MICA does not seem to play an important role in the
      pathogenesis of CD, at least at the time of diagnosis.

PMID- 15031638
TI  - Intestinal lymphocyte populations in children with regressive autism: evidence
      for extensive mucosal immunopathology.
AB  - Inflammatory intestinal pathology has been reported in children with regressive
      autism (affected children). Detailed analysis of intestinal biopsies in these
      children indicates a novel lymphocytic enterocolitis with autoimmune features;
      however, links with cognitive function remain unclear. To characterize further,
      the nature and extent of this disease we examined the mucosal infiltrate using
      flow cytometry. Duodenal, ileal, and colonic biopsies were obtained from 52
      affected children, 25 histologically normal, and 54 histologically inflamed,
      developmentally normal controls. Epithelial and lamina propria lymphocyte
      populations were isolated and examined by multicolor flow cytometry. Adjacent
      biopsies were assessed by semiquantitative histopathology. At all sites, CD3(+)
      and CD3(+)CD8(+) IEL as well as CD3(+) LPL were significantly increased in
      affected children compared with developmentally normal noninflamed control groups
      (p<0.01) reaching levels similar to inflamed controls. In addition, two
      populations--CD3(+)CD4(+) IEL and LP CD19(+) B cells--were significantly
      increased in affected children compared with both noninflamed and inflamed
      control groups including IBD, at all sites examined (p<0.01). Histologically
      there was a prominent mucosal eosinophil infiltrate in affected children that was
      significantly lower in those on a gluten- and casein-free diet, although
      lymphocyte populations were not influenced by diet. The data provide further
      evidence of a pan-enteric mucosal immunopathology in children with regressive
      autism that is apparently distinct from other inflammatory bowel diseases.

PMID- 15031639
TI  - CD28-negative CD8-positive cytotoxic T lymphocytes mediate hepatocellular damage
      in hepatitis C virus infection.
AB  - The pathogenic mechanism for hepatocellular damage in hepatitis C virus (HCV)
      infection has not been clearly understood. Analysis of costimulatory molecules on
      lymphocytes may give us insight into the pathogenic mechanism of hepatocellular
      damage in HCV infection. Peripheral blood mononuclear cells (PBMCs) and liver
      infiltrating mononuclear cells (LIMCs) isolated from the HCV-infected patients
      were analyzed with antibodies directed against a variety of costimulatory
      molecules by flow cytometry. Blocking experiment against HLA-A24-restricted HCV
      specific CTLs and immunohistochemical analysis were also performed. PBMCs
      expressing CD8, CD28, CD80, or CD154 were significantly reduced in HCV-infected
      patients compared with the healthy controls. CD28(+)CD8(+) PBMCs in the patients
      inversely correlated with ALT levels. Conversely, levels of CD28(-)CD8(+) LIMCs
      correlated with ALT levels. HCV-specific CTL activity was blocked by the
      treatment with anti-CD8 antibody, but not with anti-CD4 or anti-CD28 antibody.
      Immunohistochemical analysis revealed the accumulation of CD28(+) cells around
      the portal area in the liver of a patient with chronic active hepatitis C. These
      results suggest that CD28(+)CD8(+) T cells leave the circulation, move to the
      livers, and are activated in the portal area in proportion to the extent of liver
      diseases. CD28(-)CD8(+) T cells may finally function as effector T cells causing
      the hepatocellular damage in HCV infection.

PMID- 15031641
TI  - Alterations in protein synthesis and levels of heat shock 70 proteins in response
      to salt stress of the halotolerant yeast Rhodotorula mucilaginosa.
AB  - Responses of the halotolerant yeast Rhodotorula mucilaginosa YRH2 to salt stress
      was studied. Strain YRH2 was isolated from chemical industry park wastewater
      evaporation ponds that are characterized by large fluctuations in salinity and
      pH. Upon shift to high salt medium there is a shutdown of protein synthesis.
      Radiolabeling and separation of proteins from salt stressed and non-stressed
      cells identified down-regulated heat shock 70 proteins Ssb1/2p, by N-terminal
      sequencing and Western blotting. Ssb's role in salt stress in both R.
      mucilaginosa and S. cerevisiae was examined and we show that its response to salt
      stress and amino acid limitation is similar. Other proteins such as the heat
      shock 70 protein Kar2p/BiP and Protein Disulfide Isomerase were strongly induced
      in response to a shift to high salt in R. mucilaginosa and reacted in a manner
      similar to the effect of tunicamycin, a known unfolded protein response inducer.
      Also, assaying carboxypeptidase Y, we showed that high salt medium reduces the
      specific activity of the enzyme in R. mucilaginosa. It is suggested that the
      changes in the expression of the heat shock 70 proteins is a part of a mechanism
      which alleviates the damaging effects of high salt on protein folding in the
      yeast Rhodotorula mucilaginosa.

PMID- 15031640
TI  - Vaccination with rabies to study the humoral and cellular immune response to a T
      cell dependent neoantigen in man.
AB  - We investigated the humoral (antigen-specific immunoglobulin isotypes, IgG
      subclasses, and avidity maturation) and cellular (antigen-specific in vitro
      proliferation) immune response in 18 healthy adult volunteers, following a
      primary and a single booster vaccination with the T-cell dependent neoantigen
      rabies administered at a 3-months interval. The IgG antibody titer showed a mean
      31-fold increase (range 3-154) 4 weeks after the first vaccination and a memory
      response was observed after booster vaccination, i.e. high IgG titers, switch
      from IgM to IgG and IgA and increased antibody avidity. All healthy adults showed
      a rabies-induced proliferative response with a mean stimulation index of 45
      (range 3.5-200) after in vitro stimulation of PBMC obtained at 4 weeks after
      booster vaccination. The results obtained in this study provide a frame of
      reference for the interpretation of specific immune responses to the T-cell
      dependent neoantigen rabies in patients suspected of a primary or secondary
      immunodeficiency. Humoral and cellular immune responses to the rabies neoantigen
      provide complementary information on the condition of the immune system of an
      individual. Five patients diagnosed with a combined immunodeficiency were
      vaccinated using the same protocol and showed a number of abnormalities, either
      in the humoral or the cellular immune response to the rabies neoantigen.

PMID- 15031642
TI  - Characterization of a new xylitol-producer Candida tropicalis strain.
AB  - A xylitol-producer yeast isolated from corn silage and designated as ASM III was
      selected based on its outstanding biotechnological potential. When cultivated in
      batch culture mode and keeping the dissolved oxygen at 40% saturation, xylitol
      production was as high as 130 g l(-1) with a yield of 0.93 g xylitol g(-1) xylose
      consumed. A preliminary identification of the yeast was performed according to
      conventional fermentation and assimilation physiological tests. These studies
      were complemented by using molecular approaches based on PCR amplification,
      restriction-fragment length polymorphism analysis and sequencing of the rDNA
      segments: intergenic transcribed spacer (ITS) 1-5.8S rDNA-ITS 2, and D1/D2 domain
      of the 26S rRNA gene. Results from both the conventional protocols and the
      molecular characterization, and proper comparisons with the reference strains
      Candida tropicalis ATCC 20311 and NRRL Y-1367, led to the identification of the
      isolate as a new strain of C. tropicalis.

PMID- 15031643
TI  - Trichomonascus petasosporus sp. nov. and Sympodiomyces indianaensis sp. nov., two
      new members of the Saccharomycetales.
AB  - Two new yeasts are described that were recognized as novel from nucleotide
      divergence in domains D1/D2 of 26S rDNA. The new species and their type strains
      are the following: Trichomonascus petasosporus NRRL YB-2092T (CBS 9602T), mating
      type a, NRRL YB-2093 (CBS 9603), mating type alpha, and Sympodiomyces
      indianaensis NRRL YB-1950T (CBS 9600T). Phylogenetic analysis placed the two new
      taxa, which are sister species, in the Sympodiomyces clade near
      Blastobotrys/Stephanoascus farinosus. Placement of Trichomonascus in the
      Saccharomycetales resolves the earlier uncertainties surrounding the
      classification of this morphologically unusual genus.

PMID- 15031644
TI  - Rapid determination of vapA/vapB genotype in Rhodococcus equi using a
      differential polymerase chain reaction method.
AB  - Rhodococcus equi is a facultative pathogen of foals. Infection causes an often
      fatal pulmonary pneumonia. The organism has also been isolated from pigs, cattle,
      humans and the environment. Equine virulence has a high positive correlation with
      the expression of a 17.4 kD polypeptide of unknown function, VapA, the product of
      the plasmid-encoded vapA gene. More recently an isogene of vapA, referred to as
      vapB and encoding an 18.2 kDa polypeptide, has been identified among pig and
      human isolates. The two genes share > 80% sequence identity, yet their host
      strains apparently exhibit different pathogenicity profiles (for example by
      reference to virulence in mouse model system and host specificity). In this
      study, a polymerase chain reaction (PCR) technique was developed that permits the
      selective amplification of vapA and vapB. Using this technique the distribution
      of the two genes among 35 randomly selected isolates of Rhodococcus equi from
      various animal and environmental sources was determined. Using this technique the
      genotype of each isolate could be unambiguously assigned as vapA+, vapB+ or vap-
      (i.e., scoring negative for both vapA and vapB). No isolate scored positive for
      both vapA and vapB. 100% of equine isolates scored vapA+, confirming the status
      of vapA as a reliable marker of equine virulence. All three genotypes were found
      among human isolates; porcine isolates scored either vapB+ or vap- and no vapA+
      isolates were present in this sample. Rigorous statistical analysis using the
      Fisher Exact test confirmed that the high frequency of vapA+ among equine
      isolates is significant; however the sample size was too small to draw
      statistically significant conclusions regarding the distribution of genotypes
      among within other animal groups.

PMID- 15031646
TI  - Magnetosome chain arrangement and stability in magnetotactic cocci.
AB  - We have studied the disposition of chains of magnetosomes inside magnetotactic
      cocci with light and electron microscopy. Light microscopy of isolated cocci
      indicated that the chains of magnetosomes are disposed on opposite sides of the
      cell. Electron spectroscopic imaging of whole unprocessed bacteria, showed the
      magnetosome chains in the cells. Freeze-etching of the cell surface allowed the
      observation of the close association of the chain with the cell surface. During
      the replication process of the freeze-etching, the magnetosome chains remained
      attached to the replicas, which indicates that chains were very close to the cell
      surface before freezing. We provide evidence that the large area of the contact
      faces between magnetosomes in a chain may provide an extra mechanical stability
      that helps keep the magnetosomes in chains even after isolation from the
      bacteria. Comparison with pointed magnetosomes from different cocci present in
      the same samples showed that the maintenance of linear chains is more difficult
      to be achieved because of the geometry of the crystals.

PMID- 15031645
TI  - Morphology-associated expression of NADP-dependent glutamate dehydrogenases
      during yeast-mycelium transition of a dimorphic fungus Benjaminiella poitrasii.
AB  - Benjaminiella poitrasii, a dimorphic zygomycetous fungus possesses three
      glutamate dehydrogenases, one requiring NAD while the other two use NADP as a
      coenzyme. In the activity staining after electrophoresis on native polyacrylamide
      gel NAD- dependent glutamate dehydrogenase revealed the presence of one enzyme
      that was expressed in both, yeast- and mycelium-form cells. While in case of NADP
      dependent glutamate dehydrogenase two distinct activity bands that were
      differentially expressed in yeast- and mycelium-form cells were seen.
      Interestingly, during yeast-mycelium transition and reverse, quantitative changes
      in form-specific native NADP-dependent glutamate dehydrogenase activities were
      seen. The biochemical data on temperature and pH optima, thermostability, and
      kinetic properties confirmed the presence of two NADP-dependent proteins in B.
      poitrasii, parent strain. The monomorphic mutant (Y-5, yeast form) showed NADP-
      glutamate dehydrogenase similar to parent yeast-form enzyme. For the first time
      the significance of differential expression of these enzymes during morphological
      transition in B. poitrasii has been suggested.

PMID- 15031647
TI  - Variation in functional ascospore parts in the ascomycetous yeast Dipodascopsis
      uninucleata.
AB  - A variation in functional ascospore morphology was detected using electron
      microscopy (EM) in two varieties of the yeast Dipodascopsis uninucleata, i.e., D.
      uninucleata var. uninucleata and D. uninucleata var. wickerhamii. It was found
      that the latter produces ascospores characterized by the absence of small surface
      hooks which have been implicated in the release and re-assembly of ascospores in
      D. uninucleata var. uninucleata. These varieties are closely related on the basis
      of their mode of sexual reproduction, ascospore morphology as observed under the
      light microscope, physiological characteristics as well as the extent of
      divergence in the variable D1/D2 domain of the large subunit 26S ribosomal DNA.

PMID- 15031648
TI  - Influence of nutrients on growth and bacteriocin production by Leuconostoc
      mesenteroides L124 and Lactobacillus curvatus L442.
AB  - The aim of this study was to investigate the effect of complex nutrients on
      microbial growth and bacteriocin production, in order to improve bacteriocin
      synthesis during the growth cycle of Leuconostoc mesenteroides L124 and
      Lactobacillus curvatus L442. The fermentations were conducted at the optimum pH
      and temperature for bacteriocin production (pH 5.5+/-0.1 and temperature 25+/-0.1
      degrees C). Because of their association with the final biomass, conditions
      favouring the increase of the produced biomass resulted in the increase of
      bacteriocin activity in the growth medium. Since the produced final biomass and
      the final concentration of the bacteriocins were associated with the amount of
      the carbon (glucose) and nitrogen source, better growth of the lactic acid
      bacterial strains favoured the increase of the specific bacteriocin production.
      Additionally, the bacteriocin production was influenced by carbon/nitrogen ratio.

PMID- 15031650
TI  - Regulation of pssA and pssB gene expression in Rhizobium leguminosarum bv.
      trifolii in response to environmental factors.
AB  - Exopolysaccharide (EPS) produced by Rhizobium leguminosarum plays an important
      role in indeterminate-type nodulation. The pssA gene, encoding the first glycosyl
      transferase and pssB, encoding inositol monophosphatase, are involved in EPS
      synthesis and regulation in R. leguminosarum bv. trifolii. Using pssA-lacZ and
      pssB-lacZ plasmid-borne transcriptional fusions, a stimulating effect of
      phosphate on the transcription of both genes was observed. The increase in the
      transcription of pssA and pssB genes was correlated with a significant
      enhancement in EPS production in rhizobia grown in the high phosphate
      concentrations. In the presence of ammonium, transcription of the pss-lacZ
      fusions was repressed, especially the pssB-lacZ fusion, but EPS production still
      remained enhanced. Root exudate positively influenced the level of pss-lacZ
      transcription. These results indicate a complex regulation of pss gene
      transcription by several environmental factors. In addition, the expression of
      pssA and pssB genes in the symbiotic state was examined using pss-gusA plasmid
      borne transcriptional fusions. It was found that the pssA-gusA fusion was not
      expressed in the nodules. The pssB-gusA fusion was expressed mainly in the
      infection zone and interzone of the nodule and the pattern of expression was
      dependent on the plant phosphate availability.

PMID- 15031649
TI  - Partial purification and characterization of a mannosyl transferase involved in O
      -linked mannosylation of glycoproteins in Candida albicans.
AB  - Incubation of a mixed membrane fraction of C. albicans with the nonionic
      detergents Nonidet P-40 or Lubrol solubilized a fraction that catalyzed the
      transfer of mannose either from endogenously generated or exogenously added
      dolichol-P-[14C]Man onto endogenous protein acceptors. The protein mannosyl
      transferase solubilized with Nonidet P-40 was partially purified by a single step
      of preparative nondenaturing electrophoresis and some of its properties were
      investigated. Although transfer activity occurred in the absence of exogenous
      mannose acceptors and thus depended on acceptor proteins isolated along with the
      enzyme, addition of the protein fraction obtained after chemical de-mannosylation
      of glycoproteins synthesized in vitro stimulated mannoprotein labeling in a
      concentration-dependent manner. Other de-mannosylated glycoproteins, such as
      yeast invertase or glycoproteins extracted from C. albicans, failed to increase
      the amount of labeled mannoproteins. Mannosyl transfer activity was not
      influenced by common metal ions such as Mg(2+), Mn(2+) and Ca(2+), but it was
      stimulated up to 3-fold by EDTA. Common phosphoglycerides such as
      phosphatidylglycerol and, to a lower extent, phosphatidylinositol and
      phosphatidylcholine enhanced transfer activity. Interestingly, coupled transfer
      activity between dolichol phosphate mannose synthase, i.e., the enzyme
      responsible for Dol-P-Man synthesis, and protein mannosyl transferase could be
      reconstituted in vitro from the partially purified transferases, indicating that
      this process can occur in the absence of cell membranes.

PMID- 15031651
TI  - Comparison of phenotypic and genotypic taxonomic methods for the identification
      of dairy enterococci.
AB  - The purpose of the study was to assess the phenotypic and genotypic taxonomic
      congruence in order to allow species allocation of dairy enterococci. A total of
      364 enterococci isolated from ewes'milk and cheese from four Portuguese
      Registered Designation of Origin areas and 25 type and reference strains of
      Enterococcus spp. were characterized by a polyphasic taxonomical approach
      involving 40 physiological and biochemical tests, whole-cell protein profiles,
      amplification of 16S-23S intergenic spacer regions (ITS-PCR) and subsequent
      restriction analysis (ARDRA). Ribotyping was also performed with reference
      strains and a subset of 146 isolates. Numerical hierarchic data analysis showed
      that single-technique identification levels increase from the physiological and
      biochemical tests to the protein approach, being lower with ITS/ARDRA and
      ribotyping. Cross-analysis confirmed a higher unmatching level in all pairwise
      combinations involving physiological and biochemical data. Whole-cell protein
      profiles followed by ITS/ARDRA identified 89% of the enterococci. Reliable
      identification of enterococci from milk and cheese could be obtained by analysis
      of whole-cell protein profiles. ITS-PCR can be used to confirm E. durans and E.
      faecium and ARDRA further confirms E. faecalis. Results revealed E. faecalis, E.
      durans, E. hirae and E. faecium as the prevalent species, although species
      prevalence showed some degree of variation among the areas.

PMID- 15031652
TI  - Accumulation and release of the osmolyte glycerol is independent of the putative
      MIP channel Spac977.17p in Schizosaccharomyces pombe.
AB  - Schizosaccharomyces pombe accumulates glycerol as an osmotic regulatory solute in
      response to hyper-osmotic conditions. Upon a decrease in the external osmolarity,
      the intracellular glycerol levels should be adjusted in order to attain osmotic
      homeostasis. In this study, the patterns and kinetics of glycerol export from S.
      pombe were investigated. Upon a decrease in external osmolarity, glycerol was
      rapidly exported from cells to the external medium. The amount of glycerol
      released from the cells was proportional to the degree of change in the external
      osmolarity. The export process was well controlled and was not affected by
      reduced temperature. This points to S. pombe controlling glycerol export using
      specialized facilitating proteins as has been found in Saccharomyces cerevisiae
      where a MIP family channel protein Fps1p is involved. Analysis of the S. pombe
      databases revealed a putative transport protein (Spac977.17p) with homology to
      glycerol channel proteins of the MIP family. However, expression of the gene into
      the S. cerevisiae strain lacking a glycerol channel protein (fps1Delta mutant),
      did not complement the defect in glycerol export during hypo-osmotic stress.
      Deletion of spac977.17, did not affect glycerol accumulation or release in S.
      pombe. The patterns and kinetics of glycerol release in the mutant were similar
      to those of the wild type strains suggesting that the export process is
      independent of Spac977.17p, the only putative MIP family glycerol channel
      homologue in S. pombe. While the process of glycerol export in response to hypo
      osmotic stress is similar to budding yeast, the underlying molecular mechanism in
      S. pombe appears distinct from that described in S. cerevisiae. Further studies
      are needed to elucidate the physiological role of the Spac977.17p channel.

PMID- 15031653
TI  - Production of 3-hydroxydecanoic acid by recombinant Escherichia coli HB101
      harboring phaG gene.
AB  - Heterogenous expression of (R)-3-hydroxydecanoyl-ACP:CoA transacylase gene (phaG)
      isolated from Pseudomonas putida in Escherichia coli HB101 led to the
      extracellular production of 3-hydroxydecanoic acid (3HD) in a growth medium
      consisting of carbon source non-related to 3HD structure, while no 3HD was
      detected in the growth media inoculated with wild type E. coli HB101 and
      recombinant E. coli HB101 harboring vector pBluescript SK- only. 3HD production
      by E. coli HB101 (pLZZGPp) harboring phaG from fructose was 587 mg/l,
      approximately three times that from cultivation in glucose under same culture
      conditions. 3HD production was affected by timing of fructose addition and
      fructose concentration in the culture. As an inhibitor of fatty acid de novo
      synthesis, the presence of triclosan in the culture could increase 3HD production
      by E. coli HB101 (pLZZGPp) by about 20-40%. The results further confirmed that
      (R)-3-hydroxydecanoyl-ACP:CoA transacylase (PhaG) provides 3HD precursors for
      medium-chain-length polyhydroxyalkanoate synthesis. At the same time, this
      phenomenon showed that recombinant organisms can be used for production of
      certain fine chemicals such as hydroxyalkanoic acids.

PMID- 15031654
TI  - Xylanase and mannanase enzymes from Streptomyces galbus NR and their use in
      biobleaching of softwood kraft pulp.
AB  - Enzymatic pretreatment of softwood kraft pulp was investigated using xylanase and
      mannanase, singly or in combination, either sequentially or simultaneously.
      Enzymes were obtained from Streptomyces galbus NR that had been cultivated in a
      medium, containing either xylan of sugar cane bagasse or galactomannan of palm
      seeds, when they were used as sole carbon sources from local wastes in
      fermentation media. No cellulase activity was detected. Incubation period,
      temperature, initial pH values and nature of nutritive constituents were
      investigated. Optimum production of both enzymes was achieved after 5 days
      incubation on a rotary shaker (200 rpm) at 35 degrees C and initial pH 7.0.
      Partial purification of xylanase and mannanase in the cultures supernatant were
      achieved by salting out at 40-60 and 60-80% ammonium sulphate saturation with a
      purification of 9.63- and 8.71-fold and 68.80 and 62.79% recovery, respectively.
      The xylanase and mannanase from S. galbus NR have optimal activity at 50 and 40
      degrees C, respectively. Both enzymes were stable at a temperature up to 50
      degrees C. Xylanase and mannanase showed highest activity at pH 6.5 and were
      stable from 5.0 to 8.0 and from 5.5 to 7.5, respectively. The partial purified
      enzymes preparations of xylanase and mannanase enzymes showed high bleaching
      activity, which is an important consideration for industry. Xylanase was found to
      be more effective for paper-bleaching than mannanase. When xylanase and mannanase
      were dosed together (simultaneously), both enzymes were able to enhance the
      liberation of reducing sugars and improve pulp bleachability, possibly as a
      result of nearly additive interactions. The simultaneous addition of both enzymes
      was more effective in pulp treatment than their sequential addition.

PMID- 15031655
TI  - Phenotypic and genotypic analysis of rhizobia isolated from pasture legumes
      native of Sardinia and Asinara Island.
AB  - Thirty-five rhizobial strains were isolated from nodules of Lotus edulis, L.
      ornithopodioides, L. cytisoides, Hedysarum coronarium, Ornithopus compressus and
      Scorpiurus muricatus growing in Sardinia and Asinara Island. Basic
      characteristics applied to identification of rhizobia such as symbiotic
      properties, antibiotic- and salt-resistance, temperate-sensitivities, utilization
      of different sources of carbon and nitrogen were studied. The results from the 74
      metabolic tests were used for cluster analysis of the new rhizobial isolates and
      28 reference strains, belonging to previously classified and unclassified fast-,
      intermediate- and slow-growing rhizobia. All strains examined were divided into
      two large groups at a linkage distance of 0.58. None of the reference strains
      clustered with the new rhizobial isolates, which formed five subgroups almost
      respective of their plant origin. RFLP analysis of PCR-amplified 16S-23S rDNA IGS
      showed that the levels of similarity between rhizobial isolates from Ornithopus,
      Hedysarum and Scorpiurus, and the type strains of Rhizobium leguminosarum,
      Mesorhizobium loti, M. ciceri, M. mediterraneum, Sinorhizobium meliloti and
      Bradyrhizobium japonicum were not more than 30%. Thus, it can be assumed that
      these groups of new rhizobial isolates are not closely related to the validly
      described rhizobial species.

PMID- 15031656
TI  - Authentication and identification of Saccharomyces cerevisiae 'flor' yeast races
      involved in sherry ageing.
AB  - Yeasts involved in velum formation during biological ageing of sherry wine have
      to date been classified into four races of Saccharomyces cerevisiae (beticus,
      cheresiensis, montuliensis, rouxii) according to their abilities to ferment
      different sugars. It has been proposed that race succession during biological
      ageing is essential for the development of the organoleptical properties of
      sherry wines. In this work we studied the physiological characteristics, the
      molecular differentiation and the phylogenetic relationships of the four races
      employing type and reference strains from culture collections and natural
      environments. Using restriction analysis of the ribosomal region that includes
      the 5.8S rRNA gene and internal transcribed regions (5.8S-ITS) we were able to
      differentiate 'flor' and non-'flor' S. cerevisiae yeast strains. However, no
      correlation between fermentation profile, mitochondrial DNA restriction analysis
      or chromosomal profiles and these races was found. Moreover, sequences of the
      D1/D2 domain of the 26S rRNA gene and the 5.8S-ITS region from these strains were
      analysed and no genetic differences were noted suggesting that 'flor' yeast
      cannot be grouped into four different races and the four races are identified as
      S. cerevisiae. Since the yeasts isolated from velum in sherry wine present a
      unique 5.8S rRNA pattern different from the rest of the Saccharomyces cerevisiae
      strains we propose that they should be included as a single race or variety
      inside the S. cerevisiae taxon.

PMID- 15031657
TI  - Contribution of winery-resident Saccharomyces cerevisiae strains to spontaneous
      grape must fermentation.
AB  - The origin of the Saccharomyces cerevisiae strains that are responsible for
      spontaneous grape must fermentation was investigated in a long-established
      industrial winery by means of two different approaches. First, seven selected
      components of the analytical profiles of the wines produced by 58 strains of S.
      cerevisiae isolated from different sites and phases of the production cycle of a
      Grechetto wine were subjected to Principal Components Analysis. Secondly, the
      same S. cerevisiae isolates underwent PCR fingerprinting by means of delta
      primers. The results obtained by both methods demonstrate unequivocally that
      under real vinification conditions, the S. cerevisiae strains colonising the
      winery surfaces are the ones that carry out the natural must fermentation.

PMID- 15031658
TI  - Homokaryotic and heterokaryotic hyphae in Terfezia.
AB  - Mycelia of Terfezia pfeilii (Ascomycetes) were obtained by two methods, i.e.,
      from the sterile hyphae of fresh fruit bodies or by germinating ascospores.
      Nuclear staining revealed the existence of multinucleate cells in all mycelia.
      Paired nuclei were observed only in mycelia obtained from sterile hyphae
      proliferation, while single nuclei were found in mycelia originating from singly
      germinated spores. Co-cultivation of mycelia from two different ascospores
      apparently facilitated plasmogamy, resulting in mycelia with paired nuclei.
      Terfezia boudieri cultures originating from sterile hyphae also exhibit paired
      nuclei, indicating the possible existence of a long-term heterokaryon. The timing
      of plasmogamy and karyogamy in Terfezia is discussed.

PMID- 15031659
TI  - Isolation and properties of promitochondria from anaerobic stationary-phase yeast
      cells.
AB  - Under anaerobiosis, the mitochondrion of Saccharomyces cerevisiae is restricted
      to unstructured promitochondria. These promitochondria provide unknown metabolic
      functions that are required for growth. Since high glucose concentrations are
      mainly fermented by S. cerevisiae during stationary phase (due to nitrogen
      starvation), an optimized promitochondria isolation procedure was investigated.
      Firstly, the unusual promitochondria ultrastructure was checked in intact cells
      by electron microscopy using a cryo-fixation and freeze-substitution method. The
      rapid response of anaerobic cells toward oxygen justified the adoption of several
      critical steps, especially during spheroplasting. Control of spheroplasting was
      accompanied by a systematic analysis of spheroplast integrity, which greatly
      influence the final quality of promitochondria. Despite the presence of remnant
      respiratory chain components under anaerobiosis, characterization of isolated
      promitochondria by high-resolution respirometry did not reveal any antimycin A-
      and myxothiazol-sensitive NADH and NADPH oxidase activities. Moreover, the
      existence of a cyanide-sensitive and non-phosphorylating NADH-dependent oxygen
      consumption in promitochondria was demonstrated. Nevertheless, promitochondria
      only slightly contribute to the overall oxygen consumption capacity observed in
      highly glucose-repressed anaerobic cells.

PMID- 15031660
TI  - PCR-DGGE differentiation of strains of Saccharomyces sensu stricto.
AB  - A quick molecular biology method based on the polymerase chain reaction (PCR) and
      Denaturing Gradient Gel Electrophoresis (DGGE) was developed for distinguishing
      strains belonging to the Saccharomyces sensu stricto group. Differentiation was
      obtained between S. cerevisiae, S. paradoxus and S. bayanus / S. pastorianus
      although no distinction was possible between S. bayanus and S. pastorianus using
      the amplification of the ITS regions. The ability to distinguish between
      different strains of the Saccharomyces sensu stricto group could allow for a
      better understanding of the ecology of these species on grapes as well as in
      musts and wines and the method developed can be useful for the quick
      identification of Saccharomyces sensu stricto strains from numerous isolates.

PMID- 15031661
TI  - Diversity of Y region at HML locus in a Saccharomyces cerevisiae strain isolated
      from a Sardinian wine.
AB  - Several mutations in genes involved in Saccharomyces mating type switching may
      affect the homothallic behaviour in wine yeasts. In this study the semi
      homothallic (Hq) segregation of a flor wine yeast strain was analysed. We aimed
      to understand the molecular basis of this behaviour in a flor autochthonous
      strain, verifying the MAT locus status by a PCR-based HO gene disruption and
      sequencing of the Y region of the HML, HMR and MAT loci, after nested PCR.
      Presence of ORFs a1 and a2 in the Y region of the HML locus was found. At the ORF
      a2 at HML locus, a mutation in the stop codon was found, so the a2 ORF contains
      33 more bases.

PMID- 15031662
TI  - Induced synchrony in Cryptococcus neoformans after release from G2-arrest.
AB  - Cryptococcus neoformans was grown first to OD 4 under moderate aeration, then
      diluted 2.5 times with fresh medium, and grown under limited aeration for 5 h.
      Oxygen concentration decreased from 5-6 mg l(-1) to 1.5 mg l(-1) 1 h after the
      shift to limited aeration, and remained at a similar level thereafter. In all the
      eleven strains examined the shift caused unbudded G(2)-arrest in more than half
      of the cells. In three strains more than 80% of the cells were arrested in
      unbudded G(2), and, therefore they were selected for synchrony experiments. After
      being shifted to extensive aeration again, the cells resumed growth by
      synchronous budding, followed by synchronous nuclear division. This method has
      turned out to be a good tool to prepare synchronized culture in C. neoformans,
      especially when a large amount of synchronized cells is needed. This is worthy of
      attention, since synchronous cultures after release from G(2)-arrest have not
      been reported yet in any yeast species.

PMID- 15031663
TI  - Influence of short chain fatty acids and lysine on Salmonella typhimurium cadA
      expression.
AB  - In Salmonella typhimurium, cadA has a role in virulence expression and is an
      inducible gene that responds to external lysine concentration. In this study, a
      strain of S. typhimurium carrying a cadA: lacZ fusion was used to determine if
      the induction of cadA occurred under different lysine concentrations and mildly
      acid conditions in the presence of short chain fatty acids. Aliquots of an 18-h
      culture of S. typhimurium were placed on fresh media containing different lysine
      concentrations at pH 5.8 adjusted by addition of HCl or by 1 M short chain fatty
      acids (SCFA, acetic, propionic and butyric acid) stock solution. After an
      induction period of 2 h, beta -galactosidase activities were assayed. Expression
      of cadA in rich medium was significantly higher than that of minimal medium at
      neutral pH and different lysine concentrations. In contrast, at pH 5.8, there was
      a significant increase in cadA expression, particularly when pH was adjusted
      using HCl at all lysine levels. Addition of a mixture of organic acids yielded an
      overall lower cadA expression at all lysine levels studied when compared to HCl.
      However, each SCFA challenge (individual or as a mixture) caused a high level of
      expression, both at neutral and acidic pH. Based on these results it is apparent
      that in the presence of external lysine, SCFA and nutrient availability can
      influence cadA expression in S. typhimurium.

PMID- 15031665
TI  - Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological
      functions.
AB  - Hypoxia-inducible factor (HIF-1) is an oxygen-dependent transcriptional
      activator, which plays crucial roles in the angiogenesis of tumors and mammalian
      development. HIF-1 consists of a constitutively expressed HIF-1beta subunit and
      one of three subunits (HIF-1alpha, HIF-2alpha or HIF-3alpha). The stability and
      activity of HIF-1alpha are regulated by various post-translational modifications,
      hydroxylation, acetylation, and phosphorylation. Therefore, HIF-1alpha interacts
      with several protein factors including PHD, pVHL, ARD-1, and p300/CBP. Under
      normoxia, the HIF-1alpha subunit is rapidly degraded via the von Hippel-Lindau
      tumor suppressor gene product (pVHL)- mediated ubiquitin-proteasome pathway. The
      association of pVHL and HIF-1alpha under normoxic conditions is triggered by the
      hydroxylation of prolines and the acetylation of lysine within a polypeptide
      segment known as the oxygen-dependent degradation (ODD) domain. On the contrary,
      in the hypoxia condition, HIF-1alpha subunit becomes stable and interacts with
      coactivators such as p300/CBP to modulate its transcriptional activity.
      Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes
      under hypoxic conditions. The target genes of HIF-1 are especially related to
      angiogenesis, cell proliferation/survival, and glucose/iron metabolism. Moreover,
      it was reported that the activation of HIF-1alpha is closely associated with a
      variety of tumors and oncogenic pathways. Hence, the blocking of HIF-1a itself or
      HIF-1alpha interacting proteins inhibit tumor growth. Based on these findings,
      HIF-1 can be a prime target for anticancer therapies. This review summarizes the
      molecular mechanism of HIF-1a stability, the biological functions of HIF-1 and
      its potential applications of cancer therapies.

PMID- 15031664
TI  - Anti-stress activity of Propionibacterium freudenreichii : identification of a
      reactivative protein.
AB  - Propionibacterium freudenreichii subsp. shermanii is known to prevent mutations
      caused by various agents such as N-methyl-N'-nitro-N-nitrosoguanidine, 9
      aminoacridine, 4-nitro-quinoline-1-oxide and by UV radiation in both prokaryotic
      and eukaryotic cells. It was also shown to prevent or repair damage caused by
      H(2)O(2) or UV radiation in Salmonella typhimurium and Escherichia coli, a
      characteristic previously designated as reactivative effect. In order to
      characterise this effect at the molecular level, we have purified the active
      component from a P. freudenreichii cell-free extract using a combination of
      ammonium sulfate precipitation, anion-exchange and size-exclusion chromatography.
      The isolated 35 kDa protein was then identified using both N-terminal and
      internal peptide sequencing as a cysteine synthase. The latter was localised in
      the P. freudenreichii proteomic map. It is constitutively expressed but also
      clearly induced during adaptation to detergent and heat, but not acid, stresses.
      The biological meaning of cysteine synthase in the context of adaptation to
      oxidative and non-oxidative stresses is discussed.

PMID- 15031666
TI  - Serum concentrations of soluble 4-1BB and 4-1BB ligand correlated with the
      disease severity in rheumatoid arthritis.
AB  - Rheumatoid arthritis (RA) is a multifactorial autoimmune disease whose
      etiopathogenesis is not well understood. Although soluble (s) forms of 4-1BB (s4
      1BB) and 4-1BB legand (s4-1BBL) have been detected in the sera of RA patients,
      their significance is not known. We compared the serum levels of s4-1BB and s4
      1BBL in RA patients with those in systemic lupus erythematosus (SLE) and Behcet's
      disease (BD) patients. Serum levels of s4-1BB and s4-1BBL were significantly
      higher in RA patients compared with healthy controls, SLE or BD patients, and the
      abundance was correlated with disease severity in patients with RA. The serum
      levels of s4-1BB in RA patients were inversely corroborated with 4-1BB expression
      levels on activated T lymphocytes. In addition, there was a correlation between
      serum levels of s4-1BB and s4-1BBL. The augmented secretion of s4-1BB and s4-1BBL
      levels into the serum may reflect the clinical symptoms of RA and levels of s4
      1BB and s4-1BBL in sera at the time of diagnosis may be indicative of the
      severity and outcome of RA.

PMID- 15031667
TI  - Prolonged hypotensive effect of human tissue kallikrein gene delivery and
      recombinant enzyme administration in spontaneous hypertension rats.
AB  - To evaluate the feasibility of treating hypertension by human tissue kallikrein
      gene (KLK1) delivery and by enzyme (rK1) administration, two recombinant vectors
      expressing KLK1 cDNA were constructed for gene delivery (pcDNA-KLK1) and
      recombinant enzyme preparation (pOV-KLK1). Expression of the pcDNA-KLK1 vector in
      COS-1 cells was confirmed by immunofluorescence and in spontaneous hypertension
      rats (SHR) by enzymatic detection. Following intramuscular or intravenous
      injection with the pcDNA-KLK1 vector, systolic pressure of SHR was significantly
      decreased, which lasted for 20 d to two months depending on dose, route and/or
      time of injection. Egg white containing recombinant hK1 was prepared by injection
      of egg-laying hens with the oviduct-specific expression vector pOV-KLK1 and
      administered into SHR via oral gavage. Following administration, systolic
      pressure of the SHR was decreased to that of normal rats, which lasted for 3-5 d
      depending on the dosage used. These data suggest that both hKLK1 gene delivery
      and recombinant enzyme administration can be used as alternative strategies for
      treating human hypertension.

PMID- 15031668
TI  - Hereditary neuropathy with liability to pressure palsies (HNPP) patients of
      Korean ancestry with chromosome 17p11.2-p12 deletion.
AB  - Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal
      dominant inherited disorder characterized by recurrent pressure palsies. Most
      HNPP patients have a 1.5 mb deletion in chromosome 17p11.2-p12. The present study
      aimed at evaluating the deletion of the 17p11.2-p12 region in Korean subjects
      with families exhibiting HNPP phenotype, and to determine the clinical,
      electrophysiological and morphological aspects specifically associated with this
      deletion in HNPP patients. By genotyping six microsatellite markers (D17S921,
      D17S955, D17S1358, D17S839, D17S122 and D17S261), HNPP with the deletion was
      observed in 79% (19 of 24) of HNPP families. Nerve conduction studies were
      performed in 35 HNPP patients from these 19 families. The observed HNPP deletion
      frequency in Koreans is consistent with findings in other populations. Disease
      onset occurred at a significantly earlier age in patients with recurrent pressure
      palsies than in those with a single attack (P < 0.01). Nerve conduction studies
      demonstrated diffuse mild to moderate slowing of nerve conduction velocities that
      were worse over the common entrapment sites, regardless of the clinical
      manifestations. A long duration of compound muscle action potentials without a
      conduction block or a temporal dispersion is a characteristic of this disease. A
      sural nerve biopsy with teasing was performed in four patients, and tomacula of
      the myelin sheath was found in 56.4%. Our findings appear to support the
      existence of a phenotype/genotype correlation in HNPP patients of Korean ancestry
      with the deletion, and suggest that HNPP patients with earlier symptom onset face
      an increased chance of having recurrent attacks.

PMID- 15031669
TI  - Isolation of ethanol-induced genes in pancreatic beta-cells by representational
      difference analysis (RDA).
AB  - Recent epidemiological studies suggest that alcohol consumption is one of the
      risk factors leading to type 2 diabetes, but the direct effect of ethanol on beta
      cell gene expression is not known. Here, using cDNA RDA method, we isolated 43
      ethanol-induced genes in pancreatic beta-cells, and confirmed their differential
      expression by Northern blot or semi-quantitative RT-PCR. These genes were further
      categorized by the functional criteria based on the published data; Translation,
      Transcription, Metabolism, Signal transduction, Transport, Structure,
      Cytoskeleton, Regulation, or Putative/Unknown genes. The effects of each gene on
      beta-cell function need to be further investigated, however, the present data
      strongly suggest that these genes might be related to the metabolic alterations
      caused by ethanol as indicated in earlier study. In particular, RPS3 gene
      expression was increased by ethanol, glucosamine, and cytokines, implying that
      ethanol might decrease the metabolic activity by oxidative stress in beta-cells.
      Therefore, cloning of these genes in full-length and the detailed studies of each
      gene on beta-cell functions might provide clues on the pathophysiology of type 2
      diabetes caused by alcohol.

PMID- 15031671
TI  - Forskolin promotes astroglial differentiation of human central neurocytoma cells.
AB  - Human central neurocytoma is a kind of the brain tumors that are usually found in
      anterior part of the lateral ventricles. In this study, we established conditions
      that allowed proliferation of neurocytoma cells culture and analyzed
      characteristics of neurocytoma cells in vitro. For in vitro, a condition that
      used for culturing neural stem cells and contained basic fibroblast growth factor
      (bFGF) provided high proliferation. RT-PCR analaysis showed that nestin was found
      in neurocytoma cells, indicating that the neurocytomas possess neural stem cell
      properties. Interestingly, treatment of neurocytoma cells with forskolin
      increased expression of glial fibrillary acidic protein with a concomitant
      decrease in the nestin expression. Forskolin also induced morphological changes
      of neurocytoma cells to adopt an astrocyte-like phenotype. The results suggest
      that neurocyotma cells may have properties of multipotent neural stem cells.

PMID- 15031670
TI  - Transduction of yeast cytosine deaminase mediated by HIV-1 Tat basic domain into
      tumor cells induces chemosensitivity to 5-fluorocytosine.
AB  - Enzyme/prodrug approach is one of the actively developing areas for cancer
      therapy. In an effort to develop more effective enzyme/prodrug systems, cell
      permeable cytosine deaminase was produced by fusing yeast cytosine deaminase
      (yCD) in frame with RKKRRQRRR domain of HIV-1 Tat which is an efficient delivery
      peptide of the foreign proteins into cells. The purified Tat-yCD fusion protein
      expressed in Escherichia coli was readily transduced into mammalian cells in a
      time- and dose-dependent manner. A significant level of the transduced Tat-yCD
      protein was recovered in the cell and was stable for 24 h as indicated by both
      results of the enzymatic assay of 5-fluorocytosine (5-FC) conversion to 5
      fluorouracil (5-FU) and Western blot analysis. The cells transduced with Tat-yCD
      become highly sensitive to the cytotoxicity of 5-FC, while cells treated with yCD
      are unaffected by 5-FC. In addition, a strong bystander effect was observed with
      conditioned media from cells transduced with Tat-yCD added to non-transduced
      cells. Tat-yCD fusion protein demonstrated here for its ability to transduce into
      cells and convert nontoxic prodrug 5-FC to the toxic antimetabolite 5-FU, may be
      a useful approach for cancer therapy.

PMID- 15031672
TI  - Involvement of MAPK pathway in hypoxia-induced up-regulation of urokinase
      plasminogen activator receptor in a human prostatic cancer cell line, PC3MLN4.
AB  - Clinical studies have shown that tumor hypoxia is associated with invasive growth
      and metastasis and may be an important prognostic factor adversely influencing
      survival in patients with tumors. To investigate the mechanisms involved in
      hypoxia-induced invasive growth and metastasis, hypoxia-mediated urokinase
      plasmalogen activator receptor (uPAR) expression, cellular invasiveness, and
      mitogen activated protein kinase (MAPK) activation were measured in a prostate
      cancer cell line, PC3MLN4. The levels of uPAR expression and cellular
      invasiveness were increased in hypoxic cells. Hypoxia-induced cellular
      invasiveness was blocked by an anti-uPAR monoclonal antibody. Phosphorylations of
      ERK and p38 kinases were also more extensive in hypoxic cells than in normoxic
      cells. Hypoxia-induced uPAR up-regulation was inhibited by pre-treatments with a
      specific inhibitor of MEK, PD98059 and a specific inhibitor of p38 MAP kinase,
      SB203580. Cell growth also increased in hypoxic cells. From these results,
      hypoxia increased tumor cell invasion by up-regulating uPAR expression, which
      might be mediated through ERK and p38 kinase signaling pathways in PC3MLN4
      prostate cancer cell line.

PMID- 15031673
TI  - Angiotensin II receptor blocker attenuates overexpression of vascular endothelial
      growth factor in diabetic podocytes.
AB  - VEGF expressed in glomerular podocytes, is known to increase vascular
      permeability to macromolecules. Angiotensin II can stimulate the release of VEGF,
      and the protective effects of angiotensin II antagonist against diabetic
      glomerular injury suggest that the angiotensin II-induced VEGF is an important
      pathogenetic mechanism in the development of proteinuria during diabetic
      nephropathy although this mechanism is not fully understood. In this study, the
      changes of VEGF expression was examined in the experimental diabetic nephropathy
      to determine whether these changes were modified by renoprotective intervention
      by blockers of angiotensin II receptors. The streptozotocin- induced diabetic
      rats were treated with L-158,809, a blocker of angiotensin II receptors, for 12
      weeks. Age-matched rats with L-158,809 served as controls. RT-PCR and
      immunohistochemistry were used to assess and quantify gene and protein expression
      of VEGF. A progressive increase in urinary protein excretion was observed in
      diabetic rats. Glomerular VEGF expression was significantly higher in diabetic
      rats than in the control groups, with a significant reduction in glomerular VEGF
      expression and proteinuria in L-158,809- treated diabetic rats. VEGF mRNA was
      also significantly higher in diabetic kidneys than in the control groups, with a
      significant reduction in VEGF mRNA in L-158,809-treated diabetic kidneys. These
      results demonstrates that VEGF expression is significantly increased in diabetic
      podocytes, and angiotensin II receptor antagonist attenuated these changes in
      VEGF expression and prevented the development of proteinuria in vivo. Attenuation
      of increased VEGF expression in podocytes could contribute to the renoprotective
      effects of angiotensin II receptor antagonists in diabetic nephropathy.

PMID- 15031674
TI  - Acetoaminophen-induced accumulation of 8-oxodeoxyguanosine through reduction of
      Ogg1 DNA repair enzyme in C6 glioma cells.
AB  - Large doses of acetaminophen (APAP) could cause oxidative stress and tissue
      damage through production of reactive oxygen/nitrogen (ROS/RNS) species and
      quinone metabolites of APAP. Although ROS/RNS are known to modify DNA, the effect
      of APAP on DNA modifications has not been studied systematically. In this study,
      we investigate whether large doses of APAP can modify the nuclear DNA in C6
      glioma cells used as a model system, because these cells contain cytochrome p450
      related enzymes responsible for APAP metabolism and subsequent toxicity (Geng and
      Strobel, 1995). Our results revealed that APAP produced ROS and significantly
      elevated the 8-oxo- deoxyguanosine (8-oxodG) levels in the nucleus of C6 glioma
      cells in a time and concentration dependent manner. APAP significantly reduced
      the 8- oxodG incision activity in the nucleus by decreasing the activity and
      content of a DNA repair enzyme, Ogg1. These results indicate that APAP in large
      doses can increase the 8-oxodG level partly through significant reduction of Ogg1
      DNA repair enzyme.

PMID- 15031675
TI  - Methyl-beta-cyclodextrin inhibits cell growth and cell cycle arrest via a
      prostaglandin E(2) independent pathway.
AB  - Methyl-beta-cyclodextrin, a cyclic oligosaccharide known for its interaction with
      the plasma membrane induces several events in cells including cell growth and
      anti-tumor activity. In this study, we have investigated the possible role of
      cyclooxygenase 2 (COX-2) in cell growth arrest induced by methyl-beta
      cyclodextrin in Raw264.7 macrophage cells. Methyl-beta-cyclodextrin inhibited
      cell growth and arrested the cell cycle, and this cell cycle arrest reduced the
      population of cells in the S phase, and concomitantly reduced cyclin A and D
      expressions. Methyl-beta-cyclodextrin in a dose- and time-dependent manner, also
      induced COX-2 expression, prostaglandin E(2) (PGE(2)) synthesis, and COX-2
      promoter activity. Pretreatment of cells with NS398, a COX-2 specific inhibitor
      completely blocked PGE(2) synthesis induced by methyl-beta-cyclodextrin, however
      inhibition on cell proliferation and cell cycle arrest was not effected,
      suggesting non-association of COX-2 in the cell cycle arrest. These results
      suggest that methyl-beta-cyclodextrin induced cell growth inhibition and cell
      cycle arrest in Raw264.7 cells may be mediated by cyclin A and D1 expression.

PMID- 15031676
TI  - Increased methylation of the cytosolic 20-kD protein is accompanied by liver
      regeneration in a hepatectomized rat.
AB  - Arginine methylation has been implicated in the signal transduction pathway
      leading to cell growth. Here we show that a regenerating rat liver following
      partial hepatectomy exhibited elevated methyltransferase activity as shown by
      increased methylation of a subset of endogenous proteins in vitro. The 20-kDa
      protein was shown to be a major cytosolic protein undergoing methylation in
      regenerating hepatocytes. Methylation of the 20-kDa protein peaked at 1 d
      following partial hepatectomy, which gradually declined to a basal level within
      the next 14 d. Likewise, methylation of exogenously added bulk histones followed
      the similar time kinetics as the 20-kDa protein, reflecting time-dependent
      changes in methyltransferase activity in regenerating hepatocytes. Presence of
      exogenously added bulk histone in the in vitro methylation assay resulted in dose
      dependent inhibition of methylation of the 20-kDa protein. All the histone
      subtypes tested, histone 1, 2A, 2B, 3 or 4, were able to inhibit methylation of
      the 20-kDa protein while addition of cytochrome C, a-lactalbumin, carbonic
      anhydrase, bovine serum albumin, and g globulin minimally affected methylation of
      the 20-kDa protein. Since methylation of the 20-kDa protein preceded
      proliferation of hepatocytes upon partial hepatectomy, it is tempting to
      speculate that the methylated 20-kDa protein by activated histone-specific
      methyltransferase may be involved in an early signal critical for liver
      regeneration.

PMID- 15031677
TI  - Kinesin superfamily protein member 4 (KIF4) is localized to midzone and midbody
      in dividing cells.
AB  - In association with microtubules, a variety of kinesins play important roles in
      cellular functions such as intracellular transport of organelles or vesicles,
      signal transduction, and cell division. In a previous study we revealed that
      human kinesin superfamily protein member 4 (KIF4) is a chromokinesin that binds
      to chromosomes. Since localization of several kinds of kinesin at midzone called
      central spindle, or midbody that connects two daughter cells, or both, suggests
      their implication in cell division, we investigated KIF4 localization of during
      mitosis and cytokinesis in Hela cells. In addition to association with
      segregating chromosomes through entire mitosis, it also localized to the midzone
      and to midbody at ana/telophase through cytokinesis. Especially in cells at
      cytokinesis, KIF4 appeared as a doublet facing each other at the apical ends of
      two daughter cells. Three- dimensional analysis of architectural relationship
      between microtubule bundles and KIF4 indicated that KIF4 forms a ring structure
      wrapping around the microtubule bundles. These results suggest that KIF4 is
      involved in cytokinesis, although direct evidence was not provided in this study.

PMID- 15031679
TI  - [Diffuse, micronodular lung disease. The high-resolution CT approach. A pictorial
      essay].
AB  - Careful HRCT evaluation of the preferential distribution of micronodular lesions
      within the secondary lobule provides a fundamental contribution in the correct
      interpretation of the different associated patterns. This paper suggests a modern
      diagnostic algorithm that, together with clinical-anamnestic data and additional
      imaging features, is able to provide a definitive diagnosis or to reduce the
      possible differential diagnoses.

PMID- 15031678
TI  - AMPA, not NMDA, activates RhoA GTPases and subsequently phosphorylates moesin.
AB  - Glutamate induced rapid phosphorylation of moesin, one of ERM family proteins
      involved in the ligation of membrane to actin cytoskeleton, in rat hippocampal
      cells (JBC, 277:16576-16584, 2002). However, the identity of glutamate receptor
      has not been explored. Here we show that a-amino- 3-hydroxy-5-methyl-4
      isoxazolepropionic acid (AMPA) receptor is responsible for glutamate-induced RhoA
      activation and phosphorylation of moesin. Glutamate induced phosphorylation at
      Thr-558 of moesin was still detectible upon chelation of Ca(2+), suggesting
      involvement of AMPA receptor instead of N-methyl D-Aspartate (NMDA) receptor in
      this phosphorylation of moesin. AMPA but not NMDA- induced moesin phosphorylation
      was independent of Ca(2+). Both AMPA and NMDA but not Kainate induced moesin
      phosphorylation at similar levels. However, the kinetics of phosphorylation
      varied greatly between AMPA and NMDA where AMPA treatment rapidly increased
      phosphomoesin, which reached a maximum at 10 min after treatment and returned to
      a basal level at 30 min. In contrast, NMDA-induced phosphorylation of moesin
      reached a maximum at 30 min after treatment and was remained at higher levels at
      60 min. A possible involvement of RhoA and its downstream effector, Rho kinase in
      the AMPA receptor-triggered phosphorylation of moesin was also explored. The
      kinetics for the glutamate- induced membrane translocation of RhoA was similar to
      that of moesin phosphorylation induced by AMPA. Moreover, Y-27632, a specific Rho
      kinase inhibitor, completely blocked AMPA-induced moesin phosphorylation but had
      no effect on NMDA-induced moesin phosphorylation. These results suggest that
      glutamate-induced phosphorylation of moesin may be mediated through the AMPA
      receptor/RhoA/Rho kinase pathway.

PMID- 15031680
TI  - [Pictorial essay: foreign body of the gastrointestinal tract in emergency
      radiology].
AB  - The ingestion of a foreign body is a relatively common gastrointestinal emergency
      that causes significant morbidity. Radiological procedures play a very important
      role in revealing the presence, the location and the nature of an ingested
      foreign body, thus enabling the best therapeutic approach. We present the
      radiological features of common and uncommon foreign bodies ingested or with
      transanal insertion, differentiated on the basis of the location in the
      gastrointestinal tract. Diagnostic pitfalls are also considered.

PMID- 15031681
TI  - [Differential patterns of contrast enhancement in different focal liver lesions
      after injection of the microbubble US contrast agent SonoVue].
AB  - PURPOSE: To identify differential contrast enhancement patterns in different
      focal hepatic lesions after injection of the microbubble contrast agent SonoVue
      using high or low acoustic power imaging. MATERIAL AND METHODS: Forty-seven focal
      hepatic lesions (1-8 cm) were detected in 45 patients at unenhanced gray-scale
      ultrasound (US) and evaluated by color Doppler (CD) US with spectral analysis of
      tumoral vessels. Lesions were subsequently evaluated by US contrast specific
      modes after IV bolus administration of 2,4-4,8 ml of SonoVue, by intermittent
      high acoustic power (18 patients) or by continous low acoustic power imaging (27
      patients), during arterial, portal and late phase. Subjective evaluation of
      lesions appearance before and after SonoVue injection was performed. For final
      diagnosis multiphasic helical CT (21 patients) and/or fine needle US guided
      biopsy (24 patients) were considered as the reference procedures. RESULTS: Final
      diagnoses comprised 22 hepatocellular carcinomas (HCCs; 1,5-6 cm), 2
      macroregenerative nodules (RNNs; 1-2 cm), 10 metastasis (2-3,5 cm), 10
      hemangiomas (2-6 cm) and 3 focal nodular hyperplasias (FNHs; 1-3 cm). On CD
      evaluation HCCs revealed peripheral basket shaped (12/22) or intranodular (10/22)
      arterial pattern while, after SonoVue injection HCCs revealed diffuse contrast
      enhancement during arterial phase with contrast washout during portal and late
      phase. Metastases did not reveal flow signals on CD or contrast enhancement after
      SonoVue injection, except for 2 metastases which revealed peripheral and central
      vessels on CD and a diffuse contrast enhancement during arterial phase, appearing
      hypoechoic to the adjacent liver during portal and late phase. RNNs revealed
      dotted contrast-enhancement during portal and late phase with isoechoic
      appearance to the adjacent liver. Hemangiomas revealed some peripheral venous
      flows on CD and a peripheral nodular contrast enhancement during arterial phase
      with a centripetal fill-in during portal and late phase. FNHs revealed low
      resistance peripheral or central arterial vessels and a diffuse contrast
      enhancement during arterial phase, preceded or not by central spoke wheel shaped
      contrast enhancement, and a persistent iso-hyperechogenicity during portal and
      late phase. CONCLUSIONS: SonoVue injection has showed to identify differential
      contrast enhancement patterns in different focal hepatic lesions.

PMID- 15031682
TI  - [Focal liver lesions: characterization with quantitative analysis of T2
      relaxation time in TSE sequence with double echo time].
AB  - PURPOSE: To evaluate the accuracy of calculation of T2 relaxation time with
      simplified algorithm in characterization of liver focal lesions with Turbo Spin
      Echo (TSE) T2-weighted sequences with double echo time (TE). MATERIALS AND
      METHODS: We carried out a retrospective analysis of 113 hyperintense hepatic
      focal lesions in T2-weighted sequences (52 metastases, 51 hemangiomas and 10
      cysts). We have employed a single TSE T2-weighted sequence with effective TE of
      83 and 165 msec and turbo factor 9. Signal intensity (IS) of each lesion was
      measured on different TE. Using these values, we calculated T2 relaxation time by
      the following simplified algorithm: T2(ms)=(TE2-TE1)/ (lnIS1-lnIS2). T2
      relaxation time has been correlated with the final diagnosis, obtained by
      percutaneous biopsy, surgical resection or three months follow-up. RESULTS: The
      mean T2 relaxation time for metastases was 108,7 msec (+/-30), for hemangiomas
      166,5 msec (+/- 29) and for cysts 312,4 msec (+/-19). The difference between the
      mean T2 relaxation time for metastases and hemangiomas was statistically
      significant (p<0.0001). Most metastases were best characterized between the
      threshold value of 130 and 140 msec. The values of specificity and sensitivity of
      the diagnosis of malignant hepatic lesion was respective 0,86 and 0,88. All false
      positive diagnoses were hemangiomas of less than one centimeter. CONCLUSIONS:
      Introducing double echo time TSE sequences in the protocol of liver study concurs
      to obtain high diagnostic accuracy in the characterization of the hepatic
      lesions. The quantitative analysis of T2 represents a useful additional
      instrument to the morphologic analysis in discrimination between hepatic lesions
      and can be carried out by TSE sequences with elevated reliability reducing the
      imaging time compared with conventional sequences. The evaluation of hepatic
      lesions of less than one centimeter should always include analysis of dynamic
      gadolinium-contrast images.

PMID- 15031683
TI  - [Current state of the use of sonographic contrast agents with low acoustic
      pressure techniques in the study of focal liver lesions].
AB  - Ultrasonography is the most commonly used screening modality for focal liver
      lesions in Europe. Over the past few years, to overcome the inherent limitations
      of B-mode imaging and colour-Doppler ultrasound in identifying and characterising
      focal liver lesions, intravenous agents capable of enhancing the ultrasound
      signal emitted by vascular and parenchymal structures have been developed. From
      December 1999 to December 2001, about 400 patients with a known tumour, HCV
      related chronic cirrhotic liver disease, or with an indeterminate focal liver
      lesion discovered incidentally were evaluated by ultrasound of the liver
      parenchyma both in baseline conditions and after administration of contrast
      material. The ultrasound contrast agents used were: SonoVue (Bracco, Milan-Italy)
      and Optison (Mallinckrodt, London - UK). Our experience is based on low
      mechanical-index contrast-enhanced imaging, which acts conservatively, performed
      with different commercially available algorithms, in grey-scale mode alone (B
      mode). We report the morphological patterns displayed by the main benign and
      malignant liver lesions after the administration of second-generation ultrasound
      contrast material, and review the main imaging patterns able to provide effective
      and practical guidance in formulating a diagnosis of benignity or malignancy. Our
      clinical experience confirmed the literature findings that the introduction of
      low mechanical index methods in grey-scale imaging has allowed qualitatively
      better results for detecting and characterising focal liver lesions than those
      obtained with baseline and colour-Doppler imaging. The ease of use, substantial
      repeatability and predictability of the enhancement effects obtainable with low
      mechanical index methods are the main reasons for the success of this approach.
      Broadening the scope of studies to obtain controlled data and comparisons with
      the other imaging modalities is crucial for the definitive validation of the
      method.

PMID- 15031684
TI  - [Sonographic anatomy of the female pelvis and current technological
      developments].

PMID- 15031685
TI  - [Contrast-enhanced sonography in the diagnosis of renal artery stenosis:
      comparison with MR-angiography].
AB  - PURPOSE: To investigate the diagnostic accuracy of non-enhanced Colour-Doppler US
      and enhanced power-Doppler US in the diagnosis of renal artery stenosis compared
      with breath-hold Gd-DOTA-enhanced MR-angiography. Digital subtraction angiography
      (DSA) provided the gold standard. MATERIALS AND METHODS: A total of 51 patients
      (19 women and 32 men, age ranging from 29 to 76 years) with clinical suspicion of
      renovascular hypertension underwent Colour-Doppler US of the renal artery; 11
      subjects (21.6%) were excluded from the study as a complete and bilateral
      depiction of renal artery was not obtained. The remaining 40 subjects (14 women
      and 26 men) were investigated with power-Doppler US with time-intensity renal
      enhancement curve and with MR-Angiography. All of these subjects were also
      studied by DSA which provided the gold standard. RESULTS: As stated, in 11 of 51
      patients the diagnostic work-up was not completed because the initial US
      examination failed to depict the renal arteries. DSA showed renal artery stenosis
      in 16 of the remaining 40 patients. The sensitivity and specificity in diagnosing
      stenoses were 75% and 79.1% for conventional colour-Doppler US, 100% and 87.5%
      for enhanced power-Doppler US and 100% and 91.6% for MR-angiography. CONCLUSIONS:
      MR-angiography is the most reliable technique in the diagnosis of renal artery
      stenosis. The sensitivity and specificity of enhanced power-Doppler US are
      superior to those of colour-Doppler US. Although MR-Angiography enables a better
      evaluation of renal artery stenosis, the good diagnostic accuracy of enhanced
      power-Doppler US, its greater acceptance by the patients and its wider diffusion
      support the use of this technique in the screening of patients with clinical
      suspicion of renovascular hypertension.

PMID- 15031686
TI  - [Patient dose evaluation and optimization of uropoietic multiphasic multislice CT
      examination].
AB  - PURPOSE: The aim of this study was to optimize acquisition data during multislice
      multiphasic CT examination of the renal excretory system in order to reduce
      patient effective dose without deterioration of the imaging quality. MATERIALS
      AND METHODS: With the aid of two dedicated software programmes we evaluated the
      patient effective dose during both multislice multiphasic CT examination of the
      renal excretory system and excretory urography. With the CT acquisition protocol,
      images of a test object (Helical CT phantom, CIRS) were examined by two expert
      radiologists to assess the number of visible inserted test images. Other scans of
      the test object were then obtained utilizing decreased tube current intensity;
      among these that with minor information loss was identified. Patient effective
      dose was measured utilizing correspondent acquisition data. RESULTS: Patient
      effective dose during multiphasic multislice CT examination before optimization
      (280 mA tube current intensity) was 22.9 mSv for males and 31.1 mSv for females;
      after optimization it was 19.6 mSv and 26.7 mSv, respectively, with a 14%
      decrease. Patient effective dose during CT direct phase before optimization was
      8.9 mSv for males and 12.8 mSv for females, after optimization 7.6 mSv and 11 mSv
      with a 15% decrease. The absorbed dose for males is lower because the females
      gonads are completely included in the primary CT beam, whereas the testicles are
      hit by diffuse radiation only. DISCUSSION AND CONCLUSIONS: During CT direct phase
      the patient absorbed dose is 1.45 for males and 1.9 for females (1.2 and 1.6
      respectively after optimization) higher than that absorbed during intravenous
      pyelography; the absorbed dose of a complete multiphasic CT examination is 3.7
      for males and 4.6 for females (3.2 and 3.9 respectively after optimization)
      higher than that absorbed during intravenous pyelography. Such dosimetric data
      may be justified by diagnostic advantages in stone assessment, especially in
      males, and by the fact that multislice CT may unify different diagnostic tools
      such as intravenous pyelography, axial CT and angiography, thereby simplifying
      the entire diagnostic protocol. As far as exposure is concerned radiologists
      should follow the optimizing principle referred to each clinical query, bearing
      in mind that diagnostic accuracy is more important than the simple iconographic
      aspect.

PMID- 15031687
TI  - [Bleeding renal angiomyolipomas. CT findings].
AB  - PURPOSE: To describe our experience in three cases of abdominal haemorrhage
      caused by bleeding renal angiomyolipomas, which were studied with Computed
      Tomography (CT). MATERIALS AND METHODS: A retrospective study carried out at our
      archives identified 3 patients (aged 58.6 on average) with renal angiomyolipomas
      clinically manifested with acute abdomen and haemorrhage. The patients underwent
      an emergency CT scan of the abdomen. One patient also under-went a subsequent
      renal angiography. All patients had surgery and histological characterizations of
      the renal lesions. RESULTS: The CT study on all three patients allowed detection
      of a lesion in the kidneys with inhomogeneous density due to haemorrhage. Areas
      with fat-density values (-60 -80 UH) were always observable within the lesions.
      The lesions, measuring 5-9 cm, were located in the right kidney in two patients
      and in the left kidney in one. CONCLUSIONS: In 40% of patients, renal
      angiomyolipoma may account for a picture of hypovolemic shock, so a correct
      diagnostic approach is important to guide the surgical approach. CT allows
      detection of the angiomyolipoma as the cause of the haemorrhage in most cases.
      The diagnosis is relatively simple when the lesion has typical features such as
      adipose content, whereas it may be difficult with non-typical aspects.
      Furthermore the fat content may also be detected in varying quantities in other
      renal lesions responsible for bleeding.

PMID- 15031688
TI  - [Magnetic resonance diagnosis of traumatic penile fracture].
AB  - PURPOSE: To report our experience with MRI in the preoperative evaluation of
      patients with traumatic penile fractures. MATERIALS AND METHODS: Between January
      1998 and December 2001, we performed MRI examinations on five patients (aged 29
      48 years; mean age 40 years) with suspected traumatic fracture of the penis
      occurred during sexual intercourse. In all cases, T1-weighted SE, T2-weighted FSE
      and GRE sequences in the axial, coronal and sagittal planes were acquired. The
      study was performed without IV administration of paramagnetic contrast agents and
      in conditions of detumescence. A small-sized surface coil was used in four cases
      and a body coil was used in one case. All patients had suspected penile fracture
      with indications for surgical repair. The MR examination was performed within 12
      to 48 hours of the trauma and was requested to aid surgical planning. RESULTS:
      The MR image quality was adequate in all cases. The examination documented
      unilateral rupture of the corpus cavernosum in all patients. This finding was
      associated with haematoma located both subcutaneously and inside the corpus
      cavernosum itself. In no case was there rupture of both corpora cavernosa. In
      only one patient was there a suspicion of injuries to the urethral corpus
      spongiosum, which was confirmed by surgery along with the other MR findings.
      DISCUSSION AND CONCLUSIONS: Many imaging methods are available to evaluate
      traumatic penile lesions: ultrasound, colour-Doppler ultrasound, urethrography,
      cavernosography, angiography and MRI. In agreement with the literature, our
      experience shows that MRI is useful in evaluating penile injuries owing to its
      multiplanar capabilities, its good spatial resolution and its excellent tissue
      contrast resolution. These characteristics enabled a more adequate surgical
      approach. In our view, MRI can be regarded as an emerging method to obtain
      helpful diagnostic information, with no risks for the patient.

PMID- 15031689
TI  - [Percutaneous management of hemorrhages in pelvic fractures].
AB  - PURPOSE: To report our experience in the control of haemorrhage with the
      transcatheter embolisation technique. MATERIALS AND METHODS: Between 1999-2001,
      we treated 56 patients with important pelvic trauma. Forty-two were victims of
      car accidents and 14 of falls from great altitudes. Twenty presented acute
      symptoms due to blunt pelvic trauma, with massive bleeding, not treatable by
      drugs and blood transfusion. Diagnosis of pelvic haemorrhage was made with CT.
      When high-flow haemorrhage was found, the patient was referred for angiography.
      Embolisation was achieved after a diagnostic arteriography, with bilateral
      transfemoral approach and selective catheterisation of the internal iliac
      arteries. RESULTS: Technical success was achieved in 100% of cases: all the
      haemorragic sites were found and embolised. In only one patient with severe shock
      was it impossible to locate the site of contrast material extravasation on the
      first day; the patient was successfully treated on the second day with
      improvement of the clinical conditions. The obturator artery was involved in five
      cases, the gluteal artery in eleven. In eighteen patients, use of an angiographic
      catheter was sufficient to treat the haemorragic sites. Percutaneous control of
      the haemorrhage was obtained by using Gelfoam, Ivalon and coils. CONCLUSIONS:
      Percutaneous haemorrhage control is safe and effective, and not as costly or
      dangerous as the surgical option. We regard it as the treatment of choice in
      multiple trauma patients with important and high-flow pelvic haemorrhage.

PMID- 15031690
TI  - [Factors affecting the results of ultrasound-guided percutaneous biopsy in
      oncology].
AB  - PURPOSE: Cytological or histological sampling of a neoplastic lesion, suspect or
      non-suspect for malignancy, either primary or metastatic, is always mandatory for
      indicating and planning the therapeutic work-up. Ultrasound-guided percutaneous
      needle biopsy is the most used technique for obtaining cellular or tissue
      samples, as it is quick, easy, reliable and less expensive than other techniques.
      The aim of this paper is to evaluate the efficacy of US-guided biopsy in
      responding to the clinical query with a diagnostic result, and to analyse the
      different factors that might influence the diagnostic adequacy of the sampled
      cellular or tissue material. MATERIALS AND METHODS: The results of 1897 biopsies
      (either cytological or histological), obtained by percutaneous US guided
      technique in patients with a lesion suspect for neoplasm, were evaluated in terms
      of adequacy or inadequacy in obtaining a pathologic diagnosis. The results were
      analysed with regard to the site of the lesion, the sampling method (cytological
      or histological) and the expertise of the operator (in terms of number of
      formerly executed procedures). RESULTS: The difference in adequacy of
      histological vs cytological sampling resulted statistically significant (94.l63%
      vs 71.18%, p<0.00001). The operator's former experience resulted the most
      important factor in determining the success of the procedure. The operators with
      an experience rate below 50 former procedure have, in fact, obtained inadequate
      material more than twice (36.29% vs 15.9%) compared to the more experienced
      operators: the difference was statistically significant for histological
      samplings. CONCLUSIONS: The period of technical learning of operators may be
      considered adequate after a personal experience of almost 50 procedures learning
      or over for microhistological sampling; while the apprenticeship is continuous
      and progressive for optimisation of sampling by cytoaspiration.

PMID- 15031691
TI  - [MRI evaluation of morpho-structural alterations of the retrodiscal tissue in
      condylo-meniscal incoordination of the TMJ: usefulness of individualised T2
      weighted TSE sequences].
AB  - PURPOSE: To assess and evaluate morpho-structural alterations of the retrodiscal
      tissue of the temporomandibular joint (TMJ) that may be seen in chronic trauma of
      the condylo-meniscal incoordination through magnetic resonance (MR), using T2
      weighted TSE sequences. MATERIALS AND METHODS: The study included 40 patients, 6
      male and 34 female, age range 12-66 years, mean age 28.5 years. According to the
      Wilkes classification, TMJs of patients were graded as follows: 10 grade 1 TMJs;
      28 grade 2, 16 grade 3, and 26 grade 4. Scans were obtained with a 1.5 T MRI
      unit, and a dedicated surface coil, using T2-weighted TSE sequences (TR 3000
      3500, TE 90-100), 2 acquisitions, 256x256 matrix, 3-mm section thickness, with a
      0-mm interval, and 2'30" duration for a single acquisition. Scans were obtained
      both during opening and during closure of the mouth, on 3 planes: sagittal
      oblique, perpendicular to the condylar long axis; coronal oblique, perpendicular
      to the anteroposterior axis of the discs; and axial, perpendicular to coronal
      scans. Parameters used were the following: presence or absence of retrodiscal
      fibrosis; morphology of the retrodiscal fibrosis in scans taken during mouth
      opening in the four grades of the Wilkes classification; dimensions of the
      retrodiscal fibrosis in scans taken during mouth opening, in the four grades of
      the Wilkes classification, in an anteroposterior direction, measuring the longest
      distance on parasagittal planes on a horizontal line touching the outer edge of
      the disc and the most-distal point of fibrosis, and in a vertical direction,
      measuring the distance between the highest and lowest points of fibrosis; signal
      intensity features within the fibrotic area. RESULTS: In all TMJs analysed, it
      was possible to confirm the presence of retrodiscal tissue fibrosis, which was
      more or less evident according to the grading of the dysfunction/disease, to the
      extent of mouth opening, and to displacement with or without reduction of the
      articular disc. In grade 1 TMJs, fibrosis looked like a truncated cone; in grade
      2, fibrosis looked like a cone; in grade 3, it was either shaped like a mushroom
      placed horizontally, with the stalk towards the disc, or else ribbon-shaped; in
      grade 4, it had an inhomogeneous, irregular ribbon shape. CONCLUSIONS: MR studies
      of TMJ dysfunction through T2-weighted TSE sequences allowed us to evidence in
      all cases the sclerotic alterations of the retrodiscal tissue, and to assess
      their form and dimensions. Furthermore, it was possible to evidence both the
      pathognomonic features of retrodiscal tissue fibrosis resembling a mushroom, and
      the characteristic brace-shape the upper and lower layers take on during mouth
      opening in TMJs with a disc displacement with reduction.

PMID- 15031692
TI  - [Cardiac MRI with SENSE technology: study of ventricular and valvular
      functionality in 30 patients].
AB  - PURPOSE: The latest innovation in MR imaging is SENSE (SENSitivity Encoding), a
      technology providing an important solution for the time necessary for signal
      encoding. In the SENSitivity Encoding (SENSE) approach, an array of multiple,
      simultaneously operated receiver coils is used for signal acquisition. In
      particular, the efficacy of SENSE technology is able to reduce the number of
      phase encodings by a factor (named R factor or Reduction factor) and to evaluate
      the same k space with fewer readout lines obtaining higher spatial and temporal
      resolution. MATERIALS AND METHODS: An heterogeneous group of 30 patients with a
      variety of clinically proven diagnoses underwent Cardiac MR with SENSE technology
      to evaluate the technique's diagnostic efficacy. The sequences used were
      "Balanced" Ultrafast Gradient Echo (B-FFE) characterised by a hyper-intense blood
      signal with multislice multiphase and single slice multiphase acquisitions.
      RESULTS: In addition to reducing scan times, SENSE technology improved spatial
      and temporal resolution (40 frames/cardiac cycle) providing optimal dynamic
      evaluation of valve structures and wall kinesis. Furthermore, the use of the
      SENSE technique with B-FFE sequences (sB-FFE) enabled the qualitative evaluation
      of abnormal blood movements and transvalvular flows. CONCLUSIONS: The
      considerable time savings allowed by SENSE technology and the clear improvement
      in image quality constitute a step forward in cardiac MR imaging. The possibility
      of executing morphologic, dynamic, perfusional and spectroscopic studies in the
      same MR examination session with short acquisition times and good image quality
      are becoming more feasible.

PMID- 15031693
TI  - [Normal anatomy of the vessels of the heart with 16-row multislice computed
      tomography].
AB  - Nowadays, cardiac imaging is not part of the clinical routine for the
      radiologist. Multislice Computed Tomography (MSCT) with 4 rows allowed to start
      the non invasive evaluation of coronary arteries. The introduction of 16-row MSCT
      has significantly improved the performance and diagnostic accuracy of this
      technique, so far that MSCT angiography has been advocated as a potential
      clinical tool for the study of coronary artery disease. Therefore, it is
      mandatory to understand normal cardiac and coronary anatomy in order to evaluate
      the presence and severity of coronary artery disease. The anatomical
      visualisation provided by MSCT differs from the one of conventional coronary
      angiography because it is not a simple "lumenology" but it is capable to provide
      information on the vessel wall, until now only achieved by invasive techniques
      such as intravascular ultrasound or optical coherence tomography, and on
      neighbouring structures. Aim of this works is to provide the basics of anatomy of
      the vessels of the heart applied to MSCT.

PMID- 15031694
TI  - [Techniques for the optimisation of coronary artery opacification in non-invasive
      angiography with a 16-row multislice computed tomography].
AB  - PURPOSE: To compare two different techniques to improve vessels opacification in
      coronary angiography with multislice CT (MSCT) scanner. MATERIALS AND METHODS:
      Thirty consecutive patients were divided into two groups. In group 1, the
      synchronisation was obtained administering 20 ml of cm at 4 ml/s during a dynamic
      monitoring sequence. In group 2, the real time monitoring of the main bolus was
      used to trigger the scan. The CT angiography was performed in both groups by
      administering 100 ml of cm at 4 ml/s, with MSCT scanner and the following
      parameters: collimation 16 x 0.75 mm, rotation time 0.42 s, retrospective ECG
      gating. Three regions of interest were created in order to measure attenuation
      at: 1) ascending aorta (ROI 1); 2) descending aorta (ROI 2); 3) pulmonary artery
      (ROI 3). Attenuation was also measured at the origin of the main coronary
      arteries and their larger branches. RESULTS: The average time/density curve
      showed lower enhancement in group 1 compared to group 2 in the first 4 s and 7 s
      in ROI 1 and ROI 2, respectively (p<0.05). The maximum enhancement value were 342
      HU and 347 HU for group 1 in ROI 1 and ROI 2, and 356 HU and 352 HU for group 2
      in ROI 1 and ROI 2, respectively. The attenuation at the origin of the main
      coronary arteries was higher in group 2 than in group 1 (p<0.05). CONCLUSIONS:
      Real time monitoring technique allows to use 20% less cm and provides better and
      more homogeneous enhancement.

PMID- 15031695
TI  - [Dissection of epiaortic vessels: clinical appearance and potentiality of imaging
      techniques].
AB  - PURPOSE: To analyse the major radiological and clinical features of dissections
      of the epiaortic vessels and evaluate the potential of imaging techniques on the
      basis of the findings reported in the literature over the last few years.
      MATERIALS AND METHODS: We evaluated 9 dissections (7 carotid lesions and 2
      vertebral lesions) in 9 patients (5 women and 4 men; age range: 30-56 years) who
      came to our attention between September 1999 and June 2002. These were all
      stenoses and obstructions located in the cervical region and, in two patients,
      extended intracranially. The morphologic features were assessed in each case by
      colour-Doppler US, CT, MR or conventional angiography and correlated with
      clinical, therapeutic and distant progression patterns. Colour-Doppler US of the
      neck vessels was performed in 4 patients; CT angiography of neck and intracranial
      vessels was performed in 4 patients using a single-slice spiral scanner and a
      single contrast medium bolus injection, following unenhanced examination of the
      brain; MR angiography was performed in 6 patients after baseline examination
      using flow-dependent and/or angiographic sequences; conventional angiography was
      performed in 7 patients. Clinical manifestations at onset were peripheral
      neurological lesions in 5 cases and central ischaemic lesions in the remaining 4
      cases. All patients underwent medical therapy (anticoagulants or antiaggregants).
      The follow-up was done by colour-Doppler US, MR and/or MR angiography; follow-up
      conventional angiography at 6-9 months was also performed in 6 patients. Distant
      progression was assessed on the basis of the degree of vascular re-canalization
      and the residual signs and symptoms. RESULTS: MR- and CT-angiography were
      diagnostic in all cases. In particular, diagnosis was obtained by MR-angiography
      in 4 patients and by CT-angiography in 3 patients. Conventional angiography
      yielded a diagnosis in 2 cases which had previously undergone non-contrast brain
      CT or MR without examination of neck vessels alone. Colour-Doppler US revealed
      non-specific wall and flow alterations in 2 cases, thus requiring further
      diagnostic studies. In patients with central neurological symptoms at onset the
      diagnosis was obtained within 48-72 hours, whereas in patients with initial
      peripheral neurological symptoms the time to diagnosis was significantly longer
      (up to 10 days) due to the poor specificity of the clinical picture and/or failed
      detection of the warning symptoms. Medical treatment gave rise to no major
      complications. Overall, distant progression was good: 6 patients recovered
      completely and 3 had mild to moderate residual neurological deficits. DISCUSSION
      AND CONCLUSIONS: Dissection of epiaortic vessels should always be considered as a
      probable cause of cerebral ischaemia in adults aged 20-50 years, particularly in
      the absence of vascular risk factors. Clinical assessment is fundamental for the
      diagnosis and treatment. Currently, CT and MR imaging techniques providing
      similar information are reliable diagnostic tools that can rapidly and non
      invasively clarify suspicious clinical cases. Nevertheless, angiography continues
      to have an important role in the overall evaluation of disease severity in view
      of the possible endovascular or surgical treatment of complications.

PMID- 15031696
TI  - [MRI in ACL reconstructive surgery with PDLLA bioabsorbable interference screws:
      evaluation of degradation and osteointegration processes of bioabsorbable
      screws].
AB  - PURPOSE: Anterior cruciate ligament (ACL) reconstructive surgery has seen
      significant progress since bioabsorbable interference screws have replaced
      synthetic metallic screws for ligament graft fixation within the femoral and
      tibial osseous tunnel. Our study compared the MR images of patients who underwent
      ACL reconstruction using bioabsorbable interference screws with those of patients
      who underwent ACL reconstruction using metallic screws to evaluate the MR aspects
      of degradation and osteointegration processes of bioabsorbable interference
      screws post-operatively. MATERIALS AND METHODS: Between September 1999 and
      December 2002 we performed MRI on 40 patients who underwent arthroscopic ACL
      reconstruction with patellar tendon auto-graft using PDLLA bioabsorbable screws
      in 35 cases and metallic screws in 5 cases. After surgery, all patients underwent
      an intensive rehabilitation programme along with clinical evaluation using the
      standard knee ligament evaluation form of the International Knee Documentation
      Committee (IKDC) and radiological examinations. MR studies were performed 1, 2
      and 3 years post-operatively using a 0.5-Tesla MR scanner with T1- and T2*
      weighted and STIR sequences. RESULTS: Thirty-three patients were clinically
      classified as group A IKDC (full return to sports activity) and 7 patients as
      group B IKDC. No foreign-body reaction was found in patients treated with
      bioabsorbable interference screws, both from a clinical point of view and from
      laboratory exams. Ferromagnetic artefacts were found in all patients treated with
      metallic interference screws. In patients with bioabsorbable interference screws,
      degradation of the screws and absence of significant artefacts allowed correct
      evaluation of the signal of the reconstructed ligament throughout its length, the
      osseous tunnels and the joint cavity. In 34 of 35 patients with bioabsorbable
      interference screws, the screw could not be detected due to complete degradation.
      In 8, 12 and 4 cases, a small cyst-like formation due to screw hydrolysis was
      present at the screw site within 1, 2 and 3 years from surgery respectively. Only
      in 4 cases was the process of osteointegration of the screw and bone plug
      complete 3 years after the operation, with consequent restoration of bone
      morphology. DISCUSSION AND CONCLUSIONS: The use of bioabsorbable interference
      screws is a valuable alternative to synthetic metallic fixation implants as the
      absence of artefacts allows correct post-operative MR follow-up. MRI is the only
      technique able to visualize all the portions of the transplant and to evaluate
      the healing process. Bioabsorbable interference screws usually degrade within one
      year. However, full osteointegration requires a long time and may not be complete
      3 years after surgery. The presence of cyst-like formations at the screw site has
      to be regarded as a normal feature of the screw degradation process. Therefore,
      the use of bioabsorbable interference screws is recommended as it enables MR
      follow-up of the knee after ACL reconstruction.

PMID- 15031697
TI  - [Imaging of living donor liver transplantation].
AB  - PURPOSE: This paper presents our experience in the evaluation of 23 potential
      living liver donors examined from January 2001 to December 2002. MATERIALS AND
      METHODS: Between January 2001 and December 2002, a total of 23 potential living
      liver donors were evaluated (20 men, 3 women; mean age 30 years) with MSCT and
      MR. Vascular reconstructions (MIP and Thin MIP) and volumetric evaluation of
      liver "in toto" and of the right hepatic lobe to be harvested were obtained with
      CT. MR was performed with in- and out-of-phase GE acquisitions in order to detect
      liver steatosis and with SSFSE T2 weighted thick-slab (50 mm) coronal
      acquisitions to obtain MR cholangiography. MR cholangiography was also obtained
      with post-contrast (Gd-BOPTA 90 min) 3D GE thin (1.5 mm) coronal sequences. Ten
      potential living liver donors also underwent angiography. RESULTS: The
      radiological examinations demonstrated abnormalities of the portal vein
      bifurcation in 7/23 potential living liver donors, variants of the arterial
      anatomy in 5/23 and abnormalities of the biliary anatomy in 20/23. One case
      showed gallbladder dysmorphism. The MR examinations led to the exclusion from the
      transplantation of one potential living liver donor owing to the detection of
      liver steatosis that was subsequently confirmed by biopsy. 7/23 potential living
      liver donors were considered eligible for the surgical procedure and underwent
      preoperative colour Doppler sonography and intraoperative cholangiography.
      CONCLUSIONS: The diagnostic protocols used at our centre provide the clinician
      with important information and an exhaustive picture of the hepatic anatomy to
      evaluate the inclusion of potential living liver donors in the transplantation
      program.

PMID- 15031698
TI  - [Positive predictive value and negative predictive value of spiral CT in the
      diagnosis of closed loop obstruction complicated by intestinal ischemia].
AB  - PURPOSE: To assess the positive predictive value and the negative predictive
      value of spiral CT in the diagnosis of "closed-loop" obstruction complicated by
      intestinal ischaemia. MATERIALS AND METHODS: Between January 1999 and January
      2002, 120 patients with small intestine closed-loop obstruction who had undergone
      surgical laparotomy within 2-6 hours from abdominal and pelvic spiral CT were
      retrospectively reviewed. The CT scans were performed using 5-mm slice thickness,
      1 s scan delay, 5 x 5-mm collimation and 1.5 pitch after administering i.v.
      iodinated contrast material (120 ml volume, 60 s scan delay, 2.5-3 ml/s rate)
      with an automatic injector. For the diagnosis of closed-loop obstruction the
      following CT findings were examined: identification of the transitional area,
      'C', 'U' or 'beak' shape of the obstructed loops, radial distribution of the
      involved mesenteric vessels. For the diagnosis of loop ischaemia, the following
      findings were evaluated in addition to the CT signs described above: submucosal
      oedema, increased, reduced, or no enhancement of the loop walls, oedema of the
      mesenteric vessels, fluid within the loops or in the intraperitoneal spaces.
      RESULTS: 'U', 'C', 'beak' loop configuration with poor or no contrast enhancement
      of the obstructed loop walls, ascites, rotation and engorgement of mesenteric
      vessels enabled the diagnosis of 26 cases of closed-loop obstruction complicated
      by ischaemia, infarction. U- or C-shaped loops with radial distribution and/or
      rotation of mesenteric vessels towards the obstruction site suggested the correct
      diagnosis in 94 cases, but did not allow identification of ischaemia in 25 cases.
      The positive predictive value of spiral CT related to ischaemic loop
      complications was 100%; the negative predictive value was 73%. CONCLUSIONS:
      Spiral CT is a reliable imaging technique enabling the diagnosis of closed-loop
      obstruction with or without intestinal ischaemic complications. Any alterations
      detected in the trophic status of the loops or mesentery imply ischaemic
      complications requiring emergency surgery. On the contrary, if only CT signs of
      closed-loop obstruction are detected, the existence and/or development of
      ischaemia cannot be ruled out.

PMID- 15031699
TI  - [MEN 1 and 2: the role of diagnostic imaging].
AB  - PURPOSE: To report the results of a retrospective study on the use of the
      different imaging methods in the diagnosis of type 1 and type 2 multiple
      endocrine neoplasias, and to provide an overall evaluation of the diagnostic
      yield of the various examinations performed correlating the results with the
      surgical findings. MATERIALS AND METHODS: The study was conducted by reviewing
      the data of 12 patients, of whom four with MEN1 and eight with MEN2, assessed
      with different imaging modalities. In the patients with MEN1 the examinations
      revealed 4 parathyroid hyperplasias, 4 gastro-pancreatic endocrine-secreting
      lesions, one hypophyseal adenoma, one bronchial carcinoid and two bilateral
      adrenal hyperplasias. In the patients with MEN2 the examinations revealed 6
      medullary thyroid carcinomas (MTC), 4 pheochromocytomas and 3 parathyroid
      hyperplasias. RESULTS: In MEN1 the parathyroid hyperplasias were diagnosed by
      scintigraphy in all four cases, whereas neck ultrasound was positive in only two
      cases. The gastro-pancreatic endocrine-secreting lesions were demonstrated in all
      four patients with CT and endoscopic ultrasound (two patients also underwent
      scintigraphy with octreotide, which was positive). In only one patient with MEN1
      did the chest X-ray detect a bronchial carcinoma, confirmed by CT. CT also
      enabled identification of a single hypophyseal adenoma. The patients with MEN2
      were divided into two groups: one consisting of asymptomatic patients undergoing
      screening following positive genetic testing and one of symptomatic patients. In
      the first group the imaging examinations diagnosed one MTC and three
      pheochromocytomas; all patients in the second group had MTC (detected by positive
      ultrasound and scintigraphy examinations). DISCUSSION AND CONCLUSIONS: Given the
      rarity of this condition we believe that the only statistically important finding
      in our series concerns the sensitivity of the imaging examinations performed in
      that, with adequate clinical and laboratory data, the possible problem of false
      positive results is exceptional. The role of diagnostic imaging in the management
      of patients with MEN1 and 2 is twofold: identification of the target organs of
      lesions suspected on the basis of clinical and laboratory findings to enable
      adequate medical and/or surgical treatment; staging of malignant lesions to
      enable correct surgical planning. In particular, our study once again highlights
      the diagnostic efficacy of CT for the diagnosis of pheochromocytomas and of the
      combination of biopsy plus ultrasound and ultrasound plus scintigraphy for the
      diagnosis of MTC in MEN 2. As for MEN1 spiral CT was found to have good
      sensitivity (66%) in localising endocrine neoplasias of the gastrointestinal
      tract; endoscopic ultrasound on the other hand revealed good diagnostic efficacy,
      showing constantly positive findings. Finally, in both pathologies we believe
      that the assessment of parathyroid conditions to be mainly a matter for nuclear
      medicine.

PMID- 15031700
TI  - [Administration of iodinated contrast in patients with pre-existing renal
      failure: a review].
AB  - Contrast-induced nephropathy (CIN) is an important and well-known cause of acute
      renal failure. The published literature contains numerous clinical trials
      describing the relative performance of various contrast agents. This review
      provides a comparison of different contrast agents and assesses the relative risk
      of clinical nephrotoxicity among them in patients with pre-existing renal
      insufficiency, which appear to be the patients at highest risk for CIN with all
      classes of these agents. Overall, the nonionic dimeric agents perform similarly
      to the nonionic monomeric agents in this regard.

PMID- 15031701
TI  - [Development of a low-cost DICOM-server for teaching and research purposes].
AB  - PURPOSE: This paper describes our experience in developing a DICOM (Digital
      Imaging and Communications in Medicine) server based on widely available personal
      computers enabling to use X-ray digital images for teaching and scientific
      purposes. MATERIALS AND METHODS: The system is based on a DICOM server running on
      a widely used personal computer. The selected DICOM images are collected directly
      from the radiological equipment or from a dedicated 3D image processing
      workstation through a LAN connection and converted into one of the standard
      formats (JPEG or GIF) to allow their direct importing into multimedia
      presentations for teaching or scientific purposes. RESULTS: This system allows
      fast and easy collection of radiological images in DICOM format directly from the
      diagnostic equipment or from the graphical workstation. These images may be used
      for scientific and teaching presentations without loss of image quality and
      colour characteristics in 3D images as there is no off-line acquisition process.
      CONCLUSIONS: The extensive possibilities of implement the system described on
      widely used PCs makes the system extremely versatile and facilitates the
      preparation of teaching material and scientific publications.

PMID- 15031702
TI  - [Design and implementation of an integrated HIS-RIS-PACS system: our experience].
AB  - PURPOSE: To develop an integrated information system to support the
      administrative and healthcare work processes in a highly specialised research
      oriented healthcare institution composed of one hospital and a separate
      outpatient centre. The project, developed within the context of an ongoing
      process of technological innovation, aimed to improve the efficacy and efficiency
      of the services provided. In particular, over the past year our efforts focused
      on developing and implementing a RIS-PACS system to support the management of
      clinical data and radiological reports and images. MATERIALS AND METHODS: The RIS
      PACS system was implemented in four phases to meet the technical-functional needs
      of the Units of the Department of Diagnostic Imaging. The plan was developed
      considering the work flow between the Department, the outpatient centre and the
      hospital wards with the aim of creating a filmless and paperless organisational
      model for the Radiology Units. The four implementation phases were characterised
      by defining and developing protocols that would integrate the systems (HIS, RIS,
      PACS and modalities) to guarantee correct and complete management of the work
      flow. RESULTS: Phases I and II have already been completed and have led to
      efficient, safe and complete interaction between the hospital wards, the
      outpatient centre and the Radiology Units. Overall performance of the hospital
      has improved and the outpatient centre is now completely managed in digital mode.
      Phases III and IV will extend these positive results by enabling the routine
      distribution of radiological reports and images to all hospital wards and clinics
      and associated facilities. As a result, the use of film and printing and
      developing materials will gradually be reduced, enabling all the required
      clinical and diagnostic information to be immediately and securely shared.
      DISCUSSION AND CONCLUSIONS: This project is one of the first examples in Italy of
      the routine implementation of a single virtual radiology department distributed
      across physically remote locations. In particular, the project was successfully
      completed thanks to the approach used in planning and defining the clinical and
      functional specifications, and in the implementation phase. We conclude that
      setting up an information system truly capable of supporting the routine clinical
      activity of a Diagnostic Imaging Department requires a detailed operational
      project and careful planning of each implementation phase.

PMID- 15031703
TI  - [The usefulness of 99mTc-tetrofosmin SPECT in the detection of lung metastases
      from extrapulmonary primary tumors].
AB  - PURPOSE: The appearance of pulmonary metastases in neoplastic patients previously
      submitted to radical operation of an extrapulmonary primary tumor and with no
      recurrences and/or secondary distant localizations can markedly worsen disease
      prognosis if the lesions are in advanced stages and no longer removable by
      surgical procedures. In this study, we evaluated the usefulness of 99mTc
      tetrofosmin scintigraphy, both planar and SPECT, in the detection of pulmonary
      metastases from previously treated extrapulmonary primary tumors, comparing the
      results with those obtained with CT. MATERIALS AND METHODS: We studied 73
      patients, 33 M and 40 F, aged 24 to 79 yrs, had who undergone previously surgical
      resection extrapulmonary primary tumors; 31 patients had mammary, 13
      gastrointestinal, 13 genitourinary, 13 thyroid and 3 laryngeal carcinomas. In all
      patients CT ascertained single (42 cases) or multiple (31 cases) pulmonary
      lesions. 99mTc-tetrofosmin scintigraphy, always performed within a week of CT,
      was acquired 10 min after 740 MBq i.v. tracer injection, using a rectangular,
      large field of view, dual head gamma camera, equipped with low energy, parallel
      hole and high resolution collimators. Conventional planar acquisition, with the
      patient in the supine position, was followed by SPECT over 360 degrees with body
      contouring system, using a zoom factor of 1-1.3, a 64x64 matrix size, a 3 degrees
      angular step and an acquisition time of 30 sec/frame; image reconstruction was
      performed with the Back Projection Filtered Method using a Metz filter. In the
      coronal slices of SPECT images a semiquantitative analysis of the lesion was also
      made and the tumor-to-background (T/B) ratio was calculated; the calculation of
      the latter, considered indicative for tumor when >1.4, was performed in the
      lesion with the highest radiotracer uptake in patients with multiple lung
      lesions. The results of SPECT qualitative images were compared with those of
      planar scintigraphy and both of these with the data obtained with CT, and
      statistical difference was calculated with McNemar's test. The definitive
      diagnosis was achieved after scintigraphy by the analysis of cytologic or
      histologic specimens obtained by thoracotomy, percutaneous thoracic needle biopsy
      or bronchoscopic biopsy, and in some cases by the confirmation of instrumental
      exams at 6-8 month follow up. Pulmonary metastases were ascertained in 65/73
      cases, while benign lesions were present in the remaining 8 patients. RESULTS: CT
      was true positive in 60/65 (92.3%) patients with metastases and false negative in
      the remaining five, four with a single lesion and one with two lesions in the
      same lung. SPECT detected metastases in 62/65 (95.4%) patients, including the
      five CT false negative cases, while it was false negative in three cases with
      single lesions, all positive at CT, with a size of 1.0, 1.0, 2.0 cm,
      respectively. Planar scintigraphy was only positive in 23/65 (35.4%) patients,
      with a sensitivity value significantly (p<0.0005) lower than both SPECT and CT.
      In the patients with multiple metastases, SPECT, positive in all cases and
      capable of correctly differentiating the patients with metastases only in one
      lung from those with bilateral involvement, underestimated the number of
      micronodular lesions in respect of CT in six patients with >6 lesions < or =0.5
      cm in size, while it was more sensitive in three other cases; CT and SPECT were
      concordant in macronodular metastases detection, except in one case in which
      SPECT depicted more lesions. Planar scintigraphy had 42 false negative results
      and, when positive, underestimated the number of multiple lesions in respect of
      both SPECT and CT; it was positive but CT negative in only one case with two
      lesions. Specificity was higher for both SPECT and planar scan (87.5%) than CT
      (62.5%) but not significantly; accuracy was higher for SPECT (94.5%) than both
      planar scan (42%) and CT (89%), but the difference was significant only in
      respect of planar. The combined use of SPECT and CT achieved 100% sensitivity and
      accuracy values. The T/B ratio was >1.ratio was >1.4 in all SPECT positive cases
      (range: 1.6-5.3), indicating a suspected tumor, while it was 1.2 in the only
      benign case which turned out to be false positive at qualitative SPECT imaging.
      CONCLUSIONS: 99mTc-tetrofosmin SPECT seems to be a reliable diagnostic tool in
      the detection of pulmonary metastases from extrapulmonary primary tumors, in
      particular in the cases in which CT is indeterminate or false positive, and
      therefore contributes to a more correct patient classification. Moreover, SPECT
      image semiquantitative analysis can give additional information for a
      differential diagnosis between malignant and benign lesions as well as offering a
      more accurate selection of the lesions to be subjected to biopsy in patients with
      multiple metastases. However, only the combined use of CT and 99mTc-tetrofosmin
      SPECT can achieve the highest sensitivity and accuracy values and obtain the
      correct staging in most patients, thus suggesting that these two procedures must
      be employed together.

PMID- 15031704
TI  - [Radiotherapy of malignant gliomas: results from conventional treatment methods
      and the prospects of advanced techniques].
AB  - PURPOSE: The results of post-operative radiation therapy of malignant gliomas are
      disappointing, with mean survival time (MST) of 16-70 weeks and 2-year survival
      rates ranging from 8.5% to 25% in the literature. A slightly more favourable
      prognosis is found in the following cases: in anaplastic astrocytomas with
      respect to glioblastoma multiforme; in younger patients with respect to the more
      elderly; the longer the duration of symptoms before diagnosis; and in the event
      in which surgery has been macroscopically radical. An improvement in treatment
      outcome is foreseeable with the use of advanced volume definition techniques for
      radiation therapy. MATERIALS AND METHODS AND RESULTS: Our experience with
      conventional radiation treatment shows therapeutic results in agreement with
      other institutions. In the overall 134 cases MST was 50 weeks and the 2-year
      survival rate was 10%. In patients affected by anaplastic astrocytoma MST was 58%
      and 2-year survival rate was 17%, whereas the figures for glioblastoma multiforme
      were 47 weeks and 8% (p>0.05, not statistically significant, probably due to the
      small number of cases). Patients of sixty years of age or less showed a more
      statistically favourable prognosis: MST was 59 weeks and 2-year survival rate was
      16%, compared with 44 weeks and 4% in patients above 60 years of age (p<0.05).
      The duration of symptoms of 6 months or less had a less favourable prognosis with
      respect to symptom onset of greater than 6 months: in the former MST was 49 weeks
      and 2-year survival was 7%, and in the latter the figures were 68 weeks and 40%
      (P<0.05). Lastly, the presence of residual neoplastic tissue after surgery is an
      unfavourable element: in this case MST was 41 weeks and 2-year survival was 7%,
      compared with 68 weeks and 13% (P<0.05) after macroscopically radical surgery.
      DISCUSSION AND CONCLUSIONS: Computed tomography (CT) is still today an
      indispensable technique for radiation therapy planning. Magnetic Resonance (MR)
      imaging, nonetheless, provides greater definition of the neoplastic extension.
      The possibility of combining CT and MR neuroimaging data together with
      stereotactic radiotherapy techniques enables the optimal development of the three
      dimensional treatment plane. This translates into high dose delivery to the
      neoplastic volumes without affecting the regions of the brain with no tumour
      involvement. Furthermore, a real improvement in the prognosis of malignant
      gliomas must also consider the results from research in the fields of tumour
      biology and functional neuroimaging.

PMID- 15031706
TI  - A case manager's perspective of patient transport.
AB  - "The patient will need transportation." These simple words, frequently heard by
      case managers, identify a need that can require time-consuming research of
      possible providers and, in some instances, reveal very limited options, depending
      on the patient's medical needs, funding, and location. Patient transportation
      needs run the gamut from occasional local trips for routine physician
      appointments to air and ground transport for the medically unstable, ventilator
      dependent individual.

PMID- 15031705
TI  - Inhibition of aldose reductase by tannoid principles of Emblica officinalis:
      implications for the prevention of sugar cataract.
AB  - PURPOSE: Aldose reductase (AR) has been a drug target because of its involvement
      in the development of secondary complications of diabetes including cataract.
      Although numerous synthetic AR inhibitors (ARI) have been tested and shown to
      inhibit the enzyme, clinically synthetic ARIs have not been very successful.
      Therefore, evaluating natural sources for ARI potential may lead to the
      development of safer and more effective agents against diabetic complications. In
      the present study we have assessed the inhibition of AR by constituents of
      Emblica officinalis both in vitro and in lens organ culture. METHODS: E.
      officinalis is widely used against many chronic ailments including diabetes.
      Aqeous extract of E. officinalis and its major constituent tannoids were tested
      for inhibition against both rat lens and purified recombinant human AR. ARI
      potential of isolated tannoids of E. officinalis were also investigated against
      osmotic stress in rat lens organ culture. RESULTS: E. officinalis extract
      inhibited rat lens and recombinant human AR with IC50 values 0.72 and 0.88 mg/ml
      respectively. Since E. officinalis is a rich source of ascorbic acid, we
      investigated whether ascorbic acid was responsible for AR inhibition by E.
      officinalis extract. However, ascorbic acid did not inhibit AR even at 5 mM
      concentration. Further, we demonstrate that the hydrolysable tannoids of E.
      officinalis were responsible for AR inhibition, as enriched tannoids of E.
      officinalis exhibited remarkable inhibition against both rat lens and human AR
      with IC50 of 6 and 10 microg/ml respectively. The inhibition of AR by E.
      officinalis tannoids is 100 times higher than its aqueous extract and comparable
      to or better than quercetin. Furthermore, the isolated tannoids not only
      prevented the AR activation in rat lens organ culture but also sugar-induced
      osmotic changes. CONCLUSIONS: These results indicate that tannoids of E.
      officinalis are potent inhibitors of AR and suggest that exploring the
      therapeutic value of natural ingredients that people can incorporate into
      everyday life may be an effective approach in the management of diabetic
      complications.

PMID- 15031707
TI  - Air medical and specialty care ground transportation: a primer for case managers.

PMID- 15031708
TI  - What case managers need to know when arranging air medical transport.
AB  - Case managers struggle when arranging patient care services about which they know
      very little, especially when the patient is particularly vulnerable. Arranging
      air medical transport, for example, can be an exercise fraught with risks. The
      following questions will help you coordinate a smooth transport and help ensure
      the patient is cared for by qualified health care professionals in a safety
      conscious environment.

PMID- 15031709
TI  - Considerations in medical ground transportation.
AB  - Physicians and nurses, therapists and specialists, case managers and patients and
      families each form a piece of the health care puzzle. Each party plays a vital
      role in patient wellness, but if patients do not or cannot get to therapy, they
      cannot be expected to get better. Patient transportation is improving because
      case managers can ensure that they have proper transportation to get to
      appointments locally and out of town.

PMID- 15031711
TI  - A tribute to Gilbert B Forbes.

PMID- 15031710
TI  - Gene dosage PCR and fluorescence in situ hybridization reveal low frequency of
      egfr amplifications despite protein overexpression in invasive breast carcinoma.
AB  - The aim of this study was to assess the frequency of egfr whole gene and CA
      intron repeat amplification in invasive breast cancer as a mechanism for
      epidermal growth factor receptor (EGFR) protein overexpression. By means of
      tissue microarrays, protein overexpression and whole gene amplification were
      assessed in 222 cases of invasive breast cancer by immunohistochemistry and FISH,
      respectively. First intron CA repeat amplification was assessed by Taqman RT-PCR.
      With FISH and RT-PCR, 4.7 and 6.3% of cases showed whole gene and first intron CA
      repeat amplification, respectively. Amplification dosage varied between two- and
      four-fold in RT-PCR. By immunohistochemistry, 17.3% showed EGFR overexpression.
      There was a low correlation between the different methods. In all, 2.9% of cases
      showed both whole gene amplification and intron CA repeat amplification, and
      90.3% of cases were negative for both. Nearly 20% of cases with
      immunohistochemical protein overexpression showed intron CA repeat amplification,
      and only 2.2% of cases that were negative on immunohistochemistry showed such
      amplification. In all, 13% of cases with protein overexpression showed
      amplification by FISH, and only 1.6% of cases that were negative on
      immunohistochemistry showed such amplification. Of the cases with EGFR
      overexpression, 4 (25%) showed either whole gene or intron CA repeat
      amplification. In conclusion, whole gene amplifications of egfr are rare in
      invasive breast cancer and explain protein overexpression in only about 12.5% of
      invasive breast cancer cases. First intron first CA repeat amplification is
      another important mechanism for EGFR protein overexpression, explaining protein
      overexpression in about 18.7% of cases. However, since about 75% of cases with
      EGFR protein overexpression lack either of these amplifications, other expression
      regulating mechanisms must be considered.

PMID- 15031712
TI  - The histone methyltransferases Trithorax and Ash1 prevent transcriptional
      silencing by Polycomb group proteins.
AB  - Transcriptional on and off states of HOX genes and other developmental control
      genes are maintained by antagonistic regulators encoded by trithorax group (trxG)
      and Polycomb group (PcG) genes. The trxG proteins Ash1 and hTRX and the PcG
      repressor E(z) are histone methyltransferases (HMTases) that methylate distinct
      lysine residues in the N-terminal tail of histone H3. trxG proteins are generally
      thought to function as activators of HOX genes, but how histone methylation by
      Ash1 and Trx promotes HOX gene transcription is not clear. Here, we show that in
      ash1 and trx mutants expression of HOX genes is lost within their normal
      expression domains, but we find that, contrary to expectation, this expression is
      restored in ash1 and trx mutants that also lack PcG gene function. Moreover, such
      trxG PcG double mutants show severe misexpression of HOX genes and, hence,
      ectopic activation of HOX genes caused by the removal of PcG gene function also
      occurs in the absence of ash1 and trx function. Together, these results suggest
      that the Ash1 and Trx HMTases are not "coactivators" required for transcriptional
      activation of HOX genes, but function specifically as anti-repressors. We propose
      that histone methylation by Ash1 and Trx is required continuously throughout
      development to prevent inappropriate PcG silencing of HOX genes in cells in which
      they must stay transcriptionally active.

PMID- 15031713
TI  - Asymmetric activation of Xer site-specific recombination by FtsK.
AB  - Chromosome dimers, which frequently form in Escherichia coli, are resolved by the
      combined action of two tyrosine recombinases, XerC and XerD, acting at a specific
      site on the chromosome, dif, together with the cell division protein FtsK. The C
      terminal domain of FtsK (FtsK(C)) is a DNA translocase implicated in helping
      synapsis of the dif sites and in locally promoting XerD strand exchanges after
      synapse formation. Here we show that FtsK(C) ATPase activity is directly involved
      in the local activation of Xer recombination at dif, by using an intermolecular
      recombination assay that prevents significant DNA translocation, and we confirm
      that FtsK acts before Holliday junction formation. We show that activation only
      occurs with a DNA segment adjacent to the XerD-binding site of dif. Only one such
      DNA extension is required. Taken together, our data suggest that FtsK needs to
      contact the XerD recombinase to switch its activity on using ATP hydrolysis.

PMID- 15031714
TI  - Crystal structure of the PsbP protein of photosystem II from Nicotiana tabacum.
AB  - PsbP is a membrane-extrinsic subunit of the water-oxidizing complex photosystem
      II (PS II). The evolutionary origin of PsbP has long been a mystery because it
      specifically exists in higher plants and green algae but not in cyanobacteria. We
      report here the crystal structure of PsbP from Nicotiana tabacum at a resolution
      of 1.6 A. Its structure is mainly composed of beta-sheet, and is not similar to
      any structures in cyanobacterial PS II. However, the electrostatic surface
      potential of PsbP is similar to that of cyanobacterial PsbV (cyt c(550)), which
      has a function similar to PsbP. A structural homology search with the DALI
      algorithm indicated that the folding of PsbP is very similar to that of Mog1p, a
      regulatory protein for the nuclear transport of Ran GTPase. The structure of PsbP
      provides insight into its novel function in GTP-regulated metabolism in PS II.

PMID- 15031715
TI  - Potent inhibitors of anthrax lethal factor from green tea.
AB  - The anthrax lethal factor (LF) has a major role in the development of anthrax. LF
      is delivered by the protective antigen (PA) inside the cell, where it exerts its
      metalloprotease activity on the N-terminus of MAPK-kinases. PA+LF are cytotoxic
      to macrophages in culture and kill the Fischer 344 rat when injected
      intravenously. We describe here the properties of some polyphenols contained in
      green tea as powerful inhibitors of LF metalloproteolytic activity, and how the
      main catechin of green tea, (-)epigallocatechin-3-gallate, prevents the LF
      induced death of macrophages and Fischer 344 rats.

PMID- 15031718
TI  - Activation of Rho in the injured axons following spinal cord injury.
AB  - Axons of the adult central nervous system have very limited ability to regenerate
      after injury. This inability may be, at least partly, attributable to myelin
      derived proteins, such as myelin-associated glycoprotein, Nogo and
      oligodendrocyte myelin glycoprotein. Recent evidence suggests that these proteins
      inhibit neurite outgrowth by activation of Rho through the neurotrophin receptor
      p75(NTR)/Nogo receptor complex. Despite rapidly growing knowledge on these
      signals at the molecular level, it remained to be determined whether Rho is
      activated after injury to the central nervous system. To assess this question, we
      establish a new method to visualize endogenous Rho activity in situ. After
      treatment of cerebellar granular neurons with the Nogo peptide in vitro, Rho is
      spatially activated and colocalizes with p75(NTR). Following spinal cord injury
      in vivo, massive activation of Rho is observed in the injured neurites. Spatial
      regulation of Rho activity may be necessary for axonal regulation by the
      inhibitory cues.

PMID- 15031717
TI  - The Snf1 kinase controls glucose repression in yeast by modulating interactions
      between the Mig1 repressor and the Cyc8-Tup1 co-repressor.
AB  - Among lower eukaryotes, glucose repression is a conserved, widely spread
      mechanism regulating carbon catabolism. The yeast Snf1 kinase, the Mig1 DNA
      binding repressor and the Mig1-interacting co-repressor complex Cyc8(Ssn6)-Tup1
      are central components of this pathway. Previous experiments suggested that
      cytoplasmic translocation of Mig1, upon its phosphorylation by Snf1 in the
      nucleus, is the key regulatory step for releasing glucose repression. In this
      report we re-evaluate this model. We establish the coordinated repressive action
      of Mig1 and Cyc8-Tup1 on GAL1 transcription, but we find that Cyc8-Tup1 is not
      tethered by Mig1 to the promoter DNA. We demonstrate that both negative
      regulators occupy GAL1 continuously under either repression or activation
      conditions, although the majority of the Mig1 is redistributed to the cytoplasm
      upon activation. We show that Snf1-dependent phosphorylation of Mig1 abolishes
      interaction with Cyc8-Tup1, and we propose that regulation of this interaction,
      not the Mig1 cytoplasmic localization, is the molecular switch that controls
      transcriptional repression/de-repression.

PMID- 15031720
TI  - New breast cancer gene suggests a role for BRCA2 in sporadic cases.

PMID- 15031719
TI  - A new role for the mitotic RAD21/SCC1 cohesin in meiotic chromosome cohesion and
      segregation in the mouse.
AB  - The evolutionarily conserved cohesin complex is required for the establishment
      and maintenance of sister chromatid cohesion, in turn essential for proper
      chromosome segregation. RAD21/SCC1 is a regulatory subunit of the mitotic cohesin
      complex, as it links together all other subunits of the complex. The destruction
      of RAD21/SCC1 along chromosomal arms and later at centromeres results in the
      dissociation of the cohesin complex, facilitating chromosome segregation. Here,
      we report for the first time that mammalian RAD21/SCC1 associates with the
      axial/lateral elements of the synaptonemal complex along chromosome arms and on
      centromeres of mouse spermatocytes. Importantly, RAD21/SCC1 is lost from
      chromosome arms in late prophase I but persists on centromeres. The loss of
      centromeric RAD21/SCC1 coincides with the separation of sister chromatids at
      anaphase II. These findings support a role for mammalian RAD21/SCC1 in
      maintaining sister chromatid cohesion in meiosis.

PMID- 15031722
TI  - Rapid, in vivo, evaluation of antiangiogenic and antineoplastic gene products by
      nonviral transfection of tumor cells.
AB  - Using a nonviral, electroporation-based gene transfection approach, we
      demonstrate the efficient and consistent transfection of two poorly immunogenic
      tumor cell lines: B16F10 melanoma and renal carcinoma (RENCA). Three genes, IL
      12, angiostatin (AS), and an endostatin:angiostatin fusion protein (ES:AS) were
      subcloned into a DNA plasmid containing EBNA1-OriP, which was then transfected
      into B16F10 and RENCA cells. Significant levels of protein were secreted into the
      culture supernatants of transfected cells in vitro. Transfected tumor cells were
      injected subcutaneously into mice. All the three transgenes were capable of
      significantly delaying and reducing the formation of primary B16F10 and RENCA
      tumors, as well as B16F10 lung metastases. By day 11 post-injection, all control
      mice that received either mock-transfected or empty vector DNA-transfected B16F10
      tumor cells had developed large primary tumors. In contrast, mice that received
      IL-12-transfected B16F10 cells did not develop appreciable tumors until day 17,
      and these were significantly smaller than controls. Similar results were observed
      for the RENCA model, in which only one of the IL-12 mice had developed tumors out
      to day 31. Expression of AS or ES:AS also significantly delayed and reduced
      primary tumors. Overall, ES:AS was more effective than AS alone. Furthermore, 25%
      of the AS mice and 33% of the ES:AS mice remained tumor-free at day 17, by which
      point all control mice had significant tumors. Mouse survival rates also
      correlated with the extent of tumor burden. Importantly, no lung metastases were
      detected in the lungs of mice that had received either AS or ES:AS-transfected
      B16F10 tumor cells and significantly fewer metastases were found in the IL-12
      group. The consistency of our transfection results highlight the feasibility of
      directly electroporating tumor cells as a means to screen, identify, and validate
      in vivo potentially novel antiangiogenic and/or antineoplastic genes.

PMID- 15031723
TI  - Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of
      chemotherapeutic agents in MCF-7 human breast cancer cells.
AB  - Antiapoptotic genes such as bcl-2 or xIAP may be responsible for resistance to
      apoptosis induced by cytotoxic drugs. The aim of this study was to investigate if
      downregulation of bcl-2 or xIAP by RNA interference (RNAi) would sensitize MCF-7
      cells to etoposide and doxorubicin. FITC-siRNAs uptake was verified by
      fluorescence microscopy and downregulation of Bcl-2 or XIAP was confirmed by
      Western Blotting. Both siRNAs reduced the number of viable cells and increased
      cellular apoptosis. Treatment with siRNAs followed by treatment with etoposide or
      doxorubicin further reduced the number of viable cells, when compared to either
      of the treatments alone. Therefore, downregulation of bcl-2 or xIAP by RNAi
      enhances the effects of etoposide and doxorubicin.

PMID- 15031725
TI  - Milk fat globule epidermal growth factor 8 (MFG-E8) binds to oxidized
      phosphatidylserine: implications for macrophage clearance of apoptotic cells.

PMID- 15031726
TI  - Yeast mutants resistant to Bax lethality reveal distinct vacuolar and
      mitochondrial alterations.

PMID- 15031724
TI  - Physical and functional interaction between BH3-only protein Hrk and
      mitochondrial pore-forming protein p32.
AB  - Bcl-2 homology domain (BH) 3-only proteins of the proapoptotic Bcl-2 subfamily
      play a key role as initiators of mitochondria-dependent apoptosis. To date, at
      least 10 mammalian BH3-only proteins have been identified, and it is now being
      realized that they have different roles and mechanisms of regulation in the
      transduction of apoptotic signals to mitochondria. Hrk/DP5 is one of the
      mammalian BH3-only proteins implicated in a variety of physiological and
      pathological apoptosis, yet the molecular mechanism involved in Hrk-mediated
      apoptosis remains poorly understood. In an attempt to identify cellular proteins
      participating in Hrk-mediated apoptosis, we have conducted yeast two-hybrid
      screening for Hrk-interacting proteins and isolated p32, a mitochondrial protein
      that has been shown to form a channel consisting of its homotrimer. In vitro
      binding, co-immunoprecipitation, as well as immunocytochemical analyses verified
      specific interaction and colocalization of Hrk and p32, both of which depended on
      the presence of the highly conserved C-terminal region of p32. Importantly, Hrk
      induced apoptosis was suppressed by the expression of p32 mutants lacking the N
      terminal mitochondrial signal sequence (p32(74-282)) and the conserved C-terminal
      region (p32 (1-221)), which are expected to inhibit binding of Hrk competitively
      to the endogenous p32 protein and to disrupt the channel function of p32,
      respectively. Furthermore, small interfering RNA-mediated knockdown of p32
      conferred protection against Hrk-induced apoptosis. Altogether, these results
      suggest that p32 may be a key molecule that links Hrk to mitochondria and is
      critically involved in the regulation of Hrk-mediated apoptosis.

PMID- 15031727
TI  - The population genetics and evolutionary epidemiology of RNA viruses.

PMID- 15031728
TI  - Antimicrobial pharmacodynamics: critical interactions of 'bug and drug'.

PMID- 15031729
TI  - Cellular autophagy: surrender, avoidance and subversion by microorganisms.

PMID- 15031730
TI  - Minimal protein-folding systems in hyperthermophilic archaea.

PMID- 15031731
TI  - Cell-cycle progression and the generation of asymmetry in Caulobacter crescentus.

PMID- 15031732
TI  - The future of microbiology laboratory classes--wet, dry or in combination?

PMID- 15031733
TI  - Delivering on the promise: HPV vaccines and cervical cancer.

PMID- 15031734
TI  - Neurodegenerative diseases and oxidative stress.
AB  - Oxidative stress has been implicated in the progression of Alzheimer's disease,
      Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life
      but is also potentially dangerous, and a complex system of checks and balances
      exists for utilizing this essential element. Oxidative stress is the result of an
      imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of
      toxic reactive oxygen species. The systems in place to cope with the biochemistry
      of oxygen are complex, and many questions about the mechanisms of oxygen
      regulation remain unanswered. However, this same complexity provides a number of
      therapeutic targets, and different strategies, including novel metal-protein
      attenuating compounds, aimed at a variety of targets have shown promise in
      clinical studies.

PMID- 15031735
TI  - Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4
      lymphocytes.
AB  - Highly active antiretroviral therapy (HAART) based on combinations of drugs that
      target key enzymes in the life-cycle of human immunodeficiency virus (HIV) has
      considerably reduced morbidity and mortality from HIV infection since its
      introduction in the mid-1990s. However, the growing problem of the emergence of
      HIV strains that are resistant not only to individual drugs, but to whole drug
      classes, means that agents with new mechanisms of action are needed. Here, we
      describe the discovery and development of enfuvirtide (Fuzeon), the first drug to
      inhibit the entry of HIV-1 into host cells.

PMID- 15031736
TI  - First dose of potential new medicines to humans: how animals help.
AB  - The need for careful testing of new drugs in animal models before study in humans
      has been recognised by physicians since the First World War. Now, first human
      studies on new drugs are subject to detailed government guidelines, which in the
      European Union are presently being reinforced through the wide-ranging Clinical
      Trials Directive. However, despite their long history and widespread application,
      these guidelines are empirical and have been formulated with a paucity of
      critical scientific evidence. Here, we review the principles and the available,
      albeit limited, evidence that support the design and conduct of preclinical
      studies in a way that permits effective and safe first-dose studies of potential
      new medicines in humans.

PMID- 15031737
TI  - Dr Stanley Robbins.

PMID- 15031739
TI  - Survivin: apoptosis inhibitor and its regulation by Hsp90.

PMID- 15031740
TI  - Potential rapid assessment of breast cancer prognosis using induced chromosome
      condensation performed on cytological specimens.
AB  - We have previously shown that assessment of chromosome alteration rate by
      cytogenetics is well correlated with breast cancer prognosis factors. As
      karyotypes are usually difficult to obtain from solid tumors using conventional
      methods, a new approach is proposed. Metaphase-like chromosomes were directly
      obtained following chromosome condensation using calyculin A (okadaic acid) from
      cytologic specimens of breast cancers sampled by fine needle. Chromosome counts
      and rearrangement rates were established in a series of 45 tumors, as early as 24
      48 h after sampling. A high rate of rearranged chromosomes was found to correlate
      with high histological grade, TNM stage and S-phase fraction, loss of estrogen
      receptor expression and DNA aneuploidy. The indication of genome alteration
      provided by this method constitutes a simple, potent and early potential
      prognostic factor in breast cancer directly applied on cytological specimens.

PMID- 15031741
TI  - Genetic integrity of cryopreserved plant cells: a review.
AB  - Cryopreservation techniques exist for some 100-plant species. Cryopreservation
      for the long-term conservation of in vitro germplasm results in the exposure of
      tissues to physical, chemical and physiological stresses causing cryoinjury.
      Although, the effects of cryoinjury upon the genome are often unknown, any
      accumulative DNA polymorphisms may not be induced by cryopreservation per se but
      are the result of the whole culture-cryoprotection-regeneration process. It is
      desirable to assess the genetic integrity of plants surviving cryogenic storage
      to determine if they are true to type after cryopreservation. This can be done at
      the phenotypic, histological, cytological, biochemical and molecular levels. The
      relevance of these approaches to stability investigations is discussed with their
      limitations. This review provides a definition for Cryobionomics - a novel term
      describing the re-modelled concept of genetic stability and the re-introduction
      of cryopreserved plants into the environment.

PMID- 15031742
TI  - Mushroom cryopreservation and its effect on survival, yield and genetic
      stability.
AB  - Mycelial stock cultures of Agaricus bisporus, A. Bitorquis, Pleurotus
      flabellatus, P. Sajor-caju, P. Ostreatus, P. Sapidus, Auricularia polytricha,
      Lentinula edodes, Morchella esculenta and Volvariella volvacea were maintained by
      frequent subculturing at an interval of two months and separately as wheat grain
      spawn in liquid nitrogen with 15 percent glycerol. Preservation of mushroom stock
      cultures as wheat grain spawn under liquid nitrogen proved to be the better
      method of maintenance. The percent recoveries of stored samples were unchanged
      from the first recovery after six months to the last recovery after 42 months in
      nine out of 11 stock cultures preserved under liquid nitrogen. However, a
      marginal decline in survival of 10 % was recorded in Auricularia polytricha and
      Volvariella volvacea. Yields before preservation of mushroom stock cultures and
      after 30 months of preservation exhibited static biological efficiency and
      fruitbody weight. The comparison of Random Amplified Polymorphic DNA (RAPD) and
      Internal Transcribed Spacers (ITS) PCR amplified products did not exhibit DNA
      fragment variation in banding patterns at the intraspecific level during
      preservation of stock cultures by either method. The modified cryopreservation
      protocol and experimental demonstration of genetic stability of stock cultures
      reported here validate the use of mushroom cryopreservation techniques and
      supports studies on genetic stability of preserved biological materials.

PMID- 15031743
TI  - Cryopreservation of zygotic embryo axes and somatic embryos of European chestnut.
AB  - This work describes experiments demonstrating the feasibility of long-term
      conservation of Castanea sativa germplasm through cryopreservation of embryonic
      axes or somatic embryo clumps. Between 93 % and 100 % of excised embryonic axes
      of recalcitrant chestnut seeds survived storage in liquid nitrogen (LN) following
      desiccation in a laminar flow cabinet to moisture contents of 20-24 % (on a fresh
      weight basis), and some 63 % subsequently developed as whole plants. Desiccation
      to moisture contents less than 19 % produced damage resulting in loss of
      organized plant development after cryostorage, allowing only root growth. When 6
      8 mg clumps of globular or heart-shaped somatic embryos were precultured for 7
      days on high-sucrose medium and then desiccated to a moisture content of 25 %
      before storage in LN, the embryogenesis resumption level after thawing was 33 %.
      When the embryo clumps were precultured for 3 days on high-sucrose medium
      followed by 60 min application of PVS2 vitrification solution before cryostorage,
      the post-storage embryogenesis resumption level was 68 %.

PMID- 15031744
TI  - Cryopreservation of shoot-tips of citrus using vitrification: effect of reduced
      form of glutathione.
AB  - A commercial citrus scion cultivar, '439' tangor [C. Suavissima Hort. et Tanaka x
      C. sinensis (L.) Osbesk cv.Gailiangcheng] was used to investigate whether GSH
      (reduced form of glutathione) could improve survival of a vitrification
      procedure. The optimal pre-growth treatment was a 3-day pre-culture on basal pre
      culture medium (BPM: MT basal medium containing 0.5 mol/L glycerol and 5 %
      sucrose at pH 5.8). GSH of 40 mg/L in the pre-culture medium improved shoot tip
      survival after cryopreservation. GSH in the recovery medium also improved
      survival, with 10 mg/L giving the best result. GSH of 40 mg/L in the loading and
      vitrification solutions also improved survival. The optimal cryopreservation
      protocol was successfully applied to 12 other citrus cultivars. This is the first
      report on the successful cryopreservation of shoot-tips from commercial citrus
      scion cultivars.

PMID- 15031745
TI  - Cryopreservation of in vitro-grown shoot tips of cassava by encapsulation
      vitrification method.
AB  - Shoot tips of cassava (Manihot esculenta Crantz) in vitro plantlets were
      successfully cryopreserved using the encapsulation-vitrification technique. Nodal
      cuttings of 5 mm length with one leaf were cultured on modified MS medium in
      Petri dishes (90 mm x 20 mm) for about 28 days. Excised shoot tips were
      precultured on sucrose enriched (0.3 M) medium for 16 h, encapsulated and
      osmoprotected with a mixture of 2 M glycerol and 0.6 M sucrose for 90 min at 25
      degree c before dehydration with PVS2 at 0 degree C for 4 h, then plunged in
      liquid nitrogen. Successfully vitrified shoot tips resumed growth within 3 days,
      without intermediary callus formation, and developed shoots. Shoot tips sampled
      from 21 day-old plantlets produced the highest survival of 80 %. The percentage
      survival of vitrified shoot tips differed from 38 to 80 % depending on the day of
      excision. The protocol was successfully applied to four cultivars of cassava with
      about 80 % average percentage of survival.

PMID- 15031746
TI  - Cryopreservation of garlic shoot tips by vitrification: effects of dehydration,
      rewarming, unloading and regrowth conditions.
AB  - This paper investigates the effect of dehydration, rewarming, unloading and
      regrowth conditions and of bulb post-harvest storage duration on survival and
      regeneration of cryopreserved garlic shoot tips. PVS3 was the most effective of
      the seven vitrification solutions compared. Treating shoot tips with PVS3 for 150
      180 min ensured 92 % regeneration after freezing. An air-drying treatment,
      performed either before or after the PVS3 treatment, was detrimental to
      regeneration of cryopreserved shoot tips. Rapid rewarming in a water-bath at 37
      degree C gave higher regeneration than the slower rewarming procedures employed.
      Regeneration was similar using either sucrose or sorbitol unloading solutions.
      The growth regulator content of the recovery medium did not influence percentage
      regeneration. However, the fresh weight of explants cultured on medium containing
      0.3 mg/L zeatin and 0.3 mg/L gibberellic acid was significantly higher than on
      other media. Post-harvest storage duration of bulbs dramatically influenced
      survival and regeneration of non-cryopreserved and cryopreserved shoot tips,
      which were nil for samples cryopreserved immediately after harvest and highest
      after 3 and 6 months of storage. The optimized cryopreservation protocol was
      applied to ten different garlic varieties, with regeneration percentages ranging
      between 72 and 95 %.

PMID- 15031747
TI  - Cryopreservation of Salix species using sections from winter vegetative scions.
AB  - Twigs of Salix species are candidates for cryopreservation procedures because
      they become tolerant of freezing temperatures during mid-winter. We examined
      several variables in developing a two-step cryopreservation procedure for
      sections from these twigs. Samples of Salix triandra cooled to -30 or -35 degree
      C and then transferred to the vapor phase over liquid nitrogen gave the greatest
      percent shoot formation. Cooling rate to -35 degree C had a major influence on
      shoot formation. Samples cooled at rates greater than 10 degree C/hour showed no
      shoot formation. The highest percent of shoot formation was achieved by cooling
      at 0.21 degree C/hour. Cooling rate from -35 degree C to liquid nitrogen did not
      influence shoot formation. Warming procedures affected shoot formation.
      Transferring samples from -160 degree C to either a +2 degree C cold room or to 
      3 degree C methanol gave similar levels of shoot formation. No shoot formation
      occurred either with warming in +40 degree C water or very slowly in a Styrofoam
      box. Eight of eleven Salix taxa tested using the established protocol had
      significant levels of shoot formation after cryogenic treatment.

PMID- 15031748
TI  - [The new start,the new pursuit].
AB  - Shanghai Journal of Stomatology(Shanghai Kou Qiang Yi Xue,ISSN 1006-7248),a peer
      reviewed national journal on oral medicine, oral and maxillofacial surgery,
      prosthodontics, pediatric dentistry, preventive dentistry, oral pathology, oral
      radiology, etc, was recently accepted and included in index Medicus and MEDLINE.
      This is an exciting and encouraging event both for the Editorial Board and
      authors. The journal will do its best to improve the academic and printing
      quality in accordance with the demands of MEDLINE and international conventions.
      The Editorial Board was re-founded last year with addition of internationally
      renowned experts on stomatology. Every submitted manuscript was evaluated by a
      minimum of 2 expert reviewers. Almost all of the manuscripts were returned to the
      corresponding authors with recommendations for revision and correction. In
      addition, statistics will be addressed for each manuscript to ensure the
      scientific credibility and repeatability. To help the authors to understand and
      apply statistics soundly, a series of tutorials on statistics will be published
      in the 6 issues of this year. All the English information is revised and
      processed by our invited experts. What we should do next is to increase the
      impact factor of the journal and shorten the publication periods(currently 9 to
      12 months)as much as possible. what we wish is that the impact of this journal
      will be magnified through the joint efforts from our reviewers, editors and
      authors worldwide in the future.

PMID- 15031758
TI  - Evaluation of the impacts of dock structures and land use on tidal creek
      ecosystems in South Carolina estuarine environments.
AB  - Tidal creeks and their associated salt marshes are the primary link between
      uplands and estuaries in the southeastern region. They are also critical nursery
      and feeding grounds. In addition, the uplands surrounding creeks are preferred
      sites for homebuilding because of their natural beauty and the ability to access
      the estuary from a personal dock structure. The objective of this study was to
      evaluate the cumulative impacts of docks on tidal creek nursery habitats for both
      small and large tidal creeks. The number of docks was associated with the amount
      of impervious cover in both small and large creeks. The presence of docks had
      little measurable effect on sediment metal concentrations at the scale of small
      and large creeks. In small and large creeks, sediment polycyclic aromatic
      hydrocarbon (PAH) concentrations were related to the human activity in the upland
      that includes the presence of docks at the scale of small and large creeks. Some
      impacts on the benthic community were associated with docks and human activity in
      small creeks but not in large creeks. Suburban development may reduce fish and
      crustacean abundances, but the dock may potentially mediate the development
      effect. Individually, the harm to the marine environment resulting from dock
      shading, chrominated copper arsenate leachates, and PAH contamination was small
      at the scale of tidal creeks. However, impacts from dock structures could not be
      separated from anthropogenic watershed-scale effects. These results demonstrate
      that suburban development with its accompanying dock construction does represent
      a major source of environmental degradation to tidal creeks and associated salt
      marsh habitats.

PMID- 15031759
TI  - Indicators of sustainability: challenges and opportunities at the interface of
      science and policy.
AB  - Rising global interest in sustainability has triggered attention in indicators as
      a means of achieving a more sustainable world. Although the search for indicators
      has led to the development of criteria for good indicators, it has also been
      dominated by scientific elites. The consequences of such dominance leads to
      significant social and policy implications, particularly with regard to how the
      search for sustainability has become defined primarily as a technical/scientific
      exploration when it is actually a moral and ethical issue. Our discussion about
      sustainability and appropriate indicators centers on what constitutes the public
      interest, a question that requires inclusiveness and centers on the interface of
      science and policy. The paper reviews the rationale for selecting indicators, the
      functions they serve, and the implications and consequences involved when one
      sector-science-dominates the debate. The paper concludes with suggestions about
      appropriate roles of science, policy and the public in the indicator selection
      process.

PMID- 15031760
TI  - Quality and quantity of suspended particles in rivers: continent-scale patterns
      in the United States.
AB  - Suspended solids or sediments can be pollutants in rivers, but they are also an
      important component of lotic food webs. Suspended sediment data for rivers were
      obtained from a United States-wide water quality database for 622 stations. Data
      for particulate nitrogen, suspended carbon, discharge, watershed area, land use,
      and population were also used. Stations were classified by United States
      Environmental Protection Agency ecoregions to assess relationships between
      terrestrial habitats and the quality and quantity of total suspended solids
      (TSS). Results indicate that nephelometric determinations of mean turbidity can
      be used to estimate mean suspended sediment values to within an order of
      magnitude (r(2) = 0.89). Water quality is often considered impaired above 80 mg
      TSS L(-1), and 35% of the stations examined during this study had mean values
      exceeding this level. Forested systems had substantially lower TSS and somewhat
      higher carbon-to-nitrogen ratios of suspended materials. The correlation between
      TSS and discharge was moderately well described by an exponential relationship,
      with the power of the exponent indicating potential acute sediment events in
      rivers. Mean sediment values and power of the exponent varied significantly with
      ecoregion, but TSS values were also influenced by land use practices and
      geomorphological characteristics. Results confirm that, based on current water
      quality standards, excessive suspended solids impair numerous rivers in the
      United States.

PMID- 15031767
TI  - Modeling the suitability of potential wetland mitigation sites with a geographic
      information system.
AB  - Wetland mitigation is frequently required to compensate for unavoidable impacts
      to wetlands. Site conditions and landscape context are critical factors
      influencing the functions that created wetlands perform. We developed a spatial
      model and used a geographic information system (GIS) to identify suitable
      locations for wetland mitigation sites. The model used six variables to
      characterize site conditions: hydrology, soils, historic condition, vegetation
      cover, adjacent vegetation, and land use. For each variable, a set of suitability
      scores was developed that indicated the wetland establishment potential for
      different variable states. Composite suitability scores for individual points on
      the landscape were determined from the weighted geometric mean of suitability
      scores for each variable at each point. These composite scores were grouped into
      five classes and mapped as a wetland mitigation suitability surface with a GIS.
      Sites with high suitability scores were further evaluated using information on
      the feasibility of site modification and project cost. This modeling approach
      could be adapted by planners for use in identifying the suitability of locations
      as wetland mitigation sites at any site or region.

PMID- 15031768
TI  - Influence of woody debris on channel structure in old growth and managed forest
      streams in central Sweden.
AB  - Anecdotal information suggests that woody debris have had an important channel
      forming role in Swedish streams and rivers, but there are few data to support
      this view. We identified 10 streams within near-natural and 10 streams within
      managed forest landscapes in central Sweden, and quantified their channel
      characteristics and content of woody debris. All pieces of woody debris greater
      than 0.5 m in length and greater than 0.05 m in base diameter were included. The
      near-natural forests were situated in reserves protected from forest cutting,
      whereas the managed forests had previously faced intensive logging in the area
      adjacent to the stream. The two sets of streams did not differ in general abiotic
      characteristics such as width, slope, or boulder cover, but the number of wood
      pieces was twice as high and the wood volume almost four times as high in the
      near-natural streams. This difference resulted in a higher frequency of debris
      dams in the near-natural streams. Although the total pool area did not differ
      between the two sets of streams, the wood-formed pools were larger and deeper,
      and potentially ecologically more important than other pools. In contrast to what
      has been believed so far, woody debris can be a channel-forming agent also in
      steeper streams with boulder beds. In a stepwise multiple regression analysis,
      pool area was positively and most strongly related to the quantity of woody
      debris, whereas channel gradient and wood volume were negatively related. The
      frequency of debris dams increased with the number of pieces of woody debris, but
      was not affected by other variables. The management implications of this study
      are that the wood quantity in streams in managed forests would need to be
      increased if management of streams will target more pristine conditions.

PMID- 15031769
TI  - Bringing diabetologists from East and Central Europe closer together: new tasks
      for the Federation of International Danube-symposia on diabetes mellitus.

PMID- 15031770
TI  - The lipid triad in type 2 diabetes - prevalence and relevance of
      hypertriglyceridaemia/low high-density lipoprotein syndrome in type 2 diabetes.
AB  - Cardiovascular disease is the major cause of morbidity and mortality in type 2
      diabetes mellitus. Among the established risk factors, the lipid triad (elevated
      triglycerides, decreased high-density lipoprotein cholesterol, and small dense
      low-density lipoprotein cholesterol) is a powerful risk factor for
      atherosclerosis in type 2 diabetes. The prevalence of hypertriglyceridaemia (HTG)
      in type 2 diabetes is two to three times higher than in non-diabetics. The
      Copenhagen Male study, the AMORIS study, and several other trials showed
      hypertriglyceridaemia to be an independent predictor of coronary heart disease
      (CHD). HTG may promote risk both directly and indirectly through association with
      alterations of lipoprotein size and composition. The Veterans Affairs High
      Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) demonstrated that
      raising high-density lipoprotein cholesterol (HDL-C) in patients with low (HDL-C)
      and low-density lipoprotein cholesterol (LDL-C) is associated with a significant
      reduction in CHD risk. It was shown in the Diabetes Intervention Study,
      AFCAPS/TexCAPS, and PROCAM studies that decreased HDL-C and elevated
      triglycerides are independent risk factors for atherosclerosis, particularly in
      patients with diabetes mellitus. Several epidemiological studies demonstrated
      that total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratios or
      low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL
      C/HDL-C) ratios could be better predictors of atherosclerosis than any single
      lipid parameter. Intima-media thickness (IMT), a well established marker of early
      atherosclerosis, is associated with HTG/low HDL-cholesterol. In the Risk factors
      in IGT for Atherosclerosis and Diabetes (RIAD) study total and HDL-cholesterol
      were independent determinants of IMT in subjects at risk for type 2 diabetes.
      Postprandial HTG was also shown to be correlated with increased IMT in type 2
      diabetic patients.

PMID- 15031771
TI  - A novel 7301-bp deletion in mitochondrial DNA in a patient with Kearns-Sayre
      syndrome, diabetes mellitus, and primary amenorrhoea.
AB  - We report a 27-year-old woman with a form of mitochondrial myopathy including
      chronic progressive external opthalmoplegia, retinal pigmentary dystrophy,
      cerebellar ataxia, and cardiac conduction block (Kearns-Sayre syndrome). At age
      13 years a cardiac pacemaker was implanted. She also had sensineural hearing
      loss, delayed puberty, and primary amenorrhoea. She was weelchair-bound since the
      age of 20 years. At age 27, insulin-dependent diabetes mellitus and osteoporosis
      were diagnosed. Insulin treatment was started and associated endocrinopathies
      were investigated. DNA analysis identified a novel 7301-bp deletion in
      mitochondrial DNA, ranging from position 6530 to 13 831 corroborating the
      diagnosis of Kearns-Sayre syndrome.

PMID- 15031772
TI  - A new mutation in the hepatocyte nuclear factor-1-alpha gene (P224S) in a newly
      discovered German family with maturity-onset diabetes of the young 3 (MODY 3).
      Family members carry additionally the homozygous I27L amino acid polymorphism in
      the HNF1 alpha gene.
AB  - Mutations in the hepatocyte nuclear factor-1-alpha gene cause maturity onset
      diabetes of the young 3 (MODY 3). Here we describe a new family affected by this
      disorder carrying the so far unknown mutation Pro224Ser in exon 3. First we
      identified a 17-year-old patient. OGTT demonstrated that insulin secretion was
      severely impaired: basal insulin was 3.7 uU/ml and 60 min after an oral glucose
      load plasma insulin peaked only threefold to 10.7 uU/ml. In addition, this
      patient carries the homozygous polymorphism Ile27Leu (exon1) in the hepatocyte
      nuclear factor-1-alpha gene that was shown to be associated with insulin
      resistance. So far, we have no evidence for insulin resistance in this individual
      patient. Additionally, two other family members carry the hepatocyte nuclear
      factor-1-alpha mutation Pro224Ser and the homozygous polymorphism Ile27Leu. A
      similar case with these two mutations in the HNF-1-alpha gene has not been
      described before. This data will allow to discover more patients with MODY 3.

PMID- 15031773
TI  - Effectiveness of a disease management programme for patients with type 2 diabetes
      mellitus and albuminuria in primary care - the PROSIT project (Proteinuria
      Screening and Intervention).
AB  - Aims. To evaluate the structured PROSIT(R) disease management programme for high
      risk diabetic patients in primary care with respect to the cardio-vascular risk
      profile and mortality. Subjects and Methods. Retrospectively 55 albuminuric Type
      2 diabetic patients included into the PROSIT(R) programme from 1994 to 1999
      (intervention group: age 66.6 +/- 10.5 years, known duration of diabetes 8.9 +/-
      6.5 years) were compared with 58 albuminuric patients not participating in the
      PROSIT(R) programme (control group: age 68.5 +/- 10.4 years, known duration of
      diabetes 8.5 +/- 6.7 years). Within PROSIT(R) a structured multifactorial
      intervention programme was applied. The main characteristics of this intervention
      were strict follow-ups of the patient's risk profile every three months and the
      use of quality management methods (definition of target values, structured
      documentation, central data feedback with diagnostic and therapeutic
      recommendations based on European guidelines). The cardio-vascular risk profile,
      therapeutic intervention, and secondary diabetic complications were compared
      between both groups in 1994 and 1999. Results. In the period from 1994 to 1999
      the intervention group showed a significant improvement in the vascular risk
      profile, while the control group did not. In 1999 the mean arterial blood
      pressure was significantly lower compared to the control group (115 +/- 13 mm Hg
      vs. 125 +/- 16 mm Hg, p < 0.05). The HbA1c improved only in the intervention
      group and in 1999 it was significantly lower than in the control group (7.0 +/-
      1.3 % vs. 8.4 +/- 1.8 %, p < 0.01). Moreover, the occurrence of clinical
      endpoints in the intervention group could be reduced: Both the mortalitly rate
      (14.5 % vs. 34.5 %, p < 0.05) and the rate of new myocardial infarctions (6 % vs.
      20 %, p < 0.05) of the intervention group were significantly lower. Conclusions.
      Participation of albuminuric Type 2 diabetic patients and their physicians in a
      structured intervention programme showed positive effects on the cardio-vascular
      risk profile and endpoints compared with a group of non-participating patients
      and physicians.

PMID- 15031774
TI  - The novel missense mutation methionine 442 threonine in the thyroid hormone
      receptor beta causes thyroid hormone resistance: a case report.
AB  - We report a family with thyroid hormone resistance caused by a novel mutation
      M442T in the thyroid hormone receptor beta (TRbeta) gene. The 59-year-old
      propositus and one of his two daughters had typical clinical signs of reduced
      responsiveness of tissues to thyroid hormones. Thus, elevated free T (3) and T
      (4) plasma concentrations in coexistance with a diffuse nodular goiter,
      nonsuppressed TSH, and atrial fibrillation with tachycardia were present in the
      propositus. His affected daughter also had increased levels of free T (3) and T
      (4) with slightly elevated TSH concentrations. Both affected members harboured a
      heterozygous M442T TRbeta mutation. The unaffected child had no mutation in the
      TRbeta gene and no clinical manifestations.

PMID- 15031775
TI  - Pheochromocytoma during pregnancy: laparoscopic and conventional surgical
      treatment of two cases.
AB  - Pheochromocytoma is a rare entity. When it presents during pregnancy, rapid
      recognition and diagnosis are crucial in order to avoid the maternal and fetal
      morbidity and mortality associated with severe, uncontrolled hypertension.
      Difficulties arise from the differential diagnosis of pre-eclampsia. We report
      two patients operated on for pheochromocytoma during pregnancy. The first patient
      developed new-onset hypertension in early pregnancy. Prior to presentation, there
      had been non-specific signs of endocrine disorder, namely a mild diabetes, but no
      hypertension requiring medication. The second patient sought medical care for
      irregular heartbeat, shortness of breath, and fatigue during the 6th week of
      pregnancy. She was found to be hypertensive; diagnostic evaluation revealed
      substantially increased catecholamine levels. The diagnosis was made by elevated
      urinary catecholamines and by MRI scan as well as ultrasonography, both of which
      demonstrated an adrenal mass. Both patients underwent surgical extirpation of the
      affected adrenal gland. The procedure was performed laparoscopically in the case
      of the second patient. Pre-operatively, both patients were pre-treated with alpha
      blockade followed by secondary beta-blockade. Patient two also received
      methyldopa for control of hypertension. Both patients were readily weaned from
      antihypertensive medications post-operatively, with complete resolution of
      hypertension within a few hours. Each pregnancy progressed normally to term.

PMID- 15031776
TI  - Urinary 6-sulfatoxymelatonin excretion in hyperandrogenic women: the effect of
      cyproterone acetate-ethinyl estradiol treatment.
AB  - Evidence for a relationship between melatonin and the reproductive hormones in
      humans is based on observations of abnormal melatonin secretion in clinical
      disorders of the pituitary-gonadal axis. The aim of this study was to investigate
      melatonin production in hyperandrogenic women before and during treatment with
      cyproterone acetate and ethinyl estradiol (Diane 35). Twelve women with
      polycystic ovary syndrome (PCOS), 10 women with idiopathic hirsutism (IH), and 10
      women with late onset adrenal hyperplasia due to 21-hydroxylase deficiency
      (LOCAH) were studied. Patients were treated with Diane 35 for four months.
      Fasting blood samples for the determination of luteinizing hormone (LH), follicle
      stimulating hormone (FSH), testosterone and dihydroepiandrosterone sulfate
      (DHEAS) and 24-hour urine collections for the determination of 6
      sulfatoxymelatonin (aMT6s) excretion were obtained from all patients at baseline
      and after 4 months of treatment. Results were compared with those obtained in 15
      control women. At baseline, women with PCOS and LOCAH had significantly higher
      testosterone and aMT6s values than women with IH and controls. Diane 35 treatment
      significantly decreased testosterone, LH, FSH and aMT6s values in PCOS and LOCAH
      patients compared with pretreatment values. These results indicate that
      hyperandrogenic women with PCOS and LOCAH have increased melatonin production.
      The decrease in aMT6s excretion together with reduced serum LH, FSH, DHEAS and
      testosterone values during treatment with cyproterone acetate-ethinyl estradiol,
      suggest that sex steroids either directly or through the suppression of
      gonadotropins, modulate melatonin secretion in these patients.

PMID- 15031777
TI  - The role of oxytocin, protein kinase A, and ERK-related MAP-kinase in the control
      of porcine ovarian follicle functions.
AB  - The aim of our in vitro experiments was to study the role of oxytocin (OT),
      cAMP/protein kinase A (PKA), and mitogen-activated protein kinase (ERKs MAP
      kinase) in the control of ovarian cell functions as well as the role of PKA and
      MAPK in mediating OT effects on these processes. The whole porcine ovarian
      follicles were cultured in the presence or absence of OT (1, 10, 100 ng/ml), PKA
      inhibitor Rp-cAMPS (10 nM), MAP-kinase inhibitor PD98059 (1 microg/ml), or their
      combination. The release of prostaglandins F (PGF) and E (PGE) were determined by
      RIA, PKA (alpha-cat subunit), the proliferation-associated peptide PCNA and ERK
      1, -2 expression in cell lyzates were analysed by Western-blotting. OT stimulated
      the release of PGF and PGE, and accumulation of PKA, ERK-1/-2, and PCNA in cell
      lysate. PD98059 decreased the basal PGF and PGE output, as well as reduced both
      ERK-1 and ERK-2 accumulation in cell lysates. Rp-cAMPS decreased PKA accumulation
      in cell lysates. Rp-cAMPS prevented the OT-induced stimulation of PKA, ERK-1, ERK
      2, PGF, and PGE, PD98059 did so for PKA, PGF, and PGE. However, PD98059 reduced
      either basal or OT-induced p-ERK level. OT-stimulated PCNA accumulation was only
      slightly modified by these blockers. These observations suggest that OT, PKA, and
      ERKs MAPK can be involved in the control of PGs release and proliferation of
      ovarian cells. The influence of OT on both PKA and MAPK, and the ability of PKA
      and MAPK blockers to prevent completely or partially OT effects suggest, that
      effects of OT on PGF and PGE can be mediated by both PKA and MAPK. The role of
      MAPK and PKA in mediating the proliferative effects of OT seems to be minor
      assuming the involvement of other intracellular messengers.

PMID- 15031778
TI  - Coefficient of beta-cell failure in patients with type 2 diabetes treated with
      pioglitazone or acarbose.
AB  - AIM: A new method of assessing the coefficient of failure of pancreatic beta
      cells from any index of glycaemia has been proposed. This method of analysis has
      been used to assess data on HbA1c and fasting glucose concentrations from a
      randomised study comparing pioglitazone with acarbose. METHODS: Patients were
      treated for 26 weeks with either pioglitazone 45 mg once daily or acarbose 300
      mg/day as 3 equal doses. Plasma HbA1c concentration was measured every two months
      and fasting glucose was measured monthly. The coefficient of failure was
      determined for each patient from the slope of the least squares regression line
      over time. RESULTS: The coefficient of failure from HbA1c was - 2.65 +/- 2.13
      %/year with pioglitazone and - 1.25 +/- 3.11 %/year with acarbose, indicating
      improved beta-cell function in each case. The coefficient of failure was improved
      to a significantly greater extent with pioglitazone ( P < 0.001). Coefficient of
      failure from fasting blood glucose also showed a greater improvement with
      pioglitazone (- 53.1 +/- 95.0 mg/dl/year) than with acarbose (- 29.9 +/- 142.5
      mg/dl/year; p = 0.049). CONCLUSION: The coefficient of failure showed a
      significantly greater improvement of beta-cell function with pioglitazone than
      with acarbose during 26 weeks of treatment.

PMID- 15031780
TI  - Kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4+ T cell responses
      in HCV and Schistosoma mansoni coinfection: relation to progression of liver
      fibrosis.
AB  - The kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4(+) T cell
      responses and their role in progression of fibrosis have not previously been
      characterized. Subjects with HCV/Schistosoma mansoni coinfection have a more
      rapid progression of HCV liver fibrosis than do those with HCV infection alone.
      The present prospective longitudinal study compared the liver histology, HCV
      specific intrahepatic and peripheral CD4(+) T cell proliferative responses, and
      cytokines (enzyme-linked immunospot) in 48 subjects with unresolved acute HCV
      infection with or without S. mansoni coinfection, at 6-10 months after acute
      infection and at the end of follow-up (96+/-8.7 months), and the findings were
      correlated to the rate of progression of fibrosis per year. Coinfected subjects
      had significant worsening of fibrosis, compared with subjects with HCV infection
      alone. At baseline, subjects with HCV infection alone had stronger multispecific
      intrahepatic HCV-specific CD4(+) T helper 1 responses than did coinfected
      subjects, who had either no responses or weak, narrowly focused responses, and,
      over time, these T cell responses were maintained only in the liver. The rate of
      progression of fibrosis and virus load inversely correlated with intrahepatic HCV
      specific CD4(+) T cell response. The present prospective analysis indicates that
      enhancement of progression of liver fibrosis is associated with failure to
      develop early, multispecific, HCV-specific CD4(+) Th1 responses, suggesting that
      novel therapeutic approaches inducing strong cellular immune responses might
      limit subsequent liver damage in individuals with chronic hepatitis C.

PMID- 15031779
TI  - Synergistic inhibition of intracellular hepatitis C virus replication by
      combination of ribavirin and interferon- alpha.
AB  - Treatment of hepatitis C virus (HCV) infection with interferon (IFN)- alpha and
      ribavirin combination therapy results in superior clinical antiviral responses
      than does monotherapy with IFN. To explore the virological basis of the effects
      of combination therapy, we analyzed the effects of IFN- alpha and ribavirin,
      singly and in combination, on intracellular HCV replication by use of an HCV
      replicon system. A new replicon that expressed a selectable chimeric reporter
      protein comprising firefly luciferase and neomycin phosphotransferase was
      constructed. The replicon was highly sensitive to IFN-alpha (50% inhibitory
      concentration [IC(50)], 0.5 U/mL). Therapy with ribavirin showed weak suppression
      of HCV replication at a lower concentration (IC(50), 126 mu mol/L). The
      nucleotide sequence diversity of the replicon was increased significantly by
      therapy with ribavirin, suggesting that error-prone HCV replication was induced
      by the drug. Importantly, use of a clinically achievable concentration of
      ribavirin (approximately 10 mu mol/L) in combination with IFN showed strong
      synergistic inhibitory effects on HCV replication. Our results suggest that the
      direct effects of ribavirin on the genetic stability of the HCV subgenome and its
      synergistic action combined, with IFN-alpha, may explain the improved clinical
      responses to combination therapy.

PMID- 15031781
TI  - Quantitation of the level of hepatitis delta virus RNA in serum, by real-time
      polymerase chain reaction--and its possible correlation with the clinical stage
      of liver disease.
AB  - Some hepatitis B virus (HBV) carriers with chronic hepatitis delta virus (HDV)
      superinfection show progressive chronic hepatitis, whereas others show no
      apparent signs of liver disease. In the present study, we established a sensitive
      method for the quantitation of the level of HDV RNA in serum on the basis of real
      time reverse-transcription polymerase chain reaction (RT-PCR), to clarify the
      role that the level of HDV RNA in serum plays in the diverse natural course of
      clinical manifestation. In 48 subjects who were positive for hepatitis B surface
      antigen and for anti-hepatitis delta antibody, the levels of HDV RNA in serum
      were quantitated by RT-PCR. The levels of HBV DNA in serum were determined by a
      transcription-mediated amplification assay. The levels of HDV RNA in serum of
      subjects with chronic hepatitis and of subjects with liver cirrhosis were
      significantly higher than those in asymptomatic carrier subjects. The levels of
      HBV DNA in serum did not differ significantly among these 3 groups. In
      conclusion, HDV RNA quantification by real-time RT-PCR is possibly a useful tool
      for understanding the pathophysiology of HDV infection.

PMID- 15031782
TI  - Serology of severe acute respiratory syndrome: implications for surveillance and
      outcome.
AB  - BACKGROUND: Severe acute respiratory syndrome (SARS) is a novel infectious
      disease. No information is currently available on host-specific immunity against
      the SARS coronavirus (CoV), and detailed characteristics of the epidemiology of
      SARS CoV infection have not been identified. METHODS: ELISA was used to detect
      antibody to SARS CoV. Reverse-transcriptase polymerase chain reaction was used to
      detect SARS CoV RNA. T cells in peripheral blood of patients were quantified by
      flow cytometry. RESULTS: Of 36 patients with probable SARS CoV infection, 30
      (83.3%) were positive for IgG antibody to SARS CoV; in contrast, only 3 of 48
      patients with suspected SARS CoV infection, 0 of 112 patients with fever but
      without SARS, and 0 of 96 healthy control individuals were positive for it. IgG
      antibody to SARS CoV was first detected between day 5 and day 47 after onset of
      illness (mean +/- SD, 18.7+/-10.4). CONCLUSION: Detection of antibody to SARS CoV
      is useful in the diagnosis of SARS; however, at the incubation and initial phases
      of the illness, serological assay is of little value, because of late
      seroconversion in most patients.

PMID- 15031783
TI  - Severe acute respiratory syndrome-related coronavirus is inhibited by interferon-
      alpha.
AB  - Current treatment schemes for severe acute respiratory syndrome (SARS) include
      broad-spectrum antibiotics, glucocorticoids, and ribavirin. We evaluated the
      susceptibility of the SARS-related coronavirus (SARS CoV) to ribavirin and
      interferon (IFN)- alpha in vitro by use of cytopathic effect, plaque assay, and
      immunoblot analysis. Ribavirin did not inhibit viral growth at concentrations
      attainable in human serum. In contrast, IFN- alpha showed an in vitro inhibitory
      effect starting at concentrations of 1000 IU/mL. In conclusion, ribavirin alone
      is unlikely to be beneficial in the prophylaxis or treatment of SARS CoV
      infections. Clinical trials with IFN- alpha might be justified to determine a
      beneficial effect on the outcome of SARS.

PMID- 15031784
TI  - Isolation and characterization of circulating type 1 vaccine-derived poliovirus
      from sewage and stream waters in Hispaniola.
AB  - Twenty-one cases of acute flaccid paralysis (AFP) were reported on the island of
      Hispaniola in 2000. Laboratory analysis confirmed the presence of circulating
      vaccine-derived poliovirus (cVDPV) type 1 in stool samples obtained from
      patients. As a complement to the active search for cases of AFP, environmental
      sampling was conducted during November and December 2000, to test for cVDPV in
      sewage, streams, canals, and public latrines. Fifty-five environmental samples
      were obtained and analyzed for the presence of polioviruses by use of cell
      culture followed by neutralization and reverse-transcription polymerase chain
      reaction. Of the 23 positive samples, 10 tested positive for poliovirus type 1, 7
      tested positive for poliovirus type 2, 5 tested positive for poliovirus type 3,
      and 1 tested positive for both poliovirus type 2 and type 3. By sequence analysis
      of the complete viral capsid gene 1 (VP1), a 2.1%-3.7% genetic sequence
      difference between 7 type 1 strains and Sabin type 1 vaccine strain was found.
      Phylogenetic analysis showed that these viruses are highly related to cVDPV
      isolated from clinical cases and form distinct subclusters related to geographic
      region. Our findings demonstrate a useful role for environmental surveillance of
      neurovirulent polioviruses in the overall polio eradication program.

PMID- 15031785
TI  - Sex-based differences in saquinavir pharmacology and virologic response in AIDS
      Clinical Trials Group Study 359.
AB  - AIDS Clinical Trials Group study 359 was a controlled study of saquinavir with
      either ritonavir or nelfinavir, together with delavirdine, adefovir, or both, in
      indinavir-experienced persons. Saquinavir was common in all study arms, and the
      study investigated relationships among characteristics of patients, saquinavir
      area under the curve (AUC) and trough concentrations (C(min)), and virologic
      response. Concentrations of saquinavir were higher when it was combined with
      ritonavir than when it was combined with nelfinavir and were lower with adefovir
      containing regimens. Females had higher AUC and C(min) values than did males.
      Higher saquinavir AUC and C(min) values were associated with a greater likelihood
      of human immunodeficiency virus (HIV) RNA levels </=500 copies/mL (P=.008) and
      were better predictors of response than was the saquinavir inhibitory quotient.
      Males had a lower probability of having HIV RNA levels </=500 copies/mL at week
      16 than did females (28% vs. 42%; adjusted odds ratio, 0.43). In this study, a
      greater proportion of females had HIV RNA levels </=500 copies/mL than did males,
      which can be attributed to higher concentrations of saquinavir in females than in
      males.

PMID- 15031787
TI  - Expression of chemokine and inhibitory receptors on natural killer cells: effect
      of immune activation and HIV viremia.
AB  - We examined the cell-surface expression of chemokine and natural killer (NK) cell
      inhibitory receptors (iNKRs) on NK cells from individuals with human
      immunodeficiency virus (HIV) infection, chronic hepatitis C infection, and
      Wegener's granulomatosis (WG), an inflammatory, granulomatous vasculitis. The
      expression of CCR5 on NK cells was up-regulated in individuals with HIV viremia
      and in individuals with active WG, indicating that expression of this receptor is
      modulated by states of immune activation associated with viral infection and
      inflammatory or immune-mediated diseases. In contrast, iNKRs were shown to be up
      regulated only on NK cells of individuals with HIV viremia, and they returned to
      a normal level when viremia was controlled with effective antiviral therapy. In
      individuals with HIV-1 viremia, there was a direct correlation between the level
      of expression of p58.1, p58.2, and CD94 receptors and plasma HIV viremia,
      suggesting that ongoing active HIV replication has an effect on the expression of
      such receptors on NK cells. These results suggest that immune activation leads to
      abnormal cell-surface expression of chemokine receptors on NK cells, whereas HIV
      specific processes account for the up-regulation of iNKRs on NK cells; this may
      explain the NK cell-functional defects seen in HIV infection.

PMID- 15031786
TI  - Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and 
      experienced patients coinfected with HIV-1 and hepatitis B virus.
AB  - BACKGROUND: Coinfection with human immunodeficiency virus type 1 (HIV-1)
      increases the risk of hepatitis B virus (HBV)-associated progressive liver
      disease. Lamivudine has potent activity against both HIV-1 and HBV; however,
      lamivudine-resistance mutations in HBV frequently develop. METHODS: Substudies of
      the safety and efficacy of tenofovir disoproxil fumarate (tenofovir DF) for
      patients coinfected with HIV and HBV were undertaken within 2 phase 3 randomized
      controlled trials involving antiretroviral therapy-experienced (study 907) and 
      naive (study 903) HIV-infected populations. Inclusion criteria were detection of
      hepatitis B surface antigen, an HBV DNA level >106 copies/mL at baseline, and HBV
      DNA specimens available at week 24 (study 907) and week 48 (study 903). RESULTS:
      In study 907, the mean decrease in HBV DNA was 4.9 log(10), after 24 weeks, for
      10 patients randomized to receive tenofovir DF, compared with a mean increase of
      1.2 log(10) for 2 patients randomized to receive placebo (P=.041). The mean
      decrease in HBV DNA during tenofovir DF treatment was similar for patients with
      wild-type (5.3 log(10)) and lamivudine-resistant (4.6 log(10)) HBV strains. In
      study 903, the mean decrease in HBV DNA was 3.0 log(10), after 48 weeks, for 6
      patients randomized to receive lamivudine, compared with 4.7 log(10) for 5
      patients randomized to receive lamivudine and tenofovir DF (P=.055). Four
      patients developed tyrosine-methionine-aspartate-aspartate mutations, all in the
      lamivudine-only treatment arm. CONCLUSION: Tenofovir DF has potent anti-HBV
      efficacy in antiretroviral therapy-experienced and -naive individuals coinfected
      with HIV and HBV.

PMID- 15031788
TI  - HIV-specific cellular immune response is inversely correlated with disease
      progression as defined by decline of CD4+ T cells in relation to HIV RNA load.
AB  - The average time between infection with human immunodeficiency virus (HIV) and
      development of acquired immune deficiency syndrome is approximately 8 years.
      However, progression rates vary widely, depending on several determinants,
      including HIV-specific immunity, host genetic factors, and virulence of the
      infecting strain. In untreated HIV-infected patients with different progression
      rates, we examined HIV-specific T cell responses in combination with host genetic
      markers, such as chemokine/chemokine-receptor (CCR) polymorphisms and human
      leukocyte antigen (HLA) genotypes. HIV-specific CD4(+) T cell responses and, to a
      lesser extent, HIV-specific CD8(+) T cell responses were inversely correlated
      with progression rate. Slower progression was not related to polymorphisms in CCR
      genes, HLA genotype, or GB virus C coinfection. These data suggest that HIV
      specific T cell responses are involved in protecting the host from disease
      progression.

PMID- 15031789
TI  - Determinants of HIV-1 load in subjects with early and later HIV infections, in a
      general-population cohort of Rakai, Uganda.
AB  - Human immunodeficiency virus (HIV) type 1 RNA loads were determined for 256
      subjects with early (incident) HIV infection and for 1293 subjects with later
      (prevalent) HIV infection, in a Ugandan cohort. Prevalent infections were
      classified as latent (0-1 symptoms) and midstage disease (>/=2 symptoms), and
      deaths were ascribed to acquired immunodeficiency syndrome. Among subjects with
      incident HIV infection, HIV load did not differ by sex, but, among subjects with
      prevalent HIV infection, it was higher in males than in females. HIV load was
      highest in subjects (25-29 years old) with incident HIV infection but increased
      with age in subjects with prevalent HIV infection. Viremia was higher after
      serconversion than in latency and increased with more advanced disease. Viremia
      was increased with genital ulcer disease (GUD) in both subjects with incident
      infection and in those with prevalent infection, and with herpes simplex virus
      type 2 seropositivity in subjects with incident HIV infection. GUD was
      consistently associated with higher HIV loads in subjects with incident and those
      with prevalent HIV infection, suggesting that treatment of GUD might reduce HIV
      viremia.

PMID- 15031790
TI  - Longitudinal analysis of lymphocyte ratios and HIV-1 intracellular DNA levels in
      children.
AB  - The associations between human immunodeficiency virus type 1 (HIV-1)
      intracellular DNA and immunological markers were analyzed longitudinally for
      children with sustained, undetectable RNA levels while receiving highly active
      antiretroviral therapy (HAART) for >2 years. When DNA levels reached a plateau at
      week 104 of therapy, in contrast to findings for adults, there was no correlation
      between the CD4(+) : CD8(+) ratio and DNA levels (r=-0.02; P=.95), and naive
      CD4(+)CD45RA(+) lymphocytes predominated. These data suggest that the increased
      proportion of naive lymphocytes found in children are less susceptible to HIV-1
      infection than are the memory lymphocytes that dominate immune reconstitution in
      adults.

PMID- 15031793
TI  - Evolution of drug-resistance genes in Plasmodium falciparum in an area of
      seasonal malaria transmission in Eastern Sudan.
AB  - We investigated the evolution of drug-resistant Plasmodium falciparum in a
      village in eastern Sudan. The frequencies of alleles of 4 genes thought to be
      determinants of drug resistance were monitored from 1990 through 2001. Changes in
      frequencies of drug-resistance genes between wet and dry seasons were monitored
      from 1998 through 2000. Parasites were also typed for 3 putatively neutral
      microsatellite loci. No significant variation in frequencies was observed for the
      microsatellite loci over the whole study period or between seasons. However,
      genes involved in resistance to chloroquine showed consistent, significant
      increases in frequencies over time (rate of annual increase, 0.027/year for pfcrt
      and 0.018/year for pfmdr1). Genes involved in resistance to the second-line drug
      used in the area (Fansidar) remained at low frequencies between 1990 and 1993 but
      increased dramatically between 1998 and 2000, which is consistent with the advent
      of Fansidar usage during this period. For mutant alleles of the primary drug
      resistance targets for chloroquine and pyrimethamine, higher frequencies were
      seen during the dry season than during the wet season. This cyclical fluctuation
      in drug-resistance genes most likely reflects seasonal variation in drug pressure
      and differences in the fitness of resistant and sensitive parasites.

PMID- 15031791
TI  - Comparison of systemic and mucosal delivery of 2 canarypox virus vaccines
      expressing either HIV-1 genes or the gene for rabies virus G protein.
AB  - BACKGROUND: Since the primary routes of human immunodeficiency type 1 (HIV-1)
      infection are across mucosal barriers, a randomized trial of canarypox virus
      based vectors was conducted in 84 individuals, with delivery of vaccine by
      mucosal routes, and was accompanied by a detailed analysis of humoral, cellular,
      and mucosal immune responses. METHODS: Over the course of 6 months, HIV-1
      specific (vCP 205) and rabies (vCP 65) canarypox virus vectors were delivered
      systemically and/or mucosally into the nose, mouth, vagina, or rectum in a 4-dose
      schedule, followed by 2 doses of HIV-1 MN recombinant glycoprotein (rgp) 120 or
      subunit rabies vaccine administered by the intramuscular route. RESULTS:
      Administration of vaccine and collection of samples were well tolerated. Serum
      IgG HIV-1-specific antibodies to rgp120 were rarely seen after either systemic or
      mucosal delivery of canarypox virus vaccine. In contrast, serum IgG rabies and
      canarypox antibodies were detected in all individuals after systemic, but rarely
      after mucosal, delivery of vaccine. Suggestions of mucosal recognition of HIV-1
      antigen included a cytotoxic T lymphocyte response in 4 of 8 individuals after
      administration of vaccine by the intrarectal route and a limited immunoglobulin A
      response at the same site. CONCLUSIONS: Each of the routes of vaccine
      administration was feasible in the context of a phase 1 study with motivated
      individuals. However, with the doses and routes of administration used, canarypox
      virus was not an effective mucosal immunogen.

PMID- 15031794
TI  - Transcriptional profiling reveals suppressed erythropoiesis, up-regulated
      glycolysis, and interferon-associated responses in murine malaria.
AB  - The primary pathophysiological events contributing to fatal malaria are the
      cerebral syndrome, anemia, and lactic acidosis. The molecular basis of each event
      has been unclear. In the present study, microarray analysis of murine
      transcriptional responses during the development of severe disease revealed
      temporal, organ-specific, and pathway-specific patterns. More than 400 genes in
      the brain and 600 genes in the spleen displayed transcriptional changes. Dominant
      patterns revealed strongly suppressed erythropoiesis, starting early during
      infection, and highly up-regulated transcription of genes that control host
      glycolysis, including lactate dehydrogenase. The latter presents a mechanism that
      may contribute to metabolic acidosis. No evidence for hypoxia-mediated regulation
      of these events was observed. Interferon-regulated gene transcripts dominated the
      inflammatory response to cytokines. These results demonstrate previously unknown
      transcriptional changes in the host that may underlie the development of malarial
      syndromes, such as anemia and metabolic dysregulation, and increase the utility
      of murine models in investigation of basic malarial pathogenesis.

PMID- 15031795
TI  - Variable degree of alternative complement pathway-mediated hemolysis in Indian
      visceral leishmaniasis induced by differential expression of 9-O-acetylated
      sialoglycans.
AB  - BACKGROUND: Increased expression of linkage-specific 9-O-acetylated sialoglycans
      (9-O-AcSGs) has been demonstrated on erythrocytes from patients with visceral
      leishmaniasis (VL) by use of Achatinin-H. We assessed the capacity of this
      glycotope to influence hemolysis via activation of the alternative complement
      pathway in patients with VL, compared with that in healthy control subjects.
      METHODS: The differential expression of 9-O-AcSGs on surfaces of erythrocytes was
      measured, 9-O-AcSGs were affinity purified, and the molecular determinants were
      identified by Western blotting. The degree of alternative complement pathway
      mediated hemolysis was compared with expression of 9-O-AcSGs on erythrocytes.
      RESULTS: Enhanced expression of linkage-specific 9-O-AcSGs was demonstrated on
      erythrocytes from patients with active VL. Six distinct molecular determinants
      present only on diseased erythrocytes were affinity purified and were absent
      after elimination of parasite burden. A correlation (r2=0.9) was observed between
      the presence of 9-O-AcSGs and the degree of alternative complement pathway
      mediated hemolysis. CONCLUSION: The 9-O-AcSGs expressed on erythrocytes from
      patients with VL are potent complement activators, causing enhanced hemolysis via
      activation of the alternative complement pathway, and may account for the anemia
      that is a common manifestation of VL.

PMID- 15031796
TI  - Analysis of granzyme B activity as a surrogate marker of Leishmania-specific cell
      mediated cytotoxicity in zoonotic cutaneous leishmaniasis.
AB  - The purpose of this study was to analyze Leishmania-specific cell-mediated
      cytotoxicity in individuals with active or healed zoonotic cutaneous
      leishmaniasis (ZCL). The (51)Cr-release assay revealed a significant cytotoxicity
      against L. major-infected autologous macrophages in individuals with active or
      healed ZCL. As a surrogate marker of cytotoxic response, a test based on the
      measure of granzyme B activity in parasite-stimulated peripheral blood
      mononuclear cells was optimized and evaluated in 88 individuals. Increased
      granzyme B activity was found in 62.5% of patients with active ZCL and in only
      30% of individuals with healed ZCL. In both groups, granzyme B activity was
      significantly higher than in healthy, leishmanin skin test-negative control
      subjects (P<.05). These data provide additional evidence that Leishmania-specific
      cell-mediated cytotoxicity is part of the acquired immune response developed
      against the parasite. Its role in resistance to reinfection should be evaluated.

PMID- 15031792
TI  - Synonymous genetic polymorphisms within Brazilian human immunodeficiency virus
      Type 1 subtypes may influence mutational routes to drug resistance.
AB  - BACKGROUND: Most published data on antiretroviral-drug resistance is generated
      from in vitro or in vivo studies of subtype B virus. However, this subtype is
      associated with <10% of HIV infections worldwide, and it is essential to explore
      subtype-specific determinants of drug resistance. One potential cause of the
      differences between subtypes is the synonymous codon usage at key resistance
      positions. METHODS: We investigated the nucleotide sequences at drug resistance
      related sites, for all major Brazilian subtypes (B, C, and F1) of human
      immunodeficiency virus type 1 (HIV-1) group M. RESULTS: We identified a change at
      positions 151 and 210 of the reverse-transcriptase region in subtype F1, such
      that the emergence of these key nucleoside/nucleotide analogue resistance
      mutations required an extra nucleotide change in subtype F1, compared with
      subtypes B and C. The clinical significance of position 210 was confirmed within
      a large Brazilian database, in which we identified a lower prevalence of the
      L210W mutation in subtype F1 virus, compared with subtype B virus, in patients
      matched for thymidine-analogue experience. An inverse relationship between the
      L210W and K70R mutations was also observed. CONCLUSIONS: The findings of the
      present study illustrate an important mechanism by which a subtype may determine
      genetic routes to resistance, with implications for treatment strategies for
      populations infected with HIV-1 subtype F.

PMID- 15031797
TI  - Congenital transmission of Trypanosoma cruzi is associated with maternal enhanced
      parasitemia and decreased production of interferon- gamma in response to parasite
      antigens.
AB  - The conditions and mechanisms of congenital transmission of Trypanosoma cruzi
      remain largely unknown. In the present study, we compared the parasitic loads and
      the immune responses of pregnant T. cruzi-infected women who transmitted
      parasites to their fetus ("M+B+ mothers") with those of such women who did not
      transmit parasites to their fetus ("M+B- mothers"). M+B+ mothers had a higher
      frequency of positive results of hemoculture for T. cruzi than did M+B- mothers,
      in association with depressed production of parasite-specific interferon- gamma
      by blood cells that persisted after delivery. In contrast, the production of
      interleukin (IL)-2, IL-4, and IL-10 and transforming growth factor- beta 1 was
      similar between both groups of infected mothers, after stimulation with T. cruzi
      lysate. Flow cytometric analysis showed that T cells and monocytes of M+B+
      mothers were less activated than were those of M+B- mothers. Altogether, these
      results indicate that congenital transmission of T. cruzi is associated with high
      parasitic loads and peripheral deficient immunological responses in mothers.

PMID- 15031798
TI  - Human immunoglobulin G mediates protective immunity and identifies protective
      antigens against larval Strongyloides stercoralis in mice.
AB  - Protective immunity to larval Strongyloides stercoralis in mice has been shown to
      be dependent on antibody, complement, and granulocytes. The goals of the present
      study was to determine the following: (1) whether human serum could passively
      transfer immunity to mice, (2) the mechanism by which the serum mediated killing,
      and (3) whether the antigens (Ags) recognized by the protective human antibody
      could induce protective immunity in mice. Immunoglobulin G (IgG) from a S.
      stercoralis-seropositive individual passively transferred immunity to mice. The
      antibody required granulocytes, but not eosinophils, and complement activation to
      kill the larvae. Antibody-dependent cellular cytotoxicity was not required for
      larval killing. Immunization of mice with soluble larval Ags isolated by use of
      the protective immune IgG resulted in protective immunity. In conclusion,
      immunity could be transferred to mice by IgG from immune humans, and Ags
      identified by the immune human IgG induced protective immunity in mice, which
      thereby suggests their possible use in a vaccine against this infection.

PMID- 15031799
TI  - High prevalence of acquired antimicrobial resistance unrelated to heavy
      antimicrobial consumption.
AB  - In a very remote rural Bolivian community where the use of antimicrobials has
      been minimal and where exchanges with the exterior are very limited, 67% of
      subjects were found to be carriers of fecal Escherichia coli with acquired
      resistance to >/=1 antimicrobial agent(s); the highest rates were observed for
      tetracycline (64%), ampicillin (58%), trimethoprim-sulfamethoxazole (50%), and
      chloramphenicol (41%). The most relevant implication of these findings is that,
      in certain settings, the spread and maintenance of antimicrobial resistance can
      occur, regardless of whether selective pressure generated by the use of
      antimicrobials is present.

PMID- 15031800
TI  - Compartmentalization of tolerance to endotoxin.
AB  - BACKGROUND: Tolerance to endotoxin has been defined and analyzed either entirely
      in vivo or entirely in vitro. In contrast, the hyporeactivity of circulating
      leukocytes reported in patients with sepsis, and often referred to as the
      phenomenon of tolerance to endotoxin, is an ex vivo observation. Therefore, our
      objective was to set up an ex vivo model of tolerance to endotoxin. METHODS: Mice
      were injected intravenously with lipopolysaccharide (LPS), and their leukocytes,
      derived from different compartments, were challenged in vitro with LPS or heat
      killed Staphylococcus aureus Cowan I (SAC), for production of tumor necrosis
      factor (TNF). RESULTS: Production of TNF was observed in in vitro cultures of
      bronchoalveolar cells, peritoneal cells, splenocytes, and whole-blood samples
      harvested from mice 1-3 h after injection of LPS. Bone marrow cells, in contrast,
      did not release TNF. In parallel, cells acquired tolerance to LPS within 1-3 h
      after in vivo injection of LPS. A dramatic decrease in the production of TNF, in
      response to LPS, was observed by use of circulating leukocytes, splenocytes,
      peritoneal cells, and bone marrow cells 24 h after injection of LPS. In contrast,
      LPS-induced production of TNF by bronchoalveolar cells was far less reduced. The
      kinetics of acquisition of tolerance and recovery were different for different
      compartments. Cross-tolerance with SAC did not parallel the phenomenon of
      tolerance to endotoxin that was observed by use of LPS. CONCLUSION: These data
      show that tolerance to endotoxin, as monitored by ex vivo analysis, is
      compartmentalized and that bronchoalveolar cells are less likely than
      splenocytes, peritoneal cells, and bone marrow cells to develop tolerance to
      endotoxin.

PMID- 15031801
TI  - Intranasal vaccination with recombinant P6 protein and adamantylamide dipeptide
      as mucosal adjuvant confers efficient protection against otitis media and lung
      infection by nontypeable Haemophilus influenzae.
AB  - Nontypeable Haemophilus influenzae (NTHi) is a leading etiologic agent of otitis
      media in children and recurrent respiratory infections in patients with chronic
      obstructive pulmonary disease. The highly conserved outer membrane protein P6
      constitutes a promising vaccine candidate antigen. However, the small amount of
      P6 produced by this fastidious microorganism renders large-scale production
      difficult. Controversial data also exist concerning the suitability of
      recombinant P6 (rP6) as a vaccine antigen. Therefore, we performed a comparative
      evaluation of the immunogenicity and efficacy of native P6 and rP6 in mice
      intranasally vaccinated with adamantylamide dipeptide (AdDP) as an adjuvant. High
      titers of P6-specific serum antibodies were elicited in mice vaccinated with
      either native P6 or rP6, which cross-recognized both antigens. However, rP6
      stimulated stronger mucosal responses. Mice vaccinated with rP6 were protected
      against both pulmonary and middle-ear infections (P<.01). This demonstrates that
      rP6 plus AdDP constitutes a promising vaccine formulation against the most
      relevant forms of disease caused by NTHi.

PMID- 15031802
TI  - Time-lapse confocal imaging of development of Bacillus anthracis in macrophages.
AB  - Macrophages attempt to battle infection with Bacillus anthracis spores by
      phagocytosis of the spores. However, it is believed that B. anthracis spores may
      survive phagocytosis and may actually use the macrophages that ingest them as a
      means of transport to lymph nodes. Thus far, the events that occur after spores
      undergo phagocytosis have remained unclear. To elucidate the fate of spores
      internalized by macrophages, we have used time-lapse confocal microscopy to
      follow individual fluorescent spores over time. By use of this method, we have
      determined that some phagocytized spores survive beyond germination, to become
      bacilli that then replicate within the macrophages.

PMID- 15031803
TI  - Commentary: Wherry WB, Lamb BH. Infection of man with Bacterium tularense. J
      Infect Dis 1914; 15:331-40.

PMID- 15031804
TI  - Role of pertactin in pertussis vaccines: the jury is still out.

PMID- 15031806
TI  - Shiga toxin-producing Escherichia coli O157 more frequently cause bloody diarrhea
      than do non-O157 strains.

PMID- 15031809
TI  - The Academy of Molecular Imaging.

PMID- 15031810
TI  - Positron emission tomography: a review of basic principles, scanner design and
      performance, and current systems.

PMID- 15031811
TI  - 2-deoxy-2-[18F]fluoro-D-glucose and alternative radiotracers for positron
      emission tomography imaging using the human brain as a model.
AB  - 2-deoxy-2-[18F]fluoro-D-glucose (18FDG) is now routinely available in many
      hospitals and other institutions either via on-site production or from one of the
      dozens of regional radiopharmacies worldwide. Its reliable production has opened
      the possibility for use in both basic and clinical investigations and also in
      pairing it with other more biologically specific positron emission tomography
      tracers to provide an important functional perspective to the measurement. In
      this article, we highlight examples in which 18FDG is paired with another carbon
      11- or fluorine-18-labeled radiotracer in the same subject to correlate
      neurotransmitter-specific effects with regional metabolic effects using the human
      brain as a model. We describe studies that fall into three major areas: normal
      aging, neuropsychiatric disorders, and drug action.

PMID- 15031813
TI  - Update in PET imaging of nonsmall cell lung cancer.

PMID- 15031812
TI  - Pitfalls and artifacts in 18FDG PET and PET/CT oncologic imaging.
AB  - It is estimated that in excess of one million positron emission tomography (PET)
      scans are performed each year and PET can now truly be regarded as a routine
      imaging procedure in clinical management. Many potential pitfalls and artifacts
      have previously been described with (18)F-fluorodeoxyglucose PET imaging, but
      more continue to become apparent as worldwide experience increases. In addition,
      the advent of combined PET/CT scanners in clinical imaging practice has brought
      their own specific pitfalls and artifacts. It is essential that we learn these
      potential pitfalls so that patients can be optimally prepared for their scans and
      that accurate interpretation can be made.

PMID- 15031814
TI  - Diffuse increased uptake on bone scan: super scan.

PMID- 15031815
TI  - Absent pulmonary uptake on 99mTc MAA perfusion lung scan due to severe right-to
      left shunt.

PMID- 15031816
TI  - Pulmonary hypertrophic osteoarthropathy and its resolution.

PMID- 15031817
TI  - Outcomes after spinal cord injury: comparisons as a function of gender and race
      and ethnicity.
AB  - OBJECTIVE: To identify gender and racial and ethnic differences in subjective
      well-being (SWB), participation, and general health ratings in participants with
      spinal cord injury (SCI). DESIGN: A multisite, cross-sectional study that used
      stratified sampling to identify and maximize participation among groups of people
      traditionally underrepresented in SCI research. SETTING: Four Model Spinal Cord
      Injury Systems participated in the data collection. The primary site was a large
      southeastern specialty hospital; the other 3 were in the western and mountain
      regions of the United States. PARTICIPANTS: A total of 512 participants, 475 of
      whom were included in the analysis. This group included relatively equal portions
      of whites, African Americans, American Indians, and Hispanics. Approximately 40%
      of the sample was women. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES:
      The primary outcome measures included 2 measures of SWB (Life Situation
      Questionnaire-Revised, Older Adult Health and Mood Questionnaire), 1 measure of
      participation (Craig Handicap Assessment and Reporting Technique), and several
      items from the Behavioral Risk Factor Surveillance System. RESULTS: The majority
      of racial and ethnic differences in SWB related to specific life areas (eg,
      economics, employment), rather than more global outcomes (eg, engagement,
      health), with whites generally reporting the best outcomes, followed by African
      Americans. American Indians, and whites generally reported the highest
      participation scores, whereas limited differences were noted between the racial
      and ethnic groups on health indicators. Women reported lower satisfaction with
      health, more poor mental health days, and lower SWB related to home life, but
      higher SWB related to interpersonal relations. CONCLUSIONS: There are racial and
      ethnic differences in outcomes after SCI focused primarily on subjective outcomes
      in areas in which racial and ethnic minorities have traditionally been
      disadvantaged. The results of this study direct rehabilitation professionals to
      the outcomes that need to be targeted for intervention to eliminate inequities in
      outcomes for all persons with SCI.

PMID- 15031818
TI  - Aging, gender, and spinal cord injury.
AB  - OBJECTIVE: To identify differences in the aging experiences of men and women with
      spinal cord injury (SCI). DESIGN: This study is part of a longitudinal
      international study of aging and SCI. SETTING: Five centers in England, Canada,
      and the United States. Three were spinal cord rehabilitation facilities (Stoke
      Mandeville Hospital, Southport Hospital, Craig Hospital) and 2 were community
      agencies (Ontario and Manitoba divisions of the Canadian Paraplegic Association).
      PARTICIPANTS: A matched sample of 67 men and 67 women with SCI for at least 20
      years. The 2 groups were matched on age, country of origin, and duration of
      disability. Participants had an average age of 57 years and an average disability
      duration of almost 33 years. INTERVENTIONS: Not applicable. MAIN OUTCOME
      MEASURES: Two measures were taken by interview: demographic form and current
      status interview. Five others were self-administered and returned by mail: the
      Perceived Stress Scale, Craig Handicap Assessment and Reporting Technique, Index
      of Psychological Well-Being, Current Problem Questionnaire, and Life Satisfaction
      Index. RESULTS: Although both sexes rated their quality of life about equally,
      women characterized their aging experience as "accelerated," while men
      characterized it as "complicated." Women reported more effects of pain, fatigue,
      and skin problems and more transportation problems. Men experienced more health
      problems, more diabetes, and more adaptive equipment changes. Older men and women
      with SCI spent their time differently, consistent with traditional gender roles.
      CONCLUSIONS: These results underline the need for gender-specific consideration
      of aging experiences associated with SCI and further emphasize the need for
      primary and preventive care to promote health and well-being as people with SCI
      survive into old age.

PMID- 15031819
TI  - Medical procedures, complications, and outcomes for patients with spinal cord
      injury: A multicenter investigation comparing African Americans and whites.
AB  - OBJECTIVE: To examine the role of race on rehabilitation outcomes for a matched
      sample of patients with spinal cord injury (SCI). DESIGN: African Americans and
      whites with SCI were matched based on age group, level and completeness of
      injury, and sponsor of care to retrospectively analyze the impact of race.
      SETTING: Eighteen medical centers in the federally sponsored Model Spinal Cord
      Injury Systems project. PARTICIPANTS: A total of 628 adults with SCI.
      INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Medical procedures and
      complications; American Spinal Injury Association motor index, and FIMT
      instrument scores at admission and discharge; and discharge dispositions.
      RESULTS: Analysis revealed race-related differences in spinal surgeries,
      laparotomies, traction during acute care, and method of bladder management at
      discharge. In most cases, these were explained by cause of injury rather than
      direct affects of race. No differences were found with regard to medical
      complications functional outcomes, or discharge disposition. CONCLUSIONS:
      Although differences exist in the medical procedures given to African Americans
      and whites with SCI, they are generally accounted for by cause of injury rather
      than the direct affects of race.

PMID- 15031820
TI  - Sex differences in injury severity and outcome measures after traumatic brain
      injury.
AB  - OBJECTIVE: To investigate the effect of a patient's sex on various measures of
      injury severity and outcome after rehabilitation in a matched sample of patients
      with traumatic brain injury (TBI). DESIGN: Retrospective data were retrieved from
      a database that contains information routinely collected on all patients admitted
      for inpatient rehabilitation. SETTING: Inpatient rehabilitation unit of major
      teaching hospital in Australia. PARTICIPANTS: Fifty-four women with TBI after a
      motor vehicle crash (MVC) were identified from the Brain Injury Rehabilitation
      Database. An equal number of men were then matched for age and years of
      education. All subjects met the study admission criteria of having being involved
      in a high-speed MVC. Exclusion criteria included history of a previous head
      injury, chronic amnesia, psychiatric disturbance, and significant alcohol and/or
      substance abuse. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES:
      Differences, by sex, in patient scores on measures of injury severity and outcome
      after TBI. RESULTS: Men had significantly greater levels of injury severity as
      indicated by the Glasgow Coma Scale scores (U=994.0, P=.002) and length of
      posttraumatic amnesia (U=880.0, P=.016) when compared with women. No significant
      sex differences existed in the outcome measures or in injuries not associated
      with the central nervous system. CONCLUSIONS: Few investigations exist on the
      effect of patient sex on measures of injury severity and outcome after a TBI. In
      the present study, men's levels of injury severity were greater than women's
      despite the same admission criteria (high-speed MVC) being applied to both sexes.

PMID- 15031821
TI  - The Pittsburgh Rehabilitation Participation Scale: reliability and validity of a
      clinician-rated measure of participation in acute rehabilitation.
AB  - OBJECTIVE: To demonstrate interrater reliability and predictive validity of the
      Pittsburgh Rehabilitation Participation Scale (PRPS), a clinician-rated 6-point
      Likert-type item measuring patient participation in inpatient rehabilitation
      sessions. DESIGN: Prospective measurement of patient participation in physical
      and occupational therapy sessions during inpatient rehabilitation. SETTING:
      University-based, freestanding acute rehabilitation hospital. PARTICIPANTS: Two
      hundred forty-two inpatients, primarily elderly, with a variety of impairment
      diagnoses (eg, stroke), who were admitted for inpatient rehabilitation.
      INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Change in the 13 motor
      items from the FIM trade mark instrument, from admission to discharge. RESULTS:
      The PRPS had high interrater reliability (intraclass correlation coefficient
      [ICC]=.91 for occupational therapists; ICC=.96 for physical therapists). The
      subjects had mean PRPS scores +/- standard deviation of 4.73+/-0.76. Mean PRPS
      scores predicted rehabilitation outcome (N=242, r=.32, P<.0001), as measured by
      change in motor FIM. The strength of this association did not change in a
      multivariate model that controlled for age, gender, race, impairment group,
      medical comorbidity count, length of stay, and admission FIM. CONCLUSIONS:
      Patient participation during acute inpatient rehabilitation can be easily and
      reliably measured, and PRPS scores predict functional outcome. The PRPS may have
      applicability in clinical and research outcome measurement.

PMID- 15031822
TI  - Life-long morbidity among Danes with poliomyelitis.
AB  - OBJECTIVE: To estimate long-term morbidity in a cohort of Danish poliomyelitis
      patients. DESIGN: A historical prospective cohort study of 27,047 persons.
      SETTING: Denmark. PARTICIPANTS: A total of 5421 persons hospitalized for
      poliomyelitis between 1919 to 1954 in Copenhagen, Denmark, and 21,626 age- and
      gender-matched Danes. Participants were followed up on average for 20.6 years,
      yielding a total of 555,884 person-years of follow-up. INTERVENTIONS: Not
      applicable. MAIN OUTCOME MEASURES: The exposed (poliomyelitis) cohort and the
      unexposed (control) cohort were followed up for somatic hospitalization from 1977
      to 1999 in the Danish Hospital Discharge Register. The incidence rate ratio (IRR)
      was calculated as the ratio between the incidence rate of disease in the exposed
      and unexposed cohorts. RESULTS: Overall, polio patients had a 1.2- to 1.3-fold
      increased risk of being hospitalized with pulmonary diseases, heart diseases,
      gastrointestinal disorders, or diseases of the locomotive apparatus. Among
      paralytic polio patients, long-term morbidity seems to be associated with the
      acute severity of poliomyelitis, as well as young age at infection. Paralytic
      patients, who contracted respiratory polio under the age of 5, had the highest
      risk of being hospitalized with lung diseases (IRR=7.26; 95% confidence interval
      [CI], 3.06-18.33), diseases of the locomotive apparatus (IRR=4.05; 95% CI, 1.66
      9.86), heart diseases (IRR=1.70; 95% CI, 0.65-3.98), and diseases of the
      digestive system (IRR= 2.23; 95% CI, 1.03-4.62). Surprisingly, patients without
      paralyses, especially women, also had an increased morbidity. CONCLUSIONS:
      Overall, a history of poliomyelitis was associated with a slightly increased
      morbidity measured by hospitalizations. Long-term morbidity was highest among
      respiratory polio patients; however, patients presumably left without any
      residual symptoms also had an increased morbidity.

PMID- 15031823
TI  - A comparison of 4 questionnaires to measure fatigue in postpoliomyelitis
      syndrome.
AB  - OBJECTIVE: To assess the comparability and reproducibility of 4 questionnaires
      used to measure fatigue in postpoliomyelitis syndrome (PPS). DESIGN: Repeated
      measures at a 3-week interval. SETTING: University hospital. PARTICIPANTS:
      Convenience sample of 65 patients with PPS. INTERVENTIONS: Not applicable. MAIN
      OUTCOME MEASURES: The Fatigue Severity Scale (FSS), the Nottingham Health Profile
      (NHP) energy category, the Polio Problem List (PPL) fatigue item, and the Dutch
      Short Fatigue Questionnaire (SFQ). RESULTS: Correlations of scores between
      questionnaires were all significant (P<.01) and ranged from.43 (between the NHP
      energy category and the PPL fatigue item) to.68 (between the PPL fatigue item and
      the SFQ). Scores on the second visit, normalized to a 0 to 100 scale, were: FSS,
      78+/-15; NHP energy category, 47+/-35; PPL fatigue item, 81+/-17; and SFQ, 65+/
      22. Except for the difference between the FSS and the PPL fatigue item, the
      differences in scores between the questionnaires were significant (P<.01). Scale
      analysis indicated that all questionnaires measured the same unidimensional
      construct. The reproducibility of the FSS, the PPL fatigue item, and the SFQ was
      moderate. The smallest detectable change was 1.5 points for the FSS, 2.0 points
      for the PPL fatigue item, and 1.9 points for the SFQ. CONCLUSIONS: Although the
      questionnaires measure the same fatigue construct in PPS, the results are not
      interchangeable because the ranges of measurement differ. The NHP energy
      category, in particular, appeared to have a high detection threshold. The
      moderate reproducibility of the questionnaires indicates a lack of precision,
      especially when applied at the individual patient level.

PMID- 15031824
TI  - A new instrument for outcome assessment in rehabilitation medicine: Spinal cord
      injury ability realization measurement index.
AB  - OBJECTIVES: To introduce a new measure of disability weighted for the neurologic
      deficit in patients with spinal cord lesions and to examine the effect on the
      instrument of being in rehabilitation. DESIGN: Development of instrument and
      preliminary comparative before-after study. SETTING: Spinal department in a
      rehabilitation hospital in Israel. PARTICIPANTS: Seventy-nine patients with
      spinal cord lesions. INTERVENTIONS: Patients were repeatedly assessed during
      rehabilitation with the American Spinal Injury Association Impairment Scale (AIS)
      to measure neurologic motor impairment and with the Spinal Cord Independence
      Measure (SCIM-II) to measure disability. Scores of the 2 assessments were
      combined to create the Spinal Cord Injury Ability Realization Measurement Index
      (SCI-ARMI). MAIN OUTCOME MEASURES: A preliminary formula for the calculation of
      SCI-ARMI using the individual patients' SCIM-II and AIS motor scores and changes
      in SCI-ARMI values through rehabilitation. RESULTS: The highest observed SCIM-II
      scores at patients' AIS level correlated highly with the AIS motor scores (r=.96,
      P<.01). A regression performed for this linear relationship resulted in a
      preliminary SCI-ARMI formula. The calculated SCI-ARMI values improved during
      rehabilitation irrespective of patient age, gender, lesion level, or lesion
      severity (P<.001). CONCLUSIONS: The preliminary version of the SCI-ARMI can be
      used to assess quantitatively changes in functional ability, isolating them from
      the effect of neurologic changes.

PMID- 15031825
TI  - Optimal interelectrode distance in sensory and mixed compound nerve action
      potentials: 3- versus 4-centimeter bar electrodes.
AB  - OBJECTIVE: To evaluate the amplitude and latency for 3-cm versus 4-cm distance
      between the active and reference electrodes (electrode separation) used to obtain
      normative sensory and mixed compound nerve action potential data. DESIGN:
      Prospective, unblinded clinical test evaluating 3 nerves: mixed median and ulnar
      across wrist (8 cm), and radial antidromic sensory (10 cm). SETTING: University
      and private practice electrodiagnostic laboratories. PARTICIPANTS: One hundred
      six adult volunteers without known neuropathy. INTERVENTIONS: Not applicable.
      MAIN OUTCOME MEASURES: Peak-to-peak amplitude and onset and peak latencies.
      RESULTS: Mean onset latencies +/- standard deviation (SD) were equal for 3-cm and
      4-cm separations (median, 1.6+/-0.2 ms; radial, 1.7+/-0.2 ms; ulnar, 1.5+/-0.2
      ms). Mean peak latencies were also equal for 3-cm and 4-cm separation for radial
      (2.2+/-0.2 ms) and ulnar (1.9+/-0.2 ms) studies but differed for the median study
      (3 cm, 2.0+/-0.3 ms; 4 cm, 2.1+/-0.3 ms; P<.0001). Mean amplitudes +/- SD with 3
      cm and 4-cm separations were, respectively, 101+/-39 microV and 103+/-39 microV
      (P=.0434) for the median, 47+/-17 microV and 48+/-16 microV (P=.0209) for the
      radial, and 52+/-28 microV and 55+/-29 microV (P=.0001) for the ulnar study.
      These differences were statistically significant but clinically insignificant.
      CONCLUSIONS: The results support a hypothesized difference in amplitude but not
      latency between 3- and 4-cm separation. Clinically, however, the magnitude was
      insignificant.

PMID- 15031826
TI  - A comparison of true and premodulated interferential currents.
AB  - OBJECTIVE: To compare true and premodulated interferential currents (IFCs) in
      terms of sensory, motor, and pain thresholds; maximum electrically induced torque
      (MEIT); and comfort. DESIGN: Repeated-measures design. SETTING: Laboratory
      setting. PARTICIPANTS: University student and staff volunteers. INTERVENTIONS:
      Participants were exposed to 4 different conditions, chosen to evaluate 2
      fundamental differences between true and premodulated IFCs. The conditions were
      different combinations of (1) premodulated or constant-amplitude currents applied
      at the skin and (2) crossed or parallel current paths. MAIN OUTCOME MEASURES:
      Sensory, motor, and pain thresholds; MEIT; and subjective reports of relative
      discomfort were recorded for each of the 4 conditions. Motor to sensory threshold
      ratios were subsequently calculated to assess depth efficiency of stimulation.
      RESULTS: The major findings were that crossed currents (true IFC) had no
      advantage over parallel currents (premodulated IFC) in terms of motor to sensory
      threshold ratio, MEIT, or comfort, and that premodulated currents produced higher
      torque values and less discomfort than constant-amplitude currents (true IFC).
      These results contradict the claimed superiority of true IFC. CONCLUSIONS: The
      findings indicate that premodulated IFC, delivered via 2 large electrodes, may be
      clinically more effective than the traditional true IFC arrangement in terms of
      depth efficiency, torque production, and patient comfort.

PMID- 15031827
TI  - The wheelchair skills test, version 2.4: Validity of an algorithm-based
      questionnaire version.
AB  - OBJECTIVE: To test the hypothesis that an algorithm-based questionnaire version
      of the Wheelchair Skills Test (WST) would provide a valid assessment of manual
      wheelchair skills. DESIGN: Within-participant comparisons. SETTING:
      Rehabilitation center in Nova Scotia, Canada. PARTICIPANTS: Twenty wheelchair
      users, 11 with musculoskeletal and 9 with neurologic disorders, with a wide range
      of wheelchair experience (1wk-20y). INTERVENTION: Each participant completed the
      questionnaire (WST-Q) and then the objective skills testing (WST, version 2.4).
      MAIN OUTCOME MEASURE: The WST-Q consisted of 3 components, reported as separate
      versions: the knowledge version (WST-Q [K]) (structured oral questions only); the
      visual-aid version (WST-Q [VA]) (visual aids added for 6 of the skills); and the
      categorical perceived-ability version (WST-Q [PA]). RESULTS: The mean total
      percentage scores for the WST-Q (K), WST-Q (VA), WST-Q (PA), and WST were 60.5%,
      62.2%, 64.0%, and 59.8%, respectively. Only the WST-Q (PA) differed significantly
      from the WST (P<.05). Positive correlations existed between the objective WST and
      the WST-Q (K) (r=.91), WST-Q (VA) (r=.91), and WST-Q (PA) (r=.83). The percentage
      agreement on the individual skill scores ranged from 55% to 100%. CONCLUSIONS:
      The algorithm-based WST-Q has excellent concurrent validity in comparison with
      objective testing, when assessing the overall manual wheelchair skill levels of
      wheelchair users with a wide range of experience. It may be useful as a screening
      tool or when objective testing is impractical.

PMID- 15031828
TI  - The Wheelchair Circuit: Construct validity and responsiveness of a test to assess
      manual wheelchair mobility in persons with spinal cord injury.
AB  - OBJECTIVE: To assess the validity and responsiveness of the Wheelchair Circuit, a
      test to assess manual wheelchair mobility in persons with spinal cord injury
      (SCI). DESIGN: Longitudinal. Subjects performed the Wheelchair Circuit at the
      start (T1) and at the end (T3) of inpatient functional rehabilitation. Construct
      validity and responsiveness were assessed. SETTING: Eight rehabilitation centers
      in the Netherlands. PARTICIPANTS: Seventy-four subjects with SCI admitted for
      inpatient rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES:
      The Wheelchair Circuit consists of 8 wheelchair skills and results in 3 test
      scores: ability, performance time, and physical strain. The construct validity of
      the Wheelchair Circuit was assessed by testing whether the test scores were
      significantly related to the subjects' functional status, physical capacity,
      lesion level, motor completeness of the lesion, and age. To prove the test's
      responsiveness, it was assessed whether the test scores had significantly
      improved between T1 and T3. RESULTS: For construct validity, 4 of the 5
      hypotheses were confirmed. For test responsiveness, all 3 test scores had
      significantly improved during rehabilitation, and the standardized response mean
      values ranged from 0.6 to 0.9. CONCLUSIONS: The Wheelchair Circuit is a valid and
      responsive instrument with which to measure manual wheelchair mobility in
      subjects with SCI.

PMID- 15031829
TI  - Quantitative posturography in altered sensory conditions: a way to assess balance
      instability in patients with chronic whiplash injury.
AB  - OBJECTIVES: To quantify neck mobility and posture with and without various
      postural perturbations. DESIGN: A multivariable 2-group study with repeated
      measures and treatments. SETTING: A human performance laboratory. PARTICIPANTS:
      Eleven patients with chronic whiplash injury (mean age, 33.3+/-6.7 y; weight,
      73.4+/-11.4 kg; height, 173.3+/-7.2 cm) with a sex- and age-matched control group
      (mean age, 33.1+/-6.8 y; weight, 68+/-12.5 kg; height, 171.5+/-6.3 cm).
      INTERVENTIONS: Neck mobility and the effects of postural perturbations affecting
      the visual, vestibular, cutaneous, proprioceptive, and nociceptive systems were
      measured. MAIN OUTCOME MEASURES: Active range of motion, neck position sense, and
      postural activity. RESULTS: We found significantly reduced neck mobility and
      increased postural activity in the patient group compared with the control group.
      In patients, there was significantly greater postural activity with eyes closed,
      eyes open and speaking, and eyes closed with Achilles' tendons vibrations
      compared with eyes open with no vibrations. In the controls, there was no
      significant effect of experimental muscle pain on postural activity. CONCLUSIONS:
      Patients with chronic whiplash injury had a protective response to neck movement
      and different tuning, sequencing, and execution of the postural synergies
      probably because of excessive reliance on visual input despite a possible deficit
      and altered vestibular and/or proprioceptive activity. In healthy volunteers, the
      pain induced by a single bolus injection of hypertonic saline was probably too
      limited in intensity and spreading to decrease postural stability.

PMID- 15031830
TI  - The influence of footwear on timed balance scores of the modified clinical test
      of sensory interaction and balance.
AB  - OBJECTIVES: To determine if timed balance scores on the modified Clinical Test of
      Sensory Interaction and Balance (CTSIB) were affected by shoe wear in patients
      with balance and vestibular disorders and to determine if there is a difference
      in correlation with the Sensory Organization Test (SOT) or in the sensitivity or
      specificity based on footwear. DESIGN: Prospective correlational trial. SETTING:
      Outpatient clinic. PARTICIPANTS: Thirty persons (mean age, 63+/-17 y) currently
      undergoing vestibular physical therapy (PT). INTERVENTION: All subjects completed
      the modified CTSIB with their shoes on and off at the end of a PT session; 16 of
      them (53%) also completed the SOT on the same day. MAIN OUTCOME MEASURES: Scores
      on the modified CTSIB and SOT. RESULTS: No difference existed between scores on
      the modified CTSIB with shoes on versus off. Similar correlation was found
      between the modified CTSIB performed with the shoes on and off and SOT scores.
      The sensitivity and specificity of the modified CTSIB was similar with shoes on
      and off. CONCLUSIONS: The modified CTSIB can be performed with or without shoes,
      with no difference expected in patient score or test sensitivity or specificity.

PMID- 15031831
TI  - Children show decreased dynamic balance after mild traumatic brain injury.
AB  - OBJECTIVE: To compare the balance skills of children after mild traumatic brain
      injury (TBI) with that of noninjured children matched for age, sex, and premorbid
      level of physical activity. DESIGN: Cohort study. SETTING: Pediatric trauma
      center. PARTICIPANTS: Thirty-eight children aged 7 to 16 years (mean, 12.2+/-2.8
      y) were recruited in each group. Children with mild TBI had a mean Glasgow Coma
      Scale score of 14.8 and were considered normal on a neurologic assessment at
      hospital discharge. Noninjured children were friends of those with mild TBI.
      INTERVENTION: Assessments of balance were conducted at 1, 4, and 12 weeks after
      mild TBI and at corresponding time intervals for the controls. MAIN OUTCOME
      MEASURES: The balance subtest of the Bruininks-Oseretsky Test of Motor
      Proficiency (BOTMP), the Pediatric Clinical Test of Sensory Interaction for
      Balance (P-CTSIB), and the Postural Stress Test (PST) were used. RESULTS: Over
      the time interval of the study, analyses of variance revealed that children with
      mild TBI performed significantly worse than the noninjured group on the BOTMP
      balance subtest (P<.001) and on the PST (P=.031), as well as on the eyes-closed
      conditions in the P-CTSIB tandem position (P=.05). CONCLUSIONS: Children with a
      mild TBI still showed balance deficits at 12 weeks postinjury. These deficits
      should be taken into consideration when planning a return to physical activities,
      particularly to those that require subtle balance skills.

PMID- 15031832
TI  - Colonic transit time and constipation in children with spastic cerebral palsy.
AB  - OBJECTIVES: To evaluate colonic motility and to investigate contributing factors
      to colonic dysmotility in children with spastic cerebral palsy (CP). DESIGN:
      Cross-sectional study. SETTING: A university-based rehabilitation hospital.
      PARTICIPANTS: Thirty-eight children with spastic CP. INTERVENTIONS: Not
      applicable. MAIN OUTCOME MEASURES: Colonic transit time was measured by using a
      Sitzmarks. The nutrient intake during 3 consecutive days was analyzed by using
      the ESHA Food Processor program. RESULTS: A significant relationship between
      colon transit time and stool frequency was observed (P<.05). All children with
      constipation and 17 (60.8%) of 28 without constipation showed an abnormal
      segmental colon transit time in at least 1 segment of the colon. A transit time
      delay at the proximal segment of colon was remarkable in CP children with
      constipation. In children without constipation, a transit time delay was marked
      at the rectosigmoid colon only. Constipation and transit time delay were
      significantly related to ambulatory function (P<.05). CONCLUSIONS: A transit time
      delay at total or segmental colon was frequently observed in children with CP.
      Constipation and colonic motility were related to ambulatory function.

PMID- 15031833
TI  - Selective dorsal rhizotomy versus orthopedic surgery: a multidimensional
      assessment of outcome efficacy.
AB  - OBJECTIVE: To compare the efficacy of selective dorsal rhizotomy (SDR) and
      orthopedic surgery using multidimensional (National Center for Medical
      Rehabilitation Research disablement framework) outcome measures. DESIGN:
      Prospective outcome study. SETTING: Pediatric orthopedic hospital. PARTICIPANTS:
      Twenty-five children with spastic diplegia. Eighteen participants (mean age, 71.3
      mo) chose SDR. Seven participants (mean age, 78.6 mo) chose orthopedic surgery.
      INTERVENTIONS: Children were evaluated 2 days before surgical intervention and at
      6 months, 1 year, and 2 years postsurgically. MAIN OUTCOME MEASURES: The Gross
      Motor Performance Measure, the Gross Motor Function Measure, and the Pediatric
      Evaluation of Disability Inventory. RESULTS: The SDR group improved significantly
      in quality of movement attributes 6 months postsurgically; however, gross motor
      skills (standing; walking, running, and jumping) gains were seen 2 years
      postsurgically. The orthopedic group improved significantly in select quality of
      movement attributes 6 months postsurgically and in standing skills within the
      first postsurgical year. Self-care skills, mobility, and social function gains
      were seen earlier and with greater frequency in the SDR group. CONCLUSIONS: Both
      surgical interventions demonstrated multidimensional benefits for ambulatory
      children with spastic diplegia. The results suggest that qualitative changes in
      movement, achieved by spasticity reduction, have a greater effect on the
      enhancement of functional skill proficiency, thus independence, than recognized.

PMID- 15031834
TI  - Medical complications experienced by a cohort of stroke survivors during
      inpatient, tertiary-level stroke rehabilitation.
AB  - OBJECTIVE: To identify the most common medical complications experienced by
      stroke survivors during inpatient, tertiary-level stroke rehabilitation. DESIGN:
      Prospective, descriptive analysis. SETTING: A tertiary-level, 23-bed, inpatient
      stroke rehabilitation unit in Nova Scotia, Canada. PARTICIPANTS: All stroke
      survivors (N=133) admitted for tertiary-level stroke rehabilitation during a 1
      year period. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The attending
      physiatrist determined the presence or absence of specific complications during
      the interdisciplinary team conference held during the week of discharge for each
      patient. RESULTS: The 4 most common medical complications were depression (26%),
      shoulder pain (24%), falls (20%), and urinary tract infection (UTI) (15%). Other
      less common complications included back and hip pain (5%), gastrointestinal
      disturbances (4%), and pneumonia (2%). Seizures, pressure ulcers, and shoulder
      hand syndrome each occurred in 1.5% of the population. CONCLUSIONS: Depression,
      shoulder pain, falls, and UTIs are common complications experienced by stroke
      survivors during inpatient rehabilitation. Heightened awareness of these
      potential complications may lead to prevention or to earlier recognition and
      improved management of these conditions.

PMID- 15031835
TI  - Involvement of sympathetic reflex activity in patients with acute and chronic
      stroke: A comparison with functional motor capacity.
AB  - OBJECTIVE: To investigate sympathetic nervous system functions in patients with
      acute and chronic phase of stroke by measuring sympathetic skin reflex (SSR) and
      the relationship between sympathetic dysfunction and motor function capacity.
      DESIGN: Cross-sectional, case-control study. SETTING: A physical medicine and
      rehabilitation department in a research hospital of a university referral center
      in Turkey. PARTICIPANTS: Fifty-six patients with stroke-13 in the acute phase and
      43 in the chronic phase-and 42 age- and sex-matched healthy volunteers were
      included. INTERVENTION: SSR was recorded with electric stimulation of the
      bilateral median nerves. MAIN OUTCOME MEASURES: SSR was recorded to assess
      sympathetic reflex activity in patients in the acute and chronic phase of stroke
      and in controls. Motor functions was classified using the Brunnstrom stages.
      RESULTS: The mean SSR latency in the acute phase was significantly prolonged and
      the amplitudes were decreased compared with controls. In the chronic phase, the
      mean amplitudes were significantly attenuated compared with controls, whereas the
      mean latency did not change. The mean latency of SSR in patients in Brunnstrom
      groups 1 and 2 was longer, and the mean amplitude was smaller than in controls
      (P<.05). The mean amplitude was significantly reduced in patients classified as
      Brunnstrom groups 3 and 4 compared with controls (P<.05), but the mean latency
      was not affected. CONCLUSIONS: Depression of sympathetic reflex activity was more
      prominent in the acute phase of stroke and was associated with moderate or highly
      limited motor function capacity. Improvement of motor dysfunction may parallel
      recovery of sympathetic reflex activity.

PMID- 15031836
TI  - Acquired brain injury, visual attention, and the useful field of view test: A
      pilot study.
AB  - OBJECTIVE: To compare the findings of the Useful Field of View (UFOV) test with
      those of conventional neuropsychologic tests to determine the utility of the UFOV
      test as a measure of attention in a population with brain injury. DESIGN: Cohort
      study. SETTING: Freestanding rehabilitation hospital. PARTICIPANTS: Fifteen
      inpatients with severe brain injury. INTERVENTIONS: Not applicable. MAIN OUTCOME
      MEASURES: UFOV test, FIM?T instrument, length of stay (LOS), and standard
      neuropsychologic testing. RESULTS: The UFOV subtest UF2 correlated strongly with
      the other 2 subtests, UF1 and UF3. The UF2 subtest correlated most strongly with
      paper and pencil tests of visual attention. The UF2 predicted 52% of the FIM
      change and 60% of the LOS variance, second only to admission FIM score, which
      predicted 75% and 80% of FIM change and LOS variance, respectively. CONCLUSIONS:
      Among the patients in our study, the UFOV test can be used to determine the
      visual divided attention of patients with acquired brain injury. The results also
      showed that the UFOV test correlated with LOS and FIM change in patients with
      acquired brain injury recovering in a rehabilitation facility. Because the UFOV
      test is much more quickly administered and scored than other measures of
      attention and divided attention, these results suggest that the UFOV test may
      provide an easy means to measure a critical variable in the population with head
      injury.

PMID- 15031837
TI  - Treatment of lumbar spinal stenosis with epidural steroid injections: a
      retrospective outcome study.
AB  - OBJECTIVE: To determine patient satisfaction, relief of pain, frequency of
      injections, change of function, and subsequent surgical rate in patients who
      received epidural steroid injections (ESIs) for the diagnosis of lumbar spinal
      stenosis (LSS). DESIGN: Retrospective review conducted using a standard set of
      questions asked over the telephone, 6 to 36 months after the patient received an
      ESI. SETTING: An outpatient spine center. PARTICIPANTS: One hundred forty
      patients at or over the age of 55 years diagnosed with LSS who received ESI(s).
      INTERVENTION: Transforaminal or caudal fluoroscopically guided ESIs with 60 to
      100mg of triamcinalone in combination with local anesthetic or normal saline.
      Main outcome measures Duration and amount of pain relief, change in functional
      status, patient satisfaction, and surgical rate, assessed by a 5-item
      questionnaire. RESULTS: Of the 140 participants, 32% reported more than 2 months
      of pain relief, 39% reported less than 2 months of pain relief, and 29% reported
      no relief from the injection(s). Twenty percent subsequently had surgery. Fifty
      three percent reported improvement in their functional abilities. Seventy-four
      percent where at least somewhat satisfied with ESI as a form of treatment.
      CONCLUSIONS: ESI is a reasonable treatment for LSS, providing one third of our
      patient population with sustained relief and more than half with sustained
      improvement in function.

PMID- 15031838
TI  - Neurologic recovery of spinal cord injury patients in Italy.
AB  - OBJECTIVE: To evaluate neurologic recovery of spinal cord lesion patients and its
      relationship to some lesion and patient features. DESIGN: Retrospective review of
      the charts. SETTING: Rehabilitation hospital in Italy. PARTICIPANTS: A total of
      284 consecutive, newly injured patients were included with evaluation of lesion
      to admission time, etiology, lesion level, associated injury, medical
      complications and surgical intervention, length of stay, and American Spinal
      Injury Association (ASIA) impairment grade and motor scores. INTERVENTIONS: Not
      applicable. MAIN OUTCOME MEASURES: ASIA impairment grade and motor scores.
      RESULTS: Neurologic recovery was present in 27% of the patients. Most patients
      who improved and reached a functional status (ASIA class D) had an ASIA class C
      impairment at admission (71/129), versus ASIA class A (2/84) and ASIA class B
      (5/19). The lesion-to-admission interval was significantly longer in patients who
      did not improve (73+/-51.2d vs 47.2+/-38.4d, P=.006). CONCLUSIONS: ASIA
      impairment designations have prognostic value. Recovery from complete lesions was
      limited. Patients with ASIA class B impairment at admission had a better
      prognosis than those with ASIA class A. Patients with ASIA class C at admission
      had the best neurologic improvement. Finally, ASIA class D patients had lower
      ASIA grade improvement. Neurologic recovery was negatively associated with
      patients' age and delayed rehabilitation, but not by other lesion features.

PMID- 15031839
TI  - A new clinical test for cervicocephalic kinesthetic sensibility: "the fly".
AB  - OBJECTIVE: To investigate the reliability and discriminative ability of a new
      test designed to detect accuracy of neck movements. DESIGN: Repeated-measures.
      Case-control. SETTING: University musculoskeletal research clinic in Iceland.
      PARTICIPANTS: Twenty women (mean age +/- standard deviation [SD], 30.8+/-9.1 y;
      range, 18-49 y) with chronic whiplash-associated disorders (WAD) grades I and II
      (duration, 6 mo-6 y), with current pain score on a visual analog scale of 46.8+/
      21.8, and a disability score on the Northwick Park Neck Pain Disability Index of
      45%+/-14%. Twenty asymptomatic women (mean age +/- SD, 29.3+/-8.6 y; range, 18-48
      y) with no history of whiplash or insidious onset neck pain served as controls.
      INTERVENTION: A slowly moving object appeared on a computer screen and traced an
      unpredictable movement path that the subjects were required to follow by moving
      their heads. Three randomly ordered movement patterns were tested. MAIN OUTCOME
      MEASURE: A new software program connected to a 3Space Fastrak system was used to
      measure the mean absolute error (in millimeters) of 3 trials in each movement
      pattern. RESULTS: The mean differences (+/-2 SD) between days 1 and 2 were.01+/
      .64 mm for the asymptomatic group and.33+/-1.80 mm for the WAD group. The between
      day intraclass correlation coefficients were between.60 and.77 for the
      asymptomatic group and.79 and.86 for the WAD group. Repeated-measures analysis of
      variance revealed a significant difference between groups (P=.02). The Tukey post
      hoc test showed significant between-group differences for each movement pattern
      (P</=.05). In each successive trial, a slight improvement for the asymptomatic
      group and a slight worsening for the WAD group were detected. CONCLUSIONS: Better
      reliability was detected for the asymptomatic group than for the WAD group. The
      test could discriminate between the asymptomatic group versus the chronic WAD
      group.

PMID- 15031840
TI  - Predictive value of fear avoidance in developing chronic neck pain disability:
      consequences for clinical decision making.
AB  - OBJECTIVE: To improve clinical decision making in posttraumatic neck pain by
      investigating the additional value of fear-avoidance variables in predicting
      chronic neck pain disability. DESIGN: An inception cohort with baseline
      assessment 1 week posttrauma and outcome assessment 24 weeks posttrauma.
      Predictive factors include pain intensity, Neck Disability Index (NDI),
      catastrophizing, fear of movement (Tampa Scale for Kinesiophobia [TSK]), and
      avoidance muscle behavior. SETTING: Hospital emergency department of a general
      hospital. PARTICIPANTS: A consecutive sample of 90 people reporting of pain in
      neck or head region after a motor vehicle collision. Eighty-two subjects (91.1%)
      of the sample provided 24-week follow-up on the outcome. INTERVENTIONS: Not
      applicable. MAIN OUTCOME MEASURE: The NDI assessing physical disability of
      subjects with neck pain. RESULTS: By using a combination of the baseline NDI and
      TSK, it appears to be possible to predict chronic disability with a probability
      of 54.3% (95% confidence interval [CI], 35.2%-72.3%) after entering the NDI
      (cutoff, 15) as a first test, and with a probability of 83.3% (95% CI, 70.3%
      91.3%) after entering the TSK (cutoff, 40) in a second test. CONCLUSIONS: A
      simple rating of baseline neck pain disability within a week of the trauma,
      separately or in combination with a test for fear of movement, can be used to
      predict future outcome. Patients showing fear of movement can be offered an
      intervention that focuses on reduction of this fear.

PMID- 15031841
TI  - Delayed postanoxic encephalopathy: a case report and literature review.
AB  - Delayed postanoxic encephalopathy is a rare condition in which patients appear to
      make a complete clinical recovery after an episode of anoxia or hypoxia but then
      develop a relapse characterized by apathy, confusion, agitation, and/or
      progressive neurologic deficits. The incidence of delayed postanoxic
      encephalopathy is unclear but has been reported to range from less than 1 to 28
      per 1000 in patients who have suffered hypoxic or anoxic events. The exact
      pathogenesis remains unknown. We describe a case of an independently living 51
      year-old woman admitted to an inpatient rehabilitation unit 11 days after a
      respiratory arrest. At admission, she exhibited cognitive and visual deficits
      that were relatively mild but prevented a safe return to independent living. Two
      days later, she developed the sudden onset and rapid worsening of parkinsonian
      symptoms and excruciating bilateral lower-extremity pain. The pain was
      intractable, and over the next 2 days she progressed to being unable to walk or
      perform her activities of daily living without maximum assistance. A diagnosis of
      delayed postanoxic encephalopathy was made, and the patient responded to a trial
      of carbidopa and levodopa as well as redirection of her physical and occupational
      therapy programs. This case illustrates the unusual presentation of delayed
      postanoxic encephalopathy during inpatient rehabilitation and suggests that this
      condition should be considered if patients who have suffered an anoxic or hypoxic
      event show a sudden neurologic deterioration.

PMID- 15031842
TI  - Alcohol neurolysis of tibial nerve motor branches to the gastrocnemius muscle to
      treat ankle spasticity in patients with hemiplegic stroke.
AB  - OBJECTIVE: To evaluate the effectiveness of alcohol neurolysis of tibial nerve
      motor branches to the gastrocnemius muscle for the treatment of ankle
      plantarflexor spasticity in patients with hemiplegic stroke. DESIGN: Case series.
      SETTING: Inpatient and outpatient clinics in the rehabilitation department of a
      university hospital. PARTICIPANTS: Twenty-two patients with hemiplegic stroke
      (mean age, 48y). INTERVENTIONS: Motor branch block (MBB) of the tibial nerve to
      the gastrocnemius muscle with 50% ethyl alcohol in cases of spastic ankle. MAIN
      OUTCOME MEASURES: The severity of spasticity was assessed using the Modified
      Ashworth Scale (MAS) score of ankle plantarflexor, clonus score of the ankle, and
      the passive range of motion (PROM) of ankle dorsiflexion. RESULTS: The MAS score
      was reduced in 17 (77%) of 22 patients during the 6-month follow-up, and
      spasticity reappeared at the level of the pre-MBB state in 5 patients (23%). The
      mean values of all parameters were significantly improved. The changes of mean
      values from the pre-MBB to the 6-month post-MBB stage were as follows: MAS score,
      3.3+/-0.7 versus 1.7+/-1.1; clonus score, 1.6+/-0.7 versus 0.4+/-0.8; and PROM,
      17.1 degrees +/-13.0 degrees versus 28.6 degrees +/-4.7 degrees. No serious
      complications were observed during the 6-month follow-up period. CONCLUSIONS: MBB
      of the tibial nerve to the gastrocnemius muscle is an effective and safe
      procedure for relieving localized spasticity of the ankle plantarflexors.

PMID- 15031843
TI  - Blood lipids of cardiac patients after acute exercise on land and in water.
AB  - OBJECTIVE: To compare the effect on lipids of a single bout of high-intensity
      interval training performed on land and in water in a group of cardiac patients
      involved in an intensive cardiac rehabilitation program. DESIGN: Single-group,
      quasiexperimental, crossover design. SETTING: Swimming pool at a cardiac
      rehabilitation hospital in Australia. PARTICIPANTS: Ten men, ages 55 to 77 years,
      with ischemic heart disease. INTERVENTION: Subjects performed 15 minutes of
      interval arm ergometer work at 65% to 75% of attained heart rate, as determined
      by treadmill testing on land and in water on the same day. Each patient had his
      own exercise prescription. MAIN OUTCOME MEASURES: At each endurance phase, the
      number of revolutions and rate-pressure product (RPP) during the final minute of
      work were taken. Fasting bloods were taken at baseline and after maximum
      exercise, and lipid profiles were determined; differences were analyzed by paired
      t test. RESULTS: No significant differences in revolutions or RPP were observed,
      which indicates that workload and heart work were similar in all experiments.
      There were no significant changes in total, low-density lipoprotein cholesterol,
      triglyceride, or apolipoproteins A-I or B after exercise (paired t test). High
      density lipoprotein cholesterol (HDL-C) was increased significantly by exercise
      on land. In 6 patients with low baseline HDL-C (<0.9 mmol/L), HDL-C was increased
      only on land. CONCLUSIONS: A single bout of high-intensity interval training was
      more effective in improving HDL-C when performed on land than in water.

PMID- 15031845
TI  - On stability of cellular neural networks with polynomial interactions.
AB  - Cellular neural/nonlinear networks (CNNs) are analog dynamic processor arrays,
      that present local interconnections. CNN models with polynomial interactions
      among the cells (Polynomial type CNNs) have been recently introduced. They are
      useful for solving some complex computational problems and for real-time
      implementation of PDE-based algorithms. This manuscript provides some simple and
      rigorous sufficient conditions for stability of polynomial type CNNs. A
      particular emphasis is given to conditions that can be expressed in terms of
      template elements, since they can be exploited for design purposes.

PMID- 15031844
TI  - A method for performance evaluation using WeeFIM data collected for the Joint
      Commission on Accreditation of Healthcare Organizations' ORYX initiative: The 0.5
      band control chart analysis.
AB  - This article describes the employment of a method of data analysis for detailed
      internal program evaluation, which we call the 0.5 Band Control Chart Analysis.
      We describe how the 0.5 Band Control Chart Analysis can be used in conjunction
      with the data collected and analyzed as part of the Joint Commission on
      Accreditation of Healthcare Organizations' ORYX initiative to enhance program
      evaluation. How this procedure helped identify problems and drove performance
      improvement at our facility is also discussed.

PMID- 15031846
TI  - The role of field coupling in nano-scale cellular nonlinear networks.
AB  - We review some of our previous work on field-coupling in nano-scale cellular
      arrays. Electronic devices based on metallic and magnetic nanoscale dots and
      molecular structures have been suggested, however, no technologically viable
      architecture for nanoelectronic circuit integration has emerged so far. A natural
      architecture on the nanoscale appears to be near-neighbor cellular networking,
      and we explore promising alternative ways of integrating nanodevices by direct
      physical field coupling, i.e. either by Coulomb or by magnetic interactions. We
      review new architectures for such field-coupled nanocircuits.

PMID- 15031848
TI  - Distributed sensor networks: a cellular nonlinear network perspective.
AB  - Large-scale networks of integrated wireless sensors become increasingly
      tractable. Advances in hardware technology and engineering design have led to
      dramatic reductions in size, power consumption, and cost for digital circuitry,
      and wireless communications. Networking, self-organization, and distributed
      operation are crucial ingredients to harness the sensing, computing, and
      computational capabilities of the nodes into a complete system. This article
      shows that those networks can be considered as cellular nonlinear networks
      (CNNs), and that their analysis and design may greatly benefit from the rich
      theoretical results available for CNNs.

PMID- 15031847
TI  - Influence of system non-uniformity on dynamic phenomena in arrays of coupled
      nonlinear networks.
AB  - In this paper we investigate the influence of system non-uniformity on the
      existence and stability of synchronous motion in an array of bi-directionally
      coupled electronic circuits. In computer simulations we find the level of non
      uniformity for which synchronous behavior is sustained. We also present several
      examples of attractors, which appear when the synchronous motions is no longer
      stable.

PMID- 15031849
TI  - CNN universal machine as classificaton platform: an art-like clustering
      algorithm.
AB  - Fast and robust classification of feature vectors is a crucial task in a number
      of real-time systems. A cellular neural/nonlinear network universal machine (CNN
      UM) can be very efficient as a feature detector. The next step is to post-process
      the results for object recognition. This paper shows how a robust classification
      scheme based on adaptive resonance theory (ART) can be mapped to the CNN-UM.
      Moreover, this mapping is general enough to include different types of feed
      forward neural networks. The designed analogic CNN algorithm is capable of
      classifying the extracted feature vectors keeping the advantages of the ART
      networks, such as robust, plastic and fault-tolerant behaviors. An analogic
      algorithm is presented for unsupervised classification with tunable sensitivity
      and automatic new class creation. The algorithm is extended for supervised
      classification. The presented binary feature vector classification is implemented
      on the existing standard CNN-UM chips for fast classification. The experimental
      evaluation shows promising performance after 100% accuracy on the training set.

PMID- 15031850
TI  - ACE16k: a 128x128 focal plane analog processor with digital I/O.
AB  - This paper presents a new generation 128x128 Focal-Plane Analog Programmable
      Array Processor -FPAPAP, from a system level perspective. It has been
      manufactured in a 0.35 microm standard digital 1P-5M CMOS technology. It has been
      designed to achieve the high-speed and moderate-accuracy -8b- requirements of
      most real time -early-vision applications. External data interchange and control
      are completely digital. The chip contains close to four million transistors, 90%
      of them working in analog mode. It achieves peak computing values of 0.33TeraOPS
      while keeping power consumption at reasonable limits -82.5GOPS/W. Preliminary
      experimental results are also provided in the paper.

PMID- 15031851
TI  - CMOS realization of a 2-layer CNN universal machine chip.
AB  - Some features of the biological retina can be modelled by a 2-layer cellular
      neural network (CNN) composed of locally connected elementary nonlinear
      processors. In order to explore these complex spatiotemporal dynamics for image
      processing, a prototype chip has been designed and fabricated in a 0.5 microm
      CMOS technology. Design challenges, trade-offs, the building blocks and the tests
      results for this system with 0.5 x 10(6) transistors, most of them operating in
      analog mode, are presented in this paper.

PMID- 15031852
TI  - Realization of couplings in a polynomial type mixed-mode cellular neural network.
AB  - In this paper realization of couplings between cells in a polynomial type mixed
      mode cellular neural network (CNN) is analyzed. The choice of the multiplier is
      discussed and two multiplier types are analyzed. Also, two circuits for
      generating the second and third order polynomial terms of cell output are
      described. The accuracy of the multipliers and polynomial circuits at the
      presence of device mismatch is analyzed.

PMID- 15031853
TI  - Fingerprint image enhancement using CNN filtering techniques.
AB  - Due to noisy acquisition devices and variation in impression conditions, the
      ridgelines of fingerprint images are mostly corrupted by various kinds of noise
      causing cracks, scratches and bridges in the ridges as well as blurs. These cause
      matching errors in fingerprint recognition. For an effective recognition the
      correct ridge pattern is essential which requires the enhancement of fingerprint
      images. Segment by segment analysis of the fingerprint pattern yields various
      ridge direction and frequencies. By selecting a directional filter with correct
      filter parameters to match ridge features at each point, we can effectively
      enhance fingerprint ridges. This paper proposes a fingerprint image enhancement
      based on CNN Gabor-Type filters.

PMID- 15031854
TI  - SC-CNNs for chaotic signal applications in secure communication systems.
AB  - In this paper a CNNs based circuit for the generation of hyperchaotic signals is
      proposed. The circuit has been developed for applications in secure communication
      systems. An Saito oscillator has been designed by using a suitable configuration
      of a four-cells State-Controlled CNNs. A cryptography system based on the Saito
      oscillator has been implemented by using inverse system synchronization. The
      proposed circuit implementation and experimental results are given.

PMID- 15031855
TI  - Sensory feedback in CNN-based central pattern generators.
AB  - Central Pattern Generators (CPGs) are a suitable paradigm to solve the problem of
      locomotion control in walking robots. CPGs are able to generate feed-forward
      signals to achieve a proper coordination among the robot legs. In literature they
      are often modelled as networks of coupled nonlinear systems. However the topic of
      feedback in these systems is rarely addressed. On the other hand feedback is
      essential for locomotion. In this paper the CPG for a hexapod robot is
      implemented through Cellular Neural Networks (CNNs). Feedback is included in the
      CPG controller by exploiting the dynamic properties of the CPG motor-neurons,
      such as synchronization issue and local bifurcations. These universal paradigms
      provide the essential issues to include sensory feedback in CPG architectures
      based on coupled nonlinear systems. Experiments on a dynamic model of a hexapod
      robot are presented to validate the approach introduced.

PMID- 15031856
TI  - Analysis of multidimensional neural activity via CNN-UM.
AB  - In this paper we show that the Cellular Nonlinear Network Universal Machine (CNN
      UM) is an excellent tool for analyzing time series of multidimensional binary
      signals. The developed algorithm is dedicated to process electrophysiological
      multi-neuron recordings: our aim is to find specific multidimensional activity
      patterns, which may reflect higher order functional cell-assemblies. The analysis
      consists of two parts: first, the occurrences of different patterns are counted,
      then the statistical significance of each occurrence frequency is calculated
      separately.

PMID- 15031857
TI  - Cellular neural networks (CNN) with linear weight functions for a prediction of
      epileptic seizures.
AB  - In this paper, we present a novel approach to the prediction of epileptic
      seizures using boolean CNN with linear weight functions. Three different binary
      pattern occurrence behaviours will be discussed and analysed for several invasive
      recordings of brain electrical activity. Furthermore analogic binary pattern
      detection algorithms will be introduced for a possible prediction of epileptic
      seizures.

PMID- 15031858
TI  - Chronic allograft nephropathy.

PMID- 15031859
TI  - Chronic allograft nephropathy.

PMID- 15031860
TI  - Surgeon volume and operative mortality.

PMID- 15031861
TI  - Surgeon volume and operative mortality.

PMID- 15031862
TI  - Dysplastic nevi.

PMID- 15031863
TI  - Dysplastic nevi.

PMID- 15031864
TI  - Chronic constipation.

PMID- 15031865
TI  - Therapy for irritable bowel syndrome.

PMID- 15031866
TI  - Therapy for irritable bowel syndrome.

PMID- 15031867
TI  - Medicare. Senate hearings.

PMID- 15031868
TI  - Work strain causes real pain--no body should put up with it.

PMID- 15031869
TI  - Come together.

PMID- 15031870
TI  - Using C-Graft for aveolar bone grafting and implant surgery. Interview.

PMID- 15031871
TI  - What is Delta Dental up to?

PMID- 15031873
TI  - The chain of survival.

PMID- 15031872
TI  - Children of Massachusetts: room for improvement.
AB  - A review of health and social measurements reported in census data indicates
      that, compared with other state and national averages, the general social and
      family conditions for many of the 1.5 million young residents of Massachusetts
      are quite good. But there are many exceptions, and the challenge is not to lose
      sight of the need to improve. There are 1.5 million children living in
      Massachusetts under the age of 18 (including approximately 1.2 million Caucasian,
      158,000 Hispanic, and 107,000 African American children). This comes to about 2
      percent of the children in all of the United States. These youngsters represent
      the next generation of patients for current and future dental practitioners. Are
      these youngsters getting the right start? The Kids Count initiative along with
      other reports produced by the Annie E. Casey Foundation provides a detailed
      demographic summary of the 2000 Census and related data, which offer answers to
      this question. The Foundation report highlights many of the successful--and not
      so successful--efforts to ensure the best possible beginnings for youngsters
      throughout the country, individual states, and local communities. In an effort to
      place the demographic information of youngsters in Massachusetts in some
      comparative context, the data are matched to information at the national level
      and for New York and Connecticut.

PMID- 15031874
TI  - Abuse and neglect--a neglected subject.

PMID- 15031875
TI  - 2003 volunteer heroes.

PMID- 15031876
TI  - Medical emergencies in the pediatric patient: airway management.
AB  - Fortunately, the incidence of pediatric respiratory emergencies is extremely low
      during pediatric dental treatment. As most cardiopulmonary arrests in children
      result from a progressive deterioration in respiratory function, outcome is
      critically dependent on rapid diagnosis and evaluation of the adequacy of
      ventilation in the pediatric airway. Medically compromised children are best
      treated in facilities equipped for their care and staffed by personnel trained in
      emergency treatment. Iatrogenic complications can be reduced by strict adherence
      to recommended pediatric drug and local anesthesia dosages with a critical eye
      regarding drug interactions and the additive effects of central nervous system
      depressants.

PMID- 15031878
TI  - A clinico-pathologic correlation: pemphigus vulgaris.

PMID- 15031877
TI  - Rhinosinusitis: diagnosis, management, and dental implications.

PMID- 15031879
TI  - The business of selling treatments.

PMID- 15031880
TI  - Fortifying oral contraceptives with folic acid.

PMID- 15031881
TI  - Female OB/GYNs speak out about health practices.

PMID- 15031882
TI  - Ephedra banned.

PMID- 15031883
TI  - Creating a safe, secure health care environment.

PMID- 15031884
TI  - Screening for obesity.

PMID- 15031886
TI  - Pre-term birth risk assessment tools. Exploring fetal fibronectin and cervical
      length for validating risk.

PMID- 15031885
TI  - Understanding prematurity. Sorting fact from fiction.

PMID- 15031887
TI  - Patient page. Assessing pre-term labor and birth risk.

PMID- 15031888
TI  - Therapeutic horseback riding. Exploring this alternative therapy for women with
      disabilities.

PMID- 15031889
TI  - Improving labor & delivery shift report.

PMID- 15031890
TI  - Unlocking stillbirth. New study seeks to identify causes of death.

PMID- 15031891
TI  - AWHONN urges approval of OTC emergency contraception.

PMID- 15031892
TI  - Postpartum depression. One nurse's personal experience.

PMID- 15031893
TI  - [Structure and heterogeneity of urban vegetation landscape in Shenyang].
AB  - Studies on the structure and heterogeneity of urban vegetation landscape in
      Shenyang city showed that the most vegetation patches were in the street corner,
      accounted for more than 50% of the total vegetation patch, and their area was
      only 4.45% of the total vegetation area. In terms of the size of the patches, the
      average area of shelter vegetation and park vegetation was 66.97 hm2 and 59.31
      hm2, respectively, while that of street corner vegetation and garden vegetation
      was 0.71 hm2 and 0.38 hm2, respectively. Street corner vegetation had the highest
      index of landscape diversity, while park vegetation had the lowest one. In the
      seven districts of Shenyang city, all types of vegetation had a small landscape
      dominance and evenness, but patch vegetation had a more than 10 times of
      landscape dominance than corridor vegetation, indicating that there was somewhat
      imbalance in the allocation of different vegetation patch types. It's suggested
      that the quantity of patch vegetation should be increased, and the public
      vegetation should be distributed evenly. Increasing vegetation corridor is also
      important because it can link the downtown area to the suburb natural vegetation
      ecosystems. For example, the South Canal Belt Park of Shenyang is a good
      vegetation corridor, which can beautify Shenyang city, discharge sewage, drain
      flood, and improve microclimate.

PMID- 15031894
TI  - [Quantitative analysis of urban forest structure: a case study on Shenyang
      arboretum].
AB  - The spatial features and attribute data of urban forests in Shenyang arboretum
      were acquired by using aerial photographs and field investigation. After systemic
      and quantitative analysis of the species composition and spatial distribution
      pattern of urban forest community based on geographic information system (GIS),
      the following results were achieved: 1) the vegetation in the arboretum was rich
      and in a good condition. Phellodendron amurense, Robinia pseudoacacia, and Ulmus
      punita were the main species according to their abundant individuals and relative
      dominance. The spatial distribution pattern of this vegetation indicated that it
      was in a growing level and in the best state for ecological benefits; 2) the tree
      species relative dominance based on vegetation quantity had no distinct
      relationship with the species abundance, and the species having abundant
      individuals might have a low relative dominance; and 3) the curve displayed in
      the relationship diagram between tree individuals and tree height showed
      ascending and protruding. With the increment of tree height class, the
      individuals were unchanged nearly at the beginning, but when the height was more
      than 12 m, the individuals reduced distinctly, and the curve displayed a quickly
      declined trend. The relationship between tree individuals and tree diameter at
      the breast height (DBH) showed the same result.

PMID- 15031895
TI  - [Flora and vegetation types in the downtown area of Shenyang].
AB  - Shenyang city is located in the intersect zone among Changbai, Mongolia and North
      China flora, which has a plenty of plant species belonging to 98 families, 371
      genera and 779 species. There are 85 plant species in the largest family
      Companulaceae, and more than 20 species in the families Cyperaceae, Rosaceae,
      Leguminoseae, Polygonuceae, Labiatae, Lilaceae and Ranunculaceae. These families
      have 384 species in total, and 49.3% of them are found in Shenyang city. The
      flora had 23 geographical components types, and 89.3% of them were of the
      temperate type. Based on the epigenesis and functions of vegetation and the role
      of the dominant species, the urban vegetation in the downtown area of Shenyang
      was divided into 3 vegetation classes, 14 vegetation groups and 57 vegetation
      types, and the components, structure, dynamics and functions of 3 representative
      vegetation classes were analysised.

PMID- 15031896
TI  - [Selection of tree species composition in Shenyang's urban forest communities].
AB  - Tree species selection is the most important basis in urban forest construction,
      and the key is the selection of tree species composition. Through investigating
      and analyzing the tree species composition in the parks in Shenyang built-up
      area, the sequencing of integrate evaluation of various tree species was
      obtained. By correlation analysis among tree species with the Jaccard
      quantitative coefficient of correction, the optimal tree species composition and
      the reference tree composition of Shenyang urban forest were also obtained. The
      existing status of tree species distribution in Shenyang built-up area was
      analyzed, the keynote tree species and 8 reference skeleton tree species were
      recommended, and some advices were presented.

PMID- 15031897
TI  - [Structure and ecological benefits of urban forest in Shenyang build-up area].
AB  - Investigations were made in the sampling plots covering 243 km2 of the Shenyang
      urban area, and the results were used as the input for the Urban Forest
      Management Information System (UFMIS), which was developed based on the model of
      CITY green. With this system, and using tree species, tree density, tree height
      grade distribution, tree DBH (diameter at beast height) grade distribution, and
      tree health condition as parameters, the land use and forest structure in
      Shenyang City were analyzed. It was found that there were 1,914,500 trees in
      Shenyang, belonging to 136 species. The 25 dominant species accounted for 84.78%
      of the total number of trees, and the forest coverage was 9.765%. Trees with DBH
      < 0.25 m and > 0.5 m accounted for 82.8% of the total, and the young, middle-aged
      and old trees occupied 27%, 58% and 15% of the total, respectively. The healthy
      status of 84% of the trees was above middle level. Therefore, the forest in
      Shenyang urban is at a stable stage. According to the statistical results from
      UFMIS, the ecological value of forest in Shenyang urban is as high as 26,526,955.
      1 USD in terms of economy.

PMID- 15031898
TI  - [Dust absorption effect of urban conifers in northeast China].
AB  - Dust pollution is much heavier in winter than in other seasons in the cities of
      Northeast China, because the urban heating system consumes mainly coal as energy
      resources. Deciduous trees can hardly absorb dust because of their defoliation,
      and hence, urban conifer trees become more important in dust absorption in
      winter. This paper studied the dust absorption ability of 7 conifers under the
      same and different dust pollution status in Shenyang city, Northeast China. The
      results showed that the dust absorption ability of conifers was decreased in the
      order of Abies holophilla > Picea mongolica > P. koraiensis > Taxus cupidata >
      Pinus bungeana > P. armandi > P. tabulaeformis. Different conifers had different
      surface structures. Pinus bungeana, P. armandi and P. tabulaeformis had smooth
      surfaces, their cells and stomata arranged in order, and hence, their dust
      absorption ability was poor. P. koraiensis, Abies holophilla and Taxus cupidata
      had coarse surfaces, and their cells and stomata arranged out of order. There
      were even many tubercular things on the surface of P. koraiensis, and hence,
      their dust absorption ability was stronger. The dust absorption ability of
      conifers was related the shape of their leaf sections. The upper leaf surface of
      Pinus bungeana and P. tabulaeformis was arc, not opted to absorb the dust. The
      leaf section of P. armandi was prism, and its upper surface was narrow, and
      hence, its dust absorption ability was also poor. The leaves of Picea mongolica
      and P. koraiensis had four edges, their upper surfaces were broader and flatter
      than the former three species, and hence, they had stronger dust absorption
      ability. The leaf section's shape of Abies holophilla and Taxus cupidata was also
      broad and flat, which made the dust absorption ability of the two latter's was
      stronger than other three Pinus species and two Picea species.

PMID- 15031899
TI  - [Analysis of urban forest landscape pattern in Hefei].
AB  - Based on the theory and methodology of landscape ecology, the landscape pattern
      of the study area (17.6 km2) in the downtown of Hefei was analyzed by using the
      techniques of RS, GPS and GIS. The object was to provide a comprehensive method
      to study urban forest structure and its function in environmental improvement.
      The results showed that there were 5 major landscape elements, i.e., building and
      hard pavement surface, water, road, urban forest, and general green land in the
      area. The landscape matrix was building and pavement surface, occupied 73.13% of
      total land. Road was the typical corridor element in the city and occupied 6.89%.
      Green land occupied 11.44%, in which, urban forest patch occupied 9.18%. There
      were 408 urban forest patches, with an area of 161.16 hm2. The average area of
      the patch was 0.396 hm2, and the maximum area was 12 hm2. 48% of urban forest
      patch was identified as small scale patches with < 500 m2 of area, and only 8.6%
      of them was larger than 1 hm2. The number of general green land patch was 255,
      with an area of 39.74 hm2, which accounted for 2.26% of land area, and its
      average and maximum area was 0.1558 hm2 and 3.86 hm2, respectively. There were
      147 water patches, with an area of 149.93 hm2, and occupied 8.54% of land, and
      the average and maximum area of the patch was 1.02 hm2 and 16 hm2, respectively.
      In the study area, both of the Shannon-Weiner landscape diversity index and
      evenness were low, only 0.928 and 0.576, respectively. In addition, the dominance
      of urban forest patch and general green land was 0.39 showing that the two
      landscape elements had a certain influence on the environment of the study area.
      The concept of interior habitat for forest was introduced in this paper, which
      was employed to make a scale class system of urban forest patch. The threshold
      area with interior habitat for urban forest patch was 9800 m2, and there was
      31.69 hm2 of interior habitat of urban forest in total, which occupied 19.7% of
      the total area of urban forest patch. This situation was not favorable for
      providing more habitats to support species diversity. It's suggested that the
      concept of interior habitat could be employed to identify urban forest patch, and
      a scale system of small scale patch of urban forest-middle patch-large patch
      extra large patch was build in the paper. Based on this system, the ratio of
      different scales of urban forest patch in the study area should be 2:2:2:3. The
      authors also suggested that larger pieces (1.5-3.0 hm2) of urban forest patch
      should be built, and more urban forests should be established in the northeastern
      part of the city in the future.

PMID- 15031900
TI  - [Quantitative analysis on sharp-tooth oak stands in Qinling Mountains].
AB  - The arbor stratum of Quercus aliena var. acuteserrata stands included two
      substratums. Phanerophyta synusium was in first position, and hemicryptophyta was
      inferior to it. The DBH structures of Quercus aliena var. acuteserrata and Pinus
      armandii were sinister normal school, which could finish self-regeneration under
      the natural conditions. The small DBH class individuals of Pinus tabulaeformis
      were dominant, their DBH classes being distributed irregularly and absent very
      much. The large DBH classes of Toxicodendron vernicifluum took biggish
      proportion, belonging to declining population. Young trees were the principal
      individuals of Castanea mollissima, and in transitional age stage from the young
      to the middle. Populus davidiana was in the transitional stage from progressive
      to stable and young-middle age stands. The stands DBH structure was mainly
      influenced by the DBH variety of Quercus aliena var. acuteserrata population.
      Quantitative classification (ward's method ward) and ordination (PCA) were used
      to study the community types of sharp-tooth oak. The results showed that the
      community could be divided into 6 types: 1. Ass. Smilax stans + Rosa multiflora
      Quercus variabilis + Ulmus glaucescens-Quercus aliena var. acuteserrata; 2. Ass.
      Smilax stans + Lespedeza bicolor-Castanea mollissima-Q. aliena var. acuteserrata;
      3. Ass. Corylus mandshurica-Populus davidiana + Dendrobenthamia angustata-Q.
      aliena var. acuteserrata; 4. Ass. Prunus pseudoccrasus + Corylus mandshurica
      Toxicodendron vernicifluum-Q. aliena var. acuteserrata; 5. Ass. Corylus
      mandshurica + Rosa multiflora-Pinus armandii-Q. aliena var. acuteserrata; and 6.
      Ass. Sinarundinaria nitida-Pinus armandii + Pinus tabulaeformis-Q. aliena var.
      acuteserrata. Ward's method ward was better for classifying community types than
      the other clustering analyses in Qinling Mountains. The PCA results were
      consistent with the clustering, and demonstrated that the sharp-tooth oak stands
      were influenced by the altitude, site gradient and soil mainly.

PMID- 15031901
TI  - [Temporal-spatial distribution characteristics of microclimate in tropical
      secondary forest canopy gap in Xishuangbanna].
AB  - Based on the data obtained from vertical gradient measurements of microclimatic
      elements of canopy gap in tropical secondary forest of Xishuangbanna in fog-cool
      and dry-hot season, the daytime characteristics of temporal-spatial distribution
      and variation of trunk surface temperature, air temperature, water vapor pressure
      and relative humidity in canopy gap were discussed. The data showed that gap edge
      had not only a remarkable thermal effect, but also a significant water vapor
      effect. These effects resulted in environmental heterogeneity in canopy gap. The
      results provided a basis for further studying heat and water vapor transport,
      microclimatic formation, biodiversity, and forest succession in canopy gap.

PMID- 15031902
TI  - [Dynamics of biomass and net primary productivity in succession of south
      subtropical forests in southwest Guangdong].
AB  - Coniferous forest (Pinus massoniana community), pine-borad leaved mixed forest
      (Pinus massoniana + Castanopsis kawakamii + Schima superba + Liquidambar
      formosana) and evergreen broad-leaved forest (Ixonanthes chinensis + Artocarpus
      styacifolius + Ormosia glaberrima + Cryptocarya concinna) are the three main
      communities representing 3 major stages in a secondary succession series in
      Heishiding Nature Reserve, Guangdong Province. Their biomass and net primary
      productivity (NPP) were studied by using harvest method (for trees and lianas)
      and clear cut method (for shrub and herb). The biomass and NPP were 246.697 t.hm
      2 and 14.715 t.hm-2.yr-1 for the coniferous forest, 287.367 t.hm-2 and 17.179
      t.hm-2.yr-1 for the pine-broad leaved mixed forest, and 357.976 t.hm-2 and 18.730
      t.hm-2 yr-1 for the evergreen broad-leaved forest, respectively. These results
      indicated that these three stages were very close in the succession process, and
      that coniferous forest and mixed forest were more mature, while broad-leaved
      forest was relatively young. Therefore, under the conditions of no or only minor
      disturbance, their biomass and NPP showed an increasing trend with the succession
      of the forest communities in Heishiding.

PMID- 15031903
TI  - [Genetic diversity of rare and endangered plant Sorbus amabilis].
AB  - The genetic diversity of 13 natural populations of Sorbus amabilis Cheng ex Yu
      from different distribution regions was investigated using RAPD. Fourteen primers
      were screened from 40 ten-bp arbitrary primers, and a total of 105 DNA fragments
      were amplified among which, 30(28.6%) were polymorphic. DNA molecular dendrograms
      were established for the 13 natural populations, based on UPGMA and Neighbor
      Joining. The result showed that S. amabilis had a low genetic diversity, and its
      adaptability to environmental change was weak. The genetic diversity of S.
      amabilis among the 13 natural populations were primarily related to their
      geographic distribution. Its special evolutionary history, man-made destruction,
      natural disaster (fire, plant diseases and insect pests etc.) and genetic drift
      caused by small population were the main reasons for the low-level genetic
      diversity of S. amabilis and its endangered position.

PMID- 15031904
TI  - [Gradient distribution of soil N, P, and K along the distance from Picea
      mongolica seedlings root surface].
AB  - Six years old seedlings of Picea mongolica were planted in pots with horizontal
      and vertical root treatments. Soil samples were stratified collected, and their
      available nitrogen (N), phosphorus (P), and potassium (K) contents were
      determined. The results showed that the available contents of N, P and K in soils
      along the distance from Picea mongolica seedlings root surface had a special
      gradient distribution. Near root surface, there was a depletion zone of soil
      available N, P, and K, and along the distance from it, the nutrient element
      contents increased gradually and reached their background values in the bulk
      soil. In the horizontal root treatment, the depletion zone of soil available N,
      P, and K existed in different distance from root surface, owing to the absorption
      and the use intensity of the seedlings to these nutrient elements. The depletion
      zone of soil available N and K appeared from 1 cm from root surface, and that of
      available P existed in 0.5 cm from root surface. In the vertical root treatment
      the depletion zone of available N and K also appeared from 1 cm from root surface
      as in the horizontal root treatment, but the available P content near root
      surface was lower than that far away from root surface. It is proved that the
      absorption and the utilize intensity of soil available P by Picea mongolica
      seedlings was intense, which might become a limiting factor to its growth and
      development. Therefore, Picea mongolica should be planted on soils rich in
      phosphorus, or P and N fertilizers should be applied to improve the absorption
      and the use efficiency of available P by Picea mongolica.

PMID- 15031905
TI  - [Ecological distribution of mycorrihizal fungi associated with oak in Dandong
      district of Liaoning Province].
AB  - With plot cruising and rout investigation methods, 36 species of ectomycorrhizal
      fungi associated with oaks were found in natural secondary oak forest in Dandong
      district of Liaoning Province. They were subordinated to 7 familyies, 13 genera.
      Studies on the relationship of the ecological distribution of mycorrhizal fungi
      with tree species, tree age and seasons showed that 29 species mycorrhizal fugi
      preferred to grow with Q. mongolica, The species of Russulla were associated with
      a wider tree ages of oak, and the species of Amanita were most likely to grow
      with old tree. July and August were the occurrence peak of mycorrhizal fungi. 75%
      species occurred in July, and 100% species occurred in August. The relative
      density of the occurrence number was the highest in mid-August (19.5%) and last
      August (18.4%).

PMID- 15031906
TI  - [Calculation of parameters in forest evapotranspiration model].
AB  - Forest evapotranspiration is an important component not only in water balance,
      but also in energy balance. It is a great demand for the development of forest
      hydrology and forest meteorology to simulate the forest evapotranspiration
      accurately, which is also a theoretical basis for the management and utilization
      of water resources and forest ecosystem. Taking the broadleaved Korean pine
      forest on Changbai Mountain as an example, this paper constructed a mechanism
      model for estimating forest evapotranspiration, based on the aerodynamic
      principle and energy balance equation. Using the data measured by the Routine
      Meteorological Measurement System and Open-Path Eddy Covariance Measurement
      System mounted on the tower in the broadleaved Korean pine forest, the parameters
      displacement height d, stability functions for momentum phi m, and stability
      functions for heat phi h were ascertained. The displacement height of the study
      site was equal to 17.8 m, near to the mean canopy height, and the functions of
      phi m and phi h changing with gradient Richarson number R i were constructed.

PMID- 15031907
TI  - [Relationship between soil organic phosphorus forms in larch plantations and tree
      growth].
AB  - Using the organic phosphorus fractionation system suggested by Bowman and Cole,
      this paper studied the dynamics of labile, moderately labile, moderately
      resistant, and highly resistant organic phosphorus in rhizosphere and non
      rhizosphere soil at different development stages of larch, and their
      relationships with soil available phosphorus and tree growth yield. The results
      showed that the main components of soil organic phosphorus in larch plantation
      were moderately labile and moderately resistant organic phosphorus, amounted to
      77.07%-86.68% of the total organic phosphorus. The labile and moderately labile
      organic phosphorus in rhizosphere soil were the main sources of soil available
      phosphorus at different development stages of larch. The contents of total
      organic phosphorus, labile organic phosphorus, moderately resistant organic
      phosphorus and highly resistant organic phosphorus in rhizosphere soil decreased
      with stand ages from young stand to near mature stand, but increased from near
      mature stand to mature stand. No apparent change of the moderately labile organic
      phosphorus content was found over stand ages in rhizosphere soil. The contents of
      various organic phosphorus forms presented a fluctuating increasing tendency in
      non-rhizosphere soil as stand ages increased. There was a close relationship
      between the increments of periodic average diameter at breast height and periodic
      average height and the contents of soil labile organic phosphorus and available
      phosphorus.

PMID- 15031908
TI  - [Effect of flooding disturbance on aboveground biomass of Leymus chinensis
      grassland--a preliminary study].
AB  - To investigate the effect of flooding disturbance on the net primary productivity
      of Songnen steppe, a comparatively thorough study was conducted on Sanjiadian
      State-owned Rangeland in Da'an city, Jilin Province, which was partly flooded in
      1998. The study site was located in the south Songnen plain of Northeastern
      China, dominated by Leymus chinensis grassland. An extensively mild slope with
      flooding gradients (from un-flooded to heavily flooded) was taken as the study
      site. Two flooded transects coded FL and FH which was respectively subjected to 3
      and 9 months of flooding were designed, and an un-flooded one coded CK at a
      relatively higher elevation was set as a control. Before flooding occurred in
      1998, the slope had an almost uniform soil and L. chinensis dominated vegetation.
      Each transect was 0.2 hm2 (100 m x 20 m) in size, and the two flooded transects
      were almost paralleled each other, with the longer sides of them perpendicular to
      the retrieving direction of floodwater. In each transect twenty 1 m2 sized
      quadrats were randomly chosen to survey the community structure and the
      aboveground biomass. Comparative analyses were made on the dynamics of soil
      water, soil N and P, and species composition of grassland communities that
      occurred in responses to flooding disturbance. The results showed that the
      lightly and heavily flooded transects had a significantly larger aboveground
      biomass than the control, with the increase of 89.54% and 113.45%, respectively.
      The heavily flooded transect had a slightly but insignificantly larger
      aboveground biomass than the lightly flooded one, indicating that on flooded
      sites, water was not the limiting factor of the aboveground biomass. The acute
      changes of soil water caused by flooding led to the changes of soil nutrients and
      species assemblages, which would impact community biomass. Just as the case for
      aboveground biomass, the soil water contents of the two flooded transects were
      significantly larger than that of control, which was the direct effect of
      flooding disturbance. The contents of soil available N and P on the flooded
      transects were higher than that on the control, as resulted by the increase of
      soil water. The species composition had an obvious difference between flooded
      transects and control, and the major change on the flooded transects was the
      decrease of Xeric and Mesoxeric plants and the increase of Hygric and Hygro-mesic
      plants, compared to the control. It's deduced from the results that the
      mechanisms that the flooding disturbance influenced the net primary productivity
      were: 1) Flooding disturbance firstly changed soil water content, the leading
      limiting factor of grassland productivity, especially in dry years, and thus,
      lessened the limitation of aridity on grassland productivity. 2) Flooding induced
      increase of soil water content led to the drastic increases of nutrient
      availability, and thereby, eliminated the restriction of pre-flood nutrient
      scarcity on grassland productivity. 3) Still due to the afterward effects of
      flooding disturbance, the species composition of the community transformed from
      relatively shorter plant species assemblage towards taller and bigger plant
      species assemblage that were more productive.

PMID- 15031909
TI  - [Variations of water-soluble carbohydrate and nitrogen contents in Leymus
      chinensis and Phragmites communis under different stocking rates].
AB  - The variations of the contents of water-soluble carbohydrate and nitrogen in L.
      chinensis and Ph. communis under different stocking rates were studied by fencing
      grazing experiment on L. chinensis grassland. The results indicated that the
      water-soluble carbohydrate content in the base stem of L. chinensis and Ph.
      communis was the lowest (7.12% and 3.95%, respectively) at the beginning of
      growth period, and then increased gradually with seasons. There was no
      significant variation in the content of leaf water-soluble carbohydrate in the
      grasses. L. chinensis germinated earlier than Ph. communis, resulted in the
      difference between the water-soluble carbohydrate content in the base stem and
      the leaf of the grasses at the beginning of the experiment in May. Proper
      stocking rates were favorable for the increase of water-soluble carbohydrate
      content, and could accelerate the re-growth capability of the herbage. The
      nitrogen content was the highest at the beginning of growth period, and then
      decreased gradually with seasons, which was accorded with their phenology. Proper
      stocking rates could stimulate the assimilation of nitrogen in soil, and bring it
      to the ground, which improved the nutrition value of the herbage.

PMID- 15031910
TI  - [Growth strategies of different age classes of ramets in Kalimeris integrifolia
      population at the Songnen Plains of China].
AB  - As a perennial forage, Kalimeris integrifolia Turcz. Ex DC is a species of
      Compositea clone plant, which has a high potential in vegetative propagation by
      root crowns. Its population was constructed by three age classes of ramets. In
      the Songnen Plains the middle ten days of June is the more vigorous vegetative
      growth period of the clone ramets. The results showed that the capabilities of
      ramet growth and production were the lowest in the 1st age class and heightened
      in the 2nd and 3rd age classes. Biomass allocations were the most in stem, more
      in leaves, and the least in tapoot of three age classes of ramets. The biomass
      allocation in leaves was the most in the 1st age class, more in the 2nd age
      class, and the least in the 3rd age class, but those in stem and in taproot were
      all the least in the 1st age class lesser in the 2nd age class, and the most in
      the 3rd age class. The relationships between total weight and height, leaf weight
      and stem weight, and taproot weight and shoot weight of clone ramets were all
      power function, but the biomass allocation in taproot was linearly decreased with
      height increase in three age classes. The strategies of growth and biomass
      allocation of the population ramets were: 1) the biomass allocation in leaves was
      more in the young period to ensure the productive organ constructed continuously,
      and hence, more productive material was gradually allocated in stem and taproot
      with the growth of ramets, 2) the energy allocation of ramets was less in
      taproot, but the biomass allocation in taproot was relatively more in young
      period, and then, the prorate decreased with ramet growth, and the ratio kept
      relatively steady.

PMID- 15031911
TI  - [Spatial diversity index analysis on wildlife habitat pattern change in the
      Liaohe Delta].
AB  - Based on the study of land cover change in the Liaohe Delta with GIS and RS, the
      wildlife habitat pattern was described quantitatively, and the pattern change
      between 1988 and 1998 was analyzed with spatial diversity index. The results
      showed that the wildlife habitat pattern had an obvious change during the ten
      years caused by natural and human disturbance. The area of suitable habitat(Sd >
      or = 0.35) was becoming smaller and more fragmented, with a deteriorated quality.
      It was proved that spatial diversity index could reflect the habitat suitability
      of wildlife, and describe the habitat spatial pattern explicitly. This study
      would provide a scientific basis for protecting wild animals and their habitats.

PMID- 15031912
TI  - [Scaling effects on landscape pattern indices].
AB  - The methods of spatial data aggregation based on majority and random rules were
      used in this study to reveal the scaling effects on landscape pattern in a
      classified TM imagery with 8 land cover types. For the majority rule-based
      aggregations, the proportion of most common cover types increased slowly, while
      that of less common cover types decreased rapidly with increasing grain. For
      random rule-based aggregation, each cover remained its original area on the
      aggregated maps. The largest patch sizes of shrub decreased, and those of the
      others increased in the majority rule-based aggregations with increasing scales.
      For random rule, the largest patch size of water (smallest cover type) decreased,
      but that of the others increased. The smallest patch size of each cover type was
      equal to the square of grain sizes. The average patch size of each cover type
      increased with increasing scales. However, the average patch size of dominant
      cover types increased rapidly in majority rule-based aggregations, while that of
      less common cover types increased rapidly in random rule-based aggregation. The
      patch count of each cover types decreased substantially with increasing grain.
      Random rule-based aggregation made landscape more fragmented and remained more
      patches. The diversity decreased in majority rule-based aggregation, and
      maintained its original value in random rule-based aggregation with increasing
      scales. Aggregation indices decreased with increasing map and measurement
      resolution, and the landscape became more aggregated in majority rule-based
      aggregation. However, under fixed measurement resolution (e.g., 30 m),
      aggregation indices increased and cover types were more clustered with increasing
      resolution. Moran's I decreased rapidly with increasing measurement and map
      resolution, and each cover type tended to be arranged randomly and independently
      in space. However, under fixed measurement resolution (e.g., 30 m), Moran's I
      increased and cover types were more clustered on aggregated maps than on original
      map with increasing map resolution.

PMID- 15031913
TI  - [Dynamic monitoring on land cover in loess hilly and gully area by the methods of
      RS and GIS].
AB  - By the integration of RS and GIS, with the TM data obtained from Landsat 5 in
      1990 and the ETMplus data from Landsat 7 in 2000, and after geometrical
      rectifying and amplifying and man-machine screen decoding data image, the map of
      eco-environment and land use/cover in Yanhe watershed and its vicinities in 1990
      and 2000 was obtained respectively, and the results of statistic analyses showed
      that in comparing with 1990, the artificial land in 2000 increased by 31%, the
      area of agricultural land was stable and that of orchard was 2.82 times more, and
      the area of artificial forest increased remarkably and that of shrub was 6 times
      more. The coverage rate increased to 13.88%, and the area of wilderness was 44.8%
      of that in 1990. The quality of eco-environment was improved remarkably in this
      area.

PMID- 15031914
TI  - [Preliminary study on total sulfur in typical marsh wetland and arable soils in
      Sanjiang Plain].
AB  - Three primary marsh types including Calamagrostis angustifolia marsh, Carex
      lasiocarpa marsh and Carex meyeriana marsh and the arables land reclaimed in
      different years were selected as studying objects, and the total sulfur in these
      soils were analyzed. The results indicated that the mean total sulfur was 622.4
      mg.kg-1 in Calamagrostis angustifolia marsh soils, 820.5 mg.kg-1 in Carex
      meyerianan marsh soils, and 1,022.4 mg.kg-1 in Carex lasiocarpa marsh soils.
      Naoli River, Bielahong River, Yalu River and Nongjiang River are the four typical
      rivers in Sanjiang Plain. The mean total sulfur was 925 mg.kg-1 in Naoli Valley
      soils, 708.6 mg.kg-1 in Bielahong Valley soils, 841.8 mg.kg-1 in Yalu Valley, and
      636.5 mg.kg-1 in Nongjiang Valley. The total sulfur in both marshes and arable
      soils presented distinct regularity, namely it gradually decreased from surface
      soil to botteom. The average total sulfur in the arable land reclaimed between
      1980 and 2000 was 180.5 mg.kg-1, and it was 735.8 mg.kg-1 in natural marsh soils.
      So the total sulfur in arable land was remarkably lower than that in the marshes,
      and the reclamation could result in sulfur loss.

PMID- 15031916
TI  - [Heterosis and genetic correlation analysis of rice (Oryza sativa L.) grain
      weight development under different environmental conditions].
AB  - Two sets of test materials were derived from diallel cross among nine different
      types of selected rice varieties (lines). Based on the experimental data at
      different development stages of early and late rice, the estimation of heterosis
      and genetic correlation of rice grain weight at some development stages (0-->t)
      or at some special development phases (t--1-->t) was conducted by using additive
      dominant genetic model and developmental genetic model for quantitative traits.
      The results indicated that the heterosis over mid-parent value based on
      population mean was not significant at 5% level at the early stages (1-12 d), and
      turned to positively significant as the development process proceeded in early
      rice. The heterobeltiosis based on population mean appeared to be small negative
      during the entire courses of grain filling. The heterosis over mid-parent based
      on population mean appeared to be positively significant at the early and middle
      grain filling stages (1-18 d), but became insignificant at the late stages (19-28
      d) in late rice. The heterobeltiosis based on population mean appeared to be
      positively significant at the early grain filling stages (1-12 d), but turned to
      be significantly negative as the development process proceeded in late rice. It
      also indicated that the heterosis of grain weight development was beneficial to
      improve the quality of grain filling in late rice, compared to that in early
      rice. The genetic correlation between the grain weights per se at different
      stages and the final grain weight was mainly controlled by dominant effects, and
      became closer with the development process in the early rice, while by additive
      effects in the late rice. It's suggested that indirect selection of final grain
      weight throughout the process of grain filling would be more effective in late
      rice.

PMID- 15031915
TI  - [Quality variation of wheat planted in different regions of Tibet and Beijing].
AB  - In order to supply experimental basis for developing high quality and special use
      wheat for Tibet, multi-varieties experiments in different regions were carried
      out to study the quality variation of wheat varieties during 1998 to 2001. Field
      trials of sowing in spring and in autumn were conducted in Linzhi, Rikaze, Lasa
      and Beijing, and 5 indices including grain protein content, wet gluten content,
      sedimentation value, falling number and grain hardness were determined. The
      results showed that the quality characters were significantly different among the
      varieties, and extremely significant among the sites of same variety. The protein
      content of grains had a positive correlation to the other 4 indices, and could be
      a core index in quality characters of wheat. The parameters of quality characters
      were higher in inland varieties than in Tibet ones, the latter appearing weak or
      medium gluten, and those of the same varieties were higher in Beijing than in
      Tibet. When inland varieties were planted in Tibet, the parameters of quality
      characters would be decreased. The same variety in 3 sites of Tibet had different
      quality characters. There was a positive correlation between ecological height
      (latitude x elevation) and growth-development duration of varieties, but a
      negative correlation between growth-development duration and protein content, and
      between ecological height and protein content. Medium gluten varieties should be
      mainly planted in Tibet, and some good inland varieties could be introduced and
      planted according to the quality regionalization.

PMID- 15031917
TI  - [Long-term trial on fertilization and on use of recycled nutrients in farming
      systems V. Response of crop yields to fertilization in different precipitation
      years and estimates of water and nutrient interaction].
AB  - According to the responses of crop yields under fertilizations in 1996 with
      normal precipitation (456 mm in crop growth season) and in 1998 with higher
      precipitation (598 mm in growth season), the effect of water and nutrient
      interaction on crop yields in semihumid-semiarid region of west Liaoning Province
      were estimated. Under N application and sufficient water supply (more rainfall),
      the increase of crop yields was 3,056 kg.hm-2, of which, 1,996 kg.hm-2 was
      estimated from water-nutrient interaction, while in NP and compost treatment with
      sufficient water supply, the yield increase was 4,703 kg.hm-2, of which, 1,554
      kg.hm-2 was estimated from water-nutrient interaction.

PMID- 15031918
TI  - [Dynamics of urease activity in a long-term fertilized black soil and its
      affecting factors].
AB  - The effect of long-term fertilization on the urease activity in a typical black
      soil in Northeastern China was examined in this paper. The soil has been
      fertilized since 1980, and the dynamics of its urease activity was monitored
      during crop growth season. The results showed that a significant difference in
      soil urease activity was found at each growth stage between soils treated by
      different fertilizations. In farmyard manure treated soil, the urease activity
      was > 160 mg.kg-1.h-1 and with a low seasonal fluctuations. The soil urease
      activity had a significant positive correlation with soil biological, physical
      and chemical properties, and the N, P and K contents in plants (P < 0.01), and
      with soil moisture content and grain crude protein (P < 0.05).

PMID- 15031919
TI  - [Influence of cultivation on organic carbon in three typical soils of China Loess
      Plateau and Canada Prairies].
AB  - The dynamics of organic carbon in 3 soils of China Loess Plateau and Canada
      Prairies was significantly different: in China, the Huangmian soil (Calcaric
      Cambisols, FAO) lost 77% of total organic carbon (0-20 cm) within 5 years of
      cultivation, with a decrease rate of 2.11 tons C.hm-2.yr-1, which was mainly
      caused by water erosion and tillage erosion; and the Huihe soil (haplic greyxems,
      FAO) lost 70% of total organic carbon (0-20 cm layer) at the rate of 0.961.06
      tons C.hm-2.yr-1, because of water erosion and decomposition over 42 years.
      However, the orthic brown chernozem in Canada lost 11% and 44% of the total soil
      organic carbon (0-20 cm layer) after 40 and 80 years of cultivation,
      respectively, with a corresponding rate of 0.17 tons C hm-2.yr-1 and 0.45 tons C
      hm-2.yr-1. The improvement in tillage and rotation system, which prevented soil
      from wind erosion and increased current residues into soil, was responsible for
      the decrease of the loss rate. The dynamics of soil light fraction organic carbon
      (LFOC) was similar to that of total organic carbon: Huangmian and Heilu soil lost
      73% and 90% of LFOC, while orthic brown chernozem lost 74% and 70% of LFOC after
      breaked in 1920 and 1960, respectively. Among the test soils, Huangmian and Huihe
      soil had the fast SOC depletion due to the difference in the allocation of
      organic carbon between LFOC and HFOC.

PMID- 15031920
TI  - [Identification of agricultural resource & environment determination of the
      principle grain production area in China].
AB  - The 15 principle grain production areas and 16 non-principle grain production
      areas were determined on the basis of systematic identification and comprehensive
      analysis on agricultural resources and environment in the 31 provinces and
      regions of China, and the fundamental method for solving the problems on the
      deterioration of agricultural resources and environment has been put forward,
      which is to carry out macro-regulation of agriculture under the frame of WTO on
      the basis of developing the soft wares for agricultural macro regulation of the
      principle and non principle grain production areas.

PMID- 15031921
TI  - [Effect of straw pretreatment on soil microbial biomass and respiration
      activity].
AB  - Winter wheat straw particles (0.5 ~ 2.0mm) were soaked with 8.0 g.L-1
      H202(pH11.0), 12.5 g.L-1 Na0H or H2S04 solution for  8 h and dried at 80 degreeC.
      Soils amended with the pretreated straw and inorganic N were incubated
      aerobically at 25 degreeC for 60 days.  The C02 emission rate and soil microbial
      biomass C and N were measured at different time.  The results showed that during
      the earlier stage of incubation, the pretreatments of straw increased soil
      microbial biomass C by 1.0 ~ 1.4 folds, but decreased soil microbial respiration
      activity.  During the  later stage of incubation, the Na0H and H2S04 pretreated
      straw decreased soil microbial biomass carbon by 28% and 42%, respectively, while
      increased the soil microbial respiration activity.  The straw pretreated by H202
      increased soil microbial biomass nitrogen by 90% after the 15th day of
      incubation.  The pretreatments of straw increased  the fungi/bacteria ratio at
      different special time.  It could be concluded that soil microbial biomass and
      respiration activity could be changed after the pretreated straw was added into
      the soil.

PMID- 15031922
TI  - [Effect of doubled CO2 and O3 concentration and their interactions on
      ultrastructure of soybean chloroplast].
AB  - The effect of doubled CO2 and O3 concentration on the ultrastructure of
      chloroplast in leaf cells of soybean was tested by open-top chamber method, and
      examined under transmission electron microscope. The results showed that under
      doubled CO2 concentration, the amount and volume of starch grains in chloroplast
      increased, but the chloroplast membrane and the lamellar structure still kept
      integrated. The accumulation of starch grains was restrained, and the chloroplast
      membrane and the lamellar structure were disorganized under doubled-O3
      concentration. The ultrastructure of chloroplast was destroyed in different
      degrees under the interaction of doubled CO2 and O3 concentration. The damage to
      chloroplast arose from the abrupt doubling of CO2 and O3 was more severe than
      that from gradual increase of CO2 and O3 concentration. The negative effect of O3
      was partly compensated by the positive effect of doubled CO2.

PMID- 15031923
TI  - [Effect of methanol eluates from Ginkgo biloba root on growth and development of
      arbuscular mycorrhizal fungi cultured in vitro].
AB  - The effect of methanol eluates from Ginkgo biloba root on growth and development
      of arbuscular mycorrhizal fungi was studied under cultured in vitro. The study
      indicated that the methanol eluates from Ginkgo biloba root could significantly
      stimulate the spore germination and hyphal growth of arbuscular mycorrhizal fungi
      (Glomus mosseae, Gigaspora margarita), and the 80% methanol eluates had the most
      significant effect. There were rich flavonoids in the methanol eluates, and the
      highest flavonoids content was in the 80% methanol eluates. The mathematical
      analysis showed that there was a significantly positive correlation between the
      flavonoids content in the methanol eluates and the growth and development of
      arbuscular mycorrhizal fungi cultured in vitro.

PMID- 15031924
TI  - [Salt tolerance of wild soybeans in Jiangsu and its relation with ionic
      distribution and selective transportation].
AB  - The salt tolerance of 3 wild soybean (Glycine soja) populations was compared with
      their relative germination and seedling emergence. The results showed that the
      salt tolerance of Jiangsu wild soybean (JWS) was the strongest. Under NaCl
      stress, the dry matter accumulation in wild soybean seedlings decreased,
      root/shoot ratio increased, and these effects were greater in N23232 (salt
      sensitive) than in JWS (salt-tolerant). Determinations on the ion contents in
      different organs indicated that the Na+ content was higher in stem than in other
      organs, and the accumulation of Na+ and Cl- in roots was significantly more in
      JWS than in N23232. The contents of these ions in JWS leaves were much less than
      those in N23232 leaves. There was no significant difference between selective
      absorptions of K+ and Na+ (ASK, Na) by the two populations, but the selective
      transportation of K+ and Na+ (TSK, Na) in stem and leaf was much higher in JWS
      than in N23232, resulted in the higher K+/Na+ ratio in JWS shoots. It is
      suggested that the main reason for the salt tolerance in salt-tolerant wild
      soybean was the accumulation of Na+ and Cl- in roots and stems and the higher
      selective transportation of K+ from root to shoot.

PMID- 15031925
TI  - [Soil nitrogen mineralization and its prediction in winter wheat-summer maize
      rotation system].
AB  - The mineralization of soil nitrogen in winter wheat-summer maize growth season
      was studied with field experiment, and its prediction was made by interval
      leached aerial incubation combined with first-order dynamic model. The results
      showed that the amount of soil mineralized nitrogen had a large variation among
      years and crops. The soil nitrogen mineralization was lower in winter wheat
      growth season than in summer maize growth season, resulted in the yield increment
      of summer maize being not significant with increasing nitrogen fertilization
      rate. The amount of soil mineralized nitrogen occupied 31%-60% of the total
      nitrogen uptake by winter wheat and 62%-108% by summer maize. It was
      understandable why crop yield (especially summer maize) was not significantly
      response to applied nitrogen fertilizer. The amount of soil mineralized nitrogen
      decreased with increasing soil nitrogen supply. The mineralization was positive
      in normal nitrogen supply range(0-300 kg N.hm-2). The first order dynamic model
      could only predict the whole trend of mineralization in growth season, but could
      not reflect its variation in some growth stages. The role of the model was still
      important in view of the prediction of nitrogen mineralization before sowing.

PMID- 15031927
TI  - [Effectiveness of Eretmocerus sp. and Aschersonia aleyrodis in controlling Bemsia
      tabaci populations].
AB  - The effectiveness of Eretmocerus sp. and Aschersonia aleyrodis in controlling
      Bemisia tabaci populations on cucumber were determined in separated and combined
      greenhouse experiments. The results showed that after spraying A. aleyrodis (5 x
      10(6) spores per ml, twice per generation) and releasing Eretmocerus sp. (3
      female per plant, twice per generation), 95.74% and 57.58% of whitefly
      populations were controlled, respectively. However, when the two natural enemies
      were used together with the same rate mentioned above (A. aleyrodis spraying
      twice followed by releasing Eretmocerus sp. once or twice in one generation),
      97.02%-97.91% of whitefly populations were controlled. Moreover, the increasing
      index of whitefly population (I) subjected to both natural enemies together was
      below I, indicating the substantial reduction in whitefly population. The
      combined treatments provided a better control effect of whitefly than separated
      ones, and there was no contradicted effect between both natural enemies.

PMID- 15031926
TI  - [Tolerance of rice varieties to whitebacked planthopper Sogatella furcifera and
      variation of nutrient components in rice plants].
AB  - The study showed that the rice varieties N22, Luyuanzhan No. 1 and 94D-22 had a
      stronger tolerance to Sogatella furcifera, while Mudgo and K89-B5 had a weaker
      tolerance. The varieties Ptb33 and Zhongzu 74 were of antibiosis, and susceptible
      varieties Xiushui 11, Shanyou 63 and susceptible check varieties TN1 had no
      tolerance. After rice plants were infested by S. furcifera, the percentages of
      nitrogen content (N%) and soluble sugar content (S%) in tolerant varieties
      increased, but the ratio of nitrogen content to soluble sugar content (N/S)
      decreased obviously. For susceptible varieties, the variations of N%, S% and N/S
      were opposite to those of the tolerant varieties. In different varieties the
      contents of most kinds of free amino acid increased at various degrees, but those
      of alanine in susceptible variety TN1, alanine, threonine and methionine in
      tolerant varieties N22, and arginine in resistant variety Ptb33 decreased.

PMID- 15031928
TI  - [Effect of temperature on developmental duration of Amblyseius cucumeris].
AB  - With Polyphagotarsonemus latus as its prey, the developmental duration of
      Amblyseius cucumeris was 13.02, 9.61, 5.96, 5.26, 4.65, 4.78, and 5.80 days at
      18, 20, 23, 25, 28, 30, and 31 degrees C, respectively. The eggs of A. cucumeris
      could not hatch at 32 degrees C. The lower and upper developmental thresholds and
      the optimum developmental temperature of A. cucumeris from eggs to adults were
      12.77 degrees C, 33.50 degrees C and 23.87 degrees C, respectively.

PMID- 15031929
TI  - [Genes mapping on rice allelopathy against barnyardgrass].
AB  - By using the relay seeding technique with slight modification, a population of
      134 recombinant inbred lines (RILs) derived from a cross between indica rice
      (Oryza sativa L.) cultivar Zhong 156 x Gumei 2 and contained 168 DNA markers
      covering all 12 chromosomes with 1447.9 cM spans was employed to evaluate the
      rice allelopathic effect on barnyardgrass [Echinochloa crus-galli (I.) Beauv.].
      The phenotyping values of the biomass of barnyardgrass infested with rice
      materials were employed to map the genes of allelopathic activity on
      barnyardgrass. One main effect of QTL on 7 chromosomes was identified, which
      explained 32.30% of the phenotypic variation. Six pairs of digenic epistatic loci
      were also detected, which collectively explained 47.83% of the phenotypic
      variation. The main QTL and epistatic loci totally explained 80.13% of the
      phenotypic variation of allelopathic activity.

PMID- 15031930
TI  - [Effect of transgenic Bt rice planting on soil enzyme activities].
AB  - A pot experiment was conducted with silty loam Agrodolf as test soil and with
      transgenic Bt rice and non-Bt rice as test crops to study the effect of
      transgenic Bt rice planting on soil urease, phophatase, arylsulfatase, invertase,
      and dehydrogenase activities. The results showed that Bt toxin could be
      introduced into soil through root exudates of transgenic Bt rice, and its
      survival amount in soil varied with time. Compared with non-Bt rice treatment,
      transgenic Bt rice treatment had a significant decrease (2.47%) of soil urease
      activity and a significant increase (8.91%) of soil acid phosphatase activity,
      but no significant change in soil arylsulfatase, invertase, and dehydrogenase
      activities at the 15th day of emergence. At the 30th day of emergence, the
      transgenic Bt rice treatment still had a significant decrease of soil urease
      activity (16.36%) and a significant increase of acid phosphatase activity
      (35.69%), and no change in invertase activity. It also had significant increase
      in soil arylsulfatase (19.70%) and dehydrogenase activities (16.83%).

PMID- 15031931
TI  - [Effects of different water, fertility, and light conditions on allelopathic
      traits of rice].
AB  - The allelochemicals and allelopathic potentials of rice (Huahang No. 1) were
      investigated under different water, fertility, and light conditions with pot
      culture. The results showed that the allelopathic potential of Huahang No. 1 was
      stronger at high levels of water and fertility, but its specific allelochemicals
      contents had no significant variation at both levels. The numbers of the total
      secondary metabolites and the contents of some anti-pathogenic chemicals were
      increased at low level of water or fertility. Furthermore, the contents of
      specific allelochemicals in Huahang No. 1 were lower under strong light than
      under weak light condition. Similarity, the allelopathic potential decreased, and
      the contents of some anti-pathogenic chemicals maintained unchanged under weak
      light condition. No matter what levels of water, fertility or light conditions
      were, the allelopathic potential of Huahang No. 1 on associated weeds was weaker
      than that on non-associated ones.

PMID- 15031932
TI  - [Methane oxidation in soil profiles of broad-leaved Korean pine mixed forest in
      Changbai Mountain].
AB  - Samples were collected from dark-brown forest soil in different depths in the
      virgin broad-leaved/Korean pine mixed forest in Changbai Mountain. Laboratory
      study on methane oxidation of forest soil revealed the vertical profiles of
      methane oxidation activity. The maximum methane oxidation occurred at the horizon
      5-15 cm below the soil surface. When incubated with 400 ppmv methane, it had the
      highest uptake rate of 3.3 nmol.h-1.g-1 dw. Soil at horizon below 25 cm had a
      negligible capacity to oxidize methane. The methane-oxidation capacity of surface
      soil (0-5 cm) decreased because of the inhibition effect of high concentration
      NH4+ on methanotrophs.

PMID- 15031933
TI  - [Relationship between CH4 and N2O emissions and related microorganism populations
      in paddy soils under different water management regimes].
AB  - Methanogens, methanotrophs, nitrifiers and denitrifiers are the important
      microorganisms in the production and consumption of CH4 and N2O in soil. In order
      to understand the microbial processes related to the two greenhouse gases in
      paddy soil, the four bacteria groups in phaeozem (Hailun) and burozem (Shenyang)
      were surveyed during rice growth season by using MPN counting technique. The CH4
      and N2O emissions were measured with closed chamber method. Two different water
      management regimes, i.e., continual irrigation and intermittent irrigation, were
      used for the two paddy soils. The results of multiple regression analysis showed
      that there was a significantly positive correlation between CH4 emission and
      methanogen population in both phaeozem and burozem under two water management
      regimes. In the soil of Shenyang, there was a significantly positive correlation
      between CH4 emission and methanotropli population. The N2O emission was
      significantly correlated to the denitrifier population in both phaeozem and
      burozem under intermittent irrigation, and in the soil of Shenyang, there was a
      significantly positive correlation between N2O emission and nitrifier population
      under two water managements.

PMID- 15031934
TI  - [Seasonal variations of soil microbial biomass, respiration rate and CH4 emission
      in black earth rice fields].
AB  - The measurements of soil microbial biomass C, respiration rate and CH4 emissions
      during one rice growth period in black earth rice fields showed that the soil
      microbial biomass C and respiration rate were depressed significantly by the
      application of slow-releasing urea at the early stage of rice growth period (P <
      0.05), but almost not affected by intermittent irrigation. The CH4 emission was
      decreased by 32.5% in the intermittent irrigation treatments, but not
      significantly affected by the application of slow-releasing urea, compared to the
      control. It was significantly related to soil microbial biomass C in slow
      releasing urea treatments.

PMID- 15031935
TI  - [Effect of atrazine on urease activity in soils with different fertility].
AB  - Four soils with different fertility were treated with different concentrations of
      atrazine. The results showed that the urease activity was stimulated in the soils
      treated with low concentration of atrazine at the first day, while inhibited
      after treated with high concentration of atrazine during the whole period of the
      experiment. There was a significant difference in urease activity in soils with
      different fertility after treated with high concentration atrazine. The urease
      activity in CK and in NPK was significantly inhibited, the inhibition rate
      reached 30.35% and 28.89%, respectively, but in NPK + S and NPK + M, the
      inhibition rate was only 21.35% and 16.86%, respectively. The maximum inhibition
      rate appeared later in soils with high than with low fertility, showing that
      soils with high fertility could endure the effect of atrazine.

PMID- 15031936
TI  - [Spatial-temporal distribution and variation of atmospheric SO2 concentration in
      Hangzhou].
AB  - The feasibility of diffusible sampler for monitoring SO2 in cantonal Hangzhou was
      studied, and its correlation equation with automatic monitoring was built. The
      distribution and variation of SO2 concentration in Hangzhou were analyzed and
      mapped. Position of SO2 concentration centre was changed along with different
      climate condition. SO2 concentration centre moved towards south in summer with
      higher diffusion capability of atmosphere and enlarged in winter with thicker
      inversion layer. Intension and frequency of acid rain were consistent with change
      tendency of SO2 concentration.

PMID- 15031937
TI  - [Effect of monocrotophos on Na+/K(+)-ATPase activity and ultramicrostructure of
      Sciaenops ocellatus branchiae].
AB  - The exposure of Sciaenops ocellatus to monocrotophos at its concentration of
      0.25, 0.5, 1.0 or 2.0 mg L-1 for 4 days demonstrated that under the stress of low
      concentration (0.25 mg.L-1) monocrotophos, the chloride cells of branchiae
      proliferated, accompanied with the increase of Na+/K(+)-ATPase activity, while
      under high concentrations of monocrotophos, the damage of gill was much heavier,
      and the Na+/K(+)-ATPase activity also decreased. The damage in gill under
      sublethal monocrotophos exposure included hypertrophy and edema, and thus, the
      lamellar epithelium became thick and lifting, and the lamellae were bulbing or
      fusing. The ultramicrostructural changes of the gill of the exposure fish were
      the swollen and even rupture of rER, mitochondria, microtubule and nuclear
      membrane.

PMID- 15031938
TI  - [A research review on "fertile islands" of soils under shrub canopy in arid and
      semi-arid regions].
AB  - Due to the inclemency of climate and soil conditions and the intense disturbance
      of human beings, the soil resources heterogeneity in arid and semi-arid grassland
      ecosystems worldwide was gradually increased during the last century. The
      interaction between soil heterogeneity and shrubs induced the autogenic
      development of "fertile islands" and the increasing spread of shrubs in the
      grassland ecosystems. The development of "fertile islands" around individual
      shrubs could change the vegetation composition and structure, as well as the
      distribution patterns of soil resources, and thus, reinforced the changes of the
      ecosystem function and structure from a relative stable grassland ecosystem to a
      quasi-stable shrubland ecosystem. The study of "fertile islands" phenomenon would
      help us to understand the causes, consequences and processes of desertification
      in arid and semi-arid areas. In this paper, the causes of "fertile islands", its
      study methods and significance and its relationship with shrub spreading as well
      as the responses of vegetation to it were summarized. The problems which might
      occur in the study of this phenomenon were also pointed out. Our aim was to offer
      some references to the study of land desertification processes and vegetation
      restoration in the arid and semi-arid regions.

PMID- 15031939
TI  - [Ecological benefit assessment of urban vegetations by remote sensing and GIS].
AB  - As an important part of the urban ecosystem, urban vegetation plays an important
      role in improving urban environmental quality. The assessment of ecological
      benefits of urban or regional vegetations can help us more properly plan urban
      green space pattern, optimize urban vegetation structure, and further strengthen
      ecological construction. Through the discussion of the relevant researches at
      home and abroad, it's indicated that remote sensing and GIS could help as better
      evaluate the ecological effect of urban vegetations. This article introduced the
      UEA method adopted by AMERICAN FORESTS and CITYgreen software working with
      ArcView 3.2, as to make the best use of remote sensing and GIS in evaluating
      urban vegetation ecological effect quantitatively, and to promote sustainable
      development and ecological construction.

PMID- 15031940
TI  - [Research progress on hydrological scaling].
AB  - With the development of hydrology and the extending effect of mankind on
      environment, scale issue has become a great challenge to many hydrologists due to
      the stochasticism and complexity of hydrological phenomena and natural
      catchments. More and more concern has been given to the scaling issues to gain a
      large-scale (or small-scale) hydrological characteristic from a certain known
      catchments, but hasn't been solved successfully. The first part of this paper
      introduced some concepts about hydrological scale, scale issue and scaling. The
      key problem is the spatial heterogeneity of catchments and the temporal and
      spatial variability of hydrological fluxes. Three approaches to scale were put
      forward in the third part, which were distributed modeling, fractal theory and
      statistical self similarity analyses. Existing problems and future research
      directions were proposed in the last part.

PMID- 15031941
TI  - [Concept of system productivity and its significance in ecological reconstruction
      of pasture and agriculture transitional zone in China].
AB  - In recent years, the debate on the strategies of developing Loess Plateau has
      been ended with a consensus, i.e., instead of traditional grain production,
      grass/livestock industries together with some other specific industries such as
      fruits and forests ought to be the "polar" industries in this area. However, such
      a new pattern has not appeared. Enlightened by the basic principles of ecology,
      the intrinsic contradiction between output and maintenance/repair of agro
      ecosystem, in terms of energy requirement, could not be well coordinated and
      resolved just by raising the primary productivity or secondary productivity,
      which is particularly the case for such a ecologically fragile area as Loess
      Plateau. In this paper, a new concept of system productivity was proposed as a
      possible way that could use pluses and bypass minuses in ingeniously fitting the
      natural conditions and fully and rationally utilizing natural resources,
      especially the superiorities of climate resources, and centered on the selection
      and utilization of plant germplasms with higher water use efficiency, better
      coverage effect, and maximum biomass potential for fodder, i.e., cultivating
      fodder/feed-oriented plants for new livestock industry, thus finding an
      unprecedented approach that can harmonize the ecological reconstruction and
      development of vital industries.

PMID- 15031942
TI  - [Molecular ecological basis of high-yielding formation of rice and its
      application].
AB  - This paper introduced the developmental genetics and its molecular ecological
      basis of high yielding formation of rice in the past decade, and analyzed the
      advantage and the shortage of comparative physiological approach traditionally
      used in the research work on crop cultivation. It was emphasized to actively
      introduce the research contents and its methodology from relative disciplines to
      deeply understand the scientific issue, and suggested that the key to realize
      stable and high yielding of rice was to develop a rational cultivation system
      based on the properties of genetic effects on the traits in different
      developmental stages by controlling and regulating the traits governed by
      dominant effect genes and additive effect genes x environment in same direction,
      which was considered as the main characteristics and the technological innovation
      of modern crop genetic ecological cultivation science. Finally, the development
      trend of crop cultivation science shifting to molecular crop cultivation science
      was predicted and discussed.

PMID- 15031943
TI  - [Effect of atmospheric CO2 enrichment on soil microbes and related factors].
AB  - This paper summarized the effects of atmospheric CO2 enrichment on soil microbes
      and their related factors, including soil microflora, soil respiration, soil
      microbial biomass, and higher plant-microbe symbiosis. The factors related to
      soil microbic activity such as litter decomposition, root exudates, soil nutrient
      availability, nutrient use efficiency and soil fauna were also affected by the
      CO2 enrichment.

PMID- 15031944
TI  - [Research advance in catalytic kinetics of soil hydrolase].
AB  - Soil hydrolase is a group of soil enzymes that participated in many important
      biochemical reactions in soil and correlated with soil nutrient transformations.
      The catalytic kinetics of soil hydrolase can illuminate the characteristics of
      its catalytic processes, its substantial properties, and its response to
      environmental changes. This paper summarized the kinds of soil hydrolase and the
      main soil biochemical reactions they catalyzed, and summed up the research
      advances of their catalytic kinetics in soil. Some advices were proposed in
      understanding their action mechanism and in regulating their catalytic processes.

PMID- 15031945
TI  - [Oxygen-limited autotrophic nitrification and denitrification--a novel technology
      for biological nitrogen removal].
AB  - Oxygen-limited autotrophic nitrification and denitrification (OLAND) is a
      biological nitrogen removal process coupled with partial nitrification and
      anaerobic ammonium oxidation. In our study, the nitrification was blocked at
      nitrite stage by controlling the dissolved oxygen concentration at 0.1-0.3 mg.L
      1, and then, the denitrification proceeded, with the residual ammonium at the
      partial nitrification stage as electron donor. As a completely autotrophic
      nitrification-denitrification process, the OLAND was of many advantages (e.g.,
      low energy consumption, high nitrogen removal rate and small footprint of
      system), and suitable in particular for treating low COD/NH4(+)-N ratio
      wastewater. It has become one of the most prosperous and practicable biological
      nitrogen removal technologies. The recent research of OLAND was reviewed, and its
      microbial mechanism as well as its applicable prospect was remarked in this
      paper.

PMID- 15031946
TI  - [Research advances on controlled-release mechanisms of nutrients in coated
      fertilizers].
AB  - Using encapsulation techniques to coat easily soluble fertilizers is an important
      way to improve fertilizer use efficiency while reduce environmental hazards.
      Based on a wide range of literature collection on coated fertilizer research, the
      theories, processes, and characters of nutrient controlled-release from coated
      fertilizer were discussed, and the factors affecting nutrient controlled-release
      and the mathematical simulations on it were reviewed. The main tendencies related
      to this research in China were also put forward.

PMID- 15031947
TI  - [Advance in enzymological remediation of polluted soils].
AB  - Soils enzymes play an important role in the remediation of polluted soils. The
      enzymological remediation of polluted soils has the characteristics of high
      specialization, wide applicability, and little sensitivity to the ambient
      factors. This paper reviewed the advantages of enzymological remediation of
      polluted soils, the methods and technologies of enzyme immobilization, and the
      removal mechanisms of pollutants by oxidoreductases. The sources and
      characteristics of the enzymes used to remediation were also introduced, and some
      suggestions about the research in the future were put forward.

PMID- 15031949
TI  - [Biological evolution and specialization].
AB  - There were some disputes about the concept and mechanism of biological evolution.
      This paper tried to give more explanations on the key concepts. The biological
      adaptability was distinguished into two different concepts: biological evolution
      and specialization. The former was defined as the process of biologically gradual
      evolvement, and the latter was considered as the process of species formation at
      horizontal development. Moreover, a new conceptual framework was applied to the
      popular biological theories known by people, and the previous research results or
      discoveries were explained over again.

PMID- 15031948
TI  - [Application of terrestrial invertebrates biomarkers in soil pollution ecology
      study].
AB  - Biomarkers in terrestrial invertebrates play an important role in estimating
      either exposure or resultant effects of pollutants in soil ecosystem, which has
      received increasing attention and made significant progress. The present paper
      has drawn three important biomarkers, i.e., lysosomes, stress protein and
      mettllothioneins (MTs). The lysosomal membrane stability of coelomocytes was
      assayed as neutral-red retention time (NRR-time) resulting from toxicant stress.
      Hsp70 and Hsp60 were commonly used in the stress protein families. The
      quantification methods of different isofoms of the mettllothioneins could
      specifically indicate different metal contamination. The rationale,
      characteristics, and relevant exemplary case of assaying the biomarkers and their
      promising application to ecotoxicological diagnosing in soil contamination were
      discussed.

PMID- 15031950
TI  - [Height structures of dominant species of different subtropical evergreen
      broadleaved forest communities in Wanmulin Natural Reserve].
AB  - Based on the data of four subtropical evergreen broadleaved forest communities in
      Wanmulin Natural Reserve, whose dominant species were Tsoongiodendron odorum
      Chun, Cinnamomum micranthum Hayata, Castanopsis fabri Hance and Pinus massoniana,
      respectively, the height class and diameter class structures and the dynamics of
      height structure were analyzed. The results showed that the relationships between
      tree species, tree density, basal area at D. B. H, and height class (or diameter
      class) could be simulated by different equations. There was a significant
      positive correlation between tree species and tree density for different height
      class or different D. B. H. class. The structure dynamic analysis showed that the
      community of Tsoongiodendron odorum Chun was very unstable, and the species
      sharing degree in four communities was fairly lower, indicating that the dominant
      species were very obvious. The results could give a useful clue for the studies
      on endangered mechanism of rare species.

PMID- 15031951
TI  - [Response of an Arabidopsis mutant to elevated CO2 concentration].
AB  - The study on the response of a mutant and a wild-type of Arabidopsis to 660
      microliters.L-1 CO2 and ambient CO2 showed that under elevated CO2, the stomatal
      numbers of the mutant increased, while those of the wild-type decreased. The
      chlorophyll content and NR (nitrate reductase) activity of the mutant increased,
      but those of the wild-type had no obvious response. The mutant was not
      reproductively mature after the continuous exposure to increased CO2 for five
      months. The results provided evidence of plant response to the changes of
      atmospheric CO2 concentration, and the clues to related studies on other plants.

PMID- 15031952
TI  - Relationship between the state of the surface of four commercial quartz flours
      and their biological activity in vitro and in vivo.
AB  - Four commercial quartz dusts (flours), two inflammogenic in vivo and activating
      macrophages in vitro (Qz 2/1-c and Qz 3/1-c) and two mostly inert (Qz 5/1-c and
      Qz 11/1-c), have been compared regarding their surface properties, in order to
      detect chemical differences which may account for their different biological
      behaviour. The following features have been examined: 1) extent of the amorphous
      fraction (heat associated alpha<-->beta transition of quartz) and its solubility
      in HF; 2) potential to cleave a carbon-hydrogen bond with consequent generation
      of carbon centred radicals (spin trapping technique, EPR); 3) evolution of
      surface functionalities upon heating (FTIR spectroscopy); 4) mechanisms of
      adsorption of water on dusts outgassed at 150 degrees and at 800 degrees C
      (adsorption calorimetry). HCl treated samples have also been examined. The two
      "less toxic" quartzes are more resistant to HF attack, coordinate irreversibly
      H2O molecules and exhibit strong adsorption sites, which are absent in the other
      two and in a very pure quartz dust. Conversely all samples show the same
      potential to release free radicals. The different behaviour of the two sets of
      dust is consistent with a different level of impurities, namely aluminium ex
      kaolin, carbon and alkaline ions. The less inflammogenic quartzes appear to be
      covered by aluminium ions (and possibly iron) which strongly holds molecular
      water or carbonates, thus reducing the silanol patches to a large extent and
      changing the surface properties of the particles. We hypothesize that cellular
      response, and particularly macrophage activation and death, is mediated by strong
      interactions between silanol patches and some cell membrane components, but
      inhibited when the surface of the particle is modified by the presence of
      aluminium ions, surface carbonates and other metal contaminants. This hypothesis
      suggests that grinding procedures with little appropriate additives, e.g. kaolin,
      alumina, can reduce the biological activity of quartz dusts.

PMID- 15031953
TI  - In vitro genotoxicity assessment of commercial quartz flours in comparison to
      standard DQ12 quartz.
AB  - Crystalline silica has been classified as a human carcinogen, but there is still
      considerable debate on its variable fibrogenic and carcinogenic potential. We
      investigated genotoxicity of a panel of four quartz flours in comparison to DQ12
      standard quartz with similar size and surface area, using single cell gel
      electrophoresis (SCGE) or comet assay. A549 human lung epithelial cells were
      incubated for 4 hours with different concentrations of quartz ranging from 1.6 to
      200 micrograms/cm2 and cytotoxicity was assessed using leakage of lactate
      dehydrogenase (LDH), trypan blue exclusion and conversion of a metabolic
      substrate (MTT). DNA strand breakages were seen with all quartzes at an in vitro
      concentration of 200 micrograms/cm2. At this concentration all tests and quartz
      samples showed significant cytotoxicity. The most toxic quartz flour (Qz 2/1-C)
      but not DQ12, showed an increase in strand breaks at 40 micrograms/cm2 in cell
      culture. At this concentration no cytotoxicity was seen with LDH and MTT, but a
      significant increase in cells with trypan blue uptake was noted. No differences
      in tail moment percentage were observed at equal concentrations of different
      quartz flours. Also no correlation between DNA damage and OH-radical generation
      or surface radicals as measured by electron spin resonance was observed. We
      conclude that quartzes do not cause strand breaks without concomitant cell
      toxicity and a sufficient in vitro concentration of > 40 micrograms/cm2 can only
      be reached in vivo with instillation of massive doses (> 100 mg). Therefore, in
      vitro genotoxicity found here is unlikely to explain the genotoxicity observed in
      in vivo studies with the same and other quartzes.

PMID- 15031954
TI  - Different toxic, fibrogenic and mutagenic effects of four commercial quartz
      flours in the rat lung.
AB  - There is still intensive debate on the variability in the biological activities
      of different quartz species. Therefore we examined in a rat lung model the
      inflammatory, fibrogenic and genotoxic characteristics of four commercial quartz
      flours. The samples, two with probably low activity and two with probably high
      activity were selected from a panel of 16 samples on the basis of in vitro
      investigations. Rats were exposed by a single intratracheal injection of 0.6, 1.2
      and 2.4 mg quartz samples per lung or with 1.2 mg standard quartz DQ12. After 90
      days the inflammatory response was measured in the bronchoalveolar lavage fluid,
      as well as the content of 8-oxoguanine in the DNA of the lung cells. Additionally
      mutated p53 protein was determined. The four quartz samples revealed specific
      differences in all parameters investigated. In good agreement with the in vitro
      results the two samples expected as lowly active showed only weak inflammatory
      and no genotoxic reactions in the rat lungs. In contrast the two samples
      suspected as highly reactive induced a pronounced inflammatory response and for
      one of the samples genotoxic effects could be proven. The results raised here
      show a broad spectrum of biological activities dependent on the type of quartz
      from almost inert to genotoxic and highly inflammatory.

PMID- 15031955
TI  - Applicability of a set of diagnostic tests in indoor air health research.
AB  - Following recommendations from literature, 22 diagnostic tests for the most
      frequent complaints of indoor air health problems were selected and assessed for
      their applicability in epidemiological studies. The tests were applied seven
      times during one year to 40 volunteers who to all appearances were not affected
      by indoor air health problems. Most psychophysical tests (e.g., Continuous
      Performance Test) turned out to be suitable, but physiological tests were either
      heavily disturbed by technical problems (e.g., portable electrogastrography), or
      biased by application techniques (e.g., acoustic rhinometry), or were simply too
      time-consuming (e.g., PC-based voice analysis). Hence, as standardized
      measurements and quantitative diagnostic tests in epidemiological indoor air
      health research may contribute to a better understanding of cause-effect
      relationships and yield new approaches for preventive and therapeutic strategies,
      more research is urgently needed to develop and evaluate suitable physiological
      tests and functional measurements.

PMID- 15031956
TI  - Symptoms of ill health ascribed to electromagnetic field exposure--a
      questionnaire survey.
AB  - From June 2001, health questionnaires were distributed to people who complained
      about symptoms of ill health which they ascribed to exposure to electromagnetic
      fields (EMF). The objective of the survey was to gain a better knowledge of the
      anxieties of complainants, to obtain hints of possible problems and of actions
      that should be taken to solve the problems. The survey was not designed to
      establish a causal association between exposure to EMF and symptoms of ill
      health. Within one year, 429 questionnaires were returned of which 394 persons
      reported symptoms. The average age of the complainants was 51.0 years and 57
      percent were female. The complainants were older, had a higher educational level
      and were more likely to be married compared to the general Swiss population. A
      mean of 2.7 different symptoms were reported. Sleep disorders (58%), headaches
      (41%), nervousness or distress (19%), fatigue (18%), and concentration
      difficulties (16%) were most common complaints. Complainants related their
      symptoms most frequently to exposure to mobile phone base stations (74%),
      followed by mobile phones (36%), cordless phones (29%) and power lines (27%). No
      distinct symptoms related to a specific field source could be identified. Eighty
      five percent of the people who consulted a public authority because of their
      symptoms were unsatisfied with the response, whereas consultation of self-help
      groups or building ecologists usually fulfilled expectations. Two thirds of
      complainants had taken some action to reduce their symptoms. The most common
      measure was to avoid exposure if possible. Removing or disconnecting indoor
      sources was judged to be the most effective action.

PMID- 15031957
TI  - Effects of a single inhalative exposure to formaldehyde on the open field
      behavior of mice.
AB  - The effects of formaldehyde on the explorative behavior and locomotor activity of
      mice after a single inhalative exposure were examined in an open field. Adult
      male mice were exposed to approximately 1.1 ppm, 2.3 ppm, or 5.2 ppm formaldehyde
      vapour for 2 hours and the open field test was carried out two hours after the
      end of exposure (trial 1) and repeated 24 hours thereafter (trial 2). The
      following behavioral parameters were quantitatively examined: numbers of crossed
      floor squares (inner, peripheral, total), sniffing, grooming, rearing, climbing,
      and incidence of fecal boli. The results of the first trial revealed that the
      motion activity was significantly reduced in all exposed groups. In the 1.1 ppm
      group, the frequency of rearing was reduced and that of floor sniffing increased.
      The exposure to the two higher formaldehyde concentrations caused a significant
      decrease in total numbers of floor squares crossed by the subjects, air sniffing,
      and rearing. The open field test on the next day (trial 2) showed that the
      frequencies of floor sniffing, grooming, and rearing in all formaldehyde groups
      were significantly altered. In the 2.5 ppm group, an increased incidence of fecal
      boli was observed. From the results obtained, we conclude that the exposure of
      male mice to formaldehyde vapour affects their locomotor and explorative activity
      in the open field, and that some open field parameters are still altered in the
      exposed animals even after 24 hours.

PMID- 15031958
TI  - Effect of exposure to volatile organic compounds on plasma levels of
      neuropeptides, nerve growth factor and histamine in patients with self-reported
      multiple chemical sensitivity.
AB  - Plasma levels of substance P, vasoactive intestinal peptide and nerve growth
      factor, but not histamine, were elevated in patients with self-reported multiple
      chemical sensitivity (sMCS). Exposure to volatile organic compounds (VOC)
      increased plasma levels of all parameters in these patients, while it had no
      effect in normal subjects or patients with atopic eczema/dermatitis syndrome
      (AEDS). Exposure to VOC also enhanced skin wheal responses induced by histamine
      in patients with sMCS, while it failed to do so in normal or AEDS subjects. These
      results indicate that exposure to VOC may enhance neurogenic inflammation with
      concomitant enhancement of histamine-induced responses.

PMID- 15031959
TI  - The history of the plague and the research on the causative agent Yersinia
      pestis.
AB  - The plague is an infectious bacterial disease having a high fatality rate without
      treatment. It has occurred in three huge pandemics since the 6th century with
      millions of deaths and numerous smaller epidemics and sporadic cases. Referring
      to specific clinical symptoms of pulmonary plague the disease became known as the
      Black Death. This pandemic probably originated in central Asia and began
      spreading westward along major trade routes. Upon the arrival in the eastern
      Mediterranean the disease quickly spread especially by sea traffic to Italy,
      Greece and France and later throughout Europe by land. Until the 18th century
      many European cities were frequently affected by other great plague epidemics.
      The worldwide spread of the third pandemic began when the plague reached Hong
      Kong and Canton in the year 1894. The gram-negative coccobacillus now designated
      as Yersinia pestis has been discovered as the causative agent of plague in this
      Hong Kong outbreak. In the following years the role of rats and fleas and their
      detailed role in the transmission of plague has been discovered and
      experimentally verified. Today the plague is still endemic in many countries of
      the world.

PMID- 15031960
TI  - Commentary regarding the article by Drasch et al.: scientific comment on the
      German human biological monitoring values (HBM values) for mercury. Int. J. Hyg.
      Environ. Health 205, 509-512 (2002).

PMID- 15031961
TI  - It's all in your head.

PMID- 15031962
TI  - The surgical management of gastroesophageal reflux disease.
AB  - Laparoscopic anti-reflux surgery is a successful treatment modality for patients
      with refractory or complicated gastroesophageal reflux disease. Population based
      studies have shown an increase in the number of cases performed on a yearly basis
      throughout the country emphasizing its growing acceptance to treat this disease.
      A lower threshold for surgical intervention may be justified in the care of these
      patients, however it must be emphasized that the success of this operation
      depends on the selection of the appropriate patient and application of the proper
      surgical principles and technique.

PMID- 15031963
TI  - Gastric bypass.

PMID- 15031964
TI  - The state of laparoscopic surgery for colon carcinoma.

PMID- 15031965
TI  - Hepatocellular carcinoma.

PMID- 15031966
TI  - Supporting self-management to improve diabetes care.

PMID- 15031967
TI  - Frequency of selected surgical procedures, Rhode Island, 1999-2002.

PMID- 15031968
TI  - Miriam Hospital morbidity and mortality conference, December 3, 2003: abdominal
      pain and hematuria.

PMID- 15031970
TI  - The slow stain of contagion.

PMID- 15031969
TI  - Physicians, "wrongful life" and the Constitution.

PMID- 15031971
TI  - [Risk management in neurosurgery--is contemporary neurosurgery safe?].

PMID- 15031972
TI  - [Study of multiple cerebral aneurysms comprised of both ruptured and unruptured
      aneurysm--an analysis of incidence rate with respect to site and size].
AB  - The purpose of this investigation was to study the incidence rate of rupture with
      respect to the site and size of multiple cerebral aneurysms that include both
      ruptured and unruptured aneurysms. Site and size were investigated in 58 cases of
      this type of multiple cerebral aneurysm. All cerebral aneurysms were examined
      with MR angiography, 3D-CT angiography and digital subtraction angiography, as
      well as seeing measured using 3D-CT or digital subtraction angiography. As
      regards the site of the 58 ruptured cerebral aneurysms under study, 18 were
      internal carotid aneurysms (C2 or C3: 4 cases, IC-PC: 12 cases, IC-ancho.: 1
      case, IC terminal: 1 case), 25 were anterior communicating aneurysms, 10 were
      middle cerebral aneurysms, 4 were anterior cerebral aneurysms and 1 case was a VA
      PICA aneurysm. The ruptured internal carotid aneurysms were 4.0-21.0 mm in size,
      the anterior communicating aneurysms were 1.8-13 mm, the middle cerebral
      aneurysms were 2.0-21.3 mm, the anterior cerebral aneurysms were 3.2-9.1 mm, and
      the VA-PICA aneurysm was 4.4 mm. The sites of the 89 unruptured cerebral
      aneurysms break down as follows: 29 were internal carotid aneurysms (C2 or C3: 4
      cases, IC-PC: 10 cases, IC-ancho.: 10 cases, IC terminal: 5 cases), 18 were
      anterior communicating aneurysms, 34 were middle cerebral aneurysms, and there
      were 5 cases of posterior circulation aneurysm. In size, the unruptured internal
      carotid aneurysms were 1.0-18.3 mm, the anterior communicating aneurysms were 1.0
      6.5 mm, the middle cerebral aneurysms were 1.0-10.3 mm, the anterior cerebral
      aneurysms were 1.0-3.3 mm, and the posterior circulation aneurysms were 2.2-17.3
      mm. Out of 58 ruptured cerebral aneurysms, 44 were of the largest size category,
      and 53 (91.4%) were in the largest size category and/or anterior communicating
      aneurysms. The accumulated incidence rate of rupture of anterior communicating
      aneurysms rose suddenly upon reaching 2 mm in size, and after reaching 3 mm,
      these aneurysms accounted for a nearly uniform 55%-60% of the incidence rate of
      rupture. The accumulated incidence rate of rupture of IC-PC aneurysms rose
      drastically at 4 mm in size with the data describing a parabolic slope when
      graphed. IC-PC aneurysms represented a uniform 55% of the incidence rate of
      rupture after reaching 8 mm in size. The accumulated incidence rate of rupture of
      middle cerebral aneurysms rose in a gently sloping parabola beginning at 4 mm,
      and stabilized at 20% upon reaching 10 mm. These results suggest that each site
      is associated with a characteristic size and rate of aneurismal rupture. Special
      attention should thus be paid to large and anterior communicating aneurysms when
      operating on multiple cerebral aneurysms.

PMID- 15031973
TI  - [Pneumocystis carinii pneumonia complicating brain tumor].
AB  - Brain tumors are frequently treated with steroids due to the presence of
      peritumoral edema. However, in Japan it is not widely recognized that primary
      brain tumor patients who are receiving steroid therapy become susceptible to
      Pneumocystis carinii pneumonia (PCP). We reviewed the clinical features and risk
      factors for PCP in brain tumor patients treated at our institution between 1994
      and 2002. The treated cases consisted of 6 men and 6 women ranging in age from 47
      to 78 yr (mean age 65.3). Underlying diseases included malignant glioma in 9
      patients, malignant lymphoma in 2 patients and meningioma in one patient. All
      were diagnosed by respiratory disease specialists using bronchial washings and
      bronchoalveolar lavage or chest X ray/CT image. Radiation therapies were
      administered with 20 to 60 Gy (mean 52.9 Gy) except in one patient. Chemotherapy
      was performed with ranimustine in 4 malignant glioma patients and with
      methotrexate in 2 malignant lymphoma patients. Prednisone, begun perioperatively,
      was reduced gradually from a mean initial dosage of 38.3 mg/day orally. The
      duration of steroid treatment at the onset of PCP in these patients ranged from
      41 to 79 days (mean 61.4 days). Six patients (50%) died of PCP despite
      appropriate antibiotic therapy and 2 patients needed intensive therapy with a
      respirator. For early diagnosis of PCP, periodic serological (e.g.; the level of
      lactate dehydrogenase and beta-D-glucan) and radiological examination (e.g.;
      chest X ray and CT image) is indicated in patients with brain tumors, and
      prophylaxis against PCP might be needed for patients with intracranial neoplasms
      and who are also receiving high-dose and long-term steroid treatment.

PMID- 15031974
TI  - [Complications and diagnostic yield of stereotactic biopsy for the patients with
      malignant brain tumors].
AB  - PURPOSE: The purpose of this study was to assess the complication risk rate and
      diagnostic yield in a series of 211 procedures performed by a consistent method
      at one institute. MATERIAL AND METHOD: Two hundred and one patients underwent 211
      stereotactic biopsy procedures for diagnosis of malignant brain tumor at Niigata
      University between 1987-2001. Indication for stereotactic biopsy is decided on
      the following factors: 1) the patient is elderly or unsuitable for craniotomy; 2)
      the tumor location is in a deep, diffusing, multiple, eloquent site; 3)
      cytoreductive surgery is not needed to treat the suspected pathology. The
      specimen was obtained from the target point of CT scan by the aspiration method
      under local anesthesia except for in six patients who were children or needed
      operation for a VP shunt under general anesthesia. The lesion was located in 114
      cases of cerebral hemisphere, in 44 cases of basal ganglia, in 11 cases of
      cerebellum and in 11 cases of spreading site. RESULT: Histological diagnosis was
      obtained in 188 of 211 procedures and the diagnostic yield was 93.5%. There were
      104 high grade gliomas, 16 low grade gliomas, 5 germ cell tumors, 37 malignant
      lymphomas, 19 metastatic tumors and 13 negative/inconclusive biopsies. Sixteen
      patients incurred complications (7.6%). Four patients (1.6%) suffered
      intratumoral hemorrhage. Emergency craniotomy was performed in three patients and
      stereotactic aspiration of hematoma was carried out in one patient. Furthermore,
      of 12 complications, 9 occurred with the patient showing symptoms of worsening
      neurological deficit, 2 occurred with general convulsion and 1 occurred with
      severe facial pain. CONCLUSION: This study provided evidence that stereotactic
      biopsy was a safe and reliable tool for patients with unresectable malignant
      brain tumors.

PMID- 15031975
TI  - [Antibiotic treatment for traumatic brain injury patients without positive
      bacterial cultures].
AB  - Prophylactic administration of antibiotics is prevalent for traumatic patients
      including head injury, when the patients have contaminated wounds, CSF leakage,
      and multiple injuries. In cases with prolonged fever and inflammatory signs,
      other antibiotics must be selected without confirming the infections by cultures.
      Usually, 1st or 2nd generation cefalosporins are selected as empiric therapy for
      traumatic patients, but, successive antibiotics are usually selected according to
      the situation. In this study, we analyzed 60 cases of head injured patients with
      Glasgow Coma Scale under 12, in terms of the selection of antibiotics and the
      reasons for the antibiotic selections. CEZ > PIPC > FMOX were used for initial
      treatment without any culture results. The second selection was made without any
      positive culture results in 85.7%, and tertiary selection without culture results
      in 50% of the patients. CPR > CFSL > FMOX > PAPM/BP were mainly used as second
      selection, and IPM/CS > CPR = PIPC were mainly used as tertiary selection. In
      cases with traumatic brain injuries, it is important to prevent antibiotic
      resistances. 1) by selecting appropriate antibiotics, 2) by using antibiotics
      after excluding catheter related infections, 3) by not using antibiotics and
      performing frequent cultures when no apparent infection focuses are detected.

PMID- 15031976
TI  - [Therapeutic strategy and outcome of stenting for subclavian and innominate
      artery occlusive disease].
AB  - We performed stenting for the subclavian artery (SA) and innominate artery
      occlusive disease in 14 patients between April, 2000 and March, 2003. In 13 of 14
      patients, good dilatation was obtained with stenting. In one patient with left SA
      occlusion, true lumen could not be detained from either proximal or distal sides
      of the occluded lesion, so stent deployment was not performed. From June, 2002,
      we performed stenting using combined femoral and brachial approaches in 6 of 8
      patients. In patients in whom occlusive lesion existed in the proximal portion of
      the SA, it was useful strategy to create a "pull-through" system to stabilize the
      guiding catheter position in the aorta or the proximal portion of the SA, and to
      protect the vertebral artery (VA) with a balloon catheter. Post-operative
      morbidity was 0%. Restenosis was manifested in one patient (8%) two years after
      stent placement, and in-stent PTA was carried out. In stenting for the subclavian
      and innominate arteries, the pull-through system is considered useful for
      stabilization of the guiding catheter, and protection of the VA for prevention of
      distal embolism to the VA.

PMID- 15031977
TI  - [A case of intractable epilepsy presenting epileptic spasm treated with
      callosotomy in childhood].
AB  - We present a case of intractable epilepsy presenting epileptic spasm successfully
      treated with anterior callosotomy in childhood. A 12-year-old boy had seizures
      frequently since the age of 11 months which were diagnosed as an infantile spasm.
      He underwent various treatments including ACTH therapy, but the seizures were
      intractable. Characteristics of his seizures were an abrupt axial movement
      leading to sustained posturing, most often truncal, and neck flexion with
      pronounced arm extension and abduction. He lost consciousness transiently and
      these seizures frequently occurred in clusters and the duration of seizure was 1
      to 3 seconds. Neurologically he had no deficit, but his intelligence was below
      the standard level. Magnetic resonance image (MRI) showed no abnormalities in the
      brain. Electroencephalogram (EEG) demonstrated secondary bilateral synchrony
      (SBS) with left frontal dominance in amplitude. Subdural strip electrodes were
      implanted bilaterally over the frontal lobes to detect an epileptogenic region.
      However intracranial ictal-EEG demonstrated an abrupt bilateral desynchronization
      for 1-3 seconds. As the epileptogenic zone was not clearly identified and an
      abrupt bilateral desynchronization was identified, anterior callosotomy was
      performed. Since surgery, he has remained seizure-free for two years while taking
      anticonvulsants and the SBS has disappeared. This case may indicate that the
      corpus callosum influences the occurrence of epileptic spasm and SBS on EEG.

PMID- 15031978
TI  - [Endovascular treatment of a ruptured aneurysm associated with unilateral
      moyamoya disease].
AB  - We report a case presenting with subarachnoid hemorrhage due to a ruptured
      aneurysm associated with unilateral moyamoya disease. The patient was a 29-year
      old woman exhibiting sudden onset headache. Computed tomography revealed
      subarachnoid hemorrhage around the brain stem. Cerebral angiography showed a
      saccular aneurysm at the junction of the left P1 portion of the posterior
      cerebral artery and its perforator. The right internal carotid artery was
      occluded at the terminal portion, and the right middle cerebral artery territory
      was perfused anterogradely via abnormal moyamoya vessels in the basal ganglia.
      The aneurysm was completely embolized with preservation of the perforator. We
      suggest that as compared to surgical clipping by craniotomy, endovascular therapy
      is safe and effective for treatment of intracranial aneurysms associated with
      moyamoya disease.

PMID- 15031979
TI  - [The usefulness of MRI around the tentorial incisura for determining the
      mechanism of brain stem injury: a case report].
AB  - We report a case of isolated brain stem injury caused by the tentorium cerebelli.
      A 17-year-old male was admitted to our hospital. Thirty minutes before admission,
      he was struck by another motorcycle while driving his own motorcycle. The Glasgow
      Coma Scale (GCS) was 10. He had no extremity weakness and his pupils were normal.
      CT scan showed no evidence of intracranial lesions except for facial bone
      fractures. His consciousness level improved to GCS 13 at 6 hours after admission.
      Follow-up CT scan was normal, however MRI 3 days after admission showed a
      contusion at the left lateral midbrain. He was discharged without any
      neurological deficits on 6 days after admission. Analysis of the distance between
      the brain stem and the tentorial margin using MR cisternography showed that the
      left side was shorter than the right side. We presumed that an isolated lateral
      brain stem injury was caused by the direct impact of the tentorium cerebelli.
      Typically the location of this type of lesion is present in the same side as that
      of impact. However in this case the orientation was opposite to that. We
      considered that the distance between the brain stem and the tentorial margin
      affected the mechanism of this lesion.

PMID- 15031981
TI  - [Training of child neurologists].

PMID- 15031980
TI  - [Physiology for the stereotactic neurosurgery: a guide to stereotactic brain
      operations].

PMID- 15031982
TI  - [Rolandic epilepsy: neurophysiological aspects].
AB  - Rolandic epilepsy (RE) is a common epileptic syndrome, which child neurologists
      often see. However, many problems concerning RE remains unsolved despite previous
      extensive studies. This paper discusses the current status of knowledge and our
      own observation especially on neurophysiological aspects of RE, such as the
      morphology of rolandic discharge (RD), effectiveness of clonazepam on RD,
      rhythmic slow activity, extreme somatosensory evoked potentials, and generator of
      RD. RD is characteristic of RE, and sometimes appears to be enigmatic to child
      neurologists. RE is a representative epileptic syndrome in childhood, and should
      be investigated further to address its underlying mechanism.

PMID- 15031983
TI  - [A message for young child neurologists: a lesson from the Nobel Prize
      centennial].
AB  - The Nobel Prize was created in 1901, according to the will of Alfred Nobel who
      left tremendous estate by inventing of dynamite. In the fields of natural
      science, prizes are given to distinguished scientists in three categories, namely
      physics, chemistry, and physiology or medicine. During the past 100 years, the
      Nobel Prize have become undoubtedly the most prestigious international prize.
      Nobel laureates are always the most respected scientists in the world. There have
      been 478 recipients in the three categories, 177 of them belonging to physiology
      or medicine. In March 2002, an international forum commemorating the centennial
      of the Nobel Prize was held in Tokyo and Kyoto under the auspices of the Science
      Council of Japan, focusing upon creativity. Guest speakers including prize
      winners, officers of the Nobel Foundation, and members of the Nobel Committee
      participated actively. In particular, Japanese laureates, including Drs. Ezaki,
      Tonegawa, Shirakawa and Noyori met together at the Symposium, and discussed what
      is creativity and how it is nurtured? At about the same time the Centennial
      Exhibition of the Nobel Prize was held in the National Science Museum in Tokyo.
      From these two commemorative events, informative messages were extracted and
      given to young colleagues of the Japanese Society of Child Neurology.

PMID- 15031984
TI  - [Therapy for myopathies: from management to genetic treatment: introductory
      remarks].
AB  - Despite a wealth of recent information about the molecular basis of Duchenne
      muscular dystrophy (DMD), there is no effective treatment for this condition
      because the mechanism how dystrophin deficiency produces the muscle fiber
      degradation is unknown. Much effort has been made to develop a new treatment for
      DMD on clinical and molecular bases. This symposium consist of reports on recent
      advance of the gene, molecular and clinical therapies for DMD. It also discusses
      recent topics of therapeutic trial for glycogen storage diseases, featuring
      recombinant human acid alpha-glucosidase GAA enzyme therapy for fatal glycogen
      storage disease type II.

PMID- 15031985
TI  - [Gene therapy for muscular dystrophy].
AB  - Duchenne muscular dystrophy (DMD) is an X-linked, lethal muscle disorder caused
      by mutations in the dystrophin gene. Although an adeno-associated virus (AAV)
      vector-mediated gene transfer provides an attractive approach to the treatment of
      DMD, limitation in insertion size up to 4.9 kb excludes incorporation of a full
      length dystrophin cDNA (14 kb) into an AAV vector. We previously generated micro
      dystrophin transgenic dystrophin-deficient mdx mice. In 4.9 kb rod-truncated
      micro-dystrophin CS1 transgenic mdx mice, dystrophic phenotypes were ameliorated
      almost completely (Biochem Biophys Res Commun 2002; 293:1265-72). We therefore
      constructed an AAV vector expressing micro-dystrophin CS1 driven by a skeletal
      muscle-specific MCK promoter, as the expression of the LacZ gene driven by the
      MCK promoter is longer in an AAV vector than in the CMV promoter in the skeletal
      muscle (Gene Ther 2002; 9:1576-88). We injected the AAV-MCK delta CS1 into the
      anterior tibial (TA) muscles of 5-week-old mdx mice, which exhibit active cycles
      of muscle degeneration/regeneration. At 8 weeks after the AAV vector injection, a
      large percentage of fibers were dystrophic-positive (10 to 50%). Even 24 weeks
      after injection, 15 to 75% of myofibers expressed micro-dystrophin. Dystrophin
      positive fibers often had centrally located nuclei in the mice, however, the
      ratio was significantly reduced compared with that of dystrophin-negative fibers.
      We also measured tetanic force of AAV-MCK delta CS1-treated and non-treated mdx
      TA to evaluate functional amelioration. Non-treated mdx TA muscles showed marked
      reduction of specific tetanic force, while AAV-injected muscles showed moderate
      improvement. In conclusion, our study demonstrated that introduction of delta CS1
      micro-dystrophin with an AAV vector successfully protected mdx muscles from
      progressive dystrophic degeneration.

PMID- 15031986
TI  - [Treatment of Duchenne muscular dystrophy with gentamicin].
AB  - This article reviews the clinical application of gentamicin treatment for
      nonsense mutations. Since gentamicin is applied only for Duchenne muscular
      dystrophy caused by a nonsense mutation, genetic diagnosis of DMD is reviewed. Of
      the two reports describing gentamicin treatment of DMD, one concluded it to be
      effective, and the other to be ineffective.

PMID- 15031987
TI  - [Management of patients with Duchenne muscular dystrophy].
AB  - As there is no cure in Duchenne muscular dystrophy (DMD), we must pay attention
      to the management of its cardiopulmonary complications. In 1984, DMD patients
      died at the mean age of 18.2 years in my hospital. From autopsy findings, the
      cause of death was respiratory failure in 75% of them, and left-sided heart
      failure 12.5%. First, we had to know the relationship between cardiac and
      respiratory systems. Based on the findings of right-sided heart catheterization,
      patients with respiratory failure were classified into Forrester's subset 1'
      normal left ventricular function. These results showed that these patients
      require treatment with a respirator, but not with digitalis and/or diuretics.
      Since 1984, we tried cuirass ventilation, which prolonged their lives by about 3
      years. Since 1991, NIPPV was introduced in Japan, and prolonged their lives by
      about 5.5 years. Nowadays TIPPV with tracheostomy is not the first choice of
      treatment, but we do not hesitate to select this treatment any more. As for left
      sided heart failure, brain natriuretic peptide (BNP) is now considered a useful
      parameter of left ventricular function. Japanese clinical researcher proposed
      treatment based on values of BNP in left-sided heart failure. In 1980s, the mean
      interval from the onset of heart failure to death was only 16 months. Recently we
      feel that better results have already been accomplished. In 2002 Kawai reported
      that average age at death in Japan was 26.8 years old. More efforts must be made
      until cure of this disease is found.

PMID- 15031988
TI  - [Therapeutic trials for the patients with muscle glycogen storage diseases].
AB  - Muscle glycogen storage diseases (GSDs) are disorders of inborn error of
      metabolism, in which gene therapy restoring the deficient enzymes may ultimately
      cure the diseases. However, considering the pathophysiological basis of GSDs
      other treatments such as substrate supplementation, activation of the residual
      enzyme and enzyme replacement, are also important. Therapeutic trials in progress
      include the combined use of vitamin B6 and cornstarch for GSD type V, enzyme
      replacement therapy using rh-alpha-glucosidase for GSD type II, and ketogenic
      diet for GSD type IX.

PMID- 15031989
TI  - [Child neurology in Asia].

PMID- 15031990
TI  - [Clinical guidelines for treatment of epilepsy in children].

PMID- 15031992
TI  - [Treatment for mitochondrial diseases].

PMID- 15031991
TI  - [Selective serotonin reuptake inhibitors for behavior disorders].

PMID- 15031993
TI  - [Buccal midazolam for treatment of status epilepticus or repetitive seizures].

PMID- 15031994
TI  - University reform and introduction of the Harvard system to medical education.
AB  - At this point we may observe that problems in medical education should be sought
      for neither in the tutor-student ratio nor in the conditions of studies, but
      rather in the universities' general dilemma, in the conflict between patient
      care, research, and education. It is furthered by the absence of academic
      teaching's "market value" and of a specific didactic training. A series of
      teaching experiments, the Munich model among them, have shown that a successful
      strategy is viable toward developing a new system of teaching once the
      foundations have been laid by a clear-sighted analysis of the existing problem
      and of a precise definition of educational targets. This means groundbreaking
      work in developing a new spirit of medical education.

PMID- 15031995
TI  - Development of the ductus venosus in the SD rat.
AB  - We used scanning electron microscopy to observe the development of the ductus
      venosus in the fetal rat liver. At day 13 of gestation, the vascular system in
      the liver was already formed and the umbilical vein had branched many capillaries
      to the parenchyma of the liver and was connected to the posterior vena cava
      directly by one small ductus venosus. At day 14 of gestation, the umbilical vein
      bulged at its terminal part and bifurcated into the ductus venosus, which joined
      the posterior vena cava, and a branch that anastomosed with the vitelline vein.
      The ductus venosus had no branches and subsequently enlarged and then degenerated
      just before birth. The bulging part of the umbilical vein and its branches
      degenerated in the later stages of gestation. The vitelline vein developed to
      form the capillaries of the liver and the intestinal venous system. In the SD rat
      liver, the ductus venosus was therefore established by development of the
      terminal part of the umbilical vein, which anastomosed directly with the
      posterior vena cava.

PMID- 15031996
TI  - Functional cooperation of Ogg1 and Mutyh in preventing G: C-->T: a transversions
      in mice.
AB  - Oxygen radicals generated through normal cellular metabolism induce a variety of
      types of oxidative damage into DNA and its precursors. Among such types of
      oxidative damage, 7, 8-dihydro-8-oxoguanine (8-oxoG), an oxidized form of
      guanine, is known to be abundant and highly mutagenic. 8-OxoG can pair with
      adenine as well as cytosine, thus causing G: C to T: A transversions after DNA
      replication, if not repaired. Organisms are equipped with elaborate systems to
      avoid such mutations caused by 8-oxoG. In Escherichia coli, two DNA glycosylases
      have been identified to suppress these mutations. One is MutM, an 8-oxoguanine
      DNA glycosylase that removes 8-oxoG from 8-oxoG: C base pairs. The other is MutY,
      an adenine DNA glycosylase that excises adenine from 8-oxoG: A mismatches.
      Mammals also have such DNA glycosylases; OGG1 (Ogg1) is the functional
      counterpart of MutM, and MUTYH (Mutyh) is the MutY homologue. In order to
      investigate the roles of these two enzymes in the avoidance of 8-oxoG-related
      mutagenesis in mammals, we analyzed spontaneous mutagenesis in the small
      intestine of Ogg1-deficient (Ogg1-/-) and Ogg1-, Mutyh-double deficient (Ogg1-/-;
      Mutyh-/-) mice at the age of 4-5 weeks using the prokaryotic rpsL transgene as a
      reporter. The observed mutation frequency was 1.00 x 10(-5) in both wild type and
      Ogg1-/- mice, and 1.91 x 10(-5) in Ogg1-/-; Mutyh-/- mice, indicating that the
      overall spontaneous mutation frequency was increased in Ogg1-/-; Mutyh-/- mice,
      but not in Ogg1-/- mice. Analysis of the mutation spectrum revealed that the
      frequency of G: C to T: A transversions were significantly increased in both Ogg1
      /- and Ogg1-/-; Mutyh-/- mice; a 5-fold increase in Ogg1-/- mice, and a 41-fold
      increase in Ogg1-/-; Mutyh-/- mice when compared with wild type mice. A previous
      study in our laboratory indicated that a defect in Mutyh caused a 4-fold increase
      in the frequency of G: C to T: A transversions in mice. Combined, these
      observations suggest that a cooperative function between Ogg1 and Mutyh exists to
      prevent 8-oxoG-related mutagenesis in mammals.

PMID- 15031997
TI  - [The value of proper sputum collection instruction in detection of acid-fast
      bacillus].
AB  - PURPOSE: This study was conducted to assess clinically whether intervention with
      instruction applying respiratory rehabilitation method for expectorating sputum
      was useful or not to obtain more suitable sputum for smear examination of acid
      fast bacilli. SUBJECT: All specimens examined were sputa obtained from 163
      patients without the instruction group and 161 patients with the instruction
      group, who visited our outpatients clinic during one year from September 1, 2000
      to August 31, 2001 and the following one year, respectively. METHOD: Gross
      appearance of the sputum according to Miller & Jones' classification (M1, M2, P1
      P3) and smear positive rate by fluorescence staining method after N-Acetyl-L
      cysteine-NaOH treatment and centrifugation were compared between the two groups.
      RESULTS: M1 and P1 sputa were 21.5% and 21.5% in the no instruction group, while
      those were 8.1%, 36.6% in the instruction group. Difference in M2, P2 and P3
      sputa were not significant between the groups. Smear positive rate was 10.4% in
      the no instruction group, while it was 21.1% in the instruction group. According
      to gross appearance of M2, P1 and P2, positive rate was 11.1%, 11.4% and 30.8% in
      the no instruction group, and 17.7%, 28.8%, and 26.3% in the instruction group.
      Chest roentogenographic findings judged by type (cavitary and non-cavitary) and
      extent of the pulmonary lesions of these smear positive cases (17 in the no
      instruction group and 34 with the instruction group), revealed that the no
      instruction group consisted of more predominantly severer disease with cavity and
      moderately or far advanced lesions as compared with the instruction group.
      CONSIDERATION: We could exclude that the difference in gross appearance and smear
      positive rate of the sputum specimen between groups without and with the
      instruction might be due to differences in disease severity between the two
      groups with and without the instruction. CONCLUSION: The instruction for sputum
      expectoration seems to be useful to increase positive rate in the smear
      examination of acid-fast bacilli.

PMID- 15031998
TI  - [Relations between clinical subtypes of Mycobacterium avium pulmonary disease and
      polyclonal infections detected by IS1245 based restriction fragment length
      polymorphism analysis].
AB  - INTRODUCTION: The epidemiology of Mycobacterium avium-intracellulare (MAC)
      infections has not been completely defined. Recently some reports presented
      polyclonal MAC infections. The purpose of this study was to reveal the clonal
      diversity of Mycobacterium avium isolates and the relation between clinical
      subtype of lung disease and polyclonal infection. METHODS: We categorized
      pulmonary Mycobacterium avium infection to three clinical subtypes, tuberculosis
      like type, bronchiectasis with preexisting tuberculosis type and nodular
      bronchiectasis type. Mycobacterium avium isolates of 11 patients were studied for
      their heterogeneity using IS1245 based RFLP analysis. The insertion sequence
      IS1245 is repetitive element identified only in Mycobacterium avium. Standard
      method of IS1245 based RFLP analysis has been proposed as a suitable technique
      for typing of Mycobacterium avium isolates for epidemiological and taxonomic
      studies. At least three distinct colonies were subcultured to single clone. The
      subclones of the isolates were analyzed by IS1245 based RFLP technique and some
      subclones were also examined by antimicrobial susceptibility test. RESULTS: Two
      of three patients of tuberculosis like type were considered to be monoclonal
      infection because only a single genotype was identified. And only one of four
      patients of bronchiectasis with preexisting tuberculosis type was considered to
      be polyclonal infection despite of long-term observation. Although isolates were
      collected in two or more occasions in clinical course over one year period, only
      a single genotype was observed in two patients. In contrast, three of four
      patients of nodular bronchiectasis type had multiple genotypes. Isolates
      recovered from patients with monoclonal infection pattern following long-term
      treatment with clarithromycin monotherapy became resistant to clarithromycin. In
      contrast, three strains derived from one nodular bronchiectasis patient were
      susceptible to clarithromycin despite of long-term chemotherapy including
      clarithromycin. The susceptibility patterns of the other drugs were also
      apparently different. Strain conversion due to repeated polyclonal infection was
      considered. These results of the antimicrobial susceptibility test supported
      clonal diversity of the Mycobacterium avium infection. DISCUSSION: IS1245 based
      RFLP analysis possesses a discriminatory power between the isolates on clonal
      level. This study demonstrates that polyclonal infections are common in nodular
      bronchiectasis type and monoclonal infections are common in tuberculosis like
      type and bronchiectasis with preexisting tuberculosis type. And not only
      simultaneous polyclonal infection but also repeated polyclonal infection were
      observed in a nodular bronchiectasis type patient. Drug susceptibility test
      showed long-term chemotherapy including clarithromycin could change the
      susceptibility of clarithromycin to resistant in patients with monoclonal
      infection. In contrast patients with repeated polyclonal infection pattern would
      avoid drug resistance because of strain conversion. This multiple susceptibility
      patterns identified in this study would not have been detected by the standard
      susceptibility test without subculture. And we also need the treatment strategy
      considering the polyclonal infection. CONCLUSIONS: Polyclonal infections are
      considered to be common in pulmonary Mycobacterium avium infection, especially
      nodular bronchiectasis type. Clonal diversity of Mycobacterium avium infection is
      an important factor to perform chemotherapy and drug susceptibility test.

PMID- 15031999
TI  - [Beijing family and other genotypes of Mycobacterium tuberculosis isolates in
      Okayama district].
AB  - OBJECTIVE: The purpose of this study is to investigate the distribution of
      Mycobacterium tuberculosis genotypes, such as Beijing family and other genotypes
      in Okayama district, and to examine the relation between these genotype strains
      and prevalent strains. METHODS: The 142 M. tuberculosis strains isolated in
      Okayama City from January 2000 to December 2002 were subjected to IS6110-RFLP and
      spoligotyping for the population-based study. In addition, 13 strains having 1 to
      5 IS6110 copies isolated in Okayama Prefecture excluding Okayama City were also
      subjected to spoligotyping. RESULTS: A total of 103 (72.5%) of 142 strains
      belonged to Beijing family. Furthermore, 3 of 4 groups of prevalent strains
      belonged to the family. Twenty one strains out of 39 rest strains could be
      classified into 10 shared types (STs) of 259 STs in the worldwide spoligotype
      database. In addition, 15 out of 26 strains from inside and outside of Okayama
      City having 1 to 5 IS6110 copies showed common unique spoligotype. Moreover, the
      age of majority patients who were infected with M. tuberculosis of the Beijing
      family or other genotypes were older than 60 years. CONCLUSION: It was suggested
      that Beijing family had been the main infection source, and the spread of strains
      of Beijing family and other genotypes occurred considerably in old times, and the
      unique genotype strains remained for a long time as peculiar strains.

PMID- 15032000
TI  - [Tuberculosis control programme for the elderly with special focus on early
      detection].
AB  - 1. Epidemiological trend of TB and its diagnosis among the elderly: Masako OHMORI
      (Research Institute of Tuberculosis, JATA). It is estimated that over 10,000 TB
      patients will occur among the elderly aged over 75 years of age during 2010 and
      2020. Though the new TB patients among the elderly over 65 years of age decreased
      in number from 1987 to 2001, sputum smear positive patients, which are highly
      infectious increased by 1.3 times for the same age group, and 2.3 times for that
      of over 80 years of age. 17.6% of those elderly patients were detected in
      institutions, either hospitals or nursing homes. These indicate that the elderly
      will become higher risk of TB for causing early death and infection to others
      during their admission in the hospitals or nursing homes. 2. Clinical
      characteristics of TB among the elderly: Nobuhiko NAGATA (Department of Internal
      Medicine, National Ohmuta Hospital). Analysis of the 93 elderly TB patients shows
      that TB diagnosis was delayed among the elderly. For TB diagnosis, 43.2% took
      over 1 month, and 27.3% over 2 months among the patients over 75 years of age,
      compared to 22.9% and 9.7% respectively for the patients under 65 years. The
      prognosis was also poor. Of all who died in the hospital during TB treatment,
      40.9% (mostly complicated with other diseases) was among the elderly over 75
      years, while it was 6.5% among those under 65 years. Complication of dementia
      delayed the diagnosis. 79.4% of the smear positive patients over 75 years were
      diagnosed while admitted in a general ward, and 40% had been admitted 2 weeks or
      more before diagnosis. 3. Use of serological tests for the diagnosis of TB among
      the elderly: Atsuyuki KURASHIMA (Department of Clinical Research, National Tokyo
      Hospital). As TB diagnosis is difficult for the elderly due to non-specific
      appearances of signs/symptoms, X-ray shadows or negative tuberculin reaction,
      some serological tests, which have been recently developed, can be useful as a
      supplementary diagnostic tool. One of them is anti-lipoarabinomannan antibody.
      74.3% was positive to this among 148 bacteriologically confirmed TB cases; 77.8%
      for those aged 65 years and above, and 71.1% for those under 65 years. To anti
      TBGL antibody, 78% of 170 confirmed TB cases were positive; 75% for those aged 65
      years and above, 79.8% for those less than 65 years. Multi-lipo antibody
      developed by Japan BCG Laboratory showed higher sensitivity of 91.5%. GPL-core
      antibody may increase the sensitivity. 4. Mode of TB detection in nursing homes:
      Shinji SHISHIDO (Research Institute of Tuberculosis, JATA). 15 elderly TB
      patients who had been diagnosed in 23 nursing homes in the last 5 years were
      analyzed. The average age was 80.7 years. 10 were male and 5 were female. 11 were
      sputum smear positive. The symptoms were fever (8), cough (7), wheezing (2),
      hemoptysis (1), chest pain (1), body weight loss (1), appetite loss (1). Number
      of patients by time durations before consulting a doctor of within 2 weeks, 2
      weeks to 1 month, 1 to 2 months, 2 to 3 months, 3 to 6 months, and more than 6
      months were 6, 1, 1, 3, 2, 2 respectively. The prognosis: 4 died within 10 days
      after diagnosis, 4 needed examinations for the symptoms but were delayed in
      diagnosis as they were not admitted due to dementia or disability. The
      orientation and training to the staff of the nursing homes are needed for early
      TB diagnosis. 5. Programme for the early detection of TB among the elderly:
      Tadayuki AHIKO (Murayama Public Health Center, Yamagata Prefecture). Based on the
      analysis of 138 confirmed TB cases registered in Yamagata Prefecture in 1998,
      services for early TB detection among the elderly should be 1) periodical chest X
      ray examinations by the patients home doctors when underlying high risk diseases
      such as diabetes or cancer exist, and 2) -sputum examination for the symptomatic
      patients. A survey to 31 local governments conducting special TB services showed
      the special screening programme for the bedridden elderly in nursing homes was
      not so efficient due to low quality of the available X-ray facilities and low
      case detection rate. But these X-ray films can be utilized for comparison with
      those when any symptom arises.

PMID- 15032001
TI  - [The results of DOTS strategy].
AB  - Tuberculosis control in Japan is now on the stage of program transition since the
      declaration of emergency of tuberculosis in 1999. The "21st century DOTS, Japan
      version" has been proposed under the influence of DOTS experiences in the United
      States, where drastic reduction of tuberculosis was observed after the
      introduction of universal DOT. We cannot copy the experiences of US, considering
      the difference of epidemiological situation of tuberculosis, social background of
      TB cases and the difference of health infrastructure for TB patients. In the
      United States, many tuberculosis patients are treated under government health
      system with DOT. In Japan, TB cases are treated at clinics and hospitals under
      the integrated health system and public health centers mainly provide prevention
      services including contact examination of TB and cohort analysis of TB cases.
      21st century DOTS, Japan version, is not the universal system at present but it
      is on the process of implementation and various kind of new activities have been
      tried including activities to assure the close collaboration between public
      health centers and clinics, and DOT activities including hospital based DOT,
      ambulatory intermittent DOT at pharmacies. Here are presented with various
      experiences both in the field of collaboration between public health centers and
      clinics, and in the field of DOT. Also here are presented with the calculation
      which shows the reduction of total cost of tuberculosis treatment by the
      introduction of ambulatory DOT, considering the influence of recurrence of
      defaulter cases which would have occurred without DOT. We consider that this
      symposium is the interim report of the expansion of Japanese DOTS.

PMID- 15032002
TI  - [The improvement of quality of life of patients with aspiration pneumonia after
      surgical therapy for intractable aspiration].
AB  - Sixteen patients with recurrent aspiration pneumonia that could not be controlled
      by appropriate medical therapies. These patients had no hope of recovering
      laryngeal function. Eight underwent laryngectomy, six underwent laryngotracheal
      separation and four underwent tracheoesophageal anastomosis. After surgery, we
      evaluated the efficacy of the therapy and the patients' satisfaction with
      therapy. Before and after surgery, the following clinical markers were examined
      to evaluate the efficacy of surgery: scores of aspiration pneumonia, WBC count, C
      reactive protein, erythrocyte sedimentation rate, hematocrit, body mass index,
      total protein, albumin, and the Barthel index, an indicator of daily activity.
      Furthermore, the grade of Depression and mood, and satisfaction of patients and
      their carers among family members were scored using the Zung self-rating
      depression scale, a 20-picture face scale, the visual analog scale, and feeding
      status. After surgical therapy, we confirmed that aspiration was prevented in
      fourteen patients of sixteen, and the state of inflammation and nutrition, the
      state of depression and mood were improved. Thirteen patients from sixteen were
      able to ingest a meal orally. The quality of life of patients with intractable
      aspiration was improved.

PMID- 15032003
TI  - [Change of reactive small round cell infiltration in the stroma after pre
      operative 8 Gy irradiation using treatment to maxillary sinus carcinoma with
      Kitasato method and prognosis according to the change].
AB  - PURPOSE: In this paper, we report the results of studying the degree of reactive
      small round cell infiltration in the stroma as a prognostic indicator of
      maxillary sinus carcinoma treated with the Kitasato method and the effect of
      preoperative irradiation at 8 Gy on infiltration in the stroma. SUBJECTS: Out of
      74 patients who had been treated with this method in the 27 years from 1976 to
      2002, the following patients were enrolled in this study: (1) 17 patients from
      whom tissue specimens could be obtained with biopsies or probe antrotomies before
      preoperative irradiation, and (2) 40 patients from whom tissue specimens could be
      obtained after preoperative irradiation including those who survived five years
      and who died of a specific cause. METHOD: We classified the pattern of
      distribution of small round cell infiltration in the stroma into three degrees.
      (1) Stromal infiltration was compared before and after the operation to recognize
      the prognosis for each patient based on the pattern of distribution of small
      round cell infiltration in the stroma. (2) The correlation between the degree of
      stromal infiltration and prognosis was studied statistically. RESULTS: (1) Both
      the patients with increased stromal infiltration and those postoperatively
      preserving a preoperative score of 2+ with irradiation at 8 Gy had a good
      prognosis. (2) The five-year survival rate for patients was significantly higher
      in those with a score of 2+ for their tissue specimens. CONCLUSION: The Kitasato
      treatment method is effective and improves the QOL of patients with maxillary
      sinus carcinoma. The prognosis was good in the patients with increased or
      preserved stromal infiltration. The low-dose irradiation and chemotherapy used in
      combination seemed to be biological response modifiers.

PMID- 15032004
TI  - [Studies of time-course changes in human body balance after ingestion of long
      acting hypnotics].
AB  - Falling accidents are a serious nocosomial problem, with balance disorders after
      the ingestion of hypnotics said to be a cause. Based on the results of animal
      studies, it was postulated that this problem involves the muscle relaxation that
      is a pharmacological effect of benzodiazepines (BZP). No reports have, to our
      knowledge, been made of time-course changes in human body balance after ingestion
      of hypnotics. Accordingly, we used quazepam (Doral), a long-acting hypnotic
      considered to show comparatively weak muscle relaxation, to study static balance
      after drug ingestion in human volunteers. Briefly, informed consent was obtained
      from 8 healthy adults, then a gait analytic system (Gangas) was used to test
      static balance after drug ingestion (Mann and Romberg tests). We also measured
      circulating drug concentration over time. Our results showed that balance
      disorders occurred after quazepam ingestion with an unstable posture particularly
      striking. Given the function of quazepam receptors, it is difficult to surmise
      that balance disorders after drug ingestion were due to the drug's muscle
      relaxation. We surmised that inhibition from the central nervous system in
      connection with nerves awakening was involved. We found a strong correlation
      between the manifestation of balance disorders after drug ingestion and
      circulating drug concentration.

PMID- 15032005
TI  - [Tracheostomy in tortuous brachiocephalic artery].
AB  - Tracheostomy, frequently used to ensure airway maintenance, involves
      complications such as bleeding and pneumothorax. Major vessel damage is also a
      lethal complication that must be avoided. We report tracheostomy in a case of
      tortuous bracheocephalic artery. A 74-year-old female with slight dyspnea due to
      amyotrophic lateral sclerosis (ALS) referred for tracheostomy had a pulsating
      mass in front of the trachea, found in by magnetic resonance (MR) imaging and MR
      angiography to be a tortuous bracheocephalic artery. In surgery, the displaced
      bracheocephalic artery was confirmed between the sternothyroid muscle and lower
      pole of the thyroid gland. This vessel was carefully dissected, the thyroid gland
      was divided at the isthmus, and the anterior wall of the trachea was fenestrated
      in an inverted U shape. The flap created by fenestration protected the vessel
      wall and was sutured to the skin so the vessel would not be exposed to the
      tracheostoma. A tortuous major artery is not uncommon in the neck, and care
      should be taken to avoid damaging such a vessel during tracheostomy.

PMID- 15032006
TI  - [Antibiotic selection for the treatment of pediatric upper respiratory tract
      infections and the detection rate of drug-resistant strains].
AB  - In recent years, Streptococcus pneumoniae and Haemophilus influenzae have
      acquired resistance to some drugs; as such, a therapeutic strategy in which
      penicillins (PCs) are primarily used is currently recommended for the treatment
      of pediatric upper respiratory tract infections. In 2000, we changed the primary
      drug used for such infections in patients visiting our hospital from cephems
      (CEPs) to PCs. We examined the effect of this change on the detection rates of
      drug-resistant S. pneumoniae (DRSP) and ampicillin (ABPC)-resistant H.
      influenzae. 1. The subjects consisted of patients who had visited our hospital
      and received bacteriological examinations during 1999, 2001 or 2003. At the time
      of the examination, we questioned each patient regarding the medical institutions
      where they had received oral antibiotic therapy during the past year, how many
      antibiotic therapies they had received, and which antibiotics they had received.
      The number of patients who had only received antibiotics from our hospital was 37
      out of 52 (71%) patients in 1999, 80 out of 110 (73%) patients in 2001, and 50
      out of 71 (70%) patients in 2003. The number of therapies in which only PCs were
      used was significantly higher in 2001 and 2003 than in 1999. The number of
      therapies in which only CEPs were used was lower in 2001 and 2003 than in 1999.
      We believe that this trend reflects our therapeutic strategy. Furthermore, the
      antibiotic therapies that patients received at other hospitals were thought to
      have only a small influence on the detection rates of DRSP and ABPC-resistant H.
      influenzae. 2. The detection rate for DRSP was 30% in 1995 and 60% in 1999.
      However, the detection rate for DRSP was 37% in 2001 and 39% in 2003,
      representing a significant decrease from the detection rate in 1999. The
      detection rate for ABPC-resistant H. influenzae was 26% in 1995 and increased
      slightly to 36% in 1999. However, the detection rate for ABPC-resistant H.
      influenzae increased significantly from 36% in 1999 to 59% in 2001 and to 71% in
      2003. The reason for this trend is that PCs are considered to be less effective
      than CEPs against H. influenzae, even though they are more effective than CEPs
      against S. pneumoniae. 3. We received the patients at our hospital who required
      hospitalization for the treatment of bacterial infections. In 1999, DRSP was
      detected in 2 of the 11 (18%) patients who required hospitalization, but no ABPC
      resistant H. influenzae strains were detected. ABPC-resistant H. influenzae was
      detected in 3 of the 12 (25%) patients hospitalized in 2001 and in 4 of the 10
      (40%) patients hospitalized in 2003. Thus, the detection rate for ABPC-resistant
      H. influenzae appears to be increasing. 4. Our findings suggest that the number
      of DRSP isolates may increase when treatment policies focused on CEPs are
      employed, while the number of ABPC-resistant H. influenzae isolates may increase
      when treatment policies are focused on PCs. 5. At present, guidelines focusing on
      the use of PCs for the treatment of pediatric upper respiratory tract infection
      are recommended, but standardizing the choice of antibiotics may cause the number
      of resistant bacteria to increase. When such guidelines are employed at medical
      institutions, attention should be constantly paid to trends in drug
      susceptibility. If an increase in one type of resistant bacteria is observed,
      flexible measures should be taken, without strict adherence to the guideline.

PMID- 15032007
TI  - The impact of radical prostatectomy on patient well-being: a prospective
      urodynamic study focused on detrusor function.
AB  - Prostate cancer is common in aged men and radical prostatectomy is established as
      a therapeutic measure. However, to date there is little information about its
      impact on voiding function. We conducted a prospective clinical study to
      elucidate the impact of radical prostatectomy on voiding function in 17 patients
      with prostate cancer, by urological evaluation including filling and voiding
      cystometry (pressure flow study). The patients who were estimated as having weak
      detrusor function including very weak detrusor function at 3 months
      postoperatively had significantly more frequent urinary incontinence compared
      with the others (p < 0.05). Of 8 patients who showed urinary incontinence for
      more than 3 months, 7 (88%) patients developed weak detrusor function at 3 months
      after operation, but 4 of them were estimated as having normal detrusor function
      preoperatively. These patients revealed reduced maximum flow rate and
      significantly increased quality of life score compared with the other patients (p
      < 0.05). An initially reduced bladder compliance disclosed a tendency to a rapid
      return to normal with time after surgery. Detrusor overactivity itself and
      neoadjuvant antiandrogen therapy were not related to prolonged postoperative
      urinary incontinence. The present study indicates that caution is required when
      administering medication that could potentially affect detrusor function,
      regardless of the type of preoperative detrusor function, in patients with
      persistent urinary incontinence or a reduced urinary stream. Particular emphasis
      is laid on the importance of urodynamic assessment of post-prostatectomy detrusor
      function and appropriate management modalities based on the results.

PMID- 15032008
TI  - [The evaluation of bladder outlet obstruction using the bladder weight
      calculation nomogram].
AB  - The ultrasound estimated bladder weight (UEBW) of 15 patients (13 male, 2 female;
      mean age 64.7 years) who underwent pressure flow study (PFS) were evaluated using
      the nomogram. In the nomogram, thickness of bladder wall (T) and bladder weight
      (BW) were plotted on the horizontal axis and on the vertical axis, respectively.
      BW points calculated from various values of T by the formula were plotted on the
      volume-fixed bladder capacity curve. BW of each case was estimated by the
      nomogram from echo-measured T at maximum bladder filling and injected volume (V)
      into the bladder. Bladder outlet obstruction (BOO): was evaluated from obtained
      results, and compared with the results of PFS. The features of the distribution
      on Schafer's nomogram were also investigated. It was possible to estimate BW
      immediately after ultrasonic examination. BW was under 35 g in one patient, and
      over 35 g in 14 patients. Obstruction grade on the Schafer's nomogram ranged from
      III to VI. BOO could be evaluated quantitatively with little invasion even in
      patients who could not undergo PFS for urinary retention and urge incontinence.
      In conclusion, the bladder weight calculation nomogram immediately showed the BOO
      information of the patient with neither invasive technique, complicated
      calculation, electronic calculator nor expansive computer. This nomogram may make
      a breakthrough for utilizing UEBW.

PMID- 15032009
TI  - [Intraarterial chemotherapy with bladder preservation in patients with invasive
      bladder carcinoma].
AB  - Intraarterial chemotherapy (IAC) was carried out on patients with invasive
      bladder carcinoma to treat the bladder carcinoma while preserving the bladder.
      Fifteen patients with bladder carcinoma at stage T2-T4 were treated with
      intraarterial cisplatin (CDDP: 70 mg/m2) and adriamycin (ADM: 30 mg/m2) every 3
      to 4 weeks. The response was observed in all 15 patients. Ten (66.7%) achieved a
      complete response (CR), and 3 (20.0%) obtained a partial response (PR). With a
      mean follow-up of 22.6 months, the overall survival rate was 86.7% and 12
      patients were alive with functioning bladder. One patient received radical
      cystectomy. Although further studies and long-term follow up are required to
      clarify its effectiveness, IAC for patients with invasive bladder carcinoma might
      be an effective therapy with a preserved bladder.

PMID- 15032010
TI  - [Clinical results of infertility treatment to male patients with spinal cord
      injury].
AB  - It is difficult for male patients with spinal cord injury (SCI) to have children
      because of an ejaculation and dysfunction of spermatogenesis. However, owing to
      progress of assisted reproduction technology in recent years, it has become
      possible to have children even if the male has SCI, and the rate of success is
      improving gradually. During the 8 years from 1994 to 2002, infertility treatment
      was performed on 16 male patients with SCI consulting our hospital for acquistion
      of a child. We extracted their sperm by electroejaculation (EE) or testicular
      excision sperm extraction (TESE), and the sperm was artificially inseminated by
      the techniques such as artificial insemination with husband's semen (AIH), in
      vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI).
      Consequently, it was successful in 14 pregnancies on 10 couples, and resulted in
      11 healthy live births on 7 couples. Four cases resulted in abortion. Two spouses
      are pregnant at present. There were no remarkable differences between the success
      group and the failure group in the quality of sperm such as concentration and
      motility. The mean age of the spouses who became pregnant was slightly lower than
      that of those who did not. Assisted reproduction techniques as EE and ICSI were
      useful techniques for patients with SCI wishing to have children.

PMID- 15032011
TI  - [Successful trans-stomal operation for multiple urinary stones occurring in the
      Indiana continent urinary diversion: a case report].
AB  - A total cystectomy with the Indiana continent diversion was performed on a 73
      year-old man under the diagnosis of invasive bladder cancer in 1992. In 1994
      there appeared a few urinary stones in his Indiana continent urinary diversion.
      Extracorporeal shock wave lithotripsy (ESWL) was successfully performed. In 1999
      a few urinary stones recurred and ESWL was performed. Stones could not be
      discharged because of stricture of the efferent limb, although stones were
      crushed down into small pieces by repeated ESWL. The number and sizes of stones
      gradually increased. Dilatation of the stoma followed by a trans-stomal operation
      was performed and all of the stones except for one were extracted.

PMID- 15032012
TI  - [A case of extra-adrenal pheochromocytoma presenting with lung metastasis].
AB  - A 34-year-old man was referred to our hospital for small lung nodules. An imaging
      study including a computed tomographic scan and magnetic resonance imaging showed
      bilateral lung tumors and huge mass arising from the lower pole of the right
      kidney as well. The patient underwent right radical nephrectomy in May 2002.
      Pathological examination revealed that the tumor was pheochromocytoma, which
      developed from extra-adrenal tissue. In 6 cycles of CVD systemic chemotherapy
      (Cyclophosphamide 750 mg/m2, Vincristine 1.4 mg/m2, Dacarbazine 600 mg/m2), the
      lung tumors were decreasing in size, and were removed by a surgical procedure in
      January 2003. Pathological examination revealed that the lung tumors were
      pheochromocytomas metastasized from the primary tumor. He is alive without
      evidence of disease 5 months after the lung operation.

PMID- 15032013
TI  - [Two cases of encrusted cystitis].
AB  - Encrusted cystitis is a type of severe cystitis, which progresses chronically and
      is characterized by excessively alkaline urine and calcifications within the
      bladder wall. We report two cases of encrusted cystitis. Both cases were high
      aged and had severe anemia with chronic cystitis. They complained of gross
      hematuria, voiding frequency and pain upon urination. Urine pH was 8-9, and urine
      cytology was negative. Urine culture contained Corynebacterium Group D2.
      Abdominal computed tomography and transurethral resection revealed wall bladder
      wall calcification and inflammatory change. We diagnosed it as encrusted
      cystitis. The patients underwent excision of plaques of calcified encrustation,
      adapted antibiotic therapy and acidification of urine. It is essential to
      diagnose encrusted cystitis early and to provide adequate treatment promptly.

PMID- 15032014
TI  - [A case of brain metastasis associated with prostate cancer].
AB  - A 82-year male consulted us for elevation of prostate specific antigen, diagnosed
      as prostatic adenocarcinoma (moderated differentiated). We decided to observe him
      under androgen deprivation therapy. During the 8 months of treatment, left hemi
      paresis started to appear. Brain magnetic resonance imaging revealed the multiple
      brain metastases, suspected to have originated from the prostate cancer. Total 30
      Gy radiotherapy could not establish the improvement of activity of daily living.
      We discuss the cases of brain metastasis associated with prostate cancer.

PMID- 15032016
TI  - Benign cystic lesion of the tunica albuginea: a case report.
AB  - We describe a patient whose testicular parenchyma was displaced by a cyst.
      Histologic findings suggested that the cyst was a dilated efferent ductule
      passing through the tunica albuginea. Such a cyst is an important and benign
      consideration in the differential diagnosis of testicular masses. Although
      orchiectomy was performed in this case, early consideration and confirmation of
      benign lesions may permit testicular preservation.

PMID- 15032015
TI  - Metanephric adenoma in a 59-year-old female: a case report.
AB  - We report a case of metanephric adenoma in a 59-year-old female. The tumor was
      incidentally detected on computed tomography (CT) and ultrasound (US), and
      diagnosed as left renal cell carcinoma by radiological examination. Left
      nephrectomy was performed. The tumor measuring 4 x 3 x 3 cm had a clear margin
      and was encapslated with thick fibrous tissue. The cut surface was yellow-white
      and the boundary of renal parenchyma was clear. Histopathologically, the tumor
      showed a characteristic composition of small uniform cells with regular nuclei
      that formed a tubular pattern. Immunohistologically, they were positive for Leu-7
      and vimentin. Pathological diagnosis was metanephric adenoma. We discuss the
      radiological findings of metanephric adenoma.

PMID- 15032017
TI  - [Mixed epithelial and stromal tumor growing with polypoid pattern in the renal
      pelvis].
AB  - A 68-year-old woman was found incidentally to have right hydronephrosis and a
      renal pelvic mass by abdominal ultrasonography. Radiographic examinations
      revealed a heterogeneous renal pelvic tumor, and right nephroureterectomy was
      performed. The tumor was well circumscribed yellow-whitish solid mass with
      scattered cysts. Histologically, the tumor was composed of both mesenchymal and
      epithelial components. The mesenchymal elements consisted of fibroblasts and
      smooth muscle cells, and the epithelial elements of cystic and tubular structures
      lined by cuboidal epithelium. Atypia and mitoses were not identified. The patient
      was free of recurrence 42 months postoperatively. Mixed epithelial and stromal
      tumor of the kidney is a recently recognized neoplasm that occurs almost
      exclusively in perimenopausal woman. Similar tumors have been reported previously
      under various names, including adult mesoblastic nephroma and cystic hamartoma of
      the renal pelvis. Histogenesis of the tumor is still controversial.

PMID- 15032018
TI  - Transurethral coil embolization for the management of ureteroarterial fistula: a
      case report.
AB  - A 71-year-old woman who had undergone a total abdominal hysterectomy and pelvic
      irradiation for cervical cancer and fecal diversion for adhesive ileus was
      referred to us for a "left" ureteral stone and intermittent gross hematuria.
      Bilateral ureteral stents had been indwelled because of lower ureteral strictures
      for a long time. Hematuria continued after the removal of the ureteral stone, and
      she once went into hypovolemic shock at the time of exchange of the right
      ureteral catheter. Selective arteriography revealed a "right" ueteroarterial
      fistula. Endovascular management alone failed to resolve the fistula, but a
      subsequent transurethral metal coil embolization was effective, and the hematuria
      was relieved. She is still free from disease at 7-month followup. As far as we
      know, there has been no previous report of a transurethrally managed
      ureteroarterial fistula.

PMID- 15032019
TI  - [Prostatic cancer in a young adult: a report of 2 cases].
AB  - Patients younger than 45 years with prostate cancer are rare. Between 1999 and
      2002, we studied two cases of prostate cancer in men aged under 45 years. Case 1;
      a 45-year-old man admitted with the chief complaint of urination disorder. Serum
      level of prostate-specific antigen (PSA) was 5,000 ng/ml or higher. Transrectal
      needle biopsy of the prostate revealed moderately differentiated adenocarcinoma.
      Computed tomography (CT) and bone scan showed para-aorta lymph node metastasis
      and bone metastasis. Hormone therapy was performed. Case 2; a 37-year-old man
      admitted with the chief complaint of pollakisuria and sense of residual urine.
      Serum level of prostate-specific antigen (PSA) was 24 ng/ml. Magnetic resonance
      imaging (MRI) showed that the prostate tumor invaded the bladder wall.
      Transrectal needle biopsy revealed poorly differentiated adenocarcinoma. Hormone
      therapy and radiation therapy were performed. Twenty-one cases reported in Japan
      in addition to the present cases are reviewed.

PMID- 15032021
TI  - [Main theme of the 92th annual meeting of the Japanese Urological Association
      (discussion)].

PMID- 15032020
TI  - [A case of prostate cancer with invasion to the middle ureter].
AB  - A 69-year-old male was diagnosed as having prostate cancer with ureter invasion.
      His serum prostate specific antigen level was not so high (19.6 ng/ml) before
      treatment, but clinical stage was D2, poorly differentiated adenocarcinoma of
      prostate. He was treated with chemoendocrine therapy. Prostate cancer with
      continuous invasion to the middle ureter is rare. To the best of our knowledge,
      this is the 6th case report of such an unusual invasion of prostate cancer.

PMID- 15032022
TI  - [Notes on the history of dermatology in Puerto Rico].

PMID- 15032023
TI  - Xanthomas: a marker for hyperlipidemias.
AB  - Xanthomas are deposits of lipids in the skin and sometimes of the subcutaneous
      tissue that are expressed clinically as yellowish papules and plaques, nodules,
      and tumors. They are often, but not always, a consequence of hyperlipidemia. In
      these cases, a meticulous work-up nearly always reveals some disturbance in
      regards to the metabolism of the lipids-lack of certain lipoproteins, for
      example. Xanthoma tuberosum and tendinosum occur in persons with familiar
      hypercholesterolemia, palmar crease xanthoma in familial dysbetalipoproteinemia,
      plane xanthoma in persons with an underlying lymphoproliferative disorder (or
      normolipemic), and eruptive xanthoma in those with a genetically-transmitted
      lipoprotenemia. In sum, each type of xanthoma and any associated abnormality in
      lipid metabolism can be diagnosed with specificity. Xanthomas are deposits of
      lipid in the skin or subcutaneous tissue that manifest clinically as yellowish
      papules, nodules and tumors. They are often associated with hyperlipidemias,
      although some of them may be normolipemic. Xanthomas result when abnormalities in
      the transportation of lipids such as cholesterol, triglycerides and phospholipids
      cause these lipids to be deposited in the skin and being ingested by tissue
      macrophages. When they are deposited in the walls of arteries, they promote the
      development of atherosclerosis. Sometimes, by identifying the clinical variant of
      the xanthoma, the lipoprotein that is deposited and the clinical associations can
      be predicted. This discussion will focus on those xanthomas associated with
      hyperlipidemias.

PMID- 15032025
TI  - Acral melanoma in Puerto Ricans.

PMID- 15032024
TI  - Leprosy in Puerto Rico (1901-2001).

PMID- 15032026
TI  - Bullous pemphigoid: course of the disease. A study of 25 patients.
AB  - Different studies on the course of bullous pemphigoid have suggested that there
      may be significant variations in the survival of these patients based on their
      ethnicity or region of origin. Because of the lack of studies on patients with
      bullous pemphigoid in the Caribbean, specifically in Puerto Rico, a retrospective
      analysis about the outcome of patients with this disease in the region was
      performed. Twenty-five (25) patients were included in this study. The patients
      were diagnosed as bullous pemphigoid by clinical, histopathologic and
      immunopathologic assessment. Medical records were reviewed and those patients
      that were alive were contacted and examined on a follow up visit. Nine were men
      and sixteen were women; the age at the time of the diagnosis ranged from 54 to 90
      year-old (mean 72); 13 were alive after at least 5 years of follow-up and 12 had
      died. The age at the moment of death ranged from 67 to 95 year-old (mean 83). Of
      those patients living, 85% were in remission, while 15% had active disease. In
      general, patients had a disease of mild severity, but, still, 68% of them
      received systemic corticosteroid therapy. Five of patients had to be admitted due
      to disease; two of them died while at the hospital. This data suggests that
      bullous pemphigoid in Puerto Ricans is a disease with a relatively benign course,
      but which can be fatal in the elderly, especially, if it requires admission to
      the hospital and the patient receives high doses of systemic corticosteroids.

PMID- 15032027
TI  - Pigmented mammary Paget's disease in a man.
AB  - Mammary Paget's disease is one clinical expression of an underlying breast
      carcinoma. It manifests as persistent erythema, oozing and scaling of the nipple,
      areola or both. The occurrence of this disease in men is uncommon. This is a
      report of a pigmented lesion of Paget's disease occurring on the breast of a man.
      This presentation is unusual and may be confused with melanoma. Its early
      recognition is important so that adequate therapy may be instituted when the
      disease has a favorable prognosis.

PMID- 15032028
TI  - Extranodal B-cell lymphoma in a patient with atopic-like dermatitis.
AB  - Atopic dermatitis is a chronic relapsing skin disease that occurs commonly during
      early infancy and childhood and is frequently associated to personal and family
      history of allergic rhinitis, asthma and/or skin disease. As a rule, it follows a
      benign course. We report a case of a female patient with a chronic atopic-like
      dermatitis who eventually developed an extranodal systemic large B-cell lymphoma
      during the course of her disease.

PMID- 15032029
TI  - Granular parakeratosis.
AB  - This is a report of a 60 year-old black female patient presenting with pruritic
      brownish crusted plaques on both axillae of one month evolution. Histopathology
      revealed findings characteristic of axillary granular parakeratosis. This entity
      was first described by Northcutt et al in 1991. Since then, involvement of other
      intertriginous areas have also been reported. A review of the literature was
      performed and the term granular parakeratosis is suggested to emphasize its
      pathognomonic histopathologic features.

PMID- 15032030
TI  - [29th Central Swiss Symposium for Internal Medicine 14 June 3003].

PMID- 15032031
TI  - [Pain in tumor patients: assessment and pain drug therapy].
AB  - This review gives an overview over the diagnostic and pharmacological approach to
      pain in cancer patients. The work-up and the pharmaceutical treatment is detailed
      and several important points in the use of opiates are highlighted.

PMID- 15032032
TI  - [Nutritional support for critically ill and dying patients].
AB  - There is evidence in the literature that oral nutritional supplements, total
      enteral and parenteral nutrition can expand life expectancy and improve quality
      of life in patients suffering from undernutrition. In the present review, we
      outline whether these treatments regimens are also effective in severely ill
      patients. Moreover, the usefulness of nutritional interventions in patients sick
      unto death, e.g. by stroke, cancer or dementia, is broadly discussed. The
      controversy about terminal dehydration is shortly reviewed.

PMID- 15032033
TI  - [When there is pharyngeal obstruction].
AB  - Any narrowing of the throat not only impairs the patient's voice, but also his
      swallowing abilities and even more dramatically his airways. Changes of the
      patient's voice due to tumors, trauma or functional disturbances do not
      immediately endanger the patient's live but render his vocal communication
      abilities more difficult or even impossible. Swallowing disturbances--often not
      diagnosed at an early stage--may lead to a life threatening pneumonia due to
      repeated aspirations. Laryngeal airway obstruction can be caused by functional
      disorders of the laryngopharyngeal musculature, by benign or malignant tumors, or
      may present as a consequence of surgery and/or irradiation. A variety of
      treatment options are available to restore the patient's voice, rehabilitate his
      swallowing and maintain the airway patency. Often times minor surgical
      interventions (e.g. phonosurgery) help to improve the patient's quality of life,
      even in a palliative situation.

PMID- 15032034
TI  - [Progressive gait instability and weakness with recurrence presyncopes/syncopes.
      Multiple system atrophy].

PMID- 15032035
TI  - [Incarcerated umbilical hernia in the horse: a case with a review of the
      literature].
AB  - Umbilical hernias are common in foals. This article provides a review of the
      literature and presents a case of an 1.5-year-old Friesian mare with an
      incarcerated umbilical hernia. After reposition of the incarcerated intestine
      (with a lot of effort), the practising veterinarian referred the mare to the
      Department of Equine Sciences. Preperforative peritonitis was diagnosed, presumed
      to be caused by necrotic bowel. After laparotomy, this tentative diagnosis was
      confirmed. The necrotic part of the small intestine was resected and intensive
      medical treatment was started. Initially, the mare recovered well, but seven days
      after surgery her general condition deteriorated and she had to be euthanized. At
      necropsy, impaction of the stomach and rupture of the stomach wall were found.
      The impaction was probably a result of the generalized peritonitis.

PMID- 15032036
TI  - [Referral wisdom].

PMID- 15032037
TI  - [Moon blindness (Equine Recurrent Uveitis) in the horse].

PMID- 15032038
TI  - [Coccidiosis causes diarrhea in calves in the pasture. Pasture coccidiosis caused
      by Eimeria alabamensis].
AB  - A severe outbreak of diarrhoea in young (age 18-20 month) cattle 14 days after
      their first turnout is described. In the manure large numbers Eimeria alabamensis
      oocysts were found. This infection is considered as a case of coccidial diarrhoea
      in (older) calves at pasture.

PMID- 15032040
TI  - [Veterinary disease legislation can and has to be different].

PMID- 15032039
TI  - [Fibrosarcoma in cats].

PMID- 15032041
TI  - ['Beestenboel' journal helps veterinarians communicate with their clients. TV
      presenter Anniko van Santen receives the first edition].

PMID- 15032042
TI  - [BVD-program of the GD does what it is supposed to do].

PMID- 15032043
TI  - [Bovilis BVD: a potent immunogen vaccine].

PMID- 15032044
TI  - [A different opinion].

PMID- 15032045
TI  - [Finally some frankness from the KNMvD].

PMID- 15032046
TI  - [Has it been thought through II?].

PMID- 15032047
TI  - Professional cultism.

PMID- 15032048
TI  - Women's health and dental care.

PMID- 15032049
TI  - Bulimia & the role of the dentist.

PMID- 15032050
TI  - Your patient is pregnant ... now what?

PMID- 15032051
TI  - Matrix metalloproteinases in neuroinflammation and cerebral ischemia.

PMID- 15032052
TI  - Involvement of tight junctions during transendothelial migration of mononuclear
      cells in experimental autoimmune encephalomyelitis.

PMID- 15032053
TI  - Cytokines in stroke.

PMID- 15032054
TI  - Complement activation: beneficial and detrimental effects in the CNS.

PMID- 15032055
TI  - Inflammation in stroke: the good, the bad, and the unknown.

PMID- 15032056
TI  - Tetracycline derivatives as anti-inflammatory agents and potential agents in
      stroke treatment.

PMID- 15032057
TI  - Induction of mucosal tolerance to E-selectin targets immunomodulation to
      activating vessel segments and prevents ischemic and hemorrhagic stroke.

PMID- 15032058
TI  - Protective autoimmunity and prospects for therapeutic vaccination against self
      perpetuating neurodegeneration.

PMID- 15032060
TI  - Inflammation-mediated damage as a potential therapeutic target in acute ischemic
      stroke.

PMID- 15032059
TI  - Lessons from stroke trials using anti-inflammatory approaches that have failed.

PMID- 15032061
TI  - Design issues in selected recent or ongoing stroke trials.

PMID- 15032062
TI  - [Relationships between basic life history parameters and population size].
AB  - We consider an ideal population with a stable age composition changing according
      Lotka equation. Additional assumptions are made concerning the constancy of
      population size, independence of specific mortality rate on age, and linear
      dependence of female fecundity on its weight. A relationship has been obtained
      [formula: see text] where N0 is initial numbers of a generation, N[alpha, omega]
      is total numbers of the mature part of the population, w[alpha, omega] is a mean
      weight of a mature individual, s is sex ratio, c is specific fecundity (per unit
      of weight) and l0 is the probability of larval surviving. The growth of an
      individual is described by the Bertalanffy function. Methods of calculation of
      life history parameters are discussed. A method is proposed to calculate the age
      of maturity (alpha) and at the end (omega) of the reproduction period as first
      and second inflection points of the growth rate curve. Based upon data on
      development of 27 populations of several species of fishes of inland waters of
      Russia the following relationship have been obtained: [formula: see text] for
      populations with [formula: see text] < or = 100 g, [formula: see text] for
      populations with [formula: see text] > 100 g, and [formula: see text] for all
      populations.

PMID- 15032063
TI  - [Highest level of division in the organism classification. 1. Prokaryotes and
      eukaryotes].
AB  - The works on the general classification of all organisms are considered as a
      convenient opportunity to sum up numerous data obtained in organic world
      studying. The present stage is characterized by rapid development of the
      molecular reconstructions that have already caused considerable changes in our
      classification practice. These changes look especially impressive at studying the
      organism cellular structure. The great massive of new data allow us to compare
      Prokaryotes and Eukaryotes on the nucleic acids and especially proteins whose
      number in Eukaryote cell approaches to several thousands. Basing on the structure
      of macromolecules one can hypothesize with great certainty about Prokaryote or
      Eukaryotes origin. The article presents the detailed characteristic of
      Prokaryotes or Eukaryotes with the emphasis placed on the comparative analysis of
      biological macromolecules. Among specially considered cellular structures and
      processes are cell wall, intracellular components, cellular cycle, nucleus, DNA
      compactness, replication, genome organization, transcription, posttranscriptional
      modifications, introns, ribosomes and translation, cytoskeleton, mitosis,
      cytokinesis, cellular organelles, intracellular membranes systems, modes of
      nutrition, sexual condition. The macromolecular analysis let to carry out the
      homology of structures and to find out some new connections. It was shown that
      typology considered as a search for morphological patterns within the
      biodiversity structure has almost exhausted the subject. It was directed mostly
      to distinguishing "main" group in contrast with intermediate and aberrant ones,
      which were considered as minor phenomenon. At present due to macromolecules
      systematics it is able to estimate the whole diversity of forms including
      typologically transitive.

PMID- 15032064
TI  - [Population structure of Drosophila on quantitative measure traits and its
      seasonal changes].
AB  - In the Drosophila population the individuals of medium, small and large size
      prevail in spring, summer and autumn correspondingly. Such differences are
      genetically determined. Small individuals are characterized by the highest
      modification variability while the large individuals--by the lowest one.
      Genotypic heterogeneity of the population was also found in the body size of
      individuals, which is the highest in summer and the lowest in autumn. Dynamics of
      the individual sizes and of genetic heterogeneity is determined by radical
      seasonal changes in genotypic composition of the population. Such reconstruction
      influences the substantial part of gene pool, which defines the dimension of
      individuals. One of the possible reasons of this process is an integral selective
      action of the population density and temperature. It provides the regulation of
      variations in numbers and adaptation to the seasonal changes in life conditions.

PMID- 15032065
TI  - [RNA editing in different genetic systems].
AB  - One of the significant amendments to the central dogma of the molecular biology
      was the discovery of the RNA editing process in different genetic systems.
      Whereas other forms of co- and posttranscriptional modifications of messenger RNA
      (mRNA) (capping, polyadenilation, splicing) retain the correspondence of the
      primary structure of exon and final transcript, RNA editing disturbs this
      correspondence changing the primary structure of mRNA after its transcription.
      The variants of RNA-editing mechanisms are various and include site-specific
      insertions and deletions of one or several nucleotides (insertion-deletion
      editing) as well as specific modifications of nucleosides such as C-->U and A-->I
      deamination or U-->C transamination (conversion editing). These mechanisms differ
      greatly in different genetic systems but they always result in synthesis of
      functionally valuable proteins from "incorrect" genes and, correspondingly, can
      play a significant role in regulation of their expression.

PMID- 15032066
TI  - [Whether variable cleavage of Enoplida (Nematoda) is primitive? Notes to D.A.
      Voronov article "Comparative embryology of Nematoda and the law of embryologic
      similarity].
AB  - The early embryonic development of Nematoda proceeds by three ways, which
      strictly correspond to three phylogenetic lineages. Under the first way the
      endodermal precursor is localized in the posterior blastomere at the two-cells
      stage (such a determination is the peculiarity of all the Chromadoria, including
      Secernentea and Caenorhabditis elegans). Under the second way the endodermal
      precursor is localized in the anterior blastomere of the egg. This feature is
      very unusual for Metazoa, but it is the only way of entoderm determination in all
      the Dorylaimia orders (Mononchida, Mermithida, Trichinellida, Dioctophymida,
      Dorylaimida). The third way described for the sea Enoplida is characterized with
      variable location of blastomers and changeable localization of endodermal
      precursor before eight-cells stage. It is still unknown of these three variants
      was typical the most recent common ancestor of present Nematoda. D.A. Voronov
      (2001) produced argument in favour of variable cleavage as primitive one for
      Nematoda. This opinion is rejected because of the similarity in development
      between sea Enoplida and C. elegans. Both of them share such features as low-cell
      gastrula and neurula, identical phylotypic lima bean stage of embryogenesis,
      identity of some geometrical figures 4 or 8 blastomers, isolating of the
      endodermal precursor at the eight-cells stage, the lack in development of any
      plesiomorphous features, which are widely distributed outside Nematoda (under the
      variable cleavage of Enoplida there are no such locations of blastomers, which
      are typical for spiral or radial cleavage, there are no embryonic leaves as
      well). One can see the homology of separate cells at adult Enoplida and
      Rhabditia. Cell lineage of Triplonchida as far as it is described at Tobrilus
      gracilis doesn't exclude the hypothesis on their origin from the cleavage similar
      to one of present Dorylaimia with localization of the endodermal precursor in the
      anterior blastomere. In view of all the considerations mentioned above one should
      interpret variable cleavage of Enoplida as derivation from invariant cleavage.

PMID- 15032067
TI  - [Limnetic zooplankton run-off a high-head dam and their fate in a river with high
      current velocity (case of the Krasnoiarsk hydroelectric power station on the
      Yenisei river].
AB  - The vertical distribution of net zooplankton in head-water of Krasnoyarsk
      hydroelectric power station and its horizontal distribution in the tail-water
      were studied during two years in winter and summer seasons. In order to
      distinguish living and dead individuals the special staining was used. It was
      revealed that on average 77% of living plankton pass through high-head dam with
      deep water scoop to the tailwater. While passing through dam aggregates some
      individuals of the reservoir plankton are traumatized and die, that results in
      some increase of portion of dead individuals in the tail water near dam (from 3
      to 6%). Alive zooplankton passed through the dam aggregates is eliminated under
      the Upper Yenisei highly turbulent conditions. There is approximately 10% of it
      in 32 km from the dam if compare with biomass in 20-40 m layer of reservoir, the
      portion of dead increases to 11%. The biomass of zooplankton suspended in the
      water column of the tail-water sometimes increases (till > 1 g/m3) due to large
      Copepoda Heteroscope borealis, which inhabits near-bottom and near-shore river
      zones and can be found in the central part of the river during reproductive
      period. Limnetic zooplankton from the reservoir cannot be considered as important
      food for planktivores in the tail-water.

PMID- 15032068
TI  - Enhancing the traditional hospital design process: a focus on patient safety.
AB  - BACKGROUND: In 2002 St. Joseph's Community Hospital (West Bend, WI), a member of
      SynergyHealth, brought together leaders in health care and systems engineering to
      develop a set of safety-driven facility design principles that would guide the
      hospital design process. DESIGNING FOR SAFETY: Hospital leadership recognized
      that a cross-departmental team approach would be needed and formed the 11-member
      Facility Design Advisory Council, which, with departmental teams and the aid of
      architects, was responsible for overseeing the design process and for ensuring
      that the safety considerations were met. The design process was a team approach,
      with input from national experts, patients and families, hospital staff and
      physicians, architects, contractors, and the community. OUTCOME: The new
      facility, designed using safety-driven design principles, reflects many
      innovative design elements, including truly standardized patient rooms, new
      technology to minimize falls, and patient care alcoves for every patient room.
      The new hospital has been designed with maximum adaptability and flexibility in
      mind, to accommodate changes and provide for future growth. The architects
      labeled the innovative design. The Synergy Model, to describe the process of
      shaping the entire building and its spaces to work efficiently as a whole for the
      care and safety of patients. CONCLUSION: Construction began on the new facility
      in August 2003 and is expected to be completed in 2005.

PMID- 15032069
TI  - Using a multihospital survey to examine the safety culture.
AB  - BACKGROUND: A culture of safety survey was used to study features of the safety
      culture and their relationship with patient safety indicators. STUDY DESIGN:
      Anonymous written surveys were collected from 455 of 1,027 (44%) workers at four
      Massachusetts hospitals. Respondents characterized their organizations' patient
      safety, workplace safety, and features of a safety culture, such as leadership
      commitment, professional salience, presence of a nonpunitive environment, error
      reporting, and communication. RESULTS: Employees universally regarded patient
      safety as an essential part of their job. Two-thirds of workers worried at least
      once a day about making a mistake that could injure a patient; 43% said that the
      work load hindered their ability to keep patients safe. Workers' overall
      assessment of patient safety was associated with their perceptions of workplace
      safety (odds ratio [OR] 1.87, 95% confidence interval [CI] 1.02-3.43, p = .044)
      and leadership commitment to patient safety (OR 3.20, 95% CI 1.97-5.19, p <
      .001). Incident reporting rates correlated with survey results, while adoption of
      best practices and expert opinion did not. DISCUSSION: Patient safety is salient
      to workers, who universally embraced patient safety as an essential part of their
      job. Independent indicators of patient safety did not line up neatly with safety
      culture survey results. Incident reporting rates correlated directly, while
      adoption of best practices and expert opinion varied inversely with survey
      results. The safety culture is a complex phenomenon that requires further study.

PMID- 15032070
TI  - Do complication screening programs detect complications present at admission?
AB  - BACKGROUND: A study was undertaken to verify the accuracy of computer algorithms
      on administrative data to identify hospital complications. The assessment was
      based on a medical records indicator that differentiated hospital-acquired
      conditions from preexisting comorbidities. METHODS: The indicators for
      identifying potential hospital complications were applied to all secondary
      diagnoses to distinguish hospital-acquired from preexisting conditions for all
      1997-1998 discharges. RESULTS: Of the 95 defined complication types, cases were
      found with secondary diagnoses that met the criteria for 71 different
      complications. Sixty-nine of these complications had one or more cases with the
      trigger diagnosis coded as an acquired condition. Thirty-five complications had
      at least 30 cases with acquired conditions. Hospital complications add greatly to
      costs; for example, postoperative septicemia increased the hospital bill by more
      $25,000, added 13 hospital days to the stay, and increased hospital mortality by
      16.6%. CONCLUSIONS: Current complication algorithms identify many cases where the
      condition was actually present on hospital admission. This fact, coupled with the
      known variability in coding between institutions, makes comparisons between
      hospitals on many of the complications problematic. Collection of the present-on
      admission flag significantly reduces the noise in monitoring complication rates.

PMID- 15032071
TI  - Using statewide audit and feedback to improve hospital care in West Virginia.
AB  - BACKGROUND: Audit and feedback systems have significantly improved medical care
      in numerous settings, and they appear to work by stimulating competition rather
      than through command and control. METHODS: The West Virginia Medical Institute
      (WVMI), a Medicare-designated Quality Improvement Organization (QIO),
      periodically collected quality information on five common conditions (acute
      myocardial infarction [AMI], heart failure, pneumonia, stroke, and atrial
      fibrillation) that cause hospitalization in Medicare beneficiaries. All 44 acute
      care hospitals in West Virginia were offered written and orally presented reports
      of quality performance from 1998 through 2001. RESULTS: All indicators appeared
      to improve statewide. Several--for example, aspirin at discharge for AMI patients
      and pneumococcal vaccine for pneumonia patients--improved by more than 10
      absolute percentage points. Fourteen of 15 quality indicators showed significant
      improvement (p < .05, paired t-test) in all hospitals between the before- and
      after-feedback periods. Seven of 13 indicators assessed during the entire study
      in the largest hospitals showed no significant trends in quality before feedback
      but significant increases (p < .05, chi-square for trend) in the after-feedback
      period. DISCUSSION: The quality indicator changes reported can represent
      important health gains for West Virginia Medicare beneficiaries. Most of the
      improvement did not occur until after hospitals received feedback.

PMID- 15032072
TI  - Characteristics of successful quality improvement teams: lessons from five
      collaborative projects in the VHA.
AB  - BACKGROUND: A pre-post observational design was used to study the aggregate
      results of five national Breakthrough Series (BTS) collaboratives run within
      Veterans Health Administration (VHA) to identify the organizational,
      interpersonal, and systemic characteristics of successful improvement teams.
      METHODS: One hundred thirty-one medical quality improvement teams participated in
      five BTS collaboratives in the VHA between 1999 and 2002. Team characteristics
      were assessed using a team questionnaire before and after the BTS collaboratives.
      RESULTS: Fifty-seven percent of participating teams were rated as successful (a >
      or = 20% improvement from baseline for at least two months before the
      collaboratives' end). More high-performing medical quality improvement teams
      perceived their work to be part of their organization's key strategic goals. By
      the end of the BTS collaboratives, high-performing teams had more front-line
      staff support and stronger team leadership. DISCUSSION: Strong organizational
      support, strong team leadership, and high levels of interpersonal team skills
      help medical quality improvement teams go further to improve clinical care. It is
      recommended that quality improvement teams become integrated with their
      organization's key strategic goals, that improvement teams stay together, and
      that leadership and team training be provided to improve clinical outcomes.

PMID- 15032073
TI  - Clinical practice guidelines and performance indicators as related--but often
      misunderstood--tools.
AB  - BACKGROUND: Widespread variation in medical practice indicates that existing
      scientific evidence is often not translated into appropriate clinical care. Two
      tools have evolved that try to address this variation: clinical practice
      guidelines (CPGs) and performance indicators (PIs). TENSIONS BETWEEN CPGS AND
      PIS: CPGs present available evidence that is subsequently reviewed and frequently
      adopted by professional organizations, so that clinicians may judge whether
      specific management recommendations are appropriate for each patient. PIs are
      devised to measure and document performance to motivate organizations to improve
      through the use of common metrics. IMPLICATIONS OF THESE TENSIONS: The
      increasingly widespread use of PIs with CPGs (and clinicians' confusion of them
      with CPGs) risks lowering the standards of clinical care. PIs are not intended to
      set optimal standards of care for any individual patient. Clinicians should not
      restrict their quality monitoring to a focus on PIs because they could miss
      important opportunities to learn and to improve the care they deliver to their
      individual patients. CONCLUSION: Tensions between CPGs and PIs do not mean that
      these tools should be abandoned but rather that they need to be refined.
      Recognition of the imperfections of CPGs and PIs should not blind clinicians to
      the ultimate goals of these tools--to promote quality (through changes in
      practice and/or selection) and ensure that medical care is based on scientific
      evidence.

PMID- 15032075
TI  - Cell kinetics analysis in stage I endometrial carcinoma as determined by image
      cytometry and immunohistochemistry. Correlation with clinicopathologic
      characteristics.
AB  - OBJECTIVE: To test the significance of various proliferative indices in
      endometrial carcinoma (EC) since previous investigations failed to yield
      consistent results that would establish them as factors of clinical importance.
      STUDY DESIGN: Seventy patients with EC were evaluated for various proliferative
      indices (mitotic index, Ki-67 index, argyrophilic nucleolar organizer (AgNOR)
      number and area per nucleus, and p53 protein expression) in relation to image
      cytometry (nuclear area, diameter and roundness) and standard clinicopathologic
      features (age, histologic type and grade, and depth of invasion). We also tested
      the proliferation index (PI), which combines the Ki-67 index and AgNOR area in Ki
      67-positive nuclei. Slides from each case were double stained for Ki-67 antigen
      and AgNOR proteins for this purpose. RESULTS: Mitotic counts were significantly
      higher in papillary-serous (vs. endometrioid) tumors (P = .0001), high grade (vs.
      low grade) tumors (P = .0001), deeply invasive (P = .017) and p53-positive tumors
      (P = .017). AgNOR counts correlated only with age (higher in older women, P =
      .002), while the PI correlated with mitotic counts (P = 0.28) and marginally with
      depth of invasion (P = .06). Morphometric variables were associated just with
      histologic type and grade. p53 Protein was expressed exclusively in invasive
      tumors and was related strongly to histologic type (P = .0029) and grade (P =
      .0001). CONCLUSION: Our data reestablish the value of classic histopathologic
      features (mitotic index, histologic type and grade) as the most important tools
      for EC evaluation. In addition, we suggest that p53 immunostaining may be used
      for predicting aggressive behavior in EC.

PMID- 15032074
TI  - Multiple excitation confocal analysis of targets in nuclei of cytogenetic
      preparations.
AB  - OBJECTIVE: To demonstrate that cellular preparations requiring color analysis of
      different domains stained by molecular cytogenetic methods (fluorescence in situ
      hybridization) can be processed by spectral analysis of fluorescent emissions by
      either factor analysis of medical image sequences (FAMIS) or a META confocal
      configuration to isolate fluorescent probes. STUDY DESIGN: Three-dimensional
      sequences of images obtained by spectral analysis in a META confocal microscope
      (Carl Zeiss SAS, Jena, Germany) were analyzed by META processing and the FAMIS
      algorithm, which provides factor curves. META and factor images were then the
      result of image-processing methods that cover emission spectra. RESULTS: Factor
      curves and factor or META images can help to analyze targets inside nuclei.
      CONCLUSION: It is possible to process preparations containing numerous spots on
      different colors to differentiate stained targets and to improve visualization
      and detection.

PMID- 15032076
TI  - Immunohistochemical evaluation of urokinase plasminogen activator receptor in
      noninvasive and early invasive urothelial papillary neoplasia.
AB  - OBJECTIVE: To investigate urokinase plasminogen activator receptor (uPAR)
      expression in urothelial papilloma and in noninvasive and early invasive
      papillary carcinoma. STUDY DESIGN: The study included 40 cases of papillary
      neoplasia of the urinary bladder subdivided into 10 cases of urothelial papilloma
      (UP); 10 of papillary carcinoma, grade 1; 10, grade 2 (G2); and 10, grade 3 (G3).
      Invasion of the subepithelial connective tissue was present in 5 cases of G2 and
      7 cases of G3. According to the 2002 revision of the TNM system, these cases were
      defined as T1 and the others as Ta. uPAR expression was evaluated with an
      immunohistochemical technique in 5-microns-thick tissue sections. RESULTS:
      Difference in the distribution of positive cases in the 4 groups were
      statistically significant and greatest in G3. Statistically significant
      differences were also observed between Ta and T1 cases in terms of uPAR
      intensity. CONCLUSION: Detection of immunoreactivity for uPAR was associated with
      high grade UP carcinomas. These data indicate that uPAR is potentially an
      important prognostic factor in bladder carcinoma.

PMID- 15032077
TI  - Effects of lossy image compression on quantitative image analysis of cell nuclei.
AB  - OBJECTIVE: To investigate whether statistically significant changes occur in
      quantitative image analysis of cell nuclei when lossy image compression
      techniques are used. STUDY DESIGN: Thirty-five stoichiometric, Feulgen-stained
      samples of rat hepatocytes, human thyroid and ovarian cancer cell nuclei were
      used. Image analysis was performed by a computerized system that used AutoCyte
      LINK V1.1.1.56 software (Burlington, North Carolina, U.S.A.) for image
      acquisition and Zeiss Vision KS 400 V3.0 software (Oberkochen, Germany) for
      quantitative image analysis. After lossy JPEG compression of acquired images at
      different quality levels, some densitometric features were selected and
      measurements performed. RESULTS: We observed that nearly all the standard
      densitometric features showed statistically significant changes when images were
      compressed with the lossy JPEG algorithm. However, most invariant densitometric
      moment features remained free of statistically significant changes. CONCLUSION:
      The standard densitometric measurements that we used do not tolerate lossy
      compression. However, analyses using invariant densitometric features may be
      performed on images compressed with lossy JPEG, resulting in simpler, less
      expensive systems demanding less network bandwidth.

PMID- 15032079
TI  - Semiautomated image segmentation of bone marrow biopsies by texture features and
      mathematical morphology.
AB  - OBJECTIVE: To present the preliminary results of a method for semiautomated
      detection of fat and hematopoietic cells as well as trabecular surfaces in bone
      marrow biopsies in order to calculate the percentage of each type of tissue or
      cell area in relation to the whole area. STUDY DESIGN: The results were derived
      from selected clinical cases. Twenty-six biopsies were used, presenting varied
      distributions of cellularity and trabecular topography. The approach is based on
      digital image processing techniques and pattern recognition methods using
      textural features obtained from biopsy images. The results were improved with
      mathematical morphology filters. RESULTS: A low computational cost algorithm is
      obtained that produces highly satisfactory results. The method is faster and more
      reproducible than conventional ones, such as region growing, edge detection,
      splitting and merging. CONCLUSION: The results with this computer-assisted
      technique were compared to those obtained by visual inspection by 2 expert
      pathologists, and differences of < 9% were observed.

PMID- 15032078
TI  - Mean nuclear volume in ovarian papillary serous cystadenocarcinoma.
AB  - OBJECTIVE: To measure mean nuclear volume (MNV), estimated by the stereologic
      intercept method, in ovarian serous carcinomas and to compare that between
      omentum-positive cases (cases with omental metastasis) and -negative cases. STUDY
      DESIGN: This retrospective study consisted of 29 cases (stage I and II = 13
      cases, and stage IIIb = 16 cases) of ovarian papillary serous cystadenocarcinoma.
      MNV of all cases (at primary and metastatic sites) was estimated with an image
      cytometer. The nuclear point intersection method was used to measure nuclear
      volume. Mean intercepted diameters of at least 50 nuclei were measured. MNV was
      correlated with histologic grade, International Federation of Gynecology and
      Obstetrics (FIGO) staging of ovarian malignancy and primary tumor versus
      metastatic deposits. RESULTS: MNVs estimated in omentum-negative (FIGO stage I
      and II) and omentum-positive (FIGO stage IIIb) cases were 1,022.48 +/- 608.45 and
      2,152 +/- 1,317.51 microns 3 (P = .05, Student t test), respectively. Significant
      differences in MNV were also observed among the different grades of tumor.
      However, no significant difference was observed between MNVs of primary and
      metastatic tumors in omentum-positive cases. CONCLUSION: Estimates of MNV on
      conventional histopathology sections may provide objective and useful criteria
      for relatively subjective histopathology grading and staging (FIGO stage I and II
      vs. IIIb).

PMID- 15032080
TI  - A mathematical model of the dynamics of odontogenic cyst growth.
AB  - OBJECTIVE: To formulate a mathematical model of odontogenic cyst growth and
      establish the dynamics of cyst enlargement and role of osmotic pressure forces
      throughout its growth. STUDY DESIGN: The model assumed a spherical cyst with a
      semipermeable lining of living cells and a core consisting of degraded cellular
      material, including generic osmotic material, fed by the continuous death of
      epithelial cells in the lining. The lining cells were assumed to have both
      elastic and viscous properties, reflecting the action of physical stresses by the
      surrounding cyst capsule, composed of fibroblasts and collagen fibers. The model
      couples the cyst radius and osmotic pressure differences resulting in a system of
      2 nonlinear ordinary differential equations. RESULTS: The model predicts that in
      all parameter regimens the long-time behavior of the cyst is the same and that
      linear radial expansion results. CONCLUSION: In the early and intermediate stages
      of cystic growth, osmotic pressure differences play an important role; however,
      in very large cysts, this role becomes negligible, and cell birth in the lining
      dominates growth.

PMID- 15032082
TI  - Image morphometry of acute leukemias. Comparison between lymphoid and myeloid
      subtypes.
AB  - OBJECTIVE: To determine if image morphometry has any role in distinguishing
      blasts of acute lymphoblastic leukemia (ALL-L2) from those of acute myeloid
      leukemia (AML-M1) and (AML-M2). STUDY DESIGN: Ten cases each of ALL-L2, AML-M1
      and AML-M2 diagnosed according to the French-American-British criteria were
      studied. In all cases May-Grunwald-Giemsa-stained bone marrow aspiration smears
      were obtained. At least 100 blast cells from each case were subjected to analysis
      randomly with an image cytometer using Leica Quantimet 600 software (Cambridge,
      U.K.). The area, convex area, length, width, perimeter, convex perimeter,
      roundness, total optical density, average optical density and pixel grey value
      variance of the nuclei were measured by random selection of cells using a 40:1
      objective (1 pixel = 0.446 micron). RESULTS: Mann Whitney's nonparametric test
      showed that there was considerable overlap of morphometric variables between the
      3 subtypes. Though statistical significance was found in "roundness" between
      blasts of AML-M1 and ALL-L2, power analyses (sample size of 100 blasts of each
      subtype) did not show sufficient power for this variable. However, between blasts
      of ALL-L2 and AML-M2, "average optical density" and "pixel grey value variance"
      were statistically significant with full power using power analyses. CONCLUSION:
      Image morphometry may be helpful in differentiating blasts from lymphoid and
      myeloid leukemic subtypes.

PMID- 15032083
TI  - Nurses receive bonuses for patient satisfaction.

PMID- 15032081
TI  - Analysis of the fluorescence of monodansylcadaverine-positive cytoplasmic
      structures during 7-ketocholesterol-induced cell death.
AB  - OBJECTIVE: To analyze multilamellar cytoplasmic structures by confocal laser
      scanning microscopy (CLSM) combined with factor analysis of biomedical image
      sequences (FAMIS). STUDY DESIGN: After treatment of U937 cells with 7
      ketocholesterol (7-keto), cytoplasmic alterations were assessed with
      monodansylcadaverine (MDC). By ultraviolet excitation of a confocal laser
      scanning microscope (UV-CLSM), spectral sequences were performed to characterize
      7-keto and MDC distribution inside cells. FAMIS was used to transform the image
      sequences in factor curves and images. RESULTS: By UV-CLSM, 7-keto fluorescence
      was detected together with MDC, which revealed morphologic cytoplasmic changes in
      cells. The factor images obtained from confocal image sequences emphasized the
      view of these results. These data are in agreement with biochemical
      characterizations of MDC-positive structures. CONCLUSION: The combined use of
      confocal microscopy and FAMIS allowed us to detect MDC-positive cytoplasmic
      structures in 7-keto-treated cells and to colocalize MDC and 7-keto distribution.
      This new method confirms the usefulness of MDC as a marker of oxysterol-induced
      cell death.

PMID- 15032084
TI  - The Pennsylvania Health Care Cost Containment Council: a nursing perspective.

PMID- 15032086
TI  - [Pregnancy and chemotherapy; an apparent contradiction].
AB  - Two women aged 34 and 32, were diagnosed with cancer during pregnancy. The 34
      year-old woman with breast cancer diagnosed during the first trimester of
      pregnancy, had just undergone breast-conserving surgery. She chose to have an
      abortion before adjuvant chemotherapy was started. A year after chemotherapy
      ended she became pregnant again and gave birth to a healthy child. After 3 years
      there were no signs of metastases. In the 32-year-old woman with a malignant
      lymphoma diagnosed during the third trimester of pregnancy, chemotherapy had to
      be started because she developed V. cava superior syndrome. The dyspnoea
      disappeared and a week after the first treatment she gave birth to a healthy
      child. A year after completion of treatment she was in complete remission and her
      child was developing well. Pregnancy is not always a contraindication for
      starting chemotherapy. However, in order to reduce the risk to mother and child
      as much as possible, the duration of the pregnancy as well as different groups of
      cytostatic drugs have to be taken into consideration. A multidisciplinary
      approach to mother and child is essential.

PMID- 15032087
TI  - [The yield of breast cancer screening: the importance of observational data and
      the problems of bias].
AB  - Descriptive studies are important for the analysis of the effects of medical
      interventions. Especially in breast cancer screening, where the balance between
      gains and losses is often difficult to establish, detailed, empirical, long-term
      follow-up data on outcomes are of vital importance. Recent Dutch data comparing
      the prognosis, tumour stage at diagnosis and surgical treatment before and after
      the introduction of a population-based breast cancer screening programme reveal a
      better prognosis and a more favourable tumour stage after introduction of the
      programme. However, these data have their limitations. The interpretation of such
      figures is hampered by different types of bias (lead-time, length and over
      diagnosis). The final assessment is always subjective and prone to confirmation
      bias.

PMID- 15032088
TI  - [Childhood vaccinations anno 2004. I. Effectiveness and acceptance of the Dutch
      National Vaccination Programme].
AB  - Vaccinations are the most effective measures in public health. In the Netherlands
      after the second world war the morbidity and mortality of infectious diseases
      were a great problem. Nowadays these diseases are gone or reduced at a minimal
      level and for the greater part under control. The Dutch National Vaccination
      Programme aims at 10 infectious diseases. In the Netherlands there has always
      been a relatively small group of religious people who live together and reject
      vaccinations. Since the start of the vaccination programme in this group several
      small epidemics of poliomyelitis and measles have been observed. The other
      dispersed living non-vaccinated people are protected by herd-immunity, as long as
      the vaccination coverage is above 90%. During recent years an increasing number
      of people have doubts over the use and safety of vaccinations. There is a
      worldwide anti-vaccination movement, in the Netherlands represented by the
      'Nederlandse Vereniging Kritisch Prikken'. The finding that there is now a
      greater spread of areas with a low or insufficient vaccination coverage, is cause
      for concern because experiences in several countries have shown that infectious
      diseases with all complications will recur when the vaccination percentage
      decreases. There is no scientific support for the hypothesis that vaccinations
      overwhelm or weaken the immune system of infants and there is no objection to
      start with vaccination at the age of two months. Anthroposofic and homeopathic
      arguments are neither scientifically, nor practically supported. Good promotion
      and education about the vaccination programme is of great importance and can be
      improved. Parents should make decisions based on good, objective information.
      Possible risks and side effects of vaccination should not be concealed.

PMID- 15032089
TI  - [Childhood vaccinations anno 2004. II. The real and presumed side effects of
      vaccination].
AB  - Vaccinations protect to a high degree against infectious diseases, but may cause
      side effects. In the Netherlands since 1962 the adverse events following
      immunizations are registered and analysed by the National Institute of Health and
      Environment (RIVM). Since 1983 a permanent Committee of the Dutch Health Council
      reviews adverse events reported to the RIVM. With the so-called killed vaccines
      the side effects are mainly local (redness, swelling, pain) or general (fever,
      listlessness, irritability, sleep and eating problems). They are seen mainly
      after DPT-IPV vaccination against diphtheria, pertussis, tetanus and
      poliomyelitis. Some side effects occur rarely (collapse reactions, discoloured
      legs, persistent screaming and convulsions) and very rarely serious neurological
      events are reported. After MMR vaccination against measles, mumps and rubella,
      cases of arthritis, thrombocytopenia and ataxia are reported sporadically.
      Usually, they have a spontaneous recovery. During recent years a scala of
      diseases or symptoms have been associated with vaccination (presumed side
      effects). Careful and extensive investigations have shown that such hypotheses
      could not be supported. Examples are allergic diseases as asthma, diabetes
      mellitus, multiple sclerosis (after hepatitis B vaccination), autism and
      inflammatory bowel disease (after MMR vaccination) and sudden infant death
      syndrome. The total number of cases where at least a possible relation between
      side effects and vaccination is observed--apart from local reactions and moderate
      general symptoms--is very rare (about 0.25 per 1000 vaccinations) and does not
      balance the benefits from vaccination. There appears increasing doubt about the
      use and safety of vaccinations. More research is needed about the motives of
      people to choose for and against vaccination. The education about vaccination for
      parents and professionals who are involved with vaccination has to be improved.
      Internet can play an important role.

PMID- 15032090
TI  - [The autoimmune lymphoproliferative syndrome: a disorder of programmed cell
      death].
AB  - The autoimmune lymphoproliferative syndrome (ALPS) is a chronic, nonmalignant
      lymphoproliferative disorder caused by mutations in the genes that are involved
      in programmed cell death (apoptosis). The impaired apoptosis causes accumulation
      of lymphocytes, which underlies the clinical manifestations of lymphadenopathy,
      autoimmune phenomena and a markedly increased risk of malignant lymphomas. During
      the last few decades, great progress has been achieved in elucidating the
      aetiology of this syndrome. Several mutations have been found in the genes
      encoding proteins that are involved in the apoptotic cascade, which starts with
      the binding of the Fas ligand to the transmembranous Fas protein and which is
      followed by intracellular processes. ALPS is an autosomal dominant hereditary
      disease with variable penetrance. Unravelling the genetic abnormalities that
      cause ALPS has provided key insights into the clinical consequences of defective
      apoptosis.

PMID- 15032091
TI  - [Diagnostic image (177). A lifeless infant. Shaken baby syndrome].
AB  - In a 4-months-old male infant who had been discovered in his bed pale, apnoeic
      and cold, fundoscopy revealed multiple retinal haemorrhages due to shaken baby
      syndrome.

PMID- 15032092
TI  - [Cervical ranula].
AB  - Three patients, 2 men aged 21 and 39 years, respectively, and 1 woman aged 29
      years, presented with a unilateral swelling of the neck, with no accompanying
      symptoms. In the youngest man the diagnosis of a 'plunging ranula' was made after
      repeated fine needle aspiration yielded viscous yellowish mucus with a high
      amylase content. In the oldest man the diagnosis was made during the operation
      and in the woman the diagnosis was finally made after two surgical explorations
      in the neck. In all 3, no recurrence occurred after removal of the involved
      salivary glands. A cervical ranula is an extension of a pseudocyst of the
      glandula sublingualis. Important clues for the diagnosis of a 'plunging ranula'
      are: the simultaneous presence of a ranula in the floor of the mouth (or a
      history of one), a characteristic cystic mass in the submandibular space with an
      extension into the sublingual space on CT and/or MRI, and the aspiration of
      amylase-containing mucus. Excision of the sublingual gland as the source of
      salivary leakage is the therapy of choice in a case of 'plunging ranula', with
      drainage of mucus from the ranula into the oral cavity. As the 'plunging ranula'
      represents a pseudocyst without an epithelial lining, excision is not indicated.

PMID- 15032094
TI  - [Starting January 1, 2004, editors of the Dutch Journal of Medicine; gender
      identity in front of authors' names in the Journal].

PMID- 15032093
TI  - [Terminal sedation in mentally competent patients: no overriding medical-ethical
      arguments against it in the medical literature].

PMID- 15032095
TI  - [The haematogenous reproduction theory of Aristotle].

PMID- 15032096
TI  - In vitro embryos and DNA profiling: far from clear legal reform.

PMID- 15032097
TI  - [Bioethical principles concerning human genetic data].
AB  - UNESCO'S Universal declaration on the human genome and human rights (1997) has
      been accepted by the international scientific community. To apply these laws, it
      is necessary to get more specific rules about data regulation, human genetic
      samples and its derived information in biomedic research. Indeed, genetic
      material recollection, processing, use and storing, has potential risks over
      human rights' protection and exercise. The author, member of UNESCO'S
      intergovernmental Bioethics Committee which approved the final draft in June
      2003, has taken part in the writing of the final text of an international
      declaration about human genetic data, whose abbreviate text is described and
      commented in this communication.

PMID- 15032098
TI  - [Regulation of reproductive medicine in North America or the Wild West of
      Medicine (Part II)].

PMID- 15032099
TI  - Embryonic stem cell research: can the law balance ethical, scientific and
      economic values? (Part II).

PMID- 15032101
TI  - [Principles and juridical limits to human embryo research].
AB  - This work intends to provide a wide scope of the legal situation in Brazil
      referred to Human Embryos and how it has been developed through the 20th century.
      Across the last century, the human being got the possibility of making genetic
      experiments with human embryos. Our main goal is to assume the future
      responsibility of these actions through a juridical and ethical point of view.

PMID- 15032100
TI  - [Expansive development of the French regulation of the genetic print files after
      the recent reforms (Part I)].
AB  - French regulations related to "genetic prints" and its later incorporation to an
      automatized file in the frame of the penal process, initially deserved (1998) a
      positive judgement due to the guarantees surrounding such techniques, considering
      that with its use an interference was made with the freedom and rights of the
      individual. This primary regulation is watching a legislative evolution that
      brings serious doubts about the current guarantee system. A couple of legal
      reforms with security as their main axis (2001 and 2003) give more importance to
      the "genetic print" file by extending the causes in which it starts functioning
      going against the proportionality that must be observed when freedoms and rights
      of the individual can be affected.

PMID- 15032102
TI  - Genetic data and confidentiality, the Estonian experiment.

PMID- 15032103
TI  - [The zig-zagging legislative policies of the European Union in relation to
      transgenic products].
AB  - The author analyses the E.U. legislative policies related to transgenic products
      from the 80s until nowadays, she stops in Directive 2001/18/Ce and its conversion
      into national law. She explains how the regulatory frame is after the recent
      approval of the newest rules about tracking and labelling genetically modified
      organisms (OMG). She also studies communitary jurisprudence about this subject
      according to the legislation, concretely sentence 9 September 2003 in the affair
      C-236/01 about commercialisation of two lines of transgenic corn. Finally she
      points out how legislative policies have influenced the creation and development
      of biotechnological enterprises.

PMID- 15032104
TI  - Bio-patents, law and ethics. Critical analysis of the EU biotechnology directive.

PMID- 15032105
TI  - [Patients' rights concerning their biological samples: different legal opinions].
AB  - In these pages, my wish is to highlight the legislative lagoon in our juridical
      frame related to the storage and use from the biological sample extracted from
      the patient (source subject) in an assistance process and the rights he has over
      it. This situation has led us to have different judgements everytime that a case
      like this has been judged.

PMID- 15032106
TI  - Social risks and social perception of animal cloning.

PMID- 15032107
TI  - [The UNESCO international declaration about human genetic data ].

PMID- 15032108
TI  - [Law 25/2003, of 21 November, modifying Law 35/1988, of 22 November, concerning
      assisted reproduction techniques].

PMID- 15032109
TI  - [Organic Law 15/2003, of 25 November, modifying the Organic Law 10/1995, of 23
      November, on the Penal Code].

PMID- 15032110
TI  - Breast cancer and environmental risks: where is the link?
AB  - Environmental factors may play an important role in the etiology of female breast
      cancer. This paper reviews existing evidence to compare and analyze environmental
      agents in relation to breast cancer. The authors have reviewed multiple studies
      focusing on xenoestrogens, organochlorines, polychlorinated biphenyls, and other
      environmental agents, and the results are cited. Current use of oral
      contraceptives and prolonged use of hormone replacement therapy moderately
      increase risk. Evidence regarding organochlorine exposure and breast cancer risk
      is mixed. Atrazine is not associated with breast cancer risk, but dieldrin and
      lindane are. The effects of polychlorinated biphenyls vary according to specific
      congeners. An observational study has linked benzene to breast cancer, but
      another case control study has refuted the association. Risk of breast cancer
      with smoking is strong in families with a history of breast cancer, ovarian
      cancer, or both. Studies have shown a positive association of breast cancer with
      heterocyclic amines in women who eat well-done meat. Thus, many environmental
      factors have been significantly associated with breast cancer. Differing
      distribution of socio-demographic factors, including race/ethnicity, parity, and,
      possibly, nutritional status, may explain some of the inconsistencies across
      studies. Further research is needed to verify associations.

PMID- 15032111
TI  - Cryptosporidiosis: a brief literature review and update regarding Cryptosporidium
      in feces of Canada geese (Branta canadensis).
AB  - Canada geese are increasingly abundant in Ohio, with large nesting populations
      throughout the state, and goose feces contaminate grassy areas and pavements in
      many public, commercial, and residential sites. In 1999 the authors found a high
      prevalence of Giardia, Campylobacter, and especially Cryptosporidium in collected
      feces of Canada geese. The purpose of this follow-up study was to survey known
      Canada geese sites in three counties in Ohio (Lucas, Ottawa, and Wood) and to
      determine the prevalence of sites testing positive for Cryptosporidium. The sites
      included golf courses, cemeteries, public parks, and health care and teaching
      facilities. At each of 11 sites, 12 goose feces of wet and loose appearance were
      collected and manually compressed into one composite sample representing that
      site. The samples were tested for Cryptosporidium with a sensitive monoclonal
      enzyme immunoassay (EIA) method. In 2000 and 2001, nine of 11 sites (81.8
      percent) and nine of 10 sites (90 percent), respectively, were positive for
      Cryptosporidium. The species or genotypes of Cryptosporidium found in the geese
      feces and their potential to infect humans is unknown. A survey of the literature
      indicates, however, that while C. parvum (human genotype) is the main cause of
      cryptosporidiosis in humans, C. parvum (zoonotic genotypes), C. meleagridis (bird
      genotype), and C. felis (cat genotype) have occasionally been isolated from
      infected people. Further research is required to define the public health
      importance of Cryptosporidium in feces of Canada geese and other bird species.

PMID- 15032112
TI  - Clandestine methamphetamine labs in Wisconsin.

PMID- 15032113
TI  - Food safety programs--an improved model for media relations.

PMID- 15032114
TI  - Statutory presumption, more on statutes of limitations, and the concept of
      "closely regulated industries".

PMID- 15032115
TI  - Sampling for clandestine drugs after remediation.

PMID- 15032116
TI  - U.S. cancer incidence: prostate cancer and breast cancer are most common.

PMID- 15032117
TI  - Reinventing nursing--a charge of Texas Nurses Association.

PMID- 15032118
TI  - 2004 Colorado Women's Hall of Fame inductee--Louie Croft Boyd RN.

PMID- 15032121
TI  - What will the panthers anther? Where do we go from here? 1964.

PMID- 15032122
TI  - Nutraceuticals and other biologic therapies. Preface.

PMID- 15032123
TI  - Evidence-based medicine concepts.
AB  - Today, the busy clinician benefits from a philosophy of practice that brings
      together the best applicable evidence and the experiences of clinical work in an
      effort to provide the best care for individual patients. EBM provides a
      structured approach that recognizes the contributions of evidence and clinical
      experience. An EBM practice is efficient and effective in meeting the goal of
      assuring optimum care. The concepts of EBM make sense for veterinary medicine
      (even if there are limited numbers of randomized, blinded studies), and
      clinicians in all types of practice can apply them.

PMID- 15032124
TI  - Balancing fact and fiction of novel ingredients: definitions, regulations and
      evaluation.
AB  - Veterinarians have an opportunity to help educate their clients regarding the
      safety and efficacy of novel ingredients used by their clients. This is no small
      task because of the lack of acceptable information. Clients should be counseled
      regarding the lack of scientific evidence and be encouraged to discriminate fact
      from fiction, including many testimonials. Safety should be of primary concern,
      and clients should be encouraged not to neglect traditional therapies in lieu of
      novel ingredients unless clinical evidence of efficacy exists. Quality assurance
      is equally important and cannot be underestimated. Clients are likely to resort
      to less expensive products. Clients should be directed to the advice offered by
      the Arthritis Foundation as follows: "When a supplement has been studied with
      good results, find out which brand was used and buy that." Although skepticism is
      encouraged regarding any unknown product with medicinal indications, open
      mindedness should also guide the veterinarian as these products are considered.
      Indeed, veterinarians should take actions to ensure that the use of these
      compounds is accomplished within the confines of the veterinary-client-patient
      relationship, thus ensuring the role of the veterinarian in the health and well
      being of animals, regardless of the modality of therapy. The veterinary
      profession should support the development of standards that might guide
      manufacturers of novel ingredients to meet criteria that protect the consumer.
      Likewise, we should encourage manufacturers and agencies to fund veterinary
      clinical trials to provide evidence for the use of these potentially exciting
      compounds. Above all else, the veterinarian needs to become a credible resource
      of information about the possible role of these products. The lack of a
      regulatory mechanism that establishes the safety and efficacy of these products
      is not justification for ignoring the potential therapeutic benefit of some of
      these products. Veterinarians should follow the advice of the Arthritis
      Foundation, which notes: "Since glucosamine is self-prescribed ... health care
      professionals are not regarded [to have] objective advice. This situation must
      change. It is time for the profession to accommodate the possibility that many
      nutritional products may have valuable therapeutic effects" [61].

PMID- 15032125
TI  - The natural activities of cells, the role of reactive oxygen species, and their
      relation to antioxidants, nutraceuticals, botanicals, and other biologic
      therapies.
AB  - There have been remarkable advances in molecular and cell biology that define the
      mechanisms of how various supplements function in and around cells. Current
      evidence strongly supports the probability that cellular functions and cellular
      responses that pertain to inflammation, disease, and life and death activity can
      be modulated with supplementation; however, the complexity of each individual's
      reaction and the vast differences in physiologic influences makes clinical
      research difficult in regard to clinical studies using antioxidant and biologic
      therapies. Not enough is known specifically about each supplement and its
      interactions with cells, nor is enough understood about how the body compensates
      or reacts to such applications. What works well in one individual or species
      might work differently in another. In addition, not all antioxidants are created
      equally, and discrepancies in purity and absorption can occur. It must also be
      determined whether or not less than optimum levels or infrequent usage will
      produce the same physiological effects. Not everyone--nor every species of animal
      -responds in the same manner to supplements, which might account for the
      variations in clinical research. The cellular effects of antioxidants and other
      supplements are well defined and meaningful, and their clinical application looks
      promising despite individual variations. Combinations of antioxidants are
      synergistic and support cellular functions, effects that are often not apparent
      with individual agents. Such combinations offer a variety of mechanisms for
      reducing oxygen metabolites in tissues, altering signaling pathways, and
      modulating transcription factors, and they might play key roles in reducing the
      damage afforded by ROS. It is the author's opinion that combinations of
      antioxidants are best suited for clinical application in modulating disease and
      reducing premature aging when caused by excessive free radical accumulation.
      Clinicians should approach clinical application of these supplements based on the
      best available scientific research and species-specific information available.

PMID- 15032126
TI  - Metabolic, antioxidant, nutraceutical, probiotic, and herbal therapies relating
      to the management of hepatobiliary disorders.
AB  - Many nutraceuticals, conditionally essential nutrients, and botanical extracts
      have been proposed as useful in the management of liver disease. The most studied
      of these are addressed in terms of proposed mechanisms of action, benefits,
      hazards, and safe dosing recommendations allowed by current information. While
      this is an area of soft science, it is important to keep an open and tolerant
      mind, considering that many major treatment discoveries were in fact
      serendipitous accidents.

PMID- 15032127
TI  - Functional foods and the urinary tract.
AB  - There is no universally accepted definition of a commonly used term for a
      functional food: nutraceutical. For the purposes of this article, a nutraceutical
      is any ingredient found in foods that has a demonstrated (or proposed)
      physiologic benefit. Although a nutraceutical is generally taken to be an
      ingredient that can be isolated or purified from food, plants, or marine products
      and made available in medicinal form, this article also considers claims of
      benefit to the urinary tract for foods or food supplements in which the active
      ingredient has not yet been characterized or isolated.

PMID- 15032128
TI  - Traditional and nontraditional effective and noneffective therapies for cardiac
      disease in dogs and cats.
AB  - In this article, I presented my (admittedly biased) perspective of the current
      state of knowledge addressing the role of traditional and non-traditional
      therapeutics. The focus has been on the nontraditional therapeutics. Among these,
      the only ones I currently consider to have any documented value are taurine and,
      less commonly, L-carnitine. The role of taurine (and likely carnitine) remains
      limited to cases of documented deficiency. In the case of cats with taurine
      deficiency-induced myocardial failure, it is now clear that most cases are the
      result of formulation errors by owners and manufacturers. In dogs, it is less
      clear if the causes of taurine deficiencies represent manifestations of
      pathologic conditions or dietary formulations errors. Increasingly, it seems the
      latter may prove to be the case in most, if not all, circumstances. Finally, I
      would like to reiterate the conclusions of the last time I addressed this topic
      (with coauthors Kittleson and Sanderson) in this publication. Remember that there
      is limited evidence to support the therapeutic recommendations you read or hear
      in most circumstances. The urge to do "something" for patients can be
      overwhelmingly attractive. Nevertheless, whether it is administration of drugs or
      prescribing nutraceuticals or prescription diets, strongly consider the source of
      the information urging you to prescribe, the strength of the evidence presented,
      the financial costs to the owner, and the potential risks and benefits to the
      patient.

PMID- 15032129
TI  - Nutraceuticals, aging, and cognitive dysfunction.
AB  - Decline in cognitive function that accompanies aging in dogs might have a
      biological basis, and many of the disorders associated with aging in canines
      might be preventable through dietary modifications that incorporate specific
      nutraceuticals. Based on previous research and the results of laboratory and
      clinical studies, antioxidants might be one class of nutraceutical that benefits
      aged dogs. Brains of aged dogs accumulate oxidative damage to proteins and
      lipids, which can lead to dysfunction of neuronal cells. The production of free
      radicals and lack of increase in compensatory antioxidant enzymes might lead to
      detrimental modifications to important macromolecules within neurons. Reducing
      oxidative damage through food ingredients rich in a broad spectrum of
      antioxidants significantly improves, or slows the decline of, learning and memory
      in aged dogs; however, determining which compounds, combinations, dosage ranges,
      when to initiate intervention, and long-term effects constitute critical gaps in
      knowledge about this subject.

PMID- 15032130
TI  - Modulation of immune response through nutraceutical interventions: implications
      for canine and feline health.
AB  - Mounting research demonstrates that certain nutraceutical compounds interact with
      the immune system. These interactions may be positive or negative depending on
      the compound or dose administered to the individual. Understanding the mechanisms
      by which these compounds work should provide opportunities to design nutritional
      interventions to bolster the health of dogs and cats.

PMID- 15032131
TI  - The use of nutraceuticals in cancer therapy.
AB  - The high prevalence of nutraceutical use among human patients with cancer
      suggests that the use of nutraceuticals in pet animals with cancer is probably
      common. Dogs with a wide variety of malignant diseases have significant
      alterations in carbohydrate, protein, and fat metabolism. These metabolic
      alterations may be ameliorated by using functional foods relatively low in
      soluble carbohydrate, moderate amounts of protein that includes sources of
      arginine, and moderate amounts of fat supplemented with omega-3 long-chain
      polyunsaturated fatty acids. Well-controlled clinical studies in a variety of
      species with cancer, including rodents, people, and dogs, have documented that
      increased dietary and serum levels of omega-3 fatty acids are associated with a
      number of health benefits, including improved disease-free interval, survival
      time, and quality of life. Other nutraceuticals of interest in patients with
      cancer include antioxidant vitamins, trace minerals, glutamine, protease
      inhibitors, garlic, tea polyphenols, vitamin A, and shark cartilage.

PMID- 15032132
TI  - Use of nutraceuticals and chondroprotectants in osteoarthritic dogs and cats.
AB  - Chondroprotectants and nutraceuticals have become attractive adjunctive or
      alternative treatments for cats and dogs suffering from osteoarthritis.
      Osteoarthritic patients can be managed satisfactorily in most situations with
      optimization of body condition, exercise modification, anti-inflammatory therapy,
      and the use of chondroprotectants agents. Presently, recommendations cannot be
      made as to which chondroprotectant is best for each dog and cat afflicted with
      osteoarthritis. Head-to-head comparisons of these products have not been made,
      and it is not known when the different mediators of osteoarthritis play an
      important role. Currently, the best recommendation is to use products that have
      well-designed experimental and clinical research evaluating efficacy and safety,
      and products that are manufactured under the high quality standards practiced by
      the pharmaceutical industry.

PMID- 15032133
TI  - Pharmacognosy: phytomedicines and their mechanisms.
AB  - The more a critical look at the medicinal properties of plants is undertaken, the
      more it will be realized that nature does not make it easy to find all there is
      to know about them and the complexities of their interactions. An illustration of
      this can be found in one of the earlier scientific studies on phytomedicines, the
      Nobel laureate Albert Szent-Gyorgyi and his colleagues [170] found that flavanone
      extracts from the Capsicum spp contain an ascorbate-protective factor. It has now
      been repeatedly shown that the electron-donating properties of the phytochemical
      flavonoids, providing both nutritive and chemotherapeutic benefits, are the basis
      of their antioxidant action [171-175]. Studies by zoologists have demonstrated
      that animals, by selectively choosing specific plants, soils, and clays, maintain
      their health and treat themselves in times of ill health. The term
      zoopharmacognosy, now well researched, has been coined to describe the study of
      this recognized phenomenon. Long ago, Isaac Newton stated that for every action,
      there is an equal and opposite reaction. The same may be seen in plants and plant
      material. The same may be said of life in general. At the most basic concept, we
      are talking of electrons and their activities.

PMID- 15032134
TI  - Regulatory issues of functional foods, feeds, and nutraceuticals.
AB  - It is clear that the prospects of functional foods and nutraceuticals already
      excite the scientific community into discovering new substances that promise to
      extend healthy life. The greatest challenge will remain in the public policy and
      regulatory arenas, which will encourage research and development of products
      providing health benefits and permit remarking of products in truthful,
      nonmisleading communications while protecting public health and maintaining
      public confidence.

PMID- 15032135
TI  - Cellular effects of common nutraceuticals and natural food substances.
AB  - Tabular information of proposed cellular effects regarding the use of certain
      nutraceuticals (including antioxidants, phytonutrients, and other biological
      therapies) and herbs, compiled from scientific sources and experimental research,
      is provided.

PMID- 15032136
TI  - Cellular effects of various herbs and botanicals.
AB  - Tabular information of proposed cellular effects regarding the use of certain
      nutraceuticals (including antioxidants, phytonutrients, and other biologic
      therapies) and herbs, compiled from scientific sources and experimental research,
      is provided.

PMID- 15032137
TI  - [Allergy to house dust mites: allergy independent symptoms dominate].
AB  - A sensitisation to allergens has not always a clinical relevance. Therefore, the
      history has an uppermost importance for defining the relevance of a
      sensitisation. In contrast to the history in seasonal rhino-conjunctivitis, which
      causes typical complains in a restricted time period patients with house dust
      mite allergy seem to have less defined complaints. To define the most relevant
      symptoms of this frequent allergy, we evaluated 35 patients with clearly defined
      house dust mite allergy by a questionnaire and evaluated the same questionnaire
      also in a control group of 18 patients without sensitisation or asthma. The
      symptoms described in the patient group confirm that symptoms of house dust mite
      allergy are frequently not related to a direct allergen exposure. Some patients
      complained about itchy red eyes in the morning, but the majority of symptoms
      occurred independent from allergen exposure. These are blocked nose as well as
      exercise induced asthma. These symptoms are present all year around and are not
      only restricted to mite exposed areas. They are probably related to the underling
      eosinophilic inflammation. Thus exercise induced asthma and blocked nose are
      symptoms, which may indicate a mite allergy, particular in younger patients.

PMID- 15032138
TI  - [The role of genetics in amyotrophic lateral sclerosis].

PMID- 15032139
TI  - [Spontaneous dissection of visceral blood vesssels--a rare cause of epigastric
      pain].
AB  - A 51 year-old man presented with acute abdominal pain in our emergency room. The
      first examination revealed no pathological findings except coprostasis and after
      an enteroclysis the patient was sent home without any complaints. During a recent
      episode of abdominal pain a computer tomography was performed, showing dissection
      of the superior mesenteric and the celiac artery. Without any signs of mesenteric
      ischemia additional examinations like laboratory studies, x-rays, and abdominal
      ultrasound might be normal and therefore not helpful for diagnosis. In patients
      presenting with persistent abdominal pain and unspecific clinical and laboratory
      findings rare causes of abdominal symptoms should be considered. Despite the
      rarity of visceral artery dissection, awareness of this pathology is crucial
      because of its possible lifethreatening complications. Appropriate diagnostic
      imaging tests may avoid postmortem diagnosis by the pathologist.

PMID- 15032140
TI  - [Fleeting arthritis].

PMID- 15032141
TI  - HIV names reporting begins in Georgia.

PMID- 15032143
TI  - Clinical trials: making them work for you.

PMID- 15032144
TI  - Fuzeon treatment forum, January 2004.

PMID- 15032145
TI  - Smoking cessation: one day at a time.

PMID- 15032142
TI  - The lowdown on the "down low".

PMID- 15032148
TI  - Secondhand smoke produces asthma in adults.

PMID- 15032147
TI  - FTC warns against weight-loss scams.

PMID- 15032146
TI  - Case management changes: what can you expect?

PMID- 15032149
TI  - The maze of Medicare.

PMID- 15032150
TI  - Anesthesia: what you should know. People often fret about "going under", but
      recent improvements in anesthesia methods and materials should calm their
      concerns.

PMID- 15032152
TI  - Agitation adds to burden of Alzheimer's. Trigger management can help caregivers
      cope.

PMID- 15032151
TI  - Managing migraines. New treatments focus on relieving pain fast--or heading off
      these headaches before they begin.

PMID- 15032153
TI  - Drug combo stalls BPH progression.

PMID- 15032154
TI  - The virtues of virtual colonoscopy. Less invasive polyp-detection technique may
      motivate people to get screening.

PMID- 15032155
TI  - Vitamin D, cancer, and chronic pain. D deficiencies are problematic but
      avoidable.

PMID- 15032156
TI  - More whole grains = less weight gain.

PMID- 15032158
TI  - Replacement hormones: most who go off, stay off.

PMID- 15032157
TI  - Fatty diets mean faster AMD progression.

PMID- 15032159
TI  - New knees succeed--and last a long time.

PMID- 15032160
TI  - Osteoporosis: men are not immune.

PMID- 15032161
TI  - Automatic defibrillators save lives.

PMID- 15032163
TI  - Questions & answers. I often burp excessively, which is both embarrassing and
      uncomfortable. How can I prevent this problem?

PMID- 15032162
TI  - Pacemakers in the elderly.

PMID- 15032164
TI  - Questions & answers. What are geriatric care managers?

PMID- 15032165
TI  - Morning exercise makes for more satisfying slumber.

PMID- 15032166
TI  - A handy tip for nasal spray users.

PMID- 15032167
TI  - Water- and land-based workouts help arthritic knees and hips.

PMID- 15032168
TI  - Dysphagia. Hard to swallow.

PMID- 15032169
TI  - Health tips. The skinny on fats.

PMID- 15032170
TI  - Drug for moderate to advanced Alzheimer's approved.

PMID- 15032171
TI  - Moderate exercise reduces breast cancer risk in older women.

PMID- 15032172
TI  - Vitamin excess. Can too much be bad?

PMID- 15032173
TI  - Muscle cramps. Common and often manageable.

PMID- 15032174
TI  - Varicose veins. Newer treatments may mean quicker recovery.

PMID- 15032175
TI  - I read that the herbal supplement valerian helps people with insomnia fall
      asleep. Is valerian safe, and does it actually work?

PMID- 15032176
TI  - I've heard that some fish are raised on farms. Does this affect their omega-3
      fatty acids?

PMID- 15032177
TI  - A positive Epstein-Barr virus PCR in the CSF of an HIV-infected patient: when the
      pathogen does not match the syndrome.

PMID- 15032178
TI  - T-1249 development hits a snag.

PMID- 15032179
TI  - Controversy over ritonavir price increase.

PMID- 15032180
TI  - FDA Commissioner, Deputy receive IOM appointments.

PMID- 15032181
TI  - Antidepressant use in children.

PMID- 15032182
TI  - The FDA uses new technology to improve food security.

PMID- 15032183
TI  - First drug for moderate-to-severe Alzheimer's.

PMID- 15032184
TI  - Third drug for impotence.

PMID- 15032185
TI  - New lotion approved to treat hot flashes.

PMID- 15032186
TI  - FDA warning on unapproved performance enhancer.

PMID- 15032188
TI  - Green onions associated with hepatitis A outbreaks.

PMID- 15032187
TI  - Guidance on animal drugs and antimicrobial resistance.

PMID- 15032189
TI  - New law to improve animal drug review.

PMID- 15032190
TI  - Peanut test kits approved.

PMID- 15032191
TI  - Adverse events and Cypher stents.

PMID- 15032192
TI  - Safety of food animal clones.

PMID- 15032193
TI  - Genetics and drugs.

PMID- 15032194
TI  - Poor fitness in young adults associated with later cardiovascular problems.

PMID- 15032195
TI  - Study: distress-prone people more likely to develop Alzheimer's disease.

PMID- 15032196
TI  - Joint effort to improve the health of older Hispanic Americans.
AB  - Reducing health disparities among older Hispanic Americans is the focus of a new
      collaboration between the Food and Drug Administration and the Administration on
      Aging (AoA), two agencies within the U.S. Department of Health and Human Services
      (HHS).

PMID- 15032197
TI  - Preventing Listeria contamination in foods.
AB  - Keeping ready-to-eat foods cold is key to reducing listeriosis, a serious
      infection in humans. That's one of the conclusions of a recent Food and Drug
      Administration risk assessment on the relationships between foodborne listeriosis
      and human health.

PMID- 15032199
TI  - Advisory committees" critical to the FDA's product review process.

PMID- 15032198
TI  - FDA cautions against ultrasounds 'keepsake' images.
AB  - It's risky business taking pictures of unborn babies when there's no medical need
      to do so. That's the word from the Food and Drug Administration, which is
      concerned about companies trying to turn an important medical procedure into a
      prenatal portrait tool.

PMID- 15032200
TI  - The FDA and the fight against terrorism.

PMID- 15032201
TI  - The FDA forms Obesity Working Group.

PMID- 15032202
TI  - Keeping pets (and people) healthy.

PMID- 15032204
TI  - The importance of animals.

PMID- 15032203
TI  - Cervical cancer screening.

PMID- 15032205
TI  - Publication, citations, and impact factors of leading investigators in critical
      care medicine.
AB  - INTRODUCTION: Critical care medicine research is reported in major medical
      journals that can be accessed via computerized search engines such as PubMed
      (National Library of Medicine) or Web of Science (Thomson ISI [Institute for
      Scientific Information]). The crediting of report citations to specific journals
      or individuals is a rapidly developing and highly controversial evaluative
      process. METHODS: We conducted a citation analysis to measure the research and
      publication accomplishments of critical care medicine investigators, by tallying
      their numbers of published reports and numbers of citations to their reports.
      Major investigators were identified from the author indexes of major critical
      care medicine publications. From the Web of Science the number of publications
      and citations of their works were determined for 224 investigators for the period
      1997 through August 2003. We calculated the individual researcher's "impact
      factor" by dividing the number of citations (made by other researchers to a given
      researcher's reports) by the number of articles that researcher had published. To
      estimate which countries are producing the most research on mechanical
      ventilation, we studied the abstract books from the 2001, 2002, and 2003 American
      Thoracic Society annual international conferences and tallied the number of
      posters (pertaining to mechanical ventilation) from the various countries. We
      then calculated a "country factor" as the number of posters per million
      population of the source country. RESULTS: We considered 44, 576 citations in
      3,755 publications. Using criteria selected to recognize original works, J L
      Vincent published the greatest number of reports (129). M A Matthay received the
      most citations (2,056). G U Meduri had the highest impact factor (25.32). There
      was a balance between the number of leading investigators from Europe and North
      America. Relative to its population size, Canada warrants leadership
      acknowledgement in critical care medicine, considering its number of leading
      investigators and poster presentations. CONCLUSIONS: From criteria selected to
      attribute original work to specific authors we identified 20 leading critical
      care medicine investigators, as measured by number of publications, citations,
      and impact factors. We also report a country factor based on posters (on
      mechanical ventilation) presented at the 2001-2003 international conferences of
      the American Thoracic Society.

PMID- 15032207
TI  - The transmission of MRSA via orthopaedic marking pens--fact or fiction.

PMID- 15032206
TI  - Olecranon fractures--a reliable technique for accurate positioning of the tension
      band wire.

PMID- 15032208
TI  - A cast handle to protect extensor mechanism repair.

PMID- 15032210
TI  - Bending the rule of thirds: an accurate method for planning a long posterior flap
      transtibial amputation.

PMID- 15032211
TI  - Knee-stabilising device for lower limb orthopaedic procedures.

PMID- 15032209
TI  - Wound irrigation: simple delivery by the litre.

PMID- 15032212
TI  - A novel technique for testicular tunnelling.

PMID- 15032213
TI  - Preparing digital images for publication.

PMID- 15032214
TI  - An easy method of passing a cerclage wire around a fractured patella.

PMID- 15032215
TI  - Breast augmentation should be on the NHS: a discussion of the ethics of
      rationing.

PMID- 15032216
TI  - Breast augmentation should be on the NHS: a discussion of the ethics of
      rationing.

PMID- 15032217
TI  - Compartment syndrome following pelvic surgery in the lithotomy position.

PMID- 15032218
TI  - Compartment syndrome following pelvic surgery in the lithotomy position.

PMID- 15032219
TI  - Problem-based learning for surgical trainees.

PMID- 15032220
TI  - A simple, safe and effective method for laparoscopic port closure.

PMID- 15032221
TI  - Finding the best from the rest: evaluation of the quality of patient information
      on the Internet.

PMID- 15032222
TI  - Wroblewski wedge augmentation for recurrent posterior dislocation of the Charnley
      total hip replacement.

PMID- 15032223
TI  - Effectiveness of inactivated influenza vaccine in preventing acute otitis media
      in young children: a randomized controlled trial.

PMID- 15032224
TI  - Health status of adult long-term survivors of childhood cancer:a report from the
      Childhood Cancer Survivor Study.

PMID- 15032225
TI  - Oxygen-saturation targets and outcomes in extremely preterm infants.

PMID- 15032226
TI  - Ageism in Canada and the United States.
AB  - To compare the prevalence of ageism in Canada and the United States, in Canada,
      the Ageism Survey was published in the CARPnews Report on Ageism, and in the
      United States, the Survey was administered to a convenience sample and published
      in the Center Report and Fifty Plus. Most respondents in both countries perceived
      ageism as frequent, but it was reported more often in Canada than in the United
      States. If the Ageism Survey is used to measure the prevalence of ageism among
      various groups and countries, we can develop an "epidemiology of ageism" and
      begin to reduce ageism.

PMID- 15032227
TI  - Current awareness in NMR in biomedicine.

PMID- 15032228
TI  - Clinical response to a vacant post space.
AB  - AIM: To report a case demonstrating a radiolucency of developing adjacent to an
      unfilled post space. SUMMARY: A mandibular left first molar was root filled
      before post-space preparation. The tooth was restored coronally but the post
      space was left empty, and 14 months later, pain and furcal radiolucency
      developed. Cleaning, shaping, medicating and filling the post space resulted in
      the resolution of symptoms and healing of the radiolucency. KEY LEARNING POINTS:
      Post space should be prepared under conditions of asepsis. A post space must not
      be allowed to remain empty when a tooth is restored.

PMID- 15032229
TI  - Endodontic treatment of dens invaginatus type III with three root canals and open
      apical foramen.
AB  - AIM: To describe the conservative endodontic treatment and the 1-year follow-up
      of a permanent maxillary lateral incisor with dens invaginatus. SUMMARY:
      Frequently, the root canal treatment of invaginated teeth is challenging because
      of problems associated with gaining access to the root canals and with variations
      of canal morphology associated with this type of malformation. The present case
      describes the complex root canal treatment of dens invaginatus in a maxillary
      lateral incisor with three root canals (Oehler type III), incomplete apex
      formation, necrotic pulp and abscess formation. After gaining access to two root
      canals and the invagination with the help of a dental operating-microscope, the
      canals and the invagination were instrumented and calcium hydroxide dressing was
      applied for 6 months. Apexification and osseous bone repair were achieved, and
      the canals were filled with gutta-percha. A follow-up after 1 year showed that
      the tooth was free of any clinical symptoms and the periapical condition was
      normal. KEY LEARNING POINTS: The present case demonstrated that conservative root
      canal treatment can be performed successfully even in sever cases of dens
      invaginatus. The use of a dental operating microscope can help in the management
      of complicated cases of invaginated teeth through conventional root canal
      treatment.

PMID- 15032230
TI  - Fraudulent management of digital endodontic images.
AB  - AIM: To present examples of radiographic image reconstructions in endodontic
      treatment, to discuss the potential problems arising from the use of image
      processing software and to mention some current methods to prevent such
      counterfeit utilization of digital endodontic radiographs. SUMMARY: Conventional
      Ultra-Speed periapical films of root canal treatment were digitized with flatbed
      scanner (Umax Powerlook II, Umax Technologies, Inc., Taiwan). Digital images were
      altered with PHOTOSHOP 6.0 software (Adobe Corporation, San Jose, CA, USA).
      Carious lesions, periapical pathoses, fake root canals and artificial fillings
      were created, and inadequate treatment was corrected by application of various
      image manipulation functions of the software. KEY LEARNING POINTS: Digital
      endodontic images can be altered with image processing software. The use of
      digital radiographic data inevitably raises concerns about security, reliability
      and the potential for fraud.

PMID- 15032231
TI  - Milking goats for malaria vaccine.

PMID- 15032232
TI  - Viral treatment of MRSA.

PMID- 15032233
TI  - Pathogens maketh man.

PMID- 15032234
TI  - Learning to improve the decision-making process in research.

PMID- 15032235
TI  - Treatment of rapid-cycling bipolar disorder.

PMID- 15032236
TI  - New variation on the derivation of spectro-temporal receptive fields for primary
      auditory afferent axons.
AB  - The spectro-temporal receptive field [Hear. Res 5 (1981) 147; IEEE Trans BME 15
      (1993) 177] provides an explicit image of the spectral and temporal aspects of
      the responsiveness of a primary auditory afferent axon. It exhibits the net
      effects of the competition between excitatory and inhibitory (or suppressive)
      phenomena. In this paper, we introduce a method for derivation of the spectro
      temporal receptive field directly from a second-order Wiener kernel (produced by
      second-order reverse correlation between spike responses and broad-band white
      noise stimulus); and we expand the concept of the spectro-temporal receptive
      field by applying the new method not only to the second-order kernel itself, but
      also to its excitatory and inhibitory subkernels. This produces separate spectro
      temporal images of the excitatory and inhibitory phenomena putatively underlying
      the competition. Applied, in simulations, to models with known underlying
      excitatory and suppressive tuning and timing properties, the method successfully
      extracted a faithful image of those properties for excitation and one for
      inhibition. Applied to three auditory axons from the frog, it produced images
      consistent with previously published physiology.

PMID- 15032237
TI  - Ectoparasites--the underestimated realm.
AB  - CONTEXT: Ectoparasitoses (infestations with parasites that live on or in the
      skin) can cause considerable morbidity. Whereas pediculosis and scabies are
      ubiquitous, cutaneous larva migrans and tungiasis (sand-flea disease) occur
      mainly in hot climates. The prevalence of ectoparasitoses in the general
      population is usually low, but can be high in vulnerable groups. Scientific
      knowledge on how to deal best with parasitic skin diseases in different settings
      is scanty, and evidence-based measures for control are not available. For head
      lice and scabies the situation is daunting, because resistance of Pediculus
      humanus capitis and Sarcoptes scabiei to insecticides is spreading and
      unpredictable. STARTING POINT: J Hunter and S Barker reported different patterns
      of resistance in schoolchildren in Brisbane, Australia: full resistance to
      malathion, permethrin, and pyrethrum in two schools, whereas head lice were
      susceptible to malathion and, to a lesser extent, to pyrethrums in three other
      schools (Parasitol Res 2003; 90: 476-78). K Yoon and colleagues found different
      resistance patterns in the USA and Ecuador (Arch Dermatol 2003; 139: 994-1000).
      Head lice from Florida were less susceptible to permethrin than those from Texas,
      and parasites from Ecuador were susceptible to both insecticides tested. WHERE
      NEXT? The occurrence of resistant pediculosis and scabies is expected to increase
      numerically and geographically. Clinicoepidemiological studies are urgently
      needed to identify the factors which govern the emergence and spread of strains
      of P humanus capitis and S scabiei that are resistant to insecticide or
      acaricide. Oral treatment with ivermectin could substitute for topically applied
      compounds, particularly in resource-poor communities where polyparasitism is
      common. A better understanding of local epidemiology is required to develop
      control measures. This knowledge has to be applied in combination with
      environmental sanitation, health education, and culturally acceptable
      interventions that are affordable by the underprivileged.

PMID- 15032238
TI  - Anti-HIV plan is failing rape survivors in South Africa. Failure casts doubt on
      success of providing antiretrovirals to all who need them, says Human Rights
      Watch.

PMID- 15032239
TI  - US researchers push past stem-cell restrictions. States and private sources fund
      research denied federal support by Bush ban.

PMID- 15032240
TI  - NIH terminates WHI oestrogen-only study.

PMID- 15032241
TI  - Surgeon denied ethics approval for face transplantation.

PMID- 15032242
TI  - Pressure group urges rosuvastatin recall.

PMID- 15032244
TI  - NIH panel holds conflicts of interestmeeting.

PMID- 15032243
TI  - Merck broke AIDS drug price promise, says MSF.

PMID- 15032245
TI  - New report accuses Bush of suppressing research data. Allegations prompt
      defensive response; White House blames "poor communication".

PMID- 15032246
TI  - Erythropoietin and radiotherapy: a dangerous combination?

PMID- 15032247
TI  - [Medical and engineering cooperation in otorhinolaryngology].

PMID- 15032249
TI  - [Propyphenazone. Pharmacology and use].

PMID- 15032250
TI  - [Weight reduction with dietary supplements? Fact or fiction].

PMID- 15032251
TI  - [Drug and medicinal products for the consumer. A critical evaluation].

PMID- 15032252
TI  - [Stomach ulcer from nonsteroidal antirheumatic agents].

PMID- 15032253
TI  - [Are there allergies against husbands?].

PMID- 15032254
TI  - Leading the way against the leading preventable cause of death.

PMID- 15032255
TI  - A prescription for protecting the doctor-patient relationship.

PMID- 15032256
TI  - Tobacco control efforts in managed care: what do the doctors think?
AB  - OBJECTIVES: To use physician reports to evaluate their awareness of health plan
      tobacco control guidelines and cessation support coverage and to validate the
      extent to which health plan cessation support material had been disseminated and
      implemented in clinical settings. STUDY DESIGN: Comparison of survey responses of
      physicians with tobacco control activities reported by key informants in the
      health plans with which those physicians were associated. METHODS: A total of 100
      primary care physicians in the care delivery organizations associated with 9
      nonprofit health plans were randomly selected to receive a survey asking about
      their health plan's tobacco cessation guidelines, coverage, and support for
      clinician action. Their responses were compared to data reported by the plan with
      which they were associated. RESULTS: Responses were obtained from 91%. Although
      88% were aware of their health plan's tobacco cessation guidelines, considerably
      fewer were correctly aware of whether the health plan covered medications and
      cessation classes or counseling. Physician reports of cessation supports during
      care bore little relationship to health plan reports of those supports.
      CONCLUSIONS: Physician reports may be a useful way to verify health plan
      dissemination and implementation of tobacco control activities. Even these
      relatively high-performing plans have ample room for further improvement.

PMID- 15032257
TI  - Consumer attitudes and factors related to prescription switching decisions in
      multitier copayment drug benefit plans.
AB  - OBJECTIVES: To examine patient attitudes related to formulary medications and
      medication-related decision making in multitier copayment prescription drug
      plans. STUDY DESIGN: A cross-sectional retrospective analysis. METHODS: Data were
      collected via mail survey from a random sample of 25,008 members of a managed
      care organization. The selected members were enrolled in a variety of 2- and 3
      tier copayment plans and were taking prescription medication to treat 1 or more
      of 5 chronic disease states. RESULTS: Most respondents did not believe that
      formulary drugs were safer or more effective than nonformulary drugs, but 39.7%
      thought that formulary drugs were relatively less expensive. Most respondents
      appeared willing to consider switching from a nonformulary drug to a formulary
      drug with a lower copayment. The percent of respondents who reported they would
      be very unlikely or unlikely to switch was only 15.3% for a new prescription and
      24.2% for a refill prescription. Medication efficacy and physician opinion were
      important factors in plan members' switching decisions. Cost was an important
      factor for some members, but older plan members were less likely to report that
      cost was important. CONCLUSIONS: Multitier plan members generally believed that
      drugs are placed on the formulary for reasons of cost rather than safety or
      efficacy. Most plan members were receptive to switching from a nonformulary to a
      formulary medication, but financial incentives alone may not convince some plan
      members to make the switch.

PMID- 15032258
TI  - Physician satisfaction with formulary policies: is it access to formulary or
      nonformulary drugs that matters most?
AB  - OBJECTIVE: To assess physician satisfaction with Department of Veterans Affairs
      (VA) formulary policies and to examine the correlation between physician
      satisfaction and perceived access to formulary and nonformulary medications.
      STUDY DESIGN: Cross-sectional survey with specific questions on access to
      formulary and nonformulary medications. Statistical analyses included assessment
      of associations between physician satisfaction and various measures of access.
      PARTICIPANTS AND METHODS: Initial sample of 4015 staff physicians working in VA
      healthcare facilities. Responses were received from 1812 (49%) of the 3682
      physicians in the final eligible sample population. RESULTS: Most clinicians
      (72%) reported that their local formulary covered more than 90% of the
      medications they wanted to prescribe. Most (73%) agreed that drug restrictions
      were important to contain costs, and 86% agreed that it was important for VA to
      choose "best-value" drugs. Respondents reported an 89% approval rate for
      nonformulary drugs, though 31% indicated that approvals routinely took 3 or more
      days. We found strong associations between physician satisfaction and self
      reported approval rates for nonformulary drugs (P = .001), timely approval of
      nonformulary requests (P < .001), and percentage of nonformulary prescriptions as
      a proportion of overall prescriptions at a regional level (P< .01). There was no
      significant correlation between physician satisfaction and number of medications
      added to regional formularies or with drug costs per unique patient. CONCLUSIONS:
      VA physicians were generally supportive of VA formulary policies including
      choosing best-value drugs to control pharmaceutical expenditures. Nevertheless,
      access to nonformulary drugs and timely approval of requests for nonformulary
      medications were strong predictors of clinician satisfaction and support for cost
      containment measures.

PMID- 15032259
TI  - Cost-effectiveness of different combinations of bupropion SR dose and behavioral
      treatment for smoking cessation: a societal perspective.
AB  - OBJECTIVES: To determine the differential cost effectiveness of 2 dosing regimens
      of bupropion sustained release (SR) in combination with behavioral interventions
      of minimal intensity (tailored mailings [TM]) or moderate intensity (proactive
      telephone calls [PTC]) for smoking cessation in an actual practice setting. STUDY
      DESIGN: Open-label, randomized trial, with 1-year follow-up, conducted in a large
      health system based in Seattle, Washington. METHODS: A total of 1524 adult
      smokers interested in quitting smoking were randomly assigned to receive 150 mg
      bupropion SR daily and PTC (n = 382), 150 mg bupropion SR daily and TM (n = 381),
      300 mg bupropion SR daily and PTC (n = 383), or 300 mg bupropion SR daily and TM
      (n = 378). Sufficient medication for 8 weeks of dosing was provided to patients.
      The primary outcome measure was self-reported point-prevalence 7-day nonsmoking
      status at 12 months after the target quit date. RESULTS: Although the 300-mg dose
      was associated with a higher 12-month nonsmoking rate relative to the 150-mg dose
      with both PTC and TM, the additional cost resulted in lower cost effectiveness.
      The PTC behavioral intervention was more expensive than TM, but the additional
      effectiveness resulted in almost equivalent cost effectiveness at the 150-mg
      dose. Costs per additional 12-month nonsmoker (above that expected for placebo)
      for the 150-mg dose groups averaged 950 dollars and per additional lifetime
      quitter averaged 1508 dollars; for the 300-mg groups these costs were 1342
      dollars and 2129 dollars, respectively. Cost per life-year and quality-adjusted
      life-years (QALYs) saved varied substantially by age and treatment, but were no
      greater than 1100 dollars for all treatment groups when averaged across the age
      and sex distribution for the study population. CONCLUSIONS: Although the cost per
      life-year and QALYs saved were sufficiently low for all doses to rate these
      smoking cessation interventions as among the most cost effective of life-saving
      medical treatments, within the regimens tested 150 mg bupropion combined with
      either PTC or TM was the most cost effective.

PMID- 15032261
TI  - Does the weather influence the occurrence of abomasal displacement in dairy cows?
AB  - Aim of the study was to investigate the correlation between the occurrence of
      abomasal displacement and the weather situations. Data were collected for the
      years 2000 and 2001 in the area around Lisbon at 26 farms keeping about 6500
      Holstein-Friesian milk cows; the analysis of 372 cases of abomasal displacement
      were included in the study. The weather situation was assessed on daily basis:
      atmospheric pressure, relative humidity, precipitation, daily insolation, maximum
      air temperature, minimum air temperature and average wind velocity. These
      original parameters were modified for the statistical analyses according to
      atmospheric pressure, water vapour pressure, relative humidity, temperature,
      temperature range, precipitation, insolation and wind speed. The change of the
      weather situation was described by the mean absolute deviation (deviation of the
      meteorological parameters from the running mean over a period of 5 and 10 days)
      and by a method which was based on the principal component analysis of the entire
      data set. A weak influence of water vapour pressure, relative humidity,
      temperature, temperature range, precipitation, and insolation on the occurrence
      of abomasal displacements was found by linear correlation- and regression
      analysis. A higher probability for abomasal displacement was verified for low
      water vapour pressure, high relative humidity, low air temperature, low
      temperature range, high precipitation and low insolation. No statistically
      significant relations were found between occurrence of abomasal displacement and
      either wind velocity or atmospheric pressure. A time series analysis exhibited a
      higher prevalence for abomasal displacement for periods with a change from sunny,
      warm and dry days to cool, overcast and humid days. From the present work it can
      be concluded that the meteorological situation has an influence on the occurrence
      of abomasal displacement. Therefore, the weather situation should be included
      among the predisposing causes of the occurrence of abomasal displacements.

PMID- 15032260
TI  - Does payment drive procedures? Payment for specialty services and procedure rate
      variations in 3 HMOs.
AB  - OBJECTIVE: To study how payment for specialty services affects the rates of
      performance of invasive procedures by physicians in a number of specialties.
      STUDY DESIGN: Observational study. PATIENTS AND METHODS: Administrative data from
      1996-1997 and 1997-1998 from 3 large health maintenance organizations (HMOs) in
      the Midwestern and western United States were used to study variations in
      procedure rates associated with different methods of paying for cardiology,
      gastroenterology, ophthalmology, orthopedic, and ear, nose and throat services
      within each HMO. The age-, sex-, and comorbidity adjusted probabilities of
      undergoing selected, potentially discretionary procedures, were compared within
      each plan by payment method. RESULTS: After adjustment, rates under fee-for
      service payment tended to be higher than those under capitation or salary
      payment, whereas there was no clear pattern for salary versus capitation payment.
      Even within a single specialty in a single plan, however, rates did not always
      follow the same pattern for different procedures. CONCLUSIONS: The payment method
      for specialty services used by these 3 health plans was variably associated with
      how likely patients were to undergo a variety of invasive procedures. The effects
      of contract payment methods for specialty services on health care costs, quality,
      and outcomes should be further studied, but such studies will challenge the
      capabilities of health plan data systems.

PMID- 15032263
TI  - Does multiple oral vaccination of wild boar against classical swine fever (CSF)
      have a positive influence on the immunity?
AB  - We studied the efficacy of multiple vaccinations of wild boar against classical
      swine fever (CSF) using a C-strain vaccine. The study consisted of two
      experiments. In the first experiment, 7 to 8 months old animals were vaccinated
      either three or four times at an interval of 7 days or twice at an interval of 14
      or 28 days. In the second experiment, the efficacy of oral immunisation in young
      boars (3 months old) was examined after fivefold vaccination at intervals of 14
      or 28 days. Independently of the immunisation scheme all wild boar developed
      neutralising antibodies. An evaluation of the antibody titres 28 days after the
      initial vaccine application showed that single vaccination and triple
      immunisation at an interval of 7 days induced the highest antibody titres (X > or
      = 1/80). In multiple vaccinated young boars (vaccinated at intervals of 14 or 28
      days) the third vaccination led to a slight reduction or to an only moderate
      increase of the antibody titre. In a challenge study after the fifth vaccination
      all wild boar were protected (no viraemia, no virus excretion, no post-mortem
      virus detection in organs). This was confirmed by the fact that sentinel animals
      were not affected. Although other immunisation schemes also were effective,
      booster vaccination at an interval of 28 days is recommended as basic procedure
      for eradication of CSF in wild boar. Triple vaccination might also be used at the
      beginning of the control measures.

PMID- 15032262
TI  - Post surgical development of inflammatory adhesions and reticular function in
      cows suffering from traumatic reticuloperitonitis.
AB  - Inflammatory adhesions between reticulum and ventral abdomen in patients
      suffering traumatic reticuloperitonitis (TRP) may induce a massive inhibition of
      reticular contractions and thereby an impairment of the separation process of
      particles in the reticulorumen. However, a substantial disturbance of digesta
      passage (Hoflund-syndrome) is found only in a few TRP-cows. We hypothesized that
      this is due to a retrieval of reticular motility due to rebuilding and
      degradation of adhesions within months after the removal of the foreign body as
      the primary inflammatory stimulus. Accordingly, it was the objective of this
      study (a) to assess the extent and structure of inflammatory adhesions in cows
      with TRP over a period of six months following surgery and (b) to persecute
      reticular function by characterizing the sequence of reticular contractions
      sonographically and by assessment of particle size distribution in the faeces of
      patients by means of wet-sieving. Twenty-six cows suffering from TRP were studied
      on the day of rumenotomy (day 1) and on day 6, day 12 and 6 months post
      operationem. Additionally, six healthy control cows were investigated once. All
      cows were on a hay and concentrate diet. On day 1, the reticular floor and the
      reticular wall were affected by adhesions in varying extent in all cows; the
      contraction distance and contraction velocity of the reticulum were markedly
      reduced and the portion of large particles in the faces increased compared to
      healthy cows. On day 12, the portion of large particles did not vary any more
      from that of control cows; a tendency towards an increased contraction distance
      compared to day 1 was found. Sonographically, only marginal differences were
      detected in respect to extent and consistency of adhesions. Six months after
      rumenotomy, in 9 of 16 re-investigated cows sonography revealed no adhesions at
      the reticulum at all, in other cases the extent of adhesions shrunk considerably.
      Contraction distance and contraction velocity and particle size distribution in
      the faeces were found to be nearly comparable to that of control cows. It is
      concluded that inflammatory adhesions disappear in the majority of the TRP
      patients, as a consequence reticular function normalizes. A serious disturbance
      of digesta passage seems to develop exclusively in those patients with the most
      extensive adhesions and may be also in such cows, where the primary adhesions
      cause the development of extensive abscesses.

PMID- 15032264
TI  - [The prevalence of Actinobaculum suis in boars of breeding herds in the Omsk
      region (Russian Federation) by indirect immunofluorescence technique].
AB  - Actinobaculum suis (Corynebacterium suis, Eubacterium suis, Actinomyces suis) was
      detected in the preputial diverticulum of 64,8% of 162 boars investigated in 8
      districts of the region Omsk (Russian Federation) by indirect immunofluorescent
      technique. Until yet no informations were available about the prevalence of
      Actinobaculum (A.) suis in swine herds of the Russian Federation. The study shows
      that A. suis, as a main aetiological factor of cystitis and pyelonephritis in
      sows, is widely spread among the boars of the region Omsk. Prevalence of A. suis
      was not influenced by housing conditions, age or breed of investigated boars.
      Indirect immunofluorescent technique for detection of A. suis provides a good
      method for screening investigations with high numbers of samples.

PMID- 15032265
TI  - [Analysis of the current population of the Hanoveranian Scenthound bred in the
      kennel club Hirschmann e. V].
AB  - The Hanoveranian Scenthound is a purebred hound with a long breeding history and
      an exceptional high hunting performance. The kennel club Hirschmann e. V. has the
      goal to conserve the very high level of performance in the small population of
      the Hanoveranian Scenthound. Therefore, the structure of the current population
      was analyzed by estimating the gene contributions of the founder breeds of other
      European kennel clubs, coefficients of relationships, rates of inbreeding and
      coefficients of inbreeding. All current dogs (n = 334) were included in this
      study. The pedigrees had a degree completeness of 73.3% for 10 generations. The
      large influence of the Hanoveranian Scenthound bred in the Austrian kennel club
      was obvious. The gene contribution of these dog population was with 46.5% much
      more higher than the gene contribution from the German population with 29.8%. The
      gene contribution of Czech, Swiss and Hungarian dogs was between 4.3% and 7.6%.
      The mean coefficient of inbreeding of the current German population was 9.2% with
      the maximum at 15.6%. For the last 10 generations the increase of the coefficient
      of inbreeding per generation was 0.71%, regarding the degree of completeness of
      the pedigrees the coefficient of inbreeding per generation increased by 0.96%.
      For the last generation the rate of inbreeding amounted to 0.09%. The rate of
      inbreeding expected for the next generation is 0.02%. Also the effective
      population size (N(e)) in the current population of the Hanoveranian Scenthound
      being 70.9 exceeds the critical value of N(e) = 50. The mean coefficient of
      relationship in the current population was 11.2% with the maximum at 73.6%. The
      present incrossing of Hanoveranian Scenthounds from other European countries
      reduced the coefficient of inbreeding.

PMID- 15032266
TI  - [Carl Gillmeister: the first Doctor of veterinary medicine in Mecklenburg--and in
      Germany (1834)].
AB  - German schools and faculties of veterinary medicine did not receive the sovereign
      right to award the degree "Doctor medicinae veterinarae" until the early
      twentieth century. Until then, in the nineteenth century there were two
      possibilities for veterinarians to earn a doctoral degree, usually referred to as
      the title of "Doctor": 1. On the basis of an exceptionally excellent dissertation
      and after very stringent examination a candidate could be awarded the degree "Dr.
      med." by the faculty of a medical school, or, if the candidate had studied at a
      philosophical faculty, the degree "Dr. phil." 2. A doctoral degree specifically
      in veterinary medicine could be earned only at a medical faculty. The Medical
      Faculty of the University of Giessen awarded the degree "Doctor in arte
      veterinaria" for the first time in 1832. In this study we prove that Giessen was
      not the first German university to award a doctorate in veterinary medicine, a
      priority which has never been questioned in the literature. As early as 1829,
      veterinarians could earn the degree "Doctor artis veterinariae" at the Medical
      Faculty of the University of Rostock, where three such awards are documented
      between 1829 and 1831. The designation "medicina" was also intially avoided in
      Rostock. Therefore, of particular significance is the discovery of a fourth such
      document from the Rostock University Archives, the doctoral diploma of Carl Jacob
      Friedrich Gillmeister, who at the age of 22 was awarded the degree "Doctor
      medicinae veterinariae" in Rostock after a successful defense. This is the
      earliest, but also the last archival record of the German doctoral degree in
      veterinary medicine in the modern sense, because after Gillmeister no
      veterinarian could earn a doctoral degree in Rostock further more. Gillmeisters
      vita sheds light on the times and the difficulties of the veterinary profession
      in the poor agricultural area of Mecklenburg.

PMID- 15032267
TI  - The effects of levamisole poisoning on the haematological and biochemical
      parameters in dogs.
AB  - This study was designed to evaluate possible organ and system disorders
      associated with experimentally induced levamisole poisoning in dogs. For this
      purpose, twelve clinically healthy dogs of different ages, sexes and breeds were
      used. They were divided into two equal groups (Group A and Group B) and given
      levamisole orally at a dose of 25 mg/kg of body weight daily for three days. The
      dogs in Group B were also injected with atropin sulphate (0.04 mg/kg of body
      weight) subcutaneously (sc) 1 hour after each administration of levamisole.
      Routine clinical examinations were made and some haematological, biochemical and
      blood gas parameters were established at various times after administration of
      levamisole. The dogs in Group A developed severe neurological signs, gastric
      haemorrhage, bloody vomiting, colic, anaemia and four dogs died. In Group B these
      signs were mild and only one dog died. Levamisole poisoning was characterised by
      a significant reduction in the total number of red blood cells (RBCs),
      concentration of haemoglobin (Hb) and packed cell volume (PCV), and by anaemia.
      Peripheral blood pH, actual bicarbonate of plasma (HCO3), actual base excess
      (BE), partial pressure of oxygen (pO2) and saturated oxygen (O2SAT) increased in
      both groups of animals and these dogs developed metabolic alkalosis 48 hours
      after the first administration of levamisole. The results of the study also show
      that levamisole poisoning in dogs causes a significant increase in the activity
      of serum alanine aminotransferase (ALT) and of alkaline phosphatase (AP) and in
      the concentration of urea in both Group A and Group B. In the study, atropin
      sulphate reduced the severity of the clinical signs and the number of deaths, but
      it was not alone sufficient to remedy levamisole poisoning in dogs.

PMID- 15032268
TI  - [Case report. Diphallus in a German Holstein calf].
AB  - A diphallus was found in a German Holstein calf. Clinical examination revealed a
      duplication of glands penis, corpus penis and urethra, but no further anomalies
      were observed. Possibly, this congenital anomaly is caused by a chromosomal
      aberration.

PMID- 15032269
TI  - The benefits of haematopoietic growth factors in the management of gynaecological
      oncology.
AB  - Neutropenia and anemia are important complications of cancer chemotherapy and can
      be prevented and treated with granulocyte colony-stimulating factor and
      erythropoietin.

PMID- 15032270
TI  - The meaning of the methylation of genomic DNA in the regulation of gene
      expression levels.
AB  - INTRODUCTION: Methylation of genomic DNA is one of the major mechanisms that
      deactivates genes and regulates their tissue-specific transcription levels. Its
      patterns are based on clonal inheritance that occurs in the early stages of
      embryogenesis. All changes in the DNA methylation levels occurring especially in
      the promoter region of the genes, which involve hypo- as well as hyper
      methylation, lead to cell differentiation and growth disorders. Therefore it can
      become an impulse that initiates different pathological processes including
      carcinogenesis. MATERIAL AND METHODS: The purpose of this review was to present
      the recent knowledge concerning methylation of genomic DNA based on recent
      references and authors' experience. RESULTS AND CONCLUSION: Genome stability
      disorders could be caused either by mutations, which damage the structure of the
      genes and have not been formerly removed, or as the consequence of an epigenetic
      mechanism. Methylation plays a decisive role in the activity of many genes and
      could be a natural weapon of an organism against the expression of foreign
      genetic material that degrades the original genome structure.

PMID- 15032271
TI  - Anti human papillomavirus vaccine: the checkmate to human papillomavirus?
AB  - Cervical cancer is the second most frequently found neoplasia in women worldwide.
      At least 95% of cervical cancers contain viral DNA which, in 80% of cases,
      belongs to one of the human papillomavirus (HPV) viral types at high oncogenic
      risk: 16, 18, 31 and 45. HPV is, at this point, considered the first "necessary
      cause" of cervical cancer, against which primary prevention with a reduction in
      the risk of infection can be carried out. Numerous molecular biological studies
      have been conducted to identify the biological markers of this infection and to
      refine an effective and well tolerated vaccine capable of preventing HPV
      infection as well as possibly treating those cases in which the infection has
      already caused an HPV-related disease of the genital tract. In the near future,
      the real primary prevention of this disease will be conducted, similar to what
      occurred for Hepatitis B, using immunoprophylaxis with an anti-cancer vaccine.

PMID- 15032272
TI  - Androgens and ovarian cancers.
AB  - Ovarian cancer is one of the most lethal malignancies in women. Numerous studies
      indicate that the steroid hormones have been implicated in the etiology and/or
      progression of epithelial ovarian cancer and support a role for androgens,
      including: 1) androgen receptor (AR) is present in primate ovaries at almost all
      stages of the menstrual cycle and involve folliculogenesis and ovulation; 2) high
      androgen serum levels show high risk of ovarian cancer and ovarian cancer
      occurring after menopause when the balance of ovarian steroid production shifts
      from estrogens to androgens; 3) ovarian cancer tissue shows a 90% AR positive
      rate and is associated with favorable outcomes; 4) androgens promote or inhibit
      ovarian cancer cell growth; 5) chemotherapy decreases androgen production from
      cancer cells. This review seeks to summarize our current understanding about the
      roles of androgens, AR and AR coregulators in the initiation and/or progression
      of ovarian cancers.

PMID- 15032273
TI  - HSP27 in patients with ovarian carcinoma: still an independent prognostic
      indicator at 60 months follow-up.
AB  - OBJECTIVE: Heat shock protein 27 (HSP27) is produced in response to
      pathophysiologic stress in animal cells. The authors have previously shown that
      HSP27 is an independent prognostic indicator in patients with ovarian carcinoma.
      The present study was performed to see whether HSP27 remained an independent
      prognostic indicator with longer follow-up. METHODS: One hundred and three
      consecutive patients with epithelial ovarian carcinoma were studied. Slides were
      prepared from fresh tissue. HPS27 staining was performed as previously described.
      Patient records were examined for FIGO stage, grade, histology, level of
      cytoreduction and survival. RESULTS: One hundred and three patients were followed
      for a mean of 60 months. Twenty patients had FIGO Stage I disease, four Stage II,
      59 Stage III, and 20 Stage IV. Immunohistochemical (IHC) staining for HSP27 was
      not related to histologic grade, level of cytoreduction or histologic subtype. A
      statistically significant decrease in HSP27 staining was found to correlate with
      increased FIGO stage (p = 0.008). Using cox-regression analysis, HSP27 staining
      (p = 0.025), stage (p = 0.0012), and level of cytoreduction (p < 0.0001) were
      independent predictors of survival in these patients. CONCLUSION: Cox-regression
      analysis found HSP27 to be an independent indicator of prognosis and survival in
      patients with ovarian carcinoma who had longer follow-up. Decreased HSP27
      staining was related to decreased survival. This study confirms the authors'
      earlier report on the importance of HSP27 as a prognostic indicator in ovarian
      carcinoma.

PMID- 15032274
TI  - Are nodal metastases in ovarian cancer chemoresistant lesions? Analysis of nodal
      involvement in 105 patients treated with preoperative chemotherapy.
AB  - BACKGROUND: To report the rates of nodal involvement in epithelial ovarian cancer
      (EOC) in patients who underwent initial lymphadenectomy (before chemotherapy) and
      patients who underwent lymphadenectomy after chemotherapy. STUDY DESIGN: The
      rates of nodal involvement in 205 patients with EOC who underwent complete
      bilateral pelvic and para-aortic lympadenectomy between 1985 and 2001 were
      analyzed: 100 women underwent this surgical procedure before chemotherapy
      (initial surgery) and 105 at the end of chemotherapy (second-look surgery for 77
      patients with 6 courses of a platinum-based regimen) or during chemotherapy
      (interval debulking surgery for 28 patients with 3 courses of a platinum-based
      regimen containing paclitaxel). RESULTS: The overall frequency of lymph-node
      involvement was 35% (35/100) in patients treated with initial surgery, 54%
      (15/28) in the interval debulking surgery group and 36% (28/77) in the second
      look surgery group. In patients with Stage III disease, the rates of nodal
      involvement in patients treated with initial surgery, interval debulking surgery
      (with paclitaxel-based regimen) and second-look surgery were respectively: 53%
      (15/28), 58% (15/26) and 48% (20/42). The rates of nodal involvement in patients
      who underwent lymphadenectomy prior to or after chemotherapy were not
      statistically different whatever the stage of the disease. Adding paclitaxel to
      the platinum-based regimen does not seem to improve node sterilization rates.
      CONCLUSIONS: The rates of nodal involvement seem to be similar in patients
      treated before or after chemotherapy. Such results suggest that nodal metastases
      are not as chemosensitive as peritoneal lesions. However, further studies are
      needed to evaluate the therapeutic value of lymphadenectomy in patients with
      nodal involvement.

PMID- 15032275
TI  - Influence of stroma-derived growth factors on the estradiol-stimulated
      proliferation of human breast cancer cells.
AB  - PURPOSE OF INVESTIGATION: Estradiol is the main proliferating substance for human
      epithelial breast cells. There is evidence that proliferation is also stimulated
      by growth factors mainly synthesized by the surrounding stroma. In the present in
      vitro study we have compared the proliferating activity of three growth factors
      alone and in combination with estradiol in human breast cancer cells. METHOD: As
      a cell model the well-recognized human breast cancer cell line MCF-7 was used.
      The growth factors tested were basic fibroblast growth factor (bFGF), epithelial
      growth factor (EGF) and insulin-growth factor-1 (IGF-I) at the concentrations 10(
      10), 10(-9) and 10(-8) M alone and in equimolar combination with 10(-10) M
      estradiol. Cell proliferation was measured after seven days incubation by the ATP
      assay. RESULTS: The growth factors alone significantly stimulated proliferation
      of MCF-7 cells in the tested concentration range. The increases were about 40%
      for EGF, between 40 and 60% for FGF and between 30 and 90% for IGF-I. The
      strongest proliferating factor was estradiol alone with values between 70 and
      130%. For all three growth factors an additive effect was seen in combination
      with estradiol, which was greatest for IGF-I. CONCLUSION: These data indicate
      that estradiol is the strongest proliferating factor for human breast cancer
      cells. Therefore the predictive value of cell models using estradiol as a
      proliferative agent seems to be highly reliable. However, stromal influence by
      growth factors should not be disregarded, since proliferation of pre-existing
      malignant cells may be accelerated by the concomitant presence of estrogens and
      growth factors.

PMID- 15032276
TI  - Detection of the sentinel lymph node under local anaesthesia in early-stage
      breast cancer: feasibility study in a series of 78 unselected patients.
AB  - AIMS: To evaluate the feasibility of excision of the sentinel lymph node under
      local anaesthesia in early-stage breast cancer. METHODS: Sentinel lymph node
      detection under local anaesthesia was carried out on all patients presenting with
      breast cancer at Stage T0, T1 or T2 < 3 cm and N0, M0. The lymph node was mapped
      using a radioisotope and patent blue dye and lymphoscintigraphy was routinely
      performed. No premedication was given, and local anaesthesia was carried out with
      xylocaine. The patients underwent tumorectomy one week later under general
      anaesthesia, with or without complete axillary dissection, depending on the
      results of the definitive histopathological examination of the sentinel lymph
      node. RESULTS: 78 patients underwent this procedure over a period of 20 months.
      The procedure was successful in 76 out of the 78 patients, with one failure in
      mapping and one failure in detection (detection rate = 97.4%). The mean time to
      detection was 21 min (range: 6-45). It was unnecessary to interrupt the procedure
      due to patient discomfort in any of the cases. One allergic reaction to patent
      blue dye was noted and required corticosteroid therapy without interruption of
      the procedure. The time to detection was correlated with the experience of the
      surgeon carrying of the procedure, the patient's body mass index and the number
      of labelled lymph nodes found at lymphoscintigraphy. CONCLUSION: We have shown
      that it is feasible to detect the sentinel lymph node under local anaesthesia in
      an unselected population. Using this procedure, patients can undergo surgery with
      the knowledge of their axillary lymph node status while at the same time avoiding
      the uncertainties of an intraoperative examination of the sentinel lymph node--a
      source of many false negatives, particularly in the event of micrometastases.

PMID- 15032277
TI  - An analysis of different approaches to ovarian cysts in Italy.
AB  - The management of pelvic masses represent a rising problem due to the need to
      obtain an early diagnosis and treatment of ovarian cancers. MATERIALS AND
      METHODS: In order to evaluate the clinical and surgical approach to ovarian cysts
      in Italy, we sent a multiple choice questionnaire to 214 members of the Italian
      Society of Gynecologic Oncology (SIOG) and to 230 members of the Italian Society
      of Gynecologic Endoscopy (SEGi). Ninety-six resulted evaluable. RESULTS:
      Transabdominal and transvaginal ultrasound associated with CA125 determination
      represent the basis for the diagnosis, even if there is no univocal agreement on
      the ultrasound aspects that may define an ovarian cyst as doubtful. If an ovarian
      cyst, classified as suspicious, has been diagnosed in a postmenopausal woman, a
      wide range of therapeutic options have been reported: laparotomic hysterectomy
      and bilateral salpingo-oophorectomy represent the treatment of choice for 49% of
      SIOG members, whereas laparoscopic bilateral (45%) or monolateral (39%) salpingo
      oophorectomy represents the standard for SEGi members. Ultrasound criteria to
      distinguish among benign or probably malignant or doubtful ovarian cysts, the
      treatment of an ovarian cyst during pregnancy, and the management of an
      unexpected intraoperative diagnosis of borderline ovarian neoplasia are discussed
      on the basis of answers received by SIOG and SEGi members.

PMID- 15032278
TI  - Clinical implications of insulin-like growth factors through the presence of
      their binding proteins and receptors expressed in gynecological cancers.
AB  - Since insulin-like growth factors (IGFs) are known to play critical roles in the
      development of cancers, we examined the expression of the mRNA and protein of IGF
      binding protein (IGFBP) and cognate receptors to assess their possible
      involvement in gynecological malignancy. The specimens were obtained from 46
      endometrial, 32 cervical, and 20 ovarian cancers, and 28 normal endometrium. In
      endometrial cancers, IGFBP-1, -2, -3 and IGF-1 receptor (IGF-1R) mRNAs were
      detected in 8.7, 89.1, 95.6, and 91.3% of tumors, respectively, and the
      corresponding proteins in 54.3, 54.3, 95.6, and 91.3% of tumors, respectively.
      Clinical staging was significantly related to the expression of IGFBP-1 and -2
      proteins. In ovarian cancers, their mRNAs were detected in 10.0, 90.0, 95.0, and
      100.0%, and proteins in 15.9, 50.0, 90.0, and 80.0%. In cervical cancers, their
      mRNAs were detected in 6.3, 90.6, 96.8, and 87.5%, and proteins in 44.4, 18.8,
      84.4, and 87.5%. IGF-1R was highly expressed in all specimens. The abnormally
      balanced co-expression of IGFBPs and high levels of IGF-R in gynecological
      cancers suggest that IGF signals might be involved in the growth of these tumors.

PMID- 15032279
TI  - The role of leptin in breast cancer.
AB  - Leptin, the protein hormone produced mainly by adipocytes, placenta and mammary
      epithelium plays a significant role in, e.g., control of metabolism, reproductive
      processes, immune processes, angiogenesis, haemopoiesis and oxidation of lipids.
      Since some authors link leptin to mechanisms of mammary cancer development, the
      clinical data has been screened to allow evaluation of the hypothesis.

PMID- 15032281
TI  - Transvaginal laparoscopy proposed as an investigation procedure for patients at
      high-risk for ovarian cancer.
AB  - Transvaginal laparoscopy (TVL) was performed in 23 patients at high risk for
      ovarian cancer (OC). The patients were placed in the lithotomy position after
      sedation and a veres needle was inserted in the posterior vaginal vault. A trocar
      followed and warm normal saline was injected into the pelvis. The needle was
      removed and a telescope connected to a light source and monitor was introduced.
      Excellent visualization was achieved in all cases examined and the average time
      of TVL was 30 min. All patients except one found TVL a simple and painless
      procedure. TVL helped in the diagnosis of six benign ovarian lesions and ruled
      out OC in the other 17 cases. TVL is an easy method to learn with reliable
      results. TVL can reduce the number of unnecessary laparoscopies and/or
      laparotomies and it seems to be useful in ruling out OC.

PMID- 15032280
TI  - Paclitaxel/carboplatin versus cyclophosphamide/carboplatin in peritoneal
      carcinomatosis of the ovary.
AB  - The preceding platinum-based combination chemotherapy could possibly reduce tumor
      masses, allowing for adequate surgical debulking in advanced ovarian cancer. In
      this study, a total of 18 patients with peritoneal carcinomatosis of the ovary
      were evaluated between 1996 and 2003. All patients underwent open biopsy for the
      histopathologic confirmation of ovarian tumor. Forty-one percent of the patients
      (8/18) were administered six cycles of carboplatin/cyclophosphamide (CP) and the
      rest were administered six cycles of paclitaxel/carboplatin (TP) as a neoadjuvant
      chemotherapy (10/18). After six cycles of chemotherapy metastases to the
      peritoneum, Douglas' pouch, diaphragm, and liver serosa were higher in the CP
      group than the TP group (p < 0.05). All patients also had a better performance
      status (WHO performance status 0 or 1), but no statistical difference was
      observed between either group (p > 0.05). Optimal debulking surgery rates were
      significantly higher in the TP group (p < 0.05). In conclusion, we suggest
      paclitaxel/carboplatin in peritoneal carcinomatosis of the ovary as a neoadjuvant
      chemotherapy. However, large prospective, randomized studies should be performed
      in patients with peritoneal carcinomatosis of the ovary.

PMID- 15032282
TI  - Ovarian masses in young adolescents: imaging findings with surgical confirmation.
AB  - Functional cysts and benign neoplasms are the most common ovarian masses among
      young adolescents. Ovarian cancer on the other hand, although rare in this age
      group, is the most common genital tract malignancy. The purpose of this study was
      to define imaging characteristics of ovarian masses in adolescents between 12 and
      21 years old and correlate imaging and surgical findings. Thirty-seven female
      adolescent patients aged between 12 and 21 years were operated on because of a
      diagnosed ovarian mass between 1997 and 2002. All patients underwent pelvic
      ultrasound, five had an abdominal CT scan, two had abdominal MRI, one abdominal X
      ray and one intravenous pyelography. Ultrasound was used to define the size of
      the lesion and to characterize its gross morphologic condition as solid, simple
      cyst or complex cyst. The records were reviewed for age at presentation,
      presenting symptoms, diagnostic studies, surgical procedure and pathology
      findings, which were available for all patients. In our study 32 patients (86.5%)
      were symptomatic and five asymptomatic (13.5%). The most common presenting
      symptom was abdominal pain (59.5%). Thirty-four patients (91.1%) had benign
      lesions, two had malignant tumors (5.4%) and one patient had a borderline lesion
      (2.7%). The most common ovarian masses detected were germ cell tumors (27.5%) and
      functional cysts (25%). Twenty patients (54%) underwent operative laparoscopy and
      17 patients (46%) exploratory laparotomy. Simple resection of the ovarian mass
      was achieved in the majority of cases (84%). Bilateral salpingo-oophorectomy was
      performed in only one case (2.7%).

PMID- 15032283
TI  - The role of transvaginal ultrasonography and serum CA 125 assay combined with age
      and hormonal state in the differential diagnosis of pelvic masses.
AB  - PURPOSE OF INVESTIGATION: To evaluate the ability of CA 125 and echography, alone
      and in combination with clinical parameters (age over 50 years and post
      menopausal state), in the diagnosis of a malignant pelvic mass. METHODS: 125
      women were enrolled and underwent echography and CA 125 assay. For each
      methodology, positive and negative predictive value, sensitivity, specificity,
      diagnostic accuracy, pre- and post-test probability and likelihood ratios were
      calculated. RESULTS: Sensitivity, specificity, positive predictive value (PPV),
      negative predictive value (NPV), diagnostic accuracy (DA) and positive likelihood
      ratio were identical for echography and CA 125 considered alone. Paired with the
      patient's age, the CA 125 assay showed better results than the associations
      echography-age (LR+ 26.9 vs 10.1) or CA 125-echography (LR+ 26.9 vs 17.8).
      Furthermore the combination of the postmenopausal state with CA 125 obtained the
      best result of a positive likelihood ratio (LR+ 29.7). CONCLUSION: Our study
      pointed out that, in the prediction of a malignant adnexal mass, the best results
      were obtained from the association between CA 125 and menopause, probably because
      in this period there is a lower incidence of benign diseases related to this
      marker so that an increase of CA 125 level is more likely associated with a
      malignant mass.

PMID- 15032284
TI  - Diagnostic problems on frozen section examination of myometrial invasion in
      patients with endometrial carcinoma with special emphasis on the pitfalls of deep
      adenomyosis with carcinomatous involvement.
AB  - Frozen-section and paraffin section diagnoses were compared in 55 patients with
      Stage I endometrial adenocarcinoma. In 44 patients (80%), a corresponding depth
      of myometrial invasion and in 54 (98%) patients the same tumor grade were found.
      Regarding the depth of myometrial invasion and histologic grade, sensitivity,
      specificity, positive and negative predictive values were 70%, 86%, 73%, 83% and
      92%, 100%, 100%, 94%, respectively. Concerning myometrial invasion 9% false
      positivity and 10% false-negativity rates were noted. The histopathologic
      characteristics of false-positive and false-negative patients are emphasized
      because carcinomatous involvement of deeply situated adenomyosis and advanced
      grade tumors are the main diagnostic pitfalls. It is important for pathologists
      to be able to identify carcinomatous involvement of adenomyosis and adjacent foci
      of minimal myometrial invasion during frozen-section examination which can
      prevent aggressive surgery.

PMID- 15032286
TI  - Angiogenic properties of carcinoma in situ and microinvasive carcinoma of the
      uterine cervix.
AB  - Neovascularization is a critical step in the growth, progression and metastasis
      of tumors. The degree of angiogenesis may correlate with disease stage and
      provide prognostic information in various neoplasms. Microvessel density was
      studied in 24 patients with severe cervical intraepithelial neoplasias, 15
      patients with microinvasive carcinomas (International Federation of Gynecology
      and Obstetrics IA1) and 15 healthy controls who had undergone hysterectomy for
      benign conditions. The microvessel density (MVD) in microinvasive squamous cell
      carcinomas was 40 +/- 2.42 (mean +/- SD) and in squamous carcinomas in situ (CIS)
      20.41 +/- 2.29 (p < 0.05). Among patients with CIS and controls (13.33 +/- 1.59)
      there was also a significant difference in the number of vessels (p < 0.05). No
      significant correlation was found in relation to depth of invasion and
      histological grade of the microinvasive carcinomas. It is concluded that
      microinvasive squamous cell cervical carcinoma is an angiogenetic disorder and it
      seems that the onset of angiogenesis is an early event, usually in a preinvasive
      stage.

PMID- 15032285
TI  - The efficacy of intravenous versus epidural tramadol with patient-controlled
      analgesia (PCA) in gynecologic cancer pain.
AB  - We attempted to compare the analgesic effects of tramadol infusion intravenously
      and epidurally administered through a patient-controlled analgesia (PCA) method
      for postoperative analgesia following gynaecological cancer surgery. Forty
      patients undergoing elective cancer surgery, included in the American Society of
      Anesthesiologists (ASA) class II and III, were randomly placed into two groups.
      The patients in the intravenous (IVA) group were administered a 20 mg bolus of
      tramadol intravenously and the patients in the epideral analgesia (EA) group
      epidurally five minutes before induction. The PCA equipment was programmed to
      deliver 20 mg of tramadol as a bolus dose, with a lock-out time of 15 minutes, at
      a 10 mg/hour infusion rate in both groups. A visual analogue scale (VAS) and
      patient satisfaction as well as haemodynamic and respiratory parameters were
      determined at given times postoperatively. Total tramadol consumption at 24 hours
      and side-effects were recorded. There was no difference between groups based on
      haemodynamic and respiratory parameters whereas there was a significant
      difference based on tramadol consumption, VAS and side-effects of tramadol and
      patient satisfaction between groups. VAS values of patients, 6.85 +/- 1.34 and
      3.00 +/- 1.58, respectively, for the IVA group (group 1) and the EA group (group
      2) were found to be significantly different. Postoperative patient satisfaction
      was higher was in group 2 than in group 1 (3.45 and 2.7, respectively). In
      conclusion, epidural administration of tramadol through the PCA method following
      gynecologic cancer surgery was found to be a more effective analgesia in lower
      doses when compared to the intravenous administration.

PMID- 15032287
TI  - A clinicopathological study of the relationship between adenomyosis and other
      hormone-dependent uterine lesions.
AB  - AIM: The aim of this study was to investigate the relationship between
      adenomyosis, endometrial adenocarcinoma, hyperplasia and uterine leiomyomas.
      MATERIAL AND METHODS: 135 consecutive hysterectomy specimens showing adenomyosis
      and 82 consecutive cases of endometrial adenocarcinoma were studied in our
      laboratory in the last 5-year period. The histological sections of all cases were
      reviewed and in the cases with adenocarcinoma, the type of cancer, the degree of
      differentiation and the depth of myometrial invasion were recorded. In the
      adenomyosis group the presence of any other lesions, the extension of adenomyosis
      and the morphology of the adenomyotic glands were recorded. In ten random cases
      of adenomyosis, the presence of estrogens and progesterone receptors was
      investigated by an immunohistochemical method of peroxidase-antiperoxidase and
      DAB chromogen. In ten cases of this group the expression of E-cadherin was
      studied immunohistochemocally by an avidin-viotin method and DAB chromogen.
      RESULTS: In 47/135 cases of adenomyosis adenomatous hyperplasia coexisted (34.8%)
      and in 86/135 cases of leiomyomas (63.7%). In 31/82 cases of adenocarcinoma there
      was adenomyosis as well (37.8%), in 4/82 cases malignant changes in foci of
      adenomyosis were observed and in 1/82 cases the malignancy arose in a focus of
      adenomyosis. Immunohistochemical studies showed the presence of progesterone
      receptors in the glandular cells of adenomyosis in 9/10 cases and of estrogen
      receptors in 2/10 cases. In all study cases (10/10) a positive membrane
      immunoreaction was observed; focal (6/10) and extensive (4/10). CONCLUSION: The
      high frequency of coexistence between adenomyosis and other hormone-dependent
      uterine lesions is indicative of the presence of a hormonal factor in the
      pathogenesis of adenomyosis.

PMID- 15032289
TI  - Missed cancers on mammograms: causes and measures of prevention.
AB  - Mammographically missed breast cancers remain a major medical and legal issue. In
      order to clarify causes and methods of the limitations, we present the experience
      of our Unit on this field. During the years 1999 and 2000, 319 breast cancer
      patients were admitted for surgical treatment to our Unit. Their files were
      reviewed in order to identify cases with mammography-related delayed diagnosis.
      Thirty-three cases of mammographically missed cancers were found (10.3%). The
      usual reasons for the delayed diagnoses were: retrospectively visible cancers, in
      benign looking lesions no further action was taken, and lesions with a rather
      malignant appearance were reported as benign. Missed cancers could be reduced by
      simple measures such as the full assessment of breast patients with clinical,
      radiologic, and cytologic-histologic evaluation, the double screening of
      mammograms, and improvement of the mammographic equipment and technique.

PMID- 15032290
TI  - Solitary splenic metastasis of endometrial carcinoma ten years after
      hysterectomy. Case report and review of the literature.
AB  - Solitary carcinomatous metastases to the spleen are rare. The reports of such
      cases in the literature usually concern late stages of the disease, with
      generalized carcinomatosis and metastatic foci in several other organs. Primary
      tumors that most often metastasize to the spleen are carcinomata of the breast,
      lung and ovaries, as well as malignant melanomata. Less often, carcinomata of the
      stomach, large bowel and kidneys are reported to implicate the organ with
      metastatic disease. The presence of solitary splenic metastasis of endometrial
      origin however, is extremely rare. We present a case of a 53-year-old female
      patient who ten years after hysterectomy due to the presence of endometrial
      carcinoma developed a metastatic focus to the spleen. This focus was diagnosed on
      the grounds of histology and immunohistochemistry, after splenic excision, to be
      of endometrial origin. Together with this case presentation, several aspects of
      the disease and its differential diagnosis are discussed, in correlation with the
      current literature.

PMID- 15032288
TI  - The prognostic significance of the immunohistochemical expression of p53, bcl-2,
      c-erb B-2 and cathepsin-D in ovarian cancer patients receiving platinum with
      cyclophosphamide or paclitaxel chemotherapy.
AB  - PURPOSE: To evaluate the prognostic significance of the immunohistochemical
      expression of p53, bcl-2, c-erbB-2 and cathepsin-D in epithelial ovarian cancer
      (EOC). METHODS: We analyzed 100 patients with ovarian carcinoma, FIGO Stage IC-IV
      who underwent primary cytoreductive surgery and received adjuvant chemotherapy
      with cyclophosphamide and a platinum analogue (CP) (n = 46) or paclitaxel and a
      platinum analogue (TP) (n = 54). Immunohistochemical expression was studied on
      paraffin-embedded tissue from the primary tumor. RESULTS: After a median follow
      up of 55 months median progression-free survival (PFS) and overall survival (OS)
      were 16 and 41 months, respectively. Positive bcl-2 staining and absence of
      cathepsin-D expression were associated with an increased complete response rate
      in the CP group (p = 0.011 and p = 0.003) but not in the TP group. PFS and OS
      were not associated with the expression of any of the markers studied. FIGO stage
      (p = 0.006) and histology (p = 0.047) were the only independent prognostic
      factors for survival. CONCLUSION: Bcl-2 and cathepsin D expression are associated
      with response to CP but not TP chemotherapy. P53, bcl-2, c-erb B-2 and cathepsin
      D expression was not correlated with PFS and OS in our study.

PMID- 15032291
TI  - Hyperplastic mesothelial cells in pelvic and abdominal lymph node sinuses
      mimicking metastatic ovarian microinvasive serous borderline tumor.
AB  - Hyperplastic mesothelial cells within pelvic and abdominal lymph nodes were
      encountered in the staging procedure of a 32-year-old woman with a left ovarian
      microinvasive serous borderline tumor. Mesothelial hyperplasia was noted in the
      pelvic and abdominal peritoneum. Intranodal mesothelial cells occupied the
      subcapsular sinus with subadjacent interfollicular sinuses involved less
      strikingly. These mesothelial cells were originally misdiagnosed as a metastatic
      serous borderline tumor. Histologic review and immunohistochemistry confirmed
      mesothelial origin. This case represents the second reported example of
      mesothelial cells within the lymph nodes of patients with ovarian serous tumors.
      Similar involvement of the mediastinal, cervical and internal mammary lymph nodes
      has been described in several patients with pleural effusions without neoplastic
      cells. Intranodal mesothelial cells should be distinguished from metastasis--an
      error ending in upper staging of a case.

PMID- 15032292
TI  - Primary ovarian small cell carcinoma of the pulmonary type: a case report and
      review of the literature.
AB  - Small cell carcinoma of the ovary is a rare type of ovarian carcinoma with a poor
      prognosis. Two types should be distinguished: the hypercalcemic type and the
      pulmonary type. We report the case history of a 54-year-old woman with both a
      Stage IIIC small cell carcinoma, pulmonary type and a well-differentiated
      endometrioid adenocarcinoma of the left ovary in combination with a Brenner tumor
      in the right ovary. A review of the literature on small cell carcinoma of the
      ovary is given and the findings of our patient are brought into perspective in
      terms of both histopathogenesis and treatment outcome.

PMID- 15032293
TI  - Cellular angiofibroma of the vulva: report of a case.
AB  - A case of vulvar cellular angiofibroma in a 50-year-old woman was
      immunohistochemically examined. She presented with a right labial mass which was
      noticed four years before. Surgical excision of the mass was performed.
      Histopathological examination revealed typical characteristics of cellular
      angiofibroma. Immunohistochemically, the lesion was CD34 positive but non
      reactive for desmin, smooth muscle actin and S-100 protein. In this article, we
      present a case of vulvar cellular angiofibroma, a lesion that should be
      considered in the differential diagnosis of vulvar soft tissue tumors.

PMID- 15032294
TI  - Vaginal bleeding as a first symptom of malignant lymphoma: case reports,
      diagnosis and successful treatment.
AB  - Uncommon pathologic changes of the uterine cervix are rare but not impossible.
      Described cases of cervical lymphoma indicate the necessity of great attention
      and careful diagnosis. A watchful examination, imaging procedures and detailed
      histopathologic findings are of crucial importance in treatment planning. Each of
      our three patients underwent different types of treatment. A proper choice of
      therapeutical methods is based on individual disease and patient performance
      status features. In our patients, chemotherapy, radiotherapy (brachy- and
      teletherapy) were considered and applied as the sole method or in combination.

PMID- 15032295
TI  - Long-lasting complete remission of a patient with cervical cancer FIGO IVB
      treated by concomitant chemobrachyradiotherapy with ifosfamide and cisplatin and
      consolidation chemotherapy--a case report.
AB  - The treatment of women with already metastasized cervical cancer at initial
      diagnosis represents a challenge to gynecologic oncologists. We report on a 63
      year-old patient with locally advanced squamous cell carcinoma of the cervix
      uteri with an isolated metastasis to the left ovary. Following treatment with
      concomitant chemoradiotherapy with ifosfamide and cisplatin and three cycles of
      consolidation chemotherapy with the same drug combination a complete clinical
      remission could be documented. At present, 35 months after her disease was
      diagnosed, she is still without any evidence of disease. The very promising
      outcome of this patient might suggest that combined chemoradiation which is the
      standard treatment of locally advanced cervical cancer is justified as well in
      the metastatic setting, provided the metastatic lesion is covered within the
      usual radiation field.

PMID- 15032296
TI  - Subcutaneous metastasis of endometrial adenocarcinoma: case report of an
      incidental diagnosis during abdominal sonography.
AB  - A rare case of subcutaneous metastasis from endometrial adenocarcinoma detected
      incidentally on the anterior abdominal wall during routine abdominal sonography
      is reported. A 62-year-old woman with clinical FIGO Stage IA, grade 2 endometrial
      mixed type (endometrioid and mucinous) adenocarcinoma was found with a
      subcutaneous mass located in the abdomen 18 months after initial surgery.

PMID- 15032297
TI  - Angiomyofibroblastoma of the vulva: report of a case.
AB  - A case of solitary angiomyofibroblastoma of the vulva in a 16-year-old woman was
      examined by histology and immunohistochemistry. Microscopic examination of the
      tumor revealed typical features of a mesenchymal neoplasm, composed of bundle
      spindle cells with low cellular density, rich in collagen fibers and thin-walled
      blood vessels. Immunohistochemistry revealed immunoreactivity for progesterone
      receptor, CD34, desmin and vimentin, tumor cells expressing positivity, but not
      for estrogen receptors. The stains for the muscle-specific actin and S-100 were
      negative. These results were mostly consistent with those of previous reports and
      suggest that the tumors cells were derived from primitive mesenchymal cells which
      occur normally in this region and show the potential for diverse lines of myoid
      differentiation.

PMID- 15032298
TI  - Endometrioid adenocarcinoma arising in endometriosis foci six years after
      estrogen replacement therapy: a case report.
AB  - We present a case of a 53-year-old woman who developed an endometrioid
      adenocarcinoma six years after total abdominal hysterectomy (TAH) and bilateral
      salpingo-oophorectomy (BSO), who was on estrogenic-only hormone replacement
      therapy (HRT).

PMID- 15032299
TI  - Sclerosing stromal tumors of the ovary: a clinicopathologic, immunohistochemical
      and cytogenetic analysis of three cases.
AB  - Sclerosing stromal tumors (SSTs) are uncommon ovarian neoplasms of the sex cord
      stromal category, that usually occur below 30 years of age. In the present study
      three cases of SSTs, diagnosed during the last eight years in our hospital, were
      examined immunohistochemically with stains for estrogen receptors, alpha and
      beta, progesterone receptors, and stains for markers that have been reported to
      be of use in the diagnosis of sex cord-stromal tumors. They were also examined by
      fluoresence in situ hybridization (FISH) for the presence of trisomy 12 and 7.
      Positivity for ERbeta was observed in a significantly larger number of cells than
      ERalpha. Positivity for calretinin and A103 was observed in tumor cells. In two
      cases 20-30% of the nuclei showed trisomy 12. No aberration of chromosome 7 was
      detected. The finding of increased ERbeta expression needs further investigation.

PMID- 15032300
TI  - Pregnancy associated breast cancer: a case report.
AB  - Despite its infrequency, pregnancy associated breast cancer implies multiple
      therapeutic dilemmas. Our patient, a 32-year-old Caucasian, gravida 2, para 2,
      was diagnosed with cancer of the left breast in the 19th week of gestation.
      Shortly after she underwent quadrantectomy plus axillary lymph node dissection.
      Chemotherapy was initiated in the 22(+6) week--four cycles of a combination of
      endoxan, farmorubicin, and fluorouracil. The patient gave birth in the 35(+6)
      week to a healthy baby with no apparent malformations. During puerperium she
      received two more cycles of chemotherapy. She is currently undergoing
      radiotherapy with tangential fields. Although it is too early to draw
      conclusions, the malignancy seems to be inactive.

PMID- 15032301
TI  - Design of freeze-drying processes for pharmaceuticals: practical advice.
AB  - Design of freeze-drying processes is often approached with a "trial and error"
      experimental plan or, worse yet, the protocol used in the first laboratory run is
      adopted without further attempts at optimization. Consequently, commercial freeze
      drying processes are often neither robust nor efficient. It is our thesis that
      design of an "optimized" freeze-drying process is not particularly difficult for
      most products, as long as some simple rules based on well-accepted scientific
      principles are followed. It is the purpose of this review to discuss the
      scientific foundations of the freeze-drying process design and then to
      consolidate these principles into a set of guidelines for rational process design
      and optimization. General advice is given concerning common stability issues with
      proteins, but unusual and difficult stability issues are beyond the scope of this
      review. Control of ice nucleation and crystallization during the freezing step is
      discussed, and the impact of freezing on the rest of the process and final
      product quality is reviewed. Representative freezing protocols are presented. The
      significance of the collapse temperature and the thermal transition, denoted Tg',
      are discussed, and procedures for the selection of the "target product
      temperature" for primary drying are presented. Furthermore, guidelines are given
      for selection of the optimal shelf temperature and chamber pressure settings
      required to achieve the target product temperature without thermal and/or mass
      transfer overload of the freeze dryer. Finally, guidelines and "rules" for
      optimization of secondary drying and representative secondary drying protocols
      are presented.

PMID- 15032302
TI  - Solubilizing excipients in oral and injectable formulations.
AB  - A review of commercially available oral and injectable solution formulations
      reveals that the solubilizing excipients include water-soluble organic solvents
      (polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol,
      glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide), non
      ionic surfactants (Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha
      tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80,
      Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M
      2125CS, Labrasol, Gellucire 44/14, Softigen 767, and mono- and di-fatty acid
      esters of PEG 300, 400, or 1750), water-insoluble lipids (castor oil, corn oil,
      cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil,
      soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium
      chain triglycerides of coconut oil and palm seed oil), organic liquids/semi
      solids (beeswax, d-alpha-tocopherol, oleic acid, medium-chain mono- and
      diglycerides), various cyclodextrins (alpha-cyclodextrin, beta-cyclodextrin,
      hydroxypropyl-beta-cyclodextrin, and sulfobutylether-beta-cyclodextrin), and
      phospholipids (hydrogenated soy phosphatidylcholine,
      distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, L-alpha
      dimyristoylphosphatidylglycerol). The chemical techniques to solubilize water
      insoluble drugs for oral and injection administration include pH adjustment,
      cosolvents, complexation, microemulsions, self-emulsifying drug delivery systems,
      micelles, liposomes, and emulsions.

PMID- 15032303
TI  - Inotropic effect of digoxin in humans: mechanistic
      pharmacokinetic/pharmacodynamic model based on slow receptor binding.
AB  - PURPOSE: The purpose of this study was to construct a mechanistic
      pharmacokinetic/pharmacodynamic (PK/PD) model for digoxin that describes the
      relationship between plasma concentration and inotropic response. METHODS: On the
      basis of results obtained in the isolated perfused rat heart, a PK/PD model for
      digoxin in humans was developed. In fitting the model to previously published
      bolus dose and concentration clamp data (shortening of electromechanical
      systole), the plasma concentration-time curves were used as forcing functions in
      the computer program ADAPT II. RESULTS: The mechanistic approach allowed a
      modeling of digoxin pharmacodynamics which is consistent with available inotropic
      response data. The estimates of the receptor binding parameters were in the same
      order of magnitude as those measured in vitro for ouabain. The mechanistic model
      explained the parameters of the empirical link model (EC50, Emax and delay time
      tau) in terms of the underlying processes, suggesting that the long equilibration
      half-time of 13 h is due to slow receptor binding. The empirical link model, in
      contrast, is not compatible with a noninstantaneous receptor binding process and
      led to estimates of the delay time tau that were dependent on the digoxin
      administration schedule. CONCLUSIONS: The new, mechanistic model may provide a
      rationale for better understanding of digoxin pharmacodynamics and could become a
      tool to bridge the gap between in vitro and in vivo studies.

PMID- 15032304
TI  - A quantitative structure-property relationship for predicting drug solubility in
      PEG 400/water cosolvent systems.
AB  - PURPOSE: A quantitative structure-property relationship (QSPR) was developed to
      predict drug solubility in binary mixtures of polyethylene glycol (PEG) 400 and
      water. The ability of the QSPR model to predict solubility was assessed and
      compared to the classic log-linear cosolvency model. METHODS: The solubility of
      122 drugs, ranging in log P from -2.4 to 7.5, was determined in 0%, 25%, 50%, and
      75% PEG (v/v in water) by the shake-flask method. Solubility data from 84 drugs
      were fit by linear regression using the following molecular descriptors:
      molecular weight, volume, radius of gyration, density, number of rotatable bonds,
      hydrogen-bond donors, and hydrogen-bond acceptors. The multiple linear regression
      model was optimized by a genetic algorithm guided selection method. The remaining
      38 compounds were used to test the predictability of the model. RESULTS: QSPR
      based models developed at each volume fraction with the training set compounds
      showed a reasonable correlation coefficient (r) of approximately 0.9 and a root
      mean square (rms) error of <0.5 log unit. The model predicted solubility values
      of approximately 78% of the testing set compounds within 1 log unit. The log
      linear model was as effective as the QSPR-based model in predicting the testing
      set solubilities; however, many drugs, as expected, showed significant deviation
      from log-linearity. CONCLUSIONS: The QSPR model requires only the chemical
      structure of the drug and has utility for guiding vehicle identification for
      early preclinical in vivo studies, especially when compound availability is
      limited and experimental data such as aqueous solubility and melting point are
      unknown. When experimental data are available, the log-linear model was verified
      to be a useful predictive tool.

PMID- 15032305
TI  - Drug solubilization behavior during in vitro digestion of simple triglyceride
      lipid solution formulations.
AB  - PURPOSE: The purpose of this study was to characterize the solubilization and
      precipitation characteristics of a range of poorly water-soluble drugs during
      digestion of either long-chain or medium-chain triglyceride (TG) lipid
      formulations. METHODS: TG solution formulations of five selected drugs
      (griseofulvin, diazepam, danazol, cinnarizine, and halofantrine) were digested in
      ritro and drug distribution/solubilization behavior in the resulting digests
      assessed. RESULTS: For the less lipophilic drugs, the mass of drug dissolved in
      either medium or long-chain TG was low and the drugs partitioned rapidly into the
      aqueous digestion phase. For the higher log P drugs, drug transfer to the aqueous
      phase was limited by accumulation in undigested long-chain TG. In contrast,
      medium-chain TG was digested completely producing a dispersed aqueous phase that
      was capable, at least in the case of the high log P drugs, of supporting
      supersaturated drug concentrations. CONCLUSIONS: The solubilization behavior of
      lipophilic drugs on digestion of simple TG lipid formulations is a function of
      the lipophilicity of the drug (which dictates the drug dose and the partitioning
      behavior), the nature of the colloidal phases produced on digestion of the
      different formulation lipids, and the kinetics of drug transfer between the
      digesting formulation and the colloidal phases produced.

PMID- 15032306
TI  - Drug solubilization behavior during in vitro digestion of suspension formulations
      of poorly water-soluble drugs in triglyceride lipids.
AB  - PURPOSE: The purpose of this study was to characterize the solubilization and
      precipitation characteristics of a range of poorly water-soluble drugs during the
      in vitro digestion of long-chain or medium-chain triglyceride (TG) lipid
      suspension formulations. METHODS: TG suspensions of model drugs (present at
      double their equilibrium solubilities in the respective lipid) were digested in
      vitro and the drug solubilization and precipitation pattern in the resulting
      digests analyzed. RESULTS: For griseofulvin, diazepam, and danazol,
      solubilization of the small mass of drug originally presented in the TG lipid was
      efficient with only a small proportion of the dose precipitating and being
      recovered in the pellet phase after digestion of the TG lipid. For the more
      lipophilic and lipid-soluble drugs (cinnarizine, halofantrine), in which higher
      drug loadings were possible, significant enhancement in drug solubilization in
      the postdigestion aqueous phase was not apparent compared with simple TG lipid
      solutions. CONCLUSIONS: Suspensions of drugs, which are poorly soluble in water
      and TG lipid, may prove beneficial as the relatively high solubilizing capacity
      of the colloidal phases produced on TG digestion will likely exceed the mass of
      drug that could have been administered as a simple lipid solution. However, for
      more lipid-soluble drugs, suspension formulations may offer little benefit as
      sufficiently high drug loadings can otherwise be achieved with simple solution
      formulations that still provide for adequate solubilization after TG digestion.

PMID- 15032307
TI  - Enhanced oral absorption of paclitaxel in a novel self-microemulsifying drug
      delivery system with or without concomitant use of P-glycoprotein inhibitors.
AB  - PURPOSE: The objective of this study was to evaluate the pharmacokinetics of
      paclitaxel in a novel self-microemulsifying drug delivery system (SMEDDS) for
      improved oral administration with or without P-glycoprotein (P-gp) inhibitors.
      METHODS: Paclitaxel SMEDDS formulation was optimized, in terms of droplet size
      and lack of drug precipitation following aqueous dilution, using a ternary phase
      diagram. Physicochemical properties of paclitaxel SMEDDS and its resulting
      microemulsions were evaluated. The plasma concentrations of paclitaxel were
      determined using a HPLC method following paclitaxel microemulsion administrations
      at various doses in rats. RESULTS: Following 1:10 aqueous dilution of optimal
      paclitaxel SMEDDS, the droplet size of resulting microemulsions was 2.0 +/- 0.4
      nm, and the zeta potential was -45.5 +/- 0.5 mV. Compared to Taxol, the oral
      bioavailability of paclitaxel SMEDDS increased by 28.6% to 52.7% at various
      doses. There was a significant improvement in area under the curve (AUC) and time
      above therapeutic level (0.1 microM) of paclitaxel SMEDDS as compared to those of
      Taxol following coadministration of both formulations with 40 mg cyclosporin A
      (CsA)/kg. The oral absorption of paclitaxel SMEDDS slightly enhanced following
      coadministration of tacrolimus and etoposide, but plasma drug concentrations did
      not reach the therapeutic level. The nonlinear pharmacokinetic trend was not
      modified after paclitaxel was formulated in SMEDDS. CONCLUSIONS: The results
      indicate that SMEDDS is a promising novel formulation to enhance the oral
      bioavailability of paclitaxel, especially when coadministered with a suitable P
      gp inhibitor, such as CsA.

PMID- 15032308
TI  - Induction of cell death by saponin and antigen delivery.
AB  - PURPOSE: Saponin is the major component in the formation of immune stimulating
      complex (ISCOM), a potent adjuvant able to induce both humoral and cellular
      immune reactions. The immunogenicity induced by saponin, however, has been
      unclear. The objective of this study was to investigate the apoptotic and
      necrotic effects induced by saponin in ELA mouse lymphoma cells, expected to be a
      possible mechanism of the cytotoxic T-lymphocyte (CTL) effect elicited by the
      ISCOM. METHODS: EL4 cells were treated with saponin, and viability of the cells
      was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
      (MTT) and lactate dehydrogenase release assays. Fluorescence microscopy was used
      to detect the morphological changes by staining saponin-treated cells with
      Hoechst 33342. Extent of apoptosis and necrosis was determined by Annexin V
      FITC/propidium iodide staining, followed by flow cytometric analysis. Dendritic
      cells were cultured with either saponin-protein complexes or saponin-treated
      cells and analyzed by flow cytometry. RESULTS: Treatment of EL4 cells with
      saponin resulted in concentration-dependent cytotoxicity and the appearance of
      the hypodiploid DNA peak. Cells treated with saponin showed highly condensed
      chromatin when stained with fluorescent DNA-binding dye Hoechst 33342. Analysis
      of EL4 cells by flow cytometry after Annexin V/propidium iodide staining
      demonstrated that saponin induced both apoptosis and necrosis. Pretreatment of
      EL4 cells with zVAD-fmk, a broad-range caspase inhibitor, did not prevent cell
      death induced by saponin, indicating the non-caspase-dependent cell death.
      Dendritic cells were shown to phagocytose both the antigen-saponin complexes and
      the saponin-induced dead cells. CONCLUSIONS: Results obtained in this study
      demonstrated that saponin induced both apoptosis and necrosis in ELA cells. These
      events are critical for antigen processing and presentation.

PMID- 15032309
TI  - The transepithelial transport of a G-CSF-transferrin conjugate in Caco-2 cells
      and its myelopoietic effect in BDF1 mice.
AB  - PURPOSE: The purpose of this study was to investigate the transferrin-receptor
      (TfR)-mediated transepithelial transport of G-CSF-transferrin (Tf) conjugate in
      cultured enterocyte-like Caco-2 monolayers and the myelopoietic effect of
      subcutaneously and orally administered G-CSF-Tf in BDF1 mice. METHODS: Caco-2
      monolayers exhibiting a minimum transepithelial electrical resistance of 500 ohms
      cm2 and BDF1 mice were used as in vitro and in vivo models, respectively. TfR
      mediated transcytosis wa measured by using 125I-G-CSF-Tf and analyzing the
      downstream compartment by gamma counter. The efficacy of subcutaneously and
      orally administered G-CSF-Tf was determined by performing daily absolute
      neutrophil counts. RESULTS: Transport experiments in Caco-2 cells revealed that
      the monolayers that received 125I-G-CSF-Tf exhibited significantly higher apical
      to-basolateral transport rates compared to the monolayers that received 125I-G
      CSF. Inclusion of 100-fold excess unlabeled Tf reduced the extent of 125I-G-CSF
      Tf transport by 80%. Chromatographic and bioactivity assays revealed that the
      protein recovered from the basolateral compartment was the intact conjugate, and
      it retained full ability to stimulate the proliferation of the granulocyte-colony
      stimulating factor (G-CSF) dependent cell line, NFS-60, upon reduction.
      Subcutaneous administration of G-CSF-Tf in BDF1 mice demonstrated that the
      conjugate is able to elicit a statistically significant enhancement in
      therapeutic effect relative to filgrastim, which includes a longer duration of
      action with higher absolute neutrophil counts. Oral administration of G-CSF-Tf in
      BDF1 mice demonstrated that G-CSF-Tf is able to elicit a significant, and
      apparently dose-dependent, increase in absolute neutrophil counts whereas
      filgrastim had no effect. CONCLUSIONS: Our data indicate that G-CSF-Tf is
      transported across Caco-2 monolayers by TfR-specific processes at a rate that is
      significantly higher than the nonspecific flux of G-CSF. G-CSF-Tf is also able to
      elicit a prolonged myelopoietic effect relative to filgrastim when administered
      subcutaneously or orally in BDF1 mice. The development of an orally bioavailable
      G-CSF has the potential to provide great benefit to patients under sustained G
      CSF dosing regimes.

PMID- 15032310
TI  - Esterase-like activity of serum albumin: characterization of its structural
      chemistry using p-nitrophenyl esters as substrates.
AB  - PURPOSE: To elucidate the catalytic mechanism of the esterase-like activity of
      serum albumin (SA), the reactivity of SA from six species was investigated using
      p-nitrophenyl esters as model substrates. METHODS: The effect of pH and the
      energetic and thermodynamic profiles of SA were determined for all species for p
      nitrophenyl acetate (PNPA). Then, kinetic and thermodynamic studies using a
      series of p- and o-nitrophenyl esters with different side chains and human SA
      (HSA) were carried out. The influence of deuterium oxide was also evaluated.
      Finally, the information gained was used to construct a computer model of the
      structural chemistry of the reaction. RESULTS: The pH profiles suggest that the
      nucleophilic character of the catalytic residue (Tyr-411 in the case of HSA) is
      essential for activity. This kcat-dependent activity was found to increase with a
      decrease in the activation free energy change (deltaG). Hence, the magnitude of
      deltaG, which is dependent on activation entropy change (deltaS), as calculated
      from the thermodynamic analysis, can be regarded as an indicator of hydrolytic
      activity. It indicates that p-nitrophenyl propionate (PNPP) is the best substrate
      by evaluating the reactions of nitrophenyl esters with HSA. The findings here
      indicate that deuterium oxide has no significant effect on the rate of hydrolysis
      of PNPA by HSA. CONCLUSIONS: The results are consistent with a scenario in which
      HSA becomes acylated due to a nucleophilic attack by Tyr-411 on the substrate and
      then is deacylated by general acid or base catalysis with the participation of
      water.

PMID- 15032311
TI  - The "high solubility" definition of the current FDA Guidance on Biopharmaceutical
      Classification System may be too strict for acidic drugs.
AB  - PURPOSE: The purpose of this study was to assess if the definition of high
      solubility as proposed in the FDA Guidance on Biopharmaceutical Classification
      System (BCS) is too strict for highly permeable acidic drugs. METHODS: The
      solubility and permeability values of 20 (18 acidic and 2 non-acidic)
      nonsteroidal anti-inflammatory drugs (NSAID) were determined. The NSAIDs were
      grouped into three different sets having acetic acid, propionic acid, or other
      acidic moieties such as fenamate, oxicam, and salicylate. Two nonacidic NSAIDs
      (celecoxib and rofecoxib) were also included for comparison purposes. Equilibrium
      solubility values were determined at pH 1.2, 5.0, 7.4, and in biorelevant media
      simulating fed intestinal fluid at pH 5.0. For a select number of acids, we also
      measured solubility values in media simulating gastric and fasted intestinal
      fluids. Permeability classification was established relative to that of reference
      drugs in the Caco-2 cell permeability model. Permeability coefficients for all
      drugs were measured at concentrations corresponding to the lowest and highest
      marketed dose strengths dissolved in 250 ml volume, and their potential
      interaction with cellular efflux pumps was investigated. RESULTS: All NSAIDs with
      different acidic functional groups were classified as highly permeable based on
      their Caco-2 cell permeability. Only ketorolac appeared to have a potential for
      interaction with cellular efflux pumps. Solubility classification was based on
      comparison of equilibrium solubility at pH 1.2, 5.0. and 7.4 relative to marketed
      dose strengths in 250 ml. The pKa values for the acidic NSAIDs studied were
      between 3.5 and 5.1. and, as expected, their solubility increased dramatically at
      pH 7.4 compared to pH 1.2. Only three NSAIDs, ketorolac, ketoprofen. and acetyl
      salicylic acid, meet the current criteria for high solubility over the entire pH
      range. However, with the exception of ibuprofen, oxaprozin, and mefenamic acid,
      the remaining compounds can be classified as Class I drugs (high solubility-high
      permeability) relative to solubility at pH 7.4. The use of bio-relevant media
      simulating gastric and intestinal milieu for solubility measurements or
      increasing the dose volume to 500 ml did not provide for a better boundary for
      solubility classification. CONCLUSIONS: Based on the current definition of
      solubility, 15 of the 18 acidic NSAIDs in this study will be classified as Class
      II compounds as the solubility criteria applies to the entire pH range of 1.2 to
      7.4, although the low solubility criteria does not hold true over the entire pH
      range. Whence, of the 18 acidic drugs, 15 can be classified as Class I based on
      the pH 7.4 solubility alone. This finding is intriguing because these drugs
      exhibit Class I behavior as their absorption does not seem to be dissolution or
      solubility limited. It could then be argued that for acidic drugs, the boundaries
      for solubility are too restrictive. Solubility at pH > 5 (pH in duodenum) may be
      more appropriate because most compounds are mainly absorbed in the intestinal
      region. Consideration for an intermediate solubility classification for highly
      permeable ionizable compounds that reflects physiological conditions seems
      warranted.

PMID- 15032312
TI  - Determination of carrier-mediated transport of 2',3'-dideoxypurine nucleosides in
      the rat ileum using a bidirectional perfusion technique.
AB  - PURPOSE: Previous attempts to ascertain the role of uptake and efflux
      transporters in the oral absorption of anti-HIV dideoxypurine nucleosides have
      been inconclusive. A novel in situ intestinal perfusion technique with complete
      mesenteric arterial/venous cannulation was used to examine the asymmetry of ileal
      dideoxynucleoside permeability under near in vivo conditions. METHODS: Intestinal
      perfusions were performed in the rat ileum, with cannulation of the artery and
      vein immediately entering and leaving the segment. Urea and mannitol were used as
      passive permeability markers, and the directional transport of 2',3'
      dideoxyinosine (ddI), 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI), and 2'-beta
      fluoro-2',3'-dideoxyadenosine (F-ddA) were examined. RESULTS: Urea and mannitol
      exhibited symmetric permeability (PLtoB = PBtoL), whereas F-ddI and ddI showed
      significantly higher permeability in blood-to-lumen transport (PBtoL > PLtoB).
      PBtoL for F-ddA exceeded PLtoB, but the difference did not reach significance at
      p < 0.05. PBtoL for ddI was demonstrated to be saturable with increasing ddI
      concentrations, but PLtoB was independent of ddI concentration. PBtoL for ddI was
      shown to be dependent on sodium concentration and inhibited by probenecid.
      CONCLUSIONS: Symmetric transport was demonstrated for urea and mannitol as
      expected for these passive permeability markers. F-ddI and ddI were shown to be
      preferentially transported from blood to lumen. The basolateral to luminal
      transport of ddI is saturable, inhibited by probenecid, and sodium ion dependent.
      These results are consistent with carrier-mediated uptake on the basolateral
      membrane.

PMID- 15032313
TI  - In situ ileal absorption of insulin in rats: effects of hyaluronidase
      pretreatment diminishing the mucous/glycocalyx layers.
AB  - PURPOSE: To test the hypothesis that the ileal mucous/glycocalyx layers can be
      removed by hyaluronidase and that their significant roles in insulin absorption
      can thereby be identified. METHODS: Rat ileal segments were pretreated with
      various concentrations of hyaluronidase by "perfusion" or "exposure", and the
      absorption of insulin and 4.4-, 20-, and 40-kDa fluorescein isothiocyanate
      labeled dextrans (FDs) were studied in the in situ ileal loop system. Diminished
      mucous/glycocalyx layers following the hyaluronidase pretreatment was confirmed
      by transmission electron microscopy (TEM), whereas intra- and intercellular
      integrity and/or damage was examined by light microscopy, lactate dehydrogenase
      (LDH) leakage, and membrane electrical resistance (Rm). RESULTS: Hyaluronidase
      "perfusion" pretreatment at concentrations > or = 160 U/ml for 30 min
      significantly increased the hypoglycemic responses following in situ
      administration of insulin at 50 IU/kg. This enhancing effect was found to be
      dependent on hyaluronidase concentration and "exposure" periods and accompanied
      by the TEM observation of diminished mucous/glycocalyx layers from the
      hyaluronidase pretreatment, yet causing undetectable histological damage. In
      contrast, the absorption of FDs and the values for LDH leakage and Rm were
      unaffected by the hyaluronidase pretreatment, suggesting that the layers
      functioned insignificantly to diffusive absorption. CONCLUSIONS: Hyaluronidase
      pretreatment increased ileal absorption of insulin, but not FDs, by virtue of the
      diminished mucous/glycocalyx layers without causing detectable cellular damage.

PMID- 15032315
TI  - N-acetyltransferase 2 genotype-related efficacy of sulfasalazine in patients with
      rheumatoid arthritis.
AB  - PURPOSE: For the individual optimization of drug therapy with sulfasalazine
      (SASP), we studied the influence of the N-acetyltransferase 2 (NAT2) genotype on
      the pharmacokinetics, efficacy, and incidence of adverse reactions of SASP in
      patients. METHODS: Ninety-six rheumatoid arthritis (RA) patients were treated or
      had been treated with 0.5 and/or 1.0 g/day of SASP. The wild-type allele (NAT2*4)
      and three variant alleles (NAT2*5B, *6A, and *7B) of NAT2 were determined by the
      polymerase chain reaction-restriction fragment length polymorphism method. Plasma
      concentrations of SASP and its two metabolites, sulfapyridine (SP) and N
      acetylsulfapyridine (AcSP), were estimated by HPLC. Therapeutic efficacy and
      incidence of adverse reactions were also monitored as recommended by the American
      College of Rheumatology. RESULTS: Patients were classified into three groups by
      NAT2 genotyping: Rapid Type (homozygote for NAT2*4), Intermediate Type
      (heterozygote for NAT2*4 and variant alleles), and Slow Type (homozygote for
      variant alleles). There was no clear difference in the genotype frequencies
      between RA patients and healthy subjects. NAT2 genotypes significantly affected
      both the plasma concentration ratios of SP to AcSP (SP/AcSP) and the efficacy of
      SASP (p < 0.05). Adverse reactions to SASP were found in 26 (27.1%) out of 96
      patients, and there was no difference among the three genotype groups.
      CONCLUSIONS: NAT2 gene polymorphism is related to the plasma SP/AcSP ratio and
      the efficacy of SASP.

PMID- 15032314
TI  - Comparison of the AMPA antagonist action of new 2,3-benzodiazepines in vitro and
      their neuroprotective effects in vivo.
AB  - PURPOSE: AMPA receptor-mediated excitotoxicity is thought to be a critical
      process in diseases accompanied by neuronal cell loss following a hypoxic/anoxic
      state of the central nervous system. It has been suggested that blockade of AMPA
      receptors might result in significant protection of neurons against cellular
      damage. For testing the hypothesis, in vitro efficacy and in vivo neuroprotective
      action of new 2,3-benzodiazepine (2,3BDZ) AMPA antagonists have been compared.
      METHODS: 2.3BDZs were tested on kainate-evoked whole-cell currents in cultured
      neurons as well as on population spikes (PS) in rat hippocampal slices. Data were
      correlated with those obtained from the spreading depression (SD) experiments in
      chicken retina. Compounds were also examined in the gerbil bilateral carotid
      occlusion model (BCO), where percentage decrease of ischemia-related
      hypermotility (HM), impaired spatial memory (SA), and hypoxia-induced hippocampal
      CA1 neuronal cell death (CA1) were evaluated. RESULTS: Certain structural
      modifications of classical 2,3BDZs resulted in increased in vitro activity and
      improved in vivo efficacy. In particular, the halogen-substituted compounds EGIS
      9879 and EGIS-9883 showed the highest neuroprotective efficacy (84% and 47%
      protection in CA1, 71% and 82% decrease in HM, respectively; 4 x 5 mg/kg i.p.) in
      BCO. PS and SD were correlated to the decrease of neuronal loss in the CA1 area.
      Lack of significant correlation was found between PS and CA1 (r = 0.437, p =
      0.079) or SD and CA1 (r = 0.380, p = 0.146). CONCLUSIONS: Several new 2.3BDZ AMPA
      receptor antagonists have been synthesized at EGIS Pharmaceuticals characterized
      by remarkable in vitro and corresponding in vivo neuroprotective properties.

PMID- 15032316
TI  - Effect of cisplatin-induced acute renal failure on bioavailability and intestinal
      secretion of quinolone antibacterial drugs in rats.
AB  - PURPOSE: The aim of this study was to clarify the effects of renal failure on
      intestinal secretion of quinolone antibacterial drugs. METHODS: Pharmacokinetics
      of grepafloxacin, levofloxacin, and ciprofloxacin in cisplatin-induced acute
      renal failure (ARF) rats were evaluated, and intestinal and biliary clearance
      studies were examined. Transport experiments using culture cells were performed.
      RESULTS: The bioavailability of grepafloxacin in ARF rats was 1.2-fold higher
      than that in normal rats. On the other hand, the bioavailability of ciprofloxacin
      in ARF rats was markedly decreased to half of that in normal rats, and that of
      levofloxacin was not changed. Intestinal clearance of grepafloxacin in ARF rats
      was 75% of that in normal rats, whereas that of ciprofloxacin was 1.4-fold higher
      than in normal rats, and that of levofloxacin was comparable between normal and
      ARF rats. Transport experiments using P-glycoprotein-expressing LLC-GA5-COL150
      cells and human intestinal Caco-2 cells suggested that grepafloxacin and
      levofloxacin were substrates of P-glycoprotein and that ciprofloxacin was not,
      and that intestinal secretion of ciprofloxacin was mediated by a specific
      transport system distinct from organic cation and anion transporters and
      multidrug resistance-associated protein 2. CONCLUSIONS: Cisplatin-induced ARF
      differentially modulated the bioavailability and intestinal secretion of
      quinolones in rats.

PMID- 15032317
TI  - Biodegradable triblock copolymer microspheres based on thermosensitive sol-gel
      transition.
AB  - PURPOSE: The purpose of this study is to design microspheres for sustained
      protein delivery using thermosensitive, biodegradable tri-block copolymer, poly
      (D,L-lactide-co-glycolide)-b-poly (ethylene glycol)-b-poly (D,L-lactide-co
      glycolide) (PLGA-PEG-PLGA) without using organic solvent. METHODS: Microspheres
      of the triblock copolymer PLGA-PEG-PLGA were prepared in an aqueous-based method
      without using methylene chloride (Msp A). This method used the sol-gel transition
      property of the polymer. The size and morphology of the microspheres were
      examined by optical microscopy and scanning electron microscopy (SEM). Zinc
      crystalline recombinant human insulin was incorporated in Msp A as well as in the
      microspheres of the same polymer prepared by the conventional water-in-oil-in
      water (w/o/w) double emulsion method using methylene chloride (Msp B). Insulin
      release from both microspheres was carried out using high-performance liquid
      chromatography (HPLC) as well as circular dichroism (CD) spectroscopy of released
      insulin. FITC-insulin-loaded Msp A and Msp B were observed under confocal
      microscopy. Both microspheres were injected subcutaneously to SD rats with
      diabetes induced by streptozotocin. Blood glucose and plasma insulin levels were
      monitored. RESULTS: Although the insulin release from Msp B exhibited initial
      burst and incomplete release, Msp A showed significant reduction of initial burst
      and continuous release over 3 weeks (>85%). CD spectra of released insulin showed
      that insulin from Msp A preserved its secondary structural integrity, whereas
      that from Msp B indicated changes in conformation. Confocal microscopy of FITC
      insulin-loaded microspheres (both A and B) showed that the observed release
      profile may be attributed to homogeneous distribution of FITC-insulin within Msp
      A but inhomogeneiety in Msp B. Both microspheres were injected s.c. to diabetic
      rats. Whereas Msp B caused a burst effect (hypoglycemia) followed by quick change
      in blood glucose and insulin level, Msp A exhibited relatively sustained release
      of insulin and blood glucose level for at least 10 days. CONCLUSIONS: The PLGA
      PEG-PLGA microspheres (Msp A) demonstrated continuous release of insulin in vitro
      and in vivo without serious burst effect and incomplete release, as shown by Msp
      B.

PMID- 15032318
TI  - Uptake and cytotoxicity of chitosan molecules and nanoparticles: effects of
      molecular weight and degree of deacetylation.
AB  - PURPOSE: To evaluate the effects of molecular weight (Mw) and degree of
      deacetylation (DD) on the cellular uptake and in vitro cytotoxicity of chitosan
      molecules and nanoparticles. METHODS: Chemical depolymerization and reacetylation
      produced chitosans of Mw 213,000 to 10,000 and DD 88-46%, respectively. Chitosan
      was labeled with FITC and transformed into nanoparticles by ionotropic gelation.
      Uptake of chitosan by confluent A549 cells was quantified by fluorometry, and in
      vitro cytotoxicity was evaluated by the MTT and neutral red uptakeassays.
      RESULTS: Nanoparticle uptake was a saturable event for all chitosan samples, with
      the binding affinity and uptake capacity decreasing with decreasing polymer Mw
      and DD. Uptake fell by 26% when Mw was decreased from 213,000 to 10,000, and by
      41% when DD was lowered from 88% to 46%; the uptake data correlated with the zeta
      potential of the nanoparticles. Uptake of chitosan molecules did not exhibit
      saturation kinetics and was less dependent on Mw and DD. Postuptake quenching
      with trypan blue indicated that the cell-associated chitosan nanoparticles were
      internalized, but not the cell-associated chitosan molecules. Chitosan molecules
      and nanoparticles exhibited comparable cytotoxicity, yielding similar IC50 and
      IC20 values when evaluated against the A549 cells. Cytotoxicity of both chitosan
      entities was attenuated by decreasing polymer DD but was less affected by a
      lowering in Mw. CONCLUSIONS: Transforming chitosan into nanoparticles modified
      the mechanism of cellular uptake but did not change the cytotoxicity of the
      polymer toward A549 cells. Chitosan DD had a greater influence than Mw on the
      uptake and cytotoxicity of chitosan nanoparticles because of its effect on the
      zeta potential of the nanoparticles.

PMID- 15032319
TI  - Critical determinants in PLGA/PLA nanoparticle-mediated gene expression.
AB  - PURPOSE: The aim of the study was to determine the critical determinants in
      nanoparticle-mediated gene transfection. It was hypothesized that different
      formulation parameters could affect the nanoparticle characteristics and hence
      its gene transfection. METHODS: Nanoparticles encapsulating plasmid DNA encoding
      for firefly luciferase were formulated using polylactide (PLA) and poly (D,L
      lactide-co-glycolide) (PLGA) polymers of different compositions and molecular
      weights. A multiple-emulsion solvent-evaporation method with polyvinyl alcohol
      (PVA) as an emulsifier was used to formulate DNA-loaded nanoparticles. Gene
      expression of nanoparticles was determined in breast cancer (MCF-7) and prostate
      cancer (PC-3) cell lines. RESULTS: Nanoparticles formulated using PLGA polymer
      demonstrated greater gene transfection than those formulated using PLA polymer,
      and this was attributed to the higher DNA release from PLGA nanoparticles. Higher
      molecular-weight PLGA resulted in the formation of nanoparticles with higher DNA
      loading, which demonstrated higher gene expression than those formulated with
      lower-molecular-weight PLGA. In addition, the nanoparticles with lower amount of
      surface-associated PVA demonstrated higher gene transfection in both the cell
      lines. Higher gene transfection with these nanoparticles was attributed to their
      higher intracellular uptake and cytoplasmic levels. Further study demonstrated
      that the molecular weight and the degree of hydrolyzation of PVA used as an
      emulsifier also affect the gene expression of nanoparticles. CONCLUSIONS: Results
      thus demonstrate that the DNA loading in nanoparticles and its release, and the
      surface-associated PVA influencing the intracellular uptake and endolysosomal
      escape of nanoparticles, are some of the critical determinants in nanoparticle
      mediated gene transfection.

PMID- 15032320
TI  - Partial acetylation of polyethylenimine enhances in vitro gene delivery.
AB  - PURPOSE: Polyethylenimine (PEI) is a highly effective gene delivery vector, but
      because it is an off-the shelf material, its properties may not be optimal. To
      investigate the effects of the protonation properties of the polymer, we
      generated PEI derivatives by acetylating varying fractions of the primary and
      secondary amines to form secondary and tertiary amides, respectively. METHODS:
      Reaction of PEI with increasing amounts of acetic anhydride at 60 degrees C for
      4.5 h yielded polymers with 15%, 27%, and 43% of the primary amines modified with
      acetyl groups. Polymer-DNA complexes were characterized by dynamic light
      scattering and zeta potential measurements. Cytotoxicity of the polymers was
      assessed by XTT assay for metabolic activity, and gene delivery efficiency was
      determined as the relative expression of a luciferase gene in MDA-MB-231 and
      C2C12 cell lines. RESULTS: Acetylation of PEI decreased the "physiological
      buffering capacity," defined as the moles of protons absorbed per mole of
      nitrogen on titration from pH 7.5 to 4.5, from 0.29 mol H+/mol N to 0.17 mol
      H+/mot N, 0.12 mol H+/mol N, and 0.090 mol H+/mol N for PEI-Ac15, PEI-Ac27, and
      PEI-Ac43, respectively. In addition, acetylation decreased the zeta potential of
      polyplexes from 14 mV to 8-11 mV and increased the polyplex diameter by two- to
      threefold. Surprisingly, acetylation had a negligible effect on cytotoxicity of
      the polymers and increased gene delivery effectiveness by up to 21-fold compared
      to unmodified PEI, both in the presence and absence of serum. CONCLUSIONS:
      Reduction of the buffering capacity of PEI greatly enhanced the gene delivery
      activity of the polymer. The mechanism is not yet understood, but the enhancement
      may be caused by more effective polyplex unpackaging, altered endocytic
      trafficking, and/or increased lipophilicity of acetylated PEI-DNA complexes.
      Future studies will address these possibilities in more detail.

PMID- 15032321
TI  - Processing of spherical crystalline particles via a novel solution atomization
      and crystallization by sonication (SAXS) technique.
AB  - PURPOSE: The objective was to develop a single-step pharmaceutical particle
      engineering technique able to produce particles within a well-defined particle
      size range while controlling macroscopic spherical morphology and mesoscopic
      surface topography. METHODS: Paracetamol (acetaminophen) aerosol droplets were
      generated by spraying a solution via either an electrohydrodynamic atomizer
      (EHDA) or an air pressure atomizer. The highly supersaturated droplets were
      collected in a suitable nonsolvent of the drug and crystallized by
      ultrasonication. Suspended particles were filtered, and their physicochemical
      properties characterized. RESULTS: The SAXS processed particles showed a
      relatively homogeneous particle size distribution between 1 and 5 microm.
      Particles were nominally crystalline in structure. The chemical structure of the
      active ingredient did not apparently alter during processing. Controlling the
      solute concentration of the air pressure atomized solution provided a means of
      controlling the degree of sphericity and particle-size characteristics. In
      comparison to micronized paracetamol particles, SAXS-produced particulates were
      generally more uniform in shape with increased nanometer surface roughness.
      CONCLUSIONS: The SAXS process provides a novel means of producing crystalline
      particles in a well-defined particle size range. Furthermore, the method offers a
      range of opportunities in controlling physical properties including surface
      topography and particle shape.

PMID- 15032322
TI  - Improved tableting properties of p-hydroxybenzoic acid by water of
      crystallization: a molecular insight.
AB  - PURPOSE: To understand the influence of water in the crystal structure on the
      compaction properties of otherwise structurally similar crystals, p
      hydroxybenzoic acid anhydrate (HA) and the monohydrate (HM) were used as model
      compounds. METHODS: Bulk powder of HM was prepared by exposing HA powder to 97%
      relative humidity at 23 degrees C. Each powder, HA or HM, was uniaxially
      compressed and triaxially decompressed under various pressures to form square
      faced tablets. The tensile strength and porosity of the tablets were measured.
      RESULTS: Incorporation of water into the crystal lattice results in greater
      tablet strength and larger reduction in volume for HM crystals than for HA
      crystals. Both HA and HM crystals contain hydrogen-bonded, zigzag-shaped layers
      that lie parallel to the (401) plane. When HA crystals are compressed, the zigzag
      shaped layers mechanically interlock, inhibiting slip and reducing plasticity.
      However, water molecules in the HM crystals assume a space-filling role, which
      increases the separation of the layers. This effect allows easier slip between
      layers and provides greater plasticity of HM crystals, which increases the
      interparticulate bonding area under the same compaction pressure. However, the
      water molecules in the HM crystals increase their lattice energy by forming a
      three-dimensional hydrogen-bonding network. The greater bonding strength that
      results is reflected in greater tensile strength of HM compacts at zero porosity.
      CONCLUSIONS: The presence of water molecules in the crystal structure of p
      hydroxybenzoic acid facilitates plastic deformation of HM crystals, thereby
      enhancing their bonding strength and giving much stronger tablets than of HA
      crystals.

PMID- 15032323
TI  - The charged milieu: a major player in fertilization reactions.
AB  - In previous studies, we have found that negatively charged, but not uncharged,
      amino acids and sugars block sea urchin fertilization. These studies were
      developed from modeling work in non-living systems using derivatized agarose
      beads that suggested that charge-charge bonding may control at least some
      adhesive interactions. In the present study, the effects of positively charged,
      negatively charged and uncharged molecules were examined in the sea urchin sperm
      egg system in over 300 individual trials. The results indicate that depending on
      the specific molecules utilized, both sperm and egg are exquisitely sensitive to
      charged but not uncharged molecules and to pH changes in sea water caused by some
      of the charged molecules. It is shown that egg activation, as well as sperm
      motility and sperm-egg interactions, can be affected by charged molecules. One
      compound, fructose-1-phosphate blocked fertilization in S. purpuratus sea urchins
      but not in Lytechinus pictus sea urchins. These findings indicate that charge
      alone cannot explain all the results. In this case, the presence of a ketone
      instead of an aldehyde group indicates that species-specific components may
      control fertilization reactions. The present study is a comprehensive survey of
      the effects of charge, pH and molecular structure on the fertilization activation
      continuum in a model system of sea urchins.

PMID- 15032324
TI  - Expression of peroxisome proliferator-activated receptors in the liver of gray
      mullet (Mugil cephalus).
AB  - During the last decade, peroxisome proliferation has emerged as a novel biomarker
      of exposure to certain organic chemical pollutants in aquatic organisms.
      Peroxisome proliferation is mediated by nuclear receptors, peroxisome
      proliferator-activated receptors (PPARs). Three PPAR subtypes have been described
      in mammals: PPAR alpha, PPAR beta and PPAR gamma. PPARs have also been discovered
      in several fish species. The aim of the present study was to investigate the
      expression of PPAR subtypes and their cellular distribution patterns in the liver
      of gray mullet Mugil cephalus, a fish species widely distributed in estuaries and
      coastal areas in Europe and used as sentinel of environmental pollution. For this
      purpose, antibodies were generated against the three subtypes of mouse PPARs and
      different protocols of antigen retrieval were used. In western blots, main bands
      were detected of approximately 44 kDa for PPAR alpha, two bands of 44 and 58 kDa
      for PPAR beta and a single band of 56 kDa for PPAR gamma. Similar results were
      obtained in mouse liver and may indicate antibody recognition of two forms of the
      protein in certain cases. PPAR alpha was the subtype most markedly expressed in
      gray mullet liver, being expressed mainly in melanomacrophages, nuclei of
      hepatocytes and sinusoidal cells and connective tissue surrounding bile ducts.
      PPAR beta was expressed in the same cell types but immunolabeling was generally
      weaker than for PPAR alpha. PPAR gamma showed very weak expression; positivity
      was mainly found in melanomacrophages and connective tissue surrounding bile
      ducts. Our results demonstrate that all the three PPAR subtypes are expressed in
      gray mullet liver but in different intensities. The cellular distribution
      patterns of PPAR subtypes in gray mullet liver resembled partly those found in
      mouse liver with PPAR alpha as the main subtype expressed in hepatocytes. The
      fact that melanomacrophages, cells of the immune system in fish, show strong
      expression of both PPAR alpha and PPAR beta whereas PPAR gamma expression is
      almost restricted to this cell type suggest a significant role of PPAR-mediated
      regulation of cell function in melanomacrophages.

PMID- 15032325
TI  - Co-secretion of soluble caveolin-1 and pepsinogen in the oesophagus of the red
      legged frog Rana aurora aurora.
AB  - Caveolin-1, an integral membrane protein, is the principal component of caveolae,
      which are specialised vesicular microdomains of the plasma membrane. Caveolae are
      found in most cell types, but they are most abundant in adipocytes, endothelial
      cells, fibroblasts, and muscle cells. Functionally, they have been implicated in
      endothelial transcytosis, potocytosis, and signal transduction. Recently,
      caveolin-1 has been found unexpectedly in the cytoplasm, mitochondria and
      elements of the secretory pathways of exocrine secretory cells. We have co
      localised caveolin-1 and pepsinogen immunohistochemically in serous cells of
      oesophageal glands of the red-legged frog, Rana aurora aurora. Thus, according to
      its intracellular localisation pattern, caveolin-1 may be either a soluble
      protein, located in secretory droplets, or a protein that is inserted in caveolar
      membranes. Soluble caveolin-1, which is probably embedded in a lipid particle
      surrounded by a phospholipid shell, may be involved in intracellular and
      extracellular lipid transport. In the gut, caveolin-1-rich lipid particles can
      act as donor particles to facilitate (protein-mediated) intestinal uptake of
      cholesterol and phospholipids. Our findings strengthen the hypothesis that
      caveolin-1 has a physiological autocrine/paracrine function and demonstrate that
      secretion of this protein also occurs in vertebrates other than mammals, such as
      amphibians, which may be a useful alternative animal model to study caveolin-1.

PMID- 15032326
TI  - Effects of pinealectomy and exogenous melatonin on rat hearts.
AB  - The effects of pinealectomy and administration of melatonin, the major secretory
      product of the pineal gland, which is a direct free radical scavenger and an
      indirect antioxidant, were studied in rat hearts on the basis of cardiac
      morphology and biochemical findings. Three groups of Wistar rats were used: one
      group was the sham-operated control, one group consisted of pinealectomized rats
      and one group consisted of pinealectomized rats that were treated with melatonin.
      Serum cholesterol, tissue levels of malondialdehyde (MDA) and reduced glutathione
      (GSH), and heart weight were determined. Histochemical staining with the Van
      Gieson, PAS/Alcian blue at pH 2.5 and Masson's trichrome methods were performed
      in addition to hematoxylin-eosin staining. Levels of serum cholesterol and tissue
      MDA, and heart weight were increased in pinealectomized rats whereas GSH levels
      did not change. Melatonin administration reversed these effects. Microscopically,
      myocardial fibrosis and myxomatous degeneration of cardiac valves were detected
      in all pinealectomized rats. It can be concluded that pinealectomy of rats causes
      morphological changes in rat hearts, and short-term application of melatonin does
      not reverse these changes.

PMID- 15032328
TI  - The effects of intravenously administered methylxanthines on the proportion of
      goblet cells containing fucosylated glycoconjugates in rabbit tracheal
      epithelium.
AB  - The proportion of goblet cells containing various fucosylated glycoconjugates was
      evaluated with the use of lectin histochemistry in rabbit tracheal epithelium at
      15 and 30 min after intravenous administration of either aminophylline
      (Syntophyllin) or a mixture of etophylline and theophylline (Oxantil).
      Methylxanthine derivatives are nonspecific inhibitors of phosphodiesterases that
      are used to treat bronchial asthma; the proportion of fucosylated glycoconjugates
      strongly affects rheologic properties of respiratory tract mucus. It is concluded
      that administration of Syntophyllin dramatically lowered the proportion of goblet
      cells containing fucosylated glycoconjugates in rabbit tracheal epithelium,
      especially at 30 min after exposure. This decrease was strongest in the levels of
      alpha(1-2)-fucosylated glycoconjugates. Therefore, Syntophyllin substantially
      altered the composition and viscoelastic properties of mucus of the upper
      respiratory tract. The vasodilator Oxantil exerted less pronounced changes in the
      proportion of goblet cells, but the strongest effect was again found in the
      levels of alpha(1-2)-fucosylated glycoconjugates.

PMID- 15032327
TI  - Histopathological effects of sildenafil citrate on rat corpus cavernosum.
AB  - Sildenafil citrate (Viagra) is widely used for the treatment of erectile
      dysfunction with various etiologies. The aim of the present study was the
      investigation of histopathological effects of sildenafil citrate on rat corpus
      cavernosum using tight and electron microscopical techniques. Twenty male rats
      were divided into two groups. The first group (n = 10) was used as a control and
      the second group (n = 10) was treated with sildenafil citrate. Penile tissue was
      collected, fixed with formalin and embedded in paraffin for light microscopy, or
      fixed with gluteraldehyde and osmium tetroxide and embedded in Epon for electron
      microscopy. Light microscopical analysis showed that the corpus cavernosum was
      elongated and the number of blood vessels was increased. The amount of connective
      tissue in the penis was increased and dense collagen and smooth muscle fibers
      were observed in treated rats. Electron microscopical analysis showed that
      stromal structures of the corpus cavernosum (collagen fibers and number of
      cellular elements) were increased in treated rats. Fibroblasts showed signs of
      activation and the number of other stromal cells was increased. Immature newly
      synthesized collagen fibers were observed and penetrated endothelial basement
      membranes. In addition, endothelial cells also showed signs of activation such as
      cytoplasmic granules in treated rats, whereas the surface area of blood vessels
      was increased and basement membranes were thickened. These histopathological
      changes due to treatment with sildenafil citrate indicate that prolonged use of
      sildenafil citrate may increase the risk of fibrosis in the penis.

PMID- 15032329
TI  - Immunodetection of aromatase in mice with a partial deletion in the long arm of
      the Y chromosome.
AB  - Aromatization of androgens into estrogens is catalyzed by a microsomal enzyme,
      P450 aromatase. Males of the mouse strain B10.BR and its congenic mutant strain
      B10.BR-Ydel (with a partial deletion in the long arm of the Y chromosome) were
      used to identify the cellular source of estrogens within the testis.
      Immunocytochemistry was applied to localize aromatase in cultured Leydig cells,
      cytoplasmic droplets attached to flagella of spermatozoa, and sections of testes.
      The presence of aromatase in testes was checked by means of Western-blot
      analysis. Steroid hormones secreted by Leydig cells in vitro were measured in
      homogenates of testes using radioimmunological methods. Additionally, a Southern
      analysis was performed using the Y353/B probe to check the length of the deletion
      in the Y chromosome. In sections of testis of B10.BR mice, weak to moderate
      immunohistochemical staining of aromatase was found in Leydig cells, Sertoli
      cells, and germ cells. In testicular cells of B10.BR-Ydel mice, stronger
      immunostaining of aromatase was observed, especially in germ cells and Leydig
      cells. Positivity for aromatase was also found in the cytoplasm of cultured
      Leydig cells from both strains, but it was higher in cells derived from mutant
      males. Western-blot analysis revealed one major band of approx. 55kDa of
      aromatase in testes from both strains. Lower testosterone levels were found in
      mutant males in supernatants of culture media and homogenates of testes in
      comparison with control males. In contrast, estradiol levels were always higher
      in mutants. Therefore, it seems likely that the increased expression of aromatase
      and, as a consequence, the higher levels of endogenous estrogens enhance the
      morphological alterations in testis and affect spermatogenesis in mutant males.

PMID- 15032330
TI  - Expression of c-maf and mafB genes in the skin during rat embryonic development.
AB  - The maf oncogene (v-maf) was initially identified in an avian oncogenic
      retrovirus, AS42, which induces musculoaponeurotic fibrosarcoma in vivo and
      transforms chicken embryo fibroblasts in vitro. Genes of the maf family have
      important roles in embryonic development and cellular differentiation. Both genes
      are expressed in a wide variety of tissues including spleen, kidney, lens and
      liver. The present study was performed to analyze expression of c-maf-1 and mafB
      genes in skin of embryonic stages from 15 days onwards using in situ
      hybridization. Expression of c-maf mRNA was first detected on embryonic day (ED)
      16 in the nuclei of cells in the basal layer in developing epidermis. On ED 19,
      high expression was detected in the nucleus of basal keratinocytes and developing
      hair germs. On postnatal day (PD) 3, expression of c-maf had disappeared in
      epidermis and hair follicles. MafB showed similar expression patterns as c-maf.
      Our findings indicate that c-maf and mafB are involved in embryonic development
      of epidermis and hair follicles.

PMID- 15032331
TI  - Comparative histochemical and immunohistochemical study on xanthine
      oxidoreductase/xanthine oxidase in mammalian corneal epithelium.
AB  - We have previously found that xanthine oxidase (one form of xanthine
      oxidoreductase that generates reactive oxygen species, such as superoxide
      radicals and hydrogen peroxide) is present in corneal epithelium of normal rabbit
      eye. It was suggested that the reactive oxygen species contribute to additional
      eye damage related to prolonged continuous contact lens wear and irradiation of
      the eye with UV-B light. To further explore the potential danger of xanthine
      oxidase as a source of reactive oxygen species, we have examined in the present
      paper whether xanthine oxidoreductase and xanthine oxidase are present in corneal
      epithelium of other mammalian species, employing immunohistochemical and enzyme
      histochemical methods. In corneal epithelium of normal eyes of ox, pig, guinea
      pig, and rat xanthine oxidoreductase activity was detected by the tetrazolium
      salt reduction method and xanthine oxidase activity was localized by a method
      based on cerium ions capturing hydrogen peroxide. For the immunohistochemical
      demonstration of the enzymes, rabbit anti-bovine xanthine oxidase antibody,
      rabbit anti-human xanthine oxidase antibody and monoclonal mouse anti-human
      xanthine oxidase/xanthine dehydrogenase/aldehyde oxidase antibody were used. The
      immunohistochemical and enzyme histochemical results show that xanthine
      oxidoreductase and xanthine oxidase are present both as proteins and as active
      enzymes in the corneal epithelium of all animals studied. It is hypothesized that
      under various pathological states, xanthine oxidase-generated reactive oxygen
      species might contribute to eye damage.

PMID- 15032332
TI  - [Is the end of the physician-patient relation the medicine crisis?].

PMID- 15032333
TI  - [Medicine between depersonalization and neohumanism].

PMID- 15032334
TI  - [When and how is medical teleconsultation to doctors practising in remote areas
      of developing countries convenient and reliable? About eight clinical cases].
AB  - A poorly equipped internal medicine doctor (IMD), practising in remote areas of
      developing countries, can be assisted with expertise teleconsultations by using
      the common analogical telephone lines. By that way, the clinical cases he
      challenges became multidisciplinary and the success of the treatment enhanced.
      Eight cases are reported as examples. The expertise is made up by eight remote
      access experts on different medical fields. The effectiveness of the support of
      the consultants is compared one to the other. In laboratory, dermatology and,
      partly, cyto-pathology fields the teleconsultations are reliable and not time
      consuming, for the key tool is the digital picture sent by e-mailing. In
      cardiology (heart ultrasound scan) and radiology fields both effectiveness and
      benefit-cost ratio are disputable. Heart ultrasound scan is a dynamic test and
      filming is needed to provide the consultant with good records. In radiology
      field, the upper digestive tract X-ray scan is usually carried out with few
      shots, due to the unsustainable charges on the patient. That matter impairs the
      consultant's effectiveness to support. Although the black-outs of the
      transmission were common throughout IMD-consultant videoconferences, the physical
      examination of the patient, performed by the IMC under consultant's direct
      supervision, is highly supportive both in neurology and paediatric fields. The
      physiotherapist's show of physical rehabilitation exercises by videoconference is
      highly supportive as well.

PMID- 15032335
TI  - [Nosocomial infections in a general surgical ward].
AB  - According to the National Nosocomial Infection Surveillance system we analysed
      the post-surgical nosocomial infections in a surgery ward of Perugia University.
      Between May 2000 and April 2001, 677 patients were enrolled mean age 51.5 years:
      355 (52%) male, 462 (68%) ASA score 1, "clean" surgery in 355 cases (52%),
      cephazolin prophylaxis in 256 (38%); 11 (2%) patients deceased perioperatively. A
      total of 37 nosocomial infections, in 33 patients, were detected: 18 pneumonia
      (48.6%), 10 surgical site infections (27%) with 18 isolated: 12 gram-negative (E.
      coli 3, Acinetobacter baumannii 2, Providencia stuartii 2, Pseudomonas aeruginosa
      2, Achromobacter spp. 1, Citrobacter freundii 1, Morganella morgani 1) and 6 gram
      positive (Staphylococcus aureus meticillin resistant 3, Enterococcus faecalis 2,
      Streptococcus salivarius 1); 7 sepsis (19%) due to 7 gram-positive (S. aureus
      meticillin resistant 4, S. aureus meticillin susceptible 1, Staphylococcus
      coagulase negative 1, Clostridium spp 1), 2 urinary tract infections (5.4%).
      Patients without infections and with nosocomial infections spent in hospital 6.3
      and 16.6 days respectively. We can image that in one year 53 surgical procedure
      were lost, with a lost gain of 79.500-291.500 euro/year.

PMID- 15032336
TI  - [The gastroesophageal reflux disease (GERD) and the general practitioner].
AB  - In Italy few data are available on which patients, coming from a self-medication
      experience, turn to their general practitioners (GPs) due to gastro-oesophageal
      reflux symptoms. Aim of this study was to describe the clinical characteristics
      of these patients. METHODS: Observational trial involving a large number of GPs;
      the GPs were expected to enroll > or = 3 consecutive adult patients with typical
      reflux symptoms. During the visit, a computerized network was used to collect
      electronic data on demographics, reflux and associated symptoms, concomitant
      diseases and therapies, investigations for GERD. RESULTS: On 1345 patients
      enrolled in all (sex: 52% M; median age class: 48-52 yrs) a high prevalence of
      non-smokers (68%) was observed, regular use of coffee/tea or alcohol was seen in
      52% and 23% of patients, respectively. At study entry, the typical reflux
      symptoms prevalence was 36%, 9% and 38% for heartburn, regurgitation, heartburn
      plus regurgitation. The 71% of patients had a previous history of reflux symptoms
      (duration > 3 yrs for 39% of them). No differences found in the typical reflux
      symptoms frequency and severity between naive and relapsed patients. An average
      number of 3 associated symptoms was reported. The main associated disease
      reported was irritable bowel syndrome (27%). CONCLUSIONS: The ICEBERG study
      provides a picture of the main features of GERD at primary care level, on the
      basis of a large amount of Italian patients' data.

PMID- 15032337
TI  - [Biomedical information on the internet using search engines. A one-year trial].
AB  - The internet is a communication medium and content distributor that provide
      information in the general sense but it could be of great utility regarding as
      the search and retrieval of biomedical information. Search engines represent a
      great deal to rapidly find information on the net. However, we do not know
      whether general search engines and meta-search ones are reliable in order to find
      useful and validated biomedical information. The aim of our study was to verify
      the reproducibility of a search by key-words (pediatric or evidence) using 9
      international search engines and 1 meta-search engine at the baseline and after a
      one year period. We analysed the first 20 citations as output of each searching.
      We evaluated the formal quality of Web-sites and their domain extensions.
      Moreover, we compared the output of each search at the start of this study and
      after a one year period and we considered as a criterion of reliability the
      number of Web-sites cited again. We found some interesting results that are
      reported throughout the text. Our findings point out an extreme dynamicity of the
      information on the Web and, for this reason, we advice a great caution when
      someone want to use search and meta-search engines as a tool for searching and
      retrieve reliable biomedical information. On the other hand, some search and meta
      search engines could be very useful as a first step searching for defining better
      a search and, moreover, for finding institutional Web-sites too. This paper
      allows to know a more conscious approach to the internet biomedical information
      universe.

PMID- 15032338
TI  - [Retroperitoneal pleomorphic liposarcoma. A case of survival after ten years].
AB  - Sarcomas are malignant neoplasms which can involve both soft tissues and/or
      bones. The soft tissues sarcomas are very rare, representing about 1% of all
      malignant tumors. In the resectable cases, histologic grading, site and
      dimensions of tumor influence recurrence and survival rates. Currently, surgery
      is the only curative therapy for soft tissues sarcomas in adult patients, with
      the exclusion of retroperitoneal sarcomas, which have have poor prognosis, due to
      look of surgical radicality and low radiotherapy and chemotherapy responsiveness.
      In fact, chemotherapy by conventional regimens, as adriamicine plus ifosfamide or
      CYVADIC, allows not more than 25% of partial responses, with a median survival of
      12 months.

PMID- 15032339
TI  - [Hepatitis C in hemophiliacs].
AB  - Hepatitis C virus (HCV) infection is an important cause of morbidity and
      mortality in patients with hereditary bleeding disorders treated with non virus
      inactivated clotting factor concentrates during the 1970s. In this article, we
      briefly report the actual knowledge about HCV infection in hemophiliacs, by
      analyzing the prevalence of HCV infection, the genotype distribution, the natural
      history of the infection and the most important factors involved in the
      progression of chronic hepatitis into liver cirrhosis, hepatic decompensation and
      hepatocellular carcinoma. Finally, we describe the main advances in the treatment
      of HCV infection.

PMID- 15032340
TI  - [Gastroesophageal reflux disease: facts and uncertainties].
AB  - In these years the increasing interest regarding clinical presentation of Gastro
      Esophageal Reflux Disease (GERD) is certainly due to the complex pathogenic
      mechanism and the poor correlations between symptoms, clinical picture and
      endoscopic findings. In this paper we review clinical, pathological and
      therapeutical features of GERD focusing on controversial findings in clinical
      practice.

PMID- 15032342
TI  - [Saint Anthony's fire and herpes zoster in various pages of Antonio Tabucchi].

PMID- 15032341
TI  - [Non invasive mechanical ventilation in the domiciliary treatment of chronic
      obstructive pulmonary disease].
AB  - Since hypercapnia is a negative prognostic index in stable chronic obstructive
      pulmonary disease (COPD), the chance of applying non invasive ventilation (NIV)
      to COPD with CO2 retention has been investigated for the two last decades. Patho
      physiologic basis of its employ are resting of respiratory muscles and/or
      resetting of respiratory centres. Due to its poor tolerability, negative pressure
      NIV has been taken over by positive pressure technique. As the results of the few
      available controlled studies aren't enthusiastic and univocal, it's not possible
      to draw guidelines about the domiciliary use of NIV in COPD. In conclusion, the
      author suggests that, in order to avoid useless waste of resources, the
      application of NIV to stable COPD should be reserved to very selected cases
      (significant hypercapnia, frequent nocturnal desaturations and/or sleep
      disordered breathing and/or hospital admissions) if its compliance and
      effectiveness are demonstrated.

PMID- 15032343
TI  - Comparison of linear and non-linear equations for univariate calibration.
AB  - Univariate data accumulated for the purpose of calibration of chromatographic and
      spectroscopic methods often exhibit slight but definite curvature. In this paper
      the performance of a non-linear calibration equation with the capacity to account
      empirically for the curvature, y = a + bx(m), (m not equal to 1) is compared with
      the commonly used linear equation, y = a + bx, as well as the quadratic equation,
      y = a + bx + cx2. All equations were applied to high quality HPLC calibration
      data using unweighted least squares. Parameter estimates and their standard
      errors were calculated for each equation. Standard errors and 95% prediction
      intervals in analyte concentrations were estimated with the aid of the fitted
      equations and their respective covariance matrices. Results indicate that the non
      linear and quadratic equations each provide a better fit than the linear equation
      to the data considered here, as judged by the Akaikes information criterion
      (AIC), the adjusted coefficient of multiple determination, the magnitude and
      scatter of residuals, standard errors in estimated analyte concentrations and
      lack of fit analysis of variance (ANOVA). While the difference between the
      equations y = a + bx + cx2 and y = a + bx(m) as judged by the same criteria is
      more marginal, this work suggests that the non-linear calibration equation should
      be considered when a curve is required to be fitted to low noise calibration data
      which exhibit slight curvature.

PMID- 15032344
TI  - Peak purity determination with principal component analysis of high-performance
      liquid chromatography-diode array detection data.
AB  - A method is proposed for the determination of chromatographic peak purity by
      means of principal component analysis (PCA) of high-performance liquid
      chromatography with diode array detection (HPLC-DAD) data. The method is
      exemplified with analysis of binary mixtures of lidocaine and prilocaine with
      different levels of separation. Lidocaine and prilocaine have very similar
      spectra and the chromatograms used had substantial peak overlap. The samples
      analysed contained a constant amount of lidocaine and a minor amount of
      prilocaine (0.02-2 conc.%) and hence the focus was on determining the purity of
      the lidocaine peak in the presence of much smaller levels of prilocaine. The peak
      purity determination was made by examination of relative observation residuals,
      scores and loadings from the PCA decomposition of DAD data over a chromatographic
      peak. As a reference method, the functions for peak purity analysis in the
      chromatographic data system used (Chromeleon) were applied. The PCA method showed
      good results at the same level as the detection limit of baseline-separated
      prilocaine, outperforming the methods in Chromeleon by a factor of ten. There is
      a discussion of the interpretation of the result, with some comparisons with
      evolving factor analysis (EFA). The main advantage of the PCA method for
      determination of peak purity over methods like EFA lies in its simplicity, short
      time of calculation and ease of use.

PMID- 15032345
TI  - Saccharose effects on surface association of phenol derivatives with porous
      graphitic carbon.
AB  - In this paper, the effect of saccharose on the association of phenol derivatives
      on both the porous graphitic carbon (PGC) surface and the C18 stationary phase
      and for two methanol fractions (v/v) in the mobile phase is described. A novel
      approach based on an extended Langmuir distribution isotherms was used. The
      results demonstrated that: (i) the saccharose can be adsorbed on the PGC surface;
      (ii) the phenol derivatives can be associated with saccharose adsorbed on the PGC
      surface; and (iii) the saccharose do not interact with the C18 stationary phase.
      This was confirmed by the thermodynamic data and the Wyman equation parameters.

PMID- 15032346
TI  - Liquid chromatographic-mass spectrometric studies on the in vitro degradation of
      a poly(ether ester) block copolymer.
AB  - A detailed study on the in vitro degradation of a poly(ethylene glycol) and
      poly(butylene terephthalate) (PEOT/PBT) segmented block copolymer was carried out
      using liquid chromatography/electrospray-mass spectrometry. Accelerated
      hydrolysis of PEOT/PBT was achieved by placing the material for 14 days in a
      refluxing phosphate buffered saline (pH 7.4) solution. All major degradation
      products and several side-products were identified using both the positive and
      the negative ion mode. The data indicate that degradation does not only occur in
      the "soft", but also in the "hard" segments of the polymer. Liquid
      chromatographic separation is required to distinguish between degradation
      products with different sequences but identical molecular mass. The addition of
      ammonium and sodium ions provided important complementary information on the
      number of monomer units present in the degradation products.

PMID- 15032347
TI  - Polymer-based adsorption medium prepared using a fragment imprinting technique
      for homologues of chlorinated bisphenol A produced in the environment.
AB  - A polymer-based adsorption medium having molecular recognition ability for
      homologues of chlorinated bisphenol A produced in environment was prepared using
      a fragment imprinting technique. 2,6-Dimethyl phenol was utilized as a pseudo
      template molecule and the adsorption media prepared was evaluated by high
      performance liquid chromatography (HPLC) and solid-phase extraction (SPE). As
      results, the adsorption medium showed preferable chromatographic retention and
      specific adsorption ability for the chlorinated bisphenol As having chlorine
      substituents at 3,5-positions through fragment imprinting effect.

PMID- 15032348
TI  - Self-immobilization of poly(methyloctylsiloxane) on high-performance liquid
      chromatographic silica.
AB  - Poly(methyloctylsiloxane) (PMOS) was deposited on HPLC silica by a solvent
      evaporation procedure and this material was then extracted, using a good solvent
      for the PMOS, after different time periods, to remove unretained liquid polymer.
      Solvent extraction data reveal changes which occur at ambient temperature as a
      function of the time interval between particle loading and extraction. The
      quantity of PMOS remaining on the silica after extraction, as determined by
      elemental analysis for carbon, is attributed to strongly adsorbed polymer. This
      phenomenon is termed self-immobilization. Solid-state 29Si NMR spectra indicate
      the formation of a silicon species with a different chemical shift than the
      original PMOS. These new signals are attributed to a combination of different
      adsorbed and chemically bonded groups.

PMID- 15032349
TI  - Temperature-programmed packed capillary liquid chromatography coupled to
      evaporative light-scattering detection and electrospray ionization time-of-flight
      mass spectrometry for characterization of high-molecular-mass hindered amine
      light stabilizers.
AB  - High-molecular weight-hindered amine light stabilizers (HMW-HALSs) are of utmost
      importance in modern polyolefin stabilization technology and in-depth knowledge
      about their chemical composition, particularly the oligomers, is essential for
      development of new and more efficient stabilizers. In the present study, the
      applicability of temperature-programmed packed capillary LC coupled to
      miniaturized ELSD and positive mode ESI-TOF-MS for analysis of HMW-HALSs is
      demonstrated through extensive characterization of two state-of-the-art
      stabilizers, i.e., HALS-1 and HALS-2. Both stabilizers were individually
      separated on a 320 microm i.d. x 35 cm long Hypersil 3 microm ODS-100 column
      using a temperature program from 30 to 120 degrees C and a quaternary mixture of
      ethylacetate, acetonitrile, triethylamine (TEA) and acetic acid
      (45.0:44.9:10.0:0.1 (v/v/v/v)) as the mobile phase. The effect of using various
      amounts of ethylacetate, acetonitrile and triethylamine in the mobile phase on
      the chromatographic separation is demonstrated. Furthermore, the LC-ESI-TOF-MS
      analyses revealed that HALS-1 (oligomeric) was highly complex and consisted of at
      least five different mass series, while HALS-2, which was assumed to be
      monomeric, contained two different mass series. Chemical structures for nearly
      all species of both stabilizers are proposed.

PMID- 15032350
TI  - Optimization by experimental design and artificial neural networks of the ion
      interaction reversed-phase liquid chromatographic separation of twenty cosmetic
      preservatives.
AB  - Particular attention are recently receiving antimicrobial agents added as
      preservatives in hygiene and cosmetics commercial products, since some of them
      are suspected to be harmful to the human health. The preservatives used belong to
      different classes of chemical species and are generally used in their mixtures.
      Multi-component methods able to simultaneously determinate species with different
      chemical structure are therefore highly required in quality control analysis.
      This paper presents an ion interaction RP-HPLC method for the simultaneous
      separation of the 20 typical antimicrobial agents most used in cosmetics and
      hygiene products, that are: benzoic acid, salicylic acid, 4-hydroxybenzoic acid,
      methyl-, ethyl-, propyl-, butyl-, benzyl-benzoate, methyl-, ethyl-, propyl-,
      butyl-, benzyl-paraben, o-phenyl-phenol, 4-chloro-m-cresol, triclocarban,
      dehydroacetic acid, bronopol, sodium pyrithione and chlorhexidine. For the
      development of the method and the optimization of the chromatographic conditions,
      an experimental design was planned and models were built by the use of artificial
      neural network to correlate the retention time of each analyte to the variables
      and their interactions. The neuronal models developed showed good predictive
      ability and were used, by a grid search algorithm, to optimize the
      chromatographic conditions for the separation of the mixture.

PMID- 15032351
TI  - Simulation of size exclusion chromatography for characterization of
      supramolecular complex: a theoretical study.
AB  - A simple chromatographic model was used to simulate the retention behavior of
      supramolecular complex in size exclusion chromatography (SEC). Two fundamental
      model complexes, directional complementary couple (AB) and self-complementary
      unit (AA), were employed to investigate the influence of various parameters in
      the SEC characterization/confirmation of supramolecular association. Peak
      tailing, peak fronting, peak splitting and retention time shifting were observed
      under different conditions. It was found that the chromatographic peak shape and
      retention time were strongly affected by the association constant, sample
      concentration, as well as the addition of a reactant in the mobile phase.
      Furthermore, using the same model, the chromatographic process of Hummel-Dreyer
      procedure was simulated, and the results indicated that the procedure can be a
      good method for the determination of association constants for AB type complexes.

PMID- 15032352
TI  - Application of high-performance liquid chromatography with ultraviolet diode
      array detection and refractive index detection to the determination of class
      composition and to the analysis of gasoline.
AB  - A method of effective application of normal-phase high-performance liquid
      chromatography (NP-HPLC) with ultraviolet diode array detection (DAD) and
      refractive index detection (RID) for the determination of class composition of
      gasoline and its components, i.e. for the determination of content of alkenes,
      aromatic and saturated hydrocarbons in gasoline meeting modern quality standards,
      has been developed. An aminopropyl-bonded silica stationary phase was used along
      with n-hexane or n-heptane as the mobile phase. A DAD signal integrated over the
      207-240 nm range was used to determine alkenes. This eliminates the necessity of
      separating alkenes from saturates, because the latter do not absorb UV radiation
      above 200 nm. The content of aromatic hydrocarbons is determined by means of a
      refractive index detector. Calibration was based on hydrocarbon type composition
      determined by the fluorescent indicator adsorption method, ASTM D1319. The
      results obtained by the developed method were found to be consistent with those
      obtained by fluorescent indicator adsorption or by a multidimensional GC method
      (PIONA) (ASTM D5443). The method can be applied to gasoline meeting recent
      quality standards, irrespective of refining technology used in the production of
      gasoline components, including gasoline with various contents of oxygenates. The
      developed method cannot be used to determine the hydrocarbon type composition of
      gasoline that contains as a component the so-called pyrocondensate, i.e. the
      fraction with a boiling point up to 220 degrees C, obtained through thermal
      pyrolysis of distillation residues of crude oil or coal and, consequently, does
      not meet the quality standards. The paper includes the procedure for
      identification of this type of gasoline.

PMID- 15032353
TI  - Liquid chromatography-mass spectrometry analysis of enzyme-hydrolysed
      carboxymethylcellulose for investigation of enzyme selectivity and substituent
      pattern.
AB  - A series of celloendoglucanases: Bacillus agaradhaerens Cel 5a, Humicola insolens
      Cel 5a, H. insolens Cel 7b, H. insolens Cel 45a, Trichoderma reesei Cel 7b, and
      T. reesei Cel 45a were used to hydrolyse carboxymethylcellulose (CMC) and the
      hydrolysis products were investigated with a novel liquid chromatography-mass
      spectrometry (LC-MS) method. Separation was achieved using a graphitised carbon
      chromatographic column which allowed the use of electrospay compatible eluents.
      Analysis of the compounds produced during enzyme hydrolysis of CMC is used to
      understand enzyme selectivities and substitution pattern of CMC. Conventional
      high-performance anion-exchange chromatography (HPAEC)-pulsed amperometric
      detection (PAD), size-exclusion chromatography (SEC)-refractive index (RI)
      detection, and reducing end analysis are also used to analyse enzyme-hydrolysed
      CMC. The LC-MS method presented allows for a more detailed investigation of
      hydrolysis products, which facilitates characterisation of both enzymes and
      substrates.

PMID- 15032354
TI  - Influence of perfluorinated carboxylic acids on ion-pair reversed-phase high
      performance liquid chromatographic separation of betacyanins and 17-decarboxy
      betacyanins.
AB  - The ability of trifluoroacetic acid, pentafluoropropionic acid and
      heptafluorobutyric acid to act as ion-pairing agents for betacyanins and 17
      decarboxy-betacyanins during HPLC analysis on a Luna C18(2) reversed-phase column
      is reported. While the perfluorinated carboxylic acids affect the retention of
      both groups of compounds by changing the pH of the mobile phase, the possibility
      of ion-pair chromatography for 17-decarboxy-betacyanins was noticed. In order to
      explain the accessibility of the positive charge for the counter-anion in
      decarboxy-betacyanins, the mesomeric structures of the polymethine system at low
      pH (around a value of 1.5), when the carboxylic group in the 2 position is
      protonated, should be taken into consideration.

PMID- 15032355
TI  - Designed chimaeric galactosyl-mimodye ligands for the purification of Pseudomonas
      fluorescens beta-galactose dehydrogenase.
AB  - Two chimaeric galactosyl-mimodye ligands were designed and applied to the
      purification of Pseudomonas fluorescens galactose dehydrogenase (GaDH). The
      chimaeric affinity ligands comprised a triazine ring on which were anchored: (i)
      an anthraquinone moiety that pseudomimics the adenine part of NAD+, (ii) a
      galactosyl-mimetic moiety (D-galactosamine for ligand BM1 or shikimate for ligand
      BM2), bearing an aliphatic 'linker', that mimics the natural substrate galactose,
      and (iii) a long hydrophilic 'spacer'. The mimodye-ligands were immobilised to
      1,1-carbonyldiimidazole-activated agarose chromatography support, via the
      spacer's terminal amino-group, to produce the respective mimodye adsorbents. Both
      immobilized mimodyes successfully bound P. fluorescens GaDH but failed to bind
      the enzyme from rabbit muscle. Adsorbent BM1 bound GaDH from green peas and
      Baker's yeast, but adsorbent BM2 failed to do so. The mimodye-ligand comprising
      D(+)-galactosamine (BM1), compared to BM2, exhibited higher purifying ability and
      enzyme recovery for P. fluorescens GaDH. The dissociation constants (KD) of BM1
      and BM2 for P. fluorescens GaDH were determined by analytical affinity
      chromatography to be 5.9 microM and 15.4 microM, respectively. The binding
      capacities of adsorbents BM1 and BM2 were 18 U/mg adsorbent and 6 U/mg adsorbent,
      respectively. Adsorbents BM1 and BM2 were integrated in two different protocols
      for the purification P. fluorescens GaDH. Both protocols comprised as a common
      first step DEAE anion-exchange chromatography, with a second step of affinity
      chromatography on BM1 or BM2, respectively. The purified GaDH obtained from the
      protocols using BM1 and BM2 showed specific activities equal to 1077 and 854
      U/mg, respectively. The former is the highest reported so far and the enzyme
      appeared as a single band after sodium dodecylsulfate-polyacrylamide gel
      electrophoresis (SDS-PAGE) analysis.

PMID- 15032356
TI  - Protein pre-fractionation in detergent-polymer aqueous two-phase systems for
      facilitated proteomic studies of membrane proteins.
AB  - Pre-fractionation of a complex mixture of proteins increases the resolution in
      analytical separations of proteins from cells, tissues or organisms. Here we
      demonstrate a novel method for pre-fractionation of membrane proteins by a
      detergent-based aqueous two-phase system. Membrane proteins are strongly under
      represented in proteomic studies based on two-dimensional electrophoresis (2-DE).
      As a model system, we have isolated mitochondria from the yeast Saccharomyces
      cerevisiae. Mitochondrial proteins were fractionated in an aqueous two-phase
      system consisting of the polymer poly(ethylene glycol) and either of two commonly
      used non-ionic detergents, Triton X-114 or dodecyl maltoside (DDM). Soluble
      proteins partitioned mainly to the polymer phase while membrane proteins were
      enriched in the detergent phase, as identified from one-dimensional
      electrophoresis (1-DE) and/or 2-DE followed by mass spectrometric analysis. Pre
      fractionation was further enhanced by addition of an anionic detergent, sodium
      dodecyl sulfate, or a chaotropic salt, NaClO4, and by raising the pH in the
      system. The two-phase system pre-fractionation was furthermore combined with an
      alternative two-dimensional high-resolution separation method, namely ion
      exchange chromatography and 1-DE. By this approach a larger number of membrane
      proteins could be identified compared to separation with conventional 2-DE. Thus,
      pre-fractionation of complex protein mixtures using the aqueous two-phase systems
      developed here will help to disclose larger proportions of membrane proteins in
      different proteomes.

PMID- 15032357
TI  - Comparison of different sample treatments for the analysis of ochratoxin A in
      must, wine and beer by liquid chromatography.
AB  - Ochratoxin A (OTA) is a mycotoxin produced by some species of Aspergillus and
      Penicillium verrucosum. It has been found in foods and feed all over the world.
      There is a great concern about OTA because it is nephrotoxic and probably,
      carcinogenic to humans. Most of analytical methods developed for OTA in wine,
      beer and other products are based on LC with fluorescence detection (LC-FLD). In
      the present work, various procedures for extraction and/or clean-up for
      determination of OTA in musts, wine and beer by LC-FLD were compared: (1)
      dilution with polyethylen glycol 8000 and NaHCO3 solution and clean-up an on
      immunoaffinity column (IAC); (2) extraction with chloroform and IAC clean-up;
      solid-phase extraction (SPE) on (3) reversed-phase (RP) C18; (4) RP phenylsilane
      and (5) Oasis HLB cartridges. SPE on phenylsilane and Oasis HLB have not been
      reported for OTA analysis in beverages. The same LC-FLD conditions and
      concentration ratio were used. The former procedure was simple, rapid and
      provided flat baselines, free from most impurity peaks, high OTA recoveries and
      quite repeatable results. RP C18 using methanol-acetic acid (99.5:0.5) as elution
      solvent provided good recoveries and precision, thus becoming a cheaper but
      interesting alternative at 0.1-1 ng/ml spiking levels. Oasis HLB cartridges were
      usually better than phenylsilane. Possible binding of OTA to proteins or other
      components was tested by acid treatment before extraction but no significant
      differences with controls appeared.

PMID- 15032358
TI  - Chromatographic multivariate quality control of pharmaceuticals giving strongly
      overlapped peaks based on the chromatogram profile.
AB  - In the present paper, the simultaneous quantification of two analytes showing
      strongly overlapped chromatographic peaks (alpha = 1.02), under the assumption
      that both available equipment and training of the laboratory staff are basic, is
      studied. A pharmaceutical preparation (Mutabase) containing two drugs of similar
      physicochemical properties (amitriptyline and perphenazine) is selected as case
      of study. The assays are carried out under realistic working conditions (i.e.
      routine testing laboratories). Uncertainty considerations are introduced in the
      study. A partial least squares model is directly applied to the chromatographic
      data (with no previous signal transformation) to perform quality control of the
      pharmaceutical formulation. Under the adequate protocol, the relative error in
      prediction of analytes is within the tolerances found in the pharmacopeia (10%).
      For spiked samples simulating formulation mistakes, the errors found have the
      same magnitude and sign to those provoked.

PMID- 15032359
TI  - Determination of quinolones in chicken tissues by liquid chromatography with
      ultraviolet absorbance detection.
AB  - This paper presents an analytical method for the determination of quinolones in
      chicken tissues. The procedure involves pre-treatment by solid-phase extraction
      (SPE) and subsequent liquid chromatography (LC) with UV absorbance detection.
      Different SPE disposable cartridges and extractants of the tissue samples were
      tested, and various columns were systematically tested. The mobile phase was
      composed of acetonitrile and citric buffer at pH 4.5, with an initial composition
      of acetonitrile-water (12:88, v/v) and using linear gradient elution. Recoveries
      were 66-91% in the concentration range 30-300 microg kg(-1). The detector
      response was linear in this range. The limits of detection were 16-30 microg kg(
      1). These values were lower than the maximum residue limits established by the
      European Union.

PMID- 15032360
TI  - Countering matrix effects in environmental liquid chromatography-electrospray
      ionization tandem mass spectrometry water analysis for endocrine disrupting
      chemicals.
AB  - In recent years, despite the increasing success of liquid chromatography (LC)
      coupled to tandem mass spectrometry (MS), reports on matrix susceptibility have
      shown the limitations of the this powerful analytical technique. Matrix effects
      (MEs) result from co-eluting residual matrix components affecting the ionization
      efficiency of target analytes and can lead to erroneous results. The present work
      evaluates the matrix effect of environmental water samples on 35 endocrine
      disrupting chemicals (EDCs) in negative and positive LC-ESI-MS/MS. It was shown
      that mobile-phase additives could significantly influence matrix effects.
      Addition of acids resulted in a severe signal suppression (average ME%: <65%),
      and 1 mM ammonium formate increased the average ME% to 84%. The importance of an
      efficient sample clean-up and internal standardization also was demonstrated.
      Cleaner extracts resulted in reduced matrix effects (average ME%: 89%) and
      labeled internal standards proved to have a beneficial effect especially on
      signal reproducibility (average CV% 4.2% versus 2.6%). The results from the
      present work indicate that evaluation of matrix effects should become an
      integrated part of quantitative LC-ESI-MS/MS method development and validation.

PMID- 15032361
TI  - Estimation of uncertainty of analytical results based on multiple peaks.
AB  - The sources of the uncertainty of GC and HPLC analysis of pesticide residues,
      which consist of several components, and three methods applicable for the
      estimation of the uncertainty of the results are described. Different scenarios
      for estimating the uncertainty of measurements of multi-component residues are
      identified.

PMID- 15032362
TI  - Automated multiresidue analysis of pesticides in olive oil by on-line reversed
      phase liquid chromatography-gas chromatography using the through oven transfer
      adsorption-desorption interface.
AB  - A multiresidue, automated and rapid method for the determination of pesticide
      residues in olive oil is presented. The method employs the through oven transfer
      adsorption-desorption interface for the on-line coupling of reversed-phase liquid
      chromatography and gas chromatography. In this fully automated system, olive oil
      is directly injected with no sample pre-treatment step other than filtration.
      Methanol-water is used as eluent in the liquid chromatography pre-separation
      step. The selected liquid chromatography fraction containing the pesticides is
      automatically transferred to the gas chromatography. The liquid chromatography
      column flow during elution is different from the flow during the transfer. Using
      a flame ionisation detector, pesticide detection limits varied from 0.1 to 0.3
      mg/l.

PMID- 15032363
TI  - Correction of retention time shifts for chromatographic fingerprints of herbal
      medicines.
AB  - In this study, the combination of chemometric resolution and cubic spline data
      interpolation was investigated as a method to correct the retention time shifts
      for chromatographic fingerprints of herbal medicines obtained by high-performance
      liquid chromatography-diode array detection (HPLC-DAD). With the help of the
      resolution approaches in chemometrics, it was easy to identify the purity of
      chromatographic peak clusters and then resolve the two-dimensional response
      matrix into chromatograms and spectra of pure chemical components so as to select
      multiple mark compounds involved in chromatographic fingerprints. With these mark
      components determined, the retention time shifts of chromatographic fingerprints
      might be then corrected effectively. After this correction, the cubic spline
      interpolation technique was then used to reconstruct new chromatographic
      fingerprints. The results in this work showed that, the purity identification of
      the chromatographic peak clusters together with the resolution of overlapping
      peaks into pure chromatograms and spectra by means of chemometric approaches
      could provide the sufficient chromatographic and spectral information for
      selecting multiple mark compounds to correct the retention time shifts. The cubic
      spline data interpolation technique was user-friendly to the reconstruction of
      new chromatographic fingerprints with correction. The successful application to
      the simulated and real chromatographic fingerprints of two Cortex cinnamomi,
      fifty Rhizoma chuanxiong, ten Radix angelicae and seventeen Herba menthae samples
      from different sources demonstrated the reliability and applicability of the
      approach investigated in this work. Pattern recognition based on principal
      component analysis for identifying inhomogenity in chromatographic fingerprints
      from real herbal medicines could further interpret it.

PMID- 15032364
TI  - Monolayer-protected gold nanoparticles as an efficient stationary phase for open
      tubular gas chromatography using a square capillary model for chip-based gas
      chromatography in square cornered microfabricated channels.
AB  - The application of a dodecanethiol monolayer-protected gold nanoparticle (MPN)
      stationary phase within a microchannel environment was explored using a square
      capillary column as a model for high-speed, microfabricated gas chromatography
      (microGC). Successful deposition and evaluation of a dodecanethiol MPN phase
      within a 1.3 m long, 100 microm x 100 microm square capillary is reported. The
      thickness of the MPN phase was evaluated using SEM analysis. An average thickness
      of 15 nm along the capillary walls was determined. While the film depth along the
      walls was very uniform, the corner depths were greater with the largest observed
      depth being 430 nm. Overall, an efficient chromatographic system was obtained
      with a minimum reduced plate height, h(min), of 1.2 for octane (k = 0.22).
      Characterization of the MPN column was completed using four compound classes
      (alkanes, alcohols, ketones, and aromatics) that were used to form a seven
      component mixture with a 2-s separation. A mixture consisting of a nerve agent
      simulant in a sample containing analytes that may commonly interfere with
      detection was also separated in only 2 s, much faster than a similar separation
      previously reported using a microGC system requiring 50 s. A comparison of the
      MPN stationary phase to phases employed in previously reported microGC systems is
      also made. Application of the square capillary MPN column for a high-speed
      separation as the second column of a comprehensive 2-D gas chromatography system
      (GC x GC) was also explored.

PMID- 15032365
TI  - Novel flame photometric detector for gas chromatography based on counter-current
      gas flows.
AB  - A novel analytical device has been developed for gas chromatography. It is based
      on optical emission from a counter-current (i.e. counter-flowing) air or oxygen
      flame, which burns in an opposing stream of hydrogen and column effluent. The
      flame is typically positioned "upside down" on the upper (air) jet, which faces
      the lower (hydrogen + effluent) jet. It can also be positioned on the lower jet,
      be connected to both jets, or be suspended in the gap between them. Excellent
      stability can be obtained in any of these modes. Overall, this new "counter
      current flame photometric detector" (ccFPD) responds to analytes in the manner of
      a conventional flame photometric detector (FPD); however, it can be operated over
      a much wider range of gas flows. For instance, the same physical ccFPD burner
      easily supports stable flames of air flows between 5 and 200 ml/min and
      corresponding hydrogen flows between 5 and 10,000 ml/min. Visual observation of
      the counter-current flame, in the presence of sulfur and phosphorus as test
      analytes, reveals intense, steady luminescence under a wide variety of
      conditions. Additionally, and in contrast to the commercial FPD, flame
      conductivity signals can be obtained that are similar in quality to those
      produced by a conventional flame ionization detector (FID). Thus the ccFPD is a
      flexible, easily optimized photometric detector. The exceptional flow stability
      of the ccFPD was used to explore the earlier reported phenomenon of strong
      signal/noise (S/N) ratios, which had been obtained for hetero-elements of the
      iron group from a conventional FPD with a small, stoichiometric flame. Results
      using the ccFPD, which also exhibits this unusual response, indicate that these
      high S/N ratios are only partly due to the predictable decrease in flame noise
      with decreasing flame size. Contrary to expectations, the absolute analyte signal
      often increases as the flame size decreases to the point of extinction. The
      signal intensity and the magnitude of the observed changes depend to some degree
      on the flame composition (H2/O2 ratio).

PMID- 15032366
TI  - Gas chromatography of trimethylsilyl derivatives of alpha-methoxyalkyl
      hydroperoxides formed in alkene-O3 reactions.
AB  - The synthesis of trimethylsilyl (TMS) hydroperoxide derivatives for gas
      chromatography (GC) was studied using N-methyl-N-(trimethylsilyl)
      trifluoroacetamide (MSTFA) for derivatization of cumene hydroperoxide (CMOOH)
      (alpha,alpha'-dimethylbenzyl hydroperoxide) and alpha-methoxyalkyl hydroperoxides
      formed by liquid- and gas-phase ozonolysis of a series of terminal alkenes in the
      presence of methanol (CH3OH). Derivatization efficiencies >90% were achieved over
      a wide range of solution concentrations. The major compounds identified by GC
      mass spectrometry of the derivatized products of alkene-O3 reactions were alpha
      methoxyalkyl hydroperoxides, methyl esters, and aldehydes. Yields of alpha
      methoxyalkyl hydroperoxides and methyl esters were quantified using effective
      carbon numbers (ECNs) and used to determine the yields of stabilized Criegee
      intermediates (SCIs) from gas-phase ozonolysis reactions. Such measurements are
      important for understanding the atmospheric chemistry of alkene emissions. SCI
      yields measured for the reactions of 1-octene [CH3(CH2)5CH=CH2], 1-nonene
      [CH3(CH2)6CH=CH2 ], and 2-methyl-1-octene [CH3(CH2)5C(CH3)=CH2] are consistent
      with previous measurements or predictions based on literature data. SCI yields
      measured for the reactions of 1-decene [CH3(CH2)7CH=CH2], 1-dodecene [CH3
      (CH2)9CH=CH2], and 1-tetradecene [CH3(CH2)11CH=CH2] are much lower than expected,
      apparently due to side reactions with low volatility aldehydes that form
      peroxyhemiacetals, which are not amenable to GC analysis. In general, the results
      indicate that off-line MSTFA derivatization can be an efficient means for
      increasing the stability of thermally labile hydroperoxides for identification
      and quantitation by GC, and offers a new approach for the analysis of these
      environmentally important compounds.

PMID- 15032367
TI  - Quantitative determination of formaldehyde in cosmetics using a combined solid
      phase microextraction-isotope dilution mass spectrometry method.
AB  - Solid-phase microextraction (SPME) in conjunction with isotope dilution mass
      spectrometry (ID-MS) was employed for the analysis of formaldehyde in cosmetic
      products. The formaldehyde is derivatized in situ with pentafluorophenyl
      hydrazine. The formed hydrazone is adsorbed over a poly(dimethylsiloxane)
      divinylbenzene-coated fiber and analyzed using gas chromatography-mass
      spectrometry. The adsorption-time profiles and salting effect were studied. The
      quantitation was performed by using a stable isotope labeled analogue as an
      internal standard. The precision, recovery and detection limits were determined
      with spiked samples. The relative standard deviations from different spiked
      cosmetic samples were all less than 10% and the recoveries were between 89.00 and
      101.23%. The limit of detection was of 0.39 microg/l. Compared with other
      techniques, the study shown here provides a simple, fast and reliable method for
      the analysis of formaldehyde in cosmetic products.

PMID- 15032368
TI  - Capillary electrochromatography with monolithic silica columns III. Preparation
      of hydrophilic silica monoliths having surface-bound cyano groups:
      chromatographic characterization and application to the separation of
      carbohydrates, nucleosides, nucleic acid bases and other neutral polar species.
AB  - Two synthetic routes have been introduced and evaluated for the preparation of
      hydrophilic silica-based monoliths possessing surface-bound cyano functions. In
      one synthetic scheme, the silica monolith was reacted in a single step with 3
      cyanopropyldimethylchlorosilane to yield a cyano phase referred to as CN
      monolith. In a second synthetic route, the silica monolith was first reacted with
      gamma-glycidoxypropyltrimethoxysilane (gamma-GPTS), followed by a reaction with 3
      hydroxypropionitrile (3-HPN) to give a stationary phase denoted CN-OH-monolith.
      Although the gamma-GPTS was intended to play the role of a spacer arm to link the
      3-HPN to the silica surface, this spacer arm became an integral part of the
      hydrophilic stationary phase. Thus, the CN-OH-monolith can be viewed as a double
      layered stationary phase (i.e., stratified phase) with a hydroxy sub-layer and a
      cyano top layer. Due to its stronger hydrophilic character, the CN-OH-monolith
      yielded higher retention and better selectivity than the CN-monolith. The CN-OH
      monolith was demonstrated in the normal-phase capillary electrochromatography
      (CEC) of various polar compounds including phenols and chloro-substituted
      phenols, nucleic acid bases, nucleosides, and nitrophenyl derivatives of mono-
      and oligosaccharides. The CN-OH-monolith yielded a relatively strong
      electroosmotic flow over a wide range of mobile phase composition, thus allowing
      rapid separation of the polar compounds studied.

PMID- 15032369
TI  - On-capillary complexation of metal ions with 4-(2-thiazolylazo)resorcinol in
      capillary electrophoresis.
AB  - Co(II), Zn(II), Ni(II) and Fe(I) were successfully separated by capillary
      electrophoresis using pre-capillary and on-capillary complexation with 4-(2
      thiazolylazo)resorcinol. The influences of some crucial parameters, including
      both pre- and on-capillary complexation procedure, were investigated. For on
      capillary complexation, the complexing reaction was carried out inside the
      capillary by mixing the zones of ligand and sample during the electrophoretic
      migration. Compared with pre-capillary complexation, the method provided 30-fold
      reduction in detection limits for Co(II), 50-fold reduction for Zn(II), and 100
      fold reduction for Ni(II) and Fe(II). It was used for the analysis of a
      pharmaceutical and tap water sample.

PMID- 15032370
TI  - Speciation of V, Cr and Fe by capillary electrophoresis-bandpass reaction cell
      inductively coupled plasma mass spectrometry.
AB  - Capillary electrophoresis-dynamic reaction cell inductively coupled plasma mass
      spectrometry (CE-DRC-ICP-MS) for the speciation of iron(III/II), vanadium(V/IV)
      and chromium(VI/III) is described. Two different CE migration modes were employed
      for separating the six metal ions using pre-capillary complexation. One is
      counter-electroosmotic mode in which iron(III/II) and vanadium(V/IV) ions were
      well separated using a 60 cm x 75 microm i.d. fused silica capillary. The voltage
      was set at +22 kV and a 15 mmol l(-1) tris(hydroxymethyl)aminomethane (Tris)
      buffer (pH 8.75) containing 0.5 mmol l(-1) ethylenediaminetetraacetic acid (EDTA)
      and 0.5 mmol l(-1) ortho-phenanthroline (phen) was used as the electrophoretic
      buffer. The other is co-electroosmotic mode in which chromium(VI/III) ions were
      well separated while the applied voltage was set at -22 kV and a 10 mmol l(-1)
      ammonium citrate buffer (pH 7.7) containing 0.5 mmol l(-1)
      diethylenetriaminepentaacetic acid (DTPA) and 0.01% polybrene was used as the
      electrophoretic buffer. The mass spectra were measured at m/z 51, 52 and 56 for
      V. Cr and Fe, respectively. The interfering polyatomic ions of 35Cl16O+, 40Ar12C+
      and 40Ar16O+ on 51V+, 52Cr+ and 56Fe+ determination were reduced in intensity
      significantly by using NH3 as the reaction cell gas in the DRC. The detection
      limits were in the range of 0.1-0.5, 0.4-1.3 and 1.2-1.7 ng ml(-1) for V, Cr and
      Fe, respectively. Applications of the method for the speciation of V, Cr and Fe
      in wastewater were demonstrated. The recoveries were in the range of 92-120% for
      various species.

PMID- 15032371
TI  - Air/polymer distribution coefficients for polycyclic aromatic hydrocarbons by
      solid-phase microextraction sampling.
AB  - Two methods to estimate distribution coefficients (K) between air and
      poly(dimethylsiloxane) (PDMS) coating of solid-phase microextraction (SPME)
      fibers for eight low molecular polycyclic aromatic hydrocarbons (PAHs) there are
      presented. The PDMS phases were used for determination of the coefficients
      according to equilibrium theory with help of a developed static calibration
      system (SCS). Another way to estimate the coefficients is based on the use of a
      linear relationship between the logarithm of the coefficients (log K) and linear
      temperature-programmed retention indexes (LTPRI) of the compounds without
      necessity to calibrate. The log K values for both of methods ranged from 5.2
      (naphthalene) to 8.9 (pyrene) at 22 degrees C. Relative standard deviation
      (R.S.D.) of log K for each compound determined by static calibration was no more
      than 5.3%. R.S.D. of retention times for LTPRI indices did not exceed 0.28% for
      repeated injection. All experiments were implemented on a GC-MS system.

PMID- 15032372
TI  - Continuous solid-phase extraction and gas chromatographic determination of
      organophosphorus pesticides in natural and drinking waters.
AB  - A simple, rapid continuous-flow solid-phase extraction method with gas
      chromatographic detection for the determination of organophosphorus pesticides is
      proposed. The continuous system consists of an adsorbent column where pesticides
      are preconcentrated and subsequently eluted with ethyl acetate. Various sorbent
      materials were assayed of which RP-C18 was found to provide the best results,
      with a sorption efficiency close to 100%. A comparative study of the
      determination of pesticides in aqueous samples was conducted using gas
      chromatography with nitrogen-phosphorus (NPD) and flame ionization (FID)
      detection. The detection limits of the method for 10 ml of sample were between 50
      130 ng/l and 4.5-1 1.7 microg/l with NPD and FID detection, respectively. The
      method was used to determine organophosphorus pesticides in river, pond, well and
      tap waters, all with good precision (2.9-4.3%) and recoveries ranging from 93.8
      to 104.5%.

PMID- 15032373
TI  - Nonsteady-state flow in gas chromatography during fast changes in inlet pressure.
AB  - The steady-state assumption for describing the flow in a capillary gas
      chromatography column fails when changes in inlet pressure are introduced at a
      fast rate. To accommodate the possibility of nonsteady-state conditions, or a
      transient behavior, a second-order nonlinear differential equation for the
      pressure is suggested. Good agreement between the new theoretical model and
      representative experimental results is shown when the inlet pressure is increased
      at a rate of several hundred kPa per minute; in contrast, predictions from
      traditional steady-state calculations are relatively poor.

PMID- 15032374
TI  - Comparative analysis by gas chromatography-mass spectrometry of the essential
      oils from bark and leaves of Cedrelopsis grevei Baill, an aromatic and medicinal
      plant from Madagascar.
AB  - The essential oils from bark and leaves of Cedrelopsis grevei Baill
      (Ptaeroxylaceae), an aromatic and medicinal plant from Madagascar, are widely
      used in folk medicine. These two commercially available oils have been examined
      separately by means of GC-MS. The oil constituents were identified according to
      their mass spectra and their relative retention indices determined on both polar
      and non-polar stationary phase capillary columns. A total of 55 compounds have
      been identified constituting 76.7% (bark) and 91.6% (leaves) of the volatile
      constituents. Both oils were found to have a similar composition; however the
      relative percentages of some compounds notably differed. The bark essential oil
      contained beta-pinene (17.1%), cis-sesquisabinene hydrate (12.8%) and
      caryophyllene oxide (7.0%) as the main components whereas the leaf essential oil
      was largely dominated by trans-beta-farnesene (35.6%); beta-pinene (12.8%), cis
      sesquisabinene hydrate (9.8%) and ar-curcumene (8.6%) were also present as major
      components. As far as we know, this is the first report on the Cedrelopsis grevei
      bark and leaf essential oils which therapeutic properties may be attractive for
      aromatherapy.

PMID- 15032375
TI  - Perception of pediatric neurology among non-neurologists.
AB  - Pediatric neurology is considered a relatively new and evolving subspecialty. In
      Saudi Arabia, neurologic disorders in children are common, and the demand for
      trained pediatric neurologists is strong. The aim was to study the perception of
      the pediatric neurology specialty among practicing generalists and their referral
      practices. Attendees of a symposium on pediatric epilepsy comprehensive review
      for the generalist were included. A structured 25-item questionnaire was designed
      to examine their demographics, training, practice, and referral patterns. One
      hundred nineteen participants attended the symposium, and 90 (76%) questionnaires
      were returned. Attendees' ages were 22 to 70 years (mean 32 years), with 65.5%
      female physicians. There were 32% consultants, 51% trainees, and 17% students.
      Most physicians (67%) were practicing general pediatrics. Only 36% received a
      structured pediatric neurology rotation during training. Children with neurologic
      complaints constituted 28.5% of those seen in their practice, and they referred
      32.5% of them to pediatric neurology. Only 32% were moderately or highly
      confident in making the diagnosis or providing the appropriate treatment. Those
      who received a structured pediatric neurology rotation felt more comfortable in
      their management (P = .03). Many physicians (38.5%) had no direct access to a
      pediatric neurologist for referrals. To conclude, pediatric neurologic disorders
      are common in daily practice. Most generalists did not receive a structured
      neurology rotation during their training and were not highly confident in
      diagnosing and treating these children. Given the limited number of pediatric
      neurologists, I highly recommend that generalists receive appropriate neurologic
      training.

PMID- 15032376
TI  - The future of child neurology: a profile of child neurology residents.
AB  - Current workforce projections estimate that there is a shortage of child
      neurologists. We surveyed child neurology residents to learn more about the entry
      point for a career in child neurology: what attracts current residents to the
      field of child neurology and what the future career plans of child neurology
      residents are. Most respondents (52%) were exposed to child neurology for the
      first time in their third or fourth year of medical school, with 41% reporting
      that they chose the specialty at that time. US medical graduates identified
      having a mentor as one of the most influential exposures in their career choice.
      Respondents predict that they will spend less time on patient care and more time
      on research than current practicing child neurologists report. When asked about
      what could improve the attractiveness of the field, residents responded that
      medical students should get increased and earlier exposure to child neurology.
      Given the declining number of individuals pursuing a career in child neurology
      and that current residents predict that they will spend less time seeing patients
      than their predecessors do, understanding how to attract more candidates to child
      neurology will be essential to alleviate future shortages in child neurology.

PMID- 15032378
TI  - Study of seizure and epilepsy in Chinese children in Hong Kong: period prevalence
      and patterns.
AB  - The Hong Kong Children's Seizure and Epilepsy Registry was set up for all
      children with a history of seizures or epilepsy followed up in the Epilepsy
      Clinic of the University of Hong Kong. The aim was to study the pattern of
      seizures and epileptic disorders in Chinese children. The objective was to study
      the period prevalence of epilepsy and the pattern of epilepsy in Chinese
      children. A prospective study of seizure and epilepsy in Chinese children was
      conducted from 1985 to 1997 in Hong Kong. The population census of 1997 was used
      to calculate the period prevalence of epilepsy in Chinese children. Altogether,
      1103 children aged < 19 years at first assessment with epilepsy were included in
      the study. The period prevalence rate of epilepsy in 1997 (January to December)
      is estimated to be 4.5 per 1000 children aged < 19 years. The estimated period
      prevalence rate of children and adolescents with epilepsy in our children is 4.5
      per 1000 children.

PMID- 15032377
TI  - Neonatal general movements: an early predictor for neurodevelopmental outcome in
      infants with intrauterine growth retardation.
AB  - Intrauterine growth retardation plays a significant role in neurodevelopmental
      outcome. The assessment of general movements during the first 20 weeks is a new
      method for early detection of brain dysfunction. General movements in 31 infants
      with asymmetric intrauterine growth retardation and their appropriate for
      gestational age-matched controls were examined. General movements were scored as
      normal or abnormal by sequential videotape recordings in the writhing (term to 2
      weeks), early fidgety (9-11 weeks), and late fidgety (14-16 weeks) periods.
      Scores were compared between the groups and correlated with neurodevelopmental
      outcome at 2 years. The incidence of normal general movements was lower in the
      intrauterine growth retarded infants than in the controls (P < .001). Significant
      correlations were found between general movement quality and neurodevelopmental
      scores in the intrauterine growth retarded group. The fidgety movements were the
      most sensitive and specific for prediction of neurologic outcome. The general
      movement assessment can, therefore, serve as an additional tool for examining the
      neurologic status of the preterm and term intrauterine growth retarded infant.

PMID- 15032379
TI  - Effects of valproic acid on longitudinal bone growth.
AB  - Valproic acid is widely used in the treatment of children with epilepsy. Evidence
      indicates that valproic acid has teratogenic effects on the skeletal system. In
      addition, the use of valproic acid in children has been associated with short
      stature. Thus, we hypothesized that valproic acid could also affect bone growth
      after skeletal morphogenesis is completed. To test this hypothesis, we cultured
      fetal rat metatarsal bones in the presence of valproic acid. Valproic acid
      markedly suppressed metatarsal longitudinal growth. To determine the underlying
      mechanisms, we studied cell proliferation and hypertrophy in the growth plate,
      the site where bone growth takes place. At the end of the culture period,
      valproic acid-treated bones exhibited narrow growth plate proliferative and
      hypertrophic zones and an expanded ossification center. In addition, valproic
      acid suppressed chondrocyte proliferation in the metatarsal rudiments. Our
      results suggest that valproic acid suppresses longitudinal bone growth by
      inhibiting cartilage formation and accelerating ossification of the growth plate.
      These findings warrant a prospective study on the effects of valproic acid on
      growth in children treated with valproic acid.

PMID- 15032380
TI  - Guidelines for resuscitation in the delivery room of extremely preterm infants.
AB  - Ethical problems related to intensive care of extremely preterm newborns of < or
      = 25 weeks' gestational age and at risk of disability have been extensively
      debated. The Bioethical Committee of the Department of Paediatrics of the
      University Hospital of Padua organized and started a multidisciplinary group to
      release guidelines to help staff facing problems related to prematurity. The
      vitality limit, survival, outcome, and ethical aspects were analyzed.
      Consequently, we suggest the following: at 22 weeks' gestational age, the
      deliverance of comfort care only; at 23 weeks, in the presence of detectable
      vital signs, the practice of immediate intubation, respiratory support, and a
      reassessment of the neonatal conditions; and at 24 weeks, the provision of
      intubation, ventilatory support, and cardiovascular resuscitation. If the
      clinical age and anamnestic gestational age are different, we proceed according
      to the more advanced one. The importance of providing parents with correct
      information and the role of comfort care are outlined.

PMID- 15032381
TI  - Progressive multifocal leukoencephalopathy successfully treated with highly
      active antiretroviral therapy and cidofovir in an adolescent infected with
      perinatal human immunodeficiency virus (HIV).
AB  - Progressive multifocal leukoencephalopathy is an infectious demyelinating brain
      disease caused by the JC virus that is associated with significant morbidity and
      mortality in the immunocompromised host. We report a case of progressive
      multifocal leukoencephalopathy successfully treated with highly active
      antiretroviral therapy and cidofovir in an adolescent patient perinatally
      infected with human immunodeficiency virus (HIV).

PMID- 15032383
TI  - Profound infantile neuroretinal dysfunction in a heterozygote for the CLN3
      genetic defect.
AB  - The neuronal ceroid-lipofuscinoses are a group of diseases that are characterized
      by progressive neuroretinal symptomatology, progressive accumulation of
      autofluorescing waxy lipopigments (ceroid-lipofuscin) within the brain and other
      tissues, and cerebral atrophy. Juvenile neuronal ceroid-lipofuscinosis, or Batten
      disease, is a form of neuronal ceroid-lipofuscinosis that is characterized by
      onset of neuroretinal symptoms between 4 and 10 years. Juvenile neuronal ceroid
      lipofuscinosis is the most common type of neuronal ceroid-lipofuscinosis in the
      United States and Europe and is inherited as an autosomal recessive genetic
      disorder. Research in the last decade has led to the identification of the
      responsible gene for juvenile neuronal ceroid-lipofuscinosis, which is designated
      as CLN3. CLN3 is located on chromosome 16p11.2-12.1. The major mutation is a 1.02
      kb deletion, which removes exons 7 and 8. Both homozygotic and heterozygotic
      deletions at the CLN3 gene site have been associated with the clinical syndromes
      of juvenile neuronal ceroid-lipofuscinosis. We report a possible atypical case of
      neuronal ceroid-lipofuscinosis, an infant, who presented at 5 months of age with
      a lack of developmental milestones, poor vision, severe retinopathy, intractable
      seizures, and progressive cerebral atrophy. Extensive laboratory investigations,
      including thorough metabolic evaluations, were unremarkable except for
      neuroimaging studies, electroencephalography, and electroretinography, all of
      which showed abnormalities confirming both cerebral and retinal degeneration.
      Although skin and conjunctival biopsies did not show classic fingerprint
      cytosomes by electron microscopic study, which characterize juvenile neuronal
      ceroid-lipofuscinosis, a diagnosis of an atypical form of juvenile neuronal
      ceroid-lipofuscinosis was suspected on the basis of the clinical picture. The
      retinal abnormalities, surprisingly, were those believed to be diagnostic of
      juvenile-onset neuronal ceroid-lipofuscinosis, or Batten disease. Subsequently, a
      heterozygous mutation for the common 1.02 kb deletion characteristic of juvenile
      neuronal ceroid-lipofuscinosis was established.

PMID- 15032382
TI  - Poor outcome for neonatal-type nonketotic hyperglycinemia treated with high-dose
      sodium benzoate and dextromethorphan.
AB  - Neonatal-type nonketotic hyperglycinemia treatment remains unsatisfactory, even
      if started early. A review of six patients who underwent treatment for neonatal
      type nonketotic hyperglycinemia in our hospital is presented. All patients were
      treated with a standardized protocol. Medical histories were retrieved from case
      notes. All six patients had elevated cerebrospinal fluid plasma glycine levels
      initially. All but one had received sodium benzoate and dextromethorphan from 1
      month of age. All suffered from intractable seizures and severe mental
      retardation, and only two patients remain alive. One patient died at 5 days of
      age. No resuscitation was attempted in accordance with the family's wish after
      genetic counseling. The prognosis of neonatal nonketotic hyperglycinemia remains
      poor with current treatment. Genetic counseling helps parents cope with this
      devastating genetic disease.

PMID- 15032384
TI  - Peripheral leukocytosis in children with febrile seizures.
AB  - Peripheral blood leukocytosis has been reported following febrile seizures as a
      result of infection, the seizure, or both. To examine this relationship, 238
      consecutive children < 5 years of age who experienced their first febrile seizure
      were evaluated. Lumbar punctures were electively done on 128 of the children to
      rule out central nervous system infection. Total leukocyte counts and duration of
      fever before the seizure were negatively correlated (r = - .175, P < .05). In
      logistic regression analysis, the logarithm of fever duration before the seizure
      was negatively associated with leukocytosis (leukocyte count > or = 15,000
      cells/microL [odds ratio: 0.117, P < .05]). Cerebrospinal fluid glucose
      concentrations were significantly correlated with increased body temperature (r =
      .230, P < .05) and increased leukocyte counts (r = .255, P < .01). No significant
      association was found between leukocyte counts and the characteristics of the
      febrile seizure event. By all indications, changes in leukocyte counts appear
      more likely to be related to the length and underlying etiology of the fever than
      to the seizure itself.

PMID- 15032385
TI  - Infantile spasms in an infant with cytomegalovirus infection treated with
      ganciclovir.
AB  - A 3-month-old male infant with cytomegalovirus infection and intractable partial
      seizures was treated with ganciclovir for 6 weeks. The drug was well tolerated,
      and virus shedding in the cerebrospinal fluid and urine was eliminated, although
      infantile spasms at the age of 6 months appeared. At the age of 12 months,
      intractable seizures persisted, and the psychomotor development of the infant was
      markedly delayed. To our knowledge, no previous similar case has been reported.
      These findings suggest that treatment with ganciclovir of infants with
      cytomegalovirus infection results only in cessation of virus shedding in the
      cerebrospinal fluid and urine without having a preventive effect on the future
      appearance of infantile spasms. This may be due to the irreversibility of
      previous brain damage from the cytomegalovirus infection and the virostatic
      nature of the drug.

PMID- 15032387
TI  - Rectal biopsy in the diagnosis of neuronal intranuclear hyaline inclusion
      disease.
AB  - Neuronal intranuclear hyaline inclusion disease is a neurodegenerative disorder
      of childhood characterized by eosinophilic intranuclear inclusions and neuronal
      loss throughout the nervous system. Although most cases have been diagnosed
      postmortem, rectal biopsy may be diagnostic during life. We identified two
      patients: an 11-year-old boy (P1) with new-onset bulbar weakness and parkinsonism
      and a 15-year-old boy (P2) with severe cognitive and motor deterioration of
      uncertain etiology who presented at 4 years of age with a gait disturbance and
      motor slowing. Both patients had a history of behavioral problems marked by
      frequent temper tantrums. Both had nondiagnostic magnetic resonance imaging of
      the head and metabolic work-ups. Rectal biopsy was diagnostic 1 year (P1) and 11
      years (P2) after the initial evaluation. Rectal biopsies should be considered in
      children presenting with otherwise unexplained multisystem degeneration,
      particularly in the presence of both upper and lower motoneuron signs accompanied
      by behavioral problems.

PMID- 15032386
TI  - Speech and language deterioration in benign rolandic epilepsy.
AB  - A 5-year-old boy presented with typical clinical and electrophysiologic features
      of benign rolandic epilepsy. His neurodevelopment, language, and behavior prior
      to the onset of epilepsy were appropriately normal. He demonstrated marked
      deterioration of language and cognitive function during the course to a mild and
      then a moderate disability range. Serial sleep electroencephalographic recordings
      initially showed continuous and bilateral rolandic discharges with evolution to
      localized left rolandic spikes. Language and cognitive improvements were
      subsequently seen. Educational support and evolution of the electroencephalogram
      to a localized focus could have been contributory. It is anticipated, however,
      that he will have significant long-term problems in complex language.

PMID- 15032388
TI  - Benign neonatal sleep myoclonus mimicking status epilepticus.
AB  - Benign neonatal sleep myoclonus is a self-limited movement disorder characterized
      by neonatal-onset myoclonic jerks only during sleep, abrupt and consistent
      cessation with arousal, and absence of concomitant electrographic changes
      suggestive of seizures. It has a good outcome and was included in the
      differential diagnosis of neonatal seizures. A presumed transient serotonin
      imbalance and genetic factors may play a role in the pathogenesis of this
      disorder. We report a case of benign neonatal sleep myoclonus mimicking status
      epilepticus in an infant with a family history of nocturnal myoclonus, tic
      disorder, and sleep disturbance. We suggest that this benign entity should be
      included in the differential diagnosis of status epilepticus during the newborn
      period.

PMID- 15032389
TI  - Acute necrotizing encephalopathy of childhood associated with influenza type B
      virus infection in a 3-year-old girl.
AB  - Acute necrotizing encephalopathy of childhood represents a novel entity of acute
      encephalophathy, predominantly affecting infants and young children living in
      Taiwan and Japan. It manifests with symptoms of coma, convulsions, and
      hyperpyrexia after 2 to 4 days of respiratory tract infections in previously
      healthy children. The hallmark of acute necrotizing encephalopathy of childhood
      consists of multifocal and symmetric brain lesions affecting the bilateral
      thalami, brainstem tegmentum, cerebral periventricular white matter, or
      cerebellar medulla. The etiology and pathogenesis of this kind of acute
      encephalopathy remain unknown, and there is no specific therapy or prevention.
      The prognosis is usually poor, and less than 10% of patients recover completely.
      We report a 3-year-old previously healthy girl presenting with acute necrotizing
      encephalopathy of childhood associated with influenza type B virus infection,
      which resulted in severe neurologic sequelae. We also review the current
      knowledge of the clinical, neuroimaging, and pathologic aspects of acute
      necrotizing encephalopathy of childhood.

PMID- 15032390
TI  - Wilms' tumor in a case with Mobius' syndrome associated with arthrogryposis and
      mega cisterna magna.
AB  - Mobius' syndrome is a rare congenital anomaly characterized by paralysis of the
      7th and other cranial nerves and musculoskeletal abnormalities. We report a
      patient with Mobius' syndrome associated with arthrogryposis and mega cisterna
      magna in addition to the classic components of this syndrome. The case is
      interesting because she developed Wilms' tumor at 21 months of age. To our
      knowledge, this is the first case of this association reported in the literature.

PMID- 15032391
TI  - Radial nerve palsy owing to localized hypertrophic neuropathy (intraneural
      perineurioma) in early childhood.
AB  - Localized hypertrophic neuropathy, also termed intraneural perineurioma, is a
      rare disorder of unknown etiology that produces a slowly progressive painless
      focal lesion of a peripheral nerve. It is characterized histologically by
      concentric whorls ("onion bulbs") of epithelial membrane antigen-reactive, S-100
      protein-negative perineurial cells surrounding nerve fibers. We report a radial
      nerve palsy in a child aged 2 years in whom the diagnosis of localized
      hypertrophic neuropathy was made by biopsy. Resection of the affected nerve
      segment and sural nerve grafting produced no useful recovery after 3 years,
      probably because of the long duration of denervation. When this mononeuropathy
      presents in early childhood, uncertainty over the time of onset can lead to
      difficulty in distinguishing this potentially treatable lesion from congenital
      and other causes of nerve palsy.

PMID- 15032392
TI  - Pyridoxine-dependent seizures: magnetic resonance spectroscopy findings.
AB  - Pyridoxine-dependent seizures are an extremely rare genetic disorder. Early
      diagnosis and treatment are important for the prevention of permanent brain
      damage. Elevated levels of glutamate and decreased levels of gamma-aminobutyric
      acid (GABA) in the frontal and parietal cortices are among the characteristic
      features of this disorder. These metabolic abnormalities eventually lead to
      seizures and neuronal loss. In this case report, we present magnetic resonance
      spectroscopy findings of a 9-year-old girl with pyridoxine-dependent seizures
      with mental retardation. The N-acetylaspartate-to-creatine ratio was found to be
      decreased in the frontal and parieto-occipital cortices, which could indicate
      neuronal loss. Magnetic resonance spectroscopy could be a useful tool in the
      neuroimaging evaluation for assessment of parenchymal changes despite a normal
      appearing brain magnetic resonance image in patients with pyridoxine-dependent
      seizures.

PMID- 15032393
TI  - Lies, damned lies, and medical experts.

PMID- 15032394
TI  - Central pontine and extrapontine myelinolysis owing to disequilibrium syndrome.

PMID- 15032395
TI  - Discontinuation of anticonvulsant therapy and the electroencephalogram.

PMID- 15032397
TI  - Chemokines in Kawasaki disease: measurement of CCL2, CCL22 and CXCL10.
AB  - Kawasaki disease (KD) is a childhood-onset vascular disease. In order to
      determine whether KD is associated with altered chemokine production, we measured
      CCL2, CCL22, and CXCL10 levels in the serum of KD patients and healthy control
      subjects. The mean serum concentration of CCL2 in KD subjects was 829.0 +/- 388.2
      pg/ml, significantly higher than that seen in healthy controls (223.4 +/- 92.6
      pg/ml; p < 0.001). In addition, the mean serum CXCL10 level in KD subjects was
      2,469.4 +/- 998.8 pg/ml, again significantly higher than that in healthy controls
      (127.7 +/- 64.2 pg/ml; p < 0.001). No difference was observed in serum
      concentrations of CCL22 between KD and healthy controls (1,685 +/- 1,985
      microg/ml and 1,539 +/- 380 microg/ml, respectively). Thus, we observed the
      selective induction of a TH1-associated (CXCL10) and a TH2-associated chemokine
      (CCL2) in the serum of individuals with KD, suggesting a mixed TH1/TH2 response
      at the level of chemokine production and subsequent cell recruitment and thus
      pointing at a potential role for these chemokines in the pathology of KD.

PMID- 15032396
TI  - The role of food allergens in childhood asthma.
AB  - Eighty-eight patients' sera with allergen-specific IgE levels elevated only to
      food allergens were collected between October 1997 and March 2002 at the National
      Taiwan University Hospital. Thirty-three of the patients fulfilled the diagnostic
      criteria of asthma and were included. Most (72.7%) patients had elevated serum
      allergen-specific IgE levels only to one food allergen. The most common food
      allergens were milk and egg white. The patients with elevated soy bean-specific
      IgE levels had significantly higher levels of serum food allergen-specific IgE
      than those with either elevated milk or egg white-specific IgE levels. This study
      investigated some food allergen responses of asthmatic patients whose serum
      allergen-specific IgE levels were elevated only to food allergens. The results
      suggested that the allergic asthmatic response in our patients was most likely
      related to food rather than aeroallergens or fungal allergens.

PMID- 15032398
TI  - Induction of inflammatory cell accumulation using human mast cell tryptases.
AB  - The aim of this study was to investigate the effects of human tryptases on
      inflammatory cell accumulation in vivo. Various concentrations of purified lung
      or skin tryptases were injected into the peritoneum of BALB/c mouse. At 6 hours
      or 16 hours following injection, cells from the peritoneal lavage were collected
      and stained with modified Wright's stain. Differential cell counts were performed
      and results were expressed as absolute numbers of each cell type per mouse
      peritoneum. The results showed a dose-dependent infiltration of neutrophils with
      a maximal increase of up to 32 fold or 43 fold in numbers at 16 hours following
      an injection of skin and lung tryptases, respectively. Skin tryptase was able to
      attract more eosinophils than lung tryptase. Significant increases in lymphocyte
      and macrophage numbers were also observed. In conclusion, both skin and lung
      tryptases are able to induce nucleated cell accumulation in the peritoneum of
      mice with similar specificity and potency.

PMID- 15032399
TI  - Immunophenotypic profile of adult acute myeloid leukemia (AML): analysis of 267
      cases in Thailand.
AB  - Little data exists in Thailand and other Southeast Asian countries regarding the
      biological characteristics of adult acute myeloid leukemia (AML). In this study,
      we performed a flow cytometric analysis of 267 Thai adult AML cases to delineate
      the pattern of leukemic cell surface antigens. Forty-eight cases (18%) were
      identified as acute promyelocytic leukemia (M3) and 219 cases as non-M3. The most
      frequent subtype of AML in Thailand was M1/M2 and the least frequent was M7. M3
      immunophenotypes were characterized by their unique lack of expression of CD34
      and HLA-DR as contrast to the high mean expression of 50% and 70%, respectively,
      in non-M3. Overall, 60% of cases expressed CD34. Aberrant lymphoid antigens were
      uniquely seen in specific subtypes of Thai AML, including CD19 (33% of non-M3 vs
      23% of M3) and CD2 (12% of M3 vs 2% of non-M3). CD56 was frequently expressed in
      both M3 and non-M3 while CD16 appeared to be associated with M4/M5 (24% of cases)
      and CD7 with M1/M2 (21% of cases). Eighty-one percent of non-M3 expressed CD38
      while only 53% of M3 did. We found that most Thai adult AML patients were on
      average 15-20 years younger than those of the West or Japan with only 25% of Thai
      cases over 60 years of age, although the immunophenotypes were not markedly
      different. Biological studies of acute leukemia in various countries should help
      to provide epidemiological clues that play a role in the pathogenesis of leukemia
      in different geographic regions of the world. Our study represents the largest
      series of AML ever investigated in the Southeast Asian region.

PMID- 15032400
TI  - Determination of laboratory reference ranges for lymphocyte immunophenotype
      subsets in healthy adult Japanese using flow cytometry.
AB  - This study represents a comprehensive evaluation of normative values for
      lymphocyte immunophenotype subsets using flow cytometry techniques in a Japanese
      population. Lymphocyte reference ranges were determined for percentage and
      absolute count of T, B, and NK cells in healthy adult Japanese using an extensive
      two-color immunophenotyping panel and consistently applied quality control
      methodology. Reference values were also determined for activation markers on CD3+
      lymphocytes CD3+/CD25+, CD3+/CD38+ and CD3+/HLA-DR+. Differences in age and
      gender were observed for specific lymphocyte subsets. Comparison of the Japanese
      study with a Thai multi-center study that used similar methodology also
      demonstrated ethnic differences in lymphocyte reference ranges. The results in
      this study strongly suggest that reference values derived from studies in one
      population may not be applied to another population even when similar protocols
      for reagents, instruments and procedures are used although such studies do appear
      useful for epidemiological comparisons.

PMID- 15032401
TI  - Preliminary clinical evaluation of a protein chip for tumor marker serodiagnosis
      of various cancers.
AB  - This preliminary study aimed to investigate sensitivity and specificity of a
      protein chip system for multi-tumor marker serodiagnosis of ten types of cancers,
      and to understand the possible clinical applications of this protein chip for the
      Thai population. The specific cancers diagnosed by this protein chip are lung,
      breast, liver, cervix, colo-rectal, stomach, ovary, esophagus, prostate and
      pancreas cancers. We analyzed 215 serum samples of which 165 were obtained from
      clinically confirmed cancer patients and 50 from healthy people with no evidence
      of cancer. The sensitivity and specificity of the protein chip were 82.4% and
      94.0%, respectively. The success rate of the protein chip for detecting all 10
      types of cancers varied from 57% to 100%. The value of the simultaneous
      measurement of multiple tumor markers using the protein chip for cancer screening
      lied in the higher sensitivity compared to using single tumor markers for each
      type of cancer. In short, protein chips may be useful in mass screening for
      cancer during health checkups as well as for metastasis follow-up of cancer
      patients.

PMID- 15032402
TI  - Prevalence of bancroftian filariasis on the Thai-Myanmar border.
AB  - To achieve the goal of eliminating lymphatic filariasis by the year 2020, close
      monitoring systems and effective control strategies need to be implemented and
      the real disease burden needs to be assessed. Bancroftian filariasis is endemic
      at the Thai-Myanmar border. However, there are only limited data on the
      prevalence of this disease in Thailand available. We employed microscopic
      examination, together with ELISA kits to detect W. bancrofti-specific Og4C3
      circulating antigen and specific anti-filarial IgG4 antibodies to determine the
      burden of bancroftian filariasis in an endemic area at the Thai-Myanmar border in
      Umphang District, Tak province, Thailand. A total of 433 Thai-Karen blood samples
      were analyzed. The microfilarial rate determined by microscope was 6% and the W.
      bancrofti-specific Og4C3 antigenemia rate was 22%, while the specific anti
      filarial IgG4 antibody rate was 54%. There were statistically significant higher
      levels of W. bancrofti-specific Og4C3 antigen in the microfilaremic-antigenemic
      group than in the amicrofilaremic-antigenemic group (unpaired Student's t-test; p
      < 0.001), similar to the specific anti-filarial IgG4 antibody results (unpaired
      Student's t-test; p < 0.001). A statistically significant correlation of moderate
      degree between the presence of W. bancrofti-specific Og4C3 antigen and of
      specific anti-filarial IgG4 antibody was found in the amicrofilaremic group (r =
      0.474, p < 0.001), but not in the microfilaremic group (r = 0.291, p > 0.05). Our
      study revealed a very high prevalence of bancroftian filariasis in this endemic
      area and thus emphasized the importance of using highly sensitive and specific
      diagnostic tools to evaluate the true prevalence of the disease.

PMID- 15032403
TI  - Anergy testing in patients with head and neck cancer.
AB  - Patients with head and neck cancer were found to be deficient in were not clear
      [correction] Possible explanations include a change in T-lymphocyte numbers,
      particularly the helper/suppressor T-cell ratio, with the cause of this change
      still unknown. Tumor immunosuppressing factors and cancer-induced
      immunosuppression are proposed to be such causes. The deficiency of T cells
      resulted in an impaired cell-mediated immune response (CMIR), which lowered the
      host resistance, such facilitating the tumor to spread. As the CMIR can be
      evaluated by delayed hypersensitivity skin testing (= anergy screen), the
      objective of this study was to compare the CMIR function of patients with head
      and neck cancer to a non-cancer control group using this anergy screen. The study
      group consisted of 20 patients (17 males, 3 females, age range 10-76 years) with
      head and neck cancer, which were anti-HIV negative and had not received any
      therapy yet. The control group consisted of another 20 persons (17 males, 3
      females, age range 21-72 years) without any cancer and who were also anti-HIV
      negative. Exclusion criteria were (1) eczema or skin disease in the area to be
      tested, (2) having received oral prednisolone within the last week and (3) an
      anti-HIV positive immune status. The antigens used in this study consisted of PPD
      (5 IU), tetanus toxoid (TT) (0.8 LF/ml and 1.6 LF/ml, Candida albicans (20 PNU/
      ml and 200 PNU/ml), mumps-measles-rubella (MMR) vaccine (1:10 v/v and 1:5 v/v).
      The test was done by intradermal injection of 0.1 ml of each antigen. The anergy
      screen was considered positive when the test resulted in an erythema or
      induration larger than 5 mm at 72 hours after the injection. Complete anergy was
      diagnosed when there was no skin reaction at all, partial anergy when only 1
      antigen tested positive and no anergy when there were positive skin reactions to
      two or more antigens. In the study group, 9 (45%) patients were diagnosed with
      complete anergy, 11 (55%) with partial anergy and none with no anergy, while in
      the control group, none were complete anergic, 3 (15%) were partially anergic and
      17 (85%) had no anergy. There was a statistically significant difference (p <
      0.01) between these two groups. In conclusion, patients with head and neck cancer
      seemed to have an impaired CMIR, with at least the partial anergy being
      statistical significantly different compared to the non-cancer group.

PMID- 15032405
TI  - [Bentall intervention: 15 years later].

PMID- 15032404
TI  - Oral disodium cromoglycate and ketotifen for a patient with eosinophilic
      gastroenteritis, food allergy and protein-losing enteropathy.
AB  - We present a case report of a 10 years old boy with protein-losing enteropathy
      and eosinophilic gastroenteritis who had positive histamine release tests,
      increased allergen-specific IgE antibodies to some food items, and low levels of
      total serum protein and albumin. Upper gastrointestinal endoscopy revealed a
      number of polyps and diffuse gastritis. Biopsy specimens of the stomach and
      duodenum showed widespread eosinophilia and neutrophilia. Although a restricted
      diet was recommended, a diet which excluded foods with positive results to both
      histamine release test and allergen-specific IgE antibodies was poorly tolerated,
      and the patient rejected systemic administration of corticosteroids. Thus, we
      initiated an oral disodium cromoglycate (DSCG) and ketotifen therapy. After oral
      DSCG and ketotifen administration, the patient's condition improved gradually.
      Therefore, oral DSCG and ketotifen therapy might be considered as treatment
      option in patients with eosinophilic gastroenteritis and protein-losing
      enteropathy caused by food allergy.

PMID- 15032406
TI  - [Long term survival with the Bentall button operation in 150 patients].
AB  - Between May 1980 and May 2000, 150 patients (123 males and 27 females) underwent
      surgery with the same surgeon for ascending aortic replacement with a valvular
      conduit and coronary reimplantation with the aid of a collar of aortic wall
      (button technique). The average age was 50 +/- 16 years. Within this population,
      114 patients had isolated annulo-ectasial disease, 36 had Marfan syndrome and 20
      had dissection (5 acute and 15 chronic). A carbon fibre valve with 2 leaflets was
      implanted in 124 patients, a mono-leaflet valve in 20 and 6 others required a
      heterograft due to their age or a contra-indication to anticoagulation. The
      associated procedures were: 12 arch replacements, 5 myocardial
      revascularisations, 4 mitral replacements, 1 tricuspid plasty, 1 inter-atrial
      communication closure. In 30 patients (20%) there was a cardiovascular surgical
      re-intervention. The operative and first month mortality amounted to one sudden
      death on the 19th day, ie 0.6%. Three patients were lost to follow up. The
      average survival was 7.87 +/- 5.37 years (minimum 1, maximum 20 years). The
      actuarial survival was 85% at 10 years and 60% at 20 years. These figures are
      much higher than those reported in our previous statistics from 1994 when the
      percentage of survivors at 12 years was only 61%. In the group of patients
      undergoing surgery before 60 years of age, the survival at 14 years was 94% and
      81% at 20 years. Only four late re-interventions were attributable to the Bentall
      procedure, of which 2 were left coronary ostium stenoses. The rate of thrombosis
      and embolism was 0.42 per 100 patient-years and the rate of haemorrhagic
      accidents was identical, including minor accidents. This considerable improvement
      in long-term prognosis is explicable by the adoption of a single operative
      technique, considered to be the best, with the best myocardial protection thanks
      to coronary retro-perfusion and cold or hot cardioplegia, and also without doubt
      with the best medical survival.

PMID- 15032407
TI  - [Value of the association of D-dimer measurement and the evaluation of clinical
      probability in a non-invasive diagnostic strategy of pulmonary embolism].
AB  - New diagnostic tools in suspected pulmonary embolism complete the classical
      diagnostic strategy of pulmonary scintigraphy and pulmonary angiography to limit
      the indications of these two invasive investigations. In a prospective series of
      204 consecutive patients with suspected pulmonary embolism the association of D
      dimer measurement and clinical probability was assessed for the exclusion of the
      diagnosis of pulmonary embolism. The D-DI Liatest is a new generation, unitary,
      rapid and quantitative latex test with a comparative diagnostic performance to
      that of the reference ELISA test, and well adapted to emergency situations.The
      clinical probability was assessed by a quantitative score based on past history,
      clinical symptoms and signs. The positive diagnosis of pulmonary embolism was
      made by spiral CT scanner and/or pulmonary angiography, associated with Duplex
      ultrasonography of the leg veins in nondiagnostic results. The prevalence of
      pulmonary embolism was 42.6% and the absence of anticoagulation in patients
      considered not to have pulmonary embolism was associated with a thrombo-embolic
      incidence of 0.9% at 3 months. Fifty-six patients had D-dimer concentrations
      equal or inferior to the threshold of 500 microg/L; the sensitivity was 99% and
      the specificity 47% with a negative predictive value of 98% to 100% in cases with
      a low clinical probability. D-dimer measurement is reliable and has a high cost
      benefit value in ambulatory patients with suspected of pulmonary embolism and is
      even more valuable when the clinical probability of this diagnosis is low.

PMID- 15032408
TI  - [Localization of mitral valve prolapse zones with multiplane transesophageal
      echocardiography].
AB  - CONTEXT: There are few literature data on the localization and extent of mitral
      valve prolapse zones with transesophageal echocardiography (TEE). AIM OF THE
      STUDY: To assess a standardized imaging technique for the localization and extent
      determination of prolapse zones, based on 3 easily reproducible views with
      multiplane TEE. METHODS: Seventy patients with severe mitral regurgitation due to
      valve prolapse requiring a multiplane TEE prior to surgery (valve repair or
      replacement) have been retrospectively assessed. Data of TEE on the localization
      and extent of prolapse zones have been confronted to per-operative anatomical
      observations (gold standard). RESULTS: The sensitivity of TEE for the
      identification of isolated P2 prolapse, prolapse with commisural extension,
      isolated rupture of the posterior commisure and bi-valvular prolapses were
      respectively at 96%, 88%, 86% and 80%. The corresponding specificities were from
      98% to 100%. CONCLUSIONS: The use of a standardized technique with the use of 3
      easily reproducible incidences with multiplane TEE allows a precise definition of
      the localization and extent of mitral valve prolapse zones, in order to
      potentially indicate valve repair.

PMID- 15032409
TI  - [A multicentre trial of the diagnostic value and cost of electrocardiography in
      symptoms suggesting arrhythmia with a new event recorder with transtelephonic
      transmission].
AB  - Events recorders are used for electrocardiographic documentation of symptoms of
      arrhythmia too sporadic and short lasting to be recorded by 24 hour Holter
      monitoring. However, there are no French studies comparing the value and cost of
      event recorders with conventional diagnostic methods. Recently, a new
      telediagnostic device has become available in France leading to an assessment of
      the technique. The aim of this study was to determine the value of this event
      recorder and the cost of diagnostic ECG in the assessment of presumed arrhythmic
      symptoms such as palpitations or rare tachycardia (<3 episodes per week) of short
      duration, compared with conventional techniques. Fifty-eight patients with these
      criteria were randomised, 30 to Survcard (Group I) and 28 to conventional
      diagnostic methods (Group II). The patients were comparable with respect to age,
      sex distribution, type of symptoms and associated cardiac disease. The ECG
      diagnosis of the symptoms was established in 20 cases (66.6%) of patients in
      Group I in 17 +/- 16 days, and in 14 cases (50.0%) of Group II in 23 +/- 28 days.
      The difference between the two groups was not statistically significant. The cost
      of a positive diagnosis for Group I (Survcard) varied from 0 to 228.47 Euro with
      an average of 71.22 +/- 117.02 Euro. The cost of positive diagnosis in Group II
      varied from 76.80 to 2340.41 Euro with an average of 480.39 +/- 797.41 Euro. In
      conclusion, this study showed that the percentage of patients with a positive
      diagnosis was comparable in the two groups but that the cost was 6 times higher
      in the group investigated by conventional methods than in the Survcard group
      because of more costly medical intervention.

PMID- 15032410
TI  - [Epidemiology and aetiology of cardiac failure in the Somme].
AB  - The epidemiology of cardiac failure (CF) is little known in France. Our work,
      integrated in the prospective ETICS (epidemiology and therapeutics of cardiac
      insufficiency in the Somme) study, was aimed at determining the incidence of
      hospitalisation, the epidemiological profile, the causes of CF, as well as the
      frequency of cardiac failure with preserved systolic function in the Somme.
      METHOD: Patients hospitalised for a first attack of CF from January 1 to December
      31, 2000 in one of the 11 medical establishments in the Somme were included.
      RESULTS: During this period, 799 patients were included. The male/female ratio
      was 1.05; the mean age was 75 +/- 12 years, for males it was less than for
      females (72 +/- 12 and 78 +/- 11 years respectively p < 0.001); 60% of patients
      were > 75 years. The average length of hospitalisation was 10.8 +/- 7 days. The
      hospital mortality was 8.4% (N = 67). The standardised hospital incidence was
      1.92 percent per thousand of inhabitants per year and varied from 0.06 percent
      per thousand among those under 40 years to 14.7 percent per thousand in those
      over 80 years. The left ventricular ejection fraction, evaluated in 82.8% of
      patients, was greater than 50% in 55% of cases. The 2 principal causes found
      were: ischaemic (40%) and hypertensive (39%). CONCLUSION: The hospital incidence
      of CF in the Somme during the year 2000 was 1.92 percent per thousand. The
      proportions of males and females were equivalent. This disease preferentially
      affects the elderly. CF with preserved systolic function is common (55% of
      cases), particularly in elderly subjects.

PMID- 15032411
TI  - [Infectious endocarditis with negative blood cultures].
AB  - Blood culture is a key investigation for the diagnosis of infectious endocarditis
      (IE). When negative, there are diagnostic and therapeutic problems. The aim of
      this study was to determine the frequency, the clinical features and the
      aetiological factors of IE with negative blood cultures compared with IE with
      positive blood cultures compared with IE with positive blood cultures. The
      authors undertook a retrospective review of 98 cases of patients admitted for IE
      from 1991 to 2000 to the Department of Infectious Diseases and Cardiology of
      Sousse (Tunisia). Of the 98 patients, 48 (48.9%), 29 men and 19 women with an
      average age of 34.3 years, had negative blood cultures. An infectious agent was
      identified in 7 cases (14.5%) by serology, valve culture or cerebrospinal fluid
      including Brucella (2), Coxiella (1) and Candida (1). Therefore, in 41 cases
      (42%), the cause of IE was not determined. Transthoracic echocardiography was of
      diagnostic value in 96% of cases and transoesophageal echocardiography showed
      disease not observed on transthoracic echocardiography in 5 cases. The main
      complication was cardiac failure (27 cases). The mortality was 14.5%. Comparison
      of the two groups showed that negative blood cultures were associated with a
      higher incidence of previous antibiotic therapy, extracardiac signs of IE and
      cardiac failure. Early surgical indications and mortality were the same in both
      groups. This report confirmed the high frequency of IE with negative blood
      cultures. Previous antibiotic therapy seems to be an important aetiological
      factor but cannot explain this high frequency. Methodological problems of blood
      cultures and the absence of systematic investigation for rare infectious agents
      are other possible factors.

PMID- 15032412
TI  - [Myocardial infarction and disseminated lupus erythematosus].
AB  - Myocardial infarction is an underestimated complication of disseminated lupus
      erythematosus (DLE). Its features, treatment and prognosis are poorly understood.
      From June 1988 to December 2002, out of 1572 consecutive patients admitted during
      the first hours of acute myocardial infarction with ST elevation, 7 (5 women,
      aged 38 +/- 7 years) had DLE. The commonest risk factor was smoking (N = 4).
      There was a higher incidence of anterior infarction (N = 5). The infarct occurred
      7 +/- 5 years after diagnosis of DLE. There were other complications of DLE in
      all cases. Three patients had antiphospholipid syndromes. The culprit artery was
      usually the left anterior descending (N = 5). The lesions included stenosing
      atheroma (N = 5) and extensive thrombosis (N = 5). The coronary disease was
      usually limited to a single vessel (N = 5). Revascularisation procedures include
      pre-hospital thrombolysis (N = 3) followed by immediate angioplasty (N = 2) or
      primary angioplasty (N = 4). TIMI grade 3 flow was obtained in all cases, 278 +/-
      162 min after the onset of symptoms. The clinical course was characterised by
      acute reocclusion in 3 patients, recurrent in 2 patients with an antiphospholipid
      syndrome, and death in 1 case. Acute myocardial infarction occurs in already
      complicated cases of DLE, in young patients, associating atherosclerosis and
      extensive thrombosis. The risk of early reocclusion after reperfusion is high,
      especially in cases with the antiphospholipid syndrome.

PMID- 15032413
TI  - [Ankle-brachial index: an essential component for the screening, diagnosis and
      management of peripheral arterial disease].
AB  - The measurement of the ankle-brachial index (ABI) or the ankle/arm ratio provides
      a simple, rapid and cheap method for the evaluation of the distal perfusion of
      lower limbs. A decreased value underlines an altered arterial state. Thus, ABI is
      an excellent marker of peripheral arterial disease, even prior to the occurrence
      of functional symptoms. Beyond the diagnosis of peripheral arterial disease, ABI
      is nowadays known as a marker of atherosclerosis and a cardiovascular marker.
      Hence, ABI appears not only as a tool in the functional assessment of lower limbs
      perfusion, but also a local and general marker of atherosclerosis and
      cardiovascular events. The aim of this paper is to update data on the usefulness
      of ABI through a general review, and to present open issues. After a focus on the
      methodology of ABI measurement, the diagnostic value of ABI will be presented in
      this paper.

PMID- 15032414
TI  - [Ankle-brachial index: a marker of atherosclerosis and cardiovascular prognosis].
AB  - This article is the second part of a general review on ankle-brachial index
      (ABI). After stressing on the interest of ABI for the diagnosis, screening and
      follow-up of peripheral arterial disease, this second part focuses on the
      usefulness of ABI in the evaluation of cardiovascular prognosis. Many large scale
      epidemiological studies evidenced the predictive abilities of ABI in general
      population or in high-risk subgroups, such as diabetics. A low ABI corresponds to
      a risk excess of total and cardiovascular mortality, cardiac events and stroke.
      The interest of ABI in this issue overpasses the simple increased probability of
      presence of concomitant atherosclerotic lesions in a patient with peripheral
      arterial disease. Beyond the primary prevention, a low ABI in patients with
      coronary artery disease appears to be of poorer prognosis. In the future,
      according to the results of ongoing studies, it is possible that ABI measurement
      and the detection of any abnormal result would be followed by a more aggressive
      therapeutic management.

PMID- 15032415
TI  - [Quantification of mitral regurgitation in 2003].
AB  - Doppler echocardiography is the method of choice for quantifying mitral
      regurgitation. There are methods, especially those based on the study of the zone
      of convergence or proximal isovelocity which are remarkable advances in this
      indication. The results are compared with those of other semi-quantitative
      parameters. The comparison and concordance of these results provides a reliable
      evaluation of the severity of the regurgitation in over 90% of cases. In this
      article, the authors review the different approaches to quantification, their
      indications and limitations.

PMID- 15032416
TI  - [Troponins and chronic renal failure in dialysis patients].
AB  - Cardiovascular disease is a major cause of morbidity and mortality in dialysed
      patients with chronic renal failure. The diagnostic and prognostic value of
      cardiac troponin T (TnTc) and I (TnIc) has been questioned in this setting.
      Dialysed chronic renal failure patients often have raised TnTc and TnIc in the
      absence of acute ischaemic symptoms. This increase is the consequence of minor
      myocardial damage due to coronary artery disease, left ventricular hypertrophy
      and endothelial dysfunction. Abnormal catabolism and differences in the
      liberation or detection of bound or free forms of the troponins may also
      contribute to the finding of raised TnTc in asymptomatic chronic renal failure
      patients. In this population, TnTc has a better prognostic value than TnIc for
      the identification of patients at greater risk (mortality). Increased TnTc in
      asymptomatic dialysed chronic renal failure justifies a thorough cardiovascular
      work-up to diagnose ischaemia, left ventricular hypertrophy (which should be a
      target for treatment) and left ventricular dysfunction, especially in diabetic
      renal failure and when non-emergency surgery or renal transplantation are
      planned. The troponins (mainly TnTc) retain their value for stratification of
      risk in acute coronary syndromes of patients with renal failure. An invasive
      strategy and pharmacological treatment (at adapted doses), identical to those
      considered for patients with normal renal function, should be discussed in
      dialysis patients with chronic renal failure admitted for acute coronary
      syndromes with raised troponins.

PMID- 15032417
TI  - [Thrombosis caused by active rapamycin stents].
AB  - We report the case history of a patient aged 68 years presenting with a
      recurrence of anterior myocardial infarction complicated by cardiogenic shock
      with a thrombosis of an active rapamycin stent 77 days following the angioplasty
      procedure. This was provoked by stopping platelet anti-aggregant treatment, a
      diabetic background and in the context of scheduled surgery for cancer
      recurrence. Recent data in the literature combined with our observations prompt
      the continuation of anti-aggregant bi therapy for at least 9 months after
      endoprosthesis insertion even if an active stent is used. In the case where
      surgery is envisaged, it is necessary to wait at least 6 months after the
      rapamycin stent revascularisation procedure. If an extra-cardiac procedure is
      envisaged during the angioplasty, it would be preferable to not use an active
      stent.

PMID- 15032418
TI  - [Acute myocardial infarction in myocardial bridge treated by coronary stent].
AB  - The authors report the case of a symptomatic myocardial bridge treated in the
      acute phase of anterior wall myocardial infarction by classical stenting of the
      mid and distal left anterior descending artery. One and a half months later,
      intrastent restenosis at the two dilated sites, led to another angioplasty
      procedure with implantation of sirolimus-eluding stents. The outcome was good
      with no recurrence of angina at 16 months and control coronary angiography was
      totally normal at the 8th month.

PMID- 15032419
TI  - [Aspergillus flavus endocarditis on a native valve].
AB  - A 33 year old female had febrile aplasia following a first chemotherapy treatment
      for acute T lymphoid leukaemia. She was transferred to intensive care for acute
      respiratory distress due to bilateral pneumonia with Stenotrophomonas maltophilia
      septicaemic shock. After an initial improvement with antibiotic treatment, she
      developed multiple necrotic cutaneous lesions. A skin biopsy showed the presence
      of Aspergillus flavus in large quantities in the vascular lumina.
      Echocardiography revealed a voluminous vegetation on the mitral valve supporting
      aspergillus endocarditis. Despite antifungal treatment, shock and coma developed
      rapidly. Cerebral CT scan suggested multiple septic emboli. Within several hours,
      the scenario progressed towards multiorgan failure leading the death of the
      patient. Aspergillus endocarditis is exceptional and usually only occurs in
      immunosuppressed patients. The diagnosis is difficult, and the prognosis is
      appalling with a mortality greater than 90% despite treatment.

PMID- 15032420
TI  - Genetic relationships between sex-specific traits in beef cattle: mature weight,
      weight adjusted for body condition score, height and body condition score of
      cows, and carcass traits of their steer relatives.
AB  - Data from the first four cycles of the Germplasm Evaluation Program at the U.S.
      Meat Animal Research Center (USMARC) were used to investigate genetic
      relationships between mature weight (MW, n = 37,710), mature weight adjusted for
      body condition score (AMW, n = 37,676), mature height (HT, n = 37,123), and BCS
      (n = 37,676) from 4- to 8-yr old cows (n = 1,800) and carcass traits (n = 4,027)
      measured on their crossbred paternal half-sib steers. Covariance components among
      traits were estimated using REML. Carcass traits were adjusted for age at
      slaughter. Estimates of heritability for hot carcass weight (HCWT); percentage of
      retail product; percentage of fat; percentage of bone; longissimus muscle area;
      fat thickness adjusted visually; estimated kidney, pelvic, and heart fat
      percentage; marbling score; Warner-Bratzler shear force; and taste panel
      tenderness measured on steers were moderate to high (0.26 to 0.65), suggesting
      that selection for carcass and meat traits could be effective. Estimates of
      heritability for taste panel flavor and taste panel juiciness were low and
      negligible (0.05 and 0.01, respectively). Estimates of heritability from cow data
      over all ages and seasons were high for MW, AMW, and HT (0.52, 0.57, 0.71;
      respectively) and relatively low for BCS (0.16). Pairwise analyses for each
      female mature trait with each carcass trait were done with bivariate animal
      models. Estimates of genetic correlations between cow mature size and carcass
      composition or meat quality traits, with the exception of HCWT, were relatively
      low. Selection for cow mature size (weight and/or height) could be effective and
      would not be expected to result in much, if any, correlated changes in carcass
      and meat composition traits. However, genetic correlations of cow traits, with
      the possible exception of BCS, with HCWT may be too large to ignore. Selection
      for steers with greater HCWT would lead to larger cows.

PMID- 15032421
TI  - Elliptical selection experiment for the estimation of genetic parameters of the
      growth rate and feed conversion ratio in rabbits.
AB  - Two elliptical selection experiments were performed in two contemporary sire
      lines of rabbits (C and R) in order to optimize the experimental design for
      estimating the genetic parameters of the growth rate (GR) and feed conversion
      ratio (FCR). Twelve males and 19 females from line C, and 13 males and 23 females
      from line R, were selected from an ellipse defined by a quadratic index based on
      these traits. Data from 160 rabbits of each of the parental generations of lines
      C and R and their offspring (275 and 266 animals, respectively) were used for the
      analysis. A Bayesian framework was adopted for inference. Marginal posterior
      distributions of the genetic parameters were obtained by Gibbs sampling. An
      animal model including batch, parity order, litter size, and common environmental
      litter effects was assumed. Posterior means (posterior standard deviations) for
      heritabilities of GR and FCR were estimated to be 0.31 (0.10) and 0.31 (0.10),
      respectively, in line C and 0.21 (0.08) and 0.25 (0.12) in line R. Posterior
      means of the proportion of the variance due to common litter environmental
      effects were 0.14 (0.06) and 0.21 (0.06) for GR and FCR, respectively, in line C
      and 0.17 (0.06) and 0.22 (0.06) in line R. Posterior means of genetic correlation
      between both traits were -0.49 (0.25) in line C and -0.47 (0.32) in line R,
      indicating that selection for GR was expected to result in a similar correlated
      response in FCR in both lines.

PMID- 15032423
TI  - Genetic response to selection for weaning weight or yearling weight or yearling
      weight and muscle score in Hereford cattle: efficiency of gain, growth, and
      carcass characteristics.
AB  - An experiment involving crosses among selection and control lines was conducted
      to partition direct and maternal additive genetic response to 20 yr of selection
      for 1) weaning weight, 2) yearling weight, and 3) index of yearling weight and
      muscle score. Selection response was evaluated for efficiency of gain, growth
      from birth through market weight, and carcass characteristics. Heritability and
      genetic correlations among traits were estimated using animal model analyses.
      Over a time-constant interval, selected lines were heavier, gained more weight,
      consumed more ME, and had more gain/ME than the control. Over a weight-constant
      interval, selected lines required fewer days, consumed less ME, had more
      efficient gains, and required less energy for maintenance than control. Direct
      and maternal responses were estimated from reciprocal crosses among unselected
      sires and dams of control and selection lines. Most of the genetic response to
      selection in all three lines was associated with direct genetic effects, and the
      highest proportion was from postweaning gain. Indirect responses of carcass
      characteristics to selection over the 20 yr were increased weight of carcasses
      that had more lean meat, produced with less feed per unit of gain. At a constant
      carcass weight, selected lines had 1.32 to 1.85% more retail product and 1.62 to
      2.24% less fat trim and 10/100 to 25/100 degrees less marbling than control. At a
      constant age, heritability of direct and maternal effects and correlations
      between them were as follows: market weight, 0.36, 0.14, and 0.10; carcass
      weight, 0.26, 0.15, and 0.03; longissimus muscle area, 0.33, 0.00, and 0.00;
      marbling, 0.36, 0.07, and -0.35; fat thickness, 0.41, 0.05, and -0.18; percentage
      of kidney, pelvic, and heart fat, 0.12, 0.08, and -0.76; percentage of retail
      product, 0.46, 0.05, and -0.29; retail product weight, 0.44, 0.08, -0.14; and
      muscle score, 0.37, 0.14, and -0.54. Selection criteria in all lines improved
      efficiency of postweaning gain and increased the amount of salable lean meat on
      an age- or weight-constant basis, but carcasses had slightly lower marbling
      scores.

PMID- 15032422
TI  - Evaluation of Simmental carcass EPD estimated using live and carcass data.
AB  - This study was conducted to compare carcass EPD predicted using yearling live
      animal data and/or progeny carcass data, and to quantify the association between
      the carcass phenotype of progeny and the sire EPD. The live data model (L)
      included scan weight, ultrasound fat thickness, longissimus muscle area, and
      percentage of intramuscular fat from yearling (369 d of age) Simmental bulls and
      heifers. The carcass data model (C) included hot carcass weight, fat thickness,
      longissimus muscle area, and marbling score from Simmental-sired steers and cull
      heifers (453 d of age). The combined data model (F) included live animal and
      carcass data as separate but correlated traits. All data and pedigree information
      on 39,566 animals were obtained from the American Simmental Association, and all
      EPD were predicted using animal model procedures. The genetic model included
      fixed effects of contemporary group and a linear covariate for age at
      measurement, and a random animal genetic effect. The EPD from L had smaller
      variance and range than those from either C or F. Further, EPD from F had highest
      average accuracy. Correlations indicated that evaluations from C and F were most
      similar, and L would significantly (P < 0.05) re-rank sires compared with models
      including carcass data. Progeny (n = 824) with carcass data collected subsequent
      to evaluation were used to quantify the association between progeny phenotype and
      sire EPD using a model including contemporary group, and linear regressions for
      age at slaughter and the appropriate sire EPD. The regression coefficient was
      generally improved for sire EPD from L when genetic regression was used to scale
      EPD to the appropriate carcass trait basis. The EPD from C and F had similar
      linear associations with progeny phenotype, although EPD from F may be considered
      optimal because of increased accuracy. These data suggest that carcass EPD based
      on a combination of live and carcass data predict differences in progeny
      phenotype at or near theoretical expectation.

PMID- 15032424
TI  - The effect of dietary docosahexaenoic acid on the expression of porcine lipid
      metabolism-related genes.
AB  - To study the effect of dietary docosahexaenoic acid (DHA) on the expression of
      adipocyte determination and differentiation-dependent factor 1 (ADD1) mRNA in pig
      tissues, weaned, crossbred pigs (30 d of age) were fed either 2% (as-fed basis)
      tallow or DHA oil for 18 d. Body weight of the pigs was not affected by different
      dietary fatty acid (FA) compositions. The plasma and liver FA composition
      reflected the composition of the diet. The adipose tissue and skeletal muscle FA
      composition only partially reflected the diet, indicating either a slower FA
      turnover or that a greater proportion of the FA in these tissues is from
      endogenous FA synthesis. The ADD1 is an important transcription factor that
      modulates transcription of FA synthase to regulate the endogenous FA synthesis in
      the liver and adipose tissue. The ADD1 mRNA was decreased (P < 0.05) in the liver
      of DHA-treated pigs compared with that of the tallow-treated pigs. The diets did
      not have an effect on the ADD1 mRNA in pig adipose tissue. The ADD1 transcript
      was not detected in pig skeletal muscle. These results indicate that significant
      enrichment of liver DHA content inhibits the expression of ADD1 mRNA. Such an
      effect is similar to that reported in porcine differentiating adipocytes cultured
      with DHA. The liver and muscle acyl CoA oxidase mRNA concentration was increased
      (P < 0.05) by DHA oil treatment, suggesting that DHA treatment may increase
      peroxisomal fatty acid oxidation in these two tissues. Our present observations
      demonstrate that dietary DHA enrichment not only affects tissue DHA concentration
      but also mildly modifies the expression of genes related to fatty acid metabolism
      in the porcine liver and skeletal muscle.

PMID- 15032425
TI  - Pregnancy rates of mares inseminated with semen cooled for 18 hours and then
      frozen.
AB  - The ability to ship cooled stallion sperm for subsequent freezing at a facility
      specializing in cryopreservation would be beneficial to the equine industry.
      Stallion sperm has been centrifuged, cooled to 5 degrees C for 12 h, and frozen
      without a detrimental effect on motility in a previous study; however, no
      fertility data were available. Experiment 1 compared the post-thaw motility of
      sperm cooled for 18 h at 15 or 5 degrees C at either 400 or 200 x 10(6) sperm/mL
      and then frozen. Storage temperature, sperm concentration, or the interaction of
      temperature and concentration had no effect on total (TM) and progressive
      motility (PM) after cooling. Post-thaw TM and PM were higher for control than (P
      < 0.05) for treated samples. There was no difference in post-thaw TM and PM due
      to temperature or concentration. Experiment 2 further evaluated procedures for
      cooling before freezing. Ejaculates were either cooled to 5 degrees C for 18 h
      and centrifuged, centrifuged at room temperature and then cooled to 5 degrees C
      for 18 h before freezing, or centrifuged and frozen immediately (control). There
      was no difference among treatments on post-thaw TM or PM. In Exp. 3, mares were
      inseminated with semen that had been extended in skim milk-egg yolk without
      glycerol, centrifuged, resuspended at 200 x 10(6) sperm/mL, cooled to 5 degrees C
      for 18 h, and then frozen or not cooled for 18 h before freezing (control).
      Pregnancy rates did not differ for mares receiving semen cooled and then frozen
      (21 of 30, 70%) or semen frozen directly without prior cooling (16 of 30, 53%).
      In summary, a procedure was developed for cooling stallion sperm for 18 h before
      freezing without a resultant decrease in fertility.

PMID- 15032426
TI  - Ability of intravaginal progesterone inserts and melengestrol acetate to induce
      estrous cycles in postpartum beef cows.
AB  - Postpartum anestrous interval in beef cows is a major factor contributing to
      reproductive failure during a defined breeding season. Our objectives were to
      determine the ability of a controlled internal drug-releasing device (CIDR, 1.9 g
      of progesterone), a normal dose of melengestrol acetate (MGA, 0.5 mg x cow(-1) x
      d(-1)), or a high dose of MGA (4.0 mg x cow(-1) x d(-1)) to induce ovulation and
      to eliminate short estrous cycles. Multiparous beef cows (n = 100) were equally
      assigned to one of four treatments: CIDR, normal MGA, high MGA, or control by
      age, days postpartum, body condition, and body weight. All cows were fed carrier
      (0.9072 kg x cow(-1) x d(-1)) with (normal MGA, 0.55 mg/kg; high MGA, 4.41 mg/kg)
      or without MGA for 7 d (d -6 to 0). On d -6, CIDR were inserted and then removed
      on d 0. Estrous behavior was monitored continuously from d -6 until 29 using
      HeatWatch electronic mount detectors. Blood was collected on d -13, and three
      times weekly from d -6 to 29. Treatment influenced (P = 0.03) the percentage of
      cows that were detected in standing estrus. Beginning on d 2, more CIDR-treated
      cows had exhibited standing estrus compared with high MGA-treated or control
      cows, but CIDR- and normal MGA-treated cows did not differ. The percentage of
      CIDR-treated cows that had ovulated was greater (P < 0.05) than the percentage of
      normal MGA-treated, high MGA-treated, or control cows beginning on d 4. The
      percentage of cows that exhibited standing estrus before the first postpartum
      ovulation (CIDR = 65%, normal MGA = 57%, high MGA = 35%, control = 30%) did not
      differ (P = 0.09) among treatments. Luteal life span following the first
      ovulation postpartum and the percentage of cows with a normal luteal life span
      (i.e., progesterone > 1 ng/mL for > or = 10 d) was greater (P < 0.01) in CIDR
      treated cows (14.0 +/- 0.8 d; 20/20, 100%) compared with normal MGA-treated (6.2
      +/- 1.0 d; 3/13, 23%), high MGA-treated (9.6 +/- 1.0 d; 8/14, 57%), or control
      cows (6.1 +/- 0.9 d; 4/17, 24%), and greater (P < 0.03) in high MGA-treated cows
      than in normal MGA-treated or control cows. In the present study, treatment of
      early postpartum suckled beef cows with CIDR induced ovulation and initiated
      estrous cycles with a normal luteal life span in more cows than did treatment
      with MGA. Treatment with MGA (normal or high dose) did not induce ovulation
      earlier than in control cows, but a high dose of MGA increased the percentage of
      cows with normal luteal life spans following the first ovulation postpartum.

PMID- 15032427
TI  - Effect of phytase addition and dietary calcium and phosphorus levels on plasma
      metabolites and ileal and total-tract nutrient digestibility in pigs.
AB  - Two experiments were conducted to determine the effect of phytase on plasma
      metabolites and AA and energy digestibility in swine. In Exp. 1, eight barrows
      (surgery BW = 52 kg) were fitted with steered ileocecal cannulas. The experiment
      was a Latin rectangle and the treatments were 1) corn-soybean meal diet adequate
      in Ca and P (0.5% Ca, 0.19% available P [aP]), 2) corn-soybean meal diet with
      reduced Ca and P (0.4% Ca, 0.09% aP), 3) Diet 1 with 500 phytase units/kg, or 4)
      Diet 2 with 500 phytase units/kg. Pigs were fed twice daily to a total daily
      energy intake of 2.6 x maintenance (106 kcal of ME/kg of BW(0.75)). For each
      ileal digesta sample, digesta samples were collected for two 24-h periods and
      combined for each pig. The combination of supplementing with phytase and
      decreasing the concentration of dietary Ca and P increased average ileal AA (P <
      0.02), starch (P < 0.02), GE (P < 0.04), and DM (P < 0.03) digestibilities. In
      Exp. 2, a feeding challenge was conducted with barrows (eight per treatment;
      average BW of 53 kg). The treatments consisted of a corn-soybean meal diet or
      corn-soybean meal diet + 500 phytase units per kilogram of diet. In the diet with
      no phytase, Ca and aP were at 0.50% and 0.19%, respectively, and, in the diet
      with phytase, Ca and aP were each decreased by 0.12%. A catheter was surgically
      inserted into the anterior vena cava of each pig 6 d before the start of the
      feeding challenge. The barrows were penned individually, and the diets were fed
      for 3 d before the challenge. The pigs were held without feed for 16 h, and blood
      samples were obtained at -60, -30, and 0 min before the pigs were fed (2% of BW).
      Blood samples were then collected at 10, 20, 30, 40, 50, 60, 75, 90, 105, 120,
      150, 180, 210, 240, 270, and 300 min after feeding. Glucose area under the
      response curve and plasma glucose, insulin, urea N, and total alpha-amino N
      concentrations were increased (P < 0.05) in pigs fed the diet with reduced Ca and
      P and the phytase addition. Area under the response curve for insulin, urea N,
      and total alpha-amino N; insulin:glucose; and plasma NEFA concentration,
      clearance, and half-life were not affected by diet. In conclusion, the
      combination of Ca and P reduction and phytase addition increased nutrient and
      energy digestibility in diets for pigs and increased plasma concentrations of
      glucose, insulin, urea N, and alpha-amino N.

PMID- 15032429
TI  - Performance and carcass quality of steers fed whole raw soybeans at increasing
      inclusion levels.
AB  - Two experiments were conducted to determine the efficacy of whole raw soybeans as
      a partial or whole replacement for soybean meal in a corn/soybean meal-based
      feedlot diet. In Exp. 1, 80 crossbred steers (average BW = 441.3 kg) and, in Exp.
      2, 96 Angus-sired steers (average BW = 413.7 kg) were blocked by weight and
      assigned randomly to one of four dietary treatments. Treatments were 0, 8, 16,
      and 24% dietary inclusions of whole raw soybeans. Diets within experiments were
      isonitrogenous. Across experiments, diets were similar, differing only in amount
      of corn silage (8 vs. 15% DM) at the expense of whole, shelled corn for Exp. 1
      and Exp. 2, respectively. No treatment differences were observed for ADG or final
      BW. Dry matter intake from d 0 to d 58 decreased linearly (P < 0.05) with
      increased inclusion of whole raw soybeans in Exp. 1, with no effect on feed
      efficiency. In Exp.2 from d 0 to 72, whole raw soybean inclusion had no effect on
      DMI or feed efficiency. There tended (P < 0.10) to be a linear reduction in hot
      carcass weight when whole raw soybeans were included in Exp. 1. Unexpectedly,
      longissimus muscle area tended (P < 0.10) to respond quadratically (P < 0.10) to
      the increased inclusion of whole raw soybeans in Exp.1. No differences were
      detected in marbling score, 10th-rib backfat, or yield grade for Exp. 1 and 2
      steers. In Exp. 2, inclusion of whole raw soybeans had no effect on hot carcass
      weight or longissimus muscle area. Incrementally increasing the inclusion of
      whole raw soybeans in the diet of feedlot steers had little overall effect on
      weight gain, feed efficiency, or carcass quality in Exp. 1 and 2. There were
      subtle differences in the treatment responses observed for hot carcass weight and
      longissimus muscle area between Exp. 1 and Exp. 2 for the 24% inclusion level.
      These noted differences may indicate that inclusion levels above 24% might not be
      beneficial.

PMID- 15032428
TI  - Digestibility of nitrogen and amino acids in soybean meal with added soyhulls.
AB  - This study was designed to quantify the effect of soyhulls on N and AA
      digestibilities of soybean meal for growing pigs. Soyhulls were incorporated into
      17% CP diets containing 33.25% soybean meal (SBM) at 0, 3, 6, or 9% (as-fed
      basis) and fed to 35-kg barrows to determine their effect on apparent and true
      digestibility of DM, GE, N, and AA measured at the terminal ileum. Positive and
      negative control diets containing 1.05% lysine were formulated with 35% SBM and
      27% soy protein concentrate (SPC), respectively. A low-protein, casein-based diet
      was used to estimate endogenous AA losses. Soyhulls were incorporated into
      experimental diets at the expense of cornstarch, and SBM levels were adjusted to
      accommodate the contribution of CP from soyhulls. Fourteen pigs were surgically
      fitted with simple T-cannula at the distal ileum and fed the seven semipurified
      cornstarch diets based on a replicated 7 x 7 Latin square design. Each period
      lasted 7 d, with diet acclimation from d 1 to 5 and ileal sample collection for
      12 h on d 6 and 7. Feed was offered at a level of 90 g/kg BW(0.75) in two equal
      portions at 0800 and 2000. Apparent ileal digestibilities of DM and GE decreased
      approximately six percentage units with the addition of soyhulls (linear, P <
      0.05), whereas N was not affected. Both apparent and true ileal digestibilities
      of arginine, histidine, lysine, phenylalanine, aspartic acid, serine, and
      tyrosine also exhibited a decrease (linear, P < 0.05) of up to five percentage
      units with the addition of soyhulls. True ileal lysine digestibility of SBM
      decreased from 90.3 to 87.7% with the addition of 9% soyhulls. The endogenous
      nutrient fraction measured at the distal ileum was rich in proline, glutamic
      acid, and glycine, with losses greater than 1,000 mg/kg of DMI for each AA, and
      contained minimal amounts of tryptophan, methionine, and cystine. The current
      data suggest that a 0.2% decrease in some true ileal indispensable AA
      digestibilities may result with each 1% increase in soyhull inclusion in
      semipurified diets containing SBM as the sole source of AA as fed to growing
      pigs.

PMID- 15032430
TI  - Technical note: A proposed method to determine the extent of degradation of a
      feed in the rumen from the degradation profile obtained with the in vitro gas
      production technique using feces as the inoculum.
AB  - A method is proposed to determine the extent of degradation in the rumen
      involving a two-stage mathematical modeling process. In the first stage, a
      statistical model shifts (or maps) the gas accumulation profile obtained using a
      fecal inoculum to a ruminal gas profile. Then, a kinetic model determines the
      extent of degradation in the rumen from the shifted profile. The kinetic model is
      presented as a generalized mathematical function, allowing any one of a number of
      alternative equation forms to be selected. This method might allow the gas
      production technique to become an approach for determining extent of degradation
      in the rumen, decreasing the need for surgically modified animals while still
      maintaining the link with the animal. Further research is needed before the
      proposed methodology can be used as a standard method across a range of feeds.

PMID- 15032431
TI  - Differing effects of forage and concentrate diets on the oleic acid and
      conjugated linoleic acid content of sheep tissues: the role of stearoyl-CoA
      desaturase.
AB  - Feeding sheep concentrate-based diets increases the oleic acid content of their
      tissues, whereas the cis-9, trans-11 conjugated linoleic acid (CLA) content is
      increased by feeding forage diets. Both these metabolic transformations could be
      attributable to increased activity of stearoyl-CoA desaturase (SCD). Therefore,
      the effect of forage or concentrate feeding regimens on the fatty acid
      composition of sheep tissues were investigated to determine whether any changes
      are related to an alteration of SCD mRNA levels. Twenty-four ewe lambs were
      randomly allotted to one of three dietary treatment groups: 1) dehydrated grass
      pellets, 2) concentrate diet fed to achieve a growth rate similar to that of the
      dehydrated grass pellets, and 3) the same concentrate diet approaching ad libitum
      intake. As expected, animals fed ad libitum concentrates grew at a greater (P =
      0.001) rate (280 g/d) than those fed either of the other two diets (180 g/d),
      which were similar. In samples of liver and the three adipose tissue depots
      studied, the concentration of oleic acid from sheep fed either level of the
      concentrate diet was greater (P < 0.001) than from animals fed forage. This was
      associated with an increase (P < 0.05) in the ratio of SCD to acetyl-CoA
      carboxylase mRNA in adipose tissue and liver. Compared with concentrate-fed, the
      forage-fed lambs had increased (P < 0.05) levels of the cis-9, trans-11 isomer of
      CLA and C18:1, trans-11 in all their tissues, although the levels of SCD mRNA
      were lower. It therefore seems that the increased oleic acid content of sheep
      tissues in response to concentrate-rich diets is associated with an increase in
      SCD gene expression. By contrast, the increased concentration of CLA in animals
      fed forage-based diets is associated with an increase in substrate (C18:1 trans
      11) availability.

PMID- 15032432
TI  - Histidine utilization by growing steers is not negatively affected by increased
      supply of either ammonia or amino acids.
AB  - Two experiments were conducted with ruminally cannulated Holstein steers to
      determine effects of N supply on histidine (His) utilization. All steers received
      2.5 kg DM/d of a diet based on soybean hulls; abomasal infusion of 250 g/d amino
      acids, which supplied adequate amounts of all essential amino acids except His;
      abomasal infusion of 300 g/d glucose; and ruminal infusion of 180 g/d acetate,
      180 g/d propionate, and 45 g/d butyrate. Both experiments were 6 x 6 Latin
      squares with treatments arranged as 3 x 2 factorials. No significant (P < 0.05)
      interactions between main effects were noted for N balance criteria in either
      Exp. 1 or 2. For Exp. 1, steers (146 +/- 7 kg) received 0, 1.5, or 3 g/d of L-His
      infused abomasally in combination with 0 or 80 g/d urea infused ruminally to
      supply a metabolic ammonia load. Urea infusions increased (P < 0.05) ruminal
      ammonia concentration from 8.6 to 19.7 mM and plasma urea from 2.7 to 5.1 mM. No
      change in N retention occurred in response to urea (35.1 and 37.1 g/d for 0 and
      80 g/d urea, respectively, P = 0.16). Retained N increased linearly (P < 0.01)
      with His (31.5, 37.8, and 39.0 g/d for 0, 1.5, and 3 g/d L-His, respectively).
      Efficiency of deposition of supplemental His between 0 and 1.5 g/d averaged 65%.
      In Exp. 2, steers (150 +/- 6 kg) were infused abomasally with 0 or 1 g/d of L-His
      in combination with no additional amino acids (Control), 100 g/d of essential +
      100 g/d of nonessential amino acids (NEAA+EAA), or 200 g/d of essential amino
      acids (EAA). Retained N increased (P = 0.02) from 34.2 to 38.3 g/d in response to
      His supplementation. Supplementation with NEAA+EAA increased (P < 0.05) N
      retention (33.9, 39.3, and 35.6 g/d for Control, NEAA+EAA, and EAA,
      respectively), likely in response to increased energy supply. Plasma urea
      concentrations of steers receiving NEAA+EAA (3.8 mM) and EAA (3.8 mM) were
      greater (P < 0.05) than those of Control steers (2.7 mM). The average efficiency
      of His utilization was 63%, a value similar to the value of 65% observed in Exp.
      1, as well as the 71% value predicted by the Cornell net carbohydrate and protein
      system model. Under our experimental conditions, increases in N supply above
      requirements, as either ammonia or amino acids, did not demonstrate a metabolic
      cost in terms of His utilization for whole-body protein deposition by growing
      steers.

PMID- 15032433
TI  - Effects of biological type and dietary fat treatment on factors associated with
      tenderness: I. Measurements on beef longissimus muscle.
AB  - The objective was to evaluate chemical, mechanical, and sensory attributes
      associated with tenderness in divergent cattle breeds--Wagyu (W; n = 12),
      Limousin (L; n = 12) and F1-cross (WxL; n = 12)--fed two dietary treatments (0 or
      6% sunflower oil (DM basis)). A randomized complete block repeated measures
      design in a 3 x 2 factorial arrangement of treatments was used, and effects of
      breed, diet, block, and associated interactions were tested. Cattle were fed
      barley-based diets for an average of 259 d. Twenty-four hours postmortem (PM),
      steaks from the longissimus muscle (LM) were sliced, vacuum-packaged, aged (1, 3,
      7, 14, 28, and 56 d PM) at 2 degrees C, and frozen (-40 degrees C) until
      analyzed. Wagyu steaks had lower (P < 0.05) Warner-Bratzler shear force (WBSF)
      values than L steaks across all aging times. At 1 d PM, W steaks required
      slightly more (P > 0.05) force to shear than WxL or L (0.30 and 0.11 kg,
      respectively); however, by d 14 PM, W steaks required 0.77 kg less (P < 0.05)
      force to shear than L. Wagyu steaks received higher (P < 0.05) sensory panel
      sustained tenderness scores at d 14 PM than L. The pH decline was slower (P <
      0.05), and temperature decline more (P < 0.05) rapid, in W carcasses than L or
      WxL carcasses. Breed and diet did not affect (P > 0.10) free calcium levels (FCL)
      over time (0, 1, 3, 7, and 14 d PM), 0-h calpastatin activity (CA), d-1 percent
      collagen (OH-PRO), or d-1 collagen cross-linking (HP). Western blot analysis for
      the presence of the troponin-T (TNT) 30-kDa fragment, conducted only on samples
      from steers fed the 0% sunflower oil diet, demonstrated more proteolysis by d 3
      PM in L than W or WxL. Overall, breed differences in mechanical and sensory
      measures of tenderness were not explained by FCL, CA, OH-Pro, and HP. Even though
      the initial appearance of the TNT 30-kDa fragment was greater in L, linear slopes
      for appearance of TNT degradation product across aging time were greater for W
      and WxL (P < 0.01 and P = 0.056, respectively) than for L, suggesting that
      tenderness differences due to breed may have been facilitated by more-rapid
      proteolytic degradation over time.

PMID- 15032434
TI  - Effects of biological type and dietary fat treatment on factors associated with
      tenderness: II. Measurements on beef semitendinosus muscle.
AB  - The objective of this study was to evaluate attributes in semitendinosus muscle
      (ST) associated with tenderness in divergent breeds--Wagyu (W; n = 12), Limousin
      (L; n = 12), and Wagyu x Limousin cross cattle (WxL; n = 12)--fed two dietary
      treatments (0 or 6% sunflower oil, DM basis). A randomized complete block
      repeated measures design with a 3 x 2 factorial arrangement of treatments was
      used to measure effects of breed, diet, block, and associated interactions.
      Cattle were fed barley-based diets for an average of 259 d. Temperature and pH
      were measured at 0, 1, 3, 6, 12, and 24 h postmortem (PM). Steaks from the ST
      were removed 24 h postmortem, vacuum-packaged, aged (1, 3, 7, 14, 28, and 56 d
      postmortem) at 2 degrees C, and frozen (-40 degrees C) until analyzed. Dietary
      treatment did not (P > 0.10) affect Warner-Bratzler shear force (WBSF), collagen
      amount (OH-PRO) or cross-linking (HP), temperature, or pH. Steaks from WxL aged
      14 d postmortem had lower (P < 0.05) WBSF values than L (W were intermediate).
      Cooking time was longer (P < 0.01) in W and WxL than in L; however, breed did not
      affect (P > 0.10) cooking loss. Cooking time was not influenced by diet, but
      steaks from cattle fed 6% sunflower oil had lower (P < 0.05) cooking losses.
      Temperature decreased more (P < 0.05) rapidly, and pH more slowly (P < 0.05), in
      W and WxL than L in the first 24 h postmortem. Limousin steaks were lighter
      (higher L*) and more yellow (higher b*) in color than steaks from W and WxL (P <
      0.05). The control diet (no oil added) resulted in steaks that were lighter (P <
      0.05) than the treatment diet (6% added sunflower oil). Neither breed nor diet
      affected (P > 0.10) OH-PRO or HP concentration. The results of this study
      indicate that biological type differences may not be as great in the ST as in
      longissimus muscle; thus, to increase tenderness in ST, emphasis may need to be
      placed on processing and cooking techniques rather than genetic selection.

PMID- 15032435
TI  - Influence of early postmortem protein oxidation on beef quality.
AB  - The objective of this study was to examine the effect of early postmortem protein
      oxidation on the color and tenderness of beef steaks. To obtain a range of
      oxidation levels, the longissimus lumborum muscles (LM) from both strip loins of
      20 steers fed either a finishing diet with vitamin E (1,000 IU per steer daily,
      minimum of 126 d [VITE]; n = 10 steers) or fed the same finishing diet without
      vitamin E (CON; n = 10 steers) were used. Within 24 h after slaughter, the LM
      muscle from each carcass was cut into 2.54-cm-thick steaks and individually
      vacuum packaged. Steaks from each steer were assigned to a nonirradiated group or
      an irradiated group. Steaks were irradiated within 26 h postmortem, and were aged
      at 4 degrees C for 0, 1, 3, 7, and 14 d after irradiation. Steaks from each
      diet/irradiation/aging time treatment were used to determine color, shear force,
      and degree of protein oxidation (carbonyl content). Steaks from steers fed the
      VITE diet had higher (P < 0.01) alpha-tocopherol contents than steaks from steers
      fed the CON diet. Immediately following irradiation, steaks that had been
      irradiated had lower (P < 0.05) L* values regardless of diet. Irradiated steaks,
      regardless of diet, had lower a* (P < 0.05) and b* (P < 0.01) values than
      nonirradiated steaks at all aging times. Carbonyl concentration was higher (P <
      0.05) in proteins from irradiated steaks compared to nonirradiated steaks at 0,
      1, 3, and 7 d postirradiation. Immunoblot analysis showed that vitamin E
      supplementation decreased the number and extent of oxidized sarcoplasmic
      proteins. Protein carbonyl content was positively correlated with Warner-Bratzler
      shear force values. These results indicate that increased oxidation of muscle
      proteins early postmortem could have negative effects on fresh meat color and
      tenderness.

PMID- 15032437
TI  - Evaluation of sampling, cookery, and shear force protocols for objective
      evaluation of lamb longissimus tenderness.
AB  - Experiments were conducted to compare the effects of two cookery methods, two
      shear force procedures, and sampling location within non-callipyge and callipyge
      lamb LM on the magnitude, variance, and repeatability of LM shear force data. In
      Exp. 1, 15 non-callipyge and 15 callipyge carcasses were sampled, and Warner
      Bratzler shear force (WBSF) was determined for both sides of each carcass at
      three locations along the length (anterior to posterior) of the LM, whereas slice
      shear force (SSF) was determined for both sides of each carcass at only one
      location. For approximately half the carcasses within each genotype, LM chops
      were cooked for a constant amount of time using a belt grill, and chops of the
      remaining carcasses were cooked to a constant endpoint temperature using open
      hearth electric broilers. Regardless of cooking method and sampling location,
      repeatability estimates were at least 0.8 for LM WBSF and SSF. For WBSF,
      repeatability estimates were slightly higher at the anterior location (0.93 to
      0.98) than the posterior location (0.88 to 0.90). The difference in repeatability
      between locations was probably a function of a greater level of variation in
      shear force at the anterior location. For callipyge LM, WBSF was higher (P <
      0.001) at the anterior location than at the middle or posterior locations. For
      non-callipyge LM, WBSF was lower (P < 0.001) at the anterior location than at the
      middle or posterior locations. Consequently, the difference in WBSF between
      callipyge and non-callipyge LM was largest at the anterior location. Experiment 2
      was conducted to obtain an estimate of the repeatability of SSF for lamb LM chops
      cooked with the belt grill using a larger number of animals (n = 87). In Exp. 2,
      LM chops were obtained from matching locations of both sides of 44 non-callipyge
      and 43 callipyge carcasses. Chops were cooked with a belt grill and SSF was
      measured, and repeatability was estimated to be 0.95. Repeatable estimates of
      lamb LM tenderness can be achieved either by cooking to a constant endpoint
      temperature with electric broilers or cooking for a constant amount of time with
      a belt grill. Likewise, repeatable estimates of lamb LM tenderness can be
      achieved with WBSF or SSF. However, use of belt grill cookery and the SSF
      technique could decrease time requirements which would decrease research costs.

PMID- 15032436
TI  - Postmortem proteolysis is reduced in transgenic mice overexpressing calpastatin.
AB  - Using both in vitro and in vivo approaches, numerous studies have provided
      evidence that mu-calpain is responsible for postmortem proteolysis. This paper
      reports the effect of overexpression of calpastatin on postmortem proteolysis in
      transgenic mice. Transgenic mice (n = 8) with a human calpastatin gene, whose
      expression was driven by the human skeletal muscle actin promoter, were killed
      along with control nontransgenic littermates (n = 5). Hind limbs were removed and
      stored at 4 degrees C, and muscle samples were dissected at 0, 1, 3, and 7 d
      postmortem and analyzed individually. At time 0, active human calpastatin was
      expressed in transgenic murine skeletal muscle at a level 370-fold greater (P <
      0.001) than calpastatin in control mice. Although the native isoform of this
      protein was degraded with storage, at 7 d postmortem, approximately 78% of at
      death activity remained, indicating that degraded calpastatin retains activity.
      Calpain (mu- and m-) expression was unaffected (P > 0.05) by the transgene as
      assessed by immunoreactivity at d 0. Over 7 d, 33% of at-death 80-kDa isoform
      immunoreactivity of mu-calpain was lost in transgenics compared to an 87% loss in
      controls, indicating that autolysis of mu-calpain was slowed in transgenic mice.
      Desmin degradation was also inhibited (P < 0.05) in transgenics when compared to
      controls. Control mice lost 6, 78, and 91% of at-death native desmin at 1, 3, and
      7 d postmortem, respectively; conversely, transgenic mice lost only 1, 3, and 17%
      at the same times. A similar trend was observed when examining the degradation of
      troponin-T. Interestingly, m-calpain seemed to undergo autolysis in control mice,
      which in postmortem tissue is indicative of proteolysis. Further investigation
      revealed that both mu- and m-calpain are active postmortem in normal murine
      skeletal muscle. In conclusion, a high level of expression of active calpastatin
      was achieved, which, by virtue of its inhibitory specificity, was determined to
      be directly responsible for a decrease in postmortem proteolysis.

PMID- 15032438
TI  - Computer image analysis for measuring lean and fatty areas in cross-sectioned dry
      cured hams.
AB  - The aims of this study were 1) to apply computer image analysis to obtain
      measures of lean and fatty areas on the cross section of dry-cured hams, 2) to
      investigate variation of these measures, and 3) to evaluate reproducibility and
      repeatability of these techniques. Traits of concern were the cross-sectional
      area (SA), lean, or muscles, area (LA), and the fatty area (FA) centered on the
      cross section and surrounded by biceps femoris, semimembranosus, semitendinosus,
      and quadriceps femoris, as well as the FA-to-SA ratio (FESR). Hams were obtained
      from crossbred pigs (n = 279) slaughtered at 9 mo of age (mean BW of 169 +/- 17
      kg). Digital images of the cross section of dry-cured hams were captured using
      standardized procedures. Three replicated measures of areas were collected by
      three operators using three image analysis techniques (automatic, automatic
      assisted, and manual). Variance components were estimated using a linear model
      that included slaughter group, gender, and gender x slaughter group as fixed
      effects and operators, pig, and operator x pig as random effects. Statistical
      analyses considered all measures (n = 7,533) or measures collected after
      reinstruction of all operators for spatial calibration of the analysis system (n
      = 4,428). Average SA, LA, FA, and FESR were 350 cm2, 220 cm2, 8.7 cm2, and 2.5%,
      respectively. Variability of FA (CV = 42%) and of FESR (CV = 39%) was four times
      greater than that of SA and LA. Slaughter group, pig, operator, and operator x
      pig effects were the most (P < 0.01) important sources of variation of measures.
      Correlations between measures obtained with different techniques were greater (P
      < 0.01) than 0.90, with the exception of LA measures. Coefficients of
      reproducibility for SA and LA ranged from 87 to 94%, whereas those for FA and
      FESR ranged from 88 to 98%. Coefficients of repeatability ranged from 92 to 99%.
      Automatic-assisted and manual methods provided more reproducible and repeatable
      measures than the automatic technique. Spatial calibration of the software system
      was a key issue affecting reproducibility and repeatability. Reinstructing the
      analysts for spatial calibration enhanced both reproducibility and repeatability
      of all methods of analysis. Computer image analysis is a technique suitable for
      measuring lean and fatty areas in cross-sectioned hams, providing reproducible
      and repeatable measures, and it might be used in large sample-based studies to
      investigate causes of defective fatty areas.

PMID- 15032439
TI  - Prediction of lamb carcass composition by impedance spectroscopy.
AB  - The objective of this study was to compare impedance spectroscopy with resistance
      measurements at a single frequency (50 kHz) for the prediction of lamb carcass
      composition. The impedance spectrum is usually recorded by measuring the complex
      impedance at various frequencies (frequency domain); however, in this study, we
      also applied the faster and simpler measurement in the time domain (application
      of a current step and measurement of the voltage response). The study was carried
      out on 24 male, German Black-headed Mutton lambs with an average BW of 45 kg.
      Frequency- and time domain-based impedance measurements were collected at 20 min
      and 24 h postmortem with different electrode placements. Real and imaginary parts
      at various frequencies were calculated from the locus diagram. Left sides were
      dissected into lean, fat, and bone, and right sides were ground to determine
      actual carcass composition. Crude fat, crude protein, and moisture were
      chemically analyzed on ground samples. Frequency- and time domain-based
      measurements did not provide the same absolute impedance values; however, the
      high correlations (P < 0.001) between these methods for the "real parts" showed
      that they ranked individuals in the same order. Most of the time domain data
      correlated higher to carcass composition than did the frequency domain data. The
      real parts of impedance showed correlations between -0.37 (P > 0.05) and -0.74 (P
      < 0.001) to water, crude fat, lean, and fatty tissue, whereas the relations to CP
      were much lower (from 0.00 to -0.47, P < 0.05). Electrode placements at different
      locations did not substantially improve the correlations with carcass
      composition. The "imaginary parts" of impedance were not suitable for the
      prediction of carcass composition. The highest accuracy (R2 = 0.66) was reached
      for the estimation of crude fat percentage by a regression equation with the time
      domain-based impedance measured at 24 h postmortem. Furthermore, there was not a
      clear superiority of measurements in a wide frequency range over a single
      frequency measurement at 50 kHz for the prediction of carcass composition. Even
      though we calculated the impedance at 50 kHz based on the locus diagram, which
      allowed for a high precision for predicting this impedance trait, single
      frequency impedance devices typically used in practice cannot record the locus
      diagram and, therefore, exhibit a greater amount of uncertainty.

PMID- 15032440
TI  - Effect of early gestation feeding, birth weight, and gender of progeny on muscle
      fiber characteristics of pigs at slaughter.
AB  - Maternal nutrition and progeny birth weight affect muscle fiber development in
      the pig, thereby influencing early postnatal growth rate. The objective of the
      study was to determine the extent to which growth, morphometric characteristics,
      and area and distribution of slow-oxidative (SO), fast oxidative-glycolytic
      (FOG), and fast glycolytic (FG) fibers of three muscles (LM = longissimus muscle;
      RF = rectus femoris; ST = semitendinosus) of slaughter pigs were affected by DE
      intake level during the first 50 d of gestation. Multiparous Swiss Large White
      sows were assigned randomly to one of three energy intake treatments: 1) fed 2.8
      kg/d of a standard diet (STD; n = 6) containing 10.7 MJ DE/kg; 2) fed 2.8 kg/d of
      a low-energy diet (LE; n = 5) containing 6.6 MJ DE/kg; or 3) fed 4.0 kg/d of a
      standard diet (HE; n = 5) containing 10.7 MJ DE/kg (as-fed basis). Sows were
      subjected to energy intake treatments for the first 50 d of gestation; however,
      from d 51 to parturition, sows received 2.8 kg/d of the standard diet, and the
      amount of feed offered each sow during lactation was adjusted according to the
      litter size. Sows farrowed normally and pig birth weights were recorded. Based on
      birth weight, the two lightest (1.27 kg; Lt) and two heaviest (1.76 kg; Hvy)
      barrows and gilts from the 16 litters (n = 64) were selected at weaning and were
      offered a fixed amount of feed (170 g x BW(0.569)/d) from 25 to 105 kg BW.
      Regardless of the birth weight, progeny from HE sows grew slower (P < 0.05)
      during lactation and the growing-finishing period, had a lower (P < 0.05) gain-to
      feed ratios, and had higher (P < 0.05) percentages of adipose tissue than pigs
      born from LE sows. The ST was shorter (P = 0.03) in Lt than in Hvy pigs, and the
      ST of gilts was heavier (P = 0.01) and had a larger (P = 0.01) girth than the ST
      of barrows. Overall mean fiber area tended to be larger (P < or = 0.11) in the LM
      and light portion of the ST of Lt than in Hvy pigs, and was larger (P = 0.03) in
      the ST of gilts than barrows. The ST of progeny from LE sows had fewer (P < 0.10)
      FG fibers, which was compensated by either more (P < 0.05) FOG in the light
      portion of the ST, or more (P < 0.10) SO fibers in the dark portion, and these
      differences were more pronounced in Lt pigs than in Hvy pigs. Overall, maternal
      feeding regimen affected muscle fiber type distribution, whereas birth weight and
      gender affected muscle fiber area.

PMID- 15032441
TI  - Effects of dietary energy and starch concentrations for newly received feedlot
      calves: I. Growth performance and health.
AB  - Crossbred calves (n = 572; initial BW = 186 +/- 27 kg) purchased from northern
      Texas, Arkansas, and southeast Oklahoma auction markets were delivered to the
      Willard Sparks Beef Research Center, Stillwater, OK, and used to study the
      effects of dietary energy and starch concentrations on performance and health of
      newly received feedlot calves during a 42-d receiving period. On arrival, calves
      were assigned randomly to one of two dietary energy levels (0.85 or 1.07 Mcal
      NEg/kg DM) and one of two dietary starch levels (34 or 48% of ME from starch) in
      a 2 x 2 factorial arrangement of treatments. Cattle were weighed and serum
      samples were collected on d 0, 7, 14, 28, and 42. Individual animal records of
      morbidity were kept for all cases of respiratory and other disease. Nasal swabs
      were collected from each morbid animal and cultured for upper-respiratory
      pathogens. There were no energy x starch level interactions for performance or
      health response variables. Daily gain (1.14 kg/d) and gain efficiency (ADG:DMI =
      0.179) were not affected by increasing dietary energy or starch concentrations.
      Calves fed low-energy diets consumed (P < 0.05) more DM. No difference (P = 0.54)
      was detected in morbidity for calves fed high-energy (62.4% calves treated)
      compared with low-energy (65.8% calves treated) diets; however, calves fed the
      high-starch diets had numerically (P = 0.11) greater morbidity than calves fed
      low-starch diets (68.8 vs. 59.4% calves treated, respectively). There were no
      energy or starch effects on Mannheimia haemolytica or Pasteurella multocida
      antibody titers; however, day effects (P < 0.02) occurred. On d 7, 14, and 28,
      calves had antibody titers for P. multocida that were greater (P < 0.05) than
      titers on d 0. In addition, calves had greater antibody titers to M. haemolytica
      on d 7 and 14 than on d 0. Nasal swabs revealed that calves fed the high-energy
      diets tended (P = 0.06) to have a lower percentage of morbid calves with P.
      multocida during the first antimicrobial treatment and a lower percentage of
      Haemophilus somnus isolates during the first (P = 0.01) and second (P = 0.06)
      antimicrobial treatments than calves fed the low-energy diets. Although animal
      performance was not influenced, the present data suggest that feeding the high
      energy diet decreased the percentage of P. multocida and H. somnus pathogens in
      calves that received one or more antimicrobial treatments.

PMID- 15032442
TI  - Effects of dietary energy and starch concentrations for newly received feedlot
      calves: II. Acute-phase protein response.
AB  - Two hundred forty five market-stressed bull and steer calves (205 +/- 14 kg) were
      received in January and September 2001 to determine the response of acute-phase
      proteins to dietary energy and starch concentrations and to determine whether
      acute-phase proteins could be used as a diagnostic or prognostic tool for calves
      affected by bovine respiratory disease. On arrival, calves were randomly assigned
      to one of two dietary energy levels (0.85 or 1.07 Mcal of NEg/kg of DM) and one
      of two dietary starch levels (34 or 48% of dietary ME from starch; n = 5
      pens/treatment). All calves were weighed, and plasma and serum samples were
      collected from a subset of animals (n = 6 calves/pen; 30 calves/treatment) on d
      0, 7, 14, 28, and 42 of the receiving period. This subset of calves (n = 120) was
      used for all subsequent analyses. Concentrations of fibrinogen (Fb), haptoglobin
      (Hp), and serum amyloid-A (SaA) were determined. In addition, samples were
      collected from the subset of calves when they received medical treatment and 7 d
      following treatment to measure serum concentrations of Hp and SaA. Serum
      concentrations of Fb, Hp, and SaA did not differ among dietary treatments, but
      decreased (P < 0.03) as day of the receiving period increased. Fibrinogen (P <
      0.001) and the ratio of Fb:total blood protein were greater (P < 0.003) in calves
      treated multiple times than in calves never treated or treated once for bovine
      respiratory disease. In addition, on d 0 and 7, Hp concentration increased
      (antimicrobial treatment x day interaction, P < 0.03) as the number of
      antimicrobial treatments increased, and was greater on d 14 and 28 in calves
      treated multiple times than in calves never treated or treated once. Haptoglobin
      concentration was greater (P < 0.05) in calves on medical treatment days compared
      with recovery days (7 d after medical treatment). Although diet seemed to have
      little effect on acute-phase protein response, these results suggest that
      haptoglobin may be useful as a diagnostic tool to make management decisions
      regarding treatment protocols for calves with bovine respiratory disease.

PMID- 15032443
TI  - Effects of supplemental rumen-protected conjugated linoleic acid or linoleic acid
      on feedlot performance, carcass quality, and leptin concentrations in beef
      cattle.
AB  - Thirty-six Angus x Hereford heifers (365 kg) were used to determine effects of
      dietary lipid supplementation from two sources during the final 32 or 60 d of
      feeding on serum and adipose tissue leptin concentrations, animal performance,
      and carcass characteristics. Following an initial feeding period of 56 d, heifers
      were fed one of three diets in a 3 x 2 factorial arrangement: 1) basal diet, 2)
      basal diet plus 4% (DM basis) corn oil, or 3) basal diet plus 2% (DM basis) rumen
      protected conjugated linoleic acid (a mixture of Ca-salts of palm oil fatty acids
      with 31% conjugated linoleic acid). Jugular blood samples were collected at 28-d
      intervals (d 28 to 118) and serum subsequently harvested for leptin
      quantification via RIA. Real-time ultrasound measurements were collected at 28-d
      intervals across time on feed. At slaughter, samples were obtained from various
      adipose depots. Data were analyzed with dietary treatment, length of
      supplementation, adipose depot (when appropriate), and all two- and three-way
      (when appropriate) interactions in the repeated measures model. Measures of
      feedlot performance, including ADG, DMI, and gain:feed did not differ (P > 0.23)
      with dietary treatment or supplementation length. Heifers supplemented with corn
      oil tended (P < 0.07) to have higher marbling scores following 32 d of treatment
      than those supplemented with rumen-protected conjugated linoleic acid, with
      controls intermediate. Quality grade and hot carcass weight did not differ (P >
      0.15) with treatment or length of supplementation. Leptin concentrations were
      higher (P < 0.05) from d 57 to 118 on feed than the initial period (d 0 to 56) of
      dietary adaptation when all animals received the basal diet. Circulating leptin
      concentrations were not affected by dietary treatment. However, leptin
      concentrations in adipose tissues were greater (P < 0.05) for heifers
      supplemented with corn oil than either control or rumen-protected conjugated
      linoleic acid diets, which did not differ. Compared with adipose tissues from
      rumen-protected conjugated linoleic acid-supplemented animals, tissues from
      heifers fed corn oil contained 68% greater leptin concentration. Correlations
      between performance, carcass traits, and serum leptin concentrations were low.
      Serum leptin concentrations across time on feed were not associated with carcass
      and performance data, including ADG, DMI, and gain:feed. Based on these data,
      concentrations of leptin are not related to indices of feedlot performance and
      carcass quality in beef cattle.

PMID- 15032444
TI  - Evaluating longevity of composite beef females using survival analysis
      techniques.
AB  - Objectives were to 1) identify risk factors affecting the longevity of beef
      females, 2) evaluate the utility of measures collected early in life in
      predicting longevity, and 3) estimate the heritability of longevity when females
      were culled primarily for not being pregnant following a 45-d breeding season.
      Data were from 1,379 Composite Gene Combination (CGC; 1/2 Red Angus, 1/4
      Charolais, 1/4 Tarentaise) cows born from 1982 through 1999 at the USDA-ARS, Fort
      Keogh Livestock and Range Research Laboratory, Miles City, MT, and first calving
      at approximately 2 yr of age. The length of productive life was modeled using Cox
      regression to identify factors affecting the longevity of beef females. Age at
      first calving and calf birth weight did not influence longevity. Cows that
      experienced dystocia were at greater risk of being culled than those that calved
      without assistance (P < 0.01). On average, as breeding value for cow weight
      increased, the risk of being culled decreased (P < 0.01), whereas the risk of
      being culled increased with increasing maternal breeding values for preweaning
      gain (P < 0.05). Traits measured before 1 yr of age were not useful in predicting
      the subsequent longevity of cows. The heritability of functional longevity was
      estimated to be 0.14. Relatively low heritability and the lack of indicators of
      longevity expressed early in life suggest that genetic improvement of longevity
      will be difficult. Matching the genetic potential of cows for size and milk
      production to the production environment such that rebreeding performance is not
      compromised by concurrent lactation seems to be a consideration in retaining beef
      females when open cows are culled.

PMID- 15032445
TI  - Synchronization of estrus in postpartum beef cows and virgin heifers using
      combinations of melengestrol acetate, GnRH, and PGF2alpha.
AB  - The efficacy of various combinations of melengestrol acetate (MGA), GnRH, and
      PGF2alpha for the synchronization of estrus in Angus-based beef cattle was
      compared. Hormones were administered as follows: MGA, 0.5 mg x animal(-1) x d(-1)
      mixed in a grain carrier; GnRH, 100 microg i.m.; PGF2alpha, 25 mg i.m. In Exp. 1,
      2, and 3, cows were randomly assigned to treatments by parity and interval
      postpartum. The detection of estrus and AI were conducted from d -2 until 72 to
      96 h after PGF2alpha, at which time cows not detected to be in estrus received
      GnRH and fixed-time AI (TAI). Data were analyzed separately for primiparous and
      multiparous cows. In Exp. 1, cows (n = 799) at three locations received GnRH on d
      -7 and PGF2alpha on d 0 and either no further treatment (GnRH-PGF) or short-term
      MGA from d -6 through d -1 (STMGA). Among multiparous cows, conception rate at
      TAI was greater (P < 0.05) for STMGA (41%, 47/115) than for GnRH-PGF treated cows
      (26%, 24/92). Across herds and parity, synchronized AI pregnancy rate (SPR) was
      not affected (P > 0.10) by treatment (GnRH-PGF vs. STMGA; 54%, 210/389 vs. 57%,
      228/402). In Exp. 2, cows (n = 484) at three locations received either STMGA or
      long-term MGA from d -32 through d -19, GnRH on d -7, and PGF2alpha on d 0
      (LTMGA). Among primiparous cows, SPR was greater (P < 0.01) in LTMGA (65%, 55/85)
      than STMGA-treated cows (46%, 40/87). Treatment had no effect (P > 0.10) on SPR
      among multiparous cows (STMGA vs. LTMGA; 59%, 92/155 vs. 64%, 101/157). In Exp.
      3, cows (n = 838) at four locations received the LTMGA treatment and either no
      further treatment or an additional period of MGA exposure from d -6 through d -1
      (L&STMGA). Among primiparous cows, SPR tended to be influenced (P < 0.10) by the
      herd x treatment interaction and was greater (P < 0.01) among L&STMGA (86%,
      19/22) than LTMGA-treated cows (56%, 14/25) at a single location. Among
      multiparous cows, SPR was lower (P < 0.05) in L&STMGA (46%, 165/358) than LTMGA
      treated cows (55%, 184/336). In Exp. 4, Angus heifers (n = 155) received either
      STMGA or 14 d of MGA (d -32 through d -19) and PGF2alpha on d 0 (MGA-PGF). The
      detection of estrus and AI were conducted from d -2 to d 6. Interval to estrus
      was greater (P < 0.05) and estrous response was lower (P < 0.05) in STMGA than
      MGA-PGF-treated heifers. In conclusion, primiparous cows responded more favorably
      to longer-duration MGA treatments than did multiparous cows. All protocols
      achieved sufficient SPR to justify their use for improved reproductive management
      of postpartum beef cows.

PMID- 15032446
TI  - Growth rate and physiology of steers grazing tall fescue inoculated with novel
      endophytes.
AB  - Cattle grazing tall fescue (Festuca arundinacea Schreb.) often develop fescue
      toxicosis. This condition is thought to be caused by ergot alkaloids produced by
      the endophyte Neotyphodium coenophialum. Endophytes from wild tall fescue plants,
      which do not produce ergot alkaloids, were transferred into the endophyte-free
      tall fescue germplasm, HiMag. The novel associations also lacked the ability to
      produce ergot alkaloids. Our objective was to determine whether cattle grazing
      these novel endophyte associations showed signs of fescue toxicosis. At the
      Fayetteville, Arkansas location, tester steers (n = 72) were assigned to one of
      four pasture treatments: endophyte-free HiMag tall fescue (HiMag-); 'Kentucky-31'
      tall fescue infected with its native, toxic endophyte (KY+); and two novel
      endophyte-infected tall fescue associations, HiMag4 and HiMag9. At the Mount
      Vernon, Missouri location, steers (n = 54) were used to test three of the four
      cultivars (HiMag9 was not tested). Ergot alkaloid concentrations in the forage of
      HiMag4 and HiMag9 were low or undetectable. Respiration rate, rectal temperature,
      ADG, and hair scores were measured during the grazing period. Blood was collected
      via jugular venipuncture and used for prolactin, aspartate aminotransferase,
      alkaline phosphatase (ALP), lactate dehydrogenase (LDH), cholesterol,
      triglyceride, and creatinine analysis. Weight gains by steers grazing HiMag4 and
      HiMag9 did not differ from those of steers grazing HiMag-, but were greater than
      gains (P < 0.05) by steers on the KY+ treatment. Steers grazing KY+ had higher (P
      < 0.05) respiration rates, rectal temperatures, and hair scores than did steers
      grazing novel endophyte and HiMag- pastures. Prolactin, ALP, cholesterol, LDH,
      and triglycerides all were suppressed (P < 0.05) in steers grazing KY+ compared
      with steers grazing novel endophyte and HiMag- pastures. Steers grazing the novel
      endophyte tall fescues did not suffer from the decreased weight gains and
      toxicities associated with fescue toxicosis, resulting in enhanced animal
      production.

PMID- 15032447
TI  - Effect of supplementation frequency and supplemental urea level on dormant
      tallgrass-prairie hay intake and digestion by beef steers and prepartum
      performance of beef cows grazing dormant tallgrass-prairie.
AB  - Effect of supplementation frequency and supplemental urea level on forage use
      (Exp. 1) and performance (Exp. 2 and 3) of beef cattle consuming low-quality
      tallgrass-prairie were evaluated. For Exp. 1 and 2, a 2 x 2 factorial treatment
      structure was used, such that two supplements (30% CP) containing 0 or 30% of
      supplemental degradable intake protein (DIP) from urea were fed daily or on
      alternate days. In Exp. 1 and 2, supplement was fed at 0.41% BW daily or at 0.83%
      BW (DM basis) on alternate days. For Exp. 3, a 2 x 4 factorial treatment
      structure was used, such that four supplements (40% CP) containing 0, 15, 30, or
      45% of supplemental DIP from urea were fed daily or 3 d/wk. Supplements were
      group-fed at 0.32% BW daily or at 0.73% BW (DM basis) 3 d/wk. In Exp. 1, 16 Angus
      x Hereford steers (initial BW = 252 kg) were blocked by BW and assigned to
      treatment. Urea level x supplementation frequency interactions were not evident
      for forage intake, digestion, or rate of passage. Forage OM intake (OMI) and
      total digestible OMI (TDOMI) were not significantly affected by treatment. Total
      tract digestion of OM (P = 0.03) and NDF (P = 0.06) were greater for steers
      supplemented daily. In Exp. 2, 48 Angus x Hereford cows (initial BW = 490 kg)
      grazing winter tallgrass prairie were used. Significant frequency x urea
      interactions were not evident for BW and body condition (BC) change; similarly,
      the main effects were not substantive for these variables. In Exp. 3, 160 Angus x
      Hereford cows (initial BW = 525 kg) grazing dormant, tallgrass prairie were used.
      Supplement refusal occurred for cows fed the highest urea levels, particularly
      for cows fed the supplement with 45% of the DIP from urea 3 d/wk, and supplement
      refusal increased closer to calving. A frequency x urea interaction (P = 0.02)
      was observed for prepartum BW changes. As supplemental urea level increased,
      prepartum BW loss increased quadratically (P = 0.02); however, a greater
      magnitude of loss occurred when feeding supplements containing > or = 30% of DIP
      from urea 3 d/ wk. Cumulative BC change followed a similar trend. In conclusion,
      moderate protein (< or = 30% CP) supplements with < or = 30% of supplemental DIP
      from urea can be fed on alternate days without a substantive performance penalty.
      However, infrequent feeding of higher protein (> 30% CP) supplements with
      significant urea levels (> 15% of DIP from urea) may result in decreased
      performance compared with lower urea levels.

PMID- 15032448
TI  - Ruminal and host adaptations to changes in frequency of protein supplementation.
AB  - The effect of altering supplementation frequency on host N balance and key N
      transactions in the ruminal ecosystem were monitored. Four ruminally fistulated
      beef steers (BW = 513 kg; SEM = 6.5) were used in a 2 x 2 crossover design with
      two periods and two supplementation frequency treatments. Supplementation
      frequencies were 2 and 7 d/wk. Steers were fed tallgrass prairie hay (73.1% NDF,
      5.3% CP) ad libitum. Supplement (42% CP; DM basis) was fed at 0.36% BW/d to
      steers supplemented 7 d/wk. Steers supplemented 2 d/wk received the same amount
      of supplement per week, but it was equally split among the two supplementation
      events. Steers supplemented 7 d/wk had higher forage (P < 0.02) and total
      digestible OM intake (P < 0.06), total N intake, fecal N excretion, and N
      retention. Although both supplementation frequencies were characterized by
      positive N balance, the decrease in N retention in the steers supplemented 2 d/wk
      was due to higher (P < 0.01) urinary N loss. Ruminal fluid was sampled at 0, 2,
      4, 6, 12, 24, 48, and 72 h after supplementation beginning on a day when both
      treatments were supplemented. Frequency x hour interactions (P < 0.02) were
      observed for ruminal N metabolism criteria. Counts of peptide- and AA-fermenting
      bacteria peaked at 2 h and returned to nadir by 12 h for steers supplemented 7
      d/wk. Steers supplemented 2 d/wk peaked at 6 h with a greater population and
      returned to nadir at 48 h. Ruminal ammonia concentrations followed a similar
      trend. Specific activity of ammonia production was lower (P < or = 0.05)
      immediately after supplementation for steers supplemented 2 d/wk, but by 12 h was
      the same as for 7 d/wk steers. Ruminal peptides and free AA peaked at 2 h for
      steers supplemented 2 d/wk and were generally higher (P < or = 0.05) during the
      first 6 h compared with steers supplemented 7 d/wk. Total VFA concentration was
      not different (P = 0.35) due to supplementation frequency. Frequency x hour
      interactions (P < 0.01) were observed for all molar proportions of VFA. The molar
      proportion of acetate and acetate:propionate ratio were lower (P < 0.01) and the
      molar proportions of propionate and butyrate were higher for steers supplemented
      2 d/wk from 4 h to 24 h. In conclusion, forage use and N balance improved with
      supplementation 7 d/wk, but supplementation 2 d/wk was associated with some
      desirable shifts in select ruminal events that may contribute to moderating
      potential negative impacts of supplementing infrequently.

PMID- 15032449
TI  - Adipogenesis: usefulness of in vitro and in vivo experimental models.
AB  - The use of experimental models is the foundation of experimental biology, so it
      is important to know how much the models can tell us about actual animals.
      Inconsistent or contradictory results from in vitro models are often associated
      with the perception that a particular model or results are somehow wrong and
      therefore cannot tell us anything important about how an animal works. In fact,
      in vitro conditions do not create new biology. Differences between in vitro and
      in vivo behavior can only result from the actual cellular repertoire, which
      provides a powerful tool to uncover new information. Adipose tissue research
      provides a useful context for examining this issue because the regulation of
      adipose growth and metabolism has important economic implications for livestock
      production. Examples are discussed in which either excess skepticism or narrow
      interpretation of results slowed progress toward our current understanding of
      adipose biology. Similarly, contemporary examples using genomics are used to
      suggest that large inconsistencies are still apparent with in vitro methods.
      Careful consideration of these inconsistencies may provide new insights.

PMID- 15032450
TI  - Role of fatty acids in adipocyte growth and development.
AB  - Fat is typically added to diets as a source of energy. The alternative aspects
      considered here are the use of specific fats to alter the fatty acid profile of
      adipose tissue toward creation of value-added products and the potential for
      individual fatty acids to alter gene expression and control adipose tissue
      development. Emphasis is placed on the omega-3 fatty acids, such as those found
      in fish oil, and on CLA. The most common association of fatty acids with adipose
      tissue is related to their storage as triglycerides in mature adipocytes and the
      consequences of excess accumulation in obesity. Fatty acids and their derivatives
      also can have hormone-like effects and have been be shown to regulate gene
      expression in preadipocytes, which ultimately effects their proliferation and
      differentiation. Long-chain, saturated, and polyunsaturated fatty acids have been
      shown to regulate transcription factors, such as CCAAT/enhancer binding protein,
      peroxisome proliferator activated receptor, and other adipose-specific genes,
      very early in adipocyte development. These effects have the potential to affect
      fat cell number at maturity. Specifically, there is evidence that the fatty acids
      in fish oil, such as docosahexaenoic and eicosopentaenoic acids, and fatty acids
      in the CLA series, decrease preadipocyte proliferation in cell lines and reduce
      adiposity in rodents. There is little direct evidence of the ability of fatty
      acids to manipulate adipocyte development in non-rodent species. The genetic,
      nutritional, and pharmacological manipulation of adipose tissue in meat animals
      has long been of interest to animal scientists. An understanding of the ability
      of fatty acids to regulate factors such as adipocyte size and number,
      particularly in meat animals, would be of great interest. The evidence for
      regulatory roles of fatty acids in development from rodent and in vitro studies
      and their potential application to meat animals are reviewed.

PMID- 15032451
TI  - Adipose tissue angiogenesis.
AB  - A review of adipose tissue angiogenesis includes the morphological and
      cytochemical development of adipose tissue vasculature and the concept of
      primitive fat organs. Spatial and temporal relationships between fetal vascular
      and fat cell development are discussed, including depot- and genetic-dependent
      arteriolar differentiation. The relationship between connective tissue deposition
      and elaboration of adipose tissue vasculature is discussed with respect to
      regulating adipocyte development in a depot-dependent manner. In vitro studies
      indicated that depot-dependent vascular traits may be attributable to intrinsic
      growth characteristics of adipose tissue endothelial cells. These studies
      indicate that adipogenesis may be regulated by factors that drive angiogenesis.
      Fundamental aspects of angiogenesis, including basement membrane breakdown,
      vasculogenesis, angiogenic remodeling, vessel stabilization, and vascular
      permeability were reviewed. Critical angiogenic factors include vascular
      endothelial growth factor (VEGF), VEGF receptors, angiopoietins (Ang), ephrins,
      matrix metalloproteinases, and the plasminogen enzymatic system. Vascular
      endothelial growth factor is the most critical factor because it initiates the
      formation of immature vessels and disruption of a single VEGF allele leads to
      embryonic lethality in mice. Expression of VEGF is influenced by hypoxia,
      insulin, growth factors, and several cytokines. Angiogenic factors secreted
      and/or produced by adipocytes or preadipocytes are discussed. Vascular
      endothelial growth factor expression and secretion by adipocytes is regulated by
      insulin and hypoxia, and is associated with adipose tissue accretion. Vascular
      endothelial growth factor accounts for most of the angiogenic activity of adipose
      tissue. The proposed role of leptin as an adipogenic factor is reviewed with
      respect to efficacy on various aspects of angiogenesis relative to other
      angiogenic factors. The VEGF and leptin genes are both hypoxia inducible, but
      potential links between VEGF and leptin gene expression have not been examined.
      Finally, several studies including a study of mice treated with antiangiogenic
      factors indicate that adipose tissue accretion can be controlled through the
      vasculature per se.

PMID- 15032452
TI  - The adipocyte as an endocrine cell.
AB  - Communication between adipose and other tissues has been hypothesized since at
      least the 1940s to be bidirectional. Despite this expectation, early progress was
      largely limited to adipose tissue's role in metabolism and storage of fatty
      acids, its development, and its response to endocrine and neural cues. However,
      efforts of the last decade have identified several molecules that are secreted
      from adipocytes, apparently for the purpose of signaling to other tissues.
      Cloning of the mouse obesity gene in 1994 is perhaps the most famous impetus for
      recognition that adipocytes are active in the regulation of multiple body
      functions. The product of this gene, leptin, has since been found to inhibit
      feeding, enhance energy expenditure, and stimulate gonadotropes. Evidence for the
      roles of other adipocyte-derived signals is being generated. Resistin is a
      protein that can cause whole-body insulin resistance. Its expression is
      correlated with body fatness and is inhibited by thiazolidinediones, perhaps
      mediating the association of type 2 diabetes with obesity, and the effectiveness
      of these drugs. Resistin and a related molecule, RELM alpha, can also inhibit
      differentiation of preadipocytes. Adiponectin/Acrp30 secretion from adipocytes is
      diminished in obese states. This protein can enhance use of fatty acids in lean
      tissues, inhibit glucose production by liver, and consequently decrease both
      blood glucose and BW. Adiponectin may also be responsible for the effectiveness
      of thiazolidinediones, given that these drugs promote adiponectin secretion.
      Secretion of complement proteins has been observed in adipocytes, and these
      interact to generate a signal called acylation-stimulating protein, which can
      promote triacylglycerol synthesis. These signals seem to be largely unique to
      adipocytes. Other signals are derived from adipose tissue, and it is unlikely
      that all the adipocyte's endocrine signals have been identified. Certainly, there
      is much to learn about how these signals function; however, it is clear that
      these biomedical research discoveries comprise a useful model for our study of
      growth and development in livestock.

PMID- 15032453
TI  - Brown adipose tissue development and metabolism in ruminants.
AB  - We conducted several experiments to better understand the relationship between
      brown adipose tissue (BAT) metabolism and thermogenesis. In Exp. 1, we examined
      perirenal (brown) and sternum s.c. adipose tissue in 14 Wagyu x Angus neonates
      infused with norepinephrine (NE). Perirenal adipocytes contained numerous large
      mitochondria with well-differentiated cristae; sternum s.c. adipocytes contained
      a few, small mitochondria, with poorly developed cristae. Lipogenesis from
      acetate was high in BAT but barely detectable in sternum s.c. adipose tissue. In
      Exp. 2, we compared perirenal and tailhead adipose tissues between NE-infused
      Angus (n = 6) and Brahman (n = 7) newborn calves. Brahman BAT contained two-to
      three times as many total beta-receptors as Angus BAT. The mitochondrial UCP1:28S
      rRNA ratio was greater in Brahman BAT than in BAT from Angus calves. Lipogenesis
      from acetate and glucose again was high, but lipogenesis from palmitate was
      barely detectable. Tail-head s.c. adipose tissue from both breed types contained
      adipocytes with distinct brown adipocyte morphology. In Exp. 3, three fetuses of
      each breed type were taken at 96, 48, 24, 14, and 6 d before expected
      parturition, and at parturition. Lipogenesis from acetate and glucose in vitro
      decreased 97% during the last 96 d of gestation in both breed types, whereas the
      UCP1 gene expression tripled during gestation in both breed types. At birth,
      palmitate esterification was twice as high in Angus than in Brahman BAT and was
      at least 100-fold higher than in BAT from NE-infused calves from Exp. 2.
      Uncoupling protein-1 mRNA was readily detectable in tailhead s.c. adipose tissue
      in all fetal samples. In Exp. 4, male Brahman and Angus calves (n = 5 to 7 per
      group) were assigned to 1) newborn treatment (15 h of age), 2) 48 h of warm
      exposure (22 degrees C) starting at 15 h of age, or 3) 48 h of cold exposure (4
      degrees C) starting at 15 h of age. Brahman BAT adipocytes shrank with cold
      exposure, whereas Angus BAT adipocytes did not. Similarly, BAT from neonatal
      lambs (Exp. 5; n = 6 per group) was depleted of lipid in response to cold
      exposure, although UCP1 gene expression persisted. In Exp. 4, NE stimulated
      lipogenesis from palmitate in BAT incubated in vitro. Lipogenesis from palmitate
      was higher in Angus than in Brahman BAT, and increased with both warm and cold
      exposure. These studies suggest that BAT from Brahman calves may be exhausted of
      lipid shortly after birth during times of cold exposure.

PMID- 15032454
TI  - Annual meeting keynote address: Animal agriculture and emerging social ethics for
      animals.
AB  - Businesses and professions must stay in accord with social ethics, or risk losing
      their autonomy. A major social ethical issue that has emerged in the past three
      decades is the treatment of animals in various areas of human use. This point can
      be illustrated with numerous examples across all areas of animal use. These
      examples reflect society's moral concern having outgrown the traditional ethic of
      animal cruelty that began in biblical times and is encoded in the laws of all
      civilized societies. There are five major reasons for this new social concern,
      most importantly, the replacement of husbandry-based agriculture with industrial
      agriculture. This loss of husbandry to industry has threatened the traditional
      fair contract between humans and animals, and resulted in significant amounts of
      animal suffering arising on four different fronts. Because such suffering is not
      occasioned by cruelty, a new ethic for animals was required to express social
      concerns. Since ethics proceed from preexisting ethics rather than ex nihilo,
      society has looked to its ethic for humans, appropriately modified, to find moral
      categories applicable to animals. This concept of legally encoded rights for
      animals has emerged as a plausible vehicle for reform. The meaning of this
      ethical movement for animal agriculture is examined. Animal agriculture should
      explore ways to replace the animal husbandry lost to industrialization.

PMID- 15032455
TI  - Diabetic foot in Nigeria--a review article.
AB  - Numerous institutional reports from Nigeria on diabetic foot (DF) have appeared
      showing variations from one institution to another in the last 40 years. In the
      author's opinion, this is the first overall review on DF care in Nigeria to put
      all the pictures together and then compare with global literature. The reports
      showed varied male-female preponderance, occurrence mainly among the low
      socioeconomic group patients, mostly involved in one form of trading or another,
      with a peak incidence in the 6th decade, up from the 5th decade of the past.
      There is also a rising incidence of DF which has recently become an important
      indication for lower limb amputation in Nigeria. This review also discusses the
      peculiar situations of DF in Nigeria in relation to aetiopathogenesis, staging
      and classification, non-operative and operative treatment, and the way forward to
      reduce morbidity and mortality and improve the present disappointing outcome of
      care of DF patients in Nigeria. The roles of interventional radiology and
      revascularisation in DF management are highlighted.

PMID- 15032456
TI  - Applications of ultrasonography in oral and maxillofacial surgery: a review of
      the literature.
AB  - Ultrasonography is a diagnostic medical procedure that employs high frequency
      sound waves to produce dynamic visual images of organs, tissues, or blood flow
      inside the body. Until recently it found little application in oral and
      maxillofacial surgery despite the fact that it is readily available, non
      invasive, relatively inexpensive, painless and can be repeated as often as
      possible without risk to the patient. This article reviews the available
      literature on the ultrasonographic examination of the head and neck with
      particular reference to oral and maxillofacial surgery and evaluates the
      applications of this imaging modality in modem clinical practice. It further
      highlights the need for clinicians to explore and fully appreciate the diagnostic
      value of this highly under-utilised imaging modality.

PMID- 15032457
TI  - Management of open tibia fracture--Anderson and Hutchins technique re-visited.
AB  - Prior to September 1995, most open tibia fractures seen at the University College
      Hospital, Ibadan had hitherto been managed by the application of plaster-of-Paris
      after limited wound debridement. The outcome of this form of treatment was found,
      from the outpatient clinic follow-up records, to be associated with a high rate
      of complications including chronic osteomyelitis and joint stiffness. In most
      hospitals in the developed and developing countries, majority of these injuries
      are best managed by the use of various types of external fixators. However, these
      external fixator devices are by no means cheap and often times most patients in
      our environment are unable to afford them since the country operates a health
      care system where the patients are solely responsible for their health care
      needs. In this study, the Anderson and Hutchins technique (Steinmann's pins
      threaded through bone and incorporated in plaster-of-Paris) was used in the
      management of thirty-four open tibia fractures between September 1995 and August
      1999. Seventy-nine percent of these were severe or Type III open fractures. The
      time to radiological union was 21 weeks and pin tract infection occurred in 15
      percent of the patients, mainly in the proximal (tibia) pins. The use of a single
      stout proximal (tibia) transfixing Steinmann's pin was found to offer a stable
      fixation.

PMID- 15032458
TI  - Psychosocial problems of pre-clinical students in the University of Ibadan
      Medical School.
AB  - Recent changes in the psychosocial environment of the university campus such as
      the steep rise in student numbers, the high cost of living standards and the
      increase in violence and cult activities has prompted the need to assess the
      impact of these changes on the students. A cross sectional study was carried out
      among pre-clinical medical students to identify their psychosocial problems. A
      self-administered questionnaire was used to collect information about socio
      demographic variables including age, sex, sources of financial support, type of
      accommodation, smoking and drinking habits and use of recreational facilities.
      Causes of insecurity and depression among students were also recorded. The
      General Health Questionnaire GHQ-12 was used to assess their mental health
      status. One hundred and seventy-six students responded to the enquiry, 94 males
      (53%) and 80 females (45%). One hundred and thirty-seven (79%) live on the campus
      while 37 (21%) live off campus. Only 9 of the students (5%) were smokers and 28
      (16%) were drinkers. Monthly pocket money ranged from Naira 1,000 to Naira
      25,000. Forty-one (23%) thought their pocket money was adequate, 92 (52%) thought
      it was fair and 39 (22%) thought it was inadequate. Causes of insecurity on the
      campus were cultism 34 (19%), lack of money 27 (15%), lack of textbooks 13 (7%)
      and stealing 10 (6%). Causes of depression include fear of failure of
      examinations, 62 (35%), lack of money, 48 (27%) and family problems 17 (10%).
      Mental health scores ranged from 1 to 10. Using a cut off point of 3 to delineate
      those with traits of poor mental health, 35 (21%) fell into the category 15 boys
      and 20 girls. Mean mental health score were higher for females, those living on
      campus, smokers and drinkers but this was not statistically significant. Fear of
      failure of examinations, cultism and lack of money are major concerns among
      medical students on the main university campus. Counselling services should be
      provided to assist students with these problems.

PMID- 15032459
TI  - Noise levels in the hospital environment in Ibadan.
AB  - Noise levels were measured in 3 hospitals in Ibadan; a teaching hospital with
      approximately 800 beds and 2 general hospitals with about 200 beds each. A type 2
      digital integrating sound level meter was used to measure noise levels in
      selected sites. Children's clinics and wards in the teaching hospital recorded
      the highest noise levels, 68-73db(A) and 55-77db(A) respectively, compared to
      similar facilities for adults. High noise levels 74-89dB(A) were also recorded in
      the operating rooms. Noise levels above 80db (A) were recorded in service areas
      such as the boiler room, and laundry and generator rooms in the teaching
      hospital. Corresponding sites in the general hospitals were less noisy as such
      services are provided at a minimum in these hospitals. Sleep interference is
      known to occur at noise levels recorded in this study. Staff conversation makes a
      large contribution to noise levels in patient care areas. The use of hospital
      equipment in patient care also contributes to the noise levels especially in
      operating room. This can be reduced if attention is drawn to this as an important
      part of patient care. Noise levels in service areas need to be monitored closely
      and workers in those areas may need hearing protection and regular audiometric
      assessment.

PMID- 15032460
TI  - Determinants of prognosis among black Africans with hypertensive heart failure.
AB  - One hundred and seven consecutive Black Africans hypertensive heart failure
      patients made of 52 Gambians and 55 Nigerians (51 males + 56 females) aged 53.6
      +/- 12.1 years were followed-up for 12 months or till death. One-year survival
      curve was determined using Kaplan-Meiers method. The survivors and the deceased
      were compared using univariate and multivariate analysis. Mean blood pressures
      were 180.4 +/- 28.2 mmHg (range: 130-250 mmHg) systolic and 117.0 +/- 12.9 mmHg
      (range: 100-160 mmHg) diastolic. Duration of hypertension ranged from 0.5 to 23
      years. The rate of undetected hypertension was 44%. Overall one-year survival
      rate was 71%. Twenty two percent of deaths occurred within the first 3 months of
      HHF. One-year survival rate among the survivors of this period was 89.4%. A
      strong negative correlation existed between cumulative survival and the duration
      of heart failure (y = 0.9812, x(2) = 0.1173, R = 0.965). Compared to the
      survivors, the deceased had significantly higher systolic blood pressure (191.9
      +/- 32.2 mmHg versus 175.1 +/- 25.2 mmHg; P < 0.05), diastolic blood pressure
      (123.7 +/- 15.8mmHg versus 114.3 +/- 10.3 mmHg; P < 0.05), cardiothoracic index
      (69.2 +/- 3.9% versus 66.2 +/- 4.2%; P < 0.05) and serum creatinine (148.6 +/-
      42.2 umol/L versus 113.8 +/- 36.4 umol/L; P < 0.05). Compared to the patients
      aged 40 or more years, patients aged below 40 years had significantly lower one
      year survival rate (41.7% versus 74.1%; P < 0.05). One-year survival rate was
      significantly higher among patients on captopril medication than those without
      (75% versus 52.6%; P < 0.05). However, only serum creatinine had statistically
      differing values between the deceased and survivors (df = 1 SS = 10272, F = 7.60,
      p = 0.007). Basic clinical and biochemical parameters could therefore be useful
      prognostic markers in hypertensive heart failure.

PMID- 15032461
TI  - Observed factors responsible for resistant hypertension in a teaching hospital
      setting.
AB  - Assessment of control of hypertension by some authors has revealed that optimal
      blood pressure control is not yet achieved in many of those that are on
      treatment. Resistant hypertension, plays a part as one of the factors responsible
      for this poor control state. Because of the peculiar problems posed by this group
      of hypertensives, we assessed the burden and factors responsible for resistant
      hypertension among hypertensive subjects attending the Medical Outpatient Clinic
      of the University College Hospital, Ibadan, Nigeria. Resistant hypertension was
      defined as blood pressure [symbol: see text] 140/90 mmHg in the presence of use
      of a combination of three antihypertensive drugs, including a diuretic at near
      maximum doses for at least one month. Five hundred and sixty-six consecutive
      subjects (218 males and 348 females) with a mean age of 56.0 +/- 14.3 years were
      screened for resistant hypertension. One hundred and forty-four (mean age 54.55
      +/- 15.1 years), were fully controlled with a blood pressure of 120 +/- 9/77 +/-
      2 mmHg. 394 men age of 56.7 +/- 11.7 years had non-resistant hypertension with
      blood pressure of 167.5 +/- 23/102.3 +/- 1.2 mmHg. Only 28 (5%) of the whole
      study group (mean age 51.8 +/- 9.7 years) were found to have resistant
      hypertension with a blood pressure of 176.4 +/- 43/109.6 +/- 14.8 mmHg. The
      subjects with resistant hypertension were significantly younger than those with
      non-resistant hypertension P < 0.02. There was no significant difference between
      their systolic blood pressure (P > 0.3) whereas; there was a significant
      difference between their diastolic blood pressure P < 0.002. Among those who had
      resistant hypertension, non-compliance was documented in 14 (50%) while it was in
      73 (18.5%) of those without resistant hypertension P < 0.00053. Alcohol, tobacco,
      Obesity, use of non-steroidal anti-inflammatory drugs and excessive use of salt
      were not found as key factors responsible for resistant hypertension in this
      study.

PMID- 15032462
TI  - Bone marrow findings in patients with pulmonary tuberculosis.
AB  - The cytology and culture of bone marrow aspirate in sixty-two newly diagnosed
      patients with pulmonary tuberculosis were studied. The findings were depressed
      erythroid activity in 69% of the patients, micronormoblastic changes in 18% and
      megaloblastic changes in 16.6%. Myeloid activity was increased in 65% of the
      patients. Normal looking plasma cells above 5% was found in 17.7% of the bone
      marrow aspirates while 12.9% had eosinophilic precursors above 5% in the marrow.
      None of the marrow smears showed granuloma formation or caseation necrosis. The
      bone marrow cultures yielded no growth of Mycobaterium tuberculosis while
      stainable iron in the marrow was found to be low or negative in 88.8% of the
      patients.

PMID- 15032463
TI  - Implication of reproductive endocrine malfunction in male antifertility efficacy
      of Azadirachta indica extract in rats.
AB  - The effects of the ethanol extract of Azadirachta indica stem bark on body and
      organ weights, sperm morphology, counts and viability, serum levels of
      testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH)
      were studied in albino rats. Intraperitoneal administration (i.p) of the extract
      for ten weeks caused significant dose-dependent decreases in weights of the
      testis, epididymis and seminal vesicles but an increase in that of the adrenal
      gland. Sperm counts, morphology and viability were adversely affected in the
      extract treated rats. Rats that received 150 mgkg(-1) b.w. Azadirachta extract
      were unable to impregnate female rats throughout the duration of the study.
      However, these female rats conceived and sired physically normal litters about
      four weeks after cohabitation with untreated male rats. Azadirachta indica
      produced dose-dependent reduction in serum testosterone and LH but no change in
      FSH levels. Most of the changes produced in this study were restored in recovery
      experiments.

PMID- 15032464
TI  - The digit sucking habit and related factors: observations from a child dental
      health clinic in Nigeria.
AB  - An increased prevalence of the digit sucking habit among Nigerian children has
      been reported. Certain factors are believed to influence its occurrence. This
      study was carried out to assess these factors and determine possible correlation
      with the onset and persistence of the habit. The sample population consisted of
      81 children--52 females and 29 males aged 3-16 years who were still actively
      digit sucking. Findings in this group were compared with a control group made up
      of 80 children aged 2-16 years who were not digit suckers and had no history of
      the habit. Results showed no correlation between mode of infant feeding and the
      digit sucking habit. The duration of breast-feeding was found to have a
      significant effect on the habit. About 79% of non-suckers had been breast-fed for
      more than 6 months while only 43.2% of digit suckers were breast-fed for the same
      duration. The digit sucking habit was observed more frequently in children with
      mothers in high cadre occupations (53.1%) compared to non-suckers (23.8%). More
      digit suckers (22.2%) than non-suckers (12.5%) were reported to have a history of
      pacifier use. Neither family size nor position of the child in the family had a
      significant effect on the occurrence of the habit. In addition, 48.1% of the
      sample population had siblings with the same habit compared to 16.2% of the
      controls. The identification of significant factors may be useful in targeting
      interventions in order to prevent consequences of the prolonged habit.

PMID- 15032465
TI  - Nephrectomy at the University of Port Harcourt Teaching Hospital: a ten-year
      experience.
AB  - The case records of patients who had nephrectomy from 1989 to 1998 were
      retrieved. Data extracted for analysis included age, sex, clinical features,
      indications for nephrectomy, post-operative complications and histological
      findings. Thirty-four unilateral nephrectomies in 21 males and 13 females were
      done. The patients were aged between 1.5 to 75 years. The predominant presenting
      features were abdominal pain (76.5%), abdominal mass (70.6%), haematuria (61.8%)
      and weight loss (47.1%). Diagnostic investigations were intravenous urography and
      renal ultrasound scan. The major indications for renal exploration included non
      functioning kidney and renal mass suspected to be carcinoma. The
      histopathological findings included renal malignancy 23 (67.6%), hydronephrosis 6
      (17.6%) and renal infections 3 (8.8%). The male/female ratio in nephrectomy for
      malignancy was 1:1.09. Renal trauma was the indication in only one patient. Non
      functioning kidneys on intravenous urography (IVU) occurred in both malignant and
      infective lesions. Hypertension was found in 9 patients preoperatively. It
      resolved in 7 patients after operation. The histological finding in one kidney
      differed from what was assumed at operation. Follow-up USS showed compensatory
      hypertrophy in the remaining kidneys. Post-operative sepsis occurred in 4
      patients. One of these was a retroperitoneal abscess. Two patients with huge
      tumours died on the operating table. Two died from sepsis. Four patients died
      from metastatic disease within two years after operation. Malignancies
      constituted the commonest indication for and commonest cause of mortality in
      nephrectomy. Antibiotics prophylaxis is advocated. All nephrectomy specimens
      should be subjected to histopathological examination.

PMID- 15032466
TI  - Isolation of an anti-tumour terpenoid from stem bark of Spondianthus preussii
      var. preussii Engl.
AB  - We report a biologically monitored phytochemical separation of stem bark of
      Spondianthus preussii var. preussii against a panel of human cancer cell lines in
      vitro and the P-388 murine lymphocytic leukemia cells in culture. An ethylacetate
      extract of the stem bark exhibited selective cytotoxicity against human melanoma
      (ED50 = 10.0 ug/ml). Further activity-guided fractionation of the ethylacetate
      extract by flash chromatography and subsequent purification on preparative thin
      layer chromatography led to the identification of a lupane-type triterpene, 3beta
      hydroxy-20(29)--lupenoic acid, by spectroscopic methods. This is the first report
      of the occurrence of this compound in S. preussii var. preussii. It is also the
      first time this triterpene is being shown to exhibit in vitro anti-tumor activity
      against human melanoma (ED50 = 2.4 ug/ml). This compound could be a promising
      bioactive natural product since it has been previously reported to exhibit a
      range of biological activities including in vivo and in vitro antiplasmodial
      activity and it is not toxic.

PMID- 15032467
TI  - Village health workers' and traditional birth attendants' record keeping
      practices in two rural LGAs in Oyo State, Nigeria.
AB  - Village health workers (VHWs) and Traditional Birth attendants (TBAs) provide
      health care services to the communities in which they live, improving access to
      health care as well as serving as an important link between the periphery (the
      communities) and the health sector. The data this category of workers generates
      about their communities will strengthen primary health care management
      information system in Nigeria. The objective of this study was to assess the
      knowledge, attitude and practices of VHWs and TBAs regarding record keeping in
      Ibarapa Central and Akinyele local government areas (LGAs) of Oyo State, Nigeria.
      Using a pre-tested, semi structured questionnaire and an observation checklist,
      trained research assistants visited and interviewed all the active, registered
      VHWs and TBAs in the two LGAs. Results showed that there were a total of 62 and
      102 active VHWs/TBAs in Ibarapa Central and Akinyele LGAs respectively with most
      of them being farmers aged between 30-59 years. Over two-thirds in both LGAs knew
      the uses of record keeping for monitoring and evaluation purposes and most of
      them felt that keeping records was easy. Sixty-one percent of the respondents in
      Ibarapa Central and 96% of those in Akinyele LGA reported keeping records of
      their health activities. Of those who kept records, two thirds in Ibarapa Central
      and almost all (96%) in Akinyele LGA reported forwarding the records they keep.
      The type of records they keep was mostly on patients' treatment and (in Akinyele)
      delivery records using an exercise book. Most did not have the VHW/TBA record of
      work or the community profiles (wall chats) developed and recommended by the
      Federal Ministry of Health (FMOH) because they were not supplied. The factors
      associated with record keeping included duration as a VHW/TBA, previous training
      on record keeping, receiving feedback. Recommendations made included ensuring
      availability of materials and periodic training and re-training of the VHWs/TBAs
      by the LGAs, and regular provision of feedback by the National Primary Health
      Care Development Agency (NPHCDA).

PMID- 15032468
TI  - A comparative study of the wound healing properties of honey and Ageratum
      conyzoides.
AB  - The present study investigates the wound healing properties of methanolic
      extracts of Ageratum conyzoides leaves compared with those of honey. Thirty
      Wistar rats were randomized into 3 groups of 10 animals each. They were fed with
      standard rat cubes and Tap water weighed and acclimatized to laboratory
      conditions for one week. Under anesthesia, each animal had the skin of its
      dorsolateral flank shaved after which an area of the skin was excised. On
      achieving haemostasis, the wounds were packed with gauze soaked in the
      appropriate dressing for each group. Measurement of wound size, and wound
      biopsies were taken on the 10th day post-wound creation. Together with healed
      wound samples, these were processed for histology. Fibroblast and blood vessel
      densities per unit area of wound were determined for the healed wound samples.
      Histologically, the day 10 Ageratum sections showed fewer inflammatory cells
      compared with similar honey and Control sections. Also, healed scar sections of
      wounds dressed with the herb extract showed more fibrosis. Honey and Ageratum
      caused significant greater wound contraction than controls (p = 0.001 and 0.005
      respectively). Healed wounds from the Ageratum group had significantly fewer
      fibroblasts than honey and controls (p = 0.012 and 0.036 respectively).

PMID- 15032469
TI  - A clinicopathological study of orbito-ocular diseases in Ibadan between 1991
      1999.
AB  - To describe the pattern of ocular diseases seen during the study period.
      Retrospective review of surgical pathology and cytology records from January 1991
      to December 1999. Reference was also made to case notes where necessary. A total
      of 225 orbital and ocular surgical pathology specimens were reviewed. One hundred
      and twenty-five (56.8%) were from males and 100 from females (ratio: 1.3:1). Over
      50% of the specimens were obtained from children and young adults less than 20
      years of age. There were 168 tumours, with malignancies accounting for 73.8% of
      all tumours. Other pathological lesions included, inflammatory conditions, benign
      tumours, and degenerative conditions, which represent 21.8%, 19.6%, and 2.2% of
      all lesions respectively. Retinoblastoma accounted for 57.3% of all malignancies,
      the age range was 3 months to 12 years, mean 2.65 years. The modal age was 2
      years. Squamous cell carcinoma of the conjunctiva, accounting for 12.1% of all
      malignancies was the commonest malignancy seen in the adult age group. Malignant
      melanoma was rare and no case of Kaposi's sarcoma was seen. Commonest non
      neoplastic lesions resulting in enucleation of the eye were panophthalmitis and
      endophthalmitis. Human immunodeficiency virus screening was only done in 3 of 8
      patients with squamous cell carcinoma and was positive in 2 of them. Malignancies
      of the eye and orbit continue to make up majority of orbit and ocular pathologies
      requiring enucleation in children and young adults. Despite an observed increase
      in the frequency, insufficient information precludes evaluation of a link between
      HIV and squamous cell carcinoma as well as other obito-ocular lesions such as
      Kaposi sarcoma.

PMID- 15032470
TI  - Oral cancer awareness and prevalence of risk behaviours among dental patients in
      South-western Nigeria.
AB  - The present study, based in a tertiary hospital in South western Nigeria,
      assessed cancer awareness among patients seeking dental treatment. A specially
      designed questionnaire was used to collect information on the knowledge, beliefs
      and habits of those attending the dental hospital within a designated period of
      the year. Almost 61% of the respondents had post-secondary education. The level
      of oral cancer awareness was remarkably high (72%), but this was low compared to
      awareness about occurrence of cancer in other parts of the body (89.9%).
      Awareness was found to be closely associated with educational status. The study
      also revealed that 50% had previous information on oral cancers from mass media
      as against 20.1% who were informed through health care professionals. Almost half
      of the study sample recalled episodes of previous oral ulceration and of these,
      greater than 50% indulged in either self medication (38.1%) or no medication at
      all (18.4%). The prevalence of alcohol consumption and smoking habits among the
      respondents was low being, 16.3% and 4.2% respectively. The lack of association,
      in this study, between oral cancer incidence and the known risk behaviours, is an
      obvious indication for investigation into other predisposing factors such as
      nutrients, genetic predisposition and the role of chronic infections. Perhaps one
      or more of these might be more relevant in this environment.

PMID- 15032471
TI  - Ophthalmic manifestations of fronto-ethmoidal mucocoeles: a report of five cases.
AB  - Fronto-ethmoidal mucocoele is rare and will cause visual impairment and blindness
      when management is belated. In order to improve the awareness of its ophthalmic
      manifestations and problems associated with its management we retrospectively
      analyzed clinical, radiological and histological features in five illustrative
      cases. They all presented with unilateral supra-orbital swellings and proptosis,
      antedated by head injury in two cases. Other ophthalmic manifestations included
      eye lid swelling, progressive visual loss, unilateral ptosis, exotropia and
      diplopia. Only two patients had nasal symptoms. In all cases, x-rays of the
      paranasal sinuses revealed radiolucent frontal sinuses with eroded anterior
      walls, floors and midline septa. Brain scan in one case demonstrated
      opacification and enlargement of the corresponding sinus. Fronto-ethmoidectomy in
      four cases confirmed erosion of sinus' walls and floors and in one case of the
      contiguous supra-orbital ridge in addition to colored fluid aspirates. In all
      cases, the curetted sinus lining comprised of chronic inflammatory tissue.
      Surgical intervention was followed by prompt postoperative resolution of
      ophthalmic manifestations. A high level of suspicion is essential for early
      diagnosis and treatment of fronto-ethmoidal mucocoeles and will assist in
      preventing irreversible visual loss.

PMID- 15032472
TI  - Massive haematochezia after uterine evacuation: an uncommon cause of lower
      gastrointestinal bleeding.
AB  - We report a case of a 30-year-old Para 2 + 1 who presented with massive
      haematochezia 7 days after uterine evacuation for an incomplete abortion.
      Difficulty in pre-operative diagnosis in this type of presentation and treatment
      is highlighted and the literature reviewed.

PMID- 15032473
TI  - Medical resources on the Internet: the role of the medical librarians.
AB  - The usefulness of the Internet to the medical profession is growing rapidly. As
      the use of the Internet connectivity spreads, accessibility to more medical and
      biomedical resources is facilitated. This device if properly used can offer, free
      of charge, a large number of programs in the realm of health sciences. In this
      article, efforts are made to highlight some of the medical resources on the
      Internet, as well as review the new roles of medical librarians.

PMID- 15032474
TI  - Dental education in Nigeria: the journey so far and the way forward.

PMID- 15032475
TI  - [Retroperitoneal fibrosis].
AB  - The rare occurrence of retroperitoneal fibrosis contrasts with the multitude of
      publications. Its clinical expression also contrasts with the severity of its
      repercussion on renal function. Now, diagnostic and therapeutic are more
      standardized to improve chances of preserving renal function. However, no
      surgical or medical therapy has been tested in a randomized, controlled trial.
      This article proposes an update of knowledge on this subject.

PMID- 15032476
TI  - [Rare kidney tumors in an adult].
AB  - Rare kidney tumors can either be benign or malignant. Benign tumors include
      epithelial tumors and mesenchymatous ones developed from kidney cells. Malignant
      tumors are represented by the carcinoma of the collecting tubes as well by the
      sarcoma. Other malignant tumors of the extra-renal origin are also observed as
      lymphomas and neuro-endocrine tumors.

PMID- 15032478
TI  - [Non-secreting adrenal tumours].
AB  - This paper presents the clinical features, imaging methods and treatment of non
      secreting adrenal tumours. Adrenal incidentalomas are especially discussed. The
      main histological types of adrenal non-secreting tumours are evoked. Therapeutic
      considerations are discussed.

PMID- 15032477
TI  - [Torsion of the spermatic cord and testicular annexes].
AB  - Torsion of the spermatic cord is responsible for an ischemic necrosis of the
      testis in the absence of rapid resaturation of the perfusion. It is also
      responsible for contralateral parenchymal alterations resulting in subfertility.
      Torsion of the spermatic cord mostly occurs in newborns and adolescents. Its
      classical clinical pattern is that of an acute-onset ipsilateral scrotal pain.
      Its diagnosis is clinical and its suspicion must lead to an immediate surgical
      scrotal exploration. The surgical procedure may be preceded by an attempt of
      external detorsion, but never delayed by any para clinical exploration. If the
      diagnosis is confirmed at surgery, contra-lateral orchidopexy must be considered.
      Trophicity of the ischemic testicle and the fertility of the patient are
      uncertain. Improvement of the prognosis of patients with torsion of the spermatic
      cord needs an urgent surgical management of the patients. It also claims for the
      development of testicular parenchyma protective medical treatments. But the most
      important improvement should come from parental and teenagers educational
      information so that they urgently visit a practitioner in case of acute scrotal
      pain.

PMID- 15032479
TI  - New beauveriolides produced by amino acid-supplemented fermentation of Beauveria
      sp. FO-6979.
AB  - Five new beauveriolides were isolated from the acetone extracts of Beauveria sp.
      FO-6979 mycelia fermented in amino acid-supplemented media. The structures were
      elucidated by spectroscopic studies including NMR experiments and chemical
      degradation. All the beauveriolides are cyclodepsipeptides consisting of one 3
      hydroxy-4-methyl fatty acid, two L-amino acids and one D-amino acid in common.
      Beauveriolide VII with the structure of cyclo-[3-hydroxy-4-methyloctanoyl-L
      phenylalanyl-L-alanyl-D-valyl] inhibited lipid droplet formation and cholesteryl
      ester synthesis in macrophages, but the other beauveriolides showed only slight
      or almost no effect on lipid droplet formation.

PMID- 15032480
TI  - A novel ascochlorin glycoside from the insect pathogenic fungus Verticillium
      hemipterigenum BCC 2370.
AB  - Vertihemipterin A, the ascochlorin glycoside, and its aglycone, 4',5'-dihydro-4'
      hydroxyascochlorin, were isolated from the insect pathogenic fungus Verticillium
      hemipterigenum BCC 2370. A new analog, 8'-hydroxyascochlorin, and five known
      compounds, ascochlorin, LL-Z1272delta, 8',9'-dehydroascochlorin, ascofuranone and
      ascofuranol, were also isolated from the same fermentation broth. Structures of
      these compounds were elucidated by spectroscopic methods. Stereochemistry of the
      known compound, 4',5'-dihydro-4'-hydroxyascochlorin, was addressed by NMR
      spectral analyses and the modified Mosher's method. Antiviral (HSV-1) and
      cytotoxic activities of these ascochlorin analogs were evaluated.

PMID- 15032481
TI  - Helquinoline, a new tetrahydroquinoline antibiotic from Janibacter limosus Hel
      1+.
AB  - The ethyl acetate extract of cultures of Janibacter limosus showed a high
      biological activity against bacteria, and fungi and delivered two new natural
      products, a tetrahydroquinoline derivative designated as helquinoline (1), and
      the N-acetylkynuramine (3a), along with other known secondary metabolites. The
      structure of 1 has been elucidated as 4-methoxy-2-methyl-1,2,3,4
      tetrahydroquinoline-8-carboxylic acid on the basis of 1D and 2D NMR and mass
      spectra. The relative stereochemistry of the compound 1 was assigned as 2R*,4R*
      with the aid of coupling constants, NOESY correlation and by comparison with a
      related compound.

PMID- 15032483
TI  - Lightweight expanded clay aggregates (LECA), a new up-scaleable matrix for
      production of microfungal metabolites.
AB  - In order to compare the effects of different growth matrices on secondary
      metabolite production we compared 16 Penicillium species known to produce several
      families of bioactive compounds. The isolates were grown in rich complex media
      formulated as semisolid (agar), liquid (still), shake culture, and absorbed in
      Lightweight Expanded Clay Aggregates (LECA). Both the number of metabolites and
      their quantities were compared via a chemo-diversity index. The matrix had a
      profound effect on fungal growth and secondary metabolism in some of the
      investigated species. LECA was shown to be a powerful alternative for production
      of sporulation-associated metabolites, such as cyclopenins and viridicatins, for
      quick up-scaling from agar based media, and as an alternative for production of
      metabolites that are not induced under submerse conditions.

PMID- 15032482
TI  - Paeciloxazine, a novel nematicidal antibiotic from Paecilomyces sp.
AB  - A novel nematicidal antibiotic, paeciloxazine has been isolated from the culture
      broth of a fungus Paecilomyces BAUA3058 strain. This compound, whose structure
      was determined by spectroscopic methods, has a pyrrolobenzoxazine skeleton.
      Paeciloxazine has moderate cidal activity against Rhabditis pseudoelongata and is
      weakly active against some insects.

PMID- 15032484
TI  - Valine influences production and complex composition of glycopeptide antibiotic
      A40926 in fermentations of Nonomuraea sp. ATCC 39727.
AB  - In actinomycetes the catabolism products of branched chain amino acids provide
      biosynthetic precursors for the formation of several lipid-containing
      antibiotics. We have determined in Nonomuraea sp. ATCC 39727 the effect of valine
      on production of glycopeptide antibiotic A40926, which is a complex of factors
      structurally differing in fatty acid moieties. Addition of valine to minimal
      medium increased A40926 production and modified complex composition towards a
      mono-component. Similar results were also obtained in a rich production medium.

PMID- 15032485
TI  - Ototoxicity of a new glycopeptide, norvancomycin with multiple intravenous
      administrations in guinea pigs.
AB  - Time courses of plasma concentration of a new glycopeptide, norvancomycin (NVCM)
      after single intravenous (iv) and intraperitoneal (ip) injection, and the peak
      plasma concentrations (Cmax's) of this drug at various doses after single iv
      injection were determined in guinea pigs. There were significant differences in
      pharmacokinetic parameters between the two routes of administration and the Cmax
      linearly increased with the dose used increasing. Guinea pigs with normal hearing
      were then used to investigate ototoxic liability of NVCM after multiple
      intravenous administrations (54, 108, 216mg/kg, qd for 14 days). Postrotatory
      vestibular nystagmus (PRN), auditory brainstem response (ABR) and electron
      microscopy (SEM TEM) results showed that, similarly to vancomycin, there was no
      functional or morphological evidence of ototoxicity of NVCM at the dose of 54,
      108 mg/kg. In the high dose group (216 mg/kg), there was a 0 approximately 4 dB
      elevation of hearing threshold but no morphological changes. The results
      suggested that the ototoxicity of NVCM is absent or minimal after multiple iv
      administrations within this dose range.

PMID- 15032486
TI  - Tripropeptins, novel antimicrobial agents produced by Lysobacter sp.
AB  - Planar structures of tripropeptins (TPPs) were elucidated by spectroscopic
      studies including various NMR measurements. Stereochemistry of constituent amino
      acids of tripropeptin C (TPPC) (3) was identified by marfey's method except
      hydroxyproline which was determined by studies of NMR and CD spectra. The
      absolute structure of 3 was determined by analyses of the fragments obtained by
      Birch reduction and LiBH4 reduction of 3. The configuration of the fatty acid,
      isolated from acid hydrolysate of 3, was determined to be (3R)-hydroxy-13
      methyltetradecanoic acid from MS, NMR spectra and negative sign of the optical
      rotation.

PMID- 15032487
TI  - Cochlioquinones and epi-cochlioquinones: antagonists of the human chemokine
      receptor CCR5 from Bipolaris brizae and Stachybotrys chartarum.

PMID- 15032488
TI  - Isolation and characterization of 7-hydroxy-6-demethyl-6-deoxy-erythromycin D, a
      new erythromycin analogue, from engineered Saccharopolyspora erythraea.

PMID- 15032489
TI  - Reclassification as a Nonomuraea sp. of the strain ATCC 39727, producing the
      glycopeptide antibiotic A40926.

PMID- 15032490
TI  - [Histological investigation of the micromorphological effects of the application
      of a laser needle--results of an animal experiment].
AB  - In an experimental animal study (Sus scrofa domesticus) we investigated the
      effects of the new technique of laser needle stimulation (wavelength: 685 nm;
      energy density: 4.6 kJ/cm2 per point; application duration: 20 min). The results
      revealed changes in microcirculatory parameters of the skin resulting in an
      increase in blood flow. However, the quality and intensity of the laser light did
      not induce micromorphological alterations in the skin.

PMID- 15032491
TI  - [Development of a universal interface for the exchange of medical image data
      using magneto-optical media].
AB  - Digital images generated by medical imaging form the basis for radiological
      diagnosis and surgical planning. Despite the advent of the DICOM 3.0 standard for
      medical image communication, widespread application of the existing information
      is often limited by incompatibility of the data formatting used by different
      equipment generations, and the manufacturer-specific standards employed. An
      exchange interface based on magneto optical discs has been developed to retrieve
      and present medical image data regardless of the technological hardware and the
      specific formats used. Specially adapted routines to retrieve the data first had
      to be developed. A modular program structure was used to allow flexibility in the
      implementation of further routines and other exchange media. Over 20,000 CT and
      MRI images including header information obtained from different General Electric
      and Siemens scanners were extracted successfully from MO discs. The image data
      were used for follow up and surgical planning and were transferred to a PAC
      server. The interface proved reliable and easy to use. Support for further
      proprietary formats is currently being developed. The present exchange interface
      permits reliable retrieval of digital images for diagnostic and surgical planning
      purposes, regardless of the hardware generation and manufacturer-specific
      formats.

PMID- 15032492
TI  - [Comparative studies on the applicability of a new surface conditioning system
      (Airsonic Mini Sandblaster) in adhesive bridging technic].
AB  - The object of this work was to investigate a new surface conditioning system for
      hydrolysis-stable metal-polymer bonds in dental prosthetics. The application of
      the adhesive SiO2-interface layer was achieved tribochemically by the use of a
      miniaturised sand blasting instrument (Airsonic Mini Sandblaster, Co. Hager and
      Werken, Duisburg, Germany) using the SiO2 coated Rocatec blasting medium. An
      advantage of this instrument is the possibility of decreasing costs for dentist
      and patient and also the time of treatment by connecting the device to the dental
      chair. Evaluation of applicability was based on the composition and morphology of
      the coatings applied to different dental alloys (titanium, NiCr, CoCr). In
      addition, the strength of metal-polymer bonds prior to and after physiological
      ageing was determined by tensile shear testing. In all cases the Airsonic Mini
      Sandblaster coatings proved to be equivalent to the original Rocatec system in
      terms of the parameters tested, such as structure and composition of the coating,
      and adhesivity. Irrespective of the adhesive alloy-dependent adhesive strengths
      in the region of 24-30 MPa were achieved; no significant decrease in strength
      caused by degrading of the bonds occurred. Bonding strengths are within the range
      reported in the literature for the Rocatec system, and are appreciably above
      clinically required minimum strength of 10 MPa as enamel strength. The results
      demonstrate the applicability of the Airsonic Mini Sandblaster in practice. By
      employing the procedure at the dental chair the process of silicating and
      subsequent silanising can be transferred from the dental laboratory to the
      dentist's practice. In this way, a reduction in treatment time and costs is
      achieved, and the reliable handling of the coating system is also improved.

PMID- 15032494
TI  - Influence of contact forces on wrist photoplethysmography--prestudy for a
      wearable patient monitor.
AB  - The practical setting shows that gentle manual pressure on a photosensor suffices
      to improve the detectability of arterial pulses, but changes in the pressure
      applied may also produce signal artefacts. To study these effects, stepwise
      increasing contact forces (0.5 to 4 N) were applied to a photosensor placed over
      the radial artery. Additionally, the influence of optical coupling between sensor
      and skin surface was examined by introducing an elastic distance ring. The AC and
      DC components from the recorded photoplethysmogram were analysed. The AC
      component (absorption due to arterial pulsation) increased with the pressure
      applied; at lower forces (0.5 to 3 N) an introduction of the ring enhanced this
      effect. The characteristic of the DC component (backscattering from non-pulsating
      tissues) depends on optical coupling: without the ring the DC component increased
      stepwise with force (slope 0.035 V/N), but with the ring in place this component
      decreased (slope -0.075 V/N). Since the sensitivity of the pulse signal to
      artifacts is related to the slope of the DC component, such artefacts can be
      minimized by making the slope small. The utilization of these results to improve
      pulse detection and reduce motion artefacts in a wearable wrist device is
      discussed.

PMID- 15032493
TI  - [Temperature measurements during abrasive water jet osteotomy].
AB  - Working on bone is a major aspect of orthopaedic surgery. Despite its well-known
      appreciable thermal effects on the edges of the bone cut, the oscillating bone
      saw blade the oscillating saw remains the standard instrument both for cutting
      long bones and creating a bed for an endoprosthesis. The application of abrasive
      water jets offers the possibility of achieving an extremely precise curved cut in
      bone with no accompanying thermal effect. The thermographically measured absolute
      temperature increase at the cut edges seen with the water jet was 13 K maximum.
      The small process forces permit the application in automated handling systems.

PMID- 15032495
TI  - Analysis of simulated single ligament transection on the mechanical behaviour of
      a lumbar functional spinal unit.
AB  - The influence of the different lumbar spinal ligaments on intersegmental rotation
      is not fully understood. In order to explore this effect, a finite element model
      of the functional spinal unit L3/L4 was loaded with pure moments in the three
      main anatomic planes. The two extremes--minimum and maximum--ligament stiffness
      values reported in the literature were applied. After virtual transection of each
      of the spinal ligaments in turn, the intersegmental rotation and forces in the
      remaining ligaments were calculated. On flexion, the highest force was found for
      the posterior longitudinal ligament; on extension and lateral bending for the
      anterior longitudinal ligament; and on axial rotation for the facet capsular
      ligament. The strongest influence on intersegmental rotation is exerted by the
      interspinous ligament on flexion, by the anterior longitudinal ligament on
      extension and lateral bending, and by the facet capsular ligaments on axial
      rotation. Ligament stiffness has a strong influence on intersegmental rotation
      and forces in the ligaments, so that finite element models of spinal segments
      must be validated by experimental data. This study should help to elucidate the
      role of the various ligaments.

PMID- 15032496
TI  - [Cricoid pressure--safety necessity or unnecessary risk?].
AB  - Cricoid pressure is a simple and effective measure to prevent regurgitation of
      gastric juice and content. This procedure, which prevents a possible reflux by
      compression of the oesophagus between the cricoid cartilage and the cervical
      vertebral bodies, is generally acknowledged in clinical practice, although there
      is lack of scientific evidence regarding its effect on the outcome of patients at
      risk of aspiration. However, there is only a rare incidence of complications as
      long as cricoid pressure is used with exact indication, considering the
      contraindications and correct performance. Especially important are the optimal
      force applied on the cricoid and the duration of application. However, there is a
      lot of evidence in the literature that the knowledge of anaesthetists about the
      method and technique of cricoid pressure is rather unsatisfactory. Thus, the
      starting point for improving the efficiency and safety of cricoid pressure seems
      to be better teaching and training.

PMID- 15032497
TI  - [Iatrogenic injuries of the trachea].
AB  - As a basis for quality assurance measures, we analysed over a period of three
      years all iatrogenic tracheobronchial injuries that had to be repaired
      operatively at a university hospital. Twelve patients were affected. In most of
      these cases, the injuries were the result of an intubation during resuscitation
      attempts prior to or after admission to hospital (6 patients; 4 of them died
      later). The ruptures of 5 patients were due to complications of a dilational
      tracheostomy (1 died). In one case the laceration occurred in the course of a
      reoperation after oesophagectomy (conservative treatment after dehiscence of the
      tracheal suture). The tracheobronchial ruptures (length: 2 to 8 cm) were located
      in the pars membranacea and had surgical repair through a thoracotomy on the
      right side. During the period of this investigation, 43,773 elective intubations
      were performed. No such serious tracheal injuries were observed. The cause of
      death in the patients with tracheal injuries was mainly the underlying disease
      (resuscitation after myocardial infarction; tracheostomy because of pulmonary
      failure in septic disorders); however, it is likely that the injuries or the
      surgical intervention played an additional role in the negative outcome of the
      patients. The conclusion is that this complication rate must be reduced by in
      service training and alteration of the procedures.

PMID- 15032498
TI  - [Blunt chest trauma with total rupture of the right main stem bronchus--a case
      report].
AB  - Tracheo-bronchial lesions in blunt chest trauma are rare--the incidence is about
      1%--but potentially life-threatening events. Indirect signs such as pneumothorax,
      pneumomediastinum, subcutaneous emphysema or an insufficient expansion of the
      lungs after drainage of a pneumothorax are ominous. The fastest and most reliable
      method to assess the definite diagnosis of tracheo-bronchial lesion is fibre
      optic tracheobronchoscopy. Early surgical treatment is mandatory to prevent major
      pulmonary resection. This case shows that computer tomography might fail to
      provide the right diagnosis. Independent lung ventilation is an option to protect
      the bronchial anastomosis during the early postoperative period. Reported here is
      the case of a young man who sustained a total traumatic rupture of the right main
      stem bronchus after being thrown from the passenger seat through the windshield
      of a motor vehicle. When the emergency doctor arrived on the scene, he found the
      patient with dyspnoea and massive thoracic subcutaneous emphysema. Reduced breath
      sounds on the left and no breath sounds on the right side led to an immediate
      placement of two chest tubes and controlled mechanical ventilation. After primary
      care in a district hospital, the patient was transferred to our university
      hospital for further treatment of his head injury. On admission, the patient was
      making breath sounds on both sides and a CT scan showed no clear sign of a
      tracheo-bronchial lesion. After neurosurgical intervention, the diagnosis of a
      rupture of the right main stem bronchus was made with delay by fibre-optic
      bronchoscopy. The patient was intubated with a left-sided double lumen
      endotracheal tube followed by surgical end-to-end anastomosis of the lesion. The
      initial postoperative ventilator support consisted of BIPAP-mode ventilation of
      the left lung, while the right lung was kept open with positive airway pressure.
      Forty-eight hours later, synchronised independent lung ventilation with two
      ventilators was established to protect the surgical result. The ventilation was
      switched to conventional mode a further 48 hours later. Extubation and the
      remaining ICU stay were uneventful.

PMID- 15032499
TI  - The importance of interrupting angiotensin converting enzyme inhibitor treatment
      before spinal anaesthesia--a controlled case report.
AB  - It is generally believed that in hypertensive patients both beta adrenoreceptor
      antagonists and calcium channel blockers can be continued up to the day of
      surgery without provoking problems with cardiovascular stability intra- and
      postoperatively. The same, however, has not been definitively established for
      angiotension converting enzyme inhibitors (ACEIs). A patient who was taking the
      ACAI enalapril for hypertension underwent two similar operations--right total hip
      replacement and three years later left--both with spinal anaesthesia. In the
      initial case, she received her enalapril on the morning of surgery, while for the
      second procedure, enalapril was stopped 48 hours earlier. Hypotension occurred
      which required more than 5 times the dose of etilefrin to maintain suitable blood
      pressure during the first instance as compared to that when enalapril had been
      discontinued 48 hours earlier. Spinal anaesthesia in conjunction with an ACEI may
      result in severe hypotension as seen in this patient. In view of this, it is
      suggested that in contrast to other antihypertenisve drugs, ACEIs should be
      withdrawn well in advance of spinal anaesthesia.

PMID- 15032500
TI  - [Intraoperative ventricular fibrillation in a patient with chronic cocaine abuse-
      a case report].
AB  - With increasing drug abuse of cocaine, the chances are growing that an
      anaesthetist comes into contact with an acutely intoxicated patient or chronic
      cocaine user while on call or during his daily routine. In South America chewing
      coca leaves is daily practise, while in the industrialised world the drug is
      sniffed, smoked or injected intravenously. Clinically, cocaine is used topically
      in ENT and ophthalmology due to its local analgesic and strong vasoconstrictive
      properties. Cocaine has a similar effect on the CNS as amphetamines and produces
      euphoria and hallucinations. Cocaine acts indirectly on sympathetic stimulation,
      release of dopamine and inhibition of catecholamine metabolism. It is metabolised
      in the liver and by serum esterases. Intoxication with cocaine leads to
      respiratory depression, arrhythmias, ventricular fibrillation and death. If an
      emergency operation during acute cocaine intoxication is necessary, all
      sympathomimetic anaesthetic drugs must be avoided. A deep anaesthesia must be
      provided to reduce the risk of cardiovascular complications. In the literature,
      anaesthesia is regarded as safe for patients with chronic cocaine misuse after
      abstinence of 24 hours. This case report shows that, even without acute
      intoxication, severe cardiovascular problems are possible in patients with
      chronic cocaine abuse. Hence, we recommend a cocaine-free interval of at least
      one week before elective surgical procedures.

PMID- 15032502
TI  - Synchrotron light scattering on nanostructured V/Ce oxide films intercalated with
      Li+ ions.
AB  - Vanadium oxide and new V/Ce oxide films on a glass substrate were obtained by the
      sol-gel process. The morphology of these nanostructured and porous films was
      studied by grazing-incidence small-angle X-ray scattering (GISAXS) at the ELETTRA
      synchrotron (Italy, Trieste). The aim of performing GISAXS was to study changes,
      which might occur in the grain sizes and the porosity of vanadium oxide and V/Ce
      oxide at 38 and 55 atom % of V, upon the intercalation of Li+ ions. The average
      grain radius <R> obtained by GISAXS varied with the layer thickness and upon the
      intercalation of Li+ ions. The layer structure in V/Ce oxides was revealed by the
      grazing-incidence X-ray reflectivity (GIXR) method. The average grain radius <R>,
      obtained by GISAXS, was correlated with the intercalation of Li+ ions. The
      specific surface area of these films was also determined and generally varied
      from 0.5 nm(-1) to 0.03 nm(-1).

PMID- 15032503
TI  - Algebraic Kekule structures of benzenoid hydrocarbons.
AB  - An algebraic Kekule structure of a benzenoid hydrocarbon is obtained from an
      ordinary Kekule structure by inscribing into each hexagon the number of pi
      electrons which (according to this Kekule structure) belong to this hexagon. We
      show that in the case of catafusenes, there is a one-to-one correspondence
      between ordinary and algebraic Kekule structures. On the other hand, in the case
      of perifusenes, one algebraic Kekule structure may correspond to several ordinary
      Kekule structures.

PMID- 15032504
TI  - Classification of potential endocrine disrupters on the basis of molecular
      structure using a nonlinear modeling method.
AB  - A methodology for the classification of endocrine disruption chemicals is
      proposed. It is based on a data set of 106 substances extracted from the list of
      553 chemicals that were inspected by the European Union Commission for the
      scientific evidence of their endocrine disruption activity. The substances belong
      to different categories defined in the EU Commission report: (i) literature
      evidence for certainly active as endocrine disrupters, (ii) for potentially
      active, (iii) for less probable active--lacking evidence, and (iv) for certainty
      nonactive. 3D molecular coordinates were calculated using the AM1or the PM3
      optimization method. From 3D coordinates an extensive set of molecular
      descriptors was calculated. The classification model based on the
      counterpropagation neural network was constructed and evaluated. This is the
      first time that the counterpropagation neural network is applied for the
      classification of compounds regarding their literature evidence for the endocrine
      disruption activity. The developed classification model is proposed as a tool for
      a preliminary assessment of potential endocrine disrupters, which would help the
      assessors to make the priority list for a large amount of chemicals that have to
      be tested with more expensive in vitro and in vivo methods.

PMID- 15032506
TI  - The electronic structure of nonpolyhex carbon nanotubes.
AB  - Generalizing the folding method to any periodic two-dimensional planar carbon
      structures we have calculated the corresponding electronic structures in the
      framework of the one orbital one site tight-binding (Bloch-Huckel) method by
      solving the eigenvalue problems in a numerical way. We discussed the metallic or
      the nonmetallic behavior of the nanotubes by applying the folding vectors of
      parameters (m, n). We extended the topological coordinate method to two
      dimensional periodic planar structures as well. Nearly regular hexagonal,
      pentagonal, and heptagonal polygons were obtained. The curvatures of the final
      relaxed structures can be read from the sizes of the polygons. Thus relying only
      on the topological information we could describe the shape of the tubular
      structures and their conductivity behaviors.

PMID- 15032505
TI  - Chemical reactivity as a tool to study carcinogenicity: reaction between
      estradiol and estrone 3,4-quinones ultimate carcinogens and guanine.
AB  - In this article we study the chemical reactions between guanine and two ultimate
      carcinogens, the 3,4-quinone forms of the estrogens estrone (E1) and estradiol
      (E2). DNA was truncated to guanine, i.e. no deoxyribose moiety was included. Due
      to a complex reaction that involves proton transfer via water molecules we
      applied linear free energy relationships rather than computation of the
      transition state and activation energies. The minima corresponding to reactants
      and products were obtained on the B3LYP/6-31G(d) level. The effects of hydration
      were considered using the solvent reaction field of Tomasi and co-workers and the
      Langevin dipoles model of Florian and Warshel. No significant difference in
      reaction free energy for the reaction involving estrone and estradiol metabolites
      was found, despite the fact that for the two substances different carcinogenic
      activities were reported. Differences in carcinogenicity may be therefore
      attributed to other types of interactions or reactions such as (i) specific
      interactions of the carbonyl or hydroxyl group with DNA giving rise to different
      activation free energies for the reactions, (ii) the reaction of depurination and
      subsequent effects on the DNA, (iii) enzymatic or nonenzymatic oxidation steps
      (P450, aromatase, peroxidases, O2) and detoxification reactions (catechol-O
      methyl transferase, S-transferase), or (iv) binding of the hormone to its nuclear
      receptors.

PMID- 15032507
TI  - Counterexamples in chemical ring perception.
AB  - Ring information is a large part of the structural topology used to identify and
      characterize molecular structures. It is hence of crucial importance to obtain
      this information for a variety of tasks in computational chemistry. Many
      different approaches for "ring perception", i.e., the extraction of cycles from a
      molecular graph, have been described. The chemistry literature on this topic,
      however, reports a surprisingly large number of incorrect statements about the
      properties of chemically relevant ring sets and, in particular, about the mutual
      relationships of different sets of cycles in a graph. In part these problems seem
      to have arisen from a sometimes rather idiosyncratic terminology for notions that
      are fairly standard in graph theory. In this contribution we translate the
      definitions of concepts such as the Smallest Set of Smallest Rings, Essential Set
      of Essential Rings, Extended Set of Smallest Rings, Set of Smallest Cycles at
      Edges, Set of Elementary Rings, K-rings, and beta-rings into a more widely used
      mathematical language. We then outline the basic properties of different cycle
      sets and provide numerous counterexamples to incorrect claims in the published
      literature. These counterexamples may have a serious practical impact because at
      least some of them are molecular graphs of well-known molecules. As a
      consequence, we propose a catalog of desirable properties for chemically useful
      sets of rings.

PMID- 15032508
TI  - The footprint sorting problem.
AB  - Phylogenetic footprints are short pieces of noncoding DNA sequence in the
      vicinity of a gene that are conserved between evolutionary distant species. A
      seemingly simple problem is to sort footprints in their order along the genomes.
      It is complicated by the fact that not all footprints are collinear: they may
      cross each other. The problem thus becomes the identification of the crossing
      footprints, the sorting of the remaining collinear cliques, and finally the
      insertion of the noncollinear ones at "reasonable" positions. We show that
      solving the footprint sorting problem requires the solution of the "Minimum
      Weight Vertex Feedback Set Problem", which is known to be NP-complete and APX
      hard. Nevertheless good approximations can be obtained for data sets of interest.
      The remaining steps of the sorting process are straightforward: computation of
      the transitive closure of an acyclic graph, linear extension of the resulting
      partial order, and finally sorting w.r.t. the linear extension. Alternatively,
      the footprint sorting problem can be rephrased as a combinatorial optimization
      problem for which approximate solutions can be obtained by means of general
      purpose heuristics. Footprint sortings obtained with different methods can be
      compared using a version of multiple sequence alignment that allows the
      identification of unambiguously ordered sublists. As an application we show that
      the rat has a slightly increased insertion/deletion rate in comparison to the
      mouse genome.

PMID- 15032509
TI  - 2D mapping by Kohonen networks of the air quality data from a large city.
AB  - The 15-variable environmental data (7 concentrations: CO, SO2, O3, NOx, NO, NO2,
      particulate matter smaller than 10 micron (PM10), and 8 weather data: cloudiness,
      rainfall, insolation factor (Isfi), temperature, pressure at two locations, and
      wind intensity with direction) in a period of 45 days with 1-h intervals were
      extracted from a larger database of concentrations recorded in minute intervals
      for the same time period. The monitoring site was located in the City of Buenos
      Aires in a relatively heavy traffic crossroad of two avenues. The data required
      special pretreatment where the hourly content of rain, wind intensity, wind
      velocity, and cloudiness were concerned. The new variable named insolation factor
      (relative UV radiation) calculated on the basis of the general meteorological
      data, the geographic position of the monitoring site, cloudiness, date, and the
      time of the recording was composed. The relative intensity of UV radiation was
      modeled by a Gaussian function, multiplied by a cloudiness factor. Based on the
      14-variable input and the 1-variable output (ozone) data, first, the clustering
      of all 980 data records was made. The top map clustering showing the ozone
      concentration was related to the maps of all 14 variables. The link between O3
      clusters, NO2, and Isfi weight levels is shown and discussed. As a preliminary
      result of this study some of the most interesting correlations between the maps
      and remaining variables are given.

PMID- 15032510
TI  - Noncovalent cross-links in context with other structural and functional elements
      of proteins.
AB  - Proteins are heteropolymers with evolutionary selected native sequences of
      residues. These native sequences code for unique and stable 3D structures
      indispensable for biochemical activity and for proteolysis resistance, the latter
      which guarantees an appropriate lifetime for the protein in the protease rich
      cellular environment. Cross-links between residues close in space but far in the
      primary structure are required to maintain the folded structure of proteins. Some
      of these cross-links are covalent, most frequently disulfide bonds, but the
      majority of the cross-links are sets of cooperative noncovalent long-range
      interactions. In this paper we focus on special clusters of noncovalent long
      range interactions: the Stabilization Centers (SCs). The relation between the SCs
      and secondary structural elements as well as the relation between SCs and
      functionally important regions of proteins are presented to show a detailed
      picture of these clusters, which are believed to be primarily responsible for
      major aspects of protein stability.

PMID- 15032511
TI  - Structure-mutagenicity study of 12 trimethylimidazopyridine isomers using orbital
      energies and "spectrum-like representation" as descriptors.
AB  - The set of 12 trimethylimidazopyridine isomers with mutagenic potency toward two
      strains of Salmonella was treated in this study. Ten isomers with known mutagenic
      properties were taken to build the models. Fifteen molecular orbital energies, or
      a "spectrum-like" representation of 3D structures, were taken as descriptors. As
      modeling techniques the multiple linear regression and the counter propagation
      neural network were applied. Models were tested with the recall ability test and
      the leave-one-out cross-validation tests. For two isomers, which have not been
      synthesized yet, we report predicted values for both mutagenic potencies obtained
      with different models. The best models were found when unoccupied molecular
      orbital energies are among the descriptors.

PMID- 15032512
TI  - Improving the performance of molecular dynamics simulations on parallel clusters.
AB  - In this article a procedure is derived to obtain a performance gain for molecular
      dynamics (MD) simulations on existing parallel clusters. Parallel clusters use a
      wide array of interconnection technologies to connect multiple processors
      together, often at different speeds, such as multiple processor computers and
      networking. It is demonstrated how to configure existing programs for MD
      simulations to efficiently handle collective communication on parallel clusters
      with processor interconnections of different speeds.

PMID- 15032513
TI  - Algebraic Kekule formulas for benzenoid hydrocarbons.
AB  - By assigning two pi-electrons of CC double bonds in a Kekule valence structure to
      a benzene ring if not shared by adjacent rings and one pi-electron if CC double
      bond is shared by two rings we arrived at numerical valence formulas for
      benzenoid hydrocarbons. We refer to numerical Kekule formulas as algebraic Kekule
      valence formulas to contrast them to the traditional geometrical Kekule valences
      formulas. The average over all numerical Kekule valence structures results in a
      single numerical structure when a benzenoid hydrocarbon molecule is considered.
      By ignoring numerical values the novel quantitative formula transforms into a
      qualitative one which can replace incorrectly used notation of pi-electron
      sextets to indicate aromatic benzenoids by placing inscribed circles in adjacent
      rings-which contradicts Clar's characterization of benzenoid hydrocarbons.

PMID- 15032514
TI  - Wiener-Hosoya index--a novel graph theoretical molecular descriptor.
AB  - We describe the construction of a novel molecular descriptor, called the Wiener
      Hosoya index, in view of its structural relationship to both the Wiener number W
      and the Hosoya topological index Z. It is shown that this index has a smaller
      degeneracy than many simple topological indices, including W, Z, and the
      connectivity index chi. In a way the index can be viewed as a particular
      generalization of the Wiener number.

PMID- 15032515
TI  - Organic synthesis--art or science?
AB  - The LHASA rules for finding strategic bonds in polycyclic target structures are
      analyzed with respect to the following question: Do the strategic bonds tend to
      give the greatest simplification upon disconnection, as measured by recently
      introduced indices of molecular complexity? The answer is yes, at least for the
      more general rules. This result implies that the bonds most useful for
      retrosynthetic disconnection can now be identified by a simple calculation rather
      than by application of a body of rules. It is concluded that organic synthesis,
      as far as described by these rules, has a mathematical basis and consequently can
      be considered a science as well as an art.

PMID- 15032517
TI  - Properties of star-branched polymer brushes.
AB  - A simple model of a polymer brush was constructed. The star polymers with three
      arms were terminally attached with one arm (the stem) to an impenetrable surface
      with the other two arms (branches) free. The excluded volume effect was included
      into the model as the only interaction. Therefore, the system was studied in good
      solvent conditions. The simulations were carried out by means of the dynamic
      Monte Carlo method using the local changes of chain conformations to sample
      efficiently the conformational space. The influence of both the number of chains
      (the grafting density) and the length of chains on the static properties of the
      polymer brush was studied. The internal and local structure of a formed polymer
      layer was determined. It was shown that the size of the stems increased rapidly
      with the increase of the grafting density, while the size of the branches
      diminished. The changes of the spatial orientations of the stems and the branches
      for different grafting densities were shown and discussed.

PMID- 15032516
TI  - Properties of grafted amphiphilic chains. A computer simulation study.
AB  - The model of a heteropolymer film formed by polypeptide chains was used for
      theoretical considerations. The linear chains consisting of amino acid residues
      were approximated by alpha carbon chains. Each chain was constructed on a very
      flexible [310] lattice. The inter- and intramolecular interactions consisted of
      the long-range contact potential between residues. The chains were built of
      hydrophilic and hydrophobic residues. Chains were terminally attached to an
      impenetrable surface with lateral motions possible. The Monte Carlo simulations
      of this model were carried out by using the Metropolis algorithm. The influence
      of the grafting density, the sequence of the amino acid residues, and the
      temperature on the static properties of the formed layer were studied and
      discussed. It was shown that homopolymer chains collapsed at higher temperature
      than the heteropolymers. The size of the polymers forming brush was smaller for
      homopolymers than for heteropolymers. The structure of the resulting polymer film
      and of its external surface was determined. The block copolymers formed well
      defined hydrophobic and hydrophilic layers, while for the amphiphilic case the
      composition of the brush layers changed continuously at high temperature. It was
      observed that the latter effect vanished at the collapsed amphiphilic copolymer.

PMID- 15032518
TI  - Prediction of thermodynamic parameters in gas chromatography from molecular
      structure: hydrocarbons.
AB  - Theoretical prediction of gas-chromatographic retention times could be used as an
      additional method for a more accurate identification of organic compounds during
      GC/MS analysis. Two separate quantitative structure-property relationship models
      were introduced for the calculation of thermodynamic values (DeltaH degrees,
      DeltaS degrees) for aliphatic and aromatic hydrocarbons. These values are
      required for the calculation of retention times in temperature programmed gas
      chromatography. Seven-descriptor and five-descriptor MLR models were selected for
      the calculation of DeltaH degrees and DeltaS degrees values, respectively, based
      on the best cross-validation abilities. The final prediction capabilities of the
      models were evaluated by a test set procedure. RMS errors calculated from the
      test set were 207 cal mol(-1) and 0.58 cal mol(-1) K(-1) for DeltaH degrees and
      DeltaS degrees prediction models, respectively. To evaluate the error of the
      models represented in the time scale, several chromatograms were simulated using
      experimental Pro ezGC and theoretically calculated thermodynamic data. Afterward
      a standard deviation of retention time residuals was calculated. It was found out
      that, although the standard deviation varies from one chromatographic condition
      to another, the ratio between the standard deviation and the maximum available
      separation space for the particular set of organic compounds remains constant and
      was around 5% of the maximum separation space available at selected
      chromatographic conditions. Our prediction model was able to accurately
      differentiate between the retention times of the consecutive compounds in the n
      alkanes, 1-alkenes, and 2-alkenes homological series.

PMID- 15032519
TI  - Enumeration of conjugated circuits in nanotubes.
AB  - The resonance energy of (1,1)n "armchair" carbon nanotubes and (n,n)1 nanoribbons
      was determined by enumerating the conjugated circuits (CC) and the Kekule
      structures. The lower indices denote the number of hexagon layers. It was found
      that the resonance energy per carbon atom is equal to 0.160 eV in (1,1)n tubes
      and 0.142 eV in (n,n)1 tubes.

PMID- 15032520
TI  - Coding and ordering Kekule structures.
AB  - The concept of numerical Kekule structures is used for coding and ordering
      geometrical (standard) Kekule structures of several classes of polycyclic
      conjugated molecules: catacondensed, pericondensed, and fully arenoid benzenoid
      hydrocarbons, thioarenoids, and [N]phenylenes. It is pointed out that the
      numerical Kekule structures can be obtained for any class of polycyclic
      conjugated systems that possesses standard Kekule structures. The reconstruction
      of standard Kekule structures from the numerical ones is straightforward for
      catacondensed systems, but this is not so for pericondensed benzenoid
      hydrocarbons. In this latter case, one needs to use two codes to recover the
      geometrical Kekule structures: the Wiswesser code for the benzenoid and the
      numerical code for its Kekule structure. There is an additional problem with
      pericondensed benzenoid hydrocarbons; there appear numerical Kekule structures
      that correspond to two (or more) geometrical Kekule structures. However, this
      problem can also be resolved.

PMID- 15032521
TI  - Entropic trapping binding mechanism: its likely role in receptor-ligand and other
      biochemical systems.
AB  - Entropy-driven binding continues to be discovered in receptor-ligand systems as
      well as in other important biochemical systems. In receptor-ligand systems the
      "thermodynamic agonist-antagonist discrimination" is often found: in some such
      receptor types the binding of antagonists is entropy-driven, in others this is a
      characteristic of the agonist binding. The interpretation of the entropy-driven
      binding mechanism in the systems in question is still rather elusive.
      Experimental findings clearly indicate that the entropic binding mechanisms which
      are usually considered cannot provide a consistent interpretation in these cases.
      Entropic trapping was therefore proposed in our earlier papers as a possible
      binding model which does not contradict the experimental facts. It is pointed out
      here that through the work which has appeared subsequently the existence of such
      a mechanism has been firmly established and that its role is strongly
      corroborated by the more recent data from several biochemical systems.

PMID- 15032522
TI  - The signature molecular descriptor. 4. Canonizing molecules using extended
      valence sequences.
AB  - We present a new algorithm to canonize molecular graphs using the signature
      molecular descriptor introduced in the previous papers of this series. While
      developed specifically for molecular structures, the algorithm can be used for
      any graph and is not limited to acyclic graphs, planar graphs, bounded valence,
      or bounded genus graphs, for which polynomial time algorithms exist. The
      algorithm is tested with benzenoid hydrocarbons and a database of 126,705 organic
      compounds. The algorithm's performances are compared against Brendan Mc Kay's
      Nauty algorithm, which is believed to be the fastest graph canonization algorithm
      for general graphs, with five series of graphs each comprising up to 30,000
      vertices: 2D meshes (pericondensed benzenoids), 3D cages (fullerenes and
      nanotubes), 3D meshes (crystal lattices), 4D cages, and power law graphs (protein
      and gene networks). The algorithm can be downloaded as an open source code at
      http://www.cs.sandia.gov/ approximately jfaulon/QSAR.

PMID- 15032523
TI  - Structural interpretation of a topological index. 1. External factor variable
      connectivity index (EFVCI).
AB  - The external factor variable connectivity index (EFVCI) is interpreted by mining
      out the structural features hidden in the space spanned by the EFVCI indices
      through projection pursuit combining with number-theory net (NT-net) on the unit
      sphere U(Us). Projection pursuit is concerned with "interesting" projections of
      high-dimensional data sets to machine-pick "interesting" low-dimensional
      projections of a high-dimensional point cloud by numerically maximizing a certain
      objective function or projection index. At first, the optimal EFVCI index reaches
      to -0.80 in the correlation with a retention index of 207 hydrocarbons produced
      by insects. The EFVCI indices, with regression results of R = 0.99998, s = 3.49,
      RMSECV = 3.90, and F = 7.9560e+005, obtain high regression quality. The model is
      proven valid by leave-one-out cross validation. Second, the EFVCI index is
      interpreted by the structure information, that is, size, branch number, graph
      center, and branching position of topological structures, which is searched out
      on the unit sphere U(Us) by projection pursuit. Finally, the interpretation
      information is used to discover some chemical knowledge concerning the variation
      of the retention index with the change in chemical structures.

PMID- 15032524
TI  - Representation of the molecular topology of cyclical structures by means of cycle
      graphs. 1. Extraction of topological properties.
AB  - In this paper, a new representation model using the existing cycles in the
      topological structure of the molecules is proposed. Extracting all cycles of a
      molecule, its topological structure can be represented by means of a weighted,
      colored, and nondirected graph named "cycle graph", where the nodes represent the
      cycles in the molecule and the edges the common nodes among those cycles. In this
      paper, the capacity of cycle graph for the extraction of topological descriptors
      contributing appropriate measures of complexity, cyclicity, and symmetry of
      cyclical systems is presented.

PMID- 15032525
TI  - Chemical markup, XML, and the World Wide Web. 5. Applications of chemical
      metadata in RSS aggregators.
AB  - Examples of the use of the RSS 1.0 (RDF Site Summary) specification together with
      CML (Chemical Markup Language) to create a metadata based alerting service termed
      CMLRSS for molecular content are presented. CMLRSS can be viewed either using
      generic software or with modular opensource chemical viewers and editors enhanced
      with CMLRSS modules. We discuss the more automated use of CMLRSS as a component
      of a World Wide Molecular Matrix of semantically rich chemical information.

PMID- 15032526
TI  - Data shaving: a focused screening approach.
AB  - The number of compounds available for evaluation as part of the drug discovery
      process continues to increase. These compounds may exist physically or be stored
      electronically allowing screening by either actual or virtual means. This growing
      number of compounds has generated an increasing need for effective strategies to
      direct screening efforts. Initial efforts toward this goal led to the development
      of methods to select diverse sets of compounds for screening, methods to cluster
      actives into related groups of compounds, and tools to select compounds similar
      to actives of interest for further screening. In this work we extend these
      earlier efforts to exploit information about inactive compounds to help make
      rational decisions about which sets of compounds to include as part of a
      continuing screening campaign, or as part of a focused follow-up effort. This
      method uses the information from inactive compounds to "shave" off or
      deprioritize compounds similar to inactives from further consideration. This
      methodology can be used in two ways: first, to provide a rational means of
      deciding when sufficient compounds containing certain structural features have
      been tested and second as a tool to enhance similarity searching around known
      actives. Similarity searching is improved by deprioritizing compounds predicted
      to be inactive, due to the presence of structural features associated with
      inactivity.

PMID- 15032528
TI  - Evolutionary-algorithm-based strategy for computer-assisted structure
      elucidation.
AB  - An evolutionary algorithm (EA) using a graph-based data structure to explore the
      molecular constitution space is presented. The EA implementation proves to be a
      promising alternative to deterministic approaches to the problem of computer
      assisted structure elucidation (CASE). While not relying on any external
      database, the EA-guided CASE program SENECA is able to find correct solutions
      within calculation times comparable to that of other CASE expert systems. The
      implementation presented here significantly expands the size limit of
      constitutional optimization problems treatable with evolutionary algorithms by
      introducing novel efficient graph-based genetic operators. The new EA-based
      search strategy is discussed including the underlying data structures, component
      design, parameter optimization, and evolution process control. Typical structure
      elucidation examples are given to demonstrate the algorithm's performance.

PMID- 15032527
TI  - Combining ethnopharmacology and virtual screening for lead structure discovery:
      COX-inhibitors as application example.
AB  - Virtual screening of large libraries of organic compounds combined with
      pharmacological high throughput screening is widely used for drug discovery in
      the pharmaceutical industry. Our aim was to explore the efficiency of using a
      biased 3D database comprising secondary metabolites from antiinflammatory
      medicinal plants as a source for the virtual screening. For this study
      pharmacophore models of cyclooxygenase I and II (COX-1, COX-2), key enzymes in
      the inflammation process, were generated with structure-based as well as common
      feature based modeling, resulting in three COX hypotheses. Four different
      multiconfomational 3D databases limited in molecular weight between 300 and 700
      Da were applied to the screening in order to compare and analyze the obtained hit
      rates. Two of them were created in-house (DIOS, NPD). The database DIOS consists
      of 2752 compounds from phytochemical reports of antiinflammatory medicinal plants
      described by the ethnopharmacological source 'De material medica' of Pedanius
      Dioscorides, whereas NPD contains almost 80,000 compounds gathered arbitrarily
      from natural sources. In addition, two available multiconformational 3D libraries
      comprising marketed and development drug substances (DWI and NCI), mainly
      originating from synthesis, were used for comparison. As a test of the
      pharmacophore models' capability in natural sources, the models were used to
      search for known COX inhibitory natural products. This was achieved with some
      exceptions, which are discussed in the paper. Depending on the hypothesis used,
      DWI and NCI library searches produced hit rates in the range of 6.6% to 13.7%. A
      slight increase of the number of molecules assessed for binding was achieved with
      the database of natural products (NPD). Using the biased 3D database DIOS,
      however, the average increase of efficiency reached 77% to 133% compared to the
      hit rates resulting from WDI and NCI. The statistical benefit of a combination of
      an ethnopharmacological approach with the potential of computer aided drug
      discovery by in silico screening was demonstrated exemplified on the applied
      targets COX-1 and COX-2.

PMID- 15032529
TI  - Detection and classification of organophosphate nerve agent simulants using
      support vector machines with multiarray sensors.
AB  - The need for rapid and accurate detection systems is expanding and the
      utilization of cross-reactive sensor arrays to detect chemical warfare agents in
      conjunction with novel computational techniques may prove to be a potential
      solution to this challenge. We have investigated the detection, prediction, and
      classification of various organophosphate (OP) nerve agent simulants using sensor
      arrays with a novel learning scheme known as support vector machines (SVMs). The
      OPs tested include parathion, malathion, dichlorvos, trichlorfon, paraoxon, and
      diazinon. A new data reduction software program was written in MATLAB V. 6.1 to
      extract steady-state and kinetic data from the sensor arrays. The program also
      creates training sets by mixing and randomly sorting any combination of data
      categories into both positive and negative cases. The resulting signals were fed
      into SVM software for "pairwise" and "one" vs all classification. Experimental
      results for this new paradigm show a significant increase in classification
      accuracy when compared to artificial neural networks (ANNs). Three kernels, the
      S2000, the polynomial, and the Gaussian radial basis function (RBF), were tested
      and compared to the ANN. The following measures of performance were considered in
      the pairwise classification: receiver operating curve (ROC) Az indices,
      specificities, and positive predictive values (PPVs). The ROC Az) values,
      specifities, and PPVs increases ranged from 5% to 25%, 108% to 204%, and 13% to
      54%, respectively, in all OP pairs studied when compared to the ANN baseline.
      Dichlorvos, trichlorfon, and paraoxon were perfectly predicted. Positive
      prediction for malathion was 95%.

PMID- 15032530
TI  - A novel definition of the overall hyper-wiener index for unsaturated
      hydrocarbons.
AB  - By replacing the distances between pairs of vertices with the relative distances,
      we define a novel overall hyper-Wiener index (NOR); the novel overall hyper
      Wiener index extends the usefulness of the hyper-Wiener index and the overall
      hyper-Wiener index to unsaturated hydrocarbons.

PMID- 15032531
TI  - Designing antibacterial compounds through a topological substructural approach.
AB  - A novel application of TOPological Substructural MOlecular DEsign (TOPS-MODE) was
      carried out in antibacterial drugs using computer-aided molecular design. Two
      series of compounds, one containing antibacterial and the other containing non
      antibacterial compounds, were processed by a k-means cluster analysis in order to
      design training and predicting series. All clusters had a p-level < 0.005.
      Afterward, a linear classification function has been derived toward
      discrimination between antibacterial and non-antibacterial compounds. The model
      correctly classifies 94% of active and 86% of inactive compounds in the training
      series. More specifically, the model showed a global good classification of 91%,
      i.e., 263 cases out of 289. In predicting series, the model has shown overall
      predictabilities of 91 and 83% for active and inactive compounds, respectively.
      Thereby, the model has a global percentage of good classification of 89%. The
      TOPS-MODE approach, also, similarly compares with respect to one of the most
      useful models for antimicrobials selection reported to date.

PMID- 15032532
TI  - The Wiener distance matrix for acyclic compounds and polymers.
AB  - The relationship between the Wiener indices and the topological structures of
      alkanes is analyzed. The expressions for the Wiener distances between elements of
      these structures are derived, and the distance matrix is constructed for them;
      this matrix is naturally called the Wiener distance matrix. The expressions for
      the Wiener indices of polymers with units of arbitrary structure are obtained.

PMID- 15032534
TI  - MOLGEN-CID--A canonizer for molecules and graphs accessible through the Internet.
AB  - The MOLGEN Chemical Identifier MOLGEN-CID is a software module freely accessible
      via the Internet. For a molecule or graph entered in molfile format (2D) it
      produces, by a canonical renumbering procedure, a canonical molfile and a unique
      character string that is easily compared by computer to a similar string. The
      mode of operation of MOLGEN-CID is detailed and visualized with examples.

PMID- 15032533
TI  - Quantitative structure-property relationship modeling of beta-cyclodextrin
      complexation free energies.
AB  - CODESSA-PRO was used to model binding energies for 1:1 complexation systems
      between 218 organic guest molecules and beta-cyclodextrin, using a seven
      parameter equation with R2 = 0.796 and Rcv2 = 0.779. Fragment-based TRAIL
      calculations gave a better fit with R2 = 0.943 and Rcv2 = 0.848 for 195 data
      points in the database. The advantages and disadvantages of each approach are
      discussed, and it is concluded that a combination of the two approaches has much
      promise from a practical viewpoint.

PMID- 15032535
TI  - Comparison of an empirical and a theoretical linear solvation energy relationship
      applied to the characterization of solute distribution in a poly(ethylene) glycol
      salt aqueous biphasic system.
AB  - A Linear Solvation Energy Relationship (LSER) developed by Abraham has been
      applied to the partition of organic solutes in an Aqueous Biphasic System (ABS)
      and to published values of their 1-octanol/water partition coefficients. The
      results are compared to the application of a conceptually similar Theoretical
      Linear Solvation Energy Relationship (TLSER) developed by Famini and co-workers.
      Differences and similarities in the molecular properties highlighted by each LSER
      are discussed. The theoretical relationship of Famini, although modeled on the
      approach of Abraham, seems not to encapsulate molecular properties in the same
      way as the Abraham's empirical relationship. However, this theoretical approach
      has the great merit of computational simplicity, and it is concluded that efforts
      directed toward its improvement could be rewarding.

PMID- 15032536
TI  - QSTR with extended topochemical atom indices. 2. Fish toxicity of substituted
      benzenes.
AB  - Considering the importance of quantitative structure-toxicity relationship (QSTR)
      studies in the field of aquatic toxicology from the viewpoint of ecological
      safety assessment, fish toxicity of various benzene derivatives has been modeled
      by the multiple regression technique using recently introduced extended
      topochemical atom (ETA) indices. The toxicity data have also been modeled using
      other selected topological descriptors and physicochemical variables, and the
      best ETA model has been compared to the non-ETA ones. Principal component factor
      analysis was used as the data preprocessing step to reduce the dimensionality of
      the data matrix and identify the important variables that are devoid of
      collinearities. All-possible-subsets regression was also applied on the
      parameters to cross-check the variable selection for the best model. Multiple
      linear regression analyses show that the best non-ETA model involves 1chi,
      ALogP98, and LUMO (energy) as predictor variables and the quality of the relation
      is as follows: n = 92, Q2 = 0.718, Ra2 = 0.730, R2 = 0.738, R = 0.859, F = 82.8
      (df 3, 88), s = 0.340. On the other hand, the best ETA model has the following
      quality: n = 92, Q2 = 0.865, Ra2 = 0.876, R2 = 0.885, R = 0.941, F = 92.6 (df 7,
      84), s = 0.230. The ETA relations showed positive contributions of molecular bulk
      (size), chloro and hydroxy substitutions in the benzene ring, and the
      simultaneous presence of methyl and nitro substitutions to the toxicity. Further,
      the presence of fluoro and ether functionality, amino or nitro functionality in
      an otherwise unsubstituted ring, and nitro functionality that is ortho to a
      chloro substituent decreases toxicity. An attempt to use non-ETA descriptors
      along with ETA ones did not improve the quality in comparison to the best ETA
      model. Interestingly, the ETA model developed presently for the fish toxicity is
      better than the previously reported models on the same data set. Thus, it appears
      that ETA descriptors have significant potential in QSAR/QSPR/QSTR studies, which
      warrants extensive evaluation.

PMID- 15032538
TI  - A chemical index inspired by biological plastic evolution: valence-isoelectronic
      series of aromatics.
AB  - Plastic evolution is a new perspective of the evolutionary process conjugating
      the effect, on one hand, of the acquired characters and, on the other, of the
      relationships that emerge among the principle of evolutionary indeterminacy, the
      principle of morphologic determination, and natural selection. Plastic evolution
      is applied to design the coordination index Ic. Ic is used to characterize the
      valence-isoelectronic series of cyclopentadiene, benzene, toluene, and styrene
      and compared to charge indices for dipole moment. The parameters needed to
      calculate Ic are minus the standard enthalpy of formation T, molecular surface
      area S, and molecular weight W. With the exception of the O heteromolecule, Ic
      allows differentiating quantitatively the styrene series as well as the
      cyclopentadiene from the toluene series. Ic improves the multivariable regression
      equations for dipole moment and is a predictive index when it is used together
      with the topological charge indices. The correction introduced in the dipole
      moment is produced in the correct direction. Inclusion of the heteroatom in the
      pi-electron system is beneficial for the description of the dipole moment, owing
      to either the role of additional p and/or d orbitals provided by the heteroatom
      or the role of steric factors in the pi-electron conjugation. Principal component
      analysis groups the chemical indices in three classes, which are in agreement
      with cluster analysis.

PMID- 15032537
TI  - Artificial neural network modification of simulation-based fitting: application
      to a protein-lipid system.
AB  - Simulation-based fitting has been applied to data analysis and parameter
      determination of complex experimental systems in many areas of chemistry and
      biophysics. However, this method is limited because of the time costs of the
      calculations. In this paper it is proposed to approximate and substitute a
      simulation model by an artificial neural network during the fitting procedure.
      Such a substitution significantly speeds up the parameter determination. This
      approach is tested on a model of fluorescence resonance energy transfer (FRET)
      within a system of site-directed fluorescence labeled M13 major coat protein
      mutants incorporated into a lipid bilayer. It is demonstrated that in our case
      the application of a trained artificial neural network for the substitution of
      the simulation model results in a significant gain in computing time by a factor
      of 5 x 10(4). Moreover, an artificial neural network produces a smooth
      approximation of the noisy results of a stochastic simulation.

PMID- 15032540
TI  - Molecular symmetry perception.
AB  - An algorithm for molecular symmetry perception is presented. The method
      identifies the full set of molecular symmetry elements (proper and improper) and
      determines their coordinates. The algorithm eliminates the necessity to explore
      the entire graph automorphism group; as a result its computer application is
      extremely effective. Application to several dendrimers and fullerenes with high
      topological symmetry is presented.

PMID- 15032539
TI  - Combinatorial QSAR of ambergris fragrance compounds.
AB  - A combinatorial quantitative structure-activity relationships (Combi-QSAR)
      approach has been developed and applied to a data set of 98 ambergris fragrance
      compounds with complex stereochemistry. The Combi-QSAR approach explores all
      possible combinations of different independent descriptor collections and various
      individual correlation methods to obtain statistically significant models with
      high internal (for the training set) and external (for the test set) accuracy.
      Seven different descriptor collections were generated with commercially available
      MOE, CoMFA, CoMMA, Dragon, VolSurf, and MolconnZ programs; we also included
      chirality topological descriptors recently developed in our laboratory
      (Golbraikh, A.; Bonchev, D.; Tropsha, A. J. Chem. Inf. Comput. Sci. 2001, 41, 147
      158). CoMMA descriptors were used in combination with MOE descriptors. MolconnZ
      descriptors were used in combination with chirality descriptors. Each descriptor
      collection was combined individually with four correlation methods, including k
      nearest neighbors (kNN) classification, Support Vector Machines (SVM), decision
      trees, and binary QSAR, giving rise to 28 different types of QSAR models.
      Multiple diverse and representative training and test sets were generated by the
      divisions of the original data set in two. Each model with high values of leave
      one-out cross-validated correct classification rate for the training set was
      subjected to extensive internal and external validation to avoid overfitting and
      achieve reliable predictive power. Two validation techniques were employed, i.e.,
      the randomization of the target property (in this case, odor intensity) also
      known as the Y-randomization test and the assessment of external prediction
      accuracy using test sets. We demonstrate that not every combination of the data
      modeling technique and the descriptor collection yields a validated and
      predictive QSAR model. kNN classification in combination with CoMFA descriptors
      was found to be the best QSAR approach overall since predictive models with
      correct classification rates for both training and test sets of 0.7 and higher
      were obtained for all divisions of the ambergris data set into the training and
      test sets. Many predictive QSAR models were also found using a combination of kNN
      classification method with other collections of descriptors. The combinatorial
      QSAR affords automation, computational efficiency, and higher probability of
      identifying significant QSAR models for experimental data sets than the
      traditional approaches that rely on a single QSAR method.

PMID- 15032541
TI  - Conditional probability: a new fusion method for merging disparate virtual
      screening results.
AB  - This paper introduces a new consensus scoring approach for merging the results of
      different virtual screening methods based on conditional probabilities. The
      technique is experimentally evaluated using several ligand-based virtual
      screening methods and compared to two variations of the established Sum-rank
      fusion method where it performs as well or better than the Sum-rank methods. Our
      experiments confirm that consensus scoring increases the number of active
      compounds retrieved with respect to the best individual methods on average.

PMID- 15032542
TI  - Parameter-free structure-property correlation via progressive reaction posets for
      substituted benzenes.
AB  - Progressive reaction networks as frequently arise in chemistry are naturally
      identifiable as "partially ordered sets" (or posets). Here the direction of the
      reaction identifies the partial ordering of the set of molecular species. The
      possibility that different properties are similarly ordered is a further natural
      consideration and is here investigated for a suite of over 30 properties for
      (methyl and chloro) substituted benzenes. Such a posetic correlation is favorably
      demonstrated for these substituted benzenes, and it is illustrated how suitable
      properties may be simply predicted in an interpolative parameter-free (albeit not
      model-free) fashion through the use of the reaction poset. Some numerical model
      quality indicators are identified, and the simple approach is deemed quite
      reasonable.

PMID- 15032543
TI  - Estimation of averaged ranks by a local partial order model.
AB  - This paper continues the series of publications about applications of partial
      ordering. The focus of this publication is the derivation of approximate
      analytical expressions for the averaged rank and the ranking probabilities. To
      derive such combinatorial formulas a local partial order is suggested as an
      approximation. The performance of the approximation is rather high; we therefore
      conclude that three very simple descriptors of the local partial order seem to be
      sufficient to get a rough impression of the linear order, induced by the averaged
      ranks and the ranking probabilities of empirical partially ordered sets. Linear
      order derived from the partial order, ranking probabilities, and other
      characteristics are considered as parts of a so-called "General Ranking Model"
      (GRM). Following the local partial order, the averaged rank of an object x can be
      estimated applying the following simple formula: Rk(av) = (S+1)*(N+1)/(N+1-U). S
      is the number of successors of the object x, N is the total number of objects (of
      the quotient set), and U is the number of objects incomparable with x. More
      complex formulas for the ranking probabilities are given in the text. A list of
      abbreviations and symbols can be found in Tables 3 and 4.

PMID- 15032544
TI  - Mining high-throughput screening data of combinatorial libraries: development of
      a filter to distinguish hits from nonhits.
AB  - Kohonen neural networks generate projections of large data sets defined in high
      dimensional space. The resulting self-organizing maps can be used in many
      applications in the drug discovery process, such as to analyze combinatorial
      libraries for their similarity or diversity and to select descriptors for
      structure-activity relationships. The ability to investigate thousands of
      compounds in parallel also allows one to conduct a study based on single-dose
      experiments of high-throughput screening campaigns, which are known to have a
      greater uncertainty than IC50 or Ki values. This is demonstrated here for a data
      set of 5513 compounds from one combinatorial library. Furthermore, a method was
      developed that uses self-organizing maps not only as an indicator of structure
      activity relationships, but as the basis of a classification system allowing
      predictive modeling of combinatorial libraries.

PMID- 15032545
TI  - Numerical performance and throughput benchmark for electronic structure
      calculations in PC-Linux systems with new architectures, updated compilers, and
      libraries.
AB  - A number of recently released numerical libraries including Automatically Tuned
      Linear Algebra Subroutines (ATLAS) library, Intel Math Kernel Library (MKL), GOTO
      numerical library, and AMD Core Math Library (ACML) for AMD Opteron processors,
      are linked against the executables of the Gaussian 98 electronic structure
      calculation package, which is compiled by updated versions of Fortran compilers
      such as Intel Fortran compiler (ifc/efc) 7.1 and PGI Fortran compiler
      (pgf77/pgf90) 5.0. The ifc 7.1 delivers about 3% of improvement on 32-bit
      machines compared to the former version 6.0. Performance improved from pgf77 3.3
      to 5.0 is also around 3% when utilizing the original unmodified optimization
      options of the compiler enclosed in the software. Nevertheless, if extensive
      compiler tuning options are used, the speed can be further accelerated to about
      25%. The performances of these fully optimized numerical libraries are similar.
      The double-precision floating-point (FP) instruction sets (SSE2) are also
      functional on AMD Opteron processors operated in 32-bit compilation, and Intel
      Fortran compiler has performed better optimization. Hardware-level tuning is able
      to improve memory bandwidth by adjusting the DRAM timing, and the efficiency in
      the CL2 mode is further accelerated by 2.6% compared to that of the CL2.5 mode.
      The FP throughput is measured by simultaneous execution of two identical copies
      of each of the test jobs. Resultant performance impact suggests that IA64 and
      AMD64 architectures are able to fulfill significantly higher throughput than the
      IA32, which is consistent with the SpecFPrate2000 benchmarks.

PMID- 15032546
TI  - Drug-like annotation and duplicate analysis of a 23-supplier chemical database
      totalling 2.7 million compounds.
AB  - We have implemented five drug-like filters, based on 1D and 2D molecular
      descriptors, and applied them to characterize the drug-like properties of
      commercially available chemical compounds. In addition to previously published
      filters (Lipinski and Veber), we implemented a filter for medicinal chemistry
      tractability based on lists of chemical features drawn up by a panel of medicinal
      chemists. A filter based on the modeling of aqueous solubility (>1 microM) was
      derived in-house, as well as another based on the modeling of Caco-2 passive
      membrane permeability (>10 nm/s). A library of 2.7 million compounds was collated
      from the 23 compound suppliers and analyzed with these filters, highlighting a
      tendency toward highly lipophilic compounds. The library contains 1.6 M unique
      structures, of which 37% (607,223) passed all five drug-like filters. None of the
      23 suppliers provides all the members of the drug-like subset, emphasizing the
      benefit of considering compounds from various compound suppliers as a source of
      diversity for drug discovery.

PMID- 15032547
TI  - Hammett equation and generalized Pauling's electronegativity equation.
AB  - Substituent interaction energy (SIE) was defined as the energy change of the
      isodesmic reaction X-spacer-Y + H-spacer-H --> X-spacer-H + H-spacer-Y. It was
      found that this SIE followed a simple equation, SIE(X,Y) = -ksigma(X)sigma(Y),
      where k was a constant dependent on the system and sigma was a certain scale of
      electronic substituent constant. It was demonstrated that the equation was
      applicable to disubstituted bicyclo[2.2.2]octanes, benzenes, ethylenes,
      butadienes, and hexatrienes. It was also demonstrated that Hammett's equation was
      a derivative form of the above equation. Furthermore, it was found that when
      spacer = nil the above equation was mathematically the same as Pauling's
      electronegativity equation. Thus it was shown that Hammett's equation was a
      derivative form of the generalized Pauling's electronegativity equation and that
      a generalized Pauling's electronegativity equation could be utilized for diverse
      X-spacer-Y systems. In addition, the total electronic substituent effects were
      successfully separated into field/inductive and resonance effects in the equation
      SIE(X,Y) = -k(1)F(X)F(Y) - k(2)R(X)R(Y) - k(3)(F(X)R(Y) + R(X)F(Y)). The
      existence of the cross term (i.e., F(X)R(Y) and R(X)F(Y)) suggested that the
      field/inductive effect was not orthogonal to the resonance effect because the
      field/inductive effect from one substituent interacted with the resonance effect
      from the other. Further studies on multi-substituted systems suggested that the
      electronic substituent effects should be pairwise and additive. Hence, the SIE in
      a multi-substituted system could be described using the equation SIE(X1, X2, ...,
      Xn) = Sigma(n-1)(i=1)Sigma(n)(j=i+1)k(ij)sigma(X)isigma(X)j.

PMID- 15032548
TI  - New molecular descriptors based on local properties at the molecular surface and
      a boiling-point model derived from them.
AB  - New molecular descriptors based on statistical descriptions of the local
      ionization potential, local electron affinity, and the local polarizability at
      the surface of the molecule are proposed. The significance of these descriptors
      has been tested by calculating them for the Maybridge database in addition to our
      set of 26 descriptors reported previously. The new descriptors show little
      correlation with those already in use. Furthermore, the principal components of
      the extended set of descriptors for the Maybridge data show that especially the
      descriptors based on the local electron affinity extend the variance in our set
      of descriptors, which we have previously shown to be relevant to physical
      properties. The first nine principal components are shown to be most significant.
      As an example of the usefulness of the new descriptors, we have set up a QSPR
      model for boiling points using both the old and new descriptors.

PMID- 15032550
TI  - Topological steric effect index and its application.
AB  - This paper proposed a Topological Steric Effect Index (TSEI) of a group based on
      the relative specific volume of the reaction center screened by the atoms of the
      substituents. Investigated results show good correlations between the parameter
      TSEI and the dihedral angles between both phenyl rings determined by
      photoelectron spectroscopy for 7 alkylbiphenyl compounds and calculated by a
      molecular mechanics force field for 78 alkylbiphenyl compounds, whose correlation
      coefficients are 0.9912 and 0.9845, respectively. The TSEI value of the group is
      easily calculated and has a clear physical meaning. In addition, it is correlated
      well to dihedral angles of the 1,2-disubstituted benzene compounds,
      stereoselectivity of organomagnesium compounds addition to some cyclohexanones
      and cyclopentanones, and the relative rates of some SN2 reactions.

PMID- 15032549
TI  - An accurate QSPR study of O-H bond dissociation energy in substituted phenols
      based on support vector machines.
AB  - The support vector machine (SVM), as a novel type of learning machine, was used
      to develop a Quantitative Structure-Property Relationship (QSPR) model of the O-H
      bond dissociation energy (BDE) of 78 substituted phenols. The six descriptors
      calculated solely from the molecular structures of compounds selected by forward
      stepwise regression were used as inputs for the SVM model. The root-mean-square
      (rms) errors in BDE predictions for the training, test, and overall data sets
      were 3.808, 3.320, and 3.713 BDE units (kJ mol(-1)), respectively. The results
      obtained by Gaussian-kernel SVM were much better than those obtained by multiple
      linear regression, radial basis function neural networks, linear-kernel SVM, and
      other QSPR approaches.

PMID- 15032551
TI  - From knowledge generation to knowledge archive. A general strategy using TOPS
      MODE with DEREK to formulate new alerts for skin sensitization.
AB  - A general strategy for knowledge flow concerning skin sensitization based on the
      combined use of TOPS-MODE and DEREK expert system is proposed. TOPS-MODE is used
      as a knowledge generator, while DEREK represents the knowledge archive. A TOPS
      MODE classification model allows the identification of structural fragments and
      groups responsible for strong/moderate skin sensitization. These structural
      contributions are sorted, analyzed, and graphically displayed in an appropriate
      way allowing the identification of several structural alerts for skin
      sensitization. Nine structural alerts already implemented in DEREK are identified
      using this strategy. They comprise, among others, alkyl halides, aldehydes,
      alpha,beta-unsaturated compounds, aromatic amines, phenols, hydroquinone,
      isothiazolinone, and alkyl sulfonates. Four new hypotheses are generated using
      TOPS-MODE structural contributions to skin sensitization, which are not
      recognized as structural alerts by DEREK. They include the reduction of aromatic
      nitro groups and epoxidation reaction of double bonds as metabolic activation
      steps that can lead to reactive haptens which can trigger the skin sensitization
      mechanism. Another new alert is based on 1,2,5-thiadiazole-1,1-dioxide for which
      we have identified a possible mechanism explaining its strong skin sensitization
      profile. It is based on the existence of a tautomeric equilibrium and further
      reaction with nucleophiles, which are both supported by experimental evidence.
      Finally, we have identified a possible new mechanism for the skin sensitization
      of nonreactive compounds, which involves the formation of noncovalent complexes
      with proteins in a processing- and metabolism-independent way.

PMID- 15032552
TI  - Predicting protein-ligand binding affinities using novel geometrical descriptors
      and machine-learning methods.
AB  - Inspired by the concept of knowledge-based scoring functions, a new quantitative
      structure-activity relationship (QSAR) approach is introduced for scoring protein
      ligand interactions. This approach considers that the strength of ligand binding
      is correlated with the nature of specific ligand/binding site atom pairs in a
      distance-dependent manner. In this technique, atom pair occurrence and distance
      dependent atom pair features are used to generate an interaction score. Scoring
      and pattern recognition results obtained using Kernel PLS (partial least squares)
      modeling and a genetic algorithm-based feature selection method are discussed.

PMID- 15032553
TI  - ESP: a method to predict toxicity and pharmacological properties of chemicals
      using multiple MCASE databases.
AB  - We describe here the development of a computer program which uses a new method
      called Expert System Prediction (ESP), to predict toxic end points and
      pharmacological properties of chemicals based on multiple modules created by the
      MCASE artificial intelligence system. The modules are generally based on
      different biological models measuring related end points. The purpose is to
      improve the decision making process regarding the overall activity or inactivity
      of the chemicals and also to enable rapid in silico screening. ESP evaluates the
      significance of the biophores from a different viewpoint and uses this
      information for predicting the activity of new chemicals. We have used a unique
      encoding system to represent relevant features of a chemical in the form of a
      pattern vector and a genetic artificial neural network (GA-ANN) to gain knowledge
      of the relationship between these patterns and the overall pharmacological
      property. The effectiveness of ESP is illustrated in the prediction of general
      carcinogenicity of a diverse set of chemicals using MCASE male/female rats and
      mice carcinogenicity modules.

PMID- 15032554
TI  - Classification and regression trees--studies of HIV reverse transcriptase
      inhibitors.
AB  - In this paper, the application of Classification And Regression Trees (CART) is
      presented for the analysis of biological activity of Non-Nucleoside Reverse
      Transcriptase Inhibitors (NNRTIs). The data consist of the biological activities,
      expressed as pIC50, of 208 NNRTIs against wild-type HIV virus (HIV-1) and four
      mutant strains (181C, 103N, 100I, 188L) and the computed interaction energies
      with the Reverse Transcriptase (RT) binding pocket. CART explains the observed
      biological activity of NNRTIs in terms of interactions with individual amino
      acids in the RT binding pocket, i.e., the original data variables.

PMID- 15032555
TI  - Calculating similarities between biological activities in the MDL Drug Data
      Report database.
AB  - There are a number of licensed databases that assign biological activities to
      druglike compounds. The MDL Drug Data Report (MDDR), compiled from the patent
      literature, is a popular example. It contains several hundred distinct
      activities, some of which are therapeutic areas (e.g., Antihypertensive) and some
      of which are related to specific enzymes or receptors (e.g., ACE inhibitor).
      There are several data mining applications where it would be useful to calculate
      a similarity between any two activities. Two distinct activity labels can have a
      significant similarity for a number of reasons: two activities can be nearly
      synonymous (e.g., CCK B antagonist vs Gastrin antagonist), one activity may be a
      subset of another (e.g., Dopamine (D2) agonist vs Dopamine agonist), or an
      activity can be the mechanism by which another activity works (e.g., ACE
      inhibitor vs Antihypertensive), etc. In an ideal world, similarities for two
      activities could be calculated simply by comparing the compounds they have in
      common, but in hand-curated databases such as the MDDR the assignment of
      activities to compounds are inevitably inconsistent and incomplete. We propose a
      number of methods of calculating activity-activity similarities that hopefully
      compensate for errors in hand-curation. Two of these, TIMI and trend vector, show
      promise. Soft clustering of the activities using a union of similarity methods
      shows a reasonable association of therapeutic areas with their mechanisms.

PMID- 15032556
TI  - Prediction of transmembrane proteins based on the continuous wavelet transform.
AB  - A novel method based on continuous wavelet transform (CWT) for predicting the
      number and location of helices in membrane proteins is presented. Two bacteria
      proteins are chosen as examples to describe the prediction of transmembrane
      helices (HTM) by using this method. Selections of an appropriate dilation and
      hydrophobicity data types are discussed in the text. The results indicate that
      CWT is a promising approach for the prediction of HTM.

PMID- 15032557
TI  - A universal molecular descriptor system for prediction of logP, logS, logBB, and
      absorption.
AB  - Predictive models for octanol/water partition coefficient (logP), aqueous
      solubility (logS), blood-brain barrier (logBB), and human intestinal absorption
      (HIA) were built from a universal, generic molecular descriptor system, designed
      on the basis of atom type classification. The atom type classification tree was
      trained to optimize the logP predictions. With nine components, the final partial
      least-squares (PLS) model predicted logP of 10850 compounds in Starlist with a
      regression coefficient (r2) of 0.912, cross-validated r2 (q2) of 0.892, and root
      mean-square error of estimation (RMSEE) of 0.50 log units. The PLS models for
      solubility (logS), blood-brain barrier (logBB), and a PLS-DA (discrimination
      analysis) model for HIA were established from the same atom type descriptors. The
      seven-component PLS model derived from a diverse set of 1478 organic compounds
      predicted a 21-compound test set designed by Yalkowsky with r2 = 0.88 and RMSEP
      (RMS error of prediction) = 0.64. A predictive r2 = 0.90 and RMSEE = 0.26 were
      achieved for logBB of a 57-compound "Abraham data set" with a three-component
      model. The first three components of a five-component PLS-DA model were
      sufficient to clearly separate the 169 drug molecules, collected by Abraham, into
      three classes, according to their percentage human intestinal absorption.

PMID- 15032558
TI  - A comparative QSAR study using CoMFA, HQSAR, and FRED/SKEYS paradigms for
      estrogen receptor binding affinities of structurally diverse compounds.
AB  - The three-dimensional quantitative structure-activity relationship (QSAR)
      technique of comparative molecular field analysis (CoMFA) has demonstrated the
      ability to provide accurate predictions for diverse chemical compounds when
      trained with molecules of diverse chemical type. Although predictive, the
      derivation and utilization of models of this type are quite computationally and
      person power intensive. It is this intensity that pragmatically limits the
      widespread implementation of these models as predictive tools. In this study, two
      newer QSAR techniques were evaluated as possible alternatives to CoMFA based QSAR
      models for the purpose of rapidly identifying estrogen receptor ligands from
      diverse collections of molecules. The first of these is Hologram QSAR, or HQSAR.
      HQSAR utilizes Tripos molecular fingerprints as descriptors in conjunction with
      partial least squares (PLS) regression and cross-validation routines. The HQSAR
      technique demonstrated the ability to rapidly develop QSAR models independent of
      the intense user input (i.e. geometry optimization, conformational analysis, and
      molecular superposition were not required). Second, a newly developed QSAR
      paradigm that utilizes Molecular Design Limited (MDL) substructure keys (SKEYS)
      as descriptors in combination with an evolutionary algorithm, Fast Random
      Elimination of Descriptors (FRED), was evaluated. By utilizing the FRED/SKEYS
      algorithm, a simple substructure-based QSAR model was derived that was comparable
      in statistical robustness and predictive ability to both CoMFA and HQSAR derived
      models. A comparison of the utility of these three approaches as computational
      tools for the rapid identification of estrogen receptor ligands as potential
      endocrine disruptors as assessed by model predictive ability will be described.

PMID- 15032560
TI  - Evaluation of the utilization patterns of leukotriene modifiers in a large
      managed care health plan.
AB  - OBJECTIVE: To assess the utilization of leukotriene modifiers (LM) relative to
      national guidelines and to investigate possible emergency room utilization
      differences for LMs as monotherapy versus inhaled corticosteroid (ICS)
      monotherapy or combination ICS and LM therapy. METHODS: The utilization of
      leukotriene modifiers (montelukast sodium, zafirlukast, and zileuton), concurrent
      inhaled steroids (beclomethasone, budesonide, flunisolide, fluticasone, and
      triamcinolone), beta-agonists (albuterol, bitolterol, formoterol, isoetharine,
      levalbuterol, metaproterenol, pirbuterol, salmeterol, and terbutaline) and low
      sedating antihistamines ([LSAs] cetirizine, desloratadine, fexofenadine, and
      loratadine) were assessed from the drug claims database of a large health insurer
      for dates of service for the 12-month period from September 1, 2001, through
      August 31, 2002. New-start LM patients were identified as having no previous LM
      drug claim within a 180-day look-back period from the first date of fill for the
      LM. Claims were stratified into age cohorts of.under 16 years. and.16 years and
      older. Emergency room (ER) claims for patients utilizing LMs, ICSs, and patients
      on both LM and ICS were retrieved for analysis from the medical claims database
      for the same 12-month study period. RESULTS: More than 89% of new LM starts had
      no history of an ICS in the claims database. Overall, 61% of all (new and
      existing) LM patients did not have a claim for an ICS in their drug claims
      profile during the study period. An estimated 25% of LM utilization was not for
      asthma. No differences in ER utilization were found between ICS users and LM
      users; however, the ER utilization rate (0.090 ER visits per patient per year)
      was lower with combination therapy compared with monotherapy with ICS (0.110 ER
      visits per patient per year, P = 0.001) or LM (0.119 emergency room visits per
      patient per year, P<0.001). CONCLUSIONS: The majority of LM use in this health
      plan was initial monotherapy, contrary to national treatment guidelines for
      asthma. At the time of the study, the apparent off-label use of LM for allergic
      rhinitis was significant for this health plan.

PMID- 15032561
TI  - Stimulant treatment patterns and compliance in children and adults with newly
      treated attention-deficit/hyperactivity disorder.
AB  - OBJECTIVE: To identify newly treated cases of attention-deficit/hyperactivity
      disorder (ADHD), assess the presence of comorbid psychiatric conditions, identify
      pharmacological treatment patterns, and examine treatment compliance rates among
      children and adults with newly diagnosed and pharmacologically treated ADHD in a
      managed care population. METHODS: Children (aged 18 years or younger) and adults
      having newly treated ADHD were identified from medical and pharmacy claims in an
      administrative claims database from 6 health plans. Claims data for services or
      products provided between April 1, 1997, and September 30, 1999, was analyzed for
      the managed care population (604,538 children and 1,542,304 adults). Data on
      compliance, persistence, and pharmacological treatment patterns were collected
      for the 6 months prior to and the 18 months following each patient.s initial ADHD
      pharmacological treatment. A medication possession ratio (MPR) was calculated by
      dividing the number of days supplied in a prescription by the number of days
      until the next prescription was filled. Compliance was defined as an MPR >0.8 and
      persistence as an MPR >0.3. RESULTS: The prevalence of diagnosed ADHD in this
      population was 0.7% (11,962 [2%] of children and 2,636 [0.2%] of adults) and
      incidence of ADHD was 0.04% (735 [0.1%] of children and 162 [0.01%] of adults).
      The most common comorbid psychiatric condition for incident cases was depression
      (31.6% of children and 63% of adults). Few children and adults switched their
      initial ADHD treatment agent, 11% and 12%, respectively. Dose titration occurred
      in 67% of children and 54% of adults. On average, changes in treatment
      (switching, titrating) took place after 2 to 3 months of treatment. Although
      patients, on average, obtained more than 6 refills for a total 200 days supply,
      the majority of patients (84% of children and 88% of adults) were compliant for
      less than 2 months over the period they were refilling prescriptions. CONCLUSION:
      Although the majority of patients had dosage changes, these changes typically
      occurred after several months of treatment. Results suggest that, even though
      patients continued their ADHD medication for several months, they did not
      consistently take medication for more than 2 months. Given these treatment
      patterns, pharmacologic treatment in newly treated ADHD patients may be
      suboptimal and may impact outcomes, including the effectiveness and cost of
      treatment.

PMID- 15032562
TI  - Pediatric asthma: improving management to reduce cost of care.
AB  - BACKGROUND: The economic burden of pediatric asthma is substantial, with national
      annual health care costs of $3 billion. Successful clinical management of asthma
      in children has the potential to decrease this burden by lowering the
      disproportionate costs of hospitalization and acute care for pediatric asthma
      patients. RESULTS: Based on increased understanding of the pathogenesis of
      asthma, revised guidelines were published by the National Institutes of Health in
      1997 (with an update in 2002) and by the American Academy of Allergy, Asthma, and
      Immunology in 1999 to assist in the diagnosis and management of pediatric asthma.
      These guidelines emphasize the role of inflammation in asthma and recommend
      treatment of the underlying inflammatory process. Despite increased knowledge
      regarding the pathogenesis of the disease and the availability of effective anti
      inflammatory agents, particularly inhaled corticosteroids, the prevalence of
      asthma and disease-related morbidity continues to remain high in children.
      CONCLUSION: Asthma interventions that include the use of guideline-recommended
      inhaled corticosteroid therapy and patient and caregiver education in asthma
      management may help to reduce asthma morbidity in children and decrease the
      substantial costs of pediatric asthma.

PMID- 15032563
TI  - Comparison of risedronate to alendronate and calcitonin for early reduction of
      nonvertebral fracture risk: results from a managed care administrative claims
      database.
AB  - OBJECTIVE: Recent randomized clinical trials have shown that risedronate reduces
      the risk of nonvertebral fractures and clinical vertebral fractures within 6
      months of initiating treatment. The objective of the current study was to
      determine whether this early antifracture effect could be demonstrated in
      nonvertebral fractures for risedronate and other osteoporosis therapies in an
      observational administrative claims database. METHODS: A proprietary
      administrative claims database was used to identify managed care members who
      received a new prescription for risedronate, alendronate, or nasal calcitonin
      from July 1, 2000, to December 31, 2001. Patient records were analyzed for the
      incidence of nonvertebral fractures (clavicle, humerus, wrist, pelvis, hip, and
      leg) in the first 6 and 12 months following initiation of treatment. A Cox
      proportional hazards regression model was used to estimate relative risk (RR) of
      fracture at 6 and 12 months. RESULTS: In the 6-month analysis, 774 patients (11%)
      received calcitonin, 5,307 (75%) received alendronate, and 1,000 (14%) received
      risedronate. Twelve-month data were available for a subset (71%) of patients (656
      calcitonin [13%], 3,716 alendronate [74%], and 652 risedronate [13%]). Most were
      women (93%); mean age was similar for alendronate and risedronate, and nasal
      calcitonin patients were about 3 years older, on average. Risedronate and
      alendronate patients were more likely to have used estrogen, while nasal
      calcitonin patients were more likely to have been hospitalized and had higher use
      of concomitant medications and more physician visits. Relative risks were
      adjusted for these differences. Risedronate and alendronate patients were similar
      with respect to these indicators of general health status. In the 6-month
      analysis, nonvertebral fractures were observed in 2.2% of patients receiving
      nasal calcitonin, 1.4% of patients receiving alendronate, and 0.6% of patients
      receiving risedronate. The adjusted RR reduction was 69% for risedronate versus
      calcitonin (RR = 0.31; 95% CI, 0.12 to 0.81; P = 0.02), 54% for risedronate
      versus alendronate (RR = 0.46; 95% CI, 0.20 to 1.06; P = 0.07), and 26% for
      alendronate versus calcitonin (RR = 0.74; 95% CI, 0.43 to 1.27; P = 0.28). In the
      12-month analysis, nonvertebral fracture rates were 2.9% for nasal calcitonin,
      2.4% for alendronate, and 0.9% for risedronate patients. The adjusted RR
      reduction was 75% for risedronate versus calcitonin (RR = 0.25; 95% CI, 0.10 to
      0.64; P<0.01), 59% for risedronate versus alendronate (RR = 0.41; 95% CI, 0.18 to
      0.94; P = 0.04), and 25% for alendronate versus calcitonin (RR = 0.75; 95% CI,
      0.45 to 1.25; P = 0.27). CONCLUSIONS: This analysis of medical and pharmacy
      claims contained in an administrative database confirms the early fracture
      reduction with risedronate that was shown in randomized clinical trials.
      Risedronate was more effective than calcitonin in reducing the risk of
      nonvertebral fractures within the first 6 months of treatment. Risedronate was
      more effective than either calcitonin or alendronate in reducing the risk of
      nonvertebral fractures within 12 months of treatment.

PMID- 15032564
TI  - Improving antimicrobial use: longitudinal assessment of an antimicrobial team
      including a clinical pharmacist.
AB  - BACKGROUND: Inappropriate antimicrobial utilization in hospitalized patients has
      been associated with adverse effects, emergence of resistant bacteria, and
      increased health care cost. Participation of clinical pharmacists, working as an
      integral part of a hospital antimicrobial management team (AMT), has been shown
      to improve antimicrobial use; however, the long-term impact of such a team on
      antimicrobial use is unclear. OBJECTIVE: Our primary objective was to evaluate
      whether the number of recommendations to improve antimicrobial use made by a
      hospital AMT decreased over time. Our secondary objective was to identify and
      evaluate the acceptance of AMT recommendations with respect to the clinical
      service, site of infection, and category of suboptimal use. METHODS: We
      retrospectively reviewed antimicrobial utilization data collected by the team for
      the 3-year period from July 1996 to June 1999 at the Veterans Affairs Medical
      Center in Louisville, Kentucky. The total number of antimicrobial treatment
      episodes and the number of recommendations were grouped into periods of 6 months
      each during the 3 years. The type of recommendation, type of infection, and
      clinical service (medicine versus surgery) were reviewed for the entire 3-year
      period. RESULTS: The number of antimicrobial treatment episodes for each of the 6
      month consecutive periods was 404, 526, 406, 549, 507, and 612. The proportion of
      episodes requiring team recommendations was constant over the 5 consecutive
      periods: 39%, 37%, 36%, 36%, 35%, and 37%. (P = 0.8). Acceptance rates of AMT
      recommendations by the internal medicine and general surgery services remained
      stable over the length of the study, 84% and 69%, respectively. The distribution
      of patients treated by the site of infection also remained stable over the study
      period. CONCLUSION: Our results demonstrate that despite the long-term presence
      of an AMT, the proportion of antimicrobial episodes requiring intervention and
      the percentage of accepted recommendations remained constant over a 3-year
      period. Having new resident physicians in teaching hospitals or staff turnover in
      managed care organizations may necessitate the continued presence of an active
      AMT.

PMID- 15032565
TI  - Cost analysis of a managed care decentralized outpatient pharmacy anticoagulation
      service.
AB  - OBJECTIVES: To determine the per-patient-per-month (PPPM) cost of a decentralized
      outpatient pharmacy anticoagulation service (OPAS) in patients with chronic
      atrial fibrillation (AF) who were maintained on warfarin sodium therapy in a
      managed care setting, to compare the annual costs versus the risk for stroke, and
      to assess the quality of the anticoagulant management. METHODS: Data were
      collected retrospectively from clinical, research, and administrative claims
      databases. Patient demographic data were stratified to include age and risk
      factors for stroke. Inclusion criteria for the study were adult patients (>18
      years) who were maintained on chronic warfarin therapy with a diagnosis of AF
      (diagnosis code 427.31) and continuously enrolled during calendar year 2000. The
      cost analysis included the personnel cost of clinical pharmacy specialists,
      direct and indirect cost of laboratory tests for international normalized ratios
      (INR), and anticoagulant (warfarin plus bridge therapy with a low molecular
      weight heparin) drug cost and dispensing fee. The percentage of INR values within
      or near target was used to evaluate the effectiveness of the service. RESULTS: A
      total of 97 patients on chronic warfarin therapy for AF were identified for cost
      analysis. The demographics for these patients included the following: 71% were
      male, with 32% of the patients over the age of 75 years, and 60% had 1 or more
      identifiable risk factors for stroke. Utilizing established criteria, 80.4% of
      the sample was considered to be at high risk for ischemic stroke. A majority of
      the patients (94.8%) had nonvalvular disease, with an INR goal in the range of 2
      to 3 in 91.8% of the cases. The PPPM cost for the OPAS monitoring service was
      $51.25, distributed as $13.78 (27%) in personnel costs for monitoring
      pharmacists, $18.38 (36%) for lab tests, and $19.09 (37%) for anticoagulant drug
      costs. These costs did not significantly differ among patient groups with various
      risks for ischemic stroke. For nonvalvular AF patients, the percentage of INR
      values within each individual patient.s specific INR goal range was 60.4%; the
      percentage within or near goal was 74.6%. CONCLUSION: The average PPPM cost for
      pharmacist and laboratory monitoring as well as anticoagulant medication for CY
      2000 was estimated to be $51.25. The annual costs were comparable among AF
      patients with different risks for ischemic stroke. The percentage of INR values
      within the individual patient.s stated target goal was 60.4%. Effective
      monitoring to maintain patients within their target INR goal is relatively
      inexpensive compared with the cost of complications such as ischemic stroke or
      intracranial bleeding.

PMID- 15032566
TI  - Disease management of ADHD and measures of compliance.

PMID- 15032567
TI  - Clinical pharmacist interventions to bridge the quality chasm and methods
      necessary to hold quality improvement gains.

PMID- 15032569
TI  - Need for greater scrutiny of days supply values in DACON calculations.

PMID- 15032568
TI  - Reducing the risk of fractures--the options narrow for cost-effective therapeutic
      alternatives.

PMID- 15032570
TI  - Community pharmacists do not intentionally transmit incorrect claim information-
      but caution is warranted in days supply calculations.

PMID- 15032571
TI  - The BCR-ABL story: bench to bedside and back.
AB  - The twenty-first century is beginning with a sharp turn in the field of cancer
      therapy. Molecular targeted therapies against specific oncogenic events are now
      possible. The BCR-ABL story represents a notable example of how research from the
      fields of cytogenetics, retroviral oncology, protein phosphorylation, and small
      molecule chemical inhibitors can lead to the development of a successful
      molecular targeted therapy. Imatinib mesylate (Gleevec, STI571, or CP57148B) is a
      direct inhibitor of ABL (ABL1), ARG (ABL2), KIT, and PDGFR tyrosine kinases. This
      drug has had a major impact on the treatment of chronic myelogenous leukemia
      (CML) as well as other blood neoplasias and solid tumors with etiologies based on
      activation of these tyrosine kinases. Analysis of CML patients resistant to BCR
      ABL suppression by Imatinib mesylate coupled with the crystallographic structure
      of ABL complexed to this inhibitor have shown how structural mutations in ABL can
      circumvent an otherwise potent anticancer drug. The successes and limitations of
      Imatinib mesylate hold general lessons for the development of alternative
      molecular targeted therapies in oncology.

PMID- 15032572
TI  - Genetics, FACS, immunology, and redox: a tale of two lives intertwined.

PMID- 15032573
TI  - Self- and nonself-recognition by C-type lectins on dendritic cells.
AB  - Dendritic cells (DCs) are highly efficient antigen-presenting cells (APCs) that
      collect antigen in body tissues and transport them to draining lymph nodes.
      Antigenic peptides are loaded onto major histocompatibility complex (MHC)
      molecules for presentation to naive T cells, resulting in the induction of
      cellular and humoral immune responses. DCs take up antigen through phagocytosis,
      pinocytosis, and endocytosis via different groups of receptor families, such as
      Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for
      glycoproteins, and pattern recognition receptors, such as Toll-like receptors
      (TLRs), for microbial antigens. Uptake of antigen by CLRs leads to presentation
      of antigens on MHC class I and II molecules. DCs are well equipped to distinguish
      between self- and nonself-antigens by the variable expression of cell-surface
      receptors such as CLRs and TLRs. In the steady state, DCs are not immunologically
      quiescent but use their antigen-handling capacities to maintain peripheral
      tolerance. DCs are continuously sampling and presenting self- and harmless
      environmental proteins to silence immune activation. Uptake of self-components in
      the intestine and airways are good examples of sites where continuous
      presentation of self- and foreign antigens occurs without immune activation. In
      contrast, efficient antigen-specific immune activation occurs upon encounter of
      DCs with nonself-pathogens. Recognition of pathogens by DCs triggers specific
      receptors such as TLRs that result in DC maturation and subsequently immune
      activation. Here we discuss the concept that cross talk between TLRs and CLRs,
      differentially expressed by subsets of DCs, accounts for the different pathways
      to peripheral tolerance, such as deletion and suppression, and immune activation.

PMID- 15032574
TI  - Transcriptional control of early B cell development.
AB  - The generation of B-lymphocytes from hematopoietic stem cells is controlled by
      multiple transcription factors regulating distinct developmental aspects. Ikaros
      and PU.1 act in parallel pathways to control the development of lymphoid
      progenitors in part by regulating the expression of essential signaling receptors
      (Flt3, c-Kit, and IL-7R alpha). The generation of the earliest B cell progenitors
      depends on E2A and EBF, which coordinately activate the B cell gene expression
      program and immunoglobulin heavy-chain gene rearrangements at the onset of B
      lymphopoiesis. Pax5 restricts the developmental options of lymphoid progenitors
      to the B cell lineage by repressing the transcription of lineage-inappropriate
      genes and simultaneously activating the expression of B-lymphoid signaling
      molecules. LEF1 and Sox4 contribute to the survival and proliferation of pro-B
      cells in response to extracellular signals. Finally, IRF4 and IRF8 together
      control the termination of pre-B cell receptor signaling and thus promote
      differentiation to small pre-B cells undergoing light-chain gene rearrangements.

PMID- 15032575
TI  - Ubiquitin ligases and the immune response.
AB  - Ubiquitin (Ub)-protein conjugation represents a novel means of
      posttranscriptional modification in a proteolysis-dependent or -independent
      manner. E3 Ub ligases play a key role in governing the cascade of Ub transfer
      reactions by recognizing and catalyzing Ub conjugation to specific protein
      substrates. The E3s, which can be generally classified into HECT-type and RING
      type families, are involved in the regulation of many aspects of the immune
      system, including the development, activation, and differentiation of
      lymphocytes, T cell-tolerance induction, antigen presentation, immune evasion,
      and virus budding. E3-promoted ubiquitination affects a wide array of biological
      processes, such as receptor downmodulation, signal transduction, protein
      processing or translocation, protein-protein interaction, and gene transcription,
      in addition to proteasome-mediated degradation. Deficiency or mutation of some of
      the E3s like Cbl, Cbl-b, or Itch, causes abnormal immune responses such as
      autoimmunity, malignancy, and inflammation. This review discusses our current
      understanding of E3 Ub ligases in both innate and adaptive immunity. Such
      knowledge may facilitate the development of novel therapeutic approaches for
      immunological diseases.

PMID- 15032576
TI  - Ligands for L-selectin: homing, inflammation, and beyond.
AB  - Understanding the molecular basis of lymphocyte homing to lymphoid organs was
      originally a problem of concern only to immunologists. With the discovery of L
      selectin and its ligands, interested scientists have expanded to include
      glycobiologists, immunopathologists, cancer biologists, and developmental
      biologists. Going beyond its first discovered role in homing to lymph nodes, the
      L-selectin system is implicated in such diverse processes as inflammatory
      leukocyte trafficking in both acute and chronic settings, hematogenous metastasis
      of carcinoma cells, effector mechanisms for inflammatory demyelination of axons,
      and implantation of the early mammalian embryo. This review focuses on the
      ligands for L-selectin that are found on vascular endothelium, leukocytes,
      carcinoma cells, and at various extravascular sites. The discovery of selectins
      and their ligands has validated the long-predicted hypothesis that carbohydrate
      directed cell adhesion is relevant in eukaryotic systems. Emphasis will be given
      to the carbohydrate and sulfation modifications of the ligands, which enable
      recognition by L-selectin. The rapid "homing" of labeled cells into the lymph
      nodes presumably had its basis in the special affinity of small lymphocytes for
      the endothelium of the postcapillary venules.

PMID- 15032577
TI  - Integrins and T cell-mediated immunity.
AB  - Integrin receptors mediate adhesive events that are critical for a specific and
      effective immune response to foreign pathogens. Integrin-dependent interactions
      of lymphocytes and antigen-presenting cells (APCs) to endothelium regulate the
      efficiency and specificity of trafficking into secondary lymphoid organs and
      peripheral tissue. Within these sites, integrins facilitate cell movement via
      interactions with the extracellular matrix, and promote and stabilize antigen
      specific interactions between T lymphocytes and APCs that are critical for
      initiating T cell-activation events. In this review, we discuss the role of
      integrins in T cell-mediated immunity, with a focus on how these receptors
      participate in lymphocyte recirculation and T cell activation, how antigen
      stimulation regulates integrin activity, and how integrins define functionally
      unique subsets of T cells and APCs.

PMID- 15032578
TI  - Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived
      neurotoxin in host defense.
AB  - Mammals generate a diverse array of antimicrobial proteins, largely represented
      by defensins or cathelicidins. The direct in vitro microbicidal activity of
      antimicrobial proteins has long been considered an important innate immune
      defense, although the in vivo relevance has only very recently been established
      for certain defensins and cathelicidins. Mammalian defensins and cathelicidins
      have also been shown to have multiple receptor-mediated effects on immune cells.
      Beta-defensins interact with CCR6; murine beta-defensin-2 in addition activates
      TLR4. Cathelicidins act on FPRL1-expressing cells. Furthermore, several defensins
      have considerable immunoenhancing activity. Thus, it appears that mammalian
      antimicrobial proteins contribute to both innate and adaptive antimicrobial
      immunity.

PMID- 15032579
TI  - Starting at the beginning: new perspectives on the biology of mucosal T cells.
AB  - The gastrointestinal tract is the central organ for uptake of fluids and
      nutrients, and at the same time it forms the main protective barrier between the
      sterile environment of the body and the outside world. In mammals, the intestine
      has further evolved to harbor a vast load of commensal bacteria that have
      important functions for the host. Discrimination by the host defense system of
      nonself from self can prevent invasion of pathogens, but equivalent responses to
      dietary or colonizing bacteria can lead to devastating consequences for the
      organism. This dilemma imposed by the gut environment has probably contributed
      significantly to the evolutionary drive that has led to sophisticated mechanisms
      and diversification of the immune system to allow for protection while
      maintaining the integrity of the mucosal barrier. The immense expansion and
      specialization of the immune system is particularly mirrored in the phylogeny,
      ontogeny, organization, and regulation of the adaptive intraepithelial
      lymphocytes, or IEL, which are key players in the unique intestinal defense
      mechanisms that have evolved in mammals.

PMID- 15032580
TI  - CD40/CD154 interactions at the interface of tolerance and immunity.
AB  - Development of the acquired immune response is dependent on the signaling of CD40
      by its ligand, CD154. These molecules govern both the magnitude and quality of
      humoral- and cell-mediated immunity. A litany of studies have conclusively
      documented that blockade of this ligand-receptor pair can prevent, and also
      intervene in, the progression of antibody- and cell-mediated autoimmune diseases,
      and can instill long-lived allogeneic and xenogeneic graft tolerance. Many
      effector mechanisms of inflammation are abolished as a result of CD154 blockade,
      but we are now beginning to understand that CD154 blockade may, in some
      instances, engender long-lived, antigen-specific tolerance. In the context of
      transplantation tolerance, we present a hypothesis that alpha CD154 blockade is
      most effective at inducing long-lived allospecific tolerance if anergy and
      regulation can be elicited prior to the onslaught of inflammation that is induced
      by grafting (preemptive tolerance). This facet of alpha CD154-induced tolerance
      appears to co-opt the normal processes of peripheral tolerance induced by
      immature DCs and can be exploited to induce long-lived antigen-specific
      tolerance. The underlying science and the prospects for inducing long-lived
      antigen-specific tolerance in a model of allograft tolerance through CD154
      blockade are presented and discussed.

PMID- 15032581
TI  - The three Es of cancer immunoediting.
AB  - After a century of controversy, the notion that the immune system regulates
      cancer development is experiencing a new resurgence. An overwhelming amount of
      data from animal models--together with compelling data from human patients-
      indicate that a functional cancer immunosurveillance process indeed exists that
      acts as an extrinsic tumor suppressor. However, it has also become clear that the
      immune system can facilitate tumor progression, at least in part, by sculpting
      the immunogenic phenotype of tumors as they develop. The recognition that
      immunity plays a dual role in the complex interactions between tumors and the
      host prompted a refinement of the cancer immunosurveillance hypothesis into one
      termed "cancer immunoediting." In this review, we summarize the history of the
      cancer immunosurveillance controversy and discuss its resolution and evolution
      into the three Es of cancer immunoediting--elimination, equilibrium, and escape.

PMID- 15032582
TI  - Autoimmune and inflammatory mechanisms in atherosclerosis.
AB  - The present review focuses on the concept that cellular and humoral immunity to
      the phylogenetically highly conserved antigen heat shock protein 60 (HSP60) is
      the initiating mechanism in the earliest stages of atherosclerosis. Subjecting
      arterial endothelial cells to classical atherosclerosis risk factors leads to the
      expression of HSP60 that then may serve as a target for pre-existent cross
      reactive antimicrobial HSP60 immunity or bona fide autoimmune reactions induced
      by biochemically altered autologous HSP60. Endothelial cells can also bind
      microbial or autologous HSP60 via Toll-like receptors, providing another
      possibility for targetting adaptive or innate immunological effector mechanisms.

PMID- 15032583
TI  - The dynamic life of natural killer cells.
AB  - Natural killer (NK) cells play important roles in immunological processes,
      including early defense against viral infections. This review provides an
      overview of the dynamic in vivo life of NK cells from their development in the
      bone marrow to their mature peripheral responses and their ultimate demise, with
      particular emphasis on mouse NK cells and viral infections.

PMID- 15032584
TI  - The role of complement in the development of systemic lupus erythematosus.
AB  - Complement has both beneficial and deleterious roles in the pathogenesis of
      systemic lupus erythematosus (SLE). On the one hand, patients with SLE present
      with decreased complement levels and with complement deposition in inflamed
      tissues, suggestive of a harmful role of complement in the effector phase of
      disease. On the other hand, homozygous deficiency of any of the classical pathway
      proteins is strongly associated with the development of SLE. There are two main
      hypotheses to explain these observations. The first invokes an important role for
      complement in the physiological waste-disposal mechanisms of dying cells and
      immune complexes. The second hypothesis is based around the role of complement in
      determining the activation thresholds of B and T lymphocytes, with the proposal
      that complement deficiency causes incomplete maintenance of peripheral tolerance.
      These two hypotheses are not mutually exclusive. In addition, there is evidence
      for a contribution from other genetic factors in determining the phenotype of
      disease in the absence of complement.

PMID- 15032585
TI  - Drosophila: the genetics of innate immune recognition and response.
AB  - Because of the evolutionary conservation of innate mechanisms of host defense,
      Drosophila has emerged as an ideal animal in which to study the genetic control
      of immune recognition and responses. The discovery that the Toll pathway is
      required for defense against fungal infection in Drosophila was pivotal in
      studies of both mammalian and Drosophila immunity. Subsequent genetic screens in
      Drosophila to isolate additional mutants unable to induce humoral responses to
      infection have identified and ordered the function of components of two signaling
      cascades, the Toll and Imd pathways, that activate responses to infection.
      Drosophila blood cells also contribute to host defense through phagocytosis and
      signaling, and may carry out a form of self-nonself recognition that is
      independent of microbial pattern recognition. Recent work suggests that
      Drosophila will be a useful model for dissecting virulence mechanisms of several
      medically important pathogens.

PMID- 15032586
TI  - RAGs and regulation of autoantibodies.
AB  - Autoreactive antibodies are etiologic agents in a number of autoimmune diseases.
      Like all other antibodies these antibodies are produced in developing B cells by
      V(D)J recombination in the bone marrow. Three mechanisms regulate autoreactive B
      cells: deletion, receptor editing, and anergy. Here we review the prevalence of
      autoantibodies in the initial antibody repertoire, their regulation by receptor
      editing, and the role of the recombinase proteins (RAG1 and RAG2) in this
      process.

PMID- 15032587
TI  - The role of suppressors of cytokine signaling (SOCS) proteins in regulation of
      the immune response.
AB  - Cytokines are an integral component of the adaptive and innate immune responses.
      The signaling pathways triggered by the engagement of cytokines with their
      specific cell surface receptors have been extensively studied and have provided a
      profound understanding of the intracellular machinery that translates exposure of
      cells to cytokine to a coordinated biological response. It has also become clear
      that cells have evolved sophisticated mechanisms to prevent excessive responses
      to cytokines. In this review we focus on the suppressors of cytokine signaling
      (SOCS) family of cytoplasmic proteins that completes a negative feedback loop to
      attenuate signal transduction from cytokines that act through the janus
      kinase/signal transducer and activator of transcription (JAK/STAT) pathway. SOCS
      proteins inhibit components of the cytokine signaling cascade via direct binding
      or by preventing access to the signaling complex. The SOCS proteins also appear
      to target signal transducers for proteasomal destruction. Analyses of genetically
      modified mice in which SOCS proteins are overexpressed or deleted have
      established that this family of negative regulators has indispensable roles in
      regulating cytokine responses in cells of the immune system as well as other
      tissues. Emerging evidence also suggests that disruption of SOCS expression or
      activity is associated with several immune and inflammatory diseases, raising the
      prospect that manipulation of SOCS activity may provide a novel future
      therapeutic strategy in the management of immunological disorders.

PMID- 15032588
TI  - Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and
      negative control of immune responses.
AB  - Naturally occurring CD4+ regulatory T cells, the majority of which express CD25,
      are engaged in dominant control of self-reactive T cells, contributing to the
      maintenance of immunologic self-tolerance. Their depletion or functional
      alteration leads to the development of autoimmune disease in otherwise normal
      animals. The majority, if not all, of such CD25+CD4+ regulatory T cells are
      produced by the normal thymus as a functionally distinct and mature subpopulation
      of T cells. Their repertoire of antigen specificities is as broad as that of
      naive T cells, and they are capable of recognizing both self and nonself
      antigens, thus enabling them to control various immune responses. In addition to
      antigen recognition, signals through various accessory molecules and via
      cytokines control their activation, expansion, and survival, and tune their
      suppressive activity. Furthermore, the generation of CD25+CD4+ regulatory T cells
      in the immune system is at least in part developmentally and genetically
      controlled. Genetic defects that primarily affect their development or function
      can indeed be a primary cause of autoimmune and other inflammatory disorders in
      humans. Based on recent advances in our understanding of the cellular and
      molecular basis of this T cell-mediated immune regulation, this review discusses
      how naturally arising CD25+CD4+ regulatory T cells contribute to the maintenance
      of immunologic self-tolerance and negative control of various immune responses,
      and how they can be exploited to prevent and treat autoimmune disease, allergy,
      cancer, and chronic infection, or establish donor-specific transplantation
      tolerance.

PMID- 15032589
TI  - Phosphoinositide 3-kinase: diverse roles in immune cell activation.
AB  - Cells of the immune system carry out diverse functions that are controlled by
      surface receptors for antigen, costimulatory molecules, cytokines, chemokines,
      and other ligands. A shared feature of signal transduction downstream of most
      receptors on immune cells, as in nonhematopoietic cell types, is the activation
      of phosphoinositide 3-kinase (PI3K). The mechanism by which this common signaling
      event is elicited by distinct receptors and contributes to unique functional
      outcomes is an intriguing puzzle. Understanding how specificity is achieved in
      PI3K signaling is of particular significance because altered regulation of this
      pathway is observed in many disease states, including leukemia and lymphoma. Here
      we review recent advances in the understanding of PI3K signaling mechanisms in
      different immune cells and receptor systems. We emphasize the concept that PI3K
      and its products are components of complex networks of interacting proteins and
      second messengers, rather than simple links in linear signaling cascades.

PMID- 15032590
TI  - Immunity to tuberculosis.
AB  - Only 5 to 10% of immunocompetent humans are susceptible to tuberculosis, and over
      85% of them develop the disease exclusively in the lungs. Human immunodeficiency
      virus (HIV)-infected humans, in contrast, can develop systemic disease that is
      more quickly lethal. This is in keeping with other evidence showing that
      susceptible humans generate some level of Th1 immunity to Mycobacterium
      tuberculosis (Mtb) infection. Tuberculosis in mice is also exclusively a lung
      disease that is progressive and lethal, in spite of the generation of Th1
      mediated immunity. Thus mouse tuberculosis is a model of tuberculosis in
      susceptible humans, as is tuberculosis in guinea pigs and rabbits. Inability to
      resolve infection and prevent disease may not be a consequence of the generation
      of an inadequate number of Th1 cells but of an intrinsic deficiency in macrophage
      function that prevents these cells from expressing immunity. If this proves to be
      true, vaccinating susceptible humans against tuberculosis will be a difficult
      task.

PMID- 15032591
TI  - Molecular defects in human severe combined immunodeficiency and approaches to
      immune reconstitution.
AB  - Mutations in nine different genes have been found to cause the human severe
      combined immunodeficiency syndrome. The products of three of the genes--IL-2RG,
      Jak3, and IL-7R alpha--are components of cytokine receptors, and the products of
      three more-RAG1, RAG2, and Artemis-are essential for effecting antigen receptor
      gene rearrangement. Additionally, a deficiency of CD3 delta, a component of the T
      cell antigen receptor, results in a near absence of circulating mature CD3+ T
      cells and a complete lack of gamma/delta T cells. Adenosine deaminase deficiency
      results in toxic accumulations of metabolites that cause T cell apoptosis.
      Finally, a deficiency of CD45, a critical regulator of signaling thresholds in
      immune cells, also causes SCID. Approaches to immune reconstitution have included
      bone marrow transplantation and gene therapy. Bone marrow transplantation, both
      HLA identical unfractionated and T cell-depleted HLA haploidentical, has been
      very successful in effecting immune reconstitution if done in the first 3.5
      months of life and without pretransplant chemotherapy. Gene therapy was highly
      successful in nine infants with X-linked SCID, but the trials have been placed on
      hold due to the development of a leukemic process in two of the children because
      of insertional oncogenesis.

PMID- 15032592
TI  - Physiological control of immune response and inflammatory tissue damage by
      hypoxia-inducible factors and adenosine A2A receptors.
AB  - Immune cell-mediated destruction of pathogens may result in excessive collateral
      damage to normal tissues, and the failure to control activated immune cells may
      cause immunopathologies. The search for physiological mechanisms that
      downregulate activated immune cells has revealed a critical role for
      extracellular adenosine and for immunosuppressive A2A adenosine receptors in
      protecting tissue from inflammatory damage. Tissue damage-associated deep
      hypoxia, hypoxia-inducible factors, and hypoxia-induced accumulation of adenosine
      may represent one of the most fundamental and immediate tissue-protecting
      mechanisms, with adenosine A2A receptors triggering "OFF" signals in activated
      immune cells. In these regulatory mechanisms, oxygen deprivation and
      extracellular adenosine accumulation serve as "reporters," while A2A adenosine
      receptors serve as "sensors" of excessive tissue damage. The A2A receptor
      triggered generation of intracellular cAMP then inhibits activated immune cells
      in a delayed negative feedback manner to prevent additional tissue damage.
      Targeting A2A adenosine receptors may have important clinical applications.

PMID- 15032593
TI  - T lymphocyte-endothelial cell interactions.
AB  - Human vascular endothelial cells (EC) basally display class I and II MHC-peptide
      complexes on their surface and come in regular contact with circulating T cells.
      We propose that EC present microbial antigens to memory T cells as a mechanism of
      immune surveillance. Activated T cells, in turn, provide both soluble and contact
      dependent signals to modulate normal EC functions, including formation and
      remodeling of blood vessels, regulation of blood flow, regulation of blood
      fluidity, maintenance of permselectivity, recruitment of inflammatory leukocytes,
      and antigen presentation leading to activation of T cells. T cell interactions
      with vascular EC are thus bidirectional and link the immune and circulatory
      systems.

PMID- 15032594
TI  - Immunological memory to viral infections.
AB  - The purpose of immunological memory is to protect the host from reinfection, to
      control persistent infections, and, through maternal antibody, to protect the
      host's immunologically immature offspring from primary infections. Immunological
      memory is an exclusive property of the acquired immune system, where in the
      presence of CD4 T cell help, T cells and B cells clonally expand and
      differentiate to provide effector systems that protect the host from pathogens.
      Here we describe how T and B cell memory is generated in response to virus
      infections and how these cells respond when the host is infected again by similar
      or different viruses.

PMID- 15032595
TI  - Central memory and effector memory T cell subsets: function, generation, and
      maintenance.
AB  - The memory T cell pool functions as a dynamic repository of antigen-experienced T
      lymphocytes that accumulate over the lifetime of the individual. Recent studies
      indicate that memory T lymphocytes contain distinct populations of central memory
      (TCM) and effector memory (TEM) cells characterized by distinct homing capacity
      and effector function. This review addresses the heterogeneity of TCM and TEM,
      their differentiation stages, and the current models for their generation and
      maintenance in humans and mice.

PMID- 15032596
TI  - Control of T cell viability.
AB  - The factors affecting T cell viability vary depending on the type and status of
      the T cell involved. Naive T cells die via a Bcl-2/Bim dependent route. Their
      deaths are prevented in animals by IL-7 and contact with MHC. Activated T cells
      die in many different ways. Among these is a pathway involving signals that come
      from outside the T cell and affect it via surface receptors such as Fas.
      Activated T cells also die through a pathway driven by signals generated within
      the T cell itself, a cell autonomous route. This pathway involves members of the
      Bcl-2 family, in particular Bcl-2, Bcl-xl, Bim, and probably Bak. The viability
      of CD8+ and CD4+ memory T cells is controlled in different ways. CD8+ memory T
      cells are maintained by IL-15 and IL-7. The control of CD4+ memory T cells is
      more mysterious, with roles reported for IL-7 and/or contact via the TCR.

PMID- 15032597
TI  - Asthma: mechanisms of disease persistence and progression.
AB  - When asthma is diagnosed, eosinophilic inflammation and airway remodeling are
      established in the bronchial airways and can no longer be separated as cause and
      effect because both processes contribute to persistence and progression of
      disease, despite anti-inflammatory therapy. Th2 cells are continually active in
      the airways, even when disease is quiescent. IL-13 is the key effector cytokine
      in asthma and stimulates airway fibrosis through the action of matrix
      metalloproteinases on TGF-beta and promotes epithelial damage, mucus production,
      and eosinophilia. The production of IL-13 and other Th2 cytokines by non-T cells
      augments the inflammatory response. Inflammation is amplified by local responses
      of the epithelium, smooth muscle, and fibroblasts through the production of
      chemokines, cytokines, and proteases. Injured cells produce adenosine that
      enhances IL-13 production. We review human and animal data detailing the cellular
      and molecular interactions in established allergic asthma that promote persistent
      disease, amplify inflammation, and, in turn, cause disease progression.

PMID- 15032598
TI  - CD1: antigen presentation and T cell function.
AB  - This review summarizes the major features of CD1 genes and proteins, the patterns
      of intracellular trafficking of CD1 molecules, and how they sample different
      intracellular compartments for self- and foreign lipids. We describe how lipid
      antigens bind to CD1 molecules with their alkyl chains buried in hydrophobic
      pockets and expose their polar lipid headgroup whose fine structure is recognized
      by the TCR of CD1-restricted T cells. CD1-restricted T cells carry out effector,
      helper, and adjuvant-like functions and interact with other cell types including
      macrophages, dendritic cells, NK cells, T cells, and B cells, thereby
      contributing to both innate and adaptive immune responses. Insights gained from
      mice and humans now delineate the extensive range of diseases in which CD1
      restricted T cells play important roles and reveal differences in the role of
      CD1a, CD1b, and CD1c in contrast to CD1d. Invariant TCR alpha chains, self-lipid
      reactivity, and rapid effector responses empower a subset of CD1d-restricted T
      cells (NKT cells) to have unique effector functions without counterpart among MHC
      restricted T cells. This review describes the function of CD1-restricted T cells
      in antimicrobial responses, antitumor immunity, and in regulating the balance
      between tolerance and autoimmunity.

PMID- 15032599
TI  - Chemokines in innate and adaptive host defense: basic chemokinese grammar for
      immune cells.
AB  - Chemokines compose a sophisticated communication system used by all our cell
      types, including immune cells. Chemokine messages are decoded by specific
      receptors that initiate signal transduction events leading to a multitude of
      cellular responses, leukocyte chemotaxis and adhesion in particular. Critical
      determinants of the in vivo activities of chemokines in the immune system include
      their presentation by endothelial cells and extracellular matrix molecules, as
      well as their cellular uptake via "silent" chemokine receptors (interceptors)
      leading either to their transcytosis or to degradation. These regulatory
      mechanisms of chemokine histotopography, as well as the promiscuous and
      overlapping receptor specificities of inflammation-induced chemokines, shape
      innate responses to infections and tissue damage. Conversely, the specific
      patterns of homeostatic chemokines, where each chemokine is perceived by a single
      receptor, are charting lymphocyte navigation routes for immune surveillance. This
      review presents our current understanding of the mechanisms that regulate the
      cellular perception and pathophysiologic meaning of chemokines.

PMID- 15032600
TI  - Interleukin-10 and related cytokines and receptors.
AB  - The Class 2 alpha-helical cytokines consist of interleukin-10 (IL-10), IL-19, IL
      20, IL-22, IL-24 (Mda-7), and IL-26, interferons (IFN-alpha, -beta, -epsilon, 
      kappa, -omega, -delta, -tau, and -gamma) and interferon-like molecules (limitin,
      IL-28A, IL-28B, and IL-29). The interaction of these cytokines with their
      specific receptor molecules initiates a broad and varied array of signals that
      induce cellular antiviral states, modulate inflammatory responses, inhibit or
      stimulate cell growth, produce or inhibit apoptosis, and affect many immune
      mechanisms. The information derived from crystal structures and molecular
      evolution has led to progress in the analysis of the molecular mechanisms
      initiating their biological activities. These cytokines have significant roles in
      a variety of pathophysiological processes as well as in regulation of the immune
      system. Further investigation of these critical intercellular signaling molecules
      will provide important information to enable these proteins to be used more
      extensively in therapy for a variety of diseases.

PMID- 15032601
TI  - SNP analysis combined with protein structure prediction defines structure
      functional relationships in cancer related cytochrome P450 estrogen metabolism.
AB  - The P450 family of proteins has more than 1000 representatives, which despite
      sometimes relatively low sequence identity have a surprisingly high level of
      structural similarity. This fact makes this family of proteins ideal candidate
      for various types of modeling based on protein structure prediction. A number of
      P450 proteins, including CYPs 1A1, 1A2, 1B1, 3A4, 11B2, 17, and 19, play a role
      in the metabolism of estrogen. Inhibitors of these proteins could be very
      promising drugs for hormonal treatment of postmenopausal breast cancer.
      Population studies have yielded a significant amount of data describing the
      relationship between single nucleotide polymorphisms (SNP) in DNA and cancer risk
      related to these proteins. A combination of SNP analysis with protein structure
      prediction can be a very useful strategy in investigations of structure
      functional relations of P450 proteins and structure-based drug design. Here we
      will demonstrate how protein structure prediction combined with genetic SNP
      analysis can be useful for potential drug design and possibly, individual
      treatment of breast cancer.

PMID- 15032602
TI  - Improving the understanding of human genetic diseases through predictions of
      protein structures and protein-protein interaction sites.
AB  - Over 1,500 human disease genes have been identified, of which only a small
      fraction have experimental structural information on the protein products. To
      better understand the mechanisms of these hereditary diseases, we undertook a
      systematic study to predict the structures of disease proteins and characterize
      their interactions with other proteins. This study was facilitated by two tools
      developed previously: COBLATH, a structure-prediction method that exploits the
      complementarity of PSI-Blast and sequence-structure threading and PPISP, a method
      that predicts the residues involved in protein-protein interactions. In this
      initial study of human disease proteins, we were able to build structural models
      for 60 proteins involved in human diseases. For a number of proteins, new
      structural domains were identified. In the case of ABCD1, a protein responsible
      for adrenoleukodystrophy, the disease mutation P484R was positioned at the
      homodimer interface. This positioning is consistent with experimental observation
      that the P484R mutation impairs ABCD1 self-interaction and suggests that that the
      disease mechanism of this mutation lies in the impaired ABCD1 dimerization. This
      initial study illustrates the value of the predicted structure models and may
      serve as an example for expanded studies of other disease proteins.

PMID- 15032603
TI  - Protein structure prediction in structure based drug design.
AB  - The human genome and other genome sequencing projects have generated huge amounts
      of protein sequence information. Recently, a structural genomics project that
      aims to determine at least one representative three-dimensional structure from
      every protein family experimentally has been started. Homology modeling will play
      an essential role in structure based drug design such as in silico screening;
      because based on these representative structures the three-dimensional structures
      of the remaining proteins encoded in the various genomes can be predicted by
      homology modeling. The results of the last Critical Assessment of Techniques for
      Protein Structure Prediction (CASP5) demonstrated that the quality of homology
      modeling prediction has improved; reaching a level of reliability that biologists
      can now confidently use homology modeling. With improvements in modeling software
      and the growing number of known protein structures, homology modeling is becoming
      a more and more powerful and reliable tool. The present paper discusses the
      features and roles of homology modeling in structure based drug design, and
      describes the CHIMERA and FAMS modeling systems as examples. For a sample
      application, homology modeling of non-structural proteins of the severe acute
      respiratory syndrome (SARS) coronavirus is discussed. Many biological functions
      involve formation of protein-protein complexes; in which the protein molecules
      behave dynamically in the course of binding. Therefore, an understanding of
      protein-protein interaction will be very important for structure based drug
      design. To this end, normal mode analysis is useful. The present paper discusses
      the prediction of protein-protein interaction using normal mode analysis and
      examples of applications are given.

PMID- 15032604
TI  - Toward atomic-scale understanding of ligand recognition in the muscle nicotinic
      receptor.
AB  - The nicotinic receptor at the motor endplate has served as a prototype for
      understanding structure, function and ligand recognition in the superfamily of
      pentameric ligand-gated ion channels. Yet despite this advanced state of
      knowledge, atomic-scale understanding of such elementary processes as ligand
      recognition has remained elusive owing to the lack of a high-resolution x-ray
      structure. However, the field has recently entered a state of rapid advancement
      following the discovery and atomic structural determination of the water-soluble
      acetylcholine binding protein (AChBP), a homolog of the receptor ligand binding
      domain. The AChBP structure provides the theoretical foundation for generating
      homology models of the corresponding receptor ligand binding domains within this
      structural family of receptors. Experimental assignment of residue equivalence
      between AChBP and receptor subunits subsequently yielded homology models ready
      for experimental testing. One such test is computational determination of ligand
      docking orientation in conjunction with mutagenesis of predicted contact residues
      and measurements of ligand binding affinity. Applied to different analogs of the
      competitive antagonist curare, docking computations that incorporate intrinsic
      protein flexibility reveal fundamentally distinct orientations of each analog
      bound to AChBP. The different contact residues predicted for each analog were
      tested and confirmed by mutagenesis of AChBP followed by measurements of ligand
      binding. By applying the same computational and experimental approaches to the
      adult human muscle AChR, we find that the two curare analogs also dock in
      distinctly different orientations. Thus subtle structural changes in the ligand,
      and by extension, structural differences in non-conserved residues among receptor
      subtypes and species, can dramatically alter the orientation of the bound ligand.
      The results have important implications for design of drugs targeting nicotinic
      receptors and members of the superfamily of pentameric ligand-gated ion channels.

PMID- 15032605
TI  - Computational and experimental studies on human misshapen/NIK-related kinase MINK
      1.
AB  - We have studied the structure and function of Human Misshapen/NIK-related kinase
      (MINK-1) through a combination of computational methods and experimental
      approaches, including (1) fold recognition and sequence-structure alignment for
      each structural domain using the threading program PROSPECT, (2) gene expression
      and protein-protein interaction analysis of yeast homologs of human MINK-1
      domains, and (3) yeast two-hybrid screening for proteins that interact with human
      MINK-1. Our structure prediction dissects MINK-1 into four domains: a conserved N
      terminal kinase domain, followed by a coiled-coil region and a proline-rich
      region, and a C-terminal GCK domain. Gene expression and yeast two-hybrid
      analysis of yeast homologs of the MINK-1 domains suggest that MINK-1 may be
      involved in cell-cycle progression and cytoskeletal control. Consistent with
      these predicted functions, our in-house yeast two-hybrid screen for proteins that
      interact with human MINK-1 provides strong evidence that the coiled-coil and
      proline-rich domains of MINK-1 participate in the regulation of cytoskeletal
      organization, cell-cycle control and apoptosis. A homology model of the MINK-1
      kinase domain was used to screen the NCI open compound database in DOCK, and
      chemical compounds with pharmaceutically acceptable properties were identified.
      Further medicinal chemistry compound structure optimization and kinase assays are
      underway.

PMID- 15032606
TI  - Using property based sequence motifs and 3D modeling to determine structure and
      functional regions of proteins.
AB  - Homology modeling has become an essential tool for studying proteins that are
      targets for medical drug design. This paper describes the approach we developed
      that combines sequence decomposition techniques with distance geometry algorithms
      for homology modeling to determine functionally important regions of proteins. We
      show here the application of these techniques to targets of medical interest
      chosen from those included in the CASP5 (Critical Assessment of Techniques for
      Protein Structure Prediction) competition, including the dihydroneopterin
      aldolase from Mycobacterium tuberculosis, RNase III of Thermobacteria maritima,
      and the NO-transporter nitrophorin from saliva of the bedbug Cimex lectularius.
      Physical chemical property (PCP) motifs, identified in aligned sequences with our
      MASIA program, can be used to select among different alignments returned by fold
      recognition servers. They can also be used to suggest functions for hypothetical
      proteins, as we illustrate for target T188. Once a suitable alignment has been
      made with the template, our modeling suite MPACK generates a series of possible
      models. The models can then be selected according to their match in areas known
      to be conserved in protein families. Alignments based on motifs can improve the
      structural matching of residues in the active site. The quality of the local
      structure of our 3D models near active sites or epitopes makes them useful aids
      for drug and vaccine design. Further, the PCP motif approach, when combined with
      a structural filter, can be a potent way to detect areas involved in activity and
      to suggest function for novel genome sequences.

PMID- 15032607
TI  - Identification of functionally important residues in proteins using comparative
      models.
AB  - Rational design in protein engineering leads to significant progresses in
      medicinal chemistry research. It alleviates the difficulty of exploring
      unreasonable biological functions. Combining with analysis of biophysical
      chemical properties, a three-dimensional (3D) structure provides fruitful
      information for rational design by revealing functionally important residues.
      Comparative (homology) modeling, one of the 3D structural prediction techniques,
      takes advantage of that homologous proteins share similarity in their 3D
      structures despite the lack of sequence similarity. Of the most value, 3D models
      provide functional clues even though the function may have been modified during
      evolution. We illustrate here two applications to medicinal chemistry research
      where comparative models made a significant improvement on the understanding of
      relevant biological functions of two proteins. These multiple collaborative
      projects involve the identification of solvent-exposed residues in a membrane
      anchoring domain of human coagulation factor V, and revealing critical residues
      in the interfaces of an antibody and a polynuclear aromatic hydrocarbon ligand.
      Since the protocol of comparative modeling technique we employed is essential to
      proposing useful hypotheses for experimental testing, we also present our
      methodology underlying our modeling programs. Our results show that inaccuracies
      in comparative models do not hamper functional evaluation as long as an in depth
      analysis of 3D structures is performed.

PMID- 15032608
TI  - The Catharanthus alkaloids: pharmacognosy and biotechnology.
AB  - The Catharanthus (or Vinca) alkaloids comprise a group of about 130 terpenoid
      indole alkaloids. Vinblastine is now marketed for more than 40 years as an
      anticancer drug and became a true lead compound for drug development. Due to the
      pharmaceutical importance and the low content in the plant of vinblastine and the
      related alkaloid vincristine, Catharanthus roseus became one of the best-studied
      medicinal plants. Consequently it developed as a model system for
      biotechnological studies on plant secondary metabolism. The aim of this review is
      to acquaint a broader audience with the recent progress in this research and with
      its exciting perspectives. The pharmacognostical aspects of the Catharanthus
      alkaloids cover botanical (including some historical), phytochemical and
      analytical data. An up-to-date view on the biosynthesis of the alkaloids is
      given. The pharmacological aspects of these alkaloids and their semi-synthetic
      derivatives are only discussed briefly. The biotechnological part focuses on
      alternative production systems for these alkaloids, for example by in vitro
      culture of C. roseus cells. Subsequently it will be discussed to what extent the
      alkaloid biosynthetic pathway can be manipulated genetically ("metabolic
      engineering"), aiming at higher production levels of the alkaloids. Another
      approach is to produce the alkaloids (or their precursors) in other organisms
      such as yeast. Despite the availability of only a limited number of biosynthetic
      genes, the research on C. roseus has already led to a broad scientific spin-off.
      It is clear that many interesting results can be expected when more genes become
      available.

PMID- 15032609
TI  - Serotonin(7) receptors (5-HT(7)Rs) and their ligands.
AB  - Serotonin (5-HT) is involved in various physiological and pathological processes
      by interaction with 14 distinct receptor subtypes, grouped in seven classes of
      receptors (5-HT(1-7)) on the basis of amino acid sequence, pharmacology, and
      signal transduction pathways. The 5-HT(7)R is a G-protein coupled receptor with
      seven transmembrane domains. It was found by the application of molecular cloning
      and has been identified in rat, mouse, human, pig, and guinea pig. Although the
      biological functions of the 5-HT(7)Rs are poorly understood, preliminary evidence
      suggests that it may be involved in depression, control of circadian rhythms, and
      relaxation of vascular smooth muscles. For these reasons, the 5-HT(7)R has become
      a target for the development of novel drugs. This review will give a brief
      introduction of the pharmacology of 5-HT(7)R (molecular structure, distribution
      of 5-HT(7)R mRNA, localization of the 5-HT(7)R protein, functional correlates,
      and therapeutic potential) and a detailed survey of the 5-HT(7)R ligands, which
      have appeared in the literature in both papers and patents. Structure-activity
      relationships (SAR) of these ligands will also be described.

PMID- 15032611
TI  - Exploiting internal ribosome entry sites in gene therapy vector design.
AB  - Efficient and regulated co-expression of multiple genes is an important
      consideration in the design of gene therapy vectors. While the augmentation of a
      single therapeutic gene is often sufficient for gene therapy of simple mendelian
      disorders, strategies for the treatment of complex disorders and infectious
      diseases necessitate the introduction of multiple genes into the cell. Complex
      disorders such as cancer often involve mutations in multiple genes and a
      combination strategy targeting different defective genes simultaneously are often
      more effective than any single strategy. Likewise, approaches for treating
      infectious diseases such as HIV-1 (human immunodeficiency virus) often involve
      the blocking of multiple steps of the viral replication pathway simultaneously to
      prevent the emergence of resistant strains of the virus. Even for the treatment
      of single gene defects, the additional incorporation of a selectable marker gene
      is often necessary to achieve sustained expression of the therapeutic gene in the
      cells. Among the several different strategies to co-express multiple genes, the
      incorporation of an IRES (internal ribosome entry site) into gene therapy vector
      design represents one of the more promising strategies. IRES functions as a
      ribosome-landing pad for the efficient internal initiation of translation
      ensuring coordinate expression of several genes and are located at the 5'UTR (5'
      untranslated regions) of these genes. Currently, the most popular IRES utilized
      for gene therapy is the IRES from the EMCV (encephalomyocarditis virus). However,
      the major caveat with present vector systems utilizing this IRES is that the
      expression of the downstream gene is significantly less efficient than the
      upstream gene. This review will examine the growing list of naturally occurring
      and synthetic IRESes and how they can be exploited for human gene therapy.

PMID- 15032610
TI  - Transductional and transcriptional targeting of adenovirus for clinical
      applications.
AB  - Adenovirus (Ad) targeting is a novel approach for the design and administration
      of therapeutic agents wherein the agent is rationally designed to localize and
      restrict transgene expression to the site of disease in a self-directed manner,
      usually via exploitation of unique biophysical and genetic properties specific to
      the diseased tissue. The ablation of promiscuous native Ad tropism coupled with
      active targeting modalities has demonstrated that innate gene delivery efficiency
      may be retained while circumventing Ad dependence on its primary cellular
      receptor, the coxsackie and adenovirus receptor (CAR), to achieve CAR-independent
      vector tropism. Herein, we describe advances in Ad targeting that are predicated
      not only on fundamental understanding of vector/cell interplay, but also on the
      specific transcriptional profiles of target tissues. Further, targeting is
      discussed in the context of improving the safety and efficacy of clinical
      approaches utilizing adenoviral vectors and replication competent oncolytic
      agents. In summary, existing results suggest a critical linkage between targeted
      agents and increases in therapeutic utility.

PMID- 15032612
TI  - Fas ligand gene therapy for vascular intimal hyperplasia.
AB  - Fas, a member of the tumor necrosis factor receptor super-family, is expressed in
      all cell types examined, while physiologic expression of Fas ligand (FasL) is
      found predominantly in activated T-lymphocytes, vascular endothelial cells, and
      "immune-privileged" tissues. Activation of Fas following FasL binding activates
      caspases, which results in apoptosis. In the vasculature, there may be a delicate
      balance between cell proliferation and apoptosis in vascular smooth muscle cells.
      Shifts in this balance could account for the accumulation of vascular smooth
      muscle cells in response to arterial injury, a major feature of vascular intimal
      hyperplasia. Intimal hyperplasia occurs in more than a third of patients
      receiving percutaneous transluminal balloon angioplasty. Stenting with or without
      coating significantly reduces the incidence rate of angiographic restenosis and
      that of target vessel revascularization. However, "in-stent" intimal
      hyperplasia/restenosis remains a challenge for clinical cardiologists. Although
      both the cell types and mechanisms that contribute to intimal hyperplasia in
      response to vascular injury remain controversial, vascular smooth muscle cell
      migration and proliferation appear to play an important role in the process. In
      animal models, cytotoxic and cytostatic gene therapy strategies targeted at the
      vascular smooth muscle cells have shown therapeutic potential for the treatment
      of vascular intimal hyperplasia. However, Fas ligand-based gene therapy appears
      to offer several advantages. In this review article, we will discuss the mode of
      FasL/Fas signaling in vascular smooth muscle cells and its therapeutic
      implications. We will also compare the relative merits of FasL with other
      cytotoxic and cytostatic gene therapy approaches for the treatment of intimal
      hyperplasia.

PMID- 15032613
TI  - Replicative oncolytic herpes simplex viruses in combination cancer therapies.
AB  - Viruses that kill the host cell during their replication cycle have attracted
      much interest for the specific killing of tumor cells and this oncolytic
      virotherapy is being evaluated in clinical trials. The rationale for using
      replicative oncolytic viruses is that viral replication in infected tumor cells
      will permit in situ viral multiplication and spread of viral infection throughout
      the tumor mass thus overcoming the delivery problems of gene therapy. Improved
      understanding of the life cycle of viruses has evidenced multiple interactions
      between viral and cellular gene products, which have evolved to maximize the
      ability of viruses to infect and multiply within cells. Differences in viral-cell
      interactions between normal and tumor cells have emerged that have led to the
      design of a number of genetically engineered viral vectors that selectively kill
      tumor cells while sparing normal cells. These viruses have undergone further
      modifications to carry adjunct therapy genes to increase their anti-cancer
      abilities. Since these viruses kill cells by oncolytic mechanisms differing from
      standard anticancer therapies, there is an opportunity that synergistic
      interactions with other therapies might be found with the use of combination
      therapy. In this review, we focus on the oncolytic Herpes Simplex Virus-1 (HSV-1)
      vectors that have been examined in preclinical and clinical cancer models and
      their use in combination with chemo-, radio-, and gene therapies.

PMID- 15032614
TI  - Cancer prevention and therapy in a preclinical mouse model: impact of FHIT
      viruses.
AB  - A link between common chromosome fragile sites and frequent chromosomal deletions
      in cancer was observed two decades ago and led to the hypothesis that genes at
      fragile sites may play a role in tumor development. In 1996, the human fragile
      histidine triad gene, FHIT, was identified by positional cloning of the
      chromosome region spanning the carcinogen-sensitive, common fragile site, FRA3B
      at 3p14.2. Loss or inactivation of the FHIT gene in a large fraction of human
      tumors results in absence or reduction of Fhit protein. In vitro analyses and in
      vivo tumorigenicity studies show that restoration of Fhit protein induces tumor
      suppression in 50% of tumor cell lines tested. Viral vector-mediated FHIT gene
      transfer to Fhit-deficient mice not only prevents but reverses the carcinogen
      induced tumor development in vivo, in accordance with the oncosuppressive
      properties of Fhit protein. The strong proapoptotic activity following Fhit
      infection of cancer cells strengthens the case for further exploration of FHIT
      gene therapy in cancer prevention and treatment.

PMID- 15032615
TI  - Can the use of HIV-1 derived gene transfer vectors for clinical application be
      justified?
AB  - Vectors derived from human immunodeficiency virus type 1 (HIV-1) are an
      attractive option for many gene therapy applications as they can transduce non
      cycling cell populations, and can integrate their genome into the host cell
      chromosome. The rationale underlying the design of most retroviral vector systems
      is to segregate the viral cis sequences, which are required for transfer of the
      viral genome, from the trans sequences that encode viral proteins. This allows
      the efficient production of replication incompetent virus and has been
      successfully applied to the generation of HIV-1 vectors. Nonetheless, the
      possibility that recombination events in the vector production system can
      generate replication-competent virus, combined with the pathogenic nature of HIV
      1, raises major bio-safety issues. Numerous HIV-1 vectors have now been reported,
      with each generation significantly improved in ways designed to reduce the risk
      of replication-competent virus being produced. However, progress in vector design
      needs to be complemented by the development of methods for the quantitation of
      the probability of replication competent virus being produced. Assaying
      individual events in the multi-step pathway that can lead to the production of
      replication-competent virus, rather than relying on the detection of replication
      competent virus per se, will be important for quality control purposes. This
      review will specifically examine the approaches to HIV-1 vector design that have
      been postulated as increasing bio-safety, possible methods for evaluating bio
      safety and whether these approaches are likely to be sufficient to overcome
      resistance to the use of HIV-1 for clinical application. In addition, we discuss
      the possible justifications for developing vectors from lentiviruses other than
      HIV-1.

PMID- 15032617
TI  - Promoters and control elements: designing expression cassettes for gene therapy.
AB  - It has become apparent that the clinical success anticipated in the field of gene
      therapy has been limited by progress in several of the fundamental areas of
      genetics, molecular and cellular biology relevant to its application. Whilst a
      great deal of effort has been made in the evaluation of transgenes, it is only
      more recently with the advance of vector systems that attention has begun to be
      focused upon the means and control of transgene expression. Until recently, the
      majority of constructs have employed ubiquitous viral promoters to drive
      expression from simple gene expression cassettes using viral promoters and
      lacking introns, 3' untranslated regions (UTRs), locus control regions (LCR's),
      matrix attachment regions (MAR's) and other such genetic components. It has
      consequently emerged that these elements may have a key role in determining the
      levels and longevity of gene expression attainable in vivo, irrespective of the
      vector system utilised. The majority of gene therapy applications would also
      benefit from the specific optimisation of 'tailor-made' expression cassettes to
      optimise their therapeutic efficacy. In conjunction with modification of vector
      tropism and strategies to limit their immunogenicity, this should create vectors
      suitable for the clinical application of gene therapy. This review aims to
      highlight some of the principle considerations of gene expression in vivo, and
      the means by which it may most effectively be achieved, whether this is via the
      minimal modification of an existing eukaryotic promoter or by the more extensive
      design of a novel promoter and associated elements.

PMID- 15032616
TI  - Potential of gene therapy for the treatment of pituitary tumors.
AB  - Pituitary adenomas constitute the most frequent neuroendocrine pathology,
      comprising up to 15% of primary intracranial tumors. Current therapies for
      pituitary tumors include surgery and radiotherapy, as well as pharmacological
      approaches for some types. Although all of these approaches have shown a
      significant degree of success, they are not devoid of unwanted side effects, and
      in most cases do not offer a permanent cure. Gene therapy-the transfer of genetic
      material for therapeutic purposes-has undergone an explosive development in the
      last few years. Within this context, the development of gene therapy approaches
      for the treatment of pituitary tumors emerges as a promising area of research. We
      begin by presenting a brief account of the genesis of prolactinomas, with
      particular emphasis on how estradiol induces prolactinomas in animals. In so
      doing, we discuss the role of each of the recently discovered growth inhibitory
      and growth stimulatory substances and their interactions in estrogen action. We
      also evaluate the cell-cell communication that may govern these growth factor
      interactions and subsequently promote the growth and survival of prolactinomas.
      Current research efforts to implement gene therapy in pituitary tumors include
      the treatment of experimental prolactinomas or somatomammotropic tumors with
      adenoviral vector-mediated transfer of the suicide gene for the herpes simplex
      type 1 (HSV1) thymidine kinase, which converts the prodrug ganciclovir into a
      toxic metabolite. In some cases, the suicide transgene has been placed under the
      control of pituitary cell-type specific promoters, like the human prolactin or
      human growth hormone promoters. Also, regulatable adenoviral vector systems are
      being assessed in gene therapy approaches for experimental pituitary tumors. In a
      different type of approach, an adenoviral vector, encoding the human
      retinoblastoma suppressor oncogene, has been successfully used to rescue the
      phenotype of spontaneous pituitary tumors of the pars intermedia in mice. We
      close the article by discussing the future of molecular therapies. We point out
      that although, gene therapy represents a key step in the development of molecular
      medicine, it has inherent limitations. As a consequence, it is our view that at
      some point, genetic therapies will have to move from exogenous gene transfer
      (i.e. gene therapy) to endogenous gene repair. This approach will call for
      radically new technologies, such as nanotechnology, whose present state of
      development is outlined.

PMID- 15032618
TI  - Gene therapy: how to target the kidney. Promises and pitfalls.
AB  - The success of gene therapy strongly depends on an efficient delivery system to
      allow local transfer and expression of the therapeutic gene in the target organ
      or tissue. Vector systems have been improved and many show promise. There are two
      different categories of delivery vehicles: non-viral and viral vectors, both with
      advantages and disadvantages that must be taken into consideration in view of the
      final aim. Compared to other solid organs, the kidney offers the main advantage
      of access by different routes that dictate different sites of transfection. Thus,
      the choice of the delivery vehicle and administration route has to take account
      which cells are to be specifically targeted by the gene transfer approach. This
      concept will be discussed in the first part of the review. Using a gene therapy
      approach, improvements of renal function and interstitial inflammation have been
      achieved in experimental models of glomerulonephritis and tubulo-interstitial
      damage. Gene therapy applied to renal transplantation has shown promising results
      in rodents, almost controlling acute rejection. Finally, the development of
      animal models resembling the clinical features of human genetic renal disorders
      offers a first step towards new treatments among which gene therapy could become
      reality in the near future. The main findings concerning the suitability of gene
      therapy for slowing the progression of kidney diseases, and preventing acute
      renal graft rejection, or treating genetic disorders, are discussed.

PMID- 15032619
TI  - TGF-beta: a fibrotic factor in wound scarring and a potential target for anti
      scarring gene therapy.
AB  - Hypertrophic scar and keloid are common and difficult to treat diseases in
      plastic surgery. Results of wound healing research over the past decades have
      demonstrated that transforming growth factor-beta (TGF-beta) plays an essential
      role in cutaneous scar formation. In contrast, fetal wounds, which heal without
      scarring, contain a lower level of TGF-beta than adult wounds. How to translate
      the discovery of basic scientific research into the clinical treatment of wound
      scarring has become an important issue to both clinicians and basic researchers.
      The development of gene therapy techniques offers the potential to genetically
      modify adult wound healing to a healing process similar to fetal wounds, and thus
      reduces wound scarring. This article intends to review the roles of TGF-beta in
      the formation of wound scarring, the possible strategies of antagonizing wound
      TGF-beta, and our preliminary results of scar gene therapy, which show that wound
      scarring can be significantly reduced by targeting wound TGF-beta.

PMID- 15032620
TI  - Melatonin role in experimental arthritis.
AB  - Our perception of the function of the pineal gland and its hormone melatonin has
      attained a new dimension during the last decade. Through melatonin, the pineal
      becomes a principal organ present in vertebrates involved in the control of
      rhythmic adaptations to daily and seasonal cycles. Melatonin is synthesized and
      secreted during the dark period of the light/dark cycle. The rhythmic nocturnal
      melatonin secretion is directly generated by the circadian clock and is entrained
      to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin
      may be used as a circadian mediator to any system than can "read" the message.
      Melatonin acts as an arm of the circadian clock, giving a time-related signal to
      a number of body functions; one of them is the circadian organization of the
      immune response. This review discusses melatonin role in rheumatoid arthritis.
      Animal studies employing Freund's complete mycobacterial adjuvant (FCA) as a
      model of rheumatoid arthritis are described. Immune and neuroendocrine circadian
      rhythms were examined in FCA-injected rats, both in the preclinical phase of
      arthritis (2-3 days after FCA injection) as well as in the acute phase of the
      disease (18 days after FCA injection). In arthritic rats, the 24-h organization
      of immune and neuroendocrine responses becomes altered. Significant effects of
      immune response on diurnal rhythmicity of adenohypophysial and hypophysiotropic
      hormones occurred in arthritic rats. Melatonin treatment prevented alteration of
      24-h rhythms of serum ACTH, prolactin and luteinizing hormone in rats injected
      with FCA. In addition, melatonin treatment prevented alteration of the 24-h
      variation in hypothalamic monoamine transmitter turnover during the preclinical
      phase of Freund's adjuvant arthritis in rats. A comparison between the
      inflammatory and immune responses elicited by physiological and pharmacological
      doses of melatonin in FCA arthritis is reported. Pinealectomized rats exhibited a
      significantly less pronounced inflammatory response, which was restored to normal
      by a low melatonin dose (0.3 microg/ml of drinking water), whereas a high
      melatonin dose (30 microg/ml) that resulted in a 50-60-fold increase in plasma
      melatonin, augmented the inflammatory and immune response. These results should
      be considered in the light of recent reports that rheumatoid arthritis patients
      have increased nocturnal plasma levels of melatonin and that their synovial
      macrophages respond to melatonin with an increased cytokine production.

PMID- 15032621
TI  - CD26/dipeptidyl peptidase IV: a regulator of immune function and a potential
      molecular target for therapy.
AB  - CD26 is a 110 kDa surface-bound ectopeptidase with intrinsic dipeptidyl peptidase
      IV (DPP IV) activity, which has multiple biological functions. In this review, we
      will focus specifically on work demonstrating that CD26 has a key role in immune
      function as a T cell activation molecule and a regulator of the functional effect
      of selected biological factors through its DPP IV enzyme activity. As further
      evidence of the important role played by this multifaceted molecule in immune
      regulation, we will also discuss experimental attempts from our laboratory and
      others to influence immune-mediated conditions through CD26 monoclonal antibodies
      and DPP IV activity with various agents, including anti-CD26 monoclonal
      antibodies and DPP IV chemical inhibitors. Of special significance from a
      clinical perspective is also CD26 effect on glucose metabolism through its DPP IV
      activity and its potential role as a therapeutic target in diabetes. In addition,
      we will review recent studies that describe the physical and functional
      interaction of CD26 with other essential cellular structures and the biological
      consequences of their association. In particular, we will present recent data
      from our laboratory that demonstrates the correlation between CD26, especially
      its DPP IV activity, and the key nuclear protein topoisomerase II alpha, an
      interaction that has important clinical implications. In summary, we will examine
      the biology of the multifaceted CD26/DPP IV molecule, focusing particularly on
      its function in immune regulation and its potential role as a molecular target
      for novel treatment modalities for a number of disease states, ranging from
      autoimmune diseases, diabetes to malignancies.

PMID- 15032622
TI  - The HIV-1 Nef protein: how an AIDS pathogenetic factor turns to a tool for
      combating AIDS.
AB  - Nef is one of the six regulatory proteins coded by the Human Immunodeficiency
      Virus (HIV)-1 and -2, and by the Simian Immunodeficiency Virus (SIV).
      Accumulating experimental evidences indicate that Nef is required for the optimal
      infectivity of HIV viral particles, and that it plays a critical role in the AIDS
      pathogenesis progressing. We previously cloned and sequenced a functionally
      defective HIV-1 genome (F12HIV-1) whose nef gene showed a rather unusual feature,
      i.e. its expression blocks the HIV-1 release by interfering with the viral
      assembling/release. Such a striking phenotype appeared to be the result of three
      amino acid substitutions, and coupled with the loss of the most part of the Nef
      functions described for the wild type counterpart. The F12Nef properties
      encouraged the designing of new strategies of anti HIV-1 gene therapy we afforded
      by recovering an inducible lentivirus vector expressing F12Nef as the cytoplasmic
      domain of a transmembrane fusion protein including a selectable marker (i.e. the
      Nerve Growth Factor receptor) as the ecto- and transmembrane domains. As
      expected, the expression of such a chimeric protein resulted in a potent
      protection of transduced cells from the HIV-1 spread. In sum, and surprisingly
      enough, we generated a reagent effectively counteracting the HIV-1 replication
      through the combination of a slightly mutated AIDS pathogenetic factor together
      with a lentivirus vector, i.e. the result of artifactual modifications of the HIV
      1 genome.

PMID- 15032623
TI  - Immunological modulation by lidocaine-epinephrine and prilocaine-felypressin on
      the functions related to natural immunity in neutrophils and macrophages.
AB  - There is accumulating evidence that local anesthetics have immunological
      properties in addition to their direct anesthetic activity. Because local
      anesthetics are often used together with blood vessel contraction drugs, such as
      epinephrine and felypressin in the clinical setting, we have examined possible
      abilities of both local anesthetic alone including lidocaine, mepivacaine,
      procaine, prilocaine and tetracaine, and local anesthetics with blood vessel
      contraction drugs including lidocaine with epinephrine and prilocaine with
      felypressin on the functions related to natural immunity in neutrophils and
      macrophages. In contrast, lidocaine, mepivacaine, procaine, prilocaine and
      tetracaine all inhibited adhesion, chemotaxis, phagocytosis, and the production
      of superoxide anion and hydrogen peroxide by neutrophils and macrophages.
      Lidocaine with epinephrine and prilocaine with felypressin were effective in
      significantly inhibiting adhesion, chemotaxis, phagocytosis, and the production
      of hydrogen peroxide by neutrophils and macrophages. Interestingly, lidocaine
      with epinephrine potentiated the production of superoxide anion, whereas
      prilocaine with felypressine inhibited the production, irrespective of cells. In
      addition, epinephrine potentiated the production of superoxide anion, whereas
      epinephrine inhibited the production of hydrogen peroxide as well as lidocaine
      with epinephrine. This potentiation by epinephrine was not prevented by
      adrenergic antagonists. Furthermore, superoxide dismutase potentiated the
      production of hydrogen peroxide, which was in part prevented by epinephrine.
      These results suggest that local anesthetics may inhibit the functions related to
      natural immunity in neutrophils and macrophages. In addition, lidocaine with
      epinephrine evidently differs from prilocaine with felypressine regarding the
      molecular mechanisms underlying the modulation of superoxide anion production by
      neutrophils and macrophages.

PMID- 15032625
TI  - The utility of proteomic patterns for the diagnosis of cancer.
AB  - The advent of proteomics has brought with it the hope of discovering novel
      biomarkers that can be used to diagnose diseases, predict susceptibility, and
      monitor progression. Much of this effort has focused on the mass spectral
      identification of the thousands of proteins that populate complex biosystems such
      as serum and tissues. A revolutionary approach termed proteomic pattern analysis
      has emerged as an effective method for the early diagnosis of diseases such as
      ovarian, breast, and prostate cancer. Proteomic pattern analysis relies on the
      pattern of proteins observed and does not rely on the identification of a
      traceable biomarker. Utilizing this technology, hundreds of clinical samples per
      day can be analyzed with the potential to be a novel, highly sensitive diagnostic
      tool for the early detection of diseases or as a predictor of response to
      therapy.

PMID- 15032624
TI  - DI-2-ethylhexyl phthalate and endocrine disruption: a review.
AB  - Esters of o-phthalic acid are widely distributed in the ecosystem. The phthalate
      acid esters (PAE's) are used as plasticizers in enormous quantities for a variety
      of industrial uses in the formulation of plastics. They are also used as solvents
      in certain industrial processes and as vehicles for pesticides and have been
      described as being among the most abundant man-made environmental pollutants.
      Plasticizers have been shown to elute at a constant rate from plastic products to
      the environment. Increasing chemical use needs a better understanding of how
      these pollutants may affect human health. In particular, certain members of this
      chemical class, such as di-[2-ethylhexyl]-phthalate (DEHP), have been shown to
      cause reproductive and developmental toxicity and are suspected to be endocrine
      disruptors.

PMID- 15032626
TI  - HDL and inflammation in atherosclerosis.
AB  - Atherosclerotic vascular disease is among the most frequent causes of death
      worldwide. Current therapeutic strategies concentrate mainly on lowering of low
      density lipoprotein (LDL) cholesterol and an impressive reduction in the risk for
      cardiovascular morbidity and mortality has been achieved. Inflammatory mechanisms
      are more and more recognized to play an important role in vascular disease as
      inflammatory markers correlate with prognosis in acute and chronic coronary
      artery disease. HDL cholesterol exerts anti-inflammatory effects on the
      vasculature. Moreover, HDL is an antioxidant, inhibits thrombogenesis, and has
      pro-fibrinolytic properties. Last but not least, HDL mediates reverse cholesterol
      transport. These pleiotropic effects make HDL an ideal therapeutic target for
      novel therapeutic strategies specifically aiming at HDL elevation for the
      prevention and treatment of atherosclerotic vascular disease.

PMID- 15032627
TI  - Evidence for a putative relationship between type 2 diabetes and neoplasia with
      particular reference to breast cancer: role of hormones, growth factors and
      specific receptors.
AB  - The issue of a possible relationship between type 2 diabetes and cancer is still
      debated. Such chronic diseases show a high incidence in the general population.
      In their pathophysiology both genetic and environmental factors are involved,
      inducing important modifications of metabolism. Diabetes is associated to
      profound metabolic alterations, such as hyperinsulinemia and insulin resistance,
      which are common in various diseases, i.e. obesity, hypertension, dyslipidemia
      and hyperuricemia. Those illnesses form the so-called metabolic syndrome. Insulin
      resistance, hyperestrinism and the associated hyperandrogenism may play a role in
      the onset of some malignancies, such as endometrium cancer, breast cancer and
      prostate cancer. Low plasma levels of IGF-1 are able to reduce the risk of cancer
      in type 2 diabetes patients. This goal can be obtained with preventive measures,
      as physical activity, diet and drugs that can reduce insulin resistance
      (metformin and thiazolidinediones).

PMID- 15032628
TI  - The paracrine role played by interleukin-1 alpha in the testis.
AB  - Interleukin-1alpha (IL-1alpha) plays an important role(s) in the regulation of
      immune and inflammatory responses. The testis is an immunologically privileged
      organ and the variety of effects exerted by IL-1alpha on this organ have yet to
      be explored in detail. The aim of the present review is to describe our current
      view of the paracrine role played by IL-1alpha in testicular physiology.
      Testicular IL-1alpha is expressed during development, primarily in Sertoli cells,
      appearing in rats for the first time 20 days after birth. This cytokine is
      microheterogeneous, consisting of three molecular species with molecular weights
      of 45, 24 and 17 KDa. The 17 KDa form represents mature IL-1alpha, while the 24
      KDa IL-1alpha has been shown by our research group to be an alternately spliced
      form of the 45-KDa pro-IL-1alpha. IL-1alpha was observed to stimulate the
      proliferation of immature Sertoli cells with higher efficacy than FSH. IL-1alpha
      was also found to exert mitogenic effects both on isolated peritubular cells and
      germ cells. Furthermore, isoforms of IL-1alpha were seen to stimulate basal
      testosterone production in immature Leydig cells, but not in the corresponding
      adult cells. This effect involved induction of the steroidogenic acute regulatory
      (StAR) protein and positively regulation by p38 MAPK. Recently, we have observed
      positive interactions between IL-1alpha and hormones of the GH/IGF-I system that
      lead to enhanced androgen production by the Leydig cell. In conclusion, our
      findings suggest that isoforms of IL-1alpha may serve as paracrine mediators,
      alone or in concert with other factors, that support proper testicular cell
      functioning and, thereby, reproduction and fertility.

PMID- 15032629
TI  - Participation of maternal and fetal CRH in early phases of human implantation:
      the role of antalarmin.
AB  - The hypothalamic neuropeptide corticotropin-releasing hormone (CRH) is produced
      by several tissues of the female reproductive system. It is also secreted at
      inflammatory sites and possesses potent pro-inflammatory properties influencing
      both innate and acquired immune processes. Uterine CRH participates in local
      immune early pregnancy phenomena, such as decidualization of endometrial strom a
      and protection of the fetus from maternal immune system. This is maintained
      through induction of the expression of apoptotic FasL on invasive extravillous
      trophoblast and maternal decidual cells at the fetal-maternal interface.
      Furthermore, CRH increases apoptosis of activated T lymphocytes through FasL
      induction participating in the process of implantation and early pregnancy.
      Female rats treated with the non-peptidic CRH receptor 1 (CRHR1) specific
      antagonist antalarmin, in the first 6 days of gestation, have undergone a
      decrease of endometrial implantation sites and live embryos and markedly
      diminished endometrial FasL expression.

PMID- 15032630
TI  - Genetic and biochemical aspects of drug resistance in malaria parasites.
AB  - Drug resistance is one of the major factors contributing to the resurgence of
      malaria, especially resistance to the most affordable drugs such as chloroquine
      and Fansidar, a combination drug of pyrimethamine and sulfadoxine. Understanding
      the mechanisms of such resistance and developing new treatments, including new
      drugs, are urgently needed. Great progress has been made recently in studying the
      mechanisms of drug action and drug resistance in malaria parasites, particularly
      in Plasmodium falciparum. These efforts are highlighted by the demonstration of
      mutations in the parasite dihydrofolate reductase and dihydropteroate synthase
      genes conferring resistance to pyrimethamine and sulfadoxine, respectively, and
      by the recent discovery of mutations in the gene coding for a putative
      transporter, PfCRT, conferring resistance to chloroquine. Mutations in a
      homologue of a human multiple-drug-resistant gene, pfmdr1, have also been shown
      to be associated with responses to multiple drugs. However, except in the case of
      resistance to antifolate drugs, the mechanisms of action and resistance to most
      drugs currently in use are essentially unknown or are being debated.
      Additionally, novel mechanisms of resistance exist in different malaria
      parasites, complicating the process of developing new drugs and treatment
      strategies. Here we summarise the progress made in drug resistance research in
      malaria parasites over the past 20 years, emphasising the most recent
      developments in the genetics of drug resistance.

PMID- 15032631
TI  - Mitochondrial and plastid functions as antimalarial drug targets.
AB  - Malaria parasites possess three genomes: the nuclear chromosomes, the
      mitochondrial genome, and the plastid genome. Realization that the parasites
      contain a plastid remnant with its own genome has created much excitement not
      only from a basic biological point of view but also from the prospects for
      developing new antimalarial drugs. Both the mitochondrial and the plastid genomes
      are the smallest examples of their kind known to date. The plastid appears to be
      derived from an ancestral secondary endosymbiotic event. Interestingly, the main
      functions usually associated with a mitochondrion and a plastid, i.e. oxidative
      phosphorylation and photosynthesis, do not appear to be conserved in malaria
      parasites. Completion of the parasite genome sequence has provided the
      opportunity to assess functions assigned to these highly derivatized organelles.
      It is clear that these organelles serve vital functions since interference with
      their activity is incompatible with parasite growth. A number of antimalarial
      compounds target functions of either the mitochondrion or the plastid. This
      review will survey our current understanding of mitochondrial and plastid
      functions with a view to identify processes that are or have a potential to be
      targets for antimalarial drugs.

PMID- 15032632
TI  - Computer assisted searches for drug targets with emphasis on malarial proteases
      and their inhibitors.
AB  - The creation of databases that make enormous and diverse amounts of information
      available, the coding of algorithms that allow the collection and investigation
      of these data and the wide availability of desktop computers capable of handling
      the data and running the algorithms have set the stage for innovative approaches
      to drug target identification. Here we review the main currents in this new
      field, providing an overview of some of the databases and software used to
      generate and shorten the lists of potential drug targets using in silico methods.
      As a case study, we look at the identification and investigation of malarial
      proteases as therapeutic targets in the Plasmodium spp. parasites.

PMID- 15032633
TI  - Proteomic approaches to studying drug targets and resistance in Plasmodium.
AB  - Ever increasing drug resistance by Plasmodium falciparum, the most virulent of
      human malaria parasites, is creating new challenges in malaria chemotherapy. The
      entire genome sequences of P. falciparum and the rodent malaria parasite, P.
      yoelii yoelii are now available. Extensive genome sequence data from other
      Plasmodium species including another important human malaria parasite, P. vivax
      are also available. Powerful research techniques coupled to genomic resources are
      needed to help identify new drug and vaccine targets against malaria. Applied to
      Plasmodium, proteomics combines high-resolution protein or peptide separation
      with mass spectrometry and computer software to rapidly identify large numbers of
      proteins expressed from various stages of parasite development. Proteomic methods
      can be applied to study sub-cellular localization, cell function, organelle
      composition, changes in protein expression patterns in response to drug exposure,
      drug-protein binding and validation of data from genomic annotation and
      transcript expression studies. Recent high-throughput proteomic approaches have
      provided a wealth of protein expression data on P. falciparum, while smaller
      scale studies examining specific drug-related hypotheses are also appearing. Of
      particular interest is the study of mechanisms of action and resistance of drugs
      such as the quinolines, whose targets currently may not be predictable from
      genomic data. Coupling the Plasmodium sequence data with bioinformatics,
      proteomics and RNA transcript expression profiling opens unprecedented
      opportunities for exploring new malaria control strategies. This review will
      focus on pharmacological research in malaria and other intracellular parasites
      using proteomic techniques, emphasizing resources and strategies available for
      Plasmodium.

PMID- 15032634
TI  - QTL analysis for discovery of genes involved in drug responses.
AB  - The completed Plasmodium falciparum genome sequence poses a significant
      challenge: how do we bring this wealth of data to bear against the steady march
      of malaria parasites towards multiple-drug resistance? Studies of parasite drug
      resistance have until now focused on a qualitative, single-gene concept of
      resistance determination; however, the emergence of powerful genomics tools
      insists that these questions be rephrased. It is now possible to address the true
      genetic complexity underlying quantitative drug sensitivities. Quantitative trait
      loci (QTL) mapping is an effective tool for tracking multi-gene traits by
      partitioning genetic effects that influence these traits into specific genomic
      regions. A cross between two parasite clones captures allele combinations that
      have segregated into progeny clones that display varying sensitivity to drugs.
      The specific allele forms and their combinations contributed by each parent are,
      in effect, genetic signatures of their unique evolutionary histories. In addition
      to resistance genes, per se, a drug resistant parasite carries co-evolved gene
      combinations comprising a genetic background of drug resistance. Research into
      drug resistance necessarily has been directed at specific genes and mechanisms
      favored by a priori knowledge and assumptions about how resistance works. QTL
      mapping, by superimposing real biological phenotypes on genome sequence,
      structural polymorphisms, and gene expression data, can provide an alternative,
      unbiased view of the network of gene actions that build a complex phenotype.
      Through an integrated approach, studies can move beyond the search for markers of
      resistance to instead characterize the predisposition of parasites to develop new
      resistances and cross-resistances.

PMID- 15032635
TI  - Mapping drug resistance genes in Plasmodium falciparum by genome-wide
      association.
AB  - When alleles conferring drug resistance spread through a population of malaria
      parasites, they leave characteristic "scars" in the parasite genome. Flanking
      neutral polymorphisms "hitchhike" to high frequency with the resistance mutation,
      generating deep valleys of reduced variation and broad swathes of elevated
      linkage disequilibrium around the resistance locus. We can systematically search
      the genome for these scars by genotyping polymorphic marker loci at intervals
      throughout the genome of P. falciparum, and use them as signposts for locating
      drug resistance genes. In this review I outline the rational behind this approach
      to genetic mapping. I describe key features of P. falciparum population biology,
      such as recombination rate, inbreeding, and selection intensity that influence
      the size of genomic regions affected by selection and the choice of study
      population. I discuss suitable genetic markers, study designs, and statistical
      approaches to data analysis. Finally, to demonstrate the utility of the approach
      I describe two proof-of-principle studies documenting patterns of genetic
      variability around known drug resistance genes.

PMID- 15032636
TI  - Targeting ion channels of Plasmodium falciparum-infected human erythrocytes for
      antimalarial development.
AB  - Aside from its profound clinical importance, the human malaria parasite, P.
      falciparum, is intrinsically fascinating to the cell biologist because it resides
      within the mature red blood cell (RBC). Because the inert RBC cannot otherwise
      provide sufficient amounts of key substrates to fuel the vigorous parasite
      metabolism, the parasite must have specialized adaptations for getting these
      solutes into the RBC and scavenging them from RBC cytosol. Two unusual ion
      channels have recently been identified within the infected RBC complex; these
      channels likely function in a sequential diffusive pathway of nutrient
      acquisition by the intracellular parasite. If so, they present novel
      opportunities for identification of ion channel inhibitors that may be useful
      antimalarial compounds.

PMID- 15032637
TI  - Molecular regulation of neutrophil apoptosis and potential targets for
      therapeutic strategy against the inflammatory process.
AB  - The balance between polymorphonuclear leukocytes (PMNL) apoptosis and necrosis in
      inflamed tissues is an important determinant of the degree of tissue injury. To
      prevent senescent PMNL from releasing their toxic contents into surrounding
      tissues, these cells become apoptotic and are then internalized by tissue
      macrophages. PMNL apoptosis and subsequent ingestion by macrophages are the major
      mechanisms for clearing PMNL that have been recruited to the inflamed sites and
      thus for promoting resolution of the inflammation. PMNL have a short half-life
      that is extended at the inflamed site by pro-inflammatory cytokines including
      Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Interleukin-8 (IL-8),
      Gro-alpha, and they contact with the bacterial cell walls containing
      lipopolysaccharides (LPS). Conversely, anti-inflammatory cytokines, such as IL
      10, accelerate the apoptosis of LPS-activated PMNL. Spontaneous PMNL apoptosis
      does not require Fas ligation but involves proteolytic cascades -caspases
      (particularly caspases 3 and 8), calpains and the proteasome-that activate
      kinases, e.g. caspase 3-mediated activation of protein kinase C-delta, dissociate
      actin-binding proteins from filamentous actin, and participate in cell surface as
      well as nuclear morphological transformations. Members of the Bcl-2 protein
      family, Mcl-1 and A1, are involved in the regulation of PMNL apoptosis. Cell
      surface receptors and protein kinases, particularly mitogen-activated protein
      kinases (MAPK), also play critical roles in transducing the signals that result
      in PMNL apoptosis or extended survival. A growing understanding of the mechanisms
      regulating leukocyte apoptosis and of the molecules mediating safe phagocytic
      clearance of dying cells may yield new insights into the pathogenesis of
      inflammatory diseases. In this regard, therapeutic strategies to resolve chronic
      inflammation could usefully target PMNL. This review summarises current knowledge
      on the molecular mechanisms and components of PMNL apoptosis.

PMID- 15032638
TI  - Modulation of innate immune responses in the treatment of sepsis and pneumonia.
AB  - In the last decades several preclinical models for sepsis have been used to study
      the pathophysiologic processes during sepsis. Although these studies revealed
      promising immunomodulating agents for the treatment of sepsis, clinical trials
      evaluating the efficacy of these new agents in septic patients were
      disappointing. It should be realized that most of the preclinical models for
      sepsis lack a localized infectious source from which the infection disseminates.
      Studies on the effects of several immunomodulating strategies have demonstrated
      strikingly opposite results when using models for sepsis with a more natural
      route of infection, such as pneumonia, and when using models for sepsis lacking
      an infectious focus. In this review we will compare models for sepsis and models
      for pneumonia. We advise to use a combination of models, including models for
      sepsis and models for localized infections, to test new immunomodulating
      strategies before starting any clinical trial evaluating a new immunomodulating
      therapy.

PMID- 15032639
TI  - Drugs that target lipoxygenases and leukotrienes as emerging therapies for asthma
      and cancer.
AB  - Considerable amount of work has been done in the area of enzymatic and non
      enzymatic oxidation of arachidonic acid. This effort resulted in understanding of
      the functions of lipid mediators--eicosanoids in various aspects of health and
      disease. A mechanism by which aspirin exerts therapeutic effects puzzled
      pharmacologists for a long time until John Vane, in 1971, discovered that aspirin
      and its congeners block formation of prostaglandins, a class of lipids that
      originate from oxidation of arachidonic acid by cyclooxygenase. Since that
      discovery the pharmacology of eicosanoids has substantially progressed, which
      resulted in new drugs available in clinics. In addition to many new inhibitors of
      cyclooxygenase, two isoforms of which are known, much effort has been given to
      find inhibitors of synthesis and function of leukotrienes, a class of lipids that
      are derived from 5-lipoxygenase. These lipids are generated in asthma and their
      uncontrolled biosynthesis aggravates the symptoms of asthma. A new class of drugs
      called lukasts, inhibitors of 5-LOX products, has been developed and entered
      clinics as the first new therapy to treat asthma in nearly 20 years. New
      discoveries in the field of lipoxygenase show great opportunities for drug
      development for cancer prevention and treatment as it has been established that
      lipoxygenases and their products are required for cancer growth. Intense research
      in this field is likely to produce new drugs in the near future.

PMID- 15032640
TI  - T-cell-mediated signalling in immune, inflammatory and angiogenic processes: the
      cascade of events leading to inflammatory diseases.
AB  - In the last decade, the understanding of the molecular mechanisms of regulation
      of the inflammatory process in chronic inflammatory diseases has moved remarkably
      forward. Recent evidence in various fields has consistently indicated that T
      cells play a key role in initiating and perpetuating inflammation, not only via
      the production of soluble mediators but also via cell/cell contact interactions
      with a variety of cell types through membrane receptors and their ligands.
      Signalling through CD40 and CD40 ligand is a versatile pathway that is potently
      involved in all these processes. In this article, we review how T-cells become
      activated by dendritic cells or inflammatory cytokines, and how these T-cells
      activate, in turn, monocytes/macrophages, endothelial cells, smooth muscle cells
      and fibroblasts to produce pro-inflammatory cytokines (tumour necrosis factor
      alpha, interleukin-6), chemokines (interleukin-8, monocyte chemotactic protein
      1), tissue factor, the main initiator of the coagulation cascade in vivo, and
      finally matrix metalloproteinases, responsible for tissue destruction. Moreover,
      we discuss how CD40 ligand at inflammatory sites stimulates fibroblasts and
      tissue monocyte/macrophage production of VEGF, leading to angiogenesis, which
      promotes and maintains the chronic inflammatory process. This cascade of events
      is discussed in the context of disease initiation/progression, with particular
      reference to atherosclerosis and rheumatoid arthritis, and to potential novel
      therapeutic targets for their treatment.

PMID- 15032641
TI  - Novel non-steroidal anti-inflammatory drugs: what we have learned from animal
      studies.
AB  - The use of non-steroidal anti-inflammatory drugs (NSAIDs) is frequently
      associated with serious adverse effects related to the inhibition of
      cyclooxygenase (COX) in tissues where prostanoids exert physiological effects,
      such as gastric mucosal defence, renal homeostasis and platelet aggregation. The
      discovery of a second COX isoform (COX-2) specifically induced in pathological
      tissues led to the development of selective COX-2 inhibitors, believed to have an
      improved safety profile compared to traditional NSAIDs. Animal studies, however,
      have revealed a protective role for the COX-2 enzyme in the stomach, kidney,
      heart, vasculature and reproductive system, and therefore, the safety of COX-2
      selective inhibitors needs to be reassessed. On the other hand, new therapeutic
      indications have emerged as a result of the role played by COX-2 overexpression
      in cancer or Alzheimer's disease. A second approach aimed at obtaining safer
      NSAIDs is based on the gastroprotective effects of nitric oxide (NO). Traditional
      NSAIDs chemically linked to NO-releasing moieties retain the therapeutic
      efficacy, but not the adverse effects, of the parent NSAIDs. Moreover, additional
      therapeutic applications in cardiovascular diseases, Alzheimer's disease and
      cancer have been suggested. Animal data, however, need to be confirmed in large
      clinical trials. Finally, the increase in endogenous NO via a selective increase
      in inducible NO synthase in the gastric mucosa is the mechanism underlying the
      good gastric tolerability and the gastroprotective effects of the non-selective
      NSAID amtolmetin guacyl, documented to date in the rat.

PMID- 15032642
TI  - Antiviral therapy for chronic hepatitis B: a review.
AB  - Chronic hepatitis B virus (HBV) infection is a well-recognized risk factor for
      the development of hepatocellular carcinoma (HCC), which is becoming a more
      prevalent clinical problem, especially in HBV-endemic areas. It is estimated that
      1.25 million people in the United States and more than 300 million people
      worldwide are chronically infected with HBV. Despite the introduction of
      universal vaccination against hepatitis B in over 100 countries, persistent HBV
      infection is still a serious problem worldwide, causing an estimated annual death
      rate of one million. It may take several decades until the effect of vaccination
      will be translated into reduced transmission and morbidity. Meanwhile, patients
      with persistent HBV infection require better antiviral therapeutic modalities
      than are currently available. It is well accepted that antiviral therapy for
      chronic hepatitis B is effective to improve prognosis of patients with HBV by
      preventing development of hepatitis state and HCC. The therapeutic endpoints for
      hepatitis B treatment are: 1) sustained suppression of HBV replication, as
      indicated by HBsAg and HBeAg loss, 2) decrease of serum HBV DNA of an
      undetectable level by a non-PCR method, 3) remission of disease, as shown by
      normalization of ALT, 4) improvement in liver histology, and 5) reduction of the
      acute exacerbation, cirrhosis, and HCC. In the present, the antiviral treatment
      of hepatitis B consists of either interferon alpha or oral lamivudine alone or in
      combination with existing therapy. Each major antiviral drug of interferon alpha
      and lamivudine has pros and cons, and effect of combination therapy of both drugs
      is also still limited. More powerful and safe new antiviral therapies are
      required to achieve final goal of these therapeutic endpoints. Management of
      chronic hepatitis B requires significant knowledge of approved
      pharmacotherapeutic agents and their limitations. Therapeutic options for
      managing hepatitis infection after liver transplantation (LT) are also evolving.

PMID- 15032643
TI  - Acid-sensing ion channels (ASICs): new targets for the analgesic effects of non
      steroid anti-inflammatory drugs (NSAIDs).
AB  - Non-steroid anti-inflammatory drugs (NSAIDs) are major drugs used in the
      treatment of inflammation and pain in a wide variety of disorders. NSAIDs
      constitute a diverse group of chemicals, categorized according to their chemical
      structures that share the same therapeutic properties. Among the main compounds
      are aspirin and salicylate, diclofenac and flurbiprofen. The best-known mechanism
      of action of NSAIDs is the inhibition of prostaglandin synthesis secondary to
      their action on cyclooxygenases (COXs). However, data have been accumulating
      through the years indicating that NSAIDs also act on other targets to counteract
      pain. Their analgesic effects are not necessarily the consequence of their anti
      inflammatory action. Administration of NSAIDs reduces cutaneous and corneal pain
      induced by acidic pH in the absence of inflammation. Tissue acidosis, which is a
      dominant factor in inflammation, tumors and ischemia, has an important
      contribution in pain and hyperalgesia. This is due to direct excitation of the
      nociceptive sensory neurons by protons-gated depolarizing currents. Actually,
      these neurons bear a major category of ion channels that are sensitive to
      extracellular pH changes, the acid-sensing ion channels (ASICs). ASIC channels
      are able to induce action potential triggering on sensory neurons after a
      moderate extracellular pH decrease. They undergo transcriptional induction and
      post-translational regulation during inflammation and thus participate in the
      hypersensitization of the nociceptive system in this physiopathological
      condition. One specific ASIC isoform is also thought to mediate cardiac ischemic
      pain. COX-independent direct inhibition of their activity by different NSAIDs has
      been shown to occur at therapeutic doses of these compounds, on native ASIC
      currents on sensory neurons, as well as on ASIC channels expressed in
      heterologous systems. Moreover, NSAIDs also prevent the large inflammation
      induced increase of their expression. These two effects are thus proposed to play
      an important role in the analgesic effects of NSAIDs in addition to their well
      known action through COXs, and particularly in case of inflammation.

PMID- 15032644
TI  - Regulation of innate immunity signaling and its connection with human diseases.
AB  - Human innate immunity can respond to diverse microbial products, as well as other
      substances such as heat shock proteins, taxol, and unsaturated fatty acids.
      Mediated largely by a family of Toll-like-receptors (TLR) and associated
      intracellular downstream signaling molecules, human innate immune response serves
      multiple functions ranging from providing the first line of defense to
      coordinating cellular growth as well as other cellular functions. To date, about
      10 distinct human TLR receptors have been identified in the human genome.
      Biochemical studies and genetic analyses using transgenic mice have revealed
      specific ligands for several TLR receptors. TLR intracellular domains could then
      specifically recruit several adaptor proteins including MyD88, TIRAP/MAL, TRIF,
      and TOLLIP. These adaptor proteins subsequently associate with a family of
      interleukin-1 receptor-associated kinases (IRAK1, 2, M, and 4). Recruitments of
      numerous downstream signaling proteins lead to activation of a range of
      transcription factors such as NF kappa B, AP-1, and IRFs, which are responsible
      for specific gene transcriptions. Human innate immunity is manifested in diverse
      cells and tissues. Well-coordinated innate immunity signaling enables human cells
      and tissues to properly respond to various substances. Improper regulations of
      such event have been shown to cause various diseases including asthma,
      atherosclerosis, and cancer. TLR receptors as well as other intracellular
      signaling proteins can potentially serve as therapeutic targets for numerous
      human diseases. This review will discuss at the molecular level, regulation of
      innate immunity signaling as well as its intricate connection with human
      diseases.

PMID- 15032645
TI  - The possibilities and pitfalls for anti-complement therapies in inflammatory
      diseases.
AB  - The complement system is a key component of innate immunity, acting to protect
      the host from micro-organisms such as bacteria and other "foreign" threats,
      including tumor cells. However, excessive activation of complement can injure the
      host and can even be life threatening. These toxic effects are caused primarily
      by the excessive production of the anaphylatoxins C3a and C5a during complement
      activation and excessive formation of membrane attack complex on the host cell
      membrane. Many inflammatory diseases, including rheumatoid arthritis and
      glomerulonephritis, are thought to involve excessive activation of complement,
      both for their development and perpetuation. Uncontrolled complement activation
      is also implicated in post-ischemic inflammation and tissue damage and in sepsis.
      Therefore, it is important to regulate the complement system to treat disease.
      There are still no broadly applicable agents for the therapeutic regulation of
      excessive complement activation. However, there are now some agents in the
      development that might provide useful anti-complement therapies in the near
      future. Current strategies include the use of neutralizing antibodies, small
      synthetic antagonists, soluble recombinant forms of the natural complement
      regulators, and gene therapies to control excessive complement activation. Here
      we describe these new agents, their strengths and weaknesses and progress in
      testing the agents in relevant animal models.

PMID- 15032646
TI  - Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations
      by differential regulation of TH1/TH2 cytokine production.
AB  - Estrogen appears to play a central role in the immune response and immune
      mediated diseases. Estrogen receptors are expressed in a variety of
      immunocompetent cells, including CD4(+) and CD8(+) T cells and macrophages.
      Clinical observations indicate that some autoimmune diseases, such as rheumatoid
      arthritis and multiple sclerosis, frequently remit during pregnancy but
      exacerbate, or have their onset during the postpartum period. Pharmacological
      levels of estrogen also appear to ameliorate certain autoimmune diseases. In
      addition, estrogen is known to suppress certain infectious diseases, as well as T
      cell-mediated responses toward oxazolone, keyhol lympet hemocyanin, Listeria
      soluble protein and purified protein derivatives. The immune basis for these
      phenomena is poorly understood. Based on a distinctive profile of cytokine
      production, data accumulated thus far have revealed modulatory effects for
      estrogen on the TH1-type and TH2-type cells, which represent two polarized forms
      of the effector specific immune response. Recent evidence indicates that
      estrogens inhibit the production of TH1 proinflammatory cytokines, such as IL-12,
      TNF-alpha and IFN-gamma, whereas they stimulate the production of TH2 anti
      inflammatory cytokines, such as IL-10, IL-4, and TGF-beta. This can explain why
      estrogen suppresses and potentiates TH1- and TH2-mediated diseases, respectively.
      We hypothesize that exacerbation or suppression of inflammatory diseases by
      estrogen is mediated by skewing TH1-type to TH2-type response. This view
      represents a novel mechanism for the modulatory effect of estrogen on certain
      inflammatory diseases that can lead to beneficial or detrimental impacts
      depending on the type of immune involved. Such a concept is valuable when
      considering the application of combination therapies that include estrogen.

PMID- 15032647
TI  - Thrombin: a potential proinflammatory mediator in neurotrauma and
      neurodegenerative disorders.
AB  - Thrombin is well known in its function as the ultimate serine protease in the
      coagulation cascade. Emerging evidence indicates that thrombin also functions as
      a potent signaling molecule that regulates physiologic and pathogenic responses
      alike in a large variety of cell populations and tissues. Accompanying CNS injury
      and other cerebral vascular damages, prothrombin activation and leakage of active
      thrombin into CNS parenchyma has been documented. Due to the irreplaceable
      feature of neurons, over-reactive inflammatory reactions in the CNS often cause
      irreversible neuronal damage. Therefore, particular attention is required to
      develop strategies that restrict CNS inflammatory responses to beneficial, in
      contrast to neurotoxic ones. In this regard, thrombin not only activates
      endothelial cells and induces leukocyte infiltration and edema but also activates
      astrocytes, and particularly microglia, as recently demonstrated, to propagate
      the focal inflammation and produce potential neurotoxic effects. Recently
      revealed molecular mechanisms underlying these thrombin effects appear to involve
      proteolytic activation of two different thrombin-responsive, protease-activated
      receptors (PARs), PAR1 and PAR4, possibly in concert. Potential therapeutic
      strategies based on appreciation of the current understanding of molecular
      mechanisms underlying thrombin-induced CNS inflammation are also discussed.

PMID- 15032648
TI  - Molecular mechanisms of impaired endothelial function associated with insulin
      resistance.
AB  - Dysfunction of the endothelium in large- and medium-sized arteries plays a
      central role in atherogenesis. The insulin resistance syndrome encompasses more
      than a subnormal response to insulin-mediated glucose disposal. Patients with
      this syndrome also frequently display elevated blood pressure, hyperlipidemia,
      and dysfibinolysis, even without any clinically manifested alteration in plasma
      glucose concentrations. Of note endothelial dysfunction and atherosclerosis also
      have been demonstrated in patients with hypertension, which is one of the
      features of the syndrome of insulin resistance. Insulin-induced vasodilation,
      which is mediated by the release of nitric oxide (NO) release, is impaired in
      obese individuals who display insulin resistance. Although it is tempting to
      speculate that loss of endothelium-dependent vasodilation and increased
      vasoconstriction might be etiological factors of elevated blood pressure, the
      factors contributing to NO-mediated endothelial dysfunction in the insulin
      resistant state are not fully defined. Experimental evidences suggest that (6R)
      5,6,7,8-tetrahydrobiopterin (BH(4)), the natural and essential cofactor of NO
      synthases (NOS), plays a crucial role not only in increasing the rate of NO
      generation by NOS but also in controlling the formation of superoxide anion
      (O(2)(-)) in the endothelial cells. Under insulin-resistant conditions where
      BH(4) levels are suboptimal, in addition to a reduced synthesis of NO, an
      accelerated inactivation of NO by O(2)(-) within the vascular wall was observed.
      Furthermore, oral supplementation of BH(4) restored endothelial function and
      relieved oxidative tissue damage, through activation of eNOS in the aorta of
      insulin-resistant rats. These results indicate that abnormal pteridine metabolism
      contributes to causing endothelial dysfunction and the enhancement of vascular
      oxidative stress in the insulin-resistant state.

PMID- 15032649
TI  - Endothelial dysfunction and coronary atherosclerosis.
AB  - Increasing evidence has revealed that endothelial cells play an important role in
      the pathogenesis of development and progression of atherosclerosis. Endothelial
      dysfunction induces disruption of the balance between vasoconstrictive factors
      and vasodilatory factors secreted from endothelial cells. Among these factors, NO
      and angiotensin II are especially important factors, and have been shown to exert
      various direct effects on the endothelial functions that are closely related to
      the pathogenesis of atherosclerosis. Endothelial dysfunction induces decreased NO
      bioactivity and increased angiotensin II expression, which increase oxidative
      stress and expression of adhesion molecules, cytokines, and chemokines. These
      conditions mediate inflammation, proliferation, and thrombogenesis in vessel wall
      and promote atherosclerotic lesions. On the other hand, therapies that improve
      endothelial dysfunction, such as administration of HMG-CoA reductase inhibitors
      or angiotensin converting inhibitors, have been demonstrated to reduce
      cardiovascular events and strokes. In this article, we focus on NO and
      angiotensin II and describe their roles in the pathogenesis of atherosclerosis.

PMID- 15032650
TI  - Endothelial dysfunction and coronary artery spasm.
AB  - Coronary spasm plays an important role in the pathogenesis of not only variant
      angina but also coronary heart disease in general including acute coronary
      syndromes. The incidence of coronary spasm in Japanese patients with angina
      pectoris was about 40%. The total number of patients with angina pectoris
      increases with old age. The patients' age distribution was relatively younger in
      the coronary spasm than in the stable effort angina. The vascular endothelium has
      been reported to be a multifunctional organ whose integrity is essential to
      normal vascular physiology, and whose dysfunction can be a critical factor in the
      pathogenesis of vascular disease. Acetylcholine and methacholine cause
      vasodilation by endothelium-derived relaxing factor when endothelium is
      functioning normal, whereas they cause vasoconstriction when endothelium is
      removed or damaged. Coronary spasm can be induced by acetylcholine and
      methacholine. The patients with coronary spasm may have a disturbance in the
      endothelial function of the coronary arteries.

PMID- 15032652
TI  - Insulin resistance as a therapeutic target for improved endothelial function:
      metformin.
AB  - Endothelial dysfunction is a feature of a variety of clinical states of insulin
      resistance, and increasingly it is recognized that pre-diabetic states of insulin
      resistance are associated not only with insulin resistance but with increased
      cardiovascular risk. The metabolic syndrome which typically accompanies insulin
      resistance brings aberrations in a number of classical cardiovascular risk
      factors, but it appears that insulin resistance itself represents an additional,
      non-classical risk factor. Therefore, the approach to treating the endothelium in
      patients with the metabolic syndrome might include therapies targeting insulin
      resistance. In this review, we provide a detailed overview of the current state
      of knowledge regarding the biguanide metformin and its effects on the
      endothelium. Its mode of action is reviewed, along with the available data from
      laboratory and experimental studies related to vascular function in animals and
      in humans. Metformin has beneficial effects on endothelial function which appear
      to be mediated through its effects to improve insulin resistance. Therapeutically
      targeting insulin resistance appears to be a viable route to improving
      endothelial function in clinical states of insulin resistance.

PMID- 15032651
TI  - The possible therapeutic actions of peroxisome proliferator-activated receptor
      alpha (PPAR alpha) agonists, PPAR gamma agonists, 3-hydroxy-3-methylglutaryl
      coenzyme A (HMG-CoA) reductase inhibitors, angiotensin converting enzyme (ACE)
      inhibitors and calcium (Ca)-antagonists on vascular endothelial cells.
AB  - Several intervention studies have shown that some hypolipidemic and hypotensive
      drugs such as fibrates, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase
      inhibitors, angiotensin converting enzyme (ACE) inhibitors and calcium (Ca)
      antagonists prevent atherosclerosis. The main pathological findings in
      atherosclerosis include abnormal reactions of neutrophils, lymphocytes and
      monocytes/ macrophages, vascular smooth muscle cells and vascular endothelial
      cells, and the accumulation of cholesterol ester in the arterial wall. Therefore,
      investigating the effects of these drugs on the arterial wall may improve
      understanding of the mechanisms underlying atherosclerosis. Here, based on recent
      studies including our own, we describe the relationships between risk factors for
      atherosclerosis, especially hyperlipidemia and hypertension, and the molecular
      mechanisms that govern lipid metabolism in the arteries.

PMID- 15032654
TI  - Collagen cross-link breakers: a beginning of a new era in the treatment of
      cardiovascular changes associated with aging, diabetes, and hypertension.
AB  - Aging, diabetes, and hypertension are conditions in which arterial and myocardial
      stiffness is increased. Increased arterial stiffness is manifested by an
      increased systolic arterial pressure, pulse pressure and pulse wave velocity,
      whereas increased myocardial stiffness is manifested by impaired left ventricular
      diastolic filling. Moreover, increased arterial stiffness increases cardiac
      workload, further aggravating already existing adverse changes in left
      ventricular structure and function. Indeed, studies in human beings have clearly
      shown that increased cardiovascular stiffness is a reliable predictor of
      cardiovascular morbidity and mortality. Increased cardiovascular stiffness is
      usually attributed to the development of fibrosis (i.e., accumulation of
      collagen). It has also been recognized that the increased cardiac and vascular
      stiffness may be due to increased collagen cross-linking due to the formation of
      advanced glycosylation end-products (AGEs). In agreement with this notion is the
      finding that an inhibitor of AGEs formation improves vascular stiffness in
      diabetic rats. More recently, cross-link breakers have been developed, and the
      beneficial effects of one such agent (ALT-711) have been shown in experimental
      and clinical settings. This report briefly summarizes age related changes in
      cardiovascular structure and function and describes results of experimental and
      clinical studies involving collagen cross-link breakers.

PMID- 15032653
TI  - Microglia: neuroprotective and neurotrophic cells in the central nervous system.
AB  - Microglia are currently accepted as sensor cells in the central nervous system
      that respond to injury and brain disease. The main function of microglia is
      believed to be brain defense, as they are known to scavenge invading
      microorganisms and dead cells, and also to act as immune or immunoeffector cells.
      However, microglia are also thought to contribute to the onset of or to
      exacerbate neuronal degeneration and/or inflammation in many brain diseases by
      producing deleterious factors including superoxide anions, nitric oxide and
      inflammatory cytokines. Nonetheless, microglia have also been shown to act
      neuroprotectively by eliminating excess excitotoxins in the extracellular space.
      Moreover, there is accumulating evidence that microglia produce neurotrophic
      and/or neuroprotective molecules; in particular, it has been suggested that they
      promote neuronal survival in cases of brain injury. In general, the question of
      whether microglia act as neurotoxic cells or as neuroprotective cells in vivo has
      gained much recent attention. In this paper, we provide a review of findings
      indicating that the microglia are basically neurotrophic/neuroprotective cells in
      the nervous system. In addition, the mechanism by which neurotrophic microglia
      become oriented to a neurotoxic state is discussed.

PMID- 15032655
TI  - Current understanding of in-stent restenosis and the potential benefit of drug
      eluting stents.
AB  - Percutaneous transluminal coronary angioplasty has revolutionized the management
      of patients with coronary artery disease. Unfortunately, the procedure's utility
      is limited by a frequent complication: restenosis. Coronary stenting prevents the
      elastic recoil and negative remodeling that can occur after angioplasty but, by
      inciting varying degrees of intimal expansion, it can also produce arterial
      renarrowing, known as in-stent restenosis (ISR). The precise mechanisms involved
      in the pathogenesis of ISR are incompletely understood. The recent introduction
      of drug-eluting stents (DESs) may help prevent ISR. However, DESs have not been
      universally successful, and they may introduce new complications that require
      further refinement. This review summarizes the current understanding of the
      pathogenesis of ISR and provides an objective overview of DESs.

PMID- 15032656
TI  - Comparative receptor surface analysis of agonists for tyramine receptor which
      inhibit sex-pheromone production in Plodia interpunctella.
AB  - The quantitative structure-activity relationship (QSAR) of a set of 29 agonists
      for tyramine (TA) receptor responsible for the inhibition of sex-pheromone
      production in Plodia interpunctella, was analyzed using comparative receptor
      surface analysis (CoRSA). Using the common steric and electrostatic features of
      the most active members of a series of compounds, CoRSA generated a virtual
      receptor model, represented as points on a surface complementary to the van der
      Waals or Wyvill steric surface of the aligned compounds. Three-dimensional
      energetics descriptors were calculated from receptor surface model (RSM)/ligand
      interaction and these three-dimensional descriptors were used in genetic partial
      least squares data analysis to generate a QSAR model, giving a 3D QSAR with
      r(2)=0.969 for calibration and CV- r(2)=0.635 for the leave-one-out cross
      validation.

PMID- 15032657
TI  - Screening for inhibitors of histone deacetylase by incorporating a spraying
      method to micro-arrayed compound screening.
AB  - We have developed a method of spraying assay reagents onto a target gel in the
      Micro-Arrayed Compound Screening ( micro ARCS) format. After application of
      target gels to compound sheets, subsequent reagents can be applied by spraying
      onto the target gel. The spraying method conserves on assay reagents by up to 10
      fold, eliminates the need for casting additional agarose gels, and increases the
      throughput of a screen by 3-fold. To demonstrate the efficacy of applying the
      spraying method to micro ARCS, we screened over 600,000 compounds for inhibitors
      of histone deacetylase (HDAC). Commercially available HDAC substrate and reaction
      developer were sprayed directly onto the gel to initiate the reaction and to
      amplify the signal, respectively. Picks in the primary screen were retested at a
      density of 384 compounds per sheet in the micro ARCS format. IC(50) values for
      active compounds were confirmed in a 96-well plate assay. The screen identified
      several small molecule inhibitors of the enzyme, including members of several
      classes of known HDAC inhibitors. The combination of the high-density format of
      micro ARCS, the efficiency of the spraying method, and a timed sequence of adding
      assay reagents permitted a screening throughput of 200,000 tests an hour. We
      present the details of the screening format and the analysis of the hits from the
      screen.

PMID- 15032658
TI  - Combinatorial libraries of biocatalysts: application and screening.
AB  - Enzymes can perform intricate regioselective and/or enantioselective chemical
      transformations and can accelerate reaction rates by enormous factors all under
      mild conditions. However, enzymes almost always present problems for use on an
      industrial scale. Evolutionary design approaches can be applied to the generation
      of stable enzymes with improved or novel catalytic activities. Directed evolution
      can be considered as the biotechnological equivalent of combinatorial chemistry,
      where the expressed proteins are the combinatorial libraries of biocatalysts.
      This review will focus on the search of novel biocatalysts produced by genetic
      engineering with modified activity and stability in different environments,
      substrate specificity and enantioselectivity. Methods of screening and/or
      selection for the desired properties will also be described. Finally, the efforts
      in de novo enzyme design are mentioned.

PMID- 15032659
TI  - Machine learning based pattern recognition applied to microarray data.
AB  - MOTIVATION: Microarrays have allowed the expression level of thousands of genes
      or proteins to be measured simultaneously. Data sets generated by these arrays
      consist of a small number of observations (e.g., 20-100 samples) on a very large
      number of variables (e.g., 10,000 genes or proteins). The observations in these
      data sets often have other attributes associated with them such as a class label
      denoting the pathology of the subject. Finding the genes or proteins that are
      correlated to these attributes is often a difficult task since most of the
      variables do not contain information about the pathology and as such can mask the
      identity of the relevant features. We describe a genetic algorithm (GA) that
      employs both supervised and unsupervised learning to mine gene expression and
      proteomic data. The pattern recognition GA selects features that increase
      clustering, while simultaneously searching for features that optimize the
      separation of the classes in a plot of the two or three largest principal
      components of the data. Because the largest principal components capture the bulk
      of the variance in the data, the features chosen by the GA contain information
      primarily about differences between classes in the data set. The principal
      component analysis routine embedded in the fitness function of the GA acts as an
      information filter, significantly reducing the size of the search space since it
      restricts the search to feature sets whose principal component plots show
      clustering on the basis of class. The algorithm integrates aspects of artificial
      intelligence and evolutionary computations to yield a smart one pass procedure
      for feature selection, clustering, classification, and prediction.

PMID- 15032660
TI  - Gene expression analysis for high throughput screening applications.
AB  - To meet growing needs for high throughput gene expression profiling, we
      established a new automated high throughput TaqMan RT-PCR method for quantitative
      mRNA expression analysis. In this method, the Allegro( trade mark ) (Zymark)
      system conducts all sample tracking and liquid handling steps, and ABI PRISM 7900
      HT (Applied Biosystems) is used to conduct real-time determination of the C(t)
      value when amplification of PCR products is first detected and accumulation of
      inhibitory PCR products is unlikely to occur. The ABI PRISM 7900 HT Sequence
      Detection System features a real-time PCR instrument with 384-well-plate
      compatibility and robotic loading, and continuous wavelength detection, which
      enables the use of multiple fluorophores in a single reaction. The Allegro System
      offers an assembly line approach with a modular design that allows
      reconfiguration of the components to accommodate variations in the assay flow. In
      the present study, we have established and validated a new automated High
      Throughput (HT) TaqMan RT-PCR- based method for quantitative mRNA expression
      analysis. The data demonstrate that HT-Taqman PCR is a powerful tool that can be
      used for measuring low concentrations of mRNA, and is highly accurate,
      reproducible, and amenable to high throughput analysis. Results suggest that HT
      TaqMan is a reliable method for the quantification of low-expression genes and a
      powerful tool with HT capability for target identification/validation, structure
      activity relationship (SAR) study, compound selection for efficacy studies, and
      biomarker identification in drug discovery and development.

PMID- 15032661
TI  - Cell-based screening: a high throughput flow cytometry platform for
      identification of cell-specific targeting molecules.
AB  - Targeting of drugs and genes to specific cell types is an emerging paradigm in
      the treatment of many medical conditions. However, targeting structures such as
      peptides are susceptible to rapid inactivation in vivo. To address this problem,
      novel targeting molecules can now be rapidly synthesized using a combinatorial
      approach. Methods to screen the large libraries created in this process are often
      lacking or compatible only with solution-based screening. This report describes a
      high-throughput cell-based method utilizing flow cytometry, capable of rapidly
      screening large libraries of molecules simultaneously for biological
      functionality and stability. In this method, each library molecule is attached to
      a microsphere exhibiting a unique set of optical properties, or "fingerprint",
      conferring modularity and multiplex capability. We investigated the multiplex
      capability of our flow cytometric method to determine its capacity for high
      throughput screening. Current instrumentation in our laboratory allows the
      screening of at least 75 unique compounds in a single well, a number comparable
      to available solution-based assays. In state-of-the-art configuration, however,
      this methodology can support the screening of up to 1875 compounds per well,
      achieving high-throughput potential in a single multiwell plate. We also
      investigated the binding capability of targeted microspheres to adherent target
      cells. These microspheres exhibited a 12-fold increase in binding over control,
      untargeted microspheres. Competitive inhibition experiments with soluble ligand
      confirmed the specificity of microsphere binding. Overall, the methodology
      proposed here is capable of quickly and effectively screening large libraries of
      targeting molecules using instrumentation readily available to the greater
      research community.

PMID- 15032662
TI  - An efficient parallel synthesis of capsazepine and capsazepine analogs.
AB  - Capsazepine (CPZ, 1) is a well-known vanilloid receptor (VR1) antagonist that has
      been cited widely used in the literature. However the current synthetic methods
      used for the total synthesis of CPZ are lengthy, involve multiple purification
      steps, and produce low yields. Here we describe a new and highly efficient
      synthesis of benzazepine 3, a synthetic precursor of CPZ, in only two steps and
      59% overall yield from a commercially available tetralone 2 via a Schmidt
      reaction as a key step. Moreover, we apply parallel synthesis techniques to
      prepare CPZ and CPZ analogs. Our approach enables the possibility of preparing
      larger, and more diverse libraries of CPZ analogs.

PMID- 15032663
TI  - Automated parallel, multi-step polymer-assisted solution phase (PASP) synthesis
      of substituted benzimidazole derivatives.
AB  - The automated polymer-assisted solution phase (PASP) synthesis of a 72 member
      library of 2-alkylthio-benzimidazoles 16 and benzimidazolin-2-ones 17 using
      commercially available robotic workstations is described. By incorporating both
      automated aqueous work-ups, in-line scavenging and 'catch and release' protocols
      the desired compounds were obtained directly in good yields and excellent
      purities without the need for conventional chromatographic purification. The
      synthesis described demonstrates how both manual and automated equipment may be
      utilised together to provide a versatile approach that facilitates parallel
      compound synthesis.

PMID- 15032664
TI  - The role of emerging genomics and proteomics technologies in cancer drug target
      discovery.
AB  - Cancer drugs have traditionally been identified in screens designed to produce
      broad biological end points such as cell death. A serious undesired outcome of
      drugs discovered in these screens is that the mechanism of drug action is unknown
      and such drugs often have adverse side effects. Designing cancer drugs that act
      on specific targets offer the advantage that the mechanism of drug action can be
      understood and accurately monitored in clinical trials leading to development of
      better drugs. The pharmacological industry has recently shifted to a target
      directed drug discovery model. However, until recently potential cancer drug
      targets comprised of only a small fraction of the human genome. The human genome
      project and high-throughput structural and functional genomics have dramatically
      increased the number of cancer drug targets. Deciphering cancer drug targets
      requires the understanding of biochemical pathways that are affected in the
      cancer genome. It has been suggested that utilization of Single-nucleotide
      polymorphisms (SNPs) will aid in identifying individuals at high risk of
      developing certain cancers, and will also help in development of tailored
      medication or identify genetic profiles of specific drug action and toxicity.
      Achieving successful new cancer drug development schemes will require a merger of
      research disciplines that include pharmacology, genomics, comparative genomics,
      functional genomics, proteomics and bioinformatics. In this review the
      significance and challenges of these rapidly evolving technologies in cancer drug
      target discovery are discussed.

PMID- 15032665
TI  - Protein kinase C isozymes as potential targets for anticancer therapy.
AB  - Protein kinase C (PKC) comprises a family of isozymes (alpha, betaI, betaII,
      gamma, delta, epsilon, theta, eta, lambda/iota [mouse/human], and zeta) which are
      involved in signal transduction from membrane receptors to the nucleus.
      Activation of PKC by phorbol esters promotes tumor formation, and from that it
      was concluded that inhibitors of PKC might prevent carcinogenesis or inhibit
      tumor proliferation. However, the situation is more complicated because the exact
      function of the different PKC isozymes is not known at present. They have been
      shown to be involved in synaptic transmissions, the activation of ion fluxes,
      secretion, cell cycle control, differentiation, proliferation, tumorigenesis,
      metastasis and apoptosis. Modulators such as bryostatin-1, phospholipid
      analogues, PKC-activating adriamycin derivatives, CGP41251, UCN-01, and antisense
      oligonucleotides directed against PKCalpha, have shown antitumor activity in
      cancer patients. PKC inhibitors are not specific to PKC, but also interact with
      other signaling molecules, which may contribute to the antitumor effects.
      Modulators of PKC have also been shown to influence non-MDR1-mediated and MDR1
      mediated antitumor drug resistance. This review is focussed on the role of PKC
      isozymes in human cell proliferation, apoptosis and antitumor drug resistance,
      and on the use of PKC modulators as antitumor agents.

PMID- 15032666
TI  - Changes in the apoptotic and survival signaling in cancer cells and their
      potential therapeutic implications.
AB  - In normal healthy tissues, an equilibrium is established between cell death and
      survival. This equilibrium ensures that cells survive in the right milieu, but
      undergo programmed cell death (apoptosis) when damaged, or when the environment
      is no longer supportive. Diseases may occur with alterations in this homeostasis.
      For example, cancer cells may survive in an environment in which they would not
      normally exist. This is accomplished by alterations in the expressions or
      functions of genes controlling both survival and apoptotic signaling pathways.
      Survival signaling pathways involve the activation of cell surface receptors,
      serine threonine kinases, transcription factors as well as other molecules. In
      breast and ovarian cancers, the ErbB2 growth factor receptor is overexpressed and
      this contributes to the progression of these cancers, in part by constitutively
      activating survival signaling pathways. In contrast, apoptotic signal
      transduction pathways are often inhibited in cancer. For example, overexpression
      of Bcl-2 blocks apoptosis and this contributes to the accumulation of cells in
      follicular lymphomas and chronic lymphocytic leukemia. Furthermore, alterations
      in these signaling pathways in cancer cells may lead to drug resistance. Recent
      advances in molecular targeted therapies have taken advantage of alterations in
      survival and apoptotic signaling pathways in cancer to specifically target
      aberrantly regulated molecules. For example, Herceptin trade mark inhibits ErbB2
      function and anti-sense oligonucleotides against Bcl-2 reduce Bcl-2 expression.
      These agents can thus induce apoptosis in the specific cancer cell against which
      they have been targeted. In this review, we will discuss alteration in survival
      and apoptotic signal transduction pathways in cancer and the development of novel
      chemotherapeutic drugs to target these pathways.

PMID- 15032667
TI  - Transforming Growth Factor-beta superfamily: evaluation as breast cancer
      biomarkers and preventive agents.
AB  - The Transforming Growth Factor-beta (TGFbeta) superfamily of cytokines is
      comprised of a number of structurally-related, secreted polypeptides that
      regulate a multitude of cellular processes including proliferation,
      differentiation and neoplastic transformation. These growth regulatory molecules
      induce ligand-mediated hetero-oligomerization of distinct type II and type I
      serine/threonine kinase receptors that transmit signals predominantly through
      receptor-activated Smad proteins but also induce Smad-independent pathways.
      Ligands, receptors and intracellular mediators of signaling initiated by members
      of the TGFbeta family are expressed in the mammary gland and disruption of these
      pathways may contribute to the development and progression of human breast
      cancer. Since many facets of TGFbeta and breast cancer have been recently
      reviewed in several articles, except for discussion of recent developments on
      some aspects of TGFbeta, the major focus of this review will be on the role of
      activins, inhibins, BMPs, nodal and MIS-signaling in breast cancer with emphasis
      on their utility as potential diagnostic, prognostic and therapeutic targets.

PMID- 15032668
TI  - A rationale for inhibiting progesterone-related pathways to combat breast cancer.
AB  - Inhibitors of estrogen-related pathways have been used with some success in the
      treatment of breast cancer. These include the antiestrogens tamoxifen, more
      recently faslodex, and the aromatase inhibitor anastrazole. However, failure and
      recurrence rates are substantial with drugs countering the effects of estrogens.
      Progestins, unlike estrogens, have generally been considered to oppose breast
      cancer and have been used with reasonable efficacy after antiestrogen failure.
      However, a building body of evidence, from cell culture, animal studies, and,
      most recently, several major clinical studies involving hormone replacement
      therapy, strongly supports the notion that progestins generally stimulate breast
      cancer. Our studies and those of others suggest that progestins increase the
      numbers of breast cancer cells by both stimulating the rate of proliferation and
      inhibiting cell death. These data indicate that progestin-related pathways might
      provide effective targets for breast cancer therapy. This review addresses the
      rationale for using inhibitors of progestin-related pathways to treat breast
      cancer and comments on some possible points of attack.

PMID- 15032669
TI  - Novel fluoropyrimidines: improving the efficacy and tolerability of cytotoxic
      therapy.
AB  - The fluoropyrimidines were first synthesised nearly 50 years ago as rationally
      designed anti-cancer agents. Their target was pyrimidine and hence DNA synthesis.
      5-Fluorouracil has been the most extensively used in a wide variety of
      malignancies. In more recent years a fuller understanding of the pharmacokinetics
      of these agents has lead to their utilisation as more effective and versatile
      anti-cancer drugs than might have been initially envisaged. This in part has
      occurred due to recognition of the schedule dependency of efficacy of 5-FU and
      modulation of its activity by leucovorin. However the development of novel
      fluropyrimidines such as capcetabine, UFT, and eniluracil which can be
      administered orally, has offered equal if not superior efficacy with improved
      tolerability and patient acceptance. It is now recognised that enzyme
      polymorphism's and heterogeneity of expression of key molecules are important
      determinants of the pharmacokinetic handling and pharmacodynamic effects of these
      drugs in individual patients. Further characterisation of such inter-individual
      and inter-tumoral variability, for example in enzymes such as DPD and thymidine
      phosphorylase is ongoing. This work offers the promise of improvements in
      efficacy and tolerability by the process of individualisation of chemotherapy
      (for both patient and tumour). In contrast to the advances made in the
      understanding of the pharmacokinetics, less progress has been made in
      Fluropyrimidine pharmacodynamics. The inhibition of thymidylate synthetase by
      dFUMP and thereby dTMP and DNA synthesis is thought to be the critical mechanism.
      The incorporation of FUTP and dFUTP into RNA and DNA are also postulated to be of
      importance. While these events have been well defined, exactly how they lead to
      cell death is less clearly understood. Similarly, the mechanism of selective
      cancer cell cytotoxicity is not well understood. Pharmacokinetics and cell cycle
      kinetics provide a partial explanation. There is some evidence to suggest that
      the most important factor in determining cytotoxicity is the cellular response to
      fluoropyrimidine induced biochemical abnormalities rather than the lesions
      themselves. In this hypothesis the difference in response between normal and
      cancer cells is of critical importance. Further improvements in efficacy and
      tolerability could be made by elucidation of the molecular mechanisms behind this
      process. This knowledge in combination with the advances already made (and
      ongoing) in pharmacokinetics may allow the full potential of fluoropyrimidines as
      anti-cancer agents to be realised in the future.

PMID- 15032670
TI  - Targeted histone deacetylase inhibition for cancer therapy.
AB  - The histone deacetylase inhibitors are a new class of cytostatic agents that
      inhibit the proliferation of tumor cells in culture and in vivo by inducing cell
      cycle arrest, differentiation and/or apoptosis. Histone acetylation and
      deacetylation play important roles in the modulation of chromatin topology and
      the regulation of gene transcription. Histone deacetylase inhibition induces the
      accumulation of hyperacetyl-ated nucleosome core histones in most regions of
      chromatin but affects the expression of only a small subset of genes, leading to
      transcriptional activation of some genes, but repression of an equal or larger
      number of other genes. Non-histone proteins such as transcription factors are
      also targets for acetylation with varying functional effects. Ace-tylation
      enhances the activity of some transcription factors such as the tumor suppressor
      p53 and the erythroid differentiation factor GATA-1 but may repress
      transcriptional activity of others including T cell factor and the co-activator
      ACTR. Recent studies in our laboratory and others have shown that the estrogen
      receptor alpha (ERalpha) can be hyperacetylated in response to histone
      deacetylase inhibition, suppressing ligand sensitivity and regulating
      transcriptional activation by histone deacetylase inhibitors. Conservation of the
      acetylated ERalpha motif in other nuclear receptors suggests that acetylation may
      play an important regulatory role in diverse nuclear receptor signaling
      functions. A number of structurally diverse histone deacetylase inhibitors have
      shown potent antitumor efficacy with little toxicity in vivo in animal models.
      Several compounds are currently in early phase clinical development as potential
      treatments for solid and hematological cancers both as monotherapy and in
      combination with cytotoxics and differentiation agents. This report reviews the
      biology and clinical development of histone deacetylase inhibitors for cancer
      therapy.

PMID- 15032671
TI  - AT islands - their nature and potential for anticancer strategies.
AB  - The human genome contains a unique class of domains, referred to as AT islands,
      which consist typically of 200-1000 bp long tracts of up to 100% A/T DNA. The
      significance of AT islands as potential targets for chemotherapeutic intervention
      stems from two main aspects. First, AT islands are inherently unstable
      (expandable) minisatellites that are found in various known loci of genomic
      instability, such as AT-rich fragile sites. Second, AT islands are involved in
      the organization of the genomic DNA on the nuclear matrix by acting as
      scaffold/matrix attachment regions, S/MARs. DNA duplexes of AT islands are
      unusually flexible and prone to base unpairing, which are crucial MAR attributes.
      Various AT islands show high binding affinity for isolated nuclear matrices and
      associate with the nuclear matrix in the cell. The cellular MAR function of AT
      islands may differ in cancer and normal cells. The abnormally expanded AT islands
      in the FRA16B fragile site in leukemic CEM cells act as strong, permanent MARs,
      while their unexpanded counterparts in normal cells are loop localized. Given
      their instability and involvement in the remodeling of the nuclear architecture,
      AT islands may be a factor in cancerous phenotypes. AT islands are preferentially
      targeted by the extremely potent DNA-alkylating antitumor drugs, bizelesin and
      U78779. High lethality of lesions in AT islands is consistent with the critical
      role of MAR domains in DNA replication. The abnormal structure/function of AT
      islands, such as their expansion and acquired strong MAR properties, may
      sensitize cancer cells to AT island targeting drugs.

PMID- 15032672
TI  - Kinase chemogenomics: targeting the human kinome for target validation and drug
      discovery.
AB  - Chemogenomics is a gene family-based approach to drug discovery and target
      validation. This review will summarize the application of this interdisciplinary
      approach to the protein kinases of the human genome with emphasis upon the
      synergies and efficiencies to be gained. Specific examples from the SAPK-family
      will be discussed.

PMID- 15032673
TI  - Targeting FLT3 kinase in acute myelogenous leukemia: progress, perils, and
      prospects.
AB  - Activating mutations of the FLT3 receptor tyrosine kinase are the most common
      recurring genetic abnormality in acute myelogenous leukemia (AM). Inhibition of
      FLT3 kinase activity by small molecule inhibitors has been proposed as a novel
      therapeutic approach AML. The pre-clinical and clinical development of candidate
      FLT3 inhibitors will be reviewed.

PMID- 15032674
TI  - Therapeutically targeted anticancer agents: inhibitors of receptor tyrosine
      kinases.
AB  - The rationale to target receptor protein tyrosine kinases (RPTKs) as an approach
      to cancer chemotherapy has continued to become more compelling with time.
      Preclinical and clinical data strongly support the involvement of specific RPTKs
      in the formation and progression of a subset of solid and liquid tumors. The
      advances in our understanding of the oncogenic activation of these receptors have
      been matched by the identification of new structural classes of kinase inhibitors
      that exhibit enormous improvements with regard to potency, specificity and
      efficacy. This article summarizes current knowledge of the most promising RPTK
      inhibitors in clinical trials or known to be in late stage preclinical
      development.

PMID- 15032675
TI  - Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of
      the underlying mechanisms and potential strategies for treatment.
AB  - Following the paradigm set by STI571, protein tyrosine kinase inhibitors are
      emerging as a promising class of drugs, capable of modulating intracellular
      signaling and demonstrating therapeutic potential for the treatment of
      proliferative diseases. Although the majority of chronic phase CML patients
      treated with STI571 respond, some patients, especially those with more advanced
      disease, relapse. This article reviews the reasons for relapse and, in
      particular, analyses resistance resulting from Bcr-Abl tyrosine kinase domain
      mutations at the molecular level. Arguments are based upon the structure of the
      STI571-Abl complex, which is compared to the crystal structures of PD173955-Abl
      and PD180970-Abl, which bind to the kinase differently. Strategies to potentially
      circumvent or overcome resistance are discussed.

PMID- 15032676
TI  - New lead generation strategies for protein kinase inhibitors - fragment based
      screening approaches.
AB  - The protein kinase superfamily represents both an enormous opportunity and a
      unique challenge for drug discovery. Protein kinases play central roles in the
      cellular economy and it is well known that a large number of diseases involve
      aberrant protein kinase activity. This review discusses how fragment based
      screening strategies, such as virtual screening, NMR and high-throughput X-ray
      crystallography are being employed to identify new chemo-types to produce the
      next generation of protein kinase inhibitors.

PMID- 15032677
TI  - Exploring the phosphoproteome with mass spectrometry.
AB  - Protein phosphorylation is a reversible post-translational modification crucial
      in the control of numerous regulatory pathways. Understanding the highly
      interconnected nature of such networks requires new broader-scale analysis
      techniques. This report summarizes recent advances in the use of mass
      spectrometry to assess phosphorylation events in ever more complex systems.

PMID- 15032678
TI  - The emergence of selective 5-HT 2B antagonists structures, activities and
      potential therapeutic applications.
AB  - 5-HT(2) receptors mediate a large array of physiological and behavioral functions
      in humans via three distinct subtypes: 5-HT(2A), 5-HT(2B)and 5-HT(2C). While
      selective 5-HT(2A)antagonists have been known for some time, knowledge of the
      precise role played by the 5-HT(2B)receptor was hampered by the existence of
      solely 5-HT(2B)5-HT(2C) mixed antagonists. However, selective 5-HT(2B)antagonists
      began recently to emerge in the literature. Indeed, four structural classes
      belonging to the piperazine, indole, naphthylpyrimidine and tetrahydro-beta
      carboline scaffolds were reported. In this paper, we will briefly review the
      structural and pharmacological features of selective 5-HT(2B) antagonists,
      including patent literature of the last five years.

PMID- 15032679
TI  - Small molecule antagonists of the tachykinin NK 2 receptor.
AB  - The NK(2) receptor (member of the tachykinin receptor family) is mainly located
      in the smooth muscle of the urinary, respiratory and gastrointestinal tracts,
      with limited presence in the CNS. This has raised interest in tachykinin NK(2)
      receptor antagonists for the treatment of urological disorders, asthma. This
      review outlines progress done after 1998 in the field of NK(2) small molecule
      antagonists, both acting on the NK(1)/NK(2), NK(2)/NK(3), NK(1)/NK(2)/NK(3)
      receptors and selective for the NK(2) one.

PMID- 15032680
TI  - The impact of combinatorial methodologies on medicinal chemistry.
AB  - Combinatorial chemistry has had a major impact on the discovery and optimisation
      of potential lead compounds. This review details some of the fundamental
      principles behind combinatorial chemistry and describes a variety of methods
      employed in the search for new therapeutically interesting compounds including
      the concept of dynamic combinatorial chemistry as a method of selecting active
      compounds from a mixture. It also outlines methods used to analyse resin bound
      products and describes how solution phase library generation may be aided by the
      use of resin bound reagents and scavengers.

PMID- 15032681
TI  - Automation in medicinal chemistry.
AB  - The implementation of appropriate automation can make a significant improvement
      in productivity at each stage of the drug discovery process, if it is
      incorporated into an efficient overall process. Automated chemistry has evolved
      rapidly from the 'combinatorial' techniques implemented in many industrial
      laboratories in the early 1990's which focused primarily on the hit discovery
      phase, and were highly dependent on solid-phase techniques and instrumentation
      derived from peptide synthesis. Automated tools and strategies have been
      developed which can impact the hit discovery, hit expansion and lead optimization
      phases, not only in synthesis, but also in reaction optimization, work-up, and
      purification of compounds. This article discusses the implementation of some of
      these techniques, based especially on experiences at Millennium Pharmaceuticals
      Research and Development Ltd.

PMID- 15032683
TI  - In vitro approaches to evaluate ADMET drug properties.
AB  - In vitro assays developed for the evaluation of drug-like properties can
      accelerate the drug development process. The key assays are those for the
      evaluation of bioavailability, metabolic stability, drug-drug interaction
      potential, and toxicity. For bioavailability, the human colon carcinoma derived
      Caco-2 assay is the most widely used, allowing the evaluation of multiple
      pathways of intestinal absorption including paracellular uptake, transcellular
      uptake, and transporter-mediated uptake and efflux. For metabolic stability and
      drug-drug interactions, human liver microsomes, hepatocytes, and cDNA-expressed
      microsomes are commonly used, with human hepatocytes representing the most
      complete system, containing all metabolic enzymes and cofactors at physiological
      level and an intact plasma membrane to allow the modeling of intracellular drug
      concentrations. Primary human cells from target organs (e.g., human hepatocytes
      for human hepatotoxicity) should represent the best experimental system for the
      evaluation of human drug toxicity. These assays, when applied intelligently with
      their limitations, should greatly facilitate the selection of drug candidates
      with a high probability of clinical success.

PMID- 15032684
TI  - Organic synthesis in micro reactors.
AB  - This article reviews the current and future applications of micro reactors in the
      field of chemistry, biochemistry and drug discovery. The fabrication and physical
      characterisation of micro reactors, together with details of their use and
      operation is described. Liquid and gas phase reactions have been used to
      illustrate the advantages of performing chemical reactions in micro reactors. A
      brief evaluation of the possible advantages that micro fabrication could offer in
      developing biological applications, based on miniaturized devices is also
      presented.

PMID- 15032682
TI  - Guided docking approaches to structure-based design and screening.
AB  - With the number of protein-ligand complexes available in the Protein Data Bank
      constantly growing, structure-based approaches to drug design and screening have
      become increasingly important. Alongside this explosion of structural
      information, a number of molecular docking methods have been developed over the
      last years with the aim of maximally exploiting all available structural and
      chemical information that can be derived from proteins, from ligands, and from
      protein-ligand complexes. In this respect, the term 'guided docking' is
      introduced to refer to docking approaches that incorporate some degree of
      chemical information to actively guide the orientation of the ligand into the
      binding site. To reflect the focus on the use of chemical information, a
      classification scheme for guided docking approaches is proposed. In general
      terms, guided docking approaches can be divided into indirect and direct
      approaches. Indirect approaches incorporate chemical information implicitly,
      having an effect on scoring but not on orienting the ligand during sampling. In
      contrast, direct approaches incorporate chemical information explicitly, thus
      actively guiding the orientation of the ligand during sampling. Direct approaches
      can be further divided into protein-based, mapping-based, and ligand-based
      approaches to reflect the source used to derive the features capturing the
      chemical information inside the protein cavity. Within each category, a
      representative list of docking approaches is discussed. In view of the
      limitations of current scoring functions, it was generally found that making
      optimal use of chemical information represents an efficient knowledge-based
      strategy for improving binding affinity estimations, ligand binding-mode
      predictions, and virtual screening enrichments obtained from protein-ligand
      docking.

PMID- 15032685
TI  - Reactions in unusual media.
AB  - This review provides an introduction to three of the most well-developed solvent
      replacement strategies currently under investigation for synthetic chemistry:
      Ionic liquids, fluorous phase techniques, and supercritical carbon dioxide. They
      are all fascinating reaction media, and have considerable potential for use in
      pharmaceutical synthesis. However, this has to be balanced with problems and
      limitations of the new methods. This review aims to provide an overall account of
      recent advances in the use of unusual media for synthetic chemistry, with an
      emphasis on highlighting potential benefits, but also limitations, of each of the
      methods described.

PMID- 15032686
TI  - Microwave - assisted chemistry in drug discovery.
AB  - Microwave assisted organic synthesis (MAOS) is rapidly gaining acceptance as a
      valuable tool for relieving some of the bottlenecks in the drug discovery
      process. This article outlines the basic principles behind the technology and
      summarizes recent trends and areas in drug discovery where microwave technology
      has made an impact.

PMID- 15032687
TI  - Modulating the hypoxia-inducible factor signaling pathway: applications from
      cardiovascular disease to cancer.
AB  - Humans, like other complex aerobic organisms, possess highly evolved systems for
      the delivery of dioxygen to all the cells of the body. These systems are
      regulated since excessive levels of dioxygen are toxic. In animals hypoxia causes
      an increase in the transcription levels of specific genes, including those
      encoding for vascular endothelial growth factor and erythropoietin. At the
      transcriptional level, the hypoxic response is mediated by hypoxia-inducible
      factor (HIF), an alpha,beta-heterodimeric protein. HIF-beta is constitutively
      present, but HIF-alpha levels are regulated by dioxygen. Under hypoxic
      conditions, levels of HIF-alpha rise, allowing its dimerization with HIF-beta and
      enabling transcriptional activation. Under normoxic conditions both the level of
      HIF-alpha and its ability to enable transcription are directly controlled by its
      post-translational oxidation by oxygenases. Hydroxylation of HIF-alpha at either
      of two conserved prolyl residues enables its recognition by the von Hippel-Lindau
      tumour suppressor protein which targets it for proteasomal degradation.
      Hydroxylation of an asparaginyl residue in the C-terminal transactivation domain
      of HIF-alpha directly prevents its interaction with the coactivator p300 from the
      transcription complex. Hydroxylation of HIF-alpha is catalysed by members of the
      iron (II) and 2-oxoglutarate dependent oxygenase family. In humans, three prolyl
      hydroxylase isozymes (PHD1-3, for prolyl hydroxylase domain enzymes) and an
      asparaginyl hydroxylase (FIH, for factor inhibiting HIF) have been identified.
      Recent studies have identified additional post-translational modifications of HIF
      alpha including acetylation and phosphorylation. Modulation of the HIF mediated
      hypoxic response is of potential use in a wide range of disease states including
      cardiovascular disease and cancer. Here we review current knowledge of the HIF
      pathway focusing on its regulation by dioxygen and discussion of potential
      targets and challenges in attempts to modulate the pathway for medicinal
      application.

PMID- 15032688
TI  - B cell responses to oxidative stress.
AB  - B-lymphocytes are exposed to a reduction/oxidation environment during activation
      or inflammatory process, and the antioxidant systems are functional to protect
      themselves against harmful reactive oxygen species (ROS). The crucial roles of
      thioredoxin-2 (Trx-2) and a DNA repair enzyme APE/Ref-1 in mitochondria are
      reported in B-lymphocytes. Furthermore, ROS stimulate different signaling
      pathways in many cellular responses. Their effects often cause some diseases or
      are utilized for the treatment of other diseases. For example, the cells derived
      from Fanconi anemia (FA) patients are intolerant of oxidative stress and the
      therapeutic effect of anti-CD20 monoclonal antibody rituximab on B cell
      lymphoproliferative disorders is due to the generation of ROS. To clarify the
      oxidative stress-induced signaling pathways, we stimulated a B cell line with
      various concentrations of H(2)O(2). As a result, a protein tyrosine kinase, Syk
      was involved in the induction of G2/M arrest and protection of cells from
      apoptosis. Syk might inhibit the activation of caspase-9 through Akt thereby
      protecting cells from oxidative stress-induced apoptosis. On the other hand, Syk
      dependent PLC-gamma2 activation was required for acceleration towards apoptosis
      following oxidative stress. These findings suggest that oxidative stress-induced
      Syk activation triggers the activation of different pathways, such as pro
      apoptotic or survival pathways, and that the balance of these pathways is a key
      factor in determining the fate of the cells exposed to oxidative stress. In
      contrast, the stimulation with the millimolar concentrations of H(2)O(2) rapidly
      led to necrosis in which tyrosine phosphorylation of FAK was involved at the
      downstream of Lyn and Syk.

PMID- 15032689
TI  - The role of ROS and RNS in regulating life and death of blood monocytes.
AB  - The ability to target and accumulate monocytes and macrophages in areas of tissue
      inflammation plays an important role in innate and humoral immunity. However,
      when this process becomes uncontrolled, tissue injury and dysfunction may ensue.
      This paper will focus on understanding the role and action of reactive oxygen
      species (ROS) and reactive nitrogen species (RNS) in regulating the molecular and
      biochemical pathways responsible for the regulation of the survival of human
      monocytes. We and others have found that ROS and RNS serve as important
      intracellular signaling molecules that influence cellular survival. Human
      monocytes are influenced by intracellular production of ROS and RNS, which
      affects both monocyte survival and death, depending on the form of nitric oxide
      presented to the cell. This review will address potential mechanisms by which ROS
      and RNS promote the survival of human monocytes and macrophages.

PMID- 15032690
TI  - Provoking neuroprotection by peroxynitrite.
AB  - Peroxynitrite, the product of the reaction between nitric oxide and superoxide,
      is spontaneouly formed within most mammalian cells under physiological
      conditions. Initial work addressing the pathophysiology of peroxynitrite afforded
      the generally accepted notion that this compound would be the long-term
      neurotoxic nitric oxide-derivative. However, over the past six years a number of
      interesting studies have reported direct in vivo and in vitro evidence that, at
      nanomolar-low micromolar concentrations, peroxynitrite is actively involved in
      triggering cellular survival signals. Most such evidence came from studies
      demonstrating protection against myocardial ischemia-reperfusion injury and
      neuronal apoptosis. Although full elucidation of the precise mechanism
      responsible for such protection still requires further research, peroxynitrite
      has been shown to promote the nitration and/or phosphorylation of regulatory
      sites at tyrosine kinase receptors coupled to well-known antiapoptotic pathways,
      such as those involving phosphoinositide 3-kinase/Akt or mitogen-activated
      protein kinases. In addition, peroxynitrite-mediated transient protection of
      neurons against apoptotic death is associated with rapid stimulation of glucose
      metabolism and glutathione regeneration. In view of the potential cytoprotective
      function of peroxynitrite, further studies specifically focused on elucidating
      the possible therapeutic potential of peroxynitrite are sure to appear.

PMID- 15032691
TI  - Induction of cytoprotective genes through Nrf2/antioxidant response element
      pathway: a new therapeutic approach for the treatment of inflammatory diseases.
AB  - In the last decade, it has become recognized that reactive oxygen species (ROS)
      play important roles in the multiple biological processes involved in the
      pathophysiology of chronic inflammation such as cell proliferation, adhesion
      molecule expression, cytokine and chemoattractant production and matrix
      metalloproteinase generation. Intracellular redox homeostasis is maintained by
      balancing the production of ROS with their removal through cellular antioxidant
      defense systems. The antioxidant response element (ARE) is a cis-acting DNA
      regulatory element located in the regulatory regions of multiple genes including
      phase II detoxification enzymes as well as antioxidant proteins including
      glutathione-S-transferases, NAD(P)H:quinone oxidoreductase-1, gamma
      glutamylcysteine synthase, ferritin, and heme oxygenase-1. Nrf2 is the primary
      transcription factor that binds to the ARE, and through heterodimerization with
      other leucine-zipper containing transcription factors, activates the expression
      of these genes. It is evident that activation of ARE-regulated genes contributes
      to the regulation of cellular antioxidant defense systems. More importantly,
      there is a growing body of evidence suggesting that modulation of these
      cytoprotective genes has profound effects on immune and inflammatory responses.
      Activation of cytoprotective Nrf2/ARE-regulated genes can suppress inflammatory
      responses, whereas decreased expression of these genes results in autoimmune
      disease and enhanced inflammatory responses to oxidant insults. Thus, coordinate
      induction of cytoprotective genes through Nrf2/ARE pathway may represent a novel
      therapeutic approach for the treatment of immune and inflammatory diseases.

PMID- 15032693
TI  - Reactive oxygen species in the initiation of IL-4 driven autoimmunity as a
      potential therapeutic target.
AB  - Helper T-lymphocytes have been shown to differentiate into two mutually
      regulatory subsets. Cells primarily secreting interleukin-2 (IL-2) and interferon
      gamma are known as Th1 cells and mediate classical cell-mediated immune responses
      such as delayed-type hypersensitivity. Cells secreting interleukin-4 (IL-4) are
      known as Th2 cells and promote humoral immune responses, in particular the
      production of IgE and IgG4 (human) or IgG1 (rodents). Over-activity of either
      cell type can result in tissue-damaging autoimmune disease. A number of human
      diseases including asthma and some kidney diseases are thought to be caused by a
      Th-2 type autoimmune response. Study of an animal model of Th2-driven
      autoimmunity (mercuric chloride-induced autoimmunity in Brown Norway rats) has
      yielded insights into a possible role for oxidant stress in the generation of Th
      2 driven autoimmune responses. Mercuric chloride probably causes oxidant stress
      by the generation of free-radicals, activating NK-kappaB, a transcription factor
      for the IL-4 gene. Treatment with the antioxidants N-acetlcysteine and
      desferrioxamine has been shown to suppress vasculitis and IgE production in this
      model. These findings suggest a possible clinical role for antioxidants in the
      therapy of human autoimmune disease.

PMID- 15032694
TI  - Regulation of inflammatory responses by oxidized phospholipids: structure
      function relationships.
AB  - Increasing evidence points to the role of oxidized phospholipids as modulators of
      inflammatory processes. These modified phospholipids are derived from
      lipoproteins or cellular membranes and accumulate at sites of inflammation such
      as atherosclerotic lesions. It has been shown that oxidized phospholipids
      influence a variety of cellular functions such as chemokine production and
      expression of adhesion molecules. Furthermore, recent reports indicate that
      oxidized phospholipids act as ligands for pattern-recognition receptors which
      detect conserved pathogen-associated molecular patterns during innate immune
      defense. Thus, the diversity of individual phospholipid oxidation products
      reflects the many aspects of the inflammatory process they influence. In this
      review, we focus on structural features used to classify different oxidized
      phospholipids and how they relate to specific biological responses. As the
      chemical identification of oxidized phospholipid products proceeds, distinctive
      structural motifs emerge that can help us to understand the mechanism of action
      of these unique compounds and how to intervene for therapeutic purposes.

PMID- 15032692
TI  - Inhibition of MHC II gene transcription by nitric oxide and antioxidants.
AB  - MHC class II molecules are expressed on the surface of antigen presenting cells
      and are loaded with peptides processed from the phagosomal compartment of these
      cells. Such complexes interact with the CD4 positive T lymphocyte receptor for
      antigen and a strong interaction is followed by T cell activation and
      proliferation. As class II expression is critical for antigen specific immunity
      its expression mostly restricted to a few cell types but can be induced on others
      in response to interferon gamma. This expansion of antigen presenting ability
      plays a role in increasing the duration and intensity of the immune response.
      Nitric oxide and antioxidants attenuate this class II induction through negative
      effects on the induction of class II transactivator protein expression and on the
      binding of transcription factor NF-Y to the class II promoter.

PMID- 15032695
TI  - The relationship between inflammation and the anticoagulant pathway: the emerging
      role of endothelial nitric oxide synthase (eNOS).
AB  - Inflammation represents the interaction of the immune and coagulation systems in
      an attempt to restore normal hemostasis following injury. The underlying basis of
      the interrelationship between these two physiological systems revolves around the
      following: a) the activation of coagulation by inflammation, b) the augmentation
      of the inflammatory response by coagulation, c) the significant attenuation of
      inflammation by the anticoagulant response and d) the separate influence of the
      vascular endothelium on coagulation and inflammation as well as its mediation or
      control of the cross-talk between these two physiological systems. In hemostasis,
      the protein C anticoagulant pathway is a major mechanism that functions to
      prevent the development of a pathological thrombus through the regulation of the
      procoagulant pathway. The endothelium is essential in maintaining a physiological
      balance between the anticoagulant and procoagulant pathways with proinflammatory
      cytokines functioning, in part, to regulate endothelial-cell- surface associated
      coagulation and anticoagulation proteins. In addition to its anticoagulant
      properties, activated protein C can also function as a regulator of
      proinflammatory cytokine production. Current evidence suggests that activated
      protein C may act to control inflammation through NF-kappaB and/or nitric oxide
      synthase. A better understanding of the relationship between APC and inflammation
      may provide new targets for drug design.

PMID- 15032696
TI  - Natural anticoagulant proteins in the regulation of autoimmunity: potential role
      of protein S.
AB  - Autoimmunity results when the immune system fails to distinguish between self and
      non-self factors in the body. The cellular and biochemical mechanisms that
      underlie development of autoimmunity are only partly understood. One current
      theory is that autoimmunity can result when there is a failure to clear dying
      cells from a tissue before they undergo lysis of the plasma membrane. That is,
      cells that die by apoptosis are thought to be cleared from a tissue by
      neighboring phagocytic cells, such as macrophages, before the cells have lost
      their plasma membrane integrity. This rapid removal of early apoptotic cells is
      thought to prevent induction of an inflammatory response to intracellular
      macromolecules, thereby allowing for an immunologically silent removal of the
      dying cells. Hence, any factor or condition that inhibits phagocytosis of early
      apoptotic cells may trigger or promote an autoimmune response to intracellular
      components. Depletion of factors required for the efficient phagocytosis of dying
      cells would have a similar outcome. The recent discovery that the natural
      anticoagulant protein S is required for efficient uptake of apoptotic cells
      (Anderson, H.A., Maylock, C.A., Williams, J.A., Paweletz, C.P., Shu, H., and
      Shacter, E. (2003) Nature Immunology 4, 87-91) reveals a potential new linkage
      between autoimmunity and coagulation systems. This article will review the dual
      roles of protein S as an anticoagulant and in regulating phagocytosis of
      apoptotic cells, with emphasis on exposing a possible novel role in regulating
      autoimmunity.

PMID- 15032697
TI  - Pain treatment: a historical overview.
AB  - Pain is a common experience of mankind. Pain theories and the management of pain
      have been modified throughout the history of mankind. This article gives a brief
      review on pain, pain believes and pain management from early magico-demonic and
      magico-religious ideas and procedures to more empiric-scientific models; from
      ancient times and primitive cultures to the 20th century. Due to new anatomical,
      physiological and biochemical insights, modern pain theories developed in the
      19th and 20th century. Modern analgesics were synthesized and new invasive
      procedures were approved having a major impact on pain management strategies.
      However, older traditional beliefs and attitudes have not been replaced
      completely and have survived to some degree in modern patients.

PMID- 15032698
TI  - The orvinols and related opioids--high affinity ligands with diverse efficacy
      profiles.
AB  - The thevinols and orvinols derived from thebaine via the thebaine-methylvinyl
      ketone adduct (thevinone) were thoroughly investigated in the 1960's and 1970's
      by the Reckitt group. From this work a number of important opioids emerged.
      Buprenorphine is a mu partial agonist, kappa/delta-antagonist that is now used
      primarily in the treatment of heroin abuse and dependence though it was initially
      launched as an analgesic for the treatment of moderate to severe pain. Etorphine
      and dihydroetorphine are very potent mu agonists that have found application in
      veterinary and human medicine respectively. Diprenorphine is primarily a mu
      antagonist though it also has some kappa-partial agonist effects. It has high
      affinity for all types of opioid receptors and as a "universal" opioid ligand has
      been much in demand as a pharmacological tool. It has also been converted into a
      [11C] version for use in Positron Emission Tomography (PET) studies of brain
      function related to the opioid receptor system. More recent medicinal chemistry
      investigations have been concerned with gaining a greater understanding of
      buprenorphine's unique opioid profile. This has involved the synthesis and
      evaluation of a number of series of buprenorphine analogues in which the C20 t
      butyl group has been constrained in a ring system. These studies have suggested
      that the methyls in the t-butyl group inhibit the conformational changes in the
      kappa-receptor required for generation of an agonist response. Introduction of a
      7alpha-cinnamoylaminomethyl group in place of the orvinol tertiary alcohol
      function leads to selective irreversible mu antagonism.

PMID- 15032699
TI  - SNC 80 and related delta opioid agonists.
AB  - The discovery of the selective delta (delta) opioid agonists SNC 80 and BW373U86,
      which possess a diarylmethylpiperazine structure unique among opioids, was a
      major advance in the field of delta-opioid ligands. Much research has been
      performed to uncover the structure-activity relationships (SAR) of this class of
      ligands and also to compare the diarylmethylpiperazines with the traditional
      morphinan-based delta opioids. This review focuses on the development of the SAR
      of this unique series of ligands, and discusses questions which remain
      unanswered.

PMID- 15032700
TI  - Peripherally restricted opioid agonists as novel analgesic agents.
AB  - Mediation of antinociception via opioid receptors located in the periphery is a
      viable strategy to produce analgesia without the occurrence of side effects
      associated with stimulation of opioid receptors located in the central nervous
      system. Peripheral opioid receptors are particularly important in inflammatory
      pain states and in the responses to pruritogenic stimuli, and have been
      implicated in the transmission of visceral pain. Medicinal chemistry approaches
      to achieve peripheralization of opioid agonists have started with a centrally
      acting opioid agonist as a template, and introduced features of lipophilicity,
      hydrophilicity, or combined lipophilicity and hydrophilicity to achieve
      amphiphilicity. Quaternarization of centrally acting opioid agonists or
      identification of compounds that serve as substrates for the mdr transporter to
      achieve transport out of the brain has also been employed. The in vivo assays
      used to identify peripherally selective compounds have measured a variety of
      behavioral and pharmacokinetic endpoints, with varying degrees of predictability.
      This review focuses on a discussion of these methods, as well as a review of
      those compounds where sufficient data exist to support a claim of
      peripheralization in vivo.

PMID- 15032701
TI  - PET imaging of opioid receptors in pain: progress and new directions.
AB  - The endogenous opioid system plays a central role in pain. Recent advances have
      permitted imaging of opioid receptors by PET in human subjects while experiencing
      pain and detection of changes in receptor occupancy. The ability to perform these
      types of studies is dependent on the development of opioid tracer ligands labeled
      with positron emitting isotopes. This article follows the development and
      radiochemistry of opioid tracer molecules through their use in human subjects and
      subsequent application to the study of pain. The role of mu, delta and kappa
      opioid receptors in pain is reviewed. Occupancy changes in mu receptors have been
      observed with PET in human subjects subjected to experimental pain paradigms. The
      implication of this approach to the study of pain and pain syndromes, and
      possible clinical applications, is also addressed.

PMID- 15032702
TI  - Antisense oligonucleotide drug design.
AB  - Maneuvering single gene expression is not only an optimal way to study gene
      function but also an ambitious goal, which will lead to the treatment of a
      variety of human diseases whose main pathogenetic event is a genetic alteration.
      The recent efforts focusing on the genome project have led to array based, high
      throughput, gene expression analysis techniques that allow the study of complex
      molecular networks. Combining these powerful new technologies with modulation of
      gene expressions is making it possible to unravel complex molecular networks or,
      vice versa, to find new gene products responsible for pathological conditions on
      which exogenous modulation can be productive. Efficient and specific modulation
      of gene expression can be obtained either by producing transgenic or gene
      knockout organisms or cells (gene targeting), or by treating organisms or cells
      with short synthetic nucleic acid segments in antisense orientation with respect
      to the targeted mRNAs (mRNA targeting by antisense strategy). While genome
      manipulation is a time consuming and expensive approach, requiring invasive
      intervention, the "antisense strategy" is characterized by high flexibility
      resulting from safeness, specificity, reversibility, modulability, and low cost.
      The rationale of the antisense strategy is that, once one gene sequence is known,
      its expression can be silenced by application of synthetic single-strand nucleic
      acid segments (oligonucleotides) whose sequence is in antisense orientation
      compared to the targeted mRNA. Recently, this "informational" strategy has been
      boosted by the discovery of the RNA interference: a natural mechanism by which
      cells are thought to fight detrimental exogenous viruses and endogenous
      transposons. Despite promising futures, antisense-based therapeutics are far from
      being an established reality. This review analyses the recent improvements in
      antisense-based gene expression modulation, focuses on the treatment of diseases
      in the light of the past, and provides our personal findings on this topic.

PMID- 15032703
TI  - Current status of delivery systems to improve target efficacy of
      oligonucleotides.
AB  - The tragic failure of gene therapy resulted in rolling back the research of gene
      based medicine. Because of the poor delivery of gene-based medicines, such as
      antisense oligonucleotides, ribozyme, triplex, or gene both in vitro and in vivo,
      further development of gene-based medicines as therapeutic agents have stagnated.
      Although the delivery system plays a critical role in the overall efficacy of
      oligonucleotides, inappropriate target selection, improper evaluation methods and
      misinterpretation of results often caused the pessimistic view. Still, the
      decoding of the whole human genome has rekindled the enthusiastic development of
      delivery tools for gene-based medicine. We would like to focus on the newly
      developed delivery systems mainly for antisense oligonucleotides in this article.
      There are two ways to improve delivery efficacy of antisense oligonucleotides:
      One is the chemical modification of the antisense oligonucleotide backbone. The
      other way is by means of delivery vehicles, such as cationic liposomes, synthetic
      polymers, or non-viral vectors. We will review the current status of delivery
      vehicles both in vitro and in vivo. Delivery efficiency depends on the
      oligonucleotides' chemistry, length, size, net charge, cell/tissue type and
      administration route. It is difficult to deduce a common rule that affects
      delivery efficiency. Some cells like keratinocytes rapidly internalize
      oligonucleotides without a delivery system, which is contrary to common belief.
      Although we cannot extensively cover all reports, we will summarize several
      experiments with delivery system in vitro and in vivo. We will then address the
      possible factors promoting the efficient delivery of oligonucleotides.

PMID- 15032704
TI  - Antisense oligonucleotides as a powerful molecular strategy for gene therapy in
      cardiovascular diseases.
AB  - Antisense oligonucleotides (ODN) technology is one of the most promising
      therapeutic strategies to prevent the progress of diseases through inhibiting the
      specific gene expression. They are well established to serve as molecular tools
      for several biologic applications, from the study of single gene function up to
      complex target validations. From the theoretical simple action, sequence-specific
      inhibition of mRNA functions after complex formation and presumably enzymatic
      degradation of the target mRNA, they obviously carry a high therapeutic potential
      to treat human diseases. In addition to the potential for the treatment,
      antisense ODN may be applicable for investigations of the mechanism and
      stereochemistry of biochemical reactions, mapping of nucleic acid protein
      interactions, and diagnostic applications. However, the design of antisense ODN,
      is very difficult because many factors affecting their activity and stability
      must be considered. Especially, the modifications of ODN are very critical and
      many researchers are trying to establish ODN which have resistance to nucleolytic
      degradation, high affinity to complementary nucleic acid, high selectivity in
      binding with complementary nucleic acid, the ability to activate ribonuclease H
      that selectively degrades the RNA strand of ODN-RNA complex, cell permeability,
      and favorable pharmacokinetic and pharmacodynamic attributes. In this review we
      would like to introduce some modifications of ODN design and examples of our
      applications of antisense ODN in cardiovascular disease in animal models.

PMID- 15032705
TI  - Anti-gene strategies to down-regulate gene expression in mammalian cells.
AB  - A current goal in molecular medicine is the development of new strategies for the
      selective inhibition of cancer-critical genes. Triplex-forming oligonucleotides
      and peptide nucleic acids bind to the double helix of DNA in a sequence-specific
      manner and with great affinity. Because of these properties, these molecules have
      been proposed as anti-gene therapeutic drugs. This review summarizes recent
      results on the use of oligonucleotides and peptide nucleic acids to downregulate
      gene expression in cultured cells. The data are discussed from the perspective of
      the recent literature on new molecular strategies with potential therapeutic
      applications.

PMID- 15032706
TI  - Excitotoxic versus apoptotic mechanisms of neuronal cell death in perinatal
      hypoxia/ischemia.
AB  - Hypoxic/ischemic (H/I) neuronal degeneration in the developing central nervous
      system (CNS) is mediated by an excitotoxic mechanism, and it has also been
      reported that an apoptosis mechanism is involved. However, there is much
      disagreement regarding how excitotoxic and apoptotic cell death processes relate
      to one another. Some authors believe that an excitotoxic stimulus directly
      triggers apoptotic cell death, but this interpretation is largely speculative at
      the present time. Our findings support the interpretation that excitotoxic and
      apoptotic neurodegeneration are two separate and distinct cell death processes
      that can be distinguished from one another by ultrastructural evaluation. Here we
      review evidence supporting this interpretation, including evidence that H/I in
      the developing CNS triggers two separate waves of neurodegeneration, the first
      being excitotoxic and the second being apoptotic. The first (excitotoxic) wave
      destroys neurons that would normally provide synaptic inputs or synaptic targets
      for the neurons that die in the second (apoptotic) wave. Since neurons, during
      the developmental period of synaptogenesis, are programmed to commit suicide if
      they fail to achieve normal connectivity, this explains why neuroapoptosis occurs
      following H/I in the developing CNS. However, it does not support the
      interpretation that H/I directly triggers apoptotic neurodegeneration. Rather, it
      documents that H/I directly triggers excitotoxic neurodegeneration, and apoptotic
      neurodegeneration ensues subsequently as the natural response of developing
      neurons to a specific kind of deprivation - loss of the ability to form normal
      synaptic connections.

PMID- 15032707
TI  - Rethinking the excitotoxic ionic milieu: the emerging role of Zn(2+) in ischemic
      neuronal injury.
AB  - Zn(2+) plays an important role in diverse physiological processes, but when
      released in excess amounts it is potently neurotoxic. In vivo trans-synaptic
      movement and subsequent post-synaptic accumulation of intracellular Zn(2+)
      contributes to the neuronal injury observed in some forms of cerebral ischemia.
      Zn(2+) may enter neurons through NMDA channels, voltage-sensitive calcium
      channels, Ca(2+)-permeable AMPA/kainate (Ca-A/K) channels, or Zn(2+)-sensitive
      membrane transporters. Furthermore, Zn(2+) is also released from intracellular
      sites such as metallothioneins and mitochondria. The mechanisms by which Zn(2+)
      exerts its potent neurotoxic effects involve many signaling pathways, including
      mitochondrial and extra-mitochondrial generation of reactive oxygen species (ROS)
      and disruption of metabolic enzyme activity, ultimately leading to activation of
      apoptotic and/or necrotic processes. As is the case with Ca(2+), neuronal
      mitochondria take up Zn(2+) as a way of modulating cellular Zn(2+) homeostasis.
      However, excessive mitochondrial Zn(2+) sequestration leads to a marked
      dysfunction of these organelles, characterized by prolonged ROS generation.
      Intriguingly, in direct comparison to Ca(2+), Zn(2+) appears to induce these
      changes with a considerably greater degree of potency. These effects are
      particularly evident upon large (i.e., micromolar) rises in intracellular Zn(2+)
      concentration ([Zn(2+)](i)), and likely hasten necrotic neuronal death. In
      contrast, sub-micromolar [Zn(2+)](i) increases promote release of pro-apoptotic
      factors, suggesting that different intensities of [Zn(2+)](i) load may activate
      distinct pathways of injury. Finally, Zn(2+) homeostasis seems particularly
      sensitive to the environmental changes observed in ischemia, such as acidosis and
      oxidative stress, indicating that alterations in [Zn(2+)](i) may play a very
      significant role in the development of ischemic neuronal damage.

PMID- 15032708
TI  - White matter injury mechanisms.
AB  - White matter of the brain and spinal cord is susceptible to anoxia, ischemia,
      trauma and autoimmune attack. Irreversible injury to this tissue can have serious
      consequences for the overall function of the CNS through disruption of signal
      transmission. Like neurons, central myelinated axons are critically dependent on
      a continuous supply of oxygen and glucose. Injury causes failure of the Na-K
      ATPase and accumulation of axoplasmic Na through non-inactivating Na channels,
      which, together with membrane depolarization, promotes reverse Na-Ca exchange and
      axonal Ca overload. An equally important source of deleterious Ca originates from
      intracellular stores, released in part by a mechanism similar to "excitation
      contraction coupling" in muscle, involving activation of ryanodine receptors by L
      type Ca channels. Excitotoxic mechanisms also play an important role: glutamate
      released by reversal of Na-dependent glutamate transporters activates
      AMPA/kainate receptors to cause injury to glia and myelin. Excessive accumulation
      of cytosolic Ca in turn activates various Ca-dependent enzymes such as calpains,
      phospholipases and others resulting in irreversible injury. Reoxygenation
      paradoxically accelerates injury in many axons, and promotes cytoskeletal
      degradation. Blockers of voltage-gated Na channels represent an attractive
      therapeutic target because of their ability to simultaneously interfere
      indirectly with several Ca sourcing pathways. Alternatively, or additionally,
      AMPA/kainate receptor inhibition has also been shown to be neuroprotective in
      several white matter injury paradigms. In the clinical setting, optimal
      protection of the CNS as a whole in common disorders such as stroke, traumatic
      brain and spinal cord injury, will likely require combination therapy aimed at
      unique steps in gray and white matter regions, or intervention at common points
      in the injury cascades.

PMID- 15032709
TI  - The rise and fall of NMDA antagonists for ischemic stroke.
AB  - It has long been accepted that high concentrations of glutamate can destroy
      neurons, and this is the basis of the theory of excitotoxicity during brain
      injury such as stroke. Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists
      such as Selfotel, Aptiganel, Gavestinel and others failed to show neuroprotective
      efficacy in human clinical trials or produced intolerable central nervous system
      adverse effects. The failure of these agents has been attributed to poor studies
      in animal models and to poorly designed clinical trials. We also speculate that
      NMDA receptor antagonism may have hindered endogenous mechanisms for neuronal
      survival and neuroregeneration. It remains to be proven in human stroke whether
      NMDA receptor antagonism can be neuroprotective.

PMID- 15032710
TI  - Molecular mechanisms underlying specificity of excitotoxic signaling in neurons.
AB  - The central role of glutamate receptors in mediating excitotoxic neuronal death
      in stroke, epilepsy and trauma has been well established. Glutamate is the major
      excitatory amino acid transmitter within the CNS and it's signaling is mediated
      by a number of postsynaptic ionotropic and metabotropic receptors. Although
      calcium ions are considered key regulators of excitotoxicity, new evidence
      suggests that specific second messenger pathways rather than total Ca(2+) load,
      are responsible for mediating neuronal degeneration. Glutamate receptors are
      found localized at the synapse within electron dense structures known as the
      postsynaptic density (PSD). Localization at the PSD is mediated by binding of
      glutamate receptors to submembrane proteins such as actin and PDZ containing
      proteins. PDZ domains are conserved motifs that mediate protein-protein
      interactions and self-association. In addition to glutamate receptors PDZ
      containing proteins bind a multitude of intracellular signal molecules including
      nitric oxide synthase. In this way PDZ proteins provide a mechanism for
      clustering glutamate receptors at the synapse together with their corresponding
      signal transduction proteins. PSD organization may thus facilitate the individual
      neurotoxic signal mechanisms downstream of receptors during glutamate
      overactivity. Evidence exists showing that inhibiting signals downstream of
      glutamate receptors, such as nitric oxide and PARP-1 can reduce excitotoxic
      insult. Furthermore we have shown that uncoupling the interaction between
      specific glutamate receptors from their PDZ proteins protects neurons against
      glutamate-mediated excitotoxicity. These findings have significant implications
      for the treatment of neurodegenerative diseases using therapeutics that
      specifically target intracellular protein-protein interactions.

PMID- 15032711
TI  - Mitochondrial dysfunction and glutamate excitotoxicity studied in primary
      neuronal cultures.
AB  - Primary dissociated neuronal cultures have been intensively exploited for the
      past 15 years as model systems to investigate excitotoxic neuronal degeneration.
      Even this simplified system contains a complex web of interactions between
      calcium homeostasis, ATP production and the generation and detoxification of
      reactive oxygen species. There is increasing realization that the mitochondrion
      occupies the center stage in these processes. This review covers the normal
      bioenergetics of the cultured neuron, the ways in which mitochondrial dysfunction
      impacts upon the ability of the neuron to withstand excitotoxic stress, the
      nature of the stresses imposed by NMDA receptor activation and possible molecular
      mechanisms of excitotoxic cell death.

PMID- 15032712
TI  - Nitric oxide and its role in ischaemic brain injury.
AB  - The role of the neural messenger nitric oxide (NO) in cerebral ischaemia has been
      investigated extensively in the past decade. NO may play either a protective or
      destructive role in ischaemia and the literature is plagued with contradictory
      findings. Working with NO presents many unique difficulties and here we review
      the potential artifacts that may have contributed to discrepancies and cause
      future problems for the unwary investigator. Recent evidence challenges the idea
      that NO from neurones builds up to levels (micromolar) sufficient to directly
      elicit cell death during the post-ischaemic period. Concomitantly, the case is
      strengthened for a role of NO in delayed death mediated post-ischaemia by the
      inducible NO synthase. Mechanistically it seems unlikely that NO is released in
      high enough quantities to inhibit respiration in vivo; the formation of reactive
      nitrogen species, such as peroxynitrite, represents the more likely pathway to
      cell death. The protective and restorative properties of NO have become of
      increasing interest. NO from endothelial cells may, via stimulating cGMP
      production, protect the ischaemic brain by acutely augmenting blood flow, and by
      helping to form new blood vessels in the longer term (angiogenesis). Elevated
      cGMP production may also stop cells dying by inhibiting apoptosis and help repair
      damage by stimulating neurogenesis. In addition NO may act as a direct
      antioxidant and participate in the triggering of protective gene expression
      programmes that underlie cerebral ischaemic preconditioning. Better understanding
      of the molecular mechanisms by which NO is protective may ultimately identify new
      potential therapeutic targets.

PMID- 15032713
TI  - Astrocyte influences on ischemic neuronal death.
AB  - Glutamate excitotoxicity, oxidative stress, and acidosis are primary mediators of
      neuronal death during ischemia and reperfusion. Astrocytes influence these
      processes in several ways. Glutamate uptake by astrocytes normally prevents
      excitotoxic glutamate elevations in brain extracellular space, and this process
      appears to be a critical determinant of neuronal survival in the ischemic
      penumbra. Conversely, glutamate efflux from astrocytes by reversal of glutamate
      uptake, volume sensitive organic ion channels, and other routes may contribute to
      extracellular glutamate elevations. Glutamate activation of neuronal N-methyl-D
      aspartate (NMDA) receptors is modulated by glycine and D-serine: both of these
      neuromodulators are transported by astrocytes, and D-serine production is
      localized exclusively to astrocytes. Astrocytes influence neuronal antioxidant
      status through release of ascorbate and uptake of its oxidized form,
      dehydroascorbate, and by indirectly supporting neuronal glutathione metabolism.
      In addition, glutathione in astrocytes can serve as a sink for nitric oxide and
      thereby reduce neuronal oxidant stress during ischemia. Astrocytes probably also
      influence neuronal survival in the post-ischemic period. Reactive astrocytes
      secrete nitric oxide, TNFalpha, matrix metalloproteinases, and other factors that
      can contribute to delayed neuronal death, and facilitate brain edema via
      aquaporin-4 channels localized to the astrocyte endfoot-endothelial interface. On
      the other hand erythropoietin, a paracrine messenger in brain, is produced by
      astrocytes and upregulated after ischemia. Erythropoietin stimulates the Janus
      kinase-2 (JAK-2) and nuclear factor-kappaB (NF-kB) signaling pathways in neurons
      to prevent programmed cell death after ischemic or excitotoxic stress. Astrocytes
      also secrete several angiogenic and neurotrophic factors that are important for
      vascular and neuronal regeneration after stroke.

PMID- 15032714
TI  - What have genetically engineered mice taught us about ischemic injury?
AB  - Stroke, is the third leading cause of death and disability in the Western world.
      Stroke refers to set of ischemic conditions resulting from the occlusion or
      hemorrhage of blood vessels supplying the brain. Loss of blood flow to the brain
      results in neuronal injury due to both oxygen and nutrient deprivation and the
      activation of injurious signal cascades. Ultimately cerebral ischemia results in
      death and dysfunction of brain cells, and neurological deficits that reflect the
      location and size of the compromised brain area. Injury due to ischemic stroke
      occurs by a highly choreographed series of complex spatial and temporal events
      that evolve over hours to days. These events involve complex interactions between
      fundamental cell injury mechanisms including excitotoxicity and ionic imbalance,
      oxidative and nitrosative stress, apoptotic-like cell death and inflammatory
      responses. Genetically engineered mice have been valuable tools to probe putative
      mechanisms of neuronal death and uncover potential strategies that might render
      neurons resistant to ischemic injury. Findings from experimental stroke studies
      in genetically engineered animals are discussed.

PMID- 15032715
TI  - Thymidine phosphorylase and fluoropyrimidines efficacy: a Jekyll and Hyde story.
AB  - Thymidine phosphorylase (TP) is markedly upregulated in many solid tumors such as
      colorectal, breast and kidney cancers. Because TP is identical to platelet
      derived endothelial cell growth factor, this enzyme is believed to have
      angiogenic properties, although the precise mechanisms through which it promotes
      neoangiogenesis are still not fully elucidated. TP is involved as well in the
      tumoral activation of widely prescribed pyrimidine-derived antimetabolites such
      as 5-FU, 5'-dFUR and newly marketed capecitabine, and, in this respect, has been
      presented as a determinant to fluoropyrimidine efficacy in various in vitro and
      in vivo models. This dual and apparently contradictory role that TP plays yields
      inconsistent results in the study of relationships between this enzyme expression
      and clinical outcome in patients treated with fluoropyrimidine analogs. Some
      studies have shown that high tumoral TP expression was associated indeed with
      poor clinical response and tumor aggressiveness. Conversely, other reports
      demonstrated that tumoral TP could be considered as a good response factor in
      patients exposed to fluoropyrimidine drugs. TP exhibits then its more favorable
      profile, probably in converting 5-FU to active metabolites responsible for its
      efficacy as antitumor agent. As a result, TP-targeting as a rationale for
      anticancer therapy remains unclear. TP inhibitors are being synthesized as an
      attempt to fight neoangiogenesis, whereas promising new strategies such as
      taxotere/capecitabine or radiotherapy/fluoropyrimidines associations aim at
      nothing but boosting TP activity to optimize drug activation in tumors. Such a
      discrepancy illustrates the complexity of understanding and predicting the exact
      role of TP in the clinical outcome of patients exposed to fluoropyrimidines, a
      group of major drugs extensively used in oncology.

PMID- 15032716
TI  - Design of novel antitumor DNA alkylating agents: the benzacronycine series.
AB  - Acronycine, a natural alkaloid originally extracted from the bark of the
      Australian ash scrub Acronychia baueri, has shown a significant antitumor
      activity in animal models. Acronycine has been tested against human cancers in
      the early 1980s, but the clinical trials showed modest therapeutic effects and
      its development was rapidly discontinued. In order to optimize the antineoplastic
      effect, different benzoacronycine derivatives were synthesized. Among those, the
      di-acetate compound S23906-1 was recently identified as a promising anticancer
      drug candidate and a novel alkylating agent specifically reacting with the
      exocylic 2-NH2 group of guanines in DNA. The study of DNA bonding capacity of
      acronycine derivatives leads to the identification of the structural requirements
      for DNA alkylation. In nearly all cases, the potent alkylating agents, such as
      S23906-1, were found to be much more cytotoxic than the unreactive analogs such
      as acronycine itself or diol derivatives. Alkylation of DNA by the monoacetate
      derivative S28687-1, which is a highly reactive hydrolysis metabolite of S23906
      1, occurs with a marked preference for the N2 position of guanine. Other
      bionucleophiles can react with S23906-1. The benzacronycine derivatives, which
      efficiently alkylate DNA, also covalently bind to the tripeptide glutathione
      (GSH) but not to the oxidized product glutathione disulfide. Here we review the
      reactivity of S23906-1 and some derivatives toward DNA and GSH. The structure
      activity relationships in the benzacronycine series validate the reaction
      mechanism implicating DNA as the main molecular target. S23906-1 stands as the
      most promising lead of a medicinal chemistry program aimed at discovering novel
      antitumor drugs based on the acronycine skeleton.

PMID- 15032718
TI  - Farnesylated proteins as anticancer drug targets: from laboratory to the clinic.
AB  - The knowledge that Ras was readily prenylated by protein FTase and that the
      inhibition of this reaction has the ability to revert the transformed phenotype,
      provided the rationale for the development of FTIs as anticancer drugs. Studies
      have shown that farnesylation of Ras is the first, obligatory first step in a
      series of post-translational modifications leading to membrane association,
      which, in turn, determines the switch from an inactive to an active Ras-GTP bound
      form. Based on the theorical assumption that preventing Ras farnesylation might
      result in the inhibition of Ras functions, a range of FTIs have been synthesized.
      Their biology is fascinating since after substantial investigation and their use
      in several phase II studies and at least two phase III trials, the exact
      mechanism of action remains unclear. FTIs can block the farnesylation of several
      additional proteins, such as RhoB, prelamins A and B, centromere proteins (CENP
      E, CENP-F), etc. While the FTIs clearly do not or only partly target Ras, these
      agents appear to have clinical activity in leukemia and in some solid tumors
      regardless of their Ras mutational status. Although inhibition of FTase by these
      compounds has been well documented also in normal tissues, their toxic effects
      seem to be manageable. However, preliminary results of early Phase II-III studies
      suggest that the activity of FTIs, as a single-agent, is modest and generally
      lower than that obtained by standard cytotoxic drugs. Ongoing clinical studies
      are assessing the role of FTIs for early stage disease or in combination with
      cytotoxic agents or with other molecular targeted therapies for advanced stage
      tumors. Further insights in the molecular mechanism of action of FTIs might help
      in better define their optimal use in combination with standard therapies in the
      treatment of cancer patients.

PMID- 15032717
TI  - Recent anticancer cytotoxic agents.
AB  - In spite of the impressive progress in diagnosis, surgery and therapy that
      occurred since the Sixties, the overall cancer mortality is still high and the
      medical need is largely unmet. A number of innovative strategies, aimed to target
      malignant abnormalities of tumor cells are in development and begin to give
      important results. In alternative, angiogenesis inhibition has been addressed
      with the aim to limit the tumor ability to grow and metastasize. However, it will
      likely take some years to fully define the therapeutic role of different
      innovative drugs. Therefore, cytotoxic drugs will continue to represent a chief
      part of the therapy in the forthcoming years, possibly in combination with
      innovative agents addressing molecular targets. Most important traditional
      chemotherapeutic drugs or investigational anticancer agents were derived from
      natural sources also through synthetic structural modifications. In the Nineties,
      taxanes and camptothecins represented important success stories of this approach,
      while among DNA interacting agents anthracyclines continued to represent a
      structural platform for discovering new drugs and DNA minor groove binders
      represented a new field of investigation. Combinatorial chemistry combined with
      high-throughput screening programs are an important source of totally synthetic
      new agents, however, it should not be disregarded the fact that nature already
      performed combinatorial chemistry and leads selection through the ages. New
      natural or semisynthetic agents acting as tubulin stabilizers or DNA interactive
      agents of various mechanisms of action are presently investigated and will
      probably continue to give important contribution to cancer therapy in the near
      future. In this review, the medicinal chemistry and the development status of
      these anticancer cytotoxic agents are focused and discussed.

PMID- 15032719
TI  - Epidermal growth factor receptor inhibitors: a new prospective in the treatment
      of lung cancer.
AB  - Lung cancer is the leading cause of death worldwide. Current treatment
      modalities, including chemotherapy, radiotherapy and surgery, provide only
      limited improvement in the natural course of this disease. Therefore, the
      development of new therapeutic strategies is highly awaited. This review focuses
      on recent achievements on a novel class of anticancer drugs targeting the EGFR
      (Epidermal Growth Factor Receptor). The EGFR family is a group of four
      structurally similar growth factor receptors with tyrosine-kinase activity (EGFR,
      HER2/neu, ErbB-3, ErbB-4), which dimerize upon binding with a number of ligands,
      including EGF (Epidermal Growth Factor) and TGF (Transforming Growth Factor),
      allowing downstream transduction of mitogenic signals. Overexpression of EGFR and
      HER2 is frequently found in non-small-cell lung cancer (NSCLC), which accounts
      for over 80% of all malignant lung tumors, and has been associated with a worse
      clinical outcome. New agents developed to inhibit EGFR function include
      monoclonal antibodies and small-molecule receptor tyrosine-kinase inhibitors. In
      this review, results of most recent clinical with EGFR inhibitors including
      monoclonal antibodies, such as Trastuzumab (Herceptin), IMC-C225 (Cetuximab) and
      others (ABX-EGF, EMD 72000), and tyrosine-kinase inhibitors, such as ZD1839
      (Gefitinib, Iressa), OSI-774 (Erlotinib, Tarceva) and others (CI-1033, GW2016),
      are summarized. In particular, final results of phase II (IDEAL 1 and 2) and III
      (INTACT 1 and 2) studies of ZD1839 are reported. In IDEAL trials (ZD1839 single
      agent in patients pre-treated with chemotherapy) there was clear evidence of
      tumor regression, symptoms improvement and overall clinical benefit, whereas in
      the two INTACT trials (ZD1839 in combination with standard platinum-based
      chemotherapy in chemo-naive patients) ZD1839 did not improve either survival or
      other clinical endpoints. Possible explanations for these contradictory results
      and future perspectives are discussed.

PMID- 15032720
TI  - Extending nature's leads: the anticancer agent ellipticine.
AB  - The natural plant product ellipticine was isolated in 1959 from the Australian
      evergreen tree of the Apocynaceae family. This compound was found to be an
      extremely promising anticancer drug. The planar polycyclic structure was found to
      interact with DNA through intercalation, exhibiting a high DNA binding affinity
      (10(6) M(-1)). The presence of protonatable ring nitrogens distinguished
      ellipticine from other simple intercalators. Both monocationic and uncharged
      species were found to be present under physiological conditions. The positive
      charge stabilized the binding of ellipticine to nucleic acids, while the more
      lipophilic uncharged compound was shown to readily penetrate membrane barriers.
      The structural nature of these compounds offers a plausible basis for the
      implication of multiple modes of action, including DNA binding, interactions with
      membrane barriers, oxidative bioactivation and modification of enzyme function;
      most notably that of topoisomerase II and telomerase. Pharmacologically, a number
      of toxic side effects have been shown to be problematic, but the amenability of
      ellipticine towards systematic structural modification has permitted the
      extensive application of rational drug design. A number of successful ellipticine
      analogs have been designed and synthesized with improved toxicities and
      anticancer activities. More recently the synthetic focus has broadened to include
      the design of hybrid compounds, as well as drug delivery conjugates. Considerable
      research efforts have been directed towards gaining a greater understanding of
      the mechanism of action of these drugs that will aid further in the optimization
      of drug design.

PMID- 15032721
TI  - Plant-derived protein tyrosine kinase inhibitors as anticancer agents.
AB  - Protein tyrosine kinases play a fundamental role in signal transduction pathways
      regulating a number of cellular functions such as cell growth, differentiation
      and cell death. Tyrosine kinases are, therefore attractive targets for the design
      of new therapeutic agents, not only against cancer, but also against many other
      diseases. Numerous tyrosine kinase inhibitors have been discovered by screening
      of plant extracts based on ethnopharmacological and chemotaxonomical knowledge.
      Specific screening approaches have led to the isolation of structurally distinct
      classes of inhibitors, including phenylpropanes, chalcones, flavonoids,
      coumarins, styrenes, quinones and terpenes. These natural inhibitors have served
      as valuable leads for further design and synthesis of more active analogues. Many
      of these inhibitors have also been used in probing the molecular and cellular
      mechanisms involved in the protein tyrosine kinase mediated signal transduction.
      In this review, plant-derived protein tyrosine kinase inhibitors and their
      synthetic analogues were systematically evaluated based on their plant origin,
      structure-activity relationship and anticancer efficacy.

PMID- 15032722
TI  - Recent kinase and kinase inhibitor X-ray structures: mechanisms of inhibition and
      selectivity insights.
AB  - Recent years have seen an explosion in the number of publicly available x-ray
      crystal structures of protein kinases. These structures have provided a wealth of
      information on the regulatory mechanisms, conformational plasticity and
      drugability of this important family of enzymes. Drawing upon structural
      information, new insights into the development of protein kinase inhibitors are
      discussed including de-novo design, molecular templates for ATP competitive
      inhibitors and alternative mechanisms of inhibition. The highly conserved nature
      of the ATP binding site is of central concern to drug development and the concept
      of a selectivity profile has arisen with structure-based design emerging as a key
      tool for addressing the challenges of specificity. In addition, protein-ligand
      complexes, where the enzyme is in an inactive conformation, signify an alternate
      approach to protein kinase inhibition. The belief that an inactive kinase
      presents a less conserved target is reviewed using observations on the structural
      changes occurring during protein kinase regulation.

PMID- 15032723
TI  - Stochastic algorithm for kinase homology model construction.
AB  - A stochastic algorithm for constructing multiple loops in homology modeling of
      proteins is presented. The algorithm discards variable values in iterations based
      on a cost function and on statistical analysis of results. Values that remain are
      used for constructing an ensemble of best solutions. In test cases, the
      stochastic algorithm retains all the best solutions, compared to an exhaustive
      scan of the full set of conformations. Individual loops are constructed by adding
      dipeptide units. Dipeptide conformations are extracted from a database of
      proteins and their conformations include bond lengths and all angles. Single
      loops are constructed from both N- and C- terminals to the center, and loop
      closure is evaluated by a combination of penalties for the peptide closure and
      Miyazawa-Jernigan (MJ) [1]. residue-residue interactions with the rest of the
      protein. Large ensembles of each loop are clustered and re-evaluated with a
      refined [2]. energy term. The reduced, clustered set of each loop is then
      employed to construct simultaneously all the loops. The algorithm was applied to
      construct simultaneously six loops in c-Src kinase family proteins, incorporating
      a total of 37-40 residues. The best RMSD for reconstructing the loops is 1.45 A
      for Lck (structure 1QPE in the Protein Data Bank) and 2.54 A for human c-Src
      (structure 1FMK). The multiple loop conformations with lowest energy have higher
      RMSD values, of 2.06 A and 3.09 A, respectively. The average RMSD values for the
      first 1000 conformations are 3.00 A and 3.46 A, respectively. Models for the
      "open" structures of c-Src and of Jak-2 were constructed on the basis of 1QPE.
      The Jak-2 model is found to be more flexible in the loops region than its c-Src
      counterpart.

PMID- 15032724
TI  - Virtual screening for kinase targets.
AB  - Kinases have become a major area of drug discovery and structure-based design.
      Hundreds of 3D structures for more than thirty different kinases are available to
      the public. High structural and sequence homology within the kinase gene family
      makes the remaining kinases ideal targets for homology modeling and virtual
      screening. Somewhat surprisingly, however, the number of publications about
      virtual screening of kinases is very low. Therefore, rather than reviewing the
      field of virtual screening for kinases, we attempt here a hybrid approach of
      presenting what is known and common practice together with new studies on CDK2
      and SRC kinase. To illustrate the challenges and pitfalls of virtual screening
      for kinase targets we focus on the question of how ranking is influenced by the
      database screened, the docking scheme, the scoring function, the activity of the
      compounds used for testing, and small changes in the binding pocket. In addition,
      a case study of finding irreversible inhibitors of ErbB2 through in silico
      screening is presented.

PMID- 15032725
TI  - Property-based design of KDR kinase inhibitors.
AB  - Small molecule inhibitors of KDR kinase activity have typically possessed poor
      intrinsic physical properties including low aqueous solubility and high
      lipophilicity. These features have often conferred limited cell permeability
      manifested in low levels of cell-based KDR inhibitory activity and oral
      bioavailability. Thus, the design of inhibitors with appropriate physical
      properties has played a critical role in the development of clinical candidates.
      We present a variety of structural modifications that have afforded improvements
      in physical properties and thereby have addressed suboptimal cellular potency and
      pharmacokinetics for three unique classes of KDR kinase inhibitors.

PMID- 15032726
TI  - AlphaScreen kinase HTS platforms.
AB  - Kinases represents one of the most important family of targets in high throughput
      drug screening. Tyrosine kinases and serine/threonine kinases are known to play
      key roles in signal transduction as well as in cell growth and differentiation.
      Intense screening campaigns are underway in all major pharmaceuticals and large
      biotech companies to find kinase inhibitors for the treatment of inflammatory
      diseases, immunological disorders and cancer. The present contribution describes
      models that were developed to produce kinase assays amenable to HTS using
      AlphaScreen. Because of the flexibility allowed by AlphaScreen, kinase assays can
      be developed using direct or indirect approaches. Tyrosine kinase assays are
      usually performed with a direct format involving generic anti-phosphotyrosine
      antibodies while serine/threonine kinase assays are performed with an indirect
      format where specific antibodies are captured using protein A conjugated Acceptor
      beads. Streptavidin-coated Donor beads are used to capture either generic (ex.
      poly GT) or specific biotinylated substrates. Herein, are presented different
      methods to perform screening for inhibitors acting on the soluble beta-insulin
      receptor tyrosine kinase (IRKD), and on p38, a member of the MAP kinase family.

PMID- 15032727
TI  - Development of vascular endothelial growth factor receptor (VEGFR) kinase
      inhibitors as anti-angiogenic agents in cancer therapy.
AB  - Among the known angiogenic growth factors and cytokines implicated in the
      modulation of normal and pathological angiogenesis, the VEGF family (VEGF-A, VEGF
      B, VEGF-C, VEGF-D) and their corresponding receptor tyrosine kinases [VEGFR-1
      (Flt-1), VEGFR-2 (Flk-1, KDR), and VEGFR-3 (Flt-4)] play a paramount and
      indispensable role in regulating the multiple facets of the angiogenic and
      lymphangiogenic processes, as well as the induction of vascular permeability and
      inflammation. The receptor VEGFR-2/KDR is the principal one through which VEGFs
      exert their mitogenic, chemotactic, and vascular permeabilizing effects on the
      host vasculature. Increased expression of VEGFs by tumor cells and VEGFR-2/KDR
      and VEGFR-1/Flt-1 by the tumor-associated vasculature are a hallmark of a variety
      of human and rodent tumors in vivo and correlates with tumor growth rate, micro
      vessel density/proliferation, tumor metastatic potential, and poorer patient
      prognosis in a variety of malignancies. Approaches to disrupting the VEGF/VEGFR
      signaling cascade range from biological agents (soluble receptors, anti-VEGF and
      anti-VEGFR-2 antibodies, and VEGF transcription inhibitors) to small molecule ATP
      competitive VEGFR inhibitors. Examples from this latter class that are currently
      in clinical development include compounds from distinct chemical classes such as:
      indolin-2-ones, anilinoquinazolines, anilinophthalazines, isothiazoles, indolo-
      and indenocarbazoles. The structure activity relationships, biochemical and
      pharmacological profile of optimized representatives from each of these classes
      constitute the subject matter of this review.

PMID- 15032729
TI  - GSK-3 inhibitors: discoveries and developments.
AB  - Glycogen synthase kinase 3 (GSK-3) in the 21(st) century emerged as one of the
      most attractive therapeutic target for the development of selective inhibitors as
      new promising drugs for unmet pathologies including Alzheimer's disease, stroke,
      bipolar disorders, chronic inflammatory processes, cancer and diabetes type II.
      The full potential of GSK-3 inhibitors is just starting to be realized but the
      number of candidates in development provided by both academic centres and
      pharmaceutical companies have increased exponentially in the last two years. This
      review discloses recent discoveries and developments on peptides and small
      molecules targeting GSK-3. Focusing attention on this exciting target could thus
      reap considerable clinical and economic rewards.

PMID- 15032728
TI  - 4-thiophenoxy-N-(3,4,5-trialkoxyphenyl)pyrimidine-2-amines as potent and
      selective inhibitors of the T-cell tyrosine kinase p56lck.
AB  - We have developed a series of 4-thiophenoxy-N-(3,4,5-trialkoxyphenyl) pyrimidine
      2-amines as potent and selective inhibitors of p56lck tyrosine kinase activity.
      In particular, the most potent inhibitor shows cellular activity in T-cell
      receptor (TCR) stimulated models of cytokine release, which suggests an
      immunomodulatory role for this class of inhibitor.

PMID- 15032730
TI  - Developing inhibitors to selectively target two-component and phosphorelay signal
      transduction systems of pathogenic microorganisms.
AB  - Two-component signal transduction systems and their expanded variants known as
      phosphorelays are integral elements of the virulence and antimicrobial resistance
      responses of a wide range of pathogenic bacteria and fungi and also regulate
      essential functions. As a consequence, two-component systems and phosphorelays
      are recognized targets for the development of novel antimicrobial agents and a
      number of chemically synthesized inhibitors from different chemical classes have
      been identified by compound library screens. However, in the majority of cases
      these compounds do not appear to be selective for signal transduction pathways
      and exert their effect by multiple mechanisms of action. The key to designing
      molecules to selectively disrupt signal transduction may lie with the conserved
      features of response regulators and the structural analysis of complexes of
      signaling proteins.

PMID- 15032731
TI  - Challenges in antimicrobial drug discovery and the potential of nucleoside
      antibiotics.
AB  - Antimicrobial resistance in hospital and community settings is growing at an
      alarming rate and has been attributed to such organisms as methicillin-resistant
      staphylococcus aureus, staphylococci with decreased susceptibility to vancomycin,
      vancomycin-resistant enterococci, multi-drug resistant pseudomonas spp.,
      klebsiella spp., enterobacter spp, and acinetobacter spp., as well as
      Streptococcus pneumoniae with decreased susceptibility to penicillin and other
      antibacterials. To address the need for new therapies to combat resistant
      organisms, drug companies are refocusing their discovery efforts on developing
      novel agents with new mechanisms of action. The hope is that rapidly emerging
      technologies including combinatorial chemistry, high throughput screening,
      proteomics and microbial genomics will have a positive impact on antimicrobial
      drug discovery. These technologies should aid in the identification of novel drug
      targets and compounds with unique mechanisms of action other than those currently
      provided by the traditional antibiotics. Nucleosides are one class of compounds
      worthy of further investigation as antibacterials since some derivatives have
      shown moderate to good activity against specific bacterial strains. For example,
      5'-peptidyl nucleoside derivatives can inhibit peptide deformylase, an enzyme
      essential for bacterial survival that is not vital to human cells. This review
      also includes a list of miscellaneous nucleosides that have been synthesized as
      potential antibacterials. More detailed investigations on structure, as it
      relates to the antimicrobial activity of the various classes of nucleosides, need
      to be conducted in order to maximize the potential of developing a potent
      nucleoside for the treatment of bacterial infections. This review begins with an
      introduction to terms followed by discussions regarding the general background
      and relevance for developing novel antimicrobial agents. Challenges facing the
      antimicrobial drug discovery process are discussed along with relevant drug
      targets. An overview of nucleoside chemistry as it relates to antimicrobial
      activity is presented, followed by a discussion of the evidence which supports
      the potential of this class of compounds to yield the novel antimicrobial
      therapies needed in the new millennium.

PMID- 15032732
TI  - Retinoids and retinoid receptors in the control of energy balance: novel
      pharmacological strategies in obesity and diabetes.
AB  - Obesity and type II diabetes are closely related metabolic diseases with an
      increasing incidence worldwide. No clear-cut pharmacological treatment for these
      complex metabolic disturbances is available despite current efforts. New
      directions and perspectives for the pharmacological or nutritional treatment of
      these diseases should be defined. In recent years, a growing body of evidence
      shows that retinoids and retinoic acid receptors are involved in the control of
      biological aspects (e.g. adiposity and energy expenditure mechanisms), which
      offers great potential for research on the treatment of obesity and type II
      diabetes. All-trans retinoic acid is known to inhibit adipocyte differentiation,
      whereas, molecules activating the retinoid X-receptor (rexinoids) promote the
      differentiation of adipocytes. Treatment with rexinoids ameliorates glycemic
      control in rodent models of type II diabetes and obesity, although other findings
      indicate similar positive effects by inhibiting the receptor. Moreover, natural
      products of dietary origin, such as phytanic acid can activate RXR and thus,
      trigger adipose cell differentiation. Finally, the activation of retinoic acid
      receptors or retinoid X receptors has been reported to induce the gene expression
      of uncoupling proteins, which are mitochondrial proteins involved in the
      regulation of energy expenditure and fatty acid metabolism. Further research is
      required to exploit the capacities of the retinoid-dependent pathways of
      regulation of adiposity, insulin sensitivity and energy expenditure for drug
      development in metabolic disturbances.

PMID- 15032733
TI  - Cell signalling in vascular cells exposed to cyclic strain: the emerging role of
      protein phosphatases.
AB  - Phosphorylation of tyrosine or serine/threonine residues of intracellular
      proteins is a reversible and dynamic process which is essential in controlling
      cellular growth, migration and survival. The phosphorylation states of numerous
      intermediary signalling proteins are governed by the opposing activities of
      protein kinases and phosphatases. Abnormal phosphorylation states have been
      linked with many human diseases, including cancer, diabetes, hypertension and
      cardiac hypertrophy. Recently, several reports have described the role of
      phosphatases in regulating critical cellular functions and signalling pathways in
      vascular cells. This Review will focus on the significance of several of these
      phosphatases and present information on the role of protein phosphatase type 2a
      in endothelial cells exposed to haemodynamic forces.

PMID- 15032734
TI  - Tissue engineering of blood vessels: characterization of smooth-muscle cells for
      culturing on collagen-and-elastin-based scaffolds.
AB  - Tissue engineering offers the opportunity to develop vascular scaffolds that
      mimic the morphology of natural arteries. We have developed a porous three
      dimensional scaffold consisting of fibres of collagen and elastin interspersed
      together. Scaffolds were obtained by freeze-drying a suspension of insoluble type
      I collagen and insoluble elastin. In order to improve the stability of the
      obtained matrices, they were cross-linked by two different methods. A water
      soluble carbodi-imide, alone or in combination with a diamine, was used for this
      purpose: zero- or non-zero-length cross-links were obtained. The occurrence of
      cross-linking was verified by monitoring the thermal behaviour and the free-amino
      group contents of the scaffolds before and after cross-linking. Smooth-muscle
      cells (SMCs) were cultured for different periods of time and their ability to
      grow and proliferate was investigated. SMCs were isolated from human umbilical
      and saphenous veins, and the purity of the cultures obtained was verified by
      staining with a specific monoclonal antibody (mAb). Cultured cells were also
      identified by mAbs against muscle actin and vimentin. After 14 days, a confluent
      layer of SMCs was obtained on non-cross-linked scaffolds. As for the cross-linked
      samples, no differences in cell attachment and proliferation were observed
      between scaffolds cross-linked using the two different methods. Cells cultured on
      the scaffolds were identified with an anti-(alpha-smooth-muscle actin) mAb. The
      orientation of SMCs resembled that of the fibres of collagen and elastin. In this
      way, it may be possible to develop tubular porous scaffolds resembling the
      morphological characteristics of native blood vessels.

PMID- 15032735
TI  - Shear-stress preconditioning and tissue-engineering-based paradigms for
      generating arterial substitutes.
AB  - In situ tissue engineering using shear-stress preconditioning and adhesive
      biomolecules is a new approach to autologous tissue engineering. In the present
      study, novel tissue-engineering grafts (TEGs) were preconditioned within an in
      vitro pulsatile flow circuit, with and without the addition of fibronectin (FN),
      to establish whether low-shear-stress conditions promoted endothelial cell (EC)
      retention and differentiation. TEGs ( n =24) were generated by the contraction
      and compaction of collagen(I) by porcine aortic smooth-muscle cells (SMCs) on to
      a compliant polyester graft scaffold. ECs were radiolabelled with [(111)In]indium
      tropolonate and seeded on to the luminal surface of the TEGs. Following organ
      culture in a bioreactor (7 days), TEGs were split into four groups ( n =six TEGs
      per group): Group A acted as controls with TEGs unmodified and seeded with
      radiolabelled ECs; Group B underwent luminal pre-coating with FN (75 microg/ml)
      prior to EC seeding; Group C underwent preconditioning within a pulsatile flow
      circuit at 10-20 microN (1-2 dyn)/cm(2) for 7 days prior to EC seeding, and Group
      D TEGs were preconditioned for 7 days at 1-2 dyn/cm(2), followed by luminal pre
      coating with FN prior to EC seeding. The resistance to physiological shear stress
      of the seeded ECs was assessed using a gamma-radiation counter within a
      physiological flow circuit producing an arterial waveform with a mean shear
      stress of 93.2 microN (9.32 dyn)/cm(2). Environmental scanning electron
      microscopy (ESEM) was used to determine the distribution and degree of
      differentiation of the attached Ecs, and tissue-type-plasminogen-activator (tPA)
      assays provided a measure of function and viability. EC resistance to shear
      stress at 93.2 microN/cm(2) was significantly enhanced by a period of
      preconditioning (Group C) at 10-20 microN/cm(2), surface modification with FN
      (Group B), or both (Group D) when compared with control grafts (Group A).
      However, TEGs coated with FN whether preconditioned (Group D) or not (Group B)
      demonstrated the best results for EC retention. ESEM demonstrated near-confluent
      differentiated flattened ECs in both these cases. EC function was demonstrated by
      a steady increase in tPA production. Low-shear-stress preconditioning of TEGs
      enhances EC retention in vitro with an additional advantage demonstrated by pre
      treatment with FN prior to endothelialization. These findings may be exploited in
      the development of tissue-engineered constructs to maintain a confluent
      endothelial lining.

PMID- 15032737
TI  - Freeze-drying of proteins: some emerging concerns.
AB  - Freeze-drying (lyophilization) removes water from a frozen sample by sublimation
      and desorption. It can be viewed as a three-step process consisting of freezing,
      primary drying and secondary drying. While cryoprotectants can protect the
      protein from denaturation during early stages, lyoprotectants are needed to
      prevent protein inactivation during drying. The structural changes as a result of
      freeze-drying have been investigated, especially by FTIR (Fourier-transform IR)
      spectroscopy. In general, drying results in a decrease of alpha-helix and random
      structure and an increase in beta-sheet structure. In the case of basic
      fibroblast growth factor and gamma-interferon, enhanced FTIR showed large
      conformational changes and aggregation during freeze-drying, which could be
      prevented by using sucrose as a lyoprotectant. It is now well established that
      structural changes during freeze-drying are responsible for low activity of
      freeze-dried powders in nearly anhydrous media. Strategies such as salt
      activation can give 'activated' enzyme powders, e.g. salt-activated thermolysin
      catalysed regioselective acylation of taxol to give a more soluble derivative for
      therapeutic use. In the presence of moisture, freeze-dried proteins can undergo
      disulphide interchange and other reactions which lead to inactivation. Such
      molecular changes during storage have been described for human insulin, tetanus
      toxoid and interleukin-2. Some successful preventive strategies in these cases
      have also been mentioned as illustrations. Finally, it is emphasized that freeze
      drying is not an innocuous process and needs to be understood and used carefully.

PMID- 15032736
TI  - Grafts of microencapsulated pancreatic islet cells for the therapy of diabetes
      mellitus in non-immunosuppressed animals.
AB  - Pancreatic-islet-cell transplantation may reverse hyperglycaemia in diabetic
      recipients that undertake general pharmacological immunosuppression. A major
      challenge that remains is the need to avoid immunosuppression associated with the
      use of allogeneic or heterologous islet cells. In the present study we
      demonstrate the use of microencapsulation of cells using artificial biocompatible
      and permselective membranes prepared with alginic acid derivatives and polyamino
      acids. While characterization of the microcapsule constituent polymers continues
      to progress, other technical issues such as definition of the immunobarrier
      capacity, biocompatibility, size, shape and graft site have come into sharper
      focus. Assessment of microcapsules properties, in order to establish possible
      guidelines for fabrication of reproducible membranes, and results from both in
      vitro functional testing, and in vivo encapsulated-islet-transplant outcome in
      several animal models of diabetes are reported.

PMID- 15032738
TI  - Poly(L-lysine)-modified silica nanoparticles for the delivery of antisense
      oligonucleotides.
AB  - Silica nanoparticles were prepared in a microemulsion system, using
      polyoxyethylene nonylphenyl ether/cyclohexane/ammonium hydroxide. The surface
      charge of the particle was modified with PLL [poly(L-lysine)]. PAGE demonstrated
      the ability of PMS-NP (PLL-modified silica nanoparticles) to bind and protect
      antisense ODNs (oligonucleotides). The intracellular localization of FITC
      labelled ODN was investigated by fluorescence microscopy. The results
      demonstrated that ODN could be delivered to cytoplasm. Flow-cytometry analysis
      showed a 20-fold enhancement of ODN delivered by PMS-NP compared with free ODN
      for a serum-free medium. Blocking efficacy of c- myc antisense ODN, delivered by
      PMS-NP, was examined in HNE1 and HeLa cell lines. Significant down-regulation of
      c- myc mRNA levels was observed in both the cell lines. However, the cellular
      uptake efficiency and antisense effects on target gene decreased in the presence
      of serum-containing medium. The analysis of the filtration assay showed that PMS
      NP interacted with serum proteins. These results indicated that PMS-NP was a
      suitable delivery vector for antisense ODN, although its delivery efficiency
      decreased in the presence of a serum-containing medium.

PMID- 15032739
TI  - Modified alginate matrices for the immobilization of bioactive agents.
AB  - Bioactive agents (catalase - an enzyme, and nisin - a bacteriocin) were
      covalently immobilized on alginate activated with sodium periodate (oxidatively
      converting 2,3-dihydroxy groups into dialdehyde residues), followed or preceded
      by ionotropic gelation. For the same protein coupling yield, the retained enzyme
      activity of the immobilized enzyme (ImE) can be markedly increased by diminishing
      the bead diameter, a phenomenon that illustrates the role of substrate/product
      diffusion through the bead gel layer. When the amount of enzyme introduced for
      coupling was about 15 mg/100 mg of support and the bead diameter was about 100
      microm, a high retained specific activity (95-98%) was obtained. Diffusion
      phenomena can be markedly decreased by enzyme immobilization on the surface of
      microbeads (obtained by gelation of activated alginate prior to immobilization).
      In this case, the retained activity was approx. 75% of that of the free enzyme. A
      slightly higher K (m) value of ImE suggested that the enzyme-substrate affinity
      was almost maintained. The profiles of ImE activities at various pH values, at
      various temperatures and when undergoing proteolysis showed a overall higher
      stability for the immbolized than that for the free enzyme. Nisin immobilized on
      the microbead surface, when submitted to proteolysis, conserved its bacteriocin
      activity, strongly inhibiting the growth of Lactobacillus sake when subjected to
      an agar spot test, whereas free nisin totally lost its activity.

PMID- 15032741
TI  - Conversion of 7-deoxy-10-deacetylbaccatin-III into 6-alpha-hydroxy-7-deoxy-10
      deacetylbaccatin-III by Nocardioides luteus.
AB  - 6-alpha-Hydroxy-7-deoxy-10-deacetylbaccatin-III is an intermediate that is
      potentially useful for synthesis of analogues of paclitaxel. Screening of
      microbial strains identified an enzyme activity in Nocardioides luteus SC 13912
      (A.T.C.C. 55426) which converted 7-deoxy-10-deacetylbaccatin-III into 6-hydroxy-7
      deoxy-10-deacetylbaccatin-III with a maximum yield of 44%.

PMID- 15032740
TI  - A kinetic study of bovine haemoglobin hydrolysis by pepsin immobilized on a
      functionalized alumina to prepare hydrolysates containing bioactive peptides.
AB  - The hydrolysis kinetics of native and denatured haemoglobin, using pepsin
      immobilized on aluminium oxide, was studied in order to produce hydrolysates
      containing bioactive peptides. Pepsin was immobilized on acidic alumina and on 2
      ethanolamine- O -phosphate (2-EAOP)-modified acidic alumina. Surface charge of
      the two supports was determined as a function of pH. Kinetic studies were
      performed at 23 degrees C in 0.1 M acetate buffer, pH 4.5. At this pH, the
      surface charge of the two supports was almost the same. The coating of alumina by
      2-EAOP only introduced a two carbon spacer between alumina surface and the
      reaction medium. Adsorption on the two supports of haemoglobin, haem and peptides
      produced in the course of hydrolyses were compared. Fixation of 2-EAOP on a
      pepsin-alumina complex gave hydrolysis kinetics of urea-denatured haemoglobin
      close to that obtained with the same amount of pepsin in solution, but with
      comparatively less adsorption of peptides and complete adsorption of haem.
      Heterogeneous hydrolyses of haemoglobin with pepsin, immobilized on
      functionalized alumina, resulted in the presence of VV-haemorphin-4, VV
      haemorphin-7 and neokyotorphin in the supernatants without haem, the presence of
      which makes further purification difficult.

PMID- 15032742
TI  - One-step purification and kinetic properties of the recombinant L-asparaginase
      from Erwinia carotovora.
AB  - ECAR-LANS, the recombinant L-asparaginase from Erwinia carotovora, is a
      prospective therapeutic enzyme for leukaemia treatment. An efficient and
      economical scheme was developed for the purification, cloning and expression in
      Eschericha coli of ECAR-LANS. More than 90% purity, complemented with 72% active
      enzyme recovery, was achieved with a single chromatographic purification step.
      The activity of purified L-asparaginase was 630 i.u./mg. The ECAR-LANS K (m)
      value was 98x10(-6) M for the main physiological substrate L-Asn and 3400x10(-6)
      M for L-Gln. ECAR-LANS was found to have low relative glutaminase activity (1.2%)
      at physiological concentrations of L-Asn and L-Gln in blood. Kinetic studies of
      ECAR-LANS showed that the recombinant asparaginase combined the main advantages
      of Erw. chrysanthemi and E. coli L-asparaginases II, currently used in the
      treatment of acute lymphoblastic leukaemia.

PMID- 15032743
TI  - Changes in diffusion through the brain extracellular space.
AB  - ECS (extracellular space) works as the microenvironment of brain cells. Diffusion
      through ECS may be described through an effective diffusion coefficient, D (e),
      which in turn depends on ECS porosity, epsilon, and tortuosity, T. In the present
      research, diffusion data together with epsilon and T were collected from the
      specialized literature and analysed to seek a correlation of T versus epsilon. On
      the basis of D (e) data, upper and lower T boundaries were defined and related to
      topologically 'dense' and 'loose' cell arrangement. A possible range for T
      variation was obtained for ECS, with epsilon ranging from 0.05 to 0.6. A
      tortuosity index ( n ) in the form of T and epsilon logarithmic ratio was
      introduced. This index may be adopted for recalculation of T or epsilon if only
      one of these parameters is known. As a result of data analysis and modelling, it
      was concluded that, upon different external conditions, for instance oxygen
      depletion, the ECS porosity decreases and cells (presumably through membrane
      rearrangements) adjust the void space to keep the diffusion within a defined
      range, which gives the living tissue the ability to maintain the diffusion level
      up to two or more times higher than in conventional granular bed packing. Thus,
      even with a dramatic ECS decrease, the cellular system is still able to support a
      given diffusion by decreasing the value of T. The obtained results clearly show
      the existence of three data clusters: a region of normal brain functioning, both
      for young and adult brains, for values of epsilon comprised between 0.15 and
      0.30, and two regions of abnormal brain behaviour to the left and to the right of
      the normal region, corresponding to different states (aging, tumours, anoxia,
      brain death, etc.). The present approach allows defining the optimal range of
      epsilon and T to assure the best ECS diffusion efficiency for a specified
      macromolecule. This might be important in brain clinical treatment.

PMID- 15032744
TI  - Preparation of a highly stable, very active and high-yield multilayered assembly
      of glucose oxidase using carbohydrate-specific polyclonal antibodies.
AB  - The purified oligosaccharide chains of Aspergillus niger glucose oxidase were
      coupled to BSA with the help of the cross-linking reagent glutaraldehyde. The
      neoglycoconjugate thus obtained was purified by concanavalin A-Sepharose
      chromatography and characterized by SDS/PAGE. Immunization of rabbits with the
      neoglycoprotein raised the glycosyl-specific anti-(glucose oxidase) polyclonal
      antibodies. Antibodies were purified by (NH(4))(2)SO(4) precipitation, followed
      by DEAE-cellulose chromatography. The IgG-Sepharose was prepared by covalently
      coupling the purified polyclonal antibodies to the CNBr-activated Sepharose 4B.
      The large assembly of glucose oxidase was made on the IgG-Sepharose by alternate
      incubation of glucose oxidase and glycosyl-specific anti-(glucose oxidase)
      polyclonal IgG. The immunoaffinity-layered assembled preparations were highly
      active and, after six alternate binding cycles with enzyme and glycosyl-specific
      IgG, the amount of enzyme immobilized could be raised 30-fold. The K (m) value of
      immunoaffinity-layered glucose oxidase preparations remained unaltered, while the
      V (max) slightly decreased as compared with the soluble enzyme. A layer-by-layer
      immobilization of glucose oxidase resulted in significant improvement in
      stability against high temperature, 4.0 M urea and very high concentrations of
      water-miscible organic solvents such as acetone, dimethylformamide, dioxan and
      tetrahydrofuran.

PMID- 15032745
TI  - Separation of immunoglobulin G precipitate from contaminating proteins using
      microfiltration.
AB  - A small-scale stirred-cell device was used to separate an antivenom antibody
      precipitate from a suspension containing contaminating soluble proteins. The
      device has a total volume of 200 ml and is equipped with a filter membrane with a
      cut-off size of 3 microm. About 90% of the antibody-precipitate particles in the
      feed were 29 microm or smaller, and the concentration of solids was 12% (w/w).
      The microfiltration cell was operated in a constant-volume
      (continuous/diafiltration) mode, and its performance was compared with an
      industrial disc-stack centrifuge currently used in the manufacture of antibody
      precipitate. In terms of product purity, the separation performance of the
      microfiltration operation was found to be comparable with the disc-stack
      centrifuge, whereas the overall yield was 10% better than that obtained from the
      centrifuge. This was attributed to the ability of microfiltration to reduce
      material losses by integrating a number of operations in a single piece of
      equipment. These included separation, concentration and buffer exchange, as well
      as dissolution and final recovery of the antibody in an appropriate buffer. The
      results obtained from the stirred cell are potentially scaleable, and dynamic
      microfiltration is shown to be an attractive process option.

PMID- 15032746
TI  - Immunization with a DNA vaccine encoding the hepatitis-C-virus structural
      antigens elicits a specific immune response against the capsid and envelope
      proteins in rabbits and Macaca irus (crab-eating macaque monkeys).
AB  - In the present study, we evaluated the capability of the plasmid pIDKE2, encoding
      the HCV (hepatitis C virus) structural proteins Core, E1 and E2, to induce immune
      response against HCV antigens after injection into rabbits and Macaca irus (crab
      eating macaque). Animals were immunized intramuscularly with different amounts of
      plasmid on weeks 0, 3 and 8. Monkeys received a booster dose on week 46. All
      rabbits immunized with pIDKE2 generated a positive antibody response and,
      particularly in rabbits immunized with 2 mg, antibody titres reached values above
      1:1500 and 1:400 against the core and the envelope proteins, respectively, 28
      weeks after primary immunization. The antibody response in monkeys developed
      slowly, but antibody titres greater than 1:3500 against HCV structural antigens
      were detected at week 52. Moreover, anti-E2 antibodies recognized synthetic
      peptides covering the HVR-1 (hypervariable region-1) from different isolates
      corresponding to different genotypes. Additionally, a specific
      lymphoproliferative response against Core and E2 was detected in two out of three
      monkeys immunized with pIDKE2. The other monkey had a specific proliferative
      response to E1. Taking all these data together, immunization with pIDKE2 is able
      to elicit both humoral and cellular immunity against HCV structural antigens in
      animal models other than mice.

PMID- 15032747
TI  - Conformational stability and domain coupling in D-glucose/D-galactose-binding
      protein from Escherichia coli.
AB  - The monomeric D-glucose/D-galactose-binding protein (GGBP) from Escherichia coli
      (M(r) 33000) is a periplasmic protein that serves as a high-affinity receptor for
      the active transport and chemotaxis towards both sugars. The effect of D-glucose
      binding on the thermal unfolding of the GGBP protein at pH 7.0 has been measured
      by differential scanning calorimetry (DSC), far-UV CD and intrinsic tryptophanyl
      residue fluorescence (Trp fluorescence). All three techniques reveal reversible,
      thermal transitions and a midpoint temperature (T(m)) increase from 50 to 63
      degrees C produced by 10 mM D-glucose. Both in the absence and presence of D
      glucose a single asymmetric endotherm for GGBP is observed in DSC, although each
      endotherm consists of two transitions about 4 degrees C apart in T(m) values. In
      the absence of D-glucose, the protein unfolding is best described by two non
      ideal transitions, suggesting the presence of unfolding intermediates. In the
      presence of D-glucose protein, unfolding is more co-operative than in the absence
      of the ligand, and the experimental data are best fitted to a model that assumes
      two ideal (two-state) sequential transitions. Thus D-glucose binding changes the
      character of the GGBP protein folding/unfolding by linking the two domains such
      that protein unfolding becomes a cooperative, two two-state process. A K(A)'
      value of 5.6x10(6) M(-1) at 63 degrees C for D-glucose binding is estimated from
      DSC results. The domain with the lower stability in DSC measurements has been
      identified as the C-terminal domain of GGBP from thermally induced Trp
      fluorescence changes.

PMID- 15032748
TI  - Molecular evolution and structure-function relationships of crotoxin-like and
      asparagine-6-containing phospholipases A2 in pit viper venoms.
AB  - Some myotoxic or neurotoxic PLA2s (phospholipases A2) from pit viper venoms
      contain characteristic N6 substitutions. Our survey of the venoms of more than
      ten pit viper genera revealed that N6-PLA2s exist only in limited Asian pit
      vipers of two genera, Protobothrops and Gloydius, and exist as either monomers or
      the basic subunits of heterodimers in some New World pit vipers. For the newly
      identified N6-PLA2s, the neuromuscular blocking activities were assayed with the
      chick biventer cervicis neuromuscular tissue, whereas the increased serum
      creatine kinase level assessed their myotoxicities. The purified N6-PLA2s from
      Protobothrops mangshanensis and Gloydius intermedius saxatilis were found to be
      presynaptic neurotoxins. In contrast, all N6-PLA2s from the venoms of Sistrurus
      miliarius strackeri, S. m. barbouri, Crotalus viridis viridis, C. lepidus
      lepidus, Cerrophidion godmani and Bothreichis schlegelii were myotoxins without
      neurotoxicity even in the presence of crotoxin A. Crotoxin-like complexes were
      for the first time purified from the venoms of Sitrurus catenatus tergeminus, C.
      mitchelli mitchelli, C. horridus atricaudatus, C. basiliscus and C. durissus
      cumanensis. The cDNAs encoding six novel N6-PLA2s and subunits of the crotoxin
      like complex from S. c. tergeminus were cloned and fully sequenced. Phylogeny
      analysis showed that two structural subtypes of N6-PLA2s with either F24 or S24
      substitution have been evolved in parallel, possibly descended respectively from
      species related to present-day Protobothrops and Gloydius. Calmodulin binds all
      the N6-PLA2s but crotoxin A may inhibit its binding to crotoxin B and to other
      neurotoxic N6-PLA2s. Structure-activity relationships at various regions of the
      PLA2 molecules were extensively discussed.

PMID- 15032749
TI  - Effects of the antimicrobial peptide temporin L on cell morphology, membrane
      permeability and viability of Escherichia coli.
AB  - Antimicrobial peptides are produced by all organisms in response to microbial
      invasion and are considered as promising candidates for future antibiotics. There
      is a wealth of evidence that many of them interact and increase the permeability
      of bacterial membranes as part of their killing mechanism. However, it is not
      clear whether this is the lethal step. To address this issue, we studied the
      interaction of the antimicrobial peptide temporin L with Escherichia coli by
      using fluorescence, confocal and electron microscopy. The peptide previously
      isolated from skin secretions of the frog Rana temporaria has the sequence
      FVQWFSKFLGRIL-NH2. With regard to fluorescence microscopy, we applied, for the
      first time, a triple-staining method based on the fluorochromes 5-cyano-2,3
      ditolyl tetrazolium chloride, 4',6-diamidino-2-phenylindole and FITC. This
      technique enabled us to identify, in the same sample, both living and total
      cells, as well as bacteria with altered membrane permeability. These results
      reveal that temporin L increases the permeability of the bacterial inner membrane
      in a dose-dependent manner without destroying the cell's integrity. At low
      peptide concentrations, the inner membrane becomes permeable to small molecules
      but does not allow the killing of bacteria. However, at high peptide
      concentrations, larger molecules, but not DNA, leak out, which results in cell
      death. Very interestingly, in contrast with many antimicrobial peptides, temporin
      L does not lyse E. coli cells but rather forms ghost-like bacteria, as observed
      by scanning and transmission electron microscopy. Besides shedding light on the
      mode of action of temporin L and possibly that of other antimicrobial peptides,
      the present study demonstrates the advantage of using the triple-fluorescence
      approach combined with microscopical techniques to explore the mechanism of
      membrane-active peptides in general.

PMID- 15032752
TI  - Characterization of the ATP-hydrolysing activity of alpha-sarcoglycan.
AB  - Alpha-Sarcoglycan is a glycoprotein associated with the dystrophin complex at
      sarcolemma of skeletal and cardiac muscles. Gene defects in alpha-sarcoglycan
      lead to a severe muscular dystrophy whose molecular mechanisms are not yet clear.
      A first insight into the function of alpha-sarcoglycan was obtained by finding
      that it is an ATP-binding protein and that it probably confers ability to
      hydrolyse ATP to the purified dystrophin complex [Betto, Senter, Ceoldo,
      Tarricone, Biral and Salviati (1999) J. Biol. Chem. 274, 7907-7912]. In the
      present study, we present definitive evidence showing that alpha-sarcoglycan is
      an ATP-hydrolysing enzyme. The appearance of alpha-sarcoglycan protein expression
      was correlated with the increase in ecto-nucleotidase activity during
      differentiation of C2C12 cells. Approx. 25% of ecto-nucleotidase activity
      displayed by the C2C12 myotubes was inhibited by preincubating cells with an
      antibody specific for the ATP-binding motif of alpha-sarcoglycan. This
      demonstrates that alpha-sarcoglycan substantially contributes to total ecto
      nucleotidase activity of C2C12 myotubes. To characterize further this activity,
      human embryonic kidney 293 cells were transfected with expression plasmids
      containing alpha-sarcoglycan cDNA. Transfected cells exhibited a significant
      increase in the ATP-hydrolysing activity that was abolished by the anti-alpha
      sarcoglycan antibody. The enzyme had a substrate specificity for ATP and ADP, did
      not hydrolyse other triphosphonucleosides, and the affinity for ATP was in the
      low mM range. The ATPase activity strictly required the presence of both Mg2+ and
      Ca2+ and was completely inhibited by suramin and reactive blue-2. These results
      show that alpha-sarcoglycan is a Ca2+, Mg2+-ecto-ATPDase. The possible
      consequences of the absence of alpha-sarcoglycan activity in the pathogenesis of
      muscular dystrophy are discussed.

PMID- 15032751
TI  - Dynamic profiling of the glucose metabolic network in fasted rat hepatocytes
      using [1,2-13C2]glucose.
AB  - Recent studies in metabolic profiling have underscored the importance of the
      concept of a metabolic network of pathways with special functional
      characteristics that differ from those of simple reaction sequences. The
      characterization of metabolic functions requires the simultaneous measurement of
      substrate fluxes of interconnecting pathways. Here we present a novel stable
      isotope method by which the forward and reverse fluxes of the futile cycles of
      the hepatic glucose metabolic network are simultaneously determined. Unlike
      previous radio-isotope methods, a single tracer [1,2-13C2]D-glucose and mass
      isotopomer analysis is used. Changes in fluxes of substrate cycles, in response
      to several gluconeogenic substrates, in isolated fasted hepatocytes from male
      Wistar rats were measured simultaneously. Incubation with these substrates
      resulted in a change in glucose-6-phosphatase/glucokinase and
      glycolytic/gluconeogenic flux ratios. Different net redistributions of
      intermediates in the glucose network were observed, resulting in distinct
      metabolic phenotypes of the fasted hepatocytes in response to each substrate
      condition. Our experimental observations show that the constraints of
      concentrations of shared intermediates, and enzyme kinetics of intersecting
      pathways of the metabolic network determine substrate redistribution throughout
      the network when it is perturbed. These results support the systems-biology
      notion that network analysis provides an integrated view of the physiological
      state. Interaction between metabolic intermediates and glycolytic/gluconeogenic
      pathways is a basic element of cross-talk in hepatocytes, and may explain some of
      the difficulties in genotype and phenotype correlation.

PMID- 15032750
TI  - Acyl-CoA-binding protein, Acb1p, is required for normal vacuole function and
      ceramide synthesis in Saccharomyces cerevisiae.
AB  - In the present study, we show that depletion of acyl-CoA-binding protein, Acb1p,
      in yeast affects ceramide levels, protein trafficking, vacuole fusion and
      structure. Vacuoles in Acb1p-depleted cells are multi-lobed, contain
      significantly less of the SNAREs (soluble N -ethylmaleimide-sensitive fusion
      protein attachment protein receptors) Nyv1p, Vam3p and Vti1p, and are unable to
      fuse in vitro. Mass spectrometric analysis revealed a dramatic reduction in the
      content of ceramides in whole-cell lipids and in vacuoles isolated from Acb1p
      depleted cells. Maturation of yeast aminopeptidase I and carboxypeptidase Y is
      slightly delayed in Acb1p-depleted cells, whereas the maturation of alkaline
      phosphatase and Gas1p is unaffected. The fact that Gas1p maturation is unaffected
      by Acb1p depletion, despite the lowered ceramide content in these cells,
      indicates that ceramide synthesis in yeast could be compartmentalized. We suggest
      that the reduced ceramide synthesis in Acb1p-depleted cells leads to severely
      altered vacuole morphology, perturbed vacuole assembly and strong inhibition of
      homotypic vacuole fusion.

PMID- 15032755
TI  - Sociology and political arithmetic: some principles of a new policy science.
AB  - This paper advances the position that sociology needs to develop an approach to
      research which focuses on fundamental social problems. In doing so it shares many
      of the intellectual values and goals of political arithmetic while seeking to
      move methodologically beyond it. Since such problems are complex they will
      require, typically, interdisciplinary input and a concomitant approach to the
      development and appraisal of theories. We are not, therefore, advocating the
      primacy of sociology but arguing that it has a distinctive part to play in
      addressing the fundamental problems of the twenty-first century. However, a
      policy-oriented sociology has also to take up the task, so clearly defined by the
      tradition of political arithmetic, which is to hold governments to account.
      Consequently a central principle of a new policy science is that it should
      contribute to democratic debate about policy.

PMID- 15032756
TI  - Making social science useful.

PMID- 15032753
TI  - Biochemical analysis of the processive mechanism for epimerization of alginate by
      mannuronan C-5 epimerase AlgE4.
AB  - The enzymes mannuronan C-5 epimerases catalyse the in-chain epimerisation of beta
      D-mannuronic acid to alpha-L-guluronic acid in the last step of alginate
      biosynthesis. The recombinant C-5 epimerase AlgE4, encoded by the soil bacteria
      Azotobacter vinelandii and expressed in Escherichia coli, exhibits a non-random
      mode of action when acting on mannuronan and alginates of various monomeric
      compositions. The observed residue sequence has been suggested previously to be
      due to either a preferred attack or a processive mode of action. Based on
      methodologies involving specific degrading enzymes, NMR, electrospray ionisation
      mass spectrometry and capillary electrophoresis we show here that on average 10
      residues are epimerised for each enzyme-substrate encounter. A subsite model for
      the enzyme is analysed by the same methodology using native and 13C-labelled
      mannuronan oligomers as substrate for the AlgE4 epimerase. A hexameric oligomer
      is the minimum size to accommodate activity. For hexa-, hepta- and octameric
      substrates the third M residue from the non-reducing end is epimerised first.

PMID- 15032757
TI  - Policy and sociology.

PMID- 15032758
TI  - Talking about money: public participation and expert knowledge in the Euro
      referendum.
AB  - This paper uses the proposed UK referendum on the single European currency as a
      means of investigating the effect of democratizing science on the scrutiny of
      conflicting expert advice. Although the referendum has not happened yet, and may
      not happen at all, the campaigners for and against the Euro have none the less
      been working for several years to ensure that if, and when, it does happen they
      are in a position to win it. By exploring how campaigners on both sides of the
      debate understand the concerns of voters, the paper shows how they are working
      towards a referendum in which the political dimensions of the Euro are actively
      minimized in order to avoid alienating key 'floating voters'. Instead, the
      campaign is expected to focus on the economic costs and benefits of the Euro for
      individuals and households, with only limited discussion of issues relating to
      sovereignty. Whether or not the campaign groups, particularly those that oppose
      the Euro, can maintain this line remains to be seen but if there is a full and
      frank public debate about the economic, social and political stakes, then this
      will be despite the referendum rather than because of it.

PMID- 15032759
TI  - Social influences on corporate political donations in Britain.
AB  - It is argued that institutional features of the British state create collective
      action problems for the mobilization of corporations as donors to the
      Conservative Party. Social factors are necessary for overcoming these problems.
      Using social network analyses, the effect that interlocking directorates have on
      250 large British corporations' decisions to donate are analysed. Instead of the
      central mobilizing factor being diffuse inner circle mechanisms positively
      influencing the decision to make a donation, the results show that more
      particularistic mechanisms such as information bias and control are equally
      important.

PMID- 15032760
TI  - The sociology of subjectivity, and the subjectivity of sociologists: a critique
      of the sociology of gender in the Australian family.
AB  - In this era of reflexive sociology it is commonplace that subjectivity is of
      great sociological concern, and that the comprehension by social researchers of
      their own subject position is essential. Still, old habits die hard. Focusing on
      selected texts in the sociology of the Australian family, this paper traces the
      effects of failing to focus the sociological gaze on subjectivity and its
      variation across society. Highlighted are some patterns of analytic
      misconstruction of subjectivity, especially the substitution of measurement for a
      theory of practice, and the projection by sociologists of their own class
      specific subjectivity onto society at large. Ultimately, this misconstruction
      turns works like those discussed in this paper into a powerful denial of
      alternative subjectivities, and a reinforcement of the socially dominant
      perspective.

PMID- 15032761
TI  - Working part-time: achieving a successful 'work-life' balance?
AB  - The role of part-time employment in the balancing of women's employment and
      family lives has generated an immense literature. Using data on women working
      part-time and full-time in different level occupations in the British Household
      Panel Survey, this paper argues that it is now vital to move these balancing
      debates on from their location within work-family rhetoric and to re-position the
      study of women's working time in broader work-life discussions. Work-family
      debates tend to neglect a number of key domains that women balance in their
      lives, in addition to family and employment, including their financial security
      and their leisure. The paper shows that examining the financial situations and
      the leisure lives of female part-timers in lower level jobs reveals a less
      positive picture of their 'life balancing' than is portrayed in much work-family
      literature. Instead, they emerged as the least financially secure employees and,
      linked to this, less satisfied with their social lives too. It is concluded that
      since the work-life system is multi- and not just two-dimensional, it is
      important to examine how all life domains interrelate with each other. In this
      way, we would be in a better position to begin to assess all the benefits and
      disadvantages associated with working part-time and with other work-life
      balancing strategies.

PMID- 15032767
TI  - Conditional estimation for generalized linear models when covariates are subject
      specific parameters in a mixed model for longitudinal measurements.
AB  - The relationship between a primary endpoint and features of longitudinal profiles
      of a continuous response is often of interest, and a relevant framework is that
      of a generalized linear model with covariates that are subject-specific random
      effects in a linear mixed model for the longitudinal measurements. Naive
      implementation by imputing subject-specific effects from individual regression
      fits yields biased inference, and several methods for reducing this bias have
      been proposed. These require a parametric (normality) assumption on the random
      effects, which may be unrealistic. Adapting a strategy of Stefanski and Carroll
      (1987, Biometrika74, 703-716), we propose estimators for the generalized linear
      model parameters that require no assumptions on the random effects and yield
      consistent inference regardless of the true distribution. The methods are
      illustrated via simulation and by application to a study of bone mineral density
      in women transitioning to menopause.

PMID- 15032768
TI  - Generalized linear mixed models with varying coefficients for longitudinal data.
AB  - The routinely assumed parametric functional form in the linear predictor of a
      generalized linear mixed model for longitudinal data may be too restrictive to
      represent true underlying covariate effects. We relax this assumption by
      representing these covariate effects by smooth but otherwise arbitrary functions
      of time, with random effects used to model the correlation induced by among
      subject and within-subject variation. Due to the usually intractable integration
      involved in evaluating the quasi-likelihood function, the double penalized quasi
      likelihood (DPQL) approach of Lin and Zhang (1999, Journal of the Royal
      Statistical Society, Series B61, 381-400) is used to estimate the varying
      coefficients and the variance components simultaneously by representing a
      nonparametric function by a linear combination of fixed effects and random
      effects. A scaled chi-squared test based on the mixed model representation of the
      proposed model is developed to test whether an underlying varying coefficient is
      a polynomial of certain degree. We evaluate the performance of the procedures
      through simulation studies and illustrate their application with Indonesian
      children infectious disease data.

PMID- 15032769
TI  - Multivariate multilevel nonlinear mixed effects models for timber yield
      predictions.
AB  - Nonlinear mixed effects models have become important tools for growth and yield
      modeling in forestry. To date, applications have concentrated on modeling single
      growth variables such as tree height or bole volume. Here, we propose
      multivariate multilevel nonlinear mixed effects models for describing several
      plot-level timber quantity characteristics simultaneously. We describe how such
      models can be used to produce future predictions of timber volume (yield). The
      class of models and methods of estimation and prediction are developed and then
      illustrated on data from a University of Georgia study of the effects of various
      site preparation methods on the growth of slash pine (Pinus elliottii Engelm.).

PMID- 15032770
TI  - Bayesian experimental design for nonlinear mixed-effects models with application
      to HIV dynamics.
AB  - Bayesian experimental design is investigated for Bayesian analysis of nonlinear
      mixed-effects models. Existence of the posterior risk for parameter estimation is
      shown. When the same prior distribution is used for both design and inference,
      existence of the preposterior risk for design is also proven. If the prior
      distribution used in design is different from that used for inference, sufficient
      conditions are established for existence of the preposterior risk for design. A
      case study of design for an experiment in population HIV dynamics is provided.

PMID- 15032771
TI  - A Bayesian approach for the analysis of panel-count data with dependent
      termination.
AB  - We consider modeling and Bayesian analysis for panel-count data when the
      termination time for each subject may depend on its history of the recurrent
      events. We propose a fully specified semiparametric model for the joint
      distribution of the recurrent events and the termination time. For this model, we
      provide a natural motivation, derive several novel properties, and develop a
      Bayesian analysis based on a Markov chain Monte Carlo algorithm. Comparisons are
      made to other existing models and methods for panel-count data. We demonstrate
      the usefulness of our new models and methodologies through the reanalysis of a
      data set from a clinical trial.

PMID- 15032772
TI  - Bayesian semiparametric modeling for matched case-control studies with multiple
      disease states.
AB  - We present a Bayesian approach to analyze matched "case-control" data with
      multiple disease states. The probability of disease development is described by a
      multinomial logistic regression model. The exposure distribution depends on the
      disease state and could vary across strata. In such a model, the number of
      stratum effect parameters grows in direct proportion to the sample size leading
      to inconsistent MLEs for the parameters of interest even when one uses a
      retrospective conditional likelihood. We adopt a semiparametric Bayesian
      framework instead, assuming a Dirichlet process prior with a mixing normal
      distribution on the distribution of the stratum effects. We also account for
      possible missingness in the exposure variable in our model. The actual estimation
      is carried out through a Markov chain Monte Carlo numerical integration scheme.
      The proposed methodology is illustrated through simulation and an example of a
      matched study on low birth weight of newborns (Hosmer, D. A. and Lemeshow, S.,
      2000, Applied Logistic Regression) with two possible disease groups matched with
      a control group.

PMID- 15032773
TI  - Hierarchical Bayesian modeling in dichotomous processes in the presence of
      nonresponse.
AB  - Sampling units that do not answer a survey may dramatically affect the estimation
      results of interest. The response may even be conditional on the outcome of
      interest in the survey. If estimates are found using only those who responded,
      the estimate may be biased, known as nonresponse bias. We are interested in
      finding estimates of success rates from a survey. We begin by looking at two
      current Bayesian approaches to treating nonresponse in a hierarchical model.
      However, these approaches do not consider possible spatial correlations between
      domains for either success rate or response rate. We build a Bayesian
      hierarchical spatial model to explicitly estimate the success rate, response rate
      given success, and response rate given failure. The success rates in the domains
      of the survey are allowed to be spatially correlated. We also allow spatial
      dependence between domains in both response rate given success and response rate
      given failure. Spatial dependence is induced by a common latent spatial structure
      between the two conditional response rates. We use the 1998 Missouri Turkey
      Hunting Survey to illustrate this methodology. We find significant spatial
      correlation in the success rates and incorporating nonrespondents has an impact
      on the success rate estimates.

PMID- 15032774
TI  - Bayesian point estimation of quantitative trait loci.
AB  - In this article, we consider the problem of the estimation of quantitative trait
      loci (QTL), those chromosomal regions at which genetic information affecting some
      quantitative trait is encoded. Generally the number of such encoding sites is
      unknown, and associations between neutral molecular marker genotypes and observed
      trait phenotypes are sought to locate them. We consider a Bayesian model for
      simple experimental designs, and discuss the existing approaches to inference for
      this problem. In particular, we focus on locating positions of the best candidate
      markers segregating for the trait, a situation which is of primary interest in
      comparative mapping. We introduce a loss function for estimating both the number
      of QTL and their location, and we illustrate its application via simulated and
      real data.

PMID- 15032775
TI  - Properties of the multiallelic trend test.
AB  - Disease genes can be mapped on the basis of associations between genetic markers
      and disease status, with the case-control design having the advantage of not
      requiring individuals from different generations. When the marker loci have
      multiple alleles, there has been debate on whether the power of tests for
      association increases or decreases. We show here that the multiple-allele version
      of Armitage's trend test has increased power over the two-allele version under
      the requirement of equifrequent alleles, but not in general. The trend test has
      the advantage of remaining valid even when the sampled population is not in Hardy
      Weinberg equilibrium. A departure from Hardy-Weinberg means that association
      tests depend on gametic and nongametic linkage disequilibrium between marker and
      disease loci, and we illustrate the magnitude of these effects with simulated
      data.

PMID- 15032776
TI  - Functional form diagnostics for Cox's proportional hazards model.
AB  - We propose a new type of residual and an easily computed functional form test for
      the Cox proportional hazards model. The proposed test is a modification of the
      omnibus test for testing the overall fit of a parametric regression model,
      developed by Stute, Gonzalez Manteiga, and Presedo Quindimil (1998, Journal of
      the American Statistical Association93, 141-149), and is based on what we call
      censoring consistent residuals. In addition, we develop residual plots that can
      be used to identify the correct functional forms of covariates. We compare our
      test with the functional form test of Lin, Wei, and Ying (1993, Biometrika80, 557
      572) in a simulation study. The practical application of the proposed residuals
      and functional form test is illustrated using both a simulated data set and a
      real data set.

PMID- 15032778
TI  - Multivariate survival trees: a maximum likelihood approach based on frailty
      models.
AB  - A method of constructing trees for correlated failure times is put forward. It
      adopts the backfitting idea of classification and regression trees (CART)
      (Breiman et al., 1984, in Classification and Regression Trees). The tree method
      is developed based on the maximized likelihoods associated with the gamma frailty
      model and standard likelihood-related techniques are incorporated. The proposed
      method is assessed through simulations conducted under a variety of model
      configurations and illustrated using the chronic granulomatous disease (CGD)
      study data.

PMID- 15032777
TI  - Joint analysis of time-to-event and multiple binary indicators of latent classes.
AB  - Multiple categorical variables are commonly used in medical and epidemiological
      research to measure specific aspects of human health and functioning. To analyze
      such data, models have been developed considering these categorical variables as
      imperfect indicators of an individual's "true" status of health or functioning.
      In this article, the latent class regression model is used to model the
      relationship between covariates, a latent class variable (the unobserved status
      of health or functioning), and the observed indicators (e.g., variables from a
      questionnaire). The Cox model is extended to encompass a latent class variable as
      predictor of time-to-event, while using information about latent class membership
      available from multiple categorical indicators. The expectation-maximization (EM)
      algorithm is employed to obtain maximum likelihood estimates, and standard errors
      are calculated based on the profile likelihood, treating the nonparametric
      baseline hazard as a nuisance parameter. A sampling-based method for model
      checking is proposed. It allows for graphical investigation of the assumption of
      proportional hazards across latent classes. It may also be used for checking
      other model assumptions, such as no additional effect of the observed indicators
      given latent class. The usefulness of the model framework and the proposed
      techniques are illustrated in an analysis of data from the Women's Health and
      Aging Study concerning the effect of severe mobility disability on time-to-death
      for elderly women.

PMID- 15032779
TI  - Loglinear models for the robust design in mark-recapture experiments.
AB  - The robust design is a method for implementing a mark-recapture experiment
      featuring a nested sampling structure. The first level consists of primary
      sampling sessions; the population experiences mortality and immigration between
      primary sessions so that open population models apply at this level. The second
      level of sampling has a short mark-recapture study within each primary session.
      Closed population models are used at this stage to estimate the animal abundance
      at each primary session. This article suggests a loglinear technique to fit the
      robust design. Loglinear models for the analysis of mark-recapture data from
      closed and open populations are first reviewed. These two types of models are
      then combined to analyze the data from a robust design. The proposed loglinear
      approach to the robust design allows incorporating parameters for a heterogeneity
      in the capture probabilities of the units within each primary session. Temporary
      emigration out of the study area can also be accounted for in the loglinear
      framework. The analysis is relatively simple; it relies on a large Poisson
      regression with the vector of frequencies of the capture histories as dependent
      variable. An example concerned with the estimation of abundance and survival of
      the red-back vole in an area of southeastern Quebec is presented.

PMID- 15032780
TI  - N-mixture models for estimating population size from spatially replicated counts.
AB  - Spatial replication is a common theme in count surveys of animals. Such surveys
      often generate sparse count data from which it is difficult to estimate
      population size while formally accounting for detection probability. In this
      article, I describe a class of models (N-mixture models) which allow for
      estimation of population size from such data. The key idea is to view site
      specific population sizes, N, as independent random variables distributed
      according to some mixing distribution (e.g., Poisson). Prior parameters are
      estimated from the marginal likelihood of the data, having integrated over the
      prior distribution for N. Carroll and Lombard (1985, Journal of American
      Statistical Association 80, 423-426) proposed a class of estimators based on
      mixing over a prior distribution for detection probability. Their estimator can
      be applied in limited settings, but is sensitive to prior parameter values that
      are fixed a priori. Spatial replication provides additional information regarding
      the parameters of the prior distribution on N that is exploited by the N-mixture
      models and which leads to reasonable estimates of abundance from sparse data. A
      simulation study demonstrates superior operating characteristics (bias,
      confidence interval coverage) of the N-mixture estimator compared to the Caroll
      and Lombard estimator. Both estimators are applied to point count data on six
      species of birds illustrating the sensitivity to choice of prior on p and
      substantially different estimates of abundance as a consequence.

PMID- 15032781
TI  - Estimation of fish abundance indices based on scientific research trawl surveys.
AB  - The fish abundance index over an ocean region is defined here to be the integral
      of expected catch per unit effort (CPUE), approximated by the sum of expected
      CPUE over grid squares. When trawl surveys are done within grid squares selected
      according to a probability sampling design, several other sources of variation
      such as the fish population dynamics and the catching process are also involved.
      In such situations model-assisted methods for estimating abundance, assessed
      under both design and model perspectives, have some advantages over purely design
      based methods such as the Horvitz-Thompson (HT) estimator or purely model-based
      prediction approaches. This article develops model-assisted empirical likelihood
      (EL) methods via loglinear regression and nonparametric smoothing. The methods
      are applied to grid surveys of the Grand Bank region carried out annually by
      Fishery Products International from 1996 through 2002. The HT and EL methods
      produce similar point estimates of abundance indices. Simulation results,
      however, indicate that the EL estimator under local linear smoothing is
      associated with smaller standard errors.

PMID- 15032782
TI  - Optimal estimator for the survival distribution and related quantities for
      treatment policies in two-stage randomization designs in clinical trials.
AB  - Two-stage designs, where patients are initially randomized to an induction
      therapy and then depending upon their response and consent, are randomized to a
      maintenance therapy, are common in cancer and other clinical trials. The goal is
      to compare different combinations of primary and maintenance therapies to find
      the combination that is most beneficial. In practice, the analysis is usually
      conducted in two separate stages which does not directly address the major
      objective of finding the best combination. Recently Lunceford, Davidian, and
      Tsiatis (2002, Biometrics58, 48-57) introduced ad hoc estimators for the survival
      distribution and mean restricted survival time under different treatment
      policies. These estimators are consistent but not efficient, and do not include
      information from auxiliary covariates. In this article we derive estimators that
      are easy to compute and are more efficient than previous estimators. We also show
      how to improve efficiency further by taking into account additional information
      from auxiliary variables. Large sample properties of these estimators are derived
      and comparisons with other estimators are made using simulation. We apply our
      estimators to a leukemia clinical trial data set that motivated this study.

PMID- 15032783
TI  - Design and analysis of group sequential clinical trials with multiple primary
      endpoints.
AB  - In many phase III clinical trials, it is desirable to separately assess the
      treatment effect on two or more primary endpoints. Consider the MERIT-HF study,
      where two endpoints of primary interest were time to death and the earliest of
      time to first hospitalization or death (The International Steering Committee on
      Behalf of the MERIT-HF Study Group, 1997, American Journal of Cardiology 80[9B],
      54J-58J). It is possible that treatment has no effect on death but a beneficial
      effect on first hospitalization time, or it has a detrimental effect on death but
      no effect on hospitalization. A good clinical trial design should permit early
      stopping as soon as the treatment effect on both endpoints becomes clear.
      Previous work in this area has not resolved how to stop the study early when one
      or more endpoints have no treatment effect or how to assess and control the many
      possible error rates for concluding wrong hypotheses. In this article, we develop
      a general methodology for group sequential clinical trials with multiple primary
      endpoints. This method uses a global alpha-spending function to control the
      overall type I error and a multiple decision rule to control error rates for
      concluding wrong alternative hypotheses. The method is demonstrated with two
      simulated examples based on the MERIT-HF study.

PMID- 15032784
TI  - A bound for publication bias based on the fraction of unpublished studies.
AB  - Publication bias in meta-analysis is usually modeled in terms of an accept/reject
      selection procedure in which the selected studies are the "published" studies and
      the rejected studies are the "unpublished" studies. One possible selection
      mechanism is to suppose that only studies that report an estimated treatment
      effect exceeding (or falling short of) some threshold are accepted. We show that,
      with appropriate choice of thresholds, this attains the maximum bias among all
      selection mechanisms in which the probability of selection increases with study
      size. It is impossible to estimate the selection mechanism from the observed
      studies alone: this result leads to a "worst-case" sensitivity analysis for
      publication bias, which is remarkably easy to implement in practice. The method
      is illustrated using data on the effectiveness of prophylactic corticosteroids.

PMID- 15032785
TI  - On the construction of bounds in prospective studies with missing ordinal
      outcomes: application to the good behavior game trial.
AB  - This article is concerned with drawing inference about aspects of the population
      distribution of ordinal outcome data measured on a cohort of individuals on two
      occasions, where some subjects are missing their second measurement. We present
      two complementary approaches for constructing bounds under assumptions on the
      missing data mechanism considered plausible by scientific experts. We develop our
      methodology within the context of a randomized trial of the "Good Behavior Game,"
      an intervention designed to reduce aggressive misbehavior among children.

PMID- 15032786
TI  - Sample size calculations for surveys to substantiate freedom of populations from
      infectious agents.
AB  - We develop a Bayesian approach to sample size computations for surveys designed
      to provide evidence of freedom from a disease or from an infectious agent. A
      population is considered "disease-free" when the prevalence or probability of
      disease is less than some threshold value. Prior distributions are specified for
      diagnostic test sensitivity and specificity and we test the null hypothesis that
      the prevalence is below the threshold. Sample size computations are developed
      using hypergeometric sampling for finite populations and binomial sampling for
      infinite populations. A normal approximation is also developed. Our procedures
      are compared with the frequentist methods of Cameron and Baldock (1998a,
      Preventive Veterinary Medicine34, 1-17.) using an example of foot-and-mouth
      disease. User-friendly programs for sample size calculation and analysis of
      survey data are available at http://www.epi.ucdavis.edu/diagnostictests/.

PMID- 15032787
TI  - A new method for dealing with measurement error in explanatory variables of
      regression models.
AB  - We introduce a new method, moment reconstruction, of correcting for measurement
      error in covariates in regression models. The central idea is similar to
      regression calibration in that the values of the covariates that are measured
      with error are replaced by "adjusted" values. In regression calibration the
      adjusted value is the expectation of the true value conditional on the measured
      value. In moment reconstruction the adjusted value is the variance-preserving
      empirical Bayes estimate of the true value conditional on the outcome variable.
      The adjusted values thereby have the same first two moments and the same
      covariance with the outcome variable as the unobserved "true" covariate values.
      We show that moment reconstruction is equivalent to regression calibration in the
      case of linear regression, but leads to different results for logistic
      regression. For case-control studies with logistic regression and covariates that
      are normally distributed within cases and controls, we show that the resulting
      estimates of the regression coefficients are consistent. In simulations we
      demonstrate that for logistic regression, moment reconstruction carries less bias
      than regression calibration, and for case-control studies is superior in mean
      square error to the standard regression calibration approach. Finally, we give an
      example of the use of moment reconstruction in linear discriminant analysis and a
      nonstandard problem where we wish to adjust a classification tree for measurement
      error in the explanatory variables.

PMID- 15032788
TI  - Semiparametric models for cumulative incidence functions.
AB  - In analyses of time-to-failure data with competing risks, cumulative incidence
      functions may be used to estimate the time-dependent cumulative probability of
      failure due to specific causes. These functions are commonly estimated using
      nonparametric methods, but in cases where events due to the cause of primary
      interest are infrequent relative to other modes of failure, nonparametric methods
      may result in rather imprecise estimates for the corresponding subdistribution.
      In such cases, it may be possible to model the cause-specific hazard of primary
      interest parametrically, while accounting for the other modes of failure using
      nonparametric estimators. The cumulative incidence estimators so obtained are
      simple to compute and are considerably more efficient than the usual
      nonparametric estimator, particularly with regard to interpolation of cumulative
      incidence at early or intermediate time points within the range of data used to
      fit the function. More surprisingly, they are often nearly as efficient as fully
      parametric estimators. We illustrate the utility of this approach in the analysis
      of patients treated for early stage breast cancer.

PMID- 15032789
TI  - An early- and late-stage convolution model for disease natural history.
AB  - The standard convolution model of disease natural history posits an asymptomatic
      (preclinical) and a symptomatic (clinical) state. An augmented model includes, in
      both the preclinical and clinical states, an early and late stage of disease. In
      the case of cancer, the early stage would generally correspond to the organ
      confined stages before there is evidence of cancer spread. We compute the number
      of screen-detected (preclinical) and clinical cases in the early and late stages
      expected under a given screening program and show how the model can be fit to
      data from a screening trial using maximum likelihood. We also develop expressions
      for sojourn time, lead time, and overdiagnosis in the context of the model, where
      each of the above concepts incorporates disease stage. As an example, we fit the
      model to data from the Mayo Lung Cancer Screening trial.

PMID- 15032790
TI  - Partially supervised learning using an EM-boosting algorithm.
AB  - Training data in a supervised learning problem consist of the class label and its
      potential predictors for a set of observations. Constructing effective
      classifiers from training data is the goal of supervised learning. In biomedical
      sciences and other scientific applications, class labels may be subject to
      errors. We consider a setting where there are two classes but observations with
      labels corresponding to one of the classes may in fact be mislabeled. The
      application concerns the use of protein mass-spectrometry data to discriminate
      between serum samples from cancer and noncancer patients. The patients in the
      training set are classified on the basis of tissue biopsy. Although biopsy is
      100% specific in the sense that a tissue that shows itself to have malignant
      cells is certainly cancer, it is less than 100% sensitive. Reference gold
      standards that are subject to this special type of misclassification due to
      imperfect diagnosis certainty arise in many fields. We consider the development
      of a supervised learning algorithm under these conditions and refer to it as
      partially supervised learning. Boosting is a supervised learning algorithm geared
      toward high-dimensional predictor data, such as those generated in protein mass
      spectrometry. We propose a modification of the boosting algorithm for partially
      supervised learning. The proposal is to view the true class membership of the
      samples that are labeled with the error-prone class label as missing data, and
      apply an algorithm related to the EM algorithm for minimization of a loss
      function. To assess the usefulness of the proposed method, we artificially
      mislabeled a subset of samples and applied the original and EM-modified boosting
      (EM-Boost) algorithms for comparison. Notable improvements in misclassification
      rates are observed with EM-Boost.

PMID- 15032791
TI  - Judgement post-stratification with imprecise rankings.
AB  - Judgement post-stratification, which is based on ideas similar to those in ranked
      set sampling, relies on the ability of a ranker to forecast the ranks of
      potential observations on a set of units. In practice, the authors sometimes find
      it difficult to assign these ranks. This note shows how one can borrow techniques
      from the literature on finite population sampling to allow a probabilistic
      ranking of the units in a set, thus facilitating use of these sampling plans and
      improving estimation. The same techniques provide one approach to estimation
      using a judgement post-stratified sample with multiple rankers. The technique is
      illustrated on allometric data relating brain weight to body weight in different
      species of mammals, and on a study of student performance in graduate school.

PMID- 15032792
TI  - Exact analysis of dose response for multiple correlated binary outcomes.
AB  - The neurotoxicity of a substance is often tested using animal bioassays. In the
      functional observational battery, animals are exposed to a test agent and
      multiple outcomes are recorded to assess toxicity, using approximately 40 animals
      measured on up to 30 different items. This design gives rise to a challenging
      statistical problem: a large number of outcomes for a small sample of subjects.
      We propose an exact test for multiple binary outcomes, under the assumption that
      the correlation among these items is equal. This test is based upon an
      exponential model described by Molenberghs and Ryan (1999, Environmetrics 10, 279
      300) and extends the methods developed by Corcoran et al. (2001, Biometrics 57,
      941-948) who developed an exact test for exchangeably correlated binary data for
      groups (clusters) of correlated observations. We present a method that computes
      an exact p-value testing for a joint dose-response relationship. An estimate of
      the parameter for dose response is also determined along with its 95% confidence
      bound. The method is illustrated using data from a neurotoxicity bioassay for the
      chemical perchlorethylene.

PMID- 15032794
TI  - The case-only odds ratio as a causal parameter.
AB  - In the simplest case-only design, cases of a disease are cross-classified into a
      2 x 2 table describing a genotype attribute and exposure to some environmental
      agent. In some instances, the genetic attribute has described inherited genes; in
      other instances, it has described mutations, for instance, damage to proto
      oncogenes or tumor suppressor genes leading to cancer. Here, the population case
      only odds ratio is written as a causal parameter in terms of potential outcomes
      with and without exposure to the agent. It is shown that the case-only odds ratio
      makes sense as a causal parameter with inherited genes, but its magnitude does
      not have a causal interpretation with mutations, although deviations from 1 do
      provide information. The difference is that the environmental agent certainly did
      not cause an individual to inherit particular genes, but it may have caused the
      mutation.

PMID- 15032793
TI  - Testing for common structures in a panel of threshold models.
AB  - We consider the problem of examining the extent of (partial) similarity in the
      dynamics of a panel of independent threshold autoregressive processes. We develop
      some tests for common structure via Wald's approach and by checking whether the
      parameter estimates of the unconstrained threshold models satisfy the constraints
      defining the common structure. One test concerns the equality of independent
      ratios of normal means, which is shown to have nonstandard asymptotic null
      distribution. These tests are illustrated with a modern panel of Canadian lynx
      data; our analysis suggests that the lynx data over Canada share similar dynamics
      in the decrease phase, but they appear to be different in the increase phase.

PMID- 15032795
TI  - Testing for marginal independence between two categorical variables with multiple
      responses.
AB  - Questions that ask respondents to "choose all that apply" from a set of items
      occur frequently in surveys. Categorical variables that summarize this type of
      survey data are called both pick any/c variables and multiple-response
      categorical variables. It is often of interest to test for independence between
      two categorical variables. When both categorical variables can have multiple
      responses, traditional Pearson chi-square tests for independence should not be
      used because of the within-subject dependence among responses. An intuitively
      constructed version of the Pearson statistic is proposed to perform the test
      using bootstrap procedures to approximate its sampling distribution. First- and
      second-order adjustments to the proposed statistic are given in order to use a
      chi-square distribution approximation. A Bonferroni adjustment is proposed to
      perform the test when the joint set of responses for individual subjects is
      unavailable. Simulations show that the bootstrap procedures hold the correct size
      more consistently than the other procedures.

PMID- 15032796
TI  - A model to estimate risk of infection with human herpesvirus 8 associated with
      transfusion from cross-sectional data.
AB  - In cross-sectional studies of infectious diseases, the data typically consist of:
      age at the time of study, status (presence or absence) of infection, and a
      chronology of events possibly associated with the disease. Motivated by a study
      of how human herpesvirus 8 (HHV-8) is transmitted among children with sickle cell
      anemia in Uganda, we have developed a flexible parametric approach for combining
      current-status data with a history of blood transfusions. We model heterogeneity
      in transfusion-associated risk by a child-specific random effect. We present an
      extension of the model to accommodate the fact that there is no gold standard for
      HHV-8 infection and infection status was assessed by a serological assay. The
      parameters are estimated via maximum likelihood. Finally, we present results from
      applying various parameterizations of the model to the Ugandan study.

PMID- 15032797
TI  - Analyzing excessive no changes in clinical trials with clustered data.
AB  - This article considers clinical trials in which the efficacy measure is taken
      from several sites within each patient, such as the alveolar bone height of the
      tooth sites, or bone mineral densities of the lumbar spine sites. Since usually
      only a small portion of these sites will exhibit changes, the conventional method
      using per patient average gives a diluted result due to excessive no changes in
      the data. Different methods have been proposed for this type of data in the case
      where the observations are mutually independent. This includes the popular "two
      part model" (Lachenbruch, 2001, Statistics in Medicine 20, 1215-1234; 2002,
      Statistical Methods in Medical Research 11, 297-302), which is related to the
      "composite approach" for discrete and continuous data in Shih and Quan (1997,
      Statistics in Medicine16, 1225-1239; 2001, Statistica Sinica 11, 53-62). In this
      article, we model the data with excessive zeros (no changes) in clustered data
      using a mixture of distributions, and taking into account possible measurement
      errors. This mixture model includes the two-part model as a special case when one
      component of the mixture degenerates.

PMID- 15032798
TI  - Parametric spatial cure rate models for interval-censored time-to-relapse data.
AB  - Several recent papers (e.g., Chen, Ibrahim, and Sinha, 1999, Journal of the
      American Statistical Association 94, 909-919; Ibrahim, Chen, and Sinha, 2001a,
      Biometrics 57, 383-388) have described statistical methods for use with time-to
      event data featuring a surviving fraction (i.e., a proportion of the population
      that never experiences the event). Such cure rate models and their multivariate
      generalizations are quite useful in studies of multiple diseases to which an
      individual may never succumb, or from which an individual may reasonably be
      expected to recover following treatment (e.g., various types of cancer). In this
      article we extend these models to allow for spatial correlation (estimable via
      zip code identifiers for the subjects) as well as interval censoring. Our
      approach is Bayesian, where posterior summaries are obtained via a hybrid Markov
      chain Monte Carlo algorithm. We compare across a broad collection of rather high
      dimensional hierarchical models using the deviance information criterion, a tool
      recently developed for just this purpose. We apply our approach to the analysis
      of a smoking cessation study where the subjects reside in 53 southeastern
      Minnesota zip codes. In addition to the usual posterior estimates, our approach
      yields smoothed zip code level maps of model parameters related to the relapse
      rates over time and the ultimate proportion of quitters (the cure rates).

PMID- 15032799
TI  - A note on one-sided tests with multiple endpoints.
AB  - Testing problems with multivariate one-sided alternative hypotheses are common in
      clinical trials with multiple endpoints. In the case of comparing two treatments,
      treatment 1 is often preferred if it is superior for at least one of the
      endpoints and not biologically inferior for the remaining endpoints. Bloch et al.
      (2001, Biometrics57, 1039-1047) propose an intersection-union test (IUT) for this
      testing problem, but their test does not utilize the appropriate multivariate one
      sided test. In this note we modify their test by an alternative IUT that does
      utilize the appropriate one-sided test. Empirical and graphical evidence show
      that the proposed test is more appropriate for this testing problem.

PMID- 15032802
TI  - Sample size redetermination for repeated measures studies.

PMID- 15032800
TI  - Naive nonparametric bootstrap model weights are biased.

PMID- 15032813
TI  - Relationships between fruit exocarp antioxidants in the tomato (Lycopersicon
      esculentum) high pigment-1 mutant during development.
AB  - Development-dependent changes in fruit antioxidants were examined in the exocarp
      (epidermal and hypodermal tissues) of the monogenic recessive tomato
      (Lycopersicon esculentum L.) mutant high pigment (hp-1) and its wild-type parent
      'Rutgers' grown under non-stress conditions in a greenhouse. The hp-1 mutant was
      chosen for this study because the reportedly higher lycopene and ascorbic acid
      (AsA) contents of the fruit may alter its tolerance to photooxidative stress.
      Throughout most of fruit development, reduced AsA concentrations in the exocarp
      of hp-1 were 1.5 to 2.0 times higher than in 'Rutgers', but total glutathione
      concentrations were similar in both genotypes. Only in ripe red fruit were
      reduced AsA and total glutathione concentrations lower in hp-1 than in 'Rutgers'.
      The redox ratios (reduced : reduced + oxidized) of AsA in hp-1 and 'Rutgers'
      exocarps were similar and usually > 0.9, however, the redox ratio of glutathione
      was lower in hp-1 than in 'Rutgers' throughout development. Lycopene
      concentrations in ripe red fruit were about 5 times higher in hp-1 than in
      'Rutgers'. Large increases in the specific enzyme activities of superoxide
      dismutase (EC 1.15.1.1), ascorbate peroxidase (EC 1.11.1.11), and
      monodehydroascorbate reductase (MDHAR; EC 1.6.5.4) occurred during fruit
      development in both genotypes, with an inverse relationship between the
      activities of these enzymes and chlorophyll content. Glutathione reductase (EC
      1.6.4.2) and MDHAR-specific activities were higher in hp-1 than 'Rutgers' only at
      the later stages of fruit development. Dehydroascorbate reductase (EC 1.8.5.1)
      activities, however, were usually higher in 'Rugters' than in hp-1. Catalase
      (CAT, EC 1.11.1.6) activities increased with fruit development until the fruit
      were orange/light red, when CAT was higher in 'Rutgers' than in hp-1, but then
      declined in the ripe red fruit of both genotypes. These results suggest that
      elevated AsA in the exocarp of hp-1 fruit early in fruit development may increase
      the tolerance of hp-1 fruit to photooxidative injury at that time, but the
      increasing activities of antioxidant enzymes appear to be developmentally
      associated with fruit ripening.

PMID- 15032814
TI  - Seasonal dynamics of non-structural carbohydrates in bulbs and shoots of the
      geophyte Galanthus nivalis.
AB  - Seasonal dynamics of non-structural carbohydrates were studied in Galanthus
      nivalis L. over a 2-year period. The plants were collected in the field and
      separated into above- and below-ground biomass. The polysaccharide fraction of
      the bulbs consisted of fructans and starch. Seasonal variations suggest that the
      polysaccharides were utilized for carbon and energy supply for re-growth and
      flower development. With the re-sprouting of the bulbs in autumn the fructans
      within the bulbs were depolymerized and an increase of low degree of
      polymerization fructans as well as sucrose was observable. Within shoots the
      major polysaccharides were fructans, the starch content was much lower. Gas
      liquid chromatography and high-performance, anion-exchange chromatographyanalysis
      of the fructan fraction revealed that the fructans within the shoots were
      predominantly those with a low degree of polymerization. In addition to the two
      polysaccharides the other dominant sugar in shoots was sucrose. During the period
      of slow re-growth and flowering, fructan and starch pools were depleted to
      different degrees. Calculation of the difference between the carbohydrate content
      at the start of visible growth and at the time of lowest content revealed that
      the starch pool showed a higher depletion than the fructan pool. During the re
      growth periods in 1996/97 and 1997/98 fructans were catabolized by 39 and 32%
      only, whereas the starch pool was depleted by 92% (1996/97) and 79% (1997/98),
      respectively. During rapid shoot growth and fruiting, the bulbs and above-ground
      organs appeared to be competing sinks for the photosynthetically fixed carbon.
      Refilling of the bulbs carbohydrate reserve started in February/March In shoots,
      the period of refilling the bulbs was characterized by a low content of
      oligosaccarides and a high content of hexoses.

PMID- 15032815
TI  - Differences in structure of adventitious roots in Salix clones with contrasting
      characteristics of cadmium accumulation and sensitivity.
AB  - Various clones of Salix spp. have contrasting characteristics of accumulation,
      translocation to shoots and of sensitivity to cadmium (Cd). The aim was to
      investigate the structure of adventitious roots and find out if differences
      between groups of clones in root anatomy accounted for differences in relation to
      Cd. Stem cuttings of eight clones of Salix spp. with different combinations of
      high or low Cd accumulation, translocation of Cd to shoots and sensitivity to Cd,
      were cultivated for 3 weeks in hydroponics containing 100 micro M Ca(NO(3))(2).
      No Cd was added in this experiment. Equal-sized roots were selected for hand
      sectioning and fluorescence staining to detect the beginning of Casparian band
      formation and suberin lamellae deposition in endodermis. In addition, root apices
      were fixed, embedded, sectioned longitudinally and transversally, and stained.
      The image analysis system LUCIA was used for quantitative evaluation of tissue
      differences. The structure of adventitious root apices showed an intermediate
      open type of root apical meristem and the clones differed in organization of root
      apices. Clones with low accumulation of Cd and high Cd tolerance had smaller
      meristematic zones and more extensive vacuolation of cells in the root apices
      than clones characterized by high accumulation of, and high sensitivity to, Cd.
      The apoplastic barriers, exo- and endodermis, were developed relatively close to
      the apex. In both layers the first ontogenetic stage, the Casparian band
      development, was followed by the second stage, the suberin lamellae deposition.
      This process started in the endodermis, preferentially against phloem poles,
      which is a common phenomenon also in other plant species. However, preferential
      development of exodermis in the sectors against phloem poles was observed in this
      study for the first time in plants. Development of endodermal Casparian bands in
      clones characterized by high accumulation of Cd occurred more distant from the
      root tip than in clones with low accumulation. Furthermore, the suberin lamellae
      were more distant from the root tip in clones with high translocation of Cd
      compared with those with low translocation. This indicates that apoplastic
      movement of Cd into the stele and the upward translocation may vary due to the
      endodermal anatomy. The proportion of root apoplastic barriers, exodermis and
      endodermis as well as epidermis to other root tissues was significantly increased
      in clones with higher tolerance to Cd ions, indicating the importance of these
      tissues in protection of the root against toxic effects of Cd.

PMID- 15032816
TI  - Rhizobial nod gene-inducing activity in pea nodulation mutants: dissociation of
      nodulation and flavonoid response.
AB  - The root exudates of 24 pea (Pisum sativum L.) non-nodulating mutants,
      originating from cv. 'Finale', were tested for Rhizobium nodulation (nod) gene
      inducing activity to reveal potential differences from the wild type. The
      interaction with flavonoid receptor NodD of R. leguminosarum bv. viciae strain
      248 was monitored as the activity of the regulated operon nodABC fused to the
      reporter gene lacZ. In the uninoculated plants, the only decreased exudate
      activity was found in the line Risnod17 and ascribed to the impaired root growth
      in this line. Consequently, constitutive deficiency in the flavonoid nod gene
      inducers is not a cause of the asymbiotic phenotypes in the studied set. On the
      other hand, line Risnod5 had constitutively higher nod gene-inducing activity
      which might be responsible for its conditional nodulation and Fix(-) phenotype
      when the nodules are present. Monitoring of the response of wild-type plants to
      inoculation revealed an increase in nod gene-inducing activity (Ini response)
      starting first day after inoculation. The chosen mutant lines Risnod22 (putative
      locus sym9) and Risnod25 (putatively sym8) showed Ini as well indicating that the
      flavonoid burst can be mutationally dissociated from nodule initiation. On the
      other hand, absence of Ini in Risnod20 (assumed sym19) suggests branching of the
      signal transduction pathway downstream of this mutation and places it upstream of
      the two former mutations in the transduction of the bacterial Nod factor signal.
      More intense Ini response observed in the supernodulating mutant RisfixC,
      included in the study for its contrasting symbiotic phenotype, suggests common
      regulation of nodulation and Ini response via systemic shoot factor. The time
      shift in the exudation of isoflavonoid phytoalexin pisatin compared to Ini, its
      increased level in Risnod25 and lowered level in RisfixC are consistent with the
      regulatory role of plant defence in nodule initiation, which might be mediated
      directly by isoflavonoids as negative regulators.

PMID- 15032817
TI  - Effect of acetaldehyde, arsenite, ethanol, and heat shock on protein synthesis
      and chilling sensitivity of cucumber radicles.
AB  - Exposure to a chilling temperature of 2.5 degrees C for 96 h inhibited the
      subsequent growth of cucumber seedling radicles at 25 degrees C by 92%. Exposing
      seedling with 5 +/- 1 mm long radicles to acetaldehyde vapour (275 micro l l(-1))
      or to an aqueous ethanol solution (0.6 M) for 2 h, or to 45 degrees C for 10 min
      before chilling, increased chilling tolerance so that the chilling treatment
      reduced growth by only 47, 39 or 36%, respectively. All of these effective
      treatments induced the synthesis of a number of proteins, and suppressed de novo
      protein synthesis (i.e. the incorporation of [(35)S]-methionine) by about 70%. In
      contrast, treatment for 2 h with an aqueous arsenite solution (100 micro M) had
      no effect on chilling sensitivity or the incorporation of [(35)S]-methionine, yet
      it induced the synthesis of a complement of proteins that were similar to that
      induced by the effective heat-shock treatment. A unique protein or set of
      proteins may be responsible for heat-shock-induced chilling tolerance, but none
      was detected. The ability of various abiotic stresses to suppress protein
      synthesis may be more important in increasing tolerance to chilling injury than
      their ability to induce the synthesis of specific proteins.

PMID- 15032818
TI  - Wheat seedlings as a model to understand desiccation tolerance and sensitivity.
AB  - The coleoptiles of wheat (Triticum aestivum L.) seedlings of cultivar Tremie are
      desiccation tolerant when 3 days old, although the roots are not. Cutting some of
      the coleoptiles open prior to dehydration rapidly increased the drying rate. This
      rendered the coleoptiles sensitive to desiccation, providing a useful model with
      which to study desiccation tolerance. Both sensitive and tolerant seedlings were
      dehydrated to 0.3 g H(2)O g(-1) dry mass (g.g) and thereafter rehydrated.
      Sensitive tissues accr- ued the lipid peroxidation products H(2)O(2)and MDA, and
      substantial subcellular damage was evident in dry tissues. H(2)O(2) and MDA
      accumulated slightly only in dry tolerant coleoptiles and no subcellular damage
      was evident. The activity of antioxidant enzymes glutathione reductase
      (EC1.6.2.4), superoxide dismutase (EC 1.14.1.1) and catalase (EC 1.11.1.6)
      increased on drying in both tolerant and sensitive tissues, but were sustained on
      rehydration in only the tolerant tissues. It is proposed that free radical damage
      sustained during rapid drying exceeded the ameliorating capacity of antioxidant
      systems, allowed accrual of lethal subcellular damage. Slow drying enabled
      sufficient detoxification by antioxidants to minimize damage and allow tolerance
      to drying. Three LEA- (p11 and Asp 52) and dehydrin- (XV8) like proteins were
      detected by western blots in tolerant coleoptiles dried to 3.0 g.g and below.
      Only one (Asp 52) was induced at low water content in rapidly dried sensitive
      coleoptiles. None were present in root tissues. XV8 RNA (northern analyses) was
      induced on drying only in tolerant coleoptiles and correlated with protein
      expression. These stress-putative protein protectants (and XV8 transcripts)
      appear to be down-regulated during germination but wheat seedlings temporarily
      retain the ability to reproduce them if drying is slow. Sucrose accumulation
      during dehydration was similar for both sensitive and tolerant tissues,
      suggesting that this sugar has little role, or is not effective in isolation, in
      protecting against desiccation damage in wheat seedlings. In summary, the slower
      rate at which tolerant coleoptiles were dried allowed for the mobilization of
      protection mechanisms with which to survive desiccation. Rapid drying of tissues
      precluded induction of some putative stress protein protectants and caused damage
      in excess of the ameliorating capacity of the antioxidant protection systems.

PMID- 15032819
TI  - The role of phosphorus in aluminium-induced citrate and malate exudation from
      rape (Brassica napus).
AB  - Exudation of organic anions is believed to be a common tolerance mechanism for
      both aluminium toxicity and phosphorus deficiency. Nevertheless, which of these
      stresses that actually elicit the exudation of organic anions from rape (Brassica
      napus L) remains unknown, and the combined effects of Al toxicity and P
      deficiency on rape have not been reported before. Therefore, in the current
      study, Brassica napus var. Natane nourin plants grown with or without 0.25 mM P
      were exposed to 0 or 50 micro M AlCl(3) and several parameters related to the
      exudation of organic anions from the roots were investigated. Eight days of P
      deficiency resulted in a significant growth reduction, but P deficiency alone did
      not induce exudation of organic anions. In contrast, Al strongly induced organic
      acid exudation, while simultaneously inhibiting root growth. Increased in-vitro
      activity of citrate synthase (CS, EC 4.1.3.7), malate dehydrogenase (MDH, EC
      1.1.1.37) and phosphoenolpyruvate carboxylase (PEPC, EC 4.1.1.31), together with
      reduced root respiration, indicated that the Al-induced accumulation and
      subsequent exudation of citrate and malate were associated with both increased
      biosynthesis and reduced metabolism of citric and malic acid. Phosphorus
      sufficient plants showed more pronounced aluminium-induced accumulation and
      exudation of organic anions than P-deficient plants. A divided root chamber
      experiment showed the necessity of direct contact between Al and roots to elicit
      exudation of organic anions. Prolonged exposure (10 days) to Al resulted in a
      decrease in the net exudation of citrate and malate, and the rate of decrease was
      much more rapid in P-deficient plants than in P-sufficient plants. It is
      concluded that P nutrition affects the level of Al-induced synthesis and
      exudation of organic anions. However, the mechanism needs further investigation.

PMID- 15032820
TI  - Comparative study of the expression profiles of the Cor/Lea gene family in two
      wheat cultivars with contrasting levels of freezing tolerance.
AB  - Expression profiles of a set of Cor/Lea genes were assessed during early stages
      of cold acclimation in seedlings of two wheat cultivars, which showed contrasting
      levels of freezing tolerance. These Cor/Lea family members consisted of three EST
      clones and 13 previously identified cDNA clones of wheat and rye. Northern blot
      analysis using RNA extracted from seedling leaves and roots showed that most of
      the genes exhibited a quite similar time-course of expression, although with
      different expression levels: They rapidly responded to low temperature and their
      transcript levels reached high plateaus within 3-5 days. The overall gene
      expression profiles were correlated with the time-dependent development and the
      level of freezing tolerance under low temperature in the two cultivars. Western
      blot analysis of protein accumulation further verified this observation.
      Abscissic acid response was proved for at least four genes. Light was stimulatory
      to most of the genes, and this positive light response associated with low
      temperature occurred not only in leaf-specific genes but also in leaf/root
      expressed genes. Taken together, the present results suggest that the Cor/Lea
      gene family represents a major group of downstream genes involved in the ABA
      dependent and -independent signal pathways and that most of them are co-regulated
      in determining freezing tolerance in wheat seedlings.

PMID- 15032821
TI  - Cloning and characterization of the gene for a phloem-specific glutathione S
      transferase from rice leaves.
AB  - The N-terminal amino-acid sequence was determined for a major rice phloem protein
      with a molecular mass of 31 kDa, named RPP31. The corresponding full-length rice
      EST-clone was cloned based on the amino acid sequence. The predicted total amino
      acid sequence of RPP31 shared high similarity with plant glutathione S
      transferases (GSTs). Recombinant RPP31 produced in Escherichia coli and rice
      phloem sap showed GST activity. Immunocytological analysis indicated that RPP31
      is localized in the phloem region of leaves. In mature leaves, the signal was
      restricted to sieve element-companion cell complexes, and was stronger in sieve
      elements than in companion cells. Although some plant GSTs are known to be
      induced by xenobiotics, the amount of RPP31 was not affected by treatments with
      an herbicide, pretilachlor, and/or its safener, fenclorim. These results suggest
      that RPP31 is an active GST restricted to the phloem region of normal rice
      leaves.

PMID- 15032822
TI  - Uptake of salicylic acid 2-O-beta-D-glucose into soybean tonoplast vesicles by an
      ATP-binding cassette transporter-type mechanism.
AB  - In soybean (Glycine max L.), salicylic acid (SA) is converted primarily to SA 2-O
      beta-d-glucose (SAG) in the cytoplasm and then accumulates exclusively in the
      vacuole. However, the mechanism involved in the vacuolar transport of SAG has not
      been investigated. The vacuolar transport of SAG was characterized by measuring
      the uptake of [(14)C]SAG into tonoplast vesicles isolated from etiolated soybean
      hypocotyls. The uptake of SAG was stimulated about six-fold when MgATP was
      included in the assay media. In contrast, the uptake of SA was only stimulated
      1.25-fold by the addition of MgATP and was 2.2-fold less than the uptake of SAG
      providing an indication that the vacuolar uptake of SA is promoted by
      glucosylation. The ATP-dependent uptake of SAG was inhibited by increasing
      concentrations of vanadate (64% inhibition in the presence of 500 microM) but was
      not very sensitive to inhibition by bafilomycin A(1) (a specific inhibitor of
      vacuolar H(+)-ATPase; EC 3.6.1.3), and dissipation of the transtonoplast H(+)
      electrochemical gradient. The SAG uptake exhibited Michaelis-Menten-type
      saturation kinetics with a K(m) value of 90 microM for SAG. SAG uptake was
      inhibited 60% by beta-estradiol 17-(beta-d-glucuronide), but glutathione
      conjugates and uncharged glucose conjugates were only slightly inhibitory. Based
      on the characteristics of SAG uptake into soybean tonoplast vesicles it is likely
      that this uptake occurs through an ATP-binding cassette transporter-type
      mechanism. However, this vacuolar uptake mechanism is not universal since the
      uptake of SAG by red beet (Beta vulgaris L) tonoplast vesicles appears to involve
      an H(+)-antiport mechanism.

PMID- 15032823
TI  - Stable haploid poplar callus lines from immature pollen culture.
AB  - Embryogenesis and plant regeneration have been obtained from isolated immature
      pollen of two poplar hybrids (Populus nigra L. x hybrid 'Aue1' and 'Aue2'). In
      total, 1487 calli or embryos, respectively, larger than 1 mm were generated in a
      2-year study. By using a cytokinin containing induction medium, on average 19
      calli per responsive immature catkin were formed. Additional supplementation with
      auxin in 2002 increased the frequency to 72 calli per catkin. Microsatellite
      marker analyses confirmed haploid origin in most regenerants studied. So far six
      out of eight obtained regenerative callus lines have maintained their haploid
      level up to 24 months of development. A number of haploid and doubled haploid
      plants of different lines are available and have been transferred to soil.

PMID- 15032824
TI  - Evidence of a cross-talk regulation of a GA 20-oxidase (FsGA20ox1) by
      gibberellins and ethylene during the breaking of dormancy in Fagus sylvatica
      seeds.
AB  - Gibberellin 20-oxidase (GA 20-oxidase) is an enzyme that catalyses the last three
      steps in the synthesis of active GAs and is a potential control point in the
      regulation of GA biosynthesis. Reverse transcriptase-polymerase chain reaction
      with degenerated oligonucleotides conserved among GA 20-oxidases was used to
      isolate a cDNA clone for this enzyme in Fagus sylvatica L. seeds. This clone
      contains all the features and exhibits homology to GA 20 oxidases from several
      plant species. Expression of this clone, named FsGA20ox1, as a fusion protein
      expressed in Escherichia coli confirmed that it was able to metabolize
      [(14)C]GA(12) to [(14)C]GA(9) and [(14)C]GA(53) to [(14)C]GA(20). Analysis of
      FsGA20ox1 transcript levels showed similar low expression during stratification
      at 4 degrees C and in the presence of gibberellic acid or ethephon (compound that
      releases ethylene in solution), treatments proved to be efficient in breaking the
      dormancy of beech seeds. However, there was a drastic increase of FsGA20ox1
      transcript levels in the presence of paclobutrazol (PCB), a well-known GAs
      biosynthesis inhibitor, or of 2-aminoxyacetic acid (AOA), an inhibitor of
      ethylene biosynthesis. Furthermore, the effect of AOA was reversed by the
      addition of GA(3) and that of PCB by ethephon. This indicates that the gene
      product is subjected to down-regulation by GA and ethylene, and further suggests
      a cross-talk gene regulation by these two hormones during the transition from
      seed dormancy to germination.

PMID- 15032825
TI  - Cloning and characterization of cellulose synthase-like gene, PtrCSLD2 from
      developing xylem of aspen trees.
AB  - Genetic improvement of cell wall polymer synthesis in forest trees is one of the
      major goals of forest biotechnology that could possibly impact their end product
      utilization. Identification of genes involved in cell wall polymer biogenesis is
      essential for achieving this goal. Among various candidate cell wall-related
      genes, cellulose synthase-like D (CSLD) genes are intriguing due to their
      hitherto unknown functions in cell wall polymer synthesis but strong structural
      similarity with cellulose synthases (CesAs) involved in cellulose deposition.
      Little is known about CSLD genes from trees. In the present article PtrCSLD2, a
      first CSLD gene from an economically important tree, aspen (Populus tremuloides)
      is reported. PtrCSLD2 cDNA was isolated from an aspen xylem cDNA library and
      encodes a protein that shares 90% similarity with Arabidopsis AtCSLD3 protein
      involved in root hair tip growth. It is possible that xylem fibers that also grow
      by intrusive tip growth may need expression of PtrCSLD2 for controlling the
      length of xylem fibers, a wood quality trait of great economical importance.
      PtrCSLD2 protein has a N-terminal cysteine-rich putative zinc-binding domain;
      eight transmembrane domains; alternating conserved and hypervariable domains; and
      a processive glycosyltransferases signature, D, D, D, QXXRW; all similar to aspen
      CesA proteins. However, PtrCSLD2 shares only 43-48% overall identity with the
      known aspen CesAs suggesting its distinct functional role in cell wall polymer
      synthesis perhaps other than cellulose biosynthesis. Based on Southern analysis,
      the aspen CSLD gene family consists of at least three genes and this gene copy
      estimate is supported by phylogenetic analysis of available CSLDs from plants.
      Moreover, gene expression studies using RT-PCR and in situ mRNA hybridization
      showed that PtrCSLD2 is expressed at a low level in all aspen tissues examined
      with a slightly higher expression level in secondary cell wall-enriched aspen
      xylem as compared to primary cell wall enriched tissues. Together, these
      observations suggest that PtrCSLD2 gene may be involved in the synthesis of
      matrix polysaccharides that are dominant in secondary cell walls of poplar xylem.
      Future molecular genetic analyses will clarify the functional significance of
      CSLD genes in the development of woody trees.

PMID- 15032826
TI  - Changes in histone H3 and H4 multi-acetylation during natural and forced dormancy
      break in potato tubers.
AB  - The effects of post-harvest storage and dormancy progression on histone
      acetylation patterns were examined in potato (Solanum tuberosum L. cv. Russet
      Burbank) tubers. Storage of field-grown tubers at 3 degrees C in the dark
      resulted in the progressive loss of tuber meristem dormancy, defined as
      measurable growth after transfer to 20 degrees C for 7 days. Dormancy emergence
      was concomitant with sustained increases in histone H3.1 and H3.2 multi
      acetylation, and with transient increases in H4 multi-acetylation that peaked 4-5
      months post-harvest. Treatment of dormant tubers with bromoethane (BE) resulted
      in rapid loss of dormancy over 9 days. Similar to cold-stored field-grown tubers,
      dormancy break in BE-treated tubers occurred at the same time as transient rises
      in H4 and H3.1/3.2 multi-acetylation, peaking at days 1 and 4, respectively. BE
      treatment also resulted in small increases in RNA synthesis at day 6, and a three
      fold, sustained activation of DNA synthesis thereafter. A defined sequence of
      epigenetic events, beginning with previously characterized transient cytosine
      demethylation, followed by increased H3 and H4 histone acetylation and
      ultimately, tuber meristem re-activation, may thus exist in potatoes during
      dormancy exit and resumption of rapid growth.

PMID- 15032827
TI  - Development of a standard operating procedure (SOP) for the precise
      quantification of transgene expression levels in rice plants.
AB  - Variation in transgene expression levels can result from uncontrolled differences
      in experimental protocols. It is important to quantify and eliminate this
      unwanted variation as much as possible in order to attain precision in transgenic
      studies. Large-scale transgenic studies could, by their design, generate
      additional variation. The influence of different plant growth, sampling and
      analysis strategies in generating spurious variation in transgene expression
      level quantification in rice plant populations was assessed. The use of multiple
      independent plant phenotypic analyses (enzymatic assays in this study) was
      identified as the major source of spurious variation (doubling or tripling the
      variation). The quantification of transgene expression levels was also found to
      be significantly influenced by plant age, the choice of leaf sampled and leaf
      size. All of these factors reduced the precision of molecular genetic studies and
      generated artefactual results in transgenic studies. Identification of the
      sources of extraneous variation allowed the development of a new standard
      operating procedure (SOP) for rice, designed to control spurious variation. SOP
      allowed the influence of differences in growth period and independent phenotypic
      analyses to be minimized. The coefficient of variation in transgene expression
      levels, between and within genetically identical rice plants, was reduced to
      approximately 10 to 15% using SOP. Adoption of quality assurance (QA) criteria
      such as SOP is key to improving the reproducibility of transgenic studies.

PMID- 15032828
TI  - Polyamines and somatic embryogenesis in two Vitis vinifera cultivars.
AB  - Polyamine content and activities of enzymes of polyamine biosynthesis were
      assayed during somatic embryogenesis in Vitis vinifera callus cultures of
      Chardonnay and Brachetto 'a grappolo lungo' (Brachetto g.l.) cultivars. The
      analyses were carried out on embryogenic callus samples, embryos at different
      stages and developing plants. Polyamine content, both in the free and PCA-soluble
      conjugated form, was higher in Brachetto g.l. than in Chardonnay, and putrescine
      was present at higher concentrations than the other polyamines. In all samples of
      both cultivars, ornithine decarboxylase activity (ODC, EC 4.1.1.17) was higher
      than arginine decarboxylase (ADC, EC 4.1.1.19), with a maximum in developing
      plant roots. S-Adenosylmethionine decarboxylase (SAMDC, EC 4.1.1.50) activity
      displayed a similar trend. The activities of all three enzymes were detected both
      in the supernatant and pellet fractions, indicating for the first time the
      presence of SAMDC activity in the particulate fraction. Particularly in the
      Chardonnay cultivar, an increase in the mRNAs expression patterns of ODC and
      SAMDC during morphogenesis from small embryos to plantlets was detected by
      northern blot, suggesting a direct correlation with enzymatic activities.

PMID- 15032829
TI  - Changes in strain and deposition of cuticle in developing sweet cherry fruit.
AB  - Changes in surface area, deposition and elastic strain of the cuticular membrane
      (CM) were monitored during development of sweet cherry (Prunus avium L.) fruit.
      Fruit mass and surface area ('Sam') increased in a sigmoidal pattern between 16
      and 85 days after full bloom (DAFB) with maximum rates of 0.35 g day(-1) and 0.62
      cm(2) day(-1), respectively. Rates of total area strain, namely the sum of
      elastic plus plastic strain, were highest in cheek and stem cavity regions
      followed by stylar and suture regions. Rates of total uniaxial strain were higher
      in transverse, namely perpendicular to the stem/stylar axis, than in longitudinal
      direction, namely parallel to the stem/stylar axis. On a whole fruit basis CM
      mass remained essentially constant during fruit development. Mass of CM, dewaxed
      CM and wax per unit surface area decreased during development, particularly
      between 43 and 71 DAFB. There was no change in wax content of isolated CM. Up to
      43 DAFB the surface area of isolated CM was similar to the area prior to excision
      indicating little elastic strain, but markedly decreased thereafter. Calculating
      elastic and plastic components of total strain of the CM revealed, that initial
      deformation up to 22 to 43 DAFB was mostly plastic. Thereafter, elastic strain
      was evident and both, elastic and plastic deformation, increased linearly with an
      increase in total strain. There was no consistent difference in the relative
      contribution of elastic strain to total strain between transverse and
      longitudinal directions, but both total and elastic strain were larger in the
      transverse direction. Abrading the CM had only little effect on fruit turgor.
      However, turgor decreased when the exocarp was cut indicating that the exocarp
      provided a significant structural shell of a mature sweet cherry fruit
      ('Regina'). Our data demonstrate, that (1) surface area expansion in sweet cherry
      fruit causes elastic and plastic strain of the CM, and (2) the onset of elastic
      strain coincided with the cessation of CM formation.

PMID- 15032830
TI  - Xyloglucan endotransglucosylase/hydrolase genes in cucumber (Cucumis sativus) -
      differential expression during somatic embryogenesis.
AB  - Defined changes in the cell wall directed by many proteins accompany every
      morphogenetic process in plants. Xyloglucan endotransglucosylase/hydrolase
      proteins (XTH; EC 2.4.1.207) have the potential to modify the hemicellulose
      matrix within the cell wall. Cs-XTH1 and Cs-XTH3 genes, which encode XTH
      proteins, were found among numerous genes that are differentially expressed after
      the induction of cucumber somatic embryogenesis. The expression of these genes
      increased during somatic embryogenesis. The Cs-XTH1 gene was localized on the
      second chromosome near the centromere region, whereas Cs-XTH3 was found in the
      middle of the fifth chromosome's longer arm. Northern blot hybridization showed
      that both genes were preferentially expressed in roots. We also observed higher
      accumulation of both transcripts in somatic embryos than in the proembryogenic
      mass. The localization of mRNA by in situ hybridization revealed that the Cs-XTH1
      transcripts were largely accumulated in the presumptive cotyledon primordia of
      somatic embryos. The XTH gene family consists of a number of genes with a high
      degree of structural similarity. Screening a cucumber genomic library has
      identified other members of this gene family. The intron/exon structure, sequence
      similarities and the close chromosomal distance between some members suggest
      their common evolutionary origin. The involvement of XTH-related genes in somatic
      embryo formation is discussed.

PMID- 15032831
TI  - Copper effect on cytochrome b of photosystem II under photoinhibitory conditions.
AB  - Toxic Cu (II) effect on cytochrome b(559) under aerobic photoinhibitory
      conditions was examined in two different photosystem II (PSII) membrane
      preparations active in oxygen evolution. The preparations differ in the content
      of cytochrome b(559) redox potential forms. Difference absorption spectra showed
      that the presence of Cu (II) induced the oxidation of the high-potential form of
      cytochrome b(559) in the dark. Addition of hydroquinone reduced the total
      oxidized high-potential form of cytochrome b(559) present in Cu (II)-treated PSII
      membranes indicating that no conversion to the low-potential form took place.
      Spectroscopic determinations of cytochrome b(559) during photoinhibitory
      treatment showed slower kinetics of Cu (II) effect on cytochrome b(559) in
      comparison with the rapid loss of oxygen evolution activity in the same
      conditions. This result indicates that cytochrome b(559) is affected after PSII
      centres are photoinhibited. The high-potential form was more sensitive to toxic
      Cu (II) action than the low-potential form under illumination at pH 6.0. The
      content of the high-potential form of cytochrome b(559) was completely lost;
      however, the low-potential content was unaffected in these conditions. This loss
      did not involve cytochrome protein degradation. The results are discussed in
      terms of different binding properties of the heme iron to the protonated or
      unprotonated histidine ligand in the high-potential and low-potential forms of
      cytochrome b(559), respectively.

PMID- 15032832
TI  - Photophysiology and primary production of phytoplankton in freshwater.
AB  - In the last 10 years enormous progress has been made in developing new
      instruments to collect physiological data from natural phytoplankton. In this
      review we summarize the motivation which has powered this engagement and focus on
      new technologies used to measure fluorescence, absorption and biochemical
      compositions of natural phytoplankton cells from nature. Combining the knowledge
      of phytoplankton structure along with taxon-specific measurements of
      photosynthetic activity and biochemical cell composition, can lead to new models
      which increase the reliability of water quality prediction. Furthermore, recent
      progress in the analysis of photophysiological fitness of phytoplankton cells has
      revealed new knowledge about the phylogenetic diversity of metabolic strategies
      to cope with light and nutrient stress. Future progress in single cell analysing
      systems will be discussed.

PMID- 15032833
TI  - The respiratory chain of blue-green algae (cyanobacteria).
AB  - Electron transport components on the way from reduced substrates to the terminal
      respiratory oxidase(s) are discussed in relation to analogous and/or homologous
      enzymes and electron carriers in the generally much better known bacteria,
      mitochondria and chloroplasts. The kinetic behaviour of the components, their
      localization within the cell and their evolutionary position are given special
      attention. Pertinent results from molecular genetics are also mentioned. The
      unprecedented role of cyanobacteria for our biosphere and our whole planet earth
      appears to deserve a more extended introductory chapter.

PMID- 15032834
TI  - Modelling NADH turnover in plant mitochondria.
AB  - NADH is central to the functioning of mitochondrial respiration. It is produced
      by enzymes in, or associated with, the tricarboxylic acid cycle in the matrix,
      and it is oxidized by two respiratory chain enzymes in the inner membrane, the
      rotenone-sensitive complex I and the rotenone-insensitive internal NADH
      dehydrogenase (ND(in)). A simplified kinetic model for NADH turnover in the
      matrix of plant mitochondria is presented. Only the two main NADH-producing
      enzymes, NAD-malate dehydrogenase [EC 1.1.1.37] (MDH) and NAD-malic enzyme [EC
      1.1.1.39] (ME), are considered. This model reproduces the complex behaviour of
      malate oxidation by isolated mitochondria in response to additions of ADP (state
      3/state 4), NAD(+) and/or rotenone, as well as to changes in pH. It is found that
      MDH always operates at or close to equilibrium. Changes in the activity of
      complex I, ND(in), or ME are predicted to cause clear changes in the pattern of
      malate oxidation. In general, the model predicts high sensitivity to changes in
      the ME activity. In contrast, MDH activity can be reduced 100-fold without
      detectable changes in malate oxidation. It is demonstrated that it is not the
      high activity, but the equilibrium properties of MDH that are important for the
      redox-buffering function of MDH in the mitochondrial matrix. Binding of NAD(+)
      and NADH in the matrix reduces the concentrations of free NAD(+) and NADH,
      depending on the concentration of binding sites and the binding strength. On the
      basis of the modelling results it is estimated that a significant proportion of
      the mitochondrial NAD is bound.

PMID- 15032835
TI  - Fusicoccin affects cytochrome c leakage and cytosolic 14-3-3 accumulation
      independent of H-ATPase activation.
AB  - Fusicoccin (FC) is a well known toxin acting as a 14-3-3 protein-mediated
      activator of the plasma membrane H(+)-ATPase and the biochemical and
      physiological changes induced in the cell by this toxin have, up to now, been
      ascribed to the increased rate of proton extrusion by this pump leading to
      external acidification and cell hyperpolarization. In a recent work (Malerba M et
      al. 2003, Physiologia Plantarum, 119: 480-488) it was shown that, besides the
      previously well studied changes, FC induces a large stimulation of H(2)O(2)
      production, an activation of alternative respiration and a leakage of cytochrome
      c from mitochondria. In this article further studies on the relation between the
      H(2)O(2) overproduction and medium acidification are reported. The increase in
      the rate of H(2)O(2) accumulation is particularly evident when high
      concentrations of the toxin ensure a rapid acidification of the medium, but it is
      not obtained when the time-course of acidification is reproduced by external acid
      additions. The FC-dependent H(2)O(2) overproduction is strongly inhibited by
      inhibitors of the H(+)-ATPase activity, such as vanadate and erythrosin B, and it
      does not occur when the activation of the H(+)-ATPase is prevented by
      phenylarsine oxide (PAO), an inhibitor of the activating interaction between the
      enzyme and its regulative 14-3-3 protein. Interestingly, all these inhibitors
      only partially prevent the leakage of cytochrome c from the mitochondria. A
      kinetic analysis of FC-dependent changes of 14-3-3s shows that the initial
      increase in the plasma membrane level of these proteins, presumably due to
      translocation of free cytosolic forms, is followed by a remarkable increase in
      the level of the 14-3-3 proteins located in the cytosol. This latter change is
      not prevented by inhibitors of the activity or activation of the H(+)-ATPase.
      These results suggest that, besides the H(+)-ATPase activation, FC can induce
      other cell changes possibly mediated by changes of the regulative 14-3-3
      proteins.

PMID- 15032836
TI  - Properties of a polygalacturonase-inhibiting protein isolated from 'Oroblanco'
      grapefruit.
AB  - Polygalacturonase inhibiting protein (PGIP) was extracted from 'Oroblanco'
      grapefruit type (triploid pummelo-grapefruit) albedo tissue, purified and
      partially characterized. Extraction was carried out at 4 degrees C with a high
      ionic strength extraction buffer. After dialysis and concentration by
      ultrafiltration the extract was chromatographed on concanavalin A-Sepharose. The
      PGIP activity was bound by the lectin and then eluted using 250 mM alpha-methyl
      mannopyranoside, resulting in a 17-fold purification of the PGIP and
      demonstrating its glycoprotein nature. The anion-exchange and size-exclusion
      chromatography steps that followed gave a PGIP that was 857-fold purified
      relative to the initial tissue extract, and having a 44 kDa molecular weight, as
      estimated by SDS-PAGE electrophoresis. PGIP inhibition activity was tested with
      endo-polygalacturonase (EC 3.2.1.15) produced by Penicillium italicum and
      Botrytis cinerea. The radial diffusion and reducing sugar assays showed that P.
      italicum and B. cinerea endo-PGs were affected by PGIP, whereas no endo-PG
      activity was detected in the culture filtrate of P. digitatum. In vitro tests
      revealed that PGIP inhibited P. italicum and B. cinerea growth. By contrast, the
      influence of PGIP on P. digitatum, growth was negligible, perhaps because this
      fungus does not produce endo-PG. Following heating for 10 min at 65 degrees C the
      inhibitory activity of PGIP was reduced by 43%. PGIP activity decreased further
      as heating temperature increased, and was completely suppressed after heating at
      100 degrees C for 10 min.

PMID- 15032837
TI  - Cloning and salt-induced, ABA-independent expression of choline mono-oxygenase in
      Atriplex prostrata.
AB  - Certain plants accumulate glycinebetaine, a type of osmoprotectant, in response
      to salinity. Glycinebetaine is synthesized in these plants via the two-step
      oxidation of choline, and the first step is catalysed by choline mono-oxygenase
      (CMO; EC 1.14.15.7). Cloned by RT-PCR and 3'-RACE, the cDNA of Atriplex prostrata
      CMO (ApCMO) is 1669 bp in length and encodes a full-length protein of 438 amino
      acids. The deduced amino acid sequence of ApCMO revealed a Rieske-type [2Fe-2S]
      cluster motif and a mononuclear non-heme Fe binding motif, and shares 82.9%
      identity and 87.2% similarity with the deduced amino acid sequence of spinach
      CMO. Accumulation of CMO transcript and glycinebetaine both increased in response
      to NaCl treatment. Without salt treatment, CMO mRNA was detected in stems and 5
      day-old seedlings, but not in leaves, roots and older seedlings. With salt
      treatment, CMO mRNA accumulated dramatically in stems, leaves and roots, with the
      most abundant accumulation occurring in young stems. Although abscisic acid may
      initiate global physiological reactions in response to osmotic stress, it did not
      induce the expression of CMO in A. prostrata. In summary, salt-induction of CMO
      mRNA in A. prostrata is more substantial than that reported in spinach and sugar
      beet, and the plant may serve as a useful model to study regulation of
      glycinebetaine synthesis by environmental stress.

PMID- 15032838
TI  - Exposure of roots of cucumber (Cucumis sativus) to low temperature severely
      reduces root pressure, hydraulic conductivity and active transport of nutrients.
AB  - When root temperature dropped below 25 degrees C, there was a sharp drop in the
      root pressure (P(r)) and hydraulic conductivity of excised roots (Lp(r)) of young
      cucumber (Cucumis sativus L.) seedlings as measured with the root pressure probe.
      A detailed analysis of root hydraulics provided evidence for a larger reduction
      in the osmotic component of Lp(r) (77%) in comparison with the hydrostatic
      component (34%) in response to the exposure of the root system to 13 degrees C.
      The activity of the plasma membrane H(+)-ATPase (EC 3.6.1.35) was reduced from 30
      to 16 micro mol Pi mg(-1) protein h(-1) upon exposure to 8 degrees C for 1 day.
      Ultrastructural observations showed no evidence of loosening of the
      microstructure of endodermal cell walls in low temperature (LT)-treated roots. It
      is concluded that the rapid drop in the P(r) in response to LT is largely caused
      by a reduction in the activity of the plasma membrane H(+)-ATPase rather than by
      loosening of the endodermal wall which would cause substantial solute losses. On
      the other hand, water permeability of root cell membrane at LT was related to
      changes in the activity (open/closed state) of water channels.

PMID- 15032839
TI  - Abiotic stress alters transcript profiles and activity of glutathione S
      transferase, glutathione peroxidase, and glutathione reductase in Euphorbia
      esula.
AB  - Glutathione S-transferase (GST), glutathione peroxidase (GPX), and glutathione
      reductase (GR) are enzymes that utilize glutathione to play an important role in
      plant defense mechanisms. In leafy spurge (Euphorbia esula L.), transcript and
      activity profiles for these enzymes are differentially influenced in tissue
      exposed to xenobiotic (diclofop-methyl) and environmental stress (cold and
      drought). Five different EeGST cDNA (including phi, tau, theta, and zeta class
      GSTs), one EeGPX cDNA, and one EeGR cDNA showed differential expression patterns
      in leafy spurge plants exposed to diclofop-methyl-, cold- and drought-stress.
      Tissue treated with diclofop-methyl also had increased GST, GPX and GR activities
      that were preceded or paralleled by increased gene expression. Transcript
      profiles resulting from drought-stressed plants were similar to transcript
      profiles from diclofop-methyl-treated plants but not cold-stressed plants. GPX
      activity in leafy spurge protein extracts was not bound to either S
      hexylglutathione- or glutathione-agarose columns but instead co-migrated with
      fractions of GST activity that also were not bound by affinity chromatography.
      Fractions of GST proteins that were bound to S-hexylglutathione revealed that
      increased GST activity in diclofop-methyl-treated tissue could be identified as
      phi- and tau-type GSTs.

PMID- 15032840
TI  - Contribution of current carbon assimilation in supplying root exudates of Lolium
      perenne measured using steady-state C labelling.
AB  - Coupling growth of Lolium perenne L. in sterile solution culture with steady
      state (13)CO(2) labelling allowed quantification of the contribution of C,
      assimilated either before or after a specific time point, both to plant
      compartments and root exudates. Plants were grown for 27 days in atmospheres
      containing CO(2) with delta(13)C signatures of either -13.5 or -36.1 per
      thousand. Air supplies to plants were then reciprocally switched to the opposing
      signature (day 0), plants were destructively harvested and root exudates
      collected over the next 8 days. Following the switch, C assimilated after day 0
      and transported to the roots initially only appeared in root tips, later
      appearing in both tip and non-tip material. The delta(13)C signature of the root
      exudate changed exponentially with time. Assimilation pre- and post-day 0
      contributed equally to exudate C at 4.5 days. Beyond day 8, assimilation pre-day
      0 still contributed 41.7% of exudate C. Over all 8 days, a linear relationship
      existed between the delta(13)C signatures of root tips and exudate, suggesting
      that all newly assimilated C in the exudate was from root tips. Results imply
      pulse-labelling approaches to study root exudates are discriminative in the
      sources of exudates labelled and in the sites from which exudation occurs.

PMID- 15032841
TI  - Transcriptional regulation of proline biosynthesis in Medicago truncatula reveals
      developmental and environmental specific features.
AB  - The model legume plant Medicago truncatula accumulates free proline in response
      to hyperosmotic stress as do many other organisms. In order to analyse the
      transcriptional regulation of proline biosynthesis in M. truncatula, three cDNAs
      encoding Delta(1)-pyrroline-5-carboxylate synthetase (P5CS1, P5CS2; EC not
      assigned) and ornithine delta-aminotransferase (OAT; EC 2.6.1.13) were isolated.
      The cDNAs shared high homologies with the other plant sequences and genomic
      organization analysis indicated the presence of two P5CS and two putative OAT
      genes. The two P5CS genes showed differing transcript level regulation according
      to organs and in response to osmotic stress. MtP5CS1 steady-state transcript
      levels in the different plant organs were correlated with proline levels but
      transcript abundance was unaffected by osmotic stresses. MtP5CS2 transcripts were
      poorly detected in all organs but were strongly accumulated in shoots of salt
      stressed plants. We suggest a specific of MtP5CS1 and MtP5CS2 as a housekeeping
      product and as a stress specific isoform, respectively. MtOAT transcripts were
      predominantly detected in roots and shoots of unstressed plants. Salt-stress
      treatment induced the accumulation of MtOAT transcripts in the whole plant
      whatever the developmental stage. In salt-stressed roots, a positive correlation
      was found between proline and MtOAT transcript accumulation. These results
      suggest that both ornithine and glutamate biosynthesis pathways contribute to the
      osmotic stress-induced proline accumulation in M. truncatula.

PMID- 15032842
TI  - Resistance of Phaseolus species to ice crystallization at subzero temperature.
AB  - Dry bean (Phaseolus vulgaris L.) cultivars possess little or no freezing
      tolerance and are killed at the temperature of ice formation in their tissues. An
      increase in frost tolerance by 2-3 degrees C would expand dry bean production in
      the short growing seasons of the Canadian prairies and possibly to higher
      altitudes in the tropics where episodic frosts occur during the growing season.
      The objective of this study was to determine the differences in frost resistance
      of Phaseolus species in both controlled and field environments. Leaflets of dry
      bean cv. CDC Nighthawk, and wild relatives from the primary gene pool (P.
      vulgaris var. mexicanus Freytag and P. vulgaris var. aborigineus (Burkart)
      Baudet) and the tertiary gene pool (P. acutifolius var. tenuifolius A. Gray, P.
      filiformis Bentham, P. angustissimus A. Gray and P. ritensis M.E. Jones) were
      subjected to subzero temperatures with and without ice nucleation to determine
      the levels of tolerance and avoidance, respectively. The lethal temperature at
      which 50% of the leaflets were killed (LT(50)) was 0.5-1 degrees C lower for
      species of the tertiary gene pool compared to those from the primary gene pool.
      Leaflets of species from the tertiary gene pool were also characterized by
      extensive supercooling compared to leaflets of species from the primary gene
      pool. Resistance of Phaseolus species to spring and autumn frosts were determined
      on seedlings transplanted to the field. Phaseolus angustissimus, a species of the
      tertiary gene pool had the highest seedling survival in response to both autumn
      and spring frosts, when the minimum air temperatures were -5 and -7 degrees C,
      respectively. Frost resistance of Phaseolus angustissimus, if successfully
      introgressed into bean germplasm, may enable the development of frost resistant
      dry bean cultivars.

PMID- 15032843
TI  - Ecophysiological analysis of two arctic sedges under reduced root temperatures.
AB  - Shoot physiological activity in arctic vascular plants may be controlled by low
      soil temperatures. While leaves may be exposed to moderate temperatures during
      the growing season, root temperatures often remain near freezing. In this study,
      two tundra sedges, Eriophorum vaginatum and Carex bigellowii, were subjected to
      reduced soil temperatures, and photosynthetic parameters (light saturated
      photosynthesis A(max), variable to maximal fluorescence and F(v)/F(m) stomatal
      conductance) and abscisic acid concentrations were determined. Stomatal
      conductance and A(max) for both E. vaginatum and C. bigellowii strongly decreased
      with declining soil temperatures. Decreasing soil temperature, however, impacted
      F(v)/F(m) to a much lesser degree. Root and leaf ABA concentrations increased
      with decreasing root temperature. These observations support the contention that
      soil temperature is a significant photosynthetic driving factor in arctic sedges
      exposed to variable root and shoot temperatures. Because these two species
      comprise approximately 30% of the vascular ground cover of wet tussock tundra,
      the soil temperature responses of these sedges potentially scale up to
      significant effects on ecosystem carbon exchange.

PMID- 15032844
TI  - Effects of Rhizoctonia infection and drought on peroxidase and chitinase activity
      in Norway spruce (Picea abies).
AB  - Seedlings of Norway spruce were exposed to fungal infection and drought in order
      to investigate differences in their stress responses on the enzymatic level. Six
      week-old seedlings were infected with the root rot fungus Rhizoctonia, or
      subjected to drought, respectively. Changes at the enzymatic level were more
      rapid and significantly higher in infected plants in comparison with drought
      stressed spruce plants. Rhizoctonia infection resulted in early local and
      systemic increase in peroxidase and chitinase activity. The most prominent
      isoforms responding were highly basic peroxidases and chitinases (pI 9-9.5) and
      several acidic chitinases (pI3-4). An increased intensity of similar peroxidase
      isoforms was found in drought-affected plants. Two peroxidase isoforms (with pI <
      9) accumulated exclusively in response to drought. These results suggest that at
      an early stage of infection and drought stress, the two stresses can be
      distinguished by the temporal appearance and isoform profile of peroxidases and
      chitinases. Changes in enzyme activity appeared before changes in physiological
      parameters, thus these isoform profiles could be used as early markers of stress
      conditions in spruce.

PMID- 15032845
TI  - Methyl jasmonate and cis-jasmone do not dispose of the herbivore-induced
      jasmonate burst in Nicotiana attenuata.
AB  - The oxylipin pathway mediates wound- and herbivore-induced defense reactions in
      Nicotiana attenuata as evidenced by a transient jasmonic acid (JA)-burst that
      precedes these defense responses. The fate of this induced JA-burst remains
      unknown. Two derivatives of JA, its methylester, methyl jasmonate (MeJA) and cis
      jasmone (cisJ), are thought to be a means of disposing of JA through
      volatilization at the plant surface. In N. attenuata, the headspace quantities of
      these compounds did not change over 3 days, although levels of MeJA and cisJ
      increased 100- and 70-fold, respectively, in surface extracts of attacked leaves
      after feeding of Manduca sexta larvae or application of larval regurgitant to
      mechanical wounds. Inhibition of the wound-induced increase in JA with indole-3
      acetic acid (IAA) revealed an association between the JA accumulation and
      subsequent increases in MeJA and cisJ. Induced systemic increases of MeJA were
      not of local origin and therefore do not contribute to the inactivation of the JA
      burst in the wounded leaf. The total amount of MeJA and cisJ produced could only
      account for 9% of the JA-burst elicited by herbivore attack and therefore their
      production do not represent major disposal pathways of JA in N. attenuata.

PMID- 15032846
TI  - Ion uptake in Pinus banksiana treated with sodium chloride and sodium sulphate.
AB  - Within its wide range across Canada, jack pine is exposed to salinity from both
      natural and anthropogenic sources. To compare the effects of Cl and SO(4) on salt
      injury, sand and solution-culture grown jack pine (Pinus banksiana Lamb.)
      seedlings were treated with nutrient solutions containing 60 or 120 mM NaCl, 60
      mM Na(2)SO(4), or a mixture of 60 mM NaCl and 30 mM Na(2)SO(4). After 5 weeks of
      salt treatments, concentrations of Cl, K, Na, and SO(4) were determined in roots,
      stem and needles of the current and previous years growth, and in necrotic
      needles. To determine the role of water uptake in the absorption and
      translocation of salts in plants, total transpiration was measured as the loss of
      water from a sealed system and related to total plant uptake of Cl, Na, and
      SO(4). Sodium uptake and root-to-shoot transport rates were greater in treatments
      containing Cl. A delay in root-to-shoot transport of both Na and Cl indicates
      retention of these ions in the roots. Electrolyte leakage of needles was more
      closely related to treatment Cl concentrations than treatment Na concentrations.
      The transport of Na ions to the shoot was related to the presence of Cl, but was
      not related to transpiration rate.

PMID- 15032847
TI  - A new SBP-box gene BpSPL1 in silver birch (Betula pendula).
AB  - The SBP-box gene family represents a group of plant-specific genes encoding
      putative transcription factors. Thus far, SBP-domain protein binding sites have
      been found in the promoters of Arabidopsis APETALA1 and Antirrhinum SQUAMOSA. A
      putative SBP-domain binding element has been observed in the promoter of BpMADS5,
      a close homologue of Arabidopsis FRUITFULL in silver birch (Betula pendula). A
      novel SBP-box gene from birch named BpSPL1 has been cloned and characterized. The
      nucleotide sequence of BpSPL1 is similar to Antirrhinum SBP2 and Arabidopsis
      SPL3, apart from the unique finding that BpSPL1 does not contain an intron
      typical to all other known SBP-box genes studied thus far. According to Northern
      blot analysis, BpSPL1 is expressed in birch inflorescences as well as in shoots
      and leaves. Studies using electrophoretic mobility shift assay demonstrate that
      there are nuclear proteins in birch inflorescences which specifically bind to the
      SBP binding element of the promoter of BpMADS5. BpSPL1 expressed in Escherichia
      coli also specifically binds to this element. According to Southern blot
      analysis, there are at least two SBP-box genes in birch. The results suggest that
      SBP-box genes are involved in the regulation of flower development in birch.

PMID- 15032848
TI  - The indole alkaloids brucine, yohimbine, and hypaphorine are indole-3-acetic acid
      specific competitors which do not alter auxin transport.
AB  - The indole alkaloids brucine and yohimbine, just like hypaphorine, counteract
      indole-3-acetic acid (IAA) activity in seedling roots, root hairs and shoots, but
      do not appear to alter auxin transport in roots or in cultured cells. In roots,
      the interactions between IAA and these three alkaloids appear competitive and
      specific since these molecules interact with IAA but with neither 1
      naphthaleneacetic acid (NAA) or 2,4-dichlorophenoxyacetic acid (2,4-D), two
      synthetic auxins. The data reported further support the hypothesis that
      hypaphorine brucine and yohimbine compete with IAA on some auxin-binding proteins
      likely to be auxin receptors and that 2,4-D and NAA are not always perceived by
      the same receptor as IAA or the same component of that receptor. At certain steps
      of plant development and in certain cells, endogenous indole alkaloids could be
      involved in IAA activity regulation together with other well-described mechanisms
      such as conjugation or degradation. Hypaphorine with other active indole
      alkaloids remaining to be identified, might be regarded as a new class of IAA
      antagonists.

PMID- 15032849
TI  - Probing corticular photosynthesis through in vivo chlorophyll fluorescence
      measurements: evidence that high internal CO levels suppress electron flow and
      increase the risk of photoinhibition.
AB  - Twigs of many woody plants possess chlorenchyma under a well-developed periderm
      which lacks stomata and impedes both gas diffusion and light penetration. The so
      called corticular photosynthesis, occurring in the shade and under extremely high
      CO(2) concentrations, was probed in this study through in vivo chlorophyll
      fluorescence measurements. Field comparisons between twigs and corresponding
      leaves in five species indicated that both the dark- and light-adapted PSII
      photochemical efficiencies are considerably lower in twigs at all incident photon
      fluence rates, in spite of the significant attenuation of solar radiation by the
      periderm. Light saturation curves for linear electron transport rates (corrected
      according to the actual light intensities reaching twig chlorenchyma) were
      compatible with a shade-acclimated photosynthetic machinery, showing very low
      maximum electron transport rates (at approximately 5% of the corresponding leaf
      values) and threshold irradiances for light saturation. However, removing
      periderms from twig segments (i.e. relieving the twig interior form the high
      CO(2) partial pressures) considerably improved the light-adapted (but not the
      dark-adapted) PSII photochemical efficiency, allowing the assumption that the
      high internal CO(2) levels may interfere with the smooth functioning of
      photosynthesis. Indeed, laboratory experiments with twig segments equilibrated
      under various CO(2) levels (0.036-20%), resulted in a progressive decrease of
      light-adapted PSII photochemical yield, with the values obtained at 20% CO(2)
      being similar to those obtained with intact twigs in the field. Further
      experiments indicated that high CO(2) combined with high light suppressed the
      development of a photoprotective non-photochemical quenching through a reduction
      of its fast relaxing component, accompanied by a higher risk of photoinhibition.
      It is suggested that high internal CO(2) concentrations in twigs impede
      photosynthesis possibly through acidification of protoplasm and impairment of the
      pH-dependent high energy state quenching followed by reduction in the efficiency
      of heat dissipation.

PMID- 15032850
TI  - 14-3-3 proteins: regulation of signal-induced events.
AB  - The field of signal transduction has experienced a significant paradigm shift as
      a result of an increased understanding of the roles of 14-3-3 proteins. There are
      many cases where signal-induced phosphorylation itself may cause a change in
      protein function. This simple modification is, in fact, the primary basis of
      signal transduction events in many systems. There are a large and growing number
      of cases, however, where simple phosphorylation is not enough to effect a change
      in protein function. In these cases, the 14-3-3 proteins can be required to
      complete the change in function. Therefore signal transduction can be either the
      relatively simple process where phosphorylation alters target activity, or it can
      be a more complex, multistep process with the 14-3-3 proteins playing the major
      role of bringing the signal transduction event to completion. This makes 14-3-3
      modulated signal transduction a more complicated process with additional avenues
      for regulation and variety. Adding further complexity to the process is the fact
      that 14-3-3 proteins are present as multigene families in most organisms (Aitken
      et al. Trends Biochem Sci 17: 498-501, 1992; Ferl Annu Rev Plant Physiol Plant
      Molecular Biology 47: 49-73, 1996), with each member of the family being
      differentially expressed in various tissues and with potentially differential
      affinity for various target proteins. This review focuses on the 14-3-3 family of
      Arabidopsis as a model for further developing understanding of the roles of the
      14-3-3 proteins as modulators of signal transduction events in plants. The
      primary approaches to these questions are not unlike the approaches that would be
      used in the functional dissection of any multigene family, but the interpretation
      of these data will have wide implications since the 14-3-3 s physically interact
      with other protein families.

PMID- 15032851
TI  - Inhibition of photosynthesis by heat stress: the activation state of Rubisco as a
      limiting factor in photosynthesis.
AB  - Although the catalytic activity of Rubisco increases with temperature, the low
      affinity of the enzyme for CO(2) and its dual nature as an oxygenase limit the
      possible increase in net photosynthesis with temperature. For cotton, comparisons
      of measured rates of net photosynthesis with predicted rates that take into
      account limitations imposed by the kinetic properties of Rubisco indicate that
      direct inhibition of photosynthesis occurs at temperatures higher than about 30
      degrees C. Inhibition of photosynthesis by moderate heat stress (i.e. 30-42
      degrees C) is generally attributed to reduced rates of RuBP regeneration caused
      by disruption of electron transport activity, and specifically inactivation of
      the oxygen evolving enzymes of photosystem II. However, measurements of
      chlorophyll fluorescence and metabolite levels at air-levels of CO(2) indicate
      that electron transport activity is not limiting at temperatures that inhibit
      CO(2) fixation. Instead, recent evidence shows that inhibition of net
      photosynthesis correlates with a decrease in the activation state of Rubisco in
      both C(3) and C(4) plants and that this decrease in the amount of active Rubisco
      can fully account for the temperature response of net photosynthesis.
      Biochemically, the decrease in Rubisco activation can be attributed to: (1) more
      rapid de-activation of Rubisco caused by a faster rate of dead-end product
      formation; and (2) slower re-activation of Rubisco by activase. The net result is
      that as temperature increases activase becomes less effective in keeping Rubisco
      catalytically competent. In this opinionated review, we discuss how these
      processes limit photosynthetic performance under moderate heat stress.

PMID- 15032852
TI  - Thermal dependence of enzyme function and inhibition; implications for, herbicide
      efficacy and tolerance.
AB  - Environmental temperature is a critical factor in the lives of almost all
      organisms. Plants experience periods of thermal stress related to seasonal
      patterns of temperature and periodic water deficits. Within the range of non
      lethal temperatures, there are a number of thermal effects on metabolism that are
      a result of the thermal dependence of enzymes. The thermal dependence of enzyme
      kinetic parameters was used to predict that the efficacy of the herbicide
      pyrithiobac on Palmer amaranth would be reduced at temperatures outside a 20-34
      degrees C thermal application range. This prediction is validated in a controlled
      environment study described in this paper. Palmer amaranth was grown for 16 days
      in growth chambers with 34/18 degrees C day/night temperature regime. Pyrithiobac
      was applied to plants at 18, 27 or 40 degrees C. After 1 h at the application
      temperatures the plants were returned to the 34/18 degrees C regime for 14 days
      and post-application biomass accumulation (efficacy) was determined. Dry weight
      accumulation, as a percentage of untreated controls, was 25, 2.5 and 70% for 18,
      27 and 40 degrees C application temperatures. Pyrithiobac efficacy was highest
      for the application within the thermal application range and significantly
      reduced at temperatures above and below. The validation of the earlier prediction
      suggests that temperature-related kinetic limitations on herbicide efficacy may
      also occur in plants with bioengineered herbicide resistance based on herbicide
      metabolism. The theoretical aspects of such thermal limitations on herbicide
      resistance mechanisms are discussed.

PMID- 15032853
TI  - Developmental analysis of carbohydrate metabolism in tomato (Lycopersicon
      esculentum cv. Micro-Tom) fruits.
AB  - Carbohydrate metabolism during the development of fruits of the tomato cultivar
      Micro-Tom was studied. The metabolism of the pericarp and placental tissues was
      found to be different. Starch was degraded more slowly in the placenta in
      comparison with the pericarp, whereas soluble sugars accumulated to a greater
      extent in the pericarp. The activities of glycolytic enzymes tended to peak at 40
      days after flowering. Two of these, phosphoenolpyruvate phosphatase and pyruvate
      kinase, showed a dramatic increase in activity just before this peak, possibly
      indicating a role in up-regulating glycolysis to generate increased ATP that
      would be used during climacteric respiration. The expression of plastidial
      transporters was studied. Both the TPT and Glu6P transporter were expressed
      greatest in green fruits, before declining. The expression of the triose
      phosphate transporter was greater than that of the glucose 6-phosphate
      transporter. The ATP/ADP transporter was expressed to a low level throughout
      fruit development.

PMID- 15032854
TI  - Expression of nir, nor and nos denitrification genes from Bradyrhizobium
      japonicum in soybean root nodules.
AB  - Expression of Bradyrhizobium japonicum wild-type strain USDA110 nirK, norC and
      nosZ denitrification genes in soybean root nodules was studied by in situ
      histochemical detection of beta-galactosidase activity. Similarly, P(nirK)-lacZ,
      P(norC)-lacZ, and P(nosZ)-lacZ fusions were also expressed in bacteroids isolated
      from root nodules. Levels of beta-galactosidase activity were similar in both
      bacteroids and nodule sections from plants that were solely N(2)-dependent or
      grown in the presence of 4 mM KNO(3). These findings suggest that oxygen, and not
      nitrate, is the main factor controlling expression of denitrification genes in
      soybean nodules. In plants not amended with nitrate, B. japonicum mutant strains
      GRK308, GRC131, and GRZ25, that were altered in the structural nirK, norC and
      nosZ genes, respectively, showed a wild-type phenotype with regard to nodule
      number and nodule dry weight as well as plant dry weight and nitrogen content. In
      the presence of 4 mM KNO(3), plants inoculated with either GRK308 or GRC131
      showed less nodules, and lower plant dry weight and nitrogen content, relative to
      those of strains USDA110 and GRZ25. Taken together, the present results revealed
      that although not essential for nitrogen fixation, mutation of either the
      structural nirK or norC genes encoding respiratory nitrite reductase and nitric
      oxide reductase, respectively, confers B. japonicum reduced ability for
      nodulation in soybean plants grown with nitrate. Furthermore, because nodules
      formed by each the parental and mutant strains exhibited nitrogenase activity, it
      is possible that denitrification enzymes play a role in nodule formation rather
      than in nodule function.

PMID- 15032855
TI  - Seasonal and spatial variation of carbohydrates in mistletoes (Viscum album) and
      the xylem sap of its hosts (Populus x euamericana and Abies alba).
AB  - In the present field study we analysed the seasonal pattern of carbohydrate
      composition and contents in the xylem sap of Viscum album and the xylem sap of a
      deciduous (Populusxeuramericana) and a coniferous (Abies alba) host tree species.
      The results were compared with the soluble carbohydrate composition and contents
      of mistletoe tissues. On both hosts significant amounts of glucose, fructose, and
      sucrose were found in the xylem sap of Viscum throughout the seasons. The general
      seasonal pattern of sugar contents, i.e. high concentrations in spring and lower
      concentrations in other seasons on Populus, and intermediate concentrations
      throughout the year on Abies, largely reflected the xylem sap carbohydrate
      composition and contents of the respective host. These observations provide
      indirect evidence for carbohydrate flux from the xylem sap of the host into the
      mistletoe. However, in both hosts xylem sap seems to be deviated into the
      mistletoe without specific control of carbohydrate flux. Differences observed
      between the seasonal pattern of xylem sap carbohydrate concentrations in Viscum
      on Populus and Abies may originate from the different time of leaf development of
      these species. A clear-cut seasonal pattern of soluble carbohydrates was not
      observed in the leaves of Viscum on both hosts. Still soluble carbohydrates seem
      to be reallocated from the senescing to the newly developed leaves of Viscum
      indicating that the seasonal requirement of carbohydrate for growth and
      development can only completely be met by carbohydrate acquisition from the host
      and their own photosynthesis.

PMID- 15032856
TI  - New insights towards the function of glutamate dehydrogenase revealed during
      source-sink transition of tobacco (Nicotiana tabacum) plants grown under
      different nitrogen regimes.
AB  - The metabolic, biochemical and molecular events occurring in the different leaf
      stages along the main axis of tobacco (Nicotiana tabacum) plants grown either on
      a nitrogen-rich medium, on a medium containing ammonium as sole nitrogen source
      or on a nitrogen-depleted medium, are presented. This study shows that the
      highest induction of cytosolic glutamine synthetase (GS1) protein and transcript
      occurs when nitrogen remobilization is maximal as the result of nitrogen
      starvation, whereas both glutamate dehydrogenase (GDH) transcript and activity
      remain at a very low level. In contrast, GDH is highly induced when plants are
      grown on ammonium as sole nitrogen source, a physiological situation during which
      leaf protein nitrogen remobilization is limited. It is therefore concluded that
      GDH does not play a direct role during the process of nitrogen remobilization but
      is rather induced following a built up of ammonium provided externally or
      released as the result of protein hydrolysis during natural leaf senescence.

PMID- 15032857
TI  - Composition and desiccation-induced alterations of the cell wall in the
      resurrection plant Craterostigma wilmsii.
AB  - Resurrection plants have the unique capacity to revive from an air-dried state.
      In order to tolerate desiccation they have to overcome a number of stresses,
      mechanical stress being one. In leaves of the Craterostigma species, an extensive
      shrinkage occurs during drying as well as a considerable cell wall folding. Our
      previous microscopically analysis using immunocytochemistry on the resurrection
      plant Craterostigma wilmsii, has shown an increase in labelling of xyloglucan and
      unesterified pectins in the cell wall during drying. In this study, we have
      undertaken a biochemical approach to separate, quantify and characterize major
      cell wall polysaccharides in fully hydrated and dry leaves of C. wilmsii. Our
      results show that the overall cell wall composition of C. wilmsii leaves was
      similar to that of other dicotyledonous plants with respect to the pectin
      content. However, the structure of the hemicellulosic polysaccharide xyloglucan
      was characterized to be XXGG-type. The data also demonstrate marked changes in
      the hemicellulosic wall fraction from dry plants compared to hydrated ones. The
      most conspicuous change was a decrease in glucose content in the hemicellulosic
      fraction of dry plants. In addition, xyloglucan from the cell wall of dry leaves
      was relatively more substituted with galactose than in hydrated walls. Together
      these findings show that dehydration induces significant alteration of
      polysaccharide content and structure in the cell wall of C. wilmsii, which in
      turn might be involved in the modulation of the mechanical properties of the wall
      during dehydration.

PMID- 15032858
TI  - Growth and morphological responses to different UV wavebands in cucumber (Cucumis
      sativum) and other dicotyledonous seedlings.
AB  - We examined the influence of short-term exposure of different UV wavebands on the
      fine-scale kinetics of hypocotyl growth of dim red light-grown cucumbers (Cucumis
      sativus L.) and other selected dicotyledonous seedlings to evaluate: (1) whether
      responses induced by UV-B radiation (280-320 nm) are qualitatively different from
      those induced by UV-A (320-400 nm) radiation, and (2) whether different wavebands
      within the UV-B elicit different responses. Responses to brief (30 min)
      irradiations with 3 different UV wavebands all included transient inhibition of
      elongation during irradiation followed by wavelength specific responses.
      Irradiations with proportionally greater short wavelength UV-B (37% of UV-B
      between 280 and 300 nm) induced inhibition of hypocotyl elongation within 20 min
      of onset of irradiation, while UV-B including only wavelengths longer than 290 nm
      (and only 8% of UV-B between 290 and 300 nm) induced inhibition of hypocotyl
      elongation with a lag of 1-2 h. The response to short wavelength UV-B was
      persistent for at least 24 h, while the response to long wavelength UV-B lasted
      only 2-3 h. The UV-A treatment induced reductions in elongation rates of
      approximately 6-9 h following exposure followed by a continued decline in rates
      for the following 15-18 h. Short wavelength UV-B also induced positive
      phototropic curvature in both cucumber and Arabidopsis seedlings, and this
      response was present in nph-1 mutant Arabidopsis seedlings defective in normal
      blue light phototropism. Reciprocity was not found for the response to short
      wavelength UV-B. The short wavelength and long wavelength UV-B responses differed
      in dose-response relationships and both short wavelength responses (phototropic
      curvature and elongation inhibition) increased sharply at wavelengths below 300
      nm. These results indicate that different photosensory processes are involved in
      mediating growth and morphological responses to short wavelength UV-B (280-300
      nm), long wavelength UV-B (essentially 300-320 nm) and UV-A. The existence of two
      separate types of hypocotyl inhibition responses to UV-B, with one that depends
      on the intensity of the light source, provides alternate interpretations to
      findings in other studies of UV-B induced photomorphogenesis and may explain
      inconsistencies between action spectra for inhibition of stem growth.

PMID- 15032859
TI  - Influence of ozone on ribonuclease activity in wheat (Triticum aestivum) leaves.
AB  - Ribonucleases (RNases) degrade RNA and exert a major influence on gene expression
      during development and in response to biotic and abiotic stresses. RNase activity
      typically increases in response to pathogen attack, wounding and phosphate (P(i))
      deficiency. Activity also increases during senescence and other programmed cell
      death processes. The air pollutant ozone (O(3)) often induces injury and
      accelerated senescence in many plants, but the biochemical mechanisms involved in
      these responses remain unclear. The objective of this study was to determine
      whether RNase activity and isozyme expression was stimulated in wheat (Triticum
      aestivum L.) flag leaves following treatment with O(3). Plants were treated in
      open-top chambers with charcoal-filtered air (27 nmol O(3) mol(-1)) (control) or
      non-filtered air plus O(3) (90 nmol O(3) mol(-1)) (O(3)) from seedling to
      reproductive stage. After exposure for 56 days, RNase activity was 2.1 times
      higher in flag leaf tissues from an O(3)-sensitive cultivar in the O(3) treatment
      compared with the control, which generally coincided with foliar injury and lower
      soluble protein concentration, but not soluble leaf [P(i)]. Soluble [P(i)] in
      leaf tissue extracts from the O(3) and control treatments was not significantly
      different. RNase activity gels indicated the presence of three major RNases and
      two nucleases, and their expression was enhanced by the O(3) treatment. Isozymes
      stimulated in the O(3) treatment were also stimulated in naturally senescent flag
      leaf tissues from plants in the control. However, soluble [P(i)] in extracts from
      naturally senescent flag leaves was 50% lower than that found in green flag
      leaves in the control treatment. Thus, senescence-like pathological responses
      induced by O(3) were accompanied by increased RNase and nuclease activities that
      also were observed in naturally senescent leaves. However, [P(i)] in the leaf
      tissue samples suggested that O(3)-induced injury and accelerated senescence was
      atypical of normal senescence processes in that P(i) export was not observed in
      O(3)-treated plants.

PMID- 15032860
TI  - Isolation of a dehydrin cDNA from orange and grapefruit citrus fruit that is
      specifically induced by the combination of heat followed by chilling
      temperatures.
AB  - Dehydrins (DHNs; late embryogenesis abundant D-11) are a family of plant proteins
      induced in response to environmental stresses such as water stress, salinity and
      freezing or which occur during the late stages of embryogenesis. Previously, it
      was reported that citrus contains a small gene family encoding a unique class of
      dehydrins that differs from most other plant dehydrins in various respects, such
      as having an unusual K-segment similar to that of gymnosperms. In the present
      study, we identified by cDNA differential display analysis a 'Navel' orange 202
      bp polymerase chain reaction (PCR) fragment, which encoded the typical plant
      angiosperm-type K-segment consensus sequence, and of which the expression was
      down-regulated by exposure to low oxygen levels. The full-length cDNA sequence of
      the orange DHN, designated csDHN (for Citrus sinensis DHN), was further isolated
      by 5'-and 3'-RACE; it had a total length of 933 bp and encoded a predicted
      polypeptide of 235 amino acids. In addition, the same 202-bp 'Navel' dehydrin PCR
      fragment was used to screen a 'Star Ruby' grapefruit flavedo cDNA library, and
      its full-length grapefruit homologue, designated cpDHN (for C. paradisi DHN) was
      isolated and found to have a total length of 1024 bp and to encode a predicted
      polypeptide of 234 amino acids. The defined orange and grapefruit DHN proteins
      were completely identical in the 196 amino acids of their N-terminus but differed
      in their C-terminus region. Overall, the csDHN and cpDHN proteins share 84%
      identity and contain the conserved dehydrin serine cluster (S-segment) and a
      putative nuclear localization signal, but csDHN has one conserved dehydrin K
      segment consensus sequence, whereas cpDHN contains two dehydrin K-segments. Both
      csDHN and cpDHN represent single copy genes, in 'Navel' orange and 'Star Ruby'
      grapefruit genomes, respectively. We found that the cpDHN gene was consistently
      expressed in the fruit peel tissue at harvest, but that its message levels
      dramatically decreased during storage at either ambient or low temperatures.
      However, a pre-storage hot water treatment, given to enhance fruit-chilling
      tolerance, increased cpDHN mRNA levels during the first 3 weeks of cold storage
      at 2 degrees C, and enabled the message levels to be retained for up to a further
      8 weeks of cold storage at 2 degrees C. The hot water treatment by itself had no
      inductive effect on cpDHN gene expression when the fruits were held at non
      chilling temperatures. Other stresses applied to the fruit, such as wounding, UV
      irradiation, water stress, low oxygen and exposure to the stress hormone ethylene
      decreased DHN mRNA levels, whereas abscisic acid had no effect at all.

PMID- 15032861
TI  - Low-temperature-induced transmembrane potential changes in mesophyll cells of
      Arabidopsis thaliana, Helianthus annuus and Vicia faba.
AB  - Glass microelectrodes were inserted into mesophyll cells of intact leaves from
      higher plants: Arabidopsis thaliana, Helianthus annuus and Vicia faba var minor,
      and transient membrane potential changes were recorded in response to a sudden
      temperature drop. The cold-induced potential changes were unaffected by an anion
      channel inhibitor (anthracene-9-carboxylic acid) and potassium channel inhibitor
      (tetraethyl ammonium ion). Verapamil, a calcium channel inhibitor, caused
      significant suppression of the cold-induced potential changes. In the presence of
      calmoduline antagonists (trifluoperazine and N-6-aminohexyl-5-chloro-1
      naphtalenesulphonamide), their amplitudes decreased and their durations were
      prolonged. Neomycin, which suppresses phospholipase C, also caused substantial
      inhibition of the amplitudes of the cold-induced potential changes. It is
      concluded that cold-evoked membrane potential changes are due to calcium influxes
      from both the apoplast and internal stores.

PMID- 15032862
TI  - Induction of high affinity phosphate transporter in the duckweed Spirodela
      oligorrhiza.
AB  - Duckweed plants (Spirodela oligorrhiza) grown under phosphate (Pi)-deficient
      conditions (- P plants) exhibited more than 50-fold higher Pi uptake activity
      than plants grown under Pi-sufficient conditions (+ P plants). The Pi uptake
      activity of - P plants measured using (32)Pi was significantly inhibited by
      carbonylcyanide m-chlorophenylhydrazone, indicating that Pi uptake is energized
      by the electrochemical proton gradient across the plasma membrane (PM). When Pi
      uptake was examined at various concentrations of Pi, more active uptake of Pi was
      observed in - P plants than in + P plants, irrespective of the Pi concentrations.
      An immunoblot analysis of the PM proteins using antiserum against the conserved
      sequence of the high-affinity Pi transporter recognized the occurrence and large
      accumulation of a novel protein band at 48 kDa in - P plants. The protein was
      almost completely extracted with chloroform-methanol (2:1, v/v), but only a trace
      amount of the protein was detected in + P plants. Immunohistochemical studies of
      plant roots using the same antiserum demonstrated a large accumulation of high
      affinity Pi transporters at the outermost cortical cells of - P plants, but not
      of + P plants. When an immunoblot analysis of PM proteins was performed using
      antiserum against the PM H(+)-ATPase, a positive band of about 96 kDa was
      detected in both plants with a similar signal intensity. Furthermore, ATP
      hydrolytic and ATP-dependent H(+)-transporting activities of PM H(+)-ATPase in -
      P plants were not higher than those in + P plants. However, kinetic analyses
      showed that the PM H(+)-ATPase in - P plants had a lower K(m) value and a higher
      coupling efficiency between ATP hydrolysis and H(+) pumping than the
      corresponding values in + P plants. These results suggest that the significant
      stimulation of Pi uptake in - P plants may be due mainly to the induction and
      accumulation of the high-affinity Pi transporter in the PM, and that the
      electrochemical proton gradient across the PM may be generated by the high-ATP
      affinity and energy-efficient H(+) pump in - P plants. This would facilitate the
      acquisition of Pi in S. oligorrhiza under Pi-depleted conditions.

PMID- 15032863
TI  - Arsenic uptake, translocation and speciation in pho1 and pho2 mutants of
      Arabidopsis thaliana.
AB  - Arsenate [As (V)] is taken up by phosphate [P (V)] transporters in the plasma
      membrane of roots cells, but the translocation of As from roots to shoots is not
      well understood. Two mutants of Arabidopsis thaliana (L.) [(pho1, P deficient)
      and (pho2, P accumulator)], with defects in the regulation and translocation of P
      (V) from roots to shoots, were therefore used in this study to investigate
      uptake, translocation and speciation of As in roots and shoots of plants grown in
      soil or nutrient solution. The shoots of the pho2 mutant contained higher P
      concentrations, but similar or slightly higher As concentrations, in comparison
      with the wild type. In the pho1 mutant, the P concentration in the shoots was
      lower, and the As concentration was higher, in comparison with the wild type.
      Both pho2 and the wild type contained mainly As (III) in roots and shoot (67-90%
      of total As). Arsenic was likely to be translocated by a different pathway to P
      (V) in the pho2 and pho1 mutants. Therefore, it is suggested that As (III) is the
      main As species translocated from roots to shoots in Arabidopsis thaliana.

PMID- 15032864
TI  - Gibberellin structure and function: biological activity and competitive
      inhibition of gibberellin 2- and 3-oxidases.
AB  - Some gibberellin (GA) analogues, especially with C-16,17 modifications of GA(5),
      can inhibit growth of plants apparently by acting as competitors with the
      endogenous substrate of GA biosynthetic enzymes. Here, we directly confirm the
      competitive action of GA derivatives but also show that some analogues may retain
      significant bioactivity. A recombinant 3-oxidase from pea, which converts GA(20)
      to bioactive GA(1), was inhibited by GA(5), and 16,17-dihydro-GA(5) derivatives,
      especially if the C-17 alkyl chain length was increased by up to three carbons or
      if the C-13 hydroxyl was acetylated. Genetic confirmation that GA(5) analogues
      target 3-oxidases in vivo was provided by comparing the growth response of a WT
      (LE) pea with a 3-oxidase mutant (le-1). Two pea 2-oxidases that inactivate
      bioactive GAs, were inhibited by GA(1) and GA(3) but were generally insensitive
      to GA(5) analogues. alpha-Amylase production by barley half-seeds in response to
      GA analogues provided a method to study their action when effects on GA
      biosynthesis were excluded. This bioactivity assay showed that 16,17-dihydro
      GA(5) analogues have some inherent activity but mostly less than for GA(5) (5-50
      fold), which in turn was 100-fold less active than GA(1) and GA(3). However,
      although C-17 alkyl derivatives with one or two added carbons showed little
      bioactivity and were purely 3-oxidase inhibitors, adding a third carbon (the 17-n
      propyl-16,17-dihydro GA(5) analogue) restored bioactivity to that of GA(5).
      Furthermore, this analogue has lost its capacity to inhibit stem elongation of
      Lolium temulentum (Mander et al., Phytochemistry 49:1509-1515, 1998a), although
      it strongly inhibits the 3-oxidase. Thus, the effectiveness of a GA derivative as
      a growth retardant will reflect the balance between its bioactivity and its
      capacity to inhibit the terminal enzyme of GA biosynthesis. The weaker growth
      inhibition in dicots including pea (approximately 10%) than in monocots such as
      L. temulentum (>35%) is suggestive of taxonomic differences in the bioactivity of
      GAs and/or their effects on GA biosynthesis.

PMID- 15032865
TI  - Dual induction rather than intermediate daylength response of flowering in
      Echinacea purpurea.
AB  - Echinacea purpurea cv. Bravado and Magnus have been reported to be intermediate
      daylength plants (IDP) which flower in response to photoperiods between 13 and 16
      h. The present experiments with E. purpurea cv. Bravado show that E. purpurea is
      actually a dual induction short-long-day plant which flowers promptly and
      consistently when grown in short day (SD) followed by long day (LD) conditions,
      but not with the reverse sequence of photoperiods. The flowering response
      increased with increasing duration of both the SD and the LD treatments. A
      minimum of 4 weeks of SD followed by 12 LD was required for complete flowering.
      No flowering occurred in continuous SD or LD, whereas a high proportion of plants
      flowered in continuous 14-h daylength. However, flowering was more variable in
      intermediate daylength than after transition from SD to LD. Furthermore,
      photoperiods between 13 and 16 h could satisfy both the primary SD induction and
      the secondary LD induction requirements. As a number of dual induction plants,
      both short-long-day and long-short-day plants, have such an overlapping window of
      effective photoperiods that can trigger both the SD and LD responses, the
      rationale for maintaining IDP as a separate and genuine flowering response group
      is seriously challenged.

PMID- 15032866
TI  - Tissue-specific expression and developmental regulation of cytochrome b561 genes
      in Arabidopsis thaliana and Raphanus sativus.
AB  - Ascorbate (Asc) is an essential molecule in many aspects of development and
      stress responses in plants and animals. Cytochromes b561 (cyts b561) are tightly
      coupled to Asc homeostasis. These proteins are found in mammalian tissues, where
      they are involved in the regeneration of Asc, serving the synthesis of
      catecholamine neurotransmitters, and in intestinal iron reduction. Plant genomes
      encode homologous membrane-associated, Asc-reducible cyts b561. The expression of
      these proteins in plants, however, has so far not been studied. We have now
      examined the expression of two Arabidopsis thaliana cyt b561-encoding genes
      Artb561-1 and Artb561-2-using relative-quantitative RT-PCR and in situ
      hybridization (ISH) techniques. The genes show overlapping and distinct tissue-
      and organ-specific expression patterns. Transcripts of both genes are found in
      leaf epidermal cells, and expression seems to correlate with leaf maturation and
      cessation of cell elongation. Both genes are also expressed in the epidermal cell
      layer of stems and roots in the L1 layer of the shoot apex, in the vascular
      system of leaves, stems and roots, and in the root pericycle. In addition,
      Artb561-1 is expressed in the root cap, whereas Artb561-2 mRNA is found in the
      epidermis of lateral roots, in the root meristem, and in unfertilized ovules.
      These observations provide important information for the elucidation of the
      physiological function of cyts b561 in plants.

PMID- 15032867
TI  - Tomato LeAGP-1 is a plasma membrane-bound, glycosylphosphatidylinositol-anchored
      arabinogalactan-protein.
AB  - Arabinogalactan-proteins (AGPs) are a class of highly glycosylated,
      hydroxyproline-rich glycoproteins that function in plant growth and development.
      Tomato LeAGP-1 represents a major AGP expressed in cultured cells and plants.
      Based on cDNA and amino acid sequence analyses along with carbohydrate and other
      biochemical analyses, tomato LeAGP-1 is hypothesized to be a classical AGP
      localized to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor.
      Here, this hypothesis was tested and supported with the following experiments.
      First, tomato (Lycopersicon esculentum, cv. UC82B) cotyledon protoplasts were
      isolated following cell wall digestion with cellulase and pectinase, and LeAGP-1
      was immunolocalized to the plasma membrane with a LeAGP-1 antibody. Second, LeAGP
      1 was shown to be a major AGP component in plasma membrane vesicles from tomato
      cv. Bonnie Best suspension-cultured cells by Western blot analysis with the LeAGP
      1 antibody. Third, fluorescence microscopy of plasmolysed, transgenic tobacco
      (Nicotiana tabacum BY-2) suspension-cultured cells expressing a green fluorescent
      protein (GFP)-LeAGP-1 fusion product demonstrated localization to the plasma
      membrane and Hechtian threads. Fourth, the GFP-LeAGP-1 fusion protein was present
      in plasma membrane preparations from these transgenic tobacco cells by Western
      blot analysis with a GFP antibody. Fifth, GFP-LeAGP-1 secreted into the culture
      media contained ethanolamine, presumably attached to the C-terminal amino acid
      residue, consistent with its processing and release from the plasma membrane.
      Thus, these data support the hypothesis that LeAGP-1 is localized to the plasma
      membrane via a GPI anchor and suggest possible roles for LeAGP-1 in cellular
      signalling and matrix remodelling.

PMID- 15032868
TI  - Fluridone and norflurazon, carotenoid-biosynthesis inhibitors, promote seed
      conditioning and germination of the holoparasite Orobanche minor.
AB  - Fluridone and norflurazon, two carotenoid-biosynthesis inhibitors, shortened the
      conditioning period required by seeds of Orobanche minor in order to respond to
      the germination stimulant strigol. Neither fluridone nor norflurazon alone
      induced seed germination of O. minor, they promoted strigol-induced germination.
      In addition, these compounds restored the conditioning and germination of seeds
      at a supraoptimal temperature (30 degrees C) as well as in the light. Gibberellic
      acid (GA(3)) showed similar promotive and protective effects on the conditioning
      and germination of O. minor seeds. Although fluridone and norflurazon are known
      to prevent abscisic acid (ABA)-biosynthesis, and stresses such as supraoptimal
      temperatures have been reported to induce ABA accumulation in plants, the amount
      of ABA in the seeds or that released from the seeds into the conditioning media
      was not affected by the fluridone treatment and by exposure to the supraoptimal
      temperature. These results indicate that the promotive and protective effects of
      fluridone and norflurazon on the conditioning and germination of O. minor seeds
      would be attributed to other perturbations rather than the inhibition of ABA
      biosynthesis.

PMID- 15032869
TI  - Sequence of morphological and physiological events during natural ageing and
      senescence of a castor bean leaf: sieve tube occlusion and carbohydrate back-up
      precede chlorophyll degradation.
AB  - The development of castor bean (Ricinus communis L. var. sanguineus) leaves from
      bud break to abscission was studied to determine whether senescence of phloem
      precedes or follows chlorophyll degradation in the course of natural ageing of
      leaves. The castor bean leaf blade took 20 days for full expansion and its
      average life span was 60 days. From the day of full expansion on it suffered a
      substantial loss in N, a small loss in C, K and P and a gain in Ca, Mg and S. The
      content of soluble sugars increased with time, paralleled by a decrease of
      photosynthetic activity. Starch accumulated shortly before chlorophyll breakdown.
      The amino acid level in the leaves decreased steadily together with nitrate
      reductase and glutamine synthetase activity. Reactive oxygen species increased
      and oxidation-protecting compounds decreased during the life span of the leaves.
      Shortly after full leaf expansion an increasing number of sieve plates showed
      strong callose depositions when visualized by aniline blue method. At day 40 only
      half of the sieve tubes appeared functional. Chlorophyll breakdown followed these
      processes with a time lag of approximately 10 days. The sieve tube sap of ageing
      leaves had the same sucrose concentrations as young leaves, whereas amino acid
      concentrations decreased. High levels of reduced ascorbic acid and glutathione
      together with increasing levels of glutaredoxin indicated oxidative strain during
      senescence. We speculate that the gradual increase of reactive oxygen species
      during ageing together with the import of calcium ions lead to the stimulation of
      callose synthesis in plasmodesmata and sieve plates with the consequence of
      inhibition of phloem transport leading to carbohydrate back-up in the leaf blade.
      The latter may finally induce chlorophyll breakdown and, at the end, leaf
      abscission at the petiole base. Thus phloem blockage would precede and may be
      causal for chlorophyll degradation in leaf senescence.

PMID- 15032870
TI  - Redox regulation: an introduction.
AB  - The redox-state is a critical determinate of cell function, and any major
      imbalances can cause severe damage or death. The cellular redox status therefore
      needs to be sensed and modulated before such imbalances occur. Various redox
      active components are involved in these processes, including thioredoxins,
      glutaredoxins and other thiol/disulphide-containing proteins. The cellular
      reactions for cytoprotection and for signalling are integrated with physiological
      redox-reactions in photosynthesis, assimilation and respiration. They also
      determine the developmental fate of the cell and finally decide on proliferation
      or cell death. An international workshop on redox regulation, organized by the
      research initiative FOR 387 of the Deutsche Forschungsgemeinschaft, was held in
      Bielefeld, Germany in 2002. A selection of articles originating from the meeting
      is printed in this issue of Physiologia Plantarum.

PMID- 15032871
TI  - Control of chloroplast redox by the IMMUTANS terminal oxidase.
AB  - Variegation mutants offer excellent opportunities to study interactions between
      the nucleus-cytoplasm, the chloroplast, and the mitochondrion. Variegation in the
      immutans (im) mutant of Arabidopsis is induced by a nuclear recessive gene and
      the extent of variegation can be modulated by light and temperature. Whereas the
      green sectors have morphologically normal chloroplasts, the white sectors are
      devoid of pigments and accumulate a colourless carotenoid, phytoene. The green
      sectors are hypothesized to arise from cells that have avoided irreversible
      photooxidative damage whereas the white sectors originate from cells that are
      photooxidized. Cloning of the IMMUTANS (IM) gene has revealed that IMMUTANS (IM)
      is a plastid homologue of the mitochondrial alternative oxidase. This finding
      suggested a model in which IM functions as a redox component of the phytoene
      desaturation pathway, which requires phytoene desaturase activity. Consistent
      with this idea, IM has quinol oxidase activity in vitro. Recent studies have
      revealed that IM plays a more global role in plastid metabolism. For example, it
      appears to be the elusive terminal oxidase of chlororespiration and also
      functions as a light stress protein.

PMID- 15032872
TI  - Regulation of redox homeostasis in the yeast Saccharomyces cerevisiae.
AB  - An increasingly important area of research is based on sulphydryl chemistry,
      since the oxidation of -SH groups is one of the earliest observable events during
      oxidant-mediated damage and -SH groups play a critical role in the function of
      many macromolecular structures including enzymes, transcription factors and
      membrane proteins. Glutaredoxins and thioredoxins are small heat-stable
      oxidoreductases, conserved throughout evolution, which play key roles in
      maintaining the cellular redox balance. Much progress has been made in analysing
      these systems in the yeast Saccharomyces cerevisiae which is a very useful model
      eukaryote due to its ease of genetic manipulation, its compact genome, the
      availability of the entire genome sequence, and the current rate of progress in
      gene function research. Yeast, like all eukaryotes, contains a number of
      glutaredoxin and thioredoxin isoenzymes located in both the cytoplasm and the
      mitochondria. This review describes recent findings made in yeast that are
      leading to a better understanding of the regulation and role of redox homeostasis
      in eukaryotic cell metabolism.

PMID- 15032873
TI  - Malate valves to balance cellular energy supply.
AB  - In green parts of the plant, during illumination ATP and NAD(P)H act as energy
      sources that are generated mainly in photosynthesis and respiration, whereas in
      darkness, glycolysis, respiration and the oxidative pentose-phosphate pathway
      (OPP) generate the required energy forms. In non-green parts, sugar oxidation in
      glycolysis, respiration and OPP are the only means of producing energy. For
      energy-consuming reactions, the delivery of NADPH, NADH, reduced ferredoxin and
      ATP has to take place at the required rates and in the specific compartments,
      since the pool sizes of these energy carriers are rather limited and, in general,
      they are not directly transported across biomembranes. Indirect transport of
      reducing equivalents can be achieved by malateoxaloacetate shuttles, involving
      malate dehydrogenase (MDH) for the interconversion. Isoenzymes of MDH are present
      in each cellular compartment. Chloroplasts contain the redox-controlled NADP-MDH
      that is only active in the light. In addition, a plastid NAD-MDH that is
      permanently active and is present in all plastid types has been found. Export of
      excess NAD(P)H through the malate valves will allow for the continued production
      of ATP (1) in photosynthesis, and (2) in oxidative phosphorylation. In the latter
      case, the coupled production of NADH is catalysed by the bispecific NAD(P)-GAPDH
      (GapAB) in chloroplasts that is active with NAD even in darkness, or by the
      specific plastid NAD-GAPDH (GapCp) in non-green tissues. When plants are
      subjected to conditions such as high light, high CO(2), NH(4) (+) nutrition, cold
      stress, which require changed activities of the enzymes of the malate valves,
      changed expression levels of the MDH isoforms can be observed. In nodules, the
      induction of a nodule-specific plastid NAD-MDH indicates the changed requirements
      for energy supply during N(2) fixation. Furthermore, the induction of glucose 6
      phosphate dehydrogenase isoforms by ammonium and of ferredoxin and ferredoxin
      NADP reductase by nitrate has been described. All these findings are in line with
      the assumption that a changed redox state caused by metabolic variability leads
      to the induction of enzymes involved in redox poise.

PMID- 15032874
TI  - Microarray analysis and redox control of gene expression in the cyanobacterium
      Synechocystis sp. PCC 6803.
AB  - Expression profiles of Synechocystis sp. PCC 6803 genes in response to growth in
      iron-deficient versus iron-sufficient media and after 30 min treatment with
      H(2)O(2) were determined using a full-genome microarray. We used an anova model
      that accounted for slide and replicate (random) effects as well as dye (a fixed)
      effects to identify statistically significant, differentially expressed genes
      that changed by 1.25-fold or greater during each of these experiments. We
      utilized this microarray data to identify gene clusters that were regulated under
      these stresses, because we are interested in cellular redox control and the way
      in which the cell responds to oxidative stresses. We are particularly interested
      in using differential expression to help determine the function of genes involved
      in redox control and cluster analysis aids this process. We concentrated on four
      gene clusters, two of which were similarly affected by both stresses, and two
      that were only differentially regulated by one of the stresses. We also analysed
      the regulatory genes that responded to these oxidative stresses and discussed the
      changes in transcription of the RNA polymerase sigma factors and the other
      regulatory proteins, many of which represent two-component regulatory systems.

PMID- 15032875
TI  - Adaptation of the photosynthetic electron transport chain in cyanobacteria to
      iron deficiency: The function of IdiA and IsiA.
AB  - In this review we give an overview on the adaptational responses of photosystem
      (PS) II and PSI in cyanobacteria to iron starvation, mainly summarizing our
      results with the mesophilic Synechococcus elongatus PCC 7942. We also discuss
      this process with respect to the strong interrelationship between iron limitation
      and oxidative stress that exists in cyanobacteria as oxygenic photosynthetic
      organisms. The adaptation of the multiprotein complexes PSII and PSI to iron
      starvation is a sequential process, which is characterized by the enhanced
      expression of two major iron-regulated proteins, IdiA (iron deficiency induced
      protein A) and IsiA (iron stress induced protein A). Our results suggest that
      IdiA protects the acceptor side of PSII against oxidative stress under conditions
      of mild iron limitation in a currently unclear way, whereas prolonged iron
      deficiency leads to the synthesis of a chlorophyll a antenna around PSI-trimers
      consisting of IsiA molecules. The physiological consequences of these alterations
      under prolonged iron starvation, as shown by acridine yellow fluorescence
      measurements, are a reduction of linear electron transport activity through PSII
      and an increase of cyclic electron flow around PSI as well as an increase in
      respiratory activity. IdiA and IsiA expression are mediated by two distinct helix
      turn-helix transcriptional regulators of the Crp/Fnr family. IdiB positively
      regulates expression of idiA under iron starvation, and Fur represses
      transcription of isiA under iron-sufficient conditions. Although both
      transcriptional regulators seem to operate independently of each other, our
      results indicate that a cross-talk between the signal transduction pathways
      exists. Moreover, IdiA as well as IsiA expression are affected by hydrogen
      peroxide. We suggest that due to the interdependence of iron limitation and the
      formation of reactive oxygen species, peroxide stress might be the superior
      trigger that leads to expression of these proteins under iron starvation. The
      modifications of PSII and PSI under iron starvation influence the redox state of
      redox-sensitive components of the electron transport chain, and thus the activity
      of metabolic pathways being regulated in dependence of the redox state of these
      components.

PMID- 15032876
TI  - P signalling in unicellular cyanobacteria: analysis of redox-signals and energy
      charge.
AB  - This communication presents a short outline of the current knowledge on the
      molecular basis of P(II) signal transduction in unicellular cyanobacteria with
      respect to the perception of environmental stimuli. First, the general
      characteristics of the P(II) signalling system in unicellular cyanobacteria are
      presented, the hallmark of which is modification by serine-phosphorylation, as
      compared to the paradigmatic P(II) signal transduction system in proteobacteria,
      which is based on tyrosyl-uridylylation. Then, the focus is turned on the signals
      controlling P(II) phosphorylation state. Recently, the cellular phosphatase
      (termed PphA), which specifically dephosphorylates phosphorylated P(II) (P(II)-P)
      was identified in Synechocystis sp. strain PCC 6803. With the availability of a
      PphA-deficient mutant and the purified components for in vitro assay of PphA
      mediated P(II)-P dephosphorylation, novel insights into the signals, to which
      P(II)-P dephosphorylation responds, can be obtained. Here we present an
      investigation of the response of P(II)-P dephosphorylation towards treatments
      that affect the redox-balance of the cells. Furthermore, a possible role of
      varying ATP/ADP ratios on P(II)-P dephosphorylation was examined. From these
      studies, together with previous investigations, we conclude that P(II)-P
      dephosphorylation specifically responds to changes in the levels of central
      metabolites of carbon metabolism, in particular 2-oxoglutarate.

PMID- 15032877
TI  - Active site mutagenesis and phospholipid hydroperoxide reductase activity of
      poplar type II peroxiredoxin.
AB  - The nature of the active site and the substrate specificity of poplar type II
      peroxiredoxin, an enzyme which preferentially uses glutaredoxin as an electron
      donor, were investigated in this study. The type II peroxiredoxin is able to use
      phospholipid hydroperoxide nearly as efficiently as hydrogen peroxide. Two of the
      hyper-conserved amino acid residues in peroxiredoxins have been altered, by site
      directed mutagenesis, generating the mutants T48V and R129Q. The two mutant
      proteins are inactive with hydrogen peroxide or tertiary butyl hydroperoxide as
      substrates. On the other hand, the mutant enzymes catalyse the degradation of
      cumene hydroperoxide with low efficiency. This suggests that the thiol-dependent
      regeneration process of the catalytic cysteine is not affected by the mutations
      and that all substrates are not accommodated identically in the active site.

PMID- 15032878
TI  - The antioxidant status of photosynthesizing leaves under nutrient deficiency:
      redox regulation, gene expression and antioxidant activity in Arabidopsis
      thaliana.
AB  - Redox signals provide important information on plant metabolism during
      development and in dependence on environmental parameters and trigger
      compensatory responses and antioxidant defence. The aim of the study was to
      characterize the redox and antioxidant status of photosynthesizing leaves under
      N, P and S deficiency on a comparative basis. Therefore, redox signals,
      indicators of the cellular redox environment and parameters of antioxidant
      defence were determined and related to general growth parameters, namely (1)
      transcript levels of all chloroplast encoded genes; (2) ascorbate and
      glutathione; (3) activities of catalase (CAT) and ascorbate peroxidase (APX); and
      (4) transcript amounts of eight peroxiredoxins, three catalases and three
      ascorbate peroxidases. The results reveal distinct patterns of redox responses
      dependent on the type of nutrient deficiency. (1) Nitrogen deprivation caused up
      regulation of psbA, psbC, petA, petG and clpP transcripts, down-regulation of
      psbG, psbK and ndhA, a five-fold increase in ascorbic acid, a severe drop in CAT
      and APX activities, although cat1 mRNA levels were increased in young and old
      leaves. (2) With the exception of psbA and psaJ transcripts, P-starvation induced
      a general trend to decreased mRNA abundance of plastome genes; ascorbate and
      glutathione levels were increased, as was the activity of APX and CAT. In
      accordance with that result, transcripts of all cat genes and stromal apx, as
      well as prxIIC, prxIID, were elevated under P deprivation. (3) Sulphur depletion
      increased transcripts of petA, petB, petD, petG, ndhJ and rpo-genes. mRNAs of
      psbG, psbK, atpA, atpB, atpE and atpF were decreased. Glutathione levels dropped
      to less than 25% of control, in parallel activities of APX were stimulated in
      young leaves. Transcripts of many antioxidant enzymes were unaltered or
      decreased, only cat2 mRNA was increased. It is concluded that N-, P- and S
      nutrient deprivation trigger distinct redox changes and induce oxidative stress
      with a rather defined pattern in the context of nutrient-specific alterations in
      metabolism.

PMID- 15032879
TI  - Promoter analysis and transcription profiling: Integration of genetic data
      enhances understanding of gene expression.
AB  - It is increasingly evident that transcription control might be conserved among
      organisms. For this reason, genome sequencing and gene expression profiling
      methods, which have yielded a plethora of data in different organisms, may be
      applied in species where genomic sequence is limited to mostly expression array
      and EST data. The identification of transcription factors and promoters
      associated with gene expression profiles and ESTs could therefore contribute to
      elucidate and predict complex regulatory events in plants.

PMID- 15032880
TI  - Localization of arginine decarboxylase in tobacco plants.
AB  - The lack of knowledge about the tissue and subcellular distribution of polyamines
      (PAs) and the enzymes involved in their metabolism remains one of the main
      obstacles in our understanding of the biological role of PAs in plants. Arginine
      decarboxylase (ADC; EC 4.1.1.9) is a key enzyme in polyamine biosynthesis in
      plants. We have characterized a cDNA coding for ADC from Nicotiana tabacum L. cv.
      Petit Havana SR1. The deduced ADC polypeptide had 721 amino acids and a molecular
      mass of 77 kDa. The ADC cDNA was overexpressed in Escherichia coli, and the ADC
      fusion protein obtained was used to produce polyclonal antibodies. Using
      immunological methods, we demonstrate the presence of the ADC protein in all
      plant organs analysed: flowers, seeds, stems, leaves and roots. Moreover,
      depending on the tissue, the protein is localized in two different subcellular
      compartments, the nucleus and the chloroplast. In photosynthetic tissues, ADC is
      located mainly in chloroplasts, whereas in non-photosynthetic tissues the protein
      appears to be located in nuclei. The different compartmentation of ADC may be
      related to distinct functions of the protein in different cell types.

PMID- 15032881
TI  - Sugar and fructan accumulation during metabolic adjustment between respiration
      and fermentation under low oxygen conditions in wheat roots.
AB  - In terms of gene expression and carbohydrate metabolism, the response of wheat
      seedlings to hypoxia is dramatically different from the anoxic response. Total
      carbohydrate content of roots increased 4-fold during 6 days of hypoxia, with a
      17-fold increase in fructans. In contrast, anoxically treated roots depleted all
      soluble carbohydrates and died within 72 h. Gas exchange measurements (CO(2)
      release vs. O(2) uptake) demonstrate that hypoxia establishes a new balance
      between fermentation and aerobic respiration in the roots without altering the
      flux of carbon through glycolysis. Furthermore, the respiratory component of this
      new balance is 55% higher in roots that have been hypoxically pretreated compared
      to non-hypoxically pretreated roots. The establishment of this new homeostasis
      under hypoxia involves the induction of glycolytic (aldolase and enolase) and
      fermentative enzymes (pyruvate decarboxylase, alcohol dehydrogenase, and lactate
      dehydrogenase). Enzyme induction is generally complete within 24 h with mRNA
      induction occurring primarily during Period I (0-6 h of hypoxia), and maximal
      enzymes activities attained during Period II (6-24 h of hypoxia). Accumulation
      rates of Suc, hexoses, and fructans also change during Periods I and II. By the
      start of Period III (24-144 h of hypoxia), the metabolic adjustments are complete
      and fructans are the major carbohydrate accumulated. In anoxia, the pattern of
      enzyme induction was dramatically different: aldolase was not induced and
      declined throughout the treatment. Alcohol dehydrogenase, pyruvate decarboxylase,
      and lactate dehydrogenase were induced as in hypoxia, but rapidly declined within
      72 h of anoxia. Only enolase exhibited a similar expression pattern in both
      anoxia and hypoxia.

PMID- 15032882
TI  - Differential effects of aluminium on osmotic potential and sugar accumulation in
      the root cells of Al-resistant and Al-sensitive wheat.
AB  - The changes in osmotic potential and the concentration of osmotic solutes in the
      cell sap of the root tips exposed to Al were examined in two cultivars of wheat
      (Triticum aestivum) differing in Al resistance. Root elongation was less
      influenced by an 8-h exposure to 20 microM or 50 microM Al in Al-resistant cv.
      Atlas 66 than in Al-sensitive cv. Scout 66. After Al treatment the osmotic
      potential of the root cells was decreased in Atlas 66 but increased in Scout 66
      indicating that the Al treatment osmotically stimulated the driving force for
      water uptake in Atlas 66 but suppressed it in Scout 66. Al increased the
      concentration of soluble sugars, the major osmotic solute in the root cells in
      Atlas 66, but decreased it in Scout 66. Al at both low (5 microM) and high (50
      microM) concentrations, also increased the concentration of soluble sugars in the
      Al-resistant genotype ET8 but a high Al concentration decreased it in Al
      sensitive genotype ES8. Enzymatic analyses and thin-layer chromatography revealed
      that soluble sugars in the root cells of both Atlas 66 and Scout 66 mainly
      consisted of monosaccharides such as glucose, fructose and a small amount of
      sucrose. These results suggest that the accumulation of soluble sugars in Al
      resistant wheat Atlas 66 keeps the osmotic potential in the root cells low and
      thus, enables the root cells to take up water and to elongate against the
      pressure produced by cell wall rigidification under Al stress.

PMID- 15032883
TI  - Methyl jasmonate alters N partitioning, N reserves accumulation and induces gene
      expression of a 32-kDa vegetative storage protein that possesses chitinase
      activity in Medicago sativa taproots.
AB  - This study presents the effects of methyl jasmonate (MeJA) on growth, N uptake, N
      partitioning, and N storage in taproots of non-nodulated alfalfa (cv. Lodi). When
      compared to untreated plants, addition of 100 micro M MeJA to the nutrient
      solution for 14 days reduced total growth and modified biomass partitioning
      between shoots and roots in favour of taproots and lateral roots. MeJA decreased
      N uptake (after 7 days) and increased N partitioning towards roots after 14 days.
      This preferential N partitioning to roots was accompanied by increased N storage
      in taproots as soluble proteins. Compared to total soluble proteins, VSP
      accumulation occurred earlier (7 days), and was greater (2-fold increase) in
      plants treated with 100 micro M MeJA. Steady-state transcript levels for two VSPs
      (32 and 57 kDa) also increased markedly (about 4-fold) in roots of plants treated
      with 100 micro M MeJA. This suggests that MeJA could act directly
      (transcriptional regulation) or indirectly (via the changes of N partitioning
      among alfalfa organs) on N storage as soluble proteins and in particular, VSPs.
      Because the deduced amino acid sequence of the 32 kDa VSP clone reveals high
      homology with Class III chitinases, we propose that the 32 kDa VSP may have a
      role in pathogen defense, in addition to its function as a storage protein.

PMID- 15032884
TI  - Variation in nitrate uptake and assimilation between two ecotypes of Lotus
      japonicus and their recombinant inbred lines.
AB  - A large genetic variability was observed in the shoot NO(3) (-) content of
      recombinant inbred lines (RILs) of Lotus japonicus. To determine the cause of
      this variability, we have studied some aspects of nitrate uptake and assimilation
      in the two parental ecotypes (Gifu and Funakura) and four representatives of the
      RILs population differing both in their shoot biomass and shoot NO(3) (-)
      content. Higher shoot NO(3) (-)content was mainly due to an increase in the
      uptake of the ion regardless of the plant biomass production. The positive
      correlation observed between the shoot NO(3) (-) content and the steady state
      level of mRNA encoding high affinity NO(3) (-) transporters suggests that the
      higher NO(3) (-) influx is due to enhanced expression of the transporters. In
      contrast, neither the level of nitrate reductase mRNA, nor the potential enzyme
      activity in vivo in the different lines was correlated with the shoot NO(3) (-)
      content. This indicates that NO(3) (-) transport in Lotus is one of the main
      checkpoints controlling shoot NO(3) (-) accumulation. In addition, this study
      shows that at least in Lotus, it is possible, through breeding strategies, to
      lower the NO(3) (-) content without affecting biomass production.

PMID- 15032885
TI  - Phytohormonal responses in enod40-overexpressing plants of Medicago truncatula
      and rice.
AB  - Phytohormones are well-known regulators of the symbiotic Rhizobium-legume
      association in the plant host. The enod40 nodulin gene is associated with the
      earliest phases of the nodule organogenesis programme in the legume host and
      modifying its expression resulted in perturbations of nodule development in
      Medicago truncatula. Therefore in our pursuit to mimic the initial signal
      transduction steps of legume nodulation in the alien physiological set-up of a
      rice plant, we have expressed the Mtenod40 gene in rice. Molecular data confirm
      the stable integration, inheritance and transcription of the foreign gene in this
      non-legume. We have compared the phytohormonal responses of Mtenod40
      overexpressing and control plants in a homologous legume background (M.
      truncatula) and in the non-legume rice. An enod40-mediated root growth response,
      induced by inhibition of ethylene biosynthesis, was observed in both plants. On
      the other hand, a significant differential effect of cytokinins was observed only
      in rice plants. This suggests that ethylene inhibits enod40 action both in
      legumes and non-legumes and reinforces that some of the early signal transduction
      steps of the nodule developmental programme may function in rice.

PMID- 15032886
TI  - Interaction of spermine with a signal transduction pathway involving
      phospholipase C, during the growth of Catharanthus roseus transformed roots.
AB  - In Cantharanthus roseus transformed roots, the application of methylglyoxal
      bis(guanylhydrazone) (MGBG), an inhibitor of S-adenosylmethionine decarboxylase
      (SAMDC; EC 4.1.1.50), inhibited the root growth in a dose-dependent manner with a
      DL(50) of about 300 micro m. Spermidine and spermine (Spm) levels and SAMDC and
      phospholipase C (PLC; EC 3.1.4.3) activities were reduced in the presence of the
      inhibitor. The inhibition was reversed by the addition of Spm. Radioactivity from
      [(14)C]Spm was detected in an immunoprecipitated fraction with an antibody anti
      PLC-delta. To our knowledge, this is the first direct evidence that demonstrates
      an interaction of Spm with the signal transduction cascade phosphoinositide
      Ca(2+).

PMID- 15032887
TI  - Hyperhydricity in micropropagated carnation shoots: the role of oxidative stress.
AB  - The physiology of hyperhydricity in relation to oxidative stress, mineral
      nutrients, antioxidant enzymes and ethylene has been studied in three
      micropropagated carnation cultivars under experimentally induced hyperhydricity.
      A marked increase in Fe content in comparison with normal tissues was observed in
      the hyperhydric tissues from the three cultivars. The levels of ethylene, solute
      leakage and malondialdehyde content were also significantly higher in the
      hyperhydric tissues. In relation to the time course of H(2)O(2) production
      measured by fluorescence quenching, a similar trend could be observed for the
      three cultivars, with a clear increase in the generation of hydrogen peroxide in
      hyperhydric tissues. The activities of all the antioxidative enzymes studied,
      except lipoxygenase, were higher in the hyperhydric shoots. Phenylalanine ammonia
      lyase (PAL) showed a significant decrease in activity in the hyperhydric tissues
      in comparison with the controls for the three cultivars. Soluble guaiacol
      peroxidase had a strong increase in activity in hyperhydric shoots of the three
      cultivars. These results provide, for the first time, direct evidence of H(2)O(2)
      generation in hyperhydric tissues, characterize the response of the antioxidant
      system to an oxidative stress during hyperhydricity in carnation leaves and point
      to the accumulation of toxic forms of oxygen as the inducer of some of the
      abnormalities observed.

PMID- 15032889
TI  - Erratum.

PMID- 15032888
TI  - Vessel differentiation in the pedicel of apple and the effects of auxin transport
      inhibition.
AB  - The growth dynamics of vessel formation and the effect of auxin transport
      inhibition on vessel differentiation were investigated in the pedicel of
      developing apple (Malus domestica Borkh.). Quantitative microscopic analysis
      showed that a majority of vessels were differentiated pre-bloom with the
      commencement of pedicel extension but that the full conducting capacity of the
      xylem was attained shortly after bloom. The effect of a post-bloom application of
      N-(1-Napthyl)phthalamic acid showed that an auxin-like signal emanating from the
      young fruit not only stimulated vessel differentiation in the pedicel but also
      controlled fruit abscission and the development of the seed and fruit.

PMID- 15032890
TI  - A time of 'firsts'.

PMID- 15032891
TI  - Tooth preparation: a study on the effect of different variables and a comparison
      between conventional and channeled diamond burs.
AB  - PURPOSE: The purpose of this study was to evaluate the different variables
      involved in tooth cutting to characterize intrapulpal temperature generation,
      cutting efficiency, and bur durability when using conventional and channeled
      diamond burs. MATERIALS AND METHODS: Forty premolars and 60 molars were selected
      for the study. Four diamond burs were paired according to grit size: 125-microm
      grit: Brasseler Coarse (Control 1) and TDA System (Test 1) burs; and 180-microm
      grit: Brasseler CRF (Control 2) and NTI Turbo Diamond (Test 2) burs. Each bur was
      used twice when cutting the premolar teeth, whereas it was used for 60 cuts when
      cutting the molar teeth. The data were analyzed to compare the correlation of bur
      design, grit and wear, amount of pressure, advancement rate, revolutions per
      minute, cutting time and rate, and proximity to the pulp chamber with intrapulpal
      temperature generation, cutting efficiency, and bur longevity. The mean values of
      test and control burs in each group were compared using an ANOVA (p < 0.05 for
      significant differences) for temperature generation and an ANOVA and the Tukey
      multiple range test (p< or = 0.05) for cutting efficiency and bur longevity.
      RESULTS: No significant difference was found in intrapulpal temperature
      generation while cutting premolar and molar teeth with conventional and channeled
      diamond burs. In both groups, the mean temperature recorded during and after the
      cutting procedure was lower than the baseline temperature. For premolar teeth, no
      significant difference was established for control and test burs for the load
      required to cut into the tooth and the cutting rate. However, both test burs
      showed significantly fewer revolutions per minute when compared to their control
      counterparts. For the molar teeth, the Brasseler CRF bur required a significantly
      lower cutting load when compared to the NTI bur, whereas no difference was noted
      between the other pair of burs. The cutting rate was significantly higher for
      both control burs, whereas revolutions per minute (rpm) were greater for control
      coarser burs only. Overall, channeled burs showed a significantly lower cutting
      efficiency when compared to conventionally designed burs. CONCLUSION: Within the
      limitations of this study, channeled burs showed no significant advantage over
      conventional diamond burs when evaluating temperature generation and bur
      durability. Moreover, the cutting efficiency of conventional burs was greater
      than that of channeled burs.

PMID- 15032892
TI  - Evaluation of mechanical and thermal properties of commonly used denture base
      resins.
AB  - PURPOSE: The purpose of this investigation was to evaluate and compare the
      mechanical and thermal properties of 6 commonly used polymethyl methacrylate
      denture base resins. MATERIALS AND METHODS: Sorption, solubility, color
      stability, adaptation, flexural stiffness, and hardness were assessed to
      determine compliance with ADA Specification No. 12. Thermal assessments were
      performed using differential scanning calorimetry and dynamic mechanical
      analysis. Results were assessed using statistical and observational analyses.
      RESULTS: All materials satisfied ADA requirements for sorption, solubility, and
      color stability. Adaptation testing indicated that microwave-activated systems
      provided better adaptation to associated casts than conventional heat-activated
      resins. According to flexural testing results, microwaveable resins were
      relatively stiff, while rubber-modified resins were more flexible. Differential
      scanning calorimetry indicated that microwave-activated systems were more
      completely polymerized than conventional heat-activated materials. CONCLUSION:
      The microwaveable resins displayed better adaptation, greater stiffness, and
      greater surface hardness than other denture base resins included in this
      investigation. Elastomeric toughening agents yielded decreased stiffness,
      decreased surface hardness, and decreased glass transition temperatures.

PMID- 15032893
TI  - Effect of different ceramic surface treatments on resin microtensile bond
      strength.
AB  - PURPOSE: The objective of this study was to evaluate the effect of different
      surface treatments on the microtensile bond strength (micro-tbs) of composite
      bonded to hot-pressed ceramic. The null hypothesis tested was that neither of the
      surface treatments (silanization or fluoric acid etching) would produce greater
      bond strength of composite resin to the ceramic. MATERIALS AND METHODS: Four 7 x
      7 x 5 mm hot-pressed ceramic blocks of IPS Empress 2 were fabricated and polished
      to 600 grit followed by sandblasting with 50 microm alumina. The ceramic blocks
      were then divided into four groups and submitted to the following surface
      treatments: Group 1: 9.5% hydrofluoric (HF) acid for 20 seconds and silane (S)
      for 3 minutes; Group 2: silane for 3 minutes; Group 3: 9.5% HF acid for 20
      seconds; Group 4: no treatment. Scotchbond adhesive was applied to the treated
      ceramic surfaces and covered with Filtek Z250 composite resin. The composite
      ceramic blocks were cut with an Isomet low speed diamond saw machine producing
      sticks (n = 25), which were loaded to failure under tension in an Instron
      Universal testing machine. The mean micro-tbs was analyzed with one-way ANOVA and
      Bonferroni "t" test. RESULTS: All specimens of Group 4 experienced adhesive
      failure during the cutting of the block and were eliminated. The mean micro-tbs
      and standard deviations (SD) in megaPascals were: Group 1 = 56.8 (+/-10.4), Group
      2 = 44.8 (+/-11.6), Group 3 = 35.1 (+/-7.7). Statistical analysis showed that the
      bond strength was significantly affected by surface treatment (p < 0.0001). Group
      1 (HF + S) had the highest micro-tbs, and Group 2 (S) had higher micro-tbs than
      Group 3 (HF). The mode of fracture of the specimens was examined using scanning
      electron microscopy (SEM), and all fractures occurred within the adhesion zone.
      CONCLUSION: The results show that surface treatment is important for resin
      adhesion to ceramic and suggestthat silane treatment was the main factor
      responsible for resin bonding to ceramic.

PMID- 15032894
TI  - Crowns cemented on crown preparations lacking geometric resistance form. Part II:
      effect of cement.
AB  - PURPOSE: This study evaluated the effect of different cements on resistance to
      dislodgment of crowns cemented on preparations lacking geometric resistance form.
      MATERIALS AND METHODS: A preparation that offered no geometric resistance form,
      with 20 degrees total occlusal convergence (TOC), 0.9 mm wide shoulder finish
      line, and a 2.5 mm axial wall height was created on an ivorine tooth using a
      milling machine. Ten metal test specimen die replicas and 10 standardized metal
      crowns with recipient sites for the application of external forces through a
      universal testing machine were fabricated. The crowns were cemented on the dies
      under 5 and 10 kg external loads, the marginal openings measured, loaded to
      dislodgment, and cleaned of cement. The process was repeated using zinc oxide and
      eugenol (ZOE), zinc phosphate (ZPh), resin modified glass ionomer (RMGI), and
      composite resin (CR) cements. RESULTS: Marginal openings under 5 kg cementation
      loads were 74.63 (+/-15.04) for ZOE, 75.98 (+/-18.20) microm for ZPh, 98.58 (+/
      22.62) microm for RMGI, and 105.82 (+/-20.07) microm for CR cements respectively;
      under 10 kg cementation loads they were 57.62 (+/-15.86) microm, 59.55 (+/-15.41)
      microm, 95.00 (+/-19.52) microm, 101.30 (+/-12.52) microm respectively. Oblique
      dislodgment forces, measured with a Universal testing machine, were 40.18 (+/-
      6.76) N for ZOE, 215.65 (+/-45.79) N for ZPh, 165.43 (+/-19.53) N for RMGI, and
      181.54 (+/-30.75) N for CR respectively when crowns were cemented under 5 kg
      loads. The corresponding values for 10 kg loads were 38.62 (+/-4.19), 274.86 (+/
      54.22), 139.70 (+/-21.71), and 160.40 (+/-21.21) respectively. Only zinc
      phosphate cement produced statistically enhanced resistance when crowns were
      cemented under 10 kg force (p value = 0.035). CONCLUSIONS: Under the conditions
      of the present study only crowns cemented with zinc phosphate displayed increased
      resistance to dislodgment on preparations lacking resistance form.

PMID- 15032895
TI  - An experimental study on particular physical properties of several interocclusal
      recording media. Part I: consistency prior to setting.
AB  - PURPOSE: To evaluate the consistency prior to the setting of 5 elastomeric
      interocclusal recording materials in comparison with a wax and a zinc oxide
      eugenol paste. This property is related to the viscosity as well as to the
      working and setting times of these materials. MATERIALS AND METHODS: Testing of
      consistency was performed following a modification of the method described in ADA
      Specification No. 19, for elastomeric impression materials. Each one of the
      tested materials was mixed for 20 seconds and was then loaded into a 0.5 mL
      syringe. The material was syringed onto a 10 x 10 x 0.5 cm glass plate. A second
      575 g glass plate was placed on top of the unset interocclusal registration
      material. A total of 10 samples were tested for each material. The surface area
      covered by the materials was measured with the help of a scanner and the use of
      appropriate computer software. RESULTS: One-way ANOVA revealed significant
      differences among the materials (F = 889.493, p < 0.0005). According to Tukey's
      honest significant difference test, all materials were significantly different (p
      < 0.05) from one another. All polyvinylsiloxanes occupied a smaller area than
      that of the polyether and of the zinc oxide-eugenol paste. CONCLUSIONS: Zinc
      oxide-eugenol paste was the most fluid of all materials tested.
      Polyvinylsiloxanes displayed less flow properties than polyether.

PMID- 15032896
TI  - Retrofitting an existing implant overdenture to a new and redesigned intraoral
      framework: a clinical report.
AB  - The esthetics and function of a tissue borne, implant retained overdenture are
      two of the most important factors that define a patient's acceptance of the
      prosthesis. In this clinical report, an existing implant overdenture, which was
      esthetically acceptable to the patient but which had no incorporated retentive
      components in the substructure framework, was retrofitted to a newly designed and
      fabricated implant framework. The added retentive components on the new framework
      increased the patient's overall masticatory function, reduced the frequency of
      dental visits, and allowed the patient to retain the original overdenture.

PMID- 15032897
TI  - Retrofitting a cast dowel-core on salvaged dental implants.
AB  - Dental implant screw fracture involves attempting to retrieve the screw fragment
      or, as an alternative, attempting to salvage the dental implant. Circumstances
      that do not allow for screw retrieval require a solution in which the internal
      configuration of the dental implant can provide for a custom direct dowel
      fabrication. The proposed technique is to retrofit the fabrication of a custom
      cast dowel-core and provisional use of a direct procedure, which provides
      accuracy of fit, retention, and ease of production.

PMID- 15032898
TI  - Maximizing mandibular prosthesis stability utilizing linear occlusion, occlusal
      plane selection, and centric recording.
AB  - The stability of mandibular complete dentures may be improved by reducing the
      transverse forces on the denture base through linear (noninterceptive) occlusion,
      selecting an occlusal plane that reduces horizontal vectors of force at occlusal
      contact, and utilizing a central bearing intraoral gothic arch tracing to record
      jaw relations. This article is intended to acquaint the reader with one technique
      for providing stable complete denture prostheses using the aforementioned
      materials, devices, and procedures.

PMID- 15032905
TI  - Perspectives on hyperphalangy: patterns and processes.
AB  - Hyperphalangy is a digit morphology in which increased numbers of phalanges are
      arranged linearly within a digit beyond the plesiomorphic condition. We analyse
      patterns and processes of hyperphalangy by considering previous definitions and
      occurrences of hyperphalangy among terrestrial and secondarily aquatic extant and
      fossil taxa (cetaceans, ichthyosaurs, plesiosaurs and mosasaurs), and recent
      studies that elucidate the factors involved in terrestrial autopod joint
      induction. Extreme hyperphalangy, defined as exceeding a threshold condition of
      4/6/6/6/6, is shown only to be found among secondarily aquatic vertebrates with a
      flipper limb morphology. Based on this definition, hyperphalangy occurs
      exclusively in digits II and III among extant cetaceans. Previous reports of
      cetacean embryos having more phalanges than adults is clarified and shown to be
      based on cartilaginous elements not ossified phalanges. Developmental
      prerequisites for hyperphalangy include lack of cell death in interdigital
      mesoderm (producing a flipper limb) and maintenance of a secondary apical
      ectodermal ridge (AER), which initiates digit elongation and extra joint
      patterning. Factors of the limb-patterning pathways located in the interdigital
      mesoderm, including bone morphogenetic proteins (BMPs), BMP antagonists,
      fibroblast growth factors (FGFs), growth/differentiation factor-5 (GDF-5), Wnt-14
      and ck-erg, are implicated in maintenance of the flipper limb, secondary AER
      formation, digit elongation and additional joint induction leading to
      hyperphalangy.

PMID- 15032906
TI  - The Chinese Visible Human (CVH) datasets incorporate technical and imaging
      advances on earlier digital humans.
AB  - We report the availability of a digitized Chinese male and a digitzed Chinese
      female typical of the population and with no obvious abnormalities. The embalming
      and milling procedures incorporate three technical improvements over earlier
      digitized cadavers. Vascular perfusion with coloured gelatin was performed to
      facilitate blood vessel identification. Embalmed cadavers were embedded in
      gelatin and cryosectioned whole so as to avoid section loss resulting from
      cutting the body into smaller pieces. Milling performed at -25 degrees C
      prevented small structures (e.g. teeth, concha nasalis and articular cartilage)
      from falling off from the milling surface. The male image set (.tiff images each
      of 36 Mb) has a section resolution of 3072 x 2048 pixels ( approximately 170
      micro m, the accompanying magnetic resonance imaging and computer tomography data
      have a resolution of 512 x 512, i.e. approximately 440 micro m). The Chinese
      Visible Human male and female datasets are available at
      http://www.chinesevisiblehuman.com. (The male is 90.65 Gb and female 131.04 Gb).
      MPEG videos of direct records of real-time volume rendering are at:
      http://www.cse.cuhk.edu.hk/~crc

PMID- 15032907
TI  - Cytoarchitecture and musculotopic organization of the facial motor nucleus in
      Cebus apella monkey.
AB  - The architecture and musculotopic organization of the facial motor nucleus in the
      Cebus apella monkey (a New World primate) were investigated using histological
      techniques and a multiple labelling strategy, in which horseradish peroxidase
      conjugated neuroanatomical tracers (CTB-HRP and WGA-HRP) and fluorescent tracers
      were injected into individual facial muscles. The facial motor nucleus was formed
      by multipolar motoneurons and had an ovoid shape, with its rostrocaudal axis
      measuring on average 1875 micro m. We divided the nucleus into four different
      subnuclei: medial, intermediate, dorsal and lateral. Retrograde labelling
      patterns revealed that individual muscles were innervated by longitudinal
      functional columns of motoneurons. The columns of the orbicularis oculi,
      zygomaticus, orbicularis oris, auricularis superior, buccinator and platysma
      muscles were located in the dorsal, intermediate, lateral, medial, lateral and
      intermediate subnuclei, respectively. However, the motoneuron columns of the
      levator labii superioris alaeque nasi muscle and frontalis muscle could not be
      associated with a specific subnucleus. The present results confirm previous
      studies regarding the musculotopic organization of the facial motor nucleus.
      However, we observed some particularities in terms of the relative size of each
      column in C. apella, which might be related to the functional and behavioral
      importance of each muscle in the particular context of this primate.

PMID- 15032908
TI  - Light microscopy and computer three-dimensional reconstruction of the blood
      capillaries of the enamel organ of rat molar tooth germs.
AB  - We performed a light microscope and a computer three-dimensional reconstruction
      study of serial sections of the molar enamel organ of 3- and 5-day-old rats
      perfused with Indian ink through the arterial system. The tooth germs were fixed
      in Bouin's solution, embedded in paraffin, sectioned and stained with
      haematoxylin and eosin. For the three-dimensional reconstruction, light
      micrographs of the serial sections were digitized, and aligned using the serial
      EM Align software downloaded from http://synapses.bu.edu/tools/. After alignment,
      the boundaries of the India-ink-filled blood vessels were manually traced with a
      mouse using the software IGL trace (version 1.26b), also downloaded from the
      above website. After tracing, a three-dimensional representation of the blood
      vessel contours was generated in a VRML format and visualized with the help of
      the software Cortona Web3D viewer (version 4.0) downloaded from
      http://www.parallelgraphics.com/products/cortona/. Our results showed that in
      regions where ameloblasts are polarized the capillaries are arranged in three
      distinct levels: (1) penetrating and leaving capillaries in relation to the outer
      enamel epithelium; (2) capillaries crossing and branching inside the stellate
      reticulum; and (3) capillaries branching and anastomosing profusely within the
      stratum intermedium, thereby forming an extensive capillary plexus intimately
      associated with the cells of the stratum intermedium. The existence of a
      conspicuous capillary plexus intermingled with cells of the stratum intermedium,
      as shown in our results, suggests that some molecules produced by cells of the
      stratum intermedium could be released into the capillary plexus and thereafter
      carried to the dental follicle.

PMID- 15032909
TI  - Histological organization and its relationship to function in the femur of
      Alligator mississippiensis.
AB  - Histological analysis of a growth series of alligator femora tests the
      correlation between strain milieu and microstructure. From mid-diaphyseal cross
      sections of these femora (n = 7), vascular canal orientation and density as well
      as collagen fibre organization were recorded. Throughout ontogeny, the proportion
      of transverse-spiral (TS) collagen in the dorsal cortex is significantly greater
      than it is in the ventral cortex (P = 0.008). This regional difference in the
      proportion of TS collagen is correlated with a regional difference in the state
      of peak principal strain (compressive or tensile). Nevertheless, the predominant
      orientation of collagen fibres is longitudinal, which is inconsistent with
      biomechanical hypotheses that involve peak principal or shear strains. Although
      the density and orientation of vascular canals do not show significant regional
      differences (P = 0.26 and P = 0.26, respectively), as with collagen orientation,
      the vascular canal orientation is predominantly longitudinal. The longitudinal
      organization of both the vascular canals and the collagen fibres is probably a
      consequence of longitudinal shifting of subperiosteal osteoid during femoral
      lengthening. When taken together, these data suggest that growth dynamics is the
      dominant influence on the histological organization of primary bony tissues in
      alligator femora.

PMID- 15032910
TI  - Nutrition pathways to the symphysis pubis.
AB  - The blood supply of the symphysis pubis is still the subject of some debate.
      Classic anatomy books state that this joint is avascular, whereas some published
      works have shown blood vessels in young specimens. As several articular discs
      such as the knee menisci are known to have blood vessels in their peripheries, we
      decided to investigate the possible nutrition pathways to the interpubic disc and
      ligaments. We used 60 Wistar rats, male and female, aged between 28 and 32 days,
      or between 90 and 100 days. Samples were processed using a variety of techniques:
      regular histology, immunohistochemestry, India ink injection and corrosion
      casting. The interpubic disc consisted of an inner bearing portion and an outer
      fibrous rim. The interpubic ligaments and the fibrous rim were well vascularized
      in all groups. Marrow contacts between the interpubic disc and the subchondral
      bone were also observed. Blood vessels formed an authentic arterial circle
      embracing the joint, from which blood vessels branched into capillary loops
      facing the avascular inner bearing portion of the disc. These results confirm the
      need for future studies on the human symphysis pubis, to provide more details on
      its structure, which would enable clinicians such as physiotherapists to improve
      prognosis and treatment design. Future studies may also explain the pathways down
      which the hormone relaxin reaches its targets within this joint.

PMID- 15032911
TI  - Aromatase immunolocalization in human ductuli efferentes and proximal ductus
      epididymis.
AB  - Abstract Cytochrome P450 aromatase is a terminal enzyme that catalyses the
      conversion of androgens into oestrogens. This study investigated the
      immunohistochemical localization of aromatase in human efferent ductules and
      proximal ductus epididymis using a mouse anti-human monoclonal P450arom IgG as
      primary antibody and a goat anti-mouse biotinylated IgG as secondary antibody. A
      strong immunoreaction was observed in the epithelial cell cytoplasm of both
      ductuli efferentes and proximal ductus epididymis, whereas the smooth muscle
      cells were immunonegative in the two regions. The results show, for the first
      time in humans, that epithelial cells of ductuli efferentes and proximal caput
      epididymis express aromatase, suggesting that locally produced oestrogens may
      have a role in epididymal function.

PMID- 15032912
TI  - Specific changes of somatostatin mRNA expression in the frontal cortex and
      hippocampus of diabetic rats.
AB  - Abstract Most current studies of diabetic encephalopathy have focused on brain
      blood flow and metabolism, but there has been little research on the influence of
      diabetes on brain tissue and the causes of chronic diabetic encephalopathy. The
      technique of molecular biology makes it possible to explore the mechanism of
      chronic diabetic encephalopathy by testing the distribution of somatostatin in
      the brain. We have therefore analysed, by in situ hybridization histochemistry,
      the changes in somatostatin (SST) mRNA in the frontal cortex and hippocampus of
      rats made diabetic by the injection of streptozotocin. Ten Sprague-Dawley control
      rats were compared with ten streptozotocin-induced diabetic rats. The weight,
      blood glucose and urine glucose did not differ between the two groups before the
      injection of streptozotocin. Four weeks after the injection of streptozotocin the
      weight, blood glucose and urine glucose of the diabetic rats were, respectively,
      199.1 +/- 15.6 g, 23.7 +/- 3.25 mmol L(-1) and (++) to (+++) whereas those of the
      control group were 265.5 +/- 30.3 g, 4.84 +/- 0.63 mmol L(-1) and (-).
      Somatostatin mRNA was reduced in the diabetic rats. The number of SST mRNA
      positive neurons and the optical density of positive cells in the hippocampus and
      frontal cortex of the diabetic rats were 80.6 +/- 17.5 mm(-2) and 76.5 +/- 17.6
      compared with 150.5 +/- 21.1 mm(-2) and 115.1 +/- 18.5 in the control rats. The
      induction of diabetes is thus associated with a decreased expression of SST mRNA
      in the hippocampus and frontal cortex, which might be an important component of
      chronic diabetic encephalopathy.

PMID- 15032915
TI  - Prenatal growth and development of the modern human labyrinth.
AB  - The modern human bony labyrinth is morphologically distinct from that of all
      other primates, showing derived features linked with vestibular function and the
      overall shape of the cranial base. However, little is known of how this unique
      morphology emerges prenatally. This study examines in detail the developing fetal
      human labyrinth, both to document this basic aspect of cranial biology, and more
      specifically, to gain insight into the ontogenetic basis of its phylogenetically
      derived morphology. Forty-one post-mortem human fetuses, ranging from 9 to 29
      weeks gestation, were investigated with high-resolution magnetic resonance
      imaging. Quantitative analyses of the labyrinthine morphology revealed a number
      of interesting age-related trends. In addition, our findings show that: (1) the
      prenatal labyrinth attains an adult equivalent size between 17 and 19 weeks
      gestation; (2) within the period investigated, shape changes to all or most of
      the labyrinth cease after the 17-19-week size maturation point or after the otic
      capsule ossifies; (3) fetal cochlea development correlates with the surrounding
      petrosal morphology, but not with the midline basicranium; (4) gestational age
      related rotations of the ampullae and cochlea relative to the lateral canal, and
      posterior canal torsion are similar to documented phylogenetic trends whereas
      other trends remain distinct. Findings are discussed in terms of the ontogenetic
      processes and mechanisms that most likely led, in part, to the emergence of the
      phylogenetically derived adult modern human labyrinth.

PMID- 15032916
TI  - A multimodal, multidimensional atlas of the C57BL/6J mouse brain.
AB  - Strains of mice, through breeding or the disruption of normal genetic pathways,
      are widely used to model human diseases. Atlases are an invaluable aid in
      understanding the impact of such manipulations by providing a standard for
      comparison. We have developed a digital atlas of the adult C57BL/6J mouse brain
      as a comprehensive framework for storing and accessing the myriad types of
      information about the mouse brain. Our implementation was constructed using
      several different imaging techniques: magnetic resonance microscopy, blockface
      imaging, classical histology and immunohistochemistry. Along with raw and
      annotated images, it contains database management systems and a set of tools for
      comparing information from different techniques. The framework allows facile
      correlation of results from different animals, investigators or laboratories by
      establishing a canonical representation of the mouse brain and providing the
      tools for the insertion of independent data into the same space as the atlas.
      This tool will aid in managing the increasingly complex and voluminous amounts of
      information about the mammalian brain. It provides a framework that encompasses
      genetic information in the context of anatomical imaging and holds tremendous
      promise for producing new insights into the relationship between genotype and
      phenotype. We describe a suite of tools that enables the independent entry of
      other types of data, facile retrieval of information and straightforward display
      of images. Thus, the atlas becomes a framework for managing complex genetic and
      epigenetic information about the mouse brain. The atlas and associated tools may
      be accessed at http://www.loni.ucla.edu/MAP.

PMID- 15032917
TI  - Fission of pancreatic islets during postnatal growth of the mouse.
AB  - A cell composition analysis was made of the pancreatic islets in postnatal H253
      mice. This line has a lacZ insertion on the X chromosome so that in female
      hemizygotes 50% of cells should be positive for beta-galactosidase and 50%
      negative. Immediately after birth, the islets were of a heterogeneous cell
      composition. However, by 4 weeks some islets have become homogeneous. This
      suggests that islets progress towards monoclonality in a similar way to the
      intestinal crypts and stomach gastric glands. Pancreatic islets may therefore
      represent 'structural proliferative units' in the overall histological
      organization of the pancreas. Reduction of genetic heterogeneity might arise from
      cell turnover, fission of islets or both. Analysis of the cell composition of the
      X-inactivation mosaic mice also provides the first clear evidence for islet
      fission in pancreatic development. Irregularly shaped islets resembling dumb
      bells, with a characteristic neck of alpha-cells, were observed with decreasing
      frequency with increasing age. Three-dimensional reconstruction confirmed their
      resemblance to conjoined islets. The cell composition analysis showed: (1) the
      relatedness of the two sides of a dumb-bell islet is significantly higher than
      between two non-dumb-bell islets and (2) the relatedness of two randomly selected
      islets decreases as the distance between them increases. This suggests that dumb
      bell islets are in a state of fission rather than fusion, and that islet fission
      is a mode of islet production in the postnatal pancreas.

PMID- 15032918
TI  - Merkel cells, a new localization of prepro-orexin and orexin receptors.
AB  - Orexins (OXA and OXB) are peptides derived from a common precursor called prepro
      orexin. They act through G-protein receptors named orexin 1 receptor (OX(1)R) and
      orexin 2 receptor (OX(2)R). Orexins were first demonstrated in neurons of the
      lateral hypothalamus and found to be related to the control of food intake.
      However, it has been shown that they are widely distributed in both the nervous
      system and peripheral tissues, including endocrine organs such as the pituitary
      and adrenal glands. Merkel cells are neuroendocrine cells situated in the
      epidermis, tactile hairs and oral mucosa, and act as mechanoreceptors. Up to the
      present, various neuropeptides have been detected in these cells. The aim of the
      present study was to detect the presence of prepro-orexin and orexin receptors
      (OX(1)R and OX(2)R) in porcine Merkel cells using immunohistochemistry. Prepro
      orexin was expressed in the cytoplasm of Merkel cells in the skin of the pig
      snout. Immunoreactivity for prepro-orexin was more intense in the mature side of
      the cell, where the dense-cored granules are accumulated. Epidermal nerve
      terminals associated with Merkel cells and dermal nerve fibres showed no
      immunostaining. Both orexin receptors (OX(1)R and OX(2)R) were also demonstrated
      in the cytoplasm of Merkel cells of pig snout skin. The finding of orexins and
      their receptors in Merkel cells suggests that they have an autocrine function.
      Further studies are needed to ascertain the significance of this function.

PMID- 15032919
TI  - Microvascularization of the human digit as studied by corrosion casting.
AB  - The aim of this study was to describe microcirculation in the human digit,
      focusing on the vascular patterns of its cutaneous and subcutaneous areas. We
      injected a functional supranumerary human thumb (Wassel type IV) with a low
      viscosity acrylic resin through its digital artery. The tissues around the
      vessels were then digested in hot alkali and the resulting casts treated for
      scanning electron microscopy. We concentrated on six different areas: the palmar
      and dorsal side of the skin, the eponychium, the perionychium, the nail bed and
      the nail root. On the palmar side, many vascular villi were evident: these
      capillaries followed the arrangement of the fingerprint lines, whereas on the
      dorsal side they were scattered irregularly inside the dermal papillae. In the
      hypodermal layer of the palmar area, vascular supports of sweat glands and many
      arteriovenous anastomoses were visible, along with glomerular-shaped vessels
      involved in thermic regulation and tactile function. In the eponychium and
      perionychium, the vascular villi followed the direction of nail growth. In the
      face of the eponychium in contact with the nail, a wide-mesh net of capillaries
      was evident. In the nail bed, the vessels were arranged in many longitudinal
      trabeculae parallel to the major axis of the digit. In the root of the nail, we
      found many columnar vessels characterized by multiple angiogenic buttons on their
      surface.

PMID- 15032920
TI  - The use of four-colour immunofluorescence techniques to identify mesenchymal stem
      cells.
AB  - In stem-cell research a major difficulty is caused by the lack of distinctive
      features that allow the identification of human mesenchymal stem cells (hMSC).
      Until now, there has been no specific marker and the most common way to identify
      hMSC is by their characteristic stem-cell properties: self-replication and
      differentiation potential. However, these findings can only be revealed
      retrospectively, and, once differentiated, hMSC lose their stem-cell character.
      The aim of this study was to establish four-colour immunofluorescence of several
      markers simultaneously in order to address the problem of how to identify hMSC on
      the single-cell level. The four markers collagen-I, collagen-IV, fibronectin and
      CD44 are known to be expressed by hMSC. Antibody binding was detected using
      secondary antibodies conjugated to FITC, Alexa546, TexasRed and AMCA. Because the
      distinction between Alexa546 and TexasRed was not possible on conventional
      digital images using standard filter sets, we performed spectral image
      acquisition. The image was subsequently decomposed into its pure spectral
      components, which permitted linear unmixing. Using this procedure we were able to
      demonstrate four-colour immunofluorescence on hMSC. With the possibility of using
      more sophisticated marker profiles and/or additional markers, four-colour
      immunofluorescence offers the opportunity of identifying hMSC on the single-cell
      level without performing differentiation assays.

PMID- 15032925
TI  - Experience and inference: how far will science carry us?
AB  - This paper begins with a view of the remarkable understanding of infant and child
      development that has evolved from research and observation. The limitations of
      this contribution from science to the multi-dimensional context-based
      individuality of each human in his or her intersubjective realm are then
      considered. For a contemporary view we must recognize the influence of the
      variability of experiences and the inferences drawn from them. Inferences involve
      symbolization and culturally derived archetypes as illustrated in a clinical
      example.

PMID- 15032927
TI  - Epistemological premise, developmental idea, main motivation in Jung's and
      Kohut's psychoanalysis: looking for some analogies.
AB  - We are living the passage from the positivistic ideal to a new cultural climate
      which may be called post-modernism, subjectivism or perspectivism and in which we
      have lost the conviction that it is possible to reach an absolute knowledge. This
      climate can become a strong stimulus to a dialogue and a comparison among
      different psychoanalytical schools and between psychoanalysis and empirical
      research to find some of the reference points we need in our work. In my paper I
      will compare self psychology and analytic psychology in order to point out
      several strong analogies. Firstly, they are based on the same methodological
      option which gathers knowledge through an empathic understanding 'from within'.
      According to both Jung and Kohut the individual has within himself a psycho
      biological potential, an individual pre-formed core that asks to evolve
      completely: the central motivation of human beings is the realization of their
      own individuality. This shared theoretical and epistemological ground conveys
      convergences in the clinical field between the two disciplines (interpretation of
      dreams, respect of resistance, diminishing attitude regarding sexual drives,
      etc.) and specifically determines an attitude of the analyst, which respects the
      individual process of development, which pays attention to the inner experience,
      and which gives importance to the analyst's and the patient's subjective
      experience.

PMID- 15032926
TI  - 'Dialectical process' and 'constructive method': micro-analysis of relational
      process in an example from parent-infant psychotherapy.
AB  - Jung defined experience that takes place between therapist and patient as
      'dialectical process', achieved through 'constructive method'. Perspectives from
      attachment theory, neurobiology, cognitive science, systems thinking and infancy
      research confirm and extend his view of the centrality of relational process in
      the development of self. Interactional experiences are embedded within the
      history of the primary parent-infant relationship and structure within the mind
      implicit patterns of relating. These patterns influence capacities for managing a
      whole lifetime of affective relational experience within the self and with
      others. This paper shows how parent-infant psychotherapy seeks to intervene
      during the formation of disturbed relational patterns. I offer detailed micro
      analysis of the moment-to-moment 'dialectical process' that a mother, her four
      month-old infant and myself 'constructed' together.

PMID- 15032921
TI  - The distribution of mast cells in the human area postrema.
AB  - The topography and phenotype of mast cells in the human area postrema, together
      with correlation between mast-cell density and microvessel density (MVD), were
      analysed in 16 brains. Transverse serial sections of formalin-fixed, paraffin
      embedded brainstems were stained with toluidine blue and alcian blue/safranin
      stainings, and with anti-tryptase and anti-CD31 monoclonal antibodies. The mean
      (+/- SD) numbers of mast cells per section were 1.3 +/- 0.8 and 1.2 +/- 0.7 with
      toluidine blue and alcian blue/safranin, respectively, whereas anti-tryptase
      monoclonal antibody showed a mean of 5.1 +/- 2.4 cells. Mast cells were alcian
      blue- and safranin-positive in 56%, because of the coexistence of low-sulphated
      (blue-staining) and high-sulphated (red-staining) granules. No significant linear
      correlation between mast-cell density (4.9 mm(-2)) and MVD (114.5 mm(-2)) was
      found (r(2) = 0.19, P = 0.09). Mast cells were frequently located close to blood
      vessels (55%) (33% to venules, 22% to arterioles), indicating that their products
      play a role in the regulation of blood flow and in vessel permeability in the
      area postrema. Mast cells were located subependymally in 44% and close to the
      dorsal aspect of the nucleus of the tractus solitarius in 31%, suggesting a
      subregional distribution.

PMID- 15032928
TI  - Can there be a science of the symbolic?
AB  - Science means not just 'knowing', but knowing verified by replicability. Science
      is particularly hard to bring to depth psychology because the individual
      uniquenesses that can't be repeated are what make people most deeply themselves.
      Everyone, including the analytic investigator, however, has a science, in the
      sense of a world-view that is replicated by experience. Jung offered hermeneutics
      as an alternative mode to science for getting to know the psychological subject.
      But as Heidegger emphasized, hermeneutics always begins with the projection of a
      world-view, i.e., the science of the would-be interpreter. In the analytic
      situation, dialogue is available to test the world-view and enlarge its horizon,
      in accord with Gadamer's expansion of hermeneutics, 'the classical discipline
      concerned with the art of understanding texts', into a method of inquiry open to
      the possibilities of otherness. An example is given from an analytic training
      seminar, in which the author began by projecting his version of the theory of
      psychological types onto the dream material a candidate offered in response to
      the seminar. A dialogue with the candidate ensued which enabled the teacher to
      correct his original, somewhat rigid, application of his scientific viewpoint. In
      such a dialogue, psyche emerges as the final interpreter of what is, generating
      hypotheses that can fruitfully be applied to the understanding of other cases.

PMID- 15032929
TI  - This new science of ours: a more or less systematic history of consciousness and
      transcendence. Part I.
AB  - This paper is a search for the origins and nature of human consciousness. This
      portion, the first part of two, takes up a signal work of Jung and one of Freud,
      both published in 1911 and both deriving thinking as the first embodiment of
      higher mental functions. Thinking and consciousness (and subsequently spirit) are
      elaborated in terms of the nature and vicissitudes of libido. Jung's less well
      understood theory regarding a quantitative libido is particularly addressed as
      are his non-Cartesian ways of reasoning. Also addressed is Jung's turning away in
      the final analysis from a frankly metaphysical and transcendent position as
      compared to the pre-Socratic philosophers with whom focused thinking began in the
      western world. Differentiation is made between mechanistic and energetic field
      dynamics in how reality is viewed.

PMID- 15032930
TI  - The science and meaning of the self.
AB  - Scientists and practitioners alike invest in theorizing the self in psychology,
      but prioritize differently theoretical and practical objectives. Theorizing the
      self differs also when mapped onto the 'science versus art' debate, viewed
      historically and with reference to the philosophy of science. Jung's model of the
      psyche is compared and contrasted with social cognitive models of self-concept.
      Finally, some implications of social constructionism are considered.

PMID- 15032931
TI  - Imagination as laboratory.
AB  - The theme, 'Science and the Symbolic', may be approached via either concept. From
      one side, we may track how imagination, fantasy, and even dreams have initiated
      scientific theory and lines of research. From the other, we may look to the
      mythopoeic musings of the human mind for themes of proto-science and/or proto
      psychology, and attempt to discern if they follow a method which may be called
      scientific. Neuroscientists such as Edelman and Llinas honour imagination as the
      carrier of emergent properties, and depth psychoanalysts see it as a vector
      toward actualization. What mind imagines through what the alchemists termed 'true
      imagination' may eventually be realized through what brain and body may conceive
      and execute.

PMID- 15032932
TI  - Chaos and self-organization: emergent patterns at critical life transitions.
AB  - A feeling of chaos can accompany many real-life events over which we have little
      or no control, and latent developmental needs may create tension that manifests
      in symptoms of depression or anxiety. Particularly at critical life transitions,
      conflicts may arise which have no obvious solution. From an analytic perspective,
      recent scientific models from the area of complexity theory can prove
      illuminating as analogies to Jung's archetypal view of the individuation process.
      Throughout life, human beings, like many complex, open systems, pass from
      disordered phases to more complex stages of order. This paper shows how the
      scientific concept of self-organization can be compared with our physical and
      psychological developmental processes. From embryology, the model of the
      'epigenetic landscape' (C.H. Waddington) is introduced as an analogy to Jung's
      individuation process, with a clinical example to illustrate these parallels. The
      emergent nature of behaviour and development is seen from the viewpoint of the
      organism as a dynamical system, and Jung's concept of the archetype viewed as an
      emergent property of the activity of the brain/mind.

PMID- 15032941
TI  - Determination by GISH and FISH of hybrid status in Lilium.
AB  - In the genus Lilium, plants obtained from crosses, especially between distant
      relatives, are not always hybrids because embryos can develop as a result of
      apomixis. These plants constitute genetic material of the maternal parent only.
      In this study, verification of hybrid status of plants which have been obtained
      from the crosses 'Marco Polo'xLilium henryi and 'Expression'xL. henryi was
      performed through the use of cytological and molecular cytogenetic methods.
      According to cytological analyses, all genotypes tested had 2n = 2x = 24
      chromosomes. Genomic in situ hybridisation (GISH) was used for hybrid
      verification. In hybrid plants, this method distinguished all paternal and
      maternal chromosomes at the stage of somatic metaphase and prophase. For GISH,
      paternal genomic DNA was used as a probe and maternal DNAs were used as blocks.
      Fluorescence in situ hybridisation (FISH) with 5S rDNA and 25S rDNA probes was
      used as the second method of hybrid verification. Selected chromosome markers
      based on genome-specific localisation of rDNA loci were used for analysis of the
      F1 hybrids obtained from the crosses 'Marco Polo'xL. henryi and 'Expression'xL.
      henryi. The presence of marker chromosomes characteristic for each of the
      paternal genotypes was a confirmation that the plants obtained were hybrids.

PMID- 15032943
TI  - Genetic and demographic structure in a population of Ctenomys lami (Rodentia
      Ctenomyidae).
AB  - The variability at eight microsatellite loci was analyzed in 88 individuals of
      Ctenomys lami, a species of tuco-tucos. Initially considered as three
      subpopulations, the estimated Fst values ranged from 0.0007 to 0.0589.
      Additionally, a Bayesian approach presented probabilities of 0.9933 for the
      existence of only one population. A Fis value of 0.19 could indicate an incipient
      structure. Sexual dimorphism was observed. The reproductive period was short and
      a seasonal pattern was observed with sex ratio of 1:1 during all seasons.
      Presence of recent bottleneck is described suggesting further research in this
      population to assess more complete and detailed data.

PMID- 15032942
TI  - Genetic structure and variation in the relict populations of Alsophila spinulosa
      from southern China based on RAPD markers and cpDNA atpB-rbcL sequence data.
AB  - RAPD markers and sequences of chloroplast DNA (cpDNA) atpB-rbcL intergenic
      spacers were used to characterize the pattern of genetic variation and the
      phylogenetic relationships of the relict populations of Alsophila spinulosa
      located in Jian Feng Ling (JFL) and Diao Luo Shan (DLS), Hainan, and Tang Lang
      Shan (TLS), Ding Hu Shan (DHS), and Da Xi Shan (DXS), Guangdong, of southern
      China. 28 random primers generated 118 bands, out of which 26 (22.03%) were
      polymorphic loci, distinguishing 17 different RAPD phenotypes. Percentage of
      polymorphic loci, Shannon phenotypic diversity and Nei's gene diversity
      comprehensively indicated that JFL possessed the highest diversity, TLS and DHS
      in intermediate and DLS or DXS the least; the corresponding values of the
      population appeared correlated with the population size. Differentiation was
      detected among populations of A. spinulosa (1-Hpop/Hsp=0.7453, GST=0.7763, and
      phist=0.8145). AMOVA showed that 47.44% of the variance was partitioned among
      regions (Hainan and Guangdong), 34.01% attributed among populations within
      regions, whereas only 18.55% occurring within populations. Low level of intra
      specific diversity was maintained in A. spinulosa with Shannon diversity and gene
      diversity merely 0.0560 and 0.0590, repectively. Sequence length of atpB-rbcL
      intergenic spacer varied from 724 bp to 730 bp. Base composition was with A+T
      content between 63.17% and 63.70%. 13 haplotypes of atpB-rbcL noncoding spacers
      were identified. UPGMA dendrogram of RAPD phenotypes, principal components
      analysis based on RAPD patterns, minimum spanning network and neighbour-joining
      (NJ) tree established on atpB-rbcL haplotypes consistently suggested the
      geographical subdivision of populations of A. spinulosa between Hainan and
      Guangdong. Breeding system and conservation strategy of A. spinulosa was
      discussed based on the information of population genetic structure and variation.

PMID- 15032944
TI  - Evaluating genetic relationships between tropical maize inbred lines by means of
      AFLP profiling.
AB  - Diversity among tropical maize inbred lines that compose breeding programs, is
      not well known. The lack of this information has made the arrangement of
      heterotic groups to be used for breeding purposes difficult. Methods of molecular
      analysis have been used as efficient alternatives for evaluating genetic
      diversity, aiming at heterotic group arrangement and acquisition of new hybrids.
      In this study, AFLP (amplified fragment length polymorphism) was used to
      investigate the genetic relationships among 96 tropical maize inbred lines from
      two different origins. The polymorphism level among the genotypes and the
      possibility of their allocation in heterotic groups were evaluated. Besides,
      correlations among genetic diversity and flowering time were analyzed. Nine
      primer combinations were used to obtain AFLP markers, producing 638 bands, 569 of
      which were polymorphic. Genetic similarities (GS), determined by Jaccard's
      similarity coefficient, varied from 0.345 to 0.891, with an average of 0.543. The
      dendrogram based on the GS and on the UPGMA cluster method did not separate the
      inbred lines in well-defined groups. Aiming at separating the lines into more
      accurate groups, Tocher's optimization procedure was carried out, 17 groups being
      identified. Association between flowering time and germplasm pools was detected.
      AFLP showed itself to be a robust assay, revealing a great power of detection of
      genetic variability in the tropical germplasm, and also demonstrated to be very
      useful for guiding breeding programs.

PMID- 15032945
TI  - Reproduction pathway analysis of several Hypericum perforatum L. somaclonal
      families.
AB  - Flow cytometry seed screen of mature seeds originating from several in vitro
      regenerated Hypericum perforatum L. somaclones and their seed progenies were used
      to screen the ways of reproduction of 4 subsequent generations of several
      somaclonal families and to search for the relation between the ploidy and
      prevalent mode of reproduction. The prevalent reproduction pathway of diploid
      plants was sexual reproduction. Seed samples of plants with higher ploidy levels
      showed an extensive variation in the mode of reproduction: BII and BIII hybrid
      formation and/or aposporous pseudogamy including parthenogenetic development of a
      reduced embryo sac.

PMID- 15032946
TI  - Conserved karyotypes in the Hyla pulchella species group (Anura, Hylidae).
AB  - Cytogenetic analyses were done on specimens of Hyla marginata and on three
      populations of H. semiguttata differing in morphology and in the physical
      parameters of their advertisement call, as well as in individuals of Hyla sp.
      (aff. semiguttata). All specimens had 2n=24 chromosomes with a morphology very
      similar to that of other 24-chromosome Hyla species. Hyla semiguttata and H.
      marginata showed the same C-banding pattern but were distinguished by the
      location of the NOR on pair 1 in H. semiguttata (in the three populations) and
      Hyla sp. (aff. semiguttata), and on pair 10 in H. marginata. The H. semiguttata
      populations did not differ cytogenetically, despite variations in their
      morphology and advertisement calls. Similarly, H. semiguttata and H. p. joaquini
      studied previously had identical C-banding patterns and NOR locations, suggesting
      that they are very closely related.

PMID- 15032947
TI  - Karyotype analysis and achiasmatic meiosis in pseudoscorpions of the family
      Chthoniidae (Arachnida: Pseudoscorpiones).
AB  - Karyotypes of pseudoscorpions (Arachnida, Pseudoscorpiones) are largely unknown.
      Here we describe for the first time karyotypes of the suborder Epiocheirata,
      represented by 9 European species of two genera of Chthoniidae, Chthonius and
      Mundochthonius. Diploid chromosome numbers of males range from 21 to 37.
      Karyotypes of both genera differ substantially. Acrocentric chromosomes
      predominate in karyotypes of the genus Chthonius, whereas M. styriacus exhibits a
      predominance of metacentric chromosomes. These differences suggest that the two
      genera belong probably to distant branches of the family Chthoniidae. It is
      proposed that karyotype evolution of the genus Chthonius was characterised by a
      reduction of chromosome numbers by tandem and centric fusions as well as gradual
      conversion of acrocentric chromosomes to biarmed ones, mostly by pericentric
      inversions. A tendency towards reduced chromosome numbers is evident in the
      subgenus Ephippiochthonius. All species display X0 sex chromosome system that is
      probably ancestral in pseudoscorpions. The X chromosome exhibits conservative
      morphology. It is metacentric in all species examined, and in the majority of
      them, a subterminal secondary constriction was found at one of its arms. In
      contrast to chthoniids, secondary constriction was not reported on sex
      chromosomes of other pseudoscorpions. Analysis of prophase I chromosomes in males
      revealed an achiasmatic mode of meiosis. Findings of the achiasmatic meiosis in
      both genera, Chthonius and Mundochthonius, indicate that this mode of meiosis
      might be characteristic of the family Chthoniidae. Amongst arachnids, achiasmatic
      meiosis has only been described in some scorpions, acariform mites, and spiders.

PMID- 15032948
TI  - Marker-assisted pyramiding of brown planthopper (Nilaparvata lugens Stal)
      resistance genes Bph1 and Bph2 on rice chromosome 12.
AB  - Brown planthopper (BPH) (Nilaparvata lugens Stal) is a significant insect pest of
      rice (Oryza sativa L.). We constructed a gene-pyramided japonica line, in which
      two BPH resistance genes Bph1 and Bph2 on the long arm of chromosome 12
      independently derived from two indica resistance lines were combined through the
      recombinant selection. The gene-pyramiding was achieved based on the previously
      constructed high-resolution linkage maps of the two genes. Two co-dominant and
      four dominant PCR-based markers flanking the loci were used to select for a
      homozygous recombinant line in a segregating population that was derived from a
      cross between the parental homozygous single-gene introgression lines. BPH
      bioassay showed that the resistance level of the pyramided line was equivalent to
      that of the Bph1-single introgression line, which showed a higher level of
      resistance than the Bph2-single introgression line. The pyramid line should
      provide a useful experimental means for studying the fine structure of the
      chromosomal region covering these two major BPH resistance genes.

PMID- 15032949
TI  - Detection and physical mapping of the 18S-5.8S-26S rDNA and the pKFJ660 probe
      with microsatellite sequences derived from the rice blast fungus (Magnaporthe
      grisea) in conifer species.
AB  - Sequences homologous to the pKFJ660 probe, a fragment of DNA derived from the
      rice blast fungus (Magnaporthe grisea) carrying TC/AG repeat microsatellite
      sequences and 30 bp direct repeats were identified in the genome of Picea
      (spruce) and Pinus (pine) species by fluorescence in situ hybridization (FISH)
      and slot blot analyses. Slot blot analysis using the pKFJ660 probe revealed
      hybridization signals with genomic DNAs from various pine and spruce species.
      Further analyses indicated that the copy number of the (AG)30 motif was higher
      than 5 x 10(4) per plant genome for all plant samples tested, but the copy number
      of the sequences homologous to the whole pKFJ660 probe varies considerably among
      the 25 plant species tested. In situ hybridization of metaphase chromosomes from
      Pinus resinosa, P. banksiana and P. strobus showed the presence of sequences
      homologous to this probe on several chromosomes in a dispersed pattern. Major
      signals were observed on a few chromosomes indicating that some of these
      sequences are clustered in specific genomic locations. The locations of these
      repeats were compared to those of 18S-5.8S-26S rDNA in pine species. Chromosomal
      distribution of 18S-5.8S-26S rDNA varied among the three pine species (P.
      resinosa, P. banksiana and P. strobus) studied. Ribosomal DNA (rDNA) sites were
      identified on 14 to 20 chromosomes in these pine species.

PMID- 15032951
TI  - Delays in treatment for mental disorders and health insurance coverage.

PMID- 15032952
TI  - Relationship of nursing home staffing to quality of care.
AB  - OBJECTIVE: To compare nursing homes (NHs) that report different staffing
      statistics on quality of care. DATA SOURCES: Staffing information generated by
      California NHs on state cost reports and during onsite interviews. Data
      independently collected by research staff describing quality of care related to
      27 care processes. STUDY DESIGN: Two groups of NHs (n=21) that reported
      significantly different and stable staffing data from all data sources were
      compared on quality of care measures. DATA COLLECTION: Direct observation,
      resident and staff interview, and chart abstraction methods. PRINCIPAL FINDINGS:
      Staff in the highest staffed homes (n=6), according to state cost reports,
      reported significantly lower resident care loads during onsite interviews across
      day and evening shifts (7.6 residents per nurse aide [NA]) compared to the
      remaining homes that reported between 9 to 10 residents per NA (n=15). The
      highest-staffed homes performed significantly better on 13 of 16 care processes
      implemented by NAs compared to lower-staffed homes. CONCLUSION: The highest
      staffed NHs reported significantly lower resident care loads on all staffing
      reports and provided better care than all other homes.

PMID- 15032953
TI  - Commentary: nursing home staffing- more is necessary but not necessarily
      sufficient.

PMID- 15032954
TI  - Hospital-physician affiliations and patient treatments, expenditures, and
      outcomes.
AB  - OBJECTIVE: To determine the relationship between hospital-physician affiliations
      and the treatments, expenditures, and outcomes of patients. DATA SOURCES: Sources
      include the Medicare Provider Analysis and Review dataset, the American Hospital
      Association (AHA) Annual Survey, and the Area Resource File (ARF). STUDY DESIGN:
      A multivariate regression analysis of the relationship between hospital-physician
      affiliations (such as physician-hospital organizations [PHOs] or salaried
      employment) and the treatment of Medicare patients with a diagnosis of acute
      myocardial infarction admitted to general medical-surgical hospitals between 1994
      and 1998. Dependent variables include whether the patient received a
      catheterization or angioplasty or bypass surgery; whether a patient was
      readmitted, or died within 90 days of initial admission; and expenditures.
      Independent variables include patient, admission hospital, and market
      characteristics, as well as hospital and year fixed effects. PRINCIPAL FINDINGS:
      The integrated salary model form of hospital-physician affiliation is associated
      with slightly higher procedure rates, and higher patient expenditures. At the
      same time, there is little evidence that hospital-physician affiliations in the
      aggregate have had any measurable impact on patient treatment or outcomes.
      CONCLUSIONS: The limited effect of hospital-physician affiliations on patient
      outcomes is consistent with previous research showing that affiliations have not
      much changed the nature of health care delivery. However, the finding that the
      integrated salary model is associated with higher treatment intensity suggests
      that affiliations may have had some impact on patients, and could have more in
      the future.

PMID- 15032955
TI  - A longitudinal examination of hospital registered nurse staffing and quality of
      care.
AB  - OBJECTIVE: To evaluate previous research findings of the relationship between
      nurse staffing and quality of care by examining the effects of change in
      registered nurse staffing on change in quality of care. DATA SOURCES/STUDY
      SETTING: Secondary data from the American Hospital Association (AHA)(nurse
      staffing, hospital characteristics), InterStudy and Area Resource Files (ARF)
      (market characteristics), Centers for Medicare and Medicaid Services (CMS)
      (financial performance), and Healthcare Cost and Utilization Project (HCUP)
      (quality measures-in-hospital mortality ratio and the complication ratios for
      decubitus ulcers, pneumonia, and urinary tract infection, which were risk
      adjusted using the Medstat disease staging algorithm). STUDY DESIGN: Data from a
      longitudinal cohort of 422 hospitals were analyzed from 1990-1995 to examine the
      relationships between nurse staffing and quality of care. DATA
      COLLECTION/EXTRACTION METHODS: A generalized method of moments estimator for
      dynamic panel data was used to analyze the data. Principal Findings. Increasing
      registered nurse staffing had a diminishing marginal effect on reducing mortality
      ratio, but had no consistent effect on any of the complications. Selected
      hospital characteristics, market characteristics, and financial performance had
      other independent effects on quality measures. CONCLUSIONS: The findings provide
      limited support for the prevailing notion that improving registered nurse (RN)
      staffing unconditionally improves quality of care.

PMID- 15032956
TI  - The impact of S-CHIP enrollment on physician participation in Medicaid in Alabama
      and Georgia.
AB  - OBJECTIVE: To assess whether increasing enrollment in State Children's Health
      Insurance Programs (S-CHIPs) has an impact on the number of office physicians
      participating in Medicaid and the extent of their participation. Effects are
      measured for a freestanding S-CHIP program with an open provider panel and an S
      CHIP program that uses the state's Medicaid provider panel. DATA SOURCES:
      Children's Medicaid claims data for primary care services were used to measure
      physician participation in the program; census and enrollment data were used to
      describe market area characteristics. Study Design. This is a time series study
      of communities in two states, measuring physician Medicaid participation
      quarterly between 1998 and 2001, controlling for changes in community
      characteristics and children's program enrollment as well as other factors by
      quarter. DATA COLLECTION/EXTRACTION: Office physician participation is measured
      by practice site. Claims data are aggregated to the level of the community and
      reflect the number of limited practice sites, the ratio of Medicaid office sites
      to the number of primary care physicians in the community as reported by the
      American Medical Association (AMA), and the mean number of Medicaid office visits
      made to physician sites in the community in the quarter. FINDINGS: In Alabama,
      the state with a freestanding S-CHIP program, there is little association between
      increased S-CHIP enrollment and physician participation in Medicaid. In Georgia,
      where the same provider network serves both programs, increases in S-CHIP
      enrollment are associated with a decline in office-based physician participation
      in Medicaid in urban areas. CONCLUSION: Linkage of S-CHIP and Medicaid programs
      through the use of the same provider network, in the absence of market conditions
      that encourage the expansion of the network, can lead to a negative impact on
      access for Medicaid enrollees.

PMID- 15032957
TI  - The impact of managed care on substance abuse treatment services.
AB  - OBJECTIVE: To examine the impact of managed care on the number and types of
      services offered by substance abuse treatment (SAT) facilities. Both the number
      and types of services offered are important factors to analyze, as research shows
      that a broad range of services increases treatment effectiveness. DATA SOURCES:
      The 2000 National Survey of Substance Abuse Treatment Services (NSSATS), which is
      designed to collect data on service offerings and other characteristics of SAT
      facilities in the United States. These data are merged with data from the 2002
      Area Resource File (ARF), a county-specific database containing information on
      population and managed care activity. We use data on 10,513 facilities, virtually
      a census of all SAT facilities. STUDY DESIGN: We estimate the impact of managed
      care (MC) on the number and types of services offered by SAT facilities using
      instrumental variables (IV) techniques that account for possible endogeneity
      between facilities' involvement in MC and service offerings. Due to limitations
      of the NSSATS data, MC and specific services are modeled as binary variables.
      PRINCIPAL FINDINGS: We find that managed care causes SAT facilities to offer, on
      average, approximately two fewer services. This effect is concentrated primarily
      in medical testing services (i.e., tests for TB, HIV/AIDs, and STDs). We also
      find that MC increases the likelihood of offering substance abuse assessment and
      relapse prevention groups, but decreases the likelihood of offering outcome
      follow-up. CONCLUSION: Our findings raise policy concerns that managed care may
      reduce treatment effectiveness by limiting the range of services offered to meet
      patient needs. Further, reduced onsite medical testing may contribute to the
      spread of infectious diseases that pose important public health concerns.

PMID- 15032958
TI  - The effects of HMO penetration on preventable hospitalizations.
AB  - OBJECTIVE: To examine the effects of health maintenance organization (HMO)
      penetration on preventable hospitalizations. DATA SOURCE: Hospital inpatient
      discharge abstracts for 932 urban counties in 22 states from the Healthcare Cost
      and Utilization Project (HCUP) State Inpatient Databases (SID), hospital data
      from American Hospital Association (AHA) annual survey, and population
      characteristics and health care capacity data from Health Resources and Services
      Administration (HRSA) Area Resource File (ARF) for 1998. METHODS: Preventable
      hospitalizations due to 14 ambulatory care sensitive conditions were identified
      using the Agency for Healthcare Research and Quality (AHRQ) Prevention Quality
      Indicators. Multiple regressions were used to determine the association between
      preventable hospitalizations and HMO penetration while controlling for
      demographic and socioeconomic characteristics and health care capacity of the
      counties. PRINCIPAL FINDINGS: A 10 percent increase in HMO penetration was
      associated with a 3.8 percent decrease in preventable hospitalizations (95
      percent confidence interval, 2.0 percent-5.6 percent). Advanced age, female
      gender, poor health, poverty, more hospital beds, and fewer primary care
      physicians per capita were significantly associated with more preventable
      hospitalizations. CONCLUSIONS: Our study suggests that HMO penetration has
      significant effects in reducing preventable hospitalizations due to some
      ambulatory care sensitive conditions.

PMID- 15032959
TI  - Trends in inpatient treatment intensity among Medicare beneficiaries at the end
      of life.
AB  - OBJECTIVE: Although an increasing fraction of Medicare beneficiaries die outside
      the hospital, the proportion of total Medicare expenditures attributable to care
      in the last year of life has not dropped. We sought to determine whether
      disproportionate increases in hospital treatment intensity over time among
      decedents are responsible for the persistent growth in end-of-life expenditures.
      DATA SOURCE: The 1985-1999 Medicare Medical Provider Analysis and Review (MedPAR)
      and Denominator files. STUDY DESIGN: We sampled inpatient claims for 20 percent
      of all elderly fee-for-service Medicare decedents and 5 percent of all survivors
      between 1985 and 1999 and calculated age-, race-, and gender-adjusted per-capita
      inpatient expenditures and rates of intensive care unit (ICU) and intensive
      procedure use. We used the decedent-to-survivor expenditure ratio to determine
      whether growth rates among decedents outpaced growth relative to survivors, using
      the growth rate among survivors to control for secular trends in treatment
      intensity. Data Collection. The data were collected by the Centers for Medicare
      and Medicaid Services. PRINCIPAL FINDINGS: Real inpatient expenditures for the
      Medicare fee-for-service population increased by 60 percent, from $58 billion in
      1985 to $90 billion in 1999, one-quarter of which were accrued by decedents.
      Between 1985 and 1999 the proportion of beneficiaries with one or more intensive
      care unit (ICU) admission increased from 30.5 percent to 35.0 percent among
      decedents and from 5.0 percent to 7.1 percent among survivors; those undergoing
      one or more intensive procedure increased from 20.9 percent to 31.0 percent among
      decedents and from 5.8 percent to 8.5 percent among survivors. The majority of
      intensive procedures in the United States were performed in the more numerous
      survivors, although in 1999 50 percent of feeding tube placements, 60 percent of
      intubations/tracheostomies, and 75 percent of cardiopulmonary resuscitations were
      in decedents. The proportion of beneficiaries dying in a hospital decreased from
      44.4 percent to 39.3 percent, but the likelihood of being admitted to an ICU or
      undergoing an intensive procedure during the terminal hospitalization increased
      from 38.0 percent to 39.8 percent and from 17.8 percent to 30.3 percent,
      respectively. One in five Medicare beneficiaries who died in the hospital in 1999
      received mechanical ventilation during their terminal admission. CONCLUSIONS:
      Inpatient treatment intensity for all fee-for-service beneficiaries increased
      between 1985 and 1999 regardless of survivorship status. Absolute changes in per
      capita hospital expenditures, ICU admissions, and intensive inpatient procedure
      use were much higher among decedents. Relative changes were similar except for
      ICU admissions, which grew faster among survivors. The secular decline in in
      hospital deaths has not resulted in decreased per capita utilization of expensive
      inpatient services in the last year of life. This could imply that net hospital
      expenditures for the dying might have been even higher over this time period if
      the shift toward hospice had not occurred.

PMID- 15032960
TI  - The combined effects of participatory styles of elderly patients and their
      physicians on satisfaction.
AB  - OBJECTIVES: To test whether concordance or discordance of patient participation
      between patients and physicians is associated with higher satisfaction, and to
      examine the effects of patients' and physicians' participatory styles on
      patients' satisfaction with their physicians. DATA: Data collected in the Texas
      Tech 5000 Survey of elderly patients in West Texas were used. Patient
      satisfaction with their physicians was measured by a single item from the
      Consumer Assessment of Health Plans (CAHPS), representing patients' ratings of
      their physicians. Patient participation was measured by an index derived from a
      three-item instrument and physicians' participatory decision-making (PDM) style
      was measured by a three-item instrument developed by the Medical Outcomes Study.
      METHODS: An ordered logit multivariate regression was used to investigate the
      effects of patients' and physicians' participatory styles on satisfaction with
      physicians. The interaction between patients' participation and physicians'
      participatory styles was also included to examine the dependency of the two
      variables. RESULTS: Controlling for confounding factors, a higher PDM score was
      associated with a higher rating of patient satisfaction with physicians. A higher
      patient participation score was related to a lower physician satisfaction rating.
      The combined effect of patients' and physicians' participation styles indicated
      that for a low patient participation score, a high PDM score was not needed to
      produce high satisfaction. The greater the discordance in this direction, the
      higher the satisfaction. However, with a high patient participation score, only
      an extremely high PDM score would produce relatively high satisfaction.
      CONCLUSIONS: The current study supports the discordance hypothesis. Participatory
      physicians and patient-physician communications concerning patient participation
      can promote higher satisfaction.

PMID- 15032961
TI  - Delays in initial treatment contact after first onset of a mental disorder.
AB  - OBJECTIVE: To examine nationally representative patterns and predictors of delays
      in contacting a professional after first onset of a mental disorder. DATA
      SOURCES: The National Comorbidity Survey, a nationally representative survey of
      8,098 respondents aged 15-54. STUDY DESIGN: Cross-sectional survey. DATA
      COLLECTION: Assessed lifetime DSM-III-R mental disorders using a modified version
      of the Composite International Diagnostic Interview (CIDI). Obtained reports on
      age at onset of disorders and age of first treatment contact with each of six
      types of professionals (general medical doctors, psychiatrists, other mental
      health specialists, religious professionals, human services professionals, and
      alternative treatment professionals). Used Kaplan-Meier (KM) curves to estimate
      cumulative lifetime probabilities of treatment contact after first onset of a
      mental disorder. Used survival analysis to study the predictors of delays in
      making treatment contact. PRINCIPAL FINDINGS: The vast majority (80.1 percent) of
      people with a lifetime DSM-III-R disorder eventually make treatment contact,
      although delays average more than a decade. The duration of delay is related to
      less serious disorders, younger age at onset, and older age at interview. There
      is no evidence that delay in initial contact with a health care professional is
      increased by earlier contact with other non-health-care professionals.
      CONCLUSIONS: Within the limits of recalling lifetime events, it appears that
      delays in initial treatment contact are an important component of the larger
      problem of unmet need for mental health care. Interventions are needed to
      decrease these delays.

PMID- 15032962
TI  - Updated variable-radius measures of hospital competition.
AB  - OBJECTIVE: To calculate variable-radius measures of hospital market size and
      create measures of competition for hospitals' markets. DATA SOURCES: Discharge
      abstracts from the 1997 State Inpatient Databases of the Healthcare Cost and
      Utilization Project (HCUP) linked with the American Hospital Association (AHA)
      Annual Survey, Area Resource File (ARF), InterStudy Regional Market Analysis
      database, and Medicare's Prospective Payment System Impact Files. STUDY DESIGN:
      Hospital radii capturing 75 and 90 percent of hospital admissions regressed
      against hospital and health care market characteristics and other local area
      characteristics, where the specification was designed to maximize predictive
      ability. The number of competing hospitals and the Herfindahl-Hirschman index
      (HHI) of competition were calculated for each hospital's market. DATA COLLECTION
      METHODS: Discharge abstracts were used to create actual radii for hospitals in
      nine states. These data were linked with other data describing hospital, health
      care market, and other characteristics. PRINCIPAL FINDINGS: We explained 44.7 and
      9.6 percent of the variation among urban and rural hospitals, respectively, in
      radii that capture 90 percent of patients, and slightly less of the variation in
      radii that capture 75 percent of patients. Population density; number of other
      hospitals in the local area; and hospital characteristics such as medical school
      affiliation, percentage of admissions that are Medicaid, case mix, and service
      offerings are important correlates of a hospital's market size. CONCLUSIONS:
      Predicted radii and associated competition measures were created (matched to AHA
      hospital identifiers) for all nonfederal, short-term, general medical/surgical
      hospitals in the continental United States for which complete data were available
      in 1997 (N=4,806) and are available from the authors.

PMID- 15032964
TI  - Genes, screens, and means for advancing the diagnosis and anticipatory care of
      individuals with congenital intellectual disability.

PMID- 15032967
TI  - Advocating a gene-based template of care for congenital intellectual disability.

PMID- 15032969
TI  - Screening for Down's syndrome in early and late first and second trimester using
      six maternal serum markers.
AB  - The efficiency of six maternal serum markers for Down's syndrome (DS), alpha
      fetoprotein (AFP), human chorionic gonadotropin (hCG), free beta-hCG, pregnancy
      associated plasma protein-A (PAPP-A), the proform of eosinophil major basic
      protein (ProMBP), pregnancy-specific-beta-1-glycoprotein (SP(1)), and
      combinations thereof, was examined. Discriminant analysis in 156 DS pregnancies
      and 546 controls defined three effective combinations of serum marker logMoMs
      (multiples of the median in control samples) in three gestational age windows,
      i.e. Index I (weeks 7-9) = 0.52 logMoM ProMBP + 0.28 logMoM PAPP-A - logMoM
      SP(1); Index II (weeks 10-12) = 1.94 logMoM free beta-hCG - logMoM SP(1), and
      Index III (weeks 15-19) = 0.78 logMoM free beta-hCG + 1.12 logMoM ProMBP - logMoM
      AFP. The estimated detection rates of indices and age for a false-positive rate
      (FPR) of 5% were 73% for Index I, 69% for Index II, and 60% for Index III.
      Including the ultrasound marker nuchal translucency, using a DS at term risk of 1
      : 400 as cut-off, the detection rates of the indices increased to 86, 83, and 82%
      for FPRs of 4.3, 4.1, and 5.8%, respectively. The indices are promising markers
      for screening for DS.

PMID- 15032968
TI  - Arg120stop nonsense mutation in the RP2 gene: mutational hotspot and germ line
      mosaicism?
AB  - Mutations in the RP2 gene account for up to 20% of X-linked recessive retinitis
      pigmentosa (RP). Arg120stop is to date the most frequently reported mutation
      found in RP2. Mutation screening was performed during the course of a large
      screening program of retinal degenerative disorders (RDDs) in South Africa using
      exon 1 and 2 of RP2 in 20 unrelated families with an X-linked mode of retinal
      degenerative inheritance. Direct sequencing analysis revealed a C-->T transition
      at position 358 in the proband in a family of German origin. Subsequent analysis
      revealed that this Arg120stop mutation cosegregated with the disease in an
      additional affected family member. The nonsense mutation, Arg120stop, could not
      however, be detected in the somatic cells of the obligate carrier female. This,
      the first report of a germ line mutation for a family with RP, has many
      implications for genetic counseling of retinal degeneration (RD). To avoid
      inaccurate risk assessment for RP due to epigenetic events, such as the rare
      occurrence of germ line mosaicism, genetic counseling in families with XLRP
      should always be guided by molecular testing.

PMID- 15032970
TI  - Cryptic chromosomal rearrangement screening in 30 patients with mental
      retardation and dysmorphic features.
AB  - Mental retardation affects 1-3% of the general population, and the genetic causes
      in many cases are unknown. Cytogenetically undetected chromosomal imbalances have
      been indicated as an explanation. Nowadays, due to the development of molecular
      cytogenetic techniques, it is possible to identify cryptic rearrangements
      involving the ends of chromosomes. We report a screening using chromosome
      specific telomere fluorescence in-situ hybridization (FISH) probes, in a group of
      30 patients with a well-characterized phenotype including mental retardation,
      dysmorphic features, and a normal karyotype. Among them, two subtelomeric
      rearrangements have been detected and characterized. One of them is a de novo
      deletion of 1p36, which has been previously described as a new contiguous gene
      syndrome. The second is an unbalanced product of a cryptic translocation
      involving chromosomes 1 and 13, which results in a partial 1q trisomy and partial
      13q monosomy. These findings highlight, the importance of searching for cryptic
      subtelomeric rearrangements in non-syndromic mentally retarded patients.

PMID- 15032971
TI  - Predictive testing for Huntington's disease: relationship with partners after
      testing.
AB  - This study focuses on the partner relationship of tested persons, 5 years after
      their predictive test result for Huntington's disease (HD). We describe changes
      in marital status, quality of the relationship, and perceived changes in the
      relationship. Twenty-six carriers, 14 of their partners, 33 non-carriers, and 17
      of their partners participated in the study. Qualitative and quantitative methods
      were used. For the majority of tested persons (about 70%), the marital status was
      unchanged 5 years post test. Overall, carriers rated the quality of the
      relationship higher than their partners did and they perceived more positive
      changes. Qualitative data show that a test result leading to changed roles may
      induce significant marital distress. Another consequence of the test may be the
      changes in dynamics in asymptomatic carrier couples. A pre-test discussion of the
      possible impact of the test result on the relationship should result in a better
      preparation for and more understanding of the reactions after testing.
      Counselling after testing should stimulate an open communication between partners
      with consideration of needs and anxieties of both partners.

PMID- 15032972
TI  - Cytogenetic and molecular analysis of a family with three brothers afflicted with
      germ-cell cancer.
AB  - A thorough cytogenetic investigation and an analysis of detailed questionnaires
      were performed in a family with three brothers afflicted with germ-cell tumors
      (GCTs), in an attempt to detect a congenital factor related either to a
      hereditary genetic background or an environmental/lifestyle influence. One
      brother had an intracranial tumor in the pineal region and the two others had
      testicular tumors. Peripheral blood was studied by traditional karyotyping,
      multicolor-FISH, high-resolution comparative genomic hybridization (HR-CGH), and
      molecular analysis of selected loci on sex chromosomes (Yq11 region, TSPY, and
      the androgen receptor gene); however, no abnormalities were detected. The HR-CGH
      analysis of microdissected histological components of the overt tumors and the
      adjacent carcinoma in situ demonstrated a pattern of genomic imbalances
      characteristic for sporadic GCTs, including gain of 12p. The questionnaire and
      interview revealed a history of different cancers in the extended family, and a
      possible in utero and/or infantile exposure of the three brothers with GCTs to
      compounds suspected of endocrine-disrupting properties. Although no genetic
      aberration was detected in this family, we suspect the presence of a recessive
      hereditary factor pre-disposing to cancer, which probably was manifested as GCTs
      in the three brothers because of an adverse effect of an environmental factor on
      the early germ-cell differentiation.

PMID- 15032973
TI  - Refining the primary open-angle glaucoma GLC1C region on chromosome 3 by
      haplotype analysis.
AB  - The GLC1C locus for primary open-angle glaucoma (POAG) is inherited as an
      autosomal dominant trait. This region on chromosome 3 is 11 cM long. DNA samples
      from members of a Greek and an American GLC1C family were obtained to determine
      whether additional typing of microsatellite markers in family members might
      narrow the region. GLC1C family members were evaluated clinically for POAG on the
      basis of open angles, intraocular pressures, cupping of discs, and visual fields.
      DNA samples from the Greek and Oregon GLC1C families were used to further refine
      the GLC1C region using microsatellite markers. A total of 22 affected members
      were identified in the two families. Common alleles for D3S3637 and D3S3612 were
      present in the disease haplotype from both families, suggesting that they may
      have a common founder. A newly diagnosed patient in the American family had a
      recombination in the distal portion of the GLC1C haplotype. This recombination
      narrows the GLC1C region from 11 to 4 cM.

PMID- 15032974
TI  - Willingness to donate blood samples for genetic research: a survey from a
      community in Singapore.
AB  - Studies on the public's willingness to donate blood specimens for genetic
      research are few and are conducted mainly among Western countries. Little is
      known about the Asian community's willingness to participate in genetic research.
      A community-based survey was conducted on 548 adult Singaporeans to examine their
      willingness to donate blood samples for genetic research and its associated
      factors. The response rate was 70.3%. About 49.3% (95% CI, 45.1-53.5%) were
      willing to donate blood for genetic research. In the multivariable Cox regression
      analysis, willingness was significantly associated with belief in the benefits of
      genetic research; intention to participate in government studies; having no fear
      of pain, blood, injections, and needles; and non-concern about the loss of
      confidentiality. Reasons against donating blood were fear of pain, blood,
      injections, and needles (38.1%); no self-benefits (24.8%); fear of finding out
      about having a disease (22.3%); fear of discrimination (18.7%); and concerns
      about weakness (15.1%) and weight gain (9.4%). Public education programs to
      promote participation in genetic research should stress its benefits and address
      people's fears and concerns.

PMID- 15032975
TI  - Paternal origin of LMNA mutations in Hutchinson-Gilford progeria.

PMID- 15032976
TI  - Limb girdle muscular dystrophy: use of dHPLC and direct sequencing to detect
      sarcoglycan gene mutations in a New Zealand cohort.

PMID- 15032977
TI  - SDHD mutation analysis in seven German patients with sporadic carotid body
      paraganglioma: one novel mutation, no Dutch founder mutation and further evidence
      that G12S is a polymorphism.

PMID- 15032978
TI  - Cerebellar ataxia as atypical manifestation of the 3243A>G MELAS mutation.

PMID- 15032979
TI  - An integrated approach to management of Marfan syndrome caused by an FBN1 exon 18
      mutation in an Australian Aboriginal family.

PMID- 15032980
TI  - A novel R1347Q mutation in the predicted voltage sensor segment of the P/Q-type
      calcium-channel alpha-subunit in a family with progressive cerebellar ataxia and
      hemiplegic migraine.

PMID- 15032981
TI  - Vitamin D receptor gene variants of BsmI, ApaI, TaqI, and FokI polymorphisms in
      spinal tuberculosis.

PMID- 15032982
TI  - Memory load and the cognitive pupillary response in aging.
AB  - The effect of memory load on the cognitive pupillary response among 16 young
      adults and 16 older adults was investigated. Mean pupil dilation and reaction
      time were measured during a Sternberg memory-search task, which involved six
      levels of memory load. A classic interaction pattern was obtained in which the
      reaction times of the elderly participants increased more as a function of memory
      load than the reaction times of the young participants. In the encoding phase of
      the experiment, mean dilation increased with memory load. No age differences were
      observed here. In the search phase of the experiment, however, mean pupil
      dilation was considerably greater in the young than in the elderly participants.
      Moreover, mean dilation of the older participants was not sensitive to memory
      load, whereas mean dilation increased as a function of memory load in the young
      participants. The results suggest that the usefulness of the pupillary response
      as a correlate of subtle fluctuations in memory load diminishes with old age.

PMID- 15032983
TI  - Attention allocation in the dual-task paradigm as measured through behavioral and
      psychophysiological responses.
AB  - We investigated attention allocation in a dual-task paradigm using behavioral and
      pupillary measures. We used an auditory digit span (DS) and a simple visual
      response time (RT) task. Participants were administered four conditions in which
      they performed neither task (no-task), a single task (DS or RT only), or both
      tasks (dual). Dependent variables were DS accuracy, RT, and task-evoked pupillary
      responses (TEPRs) to digits as estimates of mental effort. Participants
      maintained almost the same level of DS accuracy on dual as on DS only and
      sacrificed speed on the RT task. As expected, TEPRs increased linearly with
      memory load in both DS only and dual. Although TEPRs were initially higher in
      dual than in DS only, the slope of the increase was shallower in dual. Results
      suggest that TEPRs can elucidate mechanisms of attention allocation by
      distinguishing between effectiveness (level of behavioral performance) and
      efficiency (the costs of that performance in mental effort).

PMID- 15032984
TI  - Visual encoding differentially affects auditory event-related potentials during
      working memory retrieval.
AB  - Previous working memory studies using auditory stimuli at both encoding and
      retrieval show amplitude decreases in event-related potentials (N100 and late
      positive wave, LPW) at retrieval as a function of memory load. This study tested
      if these effects are associated with phonological or semantic coding by
      presenting visual stimuli at encoding and auditory stimuli at retrieval. We
      hypothesized that event-related potentials associated with phonological but not
      semantic coding would be affected by modality differences at encoding and
      retrieval. Memory sets having one, three, or five visual digits were followed by
      auditory probes that subjects classified as present or absent from the set.
      Reaction time increased and LPW amplitudes decreased with increases in memory
      load, but there were no significant effects of memory load on N100 amplitude.
      Results suggest that with respect to brain activity that covaries with memory
      load, probe N100 amplitude is associated with phonological coding and LPW
      amplitude is associated with semantic coding.

PMID- 15032985
TI  - Event-related brain potentials to irrelevant auditory stimuli during selective
      listening: effects of channel probability.
AB  - The purpose of this study was to identify the cognitive process reflected by a
      positive deflection to irrelevant auditory stimuli (Pdi) during selective
      listening. Event-related brain potentials were recorded from 9 participants in a
      two-channel (left/right ears) selective listening task. Relative event
      probabilities of the relevant/irrelevant channels were 25%/75%, 50%/50%, and
      75%/25%. With increasing probability of the relevant channel, behavioral
      performances (the reaction time and hit rate) for the targets within the relevant
      channel improved, reflecting development of a more robust attentional trace. At
      the same time, the amplitude of the early Pdi (200-300 ms after stimulus onset)
      elicited by the stimuli in the irrelevant channel with a decreased probability
      was enhanced in the central region. This positive relation between the strength
      of the attentional trace and the amplitude of the early Pdi suggests that the
      early Pdi is elicited by a mismatching between an incoming irrelevant stimulus
      and an attentional trace.

PMID- 15032986
TI  - Simple, effective countermeasures to P300-based tests of detection of concealed
      information.
AB  - We found countermeasures to protocols using P300 in concealed information tests.
      One, the "six-probe" protocol, in Experiment 1, uses six different crime details
      in one run. The countermeasure: generate covert responses to irrelevant stimuli
      for each probe category. Hit rates were 82% in the guilty group; 18% in the
      countermeasure group. The average reaction time (RT) distinguished these two
      groups, but with overlap in RT distributions. The "one-probe" protocol, in the
      second experiment, uses one crime detail as a probe. Here, one group was run in 3
      weeks as a guilty group, a countermeasure group, and again as in Week 1.
      COUNTERMEASURE: Covert responses to irrelevant stimuli. In Week 1, hit rate was
      92%. In Week 2, it was 50%. In Week 3, 58%. There was no overlap in the
      irrelevant RT distribution in Week 2: Countermeasure use was detectable. However,
      in Week 3, the RT distributions resembled those of Week 1; test-beaters could not
      be caught. These studies have shown that tests of deception detection based on
      P300 amplitude as a recognition index may be readily defeated with simple
      countermeasures that can be easily learned.

PMID- 15032987
TI  - The functional locus of the lateralized readiness potential.
AB  - The lateralized readiness potential (LRP) is considered to reflect motor
      activation and has been used extensively as a tool in elucidating cognitive
      processes. In the present study, we attempted to more precisely determine the
      origins of the LRP within the cognitive system. The response selection and motor
      programming stages were selectively manipulated by varying symbolic stimulus
      response compatibility and the time to peak force of an isometric finger
      extension response. Stimulus response compatibility and time to peak force
      affected response latency, as measured in the electromyogram, in a strictly
      additive fashion. The effects of the experimental manipulations on stimulus- and
      response-synchronized LRPs indicate that the LRP starts after the completion of
      response-hand selection and at the beginning of motor programming. These results
      allow a more rigorous interpretation of LRP findings in basic and applied
      research.

PMID- 15032988
TI  - Beneficial effects of ambiguous precues: parallel motor preparation or reduced
      premotoric processing time?
AB  - The present study was designed to investigate the mechanisms underlying movement
      preprogramming in situations where informative but ambiguous precue information
      is used. In a response precuing task that involved flexion or extension movements
      with the right or left index finger, a spatially compatible precue conveyed
      partial information about side, about direction, no parameter information
      (ambiguous condition), or no information at all. Advance movement preparation was
      indicated by reaction-time shortening for all informative precue conditions. The
      analysis of stimulus- and response-locked lateralized readiness potential onsets
      revealed a clear and exclusive motoric origin of the ambiguous-precue benefit.
      Additional analyses ruled out a strategic trial by trial choice of just one of
      the two ambiguous alternatives and provided evidence for a parallel preparation
      of both response alternatives when information only about direction or ambiguous
      precue information is provided.

PMID- 15032989
TI  - Context dependence of the event-related brain potential associated with reward
      and punishment.
AB  - The error-related negativity (ERN) is an event-related brain potential elicited
      by error commission and by presentation of feedback stimuli indicating incorrect
      performance. In this study, the authors report two experiments in which
      participants tried to learn to select between response options by trial and
      error, using feedback stimuli indicating monetary gains and losses. The results
      demonstrate that the amplitude of the ERN is determined by the value of the
      eliciting outcome relative to the range of outcomes possible, rather than by the
      objective value of the outcome. This result is discussed in terms of a recent
      theory that holds that the ERN reflects a reward prediction error signal
      associated with a neural system for reinforcement learning.

PMID- 15032990
TI  - Is motor inhibition during laughter due to emotional or respiratory influences?
AB  - We compared the effects of laughter and several respiratory movements on spinal
      motor excitability to unravel their respective influences. We measured H-reflexes
      in 13 healthy volunteers during 10 different tasks (including laughter, simulated
      laughter, and various respiratory movements). We compared the percentage that
      remained of the initial H-reflex during each task with that during a neutral
      task. H-reflex percentage differed between the neutral task (79.4 +/- 16.1%),
      true laughter (43.7 +/- 17.9%), and simulated laughter (66.6 +/- 24.3%), and
      between the two latter tasks. Coughing also resulted in H-reflex suppression, but
      not as deeply as true laughter. During the other respiratory maneuvers, the H
      reflex increased compared to the neutral task. Our finding that true laughter
      evoked more H-reflex depression than simulated laughter suggests that mirth on
      its own depresses the H-reflex. This mechanism may also be involved in the
      pathophysiology of cataplexy, the main symptom of narcolepsy.

PMID- 15032991
TI  - Recognition of affective prosody: continuous wavelet measures of event-related
      brain potentials to emotional exclamations.
AB  - The affective state of a speaker can be identified from the prosody of his or her
      speech. Voice quality is the most important prosodic cue for emotion recognition
      from short verbal utterances and nonverbal exclamations, the latter conveying
      pure emotion, void of all semantic meaning. We adopted two context violation
      paradigms-oddball and priming-to study the event-related brain potentials (ERP)
      reflecting this recognition process. We found a negative wave, the N300, in the
      ERPs to contextually incongruous exclamations, and interpreted this component as
      analogous to the well-known N400 response to semantically inappropriate words.
      The N300 appears to be a real-time psychophysiological measure of spontaneous
      emotion recognition from vocal cues, which could prove a useful tool for the
      examination of affective-prosody comprehension. In addition, we developed a new
      ERP component detection and estimation method that is based on the continuous
      wavelet transform (CWT), does not rely on visual inspection of the waveforms, and
      yields larger statistical difference effects than classical methods.

PMID- 15032992
TI  - The stability of resting frontal electroencephalographic asymmetry in depression.
AB  - Although resting frontal electroencephalographic (EEG) alpha asymmetry has been
      shown to be a stable measure over time in nonclinical populations, its
      reliability and stability in clinically depressed individuals has not been fully
      investigated. The internal consistency and test-retest stability of resting EEG
      alpha (8-13 Hz) asymmetry were examined in 30 women diagnosed with major
      depression at 4-week intervals for 8 or 16 weeks. Asymmetry scores generally
      displayed good internal consistency and exhibited modest stability over the 8-
      and 16-week assessment intervals. Changes in asymmetry scores over this interval
      were not significantly related to changes in clinical state. These findings
      suggest that resting EEG alpha asymmetry can be reliably assessed in clinically
      depressed populations. Furthermore, intraclass correlation stability estimates
      suggest that although some traitlike aspects of alpha asymmetry exist in
      depressed individuals, there is also evidence of changes in asymmetry across
      assessment occasions that are not closely linked to changes in depressive
      severity.

PMID- 15032993
TI  - Staring at one side of the face increases blood flow on that side of the face.
AB  - To investigate the effect of observation on blushing, an experimenter sat next to
      28 participants and looked closely at one cheek while the participant sang
      (embarrassing) or read aloud (not embarrassing). Increases in cheek temperature
      were greater on the observed than the unobserved side during both tasks. Changes
      in cheek temperature were symmetrical when the experimenter sat next to another
      23 participants and looked straight ahead, as well as when the experimenter
      stared at one side of the participant's face through a glass window while the
      participant sang. However, increases in cutaneous blood flow were greater on the
      observed than the unobserved side of the forehead during singing. These findings
      suggest that staring at one side of the face triggers an ipsilateral increase in
      facial blood flow.

PMID- 15032994
TI  - Reduced Alpha power associated with the recall of mentation from Stage 2 and
      Stage REM sleep.
AB  - Relationships between Alpha (8-12 Hz) activity and cognitive processes during
      wakefulness raise the possibility of similar relationships between Alpha and
      cognitive activity during sleep. We hypothesized that Alpha power decreases
      during both Stage 2 and REM sleep would index the presence of sleep mentation in
      these stages. Absolute power for six classical EEG bands and three Alpha subbands
      was calculated for Stage 2 and REM sleep awakenings both with and without
      mentation recall. In both stages, recall was associated with lower Alpha power,
      especially with middle Alpha power (9.5-11.5 Hz). Unexpectedly, a similar effect
      for Delta power (0.5-4.0 Hz) was also observed. The Alpha effect may reflect
      cognitive elaboration active in the minutes preceding awakening; however,
      attention and memory processes cannot be excluded. The Delta effect is consistent
      with prior observations of regular linkages between Alpha and Delta power during
      sleep.

PMID- 15032995
TI  - Thinking and hallucinating: reciprocal changes in sleep.
AB  - Internal deliberations (focused thoughts) and endogenous percepts
      (hallucinations) vary in a reciprocal manner across the states of waking and
      sleep, paralleling changes in regional brain activation. As subjects go from
      waking through sleep onset to NREM sleep and then to REM sleep, they report
      progressively more hallucinoid imagery and progressively less thinking. We have
      investigated whether this reciprocity in cognition between NREM and REM is
      maintained throughout the night. To do so, we analyzed 229 REM and 165 NREM
      reports collected with the Nightcap sleep monitoring system from 16 participants
      in their homes over 14 nights. The reports were scored for the presence of
      hallucinations and directed thinking by external judges. As predicted,
      hallucinations were more frequent in REM than in NREM for each segment of the
      night, and directed thinking was more frequent in NREM in the first 5 h of the
      night. Late in the night, directed thinking was equally infrequent in NREM and
      REM. At the same time, hallucinations increased within both NREM and REM as the
      night progressed, whereas directed thinking decreased in NREM and remained at a
      stable, low level in REM. These findings suggest that a reciprocal shift in
      focused thinking and hallucinating is a general property of cognitive activity
      across the wake-sleep cycle. Biological evidence supports the hypothesis that
      these cognitive changes are governed by specific state regulatory and
      neurocognitive processes at several levels of the brain.

PMID- 15032996
TI  - The functional relationship between visual backward masking and prepulse
      inhibition.
AB  - This experiment demonstrated a relationship between prepulse inhibition (PPI) of
      the startle eyeblink and visual backward masking in college students. It was
      hypothesized that recovery from backward masking effects is due in part to
      sensory gating, as assessed by auditory and visual PPI. Visual presentations of
      letters served as targets or visual prepulses in an intermixed session of
      backward masking and PPI. Backward masking and PPI (both auditory and visual)
      were assessed at stimulus onset asynchronies of 30, 45, 60, 120, and 150 ms. A
      repeated-measures regression revealed that there was a relationship between
      backward masking and PPI for both visual and auditory PPI, with higher levels of
      PPI being associated with greater recovery from backward masking. The data are
      consistent with the hypothesis that recovery from backward masking effects is
      affected by sensory gating acting in part to gate out the interruptive effects of
      the mask.

PMID- 15032997
TI  - Automatic removal of eye movement and blink artifacts from EEG data using blind
      component separation.
AB  - Signals from eye movements and blinks can be orders of magnitude larger than
      brain-generated electrical potentials and are one of the main sources of
      artifacts in electroencephalographic (EEG) data. Rejecting contaminated trials
      causes substantial data loss, and restricting eye movements/blinks limits the
      experimental designs possible and may impact the cognitive processes under
      investigation. This article presents a method based on blind source separation
      (BSS) for automatic removal of electroocular artifacts from EEG data. BBS is a
      signal-processing methodology that includes independent component analysis (ICA).
      In contrast to previously explored ICA-based methods for artifact removal, this
      method is automated. Moreover, the BSS algorithm described herein can isolate
      correlated electroocular components with a high degree of accuracy. Although the
      focus is on eliminating ocular artifacts in EEG data, the approach can be
      extended to other sources of EEG contamination such as cardiac signals,
      environmental noise, and electrode drift, and adapted for use with
      magnetoencephalographic (MEG) data, a magnetic correlate of EEG.

PMID- 15032998
TI  - A comparison of several methods used to quantify prepulse inhibition of eyeblink
      responding.
AB  - Several methods of quantifying prepulse inhibition (PPI) of eyeblink responding
      were compared in adult volunteers. Blink-eliciting stimuli were noise bursts at
      85 or 100 dB, and prepulses were also noise bursts, at 55 or 70 dB and lead
      intervals of 60 or 120 ms. PPI was evaluated by comparing reactivity on prepulse
      and control trials within participants using the following methods: (1)
      difference between reactivity on prepulse and control trials; (2) reactivity on
      prepulse trials divided by that on control trials (proportion of control); (3)
      difference between reactivity on prepulse and control trials, divided by that on
      control trials (proportion of the difference from control); (4) range correction
      (maximum minus minimum reactivity, divided by the range of reactivity), across
      all control and prepulse trials; (5) z scores across all prepulse and control
      trials. Prepulses inhibited eyeblink response magnitude in all cases. Proportion
      of difference was the method least affected by differences in control reactivity,
      and is the preferred method to use when quantifying PPI, both from a practical
      and a neurophysiological perspective.

PMID- 15032999
TI  - Where to Q in PEP.
AB  - The onset of ventricular depolarization defines the start of the preejection
      period (PEP), which is commonly used as an index of myocardial contractility and
      sympathetic control of the heart. Although the fiducial point for this onset has
      traditionally been the onset of the Q wave of the electrocardiogram, other
      measurement points have also been used in the literature, including the peak of
      the Q wave (i.e., the onset of the R wave). Conceptual, physiological, and
      empirical considerations addressing the reliability and validity of these
      alternative metrics support the application of the Q-wave peak/R-wave onset as
      the fiducial point for PEP measures.

PMID- 15033001
TI  - Is there a clinically significant seasonal component to hospital admissions for
      atrial fibrillation?
AB  - BACKGROUND: Atrial fibrillation is a common cardiac dysrhythmia, particularly in
      the elderly. Recent studies have indicated a statistically significant seasonal
      component to atrial fibrillation hospitalizations. METHODS: We conducted a
      retrospective population cohort study using time series analysis to evaluate
      seasonal patterns of atrial fibrillation hospitalizations for the province of
      Ontario for the years 1988 to 2001. Five different series methods were used to
      analyze the data, including spectral analysis, X11, R-Squared, autocorrelation
      function and monthly aggregation. RESULTS: This study found evidence of weak
      seasonality, most apparent at aggregate levels including both ages and sexes.
      There was dramatic increase in hospitalizations for atrial fibrillation over the
      years studied and an age dependent increase in rates per 100,000. Overall, the
      magnitude of seasonal difference between peak and trough months is in the order
      of 1.4 admissions per 100,000 population. The peaks for hospitalizations were
      predominantly in April, and the troughs in August. CONCLUSIONS: Our study
      confirms statistical evidence of seasonality for atrial fibrillation
      hospitalizations. This effect is small in absolute terms and likely not
      significant for policy or etiological research purposes.

PMID- 15033002
TI  - Cell-based assay for the detection of chemically induced cellular stress by
      immortalized untransformed transgenic hepatocytes.
AB  - BACKGROUND: Primary hepatocytes, one of the most widely used cell types for
      toxicological studies, have a very limited life span and must be freshly derived
      from mice or even humans. Attempts to use stable cell lines maintaining the
      enzymatic pattern of liver cells have been so far unsatisfactory. Stress proteins
      (heat shock proteins, HSPs) have been proposed as general markers of cellular
      injury and their use for environmental monitoring has been suggested. The aim of
      this work is to develop a bi-transgenic hepatocyte cell line in order to evaluate
      the ability of various organic and inorganic chemicals to induce the expression
      of the HSP70 driven reporter gene. We previously described transgenic mice
      (Hsp70/hGH) secreting high levels of human Growth Hormone (hGH) following
      exposure to toxic compounds in vivo and in vitro in primary cultures derived from
      different organs. In addition, we also reported another transgenic model
      (AT/cytoMet) allowing the reproducible immortalization of untransformed
      hepatocytes retaining in vitro complex liver functions. RESULTS: The transgenic
      mouse line Hsp70/hGH was crossed with the AT/cytoMet transgenic strain permitting
      the reproducible immortalization of untransformed hepatocytes. From double
      transgenic animals we derived several stable hepatic cell lines (MMH-GH) which
      showed a highly-differentiated phenotype as judged from the retention of
      epithelial cell polarity and the profile of gene expression, including hepatocyte
      enriched transcription factors and detoxifying enzymes. In these cell lines,
      stresses induced by exposure to inorganic [Sodium Arsenite (NaAsO2) and Cadmium
      Chloride (CdCl2)], and organic [Benzo(a)Pyrene (BaP), PentaChloroPhenol (PCP),
      TetraChloroHydroQuinone (TCHQ), 1-Chloro-2,4-DiNitro-Benzene (CDNB)] compounds,
      specifically induced hGH release in the culture medium. CONCLUSIONS: MMH-GH, an
      innovative model to evaluate the toxic potential of chemical and physical
      xenobiotics, provides a simple biological system that may reduce the need for
      animal experimentation and/or continuously deriving fresh hepatocytes.

PMID- 15033004
TI  - [Strengthen the cooperation to seek a way for comprehensive advancing
      occupational health safety].

PMID- 15033003
TI  - BAG-1 in carcinogenesis.
AB  - BAG-1 is a multifunctional protein that exists as several differentially
      localised and functionally distinct isoforms. BAG-1 isoforms interact with a
      diverse array of molecular targets and regulate a wide range of cellular
      processes, including proliferation, survival, transcription, apoptosis,
      metastasis and motility. The BAG domain of BAG-1 interacts with chaperone
      molecules and this is considered important for many BAG-1 functions. The ability
      of BAG-1 to regulate such a wide variety of cellular processes suggests it might
      play an important role in many cancer types. For example, regulation of nuclear
      hormone receptor function and susceptibility to apoptosis might have a major
      impact on cancer development, progression and response to therapy. There is also
      increasing evidence that BAG-1 expression is altered in a variety of human
      malignancies relative to normal cells, and with further understanding of BAG-1
      function it might become a powerful prognostic/predictive marker in human cancer.
      This review describes the structure and function of BAG-1 isoforms and the
      potential clinical implications of their expression in tumour cells.

PMID- 15033005
TI  - [Expression of M3 receptor gene in peripheral blood lymphocytes of workers
      exposed to dimethoate].
AB  - OBJECTIVE: To study the expression of muscarinic receptor M(3) gene in peripheral
      blood lymphocytes of workers exposed to organophosphorus pesticides (OPPs) and to
      explore its role in the adverse effects of OPPs. METHODS: The lymphocytes of
      peripheral blood from 33 workers exposed to dimethoate and 15 control people were
      isolated and treated with saline and dimethoate respectively in vitro. RT-PCR
      technique was used to determine M(3) gene expression. Basal and inducible gene
      expression levels were measured. RESULTS: There was no significant difference in
      basal gene expression level between exposed group and control group, while the
      inducible gene expression level was significantly higher in exposure group (1.92
      +/- 1.07) than in control group (1.22 +/- 0.19) and basal level (1.49 +/- 0.45, P
      < 0.05). No differences in basal and inducible gene expression level were found
      between male and female people in both exposed and control group. The level of
      inducible M(3) gene expression increased with the increase in length of exposure
      time [< 5 a: (1.69 +/- 0.95), 5 - 25 a: (1.91 +/- 1.03), > 25 a: (2.09 +/- 1.25),
      the latter was significantly different from that of < 5 a (P < 0.05)].
      CONCLUSION: After long-term exposure to OPPs, the basal M(3) receptor gene
      expression level in the exposed workers did not show any difference from the
      control group, but the inducible gene expression level (treated with dimethoate
      in vitro) was increased and related to the extent of exposure to dimethoate.

PMID- 15033006
TI  - [Muscarine receptor gene expression in brain and peripheral blood lymphocytes of
      rats pretreated with dimethoate for 28 days].
AB  - OBJECTIVE: To study the tolerance of rats induced by 28 day pretreatment with low
      dosage of dimthoate and the toxic effects challenged by higher dosage of
      dimethoate, and to investigate the change of M receptor and the mechanism of
      tolerance formation. METHODS: SD rats were given 25 mg/kg dimethoate daily(sc)
      while control group was given saline daily instead for 28 days. The activity of
      whole blood acetylcholinesterase (AChE) was examined. On the 29th day three
      groups of administrated rats were challenged by saline solution, 50 mg/kg and 100
      mg/kg dimethoate, respectively. The density and mRNA level of brain M(1), M(2)
      receptor were determined. Lymphocytes of peripheral blood were isolated, and
      basal, inducible M(3) gene expression were measured by RT-PCR. RESULTS: During
      pretreatment, blood AChE activity decreased continually, it reached the lowest on
      the 13th day. And it decreased more after exposed to higher dosage of dimethoate.
      Brain AChE activity in the pretreated groups was lower than that in control group
      and decreased with the increase in challenging dosage. The density of M(1)
      receptor in negative control, pretreated, and 50, 100 mg/kg challenging groups
      were 979.15, 856.54, 539.46, 539.14 fmol/mg pro respectively. The change in
      relative levels of mRNA of M(1) receptor (2.59, 2.47, 2.20, 1.81) were consistent
      with the density of receptor but the level declined continually as the
      challenging dosage increased. The density of M(2) receptor were 507.38, 611.11,
      548.42, 337.47 fmol/mg pro respectively, which were not obviously affected by
      pretreatment but decreased as the challenging dosage increased. The change in
      levels of M(2) receptor mRNA was not obvious. The basal gene expression of M(3)
      receptor mRNA was not different among all experimental groups while the inducible
      gene expression decreased with the increase in challenging dosage. CONCLUSION:
      Low level dosage of dimethoate could induce animals to tolerate dimethoate
      toxicity. Reduction of M(1) receptor density which may be induced by the decrease
      in its gene expression may be the mechanism of tolerance. The change of M(3)
      receptor mRNA inducible expression in lymphocyte accorded with M(1) receptor mRNA
      expression in the brain.

PMID- 15033007
TI  - [Protective effect of memantine on N-methyl-D-aspartate receptor in dichlorvos
      poisoned rat brain].
AB  - OBJECTIVE: To study the protective effect of memantine on the regulation of N
      methyl-D-aspartate (NMDA) receptor in dichlorvos-poisoned rat brain, and to
      understand the mechanism of its role in organophosphate poisoning. METHODS: SD
      rats were administrated dichlorvos (25 mg/kg, ip) then three groups were treated
      with memantine at doses of 5, 15 and 45 mg/kg respectively. The activity of
      acetylcholinesterase (AChE) and binding capacity of NMDA receptor with [(3)H]MK
      801 were determined 16 h after dichlorvos injection. RESULTS: The time of onset
      of toxic symptoms in 15, 45 mg memantine treated groups [(18.40 +/- 1.14) and
      (21.40 +/- 1.52) min respectively] was higher than that in dichlorvos alone group
      [(16.75 +/- 1.62) min]; the intensity of muscle fasciculation (1.60 +/- 1.14 and
      0.80 +/- 0.84, respectively) was less than that in control group (2.85 +/- 0.37);
      the total score of poisoning symptoms (8.80 +/- 1.79 and 9.00 +/- 2.24
      respectively) was also less than that in dichlorvos group (14.60 +/- 1.70). The
      AChE activities both in blood and brain of memantine treated groups were not
      significantly different from those in dichlorvos alone group. The affinity (Kd
      value) and density (Bmax value) of brain NMDA receptor in dichlorvos exposed rats
      [(75.55 +/- 7.87) nmol/L, (0.46 +/- 0.06) pmol/mg pro respectively] were higher
      and lower respectively than those in control group [(37.37 +/- 4.17) nmol/L,
      (0.62 +/- 0.04) pmol/mg pro respectively]. Lower level of memantine (5 and 25
      mg/kg) could antagonize the dichlorvos-evoked down-regulation of [(3)H]MK-801
      binding to NMDA receptor in rat brain [Bmax value: (0.55 +/- 0.07) and (0.64 +/-
      0.07) pmol/mg pro; Kd value: (38.68 +/- 4.54) and (32.58 +/- 3.90) nmol/L
      respectively] while higher dose of memantine (45 mg/kg), the Bmax (0.45 +/- 0.06)
      pmol/mg pro and Kd (22.88 +/- 4.42) nmol/L of NMDA receptor were significantly
      decreased (P < 0.01). CONCLUSION: Memantine in certain dose range could protect
      against the down-regulation of NMDA receptor in rat brain, and alleviate
      organophosphorus poisoning symptoms to some extent. The recovery of AChE activity
      inhibition wasn't involved in the treatment with memantine on dichlorvos
      poisoning, therefore, atropine and a proper AChE reactivator (an oxime) should be
      used clinically.

PMID- 15033008
TI  - [The antiandrogenic effect of dimethachlon and its mechanism].
AB  - OBJECTIVE: To evaluate the antiandrogenic effect of heterocyclic fungicide
      dimethachlon and its mechanism. METHODS: A combination of in vivo and in vitro
      assays was selected. Hershberger assay was used to determine the antiandrogenic
      potential of dimethachlon in vivo. Six-week-old castrated male SD rats were
      administrated once daily for 7 days with testosterone propionate (TP, 100 micro
      g/d, sc) plus gavage doses of dimethachlon (50, 100 or 200 mg x kg(-1) x d(-1)),
      or procymidone (150 or 300 mg x kg(-1) x d(-1), positive control), or iprodione
      (100 mg x kg(-1) x d(-1), positive control), or flutamide (50 mg x kg(-1) x d(
      1), positive control). Transcriptional activation assay in vitro was employed to
      determine the mechanism of antiandrogenic activity of dimethachlon. Human
      hepatoma liver cells HepG2 were transiently cotransfected with human androgen
      receptor (AR) expression plasmid and AR-dependent luciferase report plasmid.
      Transfected cells were exposed to various concentrations of dimethachlon or
      flutamide with or without dihydrotestosterone to induce the expression of
      luciferase gene. RESULTS: In Hershberger assay, dimethachlon, as well as other
      known antiandrogens, caused decrease in weight of androgen dependent organs or
      tissues. In 200 mg/kg group, the weight of seminal vesicle, ventral prostate,
      dorsolateral prostate, Cowper's gland, and levator ani plus bulbocavernosus
      muscles decreased by 57.8%, 44.8%, 43.9%, 30.1%, and 34.1% respectively, but did
      not decrease in the vehicle control group. The order of their antiandrogenic
      potencies was: flutamide > procymidone > dimethachlon > iprodione. In
      transcriptional activation assay, dimethachlon could inhibit dihydrotestosterone
      dependent AR activity in transfected HepG2 cells in dose-effect relationship. The
      inhibiting potency of dimethachlon was about 1/100 of that of flutamide.
      CONCLUSION: Dimethachlon has antiandrogenic effect, and acts as an AR antagonist.
      Its antiandrogenic potency is lower than flutamide and procymidone, but higher
      than iprodione.

PMID- 15033009
TI  - [Spinal cord neuronal apoptosis induced by triorthocresyl phosphate poisoning in
      hens].
AB  - OBJECTIVE: To investigate the role of neuronal apoptosis in organophosphorus
      poisoning-induced delayed neuropathy (OPIDN) and its dynamic pathological
      changes. METHODS: To establish OPIDN animal model, triorthocresyl phosphate
      (TOCP)was given to hens with a single dose (1 000 mg/kg, im). Changes of
      neuropathology, number of neurons and apoptotic cells in the third lumbar spinal
      cord were observed by HE, Nissl and TUNEL methods 3, 5, 7, 10, 14, 18 days after
      injection. RESULTS: The hens showed OPIDN typical signs (progressive ataxia and
      hypotonia) about 9 days after TOCP exposure. HE staining revealed dark red
      nucleus in neurons of anterior horn of lumbar spinal cord 5 days after exposure,
      but this phenomenon disappeared 18 days later. Nissl method showed that the
      number of neurons in anterior horn of spinal cord decreased [from (82 +/- 4)
      cell/mm(2) to (66 +/- 6) cell/mm(2)]. TUNEL positive cells began to appear [(22
      +/- 2) cell/mm(2)] 5 days after TOCP exposure, and reached the peak [(27 +/- 3)
      cell/mm(2)] 7 days later, and disappeared 18 days later. CONCLUSION: Neuronal
      apoptosis in anterior horn of spinal cord of hens appeared in OPIDN, suggesting
      that cellular apoptosis may play an important role in the pathogenesis of OPIDN.

PMID- 15033010
TI  - [Effects of estradiol on deltamethrin-induced neurotoxicity in rat cerebro
      cortical synaptosomes].
AB  - OBJECTIVE: To investigate the neuroprotective effect of estradiol on the release
      of excitatory amino acid (EAAs) mediator, and the activity of ATPase in cerebro
      cortical synaptosome membrane of rats exposed to deltamethrin. METHODS: Using
      HPLC to detect EAAs release, and colorimeter method to measure the activities of
      Na(+)-K(+)-ATPase, Mg(2+)-ATPase, Ca(2+)-ATPase, Ca(2+)-Mg(2+)-ATPase in the
      cerebro-cortical synaptosomes of ovariectomized rats exposed to deltamethrin (2 x
      10(-5)mol/L), and treated with different doses of 17beta estradiol (10(-5), 10(
      8), 10(-11) mol/L). Meanwhile, the estrogen receptor (ER) antagonist, tamoxifen,
      was used to investigate the effect on estradiol. RESULTS: The release of Asp and
      Glu from the cerebro-cortical synaptosomes was significantly increased by 2 x 10(
      5)mol/L deltamethrin exposure at the depolarizing state evoked by 50 mmol/L KCl,
      while 10(-8), 10(-11) mol/L 17beta estradiol could partly inhibit the effect of
      deltamethrin on the release of Asp (28.42%, 24.36%, respectively), Glu (21.52%,
      14.57%, respectively). The activities of 4 kinds of ATPase were inhibited by 2 x
      10(-4) mol/L deltamethrin, and these effects could be blocked by 10(-5) mol/L
      estradiol, while the activity of Ca(2+)-ATPase was increased by 10(-8), 10(-11)
      mol/L of estradiol. However, no obvious antagonistic effect of tamoxifen on the
      function of estradial on EAAs release or the activities of ATPase was found.
      CONCLUSION: Estradiol showed certain neuroprotective effect on the release of
      EAAs and the inhibition on ATPase induced by deltamethrin. The effect of
      estradiol on synaptosomes may indicate the nongenetic mechanism of estradiol.

PMID- 15033011
TI  - [Logistic regression analysis of factors influencing clinical therapeutic effect
      on acute tetramine poisoning].
AB  - OBJECTIVE: To investigate the factors affecting clinical therapeutic effect on
      acute tetramine poisoning. METHODS: Using Logistic regression to analyze the
      relationships among the degree of tetramine poisoning, time of onset, time of
      admission, exposure history, sex, age, unithol, gastric lavage, etc with the
      death of poisonded patients. RESULTS: The fatality rate of patient with tetramine
      poisoning who got gastric lavage was less than that who did not (5.85% vs 38.00%,
      P < 0.01). In patients who got gastric lavage, the fatality rates were increased
      with the degree of tetramine poisoning (control: 0%, mild poisoning: 3.07%,
      severe poisoning: 9.14%, P < 0.05). There was no significant difference in
      fatality between using unithol and not using patients (7.22% vs 8.25%, P > 0.05).
      CONCLUSION: Unithol has no significant influence of clinical therapeutic effect
      on tetramine poisoning patients and dose not reduce the fatality rate of patient
      with tetramine poisoning, but gastric lavage and the degree of tetramine
      poisoning do. Logistic regression analysis showed that gastric lavage is the main
      factor affecting the therapeutic effect on tetramine poisoning.

PMID- 15033012
TI  - [Genetic damage in peripheral blood lymphocyte of coke oven workers].
AB  - OBJECTIVE: To investigate DNA and chromosome damage in peripheral blood
      lymphocyte of coke oven workers exposed to polycyclic aromatic hydrocarbons
      (PAHs). METHODS: One hundred and thirty-seven coke oven workers and 50 controls
      without occupational PAHs exposure were investigated. Comet assay and cytokinesis
      block micronucleus (CBMN) detection were used to evaluate DNA and chromosomal
      damage levels in peripheral blood lymphocyte. Urinary 1-hydroxypyrene level was
      used to assess the personal internal PAHs exposure dose. Personal information
      including occupational history, age, sex, smoking and drinking status was
      collected by questionnaire. RESULTS: Urinary 1-hydroxypyrene level in coke oven
      workers [(5.76 +/- 1.04) micro mol/mol Cr] was significantly higher than that in
      controls [(0.70 +/- 0.32) micro mol/mol Cr]. The rate of CBMN and comet tail
      moment of lymphocyte in coke oven workers [8.0 per thousand (0.0 per thousand -
      30.0 per thousand ) and 2.09 (0.31 - 75.41), respectively] were higher than those
      in controls [3.5 per thousand (0.0 per thousand - 13.0 per thousand ) and 1.05
      (0.11 - 6.63), P < 0.05]. In controls, the comet moment in smokers was
      significantly higher than that in non-smokers [1.44 (0.23 - 6.63) vs 0.81 (0.11 -
      3.47), P < 0.05]. According to the length of work, 137 coke oven workers were
      classified into 3 groups i.e. 0.5 yrs , 16.0 yrs and 22.0 yrs group, and the
      comet moments were 1.34 (0.31 - 37.84), 2.32 (0.49 - 52.97) and 3.20 (0.45 -
      75.41) respectively after adjusting the age, sex, smoking, drinking and level of
      urinary 1-hydroxy-pyrene. There was a rising tendency along with the increase in
      length of work. CONCLUSION: Under present PAHs exposure levels, both comet assay
      and Cytokinesis-block micronucleus test could detect PAHs-induced genotoxicity in
      coke oven workers, and comet assay is more suitable to assess the cumulative
      damage effect on DNA.

PMID- 15033013
TI  - [Analysis of the data for inpatients with acute organophosphorous pesticide
      poisoning in Wucheng].

PMID- 15033014
TI  - [Study on revising the criteria of classification of hazard conditions of
      productive dust].
AB  - OBJECTIVE: To provide scientific basis data for revising the national hygiene
      criteria of "Classification of hazard conditions of productive dust" (GB5817-86).
      METHODS: The data of the retrospective study and the field survey data were
      analyzed with correlation and regression analysis. The product of total dust
      concentration of respiratory exposure (mg/m(3)), total ventilation during
      exposure (m(3)/d per psrson), and level of free SiO(2) in dust (%) was the
      respiratory exposure dose of free SiO(2) (mg per day per person) which was used
      as dose criteria value of classification of hazard degree of dust. RESULTS: Using
      free SiO(2) exposure dose and the dose-effect relationship, the hazard degrees of
      the dust were divided into 5 grades: 0, I, II, III, IV (0 - 8.0, 8.1 - 12.0, 12.1
      - 16.0, > 24.1 mg per day per person). CONCLUSION: The exposure dose of free
      SiO(2) is closely related to the pathogenesis of silicosis. Using the exposure
      dose of free SiO(2) as the classification indicator of hazard degree of dust is
      reliable, simple and easy to execute.

PMID- 15033015
TI  - [Comparison of TGF-beta1 expression of lung cancer in Gejiu miners with that in
      non-miners in other regions].
AB  - OBJECTIVE: To investigate the different expression of transforming growth factor
      beta(1) (TGF-beta(1)) in lung cancer specimens of Gejiu miners, and non-miners in
      other regions. METHODS: Thirty specimens of Gejiu miners' lung cancer and 30
      specimens of non-miners' were observed in this experiment. The expression of TGF
      beta(1) protein and TGF-beta(1) mRNA were detected by the methods of
      immunohistochemistry and in situ hybridization. The results were quantitatively
      analyzed using image analysis system. RESULTS: The positive rate of TGF-beta(1)
      protein expression in Gejiu miners and non-miners was 75.39%and 44.78%
      respectively, and the positive rate of TGF-beta(1) mRNA was 63.96% and 34.07%
      respectively. There were significant differences between the two groups (P <
      0.01). CONCLUSION: The expression of TGF-beta(1) in lung cancer of Gejiu miners
      was significantly higher than that of non-miners. The pathogenesis of lung cancer
      may be different between Gejiu miner and non-miners. High expression of TGF
      beta(1) may be one of the reasons of high incidence of lung cancer in Gejiu
      miners.

PMID- 15033016
TI  - [One case of using pralidoxime chloride to treat acute parathion poisoning].

PMID- 15033017
TI  - [The diagnostic value and morphologic manifestation of high resolution
      computerized tomography in coal miner's pneumoconiosis with pleural pathological
      changes].
AB  - OBJECTIVE: To analyse CT and high resolution computerized tomography (HRCT)
      diagnostic value and morphologic manifestation in coal miner's pneumoconiosis
      with pleural pathological changes. METHODS: One hundred and thirty-one cases of
      coal miner patients with pneumoconiosis (0(+) type: 14 cases, type I: 46 cases,
      type II: 58 cases, type III: 13 cases) and 20 normal people as control group were
      first examined by routine CT scan at 4 fixed slices, followed by HRCT examination
      at the region of interest (ROI). Meanwhile, all of them had high-kV chest
      radiography. RESULTS: According to the national standard of the People's Republic
      of China in the diagnosis of coal miner's pneumoconiosis with pleural plaque, 68
      cases of pleural disease making up 51.91% (68/131) were found (type I accounted
      for 17.65%, type II 63.24%, type III 19.12%). The morphologic manifestation of
      pleural pathology by HRCT could be classified into four types: (1) nodular type:
      73.38%, (2) flat type: 18.71%, (3) irregular type: 7.91%, (4) mixed type. The
      pleural pathological changes were found in thoracic wall pleura (65.02%), surface
      of mediastinum (22.16%), and pericardium (12.80%), but not found in the top of
      lung and costo-phrenic angles. The thickness of pleura was often about 5
      approximately 10 mm (88.17%). CONCLUSION: Pleural pathological changes were not
      seldom seen in coal miner's pneumoconiosis. HRCT is a reliable examination method
      aiding routine CT to show pleural pathological changes, thus it has a great
      diagnostic and practical value. It is necessary to make a further comparison
      study between pathology and imagology.

PMID- 15033018
TI  - [CD59 mutation and DNA oxidative damage in A(L) cells induced by crocidolite
      fibers].
AB  - OBJECTIVE: To determine the effects of buthionine sulfoximine (BSO) and free
      radical scavenger, dimethyl sulfoxide (DMSO), on mutation frequency and the
      formation of 8-hydroxydeoxyganosine (8-OHdG) induced by crocidolite fibers in
      human-hamster hybrid (A(L)) cells. METHODS: The cytotoxicity and mutagenicity
      were determined by the formation of colonies. 8-OHdG was examined by
      immunoperoxidase staining. Non-protein sulfhydryl (NPSH) compound was assayed by
      modified Tietze's method. RESULTS: The level of NPSH in A(L) cell pretreated with
      25 micro mol/L of BSO was decreased to 2 nmol/10(7) cells, only 5% of the control
      after 24 h. The mutation frequency of CD59 gene of A(L) cell in crocidolite alone
      treated group was 208 +/- 18 while that in BSO pretreated group (397 +/- 55) was
      about twice the former (P < 0.05). The mutation frequency of CD59 gene in the
      group treated with crocidolite and in the presence of DMSO (57 +/- 8) was 72.6%
      less than that in crocidolite alone treated group. Crocidolite fibers induced a
      dose-effect relationship in the formation of 8-OHdG in A(L) cells (y = 150 + 20x,
      r = 0.9621). The level of 8-OHdG in cells was 289 +/- 6 at the dose of 6 micro
      g/cm(2) crocidolite, which was about twice the control group (137 +/- 9). In the
      presence of DMSO, 8-OHdG level decreased to 170 +/- 3 at the same dose of
      crocidolite. CONCLUSION: Free radicals are the important inducer of mutagenesis
      and DNA damage in A(L) cells caused by crocidolite, which has dose-effect
      relationship.

PMID- 15033019
TI  - [Expression and role of early growth response gene-1 in experimental silicosis of
      rat].
AB  - OBJECTIVE: To study the expression and location of early growth response gene-1
      (Egr-1), transforming growth factor-beta(1) (TGF-beta(1)), fibronectin (FN) in
      silicotic rat and to discuss the role of Egr-1 in the development of silicosis.
      METHODS: Silicotic animal model of rat was established, and the expressions of
      Egr-1, TGF-beta(1), FN in various lung cells of silicotic rat were analysed by
      using immunohistochemical technique (SP) and the image analysis. RESULTS: The
      expressions of Egr-1 in bronchial epithelial cell, pulmonary macrophage, alveolar
      epithelium cell and interstitial cell in lung silicotic tissue (gray values:
      118.58 +/- 5.65 - 168.52 +/- 5.67) were higher than those of controls (gray
      values: 166.23 +/- 5.23 - 188.12 +/- 8.35) during 1 - 28 days, and the expression
      was mainly in nucleus; the expressions of TGF-beta(1) in these cells (gray
      values: 123.49 +/- 5.65 - 170.24 +/- 3.56) were also higher than those of
      controls (166.53 +/- 6.25 - 198.56 +/- 4.53), and the expression was mainly in
      cytoplasm. The expressions of FN in bronchial epithelial cell, pulmonary
      macrophage and alveolar epithelial cell (gray values: 150.32 +/- 6.54 - 201.54 +/
      7.38) were lower, while those in interstitial cell (gray values: 121.43 +/- 5.65
      - 167.55 +/- 6.35) were higher than those of controls. The changes of TGF-beta(1)
      and Egr-1 expression level in bronchial epithelial cell, pulmonary macrophage,
      alveolar epithelium cell and interstitial cell were synchronous during the
      experiment (1 - 28 days). Both of them were correlated with each other (r = 0.61,
      P < 0.01), while the expression of FN was not correlated with Egr-1, but
      correlated to TGF-beta(1) in interstitial cell (r = 0.46, P < 0.01). CONCLUSION:
      Silicon dioxide could up-regulate the expression of nuclear transcription factor
      Egr-1 in several kinds of cell in lung. The activated Egr-1 may coordinate the
      expression of TGF-beta(1) and FN to regulate the development of silicosis.

PMID- 15033020
TI  - [The expression of lung nitric oxide synthase in rat exposed to silica].
AB  - OBJECTIVE: To evaluate the time-effect of silica on the expression of lung tissue
      nitric oxide synthase (NOS) in early inflammatory damage stage of silicotic rat.
      METHODS: Animal models were established by direct tracheal instillation of silica
      into rat lungs. Total NOS and induced NOS (iNOS) activities in bronchoalveolar
      lavage fluid (BALF) were assayed. The expression of iNOS protein in paraffin
      embedded lung sections with Streptavidin/peroxidase (SP) immunohistochemistry
      were measured by tissue microarray and Image-Pro Plus. RESULTS: Most of the
      expression of iNOS was in the cytoplasm of macrophages and neutrophils. iNOS
      integrated optical density (IOD) of lung tissue increased 1.47 x 10(5) and 2.73 x
      10(5) more respectively in silicatreated rats 3, 7 days after exposure than in
      control rats (P < 0.05), and decreased 1.11 x 10(5) more 28 days after exposure
      (P < 0.01). The activities of iNOS in BALF increased by 0.86, 1.89 and 0.92 U/ml
      respectively 3, 7, 14 days after exposure (P < 0.05 or P < 0.01). The activities
      of total NOS in BALF increased by 1.43, 2.05, 2.61 and 2.19 U/ml respectively 1,
      3, 7, 14 days after exposure (P < 0.05 or P < 0.01). CONCLUSION: After silica
      instillation, the iNOS-positive cells in rat lung tissue were mostly macrophages
      and neutrophils. There is a parabolic changing trend in the level of expression
      of lung iNOS during 1 - 28 day exposure to silica.

PMID- 15033021
TI  - [A study of high altitude environment affecting on worker's health during the
      constructing Qinghai-Xizang railway].
AB  - OBJECTIVE: To study high altitude environment affecting on worker's health
      METHODS: Using the cohort study, the altitude reaction was investigated and the
      WBC, RBC, Hb and oxygenation indexes were measured on workers in several periods,
      namely, acclimatization period, initially arrived high altitude and resident 90
      days. RESULTS: The 83.3% of men had altitude reactions with different kinds at
      initially arrived high altitude. The headache was the most. The rate of abnormal
      blood pressure increased with altitude and resident time (P < 0.01). The rate of
      90 day's group was 41.7%. The rise of diastole pressure was obvious (P < 0.01).
      As the beginning of arrived highland, the increase of WBC, RBC were significant
      (P < 0.01). The increase of Hb appeared only in 90 day's group. The level of
      malondialdehyde (MDA) obviously increased during acclimatization period and
      increased with altitude and resident time (P < 0.01). The activity of catalase
      (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) increased
      significantly in 90 day's group [(222.36 +/- 36.52) x 10(3) U/L, (158.49 +/-
      14.42) U/L, (45.74 +/- 8.31) NU/ml respectively] (P < 0.01). CONCLUSION: The high
      altitude environment may result in the abnormal blood pressure, the rise of
      diastolic pressure was important. It lead to the increase of WBC, RBC, Hb. It
      initiated activity of oxygenation reaction. The symptoms of headache, dizziness,
      loss of appetite and insomnia appeared as working in high altitude environment.

PMID- 15033022
TI  - [Crystalline nickel sulfide-induced genomic instability in transformed human
      broncho-epithelial cells].
AB  - OBJECTIVE: To detect the genomic instability in the 16 human broncho-epithelial
      (16HBE) cells induced by crystalline nickel sulfide so as to provide the
      scientific basis for further study of nickel-induced cancer molecular mechanism.
      METHODS: To analyse the genomic instability in transformed 16HBE cells induced by
      crystalline nickel sulfide by random amplified polymorphic DNA (RAPD). RESULTS:
      All the 7 random primers selected could amplify 1 - 6 clear PCR bands. There were
      no significant differences between transformed 16HBE cells and negative control
      cells in the 4th, 5th, and 7th primers, but in the rest 4 primers there were
      significant differences, with special PCR bands for the same primer, indicating
      that genomic instability in transformed 16 HBE cells was induced by crystalline
      nickel sulfide. CONCLUSION: Crystalline nickel sulfide could induce genomic
      instability in 16HBE cells.

PMID- 15033023
TI  - [Expressions of JWA protein and heat stress protein 70 induced by cell
      differentiation inducers combined with heat stress in K562 cells].
AB  - OBJECTIVE: To study how the combined effects of various differentiation inducers
      and heat stress on the expression of JWA protein in K562 cell, the relationship
      between JWA and Hsp70 expression, and the signal regulation mechanism possibly
      involved. METHODS: The experimental model was established in K562 cells. Various
      directional differentiation inducers (TPA, Ara-C, hemin, adriamycin, ATRA and
      As(2)O(3)) were used alone or combined with heat shock treatment (42 degrees C, 2
      h). Western blot was used for detecting expressions of JWA, Hsp70, heat stress
      factor 1 (HSF1) and HSF2. RESULTS: (1) The expressions of both JWA protein and
      Hsp70 were significantly up-regulated after K562 cells treated by TPA (100, 200
      ng/ml) or adriamycin (4 x 10(-8) mol/L) 48 h, and followed by heat shock (42
      degrees C, 2 h). However, the opposite effects were observed when the cells
      treated by hemin (3 x 10(-5) mol/L, 48 h), Ara-C (80 ng/ml, 48 h) and As(2)O(3)
      (1 x 10(-6) mol/L, 48 h) followed by 2 h heat shock. No obvious changes were
      found when the cells treated by ATRA (1 x 10(-6) mol/L, 48 h) alone or followed
      by heat shock. (2) Both the heat shock transcriptional factors HSF1 and HSF2 did
      not show any significant changes when K562 cells were treated with various
      differentiation inducers and followed by heat stress. CONCLUSION: JWA not only
      takes part in the regulation of K562 cellular differentiation, but also of heat
      stress, it might be the co-target gene of several differentiation inducers and
      heat stress. The expression of Hsp70 seems not mediated by both HSF1 and HSF2 in
      K562 cells undergoing directional differentiation or heat stress treatment. JWA
      is likely to be a new signal molecule similar to Hsp70 signal pathways. The
      results show that JWA takes part in the mechanism of K562 cell response to heat
      stress.

PMID- 15033024
TI  - [The condition of acute pesticide poisoning in the village of Hu Bei Province in
      1999 - 2000].

PMID- 15033025
TI  - [Expression level of p27kip1 in the coal miners' pneumoconiosis].

PMID- 15033026
TI  - [Detection of soluble interleukin-2 receptor and T lymphocyte subsets in
      silicosis].

PMID- 15033027
TI  - [Study of the therapeutic effect of gamma-interferon on early experimental
      silicosis in rats].

PMID- 15033028
TI  - [Treatment with diazepanum and dimercaptopropansulfonate sodium for acute
      tetramine intoxication].

PMID- 15033029
TI  - [The clinical study of atropine application to the patients with organophosphate
      poisoning after treatment with plasma replacement].

PMID- 15033030
TI  - [Etiologic analysis of 12 cases of silicosis with right middle lobe atelectasis].

PMID- 15033031
TI  - [Analysis of nosocomial methicillin-resistant staphylococcus aureus pulmonary
      infection in patients with coal miners' pneumoconiosis].

PMID- 15033032
TI  - [Application of percutaneous needle aspiration biopsy by the simulator guided to
      the diagnosis for pulmonary focus in coal miners' pneumoconiosis].

PMID- 15033033
TI  - [Seventy-two cases of residual organophosphorous pesticide poisoning after taking
      the vegetable].

PMID- 15033034
TI  - [Medicines to be cautiously used on pneumoconiosis patients].

PMID- 15033035
TI  - [Acute and long term respiratory damage following severe ammonia poisoning].

PMID- 15033036
TI  - [Atomic fluorescence spectrophotometry HP-AFS determination of lead-hydride
      production in the air of workplace].

PMID- 15033037
TI  - [Determination of soluble compounds of barium in the air of workplace by ICP
      AES].

PMID- 15033038
TI  - [Frequency of the mutation 677C-T of methylenetetrahydrofolate reductase gene on
      a sample of 652 Spanish liveborn infants].
AB  - BACKGROUND AND OBJECTIVE: An international study on the frequency of the mutation
      677C-T of the methylenetetrahydrofolate reductase (MTHFR) gene and its genotypes
      has been performed on a sample of consecutive liveborn infants around the world.
      In that study Spain participated through the ECEMC group. Here we present the
      distribution of the frequency of the T-allele by Spanish Regions (Autonomic
      Comunities). SUBJECTS AND METHOD: The ECEMC collaborating physicians gathered
      blood samples from 15 consecutive liveborn infants in 67 hospitals from all over
      the country during the same months, specifying the ethnicity and sex of each
      infant. The frequency of the mutation was estimated through the percentage with
      its confidence interval. The *2 of homogeneity (k-1 degrees of freedom) was used
      to confirm that the frequencies were not statistically different across the
      country. RESULTS: The frequency distribution of the TT genotype does not differ
      significantly between Spanish Regions. CONCLUSIONS: This seems to be the first
      nation-wide study on a homogeneous sample of individuals. The observed
      frequencies are in agreement with those observed in some published studies on
      specific Spanish geographic areas. The overall frequency is similar to that
      reported in Mediterranean countries.

PMID- 15033039
TI  - [Hypoparathyroidism and hypocalcemia following thyroid surgery of multinodular
      goiter. Multivariant study of the risk factors].
AB  - BACKGROUND AND OBJECTIVE: The hypoparathyroidism is one of the most important
      complications in the patients submitted to thyroid surgery. The aim is to analyze
      across a multivariate statistical analysis the risks factors for the development
      of transient and permanent hypoparathyroidism following the multinodular goiter
      (MG) surgery. PATIENTS AND METHOD: Between 1970 and 1999, 672 thyroidectomies by
      MG were reviewed. It was considered transient hypoparathyroidism when the
      calcemia was minor of 7.5 mg/dl or when being minors of 8.5 mg/dl the patient was
      presenting symptomatology for the hipocalcemia. The hypoparathyroidsm was
      considered permanent when the calcemia was minor of 8.5 mg/dl to the year of the
      surgery. RESULTS: The hypoparathyroidism appeared in 75 patients (11.2%), 20 with
      symptomatology (3%), persisting like permanent 6 cases (0.9%). The risk factors
      for the development of this were the hyperthyroidism (p = 0.0370), and the
      surgical technique (p < 0.00001) (unilateral versus bilateral surgery),
      persisting in the multivariate analysis both variables. With respect to the
      permanent hypoparathyroidism, the risk factor was the toxic MG (p = 0.0109),
      persisting as independent risk factor in the multivariate analysis (RR = 2.3).
      CONCLUSIONS: The principal risk factor of permanent hypoparathyroidism in the MG
      surgery is the presence of hyperthyroidism.

PMID- 15033041
TI  - [Differences in the nutritional and health status among illegal immigrant
      adolescents from Morocco and Algeria].
AB  - BACKGROUND AND OBJECTIVE: We decided to determine if there were differences in
      the nutritional and health status among illegal immigrant adolescents from
      Morocco and Algeria. SUBJECTS AND METHOD: We performed a retrospective cross
      sectional study (1997-2003); 120 male adolescents (86 Moroccans and 34 Algerians)
      admitted to protection centers of Zaragoza City were assessed. The nutritional
      status was assessed using the anthropometric method. The health status was
      assessed according to a standardized medical and laboratory protocol. RESULTS:
      The mean age (SDU) of the Moroccans was 15.9 (1.2) years and the mean age of the
      Algerians was 15.6 (1.5) years. Significantly lower values of weight (p = 0.027),
      upper arm circumference (p = 0.0005) and subscapular skinfold thickness (p =
      0.023) along with a significantly higher incidence of ferritin isolated
      deficiency (p = 0.027; odds ratio = 7.54; 95% CI, 0.96-59.32) were observed in
      the Moroccan adolescents. CONCLUSIONS: Illegal immigrant adolescents from Morocco
      had a significantly lower nutritional and iron reserves status than that observed
      in illegal immigrant adolesents from Algeria.

PMID- 15033040
TI  - [Burden of disease in Spanish population under 15 years old in 1999].
AB  - BACKGROUND AND OBJECTIVE: Burden of disease (DALYs) can help define health
      priorities. Our objective was to assess DALYs of those illnesses most important
      in Spanish children and teenagers. MATERIAL AND METHOD: We calculated DALYs
      components (YLL, YLD) by age groups and sex. Sources used were Spanish mortality
      data and WHO DALY's estimates. RESULTS: Total DALYs was 46.57/1000 habitants and
      it was highest in children aged less than 1 year. The first cause was represented
      by non-communicable diseases and the second by communicable-perinatal diseases in
      less than 1 year and 1-4 years and injuries in 5-14 years. CONCLUSIONS: DALYs is
      a good indicator to define health's population.

PMID- 15033042
TI  - [Controversies about hypocalcemia after thyroid gland surgery].

PMID- 15033043
TI  - [Economic assessment and the physicians].

PMID- 15033044
TI  - [Economic assessment in medicine].

PMID- 15033045
TI  - [Murine typhus. A disease to think about here and now].

PMID- 15033046
TI  - [News about therapeutic use of Cannabis and endocannabinoid system].
AB  - Growing basic research in recent years led to the discovery of the
      endocannabinoid system with a central role in neurobiology. New evidence suggests
      a therapeutic potential of cannabinoids in cancer chemotherapy-induced nausea and
      vomiting as well as in pain, spasticity and other symptoms in multiple sclerosis
      and movement disorders. Results of large randomized clinical trials of oral and
      sublingual Cannabis extracts will be known soon and there will be definitive
      answers to whether Cannabis has any therapeutic potential. Although the immediate
      future may lie in plant-based medicines, new targets for cannabinoid therapy
      focuses on the development of endocannabinoid degradation inhibitors which may
      offer site selectivity not afforded by cannabinoid receptor agonists.

PMID- 15033047
TI  - [Bronchiolitis obliterans organizing pneumonia and amiodarone: spontaneous
      resolution].

PMID- 15033050
TI  - [Differential diagnosis of parkinsonism using dopamine transporters brain SPECT].
AB  - BACKGROUND AND OBJECTIVE: Parkinsonism is a group of neurological disorders
      characterized by extrapiramidal signs. Often, the differential diagnosis between
      parkinsonism, essential tremor and drug-induced parkinsonism is difficult. The
      aim of the study was to evaluate the utility of (123I)-FP-CIT SPECT in patients
      with movement disorders. PATIENTS AND METHOD: 52 patients were referred from the
      neurology department to characterize those with parkinsonism. Patients were
      clinically evaluated and those with Parkinson's disease were assessed using the
      rating scale Hoehn & Yahr and the UPDRS motor score. Subsequently, a (123I)-FP
      CIT SPECT was performed with a qualitative analysis. RESULTS: All patients with
      essential tremor and drug-induced parkinsonism had a normal SPECT. All patients
      with parkinsonism displayed SPECT defects, except for four who had a normal SPECT
      result. Two of them were categorized as vascular parkinsonisms, one patient had a
      Shy-Drager's syndrome and the another one had probably a Parkinson's disease. The
      sensitivity and specificity were 90.47% (38/42; CI95%, 81.59%-99.35%) and 100%
      (10/10; CI95%, 69.15%-100%), respectively. CONCLUSIONS: (123I)-FP-CIT SPECT is an
      effective tool to study the integrity of the dopaminergic nigrostriatal system.
      Moreover, it permits to characterize the different types of parkinsonism.

PMID- 15033049
TI  - [Etanercept in rheumatoid arthritis patients with a poor therapeutic response to
      infliximab].
AB  - BACKGROUND AND OBJECTIVE: Knowing the efficacy of tumor necrosis factor alpha
      (TNF-alpha) antagonists infliximab or etanercept in patients with rheumatoid
      arthritis (RA), when one of these agents has failed, has important clinical
      implications. The aim of this study was to evaluate the efficacy and safety of
      etanercept in patients with RA, who had previously failed to infliximab. PATIENTS
      AND METHOD: All patients with RA of our center, who were previously treated with
      infliximab and then switched to etanercept for at least 6 months were included.
      Several clinical and biological parameters of inflammatory activity along with
      the disease activity index DAS-28 were assessed at baseline, after 6 weeks, at
      the last infusion of infliximab and after 0, 3 and 6 months on etanercept. EULAR
      criteria of response to therapy were used. RESULTS: Fourteen RA patients (13
      females) who fulfilled the inclusion criteria were selected. These patients had
      been treated with infliximab for a mean (SD) of 14.6 (8.3) months when this drug
      was stopped. Drug withdrawal owed to inefficacy in 12 patients and to adverse
      events in 2 patients. Most patients achieved a satisfactory clinical response
      within the first months of infliximab, with a subsequent loss of the therapeutic
      effects in spite of an increase in the infliximab dose or a reduction of the
      interval between infusions. In the group of 12 patients switched to etanercept
      because of infliximab inefficacy, a therapeutic response was achieved in 10 (83%)
      of them after 6 months of etanercept therapy. The DAS-28 score (SD) improved from
      5.6 (1) to 4.3 (0.8) (p = 0.019). An even better therapeutic response to
      etanercept was observed in those patients with an initial poor response to
      infliximab. No serious adverse effects were recorded during etanercept treatment.
      CONCLUSIONS: Etanercept is an efficient and safe therapy in RA patients when
      infliximab treatment has failed.

PMID- 15033051
TI  - [Association between breast arterial calcifications and degree of control and
      severity of diabetes].
AB  - BACKGROUND AND OBJECTIVE: Our goal was to analyze the association between the
      presence of arterial calcifications detected on mammography and the degree of
      control and severity of diabetes. PATIENTS AND METHOD: We included all menopausal
      women with diabetes aged between 45 and 68 years from two health districts who
      participated in the breast cancer screening campaign of the region (n = 230). We
      reviewed their mammographies to evaluate the presence of arterial calcifications
      and thus associate these findings with factors determining the control and
      severity of diabetes (glycemia, glycosylated hemoglobin, micro- and macrovascular
      chronic complications) as obtained from the patients' medical records. RESULTS:
      The prevalence of breast arterial calcification was 40%. Patients with breast
      arterial calcifications had had diabetes for longer time and had more
      microvascular chronic complications. CONCLUSIONS: The presence of arterial
      calcifications detected on mammography in menopausal women with diabetes over 45
      years of age is associated with microvascular chronic complications.

PMID- 15033052
TI  - [Use of complementary and alternative medicine in patients with chronic hepatitis
      C].
AB  - BACKGROUND AND OBJECTIVE: Complementary and alternative medicines (CAM) have
      achieved a great development in western countries. However, their use among
      patients simultaneously treated by the mainstream medicine is largely unknown.
      Our goal was to assess how many patients with chronic hepatitis C treated in a
      tertiary hospital use or have used CAM. PATIENTS AND METHOD: Analysis of the
      answers of 319 patients to a self-administered questionnaire. RESULTS: 113 (37%)
      patients had used or were using CAM, 63 (20%) because of chronic hepatitis and 50
      (17%) for other reasons. Women, those with higher education, divorced and widows
      were those who more frequently used CAM. More than half of patients felt some
      subjective improvement, yet none of them normalized their serum transaminase
      activities. CONCLUSIONS: CAM are used by a high proportion of patients who are
      simultaneously attended by 'official' physicians. The perceived efficacy of these
      practices is high but no changes in the hepatic disease could be seen in any of
      the patients who answered the questionnaire.

PMID- 15033053
TI  - [Neural networks and lineal methods in medical diagnosis: relevance of irrelevant
      variables].

PMID- 15033054
TI  - [Avian influenza. A continual threat to human beings].

PMID- 15033055
TI  - [Clinical study of 23 patients with ataxic hemiparesis].
AB  - BACKGROUND AND OBJECTIVE: To characterize the clinical features, etiology and
      prognosis in ataxic hemiparesis syndrome. PATIENTS AND METHOD: Descriptive study
      of 23 patients with ataxic hemiparesis included in the Sagrat Cor Hospital of
      Barcelona Stroke Registry over a 12 year period. RESULTS: Ataxic hemiparesis was
      caused by a lacunar infarct in 87% of patients, by atherothrombotic infarcts in
      8.7% and by cardioembolic infarct in 4.3%. Ataxic hemiparesis accounted for 0.9%
      of all acute strokes (n = 2,500), 1.25% of all cerebral infarcts (n = 1,840), and
      4.1% of all lacunar infarcts (n = 484). Internal capsule (22%), pons (13%), and
      corona radiata involvement (9%) were the most frequent cerebral topographies.
      Absence of in hospital mortality and absence of neurological deficit at discharge
      from the hospital were present in 39% of the patients. CONCLUSIONS: Lacune
      hypothesis is present in ataxic hemiparesis syndrome. Ataxic hemiparesis is
      caused by a lacunar infarct in 87% of patients. The internal capsule topography
      is the most frequent and the prognosis in ataxic hemiparesis is good.

PMID- 15033056
TI  - [Medical decision process applied to the terminal sedation. Ethical analysis].

PMID- 15033057
TI  - [Electroconvulsive therapy in children and adolescents: a review of the
      literature].
AB  - It is well-known that electroconvulsive therapy (ECT) is a safe and effective
      treatment for some mental disorders in adults. However, its use in children and
      adolescents is still the cause of some fears which may not be justified. The aim
      of this article is to clarify and to present the state of this question by
      reviewing the literature about ECT in children and adolescents, with emphasis on
      efficacy, indications, adverse effects and limitations. Results from studies in
      this population group show similar safety and efficacy data as those observed in
      adults. There exists a misinformation about the ECT technique among child
      psychologists and psychiatrists. Large follow-up studies are needed.

PMID- 15033058
TI  - [Prehospital thrombolysis in acute myocardial infarction].

PMID- 15033059
TI  - [Packs per year: the name of this index has to be changed].

PMID- 15033060
TI  - [Packs per years].

PMID- 15033061
TI  - [Control of the anticoagulant treatment by coagulemeter of capillary blood in
      primary health care].

PMID- 15033063
TI  - [Erysipelothrix rhusiopathiae bacteremia without endocarditis and reactive
      arthritis].

PMID- 15033064
TI  - [Herpes simplex encephalitis with a normal cerebrospinal fluid].

PMID- 15033066
TI  - [Rare diseases: Lesch-Nyhan syndrome].

PMID- 15033065
TI  - [Cytokines and hypercoagulative markers in elderly patients with infectious
      fever].

PMID- 15033067
TI  - [Quantitative bone ultrasound and vertebral fracture].

PMID- 15033089
TI  - [Integrated plan for ischemic cardiomyopathy (PICI)].

PMID- 15033090
TI  - [Use of pap smear for cervical cancer screening and factors related with its use
      in Spain].
AB  - OBJECTIVE: To determine the percentage of women aged 40 to 70 years who had had
      at least one preventive Pap test (cytological examination) during the preceding 5
      years, and the factors associated with use of the test. DESIGN: Population
      survey.Setting. Home interviews during October 2000. PARTICIPANTS: 2409 women
      aged 40 to 70 years residing in Spain. The nonresponse rate was 20.3%. MAIN
      MEASURES: The dependent variable was use of the Pap test, and independent factors
      examined were sociodemographic, social and health-related factors, information
      and attitude. Use of Pap tests was estimated with a 95% confidence interval (CI),
      and univariate and multivariate analysis were used to identify factors related
      with use of the test. RESULTS: Almost half (49.6%; 95% CI, 47.6%-51.6%) of the
      women had had a Pap test. The factors associated most strongly with use of the
      test were intention to have the test done (odds ratio [OR], 4.76; 95% CI, 3.40
      6.65), not having the test done because of fear of the diagnosis (OR, 3.22; 95%
      CI, 1.77-5.85), earlier testing (OR, 2.59; 95% CI, 2.06-3.27), and doctor's
      advice (OR, 2.44; 95% CI, 1.93-3.09). Other associated factors were considering
      the text necessary, upper or middle-upper socioeconomic status, access to private
      or combined private-public health care, age 40 to 50 years, and residing in a
      city with a population greater than 100000. CONCLUSIONS: Half of all Spanish
      women aged 40 to 70 years had had a Pap test. Use of the test was related most
      clearly with the woman's attitude toward the test. Health care professionals
      should be aware of the importance of their role in encouraging Pap tests for
      screening.

PMID- 15033091
TI  - [Commentary: cervical cancer prevention. What is our reality?].

PMID- 15033092
TI  - [Prediction of the total calcium intake from consumption of milk products in
      Spain adult population. INDICAD Study 2001].
AB  - OBJECTIVE: To assess the predictive value of calcium intake from milk products
      and its effect of this on the total contribution of food calcium. DESIGN: Cross
      sectional study. SETTING: Urban and rural health centres in Spain. PARTICIPANTS:
      Patients aged 20 or over who attended for consultation for whatever reason in the
      time-period set. Criterion for exclusion: terminal illness. 1546 questionnaires
      were included in the study. MAIN MEASUREMENTS: Consumption of calcium from milk
      products and from other sources. RESULTS: The intake of milk products accounted
      for 66.8% of the total intake of calcium (0%-93%). The consumption of < or =2
      rations of milk products per day supposed a total calcium intake of under 1000
      mg/day; of >3 rations, a total intake of 1000-1500 mg/day; and of >4 rations,
      1500 mg/day. In subjects with low milk product intake (< or =2 rations per day),
      the predictive value of this for total calcium was low (10%-30%); and in those
      with >4 rations, its predictive value was 70%. CONCLUSIONS: Calculation of the
      total intake of calcium in milk products is useful in the consultation, but
      undervalues the real contribution, as it takes no notice of calcium from other
      food sources. Only the intake of >4 rations of milk products a day is
      sufficiently predictive.

PMID- 15033093
TI  - [Do we spend too much on medications? Pharmaceutical expenditures, an absolutely
      essential item in European countries].
AB  - OBJECTIVE: To find out if the performance of the pharmaceutical expenditure
      between the most developed European countries come close more to a luxury good or
      a necessary good. To compare the pharmaceutical Spanish expenditure with the one
      of those countries. DESIGN: Cross-sectional study. SETTING: International.
      Europe. PARTICIPANTS: European countries members of the Organisation for Economic
      Co-operation and Development (OECD) and the European Union. METHODS: The data
      come from the OECD reports and other papers with the same source of information.
      The majority of the data refer to year 2000. The relationship between
      pharmaceutical expenditure and other variables as expenditure on health, on
      research and development (R&D), and socio-demographic variables are analysed with
      correlation and multiple linear regression. RESULTS: In both groups of countries,
      the Gross Domestic Product per capita (GDPPC) is positively and significantly
      correlated with the expenditure per capita on health (public and total) and on
      R&D, but not with pharmaceutical expenditure per capita (PhEPC). The
      pharmaceutical expenditure as part of total expenditure on health (PhE/TE) or as
      percentage of GDP (PhE/GDP), is negatively and significantly correlated with
      income (GDPPC). The regression model accepts as explicative variables of PhE/GDP:
      the income (negatively), the employment in health (negatively) and the PhEPC
      (positively). The PhEPC in Spain is situated in the average of the most developed
      European countries, and expressed as PhE/TE or as PhE/GDP is situated in the
      group of the countries with greater pharmaceutical expenditure, the majority of
      them with a lower GDPPC to the Spanish one. CONCLUSIONS: The performance of the
      pharmaceutical expenditure between the countries studied come close to a
      necessary good than to a luxury good. The PhEPC in Spain is situated in the
      average of these countries and, expressed as PhE/GDP or as PhE/TE, would be
      according to the Spanish income.

PMID- 15033095
TI  - [What can we do about the scant introduction of spirometry into primary care?].

PMID- 15033094
TI  - [Degree of understanding, treatment and control of hypertension,
      hypercholesterolemia and diabetes mellitus in the general adult population].
AB  - OBJECTIVES: To calculate the prevalence of the main cardiovascular risk factors
      (CVRF) after diagnostic confirmation using clinical criteria. To analyse the
      degree of understanding and monitoring of these factors and to evaluate the
      association of CVRF with each other, so estimating who is susceptible to
      intervention. DESIGN: Cross-sectional, descriptive, observational study. SETTING:
      Population study conducted in Health Area 20 of the Community of Valencia (county
      of the Low Plain of the River Segura). PATIENTS: People who had lived in this
      Area for >=20 years. Proportional, multi-stage randomised sampling with
      definition of sample quotas according to type of residence. SAMPLE SIZE: 2550
      people (no reply in first stage: 26%). The second stage involved the clinical
      confirmation of those identified as suffering from hypertension (HT) (374),
      hypercholesterolaemia (HCOL) (126), and diabetes (DM) (33). MEASUREMENTS:
      Patients identified were interviewed for taking blood pressure in the case of
      those with HT, and blood samples in the case of those with HCOL and DM. The
      diagnostic criteria recommended by the latest consensus were used. RESULTS: 1886
      people (78.1%) took part. Prevalences found: total HT 42+/-2.2%, diagnosed:
      11.7+/-1.4; total HCOL 26.6+/-2%; total DM 9.5+/-1.3%. Tobacco dependency was
      33.6+/-2.1% and Obesity: 31.6+/-2.1%. Degree of control: HT, 8.6%; HCOL, 21.7%;
      DM, 56.1%. Association of CVR factors with each other: 25.5% had neither HT nor
      HCOL and did not smoke. CONCLUSIONS: High prevalence of CVRF in our area,
      compared with published national findings. Tobacco dependency is less common than
      at national level. The degree of control is very low and the association of the
      main CVRF factors for ischaemic cardiopathy reflect that nearly 75% of the
      population requires a preventive intervention.

PMID- 15033096
TI  - [Management of diabetic vasculopathy in primary care: diagnosis and control].

PMID- 15033097
TI  - [Effectiveness of two health interventions to get pregnant women to give up
      smoking].
AB  - OBJECTIVE: To evaluate the effectiveness of the group intervention for getting
      pregnant women to give up tobacco consumption, measured by means of carbon
      monoxide levels in air breathed out, compared with a minimum intervention.
      DESIGN: Randomised clinical trial. SETTING: Four primary care teams from Area 9
      of IMSALUD-Madrid. PARTICIPANTS: All the pregnant women attending for
      consultation with the midwives of the four PC teams involved during the study
      period, who are smoking at least one cigarette a day when they find out they are
      pregnant and who want to take part in the study once they have been informed of
      it. Intervention. The subjects included will be randomised into 2 intervention
      groups. The minimum intervention will consist of brief personal counselling (3 to
      5 minutes) on why they should give up smoking, especially now they are pregnant.
      The group intervention will involve 3 sessions lasting approximately an hour and
      a half.

PMID- 15033098
TI  - [Acute hepatitis C in a health worker after accidental exposure].

PMID- 15033099
TI  - [Cholestasis and infection by the Epstein-Barr virus].

PMID- 15033100
TI  - [Do uropathogens have the same resistance to antibiotics in primary care and in
      hospital?].

PMID- 15033101
TI  - [Cutaneous pseudolymphoma. An example of the relevance of minor surgery in PC].

PMID- 15033102
TI  - [Mondor's disease in a male].

PMID- 15033103
TI  - [Put it on, put it on him].

PMID- 15033104
TI  - [Clinical use of serum tumour markers].

PMID- 15033106
TI  - [Present and future of interventional catheterization in congenital heart
      disease].

PMID- 15033107
TI  - [Utility of anorectal manometry in the diagnosis and treatment of encopresis].
AB  - BACKGROUND: Biofeedback based on anomanometric techniques has been shown to be
      effective in the treatment of children with encopresis. The long-term efficacy of
      biofeedback and which variables of anorectal manometry (anorectal manometry)
      could help to establish biofeedback indications are currently the subject of
      debate. OBJECTIVES: To identify which variables of anorectal manometry, in
      addition to symptoms, could be useful in deciding which patients could benefit
      from biofeedback therapy and to assess the outcome of this treatment. PATIENTS
      AND METHODS: Anorectal manometry was performed in 88 patients, who were referred
      to our service complaining of soiling at least once a month for a minimum of 6
      months after a period of normal continence of 1 year or more. The chronological
      and mental age of the patients was 4 years. All patients were otherwise in good
      health and had shown no response to medical treatment. The following variables
      were studied: anal canal profile, rectoanal inhibitory reflex (RAIR), continence
      reflex, rectal sensitivity, external anal sphincter (EAS) activity and defecatory
      maneuver. The patients were divided into two groups, according to clinical and
      anomanometric impairment, and the most affected patients (n = 41) underwent
      biofeedback therapy. The indications and outcome of biofeedback were assessed
      through clinical course and anorectal manometry. In the statistical analysis, the
      mean and standard deviation were calculated. The chi-squared test with Yates'
      correction was used to compare clinical and manometric qualitative parameters;
      Student's t-test was used to compare quantitative parameters; nonparametric tests
      consisted of the Mann-Whitney test and the Wilcoxon test was used for paired
      data. RESULTS: Patients treated with biofeedback therapy presented shorter anal
      canal, greater pressure in the rectal ampulla (P < 0.001), decreased pressure in
      the anal canal (P < 0.05), lesser distension of the EAS on provoking RAIR, lower
      presence of the continence reflex (P < 0.01), lower rectal sensitivity, and a
      worse response of the striated sphincteric muscle and of the defecatory maneuver
      (P < 0.001). Seventy-eight percent of the patients had a good response to
      biofeedback therapy. Pressure in the anal canal and rectal sensitivity improved
      (P < 0.001) with normality on straining in 11 out of 15 patients. These good
      results persisted in a long-term follow-up of 10 patients. Eight of 10 patients
      who did not undergo biofeedback therapy showed persistent encopresis (P < 0.001).
      CONCLUSIONS: Anorectal manometry detected disturbances, chiefly in the activity
      of the EAS, which are useful in indicating biofeedback therapy in children with
      secondary encopresis. Biofeedback therapy seems to produce favorable long-term
      results in the majority of the most severely affected patients.

PMID- 15033108
TI  - [Use of stents in pediatric cardiology. Initial results].
AB  - BACKGROUND AND AIM: Balloon-expandable stents are useful in treating vascular
      stenotic lesions associated with congenital heart defects. We report our
      experience of this device since 1997. PATIENTS AND METHOD: Seventeen stents were
      implanted in 12 children in 13 procedures. The mean age of the patients was 82
      months (range: 2-168 months). Eight patients had postsurgical stenoses in branch
      pulmonary arteries, three patients had aortic re-coarctation and one patient had
      a ductus-dependent complex heart defect. In the first eight patients we performed
      right catheterization, following the usual technique of percutaneous implantation
      with super-stiff wire and Mullins sheath. In the remaining patients, vascular
      access was through the femoral artery. The Palmaz stent was used in 13 patients,
      Express stents in three and Intrastent in one patient. RESULTS: After stent
      implantation, the diameter of the narrowings increased from 3.1 mm (2.8-5.6) to
      12 mm (10-15) (p < 0.002) and the gradient was reduced from 32 mmHg (21-45) to
      8.5 mmHg (0-11.5) (p < 0.002). In the patient with ductus-dependent heart defect,
      the procedure allowed prostaglandin E1 withdrawal and hospital discharge. After a
      mean follow-up of 27 months (range: 1-60 months) one occurrence of late complete
      occlusion of branch pulmonary artery and one case of side-branch partial
      occlusion (right superior lobe branch) have been detected. One patient died from
      causes unrelated to the stent (prior cardiogenic shock). The remaining patients
      are asymptomatic and medication free. CONCLUSION: The stent is a safe and
      effective device that could be used in a wide variety of stenotic vascular
      lesions.

PMID- 15033109
TI  - [Biliary atresia: Retrospective clinical study].
AB  - OBJECTIVE: To gain further insight into the natural history of patients with
      biliary atresia. PATIENTS AND METHODS: We performed a retrospective, cross
      sectional, descriptive, case series study. All patients with biliary atresia
      attended at the Pediatric Gastrointestinal and Hepatology Unit of La Fe
      Children's Hospital in Valencia (Spain) from January 1990 to December 2000 were
      included. RESULTS: Of 16 children followed-up, eight are currently stable, six
      have undergone liver transplantation and two died. The mean age at diagnosis was
      47.5 days. The most frequent clinical manifestation was jaundice (87.5%) and the
      most common biochemical finding was raised gamma-glutamyltransferase (3-4 times
      its standard value), which appeared in 100 % of the patients. Abdominal
      ultrasonography was diagnostic in 85.7% of the patients. Nuclear scintiscan
      (DISIDA) showed a sensitivity of 100%. Portoenterostomy with intraoperative liver
      biopsy was performed in all patients. Patient age at surgery was a predictor of
      long-term outcome, with more favorable results in patients aged less than 65 days
      of life. CONCLUSIONS: Biliary atresia should be suspected as soon as possible,
      since early surgical treatment is the only therapeutic measure that can improve
      outcome.

PMID- 15033111
TI  - [Nosocomial gastroenteritis and asymptomatic rotavirus and astrovirus infection
      in hospitalized children].
AB  - BACKGROUND: Nosocomial gastroenteritis is frequent in pediatric hospital wards.
      Between 20% and 50% of gastroenteritis cases caused by rotavirus and astrovirus
      are of nosocomial origin. OBJECTIVE: To determine the incidence of nosocomial
      rotavirus and astrovirus gastroenteritis in our environment, the incidence of
      asymptomatic infection with these viruses, and to identify the G serotypes of the
      rotaviruses detected. METHODS: We performed a prospective study of all children
      under 2 years of age admitted to a neonatology unit over a 1-year period who were
      followed-up for the presence of diarrhea and periodic study of feces to detect
      the presence of rotavirus and astrovirus antigens by enzyme immunoassay (EIA).
      Patients with gastroenteritis also underwent bacteria stool culture, adenovirus
      detection by EIA, calcivirus detection by polymerase chain reaction, and analysis
      of rotavirus G serotypes by EIA with monoclonal antibodies. RESULTS: Of 666
      children admitted without diarrhea, 60 presented nosocomial gastroenteritis (9 %
      of patients admitted and 1.75 per 100 days of hospital stay): 34 presented
      rotavirus (5 % of patients) and two presented astrovirus (0.3 % of patients). Of
      the 329 patients without diarrhea who were studied, viral elimination was
      detected in 27: rotavirus in 23 patients and astrovirus in four. Viral infection
      was detected on admission in 13 patients (4 %) and after 72 hours in 14 patients
      (4.2 %) (asymptomatic nosocomial infection). No differences in the distribution
      of rotavirus G serotypes were observed between community-acquired and nosocomial
      gastroenteritis. CONCLUSIONS: These data confirm the importance of viral etiology
      in nosocomial gastroenteritis and allow us to evaluate asymptomatic fecal
      elimination of rotavirus as one of the factors in the transmission of this
      infection.

PMID- 15033110
TI  - [Normal values of bone turnover markers in childhood].
AB  - OBJECTIVE: To determine the normal profile of bone turnover markers in childhood
      in order to enable evaluation of bone mineralization status in the healthy
      pediatric population and in the population at risk of osteoporosis. PATIENTS AND
      METHODS: A population of 75 healthy children aged between 6 months and 14 years
      was studied. Levels of osteocalcin and C-terminal procollagen peptide type I, as
      markers of bone apposition, were determined in serum. Levels of hydroxyproline
      and pyridinoline, as markers of bone resorption, were determined in urine
      samples. Statistical analysis of the results was performed. RESULTS: The highest
      levels of the four markers were obtained in the first 4 years of life. Markers of
      bone resorption showed a continuous statistically significant decrease until the
      age of 14 years (p < 0.05), whereas markers of bone apposition decreased slightly
      after the age of 4 years and then remained stable until the age of 14 years.
      DISCUSSION: These findings are compatible with the presence of intense bone
      turnover in the first 4 years of life and with a predominance of the phenomenon
      of bone apposition throughout the first 14 years of life. Knowledge of the normal
      profile of these markers allows evaluation of bone mineralization status in the
      healthy pediatric population and in the population at risk of osteoporosis.

PMID- 15033112
TI  - [Non-typhi Salmonella bacteremia in children: an 11-year review].
AB  - OBJECTIVES: To review the clinical and bacteriological features of pediatric
      patients with non-typhi Salmonella (NTS) bacteremia. METHODS: We reviewed the
      medical records of children aged less than 14 years with culture-proven NTS
      bacteremia in the previous 11 years in a referral hospital in Madrid, Spain.
      RESULTS: A total of 29 cases of NTS bacteremia were diagnosed. Of these, 27 were
      used for study purposes. The mean age was 11.1 months (range: 3 days to 11
      years); 48% were infants aged < 1 year. Eleven children (41%) had an underlying
      disease. These included immunodeficiency in seven (malignant disease in three,
      IgA-IgG2 deficit in one, chronic granulomatous disease in one, HIV infection in
      one, and systemic lupus erythematosus in one patient on steroid treatment), liver
      disease in three, and hypoxic-ischemic encephalopathy in one. Clinical
      manifestations at the initial visit included: fever > 39 C (85%), diarrhea (67%),
      and vomiting (37%). Seven patients had occult bacteremia. Three children (11 %)
      required intensive care management for severe sepsis. Five patients presented
      extraintestinal focal infections: arthritis in two, osteomyelitis in one, urinary
      tract infection in one, and pneumonia in one. None of the children had meningitis
      or died as a result of NTS infection. The most common serogroups isolated were
      Salmonella D9, and B4-5 (38% each). Eleven strains (38%) were resistant to
      amoxicillin and five (17%) were resistant to cotrimoxazole. Only one patient
      developed persistent bacteremia. All the children made a complete recovery
      without further complications. CONCLUSIONS: NTS bacteremia is an uncommon entity
      but it should be considered in infants and immunocompromised children. Although
      focal complications may occur, the usual outcome with appropriate antimicrobial
      treatment is a full recovery.

PMID- 15033113
TI  - [Respiratory infection due to Chlamydia trachomatis in infants. Clinical
      presentation and outcome in 18 patients].
AB  - BACKGROUND: Among other diseases, Chlamydia trachomatis causes epididymitis and
      prostatitis in men and urethritis, cervicitis and pelvic inflammatory disease in
      women. In children, it most usually causes conjunctivitis and is also responsible
      for lower respiratory tract disease, occasionally requiring hospital admission.
      OBJECTIVE: To draw attention to this disease, which is usually overlooked and
      which can be potentially serious. METHODS: We retrospectively reviewed the
      medical records of infants aged less than 6 months with symptoms of lower
      respiratory tract disease in whom C. trachomatis antigen was detected by enzyme
      immunoassay. RESULTS: We identified 18 patients with C. trachomatis between 1993
      and 2002. Of these, 17 patients required hospital admission and five required
      monitoring in the pediatric intensive care unit. The mean length of hospital stay
      was 9.6 days. Three patients were immigrants. The mean age at admission was 6.6
      weeks. Apnea occurred in five infants. Chest x-ray showed interstitial
      infiltrates in five infants. Sixteen patients were treated with erythromycin and
      all made a complete recovery. CONCLUSIONS: Although lower respiratory tract
      disease caused by C. trachomatis is usually managed on an outpatient basis, it
      sometimes requires hospital admission or even management in the intensive care
      unit. Therefore, C. trachomatis infection should be ruled out in infants aged
      less than 6 months with clinical symptoms of lower respiratory tract disease for
      which no other pathogen can be found.

PMID- 15033114
TI  - [Flexible bronchoscopy in children: Indications and general considerations].
AB  - There is considerable interhospital variability in the practice of flexible
      bronchoscopy in children. The present report aims to provide some recommendations
      that are supported by the Spanish Society of Pediatric Pulmonologists. We review
      the indications, contraindications, equipment, setting and personnel involved in
      flexible bronchoscopy, as well as the pre-procedure preparation of the patient,
      medications, post-procedure monitoring, complications, care and maintenance of
      instruments, and informed consent. These recommendations may be adopted, modified
      or rejected according to clinical needs and constraints.

PMID- 15033115
TI  - [Acute neurological symptoms in a 6-year-old patient with cyanotic congenital
      heart disease].

PMID- 15033116
TI  - [Megacystis-microcolon-intestinal hypoperistalsis syndrome: a case of prolonged
      survival].
AB  - Megacystis-microcolon-intestinal hypoperistalsis syndrome is a multisystemic
      disorder in which impaired intestinal motor activity causes recurrent symptoms of
      intestinal obstruction in the absence of mechanical occlusion, associated with
      bladder distention without distal obstruction of the urinary tract. It is an
      uncommon disorder with high morbidity and mortality, and long-term total
      parenteral nutrition may be required. We describe an 18-year-old girl with long
      term survival, followed-up by our service since birth. With medical, surgical and
      nutritional management she currently presents a good oral tolerance and good
      quality of life, only requiring parenteral nutrition during periods of
      decompensation.

PMID- 15033117
TI  - [Myositis ossificans circumscripta in the axilla].
AB  - Myositis ossificans circumscripta (MOC) is a rare benign hereditary disorder
      characterized by heterotopic bone formation in soft tissue and muscle. This
      disorder is rarely seen in childhood. MOC is most commonly located in the
      extremities. We describe a 15-year-old girl with nontraumatic MOC in the axilla.
      Imaging studies (radiographic, ultrasound) did not provide the correct diagnosis
      and did not rule out malignancy. Incisional biopsy of the mass and
      histopathologic examination gave the diagnosis of MOC. Some reports suggest that
      magnetic resonance imaging may be the first-choice diagnostic option and may
      avoid unnecessary biopsy. However, in many cases diagnosis is still histological.
      Differential diagnosis between these lesions and malignant sarcomas and
      fibrodysplasia ossificans progressiva is required. This entity has a good
      prognosis in childhood.

PMID- 15033118
TI  - [Primary hyperoxaluria].

PMID- 15033119
TI  - [Early puberty in girls adopted from developing countries].

PMID- 15033120
TI  - [Glass doors: one more danger in the pediatric age group].

PMID- 15033121
TI  - [Chromosome 21 ring (r21) and epilepsy].

PMID- 15033122
TI  - [Multiple pilomatrixomas associated with celiac disease].

PMID- 15033123
TI  - [Acute hepatitis may form part of scarlet fever].

PMID- 15033124
TI  - [Further reflections on streptococcal pharyngitis].

PMID- 15033126
TI  - [Goat's milk is not a valid alternative in patients allergic to cow's milk
      proteins].

PMID- 15033128
TI  - Iron, RLS and blood donations.

PMID- 15033129
TI  - Restless legs syndrome in blood donors.
AB  - BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) may be a cause of
      significant sleep disturbance. In a Swedish survey, the prevalence of RLS has
      been estimated to be 5.8% among men and 11.4% among women. Blood donation may
      result in iron deficiency, which is hypothesized to be one substantial cause of
      RLS. PATIENTS AND METHODS: Nine hundred and forty-six (618 men, 328 women)
      consecutive blood donors aged 18-64 years, who attended a blood donation unit in
      mid-Sweden, answered a questionnaire that included questions about sleep habits.
      Frequency of blood donation was recorded and intake of iron tablets was assessed.
      Red blood cell distribution width (RDW) was also recorded. The value of RDW
      increases in relation to iron deficiency. RESULTS: RLS affected 14.7% of male and
      24.7% of female blood donors. The mean intake of iron among the blood donors
      after each blood donation was only 781 mg, although the recommended intake is
      2000 mg. Among the women, 7.4% presented an RDW of >14.5%, which strongly
      indicates iron deficiency. In this group of women, 37.5% were affected by RLS.
      The female RLS-sufferers were more affected than the female non-RLS subjects by
      problems initiating sleep (P=0.006 maintaining sleep (P<0.0001) and were also
      less refreshed upon awakening (P<0.001). RESULTS: This study showed that RLS was
      common among female blood donors. Women with RLS were more iron-deficient than
      those without and were affected by impaired sleep.

PMID- 15033130
TI  - Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in
      patients with narcolepsy.
AB  - BACKGROUND AND PURPOSE: This study was conducted to demonstrate the long-term
      efficacy of sodium oxybate for the long-term treatment of cataplexy in patients
      with narcolepsy. PATIENTS AND METHODS: Fifty-five (55) narcoleptic patients with
      cataplexy who had received continuous treatment with sodium oxybate for 7-44
      months (mean 21 months) were enrolled in a double-blind treatment withdrawal
      paradigm. A 2-week single-blind sodium oxybate treatment phase established a
      baseline for the weekly occurrence of cataplexy. This was followed by a 2-week
      double-blind phase in which patients were randomized to receive unchanged drug
      therapy or placebo. Patients recorded the incidence of cataplexy attacks and
      adverse events in daily diaries. RESULTS: During the 2-week double-blind phase,
      the abrupt cessation of sodium oxybate therapy in the placebo patients resulted
      in a significant increase in the number of cataplexy attacks (median=21; P<0.001
      ) compared to patients who remained on sodium oxybate (median=0). Cataplexy
      attacks returned gradually with placebo patients reporting a median of 4.2 and
      11.7 cataplexy attacks during the first and second weeks, respectively. There
      were no symptoms of frank withdrawal. CONCLUSIONS: This controlled trial provides
      evidence supporting the long-term efficacy of sodium oxybate for the treatment of
      cataplexy. In contrast with antidepressant drug therapy, there is no evidence of
      rebound cataplexy upon abrupt discontinuation of treatment.

PMID- 15033131
TI  - A cognitive-behavioral weight reduction program in the treatment of obstructive
      sleep apnea syndrome with or without initial nasal CPAP: a randomized study.
AB  - BACKGROUND AND PURPOSE: To evaluate (a) whether an active weight reduction
      strategy based on the cognitive-behavioral approach and an initial very-low
      calorie diet might lead to short- and long-term weight loss and alleviation of
      OSAS; and (b) whether the results of this intervention could be enhanced by
      combining it with nasal continuous positive airway pressure (CPAP) treatment
      during the first 6 months. PATIENTS AND METHODS: Thirty-one obese male
      symptomatic sleep apnea patients underwent a 2-year weight reduction program with
      total follow-up of 36 months from baseline. The mean age (+/-SD) was 49.1+/-7.9
      years, body mass index 43.8+/-5.4, and oxygen desaturation index (ODI4) 51.3+/
      31.1. The patients were randomized to CPAP (17 patients) and non-CPAP groups (14
      patients). RESULTS: The mean weight loss was 19.1+/-10.2 kg (14% of the original
      weight) for the whole group at 6 months, 18.3+/-13.2 (13%) at 12 months and
      12.6+/-14.7 kg (9%) at 24 months. Excellent or good treatment results, as defined
      in terms of an ODI4 (average number of oxygen desaturation events p/h>4% from
      baseline) reduction of at least 50% from the baseline, were seen in 61% of
      patients at 6 months and were still observable in 42% of patients at 24 months.
      The correlations between changes in weight and in ODI4 were 0.59 (P<0.01) at 6
      months, 0.68 (P<0.01) and 0.75 (P<0.01) at 24 months. Adding CPAP treatment to
      the weight reduction therapy for the first 6 months did not result in greater
      weight loss or diminution of desaturation indices (without CPAP) at any time
      point. One year after the termination of the program the mean weight loss was
      6.6+/-12.9 kg, and 42% of patients still showed at least 5% weight loss as
      compared with their original weight. CONCLUSION: Satisfactory weight loss
      associated with improvement of OSAS could be achieved by means of a cognitive
      behavioral weight loss program. Adding CPAP in the initial phase of the weight
      reduction program did not result in significantly greater weight loss.

PMID- 15033132
TI  - Rating scales for inattention and sleepiness are correlated in adults with
      symptoms of sleep disordered breathing syndrome, but not in adults with symptoms
      of attention-deficit/hyperactivity disorder.
AB  - BACKGROUND AND PURPOSE: To evaluate relationship between sleepiness and
      inattention/hyperactivity in adult patients presenting with sleepiness or early
      childhood onset inattention. PATIENTS AND METHODS: Thirty-eight consecutive adult
      patients (29 males, nine females, mean age 48.7+/-15.5 years) presenting with
      snoring and sleepiness; and 18 consecutive adult patients (15 males, three
      females, mean age 31.9+/-12.2 years) presenting with early childhood onset
      inattention were administered the Epworth sleepiness scale (ESS) and the
      attention-deficit/hyperactivity disorder rating scale (ADHDRS with AD score
      measuring inattention and HD score measuring hyperactivity-impulsivity). All
      sleepy snorers underwent polysomnography (PSG) and multiple sleep latency test
      (MSLT) the following day. RESULTS: For the sleepy snorers, significant
      correlations included AD score with ESS (r = 0.49, P = 0.002 ), and HD score with
      lowest saturation ( r=-0.36, P = 0.025 ). MSLT or respiratory event index (REI)
      were not significantly correlated with AD or HD scores or ESS. For the
      inattentive patients, there were no significant correlations between ESS, AD or
      HD score. CONCLUSIONS: Scores on rating scales for sleepiness (ESS) and
      inattention (AD score on the ADHDRS) are not significantly correlated in adults
      with early childhood onset inattention, but they are significantly correlated in
      sleepy snorers. Thus, in patients presenting primarily with early childhood onset
      inattention, sleepiness is not associated with and does not explain the
      inattention, even though increasing sleepiness and inattention may be associated
      symptoms in sleepy snorers.

PMID- 15033133
TI  - Lactate production and catecholamine profile during aerobic exercise in
      normotensive OSAS patients.
AB  - BACKGROUND AND PURPOSE: The aim of the study was to evaluate the
      catecholaminergic activity and lactate concentration during exercise in
      normotensive patients with obstructive sleep apnoea syndrome (OSAS). PATIENTS AND
      METHODS: Thirteen normotensive patients affected by OSAS (mean age+/-standard
      error (SE), 52.6+/-2.8 yrs; mean apnoea-hypopnea index, 35.7+/-20.3) were
      enrolled in the study. Night-polysomnography and multiple sleep latency test in
      the sleep laboratory were performed for every patient. Patients also underwent an
      incremental workload exercise on a cycloergometer. We evaluated plasma
      epinephrine and norepinephrine levels in aerobic exercise conditions, relating
      them to lactate levels. RESULTS: Analysis of the venous lactate curve showed that
      exercise lactate levels were significantly higher (peak normalised levels, 782
      vs. 270%; P<0.001 ), and an earlier lactate threshold was detected, in the
      patients compared to normal controls. While plasma catecholamine levels were
      abnormally high in almost all patients at rest, exercise values were not
      significantly different from controls. Lactate/norepinephrine and
      lactate/epinephrine area ratios were significantly higher in OSAS subjects than
      in controls (2.25 vs. 1.21 and 2.37 vs. 1.03, respectively). CONCLUSIONS: The
      results indicate that abnormal production of lactate during exercise occurs in
      OSAS, possibly due to some muscular metabolic modification. While
      catecholaminergic activity is abnormally increased at rest, this activity does
      not seem to play a significant role in lactate concentration during exercise in
      these patients.

PMID- 15033134
TI  - A putative link between childhood narcolepsy and obesity.
AB  - BACKGROUND AND PURPOSE: While there have been anecdotal observations of binge
      eating in childhood-onset narcolepsy, the possible relationship between increased
      weight gain and childhood-onset narcolepsy has not been evaluated. PATIENTS AND
      METHODS: A retrospective, case-control design was used to compare the body mass
      index (BMI) of 31 narcolepsy children at the time of diagnosis with that of
      healthy, age- and gender-matched controls. RESULTS: The median BMI in the
      narcolepsy subjects was 22.93 as compared to that in controls of 20.36 (P=0.001).
      BMI did not differ significantly between narcolepsy subjects who had received
      prior psychotropic medications and those who had not. The mean BMI of 22 of 31
      narcolepsy subjects who had not received psychotropic medications prior to
      diagnosis was also significantly higher than that of controls (25.1, SEM 1.53
      versus 21.1, SEM 0.56; P=0.008 ). CONCLUSION: The tendency for increased weight
      gain is intrinsic to childhood narcolepsy and is manifested relatively early in
      the course of the disorder. Correlation of this finding with hypocretin and
      leptin metabolism may further understanding of the pathogenesis of narcolepsy.

PMID- 15033135
TI  - A case of marital discord and secondary depression with attempted suicide
      resulting from REM sleep behavior disorder in a 35-year-old woman.
AB  - A 35-year-old woman with childhood-onset parasomnia, marked by arm waving with
      talking and shouting, developed marital discord solely because her parasomnia
      disrupted her husband's sleep. She became progressively depressed after her
      husband began to sleep in a separate bedroom, eventually becoming acutely
      suicidal. There had been no psychiatric history prior to her marriage. An
      evaluation with a sleep specialist-neurologist and polysomnographic monitoring
      confirmed the diagnosis of idiopathic REM sleep behavior disorder (RBD).
      Treatment with clonazepam, 1.0-1.5 mg at bedtime controlled her RBD and she again
      slept with her husband, which fully resolved their marital discord and her
      secondary depression.

PMID- 15033136
TI  - Longitudinal change in REM sleep components in a patient with multiple system
      atrophy associated with REM sleep behavior disorder: paradoxical improvement of
      nocturnal behaviors in a progressive neurodegenerative disease.
AB  - A 60-year-old patient with multiple system atrophy (MSA) who presented with rapid
      eye movement (REM) sleep behavior disorder was investigated longitudinally by all
      night polysomnography. REM sleep components, i.e. rapid eye movements and chin
      muscle activity, were analyzed together with the frequency of behaviors/movements
      on the videorecording. Decreased frequency of elaborate motor activity during REM
      sleep with time in this patient was compatible with the observation by his wife,
      and this change seemed to correlate with predominant tonic chin electromyogram
      with relatively suppressed phasic chin muscle activity, but the reduction of the
      REM sleep behavior disorder (RBD) episodes could be interpreted as being due to
      the increased rigidity along with MSA progression. The chronological change in
      REM sleep components in RBD with neurological disorders is worth studying in
      large follow-up series to enlarge our knowledge about the mechanism of behavioral
      manifestation of RBD in humans.

PMID- 15033139
TI  - Sleep disorders and extrapyramidal diseases: an historical review.
AB  - BACKGROUND AND PURPOSE: Sleep disorders have been mentioned since the first
      descriptions of extrapyramidal diseases in James Parkinson's Essay on the Shaking
      Palsy, but only recently they have become the subject of attention, thanks to new
      acquisitions in clinical knowledge and electroencephalographic technology. In the
      late 1960s, the introduction of L-dopa permitted comparison of sleep patterns in
      drug-naive patients before and after therapy in conditions very similar to
      experimental ones. Historically, we can recognise two major lines of study, one
      dealing with descriptions of sleep behaviours modified by drugs and the other
      with polysomnographic sleep research carried out before and after treatment.
      PATIENTS AND METHODS: The data obtained from the first polysomnographic studies
      led to the definition of sleep macro- and microstructure in patients suffering
      from Parkinson's disease, but the interpretation of drug-induced changes was not
      unequivocal. RESULTS: According to some authors, the improvement in sleep
      architecture was due mainly to improvement of nocturnal motor impairment. Other
      researchers suggested a primary sleep dysfunction caused by specific
      neurodegenerative processes in the brain structures regulating the sleep-wake
      cycle. CONCLUSIONS: The latter hypothesis has recently been supported by the
      observation that distinct sleep disorders, such as REM behaviour disorder or
      restless legs syndrome, often herald extrapyramidal diseases or are a frequent
      adjunctive complaint for these patients.

PMID- 15033140
TI  - Epidemiology and clinical features of sleep disorders in extrapyramidal disease.
AB  - Sleep disturbances are common in extrapyramidal diseases, including not only
      insomnia but excessive daytime sleepiness and parasomnias. In particular,
      complaints related to sleep are extremely common among patients affected by
      Parkinson's disease (PD). The underlying causes may include: patient age,
      associated illnesses, cognitive impairment, motor dysfunction caused by disease,
      neurochemical changes related to the disease, drugs, and secondary psychological
      responses to the disease. The exact prevalence of sleep disorders in PD is
      difficult to ascertain, due to the heterogeneity of patients as well as to the
      different criteria and methods used to diagnose and classify sleep disturbances.
      In this study, we will attempt to review the epidemiological data and to describe
      the various sleep disorders, which have been identified in extrapyramidal
      diseases, with particular reference to PD. There are no data available at present
      as to the role of gender in sleep disturbances. Finally, the benefit of sleep on
      extrapyramidal diseases will be addressed, taking into account that the above
      causes may modify the effects of sleep.

PMID- 15033141
TI  - An overview of parkinsonian syndromes: data from the literature and from an
      Italian data-base.
AB  - Recent molecular biology research on neurodegenerative diseases, including
      parkinsonisms, has identified mutations in the genes that code for the proteins
      alpha-synuclein and tau, which have been used to classify them into
      synucleinopathies and tauopathies. The synucleinopathies include, besides the
      most common and well studied Parkinson's disease (PD), dementia with Lewy bodies,
      which accounts for approximately 20% of all cases of dementia in the elderly, and
      multiple system atrophy, whereas the tauopathies include rare and rapidly
      progressive syndromes, such as progressive supranuclear palsy and corticobasal
      degeneration. Data we collected at our center in over 2900 parkinsonian patients
      show that PD accounts for no more than 70% of parkinsonisms. The various
      syndromes have many features in common that make the differential diagnosis
      difficult in the early stages of disease. Our data are consistent with the
      findings reported in the international literature and provide additional
      information useful for differential diagnosis.

PMID- 15033142
TI  - Dopamine agonists and sleepiness in PD: review of the literature and personal
      findings.
AB  - BACKGROUND AND PURPOSE: This study is aimed at evaluating daytime sleepiness in a
      series of Parkinson's disease (PD) patients chronically treated with dopamine
      agonists (DAs) alone or in combination with L-Dopa. PATIENTS AND METHODS: A
      preliminary series of 22 non-demented, adult PD patients (mean age 68.9, 13 men
      and 9 women) were evaluated by means of structured sleep interview, Epworth
      sleepiness scale (ESS) and 24-h ambulatory polysomnography (A-PSG). RESULTS:
      Sleep attacks (SAs) were reported by 32% of the patients, in three of them (43%)
      after DA treatment was initiated (alone or in addition to L-Dopa). In two
      patients, both with chronic use of ropinirole, we documented NREM SAs during a
      continuous ambulatory polysomnography (A-PSG) performed in the patients' real
      life settings. The subjects experiencing SAs showed a higher degree of daytime
      sleep propensity than those without SA, having higher ESS scores and a higher
      proportion of microsleeps and intentional naps on A-PSG. Interestingly, we found
      that nocturnal total sleep time is higher in PD patients with SAs than in the
      others. CONCLUSIONS: All in all, our data indicate that SAs are an extreme
      manifestation of increased daytime sleepiness. The occurrence of SAs in our
      series of PD patients is unlikely to depend simply on the demands of homeostatic
      mechanisms.

PMID- 15033143
TI  - REM sleep behavior disorders in Parkinson's disease and other Parkinsonian
      disorders.

PMID- 15033144
TI  - PET and SPECT functional imaging in Parkinson's disease.
AB  - Neuroimaging studies of the dopaminergic system with positron emission tomography
      and single photon emission computed tomography radioligands are useful in the
      assessment of neuronal degeneration in Parkinson's disease. Abnormalities can be
      identified early in the disease process and used to monitor progression as well
      as the effect of treatment. Studies of dopamine receptors and brain metabolism
      can help identify those patients who have other Parkinsonian syndromes, such as
      multiple system atrophy, progressive sopranuclear palsy or diffuse Lewy body
      dementia. The current available diagnostic criteria for these disorders rely
      solely on the presence of signs and symptoms that may require months or years to
      become fully clinically manifest. Conversely, the use of neuroimaging techniques
      can significantly shorten the diagnostic process and prove a useful means to the
      neurologist in those cases presenting with uncertain clinical diagnosis.

PMID- 15033145
TI  - Effects of deep brain stimulation of the subthalamic nucleus on sleep
      architecture in parkinsonian patients.
AB  - Patients affected by Parkinson's disease (PD) often complain of disturbed sleep
      resulting from nighttime motor disabilities such as nocturnal akinesia, tremor
      and rigidity, motor behaviour during REM sleep or periodic leg movements (PLM)
      during sleep. Sleep may also be affected by dopaminergic and anticholinergic
      drugs or coexisting depressive syndrome. Deep brain stimulation (DBS) of
      subthalamic nucleus (STN) effectively reduces PD motor disability. The aim of
      this study is to evaluate the sleep architecture modifications after STN DBS. We
      assessed five patients (two men and three women, mean age 63.8+/-3.3 years, with
      a mean history of PD of 13.8+/-4.9 years) who underwent STN DBS. The mean
      levodopa equivalent dosage (LED) was 1010+/-318 mg before surgery and 116+/-93 mg
      3 months after surgery. Polysomnography (PSG) with audiovisual recordings was
      performed on two separate nights, the first assessment in the week before surgery
      and the second 3 months after surgery. Three months after surgery, PSG showed an
      increase in total sleep time, in the longest period of uninterrupted sleep, and
      in the percentage of stage 3-4 NREM sleep, while there was a reduction of
      wakefulness after sleep onset. PLM, apnea-hyopnea index and REM sleep behaviour
      disorder were unaffected by STN DBS. STN DBS seems to be an effective therapeutic
      option for the treatment of advanced Parkinson's disease because it improves the
      cardinal symptoms and also seems to improve sleep architecture.

PMID- 15033146
TI  - Deep brain stimulation and its effect on sleep in Parkinson's disease.
AB  - Deep Brain Stimulation (DBS) is an effective treatment for patients with advanced
      Parkinson's disease (PD) and motor complications whose condition can no longer be
      improved by adjustment of medical therapy. PD patients often report increased
      daily somnolence and night sleep abnormalities partially related to dopaminergic
      treatment. In a survey of 386 consecutive non-demented non-depressed PD patients
      seen in our clinic over a period of 3 months we found increased daily somnolence
      to be relatively uncommon in non-demented PD patients, although it may be
      associated with stable treatment with high dose dopamine agonists. Disease
      related factors seemed responsible for night sleep abnormalities. Because DBS of
      the subthalamic nucleus (STN) reduces motor disability, as well as total
      medication intake, one would expect a similar benefit on sleep abnormalities.
      Indeed, recent evidence suggests that chronic STN-DBS may improve sleep quality
      through increased nocturnal mobility and reduction of sleep fragmentation.

PMID- 15033147
TI  - Does the physical environment interact with the sleep process?

PMID- 15033148
TI  - Thermoregulation as a sleep signalling system.
AB  - Temperature and sleep are interrelated processes. Under normal environmental
      conditions, the rhythms of core body temperature Tc and sleep propensity vary
      inversely across the day and night in healthy young adults. Although this
      relationship has drawn considerable interest, particularly in recent years, it is
      still not known whether this relationship is causative or merely coincidental. As
      somnogenic brain areas contain thermosensitive cells, it is possible that the
      sleep/wake cycle may be directly affected by thermoregulatory changes themselves.
      That is, that changes in temperature may trigger, either directly or indirectly,
      somnogenic brain areas to initiate sleep. There is now an emerging body of
      evidence from both physiological and neuroanatomical studies to indicate that
      this may indeed be the case. This paper will examine the literature relating to
      this relationship and propose a model where thermoregulatory changes provide an
      additional signal to the brain regions that regulate sleep and wakefulness. The
      model attempts to explain how temperature changes before and after sleep onset
      act in a positive feedback loop to maintain a consolidated sleep bout.

PMID- 15033149
TI  - Sleep under exposure to high-frequency electromagnetic fields.
AB  - The controversy about potential health hazards associated with the exposure to
      electromagnetic fields (EMF) has been recently stimulated by the increasing use
      of mobile telecommunication devices. Attention has focused here on non-thermal
      effects of low-level high-frequency radiation, which does not lead to a heating
      of tissue. Scientific literature on the effects of high-frequency EMFs on sleep
      is reviewed. The epidemiological studies provide no evidence that sleep
      disturbances are a relevant complaint under exposure to such fields. Recent sleep
      laboratory studies have revealed a number of slight effects. Despite their
      heterogeneity, there seems to be some consistency regarding a slight sleep
      promoting effect and an increase of the alpha power of the sleep EEG induced by
      high-frequency EMFs. However, for both the epidemiological and sleep laboratory
      studies, the database concerning sleep is up to now very limited. At the present
      level of knowledge, no final conclusions can be drawn from the available data
      concerning potential health hazards. Although there seem to be some biological
      effects, these do not provide evidence for any adverse health consequences.
      However, further research is needed for a better understanding of the interaction
      between EMFs and the sleep process.

PMID- 15033150
TI  - Sleep in eating disorders.
AB  - Sleep research on eating disorders has addressed two major questions: (1) the
      effects of chronic starvation in anorexia nervosa and of rapidly fluctuating
      eating patterns in bulimia nervosa on the sleep regulating processes and (2) the
      search for a significant neurobiological relationship between eating disorders
      and major depression. At present, the latter question appears to be resolved,
      since most of the available evidences clearly underline the notion that eating
      disorders (such as anorexia and bulimia nervosa) and affective disorders are two
      distinct entities. Regarding the effects of starvation on sleep regulation,
      recent research in healthy humans and in animals demonstrates that such a
      condition results in a fragmentation of sleep and a reduction of slow wave sleep.
      Although several peptides are supposed to be involved in these regulatory
      processes (i.e. CCK, orexin, leptin), their mode of action is still poorly
      understood. In opposite to these experimentally induced sleep disturbances are
      the findings that the sleep patterns in eating disorder patients per se do not
      markedly differ from those in healthy subjects. However, when focusing on the so
      called restricting anorexics, who maintain their chronic underweight by strictly
      dieting, the expected effects of malnutrition on sleep can be ascertained.
      Furthermore, at least partial weight restoration results in a 'deepening' of
      nocturnal sleep in the anorexic patients. However, our knowledge about the
      neurobiological systems (as well as their circadian pattern of activity) that
      transmit the effects of starvation and of weight restoration on sleep is still
      limited and should be extended to metabolic signals mediating sleep.

PMID- 15033151
TI  - How do sleep disturbance and chronic pain inter-relate? Insights from the
      longitudinal and cognitive-behavioral clinical trials literature.
AB  - Sleep disturbance is perhaps one of the most prevalent complaints of patients
      with chronically painful conditions. Experimental studies of healthy subjects and
      cross-sectional research in clinical populations suggest the possibility that the
      relationship between sleep disturbance and pain might be reciprocal, such that
      pain disturbs sleep continuity/quality and poor sleep further exacerbates pain.
      This suggests that aggressive management of sleep disturbance may be an important
      treatment objective with possible benefits beyond the improvement in sleep.
      Little is known, however, about how to effectively treat sleep disturbance
      associated with pain or whether such treatment might have beneficial effects on
      reducing pain. A small, but growing literature has applied cognitive-behavioral
      therapies (CBT) for either pain management or insomnia to patients with chronic
      pain. In this article, we review the longitudinal literature on sleep disturbance
      associated with chronic pain and clinical trial literatures of cognitive-behavior
      therapy for pain management and insomnia secondary to chronic pain with the aim
      of evaluating whether the relationship between clinical pain and insomnia is
      reciprocal. While methodological problems are common, the literature suggests
      that the relationship is reciprocal and CBT treatments for pain or insomnia hold
      promise in reducing pain severity and improving sleep quality. Directions for
      future research include the use of validated measures of sleep, longitudinal
      studies, and larger randomized clinical trials incorporating appropriate
      attentional controls and longer periods of follow-up.

PMID- 15033152
TI  - Sleep in schizophrenia patients and the effects of antipsychotic drugs.
AB  - Insomnia is a common feature in schizophrenia. However, it seldom is the
      predominant complaint. Nevertheless, severe insomnia is often seen during
      exacerbations of schizophrenia, and may actually precede the appearance of other
      symptoms of relapse. The sleep disturbances of either never-medicated or
      previously treated schizophrenia patients are characterized by a sleep-onset and
      maintenance insomnia. In addition, stage 4 sleep, slow wave sleep (stages 3 and
      4), non-REM (NREM) sleep in minutes and REM latency are decreased. The atypical
      antipsychotics olanzapine, risperidone, and clozapine significantly increase
      total sleep time and stage 2 sleep. Moreover, olanzapine and risperidone enhance
      slow wave sleep. On the other hand, the typical antipsychotics haloperidol,
      thiothixene, and flupentixol significantly reduce stage 2 sleep latency and
      increase sleep efficiency. Future research should address: (1) the sleep patterns
      in subtypes of schizophrenia patients; (2) the role of neurotransmitters other
      than dopamine in the disruption of sleep in schizophrenia; (3) the functional
      alterations in CNS areas related to the pathophysiology of schizophrenia during
      NREM sleep and REM sleep (brain imaging studies); (4) the short-term,
      intermediate-term, and long-term effects of atypical antisychotics on sleep
      variables.

PMID- 15033153
TI  - Response to "sleep spindles: an overview".

PMID- 15033154
TI  - Regulation of cardiovascular calcification.
AB  - Vascular calcification is highly correlated with cardiovascular disease (CVD) and
      is a significant predictor of cardiovascular events, especially in high risk
      patients such as the end stage renal disease (ESRD) population. Vascular
      calcification can lead to serious problems including valve stenosis, decreased
      vascular compliance, calciphylaxis, and even sudden death. However, the
      contribution of vascular calcification to progression of atherosclerosis is
      unknown and needs more study. Biochemical, histological, and genetic studies
      indicate that vascular calcification is actively regulated and involves both
      positive and negative modulators. Several nonmutually exclusive theories to
      account for vascular calcification based on current studies are discussed.

PMID- 15033155
TI  - Temporal characteristics of cardiomyocyte hypertrophy in the spontaneously
      hypertensive rat.
AB  - BACKGROUND: The spontaneously hypertensive rat (SHR) is frequently used as model
      of cardiovascular disease, with considerable disparity in reported parameters of
      hypertrophy. The aim of this study was to assess the temporal changes occurring
      during the development and progression of cardiomyocyte hypertrophy in SHR,
      subsequent to pressure overload, compared to changes associated with normal aging
      using the normotensive Wistar-Kyoto (WKY) rat. METHODS: Ventricular
      cardiomyocytes were isolated from rats at 8, 12, 16, 20 and 24 weeks, and
      parameters of hypertrophy (cell dimensions, protein mass, de novo protein
      synthesis, and gene expression) and function (contraction and hypertrophic
      responsiveness in vitro) were assessed. RESULTS: Hypertension was evident at > or
      =7 weeks in SHRs. Heart:body mass ratio, cardiomyocyte protein mass and width
      were elevated (P<.05) in SHRs at 16-20 weeks compared to WKYs. In SHRs compared
      to WKYs at 16 weeks, there was a transient increase (P<.05) in protein synthesis,
      enhanced hypertrophic responsiveness to phorbol-12-myristate-13-acetate, and
      induced hypertrophic responsiveness to isoprenaline. Skeletal-alpha-actin mRNA
      was detected in SHR but not WKY cells at all ages. ANP mRNA was lower in SHR than
      in WKY cells at 8-20, but progressively increased (P<.05) from 12 to 24 weeks
      within SHRs. Contractile function increased (P<.05) at 20 weeks in SHR compared
      to WKY rats. CONCLUSION: Structural and functional changes occurring at the
      cellular level in the myocardium of SHR follow a distinct pattern, such that
      pressure overload was initially accompanied by expressional changes (8-12 weeks),
      followed by active hypertrophic growth and enhanced function (16-20 weeks), which
      subsequently decelerated as stable compensation was attained.

PMID- 15033156
TI  - Expression of coxsackievirus and adenovirus receptor in neointima of the rat
      carotid artery.
AB  - Our previous study revealed that the coxsackievirus and adenovirus receptor (CAR)
      is a homophilic cell adhesion molecule and may function as a sensor of cell-cell
      interactions in the brain and damaged heart. In this study, we investigated if
      CAR expression is involved in the formation of neointimal hyperplasia using a
      balloon injury model of rat carotid artery. Cultured vascular smooth muscle cells
      (SMCs) from rat aorta were also studied. CAR antigen was constitutively detected
      in the endothelial cells (ECs) but not in SMCs before injury. On Day 5 after
      balloon injury, CAR was expressed strongly in the first layer of medial SMCs.
      Neointimal hyperplasia was observed on Day 7, and strong expressions of CAR
      concomitantly with proliferating cell nuclear antigen (PCNA) were obvious in the
      neointimal SMCs, while CAR in medial SMCs disappeared. The expression of CAR mRNA
      reached a peak on Day 7 and declined gradually to the basal levels. When the ECs
      regenerated on Day 14, CAR antigen was observed in the ECs but disappeared in the
      neointima. CAR together with PCNA was expressed abundantly in the proliferating
      SMCs in vitro and diminished in cells grown to a confluent state. The abundant
      expression of CAR in the neointima may facilitate an adenoviral gene therapy.

PMID- 15033157
TI  - Coronary in-stent restenosis following beta brachytherapy: a histopathological
      examination.
AB  - Two cases of in-stent restenosis of a coronary artery bypass vein graft following
      beta (beta) brachytheraphy are presented. Previously unreported histopathology of
      directed atherectomy specimens of such restenotic lesions and a discussion of
      their proposed significance form the basis of this report.

PMID- 15033158
TI  - Myocardial infarction in the C57BL/6J mouse: a quantifiable and highly
      reproducible experimental model.
AB  - INTRODUCTION: The laboratory mouse is a powerful tool in cardiovascular research.
      In this report, we describe a method for a reproducible mouse myocardial
      infarction model that would allow subsequent comparative and quantitative studies
      on molecular and pathophysiological variables. METHODS: (A) The distribution of
      the major coronary arteries including the septal artery in the left ventricle of
      the C57BL/6J mice (n=20) was mapped by perfusion of latex dye or fluorescent
      beads through the aorta. (B) The territory of myocardial infarction after the
      ligation of the most proximal aspect of the left anterior descending (LAD)
      coronary artery was quantified. (C) The consistency in the histological changes
      parallel to the infarction at different time points was analyzed. RESULTS: (A)
      The coronary artery tree of the mouse is different from human and, particularly,
      in regard to the blood supply of the septum. (B) Contrary to previous belief, the
      septal coronary artery in the mouse is variable in origin. (C) A constant
      ligation of the LAD immediately below the left auricular level ensures a
      statistically significant reproducible infarct size. (D) The ischemic changes can
      be monitored at a histological level in a way similar to what is described in the
      human. CONCLUSION: We illustrate a method for maximal reproducibility of
      experimental acute myocardial infarction in the mouse model, due to a consistent
      loss of perfusion in the lower half of the left ventricle. This will allow the
      study of molecular and physiological variables in a controlled and quantifiable
      experimental model environment.

PMID- 15033159
TI  - Adipose tissue in myocardial infarction.
AB  - INTRODUCTION: The histologic evolution of myocardial infarction (MI) has been
      studied in some detail. However, there is little mention of the presence of
      adipose tissue in healed MI(HMI). Ninety-one hearts explanted during 1997-2001
      were examined to determine the extent of adipose tissue within HMI. METHODS: The
      medical records, surgical pathology reports, and all histologic sections of the
      explanted heart, from patients undergoing heart transplantation for ischemic
      heart disease, were reviewed. Adipose tissue within the areas of HMI was
      quantified. The location of the HMI, the age and gender of the patient, age of
      HMI, and whether the patient was treated with coronary artery bypass surgery
      (CABG) were noted. RESULTS: Of the 91 hearts examined, 168 HMIs were identified;
      141 (84%) contained some mature fat within the HMI. Adipose tissue increased with
      increasing age, in males, and in those patients who had CABG surgery. The amount
      of adipose tissue was not related to the location or age of the HMI. CONCLUSION:
      Adipose tissue is a prevalent histological finding in HMIs. The pathogenesis of
      adipose tissue is unknown, but may be influenced by current medical therapy for
      ischemic heart disease, thus explaining why adipose tissue in HMIs was not
      reported until 1997. The presence of fat supports the speculation that a
      regenerative cell, or multipotent stem cell, exists within the heart, and under
      the influence of microenvironmental or therapeutic factors can differentiate into
      fat, other mesenchymal tissues, and potentially even myocardium.

PMID- 15033160
TI  - Changes in plasma levels of adhesion molecules after percutaneous mitral balloon
      valvuloplasty.
AB  - BACKGROUND: Adhesion molecules are expressed on vascular endothelium and on
      immune and inflammatory cells. Recently increased levels of adhesion molecules
      have been shown in patients with rheumatic mitral stenosis. This study examined
      the serum levels of the adhesion molecules intercellular adhesion molecule 1
      (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin in patients
      with rheumatic mitral stenosis and the effects of percutaneous mitral balloon
      valvuloplasty (PMBV) on these adhesion molecules. MATERIALS AND METHODS: Thirty
      five patients (3 men, 32 women, mean age 39+/-5 years) with severe rheumatic
      mitral stenosis who underwent percutaneous balloon mitral valvuloplasty, and 35
      age and sex matched healthy control subjects were included in the study. Serum
      levels of ICAM-1, VCAM-1, and E-selectin were measured in all patients who
      underwent PMBV and in all control subjects. Blood samples were taken for
      measurement of adhesion molecules immediately before and 24 h after the mitral
      balloon valvuloplasty. RESULTS: The plasma levels of soluble adhesion molecules E
      selectin, ICAM-1 and VCAM-1 were significantly elevated in patients with mitral
      stenosis compared to control subjects: E-selectin, 97+/-59 vs. 45+/-24 ng/ml
      (P=.001), sICAM-1, 874+/-301 ng/ml vs. 238+/-82 ng/ml (P<.0001); sVCAM-1, 3056+/
      763 ng/ml vs. 985+/-298 ng/ml (P<.0001). Plasma levels of VCAM-1 significantly
      increased 24 h after the valvuloplasty procedure (3056+/-763 ng/ml vs. 3570+/
      1225 ng/ml P=.013). Plasma levels of E-selectin showed a significant decrease
      after PMBV (97+/-59 vs. 70+/-58 ng/ml, P=.043) and plasma levels of ICAM-1 did
      not show any change after PMBV (874+/-301 vs. 944+/-377 ng/ml, P=.356).
      CONCLUSION: Cellular adhesion molecules, sICAM-1, E-selectin, sVCAM-1 have shown
      changes in different directions in response to PMBV. These results necessitate
      further studies to clarify the mechanism underlying the association between
      adhesion molecules and PMBV as well as rheumatic mitral stenosis.

PMID- 15033161
TI  - Pathological analyses of long-term intracoronary Palmaz-Schatz stenting; Is its
      efficacy permanent?
AB  - BACKGROUND: Angiographic regression of luminal narrowing occurs 6 months to 3
      years poststenting. However, after 4 years lesions progressed gradually and late
      restenosis was observed in 28% of 179 Palmaz-Schatz-stented lesions during the
      past 10 years. Elucidating its pathogenesis is pivotal to developing preventive
      strategies. METHODS AND RESULTS: Histopathological and immunohistochemical
      studies were performed in 19 stented coronary arteries obtained from 19 patients
      autopsied after noncardiac death 2-7 years poststenting. The quality/severity of
      chronic inflammatory cells (T lymphocytes, macrophages and multinucleated giant
      cells) infiltration around the stent struts that is observed even in the absence
      of restenosis depended on the time elapsed from stenting: a) 2 years
      postprocedure, in spite of angiographic regression during the first year and
      pathologically expressed as maturation of the neointimal scar, there was chronic
      inflammatory response evidence: neovascularization and lymphocyte infiltration,
      b) > or = 3 years: the neointimal smooth muscle cells were sparse with abundant
      proliferation of collagen fibers. Presence of slight helper/inducer T lymphocytes
      and mild macrophage infiltration around the stent struts was evident
      immunohistochemically, c) > or = 4 years: prominent infiltration by lipid-laden
      macrophages with strong collagen-degrading matrix metalloproteinase
      immunoreactivity was observed around the struts. In two of these arteries, the
      surface contacting the stent was focally disrupted and covered by nonocclusive
      mural thrombi. CONCLUSIONS: Stainless steel stents evoke a remarkable foreign
      body inflammatory reaction to the metal. These persistent peri-strut chronic
      inflammatory cells may accelerate new indolent atherosclerotic changes and
      consequent plaque vulnerability.

PMID- 15033162
TI  - Primary cardiac precursor B lymphoblastic lymphoma in a child: a case report and
      review of the literature.
AB  - We describe an extremely rare case of primary cardiac precursor B lymphoblastic
      lymphoma (B-LBL) in a 10-year-old boy who presented with nonspecific complaints
      of fatigue and vomiting for 2 weeks and an episode of syncope. Chest X-ray showed
      cardiomegaly and echocardiography revealed a large right atrial mass, which was
      successfully resected. Pathology showed precursor B-LBL arising in the heart and
      there was no evidence of disease at any extracardiac site. A brief review of the
      literature is also presented.

PMID- 15033163
TI  - Hemangioma of the tricuspid valve: a report of two cases with review of
      literature.
AB  - We describe two cases of hemangioma affecting the tricuspid valve (TV). One
      patient was a 47-year-old male who presented with recurrent episodes of dyspnea
      on exertion for 5 years. Echocardiography revealed an echo dense 1 x 1 cm mass
      attached to the chordae tendineae of the TV. Surgical excision was done and
      histopathology of the lesion showed features of hemangioma. The other case was a
      1-day-old neonate with complex congenital abnormalities in whom multiple small
      hemangiomas affecting the TV were incidentally detected at autopsy.

PMID- 15033165
TI  - Estradiol inhibits GSK3 and regulates interaction of estrogen receptors, GSK3,
      and beta-catenin in the hippocampus.
AB  - Estrogens regulate a wide set of neuronal functions such as gene expression,
      survival and differentiation in a manner not very different from that exerted by
      neurotrophins or by growth factors. The best-studied hormonal action is the
      transcriptional activation mediated by estrogen receptors. However, the direct
      effects of estrogen on growth factor signaling have not been well clarified. The
      present data show that estradiol, in vivo, induces a transient activation of GSK3
      in the adult female rat hippocampus, followed by a more sustained inhibition, as
      inferred from phosphorylation levels of Tau. Similar data was obtained from
      cultured hippocampal neurons when treated with the hormone. The transient
      activation was confirmed by direct measure of GSK3 kinase activity. In addition,
      our results show a novel complex of estrogen receptor alpha, GSK3, and beta
      catenin. The presence of the hormone removes beta-catenin from this complex.
      There is a second complex, also affected by estradiol, in which Tau is associated
      with GSK3, beta-catenin, and elements of the PI3 kinase complex. Considering the
      role of GSK3 in neurodegeneration, our data suggest that part of the
      neuroprotective effects of estrogen may be due to the control of GSK3.

PMID- 15033164
TI  - Modulation of extracellular signal-regulated kinases cascade by chronic delta 9
      tetrahydrocannabinol treatment.
AB  - Acute Delta(9)-tetrahydrocannabinol (THC) injection increased ERK pathway (ERK,
      pCREB, and c-fos) mostly in the caudate putamen and cerebellum. This effect
      underwent to homeostatic adaptation after chronic treatment. Moreover, chronic
      THC exposure induced increases in the ERK cascade (ERK, pCREB, and Fos B) in the
      prefrontal cortex and hippocampus, suggesting that different neuronal circuits
      seem to be involved in the early phase and late phase of exposure. The
      involvement of ERK pathway in cannabinoid chronic exposure was also confirmed in
      Ras-GRF1 knock out mice, a useful model where cannabinoid-induced ERK activation
      is lost. In fact, Ras-GRF1 ko mice did not develop tolerance to THC analgesic and
      hypolocomotor effect. Our data suggest that ERK cascade could play a pivotal role
      in the induction of synaptic plasticity due to cannabinoid chronic exposure.

PMID- 15033166
TI  - Interaction of Mash1 and Phox2b in sympathetic neuron development.
AB  - The transcription factors Mash1 and Phox2b are both essential for sympathetic
      neuron development. To understand in more detail their function and interaction,
      Phox2b and Mash1 were ectopically expressed in vivo, in peripheral nerve
      precursors. Here, we demonstrate that the Phox2b-induced generation of ectopic
      noradrenergic neurons in chick peripheral nerve involves the induction of Cash1,
      the chick homolog of Mash1. All Phox2-induced neurons coexpress the noradrenergic
      marker genes TH and DBH. Conversely, Mash1 induces neuronal differentiation
      characterized by the expression of generic neuronal genes SCG10, Hu and NF160;
      however, only a subpopulation of these neurons also displays an autonomic,
      noradrenergic phenotype. This context-dependent action of Mash1 implicates
      autonomic codeterminants, required for noradrenergic differentiation in response
      to Mash1. In contrast, Phox2b coordinates generic and noradrenergic gene
      expression, recruiting Mash1/Cash1, which may have a major function in the
      control of pan-neuronal gene expression during noradrenergic neuron development.

PMID- 15033167
TI  - Regulation of caspase activation in axotomized retinal ganglion cells.
AB  - Transection of the optic nerve initiates massive death of retinal ganglion cells
      (RGCs). Interestingly, despite the severity of the injury, RGC loss was not
      observed until several days after axotomy. The mechanisms responsible for this
      initial lack of RGC death remained unknown. In the current study,
      immunohistochemical analysis revealed that caspases-3 and -9 activation in the
      RGCs were not detected until day 3 post-axotomy, coinciding with the onset of
      axotomy-induced RGC loss. Interestingly, elevated Akt phosphorylation was
      observed in axotomized retinas during the absence of caspase activation.
      Inhibiting the increase in Akt phosphorylation by intravitreal injection of
      wortmannin and LY294002, inhibitors of PI3K, resulted in premature nuclear
      fragmentation, caspases-3 and -9 activation in the ganglion cell layer. Our
      findings thus indicate that the PI3K/Akt pathway may serve as an endogenous
      regulator of caspase activation in axotomized RGCs, thereby, contributing to the
      late onset of RGC death following axotomy.

PMID- 15033168
TI  - Identification and developmental analysis of genes expressed by dopaminergic
      neurons of the substantia nigra pars compacta.
AB  - The hallmark of Parkinson's Disease is the degenerative loss of mesencephalic
      dopaminergic (mDA) neurons. Previous studies have shown that the homeobox
      transcription factors, engrailed-1 and -2, are essential for the survival of
      these cells. To identify genes downstream of engrailed-1 and -2, we performed a
      PCR-based differential display, comparing RNA from engrailed-1/2 double mutant
      and wild type ventral midbrain of different embryonic ages to adult olfactory
      bulb, a source of unrelated DA neurons. Here, we report the result of this
      experiment and describe the developmental expression pattern in the ventral
      midbrain of three of the isolated genes, HNF3alpha, synaptotagmin I, and Ebf3.
      Though not regulated by engrailed-1 and -2, the expression of all three genes is
      limited to mDA neurons and a few other brain areas. HNF3alpha appears in the
      precursors of mDA neurons at E9 and is expressed in the adult brain almost
      exclusively by this neuronal population. Synaptotagmin I is expressed from E14
      into adulthood. Ebf3, in contrast, is transiently expressed during early
      postmitotic differentiation.

PMID- 15033169
TI  - Suppression of caspase-3-dependent proteolytic activation of protein kinase C
      delta by small interfering RNA prevents MPP+-induced dopaminergic degeneration.
AB  - The cellular mechanisms underlying the neurodegenerative process in Parkinson's
      disease are not well understood. Using RNA interference (RNAi), we demonstrate
      that caspase-3-dependent proteolytic activation of protein kinase Cdelta
      (PKCdelta) contributes to the degenerative process in dopaminergic neurons. The
      Parkinsonian toxin MPP(+) activated caspase-3 and proteolytically cleaved
      PKCdelta into catalytic and regulatory subunits, resulting in persistent kinase
      activation in mesencephalic dopaminergic neuronal cells. The caspase-3 inhibitor
      Z-DEVD-FMK and the caspase-9 inhibitor Z-LEHD-FMK effectively blocked MPP(+)
      induced PKCdelta proteolytic activation. To characterize the functional role of
      PKCdelta activation in MPP(+)-induced dopaminergic cell death, RNAi-mediated gene
      knockdown was performed. Among four siRNAs designed against PKCdelta, two
      specifically suppressed PKCdelta expression. The application of siRNA abolished
      the MPP(+)-induced PKCdelta activation, DNA fragmentation, and tyrosine
      hydroxylase (TH)-positive neuronal loss. Together, these results suggest that
      proteolytic activation of PKCdelta may be a critical downstream event in the
      degenerative process of Parkinson's disease.

PMID- 15033170
TI  - Activation of cyclin-dependent kinase 5 is involved in axonal regeneration.
AB  - Cyclin-dependent kinase 5 (Cdk5) is a serine-threonine kinase that is activated
      by the binding of p35 or p39 regulatory protein. Cdk5 and p35 are highly
      localized in the growth cone of cultured neurons, and Cdk5 activity is associated
      with neurite outgrowth. Here we report evidence on the functional involvement of
      Cdk5 kinase in regenerating peripheral nerve fibers. Elevated levels of Cdk5
      protein were found in regenerating axons of facial motor neurons after nerve
      crush, and Cdk5 kinase activity was increased with a similar time course as
      increases in Cdk5 protein levels. The p35 protein was also found to be associated
      with increased Cdk5 activity in regenerating nerves. Administration of Cdk5
      inhibitors, roscovitine and olomoucine, into the crushed nerves resulted in
      decreases in Cdk5 kinase activity in nerves and retardation of nerve fiber
      regrowth. Retardation of axonal regeneration by Cdk5 inhibition was confirmed by
      reduced labeling of facial motor neurons using retrograde tracer fluorogold (FG).
      These findings provide first in vivo evidence indicating that Cdk5 activity,
      which is induced by axonal injury, may play an important role in axonal
      regeneration.

PMID- 15033171
TI  - Involvement of collapsin response mediator proteins in the neurite extension
      induced by neurotrophins in dorsal root ganglion neurons.
AB  - The pattern of sensory neuron extensions and connections is established during
      embryonic development through complex and varied guidance cues that control
      motility of growth cones and neurite morphogenesis. Semaphorins and neurotrophins
      are molecules that act as such cues. Collapsin response mediator proteins (CRMPs)
      are thought to be part of the semaphorin signal transduction pathway implicated
      in semaphorin-induced growth cone collapse. In this report, we present evidence
      that CRMPs are also involved in the neurite extension controlled by
      neurotrophins. We found that specific antibodies and the dominant-negative mutant
      protein for CRMP2 both potentiated the neurite extension induced by NGF, while
      specific antibodies and the corresponding mutant protein for CRMP1 both abolished
      the neurite extension induced by NT3. Our data suggest that CRMP2 has a negative
      effect on neurite extension induced by NGF and CRMP1 participates in the neurite
      formation/extension induced by NT3. These results point to a function for CRMPs
      in the regulation of neurite outgrowth induced by neurotrophins in sensory
      neurons.

PMID- 15033172
TI  - Targeted disruption of the FGF-2 gene affects the response to peripheral nerve
      injury.
AB  - Basic fibroblast growth factor (FGF-2) is involved in the development,
      maintenance, and survival of the nervous system. To study the physiological role
      of endogenous FGF-2 during peripheral nerve regeneration, we analyzed sciatic
      nerves of FGF-2-deleted mice by using morphometric, morphological, and
      immunocytochemical methods. Quantification of number and size of myelinated axons
      in intact sciatic nerves revealed no difference between wild-type and FGF-2 knock
      out (ko) animals. One week after nerve crush, FGF-2 ko mice showed about five
      times more regenerated myelinated axons with increased myelin and axon diameter
      in comparison to wild-types close to the injury site. In addition, quantitative
      distribution of macrophages and collapsed myelin profiles suggested faster
      Wallerian degeneration in FGF-2-deleted mice close to the lesion site. Our
      results suggest that endogenous FGF-2 is crucially involved in the early phase of
      peripheral nerve regeneration possibly by regulation of Schwann cell
      differentiation.

PMID- 15033173
TI  - GDNF family ligands activate multiple events during axonal growth in mature
      sensory neurons.
AB  - The need for medical treatment of neuronal trauma motivates the search for new
      agents to stimulate posttraumatic axonal regrowth, as well as improving
      understanding of signaling cascades regulating this process. GDNF stimulates
      axonal regeneration in the peripheral nervous system, but little is known about
      the mechanism of this effect. Neurturin, artemin and persephin are homologs of
      GDNF, and their impact on axonal regeneration in adults has not been studied yet.
      Here we show that neurturin, artemin and GDNF, but not persephin, promote axonal
      initiation in cultured dorsal root ganglion neurons from young adult mice. This
      effect requires Src-family kinase activity as it was blocked by SU6656. In
      neurons from GFRalpha2-deficient mice, neurturin does not significantly promote
      axonal initiation. We also show that neurturin and GDNF induce extensive
      lamellipodia formation on neuronal somata and growth cones. GDNF, when applied
      after the time of axonal initiation in culture, also promotes axonal elongation.

PMID- 15033174
TI  - Differential involvement of phosphatidylinositol 3-kinase and p42/p44 mitogen
      activated protein kinase pathways in brain-derived neurotrophic factor-induced
      trophic effects on cultured striatal neurons.
AB  - Brain-derived neurotrophic factor (BDNF) is a potent trophic factor for striatal
      cells that promotes survival and/or differentiation of GABAergic neurons in
      vitro. In the present study, we show that the stimulation of cultured striatal
      cells with BDNF increased the phosphorylation of Akt and p42/p44. This effect was
      specifically blocked by inhibitors of phosphatidylinositol 3-kinase (PI3-K)
      pathways (LY294002 and wortmannin) or p42/p44 mitogen-activated protein (MAP)
      kinase (PD98059 and U0126). BDNF treatment induced an increase in the number of
      calbindin-positive neurons but not in the number of GABAergic or total cells.
      Furthermore, BDNF increased the degree of dendritic arborization, soma area and
      axon length of striatal neurons. However, PD98059 was more effective blocking
      BDNF effects on calbindin- than on GABA-positive neurons, whereas LY294002
      inhibited morphological differentiation in both neuronal populations. Moreover,
      BDNF induced neuronal survival only through the activation of the PI3-K pathway.

PMID- 15033175
TI  - Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic
      apoptotic pathway in YAC transgenic mouse model of Huntington's disease.
AB  - Evidence suggests N-methyl-D-aspartate receptor (NMDAR) activation is involved in
      the degeneration of striatal medium-sized spiny neurons (MSNs) in Huntington's
      disease (HD). We tested the hypothesis that enhanced NMDAR-mediated
      excitotoxicity is mediated by the mitochondrial-associated apoptotic pathway in
      cultured MSNs from YAC transgenic mice expressing full-length huntingtin (htt)
      with a polyglutamine (polyQ) expansion of 46 or 72 (YAC46 or YAC72). NMDAR
      mediated Ca(2+) transients and mitochondrial membrane depolarization were
      significantly increased in YAC compared to wild-type mice MSNs. Inhibitors of the
      mitochondrial permeability transition (mPT), cyclosporin A and bongkrekic acid,
      and coenzyme Q10 (an anti-oxidant involved in bioenergetic metabolism)
      dramatically diminished NMDA-induced cell death and eliminated genotypic
      differences. In YAC46 MSNs, NMDA stimulated significantly higher activation of
      caspase-3 and caspase-9 but not caspase-8, and NMDA-induced caspase-3 and -9
      activation was markedly attenuated by cyclosporin A. Agents that improve
      mitochondrial function or inhibit the permeability transition may eliminate
      increased caspase activation and cell death associated with enhanced NMDAR
      activity in HD.

PMID- 15033176
TI  - IGF-I and FGF-2 coordinately enhance cyclin D1 and cyclin E-cdk2 association and
      activity to promote G1 progression in oligodendrocyte progenitor cells.
AB  - A critical question in developmental neurobiology is how stem and progenitor
      cells interpret multiple signals to decide whether to proliferate or exit the
      cell cycle. Insulin-like growth factor (IGF)-I and fibroblast growth factor (FGF)
      2 have known functions individually in development of neural stem cells as well
      as more restricted neuronal and glial progenitor cells. The goal of this study
      was to elucidate how IGF-I and FGF-2 coordinately regulate the cell cycle
      machinery in primary oligodendrocyte progenitors (OPs). IGF-I/FGF-2
      synergistically increased the numbers of OP cells recruited into S phase. IGF-I
      enhanced FGF-2 induction of cyclin D1, activation of G(1) cyclin-cyclin-dependent
      kinase (cdk) complexes, and hyperphosphorylation of retinoblastoma protein (pRb).
      Moreover, IGF-I was required for G(2)/M progression. In contrast, FGF-2 decreased
      levels of the cdk inhibitor p27(Kip1) associated with cyclin E-cdk2. These
      studies provide a mechanistic basis for coordinate regulation of cell cycle
      progression in progenitor cells by multiple growth factors.

PMID- 15033178
TI  - Reduced inflammatory pain in mice deficient in the differential screening
      selected gene aberrative in neuroblastoma.
AB  - Differential screening-selected gene aberrative in neuroblastoma (Dan) protein is
      produced in small neurons of dorsal root ganglia. Thermal and mechanical
      allodynia and Fos expression in the spinal dorsal horn evoked by inflammation and
      neuropathic pain were investigated using Dan-deficient mice. Mice showed pain
      reactions induced by the introduction of complete Freund's adjuvant (CFA) into
      their hind paw (inflammatory pain model) and after sciatic nerve ligation
      (neuropathic pain model). In the inflammatory pain model, thermal and mechanical
      pain thresholds in Dan-deficient mice were significantly higher than those of
      wild-type mice. The number of Fos-immunoreactive cells in the dorsal horn during
      the inflammatory period was significantly less in Dan-deficient mice. However, in
      the neuropathic pain model, no differences in thermal hypersensitivity,
      mechanical allodynia, or the number of Fos-immunoreactive cells in the dorsal
      horn were observed between the mice. These data suggest that Dan may be a
      neuromodulator in inflammatory pain.

PMID- 15033177
TI  - Validity of mouse models for the study of tissue transglutaminase in
      neurodegenerative diseases.
AB  - Tissue transglutaminase (tTG) is a multifunctional enzyme that catalyzes peptide
      cross-linking and polyamination reactions, and also is a signal-transducing
      GTPase. tTG protein content and enzymatic activity are upregulated in the brain
      in Huntington's disease and in other neurological diseases and conditions. Since
      mouse models are currently being used to study the role of tTG in Huntington's
      disease and other neurodegenerative diseases, it is critical that the level of
      its expression in the mouse forebrain be determined. In contrast to human
      forebrain where tTG is abundant, tTG can only be detected in mouse forebrain by
      immunoblotting a GTP-binding-enriched protein fraction. tTG mRNA content and
      transamidating activity are approximately 70% lower in mouse than in human
      forebrain. However, tTG contributes to the majority of transglutaminase activity
      within mouse forebrain. Thus, although tTG is expressed at lower levels in mouse
      compared with human forebrain, it likely plays important roles in neuronal
      function.

PMID- 15033179
TI  - Enhanced cortical and hippocampal neuronal excitability in mice deficient in the
      extracellular matrix glycoprotein tenascin-R.
AB  - Mice deficient in the extracellular matrix protein tenascin-R (TN-R-/- mice) show
      several indices of impaired perisomatic inhibition in hippocampal slices. The
      present study examined electroencephalograms (EEGs) and auditory-evoked
      potentials (AEPs) in freely moving TN-R-/- and wild-type control mice, focusing
      on the hippocampal CA1 field and cerebral cortex. TN-R-/- mice expressed normal
      high-frequency oscillations (ripples) in CA1 and only a slight reduction of peak
      theta frequency. In contrast, their hippocampal gamma oscillations were
      significantly enhanced in amplitude. Also, the amplitude of the cortical EEG of
      TN-R-/- mice was increased over a wide frequency range. The amplitude of cortical
      and, to a lesser degree hippocampal, AEPs was clearly enhanced in TN-R-/- mice.
      In addition, response habituation to repeated sound stimuli was significantly
      attenuated in TN-R-/- mice. These findings indicate that tenascin-R is involved
      in the regulation of certain inhibitory mechanisms in the intact brain.

PMID- 15033180
TI  - Expression of dominant negative cadherin in the adult mouse brain modifies
      rearing behavior.
AB  - The cadherin superfamily of cell-cell adhesion molecules (CAM) are crucial
      regulators of morphogenesis and axonal guidance during development of the nervous
      system and have been suggested to play important roles in neural plasticity of
      the brain. To study the latter, we created a mouse model that expressed a
      dominant negative classical cadherin in the brain of adult mice. The mice were
      tested for spontaneous motor activity and exploratory behavior in the open field,
      anxiety in the plus-maze, and spatial learning and memory in the water-T maze.
      Mice expressing the dominant negative cadherin displayed reduced rearing
      behavior, but no change in motor activity, in the open field, indicating deficits
      in exploratory behavior. In the water maze, animals expressing the mutant
      cadherin showed normal escape latencies and were indistinguishable from control
      littermates. Similarly, LTP in hippocampal slices of cadherin mutant and control
      mice were indistinguishable. These findings demonstrate intact spatial learning
      in mice expressing a dominant negative cadherin but altered rearing behavior,
      suggesting the involvement of classical cadherins in mechanisms mediating rearing
      behavior.

PMID- 15033181
TI  - Tyrosine hydroxylase transcription depends primarily on cAMP response element
      activity, regardless of the type of inducing stimulus.
AB  - In neurons and neuroendocrine cells, tyrosine hydroxylase (TH) gene expression is
      induced by stimuli that elevate cAMP, by depolarization, and by hypoxia. Using
      these stimuli, we examined TH promoter mutants, cAMP response element binding
      protein (CREB) phosphorylation site mutants, and transcriptional interference
      with dominant negative transcription factors to assess the relative contributions
      of CREB/AP-1 family members to the regulation of basal and inducible TH
      transcription in PC12 cells. We found that basal transcription depends on
      transcription factor activity at the partial dyad (-17 bp), CRE (-45 bp), and AP1
      (-205 bp) elements. Induced transcription is regulated primarily by activity at
      the CRE, with only small contributions from the AP1 or hypoxia response element 1
      (HRE1; -225 bp) elements, regardless of inducing stimulus. CREB, ATF-1, and
      CREMtau all mediate CRE-dependent transcription, with CREB and CREMtau being more
      effective than ATF-1. Phosphorylation of CREB on Ser133, but not on Ser142 or
      Ser143, is required for induced transcription, regardless of inducing stimulus.

PMID- 15033182
TI  - The Danish PET/depression project: performance on Stroop's test linked to white
      matter lesions in the brain.
AB  - The Stroop test (ST) assesses the integrity of prefrontal and cingulate
      functioning. Patients with major depression perform poorly on the ST, pointing to
      disturbed function in these areas. We therefore used positron emission tomography
      to study 41 in-patients with major depression and 46 age- and gender-matched
      controls during neuropsychological activation with the ST. Magnetic resonance
      imaging was used for coregistration and for description of the localization of
      white matter lesions (WML). The cerebral blood flow (CBF) changes during ST were
      mapped for each of the two study groups, and inter-group differences were
      calculated on a voxel-by-voxel basis. The patients were followed for 3 to 5 years
      to ensure diagnostic stability. The control group activated anterior cingulate
      regions, prefrontal cortices, insula, thalamus and cerebellum. Despite the
      patients' slower performance with more errors, no significant differences were
      found comparing the activations in the two groups. The performance was, however,
      correlated to the number of WML in frontal lobes, insula and adjacent to the
      basal ganglia, whereas WML in other locations was not related to performance. We
      thus partly explain the poorer performance by increased frequency of WML in
      frontostriatal pathways in the depressed patients, impairing neurotransmission.

PMID- 15033183
TI  - Biophysical changes in normal-appearing white matter and subcortical nuclei in
      late-life major depression detected using magnetization transfer.
AB  - Neuroanatomical changes have been identified in patients diagnosed with late-life
      major depressive disorder (MDD) compared with controls. These primarily comprise
      a decrease in focal brain volumes and an increase in MRI-determined high
      intensity lesions that are largely confined to the white matter. The
      physiological status of normal-appearing white matter in patients with MDD
      remains unknown. Magnetization transfer (MT) is a relatively new neuroimaging
      technique that permits us to examine the biophysical characteristics of specific
      brain regions. Using MT, we studied eight patients with late-life MDD and eight
      non-depressed controls. MT ratios (MTR), which reflect the integrity of the
      macromolecular protein pool, were ascertained in normal-appearing white matter
      and subcortical nuclei. Patients had significantly lower MTRs in the genu and
      splenium of the corpus callosum, the right caudate nucleus and putamen, and the
      occipital white matter compared with controls. The findings indicate that the
      structure of the macromolecular protein matrix may be compromised in normal
      appearing white matter and critical subcortical nuclei in patients with late-life
      major depression. These changes may provide important substrates to mood
      disorders and have implications for neuronal connectivity and its role in the
      pathophysiology of late-life depression.

PMID- 15033185
TI  - Reduction of cingulate gray matter density in poor outcome bipolar illness.
AB  - Structural brain abnormalities are associated with poor outcome unipolar
      depressive disorder. Gray matter density can be assessed with an automated,
      operator independent analysis (SPM99). We thus compared 11 poor outcome bipolar
      patients with 15 age-, sex- and IQ-matched healthy volunteers with a standard
      neuropsychological examination and an Elscint 2.0 Tesla MRI scanner. At the time
      of examination, patients were neither hypomanic nor significantly depressed, but
      were significantly impaired on the McGlashan scale. Their memory function was
      characterized by reduced performance in the California verbal learning and digit
      symbol substitution tests. Statistical parametric mapping revealed abnormal gray
      matter density, mainly in fronto-limbic cortex, but particularly widespread in
      cingulate cortex. Although causality of these changes is difficult to resolve,
      the results offer useful insights into the neural correlates of severe bipolar
      disorder.

PMID- 15033184
TI  - Age and ApoE genotype interaction in Alzheimer's disease: an FDG-PET study.
AB  - Previous positron emission tomography (PET) studies with fluorodeoxglucose (FDG)
      as tracer in healthy elders showed that the epsilon4 allele of the apolipoprotein
      E (ApoE) gene is disruptive to cerebral glucose metabolism (rCMRglu), possibly
      through the interaction with the aging process. The present study was aimed at
      assessing whether this interaction occurs in patients with Alzheimer's disease
      (AD). Eight-six AD patients, including 40 ApoE4 carriers and 46 non-carriers,
      underwent (18)F-FDG PET scanning at rest. ApoE groups were comparable for age,
      gender, age at onset and disease duration. SPM'99 was used to assess rCMRGlu
      correlations with age, differences between ApoE groups and ApoE by age
      interaction, correcting for disease severity. Results were reported at P<0.001,
      uncorrected. Correlations between age and rCMRGlu confirmed the well-known
      negative relationship for both groups. Lower rCMRGlu was found within the frontal
      and cingulate areas for ApoE4 carriers as compared with the non-carriers.
      Additionally, a significant ApoE by age interaction was detected in the frontal
      and anterior cingulate cortex, with the ApoE4 carriers having a steeper
      regression slope with respect to the non-carriers. These results indicate that
      age-related regional rCMRglu decreases within the frontal and anterior cingulate
      areas may be more severe in AD patients carrying the ApoE4 allele.

PMID- 15033187
TI  - A source-imaging (low-resolution electromagnetic tomography) study of the EEGs
      from unmedicated men with schizophrenia.
AB  - Imaging studies and quantitative electroencephalography (EEG) have often, but not
      consistently, implicated the left hemisphere and the prefrontal cortex in
      schizophrenia. To help clarify this picture, a spatial filter shown to be
      effective for enhancing differences between EEG populations was combined with low
      resolution electromagnetic tomography and used to compare the source-current
      densities from a group of 57 male subjects with schizophrenia and a group of 65
      matched controls. To elicit differences, comparisons were made during resting
      conditions and during verbal and spatial cognitive challenges to the subjects.
      Estimates of the source-current density were derived from 43-electrode recordings
      of the EEG reduced to the delta, alpha and beta frequency bands. The patients
      were unmedicated and were selected according to DSM-IV criteria. As a group, they
      were severe, chronic states with both deficit negative and superimposed florid
      psychotic symptomatology. The results confirm that schizophrenia is a left
      hemispheric disorder centered in the temporal and frontal lobes. They also
      suggest that, in schizophrenia, functions normally performed by these regions in
      controls are assumed by homologous regions in the opposite hemispheres.

PMID- 15033186
TI  - Memory impairment and auditory evoked potential gating deficit in schizophrenia.
AB  - Impaired sensory gating and memory function were reported in a study of 10
      schizophrenic patients and 10 age- and sex-matched normal subjects. The P50
      component of the auditory evoked potential was used as an index of gating.
      Explicit memory was tested with the Wechsler Memory Scale and implicit memory by
      artificial grammar learning. The schizophrenic patients showed deficits in both
      verbal paired associate and visual reproduction tasks. They demonstrated impaired
      implicit learning in color patterns but not letter strings. They also showed
      impaired P50 sensory gating. Three-dimensional brain mapping revealed a
      differential distribution of brain potentials in the processing of S1 and S2 at
      either P50 or N100 in both groups. However, the group difference was not
      statistically confirmed. In the controls, both implicit letter-string learning
      and explicit verbal paired associates were positively correlated with N100
      gating, suggesting an association of the early attentive component with lexicons.
      In the schizophrenic patients, color-pattern implicit learning was positively
      correlated with P50 gating. The modality-specific impairment of implicit learning
      in schizophrenia may reflect a failure of adaptive filtering on the flooding
      input from color patterns.

PMID- 15033188
TI  - A source-imaging (low-resolution electromagnetic tomography) study of the EEGs
      from unmedicated males with depression.
AB  - Imaging studies and quantitative EEG have often, but not consistently, implicated
      the right hemisphere and the left prefrontal cortex in depression. To help
      clarify this picture, a spatial filter shown to be effective for enhancing
      differences between EEG populations was combined with an electrical tomographic
      approach called low-resolution electromagnetic tomography and used to compare the
      source-current densities from a group of 25 male subjects with depression and a
      group of 65 matched controls. To elicit differences, comparisons were made during
      resting conditions and during verbal and spatial cognitive challenges to the
      subjects. Estimates of the source-current density were derived from 43-electrode
      recordings of the EEG reduced to the delta, alpha and beta frequency bands. The
      depressed subjects were unmedicated and selected according to DSM IV criteria.
      Regions of significantly increased current density in depression compared to
      controls were generally right hemispheric, while regions of significantly
      decreased current density were generally frontal and left hemispheric. A within
      group comparison of the depressed subjects during the two cognitive challenges
      suggested a left anterior functional hypoactivation in depression. Retrospective
      classification of the two groups indicated that the spatial challenge best
      separated the groups irrespective of frequency band.

PMID- 15033189
TI  - Microbial recognition by Toll-like receptors.
AB  - Toll-like receptors (TLRs) sense invasion of microorganisms by detecting
      microbial components that are conserved among pathogens. Recognition of microbial
      components by TLRs triggers activation of the innate immune system. Signaling
      pathways via TLRs originate from conserved cytoplasmic Toll/IL-1 receptor (TIR)
      domains. Recent accumulating evidence demonstrates that TIR domain-containing
      adaptors, such as MyD88, TIRAP/Mal, TRIF, and TRAM, regulate TLR-mediated
      signaling pathways. MyD88 is common to all TLR-mediated pathways, which lead to
      the production of inflammatory cytokines, whereas TRIF mediates induction of IFN
      beta in TLR3 and TLR4 signaling pathways. TIRAP/Mal is implicated in the TLR2-
      and TLR4-mediated MyD88-dependent signaling pathway. TRAM is specifically
      involved in the TLR4-mediated TRIF-dependent pathway. Thus, TIR domain-containing
      adaptors play a pivotal role in TLR signaling pathways, which culminate in
      pathogen-specific immune responses.

PMID- 15033190
TI  - Dermatitis herpetiformis: close to unravelling a disease.
AB  - Dermatitis herpetiformis is characterised by granular IgA precipitates in the
      papillary dermis. In contrast to other autoimmune blistering diseases, where
      tissue-deposited and circulating autoantibodies recognise the same target within
      the skin, in dermatitis herpetiformis a serum IgA reacting with a component of
      the healthy papillary dermis has not been detected. Recently, the antigenic
      specificity of pathognomic skin-bound IgA has been clarified: the immune
      precipitates contain epidermal transglutaminase, an enzyme not previously
      detected in the papillary region of normal skin. Furthermore, serum IgA in
      dermatitis herpetiformis has been found to bind epidermal transglutaminase. These
      findings may relate to the fact, that dermatitis herpetiformis is associated with
      gluten sensitive enteropathy, coeliac disease, which is characterised by IgA type
      autoantibodies to a closely related enzyme, tissue transglutaminase. The two
      transglutaminases are highly homologous, and therefore, cross reactivity of the
      two antibodies might explain why patients with gluten sensitive enteropathy, with
      or without skin disease, generally have serum autoantibodies to both enzymes.
      There is growing evidence that dermatitis herpetiformis should be considered as
      the skin manifestation of gluten sensitivity developing in those patients with
      mild coeliac disease, who produce epidermal transglutaminase autoantibodies of
      high avidity and affinity. Both the skin and the small bowel diseases are gluten
      dependent and are strongly associated with HLA DQ with no genetic differences to
      explain the two phenotypes. The question should be asked whether the rash in
      dermatitis herpetiformis is a classic autoimmune blistering disease or whether it
      has an immune complex basis, which is the most likely alternative.

PMID- 15033191
TI  - Effect of minoxidil on proliferation and apoptosis in dermal papilla cells of
      human hair follicle.
AB  - BACKGROUND: Minoxidil has been widely used to treat androgenetic alopecia, but
      little is known about its pharmacological activity or about the identity of its
      target cells in hair follicles. We hypothesized that minoxidil has direct effects
      on the proliferation and apoptosis of dermal papilla cells (DPCs) of human hair
      follicle. OBJECTIVE: To elucidate the mechanism of topical minoxidil action in
      terms of stimulating hair growth. METHODS: We evaluated cell proliferations in
      cultured DPCs by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
      (MTT) and measured the expressions of extracellular signal-regulated kinase
      (ERK), Akt, Bcl-2, and Bax by Western blot. We also measured elongation of hair
      follicles in organ culture. RESULTS: Minoxidil significantly increased the
      proliferation of DPCs. The levels of ERK phosphorylation and of phosphorylated
      Akt increased significantly 1 h post-treatment; percentage increase of ERK
      phosphorylation was 287% at 0.1 microM and 351% at 1.0 microM of minoxidil, and
      that of Akt phosphorylation was 168% at 0.1 microM and 257% at 1.0 microM of
      minoxidil. 1.0 microM of minoxidil increased Bcl-2 expression over 150%, while
      1.0 microM of minoxidil decreased Bax expression by more than 50%. Moreover, a
      significant elongation of individual hair follicles in organ culture was observed
      after adding minoxidil. CONCLUSION: Minoxidil promotes the survival of human DPCs
      by activating both ERK and Akt and by preventing cell death by increasing the
      ratio of Bcl-2/Bax. We suggest that minoxidil stimulates the growth of human
      hairs by prolonging anagen through these proliferative and anti-apoptotic effects
      on DPCs.

PMID- 15033193
TI  - Ribosomal DNA exhibits few alterations in human skin cancers.

PMID- 15033192
TI  - Reduced expression and aberrant localization of p120catenin in human squamous
      cell carcinoma of the skin.
AB  - BACKGROUND: p120catenin (p120ctn), a member of the Armadillo protein family, is
      ubiquitously expressed and binds to classical cadherins together with other
      catenins to participate in the adherens junction. p120ctn has numerous isoforms
      generated through extensive splicing and alternative usage of translation
      initiation codons. Although the involvement of p120ctn in cell growth control has
      been postulated, little has so far been known about its expression patterns in
      the skin and epidermal tumors. OBJECTIVE: To identify the isoforms expressed in
      benign and malignant keratinocytes and to analyze the expression patterns of
      p120ctn in epidermal tumor specimens. METHODS: HaCaT, DJM-1, BSCC-93, HSC-1, HSC
      5 and A431 cells along with normal skin tissue were subjected to RT-PCR to
      identify the expressed isoforms. For immunofluorescence study, surgical specimens
      including 29 squamous cell carcinomas (SSCs), 4 basal cell carcinomas (BCCs) and
      4 seborrheic keratoses as well as 3 normal skin samples were stained with
      specific antibodies to detect p120ctn and E-cadherin. RESULTS: RT-PCR revealed
      that the isoform 3A was predominantly expressed with faint expression of the
      isoform 4 and that there was no difference in expressed isoforms between the
      examined cell lines. Immunofluorescent staining indicated that the expression of
      p120ctn was significantly reduced in all of the examined squamous cell carcinomas
      and that p120ctn was frequently localized in cytoplasm. In benign tumors and
      normal samples, p120ctn was properly expressed in cell-cell boundaries.
      Furthermore, there were several SCCs where E-cadherin continued to be expressed
      with no expression of p120ctn. CONCLUSION: Reduced expression and aberrant
      localization of p120ctn are among the most common events during the development
      and/or progression of SCCs.

PMID- 15033194
TI  - Lack of association of interleukin-12 p40 gene (IL12B) polymorphism with Behcet's
      disease in the Japanese population.

PMID- 15033195
TI  - Expression of keratin and involucrin in keratoacanthoma: an immunohistochemical
      aid to diagnosis.

PMID- 15033196
TI  - Fetal stroke.
AB  - Fetal stroke, or that which occurs between 14 weeks of gestation and the onset of
      labor resulting in delivery, has been associated with postnatal epilepsy, mental
      retardation, and cerebral palsy. The entity is caused by antenatal ischemic,
      thrombotic, or hemorrhagic injury. We present seven new cases of fetal stroke
      diagnosed in utero and review the 47 cases reported in the literature. Although
      risk factors could not be assigned to 50% of the fetuses with stroke, the most
      common maternal conditions associated with fetal stroke were alloimmune
      thrombocytopenia and trauma. Magnetic resonance imaging was optimal for
      identifying fetal stroke, and prenatal imaging revealed hemorrhagic lesions in
      over 90% of studies; porencephalies were identified in just 13%. Seventy-eight
      percent of cases with reported outcome resulted in either death or adverse
      neurodevelopmental outcome at ages 3 months to 6 years. Fetal stroke appears to
      have different risk factors, clinical characteristics, and outcomes than other
      perinatal or childhood stroke syndromes. A better understanding of those risk
      factors predisposing a fetus to cerebral infarction may provide a basis for
      future therapeutic intervention trials. Ozduman K, Pober BR, Barnes P, Copel JA,
      Ogle EA, Duncan CC, Ment LR. Fetal stroke.

PMID- 15033197
TI  - Hip status in cerebral palsy after one year of continuous intrathecal baclofen
      infusion.
AB  - The purpose of this study was to assess whether reduction of muscle tone by
      continuous intrathecal baclofen infusion affects the progression of hip
      subluxation in persons with cerebral palsy. This prospective, open-label, case
      series was conducted at multiple specialty referral centers. There were 33
      subjects, ages 4 to 31 years. All had a pretreatment lower extremity Ashworth
      score of >/=3; all subjects had a significant reduction in tone after a bolus
      injection of intrathecal baclofen and received an implanted pump for continuous
      delivery of intrathecal baclofen. Subjects had hip x-rays before and 1 year after
      pump implantation. The primary outcome measure was change in absolute hip
      migration percentage. One third of the hips had an increase of absolute migration
      percentage of 5% or more; 12% of the hips had a decrease of migration percentage
      of 5% or more. Change of migration percentage class was used as a second outcome
      criterion. 90.9% of hips manifested no deterioration or had improvement of their
      migration percentage class during the year of intrathecal baclofen therapy. The
      observed changes were not associated with the subject's age or the severity of
      cerebral palsy.

PMID- 15033198
TI  - Frontal lobe epilepsy in childhood.
AB  - Frontal lobe epilepsy is poorly understood and often unrecognized by health care
      workers caring for children. We sought to better characterize frontal lobe
      epilepsy in childhood and help delineate this condition from other nonepileptic
      events. We reviewed pediatric patients admitted to the Comprehensive Epilepsy
      Program at the University of Alberta Hospitals with a proven diagnosis of frontal
      lobe epilepsy. Twenty-two patients, 13 males and 9 females, were studied. Age of
      onset was variable from 10 months to 16 years (mean 7.5 years). Seizures were
      brief (30 seconds to 2 minutes), stereotypic, nocturnal (17/21), and frequent (3
      22/night). Clinical features included explosive onset, screaming, agitation,
      stiffening, kicking or bicycling of the legs, and incontinence. The diagnosis of
      frontal lobe epilepsy was not made in any child before referral. The referring
      diagnosis was sleep disturbance (10), psychiatric problems (6), or other seizure
      types (6). Interictal electroencephalogram was usually normal (18/21). Long-term
      video electroencephalographic monitoring demonstrated frontal (9) or bifrontal
      (13) epileptic discharges. Magnetic resonance imaging was normal in most patients
      (18/21). Seizure control was difficult, with only half (11/21) the patients being
      controlled on medication. Three intractable patients went on to epilepsy surgery
      and became seizure-free. Frontal lobe epilepsy in childhood is a distinct
      epilepsy syndrome with characteristic features. The seizures are brief,
      stereotypic, nocturnal, and frequent. Electroencephalogram and magnetic resonance
      imaging are usually normal. The condition is often misdiagnosed as a sleep
      disorder or psychiatric problem. Seizures are difficult to control but may
      respond to carbamazepine, valproic acid, or epilepsy surgery.

PMID- 15033199
TI  - Extratemporal resection for childhood epilepsy.
AB  - There have been relatively few studies reporting the safety, efficacy, and
      outcome in children undergoing extratemporal resection for epilepsy. We reviewed
      the pediatric cases of extratemporal resection for intractable epilepsy performed
      by the Comprehensive Epilepsy Program at the University of Alberta Hospitals
      between 1988-1998. Thirty-five patients were studied, 14 male and 21 female. The
      age at operation ranged from 6 months to 16 years. The operations included
      frontal excisions (12), parietal (8), occipital (4), hemispherectomies or
      multilobar resections (10), and one removal of a hypothalamic hamartoma. The
      pathology at surgery included patients with focal cortical dysplasia (8), brain
      tumors (6), neurocutaneous syndrome (7), Rasmussen's encephalitis (2),
      porencephalic cysts (4), hypothalamic hamartoma (1), and nonspecific gliosis (6).
      Twenty-four of 35 patients (68.5%) had an Engel Class I outcome after surgery and
      an additional six patients (11%) had a significant decrease in seizure frequency
      (Engel Class III). Complications were observed in two patients (5%) and there
      were no deaths. Extratemporal resection is a safe and effective treatment for
      children with intractable epilepsy. Overall, 68% of patients were seizure-free
      after surgery, although outcome may be dependent on site and pathology. A wide
      range of developmental pathology was observed including focal cortical dysplasia,
      brain tumors, and lesions with neurocutaneous syndromes. Many families reported
      improvement in behavior and psychosocial function after surgery.

PMID- 15033200
TI  - Association of the nicotinic receptor beta 2 subunit and febrile seizures.
AB  - The nicotinic acetylcholine receptors are members of a superfamily of ligand
      gated ion channels that mediate fast signal transmission at synapses. Mutations
      in neuronal nicotinic acetylcholine receptor beta 2 subunit have been associated
      with autosomal dominant nocturnal frontal lobe epilepsies. A major challenge is
      to establish whether the monogenic epilepsy gene also contributes to the common
      epilepsies. Because febrile seizures represent the majority of childhood
      seizures, and a genetic predisposition, we investigated the possibility that the
      nicotinic acetylcholine receptor beta 2 subunit might be involved in the etiology
      of febrile seizures. Children were divided into two groups: those with febrile
      seizures (group 1; n = 104) and control patients (group 2; n = 83). Polymerase
      chain reaction was used to identify the G/C and T/C polymorphisms of the
      nicotinic acetylcholine receptor beta 2 subunit gene, which is mapped on
      chromosome 1. Genotypes and allelic frequencies for nicotinic acetylcholine
      receptor beta 2 subunit gene polymorphisms in both groups were compared. The
      results indicated that genotypes and allelic frequencies in both groups were not
      significantly different. These data suggest that nicotinic acetylcholine receptor
      beta 2 subunit polymorphisms are not a useful marker for prediction of the
      susceptibility to febrile seizures.

PMID- 15033201
TI  - Interobserver reliability of the Amiel-Tison neurological assessment at term.
AB  - The eligibility criteria currently used for neurodevelopmental follow-up are
      traditionally based on perinatal events and characteristics of the infants at
      birth. However, they seem unsatisfactory to target efficiently all children who
      will manifest long-term neurologic sequelae and eventually require rehabilitation
      services. The updated version of the Amiel-Tison's Neurological Assessment At
      Term (ATNAAT) is expected to allow a better prediction of the neurodevelopmental
      outcome in high-risk infants. The main objective of the present study, which was
      performed on 35 infants, was to analyze the interobserver reliability of the
      updated version of ATNAAT. The evaluator and the observer coded the items of the
      test simultaneously. Among the 35 items tested, 16 demonstrated an excellent
      reliability based on the kappa coefficient, 11 items yielded a fair to good
      reliability, whereas only two items produced an agreement below 0.40. The final
      synthesis, which was a global appreciation of the neurologic status based on the
      different findings, yielded a good reliability with a kappa coefficient of 0.76.
      Among the infants who had a nonoptimal outcome from the assessment, only 38.5%
      met the traditional criteria currently used for follow-up. It would be important
      to conduct further research on predictive validity to demonstrate the capacity of
      the ATNAAT to forecast the long-term neurologic outcome of infants at risk.

PMID- 15033202
TI  - Nijmegen breakage syndrome in 13% of age-matched Czech children with primary
      microcephaly.
AB  - The Nijmegen breakage syndrome is a rare autosomal recessive chromosomal
      instability disorder characterized by early growth retardation, congenital
      microcephaly, immunodeficiency, borderline mental development, and a high
      tendency to lymphoreticular malignancies. Most Nijmegen breakage syndrome
      patients are of Slavonic origin, and all of them known so far carry a founder
      homozygous 5 nucleotide deletion in the NBS1 gene. Microcephaly was present in
      100% of Nijmegen breakage syndrome patients in a recent large international
      cooperative study. The frequency of Nijmegen breakage syndrome among children
      with primary microcephaly was not known. Early correct diagnosis of the syndrome
      is crucial for appropriate preventive care and therapy. We tested 67 Czech
      patients of different ages with simple microcephaly for the presence of the most
      common mutation in the NBS1 gene. Three new Nijmegen breakage syndrome cases were
      detected in this cohort, representing 4.5% of the cohort. All these newly
      diagnosed Nijmegen breakage syndrome patients were younger than 10 months at the
      time of diagnosis. They were all born within a 2.5-year period. Twenty-three of
      the 67 children in the cohort were born within this 2.5-year period, representing
      a 13% incidence of Nijmegen breakage syndrome. Frequency of Nijmegen breakage
      syndrome heterozygotes among infants in the Czech Republic is 1: 130-158 and the
      birth rate is 90,000 per year, therefore in the time span of 2.5 years, three new
      Nijmegen breakage syndrome homozygotes are expected to be born. Therefore we
      assume that by DNA testing of Czech primary microcephalic children it is possible
      to detect all Nijmegen breakage syndrome patients to be expected. The age at
      correct diagnosis was lowered from 7.1 years at the time before DNA testing, to
      well under 1 year of age. All new Nijmegen breakage syndrome patients could
      receive appropriate preventive care, which should significantly improve their
      life expectancy and prognosis.

PMID- 15033203
TI  - Clinical and electroencephalographic follow-up after a first unprovoked seizure.
AB  - We studied the role of clinical and electroencephalographic factors in the follow
      up of children and adolescents after a first unprovoked seizure, and their
      correlation with recurrence and risk for epilepsy. We conducted a 24-month follow
      up of 109 patients aged 1 month to 16 years who had a first unprovoked seizure.
      We analyzed the characteristics of the first seizure, perinatal history, family
      history of seizures, electroencephalographic patterns and their influence on
      seizure recurrence, and calculated risk for subsequent epilepsy. Fifty-six
      patients (51.4%) had recurrent seizures. The bivariate statistical analysis
      revealed that maternal prenatal disease (relative risk = 2.02, P = 0.03) and an
      abnormal electroencephalogram (relative risk = 2.89, P = 0.0003) were
      significantly associated with seizure recurrence. Other factors (male sex,
      partial first seizure, vaginal delivery, family history of seizures, and sleep
      state) approached statistical significance. Logistic regression revealed that the
      only variable significantly associated with recurrence was an abnormal
      electroencephalographic pattern on the first examination (relative risk = 2.48, P
      = 0.003). Cumulative risk ranged from 50-68% at 24 months when the first
      electroencephalogram was abnormal, and from 26-36% when it was normal. We
      concluded that the electroencephalogram may have an important diagnostic value in
      the prognosis of epileptic seizure recurrence in children and adolescents.

PMID- 15033204
TI  - Acute disseminated encephalomyelitis following hepatitis A virus infection.
AB  - Acute disseminated encephalomyelitis is an immune-mediated demyelinating disorder
      usually encountered in children or adolescents and characterized by multifocal
      neurologic deficits of rapid onset. It is often preceded by various infectious
      diseases or vaccination, but acute disseminated encephalomyelitis developing
      after hepatitis A virus infection is rare. We present such a case in a 9-year-old
      patient who illustrates the importance of considering acute disseminated
      encephalomyelitis in patients who develop multifocal neurologic signs after
      hepatitis A virus infection. We suggest that patients with acute disseminated
      encephalomyelitis be screened for hepatitis A virus because of the occurrence of
      asymptomatic hepatitis A virus infection.

PMID- 15033205
TI  - Misplaced peripherally inserted central catheter: an unusual cause of stroke.
AB  - Stroke in pediatric patients occurs with a frequency of 3 to 8 per 100,000. The
      postevent evaluation attempts to identify the etiology of ischemia whether
      anatomic, hematologic, or embolic, with the intention of preventing future
      events. We present the case of a previously healthy male who developed unilateral
      facial and extremity weakness 2 weeks after receiving an appendectomy. Once the
      usual etiologies of stroke in pediatric patients were excluded, an evaluation of
      the peripheral venous catheter (placed for postoperative antibiotic delivery)
      demonstrated arterial misplacement. This article presents the first reported case
      of such an occurrence in the literature and exhibits the need to pursue all
      avenues of evaluation if the etiology of a pediatric stroke is not initially
      identified.

PMID- 15033207
TI  - A successful treatment with pyridoxal phosphate for West syndrome in
      hypophosphatasia.
AB  - We report a 2-month-old male with West syndrome associated with infantile
      hypophosphatasia. The male infant was born at term to a healthy mother after an
      uneventful pregnancy. He was born by cesarean section because of breech
      presentation. He was observed to have short extremities, and radiographs were
      consistent with achondroplasia. The serum alkaline phosphatase level was 2 IU/dL.
      Intractable tonic seizures developed 2 days after birth, and an
      electroencephalogram revealed a burst-suppression pattern for the first 2 months
      of life. The seizures were uncontrollable with conventional antiepileptic drugs.
      At the age of 2 months, he had a series of infantile spasms, and the
      electroencephalogram indicated hypsarrhythmia. Treatment with high-dose pyridoxal
      phosphate eliminated his seizures.

PMID- 15033206
TI  - 3-methylglutaconic aciduria type I in a boy with fever-associated seizures.
AB  - 3-Methylglutaconic-aciduria type I (MGA1, OMIM 250950) resulting from 3
      Methylglutaconyl-coenzyme A hydratase deficiency is a rare inherited metabolic
      disorder of l-leucine catabolism. We diagnosed this condition in a 4-year-old
      German male with generalized fever-associated seizures from the age of 12 months
      and normal psychomotor development. First he was considered to suffer from
      uncomplicated febrile seizures. After his eighth seizure, laboratory
      investigations were performed to exclude inborn errors of metabolism. Analysis of
      organic acids in urine indicated highly elevated concentrations of 3
      methylglutaconic and 3-hydroxyisovaleric acids. 3-Methylglutaconyl-coenzyme A
      hydratase activity was markedly decreased in skin fibroblasts. Mutation analysis
      in the AUH gene revealed homozygosity for a novel splice site mutation IVS9-2A>G.
      We conclude that MGA1 may be associated with fever-associated seizures even in
      children without delayed psychomotor development.

PMID- 15033208
TI  - A lethal association of congenital apnea with brainstem tegmental necrosis.
AB  - We present a female with premature birth, polyhydramnios, congenital apnea,
      cranial nerve palsies, orofacial and limb anomalies. Neuroimaging revealed
      calcifications along the vental margin of the caudal fourth ventricle.
      Neuropathologic findings at postmortem examination were consistent with brainstem
      tegmental necrosis and olivary hypoplasia, a rare lethal entity that should be
      considered in the differential diagnosis of congenital apnea.

PMID- 15033209
TI  - Life-threatening vocal cord paralysis in a patient with group A xeroderma
      pigmentosum.
AB  - We report a 19-year-old male with group A xeroderma pigmentosum who presented
      life-threatening vocal cord paralysis. At 3 months of age, he became sensitive to
      sunlight, and at the age of 4 years he was diagnosed with group A xeroderma
      pigmentosum. The neurologic symptoms progressed slowly thereafter. From the age
      of 18 years, he reported the development of occasional episodic inspiratory
      stridor and dyspnea, but the cause remained unknown. At the age of 19, he had a
      common cold and became severely dyspneic and cyanotic. Immediate examination of
      the glottis upon arrival by an otorhinolaryngologist using a fibroscope indicated
      complete paralysis of both vocal cords, and tracheal intubation resulted in
      marked improvement of respiration. Tracheostomy was performed thereafter.
      Inspiratory stridor and dyspnea are the common symptoms in this disease, and some
      patients with group A xeroderma pigmentosum undergo a tracheostomy, but the
      pathogenesis remains unknown. To our knowledge, vocal cord paralysis has never
      been reported in patients with group A xeroderma pigmentosum. This case is
      presented to illustrate the importance of fibroscopy in the examination of vocal
      cords in patients with group A xeroderma pigmentosum before the development of
      life-threatening events.

PMID- 15033210
TI  - Parental expectancies and childhood anxiety disorders: psychometric properties of
      the Parental Expectancies Scale.
AB  - The current study examined the psychometric properties of the Parental
      Expectancies Scale (PES) in childhood anxiety disorder and normative samples. The
      PES is a 20-item self-report instrument that assesses five dimensions of parental
      expectancies in academic, extra-curricular, household, social, and general
      success areas. Results indicated that the PES has high test-retest reliability
      and internal consistency. Regarding validity, PES subscale scores discriminated
      clinical and normative groups. Principal component and confirmatory factor
      analyses supported the construct validity of the scale. The PES appears to be a
      reliable and valid instrument for quantifying parental expectancies. Implications
      as to case formulation and prescriptive treatment planning with anxious youth are
      discussed.

PMID- 15033211
TI  - Mastery of Your Anxiety and Panic and brief therapist contact in the treatment of
      panic disorder.
AB  - Twenty-eight individuals with panic disorder were provided with a copy of Mastery
      of Your Anxiety and Panic II and received either four sessions of group cognitive
      behavior therapy (Group) or one meeting with a therapist plus three telephone
      contacts (Telephone). Between group repeated measures analyses revealed
      significant improvement over the course of treatment and maintenance of gains
      over the follow-up period with few treatment by trials interactions. A higher
      percentage of participants in the Telephone condition achieved high end-state
      functioning status at posttreatment compared to those who participated in group
      CBT (72% vs. 24%), but this difference disappeared at 6 months posttreatment (45%
      vs. 55%). Participants with characteristics of either borderline, dependent, or
      depressive personality disorders, as assessed by the MCMI-III, were unlikely to
      achieve high end-state functioning status at posttreatment. Trends in the data
      suggest that participants who met criteria for panic disorder with agoraphobia,
      and those with comorbid generalized anxiety disorder, were also less likely to
      achieve clinically significant outcome. These findings add to the growing
      literature indicating that self-directed treatment with brief therapist contact
      is a viable option for many people with panic disorder. Furthermore, the study
      provides preliminary data suggesting that certain comorbid conditions negatively
      impact self-directed treatment outcome.

PMID- 15033212
TI  - Traumatic stress in late pregnancy.
AB  - Traumatic stress has traditionally been studied in the aftermath of traumatic
      events. In contrast, this study aimed to explore if traumatic stress can occur
      before an event that is perceived as threatening or feared. Traumatic stress, as
      related to the forthcoming delivery, was studied in 1224 women. Background data
      and psychological characteristics were assessed in early pregnancy and traumatic
      stress and fear of childbirth in late pregnancy. Of all subjects, 2.3% met all
      DSM-IV criteria for posttraumatic stress disorder (PTSD) and 5.8% fulfilled
      criteria B, C, and D in late pregnancy. Traumatic stress and fear of childbirth
      correlated significantly. High trait anxiety, depressive symptomatology,
      psychological/psychiatric counseling related to childbirth, and self-reported
      psychological problems, measured in early pregnancy, were risk factors for
      traumatic stress and fear of childbirth in late pregnancy. Results suggest the
      occurrence of "pre"traumatic stress (i.e., a threatening forthcoming event
      provoking symptoms similar to those after a traumatic event).

PMID- 15033213
TI  - Generalized Social Phobia and social judgments: the salience of self- and partner
      information.
AB  - Individuals with Generalized Social Phobia (GSP, N = 25) and community controls
      (N = 26) participated in a social interaction task. They then rated how well they
      had performed in the situation and assigned weights and valences to the different
      types of information they used to arrive at this judgment. The GSP group weighed
      anxiety-related self-information more heavily than did the Control group. In
      contrast, their conversational partners weighed verbal behavior more heavily.
      These findings are generally supportive of cognitive models of social phobia and
      point to the negative interpersonal implications of relying on different social
      information than others.

PMID- 15033214
TI  - CO(2) hypersensitivity in recently abstinent alcohol dependent individuals:; A
      possible mechanism underlying the high risk for anxiety disorder among
      alcoholics.
AB  - Alcohol, administered acutely, is known to cause CO(2) hyposensitivity. CO(2)
      hypersensitivity associated with anxiogenic hyperventilation (HV) could
      reasonably be expected to emerge as an opponent process upon withdrawal from
      chronic alcohol use. To test this hypothesis, we applied two well-known methods
      to quantify CO(2) sensitivity in recently detoxified alcohol-dependent
      individuals and never alcohol-disordered individuals who are social drinkers. We
      found that the alcoholic group exhibited significantly greater CO(2) sensitivity
      than did controls in response to both challenges. Indirect evidence of chronic HV
      was also obtained. These findings implicate the effect of chronic alcohol use on
      CNS-based CO(2) sensitivity in heightening the vulnerability to disturbing
      anxiety symptoms and syndromes exhibited by alcoholic individuals. Future work
      must verify that pathological drinking actually causes the dysregulated
      respiratory responding observed in this study as is inferred in our conclusions.

PMID- 15033215
TI  - The role of anxiety level, coping styles, and cycle phase in menstrual distress.
AB  - Using three samples, researchers investigated the relation between various
      anxiety levels, coping strategy use, and menstrual cycle phase to menstrual
      distress. In Studies 1 and 2, women low in anxiety sensitivity used more
      acceptance coping strategies and women high in anxiety sensitivity reported using
      more maladaptive coping strategies. In Study 2, women with medium anxiety
      sensitivity reported similar coping strategies to women low in anxiety. Menstrual
      cycle phase did not differentially affect coping strategy use in women varying in
      anxiety sensitivity levels in Studies 1 and 2. In addition to depressed mood
      emerging as a significant predictor of premenstrual distress in these two studies
      for all participants, avoidance coping for women high in anxiety sensitivity and
      problem-focused coping for women low in anxiety sensitivity were also significant
      predictors of premenstrual distress. In Study 3, during the premenstrual phase,
      women with panic disorder, compared to controls, reported using more avoidance
      coping whereas controls reported used more active coping and seeking social
      support for emotional and instrumental reasons. Results are discussed within a
      continuity model from high anxiety sensitivity to anxiety disorder for
      maladaptive coping and menstrual distress.

PMID- 15033216
TI  - Panic following trauma: the etiology of acute posttraumatic arousal.
AB  - Two studies examined the contributing factors for panic symptoms following
      trauma. In Study 1, survivors of sexual and nonsexual assaults (N=105) were
      assessed at 2 weeks postcrime. Prior trauma, psychiatric history, crime
      characteristics, and peritraumatic dissociation were assessed. Posttraumatic
      panic was modestly predicted by childhood sexual abuse (CSA) experiences, a
      history of Anxiety and Depression, and peritraumatic dissociation. Childhood
      physical abuse (CPA), Adult Victimization, crime variables, and a prior history
      of Substance Use disorders and posttraumatic stress disorder (PTSD) were not
      implicated. In Study 2, the role of peritraumatic panic in predicting later
      arousal was also examined in a similar sample who were assessed within 6 weeks of
      their trauma (N=93). Presence of significant arousal during trauma predicted
      frequency of posttrauma panic attacks, but not its severity. In contrast to Study
      1, prior history of PTSD, perception of life threat, and the index trauma being a
      sexual assault all predicted posttrauma panic, whereas prior trauma exposure and
      depression did not. These findings are discussed in terms of cognitive and
      arousal factors that may influence posttrauma panic.

PMID- 15033217
TI  - Effect of psychological treatment on cognitive bias in motor vehicle accident
      related Posttraumatic Stress Disorder.
AB  - The modified or "emotional" Stroop paradigm has been frequently employed in
      previous evaluations of information processing models of Posttraumatic Stress
      Disorder (PTSD) and other anxiety disorders. These studies have frequently
      documented an attentional bias to trauma-specific threatening stimuli in PTSD
      patients. However, the response of the Stroop color-naming interference effect to
      psychological treatment has yet to be tested in a trauma population. The present
      study evaluated the effects of three treatment conditions on the Stroop
      interference effect in motor vehicle accident (MVA) survivors with PTSD.
      Following treatment, participants were classified as either treatment responders
      or nonresponders. Participants named the color of three types of stimuli: MVA
      trauma-specific words, neutral words, and nonwords. Results showed that change in
      selective color-naming interference for trauma cues was unrelated to treatment
      response or modality at either posttreatment or follow-up. Findings cast doubt on
      the clinical utility of the modified Stroop test as a measure of treatment
      outcome in this population.

PMID- 15033218
TI  - Commentary on Butcher, Arbisi, Atlis, and McNulty (2003) on the Fake Bad Scale.

PMID- 15033219
TI  - Response to Butcher et al., The construct validity of the Lees-Haley Fake-Bad
      Scale...

PMID- 15033221
TI  - Assessing multitasking in children with ADHD using a modified Six Elements Test.
AB  - The study was designed to investigate whether children with Attention Deficit
      Hyperactivity Disorder (ADHD) demonstrate a deficit in multitasking, measured by
      their performance on a modified Six Elements Test designed for use with children
      (C-SET). The C-SET was administered to 38 children, aged 7-13. The subjects
      comprised two groups: an ADHD sample (n = 19) and a community control sample (n =
      19). The results show that the ADHD group performed significantly worse on the C
      SET, in that they attempted fewer tasks than the control group. However, they did
      not commit more rule breaks. These findings suggest that children with ADHD did
      not have problems with retrospective memory, as they were as able to remember the
      rules as the control group. Rather, the ADHD children appeared to have a specific
      deficit in monitoring their ongoing behaviors and generating useful strategies
      for task completion, as indicated by the decreased number of tasks attempted
      compared to the control group. The number of tasks tried on the C-SET correlated
      significantly with a measure of working memory, but not with a measure of
      response inhibition. C-SET total tasks tried also correlated with all subscales
      of the Conner's Parent Rating Scale-Revised (Short Version). The C-SET appears to
      be a useful measure of rule-governed multitasking behavior in children.

PMID- 15033222
TI  - Comparison of Predicted-difference, Simple-difference, and Premorbid-estimation
      methodologies for evaluating IQ and memory score discrepancies.
AB  - Discrepancies between WAIS-III and WMS-III scores for a group of 39 males and 48
      females with a history of TBI were examined using three methodologies: Predicted
      difference, Simple-difference, and Premorbid-estimation methods. Overall, the
      Predicted-difference method tended to classify the fewest individuals as impaired
      based on statistical rarity of discrepancies (11-16% classified as impaired),
      while the regression-based Premorbid method tended to classify the fewest
      individuals as impaired based on clinical rarity of discrepancies (4-8%
      classified as impaired). Degree of agreement is reported and was substantial. The
      only comparison between methods to reach statistical significance was the
      Predicted-difference method classifying subjects as impaired at a higher rate
      than other methods for Auditory Delayed memory index (Cochran's Q = 7.00, P <
      .05). Findings suggest a combination of estimates of premorbid functioning and
      regression-based predicted scores is optimal for interpreting IQ/memory score
      discrepancies. Clinical implications are discussed.

PMID- 15033223
TI  - The Houston Conference revisited.
AB  - This paper presents a review and critique of the Houston Conference on Specialty
      Education and Training in Clinical Neuropsychology, together with an informal
      summary of opinions of a number of neuropsychologists. Issues regarding the role
      of the Clinical Neuropsychology Synarchy (CNS) and the applicability of the
      conference policies are offered. Several deficiencies and limitations of the
      policy statement are discussed. An informal survey of neuropsychologists
      interested in the Houston Conference indicates rather different opinions
      concerning the training and education of neuropsychologists. It is our contention
      that the results of the Houston Conference can only be considered controversial
      at best and that there is still much diversity of opinion in the field regarding
      the proper training of neuropsychologists. We hope to stimulate further
      discussion and greater involvement of the profession before final criteria for
      education and training are developed and adopted.

PMID- 15033224
TI  - Cognitive factors in Postconcussion Syndrome symptom report.
AB  - Past studies suggest a variety of factors that influence the report of
      Postconcussion Syndrome (PCS) symptoms, including head injury, depression, pain,
      and subjective expectation. Participants included 190 undergraduates across 8
      groups chosen to examine the relative contribution of these factors, as well as
      treatment-seeking behavior, in the report of both current and past PCS symptoms.
      Depressed persons, depressed persons receiving treatment, and headache sufferers
      receiving treatment reported elevated rates of PCS symptoms when compared to
      controls. Five of the eight groups reported experiencing more current than past
      symptoms. Head-injured persons and headache sufferers underestimated premorbid
      symptom rates relative to the baseline of controls. These findings are consistent
      with the growing number of studies that suggest non-neurologic factors may be
      more closely related to PCS symptom report than head injury status and raise
      further concern regarding use of self-reported PCS symptoms in the diagnosis of
      head injury.

PMID- 15033225
TI  - Is it bigger than a breadbox? Performance of patients with prefrontal lesions on
      a new executive function test.
AB  - Executive deficits of problem solving and concept formation have been associated
      with frontal lobe dysfunction. Here we describe a new clinical test of concept
      formation based on the parlor game, Twenty Questions. The Twenty Questions Test
      requires examinees to ask the fewest number of yes/no questions possible in order
      to identify a target item from an array of 30 line drawings. The items belong to
      a number of categories and subcategories that exist in a hierarchical, semantic
      structure. Patients with focal prefrontal lesions asked significantly more
      questions than controls in their attempt to guess the target items and sometimes
      exhausted the 20-question limit. Qualitative analyses revealed that patients
      tended to use ineffective categorization strategies, for example, relying
      exclusively on questions that referred to single items. Taken together with
      previous findings, we conclude that prefrontal cortex supports the on-line
      organization and conceptualization of category exemplars in concept-formation
      tasks.

PMID- 15033226
TI  - Normative data and reliability for a Spanish version of the verbal Selective
      Reminding Test.
AB  - The purpose of this paper was to extend the use of the verbal Selective Reminding
      Test to the Spanish-speaking population. Since valid and reliable tests, with
      appropriate norms are essential for an adequate assessment of cognitive
      functioning, in this study we provide normative data collected from 329 Spanish
      speaking individuals for a Spanish version of the test. Age, gender and education
      effects were analyzed. In addition, the reliability of the test was also
      investigated. The adequacy of these norms to people from other Spanish-speaking
      countries is discussed. In addition to the measures typically reported, we have
      included three new indices.

PMID- 15033227
TI  - Persistence of cognitive effects after withdrawal from long-term benzodiazepine
      use: a meta-analysis.
AB  - Despite the widespread prescribing of benzodiazepines, uncertainty still
      surrounds the potential for cognitive impairment following their long-term use.
      Furthermore, the degree of recovery that may take place after withdrawal or the
      level of residual impairment, if any, that is maintained in long-term
      benzodiazepine users is also unclear. The current paper employed meta-analytic
      techniques to address two questions: (1) Does the cognitive function of long-term
      benzodiazepine users improve following withdrawal? (2) Are previous long-term
      benzodiazepine users still impaired at follow-up compared to controls or
      normative data? Results of the meta-analyses indicated that long-term
      benzodiazepine users do show recovery of function in many areas after withdrawal.
      However, there remains a significant impairment in most areas of cognition in
      comparison to controls or normative data. The findings of this study highlight
      the problems associated with long-term benzodiazepine therapy and suggest that
      previous benzodiazepine users would be likely to experience the benefit of
      improved cognitive functioning after withdrawal. However, the reviewed data did
      not support full restitution of function, at least in the first 6 months
      following cessation and suggest that there may be some permanent deficits or
      deficits that take longer than 6 months to completely recover.

PMID- 15033228
TI  - The Test of Memory Malingering (TOMM): normative data from cognitively intact,
      cognitively impaired, and elderly patients with dementia.
AB  - This research adds to the psychometric validation of the Test of Memory
      Malingering (TOMM) by providing data for samples of elderly patients who are
      cognitively intact, cognitively impaired (non-dementia), and with dementia.
      Subjects were 78 individuals referred for evaluation of memory complaints.
      Significant group differences emerged between the dementia group and the two
      other groups (normals and cognitively impaired), although the latter two did not
      differ from each other. One hundred percent of normals and 92.7% of the
      cognitively impaired group made fewer than five errors (the suggested cut-off) on
      Trial 2 or the Retention trial of the TOMM, yielding an overall correct
      classification rate of 94.7%. However, the rate of misclassification for persons
      with dementia was high whether using a cut-point score of five, eight, or ten
      errors. This investigation extends the validity and clinical utility of this
      instrument. Results suggest that the TOMM is an useful index for detecting the
      malingering of memory deficits, even in patients with cognitive impairment, but
      only when dementia can be ruled out.

PMID- 15033229
TI  - The role of histidine residues conserved in the putative ATP-binding region of
      macrolide 2'-phosphotransferase II.
AB  - Macrolide 2'-phosphotransferase (MPH(2')) catalyzes the transfer of the gamma
      phosphate of ATP to the 2'-hydroxyl group of macrolide antibiotics. In this
      study, H198 and H205, conserved in the ATP-binding region motif 1 in the putative
      amino acid sequence of MPH(2')II, were replaced by Ala to investigate their role.
      H205 was also subsequently replaced by Asn. H198A and H205N mutant enzymes
      retained more than 50% of the specific activity of the original enzyme to
      substrate oleandomycin. On the other hand, the specific activity of the H205A
      mutant enzyme was reduced to less than 1% of that of the wild enzyme. The results
      suggested that H205 is crucial for maintaining the catalytic activity of
      MPH(2')II, and Asn can substitute for His at this position.

PMID- 15033230
TI  - Ultra-violet resonance Raman spectroscopy for the rapid discrimination of urinary
      tract infection bacteria.
AB  - The ability to identify pathogenic organisms rapidly provides significant
      benefits to clinicians; in particular, with respect to best prescription
      practices and tracking of recurrent infections. Conventional bioassays require 3
      5 days before identification of an organism can be made, thus compromising the
      effectiveness with which patients can be treated for bacterial infections. We
      analysed 20 clinical isolates of urinary tract infections (UTI) by ultra-violet
      resonance Raman (UVRR) spectroscopy, utilising 244 nm excitation delivering
      approximately 0.1 mW laser power at the sample, with typical spectral collection
      times of 120 s. UVRR results in resonance-enhanced Raman signals for certain
      chromophoric segments of macromolecules, intensifying those selected bands above
      what would otherwise be observed for a normal Raman experiment. Utilising the
      whole-organism 'fingerprints' obtained by UVRR we were able to discriminate
      successfully between UTI pathogens using chemometric cluster analyses. This work
      demonstrates significant improvements in the speed with which spectra can be
      obtained by Raman spectroscopic techniques for the discrimination of clinical
      bacterial samples.

PMID- 15033231
TI  - The C-terminal antibody binding domain of Candida albicans mp58 represents a
      protective epitope during candidiasis.
AB  - The 58-kDa surface mannoprotein of Candida albicans (mp58) elicits strong
      antibody responses during infection. Epitope mapping with sera from patients with
      candidiasis and control individuals indicated the presence of multiple IgG
      reactive continuous epitopes on the protein, expanding both the amino- and
      carboxy-terminal domains and several internal regions. These immunoreactive
      regions were similar to the ones previously identified using sera from immunized
      animals. Two of the epitopic regions (including the C-terminal domain) showed
      increased reactivity with antibodies present in sera from patients with
      candidiasis as compared to control individuals. Patients who survived the
      infection displayed increased antibody reactivity towards the C-terminal epitope
      as compared to those succumbing to candidiasis. A monoclonal antibody directed
      towards this epitopic region conferred protection in serum therapy experiments in
      a murine model of hematogenously disseminated candidiasis. Together, these
      observations indicate the carboxy-terminal antibody binding domain of C. albicans
      mp58 represents a protective epitope during candidiasis.

PMID- 15033232
TI  - Quantification of toxin-encoding mRNA from Clostridium botulinum type E in media
      containing sorbic acid or sodium nitrite by competitive RT-PCR.
AB  - Competitive reverse transcription polymerase chain reaction (cRT-PCR) was used to
      quantify the toxin-encoding mRNA production of a Clostridium botulinum type E
      strain in media containing either sorbic acid or sodium nitrite. A 10-fold
      reduction in toxin mRNA production and a 25-fold reduction in the proportion of
      toxin mRNA to total RNA, was estimated when either 1 mg ml(-1) sorbic acid or 100
      microg ml(-1) sodium nitrite were added to the medium at pH 7.0.

PMID- 15033233
TI  - Phylogenetic diversity of sulfate-reducing prokaryotes in active deep-sea
      hydrothermal vent chimney structures.
AB  - The phylogenetic diversity of sulfate-reducing prokaryotes occurring in active
      deep-sea hydrothermal vent chimney structures was characterized based on the
      deduced amino acid sequence analysis of the polymerase chain reaction-amplified
      dissimilatory sulfite reductase (DSR) gene. The DSR genes were successfully
      amplified from microbial assemblages of the chimney structures, derived from
      three geographically and geologically distinct deep-sea hydrothermal systems in
      the Central Indian Ridge (CIR), in the Izu-Bonin Arc (IBA), and the Okinawa
      Trough (OT), respectively. Phylogenetic analysis revealed seven major
      phylogenetic groups. More than half of the clones from the CIR chimney structure
      were related to DSR amino acid sequences of the hyperthermophilic archaeal
      members of the genus Archaeoglobus, and those of environmental DSR clones within
      the class Thermodesulfobacteria. From the OT chimney structure, a different group
      was obtained, which comprised a novel, deep lineage associated with the DSRs of
      the thermophilic sulfate-reducing bacterium Thermodesulfovibrio. Most of the DSR
      clones from the IBA chimney structure were phylogenetically associated with the
      delta-proteobacterial sulfate-reducing bacteria represented by the genus
      Desulfobulbus. Sequence analysis of DSR clones demonstrated a diverse sulfate
      reducing prokaryotic community in the active deep-sea hydrothermal chimney
      structures.

PMID- 15033234
TI  - DGGE method for analyzing 16S rDNA of methanogenic archaeal community in paddy
      field soil.
AB  - A denaturing gradient gel electrophoresis (DGGE) method for analyzing 16S rDNA of
      methanogenic archaeal community in paddy field soil is presented. Five specific
      primers for 16S rDNA of methanogenic archaea, which were modified from the
      primers for archaea, were first evaluated by polymerase chain reaction and DGGE
      using genomic DNAs of 13 pure culture strains of methanogenic archaea. The DGGE
      analysis was possible with two primer pairs (0348aF-GC and 0691R; 0357F-GC and
      0691R) of the five pairs tested although 16S rDNA of some non-methanogenic
      archaea was amplified with 0348aF-GC and 0691R. These two primer pairs were
      further evaluated for use in analysis of methanogenic archaeal community in
      Japanese paddy field soil. Good separation and quality of patterns were obtained
      in DGGE analysis with both primer pairs. A total of 41 DNA fragments were excised
      from the DGGE gels and their sequences were determined. All fragments belonged to
      methanogenic archaea. These results indicate that the procedure of DGGE analysis
      with the primer pair 0357F-GC and 0691R is suitable for investigating
      methanogenic archaeal community in paddy field soil.

PMID- 15033235
TI  - Annotation of the pRhico plasmid of Azospirillum brasilense reveals its role in
      determining the outer surface composition.
AB  - The plant growth-promoting soil bacterium Azospirillum brasilense enhances growth
      of economically important crops, such as wheat, corn and rice. In order to
      improve plant growth, a close bacterial association with the plant roots is
      needed. Genes encoded on a 90-MDa plasmid, denoted pRhico plasmid, present in A.
      brasilense Sp7, play an important role in plant root interaction. Sequencing,
      annotation and in silico analysis of this 90-MDa plasmid revealed the presence of
      a large collection of genes encoding enzymes involved in surface polysaccharide
      biosynthesis. Analysis of the 90-MDa plasmid genome provided evidence for its
      essential role in the viability of the bacterial cell.

PMID- 15033236
TI  - Optimization of a two-plasmid system for the identification of promoters
      recognized by RNA polymerase containing Staphylococcus aureus alternative sigma
      factor sigmaB.
AB  - We optimized a previously established two-plasmid system for the identification
      of Staphylococcus aureus promoters that are recognized by the alternative
      transcription factor sigma(B). The method allowed the identification of 18 S.
      aureus sigma(B)-dependent promoters, 12 of which are reported here for the first
      time to be sigma(B)-dependent. S1-nuclease mapping of the respective
      transcriptional start points revealed that all the promoters contained sequences
      exhibiting high similarity to the consensus sequence of Bacillus subtilis
      sigma(B)-dependent promoters. The promoters governed expression of genes encoding
      proteins proposed to be involved in various cellular functions, including the
      stress response genes and virulence-associated clfA gene for fibrinogen-binding
      clumping factor. Comparison of the nucleotide sequences upstream of the
      identified transcription start points identified a sigma(B) consensus promoter
      (GttTaa-N(12-15)-gGGTAt) that is highly homologous to that of sigma(B) of B.
      subtilis.

PMID- 15033237
TI  - A 43-kDa protein of Treponema denticola is essential for dentilisin activity.
AB  - A protease of Treponema denticola, dentilisin, is thought to be part of a complex
      with 43- and 38-kDa proteins. A sequence encoding a 43-kDa protein was located in
      the 3' region of the prcA gene upstream of the dentilisin gene (prtP). The 43-kDa
      protein was apparently generated from digestion of PrcA. To clarify the function
      of the protein, we constructed a mutant of the 43-kDa protein following
      homologous recombination. The mutant lacked detectable dentilisin activity.
      Immunoblot analysis demonstrated that the dentilisin protein was degraded in the
      mutant. The results of real-time polymerase chain reaction suggested that prtP
      mRNA expression in the mutant was somewhat decreased compared with the wild-type
      strain. These data suggest that the 43-kDa protein is involved in the
      stabilization of the dentilisin protein.

PMID- 15033238
TI  - Identification of emetic toxin producing Bacillus cereus strains by a novel
      molecular assay.
AB  - Bacillus cereus causes two types of gastrointestinal diseases: emesis and
      diarrhea. The emetic type of the disease is attributed to the heat-stable
      depsipeptide cereulide and symptoms resemble Staphylococcus aureus intoxication,
      but there is no rapid method available to detect B. cereus strains causing this
      type of disease. In this study, a polymerase chain reaction (PCR) fragment of
      unknown function was identified, which was shown to be specific for emetic toxin
      producing strains of B. cereus. The sequence of this amplicon was determined and
      a PCR assay was developed on this basis. One hundred B. cereus isolates obtained
      from different food poisoning outbreaks and diverse food sources from various
      geographical locations and 29 strains from other species belonging to the B.
      cereus group were tested by this assay. In addition, 49 non-B. cereus group
      strains, with special emphasis on food pathogens, were used to show that the
      assay is specific for emetic toxin producing B. cereus strains. The presented PCR
      assay is the first molecular tool for the rapid detection of emetic toxin
      producing B. cereus strains.

PMID- 15033239
TI  - Identification and characterization of pltZ, a gene involved in the repression of
      pyoluteorin biosynthesis in Pseudomonas sp. M18.
AB  - A new regulator gene named pltZ, which is located downstream of the plt gene
      cluster in the genome of Pseudomonas sp. M18, was identified, sequenced and
      characterized in this report. The deduced amino acid sequence of PltZ shares
      significant homology with other bacterial regulators in the TetR family. The
      chromosomal pltZ disruption mutant gave rise to 4.4-fold enhancement of
      pyoluteorin biosynthesis but did not exert significant influence on the
      accumulation of phenazine-1-carboxylic acid compared with the wild-type M18. The
      negative regulation of pltZ on pyoluteorin biosynthesis was further confirmed by
      multiplied pltZ gene dosage experiments and pltA'-'lacZ translational fusion
      analyses.

PMID- 15033240
TI  - Evidence for 1,8-dihydroxynaphthalene melanin in three halophilic black yeasts
      grown under saline and non-saline conditions.
AB  - The ascomycetous black yeasts Hortaea werneckii, Phaeotheca triangularis, and
      Trimmatostroma salinum are halophilic fungi that inhabit hypersaline water of
      solar salterns. They are characterized by slow, meristematic growth and very
      thick, darkly pigmented cell walls. The dark pigment, generally thought to be
      melanin, is consistently present in their cell walls when they grow under saline
      and non-saline conditions. We used the inhibitor tricyclazole to test the fungi
      in this study for the presence of 1,8-dihydroxynaphthalene (DHN)-melanin
      biosynthesis, since fungal melanins reportedly are derived either from DHN,
      tyrosine via 3,4-dihydroxyphenylalanine, gamma-glutaminyl-3,4-dihydroxybenzene,
      or catechol. Tricyclazole-treated cultures of the fungi were reddish-brown in
      color and contained typical intermediates of the DHN-melanin pathway, as
      demonstrated by high-performance liquid chromatography. This investigation showed
      that the three fungi synthesized DHN-melanin under saline and non-saline growth
      conditions.

PMID- 15033241
TI  - Glycerol metabolism in the extremely halophilic bacterium Salinibacter ruber.
AB  - Growth of Salinibacter ruber, a red, extremely halophilic bacterium
      phylogenetically affiliated with the Flavobacterium/Cytophaga branch of the
      domain Bacteria, is stimulated by glycerol. In contrast to glucose consumption,
      which starts only after more easily degradable substrates present in yeast
      extract have been depleted, glycerol is consumed during the earliest growth
      phases. When U-(14)C-labeled glycerol was added to the culture, up to 25% of the
      radioactivity was incorporated by the cells. Glycerol kinase activity was
      detected only in cells grown in the presence of glycerol (up to 90 nmol mg
      protein(-1) min(-1)). This enzyme functioned over salt concentrations from 0.6 to
      2.8 M KCl. No significant activity of NAD-dependent glycerol dehydrogenase was
      found. It is suggested that Salinibacter may use glycerol as one of its principal
      substrates in its habitat, the saltern crystallizer ponds.

PMID- 15033243
TI  - Which morphological forms of the fungus Aureobasidium pullulans are responsible
      for pullulan production?
AB  - Attempts were made to clarify the precise location and possible site of
      production of the alpha-glucan pullulan in different morphological forms of the
      fungus Aureobasidium pullulans. Gold-conjugated pullulanase was used as the
      specific probe for this purpose. No cell wall pullulan-like material was detected
      by transmission electron microscopy (TEM) in any morphological form of this
      fungus, although intracellular electron transparent material bound this probe.
      When silver enhancement of this gold-conjugated pullulanase probe was used, the
      data strongly suggested that only swollen cells and chlamydospores, and neither
      hyphae nor unicellular blastospores, often held responsible for pullulan
      formation, appeared to produce pullulan-like material.

PMID- 15033242
TI  - The role of a bifunctional catalase-peroxidase KatA in protection of
      Agrobacterium tumefaciens from menadione toxicity.
AB  - Agrobacterium tumefaciens is an aerobic plant pathogenic bacterium that is
      exposed to reactive oxygen species produced either as by-products of aerobic
      metabolism or by the defense systems of host plants. The physiological function
      of the bifunctional catalase-peroxidase (KatA) in the protection of A.
      tumefaciens from reactive oxygen species other than H(2)O(2) was evaluated in the
      katA mutant (PB102). Unexpectedly, PB102 was highly sensitive to the superoxide
      generator menadione. The expression of katA from a plasmid vector complemented
      the menadione-hypersensitive phenotype. A. tumefaciens possesses an additional
      catalase gene, a monofunctional catalase encoded by catE. Neither inactivation
      nor high-level expression of the catE gene altered the menadione resistance
      level. Moreover, heterologous expression of the catalase-peroxidase-encoding gene
      katG from Burkholderia pseudomallei, but not the monofunctional catalase gene
      katE from Xanthomonas campestris could restore normal levels of menadione
      resistance to PB102. A recent observation suggests that the menadione resistance
      phenotype involves increased activities of organic peroxide-metabolizing enzymes.
      Heterologous expression of X. campestris alkyl hydroperoxide reductase from a
      plasmid vector failed to complement the menadione-sensitive phenotype of PB102.
      The level of menadione resistance shows a direct correlation with the level of
      peroxidase activity of KatA. This is a novel role for KatA and suggests that
      resistance to menadione toxicity is mediated by a new, and as yet unknown,
      mechanism in A. tumefaciens.

PMID- 15033244
TI  - Angiotensin receptor blockers and heart failure: still CHARMing after VALIANT?

PMID- 15033245
TI  - Sympathetic activation and sub-clinical inflammation: a new combination to
      identify high risk subjects.

PMID- 15033246
TI  - Patent foramen ovale: the jury is still out.

PMID- 15033247
TI  - Increased heart rate and reduced heart-rate variability are associated with
      subclinical inflammation in middle-aged and elderly subjects with no apparent
      heart disease.
AB  - AIM: Elevation of inflammation markers, high heart rate, and reduced heart-rate
      variability are all strong markers of mortality in a broad spectrum of patients.
      The association between these markers has not been clarified thoroughly. We
      investigated the associations between markers of inflammation, heart rate, and
      heart-rate variability. METHODS AND RESULTS: Six hundred and forty-three healthy
      men and women between 55 and 75 years of age and with no prior history of
      cardiovascular disease or stroke were included in the study. The baseline study
      included a physical examination, fasting laboratory tests, and 24-h ambulatory
      ECG monitoring. We selected the time-domain components of heart-rate variability
      for further analyses. C-reactive protein concentration and white blood cell count
      were selected as markers of inflammation. After identifying parameters related to
      measures of heart-rate variability, we used regression analyses to evaluate
      independent associations. Heart-rate variability, as measured by the standard
      deviation of the time between normal-to-normal complexes or the standard
      deviation of the average of normal-to-normal intervals for each 5-min period, was
      negatively associated with smoking, C-reactive protein, white blood cell count,
      blood sugar and triglyceride concentration, female gender, and diabetes. In
      contrast, physical activity was strongly associated with higher heart-rate
      variability. In multivariate regression analyses, increased heart-rate and
      reduced heart-rate variability were significantly and independently related to
      white blood cell count or C-reactive protein concentration. CONCLUSION: Increased
      heart rate and reduced heart-rate variability are associated with subclinical
      inflammation in healthy middle-aged and elderly subjects. The increased mortality
      that has been reported in these settings may thus have a common aetiology. An
      autonomic imbalance in favour of the sympathetic system may interact with
      inflammatory processes to play a more important role in the process of
      atherosclerosis than previously thought.

PMID- 15033248
TI  - Assessment of endothelial damage in atherosclerotic vascular disease by
      quantification of circulating endothelial cells. Relationship with von Willebrand
      factor and tissue factor.
AB  - BACKGROUND: Increased numbers of CD146-defined circulating endothelial cells
      (CECs), as are present in the peripheral blood of patients suffering acute
      coronary syndromes, imply injury to the endothelium. Endothelial damage can also
      be assessed by the measurement of plasma levels of von Willebrand factor (vWf).
      Increased levels of procoagulant plasma tissue factor (TF), arising from
      monocytes/macrophages and endothelial cells, is present in atherosclerosis. We
      hypothesised increased CECs in patients with ischaemic rest pain (IRP) of the
      lower limb due to peripheral atherosclerosis and comparable to that seen in
      patients with acute myocardial infarction (AMI), when compared to patients with
      intermittent claudication (IC) or healthy controls that would correlate with vWf
      and TF. PATIENTS AND METHODS: We recruited 20 patients in each of four groups:
      (i) IRP of the lower limb; (ii) AMI; (iii) 'stable' IC; and (iv) healthy
      controls. CD146-expressing CECs were measured by immumomagnetic separation and
      counting under a fluorescence microscope; plasma vWf and TF by ELISA. RESULTS: In
      IRP, median (IQR) CEC levels were 3.5 (2.0-5.8) cells/ml, in IC were 1.1 (0.6
      2.9) cells/ml, and in healthy controls were 1.0 (0.5-1.7) cells/ml (p<0.001). The
      levels of vWf (p=0.034) and TF (p=0.007) were also significantly different
      between the groups, with the highest levels in patients with IRP. Levels of CECs
      correlated with vWf (rs=0.4, p=0.002) and TF ( rs=0.296, p=0.021 ). In AMI, CEC
      levels were higher than those in IRP at 4.9 (3.6-8.4) cells/ml (p=0.0385).
      CONCLUSION: This study demonstrates evidence of direct endothelial cell injury
      (i.e. raised CECs) in patients with IRP that correlated with vWf and TF, but that
      this is less severe than in AMI.

PMID- 15033249
TI  - Cardiac angiotensin II receptors as predictors of transplant coronary artery
      disease following heart transplantation.
AB  - AIMS: We tested the hypothesis that cardiac angiotensin II (Ang II) receptor gene
      transcription may predict the development of transplant coronary artery disease
      (TCAD) following heart transplantation. METHODS AND RESULTS: We examined the gene
      transcripts of Ang II type 1 (AT1R) and type 2 receptors (AT2R) in endomyocardial
      biopsy specimens from 50 heart transplant recipients. The progression of TCAD was
      measured as change in maximal intimal thickness (CMIT) and change in plaque
      volume (CPV) by intravascular ultrasound (IVUS) examinations from baseline to one
      year after transplantation. The development of transplant vasculopathy was
      defined as a CMIT of > or = 0.3 mm over one year. The level of AT(1)R mRNA was
      associated with that of AT2R in transplanted hearts (regression coefficient=1.77,
      95% CI 0.85-2.89, p<0.0001). AT1R and AT2R gene transcripts were univariate
      predictors of CMIT (AT1R: regression coefficient 0.10, 95% CI 0.06-0.14,
      p<0.0001; AT2R: regression coefficient 0.28, 95% CI 0.17-0.40, p<0.0001 ) or CPV
      (AT1R: regression coefficient 0.41, 95% CI 0.17-0.65, p<0.0001 ; AT2R: regression
      coefficient 1.25, 95% CI 0.49-2.01, p=0.002 ). By one year, 21 (46%) transplant
      recipients showed evidence of transplant vasculopathy and the rest did not. The
      vasculopathic group demonstrated a higher level of expression of cardiac AT1R
      than the non-vasculopathic group (3.7+/-2.9 vs 1.6+/-1.7 folds; p=0.006). The
      level of AT(1)R mRNA in transplanted heart was identified as a discriminator that
      predicted the development of transplant vasculopathy with a sensitivity of 75%
      and specificity of 83%. CONCLUSIONS: Cardiac Ang II receptor gene transcripts are
      associated with the progression of TCAD following heart transplantation. Only
      AT1R gene transcripts predicted the development of transplant vasculopathy in
      this preliminary study. These findings potentially support a role of Ang II
      receptors in the progression of TCAD following cardiac transplantation.

PMID- 15033250
TI  - Association between the low activity genotype of catechol-O-methyltransferase and
      myocardial infarction in a hypertensive population.
AB  - AIM: Estrogens regulate several biological processes involved in the pathogenesis
      of myocardial infarction. Catechol-O-methyltransferase (COMT) is a key enzyme in
      the degradation of estrogens. There is a functional polymorphism in the COMT gene
      (Val158Met), affecting the activity of the enzyme. We investigated if the low
      activity genotype of COMT is associated with an altered risk of myocardial
      infarction. METHODS AND RESULTS: In a prospectively followed hypertensive cohort
      we identified 174 patients who suffered a myocardial infarction during the study
      and compared them to 348 controls from the same cohort. The COMT polymorphism and
      serum levels of sex hormones were analysed. Patients homozygous for the low
      activity COMT genotype had a decreased risk of myocardial infarction compared to
      those with the high activity genotype, odds ratio 0.65 (95% CI 0.44-0.97, p=0.033
      ). The protective effect of the low activity genotype was most evident among
      older patients (> 58 years of age), odds ratio 0.43 (95% CI 0.23-0.79, p=0.006 ).
      Serum levels of estradiol were increased ( p=0.006 ) in males with the low
      activity genotype. CONCLUSIONS: Our findings suggest that the low activity COMT
      genotype is protective against myocardial infarction. One may speculate that the
      altered estrogen status could be involved in this effect.

PMID- 15033251
TI  - The effect of ITF-1697 on reperfusion in patients undergoing primary angioplasty.
      Safety and efficacy of a novel tetrapeptide, ITF-1697.
AB  - AIM: ITF-1697 is a C-reactive protein-derived tetrapeptide that, based on pre
      clinical studies, is thought to reduce reperfusion injury. We performed a dose
      finding study to assess safety, preliminary efficacy and clinical outcome of
      prolonged i.v. infusion of ITF-1697 in patients with an acute myocardial
      infarction (AMI) who were eligible for percutaneous coronary intervention (PCI).
      METHODS AND RESULTS: This was a multicentre dose-finding study that was
      randomised, double blind, and placebo-controlled. Four hundred and two patients
      were enrolled. Intravenous infusion of four dosages of ITF-1697 (0.1, 0.5, 1.0 or
      2.0 microg/kg/min) or placebo was started before PCI and continued for 24 h.
      After interim analysis of data from 242 patients the study continued with the 0.1
      and 1.0 microg/kg/min ITF-1697 regimes. Analysis did not raise any safety
      concerns. Post-procedure perfusion, assessed by TIMI flow, corrected TIMI frame
      count, blushgrade and ST-segment resolution, was similar for the placebo, 0.1 and
      1.0 microg/kg/min regimes. Furthermore, the results showed no differences between
      the treatment regimes in enzymatic infarct size or clinical outcome up to 30
      days. CONCLUSION: ITF-1697 was well tolerated. However, neither a dose-relation
      nor improvement of perfusion, clinical outcome or reduction of myocardial damage
      could be demonstrated with ITF-1697 during and after primary PCI for AMI.

PMID- 15033252
TI  - C-reactive protein elevation and disease activity in patients with coronary
      artery disease.
AB  - AIMS: We sought to assess (1) whether C-reactive protein (CRP) is an independent
      predictor of future cardiovascular events after adjustment for coronary artery
      disease (CAD) severity and (2) whether CRP levels correlate with number of
      angiographically complex coronary artery stenosis. METHODS AND RESULTS: We
      studied 825 consecutive angina patients (mean age 63+/-10 years, 74% men), 700
      with chronic stable angina (CSA) and 125 with acute coronary syndromes without ST
      segment elevation (ACS). The composite endpoint of non-fatal acute myocardial
      infarction, hospital admission with class IIIb unstable angina and cardiac death
      was assessed at one year follow-up. Hs-CRP level was higher in CSA patients with
      the combined end-point (P=0.03) after adjustment for number of diseased coronary
      arteries. Hs-CRP was also significantly higher in patients with ACS compared to
      CSA ( P=0.004) and correlated with number of complex angiographic stenoses
      (r=0.36, P=0.01). Hs-CRP was also increased in patients with NYHA functional
      class III or IV compared to those in class I or II (p<0.0001). CONCLUSIONS: CRP
      levels predict future cardiovascular events independently of CAD severity and
      correlate with number of angiographically complex coronary artery stenosis in
      patients with ACS. Thus, CRP levels are a marker of atheromatous plaque
      vulnerability and CAD activity.

PMID- 15033253
TI  - Smoking decreases the duration of life lived with and without cardiovascular
      disease: a life course analysis of the Framingham Heart Study.
AB  - AIMS: To compare the burden of cardiovascular disease in terms of lifetime risk
      and life years lived with disease between smokers and non-smokers. METHODS AND
      RESULTS: We constructed multi-state life tables describing transitions through
      various cardiovascular diseases for 4723 smokers and non-smokers observed during
      20 biannual observations in the Original Framingham Heart Study. Non-smokers live
      8.66 (95% CI 7.61-9.63) (men) and 7.59 (95% CI 6.33-8.92) (women) years longer
      than smokers and more years free of cardiovascular disease: 6.22 (95% CI 5.09
      7.30) years for males and 4.93 (95% CI 3.54-6.29) for females. But non-smokers
      spend more years with cardiovascular disease over the life course: 2.43 (95% CI
      1.72-3.16) years for males and 2.66 (95% CI 1.87-3.38) years for females. The
      risk of cardiovascular disease before age 70 is higher among smokers, but over
      the entire lifecourse male non-smokers have higher risks of coronary heart
      disease, myocardial infarction, stroke and congestive heart failure, and female
      non-smokers have higher risks of coronary heart disease and congestive heart
      failure. CONCLUSION: Smoking, by shortening life, decreases both the probability
      and duration of cardiovascular disease throughout the life course. Non-smokers
      live many years longer and longer free of cardiovascular disease than smokers,
      but at the end of their life non-smokers will have lived longer with
      cardiovascular disease.

PMID- 15033254
TI  - N-terminal proatrial natriuretic peptide predicts two-year remodelling in
      patients with acute transmural myocardial infarction.
AB  - AIMS: To evaluate whether baseline N-terminal proatrial natriuretic peptide (Nt
      proANP) or Doppler echocardiographic parameters could predict two-year left
      ventricular remodelling after acute myocardial infarction in patients without
      heart failure. METHODS AND RESULTS: Seventy-one patients were followed with
      Doppler echocardiographic examinations at baseline, 3 months, 1 and 2 years, and
      Nt-proANP was measured at baseline and 3 months. After 2 years there was a
      significant increase in end-diastolic volume index of 11% ( p=0.006 ) and end
      systolic volume index of 14% ( p=0.03 ), and no change in ejection fraction. This
      remodelling was confined to 12 patients (17%) with a significant increase in end
      diastolic volume index above 20 ml/m(2). Baseline Nt-proANP ( p<0.0005 ), 3-month
      changes in end-diastolic volume index ( p=0.007 ), and 3-month E/A ratio (
      p=0.014 ) were independent positive predictors for two-year changes in end
      diastolic volume index. Two-year dilatation above 20 ml/m2 was predicted by
      baseline Nt-proANP (p=0.014) and maximal velocity of systolic pulmonary venous
      flow ( p=0.034 ). CONCLUSION: Seventeen percent of patients with transmural
      myocardial infarction and no baseline heart failure experienced a significant
      left ventricular dilatation at 2 years, and this was best predicted by baseline
      Nt-proANP. Unstructured abstract Seventy-one patients with acute myocardial
      infarction and no heart failure were followed for two years in an observational
      Doppler echocardiographic study. There was a significant increase in end
      diastolic volume index of 11% ( p=0.006 ) and end-systolic volume index of 14%
      (p=0.03), but no change in ejection fraction after two years. Nt-proANP was the
      strongest independent predictor of two-year changes in end-diastolic volume index
      and of an increase in end-diastolic volume index above 20 ml/m2 after two years.

PMID- 15033255
TI  - Transcatheter closure of patent foramen ovale (PFO) in patients with paradoxical
      embolism. Periprocedural safety and mid-term follow-up results of three different
      device occluder systems.
AB  - AIMS: Interventional PFO closure has previously been reported to reduce the risk
      for recurrent thromboembolic events. The aim of the present study was to evaluate
      three different occluder systems in respect to (a) the safety and practicability
      and (b) the mid-term risk of recurrent thromboembolic events. METHODS AND
      RESULTS: Since 08/98 until 12/02, 307 consecutive patients (138 women, 169 men,
      mean age 43 years) with a symptomatic PFO underwent PFO closure using the PFO
      Star ( n=177), Amplatzer PFO occluder ( n=69) and CardioSeal/Starflex ( n=61 ).
      Implantation was successful in all patients. Periinterventional complications
      occurred in 9 patients (5x ST-segment elevations, 1x arteriovenous fistula, 2x
      TIA, 1x device dislodgement). All of them were reversible and not associated with
      a specific type of device. During the median follow-up of 24 months (25/75th
      percentiles: 14/37 months), the annual risk of recurrence was 0.6% for TIA, 0%
      for stroke and 0.2% for peripheral embolism (PFO-Star: 0.8%, Amplatzer PFO
      occluder: 0.7% and CardioSeal/Starflex: 1.0%). CONCLUSION: Interventional PFO
      closure appears to be safe and a promising technique in symptomatic PFO patients
      with a low incidence of periinterventional complications and recurrent
      thromboembolic events using three different devices (PFO-Star, Amplatzer PFO
      occluder or the CardioSeal/Starflex).

PMID- 15033256
TI  - Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute
      and mid-term effects.
AB  - AIM: The treatment of patients with pulmonary arterial hypertension remains a
      challenge. We set out to investigate the use of sildenafil, a selective inhibitor
      of phosphodiesterase type 5, in patients with this disease. METHODS AND RESULTS:
      Ten patients (8 females, mean age 34.5+/-3.3 years) with pulmonary hypertension
      underwent right heart catheterisation with vasodilator testing using incremental
      doses of intravenous sildenafil without adverse events. All patients were
      subsequently commenced on oral sildenafil 50 mg t.d.s. Nine patients had repeat
      right heart catheterisation 3 months after the commencement of oral therapy.
      There was a significant reduction in mean pulmonary artery pressure (from 55.8+/
      5.9 to 50.4+/-6.1 mmHg, p=0.038 ) and pulmonary vascular resistance (from 10.1+/
      1.7 to 8.6+/-1.5 Wood units, p=0.009 ), and an increase in cardiac output (from
      4.7+/-0.3 to 5.0+/-0.4 l/min, p=0.15 ). Furthermore, there was a significant
      increase in the 6-minute walk test, a mean of 112 m. In response to a quality-of
      life questionnaire, patients indicated marked clinical improvement on sildenafil.
      Sildenafil was discontinued in 1 patient due to a transient visual disturbance.
      The only patient previously awaiting transplantation was removed from the active
      transplantation list. CONCLUSIONS: Sildenafil is well tolerated in its
      intravenous and oral forms and appears to improve both pulmonary haemodynamics
      and the clinical status of patients with pulmonary hypertension after 3 months of
      oral therapy.

PMID- 15033258
TI  - Principles of prevention of cardiovascular disease.

PMID- 15033257
TI  - ESC-ERC recommendations for the use of automated external defibrillators (AEDs)
      in Europe.

PMID- 15033260
TI  - Assessing the effect of ACE inhibitors on exercise tolerance: a question of study
      design.

PMID- 15033262
TI  - Do statins really interfere with clopidogrel-induced platelet function?

PMID- 15033264
TI  - A bacterial gene homologous to ABC transporters protect Oenococcus oeni from
      ethanol and other stress factors in wine.
AB  - The wine lactic acid bacteria Oenococcus oeni has to cope with harsh
      environmental conditions including an acidic pH, a high alcoholic content, non
      optimal growth temperatures, and growth inhibitory compounds such as fatty acids,
      phenolic acids and tannins. We here describe characterisation and cloning of the
      O. oeni omrA gene encoding a protein belonging to the ATP-binding cassette
      superfamily of transporters. The OmrA protein displays the highest sequence
      similarity with the subfamily of ATP-dependent multidrug resistance (MDR)
      proteins, most notably the bacterial Lactococcus lactis LmrA homologue of the
      human MDR1 P-glycoprotein. The omrA gene proved to be a stress-responsive gene
      since its expression was increased at high temperature or under osmotic shock.
      The OmrA protein function was tested in Escherichia coli, and consistent with the
      omrA gene expression pattern, OmrA conferred protection to bacteria grown on a
      high salt medium. OmrA also triggered bacterial resistance to sodium laurate,
      wine and ethanol toxicity. The homologous LmrA protein featured the same stress
      protective pattern than OmrA when expressed in E. coli, and the contribution to
      resistance of both OmrA and LmrA transporters was decreased by verapamil, a well
      known inhibitor of the human MDR1 protein. Genes homologous to omrA were detected
      in other wine lactic acid bacteria, suggesting that this type of genes might
      constitute a well-conserved stress-protective molecular device.

PMID- 15033265
TI  - Listeria monocytogenes and listeriosis: a review of hazard characterisation for
      use in microbiological risk assessment of foods.
AB  - Considerable effort has been put into the application of quantitative
      microbiological risk assessment for Listeria monocytogenes, and data are
      available for England and Wales (probably more so than most other countries) on
      the adverse health effects, together with incidence data on different age and
      risk groups for human L. monocytogenes infections. This paper reviews aspects of
      Listeria and human listeriosis, especially from a public health perspective and
      provide hazard characterisation data, i.e. the qualitative and/or quantitative
      evaluation of the adverse health effect associated with the hazard, which is the
      relationship between exposure levels (dose) and frequency of illness. The
      majority of cases of human listeriosis are food-borne; however, the disease
      process is complex with multiple routes of infection. The dose-response
      relationship is poorly understood, and data from human volunteer studies are not
      available and would be unethical to produce. Data are available from a range of
      different animal and in vitro models, although these poorly mimic the natural
      disease process in route of infection, end point, host and history of prior
      exposure to the bacterium. Epidemiological data provide some information on
      infective doses and dose responses, but because of the characteristics of the
      disease (the hugely variable and potentially very long incubation periods, the
      low attack rates and the rarity of identification of specific food vehicles),
      this also provides limited data for calculation of dose responses. There is some,
      albeit limited, evidence for strain variation, but this is an area of
      considerable uncertainty despite great advances in the genetic basis of the
      virulence of this bacterium, and almost all strains seem capable of causing
      serious disease. A variety of mathematical approaches have been used to model
      dose responses. The review is written to provide a clinical and epidemiological
      background to the mathematically oriented, as well as to outline the mathematical
      approaches to those interested in food-borne infection.

PMID- 15033266
TI  - Diversity of enterovirus sequences detected in oysters by RT-heminested PCR.
AB  - Oysters harvested in western France, from five sites associated with outbreaks of
      food-borne norovirus gastroenteritis between February 2000 and March 2001, were
      assayed for enterovirus RNA by reverse transcriptase-heminested polymerase chain
      reaction (RT-heminested PCR). Forty percent (21/52) of shellfish samples (pool of
      seven oysters) were contaminated by enteroviruses. Infectious coxsackieviruses
      serotype A21 were isolated from three of these positive samples. Amplicons
      corresponding to 65 base sequences in the 5' untranslated region of the
      enteroviral genome were analyzed by direct sequencing. Interpretable results were
      obtained from 18 amplicons, but mixtures of sequences confused the results from 3
      samples. Sequences isolated from samples from the different sites were different
      but similarities were observed between sequences detected in shellfish from two
      sites at different dates. Sequences were also compared to sequences of human,
      bovine and porcine enteroviruses. Both human and animal origins of enterovirus
      contamination of shellfish seemed likely.

PMID- 15033267
TI  - Prevalence and characteristics of Shiga toxin-producing Escherichia coli,
      Salmonella spp. and Campylobacter spp. isolated from slaughtered sheep in
      Switzerland.
AB  - Caecum samples collected from 653 slaughtered sheep from two Swiss abattoirs were
      examined. The aim of this study was: (i) to determine the prevalence of Shiga
      toxin-producing Escherichia coli (STEC), Salmonella spp. and Campylobacter spp.;
      (ii) to further characterize isolated strains; and (iii) to discuss the results
      obtained with their relevance to food safety. The percentage of samples testing
      positive for STEC by a polymerase chain reaction was 29.9%. The prevalence of
      positive Salmonella spp. samples was 11.0% and of Campylobacter spp. 17.5%. In
      55.3% of the 76 isolated non-O157 STEC strains, stx2 variants (mostly stx2d) were
      detected. Additional virulence factors were harbored by 55.3% of the STEC
      strains, 10.5% of them being eae positive, 55.3% ehxA positive and 2.6% astA
      positive. All isolated salmonella were identified as Salmonella enterica subsp.
      diarizonae serovar 61:k:1,5,(7). Pulsed-field gel electrophoresis (PFGE) was
      performed for genotyping and 22 different restriction endonuclease digestion
      profiles were found among these strains for the different farms of origin. Of the
      114 isolated Campylobacter spp. strains, 64.9% were shown to be Campylobacter
      jejuni and 35.1% Campylobacter coli, nine strains showed resistance against
      tetracycline, ciprofloxacin/nalidixic acid or streptomycin. In conclusion, sheep
      are a reservoir for the pathogens of latent zoonoses as non-O157 STEC, S.
      enterica subsp. diarizonae and Campylobacter spp. The maintenance of slaughter
      hygiene is consequently of crucial importance. It can be measured in daily
      practice by "slaughter-process-controls" and regular microbiological monitoring
      of carcasses. These are valuable tools for verifying slaughter hygiene according
      to hazard analysis critical control point principles.

PMID- 15033268
TI  - Use of survival analysis and Classification and Regression Trees to model the
      growth/no growth boundary of spoilage yeasts as affected by alcohol, pH, sucrose,
      sorbate and temperature.
AB  - This paper describes the application of a survival analysis model and a
      Classification and Regression Trees (CART) model to a data set comprising times
      to growth of a yeast cocktail inoculated into media simulating a fruit-based or
      alcoholic food or drink, and covering over 900 combinations of five environmental
      factors (alcohol, pH, sucrose, sorbate and temperature). Growth was determined as
      either the time to growth within a 150-day time period or as no-growth after 150
      days. Models were developed which could either predict the likelihood of growth
      occurring within the 150 day period, or the time to grow, either in days or in
      one of three categories chosen to represent a rapid (1-14 days), medium (15-30
      days) or slow (31-150 days) growth response. Growth was observed in 29% of the
      experimental conditions and demonstrated that the yeasts used were able to grow
      under extreme environmental conditions, for example at a pH value of 2.1, a
      temperature of 2 degrees C, a sucrose concentration of 55% (w/w) or an alcohol
      concentration of 12% (w/v). Generally, both models provided a reasonable fit to
      the data, and successfully predicted the growth class in 84% of cases. Direct
      comparisons of the models were made to determine the more suitable for predicting
      the growth of yeasts in food systems. The survival analysis model was preferred
      for this data set because it was more fail-safe than the CART model. In food
      validation studies, the survival model generally gave reliable predictions of
      time to growth in a range of 23 different food and drink products and is
      considered to be a reliable model to predict the likelihood and speed of yeast
      spoilage for a range of fruit-based or alcoholic food or drinks.

PMID- 15033270
TI  - Photobacterium phosphoreum caused a histamine fish poisoning incident.
AB  - An incident of histamine fish poisoning (HFP) occurred due to the consumption of
      iwashi maruboshi (dried sardine) in Osaka, Japan in March 2002. A histamine
      producing bacterial strain, YS4-7, was isolated from iwashi maruboshi that
      contained 1700 mg of histamine per kilogram. This strain was identified as
      Photobacterium phosphoreum by biochemical examinations and partial sequencing of
      16S rDNA. P. phosphoreum YS4-7 showed greater capability as a histamine producer
      at 4 and 12 degrees C than Morganella morganii JCM 1672. Strain YS4-7 produced
      546 mg of histamine per kilogram in a sardine homogenate stored for 12 h at 20
      degrees C. M. morganii, Raoultella planticola and Hafnia alvei have been isolated
      from fish implicated in HFP incidents, whereas this is the first report of P.
      phosphoreum being the causative bacterium in a sporadic case of histamine food
      poisoning.

PMID- 15033269
TI  - In vitro inhibition of Escherichia coli O157:H7 by bifidobacterial strains of
      human origin.
AB  - The ability of bifidobacteria isolated from infant feces to inhibit
      enterohemorrhagic Escherichia coli serotype O157:H7 in vitro and reduce its
      adhesion to human enterocyte-like Caco-2 cells was evaluated in comparison to
      American Type Culture Collection bifidobacterial reference strains. Five
      Bifidobacterium isolates from infant feces were identified and characterized by
      morphology, fructose-6-phosphate phosphoketolase (F6PPK) assay, polymerase chain
      reaction using bifidobacterial 16S rDNA specific primers, carbohydrate
      fermentation patterns, resistance to lysozyme, acid, bile and hydrogen peroxide
      as well as their ability to inhibit E. coli O157:H7 using the agar spot
      technique. Infant isolates showed greater resistance to bile, acid, lysozyme and
      more antimicrobial activity against E. coli O157:H7 than ATCC strains. Two infant
      isolates identified as B. bifidum RBL 71 and B. bifidum RBL 460 showed good
      adhesion and significant potential for reducing adhesion of E. coli O157:H7 to
      Caco-2 cells. This effect was dependent on bifidobacterial cell concentration.
      These results show that bifidobacteria isolated from infants may be useful for
      improving probiotic formulae with respect to protection against E. coli O157:H7
      infection.

PMID- 15033271
TI  - Growth of Listeria monocytogenes in melon, watermelon and papaya pulps.
AB  - Growth of Listeria monocytogenes in low-acid fruits (melon, watermelon and
      papaya) at different times of incubation and at temperatures of 10, 20 and 30
      degrees C was studied. Fruit pulp portions with an average pH of 5.87, 5.50 and
      4.87 for melon, watermelon and papaya, respectively, were obtained aseptically,
      homogenized, weighed and inoculated with suspensions (approximately 10(2) CFU/g)
      of L. monocytogenes. Generation times of 7.12, 13.03 and 15.05 h at 10 degrees C,
      1.74, 2.17 and 6.42 h at 20 degrees C and 0.84, 1.00 and 1.16 h at 30 degrees C
      were obtained, respectively, for melon, watermelon and papaya. The results showed
      that L. monocytogenes grew in low-acid fruits at all tested temperatures,
      although growth was diminished, but not inhibited at 10 degrees C.

PMID- 15033272
TI  - Effects of several environmental factors on the anti-Listeria monocytogenes
      activity of an essential oil of Picea excelsa.
AB  - The effects of several environmental factors on the anti-Listeria monocytogenes
      activity of an essential oil of Picea excelsa were explored by determination of
      active concentrations using two methods and with survival curves. In trial
      conditions, the serovars 1/2c and 4b behaved similarly. A dose of 0.2-0.3% (v/v)
      of essential oil was bactericidal for 10(5)-10(7) cells contained in 1 ml of
      Tryptone Soy Broth Yeast Extract at pH 6 and 7 incubated at 13 and 37 degrees C
      and of medium supplemented with levan. Introduction of sodium caseinate, agar or
      fat into the test medium and use of a cheese medium decreased the bactericidal
      effects of the essential oil. Basic pH, addition of NaCl or use of Tryptone Soy
      Broth and saline solution increased its antilisterial activity. Serovar 1/2c
      survival curves exhibited an exponential death rate followed by a tailing effect
      in the presence of the minimal bactericidal concentration of the essential oil. A
      three log10 reduction of cell viability was obtained within 100 min in Tryptone
      Soy Broth Yeast Extract, within longer exposure in media supplemented with NaCl
      or at basic pH.

PMID- 15033273
TI  - Olfactory function in apoE knockout mice.
AB  - Apolipoprotein E (apoE), a lipid transporting protein, has been shown to play a
      vital role in nerve repair and remodeling. Since the olfactory system is in a
      continuous state of remodeling, the present study tested the hypothesis that apoE
      is required for normal functioning of the olfactory system. Olfactory behavior of
      wild-type (WT) and apoE-deficient (apoE KO) mice was assessed by using three
      standard olfactory tests: (1) the buried food pellet (BFP) test; (2) the odor
      choice (OC) test; and (3) the odor cued taste avoidance (OCTA) test. ApoE KO mice
      performed poorly in all the three tests as compared to WT mice, although they
      learned the tasks at a rate comparable to WT mice. ApoE KO mice had a
      significantly longer latency to find the buried pellet than WT mice. In the OC
      experiment, apoE KO mice did not differentiate water from an odorant solution.
      Furthermore, in the OCTA test the apoE KO mice were significantly less successful
      than WT mice at avoiding water containing an odorant and a bad tastant. These
      data demonstrate that apoE deficiency in apoE KO mice leads to a deficit in
      olfactory function, suggesting an important role for apoE in the olfactory
      system.

PMID- 15033274
TI  - Motility recovery during the process of regeneration in freshwater planarians.
AB  - Planarians are phylogenetically considered to be the most primitive animals to
      have acquired a central nervous system and a bilateral symmetry. However, very
      little is known about the relationship between planarian brain integration and
      motility. A behavioural and histological study was therefore undertaken in an
      aspect of planarian motility recovery during its process of regeneration.
      Quantitative analysis showed that the tail-regenerates recovered their motility
      gradually as the new heads reformed, while the non-head reforming tail fragments
      showed no signs of recovery. The head fragments recovered their motility soon
      after cutting. The cephalic margin was not a function of the motility. The brain
      regenerated back to its original form in approximately two weeks, the same amount
      of time it took for the decapitated tails to recover their motility to initial
      levels. This study provides quantitative evidence that the planarian motility
      recovered in relation to the head formation during its process of regeneration.
      Our results reinforce the view that the brain plays a functional part in
      activating planarian motility.

PMID- 15033276
TI  - Anxiety-related behaviour in C57BL/6 <--> BALB/c chimeric mice.
AB  - In a previous study on anxiety-related behaviours of the genetically and
      behaviourally distant inbred mouse strains C57BL/6 and BALB/c using the Elevated
      plus-maze (EPM) and Open-field (OF) apparatuses, we identified a number of
      variables, the factorial scores of which were grouped by principal component
      analysis (PCA) into factors specifically describing each inbred strain. We have
      now studied the effect of C57BL/6 and BALB/c haploid sets of genes on this
      behaviour by comparing EPM and OF variables of C57BL/6 and BALB/c versus C57BL/6
      x BALB/c F1 hybrids (B6CBF1) and chimeric C57BL/6 x BALB/c (CHIM) mice. CHIM mice
      were made by embryo aggregation and the chimerism degree of their brain was
      inferred from coat black/white distribution. Discriminant analysis of EPM and OF
      factorial scores of C57BL/6, BALB/c and CHIM mice showed that CHIM mice with an
      exceeding (> or =80%) C57BL/6 or BALB/c coat component had behaviours similar to
      those of the predominant strain, whereas CHIM mice with intermediate chimerism
      differed from both inbred strains. Additional MANOVA analysis showed that the
      anxiety behaviour of CHIM mice with intermediate chimerism was similar to that of
      B6CBF1 mice as for factors not describing the inbred strains, including a motor
      activity mostly limited to protected areas, with attempts to approach the
      anxiogenic areas while processing/storing the external information. We conclude
      that the balanced presence of both C57BL/6 and BALB/c genetic backgrounds, either
      when carried by the same cell or by different cells, gives rise to a novel stress
      coping strategy described by factors different from those of the inbred strains.

PMID- 15033277
TI  - Effects of estradiol and progesterone on radial maze performance in middle-aged
      female rats fed a low-calcium diet.
AB  - There is increasing evidence that ovarian steroids and calcium ions are involved
      in learning and memory. To examine the effect of ovarian steroids on learning and
      memory under a low-calcium condition, middle-aged female rats were fed either a
      low-calcium (0.02% Ca) or a normal-calcium (1.25% Ca) diet. All rats were
      ovariectomized (OVX), and these animals were divided into eight groups: 1) an OVX
      group with a normal-calcium diet (OVX-normal-Ca group), 2) an OVX group with
      17beta-estradiol treatment and a normal-calcium diet (E2 group), 3) an OVX with
      progesterone treatment and a normal-calcium diet (P4 group), 4) an OVX with
      17beta-estradiol and progesterone treatments and a normal-calcium diet (E2 + P4
      group), 5) an OVX group with a low-calcium diet (OVX-low-Ca group), 6) an OVX
      group with 17beta-estradiol treatment and a low-calcium diet (LE2 group), 7) an
      OVX group with progesterone treatment and a low-calcium diet (LP4 group), and 8)
      an OVX group with 17beta-estradiol and progesterone treatments and a low-calcium
      diet (LE2 + LP4). Seventy-seven days after the OVX operation, the learning and
      memory abilities of the rats were examined by using an eight-arm radial maze
      task. E2 and E2 + P4 groups learned in fewer trials, and performed better in the
      radial maze and the working memory task than the other groups under the normal
      calcium condition. Rats in the LE2 group learned in fewer trials, and performed
      better in the maze and working memory task than the other low-calcium groups, but
      in combination with progesterone under the low-calcium condition (LE2 + LP4
      group), the facilitative effect of estradiol in all the tasks was inhibited.
      Treatment with progesterone alone did not inhibit the learning and memory task
      performance. These results suggest the possibility that treatment with estradiol
      under low-calcium conditions cannot improve impaired learning and memory when
      progesterone is applied simultaneously, and that the intake of adequate calcium
      may be necessary and effective for patients with learning and memory hypofunction
      receiving hormone replacement therapy.

PMID- 15033275
TI  - Dorsal striatum and stimulus-response learning: lesions of the dorsolateral, but
      not dorsomedial, striatum impair acquisition of a simple discrimination task.
AB  - In the present experiment, the effects of neurotoxic lesions (quinolinic acid) of
      the dorsolateral or dorsomedial striatum were investigated on a simple
      instrumental discrimination task (CS+/CS-). Rats with lesions of the dorsolateral
      striatum were found to be impaired in the acquisition of this task, as compared
      to rats with either dorsomedial striatal or sham lesions. Furthermore,
      dorsolateral striatal lesioned animals had significantly lower levels of
      responding across the course of discrimination training, as assessed both by
      overall rate of response during CS+ presentations and number of CS+ trials
      without a response, despite having shown levels of responding during variable
      interval training that did not differ from that of sham lesioned animals. In
      contrast, animals with lesions of the dorsomedial striatum did not show an
      impairment in acquisition of the present task, but had slightly higher rates of
      responding during CS- presentations. It is argued that the poor acquisition and
      low response rates observed in animals with dorsolateral striatal lesions reflect
      a failure in stimulus-response learning, while the performance of animals with
      dorsomedial striatal lesions may have been the result of an increase in overall
      activity rate.

PMID- 15033278
TI  - Facilitation of motor skill learning by callosal denervation or forced forelimb
      use in adult rats.
AB  - Unilateral forelimb sensorimotor cortex lesions in adult rats produce a
      compensatory hyper-reliance on the forelimb ipsilateral to the lesion and
      temporally related glial and neural plasticity in the contralateral homotopic
      cortex. Recently, we found that these lesions enhance acquisition of a motor
      skills task with the ipsilateral, non-impaired, forelimb in comparison to shams.
      This effect might be related to a denervation-induced facilitation of
      neuroplastic changes in the motor cortex opposite the lesion and/or to the lesion
      induced hyper-reliance on the non-impaired forelimb. The present study assessed
      whether increased forelimb use, denervation of motor cortical callosal afferents,
      or a combination of the two influences acquisition of a skilled reaching task.
      Adult rats with partial corpus callosum transections or sham procedures were
      either forced to rely on one forelimb or permitted normal forelimb use for 8
      days. Rats were then trained for 14 days with their previously non-preferred
      forelimb (and the forced-use limb) on a unilateral pellet retrieval task.
      Compared to shams, transections produced a greater acquisition rate and
      asymptotic performance level on the task. Forced-use improved reaching
      performance relative to controls, but this effect was less enduring than the
      improvements produced by transections alone. The addition of forced-use to
      transections did not further enhance performance. These findings suggest that
      denervation-induced changes are likely to be a major contributor to the enhanced
      learning observed after unilateral sensorimotor cortex lesions.

PMID- 15033279
TI  - Dissociation of hemi-spatial and hemi-motor impairments in a unilateral primate
      model of Parkinson's disease.
AB  - Monkeys with unilateral lesions of nigrostriatal dopamine projections were tested
      on a series of spatial tasks. One task, in which monkeys were required to use one
      or the other arm to retrieve food rewards from different positions, allowed
      separate assessment of the use of each arm in each hemi-space in order to
      distinguish hemi-spatial and hemi-motor impairments. The lesioned monkeys
      exhibited a persistent neglect of contralesional space when using either arm
      which could be dissociated from a motor impairment in the contralesional arm
      alone. Another task allowed free use of either arm across peri-personal space and
      demonstrated an ipsilesional bias in the monkeys' self-determined attention
      (orientation) to a task which they were trying to perform. It is argued that the
      tendency for monkeys with this lesion to rotate ipsilesionally is due to an
      ipsilesional deviation of the 'centre of interest' (determined by telencephalic
      circuitry) relative to 'straight ahead' (determined by brainstem circuitry). The
      dopamine projections may contribute to cortico-subcortical circuits which
      determine the spatial layout of mental representation, attention and intention.
      The results in this primate model of unilateral Parkinson's disease (PD) support
      the view that patients with left-sided Parkinsonian symptoms exhibit a unilateral
      deficit in spatial mental representation as well as their well-recognised motor
      symptoms. Patients with bilateral Parkinson's symptoms may exhibit bilateral
      deficits in mental representation.

PMID- 15033280
TI  - Development of early motor learning and topical motor skills in a model of
      cerebellar degeneration.
AB  - The development of motor learning and topical motor skills has been studied
      during the first month of life in neurodeficient Lurcher mutant mice derived from
      C3H strain. The examination of motor functions was conducted using four methods
      when animals were consecutively placed on: a horizontal wire, a rotating
      cylinder, a bridge and slanting ladder (on the rotating cylinder and slanting
      ladder in three different starting positions). A total of 150 animals were used,
      half being heterozygous mutants (+/Lc), the remaining consisting of their healthy
      littermates, homozygous wild-type mice (+/+). Some animals of both types were
      confronted with the tasks in four testing days without practice while the others
      were trained in all of these methods one time daily at the age of 3, 6, 9, 12,
      15, 20, 25 and 30 days. The results of the research are expressed as a percentage
      of reaching criteria in the trained and untrained mice of both types (+/Lc, +/+),
      respectively on days 15, 20, 25, and 30. Because of their motor handicap, Lurcher
      mutants showed significantly worse results than normal mice in almost all of the
      tests. The most interesting observations of the study were obtained on the
      rotating cylinder and the slanting ladder tests where mainly untrained mutants
      were unable to cope promptly with the different starting position and failed.
      However, in 30-day-old Lurchers the effect of learning was relatively better in
      some tests when compared with the wild-type of mice. Experiments showed that, in
      spite of progressive cerebellar degeneration, the ability of motor learning in
      Lurcher mutants survived to a certain degree. The worsening of results after
      frequent training in both trained Lurchers and normal mice aged 20 days as
      compared with untrained ones is discussed within the context of the "overtraining
      reversal effect" and other possible hypotheses.

PMID- 15033281
TI  - 7-Nitroindazole blocks conditioned place preference but not hyperactivity induced
      by morphine.
AB  - The effects of 7-nitroindazole (7-NI), a neural nitric oxide synthase (nNOS)
      inhibitor, on spontaneous locomotor activity, morphine-induced hyperactivity,
      acquisition of place conditioning and morphine-induced conditioned place
      preference (CPP) were evaluated in male mice. In experiment 1, animals treated
      with 7-NI (25, 50 and 100mg/kg), morphine (40 mg/kg) or morphine (40 mg/kg) plus
      7-NI (25, 50 or 100mg/kg) were placed in an actimeter for 3h. In experiment 2,
      animals treated with the same drugs and doses were conditioned following an
      unbiased procedure. 7-NI did not affect the spontaneous locomotor activity or
      hyperactivity induced by morphine. However, the moderate and high doses of 7-NI
      produced conditioned place aversion (CPA) and the lowest dose blocked morphine
      induced CPP. Our results suggest that nitric oxide is involved in the rewarding
      properties of morphine but not in its motor effects.

PMID- 15033282
TI  - Consequences of forced disuse of the impaired forelimb after unilateral cortical
      injury.
AB  - Extreme over-reliance on the impaired forelimb following unilateral lesions of
      the forelimb representation area of the rat sensorimotor cortex (FL-SMC) leads to
      exaggeration of injury when overuse is begun during the first week, but not later
      periods, after injury. Behavioral impairment is partially worsened by the
      additional tissue loss. In the present study, we show that complete disuse of the
      impaired forelimb during the first post-operative week renders surviving tissue
      vulnerable to later overuse of the same limb, in effect extending the window of
      vulnerability in which use-dependent exaggeration of brain injury can occur.
      Behavioral recovery is disrupted by complete disuse, but the degree of impairment
      is variable depending on the nature of the behavioral test employed. Our results
      uphold the idea that mild rehabilitative training early after injury is
      beneficial, while either extreme overuse or complete disuse may disrupt
      functional recovery.

PMID- 15033283
TI  - Distinct temporal activity patterns in the rat M1 and red nucleus during skilled
      versus unskilled limb movement.
AB  - The mammalian motor system contains multiple interconnected supraspinal networks,
      but little is known about their relative roles in producing different movements
      and behaviors, particularly given their apparently fused activity in primates. We
      tested whether the task context, as well as using a phylogenetically older
      mammal, rats, could distinguish the separate contributions of these networks. We
      obtained simultaneous multi-single neuron recordings from the forelimb motor
      cortex and magnocellular red nucleus as rats performed two contextually
      different, but kinematically similar, forelimb reach-like tasks: highly learned,
      skilled reaching for food through a narrow slot, a task requiring extensive
      training, versus the swing phases of treadmill locomotion. In both the M1 and the
      mRN, large subpopulations of neurons peaked in their spike firing rates near the
      onset and the end of the swing phase during treadmill locomotion. In contrast,
      neural subgroups in the two areas displayed different temporal sequences of
      activity during the skilled reaching task. In the mRN, the majority of task
      modulated neurons peaked in their firing rate in the middle of the reach when the
      rat was preparing to project the arm through the slot, whereas large subgroups of
      M1 neurons displayed elevated firing rates during the initial and terminal phases
      of the reach. These results suggest that motor-behavioral context can alter the
      degree of overlapping activity in different supraspinal sensorimotor networks.
      Moreover, results for the skilled reaching task in rats may have highlighted a
      distinct processing role of the rubral complex: adapting natural muscle synergies
      across joints and limbs to novel task demands, in concert with cortically based
      learning.

PMID- 15033284
TI  - Greater sparing of visually guided orienting behavior after early unilateral
      occipital lesions: insights from a comparison with the impact of bilateral
      lesions.
AB  - We know that cats with bilateral lesions of occipital visual cortical areas 17,
      18 and 19 sustained during the first postnatal week exhibit a modest level of
      sparing of the ability to re-orient head and eyes to new stimuli relative to cats
      that incurred equivalent lesions in adulthood. We now report that cats with
      equivalent unilateral lesions sustained during the first postnatal week (P1-4),
      or at the end of the first postnatal month (P27-30), orient to stimuli presented
      in the contralesional field as proficiently as to stimuli introduced into the
      ipsilesional field. Moreover, levels of proficiency are indistinguishable from
      those exhibited by intact cats. Thus, the sparing is greater following unilateral
      lesions than following bilateral lesions, and the level of sparing approaches
      completeness. The difference between the bilateral and unilateral lesion results
      suggests types of pathway reorganizations that may emerge as a result of
      unilateral occipital lesions. We postulate that the greater sparing is based on
      modifications in both excitatory and inhibitory circuitry linked to the intact
      hemisphere, and we provide a framework for future investigations that should be
      relevant to the comprehension of the repercussions of early unilateral and
      bilateral lesions sustained by monkeys and humans, which also show more robust
      residual vision following early relative to later damage of occipital cortex.

PMID- 15033286
TI  - Evidence for disrupted NMDA receptor function in tissue plasminogen activator
      knockout mice.
AB  - Tissue plasminogen activator (tPA), a serine protease immediate-early gene
      product expressed in brain areas important in learning and memory, has been shown
      to cleave the NR1 subunit of the NMDA receptor leading to a potentiated Ca(2+)
      influx. Mice lacking tPA (tPA-/- mice) have disrupted late phase-LTP in the
      hippocampus, possibly as a consequence of reduced Ca(2+) flux through NMDA
      receptors. In the present experiments, we investigated whether the NMDA
      antagonist dizocilpine might alter performance in tPA-/- mice in behavioural
      tasks shown to be sensitive to hippocampal lesions. tPA-/- mice and wild-type
      controls (WT) showed similar rates of acquisition and performance of a spatial
      working memory task (eight-arm radial maze). Dizocilpine (0.03-0.3 mg/kg, i.p.),
      given acutely, disrupted performance by increasing the number of errors equally
      across both genotypes. At asymptotic performance of a differential reinforcement
      of low response rate operant task (DRL), acute dizocilpine (0.03-0.3 mg/kg)
      impaired performance, but no differences between genotypes were observed.
      However, dizocilpine (0.1 mg/kg), given repeatedly during acquisition of a
      signalled-DRL15" task, retarded acquisition in tPA-/- but not WT mice. This
      treatment regime had no effect on locomotor activity in either genotype. tPA-/-
      mice showed no spatial learning deficits, but were more sensitive to dizocilpine
      during acquisition (though not expression) of a DRL task. This supports a role
      for tPA in modification of the NMDA receptor, although absence of tPA does not
      have consequences for all forms of NMDA-dependent mediated learning.

PMID- 15033285
TI  - Chronic prenatal ethanol exposure alters hippocampal GABA(A) receptors and
      impairs spatial learning in the guinea pig.
AB  - Chronic prenatal ethanol exposure (CPEE) can injure the developing brain, and may
      lead to the fetal alcohol syndrome (FAS). Previous studies have demonstrated that
      CPEE upregulates gamma-aminobutyric acid type A (GABA(A)) receptor expression in
      the cerebral cortex, and decreases functional synaptic plasticity in the
      hippocampus, in the adult guinea pig. This study tested the hypothesis that CPEE
      increases GABA(A) receptor expression in the hippocampus of guinea pig offspring
      that exhibit cognitive deficits in a hippocampal-dependent spatial learning task.
      Timed, pregnant guinea pigs were treated with ethanol (4 g/kg maternal body
      weight per day), isocaloric-sucrose/pair-feeding, or water throughout gestation.
      GABA(A) receptor subunit protein expression in the hippocampus was measured at
      two development ages: near-term fetus and young adult. In young adult guinea pig
      offspring, CPEE increased spontaneous locomotor activity in the open-field and
      impaired task acquisition in the Morris water maze. CPEE did not change GABA(A)
      receptor subunit protein expression in the near-term fetal hippocampus, but
      increased expression of the beta2/3-subunit of the GABA(A) receptor in the
      hippocampus of young adult offspring. CPEE did not change either
      [(3)H]flunitrazepam binding or GABA potentiation of [(3)H]flunitrazepam binding,
      but decreased the efficacy of allopregnanolone potentiation of
      [(3)H]flunitrazepam binding, to hippocampal GABA(A) receptors in adult offspring.
      Correlational analysis revealed a relationship between increased spontaneous
      locomotor activity and growth restriction in the hippocampus induced by CPEE.
      Similarly, an inverse relationship was found between performance in the water
      maze and the efficacy of allopregnanolone potentiation of [(3)H]flunitrazepam
      binding in the hippocampus. These data suggest that alterations in hippocampal
      GABA(A) receptor expression and pharmacological properties contribute to
      hippocampal-related behavioral and cognitive deficits associated with CPEE.

PMID- 15033287
TI  - Chronic mild stress affects sucrose intake and sleep in rats.
AB  - Depression in humans is associated with sleep abnormalities of three types:
      altered rapid eye movement (REM) sleep, fragmented sleep, and reduced delta
      sleep. In an animal model of depression, chronic exposure to mild stressors (CMS,
      e.g. periods of soiled cage, reversed light/dark cycle, grouped housing, food
      and/or water deprivation) causes behavioral and hormonal changes which, in
      humans, often are associated with depression. In the CMS model, a reduced sucrose
      intake has been defined as one of the core symptoms of depression, anhedonia,
      although this finding is not consistent among various laboratories. In the
      present study, we investigated if the CMS procedure, in our laboratory, would
      cause decreased sucrose intake and, also, give sleep changes similar to what is
      found in depressed patients. Exposure to CMS decreased sucrose intake in our
      rats. The largest effect was obtained after 2 weeks of the stress protocol. CMS
      rats spent more time in REM sleep and showed more fragmented sleep compared to
      their baseline recording, while there were no changes in the control rats.
      Increased sleep fragmentation in CMS rats was particularly evident by increased
      number of arousals, and increased REM sleep and slow-wave-sleep-1 (SWS-1)
      episodes. The duration of sleep stage episodes was decreased. The amount of slow
      wave-sleep-2 (SWS-2) was not decreased, however SWS-2 in percent of total SWS was
      reduced. Correlation analysis showed that animals that had less consumption of
      sucrose spent more time in REM sleep and had increased number of REM sleep
      episodes. In this study, CMS appears to be a model of depression.

PMID- 15033288
TI  - Sex differences in learning deficits induced by prenatal stress in juvenile rats.
AB  - Stress during pregnancy results in neurochemical and behavioral alterations
      observed throughout adulthood and aging. We here examined the impact of prenatal
      stress (PS) on cognitive functions in juvenile-4-week-old-rats, focusing on
      putative sex differences. Dams received an unpredictable 90-min duration
      contention stress between gestational day E17 and E20. Locomotion and learning
      ability were examined in offsprings between day P24 and P29 using actimetry,
      spontaneous alternation in the Y-maze, delayed alternation in the T-maze, and
      passive avoidance. Both male and female PS rats showed increased activity. In the
      Y-maze, diminished spontaneous alternation (males: -20%; females: -29%) were seen
      for PS rats compared to non-PS rats. The number of arm entries was unchanged
      among groups. In the T-maze, PS rats failed to perform delayed alternation, as
      shown by equal time spent and number of entries in both the novel and previously
      explored arms. In the passive avoidance test, PS resulted in significant
      impairments for female offspring only of both step-through latency and percentage
      of animals to criterion. PS thus induced severe learning impairments affecting
      both short-term and long-term memories that could be observed early in lifetime,
      in 4-week-old, juvenile rats. In addition, marked sex differences were evidenced,
      particularly in the passive avoidance response that may reflect differential
      developmental neuroadaptations in precise brain structures.

PMID- 15033289
TI  - An assessment of the long-term developmental and behavioral teratogenicity of
      prenatal nicotine exposure.
AB  - Maternal tobacco use during pregnancy adversely affects prenatal and postnatal
      growth and increases the risk of developmental and behavioral deficits in
      children and adolescents. In the present study, the effects of prenatal nicotine
      exposure (infused at 6mg/kg/day) and maternal withdraw during neonatal
      development, was examined in Sprague-Dawley rats on an array of behavioral tasks
      during different stages of ontogenesis. Offspring of both genders were monitored
      for exploratory, locomotor, and novelty-seeking activity, anxiety, and learning
      and memory in an active-avoidance task. Nicotine-exposed animals showed growth
      retardation, hyperactivity, and poor adaptation in a new environment, increased
      level of anxiety during the early adolescent period, and robust cognitive
      deficits in early adulthood. In addition, the deficits were generally more severe
      in the female nicotine-exposed offspring. Cross-fostering also revealed that
      while maternal behavior and nicotine withdraw did not affect postnatal somatic
      growth retardation or cognitive ability of the offspring; measures of exploration
      and adaptation in a new environment were impacted during the post-weanling and
      early adolescence period. Nicotine-exposed offspring, and the saline-treated
      offspring cross-fostered to nicotine-exposed mothers, showed higher measures of
      anxiety in the elevated plus-maze and decreased novelty-seeking behavior on the
      hole-board apparatus. These studies demonstrated that prenatal nicotine exposure
      produced significant long-term developmental and behavioral teratogenic effects.
      The study design provides a model system for studying the mechanism(s)
      responsible for the decline in central nervous system function following prenatal
      nicotine exposure, as well as that of other neurological and behavioral
      teratogens during pregnancy.

PMID- 15033290
TI  - The effects of intracortical endothelin-1 injections on skilled forelimb use:
      implications for modelling recovery of function after stroke.
AB  - Different methods of inducing experimental brain lesions can result in distinct
      neuropathological sequelae. This could be of consequence in attempts to establish
      animal models of recovery of function following stroke, as differences in the
      progression of experimental lesion pathology may have an impact on the magnitude
      and rate of recovery of function observable with any particular lesioning method.
      In the present study, a novel method of producing a focal ischaemic lesion by
      intracortical microinjection of endothelin-1 (ET-1) was compared with excitotoxic
      (microinjection of quinolinic acid) and mechanical (aspiration) lesioning
      procedures. Lesions were unilateral and were targeted at the forelimb
      representation zone in sensorimotor cortex. It was found that all three types of
      lesion had an essentially identical effect with regard to reaching accuracy in a
      paw-reaching task. All lesioned animals displayed a similar, significant long
      term deficit in reaching accuracy and limited degree of recovery relative to sham
      animals. Off-line analysis of the performance of animals during post-lesion week
      9 indicated that animals in each lesion group also displayed a similar deficit.
      The current results suggest that the spontaneous behavioural consequences of a
      unilateral lesion of FL in the rat appear to be independent of the nature of
      lesion production. However, the increased face validity of an ET-1-induced
      lesion, coupled with the ease of control of lesion placement and extent offered
      by this technique make for a potentially important animal model for research into
      drug effects on recovery of function following stroke.

PMID- 15033291
TI  - Involvement of N-methyl-d-aspartate (NMDA) receptors in a rat model of visceral
      hypersensitivity.
AB  - N-Methyl-d-aspartate (NMDA) is known to be involved in the transmission of
      nociceptive information. In the present study, we investigated the effect of
      peripheral and central NMDA receptor antagonist MK-801 in visceral
      hypersensitivity. In an animal model of colorectal distension (CRD),
      administration of both intrathecal MK-801 (1.5 nmol) and intraperitoneal MK-801
      (0.15 mg/kg) completely abolished the CRD-induced visceral hypersensitivity of
      noxious and innocuous stimuli. Thus, the results from this experiment demonstrate
      the efficacy of MK-801 in blocking the visceral hypersensitivity mediated by
      central and peripheral mechanisms.

PMID- 15033292
TI  - Walking performance of vestibular-defective patients before and after unilateral
      vestibular neurotomy.
AB  - The present study investigated goal-directed linear locomotion in nine Meniere's
      patients before and after (1 week, 1 and 3 months) a curative unilateral
      vestibular neurotomy (UVN). Experiments were done using a 3D motion analysis
      system in subjects walking eyes open (EO) and eyes closed (EC) towards a real or
      memorized target, respectively. Locomotor pattern (velocity, step length, step
      frequency and walk ratio) and walking trajectory deviations were evaluated for
      normal and fast speeds of locomotion and compared to those recorded in 10 healthy
      subjects. Before UVN, patients showed no walking deviation but gait pattern
      changes characterized by slower walks compared to the controls, mainly due to
      step length and step frequency reductions for both visual conditions and
      locomotion speeds. In the acute stage after UVN, locomotor pattern impairments
      were significantly accentuated. On the other hand, patients showed strong walking
      deviations towards the lesioned side with EC. Opposite lateral deviation towards
      the intact side were observed with EO for normal speed only. Recovery from
      impaired locomotor pattern was achieved within 1 month for normal speed but
      remained uncompensated 3 months post-lesion for fast speed particularly in EC
      condition. Finally, the walking trajectory deviation towards the lesioned side in
      the dark was maintained up to 3 months after UVN. The results show that central
      processing of visual and vestibular cues contributes to an accurate locomotor
      pointing. They argue for an increased weight of visual reference frame on
      locomotor functions when vestibular function is unilaterally impaired.

PMID- 15033293
TI  - Circadian modulation of performance on an aversion-based place learning task in
      hamsters.
AB  - In golden hamsters, the expression of a reward-conditioned place preference (CPP)
      is regulated in a circadian pattern such that the preference is exhibited
      strongly at the circadian time of prior training but not at other circadian
      times. We now report that the same "time-stamp" phenomenon is expressed following
      context conditioning with an aversive stimulus (conditioned place avoidance,
      CPA). Animals that were trained at a specific circadian time to discriminate
      between a "safe" context and one paired with foot shock, showed strong avoidance
      of the paired context at 24 and 48 h following the last training session, and
      showed no avoidance at 32 and 40 h following training. Circadian time is a
      feature that is learned during conditioning even though timing itself is not an
      explicit discriminative cue in these experiments. The results suggest that in
      hamsters, the emotional valence associated with the place where arousing
      stimulation (rewarding and aversive) is encountered is highest at the circadian
      time of occurrence. The golden hamster may be predisposed to anticipate the
      recurrence of arousing events at circa-24 h intervals.

PMID- 15033294
TI  - Kinematics of treadmill locomotion in rats conceived, born, and reared in a
      hypergravity field (2 g). Adaptation to 1 g.
AB  - The kinematics of treadmill locomotion in rats conceived, born, and raised in a
      hypergravity environment (HG: 2g) until the age of 3 months was investigated for
      5 weeks after their exposition to earth's gravity. The locomotor performance of
      the HG rats (N=7) was compared to that of age-matched control rats (N=8) housed
      at 1g for the same period. Kinematic analysis of treadmill locomotion was
      performed up to 35 days of terrestrial life by an optoelectronic motion analyzer
      (ELITE system). Results showed that the HG rats exhibited a faster locomotor
      rhythm (increased number of steps/s), walked closer to the ground, and had a more
      dorsiflexed foot position. Also, HG rats had shorter steps. The data also
      highlight a fast adaptation to normal gravity since all the locomotor parameters
      returned to normal values within 3 weeks. The locomotor modifications may be seen
      as the persistence of a hypergravity-induced posturo-locomotor adaptation in the
      centrifuge and/or to more functional changes of sensorimotor systems. Because
      locomotor performance of HG rats is not severely affected, it is concluded that
      early development of locomotion processes is highly resistant to gravito-inertial
      changes.

PMID- 15033295
TI  - Rats with congenital learned helplessness respond less to sucrose but show no
      deficits in activity or learning.
AB  - Inbred rat strains for congenital learned helplessness (cLH) and for congenital
      resistance to learned helplessness (cNLH) were investigated as a model to study
      genetic predisposition to major depression. Congenitally helpless rats respond
      less to sucrose under a progressive ratio schedule. This is not confounded by
      locomotor hypoactivity: in contrast, cLH rats show a slight hyperactivity during
      the first 5 min of an open field test. cLH rats acquire operant responding to
      sucrose as readily as cNLH rats and exhibit normal memory acquisition and
      retrieval in the Morris water maze, thus ruling out general learning deficits as
      the cause of the decreased response to sucrose. Reduced total responses and
      reduced breaking points for sucrose in the cLH strain argue for anhedonia, which
      is an analogue to loss of pleasure essential for the diagnosis of major
      depressive episodes, and thus confirm the validity of congenitally learned
      helpless rats as a model of major depression.

PMID- 15033296
TI  - Non-linearity in combined effects of ELF magnetic field and amphetamine on motor
      activity in rats.
AB  - The effects of short-term (15 min) pre-exposure of rats to extremely low
      frequency magnetic field (ELF-MF, 50 Hz, 6 mT) on their motor (locomotor and
      stereotypic) activity induced by d-amphetamine sulphate (AMPH) at different doses
      (0.5, 1.5 and 4.5mg/kg, i.p.) were studied in the open field test. In saline
      treated rats both parameters of motor activity were unaffected by ELF-MF
      irradiation. The rats pre-exposed to ELF-MF and injected with the lowest dose of
      AMPH showed the same locomotor activity as control animals, while their
      stereotypic behaviour was significantly elevated. ELF-MF in combination with AMPH
      at higher doses significantly enhanced motor activity when compared with values
      obtained in both control and combined experiments with the lowest dose of the
      drug. However, only combined locomotor effect at the middle dose of AMPH was
      significantly greater than those observed in corresponding experiments with AMPH
      alone. These results demonstrate that acute short-term exposure to ELF-MF is able
      to modify a motor activity in dependence on the extent of AMPH-induced
      neurotransmitter imbalance.

PMID- 15033297
TI  - Avoidance learning in the crayfish (Procambarus clarkii) depends on the predatory
      imminence of the unconditioned stimulus: a behavior systems approach to learning
      in invertebrates.
AB  - Signaled avoidance learning in crayfish (Procambarus clarkii) was investigated
      when the crayfish were not confined, by indexing two types of locomotive movement
      to the escape compartment. Mild shocks, which induced tail flipping in the
      crayfish, and light illumination were used as unconditioned and conditioned
      stimuli, respectively. In Experiment 1, two groups of crayfish were trained in a
      one-way shuttle box. The crayfish in Group Forward were placed in the start
      compartment facing the escape compartment and they were able to escape/avoid
      shocks by walking forward, while the crayfish in Group Backward were placed in
      the compartment facing the opposite direction and they were able to escape by
      tail flipping. Avoidance learning was achieved only by walking, and not by tail
      flipping despite the fact that consistent tail flipping allowed the crayfish to
      avoid shocks. In Experiment 2, the experimental conditions were switched by using
      the ABA design. In this experiment, we confirmed that avoidance behavior was
      restricted to walking. These results are readily explained by the behavior
      systems approach.

PMID- 15033300
TI  - What can comparative studies of placental structure tell us?--A review.
AB  - The diversity of placental structures in Eutherian mammals is such that drawing
      generalizations from the definitive forms is problematic. There are always areas
      of reduced interhaemal distance whether the placenta is epitheliochorial,
      synepitheliochorial, endotheliochorial or haemochorial. However, the thinning may
      be achieved by different means. The presence of a haemophagous area as an iron
      transport facilitator is generally associated with endotheliochorial placentae
      but is also found in sheep and goats (synepitheliochorial) and in tenrecs and
      hyaenas (haemochorial). Although similar chorioallantoic placentae are found
      within families, structure begins to diverge at the ordinal level and there is
      little correlation at the supraordinal level of phylogeny. Differences in
      formation and function of the yolk sac provide additional variation. There would
      appear to be considerable adaptive pressure for development or retention of the
      haemochorial type of chorioallantoic placenta. This type of placenta has several
      possible drawbacks including more ready passage of fetal cells to the maternal
      organism and, should the haemochorial condition be achieved early, oxidative
      stress. At any rate no animal larger than the human and gorilla has this type of
      placenta. The endotheliochorial condition is found in animals as large as the
      bears, manatee and elephants. In addition to the ungulates, the epitheliochorial
      condition is present in the largest animals with the longest gestation periods,
      the whales. Considering the length of time since the early stages of mammalian
      evolution, it is probable that few unmodified structural features are present in
      any currently surviving mammal. Nevertheless, more complete studies of divergent
      types of mammalian placenta should help our understanding of mammalian
      interrelationships as well as placental function.

PMID- 15033301
TI  - Evolutionary conflicts in pregnancy and calcium metabolism--a review.
AB  - The maternal-fetal unit contains three distinct haplotypes at each locus: the
      maternally derived fetal haplotype (MDFH) that is shared by the mother and fetus,
      the paternally derived fetal haplotype (PDFH), and the non-inherited maternal
      haplotype (NIMH). The evolutionary forces acting on these haplotypes are
      distinct. The NIMH is absent from the offspring and could benefit from early
      abortion if this enhances the probability of the mother conceiving again and
      producing an offspring that inherits the NIMH. This raises the possibility that
      some forms of recurrent spontaneous abortion may be caused by non-inherited
      haplotypes. Such 'selfish' behaviour would be opposed by other components of the
      maternal genome. Natural selection acting on genes expressed in fetuses (or their
      placentae) favours greater maternal investment in the fetus than does natural
      selection acting on genes expressed in mothers. Furthermore, in the presence of
      genomic imprinting, the PDFH favours greater levels of investment in the fetus
      than does the MDFH. These conflicts are illustrated using the example of maternal
      fetal conflicts over the supply of calcium. Inactivation of the paternal copy of
      GNAS in proximal renal tubule is interpreted as a measure to maintain fetal bone
      mineralization in times of calcium stress at the expense of the maternal
      skeleton.

PMID- 15033302
TI  - Expression and functions of human endogenous retroviruses in the placenta: an
      update.
AB  - The placenta is unique amongst normal tissues in transcribing many different
      human endogenous retrovirus (HERV) families at high levels and this has led to
      the suggestion that HERVs may fulfil important functions in reproduction. This
      review discusses our current knowledge of the placental expression of HERVs, in
      particular the envelope proteins of ERV3 and HERV-W which may have critical roles
      in placental function.

PMID- 15033304
TI  - Early trophoblast determination and stem cell maintenance in the mouse--a review.
AB  - The first priority of a mammalian embryo is to establish an intimate relationship
      with its mother. This is accomplished by precocious differentiation of the
      trophoblast lineage, which mediates uterine implantation and initiates the
      process of placentation. Surprisingly little is known about the molecular
      mechanisms that drive trophectoderm differentiation from the equipotent
      blastomeres of the morula. Somewhat more is known about the maintenance of
      trophoblast stem cells, once this lineage has been established. The first half of
      this review will focus on determination of the mouse trophoblast lineage and the
      second half will discuss the maintenance of trophoblast stem cells.

PMID- 15033303
TI  - Implantation: embryonic signals and the modulation of the uterine environment--a
      review.
AB  - Interaction between maternal endometrium and embryo during implantation is
      mediated through the multiple molecules and signalling cascades, which are still
      not fully understood. This complex sequence of events results in the
      transformation of stromal cells into decidual cells (decidualization). The
      conceptus is essential to regulate these changes in baboon stromal fibroblasts,
      possibly through production of cytokines by the implanting embryo. The role of
      interleukin-1 (IL-1) system during implantation and its contribution to
      decidualization is discussed in this review. Decidualized endometrial stromal
      cells are thought to contribute to establishment of a successful pregnancy by
      expressing a number of gene products. One of the major products of decidual cells
      is insulin-like growth factor binding protein-1 (IGFBP-1). The IGFBP-1 serves as
      a modulator of insulin-like growth factor (IGF) protein action in the
      interactions between the decidua and invading trophoblast. The delineation of the
      mechanisms involved in cooperative action of transcription factors FKHR and
      HOXA10 leading to IGFBP-1 expression, as well as interrelationship between IL-1
      and IGF signalling cascades will contribute to the understanding of events
      leading to successful implantation.

PMID- 15033305
TI  - Genes and development--a workshop report.

PMID- 15033306
TI  - Trophoblast and the endometrium--a workshop report.

PMID- 15033307
TI  - Maternal asthma as a model for examining fetal sex-specific effects on maternal
      physiology and placental mechanisms that regulate human fetal growth.
AB  - Studying the effect of maternal asthma during pregnancy on placental function and
      fetal development has highlighted that there is a strong interaction between
      mother, placenta and fetus and these interactions appear to be sex-specific. This
      work has found that the female fetus alters maternal asthma during pregnancy by
      upregulating maternal inflammatory pathways. When asthma-associated inflammatory
      pathways are not treated with inhaled steroids during pregnancy, the female fetus
      has reduced growth and adrenal function due to alterations in placental
      glucocorticoid metabolism. When the mother uses inhaled steroid for the treatment
      of her asthma during pregnancy, female fetal growth and placental function are
      comparable to the control population. The growth of the male fetus appears to be
      unaffected by asthma or inhaled steroid use. These findings indicate there may be
      different mechanisms regulating placental glucocorticoid and immune mechanisms
      depending on fetal sex in both asthmatic and non-asthmatic pregnancies.

PMID- 15033308
TI  - The insulin-like growth factor system in mammalian pregnancy--a workshop report.

PMID- 15033309
TI  - Placental transport in early pregnancy--a workshop report.

PMID- 15033310
TI  - Maternal adaptation to high-altitude pregnancy: an experiment of nature--a
      review.
AB  - A long and productive history of studies at high altitude has demonstrated that
      chronic hypoxia plays a key role in the aetiology of intrauterine growth
      restriction (IUGR) and pre-eclampsia. Susceptibility to altitude-associated IUGR
      varies among high-altitude populations in relation to their duration of altitude
      exposure, with multigenerational residents demonstrating one-third the birth
      weight fall present in shorter-resident groups. Higher uteroplacental blood flow
      during pregnancy in multigenerational high-altitude residents suggests that such
      population differences are due, at least in part, to differences in maternal
      vascular responses to pregnancy. We hypothesize that natural selection acting on
      hypoxia-inducible factor (HIF)-targeted or -regulatory genes has enabled maternal
      vascular adaptation to pregnancy in long-resident high-altitude groups.
      Preliminary evidence in support of this hypothesis demonstrates that the potent
      HIF-targeted vasoconstrictor, endothelin-1 (ET-1), is differentially regulated by
      pregnancy and chronic hypoxia in Andean vs European residents of high altitude.
      Andeans show the normal, pregnancy-associated fall in ET-1 levels previously
      reported at low altitude, whereas Europeans have higher ET-1 levels and little
      pregnancy-associated change, like pre-eclamptic women. Single nucleotide
      polymorphisms (SNPs) in the ET-1 gene also differ in Andeans compared with low
      altitude populations. We conclude that high altitude serves as an experiment of
      nature for elucidating genetic factors underlying susceptibility to complications
      of pregnancy and fetal life. Such studies may be important for identifying
      persons at risk for these complications at any altitude.

PMID- 15033311
TI  - Trophoblast oxidative stress, antioxidants and pregnancy outcome--a review.
AB  - Placental oxidative stress has been implicated in pre-eclampsia and miscarriage.
      The review briefly summarizes the definition of oxidative stress, methods of
      estimation and likely sources in the placenta. Experimental evidence favouring a
      role for trophoblast oxidative stress in pre-eclampsia includes reports of lipid
      peroxidation and deficiencies in antioxidant defences. The potential sources of
      free radical generation include enhanced enzymatic synthesis of superoxide by
      xanthine oxidase and NAD(P)H oxidase. Studies employing immunohistochemical
      markers of oxidative stress also implicate free radical induced damage in
      placentae from women with early pregnancy loss. The overwhelming evidence for
      oxidative stress in the placenta and the maternal circulation in pre-eclampsia
      has led to the suggestion that antioxidant prophylaxis may prevent oxidant stress
      and so ameliorate or prevent the disease. Several clinical trials currently
      underway will not only determine whether antioxidants are of use in pre-eclampsia
      prevention but also provide an ideal opportunity to investigate the aetiology and
      consequences of trophoblast oxidative stress.

PMID- 15033312
TI  - Impact of trisomy 21 on human trophoblast behaviour and hormonal function.
AB  - Although trisomy 21 (T21) is the most frequent genetic abnormality and some
      maternal serum markers for this fetoplacental aneuploidy are of placental origin,
      little is known of its impact on placental development. We therefore studied the
      influence of T21 on trophoblast behaviour. Using cultured cells from 46 human T21
      pregnancies, we confirmed the defective morphological and functional
      differentiation of the villous cytotrophoblast in this setting; indeed, villous
      cytotrophoblast cells aggregate normally but fuse inefficiently to form the
      syncytiotrophoblast. This is in part related to the abnormal oxidative status of
      the T21 cytotrophoblast, characterized by a gene dosage-related increase in SOD-1
      (copper-zinc superoxide dismutase) expression and activity. This was associated
      with a significant (P < 0.01) increase in catalase activity but no significant
      change in glutathione peroxidase activity. On the basis of these in vitro
      findings and studies of large panels of maternal serum, we propose a
      pathophysiological explanation for trisomy 21 maternal serum markers of placental
      origin.

PMID- 15033313
TI  - NAD(P)H oxidase associated superoxide production in human placenta from
      normotensive and pre-eclamptic women.
AB  - Oxidative stress plays an important role in the development of pre-eclampsia.
      Recently, the superoxide producing enzyme NAD(P)H oxidase was shown to be present
      in placental trophoblast. In this pilot-study we investigated the NAD(P)H oxidase
      associated superoxide production as modulator of placental oxidative stress in
      normotensive pregnancy (n = 19; gestational age 38(+6)+/-0(+1)weeks(+days)) and
      pre-eclampsia (n = 15; gestational age 34(+3)+/-1(+5)weeks(+days)) using a
      lucigenin assay. Specificity of superoxide generation by NAD(P)H oxidase was
      assessed using the inhibitors L-NAME, rotenone, allopurinol, DPI and TIRON.
      Superoxide production was measurable in all placenta tissues and was inhibited by
      DPI and TIRON. No significant differences for total superoxide production
      (O2*total), maximal superoxide production (O2*max), or the rate of superoxide
      production were found between normotensive and pre-eclamptic women. However,
      women with early onset of disease had a higher O2*total as compared to those with
      a late onset disease. We conclude that human placenta contains a functional
      NAD(P)H oxidase that is highly active, which could be an important source of
      superoxide during pregnancy and pre-eclampsia. These data justify more detailed
      investigation of the role of NAD(P)H oxidase and placental oxidative stress in
      complicated pregnancies.

PMID- 15033314
TI  - Oxygen and trophoblast behaviour--a workshop report.

PMID- 15033315
TI  - Circulating fetal DNA: its origin and diagnostic potential-a review.
AB  - OBJECTIVE: In contrast to the traditional teaching that the placenta forms an
      impermeable barrier, multiple studies show that both intact fetal cells and cell
      free nucleic acids circulate freely in maternal blood. Complications of
      pregnancy, such as pre-eclampsia, or fetal cytogenetic abnormalities, such as
      trisomy 21, increase transfusion of both intact fetal cells and cell-free fetal
      nucleic acids into the maternal circulation. The objective of our research is to
      show that abnormal feto-maternal trafficking of nucleic acids is associated with
      fetal and placental pathology, and that these observations may lead to novel non
      invasive diagnostic and screening tests. METHODS: Real-time quantitative PCR
      amplification of DYS1 is used to measure the levels of male fetal DNA in case
      control sets of serum or plasma taken from pregnant women. In our laboratory, we
      use DYS1, a Y-chromosome specific gene, as a uniquely fetal DNA marker for the
      development of gestation-specific normal values and theoretical models. RESULTS:
      Women carrying fetuses with trisomies 21 or 13 (but not 18) have increased levels
      of fetal DNA in their fresh or archived serum and/or plasma samples. Women
      destined to develop pre-eclampsia have a characteristic bi-phasic elevation of
      cell-free fetal DNA that precedes clinical symptoms. Data obtained from a variety
      of clinical scenarios suggest that the placenta is the predominant source of the
      circulating fetal nucleic acids, although apoptotic haematopoietic cells may
      contribute to the pool as well. CONCLUSIONS: Fetal cell-free DNA is elevated in a
      number of conditions associated with placental pathology. Widespread clinical
      implementation of fetal DNA as a screening tool awaits discovery of a reliable
      gender-independent marker, which may be DNA polymorphisms, epigenetic markers, or
      mRNA. Fetal cell-free nucleic acids have potential for non-invasive monitoring of
      placental pathology.

PMID- 15033317
TI  - Clinical pathology--a workshop report.

PMID- 15033316
TI  - Fetal thrombotic vasculopathy in the placenta: a thrombophilic connection between
      pregnancy complications and neonatal thrombosis?
AB  - OBJECTIVE: Fetal thrombotic vasculopathy (FTV) has been related to pregnancy
      complications and neonatal thrombosis separately. We assessed whether a
      relationship existed in our population of women with neonates who were admitted
      to our Neonatal Intensive Care Unit (NICU). In addition, the presence of
      thrombophilic factors in children and parents was investigated. METHODS: Two
      groups were detected by a search of the departmental databases. Group A was a
      cohort of 5000 neonates admitted to our NICU (1992-2002). Infants who developed
      thrombotic complications were selected. Group B was a cohort of placentae from
      our institution (2000, n = 141). Those with a diagnosis of FTV were selected.
      Case-notes and laboratory results were obtained through the hospital information
      system. RESULTS: Of Group A, thrombosis was reported in 55 children. Of these, 20
      matching placentae were available. Eight placentae showed FTV (40 per cent). Of
      the eight corresponding pregnancies, seven were complicated by pre-eclampsia
      and/or intra uterine growth restriction (IUGR). Of the 12 placentae without FTV,
      five of the pregnancies had pre-eclampsia and/or IUGR (odds ratio for relation
      FTV-Complications: 9.8, 95 per cent CI = 0.9-107). In Group B, nine placentae
      showed FTV (6.4 per cent). Of these nine, six of the pregnancies were complicated
      by pre-eclampsia and/or IUGR. None of the neonates developed thrombosis.
      CONCLUSION: Pre-eclampsia and/or IUGR as well as neonatal thrombosis are both
      associated with fetal thrombotic vasculopathy in the placenta. However, in our
      selected-tertiary centre-population, FTV did not predict neonatal thrombosis. The
      thrombophilic investigations of parents and children were incomplete. A standard
      approach for evaluating parents at risk for FTV and evaluating neonates at risk
      for thrombosis should be developed.

PMID- 15033318
TI  - From basic research to clinical application of placental proteins--a workshop
      report.

PMID- 15033319
TI  - Pre-eclampsia--a workshop report.

PMID- 15033320
TI  - Engineering of a recombinant Fab from a neutralizing IgG directed against
      scorpion neurotoxin AahI, and functional evaluation versus other antibody
      fragments.
AB  - Antibody-based therapy is the only specific treatment for scorpion envenomation.
      However, there are still major drawbacks associated with its use; mainly because
      antivenoms are still prepared from immune equine serum raised against crude
      venoms, whereas only a limited number of neurotoxins are responsible for the
      lethality of the venom. Using a murine hybridoma that secretes a well
      characterized neutralizing IgG directed to neurotoxins AahI and AahIII from the
      venom of the scorpion Androctonus australis, we constructed a recombinant Fab
      (rFab) fragment, which was produced and purified from transformed bacteria. It
      recognized toxin AahI with a high affinity (KD = 8.2 x 10(-11)) equivalent to the
      homologous pFab prepared by papain digestion of whole IgG. Although the AahI
      neutralizing capacity of protein L-purified rFab was low compared to other
      recombinant antibody formats (scFv and diabody) investigated in parallel, the
      antibody engineering approach presented here provides an innovative way to
      synthesize novel toxin-neutralizing molecules. It may serve as a strategy for
      designing a new generation of antivenoms.

PMID- 15033321
TI  - A predictive model to estimate total skin tetrodotoxin in the newt Taricha
      granulosa.
AB  - We developed a predictive model to estimate the total amount of tetrodotoxin
      (TTX) in the skin of individual newts (Taricha granulosa) based on measures of
      the amount of TTX present in dorsal skin. We found that regions of skin on a newt
      could be reliably differentiated using granular gland density and that patterns
      of variation in granular gland density matched intra-individual variation in TTX
      levels. Tetrodotoxin is uniformly distributed in dorsal skin and TTX levels in
      dorsal skin are strongly predictive of TTX levels in other regions of skin on a
      newt. Our model is both accurate and precise and includes the effect of body size
      through surface area, variation in granular gland density, as well as positional
      variation in toxicity apparently associated with variation in granular gland
      density. This technique allows us to detect patterns that would be unclear if
      only dorsal skin toxicity or total skin toxicity based on extracts from an entire
      animal were used and demonstrates that the levels of TTX present in some
      populations of T. granulosa are remarkably high.

PMID- 15033322
TI  - The effect of intraperitoneally administered microcystin-LR on the
      gastrointestinal tract of Balb/c mice.
AB  - Microcystin-LR (MCLR) has been associated with the development of
      gastrointestinal complaints in people ingesting cyanobacterial bloom contaminated
      water. The symptoms usually present a day or two after exposure raising questions
      as to the toxic effects of MCLR on the gastrointestinal tract. This study
      investigated the apoptotic effect of ip administered MCLR over time on the
      duodenum, jejenum and ileum of mice receiving a single 75% LD(50) dose. The
      apoptotic index was significantly raised in all sections at 8 h post exposure
      (pe) and continued to rise for the 16, 24 and 32 h pe groups, while the glycogen
      levels were normal at 24 h pe. The duodenum exhibited the most significant
      increase in apoptotic index overall, followed by the jejenum and ileum.
      Immunohistochemistry indicated the presence of MCLR in the lamina propria
      suggesting a role for MCLR in the induction of apoptosis in the GIT of mice
      exposed to a single sublethal dose of MCLR.

PMID- 15033323
TI  - Neurotoxic and myotoxic actions of crotoxin-like and Crotalus durissus cascavella
      whole venom in the chick biventer cervicis preparation.
AB  - Crotoxin from Crotalus durissus cascavella venom was purified by a combination of
      molecular exclusion chromatography (Superdex 75 column) and HPLC molecular
      exclusion (Protein Pack 300SW column). Neurotoxic and myotoxic effects from C.
      durissus cascavella whole venom and its main fraction, the crotoxin-like, were
      studied in the chick biventer cervicis (CBC) nerve-muscle preparation. Both venom
      and its crotoxin showed significant (p < 0.05) blockade of neuromuscular
      transmission at concentrations as low as 0.2-1, 5 and 25 microg/ml, but no
      significant effect has been shown with a concentration of 0.04 microg/ml (n = 5
      each). The time required to produce 50% neuromuscular blockade with the venom and
      its crotoxin was 53.6+/-8.2 and 65.9+/-4.9 min (0.2 microg/ml), 29.7+/-1.9 and
      34.3+/-1.9 min (1 microg/ml), 24.8+/-1.6 and 21.1+/-1.5 min (5 microg/ml), 20.9+/
      3.7 and 20.1+/-1.4 min (25 microg/ml), respectively. The addition to the
      incubation bath of acetylcholine (55 and 110 microM) or KCl (20.1 mM), either
      before or after the venom or the crotoxin induced contracture in the presence of
      a total blockade, in all the concentrations used. Morphological analysis showed
      that the damage caused by C. durissus cascavella venom is stronger than that
      caused by crotoxin. The myonecrotic picture was more marked at higher venom and
      crotoxin doses (1, 5 or 25 microg/ml). Only at 25 microg/ml concentrations of the
      venom and crotoxin, marked muscle fiber changes were detected. We concluded that
      the crotoxin-like and the whole venom from C. durissus cascavella possess a
      preponderant and quite potent neurotoxic action in this preparation, and a
      myotoxic action which is observed only at higher doses.

PMID- 15033324
TI  - Ardiscretin a novel arthropod-selective toxin from Tityus discrepans scorpion
      venom.
AB  - A new arthropod selective toxin was purified from the venom of the Venezuelan
      scorpion Tityus discrepans, and its amino acid sequence, cDNA clone and
      biological activity are reported here. The amino acid sequence of this peptide,
      named ardiscretin (from arthropod toxin of T. discrepans) was completed by Edman
      degradation and mass spectrometry. It is a single polypeptide composed by 61
      amino acids with an amidated cysteine residue at the C-terminal end, closely
      packed by four disulfide bridges. The atomic mass unit (a.m.u.) experimentally
      determined was 7103.8 a.m.u. This peptide was shown to be specific for
      invertebrates (crickets, triatomides, crabs and squids), but non-toxic to mice,
      at the dose assayed. Ardiscretin inhibits the Na(+)-currents of squid giant axons
      in an apparent irreversible manner, whose inhibitory effect is reached at 30
      microM toxin concentration. Sequence comparison showed that it is
      phylogenetically closely related to insect-specific scorpion toxins. Ardiscretin
      produced a small depolarization and induced repetitive firing in squid axons
      resembling those of DDT [1,1'(p-chlorobenzyl)2-tricloretane] in its ability to
      slow down action potential, to induce repetitive firing, and in that the
      concentration required for any effect in squid axon is rather high.

PMID- 15033325
TI  - Nociceptive and edematogenic responses elicited by a crude bristle extract of
      Lonomia obliqua caterpillars.
AB  - Lyophilized Lonomia obliqua crude bristle extract (LOCBE) diluted in
      physiological saline (15, 35 and 50 microg of protein/paw) was injected in the
      plantar surface of the hind paw of the rat, causing a nociceptive response which
      lasted from 30 to a maximum of 50 min, peaking in the first 5 min. The animals
      also presented hematuria and nasal bleeding. Nociception was inhibited by
      indomethacin pretreatment (2.5 mg/kg, i.p., 60 min before), but not by
      guanethidine (30 mg/kg/day, s.c., for 3 days) or loratadine (5 mg/kg, p.o., 60
      min before). LOCBE injection also produced paw edema peaking 1 h after injection
      and lasting for 6 h. Loratadine pretreatment, but neither guanethidine nor
      indomethacin, reduced edema. After the period of overt nociception, a nociceptive
      aftersensation response could be evoked up to 6 h after by immersing the paw into
      cold water (15 degrees C) for 10 s. Capsaicin (1.6 microg), formalin (0.5%) or
      prostaglandin E(2) (500 ng) did not produce the same aftersensation phenomenon.
      These results suggest that LOCBE-induced nociception is largely facilitated by
      prostaglandin production, and edematogenic response seems to be facilitated by
      prostanoids and histamine. Finally, LOCBE induced a state of sensitization to
      cold, which seemed to be specific as it was not caused by other noxious
      chemicals.

PMID- 15033326
TI  - Occurrence of toxic Planktothrix rubescens blooms in lake Nantua, France.
AB  - Cyanobacteria including genus Oscillatoria are known to release toxins into
      waterbodies. To study the occurrence of toxic blooms in Lake Nantua, the
      Planktothrix rubescens species (Oscillatoria rubescens) was considered. At the
      same time, some physicochemical parameters were analysed to estimate their impact
      on toxin production. The investigations were conducted during summertime and the
      highest toxin concentration analysed by HPLC was detected in August (10.8
      microg/l of lake water). The results of this work suggested that the toxin
      production increased when the light intensity, temperature, alkaline pH and
      phosphorus contents were at low levels. Moreover, the toxin production was
      positively related with NT/PT ratio. TLC analysis of the purified fractions
      revealed the occurrence of 4-7 polypeptide or protein bands. Two of them were
      shown to be toxic using Artemia bioassays and the most toxic one was identified
      as MCYST-RR.

PMID- 15033327
TI  - Freshwater stingrays: study of epidemiologic, clinic and therapeutic aspects
      based on 84 envenomings in humans and some enzymatic activities of the venom.
AB  - Freshwater stingrays are very common in the Parana, Paraguay, Araguaia, and
      Tocantins Rivers and tributaries in Brazil. This study presents the clinical
      aspects of 84 patients injured by freshwater stingrays. Intense pain was the most
      conspicuous symptom. Skin necrosis was observed in a high percentage of the
      victims, mostly fishermen and bathers. The initial therapeutic procedures, like
      immersion of the affected member in hot water were effective in the initial
      phases of the envenoming, especially in the control of the acute pain; however,
      they did not prevent skin necrosis. By SDS-PAGE, the freshwater stingray
      (Potamotrygon falkneri) venom extract presented a major band of approximately 12
      kDa. Several other components distributed between 15 and 130 kDa were detected in
      the venom extract. Many components with molecular mass above 80 and 100 kDa have
      gelatinolytic and caseinolytic activities, respectively. Hyaluronidase activity
      was detected only in a component around 84 kDa in P. falkneri venom extract. Our
      results demonstrated that the presence of these enzymes could explain partially
      the local clinical pictures presented by patients wounded by freshwater stingray.

PMID- 15033328
TI  - Effect of microcystin-LR on protein phosphatase activity in fed and fasted
      juvenile goldfish Carassius auratus L.
AB  - Fed and fasted juvenile goldfish Carassius auratus (30 g body weight) were
      injected intraperitoneally (i.p.) with microcystin-LR (MC-LR) (125 microg/kg body
      weight) to determine the effect of alimentary status on the hepatic toxicity of
      MC-LR. The toxin accumulation pattern was similar in both fed and fasted
      treatments. MC-LR accumulated during the first 48 h post-injection and decreased
      significantly between 48 and 96 h. MC-LR accumulation induced a decrease in
      hepatic protein phosphatase activity and glycogen content. Fasted individuals
      were more severely and more rapidly affected than fed ones. Both indicators were
      significantly altered after 6 h of fasted treatment. In particular, protein
      phosphatase activity was totally inhibited after 6 h in the fasted treatment but
      only lowered and not totally suppressed in the fed one. In both treatments, the
      recovery of enzyme activity was complete after 96 h. On the other hand, hepatic
      glutathione concentration and glutathione S-transferase activity were not
      significantly affected.

PMID- 15033329
TI  - Main alkaloids from the Brazilian dendrobatidae frog Epipedobates flavopictus:
      pumiliotoxin 251D, histrionicotoxin and decahydroquinolines.
AB  - Epipedobates flavopictus, Dendrobatidae, is a small aposematic frog found in
      Brazilian Cerrado bioma. In the present work, we isolated and characterized
      chemically the most abundant alkaloids present in the cutaneous extract of E.
      flavopictus. The specimens were collected in Pirenopolis (Goias, Brazil), their
      skins were removed and extracted with methanol, and submitted to purification by
      HPLC and identification by gas chromatography and mass spectrometry. Pumiliotoxin
      251D, histrionicotoxin 285Da and two decahydroquinolines, 219A and 243A, were
      identified. The pumiliotoxin 251D was tested on isolated frog sciatic nerve and
      on isolated guinea pig ileum muscle. The pumiliotoxin 251D slightly reduced the
      action potentials amplitude of frog sciatic nerve. The crude skin extract of E.
      flavopictus and the pumiliotoxin 251D produced rhythmic contractions and
      increased the muscular tension on isolated guinea pig ileum.

PMID- 15033330
TI  - Anti-Plasmodium properties of group IA, IB, IIA and III secreted phospholipases
      A2 are serum-dependent.
AB  - Antibacterial, antiparasitidal and antiviral properties have recently been
      attributed to members of the secreted phospholipases A(2) (sPLA(2)s) superfamily.
      Seven sPLA(2)s from groups IA, IB, IIA and III, were tested here in different
      culture conditions for inhibition of the in vitro intraerythrocytic development
      of Plasmodium falciparum, the causative agent of the most severe form of human
      malaria. In the presence of human serum, all sPLA(2)s were inhibitory, with three
      out of seven exhibiting IC(50)<0.1 nM. In all cases, inhibition could be induced
      by enzymatic pre-treatment of the serum. By contrast, no effect was observed when
      parasites were grown in a semi-defined medium (AlbuMAX II) devoid of lipoproteins
      and containing 10 times less phospholipids than the medium with human serum,
      strongly suggesting that hydrolysis of serum generating toxic lipid by-products,
      rather than a direct interaction of the sPLA(2) with the infected erythrocyte, is
      a general feature of the anti-Plasmodium properties of sPLA(2)s. Furthermore, in
      serum, six out of the seven sPLA(2)s were toxic against both trophozoite and
      schizont stages of the parasite development, contrasting with the trophozoite
      selective bee venom enzyme's toxicity. Deciphering the molecular mechanisms at
      play in the phenotypic singularity of the bee venom enzyme toxicity might offer
      new prospects in antimalarial fight.

PMID- 15033331
TI  - Analysis of PSP toxins in Norwegian mussels by a post-column derivatization HPLC
      method.
AB  - The aim of this study was to investigate the agreement between the AOAC mouse
      bioassay and an HPLC method for determining Paralytic Shellfish Poisoning (PSP)
      toxicity in blue mussels from the Norwegian coast. The AOAC mouse bioassay has
      traditionally been used for determining the toxin levels. Recently, an HPLC
      method for determining PSP toxins has been implemented and run in parallel with
      the bioassay. Four hundred mussel extracts from the last six years were analysed
      with both methods. A highly significant linear correlation between the methods
      was achieved (r = 0.84). However, the relation between the two methods was best
      described by a second-degree polynom. Totally, this model explained 87% of the
      variation in the HPLC method. By agreement analysis, it was possible to establish
      cut-off levels for the HPLC method related to the AOAC mouse bioassay with kappa
      values >0.80 for toxicity levels below 500 MU/100 g. The HPLC method could
      substitute the mouse bioassay in determining PSP toxicity in Norwegian mussels.
      Additionally, about 70 mussel samples were also analysed by the MIST Alert trade
      mark test kit. The kit did not give any false negative results compared with the
      regulatory limit, but 30% of the samples below the cut point were also determined
      as positive.

PMID- 15033332
TI  - Capillary electrophoresis to characterize ricin and its subunits with matrix
      assisted laser desorption/ionization time-of-flight mass spectrometry.
AB  - Capillary electrophoresis (CE) and matrix-assisted laser desorption/ionization
      time-of-flight mass spectrometry (MALDI-TOF MS) have been employed as highly
      efficient methods to characterize ricin, its subunits, and the chemically
      deglycosylated forms. As a CE method, sodium dodecyl sulfate-capillary gel
      electrophoresis (SDS-CGE) was used because of its merit over the conventional
      slab gel techniques. SDS-CGE showed higher resolution capability over other
      analytical tools in the analysis of the ricin mixture as well as in each of its
      purified forms. The high resolution was considered to be a result of the presence
      of carbohydrates on ricin subunits, and this property was useful for identifying
      the native ricin or its A chain from their chemically deglycosylated forms.
      However, this method exhibited an overestimation of the molecular mass due to the
      carbohydrate moieties on ricin subunits, and the inaccuracies were observed to be
      dependent on the carbohydrate content of the subunits. The exact molecular masses
      were measured by MALDI-TOF MS, and the results were almost consistent with the
      expected values. This study clearly illustrates the usefulness and necessity of
      complementary use of two powerful analytical techniques to characterize ricin and
      its subunits in a various research fields such as poisoning and immunotoxin
      research.

PMID- 15033333
TI  - Variety of PSP toxins in four culture strains of Alexandrium minutum collected
      from southern Taiwan.
AB  - Paralytic shellfish poisoning (PSP) toxin profiles were compared among four
      culture strains of Alexandrium minutum. GTX-1, 2, 3 and 4 are the PSP toxins that
      occur in A. minutum, and other PSP toxins were not detected. When comparing the
      toxin profile of four A. minutum strains, GTX1 and 4 were the major toxins in
      Amtk1, Amtk2, and Amtk4, but in Amtk7, GTX3 and 2 were the major toxins. The
      results indicate that strains with various toxin profiles exist in southern
      Taiwan, and suggest that the comparison of the toxin profiles between strains at
      different localities is difficult. Additionally, the toxin profiles of A. minutum
      strains cultured in the same environment were different, suggesting that it was
      owing to the intrinsic nature of toxic algae.

PMID- 15033334
TI  - Both A chain and B chain of beta-bungarotoxin are functionally involved in the
      facilitation of spontaneous transmitter release in Xenopus nerve-muscle cultures.
AB  - In the present study, Xenopus nerve-muscle cultures were used to explore the
      functional roles of A chain (a phospholipase A(2) subunit) and B chain (a non
      phospholipase A(2) subunit) of Bungarus multicinctus beta-bungarotoxin. It was
      found that beta-bungarotoxin induced an increment of the frequency of spontaneous
      synaptic currents (SSCs) in the nerve-muscle cultures. Modification of beta
      bungarotoxin with pyridoxal-5'-phosphate or substitution of Ca(2+) with Ba(2+) in
      buffer abolished the phospholipase A(2) activity of beta-bungarotoxin and the
      facilitatory phase of SSC as well. Antibodies that were directed specifically
      against A chain or B chain effectively inhibited phospholipase A(2) activity, and
      as a consequence the SSC frequency was not greatly different from the control
      rate. These results suggest that both A and B chains are indispensable parts of
      beta-bungarotoxin for inducing the facilitation of SSC frequency with Xenopus
      nerve-muscle cultures.

PMID- 15033335
TI  - Acute toxic effect of the algal yessotoxin on Purkinje cells from the cerebellum
      of Swiss CD1 mice.
AB  - Swiss CD1 mice died less than 2 h after intraperitoneal injection of 420
      microg/kg of algal yessotoxin (YTX). The morphological, histochemical and
      immunocytochemical studies performed on the cerebellar cortex revealed damage to
      the Purkinje cells. The main cytological alterations were observed in the
      cytoplasm, while less sufferance was detected in the nucleus. The
      immunocytochemical experiments showed an increased positivity to S100 protein
      while there was a decreased response to calbindin D-28K, beta-tubulin and
      neurofilaments. These changes in intracellular Ca(2+)-binding proteins and the
      modifications in the cytoskeletal components of Purkinje cells suggest that YTX
      may be involved in neurological disorders.

PMID- 15033337
TI  - Mutations of the 2' proline in the M2 domain of the human GABAC rho1 subunit
      alter agonist responses.
AB  - Mutations of the proline residue at the 2' position (P2') within the second
      transmembrane (M2) domain of the gamma-aminobutyric acid(C) (GABA(C)) rho1
      subunit are known to produce receptors with altered pharmacology. In the present
      study, P2' was mutated to alanine (rho1P2'A), phenylalanine (rho1P2'F), glycine
      (rho1P2'G) and serine (rho1P2'S). Mutant receptors were characterized using a
      range of agonists, partial agonists and antagonists. rho1P2'A, rho1P2'G and
      rho1P2'S receptors were less susceptible than wild-type receptors to agonist
      activation. Most notably, the partial agonists, (+/-)-trans-2
      (aminomethyl)cyclopropanoic acid ((+/-)-TAMP) and imidazole-4-acetic acid (I4AA)
      were converted to antagonists at rho1P2'G and rho1P2'S receptors and the partial
      agonist CACA acted as an antagonist at rho1P2'S receptors. In contrast, rho1P2'F
      receptors were more prone to activation by agonists. A correlation was observed
      between the pharmacological properties of the mutant receptors and the
      hydrophobicity of each residue. Unlike the agonists or partial agonists, the
      affinity of competitive antagonists, (1,2,5,6-tetrahydropyridine-4
      yl)methylphosphinic acid (TPMPA) and 4,5,6,7-tetrahydroisoxazole[4,5-c]pyridine-3
      ol (THIP), did not change significantly between wild-type and mutant receptors.
      Thus, the results suggest that the agonist/competitive antagonist binding site(s)
      were not significantly affected by the mutations, but that receptor activation
      properties altered such that the more hydrophobic the residue at the 2' position,
      the more prone the receptor is to agonist activation.

PMID- 15033338
TI  - Excessive and precocious glutamate release in a mouse model of amyotrophic
      lateral sclerosis.
AB  - The release of [3H]D-aspartate ([3H]D-ASP) or [3H]GABA evoked by glycine and that
      of [3H]D-ASP or [3H]glycine evoked by GABA from spinal cord synaptosomes were
      studied in SOD1-G93A(+) mice, a transgenic model of amyotrophic lateral
      sclerosis, SOD1(+) mice and SOD1(-)/G93A(-) animals. Mutant mice were killed at
      advanced phase of pathology or during the presymptomatic period. In SOD1(-)/G93A(
      ) or SOD1(+) mice glycine evoked [(3)H]d-ASP and [(3)H]GABA release, while GABA
      caused [3H]D-ASP, but not [3H]glycine, release. The glycine-evoked release of
      [3H]D-ASP, but not that of [3H]GABA, and the GABA-evoked [3H]D-ASP release, but
      not that of [3H]glycine, were more pronounced in SOD1-G93A(+) than in SOD1(+)
      mice. Furthermore, these potentiations were already present in asymptomatic 30-
      to 40-day-old mice. Basal [3H]D-ASP release was also higher in SOD1-G93A(+) than
      SOD1(+) or SOD1(-)/G93A(-) mice. The release of endogenous glutamate and GABA was
      also enhanced in asymptomatic animals; the glycine-evoked release of endogenous
      glutamate, but not of endogenous GABA, was higher in SOD1-G93A(+) than in SOD1(+)
      animals. The effects of glycine and GABA were insensitive to receptor blockers,
      but sensitive to transporter inhibitors, indicating coexistence of glutamate and
      glycine transporters and of glutamate and GABA transporters on glutamate
      releasing terminals. The glutamate release machinery seems excessively functional
      in SOD1-G93A(+) animals.

PMID- 15033336
TI  - Induction of corticostriatal LTP by 3-nitropropionic acid requires the activation
      of mGluR1/PKC pathway.
AB  - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder
      typically affecting individuals in midlife. HD is characterized by the selective
      loss of striatal spiny neurons, while large cholinergic interneurons are spared.
      An impaired mitochondrial complex II (succinate dehydrogenase, SD) activity is
      known as a prominent metabolic alteration in HD. Accordingly, chronic treatment
      with 3-nitropropionic acid (3-NP), an irreversible SD inhibitor, mimics motor
      abnormalities and pathology of HD in several animal models. We have previously
      shown that in vitro application of 3-NP induces a long-term potentiation (LTP) of
      corticostriatal synaptic transmission through NMDA glutamate receptor. Since this
      3-NP-induced LTP (3-NP-LTP) is shown by striatal spiny neurons, but not by
      cholinergic interneurons, it might play a role in the regional and cell type
      specific neuronal death observed in HD. Here we investigate the role of group I
      metabotropic glutamate receptors (mGluRs) in the induction of 3-NP-LTP. We report
      that selectively blocking mGluR1, but not mGluR5, suppresses 3-NP-LTP induction.
      Moreover, we show that a PKC-mediated mechanism is involved in the formation of 3
      NP-LTP. Characterizing the cellular mechanisms underlying 3-NP-LTP may provide
      new insights to better understand the processes leading to the selective neuronal
      loss observed in HD.

PMID- 15033339
TI  - Pharmacological characterization of glutamatergic agonists and antagonists at
      recombinant human homomeric and heteromeric kainate receptors in vitro.
AB  - An increasing body of evidence suggests that native kainate receptors form ion
      channels from homomeric and heteromeric combinations of five receptor subunits:
      GluR5, GluR6, GluR7, KA1 and KA2. We have examined the activity of agonists and
      antagonists at recombinant human kainate receptors expressed in HEK293 cells,
      using both whole-cell electrophysiological recording and 96-well plate fluo-3
      based calcium microfluorimetry (FLIPR). Both homomeric (GluR5 and GluR6) and
      heteromeric (GluR5/6, GluR5/KA2 and GluR6/KA2) receptors were examined.
      Heteromeric receptor assemblies showed electrophysiological and pharmacological
      profiles which were distinct from homomeric channels. Several agonists, including
      AMPA, ATPA and (S)-5-iodowillardiine, and antagonists, including gamma-D
      glutamylaminomethylsulphonic acid (GAMS) and the decahydroisoquinoline compounds
      LY293558, LY377770 and LY382884, were found to act at GluR5-containing channels
      while having no effect at GluR6 homomers. AMPA, ATPA and (S)-5-iodowillardiine
      did activate GluR6/KA2 heteromers, but only as partial agonists. Additionally,
      ATPA was shown to act as an antagonist at homomeric GluR6 receptors at high
      concentrations (IC50 approximately 2 mM). Kynurenic acid was also found to
      differentiate between GluR6 and GluR6/KA2 receptors, antagonizing glutamate at
      GluR6 (IC50 = 0.4 mM), while having no effect at GluR6/KA2 channels. The results
      of the current study provide a broad pharmacological characterization of both
      homomeric and heteromeric recombinant human kainate receptors, and identify which
      compounds are likely to be useful tools for studying these various receptor
      subtypes.

PMID- 15033340
TI  - Inhibitory effects of trace amines on rat midbrain dopaminergic neurons.
AB  - Trace amines are biological compounds that are still awaiting identification of
      their role in neuronal function. Using intracellular electrophysiological
      recordings, we investigated the depressant action of two trace amines (beta
      phenylethylamine and tyramine) on the firing activity of dopaminergic neurons of
      the substantia nigra pars compacta and ventral tegmental area. This inhibition
      was due to a membrane hyperpolarisation that was blocked by the D2 dopamine
      receptor antagonist sulpiride and was not potentiated by the dopamine-uptake
      blocker, cocaine. Inhibition of the dopamine transporter did not mediate the
      effects of trace amines, because unlike cocaine, trace amines did not potentiate
      the inhibitory responses to exogenously applied dopamine. The inhibitory actions
      of beta-phenylethylamine and tyramine were present in reserpine-treated animals
      but were abolished when the dopamine-synthesis inhibitor carbidopa was applied.
      Our data suggest that trace amines cause an indirect activation of dopamine
      autoreceptors, by an increased efflux of newly synthesised dopamine. The
      inhibition of dopaminergic activity by trace amines may relate to their
      involvement in neuronal processes linked to drug addiction, schizophrenia,
      attention deficit hyperactive disorders and Parkinson's disease.

PMID- 15033341
TI  - Comparative study of the effects of desipramine and reboxetine on locus coeruleus
      neurons in rat brain slices.
AB  - Several studies have suggested that the locus coeruleus may play an important
      role in the pathophysiology of depression. The aim of this study was to
      characterize, using single-unit extracellular recordings, the in vitro effects of
      the noradrenaline reuptake inhibitors desipramine and reboxetine, on locus
      coeruleus neurons from control rats and from those chronically treated with
      desipramine. Bath application of desipramine (1-100 microM) and reboxetine (0.1
      10 microM) decreased the firing rate of locus coeruleus neurons in a
      concentration-dependent manner and the alpha(2)-adrenoceptor antagonist RX 821002
      (10 microM) reversed these effects. In addition, reserpine (5 mg/kg, 3 h before
      the experiment) almost completely blocked the inhibitory effect of desipramine.
      Both drugs (1 microM desipramine and 0.1 microM reboxetine) potentiated the
      inhibitory effect of noradrenaline (10 microM). A 7-day treatment with
      desipramine (3 mg/kg/12 h, i.p.) caused a decrease in sensitivity to the alpha(2)
      adrenoceptor agonist bromoxidine (EC(50) increased by 3.3-fold), but not to
      noradrenaline or reboxetine. In contrast, this treatment potentiated the
      inhibitory effect of desipramine with respect to control. Moreover, 14-day
      treatment with desipramine (3 mg/kg/12 h, i.p.) or reboxetine (10 mg/kg/12 h,
      i.p.) also potentiated the in vitro effect of desipramine without modifying the
      in vitro effect of reboxetine. These results show that desipramine and reboxetine
      modulate the activity of locus coeruleus neurons by noradrenaline acting on
      alpha(2)-adrenoceptors, and reveal that alpha(2)-adrenoceptor-independent
      mechanisms may also underlie the action of noradrenaline uptake inhibitors.

PMID- 15033342
TI  - Naloxone-induced morphine withdrawal increases the number and degranulation of
      mast cells in the thalamus of the mouse.
AB  - Naloxone-induced jumping in morphine-dependent mice is inhibited by cromolyn, a
      mast cell stabilizer, suggesting that this characteristic withdrawal behavior
      results from degranulation of mast cells. Because withdrawal is considered as a
      central phenomenon, degranulation of mast cells located within the CNS may
      influence aspects of opioid withdrawal. The present study evaluates
      histologically whether naloxone, injected into opioid dependent mice, induces
      degranulation of mast cells. Seventy-two hours after the s.c. implantation of a
      75 mg morphine pellet, the number and degranulation of thalamic mast cells did
      not differ from those in placebo-implanted controls. However, two injections of
      50 mg/kg of naloxone, 30 and 60 min before tissue collection, increased the
      number of degranulated mast cells compared to those in mice injected with saline.
      Analysis throughout the entire thalamus (90 40-micro sections) revealed increases
      in the total number of mast cells as well as the number that were degranulated,
      especially in sections 52-60, corresponding to Bregma -2.18 to 2.54. Here, mast
      cells were clustered in the IGL and VPL/VPM nuclei, and redistributed from the
      ventromedial to the dorsolateral aspects of the Po and PF nuclei during
      withdrawal. Degranulation was also greater throughout the LD, LP nuclei during
      withdrawal. These data reveal a novel neuroimmune reaction to opioid withdrawal
      in the CNS.

PMID- 15033343
TI  - Deletion of guanine nucleotide binding protein alpha z subunit in mice induces a
      gene dose dependent tolerance to morphine.
AB  - The mechanism underlying the development of tolerance to morphine is still
      incompletely understood. Morphine binds to opioid receptors, which in turn
      activates downstream second messenger cascades through heterotrimeric guanine
      nucleotide binding proteins (G proteins). In this paper, we show that G(z), a
      member of the inhibitory G protein family, plays an important role in mediating
      the analgesic and lethality effects of morphine after tolerance development. We
      blocked signaling through the G(z) second messenger cascade by genetic ablation
      of the alpha subunit of the G protein in mice. The Galpha(z) knockout mouse
      develops significantly increased tolerance to morphine, which depends on
      Galpha(z) gene dosage. Further experiments demonstrate that the enhanced morphine
      tolerance is not caused by pharmacokinetic and behavioural learning mechanisms.
      The results suggest that G(z) signaling pathways are involved in transducing the
      analgesic and lethality effects of morphine following chronic morphine treatment.

PMID- 15033344
TI  - Pharmacological characterisation of novel alpha 2-adrenoceptor antagonists as
      potential brain imaging agents.
AB  - Development of suitable imaging ligands to facilitate in vivo characterisation of
      alpha(2)-adrenoceptors has been limited in its success. In the present study, a
      series of iodinated derivatives and a fluorinated derivative of the classical
      alpha(2)-adrenoceptor antagonist, idazoxan, have been evaluated as potential
      imaging ligands. These compounds are based on the structure of idazoxan but more
      closely resemble the selective alpha(2)-adrenoceptor antagonists 2-methoxy
      idazoxan (RX821002) and 2-ethoxy-idazoxan (RX811059). Preliminary studies,
      investigating their affinities at alpha(2)-adrenoceptors, using brain membranes
      prepared from a variety of species, and their ability to antagonise UK14, 304
      induced inhibition of twitch in mouse vas deferens highlighted 2-iodopropoxy
      idazoxan and 2-fluoroethoxy-idazoxan as the most promising candidates. Further
      characterisation of these two compounds showed they had a good selectivity for
      alpha(2)-adrenoceptors compared with imidazoline(2)-binding sites and beta
      adrenoceptors. Additional functional studies also showed a lack of intrinsic
      activity at alpha(2)-adrenoceptors. Following intravenous injection, both
      compounds were able to cross the blood brain barrier when tested using an ex vivo
      binding assay. These data show that both 2-iodopropoxy-idazoxan and 2
      fluoroethoxy-idazoxan have binding and functional properties suitable for imaging
      ligands. Further studies using radiolabelled forms of these ligands and a more
      extensive characterisation of their binding profiles are necessary but these
      initial evaluations demonstrate their potential.

PMID- 15033345
TI  - Characterization of the convulsant action of pregnenolone sulfate.
AB  - Pregnenolone sulfate (PS) is an endogenous neurosteroid synthesized by glial
      cells, which acts as a potent convulsant when injected intracerebroventricularly
      and intraperitoneally. PS is found in relatively high concentrations in the
      hippocampus. But its convulsant action in the hippocampus has not been
      characterized. A range of PS doses were infused directly into the right
      hippocampus of 42 rats, which were subsequently monitored for behavioral and
      electrographic seizures. At the highest dose (4 micromol), PS produced status
      epilepticus (SE) and severe behavioral convulsions. As the dose of PS was
      reduced, the fraction of rats having SE diminished (ED50 for SE = 2.7 micromol).
      At doses lower than 300 nmol, PS infusion produced discrete electrographic
      seizures (ED50 = 68 nmol) associated with mild behavioral seizures. Both the
      behavioral seizure score (BSS) and the total number of seizures during the
      observation period changed in a dose-dependent manner. In separate experiments in
      cultured hippocampal neurons, PS enhanced NMDA-evoked whole-cell currents (EC50 =
      16 microM). The results demonstrate that the hippocampus is highly sensitive to
      the convulsant effects of PS and that the enhancement of NMDA currents could
      contribute to the convulsant action of PS.

PMID- 15033346
TI  - Nifedipine affects the anticonvulsant activity of topiramate in various animal
      models of epilepsy.
AB  - Topiramate (TPM), a new generation antiepileptic drug was investigated for its
      anticonvulsant effects in various models of genetically determined and chemically
      induced epilepsy in rodents. In addition, based on recent electrophysiological
      data suggesting that TPM may interact with L-type Ca(2+) channels, we evaluated
      the effects of a concomitant administration of L-type Ca(2+) channel modulators
      on TPM's antiepileptic properties. TPM, dose-dependently, protected against
      audiogenic seizures in DBA/2 mice. Concomitant treatment with TPM and a low dose
      of L-type Ca(2+) channel antagonists nifedipine or verapamil or with the L-type
      Ca(2+) channel agonist, S(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2
      (trifluoromethyl)phenyl]-3-pyridinecarboxylic acid methyl ester (Bay k 8644) was
      able to increase the ED(50) for this drug. TPM also protected against seizures
      induced by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), 4
      aminopyridine (4-AP) and pentylenetetrazole (PTZ), but this activity was not
      significantly modified by nifedipine. TPM, dose-dependently, reduced the number
      and duration of epileptic spike-wave discharges (SWDs) both in WAG/Rij rats and
      lethargic (lh/lh) mice, two genetic models of absence epilepsy. Nifedipine
      decreased TPM's activity in WAG/Rij rats but paradoxically enhanced it in lh/lh
      mice, whereas Bay k 8644 displayed opposite effects in both absence models. These
      results confirm TPM's broad spectrum of anticonvulsant activity and support the
      proposal that a modulation of neuronal L-type Ca(2+) channel activity plays an
      important role in its antiepileptic activity.

PMID- 15033347
TI  - Increased long-term potentiation in the CA1 region of rat hippocampus via
      modulation of GTPase signalling or inhibition of Rho kinase.
AB  - There is accumulating evidence that Ras, and Ras-related GTPases of the Rho
      family, such as RhoA, RhoB and Rac1, are involved in synaptic plasticity in brain
      regions such as the hippocampus. We have recently shown that Rho family GTPases
      are activated by synaptic transmission in the CA1 region of the hippocampus.
      Since the function of these GTPases is dependent on post-translational
      isoprenylation by either farnesyl or geranylgeranyl transferases, we tested the
      hypothesis that inhibition of isoprenylation would modify long-term potentiation
      (LTP). Farnesyl transferase inhibition, which suppressed activation of RhoB and
      Ras but not RhoA or Rac1, reduced the magnitude of LTP, while geranylgeranyl
      transferase inhibition, which inhibited RhoA and Rac1 but not RhoB, increased the
      magnitude of LTP. In addition, Y-27632, a specific inhibitor of a downstream
      effector of Rho GTPases-Rho-kinase-also increased the magnitude of LTP. This
      provides strong evidence that GTPases are important mediators of synaptic
      plasticity, and demonstrates that Rho-kinase acts to reduce the degree of
      plasticity at hippocampal synapses during LTP. Rho-kinase inhibitors have the
      unusual property of increasing the magnitude of LTP, and so may be potential
      cognitive enhancers.

PMID- 15033348
TI  - Pemirolast potently attenuates paclitaxel hypersensitivity reactions through
      inhibition of the release of sensory neuropeptides in rats.
AB  - The effects of anti-allergic agents on the hypersensitivity reactions to
      paclitaxel, an anti-cancer agent, were examined in rats. Intravenous injection of
      paclitaxel (15 mg/kg) caused a marked extravasation of plasma protein in lungs
      and a transient decrease in arterial partial oxygen pressure (PaO(2)). The
      paclitaxel-induced protein extravasation was inhibited by low doses (0.1-1 mg/kg)
      of pemirolast or high doses (30-100 mg/kg) of cromoglycate. However, ketotifen
      was not effective. The decrease in PaO(2) induced by paclitaxel was also
      significantly reversed by pemirolast. On the other hand, the paclitaxel-induced
      plasma extravasation was not attenuated by a histamine H(1) blocker
      diphenhydramine or an H(2) blocker famotidine, but was significantly reduced by a
      neurokinin NK(1) antagonist LY303870 (0.5 mg/kg) and an NK(2) antagonist SR48968
      (1 mg/kg). The concentrations of proteins and sensory peptides such as substance
      P, neurokinin A and calcitonin gene-related peptide but not histamine in the rat
      bronchoalveolar lavage fluid were elevated by paclitaxel injection. Both
      cromoglycate and pemirolast reduced the paclitaxel-induced rise in proteins and
      sensory peptides. Therefore, we demonstrated for the first time that sensory
      nerve peptides are involved in paclitaxel hypersensitivity and that an anti
      allergic agent pemirolast attenuates the paclitaxel response by inhibiting the
      release of sensory nerve peptides.

PMID- 15033350
TI  - Nucleosome binding by the bromodomain and PHD finger of the transcriptional
      cofactor p300.
AB  - The PHD finger and the bromodomain are small protein domains that occur in many
      proteins associated with phenomena related to chromatin. The bromodomain has been
      shown to bind acetylated lysine residues on histone tails. Lysine acetylation is
      one of several histone modifications that have been proposed to form the basis
      for a mechanism for recording epigenetically stable marks in chromatin, known as
      the histone code. The bromodomain is therefore thought to read a part of the
      histone code. Since PHD fingers often occur in proteins next to bromodomains, we
      have tested the hypothesis that the PHD finger can also interact with
      nucleosomes. Using two different in vitro assays, we found that the
      bromodomain/PHD finger region of the transcriptional cofactor p300 can bind to
      nucleosomes that have a high degree of histone acetylation. In a nucleosome
      retention assay, both domains were required for binding. Replacement of the p300
      PHD finger with other PHD fingers resulted in loss of nucleosome binding. In an
      electrophoretic mobility shift assay, each domain alone showed, however,
      nucleosome-binding activity. The binding of the isolated PHD finger to
      nucleosomes was independent of the histone acetylation levels. Our data are
      consistent with a model where the two domains cooperate in nucleosome binding. In
      this model, both the bromodomain and the PHD finger contact the nucleosome while
      simultaneously interacting with each other.

PMID- 15033349
TI  - Role of hippocampal oxidative stress in memory deficits induced by sleep
      deprivation in mice.
AB  - Numerous animal and clinical studies have described memory deficits following
      sleep deprivation. There is also evidence that the absence of sleep increases
      brain oxidative stress. The present study investigates the role of hippocampal
      oxidative stress in memory deficits induced by sleep deprivation in mice. Mice
      were sleep deprived for 72 h by the multiple platform method-groups of 4-6
      animals were placed in water tanks, containing 12 platforms (3 cm in diameter)
      surrounded by water up to 1 cm beneath the surface. Mice kept in their home cage
      or placed onto larger platforms were used as control groups. The results showed
      that hippocampal oxidized/reduced glutathione ratio as well as lipid peroxidation
      of sleep-deprived mice was significantly increased compared to control groups.
      The same procedure of sleep deprivation led to a passive avoidance retention
      deficit. Both passive avoidance retention deficit and increased hippocampal lipid
      peroxidation were prevented by repeated treatment (15 consecutive days, i.p.)
      with the antioxidant agents melatonin (5 mg/kg), N-tert-butyl-alpha-phenylnitrone
      (200 mg/kg) or vitamin E (40 mg/kg). The results indicate an important role of
      hippocampal oxidative stress in passive avoidance memory deficits induced by
      sleep deprivation in mice.

PMID- 15033351
TI  - Does native state topology determine the RNA folding mechanism?
AB  - Recent studies in protein folding suggest that native state topology plays a
      dominant role in determining the folding mechanism, yet an analogous statement
      has not been made for RNA, most likely due to the strong coupling between the
      ionic environment and conformational energetics that make RNA folding more
      complex than protein folding. Applying a distributed computing architecture to
      sample nearly 5000 complete tRNA folding events using a minimalist, atomistic
      model, we have characterized the role of native topology in tRNA folding
      dynamics: the simulated bulk folding behavior predicts well the experimentally
      observed folding mechanism. In contrast, single-molecule folding events display
      multiple discrete folding transitions and compose a largely diverse,
      heterogeneous dynamic ensemble. This both supports an emerging view of
      heterogeneous folding dynamics at the microscopic level and highlights the need
      for single-molecule experiments and both single-molecule and bulk simulations in
      interpreting bulk experimental measurements.

PMID- 15033352
TI  - Solution structure of the complex formed by the two N-terminal RNA-binding
      domains of nucleolin and a pre-rRNA target.
AB  - Nucleolin is a 70 kDa multidomain protein involved in several steps of eukaryotic
      ribosome biogenesis. In vitro selection in combination with mutagenesis and
      structural analysis identified binding sites in pre-rRNA with the consensus
      (U/G)CCCG(A/G) in the context of a hairpin structure, the nucleolin recognition
      element (NRE). The central region of the protein contains four tandem RNA-binding
      domains (RBDs), of which the first two are responsible for the RNA-binding
      specificity and affinity for NREs. Here, we present the solution structure of the
      28 kDa complex formed by the two N-terminal RNA-binding domains of nucleolin
      (RBD12) and a natural pre-rRNA target, b2NRE. The structure demonstrates that the
      sequence-specific recognition of the pre-rRNA NRE is achieved by intermolecular
      hydrogen bonds and stacking interactions involving mainly the beta-sheet surfaces
      of the two RBDs and the linker residues. A comparison with our previously
      determined NMR structure of RBD12 in complex with an in vitro selected RNA
      target, sNRE, shows that although the sequence-specific recognition of the loop
      consensus nucleotides is the same in the two complexes, they differ in several
      aspects. While the protein makes numerous specific contacts to the non-consensus
      nucleotides in the loop E motif (S-turn) in the upper part of the sNRE stem,
      nucleolin RBD12 contacts only consensus nucleotides in b2NRE. The absence of
      these upper stem contacts from the RBD12/b2NRE complex results in a much less
      stable complex, as demonstrated by kinetic analyses. The role of the loop E motif
      in high-affinity binding is supported by gel-shift analyses with a series of sNRE
      mutants. The less stable interaction of RBD12 with the natural RNA target is
      consistent with the proposed role of nucleolin as a chaperone that interacts
      transiently with pre-rRNA to prevent misfolding.

PMID- 15033353
TI  - Conformational changes modulate the activity of human RAD51 protein.
AB  - Homologous recombination provides a major pathway for the repair of DNA double
      strand breaks in mammalian cells. Defects in homologous recombination can lead to
      high levels of chromosomal translocations or deletions, which may promote cell
      transformation and cancer development. A key component of this process is RAD51.
      In comparison to RecA, the bacterial homologue, human RAD51 protein exhibits low
      level strand-exchange activity in vitro. This activity can, however, be
      stimulated by the presence of high salt. Here, we have investigated the
      mechanistic basis for this stimulation. We show that high ionic strength favours
      the co-aggregation of RAD51-single-stranded DNA (ssDNA) nucleoprotein filaments
      with naked duplex DNA, to form a complex in which the search for homologous
      sequences takes place. High ionic strength allows differential binding of RAD51
      to ssDNA and double-stranded DNA (dsDNA), such that ssDNA-RAD51 interactions are
      unaffected, whereas those between RAD51 and dsDNA are destabilized. Most
      importantly, high salt induces a conformational change in RAD51, leading to the
      formation of extended nucleoprotein filaments on ssDNA. These extended filaments
      mimic the active form of the Escherichia coli RecA-ssDNA filament that exhibits
      efficient strand-exchange activity.

PMID- 15033354
TI  - phi29 DNA polymerase-terminal protein interaction. Involvement of residues
      specifically conserved among protein-primed DNA polymerases.
AB  - By multiple sequence alignments of DNA polymerases from the eukaryotic-type
      (family B) subgroup of protein-primed DNA polymerases we have identified five
      positively charged amino acids, specifically conserved, located N-terminally to
      the (S/T)Lx(2)h motif. Here, we have studied, by site-directed mutagenesis, the
      functional role of phi29 DNA polymerase residues Arg96, Lys110, Lys112, Arg113
      and Lys114 in specific reactions dependent on a protein-priming event. Mutations
      introduced at residues Arg96, Arg113 and Lys114 and to a lower extent Lys110 and
      Lys112, showed a defective protein-primed initiation step. Analysis of the
      interaction with double-stranded DNA and terminal protein (TP) displayed by
      mutant derivatives R96A, K110A, K112A, R113A and K114A allows us to conclude that
      phi29 DNA polymerase residue Arg96 is an important DNA/TP-ligand residue,
      essential to form stable DNA polymerase/DNA(TP) complexes, while residues Lys110,
      Lys112 and Arg113 could be playing a role in establishing contacts with the TP
      DNA template during the first step of DNA replication. The importance of residue
      Lys114 to make a functionally active DNA polymerase/TP complex is also discussed.
      These results, together with the high degree of conservation of those residues
      among protein-primed DNA polymerases, strongly suggest a functional role of those
      amino acids in establishing the appropriate interactions with DNA polymerase
      substrates, DNA and TP, to successfully accomplish the first steps of TP-DNA
      replication.

PMID- 15033355
TI  - Molecular flexibility and discontinuous translocation of a non-templated
      polymerase.
AB  - Little is known regarding the translocation of non-templated nucleic acid
      polymerases with respect to single-stranded primers. VP55, the vaccinia virus
      poly(A) polymerase, translocates as it processively adds a approximately 3-7
      adenylate tail to primers possessing only three ribouridylate residues (as an
      (rU)(2)-N(15)-rU motif), and a approximately 25-30 adenylate tail to primers that
      are more U-rich. Here, three models were addressed for the translocation of VP55
      with respect to its primer, namely: (a) rigid protein/rigid nucleic acid; (b)
      flexible protein/rigid nucleic acid; (c) rigid protein/flexible nucleic acid.
      Analysis of free and covalently VP55-attached primers favored either (b) or a
      version of (c) incorporating a passive steric block, and suggested two regions of
      relative motion between polymerase and primer. Inclusion of a 6nt uridylate-rich
      patch at the primer 3' end switched the polymerase from approximately 3-7 nt to
      approximately 25-30 nt tail addition without affecting initial binding affinity.
      By synthesizing this patch as a (rU/dC) pool, discontinuous polymerase movements
      could be detected.

PMID- 15033356
TI  - The biotin repressor: modulation of allostery by corepressor analogs.
AB  - The Escherichia coli biotin repressor functions in biotin retention and
      regulation of biotin biosynthesis. Biotin retention is accomplished via the two
      step biotinylation of the biotin-dependent enzyme, acetyl-CoA carboxylase. In the
      first step of this reaction the substrates biotin and ATP are utilized in
      synthesis of the activated biotin, biotinyl-5'-AMP, while in the second step this
      activated biotin is transferred to a unique lysine residue of the biotin carboxyl
      carrier protein subunit of the carboxylase. Regulation of biotin biosynthesis is
      accomplished through binding of the repressor to the transcription control region
      of the biotin biosynthetic operon. The adenylated or activated biotin functions
      as the corepressor in this DNA binding process. The activated biotin is a mixed
      anhydride and thus labile. In efforts to develop tools for structural and
      thermodynamic studies of the biotin regulatory interactions, two analogs of the
      adenylate, a sulfamoyl derivative and an ester derivative, have been synthesized
      and functionally characterized. Results of fluorescence measurements indicate
      that both analogs bind with high affinity to the repressor and that both are
      inactive in biotin transfer to the acceptor protein. Functional studies of their
      corepressor properties indicate that while the sulfamoyl is a weak allosteric
      activator, the ester closely mimics the physiological corepressor in activation
      of assembly of the transcription repression complex. Results of these studies
      also provide further insight into the allosteric mechanism of the biotin
      repressor.

PMID- 15033357
TI  - Interconverting the catalytic activities of (betaalpha)(8)-barrel enzymes from
      different metabolic pathways: sequence requirements and molecular analysis.
AB  - The (betaalpha)(8)-barrel enzymes N'-[(5'-phosphoribosyl)formimino]-5
      aminoimidazole-4-carboxamide ribonucleotide isomerase (tHisA) and imidazole
      glycerol phosphate synthase (tHisF) from Thermotoga maritima catalyze two
      successive reactions in the biosynthesis of histidine. In both enzymes, aspartate
      residues at the C-terminal end of beta-strand 1 (Asp8 in tHisA and Asp11 in
      tHisF) and beta-strand 5 (Asp127 in tHisA and Asp130 in tHisF) are essential for
      catalytic activity. It was demonstrated earlier that in tHisA the substitution of
      Asp127 by valine (tHisA-D127V) generates phosphoribosylanthranilate isomerase
      (TrpF) activity, a related (betaalpha)(8)-barrel enzyme participating in
      tryptophan biosynthesis. It is shown here that in tHisF the corresponding
      substitution of Asp130 by valine (tHisF-D130V) also generates TrpF activity. To
      determine the effectiveness of individual amino acid exchanges in these
      conversions, each of the 20 standard amino acid residues was introduced at
      position 127 of tHisA and 130 of tHisF by saturation random mutagenesis. The
      tHisA-D127X and tHisF-D130X variants with TrpF activity were identified by
      selection in vivo, and the proteins purified and characterized. The results
      obtained show that removal of the negatively charged carboxylate side-chain at
      the C-terminal end of beta-strand 5 is sufficient to establish TrpF activity in
      tHisA and tHisF, presumably because it allows the binding of the negatively
      charged TrpF substrate, phosphoribosylanthranilate. In contrast, the double
      mutants tHisA-D8N+D127V and tHisF-D11N+D130V did not show detectable activity,
      demonstrating that the aspartate residues at the C-terminal end of beta-strand 1
      are essential for catalysis of the TrpF reaction. The ease with which TrpF
      activity can be established on both the tHisA and tHisF scaffolds supports the
      evolutionary relationship of these three enzymes and highlights the functional
      plasticity of the (betaalpha)(8)-barrel enzyme fold.

PMID- 15033358
TI  - A soluble VE-cadherin fragment forms 2D arrays of dimers upon binding to a lipid
      monolayer.
AB  - A high concentration of cadherin molecules at cell-cell adhesion sites is
      believed to be essential for generating strong intercellular junctions. In order
      to determine the interactions of cadherin domains involved in the early stages of
      lateral cluster formation on the cell surface, a recombinant fragment
      encompassing the first four domains of human VE-cadherin with a His-tag at the C
      terminus (VE-EC1-4-His) was produced. Two-dimensional crystals of VE-EC1-4-His
      were formed at the air-water interface using conventional lipids modified to
      contain a Ni(2+)-chelating group, which provides a specific site for interaction
      with the polyhistidine tag. The VE-EC1-4-His was monomeric at the concentration
      employed for crystal formation; however, the crystals exhibited a p2 symmetry and
      the presence of cis-dimer interactions between symmetry-related molecules. The VE
      EC1-4-His molecules in the crystalline array have a remarkably compact
      conformation in contrast to the elongated "string of pearls" conformation seen in
      the hexameric assembly of VE-EC1-4-His in solution, and as seen in the crystal
      structure of C-cadherin. These results indicate that VE-cadherin can exist in at
      least two oligomeric states with different interactions between domains and can
      adopt highly different conformational states. We suggest that the compact cis
      dimeric state may occur on isolated cells and that the compact form may serve to
      protect the molecule from degradation. As previously proposed we suppose that the
      trans-hexameric form is involved in intercellular adhesion.

PMID- 15033359
TI  - Crystal structure of HEL4, a soluble, refoldable human V(H) single domain with a
      germ-line scaffold.
AB  - The antigen binding site of antibodies usually comprises associated heavy (V(H))
      and light (V(L)) chain variable domains, but in camels and llamas, the binding
      site frequently comprises the heavy chain variable domain only (referred to as
      V(HH)). In contrast to reported human V(H) domains, V(HH) domains are well
      expressed from bacteria and yeast, are readily purified in soluble form and
      refold reversibly after heat-denaturation. These desirable properties have been
      attributed to highly conserved substitutions of the hydrophobic residues of V(H)
      domains, which normally interact with complementary V(L) domains. Here, we
      describe the discovery and characterisation of an isolated human V(H) domain
      (HEL4) with properties similar to those of V(HH) domains. HEL4 is highly soluble
      at concentrations of > or =3 mM, essentially monomeric and resistant to
      aggregation upon thermodenaturation at concentrations as high as 56 microM.
      However, in contrast to V(HH) domains, the hydrophobic framework residues of the
      V(H):V(L) interface are maintained and the only sequence changes from the
      corresponding human germ-line segment (V3-23/DP-47) are located in the loops
      comprising the complementarity determining regions (CDRs). The crystallographic
      structure of HEL4 reveals an unusual feature; the side-chain of a framework
      residue (Trp47) is flipped into a cavity formed by Gly35 of CDR1, thereby
      increasing the hydrophilicity of the V(H):V(L) interface. To evaluate the
      specific contribution of Gly35 to domain properties, Gly35 was introduced into a
      V(H) domain with poor solution properties. This greatly enhanced the recovery of
      the mutant from a gel filtration matrix, but had little effect on its ability to
      refold reversibly after heat denaturation. Our results confirm the importance of
      a hydrophilic V(H):V(L) interface for purification of isolated V(H) domains, and
      constitute a step towards the design of isolated human V(H) domains with
      practical properties for immunotherapy.

PMID- 15033360
TI  - Very fast folding and association of a trimerization domain from bacteriophage T4
      fibritin.
AB  - The foldon domain constitutes the C-terminal 30 amino acid residues of the
      trimeric protein fibritin from bacteriophage T4. Its function is to promote
      folding and trimerization of fibritin. We investigated structure, stability and
      folding mechanism of the isolated foldon domain. The domain folds into the same
      trimeric beta-propeller structure as in fibritin and undergoes a two-state
      unfolding transition from folded trimer to unfolded monomers. The folding
      kinetics involve several consecutive reactions. Structure formation in the region
      of the single beta-hairpin of each monomer occurs on the submillisecond
      timescale. This reaction is followed by two consecutive association steps with
      rate constants of 1.9(+/-0.5)x10(6)M(-1)s(-1) and 5.4(+/-0.3)x10(6)M(-1)s(-1) at
      0.58 M GdmCl, respectively. This is similar to the fastest reported bimolecular
      association reactions for folding of dimeric proteins. At low concentrations of
      protein, folding shows apparent third-order kinetics. At high concentrations of
      protein, the reaction becomes almost independent of protein concentrations with a
      half-time of about 3 ms, indicating that a first-order folding step from a
      partially folded trimer to the native protein (k=210 +/- 20 s(-1)) becomes rate
      limiting. Our results suggest that all steps on the folding/trimerization pathway
      of the foldon domain are evolutionarily optimized for rapid and specific
      initiation of trimer formation during fibritin assembly. The results further show
      that beta-hairpins allow efficient and rapid protein-protein interactions during
      folding.

PMID- 15033361
TI  - Studies of the collagen-like peptide (Pro-Pro-Gly)(10) confirm that the shape and
      position of the type I collagen denaturation endotherm is governed by the rate of
      helix unfolding.
AB  - The kinetics of unfolding of a collagen-like peptide, (Pro-Pro-Gly)(10), has been
      studied under isothermal conditions to gain a better understanding of the
      stabilization of the collagen triple helix. The formation process was third-order
      and relatively insensitive to temperature at concentrations of 1 mg/ml and below,
      while the unfolding process was first-order and highly temperature-dependent. The
      helix-coil transition was studied over a range of scanning rates and polymer
      concentrations, using differential scanning calorimetry and the observations were
      compared with solutions of an approximate differential equation governing the
      process. At high concentrations (24 mg/ml) and very low scanning rates (0.025
      degrees C min(-1)), the helicity, F, approached a quasistatic state in which it
      reached its equilibrium value at all temperatures. Under these conditions, the
      temperature at which the endotherm peaked, T(max), increased with chain
      concentration but was independent of scanning rate, while (dF/dT)(max) was
      dependent on the van't Hoff enthalpy and on the order of the formation process.
      On scanning from a low to a high temperature (up-scanning) at low concentrations
      (0.25-1.0 mg/ml) and higher scanning rates (0.1 degrees C min(-1) and above), the
      peak in dF/dT was taller and narrower than for slow quasistatic scanning. T(max)
      increased linearly with the logarithm of the scanning rate, and was independent
      of concentration, while (dF/dT)(max) was governed by the temperature-dependence
      of the rate of unfolding. At intermediate scanning rates, two peaks in dF/dT were
      apparent. One peak was a nascent "quasistatic peak"; the other was a nascent
      "rate peak". Comparison of this peptide data with the properties of the collagen
      denaturation endotherm showed that the collagen denaturation endotherm was
      determined only by the rate of unfolding, and not by an unobserved equilibrium.

PMID- 15033362
TI  - Quantifying structure-function uncertainty: a graph theoretical exploration into
      the origins and limitations of protein annotation.
AB  - Since the advent of investigations into structural genomics, research has focused
      on correctly identifying domain boundaries, as well as domain similarities and
      differences in the context of their evolutionary relationships. As the science of
      structural genomics ramps up adding more and more information into the databanks,
      questions about the accuracy and completeness of our classification and
      annotation systems appear on the forefront of this research. A central question
      of paramount importance is how structural similarity relates to functional
      similarity. Here, we begin to rigorously and quantitatively answer these
      questions by first exploring the consensus between the most common protein domain
      structure annotation databases CATH, SCOP and FSSP. Each of these databases
      explores the evolutionary relationships between protein domains using a
      combination of automatic and manual, structural and functional, continuous and
      discrete similarity measures. In order to examine the issue of consensus
      thoroughly, we build a generalized graph out of each of these databases and
      hierarchically cluster these graphs at interval thresholds. We then employ a
      distance measure to find regions of greatest overlap. Using this procedure we
      were able not only to enumerate the level of consensus between the different
      annotation systems, but also to define the graph-theoretical origins behind the
      annotation schema of class, family and superfamily by observing that the same
      thresholds that define the best consensus regions between FSSP, SCOP and CATH
      correspond to distinct, non-random phase-transitions in the structure comparison
      graph itself. To investigate the correspondence in divergence between structure
      and function further, we introduce a measure of functional entropy that
      calculates divergence in function space. First, we use this measure to calculate
      the general correlation between structural homology and functional proximity. We
      extend this analysis further by quantitatively calculating the average amount of
      functional information gained from our understanding of structural distance and
      the corollary inherent uncertainty that represents the theoretical limit of our
      ability to infer function from structural similarity. Finally we show how our
      measure of functional "entropy" translates into a more intuitive concept of
      functional annotation into similarity EC classes.

PMID- 15033363
TI  - Mechanistic insights into the kinetics of HIV-1 nucleocapsid protein-facilitated
      tRNA annealing to the primer binding site.
AB  - HIV-1 reverse transcriptase uses human tRNA(Lys,3) as a primer to initiate
      reverse transcription. Prior to initiation, the 3' 18 nucleotides of this tRNA
      are annealed to a complementary sequence on the RNA genome known as the primer
      binding site (PBS). Here, we show that the HIV-1 nucleocapsid protein (NC)
      enhances this annealing by approximately five orders of magnitude in vitro,
      decreasing the transition state enthalpy from approximately 20 kcal mol(-1) for
      the uncatalyzed reaction to 13 kcal mol(-1) for the NC-catalyzed process.
      Moreover, the annealing follows second-order kinetics, consistent with the
      nucleation of the intermolecular duplex being the rate-limiting step. This
      nucleation is preceded by melting of a small duplex region within the original
      structure, and is followed by much faster zipping of the rest of the 18 base-pair
      (bp) duplex. A tRNA mutational analysis shows that destabilization of the tRNA
      acceptor stem has only a minor effect on the annealing rate. In contrast,
      addition of bases to the 5' end of tRNA that are complementary to its single
      stranded 3' end interferes with duplex nucleation and therefore has a much larger
      effect on the net reaction rate. Assuming that the apparent transition free
      energy of the annealing reaction, Delta G(++) is a sum of the melting (Delta
      G(m)) and nucleation (Delta G(nuc)) free energies, we show that NC affects both
      Delta G(m) and Delta G(nuc). We estimate that ten to 100-fold of the overall rate
      enhancement is due to NC-induced destabilization of a 4 bp helix in the PBS,
      while the additional factor of 10(3)-10(4) rate enhancement is a result of NC
      facilitated duplex nucleation. The apparently similar effectiveness of wild-type
      and SSHS NC, a mutant that lacks the zinc finger structures, in facilitating the
      tRNA annealing reaction is most likely the result of the mutual cancellation of
      two factors: SSHS NC is less effective than wild-type NC as a duplex
      destabilizer, but more effective as a duplex nucleating agent.

PMID- 15033364
TI  - Integrating three views of Arf1 activation dynamics.
AB  - The proteins Arno and Gea2 of the Sec7 family can promote GDP-GTP exchange on
      Arf1, a small GTP-binding protein, which coordinates coated vesicle formation for
      protein transport within the cell. Crystal structures of the essential Sec7
      domain (Sec7d) of Gea2 in the free and Arf1-bound forms suggest that
      conformational dynamics of the Sec7d as well as those of the G-protein play a
      role in nucleotide exchange. Starting from a set of complementary crystal
      structures, we compared the collective movements of unbound Gea2 and Arno Sec7
      domains, Arf1-GDP, and the Arf1-Gea2(Sec7d) nucleotide-free complex using normal
      modes analyses. In all unbound Sec7d analyses, significant low-energy movements
      were found to lead to closure of the hydrophobic groove towards the form seen in
      the Arf1-Gea2(Sec7d) complex, suggesting that groove closure is a general feature
      of the Sec7 family. Low-energy movements in Arf1-GDP implicate critical switch 1
      and 2 residues which are coupled to modifications in the myristoylated N-terminal
      helix binding site at the other end of the "interswitch" beta hairpin. It is
      suggested that Sec7d groove closure upon docking of the two molecules may permit
      extraction of switch 1 from Arf1-GDP and prepare the complex for movement of the
      interswitch, which is central to the membrane-linked exchange activity. Large
      scale collective movements in the Arf1-Sec7d complex appear to participate in the
      insertion of the Sec7d Glu finger into the GDP binding site to promote actual
      nucleotide release.

PMID- 15033365
TI  - Flexible multi-scale fitting of atomic structures into low-resolution electron
      density maps with elastic network normal mode analysis.
AB  - A novel method is presented for the quantitative flexible docking of high
      resolution structure into low-resolution maps of macromolecular complexes from
      electron microscopy. This method uses a linear combination of low-frequency
      normal modes from elastic network description of the molecular framework in an
      iterative manner to deform the structure optimally to conform to the low
      resolution electron density map. The methodology utilizes gradient following
      techniques in collective normal modes to locally optimize the overall correlation
      coefficient between computed and measured electron density. To evaluate the
      performance of our approach, several proteins, which undergo large conformational
      changes, have been studied. We demonstrate that refinement based on normal mode
      analysis provides an accurate and fast alternative for the flexible fitting of
      high-resolution structure into a low-resolution density map. Additionally, we
      show that lower resolution (multi-scale) structural models can be used for the
      normal mode searching in lieu of fully atomic models with little loss of overall
      accuracy.

PMID- 15033366
TI  - Structural determinants of PLD2 inhibition by alpha-synuclein.
AB  - The presynaptic protein alpha-synuclein has been implicated in both neuronal
      plasticity and neurodegenerative disease, but its normal function remains
      unclear. We described the induction of an amphipathic alpha-helix at the N
      terminus (exons 2-4) of alpha-synuclein upon exposure to phospholipid vesicles,
      and hypothesized that lipid-binding might serve as a functional switch by
      stabilizing alpha-synuclein in an active (alpha-helical) conformation. Others
      have shown that alpha and beta-synucleins inhibit phospholipase D (PLD), an
      enzyme involved in lipid-mediated signaling cascades and vesicle trafficking.
      Here, we report that all three naturally occurring synuclein isoforms (alpha,
      beta, and gamma-synuclein) are similarly effective inhibitors of PLD2 in vitro,
      as is the Parkinson's disease-associated mutant A30P. The PD-associated mutant
      A53T, however, is a more potent inhibitor of PLD2 than is wild-type alpha
      synuclein. We analyze mutations of the alpha-synuclein protein to identify
      critical determinants of human PLD2 inhibition in vitro. Deletion of residues 56
      102 (exon 4) decreases PLD2 inhibition significantly; this activity of exon 4 may
      require adoption of an alpha-helical conformation, as mutations that disrupt
      alpha-helicity also abrogate inhibition. Deletion of C-terminal residues 130-140
      (exon 6) completely abolishes inhibitory activity. In addition, PLD2 inhibition
      is blocked by phosphorylation at serine 129 or at tyrosine residues 125 and 136,
      or by mutations that mimic phosphorylation at these sites. We conclude that PLD2
      inhibition by alpha-synuclein is mediated by a lipid-stabilized alpha-helical
      structure in exon 4 and also by residues within exon 6, and that this inhibition
      can be modulated by phosphorylation of specific residues in exons 5 and 6.

PMID- 15033367
TI  - Ligand-induced conformational changes and a reaction intermediate in branched
      chain 2-oxo acid dehydrogenase (E1) from Thermus thermophilus HB8, as revealed by
      X-ray crystallography.
AB  - The alpha(2)beta(2) tetrameric E1 component of the branched-chain 2-oxo acid
      (BCOA) dehydrogenase multienzyme complex is a thiamin diphosphate (ThDP)
      dependent enzyme. E1 catalyzes the decarboxylation of a BCOA concomitant with the
      formation of the alpha-carbanion/enamine intermediate, 2-(1-hydroxyalkyl)-ThDP,
      followed by transfer of the 1-hydroxyalkyl group to the distal sulfur atom on the
      lipoamide of the E2 component. In order to elucidate the catalytic mechanism of
      E1, the alpha- and beta-subunits of E1 from Thermus thermophilus HB8 have been co
      expressed in Escherichia coli, purified and crystallized as a stable complex, and
      the following crystal structures have been analyzed: the apoenzyme (E1(apo)), the
      holoenzyme (E1(holo)), E1(holo) in complex with the substrate analogue 4
      methylpentanoate (MPA) as an ES complex model, and E1(holo) in complex with 4
      methyl-2-oxopentanoate (MOPA) as the alpha-carbanion/enamine intermediate
      (E1(ceim)). Binding of cofactors to E1(apo) induces a disorder-order transition
      in two loops adjacent to the active site. Furthermore, upon binding of MPA to
      E1(holo), the loop comprised of Gly121beta-Gln131beta moves close to the active
      site and interacts with MPA. The carboxylate group of MPA is recognized mainly by
      Tyr86beta and N4' of ThDP. The hydrophobic moiety of MPA is recognized by
      Phe66alpha, Tyr95alpha, Met128alpha and His131alpha. As an intermediate, MOPA is
      decarboxylated and covalently linked to ThDP, and the conformation of the protein
      loop is almost the same as in the substrate-free (holoenzyme) form. These results
      suggest that E1 undergoes an open-closed conformational change upon formation of
      the ES complex with a BCOA, and the mobile region participates in the recognition
      of the carboxylate group of the BCOA. ES complex models of E1(holo).MOPA and of
      E1(ceim).lipoamide built from the above structures suggest that His273alpha and
      His129beta' are potential proton donors to the carbonyl group of a BCOA and to
      the proximal sulfur atom on the lipoamide, respectively.

PMID- 15033369
TI  - Prediction of functional sites in proteins using conserved functional group
      analysis.
AB  - A detailed knowledge of a protein's functional site is an absolute prerequisite
      for understanding its mode of action at the molecular level. However, the rapid
      pace at which sequence and structural information is being accumulated for
      proteins greatly exceeds our ability to determine their biochemical roles
      experimentally. As a result, computational methods are required which allow for
      the efficient processing of the evolutionary information contained in this wealth
      of data, in particular that related to the nature and location of functionally
      important sites and residues. The method presented here, referred to as conserved
      functional group (CFG) analysis, relies on a simplified representation of the
      chemical groups found in amino acid side-chains to identify functional sites from
      a single protein structure and a number of its sequence homologues. We show that
      CFG analysis can fully or partially predict the location of functional sites in
      approximately 96% of the 470 cases tested and that, unlike other methods
      available, it is able to tolerate wide variations in sequence identity. In
      addition, we discuss its potential in a structural genomics context, where
      automation, scalability and efficiency are critical, and an increasing number of
      protein structures are determined with no prior knowledge of function. This is
      exemplified by our analysis of the hypothetical protein Ydde_Ecoli, whose
      structure was recently solved by members of the North East Structural Genomics
      consortium. Although the proposed active site for this protein needs to be
      validated experimentally, this example illustrates the scope of CFG analysis as a
      general tool for the identification of residues likely to play an important role
      in a protein's biochemical function. Thus, our method offers a convenient
      solution to rapidly and automatically process the vast amounts of data that are
      beginning to emerge from structural genomics projects.

PMID- 15033368
TI  - Analysis of the interactions between HIV-1 and the cellular prion protein in a
      human cell line.
AB  - The cellular prion protein (PrP(c)) is highly conserved in mammals and expressed
      widely in different tissues but its physiological role remains elusive. Recently,
      the human PrP(c) was shown to possess nucleic acid binding and chaperoning
      properties similar to human immunodeficiency virus type 1 (HIV-1) nucleocapsid
      protein, a key viral factor in virus structure and replication. These findings
      prompted us to determine if PrP(c) could influence HIV-1 replication. We used the
      human 293T cell line as a model system, since only a very low level of PrP(c)
      accumulates in these cells. Expression of PrP at a high level resulted in a
      specific decrease of HIV-1 Env and Vpr expression. Despite similar levels of
      intracellular Gag, virus production was reduced by eightfold and infectivity by
      three- to fourfold in the presence of PrP(c). A PrP(c) mutant lacking the
      glycosylphosphatidylinositol (GPI) anchor peptide did not impair HIV-1
      production, suggesting that PrP(c) trafficking is critical for this inhibitory
      effect. Coexpressing HIV-1 and PrP(c) in these cells also caused a fraction of
      PrP(c) to become partially proteinase K-resistant (PrP(res)), further
      illustrating the interactions between HIV-1 and PrP(c).

PMID- 15033371
TI  - Effects of carbocisteine on altered activities of glycosidase and
      glycosyltransferase and expression of Muc5ac in SO2-exposed rats.
AB  - Carbocisteine is a mucoregulatory drug regulating fucose and sialic acid contents
      in mucus glycoprotein. To investigate the mechanism of carbocisteine action, we
      evaluated the effects of carbocisteine on the activity of fucosidase, sialidase,
      fucosyltransferase and sialyltransferase, and on the expression of Muc5ac mRNA in
      the airway epithelium of SO(2)-exposed rats. Wistar rats were repeatedly exposed
      to a 300-ppm SO(2) gas for 44 days. Carbocisteine (125 and 250 mg/kg x2/day) was
      administered for 25 days after 20 days of SO(2) gas exposure. These enzyme
      activities were measured by fluorogenic substrate or glycoproteinic exogenous
      acceptor method. The expression levels of Muc5ac mRNA and protein were determined
      with real-time reverse transcriptase-polymerase chain reaction (real-time RT-PCR)
      and enzyme-linked immunosorbent assay (ELISA), respectively. Carbocisteine (250
      mg/kg x2/day) inhibited all the changes in these enzyme activities and the
      expressions of Muc5ac mRNA and protein in the lung after repeated SO(2) exposure.
      These findings suggest that carbocisteine may normalize fucose and sialic acid
      contents in mucin glycoprotein through regulation of these enzyme activities, and
      inhibition of both Muc5ac mRNA and protein expressions in SO(2)-exposed rats.

PMID- 15033370
TI  - Regulation of urokinase plasminogen activator by epigallocatechin-3-gallate in
      human fibrosarcoma cells.
AB  - (-)-Epigallocatechin-3-gallate (EGCG), a main flavanol of green tea, potently
      suppressed the urokinase-type plasminogen activator (uPA) expression in human
      fibrosarcoma HT 1080 cells. EGCG induced not only the suppression of the uPA
      promoter activity but also the destabilization of uPA mRNA. EGCG inhibited the
      phosphorylation of extracellular signal-regulated kinases 1 and 2 (Erk-1/2) and
      P38 mitogen-activated protein kinase (MAPK), but not the phosphorylation of c-jun
      N-terminal kinase (JNK) and Akt. Specific inhibitors of Erk-1/2 (2'-amino-3'
      methoxyflavone, PD98059) and P38 MAPK (pyridinylimidazole, SB203580) were found
      to suppress the uPA expression and the uPA promoter activity. However, the
      specific inhibitors did not affect the uPA mRNA stability. These results suggest
      that EGCG could regulate the uPA expression by at least two different mechanisms:
      EGCG may inhibit the Erk-1/2 and P38 MAPK, leading to suppression of the uPA
      promoter activity, and EGCG may destabilize the uPA mRNA in an Erk-1/2- and p38
      MAPK-independent way.

PMID- 15033374
TI  - Single-channel activity of L-type Ca2+ channels reconstituted with the beta2c
      subunit cloned from the rat heart.
AB  - We recently cloned the beta(2c) subunit of the L-type Ca(2+) channel as a
      functional type of beta subunit from the rat heart. In order to clarify the
      contribution of the beta(2c) subunit to native Ca(2+) channel function, we
      investigated the single-channel properties of Ca(2+) channels reconstituted with
      beta(2a) or beta(2c) subunits and compared them with the properties of native
      channels. In contrast to the Ca(2+) channel with beta(2a) subunit, long-lasting
      closings were dominant in the Ca(2+) channel with beta(2c) subunit and the native
      channel. The ensemble-averaged current of the cells with beta(2c) subunits was
      comparable to that of the native cardiomyocytes. Many high P(o) sweeps (mode 2)
      were observed in the cells with beta(2a) subunits, while only a few high P(o)
      sweeps were observed in the cells with beta(2c) subunits and the native cells.
      These findings suggest that the beta(2c) subunit is one of the functional beta
      subunits in the rat heart.

PMID- 15033372
TI  - Pharmacological differentiation of the P2X7 receptor and the maitotoxin-activated
      cationic channel.
AB  - The ATP-P2X(7) receptor subtype and a maitotoxin-activated ion channel were
      studied to determine factors which identify them as separate entities in the
      control of a cytotolytic pore. Activation of ATP-P2X(7) receptors with 2'-3'-O
      (benzylbenzyl) ATP (BzATP) or maitotoxin ion channels resulted in influx of
      ethidium bromide and cell death. Maitotoxin (25-250 pM)-induced ethidium bromide
      uptake and cell death was sensitive to extracellular Ca(2+), the ionic
      composition of the buffer, reduced by the calmodulin inhibitor W7, (N-(s
      aminohexyl)-5-chloro-1-naphthalenesulfonamide), (10-100 microM) but unaffected by
      the ATP-P2X(7) receptor antagonist oxidized ATP, (adenosine 5'-triphosphate
      periodate oxidized sodium salt) (oATP). BzATP (10-200 microM)-induced ethidium
      bromide uptake and cell death were inhibited by oATP, unaffected by W7, inhibited
      by high ionic concentrations but only slightly dependant on external Ca(2+).
      These results are consistent with the existence of a pharmacological mechanism
      for controlling cell death consisting of an ATP-P2X(7) receptor, a maitotoxin
      activated ion channel and a cytolytic pore.

PMID- 15033373
TI  - Effects of terpenoid phenol derivatives on calcium current in canine and human
      ventricular cardiomyocytes.
AB  - Concentration-dependent (10-1000 microM) effects of terpenoid phenol derivatives
      were studied on L-type Ca(2+) current in isolated canine and human ventricular
      cardiomyocytes using the whole-cell configuration of patch clamp technique.
      Carvacrol, thymol and eugenol suppressed peak Ca(2+) current at +5 mV, having
      EC(50) values and Hill coefficients of 98+/-11, 158+/-7 and 187+/-15 microM and
      1.42+/-0.05, 2.96+/-0.43 and 1.6+/-0.1, respectively, in canine myocytes.
      Zingerone displayed a weak effect (estimated EC(50): 2+/-0.37 mM, Hill
      coefficient: 0.73+/-0.07), while vanillin and guaiacol failed to substantially
      modify Ca(2+) current up to the concentration of 1 mM. In addition to tonic
      block, thymol and carvacrol, but not eugenol, evoked marked rate-dependent block
      at 2 Hz. Carvacrol and eugenol accelerated inactivation of Ca(2+) current and
      caused leftward shift in the voltage dependence of steady-state inactivation
      without altering activation kinetics. Carvacrol, but not eugenol, increased the
      time constant of recovery from inactivation. These effects of carvacrol and
      eugenol developed rapidly and were largely reversible. In myocytes isolated from
      undiseased human hearts, the effect of carvacrol was similar to that observed in
      canine cells. It is concluded that suppression of cardiac Ca(2+) currents by
      phenol derivatives is influenced by the substituent in the benzene ring, and the
      blocking effect of these drugs may involve interactions with the inactivation
      machinery of the channel.

PMID- 15033375
TI  - Natural killer cell activity and anti-tumour effects of dehydrocrotonin and its
      synthetic derivatives.
AB  - In this work, the anti-tumour properties of dehydrocrotonin and its derivatives
      were investigated in vitro and in vivo using the Ehrlich ascites tumour model.
      Treatment of Ehrlich ascites tumour-bearing mice with 20 mg/kg dehydrocrotonin
      for 4 days significantly increased survival, whereas administration of
      dehydrocrotonin derivatives was ineffective in affording protection. Compound IV
      exhibited little activity against Ehrlich tumour cells in vitro. Investigation of
      the effects of dehydrocrotonin treatment on total natural killer (NK) cell
      activity of tumour-bearing mice as a possible mechanism of dehydrocrotonin action
      in vivo revealed that this sesquiterpene lactone significantly improved NK
      cytotoxicity against YAC-1, a Moloney virus-induced mouse T-cell lymphoma of A/SN
      origin. As expected, tumour growth in non-treated mice markedly suppressed NK
      cell cytolysis. No effects on NK functional activity were observed in normal mice
      receiving dehydrocrotonin. In summary, only the natural compound exhibits anti
      tumour efficacy and immunomodulatory actions in vivo, which may be related to its
      chemical structure.

PMID- 15033376
TI  - Mutational analysis of the histamine H1-receptor binding pocket of
      histaprodifens.
AB  - Histaprodifens constitute a new class of histamine H(1)-receptor agonists. These
      ligands can be regarded as hybrid molecules, consisting of a histamine moiety
      linked at the two-position of the imidazole ring by a propyl chain to two phenyl
      rings, one of the characteristic features of several H(1)-receptor antagonists.
      To delineate the binding site of various histaprodifen-like ligands, we generated
      mutant histamine H(1) receptors, in which various amino acids, involved in the
      binding of either histamine or H(1)-receptor antagonists, were replaced by
      alanine. Wild-type and mutant H(1) receptors were transiently expressed in
      African green monkey kidney cells (COS-7) and evaluated for their interaction
      with histamine and various histaprodifens by [(3)H]mepyramine radioligand-binding
      studies and by nuclear factor kappaB (NF-kappaB) reporter-gene assays. Our data
      show that, within the histamine H(1)-receptor binding pocket, histaprodifens
      interact with both agonist and antagonist binding sites, resulting in high
      affinity histamine H(1)-receptor agonists.

PMID- 15033377
TI  - Action of the muscarinic toxin MT7 on agonist-bound muscarinic M1 receptors.
AB  - The muscarinic toxin MT7 is the most selective ligand for the muscarinic M(1)
      receptors. Previous studies have shown that the toxin interacts with the
      antagonist-receptor complex and slows the antagonist dissociation rate, possibly
      by binding to an allosteric site and impeding the access to and egress from the
      orthosteric binding pocket. In the present study, we investigated the action of
      MT7 on agonist-occupied receptors in functional and radioligand binding assays of
      the cloned human muscarinic M(1) receptor expressed in Chinese hamster ovary
      cells. In time-course experiments, the addition of MT7 rapidly blocked the
      acetylcholine-stimulated guanosine-5'-O-(3-[(35)S]thio)triphosphate binding to
      membrane G proteins. Similarly, in acetylcholine-treated cells MT7 completely
      stopped the agonist-stimulated [(3)H]inositol phosphate accumulation. In
      dissociation experiments using membranes pre-equilibrated with
      [(3)H]acetylcholine, the addition of MT7 increased the rate of radioligand
      dissociation. The data indicate that MT7, while partially stabilizing the
      antagonist-receptor complex, effectively destabilizes the agonist-occupied
      muscarinic M(1) receptors.

PMID- 15033378
TI  - The mouse brain adenosine A1 receptor: functional expression and pharmacology.
AB  - The adenosinergic system is involved in many important physiological functions.
      Adenosine exerts its extracellular effects through four types of G-protein
      coupled receptors: A(1), A(2A), A(2B) and A(3). Adenosine acts as an important
      regulator of metabolic processes. In the brain adenosine mediates prominent
      neuroprotective functions via the adenosine A(1) receptor. Whereas the
      pharmacological characteristics of the rat and human adenosine A(1) receptor have
      been intensively studied, the mouse adenosine A(1) receptor has not yet been
      characterised. Accordingly, we have cloned the mouse brain adenosine A(1)
      receptor and present here a pharmacological characterisation of the mouse
      adenosine A(1) receptor using functional studies and radioligand binding assays.
      The results show that the binding affinities of several ligands for the mouse
      adenosine A(1) receptor are similar to the affinities for the rat and human
      adenosine A(1) receptor with some exceptions.

PMID- 15033379
TI  - KR-31378 protects neurons from ischemia-reperfusion brain injury by attenuating
      lipid peroxidation and glutathione loss.
AB  - Neuronal hyperexcitability and oxidative stress play critical roles in neuronal
      cell death in stroke. Therefore, we studied the effects of (2S,3S,4R)-N?-cyano-N
      (6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'
      benzylguanidine (KR-31378), possessing both antioxidant and K(+) channel
      modulating activities, on brain ischemia-reperfusion injury models. Treatment
      with KR-31378 (30 mg/kg, i.v.) significantly reduced infarct area and edema by
      24% and 36%, respectively, in rats subjected to 2 h of middle cerebral artery
      occlusion and 22 h of reperfusion with significant attenuation of elevated lipid
      peroxidation (99% of normal) and glutathione loss (60% of normal) in ischemic
      hemisphere. We further studied its neuroprotective mechanism in fetal rat primary
      mixed cortical culture. Incubation of cortical neurons with KR-31378 protected
      FeSO(4)-induced cell death in a concentration-dependent manner (IC(50)=12
      microM). Its neuroprotective effect was neither mimicked by other K(+) channel
      openers nor abolished in the presence of ATP-dependent K(+) channel (K(ATP))
      blockers, indicating that its effect was not related to K(+) channel opening
      activity. The mechanism of protection is rather attributable to the antioxidant
      property of KR-31378 since it suppressed the intracellular accumulation of
      reactive oxygen species and ensured lipid peroxidation by 120% and 80%,
      respectively, caused by FeSO(4). We further studied its effect on antioxidant
      defense, enzymatic and nonenzymatic systems. Treatment of neurons with FeSO(4)
      resulted in decrease of catalase (8% of control) and glutathione peroxidase (14%
      of control) activities, which were restored by KR-31378 treatment (70% and 57% of
      control, respectively). In addition, it attenuated the depletion of glutathione
      contents (60% of control) caused by FeSO(4). These results suggest that KR-31378
      exerts a beneficial effect in focal ischemia, which may be attributed to its
      antioxidant property.

PMID- 15033380
TI  - Pharmacological characterisation of acid-induced muscle allodynia in rats.
AB  - Previous studies have shown that repeated injections of acidic saline, given into
      the lateral gastrocnemius muscle of rats, results in a bilateral reduction in
      withdrawal threshold to tactile stimulation of the hindpaws. We have now
      characterised this model of muscoskeletal pain pharmacologically, by evaluating
      the antinociceptive effects of various analgesics after systemic administration.
      The micro-opioid receptor agonist morphine (3 and 6 mg/kg) produced a
      particularly prolonged antiallodynic effect. The glutamate receptor antagonists
      ([8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9,-tetrahydro-1H-pyrrolo[3,2
      h]-iso-quinoline-2,3-dione-3-O-(4-hydroxybutyric acid-2-yl)oxime] NS1209 and
      ketamine (6 and 15 mg/kg, respectively), the KCNQ K(+) channel openers retigabine
      and flupirtine (10 and 20 mg/kg, respectively) and the Na(+) channel blocker
      mexiletine (37.5 mg/kg) also significantly increased paw withdrawal threshold,
      although to a lesser degree than morphine. In contrast, the anticonvulsant
      lamotrigine (30 mg/kg), the cyclooxygenase-2 inhibitor carprofen (15 mg/kg) and
      the benzodiazepine diazepam (3 mg/kg) were ineffective. All antinociceptive
      effects were observed at nonataxic doses as determined by the rotarod test. These
      results suggest that in this model, muscle-mediated pain can be alleviated by
      various analgesics with differing mechanisms of action, and that once established
      ongoing inflammation does not appear to contribute to this process.

PMID- 15033381
TI  - Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic
      neurons in the medial prefrontal and occipital cortex.
AB  - The novel antidepressant mirtazapine has been shown to increase extracellular
      noradrenaline and dopamine in the medial prefrontal cortex. Our previous studies
      indicate that extracellular dopamine in the cerebral cortex originates largely
      from noradrenergic terminals, such release being controlled by alpha(2)
      adrenoceptors. Because mirtazapine inhibits alpha(2)-adrenoceptors, the
      possibility that it might corelease dopamine and noradrenaline was investigated.
      By means of microdialysis, the effect of mirtazapine on extracellular dopamine,
      3,4-dihydroxyphenylacetic acid (DOPAC) and noradrenaline in the medial prefrontal
      cortex, densely innervated by dopaminergic and noradrenergic neurons, and in the
      occipital cortex, receiving equal noradrenergic but scarce dopaminergic
      projections, was compared. Basal extracellular concentration of noradrenaline was
      similar in both cortices, while dopamine in the occipital cortex was only about
      50% lower than in the medial prefrontal cortex, reflecting noradrenergic rather
      than dopaminergic projections. The intraperitoneal (i.p.) administration of
      mirtazapine (5 and 10 mg/kg) increased extracellular dopamine, DOPAC and
      noradrenaline to approximately the same extent in both cortices, an effect
      totally suppressed by the alpha(2)-adrenoceptors agonist clonidine (0.15 mg/kg,
      i.p.). To exclude the possibility that mirtazapine-induced increase in dopamine
      might result from reduced dopamine removal from extracellular space,
      noradrenaline and dopamine uptake mechanisms were blocked by perfusing 100 microM
      desipramine into either cortex. The combined i.p. administration of mirtazapine
      (5 mg/kg) and the local perfusion of desipramine produced an additional increase
      in extracellular dopamine, DOPAC and noradrenaline in the medial prefrontal
      cortex and occipital cortex compared with the increase produced by either drug
      given alone. The results suggest that mirtazapine by inhibiting alpha(2)
      adrenoceptors produces a corelease of noradrenaline and dopamine from
      noradrenergic terminals in the cerebral cortex.

PMID- 15033382
TI  - The clinical free radical scavenger, edaravone, protects cochlear hair cells from
      acoustic trauma.
AB  - It is known that reactive oxygen species have toxicity to the cochlea. We
      investigated the effect of edaravone, a free radical scavenger for clinical use,
      on the cochleae of guinea pigs subjected to acoustic trauma. We assessed auditory
      brainstem response (ABR) thresholds to evaluate cochlear function and observed
      the sensory epithelium. After noise exposure (130 dB SPL, 3 h), we observed that
      the auditory brainstem response threshold shift in edaravone-treated ears was
      significantly less than that in untreated ears. This result suggests that
      edaravone protected the cochleae from acoustic trauma.

PMID- 15033383
TI  - Morphine withdrawal-induced c-fos expression in the heart: a peripheral
      mechanism.
AB  - We previously demonstrated that hyperactivity of cardiac noradrenergic pathways
      observed during morphine withdrawal is mediated by peripheral mechanisms. In the
      present study, naloxone methiodide (quaternary derivative of naloxone that does
      not cross the blood-brain barrier) and naloxone were administered to morphine
      dependent rats and Fos immunostaining was used as a reflection of neuronal
      activity. Dependence on morphine was induced by 7-day chronic subcutaneous (s.c.)
      implantation of six morphine pellets (75 mg). Morphine withdrawal was
      precipitated by administration of naloxone methiodide (5 mg/kg, s.c.) or naloxone
      (5 mg/kg, s.c.) on day 8. Using immunohistochemical staining of Fos, present
      results indicate that the administration of naloxone methiodide or naloxone to
      morphine-dependent rats induced marked Fos immunoreactivity within the
      cardiomyocyte nuclei. Moreover, Western blot analysis revealed a peak expression
      of c-fos in the right and left ventricles after naloxone methiodide- or naloxone
      precipitated withdrawal. In addition, in the hypothalamic paraventricular nucleus
      (PVN), Fos expression was increased after naloxone-but not after naloxone
      methiodide-administration to morphine-dependent rats. These results suggest that
      the activation of c-fos expression observed during morphine withdrawal in the
      heart is due to intrinsic mechanisms outside the central nervous system (CNS).

PMID- 15033384
TI  - 8-OH-DPAT acts on both 5-HT1A and 5-HT7 receptors to induce hypothermia in
      rodents.
AB  - Studies using selective drugs and knockout mice have demonstrated that the 5
      HT(7) receptor plays an instrumental role in serotonin-induced hypothermia. There
      is also evidence supporting an involvement of the 5-HT(1A) receptor, although
      mainly from studies using 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a 5
      HT(1A/7) receptor agonist. Here we studied the effects of 8-OH-DPAT and selective
      antagonists for the 5-HT(1A) and 5-HT(7) receptors on body temperature in rats,
      wild-type (5-HT(7)(+/+)) mice and knockout (5-HT(7)(-/-)) mice. At lower doses
      (0.3-0.6 mg/kg, i.p.), 8-OH-DPAT decreased body temperature in 5-HT(7)(+/+) mice
      but not in 5-HT(7)(-/-) mice. At a higher dose (1 mg/kg, i.p.) 8-OH-DPAT induced
      hypothermia in both 5-HT(7)(-/-) and 5-HT(7)(+/+) mice. The 5-HT(1A) receptor
      antagonist (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2
      phenylpropanamide (WAY-100135) (10 mg/kg, i.p.) inhibited the effect of 8-OH-DPAT
      at all doses in rats and mice. In 5-HT(7)(+/+) mice the selective 5-HT(7)
      receptor antagonist (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1
      sulfonyl)phenol (SB-269970) (10 mg/kg, i.p.) fully inhibited the hypothermia
      induced by 0.3 mg/kg 8-OH-DPAT, but not that of higher doses. In rats, SB-269970
      caused a 60% inhibition of the hypothermia induced by 0.3 mg/kg 8-OH-DPAT. Thus,
      both 5-HT(7) and 5-HT(1A) receptors are involved in a complex manner in
      thermoregulation, with the 5-HT(7) receptor being more important at lower,
      possibly more physiological, concentrations.

PMID- 15033385
TI  - Effect of combined administration of 5-HT1A or 5-HT1B/1D receptor antagonists and
      antidepressants in the forced swimming test.
AB  - In the present study, we examined effects of the selective serotonin (5
      hydroxytryptamine, 5-HT) reuptake inhibitor citalopram, the 5-HT/noradrenaline
      reuptake inhibitor imipramine, the selective noradrenaline reuptake inhibitor
      desipramine or the monoamine oxidase-A inhibitor moclobemide, administered in
      combination with the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1
      piperazinyl]ethyl]-N-(2-pyridynyl)cyclohexanecarboxamide (WAY 100635) or the 5
      HT(1B/1D) receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'
      methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)1,1'-biphenyl-4-carboxamide (GR 127935)
      and the 5-HT(1B) receptor antagonist N-[3-(2-dimethylamino) ethoxy-4
      methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4
      carboxamide (SB 216641) in the forced swimming test in rats. When given alone,
      citalopram (20 and 30 mg/kg), imipramine (20 mg/kg), desipramine (20 mg/kg),
      moclobemide (20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), GR 127935 (10 and 20 mg/kg)
      or SB 216641 (2 mg/kg) did not shorten the immobility time of rats. Co
      administration of WAY 100635 (0.1 and 1 mg/kg) and citalopram (20 mg/kg), or
      imipramine (20 mg/kg), or moclobemide (20 mg/kg) did not affect the immobility
      time of rats, whereas WAY 100635 given jointly with desipramine (20 mg/kg)
      induced a weak anti-immobility effect. GR 127935 (10 and 20 mg/kg) or SB 216641
      (2 mg/kg) co-administered with imipramine, desipramine or moclobemide, but not
      citalopram, produced a significant anti-immobility action in the forced swimming
      test in rats. These results indicate that the blockade of 5-HT(1B) rather than 5
      HT(1A) receptors may facilitate the anti-immobility effect of imipramine,
      desipramine or moclobemide in the forced swimming test. No interaction was
      observed between 5-HT(1A) or 5-HT(1B/1D) receptor antagonists and citalopram.

PMID- 15033386
TI  - Influence of central administration ATP-dependent K+ channel on morphine state
      dependent memory of passive avoidance.
AB  - Pre-training injection of a moderate dose of morphine (5-10 mg/kg) in a step-down
      passive avoidance task induced state-dependent learning with impaired memory
      retrieval on the test day. The impairment of memory was restored after the pre
      test administration of the same dose of the drug. We have studied the effect of
      intracerebroventricular administration of naloxone and K(ATP) channel modulators
      (glibenclamide and diazoxide) on the test day on restoration of memory by
      morphine in mice. The effect of scopolamine on restoration of memory on the test
      day by glibenclamide was studied as well. Naloxone pretreatment (0.006, 0.025 and
      0.1 microg/mouse) reversed the effect of pre-test morphine administration. The
      K(ATP) channel blocker, glibenclamide (0.1, 0.5 and 1 microg/mouse), showed
      effects similar to those of pre-test administration of morphine. Glibenclamide
      tended to potentiate the morphine response. Scopolamine (0.15 and 0.30
      microg/mouse) prevented the effect of glibenclamide on the restoration of memory.
      The pre-test administration of different doses of diazoxide (1.7, 5 and 15
      microg/mouse), a K(ATP) channel opener, showed no effect on restoration of memory
      when used alone but decreased morphine state-dependence. Diazoxide blocked the
      effects of glibenclamide on memory restoration. It is concluded that K(ATP)
      channel modulators may be involved, at least in part, in morphine state
      dependence through a cholinergic system mechanism.

PMID- 15033388
TI  - Mechanisms of antiplatelet and antithrombotic activity of midazolam in in vitro
      and in vivo studies.
AB  - Midazolam is widely used as a sedative and anesthetic induction agent. The aim of
      this study was to systematically examine the inhibitory mechanisms of midazolam
      in platelet aggregation. In this study, midazolam concentration-dependently (15
      and 30 microM) inhibited platelet aggregation in washed human platelets
      stimulated by thrombin (0.05 U/ml). Midazolam (15 and 30 microM) also inhibited
      phosphoinositide breakdown and intracellular Ca(+2) mobilization in platelets
      stimulated by thrombin (0.05 U/ml). In addition, midazolam (15 and 30 microM)
      increased the formation of cyclic AMP but not cyclic GMP or nitric oxide. The
      thrombin-evoked increase in pHi was markedly inhibited in the presence of
      midazolam (15 and 30 microM). Rapid phosphorylation of a platelet protein of
      molecular weight (Mr.) 47,000 (P47), a marker of protein kinase C activation, was
      triggered by thrombin (0.05 U/ml). This phosphorylation was markedly inhibited by
      midazolam (15 and 30 microM). Midazolam (30 microM) did not significantly reduce
      the electron spin resonance signal intensity of hydroxyl radicals in activated
      platelets. In the vivo study, intravenous injection of midazolam (10 microg/g)
      significantly prolonged the latent period of inducing platelet plug formation in
      mesenteric venules. These results indicate that midazolam can significantly
      prevent thrombus formation in vivo. Its antiplatelet activity may be involved in
      the inhibition of the activation of phospholipase C and the Na(+)/H(+) exchanger
      and increased cyclic AMP formation. These lead to lower intracellular Ca(+2)
      mobilization and phosphorylation of P47.

PMID- 15033387
TI  - Relative roles of endothelial relaxing factors in cyclosporine-induced impairment
      of cholinergic and beta-adrenergic renal vasodilations.
AB  - Vascular toxicity is a major adverse effect for the immunosuppressant drug
      cyclosporine A. The present study sought to characterize the relative roles of
      the endothelium-derived relaxing factors (nitric oxide, endothelium-derived
      hyperpolarizing factor [EDHF], and prostaglandins) in the cyclosporine-induced
      impairment of renovascular responsiveness to acetylcholine receptor or beta
      adrenoceptor activation. Changes evoked by cyclosporine in the responses to
      either vasorelaxant were evaluated in phenylephrine-preconstricted isolated
      perfused rat kidneys in the absence and presence of N(G)-nitro-l-arginine methyl
      ester (l-NAME, nitric oxide synthase inhibitor), tetraethylammonium (K(+) channel
      blocker), or diclophenac (cyclooxygenase inhibitor). Acetylcholine (0.03-2 nmol)
      vasodilations were significantly inhibited by prior treatment with l-NAME,
      tetraethylammonium, or diclophenac, suggesting a role for nitric oxide, EDHF, and
      prostaglandins in acetylcholine vasodilations. Isoprenaline (0.125-4 micromol)
      vasodilations were inhibited by l-NAME and tetraethylammonium versus no effect
      for diclophenac. Cyclosporine (1-4 microM) produced a concentration-related
      inhibition of vasodilations relaxations produced by either vasodilator.
      Cyclosporine-induced inhibition of acetylcholine vasodilations was attenuated in
      tissues pretreated with l-NAME or tetraethylammonium but not diclophenac,
      implicating nitric oxide and EDHF in cyclosporine-acetylcholine interaction. On
      the other hand, the inhibition of isoprenaline vasodilations by cyclosporine was
      virtually abolished by l-NAME. In cyclosporine-treated kidneys, exposure to l
      arginine, the substrate of nitric oxide synthesis, fully restored isoprenaline
      vasodilations to control levels and significantly increased acetylcholine
      vasodilations. It is concluded that the identity and relative contributions of
      endothelial factors to renal vasodilatory responses as well as to the inhibition
      of these responses by cyclosporine largely depend on the vasodilator stimulus.

PMID- 15033389
TI  - Protein kinase A increases electrical stimulation-induced neuronal nitric oxide
      release in rat mesenteric artery.
AB  - The aim of this study was to analyse the possible influence of cyclic AMP-protein
      kinase A (cAMP-PKA) activation on neuronal nitric oxide (NO) release induced by
      electrical field stimulation in mesenteric arteries from Wistar Kyoto (WKY) rats.
      Western blot experiments demonstrated the expression of neuronal NO synthase
      (nNOS) in mesenteric artery from WKY rats; however, electrical field stimulation
      alone did not induce detectable NO release. Preincubation with forskolin allowed
      NO release induced by electrical field stimulation, which was abolished by: the
      neuronal toxine tetrodotoxin, the nNOS inhibitors 7-nitroindazole or N(omega)
      propil-l-arginine (NPLA), and the PKA inhibitors N-(2-(p-Bromocinnamylamino)
      ethyl 5-isoquinolinesulfonamide hydrochloride (H-89) or (9R,10S,12S)-2,3,9,10,11,
      12-Hexahydro-10-9-methyl-1-oxo-9,12-epoxy-1H-diindolo(1,2,3-fg:3,2,1k)pyrrolo(3,4
      l)(1,6) benzodiazocine-10-carboxylic acid hexyl ester (KT-5720). Preincubation
      with prostacyclin also allowed the NO release induced by electrical field
      stimulation which was significantly decreased by: the neuronal toxine
      tetrodotoxin, the nNOS inhibitors 7-nitroindazole or NPLA, and the PKA inhibitors
      H-89 or KT-5720. The NOS inhibitor N(omega)-nitro-l-arginine methyl ester (l
      NAME) did not modify the vasoconstrictor response induced by electrical field
      stimulation. However, in the presence of forskolin or prostacyclin, l-NAME
      increased the vasoconstrictor response to electrical field stimulation. These
      results indicate that forskolin and prostacyclin allow neuronal NO release
      induced by electrical field stimulation through a mechanism involving cAMP-PKA
      activation in rat mesenteric arteries.

PMID- 15033390
TI  - Characterization of capsaicin-induced, capsazepine-insensitive relaxation of
      ileal smooth muscle of rats.
AB  - The mechanisms underlying the capsaicin-induced relaxation of the acetylcholine-
      as well as KCl-contraction were studied by measuring isometric force and
      phosphorylation of 20-kDa regulatory light chain subunit of myosin (MLC(20)) in
      ileal longitudinal smooth muscles of rats. Capsaicin relaxed acetylcholine- and
      KCl-stimulated preparations in a concentration-dependent manner; the former was
      less sensitive to capsaicin than the latter and maximum responses to capsaicin (a
      percentage of papaverine-induced relaxation) were 70.6+/-7.5%, n=10 and 97.1+/
      0.9%, n=13, P<0.05, respectively. The response showed no desensitization. Like
      nifedipine, capsaicin relaxed the tissue precontracted with an agonist of L-type
      Ca(2+) channels as well. The relaxant effect of capsaicin was not inhibited by
      capsazepine (a selective antagonist of vanilloid VR1 receptors), nitro-l
      arginine, indomethacin, guanethidine, nor by inhibitors of soluble guanylate
      cyclase. Capsaicin inhibited acetylcholine-induced transient contraction in a
      Ca(2+)-free, EGTA solution. Phosphorylation of MLC(20) (a percentage of
      phosphorylated to total MLC(20)) was increased 1 min after application of 10
      microM acetylcholine (7.8+/-2.0%, n=6 vs. 22.6+/-3.2%, n=6) and of 65.9 mM KCl
      (2.2+/-0.3%, n=8 vs. 10.7+/-1.7%, n=12). Capsaicin reduced the KCl-induced
      increase more markedly than acetylcholine-induced increase in MLC(20)
      phosphorylation. When the tissue was contracted for 20 min with acetylcholine,
      MLC(20) phosphorylation was increased, and capsaicin reduced markedly the
      contraction and abolished MLC(20) phosphorylation both elicited by acetylcholine.
      It is suggested that capsaicin relaxes the rat ileum via its direct action on
      smooth muscle, and that capsaicin inhibits contractile mechanisms involving
      extracellular Ca(2+) influx via non-L-type Ca(2+) channels, possibly via store
      operated Ca(2+) channels and Ca(2+) release from intracellular storage sites. The
      effects of capsaicin on acetylcholine- and KCl-induced contraction could be
      explained by a decrease in MLC(20) phosphorylation.

PMID- 15033391
TI  - Antiobesity effects of A-331440, a novel non-imidazole histamine H3 receptor
      antagonist.
AB  - Histamine affects homeostatic mechanisms, including food and water consumption,
      by acting on central nervous system (CNS) receptors. Presynaptic histamine H(3)
      receptors regulate release of histamine and other neurotransmitters, and
      histamine H(3) receptor antagonists enhance neurotransmitter release. A-331440
      [4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile]
      is a histamine H(3) receptor antagonist which binds potently and selectively to
      both human and rat histamine H(3) receptors (K(i)<==25 nM). Mice were stabilized
      on a high-fat diet (45 kcal % lard) prior to 28-day oral b.i.d. dosing for
      measurement of obesity-related parameters. A-331440 administered at 0.5 mg/kg had
      no significant effect on weight, whereas 5 mg/kg decreased weight comparably to
      dexfenfluramine (10 mg/kg). A-331440 administered at 15 mg/kg reduced weight to a
      level comparable to mice on the low-fat diet. The two higher doses reduced body
      fat and the highest dose also normalized an insulin tolerance test. These data
      show that the histamine H(3) receptor antagonist, A-331440, has potential as an
      antiobesity agent.

PMID- 15033392
TI  - Expression of heat shock protein 70 and its mRNAs during ischemia-reperfusion in
      the rat prostate.
AB  - We investigated the expression of heat shock protein (HSP) 70 and its mRNAs
      during ischemia-reperfusion in the rat prostate. Eight-week-old rats were divided
      into six groups: a control group, a 30-min ischemia group, and 30-min ischemia+30
      min, 60-min, 1-day, and 1-week reperfusion groups (groups A, B, C, D, E, and F,
      respectively). In vivo real-time blood flow and HSP 70-1 and 70-2 mRNAs and
      proteins in the prostate were measured using laser Doppler flow meter, real-time
      polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA)
      methods, respectively. Clamping of the aorta decreased blood flow to 10% of the
      basal level. The expressions of HSP 70-1/2 mRNAs increased in groups B, C, and D,
      and decreased in groups E and F. The expression of HSP 70 proteins was increased
      after a short interval of increase in their mRNAs. Our data indicated that the
      expressions of HSP 70 proteins and their mRNAs are dramatically changed during
      ischemia-reperfusion in the rat prostate.

PMID- 15033393
TI  - Muscarinic receptors mediating contraction of female mouse urinary bladder:
      effects of oestrogen.
AB  - Muscarinic receptors mediating contraction of bladder detrusor muscle from female
      mice were examined. Mice were untreated (A) or treated with oestradiol cypionate
      (200 microg/kg) 24 h (B) or 96 h (C) before experimentation, or were pregnant
      (day 17) (D). Saturation radioligand binding experiments using
      [(3)H]quinuclidinyl benzilate ([(3)H] QNB) indicated similar muscarinic receptor
      densities and affinities in bladders from groups A and B. Neither oestrogen
      treatment nor pregnancy altered pD(2) estimates for methacholine. Maximum
      responses to methacholine and high-K(+) physiological salt solution (KPSS) were
      significantly greater (P<0.05) in tissues from groups C and D than in A and B.
      Potencies of other muscarinic receptor agonists were similar in groups A and B
      with an order of acetylcholine plus physostigmine (10 microM) approximately
      methacholine plus physostigmine (10 microM)>methacholine approximately
      acetylcholine>bethanechol. Antagonist pK(B) estimates were similar in bladders
      from groups A and B with a rank order of: atropine>/=4-diphenyl acetoxy-N-methyl
      piperidine methiodide>parafluorohexahydrosiladifenidol approximately
      pirenzepine>himbacine, implicating muscarinic M(1) and/or M(5) as well as
      muscarinic M(3) receptors in mediating methacholine-induced bladder contraction.

PMID- 15033394
TI  - 6"-Azidohex-2"-yne-cannabidiol: a potential neutral, competitive cannabinoid CB1
      receptor antagonist.
AB  - Previous experiments with the mouse vas deferens have shown that cannabidiol
      produces surmountable antagonism of cannabinoid CB(1) receptor agonists at
      concentrations well below those at which it binds to cannabinoid CB(1) receptors
      and antagonizes alpha(1)-adrenoceptor agonists insurmountably. It also enhances
      electrically evoked contractions of this tissue. We have now found that subtle
      changes in the structure of cannabidiol markedly influence its ability to produce
      each of these effects, suggesting the presence of specific pharmacological
      targets for this non-psychoactive cannabinoid. Our experiments were performed
      with cannabidiol, 6"-azidohex-2"-yne-cannabidiol, abnormal-cannabidiol and 2'
      monomethoxy- and 2',6'-dimethoxy-cannabidiol. Of these, 6"-azidohex-2"-yne
      cannabidiol was as potent as cannabidiol in producing surmountable antagonism of
      (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4
      benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) in vasa deferentia.
      However, it produced this antagonism with a potency that matched its cannabinoid
      CB(1) receptor affinity, suggesting that, unlike cannabidiol, it is a competitive
      cannabinoid CB(1) receptor antagonist. Moreover, since it did not enhance the
      amplitude of electrically evoked contractions, it may be a neutral cannabinoid
      CB(1) receptor antagonist.

PMID- 15033397
TI  - Family planning care: more than contraception.

PMID- 15033395
TI  - Preventive effect of teprenone on acute gastric mucosal lesion progression in
      compound 48/80-treated rats.
AB  - The preventive effect of teprenone (6,10,14,18-teramethyl-5,9,13,17
      nonadecatetaene-2-one), an anti-ulcer drug, on acute gastric mucosal lesion
      progression was examined in rats with a single intraperitoneal (i.p.) injection
      of compound 48/80 (0.75 mg/kg). Teprenone (20, 100 or 200 mg/kg), which was
      orally administered 0.5 h after compound 48/80 treatment at which time gastric
      mucosal lesions appeared, prevented gastric mucosal lesion development at 3 h
      after the treatment dose-dependently. Gastric mucosal tissues of compound 48/80
      treated rats showed increases in myeloperoxidase (an index of neutrophil
      infiltration) and xanthine oxidase activities and thiobarbituric acid reactive
      substances (an index of lipid peroxidation) content and decreases in Se
      glutathione peroxidase activity and hexosamine and vitamin E contents at 3 h
      after the treatment. Post-administered teprenone attenuated all these changes
      dose-dependently. These results indicate that teprenone prevents acute gastric
      mucosal lesion progression in compound 48/80-treated rats possibly by suppressing
      gastric mucus depletion, neutrophil infiltration and oxidative stress in the
      gastric mucosal tissue.

PMID- 15033396
TI  - Effects of lipopolysaccharide on epithelium-dependent relaxation in coaxial
      bioassay.
AB  - This study investigated the effects of airway inflammation elicited by
      intraperitoneal and intratracheal lipopolysaccharide administration to guinea
      pigs on the activity of tracheal epithelium-derived relaxant factor (EpDRF).
      Acetylcholine induced epithelium-dependent relaxation in precontracted rat
      anococygeus muscle placed in guinea pig trachea (coaxial bioassay). Indomethacin,
      N-nitro-l-arginine methyl ester, aminoguanidine and l-canavanine did not alter
      this relaxation excluding the role of prostaglandins and nitric oxide (NO).
      Intraperitoneal lipopolysaccharide potentiated the acetylcholine response, which
      was reversed by aminoguanidine and l-canavanine while intratracheal
      lipopolysaccharide inhibited acetylcholine-induced relaxation. Lipopolysaccharide
      pretreatments did not cause epithelial damage but induced inflammatory cell
      infiltration. These results suggested that systemic lipopolysaccharide
      administration did not alter the EpDRF response but resulted in NO synthase
      induction, thus NO participated in relaxation to acetylcholine in coaxial
      bioassay system. On the other hand, airway inflammation induced by intratracheal
      lipopolysaccharide attenuated the synthesis/release of EpDRF without altering the
      epithelium morphology.

PMID- 15033398
TI  - Diaphragms in clinical trials: is clinician fitting necessary?
AB  - BACKGROUND: The need for fitting a contraceptive diaphragm has recently been
      questioned in the context of upcoming trials in which the ability of the
      diaphragm to prevent sexually transmitted infections will be tested. Being able
      to provide the same size device to all women would greatly simplify supplying the
      device and training the clinicians, provided that it does not compromise
      effectiveness. METHODS: Data from studies of Lea's Shield and FemCap, in which
      all women were sized for a standard diaphragm and half were randomized to use it
      during the studies, were reanalyzed to determine if it was feasible to give all
      women in a barrier study the same size diaphragm or, alternatively, to determine
      if diaphragm size could be predicted using an algorithm of one or more
      parameters. RESULTS: If all women received a size 70 diaphragm, rather than being
      fitted by a clinician, 33.2% would receive the same size that they would have
      received if they had been fitted by a clinician. If the definition of a "correct"
      fit were broadened to include one size larger or smaller than what the clinician
      would have prescribed, 78.0% would be "correctly" fitted. Using an algorithm that
      considered parity, body weight and other factors did not improve results.
      CONCLUSION: It would be acceptable to conduct a trial in which all women receive
      a size 70 diaphragm, provided that all women are sized; that safety,
      effectiveness and acceptability are closely monitored and that study results are
      stratified by the diaphragm size determined by clinician fitting. It would also
      be informative to use sized diaphragms as the comparator in studies of new single
      size devices.

PMID- 15033399
TI  - Randomized trial to compare perioperative outcomes of Filshie clip vs. Pomeroy
      technique for postpartum and intraoperative cesarean tubal sterilization: a pilot
      study.
AB  - OBJECTIVE: To compare, by conducting a randomized trial, Filshie clip and Pomeroy
      techniques for postpartum and intrapartum cesarean sterilizations in a United
      States teaching hospital with respect to surgeon preference and perioperative
      outcomes. METHOD: Thirty-two obstetric patients consented for sterilization were
      randomized to Pomeroy technique or Filshie clip placement. Following the surgical
      procedure, surgeons and operating room technicians completed a survey regarding
      their experience with the procedures and preference. Patient demographic data,
      time for procedure and follow-up visits were obtained by chart review. RESULTS:
      For most postpartum sterilizations, the mean duration of the procedure was almost
      7 min faster for the Filshie clip technique (p = 0.08); perioperative outcomes
      were equivalent (p = 0.05). Application of the Filshie clip was rated easier than
      Pomeroy suture application and, overall, the Filshie clip sterilization procedure
      was rated less difficult (p = 0.03). Seventy percent of surgeons preferred the
      Filshie clip technique and would choose it if only one postpartum sterilization
      method was available. CONCLUSION: For obstetric sterilization, surgeons preferred
      the Filshie clip over the Pomeroy technique. In addition, operating time was
      shorter for the Filshie clip. This pilot study suggests that use of the Filshie
      clip technique has the potential to establish a new standard of care for
      postpartum and intrapartum cesarean sterilization.

PMID- 15033400
TI  - A randomized study on the influence of oral contraceptives containing
      ethinylestradiol combined with drospirenone or desogestrel on lipid and
      lipoprotein metabolism over a period of 13 cycles.
AB  - In this open-label, randomized study we compared the influence of a new oral
      contraceptive containing 30 microg ethinylestradiol and 3 mg drospirenone (EE +
      DRSP = Yasmin), with a reference preparation containing 30 microg
      ethinylestradiol and 150 microg desogestrel (EE + DSG = Marvelon) on the lipid
      profile. The primary target variables were total high-density lipoprotein (HDL)
      cholesterol, HDL2 cholesterol and low-density lipoprotein (LDL) cholesterol.
      These and additional lipid and lipoprotein fractions were measured at baseline
      and in the 3rd, 6th and 13th treatment cycles in a total of 50 volunteers, and
      also assessed after density gradient ultracentrifugation. A slight increase in
      mean total HDL cholesterol vs. baseline was found for the DRSP group (+12.8%) and
      the DSG group (+11.8%) after 13 treatment cycles. HDL2 cholesterol did not change
      remarkably in both groups. The mean LDL cholesterol values increased by 10.6% vs.
      baseline in the DSG group and remained nearly stable in the DRSP group (+1.8%).
      All measured values remained within the reference ranges. No statistically
      significant differences were found between the two treatment groups for those
      primary endpoints. A slight rise in mean total cholesterol was found for all
      cycles after the initiation of treatment. The mean increase after 1 year of
      treatment was approximately 8% in both treatment groups. Mean triglyceride levels
      increased for both treatment groups without leaving the reference range. The
      increase for total triglycerides was +73.6 % in the DRSP group and +61.3% in DSG
      group. For total phospholipids, an increase of +13.6% (DRSP) and +18.5% (DSG)
      over 13 cycles was measured. The apolipoproteins Apo A-I, Apo A-II and Apo B
      increased slightly more during DRSP treatment than during DSG treatment. The
      reduction of Apo E was similar in both groups. Lipoprotein (a) remained stable in
      the DRSP group, whereas it increased by +10.8% in the DSG group. In conclusion,
      the combined low-dose oral contraceptive Yasmin, with 30 microg ethinylestradiol
      and 3 mg of the novel progestogen drospirenone, as well as the reference
      preparation, had little impact on the lipid profile. While both preparations
      displayed a favorable lipid profile with increased total HDL cholesterol, the
      antiandrogenic or missing androgenic activity of Yasmin may be regarded as
      responsible for the stable LDL cholesterol levels. As a result, the ratio of
      total HDL:LDL was increased, a pattern that is usually considered clinically
      beneficial with respect to cardiovascular disease risk.

PMID- 15033402
TI  - Intrauterine contraception: the role of general practitioners in four Dutch
      general practices.
AB  - The intrauterine device (IUD) use in the Netherlands and the United States is
      limited to a small group of women, though the risk of infection and pregnancy is
      small. Therefore, it was of interest to investigate the characteristics of women
      who choose an IUD as contraceptive method and the influence of general
      practitioners concerning IUD insertion. The aim of this retrospective cohort
      study was to assess differences between general practices and to investigate the
      characteristics of IUD users. Also, we wished to study changes in IUD use with
      time. Patients were selected from four academic general practices belonging to
      the continuous morbidity registration project in Nijmegen, the Netherlands. The
      population under study included 461 women registered in the academic practices
      with a code for insertion of a new IUD in the period from 1981 to 2001. More than
      half of the women were between 25 and 34 years old at the time of insertion.
      Almost one quarter were nulliparous, one quarter unmarried and the distribution
      of socioeconomic status was the same as the entire practice population. General
      practitioners have clear preferences for certain types of IUD and, in particular,
      for not inserting an IUD in nulliparous women. In conclusion, married or
      cohabiting women, around 30 years of age, with children, are in the majority in
      receiving an IUD as contraception. General practitioners clearly follow their own
      opinions about inserting IUD in nulliparous women. Currently, general
      practitioners are prescribing more Multiload Cu 375 IUDs and levonorgestrel
      releasing IUDs.

PMID- 15033401
TI  - Clinical outcomes of early postplacental insertion of intrauterine contraceptive
      devices.
AB  - OBJECTIVES: To assess the efficacy, safety and, thus, advantages and
      disadvantages, of early postplacental intrauterine device (IUD) insertion.
      METHODS: IUDs were inserted within 10 min after postplacental expulsion in term
      pregnancy both in vaginal and cesarean deliveries via a ring forceps. Of the 276
      patients enrolled, 235 were included in the study. Recipients were scheduled for
      examination before hospital discharge and at 6 weeks, 6 months and 12 months
      after postplacental insertion. RESULTS: The percentages of women returning for a
      follow-up visit were 221 (94%), 210 (89%) and 183 (78%) at 6 weeks, 6 months and
      12 months, respectively. Among IUD acceptors, 74% of the cases had vaginal
      deliveries and 26% had cesarean deliveries. Continuation rates were relatively
      high, 87.6% and 76.3%, at 6 and 12 months, respectively, after postplacental
      insertion of IUD. In this study, the 1-year cumulative expulsion rate with TCu
      380A device was 12.3%, which may be regarded as a standard expulsion rate for
      immediate postplacental insertion of similar models of IUDs. CONCLUSION: The
      evidence from this study suggests that immediate postplacental insertion of CuT
      380 models is an effective, useful, safe, convenient and low-cost procedure for
      early postpartum contraception.

PMID- 15033404
TI  - Do Mexico City pharmacy workers screen women for health risks when they sell oral
      contraceptive pills over-the-counter?
AB  - CONTEXT: In Mexico, oral contraceptives (OCs) are available to women over-the
      counter in pharmacies. While past research has suggested that nonmedical
      providers, such as pharmacy workers, are capable of screening women for
      contraindications to OCs, little is known about their practices. METHODS: After
      selecting a 10% random sample of all pharmacies in Mexico City (n = 108), we
      surveyed the first available pharmacy worker to learn more about pharmacy
      workers' screening practices when selling OCs over-the-counter to women. RESULTS:
      While nearly all of the pharmacy workers surveyed had sold OCs without a
      prescription, only 31% reported asking women any questions before selling pills.
      Among those who asked questions, the most commonly asked questions were about
      other medications a woman was taking, about blood pressure and about alcohol
      intake. Pharmacy workers did not ask these questions consistently to all clients.
      CONCLUSION: Training pharmacy workers might be one strategy to improve screening
      of women for pill contraindications. However, pharmacy workers may lack the time
      and motivation to carry out such screening. An alternative strategy might be to
      better inform women to self-screen for pill contraindications.

PMID- 15033403
TI  - Lost levonorgestrel IUD: diagnosis and therapy.
AB  - A lost intrauterine device (IUD) is an uncommon event. Recently, a new
      levonorgestrel-releasing intrauterine system was introduced. In view of several
      cases of an unusual diagnostic discrepancy in the location of a lost
      levonorgestrel-releasing IUD in our department, we sought to determine if the
      extrauterine location of lost levonorgestrel-releasing IUDs differs from that of
      lost copper IUDs. The medical files of all patients with a diagnosis of lost IUD
      who were admitted to Rabin Medical Center from 2000 to 2003 were reviewed.
      Fourteen women were identified, 9 with levonorgestrel-releasing IUDs and 5 with
      copper IUDs. In six of the nine cases of a lost levonorgestrel-releasing IUD,
      there was a clear discrepancy between the presumed location of the device by
      diagnostic evaluation and its actual location on surgical extraction. All six
      devices were embedded in the omentum; four were located in the upper abdomen. No
      such discrepancies were noted for the copper IUDs (0 vs. 66%, p < 0.05). No
      significant difference in peritoneal adhesions was noted between the groups (55%
      vs. 66%, respectively, p = 0.095). It is concluded that lost levonorgestrel
      releasing IUDs are associated with a higher rate of localization errors by
      clinical evaluation than copper IUDs. Lost levonorgestrel-releasing IUDs might be
      found in the mid-upper abdomen, embedded in omentum tissue, and this area should
      be explored first during laparoscopy.

PMID- 15033405
TI  - Side effects of the Yuzpe regimen of emergency contraception and two
      modifications.
AB  - We investigated side effects after the standard Yuzpe regimen or two
      modifications: substituting norethindrone as the progestin or eliminating the
      second dose. We also examined the impact of taking either dose with food. Nearly
      two thirds of women reported at least one side effect, the majority of which were
      mild or moderate. Women in our study experienced more side effects after the
      second dose than after the first. Taking the first dose within 1 h of a meal or
      snack was associated with increased nausea and vomiting; taking the second dose
      within 1 h of a meal or snack was associated with decreased nausea and vomiting.
      A targeted approach to prophylactic antiemetic use could reduce the number of
      women given these drugs, and the number who experience unnecessary side effects.
      The impact of counseling on side effects should be further evaluated.

PMID- 15033406
TI  - Emergency contraceptive pills over-the-counter: a population-based survey of
      young Swedish women.
AB  - One year after emergency contraceptive pills (ECP) had become prescription-free,
      we sent a questionnaire to 800 randomly selected women in mid-Sweden. The aim was
      to investigate women's knowledge, attitudes and practices regarding the method.
      The response rate was 71% (n = 564). The majority of the women, 65%, would prefer
      to purchase ECP over-the-counter (OTC) in a pharmacy. Attitudes toward the method
      were predominantly positive, but one fourth (24%) had worries about side effects
      and one third (33%) considered ECP to be a kind of abortion. Logistic regression
      showed that correct knowledge of and positive attitudes toward ECP contributed to
      estimated future use of ECP. Although women favored the OTC option, persistent
      misunderstanding about ECP implies that routine information from gynecologists
      and health professionals as well as media campaigns is needed along with the
      deregulation in order to make ECP an accepted and properly used contraceptive
      method.

PMID- 15033407
TI  - Lactational amenorrhea as a method of family planning in Egypt.
AB  - Because of the potential importance of the lactational amenorrhea method (LAM) as
      a family-planning option in Egypt, we analyzed data from the 1995 Egyptian
      Demographic and Health Survey (EDHS) to study breastfeeding practices, use of
      contraception, reproductive history and sociodemographic factors for 5504 mothers
      with children under 3 years. According to the EDHS data, about 80% of Egyptian
      women breastfed for at least 6 months, and 40% breastfed for 15-18 months. Over
      half of breastfeeding mothers used no additional contraception. Thirty-six
      percent of mothers breastfeeding children younger than 6 months who reported
      using no additional contraception were exclusively breastfeeding and amenorrheic,
      but only 4% reported relying on breastfeeding for family planning. We also held
      eight focus group discussions with breastfeeding mothers from urban and rural
      Upper and Lower Egypt on their use of contraceptive methods, breastfeeding,
      lactational amenorrhea and LAM. Participants showed strong recognition of the
      contraceptive effects of breastfeeding but differed widely in their understanding
      of lactational infecundability and knowledge of LAM as a method. These results
      suggest that LAM would be widely acceptable to Egyptian women, but that an
      educational program about the method is needed.

PMID- 15033409
TI  - Effect of a low-dose ethinylestradiol and gestodene in combination on the
      frequency of micronuclei in human peripheral blood lymphocytes of healthy women
      in vivo.
AB  - BACKGROUND: Since most oral hormonal contraceptives contain a fixed combination
      of ethinylestradiol and gestodene as an estrogenic/progestogenic component, we
      decided to evaluate the possible mutagenic effect of a low-dose contraceptive
      pills containing 20 microg ethinylestradiol and 75 microg gestodene. METHODS: A
      total of 30 healthy women received hormonal contraception during six consecutive
      menstrual cycles. A single daily dose was 20 microg ethinylestradiol and 75
      microg gestodene. The pills were taken orally in a monthly cycle of 3 weeks on
      and 1 week off. In the investigation of the mutagenic effect of these
      contraceptive pills in vivo, the cytokinesis block micronucleus (CBMN) test was
      used, and the frequency of micronuclei (MN) in peripheral blood lymphocytes was
      determined. RESULTS: Average MN frequency in women before therapy was 7.40 +/-
      0.75 MN/1000 analyzed cells, and after therapy was 7.37 +/- 0.59 MN/1000 analyzed
      cells (p > 0.05). CONCLUSION: Our data suggest that oral contraception with 20
      microg ethinylestradiol and 75 microg gestodene in combination during six
      consecutive menstrual cycles does not induce micronuclei in peripheral blood
      lymphocytes of women.

PMID- 15033408
TI  - Norplant insertions at the Zeynep Kamil Gynecologic and Pediatric Training
      Research Hospital in Istanbul.
AB  - OBJECTIVE: This study was conducted to determine sociodemographic characteristics
      and usage interval according to insertion period, observed side effects and
      reasons for discontinuation in 756 cases where Norplant was inserted and removed
      for any reasons at our hospital since 1994. METHODS: Seven-hundred and fifty-six
      cases in whom Norplant was inserted and removed since 1994 were included in our
      study. Sociodemographic characteristics, former contraception method, reasons for
      choosing this method and side effects seen during the usage period were
      determined. In all cases, reasons for discontinuation, sociodemographic
      characteristics and usage interval according to the insertion period were
      investigated. Statistical analysis of this study was performed with SPSS 9.0
      (analysis of variance). RESULTS: Mean age of cases was 26.5 +/- 4.9 years, mean
      number of living children was 2.0 +/- 1.2, and 50.4% of cases had no health
      insurance. Most of the cases used coitus interruptus previously as a
      contraceptive method and chose Norplant use because of its effectiveness.
      Insertion periods were as follows: interval, n = 513 (67.9%); postpartum, n = 127
      (16.8%) and postabortion, n = 116 (15.3%). Various side effects were detected in
      79.8% of the cases. Bleeding problems were seen in 69.8%. Pregnancy occurred in
      only one case. Mean Norplant usage interval was 3.08 +/- 1.68 years. The longer
      usage interval was seen in cases with lower educational level. When we compared
      the usage intervals between interval, postpartum and postabortion periods, we
      found that the interval group had a shorter mean duration of Norplant use.
      Discontinuation because of bleeding problems occurred in 38.1%. Removal of all
      Norplant implants was performed at a single session in 731 cases (96.4%). After
      Norplant removal, most cases selected either condom or IUD as the contraceptive
      method. CONCLUSION: It is concluded that despite the frequent occurrence of side
      effects, Norplant is a modern, long-acting, highly effective, reversible, easy-to
      use, satisfactory form of birth control, especially in selected cases.

PMID- 15033410
TI  - Contraceptive efficacy of antimicrobial peptide Nisin: in vitro and in vivo
      studies.
AB  - Sexually transmitted infections and unplanned pregnancies present a great risk to
      the reproductive health of women. Therefore, female-controlled vaginal products
      directed toward disease prevention and contraception are needed urgently. In the
      present study, efforts were made to evaluate the contraceptive potential of
      Nisin. The effect of Nisin on sperm motility was assessed under in vitro and in
      vivo conditions. The results showed that sperm motility was completely inhibited
      with Nisin. The minimum effective concentration of Nisin required to immobilize
      sperm (80-100 x 10(6)) in vitro within 20 s was found to be 50 microg in rat, 200
      microg in rabbit and 300-400 microg in monkey and human. The effect on sperm
      motility was observed to be dose- and time-dependent. Intravaginal administration
      of Nisin (200 microg) before mating during proestrus-estrous transition phase
      caused complete arrest of sperm motility and blockage of conception. Subacute
      toxicity studies in rats indicated that, repetitive intravaginal application of
      Nisin at the dose of 200 microg for 14 consecutive days induced no abnormalities
      either in the length of estrous cycle or in the morphology of vaginal epithelial
      cells. No histopathological abnormalities in vaginal tissue or any change in
      blood and serum biochemical profiles were observed. Furthermore, no adverse
      effects were observed on subsequent reproductive performance, neonate survival
      and development of pups. It is suggested that Nisin, with its antibacterial and
      spermicidal activities, could be developed as a potent vaginal contraceptive for
      future use in humans.

PMID- 15033411
TI  - As often as needed: appropriate use of emergency contraceptive pills.
AB  - Previous research has established that emergency contraceptive pills are safe and
      have the potential to reduce unintended pregnancy; however, policy makers,
      providers and even women themselves have expressed concern about repeat use of
      the method. Evidence regarding the safety, efficacy and frequency of repeat use
      show that the method is safe and effective, even when used multiple times.
      Reported rates of repeat use are actually lower than would be expected, and
      needed, based on the frequency of unprotected intercourse and contraceptive
      failure reported in most countries. Healthcare providers should encourage use of
      emergency contraceptive pills as a backup after recognizable failure of barrier
      methods or other hormonal contraceptive methods, and should expect that women may
      need emergency contraceptive pills multiple times during their reproductive
      years.

PMID- 15033412
TI  - Rates of birth defect(s) and exposure to IUD during pregnancy.

PMID- 15033414
TI  - Spinal interneurons infected by renal injection of pseudorabies virus in the rat.
AB  - The potency of spinal sympathetic reflexes is increased after spinal injury, and
      these reflexes may result in life-threatening hypertensive crises in humans. Few,
      if any, primary afferents project directly to sympathetic preganglionic neurons
      (SPN). Therefore, spinal sympathetic interneurons (IN) must play a major role in
      generating dysfunctional sympathetic activity after spinal cord injury.
      Furthermore, these IN are potentially aberrant targets, either for ascending and
      descending axons that may sprout after spinal cord injury or for axons that
      regenerate after spinal cord injury. We identified IN via the transsynaptic
      retrograde transport of pseudorabies virus (PRV) injected into the kidneys of
      rats. The proportion of infected IN ranged from approximately 1/3 to
      approximately 2/3 of the number of infected SPN. IN were heavily concentrated
      among the SPN in spinal lamina VII. However, IN were located in all lamina of the
      dorsal horn. The longitudinal distribution of infected IN was closely correlated
      with the longitudinal distribution of infected SPN. Few infected IN were found
      rostral or caudal to the longitudinal range of infected SPN. Infected IN were
      heterogeneous in both their sizes and the extent of their dendritic trees. The
      strong correlation between longitudinal distributions of infected IN and SPN
      supports physiological data demonstrating a segmental organization of spinal
      sympathetic reflexes. The paucity of infected IN in segments distant from SPN
      suggests that multisegmental sympathetic reflexes are mediated by projections
      onto IN rather than onto SPN themselves. The morphological heterogeneity of IN
      probably manifests the variety of systems that affect spinal sympathetic
      regulation.

PMID- 15033415
TI  - Sequestration of nNOS in neurofilamentous aggregate bearing neurons in vitro
      leads to enhanced NMDA-mediated calcium influx.
AB  - The significance of copper/zinc superoxide dismutase (SOD1) and neuronal nitric
      oxide synthase (nNOS) co-localization to neurofilamentous (NF) aggregates in
      amyotrophic lateral sclerosis (ALS) is unknown. In this study, we have used
      dissociated motor neurons from either C57BL/6 or mice that over-express the human
      low molecular weight neurofilament protein (hNFL+/+) to examine the relationship
      between NF aggregate formation, SOD1 and nNOS co-localization, and the regulation
      of NMDA-mediated calcium influx in vitro. The intracellular distribution of NF
      aggregates, SOD1 and nNOS was examined by confocal microscopy and NMDA-induced
      alterations in intracellular calcium levels using either Oregon green
      fluorescence or FURA-2 photometric imaging. Cell death was assessed using an
      antibody to activated caspase-3. C57 Bl/6 motor neurons expressed nNOS in a
      punctate manner, whereas SOD1 was distributed homogeneously throughout the
      cytosol. In contrast, hNFL+/+ motor neurons demonstrated co-localization of SOD1
      and nNOS by day 9 post-plating, preceding the formation of NF aggregates. Both
      proteins co-localized to NF aggregates once formed. With NMDA stimulation,
      aggregate-bearing hNFL+/+ motor neurons demonstrated significant increases in
      intracellular calcium, whereas only a minimal alteration in intracellular calcium
      was observed in C57 Bl/6 neurons. Following stimulation with 100 microM NMDA,
      75.5+/-5.5% of hNFL+/+ neurons became apoptotic, whereas only 16.3+/-5.3% of C57
      Bl/6 were. These observations suggest that the presence of NF aggregates results
      in a failure of regulation of NMDA-mediated calcium influx, and that this occurs
      due to the sequestration of nNOS to the NF aggregate, preventing its down
      regulation of the NMDA receptor.

PMID- 15033416
TI  - GABAB receptor stimulation decreases amphetamine-induced behavior and
      neuropeptide gene expression in the striatum.
AB  - The purpose of this study was to investigate whether GABA(B) receptor activation
      blocks acute amphetamine-induced behavioral activity, dopamine release, and
      neuropeptide mRNA expression in the striatum. Systemic administration of R-(+)
      baclofen (1.25 mg/kg, i.p.) did not alter total distance traveled or vertical
      rearing induced by amphetamine (2.5 mg/kg, i.p.). At 2.5 mg/kg, baclofen did not
      alter spontaneous motor activity or total distance traveled, but completely
      blocked vertical rearing induced by amphetamine. At 5.0 mg/kg, baclofen
      completely blocked both total distance traveled and vertical rearing induced by
      amphetamine. Quantitative in situ hybridization histochemistry revealed that
      baclofen (2.5 mg/kg, i.p.) decreased the ability of amphetamine to increase
      preprodynorphin (PPD), preprotachykinin (PPT), preproenkephalin (PPE), and
      secretogranin II (SGII) mRNA levels in the striatum without altering the basal
      levels of these signals. Baclofen also blocked the amphetamine-induced rise in
      SGII mRNA in the core and shell of the nucleus accumbens and cingulate cortex. In
      a separate experiment, systemic baclofen (2.5 mg/kg) decreased the amphetamine
      induced increase in dialysate dopamine levels in the striatum. These results
      suggest that reduced striatal dopamine release contributes to the ability of
      GABA(B) receptor activation to decrease acute amphetamine-induced behavioral
      activity and striatal neuropeptide gene expression.

PMID- 15033417
TI  - The role of oxidative stress, impaired glycolysis and mitochondrial respiratory
      redox failure in the cytotoxic effects of 6-hydroxydopamine in vitro.
AB  - The neurotoxin, 6-hydroxydopamine (6-OHDA) has been implicated in the
      neurodegenerative process of Parkinson's disease. The current study was designed
      to elucidate the toxicological effects of 6-OHDA on energy metabolism in
      neuroblastoma (N-2A) cells. The toxicity of 6-OHDA corresponds to the total
      collapse of anaerobic/aerobic cell function, unlike other mitochondrial toxins
      such as MPP+ that target specific loss of aerobic metabolism. The toxicity of 6
      OHDA paralleled the loss of mitochondrial oxygen (O2) consumption (MOC),
      glycolytic activity, ATP, H+ ion gradients, membrane potential and accumulation
      of the autoxidative product, hydrogen peroxide (H2O2). Removing H2O2 with
      nonenzymatic stoichiometric scavengers, such as carboxylic acids, glutathione and
      catalase yielded partial protection. The rapid removal of H2O2 with pyruvate or
      catalase restored only anaerobic glycolysis, but did not reverse the loss of MOC,
      indicating mitochondrial impairment is independent of H2O2. The H2O2 generated by
      6-OHDA contributed toward the loss of anaerobic glycolysis through lipid
      peroxidation and lactic acid dehydrogenase inhibition. The ability of 6-OHDA to
      maintain oxidized cytochrome c (CYT-C-OX) in its reduced form (CYT-C-RED),
      appears to play a role in mitohondrial impairment. The reduction of CYT-C by 6
      OHDA, was extensive, occurred within minutes, preceded formation of H2O2 and was
      unaffected by catalase or superoxide dismutase. At similar concentrations, 6-OHDA
      readily altered the valence state of iron [Fe(III)] to Fe(II), which would also
      theoretically sustain CYT-C in its reduced form. In isolated mitochondria, 6-OHDA
      had negligible effects on complex I, inhibited complex II and interfered with
      complex III by maintaining the substrate, CYT-C in a reduced state. 6-OHDA caused
      a transient and potent surge in isolated cytochrome oxidase (complex IV)
      activity, with rapid recovery as a result of 6-OHDA recycling CYT-C-OX to CYT-C
      RED. Typical mitochondrial toxins such as MPP+, azide and antimycin appeared to
      inhibit the catalytic activity of ETC enzymes. In contrast, 6-OHDA alters the
      redox of the cytochromes, resulting in loss of substrate availability and
      obstruction of oxidation-reduction events. Complete cytoprotection against 6-OHDA
      toxicity and restored MOC was achieved by combining catalase with CYT-C (horse
      heart). In summary, CYT-C reducing properties are unique to catecholamine
      neurotransmitters, and may play a significant role in selective vulnerability of
      dopaminergic neurons to mitochondrial insults.

PMID- 15033419
TI  - Hippocampal mossy fiber calcium transients are maintained during long-term
      potentiation and are inhibited by endogenous zinc.
AB  - The hippocampal mossy fiber long-term potentiation (LTP) is an N-methyl-d
      aspartate (NMDA) receptor-independent form of long-lasting synaptic plasticity
      characteristic of the zinc-enriched mossy fiber synapses. Its expression is
      generally considered to have a presynaptic locus and to be mediated by a
      persistent increase of evoked transmitter release. Because the release process is
      calcium-dependent, the observed increase in synaptic efficacy could be due to a
      persistent modification of presynaptic calcium mechanisms, triggered by the large
      calcium influx associated with long-term potentiation induction. Alternatively,
      it might be caused by an enhancement in the sensitivity to calcium of some
      components of the synaptic vesicle release system, following the large
      intraterminal calcium accumulation. We investigated the first hypothesis by
      measuring presynaptic Fura-2 calcium signals associated with electrically induced
      mossy fiber long-term potentiation. We have observed that like residual calcium,
      single presynaptic calcium changes are not enhanced during the maintenance phase
      of mossy fiber long-term potentiation. This result supports the idea that this
      form of long-term potentiation may be mediated by persistent changes of some
      process occurring after calcium entry. It has been established that voltage
      dependent calcium channels are inhibited by zinc and that endogenous zinc is
      released in a calcium-dependent way following intense mossy fiber activation.
      Because there is evidence that at these synapses zinc is also released following
      single electrical stimulation, we investigated the effect of endogenous zinc on
      single presynaptic calcium signals and on field potentials associated with mossy
      fiber LTP. We have observed that this form of LTP could be induced in the
      presence of the permeant heavy metal chelator N,N,N',N'-tetrakis(2
      pyridylmethyl)ethylenediamine (TPEN) and that application of this chelator,
      during LTP, caused an enhancement of the presynaptic calcium signals without
      affecting synaptic transmission. This enhancement is consistent with the idea
      that mossy fiber zinc, released following individual stimuli, inhibits
      presynaptic calcium mechanisms.

PMID- 15033418
TI  - Sleep deprivation induced by the modified multiple platform technique:
      quantification of sleep loss and recovery.
AB  - Vigilance status was continually monitored in socially stable groups of rats
      exposed to the modified multiple platform (MMP) technique for sleep deprivation.
      For comparison, sleep parameters were also monitored in socially isolated rats
      deprived of sleep by the single platform (SP) method. In all cases, sleep was
      continuously recorded during baseline, during 96 h of sleep deprivation and
      during 4 days of recovery. Both multiple- and single-platform techniques
      completely abolished paradoxical sleep (PS) during the deprivation period, but
      also resulted in significant decreases in slow wave sleep (SWS) (-31% and -37%,
      respectively). Unexpectedly, animals on large platforms, which are normally
      intended as controls, also showed significant reductions in PS and SWS, and these
      effects were more pronounced in rats deprived in groups than in animals deprived
      in isolation. Another control preparation, rats placed on wire-mesh grids in the
      deprivation tank, also showed PS reduction (-39%) but no loss of SWS during the 4
      test days. Paradoxical sleep rebound was observed in the first 24 h in all
      groups, except for grid controls. Overall, no significant differences were found
      between single- and multiple-platform procedures during the 4 days of
      deprivation. However, sleep rebound was more pronounced in MMP-deprived rats than
      in SP-deprived rats. Sleep loss in both control groups may reflect residual
      effect of stress that remain in the platform technique. These findings indicate
      that the MMP technique is effective in inducing PS deprivation (PSD). However,
      the fact that SWS is also affected may have implications for conclusions on
      paradoxical sleep function based upon paradoxical sleep deprivation.

PMID- 15033420
TI  - The ultrastructural distribution of alpha-synuclein-like protein in normal mouse
      brain.
AB  - The synaptic protein alpha-synuclein is found throughout the brain, although its
      function remains ill-defined. Abnormal accumulations of alpha-synuclein have been
      recognised to be associated with a number of neurodegenerative diseases,
      including Alzheimer's disease and Parkinson's disease. Nevertheless, little is
      known about the precise localisation of this protein within the normal brain,
      information which might contribute to our understanding of its role in both
      health and disease. We raised an antibody which recognises both human and murine
      alpha-synuclein and this was used to study the distribution of the protein in the
      normal mouse brain. We used morphological characteristics to classify the
      immunopositive presynaptic elements and their targets. We conclude that the
      protein is present in synaptic boutons of axons with different neurochemical
      phenotypes but that it is not present in all synaptic terminals. Furthermore, the
      protein is present in the terminals of neurons such as the dopaminergic neurons
      of the substantia nigra and the glutamatergic neurons of the hippocampus, cell
      types which accumulate alpha-synuclein in disease. Nevertheless alpha-synuclein
      is also found in terminals of neurons which have not been reported to accumulate
      the protein in neurodegenerative disorders.

PMID- 15033421
TI  - Hyperthermic pre-conditioning promotes measles virus clearance from brain in a
      mouse model of persistent infection.
AB  - Nervous tissue subjected to hyperthermic pre-conditioning is resistance to
      numerous insults although in vitro, the same treatment can increase gene
      expression and cytopathic effect of neurotropic paramyxoviruses, including
      measles virus (MV). The present work determined whether the in vivo relationship
      between hyperthermic pre-conditioning and MV infection would be to increase
      neuropathogenicity or, conversely, to promote clearance. Balb/c mice 36 h of age
      were exposed to a 41 degrees C hyperthermic treatment for 30 min. Intracranial
      inoculation of mice with Edmonston MV was performed at 6 h following the heat
      treatment, a time point exhibiting elevated levels of the major inducible 70-kDa
      heat shock protein in brain, a hallmark of pre-conditioning. Forty-seven percent
      of the non-heated animals supported a persistent cytopathic infection at 21-day
      post infection (PI) based upon the quantitative detection of viral RNA in brain
      using real time RT-PCR. Cytopathic effect in the infected brains was
      proportionate to viral RNA burden. In contrast, infected stress conditioned mice
      lacked significant cytopathic effect and clearance was demonstrated in 95% of the
      animals. Analysis of shorter post-infection intervals showed that levels of viral
      RNA in brain were equivalent between stress conditioned and non-conditioned mice
      at 2 and 7 days PI, with clearance being first evident in both groups at 14 days.
      The temporal onset and progression of clearance was correlated to splenocyte
      blastogenic responsiveness to purified MV antigen but not the production of MV
      specific antibody. Collectively, these results support the hypothesis that stress
      conditioning enhances the efficacy of cell-mediated immune responses known to
      mediate viral clearance from brain.

PMID- 15033422
TI  - Histochemical features of stress-induced aggregates in alpha-synuclein
      overexpressing cells.
AB  - alpha-Synuclein is a major component of intracytoplasmic inclusions including
      Lewy bodies (LB), Lewy neurites (LN) and glial cytoplasmic inclusions, and plays
      a key role in neurodegenerative processes in Parkinson's disease (PD) and other
      synucleinopathies. Although the molecular mechanisms of the disease process still
      remain to be elucidated, recent studies have suggested that an interaction
      between reactive oxygen species (ROS) and alpha-synuclein may be closely
      associated with the initiation and/or the progression of synucleinopathies. In
      this study, we established human dopaminergic SH-SY5Y cell lines overexpressing
      wild-type or mutant alpha-synuclein and exposed them to various ROS generators.
      After the exposure to ROS, alpha-synuclein aggregates were formed in the
      cytoplasm of these cells, and these were immunopositive for ubiquitin,
      nitrotyrosine and dityrosine, and positive for thioflavin S staining. Thus, the
      obtained cytoplasmic aggregates shared many features with inclusion bodies in
      synucleinopathies. The gamma-tubulin and molecular chaperones coexisted as well,
      suggesting that the aggregate formation is associated with the intracellular
      transport along microtubules and may reflect protective responses against
      neuronal insults. This cellular model not only will be informative for our
      understanding of the pathophysiological process in synucleinopathies, but also
      can be applied to the screening of neuroprotective molecules with therapeutic
      potential.

PMID- 15033423
TI  - Sleep deprivation increases the activation of nuclear factor kappa B in lateral
      hypothalamic cells.
AB  - Sleep deprivation increases sleep propensity in rats and mice as well as the
      production of several sleep-regulatory substances. Nuclear factor kappa B (NF
      kappa B) is a transcription factor implicated in the activation of many of these
      sleep-promoting substances. A unique population of neurons immunoreactive for the
      p65 subunit of NF-kappa B was previously localized within the caudal dorsolateral
      hypothalamus of rats. Therefore, we evaluated the effect of sleep deprivation on
      NF-kappa Bp65-immunoreactivity (IR) in cells of this region in rats as well as
      its nuclear translocation in a kappa B-lacZ transgenic mouse line. In rats after
      6 h of sleep deprivation beginning at light onset, the number of neurons with NF
      kappa Bp65-IR increased significantly in the caudal lateral hypothalamus,
      specifically the magnocellular lateral hypothalamus adjacent to the subthalamus.
      Sleep deprivation also significantly increased the number of cells expressing NF
      kappa B-dependent beta-galactosidase in the magnocellular lateral hypothalamus,
      zona incerta dorsal, as well as the adjacent subthalamus in the transgenic mice.
      These results suggest that NF-kappa B expressing cells within the lateral
      hypothalamus may be important in the maintenance of the sleep-wake cycle.

PMID- 15033424
TI  - Inhibition of the activity of the native gamma-aminobutyric acid A receptor by
      metabolites of thyroid hormones: correlations with molecular modeling studies.
AB  - To characterize the direct effects of thyroid hormones on native gamma
      aminobutyric acid(A) (GABA(A)) receptors, rapid (5 s) actions of a series of
      iodothyronines on muscimol-stimulated uptake of (36)Cl(-) were investigated in
      synaptoneurosomes prepared from rat brain. The results were correlated with
      molecular modeling of the active compounds. Dose-response curves for muscimol in
      the presence of 3,3', 5-L-triiodothyronine (L-T3) indicated a noncompetitive
      inhibition of muscimol-stimulated (36)Cl(-) uptake by the thyroid hormone.
      Synaptoneurosomes prepared from cerebellum were less sensitive to L-T3 than those
      from cerebral cortex, in terms of the potency of the hormone. The overall
      efficacy approached complete inhibition for both brain regions. Muscimol
      stimulated (36)Cl(-) uptake was inhibited differentially by iodothyronine
      derivatives. One group of compounds with IC(50) values of 18-30 microM included L
      thyroxine (L-T4), D-thyroxine (D-T4), 3,3', 5,5'-tetraiodothyroacetic acid
      (Tetrac), and 3,3', 5-triiodothyroacetic acid (Triac). A second group with values
      of 75-100 microM included 3,3', 5'-l-triiodothyronine (reverse T3; r-T3), 3,3'
      diiodo-L-thyronine (3,3'-l-T2) and 3,5-diiodo-L-thyronine (3,5-D-T2). A final
      group of inactive compounds with IC(50) values greater than 100 microM included
      3',5'-diiodo-L-thyronine (3',5'-l-T2), 3-iodo-L-thyronine (L-T1), 3'-iodo-L
      thyronine (3'-L-T1), and L-thyronine (L-T0). Molecular modeling of the active
      iodothyronines using the Gaussian03 series of programs indicated close
      correspondences with models of the GABA-inhibitory neurosteroid pregnenolone
      sulfate (PREGS), suggesting common mechanisms of action at the GABA(A) receptor.

PMID- 15033425
TI  - The effects of unilateral removal of the cerebellar hemispheres on spatial
      learning and memory in rats.
AB  - Left or right unilateral removal of a cerebellar hemisphere altered visuo-motor
      coordination as well as spatial representation of the environment. Moreover, the
      operated rats were unable to adapt their behavior to a novel situation,
      suggesting frontal dysfunctions similar to those demonstrated in human cerebellar
      syndromes.

PMID- 15033427
TI  - Differential modulation of glutamatergic and cholinergic synapses by calcineurin
      in hippocampal CA1 fast-spiking interneurons.
AB  - How signaling molecules in inhibitory interneurons modulate and coordinate the
      integration of synaptic inputs remains largely unknown. We investigated the
      kinetics and modulation of glutamatergic and cholinergic synapses on CA1 fast
      spiking interneurons in hippocampal slices by using whole-cell clamp recording.
      Spontaneous synaptic currents mediated by either AMPA-type glutamate or nicotinic
      acetylcholine receptors on the interneurons can be classified into fast, slow and
      fast-slow based on their duration and decay phase. Effects of calcineurin,
      calmodulin-dependent protein phosphatase, on these two groups of synapses were
      examined by infusing an autoinhibitory peptide of calcineurin (CaN-AIP) into the
      recording neurons. CaN-AIP enhanced the amplitude of glutamatergic fast-EPSCs, as
      well as both amplitude and frequency of cholinergic fast-EPSCs. No significant
      changes in slow-EPSCs were observed during the infusion of CaN-AIP. Our results
      indicate that signal transmission at synapses, which are mediated by either AMPA
      type glutamate or nicotinic acetylcholine receptors, appears different in the
      kinetics. The selective influence of calcineurin on different synapses in fast
      spiking interneurons may play an important role in coordinating thousands of
      synaptic inputs in order to set neuronal excitability at proper levels.

PMID- 15033426
TI  - Progesterone enhances motor, anxiolytic, analgesic, and antidepressive behavior
      of wild-type mice, but not those deficient in type 1 5 alpha-reductase.
AB  - The importance of progesterone's (P(4)) metabolism by the 5 alpha-reductase type
      I enzyme was examined in homozygous and heterozygous 5 alpha-reductase type I
      knockout mice and their wild-type siblings. P(4) (1.0 mg) or vehicle was
      administered and effects on motor, anxiety, nociceptive, and depression behavior
      were observed. After testing, whole-brain progesterone and 5 alpha-pregnan-3
      alpha-ol-20-one (3 alpha,5 alpha-THP) levels were determined by radioimmunoassay.
      Motor behavior in the horizontal crossing and open field tasks of 5 alpha
      reductase-deficient mice administered P(4) was similar to vehicle control mice
      and significantly reduced compared to wild-type mice administered P(4). In the
      open field, 5 alpha-reductase-deficient mice administered P(4) had a similar
      number of central entries as did vehicle control mice, both were lower than
      central entries of P(4)-administered wild-type mice. However, in the plus maze,
      P(4) to 5 alpha-reductase-deficient or wild-type mice significantly increased
      open arm activity compared to vehicle-administered control mice. P(4) to wild
      type, but not 5 alpha-reductase-deficient mice, significantly increased latencies
      to lick front and back paws in response to radiant heat stimuli compared to
      vehicle administration to control mice. In the forced swim test, 5 alpha
      reductase-deficient mice administered P(4) were similar to vehicle control mice
      and the latency to immobility was significantly decreased, and the duration of
      immobility was significantly increased, compared to wild-type mice administered
      P(4). Thus, these data suggest metabolism by the 5 alpha-reductase type I enzyme
      may mitigate P(4)'s effects on some tasks of motor, anxiety, nociception, and
      depression behavior.

PMID- 15033428
TI  - Sexually dimorphic regulation of estrogen receptor alpha mRNA in the ventromedial
      hypothalamus of adult whiptail lizards is testosterone dependent.
AB  - Female, but not male, whiptail lizards will respond to exogenous estrogen with an
      increase in estrogen receptor alpha (ER alpha) mRNA in the ventromedial
      hypothalamus (VMH). The current study tested whether differences in long-term
      testosterone exposure may be responsible for this sex difference. In the first
      experiment, female whiptails were gonadectomized and implanted for 6 weeks with
      either a Silastic capsule containing testosterone or an empty capsule after which
      the implant was removed. In a second experiment, male whiptail lizards were
      castrated for 1 week or for 6 weeks. In both experiments animals were then
      injected with either estradiol benzoate or steroid suspension vehicle and the
      brains collected 24 h later. Brain mRNA expression was assayed using in situ
      hybridization. Chronic testosterone treatment reduced estrogen-induced ER alpha
      mRNA levels (number of grains per cell) in the VMH in females. In contrast, there
      were no significant effects of time after castration or estrogen treatment on
      induction of ER alpha mRNA in the VMH in males. The abundance of estrogen-induced
      ER alpha mRNA in the VMH, therefore, appears to be responsive to testosterone
      environment in the female but not in the male, suggesting a difference in this
      species between the sexes in the mechanism of steroid receptor regulation.

PMID- 15033429
TI  - Glycine and D-cycloserine attenuate vacuous chewing movements in a rat model of
      tardive dyskinesia.
AB  - Presently there is no established treatment for antipsychotic drugs-induced
      tardive dyskinesia (TD), which remains a major clinical issue in psychiatry.
      Based on the principles of the glutamatergic hypothesis of schizophrenia, the
      amino acid glycine (GLY) and the antituberculosis drug D-cycloserine (DCS) have
      been assessed, during the last decade, as adjuvants to antipsychotic drugs.
      Observations stemming from these studies suggest that, in addition to improving
      schizophrenia symptoms, these compounds may also be beneficial against drug
      induced dyskinesias. In order to investigate this hypothesis, GLY and DCS effects
      were studied using the putative TD analogue vacuous chewing movements (VCM) rat
      model. Following 24 weeks of treatment with haloperidol decanoate (0.38 mg/kg/4
      weeks) rats (N=40) were randomized to receive one intraperitoneal injection with
      1.6 g/kg GLY, 10 mg/kg ("low dose") DCS; 100 mg/kg ("high dose") DCS or saline
      ("placebo"), respectively. Behavior was videotaped at intervals during the
      experiment and all VCM, rearing, grooming and immobility episodes were analyzed
      and scored. A control group (N=9) received saline for 24 weeks. Haloperidol
      administration decreased motor activity and significantly induced VCM. High dose
      DCS significantly reduced VCM without affecting other motor parameters. GLY
      treatment resulted in significantly less VCM but also reduced rearing, grooming
      and mobility. In contrast, low dose DCS and placebo did not significantly affect
      any of these parameters. These findings indicate that the use of GLY and DCS
      results in attenuation of VCM in rats and may have an effect on TD in humans.
      Clinical trials with this type of compounds for patients suffering from TD are
      warranted.

PMID- 15033430
TI  - Roles of the bHLH gene Hes1 in retinal morphogenesis.
AB  - During retinal development, common precursors give rise to various types of cells
      in a time course specific to each cell type. Previously, we demonstrated that the
      bHLH gene Hes1 inhibits neuronal differentiation whereas, in Hes1-null retina,
      precursors prematurely differentiate into neurons and form abnormal rosette-like
      structures. Thus, Hes1 is essential for maintenance of precursors and
      morphogenesis of the neural retina. However, the precise causal link between
      premature differentiation and abnormal structures remains to be determined. Here,
      we found that misexpression of Hes1 in the developing retina promotes formation
      of undifferentiated precursor-like cells, whereas in Hes1-null retina, precursors
      are not properly maintained and prematurely differentiate into ganglion cells.
      Strikingly, those prematurely differentiated ganglion cells erupt into the
      subretinal space through the regions where precursors and the outer limiting
      membrane are lost. These results indicate that Hes1 maintains precursors and the
      outer limiting membrane and thereby regulates retinal morphogenesis.

PMID- 15033431
TI  - TNF alpha-p55 receptors: medullary brainstem immunocytochemical localization in
      normal and vagus nerve-transected rats.
AB  - Tumor necrosis factor alpha (TNF(alpha)) is a potent modulator of autonomic
      reflex mechanisms that control the stomach. Evidence suggests that TNF(alpha)
      action directly on vago-vagal reflex control circuits causes the autonomic
      misregulation of digestion manifested as gastrointestinal stasis, nausea, and
      emesis associated with illness. Neurophysiological studies indicated that
      TNF(alpha) may have effects on vagal afferents in the solitary nucleus, as well
      as neurons of the solitary nucleus (NST) and dorsal motor nucleus (DMN) of the
      vagus. The aim of this study was to determine the location of the TNFR1 receptor
      (p55) in the medulla using immunocytochemical methods. We devised a technique for
      localizing the p55 receptor using heat-induced antigen recovery in fixed tissue
      sections. This protocol allowed us to demonstrate that dense p55-immunoreactivity
      (p55-ir) is constitutively present on central (but not peripheral) vagal
      afferents in the solitary tract (ST) and nucleus; p55-ir is also present on
      afferents entering the spinal trigeminal nucleus. Unilateral supra-nodose
      vagotomy eliminated p55-ir from ipsilateral central vagal afferents. Virtually
      all neurons in the brainstem appeared to express p55-ir at a low level, i.e.,
      just above background. However, vagotomy caused a dramatic up-regulation of p55
      ir in vagal motor neurons. This increase in p55-ir in axotomized neurons may play
      a pivotal role in the connection between the occurrence of the injury and the
      initiation of apoptotic processes resulting in elimination of damaged neurons.

PMID- 15033432
TI  - Nociception-driven decreased induction of Fos protein in ventral hippocampus
      field CA1 of the rat.
AB  - To test the hypothesis that the hippocampus field CA1 is recruited in nociceptive
      intensity-dependent fashion in the formalin model of inflammatory pain, we
      determined the effect of injection of formalin (0.625-2.5%) on the induction of
      Fos protein along the length of the hippocampus. Compared to injection of saline,
      injection of formalin (0.625-2.5%) evoked a concentration-dependent increase in
      nociceptive behavior and a significant linear increase in the number of Fos
      positive cells in the spinal cord, especially in the deeper laminae. Injection of
      saline also increased induction of Fos along the length of hippocampus. On the
      other hand, injection of formalin decreased the number of Fos-positive cells in
      whole CA1, CA3 and dentate gyrus, with a greater significant effect in the
      posterior-ventral regions of the hippocampus. Indeed, a formalin concentration
      dependent decrease was observed in the ventral CA1. A systematic pattern of
      change in Fos induction was not observed in the medial septum region. Of the
      regions examined, only the formalin-induced changes in Fos cell counts in the
      posterior and ventral CA1 were tightly correlated with the changes observed in
      the spinal cord. The foregoing findings suggest that nociceptive information is
      processed in distributed fashion by the hippocampus, and at least the ventral CA1
      is implicated in nociceptive intensity-dependent integrative functions.

PMID- 15033433
TI  - Territorial and extra-territorial distribution of Fos protein in the lumbar
      spinal dorsal horn neurons in rats with chronic constriction nerve injuries.
AB  - This study aimed to examine the relationship between temporal and spatial
      expression patterns of Fos protein in the spinal dorsal horn neurons and thermal
      hyperalgesia behaviors in rats with chronic constriction injury (CCI) to the
      sciatic nerve. Our results demonstrated that Fos protein expression in the spinal
      dorsal horn neurons at L5 segment ipsilateral and contralateral to CCI of the
      sciatic nerve was significantly greater than in sham rats from days 10 to 30
      postoperatively (PO 10d to 30d), and was concentrated on the injury (ipsilateral)
      side. Unlike the short-lived expression after tissue inflammation, laminae I to
      VI (especially laminae III/IV) displayed a persistent greater number of Fos-like
      immunoreactive (Fos-LI) neurons for at least 30 days after CCI of the sciatic
      nerve. After the increase in laminae III/IV, Fos-LI neurons tended to gradually
      increase in laminae I/II and V/VI at L5 segment from PO 2d to 30d, which were
      correlated with the heat hyperalgesia (48 degrees C) behaviors measured by paw
      withdrawal latency in CCI rats but not in sham rats. Interestingly, a persistent
      increase of Fos-LI neurons in laminae I to VI at L5 segment of the ipsilateral
      and contralateral sides and at the L1 segment that was out of the normal central
      terminations of the sciatic nerve suggested the probable presence of territorial
      and extra-territorial central sensitization or inadequate central nervous system
      (CNS) adaptive mechanisms. These findings may partly explain why abnormal pain
      sensations are sometimes distributed in a pattern that does not coincide with the
      territories of nerves or with the posterior roots of the peripheral nerve after
      injury.

PMID- 15033434
TI  - Glucose insufficiency alters neuronal viability and increases susceptibility to
      glutamate toxicity.
AB  - Complete glucose deprivation has been shown to induce neuronal apoptosis, but the
      effect of moderate glucose deprivation under normal and pathological conditions
      is not fully understood. We investigated the effect of a restricted supply of
      glucose on neuronal vulnerability to glutamate by assaying cellular ATP levels
      (cellular energy production), 3-[4,5-dimethylthiazol-2-yl]-2,5
      diphenyltetrazolium bromide (MTT) reduction (mitochondrial function), lactate
      dehydrogenase (LDH) release (cellular viability) and activation of caspase-3
      (apoptosis) in rat hippocampal neurons cultured in media (1.7, 5 and 25 mM
      glucose) with or without 100 microM glutamate. Cellular ATP levels were
      significantly reduced in neurons cultured in 1.7 mM glucose, while addition of
      glutamate markedly lowered cellular ATP levels even at the normal glucose
      concentration. MTT reduction was also significantly inhibited by 1.7 mM glucose;
      however, unlike cellular ATP levels, glutamate inhibition of MTT reduction was
      glucose concentration dependent. The LDH assay suggested that neuronal survival
      declines with decreasing glucose concentration in media, and glutamate
      potentiates this effect. Since low glucose media caused a decrease in cellular
      ATP and cell viability, we investigated apoptosis-related changes in cultured
      neurons by examining activity of caspase-3. Low glucose media (1.7 and 5 mM
      glucose) increased caspase-3 activity, and glutamate potentiated this effect. Our
      results suggest that a low glucose supply in culture media activates an apoptosis
      mediator and markedly increases susceptibility to glutamate toxicity. Thus, even
      moderate glucose deprivation could be a serious risk factor that potentiates the
      pathophysiological consequences of certain neurodegenerative diseases.

PMID- 15033435
TI  - Modulation of phospholipid asymmetry in synaptosomal membranes by the lipid
      peroxidation products, 4-hydroxynonenal and acrolein: implications for
      Alzheimer's disease.
AB  - Membrane lipid bilayer asymmetry is maintained by the ATP-dependent enzyme
      flippase. An early signal of synaptosomal apoptosis is the loss of phospholipid
      asymmetry and the appearance of phosphatidylserine (PS) in the outer leaflet of
      the membrane. Two highly reactive products of lipid peroxidation, 4
      hydroxynonenal (HNE) and acrolein, both elevated in Alzheimer's disease (AD)
      brain, have been shown to induce apoptosis and disrupt cellular ion homeostasis.
      These reactive aldehydes can structurally modify proteins by covalent interaction
      and inhibit enzyme function. Phospholipid asymmetry of PS is maintained by the
      ATP-requiring enzyme flippase. We have investigated the inactivation of the
      transmembrane enzyme aminophospholipid-translocase (or flippase) by HNE and
      acrolein. Flippase activity depends on a critical cysteine residue, a possible
      site of covalent modification by HNE or acrolein. The present study demonstrates
      that these alkenals induce the appearance of PS on the outer bilayer lamellae and
      suggests that increases in intracellular Ca(2+) might not be the sole cause for
      loss of flippase activity. Rather, other mechanisms that could modulate the
      function of flippase might be important in phospholipid asymmetry disruption.
      These results are discussed with potential relevance to neuronal loss in
      Alzheimer's disease brain.

PMID- 15033436
TI  - Cerebral ischemia in 5-lipoxygenase knockout mice.
AB  - Cerebral ischemia induces 5-lipoxygenase translocation and leukotriene production
      in the brain. We tried to clarify the pathological significance of 5-lipoxygenase
      on cerebral ischemia using 5-lipoxygenase knockout mice. No significant
      difference was observed in the infarct size following permanent and transient
      ischemia for 60 min between both types of mice. The present study did not support
      the idea that leukotriene production is involved in infarct expansion in focal
      cerebral ischemia.

PMID- 15033437
TI  - The vanilloid receptor-1 (TRPV1) is expressed in some rat dorsal horn NK1 cells.
AB  - The vanilloid receptor-1 (TRPV1), the capsaicin receptor, a transducer of several
      nociceptive stimuli, is principally expressed by nociceptive fibers that
      specifically target supraspinal-projecting neurons expressing the NK1 receptor.
      TRPV1 is also expressed by intraspinal neurons. Using double immunocytochemistry,
      we show that 14.2% of these TRPV1 dorsal horn cell bodies also express the NK1
      receptor suggesting that endogenous vanilloids may directly modulate second-order
      ascending neurons.

PMID- 15033438
TI  - Relationship between stress and circulating levels of S100B protein.
AB  - It has been proposed that S100B can be a marker for several pathological
      conditions including brain traumas, blood-brain barrier disruption, and ischemia.
      Because the hypothalamo-pituitary-adrenal axis is activated in these conditions,
      we investigated the role of glucocorticoids in the effects of stress on serum
      S100B. Restraint stress increased S100B levels in control and in adrenalectomized
      but not in corticosterone-injected rats. Adrenalectomy did not alter basal S100B.
      These results indicate a glucocorticoid-independent relationship between stress
      and S100B.

PMID- 15033439
TI  - Alpha 2-adrenergic receptor inhibition of cAMP accumulation is transformed to
      facilitation by tumor necrosis factor-alpha.
AB  - Activation of the alpha(2)-adrenergic receptor on neurons regulates the activity
      of neurons. Inhibition of forskolin-stimulated cAMP accumulation induced by
      alpha(2)-adrenergic receptor activation is altered following exposure of the
      neuron SH-SY5Y cell line to tumor necrosis factor-alpha (TNF). Acute (5 and 15
      min) exposure to TNF induces a transformation in alpha(2)-adrenergic regulation
      of cAMP accumulation from inhibition to facilitation. These findings support an
      autocrine role for the regulation of TNF production from neurons.

PMID- 15033440
TI  - Different dopamine D1 and D2 receptors expression after motor activity in the
      striatal critical period.
AB  - Circling training during rat striatum postnatal critical period (PN30 to 37 days)
      induces a life-lasting co-reduction of muscarinic acetylcholine receptors (mAChR)
      and dopamine D2 receptors (D2R) binding. Here, we evaluated the expression of D1R
      and D2R under similar experimental conditions. Trained rats showed a decrease of
      40% in D2R binding sites (p<0.01) and of 45% in the D2R mRNA expression which
      involve short (p<0.05) and long (p<0.01) isoforms. In contrast, D1R binding sites
      nor its mRNA expression levels were affected by training, indicating a
      differential synaptic refinement during this ontogenetically fixed period.

PMID- 15033441
TI  - The use of the novel substrate-heme complex approach in the derivation of a
      representation of the active site of the enzyme complex 17alpha-hydroxylase and
      17,20-lyase.
AB  - A novel molecular modelling technique, namely the substrate-heme complex (SHC)
      approach, is used to derive a representation of the overall active site of the
      enzyme complex 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase), a
      cytochrome P-450 dependent enzyme involved in the oxidative hydroxylation of the
      C(17) and cleavage of the C(17)-C(20) bond of the progestins (e.g., progesterone
      or pregnenolone). Using the derived model, we have rationalised the inhibitory
      activity of a number of steroidal and non-steroidal inhibitors, including
      miconazole and ketoconazole (the latter being a former potential treatment of
      hormone-dependent prostate cancer).

PMID- 15033442
TI  - Fluorous-tagged compound: a viable scaffold to prime oligosaccharide synthesis by
      cellular enzymes.
AB  - Fluorous-tagged saccharide primers could be viable scaffolds for the synthesis of
      oligosaccharides. This research demonstrates that a fluorine-containing
      saccharide derivative could actually be taken up by the cell, the saccharide
      chain elongated by cellular enzymes, and the elongated product released by the
      cells to the culture medium. A fluorous-tagged lactoside primer, 6
      (perfluorohexyl)hexyl-4-O-(beta-D-galactopyranosyl)-beta-D-glucopyranoside, was
      chemically synthesized and introduced in mouse B16 cells to prime oligosaccharide
      synthesis. Uptake of the primer by B16 cells resulted in the sialylation of the
      terminal galactose residue to afford an oligosaccharide with the same glycan
      structure as ganglioside GM3. The presence of many fluorine atoms did not have
      any adverse effects to the cells. Moreover, the number of fluorine atoms did not
      pose a steric barrier and instead, their presence possibly increased the
      hydrophobicity of the primer and enhanced membrane permeability. This strategy of
      using a fluorous-tagged primer and cells can pave the way for an easier way of
      preparing oligosaccharides via an environment-friendly approach that eliminates
      the use of large amounts of organic solvents.

PMID- 15033443
TI  - Transcription factor Sp1 mediates p38MAPK-dependent activation of the p21WAF1
      gene promoter in vascular smooth muscle cells by pyrrolidine dithiocarbamate.
AB  - Previously, we demonstrated that pyrrolidine dithiocarbamate (PDTC) induced G1
      cell cycle arrest in vascular smooth muscle cells (VSMC) through inducing p21WAF1
      expression. It has recently been reported that the transcription factors involved
      in p21WAF1 activation by certain signaling factors may vary in different cell
      types. However, little is known concerning the molecular mechanisms by which PDTC
      induces p21WAF1 gene expression in VSMC. In this report, we demonstrate that PDTC
      induces the p21WAF1 expression at the mRNA level. This increase in p21WAF1 gene
      expression was due to p38MAPK-dependent activation of the p21WAF1 promoter by
      PDTC. Transcription factor Sp1 binding site was identified as the cis-element for
      the activation of p21WAF1 promoter by PDTC, as determined by deletion and
      mutation analysis. In addition, gel shift and supershift assays demonstrated that
      this PDTC-responsive element binds specifically to the transcription factor Sp1.
      Treatment with SB203580, an inhibitor of the p38MAPK, significantly down
      regulated transactivation of PDTC-induced Sp1. Finally, the transient expression
      of VSMC with dominant negative p38MAPK plasmid suppressed PDTC-stimulated Sp1
      activity. In conclusion, we report the novel finding that transcription factor
      Sp1 that is involved in the p38MAPK-mediated control of p21WAF1 regulation on
      VSMC in response to PDTC has now been identified.

PMID- 15033445
TI  - RASL11A, member of a novel small monomeric GTPase gene family, is down-regulated
      in prostate tumors.
AB  - We performed a genome-wide search for novel loci encoding for Ras-related
      proteins based on the genome mapping coordinates of the cancer-derived EST
      dataset at GenBank. Partial sequences from two novel human genes were identified
      and subsequently used for full length transcript cloning. RASL11A and ARL9 belong
      to two novel subfamilies coding for small GTPases that we found to be highly
      conserved among eukaryotes. The Arl9/Arl10 subfamily displays a conserved
      interswitch toggle that places it evolutionarily closer to the Arf family. Rasl11
      proteins are more closely related to the Ras branch of GTPases. All orthologues
      newly identified here exhibit an Asn residue in place of the highly conserved
      Thr35 of the G domain, suggesting that the universal switch mechanism of small
      GTPases may be structurally different in this subfamily. We determined by
      Northern blot that RASL11A is transcribed in several human tissues and that it is
      down-regulated in prostate tumors as measured by quantitative real-time PCR.
      These results highlight a previously uncharacterized subfamily of Ras-related
      genes that may have a tumor suppressor role in prostate cancer.

PMID- 15033444
TI  - Regulation of Ca(2+)-activated chloride channels by cAMP and CFTR in parotid
      acinar cells.
AB  - The effect of intracellular cAMP and cystic fibrosis conductance regulator (CFTR)
      protein on the calcium-activated chloride current (ICaCl) present in parotid
      acinar cells was studied using the patch clamp technique. Application of 1 mM of
      8-(4-chlorophenylthio)adenosine 3':5'-cyclic monophosphate (CPT-cAMP), a
      permeable analog of cAMP, inhibited ICaCl only at positive potentials. This
      inhibition was partially abolished in cells dialyzed with 20 nM PKI 6-22 amide, a
      potent peptide that specifically inhibits PKA. Because cAMP is an activator of
      the CFTR Cl- channel, a known regulator of ICaCl, we also investigated if the
      inhibition of ICaCl was mediated by activation of CFTR. To test this idea, we
      added 1 mM CPT-cAMP to acinar cells isolated from knockout animals that do not
      express the CFTR channel. In these cells the cAMP effect was totally abolished.
      Thus, our data provide evidence that cAMP regulates ICaCl by a dual mechanism
      involving PKA and CFTR.

PMID- 15033446
TI  - An anti-proliferative gene BTG1 regulates angiogenesis in vitro.
AB  - B-cell translocation gene 1 (BTG1) is a member of the anti-proliferative gene
      family that regulates cell growth and differentiation. To clarify the role of
      BTG1 in angiogenesis, we examined the regulation of BTG1 expression in cultured
      endothelial cells and characterized its function in in vitro models of
      angiogenesis. BTG1 mRNA was abundantly expressed in quiescent endothelial cells.
      Addition of serum and angiogenic growth factors decreased BTG1 mRNA levels in
      endothelial cells. In contrast, BTG1 mRNA was up-regulated in tube-forming
      endothelial cells on Matrigel. This up-regulation was partially blocked by
      neutralizing antibody against transforming growth factor-beta (TGF-beta), and TGF
      beta increased BTG1 mRNA levels. Inhibition of endogenous BTG1 by overexpression
      of antisense BTG1 resulted in inhibited network formation, and overexpression of
      sense BTG1 augmented tube formation in these cell lines. BTG1-overexpressing
      endothelial cells displayed increased cell migration. These findings suggest that
      BTG1 may play an important role in the process of angiogenesis.

PMID- 15033447
TI  - Modelling extracellular domains of GABA-A receptors: subtypes 1, 2, 3, and 5.
AB  - GABA is the main inhibitory neurotransmitter in the mammalian central nervous
      system. When GABA binds to the ubiquitous GABA-A receptors on neurons, chloride
      channels are activated leading to a rapid increase in chloride conductance that
      depresses excitatory depolarization. The GABA-A receptors are targets for many
      clinically important drugs, such as the benzodiazepines, general anaesthetics,
      and barbiturates. All of these drugs enhance the chloride current activated by
      GABA. Of the GABA-A receptor family, the subtype 2 is critical for the treatment
      of anxiety spectrum disorders. To avoid unwanted side effects, it is necessary to
      find highly selective drugs that interact only with subtype 2 but not with the
      related receptors such as subtypes 1, 3, and 5. To realize such a goal, it is
      important to have not only the 3D (dimensional) structure of subtype 2 but also
      the 3D structures of subtypes 1, 3, and 5. In this study, the 3D structures of
      all the four subtypes of GABA-A receptors have been derived. The computer-modeled
      heteropentameric structures bear the following features: (1) each of the five
      subunits in the pentamer has an intrachain disulfide bond, a hallmark of ligand
      gated pentameric channels; (2) those residues which are sensitive to the binding
      of the benzodiazepine site ligands are grouped around the alpha1,2,3,5/gamma2
      interfaces; and (3) those residues which are sensitive to the binding of GABA
      molecules are grouped around the alpha1,2,3,5/beta2 interfaces. All these
      findings are fully consistent with experimental observations. Meanwhile, for
      those sensitive or key residues, a close look at their subtle difference among
      the four subtypes has been provided through a highlighted superposition picture.
      In addition to providing the atomic coordinates, the predicted structures have
      further clarified some ambiguities that could not been uniquely determined by the
      existing experimental data, such as the directionality of the subunit arrangement
      in the heteropentamers. The 3D models may provide a reasonable structural frame
      or footing for designing highly selective drugs. The present models might be also
      useful in understanding the basic mechanism of operation of the GABA-A receptors,
      stimulating novel strategies for developing more specific drugs and better
      treatments.

PMID- 15033448
TI  - Transposon-based RNAi delivery system for generating knockdown cell lines.
AB  - RNA interference is rapidly becoming a powerful tool for genetic analyses in
      mammalian systems. A potential drawback to transient small inhibitory RNA
      silencing is the short duration of downregulation it confers, usually only 24
      72h. Viral-based vector systems for the long-term delivery of RNA hairpins have
      been developed, yet they require expertise in viral production and transduction.
      Here we describe a simple plasmid-based system for the generation of long-term
      gene knockdown utilizing RNA interference combined with the gene delivery
      capabilities of the mammalian Tc1-like transposon Sleeping Beauty. Designated
      Maleficent, this system is shown to downregulate exogenous expression of GFP in a
      constitutively positive cell line. In addition, targeting of the endogenously
      expressed lamin A gene results in long-term silencing with significant reduction
      in protein levels (> 95%). Maleficent therefore provides a relatively easy,
      efficient, and stable means of delivering RNAi hairpins to generate long-term
      gene-specific knockdown cell lines.

PMID- 15033449
TI  - Stem cells with multilineage potential derived from porcine skin.
AB  - Stem cells from farm animals are valuable cell models for the study of
      development, differentiation, and are potential efficient donors for nuclear
      transfer. Here we report the isolation and characterization of stem cells from
      porcine skin. These porcine skin-originated sphere (PSOS) cells expressed the
      neural progenitor marker, nestin, as well as genes that are critical for
      pluripotency such as Oct4 and Stat3. The PSOS cells proliferated actively in
      vitro and retained normal karyotype after long-term culture. When cultured in
      defined medium, they generated cells with characteristics of neurons and
      astrocytes. A subpopulation of cells differentiated into adipocyte-like cells
      when cultured in 10% fetal bovine serum. Clonal study demonstrated that PSOS
      exhibited clonal-generating capability. Clonal populations from individual stem
      cells could form neuron-, astrocyte-, and adipocyte-like cells upon inducted
      differentiation. Our findings represent the first report of skin-originated stem
      cells isolated from non-rodent animals.

PMID- 15033450
TI  - The tea flavonoid epigallocatechin-3-gallate reduces cytokine-induced VCAM-1
      expression and monocyte adhesion to endothelial cells.
AB  - Attachment of leukocytes to the vascular endothelium and the subsequent migration
      of cells into the vessel wall are early events in atherogenesis. This process
      requires the expression of endothelial adhesion molecules. Since tea catechins
      are reputed to promote antiatherogenic activities, we investigated the effects of
      various tea catechins-i.e., epicatechin (EC), epicatechin gallate (ECG),
      epigallocatechin (EGC), and epigallocatechin-3-gallate (EGCG)-on cytokine-induced
      expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion
      molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin)
      in HUVECs by ELISA. EGCG and to a lesser extent ECG prevented the induction of
      VCAM-1 expression in a concentration-dependent manner after stimulation with TNF
      alpha, whereas EC and EGC were without effect. EGCG also inhibited the IL-1beta
      induced induction of VCAM-1 expression. Inhibition of cytokine-induced VCAM-1
      expression was manifested already on the transcriptional level. Furthermore, EGCG
      reduced the TNF-alpha-induced adhesion of THP-1 cells to HUVECs. EGCG did not
      influence TNF-alpha-stimulated NF-kappaB activation.

PMID- 15033451
TI  - A requirement of MAPKAPK2 in the uropod localization of PTEN during FMLP-induced
      neutrophil chemotaxis.
AB  - The directionality control in chemotaxis is the result of a reciprocal regulation
      of PI3-kinase and PTEN subcellular localization. MK2(-/-) neutrophils have a
      directionality loss in fMLP-induced chemotaxis. We found that in polarized WT
      neutrophils PTEN was localized in the uropod region. However, MK2(-/-)
      neutrophils or p38 MAPK inhibitor-SB203580-pretreated WT neutrophils showed a
      disrupted PTEN subcellular localization. Some PTEN was localized at the leading
      edge of the polarized neutrophils, which may lower the concentration of PI3
      kinase lipid product PtdIns(3,4,5)P3 required for directionality sensing. FMLP
      stimulated MK2(-/-) neutrophils or SB203580-pretreated WT neutrophils also had
      disrupted F-actin polarization. F-actin polymerization inhibitor lantrunculin-B
      disrupted the polarization of PTEN, but not PtdIns(3,4,5)P3. The results suggest
      that PTEN uropod polarization is F-actin polymerization-dependent and may be
      through the effect of MK2 on F-actin polarization.

PMID- 15033452
TI  - Mechanical pressure-induced phosphorylation of p38 mitogen-activated protein
      kinase in epithelial cells via Src and protein kinase C.
AB  - Mechanical stimulation is known to modulate cell physiology in a variety of
      different tissues. Particularly, epithelial cells are permanently exposed to
      mechanical stimulation generated by externally applied forces. The present in
      vitro study demonstrated mechanical pressure as a trigger-factor of the p38
      mitogen-activated protein kinase (MAPK) pathway in epithelial cells. Mechanical
      pressure applied by teflon weights (1.02g/cm(2)) led to a rapid phosphorylation
      of p38 peaking between 5 and 10min. Furthermore, phosphorylation of the small
      heat shock protein 27 (HSP27) was shown in response to mechanical pressure.
      Suppression of p38 function by using specific inhibitors blocked the pressure
      mediated phosphorylation of HSP27. In order to identify upstream regulators of
      p38, a contribution of Src and protein kinase C (PKC) in pressure-signaling was
      investigated. We could demonstrate that inhibition of Src or PKC suppressed the
      pressure-induced phosphorylation of p38. These findings suggest mechanical
      pressure as a new type of effector stimulus for the p38 pathway with implications
      to (patho-) physiological conditions.

PMID- 15033453
TI  - Functional comparison of single- and double-stranded siRNAs in mammalian cells.
AB  - The concept of small interfering RNA (siRNA) has been extended to include not
      only short double-stranded RNA of 19-25bp, but also single-stranded antisense RNA
      of the same length, since such single-stranded antisense siRNAs were recently
      found to be able to inhibit gene expression as well. We made comprehensive
      comparison of double- and single-stranded siRNA functions in RNA interference
      (RNAi), targeting multiple sites and different mRNAs, measuring RNAi effects at
      different time-points and in different cell lines, and examining response curves.
      Duplex siRNAs were found to be more potent than single-stranded antisense siRNAs.
      This was verified by the observation that single-stranded antisense siRNAs, which
      were inefficient in some cases when used alone, could be rescued from
      inefficiency by sequentially transfecting with the sense siRNAs. This result
      suggests that the structural character of siRNA molecules might be a more
      important determinant of siRNA efficiency than the cellular persistence of them.

PMID- 15033454
TI  - Rat supernatant protein factor-like protein stimulates squalene monooxygenase and
      is activated by protein kinase A.
AB  - Rat supernatant protein factor-like protein (SPF2) shares 90% sequence identity
      with rat SPF and 77% identity with human SPF, both of which have been shown to
      stimulate squalene monooxygenase in the cholesterol biosynthetic pathway. SPF2
      appears to be predominantly expressed in respiratory and epithelial tissues,
      whereas SPF is expressed in liver. To determine if SPF2 was also able to
      stimulate squalene monooxygenase activity, we have cloned, expressed, and
      purified the protein following heterologous expression in Escherichia coli. SPF2
      was only half as effective as SPF in stimulating squalene epoxidation and was
      more strongly inhibited by GTP and GDP. The inhibition by guanine nucleotides was
      fully prevented by alpha-tocopherol, a reported ligand for these proteins.
      Incubation of SPF2 with protein kinase A and ATP increased its activity by about
      twofold, has been found for SPF. These results indicate that SPF2 activity is
      modulated by guanine nucleotides and alpha-tocopherol, as well as by
      phosphorylation.

PMID- 15033455
TI  - Modulation of angiogenesis-related protein synthesis by valproic acid.
AB  - Recent studies have attested to the antiangiogenic effects of HDAC inhibitors on
      solid human tumors. The HDAC inhibitor butyrate has been reported to impair tumor
      cell-induced angiogenesis. However, due to its poor bioavailability in vivo, the
      therapeutic use of butyrate is limited. On the other hand, valproic acid has
      inhibitory effects on carcinoma cells, is known to be well tolerated, and has an
      excellent bioavailability. We therefore set out to investigate whether the HDAC
      inhibitor valproic acid also impairs angiogenesis. Our findings indicate that
      valproic acid represses the relevant angiogenic factors VEGF and FGF in Caco-2
      cells. Both, protein expression as well as mRNA levels of VEGF, were reduced to a
      similar degree. Suppression of ubiquitin-proteasome activity could be a possible
      reason for valproic acid effects on regulatory angiogenesis proteins. These
      results suggest that the HDAC inhibitor valproic acid could become a valuable new
      addition in the attempt to develop alternative therapeutic approaches in the
      treatment of colon carcinomas.

PMID- 15033456
TI  - Characterization of a region involved in binding of measles virus H protein and
      its receptor SLAM (CD150).
AB  - Signaling lymphocyte activation molecule (SLAM; also known as CD150) is a newly
      identified cellular receptor for measles virus (MV). MV Hemagglutinin protein (H)
      mediates MV entry into host cells by specifically binding to SLAM. Amino acid 27
      135 of SLAM was previously shown to be the functional domain to interact with H
      and used to screen a 10-mer phage display peptide library in this study. After
      four rounds of screening and sequence analysis, the deduced amino acid sequence
      of screened peptides SGFDPLITHA and SDWDPLFTHK showed to be highly homologous
      with amino acid 429-438 of MV H (SGFGPLITHG). Peptides SGFDPLITHA and SDWDPLFTHK
      specifically inhibited binding of H to SLAM and further inhibition of MV
      infection suggests that these peptides can be developed to MV blocking reagents
      and amino acid 429-438 in H protein is functionally involved in receptor binding
      and may constitute part of the receptor-binding determinants on H protein.

PMID- 15033457
TI  - Cholesterol modulates P-glycoprotein activity in human peripheral blood
      mononuclear cells.
AB  - P-glycoprotein (P-gp) is expressed in a wide range of cell types including
      peripheral blood mononuclear cells (PBMCs) where it may restrict intracellular
      accumulation of substrates like antineoplastic agents, HIV protease inhibitors,
      or rhodamine123. P-gp is known to be located in membrane microdomains, whose
      structure and function are susceptible to cholesterol alterations. This study
      evaluated the effect of cholesterol alteration in human PBMCs on P-gp activity.
      Whereas cholesterol depletion had no effect, cholesterol repletion of depleted
      cells significantly decreased intracellular rhodamine123 concentrations in
      lymphocytes to 32.2%+/-2.7 (p<0.001) and to 41.9%+/-3.5 (p<0.001) in monocytes.
      After cholesterol saturation of native cells intracellular rhodamine123
      fluorescence decreased to 12.4%+/-1.6 (p<0.001) in lymphocytes and 12.9%+/-3.5
      (p<0.001) in monocytes. These data demonstrate that elevated cellular cholesterol
      levels can markedly increase P-gp activity in human PBMCs.

PMID- 15033458
TI  - Expressions of inhibitory Smads, Smad6 and Smad7, are differentially regulated by
      TPA in human lung fibroblast cells.
AB  - Smad6 and Smad7 are inhibitory Smads (I-Smads) with differential inhibitory
      effects on the regulation of the cellular signalings induced by TGF-beta
      superfamily. Here, we show that phorbol ester 12-O-tetradecanoylphorbol-13
      acetate (TPA) down-regulates Smad6 mRNA expression and up-regulates Smad7 mRNA
      expression in IMR-90, a human lung fibroblast cell line. These regulations of I
      Smads by TPA were suppressed by one PKC inhibitor (Go6983), but not by another
      (Go6976). TPA treatment had little effect on the phosphorylation of novel PKCs
      (PKCdelta and PKCepsilon), but specifically induced PKCmu phosphorylation, and
      this effect was inhibited by Go6983, but not by Go6976. Additionally, Go6983 but
      not Go6976 inhibited ERK- and JNK-phosphorylation as well as Smad7 promoter
      activity induced by TPA. MEK inhibitor U0126 inhibited the down-regulation of
      Smad6 mRNA expression but not the up-regulation of Smad7 mRNA expression. In
      contrast, JNK inhibitor SP600125 had no such effects. Luciferase reporter
      analysis revealed that TPA did not induce NF-kappaB activation. In addition, TPA
      up-regulated Smad7 expression in the presence of NF-kappaB inhibitor TLCK. These
      findings indicate that TPA down-regulates Smad6 expression presumably via PKCmu
      ERK-dependent pathway and up-regulates Smad7 expression via PKCmu-dependent
      mechanism(s) which need no MAPK and NF-kappaB activation.

PMID- 15033460
TI  - An application of experimental design using mutually orthogonal Latin squares in
      conformational studies of peptides.
AB  - We address the question-can we use experimental design methods to investigate
      peptide conformation and identify conformational parameters that may contribute
      more significantly to the potential energy than others? We used mutually
      orthogonal Latin square design to sample the conformational space of peptides and
      analysed the samples using analysis of variance. We examined the equality of the
      effect of the torsion angles on the conformational potential energy. The results
      showed that different torsion angles contributed differently to the
      conformational energy. We are able to identify those parameters that may have to
      be more carefully considered in conformational studies of peptides.

PMID- 15033461
TI  - A new kinetic model of recombinant beta-galactosidase from Kluyveromyces lactis
      for both hydrolysis and transgalactosylation reactions.
AB  - Previous models based on the Michaelis-Menten kinetic equation, that glucose was
      not used as an acceptor, did not explain our experimental data for lactose
      conversion by a recombinant beta-galactosidase from Kluyeromyces lactis. In order
      to create a new kinetic model based on the data, the effects of galactose and
      glucose on beta-galactosidase activity were investigated. Galactose acted as an
      inhibitor at low concentrations of galactose and lactose, but did not inhibit the
      activity of beta-galactosidase at high concentrations of galactose (above 50mM)
      and lactose (above 100mM). The addition of glucose at concentrations below 50mM
      resulted in an increased reaction rate. A new model of K. lactis beta
      galactosidase for both hydrolysis and transgalactosylation reactions with glucose
      and lactose as acceptors was proposed. The proposed model was fitted well to the
      experimental data of the time-course reactions for lactose conversion by K.
      lactis beta-galactosidase at various concentrations of substrate.

PMID- 15033459
TI  - Phosphoinositide 3-kinase regulates the phosphorylation of NADPH oxidase
      component p47(phox) by controlling cPKC/PKCdelta but not Akt.
AB  - Superoxide production by NADPH oxidase is essential for the bactericidal
      properties of phagocytes. Phosphorylation of p47(phox), one of the cytosolic
      components of NADPH oxidase, is a crucial step of the oxidase activation. Some
      evidences suggest that phosphoinositide 3-kinase (PI3K) is involved in p47(phox)
      phosphorylation, but it has not been fully understood how PI3K regulates it. The
      aim of this study was to examine the mechanism underlying the PI3K regulation of
      p47(phox) phosphorylation. Pharmacological inhibition of PI3K attenuated both
      fMLP-stimulated p47(phox) phosphorylation and NADPH oxidase activity in HL-60
      cells differentiated to a neutrophil-like phenotype. Although fMLP elicited Akt
      activation in a PI3K-dependent manner, an Akt inhibitor had no effect on the
      oxidase activity triggered by fMLP. In vitro kinase assay revealed that Akt was
      unable to catalyze p47(phox) phosphorylation. Interestingly, the activation of
      cPKC and PKCdelta after fMLP stimulation was dependent on PI3K. Furthermore, PI3K
      inhibitors reduced the activation of phospholipase Cgamma2 without affecting
      tyrosine phosphorylation on it. These results suggest that PI3K regulates the
      phosphorylation of NADPH oxidase component p47(phox) by controlling
      diacylglycerol-dependent PKCs but not Akt.

PMID- 15033462
TI  - Association of GNB3 gene with pulse pressure and clustering of risk factors for
      cardiovascular disease in Japanese.
AB  - Heterotrimeric guanine nucleotide-binding proteins (G proteins) mediate many
      pathways including the beta-adrenergic signaling pathway. The C825T polymorphism
      in the gene coding for the beta3 subunit of G proteins (GNB3) has been shown to
      be associated with several phenotypes such as hypertension, obesity, and diabetes
      mellitus comprising the metabolic syndrome. The GNB3 C825T polymorphism may
      therefore be associated with many atherosclerosis-related phenotypes. On these
      grounds, we studied the C825T polymorphism in relation to atherosclerosis-related
      phenotypes in a large Japanese population. Analyses in general linear models
      showed that T carriers had a significantly wider pulse pressure (P=0.0089) as
      well as a significantly higher systolic blood pressure (P=0.026). In contrast,
      analyses in logistic regression models showed that the C825T polymorphism was not
      significantly associated with each of the four major classical risk factors for
      cardiovascular and cerebrovascular disease (obesity, hypertension,
      hypertriglyceridemia, and diabetes mellitus). However, a significantly higher
      percentage of subjects had none of the four disorders in CC homozygotes than in T
      carriers (P=0.026). Thus, the C825T polymorphism was significantly associated
      with clustering of these four risk factors. Although the effect of the gene on
      each phenotype appears to be weak, considering the combined impact of the effects
      of the C825T polymorphism on risk factors, the GNB3 gene may be an important gene
      for human health.

PMID- 15033463
TI  - Polymorphisms of glutathione S-transferase M1 and T1 modulate blood pressure of
      individuals chronically exposed to natural sour gas containing sulfur compounds.
AB  - In order to find the effect of genetic polymorphisms of GSTM1 and GSTT1 on blood
      pressure of individuals chronically exposed to sulfur compounds, the present
      study was done. Study subjects (38 males, 38 females) were residents of
      contaminated areas of Masjid-i-Sulaiman (southwest of Iran). The GSTM1 and GSTT1
      genotypes were determined using a polymerase chain reaction (PCR)-based method.
      The non-parametric Sign test was applied in order to detect differences between
      the GSTs genotypes of study subjects and the normal mean values according to the
      sex and age of subjects. From four combination of genotypes, systolic blood
      pressure significantly decreased in combination of null-GSTM1 and present-GSTT1
      (Z=-2.41; P=0.016), and diastolic blood pressure significantly increased in
      combination of present-GSTM1 and null-GSTT1 (Z=+2.14; P=0.032). It is speculated
      about polymorphisms of GSTs in individuals chronically exposed to natural sour
      gas, which contains H2S, fulfilling a physiological role(s) in regulating blood
      pressure.

PMID- 15033464
TI  - Bone marrow stromal cells produce nerve growth factor and glial cell line-derived
      neurotrophic factors.
AB  - Bone marrow stromal cells (BMSC) have attracted interest through their possible
      use for cell therapy in neurological diseases. Recent reports demonstrated that
      these cells are able to migrate and have potential for neuronal differentiation
      after transplantation into brain parenchyma. The objective of this work was
      determine whether rat BMSC express NGF and GDNF, in order to study its potential
      application for treatment of neurodegenerative diseases. BMSC were harvested from
      male rats and cultured in DMEM supplemented with 20% fetal bovine serum. At
      passage 6 the total RNA was isolated using TriZol reactive. RT-PCRs to evaluate
      the expression of NGF and GDNF using specific primers were carried out. Our
      results indicate that rat BMSC have potential to produce NGF and GDNF. We have
      not found any report in favor of GDNF or NGF production from rat BMSC.

PMID- 15033465
TI  - The relationship between palindrome avoidance and intragenic codon usage
      variations: a Monte Carlo study.
AB  - Several studies have shown that codon usage within genes varies, as it seems
      dependent on both codon context and codon position within the gene. Given that
      palindromes in addition often are avoided in genomes, this study aimed at finding
      out if intragenic variations in codon usage may be a way to control the amount
      and location of palindromes. A Monte Carlo algorithm was written which resampled
      the codons in genes while keeping the amino acid sequence of the translation
      product constant. On the resampled sequences, palindromes were counted and their
      intragenic positions mapped. Escherichia coli K12 uses type II restriction
      modification systems and displays pronounced codon usage phenomena. Using this as
      a reference organism it was clearly shown that the number of palindromes in genes
      is generally lower than the amount of palindromes in resampled genes; thus, the
      succession of codons seems to be a way to decrease the number of palindromes. The
      intragenic position of palindromes in resampled sequences, however, was largely
      equal to the position in the native genes, so codon usage phenomena are unlikely
      to be a way to control the intragenic position of palindromes. The analysis was
      repeated on two bacteriophages and gave similar same results, even though the
      virus genomes are much smaller. Studies on the endosymbionts Buchnera sp. APS and
      Wigglesworthia sp., which seemingly have no type II restriction-modification
      systems, showed that in these species there is only weak evidence for codon usage
      acting to control the number of palindromes.

PMID- 15033466
TI  - Neuropeptidomics of the grey flesh fly, Neobellieria bullata.
AB  - A peptidomics approach was applied to determine the peptides in the larval
      central nervous system of the grey flesh fly, Neobellieria bullata. Fractions
      obtained by high performance liquid chromatography were analysed by MALDI-TOF and
      ESI-Q-TOF mass spectrometry. This provided biochemical evidence for the presence
      of 18 neuropeptides, 11 of which were novel Neobellieria peptides. Most
      prominently present were the FMRFamide-related peptides: 7 FMRFamides, 1
      FIRFamide, and Neb-myosuppressin. The three putative capa-gene products Neb
      pyrokinin and the periviscerokinins Neb-PVK-1 and -2 were detected, as well as
      another pyrokinin. This Neb-PK-2 was also present in the ring gland along with
      corazonin, Neb-myosuppressin, and Neb-AKH-GK, an intermediate processing product
      of the adipokinetic hormone. Furthermore, the central nervous system contained
      Neb-LFamide, proctolin, and FDFHTVamide, designated as Neb-TVamide. With this
      study, we considerably increased our knowledge of the neuropeptidome of the pest
      fly N. bullata, which is an important insect model for physiological research.

PMID- 15033467
TI  - Antioxidative treatment reverses imbalances of nitric oxide synthase isoform
      expression and attenuates tissue-cGMP activation in diabetic rats.
AB  - Oxidative stress and impaired bioactivity of vascular nitric oxide (NO) play an
      important role in the pathogenesis of macro- as well as microangiopathic
      complications in diabetes mellitus. To determine the cause of this impaired
      bioactivity, we tested the effect of long-term hyperglycemia and antioxidative
      treatment on tissue-specific endothelial (e)NOS- and inducible (i)NOS-expression
      and the main target of NO action, cGMP, in diabetic rats. After 4 weeks of
      hyperglycemia, eNOS-mRNA expression was significantly down-regulated in all
      tissues tested. In contrast, iNOS-mRNA was significantly up-regulated and tissue
      generation of cGMP significantly increased. Treatment with alpha-lipoicacid
      reversed changes of NOS-isoform expression as well as cGMP-concentration without
      changing blood glucose levels. In addition, oxidative stress significantly
      decreased in diabetic rats treated with alpha-lipoicacid. Together, diabetes
      regulates NOS-isoforms differentially by down-regulating eNOS and up-regulating
      iNOS. In addition, our data suggest that the cause of impaired endothelial
      vasodilatation in experimental diabetes is not degradation or inactivation of NO.
      On the contrary, these results support the concept of decreased reactivity of the
      vascular smooth muscle to NO or increased NO activity as a possible vascular
      damaging agent, e.g., by inducing apoptosis in vascular cells. Furthermore, our
      data show that antioxidative treatment is capable of reversing changes in the NO
      cGMP system and may therefore be an important therapeutic option for preventing
      vascular damage in diabetes mellitus.

PMID- 15033468
TI  - DNA microarray analysis of the correlation between gene expression patterns and
      acquired resistance to 5-FU/cisplatin in gastric cancer.
AB  - The mechanisms of intrinsic and/or acquired anti-cancer drug resistance have been
      described in in vitro resistance models, but the clinical relevance has remained
      undefined. We undertook a prospective study to identify correlations between gene
      expression and clinical resistance to 5-FU/cisplatin. We compared expression
      profiles from gastric cancer endoscopic biopsy specimens obtained at a
      chemosensitive state (partial remission after 5-FU/cisplatin) with those obtained
      at a refractory state (disease progression), using Affymetrix oligonucleotide
      microarray technology (U133A). Using 119 discriminating probes and a cross
      validation approach, we were able to correctly identify the chemo-responsiveness
      of 7 pairs of training samples and 1 independent test pair. These exploratory
      data demonstrate that the gene expression profiles differ between chemosensitive
      and refractory state gastric cancer biopsy samples.

PMID- 15033470
TI  - Periplasmic proteins of Escherichia coli are highly resistant to aggregation:
      reappraisal for roles of molecular chaperones in periplasm.
AB  - Periplasmic proteins of Gram-negative bacteria like Escherichia coli are
      subjected to immediate affect of environmental fluctuation that may unfold
      proteins, due to the permeability of the outer membrane to small molecules. They
      are thus supposedly protected by certain molecular chaperones. Nevertheless, no
      homologues of typical molecular chaperones have so far been found in periplasm,
      and the recently reported chaperone activities of periplasmic protein disulfide
      isomerase (PDI) and peptidyl prolyl isomerase (PPI) seem to be too weak to
      satisfy such assumed needs. In an attempt to reveal whether periplasmic proteins
      exhibit certain unusual properties, we discovered that such proteins as a whole
      are highly resistant to aggregation under a wide variety of denaturing
      conditions. Furthermore, in an effort to unveil the nature behind this phenomenon
      we purified and examined four prominent periplasmic proteins. Our results
      demonstrate that these proteins unfold at rather mild denaturing conditions and
      expose hydrophobic surfaces during such unfolding process, but hardly form
      complexes with a typical molecular chaperone. Based on these observations, we
      propose that the periplasmic proteins have been evolved to resist the formation
      of aggregates when subjected to various denaturing conditions and molecular
      chaperones may thus not be needed in periplasm.

PMID- 15033469
TI  - Statins downregulate ATP-binding-cassette transporter A1 gene expression in
      macrophages.
AB  - The ATP-binding-cassette transporter A1 (ABCA1) plays an essential role in
      cellular cholesterol efflux and helps prevent macrophages from becoming foam
      cells. The statins are widely used as cholesterol-lowering agents and have other
      anti-atherogenic actions. We tested the effects of four different statins
      (fluvastatin, atorvastatin, simvastatin, and lovastatin) on ABCA1 expression in
      macrophages in vitro. The statins suppressed ABCA1 mRNA expression in RAW246.7
      and THP-1 macrophage cell lines and in mouse peritoneal macrophages. The effect
      was time- and dose-dependent and was abolished by the addition of the post
      reductase product, mevalonate. These findings imply that there is a possible
      modulation of the well-known beneficial effects of the statins on the reverse
      cholesterol transport pathway.

PMID- 15033471
TI  - Conversion of feedback regulation in aspartate kinase by domain exchange.
AB  - To elucidate the mechanism for the regulation of aspartate kinase (AK) via
      feedback inhibition, we constructed several chimeric enzymes between Bacillus
      subtilis AK II, a lysine-sensitive mesophilic enzyme, and Thermus flavus AK, a
      threonine-sensitive thermostable enzyme, each having the same alpha2beta2-type
      tetrameric structure. A chimeric AK, named BTT, composed of the chimeric alpha
      subunit that comprises of the N-terminal catalytic region from B. subtilis AK II
      and the C-terminal region from T. flavus, and the beta subunit from T. flavus,
      was inhibited only by threonine. Another chimeric enzyme, BT, which has a similar
      structure to that of BTT but lacks the beta subunit, having alpha2-type homo
      dimeric structure, was also responsive only to threonine. However, the addition
      of threonine enhanced the activity of BT. These results indicate the regulatory
      function of C-terminal region and beta subunit in AK. BTT showed extremely high
      thermostability comparable to that of T. flavus, suggesting that the beta subunit
      also contributed to the stability of the AK.

PMID- 15033472
TI  - Osteopontin as a positive regulator in the osteoclastogenesis of arthritis.
AB  - We examined the role of osteopontin (OPN) in the osteoclastogenesis of arthritis
      using collagen-induced arthritis (CIA). Cells from arthritic joints of wild-type
      (OPN +/+) mice spontaneously developed bone-resorbing osteoclast-like cells
      (OCLs). The cultured cells showed an enhanced expression of receptor activator of
      nuclear factor kappaB ligand (RANKL) and a decreased expression of
      osteoprotegerin (OPG). The addition of OPG reduced the number of OCLs, indicating
      that the osteoclastogenesis depends on the RANK/RANKL/OPG system. The cells also
      produced OPN abundantly and anti-OPN neutralizing antibodies suppressed the
      development of OCLs. Moreover, the addition of OPN increased the expression of
      RANKL and augmented differentiation of OCLs from OPN-deficient (OPN -/-) cells.
      OPN, like the combination of 1alpha,25-dihydroxyvitamin D(3) and dexamethasone,
      also enhanced the RANKL expression and decreased OPG expression in a stromal cell
      line, ST2. These results suggest that OPN acts as a positive regulator in the
      osteoclastogenesis of arthritis through the RANK/RANKL/OPG system.

PMID- 15033473
TI  - Chemotaxis-mediated biodegradation of cyclic nitramine explosives RDX, HMX, and
      CL-20 by Clostridium sp. EDB2.
AB  - Cyclic nitramine explosives, RDX, HMX, and CL-20 are hydrophobic pollutants with
      very little aqueous solubility. In sediment and soil environments, they are often
      attached to solid surfaces and/or trapped in pores and distribute heterogeneously
      in aqueous environments. For efficient bioremediation of these explosives, the
      microorganism(s) must access them by chemotaxis ability. In the present study, we
      isolated an obligate anaerobic bacterium Clostridium sp. strain EDB2 from a
      marine sediment. Strain EDB2, motile with numerous peritrichous flagella,
      demonstrated chemotactic response towards RDX, HMX, CL-20, and NO(2)(-). The
      three explosives were biotransformed by strain EDB2 via N-denitration with
      concomitant release of NO(2)(-). Biotransformation rates of RDX, HMX, and CL-20
      by the resting cells of strain EDB2 were 1.8+/-0.2, 1.1+/-0.1, and 2.6+/-0.2nmol
      h(-1)mgwet biomass(-1) (mean+/-SD; n=3), respectively. We found that commonly
      seen RDX metabolites such as TNX, methylenedinitramine, and 4-nitro-2,4
      diazabutanal neither produced NO(2)(-) during reaction with strain EDB2 nor they
      elicited chemotaxis response in strain EDB2. The above data suggested that NO(2)(
      ) released from explosives during their biotransformation might have elicited
      chemotaxis response in the bacterium. Biodegradation and chemotactic ability of
      strain EDB2 renders it useful in accelerating the bioremediation of explosives
      under in situ conditions.

PMID- 15033474
TI  - cis-Dimer formation of E-cadherin is independent of cell-cell adhesion assembly
      in vivo.
AB  - Cadherin-based cell-cell adhesions play important roles in embryonic development
      and in the maintenance of normal tissue architecture. Little is known, however,
      about the mechanisms of controlling cadherin dynamics at the cell surface. We
      previously demonstrated that E-cadherin functions as a cis (lateral)-dimer on the
      cell surface by chemical cross-linking. In this study, we examined the dynamics
      of E-cadherin cis-dimer formation during cell-cell adhesion assembly by using
      chemical cross-linking. Although treatment with cytochalasin D, a potent
      inhibitor of actin polymerization, was shown to inhibit the formation of cell
      cell contacts, the dynamics of E-cadherin cis-dimer formation was not affected.
      This result indicated that the cis-dimer formation procedure is independent of
      cell-cell adhesion assembly in vivo. However, the cell aggregation and
      dissociation assays showed that the cytochalasin D treatment shifted the cadherin
      based cell adhesion from a strong to a weak state. Taken together, these results
      strongly support the possibility that the E-cadherin cis-dimer is a minimal
      functional unit in cadherin-mediated cell-cell adhesion in vivo.

PMID- 15033475
TI  - Physical and functional interactions between Daxx and TSG101.
AB  - Daxx has been reported to mediate the Fas/JNK-dependent signals in the cytoplasm.
      However, several evidences have suggested that Daxx is located mainly in the
      nucleus and functions as a transcriptional regulator. Recently, we identified
      DMAP1, a TSG101-interacting protein as a Daxx binding partner by yeast two-hybrid
      screening. TSG101 has been shown to act as transcriptional co-repressor of
      nuclear hormone receptors. Here we examined whether TSG101also interacts with
      Daxx directly. The association of Daxx and TSG101 was confirmed using co
      expressed tagged proteins. The interaction regions in both proteins were also
      mapped, and the cellular localization of the interaction was examined. TSG101
      formed a complex with Daxx through its coiled-coil domain and co-localized in the
      nucleus. Furthermore, TSG101 enhanced Daxx-mediated repression of glucocorticoid
      receptor transcriptional activity. These results provide the novel molecular
      interactions between Daxx and TSG101, which establish an efficient repressive
      transcription complex in the nucleus.

PMID- 15033476
TI  - Transient alteration of cell fate using a nuclear and cytoplasmic extract of an
      insulinoma cell line.
AB  - We report a transient modulation of cell fate in fibroblasts briefly exposed to
      an extract derived from the rat insulin-producing beta cell line, INS-1E. Primary
      fetal rat fibroblasts were reversibly permeabilized with Streptolysin O,
      incubated for 1h in a 15,000g INS-1E nuclear and cytoplasmic extract, resealed,
      and cultured. A first marker of change in cell fate was a reduction of cell and
      nuclear size within days of exposure to extract such that in some instances the
      fibroblasts resembled INS-1E cells. Second, two beta cell transcripts, Pdx-1 and
      insulin, were detected in the fibroblasts for up to 4 weeks. Third, (pro)insulin
      labeling was detected in 5-30% of the cells for a period of 8-14 days after
      incubation in extract. These phenotypes were absent from fibroblasts exposed to
      heat-treated INS-1E extracts, a human fibroblast cell line-derived extract or
      buffer. The results indicate that the extract of an insulinoma-derived cell line
      can promote at least a transient modification of cell fate towards a beta cell
      phenotype in non-beta cells. Because they are easily accessible, cell extracts
      may represent a practical source of material for investigating the mechanisms of
      alteration of a nuclear and cellular program.

PMID- 15033477
TI  - Renin activity and angiotensin I concentration in genetically selective inbred
      line of hypertensive mice.
AB  - Blood pressure lowering kallikrein-kinin and blood pressure raising renin
      angiotensin systems play a major role in the maintenance of normal blood
      pressure. In a previous study, we have shown that a kallikrein-like prorenin
      converting enzyme (PRCE C) is elevated in the submandibular gland tissue of a
      mouse line (BPH) that was genetically selected and inbred for high blood pressure
      in comparison to normotensive line (BPN) that was derived from the ancestors of
      BPH line. In the present investigation we wanted to find out if elevated levels
      of PRCE C were involved in the modulation of tissue (local) renin-angiotensin
      system in the submandibular gland tissue. Results indicate significantly high
      renin activity but low angiotensin I level in the tissue of BPH mouse model.
      These results tend to suggest PRCE C's involvement in tissue (local) renin
      angiotensin system.

PMID- 15033478
TI  - 3-Methyladenine specifically inhibits retrograde transport of cation-independent
      mannose 6-phosphate/insulin-like growth factor II receptor from the early
      endosome to the TGN.
AB  - 3-Methyladenine (3-MA), a well-known inhibitor of autophagic sequestration, can
      also prevent class III phosphatidylinositide (PI) 3-kinase activity, which is
      required for many processes in endosomal membrane trafficking. Although much is
      known about the effects of other PI 3-kinase inhibitors, such as wortmannin and
      LY294002, on endosomal membrane trafficking, little is known about those of 3-MA.
      Here we show that the treatment of cells with 3-MA results in a specific
      redistribution of the cation-independent mannose 6-phosphate/insulin-like growth
      factor II receptor (MPR300) from the trans-Golgi network (TGN) to early/recycling
      endosomal compartments containing internalized transferrin. Importantly, in
      contrast to wortmannin and LY294002, 3-MA did not cause the enlargement of late
      endosomal/lysosomal compartments. The results suggest that the effect of 3-MA is
      restricted to the retrieval of MPR300 from early/recycling endosomes.

PMID- 15033480
TI  - Selection of a highly aggressive myeloma cell line by an altered bone
      microenvironment in the C57BL/KaLwRij mouse.
AB  - In multiple myeloma (MM), bone marrow microenvironment has an important role for
      the survival and growth of plasma cells. We previously showed that a high bone
      turnover, induced by ovariectomy, increased MM cells growth in the 5T2MM model.
      The present study characterized a new plasma cell line (5THL) which was isolated
      from 5T2MM mice previously ovariectomized. Cells were propagated unchanged in
      normal C57BL/KaLwRij mice during six generations. 5THL was compared to the
      original 5T2MM phenotype. Paraproteinemia was detected 6 weeks post injection in
      5THL mice and after 8 weeks in 5T2MM mice. All 5THL mice developed a hind-limb
      paralysis after 10 weeks. 5T2MM mice were euthanized at 16 weeks, due to a more
      progressive development of the disease. In 5THL mice, osteolytic lesions were
      observed after 8 weeks and severe bone destruction was evidenced at 10 weeks. In
      5T2MM mice, minimal lesions were observed only after 10 weeks. Like in 5T2MM
      mice, no extra osseous lesions were observed in 5THL mice. The 5THL MM model
      closely mimics human myeloma with higher and faster bone aggressiveness. This new
      aggressive cell line, with a preserved phenotype, was selected by an altered
      microenvironment due to an increased bone turnover.

PMID- 15033479
TI  - AICAR stimulates adiponectin and inhibits cytokines in adipose tissue.
AB  - 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) can be used as an
      experimental tool to activate 5'-AMP-activated protein kinase (AMPK) and has been
      shown to improve insulin sensitivity. In parallel adiponectin also seems to
      activate AMPK and to improve insulin sensitivity. We have investigated the
      effects of AICAR on the gene expression of adiponectin and on gene expression and
      release of cytokines in human adipose tissue in vitro. AICAR stimulated AMPK
      alpha1 activity 3-4-fold (p<0.001), and dose-dependently increased adiponectin
      mRNA levels with significant stimulation (2-4-fold) at AICAR concentrations of
      0.5-2mM (p<0.05). The adipose tissue protein release of tumor necrosis factor
      alpha (TNF- alpha) and interleukin-6 (IL-6) was decreased by AICAR (p<0.05). In
      conclusion, AICAR stimulated adipose tissue AMPK alpha1 activity and adiponectin
      gene expression, while attenuating the release of TNF-alpha and IL-6. Reduced
      concentrations of these cytokines and increased levels of adiponectin might play
      a role for the insulin sensitizing effects of AICAR.

PMID- 15033481
TI  - Contractions induce phosphorylation of the AMPK site Ser565 in hormone-sensitive
      lipase in muscle.
AB  - Intramyocellular triglyceride is an important energy store which is related to
      insulin resistance. Mobilization of fatty acids from this pool is probably
      regulated by hormone-sensitive lipase (HSL), which has recently been shown to
      exist in muscle and to be activated by epinephrine via PKA and by contractions
      via PKC and ERK. 5' AMP-activated protein kinase (AMPK) is an intracellular fuel
      gauge which regulates metabolism. In this study we incubated rat soleus muscle to
      investigate if AMPK influences HSL during 5min of repeated tetanic contractions.
      An eightfold increase in AMPK activity was accompanied by a 2.5-fold increase in
      phosphorylation of the AMPK-site Ser(565) in HSL (p<0.05). Inhibition of PKC by
      Calphostin C abolished the contraction-mediated HSL activation while HSL-Ser(565)
      phosphorylation was not reduced. The study indicates that during contractions
      AMPK phosphorylates HSL in Ser(565), but this phosphorylation is not directly
      responsible for the contraction-induced activation of HSL.

PMID- 15033482
TI  - Identification of a truncated ratp28-related protein expressed in kidney.
AB  - An RT-PCR based strategy to clone the membrane-associated steroid binding protein
      ratp28 additionally amplified a novel sequence-related PCR product termed HC5.
      The HC5 PCR product was cloned and sequenced and showed 94% nucleotide sequence
      similarity to ratp28. The HC5 cDNA sequence open reading frame encodes a
      predicted 75 amino acid (8.0kDa) protein, and is therefore truncated compared to
      ratp28 (195 amino acids, 21.6kDa). In vitro transcription and translation of the
      HC5 cDNA resulted in the production of 2 proteins of approximately 8 and 6kDa.
      Restriction digests from various tissues demonstrated that liver and heart
      expressed primarily ratp28 mRNA whereas kidney and blood contained both ratp28
      and HC5 transcripts. Phage display was employed to generate an antibody fragment
      to a peptide sequence conserved in ratp28 and HC5. Western blotting identified a
      10kDa protein in cytosolic fractions of rat kidney. The function of HC5 remains
      to be determined.

PMID- 15033483
TI  - S-palmitoylation modulates human estrogen receptor-alpha functions.
AB  - 17beta-Estradiol (E2)-induced rapid functions (from seconds to minutes) can be
      attributed to a fraction of nuclear estrogen receptor-alpha (ERalpha) localized
      at the plasma membrane. As a potential mechanism, we postulated that S
      palmitoylation of the Cys447 residue may explain the ability of ERalpha to
      associate to plasma membrane making possible E2-dependent rapid functions [e.g.,
      extracellular regulated kinase (ERK) activation]. Here, we report direct evidence
      that the mutation of the Cys447 residue to Ala impairs human ERalpha
      palmitoylation and E2-induced rapid ERK phosphorylation when transfected in ER
      devoid HeLa cells. Moreover, the Cys447Ala mutation significantly decreases the
      E2-induced transactivation of an estrogen responsive element construct probe.
      Similar effects were obtained treating HeLa cells transfected with wild type
      ERalpha with the palmitoyl-acyltransferase inhibitor 2-bromo-hexadecanoic acid.
      Moreover, the deletion of the A-D domains (containing the DNA binding region) of
      ERalpha had no consequences on [(3)H]palmitate incorporation, whereas no
      palmitoylation occurred in the ERalpha mutant devoid of the E domain (i.e.,
      ligand binding domain). These results point to the pivotal role of the Cys447
      residue in ERalpha palmitoylation and in the modulation of E2-induced non-genomic
      functions.

PMID- 15033484
TI  - Topology of Homer 1c and Homer 1a in C2C12 myotubes and transgenic skeletal
      muscle fibers.
AB  - mRNA transcripts for Homer 1a and Homer 1c have been detected in skeletal muscle
      [Biochem. Biophys. Res. Commun. 279 (2000) 348]. Here, the subcellular
      distribution of recombinant HA1-tagged Homer 1c and HA1-tagged Homer 1a was
      investigated in C(2)C(12) myotubes and in transgenic skeletal muscle fibers of
      the adult rat by epifluorescent and confocal microscopy. In C(2)C(12) myotubes,
      Homer 1a was homogeneously localized in the cytosol and also labeled some nuclei
      whereas Homer 1c displayed a diffuse reticular/punctuate pattern in the cytosol
      with scattered punctuate labeling around nuclei; no co-localization was observed
      with the ryanodine receptor/Ca(2+) release channel (RYR1). The subcellular
      localization of the Homer 1 isoforms was markedly different in transgenic muscle
      fibers: Homer 1c was diffusely distributed at the I band and enlightened the Z
      line, whereas Homer 1a labeled both the I band and the A band with distinct
      reinforcement of the H line; neither Homer 1c nor Homer 1a co-localized with
      either calsequestrin or RYR1, two sarcoplasmic reticulum markers. Our findings
      are discussed in relation to reported effects of Homer 1 isoforms on RYR1
      function.

PMID- 15033485
TI  - Inositol hexakisphosphate and sulfonylureas regulate beta-cell protein
      phosphatases.
AB  - In human type 2 diabetes, loss of glucose-stimulated insulin exocytosis from the
      pancreatic beta-cell is an early pathogenetic event. Mechanisms controlling
      insulin exocytosis are, however, not fully understood. We show here that inositol
      hexakisphosphate (InsP(6)), whose concentration transiently increases upon
      glucose stimulation, dose-dependently and differentially inhibits enzyme
      activities of ser/thr protein phosphatases in physiologically relevant
      concentrations. None of the hypoglycemic sulfonylureas tested affected protein
      phosphatase-1 or -2A activity at clinically relevant concentrations in these
      cells. Thus, an increase in cellular phosphorylation state, through inhibition of
      protein dephosphorylation by InsP(6), may be a novel regulatory mechanism linking
      glucose-stimulated polyphosphoinositide formation to insulin exocytosis in
      insulin-secreting cells.

PMID- 15033486
TI  - The Hoxa2 enhancer 2 contains a critical Hoxa2 responsive regulatory element.
AB  - Rhombomeres are embryonic territories arising from the transient segmentation of
      the hindbrain. Their identity is specified by Hox genes from paralogous groups 1
      4. Hoxa2 is the only Hox gene to be expressed in the second rhombomere and the
      regulatory cues leading to this region-specific expression have been poorly
      investigated. A 2.5-kb DNA fragment overlapping with the 3' end of Hoxa2 was
      previously shown to specifically direct the expression of a reporter gene in the
      second rhombomere and the rostral somites of mouse embryos. Here, we report that
      this enhancer region is activated in vitro by Hoxa2 and that this activation is
      strictly dependent on a short 10-bp sequence matching the consensus for Hox-Pbx
      recognition sites.

PMID- 15033487
TI  - Impaired E-cadherin expression in human spermatozoa in a male factor infertility
      subset signifies E-cadherin-mediated adhesion mechanisms operative in sperm
      oolemma interactions.
AB  - Cadherins comprise a family of calcium-dependent glycoproteins that function in
      mediating cell-cell adhesion in virtually all solid tissues of multicellular
      organisms. We have examined the presence of a cadherin on spermatozoon and its
      possible involvement in sperm-oocyte interaction. Spermatozoa from fertile human
      subjects showed the presence of E-cadherin on its head domains, detectable only
      after permeabilization of the surface membranes. On the contrary, spermatozoa
      from oligozoospermic subjects did not possess E-cadherin on their principal
      acrosomal and equatorial domains. Immunoprecipitation and Western blot studies
      also showed the presence of E-cadherin in spermatozoa from fertile males and its
      absence in oligozoospermic males. Using RT-PCR, we detected E-cadherin message in
      the round cells of fertile males, which was absent in the cells from
      oligozoospermic males. The presence of anti-E-cadherin antibody brought about
      quantitative reduction in the sperm-oocyte binding in vitro. These observations
      indicate the possibility of the interplay of a cadherin-dependent homophilic
      and/or heterophilic adhesion interaction between spermatozoa and oocyte during
      fertilization. The absence of a key adhesion molecule in a human male infertility
      disorder points towards genetic defects causing failure in gamete interactions.

PMID- 15033488
TI  - A molecular dissection of the interaction between the transcription factor Gata-1
      zinc finger and DNA.
AB  - The production of circulating blood cells from bone marrow stem cells during
      hematopoiesis is accompanied by overall changes in gene expression which cause
      production of required functional proteins, such as hemoglobin in erythroid
      cells, as well as control of cell growth, preventing apoptosis of differentiating
      cells. Hematopoietic gene regulation is controlled by several specific
      transcription factors, including the factor Gata-1, which is required for
      erythrocyte maturation. Based on contacts observed in the NMR structure of the
      cGata-1 binding domain in complex with DNA, the protein's key DNA interface is
      interesting in being quite hydrophobic in nature, due to the presence of three
      leucine side chains protruding toward the DNA. Given the T-rich composition of
      the GATA DNA binding site, it is possible that thymine's unique 5-methyl group
      may mediate some of these hydrophobic contacts to increase the stability of
      binding. The hypothesis that thymine methyl groups are important to the free
      energy of binding between Gata and DNA is tested by measuring binding of an
      oligonucleotide substrate in which individual thymine bases are substituted with
      uracil. To test for any important base-pair specific interactions which may be
      hydrogen-bonded in character, we have also assayed Gata binding to
      oligonucleotides with base analogs which cannot make hydrogen bonds. We report
      that out of the binding site's five thymine methyl groups, only one appeared to
      make a notable contribution to binding affinity, with removal causing a loss of
      less than 1kcal/mol of binding free energy. On the other hand, perturbing the
      potential hydrogen-bonding surface of the DNAs major groove was found to cause a
      larger decrease in binding affinity than removal of any of the thymine methyl
      groups, with a loss of 2-3kcal/mol of binding free energy.

PMID- 15033489
TI  - Proteomic identification of biomarkers expressed by human pluripotent stem cells.
AB  - The ability to effectively monitor the behaviour of pluripotent stem cells and
      their differentiation is key to their use in basic and clinical research.
      Molecules expressed in particular cell types can be used to report the status of
      cell differentiation and is a recognised means of assessing the behaviour of cell
      cultures. There are currently few useful markers of stem cells and there is no
      rapid way to accurately determine their level of expression. In this study, we
      describe for the first time the potential of surface enhanced laser
      desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS) to identify
      novel biomarkers of human pluripotent embryonal carcinoma stem cells and their
      differentiated derivatives. This approach allows the rapid and sensitive
      screening of cell samples without the need to purify the specimen prior to
      analysis. The identification of proteins expressed in specific cell populations
      will provide valuable tools for monitoring cellular development.

PMID- 15033490
TI  - Adiponectin differentially regulates cytokines in porcine macrophages.
AB  - Adiponectin, an adipocyte-derived hormone, attenuates the production of TNFalpha
      by activated human macrophages. In the present study, we used porcine blood
      derived macrophages to test the hypothesis that the anti-inflammatory action of
      adiponectin includes suppression of IL6 and an induction of IL10. Adiponectin
      suppressed both TNFalpha and IL6 production in macrophages activated with
      lipopolysaccharide (P<0.01). In contrast, adiponectin increased IL10 expression
      (P<0.05) and augmented (P<0.05) the induction of this cytokine by
      lipopolysaccharide (LPS). Mechanistically, the attenuation of proinflammatory
      cytokine production by adiponectin was associated with an attenuation of the
      translocation of NFkappaB to the nucleus. Either adiponectin or inhibition of
      ERK1/2 with U0126 diminished the induction of IL6 by LPS (P<0.05), but the
      combination of adiponectin and the inhibitor did not further reduce IL6
      production. In contrast, the inhibitory actions of adiponectin and a p38 MAPK
      inhibitor (SB203580) were additive (P<0.05). These data indicate that the anti
      inflammatory actions of adiponectin include suppression of IL6 and induction of
      IL10. In addition, we provide evidence that some of the anti-inflammatory actions
      of adiponectin are mediated in part by suppression of NFkappaB signaling and
      ERK1/2 activity.

PMID- 15033491
TI  - Cell cycle-dependent regulation of the human aurora B promoter.
AB  - Aurora B is an important regulator of mitosis, and its mRNA and protein levels
      are tightly regulated during the cell cycle. In this study, we cloned the 5'
      flanking region of the human aurora B gene and characterized its promoter
      activity. Two major transcription initiation sites were identified by primer
      extension. aurora B promoter activity was upregulated during M phase, and its
      cell cycle-dependent element (CDE) and cell cycle-gene homology region (CHR)
      upstream of the transcription initiation sites regulated the cell cycle-dependent
      promoter activity. Several CDE-binding protein complexes were identified using
      the electrophoretic mobility shift assay. Using the biotin-streptavidin pull-down
      assay, binding of E2F-1, E2F-4, and DP-2, but not of DP-1, to the CDE was
      detected. These results demonstrate that aurora B mRNA level is regulated by CDE
      CHR and that a subset of E2F/DP family proteins binds to the CDE.

PMID- 15033492
TI  - Matrix metalloproteinases and TGFbeta1 modulate oral tumor cell matrix.
AB  - The integrin beta6 has been shown to promote invasion and experimental metastasis
      by oral squamous cell carcinoma (SCC). In this study, we demonstrate that the
      expression of beta6 by oral SCC9 cells increased activation of the UPA --> MMP3 -
      > MMP9 pathway. We also demonstrate that the deposition of fibronectin and
      tenascin-C matrices by SCC9beta6 cells and peritumor fibroblast cocultures is
      counter-regulated by the UPA --> MMP3 --> MMP9 pathway. Suppression of individual
      components of this pathway increased the deposition of fibronectin, but decreased
      tenascin-C matrix assembly by the cocultures. When the SCC9beta6/PTF cocultures
      were incubated with TGFbeta1, the deposition of fibronectin and tenascin-C as
      well as the activation of MMP3 and MMP9 was increased. These results indicate
      that MMP3, MMP9, and TGFbeta1 are important for the modulation, composition, and
      maintenance of the ECM in oral SCC.

PMID- 15033493
TI  - Three-dimensional visualization analysis of in vitro cultured bone fabricated by
      rat marrow mesenchymal stem cells.
AB  - Marrow mesenchymal stem cells are well known for their differentiation into bone
      forming osteoblasts and in vitro mineralized tissue formation. However, process
      details, including tissue structure and cellular environments, remain unclear.
      The present study demonstrates three-dimensional visualization of tissue
      fabricated by culturing MSCs in the presence of calcein, a fluorescent marker for
      bone mineralization. The 3D visualization was performed by computer-assisted
      confocal laser scanning microscopy and revealed that the in vitro tissue
      consisted of layers of a mineralized matrix with round cells in the matrix
      lacunae, an unmineralized matrix (osteoid), and osteoblastic cells on the osteoid
      surface. The findings show that the mineralization by cultured MSCs is an in
      vitro counterpart of in vivo bone formation and indicate that the novel technique
      of visualization without tissue fixation could be useful for continuous
      monitoring of tissue organization in an ongoing culture.

PMID- 15033494
TI  - S100 protein translocation in response to extracellular S100 is mediated by
      receptor for advanced glycation endproducts in human endothelial cells.
AB  - The extracellular functions of S100 proteins have attracted more attention in
      recent years. S100 proteins are a group of calcium-binding proteins which exhibit
      cell- and tissue-specific expression, and different expression levels of members
      from this family have been observed in various pathological conditions. The
      reported extracellular functions of S100 proteins include the ability to enhance
      neurite outgrowth, involvement in inflammation, and motility of tumour cells. In
      our previous study, we reported translocation of S100A13 in response to the
      elevated intracellular calcium levels induced by angiotensin II. In order to
      investigate potential effects of extracellular S100A13, recombinant S100A13 was
      used here to stimulate human endothelial cells. Addition of extracellular S100A13
      to the cells resulted in both endogenous protein translocation and protein uptake
      from the extracellular space. To test specificity of this effect, addition of
      various other S100 proteins was also performed. Interestingly, translocation of
      specific S100 proteins was only observed when the cells were stimulated with the
      same extracellular S100 protein. Since the receptor for advanced glycation end
      products (RAGE) is a putative cell surface receptor for S100 proteins and is
      involved in various signal transduction pathways, we next investigated the
      interaction between the receptor and extracellular S100 proteins. We show here
      that NF-kappaB which is a downstream regulator in RAGE-mediated transduction
      pathways can be activated by addition of extracellular S100 proteins, and
      translocation of S100 proteins was inhibited by soluble RAGE. These experiments
      suggest a common cell surface receptor for S100 proteins on endothelial cells
      even though intracellular translocation induced by extracellular S100 proteins is
      specific.

PMID- 15033495
TI  - The active site of the Escherichia coli glycogen synthase is similar to the
      active site of retaining GT-B glycosyltransferases.
AB  - Bacterial glycogen synthases transfer a glucosyl unit, retaining the anomeric
      configuration, from ADP-glucose to the non-reducing end of glycogen. We modeled
      the Escherichia coli glycogen synthase based on three glycosyltransferases with a
      GT-B fold. Comparison between the model and the structure of the active site of
      crystallized retaining GT-B glycosyltransferases identified conserved residues
      with the same topology. To confirm the importance of these residues predicted by
      the model, we studied them in E. coli glycogen synthase by site-directed
      mutagenesis. Mutations D137A, R300A, K305A, and H161A decreased the specific
      activity 8100-, 2600-, 1200-, and 710-fold, respectively. None of these mutations
      increased the Km for glycogen and only H161A and R300A had a higher Km for ADP
      Glc of 11- and 8-fold, respectively. These residues were essential, validating
      the model that shows a strong similarity between the active site of E. coli
      glycogen synthase and the other retaining GT-B glycosyltransferases known to
      date.

PMID- 15033496
TI  - Effectiveness of inpatient dialectical behavioral therapy for borderline
      personality disorder: a controlled trial.
AB  - Dialectical Behavioral Therapy (DBT) was initially developed and evaluated as an
      outpatient treatment program for chronically suicidal individuals meeting
      criteria for borderline personality disorder (BPD). Within the last few years,
      several adaptations to specific settings have been developed. This study aims to
      evaluate a three-month DBT inpatient treatment program. Clinical outcomes,
      including changes on measures of psychopathology and frequency of self-mutilating
      acts, were assessed for 50 female patients meeting criteria for BPD. Thirty-one
      patients had participated in a DBT inpatient program, and 19 patients had been
      placed on a waiting list and received treatment as usual in the community. Post
      testing was conducted four months after the initial assessment (i.e. four weeks
      after discharge for the DBT group). Pre-post-comparison showed significant
      changes for the DBT group on 10 of 11 psychopathological variables and
      significant reductions in self-injurious behavior. The waiting list group did not
      show any significant changes at the four-months point. The DBT group improved
      significantly more than participants on the waiting list on seven of the nine
      variables analyzed, including depression, anxiety, interpersonal functioning,
      social adjustment, global psychopathology and self-mutilation. Analyses based on
      Jacobson's criteria for clinically relevant change indicated that 42% of those
      receiving DBT had clinically recovered on a general measure of psychopathology.
      The data suggest that three months of inpatient DBT treatment is significantly
      superior to non-specific outpatient treatment. Within a relatively short time
      frame, improvement was found across a broad range of psychopathological features.
      Stability of the recovery after one month following discharge, however, was not
      evaluated and requires further study.

PMID- 15033497
TI  - Exposure with response prevention versus habit reversal in Tourettes's syndrome:
      a controlled study.
AB  - The intentional nature of tics provides the opportunity to apply behavioural
      interventions aimed at tic reduction through interruption of stimulus-response
      sequences. The aim of this study has been to evaluate the effect of exposure and
      response prevention (ER) versus habit reversal (HR) in 43 Tourette's syndrome
      (TS) patients. The three outcome measures were: the Yale Global Tic Severity
      Scale (YGTSS), 15-min tic frequency registrations monitored at the institute and
      15-min home tic frequency registrations. Both treatment conditions resulted in
      statistically significant improvements on all outcome measures (p < 0.001). No
      significant differences were found between the treatment conditions on any of the
      outcome measures, although there was a tendency in favour of ER on the YGTSS (p =
      0.05). These results suggest that, at least in the short term, TS tic symptoms
      can be treated effectively with both types of treatment.

PMID- 15033499
TI  - Do patients with OCD and pathological gambling have similar dysfunctional
      cognitions?
AB  - The obsessive-compulsive spectrum disorder (OCSD) theory postulates that a wide
      range of disorders is closely related to OCD. Current cognitive models ascertain
      that certain beliefs leading to misinterpretation of the significance of
      intrusions are important in the etiology and maintenance of OCD. This study
      examined whether pathological gambling, a disorder belonging to the OC spectrum,
      is characterized by similar dysfunctional cognitions as OCD. Dysfunctional
      beliefs of OCD patients were compared to those of patients with pathological
      gambling, panic disorder and normal controls. These beliefs were measured by the
      Obsessive-compulsive Beliefs Questionnaire-87 (OBQ-87), which was developed by a
      group of leading OCD researchers [Behav. Res. Ther. 35 (1997) 667]. It was
      hypothesized that according to the OCSD theory, pathological gamblers would
      exhibit similar cognitions to OCD patients, as well as increased levels of OCD
      symptoms. Analysis showed that OCD patients exhibited higher OBQ-87 scores than
      both panic patients and normal controls, but equal to pathological gambling
      patients. Pathological gamblers exhibited, however, no increase in OCD symptoms.
      These mixed results do not seem to support the OC spectrum theory for
      pathological gambling, moreover being contradictory to contemporary cognitive OCD
      models.

PMID- 15033498
TI  - Predicting who benefits from psychoeducation and self help for panic attacks.
AB  - Self-help and psychoeducation have been identified as effective methods for
      delivering treatment, yet not everyone benefits from these brief interventions.
      Therefore it is clinically and economically useful to identify who is likely to
      require more intensive assistance. This paper develops a prognostic scale which
      predicts who will recover from panic attacks and who will require more
      assistance. METHOD: Random regression models were used to evaluate the
      relationship between predictive variables, baseline severity, and the rate of
      improvement in 117 people with DSMIV panic attacks who participated in a trial of
      a psycho-educational booklet, a self-help workbook, and brief group CBT over a 9
      month period. ROC analysis was used to choose cut-off points on a scale made up
      of significant predictors. RESULTS: Panic disorder and agoraphobia symptom
      measures were predicted by baseline social anxiety, and general mental health.
      There was no significant effect on the outcome for baseline depression or anxiety
      sensitivity. While general mental health (SF12 Mental Component scores) was
      predicted by the age at first panic attack, neuroticism, panic disorder and/or
      agoraphobia symptoms and a positive screen for alcohol use disorders. A
      prognostic scale based on simple additive scoring was equivalent to standard
      scores and significantly better than chance at predicting who would recover and
      who required face-to-face therapy. CONCLUSIONS: The prognostic scale may be used
      to guide the choice of psychoeducation, self-help or face-to-face therapy as the
      first step in stepped care.

PMID- 15033500
TI  - The presence of magical thinking in obsessive compulsive disorder.
AB  - Two research groups have raised the possibility that magical ideation may be a
      fundamental feature of obsessive-compulsive disorder. It has been proposed to
      underlie thought action fusion and superstitious beliefs. In this study, the
      Magical Ideation scale, the Lucky Behaviours and Lucky Beliefs scales, the
      Thought Action Fusion-Revised scale, the Padua Inventory, and the Obsessive
      Compulsive Inventory-Short Version were completed by 60 obsessive compulsive
      patients at a hospital clinic. Of all the measures, the Magical Ideation (MI)
      scale was found to be the most strongly related to obsessive compulsive symptoms.
      Large and significant relationships between MI scores and the measures of OCD
      were obtained even when alternative constructs (Lucky Behaviours, Lucky Beliefs,
      Thought Action Fusion-Revised scales) were held constant. No other variable
      remained significantly related to the Obsessive Compulsive Inventory-Short
      Version when magical ideation scores were held constant. The findings suggest
      that a general magical thinking tendency may underpin previous observed links
      between superstitiousness, thought action fusion and OCD severity.

PMID- 15033501
TI  - Validity of the Eating Disorder Examination Questionnaire (EDE-Q) in screening
      for eating disorders in community samples.
AB  - In order to examine the concurrent and criterion validity of the questionnaire
      version of the Eating Disorders Examination (EDE-Q), self-report and interview
      formats were administered to a community sample of women aged 18-45 (n = 208).
      Correlations between EDE-Q and EDE subscales ranged from 0.68 for Eating Concern
      to 0.78 for Shape Concern. Scores on the EDE-Q were significantly higher than
      those of the EDE for all subscales, with the mean difference ranging from 0.25
      for Restraint to 0.85 for Shape Concern. Frequency of both objective bulimic
      episodes (OBEs) and subjective bulimic episodes (SBEs) was significantly
      correlated between measures. Chance-corrected agreement between EDE-Q and EDE
      ratings of the presence of OBEs was fair, while that for SBEs was poor. Receiver
      operating characteristic (ROC) analysis, based on a sample of 13 cases, indicated
      that a score of 2.3 on the global scale of the EDE-Q in conjunction with the
      occurrence of any OBEs and/or use of exercise as a means of weight control,
      yielded optimal validity coefficients (sensitivity = 0.83, specificity = 0.96,
      positive predictive value = 0.56). A stepwise discriminant function analysis
      yielded eight EDE-Q items which best distinguished cases from non-cases,
      including frequency of OBEs, use of exercise as a means of weight control, use of
      self-induced vomiting, use of laxatives and guilt about eating. The EDE-Q has
      good concurrent validity and acceptable criterion validity. The measure appears
      well-suited to use in prospective epidemiological studies.

PMID- 15033502
TI  - Two studies of psychiatric morbidity among motor vehicle accident survivors 1
      year after the crash.
AB  - We assessed the psychiatric co-morbidity associated with chronic posttraumatic
      stress disorder (PTSD) (1-2 years) secondary to personal injury motor vehicle
      accidents (MVAs) in two studies. In Study 1, we compared the results of SCID
      assessments for 75 treatment-seeking MVA survivors (51 with PTSD and 24 with
      symptoms but no PTSD). In Study 2, we compared similar results among 132 MVA
      survivors who had been followed prospectively for 12+ months after their
      accidents (19 with PTSD, 32 who had PTSD but who had remitted, and 81 who never
      met criteria for PTSD). We found comparable levels of current co-morbid major
      depression (53%), any mood disorder (62-68%), generalized anxiety disorder (26%)
      and any anxiety disorder (42%) for both groups of participants with chronic PTSD.
      These rates of co-morbidity were higher than those found in non-PTSD comparison
      groups with similar MVA histories.

PMID- 15033503
TI  - Framing social information and generalized social phobia.
AB  - Patients with generalized social phobia (GSP, N = 33) and matched community
      controls (N = 31) engaged in a social interaction that was constructed to go
      well, and then received feedback that framed social cues reflecting either the
      absence of negative outcomes or the presence of positive outcomes. Following
      feedback that framed positive social cues, the GSP group predicted they would
      experience more anxiety in a subsequent interaction than did non-phobic controls.
      In contrast, following feedback framing the absence of negative outcomes, the GSP
      group did not differ from controls in their anxiety predictions. The results
      demonstrated that framing paradigms and methods can be usefully applied to the
      study of cognitive processes in social phobia and indicated that research to
      examine how GSP patients process specific types of social information is needed.

PMID- 15033504
TI  - Anxiety symptoms in Japanese and in German children.
AB  - The purpose of this study was to compare the frequency of anxiety symptoms and
      their association with gender and age in Japanese and German children using the
      Spence Children's Anxiety Scale (SCAS). A total of 1837 children (862 from
      Germany and 975 from Japan) between the age of 8 and 12 years were investigated.
      Results revealed that German children reported significantly higher symptoms of
      separation anxiety, social phobia, obsessive compulsive disorder, and generalized
      anxiety disorder than Japanese children. Conversely, Japanese children reported
      significantly higher scores on symptoms related to physical injury fear. In both
      countries, girls scored higher than boys on all the scales of the SCAS. Symptoms
      of separation anxiety and panic decreased with age, whereas social phobia
      increased with age. The findings underscore the impact of culture on children's
      anxiety.

PMID- 15033505
TI  - Application of multivariate resolution methods to the study of biochemical and
      biophysical processes.
AB  - Multivariate resolution methods make up a set of mathematical tools that may be
      applied to the analysis and interpretation of spectroscopic data recorded when
      monitoring a physical or chemical process with multichannel detectors. The goal
      of resolution methods is the recovery of chemical and/or physical information
      from the experimental data. Such data include, for example, the number of
      intermediates present in a reaction, the rate or equilibrium constants, and the
      spectra for each one of those intermediates. Multivariate resolution methods have
      been shown to be useful for the study of biophysical and biochemical processes
      such as folding/unfolding of proteins or nucleic acids. The present article
      reviews the most frequently used resolution methods, the limitations on their
      use, and their latest applications in protein and nucleic acid research.

PMID- 15033506
TI  - Use of moving optical gradient fields for analysis of apoptotic cellular
      responses in a chronic myeloid leukemia cell model.
AB  - To facilitate quantitation of cellular apoptotic responses to various
      antineoplastic agents, a laser-based technology, Optophoresis, has been developed
      to provide analysis of cells without any need for labeling or cell processing.
      Optophoresis is defined as the analysis of the motion of cells, where the motion
      is either induced or modified by a moving optical gradient field, which produces
      radiation pressure forces on the cells in an aqueous suspension. Quantitation of
      the induced motion provides a basis for distinguishing one population of cells
      from another. One Optophoretic technique, Fast Scan, measures the distribution of
      distances traversed by a population of cells when exposed to a fast-moving
      optical gradient. Fast Scan was validated using a cell-based model of chronic
      myeloid leukemia treated with Gleevec, a specific inhibitor of aberrant Bcr-Abl
      protein kinase. The Optophoretic measurements were quantitatively comparable to
      reference assays with regard to drug selectivity and potency and to target
      specificity, demonstrating the suitability of this technology for pharmaceutical
      and clinical applications.

PMID- 15033508
TI  - Single-nucleotide polymorphism detection using nanomolar nucleotides and single
      molecule fluorescence.
AB  - We have exploited three methods for discriminating single-nucleotide
      polymorphisms (SNPs) by detecting the incorporation or otherwise of labeled
      dideoxy nucleotides at the end of a primer chain using single-molecule
      fluorescence detection methods. Good discrimination of incorporated vs free
      nucleotide may be obtained in a homogeneous assay (without washing steps) via
      confocal fluorescence correlation spectroscopy or by polarization anisotropy
      obtained from confocal fluorescence intensity distribution analysis. Moreover,
      the ratio of the fluorescence intensities on each polarization channel may be
      used directly to discriminate the nucleotides incorporated. Each measurement took
      just a few seconds and was done in microliter volumes with nanomolar
      concentrations of labeled nucleotides. Since the confocal volumes interrogated
      are approximately 1fL and the reaction volume could easily be lowered to
      nanoliters, the possibility of SNP analysis with attomoles of reagents opens up a
      route to very rapid and inexpensive SNP detection. The method was applied with
      success to the detections of SNPs that are known to occur in the BRCA1 and CFTR
      genes.

PMID- 15033507
TI  - High-throughput phenotypic profiling of gene-environment interactions by
      quantitative growth curve analysis in Saccharomyces cerevisiae.
AB  - Cell-based assays are widely used in high-throughput screening to determine the
      effects of toxicants and drugs on their biological targets. To enable a
      functional genomics modeling of gene-environment interactions, quantitative
      assays are required both for gene expression and for the phenotypic responses to
      environmental challenge. To address this need, we describe an automated high
      throughput methodology that provides phenotypic profiling of the cellular
      responses to environmental stress in Saccharomyces cerevisiae. Standardized assay
      conditions enable the use of a single metric value to quantify yeast microculture
      growth curves. This assay format allows precise control of both genetic and
      environmental determinants of the cellular responses to oxidative stress, a
      common mechanism of environmental insult. These yeast-cell-based assays are
      validated with hydrogen peroxide, a simple direct-acting oxidant. Phenotypic
      profiling of the oxidative stress response of a yap1 mutant strain demonstrates
      the mechanistic analysis of genetic susceptibility to oxidative stress. As a
      proof of concept for analysis of more complex gene-environment interactions, we
      describe a combinatorial assay design for phenotypic profiling of the cellular
      responses to tert-butyl hydroperoxide, a complex oxidant that is actively
      metabolized by its target cells. Thus, the yeast microculture assay format
      supports comprehensive applications in toxicogenomics.

PMID- 15033510
TI  - Centrifugation-based isolation of myosin for measurement of its synthesis rate in
      small muscle samples.
AB  - Myosin is involved in muscle mobility which is particularly affected in many
      pathophysiological situations. It is composed of heavy (MHC) and light (MLC)
      chains and measurements of its specific fractional synthesis rate (FSR) are
      scarce, mostly because of difficulties in isolating this protein. Our aim was to
      isolate pure myosin from small rat gastrocnemius skeletal muscle samples by
      setting up a procedure compatible with determination of stable isotope
      incorporation into myosin using mass spectrometry detection, allowing calculation
      of its FSR. A centrifugation method was compared to a validated but time
      consuming elution gel electrophoresis method. Statistical analysis by the Bland
      and Altman test revealed a tight relationship between both methods (r2 >0.97, p
      <0.0001). The purity of the myosin fractions using the two procedures was
      verified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In
      addition, the centrifugation procedure allowed simultaneous purification of MLC
      and MHC, whereas the elution gel electrophoresis technique resulted only in MHC
      isolation. Finally, the FSRs of myosin and MHC were found to be 0.114+/-0.026 and
      0.140+/-0.029%/h, respectively (p not significant). In conclusion, the
      centrifugation method is a useful and reproducible procedure that results in
      sufficient amounts of pure myosin for reliable determinations of its own
      synthesis rate in vivo.

PMID- 15033509
TI  - A genetic screen to identify latent transforming growth factor beta activators.
AB  - The mechanisms by which latent transforming growth factor beta (TGFbeta) is
      converted to the active cytokine are largely unknown. Here we present a genetic
      screen that combines retroviral mutagenesis and cDNA expression cloning to reveal
      proteins involved in the extracellular regulation of latent TGFbeta activation.
      The screen employs a cell line engineered to express green fluorescent protein
      (GFP) in response to TGFbeta. The cells produce their own latent TGFbeta.
      Therefore, after transduction with a retroviral cDNA library that contains an
      insert for an activator of latent TGFbeta, cells expressing the activator are GFP
      bright. These cells are enriched by fluorescence-activated cell sorting and grown
      as individual clones. The isolated clones are cocultured with a second TGFbeta
      reporter cell line that produces luciferase in response to TGFbeta. Cells that
      have acquired the ability to activate latent TGFbeta induce luciferase expression
      in the absence but not in the presence of neutralizing antibodies to TGFbeta. The
      activator expressed by the positive clones can be identified by retrieval of the
      retrovirus cDNA insert.

PMID- 15033511
TI  - Determination of accurate KI values for tight-binding enzyme inhibitors: an in
      silico study of experimental error and assay design.
AB  - Determination of accurate K(I) values for tight-binding enzyme inhibitors is
      important from both a basic biochemistry point of view (understanding the
      differences in affinity of related molecules) and a medicinal chemistry vantage
      (developing structure-activity relationships (SAR)). It is advantageous to
      directly fit the quadratic equation describing tight-binding behavior, known
      commonly as the Morrison equation, to obtain these K(I) values. The results of
      simulated experiments that examine the effect of assay design and experimental
      error on the ability to accurately determine K(I) values at several [E]0/K(I-app)
      ratios are described. Input ("true") values of the uninhibited velocity,
      inhibition constant, and total enzyme concentration were used to calculate the
      velocity at various inhibitor concentrations. Gaussian error was introduced into
      the velocities and the simulated reactions were fit to estimate upsilon0, K(I),
      and [E]0. Recommendations for optimizing the inhibitor dilutions within the
      context of a 96-well-plate format and simple serial dilution steps are made.
      These include using three points to determine the enzyme concentration ([I]=0,
      0.5[E]0, and [E]0), using a narrow dilution series with only two or three points
      to determine the asymptote at high inhibitor concentration, and avoiding fixing
      [E]0 to a constant value in the fitting if at all possible. The risks and rewards
      of fixing [E]0 to a constant value, especially the effect on SAR, are also
      examined.

PMID- 15033512
TI  - Photochemical immobilization of proteins on microwave-synthesized photoreactive
      polymers.
AB  - We report a rapid and versatile procedure for the preparation of photoreactive
      polymers and light-induced immobilization of proteins onto such polymers.
      Photoreactive controlled-pore glass, silica gel, glass slide, and polystyrene
      microtiter plate are prepared in 40-60s by microwave irradiation of the
      respective amino polymers and 1-fluoro-2-nitro-4-azidobenzene. Azido group, now
      part of the polymer, yields highly reactive nitrene under ultraviolet (UV) light
      at 365 nm. Thus, when photoreactive polymer and horseradish peroxidase or glucose
      oxidase are exposed to UV light, the reactive nitrene immobilizes the protein
      molecules in 10 to 20 min through covalent bonding. As nitrene has a property of
      inserting into C-H bond, the method may find potential applications for
      immobilization of biomolecules irrespective of their functional groups.

PMID- 15033513
TI  - State-dependent inhibition of L-type calcium channels: cell-based assay in high
      throughput format.
AB  - The current studies describe a new, robust cell-based functional assay useful to
      characterize L-type voltage-dependent calcium channels and their antagonists. The
      basis of this assay is measurement in plate format of Ca2+ influx through the L
      type Ca2+ channel complex (alpha1C, alpha2delta, and beta2a subunits) in response
      to potassium-mediated depolarization; EC(50)=11 mM [K+](o). The Ca2+ influx was
      inhibited by the L-type Ca2+ channel antagonist, nimodipine; IC(50)=59 nM. These
      cells were also transfected with the Kir2.3 inward rectifier K(+) channel, which
      allows for changing the cell membrane potential by modulation of extracellular
      [K](o); -65 mV in physiological [K](o) and -28 mV in 30 mM [K](o) containing
      buffer. The conformational state of the voltage-sensitive Ca2+ channel is altered
      under these different conditions. Under the depolarized condition, nimodipine was
      a more potent antagonist, inhibiting Ca2+ influx with an IC(50) value of 3 nM.
      The results demonstrate that the interaction of nimodipine and other antagonists
      with the channel is modulated by changes in membrane potential and thus the state
      of the channel. Overall, this novel assay can be used to identify state-dependent
      calcium channel antagonists and should be useful for evaluating state-dependent
      inhibitory potency of a large number of samples.

PMID- 15033514
TI  - Excitation and emission wavelength ratiometric cyanide-sensitive probes for
      physiological sensing.
AB  - We characterize three new fluorescent probes that show both spectral shifts and
      intensity changes in the presence of aqueous cyanide, allowing for both
      excitation and fluorescence emission wavelength ratiometric and colorimetric
      sensing. The relatively high binding constants of the probes for cyanide enables
      a distinct colorimetric change to be visually observed with as little as 10
      microM cyanide. The response of the new probes is based on the ability of the
      boronic acid group to interact with the CN(-) anion, changing from the neutral
      form of the boronic acid group R-B(OH)(2) to the anionic R-B(-)(OH)3 form, which
      is an electron-donating group. The presence of an electron-deficient quaternary
      heterocyclic nitrogen center and a strong electron-donating amino group in the 6
      position on the quinolinium backbone provides for the spectral changes observed
      upon CN(-) complexation. We have determined the binding constants for the ortho-,
      meta-, and para-boronic acid probes to be 0.12, 0.17, and 0.14 microM(-3). In
      addition we have synthesized a control compound that does not contain the boronic
      acid moiety, allowing for structural comparisons and a rationale for the sensing
      mechanism to be made. Finally we show that the affinity for monosaccharides, such
      as glucose or fructose, is relatively low as compared to that for cyanide,
      enabling the potential detection of cyanide in physiologies up to lethal levels.

PMID- 15033515
TI  - Tools for metabolic engineering in Escherichia coli: inactivation of panD by a
      point mutation.
AB  - l-Aspartate-alpha-decarboxylase (PanD) catalyzes the decarboxylation of aspartate
      to produce beta-alanine, a precursor of Coenzyme A (CoA). The pyruvoyl-dependent
      enzyme from Escherichia coli is activated by self-cleavage at serine 25 to
      generate a 102-residue alpha subunit with the pyruvoyl group at its N terminus
      and a 24-residue beta subunit with a hydroxy at its C terminus. A mutant form of
      the panD gene from E. coli in which serine 25 was replaced with an alanine (S25A)
      was constructed. Assays conducted in vitro and in vivo confirmed that the mutant
      version was completely inactive and was incapable of undergoing self-cleavage to
      generate the active form of the enzyme. The S25A panD mutant was used to replace
      the chromosomal copy of panD in BAP1, a strain of E. coli modified for polyketide
      production. Comparison of this strain with panD2 mutant strains derived from E.
      coli SJ16 showed an equivalent dependence on exogenous beta-alanine for growth in
      liquid medium. Unlike the undefined and leaky panD2 mutation, the panD S25A
      mutation is defined and tight. The panD S25A E. coli strain enables analysis of
      intracellular acyl-CoA pools in both defined and complex media and is a useful
      tool in metabolic engineering studies that require the manipulation of acyl-CoA
      pools for the heterologous production of polyketides.

PMID- 15033517
TI  - Kinetic and substrate binding analysis of phosphorylase b via electrospray
      ionization mass spectrometry: a model for chemical proteomics of sugar
      phosphorylases.
AB  - As a general strategy for determining the chemical function of the class of
      enzymes that cleaves glycosidic linkages with phosphate, the first mass
      spectrometry and direct detection assay for sugar phosphorylases has been
      developed and used to study the inhibition and minimal binding requirements of
      rabbit muscle phosphorylase b. In contrast to the currently employed assays for
      these enzymes that measure the nonphysiologically relevant reverse reaction of
      glycosidic bond synthesis and thereby require prior knowledge of not just one but
      two sugar components, this new method has the potential to greatly reduce the
      complexity in discovering the substrate specificity of a new enzyme. Certain
      phosphorylases can catalyze the degradation of glycogen into alpha-D-glucose-1
      phosphate and are targets for the development of antidiabetic therapeutics. By
      electrospray ionization mass spectrometry analysis, the kinetic parameters K(m),
      V(max), and K(i) (for alpha/beta-D-glucose) have been determined for the rabbit
      muscle phosphorylase b. This enzyme accepts maltoheptaose, maltohexaose, and
      maltopentaose as substrates in the direction of glycogen degradation, but the
      tetrasaccharide maltotetraose cannot serve as a substrate for this phosphorylysis
      reaction.

PMID- 15033516
TI  - Separation and quantitation of peroxidized phospholipids using high-performance
      thin-layer chromatography with tetramethyl-p-phenylenediamine detection.
AB  - A simple method for the selective determination of phospholipid hydroperoxide
      (PLOOH) families in complex lipid populations has been developed. Referred to as
      HPTLC-TPD, the method is based on PLOOH separation by normal-phase high
      performance thin-layer chromatography, followed by spray detection with N,N,N',N'
      tetramethyl-p-phenylenediamine and densitometric scanning of the purple bands.
      Parental phospholipids and alcohol analogues are unreactive. Calibration curves,
      dynamic ranges, and detection limits were established for hydroperoxide standards
      prepared from phospatidylcholine, phosphatidylserine, phosphatidylethanolamine,
      and cardiolipin. For all PLOOH classes, responsiveness was linear out to at least
      10 nmol of sample load, the detection limit being 0.1-0.2 nmol. HPTLC-TPD data
      were validated by subjecting duplicate samples to more complex column
      chromatography with reductive-mode electrochemical detection. General
      applicability of the new technique was demonstrated using lipid extracts from two
      test systems: (i) photoperoxidized liposomal membranes and (ii) tumor cells that
      had been oxidatively stressed with the respiratory inhibitor antimycin A. HPTLC
      TPD provides a convenient, specific, and highly sensitive means for quantifying
      individual PLOOH families in complex natural mixtures.

PMID- 15033518
TI  - Microtiter assay for glutamine synthetase biosynthetic activity using inorganic
      phosphate detection.
AB  - A microtiter assay was developed for the improved detection of inorganic
      phosphate released from adenosine 5'-triphosphate (ATP) in the glutamine
      synthetase biosynthetic assay. In this assay, ascorbic acid replaces the
      traditionally used ferrous sulfate to reduce the phosphomolybdate complex. As a
      result, increased color development, linearity, and sensitivity are achieved.
      Additionally, in the microtiter format, multiple sets of kinetic experiments can
      be rapidly performed in parallel. The color that forms is rendered highly stable
      by the addition of sodium citrate. However, the commonly used sodium arsenite in
      this solution has been omitted, making the assay less hazardous. The assay is
      linear to 100 nmol Pi in the presence of 10mM ATP.

PMID- 15033519
TI  - Development of a microplate bioassay for monocyte chemoattractant protein-1 based
      on activation of p44/42 mitogen-activated protein kinase.
AB  - Monocyte chemoattractant protein-1 (MCP-1) is a potential therapeutic target for
      the treatment of several inflammatory conditions, including rheumatoid arthritis
      and chronic obstructive pulmonary disease. Current cell-based assays for MCP-1
      use monocyte chemotaxis or calcium flux as a readout. Here, we describe an
      alternative bioassay based on MCP-1-induced phosphorylation of the mitogen
      activated protein kinases (MAPK) p44 (ERK1) and p42 (ERK2). Adherent cells
      expressing the MCP-1 receptor CCR2B are treated with MCP-1 in 96-well plates in
      the presence or absence of inhibitors, fixed and permeabilized with methanol, and
      then probed with a monoclonal antibody that selectively recognizes the doubly
      phosphorylated form of p44/42 MAPK. Bound antibody is detected with a secondary
      antibody-peroxidase conjugate and a chromogenic substrate. The phosphorylation of
      p44/42 MAPK as detected in this assay peaks after 3-5 min of MCP-1 treatment, and
      the concentration of MCP-1 required for half-maximal p44/42 MAPK phosphorylation
      is 1-3 nM. MCP-1-induced phosphorylation of p44/42 MAPK is dependent upon the
      expression of CCR2B. The assay can be used for screening and characterization of
      small molecule inhibitors and antibodies blocking the binding of MCP-1 to its
      receptor. Since the assay is rapid and simple, it may represent a useful
      alternative to chemotaxis or calcium mobilization assays for the analysis of MCP
      1 inhibitors.

PMID- 15033521
TI  - Impact of the cold shock phenomenon on quantification of intracellular
      metabolites in bacteria.
AB  - In the present work the effect of quenching on quantification of intracellular
      metabolites in Corynebacterium glutamicum was investigated. C. glutamicum showed
      a high sensitivity to cold shock. Quenching of the cells by -50 degrees C
      buffered methanol prior to cell separation and extraction led to drastically
      reduced concentrations for free intracellular amino acids compared to those for
      nonquenched filtration. As demonstrated for glutamate and glutamine, this was
      clearly due to a more than 90% loss of these compounds from the cell interior
      into the medium during quenching. With lower methanol concentration in the
      quenching solution the metabolic losses were significantly lower but still
      amounted to about 30%. Due to the fact that quenching with ice-cold NaCl (0.9%)
      also resulted in significantly lower pool sizes for intracellular amino acids, a
      basic cold shock phenomenon is most likely the reason for the observed effects.
      The results clearly demonstrate that quenching combined with cell separation for
      concentration of the cells and removal of the medium is not applicable for
      intracellular metabolite analysis in C. glutamicum. Sampling by quick filtration
      without quenching allows complete cell separation and authentic quantification of
      intracellular metabolite pools exhibiting time constants significantly larger
      than sampling time.

PMID- 15033520
TI  - The ApoCorrect assay: a novel, rapid method to determine the biological
      functionality of radiolabeled and fluorescent Annexin A5.
AB  - We have demonstrated that imaging of programmed cell death (PCD) in patients is
      possible using 99mTc-Annexin A5. Because of the short half-life of the technetium
      label it is important to limit the time span between the preparation of 99mTc
      Annexin A5 and its administration into the patient. Therefore methods of quality
      control that determine the biological active fraction in the 99mTc-Annexin A5
      should be not only accurate and precise but also rapid. We report the development
      and validation of a rapid, simple assay measuring the biological active fraction
      of 99mTc-Annexin A5. The assay is based on a solid phase of paramagnetic beads
      which are coated with phospholipids. Annexin A5 binds to these beads with high
      affinity if phosphatidyl serine is present within the phospholipid coat.
      Furthermore the binding depends on Ca2+ ions and functional Ca2+/phospholipid
      binding sites of Annexin A5. The bead assay is specific, stability-indicating,
      repeatable, and reproducible. It allows one to determine within 25 min the
      biological active fraction of a 99mTc-Annexin A5 preparation. We dubbed this
      assay the ApoCorrect assay.

PMID- 15033522
TI  - A fluorogenic substrate for detection of organophosphatase activity.
AB  - A new fluorogenic substrate for the specific detection of organophosphatase
      (OPase) activity has been designed and evaluated. Our results indicate that 7
      diethylphospho-6,8-difluor-4-methylumbelliferyl (DEPFMU) is hydrolyzed
      specifically by the OPases, mammalian serum paraoxonase and bacterial
      organophosphorus hydrolase (OPH). The apparent K(m) of DEPFMU is 29 microM for
      OPH and 91 and 200 microM for the PON1 L(55)R(192) and PON1 L(55)Q(192) isoforms
      of human paraoxonase, respectively. DEPFMU-based assay systems are 10-100 times
      more sensitive for OPH and mammalian paraoxonase detection than existing methods.
      Importantly, DEPFMU is poorly hydrolyzed by both serum and cellular phosphatases
      and, therefore, may be used as part of a robust and sensitive assay for detecting
      not only purified, but also highly impure, preparations of OPase such as blood
      samples. The superior sensitivity of DEPFMU makes it potentially useful in the
      search for new enzymes that may hydrolyze nerve poisons such as sarin, soman, and
      VX, monitoring the decontamination of organophosphates (OPs) by OPH and
      determining serum paraoxonase activity which appears to be important for
      protection against atherosclerosis, sepsis, and OP toxicity.

PMID- 15033523
TI  - Sensitive genetic biomarkers for determining apoptosis in the brown bullhead
      (Ameiurus nebulosus).
AB  - Biomarkers are necessary for monitoring environmentally induced alterations at
      the molecular level in order to assess the impact of xenobiotic compounds on
      organism health. Apoptosis is a highly regulated cellular process that controls
      programmed cell death and is involved in tumor formation. Apoptosis thus may
      provide the basis for developing biomarkers for use in the field of ecotoxicology
      to monitor non-lethal levels of xenobiotic induced cellular stress and toxicity.
      This study shows that a brown bullhead (Ameiurus nebulosus) fibroblast cell line
      (BB-2) responds to known apoptotic inducers (staurosporine, cycloheximide, and
      tumor necrosis factor alpha (TNF-alpha)), as characterized by terminal
      deoxynucleotidyl transferase (TdT)-mediated dUTP digoxigenin nick end-labelling
      (TUNEL). Furthermore, we characterized the apoptotic process using a series of
      newly identified bullhead genetic markers. Exposure to protein kinase C
      inhibitors altered the transcription of TF-cell apoptosis-related protein (TFAR)
      15 and p23 with no effect on p53, inhibitor of apoptosis protein (IAP), or PNAS
      2. Inhibition of protein synthesis caused a consistent reduction in the
      transcription of p53 and PNAS-2. This study demonstrates that our novel
      transcriptional markers are sensitive biomarkers for the study of the effects of
      xenobiotic chemicals on apoptosis in the brown bullhead.

PMID- 15033524
TI  - An improved prediction of chloroplast proteins reveals diversities and
      commonalities in the chloroplast proteomes of Arabidopsis and rice.
AB  - Proteins that form part of the chloroplast proteome can be identified by
      computational prediction of the N-terminal presequences (chloroplast transit
      peptides, cTPs) of their cytoplasmic precursor proteins. The accuracy of four
      different cTP predictors has been evaluated on a test set of 4500 proteins whose
      subcellular localization is known, and was found to be substantially lower than
      previously reported. A combination of cTP prediction programs was superior to any
      one of the predictors alone. This combination was employed to estimate the size
      and composition of the chloroplast proteomes of Arabidopsis and rice, and about
      2100 (Arabidopsis thaliana) and 4800 (Oryza sativa) different chloroplast
      proteins with a cTP are predicted to be encoded by their nuclear genomes. A
      subset of around 900 chloroplast proteins, predominantly derived from the
      cyanobacterial endosymbiont and with functions mostly related to metabolism,
      energy and transcription, is shared by the two species. This points to the
      existence of both conserved nucleus-encoded chloroplast proteins that are
      predominantly of prokaryotic origin, and a large fraction of taxon-specific
      chloroplast-targeted proteins, in flowering plants.

PMID- 15033525
TI  - Micro-geographical differentiation in Northern Iberia revealed by Y-chromosomal
      DNA analysis.
AB  - Y-chromosome diversity has been analyzed at a micro-geographical level, examining
      10 binary polymorphisms and 7 short tandem repeats (STRs) in 443 samples
      belonging to 11 populations from two regions of Northern Spain, Galicia and
      Cantabria. Both regions, as a whole, cluster with other Iberian populations.
      However, some individual populations, particularly that from the Pas Valley in
      Cantabria, depart markedly from this general pattern, with higher genetic
      distances and reduced diversity. This unusual population is even more distinct
      than the Basques from their Iberian neighbors. Genetic drift in a small isolated
      population could explain this special behavior, and in addition to its
      anthropological interest, this finding has important forensic implications.

PMID- 15033526
TI  - ShAR1alpha and ShAR1beta: novel putative nicotinic acetylcholine receptor
      subunits from the platyhelminth blood fluke Schistosoma.
AB  - The cDNAs for two novel neuronal-type nicotinic acetylcholine receptor (nAChR)
      subunits have been cloned and characterised from the parasitic trematode blood
      fluke Schistosoma haematobium. One of these encodes a putative nAChR alpha
      subunit named ShAR1alpha, whilst the second encodes a potential non-alpha
      subunit, ShAR1beta. These ShARs possess the key structural features common to all
      nAChRs, but they are unusual in that they have very large cytoplasmic domains
      spanning M3 and M4. Overall, the ShAR1alpha and ShAR1beta proteins share 37%
      identity and 53% similarity, but excluding the residues of the M3-M4 domain this
      rises to 52% identity and 71% similarity. Sequence comparisons with other nAChR
      polypeptides indicate that both ShARs are most similar to the invertebrate alpha7
      like subunits identified in insects and nematodes, and to the vertebrate subunits
      alpha7 and alpha8. Outside of the M3-M4 domain, 45% and 40%, respectively, of the
      ShAR1alpha and ShAR1beta residues are conserved in the ACR-16 subunit from
      Caenorhabditis elegans. Phylogenetic analysis suggests that the ShARs share a
      common lineage with members of the ACR-16 group as well as alpha7 and alpha8.
      Immunolocalisation studies revealed distinct and non-overlapping patterns of
      distribution for ShAR1alpha and ShAR1beta within the parasite. ShAR1beta was
      localised within the musculature and on discrete cell bodies within the
      connective parenchyma. In contrast, ShAR1alpha was localised exclusively to the
      surface membranes, suggesting it may contribute to the regulatory nAChR we have
      characterised previously. In Xenopus oocyte expression studies, ShAR1alpha did
      not form functional channels on its own or in combination with ShAR1beta or the
      chick beta2 subunit. Furthermore, a chimera in which the M3-M4 domain of
      ShAR1alpha was replaced with that of chick alpha7 was also non-functional. We
      discuss our findings in the context of the proposed role for surface nAChRs in
      the regulation of glucose uptake in the parasite, and the potential exploitation
      of these receptors as targets for cholinergic schistosomicides.

PMID- 15033527
TI  - The 5'-upstream region of human programmed cell death 5 gene contains a highly
      active TATA-less promoter that is up-regulated by etoposide.
AB  - The PDCD5 (programmed cell death 5), a novel apoptosis related gene, is
      functionally associated with cell apoptosis, exhibits a ubiquitous expression
      pattern and is up-regulated in some types of tumor cells undergoing apoptosis. To
      study the transcriptional regulation of the PDCD5 gene, we have cloned 1.1 kb of
      its 5'-upstream region. The DNA sequencing analysis revealed a major
      transcriptional start site at 72 base pairs in front of the ATG translational
      start codon. The upstream of the transcriptional start site lacks a canonical
      TATA box and CAAT box. Transient transfection and luciferase assay demonstrate
      that this region presents extremely strong promoter activity. The 5'-deleted
      sequences fused to a luciferase reporter gene demonstrated that the -555/-383
      region from the transcription start site is crucial for transcriptional
      regulation, and the luciferase reporter gene's expression significantly increased
      in the early stage of cell apoptosis induced by etoposide. These results imply
      that the PDCD5 gene may be a target gene under the control of some important
      apoptosis-related transcriptional factors during the cell apoptosis.

PMID- 15033528
TI  - Scaffold protein JSAP1 is transported to growth cones of neurites independent of
      JNK signaling pathways in PC12h cells.
AB  - The c-Jun NH(2)-terminal kinase (JNK)/stress-activated protein kinase-associated
      protein 1 [JSAP1; also known as JNK-interacting protein 3 (JIP3)] has been
      identified as a scaffold protein for JNK mitogen-activated protein kinase signal
      transduction pathways and as a cargo adapter in the conventional kinesin-mediated
      transport system. Furthermore, a functional relationship between UNC-16, the C.
      elegans ortholog of JSAP1, and JNK signaling has been established genetically. In
      this study, we first demonstrated that the kinesin light chain is required for
      the targeting and localization of JSAP1 to the tips of neurites in PC12h cells.
      Furthermore, to understand whether JNK signaling is involved in kinesin-mediated
      JSAP1 trafficking, we established stable PC12h cell lines that expressed wild
      type JSAP1 or its mutant lacking the JNK-binding domain (JBD). Immunocytochemical
      studies of the cell lines indicated that the mutant JSAP1 was localized to the
      growth cones of differentiating PC12h cells in a similar manner to wild-type
      JSAP1. Taken together, these results suggest that the proper subcellular
      localization of JSAP1 along microtubules probably does not require JNK signaling.

PMID- 15033529
TI  - Transgene stability for three replication-competent murine leukemia virus
      vectors.
AB  - Retroviral vectors that are able to sustain multiple rounds of replication may
      find many applications. However, one critical feature of such vectors is the
      ability to maintain an intact transgene cassette during repeated rounds of
      replication. We here report on the stability of a translational cassette
      consisting of an internal ribosome entry site followed by the enhanced green
      fluorescent protein coding sequence inserted in different configurations into
      murine leukemia virus genomes. In two of the constructs, the insert was located
      in the upstream part of the U3 region while in the third construct it was
      inserted in the 3' untranslated region of the viral genome. Furthermore, in two
      of the constructs, the translational cassette was flanked by a direct repeat,
      while no such structure flanked the third construct. Our results show that
      deletion of the heterologous translational cassette is observed for all
      constructs upon extended cell culture and that the number of replication rounds
      before revertants are detected can be postponed by decreasing the length of the
      repeat flanking the translational cassette.

PMID- 15033530
TI  - Analysis of gene structures and promoter activities of the chipmunk alpha(1)
      antitrypsin-like genes.
AB  - The chipmunk hibernation-specific protein HP-55 is a component of a 140-kDa
      complex whose levels are drastically decreased in the blood during hibernation.
      It is highly homologous to alpha(1)-antitrypsin (AT). In the chipmunk, several
      alpha(1)-AT-like genes in addition to HP-55 (or CM55-ML) are expressed in the
      liver and have distinct patterns of regulation during hibernation: in hibernating
      chipmunks, the level of CM55-ML gene expression is greatly reduced, that of the
      CM55-MS gene is slightly increased, and the expression of the CM55-MM gene is
      hardly affected. As a first step towards understanding the hibernation-associated
      gene regulation of these chipmunk alpha(1)-AT-like genes, we isolated genomic
      clones for the CM55-ML, CM55-MM, and CM55-MS genes, and analyzed their promoter
      activities. These alpha(1)-AT-like genes are composed of five exons, and show a
      similar gene structure to that of the human alpha(1)-AT gene, suggesting that
      they were generated by the duplication of an ancestral alpha(1)-AT gene.
      Transient transfection studies using HepG2 and COS-7 cells revealed that for all
      three alpha(1)-AT-like genes, approximately 150-bp 5' flanking sequences were
      sufficient for the liver-specific promoter activity, and that the binding of HNF
      1 to the promoter region could transactivate transcription. In addition, analysis
      of the activity of chimeric promoters composed of CM55-ML and CM55-MS gene
      sequences indicated that the lack of a TATA box-like sequence in the CM55-MS gene
      is responsible for its weak promoter activity.

PMID- 15033531
TI  - Malic enzymes of Trichomonas vaginalis: two enzyme families, two distinct
      origins.
AB  - The cytosolic malic enzyme of the amitochondriate protist Trichomonas vaginalis
      was purified to homogeneity and characterized. The corresponding gene was
      sequenced and compared with its hydrogenosomal homologue from the same organism.
      The enzymes were found to differ in coenzyme specificity, molecular mass and
      physiological role. The cytosolic malic enzyme is a dimer consisting of two 42
      kDa subunits with strict specificity for nicotinamide adenine dinucleotide
      phosphate (NADP(+)), and has a presumed function of pyruvate and NADPH
      production. The hydrogenosomal malic enzyme is a tetramer of 60-kDa subunits that
      preferentially utilizes nicotinamide adenine dinucleotide (NAD(+)) to NADP(+).
      The hydrogenosomal enzyme supplies the hydrogenosome with pyruvate for further
      catabolic processes linked with substrate-level phosphorylation. Phylogenetic
      analysis of malic enzymes showed the existence of two distinct families of these
      enzymes in nature, which differ in subunit size. The trichomonad cytosolic malic
      enzyme belongs to the small subunit-type family that occurs almost exclusively in
      prokaryotes. In contrast, the hydrogenosomal malic enzyme displays a close
      relationship with the large subunit-type family of the enzyme, which is found in
      mitochondria, plastids and the cytosol of eukaryotes. The eubacterial origin of
      trichomonad cytosolic malic enzyme suggests an occurrence of horizontal gene
      transfer from a eubacterium to the ancestor of T. vaginalis. The presence of both
      prokaryotic and eukaryotic type of malic enzyme in different compartments of a
      single eukaryotic cell appears to be unique in nature.

PMID- 15033532
TI  - Differential gene expressions in the visual cortex of postnatal day 1 versus day
      21 rats revealed by suppression subtractive hybridization.
AB  - The neonatal visual cortex is a highly plastic structure and its development is
      guided by visual experience during early postnatal life. Rats do not open their
      eyes until the end of the second postnatal week. We hypothesized that the
      expression of genes in the visual cortex would differ before and after eye
      opening. As a first step in uncovering these differences, we compared gene
      expressions in the visual cortex of postnatal days (PND) 1 and 21 rats.
      Suppression subtractive hybridization was performed using PND1 samples as the
      tester and PND21 as the driver. More than 30 genes were expressed at a higher
      level in PND1 than PND21 samples, but 5 fragments showed higher copies than
      others. PCR product of the five fragments was gel-purified and cloned into pCRII
      vectors. They showed significant homology to cDNA of genes: (A). clone MGC:
      19375; (B). Type II iodothyronine 5'-deiodinase (D2); (C). reduced expression 3
      gene; (D). lactosylceramide synthase; and (E). septin 4, respectively. Functions
      of A, C and E are unknown. By means of RACE PCR, three full-length cDNAs not
      reported previously in the rat were obtained for A, C and E, and we named them
      "expression genes 1, 2 and 3, respectively, in the rat visual cortex (EG1RVC,
      EG2RVC and EG3RVC)". EG1RVC was further characterized by Northern blots, in situ
      hybridization and in vitro transfection. These approaches confirmed that EG1RVC
      was expressed at a significantly higher level in PND1 than in PND21 visual
      cortical samples, and that transfected PC12 cells and primary neuronal cultures
      showed expression mainly in neuronal cell bodies. Our data indicate that genes
      expressed more abundantly on PND1 are associated with various metabolic pathways
      and enzymatic changes, and may play an important role in visual cortical
      development, growth and/or plasticity.

PMID- 15033533
TI  - Structural and evolutionary analysis of the transcribed sequence of Boudicca, a
      Schistosoma mansoni retrotransposon.
AB  - Boudicca is a gypsy-like, long terminal repeat (LTR) retrotransposon that has
      colonized the genome of the human blood fluke, Schistosoma mansoni. Previous
      studies have indicated that more than 1000 copies of Boudicca reside within the
      S. mansoni genome, although many of them may be degenerate and inactive.
      Messenger RNAs transcribed from genomic copies of Boudicca were investigated by
      reverse transcription PCR. Overlapping RT-PCR products corresponding to the gag
      and pol polyproteins of Boudicca, along with relevant sequences of genomic
      fragments of Boudicca, were assembled into contigs. Consensus sequences from
      these contigs were used to predict the sequence and structure of
      transpositionally active copies of the Boudicca retrotransposon. They verified
      that Boudicca has a kabuki-like Cys-His box motif at the active site of its gag
      protein, a classic DTG motif as the active site of the protease domain of the pol
      ORF2, and indicated a contiguous integrase domain at the C-terminus of pol with
      strong identity to integrase from the LTR retrotransposons CsRn1 and kabuki, as
      well as to the conserved integrase core domain, GenBank rve (). Models of the
      secondary structure of the Boudicca transcript suggested that the first AUG was
      occluded by a stem loop structure, which in turn suggested a method of regulation
      of expression, at the level of translation, of Boudicca proteins. In addition,
      phylogenetic analysis targeting discrete domains of Boudicca revealed a
      generalized radiation in sequences among the multiple copies of Boudicca resident
      in the schistosome genome.

PMID- 15033534
TI  - Distribution of minigenes in the bacteriophage lambda chromosome.
AB  - The bar loci in the chromosome of bacteriophage lambda inhibit phage vegetative
      growth in bacteria defective for peptidyl-tRNA hydrolase (Pth). Expression of the
      bar regions results in accumulation of peptidyl-tRNA, inhibition of protein
      synthesis, and arrest of mutant cell growth. These effects have been ascribed to
      the expression of two-codon ORFs present in translatable sequences named
      'minigenes' in the lambda bar regions. To investigate the nature, frequency, and
      distribution of minigenes in the phage genome, we conducted a survey of their
      location in lambda DNA. A short-fragment random genomic DNA library was
      constructed for the identification of clones inhibitory of Pth-defective cells
      (bar-like phenotype). Three new bar-like minigenes were identified in the library
      but only one was on the sense strand and it had a rare initiation codon. This
      result contrasted with the in silico identification of over a hundred putative
      minigenes using an ad hoc computer program on both strands of lambda DNA. Unlike
      bar constructs, most of the toxic constructed clones were also toxic to wild-type
      bacteria, thus suggesting a different inhibition mechanism. Sequence analysis of
      these cloned inserts showed that they harbored minigenes, mini-ORFs, gene starts,
      gene ends, or combinations thereof. Our data suggest that minigene-like sequences
      may, at least partly, account for toxicity in wild-type cells. We propose that
      clustering of minigenes at gene ends may play a role in gene expression. Other
      minigenes identified in silico were non-toxic. It is still an open question what
      the in vivo function of these and toxic minigenes might be.

PMID- 15033535
TI  - Systematic analysis of SigD-regulated genes in Bacillus subtilis by DNA
      microarray and Northern blotting analyses.
AB  - The SigD-regulated genes in Bacillus subtilis were systematically analyzed by
      comparing the pattern of transcripts derived from wild-type cells with those from
      sigD mutant cells using DNA microarray technology. One hundred and fifty-eight
      genes were found to be SigD-dependent candidates, 46 of which being known SigD
      regulated genes. Northern blot analysis revealed that 18 of the remaining genes
      were SigD-dependent. The SigD consensus sequence was newly identified in the
      upstream regions of nine operons (11 genes): ybdO, yfmT-yfmS, hemAT, yjcP-yjcQ,
      yjfB, ylqB, yoaH, yscB and yxkC, and the other seven genes were assumed to be
      indirectly affected by a SigD mutation. Furthermore, yviE-yviF are likely to be
      SigD-dependent genes, because three independent sets of array data for yviE and
      yviF indicated they are SigD-dependent, and these genes are neighbors of flgL and
      hag transcribed by SigD RNA polymerase.

PMID- 15033537
TI  - Response of the Pacific oyster Crassostrea gigas to hydrocarbon contamination
      under experimental conditions.
AB  - Hydrocarbon contamination perturbs the metabolism of the marine bivalve
      Crassostrea gigas. To understand the response of this organism to hydrocarbon
      exposure, a suppression subtractive hybridisation method was employed to
      characterise up- and down-regulated genes during hydrocarbon exposure. The number
      of differentially expressed gene sequences obtained via this method was 258. The
      expression of genes involved in hydrocarbon detoxification (cytochrome p4501A1
      like protein, cytochrome b(5), flavin-containing monooxygenase 2 and glutathione
      S-transferase omega class), protection against oxidative stress (copper/zinc
      superoxide dismutase) and cell protection (heat shock protein 70 family) was
      analysed by RT-PCR. An increase in the mRNA level of all genes studied was
      observed. A quantification of HSP70 by Enzyme Linked Immunosorbent Assay (ELISA)
      showed a significant increase of this protein during exposure. This study
      provides a basis for studying hydrocarbon detoxification processes in marine
      bivalves, especially C. gigas.

PMID- 15033536
TI  - Characterization of CG6178 gene product with high sequence similarity to firefly
      luciferase in Drosophila melanogaster.
AB  - This is the first identification of a long-chain fatty acyl-CoA synthetase in
      Drosophila by enzymatic characterization. The gene product of CG6178 (CG6178) in
      Drosophila melanogaster genome, which has a high sequence similarity to firefly
      luciferase, has been expressed and characterized. CG6178 showed long-chain fatty
      acyl-CoA synthetic activity in the presence of ATP, CoA and Mg(2+), suggesting a
      fatty acyl adenylate is an intermediate. Recently, it was revealed that firefly
      luciferase has two catalytic functions, monooxygenase (luciferase) and AMP
      mediated CoA ligase (fatty acyl-CoA synthetase). However, unlike firefly
      luciferase, CG6178 did not show luminescence activity in the presence of firefly
      luciferin, ATP, CoA and Mg(2+). The enzymatic properties of CG6178 including
      substrate specificity, pH dependency and optimal temperature were close to those
      of firefly luciferase and rat fatty acyl-CoA synthetase. Further, phylogenic
      analyses strongly suggest that the firefly luciferase gene may have evolved from
      a fatty acyl-CoA synthetase gene as a common ancestral gene.

PMID- 15033538
TI  - Rapid chromosomal assignment of medaka mutants by bulked segregant analysis.
AB  - Genetic screens in medaka are leading to the identification of an increasing
      number of unique mutant phenotypes. However, so far only a few genes responsible
      for these phenotypes have been characterized. Furthermore, no protocols using a
      systematic positional cloning strategy have been developed to determine the
      implicated genes. The PCR-based bulked segregant analysis is a fast and reliable
      tool to accomplish the initial steps of the positional cloning of a mutation.
      Here we describe the selection of a panel of genetic markers that, evenly
      distributed over the 24 chromosomes of medaka, provide a full coverage of the
      compact medaka genome (800 Mb) when used in bulked segregant analysis. The
      reference panel, which consists of 48 EST-derived markers, is anchored to a
      collection of more than 2000 polymorphic markers, thus facilitating a rapid
      transition from chromosomal assignment to fine mapping of the mutants. More
      importantly, since most of the genetic screens have been performed in the inbred
      Cab strain (derived from the Southern population), the selection of markers
      included in this panel was intended to optimize the recognition of polymorphisms
      between Cab and the polymorphic inbred mapping strain Kaga. Here we present a
      reliable mapping panel, confirmed both by the assignment of the locus responsible
      for the medaka mutation eyeless/Rx3 to chromosome 12, and by the analysis of its
      resolution power using representative markers.

PMID- 15033539
TI  - Microarray analysis of differentiation-specific gene expression during 3T3-L1
      adipogenesis.
AB  - During cellular differentiation and development, it is recognized that many
      complex molecular mechanisms as well as precise patterns of differentially
      expressed genes occur in directing precursor cells toward a given lineage. Using
      microarray-based technology, we examined gene expression across the course of 3T3
      L1 adipocyte differentiation. Total cellular RNA was isolated at times 0, 2, 8,
      16, 24, 48, and 96 h following treatment with either standard hormonal inducers
      of differentiation; insulin, dexamethasone, isobutylmethylxanthine (IDX), or IDX
      plus trichostatin A (TsA), a histone deacetylase inhibitor and potent adipogenic
      inhibitor. cRNA was synthesized from cellular RNA and hybridized to high density
      Affymetrix MG_U74Av2 microarray gene chips containing 12,488 cDNA/Expressed
      Sequence Tags (ESTs) probe sets. From the IDX-only treated cells, all probe sets
      that were either unchanged or differentially expressed less than 2-fold
      throughout differentiation with respect to time 0 preadipocytes were excluded
      from further analyses. This selection resulted in a net of 1686 transcripts, 859
      were increased in expression, and 827 were decreased in expression at least 2
      fold across differentiation. To focus in on genes that were more specific to
      differentiation, the same analysis was performed on IDX plus TsA-treated non
      differentiating cells and all probe sets from the IDX-only group that exhibited
      similar expression profiles in the non-differentiating TsA-treated group were
      excluded leaving a total of 1016 transcripts that were regulated only under
      differentiating conditions. Six hundred and thirty-six of these transcripts were
      elevated at least 2-fold and 380 exhibited a decrease in expression relative to
      time 0 preadipocytes. This group of genes was further analyzed using hierarchical
      clustering and self-organizing maps and resulted in the identification of
      numerous genes not previously known to be regulated during adipocyte
      differentiation. Many of these genes may well represent novel adipogenic
      mediators and markers of adipogenesis.

PMID- 15033540
TI  - Molecular cloning and characterization of two thermostable carboxyl esterases
      from Geobacillus stearothermophilus.
AB  - Screening of the genomic libraries of Geobacillus stearothermophilus ATCC12980
      and ATCC7954 for esterase/lipase activity led to the isolation of two positive
      clones. The results of subclonings and sequence analyses identified two genes,
      est30 and est55, encoding two different carboxylesterases, and genetic
      rearrangement in the est55 locus was revealed from genomic comparison. The est30
      gene encodes a polypeptide of 248 amino acids with a calculated molecular mass of
      28338 Da, and the est55 gene encodes a polypeptide of 499 amino acids with a
      calculated molecular mass of 54867 Da. Both enzymes were purified to near
      homogeneity from recombinant strains of Escherichia coli. The results of enzyme
      characterization showed that while both enzymes possess optimal activities with
      short chain acyl derivatives, Est55 has a broader pH tolerance (pH 8-9) and
      optimal temperature range (30-60 degrees C) than Est30. The activation energy of
      Est55 (35.7 kJ/mol) was found to be significantly lower than that of Est30 (101.9
      kJ/mol). Both enzymes were stable at 60 degrees C for more than 2 h; at 70
      degrees C, the half-life for thermal inactivation was 40 and 180 min for Est55
      and Est30, respectively. With p-nitrophenyl caproate as the substrate and assayed
      at 60 degrees C, Est55 had K(m) and k(cat) values of 0.5 microM and 39758 s(-1)
      while Est30 exhibited values of 2.16 microM and 38 s(-1). Inhibition studies
      indicated that both Est30 and Est55 were strongly inhibited by
      phenylmethanesulfonyl fluoride, p-hydroxymercuribenzoate, and tosyl-l
      phenylalanine, consistent with the proposed presence of Ser-His-Glu catalytic
      triad of the alpha/beta hydrolase family. The enzymatic properties of Est30 and
      Est55 reported here warrant the potential applications of these enzymes in
      biotechnological industries.

PMID- 15033541
TI  - Numerous polymorphic microsatellites in the human prion gene complex (including
      PRNP, PRND and PRNT).
AB  - Microsatellite sites were analysed with DNA screening software by using about 148
      kilobases (kb) of the human genomic DNA sequence GenBank accession number (acc.
      no.) which includes the genes PRNP, PRND and PRNT. Regarding microsatellites (MS)
      with at least four repeats and base replacements within the repetitive
      motifs<10%, 127 sites were found. Sixteen of the sites were analysed and nine of
      them proved to be polymorphic with up to nine alleles per site. Frequencies<0.95
      of the predominant allele were observed for all polymorphic sites, and
      frequencies<0.4 for four sites. Some allelic DNA sequences were not only
      different in microsatellite repeats but also in flanking regions. Distances
      between microsatellite sites were in average of 1.2 kb and allow the
      identification of a number of further informative markers in the prion protein
      gene complex. The large number of polymorphic sites within a narrow chromosomal
      interval can be applied to study the origin of alleles as well as the association
      to the incidence of diseases.

PMID- 15033542
TI  - Induction of peroxisome proliferation in cultured hepatocytes by a series of
      halogenated acetates.
AB  - Trichloroacetate (TCA) and dichloroacetate (DCA) are hepatocarcinogenic
      metabolites of the environmental pollutant trichloroethylene (TCE) and are common
      water contaminants. Induction of peroxisome proliferation via activation of the
      peroxisome proliferator-activated receptor alpha (PPARalpha) has been proposed as
      a mechanism for their hepatocarcinogenic action. However, it is unclear whether
      these compounds are direct ligands of PPARalpha or whether activation occurs by a
      ligand-independent process. The present studies were undertaken to determine
      whether a primary rat hepatocyte model system could be used to examine structure
      activity relationships of haloacetates for the induction of peroxisomal palmitoyl
      CoA oxidation. The haloacetates tested differed in both type (iodo, bromo, chloro
      and fluoro) and extent (mono, di and tri) substitution. Significant differences
      were observed in both potency and efficacy. Potency varied over about two orders
      of magnitude, in the order of mono > di = tri. Within the monohalo-substituted
      series, the order of potency was iodo > bromo > chloro, with the fluoro analog
      being essentially inactive. The monoiodo- and monobromo-derivatives showed
      significant induction at 50 and 100 microM, respectively, but cytotoxicity
      precluded obtaining full concentration-response curves. The dihalo- and trihalo
      acetates had generally similar potency, and, with the exception of the diflouro-
      and dibromoacetates, showed a maximal induction of two- to three-fold.
      Difluoroacetate and dibromoacetate induced palmitoyl-CoA oxidation by nine- and
      six-fold, respectively, approaching the effectiveness of Wy-14,643 (50 microM) in
      this system. Of interest, the slopes of the concentration-dependence lines of the
      difluoro- and dibromo-acetates were markedly dissimilar from the other di- and
      tri-haloacetates, suggesting either a marked difference in the way they activate
      the PPARalpha receptor or a substantial difference in the way they are
      metabolized or transported by the hepatocytes.

PMID- 15033543
TI  - Influence of recipient gender on intrasplenic fetal liver tissue transplants in
      rats: cytochrome P450-mediated monooxygenase functions.
AB  - Rat livers display a sex-specific cytochrome P450 (P450) isoforms expression
      pattern with consecutive differences in P450-mediated monooxygenase activities,
      which have been shown to be due to a differential profile of growth hormone (GH)
      secretion. Parallel to previous investigations on P450 isoforms expression, the
      aim of the present study was to elucidate the influence of recipient gender on
      P450-mediated monooxygenase activities in intrasplenic liver tissue transplants
      in comparison to orthotopic liver. Fetal liver tissue suspensions of mixed gender
      were transplanted into the spleen of adult male or female syngenic recipients.
      Four months after grafting transplant-recipients and age-matched controls were
      treated with beta-naphthoflavone (BNF), phenobarbital (PB), dexamethasone (DEX)
      or the vehicles and sacrificed 24 or 48 h thereafter. P450-dependent
      monooxygenase activities were assessed by a series of model reactions for
      different P450 subtypes in liver and spleen 9000 g supernatants. In spleens of
      male and female control rats only very low monooxygenase activities were
      detectable, whereas with most model reactions distinct activities were observed
      in transplant-containing organs. Livers and transplant-containing spleens from
      male rats displayed higher basal ethoxycoumarin O-deethylase and testosterone
      2alpha-, 2beta-, 6beta-, 14alpha-, 15alpha-, 15beta-, 16alpha-, 16beta- and 17
      hydroxylase activities than those from females. On the other hand, like the
      respective livers, spleens from female transplant-recipients demonstrated more
      pronounced p-nitrophenol- and testosterone 6alpha- and 7alpha-hydroxylase
      activities than those from male hosts. With nearly all model reactions gender
      specific differences in inducibility by BNF, PB or DEX could be demonstrated in
      livers as well as in transplant-containing spleens. These results further confirm
      that the P450 system of intrasplenic liver tissue transplants and the respective
      orthotopic livers is similarly influenced by recipient gender.

PMID- 15033545
TI  - Assessment of primary eye and skin irritants by in vitro cytotoxicity and
      phototoxicity models: an in vitro approach of new arginine-based surfactant
      induced irritation.
AB  - Extensive efforts have been made, recently, to find surfactants with lower
      irritation potential than those presently commercially available, for use in
      pharmaceutical and cosmetic preparations. Cytotoxic and phototoxic effects of a
      novel family of dicationic arginine-diglyceride surfactant compounds, 1,2
      diacyl,3-O-(l-arginyl)-rac-glycerol with alkyl chain lengths in the range from 8
      to 14 carbon atoms, were compared to three commercial surfactants. The end-points
      used to assess toxicity were the red blood cell lysis assay and uptake of the
      vital dye neutral red 24h after dosing (NRU), respectively. Two immortalized cell
      lines, murine fibroblast cell line, 3T3, and one human keratinocyte cell line,
      HaCaT, were used as in vitro models to predict the potential phototoxicity which
      could result in irritation, determined by resazurin reduction to resorufin and
      neutral red uptake (NRU). All tested surfactants had cytotoxicity effects as
      demonstrated by and decrease of NR uptake, which showed a clear concentration
      response relationship. Concentrations resulting in 50% inhibition of NR uptake
      (IC(50)) range from 1 microM(-1) (hexadecyl trimethyl ammonium bromide) to 565
      microM(-1) (12,12-l-arginine). Erythrocyte haemolysis also showed a clear
      concentration-response relationship, the 50% of haemolysis ranged from 37 microM(
      1) (10,10-l-arginine) to 151 microM(-1) (sodium lauryl sulphate). Phototoxicity
      was performed with 12,12-l-acetyl-arginine, the most stable chemical structure.
      The validated 3T3 NRU photoxicity assay was used and revealed a phototoxic
      potential.

PMID- 15033544
TI  - Acute cadmium exposure enhances AP-1 DNA binding and induces cytokines expression
      and heat shock protein 70 in HepG2 cells.
AB  - Cadmium (Cd) has been regarded as one of the inflammation-related xenobiotics. Cd
      has been extensively studied in many cellular systems, but a lot of parameters
      have been evaluated in different experimental conditions. This study was
      undertaken to examine the effects of low cadmium concentrations in HepG2 cells in
      the oxidative stress produced, the IL-1beta, tumor necrosis factor (TNF-alpha),
      IL-6, and IL-8 expression, production of heat shock protein 70 (Hsp70) and the
      activation of nuclear factors activation protein-1 (AP-1) and NF-kappaB under the
      same experimental conditions. Also, the participation of TNF-alpha and oxidative
      stress in AP-1 activation was evaluated. Lipid peroxidation damage increased 1.5
      times after the first hour of Cd treatment and increased 1.9 times after 2h.
      Similar values were maintained until 6h. Reduced glutathione (GSH) diminished 65%
      after 6h CdCl(2) treatment. N-acetylcysteine (NAC) pre-treatment increased 332%
      GSH in Cd-treated cells. RNA was isolated from HepG2 cells after 0.5, 1, 3, or 6h
      incubation with 1, 5, or 10 microM CdCl(2). TNF-alpha and IL-1beta presented a
      maximum response after 1h treatment, while IL-6 and IL-8 maximum response was
      after 3h treatment. The Hsp70, determined by Western blot, was constitutively
      produced, and it increased after 3h Cd treatment. NF-kappaB activation,
      determined by EMSA, was not increased as a result of Cd treatment. DNA binding of
      AP-1 was detected and increased, with time up to 4h with an increment of 24 times
      control value with 5 microM CdCl(2). The HepG2 cells were pretreated with anti
      TNF-alpha antibody or 1mM N-acetylcysteine 1h before Cd treatment. Anti-TNF-alpha
      treatment reduced 67% AP-1 activation, while NAC 47.5%. These data indicate that,
      Cd-induced TNF-alpha and IL-1beta, that probably, activate AP-1 transcription
      factor and IL-6 and IL-8 were induced. Anti-TNF-alpha and NAC partially inhibited
      AP-1 activation. All imply that, a number of factors participate in AP-1 cadmium
      induced activation. The Hsp70 is produced by the HepG2 cells after cadmium
      treatment, and probably has a role in the non-participation of NF-kappaB in the
      cellular response.

PMID- 15033547
TI  - The novel anticancer drug oracin: different stereospecificity and cooperativity
      for carbonyl reduction by purified human liver 11beta-hydroxysteroid
      dehydrogenase type 1.
AB  - Inherent or acquired resistance of tumor cells to anti-cancer drugs is a problem
      of major importance in chemotherapy. In addition to detailed research into the
      mechanisms of drug inactivation, attention has also been paid to the synthesis of
      new structures. Oracin is a promising cytostatic drug, which is presently in
      phase II of clinical trials. This investigation was designed to characterize the
      metabolic inactivation of oracin by carbonyl reduction to 11-dihydrooracin (DHO).
      We identified 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) as the
      principal enzyme being responsible for oracin carbonyl reduction in human liver
      microsomes. The purified 11beta-HSD 1 catalyses this reaction in a stereospecific
      manner. Formation of (-)-DHO surpasses that of (+)-DHO by a factor of around
      four. Moreover, 11beta-HSD 1 exhibits enzyme cooperativity for the formation of
      both enantiomers (Hill coefficients of 2.26 +/- 0.20 and 1.84 +/- 0.29 for (-)
      DHO and (+)-DHO, respectively). Comparing the differences in the
      stereospecificity and Hill coefficients between the microsomes and purified
      11beta-HSD 1 could anticipate contribution of another microsomal enzyme. In case
      of oracin, this enzyme cooperativity may become important with respect to maximal
      plasma concentrations, and, by inhibition of 11beta-HSD 1, to enhance the
      chemotherapeutic efficacy of this anti-cancer drug.

PMID- 15033546
TI  - Cytoprotective effects of Glycyrrhizae radix extract and its active component
      liquiritigenin against cadmium-induced toxicity (effects on bad translocation and
      cytochrome c-mediated PARP cleavage).
AB  - Glycyrrhizae radix has been popularly used as one of the oldest and most
      frequently employed botanicals in herbal medicine in Asian countries, and
      currently occupies an important place in food products. Cadmium (Cd) induces both
      apoptotic and non-apoptotic cell death, in which alterations in cellular
      sulfhydryls participate. In the present study, we determined the effects of G.
      radix extract (GRE) and its representative active components on cell death
      induced by Cd and explored the mechanistic basis of cytoprotective effects of G.
      radix. Incubation of H4IIE cells with GRE inhibited cell death induced by 10
      microM Cd. Also, GRE effectively blocked Cd (1 microM)-induced cell death
      potentiated by buthionine sulfoximine (BSO) without restoration of cellular GSH.
      GRE prevented both apoptotic and non-apoptotic cell injury induced by Cd (10
      microM) or Cd (0.3-1 microM) + BSO. Inhibition of Cd-induced cell injury by
      pretreatment of cells with GRE suggested that the cytoprotective effect result
      from alterations in the levels of the protein(s) responsible for cell viability.
      GRE inhibited mitochondrial Bad translocation by Cd or CD+BSO, and caused
      restoration of mitochondrial Bcl(xL) and cytochrome c levels. Cd-induced poly(ADP
      ribose)polymerase cleavage in control cells or in cells deprived of sulfhydryls
      was prevented by GRE treatment. Among the major components present in GRE,
      liquiritigenin, but not liquiritin, isoliquiritigenin or glycyrrhizin, exerted
      cytoprotective effect. These results demonstrated that GRE blocked Cd-induced
      cell death by inhibiting the apoptotic processes involving translocation of Bad
      into mitochondria, decreases in mitochondrial Bcl(xL) and cytochrome c, and
      poly(ADP-ribose)polymerase cleavage.

PMID- 15033548
TI  - From corporate governance to hospital governance. Authority, transparency and
      accountability of Belgian non-profit hospitals' board and management.
AB  - As a result of multiple developments in health care and health care policy,
      hospital administrators, policy makers and researchers are increasingly
      challenged to reflect on the meaning of good hospital governance and how they can
      implement it in the hospital organisations. The question arises whether and to
      what extent governance models that have been developed within the corporate world
      can be valuable for these reflections. Due to the unique societal position of
      hospitals--which involves a large diversity of stakeholders--the claim for
      autonomy of various highly professional groups and the lack of clear business
      objectives, principles of corporate governance cannot be translated into the
      hospital sector without specific adjustments. However, irrespective of these
      contextual differences, corporate governance can provide for a comprehensive
      'frame of reference', to which the hospital sector will have to give its own
      interpretation. A multidisciplinary research unit of the university of Leuven has
      taken the initiative to develop a governance model for Belgian hospitals. As part
      of the preliminary research work a survey has been performed among 82 hospitals
      of the Flemish Community on their governance structure, the composition of the
      governance entities, the partition of competencies and the relationship between
      management and medical staff.

PMID- 15033549
TI  - Universal health coverage in Thailand: ideas for reform and policy struggling.
AB  - Inequality in health between rich and poor in Thailand was well documented;
      millions of informal workers and their families lacked health insurance; and the
      poor paid more proportionately in income for health care. The universal coverage
      is conceived as one of the means to redress the situation. But the term
      'universal coverage' may mean differently among different groups of stakeholders.
      This paper, based on empirical research of health policy reform, collected
      perceptions and ideas from stakeholders and discusses the ways and strategies
      that universal coverage might take shape in Thailand. Two sources of information
      were taken: one from the questionnaire survey (according to the Delphi technique,
      two rounds of survey were taken), another an in-depth interview. Obtained
      information for policy formulation included how best, as conceived by
      stakeholders, to implement the universal coverage, sources of finance, fiscal
      implication for Thai government, ways to prevent higher demand for unnecessary
      services, and involvement of local government. Recent policy move in Thailand
      (the so-called 30 baht for all diseases) emerged in 2001 generated hot debate
      nationwide. The programme is currently in its early phase and is likely to evolve
      overtime--i.e. whether or not this programme will be financed by certain types of
      taxes or from annual government expense still unclear; and budget allocation
      among different health providers still unsettled. Anyhow this programme may be
      interpreted as a policy shift away from the pro-market based toward a government
      supported egalitarianism.

PMID- 15033550
TI  - A note on a discussion group study of public preferences regarding priorities in
      the allocation of donor kidneys.
AB  - OBJECTIVE: To explore whether and how people wish to give differential priority
      based on certain characteristics of the potential recipient of a donor kidney.
      DESIGN: A random sample of people resident in York was invited to attend two
      focus group meetings each, a fortnight apart. SETTING: The City of York.
      PARTICIPANTS: Twenty-three randomly chosen people meeting in four groups of five
      or six. MAIN OUTCOME MEASURES: Those factors that people think should be taken
      into account when allocating donor kidneys, in addition to the expected benefits
      from transplantation. RESULTS: People are willing and able to distinguish between
      potential recipients of a kidney transplantation according to a range of
      characteristics beyond the expected benefits from treatment. There is a clear
      consensus across the four groups that one of the most important considerations is
      what will happen to the patient without treatment, and so priority is given to
      those with a poor prognosis. There is also a strong view that priority should be
      given to younger patients and to those with dependants. The time spent waiting
      for a transplant is also important, but less so. CONCLUSIONS: A sample of the
      general public, after discussion and debate, wish to take account of a number of
      patient characteristics when allocating donor kidneys. There is some degree of
      consensus about what these factors should be and this suggests that it might be
      possible to develop a set of guidelines for the allocation of donor kidneys.

PMID- 15033551
TI  - Equality or equity in health care access: a qualitative study of doctors'
      explanations to a longer doctor's delay among female TB patients in Vietnam.
AB  - Earlier studies from Vietnam have highlighted the importance of studying gender
      aspects of health-seeking and diagnosis of potential tuberculosis patients. A
      longer doctor's delay to diagnosis among female TB patients has been shown. The
      objective of the present study was to explore doctors' views about and
      explanations for the longer doctor's delay. Five focus group discussions and
      three in-depth interviews were performed in a rural province in Vietnam. Thematic
      content analysis was used to interpret the data. The doctors suggest that women
      are lost or delayed within the health care-seeking chain, mainly because of
      barriers associated with the female gender. These barriers are identified, but
      yet the patient-doctor encounter seems to be steered by an equality principle.
      This results in gender blindness since equal treatment is suggested despite needs
      being different. We argue that gender equity should be the guiding principle for
      the tuberculosis patient-doctor encounter. An equity principle emphasises that
      needs vary with factors like gender or context. We suggest more research into the
      health care-seeking chain in order to identify the specific steps where TB
      diagnosis of men and women may be delayed. Interventions are needed in order to
      reduce delay to TB diagnosis especially for women and the current TB control
      strategy, (DOTS), needs to be examined from an equity perspective.

PMID- 15033552
TI  - The effect of generic competition on the price of brand-name drugs.
AB  - BACKGROUND: Literature from the US has shown that brand-name manufacturers do not
      compete on price once generic competitors become available. This study was
      undertaken to investigate if this is also true in Canada. METHODS: Editions of
      the Ontario Drug Benefit Formulary were used to identify brand-name drugs that
      lacked generic competition in July 1990 but had acquired one or more generic
      competitors by December 1998. Prices of the brand-name drugs were compared before
      generic competition, at the point when generic competition started and subsequent
      to the initiation of competition. RESULTS: Price changes for 81 different
      products in 144 separate presentations were analysed. There was no statistically
      significant change in brand-name prices when generic competition started. The
      movement of brand-name prices was not influenced by whether the generic was made
      by the company producing the brand-name product or price freezes imposed by the
      Ontario government. When generics first became available having four or more
      generics was associated with a rise in the price of the brand-name drugs compared
      to having one, two or three generic competitor(s). INTERPRETATION: The lack of
      price competition may lead to increased costs in the private market. Private
      insurance companies generally do not require generic substitution and some
      provinces do not require generic substitution for cash-paying customers.
      Maintaining higher prices on brand-name drugs impacts on the prices of new
      patented medications coming onto the Canadian market under the current pricing
      guidelines of the Patented Medicine Prices Review Board.

PMID- 15033554
TI  - The welfare state as a determinant of women's health: support for women's quality
      of life in Canada and four comparison nations.
AB  - The case is made that characteristics associated with the advanced welfare state
      in industrialised nations are primary contributors to women's quality of life.
      This is so since women's health and well-being are particularly sensitive to
      decisions made in relation to the spending priorities of governments, the extent
      to which services are provided, and the degree to which women are supported in
      moves towards equity. Data from the Organization for Economic Cooperation and
      Development, United Nations Human Development Program, and other sources are used
      to examine these influences upon quality of life of women in Canada as compared
      to that of women in Denmark, Sweden, the UK and the US. A consistent pattern was
      seen by which national features impacting on women's quality of life are more
      likely to be seen in nations with a social welfare orientation as compared to
      nations with market approaches to policy development.

PMID- 15033553
TI  - Experiences of foreign European nurses in The Netherlands.
AB  - As a result of the shortage of nurses, Dutch health care organizations want to
      recruit nurses from outside Europe (e.g. Indonesia, South Africa). The Dutch
      government, however, is not encouraging this policy and prefers to recruit within
      the European Union. In order to better support such nurses, it is important to
      know the problems European nurses encounter in The Netherlands. This study is
      about the experience of nurses from other European countries in The Netherlands.
      This paper addresses itself to three principal questions. First, how many nurses
      qualified in other EU or EU candidate states are starting to work in The
      Netherlands. Second, why do they come to The Netherlands. And finally what
      problems do they encounter when working in The Netherlands. A questionnaire has
      been send to all registered nurses trained in another EU or EU candidate state.
      The response has been 987 or 67%. Thus, far approximately 1500 nurses from other
      EU/candidate states have come to The Netherlands. Personal reasons, including
      marriage, are the most important reasons for their coming here. Half of the
      nurses took one or more courses before starting work in nursing in The
      Netherlands. These were often Dutch language courses. The nurses had to make a
      number of adjustments. Major difficulties were unfamiliarity with Dutch laws and
      the fiscal and social security systems, recognition of their qualifications and
      application for permits. Some basic issues, such as how to write a letter of
      application, caused problems. The language and unfamiliarity with the Dutch
      health care system made it difficult to find a job. When they had gained
      employment in nursing these problems remained the most serious. The conclusion is
      that international employment mobility in nursing is rather low in the case of
      The Netherlands. If the Dutch government decides to encourage the employment of
      nurses from abroad, several measures can be taken to make working in The
      Netherlands more attractive.

PMID- 15033555
TI  - Adoption of innovations by specialised nurses: personal, work and organisational
      characteristics.
AB  - BACKGROUND: To gain insight in the factors that influence the adoption of
      professional information by specialised nurses, we studied the effects of
      individual, work and organisational characteristics on the extent to which
      continence nurses gained knowledge and made use of a book on nursing diagnosis
      and interventions for patients with urinary incontinence, which they received as
      a present. METHODS: Subjects were all members of the Dutch Association of
      Continence Nurses. Data collection took place via a postal questionnaire with
      closed questions. In total, 109 valid questionnaires (78%) were received back.
      Stepwise selected ordered logit models were estimated with reading the book and
      knowledge and use of five selected parts of it as dependent variables and
      individual, work and organisational characteristics as independent variables.
      RESULTS: The most important factors found to promote reading of the book and
      taking knowledge of the parts of it were a personal characteristic of the nurses
      called "information directedness" (or eagerness to acquire professional
      information from other sources), the presence of an "innovative atmosphere" at
      the department, and "relevance" of the information for daily nursing practice.
      The most important factors found to promote the use of the book are (again)
      information directedness, working at a (relatively) small department and having
      experience with nursing diagnosis. CONCLUSIONS: Results suggest that nurses
      differ in the degree to which they are open to innovations and that information
      directedness might be a useful indicator of this characteristic. In addition, the
      degree of innovativeness of the atmosphere at the department and the relevance of
      the innovation for nursing practice are important factors influencing the success
      or failure of innovations in nursing practice.

PMID- 15033557
TI  - Health sector policy in the first decade of Nepal's multiparty democracy. Does
      clear enunciation of health priorities matter?
AB  - Nepal experienced a significant political regime shift in 1990 from the partyless
      Panchyat system to the present multiparty form of democracy. While political
      instability existed in the decade of the 1990s, reflected in the approximately
      one government per year, there had been continued enunciation of health policy
      priorities toward the rural sector, as reflected in the Nepal National Health
      Policy, 1991 (NHP (1991)) and subsequent plans. The objective of the paper is to
      assess whether clear enunciation of health priorities have translated into
      beneficial health outcomes, reflected in reduction of the child death rate, child
      morality rate, infant mortality rate and increase in the life expectancy rate.
      This question is assessed empirically over the 10-year period of fiscal year
      1989/1990 to 1999/2000 using mainly secondary data published by His Majesty's
      Government of Nepal (HMG/N), through the perspectives of input-output model and
      extension of health services, along with an indicative regression of a Nepalese
      health production function. The results (i.e. empirical observations) suggest
      that while there have been clear enunciation of health priorities, there have not
      been significant positive effects on health sector outcomes. The paper ends with
      a number of recommendations and concludes with the necessity for effective and
      appropriate implementation.

PMID- 15033556
TI  - Malaria incidence in rural Benin: does economics matter in endemic area?
AB  - Malaria represents a major health problem with over 1 million annual deaths in
      Africa alone. There are a limited number of policies tackling the health problems
      of people at greater risk, namely the poor and rural communities. This is partly
      due to the lack of evidence available on the range of factors affecting their
      health status. Despite endemic malarial situations, there is still little
      understanding of the relative importance of economic factors that contribute to
      people acquiring malaria. This paper examines the socio-economic and economic
      factors that affect the incidence of malaria in rural community households in
      Benin, where malaria is endemic. A sample of 1585 households was determined to
      collect information on socio-economic characteristics and the presence of malaria
      symptoms. Probit estimation techniques were used to assess the impact of socio
      demographic and socio-economic factors on the incidence of malaria, comparing
      households with and without malaria patients. Predisposing characteristics of the
      household head such as age, knowledge of malaria, education and the size of the
      household significantly affect the incidence of malaria as anticipated by
      economic theory. Enabling factors reflecting higher economic status, measured by
      monthly expenditure and a socio-economic index, have a statistically significant
      and positive impact on the incidence of malaria. This could reflect that better
      off have improved case reporting and are likely to seek treatment. Variations in
      socio-economic and economic characteristics are significant in explaining the
      incidence of malaria, even in an endemic malarial setting.

PMID- 15033558
TI  - The Pharmacy-based Cost Group model: validating and adjusting the classification
      of medications for chronic conditions to the Dutch situation.
AB  - In 2002, the Dutch government implemented a Pharmacy-based Cost Group (PCG) model
      in the social health insurance sector. This model uses specific types of
      medication prescribed to individuals in a base year as markers for chronic
      conditions, which are then employed to adjust capitation payments to their
      sickness fund in the subsequent year. In this study, a classification of
      prescribed medication is derived for 22 chronic conditions, based on an
      assessment of the relation between prescribed medication and diagnoses indicated
      by physicians on their prescriptions. Of the 22 chronic conditions in this
      classification, 13 were included in the PCG model that is currently used in the
      Netherlands.

PMID- 15033559
TI  - Bovine aortic endothelial cells are susceptible to Hantaan virus infection.
AB  - Hantavirus serotype Hantaan (HTN) is one of the causative agents of hemorrhagic
      fever with renal syndrome (HFRS, lethality up to 10%). The natural host of HTN is
      Apodemus agrarius. Recent studies have shown that domestic animals like cattle
      are sporadically seropositive for hantaviruses. In the present study, the
      susceptibility of bovine aortic endothelial cells (BAEC) expressing
      alpha(V)beta(3)-integrin to a HTN infection was investigated. Viral nucleocapsid
      protein and genomic RNA segments were detected in infected BAEC by indirect
      immunofluorescence assay, Western blot analysis, and reverse transcription
      polymerase chain reaction (RT-PCR), respectively. The results of this study
      strongly support our previous observation on Puumala virus (PUU) that has been
      propagated efficiently in BAEC. These findings open a new window to contemplate
      the ecology of hantavirus infection and transmission route from animal to man.

PMID- 15033560
TI  - The prolonged culture of human immunodeficiency virus type 1 in primary
      lymphocytes increases its sensitivity to neutralization by soluble CD4.
AB  - Primary strains of human immunodeficiency virus type 1 (HIV-1) are known to adapt
      to replication in cell lines in vitro by becoming sensitive to soluble CD4 (sCD4)
      and neutralizing antibodies (NAb). T-cell lines favor isolation of variants that
      use CXCR4 as a co-receptor, while primary isolates predominantly use CCR5. We
      have now studied how a primary R5 isolate, CC1/85, adapts to prolonged
      replication in primary human peripheral blood mononuclear cells (PBMC). After 19
      passages, a variant virus, CCcon.19, had increased sensitivity to both sCD4 and
      NAb b12 that binds to a CD4-binding site (CD4BS)-associated epitope, but
      decreased sensitivity to anti-CD4 antibodies. CCcon.19 retains the R5 phenotype,
      its resistance to other NAbs was unaltered, its sensitivity to various entry
      inhibitors was unchanged, and its ability to replicate in macrophages was
      modestly increased. We define CCcon.19 as a primary T-cell adapted (PTCA)
      variant. Genetic sequence analysis combined with mutagenesis studies on clonal,
      chimeric viruses derived from CC1/85 and the PTCA variant showed that the most
      important changes were in the V1/V2 loop structure, one of them involving the
      loss of an N-linked glycosylation site. Monomeric gp120 proteins expressed from
      CC1/85 and the PTCA variant did not differ in their affinities for sCD4,
      suggesting that the structural consequences of the sequence changes were
      manifested at the level of the native, trimeric Env complex. Overall, the
      adaptation process probably involves selection for variants with higher CD4
      affinity and hence greater fusion efficiency, but this also involves the loss of
      some resistance to neutralization by agents directed at or near to the CD4BS. The
      loss of neutralization resistance is of no relevance under in vitro conditions,
      but NAbs would presumably be a counter-selection pressure against such adaptive
      changes in vivo, at least when the humoral immune response is intact.

PMID- 15033561
TI  - Sequence determination of the Crimean-Congo hemorrhagic fever virus L segment.
AB  - Crimean-Congo hemorrhagic fever (CCHF) virus is highly pathogenic for humans and
      remains the only Category A virus for which full sequence information is
      currently unavailable. In this study we completed CCHF genome characterization by
      determining the L segment sequence using Dugbe and CCHF virus-specific
      oligonucleotides. Sequence alignments revealed the presence of four previously
      described conserved regions in all Bunyaviridae polymerases. Interestingly,
      additional regions containing putative Ovarian Tumor (OTU)-like cysteine protease
      and helicase domains were identified in the L segments of CCHF and Dugbe viruses,
      suggesting an autoproteolytic cleavage process for nairovirus L proteins.

PMID- 15033562
TI  - Crimean-Congo hemorrhagic fever virus genome L RNA segment and encoded protein.
AB  - Sequence analysis of the L RNA genome segment and predicted encoded L polymerase
      protein of Crimean-Congo hemorrhagic fever (CCHF) virus (genus Nairovirus, family
      Bunyaviridae) demonstrates that they are approximately twice the size of those
      found in viruses of other bunyavirus genera. The CCHF virus L segment and encoded
      protein (12,164 nucleotides and 3944 amino acids, respectively) are similar in
      size and sequence to those of the nairovirus Dugbe virus (12,255/62% and 4036/62%
      nucleotide and amino acid length/identity, respectively). The identification of
      an ovarian tumor (OTU)-like protease motif in the L protein amino termini of the
      nairoviruses Dugbe, CCHF, and Nairobi sheep disease (NSD) indicates these
      proteins are members of the recently described OTU-like protease family and
      suggests that these large proteins may be polyproteins that are
      autoproteolytically cleaved or involved in deubiquitination.

PMID- 15033563
TI  - The tRNA-like structure of Turnip yellow mosaic virus RNA is a 3'-translational
      enhancer.
AB  - Many positive stand RNA viral genomes lack the poly(A) tail that is
      characteristic of cellular mRNAs and that promotes translation in cis. The 3'
      untranslated regions (UTRs) of such genomes are expected to provide similar
      translation-enhancing properties as a poly(A) tail, yet the great variety of 3'
      sequences suggests that this is accomplished in a range of ways. We have
      identified a translational enhancer present in the 3' UTR of Turnip yellow mosaic
      virus (TYMV) RNA using luciferase reporter RNAs with generic 5' sequences
      transfected into plant cells. The 3' terminal 109 nucleotides comprising the tRNA
      like structure (TLS) and an upstream pseudoknot (UPSK) act in synergy with a 5'
      cap to enhance translation, with a minor contribution in stabilizing the RNA.
      Maximum enhancement requires that the RNA be capable of aminoacylation, but
      either the native valine or engineered methionine is acceptable. Mutations that
      decrease the affinity for translation elongation factor eEF1A (but also diminish
      aminoacylation efficiency) strongly decrease translational enhancement,
      suggesting that eEF1A is mechanistically involved. The UPSK seems to act as an
      important, though nonspecific, spacer element ensuring proper presentation of a
      functional TLS. Our studies have uncovered a novel type of translational enhancer
      and a new role for a plant viral TLS.

PMID- 15033564
TI  - eEF1A binding to aminoacylated viral RNA represses minus strand synthesis by TYMV
      RNA-dependent RNA polymerase.
AB  - The genomic RNA of Turnip yellow mosaic virus (TYMV) has an 82-nucleotide-long
      tRNA-like structure at its 3'-end that can be valylated and then form a stable
      complex with translation elongation factor eEF1A.GTP. Transcription of this RNA
      by TYMV RNA-dependent RNA polymerase (RdRp) to yield minus strands has previously
      been shown to initiate within the 3'-CCA sequence. We have now demonstrated that
      minus strand synthesis is strongly repressed upon the binding of eEF1A.GTP to the
      valylated viral RNA. eEF1A.GTP had no effect on RNA synthesis templated by non
      aminoacylated RNA. Higher eEF1A.GTP levels were needed to repress minus strand
      synthesis templated by valyl-EMV TLS RNA, which binds eEF1A.GTP with lower
      affinity than does valyl-TYMV RNA. Repression by eEF1A.GTP was also observed with
      a methionylated variant of TYMV RNA and with aminoacylated tRNAHis, tRNAAla, and
      tRNAPhe transcripts. It is proposed that minus strand repression by eEF1A.GTP
      binding occurs early during infection to help coordinate the competing
      translation and replication functions of the genomic RNA.

PMID- 15033565
TI  - Neuropathogenic murine leukemia virus TR1.3 induces selective syncytia formation
      of brain capillary endothelium.
AB  - Exposure of newborn BALB/c mice to murine leukemia virus (MLV) TR1.3 induces
      fusion of brain capillary endothelial cells (BCEC), loss of cerebral vessel
      integrity, hemorrhagic stroke, and death. Although TR1.3 infects endothelial
      cells in multiple organs, syncytia are only observed in BCEC. To determine if
      viral and cellular factors are responsible for selective syncytia formation,
      capillary endothelial cells (CEC) from multiple organs were assayed in vitro for
      MLV infection and cell fusion. Following incubation with virus, all CEC were
      infected to an equal extent as determined by expression of MLV envelope and
      infectious virus production; however, MLV-induced syncytia were only observed in
      TR1.3-infected BCEC cultures. These in vitro results mirror the in vivo pattern
      of TR1.3 MLV infection and neuropathology, and definitively show that selective
      fusion and pathology of BCEC by MLV is determined by properties unique to BCEC as
      contrasted to other endothelial cell types.

PMID- 15033566
TI  - Avian reovirus sigmaC protein induces apoptosis in cultured cells.
AB  - The avian reovirus (ARV) infection is associated with various disease conditions
      in poultry. However, the pathogenesis mechanisms are poorly characterized. In the
      present study, we clearly demonstrated that the sigmaC of ARV S1133 strain
      induced apoptosis in both BHK-21 and Vero cells. Five kinds of assays for
      apoptosis were used in analyzing ARV-infected BHK-21 and Vero cells: (1) assay
      for DNA ladders, (2) ELISA detection of cytoplasmic histone-associated DNA
      fragments, (3) nuclear staining with acridine orange, (4) Western blot, Northern
      blot, and immunofluorescent assay (IFA), and (5) flow cytometric analysis. The
      sigmaC protein of ARV could elicit apoptosis occurring in a dose- and time
      dependent manner. The current results further our understanding of the function
      of sigmaC in cultured cells and suggest that sigmaC is a viral-encoded apoptin
      and possesses apoptosis-inducing ability. Furthermore, deletion analysis of the
      ARV sigmaC protein suggests that the carboxyl-terminus of sigmaC is important in
      mediating sigmaC-induced apoptosis because its deletion abolished the induction
      of apoptosis.

PMID- 15033567
TI  - Assembly, structure, and antigenic properties of virus-like particles rich in HIV
      1 envelope gp120.
AB  - In order to improve the immunogenicity of HIV-1 envelope glycoproteins, we have
      fused gp120 to a carrier protein, hepatitis B surface antigen (HBsAg), which is
      capable of spontaneous assembly into virus-like particles. The HBsAg-gp120 hybrid
      proteins assembled efficiently into 20-30 nm particles. The particles resemble
      native HBsAg particles in size and density, consistent with a lipid composition
      of about 25% and a gp120 content of about 100 per particle. Particulate gp120
      folds in its native conformation and is biologically active, as shown by high
      affinity binding of CD4. The particles express conformational determinants
      targeted by a panel of broadly cross-reactive neutralizing antibodies, and they
      show tight packing of gp120. Because the particles are lipoprotein micelles, an
      array of gp120 on their surface closely mimics gp120 on the surface of HIV-1
      virions. These gp120-rich particles can enhance the quality, as well as quantity,
      of antibodies elicited by a gp120 vaccine.

PMID- 15033568
TI  - A poliomyelitis model through mucosal infection in transgenic mice bearing human
      poliovirus receptor, TgPVR21.
AB  - Transgenic mice bearing the human poliovirus receptor (TgPVR) are less
      susceptible to oral inoculation, although they are susceptible to parenteral
      inoculation. We investigated the susceptibility of TgPVR 21 line [Arch. Virol.
      130 (1994) 351] to poliovirus through various mucosal routes. Intranasal
      inoculation of a neurovirulent Mahoney strain (OM1) caused flaccid paralysis with
      viral replication in the central nervous system at a dose of 10(6) cell culture
      infectious dose (CCID50), in contrast, no paralysis following oral or
      intragastric inoculation of the same dose. Intranasal inoculation of a vaccine
      strain, Sabin 1, at 10(6) CCID50, resulted in no paralysis. Initial replication
      of poliovirus in the nasal cavity was confirmed by virus isolation and detection
      of negative-stranded replicative intermediates by RT-PCR and viral antigens using
      a high-sensitive immunohistochemistry and genome/transcripts by in situ
      hybridization. Poliovirus-specific IgG antibodies were elevated in the sera of
      surviving TgPVR21. This model can be used as a mucosal infection model and for
      differentiation of neurovirulent and attenuated poliovirus strains.

PMID- 15033569
TI  - The Ozobranchus leech is a candidate mechanical vector for the fibropapilloma
      associated turtle herpesvirus found latently infecting skin tumors on Hawaiian
      green turtles (Chelonia mydas).
AB  - Fibropapillomatosis (FP) of marine turtles is a neoplastic disease of ecological
      concern. A fibropapilloma-associated turtle herpesvirus (FPTHV) is consistently
      present, usually at loads exceeding one virus copy per tumor cell. DNA from an
      array of parasites of green turtles (Chelonia mydas) was examined with
      quantitative PCR (qPCR) to determine whether any carried viral loads are
      sufficient to implicate them as vectors for FPTHV. Marine leeches (Ozobranchus
      spp.) were found to carry high viral DNA loads; some samples approached 10
      million copies per leech. Isopycnic sucrose density gradient/qPCR analysis
      confirmed that some of these copies were associated with particles of the density
      of enveloped viruses. The data implicate the marine leech Ozobranchus as a
      mechanical vector for FPTHV. Quantitative RT-PCR analysis of FPTHV gene
      expression indicated that most of the FPTHV copies in a fibropapilloma have
      restricted DNA polymerase expression, suggestive of latent infection.

PMID- 15033570
TI  - HIV-1 transgenic rats develop T cell abnormalities.
AB  - HIV-1 infection leads to impaired antigen-specific T cell proliferation,
      increased susceptibility of T cells to apoptosis, progressive impairment of T
      helper 1 (Th1) responses, and altered maturation of HIV-1-specific memory cells.
      We have identified similar impairments in HIV-1 transgenic (Tg) rats. Tg rats
      developed an absolute reduction in CD4+ and CD8+ T cells able to produce IFN
      gamma following activation and an increased susceptibility of T cells to
      activation-induced apoptosis. CD4+ and CD8+ effector/memory (CD45RC- CD62L-)
      pools were significantly smaller in Tg rats compared to non-Tg controls, although
      the converse was true for the naive (CD45RC+ CD62L+) T cell pool. Our
      interpretation is that the HIV transgene causes defects in the development of T
      cell effector function and generation of specific effector/memory T cell subsets,
      and that activation-induced apoptosis may be an essential factor in this process.

PMID- 15033571
TI  - Functional domains of the influenza A virus PB2 protein: identification of NP-
      and PB1-binding sites.
AB  - Influenza virus genomic RNA segments are packaged into ribonucleoprotein (RNP)
      structures by the PB1, PB2, and PA subunits of an RNA polymerase and a single
      strand RNA-binding nucleoprotein (NP). Assembly and function of these
      ribonucleoproteins depend on a complex set of protein-protein and protein-RNA
      interactions. Here, we identify new functional domains of PB2. We show that PB2
      contains two regions that bind NP and also identify a novel PB1 binding site. The
      regions of PB2 responsible for binding NP and PB1 show considerable overlap, and
      binding of NP to the PB2 fragments could be outcompeted by PB1. The binding
      domains of PB2 acted as trans-dominant inhibitors of viral gene expression, and
      consistent with the in vitro binding data, their inhibitory activity depended on
      the concentration of wild-type PB2, NP, and PB1. This provides evidence for
      functionally significant and potentially regulatory interactions between PB2 and
      NP.

PMID- 15033573
TI  - The M1 matrix protein controls the filamentous phenotype of influenza A virus.
AB  - We show that most isolates of influenza A induce filamentous changes in infected
      cells in contrast to A/WSN/33 and A/PR8/34 strains which have undergone extensive
      laboratory passage and are mouse-adapted. Using reverse genetics, we created
      recombinant viruses in the naturally filamentous genetic background of
      A/Victoria/3/75 and established that this property is regulated by the M1 protein
      sequence, but that the phenotype is complex and several residues are involved.
      The filamentous phenotype was lost when the amino acid at position 41 was
      switched from A to V, at the same time, this recombinant virus also became
      insensitive to the antibody 14C2. On the other hand, the filamentous phenotype
      could be fully transferred to a virus containing RNA segment 7 of the A/WSN/33
      virus by a combination of three mutations in both the amino and carboxy regions
      of the M1 protein. This observation suggests that an interaction among these
      regions of M1 may occur during assembly.

PMID- 15033572
TI  - Old and New World arenaviruses share a highly conserved epitope in the fusion
      domain of the glycoprotein 2, which is recognized by Lassa virus-specific human
      CD4+ T-cell clones.
AB  - Data from human studies and animal experiments indicate a dominant role of T
      cells over antibodies in controlling acute Lassa virus infection and providing
      immunity to reinfection. Knowledge of the epitopes recognized by T-cells may
      therefore be crucial to the development of a recombinant Lassa virus vaccine. In
      order to study human T-cell reactivity to the most conserved structural protein
      of Lassa virus, the glycoprotein 2 (GP2), seven GP2-specific CD4+ T-cell clones
      (TCCs) were generated from the lymphocytes of a Lassa antibody positive
      individual. All TCC displayed high specific proliferation, showed DR-restriction,
      and produced IFN-gamma upon stimulation with recombinant GP2. The epitope of four
      of the clones was localized to a short stretch of 13 amino acids located in the N
      terminal part of GP2 (aa 289-301, numbering according to sequence of GPC). This
      epitope is conserved in all strains of Lassa virus and lymphocytic
      choriomeningitis virus (LCMV), shows >90% similarity in all New World
      arenaviruses of clade B, and overlaps with the proposed fusion domain of GP2.
      Peptides with conservative aa exchanges, as they naturally occur in the epitope
      289-301 of the Old World arenavirus Mopeia and some New World arenaviruses,
      continued to effectively stimulate the Lassa-GP2-specific T-cell clones tested.
      The finding of a human T-helper cell epitope, which is highly conserved between
      Old and New World arenaviruses, is of importance for the design of arenavirus
      vaccines.

PMID- 15033574
TI  - Antiviral activity of a serine protease from the digestive juice of Bombyx mori
      larvae against nucleopolyhedrovirus.
AB  - A protein showing strong antiviral activity against Bombyx mori
      nucleopolyhedrovirus (BmNPV) was purified from the digestive juice of B. mori
      larvae. The molecular mass of this protein was 24271 Da. Partial N-terminal amino
      acid sequence of the protein was determined and cDNA was cloned based on the
      amino acid sequence. A homology search of the deduced amino acid sequence of the
      cDNA showed 94% identity with B. mori serine protease so the protein was
      designated B. mori serine protease-2 (BmSP-2). Analysis of BmSP-2 gene expression
      showed that this gene is expressed in the midgut but not in other tissues. In
      addition, BmSP-2 gene was shown to not be expressed in the molting and wandering
      stages, indicating that the gene is hormonally regulated. Our results suggest
      that BmSP-2, an insect digestive enzyme, can be a potential antiviral factor
      against BmNPV at the initial site of viral infection.

PMID- 15033575
TI  - The connexins.

PMID- 15033576
TI  - Regulation of connexin biosynthesis, assembly, gap junction formation, and
      removal.
AB  - Gap junctions (GJs) are the only known cellular structures that allow a direct
      transfer of signaling molecules from cell-to-cell by forming hydrophilic channels
      that bridge the opposing membranes of neighboring cells. The crucial role of GJ
      mediated intercellular communication (GJIC) for coordination of development,
      tissue function, and cell homeostasis is now well documented. In addition, recent
      findings have fueled the novel concepts that connexins, although redundant, have
      unique and specific functions, that GJIC may play a significant role in unstable,
      transient cell-cell contacts, and that GJ hemi-channels by themselves may
      function in intra-/extracellular signaling. Assembly of these channels is a
      complicated, highly regulated process that includes biosynthesis of the connexin
      subunit proteins on endoplasmic reticulum membranes, oligomerization of
      compatible subunits into hexameric hemi-channels (connexons), delivery of the
      connexons to the plasma membrane, head-on docking of compatible connexons in the
      extracellular space at distinct locations, arrangement of channels into dynamic,
      spatially and temporally organized GJ channel aggregates (so-called plaques), and
      coordinated removal of channels into the cytoplasm followed by their degradation.
      Here we review the current knowledge of the processes that lead to GJ
      biosynthesis and degradation, draw comparisons to other membrane proteins,
      highlight novel findings, point out contradictory observations, and provide some
      provocative suggestive solutions.

PMID- 15033577
TI  - Diversity in protein-protein interactions of connexins: emerging roles.
AB  - Gap junctions, specialised membrane structures that mediate cell-to-cell
      communication in almost all tissues, are composed of channel-forming integral
      membrane proteins termed connexins. The activity of these intercellular channels
      is closely regulated, particularly by intramolecular modifications as
      phosphorylations of proteins by protein kinases, which appear to regulate the gap
      junction at several levels, including assembly of channels in the plasma
      membrane, connexin turnover as well as directly affecting the opening and closure
      ("gating") of channels. The regulation of membrane channels by protein
      phosphorylation/dephosphorylation processes commonly requires the formation of a
      multiprotein complex, where pore-forming subunits bind to auxiliary proteins
      (e.g. scaffolding proteins, catalytic and regulatory subunits), that play
      essential roles in channel localisation and activity, linking signalling enzymes,
      substrates and effectors into a structure frequently anchored to the
      cytoskeleton. The present review summarises the up-to-date progress regarding the
      proteins capable of interacting or at least of co-localising with connexins and
      their functional importance.

PMID- 15033579
TI  - Chemical gating of gap junction channels; roles of calcium, pH and calmodulin.
AB  - Both Ca(2+) and H(+) play a role in chemical gating of gap junction channels,
      but, with the possible exception of Cx46 hemichannels, neither of them is likely
      to induce gating by a direct interaction with connexins. Some evidence suggests
      that low pH(i) affects gating via an increase in [Ca(2+)](i); in turn, Ca(2+) is
      likely to induce gating by activation of CaM, which may act directly as a gating
      particle. The effective concentrations of both Ca(2+) and H(+) vary depending on
      cell type, type of connexin expressed and procedure employed to increase their
      cytosolic concentrations; however, pH(i) as high as 7.2 and [Ca(2+)](i) as low as
      150 nM or lower have been reported to be effective in some cells. Some data
      suggest that Ca(2+) and H(+) affect gating by acting synergistically, but other
      data do not support synergism. Chemical gating follows the activation of a slow
      gate distinct from the fast V(j)-sensitive gate, and there is evidence that the
      chemical/slow gate is V(j)-sensitive. At the single channel level, the
      chemical/slow gate closes the channels slowly and completely, whereas the fast
      V(j) gate closes the channels rapidly and incompletely. At least three molecular
      models of channel gating have been proposed, but all of them are mostly based on
      circumstantial evidence.

PMID- 15033578
TI  - Gap junction channel gating.
AB  - Over the last two decades, the view of gap junction (GJ) channel gating has
      changed from one with GJs having a single transjunctional voltage-sensitive (V(j)
      sensitive) gating mechanism to one with each hemichannel of a formed GJ channel,
      as well as unapposed hemichannels, containing two, molecularly distinct gating
      mechanisms. These mechanisms are termed fast gating and slow or 'loop' gating. It
      appears that the fast gating mechanism is solely sensitive to V(j) and induces
      fast gating transitions between the open state and a particular substate, termed
      the residual conductance state. The slow gating mechanism is also sensitive to
      V(j), but there is evidence that this gate may mediate gating by transmembrane
      voltage (V(m)), intracellular Ca(2+) and pH, chemical uncouplers and GJ channel
      opening during de novo channel formation. A distinguishing feature of the slow
      gate is that the gating transitions appear to be slow, consisting of a series of
      transient substates en route to opening and closing. Published reports suggest
      that both sensorial and gating elements of the fast gating mechanism are formed
      by transmembrane and cytoplamic components of connexins among which the N
      terminus is most essential and which determines gating polarity. We propose that
      the gating element of the slow gating mechanism is located closer to the central
      region of the channel pore and serves as a 'common' gate linked to several
      sensing elements that are responsive to different factors and located in
      different regions of the channel.

PMID- 15033581
TI  - Selective permeability of gap junction channels.
AB  - Gap junctions mediate the transfer of small cytoplasmic molecules between
      adjacent cells. A family of gap junction proteins exist that form channels with
      unique properties, and differ in their ability to mediate the transfer of
      specific molecules. Mutations in a number of individual gap junction proteins,
      called connexins, cause specific human diseases. Therefore, it is important to
      understand how gap junctions selectively move molecules between cells. Rules that
      dictate the ability of a molecule to travel through gap junction channels are
      complex. In addition to molecular weight and size, the ability of a solute to
      transverse these channels depends on its net charge, shape, and interactions with
      specific connexins that constitute gap junctions in particular cells. This review
      presents some data and interpretations pertaining to mechanisms that govern the
      differential transfer of signals through gap junction channels.

PMID- 15033580
TI  - Regulation of gap junctions by tyrosine protein kinases.
AB  - Most of the gap junction proteins are regulated in part by post-translational
      phosphorylation. Phosphorylation has been shown to be important in gap junction
      assembly and turnover, and for channel function in the resting state. Connexin
      phosphorylation may be altered by the activation of intracellular signaling
      pathways in response to growth factors, tumor promoters, activated oncogenes,
      hormones and inflammatory mediators. In some instances altered phosphorylation
      has been associated with changes in connexin function and in other cases appears
      to be associated with changes in the levels of the connexin protein and/or mRNA.
      This review focuses on the role of tyrosine protein kinases in the regulation of
      gap junctions. The literature is most extensive for connexin43 and those studies
      are reviewed here. A great deal has been learned in recent years about how
      connexin43 is regulated by tyrosine kinase-dependent signaling pathways. These
      pathways are often complex and to some extent are cell type- and stimulus
      dependent. Although considerable progress has been made in unraveling the
      cellular pathways that regulate connexin function, significant challenges remain
      to be addressed in identifying additional phosphorylation sites and determining
      the stoichiometries of the phosphorylation events that regulate connexin function
      and it's interaction with other cellular proteins.

PMID- 15033583
TI  - Electrical synapses: a dynamic signaling system that shapes the activity of
      neuronal networks.
AB  - Gap junctions consist of intercellular channels dedicated to providing a direct
      pathway for ionic and biochemical communication between contacting cells. After
      an initial burst of publications describing electrical coupling in the brain, gap
      junctions progressively became less fashionable among neurobiologists, as the
      consensus was that this form of synaptic transmission would play a minimal role
      in shaping neuronal activity in higher vertebrates. Several new findings over the
      last decade (e.g. the implication of connexins in genetic diseases of the nervous
      system, in processing sensory information and in synchronizing the activity of
      neuronal networks) have brought gap junctions back into the spotlight. The
      appearance of gap junctional coupling in the nervous system is developmentally
      regulated, restricted to distinct cell types and persists after the establishment
      of chemical synapses, thus suggesting that this form of cell-cell signaling may
      be functionally interrelated with, rather than alternative to chemical
      transmission. This review focuses on gap junctions between neurons and summarizes
      the available data, derived from molecular, biological, electrophysiological, and
      genetic approaches, that are contributing to a new appreciation of their role in
      brain function.

PMID- 15033582
TI  - Gap junctions and connexin-mediated communication in the immune system.
AB  - Gap junctions and connexins are present in the immune system. In haematopoiesis,
      connexin 43, the most widely distributed gap junction protein, appears to be a
      key player in the development of progenitor cells and their communication with
      stromal cells. Connexin 43 is expressed by macrophages, neutrophils and mast
      cells. Lymphocytes also express connexin 43, and inhibition of gap junction
      channels in these cells by using highly specific connexin mimetic reagents has
      profound effects on immunoglobulin secretion and synthesis of cytokines.
      Lymphocytes and leukocytes also communicate directly in vitro with endothelial
      cells via gap junctions. Connexins are implicated in inflammatory reactions in a
      range of tissues. Their involvement in atherosclerotic plaque formation in the
      vascular system is also a current growth point in research, and could lead to the
      development of therapeutic interventions.

PMID- 15033584
TI  - Remodelling of gap junctions and connexin expression in heart disease.
AB  - Different combinations and relative quantities of three connexins-connexin43,
      connexin40 and connexin45-are expressed in different subsets of cardiomyocyte. In
      the healthy heart, gap junctions assembled from these different connexin
      combinations form the cell-to-cell pathways for the precisely orchestrated
      patterns of current flow that govern the normal heart rhythm. Remodelling of gap
      junction organization and connexin expression is a conspicuous feature of human
      heart disease in which there is an arrhythmic tendency. This remodelling may take
      the form of structural remodelling, involving disturbances in the distribution of
      gap junctions (i.e., disruption of the normal ordered pathways for cell-to-cell
      conduction), and remodelling of connexin expression, involving alteration in the
      amount or type of connexin(s) present. Most notable among quantitative
      alterations in connexin expression is a reduction in ventricular connexin43
      levels in human congestive heart failure. By correlating data from studies in
      experimental animal models, gap junction and connexin remodelling emerges as a
      factor to be considered in understanding the pro-arrhythmic substrate
      characteristic of many forms of heart disease. However, our knowledge of the
      functional correlates of the specific patterns of multiple connexin expression
      found in different regions of the heart in health and disease remains
      rudimentary, and the development of new experimental cell models heralds advances
      in this area over the next few years.

PMID- 15033585
TI  - Gap junctions and neurological disorders of the central nervous system.
AB  - Gap junctions are intercellular channels which directly connect the cytoplasm
      between neighboring cells. In the central nervous system (CNS) various kinds of
      cells are coupled by gap junctions, which play an important role in maintaining
      normal function. Neuronal gap junctions are involved in electrical coupling and
      may also contribute to the recovery of function after cell injury. Astrocytes are
      involved in the pathology of most neuronal disorders, including brain ischemia,
      Alzheimer's disease and epilepsy. In the pathology of brain tumors, gap junctions
      may be related to the degree of malignancy and metastasis. However, the role of
      connexins, gap junctions and hemichannels in the pathology of the diseases in the
      CNS is still ambiguous. Of increasing importance is the unraveling of the
      function of gap junctions in the neural cell network, involving neurons,
      astrocytes, microglia and oligodendrocytes. A better understanding of the role of
      gap junctions may contribute to the development of new therapeutic approaches to
      treating diseases of the CNS.

PMID- 15033586
TI  - Connexin disorders of the ear, skin, and lens.
AB  - Gap junctions provide coupled cells with a direct pathway for sharing ions,
      nutrients, and small metabolites, thus helping to maintain homeostasis in various
      tissues. Abnormal function and/or expression of specific connexin genes has been
      linked to several diseases, including genetic deafness, skin disease, peripheral
      neuropathies, and cataracts. Research has provided significant insight into the
      function of gap junction proteins in both in vitro and in vivo models; however,
      questions regarding the exact mechanisms by which connexin related diseases occur
      in mammalian systems remain. Here, we discuss the disease states that are related
      to three human connexin genes, Cx26 (GJB2), Cx46 (GJA3) and Cx50 (GJA8), and
      recent scientific evidence characterizing those diseases in various experimental
      models.

PMID- 15033587
TI  - Unraveling gene-gene interactions regulated by ligands of the aryl hydrocarbon
      receptor.
AB  - The co-expression of genes coupled to additive probabilistic relationships was
      used to identify gene sets predictive of the complex biological interactions
      regulated by ligands of the aryl hydrocarbon receptor ((Italic)Ahr(/Italic)). To
      maximize the number of possible gene-gene combinations, data sets from murine
      embryonic kidney, fetal heart, and vascular smooth muscle cells challenged
      (Italic)in vitro(/Italic) with ligands of the (Italic)Ahr(/Italic) were used to
      create predictor/training data sets. Biologically relevant gene predictor sets
      were calculated for (Italic)Ahr(/Italic), cytochrome P450 1B1, insulin-like
      growth factor-binding protein-5, lysyl oxidase, and osteopontin. Transcript
      levels were categorized into ternary expressions and target genes selected from
      the data set and tested for all possible combinations using three gene sets as
      predictors of transitional level. The goodness of prediction for each set was
      quantified using a multivariate nonlinear coefficient of determination. Evidence
      is presented that predictor gene combinations can be effectively used to resolve
      gene-gene interactions regulated by (Italic)Ahr(/Italic) ligands. (Italic)Key
      words:(/Italic) aryl hydrocarbon receptor, bioinformatics, gene networks,
      genomics. (Italic)Environ Health Perspect (/Italic)112:403-412 (2004). [Online 14
      January 2004]

PMID- 15033588
TI  - Applying new biotechnologies to the study of occupational cancer--a workshop
      summary.
AB  - As high-throughput technologies in genomics, transcriptomics, and proteomics
      evolve, questions arise about their use in the assessment of occupational
      cancers. To address these questions, the National Institute for Occupational
      Safety and Health, the National Cancer Institute, the National Institute of
      Environmental Health Sciences, and the American Chemistry Council sponsored a
      workshop 8-9 May 2002 in Washington, DC. The workshop brought together 80
      international specialists whose objective was to identify the means for best
      exploiting new technologies to enhance methods for laboratory investigation,
      epidemiologic evaluation, risk assessment, and prevention of occupational cancer.
      The workshop focused on identifying and interpreting markers for early biologic
      effect and inherited modifiers of risk.

PMID- 15033589
TI  - Toxicogenomics in risk assessment: an overview of an HESI collaborative research
      program.
AB  - The value of genomic approaches in hypothesis generation is being realized as a
      tool for understanding toxicity and consequently contributing to an assessment of
      drug and chemical safety. In 1999 the membership of the International Life
      Sciences Institute Health and Environmental Sciences Institute formed a committee
      to develop a collaborative scientific program to address issues, challenges, and
      opportunities afforded by the emerging field of toxicogenomics. Experts and
      advisors from academia and government laboratories participate on the committee,
      along with approximately 30 corporate member organizations from the
      pharmaceutical, agrochemical, chemical, and consumer products industries. The
      committee has designed, conducted, and analyzed numerous toxicogenomic
      experiments within the broad fields of hepatotoxicity, nephrotoxicity, and
      genotoxicity. The considerable body of data generated by these programs has been
      instrumental in increasing understanding of sources of biological and technical
      variability in the alignment of toxicant-induced transcription changes with the
      accepted mechanism of action of these agents and the challenges in the consistent
      analysis and sharing of the voluminous data sets generated by these approaches.
      Recognizing the importance of standardized microarray data formats and public
      repository databases as the mechanism by which microarray data can be compared
      and interpreted by the scientific community, the committee has partnered with the
      European Bioinformatics Institute to develop a database to house the data
      generated by its collaborative research.

PMID- 15033590
TI  - The utility of DNA microarrays for characterizing genotoxicity.
AB  - Microarrays provide an unprecedented opportunity for comprehensive concurrent
      analysis of thousands of genes. The global analysis of the response of genes to a
      toxic insult (toxicogenomics), as opposed to the historical method of examining a
      few select genes, provides a more complete picture of toxicologically significant
      events. Here we examine the utility of microarrays for providing mechanistic
      insights into the response of cells to DNA damage. Our data indicate that the
      value of the technology is in its potential to provide mechanistic insight into
      the mode of action of a genotoxic compound. Array-based expression profiling may
      be useful for differentiating compounds that interact directly with DNA from
      those compounds that are genotoxic via a secondary mechanism. As such, genomic
      microarrays may serve as a valuable alternative methodology that helps
      discriminate between these two classes of compounds. Key words: biomarkers, gene
      expression profile, genetic toxicology, mechanism of action, toxicogenomics.

PMID- 15033591
TI  - Overview of an interlaboratory collaboration on evaluating the effects of model
      hepatotoxicants on hepatic gene expression.
AB  - DNA microarrays and related tools offer promise for identification of pathways
      involved in toxic responses to xenobiotics. To be useful for risk assessment,
      experimental data must be challenged for reliability and interlaboratory
      reproducibility. Toward this goal, the Hepatotoxicity Working Group of the
      International Life Sciences Institute (ILSI) Health and Environmental Sciences
      Institute (HESI) Technical Committee on Application of Genomics to Mechanism
      Based Risk Assessment evaluated and compared biological and gene expression
      responses in rats exposed to two model hepatotoxins--clofibrate and
      methapyrilene. This collaborative effort provided an unprecedented opportunity
      for the working group to evaluate and compare multiple biological, genomic, and
      toxicological parameters across different laboratories and microarray platforms.
      Many of the results from this collaboration are presented in accompanying
      articles in this mini-monograph, whereas others have been published previously.
      (Italic)In vivo(/Italic) studies for both compounds were conducted in two
      laboratories using a standard experimental protocol, and RNA samples were
      distributed to 16 laboratories for analysis on six microarray platforms.
      Histopathology, clinical chemistry, and organ weight changes were consistent with
      reported effects. Gene expression results demonstrated reasonable agreement
      between laboratories and across platforms. Discrepancies in expression profiles
      of some individual genes were largely due to platform differences and approaches
      to data analysis rather than to biological or interlaboratory variability.
      Despite these discrepancies there was overall agreement in the biological
      pathways affected by these compounds, demonstrating that transcriptional
      profiling is reproducible between laboratories and can reliably identify affected
      pathways necessary to provide mechanistic insight. This effort represents an
      important first step toward the use of transcriptional profiling in risk
      assessment.

PMID- 15033594
TI  - Cross-site comparison of gene expression data reveals high similarity.
AB  - Consistency and coherence of gene expression data across multiple sites depends
      on several factors such as platform (oligo, cDNA, etc.), environmental conditions
      at each laboratory, and data quality. The Hepatotoxicity Working Group of the
      International Life Sciences Institute Health and Environmental Sciences Institute
      consortium on the application of genomics to mechanism-based risk assessment is
      investigating these factors by comparing high-density gene expression data sets
      generated on two sets of RNA from methapyrilene (MP) experiments conducted at
      Abbott Laboratories and Boehringer-Ingelheim Pharmaceuticals, Inc. using a single
      platform (Affymetrix Rat Genome U34A GeneChip) at seven different sites. This
      article focuses on the evaluation of data quality and statistical models that
      facilitate the comparison of such data sets at the probe level. We present
      methods for exploring and quantitatively assessing differences in the data, with
      the principal goal being the generation of lists of site-insensitive genes
      responsive to low and high doses of MP. A combination of numerical and graphical
      techniques reveals important patterns and partitions of variability in the data,
      including the magnitude of the site effects. Although the site effects are
      significantly large in the analysis results, they appear to be primarily additive
      and therefore can be adjusted in the statistical calculations in a way that does
      not bias conclusions regarding treatment differences.

PMID- 15033595
TI  - Quantitative PCR deconstruction of discrepancies between results reported by
      different hybridization platforms.
AB  - Differences in hybridization platforms used in gene array analysis experiments
      can lead to significant differences in hybridization results. In this study we
      used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to
      investigate discrepant results between the National Institute of Environmental
      Health Sciences cDNA and Affymetrix oligo platforms used to evaluate hepatic gene
      expression changes in rats exposed to methapyrilene. Caldesmon cDNA platform
      hybridization results showed decreases in gene expression levels for the high
      dose methapyrilene 7-day pooled samples compared with their controls. By
      contrast, the Affymetrix oligonucleotide platform showed increases in expression
      levels for these samples. Quantitative gene expression measurements provide an
      explanation for the discrepancies observed for these samples. In the case of
      caldesmon, there is a 74-base sequence in the cDNA clone that is absent in the
      Affymetrix sequence. The amplicon based on the cDNA clone shows > 100-fold
      suppression relative to the day 7 high-dose methapyrilene-pooled control. These
      data demonstrate the importance of using a "gold standard," such as qRT-PCR to
      confirm key hybridization results as well as to understand the sources of
      discrepancies resulting from different hybridization platforms.

PMID- 15033593
TI  - Interlaboratory evaluation of rat hepatic gene expression changes induced by
      methapyrilene.
AB  - Several studies using microarrays have shown that changes in gene expression
      provide information about the mechanism of toxicity induced by xenobiotic agents.
      Nevertheless, the issue of whether gene expression profiles are reproducible
      across different laboratories remains to be determined. To address this question,
      several members of the Hepatotoxicity Working Group of the International Life
      Sciences Institute Health and Environmental Sciences Institute evaluated the
      liver gene expression profiles of rats treated with methapyrilene (MP). Animals
      were treated at one facility, and RNA was distributed to five different sites for
      gene expression analysis. A preliminary evaluation of the number of modulated
      genes uncovered striking differences between the five different sites. However,
      additional data analysis demonstrated that these differences had an effect on the
      absolute gene expression results but not on the outcome of the study. For all
      users, unsupervised algorithms showed that gene expression allows the distinction
      of the high dose of MP from controls and low dose. In addition, the use of a
      supervised analysis method (support vector machines) made it possible to
      correctly classify samples. In conclusion, the results show that, despite some
      variability, robust gene expression changes were consistent between sites. In
      addition, key expression changes related to the mechanism of MP-induced
      hepatotoxicity were identified. These results provide critical information
      regarding the consistency of microarray results across different laboratories and
      shed light on the strengths and limitations of expression profiling in drug
      safety analysis.

PMID- 15033592
TI  - Clofibrate-induced gene expression changes in rat liver: a cross-laboratory
      analysis using membrane cDNA arrays.
AB  - Microarrays have the potential to significantly impact our ability to identify
      toxic hazards by the identification of mechanistically relevant markers of
      toxicity. To be useful for risk assessment, however, microarray data must be
      challenged to determine reliability and interlaboratory reproducibility. As part
      of a series of studies conducted by the International Life Sciences Institute
      Health and Environmental Science Institute Technical Committee on the Application
      of Genomics to Mechanism-Based Risk Assessment, the biological response in rats
      to the hepatotoxin clofibrate was investigated. Animals were treated with high
      (250 mg/kg/day) or low (25 mg/kg/day) doses for 1, 3, or 7 days in two
      laboratories. Clinical chemistry parameters were measured, livers removed for
      histopathological assessment, and gene expression analysis was conducted using
      cDNA arrays. Expression changes in genes involved in fatty acid metabolism (e.g.,
      acyl-CoA oxidase), cell proliferation (e.g., topoisomerase II-Alpha), and fatty
      acid oxidation (e.g., cytochrome P450 4A1), consistent with the mechanism of
      clofibrate hepatotoxicity, were detected. Observed differences in gene expression
      levels correlated with the level of biological response induced in the two in
      vivo studies. Generally, there was a high level of concordance between the gene
      expression profiles generated from pooled and individual RNA samples.
      Quantitative real-time polymerase chain reaction was used to confirm modulations
      for a number of peroxisome proliferator marker genes. Though the results indicate
      some variability in the quantitative nature of the microarray data, this appears
      due largely to differences in experimental and data analysis procedures used
      within each laboratory. In summary, this study demonstrates the potential for
      gene expression profiling to identify toxic hazards by the identification of
      mechanistically relevant markers of toxicity.

PMID- 15033596
TI  - Overview on the application of transcription profiling using selected
      nephrotoxicants for toxicology assessment.
AB  - Microarrays allow for the simultaneous measurement of changes in the levels of
      thousands of messenger RNAs within a single experiment. As such, the potential
      for the application of transcription profiling to preclinical safety assessment
      and mechanism-based risk assessment is profound. However, several practical and
      technical challenges remain. Among these are nomenclature issues, platform
      specific data formats, and the lack of uniform analysis methods and tools.
      Experiments were designed to address biological, technical, and methodological
      variability, to evaluate different approaches to data analysis, and to understand
      the application of the technology to other profiling methodologies and to
      mechanism-based risk assessment. These goals were addressed using experimental
      information derived from analysis of the biological response to three
      mechanistically distinct nephrotoxins: cisplatin, gentamicin, and puromycin
      aminonucleoside. In spite of the technical challenges, the transcription
      profiling data yielded mechanistically and topographically valuable information.
      The analyses detailed in the articles from the Nephrotoxicity Working Group of
      the International Life Sciences Institute Health and Environmental Sciences
      Institute suggest at least equal sensitivity of microarray technology compared to
      traditional end points. Additionally, microarray analysis of these prototypical
      nephrotoxicants provided an opportunity for the development of candidate bridging
      biomarkers of nephrotoxicity. The potential future extension of these
      applications for risk assessment is also discussed.

PMID- 15033598
TI  - Dye bias correction in dual-labeled cDNA microarray gene expression measurements.
AB  - A significant limitation to the analytical accuracy and precision of dual-labeled
      spotted cDNA microarrays is the signal error due to dye bias. Transcript
      dependent dye bias may be due to gene-specific differences of incorporation of
      two distinctly different chemical dyes and the resultant differential
      hybridization efficiencies of these two chemically different targets for the same
      probe. Several approaches were used to assess and minimize the effects of dye
      bias on fluorescent hybridization signals and maximize the experimental design
      efficiency of a cell culture experiment. Dye bias was measured at the individual
      transcript level within each batch of simultaneously processed arrays by
      replicate dual-labeled split-control sample hybridizations and accounted for a
      significant component of fluorescent signal differences. This transcript
      dependent dye bias alone could introduce unacceptably high numbers of both false
      positive and false-negative signals. We found that within a given set of
      concurrently processed hybridizations, the bias is remarkably consistent and
      therefore measurable and correctable. The additional microarrays and reagents
      required for paired technical replicate dye-swap corrections commonly performed
      to control for dye bias could be costly to end users. Incorporating split-control
      microarrays within a set of concurrently processed hybridizations to specifically
      measure dye bias can eliminate the need for technical dye swap replicates and
      reduce microarray and reagent costs while maintaining experimental accuracy and
      technical precision. These data support a practical and more efficient
      experimental design to measure and mathematically correct for dye bias.

PMID- 15033599
TI  - Identification of platform-independent gene expression markers of cisplatin
      nephrotoxicity.
AB  - Within the International Life Sciences Institute Committee on Genomics, a working
      group was formed to focus on the application of microarray technology to
      preclinical assessments of drug-induced nephrotoxicity. As part of this effort,
      Sprague-Dawley rats were treated with the nephrotoxicant cisplatin at doses of
      0.3-5 mg/kg over a 4- to 144-hr time course. RNA prepared from these animals was
      run on a variety of microarray formats at multiple sites. A set of 93
      differentially expressed genes associated with cisplatin-induced renal injury was
      identified on the National Institute of Environmental Health Sciences (NIEHS)
      custom cDNA microarray platform using quadruplicate measurements of pooled animal
      RNA. The reproducibility of this profile of statistically significant gene
      changes on other platforms, in pooled and individual animal replicate samples,
      and in an independent study was investigated. A good correlation in response
      between platforms was found among the 48 genes in the NIEHS data set that could
      be matched to probes on the Affymetrix RGU34A array by UniGene identifier or
      sequence alignment. Similar results were obtained with genes that could be linked
      between the NIEHS and Incyte or PHASE-1 arrays. The degree of renal damage
      induced by cisplatin in individual animals was commensurate with the number of
      differentially expressed genes in this data set. These results suggest that gene
      profiles linked to specific types of tissue injury or mechanisms of toxicity and
      identified in well-performed replicated microarray experiments may be
      extrapolatable across platform technologies, laboratories, and in-life studies.

PMID- 15033597
TI  - Identification of putative gene based markers of renal toxicity.
AB  - This study, designed and conducted as part of the International Life Sciences
      Institute working group on the Application of Genomics and Proteomics, examined
      the changes in the expression profile of genes associated with the administration
      of three different nephrotoxicants--cisplatin, gentamicin, and puromycin--to
      assess the usefulness of microarrays in the understanding of mechanism(s) of
      nephrotoxicity. Male Sprague-Dawley rats were treated with daily doses of
      puromycin (5-20 mg/kg/day for 21 days), gentamicin (2-240 mg/kg/day for 7 days),
      or a single dose of cisplatin (0.1-5 mg/kg). Groups of rats were sacrificed at
      various times after administration of these compounds for standard clinical
      chemistry, urine analysis, and histological evaluation of the kidney. RNA was
      extracted from the kidney for microarray analysis. Principal component analysis
      and gene expression-based clustering of compound effects confirmed sample
      separation based on dose, time, and degree of renal toxicity. In addition,
      analysis of the profile components revealed some novel changes in the expression
      of genes that appeared to be associated with injury in specific portions of the
      nephron and reflected the mechanism of action of these various nephrotoxicants.
      For example, although puromycin is thought to specifically promote injury of the
      podocytes in the glomerulus, the changes in gene expression after chronic
      exposure of this compound suggested a pattern similar to the known proximal
      tubular nephrotoxicants cisplatin and gentamicin; this prediction was confirmed
      histologically. We conclude that renal gene expression profiling coupled with
      analysis of classical end points affords promising opportunities to reveal
      potential new mechanistic markers of renal toxicity.

PMID- 15033601
TI  - Annotation and cross-indexing of array elements on multiple platforms.
AB  - On the surface, transcript profiling using microarrays seems to offer a way of
      looking at the global response of the cell to perturbation, with a focus on
      changes in gene expression. The difficulty, however, is that the response of a
      particular gene is actually measured on the array by an element that is a short,
      defined nucleic acid sequence. Sequences that map back to the same genetic locus
      may actually be given different names and descriptions when they are deposited in
      public sequence databases; when such sequences are used in microarray
      construction, elements that monitor the same genetic locus may have different
      names and descriptions. The algorithm described here uses a hierarchical approach
      to assign a single best annotation to the elements in a given microarray in such
      a fashion that elements from one microarray platform may be cross-indexed with
      those of another. The algorithm relies on the nucleic acid accession number for a
      given array element, and uses that to retrieve annotation from the most recent
      versions of LocusLink and UniGene. Both database resources are searched, with a
      priority being given to annotation derived from the curated LocusLink database.
      In lieu of annotation found in these databases, the default GenBank annotation is
      used. As a final outcome, a cross-chip identifier is generated that may be used
      to cross-index array elements. The program is available as a practical extraction
      and report language (Perl) script that can run under any Perl interpreter.

PMID- 15033600
TI  - Database development in toxicogenomics: issues and efforts.
AB  - The marriage of toxicology and genomics has created not only opportunities but
      also novel informatics challenges. As with the larger field of gene expression
      analysis, toxicogenomics faces the problems of probe annotation and data
      comparison across different array platforms. Toxicogenomics studies are generally
      built on standard toxicology studies generating biological end point data, and as
      such, one goal of toxicogenomics is to detect relationships between changes in
      gene expression and in those biological parameters. These challenges are best
      addressed through data collection into a well-designed toxicogenomics database. A
      successful publicly accessible toxicogenomics database will serve as a repository
      for data sharing and as a resource for analysis, data mining, and discussion. It
      will offer a vehicle for harmonizing nomenclature and analytical approaches and
      serve as a reference for regulatory organizations to evaluate toxicogenomics data
      submitted as part of registrations. Such a database would capture the
      experimental context of in vivo studies with great fidelity such that the
      dynamics of the dose response could be probed statistically with confidence. This
      review presents the collaborative efforts between the European Molecular Biology
      Laboratory-European Bioinformatics Institute ArrayExpress, the International Life
      Sciences Institute Health and Environmental Science Institute, and the National
      Institute of Environmental Health Sciences National Center for Toxigenomics
      Chemical Effects in Biological Systems knowledge base. The goal of this
      collaboration is to establish public infrastructure on an international scale and
      examine other developments aimed at establishing toxicogenomics databases. In
      this review we discuss several issues common to such databases: the requirement
      for identifying minimal descriptors to represent the experiment, the demand for
      standardizing data storage and exchange formats, the challenge of creating
      standardized nomenclature and ontologies to describe biological data, the
      technical problems involved in data upload, the necessity of defining parameters
      that assess and record data quality, and the development of standardized
      analytical approaches.

PMID- 15033603
TI  - Silent advances.

PMID- 15033604
TI  - Microarrays demystified.

PMID- 15033602
TI  - Decoding the riddle: the dawn of RNAi for the study of gene-gene and gene
      environment interactions.

PMID- 15033605
TI  - RNAi: What's all the noise about gene silencing?

PMID- 15033606
TI  - Expression and immunity: new findings on Ahr interactions.

PMID- 15033609
TI  - An overview of the mitral regurgitation.

PMID- 15033608
TI  - Effective regurgitant orifice area of rheumatic mitral insufficiency: response to
      angiotensin converting enzyme inhibitor treatment.
AB  - OBJECTIVE: This study was designed for quantification of mitral regurgitation by
      echocardiographic measurements such as regurgitant volume (RV), regurgitant
      fraction (RF) and effective regurgitant orifice area (EROA), and to assess the
      effect of angiotensin converting enzyme inhibitor (ACEI) therapy on these
      measurements. METHODS: Patients with rheumatic mitral insufficiency were divided
      into two groups: Study group (SG)-10 females, 2 males, aged 10-18 years, body
      surface area 1.49+/-0.05 m2, receiving digoxin therapy for at least one year and
      Control group (CG)-8 females, 4 males, aged 8-17 years, body surface area 1.38+/
      0.07 m2, with no treatment. Patients in the two groups had no symptoms of cardiac
      failure. Angiotensin converting enzyme inhibitor therapy was given to SG patients
      on admission. Echocardiographic examinations were applied on admission and at the
      20th day of therapy with ACEI and digoxin. RESULTS: Study group's left
      ventricular end-diastolic volume (108.03+/-41.21 ml/m2), mitral stroke volume
      (510.37+/-321.58 ml/m2) and regurgitant volume (423.48+/-305.00 ml/m2) were
      significantly higher (p<0.05) on admission than in the CG (81.98+/-21.53 ml/m2,
      315.34+/-207.38 ml/m2 and 245.77+/-179.84 ml/m2, respectively). Aortic stroke
      volume at the 20th day of therapy was significantly higher in SG than in the CG.
      Therapy with ACEI decreased significantly SG's left ventricular end-diastolic
      volume. CONCLUSION: Angiotensin converting enzyme inhibitors should be started at
      an early stage of mitral regurgitation. The effective regurgitant orifice area is
      a feasible and easy method for the outpatient follow-up of mitral regurgitation.

PMID- 15033611
TI  - [Metabolic syndrome and coronary heart disease].

PMID- 15033610
TI  - [Metabolic syndrome in patients after coronary bypass surgery: prevalence and
      compliance with treatment].
AB  - OBJECTIVE: The aim of this study was to evaluate the prevalence of metabolic
      syndrome (MS) and its components, to determine the patients' compliance with
      pharmacological therapy and lifestyle modification, and to clarify the
      association of demographic and socioeconomic factors with the MS in Turkish
      patients with prior coronary artery bypass surgery (CABG). METHODS: Two hundred
      and seventy-three patients (age range 35-77, 208 men) were interviewed and
      examined 1.0-2.2 years after CABG. RESULTS: The prevalence of MS was 44.8% (55.4%
      among women and 41.3% among men). The most prevalent metabolic risk factor was
      visceral obesity among females, and elevated blood pressure among males. Rates
      for regular physical activity were lower in patients with MS, compared with those
      without MS (36.9% vs. 47.7%, p<0.05). Compared with patients without MS, use of
      aspirin was lower among patients with MS (84.4% vs. 93.4%, p<0.05). Logistic
      regression analysis revealed an independent association of age>65 years and low
      educational level with MS. CONCLUSION: We found a high prevalence of metabolic
      syndrome and its components among patients with prior CABG. Patients with MS had
      lower rate of regular physical activity and aspirin use, compared with those
      without MS.

PMID- 15033612
TI  - [Reexploration for bleeding and tamponade in intensive care unit following open
      heart surgery].
AB  - OBJECTIVE: Following open-heart surgery some patients can need reexploration in
      the intensive care unit due to bleeding or pericardial tamponade. This study
      evaluates the impact of reexploration in the intensive care unit (ICU) on
      morbidity and mortality rates. METHODS: Between January 1990 and January 2002
      overall 18,578 open heart surgery procedures were performed in our clinic and
      among them 570 (3%) patients required reexploration due to bleeding or
      pericardial tamponade. Reexplorations were done in the operating room (OR) in 385
      (67.5%) patients and in the ICU in 185 (32.5%) patients. RESULTS: Among patients
      383(67.2%) were male and 187(32.8%) were female. Mean age for reexploration in
      the OR group was 46.9+/-16.3 years, and in the ICU group was 48.2+/-15.7 years.
      The use of fresh frozen plasma and bank blood was significantly higher in the ICU
      group (p<0.0001). Fifty patients (27%) who were reexplored in ICU had intraaortic
      balloon pump (IABP) support (p<0.0001). Sixty-six patients (17.1%) died in OR
      group and 70 patients (37.8%) died in the ICU group (p<0.001). Following
      reexploration, 24 (6.2%) patients in the OR group and 17 (9.1%) patients in the
      ICU group had major infection (p>0.05). There was no statistically significant
      difference among groups in hospital stay time. CONCLUSION: Following open-heart
      surgery, especially among hemodynamically unstable patients, to avoid possible
      problems of transfer to the OR and time lost, explorations can be done in ICU.
      This practice does not increase morbidity and hospital stay.

PMID- 15033613
TI  - [Reexploration in the intensive care unit and open heart surgery].

PMID- 15033615
TI  - [Coronary bypass surgery in very young patients].

PMID- 15033614
TI  - [Middle and late-term results of coronary artery bypass graft surgery in very
      young (20-29 years) patients].
AB  - OBJECTIVE: The purpose of this study is to evaluate the etiologic factors of
      coronary artery disease (CAD) in very young patients. We want to indicate the
      importance of selection of the bypass graft materials and to investigate mid and
      long-term results of coronary artery bypass surgery (CABG) in young patients.
      METHODS: Coronary artery bypass surgery was performed in 7734 patients in Gulhane
      Military Medical Faculty between April 1991-June 2001. The study group included
      21 patients (0.027%). Mean age was 23.9+/-2.4 years. All risk factors were
      treated and control angiography was performed in 17 patients. RESULTS:
      Hyperlipidemia was found in 15 patients, smoking in 11, diabetes mellitus in 7,
      alcohol use in 6, obesity in 5 and, hypertension in 4 patients. We recognized
      Behcet's disease in two patients including complete form in one case and
      incomplete form in the other one. Left internal mammarian artery (IMA) was used
      in 21, left and right IMA in 4, and left and right IMA and radial artery grafts
      in 2 patients. Mean cross clamp time was 16.5+/-3.4 minutes and extubation time
      was 4.6+/-1.5 hours. Patients were discharged in 5.9+/-1.7 days. CONCLUSION: We
      determined a high graft patency rate in our patients during mid and long-term
      follow-up period due to the use of arterial grafts. To increase graft patency
      rate the importance of risk factors treatment should be taken into consideration.

PMID- 15033616
TI  - Epidemiological and pharmacological profile of congestive heart failure at
      Turkish academic hospitals.
AB  - OBJECTIVE: We aimed to investigate the status of the treatment of congestive
      heart failure (CHF) in academic hospitals in Turkey. METHODS: Overall 661
      successive patients from 16 academic hospitals were included in this
      retrospective study. In addition to treatments given to the patients before
      admission to hospital, during their hospital stay, and at hospital discharge,
      data regarding their functional classifications, causes of CHF, and laboratory
      findings were also recorded. RESULTS: In our study the mean age of patients was
      61+/-12 years and the mean hospital stay 10+/-6 days. Ischemic CHF was observed
      more frequently in men (72% vs. 46%, p<0.001), while hypertension and rheumatic
      CHF were more frequent in women (27% vs. 19%, p<0.001 and 24% vs. 9%, p<0.001
      respectively). While 90% of patients were in NYHA III-IV class at admission to
      hospital, only 2% of patients were in class IV at hospital discharge. The
      proportion of smokers was greater in men than in women (68% vs. 12%). Atrial
      fibrillation was present in 35% of patients. During hospitalization, angiotensin
      converting enzyme (ACE) inhibitors were used by 77%, diuretics by 95%, digitalis
      by 76%, nitrate by 85%, beta-blockers by 3%, aspirin by 86%, anticoagulants by
      44%, Ca antagonist by 10%, positive inotropic agents by 42%; and antiarrhythmic
      agents by 15% of patients. CONCLUSION: The use of ACE inhibitors, the major
      milestone of CHF treatment, is not on an adequate level yet. The use of beta
      blockers should also be encouraged.

PMID- 15033618
TI  - Association between angiotensin converting enzyme gene polymorphism and coronary
      artery disease in individuals of the South-Eastern Anatolian population.
AB  - OBJECTIVE: The deletion (D) allele of the angiotensin-converting enzyme (ACE)
      gene has been proposed as a genetic marker of the risk of coronary artery disease
      (CAD). In this study we aimed to determine the relevance of ACE gene polymorphism
      for coronary artery disease in the South-Eastern Anatolian population. METHODS:
      Angiotensin converting enzyme genotypes were determined in 133 CAD patients who
      underwent coronary angiography. Severity of CAD was subgrouped according to the
      number of stenotic vessels on coronary angiography. The control group was
      selected from 154 healthy volunteers. Angiotensin converting enzyme genotypes
      were determined by agarose gel sizing after polymerase chain reaction (PCR)
      amplification. RESULTS: Frequency of ACE DD genotype did not differ between
      patients with CAD and control subjects. However the ACE II genotype in CAD group
      was significantly less frequent than in control group (p=0.02). The relative
      risks were 0.9 (95% CI=0.56-1.43) for the DD genotypes, and 2.2 (95% CI=1.09 -
      4.11) for the II genotype. In the 2-vessel CAD subgroups, the II genotypes were
      significantly different from control group. CONCLUSION: Our study did not confirm
      the possibility that the ACE DD genotypes may be associated with predisposition
      to CAD in this certain population but there is a relationship between the least
      frequencies of the II genotype and CAD. The II genotype seems to be an
      independent protective factor for CAD in the South-Eastern Anatolian population.

PMID- 15033619
TI  - The future of medicine: molecular medicine in a changing world.

PMID- 15033617
TI  - [Femoral vascular complications after percutaneous coronary interventions].
AB  - OBJECTIVE: We aimed to investigate peripheral vascular complications and their
      relation with treatment and clinical parameters in percutaneous transluminal
      coronary angioplasty (PTCA) patients. METHODS: We included into the study 321
      patients (aged 57+/-11 years) underwent PTCA between November 2001-August 2002.
      The age, gender, glycoprotein 2b/3a use, thrombolytic use, intraaortic balloon
      treatment, transient pacemaker treatment, reintervention history, hypertension,
      diabetes mellitus, smoking status, family history and the correlations of these
      parameters with local vascular complications were assessed in all patients.
      RESULTS: Pseudoaneurysm incidence was significantly correlated with; age [(n=13,
      68.0%) p=0.0001, OR 8.38], female gender [(n=12, 63.1%) p<0.015, OR 0.32],
      reintervention [(n=10, 52.1%) p<0.004, OR 3.6], venous sheath usage [(n=12, 63%)
      p<0.0001, OR 9.07], thrombolytic treatment [(n=5, 26.3%) p<0.0001, OR 7.9], and
      intraaortic balloon adjustment [(n=6, 31.5%) p<0.0001, OR 7.2]. No correlation
      was found between pseudoaneurysm incidence and glycoprotein 2b/3a treatment,
      smoking, diabetes mellitus, hypertension and family history. CONCLUSION: The
      present study showed that patients of female gender, with reintervention,
      thrombolytic treatment, venous sheath use and intraaortic balloon adjustment are
      at high risk for serious femoral vascular complications, especially when they are
      aged. Additionally, glycoprotein 2b/3a agents can be used without increased risk
      of peripheral vascular complications.

PMID- 15033620
TI  - [Reduced coronary collateral vessel recruitment capacity in diabetes mellitus: an
      evidence for defective ischaemic tolerance].
AB  - OBJECTIVE: Collateral channel opening is one of the components of the ischemic
      tolerance developing during subsequent coronary balloon occlusions. The effect of
      diabetes mellitus (DM) on coronary collateral recruitment (CR) is still not
      known. We therefore sought the effect of DM on CR in patients with stable angina
      pectoris (SAP) by using intracoronary pressure measurement technique. METHODS:
      Study material consisted of 44 patients (21 diabetic) with SAP. All of the
      patients had single vessel disease with more than 70% vessel narrowing and all of
      them underwent stent implantation to this vessel. After angiography, fiber-optic
      pressure monitoring guidewire was advanced distal to the stenosis to be dilated.
      Myocardial fractional flow reserve (FFRmyo) was determined under adenosine
      hyperemia by the ratio of simultaneously measured mean distal pressure to mean
      aortic pressure. During subsequent two 1 minute balloon occlusions, distal
      pressures were recorded as coronary wedge pressure (CWP). Collateral flow index
      was determined by the ratio of simultaneously measured CWP to mean aortic
      pressure. Percentage of the improvement in the coronary flow index (CFI) (first
      to second occlusion) between two occlusions was determined for each patient.
      RESULTS: There was no difference between two groups in terms of pre-intervention
      FFRmyo (0.54 +/- 0.12 in DM group and 0.50 +/- 0.11 in non-DM group). The
      baseline CFI was significantly higher in non-DM group (0.26 +/- 0.09 versus 0.17
      +/- 0.08, p<0.03). Beyond this finding, mean CFI increased by 17% (from 0.17 +/-
      0.08 to 0.20 +/- 0.09) in DM group and by 30% (from 0.26 +/- 0.09 to 0.34 +/-
      0.10) in non- DM group. There was statistically significant difference between
      these two groups in terms of improvement in CFI during subsequent balloon
      occlusions (p<0.01). CONCLUSION: In addition to poor collateral vessels seen in
      patients with DM, CR is also impaired. This finding suggests that DM abolishes
      ischemic tolerance in terms of CR as well.

PMID- 15033621
TI  - [Aspirin resistance].
AB  - Aspirin is an effective antithrombotic agent for many patients. However, patients
      taking aspirin might exhibit variable responses to in vitro tests for platelet
      aggregation and might experience breakthrough thromboembolic events. Although
      this phenomenon has been called aspirin resistance, the lack of an uniform
      definition or agreement on diagnostic criteria precludes definitive
      recommendations at this time. Aspirin resistance has been defined in patients
      with cardiovascular, cerebrovascular, and peripheral vascular disease. In this
      article, mechanisms related with aspirin resistance and clinical background in
      which resistance is defined, are reviewed.

PMID- 15033622
TI  - The use of clopidogrel in patients with coronary artery disease.
AB  - Coronary thrombosis plays a central role in the development, progression, and
      complications of atherosclerotic heart disease. As a result, pharmacologic
      manipulation of the hemostatic system has been the mainstay of treatment for
      coronary artery disease. Since platelets are the most important cellular element
      in the development of arterial thrombosis, many of the most effective therapies
      have involved the use of various antiplatelet agents. This article focuses on
      clopidogrel, an antiplatelet agent belonging to the class of drugs known as the
      thienopyridines, in the treatment of patients with coronary artery disease.

PMID- 15033623
TI  - [Primary deep vein thrombosis of the upper extremity].

PMID- 15033624
TI  - [The right ventricular outflow tract reconstruction with "Contegra VenPro"
      heterologous conduit in the Ross procedure].

PMID- 15033625
TI  - Multiple hydatid cysts of pericardium and epicardium.

PMID- 15033626
TI  - [Staged subtotal replacement of aorta in progressive aneurysms in Marfan
      syndrome].

PMID- 15033627
TI  - Extensive venous obstruction caused by a permanent pacemaker lead: a case report.

PMID- 15033628
TI  - [Ablation and implantation of implantable cardioverter defibrillator in a case of
      hypertrophic cardiomyopathy with atrioventricular nodal reentrant tachycardia].

PMID- 15033629
TI  - [Surgery approach to a young patient with chronic pulmonary embolism, pulmonary
      thromboendarterectomy: a case report].

PMID- 15033630
TI  - The use of endomyocardial biopsy in paediatric heart transplant patients: an
      institutional approach.

PMID- 15033631
TI  - [Statin added to the therapy with ACE inhibitors in hypertensive patients].

PMID- 15033632
TI  - Isolated double orifice mitral valve.

PMID- 15033633
TI  - Papillary fibroelastoma of the aortic valve in a patient with syncope.

PMID- 15033634
TI  - Mid-ventricular obstructive hypertrophic cardiomyopathy with apical aneurysm.

PMID- 15033635
TI  - [A rare coronary artery anomaly: origin from the single ostium].

PMID- 15033637
TI  - Cloning and functional characterization of the human GLUT7 isoform SLC2A7 from
      the small intestine.
AB  - Facilitated glucose transporters (GLUTs) mediate transport of sugars across cell
      membranes by using the chemical gradient of sugars as the driving force. Improved
      cloning techniques and database analyses have expanded this family of proteins to
      a total of 14 putative members. In this work a novel hexose transporter isoform,
      GLUT7, has been cloned from a human intestinal cDNA library by using a PCR-based
      strategy (GenBank accession no. AY571960). The encoded protein is comprised of
      524 amino acid residues and shares 68% similarity and 53% identity with GLUT5,
      its most closely related isoform. When GLUT7 was expressed in Xenopus oocytes, it
      showed high-affinity transport for glucose (K(m) = 0.3 mM) and fructose (IC(50) =
      0.060 mM). Galactose, 2-deoxy-d-glucose, and xylose were not transported. Uptake
      of 100 microM d-glucose was not inhibited by 200 microM phloretin or 100 microM
      cytochalasin B. Northern blotting indicated that the mRNA for GLUT7 is present in
      the human small intestine, colon, testis, and prostate. Western blotting and
      immunohistochemistry of rat tissues with an antibody raised against the predicted
      COOH-terminal sequence confirmed expression of the protein in the small intestine
      and indicated that the transporter is predominantly expressed in the enterocytes'
      brush-border membrane. The unusual substrate specificity and close sequence
      identity with GLUT5 suggest that GLUT7 represents an intermediate between class
      II GLUTs and the class I member GLUT2. Comparison between these proteins may
      provide key information as to the structural determinants for the recognition of
      fructose as a substrate.

PMID- 15033636
TI  - VEGF causes pulmonary hemorrhage, hemosiderosis, and air space enlargement in
      neonatal mice.
AB  - To determine whether increased levels of VEGF disrupt postnatal lung formation or
      function, conditional transgenic mice in which VEGF 164 expression was enhanced
      in respiratory epithelial cells were produced. VEGF expression was induced in the
      lungs of VEGF transgenic pups with doxycycline from postnatal day 1 through 2 and
      6 wk of age. VEGF levels were higher in bronchoalveolar lavage fluid (BALF) and
      lung homogenates of VEGF transgenic mice compared with endogenous VEGF levels in
      controls. Neonatal mortality was increased by 50% in VEGF transgenic mice. Total
      protein content in BALF was elevated in VEGF transgenic mice. Surfactant protein
      B protein expression was unaltered in VEGF transgenic mice. Although postnatal
      alveolar and vascular development were not disrupted by VEGF expression, VEGF
      transgenic mice developed pulmonary hemorrhage, alveolar remodeling, and
      macrophage accumulation as early as 2 wk of age. Electron microscopy demonstrated
      abnormal alveolar capillary endothelium in the VEGF transgenic mice. In many
      locations, the endothelium was discontinuous with segments of attenuated
      endothelial cells. Large numbers of hemosiderin-laden macrophages and varying
      degrees of emphysema were observed in adult VEGF transgenic mice. Overexpression
      of VEGF in the neonatal lung increased infant mortality and caused pulmonary
      hemorrhage, hemosiderosis, alveolar remodeling, and inflammation.

PMID- 15033638
TI  - Genetic regulation of cilia assembly and the relationship to human disease.

PMID- 15033639
TI  - Primary human alveolar type II epithelial cell chemokine release: effects of
      cigarette smoke and neutrophil elastase.
AB  - An early response to cigarette smoke is an influx of leukocytes into the lung.
      Alveolar epithelial type II (ATII) cells may contribute by releasing chemokines
      in response to cigarette smoke and neutrophil elastase (NE). Human ATII cells
      were purified from normal regions of lungs resected for carcinoma (n = 14). In
      vitro, these cells exhibited ATII cell characteristics: lamellar bodies, apical
      microvilli, tight junctions, and expressed surfactant apoprotein C. Basal ATII
      cell release of five chemokines ranked as follows: monocyte chemotactic protein
      (MCP)-1 > interleukin (IL)-8 > growth-related oncogene (GRO)-alpha > macrophage
      inflammatory protein (MIP)-1alpha > regulated on activation, normal T cell
      expressed and secreted (RANTES). MIP-1alpha and RANTES were often not detectable.
      After stimulation with a mixture of lipopolysaccharide/endotoxin (LPS), tumor
      necrosis factor-alpha, IL-1beta, and IFN-gamma, MCP-1 and IL-8 secretion rose 4-6
      fold, whereas GRO-alpha rose 25-fold. NE stimulated IL-8 mRNA expression, and
      10nM NE stimulated IL-8 secretion; however, 100 nM NE caused a decrease in
      extracellular IL-8, MCP-1, and GRO-alpha, attributed to proteolysis. Cigarette
      smoke extract (CSE) inhibited IL-8 mRNA expression and release of all chemokines.
      Glutathione protected against the effects of CSE, suggesting oxidative
      mechanisms. GRO-alpha, important in growth and repair, was sensitive to both
      stimulation, by LPS:cytokines, and inhibition, by CSE. Thus, contrary to the
      original hypothesis, high concentrations of NE and CSE resulted in reduced
      extracellular chemokine levels. We hypothesize that reduced ATII cell-derived
      chemokine levels compromise alveolar repair, contributing to cigarette smoke
      induced alveolar damage and emphysema.

PMID- 15033640
TI  - Containing pandemic influenza with antiviral agents.
AB  - For the first wave of pandemic influenza or a bioterrorist influenza attack,
      antiviral agents would be one of the few options to contain the epidemic in the
      United States until adequate supplies of vaccine were available. The authors use
      stochastic epidemic simulations to investigate the effectiveness of targeted
      antiviral prophylaxis to contain influenza. In this strategy, close contacts of
      suspected index influenza cases take antiviral agents prophylactically. The
      authors compare targeted antiviral prophylaxis with vaccination strategies. They
      model an influenza pandemic or bioterrorist attack for an agent similar to
      influenza A virus (H2N2) that caused the Asian influenza pandemic of 1957-1958.
      In the absence of intervention, the model predicts an influenza illness attack
      rate of 33% of the population (95% confidence interval (CI): 30, 37) and an
      influenza death rate of 0.58 deaths/1,000 persons (95% Cl: 0.4, 0.8). With the
      use of targeted antiviral prophylaxis, if 80% of the exposed persons maintained
      prophylaxis for up to 8 weeks, the epidemic would be contained, and the model
      predicts a reduction to an illness attack rate of 2% (95% Cl: 0.2, 16) and a
      death rate of 0.04 deaths/1,000 persons (95% CI: 0.0003, 0.25). Such antiviral
      prophylaxis is nearly as effective as vaccinating 80% of the population.
      Vaccinating 80% of the children aged less than 19 years is almost as effective as
      vaccinating 80% of the population. Targeted antiviral prophylaxis has potential
      as an effective measure for containing influenza until adequate quantities of
      vaccine are available.

PMID- 15033641
TI  - Potential impact of conjugate pneumococcal vaccines on pediatric pneumococcal
      diseases.
AB  - Children younger than age 2 years have the highest rates of invasive pneumococcal
      disease and play an important role in its transmission. In the United States,
      seven pneumococcal serotypes cause approximately 80% of invasive disease and
      represent approximately 60% of middle-ear isolates in children younger than age 2
      years; the majority of penicillin-resistant strains are confined to these same
      few serogroups. Although unconjugated polysaccharide pneumococcal vaccines have
      demonstrated effectiveness in preventing invasive disease in adults, these
      vaccines fail to protect against otitis media or nasopharyngeal carriage and are
      poorly immunogenic in children younger than age 2 years. A new generation of
      pneumococcal vaccines has been developed, linking the capsular polysaccharide of
      seven to 11 serotypes to a protein carrier. The only pneumococcal vaccine
      approved to date for children younger than age 2 years is a seven-valent
      conjugate vaccine (PnCRM-7) (Prevnar; Wyeth Vaccines, Pearl River, New York),
      which contains serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. PnCRM-7 is more
      immunogenic than the polysaccharide pneumococcal vaccines and is 80-100%
      effective against vaccine-type invasive disease and 50-60% effective against
      vaccine-type pneumococcal otitis media. Routine immunization with pneumococcal
      conjugate vaccines should substantially reduce the morbidity, mortality, and
      costs associated with pneumococcal disease in children.

PMID- 15033642
TI  - Community-level predictors of pneumococcal carriage and resistance in young
      children.
AB  - Pneumococcal carriage and resistance vary markedly among communities and are not
      fully explained by individual predictors. Community risk factors may explain this
      variation. The authors geocoded addresses from a multicommunity sample of 710
      Massachusetts children previously swabbed for pneumococcal carriage in 2001.
      Using regression models, the authors evaluated associations between census tract
      measures and pneumococcal carriage or resistance. Living in census tracts with an
      average household size of more than 2.9 predicted carriage (odds ratio = 3.0, 95%
      confidence interval: 1.7, 5.5), and living in socioeconomically disadvantaged
      census tracts conferred an additional two- to threefold odds of carriage equal to
      attending child care. Living in a census tract with a median household income of
      less than $35,000 predicted carriage among nonattendees (odds ratio = 2.7, 95%
      confidence interval: 1.7, 4.3). The predictive value of a low-income census tract
      was interchangeable with any of several socioeconomic measures, including
      poverty, unemployment, low educational attainment, and low owner occupancy, in
      addition to high density of children and limited household plumbing facilities.
      Furthermore, living in census tracts with low educational attainment
      significantly predicted resistance (odds ratio = 4.0, 95% confidence interval:
      1.3, 12.7) and was interchangeable with a high density of children (odds ratio =
      3.5, 95% confidence interval: 1.0, 11.7). The two- to threefold odds of
      pneumococcal carriage conferred by certain community characteristics suggest that
      these measures may target communities for interventions to decrease transmission.

PMID- 15033644
TI  - Prospective study of gestational diabetes mellitus risk in relation to maternal
      recreational physical activity before and during pregnancy.
AB  - Physical activity has been associated with a reduced risk of gestational diabetes
      mellitus, but inferences have been hampered by recall and selection bias. The
      authors examined the relation between recreational physical activity before and
      during pregnancy and risk of gestational diabetes mellitus in a prospective
      cohort study. In 1996-2000, 909 normotensive, nondiabetic women in Seattle and
      Tacoma, Washington, were questioned during early gestation about physical
      activity performed during the year before and 7 days prior to the interview
      during pregnancy. Compared with inactive women, women who participated in any
      physical activity during the year before experienced a 56% risk reduction
      (relative risk (RR) = 0.44, 95% confidence interval (CI): 0.21, 0.91). Women
      spending >/=4.2 hours/week engaged in physical activity experienced a 76%
      reduction in gestational diabetes mellitus risk (RR = 0.24, 95% CI: 0.10, 0.64),
      and those expending >/=21.1 metabolic equivalent-hours/week experienced a 74%
      reduction (RR = 0.26, 95% CI: 0.10, 0.65) compared with inactive women. Physical
      activity during pregnancy was also associated with reductions in gestational
      diabetes mellitus risk. Women who engaged in physical activity during both time
      periods experienced a 69% reduced risk (RR = 0.31, 95% CI: 0.12, 0.79). Findings
      suggest that efforts to increase maternal physical activity may contribute to
      substantial reductions in gestational diabetes mellitus risk.

PMID- 15033643
TI  - Neighborhood socioeconomic environment and incidence of coronary heart disease: a
      follow-up study of 25,319 women and men in Sweden.
AB  - In this study, the authors examined whether neighborhood socioeconomic
      environment predicted incident coronary heart disease after adjustment for
      individual-level characteristics. A random sample of the Swedish population
      (25,319 women and men aged 35-74 years) was interviewed between 1986 and 1993 and
      was followed through December 1997 for incident coronary heart disease (1,189
      events). Neighborhood socioeconomic environment was defined by small-area market
      statistics (6,145 neighborhoods) and measured by two indicators: neighborhood
      education (proportion of people with less than 10 years of education in the
      neighborhood) and neighborhood income (proportion of people with incomes in the
      lowest national income quartile). Separate multilevel Cox proportional hazards
      models showed that low neighborhood education and low neighborhood income each
      predicted incident coronary heart disease after adjustment for age, sex, and
      individual-level education and income (hazard ratios were 1.25 and 1.23,
      respectively). The authors conclude that neighborhood socioeconomic environment
      predicts incident coronary heart disease, having a significant effect on coronary
      heart disease risk beyond the individual effect.

PMID- 15033645
TI  - Childhood growth and breast cancer.
AB  - Adult height is known to be positively associated with breast cancer risk. The
      mechanism underlying this association is complex, since adult height is
      positively correlated with age at menarche, which in turn is negatively
      associated with breast cancer risk. The authors used prospective data from a
      British cohort of 2,547 girls followed from birth in 1946 to the end of 1999 to
      examine breast cancer risk in relation to childhood growth. As expected, adult
      height was positively associated with age at menarche and breast cancer. In
      childhood, cases were taller and leaner, on average, than noncases. Significant
      predictors of breast cancer risk in models containing all components of growth
      were height velocity at age 4-7 years (for a one-standard-deviation increase,
      odds ratio (OR) = 1.54, 95% confidence interval (CI): 1.13, 2.09) and age 11-15
      years (OR = 1.29, 95% CI: 0.97, 1.71) and body mass index velocity (weight
      (kg)/height (m)(2)/year) at age 2-4 years (OR = 0.63, 95% CI: 0.48, 0.83). The
      effects of these variables were particularly marked in women with early menarche
      (age <12.5 years). These findings suggest that women who grow faster in childhood
      and reach an adult height above the average for their menarche category are at
      particularly increased risk of breast cancer.

PMID- 15033646
TI  - Change in blood lead concentration up to 1 year after a gunshot wound with a
      retained bullet.
AB  - The authors studied the time course and prevalence of elevated blood lead
      concentrations and associated injury- and patient-specific factors during the
      first year following gunshot injury. They determined blood lead levels at mean
      time points of 0.3, 3.1, 18.7, 94.5, 188.3, and 349.4 days after injury in a
      volunteer sample of 451 subjects from a Los Angeles, California, trauma center
      who sustained a first-time gunshot injury with a retained projectile in 2000
      2002. In mixed-model analyses, blood lead levels increased with time postinjury
      (p < 0.0005) up to 3 months, with number of retained fragments (p < 0.0005), and
      with increasing age (p < 0.0005). Increased blood lead concentration as a
      function of fragmentation was approximately 30% higher among subjects who had
      suffered bone fracture in the torso (p < 0.0005). Subjects with bullets or
      fragments lodged near bone (p < 0.0005) or near joints (p = 0.032) had higher
      blood lead levels. Logistic models correctly predicted a blood lead elevation of
      >/=20 micro g/dl in 81% and 85% of subjects at 3 and 6 months postinjury,
      respectively. The prevalence of elevated blood lead was 11.8% at 3 months and
      2.6% at 12 months. The authors recommend continued surveillance of blood lead
      levels after gunshot injury for patients with key indicators.

PMID- 15033647
TI  - Pancreatic cancer and drinking water and dietary sources of nitrate and nitrite.
AB  - N-Nitroso compounds, known animal carcinogens, are formed endogenously from
      drinking water and dietary sources of nitrate and nitrite. The authors conducted
      a population-based case-control study of pancreatic cancer in Iowa to determine
      whether increased consumption of nitrate and nitrite from drinking water and
      dietary sources was associated with risk. They linked detailed water source
      histories to nitrate measurements for Iowa community water supplies. After
      exclusions for insufficient data, 1,244 controls and 189 pancreatic cancer cases
      were available for analysis. Among controls, the median average nitrate level
      (1960-1987) was 1.27 (interquartile range, 0.6-2.8) mg of nitrate nitrogen per
      liter of water. No association was observed between pancreatic cancer risk and
      increasing quartiles of the community water supplies' nitrate level. Increasing
      intake of dietary nitrite from animal sources was associated with an elevated
      risk of pancreatic cancer among men and women (highest quartile odds ratios =
      2.3, 95% confidence interval: 1.1, 5.1, for men and 3.2, 95% confidence interval:
      1.6, 6.4, for women). In contrast, dietary nitrate intake showed an inverse
      association with risk among women and no association among men. This study
      suggests that long-term exposure to drinking water nitrate at levels below the
      maximum contaminant level of nitrate nitrogen (10 mg/liter) is not associated
      with pancreatic cancer; however, the consumption of dietary nitrite from animal
      products may increase risk.

PMID- 15033648
TI  - A modified poisson regression approach to prospective studies with binary data.
AB  - Relative risk is usually the parameter of interest in epidemiologic and medical
      studies. In this paper, the author proposes a modified Poisson regression
      approach (i.e., Poisson regression with a robust error variance) to estimate this
      effect measure directly. A simple 2-by-2 table is used to justify the validity of
      this approach. Results from a limited simulation study indicate that this
      approach is very reliable even with total sample sizes as small as 100. The
      method is illustrated with two data sets.

PMID- 15033649
TI  - Evaluation of mortality data for older Mexican Americans: implications for the
      Hispanic paradox.
AB  - The authors evaluated underascertainment bias in Hispanic mortality rates from
      population surveys linked to the US National Death Index (NDI). They compared
      vital status through 7 years ascertained from an NDI search and from active
      follow-up for 2,886 Mexican-American subjects, aged >/=65 years at baseline in
      1993-1994, from the Hispanic Established Populations for Epidemiologic Studies of
      the Elderly (EPESE). Estimates of NDI underascertainment were applied to
      mortality rate ratios for 66,667 older Mexican Americans and non-Hispanic Whites
      from the 1986-1994 National Health Interview Surveys linked to the NDI. The NDI
      and active follow-up agreed on vital status for 91.2% of Hispanic EPESE subjects.
      The NDI did not identify 177 deaths (20.7%) reported by proxies.
      Underascertainment was greater for women and when stratified by age and nativity.
      The ratios of proxy-reported to NDI mortality rates were 1.31 (95% confidence
      interval (CI): 1.06, 1.62) for immigrant men and 1.65 (95% CI: 1.32, 2.08) for
      immigrant women. Before adjustment, National Health Interview Surveys-NDI age
      standardized mortality rate ratios comparing Mexican Americans with non-Hispanic
      Whites were 0.77 (95% CI: 0.65, 0.92) for men and 0.92 (95% CI: 0.77, 1.09) for
      women but were 0.84 and 1.18, respectively, with adjustment for
      underascertainment. Findings suggest that NDI-based Hispanic mortality rates may
      be understated.

PMID- 15033650
TI  - Re: "Childhood cancer and population mixing".

PMID- 15033651
TI  - Re: "Childhood cancer and population mixing".

PMID- 15033652
TI  - Re: "Risk analysis of aseptic meningitis after measles-mumps-rubella vaccination
      in Korean children by using a case-crossover design".

PMID- 15033656
TI  - Evolving trends in hematopoietic cell transplantation for solid tumors: tempering
      enthusiasm with clinical reality.

PMID- 15033655
TI  - True infliximab resistance in rheumatoid arthritis: a role for lymphotoxin alpha?
AB  - BACKGROUND: The combination of methotrexate and the anti-tumour necrosis factor
      alpha (TNFalpha) antibody infliximab is a very effective treatment for rheumatoid
      arthritis (RA). However, a proportion of patients are not responsive to this
      treatment. Inefficacy may represent a TNFalpha independent disease or
      insufficient drug at the site of action. CASE REPORT: A patient with RA resistant
      to repeated high dose infliximab infusions and intra-articular infliximab into an
      inflamed knee is described. No beneficial clinical effect was observed. Pre
      injection arthroscopic biopsy of the study knee demonstrated TNFalpha staining
      but also confirmed the presence of lymphotoxin alpha (LTalpha or TNFbeta) on
      immunohistochemistry. Subsequent treatment with etanercept (which blocks LTalpha
      as well as TNFalpha) resulted in clinical remission of disease. CONCLUSION: This
      case suggests that resistance to TNF blockade may occur when TNFalpha is not the
      dominant inflammatory cytokine and suggests that LTalpha may have a pathogenic
      role in RA.

PMID- 15033657
TI  - Is overall survival a realistic primary end point in advanced colorectal cancer
      studies? A critical assessment based on four clinical trials comparing
      fluorouracil plus leucovorin with the same treatment combined either with
      oxaliplatin or with CPT-11.
AB  - BACKGROUND: The adequacy of overall survival (OS) as study end point in phase III
      trials for advanced solid tumors is questionable. The present review highlights
      the limits of OS as study end point to evaluate the efficacy of new drugs.
      METHODS: Four phase III clinical trials comparing a fluorouracil-based regimen
      with the same regimen plus either CPT-11 or oxaliplatin in advanced colorectal
      cancer patients were reviewed. The primary aim of the critical assessment was to
      explain the lack of OS advantage observed in two of the four trials, despite the
      presence of increased response rate (RR) and time to progression (TTP). Four
      possible reasons for the lack of OS benefit (i.e. statistical power, cross-over,
      magnitude of the effect on RR and TTP, non-tumor-related deaths) were
      systematically reviewed in the trials, and the detectable 1-year OS difference,
      assuming a statistical power of 80%, was calculated for each. RESULTS: None of
      these reasons for the lack of OS advantage in presence of RR and TTP benefits
      convincingly explained the results of the evaluated trials. Three of the four
      trials had roughly the same statistical power to detect 1-year OS differences,
      while the fourth trial was underpowered to detect realistic OS differences. The
      lack of OS advantage observed in the two oxaliplatin trials is therefore likely
      fortuitous, and due to lack of statistical power. CONCLUSIONS: Although increase
      in OS remains the ultimate goal of many clinical trials, the choice of OS benefit
      as a mandatory requirement to register new compounds can lead to a serious
      underestimation of a drug's real efficacy.

PMID- 15033658
TI  - Treatment for Waldenstrom's macroglobulinemia.
AB  - Waldenstrom's macroglobulinemia is a rare form of indolent lymphoma characterized
      by the production of a monoclonal immunoglobulin M protein, and complications
      such as hyperviscosity, cytopenias and peripheral neuropathy. Conventional
      treatment approaches are based on alkylators or nucleoside analogs, but in the
      absence of a clearly superior regimen, a broad array of alternative therapies
      exists. Choices range from biological agents to combination chemotherapy to stem
      cell transplantation. A rational approach therefore must be based on careful
      patient assessment and individualization of therapy.

PMID- 15033659
TI  - Phase I/II trial of irinotecan plus high-dose 5-fluorouracil (TTD regimen) as
      first-line chemotherapy in advanced colorectal cancer.
AB  - BACKGROUND: We conducted a phase I/II study of weekly irinotecan [30 min
      intravenous (i.v.) infusion] combined with 5-fluorouracil (5-FU 3 g/m(2) weekly
      48 h i.v. infusion, TTD regimen) as first-line chemotherapy for patients with
      advanced colorectal cancer (CRC). PATIENTS AND METHODS: The maximum tolerated
      dose (MTD) and the dose-limiting toxicity (DLT) in the treatment of
      gastrointestinal solid tumors (in phase I), and the antitumor activity and
      toxicity of the recommended phase I dose (in phase II) were determined. RESULTS:
      Diarrhea was the DLT, and irinotecan 80 mg/m(2) plus 5-FU 3 g/m(2) was the
      recommended phase I dose. In phase II, the confirmed response rate was 44% [95%
      confidence interval (CI) 29% to 59%] and the median overall survival was 23.8
      months. However, grade 3/4 diarrhea affected 59% of patients and led to
      withdrawal of three patients. A second cohort of patients studied using the same
      schedule but with a reduced 5-FU starting dose of 2.25 g/m(2) showed improved
      tolerance (the incidence of grade 4 diarrhea decreased from 28% to 11% and
      overall grade 3/4 diarrhea to 56%, with no patient withdrawals) but the confirmed
      response rate was 28% (95% CI 14% to 45%) and median overall survival was 17.2
      months. CONCLUSIONS: We found weekly irinotecan 80 mg/m(2) plus TTD regimen (5-FU
      2.25 g/m(2) given as 48-h i.v. infusion) to be a feasible and active combined
      chemotherapy for the first-line treatment of advanced colorectal cancer.

PMID- 15033660
TI  - Weekly 5-fluorouracil and leucovorin: achieving lower toxicity with higher dose
      intensity in adjuvant chemotherapy after colorectal cancer resection.
AB  - BACKGROUND: Current standard therapy following resection of high-risk colon
      cancer is intravenous bolus 5-fluorouracil (5-FU) with leucovorin (LV), but there
      is no consensus on the optimum regimen of these drugs: practice ranges from the
      high toxicity Mayo Clinic schedule to the very low toxicity weekly QUASAR
      schedule. We present data for a weekly schedule that aims to provide moderately
      dose-intense treatment with low toxicity. PATIENTS AND METHODS: One hundred and
      sixty-two patients were studied: 60% male; median age 65 years (36% over 70
      years); 94% colorectal primary. Treatment was intravenous bolus (5 min) 5-FU 425
      mg/m(2) plus D,L-LV 45 mg flat rate once weekly, for a planned 24 weeks. Data for
      toxicity, dose-reductions, delays and stoppages were collected. RESULTS: Overall,
      20% of patients experienced any grade > or = 3 toxicity, most commonly diarrhoea
      (14% patients). Dose reductions were made in 35% of patients (although only 21%
      required 20% or more reduction); toxicity contributed to a decision to stop
      treatment before 24 weeks in 16% of patients. Median delivered dose intensity
      (DI) was 96% of planned (407 mg/m(2)/week) during treatment, and 91% of planned
      (385 mg/m(2)/week) over the full 24 week treatment plan. Female sex and age >70
      years were significantly associated with higher rates of toxicity and dose
      adjustment, and lower delivered DI. CONCLUSIONS: Weekly treatment at these doses
      is convenient and well-tolerated for the large majority of patients, and achieves
      DI comparable with the 5 days a month QUASAR schedule and other more toxic
      standard regimens.

PMID- 15033661
TI  - Prognostic significance of the expression of Smad4 and Smad7 in human gastric
      carcinomas.
AB  - BACKGROUND: Transforming growth factor-beta (TGF-beta) modulates the growth and
      function of many cells, including those with malignant transformation. Smad
      proteins have been identified as major components in the intracellular signaling
      of TGF-beta family members. PATIENTS AND METHODS: To clarify the correlations
      between clinicopathologic profiles and the patient's survival, the expression of
      common mediator Smad (Smad4) and inhibitory Smad (Smad7) were evaluated
      immunohistochemically in 304 consecutive gastric carcinomas using the tissue
      array method. RESULTS: Positive Smad4 expression was observed in 266 (87.5%)
      tumors and positive Smad7 expression in 98 (32.2%) tumors. The prognosis of
      patients with a Smad4-positive tumor was significantly better than that of the
      patients with a negative tumor. The survival rate was significantly higher in
      patients with negative Smad7 expression than those with positive Smad7
      expression. In subgroup analysis according to TNM (tumour-node-metastasis) stage,
      both Smad4 and Smad7 showed most significant prognostic differences in stage I
      gastric cancer patients. Multivariate analysis indicated that tumor size, depth
      of invasion, lymph node metastasis and Smad7 expression were independent
      prognostic factors. CONCLUSION: Enhanced expression of the TGF-beta signaling
      inhibitor Smad7 may present one of the novel mechanisms of TGF-beta resistance in
      human gastric carcinomas.

PMID- 15033662
TI  - Glycemic index, glycemic load and risk of gastric cancer.
AB  - BACKGROUND: Dietary carbohydrates have been directly associated with gastric
      cancer risk and have been considered general indicators of a poor diet. However,
      elevated levels of glucose and insulin elicited by consumption of high amounts of
      refined carbohydrates may stimulate mitogenic and cancer-promoting insulin-like
      growth factors (IGF). Glycemic index (GI) and glycemic load (GL), which represent
      indirect measures of dietary insulin demand, were analysed to understand further
      the association between carbohydrates and gastric cancer. PATIENTS AND METHODS:
      Data were derived from a hospital-based case-control study on gastric cancer,
      conducted in Italy between 1985 and 1997, including 769 cases with incident,
      histologically confirmed gastric cancer and 2081 controls admitted to the same
      hospital network as cases for acute, non-neoplastic diseases. All subjects were
      interviewed using a reproducible food frequency questionnaire. RESULTS: The
      multivariate odds ratios (OR) for subsequent quartiles of dietary GL were 1.44
      [95% confidence interval (CI) 1.11-1.87], 1.62 (95% CI 1.24-2.12) and 1.94 (95%
      CI 1.47-2.55). No consistent pattern of risk was seen with GI. The associations
      were consistent in different strata of age, education and body mass index, and
      were stronger in women. CONCLUSIONS: This study supports the hypothesis of a
      direct association between GL and gastric cancer risk, thus providing an
      innovative interpretation, linked to excess circulating insulin and related IGFs,
      for the association between carbohydrates and risk of gastric cancer.

PMID- 15033663
TI  - A phase II study of escalated-dose docetaxel with granulocyte colony-stimulating
      factor support in patients with advanced breast cancer.
AB  - PURPOSE: Docetaxel is highly active in the treatment of patients with breast
      cancer. The principal dose-limiting toxicities of the 3-weekly regimen are
      neutropenia and febrile neutropenia. In a previous phase I dose-escalation study
      with granulocyte colony-stimulating factor (G-CSF) support, the recommended dose
      was determined to be docetaxel 160 mg/m(2) 3-weekly. The objectives of this phase
      II study were to determine the response rate and toxicity of this dose and
      schedule, given as first-line in patients with advanced breast cancer.
      Mobilisation of peripheral blood stem cells (PBSCs) was also investigated.
      PATIENTS AND METHODS: Eligible women had metastatic breast cancer and were aged
      18-75 years with ECOG performance status < or =2. Strict criteria for liver
      function were followed, and adjuvant chemotherapy must have been completed at
      least 6 months previously. Treatment was docetaxel 160 mg/m(2) over 60-90 min
      every 21 days with G-CSF 5 micro g/kg/day until neutrophil recovery, for up to
      six cycles. A 3-day corticosteroid prophylaxis was given. Bloods samples to
      determine PBSC levels [CD34+, granulocyte-macrophage colony-forming cells (GM
      CFC) and burst-forming units-erythroid (BFU-E)] were taken on days 6, 8, 9 and 11
      following docetaxel. RESULTS: Twenty-five women with median age 50 years (range
      35-66) were included. Seventeen (68%) had previously received adjuvant
      chemotherapy. In total, 112 cycles were delivered (median four per patient), with
      dose reductions required in 12.5% of cycles. G-CSF was given for a median of 6
      days. The median neutrophil nadir was 0.5 x 10(9)/l and occurred a median 5 days
      after treatment. The median duration of grade 3 or 4 neutropenia was 2 days
      (range 1-7). Grade 4 neutropenia occurred in 44% of patients, but there was only
      one episode of febrile neutropenia. Five patients were taken off study due to
      toxicities that included oedema, neurosensory toxicity and asthenia. Confirmed
      partial response was seen in nine patients (37.5%; 95% confidence interval 19% to
      59%). CD34+ cells, GM-CFC and BFU-E levels peaked at day 8 following docetaxel
      administration. The median CD34+ cell peak was 6.5 x 10(4)/ml, with only 20% of
      patients <2 x 10(4)/ml, a level below which leukapheresis is not usually
      attempted. CONCLUSIONS: Docetaxel 160 mg/m(2) was delivered with G-CSF support
      with a very low rate of febrile neutropenia. Non-haematological toxicity was
      significant, causing five patients to go off study. Effective mobilisation of
      PBSCs was seen. The response rate of 37.5% was less than that obtained in first
      line studies using standard-dose docetaxel 100 mg/m(2), suggesting that there is
      no additional benefit in dose escalation of this cytotoxic agent in breast cancer
      patients using this schedule.

PMID- 15033665
TI  - c-KIT expression and correlation with chemotherapy resistance in ovarian
      carcinoma: an immunocytochemical study.
AB  - BACKGROUND: Recent studies have shown that several tumours express c-KIT, a
      growth factor receptor with tyrosine kinase activity; moreover, clinical results
      have shown the efficacy of the tyrosine kinase inhibitor, STI571, in c-KIT
      positive tumours. The aim of this study was to determine the incidence and
      correlation with chemotherapy resistance of c-KIT expression in advanced serous,
      low grade of differentiation, ovarian carcinoma. PATIENTS AND METHODS: We
      performed an immunohistochemistry analysis of 56 patients with advanced serous
      ovarian carcinomas using archival paraffin-embedded specimens. RESULTS: Intense c
      KIT immunostaining was observed in 51.7% of cases. c-KIT expression was
      statistically correlated with progression of disease after first-line
      chemotherapy (P = 0.029). CONCLUSIONS: c-KIT is also expressed in ovarian
      carcinoma and it is statistically correlated with chemotherapy resistance. This
      study suggests the necessity for clinical trials confirming the utility of the
      tyrosine kinase inhibitor, STI571, in ovarian advanced cancer patients with c-KIT
      overexpression when these patients have shown no clinical response to
      conventional chemotherapy.

PMID- 15033664
TI  - Factor V Leiden and G20210A prothrombin mutation and the risk of subclavian vein
      thrombosis in patients with breast cancer and a central venous catheter.
AB  - BACKGROUND: To analyze the influence of the prothrombotic gene mutation factor V
      G1691A (factor V Leiden) and prothrombin G20210A on the risk of a first episode
      of catheter-related deep venous thrombosis (DVT) in a group of patients with
      breast cancer treated with chemotherapy. PATIENTS AND METHODS: Between January
      1999 and February 2001, the occurrence of a first symptomatic DVT was
      investigated in a cohort of 300 consecutive patients with locally advanced or
      metastatic breast cancer treated at a single institution with fluorouracil-based
      chemotherapy, administered continuously through a totally implanted access port.
      A nested case-control study included 25 women (cases) with catheter-related DVT
      and 50 controls without DVT matched with cases for age, identical chemotherapy,
      stage of disease and prognostic features. The G1691A factor V and G20210A
      prothrombin mutation genotypes were analyzed. RESULTS: Five cases [20%; 95%
      confidence interval (CI) 9% to 39%)] and two controls (4%; 95% CI 1% to 14%) were
      heterozygous carriers of G1691A factor V (P = 0.04). The age-adjusted odds ratio
      for catheter-related DVT was 6.1 (95% CI 1.1-34.3). Only one patient (case) had
      the G20210A prothrombin gene mutation. Time from start of chemotherapy infusion
      to DVT was not significantly different between patients with (median 31 days) and
      without (median 43 days) G1691A factor V mutation (P = 0.6). CONCLUSIONS: Factor
      V Leiden carriers with locally advanced or metastatic breast cancer have an
      increased risk of developing catheter-related DVT during chemotherapy.

PMID- 15033667
TI  - Clinical outcome after laparoscopic pure management of borderline ovarian tumors:
      results of a series of 34 patients.
AB  - BACKGROUND: The aim of this study was to assess clinical outcome after
      laparoscopic treatment of borderline ovarian tumor (BOT). PATIENTS AND METHODS:
      Thirty-four patients treated initially and/or for recurrent disease using a
      laparoscopic approach for BOT from 1984 to January 2002. RESULTS: Thirty-four
      patients underwent laparoscopic pure treatment (without conversion by laparotomy
      and/or reassessment surgery by laparotomy) for BOT. Conservative treatment was
      performed in 31 (91%) patients. Median follow-up time was 45 months (range 6
      228). Six (17%) patients recurred (in the remaining ovary following conservative
      surgery in five patients and in the peritoneum in one patient). Two port-site
      metastases were observed. None of the patients had recurrent disease in the form
      of ovarian carcinoma. Nine spontaneous pregnancies were observed in six patients
      from a group of 15 patients desiring pregnancy. All patients are alive today and
      disease-free. CONCLUSION: These results seem to demonstrate that laparoscopic
      treatment can be safely performed in young patients with early stage BOT. Such a
      procedure is then feasible, but should be evaluated in patients with BOT and
      peritoneal implants.

PMID- 15033666
TI  - Familial risk of endometrial cancer after exclusion of families that fulfilled
      Amsterdam, Japanese or Bethesda criteria for HNPCC.
AB  - BACKGROUND: Endometrial cancer is the second most common lesion within hereditary
      non-polyposis colorectal cancer (HNPCC) syndrome. The importance of the non-HNPCC
      genetic predisposition to endometrial cancer is unclear, and the familial
      aggregation of endometrial cancer after exclusion of HNPCC families may offer
      valuable clues about the involvement of non-HNPCC-related genes. PATIENTS AND
      METHODS: The families of the nationwide Swedish Family-Cancer Database were
      classified as HNPCC families according to the Amsterdam I or II, the modified
      Amsterdam, the Japanese and the Bethesda criteria. Standardized incidence ratios
      (SIRs) for endometrial cancer when parents or siblings were diagnosed with cancer
      at the most common sites were calculated before and after exclusion of HNPCC
      families. RESULTS: The proportion of individuals in the families with endometrial
      cancer was highest when the criteria required three cancers within a family or
      multiple HNPCC-related cancers in the same individual. Consideration of the
      Amsterdam or the Japanese criteria hardly reduced the familial aggregation of
      endometrial cancer. After exclusion of families that fulfilled the Bethesda
      criteria, SIRs were significant when the parents were diagnosed with endometrial
      or thyroid gland cancers; 75.7% (95% confidence interval 60% to 99.1%) of the
      familial cases of endometrial cancer were not related to HNPCC according to the
      Bethesda criteria. The reduction of SIRs for cancers at the colon, pancreas,
      prostate and ovary was limited when the Bethesda criteria were applied. However,
      the Bethesda criteria identified most of the familial aggregation when
      endometrial cancers were diagnosed before the age of 55 years. CONCLUSIONS: The
      data suggest that additional effects, not related to HNPCC, contribute to the
      familial aggregation of endometrial cancer.

PMID- 15033668
TI  - Targeting pulmonary metastases of renal cell carcinoma by inhalation of
      interleukin-2.
AB  - INTRODUCTION: Pulmonary metastases of renal cell carcinoma (RCC) are associated
      with poor prognosis. Inhalation therapy with interleukin-2 (IL-2) is thus an
      appealing method for palliation. This multicenter study summarizes the national
      experience of IL-2 inhalation in patients with lung metastases of RCC. PATIENTS
      AND METHODS: Forty patients (median, 66.5 years of age) with radiologically
      documented progressing pulmonary metastases were enrolled. All patients had to be
      able to comply with inhalation technique, and were not candidates for other
      treatment options. Twenty-eight patients were systemic treatment-naive. The
      protocol included three daily inhalations of IL-2 to a total dose of 18 MU.
      Treatment had to be continued until one of the following occurred: progression; a
      complete response; a life threatening toxicity; or patient refusal. Response was
      assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) system.
      RESULTS: The disease-control rate reached 57.5%, with a partial response rate of
      2.5% and a disease stabilization rate of 55%. Median time to progression was 8.7
      months. The main side-effects were cough and weakness. CONCLUSIONS: Inhalation of
      IL-2 for the treatment of pulmonary metastases in RCC is feasible, tolerable and
      beneficial in controlling progressive disease for considerable periods of time.
      The definition of response of biological therapy may need to be re-assessed and
      modified: stable disease should be regarded as a favorable response.

PMID- 15033670
TI  - Radiation therapy versus chemotherapy as initial treatment for localized nasal
      natural killer (NK)/T-cell lymphoma: a single institute survey in Taiwan.
AB  - BACKGROUND: To clarify the role of intention to treat for patients with localized
      nasal natural killer (NK)/T-cell lymphoma, and to determine the prognostic
      factors for these patients. PATIENTS AND METHODS: We conducted a retrospective
      review of 46 patients with localized nasal NK/T-cell lymphomas treated at a
      single institute between January 1988 and July 2002. RESULTS: The type of
      intended treatment was a significant factor for overall survival (OS) (5-year OS:
      RT versus CT = 83.3% versus 28.6%, P = 0.0269) or failure-free survival (FFS) (5
      year FFS: RT versus CT = 83.3% versus 27.1%, P = 0.0247). In the intended
      chemotherapy group, salvage with radiotherapy was superior to chemotherapy alone
      for OS (5-year OS: 42.2% versus 20.0%, P = 0.0252) or FFS (5-year FFS: 41.0%
      versus 20.0%, P = 0.0352). On multivariate analysis, both N stage and serum
      lactate dehydrogenase level were independent factors for OS and FFS. No
      radiotherapy was an independent adverse factor for OS; advanced T stage and more
      than one extranodal involvement were independent adverse factors for FFS.
      CONCLUSIONS: Patients with localized nasal NK/T-cell lymphomas were better
      managed with radiotherapy as front-line therapy. The advantage of radiotherapy
      persisted even as palliative therapy after chemotherapy.

PMID- 15033671
TI  - Hodgkin's lymphoma in Chinese migrants to British Columbia: a 25-year survey.
AB  - BACKGROUND: Compared with the West, Hodgkin's lymphoma in Oriental countries is
      characterized by a lower incidence rate and a higher proportion of mixed
      cellularity histology. Both environmental and genetic factors may be involved.
      PATIENTS AND METHODS: The incidence and pattern of pathology of Hodgkin's
      lymphoma in the migrant Chinese population (0.4 million) in British Columbia
      (population 3.2 million) were studied. From a computerized database, all
      Hodgkin's lymphoma cases diagnosed in British Columbia from 1970 to 1997 were
      identified. Chinese descent was determined using patient surname by standard
      methodology and verified from the treatment record or by patient interview. The
      corresponding figures from the Chinese population in Hong Kong were used for
      comparison. For incidence rates, the age-specific incidence of Hodgkin's lymphoma
      in Hong Kong was obtained from the government cancer registry. For comparison of
      histology subtypes, 200 Hodgkin's lymphoma records from a Hong Kong regional
      referral center for the same time period were reviewed. Crude and age
      standardized incidence rates were calculated by 5-year intervals in terms of age
      and calendar year, and relative rates were compared between the three
      populations. RESULTS: From 1970 to 1997, Hodgkin's lymphoma was diagnosed in 34
      Chinese patients in BC, with 24 cases diagnosed from 1970 to 1994. Thus, the
      crude and age-adjusted incidence rates from 1970 to 1994 were 0.91 and 1.14 per
      100,000 per year in the British Columbia Chinese migrant population. Within the
      same period, 1862 cases of Hodgkin's lymphoma were diagnosed in British Columbia,
      giving a provincial background crude and age-adjusted incidence rates of 5.2 and
      4.87 per 100,000 per year. The number of cases in the Hong Kong Chinese
      population (1970-1994) was 404, giving crude and age-adjusted incidence rates of
      0.32 and 0.31 per 100,000 per year, respectively. Corrected for age and calendar
      year trends, the observed 25-year incidence of Hodgkin's lymphoma in British
      Columbia Chinese was significantly lower than expected from the British Columbia
      background population [24 observed versus 71 expected cases; standardized
      incidence ratio (SIR) = 0.34; 90% confidence interval (CI) 0.24-0.48; P <0.0001].
      On the other hand, it is higher than that expected by extrapolating from the Hong
      Kong Chinese population (24 observed versus 8.5 expected cases; SIR = 2.81; 90%
      CI 1.94-3.95; P <0.0001). The difference is mainly accounted for by young
      patients with nodular sclerosis type disease in the migrant population.
      CONCLUSIONS: Although any conclusion about the impact of migration on Hodgkin's
      lymphoma incidence and types in the Chinese population must be considered
      tentative due to the small number of observed cases and confounding variables
      such as age, changing diagnostic standards and secular trends in Hodgkin's
      lymphoma rates, our data demonstrate a tendency for the Chinese population of
      British Columbia to take on a Western pattern of Hodgkin's lymphoma. This
      observation provides additional evidence that both genetic and environmental
      influences play a role in the pathogenesis of this lymphoma, and that
      environmental factors can exert their influence over a relatively short period of
      time.

PMID- 15033669
TI  - Chemokine receptor CXCR4 and early-stage non-small cell lung cancer: pattern of
      expression and correlation with outcome.
AB  - BACKGROUND: The expression of CXCR4 has been implicated in metastatic
      dissemination in different models of breast cancer and melanoma. In the present
      study, we evaluated CXCR4 expression in non-small-cell lung cancer (NSCLC) and
      the relationship between CXCR4 expression and the prognosis of stage I disease.
      PATIENTS AND METHODS: Using immunohistochemical analysis, we retrospectively
      analyzed CXCR4 expression in specimens from 61 patients with completely resected
      pathologically confirmed stage I NSCLC for whom clinical follow-up data were
      available. RESULTS: In the present study, we have shown that: CXCR4 is expressed
      by tumor cells in stage I NSCLC; CXCR4 is located in the nucleus and/or in the
      cytoplasm of tumor cells; strong nuclear staining was observed in 17 cases
      (29.8%); patients whose tumors had CXCR4-positive nuclear staining had a
      significantly longer duration of survival than patients whose tumors had no
      nuclear expression (P = 0.039, log-rank test). Interestingly, the 5-year
      metastasis rates were 23.5% and 34.1% in patients with CXCR4-positive and CXCR4
      negative nuclear expression, respectively (P = 0.2). CONCLUSION: Strong CXCR4
      positive nuclear staining was associated with a significantly better outcome in
      early-stage NSCLC. The mechanisms underlying this clinically and biologically
      important finding need to be further explored.

PMID- 15033672
TI  - Use of the WHO lymphoma classification in a population-based epidemiological
      study.
AB  - BACKGROUND: Non-Hodgkin's lymphoma (NHL) is pathologically diverse.
      Epidemiological investigations into its increasing incidence and aetiology
      require accurate subtype classification. PATIENTS AND METHODS: Available
      pathology reports of 717 cases aged from 20 to 74 years in an Australian,
      population-based epidemiological study of NHL were reviewed by one anatomical
      pathologist to assign a World Health Organization (WHO) classification category.
      High or low confidence was assigned to the diagnosis of NHL, cell phenotype and
      WHO category and reasons given for low confidence. RESULTS: The most informative
      biopsy reports were from open tissue biopsy (79% of cases), tissue core biopsy
      (8%), cytology (4%) and bone marrow (9%); 8% of cases had inadequate biopsies for
      diagnostic purposes. Immunohistochemistry or flow cytometry reports were
      available for 96% of cases, gene rearrangement studies for 6% and cytogenetics
      for 3%. The reviewer assigned high confidence to the diagnosis of NHL in 93% of
      cases and also the phenotype in 88%. While a WHO classification could be assigned
      in 91% of cases, confidence was high in only 57.5%; insufficient
      immunophenotyping was the commonest reason for low confidence. CONCLUSIONS:
      Expert pathology review of a population-based sample of NHL can provide a WHO
      classification category for most cases. A high level of confidence in the
      classification, however, would require review of diagnostic material and
      additional phenotyping.

PMID- 15033673
TI  - Docetaxel, cisplatin and 5-fluorouracil in patients with locally advanced
      unresectable head and neck cancer: a phase I-II feasibility study.
AB  - PURPOSE: To determine the safety profile and activity of the combination of
      docetaxel, cisplatin and 5-fluorouracil (5-FU) in chemotherapy-naive patients
      with squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS:
      Patients with locally advanced unresectable SCCHN were treated with docetaxel and
      cisplatin both as a 1-h infusion on day 1 followed by a continuous infusion of 5
      FU for 5 days. Cycles were planned every 3 weeks up to four cycles, whereafter
      the patients were treated with locoregional radiotherapy. Two dose levels were
      studied. Doses in level I were 75 mg/m(2) of docetaxel, 75 mg/m(2) of cisplatin
      and 750 mg/m(2)/day of 5-FU; in level II the cisplatin dose was escalated to 100
      mg/m(2). Following chemotherapy, all patients were to receive curative
      radiotherapy according to the standards in the different institutions. RESULTS:
      Twenty-five patients were treated at dose level I with 86 cycles (median four;
      range one to four), and 23 at dose level II with 84 cycles (median four; range
      two to four). The median relative dose intensity was 0.99 (range 0.86-1.04) at
      level I and 0.94 (range 0.79-1.02) at level II. The response rate in the
      intention-to-treat population was 64% [95% confidence interval (CI) 42.5% to 82%]
      in level I and 78.3% (95% CI 56.3% to 92.5%) in level II; all were partial
      responses. The maximum tolerated dose was reached at level II with renal
      toxicity, nausea, stomatitis and thrombocytopenia as principal dose-limiting
      toxicities. The median survival of the 48 patients was 18.5 months. The survival
      at 12, 18, 24 and 30 months was 69, 54, 41 and 31%, respectively. CONCLUSIONS:
      The combination of docetaxel, cisplatin and 5-FU associated with prophylactic
      ciprofloxacin is feasible and active in patients with SCCHN. Dose level I is
      recommended for phase III testing.

PMID- 15033674
TI  - Alternating gemcitabine and cisplatin with gemcitabine and radiation in stage IV
      squamous cell carcinoma of the head and neck.
AB  - BACKGROUND: In order to improve our cisplatin-5-fluorouracil (5-FU)-based
      alternating chemo-radiotherapy regimen, in 1996 we started an investigational
      program to explore a modified alternating regimen including gemcitabine given
      both with radiosensitizing and cytotoxic intent. MATERIALS AND METHODS: Based on
      our previous feasibility trial, we conducted a second study testing the
      feasibility and activity of the following schedule: gemcitabine 800 mg/m(2) on
      day 1 and cisplatin 20 mg/m(2) on days 2-5 (weeks 1, 4, 7 and 10) alternated with
      three courses of radiotherapy (RT) (weeks 2-3, 5-6 and 8-9) with conventional
      fractionation up to 60 Gy. Gemcitabine 300 mg/m(2) was also administered on the
      Monday of each week of RT. RESULTS: Forty-seven patients with stage IV (41
      patients) unresectable squamous cell carcinoma of the head and neck (SCC-HN) or
      who had relapsed after surgery (6 patients) were enrolled. None had previously
      received chemotherapy or radiotherapy. Eight patients (18%) did not complete the
      treatment. Main grade 3-4 toxicities were as follows: neutropenia (44%);
      neutropenia with fever (12%); thrombocytopenia (37%); anemia (30% grade 3). One
      patient died in therapy due to sepsis. Most patients needed hospitalization and
      tube-feeding or parenteral nutrition. However, 44% of patients had a weight loss
      >10%. Thirty-four patients had a complete response (72%). Three partial
      responders were rendered disease-free by surgery (final complete response rate,
      79%). At a median follow-up of 38 months actuarial 3-year overall survival,
      progression-free survival and loco-regional control are 43%, 39% and 64%,
      respectively. Data of locoregional control favorably compare with those from our
      database of patients treated with alternating cisplatin-fluorouracil and
      radiation within controlled clinical trials (64% versus 40%). CONCLUSIONS: The
      inclusion of gemcitabine into an alternating regimen seems to improve the results
      achievable with the original alternating program in stage IV patients. However,
      due to the high acute toxicity correlated, this intensive regimen should be
      managed by institutions well trained in multidisciplinary treatments.

PMID- 15033675
TI  - Hematopoetic stem cell transplantation for solid tumors in Europe.
AB  - BACKGROUND: Hematopoetic stem cell transplants (HSCT) are discussed as treatment
      options for patients with solid tumors. Transplant numbers have changed
      substantially over the last decade, few controlled studies are available and
      different opinions prevail. Objective information on current practice is needed.
      PATIENTS AND METHODS: Data from 27 902 HSCT for solid tumors (2% allogeneic, 98%
      autologous), collected by the European Group for Blood and Marrow Transplantation
      (EBMT) activity survey from 1991 to 2002 were used to assess trends, transplant
      rates and coefficient of variation of transplant rates in Europe. RESULTS:
      Transplant numbers increased from 536 in 1991 to 4154 in 1997 and decreased to
      1913 in 2002. Indications were neuroblastoma (2504 HSCT; 9%), glioma (662 HSCT;
      2%), soft tissue sarcoma (1253 HSCT; 4%), germ cell cancer (3291 HSCT; 12%),
      breast cancer (13 524 HSCT; 48%), Ewing's sarcoma (1896 HSCT; 7%), lung cancer
      (387 HSCT; 1%), ovarian cancer (845 HSCT; 3%) and other solid tumors (3540 HSCT;
      14%). Allogeneic cells were used in <20 cases up to 1997; since then allogeneic
      HSCT increased to 159 in 2002, mainly for renal cell carcinoma. Low coefficients
      of variation in transplant rates (<60%) are observed for Ewing's sarcoma
      (<56.5%), suggesting consensus for this indication. CONCLUSIONS: These data give
      an overview on current practice of HSCT for solid tumors in Europe. They provide
      objective information for health-care providers and patient counselling.

PMID- 15033676
TI  - 5-Fluorouracil induces arterial vasocontractions.
AB  - BACKGROUND: From 2% to 10% of cancer patients treated with 5-fluorouracil (5-FU)
      will develop symptomatic cardiotoxicity. Nevertheless, the underlying
      pathophysiology is mostly unknown. PATIENTS AND METHODS: We investigated the
      influence of intravenous chemotherapy (CTX) on the diameter of the brachial
      artery using high resolution ultrasound in patients with malignant tumors, mostly
      gastrointestinal cancer. Cytostatic drugs included 30 cases with 5-FU and 30
      cases with non-5-FU CTX (cis/carboplatin, anthracycline and cyclophosphamide). In
      addition, plasma levels of big endothelin were assessed prior to and after CTX.
      RESULTS: Fifteen of 30 patients (50%) showed a contraction of the brachial artery
      after the end of 5-FU application (median 11%, range 4.3-18.5), whereas no single
      contraction was noticed in 30 patients following non-5-FU-based CTX. Vessel tonus
      generally normalized within 30 min after stopping 5-FU. Five patients positive
      for 5-FU associated vessel contraction were repeatedly exposed to 5-FU. Vessel
      contractions reoccurred in 86% (18/21) of these administrations. When patients
      with 5-FU bolus application were pre-treated with glyceroltrinitrate no
      contraction of the brachial artery was detected in five out of five occasions.
      There was a trend towards increased big endothelin plasma levels after 5-FU
      application (median 1.52 versus 1.99 fmol/ml; P = 0.07), whereas big endothelin
      levels remained unchanged after non-5-FU CTX (1.83 versus 1.83 fmol/ml; P =
      0.99). CONCLUSIONS: Application of 5-FU is commonly accompanied by arterial
      vessel contractions, which is likely to represent the first step in 5-FU-induced
      cardiotoxicity. 5-FU-associated vessel contractions were highly reproducible on
      re-exposure and were in the case of bolus application completely preventable by
      glyceroltrinitrate.

PMID- 15033677
TI  - A phase I study of OSI-211 and cisplatin as intravenous infusions given on days
      1, 2 and 3 every 3 weeks in patients with solid cancers.
AB  - BACKGROUND: OSI-211 (also known as NX211) is a liposomal preparation of the
      topoisomerase I inhibitor, lurtotecan, which has shown antitumor activity in
      phase I and II clinical trials. Cisplatin is a widely used antineoplastic agent
      with activity in a broad range of tumor types. This phase I trial was conducted
      to determine the recommended doses of these agents, and their pharmacokinetic
      properties and toxicities in patients with advanced solid malignancies. PATIENTS
      AND METHODS: Fourteen patients with advanced and/or metastatic solid malignancies
      were enrolled in this trial. The first planned dose level was OSI-211 0.9 mg/m(2)
      with cisplatin 25 mg/m(2) administered intravenously daily for the first three
      consecutive days of a 21-day cycle. Patients were evaluated for hematological and
      non-hematological toxicities, and pharmacokinetic studies were performed on both
      agents. RESULTS: The recommended phase II dose was determined to be 0.7 mg/m(2)
      OSI-211 given with 25 mg/m(2) cisplatin. Dose-limiting neutropenia was seen in
      two of three patients at the starting dose level. Three of 11 patients at the
      second (lower) dose level experienced dose-limiting thrombocytopenia; febrile
      neutropenia was also seen in one patient. Non-hematological toxicities were
      generally manageable and included fatigue, nausea and vomiting. Considerable
      variability was seen in both hematological toxicities and pharmacokinetics. One
      complete response and three partial responses were seen. CONCLUSIONS: The
      recommended phase II dose for this combination is 0.7 mg/m(2) OSI-211 with 25
      mg/m(2) cisplatin given as an intravenous infusion on days 1, 2 and 3 of a 21-day
      cycle. The main toxicity was myelosuppression. Preliminary evidence of antitumor
      activity was seen.

PMID- 15033678
TI  - Phase I and pharmacokinetic study of TZT-1027, a novel synthetic dolastatin 10
      derivative, administered as a 1-hour intravenous infusion every 3 weeks in
      patients with advanced refractory cancer.
AB  - BACKGROUND: TZT-1027 is a synthetic dolastatin 10 analog with antineoplastic
      properties in various cell lines and tumor xenografts. The purpose of this phase
      I study was to evaluate the safety and toxicity, maximum tolerated dose,
      pharmacokinetics and pharmacodynamics, clinical and metabolic antitumor activity
      of TZT-1027 when given as a 1-h intravenous infusion every 3 weeks in patients
      with refractory solid tumors. PATIENTS AND METHODS: Patients had a histologically
      verified refractory tumor with measurable disease, were > or = 18 years old, had
      an Eastern Cooperative Oncology Group performance status <2 and adequate bone
      marrow, liver, renal and cardiac function. Dose-limiting toxicity was defined as
      platelets <25 x 10(9)/l, neutrophils <0.5 x 10(9)/l for >5 days, febrile
      neutropenia > or = 38.5 degrees C with grade 4 (National Cancer Institute-common
      toxicity criteria) neutropenia, or grade 3/4 non-hematological toxicity excluding
      nausea and vomiting. The last dose was the dose where > or = 2 out of six
      patients experienced dose-limiting toxicity in cycle one. The maximum tolerated
      dose was one dose level below with less than two of six patients with dose
      limiting events. RESULTS: Twenty-one non-selected, fully evaluable patients were
      enrolled. The majority were male (19) and the median age was 55 years (range 39
      67). Dose levels of TZT-1027 ranged from 1.35 to 3.0 mg/m(2). The median number
      of cycles was two (range 1-4). Dose-limiting toxicities were observed in three
      patients at the 3.0 mg/m(2) dose level, including neutropenia, fatigue and a
      short lasting, reversible peripheral neurotoxic syndrome. The most common
      toxicities per patient were fatigue, anorexia, alopecia, nausea, constipation,
      leukopenia and neutropenia. Based on RECIST criteria, the best response was
      stable disease in seven patients. The pharmacokinetic evaluation revealed a
      T(1/2) of approximately 7 h and linear kinetics. CONCLUSIONS: The recommended
      dose of TZT-1027 for the 3-weekly administration is 2.7 mg/m(2). Neutropenia,
      fatigue and a reversible peripheral neurotoxic syndrome are dose-limiting with
      this schedule. TZT-1027 may be associated with neurological side-effects in
      patients previously exposed to neurotoxic compounds such as oxaliplatin.

PMID- 15033679
TI  - Clinical epidemiology of childhood cancer in Central America and Caribbean
      countries.
AB  - BACKGROUND: Countries with scarce resources have the right to appropriate
      essential health care but very few reports discuss how this can be achieved. We
      assessed the survival of a large cohort of pediatric oncological patients to
      provide hard data on which to base realistic evaluation and planning schemes.
      PATIENTS AND METHODS: This multicenter retrospective survey covered consecutively
      diagnosed and treated patients admitted to eight national level hospitals in
      seven countries in Central America and the Caribbean. The research protocol was
      discussed extensively, so the data to be collected and the criteria for their
      evaluation were clearly pre-defined. We analysed 2214 patients diagnosed between
      1996 and 1999 with various cancers, classified as hemato-oncological disorders
      (70%) and solid tumors (30%). RESULTS: Three-year overall survival was 48.4%
      [standard error (SE) 1.3]. Detailed analysis of acute lymphoblastic leukemia
      highlighted the wide intercountry variability: 3-year survival was 62.2% (SE 5.3)
      in Cuba, 74.2% (SE 3.3) in Costa Rica, 61.7% (SE 4.9) in Nicaragua, and lower in
      the other four countries. CONCLUSIONS: The yield of diagnostic-therapeutic
      protocols depends largely on the context of care in which they are applied. This
      paper documents the importance of including epidemiological research in
      interventions for cooperation in complex health areas such as pediatric oncology.

PMID- 15033680
TI  - Age-period-cohort analysis of breast cancer mortality rates in Andalucia (Spain).
AB  - BACKGROUND: The aim of this paper is to analyse breast cancer mortality in
      Andalucia (Spain) between 1975 and 1999 based on age-period-cohort. PATIENTS AND
      METHODS: Mortality data were obtained from the Mortality Registry of Andalucia.
      Deaths and population were divided into 13 age groups and five 5-year periods.
      From this, age-specific mortality rates for 17 birth cohorts were computed. These
      were plotted and fitted to Poisson regression models to assess age, period and
      cohort effects. RESULTS: The best fit was found for the complete model, which
      simultaneously considered the effects of age-period-cohort. Cohort effects were
      found to be more important than period effects in terms of model fit. CONCLUSION:
      These effects were manifest as a seemingly consistent increase in the relative
      risk of breast cancer mortality with a three-fold increase in women born in the
      1950s relative to those born in the 1890s.

PMID- 15033683
TI  - Breast conservation in patients of 35 years or younger.

PMID- 15033684
TI  - Acute dyspnea due to right phrenic palsy during infusional chemotherapy.

PMID- 15033682
TI  - With regard to "Induction chemotherapy followed by concomitant chemoradiotherapy
      in the treatment of locoregionally advanced nasopharyngeal cancer" by Oh et al.
      (AnnOnc 2003; 14: 464-569).

PMID- 15033687
TI  - An introduction to the molecular mechanisms of apoptosis.
AB  - Apoptosis is a type of cell death that has been observed and studied for more
      than a century. The process of apoptosis was described as "programmed cell death"
      in 1964, and the term apoptosis, from a Greek word meaning "to fall away from"
      and describing the fall of dead leaves from trees in autumn, was only coined in
      1972. During the last 30 years, this type of cell death has been extensively
      investigated and the molecular mechanisms underlying this cell suicide well
      characterized. Apoptosis is a physiological phenomenon necessary to tissue and
      body genesis and homeostasis, but defects in its regulation may cause numerous
      diseases, including cancer. Investigating the mechanisms of apoptosis is thus
      important to discover new cellular regulators that could be potential targets for
      new death-inducing drugs.

PMID- 15033685
TI  - Extrathymic malignancies in patients with thymoma.

PMID- 15033688
TI  - p73, the "assistant" guardian of the genome?
AB  - Although p53 is clearly involved in the salvage pathway to DNA damage, its
      frequent mutations do not explain the efficacy of radiotherapy and chemotherapy.
      Indeed, around 50% of all human cancers show mutations in p53, and a further
      fraction show a functional inactivation of the protein. Nevertheless, patients
      seem to respond to therapy that would otherwise require a functional p53. At
      least in part, these responses could be explained by the pathway mediated by p73.
      This mechanism is parallel to, but independent of the p53 pathway. Several pieces
      of evidence show a significant interaction between these two proteins. Therefore,
      while p53 can be rightly defined as the guardian of the genome, we could think of
      p73 as the "assistant" guardian of the genome!

PMID- 15033689
TI  - Apoptosis gene network: description in the GeneNet and TRRD databases.
AB  - The large volume of experimental data on apoptosis requires computer processing
      to systematize and provide an integrated "description of operation" of the gene
      network that regulates apoptosis in various cell types under varying effects. The
      database GeneNet contains the description of the apoptosis gene network:
      (http://wwwmgs.bionet.nsc.ru/systems/mgl/genenet), and the Transcription
      Regulatory Regions Database (TRRD) contains experimental data on transcription
      regulation of various genes, including apoptosis genes:
      (http://wwwmgs.bionet.nsc.ru/mgs/gnw/trrd/).

PMID- 15033690
TI  - Mitochondrial apoptosis induced by the HIV-1 envelope.
AB  - The envelope glycoprotein complex (Env), encoded by the human immunodeficiency
      virus (HIV-1), kills uninfected cells expressing CD4 and/or the chemokine
      receptor CXCR4 or CCR5, via at least three independent mechanisms. First, the
      soluble Env product gp120 can induce the apoptotic cell death of lymphocytes,
      neurons, and myocardiocytes, via interaction with surface receptors. Second, Env
      present on the surface of HIV-1 infected cells can transiently interact with
      cells expressing CD4 and CXCR4/CCR5, thereby provoking a hemifusion event that
      results in the death of the uninfected cell. Third, the interaction between Env
      on infected cells and its receptors on uninfected cells can result in syncytium
      formation. Such syncytia undergo apoptosis after a phase of latency. In several
      models of Env-induced apoptosis, early signs of mitochondrial membrane
      permeabilization (MMP) become manifest. Such signs include a loss of the
      mitochondrial transmembrane potential and the release of cytochrome c and AIF.
      The mechanisms of Env-triggered apoptotic MMP may involve an elevation of
      cytosolic Ca(2+), reactive oxygen species and/or the transcriptional activation
      of p53, with the consequent expression of pro-apoptotic proteins such as Bax,
      which permeabilizes mitochondrial membranes. The implications of these findings
      for the pathophysiology of HIV-1 infection is discussed.

PMID- 15033691
TI  - On the role of interferon regulatory factors in HIV-1 replication.
AB  - Interferons (IFNs) are pleiotropic cytokines that possess several biological
      activities and play a central role in basic and applied research as mediators of
      antiviral and antigrowth responses, modulators of the immune system, and
      therapeutic agents against viral diseases and cancer. Interferon regulatory
      factors (IRFs) have been identified together with signal transducers and
      activators of transcription (STAT) from studies on the type I IFN as well as IFN
      stimulated (ISG) gene regulation and signaling. IRFs constitute a family of
      transcriptional activators and repressors implicated in multiple biological
      processes including regulation of immune responses and host defence, cytokine
      signaling, cell growth regulation, and hematopoietic development. All members
      share a well-conserved DNA binding domain at the NH(2)-terminal region that
      recognizes similar DNA sequences, termed IRF element (IRF-E)/interferon
      stimulated response element (ISRE), present on the promoter of target genes.
      Recently, a sequence homologous to the ISRE has been identified downstream from
      the 5' human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR).
      This sequence is a binding site for IRF-1 and IRF-2. Here we briefly summarize
      the role of IRFs in the regulation of HIV-1 LTR transcriptional activity and
      virus replication. The overall effect of IRFs on HIV-1 replication will also be
      discussed in the context of strategies carried out by the virus to counteract the
      IFN-mediated host defences both in active replication and during the
      establishment of viral latency.

PMID- 15033692
TI  - PEA-15 modulates TNFalpha intracellular signaling in astrocytes.
AB  - PEA-15 is a small protein (15 kDa) that was first identified as an abundant
      phosphoprotein in brain astrocytes and subsequently shown to be widely expressed
      in different tissues and highly conserved among mammals. It is composed of an N
      terminal death effector domain (DED) and a C-terminal tail of irregular
      structure. PEA-15 is regulated by multiple calcium-dependent phosphorylation
      pathways. PEA-15 is ideally positioned to play a major role in signal
      integration. Accordingly, it has been demonstrated that PEA-15 diverts astrocytes
      from TNFalpha-triggered apoptosis and regulates the actions of the ERK MAP kinase
      cascade by binding to ERK and altering its subcellular localization. Expression
      of PEA-15 directs TNFalpha outcomes toward survival, whereas its absence allows
      the development of the cytokine-induced cell death.

PMID- 15033693
TI  - Regulation of Drosophila MKP-3 by Drosophila ERK.
AB  - DMKP-3 is a Drosophila dual-specificity phosphatase, which has high substrate
      specificity for Drosophila extracellular signal-regulated kinases (DERK). By in
      vitro reconstitution experiments, we found that DERK activates DMKP-3. Moreover,
      DMKP-3 was specifically activated by the addition of DERK but not by DJNK, Dp38,
      or Sevenmaker DERK D334N, a DMKP-3- binding mutant. The phosphatase activity of
      DMKP-3-R56A/R57A, a DERK-binding mutant, was not increased by DERK.
      Significantly, mammalian MKP-3 was also found to be activated by DERK. This cross
      reactivity suggests a high level of conservation of the activation mechanism of
      ERK-specific phosphatases in Drosophila and mammals. When DMKP-3 was co-expressed
      with DERK in Drosophila Schneider cells, DMKP-3 protein levels increased, but
      this was not observed for the co-expressions of DJNK or Dp38. The stabilizations
      of the DERK binding mutants (DMKP-3-RR and DMKP-3-CA-RR) were not increased by
      DERK co-expression. Our results suggest that DERK specifically regulates DMKP-3
      in terms of its enzyme activity and protein stability, and that direct protein
      protein interaction is an essential aspect of this regulation.

PMID- 15033694
TI  - Role of p38 MAP kinase signal transduction in apoptosis and survival of renal
      epithelial cells.
AB  - The p38 MAP kinase signal transduction pathway is activated by various forms of
      cellular stress. While, in many tissues, activation of p38 MAP kinase is
      associated with apoptosis, in some tissues p38 activation is critical for
      survival. Oxalate deposits are associated with several pathological conditions
      that involve aberrant proliferation and cellular apoptosis. Studies from our
      laboratory demonstrated that exposure of renal epithelial cells to oxalate and
      COM-crystals resulted in activation of the p38 MAP kinase pathway. Moreover, the
      inhibition of the p38 MAO kinase pathway resulted in the inhibition of oxalate as
      well as COM-crystal-induced reinitiation of the DNA synthesis. These results
      suggest a critical role for the p38 MAP kinase pathway in pathological conditions
      associated with cellular proliferation and apoptosis following deposition of
      calcium oxalate.

PMID- 15033695
TI  - Calcium-dependent apoptotic gene expression in cerulein-treated AR42J cells.
AB  - Elevated Ca(2+) concentrations within the pancreatic acinar cells represent a
      risk factor for the development of acute pancreatitis. Apoptosis is an important
      characteristic of pancreatitis, with induction of apoptotic genes and
      intraceullar increase of calcium, endonucleases, and protease. The present study,
      which aims to investigate whether (1) cerulein induces apoptotic gene expression
      (bax, bid, p53) in pancreatic acinar AR42J cells and (2) cerulein-induced gene
      expression is mediated by intracellular Ca(2+), monitored the gene expression
      profile in the cells treated with the Ca(2+) chelator BAPTA-AM. Results showed
      that cerulein (10(-7) M) evoked an initial peak Ca(2+) signal; a further Ca(2+)
      signal was induced with second treatment of cerulein. Cerulein-induced Ca(2+)
      signal could not be detected in the cells treated with the Ca(2+) chelator BAPTA
      AM. Cerulein dose-dependently induced apoptosis, determined by DNA fragmentation
      and pro-apoptotic bid expression in AR42J cells. Cerulein induced bid, bax, and
      p53 mRNA expression, which was inhibited in the cells treated with cerulein and
      cultured in the presence of BAPTA-AM. The present results suggest that increase
      in the free cytosolic Ca(2+) may be the upstream event of apoptotic gene (bax,
      bid, p53) expression, which contribute to cerulein-induced apoptosis in
      pancreatic acinar cells.

PMID- 15033697
TI  - Cytosolic and endoplasmic reticulum Ca2+ concentrations determine the extent and
      the morphological type of apoptosis, respectively.
AB  - During apoptosis, an increase in cytosolic Ca(2+) concentration ([Ca(2+)](c))
      accompanies the depletion of endoplasmic reticulum (ER). The actual roles of each
      of the two events in apoptosis are difficult to understand. In this work, we have
      modulated the basal [Ca(2+)](c) and the thapsigargin (THG)-dependent reticular
      flux (i.e., by chelating extracellular Ca(2+) or by modulating intracellular
      Ca(2+) by 3-aminobenzamide [3-ABA]). We have found that these treatments alter
      these Ca(2+) parameters in a differential way and, accordingly, affect apoptosis
      differentially. We have found that the increase in [Ca(2+)](c) is related to the
      extent of apoptosis, whereas the ER depletion affects the apoptotic nuclear
      morphology by shifting it towards the cleavage mode.

PMID- 15033696
TI  - Effects of intracellular calcium on cell survival and the MAPK pathway in a human
      hormone-dependent leukemia cell line (TF-1).
AB  - Changes in the cytoplasmic calcium concentration ([Ca(2+)](i)) regulate a wide
      variety of cellular processes. Here we demonstrate that increased [Ca(2+)](i) was
      able to induce hormone-independent survival and proliferation, as well as to
      evoke apoptosis in human myelo-erythroid GM-CSF/IL-3 dependent leukemia cells (TF
      1). Cellular responses induced by elevated [Ca(2+)](i) depended on the duration
      and amplitude of the calcium-signal. Moderate or high, but transient, elevation
      of [Ca(2+)](i) caused a transient, biphasic activation of ERK1/2 and protected
      cells from hormone withdrawal-induced apoptosis.(1) In contrast, high and long
      lasting elevation of [Ca(2+)](i) led to sustained activation of the ERK1/2
      kinases and apoptosis of TF-1 cells. Our data suggest that a time-dependent
      action of the MAPK pathway works as a decision-point between cell proliferation
      and apoptosis.

PMID- 15033699
TI  - An investigation of the MEK/ERK inhibitor U0126 in acute myeloid leukemia.
AB  - Blockade of mitogen-activated protein kinase kinase (MEK1/2), part of the
      extracellular signal-regulated kinase (ERK) or p44/42 mitogen-activated protein
      kinase (MAPK) pathway, has been shown in some instances to cause apoptosis in
      leukemic blast cells. This investigation examined the effect of the potent
      MEK/ERK inhibitor U0126 on apoptosis in acute myeloblastic leukemia (AML) cell
      lines, and acute leukemic and non-leukemic patient samples. The pro-apoptotic
      effect of the inhibitor varied across the five cell lines tested (KG1a, HEL, TF
      1, MO7e, and THP-1) from highly significant induction of apoptosis to no apparent
      response. The pro-apoptotic effect of U0126 in the most sensitive cell line,
      KG1a, appeared to be related to its CD34 positivity. Three of five leukemic bone
      marrow samples showed considerable sensitivity to the inhibitor and a similar
      association with CD34 expression was evident. Interestingly, control marrow cells
      from six non-leukemic patients did not show a significant effect when exposed to
      U0126. These results suggest that this agent may offer a potential alternative to
      standard chemotherapy with a particular role in the most primitive types of
      leukemia, these often being the most resistant to standard chemotherapy.

PMID- 15033698
TI  - G-CSF modulates LPS-induced apoptosis and IL-8 in human microvascular endothelial
      cells: involvement of calcium signaling.
AB  - Microvascular endothelial cells (mECs) circulate at higher numbers in patients
      with severe sepsis and hemophagocytic syndromes. Although these blood mECs might
      stem from damaged microvasculature, they are perfectly viable and lead to the
      establishment of cell lines. Such mECs were cultured in low-dose human serum
      pools (0.5%) and MEM-alpha medium. Antigenic profiling revealed the expression of
      CD36, factor VIIIa, CD95-ligand, and CD44, but also CD146. We studied the
      antioxidative effect of the hematopoietic growth factor G-CSF(1) after in vitro
      stimulation with LPS from E. coli 0111:B4; the growth factor appeared to exhibit
      a protective effect on organ function in patients with SIRS. mECs were stimulated
      with 1 micro g/mL of LPS for 24 h and 48 h with and without G-CSF (3x10(3) U/mL)
      preincubation. After 24 h, supernatants of the stimulated mEC were tested for IL
      8 by ELISA, and cells were tested for hemoxygenase-1 (HO-1, Hsp32) by
      immunohistochemistry and flow cytometry using OSA110 (mAb, Stressgene).
      Stimulation with LPS upregulated IL-8 by a factor of 2 to 10 in mEC.
      Preincubation with G-CSF markedly downregulated the LPS-induced IL-8 secretion
      (20-50%), but IL-6 production was not affected. Upon 48 h of LPS stimulation,
      mECs developed massive signs of apoptosis and concomitant caspase 3 activation.
      Caspase 3 activity induced by LPS (24 h) or by staurosporin (6 h) was found to be
      dramatically downregulated by the G-CSF preincubation protocol.

PMID- 15033700
TI  - The effect of p38 mitogen-activated protein kinase on mucin gene expression and
      apoptosis in Helicobacter pylori-infected gastric epithelial cells.
AB  - The loss of mucus coat continuity and apoptosis have been shown in Helicobacter
      pylori (H. pylori)-infected gastric tissues. Blockade of p38 mitogen-activated
      kinase (MAPK) produced reversal in the LPS-induced reduction in mucin synthesis
      and apoptosis in gastric epithelial cells. This study investigates whether H.
      pylori induces apoptosis, alterations in mucin gene (MUC) expression, and p38
      MAPK activation in human gastric epithelial AGS cells. After treatment of AGS
      cells with H. pylori at the ratio of 1:300, apoptosis was determined by DNA
      fragmentation and DNA laddering. MUC expression was assessed by RT-PCR. p38 MAPK
      activation and mucin protein level, using anti-mucin antibody for MUC5/6, were
      determined by Western blot analysis. As a result, H. pylori induced apoptosis and
      loss of mucin, which was supported by reduced mRNA expression of MUC5AC by H.
      pylori in AGS cells. MUC7/8 expression and p38 MAPK activation were induced in H.
      pylori-infected AGS cells. In conclusion, H. pylori induces p38 MAPK activation,
      wh3.ich may be the underlying mechanism of alterations in MUC expression and
      apoptosis in gastric epithelial cells.

PMID- 15033701
TI  - Activation of JNK in sensory neurons protects against sensory neuron cell death
      in diabetes and on exposure to glucose/oxidative stress in vitro.
AB  - Diabetes activates all three groups of MAP kinases in sensory ganglia. Inhibition
      of this activation for the ERK and p38 groups prevents nerve damage, and agents
      that improve neuronal function in diabetic rats-antioxidants and aldose reductase
      inhibitors-also inhibit activation of ERK and p38 in dorsal root ganglia (DRG).
      However, these same treatments consistently increase activation of JNK. Thus, in
      DRG from rats with streptozotocin (STZ)-induced diabetes of 12-week duration, the
      p54/56 isoforms of JNK were activated by 2.75 compared to controls (P <.05). In
      DRG from diabetic rats treated with a gamma-linolenic acid and alpha-lipoic acid
      diester (GLA/LA), the activity of the p54/56 isoform was 3.75 that of controls
      and the p46 isoform was also increased to 1.75 that of controls (both P <.05
      compared to both controls and untreated diabetics). We therefore tested the
      hypothesis that JNK activation is protective. Exposure of rats to diabetes
      increased activation of JNK in DRG, but treatment with GLA/LA increased this
      effect (P <.05). Specific inhibition of JNK in primary cultures of DRG neurons
      using a peptide inhibitor of JNK (JNKi1, 159-600-R100, 7.5 micro M, Alexis
      Biochemicals) increased the release of LDH and reduced MTT staining; both
      findings indicate an increase in neuronal damage. Taken together these findings
      indicate that multiple isoforms of JNK were activated in sensory neurons of
      diabetic rats, probably by a combination of raised glucose and oxidative stress,
      and that this activation of JNK serves to protect the neurons from damage.

PMID- 15033703
TI  - Signal transduction of cerulein-induced cytokine expression and apoptosis in
      pancreatic acinar cells.
AB  - The signaling pathways mediating cytokine production and apoptosis in pancreatic
      acinar cells have not been fully understood. We investigated the signal
      transduction of cerulein-induced cytokine IL-6 expression and apoptosis in
      pancreatic acinar AR42J cells. The wild-type cells and the cells transfected with
      mutant genes for signaling molecules (such as transcription factor NF-kappaB and
      AP-1) and ras, the upstream signal for mitogen-activated protein kinase (MAPK),
      were used. IL-6 level was determined in the medium by enzyme-linked immunosorbent
      assay (ELISA). Apoptosis was determined by viable cell counts and DNA
      fragmentation. Wild-type cells and transfected cells with control vector (pcDNA),
      IkappaB mutant gene (IkappaB mt), H-ras mutant gene (Ras N17), or c-jun dominant
      negative gene (TAM-67) were treated with cerulein for 24 hours. As a result,
      cerulein induced IL-6 expression time-dependently at 10(-8) M, and apoptosis dose
      dependently at 24 h in the wild-type cells. Cerulein-induced IL-6 expression (at
      10(-8) M) and apoptosis (at 10(-7) M) were inhibited in the transfected cells
      with mutant gene (IkappaB mt, Ras N17, TAM-67) as compared to pcDNA cells and the
      wild-type cells. In conclusion, cerulein induces cytokine expression and
      apoptotic cell death, which may be regulated by NF-kappaB, AP-1, and possibly
      MAPK in pancreatic acinar cells.

PMID- 15033704
TI  - Pro-apoptotic and anti-apoptotic molecules affecting pathways of signal
      transduction.
AB  - Selective inhibition of the "false" proliferative signals via targeting tyrosine
      kinases resulting in the induction of apoptosis by depletion of the "survival
      factors" is one of the most studied and widely accepted concepts of modern
      chemotherapy. We have synthesized a series of potent tyrosine kinase inhibitors
      and tested these compounds for apoptosis induction. Some of the tyrosine kinase
      inhibitors caused either apoptotic or cytoplasmic vacuolar cell death in various
      tumor cell cultures. The somatostatin analogue oligopeptide TT-232, which
      indirectly inhibits tyrosine kinases, exerted a dose-dependent apoptosis-inducing
      effect. The tumor growth-inhibitory effect of TT-232 and some tyrosine kinase
      inhibitors has also been proven by in vivo experiments, using human tumor
      xenografts. On the other hand, a dose-dependent pro- or anti-apoptotic activity
      of (-)-deprenyl has been shown in melanoma cell cultures, the lower doses
      inhibiting and the higher doses inducing apoptosis. Various metabolites of (-)
      deprenyl are responsible for these actions. The effect of (-)-deprenyl is
      connected with depolarization of mitochondrial membranes. The kinase inhibitors
      act on the growth factor receptor signaling pathways (survival factor pathways)
      and initiate the caspase cascade. The key enzyme for the action of both pro
      apoptotic and anti-apoptotic compounds is caspase 3.

PMID- 15033702
TI  - Inhibition of JNK by HGF/SF prevents apoptosis induced by TNF-alpha.
AB  - We investigated whether repression of JNK by hepatocyte growth factor/scatter
      factor (HGF/SF) in MDCK epithelial cells is linked to its ability to protect
      cells from apoptosis. To this purpose, cells were treated by TNF-alpha, a well
      known inducer of JNK and of cell death, and the effects of HGF/SF were
      investigated under these conditions. We identified repression of JNK as a
      signaling target of HGF/SF for protection against TNF-alpha-induced cell death.
      This effect of HGF/SF occurs via the activation of the PI3K and MEK1 pathways.

PMID- 15033705
TI  - A recombinant fragment of human surfactant protein D reduces alveolar macrophage
      apoptosis and pro-inflammatory cytokines in mice developing pulmonary emphysema.
AB  - Rapid removal of apoptotic cells is an important mechanism for immune homeostasis
      and the resolution of inflammation. Delayed clearance of apoptotic alveolar
      macrophages may cause activation of healthy bystander macrophages and contribute
      to high macrophage number and emphysema in surfactant protein D (SP-D) knock-out
      mice. Using flow cytometry and Annexin V and propidium iodide as markers for
      apoptosis and necrosis, respectively, SP-D-deficient mice were found to have a 5-
      to 10-fold increase in the number of apoptotic and necrotic alveolar macrophages
      in the lungs. SP-D-deficient mice accumulate apoptotic macrophages in the lung,
      and this accumulation can be reduced by treatment with recombinant SP-D (but not
      SP-A). The recombinant SP-D binds preferentially to apoptotic cells. The data are
      consistent with a specific role in vivo for SP-D in promoting apoptotic cell
      clearance in the lungs to limit macrophage-mediated inflammation and reveal a
      potential new mechanism for therapeutic targeting in the prevention of emphysema.

PMID- 15033706
TI  - Involvement of TNF-related apoptosis-inducing ligand (TRAIL) induction in
      interferon gamma-mediated apoptosis in Ewing tumor cells.
AB  - We investigated the effect of IFN gamma or IFN gamma/IFN alpha and IFN gamma/TNF
      treatment on the apoptosis of Ewing tumor cells (SK-N-MC). The results show that
      treatment of cells with IFN gamma resulted in 17% of cell death while no effect
      was observed when cells were treated with IFN alpha or TNF alone. Percentage cell
      death increased markedly in IFN gamma/IFN alpha- and IFN gamma/TNF-treated cells
      (42% and 67%, respectively) as compared to IFN gamma-treated cells. These results
      suggest that IFN alpha and TNF amplified the apoptotic signal(s) induced by IFN
      gamma. It was shown recently that Ewing cells undergo apoptosis upon treatment
      with recombinant TRAIL (TNF-related apoptosis inducing ligand), a member of the
      TNF family. Thus, since cytokines were reported to be able to induce TRAIL in
      other cell systems, we were prompted to investigate whether TRAIL induction was
      involved in the mechanism responsible for IFN gamma-mediated cell death in Ewing
      cells. The results reported here are consistent with the notion that cell
      associated and secreted TRAIL contribute in an autocrine or paracrine manner to
      the triggering of Ewing cell apoptosis induced by IFN gamma alone or combined
      with IFN alpha or TNF. The observations reported here might contribute to the
      development of alternative new approaches to the treatment of Ewing tumors
      resistant to conventional therapy.

PMID- 15033707
TI  - Cell death in protists without mitochondria.
AB  - Some protozoans, such as Trichomonad species, do not possess mitochondria. Most
      of the time, they harbor another type of membrane-bounded organelle, called
      hydrogenosome from its capacity to produce H(2). This is the case for the human
      parasite Trichomonas vaginalis. Some other parasites, such as the protist Giardia
      lamblia, do not harbor any of these organelles. From this observation arises
      naturally a naive question: How do cells die when the mitochondrion, the
      cornerstone of apoptotic process, is absent? Data strongly suggest that the
      mitochondrion and the hydrogenosome arose from a common ancestral endosymbiont.
      But hydrogenosomes do not appear to directly substitute for mitochondria in
      apoptotic functions. Thus, it appears judicious to examine more closely the
      genome of unicellular cells, which do not harbor mitochondria, and search for new
      molecules that could participate in the apoptotic process in these
      microorganisms.

PMID- 15033708
TI  - Study of PTPC composition during apoptosis for identification of viral protein
      target.
AB  - The permeability transition pore complex (PTPC), a mitochondrial polyprotein
      complex, has been previously described to be involved in the control of
      mitochondrial membrane permeabilization (MMP) during chemotherapy-induced
      apoptosis. PTPC may contain proteins from both mitochondrial membranes [e.g.,
      voltage-dependent anion channel (VDAC), PRAX-1, peripheral benzodiazepine
      receptor (PBR), adenine nucleotide translocator (ANT)], from cytosol (e.g.,
      hexokinase II, glycerol kinase), from matrix [e.g., cyclophilin D (CypD)], and
      from intermembrane space (e.g., creatine kinase). PTPC may also interact with
      tumor suppressor proteins (i.e., Bax and Bid), oncoprotein homologues of Bcl-2
      and some viral proteins, which can regulate apoptosis induced by pore opening.
      ANT and VDAC are the target of numerous pro-apoptotic MMP inducers. However, the
      precise composition of PTPC as well as the respective role of each PTPC component
      represent major issues in the understanding MMP process. Using several
      experimental strategies that combine co-immunoprecipitation, proteomics, and
      functional tests with proteoliposomes, we and others have been able to
      characterize some of the intra/inter-PTPC protein interactions leading to a
      better understanding of the process of MMP. In addition, this approach could
      identify new putative members and regulators of PTPC pro-apoptotic function and
      new targets of viral protein involved in the modulation of apoptosis during
      infection.

PMID- 15033711
TI  - Cisplatin-induced apoptosis in HL-60 human promyelocytic leukemia cells:
      differential expression of BCL2 and novel apoptosis-related gene BCL2L12.
AB  - The anti-apoptotic molecule BCL2 delays cell-cycle entry from quiescence. We have
      recently cloned a new member of the BCL2 family of apoptosis-related genes,
      BCL2L12. In the present study, the expression of BCL2 and BCL2L12 genes during
      cisplatin-induced apoptosis in HL-60 leukemic cells was investigated. The
      kinetics of apoptosis induction and cell toxicity were evaluated by DNA laddering
      and the MTT method, respectively. BCL2 and BCL2L12 expression was analyzed by RT
      PCR using gene-specific primers. The ratio of apoptotic cells increased with
      increasing concentrations of cisplatin and exposure time of cell culture to the
      drug. Gradual, time-dependent downregulation of BCL2 gene was observed during
      cisplatin treatment. Up-regulation of BCL2L12 was observed 3 h (no DNA
      fragmentation) and 6 h (initiation of the DNA fragmentation) after treatment with
      cisplatin, followed by a decrease of its expression after 12-h continuous
      treatment with the drug. It is known that the main anti-carcinogenic effect of
      cisplatin is due to the induction of cell apoptosis. Present results indicate
      that downregulation of the BCL2 and upregulation of the BCL2L12 gene may be the
      underlying mechanisms.

PMID- 15033709
TI  - Antagonism between apoptotic (Bax/Bcl-2) and anti-apoptotic (IAP) signals in
      human osteoblastic cells under vector-averaged gravity condition.
AB  - A functional disorder associated with weightlessness is well documented in
      osteoblasts. The apototic features of this disorder are poorly understood.
      Harmful stress induces apoptosis in cells via mitochondria and/or Fas. The Bax
      triggers cytochrome c release from mitochondria, which can be blocked by the Bcl
      2. Released cytochrome c then activates the initiator caspase, caspase-9, which
      can be blocked by the anti-apototic (IAP) family of molecules. The effector
      caspase, caspase-3, finally exerts DNA fragmentation. We conducted this study to
      examine the apoptotic effects of vector-averaged gravity on normal human
      osteoblastic cells. Cell culture flasks were incubated on the clinostat, which
      generated vector-averaged gravity condition (simulated microgravity) for 12, 24,
      48, and 96 hours. Upon termination of clinostat cultures, the cell number and
      cell viability were assessed. DNA fragmentation was analyzed on the agarose-gel
      electrophoresis. The mRNA levels for Bax, Bcl-2, XIAP, and caspase-3 genes were
      analyzed by semi-quantitative RT-PCR. Twenty-four hours after starting clinostat
      rotation, the ratios of Bax/Bcl-2 mRNA levels (indicator of apoptosis) were
      significantly increased to 136% of the 1G static controls. However, the XIAP mRNA
      levels (anti-apoptotic molecule) were increased concomitantly to 138% of the 1G
      static controls. Thus, cell proliferation or cell viability was not affected by
      vector-averaged gravity. DNA fragmentation was not observed in clinostat group as
      well as in control group. Finally, the caspase-3 mRNA levels were not affected by
      vector-averaged gravity. Simulated microgravity might modulate some apoptotic
      signals upstream the mitochondrial pathway.

PMID- 15033710
TI  - Bcl-2 prevents loss of cell viability and caspase activation induced by 3
      nitropropionic acid in GT1-7 cells.
AB  - In this study, we analyzed the effect of Bcl-2 overexpression, an important anti
      apoptotic protein, by using two hypothalamic cell lines, GT1-7puro or GT1-7bcl-2.
      3-Nitropropionic acid (3-NP) mediated a dose-dependent decrease in cell viability
      in GT1-7puro cells, as determined by following the MTT (3-(4,5-dimethylthiazol-2
      yl)-2,5-diphenyltetrazolium bromide) reduction, which was significantly prevented
      in GT1-7bcl-2 cells. In addition, activation of caspases-2, -3, and -6 induced by
      3-NP was prevented by Bcl-2 overexpression. The data suggest that irreversible
      inhibition of mitochondrial complex II induces apoptotic features of cell death
      in a process prevented by Bcl-2.

PMID- 15033712
TI  - TNFalpha potentiates 2-methoxyestradiol-induced mitochondrial death pathway.
AB  - Ewing sarcoma cells are resistant to TNFalpha-induced cell death and this
      resistance results from the activation of the transcription factor NF-kappaB.
      Here, we investigated whether NF-kappaB activation interferes with 2-Me-induced
      cell death signaling in Ewing sarcoma cells and we examined the effect of
      treatment of these cells with 2-Me either alone or in combination with TNFalpha.
      Our results show that TNFa cooperates with 2-Me to induce apoptosis in Ewing
      tumor cells through mitochondrial cell death signaling. These results suggest
      that the use of TNFalpha in combination with 2-Me may be beneficial for Ewing
      tumor treatment.

PMID- 15033713
TI  - Induction of apoptosis by ultrasound application in human malignant lymphoid
      cells: role of mitochondria-caspase pathway activation.
AB  - In the present study, we have focused on the specific question of whether
      ultrasound application (ULS) delivered with optimized parameters for cavitation
      generation can stimulate apoptosis in lymphoid cell lines. Suspended T and B
      lymphoid cell lines (Jurkat and Raji, respectively) were exposed to low frequency
      ULS (750 KHz) at an intensity level of 54.6 W/cm(2) spatial peak temporal average
      (SPTA) at focal area, which was found to be the optimal physical parameter to
      induce apoptosis in these malignant cell lines. Unsonicated cells and cells
      exposed to gamma-radiation (20 Gy) using (137)Cs source were used as control.
      Apoptosis was evaluated by cell morphology changes, cell-cycle analysis, and
      phosphatidylserine exposure. Fraction of cells with low mitochondria membrane
      potential was observed 1 h after sonication, accompanied by cytochrome c release
      from mitochondria to the cytosol and caspase-3 activation. Here we present
      evidence that ULS exposure with cavitation formation on malignant lymphoid cell
      lines differs from gamma-radiation and is associated with time-dependent
      apoptosis, which is mitochondria-caspase dependent.

PMID- 15033714
TI  - Apoptotic mitochondrial dysfunction induced by benzo(a)pyrene in liver epithelial
      cells: role of p53 and pHi changes.
AB  - How pH(i) changes, more specifically alkalinization, affect the apoptotic cascade
      has yet to be determined. The aim of the present work was to test the involvement
      of mitochondria in the apoptotic cascade triggered by benzo(a)pyrene [B(a)P] and
      to determine the role of pH(i) changes and p53 relative to mitochondria. Our
      results indicate that B(a)P-induced apoptosis might rely upon a p53-dependent and
      a pH-sensitive mitochondrial dysfunction.

PMID- 15033715
TI  - Orphan nuclear receptor Nur77 translocates to mitochondria in the early phase of
      apoptosis induced by synthetic chenodeoxycholic acid derivatives in human stomach
      cancer cell line SNU-1.
AB  - Apoptosis-inducing activity of synthetic CDCA derivatives, HS-1199 and HS-1200,
      on gastric cancer cell line SNU-1 cells was explored. CDCA derivatives
      demonstrated various apoptosis hallmarks, such as mitochondrial changes,
      activation of caspase, DNA fragmentation, and nuclear condensation. Importantly,
      the orphan receptor Nur77 (TR3) was shown to translocate from the nucleus to
      mitochondria at the early time points after CDCA derivatives treatment. These
      data support the theory that CDCA derivatives-induced apoptosis of SNU-1 gastric
      cancer cell lines is mediated by mitochondria and caspase, and, at least in part,
      by Nur77.

PMID- 15033716
TI  - Prodigiosin induces apoptosis by acting on mitochondria in human lung cancer
      cells.
AB  - Prodigiosin (PG) is a secondary metabolite, isolated from a culture of Serratia
      marcescens, which has shown potent cytotoxicity against various human cancer cell
      lines as well as immunosuppressive activity. The purpose of this study was to
      evaluate the role of mitochondria in PG-induced apoptosis. Therefore, we
      evaluated the apoptotic action of PG in GLC4 small cell lung cancer cell line by
      Hoechst 33342 staining. In these cells, we examined mitochondrial apoptosis
      inducing factor (AIF) and cytochrome c (cyt c) release to the cytosol in PG time
      response studies. These findings suggest that PG induces apoptosis in both
      caspase-dependent and caspase-independent pathways.

PMID- 15033717
TI  - Molecular interaction between cyclophilin D and adenine nucleotide translocase in
      cytochrome c release: does it determine whether cytochrome c release is dependent
      on permeability transition or not?
AB  - We propose a model for the mechanism of permeability transition (PT) related
      cytochrome c release. It is likely that the Ca(2+) requirement for the induction
      of the mitochondrial permeability transition pore (MPTP) opening might be due to
      the Ca(2+)-dependent interaction between cyclophilin D and ANT. We show here that
      the modification of adenine nucleotide translocase (ANT), which is one of the
      components of MPTP, can induce two different types of the cytochrome c release.
      One is dependent on classical PT, resulting in mitochondrial swelling, and is
      inhibited by cyclosporin A. The other is PT-independent, without swelling, and is
      insensitive to cyclosporin A.

PMID- 15033719
TI  - Restoration of TRAIL-induced apoptosis in a caspase-8-deficient neuroblastoma
      cell line by stable re-expression of caspase-8.
AB  - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively
      induces apoptosis in most tumor cells, a process sometimes potentiated by
      chemotherapeutic drugs or cycloheximide (CHX). Childhood neuroblastoma (NB) is a
      clinically and biologically heterogeneous neoplasm whose behavior can be
      explained by differential regulation of apoptosis. The non-invasive S-type NB
      cell lines are sensitive to TRAIL, whereas the invasive N-type NB cell lines are
      resistant. We have reported the silencing of caspase-8 expression in N-type cells
      as a possible mechanism of death receptor-mediated resistance to apoptosis in NB.
      The recently observed deregulation of caspase-10 in these cells prompted us to
      investigate the particular contribution of caspase-8 silencing in the resistance
      to TRAIL in N-type cells. Stable caspase-8 expression was therefore restored in
      the IGR-N91 cell line by retroviral infection. The IGR-N91-C8 cells became
      sensitive to TRAIL-mediated apoptosis, whereas the control vector-infected IGR
      N91-M cells remained resistant. Interestingly, the apoptotic response to TRAIL
      was enhanced by co-treatment of SH-EP and IGR-N91-C8 cells with CHX or with sub
      toxic concentration of doxorubicin (DOX) in a caspase-dependent manner, as cells
      could be protected from death by specific caspase-8 or pan-caspase inhibitors.
      CHX or DOX was shown to enhance TRAIL-induced caspase-8 activation and loss of
      mitochondrial transmembrane potential. In conclusion, restoration of active
      caspase-8 expression in caspase-8- and caspase-10-deficient IGR-N-91 cell line is
      necessary and sufficient to fully restore TRAIL-mediated cell death. Moreover,
      DOX and CHX were able to sensitize NB cell lines to TRAIL-induced apoptosis in a
      caspase-8-dependent manner by engaging death receptor and mitochondrial signaling
      pathways.

PMID- 15033718
TI  - Caspase-12 and ER-stress-mediated apoptosis: the story so far.
AB  - The labyrinth of the endoplasmic reticulum (ER) interweaves the cytosol and
      connects to the nucleus, mitochondria, and the plasma membrane. In the lumen of
      the ER, the essential function of lipid synthesis, Ca(2+) storage, folding, and
      maturation of proteins take place. Therefore, the tight regulation and
      maintenance of ER homeostasis is vital. Disturbance of the Ca(2+) homeostasis
      during hypoxia, or imbalance between the demand and capacity of the protein
      folding apparatus, initiates an adaptive response of the cell, termed the
      unfolded protein response (UPR, ER stress response). As a result, ER-localized
      chaperones are induced, protein synthesis is slowed down, and a protein degrading
      system is initiated. However, if the ER stress cannot be alleviated, it
      culminates in apoptosis. This paper reviews the newly outlined signaling pathways
      of the unfolded protein response and describes the central role of caspase-12 in
      the initiation of cell death. The complex role of the ER and its signaling
      pathways provides a novel angle on apoptosis research and may offer a key to
      apoptosis-associated diseases.

PMID- 15033720
TI  - Cisplatin-induced apoptosis in melanoma cells: role of caspase-3 and caspase-7 in
      Apaf-1 proteolytic cleavage and in execution of the degradative phases.
AB  - Apoptosis protease-activating factor-1 (Apaf-1), which plays a central role in
      the formation of the apoptosome, is absent or poorly expressed (because of a
      transcriptional silencing by methylation) in a substantial percentage of
      metastatic melanomas and melanoma cell lines, which are unable to activate
      caspase-9 and execute the mitochondrial pathway of apoptosis. We studied
      cisplatin-induced apoptosis of the Apaf-1-positive human metastatic Me665/2/21
      melanoma cells. Our results indicate that caspase-7 is already processed in still
      adhering cells and such activation, contrary to the common view, precedes caspase
      3 processing. As expected by the cytochrome c release into the cytosol, caspase-9
      is processed to active forms (p37 and p35), along with a yet-unidentified p28.
      Interestingly, we also demonstrate a remarkable loss of Apaf-1 protein, along
      with the appearance of a related immunoreactive fragment of approximate, equals
      26 kDa; such proteolytic degradation proves to be a caspase-3/-7-mediated event.
      Our data also indicate that the inhibition afforded by ac-DEVD-CHO on several
      components (i.e., caspase-3/-7 and caspase-9 activities), and Apaf-1 proteolytic
      degradation, does not significantly abrogate either the apoptotic morphology or
      the cleavage of canonical targets, such as poly(ADP-ribose) polymerase (PARP) and
      lamin B. These results suggest that caspase-3 and caspase-7 are dispensable for
      the execution of apoptosis and, in our cellular model, the point of no return
      could be out of the mitochondrial cascade.

PMID- 15033721
TI  - A novel antioxidant-inhibited dexamethasone-mediated and caspase-3-independent
      muscle cell death.
AB  - Dexamethasone (Dex)-mediated cell death is associated with repression of survival
      factors (AP-1, c-myc, NF-kappaB). Dex suppressed the activity of genes encoding
      antioxidant enzymes leading to impaired viability and apoptotic cell death. These
      findings suggest that reactive oxygen species inhibit protein synthesis and
      amplify m-calpain-dependent proteolysis. The events that led to death of L6
      muscle cells were most likely triggered by Dex-mediated repression of
      antioxidative defenses on the genomic level.

PMID- 15033722
TI  - Caspase inhibitors as a supplement in immune activation therapies to achieve
      eradication of HIV in its latent reservoirs.
AB  - Synthetic caspase inhibitors are known to block death receptor-induced apoptosis.
      We have reported previously that in addition to apoptosis inhibition, caspase
      inhibitors induce a switch from proapoptotic to proinflammatory signaling in T
      cells. This switch sensitizes TNF-R1 to trigger TNF-alpha-induced reactivation of
      HIV in latently infected T cells. Here we ponder the prospects of caspase
      inhibitors as a supplement in immune activation therapies (IAT) to achieve
      eradication of HIV from the latent virus reservoirs in HIV-infected patients.

PMID- 15033723
TI  - Apoptotic cell death of cybrid cells bearing Leber's hereditary optic neuropathy
      mutations is caspase independent.
AB  - Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease
      characterized by selective death of retinal ganglion cells. Three pathogenic
      mtDNA point mutations induce an impairment of oxidative phosphorylation. We have
      investigated whether the release of cytochrome c during incubation of LHON
      cybrids in galactose medium leads to activation of the executive caspase-3 and to
      alteration of the energetic status of cells. From our research, it can be
      concluded that apoptotic cell death induced in LHON cybrid by galactose medium is
      caspase independent. It remains to be explained how the significant fragmentation
      of intranucleosomal DNA observed in LHON cybrids could also occur in the absence
      of caspase activation.

PMID- 15033724
TI  - Involvement of the change in chromatin structure in thymocyte apoptosis induced
      by phosphorylation of histones.
AB  - The inhibitors of protein phosphatase such as calyculin A and okadaic acid
      induced thymocyte apoptosis. DNA fragmentation was increased in the nuclei from
      thymocytes treated with calyculin A, which accelerated phosphorylation of
      histones. Judging from the circular dichroism analysis, the structure of soluble
      chromatin was changed by the treatment with calyculin A. These results suggest
      that the change in chromatin structure may be one of the molecular mechanisms of
      internucleosomal DNA fragmentation.

PMID- 15033725
TI  - Accumulation of histones in cell lysates precedes expression of apoptosis-related
      phagocytosis signals in human lymphoblasts.
AB  - Systemic lupus erythematosus (SLE) is characterized by the production of
      autoantibodies directed against several nuclear components, such as DNA and
      histones. Apoptosis was induced in activated human lymphoblasts (n = 6) by UV-B
      irradiation for 30 sec followed by continuous culturing. An extranuclear
      accumulation of the nucleosomal histones H2A, H2B, H3, and H4 in cell lysates was
      observed very early in the process of apoptosis, even before phosphatidylserine
      externalization occurred on the outer membrane surface of apoptotically dying
      lymphoblasts. We hypothesize that a dysregulation of apoptosis during these early
      phases may contribute to the induction of autoimmunity against nuclear
      autoantigens as seen in SLE.

PMID- 15033728
TI  - Convergence of the NF-kappaB and interferon signaling pathways in the regulation
      of antiviral defense and apoptosis.
AB  - The ubiquitously expressed interferon regulatory factor 3 (IRF-3) is directly
      activated following virus infection and functions as a key activator of the
      immediate-early Type 1 interferon (IFN) genes. Using DNA microarray analysis
      (8,556 genes) in Jurkat T cells inducibly expressing constitutively active IRF-3,
      several target genes directly regulated by IRF-3 were identified. Among the genes
      upregulated by IRF-3 were transcripts for a subset of known IFN-stimulated genes
      (ISGs), including ISG56, which functions as an inhibitor of translation
      initiation. Phosphorylation of C-terminal Ser/Thr residues-
      (382)GGASSLENTVDLHISNSHPLSLTSDQY(408)-is required for IRF-3 activation. Using C
      terminal point mutations and a novel phosphospecific antibody, Ser396 was
      characterized as the minimal phosphoacceptor site required in vivo for IRF-3
      activation following Sendai virus (SeV) infection, expression of viral
      nucleocapsid, or double-stranded RNA (dsRNA) treatment. The identity of the virus
      activated kinase (VAK) activity that targets and activates IRF-3 and IRF-7 has
      remained a critical missing link in the understanding of interferon signaling. We
      report that the IKK-related kinases-IKKepsilon/TBK-1-are components of VAK that
      mediate IRF-3 and IRF-7 phosphorylation and thus functionally link the NF-kappaB
      and IRF pathways in the development of the antiviral response.

PMID- 15033726
TI  - Early activation and induction of apoptosis in T cells is independent of c-Fos.
AB  - We used c-Fos-deficient activated T cells from the spleen and c-Fos-deficient
      thymocytes to address the capacity of these cells to undergo apoptosis in
      response to various stimuli. To determine the role of c-Fos in apoptosis
      regulation in thymocytes, we challenged thymocytes from wild-type and c-Fos
      deficient mice with either TPA or the glucocorticoid dexamethasone. After various
      time points cells were stained according to the Nicoletti method and analyzed by
      FACS. Thymocytes from both genotypes exhibited similar efficiency of apoptosis in
      response to treatment with TPA or dexamethasone. Our data provide clear evidence
      that c-Fos is not required for apoptosis regulation in activated T cells as well
      as in thymocytes.

PMID- 15033727
TI  - NF-kappaB inhibition restores sensitivity to Fas-mediated apoptosis in lymphoma
      cell lines.
AB  - Failure to perform the Fas-related apoptosis pathway can account for tumor
      resistance both to chemotherapeutic agents and to immunological effectors. We
      studied the role of NK-kappaB in Fas-resistance, employing the Fas-sensitive
      human T-lymphoma HuT78 cell line and its Fas-resistant variants HuT78B1 and
      HuT78G9. All these cell lines expressed high levels of constitutively activated
      NF-kappaB. Pretreatment of cells with NF-kappaB inhibitors (PDTC, MG132, or SN50)
      strongly enhanced CH11-induced apoptosis in HuT78 and Hut78G9 cells, while only
      MG132 showed a similar potentiating effect in HuT78B1. The described synergism
      was significantly inhibited by pretreatment with the anti-Fas-blocking antibody
      ZB4 or with the pancapsase inhibitor Z-VAD-FMK, but not by capsase-8 or -9
      inhibitors. Overall, these data suggest that NF-kappaB inhibition may restore the
      Fas-pathway in Fas-resistant NF-kappaB-overexpressing tumors.

PMID- 15033730
TI  - Role of NF-kappaB and DNA repair protein Ku on apoptosis in pancreatic acinar
      cells.
AB  - Reactive oxygen species have been known to cause DNA damage and induce apoptosis.
      During DNA damage, DNA repair proteins Ku70 and Ku80 prevent cell death, but
      severe DNA damage beyond the repair capacity of the DNA repair proteins triggers
      necrosis or apoptosis. Recent reports have shown that NF-kappaB plays a critical
      role in protecting the cells from apoptosis. We investigated whether glucose
      oxidase acting on beta-D-glucose (G/GO), which continuously produces H(2)O(2),
      induces apoptosis, and whether NF-kappaB and Ku are involved in G/GO-induced
      apoptosis in pancreatic acinar AR42J cells. Electron microscopic observation
      showed that apoptotic cells with characteristic nuclear condensation and
      shrinkage as well as large vacuoles were detected after G/GO treatment. G/GO
      treatment induced apoptotic cell death, as determined by viable cell count and
      DNA fragmentation. G/GO-induced apoptosis was increased in the cells transfected
      with the Ku-dominant negative mutant (Ku D/N) and mutated IkappaBalpha gene
      (IkappaB mt) as compared to the wild-type cells (Wild) and the cells transfected
      with the control pcDNA3 vector (pcN-3). G/GO treatment caused nuclear loss of
      both Ku70 and Ku80 in Wild cells and pcN-3 cells. Even without G/GO treatment,
      nuclear loss of Ku proteins was observed in IkappaB mt cells. These results
      suggest that oxidative stress-induced reduction of nuclear Ku proteins may cause
      loss of defense against DNA damage and thus induce apoptosis in pancreatic acinar
      cells. The novel finding is that nuclear translocation of Ku proteins may be
      mediated by NF-kappaB.

PMID- 15033729
TI  - Translational upregulation of the X-linked inhibitor of apoptosis.
AB  - The X-linked inhibitor of apoptosis protein (XIAP) is the most potent and best
      studied intrinsic regulator of programmed cell death. The critical role XIAP
      plays in the control of apoptosis is also reflected in the complex ways the
      activity of XIAP is regulated. In addition to regulating the function of the
      protein, the synthesis of XIAP is also selectively regulated. XIAP is translated
      by a cap-independent mechanism of translation initiation that is mediated by a
      unique internal ribosome entry site (IRES) sequence element located in its 5'
      untranslated region. This allows XIAP mRNA to be actively translated during
      conditions of cellular stress when the majority of cellular protein synthesis is
      inhibited. The IRES regulation of XIAP translation points to an important
      mechanism in the control and regulation of apoptosis.

PMID- 15033731
TI  - PLAG proteins: how they influence apoptosis and cell proliferation.
AB  - Pleomorphic adenoma gene 1 product (PLAG1) a transcription factor with zinc
      finger domains, is upregulated in several tumors, such as pleomorphic adenomas
      and lipoblastomas. PLAGL2 is a second member of the same subfamily of zinc finger
      proteins. Cells overexpressing either of these two genes display the typical
      markers of neoplastic transformation. We investigated whether PLAG1 and PLAGL2
      could prevent cells from undergoing apoptosis, leading them to grow
      uncontrollably.

PMID- 15033732
TI  - How the nucleolar sequestration of p53 protein or its interplayers contributes to
      its (re)-activation.
AB  - The tumor suppressor p53 is a short-lived protein that under normal conditions is
      reduced to a barely detectable level. The stability of p53 protein is primarily
      regulated in normal non-transformed cells by two interplayers: Mdm2 and p14(ARF).
      Relocation of p53, Mdm2, and p14(ARF) to the nucleolus seems to regulate, at
      least partially, the steady-state of p53. Moreover, there are alternative
      pathways of the regulation of p53 stability in unstressed cells. Jun-N(amino)
      terminal kinase (JNK) and poly(ADP-ribose) polymerase-1 (PARP-1) are involved in
      the regulation of the steady-state of wild-type (wt) p53 protein. However, in
      most human cervical carcinomas, which express the high-risk human papilloma
      viruses (HPVs) E6 protein, a complete switch from Mdm2 to HPV E6-mediated
      degradation of p53 occurs. Virally encoded E6 protein utilizes the cellular
      ubiquitin-protein ligase termed E6-associated protein (E6-AP) to target p53
      protein for proteolytic degradation. We recently addressed the question of
      whether p53 protein can be generally reactivated by chemotherapy in HeLa cells
      despite the E6 activity. We observed an increase of cellular p53 after cisplatin
      (CP) treatment. p53 protein accumulated preferentially in the nucleoli. We
      checked the cellular level of E6 during CP therapy. Six hours after application
      of CP the expression of E6 protein was markedly reduced. This coincided with the
      increase of cellular p53 level and preceded the nucleolar accumulation of p53
      protein, thereby indicating that repression of virally coded E6 protein by CP
      contributes to the restoration of p53 expression.

PMID- 15033733
TI  - Combination of tumor necrosis factor-alpha with sulindac in human carcinoma cells
      in vivo.
AB  - Transcription factor NF-kappaB plays a pivotal role in cancer cells in the
      resistance to apoptosis, since NF-kappaB is frequently activated in many primary
      carcinoma cells. Indeed, several NF-kappaB inhibitors are found to be promising
      anti-cancer agents. However, some anti-cancer agents activate NF-kappaB signals
      and may reduce their potential, including tumor necrosis factor (TNF)-alpha.
      Recently, the nonsteroidal anti-inflammatory drug (NSAID) sulindac and its
      metabolites have been shown to inhibit the NF-kappaB-mediated survival signals
      through inhibition of IKK-beta by their direct interaction. We thus investigate
      whether sulindac and its metabolite can augment TNF-alpha-mediated apoptosis in
      human carcinoma cells and be applicable for in vivo clinical usage. We here
      demonstrate that sulindac inhibited TNF-alpha-mediated NF-kappaB activation and
      greatly enhanced TNF-alpha-induced apoptosis in human gastric MKN45 and cervical
      HeLa carcinoma cell lines. The in vivo tumor growth of MKN45 cells was most
      strongly inhibited by a combination of TNF-alpha with sulindac compared with TNF
      alpha or sulindac alone. Moreover, we demonstrate that sulindac sulfide further
      augmented TNF-alpha-mediated apoptosis. Our data strongly suggest that
      combination therapy of TNF-alpha with sulindac and its metabolites may sensitize
      cancer cells to TNF-alpha and augment its pro-apoptotic potential. Therefore, in
      combination with sulindac or its metabolites, TNF-alpha may become a potentially
      useful anti-cancer agent to suppress tumor.

PMID- 15033734
TI  - MNNG induces dramatic DNA damage and non-apoptotic changes in cervical carcinoma
      HeLa cells.
AB  - It has been previously reported that a short treatment of human cervix carcinoma
      HeLa cells with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induced apoptosis. We
      examined the action of MNNG on HeLa cells and compared it with that of cisplatin.
      MNNG damaged the integrity of the cell membrane and killed the cells within 3
      hours. During this period no changes characteristic for apoptosis, such as cell
      shrinkage, condensation of nuclei, chromatin fragmentation or activation of
      caspases, could be detected. However, the exposure of HeLa cells to 50 micro M
      MNNG for 1 h resulted in dramatic DNA damage. The MNNG-induced disruption of cell
      membrane associated with cell death indicates that HeLa cells die by necrosis.

PMID- 15033735
TI  - Thallium induces apoptosis in Jurkat cells.
AB  - Thallium induces swelling in mitochondria and apoptosis in Jurkat cells. Both the
      swelling and the apoptosis are inhibited by means of cyclosporine A (CsA), thus
      suggesting that these phenomena result from the opening of the membrane
      transition pore (MTP) in mitochondria. Therefore, apoptosis can be explained as
      due to the opening of the MTP in mitochondria.

PMID- 15033736
TI  - Oxalate exposure promotes reinitiation of the DNA synthesis and apoptosis of HK-2
      cells, a line of human renal epithelial cells.
AB  - Oxalate, a metabolic end product, is a major constituent of kidney stones.
      Previously, we and others have demonstrated that oxalate is toxic to renal
      epithelial cells. In the present study, we characterized oxalate-induced cell
      death in HK2 cells, a line of renal epithelial cells from the human kidney. For
      these studies, HK2 cells were exposed to oxalate for various time points. Cells
      were examined for nuclear morphology, DNA fragmentation, and expression of
      various apoptosis-related proteins. Apoptotic mode of cell death was also
      confirmed by TUNEL assay. Results from these studies revealed that oxalate
      exposure resulted in time-dependent increase in DNA fragmentation. Maximum DNA
      fragmentation was observed at 2-24 hours following oxalate exposure. Results from
      Western blot analysis demonstrated an increased expression of the FAS ligand.
      Taken together, these data reveal that oxalate-associated nephrotoxicity results
      from oxalate-induced apoptosis of renal epithelial cells.

PMID- 15033737
TI  - Triggering of T-cell apoptosis by toxin-related ecto-ADP-ribosyltransferase ART2.
AB  - Cytotoxicity induced by protein ADP-ribosylation is a common theme of certain
      bacterial toxins and of the mammalian ectoenzyme ART2. Exposure of T cells to
      NAD, the substrate for ART2-catalyzed ADP-ribosylation, induces exposure of
      phosphatidylserine, uptake of propidium iodide, and fragmentation of DNA. ART2
      specific antibodies raised by gene gun immunization block NAD-induced apoptosis.
      ART2 catalyzed ADP-ribosylation of cell membrane proteins induces formation of
      cytolytic membrane pores by activating the P2X7 purinoceptor. This alternative
      pathway to T cell apoptosis could be triggered upon the release of NAD from
      intracellular stores, for example, during inflammatory tissue damage.

PMID- 15033738
TI  - ICBP90 expression is downregulated in apoptosis-induced Jurkat cells.
AB  - Inhibition of apoptosis, resulting from an increase in anti-apoptotic protein,
      plays a fundamental role in carcinogenesis. Because ICBP90 gene expression is
      deregulated in cancer cells, we studied its expression in Jurkat cells under
      apoptotic conditions to see whether ICBP90 is involved in the regulation of
      apoptosis. We found that ICBP90 expression and the percentage of living cells
      were dose-dependently decreased in PHA and ionophore A23187-stimulated Jurkat
      cells, but not in THP-1 cells. These results suggest that apoptosis is dependent
      upon ICBP90 expression downregulation and that ICBP90 exhibits anti-apoptotic
      properties.

PMID- 15033739
TI  - 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) induces apoptosis in
      human neuroblastoma cell lines.
AB  - The former popular hypnotic chloral hydrate has been known to spontaneously
      condense with tryptamine in the body to give rise to a highly unpolar 1
      trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) derivative. Earlier
      studies have revealed the relative permeability of the molecule through the body,
      and its ability to induce Parkinson-like symptoms in rats. In this study, we
      report that TaClo is a highly cytotoxic agent that leads to apoptosis in human
      neuroblastoma cells involving caspase-3 activation.

PMID- 15033741
TI  - Antiproliferative and apoptosis-inducing effects of hemin in hepatoma cells.
AB  - Hemin is an extremely versatile molecule that may have cytotoxic or
      cytoprotective effects on certain cells. We investigated the effect of hemin on
      the growth of hepatoma cells, including the multidrug-resistant ones. Searching
      for new tools that interfere with the growth of hepatomas is an important area of
      clinical research. Cell viability and proliferation of drug-sensitive and
      multidrug-resistant hepatoma cell lines was determined using the trypan-blue
      exclusion test XTT/PMS and colony-forming ability assays. Apoptosis was assessed
      by confocal microscopy and DNA ladder assay. Hemin inhibited the proliferation
      and induced apoptosis in both drug-sensitive and multidrug-resistant hepatoma
      cells overexpressing functional P-glycoprotein. zVAD-fmk inhibited the hemin
      induced decrease in cell viability, pointing to a role of caspases in hemin
      induced apoptosis. The antiproliferative and apoptosis-inducing effects of hemin
      might be considered in the design of treatment for patients with hepatoma.

PMID- 15033740
TI  - Induction of apoptosis by erucylphospho-N,N,N-trimethylammonium is associated
      with changes in signal molecule expressionand location.
AB  - At concentrations effecting apoptosis, the alkylphosphocholine ErPC3 induced
      increased expression of the Rb protein in breast cancer (MCF-7) and leukemia (SKW
      3, AR-230) cell lines as well as hypophosphorylation (K-562, CMLT-1, DOHH-2) and
      fragmentation of Rb (BV-173, SKW-3) in leukemia cell lines. ErPC3 exerts at least
      part of its antineoplastic activity by apoptosis, and this chain of events
      comprises early changes in the lipid raft fraction of the cellular membrane as
      well as modulation of different signal molecules, such as Abl, Bcr-Abl (fusion
      protein), and Rb.

PMID- 15033742
TI  - Effect of zinc on prostatic tumorigenicity in nude mice.
AB  - Prostate epithelial cells accumulate the highest zinc levels of any cells in the
      body. Evidence indicates that zinc plays critical roles in the normal function
      and pathology of the prostate gland. We have identified two important effects of
      zinc in the prostate epithelial cells: the inhibition of m-aconitase and the
      induction of mitochondrial apoptogenesis. However, at the present time, the
      effects of zinc on prostatic cells in in vivo conditions have not yet been
      reported. The objectives of this in vivo study were to investigate the effect of
      zinc on: tumorogenicity in nude mice, zinc accumulation in tumor tissues, and the
      levels of mitochondrial membrane permeability related proteins, Bax/Bcl-2. A
      tumorigenicity animal model was established using male nude mice (4-6 weeks old)
      with inoculation of PC-3 cells (5-10x10(6)/mL) prepared in 10% Matrigel. The mice
      were treated with zinc by ALZET osmotic pumps (Durect Corporation), with a
      releasing rate of 0.25 micro l/h for 28 days. Zinc concentrations of the tumor
      tissues were determined by Atomic Absorption Spectrophotometer method. Frozen
      sections of tumor tissues were prepared for TUNEL assay. The levels of Bax and
      Bcl-2 in the tumor tissues were determined by Western blot analyses. Our study
      demonstrated that in vivo treatment of zinc increased zinc accumulation and
      citrate production in PC-3 cell induced tumor tissues and inhibited tumor growth.
      The inhibitory effect of zinc appears to result from zinc-induced apoptosis by
      regulation of mitochondrial membrane permeability-related Bax/Bcl-2 proteins.

PMID- 15033743
TI  - The selective estrogen receptor modulator 4-hydroxy tamoxifen induces G1 arrest
      and apoptosis of multiple myeloma cell lines.
AB  - Multiple myeloma (MM) is an incurable hematological malignancy for which new
      therapeutic strategies should be envisaged. The selective estrogen receptor
      modulator (SERM), 4-hydroxy tamoxifen (4-OHTam), in the range of 1 to 10 micro M,
      was able to impair the cell proliferation of MM cell lines. This was achieved by
      blocking cells at the G1 phase of the cell cycle and by inducing apoptosis. This
      cellular response was observed in five out of six tested cell lines, all five
      expressing both alpha and beta estrogen receptor forms. No modifications of Bcl
      2, Bcl-X, and Bax levels were observed, as well as no changes in Pi3K/Akt and
      JAK/STAT pathways that are often constitutively active in these cells. The
      signalization of 4-OHTam-induced cell death needs further investigation.

PMID- 15033744
TI  - Ultraviolet ray induces chromosomal giant DNA fragmentation followed by
      internucleosomal DNA fragmentation associated with apoptosis in rat glioma cells.
AB  - Giant DNA fragments (1-2 Mbp) were found in C6 rat glioma cells irradiated by a
      lethal dose of ultraviolet-C (UV-C, 254 nm) at 50 J/m(2). After irradiation, the
      fragments mutated into high-molecular-weight (100-800 kbp) DNA fragments and then
      into ladder-formed internucleosomal DNA fragments. Poly-ADP-ribose polymerase
      (PARP) activity and NAD levels were reduced during DNA fragmentation. Some
      inhibitors of caspase and protease inhibited DNA ladder formation, but not giant
      DNA fragmentation, whereas antioxidants did not inhibit DNA fragmentation. These
      results suggest that a lethal dose of UV radiation induces giant DNA
      fragmentation and leads to internucleosomal DNA fragmentation associated with
      apoptosis through some caspases and nonreactive oxygen species in cells.

PMID- 15033745
TI  - Apoptosis induced by the alkaloid sampangine in HL-60 leukemia cells: correlation
      between the effects on the cell cycle progression and changes of mitochondrial
      potential.
AB  - Sampangine, a plant-derived copyrine alkaloid extracted from the stem bark of
      Cananga odorata, primarily exhibits antifungal and antimycobacterial activities,
      but it also displays in vitro antimalarial activity against Plasmodium falciparum
      and is cytotoxic to human malignant melanoma cells. It inhibits cell aggregation,
      but no molecular target has yet been identified. We investigated the biochemical
      pathway involved in sampangine-induced cytotoxicity toward HL-60 cells. These
      leukemia cells are prone to enter apoptosis after treatment with various stimuli,
      including genotoxic compounds structurally close to sampangine, such as
      ascididemin.

PMID- 15033746
TI  - The antiproliferative alkylphospholipid S-1-O-phosphocholine-2-N-acetyl
      octadecane induces apoptosis in leukemia cell lines.
AB  - Lipids are involved in a multitude of important cellular functions. They act as
      signaling molecules and can even provoke apoptosis. In this context we
      investigated the efficacy of synthetic alkylphosphocholines (APCs) as potential
      anti-cancer membrane-affecting drugs. Leading to novel therapeutic strategies for
      cancer treatment, the new agents interact with the cell membrane and do not
      affect the DNA. The data presented here show a cell death-inducing capacity for 1
      O-phosphocholine-2[S]-O-acetyl-octadecane and 1-O-phosphocholin-2[S]-N-acetyl
      octadecane in Jurkat T cells as well as in BJAB cells. The activation of caspases
      is generally required for the induction of apoptosis as shown by experiments with
      specific caspase inhibitors. The results point on the one hand to the formation
      of a functional DISC after APC-treatment as indicated by the clustering of
      receptor molecules and on the other hand to the dependency on the instrinsic
      apoptotic machinery and the downstream of mitochondria-activated apoptosome.

PMID- 15033748
TI  - Staurosporine induces apoptotic volume decrease (AVD) in ECV304 cells.
AB  - Incubation of ECV304 cells with 1 micro M staurosporine (STS) causes apoptotic
      cell death. In the present study, we investigate whether a significant apoptotic
      volume decrease (AVD) was apparent during the very early times (1 h) of the
      apoptotic process. Our data suggest that upregulation of Cl(-) (and possibly
      K(+)) channels by STS may be a very early primary event required for the
      subsequent onset of AVD, which results in apoptosis.

PMID- 15033747
TI  - Gene expression induced by X-ray irradiation in human blood cell lines.
AB  - The response to X-ray irradiation of three different human hematopoietic cell
      lines originating from T (Jurkat), B (Raji), and promyelocytic (HL60) leukemia
      was analyzed. The survival after irradiation differed among the three cell lines,
      with Jurkat cells being the most vulnerable and HL60 being the least sensitive.
      The profile of gene expression was studied with the microarray technique in both
      Jurkat and HL60 cell lines. Out of the 13,800 different genes spotted on
      microarrays, very few genes (<0.5%) appeared to be induced more than 2-fold or
      repressed more than 2.5-fold in both cell lines.

PMID- 15033749
TI  - The role of beta-glucuronidase in induction of apoptosis by genistein combined
      polysaccharide (GCP) in xenogeneic mice bearing human mammary cancer cells.
AB  - In order to reveal the mechanisms underlying genistein combined polysaccharide
      (GCP) inhibition of tumor proliferation, we investigated the effects of GCP on
      the growth of human breast cancer cells transplanted to athymic nude mice. We
      further investigated the metabolism of genistein and its association with the
      beta-glucuronidase activity in tumor and normal tissues.

PMID- 15033752
TI  - The overexpression of Bcl-2 antagonizes the proapoptotic function of the kappa
      opioid receptor.
AB  - Opioid receptors are G-protein-coupled cell-surface receptors that are mainly
      expressed in neuronal cells. Stimulation of the kappa-opioid receptor expressed
      by cultured human epithelial cancer cells promotes staurosporine-induced
      apoptosis. In this study, while Bcl-2 did not inhibit staurosporine-induced
      apoptosis, it did inhibit the kappa-opioid receptor-mediated potentiation of
      apoptosis. The results suggest that Bcl-2 targets a step that is specific to the
      signaling pathway of the kappa-opioid receptor.

PMID- 15033750
TI  - Vitamin D protects keratinocytes from apoptosis induced by osmotic shock,
      oxidative stress, and tumor necrosis factor.
AB  - Calcitriol, the hormonal form of vitamin D, inhibited caspase-3-like activation
      in HaCaT keratinocytes exposed to hyperosmotic and oxidative stresses, heat
      shock, and the inflammatory cytokine TNF. The hormone also protected the cells
      from caspase-independent cell death induced by hyperosmotic and oxidative
      stresses. The protection against hyperosmotic stress is not affected by
      inhibitors of the EGF receptor, ERK or PI13 kinase pathways, neither is it due to
      reduced activity of the proapoptotic p38 MAP kinase. These results are in
      accordance with previous in vivo findings that vitamin D protects epidermal
      keratinocytes from apoptosis due to UV radiation or chemotherapy.

PMID- 15033751
TI  - Inhibition of apoptosis by amphiregulin via an insulin-like growth factor-1
      receptor-dependent pathway in non-small cell lung cancer cell lines.
AB  - The reciprocal activation of amphiregulin (AR) and insulin-like growth factor-1
      (IGF1) pathways has been shown to induce inhibition of serum deprivation
      apoptosis in non-small cell lung cancer (NSCLC) cell lines H358 and H322. We
      demonstrated that AR activated the IGF1 receptor (IGF1-R), which in turn induced
      the secretion of AR and IGF1. Transactivation of the IGF1-R by AR is independent
      of its binding to EGFR. Thus, AR can inhibit apoptosis in NSCLC cells through an
      IGF1-R-dependent pathway.

PMID- 15033753
TI  - Induction of apoptosis in human pancreatic cancer cells by docosahexaenoic acid.
AB  - Polyunsaturated fatty acids have been indicated to induce anti-proliferative
      and/or apoptotic effects in various tumor cells. We showed that, at a 200- micro
      M concentration, both alpha-linoleic (18:2 n-6; LA) or docosahexaenoic (22:6 n-3;
      DHA) acid inhibited cell growth, while only DHA induced apoptosis in the human
      Paca-44 pancreatic cancer cell line. Investigating the mechanism underlying DHA
      induced apoptosis, we showed that DHA induced a rapid and dramatic (>60%)
      intracellular depletion of reduced glutathione (GSH), without affecting oxidized
      glutathione (GSSG). Moreover, using two specific inhibitors of carrier-mediated
      GSH extrusion, cystathionine or methionine, we observed that GSH depletion
      occurred via an active GSH extrusion, and that inhibition of GSH efflux
      completely reversed apoptosis. These results provide the first evidence for a
      possible causative role of GSH depletion in DHA-induced apoptosis.

PMID- 15033755
TI  - The sesame seed oil constituent, sesamol, induces growth arrest and apoptosis of
      cancer and cardiovascular cells.
AB  - Sesamol is a potent inhibitor of fungal fatty acid biosynthesis. This effect is
      apparently due to inhibition of malic enzyme and the supply of NADPH that is
      required for this biosynthetic pathway. It is the ability of sesamol to reduce
      the synthesis of the coenzyme, NADPH, that makes it attractive for use in
      studying the effect of oxidants on tumor and vascular endothelial cells. By
      conducting preliminary studies on the effect of sesamol alone, it was clear that
      the compound demonstrated marked cytotoxicity. This paper describes the
      experiments performed.

PMID- 15033754
TI  - Pro-oxidant activity of low doses of resveratrol inhibits hydrogen peroxide
      induced apoptosis.
AB  - We have recently shown that efficient apoptotic signaling is a function of a
      permissive intracellular milieu created by a decrease in the ratio of superoxide
      to hydrogen peroxide and cytosolic acidification. Resveratrol, a phytoalexin
      found in grapes and wines, triggers apoptosis in some systems and inhibits the
      death signal in others. In this regard, the reported inhibitory effect on
      hydrogen peroxide-induced apoptosis has been attributed to its antioxidant
      property. Here, we provide evidence that exposure of human leukemia cells to low
      concentrations of resveratrol (4-8 micro M) inhibits caspase activation and DNA
      fragmentation induced by incubation with hydrogen peroxide or upon triggering
      apoptosis with a novel compound that kills via intracellular hydrogen peroxide
      production. At these concentrations, resveratrol elicits pro-oxidant properties
      as evidenced by an increase in intracellular superoxide concentration. This pro
      oxidant effect is further supported by our observations that the drop in
      intracellular superoxide and cytosolic acidification induced by hydrogen peroxide
      is completely blocked in cells preincubated with resveratrol. Thus, the
      inhibitory effect of resveratrol on hydrogen peroxide-induced apoptosis is not
      due to its antioxidant activity, but contrarily via a pro-oxidant effect that
      creates an intracellular environment nonconducive for apoptotic execution.

PMID- 15033756
TI  - The inducible NO synthase is downregulated during apoptosis of malignant cells
      from B-cell chronic lymphocytic leukemia induced by flavopiridol and polyphenols.
AB  - Downregulation of iNOS and NO is a pathway common for flavones and polyphenols,
      two distinct families of phytoalexins. Our data suggest that inhibition of the NO
      pathway could be one of the mechanisms involved in the proapoptotic properties of
      these phytoalexins in leukemia B-cells.

PMID- 15033757
TI  - Catha edulis (Khat) induces cell death by apoptosis in leukemia cell lines.
AB  - Khat is the Celastraceus edulis plant, a flowering evergreen tree or large shrub,
      which grows in the Horn of Africa and southwestern Arabia. Khat use has been
      associated with development of oral cancer, but its molecular effects remain
      controversial. This study describes a novel cytotoxic effect of whole khat
      extract on three leukemia cell lines. Cells were exposed to khat extract and
      harvested for analysis by fluorescent and electron microscopy, trypan blue
      exclusion, as well as immunoblotting to characterize the mode of cell death. In a
      separate series, cells were pretreated with a panel of caspase inhibitors for
      possible inhibitory effects. Khat induced a rapid cell death effect in HL-60,
      Jurkat, and NB4 cells that occurred within 2 h of exposure. The treated cells
      retained their ability to exclude trypan blue dye, a key feature in the apoptotic
      process. Exposed cells consistently developed morphological features of manifest
      apoptosis. Z-VAD, a pan-caspase inhibitor, completely inhibited toxic activity
      for up to 8 h, with partial inhibition by other caspase-specific agents. Western
      blot analysis showed specific cleavage of caspase-3 in khat-exposed cells. This
      study shows that khat induces cell death by apoptosis in a process sensitive to
      inhibition by caspase inhibitors, suggesting that subcellular interactions could
      be of particular relevance for the biological effects of khat in the cell death
      process and possibly carcinogenesis.

PMID- 15033758
TI  - Curcumin-induced cell death in two leukemia cell lines: K562 and Jurkat.
AB  - Curcumin presents strong antioxidant and anticancer properties. However,
      molecular mechanisms leading to curcumin-induced cell death are poorly
      understood. The effect of curcumin was compared in two different leukemia cell
      lines: K562 and Jurkat. Cell death was induced in both cell lines, and apoptosis
      pathways were investigated by Western blot analysis. Decreases in pro-caspase 8
      and 9 levels were observed. BH(3) interacting domain death agonist (Bid) was also
      cleaved. Jurkat cells appeared to be more sensitive to curcumin, and apoptosis
      takes place earlier.

PMID- 15033759
TI  - Sulforaphane modulates cell cycle and apoptosis in transformed and non
      transformed human T lymphocytes.
AB  - Isothiocyanates exert chemopreventive effects against chemically induced tumors
      in animals, modulating enzymes required for carcinogens'
      activation/detoxification and/or the induction of cell-cycle arrest and apoptosis
      in tumor cell lines. To investigate the chemopreventive potential of
      isothiocyanates, we studied proliferation, apoptosis induction and p53, bcl-2 and
      bax protein expression in Jurkat T-leukemia cells by the isothiocyanate
      sulforaphane. Sulforaphane caused G(2)/M-phase delay and increase of apoptotic
      cell fraction in a time- and dose-dependent manner. Necrosis was observed after
      prolonged exposure to elevated sulforaphane doses. Moreover, it markedly
      increased p53 and bax protein expression, and slightly affected bcl-2 expression.
      Since selective targeting and low toxicity for normal host tissues are
      fundamental requisites for proposed chemopreventive agents such as sulforaphane,
      we tested sulforaphane on non-transformed phytohemagglutinin-stimulated human T
      lymphocytes. We demonstrated that sulforaphane arrested cell-cycle progression in
      G1 phase by a significant down-modulation of cyclin D3. Moreover, sulforaphane
      induced apoptosis (and also necrosis), mediated by an increase in the expression
      of p53, whereas it exerted little effect on bcl-2 and bax levels. These findings
      indicate that sulforaphane can exert protective effects inhibiting leukemic cell
      growth. Moreover, sulforaphane is active not only in transformed lymphocytes but
      also in their normal counterpart. Although in vitro studies do not necessarily
      predict in vivo outcomes, our findings raise important questions regarding the
      suitability of sulforaphane for cancer chemoprevention.

PMID- 15033760
TI  - Peptides from anchovy sauce induce apoptosis in a human lymphoma cell (U937)
      through the increase of caspase-3 and -8 activities.
AB  - Various biological activities of peptides have been found. In this study, the
      induction of apoptosis in a human lymphoma cell line (U937) by peptide fraction
      separated from anchovy sauce was studied using biochemical and flow cytometric
      methods. After U937 was treated with a hydrophobic peptide fraction of the
      anchovy sauce, a sub-G1 peak, which represents apoptosis, was found in the cell
      cycle analysis. The apoptosis in the peptide-treated U937 cell was also confirmed
      by apoptotic DNA fragmentation. Furthermore, an increase of caspase-3 and -8
      activities was observed. Our results suggest that the peptide fraction separated
      from the anchovy sauce may have cancer chemopreventive effects through the
      induction of apoptosis in cancer cells.

PMID- 15033761
TI  - Alveolar cell death in hyperoxia-induced lung injury.
AB  - Exposure to high oxygen concentration causes direct oxidative cell damage through
      increased production of reactive oxygen species. In vivo oxygen-induced lung
      injury is well characterized in rodents and has been used as a valuable model of
      human respiratory distress syndrome. Hyperoxia-induced lung injury can be
      considered as a bimodal process resulting (1) from direct oxygen toxicity and (2)
      from the accumulation of inflammatory mediators within the lungs. Both apoptosis
      and necrosis have been described in alveolar cells (mainly epithelial and
      endothelial) during hyperoxia. While the in vitro response to oxygen seems to be
      cell type-dependent in tissue cultures, it is still unclear which are the death
      mechanisms and pathways implicated in vivo. Even though it is not yet possible to
      distinguish unequivocally between apo-ptosis, necrosis, or other intermediate
      form(s) of cell death, a great variety of strategies has been shown to prevent
      alveolar damage and to increase animal survival during hyperoxia. In this review,
      we summarize the different cell death pathways leading to alveolar damage during
      hyperoxia, with particular attention to the pivotal role of mitochondria. In
      addition, we discuss the different protective mechanisms potentially interfering
      with alveolar cell death.

PMID- 15033762
TI  - Hypoxic regulation of neutrophil apoptosis role: of reactive oxygen intermediates
      in constitutive and tumor necrosis factor alpha-induced cell death.
AB  - Activation of the NADPH oxidase system to generate reactive oxygen species (ROS)
      plays a key role in bacterial killing by human neutrophils. However, the
      involvement of such radicals in spontaneous and TNFalpha-driven neutrophil
      apoptosis remains uncertain. While incubation of cells under anoxic conditions
      attenuated the pro-apoptotic effect of TNFalpha, full activation of the
      respiratory burst using PAF followed by fMLP, or the addition of physiologically
      relevant concentrations of H(2)O(2), had no effect on the rate of apoptosis.
      Furthermore, the phosphoinositide 3-kinase inhibitor, LY294002, which abolishes
      receptor-mediated activation of the NADPH oxidase, and five discrete anti
      oxidants all failed to affect apoptotic thresholds. Thus ROS do not appear to
      modulate constitutive apoptosis in neutrophils or appear sufficient to mediate
      the pro-apoptotic effect of TNFalpha.

PMID- 15033763
TI  - Hypoxic stress stably alters apoptotic parameters on U937 cells.
AB  - Tumor promonocytic U937 cells cultured under a low O(2)/high CO(2) atmosphere
      display altered characteristics after restoration of normal atmosphere: increased
      resistance to apoptosis induced by different treatments; apoptotic morphology;
      lack of glutathione (GSH) extrusion in apoptosis; lack of protection by
      antioxidants; and lack of Ca(2+) mobilization with thapsigargin. These
      alterations were stably maintained for many months of culture in normal
      conditions, originating the stable U937-HX variant. Since the hypoxic treatment
      did not produce a great selective pressure, the alterations are conceivably the
      result of stable adaptative response.

PMID- 15033764
TI  - Na/Ca exchanger overexpression induces endoplasmic reticulum stress, caspase-12
      release, and apoptosis.
AB  - This paper describes a possible strategy to control Ca(2+) homeostatsis as a
      possible approach to prevent or enhance beta-cell apoptosis

PMID- 15033765
TI  - A novel gene, Jpk, induces apoptosis in F9 murine teratocarcinoma cell through
      ROS generation.
AB  - A novel gene Jpk (Jopock) has been originally isolated through yeast 1
      hybridization technique as a trans-acting factor interacting with the position
      specific regulatory element of a murine Hoxa-7. Northern analysis revealed that
      the Jpk was expressed at day 7.0 post coitum (p.c.) during early gastrulation.
      Previously it has been shown that a trace amount of JPK protein led bacterial
      cells to death. In eukaryotic F9 cells, Jpk also led the cell to death-generating
      DNA ladder: fewer than 50% of the cells survived after 72-h transfection. Flow
      cytometric analysis with cells stained with each Annexin V/7-amino-actinomycin D
      (7-AAD), MitoTracker, and hydroethidine (HE) revealed that Jpk induced apoptotic
      cell death in a time-dependent manner, reduced mitochondrial membrane potential,
      and increased ROS (reactive oxygen species) production, respectively.
      Additionally, Jpk seemed to regulate the Bcl family at the transcriptional level
      when RT-PCR was performed. Although the precise mechanism is not clear, these
      results altogether suggest that Jpk is a potent inducer of apoptosis through
      generation of ROS as well as concomitant reduction of mitochondrial membrane
      potential.

PMID- 15033767
TI  - Rescue of cells from apoptosis by antioxidants occurs downstream from GSH
      extrusion.
AB  - Antioxidants-that is, scavengers of free radicals and anaerobic conditions
      (5%CO(2), 95% N(2))-protect monocytic U937 cells from damage-induced apoptosis.
      Antioxidants rescue the cells acting on the apoptotic pathway at a step
      downstream from gluthatione extrusion. Reducing agents, such as DTT, also reduce
      stress-induced apoptosis. Thus, apoptotic GSH extrusion triggers the downstream
      events of apoptosis by leaving cells unprotected against thiol?s oxidation and
      radical production.

PMID- 15033766
TI  - Vitamin D enhances caspase-dependent and independent TNF-induced breast cancer
      cell death: the role of reactive oxygen species.
AB  - Calcitriol, the hormonal form of vitamin D, enhanced TNF-induced cytotoxicity in
      MCF-7 breast cancer cells. It increased the induction of caspase-3-like activity
      and TNF-induced caspase-independent cytotoxicity in the presence of a pan-caspase
      inhibitor. The antioxidants N-acetylcysteine, glutathione, lipoic acid, and
      ascorbic acid markedly reduced the effect of the hormone on TNF-induced caspase
      activation, attesting to the involvement of reactive oxygen species (ROS) in the
      cross-talk between the hormone and the cytokine. Calcitriol augmented the drop in
      mitochondrial membrane potential induced by TNF as assessed by the fluorescent
      probe JC-1. We postulate that the interaction of TNF and calcitriol on the level
      of the mitochondria underlies the enhancement of TNF-induced, ROS-mediated
      caspase-dependent and -independent cell death.

PMID- 15033768
TI  - Cytochrome c, glutathione, and the possible role of redox potentials in
      apoptosis.
AB  - The redox environment of the cell is now thought to be extremely important to
      control the activity of many proteins. During apoptosis, the intracellular redox
      potential (E(h)) becomes more positive, with possible consequences for the
      mechanisms of apoptosis. Glutathione and cytochrome c might both influence and be
      influenced by the cellular redox environment and therefore be important in the
      progression of apoptosis.

PMID- 15033770
TI  - The developing mouse dentition: a new tool for apoptosis study.
AB  - Developing limb or differentiating neural and blood cells are traditional models
      used to study programmed cell death in mammals. The developing mouse dentition
      can also be an attractive model for studying apoptosis regulation. Apoptosis is
      most extant during early odontogenesis in mice. The embryonic tooth pattern is
      comprised not only of anlagen of functional teeth (incisor, molars), but also of
      vestiges of ancestral tooth primordia that must be suppressed. Apoptosis is
      involved in (a) the elimination of vestigial tooth primordia in the prospective
      toothless gap (diastema) between the incisor and molars and (b) the shaping of
      germs in functional teeth. This type of apoptosis occurs in the dental epithelium
      according to a characteristic temporo-spatial pattern. Where apoptosis
      concentrates, specific signaling is also found. We proposed a hypothesis to
      explain the stimulation of apoptosis in the dental epithelium by integrating two
      concepts: (1) The regulation of epithelial budding by positional information
      generated from interactions between growth-activating and growth-inhibiting
      signals, and (2) apoptosis stimulation by the failure of death-suppressing
      signals. During the budding of the dental epithelium, local excess in growth
      inhibitors (e.g., Bmps) might lead to the epithelial cells' failure to receive
      adequate growth-activating (apoptosis-suppressing) signals (e.g., Fgfs). The
      resulting signal imbalance leads to cell "suicide" by apoptosis. Understanding of
      apoptosis regulation in the vestigial tooth primordia can help to elucidate the
      mechanism of their suppression during evolution and to identify factors essential
      for tooth survival. The latter knowledge will be important for developing a
      technology of tooth engineering.

PMID- 15033769
TI  - Apoptotic GSH extrusion is associated with free radical generation.
AB  - Reactive oxygen species (ROS) are involved in many forms of apoptosis and mediate
      apoptosis in a number of cell types. In this paper, we use a variant of U937
      monocytic cells (U937 HX) that show different biochemical features with respect
      to standard U937. Apoptotic standard U937 extrude reduced glutathione (GSH) and
      generate free radicals concomitantly with loss of mitochondria transmembrane
      potential (mt Deltapsi). These events are correlated with the extrusion of
      intracellular GSH. Conversely, apoptotic U937 HX cells retain GSH, and the loss
      of mt Deltapsi is not accompanied by generation of free radicals. The perfect
      inverse correlation between (a) ROS generation and (b) the presence of
      intracellular GSH during apoptosis suggests novel mechanisms to finely tune ROS
      generation in apoptosis.

PMID- 15033772
TI  - Surfactant protein D binds genomic DNA and apoptotic cells, and enhances their
      clearance, in vivo.
AB  - Collectins, such as surfactant protein D (SP-D), bind apoptotic cells; however,
      the ligands that they recognize on these cells are unknown. We hypothesized that
      SP-D binds to the DNA present on these cells. We show that SP-D binds and
      aggregates mouse alveolar macrophage DNA effectively. Alveolar macrophages of SP
      D((-/-)) mice contained more nicked DNA than those of SP-A((-/-)) and wild type
      mice. Our results also suggest that carbohydrate recognition domains of SP-D may
      recognize DNA present on the apoptotic cells. Therefore, cell-surface DNA could
      be a ligand for recognition of apoptotic cells by collectins.

PMID- 15033771
TI  - Innate immune collectins bind nucleic acids and enhance DNA clearance in vitro.
AB  - Collectins are a class of innate immune proteins that opsonize microbes and other
      ligands via their carbohydrate-recognition domains and enhance their clearance by
      phagocytes. We hypothesized that collectins, such as pulmonary surfactant protein
      (SP-) A and D and mannose-binding lectin (MBL), could bind nucleic acid, which is
      a pentameric sugar-based anionic polymer. We have shown that SP-D and MBL bind to
      both DNA and RNA effectively and also that SP-D enhances the uptake of DNA by
      human monocytic cells. Therefore, our results suggest that nucleic acids may be a
      novel class of ligands for collectins. This class of innate immune proteins could
      enhance the clearance of DNA that is released by necrotic cells or microbial
      cells. Our findings may have important biological implications, such as the
      alleviation of DNA-mediated tissue inflammation.

PMID- 15033773
TI  - Inhibition of HSP70 and a collagen-specific molecular chaperone (HSP47)
      expression in rat osteoblasts by microgravity.
AB  - Rat osteoblasts were cultured aboard a space shuttle for 4 or 5 days. Cells were
      exposed to 1alpha, 25 dihydroxyvitamin D(3) during the last 20 h and then
      solubilized by guanidine solution. The mRNA levels for molecular chaperones were
      analyzed by semi-quantitative RT-PCR. ELISA was used to quantify TGF-beta1 in the
      conditioned medium. The HSP70 mRNA levels in the flight cultures were almost
      completely suppressed, as compared to the ground (1 x g) controls. The inducible
      HSP70 is known as the major heat shock protein that prevents stress-induced
      apoptosis. The mean mRNA levels for the constitutive HSC73 in the flight cultures
      were reduced to 69%, approximately 60% of the ground controls. HSC73 is reported
      to prevent the pathological state that is induced by disruption of microtubule
      network. The mean HSP47 mRNA levels in the flight cultures were decreased to 50%
      and 19% of the ground controls on the 4th and 5th days. Concomitantly, the
      concentration of TGF-beta1 in the conditioned medium of the flight cultures was
      reduced to 37% and 19% of the ground controls on the 4th and 5th days. HSP47 is
      the collagen-specific molecular chaperone that controls collagen processing and
      quality and is regulated by TGF-beta1. Microgravity differentially modulated the
      expression of molecular chaperones in osteoblasts, which might be involved in
      induction and/or prevention of osteopenia in space.

PMID- 15033774
TI  - Coinduction of GTP cyclohydrolase I and inducible NO synthase in rat osteoblasts
      during space flight: apoptotic and self-protective response?
AB  - The mechanism underlying space flight-induced osteopenia is unknown. In
      osteoblasts, the inducible nitric oxide (NO) synthase (iNOS) is involved in the
      early response to mechanical strain and induction of apoptosis. GTP
      cyclohydrolase I (GTPCH) is a key enzyme that is essential for iNOS activity. The
      coordinate expression of GTPCH prevents apoptosis that is induced by iNOS/NO. The
      purpose of this study was to investigate the effects of space flight on the
      expression of apoptotic/anti-apoptotic molecules iNOS and GTPCH in rat
      osteoblasts. Rat osteoblasts were cultured aboard a space shuttle and solubilized
      on the 4th and 5th days of the mission. The mRNA levels for iNOS and GTPCH in the
      flight cultures were increased to at least 120-fold and threefold higher than the
      ground (1 x g) controls, respectively. The amount of cellular DNA per flight
      culture vessel was 53% and 58% of the ground controls on the 4th and 5th days,
      respectively. However, the increasing rate of the DNA amount from the 4th to the
      5th day was not different between the flight cultures and the ground controls.
      Morphologically, the cells grew in space as well as on the ground. Co-expression
      of GTPCH and iNOS may indicate a self-protective mode of action in osteoblasts
      against the harmful stress under microgravity.

PMID- 15033775
TI  - Apoptosis signal transduction and the maturity status of human spermatozoa.

PMID- 15033776
TI  - Opposite phenotypes of cancer and aging arise from alternative regulation of
      common signaling pathways.
AB  - Phenotypic features of malignant and senescent cells are in many instances
      opposite. Cancer cells do not "age"; their metabolic, proliferative, and growth
      characteristics are opposite to those observed with cellular aging (both
      replicative and functional). In many such characteristics cancer cells resemble
      embryonic cells. One can say that cancer manifests itself as a local,
      uncontrolled "rejuvenation" in an organism. Available evidence from human and
      animal studies suggests that the opposite phenotypic features of aging and cancer
      arise from the opposite regulation of genes participating in apoptosis/growth
      arrest or growth signal transduction pathways in cells. This fact may be
      applicable in the development of new anti-aging treatments. Genes that are
      contrarily regulated in cancer and aging cells (e.g., proto-oncogenes or tumor
      suppressors) could be candidate targets for anti-aging interventions. Their
      "cancer-like" regulation, if strictly controlled, might help to rejuvenate the
      human organism.

PMID- 15033777
TI  - Gelsolin for senescence-associated resistance to apoptosis.
AB  - One of the characteristics of the senescent cell is apoptotic resistance.
      Gelsolin, a Ca(2+)-dependent actin regulatory protein, is believed to regulate
      the intracellular movements which are necessary for cell growth, proliferation,
      and differentiation. Recently, gelsolin was suggested to play a role in apoptotic
      resistance, which led us to examine its involvement in the apoptotic resistance
      of senescent cells. We found that the protein and mRNA levels of gelsolin were
      increased in senescent human diploid fibroblasts (HDFs). Gelsolin was
      intracellularly co-localized to the actin stress fiber and distributed to the
      nucleus and mitochondria in old HDFs. To examine the anti-apoptotic function of
      gelsolin in senescent HDFs, we tried to downregulate the expression of gelsolin
      by using antisense oligonucleotide in old HDFs. We then treated the senescent
      HDFs with the apoptosis-inducing agent menadione. Downregulation of gelsolin in
      senescent HDFs resulted in increased sensitivity to menadione-induced apoptotic
      cell death. This suggests that gelsolin plays a role in the apoptotic resistance
      observed in senescent HDFs.

PMID- 15033778
TI  - An age-associated decrease in the frequency of C4B*Q0 indicates that null alleles
      of complement may affect health or survival.
AB  - We studied the distribution of complement C4, C3, and factor B allotypes in 423
      healthy Icelandic subjects from 17 to 89 years of age. A marked decrease was
      observed in the carrier frequency of variant alleles of complement C4B (C4B(*)Q0)
      and C3 (C3(*)F). These results confirm our previous observations on Hungarian
      subjects and suggest a negative effect of C4B(*)Q0 on health or survival.

PMID- 15033779
TI  - Ethanol-induced decrease of the expression of glucose transport protein (Glut3)
      in the central nervous system as a predisposing condition to apoptosis: the
      effect of age.
AB  - We measured the effect of chronic ethanol administration on the expression of
      Glut3 in the cerebellum and hippocampus of adult and old rats. Glut3 expression
      significantly decreased in aging, in ethanol-treated rats vs. age-matched
      controls, and in adult- vs. old ethanol-treated rats. These findings lend
      consistent support to the hypothesis that disturbances of glucose metabolism due
      to ethanol may constitute an unfavorable condition predisposing to neuronal
      death.

PMID- 15033781
TI  - Concerted deregulations of multiple apoptosis-controlling genes in pancreatic
      carcinoma cells.

PMID- 15033780
TI  - CUGBP2 plays a critical role in apoptosis of breast cancer cells in response to
      genotoxic injury.
AB  - Posttranscriptional control of gene expression plays a key role in regulating
      gene expression in cells undergoing apoptosis. Cyclooxygenase-2 (COX-2) is a
      crucial enzyme in the conversion of arachidonic acid to prostaglandin E2 (PGE(2))
      and is significantly upregulated in many types of adenocarcinomas. COX-2
      overexpression leads to increased PGE(2) production, resulting in increased
      cellular proliferation. PGE(2) enhances the resistance of cells to ionizing
      radiation. Accordingly, understanding mechanisms regulating COX-2 expression may
      lead to important therapeutic advances. Besides transcriptional control, COX-2
      expression is significantly regulated by mRNA stability and translation. We have
      previously demonstrated that RNA binding protein CUGBP2 binds AU-rich sequences
      to regulate COX-2 mRNA translation. In the current study, we have determined that
      expression of both COX-2 mRNA and CUGBP2 mRNA are induced in MCF-7 cells, a
      breast cancer cell line, following exposure to 12 Gy gamma-irradiation. However,
      only CUGBP2 protein is induced, but COX-2 protein levels were not altered.
      Silencer RNA (siRNA)-mediated inhibition of CUGBP2 reversed the block in COX-2
      protein expression. Furthermore, MCF-7 cells underwent apoptosis in response to
      radiation injury, which was also reversed by CUGBP2 siRNAs. These data suggest
      that CUGBP2 is a critical regulator of the apoptotic response to genotoxic injury
      in breast cancer cells.

PMID- 15033783
TI  - The role of apoptosis in pituitary adenomas in the field of conventionally used
      therapeutic approaches.
AB  - The aim of the study was to investigate the mechanism of action of somatostatin
      analogues (SSA), ionizing radiation, and their combination on pituitary adenoma
      cells with special emphasis on proliferative and apoptotic activity. In the 14 GH
      secreting adenomas pretreated with SSA before surgery, more prominent regressive
      changes were found accompanied by compensatory increase in perivascular fibrosis
      than in the reference group of 17 unpretreated adenomas. The proliferative Ki-67
      labeling index was significantly lower in the treated group (median 1.6 per 1000)
      than in the untreated patients (median 5.0 per 1000). Apoptosis was detected in
      only 2 of the 14 pretreated adenomas, and it was more frequent (9/17) and more
      prominent in the untreated group. In cell lines, the SSA had minimal
      antiproliferative effect, and they were unable to induce apoptosis. Ionizing
      radiation at doses of 5-20 Gy induced apoptosis in the corticotroph cell line
      AtT20 with no cell-cycle block. In the somatotroph GH3 cell line, the early
      (premitotic) apoptosis was detectable using only a high dose of 200 Gy; after
      irradiation with doses of 20-50 Gy, apoptosis appeared with the latency of 48-72
      hours, and was preceded by cell-cycle arrest in the G(2)/M phase. The treatment
      with somatostatin-14 during irradiation increased the percentage of apoptotic
      cells in culture 10 days after irradiation (11% versus 3% using 20 Gy).

PMID- 15033782
TI  - Nuclear translocation of a clusterin isoform is associated with induction of
      anoikis in SV40-immortalized human prostate epithelial cells.
AB  - Clusterin gene expression is potently induced in experimental models in which
      apoptosis is activated, such as rat prostate involution following castration.
      Nevertheless, its precise physiological role has not yet been established, and
      both anti-apoptotic and pro-apoptotic functions have been suggested for this
      gene. Clusterin expression level depends on cell proliferation state, and we
      recently showed that its over-expression inhibited cell cycle progression of SV40
      immortalized human prostate epithelial cells PNT2 and PNT1a. Here we studied
      clusterin expression in PNT1a cells subjected to serum-starvation with the aim of
      defining clusterin early molecular changes following apoptosis induction. Under
      serum-starvation conditions, decreased growth rate, slow rounding-up of cells,
      cell detachment, and formation of apoptotic bodies indicative of anoikis
      (detachment-induced apoptosis) were preceded by significant downregulation of 70
      kDa clusterin precursor and upregulation of 45-40 kDa isoforms. On the 8th day of
      serum-free culturing, only the higher molecular weight protein-band of about 45
      kDa was clearly induced and accumulated in detached cells and apoptotic bodies in
      which PARP was activated. Anoikis was preceded by induction and transloction of a
      45-kDa clusterin isoform to the nucleus. Thus, nuclear targeting of a specific 45
      kDa isoform of clusterin appeared to be an early and specific molecular signal
      triggering anoikis-death. Considering also that clusterin is downregulated during
      prostate cancer onset and progression, and that its upregulation has inhibited
      DNA synthesis and cell cycle progression of immortalized human prostate
      epithelial cells, we suggest that clusterin might be a new anti-oncogene in the
      prostate.

PMID- 15033784
TI  - In vivo imaging of chemotherapy-induced apoptosis in human cancers.
AB  - RATIONALE: Induction of apoptosis in sensitive tumor cells is the main mechanism
      of action of chemotherapy agents in human cancers. Also, the assessment of drug
      induced apoptosis soon after chemotherapy may be an early predictor of treatment
      efficacy. PATIENTS AND METHODS: A phase I/II study was prospectively conducted in
      15 patients presenting with proven lung cancers (n = 10), breast cancers (n = 2),
      and lymphomas (n = 3) to assess the value of the (99m)Tc-radiolabeled recombinant
      human (rh) Annexin V for imaging apoptosis immediately after completion of the
      first course of chemotherapy. Early Annexin V findings post-chemotherapy (day+1,
      day+2) were also compared to the tumor status at 6 to 12 weeks post-treatment.
      RESULTS: All lung and lymphoma patients with an increased tracer uptake post
      treatment (n = 8) had either partial or complete tumor response. Five patients
      with no tracer uptake had progressive disease. However, two breast cancers had a
      response to treatment, although no significant tracer uptake was observed. Tumor
      response and survival time were significantly correlated with the (99m)Tc-labeled
      Annexin V uptake. No serious events related to tracer administration were noted.
      CONCLUSION: : Preliminary results of this pilot study demonstrate the feasibility
      of the 99mTc-labeled Annexin V uptake for the in vivo imaging of apoptosis after
      one course of chemotherapy. If confirmed on larger series, these promising
      results may open new perspectives in the management of oncology patients.

PMID- 15033785
TI  - Effects of membrane attack complex of complement on apoptosis in experimental
      autoimmune encephalomyelitis.
AB  - Complement activation is involved in the initiation of inflammation and antibody
      mediated demyelination in experimental autoimmune encephalomyelitis (EAE). We
      investigated the role of MAC in apoptosis in myelin-induced EAE in complement C5
      deficient (C5-d) and C5-sufficient (C5-s) mice. The number of apoptotic cells
      assessed by TUNEL assay was significantly increased in C5-d mice during clinical
      recovery as compared with C5-s mice. Most of the apoptotic cells were
      lymphocytes, monocytes, and oligodendrocytes. DNA microarray was performed using
      total RNA extracted from spinal cords. Genes expressed higher in C5-s included
      members of the caspase (caspase 6, 7), TNF and TNFR families (CD27, FasL,
      lymphotoxin-beta R) and survivin. These results indicate that C5 and possibly MAC
      may be required for the limitation of inflammatory response within the central
      nervous system.

PMID- 15033786
TI  - Vaccinia virus complement control protein modulates inflammation following spinal
      cord injury.
AB  - The vaccinia virus complement control protein (VCP) possesses multiple modulatory
      functions. Functioning as a complement inhibitory protein, VCP reduces production
      of proinflammatory chemotactic factors produced during complement activation.
      Additionally, VCP binds heparin and heparan sulfate proteoglycans, resulting in
      added functions shown to block monocyte chemotaxis in vitro. Using an in vivo
      spinal cord contusive injury model in rats, the inflammation-modulating abilities
      of VCP were evaluated. The results of both myeloperoxidase assaying and H&E
      stained section counts of spinal tissue reveal that neutrophil infiltration to
      the area of the lesion was reduced in animals that received VCP as compared to
      saline-injected controls.

PMID- 15033787
TI  - Blood cell apoptosis/necrosis: some clinical and laboratory aspects.
AB  - Exposure of phosphatidyl-serine on blood cell membrane surface and
      microvesiculation as the hallmarks of apoptosis/necrosis were investigated. The
      effect of leukofiltration on the retention/generation of microvesicules,
      leukocyte subsets and major biological response modifiers were evaluated in a
      like study. It is concluded that apoptotic cells potentially contribute to
      transfusion reactions in donor/recipient-specific ways.

PMID- 15033788
TI  - T-cell survival regulator LKLF is not involved in inappropriate apoptosis of
      diabetes-prone BBDP rat T cells.
AB  - Diabetes-prone BB (dpBB) rats develop autoimmune insulin-dependent diabetes
      mellitus (IDDM) at high frequency as a consequence of a defect in T cell
      development, caused by a mutation in a single gene locus on rat chromosome 4
      (lyp) which has recently been identified as immune-associated nucleotide 4
      (ian4). A phenotype similar to dpBB rat lymphopenia has recently been described
      in the mouse as the result of the targeted inactivation of the gene for the
      transcription factor LKLF (Lung Kruppel-like factor, KLF2) in the immune system.
      We cloned the LKLF gene of the rat and screened a panel of rat/hamster radiation
      hybrid cell lines to determine its chromosomal localization. We conclude that the
      LKLF gene is not defective in dpBB rats and that its expression is not
      compromised by the lyp mutation.

PMID- 15033790
TI  - The role of apoptosis in acetaminophen-induced injury.
AB  - Apoptosis plays a critical role in acetaminophen (AAP)-induced hepatic injury,
      since inhibiting apoptosis also prevents the development of acute liver failure.
      In this study, the mechanism of apoptosis induction by AAP was investigated in
      the human hepatoblastoma cell line HuH7. AAP caused marked cytotoxicity in HuH7
      cells as a result of apoptosis. Processing of execution caspases to their
      corresponding active fragments and cleavage of cytokeratin-18 were observed,
      supporting a role of caspases in AAP-induced apoptosis. The manifestation of
      apoptosis was preceded by a translocation of cytochrome c from mitochondria to
      the cytosol. In conclusion, AAP induces apoptosis in human hepatoblastoma HuH7
      cells through mitochondrial cytochrome c release and caspase activation.

PMID- 15033789
TI  - Early activation of antioxidant mechanisms in muscle of mutant Cu/Zn-superoxide
      dismutase-linked amyotrophic lateral sclerosis mice.
AB  - A subset of familial ALS cases is associated with missense mutations in the gene
      encoding Cu/Zn-superoxide dismutase (SOD1), a free radical scavenging enzyme that
      protects cells against oxidative stress. Overexpression of these ALS-linked
      mutations confers an unidentified gain of function to the enzyme that triggers a
      series of neurological disorders characteristic of human ALS. To understand how
      skeletal muscle may counteract the progression of the disease, we explored the
      expression of different molecular effectors involved in antioxidant pathways. Our
      results are strongly indicative of the early and long-lasting activation of a
      series of molecular effectors thought to act coordinately in preventing the
      increased oxidative stress characteristic of ALS.

PMID- 15033791
TI  - CD4+ lymphocyte increases in HIV patients during potent antiretroviral therapy
      are dependent on inhibition of CD8+ cell apoptosis.
AB  - Although suppression of apoptosis contributes to immune-reconstitution during
      potent antiretroviral therapy, its relationship with the majors indicators of
      response to therapy, that is, changes in CD4(+) cell counts and in viral loads
      (VL), is still debated. We extended our previous study by collecting data on the
      relationships among apoptosis and immunological and virological parameters during
      a long-term follow-up of HIV patients with an overall positive response to potent
      antiretroviral therapy. We report results from 15 patients who completed two
      years of therapy. In a smaller group of patients, we focused our attention on
      investigating the specific contribution of the CD8(+) subset in the overall
      changes in lymphocyte apoptosis, which occur concomitantly with the response to
      the therapy. Our data, while again confirming that inhibition of PBMC apoptosis
      is a phenomenon strictly related to a positive response to potent antiretroviral
      therapy, suggest that CD4(+) cell rescue is not directly dependent on inhibition
      of CD4(+) cell apoptosis but rather on that of the CD8(+) subset.

PMID- 15033792
TI  - Characterization of antiapoptotic activities of Chlamydia pneumoniae in infected
      cells.
AB  - C. pneumoniae has the capacity to inhibit apoptosis. Here we provide further
      insight into how infection with C. pneumoniae affects the apoptotic signal
      transduction in infected human epitheloid cells. For assessing changes in the
      apoptotic response, intact cells and cell extracts were used. These results show
      that C. pneumoniae is able to interfere with the host cell's apoptotic apparatus
      at least at two steps in the signal transduction.

PMID- 15033793
TI  - NF-kappaB and Bcl-2 in Helicobacter pylori-induced apoptosis in gastric
      epithelial cells.
AB  - Helicobacter pylori (H. pylori) has been considered as an important pathogen of
      gastroduodenal inflammation and gastric carcinogenesis. However, the pathogenic
      mechanisms including H. pylori-induced apoptosis and subsequent molecular
      mechanisms have not been clarified yet. The present study examined the role of
      Bcl-2 and its relation to NF-kappaB in H. pylori-induced apoptosis in human
      gastric epithelial AGS cells. AGS cells were cultured in the presence of H.
      pylori, at a bacterium/cell ratio of 300:1, for the determination of apoptosis,
      NF-kappaB activation with IkBa degradation, and Bcl-2 level. AGS cells were
      transfected with a control vector (pCMV cells) or a full-length human Bcl-2
      expression vector (Bcl-2 cells). H. pylori-induced apoptosis and NF-kappaB
      activation were compared in the wild-type cells and the transfected cells. As a
      result, H. pylori increased apoptotic cells with chromatin condensation and
      reduced Bcl-2 levels, which were accompanied with NF-kappaB activation. H. pylori
      induced sixfold increase in the number of apoptotic cells in wild-type cells and
      pCMV cells. H. pylori-induced increment of apoptotic cells were relatively lower
      in Bcl-2 cells than pCMV cells. H. pylori-induced NF-kappaB activation and IkBa
      degradation were not different in the wild-type cells, pCMV cells, and Bcl-2
      cells. In conclusion, the reduced gastric Bcl-2 level may be the main pathogenic
      mechanism of H. pylori-induced apoptosis in gastric epithelial cells.

PMID- 15033795
TI  - Glycoprotein of nonpathogenic rabies viruses is a major inducer of apoptosis in
      human jurkat T cells.
AB  - This study sought to identify the RV protein that causes apoptosis. For this
      purpose, we first compared the ability of G and N proteins of a pathogenic and a
      nonpathogenic strain to trigger apoptosis of Jurkat rtTA by using an inducible
      Tet-on expression system. Then we analyzed apoptosis induced by a reverse genetic
      engineered recombinant rabies virus in which the G gene from a nonpathogenic
      strain was replaced by its pathogenic strain counterpart. No other virus proteins
      than G of nonpathogenic RV strains induce apoptosis, and the G polypeptide of RV
      is a critical determinant for apoptosis in human cells.

PMID- 15033794
TI  - Role of phospholipomannan in Candida albicans escape from macrophages and
      induction of cell apoptosis through regulation of bad phosphorylation.
AB  - Candida albicans, the most common opportunistic fungal pathogen of humans is a
      part of the normal microbial flora. To investigate host-parasite interaction
      related to the commensal-pathogen switch of this yeast we compared the response
      of macrophages to C. albicans and to the non-pathogenic yeast Saccharomyces
      cerevisiae. In contrast to S. cerevisiae, C. albicans survived within
      macrophages. This escape from macrophages was associated with qualitative
      differences in the sequential phosphorylation of MEK, ERK1/2, and p90RSK during
      phagocytosis. Decreased activation of this pathway was observed with C. albicans
      and was associated with a species-specific overexpression of the MEK phosphatase,
      MKP-1. Dysregulation of the ERK1/2/p90RSK signal transduction pathway by C.
      albicans was associated downstream with reduction in Bad phosphorylation,
      specifically at Ser-112, and disappearance of free Bcl-2. This ended at apoptosis
      of cells that have ingested C. albicans, as revealed by staining of
      phosphatidylserine exposure in the macrophage outer membrane. The role of
      phospholipomannan (PLM), a phylogenetically unique glycolipid with a
      phytoceramide moiety expressed at the surface of and shed by C. albicans, was
      examined. Addition of PLM to macrophages led to dysregulation similar to that
      observed with live C. albicans and promoted the survival of the sensitive S.
      cerevisiae within the cells. Evidence of externalization of membranous
      phosphatidylserine, loss of mitochondrial integrity, and DNA fragmentation after
      incubation of macrophages with PLM suggest that this molecule supported the
      activities observed with C. albicans yeast cells.

PMID- 15033796
TI  - Redox-dependent apoptosis in human endothelial cells after adhesion of Plasmodium
      falciparum-infected erythrocytes.
AB  - During Plasmodium falciparum infection leading to cerebral malaria, mechanisms
      such as cytokine generation and cytoadherence of parasitized red blood cells
      (PRBC) to post-capillary venules are clearly involved. We demonstrated that PRBC
      adhesion to human lung endothelial cells (HLEC) upregulated TNF-alpha superfamily
      genes and genes related to apoptosis and inflammation. Apoptosis was confirmed by
      standard techniques (annexin-V binding, genomic DNA fragmentation, and caspases
      activation). This apoptotic process involved the cytoplasmic pathway from a death
      receptor (DR-6, Fas, TNF-R1) through caspase 8, and the mitochondrial pathway
      though Bad and caspase 9 activation. Oxidative stress has been implicated in
      apoptosis induction in various pathological models. Superoxide anion (O(2)*(-))
      is a key molecule in the oxidative stress pathway which can form peroxynitrites
      (ONOO(-)) in association with nitric oxide (NO*). Even though the role of NO* in
      malaria physiopathology is still a matter of controversy, we demonstrated that
      PRBC-induced apoptosis in endothelial cells is mediated through an oxidative
      stress pathway. The inhibition of NO* synthesis protected the endothelial cells
      suggesting a deleterious role for NO*. In addition, the superoxide dismutase
      mimetic, MnTBAP, also protected the HLEC against PRBC-induced apoptosis,
      revealing the role of O(2)*(-) and ONOO(-).

PMID- 15033797
TI  - Apoptosis in cultured cells infected with feline calicivirus.
AB  - Caliciviruses are important pathogens of man and animals; feline calicivirus
      (FCV) is responsible for an acute upper respiratory tract disease in cats. To
      date, little is known about the mechanism of cell damage induced by these
      viruses. We set out to determine if apoptosis played any role in cell death in
      FCV infection of cultured cells. We demonstrate that caspase-2, -3, and -7 were
      activated during FCV infection, as evidenced by pro-form processing and an
      increase in acetyl-Asp-Glu-Val-Asp-7-amido-4-trifluoromethylcoumarin cleavage
      activity, as well as cleavage of poly(ADP-ribose)polymerase. Caspase activation
      coincided with the condensation of chromatin. At about 8 h post infection we also
      detected cleavage of the FCV capsid protein; this was prevented by caspase
      inhibitors. Taken together these results suggest that FCV triggers apoptosis
      within infected cells and that caspases are involved in the cleavage of the
      capsid protein.

PMID- 15033798
TI  - Inhibition of apoptosis by human T-lymphotropic virus type-1 tax protein.
AB  - Deregulation of the apoptotic process can lead to pathophysiological changes that
      result in either degenerative diseases or cancer. Although the transactivator Tax
      has been established as an essential effector of human T-lymphotropic virus type
      1 (HTLV-1)-mediated diseases, which include both a neurodegenerative pathology
      and leukemia/lymphoma, its exact role(s) in the pathogenesis remains to be
      clarified. Because the apoptotic potential of Tax is still being debated, we
      addressed this question by testing the susceptibility of Tax(-) and Tax(+) cells
      to apoptosis under conditions of growth factor withdrawal and Bax overexpression.
      Results showed that Tax(+) cells are protected from apoptosis triggered by
      depletion of growth factors. This protective effect seems to be the result of a
      block in the apoptotic program regulated by mitochondria. Furthermore, in an
      attempt to elucidate which transcriptional pathway activated by Tax is important
      in the observed Tax-induced resistance, we found that CREB/ATF activity plays a
      relevant role in protecting cells from apoptosis induced by Bax overexpression.
      All together, these data might suggest that the ability of Tax to inhibit certain
      apoptotic stimuli could be important in its role as a viral transforming protein.

PMID- 15033799
TI  - Apoptosis inversely correlates with rabies virus neurotropism.
AB  - We report that non-neurotropic rabies virus (RV) strains, currently used to
      immunize wildlife against rabies, induces not only a caspase-dependent apoptosis
      in the human lymphoblastoid Jurkat T cell line (Jurkat-vect), but also a caspase
      independent pathway. Cell redistribution of the apoptosis-inducing factor (AIF)
      was observed in Jurkat-vect infected with RV vaccine strain. Bcl-2 overproduction
      in Jurkat T cells (Jurkat-Bcl-2) abolished both caspase activation and AIF
      distribution. In contrast, strain of neurotropic RV did not induce apoptosis. The
      inverse correlation of the induction of apoptosis and the capacity of a virus
      strain to invade the brain suggests that blockage of apoptosis could be a
      strategy selected by neurotropic virus to favor its progression through the
      nervous system.

PMID- 15033800
TI  - Increased apoptotic cell death in sporadic and genetic Alzheimer's disease.
AB  - Mounting evidence indicates increased susceptibility to cell death and increased
      oxidative damage as common features in neurons from sporadic Alzheimer's disease
      (AD) patients but also from familial AD (FAD) cases. Autosomal dominant forms of
      FAD are caused by mutations of the amyloid precursor protein (APP) gene and by
      mutations of the genes encoding for presenilin 1 or presenilin 2 (PS1/2). We
      investigated the effect of the Swedish APP double mutation (APPsw) on oxidative
      stress-induced cell death mechanisms in PC12 cells. This mutation results in from
      three- to sixfold increased beta-amyloid (Abeta) production compared with wild
      type APP (APPwt). Because APPsw cells secrete low Abeta levels similar to the
      situation in FAD brains, our cell model represents a very suitable approach to
      elucidate the AD-specific cell death pathways under more likely physiological
      conditions. We found that APPsw-bearing cells show decreased mitochondrial
      membrane potential after exposure to hydrogen peroxide. In addition, activity of
      the executor caspase 3 after treatment with hydrogen peroxide was elevated in
      APPsw cells, which seems to be the result of an enhanced activation of both
      intrinsic and extrinsic apoptosis pathways. Our findings provide evidence that
      the massive neurodegeneration in early age of FAD patients could be a consequence
      of an increased vulnerability of neurons by mitochondrial abnormalities resulting
      in activation of different apoptotic pathways as a consequence to elevated
      oxidative stress levels. Finally, we propose a hypothetical sequence of the
      pathogenic steps linking sporadic AD, FAD, Abeta production, mitochondrial
      dysfunction with caspase pathway, and neuronal loss.

PMID- 15033801
TI  - Prion protein fragment 106-126 induces a p38 MAP kinase-dependent apoptosis in SH
      SY5Y neuroblastoma cells independently from the amyloid fibril formation.
AB  - Prion diseases are neurodegenerative disorders of the central nervous system of
      humans and animals, characterized by spongiform degeneration of the central
      nervous system, astrogliosis, and deposition of amyloid into the brain. The
      conversion of a cellular glycoprotein (prion protein, PrP(C)) into an altered
      isoform (PrP(Sc)) has been proposed to represent the causative event responsible
      for these diseases. The peptide corresponding to the residues 106-126 of PrP
      sequence (PrP106-126) is largely used to explore the neurotoxic mechanisms
      underlying the prion diseases. We investigated the intracellular signaling
      responsible for PrP106-126-dependent cell death in the SH-SY5Y human
      neuroblastoma cell line. In these cells, PrP106-126 treatment induced apoptotic
      cell death and the activation of caspase-3. The p38 MAP-kinase blockers (SB203580
      and PD169316) prevented the apoptotic cell death evoked by PrP106-126 and Western
      blot analysis revealed that the exposure of the cells to the peptide induced p38
      activation. However, whether the neuronal toxicity of PrP106-126 is caused by a
      soluble or fibrillar form of this peptide is still unknown. In this study, we
      correlated the structural state of this peptide with its neurotoxicity. We show
      that the two conserved glycines in position 114 and 119 prevent the peptide to
      assume a structured conformation, favoring its aggregation in amyloid fibrils.
      The substitution of both glycines with alanine residues (PrP106-126AA) generates
      a soluble nonamyloidogenic peptide, that retained its toxic properties when
      incubated with neuroblastoma cells. These data show that the amyloid aggregation
      is not necessary for the induction of the toxic effects of PrP106-126.

PMID- 15033803
TI  - Neuronal death versus synaptic pathology in Alzheimer's disease.
AB  - Neuron and synapse numeric densities as well as the average size and surface
      density of the synaptic junctional areas were measured in the hippocampus and
      cerebellum of adult, old, and demented (Alzheimer's disease) patients. Our
      findings support the notion that synaptic loss represents per se a prominent and
      early damage affecting zones of the central nervous system reported to show a
      different vulnerability to age- and pathology-related changes.

PMID- 15033802
TI  - Stable-tau overexpression in human neuroblastoma cells: an open door for
      explaining neuronal death in tauopathies.
AB  - Many neurodegenerative disorders referred to as "tauopathies" are characterized
      by the accumulation and aggregation of Tau proteins into filaments. In these
      pathologies, Tau proteins are hyperphosphorylated and also abnormally
      phosphorylated. Moreover, they differ from each other by the preferential
      aggregation of isoforms exhibiting either three microtubule-binding repeats (3R)
      or four repeats (4R) Tau. To investigate the effects of an intracellular
      accumulation of Tau, we stably transfected neuroblastoma cell line SY5Y with
      either 3R or 4R Tau. Our data showed that an increase in intracellular Tau
      expression has led to their hyperphosphorylation. Conversely, an abnormal Tau
      phosphorylation and/or aggregation were never observed. Furthermore, SY5Y cells
      transfected with 4R Tau showed an increased susceptibility to cell death.
      Finally, in apoptotic conditions, Tau proteins were degraded at their carboxy
      terminus by caspase, leading to an apparent decrease in Tau phosphorylation in
      this region. Because truncated Tau generated during apoptosis are not commonly
      found in Tau aggregates, apoptotic processes may not be of interest in
      neurofibrillary degeneration.

PMID- 15033805
TI  - A proximal gene promoter region for the beta-amyloid precursor protein provides a
      link between development, apoptosis, and Alzheimer's disease.
AB  - Abnormalities in regulation of the beta-amyloid precursor protein (APP) gene
      might be a crucial factor in Alzheimer's disease (AD). Our aim is to study the
      role of a specific proximal APP promoter element under the apoptotic condition.
      Our transfection studies with APP promoter deletion constructs indicate that each
      cell type differently regulates promoter activity. The minimum region that was
      sufficient to drive basal promoter activity in neuronal PC12 and neuroblastoma SK
      N-SH cells was -75/+104 and -47/+104 bp, respectively. In SK-N-SH cells, the 
      47/+104 construct displayed the highest promoter activity, and the -75/-46 region
      acted as a negative regulatory element. Results from the gel electrophoretic
      mobility shift assay (EMSA) indicate that the -75/-46 region binds to a distinct
      DNA-protein complex with nuclear protein(s) from HeLa, PC12, NIH-3T3, and
      neuroblastoma cells. EMSA results from HeLa cells, which were stimulated by serum
      starvation (SR), indicate a significant induction in the signal of the DNA
      protein complex from controls. EMSA results from PC12 cells, which were subjected
      to hypoxia, indicate a significant reduction in the signal. Our results suggest
      that the -75/-46 region binds to a protein that is upregulated in serum
      starvation, and downregulated in hypoxia. Because serum starvation contributes to
      the induction of apoptosis, these results suggest a role of the 30-bp proximal
      APP promoter element in enhanced apoptotic neuronal cell death.

PMID- 15033804
TI  - Does nitric oxide synthase contribute to the pathogenesis of Alzheimer's
      disease?: effects of beta-amyloid deposition on NOS in transgenic mouse brain
      with AD pathology.
AB  - Oxidative stress is a risk factor for Alzheimer's disease (AD) whose major
      hallmark includes brain depositions of the amyloid beta peptide (Abeta) derived
      from the beta-amyloid precursor protein (APP). Our aim was to determine whether
      or not excessive Abeta deposition would alter nitric oxide synthase (NOS)
      activity, and thereby affect NOS-mediated superoxide formation. We compared NOS
      activity in brain extracts between Tg mice (expressing APP Swedish double
      mutation plus presenilin [PS-1] and nontransgenic [nTg] mice. Five brain regions,
      including cerebral cortex, hippocampus, cerebellum, and striatum from both nTg
      and Tg mice showed a detectable level of neuronal (n) NOS activity. Cerebellar
      extracts from both nTg and Tg mice displayed the highest level of nNOS activity,
      which was fourfold higher than cortical extracts. Although there was an increase
      in nNOS activity in Tg brain extracts, this did not attain statistical
      significance. A similar result was obtained for inducible NOS levels. Our results
      suggest that excess levels of Abeta failed to both trigger NOS activity and
      change NOS levels.

PMID- 15033806
TI  - Induction of cyclooxygenase-2 and peroxisome proliferator-activated receptor
      gamma during nitric oxide-induced apoptotic PC12 cell death.
AB  - Inappropriate expression of inducible nitric oxide synthase (iNOS) and
      unregulated production of nitric oxide (NO) may contribute to neuronal cell death
      implicated in neurological disorders such as Alzheimer's disease. In this study,
      we have investigated the molecular mechanisms underlying nitrosative cell death
      induced by NO in cultured rat pheochromocytoma (PC12) cells. Incubation of PC12
      cells with the NO donor sodium nitroprusside (SNP) resulted in apoptotic death as
      revealed by the decrease of mitochondrial transmembrane potential (deltapsi(m)),
      cleavage of poly(ADP-ribose) polymerase (PARP), and induction of p21(Waf1/Cip1).
      It has been reported that the expression of cyclooxygenase-2 (COX-2) and
      peroxisome proliferator-activated receptor-gamma (PPARgamma) is elevated in
      Alzheimer's disease, and certain nonsteroidal anti-inflammatory drugs (NSAIDs)
      can reduce the risk and delay the onset of Alzheimer's disease. Treatment of PC12
      cells with a proapoptotic dose of SNP induced expression of both COX-2 and
      PPARgamma. Addition of the PPARgamma antagonist GW9662 to the media augmented the
      NO-induced cytotoxicity. Although cotreatment of PGE(2) (50 micro M) and SNP (0.4
      mM) aggravated the NO-induced cytotoxicity, preincubation of the same
      concentration of PGE(2) was cytoprotective. Taken together, the above findings
      suggest that the proinflammatory mediators such as PGE(2) and PPARgamma may
      regulate the nitrosative stress-induced apoptotic cell death.

PMID- 15033807
TI  - Tellurium compound AS101 induces PC12 differentiation and rescues the neurons
      from apoptotic death.
AB  - Parkinson's disease is characterized by the loss of dopaminergic neurons in the
      substantia nigra (SN). Studies show that anti-apoptotic and neurotrophic agents
      are suitable candidates to prevent delayed cell death and/or restore neural
      function. Here we present the nontoxic immunomodulating compound AS101, which has
      the ability to induce neurite outgrowth and neural differentiation in PC12 cells.
      The present study shows that components of the ras signaling pathway are crucial
      for AS101-induced PC12 differentiation. These include p21ras and its downstream
      effectors, c-raf-1 and MEK, as well as PI3K. Moreover, these components mediate
      AS101-induced upregulation of p21waf, which is obligatory for AS101-induced PC12
      differentiation. Furthermore, nitric oxide plays a significant role in these
      AS101 activities. Finally, we show that AS101 prevents apoptosis of NGF
      differentiated PC12 cells after NGF withdrawal. Taken together, these results
      suggest that AS101 induces PC12 cell differentiation and survival by activating
      the ras-ERK1/2 and ras-PI3K signal transduction pathways, as well as inducing NO
      production. Our findings may be important in understanding the regulation of
      survival/apoptosis of neurons deprived of neurotropic support. Futhermore the
      data propose that AS101 may have clinical potential in the treatment of
      neurodegenerative disorders like Parkinson's disease.

PMID- 15033808
TI  - Drugs of abuse induce apoptotic features in PC12 cells.
AB  - Drugs of abuse induce the release of dopamine in the central nervous system,
      particularly in the mesolimbic-mesocortical pathway. As dopamine may act as a
      neurotoxin, in this study, we analyzed the effects of the drugs of abuse,
      cocaine, heroin, and amphetamine, on the neurodegeneration of PC12 cells, a
      dopaminergic cell line, by evaluating the activity of caspase-3 and mitochondrial
      cytochrome c release. All the drugs were shown to induce caspase-3 activation,
      similarly to staurosporine, a classical inducer of apoptotic cell death.
      Furthermore, like staurosporine, the drugs of abuse induced a decrease in
      mitochondrial cytochrome c content, suggesting the involvement of the
      mitochondrial apoptotic pathway.

PMID- 15033809
TI  - Inhibition of CDKs: a strategy for preventing kainic acid-induced apoptosis in
      neurons.
AB  - Stimulation of ionotropic glutamate receptors are implicated in neurodegenerative
      diseases such as Alzheimer's and Parkinson's diseases. Recently this has been
      demonstrated in the expression of cell cycle proteins in vulnerable neurons in
      Alzheimer's disease. Thus, the aim of the present study was to evaluate the
      expression of cell cycle proteins in cerebellar granule cells after stimulation
      of AMPA/KA receptors and likewise to study the neuroprotective effects of CDK
      inhibitors. Our results demonstrated that after a treatment with CDK inhibitors,
      a significant decrease in apoptotic nuclei induced by kainic acid was found in
      the presence of flavopiridol and 3-ATA. We concluded that CDK activation is
      involved, at least, in part, in the pro-apoptotic effects of kainic acid.

PMID- 15033811
TI  - Dopaminergic modulation of apoptosis in human peripheral blood mononuclear cells:
      possible relevance for Parkinson's disease.
AB  - Dopamine (DA) modulates apoptosis in neuronal and non-neuronal cells, and
      dopaminergic pathways contribute to neurodegenerative disease. Human lymphocytes
      express dopaminergic receptors and DA transporters, and synthesize endogenous
      catecholamines, which may modulate apoptosis in these cells. In the present
      study, dopaminergic modulation of apoptosis was investigated in human peripheral
      blood mononuclear cells (PBMCs) obtained from healthy donors. Twenty-four-hour DA
      reduced at 0.1-5 x 3 10(-6) M and enhanced at 1-5 x 310(-4) M spontaneous
      apoptosis. DA 1 x 310(-6) M was inhibited by the D1-like receptor antagonist SCH
      23390 1 x 310(-6) M, but not by the D2-like receptor antagonists domperidone 1 x
      3 10(-6) M or haloperidol 1 x 3 10(-6) M, while the effect of DA 5 x 3 10(-4) M
      was prevented by the antioxidants glutathione 5-10 mM or N-acetyl-l-cysteine 1-10
      mM. Intracellular reactive oxygen species were respectively reduced and increased
      by 1-3 h incubation with DA 0.1-10 x 3 10(-6) M and 1-5x310(-4) M. Twenty-four
      hour DA 1 x 3 10(-6) M or 5 x 3 10(-4) M had no effect on PBMC expression of
      Cu/Zn superoxide dismutase or Bcl-2; however, DA 5 x 3 10(-4) M decreased caspase
      3 activity. In human PBMCs, DA seems to promote apoptosis through oxidative
      mechanisms but may also result in cell rescue from apoptotic death possibly
      through activation of D1-like receptors. The dual effect of DA on human PBMCs
      closely resembles that on striatal neurons. Lymphocytes of patients with
      Parkinson's disease may show reduced DA content and impaired DA transporter
      immunoreactivity. Human PBMCs may thus represent a simple and readily accessible
      model to study DA-related mechanisms relevant for neurodegenerative disease.

PMID- 15033810
TI  - Peripheral markers of apoptosis in Parkinson's disease: the effect of
      dopaminergic drugs.
AB  - In this study, we measured the lymphocyte levels of proteins involved in
      apoptosis regulation, such as Bcl-2, the peripheral benzodiazepine receptor
      (PBR), caspase-3, and Cu/Zn superoxide dismutase (Cu/Zn SOD), in patients with
      Parkinson's disease (PD), either untreated or under therapy with dopaminergic
      agents (l-Dopa alone or l-dopa + dopamine agonists) and in healthy volunteers.
      All PD groups showed increased activity of caspase-3, compared to controls,
      particularly those under treatment only with l-Dopa. In this latter group, the
      increase in caspase-3 activity was also paralleled by an increase in the
      concentration of Cu/Zn SOD. In addition, patients taking l-Dopa + dopamine
      agonists showed marked decrease in Bcl-2 levels and increased PBR expression,
      which seems in keeping with the hypothesis that PBR may be functionally related
      to Bcl-2. In conclusion, we found clear modifications in the levels of proteins
      involved in the control of apoptosis in lymphocytes of PD patients. These changes
      were disease related but also modulated by the pharmacological treatment, which
      confirms the potential role of apoptosis in PD pathogenesis and the modulatory
      influence of dopaminergic agents.

PMID- 15033812
TI  - Proteolytic activation of proapoptotic kinase PKCdelta is regulated by
      overexpression of Bcl-2: implications for oxidative stress and environmental
      factors in Parkinson's disease.
AB  - We previously demonstrated that the organochlorine pesticide dieldrin, a
      potential chemical risk factor for development of Parkinson's disease (PD),
      impairs mitochondrial function and promotes apoptosis in dopaminergic PC12 cells.
      We further demonstrated that caspase-3-dependent proteolytic activation of a
      member of the novel PKC family, protein kinase Cdelta (PKCdelta), contributes to
      apoptotic cell death in dopaminergic cells. In the present study, we report that
      the proapoptotic function of PKCdelta can be regulated by overexpression of the
      mitochondrial anti-apoptotic protein Bcl2 in dieldrin-treated dopaminergic cells.
      Exposure to dieldrin (30 or 100 micro M) for 3 h produced a dose-dependent
      increase in caspase-3 activation and DNA fragmentation in vector-transfected PC12
      cells. Overexpression of human Bcl-2 in PC12 cells completely suppressed dieldrin
      induced caspase-3 activation and DNA fragmentation. Furthermore, dieldrin-induced
      proteolytic activation of PKCdelta was also remarkably reduced in Bcl-2
      overexpressed cells. Together, these results suggest that the proapoptotic
      function of PKCdelta can be regulated by mitochondrial redox modulators during
      neurodegenerative processes.

PMID- 15033813
TI  - Molecular mechanisms for cardiovascular stem cell apoptosis and growth in the
      hearts with atherosclerotic coronary disease and ischemic heart failure.
AB  - In the heart with atherosclerotic coronary disease, chronic ischemia causes
      progressive loss of cardiovascular cells and ultimately triggers myocardial
      dysfunctions or heart failure. Various types of stem cells from embryonic and
      adult tissues have potentials for regenerating functional cardiovascular cells in
      the heart undergoing ischemic injury. However, native or exogenous stem cells in
      the ischemic hearts are exposed to various proapoptotic or cytotoxic factors.
      Furthermore, during repopulation and differentiation, certain numbers of newly
      produced cells may die by apoptosis during neocardiovascular tissue remodeling
      and morphogenesis. Embryonic and adult stem cells may have different life spans,
      as being programmed genetically to apoptosis. The endogenous and environmental
      factors play important roles in regulation of stem cells, including inflammatory
      cytokines, growth factors, surface receptors, proteolytic enzymes, mitochondrial
      respiration, nuclear proteins, telomerase activities, hypoxia-responding
      proteins, and stem cell-host cell interaction. Clarification of the molecular
      mechanisms may help us understand and design stem cell therapies.

PMID- 15033815
TI  - Glycoxidation of low-density lipoprotein increases TUNEL positivity and CPP32
      activation in human coronary cells.
AB  - Apoptosis of arterial cells induced by oxidized low-density lipoprotein (oxLDL)
      is thought to contribute to the progression of vascular dysfunction and
      atherogenesis. It is well established that diabetes mellitus is accompanied by
      both glycosylation and oxidation of LDL (glc-oxLDL), but the biological effects
      of these modified lipoproteins are poorly understood. We demonstrate here for the
      first time that glc-oxLDL increases TUNEL positivity and caspase-3 activation (by
      Western blot and immunocytochemistry) of human coronary smooth muscle cells.
      Overall, these effects induced by glc-oxLDL were greater than those achieved with
      oxLDL. Thus, glc-oxLDL activated downstream apoptotic signaling. This may
      influence the evolution of atherogenesis and vascular complications in diabetes.

PMID- 15033817
TI  - Preconditioning with cardioplegia is more effective in reducing apoptosis than is
      preconditioning with ischemia in the human myocardium.

PMID- 15033814
TI  - Oxidation of LDL, atherogenesis, and apoptosis.
AB  - A plethora of studies in cultured cells have established that oxidized low
      density lipoprotein (oxLDL) may enhance arterial apoptosis that involves both
      mitochondrial and death receptor pathways (Fas/FasL, TNF receptors I and II),
      thereby activating caspase cascade and other proteases. When apoptosis is
      inhibited by Bcl-2 overexpression, oxLDL may trigger necrosis through a calcium
      dependent pathway. Despite this effort, the pathophysiological relevance of
      apoptosis in vivo remains to be elucidated. In principle, apoptosis occurring in
      atherosclerotic areas could be involved in endothelial cell lining defects,
      necrotic core formation, and plaque rupture or fissuring. This complex pathogenic
      framework may favor coronary atherothrombotic events. To date, the pathogenic
      role of apoptosis in thrombosis is attractive, but a solid evidence is still
      needed. When the precise role of oxLDL in vascular programmed cell death
      occurring in vivo is clarified, this may aid in the development of novel
      therapeutic approaches to adverse atherogenesis and its clinical sequelae.

PMID- 15033816
TI  - TNFalpha stimulated ATP-sensitive potassium channels and attenuated deoxyglucose
      and Ca uptake of H9c2 cardiomyocytes.
AB  - Tumor necrosis factor (TNFalpha) is an inflammatory cytokine that induces
      programmed cell death in a variety of tissue types, including the heart. Recent
      experimental data suggest that the TNF expressed within the myocardium in
      response to environmental injury plays an important role in initiating
      homeostatic response. The effect of TNFalpha (10-50 ng/mL) was studied on (86)Rb
      efflux, (3)H-deoxyglucose uptake, or (45)Ca uptake in H9c2 cardiomyocytes.
      TNFalpha stimulated (86)Rb efflux from cultures, while 2 micro M glibenclamide
      blocker of ATP-sensitive potassium channels or 20 micro M zvad-fmk caspase
      inhibitor attenuated this effect. TNFalpha also depressed the stimulatory effect
      of 80 mM KCl on (45)Ca uptake in the cardiomyocytes. TNFalpha inhibited the
      stimulatory effect of 100 nM insulin on (3)H-deoxyglucose uptake. Our findings
      further suggest that TNFalpha mediated adaptive and protective effects in the
      heart during a brief environmental injury.

PMID- 15033818
TI  - Hypoxia and ischemia induce nuclear condensation and caspase activation in
      cardiomyocytes.

PMID- 15033819
TI  - Apoptosis induced in vascular smooth muscle cells by oxidative stress is partly
      prevented by pretreatment with CGRP.

PMID- 15033820
TI  - Upregulation and formation of SDS-resistant oligomers of the proapoptotic factor
      Bax in experimental atherosclerosis.

PMID- 15033821
TI  - Transient leukocytosis, granulocyte colony-stimulating factor plasma
      concentrations, and apoptosis determined by binding of annexin V by peripheral
      leukocytes in patients with severe sepsis.
AB  - This study was undertaken to clarify the relation between transient increases in
      the numbers of leukocytes and granulocyte colony-stimulating factor (G-CSF)
      plasma concentrations as well as the degree of apoptosis, as determined by
      binding of annexin V by these cells in patients with severe sepsis and septic
      shock. Over a 6-month period, annexin V binding by leukocytes was determined
      daily using flow cytometry and FITC-labeled annexin V in 33 postoperative
      patients with severe sepsis or septic shock during their intensive care unit
      stay. The percentage of annexin V binding neutrophils, monocytes, and lymphocytes
      was significantly lower, and G-CSF plasma concentrations were higher in patients
      than in controls on most days. Nine, 19, and 18 peaks in neutrophil, monocyte,
      and lymphocyte counts (increase of >/=30% within 2 days, followed by a decrease
      of >/=30% within 2 days) occurred in 6, 11, and 16 patients. During leukocyte
      peaks, the absolute numbers of annexin V binding neutrophils, monocytes, and
      lymphocytes paralleled those of neutrophil, monocyte, and lymphocyte numbers.
      However, the percentage of annexin V binding neutrophils, monocytes, and
      lymphocytes did not differ significantly from one day to another. Increased G-CSF
      serum concentrations preceded neutrophil and monocyte peaks. In conclusion,
      apoptosis of leukocytes is lowered during severe sepsis and septic shock in
      critically ill patients. Moreover, the degree of apoptosis does not increase
      during transient leukocytosis. G-CSF might contribute to the low degree of
      apoptosis of neutrophils and monocytes in those patients.

PMID- 15033823
TI  - Immunohistochemical status of p53, MDM2, bcl2, bax, and ER in invasive ductal
      breast carcinoma in Tunisian patients.
AB  - TP53 gene alterations have been associated with sporadic breast cancer. To assess
      the role of p53 in invasive ductal carcinoma (IDC) of the breast among Tunisian
      patients, p53 protein status was studied by immuno-histochemical analysis. The
      p53 protein was expressed in 41 of 70 (58%) tumors. Study of the status of its
      target gene expression showed that MDM2 was overexpressed in 43 tumors (61%),
      bcl2 in 29 (41%), and bax in only 9 (12%). Estrogen receptor (ER) was detected in
      38 tumor tissues (54%). The accumulated p53 was significantly associated with
      MDM2-positive, bcl2-negative, and ER-negative tumors (P = 0.024, P = 0.000027,
      and P = 0.000008, respectively), whereas with bax the correlaton was not
      significant. Bcl2 immunostaining displayed a positive correlation with ER (P =
      0.001). A significantly higher fraction of p53-positive cells was observed in ER
      negative SBRII-SBRIII tumors than in ER-positive SBRI-SBRII tumors (P =
      0.000066). bcl2-positive tumors were significantly correlated with ER
      positive/SBRI-SBRII tumors (P = 0.007), but negatively correlated with p53/bax (P
      = 0000004). MDM2 immunostaining displayed the same phenotype as p53 in the
      correlation with bcl2 and ER (P = 0.003), strengthened by significant
      associations between MDM2-positive/p53-positive and bcl2-negative or ER-negative,
      respectively (P = 0.00005 and P = 0.000001, respectively). MDM2-positive cells
      were significantly correlated with the p53-positive/bax-negative phenotype (P =
      0.04). These results suggest that p53 accumulated in these tumor tissues is
      associated with bad prognostic markers (ER-negative, SBRIII) of IDC. MDM2
      overexpression might be responsible for the accumulated p53 value in IDC.
      Regulation of the apoptotic process is involved in IDC; bcl2 is associated with a
      good prognostic marker (ER-positive and SBRI-II), whereas the regulation of bax
      is complex and does not necessarily correlate with the overexpression of p53.

PMID- 15033822
TI  - Evaluation of apoptosis markers in conjunctival and eyelid benign and malignant
      tumors.
AB  - The balance between cell proliferation and programmed cell death plays a crucial
      role in malignant development. Bcl-2 family proteins, including proapoptosis
      protein Bak and antiapoptosis protein Bcl-2, regulate the apoptotic process.
      Mutation of the p53 gene, which results in P53 protein accumulation, was observed
      in many types of human cancer. The aim of our study was to evaluate
      immunohistochemical Bcl-2, Bak, and P53 protein expression and the relation
      between these proteins in conjunctival and eyelid benign and malignant tumors. We
      examined a series of 42 papillomas (CEP), 12 squamous cell cancers (SCC), and 19
      cases of basal cell cancer (BCC). The age in the CEP group ranged from 18-94
      years, and in the SCC and BCC groups from 42-87 years. Staining patterns were
      correlated with sex, age, and tumor localization. P53 protein-positive
      immunostaining was observed in 71% of cases, Bcl-2 in 83.9%, and Bak in 74.2
      cases in the SCC and BCC groups. In the CEP group, P53 overexpression was
      observed in 90.5% of cases, Bcl-2 in 71.4%, and Bak in 76.2%. No statistically
      significant correlation was found between examined protein expression and sex,
      age, and tumor localization. An inverse correlation was observed between P53 and
      Bak protein expression in the CEP group. No statistically significance
      correlation was noted between Bcl-2 and P53 and Bcl-2 and Bak protein expression
      in both examined groups. The obtained data suggests that P53 and Bcl-2 protein
      expression coupled with decreasing Bak expression are associated with apoptosis
      and proliferation as well as malignant progression in conjunctival and eyelid
      tumors.

PMID- 15033824
TI  - No evidence of correlation between p53 codon 72 polymorphism and risk of bladder
      or breast carcinoma in Tunisian patients.
AB  - The TP53 gene, frequently mutated in human cancers, carries several
      polymorphisms. The one most informative and studied concerns codon 72; a single
      base changes the CGC (arginine) to CCC (proline). The arginine form was
      considered to be a significant risk factor in the development of cancer. However,
      various reports on this polymorphism are controversial. We carried out the same
      investigation in two groups of patients, a group with bladder cancer and another
      with breast cancer, and in healthy controls in two regions of our country, using
      an improved PCR-RFLP method. The number of Arg/Arg, Arg/Pro, and Pro/Pro
      genotypes was as follows: 21, 23, 3 and 13, 19, 2 for patients (total 47) and
      controls (34), respectively, in the first group; 18, 9, 3 and 19, 26, 4 for
      patients (30) and controls (49), respectively, in the second group. Statistical
      analysis of the genotype and allele frequencies did not reveal any difference
      between patients and controls in both groups except for a weak difference between
      the homozygotes to heterozygotes in the second group with a chi square of 4.1 (P
      = 0.045); the number of breast cancer patients is actually low (30) and should be
      increased in order to assess such a conclusion. Our overall results are therefore
      not consistent with a high risk associated with TP53 codon 72 polymorphism in
      breast and in bladder cancers.

PMID- 15033825
TI  - p53, Bcl-2, PCNA expression, and apoptotic rates during cervical tumorigenesis.

PMID- 15033828
TI  - Apoptosis in prostate carcinomas after short-term treatment with decapeptyl.
AB  - Altogether, 40 patients with advanced prostate cancer received the LH-RH analog,
      Decapeptyl (D), as monotherapy for 1 month. The dose of D was 3.75 mg/month,
      intramuscularly in microcapsules. Needle biopsy was taken from the prostate of 20
      patients at 24 hours, of 10 patients at 7 days, and of 10 patients at 30 days
      after the injection. The biopsy samples were investigated for mitotic and
      apoptotic indices as well as expression of p53 and Ki67 in the tumor cells. The
      effect of the LH-RH analog was manifested in very low and even absent mitotic
      activity in all points in time. The expression of mutant p53 was high (above 80%)
      in all 1-day and 7-day samples and in 8 of 10 samples taken 30 days after the
      start of the therapy. In 2 cases, the ratio of p53-expressing tumor cells was 2%
      and 5%. At day 30, the previously high ratio of Ki67-positive tumor cells
      decreased to 2-10% in 8 cases and showed focally higher values (70-90%) in 2
      cases. Extremely high (90-100%) apoptosis could be registered in scattered foci
      of the tumor tissue in all samples taken 1 and 7 days after D injection. The
      other parts of the tumor tissue showed lower (1-5%) apoptotic activity. At day 30
      after the injection, the same phenomenon was observed in 4 cases, but in 6 cases
      the apoptotic ratio became diffusely low (1-2%). Focal increase of apoptosis
      observed in the 1- and 7-day samples may be attributed to the direct effect of
      the LH-RH analog on tumor cells. The findings at day 30 indicate a considerable
      decrease in proliferating activity and, in the majority of cases, also in
      apoptotic activity, reflecting the effect of D on the pituitary-gonadal axis.

PMID- 15033826
TI  - Assessment of in vivo chemotherapy-induced DNA damage in a p53-mutated rat tumor
      by micronuclei assay.
AB  - Production of DNA damage is the basis of cancer treatments such as chemo- and
      radiotherapy. Such treatments induce mitotic catastrophe, a form of cell death
      resulting from abnormal mitosis and leading to the formation of interphase cells
      with multiple micronuclei. In this study, we compared apoptosis induction and
      micronuclei formation to assess the DNA damage provoked in vivo by cytotoxic
      agents in established 9L rat gliosarcoma tumors expressing a mutated p53 gene.
      Results from TUNEL assays revealed the efficiency of local gamma-irradiation at
      the tumor site to induce apoptosis within 9L tumor mass. However, little or no
      apoptosis was detected after systemic (ip) injection of cisplatin (1 mg/kg).
      Interestingly, the micronuclei assays showed that not only gamma-irradiation but
      also cisplatin treatment led to an increase in the emergence of binucleated cells
      with micronuclei. Apoptosis induction and micronuclei emergence are thus not
      absolutely correlated. However, micronuclei assays, rarely performed on solid
      tumors, appear more sensitive than apoptosis assays in evaluating DNA damage
      linked to chemotherapy.

PMID- 15033827
TI  - Changes in apoptotic and mitotic index, bcl2, and p53 expression in rectum
      carcinomas after short-term cytostatic treatment.
AB  - Twenty patients with rectal adenocarcinoma were endoscopically biopsied and given
      short-term cytostatic therapy [5-fluorouracil (5-FU) (600 mg/m(2)) and Ca
      folinate (60 mg/m(2)) for 2 days]. Seven days later, the tumor was resected or a
      second biopsy was performed. Apoptotic and mitotic indices as well as (mutant)
      p53 and bcl(2) expression were determined in the tumor tissue before and after
      the short-term chemotherapy. The patients were treated thereafter with long-term,
      intermittent 5-FU administration and followed up clinically for 7-26 months. Six
      patients showed progression of the disease and died, whereas 14 improved or
      showed no tumor progression. Significant increase of the apoptotic index and
      nonsignificant decrease of the mitotic index after the short-term cytostatic
      treatment were seen in the tumor tissue of responder cases. Nonresponders showed
      no change in both mitotic activity and apoptotic activity. Both survivors and
      deceased showed high mutant p53 expression, and the changes after short-term 5-FU
      treatment were not significant. Expression of bcl(2) was present in only 5 cases,
      with the postchemotherapy changes being not significant. These findings suggest
      that apoptotic response to short-term cytostatic therapy may be an additional
      predictive factor in rectal adenocarcinoma.

PMID- 15033829
TI  - Apoptosis in prostate carcinoma before and after neoadjuvant therapy with LH-RH
      analog.
AB  - This study investigated apoptosis in prostate cancer before and after neoadjuvant
      treatment with LH-RH analog, demonstrating that this therapy induced high AI and
      bax and survivin overexpression, thus acting as a proapoptotic agent in prostate
      cancer. A statistically significant correlation was found between high AI and
      overexpression of bax protein after therapy. It is probable that this kind of
      therapy is deeply implicated in promoting the apoptotic intrinsic pathway.

PMID- 15033830
TI  - Introduction of solids to the infant diet.

PMID- 15033831
TI  - Height monitoring as a diagnostic test.

PMID- 15033832
TI  - MRSA: the problem reaches paediatrics.

PMID- 15033833
TI  - Intravenous immunoglobulin for cystic fibrosis lung disease.

PMID- 15033834
TI  - Criminal injuries compensation for abused children.

PMID- 15033835
TI  - The introduction of solids in relation to asthma and eczema.
AB  - BACKGROUND: Despite scarce scientific evidence, current feeding guidelines
      recommend delayed introduction of solids for the prevention of asthma and
      allergy. AIMS: To explore whether late introduction of solids is protective
      against the development of asthma, eczema, and atopy. METHODS: A total of 642
      children were recruited before birth and followed to the age of 5(1/2) years.
      Main outcome measures were: doctor's diagnosis of eczema ever, atopy according to
      skin prick test results against inhalant allergens, preschool wheezing, transient
      wheezing, all defined at age 5-5(1/2) years. Introduction of solids as main
      exposure measure was assessed retrospectively at age 1 year. RESULTS: There was
      no evidence for a protective effect of late introduction of solids for the
      development of preschool wheezing, transient wheezing, atopy, or eczema. On the
      contrary, there was a statistically significant increased risk of eczema in
      relation to late introduction of egg (aOR 1.6, 95% CI 1.1 to 2.4) and milk (aOR
      1.7, 95% CI 1.1 to 2.5). Late introduction of egg was furthermore associated with
      a non-significant increased risk of preschool wheezing (aOR 1.5, 95% CI 0.92 to
      2.4). There was no statistical evidence of feeding practices playing a different
      role in the development of asthma and eczema after stratification for parental
      asthma and atopy status. CONCLUSIONS: Results do not support the recommendations
      given by present feeding guidelines stating that a delayed introduction of solids
      is protective against the development of asthma and allergy.

PMID- 15033836
TI  - Eczema and early solid feeding in preterm infants.
AB  - AIMS: To establish whether development of eczema is influenced by feeding
      practices in preterm infants, while taking account of confounding factors.
      METHODS: Data were assembled from 257 infants born prematurely and studied to 12
      months post-term. Logistic regression analysis was performed to establish the
      association between feeding practices and eczema, allowing for potential
      confounding factors including the infants' gender, parental atopic status, social
      background, and parental smoking habits. RESULTS: For the development of eczema
      (with or without other symptoms) by 12 months post-term, the introduction of four
      or more solid foods by or before 17 weeks post-term was a significant risk (odds
      ratio 3.49). Male infants were at significantly higher risk (odds ratio 1.84). In
      addition, having non-atopic parents who introduced solid foods before 10 weeks
      post-term or having at least one atopic parent represented a significant risk
      scenario (odds ratio 2.94). CONCLUSIONS: Early introduction of a diverse range of
      solid foods may predispose the preterm infant to eczema development by 12 months
      post-term. Furthermore, non-atopic parents who practice early as opposed to late
      introduction of solid foods may be exposing preterm infants to a greater risk of
      eczema by 12 months post-term.

PMID- 15033837
TI  - Intravenous immunoglobulin for cystic fibrosis lung disease: a case series of 16
      children.
AB  - BACKGROUND AND OBJECTIVE: Some children with severe cystic fibrosis (CF) lung
      disease develop chest tightness, recurrent dry cough, and intractable wheeze,
      often accompanied by deteriorating lung function and failure to expectorate
      sputum. In an attempt to reduce the use of regular oral corticosteroids, we
      treated a group of such children with monthly courses of intravenous
      immunoglobulin (IVIG). METHODS: This is a retrospective case note review of 16
      children, aged 3-16 years (median 13.0 years) who received 1-66 (median 7.5)
      courses of monthly IVIG, at a dose of 1 g/kg on two successive days for the first
      dose, followed by 1 g/kg monthly as a 12 hour infusion, with corticosteroid and
      antihistamine cover. RESULTS: FEV1 improved from a median (95% confidence
      interval (CI)) of 50% (39 to 61%) to 54% (48 to 66%), with a median (95% CI)
      difference of +7.5% (-1.5 to 14.5%; NS). FVC improved from 65% (60 to 77%) to 83%
      (70 to 89%), with a difference of +13% (4 to 22%, p = 0.01). The total daily
      dose/kg body weight of oral prednisolone was reduced from 0.6 (0.3 to 1.0) to 0
      (0 to 0.1) mg/kg/day, with a reduction of -0.6 (-1.0 to -0.1, p = 0.006)
      mg/kg/day. The total daily dose of inhaled corticosteroid (budesonide equivalent)
      was a median (range) of 2000 microg (800-6000 microg), which was reduced to 1500
      microg (0-3200 microg). The median (95% CI) difference was -400 microg (-1600 to
      0 microg), p<0.05. IVIG was well tolerated and the regimen acceptable to all but
      one of the children. The following transient adverse reactions were seen in only
      one patient each: headache, fever, hypotension, aseptic meningitis, and chest
      tightness. CONCLUSION: We suggest that an n = 1 trial of IVIG in carefully
      selected patients with severe obstructive CF lung disease is worth considering,
      as for some it may lead to significant benefit.

PMID- 15033840
TI  - Maternal depression and low maternal intelligence as risk factors for
      malnutrition in children: a community based case-control study from South India.
AB  - AIMS: To determine whether current and postpartum maternal depression and low
      maternal intelligence are risk factors for malnutrition in children. METHODS: In
      rural South India 72 children with malnutrition were identified from a central
      register; 72 controls were matched for age, gender, and residence. RESULTS: Major
      depression in the postpartum period (OR 5.0, 95% CI 1.0 to 24.0), current major
      depression (OR 3.2, 95% CI 1.1 to 9.5), and low maternal intelligence (OR 3.8,
      95% CI 1.3 to 11.1) were associated with malnutrition in the child. Low birth
      weight (OR 2.9, 95% CI 1.2 to 6.8) was also significantly associated with infant
      malnutrition. Conditional logistic regression adjusting for all other
      determinants yielded the following results: major depression during the
      postpartum period (OR 7.8; 95% CI 1.6 to 38.51), current major depression (OR
      3.1; 95% CI 0.9 to 9.7), low maternal intelligence (OR 4.6; 95% CI 1.5 to 14.1),
      and low birth weight (OR 2.7; 95% CI 2.5 to 6.8). The interactions between
      current maternal depression and low birth weight and between postpartum
      depression and low maternal intelligence were statistically significant. The
      level of maternal intelligence was associated with nutritional status. The
      severity of malnutrition was also significantly associated with major depression
      during the postpartum period and low maternal intelligence. CONCLUSION: There is
      evidence for an association between postpartum maternal depression, low maternal
      intelligence, and low birth weight with malnutrition in children aged 6-12
      months.

PMID- 15033838
TI  - Growth and adrenal androgen status at 7 years in very low birth weight survivors
      with and without bronchopulmonary dysplasia.
AB  - AIMS: To evaluate whether 7 year old VLBW (very low birth weight, <1500 g)
      survivors with and without bronchopulmonary dysplasia (BPD) evince similar growth
      status and higher adrenal androgen (AA) levels than term controls, and whether AA
      levels are higher in VLBW children born small for gestational age (SGA) than in
      non-SGA cases. METHODS: Assessment of height standard deviation score (SDs), body
      mass index (BMI), and serum androstenedione and dehydroepiandrostenedione
      sulphate levels in 31 VLBW children with BPD, 33 without BPD (no-BPD group), and
      33 term controls. RESULTS: Lower median (range) height SDs was found in BPD (-1.0
      (-3.4 to 1.4) SD) and no-BPD (-0.9 (-2.9 to 2.2) SD) children than in term
      controls (0.3 (-1.5 to 1.9) SD). Low BMI (below 10th centile) was more common in
      both the BPD (18 (58%)) and no-BPD (16 (49%)) children compared to term cases (3
      (9%)). The median (range) androstenedione levels tended to be higher in the BPD
      (0.8 (0 to 2.8) nmol/l) and no-BPD (0.8 (0 to 2.3) nmol/l) groups than in term
      controls (0.6 (0 to 1.8)). Higher median (range) dehydroepiandrostenedione
      sulphate levels were detected in the no-BPD compared to the term group (0.9 (0 to
      4.1) v 0.3 (0 to 2.3) micro mol/l). VLBW children born SGA had higher AA levels
      compared to non-SGA cases. CONCLUSIONS: At 7 years of age, VLBW children are
      shorter and tend to have higher AA levels than term controls, but VLBW children
      with and without BPD do not differ from each other in growth or AA status. Those
      born SGA have higher AA levels compared to non-SGA cases. The consequences of
      these findings to final height and to later metabolic and vascular health remain
      to be determined.

PMID- 15033841
TI  - Cycle helmet ownership and use; a cluster randomised controlled trial in primary
      school children in deprived areas.
AB  - AIMS: To assess the effectiveness of two different educational interventions plus
      free cycle helmets, in increasing cycle helmet ownership and use. METHODS: A
      cluster randomised controlled trial was carried out in 28 primary schools in
      deprived areas of Nottingham, involving 1213 year 5 schoolchildren (age 9 and
      10). Children received either a helmet + educational pack (educational pack and
      order form for free cycle helmet) or a helmet + multifaceted intervention
      (educational pack, order form for free cycle helmet, school assembly, lesson
      devoted to cycle helmet education, and an invitation to a school based cycling
      event). RESULTS: The helmet + educational pack was as effective as the helmet +
      multifaceted intervention in terms of helmet ownership (OR 1.51, 95% CI 0.50 to
      4.58) and wearing (OR 0.98, 95% CI 0.57 to 1.68). Helmet ownership significantly
      increased from baseline with both interventions, and wearing significantly
      increased from baseline with the helmet + educational pack. The interventions
      reduced the inequality in helmet ownership between children residing in deprived
      and non-deprived areas that had been present prior to the study. CONCLUSIONS: An
      educational pack plus a form to order a free cycle helmet is an effective way of
      increasing bicycle helmet ownership and use and reduces inequalities in helmet
      ownership among children in deprived areas. Further work is needed to determine
      the length of the effect of such interventions.

PMID- 15033842
TI  - Towards evidence based referral criteria for growth monitoring.
AB  - AIMS: To evaluate the performance of growth monitoring in detecting diseases.
      Turner's syndrome (TS) is taken as the target disease. METHODS: Case-control
      simulation study. Three archetypal screening rules are applied to longitudinal
      growth data comparing a group with TS versus a reference group from birth to the
      age of 10 years. Main outcome measures were sensitivity, specificity, and median
      referral age. RESULTS: Clear differences in performance of the rules were found.
      The best rule takes parental height into account. Combining rules could improve
      diagnostic accuracy. CONCLUSION: Growth monitoring is useful to screen for TS. A
      combined rule that takes absolute height SDS, parental height, and deflection in
      height velocity into account is the best way to do this. Similar research is
      needed for other diseases, populations, and ages, and the results should be
      synthesised into evidence based referral criteria.

PMID- 15033843
TI  - A multicentre randomised controlled trial of an intervention to improve the
      accuracy of linear growth measurement.
AB  - AIMS: To evaluate linear growth assessment and the effect of an intervention on
      measurement accuracy in primary care practices (PCP) within eight US geographical
      areas. METHODS: In this multicentre randomised controlled intervention study,
      paediatric endocrine nurses as site coordinators (SC) visited 55 randomly
      assigned PCP to evaluate growth assessment of staff performing linear
      measurements. SC observed 127 measurers assessing a total of 878 children: 307
      (baseline), 282 (3 months), and 289 (6 months). Accuracy was determined by SC re
      measuring each child with correct technique and equipment. State of the art
      equipment and a standardised growth training session were provided to the
      intervention group (IG) following the baseline visit. SC repeated data collection
      at all PCP at 3 and 6 months. RESULTS: There were no baseline differences between
      IG and CG equipment, technique, or accuracy; only 30% of measurements were
      accurate (< or =0.5 cm from SC). Post-intervention, significantly more IG
      measurements were accurate: IG = 55%, CG = 37% at 3 months; IG = 70%, CG = 34% at
      6 months. Odds ratio of accuracy for IG versus CG was 2.1 at 3 months and 4.5 at
      6 months. At 6 months, mean difference from the SC measurements was 0.5 cm in IG
      and 1.1 cm in CG. CONCLUSIONS: In PCP, children are measured inaccurately. Our
      intervention significantly improved measurement accuracy. Improved accuracy could
      yield more rapid detection and diagnosis of paediatric growth disorders.

PMID- 15033844
TI  - Extremely low birth weight and body size in early adulthood.
AB  - AIMS: To determine the body size of extremely low birth weight (ELBW, birth
      weight 500-999 g) subjects in early adulthood. METHODS: Cohort study examining
      the height and weight of 42 ELBW survivors free of cerebral palsy between birth
      and 20 years of age. Weight and height measurements were converted to Z (SD)
      scores. RESULTS: At birth the subjects had weight Z scores substantially below
      zero (mean birth weight Z score -0.90, 95% CI -1.25 to -0.54), and had been
      lighter than average at ages 2, 5, and 8 years. However, by 14, and again at 20
      years of age their weight Z scores were not significantly different from zero. At
      ages 2, 5, 8, 14, and 20 years of age their height Z scores were significantly
      below zero. Their height at 20 years of age was, however, consistent with their
      parents' height. As a group they were relatively heavy for their height and their
      mean body mass index (BMI) Z score was almost significantly different from zero
      (mean difference 0.42, 95% CI -0.02 to 0.84). Their mean BMI (kg/m2) was 24.0 (SD
      5.2); 14 had a BMI >25, and four had a BMI >30. CONCLUSIONS: Despite their early
      small size, by early adulthood the ELBW subjects had attained an average weight,
      and their height was consistent with their parents' height. They were, however,
      relatively heavy for their height.

PMID- 15033845
TI  - Many referrals under Dutch short stature guidelines.
AB  - The number of referrals under strict adherence to the Dutch consensus guidelines
      for short stature was estimated using longitudinal data from 970 children (0-10
      years). Results showed that over 38% of all children would have to be referred
      one or more times. There is therefore a clear need to revise the current
      guidelines.

PMID- 15033847
TI  - Qualitative analysis of parents' experience with early detection of hearing loss.
AB  - AIMS: To determine key themes from parents' comments on paths to diagnosis and
      intervention for their children with hearing loss, following introduction of at
      risk neonatal hearing screening and modification of distraction test screening
      for infants not at-risk. METHODS: Parents of children born in 1993 in Victoria,
      Australia, who were eligible for screening via the Victorian Infant Hearing
      Screening Program and who were subsequently diagnosed with a permanent congenital
      hearing loss and fitted with hearing aids prior to the year 2000 were asked to
      complete a semi-structured questionnaire shortly after aid fitting. Two
      researchers independently analysed parent comments using the constant comparative
      method. RESULTS: Parents of 82 children (61%) replied to the questionnaire.
      Themes analysis revealed a generally positive response to neonatal ABR screening,
      with a mixed response to the distraction test; powerful emotions experienced by
      parents at diagnosis including denial and shock; frustration arising from delays
      in diagnosis, and communication difficulties with providers. Special difficulties
      testing children with other medical and developmental problems, confusion about
      tympanostomy tube insertion, and difficulty with wearing hearing aids were also
      reported. Some children had experienced problems in the school setting.
      Experience of post-diagnostic services was generally positive. CONCLUSIONS:
      Parents need greater support both during the testing of screen failures and at
      the time of diagnosis. Providers need more training in how to communicate
      findings to parents, particularly at times when parents are experiencing strong
      emotions. Parents need more strategies to enable hearing aid wearing in very
      young children. Some children with additional medical, developmental, and
      behavioural problems need specialised approaches to testing.

PMID- 15033848
TI  - Myocardial ischaemia in children with sickle cell disease.
AB  - BACKGROUND: The heart may be involved in children affected with sickle cell
      disease (SCD) via several mechanisms. Principally, chronic anaemia increases
      cardiac output and may cause left ventricular enlargement and cardiac
      insufficiency. AIMS: To investigate whether the heart also suffers from ischaemia
      in SCD, as has already been shown for other organs (bone, brain, etc), and to
      look for risk factors predisposing to this complication. METHODS: Twenty two
      children with SCD, and chest pain or ECG or echocardiographic signs (left
      ventricle dilation or hypokinesis) suggesting myocardial ischaemia were subjected
      to thallium-201 (201Tl) single photon emission computed tomography (SPECT).
      RESULTS: Eight children had a normal SPECT, 14 an abnormal one. Myocardial
      perfusion defects were reversible in nine, fixed in five. Patients with perfusion
      defects tended to be older and have more severe disease. Five had had cardiac
      symptoms (episodes of cardiac failure in three, ventricular fibrillation in one,
      angina in one). Myocardial perfusion was reassessed after six months of
      hydroxyurea treatment in three patients, and was found to be improved.
      CONCLUSIONS: Myocardial perfusion defects are present in children with SCD and
      may be demonstrated using SPECT. Hydroxyurea improved perfusion in three
      patients.

PMID- 15033849
TI  - Bacteraemia and antibiotic use in respiratory syncytial virus infections.
AB  - AIMS: To examine the frequency of and risk factors for bacteraemia in children
      hospitalised with respiratory syncytial virus (RSV) infection; and to determine
      current use of antibiotics in hospitalised children with RSV infection. METHODS:
      Retrospective study of all children, aged 0-14 years, admitted to a tertiary
      children's hospital with proven RSV infection over a four year period. Children
      with concurrent bacteraemia and RSV infection were identified, and risk factors
      examined for bacteraemia. The case notes of a randomly selected comparison sample
      of 100 of these RSV infected children were examined to assess antibiotic use and
      population incidence of risk factors for severe RSV infection. RESULTS: A total
      of 1795 children had proven RSV infection, and blood cultures were sent on 861
      (48%). Eleven (0.6%) of the 1795 RSV positive children had bacteraemia. RSV
      positive children had a significantly higher incidence of bacteraemia if they had
      nosocomial RSV infection (6.5%), cyanotic congenital heart disease (6.6%), or
      were admitted to the paediatric intensive care unit (2.9%). Forty five (45%) of
      the random comparison sample of RSV infected children received antibiotics.
      CONCLUSIONS: Bacteraemia is rare in RSV infection. Children with RSV infection
      are more likely to be bacteraemic, however, if they have nosocomial RSV
      infection, cyanotic congenital heart disease, or require intensive care unit
      admission.

PMID- 15033851
TI  - Hospital attendance patterns in long term survivors of cancer.
AB  - AIMS: To identify attendance patterns in a childhood cancer long term follow up
      clinic, in order to inform decision making strategies for efficient, cost
      effective local and national surveillance of survivors. METHODS: Cross-sectional
      review of 385 individuals >5 years from completion of cancer therapy in childhood
      or adolescence, attending a regional paediatric oncology and haematology centre.
      RESULTS: Attenders were younger than non-attenders in the <18 age group; no
      differences were found for > or =18 year age group. Those attending clinic were
      more recently off treatment; no significant difference existed for those <7 years
      from completion of therapy. A greater proportion of attenders were in the most
      affluent socioeconomic groups with a greater proportion of non-attenders in the
      lower groups. Those in full time education or training were more likely to attend
      and those unemployed were less likely. Multiple regression analysis confirmed a
      significant trend in reduction in attendance with increasing social deprivation,
      and that attenders were more than twice as likely to be in full time education or
      training. CONCLUSIONS: Following cancer treatment in childhood and adolescence,
      attendance at long term follow up programmes is determined by social factors
      including education, employment, and deprivation.

PMID- 15033852
TI  - Emergence of methicillin resistant Staphylococcus aureus (MRSA) bacteraemia among
      children in England and Wales, 1990-2001.
AB  - Methicillin resistant Staphylococcus aureus (MRSA) is now a major cause of adult
      bacteraemia. All reports of Staphylococcus aureus bacteraemia to the Health
      Protection Agency were analysed from 1990 to 2001. There were 376 cases of MRSA
      bacteraemia in children <15 years over this time. The proportion of
      Staphylococcus aureus bacteraemia due to MRSA increased steadily from 0.9% in
      1990 to 13% in 2000. The proportion was higher in infants. MRSA bacteraemia is
      now a serious problem in children in England and Wales. More data on the risk
      factors for acquisition and spread of MRSA in children are required.

PMID- 15033850
TI  - Cardiac complications of enterovirus rhombencephalitis.
AB  - BACKGROUND: Epidemics of enterovirus 71 infection have caused the death of many
      children throughout the world. Rhombencephalitis, brain stem encephalitis, and
      heart failure were present in all of the fatal cases. However, no evidence of
      myocarditis was noted in the heart specimens, and the mechanism of heart failure
      remains unknown. AIMS: To characterise the presentation of cardiac complications
      in children with enterovirus rhombencephalitis and discuss its pathogenesis.
      METHODS: Ninety one consecutive patients with enterovirus rhombencephalitis
      underwent echocardiography. Of these, 17 patients (nine male, eight female;
      median age 14 months, range 4-57 months) with left ventricular dysfunction were
      studied. RESULTS: Tachycardia was noted in all patients and systemic hypertension
      in 12. Muscle-brain fraction of creatine kinase was >5% in 14 patients. Plasma
      norepinephrine and epinephrine levels were significantly raised in the three
      patients in whom these were analysed. Electrocardiographic abnormalities were
      noted in eight patients. Pulmonary oedema was complicated in 15 patients. The
      initial ejection fraction of the left ventricle was 22-58% (mean 37%, SD 11%).
      All patients deteriorated to hypotensive shock within 12 hours and 13 died. Heart
      specimens from seven patients showed no evidence of myocarditis, but significant
      coagulative myocytolysis, myofibrillar degeneration, and cardiomyocyte apoptosis
      were observed. CONCLUSIONS: Acute heart failure was noted in 19% of patients with
      enterovirus rhombencephalitis, which had a fatality rate of 77%. It was not
      caused by myocarditis but possibly by neurogenic cardiac damage.

PMID- 15033853
TI  - Geographic mobility following cancer treatment in Yorkshire, UK.
AB  - Long term cure and maximising reintegration into society are major goals of
      childhood cancer treatment. Whether reintegration had occurred was assessed using
      geographic mobility as an objective proxy. Age, sex, and socioeconomic status
      were identified as being independently associated with mobility whereas diagnosis
      and relapse were not.

PMID- 15033854
TI  - Switching to the Euro: still hard to swallow.

PMID- 15033855
TI  - Hypercalcaemia in infancy; a presenting feature of spinal muscular atrophy.
AB  - A 10 month old girl presented with a history of constipation from early life. She
      was found to be hypercalcaemic with hypercalciuria and nephrocalcinosis. Her mild
      motor delay and hypotonia were thought to be linked to chronic hypercalcaemia,
      but when these features failed to improve despite normocalcaemia on a low calcium
      diet the possibility of neuromuscular disease was explored in more detail. She
      was subsequently found to have spinal muscular atrophy type 2. We suspect that
      the hypercalcaemia with hypercalciuria observed in this case reflects altered
      bone turnover secondary to reduced muscular activity.

PMID- 15033857
TI  - Living with genetic rickets.

PMID- 15033858
TI  - "Fixed intestinal loop" on abdominal x ray: sine qua non of mechanical intestinal
      obstruction.

PMID- 15033856
TI  - Current status of paediatric heart, lung, and heart-lung transplantation.
AB  - Since the first successful heart transplantation by Christian Barnard in 1967,
      there have been over 60 000 heart transplants performed worldwide. Around 350
      paediatric heart transplants are now performed annually and approximately 10% of
      these are in the UK.

PMID- 15033860
TI  - Community growth monitoring in practice.

PMID- 15033861
TI  - The collusion of anonymity in paediatrics.

PMID- 15033863
TI  - Nephrotic syndrome relapse: need for a better evidence based definition.

PMID- 15033864
TI  - The Seville effect.

PMID- 15033865
TI  - Conservation analysis of small RNA genes in Escherichia coli.
AB  - MOTIVATION: Small RNA (sRNA) genes in Escherichia coli have been in focus
      recently, as 44 out of 55 experimentally confirmed sRNA genes have been precisely
      located in the genome. The object of this study is to analyze quantitatively the
      conservation of these sRNA genes and compare it with the conservation of protein
      encoding genes, function-unknown regions and tRNA genes. RESULTS: The results
      show that within an evolutionary distance of 0.26, both sRNA genes and protein
      encoding genes display a similar tendency in their degrees of conservation at the
      nucleotide level. In addition, the conservation of sRNA genes is much stronger
      than function-unknown regions, but much weaker than tRNA genes. Based on the
      conservation of studied sRNA genes, we also give clues to estimate the total
      number of sRNA genes in E.coli. SUPPLEMENTARY INFORMATION: Supplementary
      information is available at http://www.bioinfo.org.cn/SM/sRNAconservation.htm

PMID- 15033867
TI  - A systematic method to identify genomic islands and its applications in analyzing
      the genomes of Corynebacterium glutamicum and Vibrio vulnificus CMCP6 chromosome
      I.
AB  - MOTIVATION: Some genomic islands contain horizontally transferred genes, which
      play critical roles in altering the genotypes and phenotypes of organisms, and
      horizontal gene transfer has been recognized as a universal event throughout
      bacterial evolution. A windowless method to display the distribution of genomic
      GC content, the cumulative GC profile, is proposed to identify genomic islands in
      genomes whose complete genome sequences are available. Two new indices are
      proposed to assess the codon usage bias and amino acid usage bias in genomic
      islands. RESULTS: A 211 kb genomic island (CGGI-1) has been identified in the
      genome of Corynebacterium glutamicum, and three genomic islands VVGI-1, VVGI-2
      and VVGI-3, with lengths 167, 40 and 33 kb, respectively, have been identified in
      the genome of Vibrio vulnificus CMCP6 chromosome I. The CGGI-1 is flanked by two
      approximately 500 bp direct repeats, and utilizes a Val-tRNA as the integration
      site. For the VVGI-1 and VVGI-2, each has an integrase gene at 5' junction. All
      the identified genomic islands show unusual GC content, codon usage and amino
      acid usage, compared with the rest of the genomes. In addition, it is found that
      genomic islands are fairly homogenous in terms of GC content variation. An index,
      h, to quantify the homogeneity of GC content for genomic islands is proposed, and
      it is shown that h is less than 0.1 for all the genomic islands analyzed. The
      cumulative GC profile, as well as various indices to assess the codon usage bias,
      amino acid usage bias and homogeneity of the genomic islands, will be useful in
      the analysis of other genomes. AVAILABILITY: Programs used in this work and
      numerical results are available upon request.

PMID- 15033866
TI  - Extracting human protein interactions from MEDLINE using a full-sentence parser.
AB  - MOTIVATION: The living cell is a complex machine that depends on the proper
      functioning of its numerous parts, including proteins. Understanding protein
      functions and how they modify and regulate each other is the next great challenge
      for life-sciences researchers. The collective knowledge about protein functions
      and pathways is scattered throughout numerous publications in scientific
      journals. Bringing the relevant information together becomes a bottleneck in a
      research and discovery process. The volume of such information grows
      exponentially, which renders manual curation impractical. As a viable
      alternative, automated literature processing tools could be employed to extract
      and organize biological data into a knowledge base, making it amenable to
      computational analysis and data mining. RESULTS: We present MedScan, a completely
      automated natural language processing-based information extraction system. We
      have used MedScan to extract 2976 interactions between human proteins from
      MEDLINE abstracts dated after 1988. The precision of the extracted information
      was found to be 91%. Comparison with the existing protein interaction databases
      BIND and DIP revealed that 96% of extracted information is novel. The recall rate
      of MedScan was found to be 21%. Additional experiments with MedScan suggest that
      MEDLINE is a unique source of diverse protein function information, which can be
      extracted in a completely automated way with a reasonably high precision. Further
      directions of the MedScan technology improvement are discussed. AVAILABILITY:
      MedScan is available for commercial licensing from Ariadne Genomics, Inc.

PMID- 15033868
TI  - Enhancing scatterplots with smoothed densities.
AB  - MOTIVATION: Scatterplots of microarray data generally contain a very large number
      of dots, making it difficult to get a good impression of their distribution in
      dense areas. RESULTS: We present a fast and simple algorithm for two-dimensional
      histogram smoothing, to visually enhance scatterplots. AVAILABILITY: Functions
      for Matlab and R are available from the corresponding author.

PMID- 15033869
TI  - PHIRE, a deterministic approach to reveal regulatory elements in bacteriophage
      genomes.
AB  - MOTIVATION: In silico genome analysis of bacteriophage genomes focuses mainly on
      gene discovery and functional assignment. The search for regulatory elements
      contained within these genome sequences is often based on prior knowledge of
      other genomic elements or on learning algorithms of experimentally determined
      data, potentially leading to a biased prediction output. The PHage In silico
      Regulatory Elements (PHIRE) program is a standalone program in Visual Basic. It
      performs an algorithmic string-based search on bacteriophage genome sequences to
      uncover and extract subsequence alignments hinting at regulatory elements
      contained within these genomes, in a deterministic manner without any prior
      experimental or predictive knowledge. RESULTS: The PHIRE program was tested on
      known phage genomes with experimentally verified regulatory elements. PHIRE was
      able to extract phage regulatory sequences correctly for bacteriophages T7, T3,
      YeO3-12 and lambda, based solely on the genome sequence. For 11 bacteriophages,
      new predictions of conserved phage-specific putative regulatory elements were
      made, further corroborating this approach. AVAILABILITY:
      http://www.agr.kuleuven.ac.be/logt/PHIRE.htm. Freely available for academic use.
      Commercial users should contact the corresponding author.

PMID- 15033870
TI  - Phylo-VISTA: interactive visualization of multiple DNA sequence alignments.
AB  - MOTIVATION: The power of multi-sequence comparison for biological discovery is
      well established. The need for new capabilities to visualize and compare cross
      species alignment data is intensified by the growing number of genomic sequence
      datasets being generated for an ever-increasing number of organisms. To be
      efficient these visualization algorithms must support the ability to accommodate
      consistently a wide range of evolutionary distances in a comparison framework
      based upon phylogenetic relationships. RESULTS: We have developed Phylo-VISTA, an
      interactive tool for analyzing multiple alignments by visualizing a similarity
      measure for multiple DNA sequences. The complexity of visual presentation is
      effectively organized using a framework based upon interspecies phylogenetic
      relationships. The phylogenetic organization supports rapid, user-guided
      interspecies comparison. To aid in navigation through large sequence datasets,
      Phylo-VISTA leverages concepts from VISTA that provide a user with the ability to
      select and view data at varying resolutions. The combination of multiresolution
      data visualization and analysis, combined with the phylogenetic framework for
      interspecies comparison, produces a highly flexible and powerful tool for visual
      data analysis of multiple sequence alignments. AVAILABILITY: Phylo-VISTA is
      available at http://www-gsd.lbl.gov/phylovista. It requires an Internet browser
      with Java Plug-in 1.4.2 and it is integrated into the global alignment program
      LAGAN at http://lagan.stanford.edu

PMID- 15033871
TI  - Optimization models for cancer classification: extracting gene interaction
      information from microarray expression data.
AB  - MOTIVATION: Microarray data appear particularly useful to investigate mechanisms
      in cancer biology and represent one of the most powerful tools to uncover the
      genetic mechanisms causing loss of cell cycle control. Recently, several
      different methods to employ microarray data as a diagnostic tool in cancer
      classification have been proposed. These procedures take changes in the
      expression of particular genes into account but do not consider disruptions in
      certain gene interactions caused by the tumor. It is probable that some genes
      participating in tumor development do not change their expression level
      dramatically. Thus, they cannot be detected by simple classification approaches
      used previously. For these reasons, a classification procedure exploiting
      information related to changes in gene interactions is needed. RESULTS: We
      propose a MAximal MArgin Linear Programming (MAMA) method for the classification
      of tumor samples based on microarray data. This procedure detects groups of genes
      and constructs models (features) that strongly correlate with particular tumor
      types. The detected features include genes whose functional relations are changed
      for particular cancer types. The proposed method was tested on two publicly
      available datasets and demonstrated a prediction ability superior to previously
      employed classification schemes. AVAILABILITY: The MAMA system was developed
      using the linear programming system LINDO http://www.lindo.com. A Perl script
      that specifies the optimization problem for this software is available upon
      request from the authors.

PMID- 15033872
TI  - Disulfide connectivity prediction using recursive neural networks and
      evolutionary information.
AB  - MOTIVATION: We focus on the prediction of disulfide bridges in proteins starting
      from their amino acid sequence and from the knowledge of the disulfide bonding
      state of each cysteine. The location of disulfide bridges is a structural feature
      that conveys important information about the protein main chain conformation and
      can therefore help towards the solution of the folding problem. Existing
      approaches based on weighted graph matching algorithms do not take advantage of
      evolutionary information. Recursive neural networks (RNN), on the other hand, can
      handle in a natural way complex data structures such as graphs whose vertices are
      labeled by real vectors, allowing us to incorporate multiple alignment profiles
      in the graphical representation of disulfide connectivity patterns. RESULTS: The
      core of the method is the use of machine learning tools to rank alternative
      disulfide connectivity patterns. We develop an ad-hoc RNN architecture for
      scoring labeled undirected graphs that represent connectivity patterns. In order
      to compare our algorithm with previous methods, we report experimental results on
      the SWISS-PROT 39 dataset. We find that using multiple alignment profiles allows
      us to obtain significant prediction accuracy improvements, clearly demonstrating
      the important role played by evolutionary information. AVAILABILITY: The Web
      interface of the predictor is available at http://neural.dsi.unifi.it/cysteines

PMID- 15033873
TI  - Variance-stabilizing transformations for two-color microarrays.
AB  - MOTIVATION: Authors of several recent papers have independently introduced a
      family of transformations (the generalized-log family), which stabilizes the
      variance of microarray data up to the first order. However, for data from two
      color arrays, tests for differential expression may require that the variance of
      the difference of transformed observations be constant, rather than that of the
      transformed observations themselves. RESULTS: We introduce a transformation
      within the generalized-log family which stabilizes, to the first order, the
      variance of the difference of transformed observations. We also introduce
      transformations from the 'started-log' and log-linear-hybrid families which
      provide good approximate variance stabilization of differences. Examples using
      control-control data show that any of these transformations may provide
      sufficient variance stabilization for practical applications, and all perform
      well compared to log ratios.

PMID- 15033874
TI  - 404 not found: the stability and persistence of URLs published in MEDLINE.
AB  - MOTIVATION: The advent of the World Wide Web has enabled unprecedented
      supplementation of traditional journal publications, allowing access to
      resources, such as video, sound, software, databases, datasets too large to
      publish, and even supplementary information and discussion. However, unlike
      traditional publications, continued availability of these online resources is not
      guaranteed. An automated survey was conducted to quantify the growth in Uniform
      Resource Locators (URLs) published to date in MEDLINE abstracts, their current
      availability and distribution by journal. RESULTS: Of 1630 unique URLs
      identified, formatting and/or spelling errors were detected within 201 (12%) of
      them as published. After corrections were made, a survey revealed that
      approximately 63% of these URLs were consistently available, and another 19% were
      available intermittently. The rate of failure was far worse for anonymous login
      to FTP sites, with only 12 of 33 sites (36%) responding. This survey also shows
      that journals vary disproportionately in the number of web citations published,
      suggesting policy implementation among a few could have a profound impact
      overall. Out of the 306 journals with a URL published in an abstract,
      Bioinformatics published the most (12% of total). AVAILABILITY: URL database and
      program available by request.

PMID- 15033875
TI  - Degrees of differential gene expression: detecting biologically significant
      expression differences and estimating their magnitudes.
AB  - MOTIVATION: Many methods of identifying differential expression in genes depend
      on testing the null hypotheses of exactly equal means or distributions of
      expression levels for each gene across groups, even though a statistically
      significant difference in the expression level does not imply the occurrence of
      any difference of biological or clinical significance. This is because a
      mathematical definition of 'differential expression' as any non-zero difference
      does not correspond to the differential expression biologists seek. Furthermore,
      while some current methods account for multiple comparisons in hypothesis tests,
      they do not accordingly adjust estimates of the degrees to which genes are
      differentially expressed. Both problems lead to overstating the relevance of
      findings. RESULTS: Testing whether genes have relevant differential expression
      can be accomplished with customized null hypotheses, thereby redefining
      'differential expression' in a way that is more biologically meaningful. When
      such tests control the false discovery rate, they effectively discover genes
      based on a desired quantile of differential gene expression. Estimation of the
      degree to which genes are differentially expressed has been corrected for
      multiple comparisons. AVAILABILITY: R code is freely available from
      http://www.davidbickel.com and may become available from www.r-project.org or
      www.bioconductor.org SUPPLEMENTARY INFORMATION: Applications to cancer
      microarrays, an application in the absence of differential expression,
      pseudocode, and a guide to customizing the methods may be found at
      www.davidbickel.com and www.mathpreprints.com

PMID- 15033876
TI  - A statistical framework for combining and interpreting proteomic datasets.
AB  - MOTIVATION: To identify accurately protein function on a proteome-wide scale
      requires integrating data within and between high-throughput experiments. High
      throughput proteomic datasets often have high rates of errors and thus yield
      incomplete and contradictory information. In this study, we develop a simple
      statistical framework using Bayes' law to interpret such data and combine
      information from different high-throughput experiments. In order to illustrate
      our approach we apply it to two protein complex purification datasets. RESULTS:
      Our approach shows how to use high-throughput data to calculate accurately the
      probability that two proteins are part of the same complex. Importantly, our
      approach does not need a reference set of verified protein interactions to
      determine false positive and false negative error rates of protein association.
      We also demonstrate how to combine information from two separate protein
      purification datasets into a combined dataset that has greater coverage and
      accuracy than either dataset alone. In addition, we also provide a technique for
      estimating the total number of proteins which can be detected using a particular
      experimental technique. AVAILABILITY: A suite of simple programs to accomplish
      some of the above tasks is available at
      www.unm.edu/~compbio/software/DatasetAssess

PMID- 15033877
TI  - Expression of estrogen receptors alpha and beta in the fetal baboon testis and
      epididymis.
AB  - Although studies in transgenic mice suggest that estrogen is important for
      development of the testis, very little is known about the potential role of
      estrogen in maturation of the primate fetal testis. Therefore, as a first step to
      determine whether estrogen regulates maturation of the fetal primate testis, we
      used immunocytochemistry to determine estrogen receptor (ER) alpha and beta
      expression in the fetal baboon testis. Second, we established methods to quantify
      ERbeta mRNA levels by competitive reverse transcription-polymerase chain reaction
      in Sertoli cells isolated by laser capture microdissection (LCM) from the fetal
      baboon testis. ERbeta protein expression was abundant in the nuclei of Sertoli,
      peritubular, and interstitial cells in baboon fetuses at mid (Day 100) and late
      (Day 165) gestation (term is 184 days). ERbeta mRNA level was 0.03
      attomole/femtomole 18S rRNA in Sertoli cell nuclei and associated cytoplasm
      isolated by LCM. ERalpha was expressed in low level in seminiferous tubules and
      in moderate level in peritubular cells on Day 165. Germ cells expressed very
      little ERalpha or ERbeta protein, whereas the baboon fetal epididymis exhibited
      extensive ERalpha and ERbeta immunostaining at mid- and late gestation. In
      contrast to the robust expression of ERbeta, androgen receptor protein was not
      demonstrable within the cells of the seminiferous cords but was abundantly
      expressed in epididymal epithelial cells of the fetal baboon. In summary, the
      results of this study show that the fetal baboon testis and epididymis expressed
      the ERalpha and ERbeta, and we suggest that our nonhuman primate baboon model can
      be used to study the potential role of estrogen on maturation of the fetal
      testis.

PMID- 15033878
TI  - Pertussis vaccination in infancy and asthma or allergy in later childhood: birth
      cohort study.

PMID- 15033880
TI  - Association between stressful life events and exacerbation in multiple sclerosis:
      a meta-analysis.
AB  - OBJECTIVE: To quantify the association between stressful life events and
      exacerbations of multiple sclerosis. DATA SOURCES: PubMed, PsychInfo, and
      Psychological Abstracts searched for empirical papers from 1965 to February 2003
      with terms "stress", "trauma", and "multiple sclerosis". REVIEW METHODS: Three
      investigators independently reviewed papers for inclusion/exclusion criteria and
      extracted the relevant data, including methods, sample statistics, and outcomes.
      RESULTS: Of 20 studies identified, 14 were included. The meta-analysis showed a
      significant increase in risk of exacerbation in multiple sclerosis after
      stressful life events, with a weighted average effect size of d = 0.53 (95%
      confidence interval 0.40 to 0.65), P < 0.0001. The studies were homogenous, Q =
      16.62, P = 0.22, I2 = 21.8%. Neither sampling nor study methods had any effect on
      study outcomes. CONCLUSIONS: There is a consistent association between stressful
      life events and subsequent exacerbation in multiple sclerosis. However these data
      do not allow the linking of specific stressors to exacerbations nor should they
      be used to infer that patients are responsible for their exacerbations.
      Investigation of the psychological, neuroendocrine, and immune mediators of
      stressful life events on exacerbation may lead to new behavioural and
      pharmacological strategies targeting potential links between stress and
      exacerbation.

PMID- 15033881
TI  - Systematic review of topical capsaicin for the treatment of chronic pain.
AB  - OBJECTIVE: To determine the efficacy and safety of topically applied capsaicin
      for chronic pain from neuropathic or musculoskeletal disorders. DATA SOURCES:
      Cochrane Library, Medline, Embase, PubMed, an in-house database, and contact with
      manufacturers of topical capsaicin. STUDY SELECTION: Randomised controlled trials
      comparing topically applied capsaicin with placebo or another treatment in adults
      with chronic pain. DATA EXTRACTION: Primary outcome was dichotomous information
      for the number of patients with about a 50% reduction in pain. Outcomes were
      extracted at four weeks for musculoskeletal conditions and eight weeks for
      neuropathic conditions. Secondary outcomes were adverse events and withdrawals
      due to adverse events. DATA SYNTHESIS: Six double blind placebo controlled trials
      (656 patients) were pooled for analysis of neuropathic conditions. The relative
      benefit from topical capsaicin 0.075% compared with placebo was 1.4 (95%
      confidence interval 1.2 to 1.7) and the number needed to treat was 5.7 (4.0 to
      10.0). Three double blind placebo controlled trials (368 patients) were pooled
      for analysis of musculoskeletal conditions. The relative benefit from topical
      capsaicin 0.025% or plaster compared with placebo was 1.5 (1.1 to 2.0) and the
      number needed to treat was 8.1 (4.6 to 34). Around one third of patients
      experienced local adverse events with capsaicin, which would not have been the
      case with placebo. CONCLUSIONS: Although topically applied capsaicin has moderate
      to poor efficacy in the treatment of chronic musculoskeletal or neuropathic pain,
      it may be useful as an adjunct or sole therapy for a small number of patients who
      are unresponsive to, or intolerant of, other treatments.

PMID- 15033879
TI  - Systematic review of efficacy of topical rubefacients containing salicylates for
      the treatment of acute and chronic pain.
AB  - OBJECTIVE: To determine the efficacy and safety of topical rubefacients
      containing salicylates in acute and chronic pain. DATA SOURCES: Electronic
      databases and manufacturers of salicylates. STUDY SELECTION: Randomised double
      blind trials comparing topical rubefacients with placebo or another active
      treatment, in adults with acute or chronic pain, and reporting dichotomous
      information, around a 50% reduction in pain, and analyses at one week for acute
      conditions and two weeks for chronic conditions. DATA EXTRACTION: Relative
      benefit and number needed to treat, analysis of adverse events, and withdrawals.
      DATA SYNTHESIS: Three double blind placebo controlled trials had information on
      182 patients with acute conditions. Topical salicylate was significantly better
      than placebo (relative benefit 3.6, 95% confidence interval 2.4 to 5.6; number
      needed to treat 2.1, 1.7 to 2.8). Six double blind placebo controlled trials had
      information on 429 patients with chronic conditions. Topical salicylate was
      significantly better than placebo (relative benefit 1.5, 1.3 to 1.9; number
      needed to treat 5.3, 3.6 to 10.2), but larger, more valid studies were without
      significant effect. Local adverse events and withdrawals were generally rare in
      trials that reported them. CONCLUSIONS: Based on limited information, topically
      applied rubefacients containing salicylates may be efficacious in the treatment
      of acute pain. Trials of musculoskeletal and arthritic pain suggested moderate to
      poor efficacy. Adverse events were rare in studies of acute pain and poorly
      reported in those of chronic pain. Efficacy estimates for rubefacients are
      unreliable owing to a lack of good clinical trials.

PMID- 15033882
TI  - Effectiveness of nicotine patches in relation to genotype in women versus men:
      randomised controlled trial.

PMID- 15033883
TI  - The balance among immune suppression, stem cell ablation, competition, and
      engraftment.

PMID- 15033884
TI  - Role of KIR ligand incompatibility in hematopoietic stem cell transplantation
      using unrelated donors.

PMID- 15033885
TI  - Oral vitamin B12 therapy: a cautionary note.

PMID- 15033886
TI  - Brainstem death testing in the UK--time for reappraisal?
AB  - BACKGROUND: A diagnosis of brainstem death in the UK is based on clinical
      assessment rather than technical investigations, but is considered rigorous
      enough to be legally synonymous with death. METHODS: A questionnaire in five
      sections concerning clinician details, initiation of support, criteria for
      testing, conduct of the tests, and the process of organ donation, was sent to all
      members of the Neuroanaesthesia Society. RESULTS: The survey reveals evidence of
      failure to apply existing guidelines accurately and a wide variation in practice
      where the recommendations are not specific. CONCLUSIONS: In an era of scrutiny of
      medical process, it is timely to consider whether the current guidelines should
      be revisited. Clarification of the approach to biochemical derangement, and the
      role of confirmatory tests when the residual effect of sedative agents cannot be
      excluded, are two areas worthy of debate.

PMID- 15033887
TI  - Liver tissue partial pressure of oxygen and carbon dioxide during partial
      hepatectomy.
AB  - BACKGROUND: Data on tissue oxygen partial pressure (PtO2) and carbon dioxide
      partial pressure (PtCO2) in human liver tissue are limited. We set out to measure
      changes in liver PtO2 and PtCO2 during changes in ventilation and a 10 min period
      of ischaemia in patients undergoing liver resection using a multiple sensor
      (Paratrend Diametrics Medical Ltd, High Wycombe, UK). METHODS: Liver tissue
      oxygenation was measured in anaesthetized patients undergoing liver resection
      using a sensor inserted under the liver capsule. PtO2 and PtCO2 were recorded
      with FIO2 values of 0.3 and 1.0, at end-tidal carbon dioxide partial pressures of
      3.5 and 4.5 kPa and 10 min after the onset of liver ischaemia (Pringle
      manoeuvre). RESULTS: Data are expressed as median (interquartile range).
      Increasing the FIO2 from 0.3 to 1.0 resulted in the PtO2 changing from 4.1 (2.6
      5.4) to 4.6 (3.8-5.2) kPa, but this was not significant. During the 10 min period
      of ischaemia PtCO2 increased significantly (P<0.05) from 6.7 (5.8-7.0) to 11.5
      (9.7-15.3) kPa and PtO2 decreased, but not significantly, from 4.3 (3.5-12.0) to
      3.3 (0.9-4.1) kPa. CONCLUSION: PtO2 and PtCO2 were measured directly using a
      Paratrend sensor in human liver tissue. During anaesthesia, changes in
      ventilation and liver blood flow caused predictable changes in PtCO2.

PMID- 15033888
TI  - Cerebral ischaemia during cardiac surgery in children detected by combined
      monitoring of BIS and near-infrared spectroscopy.
AB  - BACKGROUND: Children frequently suffer transient cerebral ischaemia during
      cardiac surgery. We measured cerebral ischaemia in children during cardiac
      surgery by combining two methods of monitoring. METHODS: We studied 65 children
      aged between 5 months and 17 yr having surgery to correct non-cyanotic heart
      disease using hypothermic cardiopulmonary bypass (CPB). During surgery, we
      measured the Bispectral Index (BIS) and regional cerebral haemoglobin oxygen
      saturation (SrO2) with near-infrared spectroscopy (NIRS). Cerebral ischaemia was
      diagnosed if both SrO2 and BIS decreased abruptly when acute hypotension
      occurred. In each patient, the relationship between SrO2 and arterial blood
      pressure (AP) was indicated by a plot of mean SrO2 against simultaneous mean AP.
      RESULTS: We noted 72 episodes of cerebral ischaemia in 38 patients. Sixty-three
      ischaemic events were during CPB. Cerebral ischaemia was less frequent in older
      patients. Cerebral ischaemia was more common and more frequent in children under
      4 yr old. Haematocrit during CPB was lower and SrO2 was more dependent on AP in
      children under 4 yr. CONCLUSIONS: Children less than 4 yr of age are more likely
      to have cerebral ischaemia caused by hypotension during cardiac surgery.
      Ineffective cerebral autoregulation and haemodilution during CPB may be
      responsible.

PMID- 15033891
TI  - Effects of propofol on respiratory mechanic and lung histology in normal rats.
AB  - BACKGROUND: Propofol is able to reduce airway resistance in lungs with previous
      airway constriction. The aim of this study was to evaluate the effects of
      propofol on respiratory mechanics in normal rats and to correlate these
      parameters with lung histology, to define the sites of action of propofol.
      METHODS: Sixteen Wistar rats were divided into two groups of eight animals. Rats
      were sedated (diazepam) and anaesthetized with pentobarbital sodium (C) or
      propofol (P), and paralysed. Respiratory system, lung, and chest wall resistive,
      elastic, and viscoelastic/inhomogeneous pressures were computed using the end
      inflation occlusion method. RESULTS: Lung resistive pressure was smaller in group
      P (0.29 kPa (0.05)) than group C (0.37 kPa (0.04)) (P=0.007). The internal
      diameter of the central airways was greater in group P than C (P=0.01).
      CONCLUSION: Propofol acts at the airway level decreasing respiratory system and
      lung impedances as a result of central airway dilation.

PMID- 15033889
TI  - The interaction of anaesthetic steroids with recombinant glycine and GABAA
      receptors.
AB  - BACKGROUND: Anaesthetic steroids are established positive allosteric modulators
      of GABAA receptors, but little is known concerning steroid modulation of
      strychnine-sensitive glycine receptors, the principal mediators of fast,
      inhibitory neurotransmission in the brain stem and spinal cord. This study
      compared the modulatory actions of five anaesthetic pregnane steroids and two non
      anaesthetic isomers at human recombinant alpha1 glycine and alpha1beta2gamma2L
      GABAA receptors. METHODS: Recombinant alpha1 glycine or alpha1beta2gamma2L GABAA
      receptors were expressed in Xenopus laevis oocytes and agonist-evoked currents
      recorded under voltage-clamp. Steroid modulation of currents evoked by GABA, or
      glycine, was quantified by determining the potency (EC50) and maximal effect of
      the compounds. RESULTS: The anaesthetics minaxolone (EC50=1.3 microM), Org20599
      (EC50=1.1 microM) and alphaxalone (EC50=2.2 microM) enhanced currents mediated by
      GABAA receptors. The anaesthetics also enhanced currents mediated by glycine
      receptors, although with higher EC50 values (minaxolone 13.1 microM;
      Org20599=22.9 microM and alphaxalone=27.8 microM). The maximal enhancement (to
      780-950% of control) produced by the three steroids acting at the GABAA receptor
      was similar, but currents evoked by glycine were potentiated with increasing
      effectiveness by alphaxalone (199%) <Org20599 (525%) <minaxolone (1197%). The
      anaesthetic isomers, 5alpha-pregnan-3alpha-ol-20-one and 5beta-pregnan-3alpha-ol
      20-one (eltanolone) enhanced GABAA receptor-mediated currents with similar
      potency and efficacy, but only the former enhanced glycine, the latter causing
      inhibition. The non-anaesthetic steroids 5alpha-pregnan-3beta-ol-20-one and 5beta
      pregnan-3beta-ol-20-one modulated neither GABAA, nor glycine, receptors.
      CONCLUSIONS: The data demonstrate that structure-activity relationships for
      steroid modulation at glycine and GABAA receptors differ. Comparing the EC50
      values reported here with free plasma concentrations during steroid-induced
      anaesthesia indicates that a selective modulation of GABAA receptor activity is
      likely to occur in vivo.

PMID- 15033892
TI  - Optimal concentration of epidural fentanyl in bupivacaine 0.1% after thoracotomy.
AB  - BACKGROUND: The aim of this prospective, double-blind, randomized controlled
      trial was to investigate the analgesic and adverse effects of three commonly used
      concentrations of thoracic epidural fentanyl with bupivacaine in patients
      undergoing thoracotomy for lung resection. METHODS: We studied 99 patients who
      were randomized to receive fentanyl 2 microg ml(-1) (group 2), fentanyl 5 microg
      ml(-1) (group 5) and fentanyl 10 microg ml(-1) (group 10) in bupivacaine 0.1% via
      a thoracic epidural. Postoperatively, pain on coughing was assessed using a
      visual analogue scale (VAS) and an observer verbal rating score (OVRS) at 2, 8,
      16 and 24 h. At the same times, sedation, pruritus and nausea were assessed.
      RESULTS: Of 29, 28 and 32 patients who completed the study in groups 2, 5 and 10
      respectively, there was no significant difference in baseline characteristics
      between the three groups. The number of patients with episodes of unsatisfactory
      pain, i.e. VAS scores >30 mm and OVRS >1, at each of the four assessments
      postoperatively was significantly (P<0.01) higher in group 2 than in groups 5 and
      10. In group 10, 16 patients had sedation scores >1 compared with 10 each in
      groups 2 and 5. In addition, 19 patients in group 10 experienced pruritus
      compared with 12 each, in groups 2 and 5. These differences were not significant.
      Nausea was not significantly different between the three groups. CONCLUSION: We
      conclude that thoracic epidural fentanyl 5 microg ml(-1) with bupivacaine 0.1%
      provides the optimum balance between pain relief and side effects following
      thoracotomy.

PMID- 15033890
TI  - Ringer's solution but not hydroxyethyl starch or modified fluid gelatin enhances
      platelet microvesicle formation in a porcine model of septic shock.
AB  - BACKGROUND: Sepsis is associated with volume deficit and clotting system
      activation. Platelet activation in sepsis results in an increased formation of
      microvesicles, which in turn, have been associated with increased mortality. We
      hypothesized an effect of different volume replacement solutions on platelet
      derived microvesicle formation in septic shock. METHODS: Anaesthetized,
      mechanically ventilated and multi-catheterized pigs received 1 g kg(-1) body
      weight faeces into the abdominal cavity to induce sepsis and were observed over 8
      h. Five animals in each group received volume replacement therapy with modified
      fluid gelatin 4% or 8% (MFG4%, MFG8%), 6% hydroxyethylstarch (HES) 200/0.5 or
      Ringer's solution (RS) to maintain a central venous pressure of 12 mm Hg. Flow
      cytometry was used for determination of microvesicles before induction of sepsis
      (baseline) and after 8 h. Platelets and microvesicles were identified with an
      anti-platelet monoclonal Ab and a secondary antibody. Microvesicles were
      determined as the smallest 1-3% positive cells in forward scatter. Intergroup
      comparisons were performed using Wilks-Lambda and Ryan-Einot-Gabriel-Welsh F
      test. Differences within groups were compared using a two-tailed Student's t
      test. RESULTS: Baseline values were considered as 100%. While microvesicle
      formation was reduced in HES (73 (sd 19)%), MFG4% (63 (41)%) and MFG8% groups (53
      (17)%), an increase in the RS-group (210 (121)%) was observed. Eight hours after
      induction of sepsis, formation of microvesicles was significantly higher in the
      RS group compared to all colloid-treated groups. CONCLUSION: In this porcine
      septic shock model the formation of platelet-derived microvesicles was
      significantly increased by volume replacement with Ringer's solution in
      comparison to colloid solutions.

PMID- 15033893
TI  - Rhetoric and reality on acute pain services in the UK: a national postal
      questionnaire survey.
AB  - BACKGROUND: The study aimed to explore the extent to which NHS acute pain
      services (APSs) have been established in accordance with national guidance, and
      to assess the degree to which clinicians in acute pain management believe that
      these services are fulfilling their role. METHODS: A postal questionnaire survey
      addressed to the head of the acute pain service was sent to 403 National Health
      Service hospitals each carrying out more than 1000 operative procedures a year.
      RESULTS: Completed questionnaires were received from 81% (325) of the hospitals,
      of which 83% (270) had an established acute pain service. Most of these (86%)
      described their service as Monday-Friday with a reduced service at other times;
      only 5% described their service as covering 24 hours, 7 days a week. In the
      majority of hospitals (68%), the on-call anaesthetist was the sole provider of
      out of hours services. Services were categorized by respondents as thriving
      (30%), struggling to manage (52%) or non-existent (17%). There was widespread
      agreement (> or =85%) on the principles that should underpin acute pain services,
      and similar agreement on the need for better organizational approaches (95%)
      rather than new treatments and delivery techniques (19%). CONCLUSIONS: More than
      a decade since the 1990 report Pain after Surgery, national coverage of
      comprehensive acute pain services is still far from being achieved. Despite wide
      consensus about the problems, concrete solutions are proving hard to implement.
      There is strong support for a two-fold response: securing greater political
      commitment to pain services and using organizational approaches to address
      current deficits.

PMID- 15033894
TI  - Double-blind, randomized, placebo-controlled trial comparing rofecoxib with
      dexketoprofen trometamol in surgical dentistry.
AB  - BACKGROUND: Rofecoxib, a selective cyclooxygenase-2 inhibitor, and dexketoprofen
      trometamol, a single isomer non-steroidal anti-inflammatory drug (NSAID), are
      available for the treatment of acute pain. Both are claimed to have fewer adverse
      effects than traditional NSAIDs. We have compared them in a clinical setting.
      METHODS: We performed a double-blind randomized controlled trial involving 120
      patients undergoing surgical removal of a single mandibular third molar at the
      Edinburgh Dental Institute. Those who developed moderate pain within 4 h of the
      procedure were allocated to one of three groups: rofecoxib 50 mg (Group RO,
      n=37); dexketoprofen trometamol 25 mg (Group DE, n=42); or placebo (Group PL,
      n=41). Participants monitored pain intensity and pain relief for 24 h using
      visual analogue scales (VAS) and verbal rating scales (VRS). The summed, time
      weighted pain relief score to 8 h derived from the VRS (TOTPAR 8) was used as the
      primary outcome variable. RESULTS: No significant difference was demonstrated
      between Groups RO and DE using TOTPAR 8 as the primary outcome variable. Both
      drugs were significantly different compared with placebo. Rescue analgesia during
      the trial period was required by only 15 out of 37 subjects in Group RO, but 35
      out of 42 subjects in Group DE. The median times to use of rescue medication were
      150 (Group PL), 398 (Group DE) and 1440 min (Group RO). Both drugs were well
      tolerated and adverse events reported were mild to moderate in severity.
      CONCLUSIONS: Rofecoxib and dexketoprofen trometamol are effective treatments for
      acute pain using a dental pain model and are well tolerated. Rofecoxib has a
      longer duration of action as a single dose and gave adequate analgesia for over
      half of that study group; patients in the dexketoprofen trometamol group needed
      more rescue analgesia.

PMID- 15033895
TI  - Remifentanil and anaesthesia for carcinoid syndrome.
AB  - Carcinoid syndrome creates many challenges during anaesthesia, including
      hypertension, hypotension and bronchospasm. These challenges are less common and
      less severe after the routine use of octreotide. We describe the use of
      remifentanil as part of the anaesthetic management of a 67-yr-old man undergoing
      resection of a carcinoid tumour of the terminal ileum. The combination of
      perioperative octreotide administration, intraoperative remifentanil infusion and
      sevoflurane anaesthesia, with postoperative epidural analgesia proved
      satisfactory. We review the recent literature and suggest that remifentanil is a
      useful addition to the armamentarium of the anaesthetist in the management of a
      patient with carcinoid syndrome.

PMID- 15033896
TI  - Increased adenosine A2A receptors in the brain of Parkinson's disease patients
      with dyskinesias.
AB  - Brain adenosine A2A receptors have recently attracted considerable attention
      because of their interaction with the dopaminergic system and as potential
      targets for Parkinson's disease pharmacotherapy. Post mortem adenosine A2A
      receptor mRNA and [3H]SCH 58261- specific binding to adenosine A2A receptor were
      studied in the brain of Parkinson's disease patients using in situ hybridization
      and receptor binding autoradiography, respectively. Fourteen levodopa-treated
      Parkinson's disease patients, of which seven developed dyskinesias and seven did
      not, were compared with nine controls. Nigrostriatal denervation was similar
      between dyskinetic and non-dyskinetic Parkinson's disease patients, as assessed
      with catecholamine concentrations and [125I]RTI-121-specific binding to dopamine
      transporters. A2A receptor mRNA levels (+129%; P < 0.01) and [3H]SCH 58261
      specific binding (+32%, P < 0.01) were increased in the putamen (lateral and
      medial) of dyskinetic patients compared with controls. The increase of adenosine
      A2A receptor mRNA in dyskinetic Parkinson's disease patients was also significant
      compared with non-dyskinetic Parkinson's disease patients (+60%; P < 0.05) in the
      lateral putamen. Moreover, [3H]SCH 58261-specific binding to adenosine A2A
      receptors was increased in the external globus pallidus (+24%; P < 0.001) of
      Parkinson's disease patients compared with controls, regardless of the
      dyskinesigenic response to levodopa. No change of adenosine A2A receptors was
      observed in the caudate nucleus, whereas adenosine A2A receptor protein and mRNA
      levels in the internal globus pallidus were not different from background. These
      findings suggest that increased synthesis of adenosine A2A receptors in
      striatopallidal pathway neurons is associated with the development of dyskinesias
      following long-term levodopa therapy in Parkinson's disease.

PMID- 15033897
TI  - Pattern of white matter regional cerebral blood flow and autoregulation in normal
      pressure hydrocephalus.
AB  - The mean cerebral blood flow (CBF) has generally been demonstrated to be lower in
      normal pressure hydrocephalus (NPH) than in normal controls. We investigated the
      distribution of the regional peri- and paraventricular white matter CBF (WM CBF)
      in NPH at baseline and during a controlled rise in intracranial pressure (ICP).
      Twelve patients with idiopathic NPH (mean age 69 years) underwent a CSF infusion
      study. CBF was measured by H2(15)O PET at baseline and then during the steady
      state plateau of raised ICP. The PET images were co-registered and resliced to 3D
      structural T1-weighted MRIs. Ten healthy normal volunteers served as control
      subjects for baseline CBF determination only. Profiles of the regional
      distribution of the baseline WM CBF and of the percentage change in WM CBF as a
      function of distance from the ventricles were plotted. The global mean baseline
      CBF in patients (28.4 +/- 5.2 ml/100 ml/min) was lower than in the control
      subjects (33 +/- 5.4 ml/100 ml/min) (P < 0.005). In patients, the profile of the
      regional WM CBF at baseline showed an increase with distance from the ventricles
      (P < 0.0001), with a maximal reduction adjacent to the ventricles and progressive
      normalization with distance, whereas in controls no relationship was apparent (P
      = 0.0748). In 10 patients, the rise in ICP during the infusion produced a fall in
      cerebral perfusion pressure (CPP) and a significant decrease of the global mean
      CBF from 27.6 +/- 3.1 to 24.5 +/- 2.9 ml/100 ml/min (P < 0.0001). The profile of
      the percentage changes in regional WM CBF in patients showed a U-shaped
      relationship with distance from the ventricles (P = 0.0007), with a maximal
      decrease skewed on the side of the lateral ventricles at around a mean distance
      of 9 mm. The WM CBF is reduced in NPH, with an abnormal gradient from the lateral
      ventricles towards the subcortical WM. An excessive decrease in CBF is brought
      about by reductions in CPP and appears to be maximal in the paraventricular
      watershed region. These results are discussed in the light of previous hypotheses
      concerning the aetiology of periventricular CBF reduction in NPH.

PMID- 15033898
TI  - Hemispheric asymmetries for kinematic and positional aspects of reaching.
AB  - Kinematic analyses of reaching have suggested that the left hemisphere is
      dominant for controlling the open loop component of the movement, which is more
      dependent on motor programmes; and the right hemisphere is dominant for
      controlling the closed loop component, which is more dependent on sensory
      feedback. This open and closed loop hypothesis of hemispheric asymmetry would
      also predict that advance planning should be dependent on the left hemisphere,
      and on-line response modification, which defines closed loop processes, should be
      dependent on the right hemisphere. Using kinematic analyses of reaching in
      patients with left or right hemisphere damage (LHD or RHD), we examined the
      ability: (i) to plan reaching movements in advance by examining changes in
      reaction time (RT) when response amplitude and visual feedback were cued prior to
      the response; and (ii) to modify the response during implementation when target
      location changed at the RT. Performance was compared between the stroke groups,
      using the ipsilesional arm, and age-matched control groups using their right
      (RNC) or left (LNC) arm. Aiming movements to a target that moved once or twice,
      with the second step occurring at the RT, were performed with or without visual
      feedback of hand position. There were no deficits in advance planning in either
      stroke group, as evidenced by comparable group changes in RT with changes in
      amplitude and visual feedback. Response modification deficits were seen for the
      LHD group in secondary velocity only. In addition, LHD produced slower initial
      peak velocity with prolongation of the deceleration phase and faster secondary
      peak velocities, and the RHD group produced deficits in final error only. These
      differences are more consistent with the dynamic dominance hypothesis, which
      links left hemisphere specialization to movement trajectory control and right
      hemisphere specialization to position control, rather than to global deficits in
      open and closed loop processing.

PMID- 15033899
TI  - fMRI activation during spike and wave discharges in idiopathic generalized
      epilepsy.
AB  - The objectives of this study were to evaluate the haemodynamic response of the
      cerebral cortex and thalamus during generalized spike and wave or polyspike and
      wave (GSW) bursts in patients with idiopathic generalized epilepsy (IGE). The
      haemodynamic response is measured by fMRI [blood oxygenation level-dependent
      (BOLD) effect]. We used combined EEG-functional MRI, a method that allows the
      unambiguous measurement of the BOLD effect during bursts, compared with
      measurements during the inter-burst interval. Fifteen patients with IGE had GSW
      bursts during scanning and technically acceptable studies. fMRI cortical changes
      as a result of GSW activity were present in 14 patients (93%). Changes in the
      form of activation (increased BOLD) or deactivation (decreased BOLD) occurred
      symmetrically in the cortex of both hemispheres, involved anterior as much as
      posterior head regions, but were variable across patients. Bilateral thalamic
      changes were also found in 12 patients (80%). Activation predominated over
      deactivation in the thalamus, whereas the opposite was seen in the cerebral
      cortex. These results bring a new light to the pathophysiolocal mechanisms
      generating GSW. The spatial distribution of BOLD responses to GSW was unexpected:
      it involved as many posterior as anterior head regions, contrary to the usual
      fronto-central predominance seen in EEG. The presence of a thalamic BOLD response
      in most patients provided, for the first time in a group of human patients,
      confirmation of the evidence of thalamic involvement seen in animal models. The
      possible mechanisms underlying these phenomena are discussed.

PMID- 15033900
TI  - Decreased lung tumorigenesis in mice genetically deficient in cytosolic
      phospholipase A2.
AB  - Epidemiological investigations suggest that chronic lung inflammation increases
      lung cancer risk. Pharmacologic and genetic evidence in mouse models indicates
      that lipid mediators released during pulmonary inflammation enhance lung tumor
      formation. Cytosolic phospholipase A2 (cPLA2) catalyzes arachidonic acid (AA)
      release from membrane phospholipids. AA can then lead to the synthesis of several
      classes of lipid mediators, including prostaglandin (PG) biosynthesis through the
      cyclooxygenase (COX) pathway. We investigated a role for cPLA2 in mouse lung
      tumorigenesis by using mice genetically deficient in cPLA2. After multiple
      urethane injections into cPLA2 null mice and wild-type littermates, the number of
      lung tumors was determined. cPLA2 null mice developed 43% fewer tumors (from 16
      +/- 2 to 9 +/- 2 tumors/mouse; P < 0.05) than wild-type littermates. cPLA2, COX
      1, COX-2 and microsomal prostaglandin E2 synthase (mPGES), examined by
      immunohistochemistry, are present in alveolar and bronchiolar epithelia and in
      alveolar macrophages in lungs from naive mice and tumor-bearing mice. Tumors
      express higher levels of each of these four enzymes than control lungs, as
      determined by immunoblotting. No differences were detected in the contents of COX
      1, COX-2 and mPGES between wild-type and cPLA2 null mice. Although the steady
      state levels of prostaglandin E2 and prostaglandin I2 in lung tissue extracts
      prepared from wild-type or cPLA2 (-/-) mice were not significantly different,
      both prostaglandins markedly increased in tumors from wild-type mice, an increase
      that was significantly blunted in tumors from cPLA2 (-/-) mice. These results
      demonstrate a role for cPLA2 in mouse lung tumorigenesis that may be mediated by
      decreased prostaglandin synthesis.

PMID- 15033901
TI  - Chemopreventive activity of parthenolide against UVB-induced skin cancer and its
      mechanisms.
AB  - Parthenolide (PN) is a major sesquiterpene lactone of feverfew (Tanacetum
      parthanium) with known anti-inflammatory activity. However, the anticancer
      effects of PN have not been well studied. In the present investigation, we
      examined the cancer chemopreventive property of PN using a combination of in vivo
      and in vitro approaches. We first tested the anticancer effect of PN in UVB
      induced skin cancer model. Mice fed with PN (1 mg/day) showed a delayed onset of
      papilloma incidence, a significant reduction in papilloma multiplicity
      (papilloma/mouse) and sizes when compared with the UVB-only group. To our
      surprise, neither PN nor the known cyclooxygenase (COX)-2 inhibitor celecoxib
      inhibit UVB-induced COX-2 expression and epidermal prostaglandin E2 (PGE2)
      production. We next investigated the molecular mechanism(s) involved in its
      anticancer effects using cultured JB6 murine epidermal cells. Non-cytotoxic
      concentrations of PN significantly inhibited UVB-induced activator protein-1 DNA
      binding and transcriptional activity. In addition, PN pre-treatment also
      inhibited c-Jun-N-terminal kinase (JNK) and p38 kinase activation. More
      importantly, we found that impaired AP-1, JNK and p38 signaling led to the
      sensitization of JB6 cells to UVB-induced apoptosis. Data from our study for the
      first time confirm the anticancer property of PN in an animal model, and provide
      evidence that the inhibitory effects on AP-1 and mitogen-activated protein
      kinases serve as one of the underlying mechanisms for the cancer chemopreventive
      property of PN.

PMID- 15033902
TI  - Silibinin prevents ultraviolet radiation-caused skin damages in SKH-1 hairless
      mice via a decrease in thymine dimer positive cells and an up-regulation of p53
      p21/Cip1 in epidermis.
AB  - Non-melanoma skin cancer (NMSC) accounts for >1 million new cases each year in
      the US alone suggesting that more approaches are needed for its prevention and
      control. Earlier studies by us have shown that silymarin (a crude form of
      biologically active silibinin with some other isomers), isolated from milk
      thistle, affords strong protection against ultraviolet (UV) radiation-induced
      NMSC in SKH-1 hairless mice; however, the molecular mechanisms of its efficacy
      are not known. Here, we assessed the effect of silibinin on UV-induced DNA damage
      and p53-p21/Cip1 accumulation, and their roles in UV-induced cell proliferation
      and apoptosis in SKH-1 hairless mouse epidermis. Topical application of silibinin
      prior to, or immediately after, UV irradiation resulted in a very strong
      protective effect against UV-induced thymine dimer positive cells in epidermis
      accounting for 76-85% (P < 0.001) inhibition. In other studies, silibinin
      treatment resulted in a further up-regulation of p53 by approximately 1.6-fold (P
      < 0.001) together with an increase ( approximately 2-fold, P < 0.001) in p21/Cip1
      protein levels. Proliferative cell nuclear antigen staining showed that silibinin
      pre- or post-topical application significantly inhibits (40-52 and 20-40%,
      respectively, P < 0.001) UV-induced epidermal cell proliferation. In addition,
      silibinin strongly decreased UV-caused terminal deoxynucleotidyl transferase
      mediated dUTP nick end labeling-positive apoptotic/sunburn cell formation (P <
      0.001). These findings suggest that silibinin affords strong protection against
      UV-induced damage in epidermis by a decrease in thymine dimer positive cells and
      an up-regulation of p53-p21/Cip1 possibly leading to an inhibition in both cell
      proliferation and apoptosis. Comparable effects of silibinin following its pre-
      or post-UV application suggest that mechanisms other than sunscreen effect are
      operational in silibinin efficacy against UV-caused skin damages.

PMID- 15033903
TI  - Saucernetin-7 isolated from Saururus chinensis inhibits proliferation of human
      promyelocytic HL-60 leukemia cells via G0/G1 phase arrest and induction of
      differentiation.
AB  - In the present study, we investigated the in vitro effect of saucernetin-7, which
      is a dineolignan isolated from Saururus chinensis, on the proliferation, cell
      cycle-regulation and differentiation of HL-60 human promyelocytic leukemia cells.
      Saucernetin-7 potently inhibited the proliferation of HL-60 cells in both a dose-
      and time-dependent manner with an IC50, approximately 5 microM. DNA flow
      cytometry indicated that saucernetin-7 markedly induced a G1 phase arrest of HL
      60 cells. Among the G1 phase cell cycle-related proteins, the levels of cyclin
      dependent kinase (CDK)6 and cyclin D1 were reduced by saucernetin-7, whereas the
      steady-state levels of CDK2, CDK4, cyclin D2, cyclin D3 and cyclin E were
      unaffected. The protein and mRNA levels of a CDK inhibitor p21CIP1/WAF1, but not
      p27KIP1, were markedly increased by saucernetin-7 and p21CIP1/WAF1 induction is
      likely to occur at the transcriptional level because actinomycin D blocked this
      induction. In addition, saucernetin-7 markedly enhanced the binding of
      p21CIP1/WAF1 with CDK2 and CDK6, resulting in the reduced activity of both
      kinases and the hypophosphorylation of Rb protein. We furthermore suggest that
      saucernetin-7 is a potent inducer of the differentiation of HL-60 cells, based on
      observations such as a reduction of the nitroblue tetrazolium level, an increase
      in the esterase activities and phagocytic activity, morphology changes, and the
      expression of CD14 and CD66b surface antigens. In conclusion, the onset of
      saucernetin-7-induced the G0/G1 arrest of HL-60 cells prior to the
      differentiation is linked to a sharp up-regulation of the p21CIP1/WAF1 level and
      a decrease in the CDK2 and CDK6 activities. This is the first report
      demonstrating that saucernetin-7 potently inhibits the proliferation of human
      promyelocytic HL-60 cells via the G1 phase cell cycle arrest and differentiation
      induction.

PMID- 15033904
TI  - Inactivating mutations of proapoptotic Bad gene in human colon cancers.
AB  - Evidence exists that deregulation of apoptosis is involved in the mechanisms of
      cancer development, and the somatic mutations of apoptosis-related genes have
      been reported in human cancers. Bcl-XL/Bcl-2-associated death promoter (Bad), a
      proapoptotic member of Bcl-2 family, plays an important role in the intrinsic
      apoptosis pathway. To explore the possibility that the genetic alterations of Bad
      might be involved in the development of human cancers, we analyzed the entire
      coding region and all splice sites of human Bad gene in 47 colon adenocarcinomas.
      Overall, we detected two somatic missense mutations (4.3%) in Bad gene.
      Interestingly, both of the Bad mutations were detected in the gene sequences
      encoding the Bcl-2 homology3 domain of Bad, which has a crucial role in inducing
      cell death. Transfection study revealed that both of the tumor-derived Bad
      mutants had decreased apoptosis activities compared with the wild-type Bad,
      indicating that the Bad mutations reduced the cell death function of Bad. Co
      immunoprecipitation assay revealed that binding of one of the tumor-derived Bad
      mutants with Bcl-2 and Bcl-XL is reduced. This is the first report on Bad gene
      mutation in human malignancies, and our data suggest that Bad gene is
      occasionally mutated in colon cancers and that somatic mutation of Bad may
      contribute to the development of colon cancers.

PMID- 15033905
TI  - The MTHFR 677C > T polymorphism is associated with an increased risk of
      hepatocellular carcinoma in patients with alcoholic cirrhosis.
AB  - Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism,
      plays a major role in the provision of methyl groups for DNA methylation and in
      the production of dTMP for DNA synthesis. Different polymorphisms have been
      described for this enzyme, the most studied being the C677T, which has been shown
      to be associated with predisposition to colorectal cancer in patients who consume
      a high alcohol diet. The aim of this study was to determine whether the MTHFR
      polymorphism is related to hepatocellular carcinoma (HCC) in patients with
      alcoholic cirrhosis. MTHFR genotypes were determined in 300 liver transplant
      patients, 72 of whom had alcoholic cirrhosis with HCC and 122 of whom had
      alcoholic cirrhosis without HCC. The remaining patients were transplanted for HCC
      on normal liver (n = 27) or viral cirrhosis with HCC (n = 49) or without HCC (n =
      30). We also tested 80 healthy subjects. Among the group of patients transplanted
      for alcoholic cirrhosis, the frequency of MTHFR variants CC versus CT and TT was
      significantly higher in patients with HCC than in patients without macroscopic
      evidence of HCC (P = 0.02). This difference was not observed between patients
      with and without HCC developed either on viral cirrhosis or on non-cirrhotic
      liver. If we considered all the patients transplanted for HCC, the MTHFR CC
      genotype was significantly higher in patients who had developed HCC on alcoholic
      cirrhosis rather than on viral cirrhosis (P = 0.002) or on non-cirrhotic livers
      (P = 0.02). The relative risk for HCC in subjects with alcoholic cirrhosis and
      the CC genotype was 2.03. These results suggest that the MTHFR CC genotype
      increases the risk to develop HCC in patients who consume a high alcohol diet.

PMID- 15033906
TI  - p63: Molecular complexity in development and cancer.
AB  - Discovery of the p53 homologs p63 and p73 has brought new excitement to the p53
      field. Identification of homologous genes coding for several proteins with
      similar and antagonistic properties towards p53 has been both intriguing and
      perplexing. A multitude of properties have been attributed to these new homologs
      and this review will focus on the biochemical and biological aspects of one
      family member, p63. Although the most ancient member of the p53 family, p63 is
      the most recently discovered and the least is known about this family member.
      Unlike p53, whose protein expression is not readily detectable in epithelial
      cells unless they are exposed to various stress conditions, p63 is expressed in
      select epithelial cells at high levels under normal conditions. p63 is highly
      expressed in embryonic ectoderm and in the nuclei of basal regenerative cells of
      many epithelial tissues in the adult including skin, breast myoepithelium, oral
      epithelium, prostate and urothelia. In contrast to the tumor suppressive function
      of p53, over-expression of select p63 splice variants is observed in many
      squamous carcinomas suggesting that p63 may act as an oncogene. Undoubtedly, the
      biochemical and biological activities attributed to p63 over the next several
      years will be diverse and regulation of the p63 gene and its several protein
      products complex. The use of various model systems and the study of human disease
      should continue to lead to rapid advances in our understanding of the role of p63
      in development, epithelial cell maintenance and tumorigenesis.

PMID- 15033907
TI  - Allyl-isothiocyanate causes mitotic block, loss of cell adhesion and disrupted
      cytoskeletal structure in HT29 cells.
AB  - Epidemiological evidence indicates that Brassica vegetables protect against
      colorectal cancer. Brassicas contain glucosinolates, the breakdown products of
      which exert antiproliferative effects against cancer cells. We have examined the
      effects of allyl-isothiocyanate (AITC), a major breakdown product of the
      glucosinolate sinigrin, on proliferation and death of colorectal cancer cells. HT
      29 colorectal cells were exposed to AITC for 24 h and the number of adherent and
      detached cells determined. Both populations were analysed for cell-cycle
      characteristics and examined by light and electron microscopy for features of
      apoptosis and mitosis. Evidence of apoptosis was also determined by flow
      cytometric analysis of Annexin V staining in the detached population of cells.
      AITC-treated cells were also stained for alpha-tubulin. Treatment caused cells to
      round up after 7 h of exposure and subsequently detach. At 24 h these cells were
      blocked in mitosis. Detached AITC-treated cells showed no signs of apoptosis as
      assessed by morphological features or by Annexin V staining but they did show
      evidence of disrupted tubulin. AITC inhibits proliferation of cancer cells by
      causing mitotic block associated with disruption of alpha-tubulin in a manner
      analogous to a number of chemotherapeutic agents.

PMID- 15033908
TI  - Fas ligand down-regulates cytokine-induced Fas receptor expression on insulinoma
      (NIT-1), but not islet cells, from autoimmune nonobese diabetic mice.
AB  - In the pathogenesis of autoimmune type 1 diabetes, the apoptosis receptor Fas
      appears de novo on the surface of insulin-producing beta-cells. Fas expression is
      thought to be induced by proinflammatory cytokines, such as IL-1beta, interferon
      gamma (IFNgamma), and TNFalpha, released by islet-infiltrating mononuclear cells.
      To determine whether beta-cells can modulate their sensitivity to apoptosis at
      the level of Fas, we investigated the effect of Fas ligand (FasL) on surface
      expression of Fas in NIT-1 insulinoma cells from nonobese diabetic (NOD) mice
      prone to autoimmune diabetes and islet cells from NOD and nonautoimmune BALB/c
      mice. In NIT-1 insulinoma cells, Fas expression induced by the cytokine
      combination IL-1beta and IFNgamma was reduced in the presence of FasL, whereas in
      islet cells Fas expression was unaffected by FasL. The effect of FasL on NIT-1
      cells was evident during and after the induction of Fas expression by IL-1beta
      and IFNgamma. Thus, FasL down-regulates cytokine-induced Fas expression in NOD
      mouse-derived NIT-1 cells, but not in NOD or BALB/c mouse islets. The ability of
      NIT-1 cells to down-regulate Fas receptor in response to ligation is similar to
      that of a variety of tumor cells, which may use this mechanism to escape
      destruction by cytotoxic T cells. Islets apparently cannot protect themselves
      against FasL-induced apoptosis by down-regulating the Fas receptor. Understanding
      how NIT-1 insulinoma cells down-regulate Fas receptor in response to ligation by
      FasL has therapeutic implications for protecting normal beta-cells in autoimmune
      type 1 diabetes.

PMID- 15033909
TI  - Protein kinase A activation of estrogen receptor alpha transcription does not
      require proteasome activity and protects the receptor from ligand-mediated
      degradation.
AB  - 17beta-Estradiol (E2)-stimulated estrogen receptor (ERalpha) transcription is
      accompanied by protein degradation via the 26S-proteasome pathway. Inhibition of
      proteasome activity stabilizes ERalpha protein and abolishes E2-activated
      transcription, suggesting functional linkages between transcription and
      degradation. It is not known whether ligand-independent ERalpha activation is
      coupled to proteolysis. In pituitary cells, forskolin (FSK) stimulates ERalpha
      transcription through the protein kinase A (PKA) pathway. This study examined
      interactions between E2-dependent and PKA-stimulated pathways in GH(3) cells by
      measuring transcription of a transfected reporter gene and endogenous ERalpha
      levels. E2 stimulated estrogen response element-mediated transcription 2- to 3
      fold and decreased ERalpha protein levels to 40%. In contrast, FSK stimulated
      ERalpha transcription without decreasing ERalpha protein. Treatment with FSK plus
      E2 resulted in synergistic ERalpha transactivation, and FSK specifically
      prevented E2-induced ERalpha degradation. PKA is required for protection and was
      prevented by H89 (a PKA inhibitor), but not PD98059 (a MAPK kinase inhibitor).
      Propyl-pyrazole-triol and R,R-diethyl-tetrahydrochrysene, selective ERalpha
      agonists, reduced ERalpha protein by 50% while stimulating ERalpha
      transcriptional activity 4- to 8-fold. The antagonist ICI 182,780 similarly
      decreased ERalpha levels, but prevented ER activation. FSK prevented all ligand
      induced ERalpha degradation. Lactacystin, a proteasome inhibitor, abolished E2
      stimulated, but not FSK-stimulated, ERalpha transcription. Thus, stimulation of
      ERalpha transcription by the PKA-dependent pathway is dissociated from receptor
      degradation and proteasome activity. These data suggest a mechanism of ERalpha
      transcriptional activation by PKA that is distinct from E2 activation and that
      may contribute to the synergistic transcriptional activation of ERalpha by ligand
      dependent and PKA-dependent pathways.

PMID- 15033910
TI  - Impaired leptin expression and abnormal response to fasting in corticotropin
      releasing hormone-deficient mice.
AB  - Leptin has been postulated to comprise part of an adipostat, whereby during
      states of excessive energy storage, elevated levels of the hormone prevent
      further weight gain by inhibiting appetite. A physiological role for leptin in
      this regard remains unclear because the presence of excessive food, and therefore
      the need to restrain overeating under natural conditions, is doubtful. We have
      previously shown that CRH-deficient (Crh(-/-)) mice have glucocorticoid
      insufficiency and lack the fasting-induced increase in glucocorticoid, a hormone
      important in stimulating leptin synthesis and secretion. We hypothesized that
      these mice might have low circulating leptin. Indeed, Crh(-/-) mice exhibited no
      diurnal variation of leptin, whereas normal littermates showed a clear rhythm,
      and their leptin levels were lower than their counterparts. A continuous
      peripheral CRH infusion to Crh(-/-) mice not only restored corticosterone levels,
      but it also increased leptin expression to normal. Surprisingly, 36 h of fasting
      elevated leptin levels in Crh(-/-) mice, rather than falling as in normal mice.
      This abnormal leptin change during fasting in Crh(-/-) mice was corrected by
      corticosterone replacement. Furthermore, Crh(-/-) mice lost less body weight
      during 24 h of fasting and ate less food during refeeding than normal
      littermates. Taken together, we conclude that glucocorticoid insufficiency in
      Crh(-/-) mice results in impaired leptin production as well as an abnormal
      increase in leptin during fasting, and propose that the fast-induced
      physiological reduction in leptin may play an important role to stimulate food
      intake during the recovery from fasting.

PMID- 15033911
TI  - Diabetes alters the response to bacteria by enhancing fibroblast apoptosis.
AB  - Diabetics suffer from both more frequent bacterial infections and greater
      consequences of infection. However, bacteria-induced tissue destruction and the
      subsequent response in diabetics have received relatively little attention. To
      investigate this issue, we inoculated the scalp of control or db/db diabetic
      mice, with the pathogen Porphyromonas gingivalis, which causes connective tissue
      destruction in humans. Both bacteria-induced cytokine expression and tissue loss
      were similar in diabetic and control mice. However, there was a significantly
      higher rate of fibroblast-specific apoptosis in the diabetic group, which was
      measured as cells that were double positive for the terminal
      deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling assay and
      expression of vimentin. The higher rate of fibroblast apoptosis could be
      explained in the diabetic group by enhanced levels of activated caspase-3.
      Apoptosis was evident during the peak healing period and coincided with reduced
      numbers of fibroblasts, diminished collagen I and III expression, and
      significantly reduced formation of new connective tissue matrix in diabetic mice.
      Thus, diabetes may impair the healing response to bacteria-induced connective
      tissue loss by increasing the number of caspase-3-activated fibroblasts, leading
      to greater apoptosis and reduced numbers of fibroblastic cells.

PMID- 15033912
TI  - Identification and characterization of a glucagon receptor from the goldfish
      Carassius auratus: implications for the evolution of the ligand specificity of
      glucagon receptors in vertebrates.
AB  - The structural basis of ligand selectivity of G protein-coupled receptors for
      metabolic hormones has been an area of intense investigation, and yet it remains
      unresolved. One approach to delineating the mechanism of ligand-receptor
      interactions is to compare the ligand specificities of receptors expressed in
      species that emerged at different times within vertebrate evolution. In this
      paper we describe the isolation, functional, and phylogenetic characterization of
      the glucagon receptor from the goldfish Carassius auratus (Teleostei, order
      Cypriniformes), and compare its ligand specificity with that of the homologous
      rat receptor. Goldfish (gf) glucagon stimulated glucose production in a dose
      dependent manner from isolated goldfish hepatocytes, resulting in 5-fold increase
      at 1 microm. The goldfish glucagon receptor (gfGlucR) shares 56, 51, 50, and 52%
      amino acid identities with frog Rana tigrina regulosa, mouse, rat, and human
      glucagon receptors, respectively. In competitive binding experiments, the
      recombinant gfGlucR displays high affinity toward goldfish, zebrafish, and human
      glucagons (IC(50) = 0.6, 9, and 13 nm, respectively) but not toward goldfish
      glucagon-like peptide-1 or human glucagon-like peptide-1 (7-36) amide. Whereas
      both goldfish and human glucagons stimulated dose-dependent increases in
      intracellular cAMP through the recombinant gfGlucR, the recombinant rat GlucR
      interacted only with human glucagon, analogous to the specificity of the
      previously characterized glucagon receptor from the frog R. tigrina regulosa. Our
      results demonstrate that the binding pocket of gfGlucR can accommodate a broad
      range of glucagon structures and that in the frogs and mammals, there is a
      structural switch to a more restrictive conformation of glucagon receptors.

PMID- 15033913
TI  - Visceral obesity without insulin resistance in late-onset obesity rats.
AB  - We describe a line of transgenic rats in which the males develop a unique
      autosomal dominant, late-onset obesity (LOB) phenotype. LOB males gradually
      accumulate fat specifically in visceral, but not peripheral, fat depots despite a
      normal intake of a low fat diet. LOB females normally develop only mild obesity
      with advanced age. However, the phenotype can be induced rapidly in young females
      by ovariectomy and prevented by estrogen replacement. LOB males are highly
      sensitive to dietary fat. Young, nonobese LOB males gain more weight on a 30% fat
      diet and lose more weight when treated with the lipase inhibitor, Orlistat, than
      their nontransgenic littermates. Remarkably, despite severe visceral obesity, LOB
      rats have normal fasting blood glucose, insulin, and corticosterone; show normal
      or increased insulin sensitivity in glucose and insulin tolerance tests; have
      increased plasma adiponectin levels; and display a heightened response to
      treatment with rosiglitazone. Their visceral adiposity reflects a specific
      increase in visceral adipocyte number, not size. Analysis of the transgene in LOB
      rats revealed a deletion in the gene encoding the S26 subunit of the
      mitochondrial ribosome that results in the production of a truncated protein,
      which we show to be imported into mitochondria. However, the transgene integrant
      is complex, so whether this is the sole molecular disruption underlying this
      phenotype remains to be established. Nevertheless, LOB rats provide a valuable
      new model of late-onset, male-preponderant, visceral-specific obesity, clearly
      dissociated from insulin resistance.

PMID- 15033914
TI  - Transcriptional profiling of estrogen-regulated gene expression via estrogen
      receptor (ER) alpha or ERbeta in human osteosarcoma cells: distinct and common
      target genes for these receptors.
AB  - Estrogens exert many important effects in bone, a tissue that contains both
      estrogen receptors alpha and beta (ERalpha and ERbeta). To compare the actions of
      these receptors, we generated U2OS human osteosarcoma cells stably expressing
      ERalpha or ERbeta, at levels comparable with those in osteoblasts, and we
      characterized their response to 17beta-estradiol (E2) over time using Affymetrix
      GeneChip microarrays to determine the expression of approximately 12,000 genes,
      followed by quantitative PCR verification of the regulation of selected genes. Of
      the approximately 100 regulated genes we identified, some were stimulated by E2
      equally through ERalpha and ERbeta, whereas others were selectively stimulated
      via ERalpha or ERbeta. The E2-regulated genes showed three distinct temporal
      patterns of expression over the 48-h time course studied. Of the functional
      categories of the E2-regulated genes, most numerous were those encoding cytokines
      and factors associated with immune response, signal transduction, and cell
      migration and cytoskeleton regulation, indicating that E2 can exert effects on
      multiple pathways in these osteoblast-like cell lines. Of note, E2 up-regulated
      several genes associated with cell motility selectively via ERbeta, in keeping
      with the selective E2 enhancement of the motility of ERbeta-containing cells. On
      genes regulated equally by E2 via ERalpha or ERbeta, the phytoestrogen genistein
      preferentially stimulated gene expression via ERbeta. These studies indicate both
      common as well as distinct target genes for these two ERs, and identify many
      novel genes not previously known to be under estrogen regulation.

PMID- 15033915
TI  - The androgen-regulated epididymal sperm-binding protein, human beta-defensin 118
      (DEFB118) (formerly ESC42), is an antimicrobial beta-defensin.
AB  - Spermatozoa bind a variety of proteins as they pass through the proximal regions
      of the epididymis, where they acquire forward motility and fertilizing ability.
      Recent evidence indicates that certain epididymis-specific secretory proteins
      that bind sperm have antibacterial activity and may function as part of the
      innate immune system. We reported earlier that ESC42, now designated human beta
      defensin 118 (DEFB118), is a sperm-binding protein. In this study, we demonstrate
      that DEFB118 has potent antibacterial activity that is dose, time, and structure
      dependent. Incubation of Escherichia coli for 60 min with 10 microg/ml DEFB118
      reduced bacterial survival to 20% of the control, and 25 microg/ml reduced
      survival to 5% of the control. DEFB118 concentrations of 50 and 100 microg/ml
      further reduced survival to less than 2 and 1%, respectively. A biphasic effect
      of salt concentration on the antibacterial activity of DEFB118 was observed.
      Reduction of disulfide bonds and alkylation of cysteines resulted in the complete
      loss of antibacterial activity. DEFB118 caused rapid permeabilization of both
      outer and inner membranes of E. coli and striking morphological alterations in
      the bacterial surfaces visible by scanning electron microscopy consistent with a
      membrane-disruptive mechanism of bacterial killing. In contrast, eukaryotic cell
      membranes were not permeabilized by DEFB118, as indicated by the rat erythrocyte
      hemolytic assay. Studies on DEFB118 inhibition of macromolecular synthesis and
      membrane permeability in E. coli were consistent with a primary effect at the
      cell membrane level. DEFB118 may contribute to epididymal innate immunity and
      protect the sperm against attack by microorganisms in the male and female
      reproductive tracts.

PMID- 15033916
TI  - Estrogen facilitates neurite extension via apolipoprotein E in cultured adult
      mouse cortical neurons.
AB  - Literature review suggests a close relationship between estrogen and
      apolipoprotein E (ApoE) in the central nervous system. Epidemiology studies show
      that estrogen replacement therapy (ERT) decreases the morbidity from several
      chronic neurological diseases. Alleles of ApoE modify the risk for and
      progression of the same diseases. ApoE levels in the rodent brain vary during the
      estrous cycle and increase after 17beta-estradiol administration. Both estradiol
      and ApoE3, the most common isoform of human ApoE, increase the extent of neurite
      outgrowth in culture. Combined, these observations suggest a common mechanism
      whereby estrogen may increase ApoE levels to facilitate neurite growth. We tested
      this hypothesis by characterizing the effects of estradiol and ApoE isoforms on
      neurite outgrowth in cultured adult mouse cortical neurons. Estradiol increased
      ApoE levels and neurite outgrowth. ApoE2 increased neurite length more so than
      ApoE3 in the presence of estradiol. Estradiol had no effect on neurite outgrowth
      from mice lacking the ApoE gene or when only ApoE4, the isoform of ApoE that is
      associated with increased risk of neurological disease, was exogenously supplied.
      Cultures from mice transgenic for human ApoE3 or ApoE4 showed the same isoform
      specific effect. Neuronal internalization of recombinant human ApoE3 was greater
      than ApoE4, and ApoE3 was more effective than ApoE4 in facilitating neuronal
      uptake of a fatty acid. We conclude that estradiol facilitates neurite growth
      through an ApoE-dependent mechanism. The effects of ERT on chronic neurological
      diseases may vary with ApoE genotype. The clinical use of ERT may require ApoE
      genotyping for optimal efficacy.

PMID- 15033918
TI  - Saw palmetto extract suppresses insulin-like growth factor-I signaling and
      induces stress-activated protein kinase/c-Jun N-terminal kinase phosphorylation
      in human prostate epithelial cells.
AB  - A common alternative therapy for benign prostatic hyperplasia (BPH) is the
      extract from the fruit of saw palmetto (SPE). BPH is caused by nonmalignant
      growth of epithelial and stromal elements of the prostate. IGF action is
      important for prostate growth and development, and changes in the IGF system have
      been documented in BPH tissues. The main signaling pathways activated by the
      binding of IGF-I to the IGF-I receptor (IGF-IR) are the ERK arm of the MAPK
      cascade and the phosphoinositol-3-kinase (PI3K)/protein kinase B (PKB/Akt)
      cascade. We tested the hypothesis that SPE suppresses growth and induces
      apoptosis in the P69 prostate epithelial cell line by inhibiting IGF-I signaling.
      Treatment with 150 microg/ml SPE for 24 h decreased IGF-I-induced proliferation
      of P69 cells and induced cleavage of the enzyme poly(ADP-ribose)polymerase
      (PARP), an index of apoptosis. Treatment of serum-starved P69 cells with 150
      microg/ml SPE for 6 h reduced IGF-I-induced phosphorylation of Akt (assessed by
      Western blot) and Akt activity (assessed by an Akt kinase assay). Western blot
      analysis showed that SPE reduced IGF-I-induced phosphorylation of the adapter
      protein insulin receptor substrate-1 and decreased downstream effects of Akt
      activation, including increased cyclin D1 levels and phosphorylation of glycogen
      synthase kinase-3 and p70(s6k). There was no effect on IGF-I-induced
      phosphorylation of MAPK, IGF-IR, or Shc. Treatment of starved cells with SPE
      alone induced phosphorylation the proapoptotic protein JNK. SPE treatment may
      relieve symptoms of BPH, in part, by inhibiting specific components of the IGF-I
      signaling pathway and inducing JNK activation, thus mediating antiproliferative
      and proapoptotic effects on prostate epithelia.

PMID- 15033917
TI  - Rhythmic secretion of prolactin in rats: action of oxytocin coordinated by
      vasoactive intestinal polypeptide of suprachiasmatic nucleus origin.
AB  - Prolactin (PRL) is secreted from lactotrophs of the anterior pituitary gland of
      rats in a unique pattern in response to uterine cervical stimulation (CS) during
      mating. Surges of PRL secretion occur in response to relief from hypothalamic
      dopaminergic inhibition and stimulation by hypothalamic releasing neurohormones.
      In this study, we characterized the role of oxytocin (OT) in this system and the
      involvement of vasoactive intestinal polypeptide (VIP) from the suprachiasmatic
      nucleus (SCN) in controlling OT and PRL secretion of CS rats. The effect of OT on
      PRL secretion was demonstrated in cultured lactotrophs showing simultaneous
      enhanced secretion rate and increased intracellular Ca(2+). Neurosecretory OT
      cells of the hypothalamic paraventricular nucleus that express VIP receptors were
      identified by using immunocytochemical techniques in combination with the
      retrogradely transported neuronal tracer Fluoro-Gold (iv injected). OT
      measurements of serial blood samples obtained from ovariectomized (OVX) CS rats
      displayed a prominent increase at the time of the afternoon PRL peak. The
      injection of VIP antisense oligonucleotides into the SCN abolished the afternoon
      increase of OT and PRL in CS-OVX animals. These findings suggest that VIP from
      the SCN contributes to the regulation of OT and PRL secretion in CS rats. We
      propose that in CS rats the regulatory mechanism(s) for PRL secretion comprise
      coordinated action of neuroendocrine dopaminergic and OT cells, both governed by
      the daily rhythm of VIP-ergic output from the SCN. This hypothesis is illustrated
      with a mathematical model.

PMID- 15033919
TI  - Does the type II glucocorticoid receptor mediate cortisol-induced suppression in
      pituitary responsiveness to gonadotropin-releasing hormone?
AB  - Stress-like elevations in plasma cortisol suppress LH pulse amplitude in
      ovariectomized ewes by inhibiting pituitary responsiveness to GnRH. Here we
      sought to identify the receptor mediating this effect. In a preliminary
      experiment GnRH and LH pulses were monitored in ovariectomized ewes treated with
      cortisol plus spironolactone, which antagonizes the type I mineralocorticoid
      receptor (MR), or with cortisol plus RU486, which antagonizes both the type II
      glucocorticoid receptor (GR) and the progesterone receptor (PR). Cortisol alone
      reduced LH pulse amplitude, but not pulsatile GnRH secretion, indicating that it
      reduced pituitary responsiveness to endogenous GnRH. RU486, but not
      spironolactone, reversed this suppression. We next tested whether RU486 reverses
      the inhibitory effect of cortisol on pituitary responsiveness to exogenous GnRH
      pulses of fixed amplitude, frequency, and duration. Hourly GnRH pulses were
      delivered to ovariectomized ewes in which endogenous GnRH pulses were blocked by
      estradiol during seasonal anestrus. Cortisol alone reduced the amplitude of LH
      pulses driven by the exogenous GnRH pulses. RU486, but not an antagonist of PR
      (Organon 31710), prevented this suppression. Thus, the efficacy of RU486 in
      blocking the suppressive effect of cortisol is attributed to antagonism of GR,
      not PR. Together, these observations imply that the type II GR mediates cortisol
      induced suppression of pituitary responsiveness to GnRH.

PMID- 15033920
TI  - Evidence for an interaction between CB1 cannabinoid and melanocortin MCR-4
      receptors in regulating food intake.
AB  - Melanocortin receptor 4 (MCR4) and CB(1) cannabinoid receptors independently
      modulate food intake. Although an interaction between the cannabinoid and
      melanocortin systems has been found in recovery from hemorrhagic shock, the
      interaction between these systems in modulating food intake has not yet been
      examined. The present study had two primary purposes: 1) to examine whether the
      cannabinoid and melanocortin systems act independently or synergistically in
      suppressing food intake; and 2) to determine the relative position of the CB(1)
      receptors in the chain of control of food intake in relation to the melanocortin
      system. Rats were habituated to the test environment and injection procedure and
      then received intracerebroventicular injections of various combinations of the
      MCR4 receptor antagonist JKC-363, the CB(1) receptor agonist Delta(9)
      tetrahydrocannabinol, the MCR4 receptor agonist alpha-MSH, or the cannabinoid
      CB(1) receptor antagonist SR 141716. Food intake and locomotor activity were then
      recorded for 120 min. When administrated alone, SR 141716 and alpha-MSH dose
      dependently attenuated baseline feeding, whereas sub-anorectic doses of SR 141716
      and alpha-MSH synergistically attenuated baseline feeding when combined. Delta(9)
      Tetrahydrocannabinol-induced feeding was not blocked by alpha-MSH, whereas SR
      141716 dose-dependently attenuated JKC-363-induced feeding. Locomotor activity
      was not significantly affected by any drug treatment, suggesting that the
      observed effects on feeding were not due to a nonspecific reduction in motivated
      behavior. These findings revealed a synergistic interaction between the
      cannabinoid and melanocortin systems in feeding behavior. These results further
      suggested that CB(1) receptors are located downstream from melanocortin receptors
      and CB(1) receptor signaling is necessary to prevent the melanocortin system from
      altering food intake.

PMID- 15033921
TI  - The ectodomain shedding of CD30 is specifically regulated by peptide motifs in
      its cysteine-rich domains 2 and 5.
AB  - Tumor necrosis factor (TNF)-alpha converting enzyme (TACE) is responsible for the
      ectodomain release of various membrane proteins by proteolytic cleavage in close
      proximity to the cell membrane. Despite the wide spectrum of possible substrates,
      selective cleavage can be achieved by substrate cross-linking. To explore the
      underlying mechanism, we studied the TACE-mediated shedding of CD30. Whereas the
      constitutive release of the soluble ectodomain of CD30 (sCD30) from the lymphoma
      cell line Karpas 299 was enhanced by most anti-CD30 antibodies, it was inhibited
      by antibodies Ber-H2 and Ki-4. On the basis of the recognized epitopes, shedding
      seemed to depend on the availability of the cysteine-rich domains (CRD) 2 and 5
      of the CD30 ectodomain. CRD2 and 5 have almost identical amino acid sequences and
      are localized distant from the TACE-targeted cleavage site. Soluble CD30, the
      product of this enzyme reaction, did not inhibit, but on the contrary, it
      stimulated CD30 shedding in a CRD2/5-dependent manner. This process could also be
      induced by CRD2/5-derived peptides but not by a CRD1-derived control peptide.
      This example of a product-activation was CD30 selective since other TACE
      substrates such as TNFR1 or TNF-alpha were not affected. These data suggest that
      CD30 shedding is stimulated by an elevated local availability of CRD2 or 5,
      possibly by forming a docking station for the releasing enzyme through substrate
      aggregation.

PMID- 15033922
TI  - Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model
      of Alzheimer's disease.
AB  - Recent epidemiological evidence indicates that insulin resistance, a proximal
      cause of Type II diabetes [a non-insulin dependent form of diabetes mellitus
      (NIDDM)], is associated with an increased relative risk for Alzheimer's disease
      (AD). In this study we examined the role of dietary conditions leading to NIDDM
      like insulin resistance on amyloidosis in Tg2576 mice, which model AD-like
      neuropathology. We found that diet-induced insulin resistance promoted
      amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in
      the brain that corresponded with increased gamma-secretase activities and
      decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta
      production also coincided with increased AD-type amyloid plaque burden in the
      brain and impaired performance in a spatial water maze task. Further exploration
      of the apparent interrelationship of insulin resistance to brain amyloidosis
      revealed a functional decrease in insulin receptor (IR)-mediated signal
      transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta)
      Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)
      kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. This latter
      finding is of particular interest given the known inhibitory role of AKT/PKB on
      glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown
      to promote Abeta peptide generation. Most interestingly, we found that decreased
      pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK
      activation, positively correlated with the generation of brain C-terminal
      fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of
      gamma-secretase activity, in the brain of insulin-resistant relative to
      normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that
      insulin resistance may be an underlying mechanism responsible for the observed
      increased relative risk for AD neuropathology, and presents the first evidence to
      suggest that IR signaling can influence Abeta production in the brain.

PMID- 15033923
TI  - Granularin, a novel molluscan opsonin comprising a single vWF type C domain is up
      regulated during parasitation.
AB  - Snails are intermediate hosts to schistosome parasites, some of which are the
      main cause of human schistosomiasis (bilharzia), and have been used as models for
      parasite-host interactions for a long time. Here, we have characterized a novel
      internal defense peptide of the snail Lymnaea stagnalis, of which the relative
      abundance in brain tissue increases upon infection with the avian schistosome
      Trichobilharzia ocellata. This protein, named granularin, is secreted by granular
      cells, which are numerous in the connective tissue surrounding the brain. The
      protein is unique because it comprises only a single Von Willebrand factor type C
      domain that is normally found in large transmembrane and secreted extracellular
      matrix proteins. The granularin gene is twice up-regulated during parasitation.
      Purified granularin stimulates phagocytosis of foreign particles by blood
      hemocytes. Together, our data indicate that granularin represents a novel protein
      that acts as an opsonin in the molluscan internal defense response.

PMID- 15033924
TI  - Prevention of renal vascular and glomerular fibrosis by epidermal growth factor
      receptor inhibition.
AB  - Hypertension is frequently associated with the development of renal vascular and
      glomerular fibrosis. The purpose of the present study was to investigate whether
      epidermal growth factor receptor (EGFR) activation participates in the
      development of renal fibrosis and to test if blockade of EGFR activation would
      have therapeutic effects. Experiments were performed during nitric oxide (NO)
      deficiency-induced hypertension in rats (L-NAME model). After 4 weeks of L-NAME
      treatment, animals developed hypertension associated to deterioration of renal
      structure and function. Over the same period, EGFR was activated twofold within
      glomeruli. This activation was accompanied by increased activity of the mitogen
      activated protein kinase (MAPK) p42/p44 pathway and exaggerated collagen I
      expression. Gefitinib, an EGFR-tyrosine kinase inhibitor, given concomitantly
      with L-NAME, normalized MAPK activation and collagen I expression and prevented
      the decline of renal function and the development of fibrosis. Since endothelin
      mediates the L-NAME-induced fibrogenesis, the endothelin-EGFR interaction was
      tested in transgenic mice expressing luciferase under the control of collagen I
      alpha2 promoter: In renal cortex of these animals, the endothelin-induced
      collagen I gene activity was inhibited by an EGFR-phosphorylation inhibitor.
      These results provide the first evidence that EGFR activation plays an important
      role in the progression of renal vascular and glomerular fibrosis.

PMID- 15033925
TI  - Ryanodine receptors in human pancreatic beta cells: localization and effects on
      insulin secretion.
AB  - It is clear that pancreatic beta-cell dysfunction, including basal
      hyperinsulinemia and reduced insulin release in response to glucose, is a key
      determinant of disease progression in type 2 diabetes, but the underlying
      molecular defects are not known. In diabetes, the expression and function of
      ryanodine receptor (RyR) Ca2+ release channels are reduced. The present studies
      were undertaken to define the subcellular location and role of RyR in the control
      of stimulated and basal insulin release from human pancreatic beta cells. Using
      confocal microscopy, we observed RyR immunoreactivity in a vesicular pattern.
      RyRs did not colocalize with insulin secretory granules but partially colocalized
      with endosomes. Direct activation with nanomolar concentrations of ryanodine
      evoked increases in cytosolic Ca2+ that were coupled to transient insulin
      release. Insulin release stimulated by 1 nM ryanodine was sensitive to BAPTA-AM
      preincubation but independent of thapsigargin-sensitive endoplasmic reticulum
      (ER) Ca2+ pools. Blocking RyRs with micromolar concentrations of ryanodine led to
      BAPTA-resistant insulin release that was not associated with an increase in
      cytosolic Ca2+, which implicated alterations in luminal Ca2+. However, neither
      Ca2+ signals nor insulin release stimulated by glucose was blocked by 10-50
      microM ryanodine, which suggests that the CD38/cyclic ADP-ribose/RyR pathway is
      not a primary mechanism of glucose action in nontransformed beta cells. We
      provide the first evidence that RyRs directly control insulin secretion in
      primary beta cells. Unexpectedly, stimulation of insulin secretion by ryanodine
      occurs independently of glucose and by two mechanisms, including a novel
      cytosolic Ca2+-independent mechanism likely involving changes in Ca2+ within the
      lumens of non-ER organelles, such as endosomes.

PMID- 15033926
TI  - Persistent, noncytolytic infection of neurons by Borna disease virus interferes
      with ERK 1/2 signaling and abrogates BDNF-induced synaptogenesis.
AB  - Infection of the central nervous system by Borna disease virus (BDV) provides a
      unique model to study the mechanisms whereby a persistent viral infection can
      impair neuronal function and cause behavioral diseases reminiscent of mood
      disorders, schizophrenia, or autism in humans. In the present work, we studied
      the effect of BDV infection on the response of hippocampal neurons, the main
      target for this virus, to the neurotrophin BDNF. We showed that persistent
      infection did not affect neuronal survival or morphology. However, it blocked
      BDNF-induced ERK 1/2 phosphorylation, despite normal expression of the TrkB BDNF
      receptor. In addition, BDNF-induced expression of synaptic vesicle proteins was
      abrogated, which resulted in severely impaired synaptogenesis and defects in
      synaptic organization. Thus, we provide the first evidence that a virus can
      interfere specifically with neurotrophin-regulated neuroplasticity, thereby
      hampering proper neuronal connectivity. These results may help to understand the
      behavioral disorders associated with BDV infection.

PMID- 15033927
TI  - Morphine exposure and abstinence define specific stages of gene expression in the
      rat nucleus accumbens.
AB  - Intermittent exposure to addictive drugs causes long-lasting changes in
      responsiveness to these substances due to persistent molecular and cellular
      alterations within the meso-corticolimbic system. In this report, we studied the
      expression profiles of 159 genes in the rat nucleus accumbens during morphine
      exposure (14 days, 10 mg/kg s.c.) and drug-abstinence (3 weeks). We used real
      time quantitative PCR to monitor gene expression after establishing its
      sensitivity and resolution to resolve small changes in expression for genes in
      various abundance classes. Morphine-exposure (5 time points) and subsequent
      abstinence (6 time points) induced phase-specific temporal gene expression of
      distinct functional groups of genes, for example, short-term homeostatic
      responses. Opiate withdrawal appeared to be a new stimulus in terms of gene
      expression and mediates a marked wave of gene repression. Prolonged abstinence
      resulted in persistently changed expression levels of genes involved in neuronal
      outgrowth and re-wiring. Our findings substantiate the hypothesis that this new
      gene program, initiated upon morphine-withdrawal, may subserve long-term neuronal
      plasticity involved in the persistent behavioral consequences of repeated drug
      exposure.

PMID- 15033928
TI  - Aquaporins in skeletal muscle: reassessment of the functional role of aquaporin
      4.
AB  - Aquaporin-4 (AQP4) is the major water channel of the neuromuscular system, but
      its physiological function in both perivascular astrocytes and skeletal muscle
      sarcolemma is unclear. The purpose of this study was to assess the following in
      skeletal muscle: a) the expression of all cloned water cannels; b) the functional
      role of AQP4 using sarcolemma vesicles purified by means of several fractionation
      methods, and c) the functional effect of AQP4 reduction in mdx mice, the animal
      model of Duchenne muscular dystrophy (DMD). Immunofluorescence and immunoblot
      experiments performed with affinity purified antibodies revealed that only AQP1
      and AQP4 are expressed in mouse skeletal muscle: AQP1 in endothelial cells of
      continuous capillaries and AQP4 on the plasma membrane of muscle fiber. Plasma
      membrane vesicle purification was performed with a procedure extensively used to
      purify and characterize dystrophin-associated proteins (DAPs) from rabbit
      skeletal muscle. Western blot analysis showed strong co-enrichment of the
      analyzed DAPs and AQP4, indicating that the membrane vesicle preparation was
      highly enriched in sarcolemma. Stopped-flow light-scattering measurements showed
      high osmotic water permeability of sarcolemma vesicles (approximately 150
      microm/s) compatible with the AQP-mediated pathway for water movement. Sarcolemma
      vesicles prepared from mdx mice revealed, in parallel with AQP4 disappearance
      from the plasma membrane, a strong reduction in water permeability compared with
      wild-type mice. Altogether, these results demonstrate high AQP4-mediated water
      permeability of the skeletal muscle sarcolemma. Expression of sarcolemmal AQP4
      together with that of vascular AQP1 may be responsible for the fast water
      transfer from the blood into the muscle during intense activity. These data imply
      an important role for aquaporins in skeletal muscle physiology as well as an
      involvement of AQP4 in the molecular alterations that occur in the muscle of DMD
      patients.

PMID- 15033929
TI  - Direct inhibition of the mitochondrial permeability transition pore: a possible
      mechanism responsible for anti-apoptotic effects of melatonin.
AB  - Melatonin, the secretory product of the pineal gland, is known to be
      neuroprotective in cerebral ischemia, which is so far mostly attributed to its
      antioxidant properties. Here we show that melatonin directly inhibits the
      mitochondrial permeability transition pore (mtPTP). mtPTP contributes to the
      pathology of ischemia by releasing calcium and cytochrome c (cyt c) from
      mitochondria. Consistently, NMDA-induced calcium rises were diminished by
      melatonin in cultured mouse striatal neurons, similar to the pattern seen with
      cyclosporine A (CsA). When the mouse striatal neurons were subjected to oxygen
      glucose deprivation (OGD), melatonin strongly prevented the OGD-induced loss of
      the mitochondrial membrane potential. To assess the direct effect of melatonin on
      the mtPTP activity at the single channel level, recordings from the inner
      mitochondrial membrane were obtained by a patch-clamp approach using rat liver
      mitoplasts. Melatonin strongly inhibited mtPTP currents in a dose-dependent
      manner with an IC50 of 0.8 microM. If melatonin is an inhibitor of the mtPTP, it
      should prevent mitochondrial cyt c release as seen in stroke models. Rats
      underwent middle cerebral artery occlusion (MCAO) for 2 h followed by
      reperfusion. Melatonin (10 mg/kg ip) or vehicle was given at the time of
      occlusion and at the time of reperfusion. Indeed, infarct area in the brain
      sections of melatonin-treated animals displayed a considerably decreased cyt c
      release along with less activation of caspase-3 and apoptotic DNA fragmentation.
      Melatonin treatment diminished the loss of neurons and decreased the infarct
      volume as compared with untreated MCAO rats. Our findings suggest that the direct
      inhibition of the mtPTP by melatonin may essentially contribute to its anti
      apoptotic effects in transient brain ischemia.

PMID- 15033930
TI  - Disruption of Rho signaling results in progressive atrioventricular conduction
      defects while ventricular function remains preserved.
AB  - Recent studies suggest that RhoA and Rac1 mediate hypertrophic signals in cardiac
      myocyte hypertrophy. However, effects on cardiac function caused by inhibition of
      their activity in the heart have yet to be evaluated. Cardiac-specific inhibition
      of Rho family protein activities was achieved by expressing Rho GDIalpha, an
      endogenous specific GDP dissociation inhibitor for Rho family proteins, using the
      alpha-myosin heavy-chain promoter. Increased expression of Rho GDIalpha led to
      atrial arrhythmias and mild ventricular hypertrophy in adult mice (4-7 months).
      However, left ventricular systolic and diastolic function was largely preserved
      before and after the development of cardiac hypertrophy, indicating that Rho
      GTPases are not required to maintain ventricular contractile function under basal
      physiological condition. Electrocardiography and intracardiac
      electrophysiological studies revealed first-degree atrioventricular (AV) block in
      the transgenic heart at 1 week of age, which further progressed into second
      degree AV block at 4 weeks of age before the development of cardiac hypertrophy.
      Expression of connexin 40 dramatically decreased from 1 week to 4 weeks of age in
      the transgenic heart, which may contribute in part to the conduction defects in
      the transgenic mice. This study provides novel evidence for an important role of
      Rho GTPases in regulating AV conduction.

PMID- 15033931
TI  - Atm-null mice exhibit enhanced radiation-induced birth defects and a hybrid form
      of embryonic programmed cell death indicating a teratological suppressor function
      for ATM.
AB  - ATM (ataxia-telangiectasia mutated) is a genotoxic stress transducer. In this
      first report of Atm-dependent birth defects, Atm-null embryos were uniquely
      susceptible to low-dose (0.5 Gy) radiation, exhibiting severe runting, tail
      anomalies, and lethality, independent of cell cycle arrest or insulin-like growth
      factor 1. This treatment enhanced levels of p53 protein and central nervous
      system (CNS) apoptosis in wild-type mice, but not Atm-null mutants, at 6 h
      postirradiation. At 48 h, however, this pattern was reversed, with Atm-null mice
      exhibiting high levels of a hybrid form of programmed cell death within the CNS.
      Even heterozygous Atm-deficient embryos were radiosensitive to a higher radiation
      dose of 2 Gy. These results show that Atm is a novel teratologic suppressor gene
      protecting embryos from pathological cell death and teratogenesis initiated by
      even mild DNA damage.

PMID- 15033932
TI  - Targeting kallikrein 6 proteolysis attenuates CNS inflammatory disease.
AB  - Kallikrein 6 (K6, MSP) is a newly identified member of the Kallikrein family of
      serine proteases that is preferentially expressed in the adult central nervous
      system (CNS). We have previously demonstrated that K6 is abundantly expressed by
      inflammatory cells at sites of CNS inflammation and demyelination in animal
      models of multiple sclerosis (MS) and in human MS lesions. To test the hypothesis
      that this novel enzyme is a mediator of pathogenesis in CNS inflammatory disease,
      we have evaluated whether autonomously generated K6 antibodies alter the
      clinicopathological course of disease in murine proteolipid protein139-151
      induced experimental autoimmune encephalomyelitis (PLP139-151 EAE). We
      demonstrate that immunization of mice with recombinant K6 generates antibodies
      that block K6 enzymatic activity in vitro, including the breakdown of myelin
      basic protein (MBP), and that K6-immunized mice exhibit significantly delayed
      onset and severity of clinical deficits. Reduced clinical deficits were reflected
      in significantly less spinal cord pathology and meningeal inflammation and in
      reduced Th1 cellular responses in vivo and in vitro. These data demonstrate for
      the first time that K6 participates in enzymatic cascades mediating CNS
      inflammatory disease and that this unique enzyme may represent a novel
      therapeutic target for the treatment of progressive inflammatory disorders,
      including MS.

PMID- 15033933
TI  - Misfolded proinsulin accumulates in expanded pre-Golgi intermediates and
      endoplasmic reticulum subdomains in pancreatic beta cells of Akita mice.
AB  - A missense mutation of the insulin 2 gene (Cys96Tyr) in Akita mice disrupting one
      of the two interchain disulfide bonds results in intracellular accumulation of
      misfolded proinsulin. We analyzed the secretory pathway of pancreatic beta cells
      by electron microscopy and morphometry and identified sites of proinsulin
      accumulation by quantitative immunogold electron microscopy in this protein
      folding disease. In Akita mice beta cells, the volume density of dilated
      endoplasmic reticulum subdomains was increased by 2.9-fold, resulting in a 1.7
      fold increased volume density of the entire rough endoplasmic reticulum. The
      volume density of pre-Golgi intermediates was increased by 4.9-fold, and that of
      the Golgi apparatus was increase by 3.4-fold. The relative labeling intensity for
      proinsulin was 2.1-fold higher in dilated endoplasmic reticulum subdomains and
      2.9-fold higher in pre-Golgi intermediates as compared with narrow endoplasmic
      reticulum, resulting in a significantly different distribution pattern between
      Akita and control mice beta cells (Chi2= 29.97, P<0.001). The numerical density
      of insulin secretory granules was equal in Akita and control mice beta cells.
      However, their volume density and average volume were reduced to 20% and their
      average diameter to 58% in Akita mice. Together, these data demonstrate that
      misfolded proinsulin accumulates mainly in pre-Golgi intermediates and to a
      lesser extent in dilated endoplasmic reticulum subdomains, providing evidence for
      the importance of pre-Golgi intermediates in a protein folding disease.

PMID- 15033934
TI  - Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A.
AB  - Methionine adenosyltransferase (MAT) is an essential enzyme because it catalyzes
      the formation of S-adenosylmethionine (SAMe), the principal biological methyl
      donor. Of the two genes that encode MAT, MAT1A is mainly expressed in adult liver
      and MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have
      reduced hepatic SAMe content and spontaneously develop hepatocellular carcinoma.
      The current study examined the influence of chronic hepatic SAMe deficiency on
      liver regeneration. Despite having higher baseline hepatic staining for
      proliferating cell nuclear antigen, MAT1A knockout mice had impaired liver
      regeneration after partial hepatectomy (PH) as determined by bromodeoxyuridine
      incorporation. This can be explained by an inability to up-regulate cyclin D1
      after PH in the knockout mice. Upstream signaling pathways involved in cyclin D1
      activation include nuclear factor kappaB (NFkappaB), the c-Jun-N-terminal kinase
      (JNK), extracellular signal-regulated kinases (ERKs), and signal transducer and
      activator of transcription-3 (STAT-3). At baseline, JNK and ERK are more
      activated in the knockouts whereas NFkappaB and STAT-3 are similar to wild-type
      mice. Following PH, early activation of these pathways occurred, but although
      they remained increased in wild-type mice, c-jun and ERK phosphorylation fell
      progressively in the knockouts. Hepatic SAMe levels fell progressively following
      PH in wild-type mice but remained unchanged in the knockouts. In culture, MAT1A
      knockout hepatocytes have higher baseline DNA synthesis but failed to respond to
      the mitogenic effect of hepatocyte growth factor. Taken together, our findings
      define a critical role for SAMe in ERK signaling and cyclin D1 regulation during
      regeneration and suggest chronic hepatic SAMe depletion results in loss of
      responsiveness to mitogenic signals.

PMID- 15033935
TI  - Atrial natriuretic peptide contributes to physiological control of lipid
      mobilization in humans.
AB  - In humans, lipid mobilization is considered to depend mainly on sympathetic
      nervous system activation and catecholamine action. A contribution of ANP was
      hypothesized because we have previously shown that atrial natriuretic peptide
      (ANP) is a lipolytic agent on isolated human fat cells. Control of lipid
      mobilizing mechanisms was investigated using in situ microdialysis in
      subcutaneous adipose tissue (SCAT) in healthy young men during two successive
      exercise bouts performed at 35% and 60% peak oxygen consumption (VO2max) after
      placebo or acute oral tertatolol (nonselective beta-antagonist) treatment. In
      placebo-treated subjects, infusion of propranolol in the probe (100 micromol/l)
      only partially reduced (40%) the increment in extracellular glycerol
      concentration (EGC) promoted by exercise. Moreover, oral beta-adrenergic receptor
      blockade did not prevent exercise-induced lipid mobilization in SCAT while
      exerting fat cell beta-adrenergic receptor blockade. Exercise-induced increase in
      plasma ANP was potently amplified by oral tertatolol. A positive correlation was
      found between EGC and plasma ANP levels but also between extracellular cGMP
      (i.e., index of ANP-mediated lipolysis) and EGC. Thus, we demonstrate that
      exercise-induced lipid mobilization resistant to local propranolol and lipid
      mobilizing action observed under oral beta-blockade is related to the action of
      ANP. Oral beta-adrenergic receptor blockade, which potentiates exercise-induced
      ANP release by the heart, may contribute to lipid mobilization in SCAT. The
      potential relevance of an ANP-related lipid-mobilizing pathway is discussed.

PMID- 15033936
TI  - Aberrant gating, but a normal expression pattern, underlies the recessive
      phenotype of the deafness mutant Connexin26M34T.
AB  - Mutations in the gene GJB2, encoding the gap junction protein Connexin26 (Cx26),
      are the most prevalent cause of inherited hearing loss, and Cx26M34T was one of
      the first mutations linked to deafness (Kelsell et al., 1997; Nature 387, 80-83).
      We report the first characterization of the gating properties of M34T, which had
      previously been reported to be nonfunctional. Although homotypic mutant channels
      did not produce detectable currents, heterotypic pairings with wtCx26 confirmed
      that M34T formed intercellular channels, although the gating properties were
      altered. Cx26M34T displayed an inverted response to transjunctional voltage (Vj),
      mediating currents that activate in a time- and Vj-dependent manner. These
      characteristics suggest that the channel population is only partially open at
      rest, consistent with previous reports that dye transfer in M34T-expressing cells
      is reduced or abolished (e.g., Thonnissen et al., Human Genet. 111, 190-197). To
      investigate the controversial recessive/dominant behavior of this mutant, we
      coexpressed M34T with wtCx26 RNA at equimolar levels, mimicking the situation in
      heterozygotic individuals. Under these conditions, M34T did not significantly
      reduce Cx26/Cx26 coupling, or alter the electrophysiological properties of the wt
      channels, consistent with the recessive nature of the allele. Overexpression of
      the mutant did have some inhibitory effects on conductance, possibly explaining
      some of the previous reports in exogenous expression systems and some patients.
      Consistent with its electrophysiological behavior, we also show that M34T
      localizes to cell junctions in both transfected HeLa cells and patient-derived
      tissue.

PMID- 15033937
TI  - Functional analysis of the ALG3 gene encoding the Dol-P-Man: Man5GlcNAc2-PP-Dol
      mannosyltransferase enzyme of P. pastoris.
AB  - N-glycans are synthesized in both yeast and mammals through the ordered assembly
      of a lipid-linked core Glc(3)Man(9)GlcNAc(2) structure that is subsequently
      transferred to a nascent protein in the endoplasmic reticulum. Once folded,
      glycoproteins are then shuttled to the Golgi, where additional but divergent
      processing occurs in mammals and fungi. We cloned the Pichia pastoris homolog of
      the ALG3 gene, which encodes the enzyme that converts Man(5)GlcNAc(2)-Dol-PP to
      Man(6)GlcNAc(2)-Dol-PP. Deletion of this gene in an och1 mutant background
      resulted in the secretion of glycoproteins with a predicted Man(5)GlcNAc(2)
      structure that could be trimmed to Man(3)GlcNAc(2) by in vitro alpha-1,2
      mannosidase treatment. However, several larger glycans ranging from
      Hex(6)GlcNAc(2) to Hex(12)GlcNAc(2) were also observed that were recalcitrant to
      an array of mannosidase digests. These results contrast the far simpler glycan
      profile found in Saccharomyces cerevisiae alg3-1 och1, indicating diverging Golgi
      processing in these two closely related yeasts. Finally, analysis of the P.
      pastoris alg3 deletion mutant in the presence and absence of the outer chain
      initiating Och1p alpha-1,6-mannosyltransferase activity suggests that the PpOch1p
      has a broader substrate specificity compared to its S. cerevisiae counterpart.

PMID- 15033938
TI  - A syndecan-4/CXCR4 complex expressed on human primary lymphocytes and macrophages
      and HeLa cell line binds the CXC chemokine stromal cell-derived factor-1 (SDF-1).
AB  - The stromal cell-derived factor-1 (SDF-1) is a CXC chemokine, which plays
      critical roles in migration, proliferation, and differentiation of leukocytes.
      SDF-1 is the only known ligand of CXCR4, the coreceptor of X4 HIV strains. We
      show that SDF-1 binds to high- and low-affinity sites on HeLa cells.
      Coimmunoprecipitation studies demonstrate that glycanated and oligomerized
      syndecan-4 but neither syndecan-1, syndecan-2, betaglycan, nor CD44 forms
      complexes with SDF-1 and CXCR4 on these cells as well as on primary lymphocytes
      or macrophages. Moreover, biotinylated SDF-1 directly binds in a
      glycosaminoglycans (GAGs)-dependent manner to electroblotted syndecan-4, and
      colocalization of SDF-1 with syndecan-4 was visualized by confocal microscopy.
      Glycosaminidases pretreatment of the HeLa cells or the macrophages decreases the
      binding of syndecan-4 to the complex formed by it and SDF-1. In addition, this
      treatment also decreases the binding of the chemokine to CXCR4 on the primary
      macrophages but not on the HeLa cells. Therefore GAGs-dependent binding of SDF-1
      to the cells facilitates SDF-1 binding to CXCR4 on primary macrophages but not on
      HeLa cell line. Finally, an SDF-1-independent heteromeric complex between
      syndecan-4 and CXCR4 was visualized on HeLa cells by confocal microscopy as well
      as by electron microscopy. Moreover, syndecan-4 from lymphocytes, monocyte
      derived-macrophages, and HeLa cells coimmunoprecipitated with CXCR4. This
      syndecan-4/CXCR4 complex is likely a functional unit involved in SDF-1 binding.
      The role of these interactions in the pathophysiology of SDF-1 deserves further
      study.

PMID- 15033939
TI  - Mapping critical biological motifs and biosynthetic pathways of heparan sulfate.
AB  - Heparan sulfate (HS) interacts with numerous proteins at the cell surface and
      orchestrates myriad biological events. Unraveling the mechanisms of these events
      at the molecular level calls for the structural analysis of these negatively
      charged and highly heterogeneous biopolymers. However, HS is often available only
      in small quantities, and the task of structural analysis necessitates the use of
      ultra-sensitive methods, such as mass spectrometry. Sequence heterogeneity within
      HS chains required us to identify critical functional groups and their spacing to
      determine structure-function relationships for HS. We carried out structural
      analysis of HS isolated from wild type, 3-OST-1, 3-OST-3A, or 3-OST-5
      sulfotransferase-transduced Chinese hamster ovary cells and also from various
      tissues. In the context of tissue-specific HS, the data allowed us to map the
      biosynthetic pathways responsible for the placement of critical groups. As a
      means of determining the distance between critical groups within a motif, we
      determined the spacing of the rare GlcNAc-GlcA disaccharide sequence in the
      completely desulfated re-N-sulfated porcine intestinal heparin. These
      disaccharides are biosynthetic regulatory markers for 3-OST-1 modification and
      the partial structure of the antithrombin III binding site. They occur only at
      the distance of hexasaccharide, octasaccharide, decasaccharide, or
      dodecasaccharide. Thus this approach allowed us to map both the biosynthetic
      pathways for generating critical functional groups and their spacing within HS.
      Our new strategy removes two obstacles to rapid progress in this field of
      research.

PMID- 15033940
TI  - Specificity of IgG and IgE antibodies against plant and insect glycoprotein
      glycans determined with artificial glycoforms of human transferrin.
AB  - Cross-reactive carbohydrate determinants of plants are essentially a mixture of N
      glycans containing beta1,2-xylose and core alpha1,3-fucose, the latter also found
      in insect glycoproteins. To determine the relative contributions of these two
      sugar residues to antibody binding, we prepared an array of glycomodified forms
      of human apo-transferrin. Using core-alpha1, 3-fucosyltransferase (EC 2.4.1.214)
      and beta1,2-xylosyltransferase (EC 2.4.2.38) recombinantly expressed in Pichia
      pastoris and suitable glycosidases, glycoforms containing either only fucose
      (MMF), only xylose (MMX), both (MMXF), or neither (MM) linked to the common
      pentasaccharide core were generated. Additional glycoforms were obtained by
      enzymatic removal of the alpha1,3-linked mannosyl residue. These transferrin
      glycoforms served to define the binding specificity of antibodies in western
      blot, ELISA, and inhibition ELISA. Rabbit anti-horseradish peroxidase serum bound
      to both the fucosylated (MMF) and the xylosylated (MMX) glycoforms. Inhibition
      studies indicated two independent highly specific populations reacting with
      either of the two epitopes. In contrast, the monoclonal antibody YZ1/2.23 appears
      to recognize a larger structure including both the fucosyl and the xylosyl
      residue. The mannose-deficient glycoform was a poorer inhibitor for both
      antibodies. Terminal GlcNAc residues prevented antibody binding. Rabbit anti-bee
      venom serum reacted with fucosylated forms (MMF and MMXF) only. Experiments with
      sera from allergic patients suggest that glycomodified human transferrin,
      especially the MMXF glycoform, is a suitable reagent for the detection of
      antibodies against cross-reactive carbohydrate determinants. Within the panel
      studied, several sera contained high levels of fucose-reactive IgE but only a few
      sera showed any binding to MMX-transferrin.

PMID- 15033941
TI  - D-mannose transport and metabolism in isolated enterocytes.
AB  - D-mannose transport and metabolism has been studied in enterocytes isolated from
      chicken small intestine. In the presence of Na(+), the mannose taken up by the
      cells either remains free, is phosphorylated, is catabolized to H(2)O, or becomes
      part of membrane components. The mannose remaining free in the cytosol is
      released when the cells are transferred to an ice bath. The Na(+)-dependent D
      mannose transport is electrogenic and inhibited by ouabain and dinitrophenol; its
      substrate specificity differs from SGLT-1 transporter. The Glut2 transporter
      inhibitors phloretin and cytochalasin B added following 30-min mannose uptake
      reduced the previously accumulated D-mannose, whereas these two agents increased
      the cell to external medium 3-O-methyl-glucose (3-OMG) concentration ratio. D
      mannose efflux rate from preloaded D-[2-(3)H]-mannose enterocytes is Na(+)
      independent. Phloretin did not affect D-mannose efflux rate, whereas it inhibited
      that of 3-OMG. Neither mannose uptake nor efflux rate were affected by fructose.
      It is concluded that part of the mannose taken up by the enterocytes is rapidly
      metabolized and that enterocytes have two D- mannose transport systems: one is
      concentrative and Na(+)-dependent and the other is Na(+)-independent and passive.

PMID- 15033942
TI  - Donor specificity in the glycosylation of Tamm-Horsfall glycoprotein:
      conservation of the Sda determinant in pairs of twins.
AB  - The content of the Sd(a) determinant in urinary human Tamm-Horsfall glycoprotein
      (THp) has been reported to be donor-specific. This feature was further addressed
      by investigating THp from genetically identical individuals. To this end, THp was
      isolated from the urine of two monozygotic pairs of twins (A and B). The four
      samples (THp A1, A2, B1, and B2) were subjected to endo-beta-galactosidase from
      Bacteroides fragilis leading to the liberation of the Neu5Ac(alpha2-3)Gal (beta1
      4)GlcNAc(beta1-3)Gal and Neu5Ac(alpha2-3)[GalNAc(beta1-4)] Gal(beta1
      4)GlcNAc(beta1-3)Gal (Sd(a) epitope) motifs, both located at the nonreducing
      termini of complex type N-glycans. The isolated mixtures of oligosaccharides were
      analyzed for the absolute and relative amounts of the two oligosaccharides. The
      obtained data clearly indicate that in THp A1 and A2, and in THp B1 and B2, the
      molar ratios of the tetra- and Sd(a) pentasaccharide are identical for a pair of
      twins. This conservation of molar ratios points to an identical relative
      expression of beta-1,4-N-acetylgalactosaminyltransferase activity involved in the
      biosynthesis of the Sd(a) determinant. Apparently, the degree of conversion of
      the tetrasaccharidic Sd(a) precursor into the final pentasaccharidic Sd(a) form
      can be considered to result from a very closely related pattern of glycosylation
      for genetically homogeneous individuals.

PMID- 15033943
TI  - Is insulin resistance an essential component of PCOS?: The influence of
      confounding factors.
AB  - Insulin resistance is often considered a regular component of polycystic ovary
      syndrome (PCOS). Many interventional studies assume a state of insulin resistance
      in all patients. However, the evidence is based on small samples that are often
      insufficient to adjust for significant confounding factors. Moreover, several
      studies have not confirmed differences in insulin sensitivity between women with
      PCOS and healthy controls, especially in non-obese patients. This debate article
      provides an overview of the data published regarding the presence of abnormal or
      normal insulin sensitivity in PCOS. In conclusion, available data offer evidence
      that a substantial subgroup of women with PCOS have insulin sensitivity
      comparable with healthy controls if matched carefully for potential confounding
      factors.

PMID- 15033944
TI  - Is insulin resistance an essential component of PCOS?: The endometriosis
      syndromes: a clinical classification in the presence of aetiological confusion
      and therapeutic anarchy.
AB  - Clinical confusion and inappropriate management continues to surround
      endometriosis. It is poorly recognized that the disorder can exist in two
      different morphological forms that have different symptoms, signs and prognosis.
      Earlier classification systems have been useful for research but are of limited
      value in aiding day-to-day management. In the clinic, two discrete phenotypes can
      be defined by the presence or absence of palpable nodules in the deep pelvis.
      Patients with such nodules with or without associated ovarian endometrioma
      usually have severe symptoms with significant risks of bowel and urinary tract
      involvement. The predominant histological feature of these lesions is extensive
      fibromuscular hyperplasia (adenomyoma). These patients will often need extensive
      surgical intervention. Patients without such palpable lesions usually have the
      classic superficial subperitoneal lesions with endometrial-like glands and stroma
      on histological examination. This group often has less severe symptoms and has
      little risk of developing serious associated problems. These lesions may be
      helped by medications and/or simple ablative surgery. It is suggested that these
      collections of symptoms and signs or syndromes be named after the pioneers who
      first described the lesions. Cullen's syndrome can be used to describe those
      patients with severe symptoms of endometriosis associated with palpable pelvic
      nodules. Sampson's syndrome can describe those with similar symptoms associated
      with a structurally normal pelvis.

PMID- 15033945
TI  - Over-ripeness ovopathy: a challenging hypothesis for sex ratio modulation.
AB  - Current hypotheses do not explain the concerns about sex ratio modulation at
      conception, birth or during life, and particularly about sex ratio reversal, e.g.
      at very young or advanced maternal age, during 'anovulatory seasons', among those
      of low socio-economic status, or induced by specific lifestyles, etc. These
      modulations are explained by the introduction of the ovopathy concept and
      inherent preferential fertilization of non-optimally matured oocytes by Y-bearing
      sperm. Non-optimal development and implantation of male-biased fetuses results in
      perennial loss of non-optimal, male-biased fetuses before and after birth.
      Accumulation of conceptopathology in extreme conditions entrains an increasing
      male to female ratio and ultimately a decreasing one, i.e. an 'inverted dose
      response gradient' or 'dose-response fallacy'.

PMID- 15033946
TI  - What is the most relevant standard of success in assisted reproduction?:
      challenges in measuring and reporting success rates for assisted reproductive
      technology treatments: what is optimal?
AB  - For assisted reproductive technology (ART) treatments, measures of success that
      move beyond traditional measures of pregnancy and live birth and narrow the
      numerator to infant outcomes with an optimal short- and long-term prognosis are
      needed. Hence, presentation of singleton live birth delivery rates is warranted.
      Twins have greatly increased risks for morbidity and mortality in comparison with
      singletons. Success rates based on singleton live births will more completely
      inform patients evaluating which ART treatment options will maximize their chance
      for a healthy infant. Additionally, providers who limit embryos transferred can
      feel they are on an even playing field in reporting their success rates. Measures
      of success that narrow the numerator further to exclude preterm or low birth
      weight singleton births might also be informative. However, the utility of such
      measures is less clear because the aetiologies of preterm birth and low birth
      weight among singletons are probably multifactorial. While it may be desirable to
      consider adverse outcomes such as congenital anomalies in defining treatment
      success, it is unfeasible to collect complete and accurate data on anomalies in
      current ART registries. As ART use increases, continual re-examination and
      critique of the manner in which success is defined and presented to the public is
      critical.

PMID- 15033947
TI  - Y chromosome microdeletion screening in infertile men in France: a survey of
      French practice based on 88 IVF centres.
AB  - Y chromosome microdeletion screening is advised in cases of severely impaired
      spermatogenesis. Improvements in molecular biological techniques have made
      diagnosis more accessible in routine analysis. However, Y chromosome
      microdeletions are not diagnosed in all IVF centres. The aim of the present study
      was to determine the regulatory (indications, financing) and performance
      (methods, invoicing) conditions required for this analysis, in France.
      Microdeletion detection was found to be spreading fast and consistantly. It
      therefore seems necessary for a consensus to be reached on indications, with a
      view to a standardized technique, with a common effort of experts in the field.
      Financial management by the French Health Insurance bodies (Securite Sociale)
      would be an essential step towards routine adoption. Lastly, the answers to our
      questionnaire revealed a strong demand for information concerning this analysis.

PMID- 15033948
TI  - The merits of blastocyst versus cleavage stage embryo transfer: a Cochrane
      review.
AB  - This paper is based on a Cochrane review published in The Cochrane Library, issue
      2, 2002 (see www.CochraneLibrary.net for information) with permission from The
      Cochrane Collaboration and John Wiley and Sons. Cochrane reviews are regularly
      updated as new evidence emerges and in response to comments and criticisms, and
      The Cochrane Library should be consulted for the most recent version of the
      review. BACKGROUND: The aim of this study was to determine the relative merits of
      blastocyst versus cleavage stage embryo transfer, concerning the chance of
      pregnancy, live birth, multiple pregnancy and the factors contributing to these
      primary outcomes, from the best available evidence. METHODS: A systematic review
      employing the principles of the Cochrane Menstrual Disorders and Subfertility
      Group was undertaken. Fourteen randomized controlled trials, all comparing day
      2/3 with day 5/6 embryo transfer, were included in a meta-analysis. RESULTS: For
      day 2/3 versus day 5/6 transfer, there was no significant difference in the odds
      of pregnancy [odds ratio (OR) = 0.91, 95% confidence interval (CI) 0.71-1.17] nor
      of live birth (OR = 0.83, 95% CI 0.48-1.42) per treated couple. These results
      were similar whether all trials, only trials with transfer of equal numbers of
      day 2/3 versus day 5/6, or only trials with transfer of fewer day 5/6 than day
      2/3 embryos, were pooled. There was no significant difference in the odds of
      multiple pregnancy for day 2/3 versus day 5/6 transfer overall (OR 0.77, 95% CI
      0.52-1.13) nor when fewer day 5/6 than day 2/3 embryos were transferred (day 2/3
      versus day 5/6 OR 0.69, 95% CI 0.42-1.12). CONCLUSION: The current evidence fails
      to support a widespread change of practice from cleavage stage to blastocyst
      stage embryo transfer in couples undergoing IVF.

PMID- 15033951
TI  - Anovulation in the prevention of cytotoxic-induced follicular attrition and
      ovarian failure.
AB  - BACKGROUND: Gonadal failure secondary to alkylating agents may be related to
      ovulatory status. The objective of this investigation was to evaluate whether
      anovulation protected ovarian follicles during treatment with cyclophosphamide.
      METHODS: Four groups (n = 20 mature female Sprague-Dawley rats per group) were
      studied: control (group I), 5 mg/kg/day cyclophosphamide only (group II), 5
      mg/kg/day cyclophosphamide and the combination of 50 micro g ethinyl estradiol/2
      mg norgestrel (group III) and 5 mg/kg/day cyclophosphamide and 2.5 micro g
      leuprolide acetate daily (group IV). Animals were sacrificed after 4 weeks of
      treatment. Follicles were classified as medium (300-450 micro m) and large (>450
      micro m) per section of ovary. RESULTS: Group II developed a significantly
      greater number of medium and large follicles [15.1 +/- 6.1 and 4.9 +/- 1.9 (mean
      +/- SD), respectively] compared with group I [7.1 +/- 2.1 and 1.0 +/- 0.7 (mean
      +/- SD), respectively] (P </= 0.05). Groups III and IV developed a significantly
      greater number of medium follicles [13.2 +/- 2.5 and 10.8 +/- 2.3 (mean +/- SD),
      respectively) compared with group I (P < or = 0.05). There was a trend toward a
      greater number of large follicles in groups III and IV when they were compared
      with group I. There were no differences in medium follicles in groups II, III and
      IV. No differences were noted in the number of large follicles between groups III
      and IV (2.9 +/- 1.2 and 2.3 +/- 1.0, respectively). CONCLUSIONS: These results
      suggest that in the rat model, cyclophosphamide exerts a stimulatory effect on
      the ovary resulting in the greater development of both medium and large
      follicles. Anovulation conferred no protection against cyclophosphamide-induced
      gonadal toxicity. These data suggest that in the rat model, cyclophosphamide may
      result in ovarian failure by enhancing recruitment of follicles regardless of
      ovulatory status or hormonal milieu.

PMID- 15033949
TI  - Progesterone down-regulates insulin-like growth factor-I expression in cultured
      human uterine leiomyoma cells.
AB  - BACKGROUND: Insulin-like growth factor-I (IGF-I) plays crucial roles in uterine
      leiomyoma cell growth through stimulating proliferation and inhibiting apoptosis.
      The present study was conducted to elucidate whether progesterone affects IGF-I
      and its receptor expression in cultured leiomyoma cells. METHODS: Isolated
      leiomyoma cells were subcultured in Phenol Red-free Dulbecco's modified Eagle's
      medium supplemented with 10% fetal bovine serum for 120 h and then stepped down
      to serum-free conditions for an additional 48 h in the presence or absence of
      17beta-estradiol (E(2)) (10 ng/ml) or progesterone (100 ng/ml). IGF-I and its
      receptor mRNA and immunoreactive IGF-I in the cultured cells were assessed by
      quantitative RT-PCR with Southern blot analysis and by radioimmunoassay with
      Seppak C18 chromatography, respectively. The presence of estrogen receptor (ER)
      and progesterone receptor (PR) in cultured leiomyoma cells was
      immunocytochemically examined. RESULTS: Both treatment with progesterone alone
      and treatment with E(2) and progesterone combined significantly decreased IGF-I
      mRNA and protein expression in cultured leiomyoma cells compared with that in
      untreated cultures, but treatment with E(2) alone did not. IGF-I receptor mRNA
      expression in those cells was not affected by treatment with either E(2) or
      progesterone. Immunocytochemical analysis revealed that PR protein expression in
      cultured leiomyoma cells maintained in a serum-free condition for 48 h whereas ER
      protein expression in the cells remarkably decreased after 24 h culture under the
      serum-free condition. CONCLUSIONS: The present study provided evidence for the
      first time that progesterone down-regulates IGF-I mRNA and protein expression in
      cultured leiomyoma cells without affecting IGF-I receptor mRNA expression.

PMID- 15033952
TI  - Is infertility a risk factor for impaired male fertility?
AB  - BACKGROUND: Previous research has suggested an interaction between distress and
      male fertility. The present longitudinal study sought to deliver evidence for a
      negative impact of distress due to infertility on sperm concentration. METHODS:
      The sample consisted of 120 patients who twice visited an andrological clinic on
      their own initiative for fertility work-ups. Baseline and follow-up examinations
      were at least 6 months apart. Prior to each fertility work-up, patients completed
      a questionnaire assessing distress due to infertility. RESULTS: Path analyses
      revealed that the level of infertility distress at follow-up has a negative
      impact on the change in sperm quality from baseline to follow-up assessment.
      Distress scores were highly stable. As a consequence, the level of distress at
      baseline assessment provided only little additional information for the changes
      in sperm concentration. Further analysis suggested that the fertility status had
      no impact on infertility distress. CONCLUSION: The present study delivers the
      strongest evidence to date that distress due to infertility is a significant risk
      factor for a decrease in sperm quality.

PMID- 15033950
TI  - Circulating levels of free and total vascular endothelial growth factor (VEGF)-A,
      soluble VEGF receptors-1 and -2, and angiogenin during ovarian stimulation in non
      human primates and women.
AB  - BACKGROUND: In a prospective study we measured circulating levels of vasoactive
      factors and their soluble receptors in women undergoing controlled ovarian
      stimulation (COS) for IVF who were at risk for ovarian hyperstimulation syndrome
      (OHSS), and compared them to those in a primate model, the rhesus monkey.
      METHODS: A total of 23 women were enrolled in the study and serum vascular
      endothelial growth factor (VEGF)-A (free and total), soluble (s)VEGF-R1 and -R2,
      and angiogenin levels were compared in pregnant and non-pregnant women, and in
      monkeys, during follicular stimulation, the luteal phase and early pregnancy.
      RESULTS: VEGF levels were similar during the period of follicular stimulation in
      pregnant and non-pregnant women, but a significant rise in both free and total
      VEGF occurred in pregnant women during the luteal phase (P < 0.05). The level of
      sVEGF-R1 (but not -R2) increased (P < 0.05) following implantation, and the rise
      in sVEGF-R1 corresponded to an abrupt fall in free (but not total) VEGF. In
      contrast, total VEGF levels remained similar to those observed on the day of hCG
      injection. Angiogenin levels tended to decline during follicular stimulation,
      then increased marginally during the luteal phase and were unchanged in early
      pregnancy. In contrast to women, free VEGF levels were non-detectable and total
      levels remained constant through the natural menstrual cycle and COS protocols in
      monkeys. CONCLUSIONS: The levels of circulating angiogenic factors and soluble
      receptors demonstrate significant changes during COS cycles and early pregnancy
      in women. Thus, the systemic effect of these agents is influenced by ligand
      receptor protein-binding interactions, and these relationships may exhibit
      dynamic changes during COS cycles and early pregnancy, and could contribute to
      the development of OHSS.

PMID- 15033953
TI  - Time-dependent capability of human oocytes for activation and pronuclear
      formation during metaphase II arrest.
AB  - BACKGROUND: The purpose of this study was to investigate the fertilization rate
      and developmental potential of human oocytes in relation to the duration of their
      metaphase II (MII) arrest stage following the extrusion of the first polar body
      (1PB). METHODS: Immature metaphase I oocytes (MI; study oocytes, n = 468) that
      underwent meiotic maturation during brief in vitro culture and their matured in
      vivo, MII siblings (control oocytes, n = 3293) were subjected to ICSI.
      Fertilization and early cleavage were evaluated in both study and control groups.
      RESULTS: The overall fertilization rate was significantly lower in the oocytes
      matured in vitro than in those matured in vivo (42 versus 77%, P < 0.0001). A
      significant relationship was observed between oocyte activation potential and the
      length of MII arrest. The majority of study oocytes injected soon after PB
      extrusion remained unfertilized (64%; 98/154 oocytes). The proportion of normally
      activated oocytes that contained two pronuclei and two PBs gradually increased
      with prolonged time of MII arrest (43 and 61% at 2 and 3-6 h after 1PB
      extrusion). Significantly more embryos originating from the study than control
      oocytes were arrested soon after the first two cleavage divisions (39 and 17%; P
      < 0.0001) and exhibited multinucleated blastomeres (23 and 13%; P < 0.0001),
      which suggests the existence of chromosomal abnormalities. CONCLUSIONS: Human
      oocytes progressively develop the ability for full activation and normal
      development during the MII arrest stage.

PMID- 15033954
TI  - Retrograde migration of glove powder in the human female genital tract.
AB  - BACKGROUND: This study in humans was undertaken to evaluate earlier results from
      animal research showing a retrograde migration of glove powder from the vagina
      into the intra-abdominal cavity. METHODS: One study group was gynaecologically
      examined with powdered gloves the day before an abdominal hysterectomy and
      another group 4 days pre-operatively. There were two control groups similarly
      examined with powder-free gloves. Cell smears were taken from the peritoneal
      fluid and during the operation further smears were taken from the Fallopian
      tubes, uterine cavity and cervical canal. RESULTS: Statistically significant
      differences were found for large starch particles at all locations between the
      study and control groups examined 1 day pre-operatively. Considering small starch
      particles, there were significant differences in cervix (P < 0.001), uterus (P <
      0.01) and the Fallopian tubes (P < 0.01). The combined results also show
      significant differences between both large and small starch particles in cervix,
      uterus and the Fallopian tubes. There were also differences between the study and
      control groups examined 4 days pre-operatively, but these were not statistically
      significant except for small and large starch particles in uterus (P < 0.01, P <
      0.05) and cervix (P < 0.05, P < 0.05). CONCLUSIONS: This study has pointed out a
      retrograde migration of starch also in humans after a gynaecological examination
      with powdered gloves. Consequently, powder or any other potentially harmful
      substance that can migrate from the vagina should be avoided.

PMID- 15033955
TI  - No difference in natural killer or natural killer T-cell population, but aberrant
      T-helper cell population in the endometrium of women with repeated miscarriage.
AB  - BACKGROUND: The aim of this study was to assess the natural killer (NK) cell and
      natural killer T (NKT) cell populations and cytokine expression of T-helper (Th)
      cells in the endometrium of women who suffered from unexplained repeated
      miscarriage (RM). METHODS: The percentages of NK cells, NKT cells and CD4(+)
      cells expressing intracellular interferon (IFN)-gamma, interleukin (IL)-4 and
      tumour necrosis factor (TNF)-alpha were measured by flow cytometry in the
      endometrium of 20 RM women and 17 fertile control women in the mid-luteal phase
      of the menstrual cycle. RESULTS: No significant differences in CD56(+) NK cell or
      CD3(+)CD4(-)CD8(-)Valpha24(+)Vbeta11(+) NKT cell percentages were found between
      RM and control women. However, in RM women compared with control women, the
      percentages of CD3(+) cells (mean 40.3 versus 56.5%), CD4(+)IFN-gamma(+) cells
      (28.4 versus 39.5%) and CD4(+)TNF-alpha(+) cells (32.9 versus 45.8%) were
      significantly lower. The Th1/Th2 cell balance in RM women did not differ from
      that of controls. CONCLUSIONS: Immunodystrophism detected as diminution of the Th
      cell population rather than Th1 predominance, NK cell or NKT cell accentuation in
      the endometrium might underlie the pathophysiology of unexplained RM. This
      finding provokes an additional controversy on the Th1/Th2 balance concerning RM
      aetiology.

PMID- 15033956
TI  - The ovopathy concept for explaining the secondary sex ratio.

PMID- 15033957
TI  - LH/HCG as a monthly injectable contraceptive?

PMID- 15033958
TI  - Role of rib cage elastance in the coupling between the abdominal muscles and the
      lung.
AB  - The abdominal muscles expand the rib cage when they contract alone. This
      expansion opposes the deflation of the lung and may be viewed as pressure
      dissipation. The hypothesis was raised, therefore, that alterations in rib cage
      elastance should affect the lung deflating action of these muscles. To test this
      hypothesis and evaluate the quantitative importance of this effect, we measured
      the changes in airway opening pressure (Pao), abdominal pressure (Pab), and rib
      cage transverse diameter during isolated stimulation of the transversus abdominis
      muscle in anesthetized dogs, first with the rib cage intact and then after rib
      cage elastance was increased by clamping the ribs and the sternum. Stimulation
      produced increases in Pao, Pab, and rib cage diameter in both conditions. With
      the ribs and sternum clamped, however, the change in Pab was unchanged but the
      change in Pao was increased by 77% (P < 0.001). In a second experiment, the
      transversus abdominis was stimulated before and after rib cage elastance was
      reduced by removing the bony ribs 3-8. Although the change in Pab after removal
      of the the ribs was still unchanged, the change in Pao was reduced by 62% (P <
      0.001). These observations, supported by a model analysis, indicate that rib cage
      elastance is a major determinant of the mechanical coupling between the abdominal
      muscles and the lung. In fact, in the dog, the effects of rib cage elastance and
      Pab on the lung-deflating action of the abdominal muscles are of the same order
      of magnitude.

PMID- 15033959
TI  - Contribution of nNOS- and eNOS-derived NO to microvascular smooth muscle NO
      exposure.
AB  - Nitric oxide (NO) plays an important role in autocrine and paracrine manner in
      numerous physiological processes, including regulation of blood pressure and
      blood flow, platelet aggregation, and leukocyte adhesion. In vascular wall, most
      of the bioavailable NO is believed to derive from endothelial cell NO synthase
      (eNOS). Recently, neuronal NOS (nNOS) has been identified as a source of NO in
      the vicinity of microvessels and has been shown to participate in vascular
      function. Thus NO can be produced and transported to the vascular smooth muscle
      cells from 1). endothelial cells and 2). perivascular nerve fibers, mast cells,
      and other nNOS-containing sources. In this study, a mathematical model of NO
      diffusion-reaction in a cylindrical arteriolar segment was formulated. The model
      quantifies the relative contribution of these NO sources and the smooth muscle
      availability of NO in a tissue containing an arteriolar blood vessel. The results
      indicate that a source of NO derived through nNOS in the perivascular region can
      be a significant contributor to smooth muscle NO. Predicted smooth muscle NO
      concentrations are as high as 430 nM, which is consistent with reported
      experimental measurements ( approximately 400 nM). In addition, we used the model
      to analyze the smooth muscle NO availability in 1). eNOS and nNOS knockout
      experiments, 2). the presence of myoglobin, and 3). the presence of cell-free Hb,
      e.g., Hb-based oxygen carriers. The results show that NO release by nNOS would
      significantly affect available smooth muscle NO. Further experimental and
      theoretical studies are required to account for distribution of NOS isoforms and
      determine NO availability in vasculatures of different tissues.

PMID- 15033960
TI  - Observer-rated ataxia: rating scales for assessment of genetic differences in
      ethanol-induced intoxication in mice.
AB  - Identification of genetic and physiological mechanisms underlying a drug's or
      mutation's effects on motor performance could be aided by the existence of a
      simple observation-based rating scale of ataxia for mice. Rating scales were
      developed to assess ataxia after ethanol (2.75, 3.0, and 3.25 g/kg) in nine
      inbred mouse strains. Each scale independently rates a single behavior. Raters,
      blinded to dose, scored four behaviors (splay of hind legs, wobbling, nose down,
      and belly drag) at each of four time points after injection. The severities of
      hind leg splaying and wobbling were quantifiable, whereas nose down and belly
      dragging were expressed in all-or-none fashion. Interrater reliabilities were
      substantial (0.75 <or= r <or= 0.99). Splay scores (rated 0-5) displayed
      significant effects of strain, dose, and time point. Wobbling (rated 0-4) was
      dependent on strain and time point. Ethanol affected wobbling (most strains
      scored >0 at some time), but all doses were equally effective. Incidence of nose
      down and belly dragging behaviors increased strain dependently after ethanol, but
      strains did not differentially respond to dose. Ethanol-induced splaying was
      modestly, and negatively, genetically correlated with wobbling. Nose down and
      belly dragging tended to be associated with splaying and wobbling at later times.
      Four distinct ataxia-related behaviors were sensitive to ethanol. Strains
      differed in ethanol sensitivity for all measures. Modest strain mean correlations
      among behaviors indicate that these behaviors are probably under control of
      largely different genes and that ataxia rating scales should rate separate
      behaviors on discrete scales.

PMID- 15033962
TI  - Comparison of skin sympathetic nerve responses to isometric arm and leg exercise.
AB  - Measurement of skin sympathetic nerve activity (SSNA) during isometric exercise
      has been previously limited to handgrip. We hypothesized that isometric leg
      exercise due to the greater muscle mass of the leg would elicit greater SSNA
      responses than arm exercise because of presumably greater central command and
      muscle mechanoreceptor activation. To compare the effect of isometric arm and leg
      exercise on SSNA and cutaneous end-organ responses, 10 subjects performed 2 min
      of isometric knee extension (IKE) and handgrip (IHG) at 30% of maximal voluntary
      contraction followed by 2 min of postexercise muscle ischemia (PEMI) in a
      normothermic environment. SSNA was recorded from the peroneal nerve. Cutaneous
      vascular conductance (laser-Doppler flux/mean arterial pressure) and
      electrodermal activity were measured within the field of cutaneous afferent
      discharge. Heart rate and mean arterial pressure significantly increased by 16 +/
      3 and 23 +/- 3 beats/min and by 22 +/- 2 and 27 +/- 3 mmHg from baseline during
      IHG and IKE, respectively. Heart rate and mean arterial pressure responses were
      significantly greater during IKE compared with IHG. SSNA increased significantly
      and comparably during IHG and IKE (52 +/- 20 and 50 +/- 13%, respectively).
      During PEMI, SSNA and heart rate returned to baseline, whereas mean arterial
      pressure remained significantly elevated (Delta12 +/- 2 and Delta13 +/- 2 mmHg
      from baseline for IHG and IKE, respectively). Neither cutaneous vascular
      conductance nor electrodermal activity was significantly altered by either
      exercise or PEMI. These results indicate that, despite cardiovascular differences
      in response to IHG and IKE, SSNA responses are similar at the same exercise
      intensity. Therefore, the findings suggest that relative effort and not muscle
      mass is the main determinant of exercise-induced SSNA responses in humans.

PMID- 15033963
TI  - Intracerebroventricular physostigmine facilitates heat loss mechanisms in running
      rats.
AB  - The aim of this study was to evaluate the participation of central cholinergic
      transmission in the regulation of metabolic rate, core temperature, and heat
      storage in untrained rats submitted to exercise on a treadmill (20 m/min, 5%
      inclination) until fatigue. The animals were separated into eight experimental
      groups, and core temperature or metabolic rate was measured in the rats while
      they were exercising or while they were at rest after injection of 2 microl of 5
      x 10(-3) M physostigmine (Phy) or 0.15 M NaCl solution (Sal) into the lateral
      cerebral ventricle. Metabolic rate was determined by the indirect calorimetry
      system, and colonic temperature was recorded as an index of core temperature. In
      resting animals, Phy induced only a small increase in metabolic rate compared
      with Sal injection, without having any effect on core temperature. During
      exercise, the Phy-treated animals showed a lower core heating rate (0.022 +/-
      0.003 degrees C/min Phy vs. 0.033 +/- 0.003 degrees C/min Sal; P < 0.02), lower
      heat storage (285 +/- 37 cal Phy vs. 436 +/- 34 cal Sal; P < 0.02) and lower core
      temperature at fatigue point than the Sal-treated group (38.5 +/- 0.1 degrees C
      Phy vs. 39.0 +/- 0.1 degrees C Sal; P < 0.05). However, despite the lower core
      heating rate, heat storage, and core temperature at fatigue, the Phy-treated rats
      showed a similar running time compared with the Sal-treated group. We conclude
      that the activation of the central cholinergic system during exercise increases
      heat dissipation and attenuates the exercise-induced increase in core temperature
      without affecting running performance.

PMID- 15033961
TI  - Myogenin and oxidative enzyme gene expression levels are elevated in rat soleus
      muscles after endurance training.
AB  - The intent of this study was to determine whether endurance exercise training
      regulates increases in metabolic enzymes, which parallel modulations of myogenin
      and MyoD in skeletal muscle of rats. Adult Sprague-Dawley rats were endurance
      trained (TR) 5 days weekly for 8 wk on a motorized treadmill. They were killed 48
      h after their last bout of exercise. Sedentary control (Con) rats were killed at
      the same time as TR animals. Myogenin, MyoD, citrate synthase (CS), cytochrome-c
      oxidase (COX) subunits II and VI, lactate dehydrogenase (LDH), and myosin light
      chain mRNA contents were determined in soleus muscles by using RT-PCR. Myogenin
      mRNA content was also estimated by using dot-blot hybridization. Protein
      expression levels of myogenin and MyoD were measured by Western blots. CS
      enzymatic activity was also measured. RT-PCR measurements showed that the mRNA
      contents of myogenin, CS, COX II, COX VI, and LDH were 25, 20, 17, 16, and 18%
      greater, respectively, in TR animals compared with Con animals (P < 0.05). The
      ratio of myogenin to MyoD mRNA content estimated by RT-PCR in TR animals was 28%
      higher than that in Con animals (P < 0.05). Myosin light chain expression was
      similar in Con and TR muscles. Results from dot-blot hybridization to a riboprobe
      further confirmed the increase in myogenin mRNA level in TR group. Western blot
      analysis indicated a 24% greater level of myogenin protein in TR animals compared
      with Con animals (P < 0.01). The soleus muscles from TR animals had a 25% greater
      CS enzymatic activity than the Con animals (P < 0.01). Moreover, myogenin mRNA
      and protein contents were positively correlated to CS activity and mRNA contents
      of CS, COX II, and COX VI (P < 0.05). These data are consistent with the
      hypothesis that myogenin is in the pathway for exercise-induced changes in
      mitochondrial enzymes.

PMID- 15033964
TI  - Longitudinal changes in the kinetic response to heavy-intensity exercise in
      children.
AB  - The purpose of this study was to investigate longitudinal changes with age in the
      kinetic response to cycling at heavy-intensity exercise in boys and girls. Twenty
      two prepubertal children (13 male, 9 female) carried out a series of exercise
      tests on two test occasions with a 2-yr interval. On each test occasion, the
      subject completed multiple transitions from baseline to 40% of the difference
      between their previously determined V-slope and peak O(2) uptake (Vo(2)) for 9
      min on an electronically braked cycle ergometer. Each subject's breath-by-breath
      responses were interpolated to 1-s intervals, time aligned, and averaged. The
      data after phase 1 were fit with 1) a double exponential model and 2) a single
      exponential model within a fitting window that was previously identified to
      exclude the slow component. There were no significant differences in the
      parameters of the primary component between each model. Subsequent analysis was
      carried out using model 2. The Vo(2) slow component was computed as the
      difference between the amplitude of the primary component and the end-exercise
      Vo(2) and was expressed as the percent contribution to the total change in Vo(2).
      Over the 2-yr period, the primary time constant (boys 16.8 +/- 5.3 and 21.7 +/-
      5.3 s, girls 21.1 +/- 8.1 and 26.4 +/- 8.4 s, first and second occasion,
      respectively) and the relative amplitude of the slow component (boys 9.4 +/- 4.6
      and 13.8 +/- 5.3%, girls 10.3 +/- 2.4 and 15.5 +/- 2.8%, first and second
      occasion, respectively) significantly increased with no sex differences. The data
      demonstrate that children do display a slow-component response to exercise and
      are consistent with an age-dependent change in the muscles' potential for O(2)
      utilization.

PMID- 15033965
TI  - Unrestrained plethysmography is an unreliable measure of airway responsiveness in
      BALB/c and C57BL/6 mice.
AB  - There has been significant utilization of the technique described by Hamelmann et
      al. (Am J Respir Crit Care Med 156: 766-775, 1997) in which a parameter, enhanced
      pause (Penh), related to airways responsiveness is noninvasively measured by
      unrestrained plethysmography (UP). Investigating this technique, we sought to
      answer these questions: 1). How do changes in Penh compare with changes in
      traditional plethysmographic and lung mechanical parameters? 2). How do UP
      parameters perform in two different mouse strains? Awake immunized and control
      BALB/c (n = 16) and C57BL/6 (n = 14) mice were placed in the UP chamber and
      exposed to doses of aerosolized methacholine while the following parameters were
      measured at each concentration: inspiratory time (Ti), expiratory time (Te),
      total time (Ttot), Ti/Ttot, peak inspiratory pressure, peak expiratory pressure,
      Pause, Penh, tidal volume (Vt), Vt/Ti, Vt/Te, and Vt/Ttot. The next day, lung
      resistance (Rl) and compliance (Cl) were invasively measured in the same animals.
      For the BALB/c, the parameters with the highest magnitude of correlation
      coefficient vs. Rl are (in order) 1). Cl, 2). Pause and Penh, 3). parameters of
      breathing frequency (Te, Ttot, Ti), and 4). parameters related to Vt (inspiratory
      pressure, expiratory pressure). Flow parameters (Vt/Ttot, Vt/Te, Vt/Ti) and duty
      cycle parameters (Ti/Ttot) had insignificant correlations. This ordering is
      significantly different in C57BL/6 mice, in which the parameters with the largest
      correlations are 1). Cl, 2). parameters of breathing frequency, and 3). flow
      parameters. Pause, Penh, Vt, and duty cycle parameters had insignificant
      correlations. These data show that Penh is problematic in the sense that it is
      strain specific; it behaves very differently in BALB/c and C57BL/6 mice. We
      suggest that UP parameters largely originate as part of reflex control of
      breathing processes, rather than in the lung mechanics and conclude that it is
      inappropriate to use UP parameters in general, and Penh specifically, as
      substitute variables for invasive mechanical indexes such as Rl.

PMID- 15033966
TI  - 5-HT offsets homeostasis of synaptic transmission during short-term facilitation.
AB  - In this study, we approach the topic of vesicle recruitment and recycling by
      perturbing neurotransmission at the crayfish neuromuscular junction with altered
      electrical activity and the presence of the neuromodulator serotonin (5-HT).
      After induction of short-term facilitation (STF) with stimulus pulse trains (40
      Hz, 20 pulses), the amount of synaptic transmission can be maintained at a
      relatively constant level, producing a plateau in the amplitude of the excitatory
      postsynaptic potentials (EPSPs) throughout the remaining stimuli within a train
      of a few hundred milliseconds. With an increase in the frequency of the stimuli
      within a train (60 Hz, 20 pulses), an altered plateau of larger EPSP amplitudes
      occurs. This suggests that differential rates of vesicle recruitment can be
      rapidly reached and maintained. Exposure of nerve terminals to 5-HT further
      enhances the EPSP amplitudes to yet a higher plateau level. The effect of 5-HT is
      more pronounced for 40-Hz pulse trains than for 60-Hz trains. This suggests that
      5-HT can recruit vesicles into the readily releasable pool (RRP) and that the
      recruitment is limited at higher stimulation frequencies. The attainment of a
      larger amplitude in the plateaus of the EPSPs at 60 Hz compared with 40 Hz also
      suggests that the rapid induction of STF enhances the entry of vesicles into the
      RRP. By direct quantal counts, mean quantal content increases linearly during
      STF, and 5-HT offsets the linear release. We propose that 5-HT and electrically
      induced recruitment of vesicles from a reserve pool to the RRP may share similar
      recruitment mechanisms.

PMID- 15033967
TI  - The fa leptin receptor mutation and the heritability of respiratory frequency in
      a Brown Norway and Zucker intercross.
AB  - We sought to determine whether the fa (leptin receptor) mutation was a major
      determinant of the putative obesity effects on respiratory frequency in an
      intercross between the Brown Norway (low breathing frequency, nonobese strain)
      and the Zucker (moderately high breathing frequency, with the fa mutation)
      strains. The hypothesis was that rats bearing one (heterozygote) or two
      (homozygote) alleles of the Glu296Pro point mutation (fa) would have a uniformly
      high respiratory frequency in the second filial (F2) generation, compared with
      wild-type animals. In addition to breathing frequency, tidal volume and minute
      ventilation were assessed during baseline, acute hypoxic (10% O2-0% CO2-balance
      nitrogen), hypercapnic (93% O2-7% CO2), hyperoxic (100% O2-0% CO2), and combined
      (10% O2-3% CO2-balance nitrogen) challenges in fa homozygote (fa/fa; n = 24), fa
      heterozygote (fa/wt; n = 33), and wild-type (wt/wt; n = 19) animals. Phenotypes
      were adjusted with stepwise regression analyses for the effects of age, sex,
      length, and litter size. Broad-sense heritability was estimated by examining the
      variance of the traits in first filial and F2 generations. ANOVAs were used to
      determine the mode of inheritance of the fa allele in the F2 generation. As
      anticipated, weight demonstrated the greatest overall broad-sense heritability
      (77%) and was the result of the recessive mutation. Breathing parameters during
      the hypoxic, hypercapnic, and combined challenges demonstrated a wide range of
      heritability from 5 to 96%, with a very nonuniform proportion of heritability
      explained by the leptin receptor. At best, for frequency 4.5 min into the
      hypercapnic hypoxic challenge, approximately 20% of the total heritability
      (approximately 67%) could be attributed to an effect of the leptin receptor
      mutation. We conclude that, unlike its major effect on weight, the effect of the
      fa allele is not a major gene involved in the regulation of breathing frequency.

PMID- 15033969
TI  - Reproducible measurement of voluntary activation of human elbow flexors with
      motor cortical stimulation.
AB  - Voluntary activation of muscle is commonly quantified by comparison of the extra
      force added by motor nerve stimulation during a contraction [superimposed twitch
      (SIT)] with that produced at rest by the same stimulus (resting twitch). An
      inability to achieve 100% voluntary activation implies that failure to produce
      maximal force output from the muscle must have occurred at a site at or above the
      level of the motoneurons. We have used cortical stimulation to quantify voluntary
      activation. Here, incomplete activation implies a failure at or above the level
      of motor cortical output. With cortical stimulation, it is inappropriate to
      compare extra force evoked during a contraction with the twitch evoked in resting
      muscle because motor cortical and spinal cord excitability both increase with
      activity. However, an appropriate "resting twitch" can be estimated. We
      previously estimated its amplitude by extrapolation of the linear relation
      between SIT amplitude and voluntary torque calculated from 35 contractions of
      >50% maximum (Todd G, Taylor JL, and Gandevia SC. J Physiol 551: 661-671, 2003).
      In this study, we improved the utility of this method to enable evaluation of
      voluntary activation when it may be changing over time, such as during the
      development of fatigue, or in patients who may be unable to perform large numbers
      of contractions. We have reduced the number of contractions required to only
      three. Estimation of the resting twitch from three contractions was reliable over
      time with low variability. Furthermore, its reliability and variability were
      similar to the resting twitch estimated from 30 contractions and to that evoked
      by conventional motor nerve stimulation.

PMID- 15033968
TI  - Chronic intermittent hypoxia and incremental cycling exercise independently
      depress muscle in vitro maximal Na+-K+-ATPase activity in well-trained athletes.
AB  - Athletes commonly attempt to enhance performance by training in normoxia but
      sleeping in hypoxia [live high and train low (LHTL)]. However, chronic hypoxia
      reduces muscle Na(+)-K(+)-ATPase content, whereas fatiguing contractions reduce
      Na(+)-K(+)-ATPase activity, which each may impair performance. We examined
      whether LHTL and intense exercise would decrease muscle Na(+)-K(+)-ATPase
      activity and whether these effects would be additive and sufficient to impair
      performance or plasma K(+) regulation. Thirteen subjects were randomly assigned
      to two fitness-matched groups, LHTL (n = 6) or control (Con, n = 7). LHTL slept
      at simulated moderate altitude (3,000 m, inspired O(2) fraction = 15.48%) for 23
      nights and lived and trained by day under normoxic conditions in Canberra
      (altitude approximately 600 m). Con lived, trained, and slept in normoxia. A
      standardized incremental exercise test was conducted before and after LHTL. A
      vastus lateralis muscle biopsy was taken at rest and after exercise, before and
      after LHTL or Con, and analyzed for maximal Na(+)-K(+)-ATPase activity [K(+)
      stimulated 3-O-methylfluorescein phosphatase (3-O-MFPase)] and Na(+)-K(+)-ATPase
      content ([(3)H]ouabain binding sites). 3-O-MFPase activity was decreased by -2.9
      +/- 2.6% in LHTL (P < 0.05) and was depressed immediately after exercise (P <
      0.05) similarly in Con and LHTL (-13.0 +/- 3.2 and -11.8 +/- 1.5%, respectively).
      Plasma K(+) concentration during exercise was unchanged by LHTL; [(3)H]ouabain
      binding was unchanged with LHTL or exercise. Peak oxygen consumption was reduced
      in LHTL (P < 0.05) but not in Con, whereas exercise work was unchanged in either
      group. Thus LHTL had a minor effect on, and incremental exercise reduced, Na(+)
      K(+)-ATPase activity. However, the small LHTL-induced depression of 3-O-MFPase
      activity was insufficient to adversely affect either K(+) regulation or total
      work performed.

PMID- 15033970
TI  - Contraction-mediated mTOR, p70S6k, and ERK1/2 phosphorylation in aged skeletal
      muscle.
AB  - With age, skeletal muscle experiences substantial atrophy and weakness. Although
      resistance training can increase muscle size and strength, the myogenic response
      to exercise and the capacity for muscle hypertrophy in older humans and animals
      is limited. In the present study, we assessed the ability of muscle contractile
      activity to activate cellular pathways involved in muscle cell growth and
      myogenesis in adult (Y; 6 mo old) and aged (O; 30 mo old) Fischer 344 x Brown
      Norway rats. A single bout of rat hindlimb muscle contractile activity was
      elicited by high-frequency electrical stimulation (HFES) of the sciatic nerve.
      Plantaris (Pla) and tibialis anterior (TA) muscles were assayed for mammalian
      target of rapamycin (mTOR), 70-kDa ribosomal protein S6 kinase (p70(S6K)), and
      extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and total protein
      either at baseline, immediately after, or 6 h after HFES. mTOR phosphorylation
      was elevated in Pla (1.3 +/- 0.3-fold, P < 0.05) immediately after HFES and to a
      lesser extent 6 h after HFES (0.6 +/- 0.1-fold, P < 0.05) in O rats. Post-HFES,
      p70(S6K) phosphorylation increased 1.2 +/- 0.3-fold in TA (P < 0.05) and remained
      elevated 6 h later (0.6 +/- 0.2-fold, P < 0.05) in O rats. ERK phosphorylation
      was lower in O rats immediately after exercise in both TA (11.1 +/- 2.9 vs. 2.1
      +/- 0.5-fold, P < 0.05) and Pla (6.5 +/- 1.5 vs. 1.8 +/- 0.5-fold, P < 0.05) and
      returned to baseline by 6 h in both Y and O rats. Phosphorylation of mTOR,
      p70(S6K), and ERK1/2 are increased in skeletal muscle after a single bout of in
      situ muscle contractile activity in aged animals, and the response is less than
      that observed in adult animals. These observations suggest that the anabolic
      response to a single bout of contraction is attenuated with aging and may help
      explain the reduced capacity for hypertrophy in aged animals.

PMID- 15033971
TI  - Ca(2+)-induced recruitment of the secretory vesicle protein DOC2B to the target
      membrane.
AB  - Ca(2+)-dependent fusion of transport vesicles at their target can be enhanced by
      intracellular Ca2+ and diacylglycerol. Diacylglycerol induces translocation of
      the vesicle priming factor Munc13 and association of the secretory vesicle
      protein DOC2B to the membrane. Here we demonstrate that a rise in intracellular
      Ca2+ is sufficient for a Munc13-independent recruitment of DOC2B to the target
      membrane. This novel mechanism occurred readily in the absence of Munc13 and was
      not influenced by DOC2B mutations that abolish Munc13 binding. Purified DOC2B
      (expressed as a bacterial fusion protein) bound phospholipids in a Ca(2+)
      dependent way, suggesting that the translocation is the result of a C2 domain
      activation mechanism. Ca(2+)-induced translocation was also observed in cultured
      neurons expressing DOC2B-enhanced green fluorescent protein. In this case,
      however, various degrees of membrane association occurred under resting
      conditions, suggesting that physiological Ca2+ concentrations modulate DOC2B
      localization. Depolarization of the neurons induced a complete translocation of
      DOC2B-enhanced green fluorescent protein to the target membrane within 5 s. We
      hypothesize that this novel Ca(2+)-induced activity of DOC2B functions
      synergistically with diacylglycerol-induced Munc13 binding to enhance exocytosis
      during episodes of high secretory activity.

PMID- 15033972
TI  - The protein translocon of the plastid envelopes.
AB  - The Toc and Tic translocon facilitate import of preproteins into chloroplasts. In
      the past, it was speculated that several translocon subunits act specifically for
      different types of precursor proteins or in different tissues. To generate a
      comprehensive picture of the expression and tissue-specific localization of the
      translocon subunits, their transcript levels were analyzed in roots and leaves.
      Certain Tocs and Tics were found to be tissue-specific. The protein composition
      of the transloci in the envelope membranes of chloroplasts was analyzed to
      describe the function and possible stoichiometry. In contrast to Tic subunits,
      several Toc subunits seem to have a high turnover.

PMID- 15033973
TI  - Essential role of the NH2-terminal WD/EPF motif in the phosphorylation-activated
      protective function of mammalian Hsp27.
AB  - Hsp27 is expressed at high levels after mild heat shock and contributes to making
      cells extremely resistant to subsequent treatments. The activity of the protein
      is regulated at the transcriptional level, but also by phosphorylation, which
      occurs rapidly during stress and is responsible for causing the dissociation of
      large 700-kDa Hsp27 oligomers into dimers. We investigated the mechanism by which
      phosphorylation and oligomerization modulate the protective activity of Chinese
      hamster Hsp27. In contrast to oligomer dissociation, which only required Ser90
      phosphorylation, activation of Hsp27 thermoprotective activity required the
      phosphorylation of both Ser90 and Ser15. Replacement of Ser90 by Ala90, which
      prevented the dissociation of the oligomer upon stress, did cause a severe defect
      in the protective activity. Dissociation was, however, not a sufficient condition
      to activate the protein because replacement of Ser15 by Ala15, which caused
      little effect in the oligomeric organization of the protein, also yielded an
      inactive protein. Analyzes of mutants with short deletions in the NH2 terminus
      identified the Hsp27 WD/EPF or PF-rich domain as essential for protection,
      maintenance of the oligomeric structure, and in vitro chaperone activity of the
      protein. In light of a three-dimensional model of Hsp27 based on the
      crystallographic structure of wheat Hsp16.9, we propose that the conserved WD/EPF
      motif of mammalian Hsp27 mediates important intramolecular interactions with
      hydrophic surfaces of the alpha-crystallin domain of the protein. These
      interactions are destabilized by Ser90 phosphorylation, making the motif free to
      interact with heterologous molecular targets upon the additional phosphorylation
      of the nearby Ser15.

PMID- 15033974
TI  - Regulation of photosynthetic light harvesting involves intrathylakoid lumen pH
      sensing by the PsbS protein.
AB  - The biochemical, biophysical, and physiological properties of the PsbS protein
      were studied in relation to mutations of two symmetry-related, lumen-exposed
      glutamate residues, Glu-122 and Glu-226. These two glutamates are targets for
      protonation during lumen acidification in excess light. Mutation of PsbS did not
      affect xanthophyll cycle pigment conversion or pool size. Plants containing PsbS
      mutations of both glutamates did not have any rapidly inducible nonphotochemical
      quenching (qE) and had similar chlorophyll fluorescence lifetime components as
      npq4-1, a psbS deletion mutant. The double mutant also lacked a characteristic
      leaf absorbance change at 535 nm (DeltaA535), and PsbS from these plants did not
      bind dicyclohexylcarbodiimide (DCCD), a known inhibitor of qE. Mutation of only
      one of the glutamates had intermediate effects on qE, chlorophyll fluorescence
      lifetime component amplitudes, DCCD binding, and DeltaA535. Little if any
      differences were observed comparing the two single mutants, suggesting that the
      glutamates are chemically and functionally equivalent. Based on these results a
      bifacial model for the functional interaction of PsbS with photosystem II is
      proposed. Furthermore, based on the extent of qE inhibition in the mutants,
      photochemical and nonphotochemical quenching processes of photosystem II were
      associated with distinct chlorophyll fluorescence life-time distribution
      components.

PMID- 15033975
TI  - Peroxisome proliferator-activated receptor beta (delta)-dependent regulation of
      ubiquitin C expression contributes to attenuation of skin carcinogenesis.
AB  - The role of peroxisome proliferator-activated receptor-beta (PPARbeta) in the
      molecular regulation of skin carcinogenesis was examined. Increased caspase-3
      activity associated with apoptosis was found in the skin of wild-type mice after
      tumor promotion with 12-O-tetradecanoylphorbol-13-acetate, and this effect was
      diminished in PPARbeta-null mice. The onset of tumor formation, tumor size, and
      tumor multiplicity induced from a two-stage carcinogen bioassay (7,12
      dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate) were
      significantly enhanced in PPARbeta-null mice compared with wild-type mice. To
      begin to characterize the molecular changes underlying this PPARbeta-dependent
      phenotype, microarray analysis was performed and a number of differentially
      regulated gene products were identified including ubiquitin C. Subsequent
      promoter analysis, reporter gene assays, site-directed mutagenesis, and
      electrophoretic mobility shift assays provide evidence that PPARbeta regulates
      ubiquitin C expression, and that ubiquitination of proteins is influenced by
      PPARbeta. These results strongly suggest that activation of PPARbeta-dependent
      target genes provides a novel strategy to inhibit tumor promotion and
      carcinogenesis.

PMID- 15033977
TI  - Spontaneous formation of a proteolytic B1 and B2 bradykinin receptor complex with
      enhanced signaling capacity.
AB  - B1 bradykinin receptor (B1R) induction is critical in the adaptation of the kinin
      mediated inflammatory response from a B2 bradykinin receptor (B2R) subtype to a
      B1R subtype that occurs during chronic insult. Here, we show that B1R
      spontaneously forms a proteolytic plasma membrane complex with B2R along with
      increased receptor signaling capacity. Co-expression of hemagglutinin-tagged B2R
      with FLAG-tagged B1R in HEK293 cells resulted in degradation of B2R as determined
      by the diminution of the intact 65-kDa B2R species and the appearance of
      proteolytic B2R products at 30-40 kDa and by the reduction in B2R bradykinin
      binding sites. On the other hand, the 35-kDa B1R remained intact. Receptor co
      expression also led to an increase in constitutive and agonist-stimulated
      receptor signaling. Selective immunoprecipitation with epitope-specific
      antibodies revealed a spontaneously formed heterologous receptor complex, which
      was composed of the intact 35-kDa B1R and the B2R degradation products. Cellular
      fractionation, cell surface biotinylation, and immunoelectron microscopy showed
      that B2R.B1R complexes were present on the cell surface. This is the first
      evidence that a heterologous G protein-coupled receptor complex in the plasma
      membrane is linked to proteolytic degradation of a participating receptor, and
      this mechanism may contribute to the adaptation of the kinin response from a B2
      type to a B1 type during chronic insult.

PMID- 15033978
TI  - Transthyretin, a new cryptic protease.
AB  - Transthyretin (TTR) is a plasma homotetrameric protein that acts physiologically
      as a transporter of thyroxine (T(4)) and retinol, in the latter case through
      binding to retinol-binding protein (RBP). A fraction of plasma TTR is carried in
      high density lipoproteins by binding to apolipoprotein AI (apoA-I). We further
      investigated the nature of the TTR-apoA-I interaction and found that TTR from
      different sources (recombinant and plasmatic) is able to process proteolytically
      apoA-I, cleaving its C terminus after Phe-225. TTR-mediated proteolysis was
      inhibited by serine protease inhibitors (phenylmethanesulfonyl fluoride,
      Pefabloc, diisopropyl fluorophosphate, chymostatin, and N(alpha)-p-tosyl-l
      phenylala-nine-chloromethyl ketone), suggesting a chymotrypsin-like activity. A
      fluorogenic substrate corresponding to an apoA-I fragment encompassing amino acid
      residues 223-228 (Abz-ESFKVS-EDDnp) was used to characterize the catalytic
      activity of TTR, including optimum reaction conditions (37 degrees C and pH 6.8)
      and catalytic constant (K(m) = 29 microm); when complexed with RBP, TTR activity
      was lost, whereas when complexed with T(4), only a slight decrease was observed.
      Cell lines expressing TTR were able to degrade Abz-ESFKVS-EDDnp 2-fold more
      efficiently than control cells lacking TTR expression; this effect was reversed
      by the presence of RBP in cell culture media, therefore proving a TTR-specific
      proteolytic activity. TTR can act as a novel plasma cryptic protease and might
      have a new, potentially important role under physiological and/or pathological
      conditions.

PMID- 15033976
TI  - Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor.
AB  - ALS2 is the gene mutated in a recessive juvenile form of amyotrophic lateral
      sclerosis (ALS2). ALS2 encodes a large protein termed alsin, which contains a
      number of predicted cell signaling and protein trafficking sequence motifs. To
      gain insight into the overall function of alsin and to begin to evaluate its role
      in motor neuron maintenance, we examined the subcellular localization of alsin
      and the biochemical activities associated with its individual subdomains. We
      found that the Vps9p domain of alsin has Rab5 guanine nucleotide exchange
      activity. In addition, alsin interacted specifically with and acted as a guanine
      nucleotide exchange factor for Rac1. Immunofluorescence and fractionation
      experiments in both fibroblasts and neurons revealed that alsin is a cytosolic
      protein, with a significant portion associated with small, punctate membrane
      structures. Many of these membrane structures also contained Rab5 or Rac1. Upon
      overexpression of full-length alsin, the overexpressed material was largely
      cytosolic, indicating that the association with membrane structures could be
      saturated. We also found that alsin was present in membrane ruffles and
      lamellipodia. These data suggest that alsin is involved in membrane transport
      events, potentially linking endocytic processes and actin cytoskeleton
      remodeling.

PMID- 15033979
TI  - Targeting of inositol 1,4,5-trisphosphate receptors to the endoplasmic reticulum
      by multiple signals within their transmembrane domains.
AB  - Most inositol 1,4,5-trisphosphate receptors (IP3R) are expressed in the
      endoplasmic reticulum (ER), where their precise distribution underlies the
      spatially complex Ca2+ signals evoked by extracellular stimuli. The signals that
      target IP3R to the ER or, less commonly, to other membranes are unknown. We
      expressed yellow fluorescent protein-tagged fragments of type 1 IP3R alone or
      fused with a plasma membrane protein to establish the determinants of ER
      targeting in COS-7 cells. By using a combination of confocal imaging and
      glycoprotein analyses, we demonstrated that any pair of the six transmembrane
      domains (TMD) linked by a luminal loop retains the protein within the ER, and
      when attached to a plasma membrane protein (ICAM-1), prevents it from reaching
      the medial Golgi. TMD1 or TMD2 alone were accumulated in mitochondria, whereas
      TMD5 and TMD6 were retained in ER, but were unable to prevent ICAM from reaching
      the plasma membrane. We conclude that IP3R are targeted to the ER membrane only
      after synthesis of TMDs 1 and 2, and that after co-translational insertion of the
      remaining TMDs, redundant retention signals present in any pair of TMD retain
      IP3R in the ER.

PMID- 15033980
TI  - Functional differentiation in the mammalian metallothionein gene family: metal
      binding features of mouse MT4 and comparison with its paralog MT1.
AB  - This paper reports on the characterization of the metal binding abilities of
      mammalian MT4 and their comparison with those of the well known MT1. Heterologous
      Escherichia coli expression in cultures supplemented with zinc, cadmium, or
      copper was achieved for MT4 and for its separate alphaMT4 and betaMT4 domains as
      well as for MT1 and its alphaMT1 domain in cadmium-enriched medium. The in vivo
      conformed metal complexes and the in vitro substituted zinc/cadmium and
      zinc/copper MT4 aggregates were characterized. Biosynthesis of MT4 and betaMT4 in
      Cd(II)-supplemented medium revealed that these peptides failed to form the same
      homometallic species as MT1, thus appearing less effective for cadmium
      coordination. Conversely, the entire MT4 and both of its domains showed better
      Cu(I) binding properties than MT1, affording Cu(10)-MT4, Cu(5)-alphaMT4 and Cu(7)
      betaMT4, stoichiometries that make the domain dependence toward Cu(I) clear.
      Overall results allow consideration of MT4 as a novel copper-thionein, made up of
      two copper-thionein domains, the first of this class reported in mammals, and by
      extension in vertebrates. Furthermore, the in silico protein sequence analyses
      corroborated the copper-thionein nature of the MT4 peptides. As a consequence,
      there is the suggestion of a possible physiological role played by MT4 related
      with copper requirements in epithelial differentiating tissues, where MT4 is
      expressed.

PMID- 15033981
TI  - Two sensor kinases contribute to the hypoxic response of Mycobacterium
      tuberculosis.
AB  - Current estimates indicate that nearly a third of the world's population is
      latently infected with Mycobacterium tuberculosis. Reduced oxygen tension and
      nitric oxide exposure are two conditions encountered by bacilli in vivo that may
      promote latency. In vitro exposure to hypoxia or nitric oxide results in
      bacterial stasis with concomitant induction of a 47-gene regulon controlled by
      the transcription factor DosR. In this report we demonstrate that both the dosS
      gene adjacent to dosR and another gene, dosT (Rv2027c), encode sensor kinases,
      each of which can autophosphorylate at a conserved histidine and then transfer
      phosphate to an aspartate residue of DosR. Mutant bacteria lacking both sensors
      are unable to activate expression of DosR-regulated genes. These data indicate
      that DosR/DosS/DosT comprise a two-component signaling system that is required
      for the M. tuberculosis genetic response to hypoxia and nitric oxide, two
      conditions that produce reversible growth arrest in vitro and may contribute to
      latency in vivo.

PMID- 15033982
TI  - Casein kinase II-mediated phosphorylation of NF-kappaB p65 subunit enhances
      inducible nitric-oxide synthase gene transcription in vivo.
AB  - Nitric oxide (NO) produced by inducible nitric-oxide synthase (NOSII) is mainly
      regulated at the transcriptional level by the nuclear factor-kappaB (NF-kappaB).
      In the present study, we further analyzed the role of NF-kappaB in the in vivo
      transcriptional regulation of NOSII gene by comparing two clones isolated from
      the EMT-6 mouse mammary cancer cell line. In response to interleukin (IL)-1beta
      or lipopolysaccharide (LPS), EMT-6 clone J (EMT-6J) cells produce 3-fold more NO
      than EMT-6 clone H (EMT-6H) cells, an effect correlated with enhanced activation
      of NF-kappaB in EMT-6J cells. In response to IL-1beta, the kinetics of
      degradation of NF-kappaB inhibitors IkappaB-alpha and IkappaB-beta, the nucleo
      cytoplasmic shuttling of the transcription factor and its binding to a specific
      DNA sequence were similar in both clones. In contrast, an IL-1beta-induced
      phosphorylation of serine residues in NF-kappaB p65 subunit was observed in EMT
      6J, but not in EMT-6H, cells. This IL-1beta-induced phosphorylation of p65 was
      specifically prevented by pretreatment of EMT-6J cells with the casein kinase II
      inhibitor DRB. Small interfering RNA-mediated depletion of casein kinase II-alpha
      subunit also decreased NF-kappaB transcriptional activity and NOSII gene
      transcription in IL-1beta and LPS-stimulated EMT-6J cells to the levels observed
      in EMT-6H cells treated in the same conditions. Altogether, these data indicate
      that casein kinase II-mediated phosphorylation of p65 subunit can enhance the
      transcriptional activity of NF-kappaB in vivo. This post-translational
      modification of the transcription factor can be responsible for increased NOSII
      gene transcription and NO production in tumor cells exposed to either IL-1beta or
      LPS.

PMID- 15033983
TI  - ERK7 expression and kinase activity is regulated by the ubiquitin-proteosome
      pathway.
AB  - ERK7 is a unique member of the extracellular signal-regulated kinase (ERK)
      subfamily of MAP kinases. Although ERK7 shares a TEY motif in the activation loop
      of the kinase, it displays constitutive activation, nuclear localization, and
      growth inhibitory properties that are regulated by its C-terminal domain. Because
      ERK7 is expressed at low levels compared with ERK2 and its activity is dependent
      upon its expression level, we investigated the mechanism by which ERK7 expression
      is regulated. We now show that ERK7 expression is regulated by ubiquitination and
      rapid proteosomal turnover. Furthermore, both the kinase domain and the C
      terminal tail are independently degraded at a rate comparable with that of the
      intact protein. Analysis of a series of chimeras between ERK2 and ERK7 reveal
      that the N-terminal 20 amino acids of the kinase domain are a primary determinant
      of ERK7 degradation. Fusion of the N-terminal 20 amino acids is both necessary
      and sufficient to cause proteolytic degradation of both ERK2 and green
      fluorescent protein. Finally, ERK7 is stabilized by an N-terminal mutant of
      Cullin-1 suggesting that ERK7 is ubiquitinated by the Skip1-Cullin-F box complex.
      These results indicate that ERK7 is a highly regulated enzyme whose cellular
      expression and kinase activation level is tightly controlled by the ubiquitin
      proteosome pathway.

PMID- 15033984
TI  - OMTK1, a novel MAPKKK, channels oxidative stress signaling through direct MAPK
      interaction.
AB  - In common with other eukaryotes, plants utilize mitogen-activated protein kinase
      (MAPK) cascades to mediate responses to a wide variety of stimuli. In contrast to
      other eukaryotes, plants have an unusually large number of MAPK components, such
      as more than 20 MAPKs, 10 MAPK kinases (MAPKKs), and 60 MAPKK kinases (MAPKKKs)
      in Arabidopsis (MAPK Group (2002) Trends Plant Sci. 7, 301-308). Presently it is
      mostly unknown how MAPK signaling specificity is generated in plants. Here we
      have isolated OMTK1 (oxidative stress-activated MAP triple-kinase 1), a novel
      MAPKKK from alfalfa (Medicago sativa). In plant protoplasts, OMTK1 showed basal
      kinase activity and was found to induce cell death. Among a panel of hormones and
      stresses tested, only H(2)O(2) was found to activate OMTK1. Out of four MAPKs,
      OMTK1 specifically activated MMK3 resulting in an increased cell death rate. Pull
      down analysis between recombinant proteins indicated that OMTK1 directly
      interacts with MMK3 and that OMTK1 and MMK3 are part of a protein complex in
      vivo. These results indicate that OMTK1 plays a MAPK scaffolding role and
      functions in activation of H(2)O(2) -induced cell death in plants.

PMID- 15033985
TI  - HIV-1 Nef enhances both membrane expression and virion incorporation of Env
      products. A model for the Nef-dependent increase of HIV-1 infectivity.
AB  - The expression of human immunodeficiency virus Nef increases the viral
      infectivity through mechanisms still not fully elucidated. Here we report that
      wild-type (wt) human immunodeficiency virus, type 1 (HIV-1), particles were
      neutralized by higher concentrations of either anti-Env glycoprotein (gp) 41
      antibodies or recombinant soluble human CD4 compared with Deltanef HIV-1. This
      appeared to be the result of a Nef-induced increase of virion incorporation of
      both gp41 (transmembrane (TM)) and surface gp120 Env products likely originating
      from enhanced steady-state levels of cell membrane-associated Env products. This,
      in turn, seemed to be the consequence of a reduced retention of the Env
      precursor. Most interesting, we found that both the Nef-directed increase of Env
      membrane expression and the Nef-induced enhancement of HIV-1 infectivity relied
      on the presence of the intracytoplasmic domain of TM, supporting the hypothesis
      of a functional correlation between these effects. Mutagenesis studies allowed us
      to establish that the two leucine residues at the TM C terminus, which are part
      of a sorting motif involved in the control of Env membrane expression, and the
      181-210-residue Nef C-terminal region were critically involved in the Nef/Env
      functional interaction. In conclusion, we propose that Nef increases the
      infectivity of HIV-1 at least in part by enhancing the amounts of Env products
      incorporated into virus particles.

PMID- 15033986
TI  - AHNAK-mediated activation of phospholipase C-gamma1 through protein kinase C.
AB  - We have recently shown that phospholipase C-gamma (PLC-gamma) is activated by the
      central repeated units (CRUs) of the AHNAK protein in the presence of arachidonic
      acid. Here we demonstrate that four central repeated units (4 CRUs) of AHNAK act
      as a scaffolding motif networking PLC-gamma and PKC-alpha. Specifically, 4 CRUs
      of AHNAK bind and activate PKC-alpha, which in turn stimulates the release of
      arachidonic acid near where PLC-gamma1 is localized. Moreover, 4 CRUs of AHNAK
      interacted with PLC-gamma and the concerted action of 4 CRUs with arachidonic
      acid stimulated PLC-gamma activity. Stimulation of NIH3T3 cells expressing 4 CRUs
      of AHNAK with phorbol 12-myristate 13-acetate resulted in the increased
      generation of total inositol phosphates (IP(T)) and mobilization of the
      intracellular calcium. Phorbol 12-myristate 13-acetate-dependent generation of
      IP(T) was completely blocked in NIH3T3 cells depleted of PLC-gamma1 by RNA
      interference. Furthermore, bradykinin, which normally stimulated the PLC-beta
      isozyme resulting in the generation of a monophasic IP(T) within 30 s in NIH3T3
      cells, led to a biphasic pattern for generation of IP(T) in NIH3T3 cells
      expressing 4 CRUs of AHNAK. The secondary activation of PLC is likely because of
      the scaffolding activity of AHNAK, which is consistent with the role of 4 CRUs as
      a molecular linker between PLC-gamma and PKC-alpha.

PMID- 15033987
TI  - N-terminal region of FKBP12 is essential for binding to the skeletal ryanodine
      receptor.
AB  - It is known that the two types of FK506-binding proteins FKBP12 and FKBP12.6 are
      tightly associated with the skeletal (RyR1) and cardiac ryanodine receptors
      (RyR2), respectively, and their interactions are important for channel functions
      of the RyR. In the case of cardiac muscle, three amino acid residues (Gln-31, Asn
      32, and Phe-59) of FKBP12.6 could be essential for the selective binding to RyR2
      (Xin, H. B., Rogers, K., Qi, Y., Kanematsu, T., and Fleischer, S. (1999) J. Biol.
      Chem. 274, 15315-15319). In this study to identify amino acid residues of FKBP12
      that are important for the selective binding to RyR1, we mutated 9 amino acid
      residues of FKBP12 that differ from the counterparts of FKBP12.6 (Q3E, R18A,
      E31Q, D32N, M49R, R57A, W59F, H94A, and K105A), and we examined binding
      properties of these mutants to RyR1 by in vitro binding assay by using
      glutathione S-transferase-fused proteins of the mutants and Triton X-100
      solubilized, FKBP12-depleted rabbit skeletal sarcoplasmic reticulum vesicles.
      Among the nine mutants tested, only Q3E and R18A lost their selective binding
      ability to RyR1. Furthermore, co-immunoprecipitation of RyR1 with 33 various
      mutants for the 9 positions produced by introducing different size, charge, and
      hydrophobicity revealed that an integration of the hydrogen bonds by the
      irreplaceable Gln-3 and the hydrophobic interactions by the residues Arg-18 and
      Met-49 could be a possible mechanism for the binding of FKBP12 to RyR1.
      Therefore, these results suggest that the N-terminal regions of FKBP12 (Gln-3 and
      Arg-18) and Met-49 are essential and unique for binding of FKBP12 to RyR1 in
      skeletal muscle.

PMID- 15033988
TI  - Modification of the mitochondrial proteome in response to the stress of ethanol
      dependent hepatotoxicity.
AB  - Mitochondria are particularly susceptible to increased formation of reactive
      oxygen and nitrogen species in the cell that can occur in response to
      pathological and xenobiotic stimuli. Proteomics can give insights into both
      mechanism of pathology and adaptation to stress. Herein we report the use of
      proteomics to evaluate alterations in the levels of mitochondrial proteins
      following chronic ethanol exposure in an animal model. Forty-three proteins
      showed differential expression, 13 increased and 30 decreased, as a consequence
      of chronic ethanol. Of these proteins, 25 were not previously known to be
      affected by chronic ethanol emphasizing the power of proteomic approaches in
      revealing global responses to stress. Both nuclear and mitochondrially encoded
      gene products of the oxidative phosphorylation complexes in mitochondria from
      ethanol-fed rats were decreased suggesting an assembly defect in this integrated
      metabolic pathway. Moreover mtDNA damage was increased by ethanol demonstrating
      that the effects of ethanol consumption extend beyond the proteome to encompass
      mtDNA. Taken together, we have demonstrated that chronic ethanol consumption
      extends to a modification of the mitochondrial proteome far broader than realized
      previously. These data also suggest that the response of mitochondria to stress
      may not involve non-discriminate changes in the proteome but is restricted to
      those metabolic pathways that have a direct role in a specific pathology.

PMID- 15033989
TI  - Thrombospondin-1-induced focal adhesion disassembly in fibroblasts requires Thy-1
      surface expression, lipid raft integrity, and Src activation.
AB  - The hep I peptide of thrombospondin-1 is known to induce the disassembly of focal
      adhesions, a critical step in regulating cellular adhesive changes needed for
      cell motility. Fibroblasts that are heterogeneous with respect to the surface
      expression of Thy-1 differ markedly in morphology, cytoskeletal organization, and
      migration, suggesting differential regulation of focal adhesion dynamics. Here we
      demonstrate that disassembly of focal adhesions mediated by both full-length
      thrombospondin-1 and the hep I peptide in fibroblasts requires the expression of
      Thy-1, although it does not appear to function as a stable member of the hep I
      receptor complex. Consistent with a known function of Thy-1 in regulating lipid
      raft-associated signaling, intact lipid rafts are necessary for hep I-mediated
      focal adhesion disassembly. Furthermore, we establish Src family kinase (SFK)
      activation as a novel component required for hep I-induced signaling leading to
      focal adhesion disassembly. hep I induces transient phosphorylation of SFKs in
      Thy-1-expressing fibroblasts only. Therefore, we conclude that Thy-1 surface
      expression is required for thrombospondin-1-induced focal adhesion disassembly in
      fibroblasts through an SFK-dependent mechanism. This represents a novel role for
      Thy-1 in the regulation of fibroblast-matrix interactions critical to tissue
      homeostasis and remodeling.

PMID- 15033990
TI  - Co-assembly of envoplakin and periplakin into oligomers and Ca(2+)-dependent
      vesicle binding: implications for cornified cell envelope formation in stratified
      squamous epithelia.
AB  - Plakin family members envoplakin and periplakin have been shown to be part of the
      cornified cell envelope in terminally differentiating stratified squamous
      epithelia. In the present study, purified recombinant human envoplakin and
      periplakin were used to investigate their properties and interactions. We found
      that envoplakin was insoluble at physiological conditions in vitro, and co
      assembly with periplakin was required for its solubility. Envoplakin and
      periplakin formed soluble complexes with equimolar stoichiometry. Chemical cross
      linking revealed that the major soluble form of all periplakin constructs and of
      envoplakin/periplakin rod domains was a dimer, although co-assembly of the full
      length proteins resulted in formation of higher order oligomers. Electron
      microscopy of rotary-shadowed periplakin demonstrated thin flexible molecules
      with an average contour length of 88 nm for the rod-plus-tail fragment, and
      immunolabeling EM confirmed the molecule as a parallel, in-register, dimer. Both
      periplakin and envoplakin/periplakin oligomers were able to bind synthetic lipid
      vesicles whose composition mimicked the cytoplasmic side of the plasma membrane
      of eukaryotic cells. This binding was dependent on anionic phospholipids and
      Ca(2+). These findings raise the possibility that envoplakin and periplakin bind
      to the plasma membrane upon elevation of intracellular [Ca(2+)] in
      differentiating keratinocytes, where they serve as a scaffold for cornified cell
      envelope assembly.

PMID- 15033991
TI  - Sequential extracellular matrix-focused and baited-global cluster analysis of
      serial transcriptomic profiles identifies candidate modulators of renal
      tubulointerstitial fibrosis in murine adriamycin-induced nephropathy.
AB  - Transcriptome analysis using microarray technology represents a powerful unbiased
      approach for delineating pathogenic mechanisms in disease. Here molecular
      mechanisms of renal tubulointerstitial fibrosis (TIF) were probed by monitoring
      changes in the renal transcriptome in a glomerular disease-dependent model of TIF
      (adriamycin nephropathy) using Affymetrix (mu74av2) microarray coupled with
      sequential primary biological function-focused and secondary "baited"-global
      cluster analysis of gene expression profiles. Primary cluster analysis focused on
      mRNAs encoding matrix proteins and modulators of matrix turnover as classified by
      Onto-Compare and Gene Ontology and identified both molecules and pathways already
      implicated in the pathogenesis of TIF (e.g. transforming growth factor beta1-CTGF
      fibronectin-1 pathway) and novel TIF-associated genes (e.g. SPARC and Matrilin
      2). Specific gene expression patterns identified by primary extracellular matrix
      focused cluster analysis were then used as bioinformatic bait in secondary global
      clustering, with which to search the renal transcriptome for novel modulators of
      TIF. Among the genes clustering with ECM proteins in the latter analysis were
      endoglin, clusterin, and gelsolin. In several notable cases (e.g. claudin-1 and
      meprin-1beta) the pattern of gene expression identified in adriamycin nephropathy
      in vivo was replicated during transdifferentiation of renal tubule epithelial
      cells to a fibroblast-like phenotype in vitro on exposure to transforming growth
      factor-beta and epidermal growth factor suggesting a role in fibrogenesis. The
      further exploration of these complex gene networks should shed light on the core
      molecular pathways that underpin TIF in renal disease.

PMID- 15033993
TI  - Protonation state of a single histidine residue contributes significantly to the
      kinetics of the reaction of plasminogen activator inhibitor-1 with tissue-type
      plasminogen activator.
AB  - Stopped-flow fluorometry was used to study the kinetics of the reactive center
      loop insertion occurring during the reaction of N-((2-(iodoacetoxy)ethyl)-N
      methyl)amino-7-nitrobenz-2-oxa-3-diazole (NBD) P9 plasminogen activator inhibitor
      1 (PAI-1) with tissue-(tPA) and urokinase (uPA)-type plasminogen activators and
      human pancreatic elastase at pH 5.5-8.5. The limiting rate constants of reactive
      center loop insertion (k(lim)) and concentrations of proteinase at half
      saturation (K(0.5)) for tPA and uPA and the specificity constants (k(lim)/K(0.5))
      for elastase were determined. The pH dependences of k(lim)/K(0.5) reflected
      inactivation of each enzyme due to protonation of His57 of the catalytic triad.
      However, the specificity of the inhibitory reaction with tPA and uPA was notably
      higher than that for the substrate reaction catalyzed by elastase. pH dependences
      of k(lim) and K(0.5) obtained for tPA revealed an additional ionizable group
      (pKa, 6.0-6.2) affecting the reaction. Protonation of this group resulted in a
      significant increase in both k(lim) and K(0.5) and a 4.6-fold decrease in the
      specificity of the reaction of tPA with NBD P9 PAI-1. Binding of monoclonal
      antibody MA-55F4C12 to PAI-1 induced a decrease in k(lim) and K(0.5) at any pH
      but did not affect either the pKa of the group or an observed decrease in
      k(lim)/K(0.5) due to protonation of the group. In contrast to tPA, the k(lim) and
      K(0.5) for the reactions of uPA with NBD P9 PAI-1 or its complex with the
      monoclonal antibody were independent of pH in the 6.5-8.5 range. Since slightly
      acidic pH is a feature of a number of malignant tumors, alterations in PAI-1/tPA
      kinetics could play a role in the cancerogenesis. Changes in the protonation
      state of His(188), which is placed closely to the S1 site and is unique for tPA,
      has been proposed to contribute to the observed pH dependences of k(lim) and
      K(0.5).

PMID- 15033992
TI  - Identification of the glycosaminoglycan binding site of the CC chemokine, MCP-1:
      implications for structure and function in vivo.
AB  - In a recent study, we demonstrated that glycosaminoglycan (GAG) binding and
      oligomerization are essential for the in vivo function of the chemokines MCP
      1/CCL2, RANTES/CCL5, and MIP-1beta/CCL4 (1). Binding to the GAG chains of cell
      surface proteoglycans is thought to facilitate the formation of high localized
      concentrations of chemokines, which in turn provide directional signals for
      leukocyte migration. To understand the molecular details of the chemokine-GAG
      interaction, in the present study we identified the GAG binding epitopes of MCP
      1/CCL2 by characterizing a panel of surface alanine mutants in a series of
      heparin-binding assays. Using sedimentation equilibrium and cross-linking
      methods, we also observed that addition of heparin octasaccharide induces
      tetramer formation of MCP-1/CCL2. Although MCP-1/CCL2 forms a dimer in solution,
      both a dimer and tetramer have been observed by x-ray crystallography, providing
      a glimpse of the putative heparin-bound state. When the GAG binding residues are
      mapped onto the surface of the tetramer, the pattern that emerges is a continuous
      ring of basic residues encircling the tetramer, creating a positively charged
      surface well suited for binding GAGs. The structure also suggests several
      possible functional roles for GAG-induced oligomerization beyond retention of
      chemokines at the site of production.

PMID- 15033994
TI  - Immunohistochemical localization of peroxisomal enzymes during rat embryonic
      development.
AB  - Peroxisomes are cytoplasmic organelles involved in a variety of metabolic
      pathways. Thus far, the morphological and biochemical features of peroxisomes
      have been extensively characterized in adult tissues. However, the existence of
      congenital peroxisomal disorders, primarily affecting tissue differentiation,
      emphasizes the importance of these organelles in the early stages of
      organogenesis. We investigated the occurrence and tissue distribution of three
      peroxisomal enzymes in rat embryos at various developmental stages. By means of a
      highly sensitive biotinyl-tyramide protocol, catalase, acyl-CoA oxidase, and
      ketoacyl-CoA thiolase were detected in embryonic tissues where peroxisomes had
      not thus far been recognized, i.e., adrenal and pancreatic parenchyma, choroid
      plexus, neuroblasts of cranial and spinal ganglia and myenteric plexus, and
      chondroblasts of certain skeletal structures. In other tissues, i.e., gut
      epithelium and neuroblasts of some CNS areas, they were identified earlier than
      previously. In select CNS areas, ultrastructural catalase cytochemistry allowed
      identification of actively proliferating organelles at early developmental stages
      in several cell types. Our data show that in most organs maturation of
      peroxisomes parallels the acquirement of specific functions, mainly related to
      lipid metabolism, thus supporting an involvement of the organelles in tissue
      differentiation.

PMID- 15033995
TI  - Immunolocalization of enamelysin (matrix metalloproteinase-20) in the forming rat
      incisor.
AB  - In the rat model, we used the continuously growing incisor to study the
      expression pattern of matrix metalloproteinase-20 (MMP-20) during the formation
      of mineralized dental tissues. Casein zymography analysis of extracts of the
      forming part of the incisor revealed lysis bands corresponding to both the latent
      form at 57 kD and the active 46- and 41-kD forms, whereas omission of proteinase
      inhibitors during protein extraction resulted in a single band at 21 kD. A higher
      molecular weight form of 78 kD was also stained with MMP-20 and TIMP-2 antibodies
      in Western blotting, and was therefore believed to correspond to an MMP-20/TIMP-2
      complex. Immunohistochemical and immunogold electron microscopic results
      demonstrated strong MMP-20 staining in the forming outer enamel, which diminished
      near the dentino-enamel junction, but dentin and predentin were unstained. A
      strong concentration of MMP-20 was seen in the stratum intermedium (SI),
      particularly at the earlier stages of enamel development. Our results confirm the
      presence of MMP-20 protein in ameloblasts and odontoblasts of rat incisor and
      show it to be localized in the same sites of the forming enamel as amelogenin.
      Their expression is transient in odontoblasts but persists in ameloblasts, and in
      both cases the expression of amelogenin preceded that of MMP-20 suggesting a
      developmentally controlled regulation.

PMID- 15033996
TI  - Distribution of soluble epoxide hydrolase and of cytochrome P450 2C8, 2C9, and
      2J2 in human tissues.
AB  - Soluble epoxide hydrolase (sEH) hydrolyzes a wide variety of endogenous and
      exogenous epoxides. Many of these epoxides are believed to be formed by
      cytochrome P450 epoxygenases. Here we report the distribution of sEH and
      cytochrome P450 epoxygenases 2C8, 2C9, and 2J2 by immunohistochemistry. A large
      number of different tissues from different organs were evaluated using high
      throughput tissue microarrays. sEH was found in the liver, kidney, and in many
      other organs, including adrenals, pancreatic islets, pituitary gland, lymphoid
      tissues, muscles, certain vascular smooth muscles, and epithelial cells in the
      skin, prostatic ducts, and the gastrointestinal tract. Immunolabeling for sEH was
      highly specific for particular tissues and individual cell types. CYP2C9 was also
      found in almost all of these organs and tissues, suggesting that 2C9 and sEH are
      very similar in their tissue-specific patterns of expression. CYP2C8 and 2J2 were
      also widely distributed in human tissues but were less frequently associated with
      sEH. The results suggest potentially distinct pathways of endogenous fatty acid
      epoxide production and hydrolysis in a variety of human tissues.

PMID- 15033997
TI  - Experimental evidence for a direct cytotoxicity of Loxosceles intermedia (brown
      spider) venom in renal tissue.
AB  - Brown spider (Loxosceles genus) venom causes necrotic lesions often accompanied
      by fever, hemolysis, thrombocytopenia, and acute renal failure. Using mice
      exposed to Loxosceles intermedia venom, we aimed to show whether the venom
      directly induces renal damage. The experimental groups were composed of 50 mice
      as controls and 50 mice that received the venom. Light microscopic analysis of
      renal biopsy specimens showed alterations including hyalinization of proximal and
      distal tubules, erythrocytes in Bowman's space, glomerular collapse, tubule
      epithelial cell blebs and vacuoles, interstitial edema, and deposition of
      eosinophilic material in the tubule lumen. Electron microscopic findings
      indicated changes including glomerular epithelial and endothelial cell
      cytotoxicity as well as disorders of the basement membrane. Tubule alterations
      include epithelial cell cytotoxicity with cytoplasmic membrane blebs,
      mitochondrial changes, increase in smooth endoplasmic reticulum, presence of
      autophagosomes, and deposits of amorphous material in the tubules. We also found
      that the venom caused azotemia with elevation of blood urea levels but did not
      decrease C3 complement concentration or cause hemolysis in vivo. Confocal
      microscopy with antibodies against venom proteins showed direct binding of toxins
      to renal structures, confirmed by competition assays. Double-staining
      immunofluorescence reactions with antibodies against type IV collagen or laminin,
      antibodies to venom toxins, and fluorescent cytochemistry with DAPI revealed
      deposition of toxins in glomerular and tubule epithelial cells and in renal
      basement membranes. Two-dimensional electrophoresis showed venom rich in low
      molecular mass and cationic toxins. By immunoblotting with antibodies to venom
      toxins on renal extracts from venom-treated mice, we detected a renal binding
      toxin at 30 kD. The data provide experimental evidence that L. intermedia venom
      is directly involved in nephrotoxicity.

PMID- 15033998
TI  - Production of cell lines secreting TAT fusion proteins.
AB  - Transduction of proteins and other macromolecules constitutes a potent technology
      to analyze cell functions and to achieve therapeutic interventions. In general,
      fusion proteins with protein transduction domains, such as TAT, are produced in a
      bacterial expression system. Here we describe the generation of a mammalian
      expression vector coding for TAT-EGFP fusion protein. Transfection of CHO-K1
      cells by this vector and subsequent selection by Zeocin resulted in cell lines
      that express and secrete EGFP, a variant of the green fluorescent protein GFP.
      The ultimate cell line was produced by first cloning the stable integrants and
      subsequent selection of EGFP-expressing cells by flow cytometric sorting. In the
      resulting cell line approximately 98% of cells express EGFP. Using the same
      methodology, we generated cell lines that express DsRed fluorescent protein. The
      advantages of using such a mammalian expression system include the ease of
      generating TAT fusion proteins and the potential for sustained production of such
      proteins in vitro and, potentially, in vivo.

PMID- 15033999
TI  - Expression and localization of the transcription factor JunD in the duct system
      of mouse submandibular gland.
AB  - We studied the expression and localization of JunD, a component of the
      transcription factor activator protein-1 (AP-1), in the mouse submandibular gland
      with immunoblotting and immunohistochemistry. In adult mice, all seven Jun and
      Fos family members constituting the AP-1 complex were expressed more abundantly
      in the female gland than in the male gland, and JunD was the most abundant of the
      members. Immunoreactivity for JunD was localized exclusively in the duct system
      of the gland, in which it was localized to the nuclei of intercalated duct (ID)
      cells and a subpopulation of striated duct (SD) cells located adjacent to ID. In
      contrast, granular convoluted tubule (GCT) cells, which are much more abundant in
      the male gland, were devoid of JunD. During postnatal development of the male
      gland, JunD was lost from the duct cells as they differentiated to GCT cells at 3
      5 weeks postpartum. When GCT differentiation was induced in adult female gland by
      testosterone administration, many JunD-negative SD cells were temporarily induced
      to express JunD after 6-24 hr, but those cells lost JunD as they completely
      converted to GCT cells by 48 hr. These results suggested that JunD is involved in
      the differentiation of the duct system of mouse submandibular gland, in which
      there is crosstalk between the androgen/androgen receptor system and the AP-1
      complex.

PMID- 15034000
TI  - Cell type-specific expression of beta-carotene 15,15'-mono-oxygenase in human
      tissues.
AB  - We studied the cell type-specific expression of human beta-carotene 15,15'-mono
      oxygenase (BCO1), an enzyme that catalyzes the first step in the conversion of
      dietary provitamin A carotenoids to vitamin A. Immunohistochemical analysis using
      two monoclonal antibodies against different epitopes of the protein revealed that
      BCO1 is expressed in epithelial cells in a variety of human tissues, including
      mucosa and glandular cells of stomach, small intestine, and colon, parenchymal
      cells in liver, cells that make up the exocrine glands in pancreas, glandular
      cells in prostate, endometrium, and mammary tissue, kidney tubules, and in
      keratinocytes of the squamous epithelium of skin. Furthermore, BCO1 is detected
      in steroidogenic cells in testis, ovary, and adrenal gland, as well as skeletal
      muscle cells. Epithelia in general are structures that are very sensitive to
      vitamin A deficiency, and although the extraintestinal function of BCO1 is
      unclear, the finding that the enzyme is expressed in all epithelia examined thus
      far leads us to suggest that BCO1 may be important for local synthesis of vitamin
      A, constituting a back-up pathway of vitamin A synthesis during times of
      insufficient dietary intake of vitamin A.

PMID- 15034001
TI  - The use of TMA for interlaboratory validation of FISH testing for detection of
      HER2 gene amplification in breast cancer.
AB  - HER2 fluorescence in situ hybridization (FISH) testing for breast cancer is
      largely limited to academic centers and commercial laboratories. As testing
      demands increase, methods for rapid and cost-effective technical validation and
      quality assessment will be required. Tissue microarray (TMA), a technique for
      high-throughput biomarker evaluation, could help facilitate these needs. Our
      objective was to assess the usefulness of TMA technology for validation of HER2
      FISH testing. Two TMA blocks containing paired cores from 41 breast cancers were
      constructed. HER2 FISH was performed in parallel at two institutions and the
      results compared. One institution, with considerable HER2 FISH experience, served
      as the reference laboratory. HER2 chromogenic in situ hybridization (CISH) and
      immunohistochemistry (IHC) were compared to the FISH results. For positive and
      negative results, the concordance rate between laboratories was 100%. Using kappa
      statistical analysis to determine interobserver agreement, HER2 to chromosome 17
      gene copy ratios showed strong agreement between laboratories with kappa = 0.85
      (perfect agreement = 1.0). Four cases displaying low-level amplification by CISH
      contained chromosome 17 polysomy and gene copy ratios of <2.0 by FISH. Good
      concordance was observed between HER2 IHC and in situ hybridization testing. TMA
      is a robust and effective method for the technical validation of HER2 FISH
      testing and should be considered for use by quality assessment programs.

PMID- 15034002
TI  - Expression of notch receptors and ligands in the adult gut.
AB  - The Notch signaling pathway has become recognized as a vitally important pathway
      in regulating proliferative/differentiative decisions and cell fate. To explore
      the involvement of the Notch pathway in adult gut, we investigated the expression
      of Notch receptors and their ligands by Northern blotting and in situ
      hybridization. Notch receptors and ligands were expressed in both proliferative
      and post-mitotic cells throughout adult rat gut, variously in epithelial, immune,
      and endothelial cells. Expression of Notch1, Jagged1, and Jagged2 frequently
      overlapped, whereas Notch2 expression was restricted to specific crypt cells, the
      lamina propria of the large intestine, and Peyer's patch lymphocytes. We propose
      that the expression of multiple Notch receptors and ligands in a range of
      different intestinal cell types indicates that this signaling pathway underpins
      many of the processes involved in the maintenance and function of the adult gut.

PMID- 15034004
TI  - Histochemical and histofluorescence tracing of chelatable zinc in the developing
      mouse.
AB  - Zinc is an essential element in mammalian development. However, little is known
      about concentrations of zinc in specific regions/organs in the embryo. We have
      employed selenite autometallography (AMG) and TSQ histofluoroscence to detect
      histochemically reactive (chelatable) zinc in whole midsagittal embryos and
      sections from neonatal mice. Chelatable zinc exhibited a broad distribution,
      being particularly localized to rapidly proliferating tissues, such as skin and
      gastrointestinal epithelium. Zinc was also observed in various types of tissues
      such as bone and liver. In the perinatal central nervous system, zinc was present
      almost exclusively in choroid plexus. The two methods used demonstrated generally
      similar distributions with some exceptions, e.g., in liver and blood. The
      ubiquity of zinc in the embryo, particularly in rapidly proliferating tissues,
      suggests a widespread role in fetal physiology.

PMID- 15034003
TI  - Involvement of myosin II in dopamine-induced reorganization of the lactotroph
      cell's actin cytoskeleton.
AB  - We have shown that dopamine (DA), an inhibitor of prolactin secretion from
      anterior pituitary lactotrophs, stabilizes the cortical actin cytoskeleton. DA
      induced cortical actin stabilization is accompanied by cytoplasmic actin cable
      disassembly and cell rounding up. Our aim was to identify the mechanisms involved
      in DA-induced stabilization of the lactotroph's actin cytoskeleton. Here we show
      that DA increased the association of myosin II with the cell cortex, suggesting
      that DA facilitates actin-myosin interaction to stabilize cortical actin
      filaments. This notion was supported by the finding that inhibitors of actin
      myosin interaction blocked DA-evoked morphological responses. In addition, our
      results showed that DA-induced myosin association with the cell periphery may be
      mediated by inhibition of Rac1/Cdc42-dependent pathways, whereas, DA-induced
      cytoplasmic actin filament disassembly may be mediated by the inhibition of MLCK-
      and RhoA-dependent pathways. In conclusion, the present results provide evidence
      that myosin II is involved in the DA-induced remodeling of actin filaments in
      lactotrophs, and that DA-induced cortical actin filament assembly and
      stabilization involve the translocation of myosin II to the cell cortex. This
      effect requires, among other things, inhibition of the Rac1/Cdc42-dependent
      signaling pathway.

PMID- 15034005
TI  - Expression of the homeobox gene barx2 in the gut.
AB  - Barx2 is a member of the Bar class of homeobox genes and has been shown to
      regulate specific cell adhesion molecules, L1, Ng-CAM, N-CAM, and cadherin 6. By
      Northern blotting and in situ hybridization, we show that Barx2 is expressed
      throughout the gut and is located in epithelial cells of the proliferative and
      differentiative regions of the stomach, esophagus, and intestine. Barx2 was
      expressed in muscle cells of the muscularis externa and also showed a graded
      pattern of expression in intestinal enterocytes, decreasing in a crypt-to-villous
      direction. We speculate that Barx2 may regulate cell adhesion molecules in
      epithelial cells of the gut.

PMID- 15034006
TI  - Immunohistochemical and mRNA localization of the angiotensin II receptor subtype
      2 (AT2) in follicular granulosa cells of the rat ovary.
AB  - A local renin-angiotensin system (RAS), including specific angiotensin II
      receptor subtypes, is present in the rat ovary. Immunohistochemistry using a
      polyclonal antibody and mRNA in situ hybridization were performed on perfusion
      fixed, paraffin-embedded ovaries obtained from untreated sexually mature,
      normally cycling rats. Immunofluorescent staining revealed an exclusive and
      distinct labeling of follicular granulosa cells showing a plaque-like expression
      pattern at the cell borders, being detectable in different stages of atretic
      degeneration. On adjacent sections the expression of the respective mRNA could be
      shown in granulosa cells of the same follicle. The AT2 receptor may be implicated
      in the ovarian atretic process by influencing follicular cell-cell communication.

PMID- 15034007
TI  - Sperm protein 17 is expressed in human somatic ciliated epithelia.
AB  - It was once believed that sperm protein 17 (Sp17) was expressed exclusively in
      the testis and that its sole function was to bind to the oocyte during
      fertilization. However, immunohistochemistry of the human respiratory airways and
      reproductive systems show that it is abundant in ciliated cells but not in human
      cells with stereocilia and microvilli. The high degree of sequence conservation
      throughout its N-terminal half, and the presence of an A-kinase anchoring protein
      (AKAP)-binding motif within this region, suggest that Sp17 plays a regulatory
      role in a PKA-independent AKAP complex in both male germinal and ciliated somatic
      cells.

PMID- 15034008
TI  - IL-2, regulatory T cells, and tolerance.
AB  - IL-2 is a potent T cell growth factor that for many years was assumed to amplify
      lymphocyte responses in vivo. Accordingly, IL-2 has been used clinically to
      enhance T cell immunity in patients with AIDS or cancer, and blocking Abs to the
      IL-2R are used to inhibit T cell responses against transplanted tissues. It was
      later shown in mice that, unexpectedly, disruption of the IL-2 pathway results in
      lymphoid hyperplasia and autoimmunity rather than immune deficiency, indicating
      that the major physiological function of IL-2 is to limit rather than enhance T
      cell responses. This apparent paradox has recently been resolved with the
      discovery that IL-2 is critical for the development and peripheral expansion of
      CD4(+)CD25(+) regulatory T cells, which promote self-tolerance by suppressing T
      cell responses in vivo. Our new understanding of IL-2 biology prompts a re
      evaluation of how best to clinically manipulate this important immunoregulatory
      pathway.

PMID- 15034009
TI  - Cutting edge: innate immune system discriminates between RNA containing bacterial
      versus eukaryotic structural features that prime for high-level IL-12 secretion
      by dendritic cells.
AB  - RNA derived from bacterial but not eukaryotic sources, when transfected into
      human monocyte-derived dendritic cell precursors, induces high-level IL-12
      secretion in conjunction with dendritic cell maturation stimuli. In vitro
      transcribed mRNA that mimics the structure of bacterial mRNA in the lack of a
      long 3'-poly(A) tail likewise induces IL-12 secretion, but this property is lost
      upon efficient enzymatic 3'-polyadenylation. Among other tested RNAs, only
      polyuridylic acid induced IL-12 p70. This RNA response phenomenon appears
      biologically distinct from the classically defined response to dsRNA. RNA
      transfected APC also polarize T cells in an IL-12-dependent manner toward the IFN
      gamma(high)IL-5 (low) Th1 phenotype, suggesting a link between the detection of
      appropriately structured RNA and the skewing of immune responses toward those
      best suited for controlling intracellular microbes. RNA structured to emulate
      bacterial patterns constitutes a novel vaccine strategy to engender polarized Th1
      type immune responses.

PMID- 15034010
TI  - Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting
      with the poliovirus receptor (CD155).
AB  - The poliovirus receptor (PVR) belongs to a large family of Ig molecules called
      nectins and nectin-like proteins, which mediate cell-cell adhesion, cell
      migration, and serve as entry receptors for viruses. It has been recently shown
      that human NK cells recognize PVR through the receptor DNAM-1, which triggers NK
      cell stimulation in association with beta(2) integrin. In this study, we show
      that NK cells recognize PVR through an additional receptor, CD96, or T cell
      activated increased late expression (Tactile). CD96 promotes NK cell adhesion to
      target cells expressing PVR, stimulates cytotoxicity of activated NK cells, and
      mediates acquisition of PVR from target cells. Thus, NK cells have evolved a dual
      receptor system that recognizes nectins and nectin-like molecules on target cells
      and mediates NK cell adhesion and triggering of effector functions. As PVR is
      highly expressed in certain tumors, this receptor system may be critical for NK
      cell recognition of tumors.

PMID- 15034011
TI  - CCR7 directs the migration of thymocytes into the thymic medulla.
AB  - Developing thymocytes migrate from the cortex to the medulla of the thymus as a
      consequence of positive selection. This migration is likely to be essential for
      tolerance because it allows the developing cells to move into an environment that
      is optimal for negative selection. Guidance mechanisms that draw positively
      selected thymocytes into the medulla have not been clarified, but several studies
      have implicated chemokines in the process. CCR7, the receptor for the medullary
      chemokines CCL19 and CCL21, is induced on thymocytes during their positive
      selection. In this study we show that premature expression of CCR7 repositions
      CD4(+)CD8(+) double-positive cells into the medulla of transgenic mice. This
      repositioning of the thymocytes is accompanied by impairment of their
      development. The data show the involvement of CCR7 in medullary migration and
      emphasize the importance of proper thymocyte positioning for efficient T cell
      development.

PMID- 15034012
TI  - Siva-1 and an alternative splice form lacking the death domain, Siva-2, similarly
      induce apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway.
AB  - Siva-1 is a death domain-containing proapoptotic protein identified as an
      intracellular ligand of CD27 and of the glucocorticoid-induced TNFR family
      related gene, which are two members of the TNFR family expressed on lymphoid
      cells. Although Siva-1 expression is up-regulated in multiple pathological
      processes, little is known about the signaling pathway underlying the Siva
      induced apoptosis. In this study, we investigated the mechanism of the
      proapoptotic activity of Siva-1 and an alternative splice form lacking the death
      domain of Siva-1, Siva-2, in T lymphocytes in which Siva proteins, CD27, and
      glucocorticoid-induced TNFR family-related gene are primarily expressed.
      Overexpression of Siva proteins triggers a typical apoptotic process manifested
      by cell shrinkage and surface exposure of phosphatidylserine, and confirmed by
      ultrastructural features. Siva-induced apoptosis is related to the CD27-mediated
      apoptotic pathway and results in activation of both initiator and effector
      caspases. This pathway involves a mitochondrial step evidenced by activation of
      Bid and cytochrome c release, and is modulated by overexpression of Bcl-2 or Bcl
      x(L). The determinants for Siva-induced apoptosis are not contained within the
      death domain found in the central part of Siva-1, but rather in both the N
      terminal and C-terminal regions shared by both Siva proteins. The N-terminal
      region also participates in the translocation of both Siva proteins into the
      nuclear compartment. These results indicate that Siva-1 and Siva-2 mediate
      apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway that
      likely involves both cytoplasmic and nuclear events.

PMID- 15034013
TI  - Antibody targeting of the CC chemokine ligand 5 results in diminished leukocyte
      infiltration into the central nervous system and reduced neurologic disease in a
      viral model of multiple sclerosis.
AB  - Intracerebral infection of mice with mouse hepatitis virus, a member of the
      Coronaviridae family, reproducibly results in an acute encephalomyelitis that
      progresses to a chronic demyelinating disease. The ensuing neuropathology during
      the chronic stage of disease is primarily immune mediated and similar to that of
      the human demyelinating disease multiple sclerosis. Secretion of chemokines
      within the CNS signals the infiltration of leukocytes, which results in
      destruction of white matter and neurological impairment. The CC chemokine ligand
      (CCL)5 is localized in white matter tracts undergoing demyelination, suggesting
      that this chemokine participates in the pathogenesis of disease by attracting
      inflammatory cells into the CNS. In this study, we administer a mAb directed
      against CCL5 to mice with established mouse hepatitis virus-induced demyelination
      and impaired motor skills. Anti-CCL5 treatment decreased T cell accumulation
      within the CNS based, in part, on viral Ag specificity, indicating the ability to
      differentially target select populations of T cells. In addition, administration
      of anti-CCL5 improved neurological function and significantly (p < or = 0.005)
      reduced the severity of demyelination and macrophage accumulation within the CNS.
      These results demonstrate that the severity of CNS disease can be reduced through
      the use of a neutralizing mAb directed against CCL5 in a viral model of
      demyelination.

PMID- 15034014
TI  - Intralesional injection of adenovirus encoding CC chemokine ligand 16 inhibits
      mammary tumor growth and prevents metastatic-induced death after surgical removal
      of the treated primary tumor.
AB  - The CC chemokine ligand (CCL)16 exerts chemotactic activity on human monocytes
      and lymphocytes. Although no murine homologous has been defined, the TSA mouse
      adenocarcinoma cells engineered to express human CCL16 are rapidly rejected by
      syngenic mice. An adenovirus encoding CCL16 (AdCCL16) was generated using a Cre
      Lox-based system and was used to determine whether this chemokine might also
      block pre-existing tumors. Both recombinant and viral CCL16 showed in vitro
      chemotactic activity for murine CD4(+) and CD8(+) lymphocytes and dendritic cells
      (DC). AdCCL16, but not the control empty vector, when injected in established
      nodules significantly delayed tumor growth. Immunohistochemistry revealed
      accumulation of CD4(+) and CD8(+) T cells and DC in the treated tumors as well as
      in draining lymph nodes. DC from such lymph nodes stimulated IFN-gamma by a T
      cell clone specific for the known TSA tumor-associated Ag (TAA), suggesting the
      tumor origin of these cells. Lymphocytes from the same nodes showed specific CTL
      activity against TSA tumor cells and their immunodominant TAA peptide. Antitumor
      activity required CD4, CD8, and IFN-gamma production, as shown using subset
      depleted and knockout mice. Despite the robust and rapid immune response
      triggered by intratumoral injection of AdCCL16, the lesions were not completely
      rejected; however, the same treatment given before surgical excision of primary
      lesions prevented metastatic spread and cured 63% of mice bearing the 4T1 mammary
      adenocarcinoma, which is perhaps the most compelling model of spontaneous
      metastasis.

PMID- 15034015
TI  - Establishment of early lymphoid organ infrastructure in transplanted tumors
      mediated by local production of lymphotoxin alpha and in the combined absence of
      functional B and T cells.
AB  - Lymphoid organogenesis is a highly coordinated process involving orchestrated
      expression of a number of genes. Although the essential role of lymphotoxin alpha
      (LTalpha) for the normal development of secondary lymphoid organs is well
      established, it is not clear to which extent it depends upon cooperation with T
      and B lymphocytes for lymphoid neo-organogenesis. To determine whether LTalpha is
      sufficient to mediate recruitment of basic elements needed for lymphoid
      organogenesis, we made use of a LTalpha-transfected cell line as an experimental
      tool and established tumors in nude and SCID mice. Our data showed that high
      endothelial venules formed and follicular dendritic cells accumulated and
      differentiated in response to LTalpha in the absence of lymphocytes. A CD4(+)CD3(
      )CD11c(+) cell population that is found in the secondary lymphoid organ was also
      recruited into tumors expressing LTalpha. Furthermore, in nude mice, B cells
      migrated in response to LTalpha and formed intratumoral follicles. These B cell
      follicles were structurally well equipped with follicular dendritic cell networks
      and high endothelial venules; however, they were not functionally active; e.g.,
      those B cells specific for a surrogate Ag expressed by the tumor were found in
      the spleen, but not in the tumor. We show that, even in the absence of functional
      T and B lymphocytes, local expression of LTalpha in transplanted tumors induced
      typical stromal characteristics of lymphoid tissue, emphasizing that LTalpha is a
      critically important cytokine for formation of lymphoid organ infrastructure.

PMID- 15034016
TI  - Monomeric IgE stimulates NFAT translocation into the nucleus, a rise in cytosol
      Ca2+, degranulation, and membrane ruffling in the cultured rat basophilic
      leukemia-2H3 mast cell line.
AB  - Mast cells are key regulators in allergy and inflammation, and release histamine,
      cytokines, and other proinflammatory mediators. In the classical view, IgE acts
      merely to prime mast cells, attaching to FcepsilonRs but not evoking any cell
      signaling response until cross-linked by the presence of a multivalent allergen.
      However, several recent studies have reported that IgE alone can promote cell
      survival and cytokine production in the absence of cross-linking by allergen. In
      this study we demonstrate that acute addition of monomeric IgE elicits a wide
      spectrum of responses in the rat basophilic leukemia-2H3 mast cell line,
      including activation of phospholipases Cgamma and D, a rise in cytosol Ca(2+),
      NFAT translocation, degranulation, and membrane ruffling within minutes. Calcium
      transients persist for hours as long as IgE is present resulting in the
      maintained translocation of the transcription factor NFAT to the nucleus. Removal
      of IgE reverses the signaling processes. Our results indicate that, far from
      simply preparing the cells for a response to allergen, monomeric IgE can
      stimulate signaling pathways that lead to degranulation, membrane ruffling, and
      NFAT translocation. The mechanism of activation is likely to be via aggregation
      of the FcepsilonR1 because activation by IgE can be inhibited with monovalent
      hapten.

PMID- 15034017
TI  - Proinflammatory mediators and genetic background in oncogene mediated tumor
      progression.
AB  - RET/PTC3 (RP3) is an oncogenic fusion protein which is frequently expressed in
      papillary thyroid carcinomas and has been detected in thyroid tissue from
      patients diagnosed with Hashimoto's thyroiditis. The constitutive activation of
      the tyrosine kinase domain in the carboxyl-terminal end of RP3 induces signaling
      pathways within thyrocytes and causes cellular transformation. One of the
      signaling pathways activated in RP3-expressing cells involves the activity of the
      transcription factor NF-kappaB and the production of downstream targets including
      GM-CSF and macrophage chemotactic protein 1. These factors are known to be
      immunostimulatory, making RP3 a molecular adjuvant and potentially promoting
      tissue-specific immunity. However compelling, these in vitro data do not reliably
      predict gene function in vivo or the cumulative effects of time-dependent
      processes such as angiogenesis, inflammation, or the influence of genetic
      background. To address these issues, we analyzed the production of
      proinflammatory mediators in mouse thyroid organs and demonstrate consistency
      with in vitro studies performed previously that Il1alpha, Il1beta, Il6, and
      Tnfalpha and the enzyme Cox2 are produced by RP3-transgenic thyroid tissue, but
      absent from nontransgenic thyroids. Furthermore, we find that that the genetic
      background of the host is important in the observed RP3-induced inflammation and
      tumor progression. These findings provide support for the notion that oncogene
      induced cytokine secretion is important for the development and progression of
      thyroid carcinomas in genetically permissive hosts.

PMID- 15034018
TI  - Protection from fluorescein isothiocyanate-induced fibrosis in IL-13-deficient,
      but not IL-4-deficient, mice results from impaired collagen synthesis by
      fibroblasts.
AB  - Intratracheal injection of FITC results in acute lung injury and progresses to
      fibrosis by day 21 postchallenge. In response to FITC, BALB/c mice produce IL-4
      and IL-13 in the lung. To investigate whether IL-4 and/or IL-13 were important
      profibrotic mediators in this model, we examined the fibrotic response to FITC in
      mice that were genetically deficient in IL-4 (IL-4(-/-)), IL-13 (IL-13(-/-)), or
      IL-4 and IL-13 combined (IL-4/13(-/-)). Baseline levels of collagen were similar
      in all mice. In response to FITC, both BALB/c and IL-4(-/-) mice developed
      fibrosis, whereas the IL-13(-/-) and IL-4/13(-/-) mice were significantly
      protected, as measured by total lung collagen levels and histology. Total
      leukocyte recruitment to the lung was similar in all four strains of mice when
      measured on days 7, 14, and 21 post-FITC. BALB/c mice showed prominent
      eosinophilia on day 7 that was absent in IL-4(-/-), IL-13(-/-), and IL-4/13(-/-)
      mice, suggesting that eosinophilia is not necessary for development of a fibrotic
      response. There were no significant differences in the percentages of any other
      leukocytes analyzed between the genotypes. Similarly, protection in IL-13(-/-)
      mice was not associated with alterations in cytokine or eicosanoid profiles.
      Interestingly, TGF-beta1 production was not reduced in IL-13(-/-) mice. Analyses
      of fibroblasts isolated from the four genotypes demonstrated that although there
      were similar numbers of fibroblasts present in cultures of lung minces,
      fibroblasts from IL-13-deficient strains have reduced basal and stimulated levels
      of collagen production. IL-13Ralpha1 expression increases on fibroblasts during
      fibrotic responses in vivo, and IL-13 increases collagen synthesis in
      fibroblasts. Thus, IL-13 mediates its profibrotic actions through direct effects
      on fibroblast production of extracellular matrix.

PMID- 15034019
TI  - Flt3 ligand preferentially increases the number of functionally active myeloid
      dendritic cells in the lungs of mice.
AB  - In the present study, we investigated the effects of in vivo Flt3L administration
      on the generation, phenotype, and function of lung dendritic cells (DCs) to
      evaluate whether Flt3L favors the expansion and maturation of a particular DC
      subset. Injection of Flt3L into mice resulted in an increased number of CD11c
      expressing lung DCs, preferentially in the alveolar septa. FACS analysis allowed
      us to quantify a 19-fold increase in the absolute numbers of CD11c-positive,
      CD45R/B220 negative DCs in the lungs of Flt3L-treated mice over vehicle-treated
      mice. Further analysis revealed a 90-fold increase in the absolute number of
      myeloid DCs (CD11c positive, CD45R/B220 negative, and CD11b positive) and only a
      3-fold increase of lymphoid DCs (CD11c positive, CD45R/B220 negative, and CD11b
      negative) from the lungs of Flt3L-treated mice over vehicle-treated mice. Flt3L
      treated lung DCs were more mature than vehicle-treated lung DCs as demonstrated
      by a significantly higher percentage of cells expressing MHC class II, CD86, and
      CD40. Freshly isolated Flt3L lung DCs were not fully mature, because after an
      overnight culture they continued to increase accessory molecule expression.
      Functionally, Flt3L-treated lung DCs were more efficient than vehicle-treated DCs
      at stimulating naive T cell proliferation. Our data show that administration of
      Flt3L favors the expansion of myeloid lung DCs over lymphoid DCs and enhanced
      their ability to stimulate naive lymphocytes.

PMID- 15034020
TI  - Mapping of epitopes for autoantibodies to the type 1 diabetes autoantigen IA-2 by
      peptide phage display and molecular modeling: overlap of antibody and T cell
      determinants.
AB  - IA-2 is a major target of autoimmunity in type 1 diabetes. IA-2 responsive T
      cells recognize determinants within regions represented by amino acids 787-817
      and 841-869 of the molecule. Epitopes for IA-2 autoantibodies are largely
      conformational and not well defined. In this study, we used peptide phage display
      and homology modeling to characterize the epitope of a monoclonal IA-2 Ab (96/3)
      from a human type 1 diabetic patient. This Ab competes for IA-2 binding with Abs
      from the majority of patients with type 1 diabetes and therefore binds a region
      close to common autoantibody epitopes. Alignment of peptides obtained after
      screening phage-displayed peptide libraries with purified 96/3 identified a
      consensus binding sequence of Asn-x-Glu-x-x-(aromatic)-x-x-Gly. The predicted
      surface on a three-dimensional homology model of the tyrosine phosphatase domain
      of IA-2 was analyzed for clusters of Asn, Glu, and aromatic residues and amino
      acids contributing to the epitope investigated using site-directed mutagenesis.
      Mutation of each of amino acids Asn(858), Glu(836), and Trp(799) reduced 96/3 Ab
      binding by >45%. Mutations of these residues also inhibited binding of serum
      autoantibodies from IA-2 Ab-positive type 1 diabetic patients. This study
      identifies a region commonly recognized by autoantibodies in type 1 diabetes that
      overlaps with dominant T cell determinants.

PMID- 15034021
TI  - Src homology 2 domain-containing protein tyrosine phosphatase substrate 1
      regulates the migration of Langerhans cells from the epidermis to draining lymph
      nodes.
AB  - Src homology 2 domain-containing protein tyrosine phosphatase substrate 1 (SHPS
      1) is a member of the signal regulatory protein family in which the extracellular
      region interacts with its ligand, CD47. Recent studies have demonstrated that
      SHPS-1 plays an important role in cell migration and cell adhesion. We
      demonstrate in this study, using immunohistochemical and flow cytometric
      analyses, that murine Langerhans cells (LCs) express SHPS-1. Treatment of mice
      ears with 2,4-dinitro-1-fluorobenzene significantly reduced the number of
      epidermal LCs, and that reduction could be reversed by pretreatment with mAb to
      SHPS-1 or the CD47-Fc fusion protein. Treatment with the SHPS-1 mAb in vivo
      reduced the number of FITC-bearing cells in the lesional lymph nodes after the
      application of FITC to the skin. The SHPS-1 mAb inhibited the in vivo TNF-alpha
      induced migration of LCs. The emigration of dendritic cells expressing I-A(b+)
      from skin explants to the medium was also reduced by the SHPS-1 mAb. We further
      demonstrate that the chemotaxis of a murine dendritic cell line, XS52, by
      macrophage inflammatory protein-3beta was significantly inhibited by treatment
      with the SHPS-1 mAb or CD47-Fc recombinant protein. Finally, we show that
      migration of LCs was attenuated in mutant mice that lack the intracellular domain
      of SHPS-1. These observations show that the ligation of SHPS-1 with the SHPS-1
      mAb or with CD47-Fc abrogates the migration of LCs in vivo and in vitro, which
      suggests that the SHPS-1-CD47 interaction may negatively regulate LC migration.

PMID- 15034022
TI  - Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase
      activity in dendritic cells.
AB  - Human monocyte-derived dendritic cells (DCs) are capable of expressing the
      tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO), which allows them
      to suppress Ag-driven proliferation of T cells in vitro. In DCs that express IDO,
      the activity of the enzyme is tightly regulated, with the protein being
      constitutively expressed, but functional activity requiring an additional set of
      triggering signals supplied during Ag presentation. We now show that triggering
      of functional IDO obligately requires ligation of B7-1/B7-2 molecules on the DCs
      by CTLA4/CD28 expressed on T cells. When this interaction was disrupted, IDO
      remained in the inactive state, and the DCs were unable to inhibit T cell
      proliferation. Inhibition could be fully restored by direct Ab-mediated cross
      linking of B7-1/B7-2. Although both CD4(+) and CD8(+) T cells were susceptible to
      inhibition once IDO was induced, the ability to trigger functionally active IDO
      was strictly confined to the CD4(+) subset. Thus, the ability of CD4(+) T cells
      to induce IDO activity in DCs allowed the CD4(+) population to dominantly inhibit
      proliferation of the CD8(+) population via the bridge of a conditioned DC. We
      hypothesize that IDO activation via engagement of B7-1/B7-2 molecules on DCs,
      specifically, engagement by CTLA4 expressed on regulatory CD4(+) T cells, may
      function as a physiologic regulator of T cell responses in vivo.

PMID- 15034024
TI  - CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory
      lesions.
AB  - CD4(+)CD25(+) regulatory T cells (T(reg)) can inhibit a variety of autoimmune and
      inflammatory diseases, but their involvement in regulating virus-induced
      immunopathology is not known. We have evaluated the role of T(reg) in viral
      immunopathological lesion stromal keratitis. This frequent cause of human
      blindness results from a T cell-mediated immunoinflammatory response to HSV in
      the corneal stroma. The results show that lesions were significantly more severe
      if mice were depleted of T(reg) before infection. The T(reg) was also shown to
      modulate lesion expression induced by adoptive transfer of pathogenic CD4(+) T
      cells in infected SCID recipients. The mechanism of T(reg) control of stromal
      keratitis involved suppressed antiviral immunity and impaired expression of the
      molecule required for T cell migration to lesion sites. Interestingly, T(reg)
      isolated from ocular lesions in nondepleted mice showed in vitro inhibitory
      effects involving IL-10, but were not very effective in established lesions. Our
      results decipher the in vivo role of T(reg) in a virus-induced immunopathology
      and imply that manipulation of regulatory cell function represents a useful
      approach to control viral-induced immunoinflammatory disease.

PMID- 15034026
TI  - Effect of decreasing the affinity of the class II-associated invariant chain
      peptide on the MHC class II peptide repertoire in the presence or absence of H
      2M.
AB  - The class II-associated invariant chain peptide (CLIP) region of the invariant
      chain (Ii) directly influences MHC class II presentation by occupying the MHC
      class II peptide-binding groove, thereby preventing premature loading of
      peptides. Different MHC class II alleles exhibit distinct affinities for CLIP,
      and a low affinity interaction has been associated with decreased dependence upon
      H-2M and increased susceptibility to rheumatoid arthritis, suggesting that
      decreased CLIP affinity alters the MHC class II-bound peptide repertoire, thereby
      promoting autoimmunity. To examine the role of CLIP affinity in determining the
      MHC class II peptide repertoire, we generated transgenic mice expressing either
      wild-type human Ii or human Ii containing a CLIP region of low affinity for MHC
      class II. Our data indicate that although degradation intermediates of Ii
      containing a CLIP region with decreased affinity for MHC class II do not remain
      associated with I-A(b), this does not substantially alter the peptide repertoire
      bound by MHC class II or increase autoimmune susceptibility in the mice. This
      implies that the affinity of the CLIP:MHC class II interaction is not a strong
      contributory factor in determining the probability of developing autoimmunity. In
      contrast, in the absence of H-2M, MHC class II peptide repertoire diversity is
      enhanced by decreasing the affinity of CLIP for MHC class II, although MHC class
      II cell surface expression is reduced. Thus, we show clearly, in vivo, the
      critical chaperone function of H-2M, which preserves MHC class II molecules for
      high affinity peptide binding upon dissociation of Ii degradation intermediates.

PMID- 15034023
TI  - Genome-wide analysis of molecular changes in IL-12-induced control of mammary
      carcinoma via IFN-gamma-independent mechanisms.
AB  - IL-12 is a major activator of tumor-killing NK cells and CTL. IFN-gamma mediates
      most of the well-known immunological activities of IL-12. In this study, we
      report IFN-gamma-independent activities induced by therapeutic application of rIL
      12 in restricting tumor growth and metastasis in the 4T1 murine mammary carcinoma
      model. IFN-gamma-deficient mice carrying 4T1 tumor exhibit no gross defect in the
      number of tumor-infiltrating lymphocytes but have exaggerated angiogenesis in the
      tumor. Administration of IL-12 is able to constrict blood vessels in the tumor in
      the absence of IFN-gamma, and retains certain therapeutic efficacy even when
      applied late during tumor progression. IL-12 exposure in vivo does not
      irreversibly alter the immunogenicity of the tumor. Finally, global gene
      expression analysis of primary tumors reveals IL-12-induced molecular patterns
      and changes, implicating a number of novel genes potentially important for IFN
      gamma-independent immune responses against the tumor, for IL-12-mediated
      antiproliferation, antimetastasis, and antiangiogenesis activities.

PMID- 15034025
TI  - Microarray analysis of Lyn-deficient B cells reveals germinal center-associated
      nuclear protein and other genes associated with the lymphoid germinal center.
AB  - Lyn is the only member of the Src family expressed in DT40 B cells, which provide
      a unique model to study the singular contribution of this protein tyrosine kinase
      (PTK) family to cell signaling. In these cells, gene ablation of Lyn leads to
      defective B cell receptor signaling. Complementary DNA array analysis of Lyn
      deficient DT40 cells shows that the absence of Lyn leads to down-regulation of
      numerous genes encoding proteins involved in B cell receptor signaling,
      proliferation, control of transcription, immunity/inflammation response, and
      cytoskeletal organization. Most of these expression changes have not been
      previously associated with Lyn PTK signaling. They include alterations in mRNA
      levels of germinal center-associated nuclear protein (germinal center-associated
      DNA primase) (GANP), CD74, CD22, NF-kappaB, elongation factor 1alpha, CD79b,
      octamer binding factor 1, Ig H chain, stathmin, and gamma-actin. Changes in GANP
      expression were also confirmed in Lyn-deficient mice, suggesting that Lyn PTK has
      a unique function not compensated for by other Src kinases. Because Lyn-deficient
      mice have impaired development of germinal centers in spleen, the decreased
      expression of GANP in the Lyn-deficient DT40 cell line and Lyn-deficient mice
      suggests that Lyn controls the formation and proliferation of germinal centers
      via GANP. GANP promoter activity was higher in wild-type vs Lyn-deficient cells.
      Mutation of the PU.1 binding site reduced activity in wild-type cells and had no
      effect in Lyn-deficient cells. The presence of Lyn enhanced PU.1 expression in a
      Northern blot. Thus, the following new signaling pathway has been described: Lyn-
      >PU.1-->GANP.

PMID- 15034027
TI  - Intestinal intraepithelial lymphocyte gamma delta-T cell-derived keratinocyte
      growth factor modulates epithelial growth in the mouse.
AB  - Keratinocyte growth factor (KGF) promotes intestinal epithelial growth. To
      understand the relevance of intraepithelial lymphocyte (IEL)-derived KGF
      expression on epithelial growth, we used a mouse model of villus atrophy by the
      administration of total parenteral nutrition, and a model of villus hypertrophy
      by the creation of a short bowel syndrome. KGF expression was confined to
      gammadelta-TCR(+) IELs. IEL-derived KGF expression was highest in the crypts,
      somewhat less in the lower portion of villi, and markedly lower in the upper
      portion of villi. Total parenteral nutrition administration was associated with a
      down-regulation of IEL-derived KGF expression, and short bowel syndrome was
      associated with an up-regulation of IEL-derived KGF expression. In the absence of
      gammadelta-TCR(+) IEL, using gammadelta(-/-) mice, intestinal epithelial cell
      proliferation decreased in control, and in both mucosal atrophy (22% decline) and
      mucosal hypertrophy (14%) models. These results show that KGF from IELs is an
      important factor for maintenance of intestinal epithelial cell proliferation and
      villus growth.

PMID- 15034028
TI  - Separation of the New Zealand Black genetic contribution to lupus from New
      Zealand Black determined expansions of marginal zone B and B1a cells.
AB  - The F(1) hybrid of New Zealand Black (NZB) and New Zealand White (NZW) mice
      develop an autoimmune disease similar to human systemic lupus erythematosus.
      Because NZB and (NZB x NZW)F(1) mice manifest expansions of marginal zone (MZ) B
      and B1a cells, it has been postulated that these B cell abnormalities are central
      to the NZB genetic contribution to lupus. Our previous studies have shown that a
      major NZB contribution comes from the Nba2 locus on chromosome 1. C57BL/6 (B6)
      mice congenic for Nba2 produce antinuclear Abs, and (B6.Nba2 x NZW)F(1) mice
      develop elevated autoantibodies and nephritis similar to (NZB x NZW)F(1) mice. We
      studied B cell populations of B6.Nba2 mice to better understand the mechanism by
      which Nba2 leads to disease. The results showed evidence of B cell activation
      early in life, including increased levels of serum IgM, CD69(+) B cells, and
      spontaneous IgM production in culture. However, B6.Nba2 compared with B6 mice had
      a decreased percentage of MZ B cells in spleen, and no increase of B1a cells in
      the spleen or peritoneum. Expansions of these B cell subsets were also absent in
      (B6.Nba2 x NZW)F(1) mice. Among the strains studied, B cell expression of beta(1)
      integrin correlated with differences in MZ B cell development. These results show
      that expansions of MZ B and B1a cells are not necessary for the NZB contribution
      to lupus and argue against a major role for these subsets in disease
      pathogenesis. The data also provide additional insight into how Nba2 contributes
      to lupus.

PMID- 15034029
TI  - Detection of cell surface ligands for the gamma delta TCR using soluble TCRs.
AB  - The natural ligands recognized by gammadelta TCRs are still largely unknown, in
      part because immunization does not normally result in Ag-specific gammadelta T
      cell responses. Taking advantage of an established ligand for a particular
      gammadelta TCR, we demonstrated that a multimerized recombinant form of this
      gammadelta TCR can be used like a mAb to specifically detect its own ligand.
      Using the same approach for more common gammadelta TCRs whose ligands remain
      unknown, we detected on certain cell lines molecules that appear to be ligands
      for three additional gammadelta TCRs. One of these represents the mouse
      Vgamma6/Vdelta1 invariant gammadelta TCR, which predominates in the female
      reproductive tract, the tongue, and the lung, and other tissues during
      inflammation. The second represents the closely related Vgamma5/Vdelta1 invariant
      gammadelta TCR expressed by most epidermal T cells. The third is a
      Vgamma1/Vdelta6.3 TCR, representative of a variable type frequently found on
      lymphoid gammadelta T cells. We found evidence that ligands for multiple
      gammadelta TCRs may be simultaneously expressed on a single cell line, and that
      at least some of the putative ligands are protease sensitive. This study suggests
      that soluble versions of gammadelta TCRs can be as tools to identify and
      characterize the natural ligands of gammadelta T cells.

PMID- 15034030
TI  - Virus-induced activation of self-specific TCR alpha beta CD8 alpha alpha
      intraepithelial lymphocytes does not abolish their self-tolerance in the
      intestine.
AB  - TCRalphabeta CD8alphaalpha intestinal intraepithelial lymphocytes (IEL) represent
      an enigmatic subset of T cells, particularly, in regard to their potential
      functions and the apparent persistence of cells expressing self-specific TCR. We
      have used mice that are transgenic for the TCRalphabeta specific for the
      lymphocytic choriomeningitis virus (LCMV)-derived peptide gp33, and TCRalphabeta
      transgenic mice that coexpress the gp33 Ag ubiquitously, to analyze the
      functional properties of TCRalphabeta CD8alphaalpha IEL in the presence, or
      absence, of their specific MHC-restricted Ag, and to assess the impact of
      molecular mimicry during a potent LCMV infection on potentially self-reactive
      TCRalphabeta CD8alphaalpha IEL. In this study, we show that the presence of the
      specific self-Ag results in reduced expression of IL-2, IFN-gamma, and IL-10 by
      resident TCRalphabeta CD8alphaalpha IEL while expression of mRNA for TGFbeta is
      not affected. We further demonstrate that despite their secluded location in the
      epithelium, TCRalphabeta CD8alphaalpha IEL are activated after infection of the
      intestinal mucosa with LCMV. Importantly, LCMV-induced activation of self
      specific TCRalphabeta CD8alphaalpha IEL does not reverse their tolerance as no
      cytotoxic activity or up-regulated expression of proinflammatory cytokines is
      detected and no overt signs of autoimmunity are seen. Taken together, these
      results are in support of an immunoregulatory role for self-specific TCRalphabeta
      CD8alphaalpha in the intestinal mucosa and clearly speak against an involvement
      of this cell subset in inflammatory reactions and tissue destruction.

PMID- 15034031
TI  - CTLA-4+CD8+ T cells that encounter B7-2+ iris pigment epithelial cells express
      their own B7-2 to achieve global suppression of T cell activation.
AB  - Pigment epithelial (PE) cells cultured from the eye possess the novel property of
      suppressing TCR-dependent activation of T cells in vitro. Iris PE (IPE) cells
      accomplish this suppression by a direct cell contact mechanism in which B7-2
      expressed by the PE cells interacts with CTLA-4 on responding T cells. Because
      CTLA-4 expression is constitutively expressed on a very small proportion of naive
      splenic T cells and since exposure of splenic T cells to IPE leads to global T
      cell suppression, we have inquired into the mechanism by which suppression is
      achieved. Using splenic T cells and IPE from donor mice with disrupted genes for
      CD80 (B7-1), CD86 (B7-2), CTLA-4, and/or CD28, we report that B7-2(+) IPE in the
      presence of anti-CD3 supported selectively the activation of CTLA-4(+) CD8(+) T
      cells that express their own B7-2 and secrete enhanced amounts of active TGFbeta.
      By contrast, activation of CTLA-4-negative T cells, especially CD4(+) cells, in
      these cultures was profoundly suppressed. Because global suppression of T cell
      activation in these cultures was obtained only when both IPE and T cells
      possessed B7-2 genes and expressed the costimulators as surface molecules, we
      propose that T cells activated in the presence of parenchymal cells from the eye
      (an immune privileged site) express B7-2 in a manner that equips them to suppress
      bystander T cells. Thus, B7-2 expression on T cells participates in their
      eventual ability to function as regulators in vitro.

PMID- 15034032
TI  - Glucose-regulated protein 94/glycoprotein 96 elicits bystander activation of CD4+
      T cell Th1 cytokine production in vivo.
AB  - Glucose-regulated protein 94 (GRP94/gp96), the endoplasmic reticulum heat shock
      protein 90 paralog, elicits both innate and adaptive immune responses. Regarding
      the former, GRP94/gp96 stimulates APC cytokine expression and dendritic cell
      maturation. The adaptive component of GRP94/gp96 function reflects a proposed
      peptide-binding activity and, consequently, a role for native GRP94/gp96-peptide
      complexes in cross-presentation. It is by this mechanism that tumor-derived
      GRP94/gp96 is thought to suppress tumor growth and metastasis. Recent data have
      demonstrated that GRP94/gp96-elicited innate immune responses can be sufficient
      to suppress tumor growth and metastasis. However, the immunological processes
      activated in response to tumor Ag-negative sources of GRP94/gp96 are currently
      unknown. We have examined the in vivo immunological response to nontumor sources
      of GRP94/gp96 and report that administration of syngeneic GRP94/gp96- or
      GRP94/gp96-N-terminal domain-secreting KBALB fibroblasts to BALB/c mice
      stimulates CD11b(+) and CD11c(+) APC function and promotes bystander activation
      of CD4(+) T cell Th1 cytokine production. Only modest activation of CD8(+) T cell
      or NK cell cytolytic function was observed. The GRP94/gp96-dependent induction of
      CD4(+) T cell cytokine production was markedly inhibited by carrageenan,
      indicating an essential role for APC in this response. These results identify the
      bystander activation of CD4(+) T lymphocytes as a previously unappreciated
      immunological consequence of GRP94/gp96 administration and demonstrate that
      GRP94/gp96-elicited alterations in the in vivo cytokine environment influence the
      development of CD4(+) T cell effector functions, independently of its proposed
      function as a peptide chaperone.

PMID- 15034033
TI  - Maintenance, loss, and resurgence of T cell responses during acute, protracted,
      and chronic viral infections.
AB  - The acute phase of many viral infections is associated with the induction of a
      pronounced CD8 T cell response which plays a principle role in clearing the
      infection. By contrast, certain infections are not as readily controlled. In this
      study, we have used the well-defined system of lymphocytic choriomeningitis virus
      (LCMV) infection of mice to determine quantitative and qualitative changes in
      virus-specific CD8 T cell responses that rapidly resolve acute infections, more
      slowly control protracted infections, or fail to clear chronic infections. Acute
      LCMV infection elicits potent, functional, multi-epitope-specific CD8 T cell
      responses. Virus-specific CD8 T cells also expand, albeit to a lesser extent,
      during protracted LCMV infection. Under these conditions, there is a progressive
      diminution in the capacity to produce IL-2, TNF-alpha, and IFN-gamma. Changes in
      cytotoxic activities are also detectable but differ depending upon the
      specificity of the responding cells. As the infection is slowly resolved, a
      resurgence of cytokine production by virus-specific CD8 T cells is observed. CD4
      deficient mice cannot control infection with certain strains of LCMV, but do
      mount multi-epitope-specific CD8 T cell responses that also lose effector
      capabilities; however, they are not maintained indefinitely in an unresponsive
      state as these cells become deleted over time. Overall, our findings suggest that
      constant high viral loads result in the progressive diminution of T cell effector
      functions and subsequent physical loss of the responding cells, whereas if the
      viral load is brought under control a partial restoration of CD8 T cell functions
      can occur.

PMID- 15034034
TI  - CD4-directed peptide vaccination augments an antitumor response, but efficacy is
      limited by the number of CD8+ T cell precursors.
AB  - Peptide vaccination is an immunotherapeutic strategy being pursued as a method of
      enhancing Ag-specific antitumor responses. To date, most studies have focused on
      the use of MHC class I-restricted peptides, and have not shown a correlation
      between Ag-specific CD8(+) T cell expansion and the generation of protective
      immune responses. We investigated the effects of CD4-directed peptide vaccination
      on the ability of CD8(+) T cells to mount protective antitumor responses in the
      DUC18/CMS5 tumor model system. To accomplish this, we extended the amino acid
      sequence of the known MHC class I-restricted DUC18 rejection epitope from CMS5 to
      allow binding to MHC class II molecules. Immunization with this peptide (tumor
      derived extracellular signal-regulated kinase-II (tERK-II)) induced Ag-specific
      CD4(+) T cell effector function, but did not directly prime CD8(+) T cells.
      Approximately 31% of BALB/c mice immunized with tERK-II were protected from
      subsequent tumor challenge in a CD40-dependent manner. Priming of endogenous
      CD8(+) T cells in immunized mice was detected only after CMS5 challenge.
      Heightened CD4(+) Th cell function in response to tERK II vaccination allowed a
      12-fold reduction in the number of adoptively transferred CD8(+) DUC18 T cells
      needed to protect recipients against tumor challenge as compared with previous
      studies using unimmunized mice. Furthermore, tERK-II immunization led to a more
      rapid and transient expansion of transferred DUC18 T cells than was seen in
      unimmunized mice. These findings illustrate that CD4-directed peptide vaccination
      augments antitumor immunity, but that the number of tumor-specific precursor
      CD8(+) T cells will ultimately dictate the success of immunotherapy.

PMID- 15034035
TI  - Monocyte surface-bound IL-15 can function as an activating receptor and
      participate in reverse signaling.
AB  - IL-15 is a short chain, four-alpha helix cytokine that shares some biological
      function with IL-2. One striking difference between IL-2 and IL-15 is the ability
      of monocytes to express IL-15 on their cell surface after activation. In the
      current study we have investigated the ability of human monocyte cell surface IL
      15 to participate in reverse signaling. Cross-linking anti-IL-15 Abs were used as
      a surrogate ligand for surface IL-15 engagement. Ligation of cell surface
      expressed IL-15 induced monocyte adhesion that required the activity of small
      m.w. GTPases. Reverse signals through surface IL-15 activated the Rho-GTPase
      Rac3. In addition, engagement of cell surface IL-15 was found to activate a
      number of signaling pathways, including both extracellular signal-regulated
      kinase 1/2 and p38, and resulted in the secretion of IL-8. IL-8 production
      required mitogen-activated protein kinase activity. Thus, the current study has
      established that cell surface IL-15 is more than just a ligand; it can function
      as a receptor and participate in reverse signaling that results in cellular
      adhesion and production of inflammatory cytokines.

PMID- 15034036
TI  - Thymocytes between the beta-selection and positive selection checkpoints are
      nonresponsive to IL-7 as assessed by STAT-5 phosphorylation.
AB  - Interleukin-7 is widely accepted as a major homeostatic factor involved in T cell
      development. To assess the IL-7 responsiveness of thymocytes involved in
      selection processes, we used a new sensitive flow cytometry-based assay to detect
      intracellular phosphorylation of STAT-5 induced by IL-7 in defined mouse
      thymocyte subsets. Using this method, we found the earliest thymocyte subset
      (CD4(-)CD8(-)CD25(-)CD44(+)) to contain both IL-7-responsive and nonresponsive
      cells. Transition through the next stages of development (CD4(-)CD8(
      )CD25(+)CD44(+ and -)) was associated with responsiveness of all thymocytes
      within these populations. Passage of thymocytes through beta-selection resulted
      in a significant reduction in IL-7 sensitivity. In the next phases of development
      (TCR(-) and TCR(low)CD69(-)), thymocytes were completely insensitive to the
      effects of IL-7. STAT-5 phosphorylation in response to IL-7 was again observed,
      however, in thymocytes involved in the positive selection process
      (TCR(low)CD69(+) and TCR(intermediate)). As expected, CD4 and CD8 single-positive
      thymocytes were responsive to IL-7. These findings delineate an IL-7-insensitive
      population between the beta-selection and positive selection checkpoints
      encompassing thymocytes predicted to die by neglect due to failure of positive
      selection. This pattern of sensitivity suggests a two-signal mechanism by which
      survival of thymocytes at these checkpoints is governed.

PMID- 15034037
TI  - IFN-gamma stimulates the expression of a novel secretoglobin that regulates
      chemotactic cell migration and invasion.
AB  - IFNs are a family of cytokines that alert the immune system against viral
      infections of host cells. The IFNs (IFN-alpha, IFN-beta, and IFN-gamma) interact
      with specific cellular receptors and stimulate the production of second
      messengers, leading to the expression of antiviral and immunomodulatory proteins.
      We report in this study that IFN-gamma stimulates the expression of a novel gene
      that encodes a protein with 30% amino acid sequence identity with uteroglobin,
      the founding member of the newly formed Secretoglobin (SCGB) superfamily. We
      named this protein IFN-gamma-inducible SCGB (IIS), because its expression in
      lymphoblast cells is augmented by IFN-gamma treatment. IIS is expressed in
      virtually all tissues, and the highest level of expression is detectable in lymph
      nodes, tonsil, cultured lymphoblasts, and the ovary. Interestingly, although the
      expression of IIS mRNA is not significantly different in resting lymphoid cells,
      it is markedly elevated in activated CD8(+) and CD19(+) cells. Furthermore,
      treatment of lymphoblast cells with IIS antisense phosphorothioate (S)
      oligonucleotides prevents chemotactic migration and invasion. Taken together,
      these results raise the possibility that this novel SCGB has immunological
      functions.

PMID- 15034038
TI  - Plasmacytoid dendritic cells regulate Th cell responses through OX40 ligand and
      type I IFNs.
AB  - Dendritic cells (DCs) show a functional plasticity in determining Th responses
      depending on their maturational stage or on maturational signals delivered to the
      DCs. Human plasmacytoid DCs (PDCs) can induce either Th1- or Th2-type immune
      responses upon exposure to viruses or IL-3, respectively. In this study we have
      investigated the Th-polarizing capacity of PDCs after short (24-h) or long (72-h)
      culture with stimuli and have assessed the expression and function of OX40 ligand
      (OX40L) in PDC-mediated Th polarization in addition to type I IFN-dependent
      responses. IL-3-treated PDCs expressed OX40L, but produced almost no IFN-alpha in
      response to T cell stimulation (CD40 ligand or T cell interaction), resulting in
      the preferential priming of Th2 cells through OX40L-dependent mechanisms.
      Meanwhile, PDCs were rapidly endowed by viral infection (Sendai virus) with a
      high potency to develop IFN-gamma-producing Th cells depending on their capacity
      to residually produce IFN-alpha. Although Sendai virus-stimulated PDCs
      simultaneously expressed OX40L in their maturational process, the Th1-inducing
      effect of endogenous type I IFNs may overcome and thus conceal the OX40L
      dependent Th2 responses. However, during maturation in response to Sendai virus
      over the longer 72-h period, the expression level of OX40L was up-regulated,
      whereas the residual IFN-alpha-producing ability was down-regulated, and
      consequently, the PDCs with prolonged Sendai virus stimulation induced Th2
      responses to some extent. Thus, PDCs have the distinct means to dictate an
      appropriate response to environmental stimuli.

PMID- 15034039
TI  - Defining Th1 and Th2 immune responses in a reciprocal cytokine environment in
      vivo.
AB  - The ability of committed Th1 and Th2 cells to function in altered cytokine
      environments is a central issue in autoimmune and immune-mediated diseases.
      Therefore, it is of interest to study the ability of Th1 or Th2 cells to expand
      and produce cytokine reciprocal environments in vivo. Using STAT4- and STAT6
      deficient mice, we studied the expansion and cytokine production of Ag-specific
      Th1 or Th2 cells after transfer into Th1, Th2, or wild-type recipients. Our data
      show that these Th1 or Th2 cells proliferated and clonally expanded normally,
      regardless of the in vivo cytokine environment. These data have implications for
      the treatment of immune-mediated diseases by immunomodulatory agents that alter
      the cytokine milieu in vivo.

PMID- 15034040
TI  - Enrichment of lck in lipid rafts regulates colocalized fyn activation and the
      initiation of proximal signals through TCR alpha beta.
AB  - Recent results provide insight into the temporal and spatial relationship
      governing lck-dependent fyn activation and demonstrate TCR/CD4-induced activation
      and translocation of lck into lipid rafts and the ensuing activation of
      colocalized fyn. The prediction follows that directly targeting lck to lipid
      rafts will bypass the requirement for juxtaposing TCR and CD4-lck, and rescue
      cellular activation mediated by Ab specific for the constant region of TCRbeta
      chain. The present study uses a family of murine IL-2-dependent CD4(+) T cell
      clonal variants in which anti-TCRCbeta signaling is impaired in an lck-dependent
      fashion. Importantly, these variants respond to Ag- and mAb-mediated TCR-CD4
      coaggregation, both of which enable the coordinated interaction of CD4-associated
      lck with the TCR/CD3 complex. We have previously demonstrated that anti-TCRCbeta
      responsiveness in this system correlates with the presence of kinase-active,
      membrane-associated lck and preformed hypophosphorylated TCRzeta:zeta-associated
      protein of 70 kDa complexes, a phenotype recapitulated in primary resting CD4(+)
      T cells. We show in this study that forced expression of wild-type lck achieved
      the same basal composition of the TCR/CD3 complex and yet did not rescue anti
      TCRCbeta signaling. In contrast, forced expression of C20S/C23S-mutated lck
      (double-cysteine lck), unable to bind CD4, rescues anti-TCRCbeta proximal
      signaling and cellular growth. Double-cysteine lck targets lipid rafts,
      colocalizes with >98% of cellular fyn, and results in a 7-fold increase in basal
      fyn kinase activity. Coaggregation of CD4 and TCR achieves the same outcome.
      These results underscore the critical role of lipid rafts in spatially
      coordinating the interaction between lck and fyn that predicates proximal TCR/CD3
      signaling.

PMID- 15034041
TI  - Smad3 is essential for TGF-beta 1 to suppress IL-2 production and TCR-induced
      proliferation, but not IL-2-induced proliferation.
AB  - Transforming growth factor-beta1 is essential to maintain T cell homeostasis, as
      illustrated by multiorgan inflammation in mice deficient in TGF-beta1 signaling.
      Despite the physiological importance, the mechanisms that TGF-beta1 uses to
      regulate T cell expansion remain poorly understood. TGF-beta1 signals through
      transmembrane receptor serine/threonine kinases to activate multiple
      intracellular effector molecules, including the cytosolic signaling transducers
      of the Smad protein family. We used Smad3(-/-) mice to investigate a role for
      Smad3 in IL-2 production and proliferation in T cells. Targeted disruption of
      Smad3 abrogated TGF-beta1-mediated inhibition of anti-CD3 plus anti-CD28-induced
      steady state IL-2 mRNA and IL-2 protein production. CFSE labeling demonstrated
      that TGF-beta1 inhibited entry of wild-type anti-CD3 plus anti-CD28-stimulated
      cells into cycle cell, and this inhibition was greatly attenuated in Smad3(-/-) T
      cells. In contrast, disruption of Smad3 did not affect TGF-beta1-mediated
      inhibition of IL-2-induced proliferation. These results demonstrate that TGF
      beta1 signals through Smad3-dependent and -independent pathways to inhibit T cell
      proliferation. The inability of TGF-beta1 to inhibit TCR-induced proliferation of
      Smad3(-/-) T cells suggests that IL-2 is not the primary stimulus driving
      expansion of anti-CD3 plus anti-CD28-stimulated T cells. Thus, we establish that
      TGF-beta1 signals through multiple pathways to suppress T cell proliferation.

PMID- 15034042
TI  - Immune regulation by self-reactive T cells is antigen specific.
AB  - Immune regulation plays an important role in the establishment and maintenance of
      self-tolerance. Nevertheless, it has been difficult to conclude whether
      regulation is Ag specific because studies have focused on polyclonal populations
      of regulatory T cells. We have used in this study a murine transgenic model that
      generates self-reactive, regulatory T cells of known Ag specificity to determine
      their capacity to suppress naive T cells specific for other Ags. We show that
      these regulatory cells can regulate the responses of naive T cells with the same
      TCR specificity, but do not inhibit T cell proliferation or differentiation of
      naive T cells specific for other Ags. These results demonstrate that immune
      regulation may be more Ag specific than previously proposed.

PMID- 15034044
TI  - Lupus IgG VH4.34 antibodies bind to a 220-kDa glycoform of CD45/B220 on the
      surface of human B lymphocytes.
AB  - Anti-lymphocyte autoantibodies are a well-recognized component of the autoimmune
      repertoire in human systemic lupus erythematosus (SLE) and have been postulated
      to have pathogenic consequences. Early studies indicated that IgM anti-lymphocyte
      autoantibodies mainly recognized T cells and identified CD45, a protein tyrosine
      phosphatase of central significance in the modulation of lymphocyte function, as
      the main antigenic target on T cells. However, more recent work indicates that
      lupus autoantibodies can also recognize B cells and that CD45 may also represent
      their antigenic target. In particular, IgM Abs encoded by V(H)4.34 appear to have
      special tropism for B cells, and strong, but indirect evidence suggests that they
      may recognize a B cell-specific CD45 isoform. Because V(H)4.34 Abs are greatly
      expanded in SLE, in the present study we investigated the antigenic reactivity of
      lupus sera V(H)4.34 IgG Abs and addressed their contribution to the anti
      lymphocyte autoantibody repertoire in this disease. Our biochemical studies
      conclusively demonstrate that lupus IgG V(H)4.34 Abs target a developmentally
      regulated B220-specific glycoform of CD45, and more specifically, an N-linked N
      acetyllactosamine determinant preferentially expressed on naive B cells that is
      sterically masked by sialic acid on B220-positive memory B cells. Strikingly, our
      data also indicate that this reactivity in SLE sera is restricted to V(H)4.34 Abs
      and can be eliminated by depleting these Abs. Overall, our data indicate that
      V(H)4.34 Abs represent a major component of the lupus IgG autoantibody repertoire
      and suggest that the carbohydrate moiety they recognize may act as a selecting Ag
      in SLE.

PMID- 15034043
TI  - TNF receptor-associated factor 5 limits the induction of Th2 immune responses.
AB  - The TNF receptor-associated factor (TRAF) family of molecules acts as adapter
      proteins for signaling pathways initiated by several members of the TNF receptor
      (TNFR) superfamily. TRAF5(-/-) animals are viable and have normal development of
      the immune system despite interacting with several TNFR family members. A clear
      role for TRAF5 has yet to emerge. OX40 (CD134) interacts with TRAF5, suggesting
      that this pathway could be involved in regulating T cell differentiation into Th1
      or Th2 cells. In tissue culture, OX40 stimulation of TRAF5(-/-) T cells resulted
      in a pronounced Th2 phenotype with elevated levels of IL-4 and IL-5. Similarly,
      in vivo immunization with protein in adjuvant in the presence of an agonist anti
      OX40 Ab resulted in enhanced Th2 development in TRAF5(-/-) mice. Additionally,
      lung inflammation induced by T cells, which is critically controlled by OX40, was
      more pronounced in TRAF5(-/-) mice, characterized by higher levels of Th2
      cytokines. These results suggest that TRAF5 can limit the induction of Th2
      responses, and that TRAF5 can play a role in modulating responses driven by OX40
      costimulation.

PMID- 15034045
TI  - Recombinogenic phenotype of human activation-induced cytosine deaminase.
AB  - Class switch recombination, gene conversion, and somatic hypermutation that
      diversify rearranged Ig genes to produce various classes of high affinity Abs are
      dependent on the enzyme activation-induced cytosine deaminase (AID). Evidence
      suggests that somatic hypermutation is due to error-prone DNA repair that is
      initiated by AID-mediated deamination of cytosine in DNA, whereas the mechanism
      by which AID controls recombination remains to be elucidated. In this study,
      using a yeast model system, we have observed AID-dependent recombination.
      Expression of human AID in wild-type yeast is mutagenic for G-C to A-T
      transitions, and as expected, this mutagenesis is increased upon inactivation of
      uracil-DNA glycosylase. AID expression also strongly induces intragenic mitotic
      recombination, but only in a strain possessing uracil-DNA glycosylase. Thus, the
      initial step of base excision repair is required for AID-dependent recombination
      and is a branch point for either hypermutagenesis or recombination.

PMID- 15034046
TI  - Identifiying human MHC supertypes using bioinformatic methods.
AB  - Classification of MHC molecules into supertypes in terms of peptide-binding
      specificities is an important issue, with direct implications for the development
      of epitope-based vaccines with wide population coverage. In view of extremely
      high MHC polymorphism (948 class I and 633 class II HLA alleles) the experimental
      solution of this task is presently impossible. In this study, we describe a
      bioinformatics strategy for classifying MHC molecules into supertypes using
      information drawn solely from three-dimensional protein structure. Two
      chemometric techniques-hierarchical clustering and principal component analysis
      were used independently on a set of 783 HLA class I molecules to identify
      supertypes based on structural similarities and molecular interaction fields
      calculated for the peptide binding site. Eight supertypes were defined: A2, A3,
      A24, B7, B27, B44, C1, and C4. The two techniques gave 77% consensus, i.e., 605
      HLA class I alleles were classified in the same supertype by both methods. The
      proposed strategy allowed "supertype fingerprints" to be identified. Thus, the A2
      supertype fingerprint is Tyr(9)/Phe(9), Arg(97), and His(114) or Tyr(116); the A3
      Tyr(9)/Phe(9)/Ser(9), Ile(97)/Met(97) and Glu(114) or Asp(116); the A24-Ser(9)
      and Met(97); the B7-Asn(63) and Leu(81); the B27-Glu(63) and Leu(81); for B44
      Ala(81); the C1-Ser(77); and the C4-Asn(77).

PMID- 15034047
TI  - Depletion of cellular cholesterol and lipid rafts increases shedding of CD30.
AB  - CD30, a lymphoid activation marker, is shed into the cell environment after
      endoproteolytic cleavage of its ectodomain. Soluble (s)CD30 is able to suppress
      the Th1-type immune response. Because high serum levels of sCD30 and cholesterol
      lowering drugs seem to be beneficial in some Th1-type autoimmune diseases, we
      focused on a link between CD30 shedding and the amount of cellular cholesterol.
      Cholesterol depletion of human Hodgkin lymphoma- and non-Hodgkin lymphoma-derived
      cell lines by methyl-beta-cyclodextrin led to a down-regulation of membrane-bound
      CD30 and increased release of sCD30. Additionally, the cholesterol-interfering
      drugs lovastatin, cholesterol oxidase, and filipin increased CD30 shedding. Both
      the down-regulation of membrane-anchored CD30 and the release of sCD30 were
      dependent on metalloproteinases. Using specific inhibitors, we detected TNF-alpha
      converting enzyme (TACE) as the leading enzyme responsible for cholesterol
      dependent CD30 shedding. A Triton X-100-based method for lipid raft isolation
      revealed that CD30 was partially present in lipid rafts, whereas TACE was
      localized in the nonraft fractions. Disintegration of lipid rafts by cholesterol
      depletion might therefore lead to dynamic interactions of CD30 with TACE,
      resulting in enhanced shedding of CD30. Our results suggest a possible role of
      cholesterol-dependent shedding of CD30 in the pathogenesis of immune diseases.

PMID- 15034048
TI  - TNF and phorbol esters induce lymphotoxin-beta expression through distinct
      pathways involving Ets and NF-kappa B family members.
AB  - Lymphotoxin-beta (LT-beta) is a transmembrane protein expressed mainly on cells
      of the lymphoid lineage. It associates with LT-alpha on the cell surface to form
      the heterotrimeric LTalpha1,beta2 complex, which binds the LT-beta receptor.
      Membrane lymphotoxin is a crucial signal for the appropriate development of lymph
      nodes and Peyer's patches, and in the formation of B and T cell compartments in
      the spleen. In this study we report the characterization of mechanisms governing
      both basal as well as PMA- and TNF-inducible regulation of the human LT-beta
      promoter. Using a Jurkat T cell line, induction with either PMA or TNF resulted
      in an increase in mRNA levels compared with uninduced values. This induction
      corresponded to an increase in transcriptional activity of the human LT-beta
      promoter. Mutational and deletion analysis demonstrated the importance of Ets and
      NF-kappaB motifs in the regulation of basal transcription. Furthermore, the
      ability of PMA to induce activity was lost in the Ets mutant constructs.
      Interestingly, the same mutation had little effect on the ability of TNF to
      induce transcription of the LT-beta promoter. TNF inducibility was localized to
      the NF-kappaB site positioned at -83 of the promoter sequence. Thus, it appears
      that the Ets site, although playing a major role in PMA induction, did not
      mediate TNF inducibility. Therefore, our study suggests that alternative
      signaling pathways may be present to induce the expression of LT-beta in response
      to different immunological or inflammatory stimuli.

PMID- 15034049
TI  - Characterization of recombinant mannan-binding lectin-associated serine protease
      (MASP)-3 suggests an activation mechanism different from that of MASP-1 and MASP
      2.
AB  - Mannan-binding lectin (MBL)-associated serine proteases (MASP-1, -2, and -3) are
      homologous modular proteases that each associate with MBL and L- and H-ficolins,
      which are oligomeric serum lectins involved in innate immunity. To investigate
      its physicochemical, interaction, and enzymatic properties, human MASP-3 was
      expressed in insect cells. Ultracentrifugation analysis indicated that rMASP-3
      sedimented as a homodimer (s(20,w) = 6.2 +/- 0.1 S) in the presence of Ca(2+),
      and as a monomer (s(20,w) = 4.6 +/- 0.1 S) in EDTA. As shown by surface plasmon
      resonance spectroscopy, it associated with both MBL (K(D) = 2.6 nM) and L-ficolin
      (K(D) = 7.2 nM). The protease was produced in a single-chain, proenzyme form, but
      underwent slow activation upon prolonged storage at 4 degrees C, resulting from
      cleavage at the Arg(430)-Ile(431) activation site. Activation was prevented in
      the presence of protease inhibitors iodoacetamide and 1,10-phenanthroline but was
      not abolished upon substitution of Ala for the active site Ser(645) of MASP-3,
      indicating extrinsic proteolysis. In contrast, the corresponding mutations
      Ser(627)-->Ala in MASP-1 and Ser(618)-->Ala in MASP-2 stabilized the latter in
      their proenzyme form. Likewise, the MASP-1 and MASP-2 mutants were each activated
      by their active counterparts, but MASP-3 S645A was not. Activated MASP-3 did not
      react with C1 inhibitor; had no activity on complement proteins C2, C4, and C3;
      and only cleaved the N-carboxybenzyloxyglycine-L-arginine thiobenzyl ester
      substrate to a significant extent. Based on these observations, it is postulated
      that MASP-3 activation and control involve mechanisms that are different from
      those of MASP-1 and -2.

PMID- 15034050
TI  - Mutational analyses of the recombinant globular regions of human C1q A, B, and C
      chains suggest an essential role for arginine and histidine residues in the C1q
      IgG interaction.
AB  - The first step in the activation of the classical complement pathway by immune
      complexes involves the binding of the globular domain (gC1q) of C1q to the Fc
      regions of aggregated IgG or IgM. Each gC1q domain is a heterotrimer of the C
      terminal halves of one A (ghA), one B (ghB), and one C (ghC) chain. Our recent
      studies have suggested a modular organization of gC1q, consistent with the view
      that ghA, ghB, and ghC are functionally autonomous modules and have distinct and
      differential ligand-binding properties. Although C1q binding sites on IgG have
      been previously identified, the complementary interacting sites on the gC1q
      domain have not been precisely defined. The availability of the recombinant
      constructs expressing ghA, ghB, and ghC has allowed us, for the first time, to
      engineer single-residue substitution mutations and identify residues on the gC1q
      domain, which are involved in the interaction between C1q and IgG. Because C1q is
      a charge pattern recognition molecule, we have sequentially targeted arginine and
      histidine residues in each chain. Consistent with previous chemical modification
      studies and the recent crystal structure of gC1q, our results support a central
      role for arginine and histidine residues, especially Arg(114) and Arg(129) of the
      ghB module, in the C1q-IgG interaction.

PMID- 15034051
TI  - Localization of the domains in Runx transcription factors required for the
      repression of CD4 in thymocytes.
AB  - The runt family transcription factors Runx1 and Runx3 are expressed in developing
      murine thymocytes. We show that enforced expression of full-length Runx1 in CD4(
      )CD8(-) thymocytes results in a profound suppression of immature CD4/CD8 double
      positive thymocytes and mature CD4 single-positive thymocytes compared with
      controls. This effect arises from Runx1- or Runx3-mediated repression of CD4
      expression, and is independent of positively selecting signals. Runx1 is able to
      repress CD4 in CD4/CD8 double-positive thymocytes, but not in mature splenic T
      cells. Runx-mediated CD4 repression is independent of association with the
      corepressors Groucho/TLE or Sin3. Two domains are required for complete Runx
      mediated CD4 repression. These are contained within Runx1 aa 212-262 and 263-360.
      The latter region contains the nuclear matrix targeting sequence, which is highly
      conserved among runt family transcription factors across species. The presence of
      the nuclear matrix targeting sequence is required for Runx-mediated CD4
      repression, suggesting that Runx transcription factors are stabilized on the CD4
      silencer via association with the nuclear matrix.

PMID- 15034052
TI  - Identification and molecular cloning of functional chicken IL-12.
AB  - By a combination of large-scale sequencing, bioinformatics, and traditional
      molecular biology, we identified the long-searched-for cDNA sequences encoding
      the homologues of the chicken IL-12p35 and IL-12p40 chains. These molecules are
      the first discovered nonmammalian IL-12 subunits. The homologies of the chicken
      IL-12p35 and IL-12p40 proteins to the corresponding known subunits of various
      species, i.e., humans, sheep, horse, cat, bovine, mouse, and woodchuck, ranged
      between 21 and 42%, respectively. The expression of IL-12 subunits was observed
      in lymphoid cells and proved to be dependent on the cell type and stimulus, while
      expression was not detected in stimulated primary chicken embryo fibroblast
      cells. Following transient expression of both molecules in COS-7 cells, we
      confirmed the necessity of heterodimerization into IL-12p70 to yield bioactivity
      as was also shown for its mammalian counterparts. The chicken IL-12p70 molecule,
      generated either by transient coexpression of monomeric IL-12p35 and monomeric IL
      12p40 or as a fusion protein (as in a fusion linker construct), induced IFN-gamma
      synthesis and proliferative activity of freshly exposed chicken splenocytes. The
      high degree of functional similarity between chicken IL-12 and IL-12 of higher
      mammalian vertebrates, despite their poor sequence homology, illustrates the
      conservation and vital importance of the IL-12 molecule since the evolutionary
      dichotomy of birds and mammals >300 million years ago. In this article, we
      describe the first nonmammalian IL-12 molecule and show that this chicken IL-12
      molecule is bioactive.

PMID- 15034053
TI  - Cloning, expression, cellular distribution, and role in chemotaxis of a C5a
      receptor in rainbow trout: the first identification of a C5a receptor in a
      nonmammalian species.
AB  - C3a, C4a, and C5a anaphylatoxins generated during complement activation play a
      key role in inflammation. C5a is the most potent of the three anaphylatoxins in
      eliciting biological responses. The effects of C5a are mediated by its binding to
      C5a receptor (C5aR, CD88). To date, C5aR has only been identified and cloned in
      mammalian species, and its evolutionary history remains ill-defined. To gain
      insights into the evolution, conserved structural domains, and functions of C5aR,
      we have cloned and characterized a C5aR in rainbow trout, a teleost fish. The
      isolated cDNA encoded a 350-aa protein that showed the highest sequence
      similarity to C5aR from other species. Genomic analysis revealed the presence of
      one continuous exon encoding the entire open reading frame. Northern blot
      analysis showed significant expression of the trout C5a receptor (TC5aR) message
      in PBLs and kidney. Flow cytometric analysis showed that two Abs generated
      against two different areas of the extracellular N-terminal region of TC5aR
      positively stained the same leukocyte populations from PBLs. B lymphocytes and
      granulocytes comprised the majority of cells recognized by the anti-TC5aR. More
      importantly, these Abs inhibited chemotaxis of PBLs toward a chemoattractant
      fraction purified from complement-activated trout serum. Our data suggest that
      the split between C5aR and C3aR from a common ancestral molecule occurred before
      the emergence of teleost fish. Moreover, we demonstrate that the overall
      structure of C5aR as well as its role in chemotaxis have remained conserved for
      >300 million years.

PMID- 15034054
TI  - Signaling through Toll-like receptors triggers HIV-1 replication in latently
      infected mast cells.
AB  - Evidence that human progenitor mast cells are susceptible to infection with CCR5
      tropic strains of HIV-1 and that circulating HIV-1-infected FcepsilonRIalpha(+)
      cells with a similar progenitor phenotype have been isolated from AIDS patients
      has led to speculation that mast cells may serve as a potential reservoir for
      infectious HIV-1. In this study, progenitor mast cells, developed in vitro from
      CD34(+) cord blood stem cells, were experimentally infected with the CCR5-tropic
      strain HIV-1Bal after 28 days in culture as they reached their HIV-1-susceptible
      progenitor stage. HIV-1 p24 Ag levels were readily detectable by day 7
      postinfection (PI), peaked at 2-3 wk PI as mature (tryptase/chymase-positive) HIV
      1 infection-resistant mast cells emerged, and then steadily declined to below
      detectable limits by 10 wk PI, at which point integrated HIV-1 proviral DNA was
      confirmed by PCR quantitation in ( approximately 34% of) latently infected mast
      cells. Stimulation by ligands for Toll-like receptor (TLR) 2, TLR4, or TLR9
      significantly enhanced viral replication in a dose- and time-dependent manner in
      both HIV-1-infected progenitor and latently infected mature mast cells, without
      promoting degranulation, apoptosis, cellular proliferation, or dysregulation of
      TLR agonist-induced cytokine production in infected mast cells. Limiting dilution
      analysis of TLR activated, latently infected mature mast cells indicated that one
      in four was capable of establishing productive infections in A301 sentinel cells.
      Taken together, these results indicate that mast cells may serve both as a viral
      reservoir and as a model for studying mechanisms of postintegration latency in
      HIV infection.

PMID- 15034056
TI  - Subpopulations of mouse blood monocytes differ in maturation stage and
      inflammatory response.
AB  - Blood monocytes are well-characterized precursors for macrophages and dendritic
      cells. Subsets of human monocytes with differential representation in various
      disease states are well known. In contrast, mouse monocyte subsets have been
      characterized minimally. In this study we identify three subpopulations of mouse
      monocytes that can be distinguished by differential expression of Ly-6C, CD43,
      CD11c, MBR, and CD62L. The subsets share the characteristics of extensive
      phagocytosis, similar expression of M-CSF receptor (CD115), and development into
      macrophages upon M-CSF stimulation. By eliminating blood monocytes with
      dichloromethylene-bisphosphonate-loaded liposomes and monitoring their
      repopulation, we showed a developmental relationship between the subsets.
      Monocytes were maximally depleted 18 h after liposome application and
      subsequently reappeared in the circulation. These cells were exclusively of the
      Ly-6C(high) subset, resembling bone marrow monocytes. Serial flow cytometric
      analyses of newly released Ly-6C(high) monocytes showed that Ly-6C expression on
      these cells was down-regulated while in circulation. Under inflammatory
      conditions elicited either by acute infection with Listeria monocytogenes or
      chronic infection with Leishmania major, there was a significant increase in
      immature Ly-6C(high) monocytes, resembling the inflammatory left shift of
      granulocytes. In addition, acute peritoneal inflammation recruited preferentially
      Ly-6C(med-high) monocytes. Taken together, these data identify distinct
      subpopulations of mouse blood monocytes that differ in maturation stage and
      capacity to become recruited to inflammatory sites.

PMID- 15034055
TI  - Induction of a rapid and strong antigen-specific intraepithelial lymphocyte
      response during oral Encephalitozoon cuniculi infection.
AB  - Encephalitozoon cuniculi continues to pose a problem for immunocompromised
      patients. Previous studies from our laboratory have elucidated the importance of
      the CD8(+) T cell subset in the protection against systemic parasite infection.
      There have been no studies related to the mucosal immunity induced against this
      orally acquired pathogen. In the present study, the immune response generated in
      the gut after oral E. cuniculi infection was evaluated. An early and rapid
      increase of the intraepithelial lymphocyte (IEL) population of orally infected
      animals was observed. This increase in the IEL population started as early as day
      3 and peaked at day 7 postinfection with persistent elevation thereafter. At day
      7 postinfection, IELs expressed strong cytokine messages (IFN-gamma and IL-10)
      and were highly cytotoxic for parasite-infected syngeneic macrophages. At an E:T
      ratio of 80:1, these cells were able to cause >60% Ag-specific target cell lysis.
      A significant increase in the CD8alphaalpha subset of IEL in response to an oral
      E. cuniculi infection was observed. To the best of our knowledge, such an early
      expansion of an IEL population exhibiting strong ex vivo cytotoxicity has not
      been reported with infectious models. These data suggest that IELs act as
      important barriers for multiplication of this organism leading to the successful
      resolution of infection. The protective role of IELs may be due both to their
      inflammatory (IFN-gamma production and cytotoxic response) as well as
      immunoregulatory (IL-10 production) properties.

PMID- 15034057
TI  - The Ly-6Chigh monocyte subpopulation transports Listeria monocytogenes into the
      brain during systemic infection of mice.
AB  - Mononuclear phagocytes can be used by intracellular pathogens to disseminate
      throughout the host. In the bloodstream these cells are generically referred to
      as monocytes. However, blood monocytes are a heterogeneous population, and the
      exact identity of the leukocyte(s) relevant for microbial spreading is not known.
      Experiments reported in this study used Listeria monocytogenes-infected mice to
      establish the phenotype of parasitized blood leukocytes and to test their role in
      systemic dissemination of intracellular bacteria. More than 90% of the blood
      leukocytes that were associated with bacteria were CD11b(+) mononuclear cells.
      Analysis of newly described monocyte subsets showed that most infected cells
      belonged to the Ly-6C(high) monocyte subset and that Ly-6C(high) and Ly-6C(neg
      low) monocytes harbored similar numbers of bacteria per cell. Interestingly,
      systemic infection with wild-type or DeltaactA mutants of L. monocytogenes, both
      of which escape from phagosomes and replicate intracellularly, caused expansion
      of the Ly-6C(high) subset. In contrast, this was not evident after infection with
      Deltahly mutants, which neither escape phagosomes nor replicate intracellularly.
      Importantly, when CD11b(+) leukocytes were isolated from the brains of lethally
      infected mice, 88% of these cells were identified as Ly-6C(high) monocytes.
      Kinetic analysis showed a significant influx of Ly-6C(high) monocytes into the
      brain 2 days after systemic infection. This coincided with both bacterial
      invasion and up-regulation of brain macrophage chemoattractant protein-1 gene
      expression. These data indicate that the Ly-6C(high) monocyte subset transports
      L. monocytogenes into the brain and establish their role as Trojan horses in
      vivo.

PMID- 15034058
TI  - Toll-like receptor 2 (TLR2)-dependent-positive and TLR2-independent-negative
      regulation of proinflammatory cytokines by mycobacterial lipomannans.
AB  - Lipoarabinomannans (LAM) and lipomannans (LM) are integral parts of the
      mycobacterial cell wall recognized by cells involved in the innate immune
      response and have been found to modulate the cytokine response. Typically,
      mannosylated LAM from pathogenic mycobacteria have been reported to be anti
      inflammatory, whereas phosphoinositol-substituted LAM from nonpathogenic species
      are proinflammatory molecules. In this study, we show that LM from several
      mycobacterial species, including Mycobacterium chelonae, Mycobacterium kansasii,
      and Mycobacterium bovis bacillus Calmette-Guerin, display a dual function by
      stimulating or inhibiting proinflammatory cytokine synthesis through different
      pathways in murine primary macrophages. LM, but none of the corresponding LAM,
      induce macrophage activation characterized by cell surface expression of CD40 and
      CD86 and by TNF and NO secretion. This activation is dependent on the presence of
      Toll-like receptor (TLR) 2 and mediated through the adaptor protein myeloid
      differentiation factor 88 (MyD88), but independent of either TLR4 or TLR6
      recognition. Surprisingly, LM exerted also a potent inhibitory effect on TNF, IL
      12p40, and NO production by LPS-activated macrophages. This TLR2-, TLR6-, and
      MyD88-independent inhibitory effect is also mediated by LAM from M. bovis
      bacillus Calmette-Guerin but not by LAM derived from M. chelonae and M. kansasii.
      This study provides evidence that mycobacterial LM bear structural motifs
      susceptible to interact with different pattern recognition receptors with pro- or
      anti-inflammatory effects. Thus, the ultimate response of the host may therefore
      depend on the prevailing LM or LAM in the mycobacterial envelope and the local
      host cell receptor availability.

PMID- 15034059
TI  - Preferential HLA usage in the influenza virus-specific CTL response.
AB  - To study whether individual HLA class I alleles are used preferentially or
      equally in human virus-specific CTL responses, the contribution of individual HLA
      A and -B alleles to the human influenza virus-specific CTL response was
      investigated. To this end, PBMC were obtained from three groups of HLA-A and -B
      identical blood donors and stimulated with influenza virus. In the virus-specific
      CD8(+) T cell population, the proportion of IFN-gamma- and TNF-alpha-producing
      cells, restricted by individual HLA-A and -B alleles, was determined using virus
      infected C1R cells expressing a single HLA-A or -B allele for restimulation of
      these cells. In HLA-B*2705- and HLA-B*3501-positive individuals, these alleles
      were preferentially used in the influenza A virus-specific CTL response, while
      the contribution of HLA-B*0801 and HLA-A*0101 was minor in these donors. The
      magnitude of the HLA-B*0801-restricted response was even lower in the presence of
      HLA-B*2705. C1R cells expressing HLA-B*2705, HLA-A*0101, or HLA-A*0201 were
      preferentially lysed by virus-specific CD8(+) T cells. In contrast, the CTL
      response to influenza B virus was mainly directed toward HLA-B*0801-restricted
      epitopes. Thus, the preferential use of HLA alleles depended on the virus
      studied.

PMID- 15034060
TI  - HIV-specific CD8+ T cells exhibit markedly reduced levels of Bcl-2 and Bcl-xL.
AB  - Human immunodeficiency virus-specific CD8(+) T cells are highly sensitive to
      spontaneous and CD95/Fas-induced apoptosis, and this sensitivity may impair their
      ability to control HIV infection. To elucidate the mechanism behind this
      sensitivity, in this study we examined the levels of antiapoptotic molecules Bcl
      2 and Bcl-x(L) in HIV-specific CD8(+) T cells from HIV-infected individuals. Bcl
      2 expression was markedly decreased in HIV-specific CD8(+) T cells compared with
      CMV-specific and total CD8(+) T cells from HIV-infected individuals as well as
      total CD8(+) T cells from healthy donors. CD8(+) T cell Bcl-2 levels inversely
      correlated with spontaneous and CD95/Fas-induced apoptosis of CD8(+) T cells from
      HIV-infected individuals. HIV-specific CD8(+) T cells also had significantly
      lower levels of Bcl-x(L) compared with CMV-specific CD8(+) T cells. Finally, IL
      15 induces both Bcl-2 and Bcl-x(L) expression in HIV-specific and total CD8(+) T
      cells, and this correlated with apoptosis inhibition and increased survival in
      both short- and long-term cultures. Our data indicate that reduced Bcl-2 and Bcl
      x(L) may play an important role in the increased sensitivity to apoptosis of HIV
      specific CD8(+) T cells and suggest a possible mechanism by which IL-15 increases
      their survival.

PMID- 15034061
TI  - Macrophage interactions with neutrophils regulate Leishmania major infection.
AB  - Macrophages are host cells for the pathogenic parasite Leishmania major.
      Neutrophils die and are ingested by macrophages in the tissues. We investigated
      the role of macrophage interactions with inflammatory neutrophils in control of
      L. major infection. Coculture of dead exudate neutrophils exacerbated parasite
      growth in infected macrophages from susceptible BALB, but killed intracellular L.
      major in resistant B6 mice. Coinjection of dead neutrophils amplified L. major
      replication in vivo in BALB, but prevented parasite growth in B6 mice. Neutrophil
      depletion reduced parasite load in infected BALB, but exacerbated infection in B6
      mice. Exacerbated growth of L. major required PGE(2) and TGF-beta production by
      macrophages, while parasite killing depended on neutrophil elastase and TNF-alpha
      production. These results indicate that macrophage interactions with dead
      neutrophils play a previously unrecognized role in host responses to L. major
      infection.

PMID- 15034062
TI  - Toll-like receptors are temporally involved in host defense.
AB  - Toll-like receptors (TLRs) are evolutionarily conserved proteins that recognize
      microbial molecules and initiate host defense. To investigate how TLRs work
      together to fight infections, we tested the role of TLRs in host defense against
      the Gram-negative bacterial pathogen, Salmonella. We show that TLR4 is critical
      for early cytokine production and killing of bacteria by murine macrophages.
      Interestingly, later on, TLR2, but not TLR4, is required for macrophage
      responses. Myeloid differentiation factor 88, an adaptor protein directly
      downstream of TLRs, is required for both early and late responses. TLR4, TLR2,
      and myeloid differentiation factor 88 are involved in murine host defense against
      Salmonella in vivo, which correlates with the defects in host defense observed in
      vitro. We propose a model where the sequential activation of TLRs tailors the
      immune response to different microbes.

PMID- 15034063
TI  - CD14 is an acute-phase protein.
AB  - The origin of soluble CD14 (sCD14) in the circulation is uncertain. To examine
      whether CD14 could be an acute-phase protein (APP), the levels of sCD14, IL-6,
      and C-reactive protein were determined by ELISA in serum and synovial fluid (SF)
      of patients with various arthropathies, and the regulation of CD14 synthesis was
      examined in liver cells. In patients with crystal-mediated or immunologically
      mediated arthritis (rheumatoid arthritis), serum levels of sCD14 were higher than
      or similar to those found in infection-mediated arthritis (reactive arthritis),
      precluding a relation with bacteria exposure. Levels of sCD14 were similar in SF
      and serum, and did not correlate with the number of SF leukocytes, excluding an
      important source from leukocyte membrane-bound CD14, by protease-mediated
      shedding. In contrast, serum levels of sCD14 in patients correlated with those of
      C-reactive protein, a classical APP, and IL-6, a cytokine known to regulate the
      synthesis of APP in the liver. Serum levels of sCD14 also correlated with disease
      activity in rheumatoid arthritis and reactive arthritis patients. IL-6 stimulated
      the production of CD14 by HepG2 hepatoma cells. By real-time PCR, the
      inducibility of CD14 by IL-6 was also observed at the mRNA level both in HepG2
      cells and human primary hepatocytes. These in vitro results were confirmed by in
      vivo studies in IL-6(-/-) mice injected with turpentine, an experimental model of
      acute-phase response. Liver levels of CD14 mRNA increased in IL-6(+/+), but not
      in IL-6(-/-) mice. These results indicate that sCD14 can be considered as a type
      2 APP.

PMID- 15034064
TI  - Lysophosphatidic acid induces chemotaxis, oxygen radical production, CD11b up
      regulation, Ca2+ mobilization, and actin reorganization in human eosinophils via
      pertussis toxin-sensitive G proteins.
AB  - Lysophosphatidic acid (LPA) is a bioactive lipid mediator, which is generated by
      secretory type II phospholipase A(2) and is thought to play a major role in the
      pathogenesis of atopic diseases. In this study, the biological activity of LPA on
      human eosinophils was characterized. We showed by reverse transcription and PCR
      that human eosinophils express the mRNA of the LPA receptors endothelial
      differentiation gene (EDG)-2 and EDG-7. Experiments revealed that LPA has
      chemotactic activity toward eosinophils, stimulates the production of reactive
      oxygen metabolites, and induces up-regulation of the integrin CD11b. Signal
      pathway measurements indicated Ca(2+)-mobilization from intracellular stores and
      transient actin polymerization upon stimulation with LPA. Cell responses elicited
      by LPA were inhibited by pertussis toxin indicating that in eosinophils the LPA
      receptor(s), presumably EDG-2 and/or EDG-7, are coupled to G(i/o) proteins.
      Moreover, LPA-induced activation of eosinophils could be completely blocked by
      the EDG-2/EDG-7 antagonist diacylglycerol pyrophosphate. In addition, at optimal
      doses the changes induced by LPA were comparable to those obtained by the other
      well-characterized chemotaxins. These results indicate that LPA is a strong
      chemotaxin and activator of eosinophils. These findings point to a novel role of
      LPA in the pathogenesis of diseases with eosinophilic inflammation such as atopic
      diseases as chemotaxin as well as activator of proinflammatory effector
      functions.

PMID- 15034065
TI  - O-methylated catechins from tea leaves inhibit multiple protein kinases in mast
      cells.
AB  - Tea contains a variety of bioactive compounds. In this study, we show that two O
      methylated catechins, (-)-epigallocatechin-3-O-(3-O-methyl) gallate and (-)
      epigallocatechin-3-O-(4-O-methyl) gallate, inhibit in vivo mast cell-dependent
      allergic reactions more potently than their nonmethylated form, (-)
      epigallocatechin-3-O-gallate. Consistent with this, these O-methylated catechins
      inhibit IgE/Ag-induced activation of mouse mast cells: histamine release,
      leukotriene release, and cytokine production and secretion were all inhibited. As
      a molecular basis for the catechin-mediated inhibition of mast cell activation,
      Lyn, Syk, and Bruton's tyrosine kinase, the protein tyrosine kinases, known to be
      critical for early activation events, are shown to be inhibited by the O
      methylated catechins. In vitro kinase assays using purified proteins show that
      the O-methylated catechins can directly inhibit the above protein tyrosine
      kinases. These catechins inhibit IgE/Ag-induced calcium response as well as the
      activation of downstream serine/threonine kinases such as Akt and c-Jun N
      terminal kinase. These observations for the first time have revealed the
      molecular mechanisms of antiallergic effects of tea-derived catechins.

PMID- 15034066
TI  - Neutrophil elastase (NE)-deficient mice demonstrate a nonredundant role for NE in
      neutrophil migration, generation of proinflammatory mediators, and phagocytosis
      in response to zymosan particles in vivo.
AB  - Neutrophil elastase (NE) remains a controversial player in the process of
      leukocyte transmigration and much of this controversy stems from conflicting
      reports on the effects of NE inhibitors. The availability of NE-deficient mice
      (NE(-/-)) provides a clean and elegant tool for the study of leukocyte migration
      in vivo. In this study, NE(-/-) mice were used to investigate the role of NE in
      leukocyte migration through cremasteric venules, as observed by intravital
      microscopy, induced by locally administered cytokines IL-1beta and TNF-alpha and
      the particulate stimulus, zymosan. Although no defects in leukocyte responses
      induced by the cytokines were observed, zymosan-induced leukocyte firm adhesion
      and transmigration was suppressed in NE(-/-) mice. These responses were also
      inhibited in wild-type mice when zymosan was coinjected with a specific NE
      inhibitor. Quantification of inflammatory mediator levels in homogenates of
      zymosan-stimulated tissues indicated reductions in levels of IL-1beta, KC, and
      macrophage inflammatory protein-1alpha in NE(-/-) mice. Furthermore, phagocytosis
      of fluorescent zymosan particles, as observed by intravital microscopy, was
      diminished in NE-deficient animals. Collectively, the findings of this study
      indicate a nonredundant role for NE in zymosan-induced leukocyte firm adhesion
      and transmigration, and that this defect is associated with impaired generation
      of proinflammatory mediators as well as phagocytosis of zymosan particles in
      vivo.

PMID- 15034067
TI  - Immunization with glucose-6-phosphate isomerase induces T cell-dependent
      peripheral polyarthritis in genetically unaltered mice.
AB  - Rheumatoid arthritis is a chronic inflammatory disease primarily affecting the
      joints. The search for arthritogenic autoantigens that trigger autoimmune
      responses in rheumatoid arthritis has largely focused on cartilage- or joint
      specific Ags. In this study, we show that immunization with the ubiquitously
      expressed glycolytic enzyme glucose-6-phosphate isomerase (G6PI) induces severe
      peripheral symmetric polyarthritis in normal mice. In genetically unaltered mice,
      T cells are indispensable for both the induction and the effector phase of G6PI
      induced arthritis. Arthritis is cured by depletion of CD4(+) cells. In contrast,
      Abs and FcgammaR(+) effector cells are necessary but not sufficient for G6PI
      induced arthritis in genetically unaltered mice. Thus, the complex pathogenesis
      of G6PI-induced arthritis in normal mice differs strongly from the spontaneously
      occurring arthritis in the transgenic K/B x N model where Abs against G6PI alone
      suffice to induce the disease. G6PI-induced arthritis demonstrates for the first
      time the induction of organ-specific disease by systemic autoimmunity in
      genetically unaltered mice. Both the induction and effector phase of arthritis
      induced by a systemic autoimmune response can be dissected and preventive and
      therapeutic strategies evaluated in this model.

PMID- 15034068
TI  - Deletion of the mouse meprin beta metalloprotease gene diminishes the ability of
      leukocytes to disseminate through extracellular matrix.
AB  - Meprins are metalloendopeptidases expressed by leukocytes in the lamina propria
      of the human inflamed bowel, that degrade extracellular matrix proteins in vitro
      implicating them in leukocyte transmigration events. The aims of these studies
      were to 1) examine the expression of meprins in the mouse mesenteric lymph node,
      2) determine whether macrophages express meprins, and 3) determine whether
      deletion of the meprin beta gene (Mep-1beta) mitigated the ability of leukocytes
      to disseminate through extracellular matrix in vitro. These studies show that
      meprin alpha and beta are expressed in leukocytes of the mouse mesenteric lymph
      node, and meprin alpha, but not beta, decreased during intestinal inflammation.
      Deletion of Mep-1beta gene decreased the ability of leukocytes to migrate through
      matrigel compared with wild-type leukocytes. Meprin beta, but not alpha, was
      detected in cortical and medullary macrophages of the lymph node. Thus overall,
      meprin beta is expressed by leukocytes in the draining lymph node of the
      intestine, regardless of the inflammatory status of the animal, and is likely to
      contribute to leukocyte transmigration events important to intestinal immune
      responses. Thus, the expression of meprins by leukocytes of the intestinal immune
      system may have important implications for diseases such as inflammatory bowel
      diseases, which are aggravated by leukocyte infiltration.

PMID- 15034069
TI  - Aerobic exercise attenuates airway inflammatory responses in a mouse model of
      atopic asthma.
AB  - Recent reports indicate that aerobic exercise improves the overall physical
      fitness and health of asthmatic patients. The specific exercise-induced
      improvements in the pathology of asthma and the mechanisms by which these
      improvements occur, however, are ill-defined; thus, the therapeutic potential of
      exercise in the treatment of asthma remains unappreciated. Using an OVA-driven
      mouse model, we examined the role of aerobic exercise in modulating inflammatory
      responses associated with atopic asthma. Data demonstrate that moderate intensity
      aerobic exercise training decreased leukocyte infiltration, cytokine production,
      adhesion molecule expression, and structural remodeling within the lungs of OVA
      sensitized mice (n = 6-10; p < 0.05). Because the transcription factor NF-kappaB
      regulates the expression of a variety of genes that encode inflammatory
      mediators, we monitored changes in NF-kappaB activation in the lungs of
      exercised/sensitized mice. Results show that exercise decreased NF-kappaB nuclear
      translocation and IkappaBalpha phosphorylation, indicating that exercise
      decreased NF-kappaB activation in the lungs of sensitized mice (n = 6). Taken
      together, these results suggest that aerobic exercise attenuates airway
      inflammation in a mouse model of atopic asthma via modulation of NF-kappaB
      activation. Potential exists, therefore, for the amelioration of asthma
      associated chronic airway inflammation through the use of aerobic exercise
      training as a non-drug therapeutic modality.

PMID- 15034070
TI  - IL-4-dependent Th2 collateral priming to inhaled antigens independent of Toll
      like receptor 4 and myeloid differentiation factor 88.
AB  - Allergic asthma is an inflammatory lung disease thought to be initiated and
      directed by type 2 helper T cells responding to environmental Ags. The mechanisms
      by which allergens induce Th2-adaptive immune responses are not well understood,
      although it is now clear that innate immune signals are required to promote DC
      activation and Th2 sensitization to inhaled proteins. However, the effect of
      ongoing Th2 inflammation, as seen in chronic asthma, on naive lymphocyte
      activation has not been explored. It has been noted that patients with atopic
      disorders demonstrate an increased risk of developing sensitivities to new
      allergens. This suggests that signals from an adaptive immune response may
      facilitate sensitization to new Ags. We used a Th2-adoptive transfer murine model
      of asthma to identify a novel mechanism, termed "collateral priming," in which
      naive CD4(+) T cells are activated by adaptive rather than innate immune signals.
      Th2 priming to newly encountered Ags was dependent on the production of IL-4 by
      the transferred Th2 population but was independent of Toll-like receptor 4
      signaling and the myeloid differentiation factor 88 Toll-like receptor signaling
      pathway. These results identify a novel mechanism of T cell priming in which an
      Ag-specific adaptive immune response initiates distinct Ag-specific T cell
      responses in the absence of classical innate immune system triggering signals.

PMID- 15034071
TI  - Adenoviral gene delivery of elafin and secretory leukocyte protease inhibitor
      attenuates NF-kappa B-dependent inflammatory responses of human endothelial cells
      and macrophages to atherogenic stimuli.
AB  - Atherosclerosis is a chronic inflammatory disease affecting arterial vessels.
      Strategies to reduce the inflammatory responses of endothelial cells and
      macrophages may slow lesion development and prevent complications such as plaque
      rupture. The human protease human neutrophil elastase (HNE), oxidized low density
      lipoprotein, LPS, and TNF-alpha were chosen as model stimuli of arterial wall
      inflammation and led to production of the chemokine IL-8 in endothelial cells. To
      counteract the activity of HNE, we have examined the effects of adenoviral gene
      delivery of the anti-elastases elafin, previously demonstrated within human
      atheroma, and murine secretory leukocyte protease inhibitor (SLPI), a related
      molecule, on the inflammatory responses of human endothelial cells and
      macrophages to atherogenic stimuli. We developed a technique of precomplexing
      adenovirus with cationic lipid to augment adenoviral infection efficiency in
      endothelial cells and to facilitate infection in macrophages. Elafin
      overexpression protected endothelial cells from HNE-induced IL-8 production and
      cytotoxicity. Elafin and murine SLPI also reduced endothelial IL-8 release in
      response to oxidized low density lipoprotein, LPS, and TNF-alpha and macrophage
      TNF-alpha production in response to LPS. This effect was associated with reduced
      activation of the inflammatory transcription factor NF-kappaB, through up
      regulation of IkappaBalpha, in both cell types. Our work suggests a novel and
      extended anti-inflammatory role for these HNE inhibitors working as effectors of
      innate immunity to protect tissues against maladaptive inflammatory responses.
      Our findings indicate that elafin and SLPI may be gene therapy targets for the
      treatment of atheroma.

PMID- 15034072
TI  - Complex role of the IL-4 receptor alpha in a murine model of airway inflammation:
      expression of the IL-4 receptor alpha on nonlymphoid cells of bone marrow origin
      contributes to severity of inflammation.
AB  - Recent studies have suggested the IL-4Ralpha expressed on lung epithelium is
      necessary for TH2-mediated goblet cell differentiation and mucus hypersecretion
      in a murine model of allergic lung disease. However, the IL-4Ralpha is expressed
      on numerous cell types that could contribute to the overall pathology and
      severity of asthma. The relative role of the receptor on these cells has not yet
      been conclusively delineated. To dissect the contribution of IL-4Ralpha in the
      development of pulmonary allergic responses, we generated murine radiation bone
      marrow (BM) chimeras. BM from IL-4Ralpha(+) or IL-4Ralpha(-) mice was transferred
      into recipient mice that expressed or lacked IL-4Ralpha. In the absence of IL
      4Ralpha in recipient mice, there was no goblet cell metaplasia or mucus
      hypersecretion in response to OVA, even in the presence of TH2 cells and
      substantial eosinophilic infiltration. More importantly, we found that expression
      of the IL-4Ralpha on a nonlymphoid, MHC class II(+), BM-derived cell type
      contributes to the severity of inflammation and mucus production. These results
      suggest that IL-4 and IL-13 contribute to the development of allergic
      inflammation by stimulating a complex interaction between IL-4Ralpha(+) cell
      types of both bone marrow and non-bone marrow origin.

PMID- 15034073
TI  - Monomeric recombinant TCR ligand reduces relapse rate and severity of
      experimental autoimmune encephalomyelitis in SJL/J mice through cytokine switch.
AB  - Our previous studies demonstrated that oligomeric recombinant TCR ligands (RTL)
      can treat clinical signs of experimental autoimmune encephalomyelitis (EAE) and
      induce long-term T cell tolerance against encephalitogenic peptides. In the
      current study, we produced a monomeric I-A(s)/PLP 139-151 peptide construct
      (RTL401) suitable for use in SJL/J mice that develop relapsing disease after
      injection of PLP 139-151 peptide in CFA. RTL401 given i.v. or s.c. but not empty
      RTL400 or free PLP 139-151 peptide prevented relapses and significantly reduced
      clinical severity of EAE induced by PLP 139-151 peptide in SJL/J or (C57BL/6 x
      SJL)F(1) mice, but did not inhibit EAE induced by PLP 178-191 or MBP 84-104
      peptides in SJL/J mice, or MOG 35-55 peptide in (C57BL/6 x SJL/J)F(1) mice. RTL
      treatment of EAE caused stable or enhanced T cell proliferation and secretion of
      IL-10 in the periphery, but reduced secretion of inflammatory cytokines and
      chemokines. In CNS, there was a modest reduction of inflammatory cells, reduced
      expression of very late activation Ag-4, lymphocyte function-associated Ag-1, and
      inflammatory cytokines, chemokines, and chemokine receptors, but enhanced
      expression of Th2-related factors, IL-10, TGF-beta3, and CCR3. These results
      suggest that monomeric RTL therapy induces a cytokine switch that curbs the
      encephalitogenic potential of PLP 139-151-specific T cells without fully
      preventing their entry into CNS, wherein they reduce the severity of
      inflammation. This mechanism differs from that observed using oligomeric RTL
      therapy in other EAE models. These results strongly support the clinical
      application of this novel class of peptide/MHC class II constructs in patients
      with multiple sclerosis who have focused T cell responses to known
      encephalitogenic myelin peptides.

PMID- 15034074
TI  - A self T cell epitope induces autoantibody response: mechanism for production of
      antibodies to diverse glomerular basement membrane antigens.
AB  - The anti-glomerular basement membrane (GBM) Ab has been regarded as a
      prototypical example of pathogenic autoantibodies. However, the mechanism for
      elicitation of this Ab remains unknown. In the present paper, we report that the
      Ab to diverse GBM Ags was induced by a single nephritogenic T cell epitope in a
      rat model. The T cell epitope pCol(28-40) of noncollagen domain 1 of collagen
      type IV alpha3 chain not only uniformly induced severe glomerulonephritis but
      also elicited anti-GBM Ab in 76% of the immunized rats after prominent glomerular
      injury. Furthermore, we demonstrated that the anti-GBM Ab was not related to the
      peptidic B cell epitope nested in pCol(28-40); that is, 1) elimination of the B
      cell epitope, either by substitution of the critical residues of the B cell
      epitope or by truncation, failed to abrogate anti-GBM Ab production, and 2) the
      anti-GBM Ab, eluted from the diseased kidneys, reacted only with native GBM, but
      not with pCol(28-40). Confocal microscopy and immunoprecipitation further
      demonstrated that the eluted anti-GBM Ab recognized conformational B cell
      epitope(s) of multiple native GBM proteins. We conclude that autoantibody
      response to diverse native GBM Ags was induced by a single nephritogenic T cell
      epitope. Thus, anti-GBM Ab may actually be a consequence of T cell-mediated
      glomerulonephritis.

PMID- 15034075
TI  - Multiepitope Trojan antigen peptide vaccines for the induction of antitumor CTL
      and Th immune responses.
AB  - We describe in this study a strategy to produce synthetic vaccines based on a
      single polypeptide capable of eliciting strong immune responses to a combination
      CTL and Th epitopes with the purpose of treating malignancies or preventing
      infectious diseases. This strategy is based on the capacity of Trojan Ags to
      deliver exogenous Ags into the intracellular compartments, where processing into
      MHC-binding peptides takes place. Our previous work demonstrated that Trojan Ags
      containing a CTL epitope localized to intracellular compartments, where MHC class
      I-binding peptides were generated in a TAP-independent fashion by the action of
      various exopeptidases and the endopeptidase furin. In this study, we report that
      Trojan Ags containing several CTL epitopes joined via furin-sensitive linkers
      generated all of the corresponding MHC class I-binding peptides, which were
      recognized by CTL. However, Trojan Ags prepared with furin-resistant linkers
      failed to produce the MHC class I-binding peptides. We also present data
      indicating that Trojan Ags bearing both CTL and Th epitopes can generate the
      corresponding MHC class I- and II-binding peptides, which are capable of
      stimulating T cell responses. Most significantly, in vivo vaccination of mice
      with a single injection of multiepitope Trojan Ags resulted in strong CTL and Th
      responses that translated into significant antitumor responses in a model of
      malignant melanoma. The overall results indicate that Trojan Ags prepared with
      furin-sensitive linkers are ideal candidates for producing synthetic multiepitope
      vaccines for the induction of CTL and Th responses that could be used against a
      variety of diseases, including cancer.

PMID- 15034076
TI  - Pregnancy-specific down-regulation of NF-kappa B expression in T cells in humans
      is essential for the maintenance of the cytokine profile required for pregnancy
      success.
AB  - It is accepted that human pregnancy is associated with a shift away from Th1 type
      and a bias toward Th2-type immune responses. The molecular mechanisms that
      regulate this shift are as yet unknown. We assessed the expression and activity
      of NF-kappaB, a transcription factor that plays a central role in regulating
      immune responses. We isolated T cells from PBMCs from nonpregnant and pregnant
      females and demonstrated that the NF-kappaB/IkappaB signaling pathway is down
      regulated in T cells in pregnancy. Using Western blotting, high levels of NF
      kappaB (p65) were detected in all nuclear fractions of T cells from nonpregnant
      females. In contrast, low levels of p65 were detected in nuclear fractions from T
      cells from pregnant females. Levels of IkappaBalpha and -beta were also higher in
      cytoplasmic fractions from T cells from nonpregnant than from pregnant females.
      The reduction in p65 levels in pregnancy was reflected in the activity of NF
      kappaB in EMSA; T cells from pregnant females contain less active NF-kappaB than
      from nonpregnant females. Stimulation of T cells from nonpregnant females with
      PMA/ionomycin resulted in IkappaBalpha degradation, p65 translocation, and
      subsequent production of the Th1 cytokines IFN-gamma and IL-2. In contrast, PMA
      stimulation had no effect on NF-kappaB activity in T cells from pregnant females,
      and this was reflected in reduced Th1 cytokine production. Using the inhibitor of
      NF-kappaB activity, SN50, we were able to show that NF-kappaB activity was
      essential for the production of Th1 cytokines, suggesting that specific down
      regulation of NF-kappaB in T cells throughout gestation is paramount to pregnancy
      success through specific regulation of cytokine production.

PMID- 15034077
TI  - Mycobacterium tuberculosis resides in nonacidified vacuoles in endocytically
      competent alveolar macrophages from patients with tuberculosis and HIV infection.
AB  - Alveolar macrophages (AM) are the first professional phagocytes encountered by
      aerosols containing infections in the lungs, and their phagocytic capacity may be
      affected by these infections or environmental particles. The aim of this study
      was to evaluate the innate endocytic and phagocytic properties of human AM
      obtained from patients with pulmonary tuberculosis and to characterize the
      vacuoles in which Mycobacterium tuberculosis bacilli reside in vivo. AM were
      obtained by bronchoalveolar lavage from patients with suspected tuberculosis and
      from asymptomatic volunteers (controls). Clinical case definitions were based on
      mycobacterial culture of respiratory specimens and HIV serology. To assess
      phagocytosis, endocytosis, and acidification of the endosomal system, AM were
      cultured with IgG-coated polystyrene beads, dextran, and a pH-sensitive reporter
      (3-(2,4-dinitroanilino)-3-amino-N-methyldipropylamine) and were evaluated by
      light and immunoelectron microscopy. Cells from 89 patients and 10 controls were
      studied. We found no significant difference between the two groups in the ability
      of AM either to ingest beads and dextran or to deliver them to acidified
      lysosomes. In AM from patients with tuberculosis, the bacilli were located in
      vacuoles that failed to accumulate endocytosed material and were not acidified.
      We concluded that AM from patients with tuberculosis and HIV infections were
      competent to endocytose and phagocytose material and to deliver the material to
      functional, acidified lysosomes. M. tuberculosis residing in these AM arrests the
      progression of their phagosomes, which fail to fuse with acidified lysosomes.
      This confirms, for the first time in humans with tuberculosis and HIV, the
      conclusions from previous animal and in vitro studies.

PMID- 15034078
TI  - Treatment of melanoma with 5-fluorouracil or dacarbazine in vitro sensitizes
      cells to antigen-specific CTL lysis through perforin/granzyme- and Fas-mediated
      pathways.
AB  - Several factors may influence sensitivity of melanoma cells to CTL lysis. One is
      the avidity of the CTL TCR. A second is that certain cytotoxic drugs have been
      reported to sensitize cancer cells to CTL lysis through Fas-mediated apoptosis.
      In this study, we examined whether antineoplastic agents 5-fluorouracil (5-FU)
      and dacarbazine (DTIC) sensitize melanoma cells to lysis of G209 peptide-specific
      CTL. Our results show that CTL generated from PBMC are HLA-A2 restricted and
      gp100 specific. Treatment with 5-FU or DTIC sensitized melanoma cells to lysis of
      G209-specific CTL. Most importantly, 5-FU- or DTIC-treated melanoma cells also
      became sensitive to low-avidity CTL, which per se are less cytolytic to
      melanomas. We sought to identify apoptotic pathways mediating this effect. The
      enhanced cytolysis was mediated through the perforin/granzyme pathway. Although 5
      FU up-regulated FasR expression on melanoma cells, sensitization was not blocked
      by anti-Fas Ab, and the G209-specific CTL was Fas ligand (FasL) negative.
      However, when G209-specific CTL were stimulated to express FasL, FasL signaling
      also contributed to enhanced cytolysis. DTIC treatment, which did not increase
      FasR expression, also sensitized FasL-mediated killing induced by neutralizing
      anti-Fas Ab. For CD95L-positive G209-specific CTL, the sensitization was
      primarily mediated through the perforin/granzyme pathway regardless of up
      regulation of FasR. The findings demonstrate that cytotoxic drug-mediated
      sensitization primes both perforin/granzyme and Fas-mediated killing by melanoma
      specific CTL. Considering that most of autoreactive antitumor CTL are low
      avidity, the findings provide experimental basis for understanding cytotoxic and
      immunologic therapeutic synergy in melanoma.

PMID- 15034079
TI  - New loci from New Zealand Black and New Zealand White mice on chromosomes 4 and
      12 contribute to lupus-like disease in the context of BALB/c.
AB  - New Zealand Black (NZB) and New Zealand White (NZW) mice are genetically
      predisposed to a lupus-like autoimmune syndrome. To further define the loci
      linked to disease traits in NZB and NZW mice in the context of the BALB/c genetic
      background, linkage analyses were conducted in two crosses: (NZW x
      BALB/c.H2(z))F(1) x NZB and (NZB x BALB/c)F(2). Novel loci linked to autoantibody
      production and glomerulonephritis, present in both NZB and NZW mice, were
      identified on proximal chromosomes 12 and 4. The chromosome 12 locus showed the
      strongest linkage to anti-nuclear Ab production. Additionally, a number of other
      novel loci linked to lupus traits derived from both the New Zealand and non
      autoimmune BALB/c genomes were identified. Furthermore, we confirm the linkage of
      disease to a number of previously described lupus-associated loci, demonstrating
      that they are relatively background independent. These data provide a number of
      additional candidate gene regions in murine lupus, and highlight the powerful
      effect the non-autoimmune background strain has in influencing the genetic loci
      linked to disease.

PMID- 15034080
TI  - Angiogenesis-inflammation cross-talk: vascular endothelial growth factor is
      secreted by activated T cells and induces Th1 polarization.
AB  - Vascular endothelial growth factor (VEGF) and its receptors are critical in
      angiogenesis. The main player in the secretion and response to VEGF is the
      endothelial cell. We initiated this study to test whether T cells can secrete
      VEGF and are able to respond to it. Here we show that VEGF is secreted by T cells
      on stimulation by specific Ag or by IL-2 and by hypoxia; thus, activated T cells
      might enhance angiogenesis. Hypoxia also induced the expression in T cells of
      VEGFR2, suggesting that T cells might also respond to VEGF. Indeed, VEGF
      augmented IFN-gamma and inhibited IL-10 secretion by T cells responding to
      mitogen or Ag; thus, VEGF can enhance a Th1 phenotype. Encephalitogenic T cells
      stimulated in the presence of VEGF caused more severe and prolonged
      encephalomyelitis. Thus, T cells can play a role in angiogenesis by delivering
      VEGF to inflammatory sites, and VEGF can augment proinflammatory T cell
      differentiation.

PMID- 15034081
TI  - Terminal deoxynucleotidyltransferase deficiency decreases autoimmune disease in
      diabetes-prone nonobese diabetic mice and lupus-prone MRL-Fas(lpr) mice.
AB  - The wide diversity of the T and B Ag receptor repertoires becomes even more
      extensive postneonatally due to the activity of TdT, which adds nontemplated N
      nucleotides to Ig and TCR coding ends during V(D)J recombination. In addition,
      complementarity-determining region 3 sequences formed in the absence of TdT are
      more uniform due to the use of short sequence homologies between the V, D, and J
      genes. Thus, the action of TdT produces an adult repertoire that is both
      different from, and much larger than, the repertoire of the neonate. We have
      generated TdT-deficient nonobese diabetic (NOD) and MRL-Fas(lpr) mice, and
      observed a decrease in the incidence of autoimmune disease, including absence of
      diabetes and decreased pancreatic infiltration in NOD TdT(-/-) mice, and reduced
      glomerulonephritis and increased life span in MRL-Fas(lpr) TdT(-/-) mice. Using
      tetramer staining, TdT(-/-) and TdT(+/+) NOD mice showed similar frequencies of
      the diabetogenic BDC 2.5 CD4(+) T cells. We found no increase in CD4(+)CD25(+)
      regulatory T cells in NOD TdT(-/-) mice. Thus, TdT deficiency ameliorates the
      severity of disease in both lupus and diabetes, two very disparate autoimmune
      diseases that affect different organs, with damage conducted by different
      effector cell types. The neonatal repertoire appears to be deficient in
      autoreactive T and/or B cells with high enough affinities to induce end-stage
      disease. We suggest that the paucity of autoreactive specificities created in the
      N region-lacking repertoire, and the resultant protection afforded to the
      newborn, may be the reason that TdT expression is delayed in ontogeny.

PMID- 15034082
TI  - Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by
      macrophage-derived IL-6.
AB  - The immunosuppressive cytokine IL-10 is associated with poor prognosis in colon
      cancer. Although macrophages are involved in antitumor defenses, production of IL
      10 by tumor cells may permit malignant cells escape to cell-mediated immune
      defenses. To investigate interactions between macrophages and tumor cells in
      humans, we cultured macrophages isolated from patients and tested the effect of
      these macrophages on the production of IL-10 by several tumor cell lines.
      Macrophages were isolated from pleural effusions of patients with malignancy and
      from noncancer control patients. We demonstrated that culture supernatants of
      macrophages from both sources strongly stimulated IL-10 production by the three
      different human colon adenocarcinoma cell lines, Colo 205, Colo 320, and HT29.
      Recombinant IL-6, but not IL-10, TNF-alpha, and IFN-alpha, stimulated the
      secretion of IL-10 by colon tumor cells. mAbs against IL-6 and IL-6R prevented
      the effect of macrophage culture supernatants and of rIL-6, respectively, on the
      production of IL-10 by the three cell lines. Cocultures of macrophages and colon
      cancer cells showed that these tumor cells first stimulated macrophages to
      produce IL-6, which was then followed by IL-6-induced IL-10 production by colon
      cancer cells. Finally, we showed that IL-10 gene regulation was mediated by
      STAT3, which was phosphorylated after the binding of IL-6 to IL-6R. This is the
      first demonstration that IL-6, secreted by macrophages, can induce a STAT3
      mediated IL-10 production by colon tumor cells.

PMID- 15034083
TI  - Human rhinovirus infection induces airway epithelial cell production of human
      beta-defensin 2 both in vitro and in vivo.
AB  - We hypothesized that airway epithelial cells, the primary site of human
      rhinovirus (HRV) infection, provide a link between the innate and specific immune
      response to HRV via production of human beta-defensin (HBD)-2, a potent in vitro
      attractant and activator of immature dendritic cells. Infection of primary
      cultures of human epithelial cells with several HRV serotypes induced expression
      of HBD-2 mRNA and protein, indicating that HBD-2 production was independent of
      viral receptor usage or mechanisms of viral RNA internalization. Induction of HBD
      2 was dependent upon viral replication and could be mimicked by transfection of
      cells with synthetic dsRNA, but was not dependent upon epithelial production of
      IL-1. Studies with stable epithelial cell lines expressing HBD-2 promoter
      constructs, as well as inhibitor studies in primary cells, both demonstrated that
      induction of HBD-2 involves activation of the transcription factor, NF-kappaB.
      Other transcription factors must also be activated by HRV infection, however, as
      expression of HBD-3 mRNA was also induced and there is no putative NF-kappaB
      recognition sequence in the promoter of this gene. HBD-2 showed no direct
      antiviral activity against HRV. In vivo infection of normal human subjects with
      HRV-16 induced expression of mRNA for HBD-2 in nasal epithelial scrapings.
      Increases in mRNA correlated with viral titer and with increased levels of HBD-2
      protein in nasal lavages. This represents the first demonstration that HRV
      infection induces epithelial expression of HBD-2 both in vitro and in vivo, and
      supports the concept that HBD-2 may play a role in host defense to HRV infection.

PMID- 15034085
TI  - 2003 Presidential Address: A time for morphogenesis, growth, and development.

PMID- 15034084
TI  - Mechanisms for the inhibition of genital vascular responses by antidepressants in
      a female rabbit model.
AB  - Vaginal and clitoral vasodilator responses (genital vascular responses; GVRs) to
      pelvic nerve electrical stimulation in female rabbits were measured by laser
      Doppler flow needle probes. The intravenous administration of various treatments
      was evaluated. GVRs were attenuated by a nitric-oxide synthase inhibitor (48.5
      and 51.8% of control at 8 Hz in the vagina and clitoris, respectively) and
      norepinephrine (NE) (78.5 and 61.5%), whereas serotonin (5-HT) had no inhibitory
      effect. The selective 5-HT reuptake inhibitor (SSRI) escitalopram did not modify
      GVRs, whereas the SSRI paroxetine dose-dependently inhibited GVRs in female
      rabbits (43.3 and 53.1% at 5 mg/kg). GVRs were also significantly inhibited by
      the 5-HT and NE reuptake inhibitors venlafaxine (53.4 and 52.6% at 5 mg/kg) and
      duloxetine (40.9 and 37.4% at 1 mg/kg). L-arginine prevented the inhibitory
      effects of paroxetine (105.5 and 115.3%) and partially prevented duloxetine
      induced reduction of GVRs but had no effect on the inhibition of GVRs induced by
      venlafaxine. Conversely, the alpha-adrenergic receptor blocker phentolamine had
      no effect on paroxetine-induced reduction of GVRs, partially prevented the
      inhibitory effects of duloxetine, and fully prevented the effects of venlafaxine
      (93.0 and 96.7%). Duloxetine-induced inhibition of GVRs was completely prevented
      by combined administration of L-arginine and phentolamine (123.5 and 103.6%).
      Although 5-HT or the highly selective SRI escitalopram did not inhibit GVRs, NE
      or inhibition of nitric oxide (NO) synthesis did. Inhibition of the NO pathway by
      paroxetine and duloxetine or activation of alpha-adrenergic mechanisms by
      venlafaxine and duloxetine lead to antidepressant-induced inhibition of GVRs in
      female rabbits.

PMID- 15034086
TI  - Role of the coagulation/fibrinolysis system in fibrin-associated glomerular
      injury.
AB  - In the past decade, numerous experimental studies of genetically engineered mice
      have confirmed the involvement of the coagulation/fibrinolysis system during
      glomerular inflammation and repair, revealing many unexpected biologic effects
      far beyond fibrin formation and clearance. Resident glomerular cells and
      macrophages seem to act in concert to ensure the long-term consolidation of local
      injury and progression toward glomerulosclerosis. These recent advances will
      probably pave the way to a new therapeutic approach to renal diseases. However,
      the balance governing glomerular permeability is very delicate, and many issues
      will have to be dealt with before targeting this system.

PMID- 15034087
TI  - Signaling danger: toll-like receptors and their potential roles in kidney
      disease.
AB  - Toll-like receptors (TLR) are an emerging family of receptors that recognize
      pathogen-associated molecular patterns and promote the activation of leukocytes
      and intrinsic renal cells. Ligands of the TLR include exogenous microbial
      components such as LPS (TLR4), lipoproteins and peptidoglycans (TLR1, -2, -6),
      viral RNA (TLR3), bacterial and viral unmethylated cytosin-guanosin dinucleotide
      (CpG)-DNA (TLR9), and endogenous molecules including heat-shock proteins and
      extracellular matrix molecules. Upon stimulation, TLR induce expression of
      inflammatory cytokines or costimulatory molecules via the MyD88-dependent and
      MyD88-independent signaling pathways shared with the interleukin-1 receptors. TLR
      are differentially expressed on leukocyte subsets and non-immune cells and appear
      to regulate important aspects of innate and adaptive immune responses. Tubular
      epithelial cells are among the non-immune cells that express TLR1, -2, -3, -4,
      and -6, suggesting that these TLR might contribute to the activation of immune
      responses in tubulointerstitial injury (e.g., bacterial pyelonephritis, sepsis,
      and transplant nephropathy). In addition, TLR9 has been shown to be involved in
      antigen-induced immune complex glomerulonephritis and lupus nephritis by
      regulating humoral and cellular immune responses. TLR are evolutionary conserved
      regulators of innate and adaptive immune responses. It is likely that TLR are
      involved in many if not all types of renal inflammation. Here the authors provide
      an overview on the biology of TLR, summarize the present data on their expression
      in the kidney, and provide an outlook for the potential roles of TLR in kidney
      disease.

PMID- 15034088
TI  - Cerivastatin activates endothelial calcium-activated potassium channels and
      thereby modulates endothelial nitric oxide production and cell proliferation.
AB  - Statins are known to counteract the process of arteriosclerosis by exerting
      direct pleiotropic effects on vascular endothelium. The aim of this study was to
      investigate a possible effect of cerivastatin on endothelial Ca(2+)-activated K+
      channels (BK(Ca)) and to assess their contribution to cerivastatin-mediated
      changes of endothelial nitric oxide (NO) production and proliferation. Membrane
      potential was measured using bis-1,3-dibutylbarbituric acid-trimethine oxonol
      fluorescence imaging. Patch-clamp recordings of BK(Ca) were performed on cultured
      human umbilical vein endothelial cells. NO production was measured using 4,5
      diaminofluorescein-fluorescence imaging and a [(3)H]cGMP RIA. Proliferation was
      analyzed by means of cell counts and [(3)H]thymidine incorporation (TI).
      Cerivastatin (0.001 to 0.05 micromol/L) caused a significant membrane
      hyperpolarization (n = 30; P < 0.05). This effect was abolished using the BK(Ca)
      inhibitor iberiotoxin (IBX; 100 nmol/L). The addition of mevalonate (500
      micromol/L) blocked the BK(Ca) activation induced by cerivastatin (n = 19; P <
      0.05). Endothelial cGMP level was increased by acetylcholine (ACh; 1 micromol/L).
      The combination of ACh and cerivastatin additionally increased cGMP levels, with
      a maximum at 0.03 micromol/L cerivastatin (84%; n = 10, P < 0.01). ACh-induced
      increase of cGMP-level was significantly reduced by IBX (n = 10, P < 0.01) as it
      was with all combined administrations of ACh and cerivastatin. 4,5
      Diaminofluorescein-fluorescence measurements revealed a significant increase of
      NO levels by cerivastatin, which was abolished by IBX (n = 30; P < 0.05). Cell
      counts and TI demonstrated significant inhibition of human umbilical vein
      endothelial cell proliferation with a maximum at 0.03 micro mol/L (cell count, 
      32.2%; TI, -70%; n = 12; P < 0.01). These data show that cerivastatin activates
      endothelial BK(Ca), which plays an important role in the signaling of
      cerivastatin-mediated endothelial NO production and proliferation.

PMID- 15034089
TI  - Differential regulation of collecting duct Na+, K+-ATPase and K+ excretion by
      furosemide and piretanide: role of bradykinin.
AB  - In response to chronic treatment with furosemide, collecting ducts adapt their
      function to the initial loss of Na+ to prevent further Na+ loss and extracellular
      volume decrease. This adaptation, which includes the overexpression of Na+, K+
      ATPase, is thought to account for most of the kaliuretic effect of furosemide.
      Because piretanide is reported to be less kaliuretic than equidiuretic doses of
      furosemide, the authors compared the effects of 1-wk treatment with the two loop
      diuretics on urinary potassium excretion and on Na+, K+-ATPase activity in the
      collecting duct. At equidiuretic and equinatriuretic doses, furosemide increased
      urinary potassium excretion as well as collecting duct Na+, K+-ATPase activity,
      whereas piretanide had no effect on either parameter. These effects of furosemide
      were curtailed by concomitant administration of the angiotensin-converting enzyme
      inhibitor enalapril, but they were not altered either by clamping changes in
      plasma aldosterone or by blocking type I angiotensin receptors. Treatment with
      the antagonist of bradykinin B2 receptors Hoe140 mimicked the two effects of
      furosemide. In addition, the effects of Hoe140 and furosemide were not additive.
      Finally, piretanide increased urinary bradykinin excretion, whereas furosemide
      did not. These results suggest that induction of collecting duct Na+, K+-ATPase
      (a) accounts for the kaliuretic effect of furosemide, (b) is independent of the
      renin/angiotensin/aldosterone system, (c) results from increased Na+ delivery to
      the collecting duct and enhanced intracellular Na+ concentration, and (d) is
      prevented in piretanide treated rats by increased bradykinin production that may
      limit apical Na+ entry in collecting duct principal cells.

PMID- 15034090
TI  - Impaired regulation of renal K+ elimination in the sgk1-knockout mouse.
AB  - Serum- and glucocorticoid-regulated kinase 1 (Sgk1) contributes to Na+
      reabsorption in the aldosterone-sensitive distal nephron. Sgk1-knockout (sgk1-/-)
      and littermate wild-type mice (sgk1+/+) were used to test the importance of Sgk1
      in renal elimination of K+ . Intravenous application of K+ load under anesthesia
      increased plasma K+ concentration by 1.3 to 1.4 mM in both sgk1-/- (n = 6) and
      sgkl+/+ (n = 7) mice. However, the increase of absolute and fractional renal K+
      excretion observed in sgk1+/+ was significantly blunted in sgk1-/- animals. Both
      groups of mice decreased or increased renal K+ excretion to a similar extent
      after a low (<0.03%) or high (5%) K+ diet for 6 d, respectively. In sgk1+/+,
      plasma K+ concentration was not significantly modified by either high or low K+
      diet. In sgk1-/-, however, high K+ diet enhanced plasma K+ concentration by about
      1.6 mM, despite an excessive increase of plasma aldosterone concentration
      reaching values about sixfold higher than in sgk1+/+. Electrophysiological and
      immunohistochemical studies under high K+ diet indicated that reduced epithelial
      Na+ channel ENaC and/or Na+/K+-ATPase activity in the aldosterone-sensitive
      distal nephron accounted for the impaired response in sgk1-/- and that an
      enhanced apical abundance of renal outer medullary K+ channel ROMK partly
      compensated for the defect. The acute and chronic regulation of renal K+
      elimination involves Sgk1.

PMID- 15034091
TI  - Kidney-specific inactivation of the megalin gene impairs trafficking of renal
      inorganic sodium phosphate cotransporter (NaPi-IIa).
AB  - Renal reabsorption of inorganic phosphate is mediated by the type IIa sodium
      phosphate cotransporter (NaPi-IIa) of the proximal tubule. Changes in renal
      phosphate handling are mainly attributable to altered NaPi-IIa brush border
      membrane (BBM) expression. Parathyroid hormone (PTH) induces inactivation of NaPi
      IIa by endocytic membrane retrieval and degradation. The key elements triggering
      this process are not clear to date. Megalin serves as a receptor for the
      endocytosis of multiple ligands and is coexpressed with NaPi-IIa in the proximal
      tubule. Investigated was the role of megalin in the regulation of NaPi-IIa in
      steady state and during inactivation. Kidneys and tubular BBM fractions from mice
      with a renal-specific megalin gene defect and from controls were analyzed by
      light and electron microscopic histochemical techniques and Western blot test.
      Steady-state levels of NaPi-IIa in BBM were significantly enhanced, mRNA levels
      preserved, and phosphaturia reduced in the absence of megalin. Fluid-phase
      endocytosis was prevented and the apical endocytic apparatus markedly reduced.
      Systemic administration of PTH resulted in a defective retrieval and impaired
      degradation of NaPi-IIa. In vitro, the application of various stimuli of the PTH
      induced signaling cascade had no effect either. Adequate steady-state expression
      of NaPi-IIa and the capacity of the proximal tubule cell to react on PTH-driven
      inactivation of NaPi-IIa by endocytosis and intracellular translocation require
      the presence of megalin.

PMID- 15034092
TI  - Atorvastatin improves the course of ischemic acute renal failure in aging rats.
AB  - Statins increase the production of nitric oxide (NO) and have beneficial effects
      on the course of acute renal failure (ARF) in young rats. The effects of a short
      term treatment with atorvastatin (ATO) on ischemic ARF in old rats, characterized
      by a great susceptibility to ischemia, was tested. No difference was found in
      renal dynamics between young (Y, 3 mo old) and old (O, 18 mo old) rats in normal
      conditions (CON) or after ATO treatment (12 mg/kg/d for 14 d). Twenty-four hours
      after clamping of both renal arteries, a more pronounced decrease in GFR was
      observed in O rats versus Y rats after a greater renal vasoconstriction and
      hypoperfusion of aging animals. Pretreatment with ATO mitigated renal
      vasoconstriction in O rats and restored GFR values to Y rats. Nitrate excretion
      was enhanced in Y rats after ARF but was not further modified by ATO; in O rats,
      ARF did not increase nitrate excretion, which was raised after ATO treatment.
      This reflected the increase in endothelial NO synthase (eNOS)-mRNA expression and
      eNOS protein observed in old ATO-treated animals with ARF. ATO treatment had also
      a significant protective effect against the cell injury at tubular level in O,
      but not Y, rats. The Ras system was not influenced by ATO in O rats, whereas the
      activation of Rho proteins was partially inhibited by ATO. Low-dose treatment
      with ATO enhances NO availability in aging rats, improving renal dynamics and
      conferring a peculiar histologic protection at tubular level after ischemia.

PMID- 15034093
TI  - Contributions of IL-1beta and IL-1alpha to crescentic glomerulonephritis in mice.
AB  - ABSTRACT. Interleukin-1 (IL-1) is a pleiotropic proinflammatory cytokine with two
      distinct isoforms (IL-1alpha and IL-1beta) that signal through the same IL-1 type
      I receptor (IL-1RI). Contributions of IL-1beta have been demonstrated in human
      and experimental proliferative glomerulonephritis (GN), but the involvement of IL
      1alpha has received little attention. To determine the combined contribution of
      IL-1alpha and IL-1beta and to dissect the specific contribution of IL-1beta, the
      development of anti-glomerular basement membrane globulin-induced crescentic GN
      was studied in mice genetically deficient in either the IL-1 receptor type I (IL
      1RI-/-), which are unresponsive to both IL-1alpha and IL-1beta, or IL-1beta alone
      (IL-1beta-/-). IL-1beta-/- mice showed significant reductions in crescent
      formation and glomerular T cell and macrophage recruitment compared with strain
      matched controls (WT). No additional reductions of these indices of injury were
      observed in IL-1RI-/- mice. However, IL-1RI-/- mice showed greater functional
      renal protection with significantly less proteinuria and reduced serum creatinine
      compared with IL-1beta-/- mice, suggesting a significant contribution of IL
      1alpha to these parameters of injury. IL-1RI-/- mice had lower serum titers of
      antibody to the nephritogenic antigen (sheep globulin) and reduced glomerular
      deposition of complement compared with either IL-1beta-/- or WT mice. This
      suggests that in the absence of responses to both IL-1alpha and IL-1beta,
      attenuation of humoral mediators provides additional functional protection from
      renal injury that is not seen in the absence of IL-1beta alone. These studies
      indicate that IL-1beta but not IL-1alpha contributes to crescent formation and
      inflammatory cell recruitment, whereas IL-1alpha but not IL-1beta contributes to
      humoral mechanisms of glomerular injury.

PMID- 15034094
TI  - Modulation of interferon-induced genes by lipoxin analogue in anti-glomerular
      basement membrane nephritis.
AB  - Immune complex deposition is associated with the accumulation of neutrophils,
      which play an important role in the various immune-mediated diseases. A novel
      anti-inflammatory agent, the lipoxin A (LXA) analogue (15-epi-16-(FPhO)-LXA-Me)),
      a stable synthetic analogue of aspirin-triggered 15-epi-lipoxin A4 (ATLa), was
      used in experimental anti-glomerular basement membrane (GBM) antibody nephritis
      in mice. ATLa was administered before the induction of the disease, and 2 h
      later, the animals were killed. ATLa reduced the infiltrating neutrophils and
      nitrotyrosine staining in glomeruli. Subsequent changes of gene expression in the
      early phase were evaluated, and 5674 genes were present under the basal
      conditions in kidneys from normal mice; 54 upregulated genes and 25 downregulated
      genes were detected in anti-GBM nephritis. Eighteen of these upregulated genes
      were those induced by IFN-gamma. Real-time quantitative PCR analysis confirmed
      the results of the microarrays. To investigate a role of IFN-gamma in neutrophil
      infiltration, anti-GBM nephritis was induced in IFN-gamma knockout mice. The
      number of infiltrating neutrophils in these mice did not differ from those in
      wild-type mice. Also examined were CD11b expression on neutrophils from mice
      treated with ATLa by flow cytometry, but suppression of this adhesion molecule
      was not observed. Neutrophil infiltration was successfully inhibited by ATLa in
      the early phase of murine anti-GBM nephritis. Microarray analysis detected the
      change of mRNA expression in anti-GBM nephritis and demonstrated amelioration of
      various genes by ATLa, which may provide a clue to the development of novel
      therapeutic approaches in immune renal injury.

PMID- 15034095
TI  - The parietal epithelial cell: a key player in the pathogenesis of focal segmental
      glomerulosclerosis in Thy-1.1 transgenic mice.
AB  - Focal segmental glomerulosclerosis (FSGS) is a hallmark of progressive renal
      disease. Podocyte injury and loss have been proposed as the critical events that
      lead to FSGS. In the present study, the authors have examined the development of
      FSGS in Thy-1.1 transgenic (tg) mice, with emphasis on the podocyte and parietal
      epithelial cell (PEC). Thy-1.1 tg mice express the Thy-1.1 antigen on podocytes.
      Injection of anti-Thy-1.1 mAb induces an acute albuminuria and development of
      FSGS lesions that resemble human collapsing FSGS. The authors studied FSGS
      lesions at days 1, 3, 6, 7, 10, 14, and 21, in relation to changes in the
      expression of specific markers for normal podocytes (WT-1, synaptopodin, ASD33,
      and the Thy-1.1 antigen), for mouse PEC (CD10), for activated podocytes (desmin),
      for macrophages (CD68), and for proliferation (Ki-67). The composition of the
      extracellular matrix (ECM) that forms tuft adhesions or scars was studied using
      mAb against collagen IV alpha2 and alpha4 chains and antibodies directed against
      different heparan sulfate species. The first change observed was severe PEC
      injury at day 1, which increased in time, and resulted in denuded segments of
      Bowman's capsule at days 6 and 7. Podocytes showed foot process effacement and
      microvillous transformation. There was no evidence of podocyte loss or denudation
      of the GBM. Podocytes became hypertrophic at day 3, with decreased expression of
      ASD33 and synaptopodin and normal expression of WT-1 and Thy-1.1. Podocyte
      bridges were formed by attachment of hypertrophic podocytes to PEC and podocyte
      apposition against denuded segments of Bowman's capsule. At day 6, there was a
      marked proliferation of epithelial cells in Bowman's space. These proliferating
      cells were negative for desmin and all podocyte markers, but stained for CD10,
      and thus appeared to be PEC. The staining properties of the early adhesions were
      identical to that of Bowman's capsule, suggesting that the ECM in the adhesions
      was produced by PEC. In conclusion, the authors propose the following sequence of
      events leading to FSGS lesions in the Thy1.1 tg mice: (1) PEC damage and
      denudation of Bowman's capsule segments; (2) podocyte hypertrophy and bridging;
      and (3) PEC proliferation with ECM production.

PMID- 15034096
TI  - Gene therapy via blockade of monocyte chemoattractant protein-1 for renal
      fibrosis.
AB  - Monocyte chemoattractant protein (MCP)-1, also termed monocyte chemotactic and
      activating factor (MCAF)/CCL2, plays an important role in progressive organ
      fibrosis. It was hypothesized that MCP-1, through its cognate receptor, CCR2,
      regulates the pathogenesis and is therapeutically of importance for renal
      fibrosis. To achieve this goal, the therapeutic efficacy and efficiency in renal
      fibrosis induced by a unilateral ureteral obstruction nephropathy model in mice
      by the blockade of MCP-1/CCR2 signaling was studied. The delivery of N-terminal
      deletion mutant of the human MCP-1 gene, 7ND, into a skeletal muscle ameliorated
      renal fibrosis by resulting in decrease in the deposit of type I collagen and in
      reduced expression of TGF-beta. Concomitantly, gene transfer of 7ND reduced the
      cell infiltration, most of which were CCR2-positive macrophages, followed by the
      decrease in MCP-1 expression in the diseased kidneys. These observations suggest
      that MCP-1 through CCR2 signaling is responsible for Mphi recruitment, which
      augments downstream events, resulting in renal fibrosis. Moreover, these findings
      imply that gene therapy against MCP-1/CCR2 signaling via the mutant gene
      transferred strategy may serve a beneficial therapeutic application for renal
      fibrosis.

PMID- 15034097
TI  - Hypercholesterolemia in rats induces podocyte stress and decreases renal cortical
      nitric oxide synthesis via an angiotensin II type 1 receptor-sensitive mechanism.
AB  - Podocyte stress precedes proteinuria in hypercholesterolemic rats. Molsidomine, a
      nitric oxide (NO) donor, prevented podocyte stress and proteinuria in long-term
      hypercholesterolemia, suggesting that podocyte stress was due to NO deficiency.
      Podocytes express the angiotensin II type 1 receptor, which influences their
      function. Because NO counteracts angiotensin II, it was hypothesized that in a
      setting of impaired renal NO availability, angiotensin II receptor inhibition
      could prevent podocyte stress. For determining the effect of NO deficiency on
      podocyte stress, one group of female rats were fed 2% cholesterol and another
      group the arginine analogue N-omega-nitro-L-arginine (L-NNA; 40 mg/kg food) for 2
      wk. Another group of rats that were fed 2% cholesterol also received the NO donor
      molsidomine (120 mg/L water) for 2 wk before and during cholesterol feeding. For
      determining the influence of angiotensin II in the setting of decreased renal NO
      availability, rats that were treated with cholesterol or L-NNA received the
      angiotensin II type 1 antagonist losartan (200 mg/L water) for 2 wk before and
      during cholesterol or L-NNA administration. Desmin staining and electron
      microscopy were used to monitor podocyte activation. Glomerular caveolin was
      quantified by immunohistochemistry. Renal cortical NO synthesis, NO synthase
      isoforms, and caveolin-1 protein mass were also measured. Both short-term
      cholesterol and L-NNA induced podocyte stress as evidenced by enhanced desmin
      staining and electron-dense fused foot processes. Podocyte stress was prevented
      by molsidomine in short-term hypercholesterolemia. Furthermore, losartan
      prevented podocyte stress in rats that were treated with cholesterol or with L
      NNA. Finally, hypercholesterolemia decreased renal cortical NO synthase activity
      and increased caveolin-1 protein mass and glomerular caveolin staining, and these
      changes were also prevented by losartan. It is suggested that podocyte stress in
      these models of early injury results from angiotensin II, unopposed by the action
      of endogenous NO. This underscores the strategic role of angiotensin II blockers
      in early kidney disease.

PMID- 15034098
TI  - Antioxidant intervention blunts renal injury in experimental renovascular
      disease.
AB  - Atherosclerotic renovascular disease (RVD) amplifies damage in a stenotic kidney
      by inducing pro-inflammatory mechanisms and disrupting tissue remodeling.
      Oxidative stress is increased in RVD, but its direct contribution to renal injury
      has not been fully established. The authors hypothesized that chronic antioxidant
      intervention in RVD would improve renal function and attenuate tissue injury.
      Single-kidney hemodynamics and function at baseline and during vasoactive
      challenge were quantified using electron-beam computed tomography in pigs after
      12 wk of experimental RVD (simulated by concurrent hypercholesterolemia and renal
      artery stenosis, n = 7), RVD daily supplemented with antioxidant vitamins C (1
      g), and E (100 IU/kg) (RVD+Vitamins, n = 7), or controls (normal, n = 7). Renal
      tissue was studied ex vivo using Western blot analysis and immunohistochemistry.
      Basal renal blood flow (RBF) and glomerular filtration rate (GFR) were similarly
      decreased in the stenotic kidney of both RVD groups. RBF and GFR response to
      acetylcholine was blunted in RVD, but significantly improved in RVD+Vitamins (P <
      0.05 versus RVD). RVD+Vitamins also showed increased renal expression of
      endothelial nitric oxide synthase (eNOS) and decreased expression of NAD(P)H
      oxidase, nitrotyrosine, inducible-NOS, and NF-kappaB, suggesting decreased
      superoxide abundance and inflammation. Furthermore, decreased expression of pro
      fibrotic factors in RVD+Vitamins was accompanied by augmented expression of
      extracellular (matrix metalloproteinase-2) and intracellular (ubiquitin) protein
      degradation systems, resulting in significantly attenuated glomerulosclerosis and
      renal fibrosis. In conclusion, chronic antioxidant intervention in early
      experimental RVD improved renal functional responses, enhanced tissue remodeling,
      and decreased structural injury. This study supports critical pathogenic
      contribution of increased oxidative stress to renal injury and scarring in RVD
      and suggests a role for antioxidant strategies in preserving the atherosclerotic
      and ischemic kidney.

PMID- 15034099
TI  - Renal transplantation modulates expression and function of receptors and
      transporters of rat proximal tubules.
AB  - Kidney transplantation often leads to disturbances of solute and volume
      maintenance in humans. To investigate underlying mechanisms, expression and
      function of renal transporters and receptors of the proximal tubule (PT) were
      analyzed in an acute rejection model of rat kidney transplantation.
      Semiquantitative RT-PCR and Western blot, histology, immunohistochemistry, and
      microfluorometry were performed on whole kidneys and isolated PT. With acute
      rejection, Na+/H+-exchanger type-3 (NHE-3) was markedly downregulated. Na+
      HCO(3)(-)-cotransporter (NBC-1) and Na+-glucose transporter type-2 (SGLT2) were
      upregulated after transplantation. Expressions of Na+/H+-exchanger type-1 (NHE
      1), Na+/K+-ATPase (NKA), angiotensin II (AngII) receptor (AT-1), or natriuretic
      peptide receptor (GC-A) were unaltered. Microfluorometric analyses of
      intracellular pH, Na+, and Ca2+ demonstrated a decrease in NHE-3 function and
      AngII-mediated stimulation of NHE-3. AngII-mediated inhibition of NHE-1 and
      function of all other transporters tested remained unaltered. Function of AT-1
      and GC-A were unaffected. Reduced expression of NHE-3 was also confirmed by
      semiquantitative immunohistochemistry. These findings suggest that expression and
      function of transmembrane proteins involved in Na+-transport after
      transplantation and rejection is specifically modulated. The local renin
      angiotensin-system is apparently not altered. Downregulation of NHE-3 may be a
      protective mechanism occurring in the graft.

PMID- 15034100
TI  - Tubular chimerism occurs regularly in renal allografts and is not correlated to
      outcome.
AB  - Recent studies have demonstrated an integration of recipient-derived progenitor
      cells into solid allografts with differentiation into parenchymal cells. Whether
      or to what extent this phenomenon influences allograft outcome has still to be
      elucidated. To detect epithelial chimerism tubular cells were harvested from
      sequential renal allograft biopsy samples by laser microdissection in 36
      patients. Recipient-derived cells were detected by short-tandem repeat-based
      genotyping. In cases with gender-mismatched transplantation, chimerism was
      semiquantitatively evaluated by in situ hybridization for the Y-chromosome.
      Findings were correlated to different pathomechanisms of epithelial injury as
      well as to morphologic and clinical outcome. Epithelial chimerism was detectable
      as early as 8 d after transplantation and lasted for 8 yr. A total of 88% of the
      patients showed an epithelial chimerism; 72% had a stable chimerism in sequential
      biopsy samples. Evaluation of Y-chromosome by in situ hybridization revealed low
      percentages of chimerical tubular epithelial cells (2.4% to 6.6%). No correlation
      to morphology was found. Chimerism was detectable in inconspicuous protocol
      biopsy samples, cases of drug toxicity, and rejected allografts with and without
      chronic changes. No correlation was found to allograft function. Epithelial
      microchimerism is an early and persistent phenomenon after renal transplantation.
      There is no correlation to morphologic or functional outcome. Probably recipient
      derived stem cells contribute in a minor fashion to tissue homeostasis, and cell
      turnover in renal allografts is predominantly enabled by donor cell renewal.

PMID- 15034101
TI  - Modified dendritic cells coexpressing self and allogeneic major
      histocompatability complex molecules: an efficient way to induce indirect pathway
      regulation.
AB  - A feature of the tolerance that has been described in experimental models is that
      it can be transferred by CD4+ T cells to a naive recipient. Described is a novel
      approach to induce indirect pathway regulatory T cells in a rat model that
      exploits the natural processing and presentation of major histocompatability
      complex (MHC) molecules as peptide by the MHC class II molecules of the same
      cell. Dendritic cells (DC) coexpressing donor (AUG) and recipient (LEW) MHC
      molecules were rendered tolerogenic by treatment with dexamethasone. After
      injection into LEW animals followed by a single low dose of CTLA4-Ig, T cells
      were rendered unresponsive to indirectly presented AUG alloantigens, but retained
      direct pathway responsiveness to fully allogeneic AUG cells. The T cells from the
      DC-injected rats were unresponsive to (LEW x AUG)F1 stimulator cells, suggesting
      the presence of indirect pathway regulatory cells whose activity depended on the
      presence of LEW MHC molecules. Depletion of CD25+ cells from the responder
      population led to a marked increase in proliferation, and the T cells from the DC
      injected rats inhibited the response of naive LEW T cells to (LEW x AUG)F1, but
      not to AUG, stimulator cells, further indicating indirect pathway-mediated
      regulation. Most importantly, pretreatment of LEW rats with the dexamethasone
      treated DC led to the indefinite survival of AUG kidney grafts after a short
      course of cyclosporin to inhibit the early direct pathway response. Similarly
      treated AUG DC had no effect, confirming the privileged status of F1 cells in the
      induction of indirect pathway regulation.

PMID- 15034102
TI  - Evolving concepts in human renal dysplasia.
AB  - Human renal dysplasia is a collection of disorders in which kidneys begin to form
      but then fail to differentiate into normal nephrons and collecting ducts.
      Dysplasia is the principal cause of childhood end-stage renal failure. Two main
      theories have been considered in its pathogenesis: A primary failure of ureteric
      bud activity and a disruption produced by fetal urinary flow impairment. Recent
      studies have documented deregulation of gene expression in human dysplasia,
      correlating with perturbed cell turnover and maturation. Mutations of
      nephrogenesis genes have been defined in multiorgan dysmorphic disorders in which
      renal dysplasia can feature, including Fraser, renal cysts and diabetes, and
      Kallmann syndromes. Here, it is possible to begin to understand the normal
      nephrogenic function of the wild-type proteins and understand how mutations might
      cause aberrant organogenesis.

PMID- 15034103
TI  - Abnormal HDL apolipoprotein A-I and A-II kinetics in hemodialysis patients: a
      stable isotope study.
AB  - Low levels of HDL cholesterol and its major apoprotein constituents apoA-I and
      apoA-II are common in patients who have ESRD and are undergoing hemodialysis
      (HD), but the metabolic basis for the low HDL is poorly understood. This study
      aimed to investigate in vivo metabolism of apoA-I and apoA-II in five
      normotriglyceridemic ESRD-HD patients and compared it with five control subjects
      using endogenous stable isotope labeling methods coupled with a
      multicompartmental modeling. HDL cholesterol, apoA-I, and apoA-II levels were
      markedly decreased in the ESRD-HD patients by 39, 30, and 44%, respectively, in
      comparison with the control subjects. Fractional catabolic rate of apoA-I was
      found to be significantly increased by 59% to 0.360 +/- 0.084/d in ESRD-HD
      patients as compared with control subjects of 0.227 +/- 0.076/d (P = 0.028),
      whereas the production rates remained unchanged. Conversely, the apoA-II
      production rate significantly decreased by 31% to 1.50 +/- 0.61 mg/kg per d in
      the ESRD-HD patients in comparison with control subjects of 2.17 +/- 0.40 mg/kg
      per d (P = 0.047) with apoA-II fractional catabolic rate unchanged. These results
      revealed that the decreased levels of apoA-I are due solely to the increased rate
      of catabolism, whereas the reduced apoA-II levels are due primarily to the
      decreased rate of production in ESRD-HD patients. This differential regulation of
      apoA-I and apoA-II further supports the concept that apoA-I and apoA-II have
      distinct metabolic pathways.

PMID- 15034104
TI  - Environmental exposure to lead and progression of chronic renal diseases: a four
      year prospective longitudinal study.
AB  - Previous retrospective research suggests that low-level environmental lead
      exposure is associated with an acceleration of age-related impairment of renal
      function. For elucidating the long-term relationship between low-level
      environmental lead exposure and progression of chronic renal diseases in patients
      without diabetes, 121 patients who had chronic renal insufficiency, a normal body
      lead burden (BLB), and no history of exposure to lead were observed prospectively
      for 48 mo. Associations of both BLB and blood lead level (BLL) with renal
      function were evaluated, with reference to other covariates. The primary end
      point was an increase in the serum creatinine level to double the baseline value.
      Sixty-three patients had BLB > or =80 microg and < 600 microg (high-normal
      group), and 58 patients had BLB < 80 microg (low-normal group). The primary end
      point occurred in 17 patients. Fifteen of them had high-normal BLB, whereas two
      patients had low-normal BLB (hazard ratio [95% confidence interval]: 1.01 [1.00
      to 1.01] for each increment of 1 microg; P = 0.002). The BLB and BLL at baseline
      were the most important risk factors to predict progression of renal
      insufficiency. Each increase of 10 microg in the BLB or 1 microg/dl in the BLL
      reduced the GFR by 1.3 (P = 0.002) or 4.0 ml/min (P = 0.01) during the study
      period. In conclusion, low-level environmental lead exposure is associated with
      accelerated deterioration of renal insufficiency. Even at levels far below the
      normal ranges, both increased BLL and BLB predict accelerated progression of
      chronic renal diseases.

PMID- 15034105
TI  - Repeat imaging for intracranial aneurysms in patients with autosomal dominant
      polycystic kidney disease with initially negative studies: a prospective ten-year
      follow-up.
AB  - Patients with autosomal dominant polycystic kidney disease (ADPKD) have a higher
      incidence of intracranial aneurysms (ICA) than the general population. These ICA
      also rupture at an earlier age in patients with ADPKD and are associated with
      high morbidity and mortality. In a recent study, 25% of patients with ADPKD with
      a documented ICA demonstrated a new ICA on follow-up. It is not known, however,
      whether patients with ADPKD who have had a negative ICA imaging study would
      demonstrate an ICA on a repeat imaging study. Only 2 (2.6%) of 76 patients with
      ADPKD with an initially negative study demonstrated an ICA on follow-up, despite
      the high frequency of risk factors such as hypertension, smoking, and a family
      history of ruptured ICA. The mean length of follow-up was 9.8 yr (median, 9.7
      yr). These findings have important health care and economic implications in
      following patients with ADPKD.

PMID- 15034107
TI  - Septicemia in the United States dialysis population, 1991 to 1999.
AB  - The clinical epidemiology of septicemia in dialysis populations remains poorly
      defined. In this historical cohort study of 393,451 U.S. dialysis patients,
      International Classification of Disease, Ninth Revision, Clinical Modification
      discharge diagnosis codes were used to compare first-year septicemia admission
      rates in annual incident cohorts from 1991 to 1999 and to calculate subsequent
      cardiovascular event and mortality rates. Hemodialysis (compared with peritoneal
      dialysis) as initial therapy and starting dialysis in more recent years were the
      principal antecedents of septicemia. In hemodialysis patients, adjusted first
      admission rates (expressed throughout as first episodes per 100 patient-years)
      rose by 51%, from 11.6 in 1991 to 17.5 in 1999. In peritoneal dialysis patients,
      rates rose from 5.7 in 1991, peaked at 9.2 in 1997, and declined to 8.0 in 1999.
      Mortality rates after septicemia were similar to mortality rates after major
      cardiovascular events. Septicemia was associated with developing myocardial
      infarction, congestive heart failure, stroke, and peripheral vascular disease
      with adjusted risk ratios of 4.1, 5.5, 4.1, and 3.8 in the initial 6 mo after
      admission for septicemia and 1.7, 2.0, 2.0, and 1.6 after 5 yr, respectively.
      Septicemia, which is associated with increased cardiovascular and death risk, has
      become more common in dialysis patients in the United States.

PMID- 15034106
TI  - Prognostic value of echocardiographic indicators of left ventricular systolic
      function in asymptomatic dialysis patients.
AB  - Patients with end-stage renal disease (ESRD) are at high risk for heart failure,
      but the prevalence and the prognostic value of asymptomatic systolic dysfunction
      in these patients are unknown. In this prospective cohort study, the authors have
      therefore assessed by echocardiography the prevalence and the prognostic value of
      systolic function as estimated by ejection fraction (EF), fractional shortening
      at endocardial level (endoFS), and at midwall (mwFS), in a cohort of 254
      asymptomatic dialysis patients. Systolic dysfunction had a prevalence rate of 26%
      by endoFS and of 48% by mwFS. During the follow-up period, 125 patients had one
      or more fatal and nonfatal CV events. On multivariate COX regression analysis,
      the three LV systolic function indicators were independently associated with
      incident fatal and nonfatal CV events, and there were no differences in the
      predictive power of these indicators (P > 0.30). The prediction power of LV
      function indicators was largely independent of traditional and novel risk factors
      in ESRD such as C-reactive protein and asymmetric dimethyl arginine (ADMA). ADMA
      was significantly related with LV function indicators as well as with mortality
      and incident CV events, but these links were much reduced (P = NS) in models
      including LV function indicators. Of note, the risk of CV events was minimal in
      patients with normal LV mass and function, intermediate in patients with either
      LVH or systolic dysfunction, and maximal in patients displaying both alterations.
      The study of myocardial contractility by echocardiography provides prognostic
      information independently of LV mass and other risk factors in ESRD. Risk
      stratification by simple systolic function parameters may prove useful in
      secondary prevention strategies in these patients.

PMID- 15034108
TI  - Renal insufficiency and the risk of lower extremity peripheral arterial disease:
      results from the Heart and Estrogen/Progestin Replacement Study (HERS).
AB  - Renal insufficiency is a risk factor for coronary heart disease and stroke, but
      whether it predicts lower extremity peripheral arterial disease (PAD) is unknown.
      The authors evaluated was the association of baseline renal insufficiency with
      future PAD events in the Heart and Estrogen/Progestin Replacement Study (HERS)
      and follow-up study (HERS II). A total of 2763 postmenopausal women with known
      coronary heart disease were enrolled in HERS and randomly assigned to receive
      hormone therapy with conjugated estrogens and medroxyprogesterone acetate or
      placebo and followed for up to 8 yr for clinical end points. The outcome was time
      from randomization to first occurrence of either a lower extremity amputation,
      revascularization (surgical or percutaneous), or lumbar sympathectomy during
      follow-up. Incident lower extremity PAD event rates among women with creatinine
      clearances > or =60, 30 to 59, and < 30 ml/min/1.73 m(2) were, respectively,
      0.55%, 0.92%, and 2.73% per year. After multivariable proportional-hazard
      adjustment for potential confounders and other known risk factors for PAD, women
      with a creatinine clearance 30 to 59 ml/min/1.73 m(2) (hazard ratio [HR], 1.63;
      95% confidence interval [CI], 1.04 to 2.54, P = 0.032) and <30 ml/min/1.73 m(2)
      (HR, 3.24; 95% CI, 1.20 to 8.78, P = 0.021) had a significantly increased risk of
      PAD compared with participants with a creatinine clearance > or =60 ml/min/1.73
      m(2). Renal insufficiency was independently associated with future PAD events
      among postmenopausal women with coronary heart disease. Future studies should
      determine whether this association is present in other populations and
      investigate its potential mechanisms.

PMID- 15034109
TI  - Patient and graft survival in older kidney transplant recipients: does age
      matter?
AB  - An increasing gap between supply and demand of donor kidneys for transplantation
      exists. There is concern regarding the allocation of scarce organs to elderly
      patients, because the benefit obtained by the transplant may be less in elderly
      compared with younger recipients. It was the objective of this study to determine
      differences in patient and organ survival between organ recipients >65 yr and 50
      to 64 yr of age at transplantation. A retrospective cohort of 627 patients >50 yr
      who received a kidney transplant between 1993 and 2000 was assembled. Detailed
      information on patient demographics, comorbidities, and immunological and donor
      characteristics was ascertained before transplantation. Five-year patient and
      graft survival were evaluated by Kaplan-Meier survival curves and multivariate
      Cox proportional-hazard models. Five-year patient mortality was similar between
      patients aged >65 and 60 to 64 at transplantation (relative risk [RR] = 1.07; 95%
      confidence interval [CI], 0.66 to 1.74). Patients aged 50 to 59 yr showed a clear
      trend toward lower 5-yr mortality (RR = 0.66; 95% CI, 0.43 to 1.03). Compared
      with patients >65 yr, 5-yr graft loss was not different in patients aged 60 to 64
      (RR = 1.28; 95% CI, 0.82 to 2.02) or those aged 50 to 59 yr at transplantation
      (RR = 1.02; 95% CI, 0.68 to 1.53). After thorough control for confounding, 5-yr
      graft survival was not materially different by age group. Discrimination against
      older candidates for kidney transplantation on age-related grounds alone is not
      warranted.

PMID- 15034110
TI  - Relative contribution of residual renal function and different measures of
      adequacy to survival in hemodialysis patients: an analysis of the Netherlands
      Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2.
AB  - A high delivered Kt/V(urea) (dKt/V(urea)) is advocated in the U.S. National
      Kidney Foundation Dialysis Outcomes Quality Initiative guidelines on hemodialysis
      (HD) adequacy, irrespective of the presence of residual renal function. The
      contribution of treatment adequacy and residual renal function to patient
      survival was investigated. The Netherlands Cooperative Study on the Adequacy of
      Dialysis is a prospective multicenter study that includes incident ESRD patients
      older than 18 yr. The longitudinal data on residual renal function and dialysis
      adequacy of patients who were treated with HD 3 mo after the initiation of
      dialysis (n = 740) were analyzed. The mean renal Kt/V(urea) (rKt/V(urea)) at 3 mo
      was 0.7/wk (SD 0.6) and the dKt/V(urea) at 3 mo was 2.7/wk (SD 0.8). Both
      components of urea clearance were associated with a better survival (for each
      increase of 1/wk in rKt/V(urea), relative risk of death = 0.44 [P < 0.0001];
      dKt/V(urea), relative risk of death = 0.76 [P < 0.01]). However, the effect of
      dKt/V(urea) on mortality was strongly dependent on the presence of rKt/V(urea),
      low values for dKt/V(urea) of <2.9/wk being associated with a significantly
      higher mortality in anuric patients only. Furthermore, an excess of
      ultrafiltration in relation to interdialytic weight gain was associated with an
      increase in mortality independent of dKt/V(urea). In conclusion, residual renal
      clearance seems to be an important predictor of survival in HD patients, and the
      dKt/V(urea) should be tuned appropriately to the presence of renal function.
      Further studies are required to substantiate the important role of fluid balance
      in HD adequacy.

PMID- 15034111
TI  - Features of chronic hemodialysis practice after the Marmara earthquake.
AB  - After disasters, treatment of chronic hemodialysis (HD) patients is problematic
      because of logistic and medical reasons. This study analyzes features of HD
      practice in the regions affected by the Marmara earthquake that struck
      northwestern Turkey in August 1999. Questionnaires asking about HD
      infrastructure, medical/social problems of chronic dialysis patients, and the
      fate of dialysis personnel after the disaster were sent to dialysis units located
      in the affected region. Data gathered from eight HD centers that responded to
      questionnaires were then analyzed. The number of HD centers and machines were 12
      and 124, respectively, before the earthquake. The number of weekly HD sessions in
      the analyzed eight centers declined from 1093 before the disaster to 520, 616,
      and 729 1 wk, 1 mo, and 3 mo after the earthquake, respectively. In the effective
      seven centers, the number of HD personnel was 112 before the earthquake, which
      dropped to 86 and 94 1 and 3 mo after the disaster, respectively. Overall, there
      were 439 patients in the analyzed eight centers before the disaster, whereas data
      were provided on 356 (212 were male; mean age, 47.6 +/- 15.1 yr) dialysis
      patients. Six patients died, and seven were seriously and 28 mildly injured by
      the direct effects of trauma. The percentage of patients who received once-weekly
      dialysis increased from 2.3 to 7.2% within the first week, with a return to lower
      figures (4.1 and 2.8%) 1 and 3 mo afterward. Despite a decrease in the number of
      HD sessions, interdialytic weight gain decreased 1 wk after the disaster and BP
      measurements did not change significantly before and after the earthquake. A
      total of 301 and 31 patients left their dialysis centers, temporarily and
      permanently. After catastrophic earthquakes, despite a decrease in the number of
      HD sessions, patients comply with disaster conditions, likely by strictly
      following dietary and fluid restrictions.

PMID- 15034112
TI  - Increased production of urea hydrogen peroxide from Maillard reaction and a UHP
      Fenton pathway related to glycoxidation damage in chronic renal failure.
AB  - Urea hydrogen peroxide (UHP) is a stable form of H(2)O(2) and cytotoxic agent.
      This study describes examination of UHP formation from collagen glycation and
      relevant glycoxidative damage in chronic renal failure (CRF). Renal fibers were
      incubated with 50 mM ribose in either serum ultrafiltrate or phosphate-buffered
      saline in the presence of various concentrations of urea. UHP was determined by a
      modified ferrous oxidation in xylenol orange (FOX) assay. The presence of urea
      resulted in an increase in the generation of UHP in a dose-dependent manner of
      urea in these incubation systems. Pentosidine levels analyzed by HPLC also
      increased in a dose-dependent manner of urea. Blocking experiments showed that
      pentosidine and carboxymethyllysine formation was significantly enhanced by
      hydroxyl radical generated from UHP via Fenton reaction. The renal and cardiac
      levels of UHP, pentosidine, and carboxymethyllysine in patients with CRF,
      including seven predialysis and eight hemodialysis subjects, were significantly
      higher than that in controls (n = 16). The renal and cardiac levels of UHP
      closely correlated with the levels of renal and cardiac pentosidine and
      carboxymethyllysine and inversely correlated with left ventricle ejection
      fraction in CRF patients. This study provides evidence, for the first time, that
      UHP can be produced from Maillard reaction. Increased UHP in chronic renal
      failure enhances the formation of pentosidine and carboxymethyllysine via Fenton
      reaction (UHP-Fenton pathway).

PMID- 15034114
TI  - 2003 Nobel Prize in Chemistry: editor-in-chief's comments.

PMID- 15034113
TI  - Effect of donor recipient age match on survival after first deceased donor renal
      transplantation.
AB  - Donor-recipient age matching has been proposed as a means of improving overall
      outcomes in deceased donor renal transplantation. It was hypothesized that donor
      recipient age matching would improve patient survival time in younger recipients
      while not adversely affecting patient survivals in older recipients because they
      seldom outlive their grafts. By use of data from United Network of Organ Sharing
      Standard Transplant and Analysis and Research Files 50,320 patients were
      identified who underwent a first deceased donor renal transplantation between
      January 1, 1990, and December 31, 1997. Adjusted patient survival and death-with
      graft function patient survival were analyzed from the date of transplantation.
      Patient survival was affected by donor age for all recipient age groups,
      including recipients older than 55 yr. The effect of donor age on patient
      survival is greater than that seen with HLA matching. The effect of donor age on
      patient survival persisted even when censoring recipients in whom grafts failed
      before death, suggesting that both longevity and quality of graft function are
      important in patient survival. Donor-recipient age matching is occurring to a
      limited degree in this population. Donor-recipient age matching would improve
      survival in younger recipients but would adversely affect survival in older
      patients by reducing the availability of younger donor kidneys for this group.
      The issue of donor-recipient age matching needs to be debated among the public
      and transplantation community so that a logical and just system can be developed.

PMID- 15034115
TI  - Peter Agre, 2003 Nobel Prize winner in chemistry.
AB  - Peter C. Agre, an American Society of Nephrology member, is the recipient of the
      2003 Nobel Prize in Chemistry for his discovery of the aquaporin water channels.
      The function of many cells requires that water move rapidly into and out of them.
      There was only indirect evidence that proteinaceous channels provide this vital
      activity until Agre and colleagues purified aquaporin-1 from human erythrocytes
      and reported its cDNA sequence. They proved that aquaporin-1 is a specific water
      channel by cRNA expression studies in Xenopus oocytes and by functional
      reconstitution of transport activity in liposomes after the incorporation of the
      purified protein. These findings sparked a veritable explosion of work that
      affects several long-standing areas of investigation such as the biophysics of
      water permeation across cell membranes, the structural biology of integral
      membrane proteins, the physiology of fluid transport in the kidney and other
      organs, and the pathophysiological basis of inherited and acquired disorders of
      water balance. Agre's discovery of the first water channel has spurred a
      revolution in animal and plant physiology and in medicine.

PMID- 15034116
TI  - Roderick MacKinnon, MD, honored by 2003 Nobel Prize in Chemistry for work on
      elucidating the structure of ion channels.

PMID- 15034117
TI  - Statins' coat of many colors receives yet another hue.

PMID- 15034118
TI  - Donor antigen and transplant tolerance strategies: it takes two to tango!

PMID- 15034119
TI  - Trypsin cleaves exclusively C-terminal to arginine and lysine residues.
AB  - Almost all large-scale projects in mass spectrometry-based proteomics use trypsin
      to convert protein mixtures into more readily analyzable peptide populations.
      When searching peptide fragmentation spectra against sequence databases,
      potentially matching peptide sequences can be required to conform to tryptic
      specificity, namely, cleavage exclusively C-terminal to arginine or lysine. In
      many published reports, however, significant numbers of proteins are identified
      by non-tryptic peptides. Here we use the sub-parts per million mass accuracy of a
      new ion trap Fourier transform mass spectrometer to achieve more than a 100-fold
      increased confidence in peptide identification compared with typical ion trap
      experiments and show that trypsin cleaves solely C-terminal to arginine and
      lysine. We find that non-tryptic peptides occur only as the C-terminal peptides
      of proteins and as breakup products of fully tryptic peptides N-terminal to an
      internal proline. Simulating lower mass accuracy led to a large number of
      proteins erroneously identified with non-tryptic peptide hits. Our results
      indicate that such peptide hits in previous studies should be re-examined and
      that peptide identification should be based on strict trypsin specificity.

PMID- 15034121
TI  - Ageing, exercise training, and resistance vessels: more than just no NO?

PMID- 15034120
TI  - The effect of dehydroepiandrosterone on regional blood flow in prepubertal
      anaesthetized pigs.
AB  - Dehydroepiandrosterone has been implicated in vascular disease and its associated
      insulin resistance and hypertension, though little is known about its vascular
      effects. We have recently shown in prepubertal anaesthetized pigs that
      intravenous infusion of dehydroepiandrosterone caused coronary vasoconstriction
      through the inhibition of a vasodilatory beta-adrenergic receptor-mediated effect
      related to the release of nitric oxide. The present study was designed to
      investigate the effect of dehydroepiandrosterone on mesenteric, renal and iliac
      vascular beds. In prepubertal pigs of both sexes anaesthetized with sodium
      pentobarbitone, changes in superior mesenteric, left renal and left external
      iliac blood flow caused by intravenous infusion of dehydroepiandrosterone were
      assessed using electromagnetic flowmeters. Changes in heart rate and arterial
      blood pressure were prevented by atrial pacing and by connecting the arterial
      system to a pressurized reservoir containing Ringer solution. In 22 pigs,
      infusion of 1 mg h(-1) of dehydroepiandrosterone decreased mesenteric, renal and
      iliac blood flow. In a further 10 pigs, dose-response curves were obtained by
      graded increases in the infused dose of hormone between 0.03 and 4 mg h(-1). The
      mechanisms of the above response were studied in the 22 pigs by repeating the
      experiment after haemodynamic variables had returned to the control values
      observed before infusion. Blockade of alpha-adrenoceptors with intravenous
      phentolamine (five pigs) did not affect the dehydroepiandrosterone-induced
      mesenteric, renal and iliac vasoconstriction. This response was abolished by
      blockade of beta(2)-adrenoceptors with intravenous butoxamine (five pigs) and by
      blockade of mesenteric, renal and iliac nitric oxide synthase with intra-arterial
      administration of N(omega)-nitro-L-arginine methyl ester (seven pigs), even after
      reversing the increase in local vascular resistance caused by the two blocking
      agents with intravenous infusion of papaverine. In five pigs, the increase in
      measured blood flow caused by intravenous infusion of isoproterenol
      (isoprenaline) was significantly reduced by infusion of dehydroepiandrosterone.
      The present study showed that intravenous infusion of dehydroepiandrosterone
      primarily caused mesenteric, renal and iliac vasoconstriction. The mechanisms of
      this response were shown to be due to the inhibition of a vasodilatory beta(2)
      adrenergic receptor-mediated effect, which possibly involved the release of
      nitric oxide.

PMID- 15034122
TI  - Prenatal stress alters cardiovascular responses in adult rats.
AB  - Environmental factors in early life are clearly established risk factors for
      cardiovascular disease in later life. Most studies have focused on nutritional
      programming and analysed basal cardiovascular parameters rather than responses.
      In the present study we have investigated whether prenatal stress has long-term
      effects on cardiovascular responses in adult offspring. Female pregnant Sprague
      Dawley rats were subjected to stress three times daily from day 15 to day 21 of
      gestation. Litters from stressed and control females were cross-fostered at birth
      to control for mothering effects. When the offspring were 6 months old, blood
      pressure was measured in the conscious rats through implanted catheters at rest,
      during restraint stress and during recovery. Basal haemodynamic parameters were
      similar in the different groups but the pattern of cardiovascular responses
      during stress and recovery differed markedly between prenatally stressed (PS) and
      control animals. PS rats had higher and longer-lasting systolic arterial pressure
      elevations to restraint stress than control animals. They also showed elevated
      systolic and diastolic blood pressure values during the recovery phase. PS rats
      demonstrated a greater increase in blood pressure variability compared with
      control animals during exposure to restraint stress, and showed more prolonged
      heart rate responses to acute stress and delayed recovery than controls. There
      was no effect of prenatal stress on baroreflex regulation of heart rate. PS
      females showed a greater increase in systolic arterial pressure and blood
      pressure variability and delayed heart rate recovery following return to the home
      cage then did PS males. These findings demonstrate for the first time that
      prenatal stress can induce long-term, sex-related changes in the sensitivity of
      the cardiovascular system to subsequent stress.

PMID- 15034123
TI  - Characterization of the Kv channels of mouse carotid body chemoreceptor cells and
      their role in oxygen sensing.
AB  - As there are wide interspecies variations in the molecular nature of the O(2)
      sensitive Kv channels in arterial chemoreceptors, we have characterized the
      expression of these channels and their hypoxic sensitivity in the mouse carotid
      body (CB). CB chemoreceptor cells were obtained from a transgenic mouse
      expressing green fluorescent protein (GFP) under the control of tyrosine
      hydroxylase (TH) promoter. Immunocytochemical identification of TH in CB cell
      cultures reveals a good match with GFP-positive cells. Furthermore, these cells
      show an increase in [Ca(2+)](i) in response to low P(O(2)), demonstrating their
      ability to engender a physiological response. Whole-cell experiments demonstrated
      slow-inactivating K(+) currents with activation threshold around -30 mV and a bi
      exponential kinetic of deactivation (tau of 6.24 +/- 0.52 and 32.85 +/- 4.14 ms).
      TEA sensitivity of the currents identified also two different components (IC(50)
      of 17.8 +/- 2.8 and 940.0 +/- 14.7 microm). Current amplitude decreased
      reversibly in response to hypoxia, which selectively affected the fast
      deactivating component. Hypoxic inhibition was also abolished in the presence of
      low (10-50 microm) concentrations of TEA, suggesting that O(2) interacts with the
      component of the current most sensitive to TEA. The kinetic and pharmacological
      profile of the currents suggested the presence of Kv2 and Kv3 channels as their
      molecular correlates, and we have identified several members of these two
      subfamilies by single-cell PCR and immunocytochemistry. This report represents
      the first functional and molecular characterization of Kv channels in mouse CB
      chemoreceptor cells, and strongly suggests that O(2)-sensitive Kv channels in
      this preparation belong to the Kv3 subfamily.

PMID- 15034124
TI  - 'Deaf, mute and whispering' silent synapses: their role in synaptic plasticity.
AB  - Mechanisms of long-term potentiation (LTP) maintenance are discussed in the light
      of the phenomenon of silent synapses. Evidence that LTP is associated with the
      insertion of new AMPA receptors (AMPARs) in postsynaptically silent (deaf)
      synapses expressing only NMDA receptors (NMDARs) before LTP induction has led to
      the assumption that the debate on pre- versus postsynaptic locus of LTP
      expression has been resolved in favour of the latter. However, recent data
      indicate that these synapses are mainly presynaptically silent (mute or
      whispering), because the probability of glutamate release (P(r)) or glutamate
      concentration in the cleft is too low to activate AMPARs. In this case LTP could
      be explained by an increase in P(r) or enhanced glutamate concentration to
      activate low affinity AMPARs. Optical methods to probe calcium transients in
      dendritic spines have revealed an increase in P(r) during LTP with concomitant
      postsynaptic modifications. A hypothesis is considered that accounts for the
      differences in both the initial failure rates between AMPAR- and NMDAR-mediated
      responses, and the LTP-associated decrease in failures of AMPAR-mediated
      responses. According to this hypothesis, glutamate release is potentiated by the
      strong postsynaptic depolarization used to identify NMDAR-mediated responses. We
      suggest that the expression of LTP may depend on coordinated pre- and
      postsynaptic modifications whose relative contributions vary according to the
      initial state of the synapse, the experimental protocol and time after induction.

PMID- 15034125
TI  - Excitability of the T-tubular system in rat skeletal muscle: roles of K+ and Na+
      gradients and Na+-K+ pump activity.
AB  - Strenuous exercise causes an increase in extracellular [K(+)] and intracellular
      Na(+) ([Na(+)](i)) of working muscles, which may reduce sarcolemma excitability.
      The excitability of the sarcolemma is, however, to some extent protected by a
      concomitant increase in the activity of muscle Na(+)-K(+) pumps. The exercise
      induced build-up of extracellular K(+) is most likely larger in the T-tubules
      than in the interstitium but the significance of the cation shifts and Na(+)-K(+)
      pump for the excitability of the T-tubular membrane and the voltage sensors is
      largely unknown. Using mechanically skinned fibres, we here study the role of the
      Na(+)-K(+) pump in maintaining T-tubular function in fibres with reduced chemical
      K(+) gradient. The Na(+)-K(+) pump activity was manipulated by changing
      [Na(+)](i). The responsiveness of the T-tubules was evaluated from the excitation
      induced force production of the fibres. Compared to control twitch force in
      fibres with a close to normal intracellular [K(+)] ([K(+)](i)), a reduction in
      [K(+)](i) to below 60 mM significantly reduced twitch force. Between 10 and 50 mM
      Na(+), the reduction in force depended on [Na(+)](i), the twitch force at 40 mM
      K(+) being 22 +/- 4 and 54 +/- 9% (of control force) at a [Na(+)](i) of 10 and 20
      mM, respectively (n= 4). Double pulse stimulation of fibres at low [K(+)](i)
      showed that although elevated [Na(+)](i) increased the responsiveness to single
      action potentials, it reduced the capacity of the T-tubules to respond to high
      frequency stimulation. It is concluded that a reduction in the chemical gradient
      for K(+), as takes place during intensive exercise, may depress T-tubular
      function, but that a concomitant exercise-induced increase in [Na(+)](i) protects
      T-tubular function by stimulating the Na(+)-K(+) pump.

PMID- 15034126
TI  - Pharmacological plasticity of GABA(A) receptors at dentate gyrus synapses in a
      rat model of temporal lobe epilepsy.
AB  - In the lithium-pilocarpine model (Li-pilocarpine) of temporal lobe epilepsy,
      GABA(A) receptor-mediated inhibitory postsynaptic currents (GABA(A) IPSCs) were
      recorded in dentate gyrus granule cells (GCs) from adult rat hippocampal slices.
      The properties of GABA(A) IPSCs were compared before and after superfusion of
      modulators in control conditions (Li-saline rats) and in Li-pilocarpine rats 24
      48 h and 3-5 months (epileptic rats) after status epilepticus (SE). The mean peak
      amplitude of GABA(A) IPSCs increased by about 40% over Li-saline values in GCs 24
      48 h after SE and remained higher in epileptic rats. In Li-pilocarpine rats,
      studied at 24-48 h after SE, diazepam (1 microm) lost 65% of its effectiveness at
      increasing the half-decay time (T(50%)) of GABA(A) miniature IPSCs (mIPSCs).
      Diazepam had no effects on mIPSC T(50%) in epileptic rats. The benzodiazepine
      ligand flumazenil (1 microm), acting as an antagonist in Li-saline rats,
      exhibited a potent inverse agonistic effect on GABA(A) mIPSCs of GCs from Li
      pilocarpine rats 24-48 h and 3-5 months after SE. The neurosteroid
      allopregnanolone (100 nm), which considerably prolonged GABA(A) mIPSCs in Li
      saline rats, totally lost its effect in rats studied 24-48 h after SE. However,
      this decrease in effectiveness was transient and was totally restored in
      epileptic rats. In addition to the up-regulation in the number of receptors at
      individual GC synapses, we propose that these 'epileptic' GABA(A) receptors
      possess benzodiazepine binding sites with altered allosteric properties. The
      failure of benzodiazepine and neurosteroid to potentiate inhibition early after
      SE may be a critical factor in the development of epileptogenesis and occurrence
      of seizures.

PMID- 15034128
TI  - Thirty years of a very special visual area, Area V5.

PMID- 15034127
TI  - BK potassium channels control transmitter release at CA3-CA3 synapses in the rat
      hippocampus.
AB  - Large conductance calcium- and voltage-activated potassium channels (BK channels)
      activate in response to calcium influx during action potentials and contribute to
      the spike repolarization and fast afterhyperpolarization. BK channels targeted to
      active zones in presynaptic nerve terminals have been shown to limit calcium
      entry and transmitter release by reducing the duration of the presynaptic spike
      at neurosecretory nerve terminals and at the frog neuromuscular junction.
      However, their functional role in central synapses is still uncertain. In the
      hippocampus, BK channels have been proposed to act as an 'emergency brake' that
      would control transmitter release only under conditions of excessive
      depolarization and accumulation of intracellular calcium. Here we demonstrate
      that in the CA3 region of hippocampal slice cultures, under basal experimental
      conditions, the selective BK channel blockers paxilline (10 microM) and
      iberiotoxin (100 nM) increase the frequency, but not the amplitude, of
      spontaneously occurring action potential-dependent EPSCs. These drugs did not
      affect miniature currents recorded in the presence of tetrodotoxin, suggesting
      that their action was dependent on action potential firing. Moreover, in double
      patch-clamp recordings from monosynaptically interconnected CA3 pyramidal
      neurones, blockade of BK channels enhanced the probability of transmitter
      release, as revealed by the increase in success rate, EPSC amplitude and the
      concomitant decrease in paired-pulse ratio in response to pairs of presynaptic
      action potentials delivered at a frequency of 0.05 Hz. BK channel blockers also
      enhanced the appearance of delayed responses, particularly following the second
      action potential in the paired-pulse protocol. These results are consistent with
      the hypothesis that BK channels are powerful modulators of transmitter release
      and synaptic efficacy in central neurones.

PMID- 15034130
TI  - Bayesian phylogenetic model selection using reversible jump Markov chain Monte
      Carlo.
AB  - A common problem in molecular phylogenetics is choosing a model of DNA
      substitution that does a good job of explaining the DNA sequence alignment
      without introducing superfluous parameters. A number of methods have been used to
      choose among a small set of candidate substitution models, such as the likelihood
      ratio test, the Akaike Information Criterion (AIC), the Bayesian Information
      Criterion (BIC), and Bayes factors. Current implementations of any of these
      criteria suffer from the limitation that only a small set of models are examined,
      or that the test does not allow easy comparison of non-nested models. In this
      article, we expand the pool of candidate substitution models to include all
      possible time-reversible models. This set includes seven models that have already
      been described. We show how Bayes factors can be calculated for these models
      using reversible jump Markov chain Monte Carlo, and apply the method to 16 DNA
      sequence alignments. For each data set, we compare the model with the best Bayes
      factor to the best models chosen using AIC and BIC. We find that the best model
      under any of these criteria is not necessarily the most complicated one; models
      with an intermediate number of substitution types typically do best. Moreover,
      almost all of the models that are chosen as best do not constrain a transition
      rate to be the same as a transversion rate, suggesting that it is the
      transition/transversion rate bias that plays the largest role in determining
      which models are selected. Importantly, the reversible jump Markov chain Monte
      Carlo algorithm described here allows estimation of phylogeny (and other
      phylogenetic model parameters) to be performed while accounting for uncertainty
      in the model of DNA substitution.

PMID- 15034129
TI  - Mechanisms underlying cannabinoid inhibition of presynaptic Ca2+ influx at
      parallel fibre synapses of the rat cerebellum.
AB  - Activation of CB1 cannabinoid receptors in the cerebellum acutely depresses
      excitatory synaptic transmission at parallel fibre-Purkinje cell synapses by
      decreasing the probability of glutamate release. This depression involves the
      activation of presynaptic 4-aminopyridine-sensitive K(+) channels by CB1
      receptors, which in turn inhibits presynaptic Ca(2+) influx controlling glutamate
      release at these synapses. Using rat cerebellar frontal slices and fluorometric
      measures of presynaptic Ca(2+) influx evoked by stimulation of parallel fibres
      with the fluorescent dye fluo-4FF, we tested whether the CB1 receptor-mediated
      inhibition of this influx also involves a direct inhibition of presynaptic
      voltage-gated calcium channels. Since various physiological effects of CB1
      receptors appear to be mediated through the activation of PTX-sensitive proteins,
      including inhibition of adenylate cyclases, activation of mitogen-activated
      protein kinases (MAPK) and activation of G protein-gated inwardly rectifying K(+)
      channels, we also studied the potential involvement of these intracellular signal
      transduction pathways in the cannabinoid-mediated depression of presynaptic
      Ca(2+) influx. The present study demonstrates that the molecular mechanisms
      underlying the CB1 inhibitory effect involve the activation of the PTX-sensitive
      G(i)/G(o) subclass of G proteins, independently of any direct effect on
      presynaptic Ca(2+) channels (N, P/Q and R (SNX-482-sensitive) types) or on
      adenylate cyclase or MAPK activity, but do require the activation of G protein
      gated inwardly rectifying (Ba(2+)- and tertiapin Q-sensitive) K(+) channels, in
      addition to 4-aminopyridine-sensitive K(+) channels.

PMID- 15034132
TI  - Reconciling the numbers: ESTs versus protein-coding genes.
AB  - The number of expressed sequences greatly surpasses the estimated number of
      protein-coding genes in mammalian genomes. An evolutionary approach reveals that
      only 9% to 14% of human-expressed and mouse-expressed sequences are able to code
      for proteins. Clustering of these sequences using cross-species relationships
      suggests that millions of expressed sequences may correspond to only
      approximately 20,000 distinct protein-coding transcripts.

PMID- 15034131
TI  - Positive directional selection in the proline-rich antigen (PRA) gene among the
      human pathogenic fungi Coccidioides immitis, C. posadasii and their closest
      relatives.
AB  - In this study, we investigate the possibility of selection acting on the proline
      rich antigen (PRA) gene in natural populations of the two human pathogens,
      Coccidioides immitis and Coccidioides posadasii, and three of their close
      relatives, Chrysosporium lucknowense, Chrysosporium queenslandicum, and
      Uncinocarpus reesii. We addressed the following questions: Is diversifying
      selection acting on PRA in the pathogenic species as a result of avoidance of the
      host's immune system, and has adaptation to a pathogenic life style lead to
      positive directional selection and increased rate of evolution in PRA between the
      species? For these purposes, we amplified and sequenced from 40 individuals
      belonging to the five species, the entire coding region of the PRA gene, as well
      as partial sequences from the coding region of each of the three housekeeping
      genes glyderaldehyde-3-phosphate dehydrogenase, glutamine synthetase A, and
      hexokinase A. We used likelihood-based methods to compare models of different
      types of selective pressure among codons to analyze the mode of evolution of the
      genes and found that the PRA gene evolves under positive selection, but the
      investigated parts of the housekeeping genes evolve primarily under purifying
      selection. We found a very low level of intraspecific variability and no evidence
      of diversifying selection, suggesting that the increased rate of evolution in the
      PRA gene is not a result of avoidance of the host's immune system. Neither did
      likelihood-based analyses suggest that selection was stronger on the branch
      separating pathogenic and nonpathogenic species. Instead, we suggest that
      positive selection act on PRA as a consequence of spore cell-wall morphogenesis
      unique to each species.

PMID- 15034133
TI  - Twelve Group I introns in the same pre-rRNA transcript of the myxomycete Fuligo
      septica: RNA processing and evolution.
AB  - The ribosomal DNA region of the myxomycete Fuligo septica was investigated and
      found to contain 12 group I introns (four in the small subunit and eight in the
      large subunit ribosomal RNAs). We have performed molecular and phylogenetic
      analyses to provide insight into intron structure and function, intron-host
      biology, and intron origin and evolution. The introns vary in size from 398 to
      943 nt, all lacking detectable open reading frames. Secondary structure models
      revealed considerable structural diversity, but all, except one (subclass IB),
      represent the common group IC1 intron subclass. In vitro splicing analysis
      revealed that 10 of the 12 introns were able to self-splice as naked RNA, but all
      12 introns were able to splice out from the precursor rRNA in vivo as evaluated
      by reverse transcription PCR analysis on total F. septica RNA. Furthermore, RNA
      processing analyses in vitro and in vivo showed that 10 of 12 introns perform
      hydrolytic cleavage at the 3' splice site, as well as intron circularization.
      Full-length intron RNA circles were detected in vivo. The order of splicing was
      analyzed by a reverse transcription PCR approach on cellular RNA, but no strict
      order of intron excision could be detected. Phylogenetic analysis indicated that
      most Fuligo introns were distantly related to each other and were independently
      gained in ribosomal DNA during evolution.

PMID- 15034134
TI  - Plastid-derived single gene minicircles of the dinoflagellate Ceratium horridum
      are localized in the nucleus.
AB  - Recent reports show that numerous chloroplast-specific proteins of peridinin
      containing dinoflagellates are encoded on minicircles-small plasmidlike molecules
      containing one or two polypeptide genes each. The genes for these polypeptides
      are chloroplast specific because their homologs from other photosynthetic
      eukaryotes are exclusively encoded in the chloroplast genome. Here, we report the
      isolation, sequencing, and subcellular localization of minicircles from the
      peridinin-containing dinoflagellate Ceratium horridum. The C. horridum
      minicircles are organized in the same manner as in other peridinin-containing
      dinoflagellates and encode the same kinds of plastid-specific proteins, as
      previous studies reported. However, intact plastids isolated from C. horridum do
      not contain minicircles, nor do they contain DNA that hybridizes to minicircle
      specific probes. Rather, C. horridum minicircles are localized in the nucleus as
      shown by cell fractionation, Southern hybridization, and in situ hybridization
      with minicircle-specific probes. A high-molecular-weight DNA was detected in
      purified C. horridum plastids, but it is apparently not minicircular in
      organization, as hybridization with a cloned probe from the plastid-localized DNA
      suggests. The distinction between C. horridum and other peridinin-containing
      dinoflagellates at the level of their minicircle localization is paralleled by C.
      horridum thylakoid organization, which also differs from that of other peridinin
      containing dinoflagellates, indicating that a hitherto underestimated diversity
      of minicircle DNA localization and thylakoid organization exists across various
      dinoflagellate groups.

PMID- 15034135
TI  - Common pattern of evolution of gene expression level and protein sequence in
      Drosophila.
AB  - Sequence divergence scaled by variation within species has been used to infer the
      action of selection upon individual genes. Applying this approach to expression,
      we compared whole-genome whole-body RNA levels in 10 heterozygous Drosophila
      simulans genotypes and a pooled sample of 10 D. melanogaster lines using
      Affymetrix Genechip. For 972 genes expressed in D. melanogaster, the transcript
      level was below detection threshold in D. simulans, which may be explained either
      by sequence divergence between the primers on the chip and the mRNA transcripts
      or by down-regulation of these genes. Out of 6,707 genes that were expressed in
      both species, transcript level was significantly different between species for
      534 genes (at P < 0.001). Genes whose expression is under stabilizing selection
      should exhibit reduced genetic variation within species and reduced divergence
      between species. Expression of genes under directional selection in D. simulans
      should be highly divergent from D. melanogaster, while showing low genetic
      variation in D. simulans. Finally, the genes with large variation within species
      but modest divergence between species are candidates for balancing selection.
      Rapidly diverging, low-polymorphism genes included those involved in reproduction
      (e.g., Mst 3Ba, 98Cb; Acps 26Aa, 63F; and sperm-specific dynein). Genes with high
      variation in transcript abundance within species included metallothionein and
      hairless, both hypothesized to be segregating in nature because of gene-by
      environment interactions. Further, we compared expression divergence and DNA
      substitution rate in 195 genes. Synonymous substitution rate and expression
      divergences were uncorrelated, whereas there was a significant positive
      correlation between nonsynonymous substitution rate and expression divergence. We
      hypothesize that as a substantial fraction of nonsynonymous divergence has been
      shown to be adaptive, much of the observed expression divergence is likewise
      adaptive.

PMID- 15034136
TI  - Covarion shifts cause a long-branch attraction artifact that unites microsporidia
      and archaebacteria in EF-1alpha phylogenies.
AB  - Microsporidia branch at the base of eukaryotic phylogenies inferred from
      translation elongation factor 1alpha (EF-1alpha) sequences. Because these
      parasitic eukaryotes are fungi (or close relatives of fungi), it is widely
      accepted that fast-evolving microsporidian sequences are artifactually
      "attracted" to the long branch leading to the archaebacterial (outgroup)
      sequences ("long-branch attraction," or "LBA"). However, no previous studies have
      explicitly determined the reason(s) why the artifactual allegiance of
      microsporidia and archaebacteria ("M + A") is recovered by all phylogenetic
      methods, including maximum likelihood, a method that is supposed to be resistant
      to classical LBA. Here we show that the M + A affinity can be attributed to those
      alignment sites associated with large differences in evolutionary site rates
      between the eukaryotic and archaebacterial subtrees. Therefore, failure to model
      the significant evolutionary rate distribution differences (covarion shifts)
      between the ingroup and outgroup sequences is apparently responsible for the
      artifactual basal position of microsporidia in phylogenetic analyses of EF-1alpha
      sequences. Currently, no evolutionary model that accounts for discrete changes in
      the site rate distribution on particular branches is available for either protein
      or nucleotide level phylogenetic analysis, so the same artifacts may affect many
      other "deep" phylogenies. Furthermore, given the relative similarity of the site
      rate patterns of microsporidian and archaebacterial EF-1alpha proteins ("parallel
      site rate variation"), we suggest that the microsporidian orthologs may have lost
      some eukaryotic EF-1alpha-specific nontranslational functions, exemplifying the
      extreme degree of reduction in this parasitic lineage.

PMID- 15034137
TI  - Inhibition of adipogenesis by ghrelin.
AB  - Ghrelin, a novel gastric hormone, regulates food intake and energy metabolism via
      central mechanisms. The peripheral effect of ghrelin on adiposity is poorly
      understood. We established a stable 3T3-L1 cell line expressing ghrelin to study
      the direct effect of ghrelin on adipogenesis. Cells overexpressing ghrelin
      demonstrate significantly attenuated differentiation of preadipocytes into
      adipocytes. Expression of peroxisome proliferator-activator receptor-gamma is
      significantly inhibited as demonstrated by decrease of peroxisome proliferator
      activator receptor-gamma mRNA and protein. Both ghrelin overexpression and
      exogenous ghrelin stimulate cell proliferation. Phosphorylation of mitogen
      activated protein kinase is increased after treatment of cells with ghrelin.
      Ghrelin binding activity is demonstrated in both native and ghrelin
      overexpressing 3T3-L1 cells by radiolabeled ghrelin, although reverse
      transcription-polymerase chain reaction with the primer sequence of the
      previously identified ghrelin receptor subtypes detected no signal. Our results
      demonstrate that ghrelin inhibits adipogenesis by stimulation of cell
      proliferation via the mediation of a ghrelin receptor, likely a novel
      unidentified subtype.

PMID- 15034139
TI  - Different gene expression patterns in invasive lobular and ductal carcinomas of
      the breast.
AB  - Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the two
      major histological types of breast cancer worldwide. Whereas IDC incidence has
      remained stable, ILC is the most rapidly increasing breast cancer phenotype in
      the United States and Western Europe. It is not clear whether IDC and ILC
      represent molecularly distinct entities and what genes might be involved in the
      development of these two phenotypes. We conducted comprehensive gene expression
      profiling studies to address these questions. Total RNA from 21 ILCs, 38 IDCs,
      two lymph node metastases, and three normal tissues were amplified and hybridized
      to approximately 42,000 clone cDNA microarrays. Data were analyzed using
      hierarchical clustering algorithms and statistical analyses that identify
      differentially expressed genes (significance analysis of microarrays) and minimal
      subsets of genes (prediction analysis for microarrays) that succinctly
      distinguish ILCs and IDCs. Eleven of 21 (52%) of the ILCs ("typical" ILCs)
      clustered together and displayed different gene expression profiles from IDCs,
      whereas the other ILCs ("ductal-like" ILCs) were distributed between different
      IDC subtypes. Many of the differentially expressed genes between ILCs and IDCs
      code for proteins involved in cell adhesion/motility, lipid/fatty acid transport
      and metabolism, immune/defense response, and electron transport. Many genes that
      distinguish typical and ductal-like ILCs are involved in regulation of cell
      growth and immune response. Our data strongly suggest that over half the ILCs
      differ from IDCs not only in histological and clinical features but also in
      global transcription programs. The remaining ILCs closely resemble IDCs in their
      transcription patterns. Further studies are needed to explore the differences
      between ILC molecular subtypes and to determine whether they require different
      therapeutic strategies.

PMID- 15034140
TI  - The palmitoyltransferase of the cation-dependent mannose 6-phosphate receptor
      cycles between the plasma membrane and endosomes.
AB  - The cation-dependent mannose 6-phosphate receptor (CD-MPR) mediates the transport
      of lysosomal enzymes from the trans-Golgi network to endosomes. Evasion of
      lysosomal degradation of the CD-MPR requires reversible palmitoylation of a
      cysteine residue in its cytoplasmic tail. Because palmitoylation is reversible
      and essential for correct trafficking, it presents a potential regulatory
      mechanism for the sorting signals within the cytoplasmic domain of the CD-MPR.
      Characterization of the palmitoylation performing an in vitro palmitoylation
      assay by using purified full-length CD-MPR revealed that palmitoylation of the CD
      MPR occurs enzymatically by a membrane-bound palmitoyltransferase. In addition,
      analysis of the localization revealed that the palmitoyltransferase cycles
      between endosomes and the plasma membrane. This was identified by testing
      fractions from HeLa cell homogenate separated on a density gradient in the in
      vitro palmitoylation assay and further confirmed by in vivo labeling experiments
      by using different treatments to block specific protein trafficking steps within
      the cell. We identified a novel palmitoyltransferase activity in the endocytic
      pathway responsible for palmitoylation of the CD-MPR. The localization of the
      palmitoyltransferase not only fulfills the requirement of our hypothesis to be a
      regulator of the intracellular trafficking of the CD-MPR but also may affect the
      sorting/activity of other receptors cycling through endosomes.

PMID- 15034141
TI  - A point mutation in the motor domain of nonmuscle myosin II-B impairs migration
      of distinct groups of neurons.
AB  - We generated mice harboring a single amino acid mutation in the motor domain of
      nonmuscle myosin heavy chain II-B (NMHC II-B). Homozygous mutant mice had an
      abnormal gait and difficulties in maintaining balance. Consistent with their
      motor defects, the mutant mice displayed an abnormal pattern of cerebellar
      foliation. Analysis of the brains of homozygous mutant mice showed significant
      defects in neuronal migration involving granule cells in the cerebellum, the
      facial neurons, and the anterior extramural precerebellar migratory stream,
      including the pontine neurons. A high level of NMHC II-B expression in these
      neurons suggests an important role for this particular isoform during neuronal
      migration in the developing brain. Increased phosphorylation of the myosin II
      regulatory light chain in migrating, compared with stationary pontine neurons,
      supports an active role for myosin II in regulating their migration. These
      studies demonstrate that NMHC II-B is particularly important for normal migration
      of distinct groups of neurons during mouse brain development.

PMID- 15034138
TI  - The integrin beta1 subunit transmembrane domain regulates phosphatidylinositol 3
      kinase-dependent tyrosine phosphorylation of Crk-associated substrate.
AB  - Our previous studies on the transmembrane domain of human integrin subunits have
      shown that a conserved basic amino acid in both subunits of integrin heterodimers
      is positioned in the plasma membrane in the absence of interacting proteins. To
      investigate the possible functional role of the lipid-embedded lysine in the
      mouse integrin beta1 subunit, this amino acid was replaced with leucine, and the
      mutated beta1 subunit (beta1A(K756L)) was stably expressed in beta1-deficient
      GD25 cells. The extracellular domain of beta1A(K756L) integrins possesses a
      competent conformation for ligand binding as determined by the ability to mediate
      cell adhesion, and by the presence of the monoclonal antibody 9EG7 epitope.
      However, the spreading of GD25-beta1A(K756L) cells on fibronectin and laminin-1
      was impaired, and the rate of migration of GD25-beta1A(K756L) cells on
      fibronectin was reduced compared with GD25-beta1A cells. Phosphorylation of
      tyrosines in focal adhesion kinase (FAK) and the Y416 in c-Src in response to
      beta1A(K756L)-mediated adhesion was similar to that induced by wild-type beta1.
      The tyrosine phosphorylation level of paxillin, a downstream target of FAK/Src,
      was unaffected by the beta1 mutation, whereas tyrosine phosphorylation of CAS was
      strongly reduced. The results demonstrate that CAS is a target for
      phosphorylation both by FAK-dependent and -independent pathways after integrin
      ligation. The latter pathway was inhibited by wortmannin and LY294002,
      implicating that it required an active phosphatidylinositol 3-kinase.
      Furthermore, the K756L mutation in the beta1 subunit was found to interfere with
      beta1-induced activation of Akt. The results from this study identify
      phosphatidylinositol 3-kinase as an early component of a FAK-independent integrin
      signaling pathway triggered by the membrane proximal part of the beta1 subunit.

PMID- 15034142
TI  - RalA activation at nascent lamellipodia of epidermal growth factor-stimulated
      Cos7 cells and migrating Madin-Darby canine kidney cells.
AB  - RalA, a member of the Ras-family GTPases, regulates various cellular functions
      such as filopodia formation, endocytosis, and exocytosis. On epidermal growth
      factor (EGF) stimulation, activated Ras recruits guanine nucleotide exchange
      factors (GEFs) for RalA, followed by RalA activation. By using fluorescence
      resonance energy transfer-based probes for RalA activity, we found that the EGF
      induced RalA activation in Cos7 cells was restricted at the EGF-induced nascent
      lamellipodia, whereas under a similar condition both Ras activation and Ras
      dependent translocation of Ral GEFs occurred more diffusely at the plasma
      membrane. This EGF-induced RalA activation was not observed when lamellipodial
      protrusion was suppressed by a dominant negative mutant of Rac1, a GTPase
      activating protein for Cdc42, inhibitors of phosphatidylinositol 3-kinase, or
      inhibitors of actin polymerization. On the other hand, EGF-induced lamellipodial
      protrusion was inhibited by microinjection of the RalA-binding domains of RalBP1
      and Sec5. Furthermore, we found that RalA activity was high at the lamellipodia
      of migrating Madin-Darby canine kidney cells and that the migration of Madin
      Darby canine kidney cells was perturbed by the microinjection of RalBP1-RalA
      binding domain. Thus, RalA activation is required for the induction of
      lamellipodia, and conversely, lamellipodial protrusion seems to be required for
      the RalA activation, suggesting the presence of a positive feedback loop between
      RalA activation and lamellipodial protrusion. Our observation also demonstrates
      that the spatial regulation of RalA is conducted by a mechanism distinct from the
      temporal regulation conducted by Ras-dependent plasma membrane recruitment of Ral
      guanine nucleotide exchange factors.

PMID- 15034143
TI  - Regulation of spindle pole function by an intermediary metabolite.
AB  - Spore formation in the yeast Saccharomyces cerevisiae depends on a modification
      of spindle pole bodies (SPBs) at the onset of meiosis II that allows them to
      promote de novo membrane formation. Depletion of the environmental carbon source
      during sporulation results in modification of only one SPB from each meiosis II
      spindle and formation of a two-spored ascus, called a nonsister dyad (NSD). We
      have found that mutants impaired in the glyoxylate pathway, which is required for
      the conversion of acetate to glucose, make NSDs when acetate is the primary
      carbon source. Wild-type cells make NSDs when the carbon source is glycerol,
      which is converted to glucose independently of the glyoxylate pathway. During NSD
      formation in glycerol, only the two SPBs created at the meiosis I/II transition
      ("daughters") are modified. In these conditions, the SPB components Mpc70p and
      Spo74p are not recruited to mother SPBs. Moreover, cooverexpression of Mpc70p and
      Spo74p suppresses NSD formation in glycerol. Our findings indicate that flux
      through the glyoxylate pathway during sporulation regulates modification of
      mother SPBs via recruitment of Mpc70p and Spo74p. These results define a cellular
      response in which the accumulation of an intermediary metabolite serves as a
      measure of biosynthetic capacity to regulate the number of daughter cells formed.

PMID- 15034145
TI  - Tissue-specific expression and dynamic organization of SR splicing factors in
      Arabidopsis.
AB  - The organization of the pre-mRNA splicing machinery has been extensively studied
      in mammalian and yeast cells and far less is known in living plant cells and
      different cell types of an intact organism. Here, we report on the expression,
      organization, and dynamics of pre-mRNA splicing factors (SR33, SR1/atSRp34, and
      atSRp30) under control of their endogenous promoters in Arabidopsis. Distinct
      tissue-specific expression patterns were observed, and differences in the
      distribution of these proteins within nuclei of different cell types were
      identified. These factors localized in a cell type-dependent speckled pattern as
      well as being diffusely distributed throughout the nucleoplasm. Electron
      microscopic analysis has revealed that these speckles correspond to
      interchromatin granule clusters. Time-lapse microscopy revealed that speckles
      move within a constrained nuclear space, and their organization is altered during
      the cell cycle. Fluorescence recovery after photobleaching analysis revealed a
      rapid exchange rate of splicing factors in nuclear speckles. The dynamic
      organization of plant speckles is closely related to the transcriptional activity
      of the cells. The organization and dynamic behavior of speckles in Arabidopsis
      cell nuclei provides significant insight into understanding the functional
      compartmentalization of the nucleus and its relationship to chromatin
      organization within various cell types of a single organism.

PMID- 15034144
TI  - Markers for detergent-resistant lipid rafts occupy distinct and dynamic domains
      in native membranes.
AB  - Lipid rafts isolated by detergent extraction and sucrose gradient fractionation
      from mast cells are enriched for the glycosylphosphatidylinositol-linked protein
      Thy-1, the ganglioside GM1, palmitoylated LAT, and cross-linked IgE receptors,
      FcepsilonRI. This study addresses the relationship of fractionation data to the
      organization of raft markers in native membranes. Immunogold labeling and
      electron microscopy shows there is little or no colocalization of the raft
      markers Thy-1, GM1, and LAT with each other or with FcepsilonRI on native
      membrane sheets prepared from unstimulated cells. External cross-linking of Thy-1
      promotes coclustering of Thy-1 with LAT, but not with GM1. Thy-1 and LAT clusters
      occur on membrane regions without distinctive features. In contrast, external
      cross-linking of FcepsilonRI and GM1 causes their redistribution to electron
      dense membrane patches independently of each other and of Thy-1. The distinctive
      patches that accumulate cross-linked FcepsilonRI and GM1 also accumulate osmium,
      a stain for unsaturated lipids, and are sites for coated vesicle budding.
      Electron microscopy reveals a more complex and dynamic topographical organization
      of membrane microdomains than is predicted by biochemical analysis of detergent
      resistant membranes.

PMID- 15034146
TI  - Silencer elements as possible inhibitors of pseudoexon splicing.
AB  - Human pre-mRNAs contain a definite number of exons and several pseudoexons which
      are located within intronic regions. We applied a computational approach to
      address the question of how pseudoexons are neglected in favor of exons and to
      possibly identify sequence elements preventing pseudoexon splicing. A search for
      possible splicing silencers was carried out on a pseudoexon selection that
      resembled exons in terms of splice site strength and exon splicing enhancer (ESE)
      representation; three motifs were retrieved through hexamer composition
      comparisons. One of these functions as a powerful silencer in transfection-based
      splicing assays and matches a previously identified silencer sequence with hnRNP
      H binding ability. The other two motifs are novel and failed to induce skipping
      of a constitutive exon, indicating that they might act as weak repressors or in
      synergy with other unidentified elements. All three motifs are enriched in
      pseudoexons compared with intronic regions and display higher frequencies in
      intronless gene-coding sequences compared with exons. We consider that a
      subpopulation of pseudoexons might rely on negative regulators for splicing
      repression; this hypothesis, if experimentally verified, might improve our
      understanding of exonic splicing regulatory sequences and provide the
      identification of a novel mutation target for human genetic diseases.

PMID- 15034147
TI  - MUSCLE: multiple sequence alignment with high accuracy and high throughput.
AB  - We describe MUSCLE, a new computer program for creating multiple alignments of
      protein sequences. Elements of the algorithm include fast distance estimation
      using kmer counting, progressive alignment using a new profile function we call
      the log-expectation score, and refinement using tree-dependent restricted
      partitioning. The speed and accuracy of MUSCLE are compared with T-Coffee, MAFFT
      and CLUSTALW on four test sets of reference alignments: BAliBASE, SABmark, SMART
      and a new benchmark, PREFAB. MUSCLE achieves the highest, or joint highest, rank
      in accuracy on each of these sets. Without refinement, MUSCLE achieves average
      accuracy statistically indistinguishable from T-Coffee and MAFFT, and is the
      fastest of the tested methods for large numbers of sequences, aligning 5000
      sequences of average length 350 in 7 min on a current desktop computer. The
      MUSCLE program, source code and PREFAB test data are freely available at
      http://www.drive5. com/muscle.

PMID- 15034148
TI  - Calculating the statistical significance of physical clusters of co-regulated
      genes in the genome: the role of chromatin in domain-wide gene regulation.
AB  - Physical clusters of co-regulated, but apparently functionally unrelated, genes
      are present in many genomes. Despite the important implication that the genomic
      environment contributes appreciably to the regulation of gene expression, no
      simple statistical method has been described to identify physical clusters of co
      regulated genes. Here we report the development of a model that allows the direct
      calculation of the significance of such clusters. We have implemented the derived
      statistical relation in a software program, Pyxis, and have analyzed a selection
      of Saccharomyces cerevisiae gene expression microarray data sets. We have
      identified many gene clusters where constituent genes exhibited a regulatory
      dependence on proteins previously implicated in chromatin structure.
      Specifically, we found that Tup1p-dependent gene domains were enriched close to
      telomeres, which suggested a new role for Tup1p in telomere silencing. In
      addition, we identified Sir2p-, Sir3p- and Sir4p-dependent clusters, which
      suggested the presence of Sir-mediated heterochromatin in previously unidentified
      regions of the yeast genome. We also showed the presence of Sir4p-dependent gene
      clusters bordering the HMRa heterothallic locus, which suggested leaky
      termination of the heterochromatin by the boundary elements. These results
      demonstrate the utility of Pyxis in identifying possible higher order genomic
      features that may contribute to gene regulation in extended domains.

PMID- 15034151
TI  - Artificial genetic selection for an efficient translation initiation site for
      expression of human RACK1 gene in Escherichia coli.
AB  - In bacterial expression systems, translation initiation is usually the rate
      limiting and the least predictable stage of protein synthesis. Efficiency of a
      translation initiation site can vary dramatically depending on the sequence
      context. This is why many standard expression vectors provide very poor
      expression levels of some genes. This notion persuaded us to develop an
      artificial genetic selection protocol, which allows one to find for a given
      target gene an individual efficient ribosome binding site from a random pool. In
      order to create Darwinian pressure necessary for the genetic selection, we
      designed a system based on translational coupling, in which microorganism
      survival in the presence of antibiotic depends on expression of the target gene,
      while putting no special requirements on this gene. Using this system we obtained
      superproducing constructs for the human protein RACK1 (receptor for activated C
      kinase).

PMID- 15034149
TI  - Translational regulation of BACE-1 expression in neuronal and non-neuronal cells.
AB  - As the main beta-secretase of the central nervous system, BACE-1 is a key protein
      in the pathogenesis of Alzheimer's disease. Excessive expression of the protein
      might cause an overproduction of the neurotoxic beta-amyloid peptide. Therefore,
      a tight regulation of BACE-1 expression is expected in vivo. In addition to a
      possible transcriptional control, the BACE-1 transcript leader contains features
      that might constitute mechanisms of translational regulation of protein
      expression. Moreover, recent work has revealed an increase of BACE-1 protein and
      beta-secretase activity in some Alzheimer's disease patients, although a
      corresponding increase of transcript has not been reported. Here we show that
      BACE-1 translation could be modulated at multiple stages. The presence of several
      upstream ATGs strongly reduces the translation of the main open reading frame.
      This inhibition could be overcome with conditions that favour skipping of
      upstream ATGs. We also report an alternative splicing of the BACE-1 transcript
      leader that reduces the number of upstream ATGs. Finally, we show that
      translation driven by the BACE-1 transcript leader is increased in activated
      astrocytes independently of the splicing event, indicating yet another mechanism
      of translational control. Our findings might explain why increases in BACE-1
      protein or activity are reported in the brain of Alzheimer's disease patients
      even in the absence of changes in transcript levels.

PMID- 15034150
TI  - The major form of MeCP2 has a novel N-terminus generated by alternative splicing.
AB  - MeCP2 is a methyl-CpG binding protein that can repress transcription of nearby
      genes. In humans, mutations in the MECP2 gene are the major cause of Rett
      syndrome. By searching expressed sequence tag (EST) databases we have found a
      novel MeCP2 splice isoform (MeCP2alpha) which encodes a distinct N-terminus. We
      demonstrate that the MeCP2alpha mRNA splice variant is more abundant than the
      previously annotated MeCP2 mRNA (MeCP2beta) in mouse tissues and human brain.
      Furthermore, MeCP2beta mRNA has an upstream open reading frame that inhibits its
      translation. As a result of these differences, >90% of MeCP2 in mouse brain is
      MeCP2alpha. Both protein isoforms are nuclear and colocalize with densely
      methylated heterochromatic foci in mouse cells. The presence of a previously
      unknown MeCP2 isoform has implications for the genetic screening of Rett syndrome
      patients and for studies of the functional significance of MeCP2.

PMID- 15034152
TI  - Sodium ferric gluconate complex in haemodialysis patients: a prospective
      evaluation of long-term safety.
AB  - BACKGROUND: A previous single dose placebo-controlled double-blinded trial showed
      an extremely low (0.4%) intolerance rate of sodium ferric gluconate complex
      (SFGC) in SFGC-naive haemodialysis patients. No large prospective trials have
      assessed the safety of SFGC during repeated exposure in the outpatient
      haemodialysis setting. METHODS: Chronic haemodialysis patients completing the
      single-dose trial of SFGC were eligible to participate in this prospective,
      multicentre, open-label, long-term evaluation of SFGC, designed to record adverse
      events occurring up to 72 h post-dose. Patients received as many as 20 ampules
      (1250 mg total) of SFGC at an investigator-determined dose and rate over a 9
      month evaluation period. RESULTS: Among 1412 enrolled patients at 54 centres,
      1321 received 13,151 infusions of SFGC. Most doses (94.8%) were < or =125 mg and
      the majority were given over 10 min. Infusion rates ranged from <5 to 125 mg/min.
      There were no life-threatening events. Fifty-one patients (3.9%) experienced an
      adverse event, possibly related to SFGC. Of these, one experienced a serious
      event (hypotension). Five patients (0.4%) experienced an event that precluded
      SFGC readministration: pruritus (three), vasodilatation (one) and loss of taste
      (one). Among 372 patients (28.2%) receiving angiotensin-converting enzyme
      inhibitor (ACEI) therapy, adverse events were neither more common nor more severe
      than in the other patients. CONCLUSIONS: Repeated doses of SFGC are very well
      tolerated in haemodialysis patients. No life-threatening events were observed in
      over 13,000 doses administered. Administration of SFGC to patients using ACEI is
      safe and does not increase the incidence or severity of adverse events to SFGC.

PMID- 15034153
TI  - Simple and accurate quantification of dialysis in acute renal failure patients
      during either urea non-steady state or treatment with irregular or continuous
      schedules.
AB  - BACKGROUND: The quantification of dialysis in critically ill acute renal failure
      (ARF) patients requires a unifying expression that can establish kinetic
      equivalence amongst patients treated with irregular or frequent intermittent
      haemodialysis (IHD) schedules or with differing renal replacement therapies.
      EKRjc is a generalized form of the equivalent urea renal clearance (EKRc), and
      represents the equivalent continuous urea clearance that will result in the given
      time-averaged concentration of urea, for the given amount of urea removal. The
      suitability of EKRjc for the measurement of dialysis dose in this setting is
      examined. SUBJECTS AND METHODS: 420 weeks of renal replacement therapy (IHD and
      continuous renal replacement therapy) were simulated in 15 virtual 'patients'
      using a variable volume double pool urea kinetic model. Additional data from
      eight ARF patients were used to exemplify calculations. 1260 EKRjc values were
      calculated using both formal urea kinetic modelling, as well as a simplified
      method that requires input of changes in patient fluid state and blood urea
      nitrogen concentrations over a period of observation, in addition to an initial
      estimate of patient post-dialysis urea distribution volume (V(T)). RESULTS: EKRjc
      is shown to provide a unifying expression of dialysis dose irrespective of IHD
      schedule or renal replacement therapy. EKRjc is shown to be independent from the
      assumption of the urea steady state, and intrinsically normalized to patient urea
      distribution volume to allow dose comparisons between patients of different size.
      Residual renal urea clearance is easily incorporated where present. EKRjc is
      easily calculated using the simplified method without the need for iterative urea
      kinetic modelling. The accuracy of this simplified method is maintained when the
      initial estimation of V(T) is both 25% greater or smaller than the true value.
      Calculation of EKRjc is exemplified using the clinical data. CONCLUSIONS: EKRjc
      is the most suitable urea kinetic expression for the quantification of dialysis
      in critically ill ARF patients.

PMID- 15034154
TI  - A simple vascular calcification score predicts cardiovascular risk in
      haemodialysis patients.
AB  - BACKGROUND: Cardiovascular morbidity and mortality are highly prevalent in
      haemodialysis (HD) patients and have been recently associated with vascular
      calcifications. The objective of our study was to assess the value of a simple
      vascular calcification score for the prediction of cardiovascular death,
      cardiovascular hospitalizations and fatal and non-fatal cardiovascular events in
      HD patients, and to correlate this score with cardiovascular disease and with
      other known predictors of vascular disease. METHODS: In this observational,
      prospective study 123 chronic HD patients (75 males and 48 females; 20% diabetic)
      were included, who were on low-flux HD treatment for 46.6+/-52 months (mean+/
      SD). We set up a simple vascular calcification score based on plain radiographic
      films of pelvis and hands. Brachial pulse pressure and mean arterial pressure
      (MAP) were measured and cardiovascular events and hospitalization episodes were
      assessed. RESULTS: During an observational period of 37 months there were 17
      cardiovascular deaths; 28 patients needed cardiovascular hospitalizations and 32
      patients suffered fatal and non-fatal cardiovascular events. Coronary artery
      disease was diagnosed in 43 patients (35%), peripheral arterial disease in 33
      patients (26.8%), cerebrovascular disease in 16 patients (13%) and vascular
      disease (coronary artery disease or peripheral arterial disease or cerebral
      vascular disease) in 61 patients (49.6%). By binary logistic regression, diabetes
      (P = 0.01), male sex (P<0.001), age (P = 0.02), HD duration (P = 0.02) and MAP (P
      = 0.03) were independently associated with a vascular score > or =3. This score >
      or =3 was independently associated with coronary artery disease (P = 0.008),
      peripheral arterial disease (P<0.001) and vascular disease (P = 0.001). Patients
      with a vascular calcification score > or =3 had a 3.9-fold higher risk of
      cardiovascular mortality (P = 0.03), a 2.8-fold higher risk of cardiovascular
      hospitalizations (P = 0.02) and a 2.3-fold higher risk of fatal or non-fatal
      cardiovascular events (P = 0.04). CONCLUSIONS: The present vascular calcification
      scoring represents a simple tool for the assessment of cardiovascular risk
      related with vascular calcifications in chronic HD patients.

PMID- 15034155
TI  - Venography at insertion of tunnelled internal jugular vein dialysis catheters
      reveals significant occult stenosis.
AB  - BACKGROUND: Tunnelled catheters are widely used to provide vascular access for
      haemodialysis. Percutaneous insertion of these catheters requires large calibre
      tissue dilators with the potential to cause trauma to central veins, particularly
      if anatomical abnormalities are present. METHODS: We evaluated the use of
      venography to identify central vein anatomical abnormalities in 69 consecutive
      patients undergoing percutaneous placement of tunnelled right internal jugular
      vein catheters. The internal jugular vein was entered under ultrasound guidance
      and venography was performed prior to insertion of a guide-wire. Images were
      evaluated on-screen by the operator and a decision made regarding the need for
      additional fluoroscopy during insertion of the catheter. RESULTS: In 29 cases
      (42%), venography showed evidence of unexpected stenosis and/or angulation of the
      central veins of sufficient severity to warrant additional fluoroscopy during
      insertion of the dilators, or abandonment of the procedure. Patients who had
      previously had tunnelled internal jugular catheters had more than double the
      incidence of such abnormalities than those who had not [15/23 (65%) vs 14/46
      (30%); P = 0.009]. In two patients the procedure was abandoned due to severe
      stenosis. No patient suffered central vein trauma or pneumothorax. There were no
      adverse reactions to contrast injection. CONCLUSIONS: Venography performed
      immediately prior to tunnelled internal jugular dialysis catheter insertion
      detects unexpected, clinically significant anatomical abnormalities of the
      central veins in a substantial proportion of patients, particularly those with a
      history of previous tunnelled catheter insertion. We suggest that the use of
      venography may help to minimize the risk of complications from this procedure.

PMID- 15034156
TI  - Attenuation of platelet reactivity by enoxaparin compared with unfractionated
      heparin in patients undergoing haemodialysis.
AB  - BACKGROUND: Increased platelet reactivity presages adverse cardiac events.
      Because both haemodialysis and unfractionated heparin (UFH) can increase platelet
      reactivity, we compared platelet reactivity during haemodialysis when patients
      were anticoagulated with UFH or enoxaparin. METHODS: Patients (n = 20) underwent
      consecutive haemodialysis sessions with either UFH or enoxaparin in a random
      order. Blood was taken from the arterial end of the haemodialysis circuit at the
      initiation of haemodialysis before anticoagulation. Subsequently, blood was taken
      during dialysis from the venous end of the circuit 10 min after treatment with
      UFH or enoxaparin. Platelet reactivity was assessed with the use of flow
      cytometry by determining the capacity of platelets to bind fibrinogen and the
      surface expression of P-selectin in response to adenosine diphosphate (ADP, 0 and
      0.2 microM). Results were compared with the use of two-way repeated measure
      ANOVA. RESULTS: Platelet reactivity in arterial blood obtained at the beginning
      of dialysis prior to patients being treated with either UFH [0.2 microM ADP
      induced capacity to bind fibrinogen = 28+/-15% (SD)] or enoxaparin (30+/-18%) was
      similar (P = 0.15). In contrast, platelet reactivity was less after treatment
      with enoxaparin compared with UFH (P = 0.006). The 0.2 microM ADP-induced
      capacity to bind fibrinogen in venous blood obtained 10 min after anticoagulation
      was 34+/-11% after treatment with UFH and 22+/-11% after treatment with
      enoxaparin. CONCLUSIONS: Anticoagulation with enoxaparin during haemodialysis is
      associated with less platelet reactivity compared with UFH. Accordingly,
      enoxaparin use may contribute to a lesser risk of cardiac events in patients with
      end-stage renal disease treated with haemodialysis.

PMID- 15034157
TI  - Improvement of cardiac function after haemodialysis. Quantitative evaluation by
      colour tissue velocity imaging.
AB  - BACKGROUND: Overhydration and accumulation of uraemic toxins may influence the
      myocardial function in haemodialysis (HD) patients. To evaluate cardiac function
      and the effects of fluid and solute removal during a single session of HD, colour
      tissue velocity imaging (TVI) was used. This new technique, which is less load
      dependent than conventional echocardiography, allows an objective quantitative
      assessment of myocardial contractility, contraction and relaxation. METHODS:
      Conventional echocardiographic and TVI images were recorded before and after a
      single HD session in 13 clinically stable HD patients (62+/-10 years, six males)
      and in 13 sex- and age-matched healthy controls. Myocardial tissue velocities (v;
      cm/s) for isovolumetric contraction (IVC), peak systole (PS), early (E') and late
      (A') diastolic filling and strain rate (SR) were measured. RESULTS: Left
      ventricular hypertrophy (LVH) was present in 12 patients. TVI gave additional
      information in comparison with conventional echocardiography. Before HD, PS
      (5.0+/-0.8 vs 6.0+/-1.2 cm/s, P<0.05), E' (5.7+/-1.7 vs 7.3+/-2.0 cm/s, P<0.05)
      and A' (6.6+/-1.7 vs. 8.3+/-2.9 cm/s, P<0.05) velocities were lower in the
      patients than in the controls, indicating systolic and diastolic dysfunction. The
      HD session increased IVCv (4.0+/-1.7 to 5.5+/-1.9 cm/s; P<0.001), PSv (5.0+/-0.8
      to 5.7+/-0.8 cm/s; P<0.05) and SR (0.7+/-0.2 to 0.9+/-0.2 1/s; P < 0.05) and
      decreased E/E' (16.7+/-7.7 to 12.2+/-4.0, P<0.05), indicating improved systolic
      function and decreased LV filling pressure, respectively. Linear regression
      analysis demonstrated a dependency of systolic contraction (PSv) and
      contractility (IVCv) upon plasma levels of phosphate (r(2) = 0.70, P<0.005, r(2)
      = 0.33, P<0.01). CONCLUSIONS: Using TVI, HD patients demonstrate myocardial
      dysfunction, which is found less frequently when using conventional
      echocardiography. The systolic function seems to be impaired by high plasma
      levels of phosphate and an increased Ca x P product. One single session of HD
      improved systolic function as indicated by increases in IVCv, PSv and SR. Further
      studies are needed to clarify if this effect of HD is due to the acute removal of
      fluid, the removal of solutes or both.

PMID- 15034158
TI  - Cardiac work up in primary renal hypokalaemia-hypomagnesaemia (Gitelman
      syndrome).
AB  - BACKGROUND: Potassium and magnesium depletion prolongs the duration of the action
      potential of the cardiomyocyte, which predisposes to ventricular arrhythmias. In
      addition, potassium or magnesium depletion might impair cardiac performance and
      facilitate coronary artery thrombosis. METHODS: Continuous 24-h ambulatory
      electrocardiographic monitoring, treadmill exercise testing and echocardiography
      were assessed in 21 patients (11 female and 10 male subjects, aged 5.9-39, median
      19 years) with primary renal hypokalaemia-hypomagnesaemia. RESULTS: The QT
      interval corrected for heart rate was normal (between 379 and 430 ms) in 10 and
      slightly to moderately prolonged in the remaining 11 patients (between 446 and
      509 ms). Plasma potassium, magnesium and bicarbonate were similar in patients
      with normal and in those with prolonged QT interval. Continuous ambulatory
      electrocardiography over 24 h and exercise testing did not detect significant
      abnormalities of cardiac rhythm or features suggestive of myocardial ischaemia.
      Finally, echocardiographic and Doppler assessment failed to reveal any
      abnormalities in myocardial morphology and function. CONCLUSION: The QT interval
      is often prolonged in primary renal hypokalaemia-hypomagnesaemia, confirming that
      potassium and magnesium depletion tends to prolong the duration of the action
      potential of the cardiomyocyte. The results of continuous ambulatory
      electrocardiography, exercise testing and echocardiography are reassuring.
      Nonetheless, we assume that dangerous cardiac arrhythmias may occur in patients
      with very severe hypokalaemia, during medication with drugs that prolong the QT
      interval or in the context of short-term non-adherence to the recommended regimen
      of care.

PMID- 15034160
TI  - Femoral and iliac vein stenoses after prolonged femoral vein catheter insertion.
AB  - BACKGROUND/AIMS: Catheterization of the femoral vein is a safe and recommended
      method of temporary access for haemodialysis. In some patients, however, because
      of the lack of other possibilities, it is necessary to maintain long-term femoral
      cannulation. The aim of the study was to evaluate the frequency of stenosis after
      prolonged femoral cannulation. METHODS: The 24 patients incorporated in the study
      were divided into two groups. Group 1 consisted of 10 end-stage kidney failure
      patients (four females and six males, aged 32-75 years, average 55.6+/-13.6
      years) in whom femoral catheters were maintained for less than 2 weeks (5-14
      days, average 9.3+/-3.6 days). Group 2 included 14 chronic haemodialysis patients
      (six females and eight males aged 23-65 years, average 49.5+/-13.27 years). The
      time of catheter maintenance ranged from 2 to 16 weeks (average 6.4+/-4.2 weeks).
      Femoral and iliac vein status was evaluated using magnetic resonance imaging.
      RESULTS: A feature of venous stenosis of both the femoral and iliac veins was
      disclosed in four patients in whom femoral cannulation lasted more than 4 weeks.
      There were no stenoses in group 1. CONCLUSION: Long-term femoral cannulation for
      more than 4 weeks may be associated with a significant risk of stenosis in the
      femoral and/or external iliac veins.

PMID- 15034159
TI  - Factor Xa-activated whole blood clotting time (Xa-ACT) for bedside monitoring of
      dalteparin anticoagulation during haemodialysis.
AB  - BACKGROUND: Low molecular weight heparins (LMWH) like dalteparin are increasingly
      used for anticoagulation during haemodialysis (HD). The available laboratory
      tests for monitoring LMWH anticoagulation are time-consuming and expensive, and
      the suitability of the conventional activated clotting time (ACT) is
      controversial. A simple and cheap bedside test would be useful. METHODS: We
      studied the factor Xa-activated whole blood clotting time (Xa-ACT) in vitro and
      in vivo in nine patients undergoing chronic HD with i.v. dalteparin bolus
      anticoagulation and compared it with the conventional ACT. Plasma anti-factor Xa
      (antiXa) activity was determined with a chromogenic assay. Thrombin-antithrombin
      complexes were measured to detect coagulation activation. RESULTS: Xa-ACT and ACT
      were prolonged with rising dalteparin concentration. In vitro, both clotting
      times were strongly correlated with the antiXa levels (r = 0.94 and 0.89,
      respectively). Nevertheless, compared with the ACT, the Xa-ACT was considerably
      more sensitive to the LMWH in vitro (healthy blood: Xa-ACT 90 s/U vs ACT 26 s/U;
      uraemic blood: Xa-ACT 96 s/U vs ACT 31 s/U) as well as in vivo (Xa-ACT 81 s/U vs
      ACT 22 s/U) and reflected different intensities of anticoagulation. An initial
      dalteparin bolus of 80+/-11 U/kg body weight was able to prevent coagulation
      activation for up to 4 h of HD. CONCLUSION: For monitoring LMWH anticoagulation
      the Xa-ACT was superior to the conventional ACT in vitro as well as in vivo
      during HD. The Xa-ACT can be useful as a LMWH bedside test. The ACT was not
      sensitive enough to serve as a LMWH monitoring tool.

PMID- 15034161
TI  - Co-administration of ketoconazole to tacrolimus-treated kidney transplant
      recipients: a prospective randomized study.
AB  - BACKGROUND: Since the introduction of calcineurin inhibitors, there has been a
      significant improvement in the results of solid organ transplantation, including
      graft and patient survival. However, high cost, chronic nephrotoxicity and other
      side effects stand as major challenges for long-term use of these drugs. The long
      term safety and financial benefits of the combination ketoconazole-cyclosporine
      previously studied. However, data about the effect of the addition of
      ketoconazole addition to tacrolimus-treated patients are scarce. Therefore, this
      study was conducted to evaluate the safety and financial impact of that
      combination. METHODS: The subjects of this work included 70 live-donor stable
      kidney transplant recipients receiving tacrolimus. Their age ranged from 16 to 45
      years. Among them, 54 were males and 16 were females. All of them were 6 months
      or more post-transplantation. Patients were randomly divided into two equal
      groups. Group I patients initially received ketoconazole 100 mg/day in addition
      to their usual treatment, while group II patients were considered a control.
      Patients were followed-up for 6 months. RESULTS: Concomitant ketoconazole
      tacrolimus resulted in marked reduction of tacrolimus dose (by 58.7%) and cost
      (by 56.9%). It also resulted in significant improvement in graft function and
      fungal skin infection, in addition to a decrease of gastrointestinal episodes and
      hospitalization. CONCLUSION: We conclude that ketoconazole-tacrolimus combination
      in kidney transplant recipients is safe, has outstanding impact on treatment
      costs and improves patient and graft outcome.

PMID- 15034163
TI  - Gene expression analysis in renal biopsies.

PMID- 15034162
TI  - Renal expression of matrix metalloproteinases in human ANCA-associated
      glomerulonephritis.
AB  - BACKGROUND: Expression of matrix metalloproteinases (MMPs) by infiltrating and
      intrinsic renal cells is increased in inflammatory conditions, and may correlate
      with disease activity of glomerulonephritis. We analysed renal expression of
      MMPs, tissue inhibitor of metalloproteinase-1 (TIMP-1) and markers of neutrophil
      and monocyte infiltration in renal biopsies of patients with active anti
      neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. METHODS:
      Immunohistochemical expression of MMP-2, -3, -9, TIMP-1, the neutrophil- and
      monocyte-derived MMP activators cathepsin G, neutrophil elastase and
      myeloperoxidase (MPO), and the monocyte marker CD14 was determined in renal
      biopsies of active proteinase 3 (PR3)-ANCA (n = 7) and MPO-ANCA (n = 6)
      associated glomerulonephritis, and in normal renal tissue (n = 4). Double
      labelling experiments of MMPs and TIMP-1 were performed with MPO and CD68,
      labelling neutrophils and macrophages. RESULTS: MMP-2-, MMP-3-, MMP-9- and TIMP-1
      positive cells were detected in ANCA-associated glomerulonephritis in glomeruli
      with active inflammation (cellular crescents or fibrinoid necrosis), only
      occasionally in normal appearing glomeruli, and not in sclerotic glomeruli and
      positive cells were found in the tubulo-interstitium. MMPs and TIMP-1 were
      expressed predominantly by MPO-and CD68-positive cells. In normal renal tissue,
      no expression was detected, with the exception of weak mesangial staining for MMP
      2. In ANCA-associated glomerulonephritis, glomerular MMP-2, -9 and TIMP-1
      correlated with glomerular cathepsin G expression, while the number of MMP-9
      expressing cells per glomerulus correlated with the percentage of crescentic
      glomeruli. Tubulo-interstitial expression of MMPs correlated with all markers of
      neutrophil and monocyte infiltration, and interstitial MMP-9 and TIMP-1
      expression correlated with renal function at the time of renal biopsy.
      CONCLUSIONS: Expression of glomerular and interstitial MMP-2, -3, -9 and TIMP-1
      is increased in active ANCA-associated glomerulonephritis and correlates with
      inflammatory activity.

PMID- 15034164
TI  - Urinary endothelin-1 excretion according to morpho-functional damage
      lateralization in reflux nephropathy.
AB  - BACKGROUND: Reflux nephropathy (RN) is a pathophysiological human model of
      reduced nephron reserve, due to loss of renal mass, but little information exists
      about the role of urinary endothelin-1 (uET-1) in this disease. The aim of this
      study was to assess the presence of uET-1-like-immunoreactivity (uET-1L) in RN
      patients, particularly if lateralized renal damage existed. METHODS: Thirty
      patients with vescico-ureteral reflux (VUR) and consequent RN, were studied. The
      presence of VUR was established by voiding cysto-urethrography. RN was assessed
      and graded by 99mTc-dimercapto-succinic acid scan (DMSA). Renal plasma flow
      (ERPF) was evaluated by (123)I-Hippuran renal sequential scintigraphy, and
      glomerular filtration rate (GFR) by creatinine clearance. Forty-five healthy
      subjects were selected as a control group. uET-1L excretion, in both affected and
      control groups, was assayed. RESULTS: Mann-Whitney U test showed a significant
      difference between control and patient groups in both GFR and uET-1L. A good
      correlation between DMSA grading, single kidney clearance and VUR grade was
      shown. A significant relationship was also shown between uET-1L and both ERPF and
      GFR. Patients with RN were divided into two subgroups according to functional
      damage lateralization. Between the two groups, a significant difference was found
      only for uET-1L when GFR was applied as a covariate in ANCOVA analysis.
      CONCLUSION: Our preliminary results confirmed the increase of urinary ET-1L
      excretion in RN, especially when renal functional injury was lateralized.

PMID- 15034165
TI  - Acute arterio-venous fistula occlusion decreases sympathetic activity and
      improves baroreflex control in kidney transplanted patients.
AB  - BACKGROUND: The acute bradycardia induced by the occlusion of an arteriovenous
      fistula (AVF), known as the Nicoladoni-Branham sign, is considerably larger than
      that which occurs during carotid sinus massage. This suggests increased arterial
      baroreflex sensitivity during acute AVF occlusion. Moreover, the influence of
      acute AVF occlusion on muscle sympathetic nerve traffic (MSNA, by
      microneurography) is unknown. We therefore assessed the effects of acute AVF
      occlusion on baroreflex sensitivity and on MSNA in patients with stable
      functional kidney grafts and patent AVF. METHODS: We measured blood pressure
      (BP), MSNA (n = 11), heart rate (HR), cardiac output (CO) and arterial baroreflex
      sensitivity (n = 18) at baseline and during acute, 30-s pneumatic AVF occlusions
      in 23 renal transplanted recipients. RESULTS: During the first 5 s of the AVF
      occlusion, mean BP increased from 98+/-4 to 112+/-4 mmHg (P<0.0001) while MSNA
      decreased to 28+/-5% of baseline values (P<0.0001) and HR decreased from 71+/-3
      to 61+/-3 b.p.m. (P<0.0001). The largest increases in BP were accompanied by the
      most marked decreases in MSNA (r = -0.79, P = 0.003) and HR (r = -0.49; P = 0.01)
      during the first 5 s of the AVF occlusion. During AVF occlusion baseline CO of
      6.9+/-0.3 decreased to 5.6+/-0.3 l/min (P<0.0001) while baroreflex sensitivity
      increased from 10+/-1 to 17+/-2 ms/mm Hg (P<0.001). CONCLUSIONS: Arterial
      baroreceptor activation and increased arterial baroreflex sensitivity decrease
      heart rate during AVF occlusion. In addition, our study is the first to
      demonstrate that arterial baroreflex activation decreases sympathetic nerve
      traffic during the Nicoladoni-Branham sign.

PMID- 15034166
TI  - Repression of a novel isoform of disproportionating enzyme (stDPE2) in potato
      leads to inhibition of starch degradation in leaves but not tubers stored at low
      temperature.
AB  - A potato (Solanum tuberosum) cDNA encoding an isoform of disproportionating
      enzyme (stDPE2) was identified in a functional screen in Escherichia coli. The
      stDPE2 protein was demonstrated to be present in chloroplasts and to accumulate
      at times of active starch degradation in potato leaves and tubers. Transgenic
      potato plants were made in which its presence was almost completely eliminated.
      It could be demonstrated that starch degradation was repressed in leaves of the
      transgenic plants but that cold-induced sweetening was not affected in tubers
      stored at 4 degrees C. No evidence could be found for an effect of repression of
      stDPE2 on starch synthesis. The malto-oligosaccharide content of leaves from the
      transgenic plants was assessed. It was found that the amounts of malto
      oligosaccharides increased in all plants during the dark period and that the
      transgenic lines accumulated up to 10-fold more than the control. Separation of
      these malto-oligosaccharides by high-performance anion-exchange chromatography
      with pulsed-amperometric detection showed that the only one that accumulated in
      the transgenic plants in comparison with the control was maltose. stDPE2 was
      purified to apparent homogeneity from potato tuber extracts and could be
      demonstrated to transfer glucose from maltose to oyster glycogen.

PMID- 15034167
TI  - Cloning, functional expression, and characterization of the raffinose
      oligosaccharide chain elongation enzyme, galactan:galactan galactosyltransferase,
      from common bugle leaves.
AB  - Galactan:galactan galactosyltransferase (GGT) is a unique enzyme of the raffinose
      family oligosaccharide (RFO) biosynthetic pathway. It catalyzes the chain
      elongation of RFOs without using galactinol (alpha-galactosyl-myoinositol) by
      simply transferring a terminal alpha-galactosyl residue from one RFO molecule to
      another one. Here, we report the cloning and functional expression of a cDNA
      encoding GGT from leaves of the common bugle (Ajuga reptans), a winter-hardy long
      chain RFO-storing Lamiaceae. The cDNA comprises an open reading frame of 1215 bp.
      Expression in tobacco (Nicotiana plumbaginifolia) protoplasts resulted in a
      functional recombinant protein, which showed GGT activity like the previously
      described purified, native GGT enzyme. At the amino acid level, GGT shows high
      homologies (>60%) to acid plant alpha-galactosidases of the family 27 of
      glycosylhydrolases. It is clearly distinct from the family 36 of
      glycosylhydrolases, which harbor galactinol-dependent raffinose and stachyose
      synthases as well as alkaline alpha-galactosidases. Physiological studies on the
      role of GGT confirmed that GGT plays a key role in RFO chain elongation and
      carbon storage. When excised leaves were exposed to chilling temperatures, levels
      of GGT transcripts, enzyme activities, and long-chain RFO concentrations
      increased concomitantly. On a whole-plant level, chilling temperatures induced
      GGT expression mainly in the roots and fully developed leaves, both known RFO
      storage organs of the common bugle, indicating an adaptation of the metabolism
      from active growth to transient storage in the cold.

PMID- 15034169
TI  - Metabolite-initiated protein misfolding may trigger Alzheimer's disease.
AB  - Anfinsen showed that a protein's fold is specified by its sequence. Although it
      is clear why mutant proteins form amyloid, it is harder to rationalize why a wild
      type protein adopts a native conformation in most individuals, but it misfolds in
      a minority of others, in what should be a common extracellular environment. This
      discrepancy suggests that another event likely triggers misfolding in sporadic
      amyloid disease. One possibility is that an abnormal metabolite, generated only
      in some individuals, covalently modifies the protein or peptide and causes it to
      misfold, but evidence for this is sparse. Candidate metabolites are suggested by
      the recently appreciated links between Alzheimer's disease (AD) and
      atherosclerosis, known chronic inflammatory metabolites, and the newly discovered
      generation of ozone during inflammation. Here we report detection of cholesterol
      ozonolysis products in human brains. These products and a related, lipid-derived
      aldehyde covalently modify Abeta, dramatically accelerating its amyloidogenesis
      in vitro, providing a possible chemical link between hypercholesterolemia,
      inflammation, atherosclerosis, and sporadic AD.

PMID- 15034176
TI  - Overcoming an evolutionary conflict: removal of a reproductive organ greatly
      increases locomotor performance.
AB  - One potential consequence of sexual size dimorphism is conflict among characters.
      For example, a structure evolved for reproduction can impair performance during
      other activities (e.g., locomotion). Here we provide quantitative evidence for an
      animal overcoming an evolutionary conflict generated by differential scaling and
      sexual size dimorphism by obligatorily removing an undamaged reproductive organ,
      and thus dramatically enhancing its locomotor performance. The spider genus
      Tidarren (Araneae, Theridiidae) is interesting because, within several species
      presenting extreme sexual size dimorphism (males representing approximately 1% of
      the total mass of the female), males voluntarily remove one of their two
      disproportionately large pedipalps (modified copulatory organs; a single one
      represents approximately 10% of the body mass in an adult) before achieving
      sexual maturity. Whether the left or right pedipalp is removed appears to be
      random. Previous researchers have hypothesized that pedipalp removal might
      enhance locomotor performance, a prediction that has remained untested. We found
      that, for male Tidarren sisyphoides, maximum speed increased (44%) significantly
      and endurance increased (63%) significantly after pedipalp removal. Furthermore,
      spiders with one pedipalp moved approximately 300% greater distances before
      exhaustion and had a higher survival after exertion than those with two
      pedipalps. Removal of the pedipalp may have evolved in male Tidarren because of
      enhanced abilities to search for females (higher endurance and survival after
      exertion) and to out-compete rival males on the female's web (higher maximum
      speed). Our data also highlight how the evolution of conflicts can result in the
      evolution of a novel behavior.

PMID- 15034168
TI  - Recognition of single-stranded RNA viruses by Toll-like receptor 7.
AB  - Viral infection of mammalian host results in the activation of innate immune
      responses. Toll-like receptors (TLRs) have been shown to mediate the recognition
      of many types of pathogens, including viruses. The genomes of viruses possess
      unique characteristics that are not found in mammalian genomes, such as high CpG
      content and double-stranded RNA. These genomic nucleic acids serve as molecular
      signatures associated with viral infections. Here we show that TLR7 recognizes
      the single-stranded RNA viruses, vesicular stomatitis virus and influenza virus.
      The recognition of these viruses by plasmacytoid dendritic cells and B cells
      through TLR7 results in their activation of costimulatory molecules and
      production of cytokines. Moreover, this recognition required intact endocytic
      pathways. Mice deficient in either the TLR7 or the TLR adaptor protein MyD88
      demonstrated reduced responses to in vivo infection with vesicular stomatitis
      virus. These results demonstrate microbial ligand recognition by TLR7 and provide
      insights into the pathways used by the innate immune cells in the recognition of
      viral pathogens.

PMID- 15034178
TI  - Beyond the diffusion limit: Water flow through the empty bacterial potassium
      channel.
AB  - Water molecules are constrained to move with K+ ions through the narrow part of
      the Streptomyces lividans K+ channel because of the single-file nature of
      transport. In the presence of an osmotic gradient, a water molecule requires <10
      ps to cross the purified protein reconstituted into planar bilayers. Rinsing K+
      out of the channel, water may be 1,000 times faster than the fastest
      experimentally observed K+ ion and 20 times faster than the one-dimensional bulk
      diffusion of water. Both the anomalously high water mobility and its inhibition
      observed at high K+ concentrations are consistent with the view that liquid-vapor
      oscillations occur because of geometrical confinements of water in the
      selectivity filter. These oscillations, where the chain of molecules imbedded in
      the channel (the "liquid") cooperatively exits the channel, leaving behind a near
      vacuum (the "vapor"), thus far have only been discovered in hydrophobic nanopores
      by molecular dynamics simulations [Hummer, G., Rasaiah, J. C. & Noworyta, J. P.
      (2001) Nature 414, 188-190; and Beckstein, O. & Sansom, M. S. P. (2003) Proc.
      Natl. Acad. Sci. USA 100, 7063-7068].

PMID- 15034179
TI  - Toward efficient asymmetric hydrogenation: architectural and functional
      engineering of chiral molecular catalysts.
AB  - Asymmetric hydrogenation uses inexpensive, clean hydrogen gas and a very small
      amount of a chiral molecular catalyst, providing the most powerful way to produce
      a wide array of enantio-enriched compounds in a large quantity without forming
      any waste. The recent revolutionary advances in this field have entirely changed
      the synthetic approach to producing performance chemicals that require a high
      degree of structural precision. The means of developing efficient asymmetric
      hydrogenations is discussed from a mechanistic point of view.

PMID- 15034180
TI  - Visualization for constructing and sharing geo-scientific concepts.
AB  - Representations of scientific knowledge must reflect the dynamic nature of
      knowledge construction and the evolving networks of relations between scientific
      concepts. In this article, we describe initial work toward dynamic, visual
      methods and tools that support the construction, communication, revision, and
      application of scientific knowledge. Specifically, we focus on tools to capture
      and explore the concepts that underlie collaborative science activities, with
      examples drawn from the domain of human-environment interaction. These tools help
      individual researchers describe the process of knowledge construction while
      enabling teams of collaborators to synthesize common concepts. Our visualization
      approach links geographic visualization techniques with concept-mapping tools and
      allows the knowledge structures that result to be shared through a Web portal
      that helps scientists work collectively to advance their understanding. Our
      integration of geovisualization and knowledge representation methods emphasizes
      the process through which abstract concepts can be contextualized by the data,
      methods, people, and perspectives that produced them. This contextualization is a
      critical component of a knowledge structure, without which much of the meaning
      that guides the sharing of concepts is lost. By using the tools we describe here,
      human-environment scientists are given a visual means to build concepts from data
      (individually and collectively) and to connect these concepts to each other at
      appropriate levels of abstraction.

PMID- 15034181
TI  - Effect of sulfide structure on enantioselectivity in catalytic asymmetric
      epoxidation of aldehydes: mechanistic insights and implications.
AB  - Bridged bicyclic sulfide 1 was originally found to provide high levels of
      asymmetric induction in sulfur ylide-mediated epoxidations. This sulfide
      possesses chirality in the [2.2.1] thioether moiety and the [2.2.1] camphor
      derived carbocyclic moiety. To determine whether the optimal sulfide had been
      used, a diastereomer of sulfide 1 in which the stereochemistry of the [2.2.1]
      carbocycle was reversed (sulfide 5) was prepared and studied as an epoxidation
      catalyst. This diastereomer gave considerably lower levels of asymmetric
      induction than the original sulfide 1. From computational and x-ray studies it
      was found that sulfide 5 gave rise to a more hindered ylide, which reacted more
      reversibly with aldehydes leading to lower enantioselectivity. Conditions that
      reduced reversibility were also tested and high enantioselectivities were
      returned for sulfide 5 (similar to sulfide 1). The implications for the synthesis
      of chiral sulfides for asymmetric epoxidations are discussed.

PMID- 15034192
TI  - Hexosamines are unlikely to function as a nutrient-sensor in 3T3-L1 adipocytes: a
      comparison of UDP-hexosamine levels after increased glucose flux and glucosamine
      treatment.
AB  - Whether the hexosamine biosynthesis pathway acts as a nutrient-sensing pathway is
      still unclear. Glucose is directed into this pathway by GFAT. Because the
      activity of GFAT is tightly regulated, we examined whether UDP-hexosamine levels
      can increase significantly and dose-dependently in response to elevated glucose
      concentrations. In glucosamine-treated 3T3-L1 adipocytes, inhibition of insulin
      stimulated glucose uptake was highly correlated with UDP-hexosamine levels (r = 
      0.992; p < 0.0001 for UDP-GlcNAc and r = -0.996; p < 0.0001 for UDP-GalNAc).
      Incubation of 3T3-L1 adipocytes with 0.1 microM insulin for 24 h in medium
      containing 1 and 5 mM glucose increased the rate of glucose uptake by 365% and
      175% compared to untreated cells, respectively. This increase was not observed
      when the cells were incubated for 24 h with insulin in medium containing 10 or 25
      mM glucose. However, treatment of cells with insulin and 1, 5, 10, or 25 mM
      glucose resulted in similar increases in levels of UDP-GlcNAc and UDP-GalNAc that
      always amounted to approx 30-40% above baseline values. This led us to conclude
      that despite exposure of adipocytes to conditions of extreme and prolonged
      glucose disposal, the increases in cellular UDP-hexosamines were minimal and not
      dependent on the extracellular glucose concentration. Taken together, our results
      are in line with the hypothesis that in glucosamine-treated adipocytes UDP
      hexosamines influence insulin-stimulated glucose uptake. However, our
      observations in glucose-treated adipocytes argue against the possibility that UDP
      hexosamines function as a nutrient-sensor, and question the role of the
      hexosamine biosynthesis pathway in the pathogenesis of insulin resistance.

PMID- 15034191
TI  - Effects of prior 5-hydroxytryptamine exposure on rat islet insulin secretory and
      phospholipase C responses.
AB  - Glucose-induced insulin secretion is inhibited by 5-hydroxytryptamine (5HT). In
      the present studies the specificity of 5HT inhibition of release and the
      potential biochemical mechanisms involved were investigated. Dose-dependent
      inhibition of 15 mM glucose-induced secretion was induced by a prior 3 h
      incubation with 5HT. At the highest 5HT concentration (500 microM) employed, both
      first and second phase responses to 15 mM glucose were reduced 50-60%. In
      addition, this level (500 microM) of 5HT virtually abolished 10 mM glucose
      induced secretion. In contrast, secretion in response to the protein kinase C
      activator phorbol 12-myristate 13-acetate (500 nM) was immune to 500 microM 5HT
      pre-treatment. Glucose usage rates were comparable in both control and 500 microM
      5HT-pretreated islets. However, the generation of inositol phosphates and the
      efflux of 3H-inositol from 3H-inositol-prelabeled islets in response to
      stimulatory glucose were impaired in parallel with insulin secretion. Based on
      these observations the following conclusions were reached: (1) 5HT impairs
      glucose-induced insulin release by altering glucose-induced activation of
      phospholipase C. (2) Biochemical events distal to phospholipase C remain intact
      despite this proximal biochemical lesion. (3) Amperometric analysis of 5HT
      release from 5HT-pretreated islets must take into consideration its profound
      adverse impact on glucose-induced insulin secretion.

PMID- 15034190
TI  - Osteoporosis and cardiovascular disease: brittle bones and boned arteries, is
      there a link?
AB  - Both osteoporosis and cardiovascular disease (CVD) are major public health
      problems leading to increased morbidity and mortality. Although traditionally
      viewed as separate disease entities that increase in prevalence with aging,
      accumulating evidence indicates that there are similar pathophysiological
      mechanisms underlying both diseases. In addition to menopause and advanced age,
      other risk factors for CVD such as dyslipidemia, oxidative stress, inflammation,
      hyperhomocystinemia, hypertension, and diabetes have also been associated with
      increased risk of low bone mineral density (LBMD). Elevated LDL and low HDL
      cholesterol are associated with LBMD, altered lipid metabolism is associated with
      both bone remodeling and the atherosclerotic process, which might explain, in
      part, the co-existence of osteoporosis and atherosclerosis in patients with
      dyslipidemia. Similarly, inflammation plays a pivotal role in both
      atherosclerosis and osteoporosis. Elevated plasma homocysteine levels are
      associated with both CVD and osteoporosis. Nitric oxide (NO), in addition to its
      known atheroprotective effects, appears to also play a role in osteoblast
      function and bone turnover. Supporting this notion, in a small randomized
      controlled trial, nitroglycerine (an NO donor) was found to be as effective as
      estrogen in preventing bone loss in women with surgical menopause. Statins,
      agents that reduce atherogenesis, also stimulate bone formation. Furthermore, bis
      phosphonates, used in the treatment of osteoporosis, have been shown to inhibit
      atherogenesis. Intravenous bisphosphonate therapy significantly decreases serum
      LDL and increases HDL in postmenopausal women The exciting possibilities of newer
      pharmacological agents that effectively treat both osteoporosis and CVD hold
      considerable promise. However, it is important to emphasize that the current
      evidence linking both of these diseases is far from conclusive. Therefore,
      additional research is necessary to further characterize the relationship between
      these two common illnesses.

PMID- 15034193
TI  - Urodynamic effects of estradiol (E2) in ovariectomized (ovx) rats.
AB  - Whether estrogens have a beneficial effect in the urinary bladder to prevent or
      to delay occurrence of urinary bladder incontinence is an open question. Good
      animal models are missing. Therefore, in ovariectomized (ovx) rats we studied the
      effects of estradiol (E2) administered with food for 3 mo on urodynamic
      properties of the urinary bladder and the urethra. A biluminal catheter with one
      outlet in the bladder and another in the urethra in juxtaposition to the external
      sphincter was inserted in isoflurane anaesthetized animals. Within 2 x 30 s (1
      min apart) 0.5 mL Ringer's solution was infused into the bladder and the inner
      vesicular and urethral pressure were recorded. In comparison to ovx estradiol
      treated rats, ovx animals had significantly (p < 0.05) lower vesicular and
      urethral pressure. In the sham-treated ovx animals vesicular and urethral
      pressures were unstable and appeared uncoordinated, whereas estrogens increased
      vesicular and urethral pressure in a coordinated way, such that in these animals
      leaked volume was significantly lower than in the sham-treated ovx animals. By
      means of quantitative RT-PCR we demonstrate that the upper and lower part of the
      bladder and the urethra express estrogen receptor of the alpha- and beta-subtype
      (ER alpha and beta) and nerve growth factor, which is associated with painful
      sensations in inflamed urinary bladders. E2 downregulated both ERs in the bladder
      but not in the urethra, while NGF gene expression was downregulated in the
      urethra but unaffected by E2 in the bladder. It is concluded that estrogen
      deprivation causes uncoordinated function of the detrusor and sphincter muscles
      and that this effect can be prevented by estradiol.

PMID- 15034195
TI  - Comparison of voglibose and nateglinide for their acute effects on insulin
      secretion and free fatty acid levels in OLETF rat portal blood after sucrose
      loading.
AB  - OBJECTIVE: Short-term hypoglycemic effects of single dose voglibose and
      nateglinide were compared after sucrose loading in spontaneously diabetic Otsuka
      Long-Evans Tokushima fatty (OLETF) rats. MATERIALS AND METHODS: After a 17-h
      fasting period, the animals received 0.06 mg/kg of voglibose (VOG group, n = 6),
      50 mg/kg of nateglinide (NAT group, n = 6), or 0.5% methyl cellulose (control
      group, n = 6), immediately followed by 2.5 g/kg of sucrose. RESULTS: Compared to
      control group values, glucose levels after sucrose loading were significantly
      decreased in the portal blood in the VOG group and in the peripheral blood in the
      NAT and VOG groups. The portal glucose AUC0-120 min was significantly lower in
      the VOG group than in the control and NAT groups, whereas the peripheral glucose
      AUC0-120 min was significantly lower in the VOG and NAT groups than in the
      control group. Portal insulin levels in the VOG group were significantly
      decreased compared to the control group. However, portal insulin levels in the
      NAT group were acutely increased, peaking 15 min after sucrose loading. Portal
      FFA levels were decreased in the NAT group 15, 30, and 60 min after sucrose
      loading; no FFA reductions were seen in the VOG group. CONCLUSIONS: Although both
      drugs produced similar hypoglycemic effects after sucrose loading in the
      peripheral blood, these drugs generated vastly different results in portal blood.
      Reduced FFA in the portal blood, observed after single administration of
      nateglinide, may have a favorable impact not only on glucose metabolism but also
      on lipid metabolism.

PMID- 15034194
TI  - Thyrotropin-releasing hormone increases phospholipase D activity through
      stimulation of protein kinase C in GH3 cells.
AB  - Activation of phospholipase D was investigated after treatment of GH3 cells with
      thyrotropin-releasing hormone. Thyrotropin-releasing hormone treatment resulted
      in both time- and dose-dependent increases of phospholipase D activity,
      translocation of protein kinase C-alpha and -beta I isozymes from cytosol to
      membrane within 30 min, and approx 43-fold increase of phosphatidylinositol
      specific phospholipase C activity. Intracellular calcium concentration was
      rapidly increased and diacyglycerol level remained high up to 3 h after the
      treatment. Pretreatment of the cells with U73122, a potent inhibitor of
      phosphatidylinositol-specific phospholipase C, inhibited thyrotropin-releasing
      hormone-induced phospholipase D activation. Protein kinase C activity was down
      regulated by pretreatment of the GH3 cells with either protein kinase C
      inhibitors (RO320432, GF109203X) or preincubation of the cells with phorbol
      myristrate acetate (500 nM) for 24 h. This treatment largely abolished the
      thyrotropin-releasing hormone-induced activation of phospholipase D, thus further
      confirming the involvement of protein kinase C in the activation. These results
      suggest that thyrotropin-releasing hormone-induced phospholipase D activation may
      be due to phosphatidylinositol-specific phospholipase C, and activation of
      protein kinase C isozymes is responsible for this stimulation.

PMID- 15034196
TI  - Clinical and genetic features of patients with multiple endocrine tumors who have
      neither family history nor MEN1 germline mutations.
AB  - Multiple endocrine neoplasia type 1 (MEN1) is an hereditary tumor syndrome that
      involves specific endocrine organs such as parathyroids, anterior pituitary
      gland, and endocrine pancreas. The responsible gene for this syndrome, MEN1, has
      been isolated and that enabled genetic diagnosis for patients with endocrine
      tumors and early detection of asymptomatic gene carriers in affected families.
      Nevertheless, there are a considerable number of patients with MEN1 who have
      neither family history nor germline MEN1 mutations. In this article, clinical
      features of such patients are described. Among 53 MEN1 patients we have seen
      during the last 20 yr, five patients who did not have either MEN1 germline
      mutation or family history were categorized as MEN1 phenocopy. During the same
      period, we have also experienced three patients who had primary
      hyperparathyroidism and adrenocortical tumor but had no apparent family history
      of endocrine tumors. These patients were considered as MEN1 phenocopy variants
      and included in the study. The mean age of MEN1 phenocopy patients (including
      variants) at diagnosis was 48 yr, which was not significantly different from that
      of probands of familial MEN1 (46 yr) who carry heterozygous MEN1 gene mutations.
      In the majority of MEN1 phenocopy patients, primary hyperparathyroidism was due
      to a single parathyroid adenoma. In contrast to a previous report, we found that
      MEN1 phenocopy patients are not necessarily older than probands of familial MEN1.
      Phenotypic expression of such patients is variable, thus differentiation of
      familial MEN1 and MEN1 phenocopy cannot be made based on age and clinical
      phenotype alone.

PMID- 15034197
TI  - Stimulation of proinsulin biosynthesis by K+ in rat pancreatic islets.
AB  - Glucose-stimulated proinsulin biosynthesis is regulated mainly at the
      translational level. This study aims at investigating the possible role of the B
      cell K+ content in such a process. In order to increase the islet cells K+
      content, rat pancreatic islets exposed to a low D-glucose concentration (e.g.,
      2.5 mM) were incubated in the presence of 30 or 60 mM K+, as distinct from a
      control extracellular K+ concentration of 5 mM. Under these conditions, the K+
      content of the islets, as judged from the net uptake of 86Rb+ over 60 min
      incubation, was increased to a level comparable to that otherwise found in the
      presence of 16.7 mM D-glucose. In the presence of 2.5-4.0 mM D-glucose, the rise
      in K+ concentration from 5 to 30 and 60 mM caused a progressive increase in the
      incorporation of L-[4-3H]phenylalanine into both all islet peptides and
      (pro)insulin. A preferential stimulation of proinsulin biosynthesis was only
      observed in islets incubated at 60 mM K+ in the presence of 4.0 mM D-glucose. In
      relative terms, the K+-induced increase in biosynthetic variables was less
      pronounced, however, than that otherwise evoked by a rise in D-glucose
      concentration from 2.5 to 4.0 mM to 5.6 or 16.7 mM. These findings may suggest
      that the effect of D-glucose to increase the K+ content of islet cells represents
      one modality for coupling a rise in D-glucose concentration to stimulation of
      proinsulin biosynthesis.

PMID- 15034200
TI  - Multiple injury approach and its use for toxicity studies.
AB  - We present an experimental approach that allows exposure of cells plated on a
      single coverslip to multiple distinct environments. The original chamber design
      created a small region of injury using geometrically defined flows of the control
      and ischemic solutions. Modifications of the original chamber design presented in
      this article produce a range of flow patterns that can be advantageous for a
      variety of imaging applications. These applications include: experiments that
      address effects of different treatments applied to a cell network, parallel
      testing of negative and positive controls using a single coverslip, border effect
      studies, evaluation of the treatment's reversibility, and simultaneous monitoring
      of a cell layer loaded with different fluorescent indicators. The method also can
      be used to reveal both micro- and macroscopic features of propagation,
      conduction, and cell coupling in a normal or altered cardiac cell network. These
      possibilities are illustrated in cultures of neonatal rat cardiomyocytes using
      oxidant- and calcium-sensitive fluorescent indicators.

PMID- 15034199
TI  - Bioactive GLP-1 in gut, receptor expression in pancreas, and insulin response to
      GLP-1 in diabetes-prone rats.
AB  - Glucagon-like peptide-1 (GLP-1) is the most insulinogenic of the glucagon-like
      peptides secreted mainly by L cells in the small and large intestine in response
      to the ingestion of nutrients. It binds to a specific GLP-1 receptor (GLP-1R) on
      beta-cells and can increase islet neogenesis and beta-cell mass. It is not clear
      whether the transmission of information from the gut to islet beta-cells by
      messengers such as GLP-1 is different in individuals who develop autoimmune
      diabetes. In the present study the expression of bioactive GLP-1 protein in the
      gut and its receptor in the pancreas was examined in diabetes-prone BioBreeding
      (BBdp) rats in the period before overt diabetes and in age-matched control, non
      diabetes-prone BB (BBc) rats. An N-terminal directed antibody specific for the
      bioactive forms of GLP-1 (GLP-1(7-37) and GLP-1(7-36amide)) was used to mea-sure
      GLP-1 by radioimmunoassay in proximal, median, and distal gut. Pancreas GLP-1R
      area fraction, GLP-1R gene expression, and insulin content were analyzed, as were
      plasma GLP-1, glucose, and insulin. The concentration of GLP-1 protein in the
      jejunum and ileum of BBdp rats was lower than in BBc rats. Although these animals
      maintained normal blood glucose, there was impaired pancreatic endocrine
      function, characterized by low baseline insulin concentration in plasma and
      pancreas. GLP-1R mRNA expression was threefold less in islets isolated from BBdp
      rats, and GLP-1R+ islet area fraction in pancreas sections was decreased. When
      injected iv with GLP-1, BBdp rats displayed lower second-phase insulin response
      (and insulin/glucose ratios) compared with BBc rats. Thus, young BBdp rats
      displayed decreased concentrations of bioactive GLP-1 in jejunum and ileum,
      reduced GLP-1R in islets, and lower second-phase insulin response to iv GLP-1
      than controls. The decrease in insulinogenic and islet beta-cell mass-promoting
      signal from GLP-1 in BBdp rats may contribute to impaired glucoregulation and
      ineffective maintenance of normal islet mass that shifts islet homeostasis in
      favor of development of diabetes.

PMID- 15034201
TI  - Carvedilol inhibits the mitochondrial permeability transition by an antioxidant
      mechanism.
AB  - It was previously shown that carvedilol, a beta-adrenergic receptor antagonist
      with antioxidant properties, was able to inhibit the mitochondrial permeability
      transition (MPT). In the present work, the hypothesis was that the negative
      impact of carvedilol on the MPT was specifically the result of its antioxidant
      effect. For the current investigation, we used three different MPT inducers. MPT
      associated events were tested to study the protective effect of both carvedilol
      and cyclosporin-A, the known MPT inhibitor. Carvedilol inhibited mitochondrial
      swelling with calcium plus phosphate and with calcium plus t-butylhydroperoxide,
      but not with calcium plus carboxyatractyloside. Carvedilol inhibited the
      oxidation of thiol groups with calcium plus phosphate (p < 0.01) and with calcium
      plus t-butylhydroperoxide (p < 0.05), but not with calcium plus
      carboxyatractyloside--in opposition to the full protection afforded by
      cyclosporin-A when using calcium and carboxyatractyloside. Our results showed
      that carvedilol was effective only when the MPT was triggered by a primary
      oxidative process. This finding implies that the antioxidant properties of
      carvedilol are crucial for the observed effects and reinforces the advantageous
      use of carvedilol in cardiac pathologies associated with enhanced cellular
      oxidative stress.

PMID- 15034202
TI  - Inhibition of cardiac myocyte contraction by 4-hydroxy-trans-2-nonenal.
AB  - Lipid peroxidation, initiated by hydroxyl radicals, results in production of 4
      Hydroxy-trans-2-nonenal (HNE) and leads to cardiac injury. However, impact of HNE
      on ventricular function has not been clearly defined. This study was to examine
      the direct effect of HNE on cardiac contractile function at cardiac myocyte
      level. Adult male rat ventricular myocytes were isolated and electrically
      stimulated to contract at 0.5 Hz. Mechanical and intracellular Ca2+ properties
      were evaluated using an Ionoptix Myocam system. Contractile properties analyzed
      included peak shortening (PS), time-PS, time-to-90% relengthening, maximal
      velocities of shortening and relengthening (+/-dL/dt), change of electrically
      stimulated intracellular Ca2+ fura-2 fluorescent intensity, and intracellular
      Ca2+ decay. Our results indicated that short-term incubation of HNE (10(-6) to
      10(-4) M) with myocytes depressed PS, +/-dL/dt, and fura-2 fluorescent intensity;
      shortened time-PS; and elevated resting intracellular Ca2+ levels without
      affecting time-to-90% relengthening and intracellular Ca2+ decay. Interestingly,
      the HNE-induced cardiac mechanical effects (with the exception of shortened time
      PS) were abolished by either the aldehyde dehydrogenase inhibitor cyanamide or
      the p38 mitogen-activated protein kinase inhibitor SB203580. These findings
      reveal a possible role of HNE in the lipid peroxidation-associated cardiac
      contractile dysfunction that is likely mediated through HNE metabolism and
      mitogen-activated protein kinase activation.

PMID- 15034198
TI  - Pituitary adenylate cyclase activating polypeptide-mediated intracrine signaling
      in the testicular germ cells.
AB  - Pituitary adenylate cyclase activating polypeptide (PACAP) is found not only in
      the brain, but is also abundantly expressed in the testicular germ cells.
      However, the physiological role of testicular PACAP remains unknown.
      Autoradiographic studies showed a considerable number of PACAP-specific binding
      sites in the seminiferous tubules. Immunohistochemistry demonstrated PAC1
      receptor (R)-like immunoreactivity (li) in the cytoplasm of round spermatids,
      aggregated in the acrosome and coexpressed with PACAP-li. Spermatid-enriched
      fractions were examined for the subcellular localization of PACAP binding sites
      and PAC1-R-li. The highest levels of PACAP binding sites and PAC1-R-li were found
      in the cytosolic, followed by the nuclear, and the lowest levels in the membrane
      fraction. The testicular cytosolic PAC1-R-like protein showed a specific
      competitive inhibition in the radio-receptor assay for PACAP38 and 27, with a Ki
      of 0.069 nM and 0.179 nM, respectively. The addition of PACAP to the cytosol of
      spermatids only slightly activated adenylate cyclase, while it markedly
      stimulated the expression and activation of ERK-type mitogen-activated protein
      kinase (MAPK). In the PAC1-R-like protein-depleted cytosol, a PAC1-R-specific
      agonist, maxadilan, did not activate MAPK, but PACAP and VIP still did. Because
      VPAC2-R, which binds both PACAP and VIP, is expressed in the testis, the findings
      suggest that cytosolic VPAC2-R-like proteins are also present and coupled to
      MAPK. The MAPK activation does not seem to require a heterotrimeric G-protein.
      Because PACAP and its receptors are coexpressed in the cytoplasm of spermatids,
      endogenous PACAP may directly interact with the cytosolic PAC1-R-like protein
      without the ligand being released into the extracellular space. This possibility
      is supported by the observation that cytosolic endogenous PACAP in spermatids was
      co-immunoprecipitated with the cytosolic PAC1-R. This mechanism may be called
      "intracrine," and its physiological significance is discussed.

PMID- 15034203
TI  - Effects of thalidomide on QTc, inotropy, and lusitropy in the isolated guinea pig
      heart.
AB  - There has been a resurgence in the use of thalidomide over the past several
      years; however, little is known about its potential cardiac toxicity. Isolated,
      perfused guinea pig hearts were exposed to escalating concentrations of
      thalidomide or vehicle, and changes in RR interval, QT duration and QTc duration,
      and left ventricular inotropy and lusitropy comparing escalating concentrations
      of thalidomide with vehicle were sought. RR interval lengthened and QTc prolonged
      significantly at 10 microM concentrations. QT did not change. dP/dtmax increased
      and dP/dtmin decreased in response to thalidomide. Based on results using this
      preparation, thalidomide has a potential liability for lengthening QTc, but only
      at concentrations of 10 microM or greater. It possesses both positive inotropic
      and positive lusitropic properties.

PMID- 15034204
TI  - Characterization of high-salt and high-fat diets on cardiac and vascular function
      in mice.
AB  - This study compared two established dietary formulations, high salt and high fat
      high carbohydrate, separately or in combination on the induction cardiovascular
      dysfunction. One-month-old C57BL/6J mice were fed one of the following diets for
      3 mo: (1) control diet consisting of a high fat-high sim-ple carbohydrate
      (HFHSC); (2) 8% NaCl diet (HS); or (3) HFHSC diet supplemented with 1% NaCl
      (HFHS). After 3 mo, the HFHSC mice demonstrated significantly increased end
      diastolic volume and end-systolic volume, specifically increases of 35% and 78%,
      respectively (p < 0.01) and a reduction of ventricular stiffness by 27% (p =
      0.015). The HS mice exhibited arterial hyper-tension with an increase of 33% in
      maximum end-systolic pressure (p =.024) and a decrease of 44% in arterial
      elastance (p = 0.020), corroborated by an increase in the heart weight to body
      weight ratios (p = 0.002) and vascular types I and III collagen (p = 0.03 and p =
      0.0008, respectively). The HFHS group revealed a striking response of 230% to the
      alpha1-adrenergic challenge (p = 0.00034). These data suggest that the HFHSC diet
      causes dilated cardio-myopathy, whereas the HS diet produces arterial
      hypertension and the HFHS diet causes a vascular dysfunctional state that was
      highly responsive to alpha-adrenergic stimulation.

PMID- 15034205
TI  - Different global gene expression profiles in benzo[a]pyrene- and dioxin-treated
      vascular smooth muscle cells of AHR-knockout and wild-type mice.
AB  - Benzo[a]pyrene (B[a]P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are potent
      ligands for the aryl hydrocarbon receptor (AHR). High-density oligonucleotide
      microarrays were used to generate global gene expression profiles of wild-type
      and Ahr(-/-) vascular smooth muscle cells (SMCs) from mouse aorta. To determine
      whether there are signaling pathways other than the AHR involved in B[a]P
      metabolism, wild-type and AHR knockout (Ahr(-/-) SMCs were exposed to B[a]P. Two
      signaling pathways, represented by TGF-beta2 and IGF-1, were identified as
      potential candidates of an AHR alternate pathway for cells to respond to B[a]P.
      The wild-type SMCs responded similarly to B[a]P and TCDD in the regulation of a
      small set of common genes known to respond to the activated AHR (e.g., glutamine
      S-transferase). However, wild-type SMCs responded in a way that involves many
      additional genes, suggesting that a very divergent cellular response may be
      involved when SMCs are exposed to the two classic inducers of the AHR. In
      contrast, many more genes in the Ahr(-/-) cells responded similarly to B[a]P and
      TCDD, including Cyp1b1, than responded differently, which indicates that
      eliminating the AHR is effective for investigating potential alternate cellular
      mechanisms that respond to B[a]P and TCDD.

PMID- 15034206
TI  - MMP-1 polymorphic expression in aortic endothelial cells: possible role in lesion
      development in smokers and nonsmokers.
AB  - Matrix metalloproteinase-1 (MMP-1) is involved in the degradation of extra
      cellular matrix components and is thought to play a key role in atherogenesis.
      The objective of the present study was to determine: (1) whether MMP-1
      differential gene expression observed in primary cultures of human aortic
      endothelial cells (HAEC) exposed to cigarette smoke condensate (CSC) was
      associated with a single nucleotide polymorphism (SNP) in its promoter region and
      (2) if the SNP altered atherosclerotic lesion development in smokers and
      nonsmokers. Genotype analysis of six HAEC lines revealed that those homozygous
      for the 1G-variant exhibited low levels of gene expression. Cells homozygous for
      the 2G-variant or heterozygous (1G/2G) had elevated levels of both mRNA and
      protein. These relative levels were also seen after CSC expo-sure. MMP-1
      genotypes of 104 Caucasian males acquired from the Pathobiological Determinants
      of Atherosclerosis in Youth study were compared with the extent of
      atherosclerotic lesion development in the aorta. The results indicate that,
      although the MMP-1 SNP influences MMP-1 gene expression in cultured HAEC exposed
      to CSC, differences in lesion development were not observed based on this
      polymorphism in young Caucasian males.

PMID- 15034207
TI  - Vascular medial hyperplasia following chronic, intermittent exposure to 4,4'
      methylenedianiline.
AB  - 4,4'-Methylenedianiline (DAPM) is an aromatic amine used in the synthesis of
      polyurethanes and epoxy resins. Acute exposure to DAPM produces hepatobiliary
      toxicity in humans as well as animal models. However, the toxic effects of
      intermittent DAPM exposure have not been explored. We treated male and female
      rats with 25 mg DAPM/kg or vehicle once per week for 17-22 wk. Though concentric
      fibrosis around bile ducts of the liver was noted, vascular medial hyperplasia
      was also prominent. Morphometric analysis of histologic sections revealed that in
      male rats, vessel wall area increased relative to lumen area in hepatic arteries
      by 22 wk. However, in female rats, wall areas of both hepatic and pulmonary
      arteries increased relative to lumen area by 17 wk. In both male and female rats,
      increased wall thickness was localized to the medial layer; no intimal changes
      were noted. In vitro treatment of vascular smooth muscle cells (VSMC) with 25-100
      microM DAPM resulted in increased DNA synthesis and VSMC proliferation. To test
      whether the observed alterations in cell cycle control involved VSMC-mediated
      metabolism of DAPM to electrophilic intermediates, cells were treated with DAPM
      or DAPM plus 50 microM N-acetylcysteine (NAC). Coincubation with NAC afforded
      dramatic protection against DAPM-induced VSMC proliferation. Though DAPM had no
      appreciable effect on levels of reduced glutathione, oxidized glutathione, or
      oxidant production, DAPM increased glutathione-S-transferase activity in VSMC.
      These data indicate that DAPM can initiate VSMC proliferation, possibly via VSMC
      mediated metabolism of DAPM to reactive intermediates.

PMID- 15034208
TI  - Autocrine stimulation in colorectal carcinoma (CRC): positive autocrine loops in
      human colorectal carcinoma and applicable significance of blocking the loops.
AB  - Many tumors co-express growth factors and their receptors; thus, the concept of
      autocrine secretion was proposed to explain the unrestrained growth of the
      malignant cells. Autocrine stimulation refers to positive autocrine secretion,
      which functions to stimulate cell growth. Many of the positive autocrine loops
      have been demonstrated in human colorectal carcinoma (CRC), which are considered
      to play an important role in the initiation and progression of the cancer. These
      autocrine loops provide information for prognostic markers and targets for
      biological therapies of CRC. Interruption of the autocrine loops could
      potentially inhibit malignant cell growth. The field is encouraging but further
      research is needed.

PMID- 15034209
TI  - Influence of mesna on the pharmacokinetics of cisplatin and carboplatin in
      pediatric cancer patients.
AB  - Mesna, a reactive thiol, often encounters cisplatin and carboplatin in
      combination protocols involving oxazaphosphorines and platinum drugs. This co
      administration might be unfavorable based on the inactivation of platinum drugs
      by thiol groups in vitro. We investigated whether mesna influences the
      pharmacokinetics of platinum drugs when co-administered with cisplatin or
      carboplatin. The pharmacokinetics of platinum drugs were investigated in 18
      pediatric patients receiving either cisplatin or carboplatin in a combination
      with or without mesna. In cisplatin patients, a decrease in the distribution
      clearance of total platinum was observed when mesna was co-administered (CLd, 2.2
      +/- 0.1 mL/min.kg; n = 3), compared to cisplatin without mesna (CLd, 4.8 +/- 1.5
      mL/min.kg; n = 5) (p = 0.029, t-test). This might have been caused by an
      influence of mesna in slowing down the protein binding of cisplatin since a trend
      (p = 0.057) in prolonged distribution half-life of total platinum was also
      observed when mesna was present (t(1/2a) 65 +/- 21 min; n = 3) compared to
      cisplatin without mesna (t(1/2a), 32 +/- 18 min; n = 5). However, the impact of
      these changes on the area under the concentration time curve (AUC), total
      clearance (CLt), and volume of distribution (V) for total platinum and
      ultrafilterable platinum species was hardly noticeable. In carboplatin patients,
      when mesna was co-administered: AUC (2.5 +/- 0.4 mg.min/mL.400 mg/m2; n = 5) CLt,
      (6.8 +/- 5.1 mL/min.kg; n = 6), and V (0.7 +/- 0.4 L/kg; n = 6) for
      ultrafilterable platinum species were not significantly different from when
      carboplatin were administered without mesna: AUC (2.3 +/- 1.3 mg.min/mL.400
      mg/m2; n = 4), CLt (5.8 +/- 4.6 mL/min.kg; n = 5), and V (1.1 +/- 1.1 L/kg; n =
      5). Hence, mesna does not significantly influence the pharmacokinetics of
      cisplatin and carboplatin in pediatric cancer patients.

PMID- 15034210
TI  - Gliotoxin is a dual inhibitor of farnesyltransferase and
      geranylgeranyltransferase I with antitumor activity against breast cancer in
      vivo.
AB  - Gliotoxin is a natural mycotoxin with immunosuppressive and antimicrobial
      activity. Inhibition of farnesyltransferase (IC50 80 microM) and
      geranylgeranyltransferase I (IC50 17 microM) stimulated interest in the potential
      antitumor activity of this epidithiodioxopiperazine. Gliotoxin inhibited
      proliferation of six breast cancer cell lines in culture with mean +/- SD IC50
      289 +/- 328 microM (range 38-985 microM); intracellular farnesylation of Lamin B
      and geranylgeranylation of Rap1A were inhibited in a dose-dependent manner. In
      randomized controlled studies using the N-methyl-N-nitrosourea rat mammary
      carcinoma model, gliotoxin had pronounced antitumor activity in vitro and little
      systemic toxicity when administered to 10 animals at 10 mg/kg by subcutaneous
      injection weekly for 4 wk compared with 10 controls. Single doses up to 25 mg/kg
      were well tolerated. The present studies confirm that gliotoxin is a dual
      inhibitor of farnesyltransferase and geranylgeranyltransferase I with pronounced
      antitumor activity and favorable toxicity profile against breast cancer in vitro
      and in vivo.

PMID- 15034212
TI  - The value of abdominal CT scans in decision-making during chemotherapy in ovarian
      cancer.
AB  - OBJECTIVE: During chemotherapy of ovarian cancer many CT scans are performed to
      assess tumor response during treatment. The aim of this study was to determine
      the value of abdominal CT scan in the decision to continue chemotherapy or not,
      after the standard six cycles. METHODS: All ovarian cancer patients diagnosed
      between 1991 and 1997 were retrospectively included in the study. Clinical
      parameters, surgical results, diagnostic test results, and therapeutic strategies
      were collected from medical records. With logistic modeling those parameters were
      chosen that predicted best the chance of receiving additional chemotherapy. The
      chance of receiving further chemotherapy after six cycles based on these
      parameters was computed and compared to the chance based on CT scan results in
      addition to these parameters. Arbitrarily we defined a change of over 20% as
      meaningful. RESULTS: Eighteen of 50 included patients (36%) received over six
      cycles of chemotherapy; 29 patients (10%) were at low risk for receiving over six
      cycles, because they had an optimal debulking surgery and low levels of CA-125 at
      cycle six. The chance of receiving continued chemotherapy after taking into
      account positive tumor signs on CT-scan was 22%. This figure further increased to
      33% if tumor presence was based on judgment of two CT scans. High-risk patients
      were patients with suboptimal debulking surgery or patients with an optimal
      debulking, but high CA-125 levels at cycle six (n = 21). Based on these
      parameters their chance of receiving additional chemotherapy was 71%, and after
      taking into account results of one or two CT-scans, the risks increased to 74%
      and 81%, respectively. CONCLUSION: CT scans are of no value in deciding the
      number of chemotherapy cycles in the initial treatment for ovarian cancer. They
      cost a lot of money, can add a lot of confusion, and offer no benefit over
      results of debulking surgery and CA-125 levels.

PMID- 15034211
TI  - Analysis of menstrual, reproductive, and life-style factors for breast cancer
      risk in Turkish women: a case-control study.
AB  - The aim of this study was to investigate the association between menstrual,
      reproductive, and life-style factors and breast cancer in Turkish women. In a
      hospital-based case-control study in Ankara, 622 patients with histologically
      confirmed breast cancer were compared with 622 age-matched controls, admitted to
      the same hospital for acute and non-neoplastic diseases. Unconditional logistic
      regression was used to estimate odds ratios (ORs) and 95% confidence intervals
      (CI) related to risk factors. Overall, menopausal status and age at menopause
      were found to be significantly associated with breast cancer. Having a full-term
      pregnancy and early age at first birth were associated with decreased breast
      cancer risk (OR = 0.45, 95% CI = 0.30-0.66; OR = 0.34, 95% CI = 0.22-0.53,
      respectively). Postmenopausal women with lactation longer than 48 mo had reduced
      risk of breast cancer (OR = 0.36, 95% CI = 0.14-0.93). In conclusion, decreased
      parity, late age at first birth, early menopause, and shorter duration of
      lactation were the most important determinants of breast cancer risk in Turkish
      women.

PMID- 15034213
TI  - Correlation between HLA-A2 gene frequency, latitude, ovarian and prostate cancer
      mortality rates.
AB  - Molecular-target therapies are novel approaches to the treatment of prostate and
      ovarian cancer, but to ensure the best response, a very careful selection of
      patients, based on immunological characteristics, must be performed. We screened
      for HLA type, 24 patients with advanced ovarian cancer and 26 patients with
      hormone-refractory prostate cancer, in order to be recruited to vaccine
      protocols. HLA typing was performed with PCR in ovarian cancer patients and with
      serological assay in prostate cancer patients. The results were then extended to
      a population level, comparing the HLA genotype frequencies in Europe with ovarian
      and prostate cancer mortality rates. An overrepresentation of HLA-A2 phenotype
      was observed in both patient groups compared to the normal Swedish population (p
      = 0.01). As it is already known, the higher phenotype frequency of this allele
      found in Scandinavian countries decreases significantly as one moves further
      south in Europe. Ovarian and prostate cancer mortality rates decrease as well as
      the demographic changes in HLA-A2. These observations have to be confirmed by
      more extended investigations in order to elucidate if HLA-A2 higher frequency is
      already present at the diagnosis (risk factor) or is selected during the course
      of the disease (prognostic factor). Moreover, this fact would suggest different
      strategies for specific immunotherapy in addition to first line conventional
      treatments.

PMID- 15034214
TI  - Prognostic value of nm23 in gastrointestinal stromal tumors.
AB  - AIM/BACKGROUND: nm23 is suggested to represent a new class of metastasis
      suppressor genes. An inverse correlation between nm23 expression level and
      metastatic potential has been demonstrated in different malignancies. This study
      evaluated the prognostic value of nm23 in gastrointestinal stromal tumors
      (GISTs). METHODS: Immunohistochemical expression level of nm23 was studied in a
      total of 32 patients with localized GISTs. The relationship between the
      expression level of nm23 and patient outcome was investigated. RESULTS: A tumor
      size of 10 cm or more and a mitotic rate of 10 or more per 50 high-power fields
      were not significantly associated with the metastasis risk (p = 0.60 and 0.55,
      respectively). Tumors with high expression of nm23 tended to have significantly
      lower metastatic potential (p = 0.02). The median survival was significantly
      longer in patients with high expression of nm23 (p = 0.007). CONCLUSION: These
      results suggest that expression level of nm23 may be considered as a prognostic
      predictor in GISTs. Future studies with larger patient numbers will be essential
      to confirm the prognostic significance of nm23 in patients with GIST.

PMID- 15034215
TI  - Raltitrexed plus weekly oxaliplatin as first-line chemotherapy in metastatic
      colorectal cancer: a multicenter non-randomized phase ii study.
AB  - AIM: The primary aims of this study were activity and toxicity evaluation of a
      new raltitrexed and oxaliplatin-based regimen, as a first-line chemotherapy, in
      patients with metastatic colorectal cancer (MCC). Survival evaluation was
      considered a secondary endpoint. PATIENTS AND METHODS: Forty-four patients were
      enrolled into this phase II trial. Treatment consisted of raltitrexed 3 mg/m2 iv
      on d 1 and oxaliplatin 70 mg/m2 iv on d 1 and d 8 every 3 wk. RESULTS: Twenty
      patients (45.5%) achieved a response [95% confidence interval (CI): 30.1% to
      54.1%], 18 (40.9%) had stable disease, and only 6 (13.6%) developed progressive
      disease. After a median follow-up time of 14.7 mo (range 6.3-18.6 mo), the median
      time to disease progression was 6 mo (range 2.0-16.7) (95% CI: 4.4-7.6) and the
      overall survival was 14.8 mo (range 3-23) (95% CI: 11.2-18.4). Neutropenia was
      the most common hematological side effect, while transient AST/ALT increase,
      neurotoxicity, asthenia, and diarrhea were the most common nonhematological side
      effects. CONCLUSIONS: Our data confirmed that oxaliplatin administered weekly
      plus raltitrexed is an active combination in newly diagnosed patients with
      advanced colorectal carcinoma that merits further investigation versus the
      classic schedule in a randomized, phase III trial.

PMID- 15034216
TI  - Reactivation of hepatitis B virus infection with cytotoxic therapy in non
      Hodgkin's lymphoma.
AB  - In patients with non-Hodgkin's lymphoma (NHL), there are some well-known tumor
      related adverse prognostic factors that may increase the mortality rate. However,
      secondary factors such as viral hepatitis carriers that may decrease the cure
      rates are usually ignored. Reactivation of hepatitis B virus (HBV) infection in
      patients undergoing cytotoxic treatment for NHL is a well-known complication.
      Charts of 112 patients with NHL were retrospectively analyzed regarding their
      hepatitis serology, the indirect effects of seropositivity on disease outcome,
      and the precautions undertaken in these seropositive patients with NHL. Twelve
      patients (11%) with HBsAg positivity and two patients (1.7%) with antibody to
      hepatitis C virus positivity were detected. Eight out of 12 patients (67%) with
      HBsAg positivity and two patients (50%) with anti-HCV positivity showed
      reactivation of hepatitis during treatment of NHL. No reactivation was detected
      in four patients seropositive for HBV, who were given lamivudine prophylaxis
      before the initiation of chemotherapy schedules. Among patients with hepatitis
      reactivation, two were treated with lamivudine resulting in dramatic improvement
      and clinical remission of the disease. The remaining six patients with
      reactivation were left untreated, resulting in four deaths (67%) due to liver
      failure secondary to HBV and two deaths secondary to delayed treatment of NHL.
      One patient seropositive for anti-HCV also developed chronic hepatitis C.
      Determination of hepatitis serology in all patients with NHL before any
      chemotherapy administration is crucial, but insufficient, if not taken into
      consideration. In seropositive patients, HBV DNA should be determined and
      antiviral prophylaxis with lamivudine should be initiated before any treatment.

PMID- 15034217
TI  - Immunohistochemical analysis of cyclin D1 and p53 in multiple myeloma:
      relationship to proliferative activity and prognostic significance.
AB  - Conflicting data are reported on the clinical significance of cyclin D1
      deregulation in multiple myeloma. The aim of this study was to evaluate the
      incidence and prognostic significance of cyclin D1 expression and p53 mutations
      in multiple myeloma, as well as the relationship of their expression with
      selected clinical data, histological features, and proliferative activity of
      myeloma cells. We analyzed bone marrow biopsy specimens obtained from 59 patients
      with newly diagnosed multiple myeloma. Expression of cyclin D1 and p53 was
      analyzed using standard immunohistochemical method of B5-fixed and routinely
      processed paraffin-embedded bone marrow specimens. Cyclin D1 was overexpressed in
      14/59 (27%) and p53 in 5/59 (8.5%) specimens. There was no significant
      correlation between cyclin D1 overexpression and age, gender, clinical stage
      (Durie-Salmon classification), extent of osteolytic lesions, type of monoclonal
      protein, hemoglobin concentration, platelet count, serum concentration of
      creatinine, calcium, C-reactive protein, and beta2-microglobulin. No association
      was observed between the expression of cyclin D1 and the extent of bone marrow
      infiltration, histological grade, proliferative activity index (measured with Ki
      67 immunoreactivity) and response to therapy. No significant difference was
      observed regarding overall survival between cyclin D1 positive and cyclin D1
      negative patients (29 vs 36 mo, p = 0.76). Results of this study did not revealed
      prognostic significance of cyclin D1 overexpression in multiple myeloma.
      Mutations of p53 gene are rare events in myeloma, suggesting their limited role
      in the pathogenesis of the disease.

PMID- 15034218
TI  - Differences in kinetics of donor lymphoid cells in response to G-CSF
      administration may affect the incidence and severity of acute GvHD in respective
      HLA-identical sibling recipients.
AB  - Granulocyte-colony stimulating factor (G-CSF), in addition to myeloid and stem
      cells, mobilizes a large number of lymphoid cells. We examined which lymphoid
      populations were mobilized in 21 consecutive donors of peripheral blood stem
      cells (PBSC) and whether the differences in mobilization could affect the
      incidence of acute and chronic GvHD in respective HLA-identical recipients. G-CSF
      administration induced significant increases of donor B (CD3-CD19+) lymphocytes
      and slight increases of T (CD3+) and cytotoxic (CD16+CD56+) NK cells. The number
      of extrathymic cells (CD3+ cells with NK markers, or CD7+) remained unchanged
      except for an increase of CD3+CD57+CD8+ cells. Donors of patients without
      subsequent grade II-IV acute GvHD compared to donors of patients who developed
      significant acute GvHD were found to have in peripheral blood stable numbers of
      CD3+CD4+ cells producing IL2, with a concomitant increased number of
      CD3+CD4low+CD25+ T regulatory cells and decreased NK-mediated cytotoxicity,
      together with a higher number of suppressive extrathymic CD57+CD3+ cells in the
      blood and G-PBMC grafts. Increasing numbers of activated T and NK cells in the
      blood were associated with the development of chronic GvHD. We suggest that
      differences in steady-state levels and kinetics of G-CSF induced mobilization of
      donor lymphoid cells may in addition to other well-known factors affect the
      incidence of GvHD in HLA-identical recipients. However, owing to the small number
      of donor-recipient pairs studied, our results must be verified in a larger group
      of patients.

PMID- 15034219
TI  - Glutamate signaling to Ras-MAPK in striatal neurons: mechanisms for inducible
      gene expression and plasticity.
AB  - Extracellular signals can regulate mitogen-activated protein kinase (MAPK)
      cascades through a receptor-mediated mechanism in postmitotic neurons of adult
      mammalian brain. Both ionotropic and metabotropic glutamate receptors (mGluRs)
      are found to possess such an ability in striatal neurons. NMDA and AMPA receptor
      signals seem to share a largely common route to MAPK phosphorylation which
      involves first activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII)
      via Ca2+ influx, followed by subsequent induction of phosphoinositide 3-kinase
      (PI3-kinase). Through its lipid and protein kinase activity, active PI3-kinase
      may transduce signals to Ras-MAPK cascades via at least two distinct pathways. A
      novel, Ca(2+)-independent pathway is believed to mediate mGluR signals to Ras
      MAPK activation. As an information superhighway between the surface membrane and
      the nucleus, Ras-MAPK cascades, through activating their specific nuclear
      transcription factor targets, are actively involved in the regulation of gene
      expression. Emerging evidence shows that MAPK-mediated genomic responses in
      striatal neurons to drug exposure contribute to the development of
      neuroplasticity related to addictive properties of drugs of abuse.

PMID- 15034220
TI  - Pathogenesis of Parkinson's disease: prospects of neuroprotective and restorative
      therapies.
AB  - Parkinson's disease (PD) is caused by the degeneration of dopaminergic neurons of
      substantia nigra projecting to striatum. The cause of idiopathic PD is obscure,
      and most cases are sporadic. It is widely accepted that there is a genetic
      component of the disease, and the earlier the age of onset, the greater the
      likelihood that genetic factors play a dominant role. Oxidative stress of the
      substantia nigra seems to contain the driving force for neurodegeneration,
      leading to a destructive "toxic cycle." The most prevalent therapy is levodopa
      administration, but it is not efficacious after several years of treatment.
      Several alternative therapies are currently being explored, such as
      neuroprotective approaches. Compounds with potentially neuroprotective efficacy
      such as selegiline, dopamine agonists, riluzole, creatine, and coenzyme Q10 are
      currently being tested. Trophic factors represent another class of
      neuroprotective compounds, but their intracerebral administration is difficult to
      achieve. In this respect, a potentially useful therapeutic approach is grafting
      cell vectors that release trophic molecules that stimulate regeneration in the
      damaged nigrostriatal system. Promising results have been obtained with
      fibroblasts engineered to secrete glial cell line-derived neurotrophic factor
      (GDNF) or brain-derived neurotrophic factor (BDNF) or viral vectors expressing
      GDNF. We have tested the suitability of intrastriatal grafts of chromaffin cells
      obtained from the Zuckerkandl's organ, which exert beneficial effects in
      parkinsonian rats, and release trophic factors such as GDNF and transforming
      growth factor-beta1 (TGF-beta1).

PMID- 15034221
TI  - Multiple signal transduction pathways mediated by 5-HT receptors.
AB  - Among human serotonin (5-HT) receptor subtypes, each G protein-coupled receptor
      subtype is reported to have one G protein-signaling cascade. However, the
      signaling may not be as simple as previously thought to be. 5-HT5A receptors are
      probably the least well understood among the 5-HT receptors, but the authors
      found that 5-HT5A receptors couple to multiple signaling cascades. When the 5
      HT5A receptors were expressed in undifferentiated C6 glioma cells, they modulated
      the level of second messengers. For example, activation of 5-HT5A receptors
      inhibited the adenylyl cyclase activity and subsequently reduced the cAMP level,
      as previously reported. In addition to this known signaling via Gi/Go, 5-HT5A
      receptors are coupled to the inhibition of ADP-ribosyl cyclase and cyclic ADP
      ribose formation. On the other hand, activation of 5-HT5A receptors transiently
      opened the K+ channels, presumably due to the increase in intracellular Ca2+
      after formation of inositol (1,4,5) trisphosphate. The K+ currents were inhibited
      by both heparin and pretreatment with pertussis toxin, suggesting the cross-talk
      between Gi/Go protein and phopholipase C cascade. Thus, the authors results
      indicate that 5-HT5A receptors couple to multiple second messenger systems and
      may contribute to the complicated physiological and pathophysiological states.
      Although this multiple signaling has been reported only for 5-HT5A/5-HT1
      receptors so far, it is possible that other 5-HT receptor subtypes bear similar
      complexity. As a result, in addition to the wide variety of expression patterns
      of each 5-HT receptor subtype, it is possible that multiple signal transduction
      systems may add complexity to the serotonergic system in brain function. The
      investigation of these serotonergic signaling and its impairment at cellular
      level may help to understand the symptoms of brain diseases.

PMID- 15034222
TI  - Different neuronal phenotypes in the lateral hypothalamus and their role in sleep
      and wakefulness.
AB  - The sleep disorder narcolepsy is now linked with a loss of neurons containing the
      neuropeptide hypocretin (also known as orexin). The hypocretin neurons are
      located exclusively in the lateral hypothalamus, a brain region that has been
      implicated in arousal based on observations made by von Economo during the viral
      encephalitic epidemic of 1916-1926. There are other neuronal phenotypes located
      in the lateral hypothalamus that are distinct and separate from the hypocretin
      neurons. Here the authors identify these neurons based on peptides and
      neurotransmitters that they express and review roles of these neurons in sleep.
      Given the heterogeneity of the neuronal phenotypes in the lateral hypothalamus,
      it is likely that hypocretin neurons, as well as other types of neurons in the
      lateral hypothalamus, influence sleep and provide state-dependent regulation of
      physiological functions.

PMID- 15034225
TI  - Monocyte chemoattractant protein-1 promoter -2518 polymorphism may have an
      influence on clinical heterogeneity of bipolar I disorder in the Korean
      population.
AB  - The aim of this study was to investigate the association between monocyte
      chemoattractant protein-1 (MCP1) promoter -2518 polymorphism and DSM-IV-based
      bipolar I disorder (BID) in Korea. Ninety-two patients with BID and 114 healthy
      controls participated in this study. A polymerase chain reaction-based method was
      used for genotyping. Genotype and allele distributions in patients with BID were
      not different from those of the controls, nor were they different according to
      clinical factors in the patient group. However, the frequency of the A allele (p
      = 0.028) was significantly different when subdividing the patient group into
      patients with manic episode versus depressed and mixed episode. The present study
      suggests that the MCP1 promoter -2518 polymorphism may not confer susceptibility
      to BID itself, but could have an influence on the clinical heterogeneity of BID,
      at least in the Korean population.

PMID- 15034223
TI  - Ion channels and amino acid transporters support the growth and invasion of
      primary brain tumors.
AB  - The malignant growth of glial support cells causes gliomas, highly invasive,
      primary brain tumors that are largely resistant to therapy. Individual tumor
      cells spread by active cell migration, invading diffusely into the normal brain.
      This process is facilitated by Cl- channels that endow glioma cells with an
      enhanced ability to quickly adjust their shape and cell volume to fit the narrow
      and tortuous extracellular brain spaces. Once satellite tumors enlarge, their
      growth is limited by the spatial constraints imposed by the bony cavity of the
      skull and spinal column. Glioma cells circumvent this limitation by active
      destruction of peritumoral neural tissue through the release of glutamate,
      inducing peritumoral seizures and ultimately excitotoxic neuronal cell death.
      Hence, primary brain tumors support their unusual biology by taking advantage of
      ion channels and transporters that are designed to support ion homeostatic
      functions in normal brain.

PMID- 15034226
TI  - Regional glucose metabolism within cortical Brodmann areas in healthy individuals
      and autistic patients.
AB  - A new Brodmann area (BA) delineation approach was applied to FDG-PET scans of
      autistic patients and healthy volunteers (n = 17 in each group) to examine
      relative glucose metabolism (rGMR) during performance of a verbal memory task. In
      the frontal lobe, patients had lower rGMR in medial/cingulate regions (BA 32, 24,
      25) but not in lateral regions (BA 8-10) compared with healthy controls. Patients
      had higher rGMR in occipital (BA 19) and parietal regions (BA 39) compared with
      controls, but there were no group differences in temporal lobe regions. Among
      controls, better recall and use of the semantic-clustering strategy was
      associated with greater lateral and medial frontal rGMR, while decreased rGMR in
      medial-frontal regions was associated with greater perseverative/intrusion
      errors. Patients failed to show these patterns. Autism patients have dysfunction
      in some but not all of the key brain regions subserving verbal memory
      performance, and other regions may be recruited for task performance.

PMID- 15034227
TI  - Family-based association study between the monoamine oxidase A gene and obesity:
      implications for psychopharmacogenetic studies.
AB  - Family studies have reported that obesity has a strong heritable component. It
      has been suggested that a neurotransmitter dysfunction could be involved in
      mental disorders and obesity; therefore, candidate genes in psychiatric disorders
      could be a risk factor for obesity. We investigated the association between the
      monoamine oxidase A (MAO-A) gene and obesity. Fifty obese subjects and their
      parents were included in the study. Two polymorphisms designated EcoRV and
      upstream variable number tandem repeats of the MAO-A gene were analysed using
      polymerase chain reaction. For analysis of the families, the transmission
      disequilibrium test (TDT) was applied. The TDT analysis of the EcoRV polymorphism
      showed in obese subjects with a body mass index (BMI) >/=35 kg/m(2) a
      preferential transmission of the low activity-related allele (chi(2)(TDT) = 8.0,
      p = 0.005). Our findings may provide evidence of a candidate gene involved in
      obese subjects with a BMI >/=35 kg/m(2).

PMID- 15034228
TI  - Tianeptine as a slightly effective therapeutic option for attention-deficit
      hyperactivity disorder.
AB  - OBJECTIVE: Because of the hypotonic side effect of clonidine, the use of
      tianeptine was studied as an alternative because of its longer excretion half
      life, decreased sedative side effects and more selective binding profile. METHOD:
      We rated sixty-eight psychiatric outpatients diagnosed with attention-deficit
      hyperactivity disorder (ADHD) at baseline and while taking tianeptine to
      determine its efficacy as a treatment for ADHD and used comparisons of Conners'
      parent ratings within each subject to measure behavioral changes in the subjects.
      RESULTS: During tianeptine treatment, patients' mean scores improved
      significantly overall, and also for Conners' Hyperactivity, Inattention and
      Immaturity factors. CONCLUSIONS: This preliminary study indicates that tianeptine
      might be a slightly effective beneficial and useful treatment for ADHD, reducing
      hyperactive behaviors and enabling greater attentional ability with minimal side
      effects.

PMID- 15034224
TI  - Direct and remote modulation of L-channels in chromaffin cells: distinct actions
      on alpha1C and alpha1D subunits?
AB  - Understanding precisely the functioning of voltage-gated Ca2+ channels and their
      modulation by signaling molecules will help clarifying the Ca(2+)-dependent
      mechanisms controlling exocytosis in chromaffin cells. In recent years, we have
      learned more about the various pathways through which Ca2+ channels can be up- or
      down-modulated by hormones and neurotransmitters and how these changes may
      condition chromaffin cell activity and catecolamine release. Recently, the
      attention has been focused on the modulation of L-channels (CaV 1), which
      represent the major Ca2+ current component in rat and human chromaffin cells. L
      channels are effectively inhibited by the released content of secretory granules
      or by applying mixtures of exogenous ATP, opioids, and adrenaline through the
      activation of receptor-coupled G proteins. This unusual inhibition persists in a
      wide range of potentials and results from a direct (membrane-delimited)
      interaction of G protein subunits with the L-channels co-localized in membrane
      microareas. Inhibition of L-channels can be reversed when the cAMP/PKA pathway is
      activated by membrane permeable cAMP analog or when cells are exposed to
      isoprenaline (remote action), suggesting the existence of parallel and opposite
      effects on L-channel gating by distinctly activated membrane autoreceptors. Here,
      the authors review the molecular components underlying these two opposing
      signaling pathways and present new evidence supporting the presence of two L
      channel types in rat chromaffin cells (alpha1C and alpha1D), which open new
      interesting issues concerning Ca(2+)-channel modulation. In light of recent
      findings on the regulation of exocytosis by Ca(2+)-channel modulation, the
      authors explore the possible role of L-channels in the autocontrol of
      catecholamine release.

PMID- 15034229
TI  - Brain regions activated during an auditory discrimination task in insomniac
      postmenopausal patients before and after hormone replacement therapy: low
      resolution brain electromagnetic tomography applied to event-related potentials.
AB  - Electrical sources of auditory event-related potentials (ERPs) determined by
      means of low-resolution brain electromagnetic tomography (LORETA) in 48
      unmedicated insomniac postmenopausal patients aged between 46 and 67 years were
      compared with those obtained in 48 age-matched normal female controls.
      Subsequently, the patients were included in a double-blind, placebo-controlled,
      comparative, randomized 3-arm trial phase - Climodien 2/3 [estradiol valerate
      (EV) 2 mg + the progestin dienogest 3 mg] was compared with EV 2 mg and placebo -
      followed by an open-label phase in which all of them received Climodien 2/2 (EV 2
      mg + dienogest 2 mg). The double-blind and the open-label phase lasted 2 months.
      ERPs were recorded from 19 EEG leads in a two-tone oddball paradigm and
      electrical sources of standard N1 and P2 as well as target N2 and P300 components
      were estimated. In both patients and controls, LORETA revealed an activation of
      the superior temporal gyrus [auditory cortex, Brodmann areas (BA) 41, 42, 22] for
      all four components. For standard P2, an additional activation was observed
      medially parietally in the precuneus (BA 7, 5). For target N2, also a medial
      frontal source (BA 9, 10, 32) was identified. Finally, for the target P300
      component - in addition to the aforementioned sources - activations in the
      prefrontal cortex (BA 9, 10, 46, 47), the inferior parietal cortex (supramarginal
      gyrus, BA 40, 39) and the posterior cingulum (BA 31) were found. Thus, patients
      and controls did not differ in the structural processes engaged in these
      fundamental aspects of information processing. However, patients demonstrated
      significantly reduced source strength - for standard ERP components predominantly
      in the temporal lobe and for target components predominantly in the frontal lobe,
      indicating reduced energetic resources available for perceptual and cognitive
      demands of the discrimination task. While, as compared with placebo, estrogen
      alone had only minor effects on ERP source strength, Climodien generally
      increased the impressed current density at the ERP peak latencies, predominantly
      in the temporal lobe, indicating an increased stimulus-induced cortical arousal
      in the primary and higher-order auditory cortex. Specifically, Climodien enhanced
      P300 source strength in the left middle temporal gyrus and in the left superior
      frontal gyrus, brain regions that on the one hand have been shown to be affected
      by hormone therapy in positron emission tomography and functional magnetic
      resonance neuroimaging studies and that on the other hand are among those
      critical for encoding and memory processes.

PMID- 15034230
TI  - Effects of zolpidem and zaleplon on sleep, respiratory patterns and performance
      at a simulated altitude of 4,000 m.
AB  - The effects of zolpidem or zaleplon on sleep architecture, respiratory patterns
      and performance were assessed at a simulated altitude of 4,000 m. Twelve male
      healthy subjects spent 4 nights in a decompression chamber, 1 at sea level
      (baseline), 3 at 4,000 m to test zolpidem (10 mg), zaleplon (10 mg) and placebo,
      given 15 min before switching the lights off. Sleep and respiratory patterns were
      analysed using polysomnography. Cognitive and physical performance was examined
      the next morning at sea level conditions. The study demonstrates that both
      zolpidem and zaleplon improved slow wave sleep at altitude, with zolpidem showing
      more marked effects than zaleplon. Both agents did not adversely affect
      respiration at altitude during the night, or cognitive or physical performance
      the next morning at the dosages used in this study. Thus, climbers may safely use
      both hypnotic agents.

PMID- 15034231
TI  - Global approach to multichannel electroencephalogram analysis for diagnosis and
      clinical evaluation in mild Alzheimer's disease.
AB  - To establish an early diagnosis of Alzheimer's disease (AD), we evaluated brain
      spatial dynamics and cognitive function in mild AD. Seventeen patients with the
      diagnosis of mild AD and 17 age-matched controls were examined for Omega (global
      complexity), Sigma (total power) and Phi (generalized frequency) by 19-channel
      electroencephalography (EEG). As a result, the mild AD group showed significantly
      higher Omega values than the control group. The Phi values were highly correlated
      with the Mini-Mental State Examination scores and the full IQ and performance IQ
      scores of the Japanese Wechsler Adult Intelligence Scale Revised. These results
      indicate an increase in spatial complexity of the brain electric field in mild
      AD, as well as a close relationship between slowing of the global frequency of
      field changes and the cognitive decline in mild AD.

PMID- 15034232
TI  - Telomere length variation and telomerase activity expression in patients with
      congenital and acquired aplastic anemia.
AB  - Telomeres represent the nucleoprotein tails of chromosomes that get shortened
      with each cell division. When the telomere length reaches a critical point, cell
      senescence and death occur. Telomerase is a reverse transcriptase that
      counteracts telomere loss by adding telomeric sequences. In patients with
      acquired aplastic anemia, the mean telomere length (TRF) of peripheral blood
      leukocytes is generally short when compared to normal controls, without it being
      clear whether a relationship between TRF and disease severity exists.
      Additionally, increased telomerase activity (TA) is found in the bone marrow
      mononuclear cell population (MNCs) of aplastic anemia patients, especially in the
      chronic form of the disease. Fanconi anemia (FA) patients generally demonstrate
      increased TA and short telomeres in peripheral blood MNCs, a fact attributed to
      the high turnover of hematopoietic progenitor cells in combination with direct
      breakages at telomeric sequences. Furthermore, a strong correlation has been
      shown between TRF and the severity of aplastic anemia, but not with FA evolution
      towards myelodysplastic syndrome or acute myeloblastic leukemia. In respect of
      dyskeratosis congenita (DC), a disease of either X-linked or autosomal
      dominant/recessive inheritance which is characterized by premature ageing of
      highly regenerative tissues, studies have been carried out in order to elucidate
      whether the X-linked DC is caused by a defect in ribosomal RNA processing and/or
      telomere maintenance. Finally, the direct genetic link established between DC
      pathogenesis and short telomeres may lead to the development of new therapeutic
      protocols for diseases characterized by short telomere length and subsequent
      genomic instability.

PMID- 15034233
TI  - Age-dependent changes in the incidence and etiology of childhood thrombocytosis.
AB  - To determine the incidence and etiology of childhood thrombocytosis, over 15,000
      platelet counts in 7,539 patients performed at a single regional hospital were
      reviewed. When thrombocytosis was defined as > or =500 x 10(9)/l of platelet
      counts, the condition could be diagnosed in 6.0% (456 cases) of the patients. All
      patients were classified as having secondary thrombocytosis. The incidence of
      thrombocytosis dramatically changed throughout child development; it was 12.5% in
      neonates, peaked to 35.8% in 1-month-old infants and then returned to 12.9% in 6-
      to 11-month-old infants. Thereafter, it gradually decreased with age to only 0.6%
      in 11- to 15-year-old children. Frequent causes of thrombocytosis included
      infection (67.5%), Kawasaki disease (9.4%), prematurity (7.7%) and iron
      deficiency anemia (6.4%). Thrombocytosis was an incidental finding in a
      substantial population of early infants. Thrombocytosis as a reaction to several
      types of infection and Kawasaki disease was more common in children under 7 years
      old, while autoimmune disease and tissue damage were major causes in children
      aged 11-15 years. No child had thromboembolic complications. These findings
      indicate that childhood thrombocytosis is a benign condition and its incidence
      and etiology seem to depend on age.

PMID- 15034234
TI  - Soluble transferrin receptor and its ratio to erythroblasts in bone marrow may be
      a new diagnostic tool to distinguish between aplastic and refractory anemia.
AB  - Myelodysplastic syndromes (MDS), especially refractory anemia (RA) are very
      heterogeneous diseases regarding their morphological, biological and clinical
      features. One important clinical problem is the difficulty of diagnosis. Soluble
      transferrin receptors (sTfRs) reflect the erythropoietic activity in the bone
      marrow (BM). To establish whether determination of serum sTfR could be useful for
      the differential diagnosis between RA and aplastic anemia (AA), we measured the
      serum sTfR concentrations, BM cellularity and BM erythroblast percentages in 14
      untreated AA and 7 untreated RA patients. The serum sTfR levels of the RA
      patients (820.1 +/- 402.8 ng/ml) were significantly higher than those of the AA
      patients (491.1 +/- 195.2 ng/ml; p = 0.0207). However, the serum sTfR values of
      RA and AA patients also overlapped. A new index, the 'sTfR-E index' [the ratio of
      serum sTfR level (ng/ml) to BM cellularity (%) x BM erythroblasts (%)] is
      proposed, which is expected to reflect the number of transferrin receptors (TfR)
      on the cell membrane per BM erythroblast. The sTfR-E index values of the 7 RA
      patients (0.395 +/- 0.234) were significantly lower than those of the 14 AA
      patients (2.669 +/- 1.633; p = 0.0003). The sTfR-E index values of AA and RA
      patients overlapped only marginally. In conclusion, the sTfR-E index may be a
      useful new diagnostic tool to distinguish between AA and RA patients.

PMID- 15034237
TI  - Prefibrotic chronic idiopathic myelofibrosis--a diagnostic enigma?
AB  - To analyze precursor lesions of chronic idiopathic myelofibrosis (CIMF) 21
      patients were recruited who developed manifest myelofibrosis after about 70
      months, preceded by a prefibrotic stage but without interference by cytoreductive
      therapy. Prodromal bone marrow lesions included a prominent granulocytic and
      megakaryocytic proliferation with megakaryocytes showing conspicuous
      abnormalities associated with a borderline to slight anemia, thrombocytosis, and
      minimal splenomegaly. Comparison of this cohort with 211 additional patients at
      this precursor stage revealed no differences concerning clinical findings and
      bone marrow histopathology. Relative incidence of prefibrotic CIMF was 24% and
      median survival 143 months, thus contrasting overt CIMF (82 months). In CIMF
      progressive myelofibrosis occurred in more than 50% of patients according to the
      last biopsy specimen; however, this figure increased according to relevant
      clinical data in the follow-up period.

PMID- 15034235
TI  - Improvement of cardiac function in thalassemia major treated with L-carnitine.
AB  - INTRODUCTION: Heart disease secondary to chronic anemia and hemosiderosis remains
      the major cause of morbidity and mortality in thalassemic patients. Chronic
      anemia and the tissue hypoxia it induces impair free fatty acid oxidation and ATP
      production in myocardial cells. The use of L-carnitine, a butyric acid
      derivative, may help overcome some of these defects. OBJECTIVE: To investigate
      the effect of L-carnitine therapy on cardiac function in thalassemia major
      patients. MATERIALS AND METHODS: Cardiac function was evaluated in 30 patients
      attending our clinic. The mean (+/-SD) age was 15.87 +/- 3.19 years. The studies
      we performed included echocardiography, Doppler and multigated equilibrium
      radionuclide angiography (MUGA). Systolic and diastolic function was evaluated
      before starting L-carnitine treatment and after 6 months of oral L-carnitine (50
      mg/kg/day). RESULTS: Echocardiography studies revealed no significant changes in
      systolic and diastolic function after L-carnitine therapy (p > 0.05). Analysis of
      the data taken by MUGA performed in 20 of the patients, however, showed a
      significant improvement of diastolic function after 6 months of L-carnitine
      therapy. The mean peak filling rate (end-diastolic volume/s) increased from 3.15
      +/- 1.06 to 3.61 +/- 1.68 (p < 0.03). The time to peak (during filling) decreased
      significantly from 143.45 +/- 42.04 to 117.70 +/- 24.40 s (p < 0.02). Systolic
      function showed a significant increase in the left ventricular ejection fraction
      from 58.25 +/- 9.92 to 63.95 +/- 10.11% (p = 0.0001). CONCLUSION: L-carnitine may
      be an effective drug for improving the cardiac status of thalassemic patients.
      MUGA is the most accurate technique of those used here for assessing left
      ventricular function in these patients.

PMID- 15034236
TI  - The diverse molecular basis and hematological features of Hb H and AEBart's
      diseases in Northeast Thailand.
AB  - We defined the molecular basis and correlated the hematological phenotypes with
      the globin genotypes in 52 patients with Hb H disease and 29 patients with
      AEBart's disease of northeast Thailand. Among the former group, the most
      prevalent molecular defect was found to be the interaction of alpha-thalassemia 1
      (SEA type) with the Hb Constant Spring (Hb CS; 35 of 52 patients), followed by
      the deletion of three alpha-globin genes with the SEA type alpha-thalassemia 1
      and the 3.7- or 4.2-kb deletion of alpha-thalassemia 2 (14 of 52 patients) and
      the interaction of the SEA alpha-thalassemia 1 with the Hb Pakse which was found
      in the remaining 3 patients. Among the 29 patients of the latter group, in 18
      disease was caused by interactions of Hb E heterozygotes with the SEA alpha
      thalassemia 1 and Hb CS. Interaction of Hb E heterozygotes with a deletional form
      of Hb H disease was detected in 7 patients and the Hb Pakse AEBart's disease was
      found in another 3 patients. A remaining patient with an unusually severe form of
      AEBart's disease with a lower Hb E level and observable Hb H was associated with
      a hitherto undescribed condition, the interaction of Hb E heterozygote with alpha
      thalassemia 1 and an alpha2 codon 30 (GAG) deletion. Hematological
      characterization of the patients demonstrated that although disease in most of
      them was associated with thalassemia intermedia phenotypes, it was apparent that
      association with the nondeletional form of alpha-thalassemia 2 produced a more
      severe phenotype than that of the deletional one. Therefore, alpha-globin gene
      analysis of Hb H and AEBart's disease patients would be useful for predicting the
      clinical outcome and improving genetic counseling.

PMID- 15034238
TI  - Acute myeloid leukemia secondary to a myelodysplastic syndrome with t(3;3)
      (q21;q26) in an HIV patient treated with chemotherapy and highly active
      antiretroviral therapy.
AB  - We describe the first case of secondary acute myeloid leukemia (AML) with t(3;3)
      (q21;q26) occurring in a human immunodeficiency virus (HIV)-infected patient
      sequentially treated with chemotherapy and highly active antiretroviral therapy
      (HAART). The t(3;3) is a nonrandom abnormality found in a small percentage of
      patients with myelodysplastic syndrome, secondary AML or chronic myeloid leukemia
      and is strongly associated with abnormal thrombopoiesis and a particularly poor
      prognosis. So far, it has never been observed in HIV-positive patients. Sporadic
      cases of AML have been reported in HIV patients and the feasibility of
      chemotherapy in association with HAART and disease outcome are still not clearly
      defined. Despite the poor response to chemotherapy in our case, which might also
      be related to the unfavorable karyotype, the secondary nature of the disease and
      the HIV positivity, the patient had a relatively long period of survival that
      could be due to the use of HAART. The association of chemotherapy with HAART
      appeared to be feasible and tolerable and could be suggested as a choice
      treatment in this peculiar subset of HIV/AML patients.

PMID- 15034239
TI  - Expansion of TcRalphabeta+CD3+CD4-CD8- (CD4/CD8 double-negative) T lymphocytes in
      a case of staphylococcal toxic shock syndrome.
AB  - A 55-year-old woman presented with staphylococcal toxic shock syndrome (TSS).
      During the course of the disease a significant lymphocytosis appeared, and a high
      number of TcRalphabeta+CD3+CD4-CD8- (double-negative, DN) lymphocytes was
      observed both in bone marrow and in peripheral blood samples. Correction of the
      altered lymphocyte immunophenotype was observed only 6 weeks after recovery from
      TSS. The immunophenotype of circulating and bone marrow lymphocytes was also
      studied during a phase of an aspecific febrile episode observed 2 months after
      recovery, but no subset of DN lymphocytes was found. A small subset of DN
      lymphocytes can be found in normal bone marrow, liver, thymus, and skin. These
      cells show peculiar immune regulatory properties and can increase in certain
      autoimmune diseases. Our findings may represent a specific effect of lymphocyte
      stimulation by the staphylococcal exotoxin, which is the effector agent of TSS.

PMID- 15034240
TI  - T cell prolymphocytic leukemia with new chromosome rearrangements.
AB  - A 77-year-old woman presented to the outpatient hematology clinic in August 2001
      with leukocytosis, recurrent bacterial infections, sweating and weight loss. Bone
      marrow biopsy showed 80% infiltration with lymphoid cells having a prolymphocytic
      morphology. Flow-cytometric immunophenotype analysis showed that over 80% of the
      cells were positive for CD2, CD3, CD4, CD5 and CD7 antigens and negative for
      terminal deoxynucleotidyl transferase and CD1a antigens. T cell prolymphocytic
      leukemia (T-PLL) was diagnosed on the basis of these findings. The diagnosis was
      later confirmed by cytogenetic analysis and fluorescence in situ hibridization.
      The patient had the following karyotype: 46,X,der(X)t(X;3) (q28;p25)
      t(X;16)(p14;q12), der(3) t(X;3)(q28;p25), der(6) t (X;6) (p14;q25), (8) (q10),
      del(11) (q14q23), der(13) t (5;13) (q34;p11), der(13) t(13;14)(q22;q11),
      inv(14)(q11q32), der (16) t(X;16)(q28;q12), r(17)(p13q21), der(20) t(17;20) (q21;
      q13),22p+. The cytogenetic rearrangements der(6)t(X;6) (p14;q25),
      der(13)t(13;14)(q22;q11),t(5;13)(q34;p11), r(17) (p13q21) and t(17;20)(q21;q13)
      have not been described previously in the literature in patients with T-PLL.

PMID- 15034241
TI  - Coexistence of primary refractory anemia with ringed sideroblasts and T cell
      lymphoblastic non-Hodgkin lymphoma.

PMID- 15034242
TI  - Glucose-6-phosphate dehydrogenase deficiency, vitamin K, and ambiguity in medical
      textbooks.

PMID- 15034243
TI  - The role of itraconazole in preventing and treating systemic fungal infections in
      immunocompromised patients.
AB  - The increasing use of immunosuppressive chemotherapy and allogeneic transplants
      for haematological malignancies has increased the number of patients at risk of
      systemic fungal infections (SFIs). A number of antifungal agents are now
      available. This paper reports the deliberations of an expert panel that
      considered the role of itraconazole. It concluded that itraconazole has an
      important role in the prophylaxis and treatment of SFIs whether proven or not.

PMID- 15034244
TI  - Bernard Katz: his search for truth and beauty.

PMID- 15034245
TI  - Obituary: Sir Bernard Katz (1911-2003).

PMID- 15034246
TI  - Neural transmitter release: from quantal secretion to exocytosis and beyond..

PMID- 15034247
TI  - The formation and function of single transmitter release sites at mature
      amphibian motor-nerve terminals.
AB  - The extent of quantal transmitter release from single sites of synaptic vesicle
      accumulations along the length of motor-nerve terminal branches at the amphibian
      neuromuscular junction has been investigated. Such a determination involves
      development of a model for the generation of quantal potential fields at single
      styryl-dye stained sites along the length of a branch. Successful testing and
      application of this model indicates that the extent of quantal release at a dye
      stained site is proportional to the total length of active zone at the site. The
      stability of these sites and of their ensheathing terminal Schwann cell processes
      was also investigated. Following simultaneous injection of the terminal Schwann
      cell and nerve terminal with different fluorescent dyes, terminal branches were
      observed to show dynamic changes in their length, with these occurring in
      relatively short periods of hours or less. Redistribution of styryl dye stained
      sites at the ends of branches also occurred in such short periods of time. These
      were accompanied by changes in the configuration of terminal Schwann cells, which
      generally occurred prior to changes in the length of nerve terminal branches.

PMID- 15034248
TI  - Maintenance of transmitter release from neuromuscular junctions with different
      patterns of usage "in vivo".
AB  - The basic mechanisms underlying chemically-mediated neurotransmission at synapses
      are well established. Synaptic vesicles release their contents of
      neurotransmitter by exocytosis, and are then recycled and refilled before re
      priming for re-release. It is less clear, however, what determines the
      differences in the quantitative aspects of this process at synapses with
      different in vivo activity patterns, and the extent to which they can be adapted
      to changing patterns of usage. The neuromuscular junction is particularly suited
      to investigations of these issues, due to the presence of distinctive muscle
      fibre types, with well-differentiated physiological roles and hence, activity
      patterns. The relative accessibility of NMJs means that chronic recording and
      manipulation of in vivo activity patterns of single motor neurones are possible.
      Several laboratories around the world now examining how transmitter release at
      NMJs is adapted to maintain (or not) release under these identified activity
      patterns. This review will cover the current state of knowledge and briefly
      highlight areas where more research is required. For example, current knowledge
      is largely derived from invertebrate preparations, indicating a need for more
      detailed comparisons at mammalian NMJs with different activity patterns. Finally,
      it is not yet clear in any species whether adaptations observed with imposed
      activity can be driven to complete transformation, with appropriate stimulus
      regimes.

PMID- 15034250
TI  - Structural determinants of the reliability of synaptic transmission at the
      vertebrate neuromuscular junction.
AB  - The reliability of neuromuscular transmission depends on the size and molecular
      organization of the neuromuscular junction. Comparative studies show that the
      quantal release per unit area is similar at neuromuscular junctions in a number
      of species in spite of wide variation in synaptic area. They also show an inverse
      relationship between the size of the nerve terminal and the extent of
      postsynaptic folding. Evidence is presented supporting the view that the folds,
      and the voltage-gated sodium channels present in them, effectively amplify
      synaptic currents. How are the size and molecular organization of the
      neuromuscular junction determined? Studies with botulinum toxin, including our
      new work on humans, reveal striking "adaptive plasticity" of the nerve terminal.
      However, the links between synaptic size and effective transmission remain
      unclear. On the postsynaptic side, we have shown that mRNA encoding sodium
      channels is concentrated at the adult junction. During development, mRNA
      accumulates just before the protein it encodes. Throughout development the sodium
      channels are associated with ankyrinG and both proteins are initially excluded
      from the junctional acetylcholine receptor cluster, possibly accounting for the
      formation of the boundary between the domains occupied by the two key
      postsynaptic ion channels. These findings have important clinical implications.
      Reduced transmitter release may result from small nerve terminals as much as from
      defective release. Abnormal folding is likely to reduce the reliability of
      transmission. A better understanding of how the structural features that
      influence the reliability of the neuromuscular transmission are controlled should
      be of general interest to neuroscientists and of use to clinicians.

PMID- 15034249
TI  - The role of integrins in the modulation of neurotransmitter release from motor
      nerve terminals by stretch and hypertonicity.
AB  - Integrins are found at most or all synapses and play a variety of roles. At frog
      neuromuscular junctions, mechanical tension on integrins due to muscle stretch or
      hypertonicity causes a powerful modulation of release efficacy. Understanding the
      mechanism(s) of integrin-mediated modulation will likely further our
      understanding of mechanisms of neurotransmitter release. The modulation of evoked
      release with stretch occurs with no detectable delay, does not adapt, and
      bypasses the Ca(2+) triggering step in vesicle fusion. It depends primarily on
      integrin bonds to native ligands and requires that one or more proteins in the
      link between integrins and vesicle fusion be dephosphorylated. Hypertonicity,
      studied in both frog and Drosophila terminals, causes a larger but slower phasic
      tonic change in spontaneous release, which is also Ca(2+)-independent and mostly
      dependent on integrins, but not dependent on the phosphorylation state of
      molecules in its pathway of action. In Drosophila, the integrin-dependent
      component involves the cAMP/PKA pathway, and is absent in mutants lacking PKA.
      Both stretch and hypertonicity responses in frog terminals are enhanced by agents
      that elevate PKA levels, suggesting that, in frogs, the cAMP/PKA cascade
      primarily determines the size of the pool of vesicles available for release by
      the integrin-mediated mechanism and is not a direct intermediary in the
      modulation. Evoked release is affected little or even inhibited by hypertonicity.
      In Drosophila, the inhibition can be explained by a decrease in Ca(2+) influx.
      The effect of hypertonicity on evoked release in frogs may similarly be a balance
      between mechanisms that enhance spontaneous release and those that suppress I
      (Ca).

PMID- 15034251
TI  - The nerve-muscle synapse of the garter snake.
AB  - Snake nerve-muscle preparations are well-suited for study of both motor
      innervation patterns at the systems level and NMJ function at the cellular level.
      Their small size ( approximately 100 myofibers) and thinness (one fiber) allows
      access to all NMJs in one muscle. Snake NMJs are of three types, two twitch
      subtypes and a single tonic type. Properties of the NMJs supplied by a particular
      motor neuron, and of the motor unit fibers they innervate, are precisely
      regulated by the motor neuron in a manner consistent with the Henneman Size
      Principle. Unlike its amphibian or mammalian cousins, the snake NMJ comprises
      approximately 50 (twitch) or approximately 20 (tonic) individual one-bouton
      synapses, similar to synapses found in the central nervous system. Each bouton
      releases a few quanta per stimulus. Larger fibers, which require more synaptic
      current to initiate contraction, receive nerve terminals that contain more
      boutons and express receptor patches with higher sensitivity to transmitter.
      Quantal analysis suggests that transmitter release sites in one bouton do not
      behave independently; rather, they may cooperate to reduce fluctuations and
      enhance reliability. After release, two mechanisms coexist for retrieval and
      reprocessing of spent vesicles-one involving clathrin-mediated endocytosis, the
      other macropinocytosis. Unanswered questions include how each mechanism is
      regulated in a use-dependent manner.

PMID- 15034252
TI  - Monitoring synaptic vesicle recycling in frog motor nerve terminals with FM dyes.
AB  - Ultrastructural observations made in the study of the frog neuromuscular junction
      (NMJ) almost three decades ago showed that synaptic vesicle cycling functions
      through a slow pathway, requiring the use of clathrin-coated vesicles and an
      endosomal compartment. Simultaneously, a conceptually simpler model emerged,
      postulating rapid retrieval of vesicle membrane through a mechanism similar to a
      reversal of vesicle fusion. With the advent of fluorescence imaging which allows
      the investigator to monitor recycling in living nerve-muscle preparations, new
      data appeared which reconcile at least in part the two models, indicating that
      both may be important at this synapse. Two different synaptic vesicle pools can
      be defined, a readily releasable pool (RRP), consisting of quanta that are
      immediately available for release, and a reserve pool (RP) that is exocytosed
      only after prolonged stimulation. Vesicles in the RRP recycle through a fast
      endocytic pathway, which does not rely on an endosomal compartment, while
      vesicles in the RP cycle more slowly through formation of infoldings and
      endosomes and their subsequent severance into vesicles. The two pools mix slowly,
      and their recycling may be regulated by different mechanisms.

PMID- 15034253
TI  - Two synaptic vesicle pools, vesicle recruitment and replenishment of pools at the
      Drosophila neuromuscular junction.
AB  - Drosophila neuromuscular junctions ( D NMJs) are malleable and its synaptic
      strength changes with activities. Mobilization and recruitment of synaptic
      vesicles (SVs), and replenishment of SV pools in the presynaptic terminal are
      involved in control of synaptic efficacy. We have studied dynamics of SVs using a
      fluorescent styryl dye, FM1-43, which is loaded into SVs during endocytosis and
      released during exocytosis, and identified two SV pools. The exo/endo cycling
      pool (ECP) is loaded with FM1-43 during low frequency nerve stimulation and
      releases FM1-43 during exocytosis induced by high K(+). The ECP locates close to
      release sites in the periphery of presynaptic boutons. The reserve pool (RP) is
      loaded and unloaded only during high frequency stimulation and resides primarily
      in the center of boutons. The size of ECP closely correlates with the efficacy of
      synaptic transmission during low frequency neuronal firing. An increase of cAMP
      facilitates SV movement from RP to ECP. Post-tetanic potentiation (PTP)
      correlates well with recruitment of SVs from RP. Neither PTP nor post-tetanic
      recruitment of SVs from RP occurs in memory mutants that have defects in the
      cAMP/PKA cascade. Cyotochalasin D slows mobilization of SVs from RP, suggesting
      involvement of actin filaments in SV movement. During repetitive nerve
      stimulation the ECP is replenished, while RP replenishment occurs after tetanic
      stimulation in the absence of external Ca(2+). Mobilization of internal Ca(2+)
      stores underlies RP replenishment. SV dynamics is involved in synaptic plasticity
      and D NMJs are suitable for further studies.

PMID- 15034254
TI  - Genetic and molecular analysis of synaptic vesicle recycling in Drosophila.
AB  - Following exocytosis, one of the major presynaptic events is replenishing
      synaptic vesicles (SVs) to ensure the possibility of continuous synaptic
      transmission. The nerve terminal is thought to recycle SVs through clathrin
      mediated endocytosis and by a clathrin-independent pathway called "kiss and run".
      This review highlights the use of the genetic model organism, the fruit fly
      (Drosophila melanogaster), in dissecting the molecular mechanisms of clathrin
      mediated endocytosis in recycling SVs at neuromuscular junctions (NMJs). Analyses
      of endocytotic mutants in Drosophila indicate that clathrin-mediated endocytosis
      may be essential for SV recycling, including a putative fast recycling mechanism
      uncovered recently. Further, a rather complex picture begins to emerge suggesting
      that clathrin-mediated endocytosis involves several sequential steps mediated by
      a large number of proteins. Finally, these studies also reveal that SV proteins
      may be selectively retrieved into nascent SVs by clathrin accessory proteins and
      defects in protein retrieval have significant impacts on synaptic transmission.
      Following the completion of the Drosophila Genome Project and the development of
      gene targeting and RNAi approaches, genetic studies in Drosophila have become
      increasingly efficient. Hence, Drosophila is expected to continue to serve as an
      important model organism for studies of SV recycling.

PMID- 15034255
TI  - The role of nitric oxide signaling in the formation of the neuromuscular
      junction.
AB  - The formation of the vertebrate neuromuscular junction (NMJ) depends on the
      action of neural agrin on the muscle cell. The requirement for agrin and its
      receptor, muscle-specific kinase (MuSK), has been well established over the past
      20 years. However, the signaling mechanisms through which agrin and MuSK cause
      synaptic differentiation are not well understood. New evidence from studies of
      muscle cells in culture and in embryos indicates that nitric oxide (NO) is an
      effector of agrin-induced postsynaptic differentiation at the NMJ. Cyclic GMP
      (cGMP) production by guanylate cyclase appears to be an important downstream step
      in this pathway. Nitric oxide and cGMP regulate the activity of several kinases,
      some of which may influence interaction of dystrophin and utrophin with the actin
      cytoskeleton to mediate or modulate postsynaptic differentiation in muscle cells.
      These signaling molecules could also play a role in retrograde signaling to
      influence differentiation of presynaptic nerve terminals.

PMID- 15034257
TI  - Neuregulins and the neuromuscular system: 10 years of answers and questions.
AB  - The neuregulins were originally discovered in searches for the acetylcholine
      receptor-inducing activity (ARIA), glial growth factor (GGF), and a ligand for
      the oncogene neu (ErbB2/HER2). Neuregulin1 (NRG1)-mediated cell communication is
      critical in the central and peripheral nervous system, heart, breast, and other
      organ systems. This review will focus on the functions of NRG1s in the
      development and maintenance of the neuromuscular system and on the regulation of
      NRG1 signaling within this system. The roles of NRG1 signaling in the
      neuromuscular system are far more pervasive than contemplated when neuregulins
      were discovered 10 years ago. In fact, neuregulin-mediated cell communication
      plays an essential role in the biology of most components of the neuromuscular
      system--including motor and sensory neurons, muscle fibers, Schwann cells, and
      major specializations (neuromuscular synapses, muscle spindles, Golgi tendon
      organs, and peripheral nerves). It is argued here that while NRG1 proteins are
      indeed "ARIA" and "GGF", their involvement in regulating synapse-specific
      transcription and Schwann cell development is more complex than originally
      proposed. It is also argued that NRG1 isoforms differ in their signaling
      properties and that these differences tailor specific isoforms for specific
      signaling tasks; for example, some NRG1 isoforms may be specialized for paracrine
      signaling and others for juxtacrine signaling. In the first 10 years of
      neuregulin research there has been much progress in understanding the actions of
      neuregulins in shaping and maintaining the neuromuscular system. However, major
      questions, old and new, remain unanswered; and the second 10 years promises to be
      at least as exciting as the first.

PMID- 15034256
TI  - ATP induces post-synaptic gene expressions in vertebrate skeletal neuromuscular
      junctions.
AB  - In vertebrate neuromuscular junctions (nmjs), adenosine 5'-triphosphate (ATP) is
      stored at the motor nerve terminals and is co-released with acetylcholine during
      neural stimulation. Several lines of evidence suggest that the synaptic ATP can
      act as a synapse-organizing factor at the nmjs, mediated by metabotropic P2Y(1)
      receptors. P2Y(1) receptor mRNAs in chicken and rat muscles are low in embryo but
      increases markedly in the adult, and decreased after denervation. The P2Y(1)
      receptor protein is restricted to the nmjs and co-localized with AChRs in adult
      muscles. The activation of P2Y(1) receptor by adenine nucleotides in cultured
      chick myotubes stimulated the accumulation of inositol phosphates, intracellular
      Ca(2+) mobilization, protein kinase C activity and phosphorylation of
      extracellular signal-regulated kinases. The receptor activation led to an
      increase in the expression of transcripts encoding AChE catalytic subunit and
      AChR subunits. The ATP-induced post-synaptic gene expression is possibly mediated
      by the activation of signaling cascades of mitogen-activated protein kinase.
      Therefore, a model is being proposed here that the synaptic ATP has a role of
      synergy with other regulatory signals, such as neuregulin, which act via their
      post-synaptic receptors to activate second signaling molecules locally to enhance
      the transcription of AChR/AChE genes specifically in the adjacent sub-synaptic
      nuclei during the formation and, especially, the maintenance of post-synaptic
      specializations at the nmjs.

PMID- 15034258
TI  - Neuregulin: an activity-dependent synaptic modulator at the neuromuscular
      junction.
AB  - Synaptic activity in the form of neurotransmitter release and postsynaptic
      depolarization is a prime motive force that guides synaptic development
      throughout the nervous system. The molecular basis of how synaptic activity is
      converted into structural changes that build and maintain synapses is a key
      question that has recently become focused on regulatory factors that act on
      tyrosine kinase receptors on both sides of the synaptic interface. The
      neuregulins are such a family of growth and differentiation factors that exist as
      both membrane-bound and soluble forms through alternatively splicing. Neuregulin
      functions to promote the local expression of acetylcholine receptors at
      neuromuscular synapses and therefore has the potential to strengthen specific
      synaptic connections. Recent evidence suggests that synaptic activity at the
      neuromuscular junction is coupled to presynaptic neuregulin release through an
      indirect mechanism acting through the postsynaptic expression of neurotrophic
      factors. At early stages of development, this could potentiate the stability of
      more active synapses. Later in development, heparin-binding forms of neuregulin
      accumulate to high levels in the synaptic basal lamina through the
      developmentally programmed expression of heparan sulfate proteoglycans, thus
      providing a sustained source of neuregulin to the most active synapses.

PMID- 15034259
TI  - Neuregulins: primary or secondary signals for the control of synapse-specific
      gene expression.
AB  - The selective transcription of acetylcholine receptor (AChR) subunit genes in
      synaptic myonuclei leads to the accumulation of AChR subunit mRNAs at the
      neuromuscular junction (NMJ). This mechanism contributes to the concentration of
      AChRs at the postsynaptic sarcolemma, and its physiological significance is
      underscored by the cases of human congenital myasthenias caused by mutation in a
      cis-regulatory element of the AChRepsilon-subunit promoter, which is necessary
      for its synaptic expression. The signal(s) that drives synapse-specific
      expression is unknown but neuregulin-1 (Nrg-1), a group of growth-factor-like
      polypeptides encoded by the nrg-1 gene, has been a favorite candidate. Nrg-1 was
      originally thought as a nerve-derived factor, acting in parallel to pathways
      controlling AChR clustering at the synapse ( i.e. agrin signaling). However,
      recent work suggests that Nrg-1 may actually be a muscle-derived signal that is
      concentrated at the NMJ, together with its receptors, by agrin and that acts as a
      secondary, downstream signal to enhance synapse-specific AChR transcription.
      Here, I review studies for and against Nrg-1 as a secondary signal driving
      synapse-specific expression at the NMJ. In addition, I briefly present new
      evidence that raise the possibility that Nrgs encoded by the ngr-1 -related gene
      nrg-2 might have a role controlling AChR expression.

PMID- 15034260
TI  - Transcription in neuromuscular junction formation: who turns on whom?
AB  - The neuromuscular junction is a particular advantageous synapse to investigate
      the molecular processes engaged in synaptogenesis. Both the motor nerve and the
      muscle cell contribute to the patterned distribution of a definite set of
      membrane proteins into two distinct regions, a sub-synaptic end plate zone and an
      extra-synaptic region. Accordingly, the transcription of acetylcholine receptors
      is highly compartmentalized being much higher in the sub-synaptic the in the
      extra-synaptic region. In this review, we focus on the signaling pathways and the
      gene expression mechanisms that mediate the enhanced transcription in the sub
      synaptic region and the silencing of transcription in extra-synaptic regions.

PMID- 15034261
TI  - A synaptic balancing act: local and global signaling in the clustering of ACh
      receptors at vertebrate neuromuscular junctions.
AB  - The clustering of acetylcholine receptors (AChRs) in muscle is a hallmark step in
      the development of vertebrate neuromuscular junctions (NMJs). It involves
      localized signaling, which is initiated by the activation of MuSK (muscle
      specific kinase) and leads to the concentration and cytoskeletal anchoring of
      AChRs at the synapse, and global signaling, which traverses the muscle to
      disperse extra-synaptic AChR clusters. Here we review some of the recent findings
      that indicate important roles for the actin cytoskeleton and tyrosine
      phosphatases in mediating these processes.

PMID- 15034262
TI  - Signaling complexes for postsynaptic differentiation.
AB  - The receptor tyrosine kinase MuSK is activated by agrin, an extracellular matrix
      protein believed to be utilized by motoneurons to regulate the formation or
      maintenance of the neuromuscular junction (NMJ). Recent studies have shed light
      on intracellular signaling mechanisms downstream of MuSK. Agrin enhances the
      activity of Rho GTPases and PAK, which is required for AChR clustering.
      Activation of these enzymes requires not only the kinase activity of MuSK, but
      also its interaction with proteins such as Dishevelled. These results suggest
      that MuSK may function as a scaffold tyrosine kinase that forms a multi-molecule
      complex for AChR clustering.

PMID- 15034264
TI  - Postsynaptic signaling of new players at the neuromuscular junction.
AB  - The neuromuscular junction (NMJ) represents the most well studied synapse and is
      widely regarded as structurally and functionally less complicated than neuronal
      synapses in the brain. Recent studies, however, have identified the localization
      and function of new signaling molecules at the NMJ. Surprisingly, many synaptic
      proteins previously identified in the brain are indeed also concentrated on the
      postsynaptic muscle side of the NMJ. These include the serine/threonine kinase
      Cdk5, the neurotrophin receptor TrkB, Eph receptors and ephrins, NMDA receptors
      and nitric oxide synthase, various PDZ-domain scaffold proteins, and beta-amyloid
      precursor protein. These observations indicate that the molecular composition of
      NMJ is much more intricate than we originally thought. The potential significance
      of these new signaling molecules at the NMJ will be discussed.

PMID- 15034263
TI  - The postsynaptic submembrane machinery at the neuromuscular junction: requirement
      for rapsyn and the utrophin/dystrophin-associated complex.
AB  - Neuromuscular synapse formation is brought about by a complex bi-directional
      exchange of information between the innervating motor neuron and its target
      skeletal muscle fiber. Agrin, a heparin sulfate proteoglycan, is released from
      the motor nerve terminal to activate its muscle-specific kinase (MuSK) receptor
      that leads to a second messenger cascade requiring rapsyn to ultimately bring
      about AChR clustering in the muscle membrane. Rapsyn performs many functions in
      skeletal muscle. First, rapsyn and AChRs co-target to the postsynatic apparatus.
      Second, rapsyn may self associate to stabilize and promote AChR clustering.
      Third, rapsyn is essential for AChR cluster formation. Fourth, rapsyn is required
      to transduce the agrin-evoked MuSK phosphorylation signal to AChRs. Finally,
      rapsyn links AChRs to the utrophin-associated complex, which appears to be
      required for AChR stabilization as well as maturation of the neuromuscular
      junction. Proteins within the utrophin-associated complex such as alpha
      dystrobrevin and alpha-syntrophin are also important for signaling events that
      affect neuromuscular synapse stability and function. Here we review our current
      understanding of the role of the postsynaptic-submembrane machinery involving
      rapsyn and the utrophin-associated complex at the neuromuscular synapse. In
      addition we briefly review how these studies of the neuromuscular junction relate
      to GABAergic and glycinergic synapses in the CNS.

PMID- 15034266
TI  - Watching the neuromuscular junction.
AB  - To understand how synapses form, it is important to be able to watch them as they
      form. Transgenic mice in which motor axons are indelibly labeled with the Green
      Fluorescent Protein (GFP) or one of its spectral variants (XFPs) provide a new
      way to image motor nerve terminals; when combined with contrasting stains for the
      postsynaptic membrane, both pre- and postsynaptic elements can be viewed in live
      animals. The development, maturation, stability, remodeling and regeneration of
      neuromuscular junctions and motor units can then be assessed over intervals
      ranging from seconds to months.

PMID- 15034265
TI  - Expression and localization of acetylcholinesterase at the neuromuscular
      junction.
AB  - Acetylcholinesterase (AChE) was the first identified synaptic component,
      characterized by its catalytic affinity for choline esters, and for a long time
      provided the conceptual scaffold for studies of the neuromuscular junction (NMJ).
      AChE was the first protein localized to the NMJ, in the 1930s, and its local
      expression shown to be regulated by the motoneuron in 1937. By the late 1940s a
      histochemical procedure was developed to visualize the enzyme at synapses,
      opening up a new era in the study of synaptic structure and function. This enzyme
      was also the first synaptic component to be purified, quantified, and later
      crystallized for structural and functional studies. Thus, historically, AChE has
      played a pivotal role in our understanding of NMJ development and function.AChE
      occurs in multiple oligomeric forms differing in their hydrophobic character and
      association with non-catalytic subunits that act as targeting sequences to insure
      correct localization at the cellular level. The predominant, if not unique, form
      of the enzyme responsible for terminating neuromuscular transmission is the
      collagen-tailed form of the enzyme attached to the synaptic basal lamina. This
      very large protein consists of three catalytic tetramers covalently linked to the
      three-stranded collagen-like tail (ColQ). The transcripts encoding AChE in muscle
      are preferentially expressed at sites of nerve-muscle contact and the AChE
      locally synthesized and assembled. Once externalized, the enzyme appears to be
      localized through interactions with the proteoglycan perlecan and subsequently
      covalently attached to the synaptic extracellular matrix. Thus a hierarchical
      series of events involving localized transcription and translation of the
      catalytic and non-catalytic subunits, localized assembly and secretion, and
      finally localized attachment to elements of the extracellular matrix insures that
      the enzyme is targeted to the correct location.

PMID- 15034267
TI  - Activity-dependent elimination of neuromuscular synapses.
AB  - At developing neuromuscular synapses in vertebrates, different motor axon inputs
      to muscle fibers compete for maintenance of their synapses. Competition results
      in progressive changes in synaptic structure and strength that lead to the
      weakening and loss of some inputs, a process that has been called synapse
      elimination. At the same time, a single input is strengthened and maintained
      throughout adult life, consistently recruiting muscle fibers to contract even at
      rapid firing rates. Work over the last decade has led to an understanding of some
      of the cell biological mechanisms that underlie competition and how these
      culminate in synapse elimination. We discuss current ideas about how activity
      modulates neuromuscular synaptic competition, how competition leads to synapse
      loss, and how these processes are modulated by cell-cell signaling. A common
      feature of competition at neuromuscular as well as CNS synapses is that
      temporally correlated activity seems to slow or prevent competition, while
      uncorrelated activity seems to trigger or enhance competition. Important
      questions that remain to be addressed include how patterns of motor neuron
      activity affect synaptic strength, what is the temporal relationship between
      changes in synaptic strength and structure, and what cellular signals mediate
      synapse loss. Answers to these questions will expand our understanding of the
      mechanisms by which activity edits synaptic structure and function, writing
      permanent changes in neural circuitry.

PMID- 15034269
TI  - Phosphorylation reactions in activity-dependent synapse modification at the
      neuromuscular junction during development.
AB  - We have studied developmental activity-dependent synapse diminution in both an in
      vitro tissue culture chamber system and at the intact rodent neuromuscular
      junction (nmj). In both types of preparations, pre- and postsynaptic alterations
      in synapse structure and function are produced by manipulations of thrombin (Thr)
      and protein kinase C (PKC) activity. An opposing postsynaptic effect of PKC and
      protein kinase A (PKA) action on the acetycholine receptor (AChR) can be shown in
      vitro with PKA stabilizing and PKC destabilizing the nmj synapses. In vivo
      studies of normal junctional maturation show that changes in axonal inputs and
      postsynaptic receptor cluster morphology occur, to a substantial degree,
      independently of one another. Presynaptic actions of PKA are involved in the
      activity dependent synapse modulation that can be demonstrated in vitro. Late in
      the elimination process, (>12 days in vivo ) the process becomes independent of
      PKC, implying that diverse, redundant mechanisms are involved in this important
      developmental process.

PMID- 15034268
TI  - Effects of evoked and spontaneous motoneuronal firing on synapse competition and
      elimination in skeletal muscle.
AB  - Synapse elimination is a general feature of the development of neural
      connections, including the connections of motoneurons to skeletal muscle fibers.
      Our work addressed two questions: (1) how the action potentials generated in the
      set of motoneurons innervating an individual muscle ( i.e., in a motor pool) are
      correlated in time during development in vivo; (2) what influence different
      firing patterns exert on the processes of polyneuronal innervation and synapse
      elimination which characterize the establishment of muscle innervation. We
      recorded the spontaneous electromyographic activity of the tibialis anterior and
      soleus muscles of late embryonic and neonatal rats, identifying the firing of at
      least two single motor unit signals in each record. We found that a striking
      switch occurs a few days after birth from a highly synchronous type of firing to
      an asynchronous one, the first thus characterizing embryonic while the second one
      adult motoneurons. We also investigated the effects of an evoked synchronous type
      of discharge on neuromuscular synapse formation, measuring polyneuronal
      innervation and synapse elimination. This was done in an adult in vivo model of
      de novo synapse formation, while a chronic TTX nerve conduction block, placed
      centrally with respect to the stimulating electrodes, eliminated the natural
      activity of motoneurons. We found that the imposed synchronous activity greatly
      inhibits synapse elimination, causing polyneuronal innervation to persist. We
      conclude that the early synchronous firing, favors the establishment of
      polyneuronal innervation while the subsequent switch to an asynchronous one
      promotes synapse elimination.

PMID- 15034270
TI  - Activity-dependent switch from synapse formation to synapse elimination during
      development of neuromuscular junctions.
AB  - The embryonic development of neuromuscular junctions consists of two successive
      epochs, an early period marked by exuberant synapse formation and a later period
      marked by synapse elimination. In the frog muscles we have studied, myogenesis is
      protracted and overlaps the periods of synapse formation and elimination. Thus,
      the formative and regressive events of synaptic development do not occur in
      synchrony across different fibers in the muscle. We propose that local activity
      orchestrates a shift from synaptogenesis to synapse elimination at the level of
      single muscle fibers. We also present evidence that perisynaptic Schwann cells
      and the expression of ion channels in the sarcolemma play important roles in the
      development of neuromuscular junctions. Questions for future study are outlined.

PMID- 15034271
TI  - What controls the position, number, size, and distribution of neuromuscular
      junctions on rat muscle fibers?
AB  - This review focuses on mechanisms that determine the position, number, size, and
      distribution of neuromuscular junctions (NMJs) on skeletal muscle fibers. Most of
      the data reviewed derive from studies of ectopic NMJ formation on soleus (SOL)
      muscle fibers in adult rats, which recapitulates essential aspects of NMJ
      formation in normal development. Transplanted axons induce acetylcholine receptor
      (AChR) aggregates, which are multiple and irregularly distributed initially but
      subsequently undergo massive reorganization such that one or a few winners
      survive and reach a certain size while the rest are eliminated (the losers).
      Results obtained by blocking nerve activity early and stimulating the SOL
      electrically show that evoked muscle impulse activity is responsible for the
      growth of winners to a given size and the creation of refractory zones, about
      0.75 long, on each side of the winners, in which the elimination of losers
      occurs. Consequently, when two or more aggregates or NMJs survive on one fiber,
      they are, on average, at least 1.5 mm apart. Locally applied neural agrin induces
      comparable aggregation of AChRs and other postsynaptic proteins on denervated SOL
      fibers and such aggregates undergo similar activity-dependent selection for
      survival or elimination in refractory zones. In a dose-dependent way, neural
      agrin alone also induces expression of epsilon-AChR subunits and stabilizes AChRs
      to a half-life of 10 days, as found at normal NMJs. It is argued that signs of
      prepatterning of innervation sites by intrinsic muscle mechanisms may refer to
      epiphenomena that play no important role in NMJ formation. The conclusion is that
      neural agrin initiates and then maintains NMJs where motor axons happen to
      contact receptive muscle fibers and that evoked muscle impulse activity then
      ensures that the NMJs reach their appropriate size, efficiency and spatial
      distribution along each fiber.

PMID- 15034272
TI  - Assembly, plasticity and selective vulnerability to disease of mouse
      neuromuscular junctions.
AB  - Although physiological differences among neuromuscular junctions (NMJs) have long
      been known, NMJs have usually been considered as one type of synapse, restricting
      their potential value as model systems to investigate mechanisms controlling
      synapse assembly and plasticity. Here we discuss recent evidence that skeletal
      muscles in the mouse can be subdivided into two previously unrecognized subtypes,
      designated FaSyn and DeSyn muscles. These muscles differ in the pattern of
      neuromuscular synaptogenesis during embryonic development. Differences between
      classes are intrinsic to the muscles, and manifest in the absence of innervation
      or agrin. The distinct rates of synaptogenesis in the periphery may influence
      processes of circuit maturation through retrograde signals. While NMJs on FaSyn
      and DeSyn muscles exhibit a comparable anatomical organization in postnatal mice,
      treatments that challenge synaptic stability result in nerve sprouting, NMJ
      remodeling, and ectopic synaptogenesis selectively on DeSyn muscles. This
      anatomical plasticity of NMJs diminishes greatly between 2 and 6 months
      postnatally. NMJs lacking this plasticity are lost selectively and very early on
      in mouse models of motoneuron disease, suggesting that disease-associated
      motoneuron dysfunction may fail to initiate maintenance processes at "non
      plastic" NMJs. Transgenic mice overexpressing growth-promoting proteins in
      motoneurons exhibit greatly enhanced stimulus-induced sprouting restricted to
      DeSyn muscles, supporting the notion that anatomical plasticity at the NMJ is
      primarily controlled by processes in the postsynaptic muscle. The discovery that
      entire muscles in the mouse differ substantially in the anatomical plasticity of
      their synapses establishes NMJs as a uniquely advantageous experimental system to
      investigate mechanisms controlling synaptic rearrangements at defined synapses in
      vivo.

PMID- 15034274
TI  - Basal lamina and the organization of neuromuscular synapses.
AB  - Fast chemical synapses are comprised of presynaptic and postsynaptic
      specializations precisely aligned across a protein-filled synaptic cleft. At the
      vertebrate neuromuscular junction (NMJ), the synaptic cleft contains a structured
      form of extracellular matrix known as a basal lamina (BL). Synaptic BL is
      molecularly differentiated from the BL that covers the extrasynaptic region of
      the myofiber. This review summarizes current understanding of the morphology,
      composition, and function of the synaptic BL at the vertebrate NMJ. Considerable
      evidence supports the conclusion that the synaptic BL organizes and maintains pre
      and postsynaptic specializations during development and regeneration, and
      promotes robust neurotransmission in the adult.

PMID- 15034273
TI  - The relationship of neuromuscular synapse elimination to synaptic degeneration
      and pathology: insights from WldS and other mutant mice.
AB  - Neuromuscular synapse elimination, Wallerian degeneration and peripheral
      neuropathies are not normally considered as related phenomena. However, recent
      studies of mutant and transgenic mice, particularly the Wld(S) mutant-in which
      orthograde degeneration is delayed following axotomy-suggest that re-evaluation
      of possible links between natural, traumatic and pathogenic regression of
      synapses may be warranted. During developmental synapse elimination from
      polyneuronally innervated junctions, some motor nerve terminals progressively and
      asynchronously vacate motor endplates. A form of asynchronous synapse withdrawal,
      strongly resembling synapse elimination, also occurs from mononeuronally
      innervated motor endplates following axotomy in young adult Wld(S) mutant mice. A
      similar pattern is observed in skeletal muscles of several neuropathic mutants,
      including mouse models of dying-back neuropathies, motor neuron disease and
      remarkably-models of neurodegenerative diseases such as Huntington's and
      Alzheimer's diseases. Taken together with recent analysis of synaptic remodelling
      at neuromuscular junctions in Drosophila, a strong candidate for a common
      regulatory mechanism in these diverse conditions is one based on protein
      ubiquitination/deubiquitination. Axotomised neuromuscular junctions in Wld(S)
      mutant mice offer favourable experimental opportunities for examining
      developmental mechanisms of synaptic regression, that may also benefit our
      understanding of how degeneration in the synaptic compartment of a neuron is
      initiated, and its role in progressive, whole-cell neuronal degeneration.

PMID- 15034275
TI  - Activity dependent removal of agrin from synaptic basal lamina by matrix
      metalloproteinase 3.
AB  - Agrin is a heparan sulfate proteoglycan, which plays an essential role in the
      development and maintenance of the neuromuscular junction. Agrin is a stable
      component of the synaptic basal lamina and strong evidence supports the
      hypothesis that agrin directs the formation of the postsynaptic apparatus,
      including aggregates of AChRs, and junctional folds. Changes in the distribution
      of agrin during synaptic remodeling, denervation and reinnervation reveal that
      agrin can be quickly and efficiently removed from the synaptic basal lamina in a
      regulated manner. In order to fully understand this mechanism we sought to
      identify those molecules that were responsible for the removal of agrin. Matrix
      Metalloproteinases (MMPs) were the most likely molecules since MMPs are involved
      in the regulation of the pericellular space, including the cleavage of matrix
      proteins. In particular, MMP3 has been shown to be effective in cleaving heparan
      sulfate proteoglycans. Antibodies to MMP3 recognize molecules concentrated in the
      extracellular matrix of perisynaptic Schwann cells. MMP3 specific phylogenic
      compounds reveal that active MMP3 is localized to the neuromuscular junction.
      Purified recombinant MMP3 can directly cleave agrin, and it can also remove agrin
      from synaptic basal lamina. MMP3 activity is itself regulated as activation of
      MMP3 is lost in denervated muscles. MMP3 null mutant mice have altered
      neuromuscular junction structure and function, with increased AChRs, junctional
      folds and agrin immunoreactivity. Altogether these results support the hypothesis
      that synaptic activity induces the activation of MMP3, and the activated MMP3
      removes agrin from the synaptic basal lamina.

PMID- 15034276
TI  - Glycobiology of the neuromuscular junction.
AB  - Most molecules that are present at synapses are glycosylated with carbohydrates,
      and some carbohydrate structures are themselves uniquely synaptic in their
      localization. Thus, proteins or lipids at the synapse may bear distinct
      carbohydrates that alter their localization or function. Here, I will review the
      evidence that there are unique synaptic carbohydrates at the neuromuscular
      junction. Then, I will review the evidence that such carbohydrates can affect the
      function of synaptic proteins, with particular attention to agrin, dystroglycan,
      and the neural cell adhesion molecule (NCAM). Finally, I will review recent data
      that demonstrates a role for one carbohydrate structure, the cytotoxic T cell
      (CT) antigen, in neuromuscular development. These studies suggest that
      glycosylation is an important modification to consider in studies of synapse
      formation and function.

PMID- 15034277
TI  - Neurotrophic regulation of the development and function of the neuromuscular
      synapses.
AB  - Recent studies have established that one of the major functions of neurotrophic
      factors is to regulate synaptic development and plasticity. This owes a great
      deal to the studies using the neuromuscular junction (NMJ) as a model system. In
      this review, we summarize the effects of various neurotrophic factors on the
      development and function of the neuromuscular synapses. We describe experiments
      addressing the role of neurotrophins, as well as that of other factors (GFLs, TGF
      betas, and Wnts). The synaptic effects of neurotrophic factors are divided into
      two categories: acute effects on synaptic transmission and plasticity occurring
      within seconds or minutes after cells are exposed to a particular factor, and
      long-term regulation of synaptic structure and function that takes days to
      accomplish. We consider the presynaptic effects on the release of the
      neurotransmitter ACh, as well as the postsynaptic effects on the clustering of
      ACh receptors. Further studies of the mechanisms underlying these regulatory
      effects will help us better understand how neurotrophic factors can achieve
      diverse and synapse-specific modulation in the brain.

PMID- 15034278
TI  - Cytokines, growth factors and sprouting at the neuromuscular junction.
AB  - The formation of neuronal sprouts, either from synaptic terminals or nearby nodes
      of Ranvier, is a widely known form of plasticity of motoneurons. Sprouts form in
      response to several stimuli, but most notably in partially denervated or
      paralyzed muscle. In search of the cellular or molecular basis of this
      phenomenon, several largely parallel lines of investigation have been pursued.
      Strong evidence is presented that at least four cytokines or growth factors may
      be involved in motoneuron sprouting, each of which uses a distinctive signaling
      pathway. Three of the different proposed sprouting molecules: neuroleukin,
      insulin-like growth factor, and neural cell adhesion molecules can be viewed as
      muscle-derived retrograde signaling molecules of roughly equal potency to induce
      motoneurons to sprout. A fourth molecule, ciliary neurotrophic factor (CNTF) is
      likely to form an essential anterograde signal, from Schwann cells to muscle
      fibers, that ultimately produces sprouting. Other cytokines and growth factors
      such a neurotrophins or GDNF family members are discussed, but their role in
      motoneuron sprouting is less clear. These cytokines and growth factors could
      represent redundant mechanisms for self-repair of the neuromuscular junction or
      they could interact at different levels of their cellular pathways.

PMID- 15034279
TI  - Mechanisms controlling axonal sprouting at the neuromuscular junction.
AB  - This review considers the relative roles of sprouting stimuli, perisynaptic
      Schwann cells and neuromuscular activity in axonal sprouting at the neuromuscular
      junction in partially denervated muscles. A number of sprouting stimuli,
      including insulin-like growth factor II, which are generated from inactive muscle
      fibers in partially denervated and paralyzed skeletal muscles, has been
      considered. There is also evidence that perisynaptic Schwann cells induce and
      guide axonal sprouting in adult partially denervated muscles. Excessive
      neuromuscular activity significantly reduces bridging of perisynaptic Schwann
      cell processes between innervated and denervated endplates and thereby inhibits
      axonal sprouting in partially denervated adult muscles. Elimination of
      neuromuscular activity is also detrimental to sprouting in these muscles,
      suggesting that calcium influx into the nerve is crucial for axonal sprouting.
      The role of neuromuscular activity in axonal sprouting will be considered
      critically in the context of the roles of sprouting stimuli and perisynaptic
      Schwann cells in the process of axonal sprouting.

PMID- 15034280
TI  - Terminal Schwann cells guide the reinnervation of muscle after nerve injury.
AB  - Schwann cells and axons labeled by transgene-encoded, fluorescent proteins can be
      repeatedly imaged in living mice to observe the reinnervation of neuromuscular
      junctions. Axons typically return to denervated junctions by growing along
      Schwann cells contained in the old nerve sheaths or "Schwann cell tubes". These
      axons then commonly "escape" the synaptic sites by growing along the Schwann cell
      processes extended during the period of denervation. These "escaped fibers" grow
      to innervate adjacent synaptic sites along Schwann cells bridging these sites.
      Within the synaptic site, Schwann cells, originally positioned above the synaptic
      site continue to cover the acetylcholine receptors (AChRs) immediately following
      denervation, but gradually vacate portions of this site. When regenerating axons
      return, they first deploy along the Schwann cells and ignore sites of AChRs
      vacated by Schwann cells. In many cases these vacated sites are never
      reinnervated and are ultimately lost. Following partial denervation, Schwann
      cells grow in an apparently tropic fashion from denervated to nearby innervated
      synaptic sites and serve as the substrates for nerve sprouting. These experiments
      show that Schwann cells provide pathways that stimulate axon growth and insure
      the rapid reinnervation of denervated or partially denervated muscles.

PMID- 15034281
TI  - Roles of glial cells in the formation, function, and maintenance of the
      neuromuscular junction.
AB  - Like other vertebrate synapses, the neuromuscular junction (NMJ) has glial cells
      that are closely associated with the pre- and post-synaptic components. These
      "perisynaptic Schwann cells" (PSCs) cover nerve terminals and are in close
      proximity to the synapse, yet their role at the NMJ has remained mysterious for
      decades. In this review we explore historical perspectives on PSCs and highlight
      key developments in recent years that have provided novel insight into PSC
      functions at the NMJ. First among these developments is the generation of
      specific antibody probes for PSCs. Using one such antibody and the principle of
      complement-mediated cell lysis, we have developed a novel technique to
      selectively ablate PSCs en masse from frog NMJs in vivo. Applying this approach,
      we have shown that PSCs are essential for the long-term maintenance of synaptic
      structure and function. In addition, PSCs are essential for the growth and
      maintenance of NMJs during development. Probes for PSCs also allow us to observe
      in vivo that processes extended by PSCs guide nerve terminals during synapse
      development, remodeling, and regeneration. PSCs may therefore dictate the pattern
      of innervation at the NMJ. Finally, PSCs may also induce postsynaptic
      acetylcholine receptor expression and aggregation. This wealth of recent findings
      about PSCs suggests that these synapse-associated glial cells are a more integral
      and essential component of the NMJ than previously appreciated. New approaches
      currently being applied at the NMJ may further support the emerging view that
      glial cells help make bigger, stronger, and more stable synapses.

PMID- 15034282
TI  - Modulation of neurotransmission by reciprocal synapse-glial interactions at the
      neuromuscular junction.
AB  - Perisynaptic Schwann cells are glial cells that are closely associated with pre-
      and postsynaptic elements of the neuromuscular junction. Recent evidence shows
      that these cells detect and modulate neurotransmission in an activity-dependent
      fashion. Through G-protein signalling and Ca(2+) released from internal stores
      they can decrease or increase neurotransmitter release, respectively. Thus, they
      help to establish the level of neurotransmission associated with activity
      dependent short-term synaptic plasticity. We discuss evidence implicating
      perisynaptic Schwann cells as being active partners in neurotransmission at the
      neuromuscular junction, with emphasis on the modulation of short-term plasticity
      and potential implications for long-term changes.

PMID- 15034283
TI  - Congenital myasthenic syndromes: A diverse array of molecular targets.
AB  - The neuromuscular junction (NMJ) has served as a prototype for understanding
      mechanisms underlying synaptic transmission over the past 50 years. More
      recently, analysis of congenital myasthenic syndromes (CMS) revealed a diverse
      array of molecular targets and delineated their contributions to synaptic
      function. Clinical, electrophysiologic and morphologic studies have paved the way
      for detecting CMS-related mutations in proteins such as choline acetyltransferase
      acetylcholinesterase, the acetylcholine receptor, rapsyn, and the voltage-gated
      sodium channel of the Na(v)1.4 type. Further studies of the mutant proteins have
      allowed us to correlate the effects of the mutations with predicted alterations
      in protein structure. In this review, we focus on the symptomatology of the CMS,
      consider the factors that impair neuromuscular transmission, survey the mutations
      that have been uncovered in the different synaptic proteins, and consider the
      functional implications of the identified mutations.

PMID- 15034284
TI  - [Reverse cholesterol transport in cultured gallbladder epithelial cells].
AB  - Bile is the major route of cholesterol excretion from the body. It is
      concentrated in the gallbladder, and often results in supersaturation of
      cholesterol. The high levels of cholesterol in gallbladder bile has clinical
      implications with respect to cholesterol gallstone formation and cholesterolosis
      of the gallbladder wall. Gallbladder epithelial cells (GBEC) are exposed to high
      cholesterol concentrations on their apical surfaces. Therefore, GBEC are uniquely
      positioned to play an important role in modulating biliary cholesterol
      concentrations. Recently, it has been documented that the key-transporter for
      polarized cholesterol and phospholipid efflux in GBEC is ATP-binding cassette
      transporter A1 (ABCA1) and Liver X receptor (LXR) and retinoid X receptor (RXR)
      in the nucleus of GBEC have a role that regulates ABCA1 expression. In addition,
      GBEC synthesize apolipoprotein A-I and E as cholesterol acceptors. These results
      indicate that GBEC has a perfect system for reverse cholesterol transport. We
      introduce the roles and mechanisms of ABCA1, scavenger receptor class B-I, LXR
      and RXR related to reverse cholesterol transport in GBEC with a review of our
      study experience and related literature.

PMID- 15034285
TI  - [Therapeutic effect of low-dose omeprazole vs. standard-dose ranitidine in mild
      to moderate reflux esophagitis].
AB  - BACKGROUND/AIMS: Proton pump inhibitors (PPI) and H2-receptor antagonists (H2RA)
      are commonly prescribed for the treatment of mild to moderate reflux esophagitis
      (MMRE). There remains great controversy in their usefulness as the first choice
      and the appropriateness. We prospectively compared the efficacy and safety of the
      8-week low-dose PPI vs. standard-dose H2RA in MMRE. METHODS: One hundred patients
      with MMRE were randomized to receive either low-dose of omeprazole (L-OMP: 10 mg,
      q.d.) or standard-dose of ranitidine (S-H2RA: 150 mg, b.i.d.) for 8 weeks. The H.
      pylori status using rapid urease test, histological examination and culture,
      reflux esophagitis (RE) grading, gastrointestinal symptoms using 4-point scale,
      adverse event and the standard laboratory examination were assessed at baseline
      and 8-week end point of therapy. RESULTS: Improvement rate of RE [intention to
      treat (n=82)/per protocol (n=72)] were shown in 69.1%/63.9% for L-OMP and
      65.0%/63.9% for S-H2RA group (p=0.697, p=1.000). Complete healing rates of RE
      were 54.7%/50.0% for L-OMP and 42.5%/41.7% for S-H2RA. No significant difference
      in healing rate, the rapidity of symptom resolution, adverse events, and
      laboratory monitoring was found between the two groups. CONCLUSIONS: The low-dose
      omeprazole therapy produced similar healing rates and safety in the treatment of
      MMRE. In addition, L-OMP is advantageous in its once-a-day dosing and might be an
      alternative to S-H2RA, especially in Korean patients with MMRE.

PMID- 15034286
TI  - [The effect of mosapride on quality of life in functional dyspepsia].
AB  - BACKGROUND/AIMS: It is unknown whether the prokinetics improve the quality of
      life in patients with functional dyspepsia. Thus, we evaluate the effect of the
      mosapride, selective 5-HT4 agonist, on the symptom and life quality of patients
      with functional dyspepsia using the Nepean dyspepsia index-Korean version (NDI
      K), a reliable and validated disease-specific quality of life questionnaire.
      METHODS: A single, open trial was performed in 129 patients with functional
      dyspepsia. Patients were received mosapride 5 mg t.i.d before each meal for 4
      weeks. The symptoms and quality of life were measured with the NDI-K at baseline
      and 4 weeks. The responsiveness of the NDI-K was evaluated by correlation with
      symptom scores. RESULTS: All the 15 symptom scores and the dyspepsia score
      decreased after treatment (p<0.05). The total symptom score decreased from 60.9
      +/- 25.8 to 24.7 +/- 20.4 (p=0.001). Correlations were observed between the total
      symptom score and the NDI-K score (r=0.47, p=0.001), and between the total
      symptom score and each score in 5 subscales (r=0.25-0.44, p=0.001). The NDI-K
      score was significantly increased in the effective group whose dyspepsia score
      decreased more than 50% of the score at baseline, compared with that of
      ineffective group. Any significant adverse effect and prolongation of QT interval
      were not occurred in all patients. CONCLUSIONS: A prokinetic drug, mosapride
      improves the symptoms and the quality of life in patients with functional
      dyspepsia.

PMID- 15034287
TI  - [Characteristics and risk factors of synchronous and metachronous polyp in
      colorectal cancer].
AB  - BACKGROUND/AIMS: Detection and removal of adenomatous polyps with colonoscopy is
      known to be the best preventive method for the colon cancer. With removal of
      synchronous colon polyps, the risk of metachronous cancer seems to be decreased
      effectively. However, the preoperative evaluation of entire colon is frequently
      impossible due to luminal obstructive lesion. Therefore, it is important to
      evaluate entire colon in postoperative period as earlier as possible. The aim of
      current study is to analyze the characteristics and risk factors of synchronous
      as well as metachronous polyps. METHODS: From Jan. 1998 to Dec. 2001, among the
      patients who received operative treatment for colon cancer in Yonsei University,
      Severance Hospital, 972 patients, who had underwent preoperative endoscopic
      evaluation and surveillance above one year after operation, were enrolled.
      RESULTS: In 617 patients who had completed total colonic evaluation within one
      year after operation, 45.93% of cases had synchronous polyps, 17.0% advanced
      polyps, and 5.8% synchronous cancer. The incidence of synchronous and advanced
      synchronous polyps was high in elderly (>or=60 year), male patients (p<0.05). In
      166 patients who had underwent postoperative colonoscopy after one year, 25.3%
      had metachronous polyps, 3.0% advanced polyps, and 0.6% metachronous cancer. The
      presence of synchronous polyps was associated with the risk of metachronous
      polyps (p<0.05). CONCLUSIONS: Complete colonic evaluation during perioperative
      period should be recommended to identify precancerous lesions, which can
      contribute to reduce the development of colon cancer.

PMID- 15034288
TI  - [Deoxycholic acid-induced signal transduction in HT-29 cells: role of NF-kappa B
      and interleukin-8].
AB  - BACKGROUND/AIMS: Deoxycholic acid (DCA) has been appeared to be an endogenous
      colon tumor promoter. In this study, we investigated whether DCA induces nuclear
      factor-kappa B (NF-kappa B) activation and IL-8 expression, and
      tauroursodeoxycholic acid (TUDC) inhibits this signaling in HT-29 cells. METHODS:
      After DCA treatments, time courses of NF-kappa B binding activity were determined
      by electrophoretic mobility shift assay (EMSA). Also, we performed Western
      blotting of I kappa B alpha to confirm NF-kappa B activation. Time and
      concentration courses of DCA-induced secretion of IL-8 were measured with ELISA
      in supernatants of cultured media from the cells. To evaluate the role of NF
      kappa B, IL-8 levels were assessed after pretreatment with using phosphorothioate
      modified anti-sense oligonucleotides (ODN). Moreover, DCA-induced secretions of
      IL-8 were measured after pretreatment with TUDC. RESULTS: DCA dose-dependently
      induced prominent NF-kappa B binding complexes from 30 min to 8 hr and
      degradation of I kappa B alpha. The secretions of IL-8 were increased with DCA
      (50-200 micro M) treatment in a time and dose-dependent manner. Pre-incubation of
      the cells with TUDC (0.1-10 micro M) for 2 hours caused significant decreases in
      DCA induced IL-8 secretion. However, transient transfection using p50 or p65 AS
      ODN showed no effect on IL-8 secretion. CONCLUSIONS: DCA may play as a colonic
      tumor promoter through anti-apoptotic effect of NF-kappa B activation and IL-8
      expression, and DCA-induced NF-kappa B independent IL-8 expression is inhibited
      by TUDC.

PMID- 15034289
TI  - [Therapeutic effect of the endoscopic N-butyl-2-cyanoacrylate injection for acute
      esophagogastric variceal bleeding: comparison with transjugular intrahepatic
      portosystemic shunt].
AB  - BACKGROUND/AIMS: Though endoscopic therapies such as variceal ligation and
      sclerotherapy has been performed, bleeding from the large esophageal and gastric
      varices still poses significant risk of death. Decrease of portal pressure by
      TIPS (transjugular intrahepatic portosystemic shunt) or surgical shunt was
      indicated as cause of failure of endoscopic therapies. Treatment of N-butyl-2
      cyanoacrylate has been especially effective for gastric variceal bleeding, but
      comparison with other treatments had not been reported yet. In this study, the
      effect of cyanoacrylate injection therapy was cross-examined with the result of
      TIPS in acute esophagogastric variceal bleedings. METHODS: From April 1995 to
      June 2002, endoscopic cyanoacrylate injection therapy (43 cases) and TIPS (63
      cases) were performed in our hospital. Each group was analysed regarding their
      clinical results including initial hemostasis rate, rebleeding rate, survival
      duration, mortality and morbidity. RESULTS: Initial hemostasis rate was 95.3% in
      cyanoacrylate group and 92.1% in TIPS group. Cumulative probability of rebleeding
      was not different between two groups. Overall complication rates associated with
      the procedure were 50.8% in TIPS group and 9.3% in cyanoacrylate group. There was
      no significant difference between two groups in their survival rates.
      CONCLUSIONS: Cyanoacrylate injection therapy was relatively safe, and has
      comparable results with TIPS for uncontrollable and severe esophagogastric
      variceal bleedings.

PMID- 15034290
TI  - [Therapeutic efficacy of balloon-occluded retrograde transvenous obliteration in
      the treatment of gastric varices in cirrhotic patients with gastrorenal shunt].
AB  - BACKGROUND/AIMS: Rupture of gastric varices was one of the most dreadful
      complications of cirrhosis. Recently, a new interventional procedure, balloon
      occluded retrograde transvenous obliteration (B-RTO) was introduced for the
      treatment of gastric variceal bleeding. This study was performed to evaluate the
      therapeutic efficacy of B-RTO in the treatment of gastric varices with gastro
      renal shunts. METHODS: From March 2000 to June 2003, we performed B-RTO in 17
      patients with gastric varices and gastrorenal shunts. All patients had history or
      high risk factors of gastric variceal bleeding. For the evaluation of therapeutic
      efficacy, we performed esophagogastroduodenoscopy (EGD) and computed tomography
      (CT) at 1, 6 and 12 months after B-RTO. Successful B-RTO was judged by combined
      CT findings and EGD findings (disappearance of gastric varices or markedly
      reduced gastric variceal size or bleeding risk) during follow-up periods (1-14
      months, mean:6.18). We analyzed the clinical factors related to clinical success
      of B-RTO. RESULTS: Technical success were achieved in all patients except one
      (94.1%). Gastric varices were disappeared or decreased after B-RTO in 13 patients
      (81.2%). Complications related to procedure included transient hematuria (n=5),
      puncture site oozing (n=1) and partial splenic infarction (n=1), and all were
      conservatively managed. During the follow up periods, neither significant hepatic
      nor renal functional damages occurred. Statistically, no significant factors
      related with B-RTO success. CONCLUSIONS: B-RTO is effective and safe in the
      management of gastric varices in cirrhotic patients with gastrorenal shunt.

PMID- 15034292
TI  - A case of Brunner's gland hamartoma presenting as obscure gastrointestinal
      hemorrhage.
AB  - Brunner's gland hamartomas are rare tumors of duodenum, they are often discovered
      incidentally during esophagogastroduodenoscopy or upper gastrointestinal series.
      These tumors arise mainly in the duodenal bulb and can present with
      gastrointestinal hemorrhage and intestinal obstruction. Most of Brunner's gland
      hamartomas are located within the range of the standard
      esophagogastroduodenoscope. However, they are rarely located below the third
      portion of duodenum. As well known, the small intestine, including the 4th
      portion of duodenum, jejunum, and ileum, is relatively inaccessible with routine
      endoscopy. Thus, the diagnosis of Brunner's gland hamartoma in these area can be
      delayed up to several months after onset of symptoms. We report a case of
      Brunner's gland hamartoma which was located in the fourth portion of the duodenum
      and presented as obscure gastrointestinal hemorrhage. Radiologic, surgical, and
      pathologic appearances are presented.

PMID- 15034291
TI  - [Type of electric currents used for standard endoscopic sphincterotomy does not
      determine the type of complications].
AB  - BACKGROUND/AIMS: The blended current is usually used for endoscopic
      sphincterotomy (EST) to minimize bleeding. The pure cutting current may induce
      less edema of the ampulla and therefore result in less injury to the pancreas
      theoretically. The aim of this study was to evaluate effects of electric currents
      used on the development of serum pancreatic enzyme evaluation, clinical
      pancreatitis or bleeding after EST. METHODS: One hundred and eighteen consecutive
      patients who underwent EST with standard papillotome alone for the treatment of
      choledocholithiasis were reviewed. All EST had been performed by two endoscopists
      whose experience on EST was similar: one uses 'blended current' (BC group, n=74),
      while the other uses 'pure cutting current' (PC group, n=44). RESULTS: Baseline
      clinical, laboratory, and procedural parameters were similar in both groups. The
      incidences of hyperamylasemia and hyperlipasemia were similar between two groups.
      There was no significant difference in the incidence of clinical pancreatitis
      between two groups (BC 6.8% vs PC 0.0%, p=0.1557). All episodes of pancreatitis
      were mild. No episodes of significant bleeding occurred after EST. The incidences
      of sepsis, cholangitis and perforation were also not different between two
      groups. CONCLUSIONS: Development of complications after standard EST such as
      hyperamylasemia, clinical pancreatitis, and bleeding may not depend on the
      electric current used.

PMID- 15034293
TI  - [A case of metastatic hepatocellular carcinoma of the ovary].
AB  - Although advances in imaging technology have allowed for earlier detection of
      disease, hepatocellular carcinoma is usually asymptomatic and discovered at an
      advanced stage with metastasis. The most common sites of metastasis include lung,
      peritoneum, adrenal gland, and bone, but rarely, the nasal cavity, orbit,
      gallbladder, and ovary can be metastatic sites. We experienced a case of
      metastatic hepatocellular carcinoma of the ovary in a living patient. The
      differential diagnosis includes hepatoid yolk sac tumor of the ovary, primary or
      metastatic hepatoid carcinoma and primary or metastatic oxyphil cell tumor of the
      ovary. To the best of our knowledge, there have been eight cases of metastatic
      hepatocellular carcinoma of the ovary in the English literature and only six
      cases discovered in living patients. This is the first report of a metastatic
      hepatocellular carcinoma of the ovary in Korea.

PMID- 15034295
TI  - Inadvertent cancer research.

PMID- 15034294
TI  - Glucocorticoids induce G1 arrest of lymphoblastic cells through retinoblastoma
      protein Rb1 dephosphorylation in childhood acute lymphoblastic leukemia in vivo.
AB  - Childhood Acute Lymphoblastic Leukemia (ALL) represents approximately 40% of
      pediatric cancers, but molecular mechanisms involved in the therapeutic
      resistance of ALL are still unclear. The disregulation of cell cycle could be a
      mechanism of progression of leukemic blasts and glucocorticoids (GCs), the main
      pharmacological agent in the treatment of ALL, could affect cell cycle
      distribution. In our study we have evaluated cell cycle distribution and the
      expression of several molecules involved in cell cycle regulation in blasts
      collected from 32 patients with ALL before and 48 h after treatment with GCs. A
      significant increase of the percentage of ALL blasts in G(0)/G(1) phase was
      recorded after treatment with GCs in 22 (69%) out of 32 patients and 18 of these
      patients were also good responders to GC therapy. In these patients an increase
      of the expression of at least one of the 4 evaluated CDKIs (p15, p16, p21 and
      p27) was found in 29 out of 32 patients (90.6%) without any change in CDK2 and 4
      expression. All patients expressed detectable levels of Rb-1 phosphorylation at
      the diagnosis. Twenty (63%) patients showed a decrease, while two patients showed
      an increase of p110 Rb-1 phosphorylation and no changes were detected in the
      remaining 10 patients after GC therapy. The univariate analysis showed that the
      reduction of pRb-1 phosphorylation was significantly higher in B-cell lineage
      patients and in good responders. In conclusion, this is the first report that
      evaluate the Rb-1 function as predictor of response in childhood ALL and our data
      suggest that its hypophosphorylation and, consequently, reduced activity
      correlates with a statistical significance with the responsiveness to GC therapy.
      These results suggest that Rb-1 can be a useful molecular target for the therapy
      of this subset of patients.

PMID- 15034296
TI  - Cycling without the cyclosome: modeling a yeast strain lacking the APC.
AB  - The construction of viable Saccharomyces cerevisiae strains that lack the
      anaphase promoting complex (APC) was recently reported. The normally lethal
      deletions of APC genes were suppressed by the double deletion of the PDS1 and
      CLB5 genes in conjunction with the insertion of multiple copies of the SIC1 gene
      controlled by its endogenous promoter. It was proposed that cyclic expression and
      degradation of Sic1 results in oscillations of Clb/CDK activity necessary for the
      cell cycle. We have used an updated version of a mathematical model of the yeast
      cell cycle to model strains that lack the APC. With a few modifications, the
      model accurately simulates the viability of Apc- strains, as well as the
      phenotypes of 27 other previously characterized strains. We discuss a few minor
      inconsistencies between the model and experiment, and how these may inform future
      revisions to the model.

PMID- 15034297
TI  - Cellular targets of the SV40 small-t antigen in human cell transformation.
AB  - SV40 LT and ST antigens cooperate to induce the proliferation and eventual
      transformation of several human cell types. In natural virus infections, ST often
      enhances the function of LT when both proteins are present, and it can be
      difficult to completely separate the roles of the individual proteins. By
      studying ST in the absence of LT or by replacing ST function with combinations of
      cellular proteins, several themes have emerged which help define the requirement
      for ST in human cell transformation. These include the activation of
      transcription of two cyclins, D and A, along with downregulation of the cyclin
      kinase inhibitor p27. Modification of these key cell cycle regulators may be
      influenced by the activation of key downstream targets in the PI3K pathway.

PMID- 15034298
TI  - Activation of the DNA damage response by telomere attrition: a passage to
      cellular senescence.
AB  - Critical telomere shortening induces senescence in many normal human cell types
      grown in culture. Recent data have revealed that dysfunctional telomeres can
      resemble certain forms of DNA damage, and point to a role for DNA damage
      signaling in the establishment and maintenance of telomere-initiated senescence.
      Here, we review these new observations and highlight potential avenues of future
      research. We consider the identities of the key DNA damage response factors
      involved in senescence and discuss a model for the molecular events occurring in
      pre-senescent cells that ultimately lead to a permanent cell cycle arrest
      phenotype.

PMID- 15034299
TI  - Double strand break metabolism and cancer susceptibility: lessons from the mre11
      complex.
AB  - Hypomorphic mutants affecting the Mre11 complex components Mre11
      (Mre11(ATLD1/ATLD1)) and Nbs1 (Nbs1(DeltaB/DeltaB)) have been established in the
      mouse. These mutations recapitulate those inherited in human chromosome fragility
      syndromes, the ataxia-telangiectasia like disorder and Nijmegen breakage
      syndrome. At the cellular level, the human and murine mutants exhibit defects in
      the intra S and G2/M checkpoints and marked chromosome instability. Whereas these
      outcomes are associated with predisposition to malignancy in humans, similar
      predisposition was not observed in either Mre11(ATLD1/ATLD1) or
      Nbs1(DeltaB/DeltaB) mice. These data demonstrate that chromosome breakage per se
      is insufficient to significantly enhance the initiation of tumorigenesis.
      However, these mutations greatly enhanced the risk of malignancy in p53+/- mice.
      We propose that proper metabolism of chromosome breaks arising during DNA
      replication is uniquely important for suppressing loss of heterozygosity and thus
      the penetrance of recessive oncogenic lesions.

PMID- 15034301
TI  - New pathways to pancreatic cancer.

PMID- 15034300
TI  - Identification of toposome, a novel multisubunit complex containing topoisomerase
      IIalpha.
AB  - Topoisomerase IIalpha plays essential roles in chromosome segregation. However,
      it is not well understood how topoisomerase IIalpha exerts its function during
      mitosis. In this report, we find that topoisomerase IIalpha forms a multisubunit
      complex, named toposome, containing two ATPase/helicase proteins (RNA helicase A
      and RHII/Gu), one serine/threonine protein kinase (SRPK1), one HMG protein
      (SSRP1), and two pre-mRNA splicing factors (PRP8 and hnRNP C). Toposome separates
      entangled circular chromatin DNA about fourfold more efficiently than
      topoisomerase IIalpha. Interestingly, this decatenation reaction yields knotted
      circles, which are not seen in reactions provided with monomeric circular DNA.
      Our results also show that interaction among toposome-associated proteins is
      highest in G2/M phase but drastically diminishes in G1/S phase. These results
      suggest that toposome is a dynamic complex whose assembly or activation is
      subject to cell cycle regulation.

PMID- 15034302
TI  - TGFbeta1, back to the future: revisiting its role as a transforming growth
      factor.
AB  - TGFbeta1 was initially identified in culture media from transformed cells as part
      of a factor that could produce a transformed phenotype in a nontransformed cell
      line. Subsequently this activity was separated into TGFbeta and TGFalpha an EGF
      receptor ligand. With the discovery that TGFbeta1 was a potent growth inhibitor
      of epithelial cells, and the identification of inactivating mutations within the
      TGFbeta1 signaling pathway in cancers it became clear that TGFbeta1 signaling is
      a tumor suppressor pathway for early stages of cancer. However many human
      carcinomas overexpress TGFbeta1 and this is associated with poor patient
      prognosis and increased frequency of metastasis. Similar results have been
      obtained with tumor cell lines and experimental animal models. Thus stage
      specific duality of function is the emerging paradigm for the role of TGFbeta1 in
      cancer. This review will focus on the evidence for TGFbeta1 as a tumor promoting
      and metastasis factor and examine the biological and molecular basis for these
      effects. It is proposed that the switch from tumor suppressor to oncogene
      reflects genetic or epigenetic alterations in signaling pathways in tumor cells
      that alter the readout from the TGFbeta1 pathway.

PMID- 15034304
TI  - A portrait of AKT kinases: human cancer and animal models depict a family with
      strong individualities.
AB  - More than a decade after their discovery, the three AKT kinase family members
      have emerged as central players in the signaling cascades that regulate cell
      growth, proliferation, survival and various aspects of intermediary metabolism.
      The mechanisms of activation of AKT kinases have been defined in relatively
      precise terms and new substrates are currently being validated in vivo. However,
      it is presently unclear whether AKT1, AKT2 and AKT3 are functionally redundant or
      whether each one performs specific functional role(s). In this review, we will
      summarize the signaling properties and highlight the specificities of AKT kinases
      that have emerged from the study of human cancer and animal models. While AKT
      kinases are an attractive target for pharmacological intervention, knowledge of
      the precise individual roles of AKT family members will improve the design of
      highly specific AKT-based therapeutics having reduced toxicity and improved
      efficacy.

PMID- 15034305
TI  - The frequency of homologous recombination in human ALT cells.
AB  - Instead of telomerase, some immortal cells use the alternative lengthening of
      telomeres pathway (ALT) to maintain their telomeres. There is good evidence that
      homologous recombination contributes to the ALT mechanism. Using an inducible GFP
      reporter system to measure the frequency of homologous recombination, we asked
      whether or not ALT cells exhibited a general change of the recombination
      machinery. Our results show that the frequency of homologous recombination for
      non-telomeric sequences in ALT cells is identical to that in telomerase positive
      cells, irrespective of whether the reporter was present at an intra-chromosomal
      location or next to a telomeric sequence. We conclude that the underlying
      recombination defect in ALT cells is restricted to telomeric sequences.

PMID- 15034306
TI  - EURO-EUS 2003: pancreatic tumor: impact of endoscopic ultrasonography on
      diagnosis, staging and treatment.

PMID- 15034307
TI  - Oncogenic tyrosine kinases, DNA repair and survival: the role of Bcl-xL
      deamidation in transformation and genotoxic therapies.
AB  - Dysfunctional tyrosine kinases comprise an important class of oncogenes. We have
      generated a mouse model in which an oncogenic tyrosine kinase (OTK) causes T
      lineage tumors. The model facilitates investigation of early oncogenic events in
      pretumorigenic thymocytes. The OTK transforms thymocytes by a 'double whammy'
      mechanism whereby on the one hand it inhibits DNA repair, leading to genomic
      instability, and on the other blocks DNA damage-induced apoptosis. The OTK
      mediated blockade of apoptosis involves inhibition of DNA-damage triggered Bcl-xL
      deamidation, thereby preserving the protein's pro-survival functions. The
      pharmaceutical promotion of Bcl-xL deamidation might render cancer cells more
      sensitive to genotoxic attack.

PMID- 15034303
TI  - MDR1 promoter hypermethylation in MCF-7 human breast cancer cells: changes in
      chromatin structure induced by treatment with 5-Aza-cytidine.
AB  - Resistance to the cytotoxic actions of antineoplastic drugs, whether intrinsic or
      acquired, remains a barrier to the establishment of curative chemotherapy
      regimens for advanced breast cancer. Over-expression of P-glycoprotein (P-gp),
      encoded by the MDR1 gene and known to mediate resistance to many antineoplastic
      drugs, may contribute to poor breast cancer treatment outcome. Nonetheless, the
      precise molecular mechanisms responsible for high or low level P-gp expression in
      breast cancer cells have not been established. We assessed the role of DNA
      hypermethylation near the MDR1 transcriptional regulatory region in MDR1
      expression in MCF-7 breast cancer cells, which fail to express MDR1 mRNA, and MCF
      7/ADR cells, known to express high MDR1 mRNA levels. When compared to MCF-7/ADR
      cells, MCF-7 cells manifested markedly diminished MDR1 transcription rates by
      nuclear run-off assay, but equivalent MDR1 promoter trans-activation activity in
      transient transfection experiments, indicating that cis factors were most likely
      responsible for the differences in MDR1 transcription between MCF-7/ADR cells and
      MCF-7 cells. Bisulfite genomic sequencing analyses revealed substantially less
      extensive MDR1 promoter methylation in MCF-7/ADR cells than in MCF-7 cells,
      suggesting that CpG dinucleotide methylation might contribute to the observed
      MDR1 transcription differences. Chromatin immunoprecipitation analyses indicated
      an inactive MDR1 chromatin conformation in MCF-7 cells, with a paucity of
      acetylated histones and the presence of 5-mC-binding proteins MeCP2 and MBD2, and
      an active MDR1 chromatin conformation in MCF-7/ADR cells, with an abundance of
      acetylated histones and the presence of the transcriptional trans-activator YB-1.
      Stable MCF-7 sublines which had been treated with the DNA methyltransferase
      inhibitor 5-azacytidine, exhibited a reduction in MDR1 promoter methylation and a
      complex MDR1 chromatin configuration, characterized by the simultaneous presence
      of transcriptional activators and repressors. In this state, MDR1 expression was
      markedly sensitive to treatment with the histone deacetylase inhibitor
      trichostatin A.

PMID- 15034309
TI  - Enterococci: susceptibility patterns and therapeutic options.
AB  - Enterococcal isolates are increasingly responsible for nosocomial infections in
      the last decade and they are recently cited as being the second most common
      pathogen isolated from hospitalized patients. Enterococcal infections can be
      localized at different sites: endocarditis, CNS, intrabdominal, pelvic. The
      epidemiological trend may be a consequence of predisposing risk factors due to
      hospitalization such as instrumentation, immunosuppression, long-term
      hospitalization. Nevertheless the most alarming aspect of the problem is the
      increasing detection of antibiotic resistance Enterococcal strains, especially
      the high level resistance (HLR) to aminoglycosides, penicillin and glycopeptides
      must not be underestimated. Optimal antibiotic regimes for the treatment of
      multiple resistant strains in severe enterococcal infections are not been defined
      yet and antibiotic association such as aminoglycosides + glycopeptides or
      glycopeptides + fluoroquinolones could be suggested.

PMID- 15034308
TI  - [Not Available].
AB  - Rhodococcus equi is a facultative intracellular, obligate aerobe, partially acid
      fast, gram-positive pathogen that causes cavitary pneumonia in animals and
      immunocompromised humans. We describe 8 cases of R. equi pneumonia in patients
      with advanced HIV infection (CD4 counts less than 100/mm3), 7 males and 1 female
      (mean age 30.8 years), observed between 1991 and 1994. A history of exposure to
      farm animals was found in 4 patients. The most common presenting symptoms were
      fever, malaise, dyspnea, cough and hemoptysis, chest pain and weight loss. Chest
      x-rays showed tipical focal area of consolidation throughout the lung (3 upper, 3
      lower and 2 middle fields) associated with cavitation in 4 cases. The definitive
      diagnosis in our hands was delayed only in the first case in which conflicting
      data resulted from blood culture (Bacillus sp. isolation) and sputum examen (acid
      fast bacterium in the Ziehl-Neelsen stain). Final microbiological diagnosis
      depended on blood cultures (n=5), bronchoalveolar lavage (n=1), sputum (n=1),
      lung biopsy (n=1). All the patients were treated with prolonged courses of
      antibiotic therapy (259 days, range 120-340 in 6 dead patients; more than one
      year and two months respectively in two patients alive). According to microbial
      susceptibility TMP/SMX, vancomycin, imipenem, rifampin, aminoglycosides,
      macrolides and quinolons were more frequently used. Resistant R. equi mutants
      were selected during therapy with TMP/SMX (n=2), rifampin (n=1) and erythromycin
      (n=1). Five patient underwent pulmonary lobectomy after exclusion of metastatic
      bacterial lesions. Only 2 patients are alive, one after 365 days of antibiotic
      therapy and upper lung lobectomy, one after 60 days of antibiotic therapy.
      Optimal antimicrobial therapy and the role of surgery remain, in our experience,
      uncertain.

PMID- 15034310
TI  - Audit of Pseudomonas aeruginosa in a general hospital in Saudi Arabia.
AB  - All isolates of Pseudomonas aeruginosa in our laboratory from hospitalised
      patients were collected over a 4-month period in 1993/94. Details of the patients
      including length of stay, transfer from another hospital, nationality, diagnosis
      and antibacterial treatment were noted. Each patient was assessed as to whether
      the first isolate during the study period was of clinical significance and
      whether the infection or colonization was nosocomially acquired. The isolates of
      P. aeruginosa were identified and sensitivity was determined by recognized
      methods. Isolates were serotyped. 108 different patients were included in the
      study (median age 50 years, 58% males). 57/77 (74%) isolates where information
      was noted were nosocomial acquired. Length of patient stay for the nosocomial
      acquired isolates ranged from less than 1 day to more than 1 year. 19% of
      patients were transfers from other hospitals. Clinical significance was graded
      31% isolates were judged to be highly significant and 44% to have little or no
      clinical significance. 41% isolates were from superficial sites including wounds,
      27% from respiratory sites, 23% from urine and 6% were from blood cultures. Heavy
      growth of P. aeruginosa was correlated with clinical significance. Coliforms were
      the other organisms most frequently isolated with the P. aeruginosa but highly
      significant isolates were usually in pure culture. Serotypes 11, 2 and 4 were the
      dominant isolates. Serotype 11 was also the most common environmental isolate
      from the hospital. 60% patients were receiving antibacterial agents when the
      sample was taken but only 12% patients were receiving potentially anti
      pseudomonal agents.

PMID- 15034311
TI  - [Not Available].
AB  - The authors briefly report the epidemiological status of HIV-1 and HIV-2
      infections among patients affected by tuberculosis in Guinea Bissau and evaluate
      the therapeutic follow up in 177 patients contemporarily affected by TBC and HIV
      2 infection. The evaluation of the surviving times has been done according to the
      Kaplan-Meier curve by considering the following determinants: 1) sex; 2) sputum
      positive for acid-fast bacilli; 3) age range: A) 10-30 years - B) 31-45 years -
      C) more than 45 years. The total number days/person was 1417. The drop out was
      moderate. The serum prevalence for HIV-2 in patients affected by tuberculosis in
      Guinea Bissau is about 20% but in the last two years HIV-1 infection is
      increasing. There is no significant difference in the surviving curves due to the
      sex. Tbc-HIV-2+ patients have a longer survival than tbc-HIV-1+ patients reported
      by European and North America epidemiological data. The present epidemiological
      data were obtained in an African environment and, due to the low financial
      support, it was not possible to correlate them with the immunological and
      microbiological ones.

PMID- 15034312
TI  - [Not Available].
AB  - The author describes three cases of pirogenic reaction in patients in treatment
      with hemodialysis: Pseudomonas aeruginosa and Enterobacter cloacae were isolated
      from water of dyalisis machines. He, moreover, analyses different antibacterial
      decontamination systems

PMID- 15034313
TI  - [Colera therapy in the 30th year of the 19th century].

PMID- 15034314
TI  - [Bacterial infections in intensive care units: etiology and pathogenesis].
AB  - Bacterial infections represent the main cause of morbidity and mortality in
      Intensive Care Units (ICU). The infections developed in ICU correspond to 24% of
      the overall nosocomial infections. Endogenous bacterial flora sustains 85% of
      infectious episodes. In fact in ICU cutaneous, oro-pharyngeal and gastro
      intestinal flora are substantially modified being replaced by nosocomial
      microrganisms which will become responsible for sepsis and infections localized
      at respiratory and urinary tract. The Authors review these main diseases acquired
      in ICU analysing the epidemiologic features, pathogenesis, ways of transmission
      and diagnostic criteria. Finally it is underlined the importance of microbiology
      in any surveillance program of ICU acquired infections. It is desirable that each
      unit carries out an epidemiological evaluation by means of own microbiological
      data in order to establish, together with clinical epidemiologists and infectious
      diseases specialists, accurate programs of prevention.

PMID- 15034315
TI  - [Bacterial meningitis and CSF cytokines].
AB  - Aim of study is the determination of concentrations of two important cytokines:
      TNF alfa and IL8 in children with bacterial meningitis to establish a correlation
      between infection, CSF concentration of cytokines and neurological sequelae. TNF
      alfa and IL8 concentrations in CSF have been measured by quantitative
      immunometric enzyme assay during the course of the disease. In the purulent
      meningitis we observed that CSF concentrations of these cytokines decreased to
      undectable values 24 to 48 hours after beginning of the antibiotic therapy.
      Conversely, in the 3 patients with mycobacterial meningitis (TBM) the
      concentrations of IL8 were higher for a longer period, being detectable in the
      CSF between 4 and 8 weeks after the beginning of the specific treatment. We found
      no significant differences of the values of IL8 in children with neurological
      sequelae compared with children without sequelae.

PMID- 15034316
TI  - [Anti-HAV screening patients with chronic hepatitis].
AB  - Following the decrease in HAV endemic levels in the last decades, nowadays in
      Italy most people aged less than 30 years are susceptible to the infection. We
      have tested for serum anti HAV IgG 194 chronic hepatitis patients from Naples to
      evaluate the level of protection against HAV in a category of patients in whom an
      acute necrosis due to HAV might induce liver failure. The study shows that 90.7%
      of Neapolitan chronic hepatitis patients has serologic evidence of prior HAV
      infection. Specifically, 98.1% of the patients over 40 years of age, but only
      54.6% of those under 40 tested positive for anti HAV IgG. 102 patients had
      cirrhosis and only one tested negative. The data suggest that HAV vaccination in
      susceptible chronic hepatitis patients should be judged by the physicians in care
      on the basis of the severity of disease, patient's age, real risk of exposure to
      the infection, and level of education.

PMID- 15034317
TI  - The ursodeoxycholic acid for the treatment of HCV infections.
AB  - Hepatitis C is a very serious disease. If it is not treated, it leads to chronic
      hepatitis and cirrhosis in 50% and 20% of cases, respectively. Furthermore,
      patients with cirrhosis might develop hepatocarcinoma. Interferon seems to be the
      therapy of choice in the treatment of the disease. However, since the molecule
      cannot always be used (non-compliant patient; severe side effects; liver
      associated pathologies; patient age) alternative therapies have been
      investigated. Ursodeoxycholic acid (UDCA) stands out among recommended non
      antiviral molecules. 74 patients affected by HCV chronic infections were enrolled
      in this single-blind study. One group (A: 37 patients) was treated with UDCA (600
      mg/day for 12 months) and compared with a control group (B: 37 patients) in order
      to assess the therapy efficacy in reducing cytolysis index and to estimate
      viraemia and histologic score variation. RESULTS: 13 patients did not complete
      the study (8 belonging to group A; 5 to group B). 65,5% of the patients treated
      with UDCA showed ALT reduction; 42,1% of them with complete response. The
      situation remained unchanged in 15 patients all the treatment along. In the group
      B, only 12,5% showed a significant ALT reduction. During the follow-up, in 69,4%
      of group-A responders ALT was found to return to pre-treatment values. No
      variation was observed in the viraemia and histologic score of patients who had
      accepted a control biopsy. CONCLUSIONS: UDCA is undoubtedly suitable for reducing
      cytolysis index in patients with HCV chronic infections. It is well tolerated but
      it does not modify the disease natural course.

PMID- 15034318
TI  - [Spontaneous bacterial peritonitis in patients with liver cirrhosis. Differential
      aspects with portal thrombosis].
AB  - In a series of 155 patients with decompensated liver cirrhosis spontaneous
      bacterial peritonitis (SBP) was diagnosed in 15 cases (9.7%) and portal
      thrombosis (PT) in 8 (5.1%) by mean of standard criteria. The main clinical and
      laboratory characteristics were similar in the two groups of patients; fever was
      more frequently recorded in the SBP patients. Cytological examination of the
      ascites showed an increase in total cell count and in neutrophils count higher in
      SBP group than in PT. The diagnosis of PT was confirmed by ultrasonography. The
      data suggest that a cytological examination of the ascites should be performed in
      all patients with decompensated cirrhosis and may contribute to the differential
      diagnosis of SBP or PT.

PMID- 15034319
TI  - [HIV Antigens as complement fixing circulating immune complexes].
AB  - To detect HIV antigens in circulating complement fixing immune complexes (ICs) we
      assessed an ELISA using wells of microtitre plates coated with F(ab)2 anti-C3b
      and monoclonal antibodies anti-HIV gp120 and anti-HIV p24. We tested 24 anti-HIV
      positive subjects (Group A), 10 anti-HIV negative subjects at risk of acquiring
      HIV infection (Group B), 20 normal controls (Group C) and 2 seroconversion
      panels. We found HIV antigens in ICs in all sera from seroconversion panels, in
      25.5% of sera from subjects in Group A, in 28.6% of sera from subjects in Group B
      and in no serum from subjects in Group C. A subject in Group B acquired HIV
      infection during the observation. HIV antigens in ICs by our assay were detected
      8 months before Anti-HIV and Ag by commercial ELISA.

PMID- 15034320
TI  - [Neurological disorder associated to EBV: three case reports].
AB  - Epstein-Barr virus (EBV) is associated with a wide range of clinical
      manifestations. Neurological involvement (NI) during Infectious Mononucleosis
      occur in 1-5% of the cases, the only NI is more rare. From January 1995 to
      December 1996 three patients with NI and EBV infection have been observed in our
      department. The diagnosis were: meningoradiculitis (1 case), meningoencephalitis
      (1 case), aseptic meningitis (1 case). The diagnosis was based on the results of
      the lumbar puncture and on the serology: IgM VCA positive at the onset of the
      symptoms and a significant increase of the IgG VCA after three weeks. No other
      etiology was apparent. All the patients have been treated with dexamethasone,
      glycerol and acyclovir obtaining a complete remission of the disease. In these
      cases the NI has been the only clinical manifestation of the EBV infection.
      Therefore the authors believe that it is important recognize that EBV can cause a
      myriad of neurological illness with or without the stigmata of infectious
      mononucleosis and recommend the need to suspect this infection in any acute
      neurologic disorder.

PMID- 15034321
TI  - [Intestinal amoebiasis with hepatic abscess: a case report].
AB  - The Authors report an imported case of intestinal amoebiasis with hepatic abscess
      in a Sicilian young man, living in Venezuela. The clinical aspects (anamnesis
      about residence in endemic area, abdomen disorders, pain in right hipocondrium,
      fever, hepatomegaly, slimming), the diagnostic aspects (faeces parasitologic
      test, bio-humoral and serological tests, ultrasonography, scintigraphy and T.C.
      of the liver) and therapy (medical and surgical treatment, drainage of abscess
      cavity) are described. Medical therapy (metronidazole plus chloroquine plus
      paronomycine) cleared up intestinal infection and reduced hepatic abscess.

PMID- 15034322
TI  - [Cholera in Bologna in XIX century. A brief report on the scientific knowledge of
      the period].

PMID- 15034471
TI  - [Proceedings of the 8th session on therapeutics and neurology: neuromuscular
      diseases. Paris, France, December 6-7, 2002].

PMID- 15034472
TI  - [Seronegative myasthenia gravis].
AB  - Six to 20 p.cent of patients with generalized myasthenia gravis and 30 to 50
      p.cent of those with ocular myasthenia gravis do not have anti AchR antibodies.
      Strict clinical, pharmacological and electrophysiological criteria are needed for
      the diagnosis of sero-negative myasthenia gravis. Sero-negative myasthenia gravis
      is an autoimmune disorder. But thymic hyperplasia is generally absent. Antibodies
      directed against the muscle receptor of tyrosine kinase (anti MuSK antibodies)
      were recently demonstrated in 40 to 70 p.cent of patients with sero-negative
      myasthenia gravis. Sero-negative and sero-positive myasthenia gravis may be
      clinically very similar. But sero-negative myasthenia gravis may express
      predominantly severe oculobulbar weakness or mainly neck, shoulder and
      respiratory muscle weakness. Sero-negative myasthenia gravis is never associated
      with thymoma. Sero-negative myasthenia gravis responds to immunodulation but
      perhaps less well than sero-positive myasthenia gravis.

PMID- 15034473
TI  - [Congenital myasthenic syndromes: phenotypic expression and pathophysiological
      characterisation].
AB  - Congenital Myasthenic Syndromes (CMS) are a heterogeneous group of diseases
      caused by genetic defects affecting neuromuscular transmission. The twenty five
      past Years saw major advances in identifying different types of CMS due to
      abnormal presynaptic, synaptic, and postsynaptic proteins. CMS diagnosis requires
      two steps: 1) positive diagnosis supported by myasthenic signs beginning in
      neonatal period, efficacy of anticholinesterase medications, positive family
      history, negative tests for anti-acetylcholine receptor (AChR) antibodies,
      electromyographic studies (decremental response at low frequency, repetitive CMAP
      after one single stimulation); 2) pathophysiological characterisation of CMS
      implying specific studies: light and electron microscopic analysis of endplate
      (EP) morphology, estimation of the number of AChR per EP, acetylcholinesterase
      (AChE) expression, molecular genetic analysis. Most CMS are postsynaptic due to
      mutations in the AChR subunits genes that alter the kinetic properties or
      decrease the expression of AChR. The kinetic mutations increase or decrease the
      synaptic response to ACh resulting respectively in Slow Channel Syndrome
      (characterized by a autosomal dominant transmission, repetitive CMAP,
      refractoriness to anticholinesterase medication) and fast channel, recessively
      transmitted. AChR deficiency without kinetic abnormalities is caused by recessive
      mutations in AChR genes (mostly epsilon subunit) or by primary rapsyn deficiency,
      a post synaptic protein involved in AChR concentration. Recently, mutations in
      SCN4A sodium channel have been reported in one patient. AChE deficiency is
      identified on the following data: recessive transmission, presence of repetitive
      CMAP, refractoriness to cholinesterase inhibitors, slow pupillary response to
      light and absent expression of the enzyme at EP. This synaptic CMS is caused by
      mutations in the collagenic tail subunit (ColQ) that anchors the catalytic
      subunits in the synaptic basal lamina. The most frequent presynaptic CMS is
      caused by mutations of choline acetyltransferase. Several CMS are still not
      characterized. Many EP molecules are potential etiological candidates. In these
      unidentified cases, other methods of investigations are required: linkage
      analysis, when sufficient number of informative relatives are available,
      microelectrophysiological studies performed in intercostal or anconeus muscles.
      Prognosis of CMS, depending on severity and evolution of symptoms, is difficult
      to assess, and it cannot not be simply derived from mutation identification. Most
      patients respond favourably to anticholinesterase medications or to 3,4 DAP which
      is effective not only in presynaptic but also in postsynaptic CMS. Specific
      therapies for slow channel CMS are quinidine and fluoxetine that normalize the
      prolonged opening episodes. Clinical benefits derived from the full
      characterisation of each case include genetic counselling and specific therapy.

PMID- 15034474
TI  - Lambert-Eaton myasthenic syndrome.
AB  - The Lambert-Eaton Myasthenic Syndrome (LEMS) is characterised by proximal muscle
      weakness initially affecting gait, autonomic symptoms (dry mouth, constipation,
      erectile failure), augmentation of strength during initial voluntary activation,
      and depressed tendon reflexes with post-tetanic potentiation. The disorder is
      paraneoplastic (small cell lung cancer) in about 60p. cent (P-LEMS); no cancer is
      associated in the remainder (NP-LEMS). LEMS affects all races. NP-LEMS can occur
      in childhood as well as adult life; P-LEMS is unusual at<30 Years. The weakness
      results from a reduction in the quantal release of acetylcholine from motor nerve
      terminals, caused by autoantibodies to P/Q-type voltage-gated calcium channels
      (VGCCs) that are provoked by tumour VGCCs in P-LEMS; the stimulus in NP-LEMS is
      not known. These antibodies may be implicated in the rarely associated cerebellar
      degeneration. The diagnosis can be confirmed by detecting the specific antibody
      in a radioimmunoprecipitation assay, and by finding a reduced compound muscle
      action potential amplitude that increases by>100p. cent following maximum
      voluntary activation. Most patients benefit from 3,4-diaminopyridine;
      pyridostigmine is less effective. Specific tumour therapy in P-LEMS will often
      ameliorate the neurological disorder. In those with severe weakness, IVIg or
      plasmapheresis confers short-term benefits. Prednisone alone or combined with
      azathioprine or cyclosporin can achieve long-term control of the disorder.

PMID- 15034475
TI  - [Molecular diagnosis of hereditary neuropathies such as Charcot-Marie-Tooth
      disease].
AB  - During the last decade, molecular biology has demonstrated the extraordinary
      heterogeneity of genetic abnormalities in Charcot-Marie-Tooth disease (CMT). The
      main phenotypes are either of the demyelinating or axonal type, transmitted with
      dominant or recessive autosomal inheritance. X-linked CMT is less rare than it
      was initially described and is often misdiagnosed as autosomal dominant type.
      Linked phenotypes are Dejerine-Sottas disease, congenital hypomyelinization and
      hereditary neuropathy with susceptibility to pressure palsies. Each phenotype can
      be due to different genotypes and concerned genes are numerous. Conversely, each
      genotype can express different phenotypes. Molecular diagnostic strategy of CMT
      is mainly baised on three elements: - phenotypic expertise which is based on the
      analysis of the inheritance mode and on electrophysiological data, which are
      peculiar in CMTX - knowledge of respective occurrence of the different genotypes
      and phenotypes which is increasing - technical feasibility of molecular biology
      methods which is important to consider, even though progress are fastly coming.
      According to these considerations, a strategy is proposed for molecular diagnosis
      of CMT.

PMID- 15034476
TI  - [Paraneoplastic peripheral neuropathies].
AB  - Paraneoplastic peripheral neuropathies constitute a heterogeneous group of
      conditions. A link between the tumor and the neuropathy has been demonstrated in
      a subgroup only. Definite paraneoplastic neuropathies correspond to neuropathies
      associated with antibodies reacting with antigens common to the peripheral
      nervous system and the cancer. Neuropathies associated with anti-Hu antibodies
      are the most frequent and consist mainly in subacute sensory neuronopathy.
      Sensory or sensory-motor neuropathies with anti-CV2 antibodies are less frequent.
      The link between the cancer and the neuropathy is less clear in the other forms.
      The frequency of cancer in this group varies from 1 to 18 p.cent.These
      neuropathies include inflammatory demyelinating neuropathies, neuropathy and
      vasculitis, lower motor neurone diseases, and autonomic neuropathies.
      Occasionally, the neuropathy improves with treatment of the tumor. Recent data
      suggest that gangliosides may be the target of the immune process in neuropathies
      associated with melanoma.

PMID- 15034477
TI  - [Neuropathic pain: experimental advances and clinical applications].
AB  - Neuropathic pain is a clinical entity designating the different types of pain
      associated with a lesion of the nervous system including a wide range of
      pathological conditions from painful peripheral lesions (for example diabetic
      neuropathy, post-zoster pain, trauma-induced nerve injury) and central pain
      (particularly stroke-induced pain, spinal lesions, and multiple sclerosis).
      Despite this wide range of etiologies, neuropathic pain has well characterized
      clinical features which generally allow distinction from other types of pain:
      continuous often burn-like pain, paroxysmal pain (electrical discharge, knife
      stab), evoked pain, highly invalidating pain (allodynia, hyperalgesia), and
      associated dysethesia and/or paresthesia. Over the last ten Years, very little
      work has been published on neuropathic pain, which is now becoming a very active
      domain of research in neurobiology. Advances to date have not been spectacular
      although better tolerated agents have been recently marketed. Future progress
      should enable an appropriate response to the therapeutic challenge of neuropathic
      pain.

PMID- 15034478
TI  - [Recent acquisitions in the treatment of chronic immune-mediated
      polyneuropathies].
AB  - Chronic immune-mediated polyneuropathies encompass chronic inflammatory
      demyelinating polyneuropathies, polyneuropathies associated with monoclonal
      gammopathy and multifocal motor neuropathy with persistent conduction blocks.
      Their diagnosis is made on clinical, electrophysiological and sometimes
      immunochemical and pathological criteria. The efficacy of intravenous
      immunoglobulins has been reported in the short-term treatment of these
      neuropathies in the same way than corticosteroids and plasma exchanges, depending
      on the type of the polyneuropathy. The efficacy of long-term treatments needs
      further evaluation.

PMID- 15034479
TI  - [Distal myopathies].
AB  - Distal myopathies are a heterogeneous group of genetic disorders characterized
      clinically by progressive muscular weakness and atrophy beginning in the hands or
      feet, and pathologically by myopathic changes in skeletal muscles. Five distinct
      distal myopathies are identified, among them four have been recently defined by
      their gene and causative mutations. They are classified according to age at
      onset, mode of inheritance, and muscle groups initially involved into the
      following: Laing myopathy (infancy onset, autosomal dominant inheritance, onset
      in anterior compartment of legs) caused by mutations in a myosin gene (MYH7) on
      chromosome 14q; Nonaka myopathy (early adult onset, autosomal recessive
      inheritance, onset in anterior compartment of legs), identical to quadriceps
      sparing familial inclusion myopathy, caused by mutations in the GNE gene on
      chromosome 9p-q; Miyoshi myopathy (early adult onset, autosomal recessive
      inheritance, onset in posterior compartment of legs) caused by mutations in the
      dysferlin gene on chromosome 2p; Welander myopathy (late adult onset, autosomal
      dominant inheritance, onset in hands) linked to chromosome 2p; Udd/Markesbery
      Griggs myopathy (late adult onset, autosomal dominant inheritance, onset in
      anterior compartment of legs) caused by mutations in the titin gene on chromosome
      2q. Except for Miyoshi myopathy, which has a striking elevated serum creatine
      kinase level and the typical findings of muscular dystrophy, most of the distal
      myopathies have normal or midly elevated creatine kinase levels and share the
      common pathologic feature of rimmed vacuoles.

PMID- 15034480
TI  - [Exercise-intolerance and exercise-induced rhabdomyolisis: etiology and
      diagnosis].
AB  - Exercise intolerance, sometimes complicated by rhabdomyolysis is a frequent
      complaint of patients consulting in neuromuscular centers. It may be the main
      clinical manifestation of many metabolic myopathies and muscular dystrophies. The
      first step of diagnosis relies on the performance of in vivo metabolism
      investigations: forearm or bicycle ergometer exercise tests, phosphorus nuclear
      magnetic resonance spectroscopy. A few enzymatic defects may be directly assessed
      on blood samplings, in particular carnitine palmitoyltransferase deficiency; but
      muscle biopsy is necessary in most cases in order to precise the etiology. When
      CK levels are elevated at rest, a muscle CT scan should be performed in order to
      detect muscles fatty replacement suggestive of a muscular dystrophy; this
      diagnosis will be confirmed with immunohistochemical and western-blot analysis of
      muscle proteins. We present a description of the main metabolic myopathies
      manifesting by exercise intolerance with an overview of clinical and laboratory
      evaluation leading to diagnosis. Differential diagnosis are also discussed.

PMID- 15034481
TI  - [Spinal muscular atrophies in the adult].
AB  - Spinal muscular atrophies are heterogeneous group. The diagnostic process should
      be careful to uncover the main differential diagnoses and to identify familial
      cases. Clinical phenotype is highly variable. In familial ALS cases with SOD1
      mutation, the clinical scene may mimic spinal muscular atrophy. A careful
      questionning and a complete electroneuromyographic exam are warranted to allow
      the neurologist to choose among more invasive investigations for differential and
      positive diagnosis such as MRI, nerve or muscle biopsy, genetic analysis.

PMID- 15034482
TI  - [Post-polyiomyelitis syndrome].
AB  - Postpoliomyelitis syndrome is a clinical syndrome characterized by late
      progression of symptoms, neuromuscular weakness, fatigue and pain, several (more
      than 20) Years after acute anterior poliomyelitis. In the United States, where it
      has been mainly described, frequency is estimated between 20 and 30p.100 in
      patients with sequelae of poliomyelitis. Although the cause is still unknown,
      postpoliomyelitis syndrome is likely due to degeneration and dysfunction of
      terminal axons of enlarged post-polio units, with a possible role of inflammatory
      reaction driven by persistence of the polio virus. Due to lack of specific
      therapy, rational therapeutic approaches are symptomatic, including exercise,
      reassurance and life-strategies for fatigue.

PMID- 15034483
TI  - [Physiopathology of ALS: therapeutic approach].
AB  - The finding in 1993 of a mutation of the copper zinc super oxyde dismutase (SOD1)
      provides a major breakthrough in the understanding of the etiopathogenic
      mechanism of amyotrophic lateral sclerosis. Various mechanisms are commonly
      implied in the motor neurons degeneration. Excitotoxicity and calcium metabolism
      abnormalities are one of the most frequently confirmed hypotheses. It allowed
      proposing riluzole which remains the only one drug proved to be active in the
      disease. The role of growth factors remains controversial and all therapeutic
      trials performed with these molecules remained negative. Oxidative stress
      abnormalities are demonstrated by number of studies but their direct therapeutic
      application remains to be demonstrated. Apoptosis and the role of mitochondria
      has been definitely confirmed and open a new therapeutic avenue for the next few
      years.

PMID- 15034484
TI  - [Review of nutritional and respiratory support in ALS].
AB  - During the evolution of amyotrophic lateral sclerosis (ALS), quality of life and
      survival of patients are related to respiratory and nutritional status. After
      diagnosis, a multidisciplinary care has to be promptly organized and coordinated
      by the referring neurologist. The nutritional and respiratory support imply that
      neurologists know their specific means of evaluation with their sensitivity and
      sensibility and be able to recognize clinical risk situations. The informations
      of patients on assisted-ventilation and nutritional support by using gastrostomy
      may be done early, precisely and trustfully. Well informed patient's choices must
      be respected. Nutritional and respiratory supports may be based on
      recommendations established by the American Academy of Neurology. This review
      will present and discuss their main aspects in patients with ALS.

PMID- 15034485
TI  - [Genetic complexity of Alzheimer's disease].
AB  - The discovery of pathogenic mutations in the amyloid precursor protein (APP) gene
      and the presenilin (PS1, PS2) genes, causing familial early-onset AD has lead to
      the hypothesis of the amyloid cascade. The epsilon4 allele of the apolipoprotein
      E (APOE) gene, the only recognized genetic risk factor for AD, may be involved in
      the mechanism. However, to date, search for new genetic determinants has been
      hampered by methodological limitations. Some loci, for instance on chromosome 12,
      have been characterized by linkage studies performed in familial cases, but the
      regions of interest are very large and contain numerous genes. Furthermore,
      search for polymorphisms implicated in the development of AD, should not be
      limited to the coding part of the genes, but should also involve the non
      translated sequences of the genes, for instance in the regions regulating gene
      expression. Indeed, these genetic variations may have important impact on key
      proteins of the pathologic process. Although this task is difficult, the
      identification of new susceptibility genes should lead to a better understanding
      of the development of AD.

PMID- 15034486
TI  - [Towards a prevention of dementia?].
AB  - Many studies have shown that high blood pressure and, to a lesser extent, other
      vascular risk factors could be the target of interventions aiming to reduce the
      incidence of dementia. Two large controlled trials have demonstrated that blood
      pressure lowering drugs have a significant effect on the risk of dementia
      including Alzheimer's disease. On another hand, large epidemiological studies
      have shown associations between different vascular factors and dementia. Overall,
      these data suggest that interventions aiming to reduce the level of vascular risk
      factors might prevent dementia. The expected benefit of these interventions could
      be estimated from data provided by epidemiological studies, but large population
      based controlled studies are needed to demonstrate the efficacy of preventive
      interventions.

PMID- 15034494
TI  - The fasting woman.

PMID- 15034487
TI  - [Treatment of Alzheimer's disease: general methodological aspects].
AB  - The availability of many etiological hypothesis for Alzheimer's disease raise the
      possibility of treatments aiming at slowing down disease progression. Clinical
      trial designs and relevant outcomes are available to test these hypothesis. A
      preventive approach based on individual risk assessment may be possible, which
      will increase the number of consultations for neurologists in the near future.

PMID- 15034497
TI  - Medical burden, cerebrovascular disease, and cognitive impairment in geriatric
      depression: modeling the relationships with the CART analysis.
AB  - Herein, the background information reflecting roles of medical burden,
      cerebrovascular disease and risk factors, and cognitive impairment in geriatric
      depression are reviewed. The authors then propose a nonparametric statistical
      approach to the data analysis of multiple putative causal variables for late-life
      depression, the Classification and Regression Tree Analysis. This analysis
      presents a useful approach to modeling nonlinear relationships and interactions
      among variables measuring physical and mental health, as well as magnetic
      resonance imaging and cognitive measures in depressed elderly. This method
      uncovers the existing interactions among multiple predictor variables, and
      provide thresholds for each variable, at which its predictive power becomes
      statistically significant. It presents a "hierarchy" of the predictors in a form
      of a decision tree by finding the best combination of predictors of an outcome.
      The authors present two models based on demographic variables, measures of
      vascular and nonvascular medical burden, neuroimaging indices, the Mini-Mental
      State Examination score, and neuropsychological test scores of 81 elderly
      depressed subjects. Cognitive tests of verbal fluency and executive function are
      identified as the best predictors of depression, followed by the frontal lobe
      volume and Mini-Mental State Examination. The authors observed that an
      interaction between frontal lobe volume, total lesion volume, and medical burden
      was predictive of depression.

PMID- 15034498
TI  - Treatment-resistant depression in late life.
AB  - Treatment resistance is reported in up to 40% of older patients with major
      depression. Before labeling an episode of depression as treatment resistant, it
      is important to ensure that the diagnosis is correct and that the patient has
      received and adhered to an adequate dose of treatment for an appropriate length
      of time. It is also important to assess the patient for comorbid physical and
      psychiatric conditions that can contribute to treatment resistance. In patients
      who do not experience remission of symptoms with an adequate trial of medication,
      the following options can be considered: augmenting the antidepressant with a
      drug that is not primarily an antidepressant, adding a second antidepressant to
      the first, switching to a different antidepressant medication, or switching to
      electroconvulsive therapy. This paper reviews the concept of treatment-resistant
      depression and discusses its assessment and management in the elderly. The author
      concludes that when a systematic stepped-care approach to treatment is followed,
      most older patients with major depression will experience remission of symptoms.

PMID- 15034496
TI  - The cerebrovascular model of depression in late life.
AB  - Depression in older people, especially depression with an older age of onset, may
      be a manifestation of acquired brain disease. The cerebrovascular model of
      depression, often referred to as "vascular depression," hypothesizes that
      otherwise clinically occult small vessel brain disease contributes to the
      pathogeneses of some late-life depressive conditions. This paper reviews several
      lines of evidence supporting the cerebrovascular model and addresses the
      limitations of the existing literature. Several directions for future research
      are noted, including empirical testing of the notion that cerebrovascular disease
      might underlie the pathogeneses of depression with prominent executive
      dysfunction or other cognitive impairments. At this time, there are no specific
      therapeutic options for patients with suspected vascular depression beyond
      standard approaches to depression treatments, although education about the
      possibly greater risks of chronicity should be included in treatment planning.
      Therapy of cerebrovascular risk factors and stroke-risk reduction are important
      as consistent with general practice guidelines, although it is not known whether
      this will reduce the incidence or improve the outcome of late-life depression.

PMID- 15034500
TI  - Trichotillomania in a schizophrenia patient.
AB  - Comorbidity of trichotillomania with different psychiatric disorders is common.
      However, until recently there have been no reports of trichotillomania in
      schizophrenia patients. In this article, the case of a female schizophrenia
      patient with trichotillomania is reported. Her schizophrenia was being treated
      with risperidone. Citalopram was later administered as an augmentation to
      risperidone. This combination therapy presented a partial response of
      trichotillomania without exacerbating schizophrenia symptoms.

PMID- 15034499
TI  - Cholinesterase-inhibitor therapy for dementia: novel clinical substrates and
      mechanisms for treatment response.
AB  - Historically, drugs that increase central cholinergic transmission have primarily
      been investigated for relieving cognitive symptoms in mild-to-moderate
      Alzheimer's disease. These efforts have led to the somewhat unexpected findings
      that cholinergic therapy has a beneficial effect on selected neuropsychiatric
      symptoms in AD across disease stages. In Parkinson's disease with dementia and
      dementia with Lewy bodies, cholinergic deficits are more severe than in AD, and
      there is emerging evidence that cholinesterase inhibitors are efficacious in
      treating core symptoms of attentional disturbance and psychosis. Recent data also
      suggest a rational basis for cholinergic therapy in vascular dementia. The
      cognitive and neuropsychiatric effects of cholinergic therapy observed in AD and
      other dementias form the crux of an integrative model of cholinergic therapeutic
      efficacy that encompasses the diverse central nervous system actions of
      acetylcholine and its complementary interactions with central monoamine
      transmitters. This heuristic framework highlights the broader therapeutic
      potential of cholinergic therapy for symptom-based indications in other
      neuropsychiatric disorders.

PMID- 15034501
TI  - Vaccines and immunotherapies for the prevention of infectious diseases having
      cutaneous manifestations.
AB  - Although the development of antimicrobial drugs has advanced rapidly in the past
      several years, such agents act against only certain groups of microbes and are
      associated with increasing rates of resistance. These limitations of treatment
      force physicians to continue to rely on prevention, which is more effective and
      cost-effective than therapy. From the use of the smallpox vaccine by Jenner in
      the 1700s to the current concerns about biologic warfare, the technology for
      vaccine development has seen numerous advances. The currently available vaccines
      for viral illnesses include Dryvax for smallpox; the combination measles, mumps,
      and rubella vaccine; inactivated vaccine for hepatitis A; plasma-derived vaccine
      for hepatitis B; and the live attenuated Oka strain vaccine for varicella zoster.
      Vaccines available against bacterial illnesses include those for anthrax,
      Haemophilus influenzae, and Neisseria meningitidis. Currently in development for
      both prophylactic and therapeutic purposes are vaccines for HIV, herpes simplex
      virus, and human papillomavirus. Other vaccines being investigated for prevention
      are those for cytomegalovirus, respiratory syncytial virus, parainfluenza virus,
      hepatitis C, and dengue fever, among many others. Fungal and protozoan diseases
      are also subjects of vaccine research. Among immunoglobulins approved for
      prophylactic and therapeutic use are those against cytomegalovirus, hepatitis A
      and B, measles, rabies, and tetanus. With this progress, it is hoped that
      effective vaccines soon will be developed for many more infectious diseases with
      cutaneous manifestations.

PMID- 15034502
TI  - Micellar paclitaxel improves severe psoriasis in a prospective phase II pilot
      study.
AB  - BACKGROUND: Taxanes (eg, paclitaxel) are chemotherapeutic agents that have
      antiproliferative, antiangiogenic, and antiinflammatory properties. OBJECTIVE: We
      sought to explore the safety and efficacy of paclitaxel in individuals with
      severe psoriasis. METHODS: An open-label, prospective, phase II pilot study was
      conducted at the National Institutes of Health Clinical Center, a federal
      government medical research facility, in Bethesda, Maryland. Twelve patients with
      severe psoriasis, as defined by a baseline Psoriasis Area and Severity Index
      (PASI) score of >or= 20), were studied. Initially, patients received 6
      intravenous infusions of micellar paclitaxel, 75 mg/m(2), at 4-week intervals
      (stage I). Later patients received 9 intravenous infusions of micellar paclitaxel
      at 2-week intervals (37.5 mg/m(2) for 3 doses followed by 50 mg/m(2) for six
      additional doses) (stage II). The primary end point was the percent change in the
      PASI from week 0 to week 24 in stage I and from week 0 to week 20 in stage II.
      RESULTS: In stage I, all 5 patients improved (mean = 59.7% decrease in PASI,
      median = 59.6%, range: 40.3%-79.2%). Four of the 7 patients completed stage II
      and all of these patients improved (mean = 45.9% decrease in PASI, median =
      45.0%, range: 14.6%-79.1%). Micellar paclitaxel was well tolerated by most
      patients. CONCLUSIONS: Micellar paclitaxel demonstrates therapeutic activity in
      patients with severe psoriasis.

PMID- 15034503
TI  - A randomized, placebo-controlled trial of 5% and 2% topical minoxidil solutions
      in the treatment of female pattern hair loss.
AB  - BACKGROUND: To pical minoxidil solution 2% stimulates new hair growth and helps
      stop the loss of hair in men with androgenetic alopecia and women with female
      pattern hair loss. Results can be variable, and historic experience suggests that
      higher concentrations of topical minoxidil may enhance efficacy. OBJECTIVE: The
      purpose of this 48-week, double-blind, placebo-controlled, randomized,
      multicenter trial was to compare the efficacy and safety of 5% topical minoxidil
      with 2% topical minoxidil and placebo in the treatment of female pattern hair
      loss. METHODS: A total of 381 women (18-49 years old) with female pattern hair
      loss applied 5% topical minoxidil solution (n = 153), 2% topical minoxidil
      solution (n = 154), or placebo (vehicle for 5% solution; n = 74) twice daily.
      Primary efficacy variables were change in nonvellus hair count at week 48, and
      patient and investigator assessments of change in hair growth/scalp coverage at
      week 48. RESULTS: After 48 weeks of therapy, 5% topical minoxidil was superior to
      placebo for each of the 3 primary efficacy measures. The 2% topical minoxidil
      group demonstrated superiority over placebo for hair count and investigator
      assessment of hair growth/scalp coverage at week 48; differences in patient
      assessment of hair growth at week 48 were not significantly different from
      placebo. The 5% topical minoxidil group demonstrated statistical superiority over
      the 2% topical minoxidil group in the patient assessment of treatment benefit at
      week 48. Both 5% and 2% topical minoxidil helped improve psychosocial perceptions
      of hair loss in women with female pattern hair loss. An increased occurrence of
      pruritus, local irritation, and hypertrichosis was observed with 5% topical
      minoxidil versus 2% topical minoxidil and placebo. CONCLUSION: In this 48-week
      study of 381 women with female pattern hair loss, 5% topical minoxidil was
      superior to placebo on each of the 3 primary efficacy end points: promoting hair
      growth as measured by change in nonvellus hair count and patient/investigator
      assessments of hair growth and scalp coverage. Application of 2% topical
      minoxidil was superior to placebo for assessments of nonvellus hair counts and
      investigator assessment of hair growth/scalp coverage at week 48; differences in
      patient assessment of hair growth at week 48 were not significantly different
      from placebo. At week 48, the 5% topical minoxidil group demonstrated statistical
      superiority over the 2% topical minoxidil group in the patient assessment of
      treatment benefit. Both concentrations of topical minoxidil were well tolerated
      by the women in this trial without evidence of systemic adverse effects. With the
      introduction of numerous herbal remedies for hair loss, of which most have not
      been tested in randomized, double-blind, placebo-controlled trials, it is
      important to describe well-controlled trials that demonstrate the efficacy and
      safety of topical drugs.

PMID- 15034504
TI  - Vulvar melanoma: a report of 20 cases and review of the literature.
AB  - BACKGROUND: Vulvar melanoma is the second most common vulvar malignancy and
      represents a significant women's health issue. OBJECTIVE: To report experience
      with 21 cases of vulvar melanoma in 20 patients and to review the literature
      about the condition. METHODS: Parameters retrospectively reviewed included age at
      diagnosis, family history of melanoma, location on the vulva, atypical nevi,
      Breslow depth, ulceration status, histologic pattern, presenting signs and
      symptoms, and the results of sentinel lymph node biopsy. Molecular
      characterization of the melanocortin type 1 receptor was performed in 1 patient.
      RESULTS: A family history of cutaneous melanoma was present in 15% of cases. The
      mean Breslow depth was 2.8 mm (range, 0.0-11.0 mm). Ten patients successfully
      underwent sentinel lymph node biopsy, results of which were positive in 2 (20%).
      Reported for the first time is that one patient had a germline mutation in the
      melanocortin type 1 receptor. CONCLUSION: Vulvar and cutaneous melanoma behave
      similarly despite their unique pathogeneses. Sentinel lymph node biopsy can be
      performed successfully for vulvar melanoma.

PMID- 15034505
TI  - Chemoprevention of squamous cell carcinoma in recessive dystrophic epidermolysis
      bullosa: results of a phase 1 trial of systemic isotretinoin.
AB  - BACKGROUND: Patients with recessive dystrophic epidermolysis bullosa (RDEB) are
      at high risk of developing squamous cell carcinoma on or after midadolescence,
      and most patients die of metastatic squamous cell carcinoma within 5 years of
      diagnosis of their first squamous cell carcinoma. OBJECTIVE: We sought to
      determine whether isotretinoin can be safely administered to patients with RDEB
      as a possible chemopreventive agent. METHODS: A total of 20 patients with RDEB
      aged 15 years or older were treated daily for 8 months with isotretinoin (with a
      targeted dosage of 0.5 mg/kg/d). RESULTS: No unusual adverse reactions were noted
      in this patient population. Several patients experienced reduced blistering at
      lower doses and increased mechanical fragility at maintenance dosage.
      CONCLUSIONS: Isotretinoin, at least up to a dosage of 0.5 mg/kg/d, may be safely
      used in patients with RDEB. Although increased fragility may occur, patients
      tolerated this drug well and were receptive to its long-term use for possible
      chemoprevention of cancer. Whether such an effect will occur is yet to be proven.

PMID- 15034507
TI  - Facial psoriasis: comparison of patients with and without facial involvement.
AB  - BACKGROUND: Facial involvement in psoriasis has received little attention in
      standard descriptions of the disease because the face has long been thought of as
      rarely involved. A few reports have suggested that facial involvement might be a
      sign of severe psoriasis. However, there have been no comparison studies on the
      severity of psoriasis between patients with and without facial involvement.
      OBJECTIVE: We sought to evaluate the prevalence and characteristics of facial
      involvement, and to compare the severity of psoriasis between the patients with
      and without facial psoriasis. METHODS: A total of 282 consecutive patients with
      psoriasis seen in our psoriasis clinic between May 2002 and November 2002 were
      enrolled in this study. RESULTS: Facial involvement was a marker of severe
      psoriasis. The face was often involved for patients with long duration or early
      onset of disease; with nail or joint involvement; and those requiring more
      extensive treatments. Patients with facial involvement were found to have more
      frequent pruritus, positive family history, and history of Koebner response.
      CONCLUSION: Early recognition of facial psoriasis as a marker of severe disease
      can contribute to treatment of patients with psoriasis.

PMID- 15034506
TI  - Relative extent of skin involvement in inherited epidermolysis bullosa (EB):
      composite regional anatomic diagrams based on the findings of the National EB
      Registry, 1986 to 2002.
AB  - BACKGROUND: Inherited epidermolysis bullosa (EB) encompasses 4 major types and at
      least 23 clinically distinctive phenotypes. Although considerable variability in
      cutaneous disease activity is known to exist within each, severity and anatomic
      distribution of skin lesions remain the major criteria used for
      subclassification. OBJECTIVE: We sought to generate accurate anatomic "density"
      diagrams depicting the relative extent and location of skin lesions within each
      major EB subtype. METHODS: Diagrams were created for each major EB type, on the
      basis of medical history and physical examination findings obtained from 1986 to
      2002 from 3280 consecutive enrollees in the National EB Registry. RESULTS: An
      anatomic diagram was created for each of the major EB subtypes, representing a
      prototypic composite photograph of cutaneous disease activity. CONCLUSIONS:
      Marked variability exists in the extent of skin involvement within each major EB
      subtype. The use of these diagrams, generated from the world's largest cohort of
      patients with EB, should assist the clinician in more accurately subclassifying
      newly encountered patients.

PMID- 15034508
TI  - Intravascular or intralymphatic histiocytosis associated with rheumatoid
      arthritis: a report of 4 cases.
AB  - BACKGROUND: Various skin lesions occur in association with rheumatoid arthritis
      (RA). OBSERVATION: We report a distinctive skin lesion observed in 4 patients
      with RA. All patients had RA for many years and developed asymptomatic,
      irregularly shaped erythema over the swollen elbow joints and the nearby part of
      the forearm. Histopathologically, all cases showed massive aggregates mainly
      composed of histiocytes in markedly dilated vessels in the dermis, accompanied by
      a dermal infiltrate of lymphocytes, plasma cells, neutrophils, or a combination
      of these. A total of 9 cases, including ours, showing similar histopathologic
      findings have been reported in the literature, of which 7 were associated with RA
      and presented relatively common clinical appearance. CONCLUSION: In spite of some
      disagreement as to whether the dilated vessels are blood vessels or lymphatics,
      it is most likely that these 7 cases belong to the same clinical entity closely
      associated with RA.

PMID- 15034509
TI  - The scarring mechanism of smallpox.
AB  - BACKGROUND: Smallpox is notorious for leaving its survivors with disfiguring
      scars, but it is unclear how these scars are produced. Modern dermatopathology
      textbooks report that smallpox produced epidermal lesions, yet the process of
      scarring requires dermal involvement. OBJECTIVES: Our goal was to uncover past
      theories on the mechanism of smallpox scarring. METHODS: We conducted a
      comprehensive review of English-language textbooks and English-translations of
      textbooks in general medicine, dermatology, pathology, and dermatopathology from
      the past 150 years as well as relevant journal publications for the same time
      period. RESULTS: We identified five different theories to explain the scarring of
      smallpox. The five proposals are that scarring resulted from: the extension of
      suppuration into the dermis; the extension of suppuration into the dermis along
      with inappropriate treatment and scratching; secondary bacterial ecthyma; the
      destruction of elastic fibers; or the destruction of sebaceous glands.
      CONCLUSION: The theory that best fits clinical and histological observations is
      that smallpox caused scars through the destruction of sebaceous glands, first
      proposed by Gerrit Bras in 1952. Although this explanation is not found in any
      dermatopathology text, it is supported by today's leading authorities on
      smallpox. However, since variola virions have never actually been identified in
      sebaceous glands, or even in the dermis, further study of preserved tissue is
      warranted. Until then, the mechanism of scar formation remains speculative.

PMID- 15034510
TI  - Annular lichen planus: a case series of 20 patients.
AB  - BACKGROUND: Annular lichen planus (ALP) is a long-recognized clinical variant of
      lichen planus, but is often considered uncommon in occurrence. The typical
      distribution and presentation of this variant have not been well described.
      OBJECTIVE: We sought to better define the sites affected and clinical
      characteristics of the annular variant of lichen planus, along with the age and
      race of patients affected with this disorder. METHODS: We conducted a
      retrospective review of 20 patients given a diagnosis of ALP during an 18-year
      period. The diagnosis was confirmed histologically in all but 3 cases of classic
      ALP that presented on the glans penis. RESULTS: Patients ranged in age from 24 to
      76 years. There were 18 men and 2 women; 15 were Caucasian and 5 were African
      American. Sites of involvement in order of decreasing frequency included: axilla
      (35%); penis (25%); extremities (25%); groin (including the inguinal creases and
      scrotum) (20%); back (15%); buttocks (10%); flanks (5%); neck (5%); and eyelids
      (5%). None of the patients had oral mucosal, vulval, scalp, or nail lesions. A
      total of 18 patients had purely annular lesions, whereas 2 of the 20 had a few
      purple polygonal papules in the vicinity of the annular forms. Some eruptions
      were macular, whereas the majority had a slightly raised edge with central
      clearing. In all, 6 patients had solitary lesions whereas only 4 had 10 or
      greater lesions. None exhibited a linear Koebnerized response or generalized
      lesions. Most patients were asymptomatic. CONCLUSIONS: ALP commonly involves the
      male genitalia but also has a predilection for intertriginous areas such as the
      axilla and groin folds. Eruptions typically consist of a few lesions localized to
      one or a few sites. Distal aspects of the extremities, and less commonly the
      trunk, may also be involved. ALP is a subtype of lichen planus that may be more
      common than is reflected in the literature.

PMID- 15034511
TI  - Tazarotene 0.1% gel for refractory mycosis fungoides lesions: an open-label pilot
      study.
AB  - BACKGROUND: Topical skin-directed therapies are used to induce remissions in
      early-stage mycosis fungoides (MF). They are rarely curative, and responding
      patients are subject to frequent relapses, emphasizing the need for alternative
      therapies. OBJECTIVE: We sought to evaluate the efficacy and tolerability of
      topical tazarotene 0.1% gel as adjuvant therapy in the treatment of refractory MF
      lesions. METHODS: A total of 20 adult patients with early patch or plaque MF
      limited to less than 20% body surface area (BSA) involvement whose lesions were
      either stable or refractory to therapy for at least 8 weeks enrolled in an open
      label pilot study. Tazarotene 0.1% gel was applied to MF lesions once daily for
      24 weeks. Continued concomitant use of other medications such as low- to mid
      potency topical corticosteroids was permitted for the alleviation of skin
      irritation. Global improvement, overall disease severity, percent BSA
      involvement, and pruritus were evaluated every 4 weeks. Up to 6 index lesions
      were followed up for area, plaque elevation, scaling, and erythema scores. Skin
      biopsy specimens were to be taken at baseline, week 8, and week 24. Evaluable
      specimens were stained with hematoxylin and eosin, CD8 antibody, and CD45RO
      antibody. RESULTS: In all, 20 patients enrolled, 19 received treatment, and 16
      completed at least 4 weeks of topical treatment. By intent-to-treat analysis, 11
      of 19 patients (58%) achieved at least a moderate (>50%) global improvement in
      BSA, and 35% of 99 index lesions cleared completely. Significant reductions (mean
      differences) were also found in the median lesional area score (-37, P =.0013),
      mean plaque elevation score (-.67, P =.016), mean scaling (-0.70, P =.033), and
      mean erythema score (-1.03, P =.002). Analysis of overall disease also disclosed
      statistical differences in percent of change for BSA involvement of 22% (P =.013)
      and of mean overall disease severity score of 34% (P =.011). Of 19 patients, 16
      (84%) experienced mild or moderate local skin irritation manifested by peeling,
      erythema, burning, and tenderness that was managed successfully with topical
      steroids or reducing the frequency of treatment. Histopathology and
      immunohistochemistry results showed reductions in lymphocytic infiltrates and
      percentage of CD45RO(+) lymphocytes, and increases in the percentage of CD8(+)
      lymphocytes during the course of therapy. CONCLUSION: In this small pilot study,
      tazarotene 0.1% gel was a well-tolerated and effective adjuvant topical for the
      treatment of refractory MF lesions by clinical and histologic assessments.

PMID- 15034513
TI  - Psoriasis.

PMID- 15034512
TI  - Epithelial and mesenchymal hamartomatous changes in a mature port-wine stain:
      Morphologic evidence for a multiple germ layer field defect.
AB  - The port-wine stain (PWS) is a congenital cutaneous venulocapillary malformation
      of unknown pathogenesis. Many patients with facial PWS develop thickening with
      cobblestoning and nodularity during adult life. The histologic correlates of this
      maturational change are poorly documented and its mechanisms remain unclear. In
      this case study we present new histologic observations that may elucidate this
      phenomenon. An extensive PWS on the face of a 75-year-old man exhibited gross
      thickening with cobblestoning and nodularity. Histologic examination revealed not
      only the expected vascular abnormalities, but also a number of widely distributed
      epithelial, neural, and mesenchymal hamartomatous changes. Epithelial changes
      included epidermal nevus, sebaceous trichofolliculoma, and basaloid follicular
      hamartoma. Changes of connective tissue nevus, smooth-muscle hamartoma, neural
      hamartoma, and subcuticular hamartoma were also noted. The complex hamartomatous
      changes observed in the PWS of this patient involved multiple germ lines and were
      distributed in a widespread pattern. These changes not only offer an explanation
      for the skin thickening and nodularity of this patient, but also suggest a
      genetically determined, multilineage developmental field defect in the
      pathogenesis of this lesion. Further studies of other patients are necessary to
      understand the full implications of these findings in the late stage of PWS.

PMID- 15034514
TI  - Cost analysis of narrowband UVB phototherapy in psoriasis.
AB  - BACKGROUND: There are few data available to health care providers regarding the
      costs of treating patients with psoriasis, and specifically the cost of
      phototherapy. OBJECTIVES: As narrowband UVB (TL-01) has now become an established
      therapy for patients with psoriasis requiring phototherapy, we determined the
      annual cost of delivering TL-01 treatment in a university hospital. METHODS: The
      costing evaluation was from a hospital perspective and the strategy used was a
      microcosting detailed collection of resources used. RESULTS: The annual cost of
      TL-01 treatment in our teaching hospital was 53,555.00 euros. Staffing accounted
      for 70% of the cost. The average individual costs were 325.00 euros (range: 57.20
      972.40). CONCLUSION: These costs are significant but remain less expensive than
      inpatient treatment.

PMID- 15034515
TI  - A man with distinctive facial features and recurrent pyoderma, pneumonia, and
      skeletal fractures.

PMID- 15034516
TI  - Framework for improved communication: the Dermatology Lexicon Project.
AB  - A standardized dermatology vocabulary is central to our collective ability to
      gather clinical information consistently for patient care, to retrieve
      information for research or disease management, as well as to conduct outcomes
      analysis for quality improvement. The deficiencies of current classifications
      have been recognized by the National Institute of Arthritis and Musculoskeletal
      and Skin Diseases (NIAMS) in their decision to fund the development of a standard
      complete reference terminology for dermatology. The Dermatology Lexicon will have
      a major impact both on clinical care and on dermatologic research. Accuracy in
      medical records and telemedicine communications will be improved. Reliable
      terminology will provide for more complete and consistent documentation and data
      aggregation and reporting. In order to create a useful, sustainable lexicon,
      involvement of the dermatology community is essential.

PMID- 15034517
TI  - What is the point of databases of reviews for dermatology if all they compile is
      "insufficient evidence"?
AB  - BACKGROUND: The use of review databases for dermatology has been questioned
      because of the impression that these reviews frequently report finding
      insufficient evidence to guide therapeutic recommendations. OBJECTIVE: We sought
      to determine the number of review database entries most relevant to dermatology
      (addressing diseases with skin manifestations whereby a dermatologist may be the
      primary caregiver) and the percentage of these entries that report sufficient
      evidence to guide clinical decision making. METHODS: We conducted computerized
      searches and analysis of reviews in the Cochrane Database of Systematic Reviews
      and the Database of Abstracts of Reviews of Effectiveness. Database entries were
      categorized using the face value reports of the original reviewers as: (1)
      finding sufficient evidence to inform clinical decisions; (2) finding
      insufficient evidence; or (3) unable to classify with regard to degree of
      evidence found. RESULTS: Of all review database entries, 3% (54/1235 in Cochrane
      Database of Systematic Reviews and 65/2208 in the Database of Abstracts of
      Reviews of Effectiveness) were deemed relevant to dermatology. In all, 14 entries
      from the Database of Abstracts of Reviews of Effectiveness were in the process of
      being written and not available for further evaluation. Of the remaining entries,
      40% (42/105) reported finding sufficient evidence. Of the 10 most common
      dermatologic diagnoses, 8 were addressed in 30% (31/105) of these reviews. Of
      entries addressing common dermatologic diagnoses, 32% (10/31) reported finding
      sufficient evidence. CONCLUSIONS: Although few (3%) entries in review databases
      currently address dermatology topics, entries address many (8/10) of the top 10
      dermatology diagnoses. Contrary to popular belief, a substantial number (40%) of
      such reviews report sufficient evidence to inform clinical decisions making.

PMID- 15034518
TI  - Surgical Pearl: the use of methylene blue temporary tattoos for tissue
      orientation in Mohs micrographic surgery.

PMID- 15034519
TI  - Surgical Pearl: a rapid sanitary technique for surgical waste disposal.

PMID- 15034520
TI  - Minimal change nephropathy associated with pemphigus vulgaris: a new
      relationship?

PMID- 15034521
TI  - Ultraviolet A1 in the treatment of generalized lichen planus: a report of 4
      cases.

PMID- 15034522
TI  - Rofecoxib-induced pseudoporphyria.

PMID- 15034523
TI  - Aphthous stomatitis induced by piroxicam.

PMID- 15034524
TI  - Cutaneous sarcoidosis associated with pegylated interferon alfa and ribavirin
      therapy in a patient with chronic hepatitis C.

PMID- 15034525
TI  - Acute generalized exanthematous pustulosis precipitated by hydroxychloroquine.

PMID- 15034526
TI  - Chronic erosive and ulcerative oral lesions caused by incorrect administration of
      alendronate.

PMID- 15034527
TI  - Erythema elevatum diutinum associated with lupus panniculitis in a patient with
      discoid lesions of chronic cutaneous lupus erythematosus.

PMID- 15034529
TI  - Punch technique to improve granulation over exposed tendons in chronic wounds.

PMID- 15034528
TI  - Isotopic cutaneous lichen planus possibly related to dental amalgam.

PMID- 15034530
TI  - Chloracne with acantholytic dyskeratosis associated with herbicides: A new
      histological variant?

PMID- 15034531
TI  - EBMT 2004. Abstracts of the 30th Annual Meeting of the European Group for Blood
      and Marrow Transplantation, the 20th Meeting of the EBMT Nurses Group, and the
      3rd Meeting of the EMBT Data Management Group. Barcelona, Spain, March 28-31,
      2004.

PMID- 15034541
TI  - High-dose acyclovir and pre-emptive ganciclovir in prevention of cytomegalovirus
      disease in pediatric patients following peripheral blood stem cell
      transplantation.
AB  - Cytomegalovirus (CMV) disease remains an important cause of morbidity and
      mortality in patients undergoing hematopoietic stem cell transplantation (HSCT).
      We evaluated high-dose acyclovir (HDACV) and pre-emptive ganciclovir to prevent
      CMV disease in 76 children who underwent peripheral blood stem cell
      transplantation (PBSCT) and were at risk for CMV reactivation and disease (both
      recipient and donor seropositive) from May 1998 to April 2003. All received HDACV
      from day -9 to 6 months post transplant in conjunction with weekly CMV pp65
      antigenemia monitoring. The incidence of antigenemia in this cohort was 19.7%, at
      a median of 22 days post-PBSCT. The frequencies were 26.4 and 4.4% in allogeneic
      and autologous groups, respectively (P=0.03). Patients with nonmalignant disease
      had higher CMV antigenemia than those with malignant disease (30.8 vs 8.1%,
      P=0.02). Age at PBSCT, sex, graft-versus-host disease (GVHD) prophylaxis regimen
      and presence of acute GVHD did not affect the risk of CMV antigenemia. None of
      the patients who had positive pp65 antigenemia developed CMV disease during the
      study period. We conclude that pp65 antigenemia-guided HDACV and pre-emptive
      ganciclovir may prevent CMV disease in children undergoing PBSCT.

PMID- 15034540
TI  - Incidence and clinical complications of vancomycin-resistant enterococcus in
      pediatric stem cell transplant patients.
AB  - Vancomycin-resistant enterococcus (VRE) are increasingly important pathogens in
      stem cell transplant (SCT). In all, 61 pediatric SCT patients had surveillance
      stool cultures for VRE between July 1999 and November 2002. When VRE was
      identified, the patients were placed on strict contact isolation. VRE was
      detected in 15 patients (24.6%). The median age was 3.6 years (range 0.6-18.5
      years). Of the 15, 13 (87%) received an allogeneic transplant (six unrelated and
      seven related). Five of the 15 (33%) colonized patients developed VRE bacteremia.
      The bacteremia resolved in all five patients after therapy with
      quinupristin/dalfopristin; three patients required central line removal. Four
      patients died (38-153 days) post-SCT due to relapse or transplant complication
      not related to VRE. Of the 11 surviving patients, seven cleared the colonization
      at a median of 144 days (range 61-198 days) postcolonization. Four patients
      remain colonized at 68-702 days after the first positive culture. Intestinal
      colonization with VRE occurred commonly in pediatric SCT patients. Although the
      morbidity from VRE was not substantial, transplant patients were colonized for
      prolonged periods. Our results indicate that surveillance for VRE is an effective
      way to identify colonized patients and may lead to a decrease in transmission to
      other patients.

PMID- 15034542
TI  - Psychosocial adjustment and quality of life among multiple myeloma patients
      undergoing evaluation for autologous stem cell transplantation.
AB  - Stem cell transplantation has assumed a prominent place in the treatment of
      multiple myeloma, but relative to patients with other malignancies there is
      surprisingly little information about the adjustment difficulties and quality-of
      life changes that these patients experience. This study examined psychosocial and
      functional deficits among myeloma patients assessed at a uniform period during
      their initial diagnostic evaluation, prior to beginning protocols at a transplant
      center. Validated self-report measures and clinician rating scales were used to
      assess 213 patients. Outcomes evaluated included emotional distress (Hospital
      Anxiety and Depression Scale, Brief Symptom Inventory), depression (Hamilton
      Depression Rating Scale), physical functioning, pain, and energy (SF-12). A
      significant proportion of patients experienced compromised psychosocial and
      physical functioning. Roughly one-third reported clinically elevated levels of
      distress, anxiety, and depression. In all, 59% scored below age-adjusted norms
      for daily physical functioning, 58% reported at least moderate levels of pain,
      and over 80% noted at least moderate fatigue. Clinical and demographic correlates
      of these outcomes were examined. These findings are among the first to
      characterize quality-of-life outcomes among myeloma patients in the transplant
      setting, and indicate that many patients experience considerable supportive care
      needs even prior to beginning aggressive regimens. Results highlight the
      importance of early screening.

PMID- 15034543
TI  - Prediction of mobilisation failure in patients with non-Hodgkin's lymphoma.
AB  - Factors affecting progenitor cell mobilisation in patients with non-Hodgkin's
      lymphoma (NHL) are incompletely understood. We have analysed factors predicting
      mobilisation failure in 97 consecutive patients with NHL (59 males, 38 females;
      median age 49 years) who received mobilisation with intermediate-dose CY (4
      g/m(2)) followed by G-CSF. The histology included large cell B (N=50), mantle
      cell (N=16), follicular (N=16) and other NHL (N=15). The disease status was
      1CR/PR/primary refractory in 66 patients and >1 CR/PR in 31 patients. The minimum
      criterion for successful mobilisation was the collection of >or=1.5 x 10(6)/kg
      CD34(+) cells. In all, 18 patients (19%) failed to reach this threshold. In
      univariate analysis, premobilisation factors associated with mobilisation failure
      included BM involvement at the time of diagnosis (P=0.001) or prior to
      mobilisation (P=0.001) and low platelet count just prior to mobilisation
      (P=0.001). In multivariate analysis, only BM involvement at diagnosis (P=0.004)
      and platelet count just prior to mobilisation (P=0.01) were associated with
      mobilisation failure. A mathematical model based on these two factors and
      presented in the form of a receiver operating characteristics curve showed a
      sensitivity of 0.71 and a specificity of 0.77 in the prediction of mobilisation
      failure. Patients at a high risk of mobilisation failure may benefit from novel
      approaches.

PMID- 15034544
TI  - Rituximab-related late-onset neutropenia after autologous stem cell
      transplantation for aggressive non-Hodgkin's lymphoma.
AB  - Rituximab, an anti-CD20 monoclonal antibody, is increasingly used in the
      treatment of B-cell non-Hodgkin's lymphoma. Late-onset neutropenia in relation to
      rituximab has been recently described. In this report, we present six cases
      occurring after stem cell transplantation and discuss the potential impact of
      this complication.

PMID- 15034545
TI  - Rituximab and autologous stem cell transplantation for malignant lymphoma after
      liver transplantation.

PMID- 15034546
TI  - Secondary antifungal prophylaxis with voriconazole to adhere to scheduled
      treatment in leukemic patients and stem cell transplant recipients.
AB  - Although the efficacy and safety of voriconazole to treat invasive fungal
      infections have been demonstrated in prospective trials, its use for secondary
      prophylaxis to prevent reactivation of these infections remains unknown. Delaying
      the scheduled treatment of leukemia until complete resolution of fungal infection
      may have major implications for prognosis. We report 11 leukemic patients with
      previous aspergillus (n=10) and candida (n=1) infection who received voriconazole
      400 mg/day intravenously or orally for between 44 and 245 days. Nine patients
      were scheduled for allogeneic stem cell transplant, and two for consolidation
      therapy for acute leukemia. None of the patients had a relapse of fungal
      infection, and scheduled treatment was delayed only once. Voriconazole was well
      tolerated, except in one patient who had abnormal liver tests secondary to
      hepatic graft-versus-host disease, and one who had visual disturbances. This
      small but homogeneous series indicates that voriconazole may be useful to prevent
      fungal relapse during at-risk periods in leukemic patients. Prospective trials
      are warranted to confirm these encouraging results.

PMID- 15034547
TI  - Prodrug chemotherapeutics bypass p-glycoprotein resistance and kill tumors in
      vivo with high efficacy and target-dependent selectivity.
AB  - Doxorubicin intercalates into DNA, causes double-strand breaks, and leads to
      apoptotic death. Limitations to the efficacy and therapeutic index of doxorubicin
      include poor tumor selectivity, high systemic toxicity, and the development of
      resistance, especially p-glycoprotein (p-gp)-mediated. We chemically coupled
      doxorubicin to a monoclonal antibody directed to the insulin-like growth factor-1
      receptor, a receptor highly overexpressed in most tumors and validated as a tumor
      target. The prodrug conjugate bounded to tumor cells selectively, and accumulated
      efficiently and only in receptor-expressing cells. The conjugate was processed to
      release free doxorubicin inside target cells leading to selective toxicity, had
      >200-fold improved therapeutic index, and in vivo reduced tumor load with no
      systemic toxicity. Importantly, the prodrug conjugate is not subject to p-gp
      efflux and can bypass resistance in vivo. Our studies define a strategy to
      develop improved and more selective anticancer agents.

PMID- 15034548
TI  - Bcl-2 inhibition of T-cell proliferation is related to prolonged T-cell survival.
AB  - Bcl-2 promotes oncogenesis by inhibiting cell death. Bcl-2 also inhibits
      proliferation and suppresses tumorigenesis in some settings. To clarify the role
      of the antiproliferative function of Bcl-2, mice expressing a mutant form of Bcl
      2 reported to lack antiproliferative activity were generated (tyrosine 28 to
      alanine, Bcl-2-Y28A). As expected, both wild type (WT) and Bcl-2-Y28A inhibited
      apoptosis similarly. In contrast to previous results in cell lines, Bcl-2-Y28A
      inhibited T-cell proliferation identical to WT-Bcl-2. Significantly, both Bcl-2
      Y28A and WT-Bcl-2 inhibited proliferation of T cells isolated from older animals,
      but not proliferation of T cells from immature mice. Instead, inhibition of cell
      activation correlated with T-cell size, p27 levels, and RNA content, all
      indicators of quiescent G0 arrest. Consistent with this model, Bcl-2 inhibition
      of T-cell proliferation was reversed by expression of Bax, again correlating cell
      proliferation with cell size. These experiments do not support genetically
      separate effects of Bcl-2 on apoptosis and proliferation. Instead, the data
      support a model in which Bcl-2 and Bax regulate T-cell proliferation by changes
      in T-cell size and by increasing the markers of quiescent G0 arrest. These
      changes likely result from prolonged T-cell survival.

PMID- 15034549
TI  - Molecular ordering of hypoxia-induced apoptosis: critical involvement of the
      mitochondrial death pathway in a FADD/caspase-8 independent manner.
AB  - Dys-regulated growth and improper angiogenesis commonly lead to areas of hypoxia
      in human tumors. Hypoxia is known to be associated with a worse outcome since a
      lack of oxygen interferes with the efficacy of chemotherapy or radiotherapy. In
      parallel, hypoxia-induced apoptosis may also impose a selection pressure favoring
      growth of more resistant tumor cells. However, the mechanisms of hypoxia-induced
      apoptosis and the relative contribution of intrinsic and extrinsic apoptotic
      pathways are not understood. Therefore, Jurkat cell lines with defined defects in
      the extrinsic or intrinsic signaling cascades were used to evaluate the role of
      either pathway for induction of apoptosis under hypoxic conditions. Jurkat cells
      were incubated in hypoxia and the rate of apoptosis induction was determined by
      Western blotting, fluorescence microscopy and flow cytometry. Hypoxia-induced
      apoptosis was not affected by lack of caspase-8 or FADD, whereas overexpression
      of Bcl-2 or expression of dominant-negative caspase-9 mutant rendered the cells
      resistant to hypoxia-induced apoptosis. These results suggest that hypoxia
      induced apoptosis mainly relies on intrinsic, mitochondrial pathways, whereas
      extrinsic pathways have no significant implications in this process. Thus, in
      human tumors, hypoxia will mainly lead to the selection of hypoxia-resistant
      cells with defects in mitochondrial apoptosis signaling pathways.

PMID- 15034550
TI  - Computational redesign of protein-protein interaction specificity.
AB  - We developed a 'computational second-site suppressor' strategy to redesign
      specificity at a protein-protein interface and applied it to create new
      specifically interacting DNase-inhibitor protein pairs. We demonstrate that the
      designed switch in specificity holds in in vitro binding and functional assays.
      We also show that the designed interfaces are specific in the natural functional
      context in living cells, and present the first high-resolution X-ray
      crystallographic analysis of a computer-redesigned functional protein-protein
      interface with altered specificity. The approach should be applicable to the
      design of interacting protein pairs with novel specificities for delineating and
      re-engineering protein interaction networks in living cells.

PMID- 15034551
TI  - eIF4AIII binds spliced mRNA in the exon junction complex and is essential for
      nonsense-mediated decay.
AB  - The exon junction complex (EJC), a set of proteins deposited on mRNAs as a
      consequence of pre-mRNA splicing, is a key effector of downstream mRNA
      metabolism. We have identified eIF4AIII, a member of the eukaryotic translation
      initiation factor 4A family of RNA helicases (also known as DExH/D box proteins),
      as a novel EJC core component. Crosslinking and antibody inhibition studies
      suggest that eIF4AIII constitutes at least part of the platform anchoring other
      EJC components to spliced mRNAs. A nucleocytoplasmic shuttling protein, eIF4AIII
      associates in vitro and in vivo with two other EJC core factors, Y14 and Magoh.
      In mammalian cells, eIF4AIII is essential for nonsense-mediated mRNA decay (NMD).
      Finally, a model is proposed by which eIF4AIII represents a new functional class
      of DExH/D box proteins that act as RNA clamps or 'place holders' for the sequence
      independent attachment of additional factors to RNAs.

PMID- 15034552
TI  - Genes and ligands for odorant, vomeronasal and taste receptors.

PMID- 15034554
TI  - Visual object understanding.

PMID- 15034553
TI  - Specific long-term memory traces in primary auditory cortex.

PMID- 15034555
TI  - Information processing in the axon.

PMID- 15034556
TI  - Src kinases: a hub for NMDA receptor regulation.

PMID- 15034557
TI  - Thomas Willis (1621-1675), the founder of clinical neuroscience.

PMID- 15034558
TI  - Importance of studying the contributions of early adverse experience to
      neurobiological findings in depression.
AB  - Almost four decades of intensive research have sought to elucidate the
      neurobiological bases of depression. Epidemiological studies have revealed that
      both genetic and environmental factors contribute to the risk for depression.
      Adverse early-life experiences influence neurobiological systems within genetic
      limits, leading to the neurobiological and behavioral manifestations of
      depression. We summarize the burgeoning evidence concerning a pre-eminent role of
      early adverse experience in the pathogenesis of depression. The available data
      suggest that (1) early adverse experience contributes to the pathophysiology of
      depression, (2) there are neurobiologically different subtypes of depression
      depending on the presence or absence of early adverse experience, likely having
      confounded previous research on the neurobiology of depression, and (3) early
      adverse experience likely influences treatment response in depression.
      Classification of depression based on developmental and neurobiological features
      will likely considerably improve future research in the field of depression, and
      might lead to optimized treatment strategies that directly target different
      neurobiological pathways to depression.

PMID- 15034559
TI  - A photolabile hydrogel for guided three-dimensional cell growth and migration.
AB  - Tissue engineering aims to replace, repair or regenerate tissue/organ function,
      by delivering signalling molecules and cells on a three-dimensional (3D)
      biomaterials scaffold that supports cell infiltration and tissue organization. To
      control cell behaviour and ultimately induce structural and functional tissue
      formation on surfaces, planar substrates have been patterned with adhesion
      signals that mimic the spatial cues to guide cell attachment and function. The
      objective of this study is to create biochemical channels in 3D hydrogel matrices
      for guided axonal growth. An agarose hydrogel modified with a cysteine compound
      containing a sulphydryl protecting group provides a photolabile substrate that
      can be patterned with biochemical cues. In this transparent hydrogel we
      immobilized the adhesive fibronectin peptide fragment, glycine-arginine-glycine
      aspartic acid-serine (GRGDS), in selected volumes of the matrix using a focused
      laser. We verified in vitro the guidance effects of GRGDS oligopeptide-modified
      channels on the 3D cell migration and neurite outgrowth. This method for
      immobilizing biomolecules in 3D matrices can generally be applied to any
      optically clear hydrogel, offering a solution to construct scaffolds with
      programmed spatial features for tissue engineering applications.

PMID- 15034560
TI  - Stimuli-responsive polypeptide vesicles by conformation-specific assembly.
AB  - In biology, lipids are well known for their ability to assemble into spherical
      vesicles. Proteins, in particular virus capsids, can also form regular vesicle
      like structures, where the precise folding and stable conformations of many
      identical subunits directs their self-assembly. Functionality present on these
      subunits also controls their disassembly within the cellular environment, for
      example, in response to a pH change. Here, we report the preparation of diblock
      copolypeptides that self-assemble into spherical vesicular assemblies whose size
      and structure are dictated primarily by the ordered conformations of the polymer
      segments, in a manner similar to viral capsid assembly. Furthermore,
      functionality was incorporated into these molecules to render them susceptible to
      environmental stimuli, which is desirable for drug-delivery applications. The
      control of assembly and function exhibited in these systems is a significant
      advance towards the synthesis of materials that can mimic the precise three
      dimensional assembly found in proteins.

PMID- 15034561
TI  - Oxidation of plutonium dioxide.
AB  - The physics and chemistry of the actinide elements form the scientific basis for
      rational handling of nuclear materials. In recent experiments, most unexpectedly,
      plutonium dioxide has been found to react with water to form higher oxides up to
      PuO(2.27), whereas PuO(2) had always been thought to be the highest stable oxide
      of plutonium. We perform a theoretical analysis of this complicated situation on
      the basis of total energies calculated within density functional theory combined
      with well-established thermodynamic data. The reactions of PuO(2) with either
      O(2) or H(2)O to form PuO(2+delta) are calculated to be endothermic: that is, in
      order to occur they require a supply of energy. However, our calculations show
      that PuO(2+delta) can be formed, as an intermediate product, by reactions with
      the products of radiolysis of water, such as H(2)O(2).

PMID- 15034562
TI  - Sequential switch of biomineral crystal morphology using trivalent ions.
AB  - Many biominerals are laminated such that crystal shape or habit changes from
      layer to layer thus yielding exquisitely designed composite materials with
      tightly controlled properties. Although lamination in biominerals is usually
      performed using peptides and proteins, here we introduce a new strategy by which
      sequential addition or depletion of inorganic trivalent ions in a supersaturated
      solution can be used to switch the surface morphology of calcium oxalate
      monohydrate (COM) back and forth, resulting in either the growth of flat
      crystalline sheets or of nanostructures oriented perpendicular to the surface. We
      propose that the occupation of a Ca(2+) site by Eu(3+) ion switches the
      orientation of the COM unit cell. The need to compensate the third charge forces
      coordination of Eu(3+) to an additional oxalate ion ((-)OOC-COO(-)) in an
      orientation that is not compatible with the initial unit cell. This mechanism of
      switching the orientation of the unit cell is unique, as it does not involve the
      use of expensive and thermally labile biomolecules. Suggestions of how to extend
      this strategy to engineer non-biological nanocomposites are given.

PMID- 15034563
TI  - Anomalous Hall effect governed by electron doping in a room-temperature
      transparent ferromagnetic semiconductor.
AB  - Ferromagnetic semiconductors are believed to be suitable for future spintronics,
      because both charge and spin degrees of freedom can be manipulated by external
      stimuli. One of the most important characteristics of ferromagnetic
      semiconductors is the anomalous Hall effect. This is because the
      ferromagnetically spin-polarized carrier can be probed and controlled
      electrically, leading to direct application for electronics. Control of the Curie
      temperature and magnetization direction by electronic field, and photo-induced
      ferromagnetism have been performed successfully using the anomalous Hall effect
      for group III-V ferromagnetic semiconductors. In these cases, the operation
      temperature was much below room temperature because of the limited Curie
      temperature of less than 160 K (ref. 6). Here, we report on the anomalous Hall
      effect governed by electron doping in a room-temperature transparent
      ferromagnetic semiconductor, rutile Ti(1-x)Co(x)O(2-delta) (of oxygen deficiency
      delta). This result manifests the intrinsic nature of ferromagnetism in this
      compound, and represents the possible realization of transparent semiconductor
      spintronics devices operable at room temperature.

PMID- 15034564
TI  - Enhancement of nonlinear effects using photonic crystals.
AB  - The quest for all-optical signal processing is generally deemed to be impractical
      because optical nonlinearities are usually weak. The emerging field of nonlinear
      photonic crystals seems destined to change this view dramatically. Theoretical
      considerations show that all-optical devices using photonic crystal designs
      promise to be smaller than the wavelength of light, and to operate with
      bandwidths that are very difficult to achieve electronically. When created in
      commonly used materials, these devices could operate at powers of only a few
      milliwatts. Moreover, if these designs are combined with materials and systems
      that support electromagnetically induced transparency, operation at single-photon
      power levels could be feasible.

PMID- 15034565
TI  - Large anomalous Hall effect in a silicon-based magnetic semiconductor.
AB  - Magnetic semiconductors are attracting great interest because of their potential
      use for spintronics, a new technology that merges electronics with the
      manipulation of conduction electron spins. (GaMn)As and (GaMn)N have recently
      emerged as the most popular materials for this new technology, and although their
      Curie temperatures are rising towards room temperature, these materials can only
      be fabricated in thin-film form, are heavily defective, and are not obviously
      compatible with Si. We show here that it is productive to consider transition
      metal monosilicides as potential alternatives. In particular, we report the
      discovery that the bulk metallic magnets derived from doping the narrow-gap
      insulator FeSi with Co share the very high anomalous Hall conductance of
      (GaMn)As, while displaying Curie temperatures as high as 53 K. Our work opens up
      a new arena for spintronics, involving a bulk material based only on transition
      metals and Si, which displays large magnetic-field effects on its electrical
      properties.

PMID- 15034566
TI  - Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol
      levels to activation of innate immunity signaling pathways.
AB  - Atherosclerosis, the leading cause of death in developed countries, has been
      linked to hypercholesterolemia for decades. More recently, atherosclerotic lesion
      progression has been shown to depend on persistent, chronic inflammation in the
      artery wall. Although several studies have implicated infectious agents in this
      process, the role of infection in atherosclerosis remains controversial. Because
      the involvement of monocytes and macrophages in the pathogenesis of
      atherosclerosis is well established, we investigated the possibility that
      macrophage innate immunity signaling pathways normally activated by pathogens
      might also be activated in response to hyperlipidemia. We examined
      atherosclerotic lesion development in uninfected, hyperlipidemic mice lacking
      expression of either lipopolysaccharide (LPS) receptor CD14 or myeloid
      differentiation protein-88 (MyD88), which transduces cell signaling events
      downstream of the Toll-like receptors (TLRs), as well as receptors for
      interleukin-1 (IL-1) and IL-18. Whereas the MyD88-deficient mice evinced a marked
      reduction in early atherosclerosis, mice deficient in CD14 had no decrease in
      early lesion development. Inactivation of the MyD88 pathway led to a reduction in
      atherosclerosis through a decrease in macrophage recruitment to the artery wall
      that was associated with reduced chemokine levels. These findings link elevated
      serum lipid levels to a proinflammatory signaling cascade that is also engaged by
      microbial pathogens.

PMID- 15034567
TI  - A CD4(+) T-cell immune response to a conserved epitope in the circumsporozoite
      protein correlates with protection from natural Plasmodium falciparum infection
      and disease.
AB  - Many human T-cell responses specific for epitopes in Plasmodium falciparum have
      been described, but none has yet been shown to be predictive of protection
      against natural malaria infection. Here we report a peptide-specific T-cell assay
      that is strongly associated with protection of humans in The Gambia, West Africa,
      from both malaria infection and disease. The assay detects interferon-gamma
      secreting CD4(+) T cells specific for a conserved sequence from the
      circumsporozoite protein, which binds to many human leukocyte antigen (HLA)-DR
      types. The correlation was observed using a cultured, rather than an ex vivo,
      ELISPOT assay that measures central memory-'type T cells rather than activated
      effector T cells. These findings provide direct evidence for a protective role
      for CD4(+) T cells in humans, and a precise target for the design of improved
      vaccines against P. falciparum.

PMID- 15034568
TI  - CDC91L1 (PIG-U) is a newly discovered oncogene in human bladder cancer.
AB  - Genomic amplification at 20q11-13 is a common event in human cancers. We isolated
      a germline translocation breakpoint at 20q11 from a bladder cancer patient. We
      identified CDC91L1, the gene encoding CDC91L1 (also called phosphatidylinositol
      glycan class U (PIG-U), a transamidase complex unit in the
      glycosylphosphatidylinositol (GPI) anchoring pathway), as the only gene whose
      expression was affected by the translocation. CDC91L1 was amplified and
      overexpressed in about one-third of bladder cancer cell lines and primary tumors,
      as well as in oncogenic uroepithelial cells transformed with human papillomavirus
      (HPV) E7. Forced overexpression of CDC91L1 malignantly transformed NIH3T3 cells
      in vitro and in vivo. Overexpression of CDC91L1 also resulted in upregulation of
      the urokinase receptor (uPAR), a GPI-anchored protein, and in turn increased STAT
      3 phosphorylation in bladder cancer cells. Our findings suggest that CDC91L1 is
      an oncogene in bladder cancer, and implicate the GPI anchoring system as a
      potential oncogenic pathway and therapeutic target in human cancers.

PMID- 15034569
TI  - Noninvasive electrocardiographic imaging for cardiac electrophysiology and
      arrhythmia.
AB  - Over 7 million people worldwide die annually from erratic heart rhythms (cardiac
      arrhythmias), and many more are disabled. Yet there is no imaging modality to
      identify patients at risk, provide accurate diagnosis and guide therapy. Standard
      diagnostic techniques such as the electrocardiogram (ECG) provide only low
      resolution projections of cardiac electrical activity on the body surface. Here
      we demonstrate the successful application in humans of a new imaging modality
      called electrocardiographic imaging (ECGI), which noninvasively images cardiac
      electrical activity in the heart. In ECGI, a multielectrode vest records 224 body
      surface electrocardiograms; electrical potentials, electrograms and isochrones
      are then reconstructed on the heart's surface using geometrical information from
      computed tomography (CT) and a mathematical algorithm. We provide examples of
      ECGI application during atrial and ventricular activation and ventricular
      repolarization in (i) normal heart (ii) heart with a conduction disorder (right
      bundle branch block) (iii) focal activation initiated by right or left
      ventricular pacing, and (iv) atrial flutter.

PMID- 15034570
TI  - A new role for Nogo as a regulator of vascular remodeling.
AB  - Although Nogo-A has been identified in the central nervous system as an inhibitor
      of axonal regeneration, the peripheral roles of Nogo isoforms remain virtually
      unknown. Here, using a proteomic analysis to identify proteins enriched in
      caveolae and/or lipid rafts (CEM/LR), we show that Nogo-B is highly expressed in
      cultured endothelial and smooth muscle cells, as well as in intact blood vessels.
      The N terminus of Nogo-B promotes the migration of endothelial cells but inhibits
      the migration of vascular smooth muscle (VSM) cells, processes necessary for
      vascular remodeling. Vascular injury in Nogo-A/B-deficient mice promotes
      exaggerated neointimal proliferation, and adenoviral-mediated gene transfer of
      Nogo-B rescues the abnormal vascular expansion in those knockout mice. Our
      discovery that Nogo-B is a regulator of vascular homeostasis and remodeling
      broadens the functional scope of this family of proteins.

PMID- 15034571
TI  - Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease
      progression in ALS mice.
AB  - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in
      which motoneurons of the spinal cord and motor cortex die, resulting in
      progressive paralysis. This condition has no cure and results in eventual death,
      usually within 1-5 years of diagnosis. Although the specific etiology of ALS is
      unknown, 20% of familial cases of the disease carry mutations in the gene
      encoding Cu/Zn superoxide dismutase-1 (SOD1). Transgenic mice overexpressing
      human mutant SOD1 have a phenotype and pathology that are very similar to that
      seen in human ALS patients. Here we show that treatment with arimoclomol, a
      coinducer of heat shock proteins (HSPs), significantly delays disease progression
      in mice expressing a SOD1 mutant in which glycine is substituted with alanine at
      position 93 (SOD1(G93A)). Arimoclomol-treated SOD1(G93A) mice show marked
      improvement in hind limb muscle function and motoneuron survival in the later
      stages of the disease, resulting in a 22% increase in lifespan. Pharmacological
      activation of the heat shock response may therefore be a successful therapeutic
      approach to treating ALS, and possibly other neurodegenerative diseases.

PMID- 15034572
TI  - Antisickling effects of an endogenous human alpha-like globin.
AB  - Gene replacement or gene reactivation therapies for sickle-cell disease (SCD)
      typically target the mutant beta(S)-globin subunits of hemoglobin-S
      (alpha(2)beta(S)(2)) for substitution by nonpathological beta-like globins. Here
      we show, in vitro and in vivo in a transgenic mouse model of SCD, that the
      adverse properties of hemoglobin-S can be reversed by exchanging its normal alpha
      globin subunits for zeta-globin, an endogenous, developmentally silenced, non
      beta-like globin.

PMID- 15034573
TI  - Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie
      Tooth disease.
AB  - Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral
      neuropathy, affecting 1 in 2,500 people. The only treatment currently available
      is rehabilitation or corrective surgery. The most frequent form of the disease,
      CMT-1A, involves abnormal myelination of the peripheral nerves. Here we used a
      mouse model of CMT-1A to test the ability of ascorbic acid, a known promoter of
      myelination, to correct the CMT-1A phenotype. Ascorbic acid treatment resulted in
      substantial amelioration of the CMT-1A phenotype, and reduced the expression of
      PMP22 to a level below what is necessary to induce the disease phenotype. As
      ascorbic acid has already been approved by the FDA for other clinical
      indications, it offers an immediate therapeutic possibility for patients with the
      disease.

PMID- 15034574
TI  - Identification of a new human coronavirus.
AB  - Three human coronaviruses are known to exist: human coronavirus 229E (HCoV-229E),
      HCoV-OC43 and severe acute respiratory syndrome (SARS)-associated coronavirus
      (SARS-CoV). Here we report the identification of a fourth human coronavirus, HCoV
      NL63, using a new method of virus discovery. The virus was isolated from a 7
      month-old child suffering from bronchiolitis and conjunctivitis. The complete
      genome sequence indicates that this virus is not a recombinant, but rather a new
      group 1 coronavirus. The in vitro host cell range of HCoV-NL63 is notable because
      it replicates on tertiary monkey kidney cells and the monkey kidney LLC-MK2 cell
      line. The viral genome contains distinctive features, including a unique N
      terminal fragment within the spike protein. Screening of clinical specimens from
      individuals suffering from respiratory illness identified seven additional HCoV
      NL63-infected individuals, indicating that the virus was widely spread within the
      human population.

PMID- 15034575
TI  - Induction of T cell development and establishment of T cell competence from
      embryonic stem cells differentiated in vitro.
AB  - Embryonic stem cells (ESCs) have the potential to serve as a renewable source of
      transplantable tissue-specific stem cells. However, the molecular cues necessary
      to direct the differentiation of ESCs toward specific cell lineages remain
      obscure. Here we report the successful induction of ESC differentiation into
      mature functional T lymphocytes with a simple in vitro coculture system. The
      directed differentiation of ESCs into T cells required the engagement of Notch
      receptors by Delta-like 1 ligand (DL1) expressed on the OP9-DL1 stromal cell
      line. We found a normal program of T cell differentiation in ESC-OP9-DL1 cell
      cocultures. ESC-derived T cell progenitors effectively reconstituted the T cell
      compartment of immunodeficient mice, enabling an effective response to a viral
      infection. These findings provide a powerful tool for the molecular analysis of T
      cell development and open new avenues for the development of immunotherapeutic
      approaches using defined sources of stem cells.

PMID- 15034576
TI  - Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis
      airway.
AB  - In cystic fibrosis, dysregulated neutrophilic inflammation and chronic infection
      lead to progressive destruction of the airways. The underlying mechanisms have
      remained unclear. Lipoxins are anti-inflammatory lipid mediators that modulate
      neutrophilic inflammation. We report here that lipoxin concentrations in airway
      fluid were significantly suppressed in patients with cystic fibrosis compared to
      patients with other inflammatory lung conditions. We also show that
      administration of a metabolically stable lipoxin analog in a mouse model of the
      chronic airway inflammation and infection associated with cystic fibrosis
      suppressed neutrophilic inflammation, decreased pulmonary bacterial burden and
      attenuated disease severity. These findings suggest that there is a
      pathophysiologically important defect in lipoxin-mediated anti-inflammatory
      activity in the cystic fibrosis lung and that lipoxins have therapeutic potential
      in this lethal autosomal disease.

PMID- 15034578
TI  - Limited number of patrilines in horse domestication.
AB  - Genetic studies using mitochondrial DNA (mtDNA) have identified extensive
      matrilinear diversity among domestic horses. Here, we show that this high degree
      of polymorphism is not matched by a corresponding patrilinear diversity of the
      male-specific Y chromosome. In fact, a screening for single-nucleotide
      polymorphisms (SNPs) in 14.3 kb of noncoding Y chromosome sequence among 52 male
      horses of 15 different breeds did not identify a single segregation site. These
      observations are consistent with a strong sex-bias in the domestication process,
      with few stallions contributing genetically to the domestic horse.

PMID- 15034579
TI  - A previously unidentified MECP2 open reading frame defines a new protein isoform
      relevant to Rett syndrome.
AB  - Rett syndrome is caused by mutations in the gene MECP2 in approximately 80% of
      affected individuals. We describe a previously unknown MeCP2 isoform. Mutations
      unique to this isoform and the absence, until now, of identified mutations
      specific to the previously recognized protein indicate an important role for the
      newly discovered molecule in the pathogenesis of Rett syndrome.

PMID- 15034580
TI  - ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP
      channel gating.
AB  - Stress tolerance of the heart requires high-fidelity metabolic sensing by ATP
      sensitive potassium (K(ATP)) channels that adjust membrane potential-dependent
      functions to match cellular energetic demand. Scanning of genomic DNA from
      individuals with heart failure and rhythm disturbances due to idiopathic dilated
      cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory
      SUR2A subunit of the cardiac K(ATP) channel. These missense and frameshift
      mutations mapped to evolutionarily conserved domains adjacent to the catalytic
      ATPase pocket within SUR2A. Mutant SUR2A proteins showed aberrant redistribution
      of conformations in the intrinsic ATP hydrolytic cycle, translating into abnormal
      K(ATP) channel phenotypes with compromised metabolic signal decoding. Defective
      catalysis-mediated pore regulation is thus a mechanism for channel dysfunction
      and susceptibility to dilated cardiomyopathy.

PMID- 15034581
TI  - Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in
      colorectal cancer.
AB  - Aberrant WNT pathway signaling is an early progression event in 90% of colorectal
      cancers. It occurs through mutations mainly of APC and less often of CTNNB1
      (encoding beta-catenin) or AXIN2 (encoding axin-2, also known as conductin).
      These mutations allow ligand-independent WNT signaling that culminates in
      abnormal accumulation of free beta-catenin in the nucleus. We previously
      identified frequent promoter hypermethylation and gene silencing of the genes
      encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer. SFRPs
      possess a domain similar to one in the WNT-receptor frizzled proteins and can
      inhibit WNT receptor binding to downregulate pathway signaling during
      development. Here we show that restoration of SFRP function in colorectal cancer
      cells attenuates WNT signaling even in the presence of downstream mutations. We
      also show that the epigenetic loss of SFRP function occurs early in colorectal
      cancer progression and may thus provide constitutive WNT signaling that is
      required to complement downstream mutations in the evolution of colorectal
      cancer.

PMID- 15034582
TI  - Inclusion body myopathy associated with Paget disease of bone and frontotemporal
      dementia is caused by mutant valosin-containing protein.
AB  - Inclusion body myopathy associated with Paget disease of bone and frontotemporal
      dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome
      9p21.1-p12. We investigated 13 families with IBMPFD linked to chromosome 9 using
      a candidate-gene approach. We found six missense mutations in the gene encoding
      valosin-containing protein (VCP, a member of the AAA-ATPase superfamily)
      exclusively in all 61 affected individuals. Haplotype analysis indicated that
      descent from two founders in two separate North American kindreds accounted for
      IBMPFD in approximately 50% of affected families. VCP is associated with a
      variety of cellular activities, including cell cycle control, membrane fusion and
      the ubiquitin-proteasome degradation pathway. Identification of VCP as causing
      IBMPFD has important implications for other inclusion-body diseases, including
      myopathies, dementias and Paget disease of bone (PDB), as it may define a new
      common pathological ubiquitin-based pathway.

PMID- 15034583
TI  - The X-linked mental retardation protein oligophrenin-1 is required for dendritic
      spine morphogenesis.
AB  - Of 11 genes involved in nonspecific X-linked mental retardation (MRX), three
      encode regulators or effectors of the Rho GTPases, suggesting an important role
      for Rho signaling in cognitive function. It remains unknown, however, how
      mutations in Rho-linked genes lead to MRX. Here we report that oligophrenin-1, a
      Rho-GTPase activating protein that is absent in a family affected with MRX, is
      required for dendritic spine morphogenesis. Using RNA interference and antisense
      RNA approaches, we show that knock-down of oligophrenin-1 levels in CA1 neurons
      in rat hippocampal slices significantly decreases spine length. This phenotype
      can be recapitulated using an activated form of RhoA and rescued by inhibiting
      Rho-kinase, indicating that reduced oligophrenin-1 levels affect spine length by
      increasing RhoA and Rho-kinase activities. We further demonstrate an interaction
      between oligophrenin-1 and the postsynaptic adaptor protein Homer. Our findings
      provide the first insight into how mutations in a Rho-linked MRX gene may
      compromise neuronal function.

PMID- 15034584
TI  - Tenascin-R mediates activity-dependent recruitment of neuroblasts in the adult
      mouse forebrain.
AB  - Neuroblasts arising in the adult forebrain that travel to the olfactory bulb use
      two modes of migration: tangentially, along the rostral migratory stream, and
      radially, in the core of the olfactory bulb where they start to ascend to the
      outer layers. Although the mechanisms of tangential migration have been
      extensively studied, the factors controlling radial migration remain unexplored.
      Here we report that the extracellular matrix glycoprotein tenascin-R, expressed
      in the adult mouse olfactory bulb, initiates both the detachment of neuroblasts
      from chains and their radial migration. Expression of tenascin-R is activity
      dependent, as it is markedly reduced by odor deprivation. Furthermore, grafting
      of tenascin-R-transfected cells into non-neurogenic regions reroutes migrating
      neuroblasts toward these regions. The identification of an extracellular
      microenvironment capable of directing migrating neuroblasts provides insights
      into the mechanisms regulating radial migration in the adult olfactory bulb and
      offers promising therapeutic venues for brain repair.

PMID- 15034585
TI  - Stability of dendritic spines and synaptic contacts is controlled by alpha N
      catenin.
AB  - Morphological plasticity of dendritic spines and synapses is thought to be
      crucial for their physiological functions. Here we show that alpha N-catenin, a
      linker between cadherin adhesion receptors and the actin cytoskeleton, is
      essential for stabilizing dendritic spines in rodent hippocampal neurons in
      culture. In the absence of alpha N-catenin, spine heads were abnormally motile,
      actively protruding filopodia from their synaptic contact sites. Conversely,
      alpha N-catenin overexpression in dendrites reduced spine turnover, causing an
      increase in spine and synapse density. Tetrodotoxin (TTX), a neural activity
      blocker, suppressed the synaptic accumulation of alpha N-catenin, whereas
      bicuculline, a GABA antagonist, promoted it. Furthermore, excess alpha N-catenin
      rendered spines resistant to the TTX treatment. These results suggest that alpha
      N-catenin is a key regulator for the stability of synaptic contacts.

PMID- 15034586
TI  - Parietal somatosensory association cortex mediates affective blindsight.
AB  - To investigate the neural substrates underlying emotional feelings in the absence
      of a conscious stimulus percept, we presented a visual stimulus in the blind
      field of partially cortically blind patients and measured cortical activity (by
      functional magnetic resonance imaging, fMRI) before and after the stimulus had
      been paired with an aversive event. After pairing, self-reported negative
      emotional valence and blood oxygen level-dependent (BOLD) responses in
      somatosensory association areas were enhanced, whereby somatosensory activity
      predicted highly corresponding reported feelings and startle reflex amplitudes
      across subjects. Our data provide direct evidence that cortical activity
      representing physical emotional states governs emotional feelings.

PMID- 15034588
TI  - A psychophysical test of the vibration theory of olfaction.
AB  - At present, no satisfactory theory exists to explain how a given molecule results
      in the perception of a particular smell. One theory is that olfactory sensory
      neurons detect intramolecular vibrations of the odorous molecule. We used
      psychophysical methods in humans to test this vibration theory of olfaction and
      found no evidence to support it.

PMID- 15034587
TI  - Cholecystokinin-mediated suppression of feeding involves the brainstem
      melanocortin system.
AB  - Hypothalamic pro-opiomelanocortin (POMC) neurons help regulate long-term energy
      stores. POMC neurons are also found in the nucleus tractus solitarius (NTS), a
      region regulating satiety. We show here that mouse brainstem NTS POMC neurons are
      activated by cholecystokinin (CCK) and feeding-induced satiety and that
      activation of the neuronal melanocortin-4 receptor (MC4-R) is required for CCK
      induced suppression of feeding; the melanocortin system thus provides a potential
      substrate for integration of long-term adipostatic and short-term satiety
      signals.

PMID- 15034589
TI  - Reverse propagation of sound in the gerbil cochlea.
AB  - It is commonly believed that the cochlea emits sounds through backward-traveling
      waves. In the present experiment using a scanning-laser interferometer, I
      detected forward-traveling but not backward-traveling waves and found that the
      stapes vibrates earlier than the basilar membrane. These results contradict the
      current theory and show that the ear emits sounds through the cochlear fluids as
      compression waves rather than along the basilar membrane as backward-traveling
      waves.

PMID- 15034591
TI  - Too little, too late: when is the right time for new leadership in biotech?

PMID- 15034590
TI  - Differential control over cocaine-seeking behavior by nucleus accumbens core and
      shell.
AB  - Nucleus accumbens (NAc) dopamine is widely implicated in mediating the
      reinforcing effects of drugs of abuse. However, the precise function of the NAc
      itself in drug self-administration has been difficult to establish. Here we show
      a neural double-dissociation of the behavioral processes that underlie cocaine
      self-administration in rats. Whereas selective excitotoxic lesions of the NAc
      core had only a minor effect on the acquisition of responding for cocaine under a
      standard schedule of continuous reinforcement, these lesions profoundly impaired
      the acquisition of drug-seeking behavior that was maintained by drug-associated
      conditioned reinforcers and assessed using a second-order schedule of cocaine
      reinforcement. In contrast, selective excitotoxic lesions of the NAc shell did
      not impair drug self-administration or the acquisition of cocaine-seeking, but
      they did attenuate the psychostimulant effects of cocaine. These results further
      our understanding of how the NAc controls drug-seeking and drug-taking behavior.

PMID- 15034592
TI  - Reversible site-selective labeling of membrane proteins in live cells.
AB  - Chemical and biological labeling is fundamental for the elucidation of the
      function of proteins within biochemical cellular networks. In particular,
      fluorescent probes allow detection of molecular interactions, mobility and
      conformational changes of proteins in live cells with high temporal and spatial
      resolution. We present a generic method to label proteins in vivo selectively,
      rapidly (seconds) and reversibly, with small molecular probes that can have a
      wide variety of properties. These probes comprise a chromophore and a metal-ion
      chelating nitrilotriacetate (NTA) moiety, which binds reversibly and specifically
      to engineered oligohistidine sequences in proteins of interest. We demonstrate
      the feasibility of the approach by binding NTA-chromophore conjugates to a
      representative ligand-gated ion channel and G protein-coupled receptor, each
      containing a polyhistidine sequence. We investigated the ionotropic 5HT(3)
      serotonin receptor by fluorescence measurements to characterize in vivo the probe
      receptor interactions, yielding information on structure and plasma membrane
      distribution of the receptor.

PMID- 15034593
TI  - Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in
      myocardial infarcts.
AB  - The mammalian heart has a very limited regenerative capacity and, hence, heals by
      scar formation. Recent reports suggest that haematopoietic stem cells can
      transdifferentiate into unexpected phenotypes such as skeletal muscle,
      hepatocytes, epithelial cells, neurons, endothelial cells and cardiomyocytes, in
      response to tissue injury or placement in a new environment. Furthermore,
      transplanted human hearts contain myocytes derived from extra-cardiac progenitor
      cells, which may have originated from bone marrow. Although most studies suggest
      that transdifferentiation is extremely rare under physiological conditions,
      extensive regeneration of myocardial infarcts was reported recently after direct
      stem cell injection, prompting several clinical trials. Here, we used both
      cardiomyocyte-restricted and ubiquitously expressed reporter transgenes to track
      the fate of haematopoietic stem cells after 145 transplants into normal and
      injured adult mouse hearts. No transdifferentiation into cardiomyocytes was
      detectable when using these genetic techniques to follow cell fate, and stem-cell
      engrafted hearts showed no overt increase in cardiomyocytes compared to sham
      engrafted hearts. These results indicate that haematopoietic stem cells do not
      readily acquire a cardiac phenotype, and raise a cautionary note for clinical
      studies of infarct repair.

PMID- 15034594
TI  - Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic
      myocardium.
AB  - Under conditions of tissue injury, myocardial replication and regeneration have
      been reported. A growing number of investigators have implicated adult bone
      marrow (BM) in this process, suggesting that marrow serves as a reservoir for
      cardiac precursor cells. It remains unclear which BM cell(s) can contribute to
      myocardium, and whether they do so by transdifferentiation or cell fusion. Here,
      we studied the ability of c-kit-enriched BM cells, Lin- c-kit+ BM cells and c
      kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells to
      regenerate myocardium in an infarct model. Cells were isolated from transgenic
      mice expressing green fluorescent protein (GFP) and injected directly into
      ischaemic myocardium of wild-type mice. Abundant GFP+ cells were detected in the
      myocardium after 10 days, but by 30 days, few cells were detectable. These GFP+
      cells did not express cardiac tissue-specific markers, but rather, most of them
      expressed the haematopoietic marker CD45 and myeloid marker Gr-1. We also studied
      the role of circulating cells in the repair of ischaemic myocardium using GFP+
      GFP- parabiotic mice. Again, we found no evidence of myocardial regeneration from
      blood-borne partner-derived cells. Our data suggest that even in the
      microenvironment of the injured heart, c-kit-enriched BM cells, Lin- c-kit+ BM
      cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic
      stem cells adopt only traditional haematopoietic fates.

PMID- 15034595
TI  - Stem cells: lost in translation.

PMID- 15034596
TI  - Adult bone marrow-derived cells trans-differentiating into insulin-producing
      cells for the treatment of type I diabetes.
AB  - Recent findings suggest that bone marrow (BM) cells have the capacity to
      differentiate into a variety of cell types including endocrine cells of the
      pancreas. We report that BM derived cells, when cultured under defined
      conditions, were induced to trans-differentiate into insulin-producing cells.
      Furthermore, these insulin-producing cells formed aggregates that, upon
      transplantation into mice, acquired architecture similar to islets of Langerhans.
      These aggregates showed endocrine gene expression for insulin (I and II),
      glucagon, somatostatin and pancreatic polypeptide. Immunohistochemistry also
      confirmed that these aggregates were positive for insulin, somatostatin,
      pancreatic polypeptide and C-peptide. Also, Western and ELISA analysis
      demonstrated expression of proinsulin and/or secretion of active insulin upon
      glucose challenge. Subcapsular renal transplantation of these aggregates into
      hyperglycemic mice lowered circulating blood glucose levels and maintained
      comparatively normal glucose levels for up to 90 days post-transplantation. Graft
      removal resulted in rapid relapse and death in experimental animals. In addition,
      electron microscopy revealed these aggregates had acquired ultrastructure
      typically associated with mature beta (beta) cells. These results demonstrate
      that adult BM cells are capable of trans-differentiating into a pancreatic
      lineage in vitro and may represent a pool of cells for the treatment of diabetes
      mellitus.

PMID- 15034598
TI  - Short consensus probes with 3'-minor groove binder of the immunoglobulin heavy
      chain gene for real-time quantitative PCR in B-cell non-Hodgkin lymphomas.
AB  - We used 3'-minor groove binder (MGB) technology to develop consensus
      fluorogenically labeled probes of the immunoglobulin heavy-chain (IgH) gene for
      detecting minimal residual disease (MRD) in B-cell non-Hodgkin lymphoma (B-NHL).
      Sequence data from 59 patients with B-NHLs revealed a narrow consensus region as
      a result of somatic hypermutations and variable VH usage, indicating that it
      would be difficult to design ordinary non-MGB probes. MGB probes, characterized
      by shorter length but higher melting temperature, are more suitable for this
      situation than ordinary non-MGB probes. In fact, the present data indicated that
      about 20% more cases were detectable with MGB probes (34/59, 57.6%) than with the
      non-MGB probes (23/59, 39.0%) designed by Donovan et al. MGB technology is useful
      for the design of consensus fluorogenically labeled probes of the IgH gene for
      detecting MRD.

PMID- 15034597
TI  - Human heparanase nuclear localization and enzymatic activity.
AB  - In previous studies, we have demonstrated that human heparanase (endo-beta-D
      glucuronidase) is localized primarily in a perinuclear pattern within lysosomes
      and late endosomes, and occasionally may be surface associated and secreted. The
      presence of two potential nuclear localization sequences in human heparanase, led
      us to investigate heparanase translocation into the nucleus and subsequent
      degradation of nuclear heparan sulfate. Applying cell fractionation, Western blot
      analysis, determination of heparanase activity and confocal microscopy, we
      identified heparanase within the nuclei of human glioma and breast carcinoma
      cells and estimated its amount to be about 7% of the cytosolic enzyme. Our
      results indicate that nuclear heparanase colocalizes with nuclear heparan sulfate
      and is enzymaticaly active. Moreover, following uptake of latent 65 kDa
      heparanase by cells that do not express the enzyme, an active 50 kDa heparanase
      was detected in the cell nucleus, capable of degrading both nuclear and
      extracellular matrix-derived heparan sulfate. Immunohistochemical examination of
      human squamous cell carcinoma specimens revealed a prominent granular staining of
      heparanase within the nuclei of the epithelial tumor cells vs no nuclear staining
      in the adjacent stromal cells. Taken together, it appears that heparanase is
      translocated into the cell nucleus where it may degrade the nuclear heparan
      sulfate and thereby affect nuclear functions that are thought to be regulated by
      heparan sulfate. Nuclear localization of heparanase suggests that the enzyme may
      fulfill nontraditional functions (ie, regulation of gene expression and signal
      transduction) apart of its well-documented involvement in cancer metastasis,
      angiogenesis and inflammation.

PMID- 15034599
TI  - The significance of key regulators of apoptosis in the development and prognosis
      of prostate carcinoma. I. Proteins of the Bcl-2 family and protein p53.
AB  - The molecular basis for the transition of carcinoma of the prostate from androgen
      dependent to androgen-independent growth is largely unknown. Currently for
      example, it is not clear whether the androgen-independent phenotype is a result
      of selection of a subgroup of genetically distinct prostate tumour cells which
      are already hormone-resistant or a genetic adaptation of prostate tumour cells to
      the hormone therapy itself. It has also been established that prostate tumour
      transformation is a result of homeostatic control defects, a line of thinking
      directed toward elucidating the apoptotic profile of prostate tumour cells that
      may be important in determining prognosis, response to therapy and illness
      progression. Main consideration in this part of rewiev is given to the role of
      Bcl-2 and members of the Bcl-2 family, and tumour suppressor gene p53.

PMID- 15034600
TI  - The significance of key regulators of apoptosis in the development and prognosis
      of prostate carcinoma. II. Products of suppressor genes Rb and PTEN, CDKI, Fas.
AB  - The molecular basis for the transition of carcinoma of the prostate from androgen
      dependent to androgen-independent growth is largely unknown. Currently for
      example, it is not clear whether the androgen-independent phenotype is a result
      of selection of a subgroup of genetically distinct prostate tumour cells which
      are already hormone-resistant or a genetic adaptation of prostate tumour cells to
      the hormone therapy itself. It has also been established that prostate tumour
      transformation is a result of homeostatic control defects, a line of thinking
      directed toward elucidating the apoptotic profile of prostate tumour cells that
      may be important in determining prognosis, response to therapy and illness
      progression. Main consideration in this part of rewiev is given to the role of
      tumour suppressor genes pRb and PTEN and also the natural inhibitors of cyclin
      dependent kinases - proteins p21(Waf1/Cip1) and p27(Kip1). Attention is also
      given to the role of FAS-mediated pathways in apoptosis induction.

PMID- 15034601
TI  - The mechanism of action of the tumour suppressor gene PTEN.
AB  - Intracellular levels of phosphorylation are regulated by the coordinated action
      of protein kinases and phosphatases. Disregulation of this balance can lead to
      cellular transformation. Here we review knowledge of the mechanisms of one
      protein phosphatase, the tumour suppressor PTEN/MMAC/TEP 1 apropos its role in
      tumorigenesis and signal transduction. PTEN plays an important role in the
      phosphatidyl-inositol-3-kinase (PI3-K) pathway by catalyzing degradation of
      phosphatidylinositol-(3,4,5)-triphosphate generated by PI3-K. This inhibits
      downstream targets mainly protein kinase B (PKB/Akt), cell survival and
      proliferation. PTEN contributes to cell cycle regulation by blockade of cells
      entering the S phase of the cell cycle, and by upregulation of p27(Kip1) which is
      recruited into the cyclin E/cdk2 complex. PTEN also modulates cell migration and
      motility by regulation of the extracellular signal-related kinase - mitogen
      activated protein kinase (ERK-MAPK) pathway and by dephosphorylation of focal
      adhesion kinase (FAK). We also emphasize the increasingly important role that
      PTEN has from an evolutionary point of view. A number of PTEN functions have been
      elucidated but more information is needed for utilization in clinical application
      and potential cancer therapy.

PMID- 15034602
TI  - Pathogenesis of prosthesis-related infection.
AB  - In spite of its incidence decreasing to 1% nowadays, prosthesis-related infection
      remains a research, diagnostic, therapeutic and cost-related problem. It can be
      defined as a presence of bacteria in the artificial joint space, which is
      significantly associated with evident laboratory and/or tissue markers, and
      clinical signs of running infection. We believe that the more precise
      understanding of pathogenesis, the more effective preventative and therapeutic
      measures, and the lower infection rate. The implants are colonized by airborne,
      skin-, and/ or surgeon-related bacteria during surgery despite being operated in
      closely respected operating regime. Some prosthetic characteristics are
      advantageous and may play important roles in the process of bacterial adherence.
      After successful attachment on the biomaterial surface bacteria multiply and
      physiologically transform into a "biofilm" community, making them much more
      resistant to antibiotic therapy and host immunity. Bacterial resistance is a
      complex phenomenon influenced by intrinsic and extrinsic factors, including the
      cell configuration in the biofilm community. So the cure of periprosthetic sepsis
      without removing of all foreign bodies and necrotic bone fragments is often
      ineffective. Acute hematogenous sepsis is suggestive of a distortion of a
      previously aseptic joint space by invasion of bacteria through the vessels.

PMID- 15034603
TI  - Pathobiology of androgenetic alopecia.
AB  - Human hair morphogenesis is a dynamic process caused by the remodelling of the
      skin. Hair growth is cyclic in mammals consisting of three distinct stages: an
      active stage (anagen), a regressive stage (catagen), and a resting stage
      (telogen). One disorder in this process is gradual balding of the scalp called
      androgenetic alopecia. Little is known about the cell biological or molecular
      mechanisms involved and thus very little treatment is currently available. In
      this review we focus on the most significant parameters affecting hair growth
      which participate in baldness.

PMID- 15034604
TI  - Haemangiomas of the orbit.
AB  - The authors describe their experience with systemic therapy of cavernous
      haemangiomas making use of interferon alpha. They have successfully used the
      method in treating two female patients with cavernous haemangiomas in the orbit.
      In the first patient, the IFN therapy was followed by surgical removal of the
      tumour. In the second patient, surgical operation was not suitable. After the IFN
      therapy, the patient's state improved both subjectively and objectively.
      Decreased level of bFGF in urine prove to be the criterion for successful
      treatment by IFN. The authors also stress the risk of complications in sucklings.
      When choosing the method of treatment, they emphasize the necessity of
      interdisciplinary cooperation.

PMID- 15034605
TI  - Bone defects of the facial skeleton - replacement with biomaterials.
AB  - The authors report on their experience with bone defect treatment following
      surgery of jaw-bone cysts. This is based on the use of cadaveric ground
      spongiosis saturated with tetracycline and metronidazol solution. The study shows
      the above mentioned material is very suitable for bone defect therapy, and cost
      effective. The results were verified by clinical and X-ray examination.

PMID- 15034606
TI  - Left ventricular diastolic filling in young persons with type 1 diabetes
      mellitus.
AB  - The purpose of this study was to evaluate the influence of diabetes mellitus on
      left ventricular function. Using Doppler echocardiography we examined a group of
      49 young (20-32 years old) persons with type 1 diabetes mellitus and a group of
      healthy age-matched men and evaluated the parameters of diastolic filling of the
      left ventricle (LV). We found significant differences in peak velocity of early
      filling of the left ventricle ((70.07+/-10.84 vers. 78.2+/-10.59 cm.s(-1), p+/-0.
      01), peak velocity of late diastolic filling of LV (A = 47.74+/-11.6 vers.
      43.15+/-7.48 cm.s(-1), p < or = 0.027), ratio E/A (1.53+/-0.4 vers. 1.84+/-0.33),
      time velocity integral of peak E (TVIE = 0.083+/-0.014 vers. 0.1+/-0.022 m, p <
      or = 0.001), time velocity integral of peak A (TVIA = 0.039+/-0.011 vers. 0.037+/
      0.012 m, p < or = 0.3), ratio TVIE/TVIA (2.3+/-0.73 vers. 2.9+/-0.9, p < or =
      0.001), time E (204.4+/-31.59 vers. 198.4+/-19.09 ms, p < or = 0.27), time A
      (126.9 < or = 23.0 vers. 113.5+/-15.59 ms, p < or = 0.002), time E/time A (1.64+/
      0.3 vers. 1.76+/-0.22, p < or = 0.039) and duration of isovolumic relaxation
      period (IVRT = 88.2+/-10.8 vers. 71.13+/-8.4 ms, p < or = 0.0001). Despite
      significant differences all the results were in the range of values for the
      healthy population. However in detailed analysis we found that the values
      measured in young (20-32 years old) persons with type 1 diabetes mellitus
      corresponded with diastolic parameters of healthy men of the age of 50 years and
      more. Thus, diabetes mellitus can influence the relaxation properties of the left
      ventricle.

PMID- 15034607
TI  - Resistin - concentrations in persons with type 2 diabetes mellitus and in
      individuals with acute inflammatory disease.
AB  - Resistin is a recently discovered signal molecule, which could help elucidation
      of the pathophysiology of the insulin resistance and its correlation with
      obesity. As little information was available about resistin determination in
      venous blood at the time of our study, we focused on the question whether any
      correlation exists between persons with type 2 diabetes mellitus, with systemic
      inflammation, healthy persons and resistin concentrations and laboratory markers
      of inflammation, peptone, BMI. Differences of resistin values in these types of
      volunteers were studied as well. METHODS: Persons under study were divided into 3
      groups: group A - with clinical signs of inflammatory disease of respiratory
      tract, leukocytosis > 10000/ul and CRP concentration > 50 mg/l (n = 35); group B 
      with well controlled type 2 DM treated by oral antidiabetic drugs, without
      clinical signs of inflammation and negative case history of acute disease (n =
      12); group C - without clinical signs of inflammation and negative case history
      of acute disease (n = 77). For all volunteers we determined BMI index and
      examined resistin, leptin, interleukin 6, TNF-alpha, Na, K, Cl, insulin,
      cholesterol, HDL-cholesterol, LDL-cholesterol, triacylglycerols, creatinine, uric
      acid, ALT, AST, GMT, P, Mg and albumin in serum. RESULTS: Persons with clinical
      signs of severe inflammation had higher concentrations of Il6, CRP, resistin and
      a markedly lower BMI, decreased values of glucose, sodium, triacylglycerols,
      cholesterol, LDL-cholesterol and HDL-cholesterol compared to diabetics of type 2
      (p < 0.05). Persons with clinical signs of severe inflammation showed
      significantly higher concentrations of TNF-alpha, Il6, CRP, resistin, glucose,
      leptin and considerably lower values of albumin, sodium and HDL-cholesterol than
      healthy individuals (p < 0.05). Persons with type 2 DM had markedly higher values
      of BMI, CRP, glucose, triacylglycerols, LDL-cholesterol, GMT and leptin, compared
      to healthy volunteers (p < 0.05). None of the three groups differed markedly in
      age or sex. Healthy volunteers show a significant correlation between leptin and
      resistin (correlation coefficient 0.82); this correlation was not found in
      patients with inflammation and type 2 DM. The group of volunteers with
      inflammations was found to have a significant positive correlation between
      resistin and inflammatory markers (correlation coefficient 0.3-0.5), negative
      correlation between resistin and cholesterol. We also found positive correlations
      between leptin and BMI as well as negative correlations between leptin and CRP.
      No significant correlations between resistin and other studied parameters were
      found in persons with type 2 DM. CONCLUSION: In healthy population a correlation
      was found between leptin and resistin concentrations in serum. In patients with
      severe inflammatory disease a correlation between resistin concentration and
      laboratory markers of inflammation was shown, however, no correlation was found
      between leptin and resistin. Resistin concentration in the serum of these
      patients is significantly higher ( p < 0.01) compared to healthy subjects and
      well controlled persons with type 2 DM with signs of insulin resistance. This may
      be due to a direct effect of inflammatory cytokines on resistin production. In
      persons with type 2 DM no significant correlations were found between resistin
      and other individual parameters ( insulin sensitivity markers, BMI or leptin).
      Resistin concentrations in persons with type 2 DM do not differ from
      concentrations of common population.

PMID- 15034608
TI  - Application of determined NT-proBNP in physical standardized exercise.
AB  - Natriuretic peptides can be used as markers of heart failure, its severity and
      also in the differential diagnosis of dyspnea. Moreover, the dynamics of
      natriuretic peptides in physical standardized exercise may be used in the
      assessment of latent heart failure. AIM OF THE STUDY: Can determination of NT
      proBNP be used in the diagnosis of exercise-induced ischemia or latent heart
      failure? 18 probands (10 men, 8 women) under study were risk persons with
      unspecified ECG, without signs of manifest heart failure. They were subjected to
      ergometric bike exercises up to the subjective maximum, SPECT myocardium with
      estimated ejection fraction of the left ventricle at peak ergometric exercise.
      The following parameters were followed-up: a) before ergometric exercise: NT
      proBNP, CRP, TNF-alpha, Hb, Htc, lactate b) at subjective maximum: NT-proBNP, Hb,
      Htc, lactate c) 30 min after stopping the exercise: NT-proBNP d) 60 min after
      stopping the exercise: NT-proBNP. The volume blood changes were taken into
      account (estimation from the dynamics of Htc, Hb with calculation of metabolic
      changes of NT-proBNP). To evaluate the dynamics of NT-proBNP, the group was
      divided into subgroups according to the results obtained in ergometric exercises.
      RESULTS: initial values of NT-proBNP within normal limits (< 59 pmol/l, 500 ng/l)
      in 94%, the submaximal pulse rate was reached in 94%, ischemic changes in ECG
      were observed in 59%, typical clinical signs of heart ischemia were recorded in
      35%. Signs of heart dysfunction according to SPECT were found in 47% and ischemic
      symptoms were observed in 43%. In general, the plasmatic volume decreased by 24%
      at maximal exercise. Lactate concentration in the plasma increased in all cases.
      Conversion of NT-proBNP into volume blood changes revealed that increased NT
      proBNP occurred only in 22%. Differences between NT-proBNP before exercises and
      at maximal exercise prior and after correction into volume blood changes were
      statistically insignificant. 30 and 60 min after the exercise, no significant
      differences were found in NT-proBNP concentrations. Dividing into subgroups
      according to the results of ergometric exercises, showed no significant
      differences in NT-proBNP concentrations. Dynamics of NT-proBNP changes during and
      after ergometric exercises cannot be used for the diagnosis of exercise-induced
      heart failure. The high stability of NT-proBNP related to physical activity was
      confirmed.

PMID- 15034609
TI  - Levels of immunoglobulins of isotype IgG and IgG2 in subjects lacking formation
      of IgG antibodies against lipopolysaccharide of Chlamydia.
AB  - In some patients with antibodies against LPS antigen of Chlamydia, specific
      immunoglobulins G are not present. The findings of isolated anti-LPS IgA/IgM
      antibodies are to be considered as possibly non-specifically or "false" positive.
      The aim of this study was to investigate if there is any difference in the level
      of total immunoglobulins of isotypes IgG and IgG2 in probands with isolated
      positivity anti-LPS IgA (i.e. without simultaneous presence of specific IgG; n =
      34) as compared with a control group of subjects presenting positive anti-LPS IgA
      and IgG antibodies (n = 44). Antibodies against LPS antigen of Chlamydia were
      determined by ELISA method ("Chlamydien--rELISA", medac, Germany). Total
      immunoglobulin levels were determined by nephelometry using the following kits:
      "Immunoglobulin G Reagent, ARRAY Systems", Beckman Coulter, USA and "Human IgG2
      Subclass Beckman ARRAY Kits", The Binding Site, UK. The measured values were
      related to the age-dependent laboratory standard values and the differences
      between the tested groups were statistically evaluated (chi(2) test). Decreased
      total IgG have been demonstrated in 4 (11.8 %) probands and in 5 (11.4 %)
      subjects of the control group; increased total IgG were found in 2 (5.9 %)
      probands and in 1 (2.3 %) subject of the control group. Decreased levels of total
      IgG2 were not determined in any proband and were found in 1 (2.3 %) subject of
      the control group. Increased levels of IgG2 were registered in 12 (35.3 %)
      probands and in 15 (34.1 %) control subjects. No statistically significant
      differences were found between the two groups. It can be concluded that no
      relationship was proved between the levels of total IgG and IgG2 and the absence
      of formation of specific anti-Chlamydia-LPS IgG. Further research will be
      necessary for the elucidation of this phenomenon (e.g. the presence of specific
      anti-LPS IgG in immunocomplexes).

PMID- 15034610
TI  - In reference to phonation larynx fixation: computer graphic record.
AB  - The vocal apparatus serves phonation. It represents a biocybernetic self
      regulating system, disposing of a feedback network of the central nervous system.
      The larynx is a self-induced vibrating system. The larynx, functioning as the
      phonation apparatus of the vocal apparatus, is a source of human voice. In every
      individual its frequency range corresponds to about eight semitones in speech and
      about two octaves of the so-called chest register in singing, denoted also as a
      thoracic or modal voice. This is followed by one more octave of the so-called
      cranial register or falsetto voice. We were interested in changes of the larynx
      positions at intonation in the fundamental singing registers, both modal and
      falsetto, in professional male singers. At our disposal were 11 professional male
      singers. We investigated changes in the position of the laryngeal structures
      simultaneously with the aid of an X-ray apparatus, the acoustic and mechanical
      signals registered by means of the B & K 4369 acceleration recorder. It has been
      found that at phonation with the modal voice a change in the position of the
      laryngeal structures takes place in two different ways, whereas the larynx
      movements at falsetto remain the same. It has been suggested that a complex
      fixation apparatus participates in the phonation larynx movements. Of the same
      complex character are also the problems connected with the examination of the
      entire vocal apparatus. For the purpose of compiling the present pieces of
      knowledge in the field of human voice studies, we have made the most advantageous
      use of the presently most complex system Authorware for the production of some
      interactive multimedial programmes on personal computers.

PMID- 15034611
TI  - Socio-economic Predictors of Life Style. A pilot study.
AB  - In epidemiological studies there exists the evidence of relationship between
      socio-economic status (SES) and health. The suspicious cause of these differences
      is life-style. The aim of the presented study was to identify the relationship
      between SES, demographic characteristics and the life-style in an industrial
      region. A structured questionnaire was distributed to a random sample of some
      3,000 aged 25-70 and collected by postal delivery. The SES and demographic
      factors being analysed were sex, age, education, marital status and economic
      situation of the family in the relationship with a wide range of information on
      life style. The data was analysed using the chi-square test and logistic
      regression. The total number of analysed questionnaires was 634. The lowest
      response-rate was in the group with the basic education. Significant differences
      were found by sex in education (less women with university degree) and household
      income (more women in the lowest income category, men in the highest one). A
      detail analysis of the aggregated variables (adjusted for all SES variables)
      found: passivity and contentment were in adverse correlation with the level of
      education and economic situation; psychical well-being was correlated with family
      status and economic situation, risk behaviour was correlated with all SES factors
      except sex and education. Among the analysed factors economical situation of
      respondents, family and education were the most significant determinants of the
      differences in life-style.

PMID- 15034612
TI  - Incapacity for work of employees of the selected metallurgical plant related to
      age.
AB  - Evaluation of the health state of employees in relation to the working
      environment is one of the main tasks of occupational medicine. The specified
      results represent a part of a methodically oriented project which was focused on
      evaluation of: age structures of employees in the metallurgical plant being
      monitored in comparison with the age structure in the whole region, evaluation of
      the health status of employees in the plan by means of absolute and relative
      indicators of morbidity and even their dependence on age. The analysis was
      carried out during three successive years in approximately 10 000 employees of a
      metallurgical plant. The selected six groups of diagnoses represented from 40 %
      to 50 % of all employees suffering from a disease. Particularly the following
      diagnoses according to the International Classification of Diseases were involved
      there: I10-I15 (hypertensive disease), I20-I25 (ischaemic heart disease), J00-J06
      (acute infections of upper respiratory airways), K20-K31 (diseases of oesophagus,
      stomach and duodenum), M15-M19 (arthroses) and M50-M54 (dorsopathies). The age
      structure of employees related to men and women was considerably statistically
      significantly different from the age structure of the region. From the economic
      point of view on incapacity for work, we consider the number of days of absence
      from work for the reason of the disease as an indicator with the highest
      informative value. We noted two dominative maxima in men and women for this
      characteristic. A proportion of patients with acute infections of upper
      respiratory airways ranged from 40 % to 50 % out of total cases of diagnoses we
      have followed up, the highest number of patients was in men aged 20-24 with a
      subsequent significant decrease. We did not find any noticeable dependence on age
      for this diagnosis in women, only a slight increase in older age categories was
      evident. Dorsopathies are the second most frequent group; they were from 30 to 38
      % out of all monitored diseases. The age dependence was evident especially in
      women aged 40+. Considering duration of incapacity for work and its
      repeatability, dorsopathies seem to be the most relevant health problem in
      employees in heavy industry, and especially in women. The participation of the
      remaining four selected groups of diseases is relatively low. Both in men and
      women, the hypertensive disease ranged from 1.9 %-3.7 %, ischaemic heart disease
      from 0.4 %-6.5 %, diseases of oesophagus, stomach and duodenum from 5.3 %-9.0 %
      and arthroses from 4.7 %-6.8 % in three years in question.

PMID- 15034613
TI  - Methodical approach to data processing from a questionnaire survey.
AB  - For conducting questionnaire studies there exist generally recommended methods
      that were also respected during the project funded by the Grant Agency MoH CR -
      "Subjective approach of inhabitants of Ostrava to their health in association
      with their life-style, socio-economic status and education". The preparatory
      phase included the collection of literature and information on the investigated
      theme. The questionnaire had got five parts - A. General questions, B.
      Employment, C. Way of life, D. Health state and E. Personality. The validity of
      questionnaire was tested in the pre-research. In the main questionnaire study
      3,000 questionnaires were sent. The total response rate was 21.1% (634 completed
      questionnaires). In the sample there were no differences in percentage rate by
      sex and age, but there are differences in the educational structure. After
      realizing the main questionnaire study, the repeatability study was carried out
      to find out the reliability of the answers. The response rate was 60.3% (181
      questionnaires). The Kappa index and the total percentage of agreement were used
      for the evaluation of the repeatability study. The agreement was almost perfect
      and good in the total of 62.3 % of the questions. The quality of data was ensured
      by double data entry and by choosing the appropriate software. The selection of
      data for the complex analysis was based on the results of the repeatability
      study. On the basis of individual information from the questionnaire, new groups
      of individuals were generated. These groups of individuals were analysed further
      in relation to health and life-style by socio-economic factors in the models.

PMID- 15034614
TI  - Computer literacy enhancement in the Teaching Hospital Olomouc. Part I: project
      management techniques. Short communication.
AB  - Information explosion and globalization make great demands on keeping pace with
      the new trends in the healthcare sector. The contemporary level of computer and
      information literacy among most health care professionals in the Teaching
      Hospital Olomouc (Czech Republic) is not satisfactory for efficient exploitation
      of modern information technology in diagnostics, therapy and nursing. The present
      contribution describes the application of two basic problem solving techniques
      (brainstorming, SWOT analysis) to develop a project aimed at information literacy
      enhancement.

PMID- 15034616
TI  - Formation of LacNAc mimetics employing novel donor substrates for enzymatic beta
      1-->4 galactosylation.
AB  - In examining C-6 modified 4-nitrophenyl beta-D-galactopyranosides as donor
      structures the beta-galactosidase (Bacillus circulans) revealed an unexpectedly
      broad substrate specificity which allowed successful syntheses of various
      disaccharide components.

PMID- 15034615
TI  - Multivalent binding of galactosylated cyclodextrin vesicles to lectin.
AB  - Amphiphilic beta-cyclodextrins with alkylthio chains at the primary-hydroxyl side
      and galactosylthio-oligo-(ethylene glycol) units at the secondary-hydroxyl side,
      which form nanoparticles and vesicles, show multivalent effects in their binding
      to lectin.

PMID- 15034617
TI  - A short and efficient preparation of methyl-[1,2,4]oxadiazolium derivatives with
      plant-inducing activity.
AB  - We have developed a concise and efficient synthetic method leading to a
      structurally diverse array of salicylic acid and oxadiazolium derivatives,
      starting from commercially available halogenated phenols.

PMID- 15034618
TI  - Manganese(III) acetate mediated synthesis of oxygen heterocycles. Influence of
      copper(II) salts on product distribution.
AB  - Unsaturated malonates bearing pendant alcohols yield carbocycles tethered to
      oxygen heterocycles on exposure to manganese(iii) acetate and an appropriate
      copper(ii) salt.

PMID- 15034619
TI  - Transition state stabilization and substrate strain in enzyme catalysis: ab
      initio QM/MM modelling of the chorismate mutase reaction.
AB  - To investigate fundamental features of enzyme catalysis, there is a need for high
      level calculations capable of modelling crucial, unstable species such as
      transition states as they are formed within enzymes. We have modelled an
      important model enzyme reaction, the Claisen rearrangement of chorismate to
      prephenate in chorismate mutase, by combined ab initio quantum
      mechanics/molecular mechanics (QM/MM) methods. The best estimates of the
      potential energy barrier in the enzyme are 7.4-11.0 kcal mol(-1)(MP2/6-31+G(d)//6
      31G(d)/CHARMM22) and 12.7-16.1 kcal mol(-1)(B3LYP/6-311+G(2d,p)//6
      31G(d)/CHARMM22), comparable to the experimental estimate of Delta H(++)= 12.7 +/
      0.4 kcal mol(-1). The results provide unequivocal evidence of transition state
      (TS) stabilization by the enzyme, with contributions from residues Arg90, Arg7,
      and Arg63. Glu78 stabilizes the prephenate product (relative to substrate), and
      can also stabilize the TS. Examination of the same pathway in solution (with a
      variety of continuum models), at the same ab initio levels, allows comparison of
      the catalyzed and uncatalyzed reactions. Calculated barriers in solution are 28.0
      kcal mol(-1)(MP2/6-31+G(d)/PCM) and 24.6 kcal mol(-1)(B3LYP/6-311+G(2d,p)/PCM),
      comparable to the experimental finding of Delta G(++)= 25.4 kcal mol(-1) and
      consistent with the experimentally-deduced 10(6)-fold rate acceleration by the
      enzyme. The substrate is found to be significantly distorted in the enzyme,
      adopting a structure closer to the transition state, although the degree of
      compression is less than predicted by lower-level calculations. This apparent
      substrate strain, or compression, is potentially also catalytically relevant.
      Solution calculations, however, suggest that the catalytic contribution of this
      compression may be relatively small. Consideration of the same reaction pathway
      in solution and in the enzyme, involving reaction from a 'near-attack conformer'
      of the substrate, indicates that adoption of this conformation is not in itself a
      major contribution to catalysis. Transition state stabilization (by electrostatic
      interactions, including hydrogen bonds) is found to be central to catalysis by
      the enzyme. Several hydrogen bonds are observed to shorten at the TS. The active
      site is clearly complementary to the transition state for the reaction,
      stabilizing it more than the substrate, so reducing the barrier to reaction.

PMID- 15034621
TI  - A novel phase-switching protecting group for multi-step parallel solution phase
      synthesis.
AB  - A new phase-tag 1 which facilitates the parallel solution phase synthesis of
      carboxylic acids, esters, and carboxamides is reported. The new phase tag assists
      compound purification by enabling the selective resin capture of reaction
      products in either a reversible pH dependent manner (solid-phase extraction), or
      irreversibly in a Diels-Alder reaction.

PMID- 15034620
TI  - Synthesis and evaluation of analogues of 10H-indolo[3,2-b]quinoline as G
      quadruplex stabilising ligands and potential inhibitors of the enzyme telomerase.
AB  - We report here the synthesis and evaluation for telomerase-inhibitory and
      quadruplex DNA binding properties of several rationally-designed quindoline
      analogues, substituted at the 2- and 7- positions. The ability of these compounds
      to interact with and stabilise an intramolecular G-quadruplex DNA against
      increases in temperature was evaluated by a fluorescence-based (FRET) melting
      assay. The resulting T(m) values were found to correlate with their potency for
      telomerase inhibition, as measured in an in vitro telomerase TRAP assay. The
      interactions of a number of compounds with a quadruplex DNA molecular structure
      were simulated by molecular modelling methods. It is concluded that this class of
      compound represents a new chemical type suitable for further development as
      telomerase inhibitors.

PMID- 15034622
TI  - Do the interstellar molecules CCCO and CCCS rearrange when energised?
AB  - Neutrals CCCO, CC(13)CO, CCCS and CC(13)CS have been prepared by one-electron
      vertical (Franck-Condon) oxidation of the precursor anion radicals (CCCO)(-*),
      (CC(13)CO)(-*), (CCCS)(-*) and (CC(13)CS)(-*)respectively in collision cells of a
      reverse sector mass spectrometer. Ionisation of the neutrals to decomposing
      cations shows the neutrals to be stable for the microsecond duration of the
      neutralisation-ionisation ((-)NR(+)) experiment. No rearrangement of the label in
      energised CC(13)CO or CC(13)CS occurs during these experiments. In contrast,
      minor rearrangement of (CC(13)CO)(+*) is observed [(CC(13)CO)(+*)-
      >(OCC(13)C)(+*), while significant rearrangement occurs for (CC(13)CS)(+*)
      [(CC(13)CS)(+*)-->(SCC(13)C)(+*)]. Theoretical calculations at the CCSD(T)/aug-cc
      pVDZ//B3LYP/6-31G(d) level of theory show that the cationic rearrangements occur
      by stepwise processes via key rhombic structures. Overall, the degenerate
      processes result in O and S migration from C-3 to C-1. The cations (CCCO)(+*) and
      (CCCS)(+*) require excess energies of > or = 516 and > or = 226 kJ mol(-1)
      respectively to effect rearrangement.

PMID- 15034623
TI  - Conformation inversion of an inositol derivative by use of silyl ethers: a
      modified route to 3,6-di-O-substituted-L-ido-tetrahydroxyazepane derivatives.
AB  - The trans-diequatorial 3,4-diol of 2,5-di-O-benzyl-D-chiro-inositol cleaved
      selectively with the periodate ion in the presence of the trans-diaxial 1,6-diol
      to give a dialdehyde (dialdose) from which 3,6-di-O-benzyl-D-manno
      tetrahydroxyazepane (1) was made. The trans-diaxial 1,6-diol of 3,4-di-O-allyl
      2,5-di-O-benzyl-D-chiro-inositol was not cleaved satisfactorily by periodate, but
      replacement of the allyl substituents with tert-butyldimethylsilyl groups caused
      conformational inversion of the inositol ring, and the resulting trans
      diequatorial 1,6-diol cleaved efficiently to give a dialdehyde from which 3,6-di
      O-benzyl-L-ido-tetrahydroxyazepane (2) can be prepared.

PMID- 15034624
TI  - The remote-oxyfunctionalization of unactivated carbons in (5 beta)-3-oxobile
      acids by 2,6-dichloropyridine N-oxide catalyzed by ruthenium-porphyrin and HBr: a
      direct lactonization at C-20.
AB  - Remote-oxyfunctionalization induced by 2,6-dichloropyridine N-oxide (DCP N-oxide)
      as an oxygen donor and a (5,10,15,20-tetramesitylporphyrinate) ruthenium(II)
      carbonyl complex (Ru-porphyrin) and HBr as catalysts was examined for a series of
      methyl ester-peracetylated derivatives of (5 beta)-3-oxobile acids. Using the DCP
      N-oxide/Ru-porphyrin/HBr system, 5 beta-hydroxylation predominated for the
      substrates having a 12-acetoxyl substituent due to steric hindrance, but the
      presence of a 7-acetoxyl substituent decreased the reactivity of the 5 beta
      position allowing for the competitive (20S)-20-oxyfunctionalization, subject to
      electronic constraints. A variety of novel 5 beta-hydroxylation and (20S)-24,20
      gamma-lactonization products, as well as their double-oxyfunctionalization and
      dehydration products, were obtained in one-step. The alkaline hydrolysis of the
      gamma-lactones gave the corresponding stereoselective (20S)-20-hydroxy-carboxylic
      acids.

PMID- 15034625
TI  - Efficient conversion of 6-cyanopurines into 6-alkoxyformimidoylpurines.
AB  - An extremely simple method for the selective synthesis of 9-aryl and 9-alkyl 6
      alkoxy or 6-alkoxyformimidoylpurines from the corresponding 6-cyanopurines is
      described. The reaction is carried out with methanol or ethanol in the presence
      of DBU. At room temperature, nucleophilic attack by the primary alcohol occurs
      selectively on the cyano carbon atom, leading to 6-alkoxyformimidoylpurines in
      good yields. Heating the reaction mixture at a temperature greater than or equal
      to 78 degrees C leads to nucleophilic substitution of the substituent in the 6
      position by the alkoxy group, generating the corresponding 6-alkoxypurines, also
      in excellent yields. The 6-alkoxyformimidoylpurines were used as intermediates in
      the synthesis of 6-carboxamidinopurines by reaction with methylamine (for 9
      methylpurine 5a) or methyl ammonium chloride (for 9-arylpurines and 5b and 5c).

PMID- 15034626
TI  - Synthesis of the tetraethyl substituted pH-sensitive nitroxides of imidazole
      series with enhanced stability towards reduction.
AB  - The synthesis of 2,2,5,5-tetraethylimidazole nitroxides from 3-ethylpent-2-ene is
      described. The newly synthesized nitroxides, namely 4-methyl-2,2,5,5-tetraethyl
      2,5-dihydro-1H-imidazol-1-yloxy (1), 3,4-dimethyl-2,2,5,5
      tetraethylperhydroimidazol-1-yloxy (2) and 2,2,5,5-tetraethyl-4-pyrrolidin-1-yl
      2,5-dihydro-1H-imidazol-1-oxyl (3), were found to be pH sensitive spin probes,
      with pK values of 1.2, 4.95 and 7.4, respectively. The most important finding was
      the fact that these new nitroxides were 20-30 times more stable in the presence
      of ascorbate and had significantly longer halflifes in rat blood as compared to
      2,2,5,5-tetramethyl analogs. The latter observation provides a unique advantage
      for the application of tetraethyl substituted imidazole nitroxides as functional
      EPR probes.

PMID- 15034627
TI  - Enantiopure bicyclic piperidinones: stereoselectivity in lactam enolate
      alkylations.
AB  - The synthesis and alkylation of [4.3.0]-bicyclic lactams, derived from 6
      oxopipecolic acid, have been investigated. Alkylation can proceed with
      predominantly exo-diastereoselectivity, but the efficiency of this process
      depends on the substitution at the hemiaminal ether system. These products can be
      readily deprotected to give substituted hydroxymethyl lactams in good yield.

PMID- 15034628
TI  - Pi-extended o-quinoidal tropone derivatives: experimental and theoretical studies
      of naphtho[2,3-c]tropone and anthro[2,3-c]tropone.
AB  - pi-Extended o-quinoidal tropone derivatives, naphtho[2,3-c]tropone (3) and
      anthro[2,3-c]tropone (4), have been investigated theoretically as well as
      experimentally. The geometrical optimization of 3,4 and related compounds at the
      B3LYP level employing 6-31G* basis set as well as the GIAO calculations at the
      RHF level employing the 6-31+G* basis set have been performed to evaluate the
      contributions of the polarized resonance forms to these molecules. The GIAO
      calculated NICS(1) values indicate that the aromaticities of the tropone rings of
      o-quinoidal 3 and 4 are significantly increased as compared with that of parent
      tropone (1) at the expense of the fused benzenoid rings, consistent with the
      significant electronic polarization of these molecules in the ground state. On
      the other hand, the fusion of a benzene or naphthalene ring to the 2,3- or 4,5
      position of tropone leads to diminution of aromaticity in the resulting tropone
      moiety. Experimentally, irradiation of 6,7-(2',3'-naphtho)bicyclo[3.2.0]hepta-3,6
      dien-2-one (10) in a rigid glass at -196 degrees C leads to the formation of,
      which exhibits a characteristic UV-Vis absorption extending to 700 nm and
      undergoes rapid [pi 12 + pi 14] dimerization upon thawing the glass. In contrast,
      6,7-(2',3'-anthro)bicyclo[3.2.0]hepta-3,6-dien-2-one (11) showed no sign of
      isomerization to 4 under the same reaction conditions.

PMID- 15034629
TI  - Stereocontrol in organic synthesis using silicon-containing compounds. Studies
      directed towards the synthesis of ebelactone A.
AB  - Several approaches to the synthesis of ebelactone A 2 are described, culminating
      in the synthesis of the benzenesulfonate of 2-epi-ebelactone A 161. All the
      approaches were based on three fragments A, B and C, originally defined in
      general terms in, but eventually used as the aldehyde 72, the allenylsilane 3 and
      the aldehyde 139, respectively. They were joined, first B with C, and then B+C
      with A. In the main routes to fragments A and C, the relative stereochemistry was
      controlled by highly stereoselective enolate methylations 67-->67, 68-->69, and
      135-->136, in each case anti to an adjacent silyl group, and by a highly
      stereoselective hydroboration of an allylsilane 137-->138, also anti to the silyl
      group. The hydroxyl groups destined to be on C-3 and C-11 were unmasked by silyl
      to-hydroxy conversions 69-->70 and 138-->139 with retention of configuration. The
      stereochemistry created in the coupling of fragment B to C was controlled by the
      stereospecifically anti S(E)2' reaction between the enantiomerically enriched
      allenylsilane 3 and the aldehyde 139. The double bond geometry was controlled by
      syn stereospecific silylcupration 148-->151, and preserved by iododesilylation
      151-->152 of the vinylsilane with retention of configuration, and Nozaki-Hiyama
      Kishi coupling with the aldehyde 72 gave the whole carbon skeleton 153 of
      ebelactone A with the correct relative configuration, all of which had been
      controlled by organosilicon chemistry. In the steps to remove the superfluous
      allylic hydroxyl, an intermediate allyllithium species 156 abstracted the proton
      on C-2, and its reprotonation inverted the configuration at that atom. Other
      routes to the fragments A and C were also explored, both successful and
      unsuccessful, both silicon-based and conventional, and a number of unexpected
      side reactions were investigated.

PMID- 15034630
TI  - Relative reactivity of three and four membered rings--the absence of charge
      effect.
AB  - Radical (neutral) and electrophilic (cationic) ring opening reactions were
      studied computationally in order to probe the difference in reactivity between
      three and four membered rings. Using the Marcus equation we have shown that the
      activation energy for the four membered ring opening is close to the Marcus
      predicted barrier whereas three membered rings display much higher reactivity
      than that predicted by the Marcus equation. Thus, the reactivity of the three
      membered rings is enhanced, in addition to the strain release, by another factor
      which is not operative in the four membered rings. It is clear also that this
      factor is not charge dependent. The possible origin of this effect is discussed.

PMID- 15034631
TI  - Designer phytoalexins: probing camalexin detoxification pathways in the
      phytopathogen Rhizoctonia solani.
AB  - To probe the specificity of a camalexin detoxifying enzyme(s) produced by
      Rhizoctonia solani, the putative 5-camalexin hydroxylase (5-CAHY), the naturally
      occurring phytoalexin 1-methylcamalexin and designer phytoalexins in which the H
      5 of camalexin was replaced with either a methyl group or a fluorine atom were
      synthesised. This investigation showed that biotransformation of 5
      fluorocamalexin by R. solani was substantially slower than that of camalexin (12
      days vs. six to eight hours), 5-methylcamalexin (5-6 days) or 1-methylcamalexin
      (5-6 days). Antifungal bioassays showed that 5-fluorocamalexin, 5-methylcamalexin
      and 1-methylcamalexin were more inhibitory to R. solani than camalexin, whereas
      their metabolic products displayed substantially lower inhibitory activity. It
      was concluded that detoxification via oxidation of the indole moiety of
      camalexins is predominant in the biotransformation of both camalexin and 5
      methylcamalexin and likely catalysed by a specific 5-CAHY. By contrast, the
      pathways for detoxification of 1-methylcamalexin and 5-fluorocamalexin are likely
      catalysed by non-specific "house-keeping" enzymes. Most importantly, because 1-
      methylcamalexin showed stronger antifungal activity and was metabolised at
      substantially slower rate than camalexin this work suggested that, from a plant's
      perspective 1-methylcamalexin could be a more effective antifungal defence than
      camalexin.

PMID- 15034632
TI  - Direct catalytic asymmetric aldol reactions of pyruvates: scope and mechanism.
AB  - The direct aldol reaction of 2-ketoesters catalyzed by chiral bisoxazoline
      copper(II) complexes has been investigated. First the direct homo-aldol reaction
      of ethyl pyruvate is reported which proceeds to give diethyl 2-hydroxy-2-methyl-4
      oxoglutarate. This was isolated as the more stable optically active isotetronic
      acid in good yield and enantiomeric excess in the absence of bases such as
      amines. Detailed investigations of the use of different chiral Lewis acids as the
      catalyst, amines, ratios of chiral bisoxazoline copper(II) salts:amine, and
      solvents gave up to 96% ee of the isotetronic acid. Then the reaction was
      extended to a cross-aldol reaction of various 2-ketoesters with activated
      carbonyl compounds to give the cross-aldol adduct with excellent enantiomeric
      excess. Furthermore, the synthesis of the isotetronic acids was investigated from
      these cross-aldol adducts giving important information about the formation of the
      stereogenic centers during the aldol reaction. Based on the absolute
      configuration of the homo-aldol adduct the mechanism for the aldol reaction is
      discussed.

PMID- 15034633
TI  - Stability improvement of immobilized Candida antarctica lipase B in an organic
      medium under microwave radiation.
AB  - The influence of microwave heating on the stability of immobilized Candida
      antarctica lipase B was studied at 100 degrees in an organic medium. The
      microwave radiation was carried out before enzymatic reaction (storage
      conditions) or during the enzymatic catalysis (use conditions). In both cases,
      enzymatic stability was higher under microwave heating than under conventional
      thermal heating, in strictly identical operating conditions. Furthermore, the
      gain of enzymatic stability under microwave heating appears to be higher in a
      more polar solvent, which interacts strongly with the microwave field. Our
      results suggest that microwave radiation has an effect, not related to
      temperature, on the process of enzymatic inactivation.

PMID- 15034634
TI  - Alkylation of guanosine and 2'-deoxyguanosine by o-quinone alpha-(p
      anisyl)methide in aqueous solution.
AB  - Rates of alkylation of guanosine and 2'-deoxyguanosine with o-quinone alpha-(p
      anisyl)methide were measured by flash photolysis in a series of aqueous sodium
      hydroxide solutions and bicarbonate ion, t-butylhydrogenphosphonate ion, and
      biphosphate ion buffers. The data so obtained provide rate profiles for these
      nucleoside plus quinone methide reactions over the range pH = 7-14, which furnish
      guanosine and deoxyguanosine acidity constants consistent with literature
      information. These profiles also provide rate constants that show the reaction of
      o-quinone alpha-(p-anisyl)methide with guanosine and deoxyguanosine to be fairly
      fast processes, considerably faster than the biologically wasteful reaction of
      the quinone methide with water, which is the ubiquitous medium in biological
      systems; that makes the quinone methide a potent guonosine and deoxyguanosine
      alkylator.

PMID- 15034635
TI  - The synthesis of fused and spiro annulated carbohydrate structures using
      copper(I) catalysed intramolecular photoannulation of glucose derivatives.
AB  - Intramolecular [2 + 2] photoannulation catalysed by copper(i)triflate has been
      applied to a series of carbohydrate derivatives obtained from glucose. Dienes 1a
      and 1b lead to cyclobutanes 3a and 3b whereas the diastereoisomeric dienes 5a and
      5b gave diastereoisomeric products 7a and 7b. These results demonstrate that the
      reaction is stereospecific. Products 3a and 7a were converted into bromoesters 4
      and 9 respectively. The Vasella elimination of 8 lead to the expected bicyclic
      aldehyde 10 and the ring expanded hydroxy ketone 12. The stereospecific formation
      of enantiomerically pure spiro annulated carbohydrates 18a and 18b was
      demonstrated whereas in example 19 no selectivity in the formation of 20 and 21
      was observed.

PMID- 15034636
TI  - Thorpe-Ingold effects in cyclizations to five-membered and six-membered rings
      containing planar segments. The rearrangement of N(1)-alkyl-substituted
      dihydroorotic acids to hydantoinacetic acids in base.
AB  - While the gem-dimethyl effect (GDME) is quantitatively similar for cyclizations
      to cyclopentane and cyclohexane rings and their homomorphs, in systems containing
      planar segments the GDME is stronger for the formation of five-membered rings.
      Planar pentagons have smaller angles than planar hexagons and their formation is
      helped by the decrease in the potential internal bond angle caused by
      substituents, as suggested by Thorpe and Ingold for small rings. The phenomenon
      is illustrated with crystal structure data on five-membered hydantoins and six
      membered dihydrouracils containing four-atom planar segments. Such a Thorpe
      Ingold effect explains the rearrangement in base of N-alkyl substituted
      dihydroorotic acids 1 to hydantoinacetic acids 3. The reaction involves initial
      hydrolysis to N-(N-alkylcarbamoyl)aspartic acids 2 and their subsequent
      cyclization. The unsubstituted N-carbamoylaspartic acid 2a is stable in 1 M KOH,
      the N(1)-methyl and ethyl compounds 2b and 2c are in equilibrium with the
      hydantoinacetic acids 3, while the cyclization of the N(1)-isopropyl and
      cyclohexyl derivatives 2d and 2e is irreversible. Experimental data on equilibria
      and pK(a)s for ionization of the carboxy and NH groups allow equilibria and rates
      involving the N-unsubstituted compounds to be estimated and compared with those
      for the N-alkyl derivatives. The strongest effect is observed on the equilibrium
      [3(2-)]/2[(2-)], where substitution of H by methyl increases K 600-fold. In vitro
      the kinetic regioselectivity for acid catalyzed cyclization of N
      carbamoylaspartic to hydantoinacetic acid against dihydroorotic acid is only
      10:1. This, together with the weaker acidity of the remote carboxyl group,
      favours cyclization to dihydroorotic acid under biological conditions.

PMID- 15034637
TI  - [Tinnitus after anaesthesia].
AB  - Possible connections between different forms of anaesthesia and the occurrence of
      tinnitus or increasing levels of tinnitus are described. After general
      anaesthesia no increase in the occurrence or level of tinnitus is to be expected,
      but there exists a very rare, but specific form of low frequency tinnitus
      combined with low frequency sensory hearing loss following spinal anaesthesia.
      Reversible tinnitus and hearing disorders following local anaesthesia normally
      occur in cases of central nervous system toxicity.

PMID- 15034639
TI  - Inhibitory effects of KAT-681, a liver-selective thyromimetic, on development of
      hepatocellular proliferative lesions in rats induced by 2-acetylaminofluorene and
      partial hepatectomy after diethylnitrosamine initiation.
AB  - To examine the potential inhibitory effects of a novel liver-selective
      thyromimetic, KAT-681 (KAT), on the development of hepatocellular proliferative
      lesions, male F344 rats were given a single intraperitoneal injection of 150
      mg/kg diethylnitrosamine (DEN), followed by gavage administration of 7.5 mg/kg
      per day of 2-acetylaminofluorene (2-AAF) twice daily from weeks 2 to 4 with
      partial hepatectomy (PH) at week 3. From 5 weeks after the completion of 2-AAF
      administration, the rats were orally dosed with 0.04, 0.1, or 0.25 mg/kg per day
      KAT for 3 weeks, and subjected to morphometric analysis of the induced
      glutathione S-transferase placental form (GST-P)-positive lesions and
      hepatocellular adenomas (HCAs). Administration of KAT significantly and dose
      dependently reduced the total area of GST-P-positive lesions (by 34-48%) and also
      their numbers (by 20-44%), their mean size not being significantly changed. No
      effects on the number of HCAs were apparent, although a reduction in their mean
      size was detected at a dose of 0.25 mg/kg per day KAT (by 34%). On biochemical
      analysis, serum activity of gamma-glutamyl transpeptidase, an enzyme related to
      hepatocarcinogenesis, was markedly reduced in rats given 0.25 mg/kg per day KAT
      (by 64%). The results of the present study thus suggest that KAT inhibits the
      development of altered hepatocellular foci and might be a promising
      chemopreventive agent for hepatocarcinogenesis.

PMID- 15034640
TI  - Short-term black tea intake modulates the excretion of urinary mutagens in rats
      treated with 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ): role of CYP1A2
      upregulation.
AB  - Rats were exposed to black tea (2.5% w/v) as their sole drinking liquid for
      either 1 day or 1 month, while controls were maintained on water. After this
      treatment period, all animals received a single oral dose IQ (2-amino-3
      methylimidazo-[4,5-f]quinoline), and urine was collected for 48 h. Mutagenic
      activity of the urine was determined in the Ames test in the presence and absence
      of an activation system. The excretion of direct-acting mutagens was markedly
      reduced following tea intake, and was more pronounced after the 1-day treatment.
      Similarly, both tea treatments suppressed the excretion of indirect-acting
      mutagens. Furthermore, both tea treatments induced hepatic CYP1A2 activity and
      expression, but cytosolic glutathione S-transferase activity was only modestly
      induced in the group of animals receiving tea for 1 day, and only when DCNB (1,2
      dichloro-4-nitrobenzene) was used as substrate; glucuronosyl activity was
      elevated modestly only in the animals receiving the tea for a month. It is
      concluded that even short-term exposure to black tea is capable of influencing
      the metabolic fate of IQ, and this is most likely related to the upregulation of
      CYP1A2.

PMID- 15034638
TI  - [Opioid-induced hyperalgesia. Pathophysiology and clinical relevance].
AB  - Opioids are the drugs of choice for the treatment of moderate to severe acute and
      chronic pain. However, clinical evidence suggests that opioids can elicit
      increased sensitivity to noxious stimuli suggesting that administration of
      opioids can activate both pain inhibitory and pain facilitatory systems. Acute
      receptor desensitization via uncoupling of the receptor from G-proteins, up
      regulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA)
      receptor system, as well as descending facilitation, have been proposed as
      potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports
      exist demonstrating that opioid-induced hyperalgesia is observed both in animal
      and human experimental models. Brief exposures to micro-receptor agonists induce
      long-lasting hyperalgesic effects for days, which might by reflected by clinical
      observations that large doses of intraoperative micro-receptor agonists increased
      postoperative pain and morphine consumption. Furthermore, the prolonged use of
      opioids in patients often requires increasing doses and may be accompanied by the
      development of abnormal pain. Successful strategies that may decrease or prevent
      opioid-induced hyperalgesia include the concomitant administration of drugs like
      NMDA-antagonists, alpha(2)-agonists, or non-steroidal anti-inflammatory drugs
      (NSAIDs), opioid rotation or combinations of opioids with different receptor
      selectivity.

PMID- 15034641
TI  - Phylogenetic analysis of the lux operon distinguishes two evolutionarily distinct
      clades of Photobacterium leiognathi.
AB  - The luminous marine bacterium Photobacterium mandapamensis was synonymized
      several years ago with Photobacterium leiognathi based on a high degree of
      phenotypic and genetic similarity. To test the possibility that P. leiognathi as
      now formulated, however, actually contains two distinct bacterial groups
      reflecting the earlier identification of P. mandapamensis and P. leiognathi as
      separate species, we compared P. leiognathi strains isolated from light-organ
      symbiosis with leiognathid fishes (i.e., ATCC 25521(T), ATCC 25587, lequu.1.1 and
      lleuc.1.1) with strains from seawater originally described as P. mandapamensis
      and later synonymized as P. leiognathi (i.e., ATCC 27561(T) and ATCC 33981) and
      certain strains initially identified as P. leiognathi (i.e., PL-721, PL-741,
      554). Analysis of the 16S rRNA and gyrB genes did not resolve distinct clades,
      affirming a close relationship among these strains. However, strains ATCC
      27561(T), ATCC 33981, PL-721, PL-741 and 554 were found to bear a luxF gene in
      the lux operon ( luxABFE), whereas ATCC 25521(T), ATCC 25587, lequu.1.1 and
      lleuc.1.1 lack this gene ( luxABE). Phylogenetic analysis of the luxAB(F)E region
      confirmed this distinction. Furthermore, ATCC 27561(T), ATCC 33981, PL-721, PL
      741 and 554 all produced a higher level of luminescence on high-salt medium, as
      previously described for PL-721, whereas ATCC 25521(T), ATCC 25587, lequu.1.1 and
      lleuc.1.1 all produced a higher level of luminescence on low-salt medium, a
      characteristic of P. leiognathi from leiognathid fish light organs. These results
      demonstrate that P. leiognathi contains two evolutionarily and phenotypically
      distinct clades, P. leiognathi subsp. leiognathi (strains ATCC 25521(T), ATCC
      25587, lequu.1.1 and lleuc.1.1), and P. leiognathi subsp. mandapamensis (strains
      ATCC 27561(T), ATCC 33981, PL-721, PL-741 and 554).

PMID- 15034642
TI  - Novel transcriptional regulators of Legionella pneumophila that affect
      replication in Acanthamoeba castellanii.
AB  - Legionella pneumophila is commonly found in freshwater environments and is able
      to invade and replicate within amoebae and ciliated protozoa. Moreover, this
      bacterium is also able to replicate within human alveolar macrophages causing a
      severe form of pneumonia, designated Legionnaires' disease. L. pneumophila
      pathogenesis is not yet completely understood, but the genes responsible for
      infection and intracellular replication are becoming known. Nonetheless,
      knowledge as to how these genes are controlled is still very limited. The
      partially sequenced genome of L. pneumophila was searched for open reading frames
      encoding proteins with sequence similarity to members of the LuxR family of
      transcriptional regulators. These were designated LpnR1, LpnR2, LpnR3, and LpnR4.
      Although these proteins could not be identified as true LuxR proteins, they do
      act as regulators, as illustrated in this report. LpnR1 negatively affected rpoS
      expression, whereas LpnR2 and LpnR3 positively affected flagellin expression.
      Furthermore, LpnR2 proved to be necessary for efficient invasion of Acanthamoeba
      castellanii and LpnR3 for intracellular replication in this protozoan host. LpnR4
      was recently identified as LetA.

PMID- 15034644
TI  - No effect of vitamin A intake on bone mineral density and fracture risk in
      perimenopausal women.
AB  - In recent studies from Sweden and the United States, a high vitamin A intake has
      been associated with low bone mineral density (BMD) and increased fracture risk.
      In Sweden and the United States, food items such as milk and breakfast cereals
      are fortified with vitamin A, whereas in Denmark there is no mandatory
      fortification with vitamin A. In the present study, we investigated relations
      between vitamin A intake and BMD and fracture risk in a Danish population
      consuming mostly unfortified food items. Within a population-based cohort study
      in 2,016 perimenopausal women, associations between BMD and vitamin A intake were
      assessed at baseline and after 5-year follow-up. Moreover, associations between
      baseline vitamin A intake and 5-year changes in BMD were studied. Finally,
      fracture risk was assessed in relation to vitamin A intake. In our cohort,
      dietary retinol intake (0.53 mg/day) was lower than the intake reported in recent
      studies form Sweden (0.78 mg/day) and the United States (1.66 mg/day). Cross
      sectional and longitudinal analyses showed no associations between intake of
      vitamin A and BMD of the femoral neck or lumbar spine. Neither did BMD differ
      between those 5% who had the highest, and those 5% who had the lowest, vitamin A
      intake. During the 5-year study period, 163 subjects sustained a fracture
      (cases). Compared to 978 controls, logistic regression analyses revealed no
      difference in vitamin A intake. Thus, in a Danish population, average vitamin A
      intake is lower than in Sweden and the United States and not associated with
      detrimental effects on bone.

PMID- 15034645
TI  - The effect of an ankle brace on the 3-dimensional kinematics and tibio-talar
      contact condition for lateral ankle sprains.
AB  - Ten fresh-frozen cadaveric ankles were studied to investigate the effect of an
      ankle brace (Air-Stirrup) on the three-dimensional (3-D) motion and contact
      pressure distribution of the talo-tibial joint with lateral ligamentous injury.
      Three-dimensional motion and contact-pressure distribution were simultaneously
      measured under dynamic conditions employing a direct linear-transformation
      technique and a dynamic-pressure sensor, respectively. Inversion increased
      significantly upon severing of the anterior talo-fibular (ATF) ligament and
      calcaneo-fibular (CF) ligaments; however, restoration to the intact level was
      observed following application of the ankle brace. Internal rotation also
      increased upon severing of the lateral ligaments in the plantar flexion; however,
      this difference was not altered by using the ankle brace. The contact area on the
      articular surface of the talus shifted from posterior to anterior between plantar
      flexion and dorsal flexion; additionally, a high pressure area was evident in the
      medial aspect of the talus following severing of the lateral ligaments. Upon
      application of the ankle brace, however, no significant changes were apparent in
      the contact condition. The results of this study suggest that stabilization
      against inversion is the major function of braces in terms of protection of ankle
      sprains. Ankle sprains, however, often occur in combinations of inversion,
      plantar flexion and internal rotation; therefore, restriction of plantar flexion
      and internal rotation may also be an important function of the ankle brace.

PMID- 15034643
TI  - Bone loss is more severe in primary adrenal than in pituitary-dependent Cushing's
      syndrome.
AB  - Either exogenous or endogenous glucocorticoid excess is an established cause of
      osteoporosis and fractures. Glucocorticoids exert their negative effects on bone
      through mechanisms that are not yet completely elucidated; however, as many as
      50% of patients with Cushing's syndrome suffer from osteoporosis. Bone loss
      induced by glucocorticoids is potentially reversible after resolution of
      glucocorticoid excess. It is presently unknown if Cushing's disease (CD)
      sustained by a pituitary ACTH-producing adenoma and adrenal-dependent Cushing's
      syndrome (ACS) sustained by an adrenocortical adenoma have a different potential
      of inducing osteopenia. The aim of the present study was to retrospectively
      analyze bone mineral density (BMD) in 26 patients with CD (4 men, 22 women, aged
      14-79 years), 12 patients with ACS (4 men, 8 women, aged 32-79 years) and 38
      healthy subjects carefully matched for sex, age and body mass index (BMI).
      Measurement of BMD was performed by dual-energy X-ray absorptiometry (DXA) using
      the Hologic QDR 4500 W instrument. Data were analyzed using absolute BMD values
      (g/cm2), T-score and Z-score referred to the manufacturer's normative data for
      the lumbar spine and to the NHANES III dataset for the hip. The patients with CD
      and ACS were comparable for age, BMI, estimated duration of disease, urinary free
      cortisol (UFC) levels, midnight serum cortisol and gonadal function. The analysis
      of variance demonstrated that lumbar bone densitometric parameters were
      significantly different among the three groups. They were more reduced in
      patients with ACS (BMD, 0.76+/-0.03 g/cm2; T-score, -2.78+/-0.28; Z-score, 
      2.25+/-0.30) while patients with CD (BMD, 0.87+/-0.02 g/cm2; T-score, -1.74+/
      0.24; Z-score, -0.99+/-0.32) showed DXA values between the first group and
      controls (BMD, 1.02+/-0.02 g/cm2; T-score, -0.35+/-0.19; Z-score, 0.33+/-0.16).
      The difference in BMD at the spine remained statistically significant ( P=0.04)
      after adjustment for the non-significant differences in age, UFC and fat mass
      between CD and ACS. Conversely, femoral bone densitometric parameters were not
      significantly different between patients with ACS and CD, even if they were more
      reduced than in controls. In patients with ACS, we observed a reduction of DHEA-S
      levels, expressed as standard score ( Z-score) values referred to a group of 180
      healthy subjects stratified by sex and different age groups (<40 years, between
      40 and 60 years, >60 years) to circumvent the pronounced effect of gender and age
      on such hormone (ACS DHEA-S Z-score -0.88+/-1.4 versus CD DHEA-S Z-score 2.25+/
      2.35, P=0.0001). DHEA-S Z-score values were significantly correlated with lumbar
      BMD ( r=0.41, P=0.02) and femoral BMD ( r=0.43, P=0.01). DHEA-S Z-score values
      were also significantly correlated with osteocalcin levels ( r=0.45, P=0.01). Our
      data suggest that bone loss is greater in ACS than in CD. A plausible explanation
      comes from the reduced DHEA-S level in ACS since DHEA-S has well known anabolic
      actions on bone. However, this hypothesis needs to be confirmed in large,
      prospective series of patients with Cushing's syndrome of different etiology.

PMID- 15034646
TI  - Open reconstruction of anterior glenoid rim fractures.
AB  - The present study evaluates the clinical and radiological results of patients
      with anterior glenoid rim fractures treated with two different open surgical
      techniques depending on the size of the bony fragment. In patients with displaced
      glenoid rim fractures involving less than 25% of the glenoid surface (Type I, II
      and IIIA fractures) suture anchor repair was performed. Patients with a bony
      defect involving more than 25% of the glenoid surface (Type IIIB fractures)
      underwent open reduction and internal fixation using cannulated screws. After a
      mean follow-up of 22 months, 15 patients (mean age 42.2 years) treated with
      suture anchor repair achieved an average Constant Score of 85.5 points (range
      67.1-100) and an average Rowe Score of 94 points (range 70-100). In six patients
      the bony fragment was located in an unimproved medial position compared to the
      preoperative X-ray. In another six patients the fragment was consolidated
      medially to the level of the glenoid rim, and in three cases an anatomic
      situation was found. Patients treated with cannulated screws (ten cases, mean age
      46.6 years) had a mean follow-up of 30 months and achieved a mean Constant Score
      of 81.9 points (range 61.7-96.1) and a mean Rowe Score of 90 points (range 70
      100). Radiologically, the bony fragment was consolidated in an anatomic position
      in nine out of ten cases. Three patients suffered from screw impingement and one
      patient had screw loosening. No recurrent subluxations or dislocations were
      observed in either group. Three patients in group one and one patient in group
      two had glenohumeral osteoarthritic changes. In cases of small glenoid-rim
      fractures (Type I, II and IIIA fractures), suture anchor repair resulted in an
      excellent clinical outcome; however, the radiological results of chronic Type I
      fractures revealed in many cases a non-anatomical glenoidal reconstruction. For
      Type IIIB fractures with significant loss of glenoid concavity, open reduction
      and internal fixation with cannulated screws gave good clinical and radiological
      results; however the early complication rate was higher.

PMID- 15034647
TI  - Hyperbaric oxygen in systemic inflammatory response.

PMID- 15034648
TI  - Endotracheal suctioning: from principles to practice.
AB  - OBJECTIVE: This paper aims to highlight the physical principles of pressure and
      flow dynamics underlying endotracheal suctioning, to demonstrate these on a
      simple illustrative model and to discuss the clinical implications of these
      principles for paediatric practice. DESIGN: Prospective in vitro study. SETTING:
      Paediatric intensive care unit of a tertiary, academic hospital. MEASUREMENTS AND
      MAIN RESULTS: The peak pressure change (DeltaP) obtained in a "bag-in-box" model
      was recorded during suctioning, using different combinations of endotracheal tube
      (ETT) and catheter sizes, different suction pressures and techniques. Suction was
      also performed on three different consistencies of gelatine, using a range of
      suction catheter sizes and vacuum pressures. The mass of gelatine suctioned per
      second was calculated. A large DeltaP was measured when using neonatal-sized
      ETTs. There was a linear relationship (r=0,8, p<0.05) between DeltaP and the
      ratio of external catheter area to area difference (internal ETT area-external
      catheter area). Significantly greater DeltaP was measured when using a short
      versus long suction catheter ( p<0.001) and when applying suction for longer
      duration ( p<0,001) and with higher vacuum pressures ( p<0.05). The amount of
      mucus suctioned in a given time was related to catheter size, suction pressure
      and mucus density. CONCLUSION: Applied clinically, these results indicate that
      intrapulmonary pressure changes generated by the endotracheal suctioning of
      intubated neonates are likely to be considerable, possibly translating into loss
      of lung volume.

PMID- 15034649
TI  - Variation in intensive care unit outcomes by day of week: no weak-end.

PMID- 15034651
TI  - Cervical spinal epidural abscess and meningitis due to Prevotella oris and
      Peptostreptococcus micros after retropharyngeal surgery.

PMID- 15034650
TI  - Respiratory changes in inferior vena cava diameter are helpful in predicting
      fluid responsiveness in ventilated septic patients.
AB  - OBJECTIVE: To evaluate the extent to which respiratory changes in inferior vena
      cava (IVC) diameter can be used to predict fluid responsiveness. DESIGN:
      Prospective clinical study. SETTING: Hospital intensive care unit. PATIENTS:
      Twenty-three patients with acute circulatory failure related to sepsis and
      mechanically ventilated because of an acute lung injury. MEASUREMENTS: Inferior
      vena cava diameter (D) at end-expiration (Dmin) and at end-inspiration (Dmax) was
      measured by echocardiography using a subcostal approach. The distensibility index
      of the IVC (dIVC) was calculated as the ratio of Dmax - Dmin / Dmin, and
      expressed as a percentage. The Doppler technique was applied in the pulmonary
      artery trunk to determine cardiac index (CI). Measurements were performed at
      baseline and after a 7 ml/kg volume expansion using a plasma expander. Patients
      were separated into responders (increase in CI > or =15%) and non-responders
      (increase in CI <15%). RESULTS: Using a threshold dIVC of 18%, responders and non
      responders were discriminated with 90% sensitivity and 90% specificity. A strong
      relation (r = 0.9) was observed between dIVC at baseline and the CI increase
      following blood volume expansion. Baseline central venous pressure did not
      accurately predict fluid responsiveness. CONCLUSION: Our study suggests that
      respiratory change in IVC diameter is an accurate predictor of fluid
      responsiveness in septic patients.

PMID- 15034652
TI  - [Acetabular shape and cementless cups. Comparison of osteoarthritic hips and
      implant design].
AB  - The anatomy of the hip must be taken into account in order to ensure primary
      stability of cementless acetabular implants. In this study we analyzed the shapes
      of osteoarthritic acetabula and compared these to normal non-degenerative
      acetabula and to pressfit implants. We measured 92 acetabula with osteoarthritic
      deformations and 35 non-degenerative acetabula. Bone tissue samples from 50
      osteoarthritic acetabula were microradiographically analyzed. Furthermore, the
      size of the entrance plane of 37 pressfit cups was determined. The craniocaudal
      and ventrodorsal diameters of osteoarthritic acetabula correlate strongly (
      r=0.87). In craniocaudal direction, the acetabular diameter correlates
      significantly to both the radius of the lunate surface ( r=0.42) and the
      acetabular base ( r=0.54). Osteoarthritic acetabula have a deeper shape as
      degeneration increases and the entrance plane becomes significantly more circular
      ( p<0.05). When comparing osteoarthritic and non-arthrotic acetabula, the
      following values differ significantly (p<0.05): craniocaudal radius of the
      acetabular base, craniocaudal and ventrodorsal radius of the lunate surface, and
      ventrodorsal divergence between lunate surface and acetabular base. To
      reconstruct an acetabular offset which concurs with central points of the femoral
      head and the radius of the lunate surface, the level of the insert's entrance
      plane must be outside the entrance planes of the cup and acetabulum. The rims of
      hemispheric cups need to be trimmed to prevent these cups from extending beyond
      the acetabular rim.

PMID- 15034653
TI  - [Problems with expert opinion for the assessment of septic arthritis].
AB  - Bacterial arthritis is a rare and usually protracted disease and complication
      which can cause substantial permanent damage. At the first indication of such an
      infection, rapid and efficient therapy is required. In general, after a rapid
      diagnosis and subsequent therapy in early stage of the disease, a complete cure
      should be effected. In the case of children timely diagnosis and therapy lead to
      a very good chance of cure. In the case of adults under 50 years, the chances of
      a cure after an infectious arthritis are still good to very good. For patients
      older than 50, however, the chances of permanent damage after a joint infection
      are high. Severe damage in the region of a joint frequently leads to the
      accusation of medical error. Due to the often undetermined reasons for an
      infection, common pre- and concurrent illnesses, the long course of the disease,
      and the often substantial long-term damage, it is necessary for the medical
      specialist asked for an expert opinion on the question of cause to be
      particularly careful. The expert must take into consideration not only the
      permanent damage but must also estimate the future consequences of the disease.

PMID- 15034655
TI  - [Biceps tendon disorders: ultrasound, MR imaging and MR arthrography].
AB  - Ultrasound and MR imaging are competitive imaging modalities for the diagnosis of
      pathologic conditions of the biceps tendon. MR imaging has substantial advantages
      over ultrasound because biceps tendon lesions are most commonly located in the
      proximal part where lesions are hidden under the acromion for ultrasound
      assessment. The value of MR arthrography is substantiated by the capability to
      assess associated diagnoses which are otherwise difficult to assess. Associated
      diagnoses include full- and partial thickness tears of supraspinatus and
      subscapularis tendons, pulley lesions, and adhesive capsulitis (frozen shoulder).
      Moreover, MR arthrography is the method of choice for the assessment of superior
      labral anterior posterior (SLAP) lesions.

PMID- 15034657
TI  - [Thrombotic thrombocytopenic purpura. Reduced activity of von Willebrand factor
      cleaving protease].
AB  - Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy.
      Besides anemia and thrombocytopenia, neurological impairment is common in TTP. A
      42-year-old woman was admitted to a department of obstetrics/gynecology because
      of severe vaginal bleeding due to thrombocytopenia. After platelet transfusion,
      the patient developed a reduced level of consciousness, confusion, headache, and
      fever. CT scan did not show pathological changes. Transcranial Doppler sonography
      revealed increased blood flow velocities of all basal cerebral arteries. Because
      encephalitis was suspected the patient was transferred to the neurological
      department. CSF and cerebral magnetic resonance imaging studies were normal.
      Finally, the detection of schistocytes in the peripheral blood smear and the
      strong elevation of LDH led to the diagnosis of TTP. After plasma exchange over 3
      consecutive days the patient achieved complete remission. The diagnosis was
      confirmed by laboratory tests (activity of ADAMTS13 <5%, IgG antibodies against
      ADAMTS13). Platelet transfusion may adversely affect the outcome of patients with
      suspected TTP. Severely deficient activity of the von Willebrand factor cleaving
      protease (ADAMTS13) is specific for thrombotic thrombocytopenic purpura.

PMID- 15034656
TI  - [Radiofrequency ablation of lung tumors and -metastases].
AB  - BACKGROUND AND PURPOSE: Radiofrequency ablation is increasingly used to treat
      tumors "beyond the liver". The aim of this article is to perform a structured and
      critical review of the current literature concerning RFA of the lung and to
      compare these results with our own experience. MATERIAL AND METHODS: 16 patients
      with tumors or metastases of the lung were treated in our institution within 18
      months. 8 of these 16 patients were treated in a multicenter trial. For this
      article we compared our results to the results of all publications concerning RFA
      of the lung since 1995. RESULTS: 8 of our 16 patients were not included in the
      international multicenter trial and were followed-up at least 15 months. Within
      this observation period, 2 of 8 patients had recurrence of the tumors while in 6
      patients no recurrence was detected. Lee et al. published a study with 30
      patients. In 10 of these 30 patients RFA was performed in a curative intention
      with a therapeutical success in 8 of 10 patients after one year. DISCUSSION:
      Radiofrequency ablation of lung tumors smaller than 3 cm appears to be an
      alternative to surgical removal. Moreover, RFA offers a higher quality of life
      for the patients due to a low morbidity and mortality. However, more studies with
      longer observation periods are necessary for a definite conclusions.

PMID- 15034659
TI  - [Iatrogenic Wernicke-Korsakow syndrome with unusual neurological deficits and MRI
      lesions].
AB  - Wernicke-Korsakow Syndrome (WKS) is caused by thiamine (vitamin B1) deficiency
      and usually occurs in conjunction with chronic alcohol abuse. Our report concerns
      a 64-year-old, nonalcoholic, woman with no history of alcohol abuse, who became
      ill with WKS after 3 weeks of parenteral nourishment. As an unusual initial
      symptom she went blind in both eyes; this was followed a few days later by
      impaired consciousness and spastic tetraparesis. A cranial MRI examination showed
      symmetrical signal alteration (T2, FLAIR and diffusion weighting) in the medial
      thalamus, periaqueductal mesencephalon including the quadrigeminal plate,
      mamillary bodies and-most unusually-both paracentral gyri. Laboratory tests
      confirmed the diagnosis of WKS as significant thiamine deficiency was detected.
      Following several weeks of intravenous thiamine supplementation the MRI lesions
      were almost completely reversed but the neurological deficits regressed only
      partially.

PMID- 15034658
TI  - [Neurological complications of infective endocarditis].
AB  - Infective endocarditis involves the brain in 20-40% of cases. The neurologic
      syndrome often is the presenting feature. The most frequent neurologic
      complication is cerebral ischemia. In these patients and those with intracranial
      hemorrhage, a heart murmur as well as systemic signs of inflammation point to
      endocarditis. The encephalopathy in endocarditis is mostly due to cerebral
      infarction. In bacterial meningitis and brain abscess an uncommon isolate arouses
      suspicion. The most important therapy is antibiotic treatment. Valve replacement
      improves outcome; in the acute phase of endocarditis, however, it is only
      necessary in a third of the patients. Neurologic complications interfere with the
      timing of the valve replacement. If it is urgently required, its risk is
      reasonable within 3 days after cerebral ischemia; if possible 2-4 weeks should be
      waited. Cases of successful valve replacement within 4 weeks after intracranial
      hemorrhage have been reported, but it is recommended to postpone it for 4-6
      weeks. There are no data available for the other neurologic complications. Even
      today patients with endocarditis challenge the diagnostic and therapeutic
      capacity of various disciplines.

PMID- 15034661
TI  - Is dauer pheromone of Caenorhabditis elegans really a pheromone?
AB  - Animals respond to signals and cues in their environment. The difference between
      a signal (e.g. a pheromone) and a cue (e.g. a waste product) is that the
      information content of a signal is subject to natural selection, whereas that of
      a cue is not. The model free-living nematode Caenorhabditis elegans forms an
      alternative developmental morph (the dauer larva) in response to a so-called
      'dauer pheromone', produced by all worms. We suggest that the production of
      'dauer pheromone' has no fitness advantage for an individual worm and therefore
      we propose that 'dauer pheromone' is not a signal, but a cue. Thus, it should not
      be called a pheromone.

PMID- 15034660
TI  - The mechanisms of lift enhancement in insect flight.
AB  - Recent studies have revealed a diverse array of fluid dynamic phenomena that
      enhance lift production during flapping insect flight. Physical and analytical
      models of oscillating wings have demonstrated that a prominent vortex attached to
      the wing's leading edge augments lift production throughout the translational
      parts of the stroke cycle, whereas aerodynamic circulation due to wing rotation,
      and possibly momentum transfer due to a recovery of wake energy, may increase
      lift at the end of each half stroke. Compared to the predictions derived from
      conventional steady-state aerodynamic theory, these unsteady aerodynamic
      mechanisms may account for the majority of total lift produced by a flying
      insect. In addition to contributing to the lift required to keep the insect
      aloft, manipulation of the translational and rotational aerodynamic mechanisms
      may provide a potent means by which a flying animal can modulate direction and
      magnitude of flight forces for manoeuvring flight control and steering behaviour.
      The attainment of flight, including the ability to control aerodynamic forces by
      the neuromuscular system, is a classic paradigm of the remarkable adaptability
      that flying insects have for utilising the principles of unsteady fluid dynamics.
      Applying these principles to biology broadens our understanding of how the
      diverse patterns of wing motion displayed by the different insect species have
      been developed throughout their long evolutionary history.

PMID- 15034662
TI  - Multiple UV reflectance peaks in the iridescent neck feathers of pigeons.
AB  - Recent studies of colorful plumage signals in birds have been aided by the
      finding that birds can see ultraviolet (UV) light and thus may communicate using
      colors invisible to humans. Some of the pioneering and more pivotal work on avian
      color vision was performed with domestic pigeons ( Columba livia), yet
      surprisingly there have been few detailed reports of the UV-reflecting properties
      of pigeon feathers. Here, I use UV-VIS fiber-optic spectrometry to document the
      full-spectrum reflectance characteristics of iridescent purple and green neck
      plumage in pigeons. Neck feathers that appear purple to the human eye exhibit
      four reflectance peaks-two in the UV and one in the blue and red regions-and thus
      exhibit a UV-purple hue. Neck feathers that appear green to the human eye are
      characterized by five spectral peaks: two in the UV (UVA and UVB), a predominant
      green peak, and secondary violet and red peaks, conferring a UV-purple-green
      color. Such elaborate UV coloration suggests that birds may use an even more
      complex and 'hidden' UV signaling system than previously thought.

PMID- 15034663
TI  - Light-dependent magnetoreception in birds: interaction of at least two different
      receptors.
AB  - Passerine migrants require light from the blue-green part of the spectrum for
      magnetic compass orientation; under yellow light, they are disoriented. European
      robins tested under a combination of yellow light and blue or green light showed
      a change in behavior, no longer preferring their seasonally appropriate migratory
      direction: in spring as well as in autumn, they preferred southerly headings
      under blue-and-yellow and northerly headings under green-and-yellow light. This
      clearly shows that yellow light is not neutral and suggests the involvement of at
      least two types of receptors in obtaining magnetic compass information, with the
      specific interaction of these receptors being rather complex.

PMID- 15034664
TI  - Influence of the female sexual cycle on BALB/c mouse calling behaviour during
      mating.
AB  - Real-time recording technology was used in this study to analyse calling activity
      during heterosexual encounters in BALB/c mice. The spectrographic analyses
      revealed distinct types of calls that could be linked to a precise pre
      ejaculatory behavioural sequence. In addition, the oestrous cycle of the female
      was observed to influence the vocalization emission pattern. The recording
      technology used in this study provides numerous improvements in the
      characterization description of mice calling behaviour during mating and is
      expected to be useful in studies of vocal communication in many rodent species.

PMID- 15034665
TI  - Is the "Lost World" really lost? Palaeoecological insights into the origin of the
      peculiar flora of the Guayana Highlands.
AB  - The peculiar biogeography of the so-called "Lost World", i.e. the summits of
      sandstone tableaux ( tepuis) in the Neotropical Guyana region of Venezuela, has
      generated a debate regarding the factors that are thought to account for modern
      vegetation patterns in the region. Some argue that plant communities on these
      high-elevation summits reflect a long history of evolution in isolation, while
      others surmise that there has been substantial biotic interchange with the
      surrounding lowlands during glacial times. Until now, these apparently competing
      hypotheses have not been tested using palaeoecological methods. I used pollen
      analysis of Quaternary sediments and documented past vertical migrations of
      vegetation in response to climate changes, which supports the second hypothesis.
      Physiographical analysis, however, shows that about half the tableaux summits are
      too high for their flora to have reached the lowlands during the last glaciation,
      suggesting that a portion of the tableaux vegetation has always experienced some
      degree of biotic isolation. Thus, a component of the summit vegetation evolved in
      isolation, whereas other taxa experienced interchange, as reflected in endemism
      patterns among the tableaux summits. Biogeographical patterns on the summits are
      the result of complex evolutionary processes. The two hypotheses invoked to
      explain the vegetation patterns are not mutually exclusive, but instead
      complement one another.

PMID- 15034666
TI  - Predatory spider mimics acquire colony-specific cuticular hydrocarbons from their
      ant model prey.
AB  - The integrity of social insect colonies is maintained by members recognising and
      responding to the chemical cues present on the cuticle of any intruder.
      Nevertheless, myrmecophiles use chemical mimicry to gain access to these nests,
      and their mimetic signals may be acquired through biosynthesis or through contact
      with the hosts or their nest material. The cuticular hydrocarbon profile of the
      myrmecophilous salticid spider Cosmophasis bitaeniata closely resembles that of
      its host ant Oecophylla smaragdina. Here, we show that the chemical resemblance
      of the spider does not arise through physical contact with the adult ants, but
      instead the spider acquires the cuticular hydrocarbons by eating the ant larvae.
      More significantly, we show that the variation in the cuticular hydrocarbon
      profiles of the spider depends upon the colony of origin of the ant larvae prey,
      rather than the parentage of the spider.

PMID- 15034668
TI  - [Industry sponsoring and the results of research into accident surgery].

PMID- 15034670
TI  - [Psychotherapeutic care of dysphonic patients].
AB  - The diagnosis of vocal dysfunction is a prerequisite for referring a patient for
      specialized medical therapy. This mostly requires a holistic approach, and should
      also consider related symptoms and the social environment of the patient.
      Regulations on psychotherapy, promulgated in 1999, have provided clarity in
      relation to the indications for treatment in an inpatient and outpatient basis.
      Within the German health care system, every individual can now directly contact
      an officially certified psychotherapist (so called psychological psychotherapist)
      for probationary sessions, aimed at determining a basis and indication for
      further psychotherapy. In case of psychotherapy provided from others than
      physicians, an additional medical report from a physician is obligatory. Patients
      with functional and psychogenic voice problems often believe that organic
      disorders are the reason for their dysphonia. Thus, when caring for voice
      disordered patients and sending them to a psychotherapist, it is of great
      importance that physicians facilitate their referral by reacting in an empathic,
      fear reducing, and professional way.

PMID- 15034671
TI  - [Emergent surgery for body packing - what happens to the drugs?].
AB  - Body packing is a well recognized method of drug trafficking by smuggling drug
      containers in the gastrointestinal tract. Medical professionals might get
      involved with body packers after presentation by law enforcement or in case of
      medical emergencies such as drug overdose or mechanical intestinal obstruction
      due to the containers within the gastrointestinal tract. Besides the medical
      aspects in treating these patients, physicians must be aware of all the different
      legal specifics in dealing with body packers. In case of medical emergencies,
      drug traffickers have the legal status of regular patients with respect to
      professional medical discretion. The question remains of what physicians should
      do with the drugs after surgical removal? Even though the body packer remains the
      legal owner of the drugs, physicians may not return the drugs, since that
      constitutes the criminal offence of dealing in narcotics. Returning the drugs to
      law enforcement authorities is also prohibited because of professional medical
      discretion. The only way out of this predicament is for physicians to destroy the
      drugs under the observation of witnesses.

PMID- 15034672
TI  - [Interdisciplinary aspects of surgery of the pelvis minor and retroperitoneum].
AB  - Surgery of diseases of the pelvis minor and retroperitoneum such as inflammatory
      disease, malignant tumours, or trauma of pelvic organs need the close
      interdisciplinary collaboration of visceral surgeons, gynaecologists, and
      urologists. This collaboration begins in planning diagnostic and therapeutic
      procedures. It has to be clear who performs which operative step and when.
      Excellent long-term results in malignant disease show that the greater effort is
      worthwhile. The rate of postoperative morbidity after these multivisceral
      resections is high also in specialised centers, but mortality is below 5%.
      Because of the growing number of long-term survivors, preservation of quality of
      life becomes more and more important.

PMID- 15034673
TI  - Anandamide is an endogenous inhibitor for the migration of tumor cells and T
      lymphocytes.
AB  - Cell migration is of paramount importance in physiological processes such as
      immune surveillance, but also in the pathological processes of tumor cell
      migration and metastasis development. The factors that regulate this tumor cell
      migration, most prominently neurotransmitters, have thus been the focus of
      intense investigation. While the majority of neurotransmitters have a stimulatory
      effect on cell migration, we herein report the inhibitory effect of the
      endogenous substance anandamide on both tumor cell and lymphocyte migration.
      Using a collagen-based three-dimensional migration assay and time-lapse
      videomicroscopy, we have observed that the anandamide-mediated signals for CD8+ T
      lymphocytes and SW 480 colon carcinoma cells are each mediated by distinct
      cannabinoid receptors (CB-Rs). Using the specific agonist
      docosatetraenoylethanolamide (DEA), we have observed that the norepinephrine
      induced migration of colon carcinoma cells is inhibited by the CB1-R. The SDF-1
      induced migration of CD8+ T lymphocytes was, however, inhibited via the CB2-R, as
      shown by using the specific agonist JWH 133. Therefore, specific inhibition of
      tumor cell migration via CB1-R engagement might be a selective tool to prevent
      metastasis formation without depreciatory effects on the immune system of cancer
      patients.

PMID- 15034674
TI  - CpG-Oligodeoxynucleotides activate tyrosinase-related protein 2-specific T
      lymphocytes but do not lead to a protective tumor-specific memory response.
AB  - PURPOSE: Peritumoral CpG-oligodeoxynucleotide (ODN) treatment has been successful
      in tumor mouse models expressing strong antigens to induce activation of tumor
      specific CD8+ T lymphocytes which contribute to the control of tumor growth. To
      get near to clinical reality, the tumor-specific CD8+ response was investigated
      in mice bearing the weakly immunogenic B16 melanoma tumor and using the
      melanocyte differentiation tyrosinase-related protein 2 (TRP-2) as a tracking
      antigen. METHODS: The expansion and activation of TRP-2-specific T lymphocytes by
      CpG-ODNs was analyzed by tetramer staining and IFN-gamma production assays, while
      the activity of these cells in both memory and primary response was evaluated in
      vivo. RESULTS: After CpG-ODN treatment, the number of TRP-2 tetramer-stained CD8+
      T lymphocytes was not significantly modified, but these cells produced higher
      levels of interferon gamma (IFN-gamma) in response to the antigen than those from
      untreated mice. Mice possessing these activated T lymphocytes, when evaluated for
      their antitumor memory response, showed marginal protection against intravenous
      (i.v.) and subcutaneous (s.c.) tumor rechallenge. These cells were not crucial
      for the control of primary tumor growth since strong reduction of subcutaneous
      tumor was observed after CpG-ODN treatment in both CD8+ T cell depleted or
      nondepleted mice. On the contrary, NK cell depletion markedly reduced CpG-ODN
      induced tumor growth inhibition. CONCLUSIONS: Altogether, these data indicate the
      CpG treatment activates tumor-reactive effector CD8+ T lymphocytes, but,
      paralleling recent clinical observations, our model indicates that the mere
      activation of antitumor T cells is insufficient to result in a clinical response.

PMID- 15034675
TI  - Assessment of recurrent colorectal cancer following 5-fluorouracil chemotherapy
      using both 18FDG and 18FLT PET.

PMID- 15034676
TI  - Why should the radioiodine dose be different in patients with differentiated
      thyroid carcinoma prepared with recombinant human TSH?

PMID- 15034678
TI  - Monte Carlo-based down-scatter correction of SPECT attenuation maps.
AB  - Combined acquisition of transmission and emission data in single-photon emission
      computed tomography (SPECT) can be used for correction of non-uniform photon
      attenuation. However, down-scatter from a higher energy isotope (e.g. 99mTc)
      contaminates lower energy transmission data (e.g. 153Gd, 100 keV), resulting in
      underestimation of reconstructed attenuation coefficients. Window-based
      corrections are often not very accurate and increase noise in attenuation maps.
      We have developed a new correction scheme. It uses accurate scatter modelling to
      avoid noise amplification and does not require additional energy windows. The
      correction works as follows: Initially, an approximate attenuation map is
      reconstructed using down-scatter contaminated transmission data (step 1). An
      emission map is reconstructed based on the contaminated attenuation map (step 2).
      Based on this approximate 99mTc reconstruction and attenuation map, down-scatter
      in the 153Gd window is simulated using accelerated Monte Carlo simulation (step
      3). This down-scatter estimate is used during reconstruction of a corrected
      attenuation map (step 4). Based on the corrected attenuation map, an improved
      99mTc image is reconstructed (step 5). Steps 3-5 are repeated to incrementally
      improve the down-scatter estimate. The Monte Carlo simulator provides accurate
      down-scatter estimation with significantly less noise than down-scatter estimates
      acquired in an additional window. Errors in the reconstructed attenuation
      coefficients are reduced from ca. 40% to less than 5%. Furthermore, artefacts in
      99mTc emission reconstructions are almost completely removed. These results are
      better than for window-based correction, both in simulation experiments and in
      physical phantom experiments. Monte Carlo down-scatter simulation in concert with
      statistical reconstruction provides accurate down-scatter correction of
      attenuation maps.

PMID- 15034679
TI  - Requirements for clinical PET: clarification of the situation in Sweden.

PMID- 15034680
TI  - Requirements for clinical PET: the situation in Switzerland.

PMID- 15034682
TI  - Musculoskeletal disorders associated with HIV infection and AIDS. Part I:
      infectious musculoskeletal conditions.
AB  - The musculoskeletal system can be affected by a variety of abnormalities in
      association with human immunodeficiency virus (HIV) infection. Although not as
      common as complications involving other organ systems, such as the pulmonary and
      the central nervous systems, HIV-associated musculoskeletal disorders are
      sometimes the initial presentation of the viral illness. Knowledge of the
      existence and the characteristic appearance of the conditions affecting bone,
      joint, and muscle in HIV-infected patients is valuable to radiologists for
      diagnosis and to clinicians for detection and appropriate treatment. We reviewed
      recent literature to provide a comprehensive assessment of the HIV-associated
      musculoskeletal disorders, and present radiologic examples from our own
      collection. This article is divided into two parts. In the first part we review
      the infectious musculoskeletal disorders associated with HIV illness and AIDS,
      including cellulitis, abscesses, pyomyositis, septic bursitis, septic arthritis,
      osteomyelitis, and bacillary angiomatosis. We also present a comprehensive
      spectrum of mycobacterial infections, consisting of tuberculous spondylitis and
      spondylodiskitis, arthritis, osteomyelitis, and tenosynovitis, as well as
      infections caused by atypical mycobacteria. Part II of this review will
      concentrate on non-infectious musculoskeletal conditions, including rheumatic
      disorders and neoplasms.

PMID- 15034683
TI  - Compactin-a review.
AB  - Compactin, a hypocholesterolemic molecule, is a competitive inhibitor of 3
      hydroxy-3-methyl-glutaryl (HMG)-CoA reductase, which is a regulatory enzyme for
      cholesterol biosynthesis. The structural similarity and high affinity of the acid
      form of compactin and HMG, the natural substrate of enzyme, results in specific
      and effective inhibition of this enzyme. Inhibition results in reduced levels of
      mevalonic acid in the body, leading to pleiotropic effects. Various fungi have
      been used for the commercial production of compactin. Using different strategies
      for improving production levels, yields have been increased to around 900 times
      of the amount originally produced. Recently, the gene sequence responsible for
      compactin production has been cloned and sequenced. This review deals with the
      chemistry, mode of action, pharmacology, biosynthesis, and production of
      compactin. A comparative study of various reports dealing with the production of
      compactin is also included.

PMID- 15034684
TI  - Membrane-aerated biofilm reactor for the removal of 1,2-dichloroethane by
      Pseudomonas sp. strain DCA1.
AB  - A membrane-aerated biofilm reactor (MBR) with a biofilm of Pseudomonas sp. strain
      DCA1 was studied for the removal of 1,2-dichloroethane (DCA) from water. A
      hydrophobic membrane was used to create a barrier between the liquid and the gas
      phase. Inoculation of the MBR with cells of strain DCA1 grown in a continuous
      culture resulted in the formation of a stable and active DCA-degrading biofilm on
      the membrane. The maximum removal rate of the MBR was reached at a DCA
      concentration of approximately 80 micro M. Simulation of the DCA fluxes into the
      biofilm showed that the MBR performance at lower concentrations was limited by
      the DCA diffusion rate rather than by kinetic constraints of strain DCA1. Aerobic
      biodegradation of DCA present in anoxic water could be achieved by supplying
      oxygen solely from the gas phase to the biofilm grown on the liquid side of the
      membrane. As a result, direct aeration of the water, which leads to undesired
      coagulation of iron oxides, could be avoided.

PMID- 15034686
TI  - Abstracts of the Society for Pediatric Radiology 47th Annual Meeting and
      Postgraduate Course. Savannah, Georgia, USA. 27 April-1 May 2004.

PMID- 15034695
TI  - Angioplasty of symptomatic high-grade internal carotid artery stenosis with
      intraluminal thrombus: therapeutic approach.
AB  - Intraluminal thrombus in the internal carotid artery (ICA) is usually found in
      patients with severe atheromatous stenosis. Having reviewed 300 carotid
      angioplasties for symptomatic >70% ICA stenosis, we found three patients (1%)
      with intraluminal thrombus. Conservative treatment with anticoagulants and double
      antiplatelet coverage can result in lysis of the thrombus without severe risks.
      Percutaneous transluminal angioplasty and stenting, preferably with distal
      protection, can be an excellent alternative to carotid endarterectomy.

PMID- 15034685
TI  - RT1.L: a family of MHC class Ib genes of the rat major histocompatibility complex
      with a distinct promoter structure.
AB  - RT1.L class I antigens have originally been identified in LEW rats by LEW.1LV3
      anti-LEW.1LM1 antisera and have been classified as nonclassical. We report now
      that LEW.1LV3-anti-LEW.1LM1 antisera react with three different antigens, termed
      RT1.L1, RT1.L2, and RT1.L3. This was found by serological analysis of a panel of
      transfectants expressing different class I genes of strain LEW with a LEW.1LV3
      anti-LEW.1LM1 antiserum and two monoclonal antibodies (mAbs HT20 and HT21)
      generated in the same strain combination. The antiserum reacted with all three
      antigens: the two mAbs with RT1.L1 and RT1.L2, respectively. Sequence analysis
      showed that the genes encoding RT1.L1, RT1.L2, and RT1.L3 cluster together in a
      phylogenetic analysis of rat and mouse alpha(1)-alpha(2) sequences and that they
      share an unusual MHC class I promoter in which Enhancer A and B, as well as the
      interferon response element (IRE), are missing. Exchange of the promoter in
      RT1.L2 against the classical RT1.A promoter resulted in high surface expression
      in appropriate transfectants, indicating that the deviant promoter is responsible
      for the weak surface expression of the RT1.L2 gene. The very similar promoter
      structures of RT1.L1 and RT1.L3 are likely to contribute also to the weak
      expression of these genes. As RT1.L3 maps closely to the deletion in the mutant
      haplotype lm1, the RT1.L family can be located in the class I region extending
      from Bat1 to Pou5f1. Different from other allogeneic mAbs detecting known class I
      molecules encoded by genes of the RT1.C/E region, HT20 and HT21 react with a wide
      panel of strains carrying different RT1 haplotypes. This suggests that
      nonclassical class I genes of the RT1.L family are present in most RT1
      haplotypes.

PMID- 15034697
TI  - Degenerative diseases of the cervical spine: comparison of a multiecho data image
      combination sequence with a magnetisation transfer saturation pulse and cervical
      myelography and CT.
AB  - Assessing degenerative disease in the cervical spine remains a challenge. There
      is much controversy about imaging the cervical spine using MRI. Our aim in this
      prospective study was to compare a T2*-weighted 2D spoiled gradient-echo
      multiecho sequence (MEDIC) with a magnetisation transfer saturation pulse with
      cervical myelography and postmyelographic CT. Using an assessment scale we looked
      at the vertebral bodies, intervertebral discs, neural foramina, anterior and
      posterior nerve roots, grey matter, ligamentaflava, oedema in the spinal cord and
      stenosis of the spinal canal. We also evaluated postmyelography CT and the MEDIC
      sequence for assessing narrowing of the neural foramina in a cadaver cervical
      spine. We examined 67 disc levels in 18 patients, showing 18 disc prolapses and
      21 osteophytes narrowing the spinal canal or the neural foramina. All MRI studies
      showed these abnormalities findings equally well. Postmyelography CT was
      significantly better for showing the bony structures and the anterior and
      posterior nerve roots. The MEDIC sequence provided excellent demonstration of
      soft-tissue structures such as the intervertebral disc and ligamentum flavum. No
      statistical differences between the imaging modalities were found in the
      assessment of narrowing of the neural foramina or the extent of spinal stenosis.
      The cadaver measurements showed no overestimation of abnormalities using the
      MEDIC sequence.

PMID- 15034698
TI  - Stroke-like pattern in DTI and MRS of childhood mitochondrial
      leukoencephalopathy.
AB  - In a 13-month-old boy with recurrent motor deterioration provoked by fever MRI
      and proton MRS detected a leukoencephalopathy with reduced cerebral metabolites
      and elevated lactate. At follow-up 6 and 16 months later these abnormalities
      improved gradually. Serial diffusion tensor imaging revealed a stroke-like
      pattern with an initial strong reduction of the apparent diffusion coefficient
      followed by elevated values 6 months later. The relative diffusion anisotropy
      remained reduced. Muscle biopsy confirmed a mitochondrial encephalomyopathy.

PMID- 15034699
TI  - Aneurysmal sub-arachnoid haemorrhage in patients with Noonan syndrome: a report
      of two cases and review of neurovascular presentations in this syndrome.
AB  - To date, intracranial aneurysms have been reported in two patients with Noonan
      syndrome. We report two unrelated patients with Noonan syndrome who presented
      with sub-arachnoid haemorrhage secondary to intracranial aneurysms. These cases
      are discussed and other cerebrovascular abnormalities that have been described in
      association with Noonan syndrome are reviewed. Ultrastructural and genetic
      factors contributing to these associations are considered.

PMID- 15034700
TI  - Characterization of necrotic meningioma using diffusion MRI, perfusion MRI, and
      MR spectroscopy: case report and review of the literature.
AB  - Necrotic meningiomas are relatively rare, accounting for 1.3-3.9% of primary
      intracranial tumours and for 10-15% of meningiomas, but are of special clinical
      importance as they may resemble metastases or malignant gliomas. We report the
      magnetic resonance findings of diffusion-weighted imaging, perfusion-weighted
      imaging, and spectroscopy in a patient with a necrotic meningioma, in whom
      clinical symptoms and signs suggested a central nervous system infection.

PMID- 15034701
TI  - Double spinal dural arteriovenous fistulas: case report and review of the
      literature.
AB  - Spinal dural arteriovenous fistula (SDAVF) is the most common spinal vascular
      malformation. It mainly affects men after the fifth decade and is usually an
      acquired lesion with an unknown etiology. We report on a patient with the unusual
      finding of two separate SDAVFs at the level of L1 on the right and L2 on the left
      side. Initial selective spinal digital subtraction angiography (DSA) was
      terminated with demonstration of a SDAVF at the level of L1 but incomplete
      demonstration of all segmental arteries. Due to a recurrent deterioration of the
      patient's neurological status, and persistent pathological vessels seen on MRI, a
      second spinal DSA was performed 6 years later, demonstrating the second fistula
      at the level of L2 on the left side with a separate venous drainage pattern. A
      retrospective analysis of the angiographic films suggested that both fistulas had
      already been present 6 years previously. This conclusion is justified because of
      a transient and faint opacification of the left L2 fistula demonstrated on the
      films after injection of the right L2 segmental artery. We conclude that in the
      case of incomplete angiography and persistent clinical and MR findings not only
      reopening of the treated SDAVF has to be taken into account but also the
      existence of a second fistula. Since this is the first case of a double fistula
      in our series of 129 SDAVFs, and given the few reported cases of double SDAVFs,
      we do not think that completion of selective spinal DSA has to be postulated
      routinely after a fistula has been found. However, repeat angiography should be
      performed in patients who continue to deteriorate, fail to improve with
      persisting MRI pathologies, or demonstrate delayed deterioration after a period
      of improvement.

PMID- 15034705
TI  - A future for nuclear analytical techniques? Why not?
AB  - The choices of universities and national research institutions in supporting
      scientific research are increasingly justified on the basis of, amongst others,
      the relevance that has to be reflected by external, preferably sustainable
      funding of the research programs. Many traditional fields of application such as
      environmental sciences do not offer a promising outlook in this respect. As a
      consequence, university research reactors face closure because of reallocations
      of university funds to more contemporary sciences such as molecular biology and
      nanotechnology. Therefore, laboratories operating nuclear analytical techniques
      (NAA, (TR)XRF, and PIXE) need to use their creativity in finding ways for
      participation in, for example, nanotechnology, cancer research, or genomics. This
      requires an open mind in terms of the opportunities, strengths, and weaknesses of
      the techniques, and a departure of technique-oriented research towards problem
      oriented research in which other nuclear techniques can be used. The unique
      features of radiotracers, nuclear imaging, and nuclear beam techniques are
      discussed in view of the new areas mentioned above. Some examples of
      opportunities for nuclear analytical techniques in the above-mentioned fields are
      given.

PMID- 15034703
TI  - The problem of underdosing of angiotensin-converting enzyme inhibitors is
      markedly overrated: results from a study of patients discharged from hospital
      after an acute myocardial infarction.
AB  - OBJECTIVE: The use of angiotensin-converting enzyme (ACE) inhibitors has
      increased markedly during the last decade. It has been claimed that doses of ACE
      inhibitors prescribed in clinical practice are considerably lower than the target
      doses used in randomized clinical trials. The aim of the study was to investigate
      dosing of ACE inhibitors in patients discharged from the hospital after an acute
      myocardial infarction (AMI) and, furthermore, to compare these doses with the
      doses actually reached in clinical trials. METHODS: From 16 hospitals, we drew a
      sample of patients who were discharged alive with the diagnosis of AMI during a 3
      month period in 1999/2000. From medical records, physicians in each hospital
      obtained the observed rate of cardiovascular drugs at discharge, including type
      and doses of ACE inhibitors. The clinicians' main indication for ACE inhibitor
      use was also reported. Outcome variables, including deaths and drug utilization
      with dosing after 6 months, were collected. RESULTS: Of a total of 767 patients
      discharged alive, 274 patients received an ACE inhibitor. The daily mean doses of
      the four ACE inhibitors used in the study were as follows: captopril 69.8+/-36.9
      mg (n=44), enalapril 13.6+/-8.1 mg (n=75), lisinopril 11.0+/-7.2 mg (n=114), and
      ramipril 8.4+/-4.5 mg (n=38). The doses were unchanged after 6 months except for
      captopril, which showed a rise in mean daily dose to 84.4+/-36.7 mg. Ramipril
      compared most favorably with clinical trial medications, while captopril deviated
      most. The indication of hypertension was associated with slightly higher doses
      than the indication of secondary prevention. CONCLUSION: AMI patients were
      discharged from the hospital with ACE inhibitor doses fairly close to the ones
      achieved in clinical trials showing survival benefits for ACE inhibitors. A
      distinction should be made between target doses and doses actually obtained in
      clinical trials.

PMID- 15034704
TI  - Rifampicin seems to act as both an inducer and an inhibitor of the metabolism of
      repaglinide.
AB  - OBJECTIVE: To investigate if rifampicin is both an inducer and an inhibitor of
      repaglinide metabolism, it was determined whether the timing of rifampicin co
      administration influences the pharmacokinetics of repaglinide. METHODS: Male
      volunteers ( n=12) participated in a randomised, two-period, crossover trial
      evaluating the effect of multiple doses of 600 mg rifampicin once daily for 7
      days on repaglinide metabolism. Subjects were, after baseline measurements of
      repaglinide pharmacokinetics, randomised to receive, on either day 7 or day 8 of
      the rifampicin administration period, a single dose of 4 mg repaglinide and vice
      versa in the following period. RESULTS: When repaglinide was given, together with
      the last rifampicin dose, on day 7, an almost 50% reduction of the median
      repaglinide area under the plasma concentration-time curve (AUC) was observed.
      Neither the peak plasma concentration (C(max)), time to reach C(max) (t(max)) nor
      terminal half-life (t(1/2)) was statistically significantly affected. When
      repaglinide was given on day 8, 24 h after the last rifampicin dose, an almost
      80% reduction of the median repaglinide AUC was observed. The median C(max) was
      now statistically significantly reduced from 35 ng/ml to 7.5 ng/ml. Neither
      t(max) nor t(1/2) was significantly affected. CONCLUSION: When rifampicin and
      repaglinide are administered concomitantly, rifampicin seems to act as both an
      inducer and an inhibitor of the metabolism of repaglinide. After discontinuing
      rifampicin administration, while the inductive effect on CYP3A4 and probably also
      CYP2C8 is still present, an even more marked reduction in the plasma
      concentration of repaglinide was observed. Our results suggest that concomitant
      administration of rifampicin and repaglinide may cause a clinically relevant
      decrease in the glucose-lowering effect of repaglinide, in particular when
      rifampicin treatment is discontinued or if the drugs are not administered
      simultaneously or within a few hours of each other.

PMID- 15034706
TI  - The internal comparator method.
AB  - An internal comparator method is proposed which offers reliable instrumental
      neutron activation analysis (INAA) results for samples with an irregular geometry
      and/or measured at the closest position to the Ge detector. Because the selected
      internal comparator in the sample analyzed will receive exactly the same thermal
      neutron flux as the other components, this method can be applied to the INAA of
      materials suffering from thermal neutron self-shielding. To apply the internal
      comparator method, the k(0)-method must be installed and the analytes, including
      the internal comparator, should be homogeneously distributed in the test portion.

PMID- 15034707
TI  - Sampling modulation technique in radio-frequency helium glow discharge emission
      source by use of pulsed laser ablation.
AB  - An emission excitation source comprising a high-frequency diode-pumped Q-switched
      Nd:YAG laser and a radio-frequency powered glow discharge lamp is proposed. In
      this system sample atoms ablated by the laser irradiation are introduced into the
      lamp chamber and subsequently excited by the helium glow discharge plasma. The
      pulsed operation of the laser can produce a cyclic variation in the emission
      intensities of the sample atoms whereas the plasma gas species emit the radiation
      continuously. The salient feature of the proposed technique is the selective
      detection of the laser modulation signal from the rest of the continuous
      background emissions, which can be achieved with the phase sensitive detection of
      the lock-in amplifier. The arrangement may be used to estimate the emission
      intensity of the laser ablated atom, free from the interference of other species
      present in the plasma. The experiments were conducted with a 13.56 MHz radio
      frequency (rf) generator operated at 80 W power to produce plasma and the laser
      at a wavelength of 1064 nm (pulse duration:34 ns, repetition rate:7 kHz and
      average pulse energy of about 0.36 mJ) was employed for sample ablation. The
      measurements resulted in almost complete removal of nitrogen molecular bands
      (N(2)(+) 391.44 nm). Considerable reduction (about 75%) in the emission intensity
      of a carbon atomic line (C I 193.03 nm) was also observed.

PMID- 15034708
TI  - Removal of major interference sources in aqueous near-infrared spectroscopy
      techniques.
AB  - This work describes a hybrid procedure for eliminating major interference sources
      in aqueous near-infrared (NIR) spectra, that include aqueous influence, noise,
      and systemic variations irrelevant to concentration. The scheme consists of two
      parts: extension of wavelet prism (WPe) and orthogonal signal correction (OSC).
      First, WPe is employed to remove variations due to aqueous absorbance and noise;
      then OSC is applied to remove systemic spectral variations irrelevant to
      concentration. Although water possesses strong absorption bands that overshadow
      and overlap the absorption bands of analytes, along with noise and systematic
      interference, successful calibration models can be generated by employing the
      method proposed here. We show that the elimination of major interference sources
      from the aqueous NIR spectra results in a substantial improvement in the
      precision of prediction, and reduces the required number of PLS components in the
      model. In addition, the strategy proposed here can be applied to various
      analytical data for quantitative purposes as well.

PMID- 15034709
TI  - Simultaneous determination of radionuclides separable into natural decay series
      by use of time-interval analysis.
AB  - A delayed coincidence method, time-interval analysis (TIA), has been applied to
      successive alpha- alpha decay events on the millisecond time-scale. Such decay
      events are part of the (220)Rn-->(216)Po ( T(1/2) 145 ms) (Th-series) and (219)Rn
      ->(215)Po ( T(1/2) 1.78 ms) (Ac-series). By using TIA in addition to measurement
      of (226)Ra (U-series) from alpha-spectrometry by liquid scintillation counting
      (LSC), two natural decay series could be identified and separated. The TIA
      detection efficiency was improved by using the pulse-shape discrimination
      technique (PSD) to reject beta-pulses, by solvent extraction of Ra combined with
      simple chemical separation, and by purging the scintillation solution with dry
      N(2) gas. The U- and Th-series together with the Ac-series were determined,
      respectively, from alpha spectra and TIA carried out immediately after Ra
      extraction. Using the (221)Fr-->(217)At ( T(1/2) 32.3 ms) decay process as a
      tracer, overall yields were estimated from application of TIA to the (225)Ra (Np
      decay series) at the time of maximum growth. The present method has proven useful
      for simultaneous determination of three radioactive decay series in environmental
      samples.

PMID- 15034710
TI  - Luminescent optical sensors.

PMID- 15034711
TI  - Density-based clustering for exploration of analytical data.

PMID- 15034712
TI  - Impaired executive function in male MDMA ("ecstasy") users.
AB  - RATIONALE: Long-term users of ecstasy have shown impaired performance on a
      multitude of cognitive abilities (most notably memory, attention, executive
      function). Research into the pattern of MDMA effects on executive functions
      remains fragmented, however. OBJECTIVES: To determine more systematically what
      aspects of executive function are affected by a history of MDMA use, by using a
      model that divides executive functions into cognitive flexibility, information
      updating and monitoring, and inhibition of pre-potent responses. METHODS: MDMA
      users and controls who abstained from ecstasy and other substances for at least 2
      weeks were tested with a computerized cognitive test battery to assess their
      abilities on tasks that measure the three submodalities of executive function,
      and their combined contribution on two more complex executive tasks. Because of
      sex-differential effects of MDMA reported in the literature, data from males and
      females were analyzed separately. RESULTS: Male MDMA users performed
      significantly worse on the tasks that tap on cognitive flexibility and on the
      combined executive function tasks; no differences were found on the other
      cognitive tasks. Female users showed no impairments on any of the tasks.
      CONCLUSIONS: The present data suggest that a history of MDMA use selectively
      impairs executive function. In male users, cognitive flexibility was impaired and
      increased perseverative behavior was observed. The inability to adjust behavior
      rapidly and flexibly may have repercussions for daily life activities.

PMID- 15034713
TI  - Vasorelaxation and hyperpolarisation of rat small mesenteric artery by the
      quaternary anion tetraphenylboron.
AB  - This study characterises the vasorelaxation and hyperpolarisation effects of the
      negatively charged quaternary compound tetraphenylboron (TPB) in the rat small
      mesenteric artery. Segments of rat small mesenteric artery were mounted in a
      myograph and vessel tone and membrane potential were measured simultaneously. In
      vessels pre-contracted with vasopressin (0.3-0.6 nM), U46619 (30-90 nM) or
      methoxamine (0.3-3 microM), TPB (0.1-100 microM) produced a marked endothelium
      independent relaxation. However, vasorelaxation responses to TPB were abolished
      in tissues pre-contracted with K(+) (50 mM), and significantly inhibited by
      glibenclamide (glib, 10 microM). In the absence of tone, TPB (1-30 microM) caused
      a concentration-dependent membrane hyperpolarisation of rat mesenteric artery
      smooth muscle cells, which was not dependent on the endothelium, but sensitive to
      glibenclamide (10 microM). In methoxamine (0.3-3 microM) pre-contracted vessels,
      the relaxation response was associated with a marked hyperpolarisation, which was
      also sensitive to glibenclamide (10 microM), further inhibited by a combination
      of K(+) channel blockers (glib [10 microM], charybdotoxin [100 nM], apamin [100
      nM], 4-aminopyridine [1 mM] and Ba(2+) [30 microM]) and abolished by 50 mM K(+).
      The results of this study show that TPB causes a vasorelaxation and
      hyperpolarisation response in the rat small mesenteric artery through a direct
      action on the vascular smooth muscle. TPB exerts its effects partially via the
      activation of K(ATP) channels, but also by another mechanism involving K(+)
      dependent hyperpolarisation.

PMID- 15034714
TI  - Expression of a SoxB and a Wnt2/13 gene during the development of the mollusc
      Patella vulgata.
AB  - We cloned and analysed the expression of a SoxB gene ( PvuSoxB) in the marine
      mollusc, Patella vulgata. Like its orthologues in deuterostomes, after an early
      broad ectodermal distribution, PvuSoxB expression only persists in cells
      competent to form neural structures. In the post-gastrulation larva, PvuSoxB is
      expressed in the prospective neuroectoderm in the head and in the trunk. No
      expression can be seen dorsally, around the mouth and the anus, or along the
      ventral midline. We also report the expression of a Wnt2/13 orthologue ( PvuWnt2)
      in Patella. After gastrulation, PvuWnt2 is expressed in the posterior part of the
      mouth, along the ventral midline and around the anus. This expression seems to be
      complementary to that of PvuSoxB in the trunk. We suggest the existence of a
      fundamental subdivision of the Patella trunk ectoderm into midline (mouth,
      midline, anus) and more lateral structures.

PMID- 15034715
TI  - Regulation and a conserved intron sequence of liguleless3/4 knox class-I homeobox
      genes in grasses.
AB  - The nine class-I maize (Zea mays L.) knox genes are putative transcription
      factors normally expressed in shoot apices, but not in leaves. knotted1 (kn1)
      seems to function in shoot apical meristem maintenance, and rough sheath1 (rs1)
      like genes may act in internode elongation. The function of liguleless3 (lg3)
      type genes is still unknown. Here, we characterized lg3 as well as the two most
      closely related genes liguleless4a (lg4a, formerly knox11) and liguleless4b
      (lg4b, formerly knox5). We termed this subclass of knox genes lg3/4 genes. We
      studied the expression patterns of lg3/4 genes and compared their sequences. We
      obtained knockout mutants of lg3 by finding Mu transposon insertions into exons.
      Our results show that lg3 was not essential for plant development, and that lg4a
      and lg4b were likely to encode the redundant function. In addition, lg4a but not
      lg4b was ectopically expressed in the Lg4-O mutant, suggesting that this mutant
      was affected at the lg4a locus. We found that the lg3 gene was unique among knox
      genes as it was co-induced in the leaves of leaf mutants that ectopically
      expressed knox genes in the leaves. The leaf phenotype expressed in the dominant
      Rs1-O mutant was not altered when lg3 function was removed using the knockout.
      Genomic sequence comparisons of lg3, lg4a and lg4b from maize and the two
      homologous genes, osh6 and osh71, from rice revealed a 14-bp phylogenetic
      footprint in intron II. This sequence was conserved in nucleotide composition,
      position and polarity in the lg3/4 genes of divergent grasses representing six
      Gramineae subfamilies. In an independent experiment, this same conserved sequence
      was found in a yeast reverse one-hybrid screen for putative binding sites of the
      LG3 homeodomain protein. Distribution of this 14-bp sequence was examined within
      the public rice database. The possible function of this sequence in regulation of
      lg3/4 genes is discussed.

PMID- 15034716
TI  - ERECTA is required for protection against heat-stress in the AS1/ AS2 pathway to
      regulate adaxial-abaxial leaf polarity in Arabidopsis.
AB  - In seed plants, formation of the adaxial-abaxial polarity is of primary
      importance in leaf patterning. Since Arabidopsis thaliana (L.) Heynh. genes
      ASYMMETRIC LEAVES1 ( AS1) and ASYMMETRIC LEAVES2 ( AS2) are key regulators in
      specifying adaxial leaf identity, and ERECTA is involved in the AS1/ AS2 pathway
      for regulating adaxial-abaxial polarity [L. Xu et al. (2003) Development 130:4097
      4107], we studied the physiological functions of the ERECTA protein in plant
      development. We analyzed the effects of different environmental conditions on a
      special leaf structure in the as1 and as2 mutants. This structure, called the
      lotus-leaf, reflects a severe loss of adaxial-abaxial polarity in leaves. Higher
      concentrations of salt or other osmotic substance and lower temperature severely
      affected plant growth both in the wild type and the mutants, but did not affect
      lotus-leaf frequency in the as1 and as2 mutants. as1 and as2 mutants exhibited a
      very low lotus-leaf frequency at 22 degrees C, a temperature that favors
      Arabidopsis growth. The lotus-leaf frequency rose significantly with an increase
      in growth temperature, and only in plants that are in the erecta mutation
      background. These results suggest that ERECTA function is required for reducing
      plant sensitivity to heat stress during adaxial-abaxial polarity formation in
      leaves.

PMID- 15034718
TI  - Acute effects of continuous and intermittent vibration on finger circulation.
AB  - OBJECTIVES: To compare the acute response of finger circulation to continuous and
      intermittent vibration having the same total duration of vibration exposure and
      the same energy-equivalent acceleration magnitude. METHODS: Finger blood flow
      (FBF) was measured in the middle and little fingers of both hands of ten healthy
      men. Finger skin temperature (FST) was measured in the middle right finger. With
      a static load of 10 N, the middle finger of the right hand was exposed to 125 Hz
      at 44 m s(-2) root mean square (r.m.s.) in five conditions: (1). 30 min
      continuous exposure, (2). two periods of 15 min, separated by a 15 min period
      with no vibration, (3). four periods of 7.5 min, separated by 7.5 min periods
      with no vibration, (4). eight periods of 3.75 min, separated by 3.75 min periods
      with no vibration, (5). 16 periods of 1.88 min, separated by 1.88 min periods
      with no vibration. All five exposures correspond to an 8 h energy-equivalent
      frequency-weighted acceleration magnitude of 1.4 m s(-2) r.m.s. according to
      International Standard ISO 5349-1 (2001). Finger circulation was measured in all
      four digits before the application of vibration and at fixed intervals during
      vibration exposure and during a 45 min recovery period. RESULTS: The FST did not
      change during vibration exposure, whereas all vibration conditions produced
      significant reductions in FBF of the vibrated finger when compared with the pre
      exposure FBF. During vibration exposure, the vibration caused a similar degree of
      vasoconstriction in the vibrated finger without evidence of cumulative effects
      during intermittent exposure. After the end of exposure to 30 min of continuous
      vibration there was a progressive decrease in the FBF, whereas there was no
      statistically significant reduction following exposure to intermittent vibration.
      CONCLUSIONS: For the vibration stimuli investigated (exposure durations varying
      from 1.88 min to 30 min, with rest periods varying from 1.88 min to 15 min), the
      reduction of FBF during exposure was the same for continuous and intermittent
      vibration. The after effect of vibration was greater following the continuous
      vibration exposure. Although some evidence from this study is consistent with the
      notion that intermittent vibration has a less severe effect than continuous
      vibration, this evidence is not yet conclusive.

PMID- 15034717
TI  - Pathophysiology of pain.
AB  - Pain is a major symptom of many different diseases. Modern pain research has
      uncovered important neuronal mechanisms that are underlying clinically relevant
      pain states, and research goes on to define different types of pains on the basis
      of their neuronal and molecular mechanisms. This review will briefly outline
      neuronal mechanisms of pathophysiological nociceptive pain resulting from
      inflammation and injury, and neuropathic pain resulting from nerve damage. Pain
      is the sensation that is specifically evoked by potential or actual noxious (i.e.
      tissue damaging) stimuli or by tissue injury. Pain research has not only explored
      the neuronal and molecular basis of the "pain system" of the healthy subject but
      has also provided insights into the function and plasticity of the "pain system"
      during clinically relevant pains such as post-injury pain, inflammatory pain,
      postoperative pain, cancer pain and neuropathic pain. This review will briefly
      describe the "pain system" and then address neuronal mechanisms that are involved
      in clinical pain states.

PMID- 15034719
TI  - Localization of thrombomodulin in pericryptal fibroblasts of the rat duodenum.
AB  - Thrombomodulin (TM) contributes to the inactivation of thrombin which activates
      protein C, a major anticoagulant and anti-inflammatory protein. This report
      describes the distribution and localization of TM in the rat duodenum by light
      and electron microscopic immunohistochemistry. In addition to the endothelium of
      the entire vasculature, TM was found on the non-vascular structures, cellular
      networks of pericryptal fibroblasts surrounding the bases of the glandular
      crypts. TM was localized on the plasma membrane of the pericryptal fibroblasts
      which existed in the pericryptal spaces between the basal lamina of the
      epithelium and the collagenous sheets around the base of the crypt. TM
      immunoreactive pericryptal fibroblasts were stellate-shaped cells and contacted
      with each other by their cytoplasmic processes forming an anastomosing syncytium
      around the base of the crypt. In contrast to pericryptal fibroblasts, TM was not
      localized in subepithelial fibroblasts in the villi or smooth muscle cells in the
      lamina muscularis mucosae and the muscularis. The functional significance of TM
      in pericryptal fibroblasts is discussed.

PMID- 15034721
TI  - The lymphatic system in the dorsal skinfold chamber of the Syrian golden hamster
      in vivo.
AB  - The lymphatic network contributes to maintaining tissue homeostasis and
      immunological function by transporting fluid, plasma protein and cells from
      peripheral tissue via the lymph nodes into the blood vascular system. In contrast
      to the blood circulatory system, little is known about the lymphatic system. In
      particular, suitable animal models are lacking. Therefore, the dorsal skinfold
      chamber model was used to investigate the existence of a lymphatic system. To
      analyze the lymphatic network Syrian golden hamsters (n=12) fitted with titanium
      chambers were used. FITC-dextran of different concentrations (5% or 25%) and
      different molecular weights (4, 40 or 150 kDa) was used to contrast lymphatic
      vessels and measure initial lymph flow velocity. Intravital fluorescence
      microscopy enabled the quantification of diameter, velocity and branching order.
      Histology and electron microscopy supported the in vivo findings. Immediately
      after intradermal injection of FITC-dextran the lymphatics including valves were
      visible. The diameters of the lymphatic vessels (n=189) ranged from 133+/-5.4
      microm (branching order 1) to 26+/-4.0 microm (branching order 5). Using
      different molecular weights of FITC-dextran, no significant differences in
      velocity were measured (327+/-157 microm/s with 4 kDa, 391+/-126 microm/s with 40
      kDa, and 378+/-175 microm/s with 150 kDa). Blood and lymphatic vessels could not
      be differentiated clearly by H&E staining. However, endothelial cells of vessels
      with an irregularly shaped lumen containing no erythrocytes in cross section
      showed a weaker signal for CD31 staining as compared to endothelial cells of
      vessels containing erythrocytes. Moreover, transmission electron microscopy
      identified the dye-containing vessels as lymphatics after intradermal injection
      of Berlin Blue. In conclusion, a lymphatic network was characterized in the
      dorsal skinfold chamber model of the Syrian golden hamster. Thus, this well
      established animal model for intravital microscopy provides the opportunity to
      elucidate the physiological and pathological function of the lymphatic vascular
      system.

PMID- 15034720
TI  - Evaluation of placental drainage as a method of placental delivery in vaginal
      deliveries.
AB  - METHODS: We describe a prospective study, done over a 2-year period in which a
      total of 958 women having a vaginal delivery were randomised to the drainage
      method (478 women) or controlled cord traction method (480 women) for placental
      delivery. RESULTS: The mean age, parity, gestation and birth weight were similar
      in the two groups. The mean duration of third stage of labor was 3.24 min and 3.2
      min in the placental drainage group in contrast to 8.57 min and 6.20 min in
      controlled cord traction method in primigravida and multigravida respectively.
      CONCLUSION: Placental drainage significantly reduces the duration of third stage
      of labour in vaginal deliveries.

PMID- 15034722
TI  - Structure-activity relationships of three differently substituted 2,7,12,17
      tetrakis-(beta-methoxyethyl) porphycene derivatives in vitro.
AB  - The subcellular localization, efficacy and photooxidative mechanism of three new
      photosensitizing porphycenes (HexoTMPn, PeloTMPn, CpoTMPn) for photodynamic
      therapy with different substituents at position 9 of the tetrapyrrole macrocycle
      were investigated in vitro using different human skin-derived cell lines (HaCaT,
      SCL I, SCL II) with the aim of customizing the side-chain chemistry to accelerate
      cellular uptake and so enhance photodynamic activity. Cells were incubated with a
      porphycene and costained with organelle-specific markers. Subcellular
      localization was determined by fluorescence microscopy. Also, cells were
      incubated with different sensitizer concentrations (0-1000 nmol/l) and irradiated
      by an incoherent light source (lambda(em) = 600-750 nm, 40 mW/cm(2), 24 J/cm(2))
      with/without quenchers or enhancers (NaN(3), histidine, mannitol or D(2)O). Cell
      viability was assessed. All porphycenes were localized in perinuclear lysosomes
      and induced a decrease in mitochondrial activity following irradiation. HexoTMPn
      was the most efficient in all three cell lines (EC(50) in HaCaT cells: HexoTMPn
      14 nmol/l, CpoTMPn 62 nmol/l, PeloTMPn 89 nmol/l). Addition of either NaN(3) or
      histidine reduced the phototoxicity significantly. Due to the short lifetime of
      singlet oxygen, the sites of sensitizer localization are the initial subcellular
      targets. The cytotoxicity of each sensitizer varied depending on singlet oxygen
      quantum yield and cell line. Despite the different chemical structures, the
      biological effects were not very distinct, since they seemed to be mostly
      determined by the tetrapyrrole ring and only slightly modified by the substituent
      at position 9. Also, there was only a narrow margin between biological
      compatibility and efficacy.

PMID- 15034724
TI  - Combination of femoral fracture treatment and corrective osteotomy in a child
      with osteogenesis imperfecta.
AB  - The main feature of osteogenesis imperfecta is an excessive fragility and
      deformability of the bones owing to reduced mass and bone quality. This leads to
      angular deformity and frequent fractures. These fractures usually heal rapidly,
      and conservative treatment is the norm. In displaced and unstable fractures,
      elastic intramedullary nailing is a treatment option. We report a case of a 3
      year-old child with osteogenesis imperfecta type I who suffered an undisplaced
      femoral shaft fracture in the presence of a preexisting 32 degrees femoral
      antecurvation. This deformity greatly increases the risk of a refracture due to
      the pathological induction of stress risers. Therefore, fracture treatment by
      unreamed elastic intramedullary nailing was combined with simultaneous correction
      osteotomy, resulting in anatomic alignment and uncomplicated fracture healing.
      The single-stage surgical stabilization performed allowed rapid mobilization
      along with a decreased likelihood of refracture.

PMID- 15034723
TI  - Effects of reinforcement with the iliotibial tract flap in ACL reconstruction
      using bone-patellar tendon-bone.
AB  - INTRODUCTION: We attempted to reinforce the transplanted ligament by wrapping it
      with the iliotibial tract (ITT) flap to get more volume and to protect the graft
      from impingement in the intercondylar space postoperatively in reconstruction of
      the anterior cruciate ligament (ACL) using bone-patellar tendon-bone (BTB), and
      investigated the results in comparison with those of BTB alone. MATERIALS AND
      METHODS: The study included 88 cases (88 knees). Group A comprised 43 knees with
      the reinforcement and group B 45 knees with BTB alone. Both groups were evaluated
      by second-look arthroscopy, magnetic resonance imaging (MRI), manual testing,
      International Knee Documentation Committee (IKDC) score, and histopathological
      evaluation more than 2 years after the reconstruction. RESULTS: In the second
      look arthroscopic findings, 84% of the reconstructed ACL in group A had good
      appearance, and no fibrous split was observed. The ratio of fibrous disorder was
      significantly less in group A in comparison with group B (p=0.0037). Distinct
      reduction of the tension of the reconstructed ligament was observed in 9% of
      group A and 36% of group B (p=0.0088). Regarding the results of the Lachman test,
      the ratio of the negative group was higher in group A (p=0.0067). In the MRI
      findings fulfilled pictures to the inside of the reconstructed ligament were
      observed in 77% of the patients photographed in group A. In contrast, the fibrous
      split was observed in 55% in group B. CONCLUSIONS: Reinforcement by wrapping with
      the ITT flap for the BTB autograft was effective in ACL reconstruction. The ratio
      of fibrous disorder and reduction of tension in the reconstructed ligament
      decreased.

PMID- 15034725
TI  - A comparison of two osteotomy techniques for tibial lengthening.
AB  - INTRODUCTION: There are various methods of long bone lengthening. The quality of
      the regenerated bone depends on stable external fixation, low energy corticotomy,
      latency period, optimum lengthening rate and rhythm, and functional use of the
      limb. Percutaneous corticotomy and ostetomy with multiple drill holes yield the
      best results for the quality of the regenerated bone. An alternative low energy
      osteotomy, which respects the periosteum, is the Afghan percutaneous osteotomy.
      The purpose of the current study was to compare a percutaneous multiple drill
      hole osteotomy with a Gigli saw osteotomy in terms of the healing index (HI).
      MATERIALS AND METHODS: Forty-four tibias of 41 patients were lengthened at our
      institution between 1995 and 2000. All patients underwent limb lengthening
      without any deformity correction by the Ilizarov device. The etiology of the limb
      length discrepancy was sequelae to poliomyelitis in 16 tibias, idiopathic
      hypoplasia in 17 tibias, posttraumatic discrepancy in 5 tibias, bilateral tibial
      lengthening in achondroplastic dwarfism in 3 patients. Patients with metabolic
      bone diseases were not included in this series. RESULTS: The mean amount of
      length discrepancy was 5.7 cm (range 2-12 cm). The mean HI of the whole group was
      1.65 month/cm (range 1.1-2.4 month/cm). When comparing the osteotomy methods
      without taking the etiology into consideration, the percutaneous, multiple drill
      hole group yielded a mean HI of 1.98 month/cm (range 1.4-2.4 month/cm), while the
      Gigli saw group yielded a mean HI of 1.37 month/cm (range 1.1-1.8 month/cm).
      There was a statistically significant difference between the two groups (
      p=0.022). The Gigli saw patients with poliomyelitis had a significantly better HI
      compared with patients who underwent lengthening by the other form of osteotomy
      (1.1 vs 1.9 month/cm; p=0.027). CONCLUSION: Our results confirm the biologic
      superiority of the Gigli saw technique.

PMID- 15034726
TI  - An isomorphic subtype of long-term epilepsy-associated astrocytomas associated
      with benign prognosis.
AB  - The semi-benign nature of diffuse astrocytomas is characterized by an increased
      risk for tumor recurrence and malignant transformation. In patients with
      intractable seizures, however, length of history and clinical follow-up studies
      indicate a better prognosis of this tumor entity. Here, we present a clinico
      neuropathological study of 19 patients with chronic seizures and diffuse
      astrocytomas. In 6 patients, long-term survival and lack of tumor progression
      after a maximal follow-up time of 13 years appeared to correlate with a
      histologically isomorphic phenotype. Cytological hallmarks comprise low
      cellularity, lack of mitotic activity and highly differentiated astroglial
      elements infiltrating into adjacent brain parenchyma. Compared to "classical"
      variants of diffuse astrocytomas (WHO grade II), immunohistochemical reactions
      revealed a cellular proliferation below 1%, absence of nuclear p53 accumulation,
      and a lack of glial MAP2 and CD34 expression. Histopathologically, the isomorphic
      astrocytoma subtype can be distinguished from gangliogliomas, pilocytic
      astrocytomas and dysembryoplastic neuroepithelial tumors as well as from cortical
      dysplasia or reactive gliosis. Our data support the concept of a rare variant of
      diffuse astrocytomas occurring in young adults with long-term epilepsy and a
      favorable prognosis, which corresponds to WHO grade I.

PMID- 15034727
TI  - Anismus: a marker of multi-site functional disorders?
AB  - PURPOSE: This study was undertaken to assess the clinical significance of anismus
      in patients who complain of constipation. PATIENTS AND METHODS: Thirty control
      subjects and 93 consecutive patients complaining of functional constipation took
      part in the study. Colonic transit time study and anorectal manometry were
      performed. Questions about depression and urinary and sexual diseases were added
      to a questionnaire based on the Rome II criteria, and visual analog scales about
      four items (constipation, diarrhoea, abdominal bloating and abdominal pain).
      RESULTS: Constipated patients have lower threshold sensation volume, lower
      constant sensation volume, and lower maximum tolerable volume than controls.
      Thirty-seven patients (40%) were found to have anismus, based on anorectal
      manometry. No significant difference was found between constipated patients with
      anismus and constipated patients without anismus, using anorectal manometry.
      Constipated patients had longer colorectal transit time than controls, but
      neither total nor segmental colonic transit time was correlated with the presence
      or absence of anismus. In patients with anismus, a higher frequency of
      oesophageal symptoms, dysmotility-like dyspepsia, aerophagia, functional bowel
      disorders, functional abdominal pain, soiling, and dyschezia was found. In
      addition, a higher frequency of urinary complaints, sexual complaints, and
      depression was found. Anismus was associated with increased awareness of
      constipation, abdominal bloating, and abdominal pain, but not with diarrhoea.

PMID- 15034728
TI  - Effects of lipid administration on liver apoptotic signals in a mouse model of
      total parenteral nutrition (TPN).
AB  - Lipids are an important component of total parenteral nutrition (TPN),
      contributing the largest caloric load per volume of solution and providing
      essential fatty acids necessary for survival. However, lipids are known to be
      causative factors in oxidative stress, which are expressed via the Bcl-2 family
      of proteins and/or Fas-mediated apoptosis in several tissues. Interestingly, we
      have recently observed an increase in hepatocyte apoptosis with administration of
      TPN. To address the mechanism of this apoptosis, we investigated the effects of
      parenteral lipid administration on apoptotic signaling in a mouse model. C57BL/6J
      male mice received physiologic saline and standard chow (control) or standard TPN
      solution with (TPN+L) or without lipid (TPN-L) emulsion. After 7 days of
      infusion, apoptosis increased in the TPN+L at a significantly higher rate
      compared with control and TPN-L groups ( p<0.05). Both TPN, with and without
      lipids, suppressed the pro-apoptotic signals Bid and Bcl-xs ( p<0.05). In
      contrast, TPN with lipid increased the expression of Fas and both the pro
      apoptotic factor Bad and the anti-apoptotic factor Bcl-xl ( p<0.05). These
      changes may contribute to TPN-induced hepatocyte injury (apoptosis) or suppress
      the ability of liver hepatocytes to regenerate.

PMID- 15034729
TI  - Diagnosis of Chiari I malformation and related syringomyelia: radiological and
      neurophysiological studies.
AB  - INTRODUCTION: The diagnosis of Chiari I malformation relies mainly on the
      anatomical demonstration of the abnormal position of the cerebellar tonsils below
      the foramen magnum, and of the associated bony anomalies of the posterior cranial
      fossa and craniocervical junction, as well as of the eventually-associated spinal
      cord cavitations. Consequently, the neuroradiological work-up plays a fundamental
      role in the definition of the malformation and in the follow-up of operated
      patients. REVIEW: The authors review the pertinent literature on the
      neuroradiology of the Chiari I malformation, with special regard to MRI, with the
      aim of providing the reader with an updated instrument for its diagnosis.

PMID- 15034730
TI  - Moderate physical exercise increases cardiac autonomic nervous system activity in
      children with low heart rate variability.
AB  - OBJECT: Our objective was to investigate the effect of a long-term moderate
      exercise program on cardiac autonomic nervous system (ANS) activity in healthy
      children. METHODS: Three hundred and five children aged 6-11 years participated
      in a 12-month school-based exercise training program (130-140 bpm, 20 min/day, 5
      days/week). Cardiac ANS activities were measured using heart rate variability
      (HRV) power spectral analysis in resting conditions. Following the first
      measurement, 100 children from the lowest total power (TP) HRV were chosen as
      experimental samples and the same number of age-, height-, and weight-matched
      controls (CG) was randomly selected from the remaining children. RESULTS: In the
      low group (LG), all the frequency components of the HRV were significantly
      increased after the training period, whereas only low-frequency power was
      augmented in the control group (CG). CONCLUSION: Our data suggest that the 12
      month moderate exercise training has a positive effect on cardiac ANS activity in
      the children who initially had low HRV.

PMID- 15034732
TI  - Blood-respiratory and acid-base changes during extended diving in the bimodally
      respiring freshwater turtle Rheodytes leukops.
AB  - Changes in blood-gas, acid-base, and plasma-ion status were investigated in the
      bimodally respiring turtle, Rheodytes leukops, during prolonged dives of up to 12
      h. Given that R. leukops routinely submerges for several hours, the objective of
      this study was to determine whether voluntarily diving turtles remain aerobic and
      simultaneously avoid hypercapnic conditions over increasing dive lengths. Blood
      PO(2), PCO(2), and pH, as well as plasma concentrations of lactate, glucose,
      Na(+), K(+), Cl(-), total Ca, and total Mg were determined in venous blood
      collected from the occipital sinus. Blood PO(2) declined significantly with dive
      length; however, oxy-haemoglobin saturation remained greater than 30% for all R.
      leukops sampled. No changes were observed in blood PCO(2), pH, [HCO(3)(-)], or
      plasma glucose, with increasing dive length. Despite repeated dives lasting more
      than 2 h, plasma lactate remained less than 3 mmol l(-1) for all R. leukops
      sampled, indicating the absence of anaerobiosis. Compensatory acid-base
      adjustments associated with anaerobiosis (e.g. declining [Cl(-)], increasing
      total [Ca] and [Mg]) were likewise absent, with plasma-ion concentrations
      remaining stable with increasing dive length. Results indicate that R. leukops
      utilises aquatic respiration to remain aerobic during prolonged dives, thus
      effectively avoiding the development of a metabolic and respiratory acidosis.

PMID- 15034734
TI  - [Dermal hyperpigmentation and hyperkeratosis with conjunctival papillomatosis. A
      59-year old male patient with foreign body sensation and periorbital cutaneous
      changes].

PMID- 15034733
TI  - Discrimination of conspecific sex and reproductive condition using chemical cues
      in axolotls ( Ambystoma mexicanum).
AB  - Chemosensory cues play an important role in the daily lives of salamanders,
      mediating foraging, conspecific recognition, and territorial advertising. We
      investigated the behavioral effects of conspecific whole-body odorants in
      axolotls, Ambystoma mexicanum, a salamander species that is fully aquatic. We
      found that males increased general activity when exposed to female odorants, but
      that activity levels in females were not affected by conspecific odorants.
      Although males showed no difference in courtship displays across testing
      conditions, females performed courtship displays only in response to male
      odorants. We also found that electro-olfactogram responses from the olfactory and
      vomeronasal epithelia were larger in response to whole-body odorants from the
      opposite sex than from the same sex. In males, odorants from gravid and recently
      spawned females evoked different electro-olfactogram responses at some locations
      in the olfactory and vomeronasal epithelia; in general, however, few consistent
      differences between the olfactory and vomeronasal epithelia were observed.
      Finally, post hoc analyses indicate that experience with opposite-sex
      conspecifics affects some behavioral and electrophysiological responses. Overall,
      our data indicate that chemical cues from conspecifics affect general activity
      and courtship behavior in axolotls, and that both the olfactory and vomeronasal
      systems may be involved in discriminating the sex and reproductive condition of
      conspecifics.

PMID- 15034735
TI  - [Retinal ICG-accumulation after ILM-staining during macular hole surgery?].
AB  - BACKGROUND: In earlier animal studies retinal accumulation of ICG after
      intravitreous application with subsequent transport to the optic nerve could be
      observed. In order to evaluate the possible retinal accumulation of ICG after ILM
      staining during macular hole surgery and to examine the potential changes in
      optic nerve function, a prospective study was initiated. METHODS: In 20 patients
      with macular holes grade 3, vitrectomy with ICG staining of the ILM (0.3 ml of a
      1:10 diluted ICG solution under air), consecutive ILM peeling, and finally gas
      tamponade were performed. Preoperatively and 2, 4, 8, 12, and 24 weeks after
      vitrectomy, all patients underwent normal ophthalmological examination, native
      ICG picture, VEP examinations, and central visual field examination. RESULTS:
      Retinal ICG accumulation in the area of the macular hole, in the retinal axons at
      the temporal arcades, and around the optic disc could be observed in all 20
      patients. This staining with ICG was progressively transformed towards the optic
      disc at the 4- and 8-week examinations. At the 12-week examination, ICG staining
      around the optic disc was still visible in all patients. The function of the
      optic nerve (VEP) demonstrated only minor changes during follow-up, and in the
      visual field examinations no peripheral changes could be observed. CONCLUSIONS:
      After ILM staining with ICG during macular hole surgery even with highly diluted
      ICG solutions an accumulation of ICG in the retinal ganglion axons was observed.
      This accumulation was visible shortly after surgery at the macular hole, temporal
      arcades, and the optic disc. The predominant staining of ICG at the optic disc
      during follow-up can be interpreted as transport of the accumulated ICG in the
      retinal axons and optic nerve. There seem to be no functional implications for
      optic nerve function and visual field examinations.

PMID- 15034736
TI  - [Transposition flaps for reconstruction of deep defects of the medial eyelids.
      Fasciocutaneous rotations- and transposition flaps and modified pure fascial
      transposition flap].
AB  - Tumor resection in the medial canthal area may result in deep defects with
      involvement of the ethmoidal bone and destruction of the lacrimal ducts. While
      shallow defects with little involvement of bone can be covered with the classic
      glabellar flap, deep defects require larger fasciocutaneous flaps from the
      forehead that can also be used for the reconstruction of the involved medial
      parts of the eyelids. The preferred techniques of the median or paramedian
      transposition flaps and a modified paramedian fascial flap for reconstruction of
      the medial orbital wall and support of the orbit are described.

PMID- 15034738
TI  - [Ocular involvement in systemic Loa-Loa filariasis. Case report and review of the
      literature].
AB  - BACKGROUND: Within the last few years there is more and more evidence for
      nonspecific ocular symptoms caused by "exotic" pathogens. We herewith report
      another case of such an infection to underline the increasing importance and
      diagnostic relevance even of rare diseases. PATIENT: A 35-year-old female German
      patient presented with recurrent left retrobulbar "feeling of pressure" after a 6
      month-stay in Central Africa 5 years ago. In addition, she reported on repeated
      swelling of the skin and joints of her hands and arms. Multiple ophthalmologic
      and rheumatologic investigations had been carried out without diagnostic results.
      Her ophthalmologist referred her with the presumed diagnosis of a subconjunctival
      worm. RESULTS: Slit-lamp biomicroscopy confirmed the original suspicion, and
      after topical anesthesia a female Loa-Loa worm was easily removed with forceps
      through a conjunctival incision. The general examination showed symptoms of
      systemic infection (calabar swelling, eosinophilia). Classification and
      initiation of treatment with diethylcarbamazine and mebendazole were carried out
      by the University Institute of Parasitology. CONCLUSION: Loa-Loa is a parasitic
      infection endemic in the tropical rain forests of Western, Central, and Eastern
      Africa. It is transmitted by the Chrysops fly. An increasing number of
      oculosystemic infections in non-African patients with Loa-Loa are being
      published. Therefore, any patient with an unclassifiable eye affection should
      also be investigated for those rare pathogens.

PMID- 15034737
TI  - [Lateral orbital decompression for Graves' orbitopathy. Indication, surgical
      technique, and treatment success].
AB  - PURPOSE: In Graves' disease a discrepancy between volume increase of the orbital
      soft tissues and fixed volume of the orbital cavity leads to exophthalmos. The
      patients do not only feel cosmetically disfigured, they often complain about more
      or less painful retroorbital pressure sensation or show symptoms of compressive
      optic neuropathy or corneal exposure because of a significant lid lag. To solve
      this problem, different orbital decompression techniques have been developed.
      This is to report about our results with a modified Dollinger technique for
      lateral orbital decompression. PATIENTS AND METHODS: A total of 27 patients aged
      19-76 years (mean: 45.1 years) with Grave's ophthalmopathy were recorded who had
      undergone orbital decompression by a lateral approach between June 1999 and April
      2003. The modified Dollinger technique was performed by deepening the osteotomy
      to the level of the sphenoid wing and by additional resection of intraconal fat.
      RESULTS: The reduction of exophthalmos achieved after decompressive surgery
      averaged 2.9 +/- 1.1 mm. Of the patients whose indication for orbital
      decompression was a compressive neuropathy, the visual acuity improved
      postoperatively for 3 lines. Of the 16 patients with preoperative retrobulbar
      pressure sensation, 12 had no complaints after the operation. Remarkably no
      significant impairment of the ocular motility resulted after surgery.
      CONCLUSIONS: Decompression of the orbit by the modified Dollinger technique is a
      safe and effective approach to reduce exophthalmos, retrobulbar pressure
      sensation, and compression neuropathy as a result of diffusely elevated orbital
      tissue tension. In the case of direct compression of the optic nerve in the
      orbital apex, additional medial orbital wall decompression has to be considered.

PMID- 15034739
TI  - The role of high-dose chemotherapy in relapsed germ cell tumors.
AB  - Overall, patients with relapsed or progressive germ cell tumors after cisplatin
      based chemotherapy have a low chance of cure. Using conventional-dose
      chemotherapy (CDCT) as salvage treatment, only 15-30% of the patients will become
      long-term survivors. It is well known that the majority of these patients will
      ultimately die of their disease. Therefore, improvement of the standard treatment
      is clearly desirable. In the last years, high-dose chemotherapy (HDCT) has been
      established as an effective salvage modality. A matched-pair analysis showed an
      advantage for HDCT compared with CDCT with an improvement in event-free and
      overall survival. Furthermore, due to increasing clinical experience in the
      management of side-effects, the use of peripheral blood progenitor cells and the
      availability of hematopoietic growth factors, HDCT has become relatively safe.
      Therefore, HDCT should be administered in patients with first relapse and
      unfavorable prognostic factors, and as second or subsequent salvage treatment
      followed by complete resections of tumor residuals. Patients with relapse or
      progressive disease after HDCT who do not qualify for desperation surgery could
      be salvaged with palliative chemotherapy combinations using gemcitabine,
      oxaliplatin and paclitaxel. This report reviews the current treatment strategies
      and recent developments with respect to HDCT given as salvage treatment and
      discusses the role of prognostic factors in the management of such situations.

PMID- 15034741
TI  - Laparoscopic retroperitoneal lymph node dissection for nonseminomatous testicular
      carcinoma.
AB  - Retroperitoneal lymph node dissection (RPLND) is still the most sensitive and
      specific method for the detection of lymph node metastases in stage I
      nonseminomatous testicular carcinoma. In stage II disease, residual malignant
      tumor and mature teratoma can be removed. Acceptance of this operation, however,
      has decreased due to the morbidity caused by the open approach. To reduce this
      morbidity, and to improve the acceptance of RPLND, laparoscopy has been
      introduced. Clinical data with long-term follow-up are now available which
      demonstrate the technical feasibility of laparoscopic RPLND. Studies comparing
      laparoscopy and open surgery show advantages for the laparoscopic approach in
      terms of reduced blood loss, intraoperative complications and operative time.
      Mainly minor complications, such as chylous ascites or lymphocele formation, are
      observed. The conversion rate to open surgery, mainly due to intraoperative
      bleeding, is acceptable at less than 10%. As in open surgery, antegrade
      ejaculation can be preserved successfully. RPLND has also been shown to provide
      adequate oncological results. In stage I disease, lymph node metastasis is found
      in 25-41% of cases. Patients with histologically proven retroperitoneal tumor
      receive adjuvant chemotherapy whereas individuals without evidence of
      retroperitoneal disease do not require additional treatment. Follow-up controls
      in both groups, without local recurrence, demonstrate the excellent diagnostic
      accuracy of this procedure. Meanwhile laparoscopic RPLND has also been introduced
      successfully in the management of stage II disease. Small volume residual tumors
      can be removed with an acceptable complication rate. However, this operation is
      technically demanding and should be performed only at institutions with
      considerable laparoscopic experience. In conclusion, laparoscopic RPLND is a safe
      method for low-stage germ cell tumors with minimal invasiveness and excellent
      clinical results. Thus laparoscopy might contribute to a better acceptance of
      RPLND.

PMID- 15034743
TI  - Sensitivity of T2-weighted FSE sequences towards physiological iron depositions
      in normal brains at 1.5 and 3.0 T.
AB  - To evaluate the sensitivity of T2-weighted fast spin-echo (FSE) sequences to
      physiological iron depositions in normal brains at MR imaging field strengths of
      1.5 and 3.0 T. T2-weighted FSE sequences acquired at 1.5 and 3.0 T clinical
      imaging systems (Gyroscan Intera, Philips Medical Systems, Best, The Netherlands)
      were compared by means of MRI in phantoms ( n=6) and healthy volunteers ( n=10).
      Contrast-to-noise ratios (CNRs) of tubes doped with iron oxides at different
      concentrations and of brain areas with physiological iron depositions (nucleus
      ruber, substantia nigra, globus pallidus) were calculated for either field
      strength. Apparent susceptibility effects of iron-containing brain structures
      were qualitatively analyzed by comparing the degree of visible hypointensity by a
      score system at either field strength. The mean CNR of iron oxide tubes and iron
      containing brain areas was significantly decreased at 3.0 T. Qualitative analysis
      confirmed these measurements. Detection and diagnosis of brain disorders with
      altered iron content such as neurodegenerative parkinsonian disorders (NPD) or
      intracerebral hemorrhage should benefit from the increased sensitivity of T2
      weighted FSE sequences to susceptibility effects at 3.0 T.

PMID- 15034742
TI  - Selective intra-arterial chemoembolization of pelvic and spine bone metastases.
AB  - The purpose of this study was to determine the effect of interventional
      palliative therapy by using chemoembolization on metastatic bone pain and tumor
      bulk in inoperable metastases where chemotherapy and radiotherapy had failed.
      Twenty-five patients (mean age: 59 years) underwent chemoembolization of
      symptomatic lytic lesions involving the spinal column (n=10), iliac bone and
      sacrum (n=15). The study design consisted of at least three procedures based on
      combined chemoembolization performed under analog-sedation. Therapeutic agents
      were carboplatin for selective chemotherapy and pirarubicin mixed with polyvinyl
      alcohol foam for chemoembolization. Fifteen of 18 (83%) patients had significant
      pain relief, as shown by the decrease of analgesic drug use. Mean clinical
      response duration was 12 months. Radiologically, ten patients were stable. A
      partial response was observed in four patients, while a complete response was
      seen in two others. Selective intra-arterial chemoembolization gives longer pain
      relief than embolization, compared to the literature data, probably because of
      partial response with local anti-cancer drugs.

PMID- 15034744
TI  - Assessment of a theoretical formalism for dose estimation in CT: an
      anthropomorphic phantom study.
AB  - Dose assessment in computed tomography (CT) is challenging due to the vast
      variety of CT scanners and imaging protocols in use. In the present study, the
      accurateness of a theoretical formalism implemented in the PC program CT-EXPO for
      dose calculation was evaluated by means of phantom measurements. Phantom
      measurements were performed with four 1-slice, four 4-slice and two 16-slice
      spiral CT scanners. Firstly, scanner-specific nCTDIw values were measured and
      compared with the corresponding standard values used for dose calculation.
      Secondly, effective doses were determined for three CT scans (head, chest and
      pelvis) performed at each of the ten installations from readings of
      thermoluminescent dosimeters distributed inside an anthropomorphic Alderson
      phantom and compared with the corresponding dose values computed with CT-EXPO.
      Differences between standard and individually measured nCTDIw values were less
      than 16%. Statistical analysis yielded a highly significant correlation (P <
      0.001) between calculated and measured effective doses. The systematic and random
      uncertainty of the dose values calculated using standard nCTDIw values was about 
      9 and +/- 11%, respectively. The phantom measurements and model calculations were
      carried out for a variety of CT scanners and representative scan protocols
      validate the reliability of the dosimetric formalism considered-at least for
      patients with a standard body size and a tube voltage of 120 kV selected for the
      majority of CT scans performed in our study.

PMID- 15034745
TI  - Application of artificial neural networks to the analysis of dynamic MR imaging
      features of the breast.
AB  - The discriminative ability of established diagnostic criteria for MRI of the
      breast is assessed, and their relative relevance using artificial neural networks
      (ANNs) is determined. A total of 89 women with 105 histopathologically verified
      breast lesions (73 invasive cancers, 2 in situ cancers, and 30 benign lesions)
      were included in this study. A T1-weighted 3D FLASH sequence was acquired before
      and seven times after the intravenous administration of gadopentetate dimeglumine
      at a dose of 0.2 mmol/kg body weight. ANN models were built to test the
      discriminative ability of kinetic, morphologic, and combined MR features. The
      subjects were randomly divided into two parts: a training set of 59 lesions and a
      verification set of 46 lesions. The training set was used for learning, and the
      performance of each model was evaluated on the verification set by measuring the
      area under the ROC curve (Az). An optimally minimized model was constructed using
      the most relevant input variables that were determined by the automatic relevance
      determination (ARD) method. ANN models were compared with the performance of a
      human reader. Margin type, time-to-peak enhancement, and washout ratio showed the
      highest discriminative ability among diagnostic criteria and comprised the
      minimized model. Compared with the expert radiologist (Az = 0.799), using the
      same prediction scale, the minimized ANN model performed best (Az = 0.771),
      followed by the best kinetic (Az = 0.743), the maximized (Az = 0.727), and the
      morphologic model (Az = 0.678). The performance of a neural network prediction
      model is comparable to that of an expert radiologist. A neurostatistical approach
      is preferred for the analysis of diagnostic criteria when many parameters are
      involved and complex nonlinear relationships exist in the data set.

PMID- 15034740
TI  - Clinical epidemiology of testicular germ cell tumors.
AB  - Clinical epidemiology is sometimes called the basic science of clinical medicine.
      In terms of the pathogenesis of testicular germ cell tumors (GCTs), clinical
      epidemiology analyzes suspected risk factors. The present review highlights the
      risk factors established so far and briefly summarizes those factors currently
      under investigation. In analogy to the methods of evidence based medicine, this
      review attributes levels of evidence to each of the putative risk factors. Level
      I represents highest quality of evidence while level V denotes the lowest level.
      So far, undescended testis (UDT), contralateral testicular GCT and familial
      testis cancer are established risk factors attaining high levels of evidence
      (levels I-III a). In a meta-analysis of 21 studies exploring the association of
      UDT with GCT risk, an over-all relative risk (RR) of 4.8 (95% confidence interval
      4.0-5.7) was found. Contralateral testicular GCT involves a roughly 25-fold
      increased RR of GCT, while familial testis cancer constitutes a RR of 3-10.
      Infertility, testicular atrophy, and twin-ship represent risk factors with lesser
      levels of evidence (level III a). There is also some evidence for HIV infection
      being a predisposing factor for GCT (level IV a). Scrotal trauma is probably not
      associated with GCT risk. The estrogen excess theory implies high estrogen levels
      during the first trimester of pregnancy. As a consequence, primordial germ cells
      lose track of the normal developmental line and transform into premalignant cells
      that later become testicular intraepithelial neoplasia (TIN), the precursor of
      full-blown testicular GCT. Surrogate parameters for high gestational estrogen
      levels are investigated in case control studies. Such factors are maternal age
      >30 years, first-born, low birth weight, maternal breast cancer, high sex-ratio
      of siblings. So far, the sum of evidence is promising but still conflicting
      (especially for level III b). Another novel theory is the childhood nutrition
      hypothesis. This concept postulates a modulating or "catalyzing" effect by high
      dietary intake during childhood on the pathogenesis of testicular GCT. A
      surrogate parameter of early childhood nutrition is adult height. So far, 12
      controlled studies have looked to the possible association of attained height and
      GCT risk of which six demonstrated a significant association. Thus, the sum of
      evidence corresponds to level III b. This concept is appealing because it would
      explain several hitherto unexplained epidemiological features of GCT.

PMID- 15034747
TI  - Refined glufosinate selection in Agrobacterium-mediated transformation of soybean
      [Glycine max (L.) Merrill].
AB  - Modern genetic analysis and manipulation of soybean ( Glycine max) depend heavily
      on an efficient and dependable transformation process, especially in public
      genotypes from which expressed sequence tag (EST), bacterial artificial
      chromosome and microarray data have been derived. Williams 82 is the subject of
      EST and functional genomics analyses. However, it has not previously been
      transformed successfully using either somatic embryogenesis-based or cotyledonary
      node transformation methods, the two predominant soybean transformation systems.
      An advance has recently been made in using antioxidants to enhance Agrobacterium
      infection of soybean. Nonetheless, an undesirable effect of using these
      antioxidants is the compromised recovery of transgenic soybean when combined with
      the use of the herbicide glufosinate as a selective agent. Therefore, we
      optimized both Agrobacterium infection and glufosinate selection in the presence
      of L-cysteine for Williams 82. We have recovered transgenic lines of this
      genotype with an enhanced transformation efficiency using this herbicide
      selection system.

PMID- 15034746
TI  - Abiotic stress response in the moss Physcomitrella patens: evidence for an
      evolutionary alteration in signaling pathways in land plants.
AB  - The mechanisms plants use to adapt to abiotic stress have been widely studied in
      a number of seed plants. Major research has been focused on the isolation of
      stress-responsive genes as a means to understand the molecular events underlying
      the adaptation process. To study stress-related gene regulation in the moss
      Physcomitrella patens we have isolated two cDNAs showing homology to highly
      conserved small hydrophobic proteins from different seed plants. The
      corresponding genes are up-regulated by dehydration, salt, sorbitol, cold and the
      hormone abscisic acid, indicating overlapping pathways are involved in the
      control of these genes. Based on the molecular characterization of the moss
      homologs we propose that signaling pathways in response to abiotic stress may
      have been altered during the evolution of land plants.

PMID- 15034748
TI  - Development of a non-lethal selection system by using the aadA marker gene for
      efficient recovery of transgenic rice (Oryza sativa L.).
AB  - The application of aminoglycoside-3"-adenyltransferase ( aadA) gene-mediated
      streptomycin resistance for non-lethal selection of transgenic rice resulted in
      plant regeneration frequencies under selection pressure as high as those in non
      transformed controls without selection. Since streptomycin does not kill non
      transgenic cells, and allows plant regeneration from them, a selection procedure
      was developed that made the visual identification of transgenic calli and
      regenerants possible. For callus-level selection, a vital pH indicator
      Chlorophenol Red-was applied together with streptomycin, making use of the
      phenomenon that fast-growing cell lines lower the pH in the culture medium.
      Transgenic plants were selected according to their main distinctive features;
      their green colour (photomixotrophic assimilation), and more intense growth. At
      the same time, non-transgenic regenerants were bleached (heterotrophic
      assimilation), and growth was retarded in the presence of streptomycin and
      sucrose. The final efficiency of genetic transformation based on streptomycin
      resistance was found to be double that of transformations where the selective
      agent was l-phosphinothricin, and nearly three times more compared to
      transformations resulting in hygromycin-resistant regenerants. To the best of our
      knowledge, this is the first report on producing nuclear transformed rice plants
      by using a non-lethal selection strategy based on the chimaeric aadA gene.

PMID- 15034750
TI  - Evaluation of classification criteria for juvenile-onset spondyloarthropathies.
AB  - OBJECTIVE: The aim of this study was to investigate the adequacy of the following
      criteria for the classification of juvenile-onset spondyloarthropathies (JSpA):
      European Spondyloarthropathy Study Group criteria (ESSGCr) and Amor criteria
      (ACr) (proposed for adult SpA), Garmisch-Partenkirchen (G-PCr), seronegative
      enthesopathy and arthropathy syndrome (SEACr), and atypical spondyloarthropathies
      classification criteria (ASpCr) (proposed for JSpA). METHODS: Sixty-two patients
      with JSpA (48 male and 14 female) and 64 with juvenile idiopathic arthritis (27
      male and 37 female) (excluding enthesitis-related and psoriatic arthritis) were
      enrolled in the study group. Twenty-nine of the patients with JSpA were diagnosed
      with definite JSpA and the remaining 35 with undifferentiated JSpA. One hundred
      six patients in the study group were evaluated by one investigator, who was
      unaware of the diagnosis, according to the following: ESSGCr, ACr, G-PCr, ASpCr,
      and SEACr. RESULTS: Analysis of the patients diagnosed with JSpA showed 83.9%,
      82.3%, 95.2%, 61.3%, and 62.9% sensitivity and 87.5%, 95.3%, 78.1%, 98.4%, and
      92.2% specificity for the ESSGCr, ACr, G-PCr, ASpCr, and SEACr sets,
      respectively. CONCLUSION: None of the criteria evaluated above is sufficient for
      the classification of JSpA. There is a definite need for a new set of criteria
      with high specificity and sensitivity for early recognition and classification.

PMID- 15034751
TI  - Conn's syndrome (primary hyperaldosteronism) simulating polymyositis.
AB  - A 44-year-old woman presented with typical polymyositis findings associated with
      hypokalemia. Abdominal CT as well as plasma renin and aldosterone levels showed a
      right surrenal adenoma secreting aldosterone. Unilateral adrenalectomy was
      performed and resolved all the clinical and laboratory manifestations.
      Hypokalemia should be considered in the differential diagnosis of polymyositis,
      even in the face of inflammatory cell infiltration in the muscle biopsy.

PMID- 15034752
TI  - The rpl5- rps14 mitochondrial region: a hot spot for DNA rearrangements in
      Solanum spp. somatic hybrids.
AB  - Southern analysis with rpl5 and rps14 mtDNA gene probes of Solanum tuberosum, S.
      commersonii and a sample of somatic hybrids detected polymorphisms between
      parents and the appearance of a novel restriction fragment in various hybrids. In
      one of them, detailed mtDNA analyses revealed various configurations of the rpl5-
      rps14 region present at different stoichiometries. Multiple inter-parental
      recombination events across homologous sequences were assumed to have caused
      these rearrangements. Sequence similarity searches detected one sequence
      putatively involved in the recombination upstream of the rpl5 gene. The presence
      of a second recombinogenic sequence was inferred. We propose two models to
      explain the mechanism responsible for obtaining the different rpl5- rps14
      arrangements shown after somatic hybridization. Variability in the rpl5- rps14
      region observed in both the parental species and their somatic hybrids suggests
      this region is a hot spot for mtDNA rearrangements in Solanum spp.

PMID- 15034754
TI  - Cytotoxicity of the organic ruthenium anticancer drug Nami-A is correlated with
      DNA binding in four different human tumor cell lines.
AB  - PURPOSE: The cytotoxicity, intracellular accumulation and DNA adduct formation of
      the ruthenium complex imidazolium trans-imidazoledimethylsulfoxide
      tetrachlororuthenate (ImH[ trans-RuCl(4)(DMSO)Im], Nami-A) were compared in vitro
      with those of cisplatin in four human tumor cell lines: Igrov-1, 2008, MCF-7, and
      T47D. METHODS: Cytotoxicity was assessed in vitro using a growth inhibition
      assay. Accumulation was determined by flameless atomic absorption spectroscopy
      (AAS). GG and AG intrastrand adducts were measured using the (32)P-postlabeling
      assay. RESULTS: Nami-A was on average 1053 times less cytotoxic than cisplatin.
      The cytotoxicity of cisplatin was linearly related to both intracellular platinum
      accumulation and DNA binding, while the cytotoxicity of Nami-A was significantly
      related only to DNA binding and not to intracellular ruthenium accumulation. The
      levels of accumulation of Nami-A measured as ruthenium and of cisplatin measured
      as platinum were correlated linearly with the incubation concentration over a
      concentration range of 0 to 600 micro M of both drugs. Ruthenium intracellular
      accumulation and DNA binding were on average 4.8 and 42 times less, respectively,
      than those of cisplatin. In addition, the numbers of GG and AG intrastrand
      adducts induced by Nami-A were 418 and 51 times fewer, respectively. Nami-A and
      cisplatin had the same binding capacity to calf thymus DNA. Nami-A was 25-40%
      less bound to cellular proteins than cisplatin. CONCLUSIONS: There was no
      saturation of the uptake and DNA binding capacity of either Nami-A or cisplatin.
      Furthermore, the low binding of Nami-A to cellular DNA cannot simply be explained
      by a lower capacity to bind to DNA, because the absolute level of binding in
      vitro to calf thymus DNA was the same for Nami-A and cisplatin. Finally, the
      lower cytotoxicity of Nami-A on a molar basis than that of cisplatin can at least
      partly be explained by its reduced reactivity to DNA in intact cells.

PMID- 15034753
TI  - Shuttle vectors for Candida albicans: control of plasmid copy number and elevated
      expression of cloned genes.
AB  - Plasmids containing the inosine monophosphate dehydrogenase gene CaIMH3 from
      Candida albicans strain ATCC 32354 transform their host to resistance against
      mycophenolic acid (MPA). The transformants maintain the plasmids at a high copy
      number (20-40 per cell) and express the CaIMH3 gene at very high levels relative
      to untransformed controls. The plasmid copy number can be controlled by the
      concentration of MPA in the media. The transformation procedure is reproducible
      and the efficiency of transformation is high, up to 15,000 per microgram.
      Unrearranged plasmids are readily recovered by transforming total DNA from
      transformants back into Escherichia coli. C. albicans genes cloned into the
      plasmid are expressed at elevated levels relative to untransformed controls. A
      derivative vector containing the CaMAL2 promoter and termination sequences
      expresses the CaERG11 ORF at high levels and confers moderate resistance to
      fluconazole. These shuttle vectors should facilitate global genomics approaches
      in C. albicans that have been hampered by its diploid genome.

PMID- 15034755
TI  - Inhibition of gamma-glutamyl transpeptidase activity decreases intracellular
      cysteine levels in cervical carcinoma.
AB  - PURPOSE: To determine whether gamma-glutamyl transpeptidase (gamma-GT) is
      involved in the maintenance of elevated cysteine levels in cervical carcinoma.
      METHODS: Four cervical carcinoma cell lines were tested in vitro for cysteine
      accumulation and gamma-GT levels. The highest and lowest gamma-GT-expressing cell
      lines were used in in vivo experiments to determine the effect of gamma-GT
      inhibition on cysteine levels. RESULTS: Treatment of a series of cervical
      carcinoma cell lines with acivicin decreased intracellular cysteine
      concentrations. Cysteine depletion was evident in Me180 cells which had the
      greatest levels of gamma-GT activity, and had a more pronounced cysteine decrease
      in medium with glutathione and cysteine concentrations simulating the in vivo
      situation. Also investigated were the effects of inhibition of gamma-GT activity
      on intracellular cysteine levels in xenografts grown in severe combined
      immunodeficient (SCID) mice. With the use of 35 mg/kg of acivicin, gamma-GT
      activity decreased to basal levels of detection in both tumour types and
      significant decreases in cysteine levels were seen in the high gamma-GT
      expressing tumours (Me180). Thus, inhibition of gamma-GT activity may have
      therapeutic potential in high-expressing cancers. CONCLUSIONS: In tumours and
      cell lines with elevated levels of gamma-GT activity, inhibition of this enzyme
      led to decreases of cysteine levels.

PMID- 15034756
TI  - Induction of histone acetylation and inhibition of growth by phenyl alkanoic
      acids and structurally related molecules.
AB  - PURPOSE: A structure-activity study was undertaken to determine the influence of
      side chain length of phenyl alkanoic acids and the degree of unsaturation of
      phenyl alkenoic acids on the induction of histone acetylation and inhibition of
      cancer cell proliferation. MATERIALS AND METHODS: Studies on cell proliferation
      were performed with DS19 mouse erythroleukemic cells, PC-3 human prostate cancer
      cells and Caco-2 human colon cancer cells. Actions on histone deacetylase and the
      induction of histone acetylation were compared for 4-phenylbutyrate and
      structurally related molecules. RESULTS: Increasing inhibition of cell
      proliferation by phenyl alkanoic acids together with a decrease in cells in S
      phase and an increase in apoptotic cells was observed with increased chain length
      between four and ten carbons. Introduction of double bonds into the side chain
      was associated with increased growth inhibition. In contrast, 4-phenylbutyrate
      was a more potent inhibitor of histone deacetylase and inducer of histone
      acetylation than the other phenyl alkanoic acids examined. CONCLUSIONS: In
      comparison with the action of 4-phenylbutyrate, actions other than inhibition of
      histone deacetylase appear to be more important for growth inhibition by longer
      chain phenyl alkanoic and phenyl alkenoic acids.

PMID- 15034757
TI  - A male with angioimmunoblastic T-cell lymphoma and proliferative
      glomerulonephritis.
AB  - In this article we present the case report of a 67-year-old male with a nephrotic
      syndrome due to a proliferative glomerulonephritis, associated with an
      angioimmunoblastic T-cell lymphoma. Diagnosis was made on an axillary lymph node
      biopsy and showed expanded T-cell areas with multiple blood vessels, small mature
      lymphocytes, eosinophils, and plasma cells. A kidney biopsy was suggestive for a
      proliferative glomerulonephritis with intra- and extracapillary proliferation.
      Hypercellular glomeruli were seen, as well as multiple floride crescents.
      Interstitial edema and fibrosis were absent. Immunohistochemical reactions were
      negative; there was some mesangial reaction with IgM in the glomeruli. Treatment
      with high-dose corticosteroids was initiated, with clinical improvement, and was
      immediately followed by therapy with cyclophosphamide, hydroxydaunomycin,
      vincristine, and prednisone (CHOP), which induced complete remission with a
      follow-up of 1 year. To our knowledge, the association of angioimmunoblastic T
      cell lymphoma and proliferative glomerulonephritis has only been described twice.
      It concerned elderly men who developed acute renal failure a couple of months
      after the diagnosis of an angioimmunoblastic T-cell lymphoma. In both,
      immunoglobulin-containing dense deposits within glomeruli were observed, which
      was not the case in our patient, where only some mesangial colorization of the
      IgM in the glomeruli was seen.

PMID- 15034758
TI  - Risk-adapted induction and consolidation therapy in adults with de novo AML aged
      </= 60 years: results of a prospective multicenter trial.
AB  - We treated 305 de novo acute myeloid leukemia (AML) patients aged </=60 years
      with risk-adapted therapy. Patients with CBF leukemias or normal karyotype and
      good response to induction I [</=5% bone marrow (BM) blasts on day 15] were
      considered standard risk (SR), all others as high risk (HR). Patients with
      t(15;17) were excluded. Chemotherapy comprised double induction followed by early
      consolidation. As late consolidation, SR patients received high-dose
      cytarabine/daunorubicin (AraC/DNR). SR patients with normal karyotype were
      allotransplanted from HLA-matched siblings. HR patients were allotransplanted or
      if no sibling donor was available autotransplanted with peripheral blood
      progenitor cells (PBSC) harvested after early consolidation. 89% of the SR and
      60% of the HR patients achieved CR. The continuous complete remission (CCR) rate
      at 80 months (median follow-up: 48 months) was 48% for SR and 32% for HR. The CCR
      rate was 54% for t(8;21), 47% for normal karyotype, and 33% for inv(16) patients.
      In the HR group, the CCR rate did not differ significantly for patients with bad
      response to IVA-I, unfavorable karyotype, or both. Forty-five HR patients were
      autotransplanted (n=20) or allotransplanted (n=25). The probability of CCR was
      44% for autotransplantation vs 33% for allotransplantation. In conclusion, our
      risk-adapted strategy produced encouraging results in SR patients. Early response
      to therapy is a strong prognostic factor that predicts the probability of CR and
      long-term outcome.

PMID- 15034759
TI  - Herpes zoster during treatment with arsenic trioxide.

PMID- 15034760
TI  - PRV-1 mRNA expression discriminates two types of essential thrombocythemia.
AB  - Essential thrombocythemia (ET) is a heterogeneous disorder. For example, the
      growth of erythropoietin-independent erythroid colonies, termed "endogenous
      erythroid colonies (EECs)", has previously been observed in only 50% of ET
      patients. We have recently described the overexpression of a hematopoietic
      receptor, PRV-1 (polycythemia rubra vera-1), in patients with polycythemia vera
      (PV). Here, we compare PRV-1 expression and EEC formation in a cohort of 30
      patients with ET; 50% of the ET patients in our cohort displayed EEC growth.
      Likewise, 50% of the ET patients overexpressed PRV-1. Remarkably, only the 15 ET
      patients displaying EEC growth showed elevated PRV-1 expression, while the 15 EEC
      negative ET patients expressed normal PRV-1 levels. It has previously been
      reported that EEC-positive ET patients develop PV during long-term follow-up.
      Here, we show that 40% of the PRV-1-positive patients develop symptoms of PV
      during the course of their disease. In contrast, none of the 15 PRV-1-negative
      patients displayed such symptoms (p=0.017). Moreover, PRV-1-positive patients had
      a significantly higher number of thromboembolic or microcirculatory events
      (p=0.003). We propose that PRV-1-positive ET comprise a pathophysiologically
      distinct subgroup of patients, one that is at risk for the development of
      complications and for the emergence of PV.

PMID- 15034761
TI  - Production of matrix metalloproteinase-9 by cord blood CD34+ cells and its role
      in migration.
AB  - The transmigration of hematopoietic progenitor cells is a crucial step in the
      homing of transplanted stem cells into bone marrow (BM) microenvironment;
      however, the molecular basis for this is not fully understood. Matrix
      metalloproteinases (MMPs), which are implicated in the migration of leukocytes,
      are important in degrading components of extracellular matrix molecules. In this
      study, using zymographic analysis and enzyme-linked immunosorbent assay (ELISA),
      we investigated the production of MMP-9 in CD34(+) cells from cord blood (CB) and
      BM, compared their spontaneous migration across a reconstituted basement membrane
      coated filter in transwell, and studied the role of MMP-9 in the transmigration.
      Zymography and ELISA showed that MMP-9 is produced by freshly isolated CD34(+)
      stem/progenitor cells obtained from CB. CB CD34(+) cells showed significantly
      higher migrational capacity than BM CD34(+) cells ( p=0.008). Furthermore, the
      migrational ability of CB CD34(+) cells over the extracellular matrix (ECM) was
      significantly inhibited by the inhibitor of MMP, o-phenanthroline and anti-MMP-9
      monoclonal antibody (73.3+/-11.8% and 37.5+/-10.4% inhibition, respectively). Our
      results strengthen the potential role of MMP-9 in the higher migrational capacity
      of CB CD34(+) cells, which may be beneficial to homing of these cells to the BM
      environment.

PMID- 15034763
TI  - Methods of estimating seed banks with reference to long-term seed burial.
AB  - We compared two standard seed-bank estimation techniques using buried seed
      populations that had been covered to depths of >1 m by volcanic deposits for 20
      years. Some seeds were germinated in a greenhouse (germination method [GM]), and
      other seeds were extracted by flotation using 50% K(2)CO(3) solution (flotation
      method [FM]). In total, FM could detect more species and seeds in the soils than
      GM. However, many species that were extracted by FM did not germinate by GM and
      smaller seeds were extracted to a lesser extent by FM. FM and GM have distinct
      advantages and disadvantages. We concluded that the application of a single
      method should be avoided in estimating seed banks, in particular for long-lived
      seed banks, because the seeds cannot be readily germinated and are structurally
      weak.

PMID- 15034762
TI  - Discrimination of chronic lymphocytic leukemia (CLL) and CLL/PL by cytomorphology
      can clearly be correlated to specific genetic markers as investigated by
      interphase fluorescence in situ hybridization (FISH).
AB  - Although interphase fluorescence in situ hybridization (FISH) is routinely used
      in chronic lymphocytic leukemia (CLL), differences in the chromosomal pattern
      with respect to morphological subtypes of CLL (typical CLL, CLL/PL, PLL) are
      still under debate. We studied 153 patients with CLL and correlated
      cytomorphology on peripheral blood stains with FISH analysis and other prognostic
      markers. The percentage of prolymphocytes was calculated as a continuous variable
      and followed published thresholds in parallel while being correlated to FISH
      analysis. Higher percentages of prolymphocytes were associated significantly with
      deletion of 17p13. Deletion of 17p13 was most frequently observed in patients
      with more than 30% prolymphocytes. Trisomy 12 was found mainly in cases with 6
      30% prolymphocytes. The percentage of prolymphocytes did not correlate with
      deletions of 11q23 or with 13q14 abnormalities. In conclusion, we suggest that
      further research focus on the percentage of prolymphocytes in CLL. Doing so,
      biologically relevant thresholds for the percentages of prolymphocytes in the
      peripheral blood and their association to underlying genetic markers could be
      investigated together with other biologically and especially prognostic markers.

PMID- 15034765
TI  - Body orientation and face orientation: two factors controlling apes' behavior
      from humans.
AB  - A number of animal species have evolved the cognitive ability to detect when they
      are being watched by other individuals. Precisely what kind of information they
      use to make this determination is unknown. There is particular controversy in the
      case of the great apes because different studies report conflicting results. In
      experiment 1, we presented chimpanzees, orangutans, and bonobos with a situation
      in which they had to request food from a human observer who was in one of various
      attentional states. She either stared at the ape, faced the ape with her eyes
      closed, sat with her back towards the ape, or left the room. In experiment 2, we
      systematically crossed the observer's body and face orientation so that the
      observer could have her body and/or face oriented either towards or away from the
      subject. Results indicated that apes produced more behaviors when they were being
      watched. They did this not only on the basis of whether they could see the
      experimenter as a whole, but they were sensitive to her body and face orientation
      separately. These results suggest that body and face orientation encode two
      different types of information. Whereas face orientation encodes the observer's
      perceptual access, body orientation encodes the observer's disposition to
      transfer food. In contrast to the results on body and face orientation, only two
      of the tested subjects responded to the state of the observer's eyes.

PMID- 15034764
TI  - Clivus fractures: clinical presentations and courses.
AB  - Fractures in the clivus region are usually associated with blunt head trauma.
      They may cause many cranial nerve deficits and vascular complications. The
      mortality rate is high because of brainstem trauma or vertebrobasilar occlusion.
      The diagnosis of clivus fracture (CF) is difficult with routine cranial
      radiography due to the presence of dense petrous temporal bones. Because of this,
      few cases have been described in the past. In this study, we report nine cases of
      CF observed and treated in our department during the last 5 years. Computed
      tomographic (CT) scanning revealed CF in nine of 2500 patients with head trauma
      (0.36%). The patients ranged in age from 17 to 68 years (mean 38.3). Five
      patients had had motor vehicle accidents, three were injured in falls, and one
      was a pedestrian injured by a motor vehicle. Five patients had longitudinal
      fractures and four had transverse fractures. Cranial nerve deficits were recorded
      in all patients. Deficits of cranial nerves VI and VII were the most frequently
      observed (six patients, 66.6%). We review the literature to highlight the
      differences in clinical presentation and the course in cranial nerve deficits.
      The diagnosis of CF is made by high-resolution, fine-cut CT using standard and
      bone window settings. Its presence should alert clinicians to the potential
      complications.

PMID- 15034767
TI  - Resistance to adhesion formation: a comparative study of treated and untreated
      mesh products placed in the abdominal cavity.
AB  - BACKGROUND: New materials have been devised to prevent postoperative adhesions
      when placing a prosthesis in contact with abdominal contents. METHODS: Eighty
      rats underwent laparotomy and denudation of the serosa of the cecum and
      peritoneal covering of the abdominal wall. Five treated mesh products (Parietex
      Composite, Parietene Composite, Bard Composix E/X, Sepramesh, and Gore-Tex Dual
      Mesh) and one untreated mesh product (untreated Parietene) were randomly placed
      between the cecum and abdominal wall. A group without mesh was used as control.
      The animals were sacrificed at 21 days following surgery and analyzed for the
      presence of adhesions. RESULTS: The incidence of adhesion formation, mean
      adhesion area, maximum adhesion length, and strength of adhesion separation were
      similar between Parietex Composite, Parietene Composite, and Bard Composix E/X,
      and they were significantly less than with Sepramesh, untreated Parietene, and
      the control group. Gore-Tex Dual Mesh resulted in less adhesions, adhesion area,
      mean strength of separation, and work of separation than the untreated Parietene
      group and the control group. Sepramesh resulted in less strength and work of
      separation compared to the control group. CONCLUSIONS: The incidence of adhesions
      and work and strength of adhesion separation are reduced when using a treated
      mesh, compared to the untreated mesh and the control group without mesh. Parietex
      Composite, Parietene Composite, Bard Composix E/X, and Gore-Tex Dual Mesh were
      superior to Sepramesh, untreated Parietene, and the control group in the
      prevention of adhesion formation.

PMID- 15034768
TI  - Gallbladder strangulation within an incisional hernia.
AB  - We describe here the first case in the literature of gallbladder strangulation
      within an incisional hernia. A patient with a history of rectal cancer operation
      presented with a "surgical abdomen" and a palpable right upper quadrant mass at
      the site of the previous colostomy. At surgery, a strangulated gallbladder was
      found in the subcutaneous tissue. Cholecystectomy was performed, and patient
      recovery was uneventful. If gallbladder strangulation is suspected, the surgeon
      should avoid forceful attempts at hernia reduction, as this may cause rupture of
      the gallbladder and subsequent contamination.

PMID- 15034766
TI  - Evidence of linkage and association on chromosome 20 for late-onset Alzheimer
      disease.
AB  - Recently, we reported evidence of linkage on chromosome 20 for Alzheimer disease
      (AD) using a novel statistical approach to incorporate covariates (e.g., age,
      ApoE genotype) into the analysis. These results suggest that very elderly
      subjects (>85 years), and individuals who carry an epsilon2 allele at the ApoE
      locus are more likely to be linked to this candidate region. The region on
      chromosome 20 includes a strong candidate gene, cystatin C (CST3), which has
      previously been associated with AD in case-control studies. We investigated these
      findings further by genotyping additional markers to narrow the candidate region,
      and to identify evidence of linkage disequilibrium as additional support for a
      susceptibility locus on chromosome 20. We selected 43 elderly sibships (89
      subjects) from the NIMH AD Genetics Initiative based on current age older than 84
      years, and identified 129 unrelated control subjects who were older than 84 years
      from the Oregon Brain Aging Study to conduct linkage and association studies in
      this region. Fourteen additional markers were evaluated, including 4 markers
      located within or near CST3. We narrowed the candidate region on chromosome 20 to
      an 11.8-cM region between markers D20S174 and D20S471, which includes the CST3
      candidate gene. In addition, we observed evidence of association for markers
      located near the CST3 candidate gene, with P values between 0.002 and 0.08 for
      two-locus haplotypes. These results support the presence of a susceptibility
      locus for AD in the vicinity of CST3 for very elderly subjects with AD.

PMID- 15034769
TI  - Structure-dependent in vitro cytotoxicity of the isomeric complexes [Ru(L)2Cl2]
      (L= o-tolylazopyridine and 4-methyl-2-phenylazopyridine) in comparison to
      [Ru(azpy)2Cl2].
AB  - The dichlorobis(2-phenylazopyridine)ruthenium(II) complexes, [Ru(azpy)(2)Cl(2)],
      are under renewed investigation due to their potential anticancer activity. The
      three most common isomers alpha-, beta- and gamma-[RuL(2)Cl(2)] with L= o
      tolylazopyridine (tazpy) and 4-methyl-2-phenylazopyridine (mazpy) (alpha
      indicating the coordinating Cl, N(pyridine) and Nazo atoms in mutual cis, trans,
      cis positions, beta indicating the coordinating Cl, N(pyridine) and Nazo atoms in
      mutual cis, cis, cis positions, and gamma indicating the coordinating Cl,
      N(pyridine) and Nazo atoms in mutual trans, cis, cis positions) are synthesized
      and characterized by NMR spectroscopy. The molecular structures of gamma
      [Ru(tazpy)(2)Cl(2)] and alpha-[Ru(mazpy)(2)Cl(2)] are determined by X-ray
      diffraction analysis. The IC(50) values of the geometrically isomeric
      [Ru(tazpy)(2)Cl(2)] and [Ru(mazpy)(2)Cl(2)] complexes compared with those of the
      parent [Ru(azpy)(2)Cl(2)] complexes are determined in a series of human tumour
      cell lines (MCF-7, EVSA-T, WIDR, IGROV, M19, A498 and H266). These data
      unambiguously show for all complexes the following trend: the alpha isomer shows
      a very high cytotoxicity, whereas the beta isomer is a factor 10 less cytotoxic.
      The gamma isomers of [Ru(tazpy)(2)Cl(2)] and [Ru(mazpy)(2)Cl(2)] display a very
      high cytotoxicity comparable to that of the gamma isomer of the parent compound
      [Ru(azpy)(2)Cl(2)] and to that of the alpha isomer. These biological data are of
      the utmost importance for a better understanding of the structure-activity
      relationships for the isomeric [RuL(2)Cl(2)] complexes.

PMID- 15034770
TI  - A quantitative appraisal of the ambivalent metal ion binding properties of
      cytidine in aqueous solution and an estimation of the anti-syn energy barrier of
      cytidine derivatives.
AB  - The recently defined log K (M)(M)(L) versus pK(H)(H)(L) straight-line plots for L
      = pyridine-type (PyN) and ortho-aminopyridine-type (oPyN) ligands now allow the
      evaluation in a quantitative manner of the stability of the 1:1 complexes formed
      between cytidine (Cyd) and Ca(2+), Mg(2+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+)
      or Cd(2+) (M(2+)); the corresponding stability constants, K(M)(M)(Cyd) including
      the acidity constant, K(H)(H)(Cyd) for the deprotonation of the (N3)H(+) site had
      been determined previously under exactly the same conditions as the mentioned
      plots. Since the stabilities of the M(PyN)(2+) and M(oPyN)(2+) complexes of
      Ca(2+) and Mg(2+) are practically identical, it is concluded that complex
      formation occurs in an outer-sphere manner, and this is in accord with the fact
      that in the p K(a) range 3-7 metal ion binding is independent of K(H)(H)(Pyn) or
      K(H)(H)(oPyN). Ca(Cyd)(2+) and Mg(Cyd)(2+) are more stable than the corresponding
      (outer-sphere) M(PyN)(2+) complexes and this means that the C2 carbonyl group of
      Cyd must participate, next to N3 which is most likely outer-sphere, in metal ion
      binding, leading thus to chelates; these have formation degrees of about 50% and
      35%, respectively. Co(Cyd)(2+) and Ni(Cyd)(2+) show no increased stability based
      on the log K(M)(M)(oPyN) versus pK(H)(H)(oPyN) hence, the (C2)O group does not
      participate in metal ion binding, but the inner-sphere coordination to N3 is
      strongly inhibited by the (C4)NH(2) group. In the M(Cyd)(2+) complexes of Mn(2+),
      Cu(2+), Zn(2+) and Cd(2+), this inhibiting effect on M(2+) binding at N3 is
      partially compensated by participation of the (C2)O group in complex formation
      and the corresponding chelates have formation degrees between about 30% (Zn(2+))
      and 83% (Cu(2+)). The different structures of the mentioned chelates are
      discussed in relation to available crystal structure analyses. (1). There is
      evidence (crystal structure studies: Cu(2+), Zn(2+), Cd(2+)) that four-membered
      rings form, i.e. there is a strong M(2+) bond to N3 and a weak one to (C2)O. (2).
      By hydrogen bond formation to (C2)O of a metal ion-bound water molecule, six
      membered rings, so-called semichelates, may form. (3). For Ca(2+) and Mg(2+), and
      possibly Mn(2+), and their Cyd complexes, six-membered chelates are also likely
      with (C2)O being inner-sphere (crystal structure) and N3 outer-sphere. (4).
      Finally, for these metal ions also complexes with a sole outer-sphere interaction
      may occur. All these types of chelates are expected to be in equilibrium with
      each other in solution, but, depending on the metal ion, either the one or the
      other form will dominate. Clearly, the cytidine residue is an ambivalent binding
      site which adjusts well to the requirements of the metal ion to be bound and this
      observation is of relevance for single-stranded nucleic acids and their
      interactions with metal ions. In addition, the anti- syn energy barrier has been
      estimated as being in the order of 6-7.5 kJ/mol for cytidine derivatives in
      aqueous solution at 25 degrees C.

PMID- 15034771
TI  - Comparison of the cleavage profiles of oligonucleotide duplexes with or without
      phosphorothioate linkages by using a chemical nuclease probe.
AB  - A manganese porphyrin complex, Mn-TMPyP, associated with KHSO(5) is a chemical
      nuclease able to selectively recognize the minor groove of three consecutive AT
      base pairs of DNA and to mediate very precise cleavage chemistry at that
      particular site. This specific recognition and cleavage were used to probe the
      accessibility of the minor groove of DNA duplexes composed of one phosphodiester
      strand and one phosphorothioate strand. The cleavage of 5'-GCAAAAGC/5'-GCTTTTGC
      duplexes by Mn-TMPyP/KHSO(5) was monitored by HPLC coupled to electrospray mass
      analysis. Each single strand was synthesized with all-phosphate, all- Rp
      phosphorothioate and all- Sp-phosphorothioate internucleotide bonds. We found
      that the manganese porphyrin was able to recognize its favorite (AT)(3)-box
      binding site within the heteroduplexes, as in the case of natural DNA. Molecular
      modeling studies on the interactions of the reactive porphyrin manganese-oxo
      species with both types of duplexes confirmed the experimental data.

PMID- 15034773
TI  - Simultaneous measurement of intramuscular pressure and surface electromyography
      of the multifidus muscle.
AB  - The anatomic proof of a spinal compartment and the clinical symptoms of
      compartment syndrome in patients with chronic back pain are inconsistent with the
      rarely met measuring criteria of intramuscular pressure (IMP). Previous studies
      assume a dependence of the IMP on spinal alignment (degree of lumbar spine
      flexion) and the degree of muscle activation. The significance of these
      disturbance variables in the interpretation of IMP could explain the above
      discrepancy. This study therefore investigates the influence of both a 30%
      increase in trunk flexion and alterations in muscle contraction from 100% to 60%.
      Sixteen healthy subjects participated in the study. The IMP and mean rectified
      amplitude of the multifidus surface EMG signal were determined at rest and 0
      degrees and approximately 30 degrees of lumbar spine flexion, and they were
      compared. Subsequently, both parameters were measured during both 100% and 60%
      maximal voluntary contraction (MVC) of the muscle and then correlated. During
      rest and 0 degrees flexion, the median IMP was 9.3 mmHg (range 0.0-22.5) while
      the median mean rectified amplitude (MRA) of the EMG signal was 1.98 microV
      (range 1.32-7.38). In 30 degrees flexion, the median IMP went up to 24.3 mmHg
      (range 1.4-97.3) with hardly any increase in the median MRA of 2.32 microV (range
      1.20-9.72). Under 60% MVC, the median IMP rose to 186.6 mmHg (range 15.4-375.4)
      and the median MRA to 21.02 microV (range 4.63-43.63). During 100% MVC, the
      median MRA increased to 34.38 microV (range 12.99-102.54) while the median IMP
      rose to 273.4 mmHg (range 90.4-395.1). Spearman's rank correlation coefficient
      for the IMP and MRA quotients of the 100/60% MVC values was r= -0.21. To sum up,
      it can be said that IMP was subject to great interindividual variation in all the
      experiments. This parameter is highly dependent on spinal alignment and muscular
      activity. Further studies are needed so that the IMP can be interpreted properly
      when diagnosing a chronic compartment of the erector spinae muscles.

PMID- 15034772
TI  - Spinal fusion using an autologous growth factor gel and a porous resorbable
      ceramic.
AB  - Augmenting healing through a single application of an exogenous growth factor or
      bone morphogenetic protein is not a new concept. The use of autologous growth
      factors through platelet isolation and concentration provides multiple endogenous
      growth factors to the healing site. A posterolateral fusion model in aged sheep
      (5- to 6-year-old ewes) was used to examine the effects of the addition of growth
      factors through autologous platelet isolation on the biomechanic and histologic
      properties of the fusion using a resorbable coral bone graft substitute. At 6
      months the combination of autologous growth factors to the Pro Osteon 500R plus
      aspirated bone marrow resulted in the greatest bending stiffness but not ultimate
      load. Autologous growth factors can be isolated from platelets and concentrated
      to provide multiple growth factors to the fusion site to aid in spinal fusion.

PMID- 15034774
TI  - Low back pain in Mozambican adolescents.
AB  - Recent literature shows that the prevalence of low back pain (LBP) in adolescents
      living in Western countries approaches that of adults 18-55 years of age.
      Moreover, epidemiological studies have also shown that the frequency of different
      rheumatic disorders in developing countries is similar to that found in Western
      industrialized regions. The purpose of this study was to ascertain the prevalence
      of LBP and to explore some risk factors among adolescents living in different
      zones of Mozambique. A previously validated questionnaire was distributed to
      schoolchildren of grades 6 and 7 living in three different residential/social
      regions of the country. Two hundred four (204) children participated in the
      survey. Median age was 13 years (age range 11-16 years) and 46% were boys.
      Several episodes of LBP interfering with usual activities during the previous
      year were reported by 13.5% of the sample. Living in the wealthier urban center
      (as compared with the peripheral regions) and walking >30 min per day to and from
      school were associated with an increased risk of LBP (OR 3.1, 95% CI 0.99-9.48,
      and OR 4.8, 95% CI 1.61-14.28, respectively).

PMID- 15034775
TI  - [Treatment of extreme tumour pain with morphine and s-ketamine A case report of
      an 11-year old girl].
AB  - We are reporting on the case of an 11-year old girl with a malignant tumour. The
      extreme pain throughout the body could not be treated by conventional methods. By
      intravenous application of a morphine and s-ketamine mixture we were able to
      achieve a very effective analgesic result. Apart from the opiate effect of the
      morphine the decisive factor was the NMDA-antagonism of the s-ketamine. The
      latter suppresses central sensitisation and chronic pain and reduces or even
      prevents the development of opioid tolerance. It was possible to use smaller
      opiate doses more effectively, thus reducing the side effects of the pain
      therapy. Under associated whole-body thermochemotherapy the girl experienced
      general pain relief and we were able to return to conventional therapy with a
      fentanyl plaster.

PMID- 15034776
TI  - [Pain management in shoulder surgery].
AB  - Surgical procedures in the region of the shoulder joint are among the most
      painful interventions in orthopedic practice. For this reason, in addition to
      intravenous pain therapy with opioids, blockade of the brachial plexus has become
      established as an effective method to provide analgesia.High-resolution
      ultrasound offers the possibility of performing nerve blockades under visual
      monitoring. Studies on interscalene blockade performed under sonographic control
      provide evidence for both the high efficacy and safety of the procedure.
      Clinically manifest signs of nerve damage have not appeared with use of this
      method. Smaller operations can usually be adequately managed with perioperative
      single-shot blockade. More extensive operations for which severe pain lasting for
      several days can be expected and surgical interventions involving preexistent
      shoulder stiffness necessitate catheterization for uninterrupted pain therapy.
      Successful rehabilitation after shoulder surgery requires diligent perioperative
      pain blockade, which can primarily be provided by interscalene plexus blockade.

PMID- 15034777
TI  - Liquid-feeding performances of ants (Formicidae): ecological and evolutionary
      implications.
AB  - Disparities in liquid-feeding performances of major ant taxa have likely been
      important to resource partitioning among ants, to the nature and composition of
      ant partnerships with plants and sap-feeding trophobionts, and to ecological and
      evolutionary diversification of ant taxa. We measured performance volumetrically
      for individual workers of 77 ant species from lowland rain forests of Amazonia
      and Borneo and three key North American taxa. In trials with 9% sucrose solution,
      performances were strongly related to body size (and alitrunk length) and to
      proventricular structure at generic to subfamilial levels. Highly modified
      proventriculi were associated with disproportionately large load sizes in
      Formicinae and certain small-bodied Dolichoderinae. These same taxa also ingested
      liquids more rapidly during foraging than did similar-sized species with
      plesiomorphic proventriculi. Secondarily reduced foraging performances of several
      formicines likely reflect ecological or evolutionary trade-offs related to
      dietary specialization or anti-predator defenses. Across formicines and
      dolichoderines, performances differed by functional group. Relatively small loads
      and slow uptake characterized species tending trophobionts (mainly Hemiptera) day
      and night in large worker aggregations. Large loads and rapid uptake typified
      solitary, diurnal "leaf-foragers." Intermediate feeding performances
      characterized a few species that both tended trophobionts in small aggregates and
      frequently foraged alone.

PMID- 15034778
TI  - Hierarchy of responses to resource pulses in arid and semi-arid ecosystems.
AB  - In arid/semi-arid ecosystems, biological resources, such as water, soil
      nutrients, and plant biomass, typically go through periods of high and low
      abundance. Short periods of high resource abundance are usually triggered by
      rainfall events, which, despite of the overall scarcity of rain, can saturate the
      resource demand of some biological processes for a time. This review develops the
      idea that there exists a hierarchy of soil moisture pulse events with a
      corresponding hierarchy of ecological responses, such that small pulses only
      trigger a small number of relatively minor ecological events, and larger pulses
      trigger a more inclusive set and some larger ecological events. This framework
      hinges on the observation that many biological state changes, where organisms
      transition from a state of lower to higher physiological activity, require a
      minimal triggering event size. Response thresholds are often determined by the
      ability of organisms to utilize soil moisture pulses of different infiltration
      depth or duration. For example, brief, shallow pulses can only affect surface
      dwelling organisms with fast response times and high tolerance for low resource
      levels, such as some species of the soil micro-fauna and -flora, while it takes
      more water and deeper infiltration to affect the physiology, growth or
      reproduction of higher plants. This review first discusses how precipitation,
      climate and site factors translate into soil moisture pulses of varying magnitude
      and duration. Next, the idea of the response hierarchy for ecosystem processes is
      developed, followed by an exploration of the possible evolutionary background for
      the existence of response thresholds to resource pulses. The review concludes
      with an outlook on global change: does the hierarchical view of precipitation
      effects in ecosystems provide new perspectives on the future of arid/semiarid
      lands?

PMID- 15034779
TI  - Interaction between ants and fruits of Guapira opposita (Nyctaginaceae) in a
      Brazilian sandy plain rainforest: ant effects on seeds and seedlings.
AB  - This study examines the dispersal system of Guapira opposita in a tropical sandy
      rainforest in southeast Brazil. Guapira trees produce small fruits with a high
      protein content (28.4%) and low lipid content (0.3%), and the plant is primarily
      dispersed by birds. Mature fruits of G. opposita can fall spontaneously with the
      pulp intact, or be dropped by birds with bits of pulp attached. In either case,
      ground-dwelling ants rapidly remove the fruits to their nest (93% after 12 h).
      The ponerine ants Odontomachus chelifer and Pachycondyla striata are the main
      seed vectors among the ants, and together account for 56% (20 of 36) of the ant
      fruit interactions recorded on the forest floor. Individual workers of O.
      chelifer and P. striata transport single fruits to their nests. Bits of pulp are
      fed to larvae and worker nestmates, and intact seeds are discarded outside the
      nest. Germination success in Guapira is higher for cleaned seeds (pulp removed)
      than for seeds coated by pulp. Guapira seedlings and juveniles are more frequent
      close to Odontomachus nests than at sites without such nests. Soil samples from
      Odontomachus nests had greater penetrability, and higher concentrations of P, K,
      and Ca than random soil samples. Field experiments suggest that the association
      between G. opposita seedlings and O. chelifer nests can potentially render the
      plant some protection against herbivores. Results indicate that fruit
      displacement by ponerine ants play an important role in the biology of G.
      opposita seeds and seedlings in the sandy forest, and illustrate the complex
      nature of the dispersal ecology of tropical tree species.

PMID- 15034781
TI  - Variants of CYP46A1 may interact with age and APOE to influence CSF Abeta42
      levels in Alzheimer's disease.
AB  - Recent studies have suggested that variants of CYP46A1, encoding cholesterol 24
      hydroxylase (CYP46), confer risk for Alzheimer's disease (AD), a prospect
      substantiated by evidence of genetic association from several quantitative traits
      related to AD pathology, including cerebrospinal fluid (CSF) levels of the 42
      amino-acid cleavage product of beta-amyloid (Abeta42) and the tau protein. In the
      present study, these claims have been explored by the genotyping of previously
      associated markers in CYP46A1 in three independent northern European case-control
      series encompassing 1323 individuals and including approximately 400 patients
      with measurements of CSF Abeta42 and phospho-tau protein levels. Tests of
      association in case-control models revealed limited evidence that CYP46A1
      variants contributed to AD risk across these samples. However, models testing for
      potential effects upon CSF measures suggested a possible interaction of an
      intronic marker (rs754203) with age and APOE genotype. In stratified analyses,
      significant effects were evident that were restricted to elderly APOE epsilon4
      carriers for both CSF Abeta42 ( P=0.0009) and phospho-tau ( P=0.046).
      Computational analyses indicate that the rs754203 marker probably does not impact
      the binding of regulatory factors, suggesting that other polymorphic sites
      underlie the observed associations. Our results provide an important independent
      replication of previous findings, supporting the existence of CYP46A1 sequence
      variants that contribute to variability in beta-amyloid metabolism.

PMID- 15034782
TI  - Fine mapping of the Schnyder's crystalline corneal dystrophy locus.
AB  - Schnyder's crystalline corneal dystrophy (SCCD) is a rare autosomal dominant eye
      disease with a spectrum of clinical manifestations that may include bilateral
      corneal clouding, arcus lipoides, and anterior corneal crystalline cholesterol
      deposition. We have previously performed a genome-wide linkage analysis on two
      large Swede-Finn families and mapped the SCCD locus to a 16-cM interval between
      markers D1S2633 and D1S228 on chromosome 1p36. We have collected 11 additional
      families from Finland, Germany, Turkey, and USA to narrow the critical region for
      SCCD. Here, we have used haplotype analysis with densely spaced microsatellite
      markers in a total of 13 families to refine the candidate interval. A common
      disease haplotype was observed among the four Swede-Finn families indicating the
      presence of a founder effect. Recombination results from all 13 families refined
      the SCCD locus to 2.32 Mbp between markers D1S1160 and D1S1635. Within this
      interval, identity-by-state was present in all 13 families for two markers D1S244
      and D1S3153, further refining the candidate region to 1.58 Mbp.

PMID- 15034784
TI  - Genetic analysis of RSC58, which encodes a component of a yeast chromatin
      remodeling complex, and interacts with the transcription factor Swi6.
AB  - Before transcription can begin, the chromatin structure must be rearranged at the
      nucleosome level. In yeast the nucleosome remodeling complex RSC is involved in
      this process and it is essential for growth. Recent analysis of the RSC by mass
      spectrometry has suggested that the product of YLR033w, an essential gene of
      unknown function, is a novel component of the complex, and the gene has been
      renamed RSC58. Rsc58 is predicted to be 502 amino acids long. We have isolated
      five temperature-sensitive mutations in RSC58 and studied the cellular function
      of the gene. Our major findings are the following. (1) Two of the alleles have a
      frameshift mutation near the 3' end of the gene, in codons 482 and 485,
      respectively. The first mutation is associated with the more severe phenotype.
      This is compatible with the finding that removal of the C-terminal 25 residues of
      Rsc58 is lethal to cells. These results suggest that C-terminal region is
      essential for Rsc58 function. (2) RSC4, which codes for another member of the
      RSC, was found to be a multicopy suppressor of the phenotype of one of the
      temperature-sensitive mutants. (3) Two-hybrid analysis identified Swi6, a
      transcription factor, as a candidate interactor with Rsc58. An interaction
      between Rsc58 and Swi6 is also suggested by the fact that rsc58-ts Deltaswi6
      double mutants show a more severe growth defect than either mutation alone. These
      results suggest the possibility that Rsc58 mediates between nucleosome remodeling
      and the initiation of transcription.

PMID- 15034785
TI  - The severity of mouse pathologies caused by the bird schistosome Trichobilharzia
      regenti in relation to host immune status.
AB  - Cercariae of the nasal bird schistosome Trichobilharzia regenti are able to
      penetrate into mammalian skin and migrate to the mouse central nervous system
      (CNS) causing tissue injury in certain cases. Our study shows that the severity
      of T. regenti pathologies in the CNS closely depends on the host immune status.
      During the primary infection of immunocompetent mice, the parasites evoked an
      acute inflammatory reaction in the skin and the CNS involving focal oedema and
      cellular infiltration of the tissue. Challenge infections resulted in the
      development of extensive inflammatory foci in the host skin which precluded the
      subsequent migration of the schistosomula to the CNS. On the other hand, during
      primary as well as challenge infections of immunodeficient mice (SCID), no
      significant immune response against the parasites was detected in any of the host
      organs examined; however, in contrast to immunocompetent mice, the infections
      were frequently manifested by severe leg paralysis.

PMID- 15034786
TI  - Four-year monitoring of parasite communities in gobiid fishes of the south
      western BalticII. Infracommunity.
AB  - The parasite infracommunity of five goby species (Pomatoschistus minutus, P.
      pictus, P.microps, Gobiusculus flavescens, Gobius niger) from the south-western
      Baltic was investigated during spring, summer and autumn of the years 1997-2000.
      The mean parasite species number in single hosts was high, ranging between 1.1
      (P. minutus), 2.1 (P. pictus) to even 3.3 (P. microps). Gobius niger is the only
      host which lives longer than a year and is infested by almost identical parasites
      for longer times, i.e. the parasite species composition has greater homogeneity.
      Most intensity of infestation values peaked in summer and were lowest in autumn;
      only a few exceptions were found in spring or autumn. Only the Digenea Podocotyle
      atomon and Cryptocotyle concavum were abundant enough to show a clear seasonal
      fluctuation in Pomatoschistus minutus, P. pictus and Gobiusculus flavescens.
      Aphalloides timmi and Apatemon gracilis (Digenea) also attained high intensities
      in P. microps. These four parasite species and, additionally, Cryptocotyle lingua
      (Digenea), and Hysterothylacium sp. (Nematoda) can be strongly accumulated from
      either prey or free-swimming larvae and, thus, decisively influence the structure
      of the infracommunities. Due to selection by filter mechanisms, rare parasites
      settle rather by chance after competition with other species. The number of
      parasite species usually increased significantly with host growth. As many as
      four parasite species were found at the same time in the intestinal tract
      microhabitat of Gobius niger and P. minutus; at most three parasite species were
      present on the skin and fins or in the body cavity. The level of infection is due
      to the respective life history patterns and the kinds of prey, which harbour
      different parasites as intermediate hosts. Additionally, it depends on the time
      of appearance of goby offspring in the course of the year.

PMID- 15034792
TI  - Tumor with features of renal cell carcinoma and of transitional cell carcinoma.

PMID- 15034788
TI  - Primary central nervous system lymphoma in Japan 1995-1999: changes from the
      preceding 10 years.
AB  - PURPOSE: Previously, we conducted a nationwide survey of primary central nervous
      system lymphoma (PCNSL) treated between 1985 and 1994 in Japan. In the present
      study, we conducted further investigations of PCNSL patients treated between 1995
      and 1999 to clarify possible changes with time in the clinical features,
      treatment, and outcome of this disease. METHODS: Thirteen Japanese institutions
      were surveyed, and data on 101 patients with histologically-confirmed PCNSL were
      collected. These data were compared with those of 167 patients treated at the
      same institutions between 1985 and 1994. RESULTS: Regarding patient and tumor
      characteristics, the proportion of patients with good performance status (PS) was
      significantly higher in the group treated during 1995-1999 than in that treated
      during 1985-1994, but other characteristics were not significantly different.
      Regarding treatment, more patients in the more recent period (66%) received
      systemic chemotherapy than those in the preceding period (53%, P = 0.049). For
      all patients, including those who did not complete radiotherapy, the median
      survival time was 17 months and 30 months in patients treated between 1985 and
      1994 and those treated between 1995 and 1999, respectively, and the 5-year
      survival rate was 15% versus 31% (P = 0.0003). In both patient groups, higher age
      and tumor multiplicity were associated with poor prognosis in multivariate
      analysis. In patients treated between 1995 and 1999, those who received systemic
      chemotherapy showed significantly better prognosis than those who did not (P =
      0.0049), but the difference was not significant in multivariate analysis (P =
      0.23). CONCLUSIONS: The high survival rates observed in the present survey are
      comparable with those of recent prospective studies employing intensive
      chemoradiotherapy. The improvement in prognosis appeared to result, at least in
      part, from the increase in the proportion of patients with better PS. Since the
      clinical feature and treatment outcome of patients with PCNSL can thus change
      with the era, historical control data should not be used in comparing different
      treatment modalities.

PMID- 15034794
TI  - Contribution of the hemostatic system to angiogenesis in cancer.
AB  - It is now recognized that the hemostatic system plays an important role in cancer
      growth and dissemination, processes known to be vitally dependent on new tumor
      blood vessel formation (angiogenesis). There is also an increasing body of
      evidence supporting the link between the various components of the
      coagulation/fibrinolysis systems and angiogenic activity in cancer patients.
      Tissue factor (TF), thrombin, fibrinogen, fibrin, and plasminogen activation
      system, as well as platelets, all are able to promote angiogenesis. On the other
      hand, coagulation inhibitors, as well as cryptic (proteolytically released)
      domains of hemostatic proteins, are also known to act as angiogenesis inhibitors.
      Indeed, modulation (stimulation or inhibition) of angiogenesis may result from
      either classical functions of various molecular components of the hemostatic
      cascade, their less studied "alternative" activities, or both. Although much
      remains to be understood about this complex circuitry these considerations
      support the judicious use of anticoagulants in patients with malignancy as well
      as encourage the search for novel antiangiogenic activities that may reside
      within molecular and cellular components of the hemostatic system.

PMID- 15034789
TI  - Volume reduction surgery for advanced hepatocellular carcinoma.
AB  - PURPOSE: The aim of this study was to evaluate the prognostic impact of reductive
      surgery on the survival of patients with advanced hepatocellular carcinoma (HCC).
      METHODS: Eligible patients had a main tumor greater than 10 cm in diameter with
      multiple intrahepatic metastases (>5 nodules), and good liver function (Child
      Pugh class A), but no tumor thrombus in the main portal vein. The main tumor was
      surgically removed but the metastases were not removed and were treated with
      repeated transcatheter hepatic arterial chemo-embolization (TAE). RESULTS: From
      Jun 1997 to May 2003, 13 patients (median age 61 years, range: 48-74) were
      prospectively enrolled. The median diameter of the main tumor was 14 cm (range
      11.5-18.0). No major surgical complications were observed and the median hospital
      stay was 12 days (range 7-20). The first TAE was performed 1 month after
      hepatectomy in all patients and was repeated for median of 5 (range: 1 to 16)
      times. Complete remission was observed in two patients. One patient had
      recurrence afterwards but another patient survived 41 months without recurrence.
      Three patients survived more than 3 years. The overall 1-, 3-, and 4-year
      survival rates of the 13 patients were 67.7%, 40.6%, and 40.6%, respectively.
      CONCLUSIONS: Volume reduction surgery followed by TAE might prolong the survival
      of patients with a large HCC and intrahepatic metastases, especially those with a
      main tumor on the right side.

PMID- 15034787
TI  - Angiogenesis in hepatocellular carcinoma: the retrospectives and perspectives.
AB  - Hepatocellular carcinoma (HCC) is a typical hypervascular tumor. Many angiogenic
      factors have been studied in HCC, and several anti-angiogenic therapies have been
      tested in animal models and patients. This paper summarizes the latest findings,
      especially regarding the clinical significance of endothelial cell markers and
      angiogenic factors in HCC, and experimental and clinical anti-angiogenesis
      therapies. Further developments in this area, such as endothelial cell-oriented
      research and better experimental and clinical designs in the evaluation of anti
      angiogenic therapies are discussed.

PMID- 15034795
TI  - Oncogenes as regulators of tissue factor expression in cancer: implications for
      tumor angiogenesis and anti-cancer therapy.
AB  - Up-regulation of tissue factor (TF) is often observed in cancer. TF is a cell
      associated receptor for coagulation factor VII/VIIa, an interaction known to
      activate the coagulation cascade. At the same time, TF is also known as a
      mediator of intracellular signaling events that can alter gene expression
      patterns and cell behavior. Both aspects of TF activity are of possible relevance
      to tumor growth, metastasis, and angiogenesis, including up-regulation of
      vascular endothelial growth factor (VEGF). TF up-regulation is often observed on
      the surfaces of tumor-associated endothelial cells, inflammatory cells, and
      particularly on cancer cells themselves. In the last case, high TF levels may be
      associated with poor prognosis and parallel clinical (and genetic) tumor
      progression. We have proposed elsewhere that TF may be a target of oncogenic
      events in cancer. Here we discuss our observations suggesting that oncogene
      targeting agents may down-regulate TF expression. Such is the effect of treatment
      with the neutralizing monoclonal antibody (C225) raised against the epidermal
      growth factor receptor (EGFR) in EGFR-dependent squamous cell carcinoma cells
      (A431). This two- to threefold TF down-regulation by C225 treatment is paralleled
      by a decrease in expression of VEGF. It is conceivable that TF participates in
      signals that regulate VEGF and angiogenesis triggered by activated oncogenic
      pathways. Therefore, direct targeting of TF in cancer should be considered in
      combination with other treatment modalities such as oncogene-directed therapies,
      antiangiogenic agents (e.g., VEGF antagonists), and anti-cancer chemotherapy.

PMID- 15034796
TI  - Tissue factor and fibrin in tumor angiogenesis.
AB  - The hypercoagulability exhibited by most cancer patients leads to serious
      complications such as venous thromboembolism and contributes to the pathogenesis
      of tumor growth and metastasis by promoting angiogenesis. The key player in this
      vicious cycle is tissue factor (TF), the initiator of blood coagulation. Although
      TF normally safeguards vascular integrity by inducing hemostasis upon injury,
      abnormal expression of TF in different tumors and related vascular endothelial
      cells contributes to unnecessary clot formation in cancer patients. Clotting
      dependent induction of tumor angiogenesis is primarily mediated by TF-induced
      generation of thrombin and subsequent deposition of cross-linked fibrin. A cross
      linked fibrin network provides a provisional proangiogenic matrix that
      facilitates blood vessel infiltration. Clotting-independent mechanisms of TF
      induced tumor angiogenesis have also been described, mediated primarily by the
      cytoplasmic tail of the TF receptor. TF activation could contribute to the venous
      thromboembolism that has been reported as a complication of the use of novel
      antiangiogenic agents in combination with chemotherapy. Anticoagulants, such as
      low-molecular-weight heparin, may act to prevent these complications both by
      interfering with TF-mediated activation of clotting and by directly down
      regulating angiogenesis. Thus, TF may prove to be a novel target for cancer
      therapy.

PMID- 15034797
TI  - The contact system and angiogenesis: potential for therapeutic control of
      malignancy.
AB  - We have demonstrated that domain 5 (D5, kininostatin) and cleaved high-molecular
      weight kininogen (HKa) inhibit endothelial proliferation, migration, and
      neovascularization in the in ovo chicken chorioallantoic membrane (CAM) assay,
      and that D5 and HKa act by stimulating apoptosis and interfering with the cell
      cycle at the G (1)-S transition. Both intact high-molecular-weight kininogen (HK)
      and low-molecular-weight kininogen induce angiogenesis in the CAM assay by
      releasing bradykinin. A monoclonal antibody, mAb C11C1, targeted to HK D5,
      inhibits FGF2- (fibroblast growth factor-2) and vascular endothelial growth
      factor-stimulated angiogenesis in the CAM assay by interfering with the binding
      of HK to endothelial cells. We also demonstrate the inhibitory effects of both
      mAb C11C1 and glutathione-S-transferase-D5 on the growth of a human tumor
      supplied by CAM vessels.

PMID- 15034798
TI  - Role of thrombin in angiogenesis and tumor progression.
AB  - Clinical, laboratory, histopathological, and pharmacological evidence support the
      notion that the coagulation system, which is activated in most cancer patients,
      plays an important role in tumor biology. Our laboratory has provided evidence
      that thrombin activates angiogenesis, a process which is essential in tumor
      growth and metastasis. This event is independent of fibrin formation. At the
      cellular level many actions of thrombin can contribute to activation of
      angiogenesis: (1). Thrombin decreases the ability of endothelial cells to attach
      to basement membrane proteins. (2). Thrombin greatly potentiates vascular
      endothelial growth factor- (VEGF-) induced endothelial cell proliferation. This
      potentiation is accompanied by up-regulation of the expression of VEGF receptors
      (kinase insert domain-containing receptor [KDR] and fms-like tyrosine kinase [Flt
      1]). (3). Thrombin increases the mRNA and protein levels of alpha (v)beta (3)
      integrin and serves as a ligand to this receptor. Furthermore, thrombin increases
      the secretion of VEGF and enhances the expression and protein synthesis of matrix
      metalloprotease-9 and alpha (v)beta (3) integrin in human prostate cancer PC-3
      cells. These results could explain the angiogenic and tumor-promoting effect of
      thrombin and provide the basis for development of thrombin receptor mimetics or
      antagonists for therapeutic application.

PMID- 15034799
TI  - The fibrinolytic system and matrix metalloproteinases in angiogenesis and tumor
      progression.
AB  - Angiogenesis is the formation of new microvessels from existing vasculature. It
      is a crucial component of normal embryogenic development and of some
      physiological processes in adulthood. Pathological conditions such as tumor
      growth and metastasis, which involve tissue remodeling and inflammation, are
      usually associated with vascular leakage and subsequent angiogenesis. Tumor
      angiogenesis often augments tumor survival, progression, and metastasis, thus
      enhancing the malignant characteristics of the disease. Proteolytic degradation
      of the extracellular matrix that surrounds both the capillary sprouts and the
      migrating tumor cells is an essential part of tumor angiogenesis and tumor
      growth. In particular, proteases of the fibrinolytic system and the matrix
      metalloproteinase family play a role in these processes. In addition to
      proangiogenic effects, proteases also can negatively regulate angiogenesis.
      Protein fragments that result from proteolytic degradation of extracellular
      matrix components and other proteins can exhibit potent antiangiogenic
      properties. A thorough understanding of tumor-associated proteolytic processes is
      required to identify specific targets that are suitable for protease-based tumor
      therapy.

PMID- 15034800
TI  - Angiostatin.
AB  - The quiescent vascular system in the adult body represents the imbalanced net
      outcome of overproduction of endogenous angiogenesis inhibitors and reduced
      levels of angiogenic factors. While some endogenous inhibitors are expressed
      under physiological conditions, they can also be generated in association with
      tumor growth. Angiostatin is such a specific angiogenesis inhibitor produced by
      tumors. It inhibits primary and metastatic tumor growth by blocking tumor
      angiogenesis. Having demonstrated potent antitumor activity in animal studies,
      angiostatin is now in clinical trials for human cancer therapy. Angiostatin is
      not a novel protein molecule coded by novel DNA sequences. Instead, it is an
      internal proteolytic fragment of a known protein, plasminogen. Surprisingly, most
      kringle domains of plasminogen only inhibit angiogenesis when cleaved as
      fragments from their parent protein that lacks antiangiogenic activity. These
      findings suggest that they are cryptic fragments hidden in large protein
      molecules. Thus, proteolytic processing plays a critical role in down-regulation
      of angiogenesis. Despite proteolytic processing, the antiangiogenic mechanism of
      angiostatin remains an enigma. Without knowing the mechanisms, it is difficult to
      predict the ultimate outcome of ongoing clinical trials. In this article, we
      discuss what is known about angiostatin and how this molecule specifically
      inhibits angiogenesis. We hope that the information will be useful for further
      development of angiostatin and its related inhibitors as therapeutic agents.

PMID- 15034801
TI  - Platelets and angiogenesis in malignancy.
AB  - There is increasing evidence that platelets play an important role in the process
      of tumor angiogenesis. Thrombocytosis is a frequent finding in cancer patients
      (10-57%). Although the mechanisms underlying thrombocytosis are not yet fully
      elucidated, tumor-derived factors with thrombopoietin-like activity and growth
      factors, platelet-derived microparticles, and factors secreted from bone marrow
      endothelial cells, as well as growth factors released by megakaryocytes (acting
      via an autocrine loop), are postulated to influence this process. The progression
      of cancer is associated with hypercoagulability, which results from direct
      influences of tumor cells and diverse indirect mechanisms. Activated platelets
      serve as procoagulant surfaces amplifying the coagulation reactions. It is well
      known that hemostatic proteins are involved in different steps of the angiogenic
      process. Furthermore, platelets adhering to endothelium facilitate adhesion of
      mononuclear cells (which exert various proangiogenic activities) to endothelial
      cells and their transmigration to the extravascular space. It was also documented
      that platelets induce angiogenesis in vivo. Platelets are a rich source of
      proangiogenic factors. They also store and release angiogenesis inhibitors. In
      addition, platelets express surface growth factor receptors, which may regulate
      the process of angiogenesis. Platelets also contribute directly to the process of
      basement membrane and extracellular matrix proteolysis by releasing proteinases,
      or indirectly via inducing endothelial cells and tumor cells to release
      proteolytic enzymes, as well as through the proteolytic activities of platelet
      derived growth factors. The multidirectional activities of platelets in the
      process of new blood vessel formation during tumor development and metastasis
      formation may create the possibility of introducing antiplatelet agents for
      antiangiogenic therapy in cancer patients. Thus far experimental studies
      employing inhibitors of glycoprotein IIb-IIIa have yielded promising results.

PMID- 15034802
TI  - Endothelial cell development, vasculogenesis, angiogenesis, and tumor
      neovascularization: an update.
AB  - In the embryo, blood vessel formation de novo (vasculogenesis) and from existing
      vessels (angiogenesis) results in blood vessels lined by endothelial cells (ECs).
      The relationship between ECs and blood cells suggested by their physical
      closeness was recently confirmed with the demonstration of progenitors that give
      rise to both cell types. In tumors, new blood vessel formation has been thought
      to occur primarily via angiogenesis. Recent evidence, however, suggests that
      postnatal vasculogenesis also contributes to tumor neovascularization. In this
      article, we provide an update on EC development, including early lineage
      specification, morphogenesis or differentiation to form functional blood vessels,
      and regulation of EC survival and senescence. Furthermore, we review the latest
      findings on tumor neovascularization and therapeutic potentials of molecules
      critical to this process.

PMID- 15034803
TI  - Eicosanoid regulation of angiogenesis in tumors.
AB  - Tumor angiogenesis, the formation of new capillary blood vessels in tumors from
      pre-existing vasculature, is required for tumor growth and progression.
      Eicosanoids, the bioactive lipids derived from arachidonic acid, possess potent
      and diverse biological activities. In response to stimuli, arachidonic acid is
      mobilized from phospholipid pools and metabolized by cyclooxygenases (COX),
      lipoxygenases (LOX), and p450 epoxygenases (EOX) to form a variety of
      eicosanoids. The involvement of eicosanoids in tumor angiogenesis and progression
      is implicated by the observations that nonsteroidal anti-inflammation drugs
      (NSAIDs) reduce tumor growth and angiogenesis. Subsequently, it is found that the
      levels of COX-2 and/or 12-LOX are frequently increased in various cancers.
      Further studies using molecular and pharmacological approaches have found that
      COX-2 and 12-LOX, when overexpressed in carcinoma cells, enhance their angiogenic
      potential and stimulate tumor growth. In this article, we discuss how COX and LOX
      in cancer cells modulate tumor angiogenesis and present the possibility of using
      NSAIDs and LOX inhibitors as antiangiogenesis agents.

PMID- 15034804
TI  - Mechanisms of thrombospondin-1-mediated metastasis and angiogenesis.
AB  - The major route of tumor spread is through the bloodstream. Once in circulation,
      the tumor cells aggregate in clumps with platelets, which enhances the tumor cell
      survival. The tumor emboli will then adhere to the endothelium and by the release
      of proteases extravasation of the cells will occur. One of the platelet-secreted
      proteins is thrombospondin-1. In this article, thrombospondin-1 will be described
      as a modulator of angiogenesis through its role in regulating endothelial cell
      apoptosis, protease expression, and vascular endothelial growth factor
      expression. We hope to convey the idea that activity of thrombospondin-1 in tumor
      progression is dependent upon its interaction with several host- and tumor
      associated proteins.

PMID- 15034805
TI  - The control of angiogenesis and tumor invasion by platelet factor-4 and platelet
      factor-4-derived molecules.
AB  - Platelet factor-4 (PF-4) is an ELR-negative chemokine that exhibits
      antiangiogenesis properties. PF-4 inhibits endothelial cell proliferation and
      migration, angiogenesis in vitro and in vivo, and tumor growth. However, tumor
      cells are not directly inhibited by PF-4. To date, a cell surface receptor that
      would explain the biological effects mediated by PF-4 has not been identified. PF
      4 is able to interact directly with angiogenesis growth factors such as
      fibroblast growth factors (FGFs) and vascular endothelial growth factors and
      inhibits their interaction with cell surface receptors. Furthermore, dimerization
      of fibroblast growth factors is abrogated by PF-4. Whether PF-4 plays a role as
      an endogenous angiogenesis regulator is at present not clear. Several PF-4
      fragments and modified molecules have been made that exhibit antiangiogenesis
      properties. Among these is a C-terminal fragment that has a defined structure,
      retains all the antiangiogenesis properties of the parent molecule, inhibits
      growth factor receptor binding, associates with FGFs, and destabilizes their
      three-dimensional structure. The relevance of these observations for the
      treatment of malignant disease is discussed.

PMID- 15034806
TI  - Interfering with hemostatic system components: possible new approaches to
      antiangiogenic therapy.
AB  - Inhibition of angiogenesis has progressed from a theoretical and esoteric
      discipline scrutinized in but a few laboratories far removed from the clinic, to
      mainstream experimental clinical cancer therapeutics. Dramatic progress in this
      field represents a triumph of the concept of translational biomedical research.
      Growth of knowledge in this discipline has brought to light a bewildering yet
      tantalizing array of interacting enzymatic algorithms that participate in the
      highly orchestrated process of new blood vessel formation critical for tumor
      growth and dissemination. It is clear that pathways of blood coagulation (in
      broad context) and angiogenesis are inextricably linked. The facts that much is
      already known about many components of these pathways and that stalling of tumor
      growth has already been demonstrated for several interventions aimed at
      participants in these reactions send a clear signal that more effective and less
      toxic cancer therapy may be at hand in the near future. There is no lack of
      candidate targets for intervention brought to light by preclinical scientists.
      Numerous well-characterized investigational agents are on hand for testing. The
      challenge is clearly in the hands of the clinical investigators to proceed with
      human intervention studies while armed with knowledge of opportunities and
      pitfalls that should guide insightful clinical trial design. A particularly
      compelling feature of this treatment paradigm is that it is not aimed directly at
      destruction of tumor through inhibition of the DNA replication machinery of the
      cell. Rather it is aimed at restoring the normal state by modulating the
      dysregulated interaction of tumor cells with their environment that is
      characteristic of cancer.

PMID- 15034808
TI  - Incorporating skin care into a facial plastic surgery practice.
AB  - Starting a skin care practice takes patience and dedication, but it provides your
      patients with a necessary service for a comprehensive facial plastic and
      reconstructive surgery practice. This article discusses the differences between
      physician-directed skin care and spa-directed skin care and emphasizes procedures
      that may be performed by an aesthetician in a physician's office. Skin care
      practice can be classified into skin care regimens: chemical peels,
      microdermabrasion, and makeup. Optimal skin care regimens incorporate
      pharmaceutical-grade ingredients, including tretinoin, topical vitamin C, and
      hydroquinone. Microdermabrasion and superficial chemical peels, such as glycolic,
      salicylic, and trichloroacetic acid peels, are discussed. Noninvasive procedures
      by the physician, such as Botox and laser treatments, complement the procedures
      performed by the aesthetician. However, the physician is ultimately responsible
      for the philosophy of the skin care practice. Patient education, customer
      service, and skin health are key ingredients for success.

PMID- 15034809
TI  - Facial rejuvenation using botulinum toxin A: review and updates.
AB  - The aesthetic applications of botulinum toxin A (Botox) are well known to certain
      medical and nonmedical communities. This nonsurgical rejuvenation modality
      continues to be in high demand in part because of the immediacy of its effects,
      its high safety profile, and its no-downtime recovery period. The physician
      interested in using Botox for facial rejuvenation needs to have a working
      knowledge of facial anatomy and botulinum toxin pharmacology and clinical
      experience with Botox injections.

PMID- 15034810
TI  - Review of injectable materials for soft tissue augmentation.
AB  - Although a variety of injectable agents are available for soft tissue
      augmentation, no perfect filler material exists. The advantages and disadvantages
      of commonly used materials such as bovine collagen have been well documented.
      However, many newer injectables are still undergoing experimentation to determine
      their clinical efficacy and long-term safety. This article details recent
      scientific work to compare injectable materials from the following categories:
      xenografts (bovine collagen and hyaluronic acid derivatives), autografts
      (autologous fat, Isolagen, and Autologen), homografts (Dermalogen and Cymetra),
      and synthetic materials (fluid silicone and Artecoll).

PMID- 15034811
TI  - Lip augmentation.
AB  - Lip augmentation has become increasingly popular in recent years as a reflection
      of cultural trends emphasizing youth and beauty. Techniques to enhance the
      appearance of the lips have evolved with advances in biotechnology. An
      understanding of lip anatomy and aesthetics forms the basis for successful
      results. We outline the pertinent anatomy and aesthetics of the preoperative
      evaluation. A summary of various filler materials available is provided.
      Augmentation options include both injectable and open surgical techniques. The
      procedures and materials currently favored by the authors are described in
      greater detail.

PMID- 15034812
TI  - Repair of the torn earlobe.
AB  - There exists a variety of techniques to repair torn earlobes. Some of these
      methods preserve the original earring hole during the earlobe repair, but many
      authors advocate complete closure of the torn earlobe and repiercing it at a
      later time. This article reviews the published techniques for earlobe repair.
      Illustrations accompany some of the different methods, and helpful
      recommendations are listed for a surgical approach to torn earlobes.

PMID- 15034813
TI  - Microdermabrasion: a review.
AB  - Microdermabrasion is used by clinicians and aestheticians worldwide to rejuvenate
      facial skin. The microdermabrator contains aluminum oxide or sodium chloride
      crystals that strike the skin and produce superficial trauma. It is theorized
      that the repetitive intraepidermal injury causes gradual improvement in damaged
      skin by stimulating fibroblast proliferation and collagen production, leading to
      new collagen deposition in the dermis. In this review of microdermabrasion, we
      discuss studies performed to elucidate the mechanism of action by which
      microdermabrasion promotes facial resurfacing. We also discuss other existing
      techniques for facial rejuvenation and resurfacing.

PMID- 15034814
TI  - Microcoblation: nonablative skin rejuvenation.
AB  - Microcoblation is the application of a controlled high-energy plasma field to
      intact aging skin. The treatment is nonablative and yields predictable,
      reversible histological changes in the epidermis, which result in skin
      rejuvenation. Recovery time and side effects are minimal. Although the mechanism
      of action is different, patient satisfaction with microcoblation compares very
      favorably with microdermabrasion, the traditional method of superficial skin
      rejuvenation.

PMID- 15034815
TI  - Nonablative resurfacing.
AB  - In expert hands, ablative laser resurfacing has a long history of excellent
      results in the treatment of photodamage-induced rhytids, depressed acne scars,
      and other signs of cutaneous aging. Over the last decade there have been a
      growing number of reports in the emerging area of nonablative resurfacing.
      Nonablative modalities provide less impressive clinical results for rhytid
      reduction but have shown particular promise for the treatment of scars and
      superficial dyschromias. It is also ideally suited for those patients seeking a
      minimally invasive, greatly reduced downtime procedure.

PMID- 15034816
TI  - Laser treatment of pigmented and vascular lesions in the office.
AB  - The treatment of vascular and pigmented lesions has been greatly improved since
      the introduction of laser technology. Utilizing the principles of selective
      photothermolysis, physicians can be very specific in their treatment, maximizing
      injury of the selected target and minimizing damage to surrounding structures.
      Treatment of vascular lesions is accomplished with a variety of wavelengths. The
      pulsed-dye laser system remains the gold standard with which all others are
      compared. A variety of advances in technology in recent years have greatly
      improved laser treatments. These include the addition of longer pulse widths,
      variable spot sizes, and a variety of skin-cooling techniques. With today's laser
      technology, most facial telangiectasias can be treated in a single session with
      minimal downtime. Angiomas often require more than one treatment. Port wine
      stains and hemangiomas still require multiple treatments, but treatment sessions
      are less painful and recovery is quicker. The treatment of pigmented lesions has
      also improved with new technology. Q-switched systems provide optimal treatment
      for most pigmented lesions. In general, superficial pigmented lesions are treated
      with shorter-wavelength systems, and deeper lesions are treated with longer
      wavelength systems. The CO2 laser continues to have a role in difficult-to-treat
      lesions.

PMID- 15034817
TI  - Practical considerations in the treatment of capillary vascular malformations, or
      port wine stains.
AB  - Port wine stains (PWSs) represent the most common type of vascular malformation.
      With the advent of pulsed-dye laser therapy, treatment of these lesions has
      become achievable with minimal prospect of adverse scarring. Although many
      scientific articles have heralded the favorable outcomes in patients who have
      undergone pulsed-dye laser treatments, few articles address the practical
      considerations (pre-, intra-, and postoperative) that must be followed to ensure
      success. This article presents the 10-year experience of the senior author (EFW)
      in the management of port wine malformations and the clinical insights that have
      been gleaned from that extensive experience. Introductory remarks are made as to
      the nature of PWSs, related syndromes, and the evolution of treatment; practical
      management guidelines are then discussed.

PMID- 15034818
TI  - Use of the KTP laser in the treatment of rosacea and solar lentigines.
AB  - Numerous techniques have evolved in facial plastic surgery to treat rosacea and
      solar lentigines. The treatment regimens range from avoidance of causative
      factors to the use of topical agents or other modalities that target the
      superficial layers of the skin. Of the modalities that target the epidermis,
      lasers offer the physician and patient the ability to target specific
      chromophores in the skin. Advances in laser technology led to the implementation
      of targeting certain characteristic pigments of abnormal areas with minimal
      damage to surrounding normal tissue. Rosacea and solar lentigines have
      characteristic cells that are targeted by a potassium-titanyl-phosphate (KTP)
      laser. The lesions are different in their origins but share the ability to be
      treated successfully with the KTP laser. A review of both conditions and other
      treatment options is discussed.

PMID- 15034819
TI  - Laser hair removal.
AB  - Laser hair removal is a minimally invasive cosmetic procedure that is well suited
      to the office-based practice. A great deal of improvement has occurred in the
      past 5 years with the technology and the understanding of how and for whom the
      procedure works. A review of the physics of laser-skin interactions is included
      as well as guidelines for safe and effective clinical treatments. Four
      wavelengths of lasers and intense light sources have proven successful for a
      variety of skin types. Average rates of long-term hair reduction, for properly
      treated subjects, are consistently reported between 70 and 90% at a minimum of 6
      months. When performed by physician extenders under the supervision of a
      physician, maximal use of time and resources can be achieved.

PMID- 15034820
TI  - Wound dressings for office-based surgery.
AB  - Since the turn of the 20th century, our understanding of wound healing has
      changed completely. Because of this, we now realize that wounds heal better under
      occlusive or semi-occlusive conditions. This revelation has led to the creation
      of a vast array of wound-dressing techniques and products that any office-based
      surgeon must use on a daily basis. This article reviews these techniques and
      products and offers the reader a framework of techniques that will help to
      achieve optimal surgical outcomes while at the same time maximize patient comfort
      and convenience.

PMID- 15034821
TI  - The public's response to severe acute respiratory syndrome in Toronto and the
      United States.
AB  - Using data from 13 surveys of the public, this article compares the public's
      response to severe acute respiratory syndrome (SARS) in Ontario (specifically,
      Toronto), the other Canadian provinces, and the United States, which had
      substantial differences in the number of SARS cases. Findings suggest that, even
      at a relatively low level of spread among the population, the SARS outbreak had a
      significant psychological and economic impact. They also suggest that the success
      of efforts to educate the public about the risk of SARS and appropriate
      precautions was mixed. Some of the community-wide problems with SARS might have
      been avoided with better communication by public health officials and clinicians.

PMID- 15034822
TI  - What is in a word?

PMID- 15034823
TI  - Role of infectious diseases consultants in management of antimicrobial use in
      hospitals.
AB  - The Infectious Diseases Society of America Emerging Infections Network (EIN)
      surveyed its members to characterize antimicrobial restriction policies in their
      hospitals and the involvement of infectious diseases consultants in this process.
      Of the 502 respondents (73%), 250 (50%) indicated that their hospital pharmacies
      would not dispense certain antimicrobials without approval of infectious diseases
      consultants. Moreover, 89% agreed that infectious diseases consultants need to be
      directly involved in the approval process. At hospitals with control policies,
      commonly restricted agents included lipid formulations of amphotericin B,
      carbapenems, fluoroquinolones, piperacillin-tazobactam, and vancomycin. Only 46
      EIN members (18%) reported remuneration of infectious diseases consultants for
      participation in the approval process. Pediatric infectious diseases consultants
      were more likely to practice in hospitals with restriction policies than were
      adult infectious diseases consultants (64% vs. 45%; P<.001). Similarly, teaching
      hospitals were more likely to have antimicrobial-control policies than were
      nonteaching facilities (60% vs. 17%; P<.001).

PMID- 15034824
TI  - Minimizing antimicrobial resistance: the key role of the infectious diseases
      physician.

PMID- 15034825
TI  - Elevated concentrations of CCL2 and tumor necrosis factor-alpha in chagasic
      cardiomyopathy.
AB  - Chronic myocarditis is the main pathological finding associated with Chagas
      disease-related morbidity. Concentrations of CCL2, CCL3, tumor necrosis factor
      (TNF)-alpha, and brain natriuretic peptide (BNP) were evaluated in plasma samples
      obtained from patients with different clinical forms of chronic chagasic
      cardiomyopathy. Patients with more-severe Chagas disease had elevated plasma
      concentrations of TNF-alpha, CCL2, and BNP, and there was a good correlation
      between levels of these proteins (especially TNF-alpha ) and the degree of heart
      dysfunction. Indeed, TNF-alpha level was an excellent predictor of heart failure.
      Peripheral blood mononuclear cell samples obtained from patients with mild or
      severe chagasic cardiomyopathy produced greater amounts of TNF-alpha and CCL2
      than did those obtained from noninfected individuals. The elevation of TNF-alpha
      and CCL2 levels in the plasma of patients appears to be secondary to the degree
      of heart dysfunction, whereas spontaneous production of TNF-alpha and CCL2 by
      mononuclear cells is secondary not only to heart dysfunction, but also to the
      underlying inflammation in the heart of chagasic patients. Measurement of the TNF
      alpha level could be a useful tool in the identification of patients with heart
      dysfunction who may benefit from further investigation and treatment.

PMID- 15034826
TI  - Short-course azithromycin for the treatment of uncomplicated typhoid fever in
      children and adolescents.
AB  - We studied 149 children and adolescents 3-17 years of age with clinical typhoid
      fever who were treated with either oral azithromycin (20 mg/kg per day; maximum
      dose, 1000 mg/day) or intravenous ceftriaxone (75 mg/day; maximum dose, 2.5
      g/day) daily for 5 days. Blood and stool specimens were obtained for culture
      before the initiation of therapy and were repeated on days 4 and 8 of treatment.
      Isolation of Salmonella enterica serovar Typhi or S. enterica serovar Paratyphi
      from the initial culture was required for inclusion in the final analysis. S.
      Typhi was isolated from 68 patients, 32 of whom were receiving azithromycin. Cure
      was achieved in 30 (94%) of 32 patients in the azithromycin group and in 35 (97%)
      of 36 patients in the ceftriaxone group (P=NS). Mean time to clearance of
      bacteremia was longer in the azithromycin group than in the ceftriaxone group. No
      patient who received azithromycin had a relapse, compared with 6 patients who
      received ceftriaxone. A 5-day course of azithromycin was found to be an effective
      treatment for uncomplicated typhoid fever in children and adolescents.

PMID- 15034827
TI  - Urticaria, exanthems, and other benign dermatologic reactions to smallpox
      vaccination in adults.
AB  - A phase 1 smallpox vaccine trial involving 350 adult volunteers was conducted. Of
      these subjects, 250 were naive to vaccinia virus vaccine (i.e., "vaccinia
      naive"). Volunteers received a new cell-cultured smallpox vaccine or a live
      vaccinia virus vaccine. Nine self-limiting rashes (3.6%) were observed in the
      vaccinia-naive group. None of the vaccinia-experienced patients had a rash.
      Rashes appeared 6-19 days after vaccination and had 5 different clinical
      presentations. Five volunteers had urticarial rashes that resolved within 4-15
      days, 1 had an exanthem that lasted 20 days, and 1 each presented with
      folliculitis, contact dermatitis, and erythematous papules found only on the
      hands and fingers. Volunteers reported pruritus, tingling, and occasional
      headaches. Relief was obtained with antihistamine and acetaminophen therapy. No
      volunteer experienced fever or significant discomfort.

PMID- 15034828
TI  - Large-scale evaluation of enzyme-linked immunospot assay and skin test for
      diagnosis of Mycobacterium tuberculosis infection against a gradient of exposure
      in The Gambia.
AB  - The purified protein derivative (PPD) skin test for Mycobacterium tuberculosis
      infection lacks specificity. We assessed 2 more specific M. tuberculosis antigens
      (ESAT-6 and CFP-10) by enzyme-linked immunospot assay (ELISPOT) compared with PPD
      by ELISPOT and skin test in The Gambia. Of 735 household contacts of 130 sputum
      smear-positive tuberculosis cases, 476 (65%) tested positive by PPD ELISPOT, 300
      (41%) tested positive by PPD skin test, and 218 (30%) tested positive by ESAT
      6/CFP-10 ELISPOT. Only 15 (2%) had positive ESAT-6/CFP-10 results and negative
      PPD results by ELISPOT. With increasing M. tuberculosis exposure, the percentage
      of subjects who were PPD skin test positive/ESAT-6/CFP-10 ELISPOT negative
      increased (P<.001), whereas the percentage of subjects who were PPD skin test
      negative/PPD ELISPOT positive decreased (P=.011). Eighteen (31%) ESAT-6/CFP-10
      ELISPOT-positive subjects in the lowest exposure category had negative PPD skin
      test results. ESAT-6/CFP-10 ELISPOT probably offers increased specificity in the
      diagnosis of M. tuberculosis infection in this tropical setting of endemicity, at
      the cost of some sensitivity.

PMID- 15034829
TI  - Intranasal influenza vaccine in a working population.
AB  - In the present study, we assessed the incidence of adverse events and influenza
      like symptoms in a working population in Switzerland that was vaccinated against
      influenza. A total of 12,582 individuals of working age (<65 years old) were
      offered a free influenza vaccine of their choice (injectable or intranasal
      vaccine) in October and November 2000. Of these individuals, 1600 were vaccinated
      against influenza. Ninety-seven percent of the vaccine recipients chose the
      intranasal vaccine, and 3% chose the injectable influenza vaccine. The incidence
      of influenza-like symptoms and side effects was 13% and 36%, respectively.
      Individuals who chose the intranasal vaccine were more likely to report side
      effects (OR, 3.23; 95% CI, 1.29-8.08). Facial paralysis was observed in 11
      patients and was the most severe adverse event associated with the intranasal
      influenza vaccine. As a result of these adverse events, the intranasal vaccine
      was removed from the market in the fall of 2001.

PMID- 15034830
TI  - Human metapneumovirus: a new player among respiratory viruses.
AB  - The human metapneumovirus (hMPV) is a newly described member of the
      Paramyxoviridae family belonging to the Metapneumovirus genus. Since its initial
      description in 2001, hMPV has been reported in most parts of the world and
      isolated from the respiratory tract of subjects from all age groups. Despite the
      fact that prospective and case-control studies have been limited, the
      epidemiology and clinical manifestations associated with hMPV have been found to
      be reminiscent of those of the human respiratory syncytial virus, with most
      severe respiratory tract infections occurring in infants, elderly subjects, and
      immunocompromised hosts. Additional research is needed to define the pathogenesis
      of this viral infection and the host's specific immune response.

PMID- 15034831
TI  - The strange case of Mr. Keats's tuberculosis.

PMID- 15034832
TI  - Daptomycin: another novel agent for treating infections due to drug-resistant
      gram-positive pathogens.
AB  - Daptomycin is a novel cyclic lipopeptide antibiotic that provides rapid
      bactericidal activity against gram-positive pathogens in vitro, including
      methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus,
      vancomycin-resistant S. aureus, penicillin-resistant Streptococcus pneumoniae,
      and ampicillin- and vancomycin-resistant enterococci. The United States Food and
      Drug Administration recently approved daptomycin for treatment of complicated
      skin and skin-structure infections. Its efficacy in the treatment of more-serious
      infections (e.g., staphylococcal bacteremia) is under investigation. As an
      intravenous agent that is administered once per day, it offers a convenient
      regimen for therapy that is continued after discharge, with a side effect profile
      that appears minimal and manageable. Spontaneous acquisition of resistance in
      vitro is rare, and hopefully this characteristic will extrapolate into the
      clinical setting. The rapid bactericidal activity, low potential for resistance,
      and promising safety profile associated with this agent will make it a useful
      addition to our growing armamentarium of antibiotics active against gram-positive
      pathogens.

PMID- 15034833
TI  - Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy:
      does HIV status matter?
AB  - To identify factors that affect normalization of laboratory measures after
      treatment for neurosyphilis, 59 subjects with neurosyphilis underwent repeated
      lumbar punctures and venipunctures after completion of therapy. The median
      duration of follow-up was 6.9 months. Stepwise Cox regression models were used to
      determine the influence of clinical and laboratory features on normalization of
      cerebrospinal fluid (CSF), white blood cells (WBCs), CSF protein concentration,
      CSF Venereal Disease Research Laboratory (VDRL) reactivity, and serum rapid
      plasma reagin (RPR) titer. Human immunodeficiency virus (HIV)-infected subjects
      were 2.5 times less likely to normalize CSF-VDRL reactivity than were HIV
      uninfected subjects. HIV-infected subjects with peripheral blood CD4+ T cell
      counts of < or =200 cells/ mu L were 3.7 times less likely to normalize CSF-VDRL
      reactivity than were those with CD4+ T cell counts of >200 cells/ mu L. CSF WBC
      count and serum RPR reactivity were more likely to normalize but CSF-VDRL
      reactivity was less likely to normalize with higher baseline values. Future
      studies should address whether more intensive therapy for neurosyphilis is
      warranted in HIV-infected individuals.

PMID- 15034834
TI  - The great pox.

PMID- 15034835
TI  - Clinical features related to antiphospholipid syndrome in patients with chronic
      viral infections (hepatitis C virus/HIV infection): description of 82 cases.
AB  - We analyzed the spectrum of clinical features related to antiphospholipid
      syndrome (APS) in patients with chronic viral infections, such as hepatitis C
      virus (HCV) infection and human immunodeficiency virus (HIV) infection. We
      selected patients from the HISPAMEC registry who repeatedly tested positive for
      antiphospholipid antibodies (aPL) and who had features of APS, and we searched
      the MEDLINE database for additional cases. A total of 82 patients were included
      (45 had chronic HCV infection, 32 had HIV infection, and 5 had HCV-HIV
      coinfection). The main features of APS were avascular bone necrosis (20
      patients), peripheral thrombosis (17), thrombocytopenia (15), neurologic features
      (13), cardiac manifestations (12), pulmonary embolism (9), gastrointestinal
      manifestations (8), and cutaneous manifestations (8). The main APS-related
      features in HCV-infected patients were intraabdominal thrombosis and myocardial
      infarction, whereas, in HIV-infected patients, the main features were avascular
      bone and cutaneous necrosis. These viruses might act in some patients as chronic
      triggering agents that induce a heterogeneous, atypical presentation of APS.

PMID- 15034836
TI  - Risk of metabolic abnormalities in patients infected with HIV receiving
      antiretroviral therapy that contains lopinavir-ritonavir.
AB  - The evolution of fasting glucose, triglyceride, and total and high-density
      lipoprotein (HDL) cholesterol level and the factors associated with development
      of clinically significant abnormalities in these metabolic parameters at 6 months
      were assessed in 353 consecutive human immunodeficiency virus (HIV)-infected
      patients who were receiving antiretroviral therapy containing lopinavir
      ritonavir. Although glucose and HDL cholesterol levels did not change,
      triglyceride and total cholesterol levels significantly increased (P<.0001 for
      each), as did the proportion of patients with a triglyceride level of >400 mg/dL
      and a total cholesterol level of >240 mg/dL (P=.002). A baseline triglyceride
      level of >400 mg/dL and a baseline total cholesterol level of >240 mg/dL were
      identified as independent factors predicting clinically significant
      hypertriglyceridemia and hypercholesterolemia, respectively, at 6 months. These
      findings may have clinical implications when the therapeutic option of lopinavir
      ritonavir is considered.

PMID- 15034837
TI  - Changes in hepatitis B virus DNA levels with acute HIV infection.
AB  - We hypothesized that acute infection with human immunodeficiency virus (HIV)
      would diminish immunoregulation of chronic hepatitis B (CHB), resulting in higher
      blood hepatitis B virus (HBV) DNA levels. To test this hypothesis, we evaluated
      sequential HBV DNA levels in stored serum samples obtained from 9 men with CHB
      who acquired HIV infection. Three patterns of changes in HBV DNA levels were
      noted after HIV seroconversion. One man experienced the expected increase in HBV
      DNA, 3 men had stable HBV DNA levels, and, unexpectedly, 5 men had a mean
      decrease of 6.29 log10 copies/mL in the HBV DNA level, with hepatitis B e antigen
      no longer detectable in 4. Acute HIV infection is not consistently associated
      with an increased blood HBV DNA level. Additional research is needed to
      understand the mechanism for the unexpected reductions in HBV DNA levels
      associated with acute HIV infection.

PMID- 15034838
TI  - Consideration of highly active antiretroviral therapy in the prevention and
      treatment of severe acute respiratory syndrome.
AB  - We observed that 0 of 19 patients with human immunodeficiency virus type 1 (HIV
      1) infection, including those with acquired immunodeficiency syndrome (AIDS), who
      were hospitalized together and who had close contact with 95 patients with severe
      acute respiratory syndrome (SARS) on the same hospital floor contracted SARS,
      whereas 6 of 28 medical workers who served on this floor contracted SARS while
      caring for these patients. Our investigation found that most of the patients with
      HIV-1/AIDS were receiving treatment of highly active antiretroviral therapy
      (HAART) during hospitalization. Coincidentally, a research group from Hong Kong
      recently reported that patients with SARS who received treatment with the anti
      HIV-1 drug lopinavir-ritonavir experienced significantly better clinical outcomes
      than did those who did not receive lopinavir-ritonavir. On the basis of these
      observations and studies, we propose that HAART should be considered for patients
      with SARS and their close contacts when the SARS epidemic reemerges.

PMID- 15034839
TI  - Interval between births and risk of congenital cytomegalovirus infection.
AB  - To examine the effect of the interval between maternal cytomegalovirus (CMV)
      infection and conception on the risk of congenital CMV infection, the congenital
      CMV infection rate was evaluated relative to the intervals between deliveries in
      young women. Among mothers who seroconverted between deliveries, the rate of
      congenital CMV infection among their offspring was highest when the delivery
      interval was < or =24 months. However, the risk of transmission remained elevated
      for women with delivery intervals of 25-48 months and for those with delivery
      intervals >48 months apart.

PMID- 15034840
TI  - Congenital cytomegalovirus infection and its prevention.

PMID- 15034841
TI  - Treatment of candidal cholangitis with caspofungin therapy in a patient with a
      liver transplant: documentation of biliary excretion of caspofungin.

PMID- 15034842
TI  - Haemophilus influenzae serotype e meningitis in an infant.

PMID- 15034843
TI  - Ribavirin-associated hemoglobinuria with treatment of hepatitis C virus
      infection.

PMID- 15034844
TI  - Central diabetes insipidus complicating West Nile encephalitis.

PMID- 15034846
TI  - Universal precautions studios presents: ID creature features.

PMID- 15034845
TI  - Apparent failure of moxifloxacin to prevent ciprofloxacin- and levofloxacin
      susceptible Pseudomonas aeruginosa bacteremia in neutropenic patients undergoing
      peripheral blood stem cell transplantation.

PMID- 15034847
TI  - Visual loss with West Nile virus infection: a wider spectrum of a "new" disease.
AB  - We describe a case of severe visual loss as a result of West Nile virus (WNV)
      infection. Associated headache and fever led to the proper diagnosis and
      management, but the findings of optic neuritis, retinitis, and uveitis were a
      surprising and prominent component of the patient's meningitis syndrome.
      Physicians diagnosing and treating patients with WNV infection should be alerted
      to the possibility of ocular and optic nerve involvement, which may leave
      permanent neuropathic residua.

PMID- 15034848
TI  - Lower-limb hypoplasia due to intrauterine infection with herpes simplex virus
      type 2: possible confusion with intrauterine varicella-zoster syndrome.
AB  - A neonate with lower-limb hypoplasia, cutaneous scars, bilateral chorioretinitis,
      and multiple brain abnormalities is presented. Intrauterine herpes simplex virus
      type 2 (HSV-2) infection was established on the basis of serological testing of
      the mother and viral cultures of the child's cutaneous lesions, obtained soon
      after birth. This is, to the best of our knowledge, the first case of a patient
      with in utero-acquired HSV-2 infection presenting with a limb hypoplasia. It
      illustrates that, in addition to congenital varicella-zoster syndrome, HSV-2
      infection should also be considered in patients presenting with limb hypoplasia.

PMID- 15034849
TI  - Legionella micdadei infection presenting as severe secretory diarrhea and a
      solitary pulmonary mass.
AB  - Sixty percent of infections with non-pneumophila species of Legionella are caused
      by Legionella micdadei. Although diarrhea is a common symptom of legionellosis,
      including that due to L. micdadei infection, severe, life-threatening diarrhea is
      rare. We describe a patient with profound secretory diarrhea (secretion rate, up
      to 8 L/day) that was secondary to culture-proven L. micdadei pneumonia. In
      addition, a 3-cm pulmonary nodule was detected, which completely resolved after
      proper treatment for Legionella infection. Resolving pulmonary nodules have been
      previously reported in association with treatment of L. micdadei infections.

PMID- 15034851
TI  - Stroke and neurodegenerative disorders. 2. Stroke: comorbidities and
      complications.
AB  - This self-directed learning module highlights diagnosis and treatment of
      comorbidities and complications encountered by patients with stroke. It is part
      of the study guide on stroke and neurodegenerative disorders in the Self-Directed
      Physiatric Education Program for practitioners and trainees in physical medicine
      and rehabilitation. This article specifically focuses on cardiopulmonary
      complications and examines neurologic sequelae, risk factors for falls, and
      prevention strategies. It also discusses upper-limb pain, fatigue, and depression
      and highlights diagnosis and management of genitourinary complications. OVERALL
      ARTICLE OBJECTIVE: To summarize common comorbidities and complications
      encountered by patients after stroke.

PMID- 15034850
TI  - Stroke and neurodegenerative disorders. 1. Acute stroke evaluation, management,
      risks, prevention, and prognosis.
AB  - This self-directed learning module highlights recent developments in the acute
      care of stroke patients, prediction of outcome after stroke, evaluation of risk
      factors, secondary prevention of stroke, and the evaluation of the young adult
      with stroke. It is part of the study guide on stroke and neurodegenerative
      disorders in the Self-Directed Physiatric Education Program for practitioners and
      trainees in physical medicine and rehabilitation. This article contains sections
      on the acute evaluation and management of the stroke patient, prediction of
      functional outcome after stroke, and secondary prevention of stroke. Special
      emphasis is given to the evaluation of the young adult with stroke. OVERALL
      ARTICLE OBJECTIVES: (a) To summarize the acute evaluation and management of
      stroke, particularly in the young stroke patient; and (b) to review the risk
      factors for stroke and secondary prevention measures.

PMID- 15034852
TI  - Stroke and neurodegenerative disorders. 3. Stroke: rehabilitation management.
AB  - This self-directed learning module highlights common rehabilitation issues in
      stroke survivors. Topics include spasticity, constraint-induced movement therapy,
      partial body weight-supported treadmill training, virtual reality training,
      vestibular retraining, aphasia treatment, and cognitive retraining. It is part of
      the study chapter on stroke and neurodegenerative disorders in the Self-Directed
      Physiatric Education Program for practitioners and trainees in physical medicine
      and rehabilitation. OVERALL ARTICLE OBJECTIVES: (a) To identify and review the
      treatment options for poststroke spasticity; (b) to review the use of body weight
      supported treadmill training in stroke patients; (c) to describe virtual reality
      training as an adjunct in stroke rehabilitation; (d) to review vestibular
      rehabilitation; (e) to discuss advances in aphasia treatment; (f) to discuss
      cognitive retraining; and (g) to provide an update on treatment of neglect
      syndromes.

PMID- 15034854
TI  - Rehabilitation of movement disorders.
AB  - This self-directed learning module highlights several movement disorders. These
      include dystonia, chorea, tremors, and myoclonus. A description of the clinical
      presentation and associated disease processes is presented. Although the
      discussion on treatment focuses on pharmacologic intervention, surgical options
      are presented when appropriate. Other movement disorders (ie, parkinsonism) are
      discussed elsewhere in the Study Guide. OVERALL ARTICLE OBJECTIVES: (a) To define
      the various symptoms and etiologies of dystonia; (b) to define chorea and its
      treatment; (c) to define tremors, including associated neurologic disorders, plus
      pharmacologic and potential surgical interventions; and (d) to describe the
      symptoms, classification, and treatment of primary and secondary myoclonus.

PMID- 15034853
TI  - Stroke and neurodegenerative disorders. 4. Neurodegenerative disorders.
AB  - This self-directed learning module highlights diagnosis, treatment, and
      rehabilitation issues in patients with neurodegenerative disorders, including
      multiple sclerosis (MS), Parkinson's disease, and amyotrophic lateral sclerosis
      (ALS). It is part of the study guide on stroke and neurodegenerative disorders in
      the Self-Directed Physiatric Education Program for practitioners and trainees in
      physical medicine and rehabilitation. This article specifically focuses on the
      differential diagnosis, diagnostic evaluation, medical management, and
      rehabilitation issues in MS. Similarly, the differential diagnosis treatment and
      rehabilitation in Parkinson's disease is discussed. Electrodiagnosis,
      pharmacologic treatment, and rehabilitation options for ALS are also discussed.
      OVERALL ARTICLE OBJECTIVES: To review the differential diagnosis, evaluation,
      medical treatment, and rehabilitation management of patients with MS, Parkinson's
      disease, and ALS.

PMID- 15034855
TI  - Sports and performing arts medicine. 1. General considerations for sports and
      performing arts medicine.
AB  - This self-directed learning module highlights general considerations in sports
      and performing arts medicine. It is part of the study guide on sports and
      performing arts medicine in the Self-Directed Physiatric Education Program for
      practitioners and trainees in physical medicine and rehabilitation. OVERALL
      ARTICLE OBJECTIVE: To discuss similarities and differences of injuries sustained
      in sports and performing arts using case vignettes.

PMID- 15034857
TI  - Sports and performing arts medicine. 3. Lower-limb injuries in endurance sports.
AB  - This self-directed learning module highlights new advances in this topic area. It
      is part of the study guide on sports medicine and performing arts in the Self
      Directed Physiatric Education Program for practitioners and trainees in physical
      medicine and rehabilitation. This article uses case vignettes as a vehicle to
      elaborate on (1) ankle pain in a runner, (2) heel pain in an adolescent, (3)
      anterior knee pain in a runner, (4) lateral knee pain in a cyclist, (5) shin
      splints in a runner, (6) buttock pain in a hiker, and (7) collapse of a
      marathoner from hyponatremia. OVERALL ARTICLE OBJECTIVE: To summarize lower-limb
      injuries commonly seen in endurance sports.

PMID- 15034856
TI  - Sports and performing arts medicine. 2. Shoulder and elbow overuse injuries in
      sports.
AB  - This self-directed learning module discusses classic topics and highlights new
      advances in this area. This article discusses upper-limb sports injuries as part
      of a section of the study guide on sports and performing arts medicine in the
      Self-Directed Physiatric Education Program for practitioners and trainees in
      physical medicine and rehabilitation. This article uses case vignettes as a
      vehicle to elaborate on shoulder and elbow pain in the athlete. OVERALL ARTICLE
      OBJECTIVE: To discuss shoulder and elbow overuse injuries in sports.

PMID- 15034858
TI  - Sports and performing arts medicine. 4. Traumatic injuries in sports.
AB  - This self-directed learning module focuses on injuries often seen in contact
      sports. It includes information on trauma to the cervical spine, wrist, shoulder,
      knee, ankle, foot, and chest and also discusses concussion in sport. It is part
      of the study guide on sports and performing arts medicine in the Self-Directed
      Physiatric Education Program for practitioners and trainees in physical medicine
      and rehabilitation. This article specifically focuses on the etiology,
      differential diagnoses, treatment, and return-to-play criteria for traumatic
      sports injuries. OVERALL ARTICLE OBJECTIVE: To summarize the approach to common
      traumatic sports injuries.

PMID- 15034859
TI  - Sports and performing arts medicine. 5. Issues relating to musicians.
AB  - This self-directed learning module discusses classic topics and highlights new
      advances in this topic area. This article, which discusses upper-limb injuries in
      musicians, is a section of the study guide on sports and performing arts medicine
      in the Self-Directed Physiatric Education Program for practitioners and trainees
      in physical medicine and rehabilitation. This article uses case vignettes to
      elaborate on issues relating to musicians. OVERALL ARTICLE OBJECTIVE: To
      summarize overuse injury, nerve entrapment, and focal dystonia in instrumental
      musicians.

PMID- 15034860
TI  - Sports and performing arts medicine. 6. Issues relating to dancers.
AB  - This self-directed study module highlights biomechanics unique to dance that
      predispose to common injuries of the lower extremity and discusses preventative
      strategies. It is part of the study guide on sports and performing arts medicine
      in the Self-Directed Physiatric Education Program for practitioners and trainees
      in physical medicine and rehabilitation. OVERALL ARTICLE OBJECTIVE: To summarize
      lower-limb and back injuries commonly seen in dancers.

PMID- 15034861
TI  - Core strengthening.
AB  - Core strengthening has become a major trend in rehabilitation. The term has been
      used to connote lumbar stabilization, motor control training, and other regimens.
      Core strengthening is, in essence, a description of the muscular control required
      around the lumbar spine to maintain functional stability. Despite its widespread
      use, core strengthening has had meager research. Core strengthening has been
      promoted as a preventive regimen, as a form of rehabilitation, and as a
      performance-enhancing program for various lumbar spine and musculoskeletal
      injuries. The intent of this review is to describe the available literature on
      core strengthening using a theoretical framework. OVERALL ARTICLE OBJECTIVE: To
      understand the concept of core strengthening.

PMID- 15034862
TI  - Role of inherited defects of MYH in the development of sporadic colorectal
      cancer.
AB  - Biallelic germ-line variants of the 8-hydroxyguanine repair gene MYH have been
      associated with multiple colorectal adenomas that display somatic G:C-->T:A
      transversions in APC. However, the effect of single germ-line variants has not
      been widely studied. To examine the relationship between monoallelic MYH variants
      and susceptibility to sporadic colorectal cancer (CRC), 92 cases of sporadic CRC,
      19 cases of familial CRC not meeting the Bethesda guidelines, 17 cases with
      multiple adenomas, and 53 normal blood donors were screened for 8 potentially
      pathogenic germ-line MYH variants. Loss of heterozygosity (LOH) at 1p adjacent to
      the MYH locus, microsatellite instability (MSI) status, and somatic mutations in
      KRAS2 and APC were analyzed in sporadic cancers. Neither homozygote nor compound
      heterozygote MYH variants were observed in the germ-line of any subjects with
      sporadic CRC. There was no difference in the incidence of monoallelic variants
      between this group (20 of 92, 22%) and cancer-free controls (14 of 53, 26%).
      However, the presence of monoallelic germ-line MYH variants was negatively
      associated with an MSI-high (MSI-H) tumor phenotype, with an incidence of only 1
      of 23 (4%) MSI-H CRCs as contrasted with 19 of 69 (28%) non-MSI-H (P=0.02).
      Further, 4 of 5 tumors with 1p LOH contained monoallelic MYH variants compared
      with 15 of 53 without 1p LOH (P=0.04) and the normal population (P=0.03). The
      presence of G:C-->T:A transversions in KRAS2 or APC was significantly more common
      in single MYH variant tumors (9 of 12) than in MYH wild-type tumors (11 of 33;
      P=0.02). These results suggest that single germ-line variants of MYH may
      influence genetic pathways in CRC.

PMID- 15034863
TI  - Interphase fluorescence in situ hybridization for detection of 8q24/MYC
      breakpoints on routine histologic sections: validation in Burkitt lymphomas from
      three geographic regions.
AB  - A chromosomal translocation involving the MYC gene is characteristic of Burkitt
      lymphoma (BL) and represents a molecular disease marker with diagnostic and
      clinical implications. The detection of MYC breakpoints is hampered by technical
      problems, including the distribution of the breakpoints over a very large genomic
      region of approximately 1,000 kb. In this article, we report on the testing and
      validation of a segregation fluorescence in situ hybridization (FISH) assay for
      MYC breakpoints on a large series of BLs. A contig of overlapping genomic clones
      was generated, and two probe sets flanking the MYC gene were selected. Both probe
      sets were tested in an interphase FISH segregation assay on 8 B-cell lymphoma
      cell lines and 32 lymphoma samples with proved 8q24/MYC abnormalities and
      validated in 47 BLs from The Netherlands, Brazil, and Uganda. MYC translocation
      breakpoints were identified in 98% of the tumors of the test series and in 89% of
      the cases of the validation series. In 89% of all positive samples, the
      breakpoints were located between 190 kb 5' and 50 kb 3' of MYC. Nine cases had
      more distant breakpoints, and in one patient an insertion of MYC into the IGH
      region was detected. In two of the three BLs lacking CD10 expression, no
      breakpoint could be detected, suggesting that CD10 is a discriminative marker of
      BL. We did not find consistent differences between BL and atypical BL in
      incidence of an MYC breakpoint.

PMID- 15034864
TI  - Gene copy mapping of the ERBB2/TOP2A region in breast cancer.
AB  - ERBB2 is one of the most important oncogenes in breast cancer, and its disordered
      expression is commonly associated with gene amplification. Amplification of at
      least one gene near ERBB2, topoisomerase IIalpha (TOP2A), has been shown to be
      clinically significant, but the prevailing patterns of gene amplification in this
      region of chromosome arm 17q have not been studied systematically in clinical
      cases of breast cancer. For characterizing this region, a commercial ERBB2
      containing contig probe and 7 probes prepared from single overlapping BAC and P1
      clones lying telomeric to ERBB2 and including TOP2A were hybridized to 77 ERBB2
      amplified archival breast tumor specimens from 75 patients. The 7 single-clone
      probes covered a region of approximately 650 kb starting 114 kb telomeric to
      ERBB2. Amplification of the ERBB2 contig target alone was found in 32% of the
      tumors, whereas all 8 probe targets were amplified in 12% of the tumors, based on
      an amplification criterion of there being more than or equal to 2 targets per
      chromosome 17 centromere. When one of the 7 overlapping probes encompassing TOP2A
      indicated amplification within a specimen, all probes telomeric to that probe
      usually showed amplification. Only 5 specimens had regions of normal or deleted
      targets separating 2 amplified targets. Also, tumors that showed deletion of
      TOP2A usually showed deletion of one or more contiguous targets. The observed
      patterns of amplification and deletion are consistent with the break-fusion
      bridge model for gene amplification. TOP2A was amplified in 25% of all tumor
      specimens and was deleted in 24%, based on a deletion criterion of there being
      fewer than or equal to 0.75 targets per chromosome 17 centromere. Considering the
      relevance of the TOP2A gene product to anthracycline therapy and the wealth of
      other cancer-associated genes within the ERBB2/TOP2A region, the pattern of
      amplification and deletion near ERBB2 and TOP2A may have a dramatic effect on the
      malignant potential of breast carcinomas and their response to therapy.

PMID- 15034866
TI  - Identification of preleukemic precursors of hyperdiploid acute lymphoblastic
      leukemia in cord blood.
AB  - Previous studies involving identical twins with concordant leukemia and
      retrospective scrutiny of archived neonatal blood spots have shown that common
      chromosome translocations of pediatric leukemia frequently arise before birth.
      The IGH/TCR clonotypic sequences used as surrogate molecular markers suggest this
      is also likely to be true for hyperdiploid acute lymphoblastic leukemia (ALL).
      Yet evidence that hyperdiploidy itself is an early or initiating event occurring
      prenatally has been limited. Now, however, we can provide direct evidence of this
      from our identification of CD34+/CD19+ B-lineage progenitor cells with triploid
      chromosomes in the stored cord blood of an individual who subsequently developed
      hyperdiploid ALL.

PMID- 15034865
TI  - ASK1 (MAP3K5) as a potential therapeutic target in malignant fibrous
      histiocytomas with 12q14-q15 and 6q23 amplifications.
AB  - Malignant fibrous histiocytomas (MFHs) are aggressive tumors without any
      definable line of differentiation. We recently demonstrated that about 20% of
      them are characterized by high-level amplifications of the 12q14-q15 chromosome
      region, associated with either 1p32 or 6q23 band amplification. This genetic
      finding, very similar to that in well-differentiated liposarcomas, strongly
      suggests that these tumors actually correspond to undifferentiated liposarcomas.
      It also suggests that the lack of differentiation could be the consequence of
      amplification of target genes localized in the 1p32 or 6q23 bands. We report here
      the characterization by array CGH of the 6q23 minimal region of amplification.
      Our findings demonstrate that amplification and overexpression of ASK1 (MAP3K5),
      a gene localized in the 6q23 band and encoding a mitogen-activated protein kinase
      kinase kinase of the JNK-MAPK signaling pathway, could inhibit the adipocytic
      differentiation process of the tumor cells. Treatment of a cell line with
      specific inhibitors of ASK1 protein resulted in the bypass of the differentiation
      block and induction of a strong adipocytic differentiation. These observations
      indicate that ASK1 is a target for new therapeutic management of these aggressive
      tumors.

PMID- 15034868
TI  - Estrogen receptor alpha (ESR1) mutant A908G is not a common feature in benign and
      malignant proliferations of the breast.
AB  - Alterations in estrogen responsive pathways are thought to contribute to benign
      and malignant breast disease. It has been reported previously that more than a
      third of typical epithelial hyperplasia lesions harbor the missense mutation
      A908G in the estrogen receptor alpha (ESR1) gene. This substitution of an
      arginine for a lysine at codon 303 was reported to confer mitogenic
      hypersensitivity to estrogen. To explore this finding further, we analyzed ESR1
      for this mutation in a series of breast tissues ranging from typical hyperplasia
      to invasive cancer. In contrast to previous studies, no evidence for this
      mutation was found in 36 invasive cancers, 11 in situ carcinomas, 14 epithelial
      hyperplasias with atypia, 11 epithelial hyperplasias without atypia, and 11
      breast cancer cell lines. These results indicate that ESR1 mutant A908G does not
      occur with significant frequency in either benign or malignant proliferations of
      breast epithelia.

PMID- 15034867
TI  - Molecular and cytogenetic characterization of a novel translocation t(4;22)
      involving the breakpoint cluster region and platelet-derived growth factor
      receptor-alpha genes in a patient with atypical chronic myeloid leukemia.
AB  - We report a case of BCR-ABL-negative atypical chronic myeloid leukemia (CML) with
      translocation t(4;22) (q12;q11.2) juxtaposing the breakpoint cluster region (BCR)
      and platelet-derived growth factor receptor-alpha (PDGFRA) genes. The patient was
      a 57-year-old man with a history of stage IV diffuse large B-cell lymphoma,
      status post-6 cycles of combination chemotherapy in 1999, who presented in August
      2002 with enlarged lymph nodes, anemia, and marked leukocytosis (50 x 10(9) g/dL)
      consistent with a myeloproliferative disorder (MPD). A bone marrow biopsy showed
      granulocytic hyperplasia, neutrophilia, and mild eosinophilia. Initial
      cytogenetic evaluation by interphase FISH for BCR-ABL, to rule out a
      translocation 9;22, showed a variant signal pattern consistent with rearrangement
      of BCR at 22q11.2, but not ABL at 9q34. Analysis of the patient's cDNA by
      polymerase chain reaction (PCR) for BCR-ABL was negative. Cytogenetic analysis
      showed an abnormal karyotype with rearrangement of chromosomes 4 and 22. PCR
      amplification and subsequent sequence analysis demonstrated an in-frame 5'-BCR/3'
      PDGFRA fusion in the patient's cDNA. PDGFRA encodes a receptor tyrosine kinase
      and shares structural and organizational homology with the KIT and CSf1R receptor
      genes. However, although the incidence of MPD involving translocations of PDGFRB
      has been well established, to our knowledge there are only two previous reports
      describing a BCR-PDGFRA fusion gene, in 3 patients diagnosed with atypical CML.
      Here, we report the molecular and cytogenetic characterization of a patient with
      BCR-PDGFRA-positive MPD who had a complete hematologic response after treatment
      with imatinib mesylate.

PMID- 15034869
TI  - Gene amplification of atypical PKC-binding PARD3 in radiation-transformed
      neoplastic retinal pigment epithelial cell lines.
AB  - Neoplastic transformation induced by ionizing radiation was studied using a human
      retinal pigment epithelial cell line immortalized by telomerase. Radiation
      transformed cell clones were tumorigenic in athymic mice and were analyzed by G
      banding and comparative genomic hybridization (CGH). Radiation-transformed cloned
      cell lines and cell lines derived from tumors produced in athymic nude mice
      following transplantation exhibited a recurrent karyotype:45,XX,der(10),-13. CGH
      showed an amplification of 10p11.2 and a deletion of the remaining 10p.
      Positional cloning of the amplified region by FISH analysis and subsequent
      sequence analysis of BAC clones showing amplified FISH signals identified the
      candidate gene PARD3. This gene also was found to be transcriptionally expressed
      at an increased level. The findings indicate that PARD3 may play an important
      role in radiation-induced carcinogenesis of RPE cells. This is the first evidence
      for PARD3 amplification in human cancer cells.

PMID- 15034870
TI  - Delineation of a minimal region of deletion at 6q16.3 in follicular lymphoma and
      construction of a bacterial artificial chromosome contig spanning a 6-megabase
      region of 6q16-q21.
AB  - Regional deletions of 6q are frequent karyotypic alterations in malignant
      lymphoma and are associated with an adverse clinical outcome. One such region of
      recurrent deletion is 6q16-q21; however, the specific genes affected have not
      been identified. Our objective in this study was to identify cases with deletion
      of 6q16-q21 in follicular lymphoma and to define a minimal region of deletion. A
      physical map of 6q16.2-q21 was constructed using map information from both
      sequence-based and bacterial artificial chromosome (BAC) fingerprint-based maps.
      Forty-three BAC clones spanning a 6-Mb region of 6q16.2-q21 were identified and
      obtained from the RP-11 library. Selected BACs were fluorescence-labeled and
      hybridized to a series of 34 follicular lymphomas with a regional 6q deletion
      detected by G banding. Twenty-four cases with deletion of the 6q16.3 region were
      detected. A minimal deletion of 2.3 Mb was defined. Our study has identified a
      limited region of deletion of 6q16.3 that may implicate four known genes in
      follicular lymphoma and possibly in other cancers. A BAC contig spanning a 6-Mb
      region has been anchored to the 6q16.2-q21 region. This map represents a useful
      resource for gene identification in this region, not only in lymphoma but also in
      other neoplasms with 6q alterations.

PMID- 15034871
TI  - Computational BAC clone contig assembly for comprehensive genome analysis.
AB  - Comparative genomic hybridization (CGH) has proved to be a powerful tool for the
      detection of genome copy number changes in human cancers and in other diseases
      caused by segmental aneusomies. Array versions of CGH allow the definition of
      these aberrations, with resolution determined by the size and distribution of the
      array elements. Resolution approaching 100 kb can be achieved by use of arrays
      comprising bacterial artificial chromosomes (BACs) distributed contiguously
      across regions of interest. We describe here a computer program that
      automatically assembles contigs of minimally overlapping BAC clones, using
      information about BAC end-sequences and the normal genome DNA sequence. We
      demonstrate the characteristics of contigs assembled and annotated by use of this
      approach for regions of recurrent abnormality in human ovarian and breast cancers
      at chromosome bands 3q25-q27 and 8q24 and chromosome arm 20q. We also show
      illustrative analyses of regions of amplification in these regions in breast and
      ovarian tumor cell lines by use of array CGH with arrays comprising contiguous
      BACs.

PMID- 15034872
TI  - Method for manufacturing whole-genome microarrays by rolling circle
      amplification.
AB  - Comparative genomic hybridization (CGH) to metaphase chromosomes is a method for
      genome-wide detection of chromosomal aberrations in DNA samples. Recent advances
      in microarray technology have improved CGH by replacing metaphase chromosomes
      with a collection of mapped genomic clones placed on glass slides. However, it is
      quite expensive and labor-intensive to prepare DNA from the genomic clones for
      use in constructing genomic microarrays. Here we used strand-displacement rolling
      circle amplification (RCA) to manufacture whole-genome microarrays by using a
      collection of about 4,500 mapped RPCI-11 BAC clones that cover the human genome
      at approximately a 1-Mb resolution. These genomic microarrays detected all major
      chromosomal aberrations in cancer cells lines and in cell lines with aneuploidy.
      In this article, we discuss the advantages of using RCA for the manufacturing of
      large genomic microarrays.

PMID- 15034876
TI  - Nanostructured polyaniline sensors.
AB  - The conjugated polymer polyaniline is a promising material for sensors, since its
      conductivity is highly sensitive to chemical vapors. Nanofibers of polyaniline
      are found to have superior performance relative to conventional materials due to
      their much greater exposed surface area. A template-free chemical synthesis is
      described that produces uniform polyaniline nanofibers with diameters below 100
      nm. The interfacial polymerization can be readily scaled to make gram quantities.
      Resistive-type sensors made from undoped or doped polyaniline nanofibers
      outperform conventional polyaniline on exposure to acid or base vapors,
      respectively. The nanofibers show essentially no thickness dependence to their
      sensitivity.

PMID- 15034873
TI  - Identification of a novel gene, FGFR1OP2, fused to FGFR1 in 8p11
      myeloproliferative syndrome.
AB  - The 8p11 myeloproliferative syndrome (EMS) is an aggressive hematological
      malignancy caused by the fusion of diverse partner genes to fibroblast growth
      factor receptor 1 (FGFR1). The partner proteins promote dimerization and ligand
      independent activation of FGFR1-encoded tyrosine kinase, deregulating hemopoiesis
      in a manner analogous to BCR-ABL in chronic myeloid leukemia. Here, we describe
      the identification of a new FGFR1 fusion gene in a patient who presented with T
      cell lymphoblastic lymphoma in conjunction with an acquired
      ins(12;8)(p11;p11p22). Initial FISH analysis and Southern blotting confirmed that
      FGFR1 was disrupted. Using 5'-RACE PCR, we identified part of a novel gene,
      FGFR1OP2, at chromosome band 12p11 that was fused to exon 9 of FGFR1.FGFR1OP2 is
      predicted to be translated into an evolutionarily conserved protein containing
      coiled-coil domains but no other recognizable motifs. The presence of the
      chimeric gene was confirmed by RT-PCR, genomic DNA PCR, and FISH. These data
      further support the central role of deregulated FGFR1 in the pathogenesis of EMS.

PMID- 15034877
TI  - Shape-persistent macrocycles: from molecules to materials.
AB  - Shape-persistent macrocycles with an interior in the nanometer regime allow the
      attachment of (functional) side groups at defined positions at the ring. These
      side groups can have either a fixed orientation relative to the molecular
      backbone or they can adapt their orientation according to an external stimulus.
      The properties and applications of the compounds depend strongly on the
      orientation of these side groups. Macrocycles with intraannular or adaptable long
      alkyl groups display a new design principle for discotic liquid crystals.
      Macrocycles with extraannular (oligo)alkyl groups can be used for surface
      patterning in the nanometer regime and rings with extraannular oligostyryl groups
      are able to aggregate to supramolecular hollow polymer brushes.

PMID- 15034879
TI  - Ligand design for alkali-metal-templated self-assembly of unique high-nuclearity
      CuII aggregates with diverse coordination cage units: crystal structures and
      properties.
AB  - The construction of two unique, high-nuclearity Cu(II) supramolecular aggregates
      with tetrahedral or octahedral cage units, [(mu(3)-Cl)[Li subset Cu(4)(mu
      L(1))(3)](3)](ClO(4))(8)(H(2)O)(4.5) (1) and [[Na(2) subset Cu(12)(mu-L(2))(8)(mu
      Cl)(4)](ClO(4))(8)(H(2)O)(10)(H(3)O(+))(2)](infinity) (2) by alkali-metal
      templated (Li(+) or Na(+)) self-assembly, was achieved by the use of two newly
      designed carboxylic-functionalized diazamesocyclic ligands, N,N'-bis(3
      propionyloxy)-1,4-diazacycloheptane (H(2)L(1)) or 1,5-diazacyclooctane-N,N'
      diacetate acid (H(2)L(2)). Complex 1 crystallizes in the trigonal R3c space group
      (a = b = 20.866(3), c = 126.26(4) A and Z = 12), and 2 in the triclinic P1 space
      group (a = 13.632(4), b = 14.754(4), c = 19.517(6) A, alpha = 99.836(6), beta =
      95.793(5), gamma = 116.124(5) degrees and Z = 1). By subtle variation of the
      ligand structures and the alkali-metal templates, different polymeric motifs were
      obtained: a dodecanuclear architecture 1 consisting of three Cu(4) tetrahedral
      cage units with a Li(+) template, and a supramolecular chain 2 consisting of two
      crystallographically nonequivalent octahedral Cu(6) polyhedra with a Na(+)
      template. The effects of ligand functionality and alkali metal template ions on
      the self-assembly processes of both coordination supramolecular aggregates, and
      their magnetic behaviors are discussed in detail.

PMID- 15034878
TI  - Synthesis and properties of para-substituted NCN-pincer palladium and platinum
      complexes.
AB  - A variety of para-substituted NCN-pincer palladium(II) and platinum(II) complexes
      [MX(NCN-Z)] (M=Pd(II), Pt(II); X=Cl, Br, I; NCN-Z=[2,6-(CH(2)NMe(2))(2)C(6)H(2)-4
      Z](-); Z=NO(2), COOH, SO(3)H, PO(OEt)(2), PO(OH)(OEt), PO(OH)(2), CH(2)OH, SMe,
      NH(2)) were synthesised by routes involving substitution reactions, either prior
      to or, notably, after metalation of the ligand. The solubility of the pincer
      complexes is dominated by the nature of the para substituent Z, which renders
      several complexes water-soluble. The influence of the para substituent on the
      electronic properties of the metal centre was studied by (195)Pt NMR spectroscopy
      and DFT calculations. Both the (195)Pt chemical shift and the calculated natural
      population charge on platinum correlate linearly with the sigma(p) Hammett
      substituent constants, and thus the electronic properties of predesigned pincer
      complexes can be predicted. The sigma(p) value for the para-PtI group itself was
      determined to be -1.18 in methanol and -0.72 in water/methanol (1/1). Complexes
      substituted with protic functional groups (CH(2)OH, COOH) exist as dimers in the
      solid state due to intermolecular hydrogen-bonding interactions.

PMID- 15034881
TI  - Is water templating nanoporous materials?
AB  - (H(2)O)(17), a cluster with pentagonal water arrangements, squeezed in the
      sodalite cage of the crystal structure MIL-74
      (Zn(6)Al(12)P(24)O(96).[N(CH(2)CH(2)NH(3))(3)](8).(H(2)O)(34)), has its oxygen
      atoms well located by X-ray powder diffraction. Positioning of hydrogen atoms has
      been performed by a dynamic partial atomic charges and hardnesses analysis
      calculation, in which partial charges are recalculated for each hydrogen sub
      network modification. Hydrogen atoms are therefore positioned by energy
      minimization. A quantitative estimation of the hydrogen bonds energy for each H
      bond and for the network in the MIL-74 nanoporous compound has been obtained.
      This result allows a discussion of the effect of imprinting the nanoporous
      structure onto water or alternatively the templating effect of the cluster onto
      the inorganic framework.

PMID- 15034882
TI  - A rationale for the large breathing of the porous aluminum terephthalate (MIL-53)
      upon hydration.
AB  - Aluminum 1,4-benzenedicarboxylate Al(OH)[O(2)C-C(6)H(4)-CO(2)]. [HO(2)C-C(6)H(4)
      CO(2)H](0.70) or MIL-53 as (Al) has been hydrothermally synthesized by heating a
      mixture of aluminum nitrate, 1,4-benzenedicarboxylic acid, and water, for three
      days at 220 degrees C. Its 3 D framework is built up of infinite trans chains of
      corner-sharing AlO(4)(OH)(2) octahedra. The chains are interconnected by the 1,4
      benzenedicarboxylate groups, creating 1 D rhombic-shaped tunnels. Disordered 1,4
      benzenedicarboxylic acid molecules are trapped inside these tunnels. Their
      evacuation upon heating, between 275 and 420 degrees C, leads to a nanoporous
      open-framework (MIL-53 ht (Al) or Al(OH)[O(2)C-C(6)H(4)-CO(2)]) with empty pores
      of diameter 8.5 A. This solid exhibits a Langmuir surface area of 1590(1) m(2)g(
      1) together with a remarkable thermal stability, since it starts to decompose
      only at 500 degrees C. At room temperature, the solid reversibly absorbs water in
      its tunnels, causing a very large breathing effect and shrinkage of the pores.
      Analysis of the hydration process by solid-state NMR ((1)H, (13)C, (27)Al) has
      clearly indicated that the trapped water molecules interact with the carboxylate
      groups through hydrogen bonds, but do not affect the hydroxyl species bridging
      the aluminum atoms. The hydrogen bonds between water and the oxygen atoms of the
      framework are responsible for the contraction of the rhombic channels. The
      structures of the three forms have been determined by means of powder X-ray
      diffraction analysis. Crystal data for MIL-53 as (Al) are as follows:
      orthorhombic system, Pnma (no. 62), a = 17.129(2), b = 6.628(1), c = 12.182(1) A;
      for MIL-53 ht (Al), orthorhombic system, Imma (no. 74), a = 6.608(1), b =
      16.675(3), c = 12.813(2) A; for MIL-53 lt (Al), monoclinic system, Cc (no. 9), a
      = 19.513(2), b = 7.612(1), c = 6.576(1) A, beta = 104.24(1) degrees.

PMID- 15034880
TI  - Magneto-structural characterization of metallocene-bridged nitronyl nitroxide
      diradicals by X-Ray, magnetic measurements, solid-state NMR spectroscopy, and ab
      initio calculations.
AB  - Crystallization of ferrocene and ruthenocene substituted in the 1- and 1'
      positions by two nitronyl nitroxide radicals gave the new crystal phases beta-1
      (besides the known phase alpha-1), alpha-2, and beta-2 whose structures were
      determined by X-ray analysis. In beta-1 the radical moieties adopt transoid
      positions, whereas two different cisoid conformations are adopted by alpha-2 and
      beta-2. These conformations result from inter- and intramolecular hydrogen bonds,
      respectively. All compounds experience antiferromagnetic interactions, and J/k(B)
      values up to -7 K have been found by fitting the experimental magnetic
      susceptibilities to a modified Bleaney-Bowers equation. The solid diradicals
      alpha-1, beta-1, alpha-2, and beta-2 as well as the ferrocene 3, which was
      substituted by a unique nitronyl nitroxide, were investigated by (13)C and (1)H
      NMR spectroscopy with magic angle spinning. The carbon signals cover a range of
      2000 ppm, and are well resolved such that the structure could be confirmed.
      Conversion of the signal shifts into spin densities disclosed the mechanisms by
      which spin delocalization from the nitronyl nitroxide substituents to the
      metallocene core occurs. The spin density distribution in alpha-1, beta-1, and 3
      was also predicted by DFT calculations. There is good agreement between the
      experimental and theoretical trends of the spin delocalization. The magnetic
      interactions were discussed in the light of intramolecular spin transfer and its
      dependence on geometric constraints, demonstrating that the 1,1'-metallocenylene
      bridge is not a robust magnetic coupler.

PMID- 15034883
TI  - Self-assembly of tris(2-ureidobenzyl)amines: a new type of capped, capsule-like
      dimeric aggregates derived from a highly flexible skeleton.
AB  - A set of tris(2-ureidobenzyl)amines 3 was prepared and their dimerization
      processes thoroughly investigated. In spite of their inherent flexibility,
      tris(ureas) 3 form dimeric aggregates both in the solid state and in solution.
      Evidence for the existence of these dimeric species was provided by a combination
      of techniques (X-ray analysis, NMR and IR spectroscopy, and ESI-MS). The
      association constants and thermodynamic parameters for the dimerization processes
      of selected tris(ureas) were determined and show that they are enthalpically
      driven. Heterodimerization experiments in solution reveal a high degree of self
      recognition or narcissistic self-sorting. On the other hand, desymmetrized
      tris(ureas) derived from 3 self-assemble with modest regioselectivities depending
      on the terminal substituent of every urea functionality.

PMID- 15034884
TI  - Synthesis and characterization of dendritic multichromophores based on rylene
      dyes for vectorial transduction of excitation energy.
AB  - The synthesis of dendritic multichromophores based on a rigid polyphenylene
      scaffold is presented. Different rylene chromophores are incorporated into the
      core, the branches, and the surface of the dendrimer. In this way, two
      generations of dendritic dyads consisting of a terrylenediimide core, a stiff
      polyphenylene scaffold, and a perylenemonoimide periphery were obtained.
      Furthermore, the first synthetic approach to a dendritic triad is introduced. The
      outer sphere of this macromolecule is formed by naphthalenemonoimide
      chromophores, whereas perylenemonoimide groups are located in the dendritic
      scaffold, and the terrylenediimide chromophore serves as a core molecule. This
      multichromophore absorbs over the whole range of the visible spectrum and shows
      well-separated absorption envelopes. In the course of dendrimer synthesis new
      attempts towards a straightforward functionalization strategy for rylene dyes are
      also presented.

PMID- 15034885
TI  - Self-assembly of normal alkanes on the Au (111) surfaces.
AB  - The self-assembled monolayers (SAMs) of normal alkanes (n-C(n)H(2n+2)) with
      different carbon chain lengths (n=14-38) in the interfaces between alkane
      solutions (or liquids), and the reconstructed Au (111) surfaces have been
      systematically studied by means of scanning tunneling microscopy (STM). In
      contrast to previous studies, which concluded that some n-alkanes (n=18-26) can
      not form well-ordered structures on Au (111) surfaces, we observed SAM formations
      for all these n-alkanes without any exceptions. We find that gold reconstruction
      plays a critical role in the SAM formation. The alkane monolayers adopt a
      lamellar structure in which the alkane molecules are packed side-by-side, to form
      commensurate structures with respect to the reconstructed Au (111) surfaces. The
      carbon skeletons are found to lie flat on the surfaces, which is consistent with
      the infrared spectroscopic studies. Interestingly, we find that two-dimensional
      chiral lamellar structures form for alkanes with an even carbon number due to the
      specific packing of alkane molecules in a tilted lamella. Furthermore, we find
      that the orientation of alkane molecules deviates from the exact [011] direction,
      because of the intermolecular interactions among the terminal methyl groups of
      neighboring lamellae; this results in differences of molecular orientation
      between mirror structures of adjacent zigzag alkane lamellae. Structural models
      have been proposed, that shed new light on monolayer formation.

PMID- 15034886
TI  - Oxasmaragdyrin-ferrocene and oxacorrole-ferrocene conjugates: synthesis,
      structure, and nonlinear optical properties.
AB  - Ferrocenyl macrocyclic conjugates involving 22 pi oxasmaragdyrins and 18 pi
      oxacorroles have been synthesized and characterized. The direct covalent linkage
      of the ferrocenyl moiety to the meso position of the macrocycle is achieved by
      simple oxidative coupling of appropriate precursors with trifluoroacetic acid as
      catalyst. The electronic coupling between the ferrocenyl moiety and the
      macrocyclic pi system is apparent from: a) the red shifts (293-718 cm(-1)) of the
      Soret and Q-bands in the electronic absorption spectra of ferrocenyl conjugates;
      b) the shift of oxidation potentials (50-130 mV) of both the ferrocene and the
      corrole rings to the positive potentials; and c) considerable shortening of the C
      C bond which connects the ferrocene and the meso-carbon atom of the macrocycle.
      The single-crystal X-ray structure of oxasmaragdyrin-ferrocene conjugate 9
      reveals the planarity of the 22 pi skeleton with very small deviations of the
      meso-carbon atoms. The meso-ferrocenyl substituent has a small dihedral angle of
      38 degrees, making way for mixing of the molecular orbitals of the ferrocene and
      the macrocycle. However, the other two meso substituents are almost perpendicular
      to the mean plane, defined by the three meso carbon atoms. Classical C-H...O and
      nonclassical C-H...pi interactions lead to a two-dimensional supramolecular
      network. Ferrocene-smaragdyrin conjugate 9 bonds to a chloride ion in the
      protonated form and a rhodium(i) ion in the free base form. Nonlinear optical
      measurements reveal a larger nonlinear refractive index (-5.83 x 10(-8)cm(2)W(
      1)) and figure of merit (2.28 x 10(-8)cm(3)W(-1)) for the rhodium smaragdyrin
      ferrocene conjugate 19 than for the others, suggesting its possible application
      in optical devices.

PMID- 15034887
TI  - Synthesis and conformational analysis of novel N(OCH3)-linked disaccharide
      analogues.
AB  - N(OMe)-linked disaccharide analogues, isosteric to the corresponding natural
      disaccharides, have been synthesized by chemoselective assembly of unprotected
      natural monosaccharides with methyl 6-deoxy-6-methoxyamino-alpha-D
      glucopyranoside in an aqueous environment. The coupling reactions were found to
      be chemo- and stereoselective affording beta-(1-->6) disaccharide mimics when
      using Glc and GlcNAc; in the case of Gal, the beta-anomer was prevalent
      (beta:alpha=7:1). An iterative method for the synthesis of linear N(OMe)
      oligosaccharide analogues was demonstrated, based on the use of an unprotected
      monosaccharide building block in which an oxime functionality at C-6 is converted
      during the synthesis into the corresponding methoxyamino group. The
      conformational analysis of these compounds was carried out by using NMR
      spectroscopy, ab initio, molecular mechanics, and molecular dynamics methods.
      Optimized geometries and energies of fourteen conformers for each compound have
      been calculated at the B3LYP/6-31G* level. Predicted conformational equilibria
      were compared with the results based on NMR experiments and good agreement was
      found. It appears that N(OMe)-linked disaccharide analogues exhibit a slightly
      different conformational behavior to their parent natural disaccharides.

PMID- 15034888
TI  - Diaroyl(methanato)boron difluoride compounds as medium-sensitive two-photon
      fluorescent probes.
AB  - This paper evaluates the use of diaroyl(methanato)boron difluoride compounds for
      designing efficient fluorescent probes through two-photon absorption. Three
      different pathways allowing for the syntheses of symmetrical and dissymmetrical
      molecules are reported. The stable diaroyl(methanato)boron difluoride derivatives
      can be easily obtained in good yields. They exhibit a large one-photon absorption
      that is easily tuned in the near-UV range. Their strong fluorescence emission
      covers the whole visible domain. In addition to these attractive linear
      properties, several diaroyl(methanato)boron difluoride derivatives possess
      significant cross sections for two-photon absorption. The derived structure
      property relationships are promising for designing new generations of molecules
      relying on the diaroyl(methanato)boron difluoride backbone.

PMID- 15034889
TI  - Diorganotin(IV) derivatives of substituted benzohydroxamic acids with high
      antitumor activity.
AB  - A series of diorganotin(IV) and dichlorotin(IV) derivatives of 4-X
      benzohydroxamic acids, [HL(1) (X = Cl) or HL(2) (X = OCH(3))] formulated as
      [R(2)SnL(2)] (R = Me, Et, nBu, Ph or Cl; L = L(1) or L(2)), along with their
      corresponding mixed-ligand complexes [R(2)Sn(L(1))(L(2))] have been prepared and
      characterized by FT-IR, (1)H, (13)C, and (119)Sn NMR spectroscopy, mass
      spectrometry, elemental analysis, and melting points. In addition, single-crystal
      X-ray diffraction analyses were carried out for [Me(2)SnL(2)] (L = L(1) or L(2)),
      which show coordination structures intermediate between distorted octahedra and
      bicapped tetrahedra. The hydroxamate ligands are asymmetrically coordinated by
      the oxygen atoms, the carbonyl oxygen atom is further away from the metal center
      than the other oxygen atom. The complexes are stable monomeric species; most of
      them are soluble not only in chlorohydrocarbon solvents, but also in alcohols and
      hydroalcoholic solutions. In polar solvents, the mixed-ligand complexes gradually
      decompose into the corresponding single-ligand complex couples. The complexes
      exhibit in vitro antitumor activities (against a series of human tumor cell
      lines) which, in some cases, are identical to, or even higher than, that of
      cisplatin. For the dialkyltin complexes, the activity increases with the length
      of the carbon chain of the alkyl ligand and is higher in the case of the chloro
      substituted benzohydroxamato ligand. The [nBu(2)Sn(L(1))(2)] complex displays a
      high in vivo activity against H22 liver and BGC-823 gastric tumors, and has a
      relatively low toxicity.

PMID- 15034890
TI  - Mechanism of the reaction of the [W3S4H3(dmpe)3]+ cluster with acids: evidence
      for the acid-promoted substitution of coordinated hydrides and the effect of the
      attacking species on the kinetics of protonation of the metal-hydride bonds.
AB  - The cluster [W(3)S(4)H(3)(dmpe)(3)](+) (1) (dmpe=1,2
      bis(dimethylphosphino)ethane) reacts with HX (X=Cl, Br) to form the corresponding
      [W(3)S(4)X(3)(dmpe)(3)](+) (2) complexes, but no reaction is observed when 1 is
      treated with an excess of halide salts. Kinetic studies indicate that the hydride
      1 reacts with HX in MeCN and MeCN-H(2)O mixtures to form 2 in three kinetically
      distinguishable steps. In the initial step, the W-H bonds are attacked by the
      acid to form an unstable dihydrogen species that releases H(2) and yields a
      coordinatively unsaturated intermediate. This intermediate adds a solvent
      molecule (second step) and then replaces the coordinated solvent with X(-) (third
      step). The kinetic results show that the first step is faster with HCl than with
      solvated H(+). This indicates that the rate of protonation of this metal hydride
      is determined not only by reorganization of the electron density at the M-H bonds
      but also by breakage of the H-X or H(+)-solvent bonds. It also indicates that the
      latter process can be more important in determining the rate of protonation.

PMID- 15034891
TI  - DFT description of the electronic structure and spectromagnetic properties of
      strongly correlated electronic systems: NiII, CuII and ZnII o-dioxolene
      complexes.
AB  - The spectroscopic and magnetic properties of dioxolene complexes of zinc, copper
      and nickel were studied by DFT calculations on model complexes of formulas
      [(NH(3))(4)M(II)(SQ)](+) (M=Zn, Ni; SQ=semiquinonato) and
      [(NH(3))(2)Cu(II)(SQ)](+). Standard approaches such as time-dependent DFT
      (TDDFT), the Slater transition state (STS), and broken symmetry (BS) were found
      to be unable to completely account for the physical properties of the systems,
      and complete active space-configuration interaction (CAS-CI) calculations based
      on the Kohn-Sham (KS) orbitals was applied. The CAS-CI energies, properly
      corrected with multireference perturbation theory (MR-PT), were found to be in
      good agreement with experimental data. We present here a calculation protocol
      that has a low CPU cost/accuracy ratio and seems to be very promising for
      interpreting the properties of strongly correlated electronic systems in
      complexes of real chemical size.

PMID- 15034892
TI  - Modification of (1R,2S)-1,2-diphenyl-2-aminoethanol for the highly
      enantioselective, asymmetric alkylation of N-diphenylphosphinoyl arylimines with
      dialkylzinc.
AB  - Experimental studies on the modification of (1R,2S)-1,2-diphenyl-2-aminoethanol,
      which is used to promote the alkylation of N-diphenylphosphinoyl benzalimine with
      diethylzinc, revealed that N-monosubstituted amino alcohols exhibited higher
      enantioselectivities than their N,N-disubstituted counterparts and imino
      alcohols. Application of the optimal chiral ligand 3c to activate the reaction of
      N-diphenylphosphinoyl arylimines with diethylzinc and dibutylzinc resulted in
      excellent enantiomeric selectivities of up to 98% ee. The origin of the
      experimentally observed enantioselectivities was revealed by density functional
      calculations (B3LYP/6-31G*) on the transition structures of several model
      reactions.

PMID- 15034893
TI  - Towards ordered architectures: self-assembly and stepwise procedures to the
      hexameric metallomacrocycles [arylbis(terpyridinyl)6FeII6-n-RuIIn] (n=0,2,3,5).
AB  - Hexameric metallomacrocycles are a new class of ordered rigid-macromolecules
      which possess unique structural, electronic, and physical characteristics.
      Directed- and self-assembly methods for the construction of these stable
      bis(terpyridine)-based materials are investigated by using both Fe(II) and Ru(II)
      as the coordinating metals. These heterometallomacrocycles and their
      homocounterparts are structurally compared, and their attendant electrochemical
      properties are analyzed and evaluated. These studies demonstrate the potential to
      create stable, nanoscale, doughnut-shaped, molecular assemblies with envisioned
      ramifications for energy storage and release, as well as nanoscale molecular
      electronic and magnetic devices.

PMID- 15034894
TI  - Heck coupling reaction of iodobenzene and styrene using supercritical water in
      the absence of a catalyst.
AB  - Heck coupling reaction of iodobenzene and styrene proceeds rapidly and
      selectively in supercritical water even without any catalyst in the presence of
      base. Both the choice of base and the reaction conditions had a significant
      effect on the conversion and the selectivity of the coupling products. The
      addition of a relatively mild base such as potassium acetate facilitated the
      cross-coupling reaction, while the hydrolysis of phenyl halide was favored in the
      presence of a strong base. The conversion and the yields of coupling products
      increased with increasing temperature, reaching a maximum at 650 K near the
      critical temperature of water, and then decreased as the temperature was further
      increased. Water density had a significant influence on the reaction rate,
      showing nearly 30% augmentation with a slight increase in density from 0.45 to
      0.56 g cm(-3), but had less effect on the product selectivity. Two possibilities
      of the role of water responsible for the noncatalytic Heck coupling reaction in
      supercritical water, that is, ion and water-catalyzed mechanisms have been
      considered.

PMID- 15034895
TI  - Ginkgolides and glycine receptors: a structure-activity relationship study.
AB  - Ginkgolides from the Ginkgo biloba tree are diterpenes with a cage structure
      consisting of six five-membered rings and a unique tBu group. They exert a
      variety of biological properties. In addition to being antagonists of the
      platelet activating factor receptor (PAFR), it has recently been shown that
      native ginkgolides are potent and selective antagonists of the inhibitory glycine
      receptor. Forty new ginkgolide derivatives have been prepared in good to high
      yields on milligram scales and investigated for their antagonistic properties at
      homomeric alpha 1 glycine receptors, thus providing the first structure-activity
      relationship study of ginkgolides at glycine receptors. A high-throughput
      screening assay showed that native ginkgolide C was the most potent ligand, and
      that manipulation of any of the hydroxyl groups led to loss of activity at alpha
      1 glycine receptors.

PMID- 15034896
TI  - Multistate/multifunctional behaviour of 4'-hydroxy-6-nitroflavylium: a write
      lock/read/unlock/enable-erase/erase cycle driven by light and pH stimulation.
AB  - We have investigated the network of reactions observed for the photochromic 4'
      hydroxy-6-nitroflavylium compound in aqueous solutions upon pH changes (including
      pH jump and stopped flow experiments) and light excitation. The changes observed
      in the NMR and UV/Vis spectra allowed identification of ten different forms in
      which this compound can be transformed depending on the experimental conditions.
      Equilibrium and kinetic constants have been determined. Compared with other
      members of the flavylium family, 4'-hydroxy-6-nitroflavylium is characterized by
      a large cis-->trans isomerization barrier, and a very efficient hydration
      reaction. These peculiar features allow writing, reading, storing and erasing
      photonic information on 4'-hydroxy-6-nitroflavylium by a novel cyclic process
      that involves the following steps: write-lock/read/unlock/enable-erase/erase.

PMID- 15034898
TI  - Stereocontrolled synthesis of the C21-C38 fragment of the unnatural enantiomer of
      the antibiotic nystatin A1.
AB  - The C(21)-C(38) fragment all-trans-41 of the unnatural enantiomer 1 of nystatin
      A(1) was prepared starting from the N-propionyl oxazolidinone 9. Aldol adduct ent
      8 (ee > 96 %) derived in two steps was hydroborated with (thexyl)BH(2). Oxidative
      work-up and treatment with acid furnished delta-lactone 4. It contains the
      complete stereotetrade of the target molecule. The alpha,beta-unsaturated ester
      28 was reached after another four steps. It should be a precursor for the polyene
      moieties of a variety of polyol,polyene macrolides. Illustrating that, the
      alpha,beta-unsaturated aldehyde 29 obtained from 28 and DIBAL was extended by 10
      C atoms in four steps yielding the C(21)-C(38) segment 41. The latter set of
      transformations included the regio- and stereoselective Claisen rearrangement 32-
      >35.

PMID- 15034897
TI  - Strategy for enantio- and diastereoselective syntheses of all possible
      stereoisomers of 1,3-polyol arrays based on a highly catalyst-controlled
      epoxidation of alpha,beta-unsaturated morpholinyl amides: application to natural
      product synthesis.
AB  - We describe a new strategy for enantio- and diastereoselective syntheses of all
      possible stereoisomers of 1,3-polyol arrays. This strategy relies on a highly
      catalyst-controlled epoxidation of alpha,beta-unsaturated morpholinyl amides
      promoted by the Sm-BINOL-Ph(3)As[double bond]O (1:1:1) complex, followed by a
      conversion of morpholinyl amides into ketones and diastereoselective ketone
      reduction. Highly enantio- (up to >99 % ee) or diastereoselective (up to
      >99.5:0.5) epoxidation was achieved using 5-10 mol % of the Sm complex to afford
      synthetically very useful, nearly optically pure alpha,beta-epoxy morpholinyl
      amides. Stereoselectivity of the epoxidation was controlled by the chirality of
      BINOL with overwhelming inherent diastereofacial preference for the substrate.
      Combination with the syn- and anti-selective ketone reduction with the highly
      catalyst-controlled epoxidation allowed for an iterative strategy for the
      syntheses of all possible stereoisomers of 1,3-polyol arrays. Eight possible
      stereoisomers of 1,3,5,7-tetraol arrays were synthesized with high to excellent
      stereoselectivity. Moreover, the efficiency of the present strategy was
      successfully demonstrated by enantioselective syntheses of several 1,3
      polyol/alpha-pyrone natural products, for example, cryptocaryolone diacetate.

PMID- 15034899
TI  - Structure and lithium dynamics of Li2AuSn2--a ternary stannide with condensed
      AuSn4/2 tetrahedra.
AB  - The new stannide Li(2)AuSn(2) was prepared by reaction of the elements in a
      sealed tantalum tube in a resistance furnace at 970 K followed by annealing at
      720 K for five days. Li(2)AuSn(2) was investigated by X-ray diffraction on
      powders and single crystals and the structure was refined from single-crystal
      data: Z=4, I4(1)/amd, a=455.60(7), c=1957.4(4) pm, wR2=0.0681, 278 F(2) values,
      10 parameters. The gold atoms display a slightly distorted tetrahedral tin
      coordination with Au-Sn distances of 273 pm. These tetrahedra are condensed
      through common corners leading to the formation of two-dimensional AuSn(4/2)
      layers. The latter are connected in the third dimension through Sn-Sn bonds (296
      pm). The lithium atoms fill distorted hexagonal channels formed by the three
      dimensional [AuSn(2)] network. Modestly small (7)Li Knight shifts are measured by
      solid-state NMR spectroscopy that are consistent with a nearly complete state of
      lithium ionization. The noncubic local symmetry at the tin site is reflected by a
      nuclear electric quadrupolar splitting in the (119)Sn Mossbauer spectra and a
      small chemical shift anisotropy evident from (119)Sn solid-state NMR
      spectroscopy. Variable-temperature static (7)Li solid-state NMR spectra reveal
      motional narrowing effects at temperatures above 200 K, revealing lithium atomic
      mobility on the kHz time scale. Detailed lineshape as well as temperature
      dependent spin lattice relaxation time measurements indicate an activation energy
      of lithium motion of 27 kJ mol(-1).

PMID- 15034903
TI  - Diastereoselective C-arylation of prochiral enolates by the SRN1 reaction.
AB  - Chiral phenyl acetamide enolate ions were diastereoselectively arylated using
      aromatic substrates by means of the S(RN)1 reaction. The substitution took place
      with a diastereomeric excess that varied from 31-98%, depending on the enolate
      counterion, the reaction temperature, the solvent, and the aromatic substrate.
      The absolute configuration of the new stereogenic center of the products (4R,5S)
      1,5-dimethyl-4-phenyl-3-[2'-phenyl-2'-arylacetyl]-imidazolidin-2-one (Aryl = 3
      quinolyl, 1-naphthyl, 4-anisyl, 4-benzonitryl, 4-tolyl, 9-phenanthryl) was
      determined by (1)H NMR spectroscopy and theoretical calculations.

PMID- 15034900
TI  - First preparation of nanocrystalline zinc silicate by chemical vapor synthesis
      using an organometallic single-source precursor.
AB  - A method is presented to prepare nanocrystalline alpha-Zn(2)SiO(4) with the
      smallest crystal size reported so far for this system. Our approach combines the
      advantages of organometallic single-source precursor routes with aerosol
      processing techniques. The chemical design of the precursor enables the
      preferential formation of pure zinc silicates. Since gas-phase synthesis reduces
      intermolecular processes, and keeps the particles small, zinc silicate was
      synthesized from the volatile organometallic precursor [[MeZnOSiMe(3)](4)],
      possessing a Zn-methyl- and O-silyl-substituted Zn(4)O(4)-heterocubane framework
      (cubane), under oxidizing conditions, using the chemical vapor synthesis (CVS)
      method. The products obtained under different process conditions and their
      structural evolution after sintering were investigated by using various
      analytical techniques (powder X-ray diffraction, transmission electron
      microscopy, EDX analysis, solid-state NMR, IR, Raman, and UV/Vis spectroscopy).
      The deposited aerosol obtained first (processing temperature 750 degrees C) was
      amorphous, and contained agglomerates with primary particles of 12 nm in size.
      These primary particles can be described by a [Zn-O-Si] phase without long-range
      order. The deposit obtained at 900 degrees C contained particles with embedded
      nanocrystallites (3-5 nm) of beta-Zn(2)SiO(4), Zn(1.7)SiO(4), and ZnO in an
      amorphous matrix. On further ageing, the as-deposited particles obtained at 900
      degrees C form alpha-Zn(2)SiO(4) imbedded in amorphous SiO(2). The crystallite
      sizes and primary particle sizes in the formed alpha-Zn(2)SiO(4) were found to be
      below approximately 50 nm and mainly spherical in morphology. A gas-phase
      mechanism for the particle formation is proposed. In addition, the solid-state
      reactions of the same precursor were studied in detail to investigate the
      fundamental differences between a gas-phase and a solid-state synthesis route.

PMID- 15034904
TI  - Study of the characterization and crystallization of 4-hydroxy-2-pyrrolidone.
AB  - A systematic study of the characterization for racemic species of 4-hydroxy-2
      pyrrolidone was undertaken. The melting point phase diagram of (R)- and (S)-4
      hydroxy-2-pyrrolidone was determined by differential scanning calorimetry. The
      ternary phase diagram of (R)- and (S)-4-hydroxy-2-pyrrolidone with isopropanol
      was constructed at 15, 20, 25, and 35 degrees C. The crystalline nature of 4
      hydroxy-2-pyrrolidone racemate was also characterized by means of comparison of
      solid-state FTIR spectra and powder X-ray diffraction patterns of the racemic
      mixture with those of one of the enantiomers. It is shown that (+/-)-4-hydroxy-2
      pyrrolidone is a racemic conglomerate. The enthalpies of fusion of (R)-4-hydroxy
      2-pyrrolidone and (+/-)-4-hydroxy-2-pyrrolidone and entropy of mixing of (R)- and
      (S)-4-hydroxy-2-pyrrolidone were calculated using the thermodynamic data. The
      solubility and supersolubility diagrams of (R)- and (S)-4-hydroxy-2-pyrrolidone
      in isopropanol were determined over a temperature range of 4-35 degrees C. The
      optical resolution of (+/-)-4-hydroxy-2-pyrrolidone was successfully achieved by
      preferential crystallization.

PMID- 15034905
TI  - Absolute configuration of chiral terpenes in marking pheromones of bumblebees and
      cuckoo bumblebees.
AB  - The absolute configurations of citronellol, 2,3-dihydrofarnesol, and 2,3
      dihydrofarnesal in male marking pheromones of seven species of bumblebees and
      cuckoo bumblebees were determined by enantioselective gas chromatography on a
      capillary column coated with 60% heptakis(2,3-di-O-acetyl-6-O-TBDMS)-beta
      cyclodextrin in polysiloxane PS 268. Pure (-)-S-enantiomers of all three terpenes
      were found in the labial glands of all investigated specimens of the following
      species: Bombus (Bombus) terrestris, B. (Bombus) lucorum, B. (Pyrobombus)
      pratorum, B. (Pyrobombus) pyrenaeus, B. (Pyrobombus) jonellus, B. (Pyrobombus)
      impatiens, and the cuckoo bumblebee B. (Ashtonipsithyrus) bohemicus. Within
      species, specimens were collected at different localities and in different years.
      Except for 2,3-dihydrofarnesol in B. terrestris, this is the first report on the
      absolute configuration of terpenes in marking pheromones of bumblebees.

PMID- 15034907
TI  - Circular dichroism of 1,3-dioxane-type (2'-naphthyl)methylene acetals of
      glycosides.
AB  - The CD spectra are reported for a series of 1,3-dioxane-type 4,6-O-(2'
      naphthyl)methylene acetals of carbohydrates with and without interacting aromatic
      protective groups on the C-1, C-2, and C-3 hydroxy groups. In the absence of
      interacting chromophores, the signs of the (1)B transitions are not sensitive to
      the configuration of C-4, while the signs of the weak (1)L(a) bands are opposite
      in the galacto and gluco derivatives. The equatorial parallel conformation is
      found to be the preferred conformation of the 2-naphthyl group in the solid state
      by X-ray diffraction. The intense (1)B(a) and (1)B(b) transitions of the
      naphthalene chromophore allowed a safe configurational assignment by exciton
      coupled interaction with the aromatic protective groups in para-methoxyphenyl
      beta-D-glycosides. The origin of the observed CEs were deduced and the additivity
      of the interactions was studied. The direction of the hydrogenolytic cleavage of
      4,6-O-(2'-naphthyl)methylene acetal of carbohydrates could also be detected by
      the (1)B(b) transition of the 2-naphthyl chromophore.

PMID- 15034906
TI  - Calculations of protein circular dichroism from first principles.
AB  - Understanding the relationship between the amino acid sequence of a protein and
      its unique, compact 3D structure is one of the grand challenges in molecular
      biophysics. One particularly exciting approach is time-resolved electronic
      circular dichroism (CD) spectroscopy, which offers resolution on a nanosecond (or
      faster) time scale, although it does not provide the spatial resolution of
      techniques like X-ray crystallography or NMR. The thrust of our work is to
      underpin fast time scale spectroscopic studies of protein folding with a stronger
      theoretical foundation. Ultimately, we seek to use molecular dynamics simulations
      to study the influence of conformational dynamics and conformational transitions
      on the electronic CD spectra of proteins. We discuss how improved quantum
      chemical models of individual chromophores, including aromatic sidechains, can be
      incorporated into calculations of the electronic structure of proteins and their
      CD.

PMID- 15034908
TI  - Transfer of chirality by dithiophosphate ligands and chiral discrimination in the
      stereoselective formation of square-planar Ni(II) complexes.
AB  - In the formation reaction of Ni(2+) with the chiral racemic ligand, (R)(R)bdtp(
      )/(S)(S)bdtp(-), bdtp(-) = [SSPOCH)CH(3))CH(CH(3))O](-), cyclo- O,O'-[1,2
      dimethylethylene] dithiophosphato ion, the meso-complex
      Ni[(R)(R)(lambda)bdtp][(S)(S)(delta)-bdtp] is stereoselectively produced. The
      meso-complex was compared with the enantiopure crystals of
      (+)(589)Ni[(R)(R)(lambda)bdtp](2) or (-)(589)Ni[(S)(S)(delta)bdtp](2), as well as
      racemic crystals, rac-(+/-)Ni[bdtp](2), which were prepared from the solution
      containing the two enantiomers in a 1:1 ratio. Dissociation constants in
      solutions indicate different stability of the meso and enantiopure complexes
      depending on the solvent, whereas a more efficient crystal packing, weak H
      bonding, and nonbonding interactions contribute to stabilization of the meso
      species over the racemic one. Molecular structures show that the outer five
      membered ligand ring adopts the half-chair conformation C(2) with either the
      lambda or the delta chirality and the methyl groups are in equatorial (e)
      positions. Enantiopure ligands of (+)(589)Ni[(R)(R)(lambda)bdtp](2) and (
      )(589)Ni[(S)(S)(delta)bdtp](2) induce chirality into the symmetric SSNiSS
      chromophore with slightly helical distortion. Thus, their CD spectra exhibit weak
      negative or positive Cotton effects at 662 nm. CD spectra in L(+)- and D(
      )diethyltartrate of the meso-complex and racemic crystal, rac-(+/-)Ni[bdtp](2),
      exhibit different weak Cotton effects of opposite sign. Complexes dissociate in
      methanol; rac-(+/-)Ni[bdtp](2) in methanol undergoes a crystallization-induced
      second-order asymmetric transformation which finally yields crystals of the meso
      Ni[(R)(R)(lambda)bdtp][(S)(S)(delta)bdtp] complex.

PMID- 15034909
TI  - Enantioseparation of hydrochloride salts using carbon dioxide-based mobile phases
      with on-line polarimetric detection.
AB  - Most HPLC enantioseparations of amine analytes are performed using normal-phase
      systems containing mobile phases of heptane with ethanol (or 2-propanol) and an
      amine additive. Since salt-forms of amine analytes are usually insoluble in
      normal-phase eluents, free-base forms are synthesized for preparative
      chromatography. It would be highly desirable to directly chromatograph salt forms
      of amine analytes using mobile phases of carbon dioxide (CO(2)) and methanol
      (MeOH). Such separations would be readily suitable for preparative
      chromatography, since most amine salts are highly soluble in MeOH. In this
      article, advantages are shown for the use of supercritical fluid chromatography
      (SFC) instrumentation with tandem UV and polarimetric detection for confirming
      enantioseparation as well as for determining optimum preparative column
      injections. Examples are shown for racemic mixtures of propranolol HCl (I),
      thioridazine HCl (II), tramadol HCl (III), and flurbiprofen (IV), all of which
      resolved on Chiralpak AD-H chiral stationary phase using mobile-phase systems of
      CO(2) and MeOH without the use of basic or acidic additives.

PMID- 15034910
TI  - Utilizing hydrolases of opposite enantiopreference for the preparation of both
      enantiomers of (1R,7aR)-(-)- and (1S,7aS)-(+)-3,6,7,7a-tetrahydro-1-hydroxy-7a
      methyl-1H-inden-5(2H)-one.
AB  - Four racemic esters of (1R*,7aR*)-3,6,7,7a-tetrahydro-1-hydroxy-7a-methyl-1H
      inden-5(2H)-one were prepared and subjected to hydrolysis with two types of
      hydrolases, including alcalase and three lipases. Alcalase and lipase showed
      opposite enantiopreference on these esters. Based on this result, we developed a
      gram-scale procedure using butanoate as the substrate, which was treated
      consecutively with alcalase and lipase from Candida rugosa (CRL), to give both
      enantiomers of the title compound in high yields and high enantiomeric excess.

PMID- 15034911
TI  - Chiral recognition ability of curdlan triacetate: solvent and temperature
      effects.
AB  - The chiral recognition ability of the chiral stationary phase (CSP) consisting of
      curdlan (beta-1,3-glucan) triacetate coated on silica gel was clearly changed by
      the contacting solvents and heat treatment. The chiral recognition ability
      significantly decreased, particularly at temperatures above 45 degrees C,
      depending on the racemates. The molecular weight of the curdlan triacetate
      slightly influenced its ability. The recognition abilities of curdlan tricetate
      that was lost by heat treatment were partially recovered by contact with
      methanol. However, when it was contacted with ethanol a different selectivity was
      observed. The labile chiral recognition ability of curdlan triacetate is in
      striking contrast to the very stable chiral recognition of cellulose (beta-1,4
      glucan) triacetate (Chiralcel OA). This difference may be ascribed to the
      conformational stability of the acetates consisting of curdlan (beta-1,3-glucan)
      and cellulose (beta-1,4-glucan) with different sugar linkages.

PMID- 15034913
TI  - Alcohol-withdrawn animals have a prolonged increase in dopamine D2high receptors,
      reversed by general anesthesia: relation to relapse?
AB  - The biochemical basis for alcohol addiction and relapse is not known. Although
      ethanol promotes the release of dopamine like other drugs of abuse, many unknown
      factors remain to be investigated concerning the biochemical abnormalities which
      persist after ethanol drinking and which contribute to alcohol relapse. Although
      ethanol withdrawal is associated with enhanced sensitivity to dopamine in animals
      and humans, only minor changes in the striatal density of dopamine D2 receptors
      have been found in humans, and animals show a small reduction in striatal D2
      receptors. But how can dopamine-related functions be increased in ethanol
      withdrawal in the face of an unchanged or reduced density of dopamine D2
      receptors? Considering that ethanol sensitizes rats to amphetamine, and that the
      high-affinity state of D2, or D2High, is markedly increased in striata from
      amphetamine-sensitized rats, we measured the density of D2High in striata from
      rats withdrawn from ethanol. These sites were elevated by 360% (7.2 pmol/g) for
      at least 8 days after stopping ethanol and returned to normal levels of 2 pmol/g
      after 2 weeks of ethanol withdrawal. In addition, 1 h of deep general anesthesia
      given 5 days into withdrawal resulted in a normal level of D2High within 24 h.
      Because the D2High states are the functional form of D2, their elevated density
      in ethanol withdrawal may be related to ethanol relapse in humans. General
      anesthesia may alleviate aspects of alcohol or amphetamine abuse or psychosis
      associated with elevated D2High.

PMID- 15034914
TI  - Effects of extracellular pH on the dynorphin A inhibition of N-methyl-D-aspartate
      receptors expressed in Xenopus oocytes.
AB  - Dynorphin A (Dyn A) (1-17), the postulated endogenous ligand for the kappa-opioid
      receptor, inhibits N-methyl-D-aspartate (NMDA) receptor-mediated currents in
      neuronal preparations and in Xenopus oocytes expressing recombinant NMDA
      receptors. Although direct interactions of Dyn A with the NMDA receptor have been
      reported, the mechanisms mediating the inhibitory actions of Dyn A are unknown.
      Extracellular pH is a crucial factor regulating NMDA receptor function. To date,
      however, the influence of pH on the inhibitory actions of Dyn A has not been
      examined. In the present study we used voltage-clamp recording techniques in
      Xenopus oocytes expressing recombinant NR1A/2A receptors to address this issue.
      We report that decreasing the pH of the external solution from 7.5 to 6.7
      significantly enhances Dyn A inhibition of NMDA receptor-mediated currents. On
      the contrary, increasing the pH of the external solution to 9.2 prevents the
      inhibitory action of Dyn A. The influence of external pH was independent of
      membrane potential and the potentiation of inhibition with decreasing pH was not
      associated with alterations in the charge of the Dyn A molecule. These findings
      demonstrate that Dyn A inhibition of the NMDA receptor current is pH-dependent.
      They further suggest that the efficacy of neuronally released Dyn A in inhibiting
      NMDA receptor function may be increased in response to nerve injury and other
      conditions associated with decreased extracellular pH.

PMID- 15034915
TI  - Quantitative validation of an intracerebral beta-sensitive microprobe system to
      determine in vivo drug-induced receptor occupancy using [11C]raclopride in rats.
AB  - In this study, we evaluated the potential of using a new beta-sensitive
      microprobe system for in vivo quantification of [11C]raclopride binding and for
      in vivo determination of drug-induced receptor occupancy in the rat striatum. To
      validate this system, an ex vivo tissue dissection method was used to corroborate
      in vivo beta-microprobe measurements. Our data showed that the beta-microprobe
      derived [11C]raclopride binding kinetics in striatum could be quantified using a
      tissue compartmental model with a cerebellar reference region. Haloperidol (0.001
      0.1 mg/kg; i.v.) induced a dose-dependent decrease in [11C]raclopride binding in
      striatum as measured using the beta-microprobe with an ED50 value of 0.013 mg/kg.
      Highly significant relationships (P < 0.0001) were observed, within the same
      animals, between in vivo and ex vivo measures of haloperidol-induced D2-receptor
      occupancy (r = 0.98) as well as between in vivo and ex vivo measures of
      [11C]raclopride binding potentials (r = 0.99). Results from pretreatment and
      displacement studies with unlabeled raclopride and amphetamine conformed to the
      effect of these drugs as observed in humans using [11C]raclopride and PET and
      allowed estimation of the in vivo k(off) value of raclopride to 0.025 +/- 0.004
      min(-1). However, allowing the system to stabilize before measurements and
      shielding the photomultiplier tubes were critical for obtaining these consistent
      results. This study demonstrates that the beta-microprobe provides reliable
      measurements of [11C]raclopride binding kinetics in rodents, allows for
      quantitative in vivo measurements of antipsychotic drug action in brain, and
      represents a valid and cost-effective alternative to positron emission tomography
      imaging in small animals.

PMID- 15034916
TI  - Molecular, chemical, and anatomical characterization of globus pallidus dopamine
      D2 receptor mRNA-containing neurons.
AB  - Essential for normal movement, the globus pallidus (GP) is a prominent nucleus
      whose neurons project to all other basal ganglia nuclei. The GP is composed of at
      least two distinct neuron populations. GP neurons of the rodent contain either
      the calcium-binding protein parvalbumin (PV) or preproenkephalin (PPE) mRNA,
      differentially innervate several basal ganglia structures, and have distinct
      immediate early gene responses to dopamine agonists or antagonists. Recent
      research has revealed that dopamine directly influences GP neurons, with D2
      receptors contributing to both pre- and postsynaptic effects of dopaminergic
      agents. The existence of D2 mRNA-expressing (D2+) GP neurons has been
      established, but little is known concerning their numbers, regional distribution,
      or relationship to pallidal subpopulations identified on the basis of PV
      immunocytochemistry, PPE mRNA, or axonal targets. Detection of pallidal D2 mRNA
      with a 35S-cRNA probe revealed that D2+ neurons are found throughout the GP,
      comprising approximately one-half of pallidal neurons, but they are most dense
      within a dorsoventral band in lateral GP. While a substantial proportion (42-51%)
      of all chemically and anatomically labeled pallidal neuron subpopulations
      expressed D2 transcript, the D2+ neurons exhibited both population-based and
      regional heterogeneities. Overall, the pallidostriatal cells had a greater
      density of D2 mRNA than did pallidosubthalamic cells. Also, compared to other
      pallidal regions, the ventromedial GP contained fewer D2+ cells, and the PPE mRNA
      expressing cells in this region had lower densities of D2 mRNA per neuron. These
      results reveal heterogeneous chemical and anatomical properties of the extensive
      population of D2+ GP neurons, a potential cellular substrate for dopamine's
      effects in pallidum.

PMID- 15034918
TI  - Kinetics of beta-funaltrexamine binding to wild-type and mutant mu-opioid
      receptors expressed in Chinese hamster ovary cells.
AB  - The two-stage reaction whereby the antagonist beta-funaltrexamine (beta-FNA)
      binds covalently to micro opioid receptors makes it a highly discriminating probe
      into the tertiary structure of the receptor's recognition pocket. To obtain a
      quantitative measure of how well this pocket is preserved in a mutated form of
      the receptor, in which His-297 is substituted with glutamine, we employed [3H]
      beta-FNA to evaluate the kinetic rate constants for both the reversible as well
      as the irreversible stages of its binding to wild-type and mutant H297Q micro
      receptors stably expressed in Chinese hamster ovary cells. The expression levels
      of the wild-type and mutant H297Q receptors were matched by exploiting the
      variation in receptor density as a function of plating day and by raising the
      expression level by pretreatment with naloxone. We found that all of the kinetic
      rate constants for [3H]-beta-FNA were diminished by about one-half at the mutant
      H297Q micro receptors with respect to wild-type receptors. By comparison, the
      association rate constant of [3H]-naloxone likewise decreased by one-half;
      however, the dissociation rate constant increased 5-fold at the mutant H297Q
      receptor. We conclude that the mutation has had only minor influence on the
      recognition site and that the function of position 297 is more likely as a link
      in the transduction chain.

PMID- 15034917
TI  - Clozapine modulates midbrain dopamine neuron firing via interaction with the NMDA
      receptor complex.
AB  - The mode of action by which the atypical antipsychotic drug clozapine exerts its
      superior efficacy to ameliorate both positive and negative symptoms is still
      relatively unknown. A recent study shows that a pharmacologically increased
      concentration of brain kynurenic acid, an endogenous antagonist at the glycine
      site of the NMDA receptor as well as at the alpha7* nicotinic receptor, reverses
      the excitatory effects of clozapine on ventral tegmental area (VTA) dopamine (DA)
      neurons into an inhibitory action. In the present in vivo electrophysiological
      study, we further investigated the mechanisms of action of clozapine on VTA DA
      neurons. In control rats intravenously administered clozapine (1.25-10 mg/kg) was
      associated with increased firing rate and burst firing activity of VTA DA
      neurons. However, administration of the N-methyl-D-aspartate (NMDA)-receptor
      antagonist MK 801 blocked the excitatory action of clozapine. Moreover, in rats
      pretreated with the antagonist of the glycine-site of the NMDA receptor, L
      701,324, the effects of clozapine on VTA DA neurons were converted to purely
      inhibitory responses, including a decrease in firing rate and burst firing
      activity. Pretreatment with the alpha7* nicotinic receptor antagonist MLA did not
      affect the excitatory action of clozapine on VTA DA neurons. The results of the
      present study suggest that clozapine interacts with the NMDA receptor complex. In
      this regard, clozapine could affect the glycine site of the NMDA receptor or
      tentatively inhibit the glycine transporter. The inhibitory action of clozapine
      on VTA DA neurons may account for its beneficial effects in ameliorating symptoms
      of schizophrenia and may suggest further studies to investigate a role of the
      glycine site of the NMDA receptor as a target for novel antipsychotics.

PMID- 15034919
TI  - ADAM is an effective tool for in vivo study of serotonergic function: validation
      in rat models.
AB  - ADAM, 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine, is a recently
      described SPECT tracer for exploration of the serotonin transporter. We evaluated
      its potential to detect abnormalities in serotonergic function in the rat using
      1) a model of serotonergic neuron lesion induced with 5,7-dihydroxytryptamine
      (5,7-DHT), and 2) experimental induction of acute decrease in endogenous brain
      serotonin levels. Cerebral biodistribution studies of [125I]ADAM were performed
      in normal conditions, in 5,7-DHT-lesioned rats, and after acute serotonin
      depletion obtained with p-chlorophenylalanine (pCPA). Around 50% reduction in
      accumulation of ADAM was observed in the hypothalamus and hippocampus 3 weeks
      after lesion of serotonergic neurons, whereas a more modest decrease of 15-30%
      occurred in the thalamus, frontal cortex, and striatum. This demonstrated the
      ability of the tracer to detect serotonergic neuron loss in vivo. After inducing
      acute 5-HT depletion with pCPA, we observed an increase in in vivo [125I]ADAM
      binding in all brain areas studied. The higher in vivo binding of [125I]ADAM in
      pCPA-treated rats than in controls was mainly due to an increase in specific
      binding to the SERT, as demonstrated by greatly reduced binding in the presence
      of a saturating dose of paroxetine. This may indicate in vivo competition between
      ADAM and 5-HT for binding to the SERT. The present findings thus demonstrate that
      ADAM is a specific SERT radioligand which can be used for in vivo study of
      central serotonin systems, and supports its use as a tracer for SPECT studies in
      human disorders involving dysfunction of serotonergic neurotransmission.

PMID- 15034920
TI  - Prefrontal cortical up states are synchronized with ventral tegmental area
      activity.
AB  - The innervation of the prefrontal cortex (PFC) by the ventral tegmental area
      (VTA) has an important role in incentive-motivation and cognitive functions.
      Although this projection has been extensively studied, the precise actions of its
      transmitters, dopamine (DA) and GABA, on PFC pyramidal neurons remain to be
      determined. We have recently shown that VTA stimulation elicits a sustained
      depolarization in PFC pyramidal neurons resembling the periodic depolarizations
      (up states) these neurons exhibit. This response was shortened by a D1
      antagonist, suggesting that DA may sustain depolarized up states in PFC neurons.
      Here, we tested whether spontaneous PFC up states in vivo require spontaneous VTA
      activity. Intracellular recordings from PFC neurons conducted simultaneously with
      VTA local field potentials (LFPs) revealed PFC membrane potential fluctuations
      occurring synchronously with VTA field potential transitions. Extracellular PFC
      recordings performed simultaneously with VTA LFPs also indicated a high coherence
      between these two regions, with VTA oscillations trailing PFC oscillations by a
      few milliseconds. Furthermore, blockade of VTA activity with lidocaine
      transiently eliminated PFC LFPs, but not PFC cell up states; instead, up states
      became irregular during intra-VTA lidocaine administration. These results suggest
      that baseline levels of VTA activity are necessary for synchronizing PFC
      pyramidal neurons in the up-down oscillations observed in the anesthetized
      preparation, allowing the emergence of slow EEG components.

PMID- 15034921
TI  - Effect of acute antipsychotic administration on dopamine synthesis in rodents and
      human subjects using 6-[18F]-L-m-tyrosine.
AB  - Clinical effects of antipsychotic drugs are thought to be mediated primarily
      through antagonism of the dopamine D2 receptors. Recent studies have demonstrated
      increased aromatic decarboxylase activity following acute administration of
      dopamine D2 receptor antagonists both in vivo and ex vivo. However, this effect
      has never been demonstrated in human subjects. We studied the effect of acute
      antipsychotic administration on dopamine synthesis in rodents and healthy human
      subjects using 6-[18F]-L-m-tyrosine. In rats, we studied the effect of a single
      subcutaneous injection of haloperidol and risperidone on dopamine synthesis using
      6-[18F]-L-m-tyrosine. In our human study, six healthy volunteers underwent two 6
      [18F]-L-m-tyrosine PET scans, before and after 3 mg risperidone to measure the
      rate of accumulation of radioactivity in the striatum as an index of dopamine
      synthesis. The striatal/cerebellar radioactivity count ratio and the ratio of
      dopamine metabolites to dopamine concentration was significantly higher in all
      rodent treatment groups compared to controls. In the PET study we found no
      significant change in the rate of uptake in the striatum. Our results suggest
      that 6-[18F]-L-m-tyrosine PET may not be a useful tool in the study of the effect
      of antipsychotics on dopamine synthesis in human subjects.

PMID- 15034922
TI  - L-DOPA-induced modulation of GABA and glutamate release in substantia nigra pars
      reticulata in a rodent model of Parkinson's disease.

PMID- 15034923
TI  - Cell cycle regulatory protein p27KIP1 is a substrate and interacts with the
      protein kinase CK2.
AB  - The protein kinase CK2 is constituted by two catalytic (alpha and/or alpha') and
      two regulatory (beta) subunits. CK2 phosphorylates more than 300 proteins with
      important functions in the cell cycle. This study has looked at the relation
      between CK2 and p27(KIP1), which is a regulator of the cell cycle and a known
      inhibitor of cyclin-dependent kinases (Cdk). We demonstrated that in vitro
      recombinant Xenopus laevis CK2 can phosphorylate recombinant human p27(KIP1), but
      this phosphorylation occurs only in the presence of the regulatory beta subunit.
      The principal site of phosphorylation is serine-83. Analysis using pull down and
      surface plasmon resonance (SPR) techniques showed that p27(KIP1) interacts with
      the beta subunit through two domains present in the amino and carboxyl ends,
      while CD spectra showed that p27(KIP1) phosphorylation by CK2 affects its
      secondary structure. Altogether, these results suggest that p27(KIP1)
      phosphorylation by CK2 probably involves a docking event mediated by the CK2beta
      subunit. The phosphorylation of p27(KIP1) by CK2 may affect its biological
      activity.

PMID- 15034924
TI  - Tau isoforms which contain the domain encoded by exon 6 and their role in neurite
      elongation.
AB  - The regulation of tau protein expression during different stages of cellular
      differentiation and development as well as its functional role in morphogenesis,
      neurofibrillary tangle formation, and neurodegeneration have been topics of
      extensive study but have not been completely clarified yet. Tau undergoes complex
      regulated splicing in the mammalian nervous system. Our previous study with tau
      exon 6 demonstrated that it shows a splicing regulation profile which is distinct
      from that of the other tau exons as well as a unique expression pattern which is
      spatially and temporally regulated. In this study, we investigated the
      expression, localization, and effects of tau isoforms which contain exon 6 in
      neuroblastoma cells which stably overexpress them. We found that expression of
      one particular combination of tau exons (the longest adult isoform plus the
      domain of exon 6) significantly inhibits neurite elongation.

PMID- 15034926
TI  - Functional role of centrosomes in spindle assembly and organization.
AB  - The centrosome is the main MT organizing center in animal cells, and has
      traditionally been regarded as essential for organization of the bipolar spindle
      that facilitates chromosome segregation during mitosis. Centrosomes are
      associated with the poles of the mitotic spindle, and several cell types require
      these organelles for spindle formation. However, most plant cells and some female
      meiotic systems get along without this organelle, and centrosome-independent
      spindle assembly has now been identified within some centrosome containing cells.
      How can such observations, which point to mutually incompatible conclusions
      regarding the requirement of centrosomes in spindle formation, be interpreted?
      With emphasis on the functional role of centrosomes, this article summarizes the
      current models of spindle formation, and outlines how observations obtained from
      spindle assembly assays in vitro may reconcile conflicting opinions about the
      mechanism of spindle assembly. It is further described how Drosophila mutants are
      used to address the functional interrelationships between individual centrosomal
      proteins and spindle formation in vivo.

PMID- 15034925
TI  - Ets proteins in biological control and cancer.
AB  - The Ets family consists of a large number of evolutionarily conserved
      transcription factors, many of which have been implicated in tumor progression.
      Extensive studies on this family of proteins have focused so far mainly on the
      biochemical properties and cellular functions of individual factors. Since most
      of the Ets factors can bind to the core consensus DNA sequence GGAA/T in vitro,
      it has been a challenge to differentiate redundant from specific functions of
      various Ets proteins in vivo. Recent findings, however, suggest that such
      apparent redundancy may in fact be a central component of a network of
      differentially regulated specific Ets factors, resulting in distinct biological
      and pathological consequences. The programmed "Ets conversion" appears to play a
      critical role during tumor progression, especially in control of cellular changes
      during epithelial-mesenchymal transition and metastasis. Coordination of multiple
      Ets gene functions also mediates interactions between tumor and stromal cells. As
      such, these new insights may provide a novel view of the Ets gene family as well
      as a focal point for studying the complex biological control involved in tumor
      progression.

PMID- 15034927
TI  - SPARC regulates TGF-beta1-dependent signaling in primary glomerular mesangial
      cells.
AB  - Secreted protein acidic and rich in cysteine (SPARC), a member of the family of
      matricellular proteins, regulates the interaction of cells with pleiotropic
      factors and proteins of the extracellular matrix (ECM). Although it has been
      appreciated that transforming growth factor beta 1 (TGF-beta1) induces SPARC and
      collagen type I, we have recently shown that SPARC regulates the expression of
      TGF-beta1 and collagen type I in renal mesangial cells via a TGF-beta1-dependent
      pathway, and have proposed a reciprocal, autocrine regulatory feedback loop
      between SPARC and TGF-beta1. Herein, we sought to determine how SPARC regulates
      TGF-beta1-dependent signal transduction. Our data indicate that SPARC modulates
      the TGF-beta1-dependent phosphorylation of Smad-2 in primary mesangial cells
      derived from wild-type and SPARC-null mice. We also show that SPARC regulates the
      levels and activation of the stress-activated c-jun-N-terminal kinase (JNK) in
      mesangial cells by augmentation of the stimulatory effects of TGF-beta1.
      Furthermore, we found that SPARC increases the levels and the activity of the
      transcription factor c-jun. These effects of SPARC on the TGF-beta1 signaling
      pathway appear to be mediated through an interaction with the TGF-beta1-receptor
      complex, but only in the presence of TGF-beta1 bound to its cognate type II
      receptor. That SPARC is directly involved in the regulation of the TGF-beta1
      signaling cascade is consistent with the paradigm that matricellular proteins
      modulate interactions among cells, growth factors, and their respective
      receptors.

PMID- 15034928
TI  - The role of the cytoskeleton in cellular adhesion molecule expression in tumor
      necrosis factor-stimulated endothelial cells.
AB  - Leukocyte infiltration is a hallmark of the atherosclerotic lesion. These cells
      are captured by cellular adhesion molecules (CAMs), including vascular cell
      adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1),
      platelet-endothelial cell adhesion molecule (PECAM), and E-selectin, on
      endothelial cells (EC). We examined the role of the actin cytoskeleton in tumor
      necrosis factor-alpha (TNF-alpha)-induced translocation of CAMs to the cell
      surface. Human aortic EC were grown on 96-well plates and an ELISA was used to
      assess surface expression of the CAMs. TNF-alpha increased VCAM-1, ICAM-1, and E
      selectin by 4 h but had no affect on the expression of PECAM. A functioning actin
      cytoskeleton was important for VCAM-1 and ICAM-1 expression as both cytochalasin
      D, an actin filament disruptor, and jasplakinolide, an actin filament stabilizer,
      attenuated the expression of these CAMs. These compounds were ineffective in
      altering E-selectin surface expression. Myosin light chains are phosphorylated in
      response to TNF-alpha and this appears to be regulated by Rho kinase instead of
      myosin light chain kinase. However, the Rho kinase inhibitor, Y27632, had no
      affect on TNF-alpha-induced CAM expression. ML-7, a myosin light chain kinase
      inhibitor, had a modest inhibitory effect on the translocation of VCAM-1 but not
      on ICAM-1 or E-selectin. These data suggest that the surface expression of VCAM-1
      and ICAM-1 is dependent on cycling of the actin cytoskeleton. Nevertheless,
      modulation of actin filaments via myosin light chain phosphorylation is not
      necessary. The regulation of E-selectin surface expression differs from that of
      the other CAMs.

PMID- 15034929
TI  - Cellular injury induces activation of MAPK via P2Y receptors.
AB  - Wound healing is a complex process that involves cell communication, migration,
      proliferation, and changes in gene expression. One of the first events after
      injury is the rapid release of Ca(2+) that propagates as a wave to neighboring
      cells (Klepeis et al. [2001]: J. Cell. Sci. 114:4185-4195). Our goal was to
      examine the signaling events induced by cellular injury and identify
      extracellular molecules that induce the activation of extracellular signal
      responsive kinase (ERK) (p42/44). In this study we demonstrated that injury
      induced ERK1/2 activation occurred within 2 min and was negligible by 15 min.
      Treatment of unwounded cells with wound media caused activation of ERK that could
      be inhibited by apyrase III. Stimulation with epidermal growth factor (EGF) did
      not mimic the injury response and it was not detected in the wound media. To
      identify the active component, size fractionation was performed and factor(s)
      less than 3 kDa that induced the release of Ca(2+) and activation of ERK1/2 were
      identified. Activity was not altered by heat denaturation, incubation with
      proteinase K but it was lost by treatment with apyrase. Adenosine triphosphate
      (ATP), uridine triphosphate (UTP), adenosine diphosphate (ADP), and uridine
      diphosphate (UDP) promoted activation by 2 min with similar profiles as that
      generated by injury. Preincubation with phospholipase C inhibitor, U73122,
      inhibited activation that was induced by injury and/or nucleotides. Lack of
      activation by alpha-beta-methylATP (alpha, beta-MeATP) and beta-gamma-methylATP
      (beta, gamma-MeATP) to purinergic (P)2X receptors further indicated that
      activation occurs via P2Y and not P2X purinergic receptors. These results
      indicate that injury-induced activation of ERK1/2 is mediated by a P2Y signaling
      pathway.

PMID- 15034930
TI  - Superinduction of IL-6 by cycloheximide is associated with mRNA stabilization and
      sustained activation of p38 map kinase and NF-kappaB in cultured caco-2 cells.
AB  - Protein synthesis inhibitors paradoxically increase the expression of early-gene
      products, including various cytokines, through a process known as superinduction.
      Superinduction is cell-specific and the mechanisms involved are not fully
      understood but are usually attributed to decreased mRNA degradation. There is,
      however, increasing evidence that activation of signaling cascades and increased
      transcriptional activation may be involved as well. Recent studies suggest that
      IL-6 production in the intestinal mucosa is particularly important due to its
      anti-inflammatory and protective effects. The effect of protein synthesis
      inhibitors on IL-6 production in enterocytes, however, is unknown. Treatment of
      Caco-2 cells with cycloheximide (10 microg/ml) increased IL-6 mRNA and protein
      levels in IL-1beta-treated cells and this was associated with increased mRNA
      stabilization. In addition, cycloheximide suppressed IkappaBalpha resynthesis and
      prolonged p38MAP kinase activation and these changes were associated with
      sustained activation of the transcription factor NF-kappaB. NF-kappaB activation,
      in turn, was prevented by the specific p38MAP kinase inhibitor SB208350. Our
      results suggest that superinduction of IL-6 by cycloheximide in enterocytes
      results from both increased mRNA stabilization and upregulated transcriptional
      activity mediated by prolonged activation of the p38 MAP kinase and NF-kappaB.

PMID- 15034931
TI  - Autocrine and paracrine nitric oxide regulate attachment of human osteoclasts.
AB  - Nitric oxide (NO) can reduce bone loss in chronic bone diseases. NO inhibits or
      kills osteoclasts, but the mechanism of action of NO in human bone turnover is
      not clear. To address this, we studied effects of NO on attachment and motility
      of human osteoclasts on mineralized and tissue culture substrates under defined
      conditions. Osteoclasts were differentiated in vitro from CD14 selected monocytes
      in RANKL and CSF-1, and characterized by cathepsin K expression, tartrate
      resistant acid phosphatase (TRAP) activity, acid secretion, and lacunar
      resorption. Cell attachment was labeled with monoclonal antibody 23C6, specific
      for a binding domain of a key osteoclast attachment protein, the CD51/CD61
      integrin dimer (alpha(v)beta(3)), with or without cell permeabilization. A ring
      of integrin attachment during bone degradation delimits an extracellular acid
      compartment, while alpha(v)beta(3) forms focal attachments on non-resorbable
      substrates. On resorbable substrate but not non-resorbable substrate,
      alpha(v)beta(3) labeling required cell permeabilization, in keeping with the
      membrane-matrix apposition that excludes large molecules and allows extracellular
      acidification. Acid secretion was labeled with the fluorescent weak base
      indicator lysotracker. NO donors, S-nitroso-N-acetyl penicillamine (SNAP) or
      sodium nitroprusside (SNP), downmodulated acid secretion simultaneously with
      cytoskeletal rearrangement, with alpha(v)beta(3) redistributed to a discontinuous
      pattern that labeled, on bone substrate, without membrane permeabilization. These
      effects were reversible, and an inhibitor of NO synthesis, N(G)-monomethyl-L
      arginine (l-NMMA), increased acid secretion and decreased heterogeneity of
      attachment structures, showing that NO is an autocrine regulator of attachment. A
      hydrolysis-resistant activating cGMP analog 8-(4-chlorophenylthio)guanosine-3',5'
      cyclic monophosphate replicated effects of NO donors, while an inhibiting analog,
      8-(4-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate, Rp-isomer,
      opposed them. On tissue culture or mineralized substrates, NO or cGMP analogs
      directly regulated motility; after washout cells reattached and survived for
      days. We conclude that NO is produced by human osteoclasts and regulates acid
      secretion and cellular motility, in keeping with autocrine and paracrine NO
      regulation of the resorption cycle.

PMID- 15034932
TI  - Inhibition of AP-1 transcription activator induces myc-dependent apoptosis in
      HL60 cells.
AB  - Transcriptional activation of AP-1 is intricately involved in cell proliferation
      and transformation. The natural product, nordihydroguaiaretic acid (NDGA) shows
      an inhibitory effect on the binding of jun/AP-1 protein to the AP-1 site in 12-O
      tetradecanoylphorbol-13-acetate (TPA)-stimulated HL60 cells. The NDGA inhibits
      the auto-regulated de novo synthesis of c-jun mRNA in TPA-stimulated HL60 cells.
      Our data also determine that this compound induces proliferation inhibition and
      apoptosis in human leukemia HL60 cells. To obtain information on the functional
      role of the AP-1 inhibition by NDGA in apoptosis signaling, the effects of
      pharmacological inhibition of AP-1 binding on c-myc, p53, and bax protein level
      were determined. Our results indicate that treatment of cells with NDGA enhances
      c-myc, p53, and bax protein levels. To rule out the possibility that NDGA will
      induce apoptosis because of the effects on proteins other than AP-1, we
      investigated the effect of another AP-1 inhibitor, SP600125, which is specific to
      Jun-N-terminal kinase. SP600125 decreased not only the phosphorylation level of
      jun protein but also AP-1/DNA binding activity. Also, apoptosis was observed to
      be induced by SP600125, concomitant with the increase in c-myc, p53, and bax
      protein level. In addition, apoptosis induced by both AP-1 inhibitors was
      accompanied by the activation of a downstream apoptotic cascade such as caspase
      9, caspase 3, and poly[ADP-ribose]polymerase (PARP). When the cells were treated
      with NDGA or SP600125 in the presence of antisense c-myc oligonucleotides,
      apoptosis was not observed and an increase of c-myc, p53, and bax proteins was
      not manifested. All these results show that the inhibition of the transcription
      factor AP-1 action is related with either the drug-induced apoptosis or the drug
      toxicity of the HL60 cells. The apoptosis induced by AP-1 inhibition may be
      dependent on c-myc protein levels suggesting that the c-myc protein induces
      apoptosis at a low level of AP-1 binding activity. Altogether, our findings
      suggest that the presence of the AP-1 signal acts as a survival factor that
      determines the outcome of myc-induced proliferation or apoptosis.

PMID- 15034933
TI  - BRCA1 interacts with dominant negative SWI/SNF enzymes without affecting
      homologous recombination or radiation-induced gene activation of p21 or Mdm2.
AB  - BRCA1 is a tumor suppressor gene linked to familial breast and ovarian cancer.
      The BRCA1 protein has been implicated in a diverse set of cellular functions,
      including activation of gene expression by the p53 tumor suppressor and control
      of homologous recombination (HR) during DNA repair. Prior reports have
      demonstrated that BRCA1 can exist in cells in a complex with the BRG1-based
      SWI/SNF ATP-dependent chromatin remodeling enzymes and that SWI/SNF components
      contribute to p53-mediated gene activation. To investigate the link between
      SWI/SNF function and BRCA1 mediated effects on p53-mediated gene activation and
      on mechanisms of homologous recombination, we have utilized mammalian cells that
      inducibly express an ATPase-deficient, dominant negative SWI/SNF enzymes. Mutant
      SWI/SNF ATPases retain the ability to interact with BRCA1 in cells. We report
      that expression of dominant negative SWI/SNF enzymes does not affect p53-mediated
      induction of the p21 cyclin dependent kinase inhibitor or the Mdm2 E3 ubiquitin
      ligase that regulates p53 in cells exposed to UV or gamma irradiation. Similarly,
      integration of a reporter that monitors homologous recombination by gene
      conversion into these cells demonstrated no change in the recombination rate in
      the absence of functional SWI/SNF enzyme. We conclude that the SWI/SNF chromatin
      remodeling enzymes may contribute to but are not required for these processes.

PMID- 15034935
TI  - Atomic structure of a CK2alpha human kinase by microfocus diffraction of extra
      small microcrystals grown with nanobiofilm template.
AB  - Extra-small microcrystals of a human kinase CK2alpha were obtained for the first
      time by the optimization of a recent protein crystallization method based on
      highly packed protein nanofilm template. Protein crystal induction and growth
      appear indeed optimal at high surface pressure of the film template yielding high
      protein orientation and packing. The resulting extra-small CK2alpha microcrystals
      (of about 20 microm in diameter) was subsequently used for synchrotron radiation
      diffraction data collection, which proves possible by means of the Microfocus
      Beamline at the ESRF Synchrotron in Grenoble. The quality of the resulting
      crystal diffraction patterns and of its resulting atomic structure at 2.4 A
      resolution proves the unique validity of the above two combined frontier
      technologies in defining a new approach to structural proteomics capable to solve
      the atomic structure of proteins so far never been crystallized and of
      pharmaceutical relevance. Physical explanation in terms of template dipole
      moments and possibility of generalization of this method to the wide class of
      proteins not yet crystallized are finally discussed. The structure of our
      CK2alpha mutant is in the Protein Data Bank (PDB ID Code 1NA7, deposited on 27
      November 2002).

PMID- 15034934
TI  - Functional idiotypic mimicry of an adhesion- and differentiation-promoting site
      on acetylcholinesterase.
AB  - Acetylcholinesterase mediates cell adhesion and neurite outgrowth through a site
      associated with the peripheral anionic site (PAS). Monoclonal antibodies raised
      to this site block cell adhesion. We have raised anti-idiotypic antibodies to one
      of these antibodies. The anti-idiotypic antibodies recognized the immunogenic
      antibody and non-specific mouse IgG, but not acetylcholinesterase. Five
      antibodies (out of 143 clones, an incidence of 3.5%) were able to promote neurite
      outgrowth in human neuroblastoma cells in vitro in a similar manner to
      acetylcholinesterase itself, suggesting that these antibodies carry an internal
      image of the neuritogenic site. Two of the antibodies were significantly more
      effective (P < 0.01) than acetylcholinesterase in this regard. The antibodies
      also bound specifically to mouse laminin-1 and human collagen IV, as does
      acetylcholinesterase. This binding was displaced by unlabelled antibody, as well
      as by acetylcholinesterase itself, indicating competition with
      acetylcholinesterase. We have also investigated the development of anti-anti
      idiotypic antibodies in mice in vivo, and have observed that four of these (out
      of 318 clones, an incidence of 1.26%) mimic the idiotypic antibody and abrogate
      adhesion in neuroblastoma cells. We have thus demonstrated functional mimicry of
      the neuritogenic site on acetylcholinesterase in anti-idiotypic antibodies,
      enhancement of this activity in one antibody, and mimicry of the idiotypic
      antibody site in anti-anti-idiotypic antibodies. Implications of these findings
      for differentiation-promoting cancer therapy are discussed.

PMID- 15034936
TI  - Signaling pathway of magnolol-stimulated lipolysis in sterol ester-loaded 3T3-L1
      preadipocyes.
AB  - The aims of the present study were to examine the effect of magnolol on lipolysis
      in sterol ester (SE)-loaded 3T3-L1 preadipocytes and to determine the signaling
      mechanism involved. We demonstrate that magnolol treatment resulted in a
      decreased number and surface area of lipid droplets, accompanied by release of
      glycerol. The lipolytic effect of magnolol was not mediated by PKA based on the
      facts that magnolol did not induce an elevation of intracellular cAMP levels, and
      protein kinase A (PKA) inhibitor KT5720 did not block magnolol-induced lipolysis.
      Calcium/calmodulin-dependent protein kinase (CaMK) was involved in this signaling
      pathway, since magnolol-induced a transient rise of intracellular [Ca(2+)] and
      Ca(2+) influx across the plasma membrane, and CaMK inhibitor significantly
      abolished magnolol-induced lipolysis. Moreover, magnolol increased the relative
      levels of phosphorylated extracellular signal-related kinases (ERK1 and ERK2). In
      support of the involvement ERK, we demonstrated that magnolol-induced lipolysis
      was inhibited by PD98059, an inhibitor of mitogen-activated protein kinase kinase
      (MEK), and PD98059 reversed magnolol-induced ERK phosphorylation. Further, the
      relationship between CaMK and ERK was connected by the finding that CaMK
      inhibitor also blocked magnolol-induced ERK phosphorylation. Taken together,
      these findings suggest that magnolol-induced lipolysis is both CaMK- and ERK
      dependent, and this lipolysis signaling pathway is distinct from the traditional
      PKA pathway. ERK phosphorylation is reported to enhance lipolysis by direct
      activation of hormone sensitive lipase (HSL), thus magnolol may likely activate
      HSL through ERK and increase lipolysis of adipocytes.

PMID- 15034937
TI  - Characterizing the new transcription regulator protein p60TRP.
AB  - Active cell death ('apoptosis' or 'programmed cell death') is essential in the
      development and homeostasis of multicellular organisms and abnormal inhibition of
      apoptosis is an indicator of cancer and autoimmune diseases, whereas excessive
      cell death might be implicated in neurodegenerative disorders such as Alzheimer's
      disease (AD). Using bioinformatics-, Western-blotting-, yeast-two-hybrid-system-,
      polymerase chain reaction (PCR)-, and fluorescence microscopy-analyses, we
      demonstrate here that the neuroprotective protein p60TRP (p60-transcription
      regulator-protein) is a basic helix-loop-helix (bHLH) domain-containing member of
      a new protein family that interacts with the Ran-binding-protein-5 (RanBP5) and
      the protein-phosphatase-2A (PP2A). The additional findings of its influence on
      NNT1 and p48ZnF (new-neurotrophin-1, p48-zinc-finger-protein)-signaling and its
      down-regulation in the brain of AD subjects point to a possible pivotal role of
      p60TRP in the control of cellular aging and survival.

PMID- 15034938
TI  - Mechanism of taxol-induced apoptosis in human SKOV3 ovarian carcinoma cells.
AB  - Taxol is extensively used clinically for chemotherapy of patients with ovarian,
      breast, and lung cancer. Although taxol induces apoptosis of cancer cells, its
      exact mechanism of action is not yet known. To determine the mechanism of action
      of taxol in ovarian cancer, we tested the effects of the drug, on the human
      ovarian carcinoma cell line, SKOV3. We observed that taxol-induced apoptosis of
      these cells by phosphatidylserine (PS) externalization and DNA fragmentation.
      While treatment of cells with taxol resulted in bcl-2 phosphorylation and
      mitochondrial depolarization, cytochrome c was not released and pro-caspase-3 was
      not activated. Treatment of SKOV3 cells with taxol, however, resulted in the
      translocation of AIF from the mitochondria to the nucleus via the cytosol. Taken
      together, these findings suggest that in SKOV3 cells, taxol induces caspase
      independent AIF-dependent apoptosis.

PMID- 15034939
TI  - Interleukin (IL)-17 enhances tumor necrosis factor-alpha-stimulated IL-6
      synthesis via p38 mitogen-activated protein kinase in osteoblasts.
AB  - Inflammatory cytokines are well known to play crucial roles in the pathogenesis
      of rheumatoid arthritis. Among them, interleukin (IL)-17 is a cytokine that is
      mainly synthesized by activated T cells and its receptors are present in
      osteoblasts. The synthesis of IL-6, known to stimulate osteoclastic bone
      resorption, is reportedly responded to bone resorptive agents such as tumor
      necrosis factor-alpha (TNF-alpha) in osteoblasts. It has been reported that IL-17
      enhances TNF-alpha-stimulated IL-6 synthesis in osteoblast-like MC3T3-E1 cells.
      We previously showed that sphingosine 1-phosphate (S1-P) mediates TNF-alpha
      stimulated IL-6 synthesis in these cells. In the present study, we investigated
      the mechanism of IL-17 underlying enhancement of IL-6 synthesis in MC3T3-E1
      cells. IL-17 induced phosphorylation of p38 mitogen-activated protein (MAP)
      kinase. SB203580 and PD169316, specific inhibitors of p38 MAP kinase,
      significantly reduced the enhancement by IL-17 of TNF-alpha-stimulated IL-6
      synthesis. IL-17 also amplified S1-P-stimulated IL-6 synthesis, and the
      amplification by IL-17 was suppressed by SB203580. Anisomycin, an activator of
      p38 MAP kinase, which alone had no effect on IL-6 level, enhanced the IL-6
      synthesis stimulated by TNF-alpha. SB203580 and PD169316 inhibited the
      amplification by anisomycin of the TNF-alpha-induced IL-6 synthesis. Taken
      together, our results strongly suggest that IL-17 enhances TNF-alpha-stimulated
      IL-6 synthesis via p38 MAP kinase activation in osteoblasts.

PMID- 15034940
TI  - Low doses and high doses of heparin have different effects on osteoblast-like
      Saos-2 cells in vitro.
AB  - Long-term treatment with heparin has been associated with an increased risk of
      osteoporosis. Given the importance of heparan sulfate proteoglycans for bone
      metabolism, it can be anticipated that heparin due to its structural similarity
      with heparan sulfate chains somehow interferes with the biological activities of
      these cell surface- and extracellular matrix-associated molecules. Initially in
      order to study the effect(s) of heparin on osteoblasts that possibly contribute
      to the development of heparin-induced osteoporosis, we treated osteoblast-like
      Saos-2 cells in monolayer culture for different periods of time with different
      concentrations of heparin. None of the heparin concentrations tested led to an
      inhibition of osteoblast proliferation during the early proliferative phase.
      After longer incubation times, however, cultures treated with higher
      concentrations of heparin (>/=5 microg/ml) exhibited a reduction in cell number
      as well as an inhibition of matrix deposition and mineralization. These effects
      could not be observed with lower heparin concentrations. On the contrary, low
      concentrations of heparin (5-500 ng/ml) even promoted matrix deposition and its
      subsequent mineralization. Apparently, heparin has a biphasic effect on
      osteoblast-like Saos-2 cells, being inhibitory at high concentrations but
      stimulatory at low concentrations. These results imply that heparin at
      concentrations well below those used for antithrombotic therapy might eventually
      turn out to be beneficial for bone formation.

PMID- 15034943
TI  - A self-stabilizing learning rule for minor component analysis.
AB  - The paper reviews single-neuron learning rules for minor component analysis and
      suggests a novel minor component learning rule. In this rule, the weight vector
      length is self-stabilizing, i.e., moving towards unit length in each learning
      step. In simulations with low- and medium-dimensional data, the performance of
      the novel learning rule is compared with previously suggested rules.

PMID- 15034944
TI  - Multi-layered greedy network-growing algorithm: extension of greedy network
      growing algorithm to multi-layered networks.
AB  - In this paper, we extend our greedy network-growing algorithm to multi-layered
      networks. With multi-layered networks, we can solve many complex problems that
      single-layered networks fail to solve. In addition, the network-growing algorithm
      is used in conjunction with teacher-directed learning that produces appropriate
      outputs without computing errors between targets and outputs. Thus, the present
      algorithm is a very efficient network-growing algorithm. The new algorithm was
      applied to three problems: the famous vertical-horizontal lines detection
      problem, a medical data problem and a road classification problem. In all these
      cases, experimental results confirmed that the method could solve problems that
      single-layered networks failed to. In addition, information maximization makes it
      possible to extract salient features in input patterns.

PMID- 15034941
TI  - Inducible superoxide dismutase 1 aggregation in transgenic amyotrophic lateral
      sclerosis mouse fibroblasts.
AB  - High molecular weight detergent-insoluble complexes of superoxide dismutase 1
      (SOD1) enzyme are a biochemical abnormality associated with mutant SOD1-linked
      familial amyotrophic lateral sclerosis (FALS). In the present study, SOD1 protein
      from spinal cords of transgenic FALS mice was fractionated according to
      solubility in saline, zwitterionic, non-ionic or anionic detergents. Both
      endogenous mouse SOD1 and mutant human SOD1 were least soluble in SDS, followed
      by NP-40 and CHAPS, with an eight-fold greater detergent resistance of mutant
      protein overall. Importantly, high molecular weight mutant SOD1 complexes were
      isolated with SDS-extraction only. To reproduce SOD1 aggregate pathology in
      vitro, primary fibroblasts were isolated and cultured from neonatal transgenic
      FALS mice. Fibroblasts expressed abundant mutant SOD1 without spontaneous
      aggregation over time with passage. Proteasomal inhibition of cultures using
      lactacystin induced dose-dependent aggregation and increased the SDS-insoluble
      fraction of mutant SOD1, but not endogenous SOD1. In contrast, paraquat-mediated
      superoxide stress in fibroblasts promoted aggregation of endogenous SOD1, but not
      mutant SOD1. Treatment of cultures with peroxynitrite or the copper chelator
      diethyldithiocarbamate (DDC) alone did not modulate aggregation. However, DDC
      inhibited lactacystin-induced mutant SOD1 aggregation in transgenic fibroblasts,
      while exogenous copper slightly augmented aggregation. These data suggest that
      SOD1 aggregates may derive from proteasomal or oxidation-mediated oligomerisation
      pathways from mutant and endogenous subunits respectively. Furthermore, these
      pathways may be affected by copper availability. We propose that non-neural
      cultures such as these transgenic fibroblasts with inducible SOD1 aggregation may
      be useful for rapid screening of compounds with anti-aggregation potential in
      FALS.

PMID- 15034945
TI  - Automatic kernel regression modelling using combined leave-one-out test score and
      regularised orthogonal least squares.
AB  - This paper introduces an automatic robust nonlinear identification algorithm
      using the leave-one-out test score also known as the PRESS (Predicted REsidual
      Sums of Squares) statistic and regularised orthogonal least squares. The proposed
      algorithm aims to achieve maximised model robustness via two effective and
      complementary approaches, parameter regularisation via ridge regression and model
      optimal generalisation structure selection. The major contributions are to derive
      the PRESS error in a regularised orthogonal weight model, develop an efficient
      recursive computation formula for PRESS errors in the regularised orthogonal
      least squares forward regression framework and hence construct a model with a
      good generalisation property. Based on the properties of the PRESS statistic the
      proposed algorithm can achieve a fully automated model construction procedure
      without resort to any other validation data set for model evaluation.

PMID- 15034946
TI  - Generalization of features in the assembly neural networks.
AB  - The purpose of the paper is an experimental study of the formation of class
      descriptions, taking place during learning, in assembly neural networks. The
      assembly neural network is artificially partitioned into several sub-networks
      according to the number of classes that the network has to recognize. The
      features extracted from input data are represented in neural column structures of
      the sub-networks. Hebbian neural assemblies are formed in the column structure of
      the sub-networks by weight adaptation. A specific class description is formed in
      each sub-network of the assembly neural network due to intersections between the
      neural assemblies. The process of formation of class descriptions in the sub
      networks is interpreted as feature generalization. A set of special experiments
      is performed to study this process, on a task of character recognition using the
      MNIST database.

PMID- 15034947
TI  - Rough sets and genetic algorithms in learning cellular neural networks cloning
      template for decision making system.
AB  - We purpose to find a new beneficial method for accelerating the Decision-Making
      and classifier support applied on imprecise data. This acceleration can be done
      by integration between Rough Sets theory, which gives us the minimal set of
      decision rules, and the Cellular Neural Networks. Our method depends on Genetic
      Algorithms for designing the cloning template for more accuracy. Some
      illustrative examples are given to demonstrate the effectiveness of the proposed
      method, whose advantages and limitations are also discussed.

PMID- 15034948
TI  - Antibiotics and surgery for vesicoureteric reflux: a meta-analysis of randomised
      controlled trials.

PMID- 15034949
TI  - [Treatment of Chagas disease with benznidazole and thioctic acid].
AB  - A multicenter, randomized, triple blind and controlled trial was designed to
      determine whether the combination with thioctic acid (TA), an antioxidant agent,
      can reduce the intolerance rate to Benznidazol (BZ) in patients infected with
      Trypanosoma cruzi. Four regimens were assigned randomly for 3 age intervals,
      administrating placebo or TA orally at daily doses of 50 to 100 mg in association
      with BZ at a dose of 5 mg/k/day for 30 days. In some, medication was given during
      a run-in period. Safety controls were carried out on days 10, 20, 37 and 52 days
      after therapy initiation. A total of 249 patients between 15 and 44 years old
      were enrolled. At the end of the trial, 70.3% of the patients had completed the
      treatment, while 17.7% required its suspension due to BZ related adverse
      reactions. The proportion of individuals affected with at least one side effect
      ranged from 54.8% to 58%; however, none were serious. Reported side effects
      included: cutaneous maculopapular rush (28%), pruritus (13.6%), headache (8%),
      epigastralgia (6.2%), fever (6.2%), fatigue (4.3%), nausea (4%), myalgias (4.3%),
      others (21.5%). The incidence of these reactions did not differ significantly
      among the 4 therapeutic regimens, nor even among the age intervals considered. It
      can be concluded that the association with TA did not prevent the occurrence of
      adverse reactions related to BZ administration. However, a single month cycle of
      this parasiticide permitted a high compliance rate to therapy among infected
      outpatients.

PMID- 15034950
TI  - Epidemiology of palpable goiter in greater Buenos Aires, an iodine-sufficient
      area [corrected].
AB  - The Hospital de Clinicas organized a free program of goiter detection by
      palpation. This campaign was aimed at the population of the metropolitan area of
      Greater Buenos Aires (11 million inhabitants), with the prerequisite that each
      participant should be quite unaware whether he/she was a carrier of any thyroid
      disease. Attendees were split into two groups, i.e., Random and Induced. The
      former consisted of 542 individuals who came to consultation due to mere
      curiosity, while the latter involved 500 subjects, comprising consanguineous
      family members of patients with thyroid disorders and also individuals who
      suffered from other ailments. Ages ranged from 2 to 85 years. In the Random
      Group, goiter prevalence of 8.7% was observed, while in the Induced Group it
      climbed to 14.4%. Since both groups were mostly made up of women (87.2%), a
      correction based on the masculinity index was applied to members of the Random
      Group. Thus, the total observed prevalence of goiter was 6%, diffuse goiters
      corresponding to 3.5% and nodular ones to 2.5%. The frequency of nodules
      increased with age, 90.5% occurring in those over 40 years. In the Induced Group,
      goiter prevalence among relatives of patients with thyroid disorders proved to be
      13.1%, rising to 17.8% in those who suffered from other complaints. The epidemic
      data presented herein are the first arising from a screening survey carried out
      in a large iodine-sufficient population of the southernmost tip of the American
      continent. These results are useful to build up the world map of goiter
      prevalence in non-endemic areas.

PMID- 15034951
TI  - Adult growth hormone deficiency. Metabolic alterations and evaluation of
      different risk groups.
AB  - Adult growth hormone deficiency (AGHD) is an heterogeneous clinical entity
      characterized by increased cardiovascular morbidity and mortality, alterations in
      body composition, osteoporosis and impaired quality of life. In order to
      characterize higher risk subpopulations we studied 77 patients with AGHD, 35 with
      childhood onset (AGHD-CO): CA 18-44 yr.; 13 females and 22 males, and 42 with
      adult onset (AGHD-AO): CA 25-70 yr.; 22 females and 20 males. IGF-I, lipid
      profile, glycemia and glycosylated hemoglobin were measured. Cardiological
      evaluation: blood pressure, electrocardiogram, ergometry and 2D echocardiogram
      with mitral Doppler, evaluation of diastolic function (A/E waves ratio and
      deceleration time), systolic function (ejection and shortening fractions) and
      Cardiac Mass Index (CMI). The Body Mass Index and waist circumference were
      recorded. Total body composition and bone mineral density were evaluated by
      densitometry, and the following bone markers were measured: osteocalcin, bone
      specific alkaline phosphatase, carboxyterminal propeptide of type I procollagen,
      Pyridinoline and Deoxipyridinoline. The subset of females with AGHD-AO had higher
      levels of total cholesterol: 240 mg/dl (156-351) (p < 0.005), LDL: 140 mg/dl (62
      262) (p < 0.04) and of total cholesterol/HDL: 4.04 (3.12-12.7) (p < 0.04); while
      females with AGHD-CO had a decreased CMI: 62 g/m2 (53-107) (p < 0.01), lower A/E
      waves ratio: 0.56 (0.39-0.72) (p < 0.01) and lower deceleration time: 164 msec.
      (135-210) (p < 0.01). The subset of males with AGHD-AO had a greater waist
      circumference: 98 cm (83-128) (p < 0.03) and males with AGHD-CO had a lower
      shortening fraction: 41% (30-49) (p < 0.006) and lower deceleration time: 153.5
      msec. (127-230) (p < 0.03). In both genders, the bone mineral content was lower
      in patients with AGHD-CO (females p < 0.02, males: p < 0.0008). Our findings
      confirm the differences in impairment in AGHD patients, which are mainly
      dependent on gender and the time of onset of the deficiency, and thus demonstrate
      the heterogeneity of the syndrome.

PMID- 15034952
TI  - Trastuzumab in the treatment of advanced breast cancer. Our single-center
      experience and spotlights of the latest national consensus meeting.
AB  - Human epidermal growth factor receptor (HER 2) is amplified in 25 to 30% of
      breast cancer patients and those whose tumors demonstrate HER 2 gene
      amplification and protein overexpression have an inferior prognosis manifested by
      shorter disease-free and overall survival. Trastuzumab, the humanized murine anti
      HER 2 monoclonal antibody, inhibits tumor growth when used alone and has
      synergistic and additive effects when used with chemotherapeutic agents
      (paclitacel-doxorrubicine). At the present time, the accurate diagnostic
      assessment of HER 2 is essential for appropriate application of the humanized
      anti HER 2 monoclonal antibody, trastuzumab, for the treatment of patients with
      metastatic breast cancer. FDA has approved its use for patients with metastatic
      breast cancer with HER 2 over-expression since 1998, as a first line treatment in
      association with paclitaxel or as a second or third line monotherapy. In
      Argentina, two Consensus Meetings of HER 2 Diagnosis have taken place: the first
      one on May 15th, 2002 and the second on April 11th, 2003, supported by Roche
      Laboratories (Herceptin). In this paper, some topics of these meetings are
      reviewed. Our single-public center experience is discussed.

PMID- 15034953
TI  - [Effects of the early administration of losartan on ventricular remodeling in
      rabbits with experimental myocardial infarction].
AB  - This study was carried out to investigate the effects of early administration of
      losartan on ventricular remodelling (VR) in rabbits with experimental myocardial
      infarction (MI). New Zealand rabbits underwent left coronary artery ligation.
      Four groups were analyzed: sham (G1; n = 13), MI (G2; n = 13), sham + Los (G3; n
      = 13) and MI + Los (G4; n = 13). Los (12.5 mg/kg/d) was administered 3 hours post
      MI during 35 days when the animals were sacrificed. The hearts were isolated and
      perfused using Langendorff's technique to determine systolic and diastolic
      pressure-volume (P/V) curves. Hearts were weighed, fixed in formaline, cut from
      apex to base, and stained with Masson's trichrome and pricrosirius red. The heart
      weight (HW)/body weight (BW) ratio was used as an index of hypertrophy. Infarct
      size (IS; %), septum (SeT, mm) and scar thickness (ST, mm) were measured using
      morphometric analysis. Results were expressed as mean +/- SEM. IS was G2 = 25.38
      +/- 5.31; G4 = 21.85 +/- 4.13 (NS). HW/BW was 3.45 +/- 0.16; 3.23 +/- 0.25; 2.87
      +/- 0.16; 3.23 +/- 0.18 in G1, G2, G3 and G4, respectively. Los shifted the
      diastolic P/V relationship to the right in sham and MI (p < 0.05 vs sham), and
      did not modify the systolic relationship. Scar collagen concentration was lower
      in G4 (p < 0.05 vs G2). SeT was lower in G3 and G4 (p < 0.05 vs G2). In
      conclusion, the early administration of Los unfavorably modified post-MI-VR,
      increasing ventricular dilation and reducing scar collagen concentration and
      thickness.

PMID- 15034954
TI  - [Effect of different doses of aspirin on preconditioning against stunning in
      conscious sheep].
AB  - Non-steroid antiinflammatory drugs, inhibitors of cyclooxigenase (COX), have been
      postulated to have deletereous effects on the heart. Recently, COX-2 inhibitors
      have also been found to block late preconditioning (LP) protection. Aspirin is
      the most widely clinically used non-steroid antiinflammatory drug; yet its effect
      on LP in big mammals has not been determined. It inhibits the two cyclooxigenase
      isoenzymes (COX-1 and COX-2), at high doses being used as an antiinflammatory
      drug and at low doses as an antithrombotic agent. The goal of this study was
      thus, to analyse the effect of different aspirin doses on LP protection against
      stunning and arrhythmias in a conscious sheep model. The animals were divided in
      5 groups: control (C): 12 min ischemia (I)-2 hr reperfusion (R); LP: 6 periods of
      5 min I-5 min R, 24 hr before 12 min I, and three groups same as LP, but with 1.5
      (LPA1.5), 8 (LPA8) and 20 (LPA20) mg/kg aspirin respectively, administered 10 min
      before the first preconditioning I. Results showed that the antiinflammatory dose
      of aspirin (20 mg/kg) was able to inhibit LP against stunning (C vs LPA20, NS),
      whereas low (1.5 mg/kg) and intermediate (8 mg/kg) doses did not interfere with
      the protection (C vs LP, LPA1.5 and LPA8, p < 0.01). Moreover, no dose altered
      the protection against arrhythmias. CONCLUSION: Antithrombotic aspirin doses
      would not inhibit LP protection against stunning, whereas high antiinflammatory
      doses would be potentially deletereous. Since high doses of aspirin blocked LP
      when administered before the triggering episodes, our results show that the COX
      pathway might be involved as a trigger of LP against stunning.

PMID- 15034955
TI  - [Survey on bioethics in a pediatric hospital. Basis for new strategies].
AB  - Although medical ethics is part of medicine since its beginning, it is only in
      the last decades that it is recognized as a necessary discipline. A survey of
      pediatricians of Hospital de Ninos Ricardo Gutierrez was carried out to determine
      a) the knowledge of basic concepts of bioethics b) the place and function of the
      committee. A total of 150 surveys were given out, 90 responses were obtained
      (60%). Basic concepts of bioethics (definition of bioethics, end of life,
      autonomy, justice, beneficence, and informed consent) were correctly answered by
      75.2%; 97.8% knew of the existence of the committee in the hospital, it had been
      consulted by 61.1%. From the group that had consulted the recommendations
      suggested by the committee to solve the ethical dilemma was considered: useful by
      23.6%, partially useful by 45.5% and not useful by 27.3%; 37.8% had never
      consulted the committee. Of these, 64.7% had never had a dilemma, 11.7%
      considered not useful any possible answer of the committee, and 11.7% did not
      give a reason. The majority of the responders had appropriate information of the
      basic bioethical concepts. Both the index of consultation to the committee and
      the assessment of its judgements as totally or partially useful (69.1%) guarantee
      its presence. It is peculiar that the principal argument for not consulting the
      committee was the absence of dilemmas. Both the committee in the hospital and the
      universities should intensify the teaching of medical ethics (mainly practical
      ethics), in order to facilitate the detection of ethical dilemmas by the health
      team.

PMID- 15034956
TI  - [New epidemiologic and molecular evidence of person to person transmission of
      hantavirus Andes Sout].
AB  - After the Hantavirus Pulmonary Syndrome (HPS) outbreak occurred in Southern
      Argentina (Patagonia) in 1996, a new mechanism of hantavirus spread was described
      for Andes virus (AND): person-to-person transmission. Since then, this mode of
      transmission has been limited to the endemic area of AND Sout lineage. We report
      here an HPS case, patient A, with residence in Buenos Aires Province, whose
      unique epidemiological risk factor was to have shared a trip to Southern
      Argentina with an already ill person, later confirmed as an HPS case (patient I).
      A third case (patient B), with residence in Buenos Aires Province, developed HPS
      after several contact events with patient A, with no additional risk factors.
      Hantavirus infection was confirmed in all three patients by serological diagnosis
      and viral genetic characterization. The viral lineage characterized was AND Sout,
      being the same strain in the three cases. The clinical picture of patient A
      showed profound compromise, with gastrointestinal symptoms, with no clinical
      evidence of pulmonary involvement. In this work we present new evidence
      supporting person-to-person transmission for AND Sout lineage, where there was an
      only contact with the index case, occasional, prolonged and non-repeated,
      established out of the endemic area for AND Sout lineage.

PMID- 15034957
TI  - [American integumentary leishmaniasis associated with AIDS in Argentina].
AB  - Migration of HIV infected individuals from cities to small towns and rural areas
      spreads AIDS among non urban population, superimposing HIV with other endemic or
      epidemic infections as parasitoses. This situation is a big challenge to public
      health because in most cases the association between these infections worsens
      both prognoses. We present here the first case in Argentina of AIDS associated to
      a mucocutaneous form of American tegumentary leishmaniasis. The patient was from
      Oran, an area where in the middle eighties, an epidemic outbreak took place. By
      now more than 2000 cases have been parasitologically confirmed in our Institute
      and the causing species were identified as Leishmania (V.) braziliensis and L.
      (L.) amasonensis. Considering the existence of co-infection of HIV and
      Leishmania, it is recommended that in patients from endemic areas with records of
      cutaneous or mucocutaneous ulcers, even healed, leishmaniasis must be
      investigated, among other diseases.

PMID- 15034958
TI  - [First degree atrio-ventricular block in acute thyrotoxicosis].
AB  - Thyrotoxicosis may present with a variety of cardiovascular symptoms. Sinus
      tachycardia is the most frequently encountered electrocardiographic abnormality
      and conduction disturbances are extremely uncommon. We present a case of first
      degree atrio-ventricular block in a patient with newly diagnosed hyperthyroidism
      and discuss the underlying pathophysiological mechanisms and the clinical
      implications from the internist's standpoint.

PMID- 15034959
TI  - [Collagen diseases and recurrent meningitis in an 88 year old patient].
AB  - Recurrent aseptic meningitis (RAM) infrequent in elderly patients and generally
      secondary to drugs. Its association with rheumatologic diseases is also seldom
      reported in the elderly. Sjogren Syndrome (SS) sometimes affects the central
      nervous system, but the association between recurrent meningitis and SS is rare,
      specially in this age-group. We present an 88 year-old auto-valid patient, with a
      history of xerostomia, xerophthalmia, Raynaud, dysphagia, and recurrent parotid
      enlargement. In 2001 she developed a lymphocytic meningitis with a complete
      remission. A year later, she developed again an aseptic lymphocytic meningitis.
      We ruled out infectious causes. We found a FAN titer 1/160 with a nucleolar
      mottled pattern, positive anti Ro and anti RNP antibodies and a positive lupus
      anticoagulant. We confirmed the ocular dryness and the lip biopsy was compatible
      with the diagnosis of SS. She had a good outcome with a complete remission
      without treatment in 10 days. We believe that this is a case of mixed connective
      tissue disease (MCTD) with predominant symptoms of SS, that developed a recurrent
      meningitis in its pure form. MCTD and SS should be considered in the differential
      diagnoses of RAM, also in the elderly.

PMID- 15034960
TI  - [Membranous kidney diseases in adults].
AB  - Membranous nephropathy is the most common histologic phenotype associated with
      the primary nephrotic syndrome in adults and the second most common etiological
      diagnosis in over sixteen hundred renal biopsies on native kidneys processed at
      our institution over a 30 year period. Renal survival at 10 years is about 70%,
      but the course of the disease is related to a series of factors which have
      constituted the basis for mathematical models developed to predict the natural
      history in a given individual. These factors are gender, age, renal function at
      the time of diagnosis, presence of the nephrotic syndrome, high blood pressure
      and the degree of structural damage. Although in low risk patients a period of
      observation and the use of ACE inhibitors is a reasonable option, most
      nephrologists would elect to use pharmacological treatment to induce remissions
      of proteinuria and preserve renal function. The use of steroids and cytotoxic
      agents in alternating monthly cycles over six months is firmly supported by
      controlled, randomized clinical trials. If patients are resistant to this regimen
      or clinical considerations indicate it may be inappropriately toxic, the use of
      cyclosporin over 6 to 12 months is also a good choice, and it has been shown to
      be useful even in the context of deteriorating renal function. Mycophenolate
      mofetil and possibly rituximab may be options of last resort before considering
      the patient resistant to therapy. At all times, treatment of hypertension, non
      specific antiproteinuric measures, and preventing complications of the nephrotic
      state should be top priorities in the overall therapeutic strategy.

PMID- 15034961
TI  - [Chemoprevention of breast cancer. Clinical trials in pharmacological
      prevention].
AB  - The following review article focuses on chemoprevention clinical trials of breast
      cancer. To date, SERMs (Selective Estrogen Receptor Modulators) have been the
      most studied drugs. Four randomized trials with tamoxifen vs. placebo have been
      performed and two with raloxifene are being carried out. Two tamoxifen trials
      showed between 30 and 50% reduction in breast cancer incidence. However, two
      other studies showed no statistical differences. Moreover, the real impact on
      mortality that these therapies could have is still unknown. This article includes
      a revision of trials that evaluated the relationship between daily vitamin intake
      and breast cancer. A follow up of these trials will give us answers about which
      patients will benefit from chemoprevention therapies.

PMID- 15034962
TI  - [The paradox of polyomaviruses. Lytic infection or tumor induction?].
AB  - Murine polyomaviruses can produce lytic infections in mouse cell cultures or
      transform in vitro rat fibroblasts through a complex interaction with key
      cellular regulators. After infection of newborn mice, some strains of
      polyomavirus induce epithelial and mesenchymal tumors. It has been described that
      there is a direct relationship between viral dissemination in the mouse and tumor
      induction. However, at a single cell level lytic infection and transformation
      would not be able to coexist. The existence of 3 distinct cell populations in
      polyoma-induced tumors, classified according to the presence or absence of viral
      DNA and viral capsid protein VP-1 have been described. We have reported a fourth
      type of cell in the neoplasms, that can express the early and the late viral
      genes but do not allow virus assembly, probably due to underphosphorylation of VP
      1. The mechanisms of polyoma intracellular migration and dissemination in the
      mouse are discussed, related to the virus' ability of tumor induction.

PMID- 15034963
TI  - [Role of interleukin-12 in cancer immunotherapy].

PMID- 15034965
TI  - [Researching and publishing in public health in Argentina].

PMID- 15034964
TI  - [The advantage of heterozygotes].

PMID- 15034966
TI  - [Mauricio Rosenbaum (1921-2003)].

PMID- 15034968
TI  - [Euthanasia, not causing death].

PMID- 15034967
TI  - [Clinicopathological conferences].

PMID- 15034969
TI  - [Conflict of interest].

PMID- 15034970
TI  - Antiretroviral treatment roll-out policy is in place--now for the implementation
      challenges.

PMID- 15034972
TI  - MRC mapping--extending the use of spatial data in health.

PMID- 15034971
TI  - The prevention of mother-to-child HIV transmission programme and infant feeding
      practices.

PMID- 15034973
TI  - The medical situation in Palestine.

PMID- 15034974
TI  - Healers 'get real' about tackling AIDS.

PMID- 15034975
TI  - Can we dance towards health?

PMID- 15034977
TI  - SANDF spearheads mobile telemedicine.

PMID- 15034976
TI  - Doctors fret while government drags heels.

PMID- 15034978
TI  - Children could be worst hit by flu this season.

PMID- 15034979
TI  - Department of Health recommendations pertaining to the use of viral vaccines-
      influenza, 2004.

PMID- 15034980
TI  - Improved malaria control boosts tourism.

PMID- 15034981
TI  - Urgent work needed to rebuild health care systems.

PMID- 15034982
TI  - Business planning, Part IV.

PMID- 15034983
TI  - Anatomists' attitudes towards the concept of race.

PMID- 15034984
TI  - Disseminated tuberculous osteitis.

PMID- 15034985
TI  - Sex slavery in India--an eye opener for South Africa?

PMID- 15034986
TI  - Recommendations pertaining to the use of viral vaccines: influenza, 2004.

PMID- 15034987
TI  - Smoking--is the public aware of the magnitude of the burden?

PMID- 15034988
TI  - Ventricular fibrillation in a clinically normal heart.

PMID- 15034989
TI  - HIV transmission during paediatric health care in sub-Saharan Africa--risks and
      evidence.
AB  - Health care systems in sub-Saharan Africa are challenged not only to improve care
      for the increasing number of HIV-infected children, but also to prevent
      transmission of HIV to other children and health care workers through
      contaminated medical procedures and needlestick accidents. HIV-infected children
      aged to 1 year typically have high viral loads, making them dangerous reservoirs
      for iatrogenic transmission. Most vertically infected children experience HIV
      related symptoms early, though many survive beyond 5 years. This leads to high
      HIV prevalence among inpatient and outpatient children. In nine African studies,
      HIV prevalence in inpatient children ranged from 8.2% to 63%, roughly 1-3 times
      the prevalence in antenatal women. Investigations of large iatrogenic outbreaks
      in Russia, Romania, and Libya demonstrate efficient HIV transmission through
      paediatric health care. Unexplained HIV infections in African children are not
      rare-studies published through 2003 have recorded more than 300 HIV-infected
      children with HIV-negative mothers. In addition, several studies have reported
      much higher HIV prevalence in children 5-14 years old than could be expected from
      mother-to-child transmission alone. Research is required to determine the extent
      of iatrogenic HIV infection among African children as well as to identify high
      risk procedures and settings. Such research can motivate and direct prevention
      efforts.

PMID- 15034990
TI  - Evidence-based obstetric care in South Africa--influencing practice through the
      'Better Births Initiative'.
AB  - Ensuring that health professionals practise according to evidence-based standards
      is important since it affects the quality and cost of care patients receive. The
      purpose of this research was to use a focused change programme (the Better Births
      Initiative) to influence obstetric practice of 10 hospitals in Gauteng, South
      Africa. The findings show some important improvements in practice following the
      implementation of the BBI; providers at some sites reduced the use of enemas,
      shaving and episiotomy, and increased use of oral fluids and companionship during
      labour. Qualitative data suggest that an interactive approach to implementing
      evidence-based practice can influence health professionals decisions to change
      practice, and that good working relationships and enthusiastic staff are central
      to effective change.

PMID- 15034991
TI  - An evaluation of nine probiotics available in South Africa, August 2003.
AB  - BACKGROUND AND OBJECTIVE: Although probiotics are not new, 5 new commercially
      available products have been launched onto the South African market in the last 2
      years.  Evaluations of products in the USA and Europe shown poor correlation
      between label claims and actual contents.  We undertook an evaluation of 9
      products currently available on the shelves in South Africa. METHODS AND
      ANALYSIS: An independent laboratory was used.  A culture method involving serial
      dilutions on selective media was used to obtain a colony count per gram for
      indicated organisma.  A non-culture method, denaturing gradient gel
      electrophoresis (DGGE), was used to determined the organisms present in the
      products. RESULTS: Disturbingly, we found a relatively poor correlation between
      the advertised and determined bacterial content. Only 3 of the 9 products tested
      contained the bacteria indicated on the label and 5 products contained sufficient
      bacteria for a probiotic effect.  The Enterococcus faecium, a potential pathogen
      and Saccharomyces cerevisiae found in 2 of the products are of concern.
      CONCLUSION: This evaluation confirms that the contents of several probiotics
      available in South Africa do not correspond to the label claims.  This is of
      concern as clinical efficacy is dependent on strain specificity and organism
      numbers.  Current regulatory requirements do not address this discrepancy.  As
      such,  we recommend that commercially available probiotic products be screened
      annually and the results of such quality control measures be made available to
      the Medicines Control Council (MCC).

PMID- 15034993
TI  - Europe: a challenging niche.

PMID- 15034992
TI  - Prevalence of HIV in workforces in southern Africa, 2000-2001.
AB  - OBJECTIVES: Most data on HIV prevalence in low-risk populations in sub-Saharan
      Africa are drawn from sentinel surveys of pregnant women attending antenatal
      clinics and are not representative of formal sector workforces. We surveyed
      workforces in southern Africa to determine HIV prevalence among formally
      employed, largely male populations. METHODS: Voluntary, anonymous, unlinked
      seroprevalence surveys of 34 workforces with 44,000 employees were carried out in
      South Africa, Botswana, and Zambia in 2000-2001. Results were stratified to
      obtain estimates of prevalence by industrial sector, location, age, sex, and job
      level. RESULTS: Average HIV prevalence for the entire sample was 16.6% (95% CI:
      16.3-17.0%). Country-wide prevalence was 14.5% (14.1-14.9%) in South Africa,
      17.9% (17.1-18.7%) in Zambia, and 24.6% (23.6-25.7%) in Botswana. Among
      industrial sectors, mining (18.0%, 17.6-18.5%) and metal processing (17.3%, 15.9
      18.7%) had the highest infection rates. Males, who comprised 85% of participants
      of known sex, were more likely (16.3%, 15.3-17.4%) to be infected than were
      females (10.7%, 8.7-12.7%). Contract (23%, 21.9-24.1%), unskilled (18.3%, 17.5
      19.1%), and semi-skilled workers (18.7%, 18.1-19.4%) were much more likely to be
      infected than were skilled workers (10.5%, 9.5-11.4%) and managers (4.5%, 3.4
      5.6%). Participation in the surveys averaged 63% of eligible employees.
      CONCLUSIONS: HIV prevalence among formally employed workers in southern Africa
      shows different patterns than among antenatal clinic attendees. Anonymous
      workplace surveys generate prevalence estimates for demographic groups that are
      not represented in antenatal surveys and can strengthen support for prevention
      and treatment interventions.

PMID- 15035003
TI  - Shrinking genomics.
AB  - Two bacteria are featured this month, and both are at the lower end of the genome
      size scale. The first, Mycoplasma gallisepticum, belongs to a group of bacteria
      that have been studied both as important human and animal pathogens and in the
      pursuit of understanding the essential functions of a self-replicating minimal
      cell. The second, Nanoarchaeum equitans, is an obligate symbiont that only grows
      in co-culture with another archaeon. N. equitans seems to be the coelacanth of
      the microbial world--it has been assigned to a new phylum and represents a
      primitive form of prokaroytic life.

PMID- 15035004
TI  - Schistosomiasis.

PMID- 15035005
TI  - The origin of malaria: mixed messages from genetic diversity.
AB  - Over the past 35 years, the incidence of malaria has increased 2-3-fold. At
      present, it affects 300-500 million people and causes about 1 million deaths,
      primarily in Africa. The continuing upsurge has come from a coincidence of drug
      resistant parasites, insecticide-resistant mosquitoes, global climate change and
      continuing poverty and political instability. An analogous rapid increase in
      malaria might have taken place about 10,000 years ago. Patterns of genetic
      variation in mitochondrial DNA support this model, but variation in nuclear genes
      gives an ambiguous message. Resolving these discrepancies has implications for
      the evolution of drug resistance and vaccine evasion.

PMID- 15035006
TI  - Chlamydia pneumoniae--an infectious risk factor for atherosclerosis?
AB  - Cardiovascular disease, of which atherosclerosis is an important component, is
      the leading cause of death in the western world. Although there are well-defined
      risk factors for atherosclerosis, these factors do not account for all incidences
      of the disease. Because atherosclerotic processes are typified by chronic
      inflammatory responses, which are similar to those that are elicited by chronic
      infection, the role of infection in promoting or accelerating atherosclerosis has
      received renewed attention. This review focuses on the accumulating evidence that
      chronic infection with Chlamydia pneumoniae, a ubiquitous human respiratory
      pathogen, might contribute to atherosclerotic lesion progression.

PMID- 15035007
TI  - The role of sexually transmitted diseases in HIV transmission.
AB  - More than 42 million people worldwide are now infected with HIV, in spite of
      sustained prevention activities. Although the spread of HIV has been primarily
      sexual, epidemiological studies have indicated that the efficiency of the spread
      of HIV is poor, perhaps as infrequently as 1 in every 1,000 episodes of sexual
      intercourse. However, sexually transmitted diseases (STDs) that cause ulcers or
      inflammation greatly increase the efficiency of HIV transmission--by increasing
      both the infectiousness of, and the susceptibility to HIV infection. STDs might
      be particularly important in the early stages of a localized HIV epidemic, when
      people with risky sexual behaviour are most likely to become infected. In China,
      eastern Europe and Russia, there has been a remarkable increase in the incidence
      of STDs in recent years, and this is reflected in the rapid increase in the
      spread of HIV in these areas. Targeted STD detection and treatment should have a
      central role in HIV prevention in these emerging epidemics.

PMID- 15035008
TI  - Trichoderma species--opportunistic, avirulent plant symbionts.
AB  - Trichoderma spp. are free-living fungi that are common in soil and root
      ecosystems. Recent discoveries show that they are opportunistic, avirulent plant
      symbionts, as well as being parasites of other fungi. At least some strains
      establish robust and long-lasting colonizations of root surfaces and penetrate
      into the epidermis and a few cells below this level. They produce or release a
      variety of compounds that induce localized or systemic resistance responses, and
      this explains their lack of pathogenicity to plants. These root-microorganism
      associations cause substantial changes to the plant proteome and metabolism.
      Plants are protected from numerous classes of plant pathogen by responses that
      are similar to systemic acquired resistance and rhizobacteria-induced systemic
      resistance. Root colonization by Trichoderma spp. also frequently enhances root
      growth and development, crop productivity, resistance to abiotic stresses and the
      uptake and use of nutrients.

PMID- 15035009
TI  - The regulation of bacterial transcription initiation.
AB  - Bacteria use their genetic material with great effectiveness to make the right
      products in the correct amounts at the appropriate time. Studying bacterial
      transcription initiation in Escherichia coli has served as a model for
      understanding transcriptional control throughout all kingdoms of life. Every step
      in the pathway between gene and function is exploited to exercise this control,
      but for reasons of economy, it is plain that the key step to regulate is the
      initiation of RNA-transcript formation.

PMID- 15035010
TI  - Molecular Koch's postulates applied to bacterial pathogenicity--a personal
      recollection 15 years later.
AB  - Koch's postulates were derived from Robert Koch's work on infectious diseases,
      such as anthrax and tuberculosis, which still engage us to this day. These
      guidelines were an attempt to establish a standard for identifying the specific
      causation of an infectious disease and to convince sceptics that microorganisms
      could cause disease. They were also established to encourage an increasing number
      of novice microbiologists to use more rigorous criteria before claiming a causal
      relationship between a microorganism and a disease.

PMID- 15035011
TI  - Can better prescribing turn the tide of resistance?
AB  - In the wake of concerns about the level of antibiotic resistance, governments
      worldwide are pressing for reduced antibiotic use, hoping thereby to reverse
      resistance trends. Is success likely? The evidence is mixed, and expectations
      should be tempered by the growing realization that many resistant bacteria are
      biologically fit, making them difficult to displace. If resistance is unlikely to
      be reduced significantly by changing prescription practices, how can clinicians
      outpace increased resistance, particularly when much of 'big pharma' is
      abandoning antibiotic development?

PMID- 15035012
TI  - Charity is not enough.

PMID- 15035020
TI  - Pathogenomics.
AB  - The genomes described this month reflect the overall historical bias of microbial
      genomics towards pathogenic bacteria. Although the balance is now being redressed
      to some extent, especially through the study of extremophiles, it is still the
      case that the opportunities provided by genomic studies are primarily taken up by
      those who study bacterial pathogenicity. This part of the field is, however,
      being broadened by including the study of pathogens of animals, insects and
      plants alongside those that afflict humans.

PMID- 15035021
TI  - Onchocerciasis.

PMID- 15035022
TI  - HIV-1 dynamics in vivo: implications for therapy.
AB  - The advent of potent combination antiretroviral therapy has been an important
      breakthrough in the treatment of HIV-1 infection, resulting in marked reductions
      in HIV-1-related morbidity and mortality. Antiretroviral therapy has also
      provided researchers with a powerful tool to perturb the equilibrium of viral
      production and viral clearance, allowing them to dissect the underlying dynamics
      that control the pathogenesis of AIDS. Here, we review our current understanding
      of the sources of HIV-1 production, the estimates for the virion and the host
      cell half-lives, and the pathways of virion trafficking and clearance. We also
      discuss the obstacles that result from the ability of HIV-1 to remain dormant for
      a prolonged period of time in a subset of long-lived cells, despite an apparently
      effective antiretroviral treatment.

PMID- 15035023
TI  - Cyanobacterial circadian clocks--timing is everything.
AB  - For more than three billion years, the organisms on this planet have known, like
      Little Orphan Annie, that "The sun'll come out tomorrow", and many have honed
      their biochemistry to exploit this knowledge. The cyanobacteria have had ample
      time to fashion a suitable timepiece, as they are among the oldest inhabitants of
      the earth. For these organisms, light is food, and it is a nutrient that shows up
      at the same time every day. Not surprisingly, cyanobacteria have learned to
      arrange their days around dinnertime.

PMID- 15035024
TI  - Psychrophilic enzymes: hot topics in cold adaptation.
AB  - More than three-quarters of the Earth's surface is occupied by cold ecosystems,
      including the ocean depths, and polar and alpine regions. These permanently cold
      environments have been successfully colonized by a class of extremophilic
      microorganisms that are known as psychrophiles (which literally means cold
      loving). The ability to thrive at temperatures that are close to, or below, the
      freezing point of water requires a vast array of adaptations to maintain the
      metabolic rates and sustained growth compatible with life in these severe
      environmental conditions.

PMID- 15035025
TI  - SARS--beginning to understand a new virus.
AB  - The 114-day epidemic of the severe acute respiratory syndrome (SARS) swept 29
      countries, affected a reported 8,098 people, left 774 patients dead and almost
      paralyzed the Asian economy. Aggressive quarantine measures, possibly aided by
      rising summer temperatures, successfully terminated the first eruption of SARS
      and provided at least a temporal break, which allows us to consolidate what we
      have learned so far and plan for the future. Here, we review the genomics of the
      SARS coronavirus (SARS-CoV), its phylogeny, antigenic structure, immune response
      and potential therapeutic interventions should the SARS epidemic flare up again.

PMID- 15035026
TI  - The pathogenesis of streptococcal infections: from tooth decay to meningitis.
AB  - The development of bacterial disease has been likened to a 'molecular arms race',
      in which the host tries to eliminate the bacteria, while the bacteria try to
      survive in the host. Although most bacteria do not cause disease, some cause
      serious human infection in a large proportion of encounters. Between these two
      extremes are bacteria that can coexist with humans in a carriage state but, under
      appropriate circumstances, cause disease. The streptococci exemplify this group
      of organisms, and by studying them we can begin to address why bacteria cause
      such a wide spectrum of disease.

PMID- 15035027
TI  - Studying the global distribution of infectious diseases using GIS and RS.
AB  - West Nile virus, severe acute respiratory syndrome and monkeypox are infectious
      diseases that have recently been introduced into areas far from their region of
      origin. The greatest risk of new diseases comes from zoonoses--pathogens that
      circulate among wild animals and are occasionally transferred to humans by
      intermediate invertebrate hosts or vectors that are sensitive to climatic
      conditions. Analytical tools that are based on geographical information systems
      and that can incorporate remotely sensed information about the environment offer
      the potential to define the limiting conditions for any disease in its native
      region for which there are at least some distribution data. The direction,
      intensity or likelihood of its spread to new regions could then be predicted,
      potentially allowing disease early-warning systems to be developed.

PMID- 15035028
TI  - Clostridia in cancer therapy.
AB  - During the past decade, the search for an effective system for the selective
      delivery of high therapeutic doses of anti-cancer agents to tumours has explored
      a variety of ingenious and increasingly complex biological systems. These systems
      are most often based on gene therapy and use viral vectors as the delivery
      vehicle. Invariably, such systems have been found wanting with respect to a lack
      of tumour specificity, poor levels of transgene expression and inefficient
      distribution of the vector throughout the tumour mass. By contrast, the ability
      of intravenously injected clostridial spores to infiltrate, then selectively
      germinate in, the hypoxic regions of solid tumours seems to be a totally natural
      phenomenon, which requires no fundamental alterations and is exquisitely
      specific.

PMID- 15035029
TI  - Will antibiotic misuse now stop?

PMID- 15035037
TI  - Fitting the niche by genomic adaptation.
AB  - Studying microbial genomics has shown that the genomes of bacteria are extremely
      dynamic in evolutionary terms. Many research groups have linked the adaptation of
      an organism to a niche to large changes in genome size and content. A number of
      recent papers have underlined the degree to which the genomes of different
      organisms are a reflection of the opportunities and constraints imposed by their
      chosen niche.

PMID- 15035038
TI  - Leprosy.

PMID- 15035039
TI  - Tuberculosis: a problem with persistence.
AB  - Mycobacterium tuberculosis is one of most successful pathogens of mankind,
      infecting one-third of the global population and claiming two million lives every
      year. The ability of the bacteria to persist in the form of a long-term
      asymptomatic infection, referred to as latent tuberculosis, is central to the
      biology of the disease. The persistence of bacteria in superficially normal
      tissue was recognized soon after the discovery of the tubercle bacillus, and much
      of our knowledge about persistent populations of M. tuberculosis dates back to
      the first half of the last century. Recent advances in microbial genetics and
      host immunity provide an opportunity for renewed investigation of this persistent
      threat to human health.

PMID- 15035040
TI  - The biology of mating in Candida albicans.
AB  - Candida albicans has maintained an elaborate--but largely hidden--mating
      apparatus, which shares some features with the closely related 'model' yeast
      Saccharomyces cerevisiae, but which also has some important differences. The
      differences are particularly noteworthy, as they could indicate the strategies
      that allow C. albicans to survive and mate in the hostile environment of a
      mammalian host. Indeed, some features of C. albicans mating seem to be intimately
      connected to its host.

PMID- 15035041
TI  - Regulation of endospore formation in Bacillus subtilis.
AB  - Spore formation in bacteria poses a number of biological problems of fundamental
      significance. Asymmetric cell division at the onset of sporulation is a powerful
      model for studying basic cell-cycle problems, including chromosome segregation
      and septum formation. Sporulation is one of the best understood examples of
      cellular development and differentiation. Fascinating problems posed by
      sporulation include the temporal and spatial control of gene expression,
      intercellular communication and various aspects of cell morphogenesis.

PMID- 15035042
TI  - Comparative genomics, minimal gene-sets and the last universal common ancestor.
AB  - Comparative genomics, using computational and experimental methods, enables the
      identification of a minimal set of genes that is necessary and sufficient for
      sustaining a functional cell. For most essential cellular functions, two or more
      unrelated or distantly related proteins have evolved; only about 60 proteins,
      primarily those involved in translation, are common to all cellular life. The
      reconstruction of ancestral life-forms is based on the principle of evolutionary
      parsimony, but the size and composition of the reconstructed ancestral gene
      repertoires depend on relative rates of gene loss and horizontal gene-transfer.
      The present estimate suggests a simple last universal common ancestor with only
      500-600 genes.

PMID- 15035044
TI  - Microorganisms and autoimmunity: making the barren field fertile?
AB  - Microorganisms induce strong immune responses, most of which are specific for
      their encoded antigens. However, microbial infections can also trigger responses
      against self antigens (autoimmunity), and it has been proposed that this
      phenomenon could underlie several chronic human diseases, such as type 1 diabetes
      and multiple sclerosis. Nevertheless, despite intensive efforts, it has proven
      difficult to identify any single microorganism as the cause of a human autoimmune
      disease, indicating that the 'one organism-one disease' paradigm that is central
      to Koch's postulates might not invariably apply to microbially induced autoimmune
      disease. Here, we review the mechanisms by which microorganisms might induce
      autoimmunity, and we outline a hypothesis that we call the fertile-field
      hypothesis to explain how a single autoimmune disease could be induced and
      exacerbated by many different microbial infections.

PMID- 15035046
TI  - Big spenders: small, rural hospitals fuel supply chain.

PMID- 15035045
TI  - Life-on-a-chip.
AB  - Mechanistic studies of cellular processes are usually carried out with large
      populations of cells. However, parameters that are measured as averages of large
      populations can be misleading. For instance, an apparently linear response to a
      signal could, in fact, reflect an increasing number of cells in the population
      that have switched from 'off' to 'on', rather than a graded increase in response
      by all the cells. At present, the study of single cells is challenging, but new
      technologies mean it might soon be a reality.

PMID- 15035043
TI  - The versatile bacterial type IV secretion systems.
AB  - Bacteria use type IV secretion systems for two fundamental objectives related to
      pathogenesis--genetic exchange and the delivery of effector molecules to
      eukaryotic target cells. Whereas gene acquisition is an important adaptive
      mechanism that enables pathogens to cope with a changing environment during
      invasion of the host, interactions between effector and host molecules can
      suppress defence mechanisms, facilitate intracellular growth and even induce the
      synthesis of nutrients that are beneficial to bacterial colonization. Rapid
      progress has been made towards defining the structures and functions of type IV
      secretion machines, identifying the effector molecules, and elucidating the
      mechanisms by which the translocated effectors subvert eukaryotic cellular
      processes during infection.

PMID- 15035047
TI  - Gown prices head downward.

PMID- 15035048
TI  - Capitated providers may gain from Medicare Advantage.

PMID- 15035049
TI  - For-profit, not-for-profit plans not so different in treatment.

PMID- 15035050
TI  - Use these detailed practice cost benchmarks to help conduct line item expense
      review.

PMID- 15035051
TI  - Improved HMO profitability may shift contracting power.

PMID- 15035052
TI  - [Histopathology and differential diagnosis of celiac sprue].
AB  - Marsh' classification of celiac disease or malabsorption syndrome sensu stricto
      is based on increased number of intraepithelial lymphocytes, as the first and
      constant sign/feature of the disease. Thereafter follow structural alterations of
      the mucous membrane, particularly of villous architecture, crypt height and
      enterocytes. According to the Marsh' classification, type 0 corresponds to normal
      mucous membrane, and type 1, the infiltrative type, is characterised by an
      increase in intraepithelial lymphocytes (IEL), which amount to more than 40
      lymphocytes/100 enterocytes. Type 2 has normal villous architecture, an increase
      in IEL numbers and crypt hyperplasia. Type 3, the destructive type, is
      characterised by villous atrophy and may be divided into three sub-groups
      depending on the degree of the atrophy-mild, marked, and total (flat mucosa).
      Combination of these histopathological findings, patient's history and clinical
      course may result in the definition of six "states" of celiac disease. Marsh'
      classification is helpful for an early diagnosis of the disease and should be
      applied in any case of the bioptical examination of the malabsorption syndrome.
      The disadvantage of this system, applied on formol-paraffin tissue sections, is
      impossibility of revealing disacharidases (particularly lactase) deficiency. From
      this point of view, histochemical detection of disacharidases should accompany
      the bioptical examination of jejunal mucosa.

PMID- 15035053
TI  - The histological findings in the gastroesophageal junction of fetuses.
AB  - The development of the esophageal and gastric mucosa in the gastroesophageal
      junction was studied in 61 fetuses of 13-41 weeks of the gestational age. During
      the 13th-15th week, the esophageal multilayered epithelium was covered by a
      continuous layer of columnar mucous ciliated cells which were present only
      focally till the 25th week and disappeared later. Before the 15th week, the
      gastric mucosa was formed by pits only. The glands started as proliferating
      tubules in the basal parts of the pits in the 15th week. Further, they
      differentiated into oxyntic glands. The mucosa of the corpus was fully developed
      in the 27th week. The cardiac mucosa was absent in all the 10 fetuses examined
      between the 27th and 41st week of gestation. This supports the view that the
      gastric cardiac mucosa is not a physiological structure but that it results from
      glandular metaplasia of the distal esophageal mucosa due to gastroesophageal
      reflux.

PMID- 15035054
TI  - [What is your diagnosis? Answer: adenomatoid tumor of the uterus].

PMID- 15035055
TI  - [Combined radiologic and microscopic examination of nonpalpable breast lesions
      with microcalcification].
AB  - Radiograms of nonpalpable breast lesions containing calcifications represent one
      of the most important fields of using x-ray in breast pathology. An analysis of a
      group of 52 nonpalpable lesions of breast with calcifications revealed a
      discrepancy between the presence of calcifications in radiograms and in
      histological sections. An absence of calcifications was observed in 47 of 301
      (15.7%) paraffin blocks. Calcifications were lost by cutting them off from the
      blocks, by leaving them deeper in blocks so that they were absent in sections, or
      by losing them by various other ways during processing of the blocks. An
      algorithm for examination of nonpalpable calcified lesions of breast has been
      developed. During the procedure, tissue slices and paraffin block were x-rayed,
      thus increasing the detection of calcifications in blocks from 76% to 84.3%.

PMID- 15035056
TI  - [Thyroid peroxidase in the differential diagnosis of thyroid gland lesions. A
      marker of biological behavior or differentiation?].
AB  - Human thyroid peroxidase (hTPO) is a membrane protein with a key role in the
      thyroid hormones synthesis. Loss of hTPO was described in malignant tumours of
      the thyroid gland. hTPO was tested as a marker of malignancy. Immunohistochemical
      study of hTPO in 321 thyroid lesions (45 malignant tumours, 72 benign tumours,
      199 benign non-tumours lesions, and 5 normal thyroid glands) is presented. The
      sensitivity of hTPO in predicting malignancy in thyroid is 64%, and the
      specificity is 87%. Thus, hTPO is of limited value in the diagnosis of thyroid
      malignancy. The authors discuss the role of hTPO as a marker of differentiation.

PMID- 15035057
TI  - [Bone marrow fibrosis during therapy of hairy cell leukemia].
AB  - The influence of Cladribin therapy to bone marrow fibrosis in patients with hairy
      cell leukemia was studied. Eighteen patients were included in the study; bone
      marrow fibrosis was graded 0-4 according to the quantity and pattern of
      distribution of reticulin. The grade of bone marrow fibrosis was established
      before the therapy and then in 12- and 24-month intervals. Patients showed
      complete remission after the therapy and remarkable reduction of bone marrow
      fibrosis.

PMID- 15035058
TI  - [Recurrent polyomavirus infections in kidney transplants (BK virus nephropathy)].
AB  - BK-virus nephropathy was recently recognised as a new complication that affects
      renal allografts and causes dysfunction. We report a case of a recipient of
      simultaneous kidney-pancreas allografts. Fourteen months after the transplant,
      the renal allograft became dysfunctional with elevation of serum creatinine
      level. The diagnosis of BK-virus nephropathy was established by needle renal
      biopsy with immunohistochemical detection of human polyoma virus.
      Immunosuppressive therapy was reduced but progressive dysfunction developed and
      the patient had to undergo a renal retransplantation 11 months after the
      diagnosis of the infection. Due to repeated renal dysfunction, needle biopsy was
      performed, and the diagnosis of repeated BK-virus nephropathy was established six
      months after the retransplantation. The pancreas allograft has functioned well
      for the entire period.

PMID- 15035059
TI  - [History of pathologic anatomy--part 3].

PMID- 15035060
TI  - [Remembrance of Dr. Jan Vignati].

PMID- 15035061
TI  - [Detection of new antidepressive agents using thin-layer chromatography].
AB  - Series of new antidepressants appeared in the treatment of central nervous system
      disorders in the last years. Into this group belong: 1. antidepressants of the
      3rd generation which selectively inhibit serotonine reuptake; 2. thymoleptics--a
      group of compounds which have no anticholinergic effects and act as noradrenaline
      reuptake inhibitors or noradrenaline and serotonine reuptake inhibitors; 3.
      antipsychotics from the group of selective serotonine and dopamine antagonists.
      All they have less undesirable side-effects than classical tricyclic
      antidepressants of the first generation and thymoleptics of the second
      generation. Thus they are nowadays more often used as the drugs of the first
      choice and are therefore met more often in the biological material analyzed in
      toxicological laboratories. This contribution deals with the detection and
      identification of paroxetine, sertraline, venlafaxine, mirtazapine, tianeptine,
      risperidone and quetiapine in urine by thin layer chromatography.

PMID- 15035062
TI  - [Trends in toxicologic examinations in clinical practice].
AB  - Review presented on the occasion of the significant life jubilee of Prof. J.
      Tesar, MD, DrSc., 16.12.2002 in the Medical House in Prague deals with the
      development and application of analytical technologies in toxicological practice
      in the last fifty years, with demands on decreasing the size of biological
      samples, detection limits achievable, with possibilities of interpretation
      deduced from analyses of alternative matrices. The paper also informs about
      scientific guidelines applied in Europe with attention focused on the reliable
      detection of illicit drugs in the workplace or drugs and driving. Based on more
      advanced analytical strategy, more complete and more precise information can be
      achieved and consequently more perfect interpretation based on objective evidence
      can be gained and it can comply to "Evidence Based Forensic Toxicology".

PMID- 15035063
TI  - [Molecular epidemiology of the leprosy].
AB  - Application of molecular biological techniques to the epidemiological study of
      leprosy is described. Studies of detecting Mycobacterium leprae DNA in samples of
      the nasal mucus are discussed in terms of the epidemiology and the significance
      of high prevalence. Epidemiological studies on the transmission of leprosy and
      correlation between geographic distribution of different M. leprae rpoT genotypes
      and prehistoric spread of the leprosy by genotyping based on the genomic
      polymorphism are introduced.

PMID- 15035064
TI  - Studies of lipoproteins of Mycobacterium leprae.
AB  - The deciphering of the genomic sequence of Mycobacterium leprae has made possible
      to predict the possible lipoproteins. The consensus sequence at the N-terminal
      region of the protein, including the cysteine residue to which the lipid moiety
      gets attached, provides a clue to the search. As such, more than 20 putative
      lipoproteins have been identified from Mycobacterium leprae genomic sequence.
      Lipoprotein LpK (Accession no. ML0603) which encodes for 371 amino acid precursor
      protein, was identified. Expression of the protein, in Escherichia coli revealed
      a 33 kD protein, and metabolic labeling experiments proved that the protein was
      lipidated. The purified lipoprotein was found to induce production of IL-12 in
      human peripheral blood monocytes which may imply that M. leprae LpK is involved
      in protective immunity against leprosy. Pursuit of such lipoproteins may reveal
      insights into the pathogenesis of the disease.

PMID- 15035065
TI  - [Ocular impairment in leprosy].
AB  - Leprosy causes several ocular disorders, and it also causes aftereffect with high
      frequency in various ways. Primary impairment is the ocular disturbance caused
      with direct invasion of nerve and ocular tissue by Mycobacterium leprae.
      Secondary impairment is the complication of nerve paralysis and residual
      inflammation due to primary disorder. Main work at Japanese national leprosariums
      has been the control of primary and secondary impairment in recent years.
      Clinical ophthalmic study in the leprosarium revealed a increase of age-related
      ocular disease in addition to aftereffect of leprosy. Severe sequelae due to
      sensory and functional disturbance will require suitable applications of advanced
      clinical technologies.

PMID- 15035066
TI  - [Global situation of leprosy and recent progress in molecular epidemiology of the
      disease].
AB  - Recent discovery of genetic diversity of Mycobacterium leprae such as variable
      number of tandem repeats opened a new era in molecular epidemiology of leprosy
      infection. It was revealed that the leprosy bacillus in residential environment
      of endemic villages is an important source of infection. The global elimination
      strategy will be revised taking new molecular epidemiological knowledge into
      account. Responsibility of leprosy specialist is to propose feasible control
      program to local administration based on the epidemiological analysis on
      transmission of the disease.

PMID- 15035067
TI  - [The history of Yunosawa village and the policy of leprosy of Japan. IV].
AB  - There was a village which was called Yunosawa, lots of leprosy patients lived,
      existed from 1887 to 1941, Kusatu town, Gunnma Prefecture, Japan. It was the only
      place continued securing self-government to the last as area was free from the
      isolation policy of State in prewar days there. The aim of this study will make
      clear the dynamism of "The protection from the tension of the society of leprosy
      patient currently persecuted" to "The defense of the society from the leprosy
      patient who is a source of infection". In this study, explained the factor of
      confusion to a National Leprosarium Kuryu Rakusen-en during World War II and
      considered relation between patient movement and residents of Yunosawa village at
      the postwar period.

PMID- 15035068
TI  - [Guideline for the treatment of leprosy by new quinolones].
AB  - Ofloxacin(OFLX) is often applied today as a substitution drug of MDT for drug
      resistance to dapsone, rifampicin or clofazimine. However, OFLX resistance is
      also becoming a great concern. Low and/or irregular administration are considered
      to be the major causes of OFLX resistance. OFLX should be used as a combined
      therapy, and minimal daily dose of 400 mg of OFLX or 200-300 mg of levofloxacin
      is required. Quinolone resistance should be considered when no improvement of
      clinical and/or bacterial index is observed after the treatment for 6 months. In
      such cases, resistance gene detection is necessary.

PMID- 15035069
TI  - [Individual temperature management during thoracoabdominal aortic aneurysm repair
      using separate perfusion of upper and lower torso].
AB  - We report thoracoabdominal aortic aneurysm repair using separate perfusion of
      upper and lower torso that can control temperature of each organ individually.
      This novel modality can maintain mild hypothermic organ perfusion in upper torso
      and protect the heart under empty beating, while lower torso is further cooled to
      protect the spinal cord and visceral organs. Therefore this technique may be
      useful for patients with heart disease who require complex reconstruction of the
      intercostal arteries or visceral branches. We used this technique successfully in
      a patient who has a history of surgical repair of the aortic arch and the
      abdominal aorta. A 70-year-old male who had a history of abdominal aortic
      aneurysm repair and aortic arch aneurysm repair using stented elephant trunk
      underwent Crawford's type II thoracoabdominal aortic aneurysm repair. Three pairs
      of the intercostal arteries and 4 visceral branches were reconstructed using this
      technique successfully.

PMID- 15035070
TI  - [Familial spontaneous pneumothorax].
AB  - A case of familial spontaneous pneumothorax was reported. A 52-year-old man was
      referred to our hospital complaining of exertional dyspnea. He had experienced
      right spontaneous pneumothorax and cured with tube drainage last year. Five of
      his 7 brothers and his son too had had spontaneous pneumothorax. Chest X-ray film
      and computed tomography (CT) scan on admission showed giant bulla of the left
      lung with compression of normal lungs. Pulmonary function studies revealed
      obstructive pulmonary disease and mild hypoxemia. Partial resection of the lung
      with open thoracotomy surgery was performed. Air leaks sealed in 14 days and the
      patient discharged the hospital with inadequate expansion of the left lung. Three
      years later the patient experienced right hemicolectomy for colon cancer and died
      for recurrence 7 years later with adequate expansion of the left lung.

PMID- 15035071
TI  - [Natural Y-grafting using internal thoracic artery branches for off-pump coronary
      artery bypass].
AB  - The excellent long-term patency rates achieved utilizing the internal thoracic
      arteries (ITAs) have stimulated a variety of approaches to expand the use of
      these conduits in coronary revascularization. The ITA divides at the level of the
      fifth or sixth intercostal space into the superior epigastric and musculophrenic
      branches. If these terminal branches of the ITA are large and long enough for
      grafting, they can be used to construct a "Y" anastomosis to the coronary
      arteries. We experienced 2 patients who underwent multivessel off-pump coronary
      artery bypass (OPCAB) using these ITA branches. In both patients the bilateral
      ITAs and the right gastroepiploic artery were taken down using the
      skeletonization technique as in situ grafts. One patient had 5 grafts including
      the right ITA terminal branches which were used for the left anterior descending
      branch (LAD) and diagonal branch. Another patient had 6 grafts including the left
      ITA terminal branches which were used for the posterolateral branch (PL)1 and
      PL2. Postoperative angiography revealed widely patent grafts in both patients. We
      believe that one of the advantages of applying the off-pump technique when the
      ITA branches are used is that it might be easier to arrange the angle of
      constructing a natural "Y" configuration compared with conventional coronary
      artery bypass grafting (CABG). In conclusion, the terminal branches of the ITA,
      if of suitable size, should be considered for "Y" grafts to diseased coronary
      arteries when performing complete arterial revascularization with only in situ
      grafts.

PMID- 15035073
TI  - [Two-port video-assisted thoracoscopic excision of an intercostal schwannoma].
AB  - We report a thoracoscopic resection of a benign schwannoma of the ninth
      intercostal nerve in a 62-years-old man. The extraction of the tumor from the
      chest was performed through only 2 thoracic trocars. The 2 trocar technique is
      associated with better cosmetic results, less operative damage, and shorter
      hospitalizations. We consider that the 2 trocar thoracoscopic technique for an
      intercostal schwannoma, presenting as a small chest wall tumor, may be a useful
      approach.

PMID- 15035072
TI  - [The efficiency of nifekalant hydrochloride for the prevention of ventricular
      tachycardia during cardiac surgery].
AB  - Many cases have been successfully treated by us with experimented nifekalant
      hydrocholoride to prevent ventricular tachycardia (VT) during cardiac surgery.
      The 13 patients who underwent cardiac surgery at our hospital from 1999 to 2002
      were retroactively given nifekalant hydrocholoride against VT. Lidocaine
      hydrochloride was not effective for VT, and it was difficult for 3 patients to be
      weaned for cardio-pulmonary bypass, while 6 patients needed aortic balloon
      pumping or percutaneous cardio-pulmonary support. Nifekalant hydrochloride
      suppressed VT induction in 9 patients (69.2%). Blood pressure and heart rate did
      not change, but QTc intervals were significantly increased with nifekalant
      hydrochloride (p < 0.005). Proarrhythmic events (Torsades de pointes) occurred in
      2 patients, but none of the cases showed drug-induced worsening of cardiac
      function. Nifekalant hydrochloride is a class III antiarrhythmic drug that has
      been found to be effective against VT and ventricular fibrillation. While class I
      antiarrhythmic drugs are usually ineffective and induce severe heart failure,
      nifekalant hydrochloride can be effective.

PMID- 15035074
TI  - [Management for type A acute dissection].
AB  - From March 1998 to May 2002, we experienced 46 patients with type A acute
      dissection (AAD). Fifteen patients managed initially with conservative treatment
      because of intramular hematoma (IH, n = 10), broad cerebral infarction (n = 3),
      others (n = 2). One who diagnosed IH at admission progressed to AAD and underwent
      surgery. However his diagnosis of IH at admission was proved to be misdiagnosis
      retrospectively. In 8 of the remaining 9 patients, hematoma disappeared during
      the follow-up of 6 months to 1 year. In patients with broad cerebral infarction,
      2 died early after admission and 1 discharged with hemiplegia. Thirty-two
      patients underwent surgery and 1 with preoperative broad cerebral infarction died
      36 days after surgery. In the remaining 31 patients, 30 patients discharged
      ambulatory.

PMID- 15035075
TI  - [Two delayed cases of traumatic diaphragmatic hernia].
AB  - This report concerns 2 cases with blunt traumatic hernia of the diaphragm. The
      diagnosis of these cases had been delayed by 1 month and 6 years, respectively.
      The former was a left sided case, which had suddenly suffered severe dyspnea. An
      emergency operation revealed the dislocated stomach into the left thoracic
      cavity. The latter was a right sided case, which was discovered by chance during
      the laparoscopic cholecystectomy. The right lobe of the liver dislocated into the
      right thoracic cavity. The delayed case of traumatic diaphragmatic hernia tends
      to be overlooked without suspicion. In all patients with thoracoabdominal blunt
      injury, a rupture of the diaphragm must be suspected.

PMID- 15035076
TI  - [The ischemic mitral valve regurgitation due to acute coronary thromboembolism;
      report of a case].
AB  - A 71-year-old man with congestive heart failure due to acute myocardial
      infarction was referred to our hospital. He was under the support of mechanical
      ventilation and the intraaortic balloon pumping (IABP) and coronary angiogram
      revealed the thromboembolism of the obtuse marginal artery. We completed the
      revascularization by the direct percutaneous coronary intervention. However,
      grade II mitral valve regurgitation and heart failure were worsening. Mitral
      valvuloplasty and the modified maze procedure through the partial lower
      sternotomy were performed. He is still in good condition 4 years later. Ischemic
      mitral valve regurgitation due to the coronary thromboembolism is very rare.
      Careful follow-up on the grade of ischemic mitral valve regurgitation is
      necessary even after the early coronary recanalization. The surgical approach of
      the partial sternotomy should be used in such a case of acute mitral valve
      regurgitation.

PMID- 15035077
TI  - [Right ventricular myxoma with syncopal attach; report of a case].
AB  - Cardiac myxoma of right ventricle is rare. We report a 16-year-old girl who
      underwent an emergent surgical resection of right ventricular myxoma. She had
      syncopal attach in going to school and was referred to our hospital in emergency.
      There were no abnormal findings in brain computed tomography (CT) and
      electroencephalogram, but Levine IV/VI systolic ejection murmur was heard.
      Echocardiography and magnetic resonance imaging (MRI) revealed the presence of
      large mass in the right ventricle which was floating into the pulmonary artery.
      The tumor was removed completely through the both of main pulmonary artery and
      right atrium using cardiopulmonary bypass. The tumor was attached to the right
      ventricle free wall by a pedicle, which was 5 x 3 cm in size and was diagnosed as
      myxoma by histopathological examination.

PMID- 15035078
TI  - [Total aortic arch replacement for aortic arch aneurysm in a 90-year-old woman;
      report of a case].
AB  - A 90-year-old woman was transferred to our hospital because of severe chest and
      back pain. Chest computed tomography (CT) scan showed impending rupture of the
      true aneurysm of the aortic arch. Emergent operation was performed under deep
      hypothermia and retrograde cerebral perfusion through median sternotomy.
      Ascending and transverse aorta were totally replaced with arch graft with 4
      branches using the arch vessels first technique. Postoperative course was
      uneventful expect for urinary tract infection. She discharged from our hospital
      76 days after the operation and is now doing well.

PMID- 15035079
TI  - [Mitral regurgitation due to sole punched out lesion of the mitral anterior
      leaflet in infective endocarditis; report of a case].
AB  - Mitral regurgitation (MR) due to only punched out lesion is extremely rare in
      infective endocarditis. A 31-year-old male was admitted to our hospital due to
      unusual cause of MR. Echocardiography showed MR due to punched out lesion of the
      mitral anterior leaflet, which is extremely rare. A round shape punched out
      lesion (about 16 mm in size) was found intraoperatively in the anterior leaflet
      of the mitral valve. The surface around the punched out lesion was smooth, and
      the leaflet displayed good movability. Neither vegetation nor calcification was
      found. Punched out lesion was successfully closed with autologous pericardial
      patch and annuloplasty was performed.

PMID- 15035080
TI  - [Aortic valve papillary fibroelastoma; report of a case].
AB  - Papillary fibroelastoma is a rare cardiac tumor. We report a case of surgical
      treatment for aortic valve papillary fibroelastoma. The patient was a 64-year-old
      female. She admitted our hospital for the evaluation of cardiogenic cerebral
      infarction. The echocardiogram revealed a mobile rounded mass (10 x 6 mm) of the
      aortic valve and aortic regurgitation. On the basis of these echo findings, we
      performed operation. Under cardiopulmonary bypass, aortotomy was made and aortic
      valve was observed. A tumor was on the non-coronary-cusp of the aortic valve,
      which was successfully removed followed by aortic valve replacement with 21 A
      Carpentier-Edwards bio-prosthetic valve. The tumor was histologically diagnosed
      papillary fibroelastoma. Following uncomplicated postoperative course, the
      patient was discharged on twenty-first postoperative day.

PMID- 15035081
TI  - [Successful treatment for tachyarrhythmia with ultra short acting beta-blocker
      during beating coronary artery bypass grafting; report of a case].
AB  - A 62-year-old man with supraventricular/ventricular tachycardia associated with
      myocardial infarction developed tachycardia during beating coronary artery bypass
      grafting (CABG). Intravenous administration of an ultra short acting beta
      blocker, landiolol hydrochloride, controlled heart rate and improved
      tachyarrhythmia without significant change of blood pressure. Landiolol
      hydrochloride is effective and useful for the treatment of tachyarrhythmia during
      beating CABG.

PMID- 15035082
TI  - [One-staged operation for multiple aortic aneurysms of the descending thoracic
      aorta and abdominal aorta; report of a case].
AB  - A 66-year-old man underwent successfully on one-staged operation for aneurysms of
      the descending thoracic aorta and abdominal aorta. For the operation of
      descending thoracic aortic aneurysm, a temporary bypass was used from the
      proximal side of aneurysm to the distal one. The sacculer aneurismal wall of the
      descending thoracic aorta was repaired by patch formation using a knitted graft.
      Abdominal aortic aneurysm was replaced using a Gelsoft graft. The operation time
      was 7 hours and 35 minutes. Blood transfusion was not needed. The postoperative
      course was uneventful. It is suggested that one-staged operation for descending
      thoracic aortic aneurysm under the assist of temporary bypass and abdominal
      aortic aneurysm is possible.

PMID- 15035083
TI  - [Acute aortic dissection 16 months after aortic valve replacement; report of a
      case].
AB  - A 63-year-old man complained of chest pain and back pain 16 months after aortic
      valve replacement. Computed tomography (CT) showed acute aortic dissection
      (Stanford A) and we decided to perform operation. We found an entry at aortotomy
      on operative findings. Under hypothermic circulatory arrest graft replacement of
      ascending aorta was performed. Postoperative course was uneventful.

PMID- 15035084
TI  - [Mediastinal non seminomatous germ cell tumor successfully treated with
      chemotherapy and curative surgery; report of a case].
AB  - A 20-year-old male was clinically diagnosed as having a mediastinal non
      seminomatous germ cell tumor because of the elevation of the serum AFP and a
      large mass lesion in the anterior mediastinal and right thoracic cavity. After 3
      courses of chemotherapy with cisplatin (CDDP) and etoposide (VP-16), the serum
      level decreased to normal range. But, the mediastinal mass enlarged after
      chemotherapy due to hemorrhage. The tumor was completely removed with sternotomy
      and right thoracotomy. Postoperative course was uneventful, and he has been free
      of recurrence for 2 years.

PMID- 15035085
TI  - [Pulmonary undifferentiated carcinoma associated with severe inflammatory
      response; report of 2 cases].
AB  - We present 2 cases with pulmonary undifferentiated carcinoma accompanying severe
      inflammatory responses. Both patients initially complained high-grade fever.
      Laboratory data on admission showed leukocytosis and elevation of serum CRP
      level. In both cases, the tumors were characterized by a low-density mass with
      the enhanced wall on chest computed tomography (CT). The presence of tumor cells
      could not be identified by bronchoscopical examination. One patient was suffered
      from left adrenal metastasis at the diagnosis. Both patients underwent pulmonary
      resection for the primary tumor. The tumors consisted of marked necrotic tissue
      and were histologically diagnosed as pulmonary undifferentiated carcinoma cells
      with sarcomatous elements, which was compatible with pleomorphic carcinoma by new
      World Health Organization (WHO) classification (1999). After operation, systemic
      inflammatory response such as high-grade fever, leukocytosis, high level of serum
      CRP continued and progressed. Furthermore, extrathoracic metastatic lesions newly
      appeared. Both patients died within 100 days after operation.

PMID- 15035086
TI  - [Mucosa-associated lymphoid tissue (MALT) lymphoma of the lung; report of a
      case].
AB  - We experienced a case of mucosa-associated lymphoid tissue (MALT) lymphoma of the
      lung. The patient was 50-year-old woman. She had been pointed out a lung abnormal
      shadow on chest X-ray. A lung biopsy by a bronchofiberscope failed to diagnose,
      and an open lung biopsy under video-assisted thoracoscopic surgery (VATS) offered
      diagnosis as a MALT lymphoma. We performed the tumor resection (a upper-middle
      lobectomy of the right lung with hilar and mediastinal lymph node dissection
      under VATS). The post-operative course of the patient was uneventful and she has
      been free from the disease until now. MALT lymphoma has been a comparatively rare
      disease, but once the curative resection is performed the prognosis of the
      disease is good.

PMID- 15035087
TI  - [Surgically repaired bilateral giant bullae after long-time follow-up; report of
      a case].
AB  - A 44-year-old male was admitted to our hospital owing to severe dyspnea of sudden
      onset. Chest X-ray disclosed bilateral giant bullae. His pulmonary function was
      severely depressed. VC (%) was 2.61 l (66.3%) and FEV1% (%) was 1.47 l (64.5%).
      Indication of surgical repair of giant bullae are; space occupying lesion more
      than 25-50% in 1 thorax, progressive dyspnea, enlargement over time irrespective
      of symptoms, and expectation that re-expand the normal lung. He was conducted two
      staged bullectomy using video-assisted thoracoscopic surgery (VATS) with small
      incisions. First operation was performed to left lung. Pulmonary function
      improved. VC (%) increased 3.02 l (76.8%) and FEV1% (%) 2.36 l (76.6%). After
      second operation, which was performed to right lung, VC (%) was 2.40 l (60.5%)
      and FEV1% (%) was 2.21 l (92.1%). Hugh-Jones grade improved class IV to class I.
      Postoperative course was uneventful and he was discharged 15 days after second
      operation. Two-staged bullectomy was appropriate in this case, because he might
      have suffered from re-expansion pulmonary edema after first surgery. The extent
      of recovery of pulmonary function was unpredictable. And performing right lung
      bullectomy just after the left bullectomy may be dangerous, because the patient
      have to receive anesthesia with his resected left lung. There is some possibility
      that patient who has bilateral giant bullae shows severe dyspnea during the
      progress, care should be taken to conduct operation as soon as possible.

PMID- 15035088
TI  - [Giving Priority to public education on osteoporosis].

PMID- 15035089
TI  - [Interventions for osteoporosis in the era of high-aged population].

PMID- 15035090
TI  - [Recent advance in basic research for osteoporosis].

PMID- 15035091
TI  - [Treatment of osteoporosis--a new paradigm].

PMID- 15035092
TI  - [Advancement and problem related to surgical treatments for osteoporotic
      fractures].

PMID- 15035093
TI  - [Recent advances in the regulation of bone remodeling].

PMID- 15035094
TI  - [Regulatory mechanism of osteoblast differentiation and bone formation].

PMID- 15035095
TI  - [Bone morphogenetic proteins].

PMID- 15035097
TI  - [fosB/IL-11].

PMID- 15035096
TI  - [Multifunctional roles of Runx2/Cbfa1 in skeletal development].

PMID- 15035098
TI  - [IGF-I].

PMID- 15035099
TI  - [TGF-beta].

PMID- 15035101
TI  - [Leptin].

PMID- 15035100
TI  - [C-type natriuretic peptide(CNP)--a novel stimulator of bone growth formed
      through endochondral ossification].

PMID- 15035102
TI  - [Cell-cell interaction mediated by cadherin].

PMID- 15035103
TI  - [Regulatory mechanism of osteoclast differentiation and function].

PMID- 15035104
TI  - [Possible role of RANKL in bone resorption].

PMID- 15035105
TI  - [OPG(osteoprotegerin)/OCIF(osteoclastogenesis inhibitory factor)].

PMID- 15035106
TI  - [Stimulator of bone resorption interleukin-1, interleukin-6 and gp-130 cytokine
      family].

PMID- 15035107
TI  - [TNF-alpha].

PMID- 15035108
TI  - [LPS].

PMID- 15035109
TI  - [Role of prostaglandin E2 in bone].

PMID- 15035110
TI  - [Adhesion molecules in the context with bone remodeling and osteoporosis].

PMID- 15035111
TI  - [Collagen].

PMID- 15035113
TI  - [Bone sialoprotein].

PMID- 15035112
TI  - [Osteocalcin/bone Gla protein(BGP)].

PMID- 15035114
TI  - [Osteopontin].

PMID- 15035115
TI  - [Proteoglycans].

PMID- 15035116
TI  - [Genetic study of osteoporosis].

PMID- 15035117
TI  - [Association of vitamin D receptor gene polymorphisms with osteoporosis].

PMID- 15035118
TI  - [Estrogen receptor gene polymorphisms].

PMID- 15035119
TI  - [Association of beta 3-adrenergic receptor(beta 3-AR) gene polymorphism with
      osteoporosis].

PMID- 15035120
TI  - [Tumor necrosis factor receptor(TNFR) gene polymorphism].

PMID- 15035121
TI  - [Interleukin-6 gene polymorphism].

PMID- 15035122
TI  - [Type I collagen gene polymorphism].

PMID- 15035123
TI  - [Human klotho gene polymorphisms associated with bone density of aged
      postmenopausal women].

PMID- 15035124
TI  - [Prevalence of osteoporosis in Japan and the international comparison].

PMID- 15035125
TI  - [Incidence of spine fracture].

PMID- 15035126
TI  - [Incidence of hip fracture].

PMID- 15035128
TI  - [The change of bone mineral density in cohort studies].

PMID- 15035127
TI  - [Falls and fractures of the elderly].

PMID- 15035129
TI  - [Natural history of osteoporosis--strategy of prevention for osteoporotic
      fractures].

PMID- 15035130
TI  - [WHO diagnostic criteria for osteoporosis and trends in Europe and USA].

PMID- 15035131
TI  - [Diagnostic criteria of primary osteoporosis in Japan].

PMID- 15035132
TI  - [Classification, pathophysiology and therapeutics of osteoporosis].

PMID- 15035133
TI  - [Clinical symptoms and findings of osteoporosis].

PMID- 15035134
TI  - [Assessment of spinal osteoporosis by spine X-ray picture].

PMID- 15035135
TI  - [Measurement of bone mineral density for the primary prevention of osteoporosis].

PMID- 15035136
TI  - [Bone mass measurement and evaluation of therapeutical response].

PMID- 15035137
TI  - [Three-dimensional morphological analysis of trabecular bone microarchitectures].

PMID- 15035138
TI  - [DXA].

PMID- 15035139
TI  - [pQCT].

PMID- 15035140
TI  - [A-1000].

PMID- 15035141
TI  - [AOS-100].

PMID- 15035142
TI  - [CM-100].

PMID- 15035143
TI  - [Cross-calibration of bone volume assessment].

PMID- 15035144
TI  - [Radiographic absorptiometry].

PMID- 15035145
TI  - [Compact MRI].

PMID- 15035147
TI  - [The significance of bone biochemical markers and its application for clinics].

PMID- 15035146
TI  - [Guideline for adequate use of metabolic bone markers in osteoporosis].

PMID- 15035148
TI  - [Bone alkaline phosphatase(BAP)].

PMID- 15035149
TI  - [Carboxyl-terminal propeptide of type I collagen(PICP)].

PMID- 15035150
TI  - [Tartrate resistant acid phosphatase].

PMID- 15035151
TI  - [Deoxypyridinoline(DPD)].

PMID- 15035152
TI  - [Cross-linked N-telopeptides of type I collagen(NTX)].

PMID- 15035153
TI  - [Type I collagen crosslinked C-telopeptides].

PMID- 15035154
TI  - [Serum beta-CTx(beta-CrossLaps)].

PMID- 15035155
TI  - [Serum PINP(N-terminal propeptide of type I procollagen)].

PMID- 15035156
TI  - [FGF-23].

PMID- 15035157
TI  - [New guideline for the treatment of osteoporosis].

PMID- 15035158
TI  - [Treatment of osteoporosis with active vitamin D3].

PMID- 15035159
TI  - [Treatment of osteoporosis with estrogen].

PMID- 15035160
TI  - [Treatment of osteoporosis with vitamin K2].

PMID- 15035161
TI  - [Treatment of osteoporosis with etidronate].

PMID- 15035162
TI  - [Treatment of osteoporosis with alendronate].

PMID- 15035163
TI  - [Risedronate treatment for osteoporosis].

PMID- 15035164
TI  - [Treatment of osteoporosis with calcitonin].

PMID- 15035165
TI  - [Fracture Intervention Trial I and II(alendronate)].

PMID- 15035166
TI  - [VERT(Vertebral Efficacy with Risedronate Therapy)-MN(Multinational) Study and
      VERT-NA(North America) Study].

PMID- 15035167
TI  - [HERS and WHI studies of hormone replacement therapy].

PMID- 15035168
TI  - [MORE study(raloxifene)].

PMID- 15035169
TI  - [PROOF study(calcitonin)].

PMID- 15035170
TI  - [Efficacy and safety of long-term treatment with bisphosphonate for osteoporosis
      in Japanese].

PMID- 15035171
TI  - [Treatment of osteoporosis combined with a bisphosphonate and vitamin D3].

PMID- 15035172
TI  - [Concurrent treatment of osteoporosis with bisphosphonate and vitamin K2].

PMID- 15035173
TI  - [Combination therapy of bisphosphonate and estrogen for osteoporosis].

PMID- 15035174
TI  - [Vitamin D3 + estrogen/combination therapy].

PMID- 15035175
TI  - [Effect of combined administration of vitamin D3 and vitamin K2].

PMID- 15035176
TI  - [Effect of vitamin K2 and estrogen administration on bone formation].

PMID- 15035177
TI  - [Statins with hormone replacement therapy in postmenopausal women with low bone
      mineral density].

PMID- 15035179
TI  - [Compliance of hormone replacement therapy in postmenopausal women in Japan].

PMID- 15035178
TI  - [Practical problems about tolerance of bisphosphonate].

PMID- 15035180
TI  - [The effects of exercise for osteoporosis on bone metabolism].

PMID- 15035181
TI  - [Exercise prescription for patients with osteoporosis].

PMID- 15035182
TI  - [Effect of exercises on bone mineral density and physical strength in elderly
      women].

PMID- 15035183
TI  - [Optimal dietary status for primary and secondary prevention of osteoporosis].

PMID- 15035185
TI  - [Raloxifene hydrochloride].

PMID- 15035184
TI  - [Study of prophylactic effect of food in osteoporosis].

PMID- 15035186
TI  - [Ibandronate].

PMID- 15035187
TI  - [ED-71].

PMID- 15035188
TI  - [hPTH(1-34) injection].

PMID- 15035189
TI  - [Tibolone].

PMID- 15035191
TI  - [Repair of bone tissue using rhBMP-2].

PMID- 15035190
TI  - [Osteoclastogenesis inhibitory factor/osteoprotegerin(OCIF/OPG)].

PMID- 15035192
TI  - [Rho-kinase inhibitor].

PMID- 15035193
TI  - [Geranylgeranylacetone, an antiulcer drug, potently inhibits formation and
      function of human osteoclasts in vitro and bone loss in ovariectomized rats].

PMID- 15035195
TI  - [Prevention of falls and the related fractures].

PMID- 15035194
TI  - [Predictors for osteoporotic fracture].

PMID- 15035196
TI  - [Prevention of hip fractures by hip protectors].

PMID- 15035197
TI  - [Prevention of fractures with therapeutic agents for osteoporosis].

PMID- 15035198
TI  - [Prevention of bone fractures by exercises].

PMID- 15035199
TI  - [Prophylactic effect of bone fracture due to improvement of dietary life].

PMID- 15035200
TI  - [Assessments of QOL in osteoporotic patients].

PMID- 15035201
TI  - [Quality of life in osteoporotic patients with spinal column deformity].

PMID- 15035202
TI  - [Quality of life before and after medical treatments in osteoporosis patients].

PMID- 15035203
TI  - [Complications of secondary spinal instability due to osteoporotic fractures (OP
      OA-OP syndrome)].

PMID- 15035204
TI  - [Complications of the bed-ridden elderly with osteoporosis].

PMID- 15035205
TI  - [Recommendations for the diagnosis and treatment of glucocorticoid-induced
      osteoporosis].

PMID- 15035206
TI  - [Glucocorticoid-induced osteoporosis--epidemiology and pathogenesis].

PMID- 15035207
TI  - [Glucocorticoid-induced osteoporosis in patients with rheumatoid arthritis and
      collagen diseases].

PMID- 15035208
TI  - [Secondary osteoporosis due to systemic autoimmune diseases and rheumatic
      diseases].

PMID- 15035209
TI  - [Steroid induced osteoporosis in the management of bronchial asthma].

PMID- 15035210
TI  - [Disuse osteoporosis].

PMID- 15035211
TI  - [Hypogonadism and osteoporosis].

PMID- 15035212
TI  - [Bone loss induced by GnRH agonist treatment].

PMID- 15035214
TI  - [Osteoporosis in patients with hyperthyroidism].

PMID- 15035213
TI  - [Skeletal complications of renal insufficiency].

PMID- 15035215
TI  - [Bone status in primary hyperparathyroidism].

PMID- 15035216
TI  - [Abnormality of bone mineral metabolism in type 2 diabetes mellitus].

PMID- 15035217
TI  - [Osteoporosis associated with chronic liver disease].

PMID- 15035218
TI  - [Osteoporosis and spondylosis deformans].

PMID- 15035220
TI  - [Community-based prevention for osteoporosis].

PMID- 15035219
TI  - [Osteoporosis induced by immunosuppressant].

PMID- 15035221
TI  - [Health examination of osteoporosis by the local government].

PMID- 15035222
TI  - [The ovariectomized animal model of postmenopausal bone loss].

PMID- 15035223
TI  - [Gene-targeting animals for osteoporosis].

PMID- 15035224
TI  - [Animal models of accelerated senescence].

PMID- 15035225
TI  - [Csf1op/Csf1op(op/op) mouse].

PMID- 15035227
TI  - [Stimulation of bone formation by statins].

PMID- 15035226
TI  - [The role of mevalonate pathway in osteogenic cells].

PMID- 15035228
TI  - [The role of PPAR gamma for the osteoblastic differentiation].

PMID- 15035229
TI  - [Future perspectives on the osteoporosis gene therapy].

PMID- 15035230
TI  - [Novel therapeutic approach to bone metabolic disorders using RANKL vaccination].

PMID- 15035232
TI  - 2004 national patient safety goals adapted for programs.

PMID- 15035231
TI  - [Perspective for the tailor--made medicine of osteoporosis].

PMID- 15035233
TI  - Interim weighted decision rules not applied under certain circumstances.

PMID- 15035234
TI  - Clarifications to "medical staff" requirements.

PMID- 15035235
TI  - Accreditation participation requirement promotes continuous public engagement.

PMID- 15035236
TI  - Contemplation. A vital step in the process of change.

PMID- 15035237
TI  - Advocating the ecocentric paradigm in nursing.

PMID- 15035238
TI  - Homeless adolescent.

PMID- 15035239
TI  - Adaptation of a wellness intervention for women with chronic disabling
      conditions.
AB  - Women with chronic disabling conditions live with multiple symptoms that decrease
      their ability to function in society, and they may be at elevated risk for
      further morbidity with age. Despite research indicating that health-promoting
      behaviors decrease the risk for further morbidity, few interventions have been
      designed to help women with chronic disabling conditions promote their health.
      The purpose of this article is to present the results of a pilot study of a
      wellness intervention adapted for use with women with fibromyalgia syndrome
      (FMS). First, the development of the original wellness intervention for women
      with multiple sclerosis (MS) will be described. Next, the steps taken to adapt
      the intervention to the needs of women with FMS will be described. Finally, it
      wil be argued that commonalities in symptoms and social experiences and the
      universal need for health-promoting skills make this intervention adaptable to
      multiple groups of women with chronic disabling conditions.

PMID- 15035240
TI  - Parents' positioning and distracting children during venipuncture. Effects on
      children's pain, fear, and distress.
AB  - The purpose of this study was to determine the effectiveness of parental
      positioning and distraction on the pain, fear, and distress of pediatric patients
      undergoing venipuncture. An experimental-comparison group design was used to
      evaluate 43 patients (20 experimental and 23 comparison) who were 4 to 11 years
      old. Experimental participants used parental positioning and distraction. All
      participants rated their pain and fear; parents and child life specialists (CLS)
      rated the child's fear, and CLS rated the child's distress. Self-reported pain
      and fear were highly correlated (p < .001) but not significantly different
      between the two groups. Fear rated by CLS (p < .001) and parents (p = .003) was
      significantly lower in experimental participants. Although no differences was
      found in distress between the two groups, a significant time trend was discovered
      (p < .001). The parental positioning-distraction intervention has the potential
      to enhance positive clinical outcomes with a primary benefit of decreased fear.
      Further research is warranted.

PMID- 15035241
TI  - Parse's theory in practice. An interpretive analysis.
AB  - Parse's theory of human becoming provides a foundation for understanding holistic
      nursing practice. The purpose of this article is to provide a description of
      Parse's theory based on an interpretive analysis of the author's nursing practice
      experiences. The interpretive analysis is not an outcome of formal study but
      results from reflective thought and journal writing. Details from reflections on
      nursing care experiences were analyzed for the concepts, processes, and rhythms
      inherent to Parse's theory. Praxis of Parse's theory creates the opportunity for
      nurses, patients, and families to reach profound dimensions of the human
      experience and participate in multidimensional healing. Outcomes of praxis for
      nurses also include personal and professional growth as well as discernment of
      holistic nursing practice.

PMID- 15035242
TI  - Technical, practical, and emancipatory reflection for practicing holistically.
AB  - The intention to practice holistically brings with it many complexities in
      deciding how to manage the contingencies of practice in such a way as to embody
      the central tenets of holistic nursing. The challenge of making sense of daily
      work procedures, interpersonal interactions, and issues of power can be eased by
      attention to reflective processes designed for nursing practice. Reflective
      nurses who practice holistically optimize the likelihood of thinking
      systematically through practice issues as they encounter the world of nursing and
      the people and events within it. This article is an exploration of the phenomena
      of holism and reflection as they relate to technical, practical, and emancipatory
      reflective processes used by nurses in their daily work.

PMID- 15035243
TI  - Human holistic and energetic responses following a tornado.
AB  - After an F-4 tornado destroyed a large section of our town, I gave 50
      complementary energy treatments to tornado victims. I discovered that the same
      energetic, physical, emotional, mental, and spiritual disruption occurred in
      people directly and indirectly exposed to the tornado, and that the damage did
      not repair spontaneously over time. This article describes the energetic damage
      people sustained from the tornado and their physical, mental, emotional, and
      spiritual responses. It also describes the energetic treatment that effectively
      eliminated the trauma, returning the tornado victim to a stable state. The
      article concludes with clinical and research implications and relates the
      treatment of the tornado victims to holistic nursing. The treatment holds promise
      for victims of posttraumatic stress disorder.

PMID- 15035244
TI  - [Fibrositis--100 years and still no wiser?].
AB  - The past centennium has witnessed scientific progress in the elucidation of the
      mechanisms involved in the formal pathogenesis of so-called muscular pathogenesis
      of so-called muscular rheumatism (recently fibromyalgia), but the aetiology of
      this widespread syndrome and the pathways to its appropriate treatment are still
      not known. Careful diagnosis based on consideration of numerous conditions
      relevant for differential diagnosis, patient education and shared decision-making
      are prerequisites to the efficacy of a complex treatment and rehabilitation plan
      which should comprise a reasonable combination of physio-, psycho-, and
      pharmacotherapeutic measures. Medication should be sparingly prescribed and the
      patient advised that in the end these drugs have a symptomatic effect only.
      Ultimately, active participation which the physician should continuously demand
      of the patient is imperative to the success of treatment.

PMID- 15035245
TI  - Classification of outcomes events in the Dutch TIA trial: prognostic value of
      accepted and rejected events.
AB  - OBJECTIVE: In large multicentre clinical trials adjudication of outcome events
      most often is done centrally. Some of these events would eventually be judged not
      to meet the criteria and hence would be rejected. If the classification
      procedures work correctly one would expect a higher risk of future vascular
      events after an 'accepted' rather than after a 'rejected event. In the present
      study we aimed at testing the adequacy of a classification procedure in a trial
      of patients with a transient ischemic attack (TIA) or minor ischemic stroke by
      comparing the further outcome between patients in whom a possible event was
      either rejected or accepted for the final analysis in this trial. RESEARCH DESIGN
      AND METHODS: The vascular outcome events were analysed in 3150 patients with TIA
      or minor stroke who participated in the Dutch TIA trial. We identified the
      patients with a first 'accepted' or 'rejected' non-fatal stroke or myocardial
      infarction (MI). In these two groups of patients we determined the occurrence of
      the subsequent vascular events (vascular death, stroke or MI). The incidence was
      compared with survival analysis techniques. RESULTS: Among 308 patients with a
      first nonfatal 'accepted' event in 81 (26.3%) a new vascular event occurred;
      among the 51 patients with a 'rejected' event there were 12 (23.5%) such events.
      The hazard ratio for new vascular events was 1.22 (95% CI 0.67-2.22). After
      multivariate adjustment for age, type of qualifying event, history of smoking,
      angina pectoris and myocardial infarction, and Rankin score > or = 3, the hazard
      ratio was 1.49 (95% CI 0.78-2.84). CONCLUSION: our study suggested that the
      adjudication process of outcome events in the Dutch TIA trial was done correctly
      because a trend towards a higher recurrence rate of vascular events among
      patients with 'accepted' outcome events was found.

PMID- 15035246
TI  - The third international conference on osteopontin and related proteins, San
      Antonio, Texas, May 10-12, 2002.

PMID- 15035247
TI  - Does botulinum toxin make sense in pain therapy?

PMID- 15035248
TI  - Improving informed consent: a comparison of four consent tools.

PMID- 15035249
TI  - A pilot seminar on ethical issues in clinical trials for cancer researchers in
      Vietnam.

PMID- 15035250
TI  - Should nonresponders dictate the use of placebos?

PMID- 15035251
TI  - Bioethics, power and injustice: for an ethics of intervention.
AB  - Bioethics of the so-called "peripheral countries" should be preferably concerned
      with the persistent situations, that is, with those problems that are still
      happening, but should not happen anymore in the 21st century. The resulting
      conflicts cannot be exclusively analyzed based on the ethical theories (or
      bioethical) arriving from "central countries". The authors alert for the
      increasing depoliticization of moral conflicts and for the lack of capacity of
      human indignation. The indiscriminate utilization of bioethics justification as a
      neutral methodological tool softens and even cancels out the gravity of different
      problems, even those that might result in the most profound social distortion.
      The current study sets as a theoretical reference the finitude of natural
      resources (which are all of them...) and corporality, pleasures and pain. From
      these premises and the introduction of the concept that equity means "to treat
      unevenly the unequal", the authors introduced a proposal of a hard bioethics or
      intervention bioethics, in support of the interest and the historical rights of
      the population economically and socially excluded from the international
      development practice.

PMID- 15035252
TI  - New CMA data confirm access-to-care concerns rising.

PMID- 15035253
TI  - The globalization of clinical trials: a growing challenge in protecting human
      subjects: executive summary (2001).

PMID- 15035254
TI  - [Bayer confirms its decision to develop in health care].

PMID- 15035255
TI  - Early MRI findings of central pontine myelinolysis following "rapid" correction
      of hyponatraemia during diabetic ketoacidosis. A curious pontine lesion
      (2003:12b).
AB  - We describe a diabetic patient with hyponatraemia and ketoacidosis who developed
      central pontine myelinolysis (CPM) after a very rapid correction of serum sodium.
      In diabetic ketoacidosis, the marked shifts in osmolarity make these patients
      more susceptible to the development of CPM. The dramatic early MRI findings
      (after three weeks) should raise awareness of the risk of permanent damage to the
      brain associated with hydration therapy in this susceptible group. Magnetic
      resonance imaging might be a useful investigation at presentation and follow-up
      of diabetic patients with extreme metabolic derangements.

PMID- 15035256
TI  - Curious pulmonary and hepatic lesions (2004:3a).

PMID- 15035257
TI  - [Regression of electrocardiographic left ventricular hypertrophy by losartan
      versus atenolol. Results of LIFE study].

PMID- 15035258
TI  - [Treatment of cardiovascular diseases with beta-blockers: the place of metoprolol
      and its various drug formulations].

PMID- 15035259
TI  - [From control of impaired carbohydrate tolerance to primary prevention of
      atherosclerosis. Encouraging results of the STOP-NIDDM trial].

PMID- 15035260
TI  - [What determines economic effectiveness of treatment of arterial hypertension].

PMID- 15035262
TI  - Wake up to the risks of drowsy driving.

PMID- 15035261
TI  - The new Medicare drug benefit: much ado about little?
AB  - After many years of debate, Congress recently approved a new, voluntary "Medicare
      Part D" benefit that provides some coverage for prescription drugs. The goal of
      this coverage is to reduce financial barriers that might prevent beneficiaries
      from obtaining needed drugs. The degree to which this goal is achieved depends on
      how well the benefit reaches seniors with previously unmet needs; conversely, it
      may do little to improve seniors' health if it replaces existing sources of
      coverage, or encourages overuse of drugs. This Issue Brief reviews data on
      current patterns of drug spending among Medicare beneficiaries and summarizes
      aspects of the new benefit. It explores the likely effect of the coverage on
      overall use of and spending for prescription drugs and considers whether any
      additional use is likely to represent needed care that had been forgone because
      of a cost barrier.

PMID- 15035263
TI  - Fast food: a healthful pit stop?

PMID- 15035264
TI  - A 32-year-old man with skin lesions.

PMID- 15035265
TI  - [Post-exposure prevention after occupational exposure to HBV, HCV and HIV].
AB  - After occupational exposure to HBV, HCV, and HIV, the patient from whom the
      potentially infectious material originates (index patient) as well as the exposed
      person should undergo serological and, if needed, molecular screening. Active and
      passive immunoprophylaxis after exposure to HBV is an effective tool against
      infection with hepatitis B virus in unvaccinated persons. The post-exposure
      prophylaxis (PEP) should be given within 24 h after exposure of an unprotected
      person to HBV-positive material. Once acute hepatitis B infection is diagnosed,
      therapy is not recommended for immunocompetent persons. At present, PEP against
      HCV infection is not available. Monotherapy with interferon-alpha avoids
      chronification in most patients suffering from acute hepatitis C. After exposure
      with an increased risk for transmission of HIV (percutaneous needle stick injury,
      cut), PEP should be recommended and can also be offered for further indications.
      PEP should be started as early as possible and carried out for 28 days. The
      recommended PEP consists of two inhibitors of the reverse transcriptase and one
      inhibitor of the protease.

PMID- 15035266
TI  - It's a pipeline issue: women in leadership.

PMID- 15035267
TI  - [Dengue fever].

PMID- 15035268
TI  - Subcortical stimulation mapping.

PMID- 15035269
TI  - High-dose mannitol.

PMID- 15035270
TI  - Intraoperative subcortical stimulation mapping for hemispherical perirolandic
      gliomas located within or adjacent to the descending motor pathways: evaluation
      of morbidity and assessment of functional outcome in 294 patients.
AB  - OBJECT: Intraoperative stimulation mapping of subcortical white matter tracts
      during the resection of gliomas has become a valuable surgical adjunct that is
      used to reduce morbidity associated with tumor removal. The purpose of this
      retrospective analysis was to assess the morbidity and functional outcome
      associated with this method, thus allowing the surgeon to predict the likelihood
      of causing a temporary or permanent motor deficit. METHODS: In this study, the
      authors report their experience with intraoperative stimulation mapping to locate
      subcortical motor pathways in 294 patients who underwent surgery for hemispheric
      gliomas within or adjacent to the rolandic cortex. Data were collected regarding
      intraoperative cortical and subcortical stimulation mapping results, along with
      the patient's neurological status pre- and postoperatively. For patients in whom
      an additional motor deficit occurred postoperatively, its evolution was examined.
      Of 294 patients, an additional postoperative motor deficit occurred in 60
      (20.4%). Of those 60, 23 (38%) recovered to their preoperative baseline status
      within the 1st postoperative week. Another 12 (20%) recovered from their
      postoperative motor deficit by the end of the 4th postoperative week, and 11 more
      recovered to their baseline status by the end of the 3rd postoperative month.
      Thus, 46 (76.7%) of 60 patients with postoperative motor deficits regained their
      baseline function within the first 90 days after surgery. The remaining 14
      patients (4.8% of the entire study population of 294) had a persistent motor
      deficit after 3 months. Patients whose subcortical pathways were identified with
      stimulation mapping were more prone to develop an additional (temporary or
      permanent) motor deficit than those in whom subcortical pathways could not be
      identified (27.5% compared with 13.1%, p = 0.003). This was also true when
      additional (permanent) motor deficits lasted more than 3 months (7.4% when
      subcortical pathways were found, compared with 2.1% when they were not found; p =
      0.041). CONCLUSIONS: In patients with gliomas that are located within or adjacent
      to the rolandic cortex and, thus, the descending motor tracts, stimulation
      mapping of subcortical pathways enables the surgeon to identify these descending
      motor pathways during tumor removal and to achieve an acceptable rate of
      permanent morbidity in these high-risk functional areas.

PMID- 15035271
TI  - Successful use of the new high-dose mannitol treatment in patients with Glasgow
      Coma Scale scores of 3 and bilateral abnormal pupillary widening: a randomized
      trial.
AB  - OBJECT: The authors evaluated long-term clinical outcomes in selected acutely
      comatose patients with severe diffuse brain swelling and recent clinical signs of
      impending brain death who received a novel high-dose mannitol treatment compared
      with those who received conventional-dose mannitol in the emergency room.
      METHODS: Forty-four adult patients with traumatic, nonmissile-inflicted, acute,
      severe diffuse brain swelling were prospectively and randomly evaluated. All
      patients were selected based on the presence of recent clinical signs of
      impending brain death on the first emergency room evaluation. These signs
      included bilateral abnormal pupillary widening and lack of motor responses to
      painful stimulation (Glasgow Coma Scale score of 3). The study group (23
      patients) received ultra-early and fast intravenous high-dose mannitol treatment
      (approximately 1.4 g/kg), whereas the control group (21 patients) received half
      that dose (approximately 0.7 g/kg). Ultra-early improvement of bilateral abnormal
      pupillary widening was significantly more frequent in the high-dose mannitol
      group than in the conventional-dose group (p < 0.02). High-dose mannitol
      treatment in the emergency room was also associated with significantly better 6
      month clinical outcomes (p < 0.02); the best rate of favorable outcomes was
      43.5%, compared with only 9.5% in the conventional-dose mannitol group. The two
      groups of patients were well matched with respect to all emergency room and head
      computerized tomography findings, as well as the timing of initial mannitol
      treatment (approximately 80-90 minutes after the first evaluation at the scene of
      the injury). Comparative evaluation of bilateral pupillary widening between the
      scene of the injury and the emergency room showed no significant differences
      between groups, whereas mannitol dose dependence was statistically significant (p
      < 0.05), insofar as early pupillary improvement in the emergency room was
      concerned. CONCLUSIONS: Ultra-early high-dose mannitol administration in the
      emergency room is the first known treatment strategy significantly to reverse
      recent clinical signs of impending brain death, and also to contribute directly
      to improved long-term clinical outcomes for these patients who have previously
      been considered unsalvageable.

PMID- 15035272
TI  - Ruptured distal middle cerebral artery aneurysm.
AB  - OBJECT: Ruptured distal middle cerebral artery (MCA) aneurysms are uncommon, and
      their clinical and radiological features are poorly understood. To clarify
      characteristics of these lesions, the authors undertook a retrospective analysis
      of nine patients with ruptured distal MCA aneurysms. METHODS: The medical records
      of patients who underwent surgical repair of ruptured intracranial aneurysms
      between 1988 and 2002 at Shinshu University Hospital and its affiliated hospitals
      were retrospectively evaluated. The authors found only nine patients with a
      ruptured distal MCA aneurysm, and their clinical, neuroimaging, and
      intraoperative findings were evaluated. CONCLUSIONS: This study of nine patients
      with distal MCA aneurysms is the largest series to date. Eight lesions were
      saccular aneurysms that were clipped and the remaining one was a mycotic aneurysm
      that was trapped. Eight of the nine patients suffered cerebral hematomas with
      subarachnoid hemorrhage. All patients had good outcomes after obliteration of
      their aneurysm, although their preoperative condition was not good.

PMID- 15035273
TI  - Monitoring of motor evoked potentials compared with somatosensory evoked
      potentials and microvascular Doppler ultrasonography in cerebral aneurysm
      surgery.
AB  - OBJECT: The aims of this study were to compare the efficiency of motor evoked
      potentials (MEPs), somatosensory evoked potentials (SSEPs), and microvascular
      Doppler ultrasonography (MDU) in the detection of impending motor impairment from
      subcortical ischemia in aneurysm surgery; to determine their sensitivity for
      specific intraoperative events; and to compare their impact on the surgical
      strategy used. METHODS: Motor evoked potentials, SSEPs, and MDU were monitored
      during 100 operations for 129 aneurysms in 95 patients. Intraoperative events,
      monitoring results, and clinical outcome were correlated in a prospective
      observational design. Motor evoked potentials indicated inadequate temporary
      clipping, inadvertent occlusion, inadequate retraction, vasospasm, or compromise
      to perforating vessels in 21 of 33 instances and deteriorated despite stable
      SSEPs in 18 cases. Microvascular Doppler ultrasonography revealed inadvertent
      vessel occlusion in eight of 10 cases and insufficient clipping in four of four
      cases. Stable evoked potentials (EPs) allowed safe, permanent vessel occlusion or
      narrowing despite reduced flow on MDU in five cases. Two patients sustained
      permanent and 10 showed transient new weakness, which had been detected by SSEPs
      in two of 12 patients and MEPs in 10 of 11 monitored cases. The surgical strategy
      was directly altered in 33 instances: by MEPs in 16, SSEPs in four, and MDU in
      13. CONCLUSIONS: Monitoring of MEPs is superior to SSEP monitoring and MDU in
      detecting motor impairment, particularly that from subcortical ischemia.
      Microvascular Doppler ultrasonography is superior to EP monitoring in detecting
      inadvertent vessel occlusion, but cannot assess remote collateral flow. Motor
      evoked potentials are most sensitive to all other intraoperative conditions and
      have a direct influence on the course of surgery in the majority of events. A
      controlled study design is required to confirm the positive effect of monitoring
      on clinical outcome in aneurysm surgery.

PMID- 15035274
TI  - Poor-grade aneurysmal subarachnoid hemorrhage: relationship of cerebral
      metabolism to outcome.
AB  - OBJECT: The majority of patients with poor-grade subarachnoid hemorrhage (SAH),
      that is, World Federation of Neurosurgical Societies (WFNS) Grades IV and V, have
      high morbidity and mortality rates. The objective of this study was to
      investigate cerebral metabolism in patients with low- compared with high-grade
      SAH by using bedside microdialysis and to evaluate whether microdialysis
      parameters are of prognostic value for outcome in SAH. METHODS: A prospective
      investigation was conducted in 149 patients with SAH (mean age 50.9 +/- 12.9
      years); these patients were studied for 162 +/- 84 hours (mean +/- standard
      deviation). Lesions were classified as low-grade SAH (WFNS Grades I-III, 89
      patients) and high-grade SAH (WFNS Grade IV or V, 60 patients). After approval by
      the local ethics committee and consent from the patient or next of kin, a
      microdialysis catheter was inserted into the vascular territory of the aneurysm
      after clip placement. The microdialysates were analyzed hourly for extracellular
      glucose, lactate, lactate/pyruvate (L/P) ratio, glutamate, and glycerol. The 6-
      and 12-month outcomes according to the Glasgow Outcome Scale and functional
      disability according to the modified Rankin Scale were assessed. In patients with
      high-grade SAH, cerebral metabolism was severely deranged compared with those who
      suffered low-grade SAH, with high levels (p < 0.05) of lactate, a high L/P ratio,
      high levels of glycerol, and, although not significant, of glutamate. Univariate
      analysis revealed a relationship among hyperglycemia on admission, Fisher grade,
      and 12-month outcome (p < 0.005). In a multivariate regression analysis performed
      in 131 patients, the authors identified four independent predictors of poor
      outcome at 12 months, in the following order of significance: WFNS grade, patient
      age, L/P ratio, and glutamate (p < 0.03). CONCLUSIONS: Microdialysis parameters
      reflected the severity of SAH. The L/P ratio was the best metabolic independent
      prognostic marker of 12-month outcome. A better understanding of the causes of
      deranged cerebral metabolism may allow the discovery of therapeutic options to
      improve the prognosis, especially in patients with high-grade SAH, in the future.

PMID- 15035275
TI  - Stereotactic radiosurgery for brainstem arteriovenous malformations: factors
      affecting outcome.
AB  - OBJECT: Management options for arteriovenous malformations (AVMs) of the
      brainstem are limited. The long-term results of stereotactic radiosurgery for
      these disease entities are poorly understood. In this report the authors reviewed
      both neurological and radiological outcomes following stereotactic radiosurgery
      for brainstem AVMs over 15 years of experience. METHODS: Fifty patients with
      brainstem AVMs underwent gamma knife surgery between 1987 and 2002. There were 29
      male and 21 female patients with an age range of 7 to 79 years (median 35 years).
      Anatomical locations of these AVMs included the midbrain (39 lesions), pons (20
      lesions), and medulla oblongata (three lesions). The radiation dose applied to
      the margin of the AVM varied from 12 to 26 Gy (median 20 Gy). Forty-five patients
      were followed up from 5 to 176 months (mean 72 months). The angiographically
      confirmed actuarial obliteration rate was 66% at the final follow-up examination.
      Two patients experienced a hemorrhage before obliteration. The annual hemorrhage
      rate was 1.7% for the first 3 years after radiosurgery and 0% thereafter.
      Patients who had received irradiation at two or fewer isocenters had higher
      obliteration rates (80% compared with 44% for > two isocenters, p = 0.006), and
      this was related to a more spherical nidus shape. The rate of persistent
      neurological complications in patients treated using magnetic resonance imaging
      based dose planning after 1993 was 7%, compared with 20% in patients treated
      before 1993. An older patient age, a lesion located in the tectum, and a higher
      radiosurgery-based score were significantly associated with greater neurological
      complications. CONCLUSIONS: Stereotactic radiosurgery provided complete
      obliteration of AVMs in two thirds of the patients with a low risk of latency
      interval hemorrhage. Better three-dimensional imaging studies and conformal dose
      planning reduced the risk of adverse radiation effects. Younger patients
      harboring more spherical AVMs that did not involve the tectal plate had the best
      outcomes.

PMID- 15035276
TI  - Efficacy of multiple intraarterial papaverine infusions for improvement in
      cerebral circulation time in patients with recurrent cerebral vasospasm.
AB  - OBJECT: Cerebral vasospasm that is caused by aneurysmal subarachnoid hemorrhage
      and that is refractory to maximal medical management can be treated with
      selective intraarterial papaverine infusions. The effects of single papaverine
      treatments on cerebral circulation time are well known. The purpose of this study
      was to assess the efficacy of multiple, repeated papaverine infusions on the
      cerebral circulation time in patients with recurrent vasospasm. METHODS: A
      retrospective study was conducted in 17 patients who received multiple
      intraarterial papaverine infusions in 91 carotid artery (CA) territories for the
      treatment of cerebral vasospasm. Cerebral circulation times were measured from
      the first angiographic image, in which peak contrast was seen above the
      supraclinoid internal CA, to the peak filling of cortical veins. Glasgow Outcome
      Scale (GOS) scores assessed 12 months after discharge were reviewed. Cerebral
      circulation times in 16 CA territories were measured in a control group of 11
      patients. Seventeen patients received a total of 91 papaverine treatments.
      Prolonged cerebral circulation times improved after 90 (99%) of 91 papaverine
      treatments. The prepapaverine mean cerebral circulation time was 6.54 seconds
      (range 3.35-27 seconds) and the immediate postpapaverine mean cerebral
      circulation time was 4.19 seconds (range 2.1-12.6 seconds), an overall mean
      decrease of 2.35 seconds (36%, p < 0.001). Recurrent vasospasm reflected by
      prolonged cerebral circulation times continued to improve with subsequent
      papaverine infusions. Repeated infusions were just as successful quantitatively
      as the primary treatment (mean change 2.06 seconds). The mean cerebral
      circulation time in the control group was 5.21 seconds (range 4-6.8 seconds). In
      five patients a dramatic reversal of low-attenuation changes was detected on
      computerized tomography scans. The mean GOS score at 12 months after discharge
      was 3.4. CONCLUSIONS: The preliminary results indicate that multiple
      intraarterial papaverine treatments consistently improve cerebral circulation
      times, even with repeated infusions in cases of recurrent vasospasm.

PMID- 15035277
TI  - Preoperative neuroimaging findings as a predictor of the surgical plane of
      cleavage: prospective study of 100 consecutive cases of intracranial meningioma.
AB  - OBJECT: To understand the cause and prevention of postoperative ischemic and/or
      venous parenchymal infarcts after intracranial meningioma resection, the authors
      describe the value of neuroimaging in predicting the surgical plane of cleavage.
      METHODS: A prospective study of 100 meningiomas was performed, in which tumor
      size, absence or presence of peritumoral edema, tumor-parenchyma interface, and
      types of arterial vascularization (that is, dural-meningeal, pial-cortical, or
      mixed) were correlated with the type of dissection plane (extrapial, subpial, or
      mixed) encountered at surgery. A direct correlation was found between the tumor
      size identified on T1-weighted magnetic resonance (MR) imaging sequences and the
      degree of subpial (nonextrapial) surgical plane of cleavage (p < 0.00001). A
      similar correlation was found with the grade of peritumoral edema identified on
      preoperative computerized tomography (CT) scanning (p < 0.0001) or T2-weighted MR
      imaging sequences (p < 0.00001) and tumor pial vascularization as seen on
      angiography (p < 0.0001). Nevertheless, the tumor-parenchyma interface on
      preoperative T2-weighted MR imaging sequences was not predictive of the surgical
      plane (p > 0.5). The worst clinical outcome was found in the tumors located in
      eloquent areas and in which a subpial plane was encountered at surgery (p =
      0.03). CONCLUSIONS: Peritumoral edema on preoperative CT and MR studies and tumor
      pial vascularization as seen on selective angiography can be used to predict the
      surgical plane of cleavage in meningiomas. The association between tumor size and
      a subpial surgical plane may be explained by a more pial vascularization seen on
      angiography. Meningiomas with a location in eloquent cortex and a subpial
      dissection plane should be considered a high-risk group.

PMID- 15035278
TI  - Surgical removal of corpus callosum infiltrated by low-grade glioma: functional
      outcome and oncological considerations.
AB  - OBJECT: Although still controversial, many authors currently advocate extensive
      resection in the treatment of low-grade gliomas (LGGs). Because these tumors
      usually migrate along white matter pathways, the corpus callosum is often
      invaded. Nevertheless, there is evidently no specific study featuring resection
      of the corpus callosum infiltrated by glioma, despite abundant literature
      concerning callosotomy in epilepsy surgery or transcallosal ventricular
      approaches. The aim of this paper was to analyze functional outcome following
      removal of corpus callosum invaded by LGG and to analyze the impact of this
      callosectomy on the quality of resection. METHODS: Between 1996 and 2002, a total
      of 32 patients harboring an LGG involving part of the corpus callosum and having
      no or only a mild preoperative deficit underwent surgery aided by intraoperative
      electrical mapping to preserve eloquent structures identified on stimulation and
      to perform the most extensive resection possible. Preoperatively, no clinical
      response was elicited on stimulation of the corpus callosum; thus, the part of
      this structure that was invaded by LGG was removed. Despite immediate
      postoperative neurological worsening, all patients but one recovered within 3
      months and returned to a normal socioprofessional life. The additional
      callosectomy allowed for nine total resections, 18 subtotal resections, and five
      partial resections. Furthermore, only two cases of contralateral hemispherical
      migration occurred during a median follow up of 3 years. CONCLUSIONS: Resection
      of the corpus callosum infiltrated by glioma improves the quality of tumor
      removal without increasing the risk of sequelae.

PMID- 15035279
TI  - Gamma knife surgery for treatment of residual nonfunctioning pituitary adenomas
      after surgical debulking.
AB  - OBJECT: Radiation therapy diminishes the risk of recurrence of incompletely
      removed nonfunctioning pituitary adenoma (NPA). The authors evaluated the
      efficacy and safety of gamma knife surgery (GKS) in patients with residual NPA
      following surgical debulking of the tumor. METHODS: Fifty-four patients, 26 men
      and 28 women, ranging in age from 29 to 72 years underwent gamma knife treatment.
      Baseline and follow-up studies involved magnetic resonance imaging, hormone
      evaluation, and neuroophthalmological examination 6 and 12 months after GKS and
      at yearly intervals thereafter. The mean follow up after GKS was 41.1 +/- 3.1
      months. Two of 52 patients undergoing follow up had a recurrence 40 and 49 months
      after GKS. In both of these patients the treated lesion had reduced in size, but
      a new lesion appeared in the contralateral side of the sella turcica. The
      recurrence-free interval at 5 years was 88.2% (95% confidence interval 72.6
      100%). Tumor volume decreased from a baseline value of 2.3 +/- 0.2 to 1.7 +/- 0.2
      cm3 at the last follow up (p < 0.001). Twenty-two patients (42.3%) had a 20% or
      greater reduction in tumor volume. The administered radiation dose had been
      significantly higher in patients who experienced tumor reduction. Visual function
      and motility did not deteriorate in any patient. New cases of hypogonadism,
      hypothyroidism, and hypoadrenalism occurred in 12.5, 8.6, and 2.3%, respectively,
      of assessable patients at risk. CONCLUSIONS: Gamma knife surgery was effective in
      controlling the growth of residual NPA after previously performed maximal
      surgical debulking. The major advantage of GKS compared with fractionated
      radiotherapy seems to be a lower risk of side effects, especially a lower risk of
      hypopituitarism.

PMID- 15035280
TI  - The role of transsphenoidal surgery in the treatment of craniopharyngiomas.
AB  - OBJECT: The optimal approach for the surgical treatment of craniopharyngiomas is
      still debated. In all cases involving the sella turcica, the authors have
      exclusively used transsphenoidal surgery (TSS), assuming that this approach is
      less traumatic than an intracranial one. Moreover, TSS was also performed in some
      cases of purely suprasellar craniopharyngiomas. In this study the surgical
      indications and the results obtained in all patients who had undergone TSS were
      analyzed. METHODS: In a series of 92 patients who underwent surgery for
      craniopharyngiomas, TSS was the first choice of approach in 57 cases (62%)
      consisting of 29 female and 28 male patients with ages ranging from 12 to 79
      years (mean 35 years). The follow-up duration ranged from 2 to 20 years. A
      standard transsphenoidal approach was used in patients with an exclusively
      intrasellar (11 patients) or an intrasellar and suprasellar tumor (37 patients);
      in nine cases of tumors located exclusively above the sella turcica, a
      transsphenoidal presellar approach (seven patients) or a transsellar
      transdiaphragmatic approach (two patients) was used. Total removal was performed
      in 36 patients (63%). All patients had good clinical results. Postoperative
      cerebrospinal fluid leakage occurred in 10 cases, but only one case required a
      surgical repair of the sella. Two patients died of late complications (3.5%).
      There were eight cases (14%) of tumor regrowth. CONCLUSIONS: The authors assert
      that, when used in appropriately located craniopharyngiomas and by neurosurgeons
      with extensive experience in pituitary surgery, TSS offers excellent results with
      minor risks.

PMID- 15035281
TI  - Multimodality image-guided surgery for the treatment of medically refractory
      epilepsy.
AB  - OBJECT: The aim of this study was to review seizure outcome, imaging modalities
      used, and complications following surgery in patients with epilepsy who had
      undergone multimodality image-guided surgery at our institution. METHODS: Data
      from patients with epilepsy who had undergone surgery between April 1999 and
      October 2001 were reviewed. During this time period, 116 operations were
      performed in 109 patients with medically refractory epilepsy. Among these
      patients, 22 were selected to undergo multimodality image-guided surgery
      primarily on the basis of whether they had no lesion visible on conventional
      magnetic resonance (MR) imaging sequences, multiple lesions, or one very large
      lesion that could not be completely resected without the risk of significant
      postoperative morbidity. A fourth group of patients in whom there was a single
      lesion in the eloquent cortex, a location associated with a significant risk of
      postoperative morbidity, was also included in the analysis. This latter group was
      assessed with the aid of intracranial grid electrodes that were coregistered to
      the MR image and were used intraoperatively to minimize electrode position error.
      Other imaging modalities used included positron emission tomography (PET), fluid
      attenuated inversion recovery (FLAIR) MR imaging, and subtracted ictal-interictal
      single-photon positron emission computerized tomography (SPECT) coregistered with
      MR imaging (SISCOM). After coregistration, images were then downloaded onto an
      image-guided surgical system and the epileptogenic area was then resected. The
      mean patient age was 33 years (range 17-46 years), and there was a mean follow up
      of 27 months (range 14-41 months). Multimodality coregistrations used were as
      follows: nine PET scans, seven subdural electrode grids, four SISCOM studies, one
      FLAIR MR image, and one combined PET/subdural grid. Seizure outcome was excellent
      in 17 patients (77%) and not excellent in five (23%), or favorable in 19 (86%)
      and unfavorable in three (14%). Six patients (27%) had a transient neurological
      deficit, one patient (5%) a permanent major deficit, and three patients (15%) a
      permanent minor deficit. Five patients (24%) had a transient psychiatric problem
      postoperatively. CONCLUSIONS: Multimodality image-guided surgery offers a new
      perspective in surgery for epilepsy. Functional imaging modalities previously
      lateralized and often localized a seizure focus, but did not provide enough
      anatomical information to resect the epileptogenic zone confidently and safely.
      The coregistration of these modalities to a volumetric MR image and their
      incorporation into an image-guided system has allowed surgeons to offer surgery
      to patients who may not previously have been considered eligible, with outcomes
      comparable to those in patients with more straightforward lesional epilepsy.

PMID- 15035282
TI  - Adding or repositioning intracranial electrodes during presurgical assessment of
      neocortical epilepsy: electrographic seizure pattern and surgical outcome.
AB  - OBJECT: The aim of this study was to investigate changes in
      electroencephalography (EEG) patterns obtained from added or repositioned
      electrodes after those initially implanted had failed to indicate the true local
      ictal onset zone. The authors focused on the following matters: rationale for
      adding or repositioning electrodes, topographic and frequency characteristics of
      ictal onset before and after adding or repositioning electrodes, the effect of
      the procedures, and the relationship between changes in intracranial EEG onset
      patterns and surgical outcomes. METHODS: Of 183 patients with intracranial
      recordings, 18 experienced repositioning of existing or implanting of additional
      electrodes 7 or 10 days later. All patients underwent resection and were followed
      up for more than 1 year. In particular, the relationship between surgical outcome
      and distribution/frequency of intracranial seizure onset was analyzed. Results of
      noninvasive presurgical evaluations in patients who had undergone single and
      double invasive studies were also evaluated. By adding or repositioning
      electrodes, a new ictal onset zone was revealed in 13 patients. In another four,
      the second evaluation led to a change in defining the resection margin. Ictal
      onset in the partially sampled area, simultaneous or independent onset in two
      separate areas, and onset in the distal end of the electrode strip or grid were
      common reasons for failing to localize the ictal onset zone during the initial
      evaluation. Seven of 11 patients who were ultimately found to have a focal ictal
      onset zone on the second evaluation became seizure free after the operation. Only
      one of six patients with a regional ictal onset zone identified on the second
      evaluation became seizure free. There was no relationship between the frequency
      of the ictal rhythm and surgical outcome. Note, however, that surgical outcome
      was more favorable in patients who had undergone a single invasive study than in
      those who had undergone double invasive studies. The patients who needed a second
      evaluation had less localizing information and less concordant results on
      presurgical evaluations. When comparing nonlesional cases, surgical outcomes were
      not significantly different among patients with a single invasive study and those
      with double invasive studies. No additional morbidity or death occurred during
      the second study. CONCLUSIONS: The addition or reposition of intracranial
      electrodes with a short-term interval should be considered in selected patients.
      Spatial restriction of the ictal onset rhythm identified on repeated evaluation
      is the most important predictor of a good surgical outcome.

PMID- 15035283
TI  - Convection-enhanced delivery of paclitaxel for the treatment of recurrent
      malignant glioma: a phase I/II clinical study.
AB  - OBJECT: A minority of patients with recurrent glioblastomas multiforme (GBMs)
      responds to systemic chemotherapy. The authors investigated the safety and
      efficacy of intratumoral convection-enhanced delivery (CED) of paclitaxel in
      patients harboring histologically confirmed recurrent GBMs and anaplastic
      astrocytomas. METHODS: Fifteen patients received a total of 20 cycles of
      intratumoral CED of paclitaxel. The patients were observed daily by performing
      diffusion-weighted (DW) magnetic resonance (MR) imaging to assess the convective
      process and routine diagnostic MR imaging to identify the tumor response.
      Effective convection was determined by the progression of the hyperintense signal
      within the tumor on DW MR images, which corresponded to a subsequent lytic tumor
      response displayed on conventional MR images. Of the 15 patients, five complete
      responses and six partial responses were observed, giving a response rate of 73%.
      The antitumor effect was confirmed by one biopsy and three en bloc resections of
      tumors, which showed a complete response, and by one tumor resection, which
      demonstrated a partial response. Lack of convection and a poor tumor response was
      associated with leakage of the convected drug into the subarachnoid space,
      ventricles, and cavities formed by previous resections, and was seen in tumors
      containing widespread necrosis. Complications included transient chemical
      meningitis in six patients, infectious complications in three patients, and
      transient neurological deterioration in four patients (presumably due to
      increased peritumoral edema). CONCLUSIONS: On the basis of our data we suggest
      that CED of paclitaxel in patients with recurrent malignant gliomas is associated
      with a high antitumor response rate, although it is associated with a significant
      incidence of treatment-associated complications. Diffusion-weighted MR images may
      be used to predict a response by demonstrating the extent of convection during
      treatment. Optimization of this therapeutic approach to enhance its efficacy and
      reduce its toxicity should be explored further.

PMID- 15035284
TI  - Endolymphatic sac tumors in von Hippel-Lindau disease.
AB  - OBJECT: Von Hippel-Lindau (VHL) disease is a hereditary multiple-neoplasia
      syndrome mapping to chromosome 3p25-26. Endolymphatic sac (ELS) tumors have been
      identified as a neoplastic manifestation of VHL disease. The purpose of this
      study was to evaluate comprehensively the natural history of inner ear disease in
      a large population of patients with confirmed or suspected VHL disease and to
      correlate the clinical features with the VHL genotype. METHODS: The authors
      collated and analyzed clinical and genotypic data obtained in patients enrolled
      in an Institutional Review Board-approved protocol in which families and
      individuals affected by VHL disease were studied. These data included results
      from multidisciplinary history workups and physical examinations, imaging
      studies, and a battery of audiological tests. One hundred seventy-five patients
      were enrolled in the study, 129 with confirmed VHL disease and 46 of their family
      members in whom test results for VHL disease were negative and who served as
      controls. Twenty-one patients had ELS tumors that were evident on magnetic
      resonance images; three of them had bilateral ELS lesions. Hearing loss, often
      sudden in onset and severe to profound in nature, vestibulopathy, aural fullness,
      and tinnitus represented the primary symptoms of ELS tumor. Distinct patterns of
      auditory and vestibular dysfunction occurred at different stages of the disease.
      Phenotypic data showed that 17 of 21 patients with ELS tumors did not have
      pheochromocytomas, whereas all had VHL disease affecting the kidney, all but two
      had VHL disease affecting the central nervous system, and all but one had disease
      affecting the pancreas. Genotyping revealed 10 rearrangements (partial
      deletions), eight single bp substitutions, and one 3-bp insertion. Although there
      was no difference in the incidence of hearing loss between populations, symptoms
      of imbalance and aural fullness were more common in patients with VHL disease but
      without imaging evidence of ELS tumor than they were in family members who did
      not have VHL disease (p < 0.01). CONCLUSIONS: Endolymphatic sac tumors are
      frequently associated with VHL disease. Symptoms of disequilibrium or aural
      fullness in patients with VHL disease may be an early indication of endolymphatic
      dysfunction. Patients with VHL disease provide a unique opportunity to examine
      the effects of specific gene mutations and a discrete neoplastic process on the
      human inner ear. The study of ELS tumors in this group also provides a
      pathological model of ELS function and supplies evidence for a role of the ELS in
      clinical Meniere-like disease(s).

PMID- 15035285
TI  - Endolymphatic sac tumors in patients with and without von Hippel-Lindau disease:
      the role of genetic mutation, von Hippel-Lindau protein, and hypoxia inducible
      factor-1alpha expression.
AB  - OBJECT: Endolymphatic sac (ELS) tumors are low-grade malignancies of the temporal
      bone that are associated with von Hippel-Lindau (VHL) disease but can also occur
      sporadically. The VHL gene product VHL protein is important in the regulation of
      hypoxia inducible factor (HIF)-1alpha, which controls expression of molecules
      that are important in angiogenesis and cell metabolism. In this study the authors
      examine the role of VHL and HIF-1 in ELS tumors. METHODS: The ELS tumors from
      three patients were examined using the following method: DNA from tumor tissue
      was isolated, amplified by polymerase chain reaction and the VHL gene sequence
      was compared with the known wild-type sequence. Loss of heterozygosity (LOH)
      studies were performed to confirm the sequencing data. Immunohistochemical
      evaluation for VHL, HIF-1alpha, vascular endothelial growth factor (VEGF), and
      carbonic anhydrase IX (CA IX) was performed. Snap-frozen tumor tissue was
      examined using Western blot and HIF-1 immunoassays for HIF-1alpha and VHL
      expression. Two patients had sporadic ELS tumors and the other one suffered from
      VHL disease. Results of VHL gene sequencing were normal in the tissue derived
      from the sporadic ELS tumors. The ELS tumor, pheochromocytoma, and spinal
      hemangioblastoma were heterozygous for the same C-to-A transversion found in the
      germline carried by the patient with VHL disease. No LOH was detected in the
      tumor tissue obtained in the patient with VHL disease. Expression of HIF-1alpha,
      VEGF, and CA IX evaluated using immunohistochemical studies was elevated in the
      VHL-associated tumors. Nevertheless, Western blots and immunoassays for HIF
      1alpha did not show elevated expression in these tumors. CONCLUSIONS: The
      sporadic and VHL disease-associated ELS tumors in this study had normal VHL
      mediated HIF-1 regulation. This is a result of normal VHL gene expression in the
      case of the sporadic ELS tumor. In the VHL-associated ELS tumor, this is due to
      one normal copy of the VHL gene and adequate VHL gene expression.

PMID- 15035286
TI  - Comparison of waterjet dissection and ultrasonic aspiration: an in vivo study in
      the rabbit brain.
AB  - OBJECT: The waterjet method of dissection has been shown to enable the precise
      dissection of the parenchyma vessels while preserving blood in cadaveric pig
      brains. The waterjet device has also been applied clinically to treat various
      diseases and disorders without complications. Evidence still remains to be
      gathered as to how the instrument performs in reducing surgical trauma,
      intraoperative blood loss, and postsurgical brain edema. In the present study the
      authors investigate these parameters in a comparison between waterjet dissection
      and ultrasonic aspiration in the rabbit brain in vivo. METHODS: Thirty-one
      rabbits received identical bilateral frontal corticotomies, which were created
      using the waterjet device or an ultrasonic aspirator. The animals were killed 1,
      3, or 7 days, or 6 weeks after surgery and their brains were processed for
      immunohistological analysis. Blood vessel preservation, intraoperative
      hemorrhage, postsurgical brain edema, and posttraumatic microglial and astoglial
      reactions were evaluated. Only in animals subjected to waterjet dissection were
      preserved vessels observed within the corticotomies. In addition, less
      intraoperative bleeding occurred in animals in which the waterjet was used. The
      microglial reaction was significantly reduced by waterjet dissection compared
      with ultrasonic aspiration; however, no difference in edema formation or
      astrocytic reactivity was observed. CONCLUSIONS: These results demonstrate that
      waterjet dissection appears to be less traumatic than ultrasonic aspiration with
      respect to intraoperative hemorrhage and postoperative microglial reactivity in
      the rabbit model. Nevertheless, no difference in edema formation could be
      demonstrated. It remains to be proven that the observed differences are of
      clinical relevance.

PMID- 15035287
TI  - Increase of metabolic activity and disruption of normal contractile protein
      distribution by bilirubin oxidation products in vascular smooth-muscle cells.
AB  - OBJECT: Cerebral vasospasm is a common cause of morbidity and death following
      aneurysmal subarachnoid hemorrhage (SAH). Previous research has shown that
      bilirubin oxidation products (BOXes) are present in the cerebral spinal fluid in
      patients with SAH-induced cerebral vasospasm and can contribute to
      vasoconstriction and vasospasm in vitro and in vivo. The events leading to
      cerebral vasospasm are not understood; however, one component of the occlusion
      may be due to vascular remodeling. In this study the authors have investigated
      the actions of BOXes, okadaic acid ([OA], a phosphatase inhibitor), and phorbol
      12 myristate-13 acetate ([PMA], a protein kinase activator) on vascular smooth
      muscle cell (VSMC) morphology and metabolism. METHODS: Immunohistochemical
      analysis was performed to assess VSMC morphology and alpha-smooth-muscle actin
      (alphaSMA) distribution following the application of BOXes, OA, or PMA. Changes
      in the level of lactate dehydrogenase (LDH) release and oxidative metabolism were
      also measured. The BOXes, OA, or PMA caused VSMCs to change their shape and
      exhibit altered alphaSMA distribution. These treatments increased LDH release (p
      < 0.05), which is an index of increased cell stress. Oxidative metabolism
      significantly increased at low and high doses of BOXes, that is, 143 +/- 8.5% and
      180 +/- 11.8%, respectively (p < 0.0001). Both PMA and OA also caused a
      significant increase in metabolism. CONCLUSIONS: The authors concluded that
      BOXes, OA, and PMA alter VSMC morphology and metabolic activity, events that have
      been observed during vascular remodeling. Although the mechanism remains unclear,
      the results indicate that BOXes may play a role in the vascular remodeling that
      occurs following aneurysmal SAH.

PMID- 15035288
TI  - Evaluation of cardiac sympathetic nerve function by myocardial 123I
      metaiodobenzylguanidine scintigraphy before and after endoscopic sympathectomy.
AB  - OBJECT: The purpose of this study was to analyze the change in cardiac
      sympathetic function by performing a 123I-metaiodobenzylguanidine (MIBG) imaging
      study after endoscopic upper thoracic sympathectomy (EUTS) in patients with
      palmar hyperhidrosis before and after surgery. METHODS: Between February 1999 and
      February 2002, 135 patients underwent bilateral EUTS to treat palmar
      hyperhidrosis. Between September 2001 and February 2002, 12 of these
      consecutively enrolled patients were also included in a 123I-MIBG imaging study.
      These patients underwent cardiac 123I-MIBG imaging 1 day before and 7 days after
      they had undergone EUTS. The heart/mediastinum (H/M) ratio and the washout rate
      were calculated for both early and late phases, and single-photon emission
      computerized tomography (SPECT) imaging of the early phase was performed.
      Excessive perspiration from the palms disappeared immediately after EUTS in all
      patients, and they showed no symptoms of a circulatory condition following the
      procedure. On the 123I-MIBG imaging studies, the early H/M ratio before EUTS was
      2.35 +/- 0.26 and postoperatively it was 2.29 +/- 0.23. The delayed H/M ratio
      before EUTS was 2.59 +/- 0.3 and after the procedure it was 2.66 +/- 0.27. There
      was no significant difference between the H/M ratio before and after EUTS. The
      washout rate after EUTS (14.27 +/- 4.71%) was significantly lower than that
      measured before EUTS (18.36 +/- 5.13%: p < 0.01). No apparent local defects of
      accumulation of MIBG were found on SPECT images obtained post-EUTS. CONCLUSIONS:
      Endoscopic upper thoracic sympathectomy is a minimally invasive procedure; no
      local denervation was found after EUTS. Findings on 123I-MIBG imaging studies
      indicate that EUTS suppresses the activation of the sympathetic nervous system
      slightly, similar to beta-blocker therapy.

PMID- 15035289
TI  - The anatomical basis for surgical preservation of temporal muscle.
AB  - OBJECT: Mobilizing the temporal muscle is a common neurosurgical maneuver.
      Unfortunately, the cosmetic and functional complications that arise from
      postoperative muscular atrophy can be severe. Proper function of the muscle
      depends on proper innervation, vascularization, muscle tension, and the integrity
      of muscle fibers. In this study the authors describe the anatomy of the temporal
      muscle and report technical nuances that can be used to prevent its postoperative
      atrophy. METHODS: This study was designed to determine the susceptibility of the
      temporal muscle to injury during common surgical dissection. The authors studied
      the anatomy of the muscle and its vascularization and innervation in seven
      cadavers. A zygomatic osteotomy was performed followed by downward mobilization
      of the temporal muscle by using subperiosteal dissection, which preserved the
      muscle and allowed a study of its arterial and neural components. The temporal
      muscle is composed of a main portion and three muscle bundles. The muscle is
      innervated by the deep temporal nerves, which branch from the anterior division
      of the mandibular nerve. Blood is supplied through a rich anastomotic connection
      between the deep temporal arteries (anterior and posterior) on the medial side
      and the middle temporal artery (a branch of the superficial temporal artery
      [STA]) on the lateral side. CONCLUSIONS: Based on these anatomical findings, the
      authors recommend the following steps to preserve the temporal muscle: 1)
      preserve the STA; 2) prevent injury to the facial branches by using subfascial
      dissection; 3) use a zygomatic osteotomy to avoid compressing the muscle,
      arteries, and nerves, and for greater exposure when retracting the muscle; 4)
      dissect the muscle in subperiosteal retrograde fashion to preserve the deep
      vessels and nerves; 5) deinsert the muscle to the superior temporal line without
      cutting the fascia; and 6) reattach the muscle directly to the bone.

PMID- 15035291
TI  - An investigation of structural degradation of cerebrospinal fluid shunt valves
      performed using scanning electron microscopy and energy-dispersive x-ray
      microanalysis.
AB  - OBJECT: Surveys of cerebrospinal fluid (CSF) shunts that have been removed from
      patients have shown that even when the ventricular catheter is the cause of the
      obstruction, the valve may be obstructed or underperforming. The aim of this
      pilot study was to investigate the degradation of shunt valve structure over time
      due to the deposition of debris. The findings were compared with findings in
      unused valves. METHODS: Scanning electron microscopy was used to visualize the
      structures of the valves. The items that were examined included two unused and
      nine explanted cylindrical medium pressure valves, one unused and six explanted
      Delta 1.5 valves (PS Medical, Goleta, CA), and one explanted Medos Programmable
      valve (Codman Johnson & Johnson, LeLocle, Switzerland). The valves were cut open,
      disassembled, and coated in gold. The areas that were analyzed included the main
      valve chamber, the diaphragm unit, and the antisiphon device. For areas with
      abnormal deposits, energy-dispersive x-ray microanalysis was performed to
      establish the chemical composition of the deposits. The reference unused valves
      had smooth surfaces with no deposits in any areas. All explanted valves had
      extensive deposits in all surveyed areas. The deposits varied from small clusters
      of crystals to large areas that displayed a cobblestone appearance. In diaphragm
      valves the deposits extensively affected the surface of the diaphragm and the gap
      between the diaphragm and the surrounding case, where normally CSF flows; in the
      Medos valve the deposits affected in the spring and "staircase" unit. Deposits
      were present as early as 2 weeks after implantation. On some valves there was a
      complete film covering the entire outlet of the valve, which formed a cast inside
      the valve stretching from wall to wall. The deposits consisted mostly of sodium
      and chloride, but occasionally contained calcium. In all infected and some
      noninfected valves there was a significant peak of carbon, indicating the
      presence of protein deposits. CONCLUSIONS: It appears that the continuous flow of
      CSF through shunt valves causes surface deposits of sodium chloride and other
      crystals on all aspects of the valve, including the outlet pathways. The
      formation of deposits may be encouraged by the adhesive properties of the
      materials that constitute the valve parts.

PMID- 15035290
TI  - Inverse correlation of epidermal growth factor receptor messenger RNA induction
      and suppression of anchorage-independent growth by OSI-774, an epidermal growth
      factor receptor tyrosine kinase inhibitor, in glioblastoma multiforme cell lines.
AB  - OBJECT: Quantitative and qualitative alterations in the epidermal growth factor
      receptor (EGFR) commonly occur in many cancers in humans, including malignant
      gliomas. The aim of the current study was to evaluate molecular and cellular
      effects of OSI-774, a novel EGFR tyrosine kinase inhibitor, on nine glioblastoma
      multiforme (GBM) cell lines. METHODS: The effects of OSI-774 on expression of
      EGFR messenger (m)RNA and protein, proliferation, anchorage-independent growth,
      and apoptosis were examined using semiquantitative reverse transcription
      polymerase chain reaction, immunocytochemical analysis, Coulter counting, soft
      agar cloning, and terminal deoxynucleotidyl transferase-mediated deoxyuridine
      triphosphate nick-end labeling/fluorescence-activated cell sorting, respectively.
      All p53 genes were completely and bidirectionally sequenced. Suppression of
      anchorage-independent growth by OSI-774 was inversely correlated to the induction
      of EGFR mRNA during relative serum starvation (r = -0.74) and was unrelated to
      p53 status. Overall, suppression of anchorage-independent growth was a
      considerably stronger effect of OSI-774 than inhibition of proliferation. The
      extent of OSI-774-induced apoptosis positively correlated with both proliferation
      and anchorage-independent growth of GBM cell lines (r = 0.75 and 0.79,
      respectively). In a single cell line derived from a secondary GBM, exposure to
      concentrations of greater than or equal to 1 micromol/L resulted in a substantial
      net cell loss during proliferation studies. CONCLUSIONS: The induction of EGFR
      mRNA may constitute a cellular mechanism to counteract the inhibitory effect of
      OSI-774 on the anchorage-independent growth of GBM cells. In contrast, no
      considerable correlation could be established between baseline expression levels
      of EGFR (both mRNA and protein) in GBM cell lines and their biological response
      to OSI-774. The OSI-774 induced greater (p53-independent) apoptosis in more
      malignant GBM phenotypes and may be a promising therapeutic agent against
      secondary GBM.

PMID- 15035292
TI  - Determining the position and size of the subthalamic nucleus based on magnetic
      resonance imaging results in patients with advanced Parkinson disease.
AB  - OBJECT: The subthalamic nucleus (STN) is a target in surgery for Parkinson
      disease, but its location according to brain atlases compared with its position
      on an individual patient's magnetic resonance (MR) images is incompletely
      understood. In this study both the size and location of the STN based on MR
      images were compared with those on the Talairach and Tournoux, and Schaltenbrand
      and Wahren atlases. METHODS: The position of the STN relative to the
      midcommissural point was evaluated on 18 T2-weighted MR images (2-mm slices). Of
      35 evaluable STNs, the most anterior, posterior, medial, and lateral borders were
      determined from axial images, dorsal and ventral borders from coronal images.
      These methods were validated using histological measurements in one case in which
      a postmortem examination was performed. The mean length of the anterior
      commissure-posterior commissure was 25.8 mm. Subthalamic nucleus borders derived
      from MR imaging were highly variable: anterior, 4.1 to -3.7 mm relative to the
      midcommissural point; posterior, 4.2 to 10 mm behind the midcommissural point;
      medial, 7.9 to 12.1 mm from the midline; lateral, 12.3 to 15.4 mm from the
      midline; dorsal, 0.2 to 4.2 mm below the intercommissural plane; and ventral, 5.7
      to 9.9 mm below the intercommissural plane. The position of the anterior border
      on MR images was more posterior, and the medial border more lateral, than its
      position in the brain atlases. The STN was smaller on MR images compared with its
      size in atlases in the anteroposterior (mean 5.9 mm), mediolateral (3.7 mm), and
      dorsoventral (5 mm) dimensions. CONCLUSIONS: The size and position of the STN are
      highly variable, appearing to be smaller and situated more posterior and lateral
      on MR images than in atlases. Care must be taken in relying on coordinates
      relative to the commissures for targeting of the STN.

PMID- 15035293
TI  - Histological analysis of the location of effective thalamic stimulation for
      tremor. Case report.
AB  - Chronic electrical stimulation of the thalamus is an effective treatment for
      essential and parkinsonian tremor. Although the preferred surgical target is
      generally accepted to lie within the ventral intermediate nucleus (Vim), the
      relationship between the surgically defined target and the true histologically
      defined target is addressed in only a few reports, due in large measure to the
      need for advanced cytoarchitectonic techniques to define the borders of the
      thalamic nuclei. The authors report on a patient who underwent effective thalamic
      deep brain stimulation (DBS) for tremor. By defining the boundaries of the
      thalamic nuclei, they were able to relate effective DBS to electrode location
      within the anterior region of the ventral posterior lateral nucleus--the
      proprioceptive shell of the sensory nucleus--and the posteroventral region of the
      ventral lateral nucleus, which are equivalent to the Vim defined by Hassler, et
      al.

PMID- 15035294
TI  - Subthalamic nucleus deep brain stimulation in a patient with levodopa-responsive
      multiple system atrophy. Case report.
AB  - The authors report the clinicopathological findings in a patient in whom levodopa
      responsive parkinsonism developed at 45 years of age. The patient experienced
      asymmetrical onset of symptoms, sustained benefit from levodopa, and motor
      fluctuations and dyskinesias, but there were no prominent autonomic, cerebellar,
      or pyramidal signs. He was diagnosed clinically with Parkinson disease (PD) and
      underwent bilateral subthalamic nucleus deep brain stimulation (DBS) surgery 9
      years after symptom onset. He did not respond to stimulation or medication
      postoperatively, however, and died 12 weeks after surgery of repeated aspiration
      pneumonias. Postmortem examination revealed neuron loss in the substantia nigra
      and basal ganglia, and numerous alpha-synuclein-positive glial cytoplasmic
      inclusions in the subcortical nuclei, cerebellum, and brainstem, findings that
      established a neuropathological diagnosis of multiple system atrophy (MSA).
      Furthermore, there was an atypical and robust inflammatory reaction, as well as
      numerous glial cytoplasmic inclusions surrounding both DBS electrode termination
      sites. The authors speculate that the presence of alpha-synuclein in the
      striatum, combined with the inflammation surrounding the electrodes, contributed
      to the ineffectiveness of stimulation and dopaminergic medications
      postoperatively. This case demonstrates the ineffectiveness of DBS in MSA, even
      when the patient is responsive to levodopa, and emphasizes the need for
      diagnostic modalities that can be used to distinguish PD from MSA and other
      parkinsonian syndromes in which the levodopa response pattern is typical of PD.

PMID- 15035295
TI  - Intrasellar aneurysm and a growth hormone-secreting pituitary macroadenoma. Case
      report.
AB  - An aneurysm completely included within a pituitary adenoma that lies inside the
      sella turcica is rare and challenging from both a diagnostic and treatment
      viewpoint. A 39-year-old woman presented with symptoms and signs of acromegaly.
      Magnetic resonance imaging revealed a pituitary macroadenoma, which was
      associated with an intrasellar aneurysm. Digital subtraction angiography
      confirmed the presence of the cavernous carotid artery aneurysm. Complete
      endovascular obliteration of the aneurysm was achieved using Guglielmi Detachable
      Coils and the patency of the internal carotid artery was maintained. The
      pituitary adenoma was resected subtotally via a transsphenoidal microsurgical
      approach 8 months later. Preoperative detection of a coexisting intrasellar
      aneurysm in a patient with a pituitary adenoma is mandatory to avoid life
      threatening hemorrhagic complications. Endovascular coil placement is an
      effective treatment option when performed before the transsphenoidal removal of
      the adenoma.

PMID- 15035296
TI  - Magnetic and electrical stimulation of the auditory cortex for intractable
      tinnitus. Case report.
AB  - Tinnitus is a distressing symptom that affects up to 15% of the population for
      whom no satisfactory treatment exists. The authors present a novel surgical
      approach for the treatment of intractable tinnitus, based on cortical stimulation
      of the auditory cortex. Tinnitus can be considered an auditory phantom phenomenon
      similar to deafferentation pain, which is observed in the somatosensory system.
      Tinnitus is accompanied by a change in the tonotopic map of the auditory cortex.
      Furthermore, there is a highly positive association between the subjective
      intensity of the tinnitus and the amount of shift in tinnitus frequency in the
      auditory cortex, that is, the amount of cortical reorganization. This cortical
      reorganization can be demonstrated by functional magnetic resonance (fMR)
      imaging. Transcranial magnetic stimulation (TMS) is a noninvasive method of
      activating or deactivating focal areas of the human brain. Linked to a navigation
      system that is guided by fMR images of the auditory system, TMS can suppress
      areas of cortical plasticity. If it is successful in suppressing a patient's
      tinnitus, this focal and temporary effect can be perpetualized by implanting a
      cortical electrode. A neuronavigation-based auditory fMR imaging-guided TMS
      session was performed in a patient who suffered from tinnitus due to a cochlear
      nerve lesion. Complete suppression of the tinnitus was obtained. At a later time
      an extradural electrode was implanted with the guidance of auditory fMR imaging
      navigation. Postoperatively, the patient's tinnitus disappeared and remains
      absent 10 months later. Focal extradural electrical stimulation of the primary
      auditory cortex at the area of cortical plasticity is capable of suppressing
      contralateral tinnitus completely. Transcranial magnetic stimulation may be an
      ideal method for noninvasive studies of surgical candidates in whom stimulating
      electrodes might be implanted for tinnitus suppression.

PMID- 15035297
TI  - Partial epilepsy presenting as episodic dyspnea: a specific network involved in
      limbic seizure propagation. Case report.
AB  - The authors describe a patient who experienced stereotypical episodes of dyspnea
      and presyncopal sensation without loss of consciousness during a 4-month period.
      Further evaluation established intermittent arterial O2 desaturations associated
      with this dyspnea. After an extensive cardiopulmonary workup was performed for
      presumptive diagnosis of pulmonary embolism, a brain magnetic resonance image
      revealed a right medial temporal lobe lesion. The patient's dyspnea was then
      suspected to be a symptom of a seizure. His shortness of breath and O2
      desaturation resolved with administration of phenytoin. This case, to the
      authors' knowledge, is the first documented example of simple partial seizures
      presenting with episodic autonomic cardiopulmonary symptoms in the absence of
      other ictal behavior. This case may also illustrate one specific limbic autonomic
      network.

PMID- 15035298
TI  - The intriguing encounters of Pavlov and Cushing.
AB  - Ivan Petrovich Pavlov and Harvey William Cushing were two of the most prominent
      neuroscientists of the early 20th century. Their contributions helped advance the
      understanding of the brain and its disorders, and propelled neuroscience into a
      new era of research and treatment. Although separated geographically and
      culturally, Pavlov and Cushing exchanged letters and followed one another's
      careers from afar. They met only a few times, during international scientific
      gatherings in the US and abroad. These encounters were captured in journal
      entries, letters, and photographs, and provide a glimpse into the lives of these
      two great men and the history of neuroscience at the turn of the last century.

PMID- 15035299
TI  - Aneurysm size.

PMID- 15035300
TI  - Rotational injury.

PMID- 15035301
TI  - Cerebral metabolism.

PMID- 15035302
TI  - [Ulcus cruris and other problem cases. How suppurative wounds heal].

PMID- 15035303
TI  - ["Tropical climate" accelerates healing].

PMID- 15035304
TI  - [Laser correction for vision disorders is ever more popular. Are risks for the
      eye underestimated? (interview by Waltraud Paukstadt)].

PMID- 15035305
TI  - [References from colleagues for weight loss. How do you motivate the obese
      patient? (interview by Andrea Scholz-Wagner)]].

PMID- 15035306
TI  - [When is death judged "unnatural"? Autopsy with forensic footnotes].

PMID- 15035307
TI  - [Breast cancer risk with hormone replacement therapy. A matter of
      interpretation].

PMID- 15035308
TI  - [Acute coronary syndrome you can hear the prognosis].

PMID- 15035313
TI  - [Every third German has a sick thyroid gland. Nodules and goiter are a challenge
      that needs to be met].

PMID- 15035314
TI  - [Diagnosis and treatment of benign goiter].
AB  - Although the German population is now appreciably better supplied with iodine,
      this is still not adequate in all regions and in all situations, e.g. during
      pregnancy and breast feeding. As a result, more than 20 million Germans have an
      iodine-deficiency goiter that requires treatment. Investigation of a goiter is
      effected with sonography and the determination of serum TSH. If the results
      indicate euthyroid diffuse goiter, medical treatment should be initiated. In
      recent years, the combination of thyroid hormone and iodine has proved
      particularly effective. In contrast to monotherapy with levothyroxine goiter
      recurrence after discontinuation of treatment is less common, and the combination
      is usually tolerated better.

PMID- 15035315
TI  - [How to treat benign thyroid gland nodules].
AB  - Investigations within the framework of the thyroid gland initiative "Papillon"
      turned up an unexpectedly high level of pathogenic findings. Determination of TSH
      and sonography are considered the pillars of the diagnostic evaluation of the
      thyroid gland. Useful further investigations aimed at excluding functional
      disorders are, for example, the determination of FT3 and FT4 or a search for
      autoantibodies. To investigate suspicious nodules and to exclude malignant
      processes, additional scintigraphy and, were indicated, fine-needle puncture can
      be applied. Depending on the individual situation of the patient, the therapeutic
      option of choice is surgical operation or treatment with iodine-31 therapy.
      Medical treatment of nodular goiter is currently still controversial.

PMID- 15035316
TI  - [Diagnosis and treatment of autoimmune thyroiditis].
AB  - In Germany, autoimmune thyroiditis usually manifests as atrophic thyroiditis with
      functional hypothyroidism affecting elderly women in particular. Sonography and
      thyroid peroxidase antibodies (TPO antibodies) point the way to the diagnosis.
      Manifest hypothyroidism always requires substitution with levothyroxine. Many
      patients with subclinical hypothyroidism, especially those with positive thyroid
      antibodies, benefit from at least partial thyroxine substitution. Early treatment
      not only alleviates the clinical symptoms, but may possibly also diminish the
      associated cardiovascular risk. In pregnant and sterile women subclinical
      hypothyroidism should always be treated.

PMID- 15035317
TI  - [Hypovolemic shock].

PMID- 15035318
TI  - [The most important rules for pain relief].

PMID- 15035319
TI  - [General practice tax and chronic patient regulation. Caution about angry
      misunderstandings!].

PMID- 15035320
TI  - [East German physicians should be quiet... and hospitals should replace family
      physicians].

PMID- 15035321
TI  - [Brown spot in the sclera].

PMID- 15035322
TI  - [Polypectomy in the colon].

PMID- 15035323
TI  - [Multiple abscesses in a homeless person].

PMID- 15035324
TI  - Translation and recognition.

PMID- 15035325
TI  - Contrast polarities determine the direction of Cafe Wall tilts.
AB  - We propose an explanatory approach to Cafe Wall type illusions that is simple yet
      fairly comprehensive. These illusions are constructed out of basic elementary
      units in a jigsaw-like manner. Each unit, in general, contains both a solid body
      and a thin tail: the contrast polarity between the two determines the direction
      of the contributory illusory tilt produced by that element-according to a
      heuristic rule illustrated in figure 1. Ensembles of these elements exhibit
      illusory tilts only when the tails of the elements align along a common line in
      an additive manner. When elements of opposing polarity alternate, the illusion is
      cancelled. This approach extends and supersedes those presented in Pinna's
      illusion of angularity and Kitaoka's 'acute' corner effect. Furthermore, it
      appears to be, in part, compatible with existing mechanisms proposed to account
      for the emergence of local tilt cues, and it suggests several novel variations on
      the Cafe Wall theme.

PMID- 15035326
TI  - Effects of 3-D complexity on the perception of 2-D depictions of objects.
AB  - In a recent study, Pelli (1999 Science 285 844-846) performed a set of perceptual
      experiments using portrait paintings by Chuck Close. Close's work is similar to
      the 'Lincoln' portraits of Harmon and Julesz (1973 Science 180 1194-1197) in that
      they are composite images consisting of coarsely sampled, individually painted,
      mostly homogeneous cells. Pelli showed that perceived shape was dependent on
      size, refuting findings that perception of this type is scale-invariant. In an
      attempt to broaden this finding we designed a series of experiments to
      investigate the interaction of 2-D scale and 3-D structure on our perception of 3
      D shape. We present a series of experiments where field of view, 3-D object
      complexity, 2-D image resolution, viewing orientation, and subject matter of the
      stimulus are manipulated. On each trial, observers indicated if the depicted
      objects appeared to be 2-D or 3-D. Results for face stimuli are similar to
      Pelli's, while more geometrically complex stimuli show a further interaction of
      the 3-D information with distance and image information. Complex objects need
      more image information to be seen as 3-D when close; however, as they are moved
      further away from the observer, there is a bias for seeing them as 3-D objects
      rather than 2-D images. Finally, image orientation, relative to the observer,
      shows little effect, suggesting the participation of higher-level processes in
      the determination of the 'solidness' of the depicted object. Thus, we show that
      the critical image resolution depends systematically on the geometric complexity
      of the object depicted.

PMID- 15035327
TI  - Early computation of contour curvature and part structure: evidence from holes.
AB  - We used holes to study unilateral border ownership and in particular the
      information carried by the sign of the curvature along the contour (ie the
      difference between convex and concave regions). When people perceive a hole, its
      shape has a reversed curvature polarity (ie a changed sign of curvature) compared
      to the same region perceived as an object. Bertamini (2001 Perception 30 1295
      1310), and Bertamini and Croucher (2003 Cognition 87 33-54) suggested and found
      evidence to support the hypothesis that, because convex regions are perceived as
      parts, positional information is more readily available for convex regions.
      Therefore a change is predicted when a given region is perceived as either a hole
      or a figure. We confirm that finding in this study, using holes defined by
      binocular disparity. We conclude that a change from figure to hole always
      reverses the encoding of curvature polarity. In turn, polarity obligatorily
      affects perceived part structure and the processing of position.

PMID- 15035328
TI  - The contributions of static visual cues, nonvisual cues, and optic flow in
      distance estimation.
AB  - By systematically varying cue availability in the stimulus and response phases of
      a series of same-modality and cross-modality distance matching tasks, we examined
      the contributions of static visual information, idiothetic information, and optic
      flow information. The experiment was conducted in a large-scale, open, outdoor
      environment. Subjects were presented with information about a distance and were
      then required to turn 180 before producing a distance estimate. Distance encoding
      and responding occurred via: (i) visually perceived target distance, or (ii)
      traversed distance through either blindfolded locomotion or during sighted
      locomotion. The results demonstrated that subjects performed with similar
      accuracy across all conditions. In conditions in which the stimulus and the
      response were delivered in the same mode, when visual information was absent,
      constant error was minimal; whereas, when visual information was present,
      overestimation was observed. In conditions in which the stimulus and response
      modes differed, a consistent error pattern was observed. By systematically
      comparing complementary conditions, we found that the availability of visual
      information during locomotion (particularly optic flow) led to an 'under
      perception' of movement relative to conditions in which visual information was
      absent during locomotion.

PMID- 15035329
TI  - How many faces can be processed during a single eye fixation?
AB  - The purpose of our study was to estimate the perceptual span for facial
      information: how many faces can be processed during a single eye fixation. We
      used a visual-search task, in which the targets and distractors were facial
      photographs. The task of the observer was to search for and identify a target
      face in an array of faces. We measured the time needed for one search--threshold
      search time--by using a multiple-alternative staircase method. The threshold
      represents the duration of stimulus presentation at which the probability of
      correct responses was 79%. The array size was varied from 2 x 2 to 8 x 8 faces.
      Simultaneously with the performance measurements we measured eye movements with a
      video eye tracker. We found that threshold search time increased with increasing
      set size nearly linearly. The number of fixations also increased linearly from
      unity at the smallest set size to about fifteen at the largest set size. The
      result of 2 x 2 faces during a single fixation gave an estimate of 4 faces for
      the perceptual span. If, on average, only half of the elements had to be scanned
      for finding the target, 15 fixations at the largest set size (8 x 8) gave another
      estimate of 2.13 faces. The mean fixation duration was around 200 ms. Thus, the
      results suggest that 2-4 faces can be processed during one fixation of about 200
      ms.

PMID- 15035330
TI  - Size perception is less context-sensitive in males.
AB  - Context sensitivity of size perception has previously been used to study
      individual differences related to the distinction between local, analytic, or
      field-independent and global, holistic, or field-dependent perceptual styles. For
      example, it has been used in several recent studies of autistic spectrum
      disorders, which may involve an excessive bias toward local processing. Autism is
      much more common in males, and there is evidence that this may be in part because
      males in general tend to be less context-sensitive than females, and thus are
      more affected by conditions that further reduce context sensitivity. There is
      also evidence that a bias to local processing is more common in professions that
      require attention to detail. Context sensitivity of size perception was therefore
      studied as a function of sex and academic discipline in sixty-four university
      staff and students by a simple, sensitive, and specific psychophysical measure
      based on the Ebbinghaus illusion. The results show that in this task males are on
      average less context-sensitive than females, that the overlap is large, and that
      subjects with very high or very low context sensitivity tend to have the sex and
      profession predicted by the above hypotheses.

PMID- 15035331
TI  - What happens next? The predictability of natural behaviour viewed through CCTV
      cameras.
AB  - Can potentially antisocial or criminal behaviour be predicted? Our study aimed to
      ascertain (a) whether observers can successfully predict the onset of such
      behaviour when viewing real recordings from CCTV; (b) where, in the sequence of
      events, it is possible to make this prediction; and (c) whether there may be a
      difference between naive and professional observers. We used 100 sample scenes
      from UK urban locations. Of these, 18 led to criminal behaviour (fights or
      vandalism). A further 18 scenes were matched as closely as possible to the crime
      examples, but did not lead to any crime, and 64 were neutral scenes chosen from a
      wide variety of noncriminal situations. A signal-detection paradigm was used in
      conjunction with a 6-point rating scale. Data from fifty naive and fifty
      professional observers suggest that (a) observers can distinguish crime sequences
      from neutral sequences and from matches; (b) there are key types of behaviour
      (particularly gestures and body position) that allow predictions to be made; (c)
      the performance of naive observers is comparable to that of experts. However,
      because the experts were predominantly male, the absence of an effect of
      experience may have been due to gender differences, which were investigated in a
      subsidiary experiment. The results of experiment 2 leave open the possibility
      that females perform better than males at such tasks.

PMID- 15035332
TI  - Vibro-tactile and visual asynchronies: sensitivity and consistency.
AB  - We investigated the consistency between tactually and visually designated empty
      time intervals. In a forced-choice discrimination task, participants judged
      whether the second of two intervals was shorter or longer than the first
      interval. Two pulses defined the intervals. The pulse was either a vibro-tactile
      burst presented to the fingertip, or a foveally presented white square. The
      comparisons were made for uni-modal and cross-modal intervals. We used four
      levels of standard interval durations in the range of 100- 800 ms. The results
      showed that tactile empty intervals must be 8.5% shorter to be perceived as long
      as visual intervals. This cross-modal bias is larger for small intervals and
      decreases with increasing standard intervals. The Weber fractions (the threshold
      divided by the standard interval) are 20% and are constant over the standard
      intervals. This indicates that the Weber law holds for the range of interval
      lengths tested. Furthermore, the Weber fractions are consistent over uni-modal
      and cross-modal comparisons, which indicates that there is no additional noise
      involved in the cross-modal comparisons.

PMID- 15035333
TI  - Reduced discriminability following perceptual learning with odours.
AB  - In this experiment, the effects of prior experience on odour perception and
      discrimination were explored. Participants repeatedly sniffed a mixture composed
      of two odours, AX, as well as smelling two further odours alone, B and Y. After
      this training phase, participants were asked to rate the similarity of the odours
      A and X, B and Y, and a non-exposed pair C and Z. A and X were judged as
      significantly more alike than the other pairs. Exactly the same pattern emerged
      on a second test, in which participants were asked to select the odd odour out of
      sets of three. It was consistently harder for participants to pick the odd odour
      when the stimuli were drawn from the AX pair (eg A versus AX versus AX). Not only
      do these findings demonstrate that prior experience can affect odour perception,
      a finding not predicted by theories of odour perception based solely upon the
      physiochemical properties of odours, they also suggest that experience can act to
      selectively decrease discriminability.

PMID- 15035334
TI  - Steady viewing dissipates global structure.

PMID- 15035335
TI  - Disorders of consciousness: anatomical and physiological mechanisms.
AB  - The anatomical and physiological mechanisms of consciousness are reviewed,
      focussing on the wakefulness mechanisms, which are one aspect, albeit an
      indispensable one, of consciousness. In trying to understand disorders of
      consciousness, it must be remembered that wake physiology is linked to sleep
      physiology and a brief summary of the phenomenology and regulation of the wake
      sleep cycle is therefore presented. Wakefulness is produced and maintained by a
      complex neural network composed of at least ten groups of neurones, which spread
      out from the medulla oblongata to the telencephalic structures. Some of these
      elements (reticular formation and diffuse thalamic nuclei) contribute to the
      arousal and general activation of the brain, while others (aminergic and
      peptidergic neurones) contribute to the quality of wakefulness, as well as to
      general activation. Disorders of wakefulness may be due to dysfunction of one or
      several elements of the wake network or sleep disorders, as well as to sleep
      deprivation.

PMID- 15035336
TI  - Advances in craniosynostosis research and management.
AB  - The purpose of the present paper is to analyze the most recent advances in the
      field of craniosynostosis basic and clinical research and management, and to give
      an overview of the more frequently adopted surgical strategies. After reviewing
      some basic concepts regarding normal craniofacial embryology and growth,
      aetiopathogenesis of craniosynostosis and craniofacial dysostosis, classification
      and diagnosis and historical evolution of surgical treatment, the authors
      elaborate on a selection of topics that have modified our current understanding
      of and therapeutical approach to these disease processes. Areas covered include
      advances in molecular biology and genetics, imaging techniques and surgical
      planning, resorbable fixation technology, bone substitutes and tissue
      engineering, distraction osteogenesis and the spring-mediated cranioplasties,
      resorbable distractor devices, minimally invasive surgery and in utero surgery. A
      review of the main subtypes of craniosynostosis and craniofacial dysostosis is
      presented, including their specific clinical features and a commentary on the
      presently available surgical options.

PMID- 15035337
TI  - Preoperative clinical evaluation, outline of surgical technique and outcome in
      temporal lobe epilepsy.
AB  - Temporal lobe epilepsy (TLE) is the most common type of refractory epilepsy. The
      mechanisms of epileptogenesis and seizure semiology of the mesial and neocortical
      temporal lobe epilepsy are discussed. The evaluation and selection of patients
      for TLE surgery requires team work: the different clinical aspects of
      neuropsychological evaluation, magnetic resonance and functional imaging
      (positron emission tomography, single photon emission computed tomography and
      magnetoenephalography) are reviewed. In our programme of epilepsy surgery at
      Kuopio University Hospital, Finland, we have performed 230 temporal resections
      from 1988 until 2002. Preoperative diagnostic EEG-videotelemetry often required
      intracranial monitoring and it has proved to be safe and efficient. The
      indications and technique for tailored temporal lobe resection with
      amygdalohippocampectomy used in our institution, as well as the complications,
      are described. Our analysis of outcome after temporal lobe surgery included 140
      consecutive adult patients between 1988 and 1999; one year after the operation in
      unilateral TLE the Engel I-II outcome was observed in 68% of the patients.
      Outcome of surgery improved significantly after introduction of the standardised
      MR imaging protocol from 1993; 74% of patients with unilateral TLE achieved Engel
      I-II outcome.

PMID- 15035338
TI  - Motor evoked potential monitoring for spinal cord and brain stem surgery.
AB  - Intraoperative Neurophysiology (ION) has established itself as one of the means
      by which modern neurosurgery can improve surgical results while minimizing
      morbidity. The advent of motor evoked potential (MEP) monitoring represents a
      landmark in this recent progress. ION consists of monitoring (the continuous "on
      line" assessment of the functional integrity of neural pathways) and mapping (the
      functional identification and preservation of anatomically ambiguous nervous
      tissue) techniques. In this chapter we have attempted to critically review the
      evolution of MEP use during monitoring and mapping techniques for neurosurgical
      procedures in the brainstem and the spinal cord, providing the neurophysiological
      theoretical background and practical aspects of clinical applications. According
      to the experience from our and other groups involved in ION, we suggest the
      following: 1) ION is mandatory whenever neurological complications are expected
      as predicted by a known pathophysiological mechanism. It is therefore advisable
      to perform ION when dealing with brain stem and intramedullary spinal cord
      lesions. 2) MEP monitoring after transcranial electrical stimulation is today a
      feasible and reliable technique for use under general anesthesia. MEP monitoring
      is the most appropriate technique to assess the functional integrity of
      descending motor pathways in the brainstem and, foremost, in the spinal cord. 3)
      Mapping of the corticospinal tract at the level of the cerebral peduncle as well
      as mapping of the VII, IX-X and XII cranial nerve motor nuclei on the floor of
      the fourth ventricle is of great value with which to identify "safe entry zones"
      into the brainstem. 4) Other techniques, although safe and feasible, still lack
      rigorous validation in terms of prognostic value and correlation with the
      postoperative neurological outcome. These techniques include mapping of the
      corticospinal tract within the spinal cord and monitoring of the corticobulbar
      tracts. These techniques, however, are expected to open new perspectives in the
      near future.

PMID- 15035339
TI  - Motor evoked potential monitoring for the surgery of brain tumours and vascular
      malformations.
AB  - Brain surgery incurs a significant risk of a new motor deficit in lesions within
      or adjacent to the motor areas and pathways which, for the patient, presents one
      of the most disabling complications of such operations. It is a major concern of
      intracranial procedures to delineate and monitor motor regions in order to
      preserve their structural and functional integrity, while still achieving maximal
      cytoreduction. The technique of motor evoked potential recording has had to be
      adapted to intraoperative recording conditions under general anaesthesia, but has
      been available for clinical use now for almost ten years. This contribution
      summarizes the current technique and related methods, as well as our clinical
      experience in some 400 cases of MEP monitoring in supratentorial tumors, lesions
      in and around the brainstem, and aneurysm surgery. Intraoperative MEP recordings
      have been shown to reliably reflect an impending new motor deficit. Irreversible
      MEP deterioration heralds new paresis, and unaltered recordings predict preserved
      motor function. This is also true in aneurysm surgery where conventional SEP
      monitoring may yield false-negative results with regard to development of a new
      motor deficit. Moreover, if MEP deterioration can be reversed, or halted by early
      surgical intervention, the presence of only a transient motor deficit, or even
      the lack of a new postoperative deficit, indicates the success of the MEP
      monitoring method in the prevention of a significant motor impairment. Certain
      complicated lesions can only be operated on at all because MEP monitoring is
      available. In conclusion, intraoperative MEP monitoring is a useful aid in brain
      surgery with which to avoid a new motor deficit without compromise to the
      surgical result. Controlled prospective studies will be required to verify the
      clinical value of the method.

PMID- 15035340
TI  - Functional neuronavigation and intraoperative MRI.
AB  - Our concept of computer assisted surgery is based on the combination of
      intraoperative magnetic resonance (MR) imaging with microscope-based
      neuronavigation, providing anatomical and functional guidance simultaneously.
      Intraoperative imaging evaluates the extent of a resection, while the additional
      use of functional neuronavigation, which displays the position of eloquent brain
      areas in the operative field, prevents increasing neurological deficits, which
      would otherwise result from extended resections. Up to mid 2001 we performed
      intraoperative MR imaging using a low-field 0.2 Tesla scanner in 330 patients.
      The main indications were the evaluation of the extent of resection in gliomas,
      pituitary tumours, and in epilepsy surgery. Intraoperative MR imaging proved to
      serve as intraoperative quality control with the possibility of an immediate
      modification of the surgical strategy, i.e. extension of the resection.
      Integrated use of functional neuronavigation prevented increased neurological
      deficits. Compared to routine pre- or postoperative imaging being performed with
      high-Tesla machines, intraoperative image quality and sequence spectrum could not
      compete. This led to the development of the concept to adapt a high-field MR
      scanner to the operating environment, preserving the benefits of using standard
      microsurgical equipment and microscope-based neuronavigational guidance with
      integrated functional data, which was successfully implemented by April 2002. Up
      to the end of 2002, 95 patients were investigated with the new setup. Improved
      image quality, intraoperative workflow, as well as enhanced sophisticated
      intraoperative imaging possibilities are the major benefits of the high-field
      setup.

PMID- 15035341
TI  - Surgical anatomy of the insula.
AB  - The insula is the only cortical part of the brain which is not visible on the
      surface of the hemisphere. This is due to the fact that it is totally covered by
      the fronto-parietal and temporal opercula. The insula has a triangular shape, and
      is separated from the opercula by the anterior, superior, and inferior
      periinsular sulci. The limen insulae is the antero-inferiorly located insular
      cortical surface which conjoins the inferior insular point, the anterior
      perforated surface, and the temporo-mesial surface. The insula is morphologically
      divided into two parts by the central insular sulcus. The anterior part of the
      insula bears 3 gyri: the anterior, middle, and posterior short insular gyri,
      separated by the anterior and precentral insular sulcus. The posterior part of
      the insula contains the anterior and posterior long insular gyri, separated by
      the postcentral insular sulcus. The vascular supply of the insula is mainly
      provided by the M2 segment of the middle cerebral artery, which constitutes a
      substantial obstacle to any open or stereotactic procedure aiming at the insular
      region. Histologically, the insula is a part of the paralimbic cortex, as it
      bears in its antero-inferior part an allo and mesocortical area. The insula is
      functionally involved in cardiac rhythm and arterial blood pressure control, as
      well as in viscero-motor control and in viscero-sensitive functions. There is
      considerable evidence for the involvement of the insula as a somesthetic area,
      including a major role in the processing of nociceptive inputs. Its possible role
      in some epilepsies may explain some failures of temporal lobe resection. Surgery
      of the insular lobe is a technical challenge, whose risks can be minimized by the
      use of intra-operative direct cerebral stimulation.

PMID- 15035342
TI  - The ethic of "the organizational good": is doing the right thing enough?
AB  - An organization whose members are acculturated to behave morally according to
      specified principles practices "the organizational good." "The organizational
      good" is the soul of an organization; it should not change. If the Board of
      Directors, Chief Executive Officer, managers, and members reinforce ethical
      principles by modeling them, an organization can thrive; if not, the organization
      may become ethically bankrupt. It is the premise of this article that the
      increasingly common errant behavior of some organizations and their Chief
      Executive Officers today is because they do not practice the ethic of "the
      organizational good."

PMID- 15035343
TI  - Self-promotion: a strategy for career advancement.
AB  - Self-promotion is a technique that many managers feel is contradictory to
      appropriate behavior. However, without self-promotion, many managers can cause
      their abilities to go unnoticed and to actually be their own worst enemy. This
      article presents strategies for self-promotion that can advance a manager's
      career and assist in marketing ideas and abilities to end the manager up in
      center stage.

PMID- 15035344
TI  - The history of US national health plans: will these same issues resurface in
      2004?
AB  - Health care managers are an important aspect of any proposed national health care
      plan; the implementation of such a plan will change their work lives in
      significant ways, no matter which type of plan is adopted. It is important to
      occasionally revisit historical developments, especially when they resurface in
      the people's consciousness. It appears that health care reform and various
      national health plan proposals may become an important part of the 2004 election,
      particularly given the economic concerns today. This article reviews health care
      plans in a historical perspective, particularly from the time of the 1930s
      onward, with a special longer look at Clinton's failure to implement a national
      health plan when the timing for such seemed perfect. Whether an individual
      manager is a supporter of national health plans or not, this article seeks to
      educate the manager on past efforts to better understand what may develop in the
      future.

PMID- 15035345
TI  - Utilization of performance appraisal systems in health care organizations and
      improvement strategies for supervisors.
AB  - Performance appraisal systems that are designed to objectively evaluate an
      employee's performance and then outline measures to be taken for improvements are
      essential for an organization to move ahead. These systems are often organization
      specific and health care organizations are no exception. However, health care
      managers seem to be more vocal and have often expressed dissatisfaction with the
      use of their company's performance appraisal system. This article is based on a
      case study of a health care organization's current performance appraisal
      techniques. This organization's current use of performance appraisals are
      discussed in brief, and strategies for health care organizations to improve their
      performance appraisal system have also been identified.

PMID- 15035347
TI  - Health care in the Sultanate of Oman from a graduate internship experience
      perspective.
AB  - This article presents an overview of health care in the Sultanate of Oman,
      focusing on areas such as organization, financing, and staffing issues. It
      further relates the experiences of one graduate student during an administrative
      graduate internship in the Sultanate of Oman. The student interned at 4 hospital
      facilities, observing different departments (such as Nursing, Pharmacy,
      Laboratory, Health Information Management) and shadowing facility administrators.
      Also presented are student recommendations that were developed for various areas
      of the facilities (health information management, ancillary services, patient
      care areas, etc.) based on the student's graduate coursework and observations
      during the internship.

PMID- 15035346
TI  - HIPAA compliance: deadlines and beyond.
AB  - The deadline has passed for the Health Insurance Portability and Accountability
      Act (HIPAA) Privacy Rule and the Transactions and Code Sets Rule. With that in
      mind, many health care professionals feel that they can sit back and take a deep
      breath. But do not be fooled, both rules require continuous follow-up and
      monitoring. Additionally, the Security Rule requires compliance by April 2005.
      During implementation of future HIPAA regulations, health care professionals can
      benefit greatly from their experiences in meeting requirements of the Privacy
      Rule and the Transactions and Code Sets Rule. Many of the same tools and
      techniques may be used to ensure compliance with future HIPAA regulations. This
      article will discuss the need for ongoing compliance with the Privacy Rule, the
      Transactions and Code Sets Rule, and the implementation of the Security Rule.

PMID- 15035348
TI  - Conflict management styles of Asian and Asian American nurses: implications for
      the nurse manager.
AB  - Foreign nurses and American nurses who are culturally diverse make up an
      increasing number of the US nursing workforce. Of foreign nurses, Asians
      constitute the largest number. Conflict is an inevitable aspect of human
      relations in health care settings. Nurses and other health team members with
      diverse cultural background bring to the workplace different conflict behaviors
      that directly impact the outcomes of conflicts. It is essential for health care
      team members and managers to be cognizant of different conflict behaviors as well
      as different conflict management styles so that strategies can be designed to
      build a culturally diverse health care team that is able to effectively achieve
      group and organizational objectives.

PMID- 15035349
TI  - Nursing generations: an expanded look at the emergence of conflict and its
      resolution.
AB  - Never before have so many generations in nursing been asked to work together. The
      coexistence of 3 generations in nursing is leading to intergenerational conflict.
      The current intergenerational conflict is not enticing Generation X to seek or
      maintain nursing careers, therefore exacerbating the current nursing shortage.
      Using the theoretic frameworks of Conflict and Cohort theories, this article will
      examine and suggest the impact of generational diversity on the future of
      nursing.

PMID- 15035350
TI  - Improving productivity through more effective time management.
AB  - Effective time management has become increasingly important for managers as they
      seek to accomplish objectives in today's organizations, which have been
      restructured for efficiency while employing fewer people. Managers can improve
      their ability to manage time effectively by examining their attitudes toward
      time, analyzing time-wasting behaviors, and developing better time management
      skills. Managers can improve their performance and promotion potential with more
      effective time utilization. Strategies for improving time management skills are
      presented.

PMID- 15035351
TI  - Can the value of training be measured? A simplified approach to evaluating
      training.
AB  - Measuring the value of any training intervention has long baffled trainers and
      managers alike. Complex models for calculating the return on investment offer
      little help in attempting to measure the results of these programs.
      Unfortunately, while the difficulty in measuring these programs has not lessened,
      the need to justify training costs in the health care field has increased
      dramatically. In this article, the authors offer a perspective of how 1 hospital
      dealt with this complex issue and offer a guide for a simpler approach to
      measuring the value of training programs that can be used by trainers and
      managers without resorting to complicated formulas.

PMID- 15035352
TI  - The comprehensive organizational plan: how a COP can protect and serve your
      health care organization.
AB  - In today's hyperturbulent and competitive health care environment, health care
      organizations must improve operating efficiency, reduce duplication, and compete
      effectively in the health care market to survive. The comprehensive
      organizational plan is a 5-stage development tool for health care organizations
      that is intended to protect and serve the health care organization in its
      survival efforts. Through its 5 planning stages-competitive, facilities,
      financial, human resources, and marketing-the comprehensive organizational plan
      assists the organization in optimizing the goals of cost containment, quality
      preservation, and universal access.

PMID- 15035353
TI  - The causes and consequences of conflict and violence in nursing homes: working
      toward a collaborative work culture.
AB  - Interpersonal conflict, often spiraling to violence and abuse, is one of the most
      daunting challenges facing nursing home administrators and their departmental
      heads. Mounting evidence documents how they spend an inordinate amount of time
      dealing with angry families, adversarial ombudsmen, regulators, and other hostile
      parties as well as handling the aftermath of the ubiquitous conflict between the
      residents and their direct caregivers. All this is in addition to coping with the
      normal interdepartmental and line staff forms of conflict that typify any
      organization. This paper details the special dynamics that accelerate
      dysfunctional conflict in nursing homes and presents strategies, tactics, and
      style recommendations that will help nursing home leaders build more
      collaborative work cultures to minimize the effects of dysfunctional conflict.

PMID- 15035354
TI  - Effect of hot water and hydrogen peroxide treatments on survival of salmonella
      and microbial quality of whole and fresh-cut cantaloupe.
AB  - Cantaloupe melon has been associated with outbreaks of salmonellosis.
      Contamination might be introduced into the flesh from the rind by cutting or by
      contact of cut pieces with contaminated rinds. Our objectives were to investigate
      the efficacy of hot water or hot 5% hydrogen peroxide treatments in reducing the
      population of native microflora and inoculated Salmonella on cantaloupe rind and
      transfer to fresh-cut tissue during cutting. Whole cantaloupes, inoculated with a
      cocktail of Salmonella serovars to give 4.6 log CFU/cm2 and stored at 5 or 20
      degrees C for up to 5 days, were treated with hot water (70 or 97 degrees C) or
      5% hydrogen peroxide (70 degrees C) for 1 min at 0, 1, 3, or 5 days
      postinoculation. Aerobic mesophilic bacteria and yeast and mold on treated whole
      melon and fresh-cut pieces were significantly (P < 0.05) reduced by all three
      treatments. Treatments with hot water (70 and 97 degrees C) caused a 2.0- and 3.4
      log CFU/cm2 reduction of Salmonella on whole cantaloupe surfaces irrespective of
      days of postinoculation storage prior to treatment up to 5 days at 5 or 20
      degrees C, respectively. Treatment with 5% hydrogen peroxide (70 degrees C)
      caused a 3.8-log CFU/cm2 reduction of Salmonella. Fresh-cut pieces prepared from
      untreated inoculated melons and those treated with 70 degrees C hot water were
      positive for Salmonella. However, fresh-cut pieces prepared from inoculated whole
      melon dipped in water (97 degrees C) or hydrogen peroxide (70 degrees C) for 60 s
      were negative for Salmonella, as determined by dilution plating onto agar medium,
      but were positive after enrichment at days 3 and 5 of storage at 5 degrees C. The
      ability to detect Salmonella in fresh-cut pieces was dependent on the initial
      level of inoculation. The results of this study indicate that the use of hot
      water (97 degrees C) or heated hydrogen peroxide to reduce the population of
      Salmonella on contaminated whole cantaloupes will enhance the microbial safety of
      the fresh-cut product.

PMID- 15035355
TI  - Ethylene modulates development and toxin biosynthesis in aspergillus possibly via
      an ethylene sensor-mediated signaling pathway.
AB  - Ethylene, a biologically active natural compound, inhibited aflatoxin
      accumulation by Aspergillus parasiticus on a solid growth medium in a dose
      dependent manner at concentrations of 0.1 to 150 ppm. The activity of the nor-1
      promoter (an early aflatoxin gene) was reduced to nondetectable levels by similar
      quantities of ethylene, suggesting that the inhibitory effect on toxin synthesis
      occurred, at least in part, at the level of transcription. The inhibitory effect
      of ethylene on aflatoxin accumulation was also observed when A. parasiticus was
      grown on raw peanuts. Under similar growth conditions and doses, ethylene
      strongly inhibited development of asci and ascospores in Aspergillus nidulans,
      with no detectable effect on Hulle cell formation, conidiation, or
      sterigmatocystin accumulation. During early growth, A. parasiticus and A.
      nidulans produced ethylene with approximately twofold higher quantities measured
      in continuous light than in the dark. 1-Methylcyclopropene (an inhibitor of
      ethylene receptors in plants), light, CO2, temperature, and growth medium
      composition altered the effect of ethylene on A. nidulans and A. parasiticus.
      These observations are consistent with the existence of an ethylene sensor
      molecule that mediates the function of an ethylene-responsive signaling
      pathway(s) in Aspergillus.

PMID- 15035356
TI  - Antibiotic resistance of Salmonella isolated from hog, beef, and chicken carcass
      samples from provincially inspected abattoirs in Ontario.
AB  - The emergence of antimicrobial-resistant Salmonella organisms, especially
      Salmonella Typhimurium DT104, has been reported in many countries, including the
      United States and Canada. The purposes of this study were to determine the
      antimicrobial resistance patterns of Salmonella isolated from hog, beef, and
      chicken carcasses from provincially inspected abattoirs in Ontario and to
      determine the agreement between the agar dilution method and the microbroth
      dilution method for measurement of antimicrobial resistance of the isolates.
      Antimicrobial resistance of Salmonella isolates from hogs (n = 71), beef (n =
      24), and chicken (n = 295) to amikacin, ampicillin, cephalothin, chloramphenicol,
      ciprofloxacin, gentamicin, streptomycin, sulfamethoxazole, and tetracycline was
      determined using the two methods. None of the 390 isolates were resistant to
      ciprofloxacin at levels of 0.125 microg/ml. All chicken and hog isolates were
      sensitive to amikacin, whereas all beef isolates were sensitive to both amikacin
      and gentamicin. Multiple antimicrobial resistance (resistance to more than one
      antimicrobial) was found in 29% of bovine isolates and 42% of porcine isolates
      using both methods for testing and in 42% by the agar dilution and 33% by the
      microbroth dilution methods in the chicken isolates. Overall, there was good
      agreement between the two test methods for resistance to most of the
      antimicrobials, with disagreement found in the results in 1.3% of the isolates
      for ampicillin and sulfamethoxazole, 8.2% for streptomycin, 5.6% for cephalothin,
      and 1.0% of the isolates for tetracycline. The lack of agreement between the two
      test methods was found mostly among the chicken isolates.

PMID- 15035357
TI  - Attachment of Listeria monocytogenes on ready-to-eat meats.
AB  - Five individual strains of Listeria monocytogenes and a mixed cocktail of all
      five were studied for attachment on frankfurters, ham, bologna, and roast beef
      relative to their cell surface characteristics. The ratio of strongly attached
      (sessile) L. monocytogenes cells compared with total (sessile and planktonic)
      attached cells on ready-to-eat meats was also determined. Because bacterial cell
      surfaces were characterized by net negative charge and hydrophobicity,
      electrostatic interaction chromatography and cationized ferritin methods were
      chosen to study net negative charge distribution on the bacterial cell surface,
      whereas hydrophobic interaction chromatography and contact angle measurement were
      used to examine the cell surface hydrophobicity. No differences (P > 0.05) were
      observed in cell surface charge or cell surface hydrophobicity among strains.
      Approximately 84 to 87% L. monocytogenes were found to attach strongly to ready
      to-eat meats within 5 min. No differences (P > 0.05) were found among strains or
      among meats. Micrographs observed from scanning electron microscopy showed no
      differences among the strains but showed a difference in age of cells (mixed
      culture) in terms of surface negative charge distribution. More surface
      negatively charged sites were observed at 0 and 7 days and much fewer at 3 days
      during storage of washed, harvested cells in buffer at 4 degrees C (aged cells
      under cold and nutrient deprivation), indicating a possible change in cell
      surface properties. Because no difference in strains was observed, the contact
      angle measurement study was carried out with the five-strain mixed culture. The
      surface hydrophobicity increased in frankfurters, decreased in roast beef, and
      was unchanged in ham and bologna as a result of inoculation.

PMID- 15035358
TI  - Temperature effect on Listeria monocytogenes growth in the event of contamination
      of cooked pork products.
AB  - The aim of this study was to describe the effect of temperature on the growth of
      Listeria monocytogenes in the event of postprocess contamination of packaged pork
      meats. This study was carried out in two steps. In the first step, the effect of
      temperature on L. monocytogenes growth rates was determined in duplicates at 13
      temperatures between 2 and 43 degrees C by turbidimetric methods and adjusted by
      a quantitative secondary model. Then, seven sets of growth kinetics were
      collected by challenge testing in white pudding and roulade, both cooked pork
      products prepared according to an industrial process and stored at suboptimal
      temperatures ranging from 2 to 20 degrees C. In the second step, objectives were
      to (i) collect direct information on the temperature effect of L. monocytogenes
      on the two pork products, (ii) compare the two products regarding L.
      monocytogenes exposure, and (iii) compare results given by modeling (step i) with
      results obtained independently and then evaluate the model application domain.
      Each kinetic was built with at least 10 experimental data and two replicates.
      Comparison between L. monocytogenes behavior at 4 degrees C on white pudding and
      roulade indicated that both meat products were affected by food safety problems.
      Indeed, after contamination and storage for 10 days at 4 degrees C, the bacterial
      population increased by 2 log CFU/g in both products. Comparison between growth
      kinetic simulations and experimental data obtained separately gave satisfactory
      conclusions; the difference between observed and predicted bacterial population
      values was always less than 1 log CFU/g and a bias factor of 1.18 when growth
      rates were compared. These results applied to L. monocytogenes contamination of
      white pudding or roulade can now be used either in the management of optimal
      process and distribution networks or in risk assessment (exposure assessment).

PMID- 15035359
TI  - Radiation resistance and virulence of Listeria monocytogenes Scott A following
      starvation in physiological saline.
AB  - The influence of starvation on the resistance of Listeria monocytogenes Scott A
      to electron beam irradiation in 0.85% (wt/vol) NaCl (saline) and in ground pork
      was investigated. Exponential- or stationary-phase cells (control) were grown at
      35 degrees C in tryptic soy broth supplemented with 0.6% yeast extract. Washed
      cells were starved for 12 days in saline, and virulence of the pathogen was
      evaluated at 0, 8, and 12 days during starvation. Samples of saline and
      irradiation-sterilized ground pork, inoculated with control or starved cells,
      were irradiated at doses ranging from 0.0 to 2.5 kGy. L. monocytogenes survivors
      were determined by plating diluted samples of saline or pork on tryptic soy agar
      supplemented with 0.6% yeast extract and counting bacterial colonies following
      incubation (35 degrees C, 48 h). Virulence of starved cells and control was not
      significantly different (P > 0.05). Cells exhibited the highest radiation
      resistance at 8 days of starvation. Irradiation (0.5 kGy) in saline resulted in
      approximately 7.14, 5.55, and 2.38 log reduction in exponential, stationary, and
      starved cells, respectively. Irradiation of ground pork at 2.5 kGy reduced
      controls by approximately 6.0 log, whereas starved cells were reduced by only 3.8
      log. Starved cells consistently exhibited higher irradiation D10-values than
      controls (P < 0.05). D10-values for exponential, stationary, and starved cells
      were 0.07, 0.09, and 0.21 kGy and 0.35, 0.42, and 0.66 kGy in saline and ground
      pork, respectively. These results indicate that starvation cross-protects L.
      monocytogenes Scott A against radiation inactivation and should be considered
      when determining this pathogen's irradiation D-value.

PMID- 15035360
TI  - Development and characterization of an antimicrobial packaging film coating
      containing nisin for inhibition of Listeria monocytogenes.
AB  - The purpose of this study was to develop and characterize a packaging film
      coating containing nisin. A spot-on-lawn assay was used to determine the effect
      of acid type (ascorbic, acetic, hydrochloric, lactic) and nisin level (equal
      increments from 10,000 IU to 9 IU) to be used in the formulation of the film
      coating. Zones of inhibition were measured after incubation on tryptic soy agar
      (37 degrees C, 48 h). Low-density polyethylene films coated with differing levels
      of nisin were characterized by field emission scanning electron microscopy,
      tensile strength, elongation, and water vapor transmission rate. The MIC of nisin
      in solution was 157 mg/ml. All acids were equally inhibitory (P > 0.05), but
      acetic acid produced the largest zone of inhibition (21 mm). Field emission
      scanning electron microscopy confirmed that the cloudy appearance of the films
      was due to sodium chloride found in the commercially prepared nisin. Tensile
      strength increased as nisin concentration increased, which also corresponded to
      increasing film thickness. The nisin coatings (10,000 and 2,500 IU/ml) did not
      have a significant effect (P > 0.05) on the water vapor transmission rate of the
      low-density polyethylene film.

PMID- 15035361
TI  - Inhibition of Listeria monocytogenes on the surface of individually packaged hot
      dogs with a packaging film coating containing nisin.
AB  - The objective of this study was to determine the effectiveness of packaging films
      coated with a methylcellulose/hydroxypropyl methylcellulose-based solution
      containing 10,000, 7,500, 2,500, or 156.3 IU/ml nisin for controlling Listeria
      monocytogenes on the surfaces of vacuum-packaged hot dogs. Barrier film coated
      with a methylcellulose/hydroxypropyl methylcellulose-based solution containing
      nisin or no nisin (control) was heat sealed to form individual pouches. Hot dogs
      were placed in control and nisin-containing pouches and inoculated with a five
      strain L. monocytogenes cocktail (approximately 5 log CFU per package), vacuum
      sealed, and stored for intervals of 2 h and 7, 15, 21, 28, and 60 d at 4 degrees
      C. After storage, hot dogs and packages were rinsed with 0.1% peptone water.
      Diluent was spiral plated on modified oxford agar and tryptic soy agar and
      incubated to obtain counts (CFU per package). L. monocytogenes counts on hot dogs
      packaged in films coated with 156.3 IU/ml nisin decreased slightly (approximately
      0.5-log reduction) through day 15 of refrigerated storage but was statistically
      the same (P > 0.05) as hot dogs packaged in films without nisin after 60 d of
      storage. Packaging films coated with a cellulose-based solution containing 10,000
      and 7,500 IU/ml nisin significantly decreased (P < 0.05) L. monocytogenes
      populations on the surface of hot dogs by greater than 2 log CFU per package
      throughout the 60-d study. Similar results were observed for hot dogs packaged in
      films coated with 2,500 IU/ml nisin; however, L. monocytogenes populations were
      observed to be approximately 4 log CFU per package after 60 d of refrigerated
      storage from plate counts on tryptic soy and modified oxford agars.

PMID- 15035362
TI  - Characterization of colicinogenic Escherichia coli strains inhibitory to
      enterohemorrhagic Escherichia coli.
AB  - A previously identified set of anti-Escherichia coli O157:H7 colicinogenic E.
      coli were characterized to assess the suitability of these isolates as a
      preharvest food safety intervention in cattle. This collection of 23 E. coli
      strains were screened for virulence factors, antibiotic resistance, type of
      colicin(s) present, and their ability to inhibit other pathogenic E. coli. With
      the use of PCR, pathogen genes were detected in six of the 23 colicinogenic E.
      coli. When the nonpathogenic strains were assessed for antibiotic resistance,
      four strains showed resistance to at least one antibiotic. The remaining set of
      14 strains were evaluated for the presence of previously identified colicins.
      Seven colicins (B, El, E2/E7, E7, Ia/Ib, K, and M) were detected. One half of the
      strains possessed multiple types of colicins. The most commonly detected colicins
      were B, E2/E7, and M, which were found in six strains each. DNA sequencing was
      also performed in order to classify the E2/E7 colicins separately from E7
      colicins. The 14 colicinogenic E. coli also were evaluated for their ability to
      inhibit 10 different non-O157 pathogenic E. coli. Six of the colicinogenic E.
      coli were capable of inhibiting all 10 pathogens, and the remaining eight strains
      could each inhibit between six to eight of the pathogenic E. coli. This strain
      collection has great potential for inhibiting E. coli O157:H7 in cattle.

PMID- 15035363
TI  - Thermal lethality of salmonella in chicken leg quarters processed via an
      air/steam impingement oven.
AB  - Chicken leg quarters were injected with 0.1 ml of the cocktail culture per cm2 of
      the product surface area to contain about 7 log(CFU/g) of Salmonella. The
      inoculated leg quarters were processed in an air/steam impingement oven at an air
      temperature of 232 degrees C, an air velocity of 1.4 m/s, and a relative humidity
      of 43%. The endpoint product temperatures were correlated with the cooking times.
      A model was developed for pathogen thermal lethality up to 7 log(CFU/g)
      reductions of Salmonella in correlation to the product mass (140 to 540 g) and
      cooking time (5 to 35 min). The results from this study are useful for validating
      thermal lethality of pathogens in poultry products that are cooked via
      impingement ovens.

PMID- 15035364
TI  - Inhibitory activity of essential oils of garlic and onion against bacteria and
      yeasts.
AB  - The essential oils of garlic and onion and their constituent sulfides with three
      or more sulfur atoms were potent inhibitors of yeast growth. The minimum
      inhibitory concentrations of garlic oil, onion oil, diallyl trisulfide, diallyl
      tetrasulfide, and dimethyl trisulfide for all the yeasts tested ranged between 2
      and 45 ppm. The oils and their constituent sulfides, however, were only very
      weakly antibacterial, showing minimum inhibitory concentrations of greater than
      300 ppm for most of the bacteria tested. The antiyeast activity of garlic oil and
      onion oil was storage stable and was not influenced by pH. Film formation on soy
      sauce by Zygosaccharomyces rouxii SS1 was completely prevented for 30 days by the
      addition of 30 and 40 ppm of garlic oil and onion oil, respectively.

PMID- 15035365
TI  - Pressure inactivation kinetics of phage lambda cI 857.
AB  - Inactivation curves of phage lambda cI 857 inactivated by high hydrostatic
      pressure were obtained at three pressure levels (300, 350, and 400 MPa) in
      buffered media and ultrahigh-temperature 2% reduced fat milk. Pressurization of
      phage lambda in buffered media at 300 MPa for 300 min, 350 MPa for 36 min, and
      400 MPa for 8 min reduced the titer of phage lambda by 7.5, 6.7, and 7.7 log,
      respectively. Pressurization of phage lambda in milk at 300 MPa for 400 min, 350
      MPa for 80 min, and 400 MPa for 20 min reduced the titer of phage lambda by 5.4,
      6.4, and 7.1 log, respectively. Tailing was observed in all inactivation curves,
      indicating that the linear model was not adequate for describing these curves.
      Among the three nonlinear models studied, the Weibull and log-logistic models
      consistently produced best fits to all inactivation curves, and the modified
      Gompertz model the poorest. Because there were no significant differences in the
      values of shape factor (n) for suspension medium buffer, we reduced the number of
      parameters in the Weibull model from two to one by setting n at the mean value.
      The simplified Weibull model produced a fit comparable to the full model.
      Additionally, the simplified Weibull model allowed predictions to be made at
      pressures different from the experimental pressures. Menstruum was found to
      significantly affect the pressure resistance of phage lambda. Comparison of
      pressure inactivation of hepatitis A virus and phage lambda indicated that phage
      lambda is more sensitive to pressure than hepatitis A virus in Dulbecco's
      modified Eagle medium with 10% fetal bovine sera.

PMID- 15035366
TI  - Food safety knowledge, attitudes, and behaviors among Puerto Rican caretakers
      living in Hartford, Connecticut.
AB  - Household food safety education is needed to minimize the risk of exposure to
      foodborne pathogens. The Latino population in the United States is growing at a
      fast rate and has become the largest minority group in this country. However,
      little research has been done to identify the food safety behavioral risks faced
      by Puerto Ricans. Ten in-depth household observations and a quantitative survey
      on food safety knowledge, attitudes, and behaviors (n = 100) were conducted to
      understand food-handling techniques among Puerto Rican caretakers of young
      children. This was followed by two focus groups (n = 12) to further characterize
      food safety knowledge, attitudes, and behaviors and the proper media channels for
      the delivery of food safety education. Even though 97% of survey participants
      reported washing their hands with soap and water before preparing foods, only 1
      of the 10 participants in the household observations actually did it. About 60%
      of the household participants washed the cutting boards with soap and water
      compared with 89% of survey participants who claimed to do it. In the survey, 5%
      reported to know the meaning of cross-contamination, and 71% (n = 80) to use the
      same cutting board for meats and vegetables. Overall, 96% of survey participants
      did not use a thermometer to check if meats were cooked properly and only 10%
      defrosted their meats in the refrigerator. Statistically significant
      relationships (P < 0.05) were found between speaking English and knowing the
      meaning of cross-contamination and how to use a meat thermometer. Employed
      individuals and those with higher education were also more likely to be familiar
      with the term pasteurization. These results fully justify the delivery of
      culturally appropriate food safety education in this community.

PMID- 15035367
TI  - Survival of Cryptosporidium parvum oocysts after prolonged exposure to still
      natural mineral waters.
AB  - The survival kinetics of purified Cryptosporidium parvum oocysts of both human
      and ovine origin, immersed in four still natural mineral waters (total dissolved
      salts ranging from 91 mg/liter to 430 mg/liter) and reverse osmosis water was
      assessed by inclusion or exclusion of the fluorogenic vital dyes 4',6-diamidino-2
      phenylindole and propidium iodide over a 12-week period. Semipermeable chambers
      were used to contain the oocysts while immersed in each mineral water type,
      permitting both intimate interactions between oocysts and matrices and
      straightforward sampling for viability assessments. The viability of both oocyst
      types, assessed at weekly intervals, remained unaltered after 12 weeks at 4
      degrees C, whereas a progressive decline in the viability of both oocyst isolates
      was observed when immersed in mineral waters at 20 degrees C. At 20 degrees C,
      approximately 30% of oocysts remained viable after 12 weeks incubation. Here,
      temperature was the major factor that adversely affected oocyst survival,
      although higher mineral content was also proportionally and significantly
      associated with this increased oocyst inactivation. The prolonged survival of
      oocysts at 4 degrees C in our studies indicates that they could survive for
      prolonged periods of time in U.K. groundwaters (average temperature approximately
      10 degrees C) and thus represent a potential public health hazard if
      contamination of mineral water sources by viable oocysts were to occur.

PMID- 15035368
TI  - Optimization of DNA extraction and molecular detection of Cryptosporidium oocysts
      in natural mineral water sources.
AB  - The numerous published methods for extracting DNA from Cryptosporidium oocysts
      for PCR identify the lack of an optimized standard method for clinical,
      environmental, and public health investigations of cryptosporidiosis. A method
      that maximizes DNA extraction reliably, particularly from small numbers of
      partially purified or purified oocysts present in mineral waters and
      environmental samples, is required. We describe a maximized method for liberating
      DNA from Cryptosporidium parvum oocysts by 15 cycles of freezing (liquid
      nitrogen) and thawing (65 degrees C) in lysis buffer containing sodium dodecyl
      sulfate. The inhibitory effects of sodium dodecyl sulfate are abrogated by the
      addition of Tween 20 to the PCR reaction. We tested seven different C. parvum
      oocyst isolates, consistently detecting fewer than five oocysts following direct
      PCR amplification of a segment of the 18S rRNA gene. Older oocysts, which were
      more refractory to freeze-thawing, were disrupted effectively. A single oocyst in
      each of two mineral water concentrates was detected by both microscopy and
      PCR/Southern blotting. We recommend 15 cycles of freeze-thawing, with thawing at
      65 degrees C in lysis buffer, to maximize oocyst disruption and DNA extraction,
      particularly when isolate history and oocyst age are unknown. Both the DNA
      extraction method and the PCR described can be used for clinical, environmental,
      and public health investigations of cryptosporidiosis.

PMID- 15035369
TI  - Mycotoxin-forming ability of two Penicillium roqueforti strains in blue moldy
      tulum cheese ripened at various temperatures.
AB  - Isolated and identified toxigenic and nontoxigenic Penicillium roqueforti (PR)
      strains from moldy tulum cheeses were inoculated into tulum cheeses made in the
      laboratory and ripened at 5 and 12 degrees C. Mycotoxin (patulin, penicillic
      acid, PR toxin, and roquefortine) formation in the control and mold-inoculated
      cheeses were detected by thin-layer chromatography on the first through fourth
      months of ripening. Patulin, penicillic acid, and PR toxin were not detected in
      the experimental cheeses. Only roquefortine was detected in cheese inoculated
      with the toxigenic strain of the mold and ripened at 5 and 12 degrees C on the
      third and first months of ripening, respectively. Toxin in cheeses ripened at 5
      and 12 degrees C was 2.1 to 2.4 and 2.1 to 3.8 mg/kg cheese, respectively.

PMID- 15035370
TI  - Multiplex real-time PCR detection of fumonisin-producing and trichothecene
      producing groups of Fusarium species.
AB  - Some species of Fusarium can produce mycotoxins during food processing procedures
      that facilitate fungal growth, such as the malting of barley. The objectives of
      this study were to develop a 5' fluorogenic (Taqman) real-time PCR assay for
      group-specific detection of trichothecene- and fumonisin-producing Fusarium spp.
      and to identify Fusarium graminearum and Fusarium verticillioides in field
      collected barley and corn samples. Primers and probes were designed from genes
      involved in mycotoxin biosynthesis (TRI6 and FUM1), and for a genus-specific
      internal positive control, primers and a probe were designed from Fusarium rDNA
      sequences. Real-time PCR conditions were optimized for amplification of the three
      products in a single reaction format. The specificity of the assay was confirmed
      by testing 9 Fusarium spp. and 33 non-Fusarium fungal species. With serial
      dilutions of purified genomic DNA from F. verticillioides, F. graminearum, or
      both as the template, the detection limit of the assay was 5 pg of genomic DNA
      per reaction. The three products were detectable over four orders of magnitude of
      template concentration (5 pg to 5 ng of genomic DNA per reaction); at 50 ng
      template per reaction, only the TRI6 and FUM1 PCR products were detected. Barley
      and corn samples were evaluated for the presence of Fusarium spp. with
      traditional microbiological methods and with the real-time PCR assay. The 20
      barley samples and 1 corn sample that contained F. graminearum by traditional
      methods of analysis tested positive for the TRI6 and internal transcribed spacer
      (ITS) PCR products. The five corn samples that tested positive for F.
      verticillioides by traditional methods also were positive for the FUMI and ITS
      PCR products. These results indicate that the described multiplex real-time PCR
      assay provides sensitive and accurate differential detection of fumonisin- and
      trichothecene-producing groups of Fusarium spp. in complex matrices.

PMID- 15035371
TI  - Monoclonal antibody-based sandwich enzyme-linked immunosorbent assay for
      sensitive detection of prohibited ruminant proteins in feedstuffs.
AB  - Regulations aimed to control the epidemic of bovine spongiform encephalopathy
      have banned the use of certain animal products, i.e., ruminant meat and bone
      meals, in ruminant animal feeds. A sensitive enzyme-linked immunosorbent assay
      has been developed to detect prohibited bovine and ovine muscles in feedstuffs.
      The assay utilizes a pair of monoclonal antibodies (MAbs) against skeletal
      troponin I (TnI). MAb 5G9, specific to bovine and ovine TnI, was used as the
      capture antibody and the biotin-conjugated MAb 2G3, reacting to all heterologous
      TnI, was used as the detection antibody. Quantitative procedures were applied to
      samples containing 5, 0.5, and 0.05% (wt/wt) of heat-treated (132 degrees C/2
      bar, 2 h) bovine and ovine meat meals in three different feeds, coexisting with
      porcine, chicken, or turkey meat meal. The presence of these nonprohibited
      species did not affect the detection of bovine and ovine meat meals in the feed
      samples (P > 0.05). Quantitative determinations of extractable bovine and ovine
      TnI, with a detection limit of 5.0 and 4.0 ng/ml, respectively, were achieved
      when the matching feed matrixes were used in the calibration curves. This new
      assay provides a rapid and reliable way to detect animal protein products
      containing a trace amount of bovine or ovine muscle tissue in feedstuffs.

PMID- 15035373
TI  - Feasibility of using half-life multipliers to estimate extended withdrawal
      intervals following the extralabel use of drugs in food-producing animals.
AB  - Under the Animal Medicinal Drug Use Clarification Act of 1994, veterinarians are
      legally allowed to use drugs in food-producing animals in an extralabel manner.
      This could potentially lead to violative residues in food of animal origin. It is
      therefore essential that an appropriately extended withdrawal interval be
      established. Ideally, these extended withdrawal intervals should be calculated on
      the basis of the tissue half-life of the drug in the target animal. However,
      these data are not readily available for all drugs of extralabel use in food
      producing animals. For this reason, the use of a half-life multiplier has been
      proposed as a simple alternative method to estimate the effective tissue half
      life of a drug. Extended withdrawal intervals, estimated using various half-life
      multipliers, were compared with the withdrawal intervals calculated using actual
      tissue half-lives. For the group of drugs investigated, a half-life multiplier of
      5 resulted in estimates of extended withdrawal intervals that were potentially
      inadequate to prevent violative tissue residues for drugs that had relatively
      long tissue half-lives, high tolerances, or both. This is possibly because fewer
      half-lives are required for these drugs to reach the target tissue concentrations
      following administration at label doses. Use of a smaller half-life multiplier
      (in this case 3) is therefore suggested to ensure that extended withdrawal
      intervals are adequate to prevent violative tissue residues.

PMID- 15035372
TI  - Real-time PCR detection of ruminant DNA.
AB  - To control the spread of bovine spongiform encephalopathy, several DNA methods
      have been described for the detection of the species origin of meat and bone
      meal. Most of these methods are based on the amplification of a mitochondrial DNA
      segment. We have developed a semiquantitative method based on real-time PCR for
      detection of ruminant DNA, targeting an 88-bp segment of the ruminant short
      interspersed nuclear element Bov-A2. This method is specific for ruminants and is
      able to detect as little as 10 fg of bovine DNA. Autoclaving decreased the amount
      of detectable DNA, but positive signals were observed in feeding stuff containing
      10% bovine material if this had not been rendered in accordance with the
      regulations, i.e., heated at 134 degrees C for 3 instead of 20 min.

PMID- 15035374
TI  - Changes in growth and antioxidant status of alfalfa sprouts during sprouting as
      affected by gamma irradiation of seeds.
AB  - Viking 3000 alfalfa seeds irradiated with gamma rays to doses of 0, 1, 2, 3, or 4
      kGy were sprouted and allowed to grow for up to 8 days at 23 degrees C.
      Germination, growth (yield and length), antioxidant capacity, and ascorbic acid
      (AA) were measured during sprouting. Results showed percent germination of the
      seeds and the rates of growth of the sprouts were inversely related to the
      radiation dose absorbed by the seeds. Both antioxidant capacity and AA content
      expressed on a fresh weight basis decreased during growth of the sprouts. Sprouts
      grown from irradiated seeds had greater antioxidant capacity and AA content on a
      fresh weight basis than those grown from nonirradiated seeds. However, when the
      nutritive values were expressed on a per gram of seed basis, irradiation had no
      effect on the nutritive values of sprouts.

PMID- 15035375
TI  - Volatile compounds produced in cheese by Enterobacteriaceae strains of dairy
      origin.
AB  - The formation of volatile compounds in fresh cheese by 10 Enterobacteriaceae
      strains of dairy origin (4 Hafnia alvei, 2 Serratia liquefaciens, 1 Enterobacter
      cloacae, 1 Enterobacter sakazakii, and 2 Escherichia coli strains) was
      investigated. Small cheeses were made from pasteurized cow's milk separately
      inoculated with 1-3 x 10(3) CFU/ml of each of the Enterobacteriaceae strains,
      with glucono-8-lactone added to achieve a pH value of 5.2 in the curds. All
      strains reached counts close to 10(8) CFU/g in 1-day-old cheeses and survived
      well from day 1 to day 8. Cheeses were analyzed for volatile compounds by gas
      chromatography-mass spectroscopy, after extraction by dynamic headspace using a
      purge and trap apparatus. Sixty-one volatile compounds were determined in
      cheeses, 31 of which were further investigated. Significant increases of
      aldehydes, sulfur compounds, and aromatic compounds were recorded from 2-h curd
      to 1-day-old cheese, and of ketones, alcohols, and acids from 2-h curd to 8-day
      old cheese. Acetaldehyde, 2-methyl propanal, and 3-methyl butanal predominated
      among aldehydes; 2,3-butanedione, 2,3-pentanedione, and 3-hydroxy 2-butanone
      among ketones; ethanol, 2-methyl propanol, and 3-methyl butanol among alcohols;
      and ethyl acetate among esters. Hierarchical cluster analysis of strains using
      the data of 31 volatile compounds separated clearly the strain of E. sakazakii,
      which produced high amounts of volatile compounds, from the other
      Enterobacteriaceae strains.

PMID- 15035376
TI  - Fate of Escherichia coli O157:H7 in manure compost-amended soil and on carrots
      and onions grown in an environmentally controlled growth chamber.
AB  - Studies were done to determine the fate of Escherichia coli O157:H7 in manure
      compost-amended soil and on carrots and green onions grown in an environmentally
      controlled growth chamber. Commercial dairy cattle manure compost was inoculated
      with a five-strain mixture of green fluorescent protein-labeled E. coli O157:H7
      at 10(7) CFU g(-1) and mixed with unsterilized Tifton sandy loam soil at a ratio
      of 1:5. Baby carrot or green onion seedlings were planted into the manure compost
      amended soil in pots, and soil samples surrounding the plant, edible carrot roots
      and onion bulb samples, and soil immediately beneath the roots were assayed for
      E. coli O157:H7 in triplicate at weekly intervals for the first 4 weeks, and
      every 2 weeks for the remainder of the plant growth cycle (up to 3 months). E.
      coli O157:H7 cell numbers decreased within 64 days by 3 log CFU/g in soil and
      soil beneath the roots of green onions and by more than 2 log CFU/g on onions. E.
      coli O157:H7 survived better during the production of carrots, with a 2.3-log
      CFU/g reduction in soil and a 1.7-log CFU/g reduction on carrots within 84 days.
      These results indicate that the type of plant grown is an important factor
      influencing the survival of E. coli O157:H7 both on the vegetable and in the soil
      in which the vegetable is grown.

PMID- 15035377
TI  - Decontamination of cattle hides prior to slaughter using washes with and without
      antimicrobial agents.
AB  - Two trials were conducted to determine the efficacy of cattle wash treatments in
      reducing pathogens on hides of cattle before slaughter. In trial I, live cattle
      (n = 120) were washed in an automated, commercial cattle wash system with one of
      four treatments (single water wash, double water wash, water wash with 0.5% L
      lactic acid, or water wash with 50 ppm chlorine). Samples were collected at three
      locations (brisket, belly, and inside round) pre- and posttreatment to evaluate
      the effectiveness of treatments on the reduction of aerobic plate counts,
      coliforms, Escherichia coli and the incidence of Salmonella. For all three
      locations, bacterial numbers increased from 0.1 to 0.8 log CFU/cm2 posttreatment.
      In trial II, hide samples were inoculated in the laboratory with 6.0 log CFU/cm2
      of rifampicin-resistant Salmonella serotype Typhimurium. Hide wash treatments
      included higher concentrations of chlorine (100, 200, and 400 ppm) and L-lactic
      acid (2, 4, and 6%), as well as other antimicrobial agents such as ethanol (70,
      80, and 90%), acetic acid (2, 4, and 6%), and Oxy-Sept 333 (0.5, 2, and 4%).
      Spray wash treatments with ethanol and 4 to 6% concentrations of lactic acid had
      greater (P < 0.05) mean log reductions than 2% solutions of acetic or lactic
      acid, as well as 100, 200, and 400 ppm chlorine and the control water wash
      treatment. Spray wash treatments with Oxy-Sept 333 and 100, 200, or 400 ppm
      chlorine were not effective (P > 0.05) in reducing Salmonella Typhimurium
      compared to the (control) distilled water spray wash treatment. Several effective
      cattle hide interventions were identified in a controlled laboratory setting, but
      the high concentrations required for effectiveness would likely present problems
      from an animal welfare standpoint.

PMID- 15035378
TI  - Stationary-phase acid resistance and injury of recent bovine Escherichia coli
      O157 and non-O157 biotype I Escherichia coli isolatest.
AB  - Stationary-phase acid resistance and the induction of acid resistance were
      assessed for recent bovine carcass isolates of Escherichia coli, including 39
      serotype O157 strains and 20 non-O157 strains. When grown to stationary phase in
      the absence of glucose and without prior acid exposure, there was a range of
      responses to a pH challenge of 6 h at pH 2.5. However, populations of 53 of the
      59 E. coli isolates examined were reduced by less than 2.00 log CFU/ml, and
      populations of 24 of these isolates were reduced by less than 1.00 log CFU/ml. In
      contrast, there was little variation in population reductions when the E. coli
      were grown with glucose and preadapted to acidic conditions. With few exceptions,
      acid adaptation improved survival to the acid challenge, with 57 of the 59
      isolates exhibiting a log reduction of less than 0.50. Differences in acid
      resistance or the ability to adapt to acidic conditions between E. coli O157:H7
      and non-O157 commensal E. coli were not observed. However, we did find that the
      E. coli O157 were disposed to greater acid injury after the low pH challenge than
      the non-O157 E. coli, both for cells that were and were not adapted to acidic
      conditions before the challenge. The enhancement of low pH survival after acid
      adaptation that was seen among these recent natural isolates of E. coli O157
      further supports the idea that the previous environment of this pathogen should
      be a consideration when designing microbial safety strategies for foods preserved
      by low pH and acid.

PMID- 15035379
TI  - Viability of acid-adapted Escherichia coli O157:H7 in ground beef treated with
      acidic calcium sulfate.
AB  - The effects of lactic acid, acetic acid, and acidic calcium sulfate (ACS) on
      viability and subsequent acid tolerance of three strains of Escherichia coli
      O157:H7 were determined. Differences in tolerance to acidic environments were
      observed among strains, but the level of tolerance was not affected by the
      acidulant to which cells had been exposed. Cells of E. coli O157:H7 adapted to
      grow on tryptic soy agar acidified to pH 4.5 with ACS were compared to cells
      grown at pH 7.2 in the absence of ACS for their ability to survive after
      inoculation into ground beef treated with ACS, as well as untreated beef. The
      number of ACS-adapted cells recovered from ACS-treated beef was significantly
      (alpha = 0.05) higher than the number of control cells recovered from ACS-treated
      beef during the first 3 days of a 10-day storage period at 4 degrees C,
      suggesting that ACS-adapted cells might be initially more tolerant than unadapted
      cells to reduced pH in ACS-treated beef. Regardless of treatment of ground beef
      with ACS or adaptation of E. coli O157:H7 to ACS before inoculating ground beef,
      the pathogen survived in high numbers.

PMID- 15035380
TI  - Inhibition of Bacillus subtilis and Listeria innocua by nisin in combination with
      some naturally occurring organic compounds.
AB  - The application of combined preservative factors (hurdle technology) is very
      effective in controlling the growth of food spoilage and foodborne pathogenic
      bacteria. Antimicrobial activity of nisin alone and in combination with some
      natural organic compounds (carvacrol, cinnamic acid, eugenol, diacetyl, and
      thymol) on the growth of gram-positive bacteria Bacillus subtilis and Listeria
      innocua was-investigated. All the organic compounds tested exhibited
      antimicrobial activity against the microorganisms used; however, the MICs varied
      between 0.8 and 15.0 mM depending on the potency of the compound or the
      sensitivity of the target strain. Investigation of the interaction between the
      organic compounds and nisin against the test organisms revealed different
      patterns, varying from synergistic to antagonistic. Combinations of nisin with
      carvacrol, eugenol, or thymol resulted in synergistic action against both test
      organisms. Activity of nisin and cinnamic acid together was synergistic against
      L. innocua, but only additive against B. subtilis. In contrast, the combination
      of diacetyl and nisin resulted in an antagonistic effect against both test
      organisms. This study highlights the potential of the combination of these
      compounds with nisin to inhibit pathogen growth in food.

PMID- 15035381
TI  - Sodium lactate addition on the quality and shelf life of refrigerated sliced
      poultry sausage packaged in air or nitrogen atmosphere.
AB  - The aim of this study was to determine the effect of sodium lactate addition on
      shelf-life extension of sliced poultry sausage packaged both in air and nitrogen
      atmospheres and stored in refrigerated conditions. Basic chemical composition,
      pH, and malonaldehyde content were assayed and color measurement using the
      reflection method was carried out. Microbiological examination consisted of
      determination of total number of aerobic psychrotrophic bacteria and number of
      lactic acid bacteria. Sensory evaluation of products was performed.
      Microbiological and sensory quality of sliced poultry meat sausage was dependent
      on the addition during production of sodium lactate and the composition of gases
      (air or nitrogen) used in packaging. Slices of poultry sausage with 1% as well as
      2% of sodium lactate maintained their initial quality of evaluated sensory
      attributes longer, irrespective of the applied gases. Sodium lactate inhibited
      growth of aerobic psychrotrophic bacteria and lactic acid bacteria during
      refrigerated storage. Sodium lactate also inhibited the formation of
      malonaldehyde in sliced poultry sausage during refrigerated storage. The
      effectiveness of this process depended on the concentration of sodium lactate
      addition. It was concluded that 1% as well as 2% addition of sodium lactate could
      extend the shelf life of sliced poultry sausage packaged in air atmosphere and
      stored at 5 to 7 degrees C by 3 or 4 times, respectively. Sliced poultry sausage
      treated with 2% sodium lactate packed in nitrogen had the longest (35-day) shelf
      life. This was a sevenfold increase in the shelf life of sliced poultry sausage
      compared with the control.

PMID- 15035382
TI  - Biogenic amines in restructured beef steaks as affected by added walnuts and cold
      storage.
AB  - This article evaluates changes in biogenic amines and how these relate to
      microbiological growth in chilled, fresh restructured beef steaks containing
      transglutaminase as a cold binding agent and different amounts of walnut. Added
      walnut and chilling favored higher total and lactic acid bacteria counts during
      storage, whereas Enterobacteriaceae were not affected. The highest initial
      biogenic amine concentrations were identified as spermidine, spermine, and
      tyramine. Both added walnut and cold storage generally favored the formation of
      amines (tyramine, histamine, putrescine, and cadaverine), which was more
      obviously apparent by the end of the storage period. Agmatine, on the other hand,
      was not generally affected by the walnut.

PMID- 15035383
TI  - A PCR assay for detection of acetic acid-tolerant lactic acid bacteria in acidic
      food products.
AB  - A PCR assay for the detection of acetic acid-tolerant lactic acid bacteria in the
      genera of Lactobacillus and Pediococcus was developed in this study. Primers
      targeting the bacterial 16S rRNA gene were newly designed and used in this PCR
      assay. To determine the specificity of the assay, 56 different bacterial strains
      (of 33 genera), 2 fungi, 3 animals, and 4 plants were tested. Results were
      positive for most tested bacterial members of 16S rRNA gene-based phylogenetic
      groups (classified in the Lactobacillus casei and Pediococcus group), including
      Lactobacillus fructivorans, Lactobacillus brevis, Lactobacillus buchneri,
      Lactobacillus plantarum, and Lactobacillus paracasei. For all other bacterial
      strains and eukaryote tested, results were negative. Bacterial DNA for PCR was
      prepared with a simple procedure with the use of Chelex 100 resin from culture
      after growth in deMan Rogosa Sharpe broth (pH 6.0). To test this PCR assay for
      the monitoring of the acetic acid-tolerant lactic acid bacteria, L. fructivorans
      was inoculated into several acidic food as an indicator. Before the PCR, the
      inoculation of 10 to 50 CFU of bacteria per g of food was followed by a 28-h
      enrichment culture step, and the PCR assay allowed the detection of bacterial
      cells. Including the enrichment culture step, the entire PCR detection process
      can be completed within 30 h.

PMID- 15035384
TI  - Intensive investigation of bacterial foodborne disease outbreaks: proposed
      guidelines and tools for the collection of dose-response data by local health
      departments.
AB  - Local health departments that investigate foodborne disease outbreaks do not have
      adequate guidelines for collecting data that could be used to estimate dose
      response relationships, a key component of hazard characterization in
      quantitative microbial risk assessment. To meet this need, criteria and a
      questionnaire template for the collection of appropriate dose-response data in
      the context of outbreaks were developed and applied in the investigation of a
      point-source outbreak linked to Salmonella serotype Enteritidis in a salmon
      entree in February 2000. In this outbreak, the attack rate and risk of
      hospitalization increased with the amount of salmon entree consumed, and detailed
      data were obtained on illness severity measures and host susceptibility factors.
      Local health departments might consider broadening investigations to include the
      collection of additional data when investigating outbreaks that have met a
      specific set of conditions. These data could provide information needed by
      federal regulatory agencies and other organizations for quantitative microbial
      risk assessment. Intensive investigations of outbreaks could prevent future
      illnesses by providing information needed to develop approaches to minimizing
      risk.

PMID- 15035385
TI  - Tributes to J. Donald M. Gass, M.D.

PMID- 15035386
TI  - Serous detachment of the retinal pigment epithelium. 1966.

PMID- 15035387
TI  - Cystoid macular edema and papilledema following cataract extraction: a
      fluorescein fundoscopic and angiographic study. 1966.

PMID- 15035388
TI  - Acute posterior multifocal placoid pigment epitheliopathy. 1968.

PMID- 15035389
TI  - Drusen and disciform macular detachment and degeneration. 1972.

PMID- 15035390
TI  - Nicotinic acid maculopathy. 1973.

PMID- 15035391
TI  - An unusual hamartoma of the pigment epithelium and retina simulating choroidal
      melanoma and retinoblastoma. 1973.

PMID- 15035392
TI  - Choroidal osteoma. 1978.

PMID- 15035393
TI  - Diffuse unilateral subacute neuroretinitis. 1978.

PMID- 15035394
TI  - Observation of suspected choroidal and ciliary body melanomas for evidence of
      growth prior to enucleation. 1980.

PMID- 15035395
TI  - Vitiliginous chorioretinitis. 1981.

PMID- 15035396
TI  - Uveal effusion syndrome: a new hypothesis concerning pathogenesis and technique
      of surgical treatment. 1983.

PMID- 15035397
TI  - Multifocal pigment epithelial detachments by reticulum cell sarcoma: a
      characteristic funduscopic picture. 1984.

PMID- 15035398
TI  - Serous retinal pigment epithelial detachment with a notch: a sign of occult
      choroidal neovascularization. 1984.

PMID- 15035399
TI  - Comparison of prognosis after enucleation vs cobalt 60 irradiation of melanomas.
      1985.

PMID- 15035400
TI  - Idiopathic senile macular hole: its early stages and pathogenesis. 1988.

PMID- 15035401
TI  - Bilateral diffuse uveal melanocytic proliferation in patients with occult
      carcinoma. 1990.

PMID- 15035403
TI  - An Advisory Committee Statement (ACS). National Advisory Committee on
      Immunization (NACI). Update: statement on influenza vaccination for the 2003-04
      season.
AB  - The National Advisory Committee on Immunization (NACI) provides Health Canada
      with ongoing and timely medical, scientific, and public health advice relating to
      immunization. Health Canada acknowledges that the advice and recommendations set
      out in this statement are based upon the best current available scientific
      knowledge and is disseminating this document for information purposes. People
      administering or using the vaccine should also be aware of the contents of the
      relevant product monograph(s). Recommendations for use and other information set
      out herein may differ from that set out in the product monograph(s) of the
      Canadian licensed manufacturer(s) of the vaccine(s). Manufacturer(s) have sought
      approval of the vaccine(s) and provided evidence as to its safety and efficacy
      only when it is used in accordance with the product monographs.

PMID- 15035402
TI  - Acute zonal occult outer retinopathy: Donders Lecture: The Netherlands
      Ophthalmological Society, Maastricht, Holland, June 19, 1992. 1993.

PMID- 15035404
TI  - Measuring up: results from the National Immunization Coverage Survey, 2002.

PMID- 15035405
TI  - Commission publishes proposal for establishing a European Centre for Disease
      Prevention and Control (ECDC).

PMID- 15035406
TI  - [Why you should treat early. Brain damage due to migraine].

PMID- 15035407
TI  - [Practice due for the deceased Grandpa?].

PMID- 15035408
TI  - [Many leisure runners ignore body signals and overburden themselves. In running
      much goes wrong].

PMID- 15035409
TI  - [After insurance mega-study. Is now the effectiveness of acupuncture proven?].

PMID- 15035410
TI  - [Successful reducing diet. In 2 years 55 kg lost].

PMID- 15035412
TI  - [Alleged or actual mistakes by the physician? The right way to respond].

PMID- 15035411
TI  - [Children with compulsive disorders -- the family suffers, too The little house
      tyrant].

PMID- 15035413
TI  - [Physician's errors--legal advise for physicians accused of malpractice].
AB  - At some time or other, every doctor may be confronted by a claim for damages, and
      he/she should be familiar with the most important rules on how to react. Of
      relevance with regard to liability are improper treatment and the provision of
      inadequate information to the patient. The essential basis for a defense against
      the charge of malpractice is proper patient documentation. Since this latter is
      accepted by the court as evidence, the physician should take great care to ensure
      complete and accurate records. Before court proceedings are initiated, it is
      recommended that arbitration or an expert opinion be sought, which in many cases
      may result in an out-of-court settlement. Criminal and civil proceedings are
      separate, and may lead to different outcomes. In the case of the latter, the
      patient may be awarded compensation and damages for pain and suffering.

PMID- 15035414
TI  - [Typical and avoidable doctor's errors in surgical gastroenterology].
AB  - Everyone makes mistakes, and even the greatest efforts may fail to eliminate them
      completely. In contrast, typical errors and miscalculations--which by the very
      fact of being typical are predictable--can and must be avoided. The reasons for
      such mistakes may be lack of experience, inadequate interdisciplinary
      cooperation, and ignorance of the current state of the art. This applies equally,
      and in particular, to the field of surgical gastroenterology. Intensive
      interdisciplinary discussions, a healthy surgical hierarchy, a knowledge of
      pertinent guidelines and the latest literature and, last, but not least--against
      the present background of discussions about working hour and diagnosis-related
      groups--a rested and motivated physician, are the pillars of error-free patient
      management.

PMID- 15035415
TI  - [The tightrope walk between benefiting and harming the patient. How much
      diagnostic effort can the patient tolerate?].

PMID- 15035416
TI  - [Methicillin-resistant Staphylococcus aureus (MRSA)--an interdisciplinary
      challenge].

PMID- 15035417
TI  - [Suspected intoxication/poisoning].

PMID- 15035418
TI  - [Allergy counseling in the doctor's office. From allergy to asthma is only a
      small step].

PMID- 15035419
TI  - [Congress travel with leisure time participation sponsored. Physicians are
      threatened by penalty up to 50,000 Euro!].

PMID- 15035420
TI  - [Law demands quality management in the practice. Don't let yourself be taken by
      surprise].

PMID- 15035421
TI  - [Homeopathy suppresses COX- and LOX activity. Soft therapy for arthrosis ills].

PMID- 15035423
TI  - [Model project has to decrease stroke rate. "Great response need in the
      prevention"].

PMID- 15035422
TI  - [Diabetic patients have to be tested regularly for microalbuminuria. Almost every
      second one has already kidney damage].

PMID- 15035424
TI  - [From hearing loss to arrhythmia. What is magnesium substitution worth?].

PMID- 15035425
TI  - [Error source in blood sugar self-monitoring. Drugs can falsify glucose values].

PMID- 15035426
TI  - [Alarming result after Europe-wide survey. Every 5th person is afflicted by
      chronic pain].

PMID- 15035427
TI  - [Late diagnosis. Only after infarct is diabetes detected].

PMID- 15035428
TI  - [Cirrhotic liver gives up in breaking up of ammonia. Poison for the brain].

PMID- 15035429
TI  - [Oral benfotiamine therapy. Thus you protect the nerves of diabetic patients].

PMID- 15035430
TI  - [Diabetes mellitus. Retinal lesions should not exist!].

PMID- 15035431
TI  - [The 10-minute office visit. Fluor vaginalis].

PMID- 15035432
TI  - [Look diagnosis. Hard tendon in the palm].

PMID- 15035433
TI  - Nuclear architecture--5th Junior Scientist Conference of the German Society for
      Cell Biology (DGZ) held in Jena, September 25th to 27th, 2003.

PMID- 15035434
TI  - Down-regulating effect of nicotine on connexin43 gap junctions in human umbilical
      vein endothelial cells is attenuated by statins.
AB  - We investigated the effect of nicotine on connexin43 (Cx43) expression and gap
      junctional communication in human umbilical vein endothelial cells (HUVEC). We
      also evaluated whether the effect requires activation of acetyl choline receptors
      sensitive to nicotine (nAChRs) and is altered by statins. The results showed that
      expression of Cx43 protein is reduced by nicotine in a dose-dependent manner (6 x
      10(-4) M nicotine vs control, 33% reduction, p < 0.01), though Cx43 mRNA is up
      regulated (6 x 10(-4) M nicotine vs control, 36% increase, p < 0.01).
      Concomitantly, the communication function, determined by fluorescence recovery
      after photobleaching, is decreased (6 x 10(-4) M nicotine vs control, 38%
      reduction, p < 0.05). Such a down-regulation of Cx43 gap junctions by nicotine
      disappears in the presence of the nAChRs antagonist, dihydro-beta-erythroidine,
      and protease inhibitors leupeptin plus N-acetyl-Leu-Leu-Norleu-al (ALLN).
      Similarly, the effect of nicotine is attenuated by statins, including
      fluvastatin, lovastatin, pravastatin, and simvastatin, even at the presence of
      mevalonate. We concluded that i) nicotine down-regulates Cx43 expression and gap
      junctional communication in HUVEC via post-transcriptional modification, which
      involves enhancement of Cx43 proteolysis; ii) the effect of nicotine is mediated
      via activation of nAChRs; and iii) the effect of nicotine is attenuated by
      statins through mechanisms outside the hypolipidemic pathway.

PMID- 15035435
TI  - Inhibition of bFGF/EGF-dependent endothelial cell proliferation by the hyaluronan
      binding protease from human plasma.
AB  - Recently we identified a plasma serine protease with a high affinity to
      glycosaminoglycans like heparin or hyaluronic acid, termed hyaluronan-binding
      protease (HABP). Since glycosaminoglycans are found on cell surfaces and in the
      extracellular matrix a physiological role of this plasma protease in a
      pericellular environment was postulated. Here we studied the influence of HABP on
      the regulation of endothelial cell growth. We found that HABP efficiently
      prevented the basic fibroblast growth factor/epidermal growth factor (bFGF/EGF)
      dependent proliferation of human umbilical vein endothelial cells. Proteolytic
      cleavage of adhesion molecules was found to be involved, but was not solely
      responsible for the anti-proliferative activity. Pre-treatment of growth factor
      supplemented cell culture medium with HABP indicated that no direct contact
      between the active protease and cells was required for growth inhibition. In
      vitro studies revealed a growth factor-directed activity of HABP, resulting in
      complexation and partial hydrolysis and, thus, inactivation of basic fibroblast
      growth factor, a potent mitogen for endothelial cells. Heparin and heparan
      sulfate fully protected bFGF from complexation and cleavage by HABP, although
      these glycosaminoglycans are known to enhance the proteolytic activity of HABP.
      This finding suggested that free circulating bFGF rather than bFGF bound to
      heparan sulfate proteoglycans would be a physiologic substrate. In conclusion,
      down-regulation of bFGF-dependent endothelial cell growth represents an important
      mechanism through which HABP could control cell growth in physiologic or
      pathologic processes like angiogenesis, wound healing or tumor development.

PMID- 15035436
TI  - Two novel LEM-domain proteins are splice products of the annotated Drosophila
      melanogaster gene CG9424 (Bocksbeutel).
AB  - The LEM motif is a sequence of 40-50 amino acids that has been identified in a
      number of non-related proteins of the inner nuclear membrane including the lamina
      associated polypeptides 2 (LAP2), emerin, MAN1 and the Drosophila protein otefin.
      This evolutionary conserved sequence motif can mediate via the interaction with
      the small protein BAF the binding of LEM-domain proteins to DNA. Taking advantage
      of its sequenced genome we analyzed whether Drosophila possesses beside otefin
      additional genes coding for proteins with a LEM motif. A putative candidate gene
      was the annotated gene CG9424 which we named Bocksbeutel. Of all putative
      Drosophila LEM-domain proteins, otefin and Bocksbeutel exhibited the highest
      similarity in the LEM motif (53% identical amino acids). The Bocksbeutel gene can
      code for two isoforms of 399 and 351 amino acids that are produced by alternative
      splicing. In the alpha-isoform a transmembrane domain is localized close to the
      carboxyterminus. This segment is absent in the shorter beta-isoform. By RT-PCR we
      could show that in the embryo the mRNA coding for the alpha-isoform and in
      significantly lower amounts the mRNA coding for the beta-isoform are expressed.
      When expressed in transfected cells as GFP fusion proteins, the beta-isoform is
      localized predominantly in the nucleoplasm and the alpha-isoform is targeted to
      the nuclear envelope, indicating that Bocksbeutel-alpha is localized in the inner
      nuclear membrane. Bocksbeutel-alpha is the predominant isoform expressed in
      cells, larvae, and flies. Indirect immunofluorescence with Bocksbeutel-specific
      antibodies on tissues and cultured cells revealed that Bocksbeutel proteins are
      localized in the nuclear envelope and in the cytoplasm. By RNA interference we
      have down-regulated the expression of Bocksbeutel, BAF, otefin, and lamin DmO in
      Drosophila Kc167 cells. The down-regulation of Bocksbeutel and otefin had no
      influence on the viability of Kc167 cells and the intracellular localization of
      all other nuclear and nuclear envelope proteins analyzed. In contrast, when lamin
      DmO was reduced by RNAi the distribution of Bocksbeutel and otefin in the nuclear
      envelope of Kc167 cells was significantly altered. We conclude that the two LEM
      domain proteins Bocksbeutel and otefin are no limiting components for the
      maintenance of the nuclear architecture in cultured Drosophila cells at
      interphase.

PMID- 15035437
TI  - [Slow progress in therapy of breast carcinoma].

PMID- 15035439
TI  - [Practice due. Politicians want thus to take down our status].

PMID- 15035438
TI  - [When harmless intestinal diverticula become life-threatening. Niches with
      inflammable stuff].

PMID- 15035440
TI  - [Practice dues. Politicians want thus to take down our status].

PMID- 15035441
TI  - [Insurance propagates nasal irrigations: inexpensive prescription for common
      cold?].

PMID- 15035442
TI  - [The neglected vascular system--4,5 million Germans suffer from lymphedema].

PMID- 15035443
TI  - [Lymphedema--anatomy, pathophysiology and diagnosis].
AB  - Lymphedema is a protein-rich edema that develops as a result of diseased or
      traumatized lymphatic vessels and/or lymph nodes. Four stages of the disease are
      recognized. In primary lymphedema, congenital obstruction of lymphatic flow
      presents, and this can manifest at anytime during the course of a person's
      lifetime. Secondary lymphedema is a sequela of a malignant tumor, inflammatory
      processes, injuries, surgery or irradiation. The diagnosis is established on the
      basis of careful history-taking, inspection, and physical examination including
      measurements of circumference, which are of importance in particular for follow
      up purposes, and a comparison of skinfold thickness between the healthy and
      afflicted sides. The use of diagnostic equipment is rarely required, with
      indirect lymphography and lymphoscintigraphy heading the list of options.

PMID- 15035445
TI  - [Lymphedema--treatment].
AB  - Treatment of lymphedema utilizes complex physical (or decongestive) therapy
      (CDT), so-called. This covers a number of measures including compression, lymph
      drainage, skin care and individualized exercises. CDT is divided into two phases-
      an intensive phase during which daily treatment is applied over a period of two
      to four weeks, and a maintenance phase in which especially compression therapy is
      continued in order to secure the positive effects achieved during the first
      phase. Treatment should be initiated in an early stage of the condition, and the
      aim is to return the patient to the symptom-free latency stage. Neither isolated
      manual lymph drainage nor equipment-based decongestion is considered for the
      treatment of lymphedema. To date, the efficacy of various drugs, including
      selenium, has not been confirmed.

PMID- 15035444
TI  - [Lymphedema--differential diagnoses].

PMID- 15035446
TI  - [The diagnosis of an autonomic dysfunction of the lower limb as a major aspect of
      the neurological investigation and risk assessment of a diabetic foot syndrome].
AB  - Sensomotoric diabetic polyneuropathy is often associated with damage to autonomic
      nerve fibers. In the case of the lower extremity, this manifests in the form of a
      sudomotoric and/or vasomotoric disorder. This in turn is believed to be closely
      related to the development of neurotrophic ulcerations of the foot. The
      sudomotoric disorder leads to anhidrosis of the skin of the foot, leading to the
      formation of rhagades and fissures. Neurovascular problems with disordering of
      microvascular perfusion and trophic disturbances then become risk factors for
      foot ulcers, in particular when skin traumata occur in addition. Various methods
      for identifying an autonomic function disturbance in the lower limb are based
      either on the measurement of sweat secretion or on the investigation of
      peripheral microvascular function. A purposeful assessment of risk and prevention
      of neurotrophic damage in the lower limb is possible only on the basis of a
      rigorous differential diagnostic work-up of the diabetic polyneuropathy.

PMID- 15035447
TI  - [Influenza surveillance in Germany].
AB  - Currently, two systems for the monitoring of influenza are in use in Germany,
      which, if appropriate cooperation is forth-coming, may complement each other: The
      system of the influenza working group at the Robert Koch Institute that makes use
      of the measuring parameters ARD (acute respiratory disease) and viral detection
      (PCR/isolation) together with a sentinel system of reporting physicians to
      establish morbidity and mortality, provides information via the Internet. The
      delay associated with reporting is approximately one week and is longer for viral
      isolation. Cooperation in the European influenza surveillance system (EISS)
      and,via the National Reference Centers, with the WHO global monitoring system.
      The RealFlu system employing the parameters ILI (influenza-like illness) and
      rapid influenza tests with a sentinel system of reporting physicians, which is
      designed to provide accurate and regional information on influenza activity. The
      information is updated on a day-to-day basis, and is available to anyone on the
      Internet.

PMID- 15035448
TI  - [New TBE vaccine formulations--free of proteineous stabilizer and preservatives.
      Overview of clinical studies and first year post-marketing experience].

PMID- 15035449
TI  - [Practice dues. What are the accounting costs?].

PMID- 15035450
TI  - [A new long-acting insulin analog. "Fewer hypoglycemias observed"].

PMID- 15035451
TI  - [Diagnosis quiz: burning in the lower legs and thick fingers].

PMID- 15035452
TI  - [How does it function? Hematogenous oxidation therapy].

PMID- 15035453
TI  - The role of intrauterine bacteria in brain injury.
AB  - Organisms appear to be present in human fetal membranes without any apparent
      impact on pregnancy maintenance or the fetal brain. A clear link between
      chorioamnionitis and fetal brain damage suggests that tissue responses at the
      feto-maternal interface may be the key determinant of whether preterm labour and
      brain damage occur.

PMID- 15035454
TI  - Antenatal corticosteroid therapy: benefits and risks.
AB  - Antenatal glucocorticoid therapy remains one the most striking successes in
      perinatal management of complicated pregnancies leading to premature birth. All
      women at risk of preterm delivery before 34 weeks gestation should be treated,
      given the anti-inflammatory and maturative properties of fluorocorticoids.
      Betamethasone is preferred to dexamethasone and no more than two courses, two
      weeks apart, should be given, until the evidence from further controlled trials
      on repeated doses becomes available.

PMID- 15035455
TI  - Posthaemorrhagic ventricular dilatation: new mechanisms and new treatment.
AB  - Post haemorrhagic ventricular dilatation is associated with a high rate of
      disability, multiple impairments and adverse effects of shunt surgery for
      hydrocephalus. Post haemorrhagic ventricular dilatation results initially from
      multiple small blood clots throughout the cerebrospinal fluid channels impeding
      circulation and re-absorption. Transforming growth factor beta is released into
      the cerebrospinal fluid and there is evidence that this cytokine stimulates the
      laying down of extracellular matrix proteins which produce permanent obstruction
      to the cerebrospinal fluid pathways. Prolonged raised pressure, pro-inflammatory
      cytokines and free radical damage from iron may contribute to periventricular
      white matter damage and subsequent disability. Interventions such as early lumbar
      punctures, diuretic drugs to reduce cerebrospinal fluid production and
      intraventricular fibrinolytic therapy have been tested and, not only fail to
      prevent shunt dependence, death or disability, but have significant adverse
      effects. Surgical interventions such as subcutaneous reservoir, external drain,
      choroid plexus coagulation and third ventriculostomy have not been subject to
      controlled trial. Ventriculoperitoneal shunt is not feasible in the early phase
      after intraventricular haemorrhage but, despite the problems with blockages and
      infections, remains the only option for infants with excessive head expansion
      over periods of weeks. We have piloted drainage, irrigation and fibrinolytic
      therapy as a way of removing blood early enough to stop the progressive
      deposition of matrix proteins, permanent hydrocephalus and shunt dependence.

PMID- 15035456
TI  - Haemopoietic growth factors for neonates: assessing risks and benefits.
AB  - This review summarises the rationale, clinical trial evidence for benefit and
      potential toxicities of Erythropoietin, Thrombopoietin, Granulocyte Colony
      Stimulating Factor and Granulocyte-Macrophage Colony Stimulating Factor.
      Erythropoietin has failed to have a clinical impact on red cell transfusion
      requirement in very low birth weight infants; it is uncertain whether
      Thrombopoietin will find a significant clinical role in neonatal thrombocytopenia
      and there is, as yet, insufficient evidence for the routine use of Granulocyte-
      or Granulocyte-Macrophage Colony Stimulating Factor to prevent or treat bacterial
      infection. A number of theoretical risks of haemopoietic growth factor use in
      neonates have been suggested, but no toxicities have been observed during their
      clinical use. Exploring the potential for benefit in selected groups of infants
      should be encouraged.

PMID- 15035457
TI  - Pentoxyfylline in and prevention and treatment of chronic lung disease.
AB  - The anti-inflammatory effects of pentoxfylline are associated with a number of
      clinical benefits. These include reduction in mortality in patients who have
      undergone bone marrow transplants or suffer peritonitis. In infants with sepsis,
      a reduction in mortality has also been associated with pentoxyfylline
      administration. The anti-inflammatory effects of pentoxyfylline, as well as its
      bronchodilator, diuretic and respiratory muscle stimulant effects suggest it may
      have a useful role in BPD. Interim analysis of a prophylactic trial suggests
      pentoxyfylline may reduce treatment requirements after the neonatal period and
      that, in established BPD, pentoxyfylline and dexamethasone may be of similar
      efficacy.

PMID- 15035459
TI  - Appropriate levels of oxygen saturation for preterm infants.
AB  - Although oxygen is probably the most common therapy delivered to small or sick
      newborns in the past 75 years, what constitutes appropriate oxygenation for these
      infants remains highly controversial. The lack of direct evidence, in the form of
      randomised trials, of the effects of different oxygen levels on meaningful, long
      term outcomes has fuelled this controversy and contributed to the significant
      variation in practice currently seen. Conclusions drawn from the existing
      evidence regarding oxygen saturation levels for preterm infants include that
      retinopathy of prematurity rates may be reduced if lower saturation ranges are
      targeted in the early weeks of life. There is, however, no recent, good quality,
      trial information that has directly addressed this question. Retinopathy outcomes
      may also be improved if oxygen saturation is targeted higher in a subset of
      preterm infants with more severe eye disease in the post-acute phase. There is
      now direct evidence, from randomised trials, that routine higher oxygen
      saturation targeting in the chronic phase confers no short- or long-term growth
      or development benefits. Evidence is now mounting regarding the adverse pulmonary
      sequelae associated with routine higher, and thus longer, oxygen exposure.
      Information regarding oxygen saturation levels and early mortality is
      inconclusive. The major unanswered question that requires urgent resolution is
      the important long-term effects of targeting lower versus higher oxygen
      saturation ranges during the first days/weeks of a preterm infant's life. Such an
      important clinical question can only be answered rigorously and definitively
      using the randomised trial methodology.

PMID- 15035458
TI  - Nosocomial respiratory syncytial virus infection in neonatal units in the United
      Kingdom.
AB  - Nosocomial Respiratory Syncytial Virus infections are frequently reported and
      tend to be more severe, because of comorbidity, such reports, however, are
      frequently from a single centre. The incidence and outcomes of nosocomial
      Respiratory Syncytial Virus infection in UK neonatal units over a five year
      period were estimated by interrogating the Capse Health Care Knowledge Systems
      database, which contains anonymised details of 55% of UK hospital admissions. A
      total of 79,642 admissions commenced on the infants' date of birth and contained
      an ICD-10 code for low birth weight or immaturity. Thirty-seven of the 79,642
      admissions also contained a Respiratory Syncytial Virus code. Two (5.4%) with
      Respiratory Syncytial Virus and 2,736 (3.4%) without Respiratory Syncytial Virus
      died. Survivors with Respiratory Syncytial Virus codes experienced significantly
      increased length of stay. In the extreme immaturity sub-group the length of stay
      was 117.5 days with Respiratory Syncytial Virus and 51.3 days without Respiratory
      Syncytial Virus (p = 0.0002). In the low birth weight or other preterm sub-group
      the length of stay with Respiratory Syncytial Virus was 69.2 and without
      Respiratory Syncytial Virus 14.7 days (p < 0.0001). The observed low rate for
      nosocomial Respiratory Syncytial Virus (0.46/1000 admissions) should be regarded
      as a minimum. The increased length of stay in infants with Respiratory Syncytial
      Virus infection emphasises that units should have guidelines to prevent and deal
      with Respiratory Syncytial Virus outbreaks.

PMID- 15035461
TI  - Replica-molded high-Q polymer microresonators.
AB  - Ultrahigh-Q microtoroids on a chip are applied as replication masters to
      demonstrate replica-molded high-Q microresonator arrays. Replica Q factors are
      nearly material loss limited, affirming the integrity of the replication process,
      and are as high as 5 x 10(6), or nearly a factor of 40 greater than previous
      polymer-based devices. Because the molding process is nondestructive, both the
      master and the molds can be reused. Additionally, by using a novel optical
      polymer (Vicast), we demonstrate storage of high-Q microresonators in the mold
      for weeks, providing a method to preserve the whispering-gallery Q factor.

PMID- 15035460
TI  - Recent advances in diagnosis and management of pulmonary hypertension in chronic
      lung disease.
AB  - Pulmonary hypertension with elevated pulmonary vascular resistance is a common
      cardiovascular complication associated with increased morbidity and mortality in
      preterm infants with chronic lung disease. Injury to the developing pulmonary
      circulation results in structural and functional abnormalities of the pulmonary
      vasculature. Animal studies have demonstrated that disruption of angiogenesis may
      contribute to the failure of normal alveolarisation in chronic lung disease.
      Levels of vascular endothelial growth factor in bronchoalveolar lavage fluid are
      lower in infants with chronic lung disease compared to preterm controls.
      Supplemental oxygen is commonly used to prevent and treat pulmonary hypertension,
      although optimal arterial oxygen saturation levels remain uncertain. Other
      vasodilators such as inhaled nitric oxide appear promising, but as yet have not
      been evaluated in the form of randomised controlled trials. Further studies are
      required to investigate the long-term effectiveness of pulmonary vasodilator
      therapy.

PMID- 15035462
TI  - Complex degree of mutual polarization.
AB  - Starting from the concepts of coherence and polarization, we generalize the
      conventional degree of polarization, introducing a two-point parameter, the
      complex degree of mutual polarization V, which is defined in terms of measurable
      quantities. We demonstrate the physical significance of this new quantity for the
      case of fully correlated, pure states of polarization at the two points, showing
      that the magnitude of V is a measure of the similarity between the states of
      polarization at two different points in space.

PMID- 15035463
TI  - Emergent polarization singularities.
AB  - Polarization singularities are shown to emerge spontaneously from the incoherent
      addition of uncorrelated optical fields that individually need not contain
      singularities. Examples of this phenomenon are given for both vector and ellipse
      fields. The incoherent addition of vector fields whose singularities have integer
      winding numbers is shown to yield fields whose singularities have half-integer
      winding numbers. These findings are used to make predictions about the
      singularities of the polarized component of the cosmic microwave background.

PMID- 15035464
TI  - High-efficiency, high-dispersion diffraction gratings based on total internal
      reflection.
AB  - We report a new class of high-dispersion immersed diffraction gratings for which
      the reflective nature of the diffraction is provided by the phenomenon of total
      internal reflection (TIR) regardless of grating tooth shape. Thus, the component
      can be fabricated from a single dielectric material and requires no metallic or
      dielectric film layers for high reflection diffraction efficiency. With the
      absence of metallic absorption, diffraction efficiencies of these TIR gratings
      can reach more than 99% for 15-20-nm spectral bandwidths, making them suitable
      for many laser-based technologies.

PMID- 15035465
TI  - Effective Raman gain characteristics in germanium- and fluorine-doped optical
      fibers.
AB  - We describe the dopant dependence of Raman gain in germanium- and fluorine-doped
      optical fibers. We clarify, both theoretically and experimentally, the effective
      Raman gain characteristic in an optical fiber, which is closely related to the
      fiber's refractive-index profile and electromagnetic field profile. We also show
      that this experimentally determined relationship can be used to evaluate the
      effective Raman gain characteristic in a germaninum- or a fluorine-doped optical
      fiber with an arbitrary index profile.

PMID- 15035466
TI  - Fiber dispersion cancellation by all-optical quantum signal processing based on
      quantum correlations.
AB  - A quantum dispersion canceller is proposed that uses all-optical quantum signal
      processing based on strong quantum correlations in the signal and idler waves
      amplified by an optical parametric amplifier at the receiver end. It cancels the
      even-order dispersion and can regenerate an optical data packet without any
      ambiguity.

PMID- 15035467
TI  - Mode multiplexing in optical frequency mixers.
AB  - Asymmetric Y junctions allow the development of a new class of optical frequency
      mixers that utilize higher-order waveguide modes for signal processing. We
      measure high-contrast (>30 dB) mode sorting in asymmetric Y junctions by use of a
      novel technique: efficient TM00, TM10, and TM20 mode mixing in a periodically
      poled lithium niobate waveguide. We also demonstrate an odd-to-even mode
      wavelength converter capable of spectral inversion without offset or
      bidirectional wavelength conversion.

PMID- 15035469
TI  - Photonic bandgap fiber with a silica core and multilayer dielectric cladding.
AB  - A new technique for fabricating a photonic bandgap fiber is proposed. A
      multilayer Si--SiO2 film is deposited upon a silica glass fiber, and a clear
      bandgap is observed in the loss spectrum. The properties of the bandgap are
      easily controlled by adjustment of the thickness and the refractive index of the
      multilayer film.

PMID- 15035468
TI  - High-temperature sustainability of strong fiber Bragg gratings written into Sb-Ge
      codoped photosensitive fiber: decay mechanisms involved during annealing.
AB  - An antimony--germanium- (Sb--Ge-) codoped fiber specially designed for the
      fabrication of fiber Bragg gratings (FBGs) with high temperature sustainability
      has been developed. The photosensitivity and the high-temperature sustainability
      of FBGs that have been written into this fiber were tested. The results obtained
      showed that the FBG written into this fiber has a very high temperature
      sustainability of 900 degrees C. A decay mechanism that involves cation hopping
      is presented to explain the observed high temperature sustainability of the
      grating written into this fiber.

PMID- 15035470
TI  - High focal depth with fractional-power wave fronts.
AB  - We explore the use of phase profiles with fractional power for tailoring
      modulation transfer functions with high focal depth at high pupil apertures. We
      present numerical simulations of the images that can be obtained with certain
      fractional-power profiles.

PMID- 15035471
TI  - Information-optimized phase diversity speckle imaging.
AB  - Fisher-information-based optimization of a conventional phase diversity speckle
      imaging system is presented. I demonstrate how Fisher information can be used to
      determine the optimum value of defocus in the diversity channel for estimating
      the mid-frequency integrated object power spectrum. This approach is likely to be
      useful in optimizing the design and performance of a general imaging system.

PMID- 15035472
TI  - Absolute frequency measurement of a 1.5-microm acetylene standard by use of a
      combined frequency chain and femtosecond comb.
AB  - We have developed and characterized a pair of Doppler-free acetylene-stabilized
      diode laser frequency standards as optical communications references. The Allan
      deviation sigma/f of an individual system reaches a minimum of 4 x 10(-14) at a
      sampling time of 5000 s, and the long-term lock-point repeatability is found to
      be 0.4 kHz (one standard uncertainty), corresponding to a fractional uncertainty
      of 2 x 10(-12). Using a combination of a frequency chain and a self-referenced
      femtosecond comb, we have measured the frequency of line P(16) of the v1 + v3
      overtone band of 13C2H2 to be 194,369,569,385.9 (3.0) kHz. The uncertainty of
      this number is limited solely by the reproducibility of the standards.

PMID- 15035473
TI  - Attoliter detection volumes by confocal total-internal-reflection fluorescence
      microscopy.
AB  - We report a confocal total-internal-reflection fluorescence (TIRF) microscope
      that generates a detection volume for analyte molecules of less than 5 al (5 x
      10(-18) l) at a water-glass interface. Compared with conventional confocal
      microscopy, this represents a reduction of almost 2 orders of magnitude, which is
      important in isolating individual molecules at high analyte concentrations, where
      many biologically relevant processes occur. Diffraction-limited supercritical
      focusing and fluorescence collection is accomplished by a parabolic mirror
      objective. The system delivers TIRF images with excellent spatial resolution and
      detects single molecules with a high signal-to-background ratio.

PMID- 15035474
TI  - Far-field emission of a semiconductor nanowire laser.
AB  - The polarization properties and angular distribution of intensity of the far
      fields from a nanowire laser are investigated. The far-field emission depends
      strongly on the mode type (HE11, TE01, TM01) and the radius of the nanowire. The
      emission is weakly directional, and a large part of it can be emitted in the
      backward direction. Our results can be applied for experimental determination of
      a lasing mode by its far fields as well as for optimization of laser emission.

PMID- 15035475
TI  - Linewidth and tuning characteristics of terahertz quantum cascade lasers.
AB  - We have measured the spectral linewidths of three continuous-wave quantum cascade
      lasers operating at terahertz frequencies by heterodyning the free-running
      quantum cascade laser with two far-infrared gas lasers. Beat notes are detected
      with a GaAs diode mixer and a microwave spectrum analyzer, permitting very
      precise frequency measurements and giving instantaneous linewidths of less than 
      30 kHz. Characteristics are also reported for frequency tuning as the injection
      current is varied.

PMID- 15035476
TI  - Algorithm for solving the equation of radiative transfer in the frequency domain.
AB  - We present an algorithm that provides a frequency-domain solution of the equation
      of radiative transfer (ERT) for heterogeneous media of arbitrary shape. Although
      an ERT is more accurate than a diffusion equation, no ERT code for the widely
      employed frequency-domain case has been developed to date. In this work the ERT
      is discretized by a combination of discrete-ordinate and finite-volume methods.
      Two numerical simulations are presented.

PMID- 15035477
TI  - Label-free detection of microarrays of biomolecules by oblique-incidence
      reflectivity difference microscopy.
AB  - We developed an oblique-incidence reflectivity difference (OI-RD) scanning
      microscope for label-free imaging of microarrays of biomolecules upon solid
      substrates. We demonstrate that hybridization reactions in an oligonucleotide
      microarray fabricated upon a glass slide can be detected by such an OI-RD
      microscope.

PMID- 15035478
TI  - Time-resolved fluorescence anisotropy imaging applied to live cells.
AB  - We have developed a wide-field time-resolved imaging system to image
      quantitatively both the fluorescence lifetime and the rotational correlation time
      of a fluorophore. Using a polarization-resolved imager, we simultaneously image
      orthogonal polarization components of the fluorescence emission onto a time-gated
      intensified CCD. We demonstrate imaging of solvent viscosity variations through
      the rotational correlation time of fluorescein in a multiwell plate and apply
      this technique to probe the microviscosity in live cells.

PMID- 15035480
TI  - Self-healing femtosecond light filaments.
AB  - A recent experiment [Appl. Phys. Lett. 83, 213 (2003)] indicated that filaments
      created in femtosecond high-power pulses propagating in air are surprisingly
      robust when interacting with microscopic water droplets. We present numerical
      modeling of the dynamics of the filament-droplet interaction. Our simulation
      results provide further insight into the interplay between the filament's core
      and the wide transverse pedestal of the pulse. It is shown that the robustness of
      the filament comes from the transverse low-intensity pedestal that controls the
      formation of the central hot spot. Implications for penetration of wide, high
      power beams through obscurants are discussed.

PMID- 15035479
TI  - Integrated endoscopy system for simultaneous imaging and spectroscopy for early
      lung cancer detection.
AB  - An integrated endoscopy system for simultaneous imaging and spectroscopy was
      developed to facilitate more accurate and convenient detection of early lung
      cancers. A specially designed three-CCD camera in combination with a dedicated
      light source permits capture of both white-light color images and tissue
      autofluorescence images without the need to switch between two different cameras.
      A mirror with an optical fiber at its center, placed at an interim imaging plane
      inside the camera unit, facilitates simultaneous imaging and spectroscopy
      measurements in either white-light reflectance mode or fluorescence mode. The
      system has been successfully tested in a clinic, demonstrating a practical
      approach to improve both diagnostic sensitivity and specificity at the same time.

PMID- 15035481
TI  - Second-harmonic generation in vortex-induced waveguides.
AB  - We study the second-harmonic generation and localization of light in a
      reconfigurable waveguide induced by an optical vortex soliton in a defocusing
      Kerr medium. We show that the vortex-induced waveguide greatly improves
      conversion efficiency from the fundamental to the second-harmonic field.

PMID- 15035482
TI  - One-dimensional spatial soliton families in optimally engineered quasi-phase
      matched lithium niobate waveguides.
AB  - The advantage for quadratic soliton generation of engineering the quasi-phase
      matching period near the input of lithium niobate slab waveguides is
      demonstrated. This approach allows members of one-dimensional quadratic soliton
      families with different values of the wave-vector mismatch to be cleanly excited
      and to be characterized by quantitative intensity-profile measurements of both
      the fundamental and the second-harmonic soliton components.

PMID- 15035483
TI  - Simultaneous achievement of polarization attraction and Raman amplification in
      isotropic optical fibers.
AB  - We present a theoretical analysis and experimental demonstration of the combined
      effects of polarization attraction and Raman amplification in isotropic optical
      fibers. The polarization attraction process is based on four-wave mixing
      interaction of counterpropagating pump and signal waves. We show that this
      technique can be used for the design of a highly efficient nonlinear system that
      permits the simultaneous processing of repolarization and amplification of light
      waves in dielectric media.

PMID- 15035484
TI  - Dispersion of the nonlinear refractive index in sapphire.
AB  - The nonlinear refractive index, n2, of sapphire was experimentally measured in
      the 550-1550-nm wavelength range by use of a picosecond Z-scan technique. It was
      found that in this spectral region the value of n2 decreases monotonically from
      approximately 3.3 x 10(-16) to approximately 2.8 x 10(-16) cm2/W. An empirical
      expression for the wavelength dependence of the nonlinear refractive index in the
      270-1550-nm range was obtained.

PMID- 15035485
TI  - Experimental characterization of simultaneous spatial and spectral filtering by
      an optical resonant filter.
AB  - Simultaneous spatial and spectral filtering by an optical resonant filter has
      been characterized experimentally to furnish additional insight into the
      operation and applications of optical resonant filters. Our experimental study
      can be useful for applications that depend on spatial filtering, spectral
      filtering, spatial-spectral filtering, and polarization selectivity. One
      significant application is the integration of an optical resonant filter with
      semiconductor lasers to control the spatial-spectral radiation for optimum
      performance.

PMID- 15035486
TI  - Terabit all-optical logic based on ultrafast two-dimensional transmission gating.
AB  - Terabit all-optical complementary logic is proposed using two successive time
      slots to represent a unique logical status. An organic molecular thin film is
      used as an array of optically controlled optical switches. By utilizing the
      planar structure of the film and its ultrafast optical response, proof-of
      principle fully optical NOT and AND logic operations were demonstrated with 400
      fs interval pulses.

PMID- 15035488
TI  - Fourier algorithm method for reconstruction of large-aperture digital holograms
      based on phase compensation.
AB  - To simplify the reconstruction calculation of a large-aperture digital hologram
      we propose a novel Fourier-transformation reconstruction algorithm. When the
      reconstructed wave is the same as or similar to the reference wave, the higher
      order phase term of reconstruction can be compensated for. For example, the
      variation between the higher-order phase term and the aperture angle with a
      different field of view in in-line phase-shifting digital holography is analyzed.

PMID- 15035487
TI  - Reduction of coherent artifacts in dynamic holographic three-dimensional displays
      by diffraction-specific pseudorandom diffusion.
AB  - An electroholographic display based on diffraction-specific computation can
      reduce speckle by electronic diffusion through selective addition of a
      pseudorandom sequence. Intensity fluctuation as a result of the introduction of
      pseudorandom noise does not affect three-dimensional (3-D) images significantly
      since spatial windows formed by diffused basis fringes do not widen noticeably at
      low pseudorandom spread, whereas the features of the fluctuation are much smaller
      than human visual resolution. Experimental results obtained on the Massachusetts
      Institute of Technology holographic video system confirmed that the diffusion
      smooths 3-D images and improves the intensity nonuniformity among horizontal
      holographic lines.

PMID- 15035489
TI  - Dispersion-based beam splitter in photonic crystals.
AB  - A novel implementation of a dispersion-based beam splitter in a photonic crystal
      (PhC) is proposed. The beam splitter consists of two periodic structures: a
      nonchannel dispersion-guiding region and a splitting structure operating inside
      the photonic bandgap. The dispersion-guiding PhC structure is used to route the
      optical wave by exploiting the dispersion properties of the lattice. An arbitrary
      power ratio between the output beams can be achieved by varying the parameters of
      the splitting structure. Within the studied range of splitting structures, high
      output power was observed and verified experimentally.

PMID- 15035490
TI  - Damage to extreme-ultraviolet Sc/Si multilayer mirrors exposed to intense 46.9-nm
      laser pulses.
AB  - The damage threshold and damage mechanism of extreme-ultraviolet Sc/Si multilayer
      mirror coatings are investigated with focused nanosecond pulses at 46.9-nm
      radiation from a compact capillary-discharge laser. Damage threshold fluences of
      approximately 0.08 J/cm2 are measured for coatings deposited on both borosilicate
      glass and Si substrates. The use of scanning and transmission electron microscopy
      and small-angle x-ray diffraction techniques reveals the thermal nature of the
      damage mechanism. The results are relevant to the use of newly developed high
      flux extreme-ultraviolet sources in applications.

PMID- 15035491
TI  - Effect of detector size on optical resolution in phase contrast microscopes.
AB  - We examine the effects of detector size on the imaging properties of a scanning
      phase contrast microscope. The lateral size of the point-spread function is found
      to be wider when a point detector is used than when a much larger detector is
      used. Combining this finding with the well-known difficulties involved in using a
      confocal microscope in transmission mode suggests that a phase contrast
      microscope employing a point detector will in general have inferior imaging
      properties compared with one employing a large detector.

PMID- 15035492
TI  - Tunable delay line with interacting whispering-gallery-mode resonators.
AB  - We theoretically study a parallel configuration of two interacting whispering
      gallery-mode optical resonators and show a narrowband modal structure as a basis
      for a widely tunable delay line. For the optimum coupling configuration the
      system can possess an unusually narrow spectral feature with a much narrower
      bandwidth than the loaded bandwidth of each individual resonator. The effect has
      a direct analogy with the phenomenon of electromagnetically induced transparency
      in quantum systems for which the interference of spontaneous emission results in
      ultranarrow resonances.

PMID- 15035493
TI  - All-optical phase locking of two femtosecond Ti:sapphire lasers: a passive
      coupling mechanism beyond the slowly varying amplitude approximation.
AB  - Two independently tunable femtosecond Ti:sapphire lasers are passively
      synchronized with a stable relative carrier-envelope offset phase. By
      heterodyning the spectral overlap of the two frequency combs, we observe multiple
      regimes for the cavity length difference in which the relative round-trip phase
      slip is effectively locked to zero. The strong correlation of the femtosecond
      pulse trains is maintained over minutes without any external stabilization, and
      relative cavity length variations of 50 nm are compensated. The phase
      synchronization relies on phase-dependent cross-phase modulation, taking full
      advantage of the nonresonant optical nonlinearity of the shared gain medium,
      which is much faster than the optical cycle.

PMID- 15035494
TI  - Self-stabilization of carrier-envelope offset phase by use of difference
      frequency generation.
AB  - Self-stabilized carrier-envelope offset phase is achieved by use of difference
      frequency (DF) generation. The spectrum from a Ti:sapphire oscillator is
      broadened in a photonic crystal fiber, and a DF (900 nm) between the blue
      component (490 nm) and the infrared component (1080 nm) is generated. The beat
      signal between the fundamental and the DF signal is clearly observed. The
      wavelength of the DF signal can be tuned down to 780 nm, and hence the signal can
      be used for injection seeding of a Ti:sapphire oscillator.

PMID- 15035495
TI  - Demonstration of coherent addition of multiple gratings for high-energy chirped
      pulse-amplified lasers.
AB  - Petawatt solid-state lasers require meter-sized gratings to reach multiple
      kilojoule energy levels without laser-induced damage. As an alternative to large
      single gratings, we demonstrate that smaller, coherently added (tiled) gratings
      can be used for subpicosecond-pulse compression. A Fourier-transform-limited, 650
      fs chirped-pulse-amplified laser pulse is maintained by replacing a single
      compression grating with a tiled-grating assembly. Grating tiling provides a
      means to scale the energy and irradiance of short-pulse lasers.

PMID- 15035496
TI  - Characterization of stimulated Brillouin scattering spectra by use of optical
      single-sideband modulation.
AB  - We introduce an enhanced method for the characterization of stimulated Brillouin
      scattering (SBS) spectra in single-mode fiber that is based on optical single
      sideband modulation. This novel technique is shown to provide high-resolution
      characterization of SBS even under saturation operation in a simple and stable
      setup in which the spectrum is translated from the optical to the electrical
      domain, sweeping the frequency of an electrical signal generator. Experimental
      results are used to demonstrate the performance of the system in measuring the
      detailed structure of acoustic modes in three types of single-mode fiber.

PMID- 15035497
TI  - First international comparison of femtosecond laser combs at the International
      Bureau of Weights and Measures.
AB  - The first international comparison of femtosecond laser combs has been carried
      out at the International Bureau of Weights and Measures (BIPM). Three comb
      systems were involved: BIPM-C1 and BIPM-C2 from the BIPM and ECNU-C1 from the
      East China Normal University (ECNU). The agreement among the three combs was
      found to be on the subhertz level in the vicinity of 563 THz. A frequency
      difference measurement scheme was demonstrated that is suitable for general comb
      comparisons.

PMID- 15035498
TI  - General ultrafast pulse measurement using the cross-correlation single-shot
      sonogram technique.
AB  - The cross-correlation single-shot sonogram technique offers exact pulse
      measurement and real-time pulse monitoring via an intuitive time-frequency trace
      whose shape and orientation directly indicate the spectral chirp of an ultrashort
      laser pulse. We demonstrate an algorithm that solves a fundamental limitation of
      the cross-correlation sonogram method, namely, that the time-gating operation is
      implemented using a replica of the measured pulse rather than the ideal delta
      function-like pulse. Using a modified principal-components generalized
      projections algorithm, we experimentally show accurate pulse retrieval of an
      asymmetric double pulse, a case that is prone to systematic error when one is
      using the original sonogram retrieval algorithm.

PMID- 15035499
TI  - A model for presenting systematic data on the Internet.

PMID- 15035500
TI  - New angles in mycology: studies in directional growth and directional motility.
AB  - Mycology is changing as an era of extensive genome sequencing comes of age and
      provides vital information that enables questions to be addressed about fungi in
      all the major taxonomic groups. As technology transfer facilitates what was once
      only possible for a very small number of model species, it becomes possible to
      explore the biology and biodiversity of fungi as a whole. The availability of
      genome sequence information and reverse genetic technologies allows hypotheses
      that emerge from biological observations to be tested. Genomic and post-genomic
      technologies will underline the importance of fungi as excellent models for the
      study of fundamental biological phenomena. Two enduring areas of research in my
      own laboratory are described that are now being extended using post-genomic
      approaches. These projects relate to how fungal hyphae extend and guide their
      tips and secondly how plant pathogenic oomycete zoospores are guided on their
      journey to the plant surface.

PMID- 15035501
TI  - Fungal secondary metabolites as inhibitors of infection-related morphogenesis in
      phytopathogenic fungi.
AB  - The life-cycle of many plant-pathogenic fungi, especially those infecting aerial
      plant organs, contains several specific developmental stages. If these are
      sufficiently distinct in their physiology from vegetative hyphal growth, they
      present potential targets for non-fungitoxic plant protectants. The present
      review identifies such targets especially in the pre-penetration stages of the
      infection cycle of Magnaporthe grisea and other fungi infecting from air-borne
      spores. Examples of non-toxic natural products with activity against spore
      germination, attachment, appressorium formation, appressorium maturation and
      penetration of the host surface are given. In contrast, no substances selectively
      active against in planta growth or sporulation appear to be known. The selective
      activity of numerous secondary metabolites against specific infection stages
      without accompanying toxicity against vegetatively growing hyphae indicates a
      direction for the development of future natural product-derived fungicides which
      are more easily degraded in the environment and possess fewer non-target effects.
      Such substances are produced by many saprotrophic and endophytic fungi in pure
      culture. The paucity of data on the production of biologically active substances
      in natural situations limits the interpretation of their ecophysiological
      significance for the producer.

PMID- 15035502
TI  - A natural classification of Lasiosphaeria based on nuclear LSU rDNA sequences.
AB  - The current circumscription of Lasiosphaeria includes taxa with a wide variety of
      ascomatal walls, ascomatal wall vestitures, and ascospore morphologies and a
      broad range of putative anamorphs. Despite the complexity of morphological
      characters in the genus, species within Lasiosphaeria can be arranged into four
      groups based on ascospore morphology. Taxa which possessed ascospores in each of
      the four groups were used in phylogenetic analyses of partial nuclear large
      subunit (LSU) rDNA sequences to test the monophyly of the genus and determine
      relationships among its species. Lasiosphaeria was found to be highly
      polyphyletic in that species segregated into seven well-supported monophyletic
      clades dispersed among several orders. Three new genera, Echinosphaeria,
      Hilberina, and Immersiella, are erected for three of these clades while the genus
      Lasiosphaeris is reintroduced for a fourth clade. These data support Ruzenia as a
      previously established genus and the transfer of Lasiosphaeria raciborskii to
      Chaetosphaeria. The circumscription of Lasiosphaeria has been considerably
      narrowed to better reflect a natural classification. These taxonomic changes are
      additionally supported by a combination of morphological characters which are
      discussed in relation to the phylogenetic trees.

PMID- 15035503
TI  - Fusarium species and Fusarium wilt pathogens associated with native Gossypium
      populations in Australia.
AB  - Fusarium isolates were extracted from stems and rhizosphere soils of 79
      populations of four Gossypium species native to two regions of inland Australia
      in 2001. Six Fusarium species were isolated from 31 (3%) of the 919 stem samples.
      F. semitectum was predominant, occurring mostly in G. bickii populations and
      accounting for 81% of the isolates recovered. Twenty Fusarium species were
      isolated from 68 (87%) of the 78 composite soil samples, with F. solani (71%), F.
      compactum (8%), F. oxysporum (5%), F. graminearum (3%), and F. crookwellense (3%)
      being the most prevalent. Significant differences in the relative densities
      indicated that F. solani was more common in the soil from G. sturtianum
      populations than from G. bickii populations, and that F. crookwellense was more
      common in South Australian soils than in Queensland and Northern Territory soils.
      Fusarium oxysporum had a relatively greater relative density in the rhizosphere
      soils of G. australe plants than in that of sympatrically growing G. sturtianum
      plants. Fifteen (17%) of the 89 F. oxrysporum isolates produced typical Fusarium
      wilt symptoms on cultivated cotton (G. hirsutum cv. 'Siokra 1-4'), therefore they
      were classified as wild Fov. Soil samples collected from G. sturtianum
      populations in the Arkaroola-Leigh Creek region in South Australia had the
      highest incidence of wild Fov (24%). Two wild Fov isolates were similar in
      virulence to a cotton field Fov isolate in the glasshouse experiments, indicating
      that they could incite Fusarium wilt disease in cotton fields. The presence of
      wild Fov in native Gossypium populations suggests that the Fov occurring in
      Australian cotton fields may be of indigenous origins.

PMID- 15035504
TI  - Characterization of Guignardia mangiferae isolated from tropical plants based on
      morphology, ISSR-PCR amplifications and ITS1-5.8S-ITS2 sequences.
AB  - Phenotypic and genotypic variability of 18 endophytic Guignardia strains from
      different host plants (Anacardiaceae: Anacardium giganteum, Myracrodruon
      urundeuva, Spondias mombin; Apocynaceae: Aspidosperma polyneuron; Ericaceae:
      Rhododendron sp.; Fabaceae: Bowdichia nitida; Leguminosae: Cassia occidentalis;
      Rutaceae: Citrus aurantium) growing in different sites in Brazil was assessed by
      means of morphometric measurements and inter-single-sequence-repeat-anchored
      polymerase chain reaction (ISSR-PCR) amplifications of the DNA. Morphology of
      conidia and ascospores and growth rates of the Brazilian isolates corresponded
      well with those of G. mangiferae. Multiple correspondence analysis (MCA) of the
      ISSR-PCR data yielded three groups of strains, which did, however, not correspond
      either to the host or to the geographic origin. The same individual tree hosted
      genotypically different strains indicating multiple infections. Phylogeny based
      on ITS1-5.8S-ITS2 sequence analyses confirmed conspecificity of the Brazilian
      isolates with G. mangiferae (syn. G. endophyllicola).

PMID- 15035505
TI  - Diversity and molecular relationships of endophytic Colletotrichum isolates from
      the Iwokrama Forest Reserve, Guyana.
AB  - The diversity and host specificity were studied of a collection of Colletotrichum
      strains derived from endophytic colonies in leaves of 12 tree species in the
      Iwokrama Forest Reserve, Guyana. Analysis included ISSR-PCR and RAPD molecular
      fingerprinting techniques, rDNA ITS sequencing and morphological and cultural
      characterization. Most strains belonged to one of two species, C. gloeosporioides
      and a further taxon which is probably referable to C. boninense. Almost no
      strains were found to be genetically identical, indicating that clonal
      reproduction does not play a prominent role. No degree of host specificity could
      be detected even at molecular fingerprint level. The implications for estimation
      of fungal diversity in closed tropical forests may be profound.

PMID- 15035506
TI  - Migrational capacity of Fennoscandian populations of Venturia tremulae.
AB  - Genetic variation in three multiallelic loci was analysed with Temperature
      Gradient Gel Electrophoresis in order to assess the genetic population structure
      of Venturia tremulae var. tremulae in order to understand the evolutionary
      potential of the pathogen against resistance breeding. Also the identification of
      the fungus was verified with molecular analysis of reference isolates. The Fst
      and Gst values were very low indicating no substructuring or restrictions to gene
      flow between Fennoscandian populations of V. tremulae. The results imply high
      epidemiological efficiency of the fungus and therefore continuous breeding
      programme should be implemented for Venturia resistance of aspen.

PMID- 15035507
TI  - Size and sequence heterogeneity in the ITS1 of Xylaria hypoxylon isolates.
AB  - During a survey of 375 strains of the Xylariales, one isolate (F127076) was
      observed to have an ITS1 size of 833 bp. This size exceeds the average ITS1 size
      in the Xylariales (mean = 209 +/- 57 bp). Comparison of the DNA sequence with
      GenBank and with a proprietary DNA database revealed low homology with Xylaria
      hypoxylon ATCC 42768, and with one undescribed Xylaria species. When the ITS2
      sequence was compared, these isolates were 96-98% homologous. Sequences of other
      variable genes confirmed the relatedness among these strains. A closer
      observation of the ITS sequence of this isolate revealed the presence of three
      repeated domains of 250 bp plus one truncated domain, showing 52-75% homology.
      Sequence similarity suggests that the repeated domain is derived from the fusion
      of the ITS1 with a DNA fragment derived from the gamma-glutamyltranspeptidase
      gene. This example suggests that the rate of evolution of ITS1 can be independent
      of the rate of evolution of other genes, even when this variability is not a
      result of slipped strand misspairing events like in other Xylariales. This
      observation also indicates that recombination with other nuclear genes could
      participate in the evolution of the internal transcribed spacer.

PMID- 15035508
TI  - Determination of Acaulospora longula and Glomus subgroup Aa in plant roots from
      grassland using new primers against the large subunit ribosomal DNA.
AB  - Molecular techniques have become increasingly important for the identification of
      arbuscular mycorrhizal fungi (AMF). In this work Acaulospora longula and Glomus
      mosseae have been detected in plant roots from pastures using specific nucleotide
      primers for the two species. Part of the 5' end of the large subunit of the
      ribosomal RNA gene was amplified by nested PCR and sequenced. The distribution of
      the fungi within three different plant species, Plantago lanceolata, Trifolium
      repens, and Holcus lanatus, and two different types of grassland, have been
      studied. Neither the fungi nor the plants showed specific preference for their
      symbiotic partnership.

PMID- 15035509
TI  - Development of extraradical mycelium of Scutellospora reticulata under root-organ
      culture: spore production and function of auxiliary cells.
AB  - The development of the extraradical mycelium and auxiliary cells and spore
      production of Scutellospora reticulata in association with Ri T-DNA transformed
      carrot roots was followed under root-organ culture conditions. Extraradical
      mycelium development followed classical lag-exponential-plateau phases, with an
      additional late decline phase in number of auxiliary cells. Spore production
      started in parallel with a critical extraradical mycelium biomass produced,
      continued long after root growth ceased and during the late decline in auxiliary
      cells number. Isolated auxiliary cells were shown to exhibit hyphal re-growth,
      but not root colonization, either in situ or in vitro. These results showed that
      root and extraradical mycelium development were intimately associated in a
      sequence where both grew together during active root growth, followed during root
      aging by a period in which only the fungus developed. Spore production appeared
      dependent on a critical extraradical mycelium biomass and on the re-allocation of
      resources from both the intraradical mycelium and the auxiliary cells via the
      hyphal network.

PMID- 15035510
TI  - Production and processing of Metarhizium anisopliae var. acridum submerged
      conidia for locust and grasshopper control.
AB  - Currently, mycopesticide development for locust and grasshopper control depends
      on aerial conidia or submerged spores of entomopathogenic fungi. In our study,
      the production of submerged conidia of Metarhizium anisopliae var. acridum (IMI
      330189) was investigated in a liquid medium containing 3% biomalt and 1% yeast
      extract (BH-medium). The effects of freeze and spray drying techniques on the
      quality of submerged conidia were determined. The influence of different
      additives on the viability of fresh submerged conidia and their suitability for
      oil flowable concentrate formulation development was assessed. In a BH medium
      maintained at 180 rev min(-1), at 30 degrees C for 72 h, IMI 330189 produced a
      green pigmented biomass of submerged conidia whereas in Adamek medium it produced
      a yellowish biomass of submerged spores. The spore concentration was high in both
      media; however, the size of the spores produced in the BH medium was
      significantly lower than those produced in Adamek medium (P < 0.001). Submerged
      conidia can be effectively dried using either freeze or spray drying techniques.
      The viability and speed of germination were significantly affected by the drying
      and pulverizing process (P < 0.001). The initial viability was significantly
      higher for spray-dried submerged conidia than for freeze-dried spores.
      Pulverizing of freeze-dried submerged conidia reduced the speed of germination
      and the viability by 63-95%. Dried submerged conidia can be stored over 45 wk at
      low temperatures (< 10 degrees) without suffering a significant loss in
      viability. Furthermore, we have identified carriers that are suitable for oil
      flowable concentrate formulation development.

PMID- 15035512
TI  - Umbelopsis dimorpha sp. nov., a link between U. vinacea and U. versiformis.
AB  - The new species Umbelopsis dimorpha sp. nov. was isolated from a soil sample in
      the Red Hills area of Mt Richmond Forest Park, in the northern part of the South
      Island of New Zealand. It has two kinds of pale pinkish sporangia: (1) single
      spored, indistinguishable from those of U. versiformis; and (2) multi-spored,
      similar to those of U. vinacea. ITS sequences place the species in the immediate
      vicinity of the former species.

PMID- 15035511
TI  - Fungal enzymes transferred by leaf-cutting ants in their fungus gardens.
AB  - Leaf-cutting ants finely fragment the leaf material that they bring to the nest
      and place faecal droplets on this substrate before incorporating it in the upper
      part of the fungus-garden. The faecal droplets contain enzymes of which some have
      been shown to be of fungal origin. Here we explicitly address the enzymatic
      activity of faecal droplets in the leaf-cutting ants Acromyrmex echinatior and
      Atta colombica. We used isoelectric focusing and specific staining to show that
      faecal droplets of both species contain carboxymethylcellulases, laccases,
      proteases, and pectinases (both pectin esterases and pectin lysases) and we
      demonstrate that these enzymes originate from the symbiotic fungus and not from
      the ants themselves. The level of activity of fungal pectin lyase in faecal
      droplets indicates that fungal enzymes may be protected and possibly concentrated
      during their passage through the ant gut. This would imply that enzymes that are
      transferred by ants from mature parts of the fungus gardens may play an important
      role for the colonization of new substrate by new mycelium of the same fungal
      clone.

PMID- 15035513
TI  - Computer-assisted radiology.

PMID- 15035514
TI  - Automatic detection of calcifications in the aorta from CT scans of the abdomen.
      3D computer-aided diagnosis.
AB  - RATIONALE AND OBJECTIVES: Automated detection and quantification of arterial
      calcifications can facilitate epidemiologic research and, eventually, the use of
      full-body calcium scoring in clinical practice. An automatic computerized method
      to detect calcifications in CT scans is presented. MATERIALS AND METHODS: Forty
      abdominal CT scans have been randomly selected from clinical practice. They all
      contained contrast material and belonged to one of four categories: containing
      "no," "small," "moderate," or "large" amounts of arterial calcification. There
      were ten scans in each category. The experiments were restricted to the vertical
      range from the point where the superior mesenteric artery branches off of the
      descending aorta until the first bifurcation of the iliac arteries. The automatic
      method starts by extracting all connected objects above 220 Hounsfield units (HU)
      from the scan. These objects include all calcifications, as well as bony
      structures and contrast material. To distinguish calcifications from non
      calcifications, a number of features are calculated for each object. These
      features are based on the object's size, location, shape characteristics, and
      surrounding structures. Subsequently a classification of each object is performed
      in two stages. First the probability that an object represents a calcification is
      computed assuming a multivariate Gaussian distribution for the calcifications.
      Objects with low probability are discarded. The remaining objects are then
      classified into calcifications and non-calcifications using a 5-nearest-neighbor
      classifier and sequential forward feature selection. Based on the total volume of
      calcifications determined by the system, the scan is assigned to one of the four
      categories mentioned above. RESULTS: The 40 scans contained a total of 249
      calcifications as determined by a human observer. The method detected 209
      calcifications (sensitivity 83.9%) at the expense of on average 1.0 false
      positive object per scan. The correct category label was assigned to 30 scans and
      only 2 scans were off by more than one category. Most incorrect classifications
      can be attributed to the presence of contrast material in the scans. CONCLUSION:
      It is possible to identify the majority of arterial calcifications in abdominal
      CT scans in a completely automatic fashion with few false positive objects, even
      if the scans contain contrast material.

PMID- 15035515
TI  - Model-based detection of lung nodules in computed tomography exams. Thoracic
      computer-aided diagnosis.
AB  - RATIONALE AND OBJECTIVES: In this study, we developed a prototype model-based
      computer aided detection (CAD) system designed to automatically detect both solid
      and subsolid pulmonary nodules in computed tomography (CT) images. By using this
      CAD algorithm, along with the radiologist's initial interpretation, we aim to
      improve the sensitivity of radiologic readings of CT lung exams. MATERIALS AND
      METHODS: We have developed a model-based CAD algorithm through the use of precise
      mathematic models that capture scanner physics and anatomic information. Our
      model-based CAD algorithm uses multiple segmentation algorithms to extract
      noteworthy structures in the lungs and a Bayesian statistical model selection
      framework to determine the probability of various anatomical events throughout
      the lung. We tested this algorithm on 50 low-dose CT lung cancer screening cases
      in which ground truth was produced through readings by three expert chest
      radiologists. RESULTS: Using this model-based CAD algorithm on 50 low-dose CT
      cases, we measured potential sensitivity improvements of 7% and 5% in two
      radiologists with respect to all noncalcified nodules, solid and subsolid,
      greater than 5 mm in diameter. The third radiologist did not miss any nodules in
      the ground truth set. The CAD algorithm produced 8.3 false positives per case.
      CONCLUSION: Our prototype CAD system demonstrates promising results as a tool to
      improve the quality of radiologic readings by increasing radiologist sensitivity.
      A significant advantage of this model-based approach is that it can be easily
      extended to support additional anatomic models as clinical understanding and
      scanning practices improve.

PMID- 15035516
TI  - Multidetector helical computed tomography of the liver: comparison of hepatic
      enhancement using two different contrast media strategies.
AB  - RATIONALE AND OBJECTIVES: The purpose of this study was to compare hepatic
      enhancement characteristics using two different contrast media injection
      protocols with multidetector helical computed tomography. MATERIALS AND METHODS:
      Twenty-three patients with known or suspected liver lesions scheduled to undergo
      biphasic hepatic multidetector helical computed tomography were randomized into
      one of two groups: (1) 150 mL of iopamidol (300 mgI/mL) at 5 mL/second, or (2)
      100 mL of iopamidol (370 mgI/mL) at 4 mL/second. Unenhanced images were acquired
      initially, followed by both hepatic arterial phase (scan delay, 33 seconds) and
      portal venous phase (PVP; scan delay, 65 seconds) imaging. Three abdominal
      radiologists independently graded the images on a scale from 1-5 for enhancement
      and overall scan quality. Time-attenuation curves were generated from operator
      defined region-of-interest measurements of liver parenchyma and aorta. RESULTS:
      Qualitatively, the three reviewers found no significant difference between the
      two study groups in terms of overall scan quality (P = .23) or aortic enhancement
      (hepatic arterial phase, P = .9; PVP, P = .24). However, liver enhancement during
      the PVP was considered to be less in the Isovue 370 group (P = .04).
      Quantitatively, during the hepatic arterial phase, there was no statistically
      significant difference between the two injection protocols comparing either
      aortic or hepatic parenchymal enhancement (P = .62 and .80, respectively). During
      the PVP, these differences were statistically significant, with both aortic and
      hepatic parenchymal enhancement lower in the Isovue 370 group (P < .01 and P =
      .04, respectively). CONCLUSION: It is important to consider the amount of iodine
      injected per second and the duration of the injection when setting up protocols
      to achieve target organ enhancement. 100 mL of iopamidol 370 at 4 mL/second can
      be used to obtain images of the liver with good diagnostic quality compared to
      more conventional protocols using 150 mL of iopamidol 300 at 5 mL/second.
      However, the degree of liver parenchymal enhancement during the PVP using the
      latter injection scheme is lower, which in turn could potentially reduce hepatic
      lesion conspicuity.

PMID- 15035517
TI  - Performance of computer-aided diagnosis in the interpretation of lesions on
      breast sonography.
AB  - RATIONALE AND OBJECTIVES: To investigate the potential usefulness of computer
      aided diagnosis as a tool for radiologists in the characterization and
      classification of mass lesions on ultrasound. MATERIALS AND METHODS: Previously,
      a computerized method for the automatic classification of breast lesions on
      ultrasound was developed. The computerized method includes automatic segmentation
      of the lesion from the ultrasound image background and automatic extraction of
      four features related to lesion shape, margin, texture, and posterior acoustic
      behavior. In this study, the effectiveness of the computer output as an aid to
      radiologists in their ability to distinguish between malignant and benign
      lesions, and in their patient management decisions in terms of biopsy
      recommendation are evaluated. Six expert mammographers and six radiologists in
      private practice at an institution accredited by the American Ultrasound
      Institute of Medicine participated in the study. Each observer first interpreted
      25 training cases with feedback of biopsy results, and then interpreted 110
      additional ultrasound cases without feedback. Simulating an actual clinical
      setting, the 110 cases were unknown to both the observers and the computer.
      During interpretation, observers gave their confidence that the lesion was
      malignant and also their patient management recommendation (biopsy or follow-up).
      The computer output was then displayed, and observers again gave their confidence
      that the lesion was malignant and theirpatient management recommendation.
      Statistical analyses included receiver operator characteristic analysis and
      Student t-test. RESULTS: For the expert mammographers and for the community
      radiologists, the Az (area under the receiver operator characteristic curve)
      increased from 0.83 to 0.87 (P = .02) and from 0.80 to 0.84 (P = .04),
      respectively, when the computer aid was used in the interpretation of the
      ultrasound images. Also, the Az values for the community radiologists with aid
      and for the expert mammographers without aid are similar to the Az value for the
      computer alone (Az = 0.83). CONCLUSION: Computer analysis of ultrasound images of
      breast lesions has been shown to improve the diagnostic accuracy of radiologists
      in the task of distinguishing between malignant and benign breast lesions and in
      recommending cases for biopsy.

PMID- 15035518
TI  - Mixture distribution analysis of a computer assisted diagnostic method for the
      evaluation of pulmonary nodules on computed tomography scan.
AB  - RATIONALE AND OBJECTIVES: To compare the effectiveness of a new computational
      scheme for pulmonary nodule detection in computed tomography images against human
      observers. MATERIALS AND METHODS: The study involved evaluation of 81 potential
      nodules by four radiologists. Each radiologist separately evaluated the potential
      nodules and provided a confidence level for the presence of pulmonary nodules.
      Their performance was compared with that of the new computational scheme by
      mixture distribution analysis. RESULTS: Mixture distribution analysis of the
      results of the four radiologists demonstrated a relative proportion agreement of
      0.84. The kappa statistic was used to compare the agreement of the computational
      scheme with the results of the four radiologists. A kappa value of .65 (se = .11)
      was shown to be significantly different from chance (P = .99). CONCLUSION: The
      new computational scheme correlates well with the radiologists' subjective
      rankings of pulmonary nodules on computed tomography scans and may prove a useful
      tool in the evaluation of algorithms for the screening and diagnosis of lung
      cancer.

PMID- 15035519
TI  - Is coronary artery calcium mass related to Agatston score?
AB  - RATIONALE AND OBJECTIVES: The objective of this study was to investigate the
      relationship between the coronary calcium mass and Agatston score measured on
      multidetector row computed tomography. MATERIALS AND METHODS: Eighty-three
      consecutive subjects (60 men and 23 women) referred for coronary screening were
      examined prospectively by electrocardiogram-triggered sequential multidetector
      row computed tomography scan (4 x 2.5-mm collimation). Their coronary calcium was
      quantitated by means of the Agatston scoring and mass method. The values of score
      and mass were transformed by taking the natural logarithm (ln(value + 1)) to
      reduce skewness. The relationship between the mass and score was analyzed with
      multiple regression analysis. RESULTS: Fifty-one subjects had a total of 328
      calcified lesions detected and measured. The relationship between the calcium
      mass and score in 51 subjects conformed well to a linear relationship (r2 =
      0.96). When analyzed in the total of 328 lesions, the relationship had a good
      empiric fit with a nonlinear (quadratic) model (r2 = 0.96). The best-fit equation
      was ln(lesion mass + 1) = -0.87 + 0.67 x ln(lesion score + 1) + 0.10 x (ln(lesion
      score + 1) - 2.86)2. This relationship was consistent in different coronary
      vessels and at different heart levels (r2 = 0.96 - 0.99), although there was a
      higher image noise at lower heart levels (paired t-tests, P < .0001). CONCLUSION:
      A nonlinear (quadratic) relationship existed strongly and consistently between
      coronary calcium mass and score, demonstrating a possible cross-sectional
      conversion between the two measurements.

PMID- 15035520
TI  - Stereotactic and sonographic large-core biopsy of nonpalpable breast lesions:
      results of the Radiologic Diagnostic Oncology Group V study.
AB  - RATIONALE AND OBJECTIVES: To determine the diagnostic accuracy of
      stereotactically and sonographically guided core biopsy (CB) for the diagnosis of
      nonpalpable breast lesions. MATERIALS AND METHODS: Twenty-two institutions
      enrolled 2,403 women who underwent imaging-guided fine needle aspiration followed
      by imaging-guided large-CB of nonpalpable breast abnormalities. All mammograms
      were reviewed for study eligibility by one of two breast imaging radiologists.
      The protocol for image-guided biopsy, using either ultrasound (USCB) or
      stereotactic (SCB) guidance, was standardized at all institutions and all biopsy
      specimens were over-read by one of three expert pathologists. Patients with
      atypical ductal hyperplasia (ADH), atypical lobular hyperplasia, or lobular
      neoplasia on CB underwent surgical excision. Those with negative CB but
      suspicious ("discordant") pre-biopsy mammography also underwent surgical
      excision. Patients having a negative CB that was concordant with the pre-biopsy
      mammography suspicion were assigned to follow-up mammography at 6, 12, and 24
      months following CB. RESULTS: A gold standard diagnosis based on definitive
      histopathologic diagnosis, mammography follow-up, or an imputed gold standard
      diagnosis was established for 1,681 patients. Of 310 cases with a gold standard
      diagnosis of invasive breast carcinoma, 261 (84.2%) were invasive carcinoma, 31
      (10%) were ductal carcinoma in situ (DCIS), four (1.3%) were ADH, one (0.3%) was
      a non-breast cancer, and 13 (4.2%) were benign on CB. For 138 cases with a gold
      standard diagnosis of DCIS, 113 (81.9%) were DCIS, 20 (14.5%) were ADH, and five
      (3.6%) were benign on CB. For 57 cases (13 masses, 44 calcifications) with an
      initial CB diagnosis of ADH, atypical lobular hyperplasia or lobular neoplasia,
      20 (35.1%) had a gold standard diagnosis of DCIS (4 masses, 16 calcifications)
      and four (7.0%) had a gold standard diagnosis of invasive cancer (4
      calcifications). Of 144 cases (22 masses, 122 calcifications) with an initial CB
      diagnosis of DCIS, 31 (21.5%) had a gold standard diagnosis of invasive cancer
      (10 masses, 21 calcifications). The sensitivity, specificity and accuracy for CB
      by either imaging guidance method in this trial were .91, 1.00, and .98,
      respectively. The sensitivity, predictive value negative, and accuracy of CB for
      diagnosing masses (.96, .99, and .99, respectively) were significantly greater (P
      < .001) than for calcifications (.84, .94, and .96, respectively). The
      sensitivity (.89) of SCB for diagnosing all lesions was significantly lower (P =
      0.029) than that of USCB (.97) because of the preponderance of calcifications
      biopsied by SCB versus USCB. There was no difference between USCB and SCB in
      sensitivity, predictive value negative, or accuracy for the diagnosis of masses
      (97.3, 98.9, and 99.2, respectively for USCB; 95.6, 98.5, and 98.9 respectively
      for SCB). CONCLUSION: Percutaneous, imaged-guided core breast biopsy is an
      accurate diagnostic alternative to surgical biopsy in women with mammographically
      detected suspicious breast lesions.

PMID- 15035521
TI  - Potential usefulness of biological fingerprints in chest radiographs for
      automated patient recognition and identification.
AB  - RATIONALE AND OBJECTIVES: The purpose of this study was to demonstrate the
      potential usefulness of "biological fingerprints" in chest radiographs for
      automated patient recognition and identification. MATERIALS AND METHODS: Thoracic
      fields, cardiac shadows, the superior mediastinum, lung apices, a part of the
      right lung, and the right lower lung that includes the costophrenic angle were
      used as biological fingerprints in chest radiographs. Each of the biological
      fingerprints in a current chest radiograph was used as a template for
      determination of the correlation value with the corresponding biological
      fingerprint in a previous chest radiograph for patient recognition and
      identification. The overall performance of the method developed was examined in
      terms of receiver operating characteristic curves. RESULTS: Receiver operating
      characteristic curves obtained with different biological fingerprints, except for
      the part of the right lung, indicated a high performance in identifying patients.
      These results showed that a new concept of biological fingerprints in radiologic
      images would be useful in patient recognition and identification. The low
      performance with the part of the right lung seems to be related to a general
      observation that this region does not usually include features unique to a
      specific patient. The performance of the artificial neural networks by use of a
      combination of five biological fingerprints was higher than results obtained with
      each biological fingerprint. CONCLUSION: The use of automated patient
      identification based on biological fingerprints in chest radiographs is promising
      for helping to discover misfiled patient images, especially in a picture
      archiving and communication system environment.

PMID- 15035522
TI  - Using 18-fluoro-2-deoxyglucose positron emission tomography in detecting
      infectious endocarditis/endoarteritis: a preliminary report.
AB  - RATIONALE AND OBJECTIVES: We evaluated the effectiveness of positron emission
      tomography (PET) with 18-fluoro-2-deoxyglucose (FDG) in the detection of
      infectious endocarditis/endoarteritis. MATERIALS AND METHODS: For this study, we
      recruited 6 patients (4 women, 2 men; age range, 35 - 78 years; mean age, 55.8 +/
      16.8 years) who were clinically diagnosed as having infective
      endocarditis/endoarteritis by their echocardiographic findings and by Duke
      criteria. RESULTS: For all 6 patients, we also found increased FDG uptakes in the
      corresponding areas detected in echocardiography. CONCLUSION: FDG-PET appears to
      be a promising tool in diagnosing infective endocarditis/endoarteritis, and
      further prospective studies on a large scale to fully exploit the usefulness of
      FDG-PET for infective endocarditis/endoarteritis are needed.

PMID- 15035523
TI  - Radiology and patient safety.

PMID- 15035524
TI  - A primer on molecular biology for imagers: II. Transcription and gene expression.
AB  - The process of gene expression is complex and highly regulated to ensure that the
      right gene is expressed at the right place, at the right time, and in regulated
      amounts. The cell has multiple levels at which it controls the expression of a
      transcript including gene expression, alternate splicing, and stability of the
      transcript. Alternate splicing to generate different RNA species from a given
      gene and DNA rearrangements where genes are rearranged during cellular
      differentiation (eg, immunoglobulin genes) are additional mechanisms used to
      generate diversity in complex organisms. Epigenetic mechanisms such as
      methylation where CpG-rich islands in the promoter region depending on their
      methylation status can also modulate gene expression. The reader is requested to
      refer to the books, review articles, and web sites for additional information.

PMID- 15035525
TI  - A neuroinformatics database system for disease-oriented neuroimaging research.
AB  - Clinical databases are continually growing and accruing more patient information.
      One of the challenges for managing this wealth of data is efficient retrieval and
      analysis of a broad range of image and non-image patient data from diverse data
      sources. This article describes the design and implementation of a new class of
      research data warehouse, neuroinformatics database system (NIDS), which will
      alleviate these problems for clinicians and researchers studying and treating
      patients with intractable temporal lobe epilepsy. The NIDS is a secured, multi
      tier system that enables the user to gather, proofread, analyze, and store data
      from multiple underlying sources. In addition to data management, the NIDS
      provides several key functions including image analysis and processing, free text
      search of patient reports, construction of general queries, and on-line
      statistical analysis. The establishment of this integrated research database will
      serve as a foundation for future hypothesis-driven experiments, which could
      uncover previously unsuspected correlations and perhaps help to identify new and
      accurate predictors for image diagnosis.

PMID- 15035526
TI  - Should pay in radiology be tied to productivity?

PMID- 15035527
TI  - 25th year of publication of Seminars in Ultrasound, CT and MRI.

PMID- 15035528
TI  - Sixteen-row multislice computed tomography: basic concepts, protocols, and
      enhanced clinical applications.
AB  - Since its introduction, spiral computed tomography (CT) technology underwent a
      continuous and fast technical and clinical development. In particular, spatial
      and temporal resolutions were constantly increased during the last decade. The
      main breakthrough for clinical application was the introduction of multislice
      technology, first with 2-row and 4-row equipment and more recently with 16-row
      scanners. A high-resolution sub-millimeter CT dataset can be acquired easily,
      although with an increased x-ray exposure for the patient. The high speed of the
      scan requires up-to-date and careful protocol optimization. Scanner technology
      and geometry affect image formation procedure and imaging protocols should be
      adapted accordingly. The technical foundations of spiral CT imaging and the main
      scan and reconstruction parameters are described in this article. Updated
      protocols and clinical examples of the latest applications are also discussed.

PMID- 15035529
TI  - Review of radiation issues for computed tomography.
AB  - Over the past three decades, computed tomography (CT) has proven to be central in
      imaging evaluation. Multidetector technology continues to drive practice patterns
      by combining fast scanning with high quality data sets. This has resulted in new
      applications as well as improved use in traditional applications. With this
      recognition has also come the realization that there are potential costs of CT.
      One major cost is the radiation dose. Therefore, in order to begin to assess
      benefits (which are relatively familiar to radiologists) versus costs (which are
      less familiar), the issues related to CT radiation need to be addressed.
      Familiarity with measures of CT radiation and the actual doses delivered by CT
      are important issues as they provide a basis for understanding the potential
      cancer risks from CT radiation. Moreover, these justify development of strategies
      to minimize radiation dose. Strategies include obtaining only necessary CT
      examinations and adjusting the examinations based on scan indication, region
      examined, and patient size. These strategies must also be combined with efforts
      by manufacturers in development and implementation of technology aimed at
      radiation dose management, as well as efforts in research, education, and CT
      standards and regulation. This article reviews the subject of radiation dose with
      multidetector CT technology, including measures of CT radiation, the dose that
      can result from CT examinations, the risks of this amount of radiation, and
      strategies for minimizing CT radiation dose.

PMID- 15035530
TI  - Multidetector-row CT angiography of the aorta and visceral arteries.
AB  - Within recent years, technical developments of multidetector-row CT (MDCT) have
      dramatically changed the application of CT angiography in the assessment of
      abdominal vascular pathologies. The simultaneous acquisition of multiple thin
      collimated slices in combination with enhanced gantry rotation speed offers thin
      slice coverage of extended volumes without any loss in spatial resolution. Using
      4 detector-row CT scanners, the scan volume still has to be restricted and
      focused on dedicated abdominal vessel territories in order to provide high
      spatial resolution (1-2 mm), while 16 detector-row technology now enables full
      abdominal coverage from the diaphragm to the groin with full spatial resolution.
      Therefore, comprehensive CT angiography of the abdomen can be performed without
      the necessity of focusing on any vascular territory. This technique enables the
      evaluation of the whole arterial visceral vasculature (e.g., hepatic vessels,
      mesenteric vessels, renal arteries) and the aortic-iliac axis in a single data
      acquisition.

PMID- 15035532
TI  - Multidetector CT of the spine.

PMID- 15035531
TI  - Multidetector CT urography: techniques, clinical applications, and pitfalls.
AB  - For two decades, computed tomography (CT) has challenged intravenous urography
      (IVU) in the evaluation of urinary tract abnormalities. Compared with IVU, CT is
      more sensitive and specific in the detection and characterization of a variety of
      urinary tract disorders, including renal masses and urolithiasis. The last
      purported advantage of IVU has been its ability to depict subtle and mucosal
      abnormalities of the urothelium. Now, using multidetector CT (MDCT), this
      challenge has been overcome. In this article, we review the current role of MDCT
      urography in the evaluation of the urinary tract.

PMID- 15035533
TI  - CT venography in suspected pulmonary thromboembolism.
AB  - Pulmonary embolism (PE) and deep venous thrombosis (DVT) are a continuum and are
      difficult to diagnose clinically. Combined CT venography and pulmonary
      angiography (CTVPA) is a single examination that combines multidetector CT
      pulmonary angiography (CTPA) and CT venography (CTV) of the abdomen, pelvis, and
      lower extremities, providing "one-stop shopping" for venous thromboembolism
      without additional venipuncture or i.v. contrast, and it adds only a few
      additional minutes to scanning time. CTVPA rapidly and accurately examines the
      deep veins, reveals the presence, absence, and extent of deep venous thrombosis,
      serves as a baseline, and helps guide patient management. Multiple investigators
      have reported a high degree of accuracy when CTV is compared with venous
      ultrasound. There are some pitfalls in image interpretation, especially with
      regard to mixing artifacts, and there are continuing controversies as to exactly
      which parts of the abdomen, pelvis, and legs should be scanned routinely, the
      ideal timing of CTV acquisition relative to contrast injection, and the slice
      thickness and gap, if any, that should be used.

PMID- 15035535
TI  - [Image of the month. "Non-bacterial" thrombotic endocarditis].

PMID- 15035536
TI  - [How I prevent...skin cancers: from information to the telly-belly syndrome].
AB  - During the past decades, the incidence of skin cancers has been on the rise in
      Wallonia as in other regions of similar latitude in the rest of the world.
      Awareness of the population to the dangers of sun exposure and to the benefit of
      early cancer diagnosis is of the upmost importance and undisputed. The impact of
      the information delivered by the media and of the actions initiated by physicians
      is heterogeneous. The positive and unquestionable aspect is hampered if the
      population at risk is not properly targeted. It is also reduced if the problem
      understanding creates a surge in telly-belly syndrome.

PMID- 15035537
TI  - [How I treat...acute pancreatitis: a literature review].
AB  - The article gives an overview of the current status of treatment of AP. The
      different therapeutical strategies are described and compared. The basic
      treatment for severe AP remains a medical therapy in an Intensive Care Unit.
      Surgical therapy is indicated in case of infection of necrotizing areas or other
      severe complications. The potential benefit of antiprotase agents and other new
      molecules is discussed.

PMID- 15035538
TI  - [Clinical case of the month. Acute focal bacterial nephritis].
AB  - Focal acute bacterial nephritis (lobar nephronia) is a localized bacterial
      infection of the kidney that has rarely been described in childhood. It is
      frequently associated to urinary tract anomalies and malformations and its
      diagnosis is based upon renal ultrasonography and computed tomography. In this
      article, we report a case in an 8 year old boy admitted to hospital in a septic
      state.

PMID- 15035539
TI  - [The sleep obstructive apnea and hypopnea syndromes].
AB  - Since two decades, sleep breathing disorders are more wisely recognized by the
      Belgian medical community. Among these, the Obstructive Sleep Apnea Syndrome
      (OSA) is the best known but its frontiers with others syndromes such as the Upper
      Airway Resistance Syndrome (UARS), the Central Sleep Apnea Syndrome (CSAS) or the
      Overlap Syndrome are still matter of discussion. Its causes are plurifactorial,
      and many recent publications draw the attention to its long term effects in the
      cardiovascular and neuropsychiatric fields. This article summarizes the present
      definitions and features associated with OSA, from clinical and
      neurophysiological perspectives, and the different consequences to which
      untreated or underdiagnosed patients are exposed.

PMID- 15035540
TI  - [Hematochromatosis and diabetes].
AB  - Nowadays, haemochromatosis is often diagnosed when the patient is
      monosymptomatic. Diabetes is frequently the first expression of the disease. So,
      it is important to know the clinical and biologic characteristics to evoke
      diagnosis as early as possible. Uncommon presentations request systematic
      screening.

PMID- 15035541
TI  - [Paradox: when a prothrombotic disorder is responsible for an upper
      gastrointestinal bleeding. Case report of hepatoportal sclerosis].
AB  - Variceal bleeding is frequently the initial presentation of a previously unknown
      cirrhosis. Portal hypertension and its complications without liver cirrhosis
      should raise the possibility of presinusoidal portal hypertension, and the
      diagnosis of hepatoportal sclerosis. These patients need to be investigated for
      coagulation disorders. A hypercoagulable state is often associated. Risks and
      benefits of anticoagulation should be further investigated in these patients.

PMID- 15035542
TI  - [New anesthetic and resuscitation techniques in adult cardiac surgery].
AB  - Anesthetic techniques and treatment of cardiac surgery patients have considerably
      evolved over the past twenty years. The demand for cardiac surgical procedures is
      increasing. This demand coincides with a change in the profile of patients
      presenting for surgery, requiring modification in perioperative management
      strategies. Several new anesthetics, related drugs, and technologies have become
      available in recent years that inevitably have made new approaches with patient
      management possible. In parallel to these new developments, there have appeared
      real opportunities to apply novel physiologic and pharmacologic concepts that may
      redefine our clinical practice. Fast-tracking, which emphasizes the major role of
      anesthetic management in postoperative outcome, is one such line of
      investigation. Fast-tracking was first introduced in an attempt to decrease the
      time to tracheal extubation and reduce expensive time in intensive care unit
      areas. Large doses of opioids have been clearly identified as a factor in
      delaying weaning from mechanical ventilatory support after cardiac surgery. Thus,
      early investigations emphasized the importance of limiting the dose of potent
      opioid analgesics during the intraoperative period to achieve early recovery.
      Supplementation with hypnotic drugs allows reduction of the opioid dose, enabling
      earlier extubation without compromising hemodynamic stability. Fast track cardiac
      anesthesia (FTCA) is becoming an accepted practice for perioperative management
      of cardiac surgical patients. FTCA is a key component to successful conduction of
      fast-track cardiac surgery. Also, analgesia management in cardiac surgery is
      becoming more important with the establishment of minimally invasive direct
      coronary artery bypass surgery and fast track management of conventional cardiac
      surgery patients.

PMID- 15035543
TI  - [Xanthomas].
AB  - Xanthomas are cutaneous lesions due to a local accumulation of spumous cells in
      the dermal tissue or the tendons. Histologically, they are characterized by the
      presence of histiocytes, fibroblasts, macrophages and Touton cells full of
      lipids. Xanthomas may be found on any part of the body and are usually yellow
      orange in color. They may or may not be associated to hyperlipoproteinemia which
      may be genetic or secondary. A blood test and a complete physical examination are
      necessary in case such a lesion is discovered. When there is no hyperlipemia some
      types of xanthomas may be associated to rare diseases. Xanthomas are classified
      according to their clinical features.

PMID- 15035544
TI  - [How I investigate...respiratory muscle disorders].
AB  - As for other skeletal muscles, ventilatory muscle performance can be described in
      terms of strength and endurance. Ventilatory muscle strength is measured, for
      example, as the maximum inspiratory and expiratory mouth pressures. It is now a
      routine procedure in many pulmonary function laboratories. Measurements of
      ventilatory muscle endurance are more difficult but two general types of tests
      are used: maximum voluntary ventilation and inspiratory threshold loading.

PMID- 15035545
TI  - [Drug of the month. Rosuvastatin (Crestor)].
AB  - Rosuvastatin (Crestor) has been recently launched in Belgium by AstraZeneca. This
      new statin is indicated for the treatment of primary hypercholesterolaemia or
      combined dyslipidaemia, when changes in dietary habits are insufficient. Direct
      comparative randomised clinical trials with other statins demonstrated that
      rosuvastatin exerts a more favourable impact on lipid profile. When compared on a
      mg basis to other statins, rosuvastatin is associated with a greater reduction in
      total and LDL cholesterol levels and a greater increase of HDL cholesterol
      concentration, with a similar decrease in triglyceride levels. At the usual
      dosage of 10 mg, rosuvastatin allowed to reduce LDL cholesterol below recommended
      target levels for at risk patients among almost 80% of treated individuals in
      phase III clinical trials. If necessary, the daily dosage may be increased to 20
      mg, or up to 40 mg (maximal dose), mostly in case of severe familial
      hypercholesterolaemia. Safety profile is good and similar to that of other
      commercialised statins. Rosuvastatin is currently evaluated in an extensive
      programme of randomised clinical trials (Galaxy programme) in order to
      demonstrate its efficacy in both prevention of atherosclerosis and reduction of
      cardiovascular morbidity and mortality.

PMID- 15035546
TI  - Gamete imprinting: implications for assisted reproductive technologies.

PMID- 15035548
TI  - Leptin and soluble leptin receptor in follicular fluid.
AB  - PURPOSE: Previous studies suggest that follicular fluid leptin levels predict
      successful assisted reproduction. The relationship between intrafollicular leptin
      and the soluble leptin receptor, ovarian hormones, and oocyte quality was
      examined to determine potential factors contributing to this finding. METHODS:
      Follicular fluid leptin, soluble leptin receptor, hormones, and oocyte quality
      were examined in 84 individual follicles from 30 women undergoing in vitro
      fertilization. RESULTS: Follicular fluid leptin and soluble leptin receptor
      levels correlated inversely with each other (r = -0.354; p = 0.001). Follicular
      fluid leptin levels correlated with intrafollicular estradiol (r = 0.42; p <
      0.001), progesterone (r = 0.48; p < 0.001), and androstenedione (r = 0.49; p <
      0.001), whereas soluble leptin receptor levels correlated with activin (r = 0.38;
      p < 0.001) and follistatin (r = 0.35; p < 0.002). There was no relationship
      between follicular fluid leptin or soluble leptin receptor levels and
      pretreatment serum hormone levels, stimulated serum estradiol, follicle number,
      oocyte quality, fertilization, or embryo grade. CONCLUSION: The data demonstrate
      that leptin and the soluble leptin receptor are highly interrelated with each
      other and with other intrafollicular hormones, but not with markers of oocyte
      quality, fertilization, or embryo grade.

PMID- 15035549
TI  - Involvement of interleukin-1 and the interleukin-1 receptor antagonist in in
      vitro embryo development among women undergoing in vitro fertilization-embryo
      transfer.
AB  - PURPOSE: To examine the roles of Interleukin-1 (IL-1) and IL-1 receptor
      antagonist (IL-1ra), in in vitro embryo development and subsequent pregnancy
      outcome. METHODS: Maternal serum utilized to supplement embryo growth in IVF
      cycles was analyzed for the presence of IL-1 cytokines. RESULTS: The maternal
      serum that was utilized to supplement the embryo media was found to have
      measurable amounts of IL-1beta and IL-1ra. CONCLUSIONS: Relative antagonism of
      the IL-1 system was positively associated with embryo development and pregnancy
      outcome.

PMID- 15035547
TI  - Psychogenic infertility--myths and facts.
AB  - PURPOSE: The hypothesis of this review is that the role of psychological factors
      as the sole cause of infertility is generally overrated. METHODS: A review is
      given of studies concerning the influence of psychological factors on the
      development of infertility. RESULT: A prevalence of psychogenic infertility of 10
      15 per cent must be discussed critically. A value of approximately 5 per cent is
      more realistic. Equating unexplained infertility with psychogenic infertility is
      not justified. A definition of psychogenic infertility according to the German
      guidelines Psychosomatics in Reproductive Medicine is presented. Spontaneous
      pregnancies following adoption or the decision to remain childless are the
      absolute exception. The association of stress and infertility in humans is still
      unclear. For many women the effect of infertility and notably of medical therapy
      is a considerable emotional stress. This may make psychosocial counseling
      necessary in certain cases. CONCLUSIONS: An exclusive
      psychological/psychodynamical point of view on the complexity of infertility is
      as inadequate as a strictly somatic point of view. Infertility should always be
      treated as a psychosomatic entirety.

PMID- 15035550
TI  - Human oocyte maturity in vivo determines the outcome of blastocyst development in
      vitro.
AB  - PURPOSE: To date, the impact of oocyte maturity at aspiration on the blastocyst
      formation in vitro has not been fully evaluated. This study was undertaken to
      assess the influence of oocyte maturity in patients undergoing in vitro
      fertilization and blastocyst transfer program. METHODS: A total of 1278 oocytes
      derived from 147-IVF cycles were retrospectivly analyzed. Oocyte maturity was
      graded on a scale from 1 to 5 based on the morphology of the ooplasm, cumulus
      mass, corona radiata, and membrana granulosa cells. RESULTS: Mature oocytes
      yielded the highest fertilization rates. Although the cleavage rates were similar
      in both groups, the percentage of poor morphology, day-3 embryos from the
      nonmature-oocyte group was significantly higher than from the mature-oocyte group
      (54.7% vs. 15.5%, P < 0.001). Although good morphology, day-3 embryos were
      collected from nonmature oocytes, the incidence of these embryos developing to
      the blastocyst stage was significantly less than from mature oocytes (33.3% vs.
      71.2%, P < 0.001). Although blastocyst stage embryos were collected from
      nonmature oocytes, the incidence of these embryos developing to the top-scoring
      blastocysts was significantly less than from mature oocytes (58.3% vs. 89.5%, P <
      0.001). CONCLUSIONS: These phenomena suggest that oocyte maturity produced in
      vivo determine the fertilization potential and subsequent blastocyst quality in
      vitro.

PMID- 15035551
TI  - Administration of beta2-adrenergic agonists during the peri-implantation period
      does not improve implantation or pregnancy rates in intracytoplasmic sperm
      injection (ICSI) cycles.
AB  - PURPOSE: The objective of the present investigation was to determine implantation
      and pregnancy rates in patients undergoing ICSI and treated with beta2-adrenergic
      agonists, considering the uterine-relaxing action of these agents. METHODS: A
      total of 225 women undergoing ICSI at the Center for Human Reproduction, "Sinha
      Junqueira" Maternity Foundation, entered the study. Patient participation in each
      group was random, by drawing lots, using a randomization table previously
      elaborated for the study (2:2:1). The group I (90 women) received 10 mg of
      terbutaline daily for 15 days starting on the day of oocyte retrieval; group II
      (90 women) received 20 mg of ritodrine daily during the same period of time as
      group I; group III (45 patients) received no treatment and was used as control.
      The evaluation was interrupted in 3 patients of group I and in 30 patients of
      group II because of a high incidence of side effects. RESULTS: Pregnancy,
      implantation, and miscarriage rates were not significantly different (p > 0.05)
      between the three groups: 29.88%, 13.25%, and 26.9% for group I; 33.33%, 17.5%,
      and 10.0% for group II; 28.88%, 15.07%, and 15.38% for group III, respectively.
      CONCLUSIONS: The results of this study do not support the routine use of beta2
      adrenergic agonists during the peri-implantation period in assisted reproductive
      technology cycles.

PMID- 15035552
TI  - Effects of vaginal progesterone administration starting on the day of oocyte
      retrieval on pregnancy rates.
AB  - PURPOSE: Vaginal progesterone administration starting on the day of oocyte
      retrieval induced a decrease in uterine contraction frequency on the day of
      embryo transfer (ET) as compared with preovulatory values. Uterine relaxation
      before ET is likely to improve outcome by avoiding displacement of the embryo
      from the uterine cavity (Fanchin, Righini, de Ziegler, Oliviennes, Ledee,
      Frydman: Fertil Steril 2001;75:1136-1140). The objective of the present study was
      to determine whether the early use of vaginal progesterone on the day of oocyte
      retrieval may alter the embryo implantation and pregnancy rates. METHODS: A total
      of 103 patients were submitted for ovarian stimulation with GnRH-a and
      recombinant FSH (Puregon, Organon) for the application of invasive assisted
      reproduction techniques (ICSI). The patients were divided into two groups in a
      prospective and randomized manner: Group A (n = 51) where application of vaginal
      progesterone started (Utrogestan, Besins International) at the dose of 400 mg
      from the evening of the day of oocyte retrieval, and Group B (n = 52) started to
      apply vaginal progesterone at the same dose but from the evening of embryo
      transfer (2nd day). RESULTS: The age of Group A patients (34.2 +/- 4.6) was
      similar (p = 0.50) to that of Group B patients (34.8 +/- 4.9). The number of
      oocytes retrieved and at metaphase II from Group A patients (10.6 +/- 6.9 and 7.8
      +/- 6.0; respectively) did not differ significantly (p = 0.84 and p = 0.49,
      respectively) from the number of oocytes retrieved and metaphase II from Group B
      patients (10 +/- 5.6 and 6.7 +/- 4.7, respectively). Also, there was no
      difference (p = 0.48) in number of embryos transferred to Group A patients (2.7
      +/- 0.8) versus Group B patients (2.7 +/- 0.9). Embryo implantation and pregnancy
      rates for Group A patients (12.6 and 27.4%, respectively) were equal (p = 0.98
      and p = 1.0, respectively) to those for Group B patients (13.4 and 28.8%,
      respectively). CONCLUSION: Vaginal progesterone at the dose of 400 mg started on
      the day of oocyte retrieval did not increase implantation or pregnancy rates when
      compared to the same dose started on the day of embryo transfer.

PMID- 15035553
TI  - Early hormonal markers of pregnancy outcome after in vitro fertilization and
      embryo transfer.
AB  - PURPOSE: To investigate the relative power of HCG, estradiol, and progesterone
      determinations in the prediction of pregnancy outcome after IVF. These prognostic
      hormonal factors were studied as single and combined predictors. METHODS: Serum
      concentrations of beta-HCG, progesterone, and estradiol were measured 12-13 days
      after embryo transfer (study point 1) and 7 days later (study point 2) in a
      series of 20 consecutive infertile patients having a first-trimester spontaneous
      clinical abortion after an IVF-embryo transfer cycle. As a control group (n =
      60), the next three IVF-embryo transfer cycles resulting in an ongoing pregnancy
      after each miscarried IVF cycle in our assisted reproduction program was used.
      The discrimination attained between the two study groups (ongoing pregnancies and
      miscarriages) was evaluated by logistic regression and receiver operating
      characteristic (ROC) curve analysis. RESULTS: Mean hormone concentrations at
      study points 1 and 2 were higher in the ongoing pregnancy than in the abortion
      group. Regarding pregnancy outcome the percentage increment of HCG serum levels
      (> or = 1321%), with an accuracy (predictive value of pregnancy outcome) of 81.2%
      (sensitivity 98%, specificity 50%), had the best prognostic reliability but no
      significant differences were found when this parameter was compared with the
      predictive value of HCG concentration (> or = 72 IU/l) at study point 1
      (diagnostic accuracy 80.5%; sensitivity 70%; specificity 80%). When ROC analysis
      was used, the best predictor of ongoing pregnancy according to the AUC(ROC) was
      HCG concentration at study point 2 but again no significant differences were
      found when this parameter was compared with the predictive value of HCG serum
      levels at study point 1. A multiple marker strategy did not help distinguish
      viable from nonviable pregnancies. CONCLUSION: A single, early (days 12-13 after
      embryo transfer) HCG quantitative serum measurement in IVF cycles not only is
      diagnostic but also has good predictive value for pregnancy outcome.

PMID- 15035554
TI  - Prevention and management of osteoporosis.
AB  - Osteoporotic fractures are a growing public health issue. Prevention and
      management of osteoporosis are becoming increasing concerns especially as the
      number of individuals reaching old age continues to grow, euphemistically "as the
      baby boomers come of age." Identification of those individuals who are at an
      increased risk for fracture is important for planning and implementing proper
      prevention and management strategies. Although diagnostic tools are available for
      identifying decreased bone density and effective therapies exist for treatment of
      existing disease, clinical guidelines based on cost-effective approaches are
      still needed to more accurately identify which patients would benefit from early
      intervention (either prevention or treatment).

PMID- 15035555
TI  - Mechanisms of osteoporosis therapy: a bone strength perspective.
AB  - Bone density and bone quality have been cited as primary contributors to bone
      strength. Although a precise definition of bone quality remains elusive,
      characteristics other than bone density, such as trabecular architecture, bone
      turnover, and mineralization of the bone matrix may be important factors in the
      pathophysiology of osteoporosis and the mechanisms that underlie fracture. Small
      increases in bone mineral density (BMD) have resulted in greater than expected
      reductions in the risk of fracture. Indeed, therapeutic increases in BMD account
      for only a small proportion of the reduction in fracture risk. This observation
      suggests that the size, shape, distribution, and composition of bone may have
      important effects on bone strength and, therefore, the risk of fracture.

PMID- 15035556
TI  - Pathogenesis of osteoporotic hip fractures.
AB  - Osteoporosis is characterized late in the course of the disease by an increased
      risk of fracture, particularly in the elderly. It occurs in both sexes, affecting
      approximately 8 million women and 2 million men aged > or = 50 years (1). While
      low bone density is a predictor of fractures, it is not the only determinant of
      fracture risk. Other factors include advanced age, altered bone quality, a
      personal or family history of falls, frailty, poor eyesight, debilitating
      diseases, and high bone turnover. A diet with sufficient calcium and vitamin D is
      important to minimize bone loss and, along with regular exercise, to maintain
      muscle strength. Bisphosphonates have been shown to reduce the risk of hip
      fracture. For elderly patients, the use of hip protectors may be used as a
      treatment of last resort. Regardless of the age of the patient, individual
      patient risk factors must be considered to target appropriate treatment and
      prevent fracture.

PMID- 15035557
TI  - Speech perception with a cochlear implant used in conjunction with a hearing aid
      in the opposite ear.
AB  - The aim of this study was to determine the improvement in speech recognition
      provided by a cochlear implant (CI) in conjunction with a hearing aid (HA) in the
      opposite ear. The study was a retrospective cohort study in the context of a
      university teaching hospital CI programme. Seven CI patients who still use their
      HA in the opposite ear were tested. The scores with the CI alone and the CI in
      conjunction with an HA were evaluated by using three speech perception tests in
      quiet (Freiburger Numbers. Freiburger Monosyllables, and Innsbrucker Sentence
      Test). In the majority of tests and subjects. the CI alone performed better than
      the HA alone, and the bimodal (CI + HA) condition was superior to the CI alone.
      On the sentence test, the patients as a group improved from 47 96% (mean: 79%; CI
      alone) to 50-100% (mean: 88.1%; CI + HA, pv < 0.05). With the more difficult
      monosyllable test, the scores improved from 15-52% (mean: 37.2%; CI alone) to 15
      82% (mean: 48.7%; CI + HA, p < 0.05). On the numbers test. scores increased from
      65-98% (mean: 83%; CI alone) to 75-98% (mean: 88.7%; CI + HA, p < 0.05). All
      patients in this study were implanted in the poorer ear. The results of the
      present study suggest the advantage of CI usage in conjunction with an HA in the
      opposite ear.

PMID- 15035559
TI  - A time-frequency feature extraction scheme for the automated detection of
      binaural interaction in auditory brainstem responses.
AB  - The binaural interaction component (BIC), the difference between the summed
      monaurally evoked potentials of each ear and the binaurally evoked brainstem
      potentials, has been shown to be related to directional hearing. However, the
      detection of the beta-peak as the most consistent part of the BIC is often
      difficult. Furthermore, there is no clearly defined signal feature characterizing
      the difference between the monaurally and the binaurally evoked brainstem
      responses. A closer look at the signals shows that amplitude differences as well
      as latency differences and variations in wave V slopes could be the reason for
      the formation of a beta-peak. Using a time-scale feature extraction scheme, we
      were able to define a signal feature (morphological local discriminant bases
      (MLDB) coefficient 1) that accounts for the difference between the sum of the
      monaurally and binaurally evoked brainstem potentials. With use of this signal
      feature, reliable automated detection of differences between monaurally and
      binaurally evoked potentials is possible. As coefficient 1 replicates the
      behaviour of subjective measurements as well as of the BIC measurements, it can
      also be seen as a correlate of binaural interaction. With use of this signal
      feature, it is possible to judge from a given binaurally evoked potential whether
      it contains information on binaural interaction or not, without comparing it to
      the sum of the monaurally evoked brainstem responses Consequently, binaural
      interaction can be assessed by one, instead of three, measurements by using the
      method described in this paper.

PMID- 15035558
TI  - Laterality of vestibular evoked myogenic potentials.
AB  - To clarify the laterality of acoustically evoked vestibulocollic reflexes with a
      short latency (vestibular evoked myogenic potentials, VEMPs). responses on the
      bilateral sternocleidomastoid muscles (SCMs) to unilateral acoustic stimulation
      were studied. Twenty-one healthy volunteers were enrolled. Surface electrodes
      were placed on the upper half of each SCM (active) and on the lateral end of the
      upper sternum (reference). Clicks and 500-Hz tone-bursts (95dB nHL) were used.
      All subjects showed positive-negative biphasic responses on the ipsilateral SCM
      by clicks and tone-bursts. Click-stimulation of 41 of the 42 ears did not evoke
      any response on the contralateral SCM. However, in one ear, positive-negative
      biphasic responses were evoked on the contralateral SCM. Recordings on the
      contralateral SCM by tone-bursts showed no response in 32 ears, small positive
      negative biphasic responses in four ears, and small negative-positive biphasic
      responses in six ears. These findings show that VEMPs are ipsilateral-dominant,
      basically consistent with the hypothesis that they are of saccular origin.

PMID- 15035560
TI  - Modelling the risk of noise-induced hearing loss among military pilots.
AB  - Noise is a significant risk factor in aviation, especially in military aviation.
      Even though our earlier studies have shown that the risk of noise-induced hearing
      loss (NIHL) among military pilots is small and the monitoring of their hearing is
      effective, we still need to develop methods of assessing the risk of NIHL more
      effectively at both the general and individual levels. In addition, many other
      risk factors are considered to contribute to the development of hearing
      impairment. The novel NoiseScan data management system enables assessment of the
      risk of developing hearing impairment on the basis of known risk factors. This
      study investigates the risk of hearing impairment among Finnish Air Force pilots
      using reasonably accurate noise exposure data and other risk factors for hearing
      impairment. This risk is also compared with that of industrial workers, whose
      risk followed the ISO 1999 prediction. Hearing among Finnish military pilots
      turned out to be better than predicted by the ISO 1999 model. The industrial
      workers had a larger number of risk factors than the pilots. Owing to the small
      number of risk factors, the hearing of pilots corresponds to approximately the
      80th percentile, being 9-13 dB better than the 50th percentile obtained with the
      industrial population.

PMID- 15035561
TI  - The Speech, Spatial and Qualities of Hearing Scale (SSQ).
AB  - The Speech, Spatial and Qualities of Hearing Scale (SSQ) is designed to measure a
      range of hearing disabilities across several domains. Particular attention is
      given to hearing speech in a variety of competing contexts, and to the
      directional, distance and movement components of spatial hearing. In addition,
      the abilities both to segregate sounds and to attend to simultaneous speech
      streams are assessed, reflecting the reality of hearing in the everyday world.
      Qualities of hearing experience include ease of listening, and the naturalness,
      clarity and identifiability of different speakers, different musical pieces and
      instruments, and different everyday sounds. Application of the SSQ to 153 new
      clinic clients prior to hearing aid fitting showed that the greatest difficulty
      was experienced with simultaneous speech streams, ease of listening, listening in
      groups and in noise, and judging distance and movement. SSQ ratings were compared
      with an independent measure of handicap. After differences in hearing level were
      controlled for, it was found that identification, attention and effort problems,
      as well as spatial hearing problems, feature prominently in the disability
      handicap relationship,. along with certain features of speech hearing. The
      results implicate aspects of temporal and spatial dynamics of hearing disability
      in the experience of handicap. The SSQ shows promise as an instrument for
      evaluating interventions of various kinds, particularly (but not exclusively)
      those that implicate binaural function.

PMID- 15035562
TI  - Interaural asymmetry of hearing loss, Speech, Spatial and Qualities of Hearing
      Scale (SSQ) disabilities, and handicap.
AB  - A series of comparative analyses is presented between a group with relatively
      similar degrees of hearing loss in each ear (n = 103: symmetry group) and one
      with dissimilar losses (n = 50: asymmetry group). Asymmetry was defined as an
      interaural difference of more than 10dB in hearing levels averaged over 0.5. 1, 2
      and 4kHz. Comparison was focused on self-rated disabilities as reflected in
      responses on the Speech, Spatial and Qualities of Hearing Scale (SSQ). The
      connections between SSQ ratings and a global self-rating of handicap were also
      observed. The interrelationships among SSQ items for the two groups were analysed
      to determine how the SSQ behaves when applied to groups in whom binaural hearing
      is more (asymmetry) versus less compromised. As expected, spatial hearing is
      severely disabled in the group with asymmetry; this group is generally more
      disabled than the symmetry group across all SSQ domains. In the linkages with
      handicap, spatial hearing, especially in dynamic settings, was strongly
      represented in the asymmetry group, while all aspects of hearing were moderately
      to strongly represented in the symmetry group. Item intercorrelations showed that
      speech hearing is a relatively autonomous function for the symmetry group,
      whereas it is enmeshed with segregation, clarity and naturalness factors for the
      asymmetry group. Spatial functions were more independent of others in the
      asymmetry group. The SSQ shows promise in the assessment of outcomes in the case
      of bilateral versus unilateral amplification and/or implantation.

PMID- 15035563
TI  - Living with cochlear implants: experiences of 17 adult patients in Sweden.
AB  - The aim of this grounded theory study was to gain a deeper understanding of what
      it means to profoundly deaf adults to undergo cochlear implantation and their
      experience of living with it daily. The aim of grounded theory is theorizing,
      i.e. constructing from data an explanatory scheme that systematically integrates
      various concepts and their relationships. The study group consisted of 10 women
      and seven men (age 29-78 years; mean age 56.5 years), who had had their cochlear
      implant (CI) for between 1 and 12 years (mean 4.1 years). Open taped interviews
      were carried out and analysed. The core category, coming back to life, defines a
      psychological process basic to existence, elucidating the existential value of
      hearing, including perceived harmony in life and becoming a part of the living
      world as important dimensions. This core concept is related to four additional
      emerging categories in a temporal order. Preventing disappointment concerns the
      decision to undergo the operation governed by the conception of having nothing to
      lose combined with low expectations of successful outcomes. Waiting in silence
      relates to experiences during the postoperative period such as sensations from
      the head and uncertainty about the outcome of surgery. The 'switch-on' was
      experienced as a significant revelation and the emotionally loaded starting point
      for their coming back to life. Retraining the brain concerns the lengthy
      audiovisual learning process. finally resulting in 'a car sounding like a car'.
      Strengthening of self-worth concerns psychosocial outcomes of cochlear
      implantation, in terms of less dependency and increased social participation. CIs
      provide a substantial improvement in the quality of life, as identified in the
      emerging generic process of coming back to life, fundamental for psychological
      existence.

PMID- 15035564
TI  - Particle deposition of therapeutic aerosols in the nose and paranasal sinuses
      after transnasal sinus surgery: a cast model study.
AB  - BACKGROUND: The topical administration of steroids or antibiotics to the nose and
      the sinuses is one of the important postsurgical therapies of endoscopic sinus
      surgery (ESS). METHODS: To investigate the effective deposition of aerosols in
      the paranasal sinuses after ESS, we restored the human nasosinus model that
      underwent ESS and studied the particle depositions on the ostiomeatal complex
      (OMC), maxillary, and ethmoid sinuses quantitatively. RESULTS: A 45 degree nozzle
      insertion angle significantly increased the particle depositions more than the 30
      degree angle (p < 0.05). A computer simulation-assisted analysis shows that the
      inertial deposition at OMC increased with a nozzle angle of 45 degrees versus 30
      degrees. The particles with 5.63 microm in diameter significantly deposit on OMC
      and maxillary sinus compared with the particles with 16.37 microm (p < 0.05).
      CONCLUSION: The topical administration of drugs to the paranasal sinuses
      postoperatively must be performed in consideration with aerodynamics of aerosols.

PMID- 15035566
TI  - Objective assessment of lower airway involvement in chronic rhinosinusitis.
AB  - BACKGROUND: When associated with lower airway involvement, the morbidity and the
      cost of chronic rhinosinusitis (CRS) can increase. The aim of this prospective
      study was to assess the clinical and radiological characteristics of the upper
      airways in CRS patients scheduled for functional endoscopic sinus surgery and to
      correlate these findings with the functional changes of the lower airways.
      METHODS: Twenty-five adult patients with CRS were subjected to clinical and
      endoscopic assessments, computed tomography scan, and allergic assessments using
      validated scoring systems. Lower airways were assessed by clinical history,
      pulmonary function test, histamine bronchial provocation test, and chest x rays.
      RESULTS: Sixty percent of CRS patients were shown to have associated lower airway
      involvement, i.e., 24% had asthma and 36% had small airway disease (SAD). Nasal
      congestion and nasal polyps were the most common clinical findings in both of
      these subgroups of patients. In addition, there was a negative correlation
      between computed tomography scan findings of the sinuses and the obstructive
      parameters on pulmonary function test in SAD but not in the asthma subgroup.
      CONCLUSION: These results showed that different kinds of lower airway involvement
      frequently could be associated with CRS. Some are manifest such as asthma and
      some are hidden such as SAD and histamine bronchial hyperresponsiveness.

PMID- 15035565
TI  - Fungal DNA is present in tissue specimens of patients with chronic
      rhinosinusitis.
AB  - BACKGROUND: It has been postulated that fungal organisms might represent the
      immunologic target initiating and maintaining the disease process in patients
      with chronic rhinosinusitis (CRS). The presence of fungi in nasal mucus has been
      established by different groups, but so far it has not been shown how the immune
      system could even recognize such extramucosal--extracorporal--fungal targets. The
      aim of this study was to determine whether fungal DNA is present in tissue
      specimens taken from patients with polypoid CRS. METHODS: Twenty-seven surgical
      specimens were collected from patients suffering from CRS. Fifteen surgical
      specimens from healthy ethmoidal mucosa served as controls. A second set of
      controls consisted of five surgical specimens of acoustic neuroma, which were
      included to rule out contamination within the protocol. All paranasal tissue
      samples were treated and rinsed carefully with a solution of Dithiothreitol to
      digest any nasal mucus and ensure that only tissue was examined. A highly
      sensitive two-step polymerase chain reaction (PCR) was applied to detect fungal
      DNA, using one universal primer for unspecific detection of fungal DNA and a
      second primer pair specific for Alternaria. RESULTS: Fungal DNA was detected in
      all 27 CRS specimens equally with both PCR primers. Controls from healthy
      paranasal mucosa were positive using the panfungal primers in 10 of 15 cases but
      were all negative for Alternaria DNA. PCR was negative for fungal DNA in all five
      neuroma specimens. CONCLUSIONS: Fungal DNA can be detected within sinonasal
      tissue specimens of patients suffering from CRS. These findings need to be
      discussed with respect to the proposed hypothesis of the immune system
      recognizing extramucosal organisms and initiating an immune response in
      sensitized patients.

PMID- 15035567
TI  - Treatment of allergic rhinitis during pregnancy.
AB  - BACKGROUND: Allergic rhinitis (AR) affecting approximately 20-30% of women in
      childbearing age can be considered one of the most common group of medical
      conditions that complicate pregnancy. AR with symptoms of nasal obstruction,
      sneezing, and itching may require pharmacotherapy. However, there are concerns
      regarding the safety of different available agents that can be used during
      pregnancy with respect to both maternal and fetal well being. CONCLUSIONS: The
      best first-line approach in the management of AR is avoidance of allergens. If
      environmental modification is ineffective, then the pharmacologic agents should
      be chosen. For symptoms of rhinorrhea, sneezing, or itching, intranasal cromolyn,
      with its excellent safety profile, should be considered as first-line therapy. If
      cromolyn is ineffective or poorly tolerated, first-generation (e.g.,
      chlorpheniramine and tripelennamine) and second generation (e.g., cetirizine and
      loratadine) antihistamines can be given. Intranasal steroids (e.g.,
      beclomethasone dipropionate, and budesonide) can be added to first-line therapy
      especially for severe nasal obstruction. There are no epidemiological studies
      with newer intranasal steroids (e.g., flunisolide, triamcinolone acetonide,
      fluticasone propionate, and mometasone furoate) during the first trimester of
      pregnancy. Immunotherapy has not proven to be teratogenic and is clinically
      useful in improving symptoms. Oral and topical decongestants can be considered as
      second-line therapy, for short-term relief, when no safer alternative is
      available.

PMID- 15035568
TI  - Local and systemic administration of corticosteroids in the treatment of
      olfactory loss.
AB  - BACKGROUND: The aim of this study was to evaluate the benefit of patients with
      olfactory dysfunction from local (group A) or systemic (group B) administration
      of corticosteroids. METHODS: This unblinded study was conducted at a smell and
      taste outpatient clinic of an institutional referral center. Patients with
      olfactory loss after infections of the upper respiratory tract, patients with
      apparent sinonasal disease, and patients suffering from "idiopathic" smell loss
      were included. Effects of mometasone nasal spray, administered for 1-3 months,
      were studied in 37 patients. In addition, effects of oral prednisolone were
      analyzed in 55 patients who received decreasing doses over 21 days, starting with
      a dose of 40 mg. Olfactory function before and after treatment was measured.
      RESULTS: Although odor identification scores tended to increase (p = 0.05),
      mometasone nasal spray did not significantly improve olfactory function, when
      looking at the entire group of patients or when analyzing the three diagnostic
      categories separately. In contrast, after systemic administration of
      corticosteroids, improvement of olfactory function was seen over all diagnostic
      categories (p < 0.001). Interestingly, olfactory function also improved in
      patients diagnosed with olfactory loss after upper respiratory tract infection (p
      = 0.05) and in patients initially diagnosed with "idiopathic," olfactory
      dysfunction (p = 0.008). CONCLUSION: In many patients, local application of
      corticosteroids appears to have little or no positive effect on olfactory
      dysfunction, especially when considering long-term changes. Duration of disease,
      the patient's age/sex, or the presence of parosmia does not appear to predict the
      response to therapy with corticosteroids.

PMID- 15035569
TI  - The low skull base: an invitation to disaster.
AB  - BACKGROUND: Knowledge of anatomy including variations observed with endoscopy or
      computerized tomography scan is vital to the performance of safe endoscopic sinus
      surgery. The lower-than-normal skull base/cribriform plate is an anatomic
      variation, which if not noted preoperatively, can lead to entrance into the brain
      causing major injury. METHODS: Four case studies of chronic rhinosinusitis are
      reviewed in which either the whole anterior skull base or the cribriform plate is
      lower than usual and major complications occurred. RESULTS: All four cases had
      unilateral or bilateral entrance into the skull base/cribriform plate of the
      brain in the biopsy specimen, postoperative cerebrospinal fluid leak, and/or
      brain hemorrhage. One patient died from the injury, three patients had marked
      neurological sequelae. The low skull base and its meaning for the surgeon is
      discussed at length. CONCLUSION: The preoperative anatomy as determined by
      endoscopy and computerized tomography scanning has to be identified. Variations
      or abnormalities should be noted and taken into consideration for preoperative
      and operative planning. Failure to note skull base or cribriform anatomy
      variations may lead to brain entrance, injury, and death.

PMID- 15035570
TI  - Nasal dyspnea: the place of rhinomanometry in its objective assessment.
AB  - BACKGROUND: "Nasal dyspnea" describes the common symptom of nasal airway
      obstruction, which usually is assessed subjectively. Objective, quantitative
      methods are needed to assess the nasal airway adequately. METHODS:
      Rhinomanometry, in use for >30 years, was reviewed. RESULTS: No other symptom of
      rhinitis can be measured as objectively and accurately as that of nasal
      obstruction. Determinations by rhinomanometry are precise, usually better than
      5%. Most rhinomanometers meet the published requirements of standardization by
      the International Rhinologic Society. An improved system for scoring symptoms of
      nasal dyspnea is suggested. Rhinomanometry, potentially a gold standard for the
      objective measurement of obstructed nasal airflow, has a proven place in the
      selection of patients for septal and nasal valve reconstruction. CONCLUSION:
      Recommendations are given for extension of the standards to account for the near
      universal computerization of equipment. Miniaturization of equipment will
      increase its application to trials of drugs for rhinitis.

PMID- 15035571
TI  - Immediate correction of nasal septum dislocation in newborns: long-term results.
AB  - BACKGROUND: The authors present the results of a long-term follow-up after an
      immediate reduction of nasal septum luxation in newborn infants. METHODS: Forty
      nine children, who underwent a treatment for septal dislocation within 48 hours
      after birth, were reexamined in 2002 at a mean age of 13.2 years (range, 10-17
      years). The examination was performed through inspection of the nasal pyramid,
      anterior rhinoscopy, nasal endoscopy, rhinomanometry, and acoustic rhinometry.
      RESULTS: Anatomic and functional findings showed satisfactory results for all
      children affected by septal dislocation. Three patients presenting irreplaceable
      septal-pyramidal deformity had no spontaneous reduction at 7-, 10-, and 11-year
      follow-ups and thus required surgical intervention. CONCLUSIONS: Considering the
      simplicity and the safety of the reduction maneuver, the importance of early
      detection and treatment of neonatal septal dislocations is stressed. This is the
      longest follow-up study reported in international literature to date.

PMID- 15035572
TI  - A post-traumatic nasal epidermoid: an endoscopic approach.
AB  - BACKGROUND: Epidermoid cysts are thought to arise as a result of implantation of
      epidermal cells into the deeper dermal elements. These cysts have previously been
      described postsurgery but not after accidental nasal trauma. METHODS: We outline
      a case of a nasal epidermoid occurring post-blunt nasal trauma and its subsequent
      excision. RESULTS: The lesion was excised successfully endoscopically without
      recourse to an open technique. CONCLUSION: We describe, for the first time, the
      successful intranasal removal of a post-traumatic epidermoid cyst via an
      endoscopic approach.

PMID- 15035573
TI  - Nasal pyriform aperture stenosis in adults.
AB  - BACKGROUND: Congenital nasal pyriform aperture stenosis (CNPAS) leading to
      respiratory insufficiency in infants has been well documented. Nevertheless, the
      nasal pyriform aperture stenosis (NPAS) entity in adulthood has not been
      discussed at all. The normative data of the width of the pyriform aperture, which
      has not been revealed before, is necessary for evaluation of the adult subjects
      with nasal bony inlet stenosis. The aim of this study was to define the normative
      data about the pyriform aperture width measured in 80 adult subjects with
      paranasal sinus symptoms without nasal obstruction and, additionally, to report
      the surgical results of two representative cases with NPAS. METHODS: The nasal
      bony inlet width measurements have been achieved in axial computerized
      tomographic sections to establish normative data. The maximal distance between
      the nasal processes of the opposite maxillary bones was measured. Two adult males
      complaining of nasal obstruction with overt pyriform aperture stenosis were
      treated surgically via a sublabial approach. RESULTS: The mean widest dimension
      of the nasal pyriform aperture was 21.6 +/- 2.2 mm (range, 17-27 mm) in 80 adult
      subjects. This width was 21.9 +/- 2.1 mm (range 18-27 mm) in men and 21 +/- 2.2
      mm (range, 17-26 mm) in women. Stenotic pyriform apertures in two patients were
      widened surgically by drilling via a sublabial approach from 12 and 10 mm to 24
      and 21 mm, respectively. CONCLUSION: NPAS should be included in the list of
      differential diagnosis for nasal obstruction. Surgical enlargement using a
      sublabial approach was found an effective and adequate treatment in pyriform
      aperture stenosis.

PMID- 15035574
TI  - Sherman sign predicts aortic regurgitation. From foot fetish to clinical pearl.

PMID- 15035575
TI  - Assessment and counseling of older drivers.

PMID- 15035576
TI  - Food-drug interactions: Careful drug selection and patient counseling can reduce
      the risk in older patients.
AB  - Older patients are at high risk for food-drug Interactions. These patients are
      commonly on multiple medications for chronic medical conditions. Age-related
      physiologic changes affecting drug absorption, distribution, metabolism and
      excretion, as well as drug action occur in these patients, and this variability
      in drug action may be further potentiated by interactions with foods. The most
      prominent interactions involve drug absorption from the GI tract; however
      alterations in drug metabolism are also highly significant. Food-drug
      interactions have been reported amongst a wide range of therapeutic drug classes,
      including, but not limited to, cardiovascular, psychoactive, anti-infective,
      endocrinologic, gastrointestinal, and respiratory agents. Health care providers
      can prevent significant drug therapy-related morbidity by carefully selecting
      drugs for geriatric patients and thoroughly counseling these patients about drug
      interactions with the foods they eat.

PMID- 15035577
TI  - Papules with minimal perilesional erythema. Intermittently painful, yellow-white
      "bumps" drain chalky substance.

PMID- 15035578
TI  - Evaluating the effects of medical disorders on sleep in the older patient.
AB  - Older adults often experience sleep disturbances, but most fall to mention these
      sleep problems to their physicians out of a false belief that sleep troubles are
      just a consequence of getting older. On the contrary, sleep complaints in older
      adults are often the result of medical or psychiatric illnesses that can be
      managed, resulting in a return to restful sleep. It is important for physicians
      and patients to communicate about sleep disturbances, and for physicians to ask
      appropriate questions targeted at identifying the underlying cause of the sleep
      problem, particularly in patients with chronic medical conditions.

PMID- 15035579
TI  - How to help demented or psychotic patients await a psychiatric consultation.

PMID- 15035580
TI  - Keep it clean and do the research.

PMID- 15035581
TI  - NGWA Interest Group report from Orlando.

PMID- 15035582
TI  - Geochemical imaging of flow near an artificial recharge facility, Orange County,
      California.
AB  - Critical for the management of artificial recharge operations is detailed
      knowledge of ground water dynamics near spreading areas. Geochemical tracer
      techniques including stable isotopes of water, tritium/helium-3 (T/3He) dating,
      and deliberate gas tracer experiments are ideally suited for these
      investigations. These tracers were used to evaluate flow near an artificial
      recharge site in northern Orange County, California, where approximately 2.5 x
      10(8) m3 (200,000 acre-feet) of water are recharged annually. T/3He ages show
      that most of the relatively shallow ground water within 3 km of the recharge
      facilities have apparent ages < 2 years; further downgradient apparent ages
      increase, reaching > 20 years at approximately 6 km. Gas tracer experiments using
      sulfur hexafluoride and xenon isotopes were conducted from the Santa Ana River
      and two spreading basins. These tracers were followed in the ground water for
      more than two years, allowing subsurface flow patterns and flow times to be
      quantified. Results demonstrate that mean horizontal ground water velocities
      range from < 1 to > 4 km/year. The leading edges of the tracer patch moved at
      velocities about twice as fast as the center of mass. Leading edge velocities are
      important when considering the potential transport of microbes and other "time
      sensitive" contaminants and cannot be determined easily with other methods. T/3He
      apparent ages and tracer travel times agreed within the analytical uncertainty at
      16 of 19 narrow screened monitoring wells. By combining these techniques, ground
      water flow was imaged with time scales on the order of weeks to decades.

PMID- 15035583
TI  - Numerical implementation of a backward probabilistic model of ground water
      contamination.
AB  - Backward location and travel time probabilities can be used to characterize known
      and unknown sources or prior positions of ground water contamination. Backward
      location probability describes the position of the observed contamination at some
      time in the past; backward travel time probability describes the amount of time
      prior to observation that the contamination was released from its source or was
      at a particular upgradient location. The governing equation for backward
      probabilities is the adjoint of the governing equation for contaminant transport,
      but with new load terms. Numerical codes that have been written to solve the
      forward equations of contaminant transport, e.g., the advection-dispersion
      equation, can also be used to solve the adjoint equation for location and travel
      time probabilities; however, the interpretation of the results is different and
      some new approximations must be made for the load terms. We present the governing
      equations for backward location and travel time probabilities, and provide
      appropriate numerical approximations for these load terms using the cell-centered
      finite difference method, one of the most popular numerical methods in ground
      water hydrology. We discuss some additional numerical considerations for the
      backward model including boundary conditions, reversal of the flow field, and
      interpretation of the results. We illustrate the implementation of the backward
      probability model using hypothetical examples in one- and two-dimensional
      domains. We also present a three-dimensional application of a pump-and-treat
      remediation capture zone delineation at the Massachusetts Military Reservation.
      The illustrations are performed using MODFLOW-96 for flow simulations and MT3DMS
      for transport simulations.

PMID- 15035584
TI  - Spatial interpolation methods for nonstationary plume data.
AB  - Plume interpolation consists of estimating contaminant concentrations at
      unsampled locations using the available contaminant data surrounding those
      locations. The goal of ground water plume interpolation is to maximize the
      accuracy in estimating the spatial distribution of the contaminant plume given
      the data limitations associated with sparse monitoring networks with irregular
      geometries. Beyond data limitations, contaminant plume interpolation is a
      difficult task because contaminant concentration fields are highly heterogeneous,
      anisotropic, and nonstationary phenomena. This study provides a comprehensive
      performance analysis of six interpolation methods for scatter-point concentration
      data, ranging in complexity from intrinsic kriging based on intrinsic random
      function theory to a traditional implementation of inverse-distance weighting.
      High resolution simulation data of perchloroethylene (PCE) contamination in a
      highly heterogeneous alluvial aquifer were used to generate three test cases,
      which vary in the size and complexity of their contaminant plumes as well as the
      number of data available to support interpolation. Overall, the variability of
      PCE samples and preferential sampling controlled how well each of the
      interpolation schemes performed. Quantile kriging was the most robust of the
      interpolation methods, showing the least bias from both of these factors. This
      study provides guidance to practitioners balancing opposing theoretical
      perspectives, ease-of-implementation, and effectiveness when choosing a plume
      interpolation method.

PMID- 15035585
TI  - Effects of rate-limited mass transfer on water sampling with partially
      penetrating wells.
AB  - Nonequilibrium concentration type curves are numerically developed and
      sensitivity analyses are performed to examine the relationships between effluent
      concentrations in partially penetrating monitoring/extraction wells, the vertical
      plume shape, and the mass transfer characteristics of the aquifer. The governing
      two-dimensional, axisymmetric nonequilibrium solute transport equation is solved
      in three stages using an operator-splitting approach. In the first two stages,
      the advection and dispersion terms are solved with the Eulerian-Lagrangian
      method, based on the backward method of characteristics for advection and the
      standard implicit Galerkin finite element method for dispersion. In the third
      step, the first-order, immobile-mobile domain mass transfer term is computed
      analytically for both two-site and lognormally distributed, multirate models.
      Effluent concentration variations with time and contour plots of the pore water
      concentration distribution in the aquifer are compared for a wide range of field-
      and laboratory-measured mass transfer rates, various plume shapes, and relevant
      physical/chemical parameter values, including pumping rate, vertical anisotropy
      ratio, retardation factor, and porosity. The simulation results show that rate
      limited mass transfer can have a significant impact on sample and aquifer pore
      water concentrations during three-dimensional transport to a partially
      penetrating well. An alternative dimensionless form of the nonequilibrium solute
      transport equation is derived to illustrate the key parameter groupings that
      quantify rate-limited sorption effects and show the relative importance of
      individual parameters. A hypothetical field application example demonstrates the
      fitting of dimensional type curves to discrete-interval sampling data in order to
      evaluate the mass transfer characteristics of an aquifer and shows how type curve
      superposition can be used to model complex plume shapes.

PMID- 15035586
TI  - Importance of the vadose zone in analyses of unconfined aquifer tests.
AB  - Analytical models commonly used to interpret unconfined aquifer tests have been
      based on upper-boundary (water table) conditions that do not adequately address
      effects of time-varying drainage from the vadose zone. As a result, measured and
      simulated drawdown data may not agree and hydraulic parameters may be
      inaccurately estimated. A 72-hour aquifer test conducted in Cape Cod,
      Massachusetts, in a slightly heterogeneous, coarse-grained, glacial outwash
      deposit was found to be a good candidate for testing models with different upper
      boundary conditions. In general, under the commonly invoked assumption of
      instantaneous drainage, measured and simulated drawdowns were found to agree with
      one another only at late time and early time. In the intermediate-time range,
      because of delayed drainage, measured drawdowns always exceeded simulated values,
      most noticeably in piezometers located near the water table. To reduce these
      discrepancies, an analytical model was developed that can fully account for time
      varying drainage given that the aquifer is not strongly heterogeneous. The
      approach is flexible as the model, which makes use of empirical relations, does
      not constrain drainage to follow any particular functional relation. By this
      approach, measured and simulated drawdowns agree over the complete time range,
      and the estimated parameters are consistent with prior studies and with what is
      known about the aquifer geometry, stratigraphy, and composition. By properly
      accounting for vadose zone drainage, it was found that realistic estimates of all
      hydraulic parameters, including specific yield, could be obtained with or without
      the use of late-time data.

PMID- 15035587
TI  - Ground water whirls.
AB  - Numerical experiments with steady-state ground water flow models show that
      spiraling flow lines occur in layered aquifers that have different anisotropic
      horizontal hydraulic conductivities in adjacent layers. Bundles of such flow
      lines turning in the same direction can be referred to as ground water whirls. An
      anisotropic layered block in a field of uniform horizontal flow results in one or
      more whirls with their axes in the uniform flow direction. The number of whirls
      depends on the number of interfaces between layers with different anisotropic
      properties. For flow to a well in an aquifer consisting of two anisotropic
      layers, with perpendicular major principal directions, whirls are found to occur
      in quadrants that are bounded by the principal directions of the hydraulic
      conductivity. The combined effect of flow to a well and a layered anisotropy
      implies that a single well in a system with a single anisotropic layer within an
      otherwise isotropic aquifer causes eight whirls. All adjacent whirls rotate in
      opposite directions.

PMID- 15035588
TI  - Delineating and quantifying ground water discharge zones using streambed
      temperatures.
AB  - Streambed temperature mapping, hydraulic testing using minipiezometers, and
      geochemical analyses of interstitial water of the streambed were used to
      delineate the pattern of ground water discharge in a sandy streambed and to
      develop a flux-based conceptual model for ground water/surface water
      interactions. A new and simple empirical method was used to relate fluxes
      obtained from minipiezometer data to streambed temperatures. The relationship
      allowed flux to be calculated at locations where only streambed temperature
      measurements were made. Slug testing and potentiomanometer measurements at 34
      piezometers indicated ground water discharge ranged from 0.03 to 446 L/m2/day
      (and possibly as high as 7060 L/m2/day) along a 60 m long by 11 to 14 m wide
      reach of river. Complex but similar plan-view patterns of flux were calculated
      for both summer and winter using hundreds of streambed temperatures measured on a
      1 by 2 m grid. The reach was dominated by ground water discharge and 5% to 7% of
      the area accounted for approximately 20% to 24% of the total discharge. < 12% of
      the total area consisted of recharge zones or no-discharge zones. A conceptual
      model for ground water/surface water interactions consisting of five different
      behaviors was developed based on the magnitude and direction of flux across the
      surface of the streambed. The behaviors include short-circuit discharge (e.g.,
      high-flow springs), high discharge (e.g., preferential flowpaths), low to
      moderate discharge, no discharge (e.g., horizontal hyporheic or ground water
      flow), and recharge. Geological variations at depth played a key role in
      determining which type of flow behavior occurred in the streambed.

PMID- 15035589
TI  - Evaluation of volatilization as a natural attenuation pathway for MTBE.
AB  - Volatilization and diffusion through the unsaturated zone can be an important
      pathway for natural attenuation remediation of methyl tert-butyl ether (MTBE) at
      gasoline spill sites. The significance of this pathway depends primarily on the
      distribution of immiscible product within the unsaturated zone and the relative
      magnitude of aqueous-phase advection (ground water recharge) to gaseous-phase
      diffusion. At a gasoline spill site in Laurel Bay, South Carolina, rates of MTBE
      volatilization from ground water downgradient from the source are estimated by
      analyzing the distribution of MTBE in the unsaturated zone above a solute plume.
      Volatilization rates of MTBE from ground water determined by transport modeling
      ranged from 0.0020 to 0.0042 g m(-2)/year, depending on the assumed rate of
      ground water recharge. Although diffusive conditions at the Laurel Bay site are
      favorable for volatilization, mass loss of MTBE is insignificant over the length
      (230 m) of the solute plume. Based on this analysis, significant volatilization
      of MTBE from ground water downgradient from source areas at other sites is not
      likely. In contrast, model results indicate that volatilization coupled with
      diffusion to the atmosphere could be a significant mass loss pathway for MTBE in
      source areas where residual product resides above the capillary zone. Although
      not documented, mass loss of MTBE at the Laurel Bay site due to volatilization
      and diffusion to the atmosphere are predicted to be two to three times greater
      than mass loading of MTBE to ground water due to dissolution and recharge. This
      result would imply that volatilization in the source zone may be the critical
      natural attenuation pathway for MTBE at gasoline spill sites, especially when
      considering capillary zone limitations on volatilization of MTBE from ground
      water and the relative recalcitrance of MTBE to biodegradation.

PMID- 15035590
TI  - Effect of iron type on kinetics and carbon isotopic enrichment of chlorinated
      ethylenes during abiotic reduction on Fe(0).
AB  - Four samples of two commercially available iron brands used as substrate for iron
      permeable reactive barriers (PRBs) were tested for suitability for remediation of
      perchloroethylene (PCE), trichloroethylene (TCE), cis-dichloroethylene (cDCE) and
      vinyl chloride (VC). Kinetic studies indicate that rates of reaction are enhanced
      for cDCE and VC on Connelly iron (2.8 x 10(-4) to 6.9 x 10(-4) L/m2/hr and 2.0 x
      10(-4) to 9.0 x 10(-4) L/m2/hr, for cDCE and VC, respectively) vs. Peerless iron
      (3.1 x 10(-5) to 4.6 x 10(-5) L/m2/hr and 2.4 x 10(-5) to 4.1 x 10(-5) L/m2/hr,
      for cDCE and VC, respectively). Carbon isotopic analyses of the residual
      chlorinated ethylene (CE) during degradation indicate significant fractionation
      occurs during reductive dechlorination, with, for example, up to 70% enrichment
      in carbon isotopic values observed when VC is more than 99% degraded. Comparison
      of fractionation factors (epsilon) indicates significant differences in carbon
      isotopic fractionation for different iron types and for different CEs. For the
      lower CEs (cDCE and VC) in particular, both slower reaction rates and larger
      fractionation are observed for degradation on Peerless vs. Connelly iron. This is
      the first study to establish a correlation between the rate of abiotic
      degradation on Fe(0) and the extent of isotopic fractionation, and the first to
      confirm consistent differences in these two parameters as a function of iron
      type. The possibility that these differences in kinetics and carbon isotopic
      fractionation for cDCE and VC are related to differences in branching ratios
      between competing hydrogenolysis and beta-elimination reactions during reductive
      dechlorination on the iron surfaces is discussed.

PMID- 15035591
TI  - Validation of numerical ground water models used to guide decision making.
AB  - Many sites of ground water contamination rely heavily on complex numerical models
      of flow and transport to develop closure plans. This complexity has created a
      need for tools and approaches that can build confidence in model predictions and
      provide evidence that these predictions are sufficient for decision making.
      Confidence building is a long-term, iterative process and the author believes
      that this process should be termed model validation. Model validation is a
      process, not an end result. That is, the process of model validation cannot
      ensure acceptable prediction or quality of the model. Rather, it provides an
      important safeguard against faulty models or inadequately developed and tested
      models. If model results become the basis for decision making, then the
      validation process provides evidence that the model is valid for making decisions
      (not necessarily a true representation of reality). Validation, verification, and
      confirmation are concepts associated with ground water numerical models that not
      only do not represent established and generally accepted practices, but there is
      not even widespread agreement on the meaning of the terms as applied to models.
      This paper presents a review of model validation studies that pertain to ground
      water flow and transport modeling. Definitions, literature debates, previously
      proposed validation strategies, and conferences and symposia that focused on
      subsurface model validation are reviewed and discussed. The review is general and
      focuses on site-specific, predictive ground water models used for making
      decisions regarding remediation activities and site closure. The aim is to
      provide a reasonable starting point for hydrogeologists facing model validation
      for ground water systems, thus saving a significant amount of time, effort, and
      cost. This review is also aimed at reviving the issue of model validation in the
      hydrogeologic community and stimulating the thinking of researchers and
      practitioners to develop practical and efficient tools for evaluating and
      refining ground water predictive models.

PMID- 15035593
TI  - A missing link in the historical development of hydrogeology.

PMID- 15035592
TI  - Magnetic resonance sounding: new method for ground water assessment.
AB  - The advantage of magnetic resonance sounding (MRS) as compared to other classical
      geophysical methods is in its water selective approach and reduced ambiguity in
      determination of subsurface free water content and hydraulic properties of the
      media due to the nuclear magnetic resonance (NMR) principle applied. Two case
      examples are used to explain how hydrogeological parameters are obtained from an
      MRS survey. The first case example in Delft (the Netherlands) is a multiaquifer
      system characterized by large signal to noise ratio (S/N = 73), with a 24 m
      thick, shallow sand aquifer, confined by a 15 m thick clay layer. For the shallow
      aquifer, a very good match between MRS and borehole data was obtained with regard
      to effective porosity n(e) approximately 28% and specific drainage S(d)
      approximately 20%. The MRS interpretation at the level deeper than 39 m was
      disturbed by signal attenuation in the low resistivity (approximately 10
      omega(m)) media. The second case of Serowe (Botswana) shows a fractured sandstone
      aquifer where hydrogeological parameters are well defined at depth > 74 m below
      ground surface despite quite a low S/N = 0.9 ratio, thanks to the negligible
      signal attenuation in the resistive environment. Finally, capabilities and
      limitations of the MRS technology are reviewed and discussed. MRS can contribute
      to subsurface hydrostratigraphy description, hydrogeological system
      parameterization, and improvement of well siting. The main limitations are survey
      dependence upon the value of the S/N ratio, signal attenuation in electrically
      conductive environments, nonuniformity of magnetic field, and some instrumental
      limitations. At locations sufficiently resistive to disregard the signal
      attenuation problems, the MRS S/N ratio determines how successfully MRS data can
      be acquired. Both signal and noise vary spatially; therefore, world scale maps
      providing guidelines on spatial variability of signal and noise are presented and
      their importance with respect to the MRS survey results is discussed. The noise
      varies also temporally; therefore, its diurnal and seasonal variability impact
      upon the MRS survey is covered as well.

PMID- 15035595
TI  - Outcomes research in the Medicare drug benefit.

PMID- 15035594
TI  - Peroxides and macrophages in the toxicity of fine particulate matter in rats.
AB  - Epidemiologists have observed a positive association between human morbidity and
      mortality and the atmospheric concentrations of fine particulate matter (PM), but
      the mechanisms underlying the toxic effects of PM have not been elucidated.
      Various components of ambient PM have been implicated in toxicity (including
      ultrafine particles, transition metals, organics and oxidants). Our research
      focused on hydrogen peroxide (H2O2). We speculated that fine PM transports H2O2
      into the lower lung, leading to tissue injury and to accumulation and activation
      of macrophages in these regions. The macrophages release cytotoxic mediators and
      proinflammatory cytokines that contribute to the pathogenesis of tissue injury.
      To test this hypothesis, we conducted studies to determine (1) whether tissue
      injury induced by aerosols is mediated by cytotoxic H2O2 carried into the lower
      lung by fine particles and (2) whether exposure of rats to fine PM leads to
      accumulation of activated macrophages in the lung. For our studies, systems were
      designed to generate model atmospheric fine PM and atmospheric peroxides
      consisting of an ammonium sulfate [(NH4)2SO4] aerosol (mass median diameter, 0.46
      +/- 0.14 microm) and H2O2. We also constructed a 6-port nose-only exposure
      chamber. Female Sprague Dawley rats were exposed for 2 hours to aerosols
      consisting of (NH4)2SO4 (430 microg/m3), (NH4)2SO4 + 10, 20 or 100 ppb H2O2,
      vapor-phase H2O2 (10, 20 or 100 ppb), or particle-free air. Studies using oxygen
      18 (18O)-labeled H2O2 were conducted to validate the transport of H2O2 into the
      lower lung with (NH4)2SO4. Rats were killed immediately (0 hours) or 24 hours
      after exposure. Compared with control animals, inhalation of (NH4)2SO4 and H2O2,
      alone or in combination, had no major effect on cell number or viability, protein
      content, or lactate dehydrogenase (LDH) levels in bronchoalveolar lavage (BAL)
      fluid collected either immediately or 24 hours after exposure. However, electron
      microscopy revealed that a larger number of neutrophils in pulmonary capillaries
      adhered to the vascular endothelium, especially in lungs of rats exposed to
      (NH4)2SO4 + H2O2. Inhalation of (NH4)2SO4 + H2O2 was also found to be associated
      with altered macrophage functional activity. Thus, exposing rats to (NH4)2SO4 +
      20 ppb H2O2 or 20 ppb H2O2 alone caused a level of tumor necrosis factor alpha
      (TNF-alpha) production by lung macrophages that was higher than in controls. This
      higher level was observed immediately after exposure and persisted for at least
      24 hours. Greater TNF-alpha production was also detected 24 hours after exposure
      to (NH4)2SO4 + 10 ppb H2O2. Immediately after rats inhaled (NH4)2SO4 + 10 ppb
      H2O2 or 20 ppb H2O2 alone, we also observed a transiently higher production of
      superoxide anion (O2-) by alveolar macrophages. Macrophages isolated 24 hours
      after exposure to 20 ppb H2O2 also produced larger quantities of superoxide
      anion. In contrast, immediately after exposure, macrophages from rats exposed to
      (NH4)2SO4 + 10 ppb H2O2 or to 20 ppb H2O2 alone generated less nitric oxide (NO).
      Reduced nitric oxide production was also observed 24 hours after exposure to
      (NH4)2SO4 + 10 ppb H2O2 or to 10 or 20 ppb H2O2 alone. Reduced nitric oxide
      production may have been due to superoxide anion-driven formation of
      peroxynitrite (ONOO-) anions. In this regard, nitrotyrosine, an in vivo marker of
      peroxynitrite, was detected in lung tissue immediately after rats were exposed to
      (NH4)2SO4 + H2O2 or to H2O2 alone (10 or 20 ppb). We also found that alveolar
      macrophages from rats exposed to (NH4)2SO4 + H2O2 showed a greater expression of
      the antioxidant enzyme heme oxygenase-1 (HO-1) when stimulated with
      lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Similar results were
      observed after exposure of rats to an organic peroxide aerosol (cumene
      hydroperoxide). Taken together, the results of our studies demonstrate that
      biological effects of inhaled H2O2 are augmented by fine PM. Moreover, tissue
      injury induced by (NH4)2SO4 + H2O2 may be related to altered production of
      cytotoxic mediators by alveolar macrophages. Determining the relevance of these
      toxicologic results to human health will be important in future studies for
      evaluating the risk of exposure.

PMID- 15035596
TI  - Consumer knowledge and perceptions of formularies.
AB  - A study was undertaken to determine consumer knowledge and perceptions of
      formularies. A prevalidated survey containing 11 scored items was administered to
      714 consumers waiting to receive prescription medications at 72 community
      pharmacies in Houston. Overall, these consumers were satisfied with their
      prescription insurance plans, but their attitudes toward formularies were
      negative, and the negative perceptions were significantly correlated with
      satisfaction scores. However, only 25% of the surveyed population had a copy of
      the formulary, so that a large majority had no knowledge of their formulary or
      the types of drugs it covered. Efforts to educate patients may reduce the
      difficulty faced by pharmacists in explaining formulary issues to consumers.

PMID- 15035597
TI  - Off-label pharmaceutical use: balancing information, risks, and benefits.

PMID- 15035598
TI  - Clinical and economic effects of suboptimally controlled asthma.
AB  - Patients with difficult-to-treat or suboptimally controlled asthma consume a
      disproportionate share of asthma health care resources. Treatment strategies that
      minimize exacerbations may decrease the need for unscheduled medical services,
      reduce emergency department visits, and minimize asthma-related hospitalizations.
      Clinical trial evidence indicates the immunoglobulin-E blocker omalizumab reduces
      the frequency of asthma exacerbations, minimizes symptoms, and improves lung
      function in patients with moderate-to-severe asthma that is inadequately
      controlled by inhaled corticosteroid therapy. Treatment with omalizumab of
      patients with suboptimally controlled asthma may reduce the clinical and economic
      burden of asthma.

PMID- 15035599
TI  - California's controversial "play or pay" law: short-lived experiment or overdue
      solution?
AB  - Controversial legislation that guarantees health coverage for most private-sector
      workers was recently passed in California. Known as the Health Insurance Act of
      2003, the legislation will most likely be subject to a variety of legal
      challenges. The author presents a comprehensive description of how the Act works
      and the constitutional challenges it may face.

PMID- 15035600
TI  - The dark side of ERISA: when things go awry.

PMID- 15035601
TI  - Zinc and sulfur: a critical biological partnership.

PMID- 15035602
TI  - The HPV16 E7 viral oncoprotein self-assembles into defined spherical oligomers.
AB  - Despite the fact that E7 is a major transforming oncoprotein in papillomavirus,
      its structure and precise molecular mechanism of action remain puzzling to date.
      E7 proteins share sequence homology and proteasome targeting properties of tumor
      suppressors with adenovirus E1A and SV40 T antigen, two other paradigmatic
      oncoproteins from DNA tumor viruses. High-risk HPV16 E7, a nonglobular dimer with
      some properties of intrinsically disordered proteins, is capable of undergoing pH
      dependent conformational transitions that expose hydrophobic surfaces to the
      solvent. We found that treatment with a chelating agent produced a protein that
      can readily assemble into homogeneous spherical particles with an average
      molecular mass of 790 kDa and a diameter of 50 nm, as determined from dynamic
      light scattering and electron microscopy. The protein undergoes a substantial
      conformational transition from coil to beta-sheet structure, with concomitant
      consolidation of tertiary structure as judged by circular dichroism and
      fluorescence. The assembly process is very slow, in agreement with a substantial
      energy barrier caused by structural rearrangements. The resulting particles are
      highly stable, cooperatively folded, and capable of binding both Congo Red and
      thioflavin T, reporters of repetitive beta-sheet structures similar to those
      found in amyloids, although no fibrillar or insoluble material was observed under
      our experimental conditions.

PMID- 15035603
TI  - Absence of large-scale displacement of quinone QB in bacterial photosynthetic
      reaction centers.
AB  - Photosynthesis transforms light into chemical energy by coupling electron
      transfer to proton uptake at the quinone Q(B). The possibility of initiating this
      process with a brief pulse of light and the known X-ray structure makes the
      photosynthetic bacterial reaction center a paradigm for studying coupled electron
      proton transfer in biology. It has been established that electron transfer from
      the primary quinone Q(A) to Q(B) is gated by a protein conformational change. On
      the basis of a dramatic difference in the location of Q(B) in structures derived
      from crystals cooled to 90 K either under illumination or in the dark, a
      functional model for the gating mechanism was proposed whereby neutral Q(B) moves
      4.5 A before receiving the electron from Q(A)(-) [Stowell, M. H. B., McPhillips,
      T. M., Rees, D. C., Soltis, S. M., Abresch, E., and Feher, G. (1997) Science 276,
      812-816]. Isotope-edited FTIR difference spectroscopy of Q(B) photoreduction at
      290 and 85 K is used to investigate whether Q(B) moves upon reduction. We show
      that the specific interactions of the carbonyl groups of Q(B) and Q(B)(-) with
      the protein at a single binding site remain identical at both temperatures.
      Therefore, the different locations of Q(B) reported in many X-ray crystal
      structures probably are unrelated to functional electron transfer from Q(A)(-) to
      Q(B).

PMID- 15035604
TI  - Subunit interface residues of glutathione S-transferase A1-1 that are important
      in the monomer-dimer equilibrium.
AB  - Alpha class glutathione S-transferase, isozyme A1-1, is a dimer (51 kDa) of
      identical subunits. Using the crystal structure, two main areas of subunit
      interaction were chosen for study: (1) the hydrophobic ball and socket comprised
      of Phe52 from one subunit fitting into a socket formed on the other subunit by
      Met94, Phe136, and Val139 and (2) the Arg/Glu region consisting of Arg69 and
      Glu97 from both subunits. We introduced substitutions of these residues, by site
      directed mutagenesis, to evaluate the importance of each at the subunit interface
      and to determine if monomeric enzymes could be generated using single mutations.
      Mutating each residue of the socket region to alanine results in little change in
      the kinetic parameters, and all are dimeric enzymes. In contrast, when Phe52, the
      ball residue, is replaced with alanine, the enzyme has very low activity and a
      weight average molecular mass of 31.9 kDa, as determined by sedimentation
      equilibrium experiments. Substitutions for Glu97 which eliminate the charge cause
      no appreciable changes in the kinetic parameters or molecular mass. Eliminating
      the charge on Arg69 (as in R69Q) results in a dimeric enzyme; however, when the
      charge is reversed (as in R69E), the weight average molecular mass is greatly
      shifted toward that of the monomer (33 kDa) and the changes in kinetic parameters
      are reasonably small. We determined the molecular masses in the presence of
      glutathione for F52A and R69E to ascertain whether the monomeric species retains
      activity. For R69E, it appears that the monomer is active, albeit less so than
      the dimer, while for F52A, the monomer and dimer both appear to exhibit very low
      activity. The dimeric species is needed to obtain high specific activity. We
      conclude that, of the residues that were studied, Phe52 and Arg69 are the major
      determinants of dimer formation and a single mutation at either position
      substantially hinders dimerization. The use of a mutant glutathione S-transferase
      which retains activity yet has a greatly weakened tendency to dimerize (such as
      R69E) may be advantageous for certain applications of GST fusion proteins.

PMID- 15035605
TI  - Effects of chaotropic and kosmotropic cosolvents on the pressure-induced
      unfolding and denaturation of proteins: an FT-IR study on staphylococcal
      nuclease.
AB  - FT-IR spectroscopy was used to study the effects of various chaotropic and
      kosmotropic cosolvents (glycerol, sucrose, sorbitol, K(2)SO(4), CaCl(2), and
      urea) on the secondary structure and thermodynamic properties upon unfolding and
      denaturation of staphylococcal nuclease (Snase). The data show that the different
      cosolvents have a profound effect on the denaturation pressure and the Gibbs free
      energy (DeltaG(o)) and volume (DeltaV(o) change of unfolding. Moreover, by
      analysis of the amide I' infrared bands, conformational changes of the protein
      upon unfolding in the different cosolvents have been determined. An increase, a
      reduction, or an independence of the volume change of unfolding is observed,
      depending on the type of cosolvent, which can at least in part be attributed to
      the formation of a different unfolded state structure of the protein. The data
      are compared with the corresponding thermodynamic values of DeltaV(o) for the
      temperature-induced unfolding process of Snase as obtained by pressure
      perturbation calorimetry, and significant differences are observed and discussed.

PMID- 15035606
TI  - The folding pathway of barnase: the rate-limiting transition state and a hidden
      intermediate under native conditions.
AB  - The nature of the rate-limiting transition state at zero denaturant (TS(1)) and
      whether there are hidden intermediates are the two major unsolved problems in
      defining the folding pathway of barnase. In earlier studies, it was shown that
      TS(1) has small phi values throughout the structure of the protein, suggesting
      that the transition state has either a defined partially folded secondary
      structure with all side chains significantly exposed or numerous different
      partially unfolded structures with similar stability. To distinguish the two
      possibilities, we studied the effect of Gly mutations on the folding rate of
      barnase to investigate the secondary structure formation in the transition state.
      Two mutations in the same region of a beta-strand decreased the folding rate by
      20- and 50-fold, respectively, suggesting that the secondary structures in this
      region are dominantly formed in the rate-limiting transition state. We also
      performed native-state hydrogen exchange experiments on barnase at pD 5.0 and 25
      degrees C and identified a partially unfolded state. The structure of the
      intermediate was investigated using protein engineering and NMR. The results
      suggest that the intermediate has an omega loop unfolded. This intermediate is
      more folded than the rate-limiting transition state previously characterized at
      high denaturant concentrations (TS(2)). Therefore, it exists after TS(2) in
      folding. Consistent with this conclusion, the intermediate folds with the same
      rate and denaturant dependence as the wild-type protein, but unfolds faster with
      less dependence on the denaturant concentration. These and other results in the
      literature suggest that barnase folds through partially unfolded intermediates
      that exist after the rate-limiting step. Such folding behavior is similar to
      those of cytochrome c and Rd-apocyt b(562). Together, we suggest that other small
      apparently two-state proteins may also fold through hidden intermediates.

PMID- 15035607
TI  - Elimination of a misfolded folding intermediate by a single point mutation.
AB  - We present an analysis of the folding behavior of the 159-residue major birch
      pollen allergen Bet v 1. The protein contains a water-filled channel running
      through it. Consequently, the protein has a hydrophobic shell, rather than a
      hydrophobic core. During the folding of the protein from either the urea-, pH-,
      or SDS-denatured state, Bet v 1 transiently populates a partially folded
      intermediate state. This state appears to be misfolded, since it has to unfold at
      least partially to fold to the native state. The misfolded intermediate is not,
      however, a result of the water-filled channel in Bet v 1. The intermediate
      completely disappears in the mutant Tyr --> Trp120, in which the channel is still
      present. Tyr120 appears to behave as a "negative gatekeeper" which attenuates
      efficient folding. The close structural homologue, the apple allergen Mal d 1,
      also folds without any detectable folding intermediates. However, the position of
      the transition state on the reaction coordinate, which is a measure of its
      overall compactness relative to the denatured and native states, is reduced
      dramatically from ca. 0.9 in Bet v 1 to around 0.5 in Mal d 1. We suggest that
      this large shift in the transition state structure is partly due to different
      local helix propensities. Given that individual mutations can have such large
      effects on folding, one should not a priori expect structurally homologous
      proteins to fold by the same mechanism.

PMID- 15035608
TI  - Kinetics of factor Xa inhibition by recombinant tick anticoagulant peptide: both
      active site and exosite interactions are required for a slow- and tight-binding
      inhibition mechanism.
AB  - Recombinant tick anticoagulant peptide (rTAP) is a competitive slow- and tight
      binding inhibitor of factor Xa (FXa) with a reported equilibrium dissociation
      constant (K(I)) of approximately 0.2 nM. The inhibitory characteristics and the
      high selectivity of rTAP for FXa are believed to arise from the ability of the
      inhibitor to specifically interact with the residues of both the active site as
      well as those remote from the active site pocket of the protease. To localize the
      rTAP-interactive sites on FXa, the kinetics of inhibition of wild-type and 18
      different mutants of recombinant FXa by the inhibitor were studied by either a
      discontinuous assay method employing the tight-binding quadratic equation or a
      continuous assay method employing the slow-binding kinetic approach. It was
      discovered that K(I) values for the interaction of rTAP with four FXa mutants
      (Tyr(99) --> Thr, Phe(174) --> Asn, Arg(143) --> Ala, and a Na(+)-binding loop
      mutant in which residues 220-225 of FXa were replaced with the corresponding
      residues of thrombin) were elevated by 2-3 orders of magnitude for each mutant.
      Further studies revealed that the characteristic slow type of inhibition by rTAP
      was also eliminated for the mutants. These findings suggest that the interaction
      of rTAP with the P2-binding pocket, the autolysis loop, and the Na(+)-binding
      loop is primarily responsible for its high specificity of FXa inhibition by a
      slow- and tight-binding mechanism.

PMID- 15035609
TI  - Same fold with different mobility: backbone dynamics of small protease inhibitors
      from the desert locust, Schistocerca gregaria.
AB  - SGCI (Schistocerca gregaria chymotrypsin inhibitor) and SGTI (Sch. gregaria
      trypsin inhibitor) are small, 35-residue serine protease inhibitors with
      intriguing taxon specificity: SGTI is specific for arthropod proteases while SGCI
      is an excellent inhibitor on both mammalian and arthropodal enzymes. Here we
      report the cloning, expression, and (15)N backbone dynamics investigations of
      these peptides. Successful expression could be achieved by a "dimeric" construct
      similar to the natural precursor of the inhibitors. An engineered methionine
      residue between the two modules served as a unique cyanogen bromide cleavage site
      to cleave the precursor and physically separate SGCI and SGTI. The overall
      correlation time of the precursor (5.29 ns) as well as the resulted SGCI (3.14
      ns) and SGTI (2.96 ns) are as expected for proteins of this size. General order
      parameters (S(2)) for the inhibitors are lower than those characteristic of well
      folded proteins. Values in the binding loop region are even lower. Interestingly,
      the distribution of residues for which a chemical exchange (R(ex)) term should be
      considered is strikingly different in SGCI and SGTI. Together with H-D exchange
      studies, this indicates that the internal dynamics of the two closely related
      molecules differ. We suggest that the dynamic properties of these inhibitors is
      one of the factors that determine their specificity.

PMID- 15035611
TI  - Solution structure and backbone dynamics of the Cu(I) and apo forms of the second
      metal-binding domain of the Menkes protein ATP7A.
AB  - The second domain of the human Menkes protein (MNK2), formed by 72 residues, has
      been expressed in Escherichia coli, and its structure has been determined by NMR
      in both the apo and copper-loaded forms. The structures, obtained with (13)C- and
      (15)N-labeled samples, are of high quality with backbone rmsd values of 0.51 and
      0.41 A and CYANA target functions of 0.39 and 0.38 A(2), respectively. The loop
      involved in copper binding is part of a hydrophobic patch, which is maintained in
      both forms. Conformational mobility is observed in the apo form in the same loop.
      A comparison with metallochaperones and soluble domains of P-type ATPases allows
      us to relate the primary structure to the occurrence of structural rearrangements
      upon copper binding.

PMID- 15035610
TI  - Structure of subtilosin A, a cyclic antimicrobial peptide from Bacillus subtilis
      with unusual sulfur to alpha-carbon cross-links: formation and reduction of alpha
      thio-alpha-amino acid derivatives.
AB  - The complete primary and three-dimensional solution structures of subtilosin A
      (1), a bacteriocin from Bacillus subtilis, were determined by multidimensional
      NMR studies on peptide produced using isotopically labeled [(13)C,(15)N]medium
      derived from Anabaena sp. grown on sodium [(13)C]bicarbonate and [(15)N]nitrate.
      Additional samples of 1 were also generated by separate incorporations of [U
      (13)C,(15)N]-L-phenylalanine and [U-(13)C,(15)N]-L-threonine using otherwise
      unlabeled media. The results demonstrate that in addition to having a cyclized
      peptide backbone (amide between N and C termini), three cross-links are formed
      between the sulfurs of Cys13, Cys7, and Cys4 and the alpha-positions of Phe22,
      Thr28, and Phe31, respectively. The stereochemistry of all residues in 1 except
      for the three modified ones was confirmed to be L by complete desulfurization
      with nickel boride, acid hydrolysis to the constituent amino acids, and
      conversion of these to the corresponding pentafluoropropanamide isopropyl esters
      for chiral GC MS analysis. The stereochemistry at the modified residues was
      determined by subjecting each of the eight possible stereoisomers of 1 to eight
      rounds of ARIA structure calculations, starting with the same NMR peak files and
      assignments. The stereoisomer with the l stereochemistry at Phe22 (alpha-R) and d
      stereochemistry at Thr28 (alpha-S) and Phe31 (alpha-S) (LDD isomer) fit the NMR
      data, giving the lowest energy family of structures with the best rmsd. Thus,
      biochemical formation of the unusual thio links proceeds with net retention of
      configuration at Phe22, and inversion at Thr28 and Phe31. Model amino acid
      derivatives bearing a sulfide moiety at the alpha-carbon were synthesized by
      reaction of the corresponding alpha-alkoxy compounds with benzyl thiol and
      SnCl(4). Separation of their pure stereoisomers and desulfurization with nickel
      boride demonstrated that the reduction of such compounds proceeds with
      epimerization, in contrast to the previously reported retention of
      stereochemistry for analogous reaction of steroidal sulfides. However,
      desulfurization of subtilosin A to cyclic peptide 14, which is inactive as an
      antimicrobial agent, occurs with inversion of stereochemistry at the alpha
      carbons of Phe22 and Thr28 and with 4:1 retention at Phe31. This indicates that
      the desulfurization reaction proceeds via an N-acyl imine and that the structure
      of the surrounding peptide controls the geometry of reduction. Posttranslational
      linkage of a thiol to the alpha-carbon of an amino acid residue is unprecedented
      in ribosomally synthesized peptides or proteins, and very rare in secondary
      metabolites. Subtilosin A (1) represents a new class of bacteriocins.

PMID- 15035612
TI  - Mutational, NMR, and NH exchange studies of the tight and selective binding of 8
      oxo-dGMP by the MutT pyrophosphohydrolase.
AB  - The solution structure of the ternary MutT enzyme-Mg(2+)-8-oxo-dGMP complex
      showed the proximity of Asn119 and Arg78 and the modified purine ring of 8-oxo
      dGMP, suggesting specific roles for these residues in the tight and selective
      binding of this nucleotide product [Massiah, M. A., Saraswat, V., Azurmendi, H.
      F., and Mildvan, A. S. (2003) Biochemistry 42, 10140-10154]. These roles are here
      tested by mutagenesis. The N119A, N119D, R78K, and R78A single mutations and the
      R78K/N119A double mutant showed very small effects on k(cat) (<or=2-fold) and
      K(m) (<or=4-fold) in the hydrolysis of dGTP, indicating largely intact active
      sites. (1)H-(15)N HSQC spectra showed largely intact protein structures for all
      of these mutants. However, the N119A mutation profoundly and selectively weakened
      the active site binding of 8-oxo-dGMP, increasing the K(I)(slope) of this product
      inhibitor 1650-fold, while increasing the K(I)(slope) of dGMP and dAMP less than
      2-fold. The N119D mutation also selectively weakened 8-oxo-dGMP binding but only
      by 37-fold, suggesting that Asn119 both donated a hydrogen bond to the C8=O group
      and accepted a hydrogen bond from the N7H group of 8-oxo-dGMP, while Asp119
      functioned as only an acceptor. Direct binding of 8-oxo-dGMP to N119A, monitored
      by continuous changes in the (15)N and/or NH chemical shifts of 12 residues,
      revealed fast exchange, and a K(D) of 237 +/- 130 microM for 8-oxo-dGMP,
      comparable to its K(I)(slope) of 81 +/- 22 microM. While formation of the wild
      type MutT-Mg(2+)-8-oxo-dGMP complex slowed the backbone NH exchange rates of 45
      residues distributed throughout the protein, the same complex of the N119A mutant
      slowed the exchange rates of only 11 residues at or near the active site,
      indicating an increase in the conformational flexibility of the N119A mutant. The
      R78K and R78A mutations selectively increased the K(I)(slope) of 8-oxo-dGMP by
      factors of 17 and 6.6, respectively, indicating a smaller role for Arg78 than for
      Asn119 in the binding of 8-oxo-dGMP, likely donating a hydrogen bond to its C6=O
      group. The much greater contribution of Asn119 (4.0 kcal/mol) than of Arg78 (1.0
      kcal/mol) to the selectivity of binding of 8-oxo-dGMP versus dGMP indicates a 2
      order of magnitude smaller contribution of a structure with the reversed
      orientation of the 8-oxo-dG ring. The R78K/N119A double mutant weakened the
      binding of 8-oxo-dGMP by a factor (63,000 +/- 22,000) which overlaps within error
      with the product of the effects of the two single mutants (28,000 +/- 15,000).
      Such additive effects of the two single mutants in the double mutant are most
      simply explained by the independent functioning of Asn119 and Arg78 in the
      binding of 8-oxo-dGMP. Independent functioning of these two residues in
      nucleotide binding is consistent with their locations in the MutT-Mg(2+)-8-oxo
      dGMP complex, on opposite sides of the active site cleft, with a minimal distance
      of 8.4 +/- 0.5 A between their side chain nitrogens.

PMID- 15035613
TI  - Structural studies of inhibition of S-adenosylmethionine synthetase by slow,
      tight-binding intermediate and product analogues.
AB  - S-Adenosylmethionine synthetase (ATP: L-methionine S-adenosyltransferase)
      catalyzes a two-step reaction in which tripolyphosphate (PPPi) is a tightly bound
      intermediate. Diimidotriphosphate (O(3)P-NH-PO(2)-NH-PO(3); PNPNP), a non
      hydrolyzable analogue of PPPi, is the most potent known inhibitor of AdoMet
      synthetase with a K(i) of 2 nM. The structural basis for the slow, tight-binding
      inhibition by PNPNP has been investigated by spectroscopic methods. UV difference
      spectra reveal environmental alterations of aromatic protein residues upon PNPNP
      binding to form the enzyme.2Mg(2+).PNPNP complex, and more extensive changes upon
      formation of the enzyme.2Mg(2+).PNPNP.AdoMet complex. Stopped-flow kinetic
      studies of complex formation revealed that two slow isomerizations follow PNPNP
      binding in the presence of AdoMet, in contrast to the lower affinity, rapid
      equilibrium binding in the absence of AdoMet. (31)P NMR spectra of enzyme
      complexes with PNPNP revealed electronic perturbations of each phosphorus atom by
      distinct upfield chemical shifts for each of the three phosphoryl groups in the
      enzyme.2Mg(2+).PNPNP complex, and further upfield shifts of at least 2 resonances
      in the complex with AdoMet. Comparison of the chemical shifts for the enzyme
      bound PNPNP with the enzyme complexes containing either the product analogue
      O(3)P-NH-PO(3) or O(3)P-O-PO(2)-NH-PO(3) indicates that the shifts on binding are
      largest at the binding sites corresponding to those for the alpha and gamma
      phosphoryl groups of the nucleotide (-3.1 to -4.1 ppm), while the resonance at
      the beta phosphoryl group position shifts by -2.1 ppm. EPR spectra of Mn(2+)
      complexes demonstrate spin coupling between the two Mn(2+) in both
      enzyme.2Mn(2+).PNPNP and enzyme.2Mn(2+).PNPNP.AdoMet, indicating that the metal
      ions have comparable distances in both cases. The combined results indicate that
      formation of the highest affinity complex is associated with protein side chain
      rearrangements and increased electron density at the ligand phosphorus atoms,
      likely due to ionization of an -NH- group of the inhibitor. The energetic
      feasibility of ionization of a -NH- group when two Mg(2+) ions are bound to O(3)P
      NH-PO(3) is supported by density functional theoretical calculations on model
      chelates. This mode of interaction is uniquely available to compounds with P-NH-P
      linkages and may be possible with other proteins in which multiple cations
      coordinate a polyphosphate chain.

PMID- 15035614
TI  - Molecular basis for the binding of competitive inhibitors of maize polyamine
      oxidase.
AB  - Maize polyamine oxidase (MPAO), the only member of the polyamine oxidase (PAO)
      family whose three-dimensional structure is known, is characterized by a 30 A
      long U-shaped catalytic tunnel located between the substrate binding domain and
      the FAD. To shed light on the MPAO ligand binding mode, we studied the inhibition
      properties of linear diamines, agmatine, prenylagmatine (G3), G3 analogues, and
      guazatine, and analyzed the structural determinants of their biological activity.
      Linear diamines competitively inhibited MPAO, with the inhibitory activity
      increasing as a function of the number of methylene groups. With regard to the
      guanidino competitive inhibitors, including agmatine, G3, and G3 analogues, the
      presence of a hydrophobic substituent constitutes the principal factor
      influencing MPAO inhibition, as the addition of a hydrophobic substituent to the
      guanidino group of both G3 and G3 analogues greatly increases the inhibitory
      activity. Moreover, results obtained by a molecular modeling procedure indicated
      that in their preferred orientation, G3 analogues point the ammonium group toward
      the narrow entrance of the tunnel, while the terminal hydrophobic group is
      located within the large entrance. The high binding affinity for MPAO exhibited
      by G3 and G3 analogues bearing a prenyl group as a substituent on the guanidino
      moiety is in agreement with the observation that the prenyl group binds in a well
      defined hydrophobic pocket, mainly formed by aromatic residues. Finally, docking
      simulations performed with the charged and uncharged forms of MPAO inhibitors
      indicate that the stereoelectronic properties of the MPAO active site are
      consistent with the binding of inhibitors in the protonated form.

PMID- 15035615
TI  - Role of phosphate chain mobility of MgATP in completing the 3-phosphoglycerate
      kinase catalytic site: binding, kinetic, and crystallographic studies with ATP
      and MgATP.
AB  - The complexes of pig muscle 3-phosphoglycerate kinase with the substrate MgATP
      and with the nonsubstrate Mg(2+)-free ATP have been characterized by binding,
      kinetic, and crystallographic studies. Comparative experiments with ADP and MgADP
      have also been carried out. In contrast to the less specific and largely ionic
      binding of Mg(2+)-free ATP and ADP, specific occupation of the adenosine binding
      pocket by MgATP and MgADP has been revealed by displacement experiments with
      adenosine and anions, as well as supported by isothermal calorimetric titrations.
      The Mg(2+)-free nucleotides similarly stabilize the overall protein structure and
      restrict the conformational flexibility around the reactive thiol groups of helix
      13, as observed by differential scanning microcalorimetry and thiol reactivity
      studies, respectively. The metal complexes, however, behave differently. MgADP,
      but not MgATP, further increases the conformational stability with respect to its
      Mg(2+)-free form, which indicates their different modes of binding to the enzyme.
      Crystal structures of the binary complexes of the enzyme with MgATP and with ATP
      (2.1 and 1.9 A resolution, respectively) have shown that the orientation and
      interaction of phosphates of MgATP largely differ not only from those of ATP but
      also from the previously determined ones of either MgADP [Davies, G. J., Gamblin,
      S. J., Littlechild, J. A., Dauter, Z., Wilson, K. S., and Watson, H. C. (1994)
      Acta Crystallogr. D50, 202-209] or the metal complexes of AMP-PNP [May, A., Vas,
      M., Harlos, K., and Blake, C. C. F. (1996) Proteins 24, 292-303; Auerbach, G.,
      Huber, R., Grattinger, M., Zaiss, K., Schurig, H., Jaenicke, R., and Jacob, U.
      (1997) Structure 5, 1475-1483] and are more similar to the interactions formed
      with MgAMP-PCP [Kovari, Z., Flachner, B., Naray-Szabo, G., and Vas, M. (2002)
      Biochemistry 41, 8796-8806]. Mg(2+) is liganded to both beta- and gamma
      phosphates of ATP, while beta-phosphate is linked to the conserved Asp218, i.e.,
      to the N-terminus of helix 8, through a water molecule; the known interactions of
      either MgADP or the metal complexes of AMP-PNP with the N-terminus of helix 13
      and with Asn336 of beta-strand J are absent in the case of MgATP. Fluctuation of
      MgATP phosphates between two alternative sites has been proposed to facilitate
      the correct positioning of the mobile side chain of Lys215, and the catalytically
      competent active site is thereby completed.

PMID- 15035616
TI  - Multiconformational states in phosphoglycerate dehydrogenase.
AB  - Phosphoglycerate dehydrogenase (PGDH) catalyzes the first step in the serine
      biosynthetic pathway. In lower plants and bacteria, the PGDH reaction is
      regulated by the end-product of the pathway, serine. The regulation occurs
      through a V(max) mechanism with serine binding and inhibition occurring in a
      cooperative manner. The three-dimensional structure of the serine inhibited
      enzyme, determined by previous work, showed a tetrameric enzyme with 222 symmetry
      and an unusual overall toroidal appearance. To characterize the allosteric,
      cooperative effects of serine, we identified W139G PGDH as an enzymatically
      active mutant responsive to serine but not in a cooperative manner. The position
      of W139 near a subunit interface and the active site cleft suggested that this
      residue is a key player in relaying allosteric effects. The 2.09 A crystal
      structure of W139G-PGDH, determined in the absence of serine, revealed major
      quaternary and tertiary structural changes. Contrary to the wildtype enzyme where
      residues encompassing residue 139 formed extensive intersubunit contacts, the
      corresponding residues in the mutant were conformationally flexible. Within each
      of the three-domain subunits, one domain has rotated approximately 42 degrees
      relative to the other two. The resulting quaternary structure is now in a novel
      conformation creating new subunit-to-subunit contacts and illustrates the unusual
      flexibility in this V(max) regulated enzyme. Although changes at the regulatory
      domain interface have implications in other enzymes containing a similar
      regulatory or ACT domain, the serine binding site in W139G PGDH is essentially
      unchanged from the wildtype enzyme. The structural and previous biochemical
      characterization of W139G PGDH suggests that the allosteric regulation of PGDH is
      mediated not only by changes occurring at the ACT domain interface but also by
      conformational changes at the interface encompassing residue W139.

PMID- 15035617
TI  - Cooperative interaction of arginine-19 and the N-terminal signaling domain in the
      affinity and potency of parathyroid hormone.
AB  - Residue 19 of parathyroid hormone (PTH) plays a unique role in the interaction
      process with the PTH1 receptor. A Glu(19) --> Arg(19) substitution, based on the
      Arg(19) of the PTH-related protein (PTHrP), increases the binding affinity when
      incorporated into the N-terminus of PTH [i.e., PTH(1-20)] and has no effect when
      introduced into the C-terminus of PTH [i.e., PTH(15-31)]. To explore Arg(19) and
      the midregion (residues 10-15), we designed the novel PTH scaffold peptide, PG5,
      which has the PTH(1-9) domain linked to the PTH(15-31) segment via a pentaglycine
      spacer. Substitution of Glu(19) with Arg(19) in PG5 resulted in a 9-fold increase
      in binding affinity. Additionally, the substitution enhanced stimulated cAMP
      formation in cells expressing PTH1-delNt, a PTH1 receptor construct lacking most
      of the N-terminus, confirming that residue 19 is interacting with the
      juxtamembrane portion of PTH1. The binding and signaling capacities of the PG5
      analogues were diminished relative to those of PTH(1-34), indicating that the
      residue 10-14 region of PTH provides more than just a simple linker function. To
      probe this further, the structural consequences of the glycine linker and its
      interaction with PTH1 were examined by circular dichroism, (1)H NMR, and
      extensive ligand/receptor molecular dynamics simulations. The structural data
      clearly illustrate the helix-stabilizing effect of Arg(19) substitution
      propagating N-terminally from position 19 to the pentaglycine linker. Overall,
      these studies suggest that an alpha-helix is the preferred conformation for the
      residue 15-20 region of PTH and that residues 10-14 are also required for full
      affinity and potency of the hormone.

PMID- 15035618
TI  - Membrane binding and translocation of cell-penetrating peptides.
AB  - Cell-penetrating peptides (CPPs) have been extensively studied during the past
      decade, because of their ability to promote the cellular uptake of various cargo
      molecules, e.g., oligonucleotides and proteins. In a recent study of the uptake
      of several analogues of penetratin, Tat(48-60) and oligoarginine in live
      (unfixed) cells [Thoren et al. (2003) Biochem. Biophys. Res. Commun. 307, 100
      107], it was found that both endocytotic and nonendocytotic uptake pathways are
      involved in the internalization of these CPPs. In the present study, the membrane
      interactions of some of these novel peptides, all containing a tryptophan residue
      to facilitate spectroscopic studies, are investigated. The peptides exhibit a
      strong affinity for large unilamellar vesicles (LUVs) containing zwitterionic and
      anionic lipids, with binding constants decreasing in the order penetratin > R(7)W
      > TatP59W > TatLysP59W. Quenching studies using the aqueous quencher acrylamide
      and brominated lipids indicate that the tryptophan residues of the peptides are
      buried to a similar extent into the membrane, with an average insertion depth of
      approximately 10-11 A from the bilayer center. The membrane topology of the
      peptides was investigated using an assay based on resonance energy transfer
      between tryptophan and a fluorescently labeled lysophospholipid, lysoMC,
      distributed asymmetrically in the membranes of LUVs. By determination of the
      energy transfer efficiency when peptide was added to vesicles with lysoMC present
      exclusively in the inner leaflet, it was shown that none of the peptides
      investigated is able to translocate across the lipid membranes of LUVs. By
      contrast, confocal laser scanning microscopy studies on carboxyfluorescein
      labeled peptides showed that all of the peptides rapidly traverse the membranes
      of giant unilamellar vesicles (GUVs). The choice of model system is thus crucial
      for the conclusions about the ability of CPPs to translocate across lipid
      membranes. Under the conditions used in the present study, peptide-lipid
      interactions alone cannot explain the different cellular uptake characteristics
      exhibited by these peptides.

PMID- 15035619
TI  - Residues in the hydrophilic face of putative helix 8 of oxytocin receptor are
      important for receptor function.
AB  - Oxytocin receptor (OTR) activates the GTP-binding protein Galpha(q). To
      investigate whether the N-terminal region of the fourth intracellular domain of
      this receptor, which forms putative helix 8, plays a role in coupling, its
      hydrophilic residues (H7.59, H7.62, E7.63, Q7.66, and R7.67) were mutated
      individually to alanine. In COSM6 cells, these mutants were expressed at
      equivalent concentrations, but at lower concentrations than OTR. Alanine
      substitution for H7.62 or Q7.66 did not substantially affect the affinity for OT
      (K(d) = 0.63 and 0.48 nM, respectively, vs 0.52 nM for the wild type), whereas
      substitution for H7.59, E7.63, or R7.67 reduced the affinity 5-6-fold. When
      expressed at equal concentrations, OTR-H7.62/A and OTR-Q7.66/A stimulated
      phosphatidylinositide turnover as well as OTR, whereas OTR-H7.59/A, OTR-E7.63/A,
      and OTR-R7.67/A exhibited an impaired ability to respond to OT. Therefore,
      residues H7.59, E7.63, and R7.67 within the putative hydrophilic interface
      appeared to influence both the OTR conformation and Galpha(q) coupling. To
      explore this further, five multiple alanine substitution mutants were
      constructed. Alanine modification at H7.62 and Q7.66 did not substantially affect
      the affinity for OT (K(d) = 0.75 nM), whereas any combination of alanine
      substitutions for H7.59, E7.63, and R7.67 produced mutant receptors that lost
      high-affinity ligand binding. While OTR-(H7.62,Q7.66)/A exhibited PLC activation
      equivalent to that of OTR, receptors with two or more changes in H7.59, E7.63,
      and R7.67 lost the ability to respond to OT in a dose-dependent manner. Five
      residues (L7.60, F7.61, L7.64, V7.65, and F7.68) in the opposite hydrophobic
      interface were also mutated to alanine. None of these substitutions affected
      ligand binding; only OTR-(L7.60,F7.61)/A had a somewhat weaker ability to
      activate PLC. These data are consistent with the prediction that these residues
      lie within an amphipathic alpha-helix and emphasize the importance of this
      hydrophilic interface, and particularly of H7.59, E7.63, and R7.67, in OTR
      function.

PMID- 15035621
TI  - Roles of curvature and hydrophobic interstice energy in fusion: studies of lipid
      perturbant effects.
AB  - We have examined the effects of small amounts (1-4 mol %) of lipids of different
      molecular shapes, long chain lipids, and hydrocarbon on the kinetics of PEG
      mediated fusion of 1,2-dioleoyl-3-sn-phosphatidylcholine/1,2-dioleoyl-3-sn
      phosphatidylethanolamine/sphingomyelin/cholesterol (DOPC/DOPE/SM/CH, 35:30:15:30)
      sonicated vesicles. The effects of these lipid perturbants were different for
      different steps in the fusion process and varied with the ratio of the cross
      sectional areas of headgroup to acyl chain moieties. For lipids with a ratio <1
      (negative intrinsic curvature), a decrease in this ratio led to a dramatic
      increase in the initial rate of vesicle contents mixing but left the initial rate
      of lipid mixing roughly unchanged. For lipids with ratios >1 (positive intrinsic
      curvature), the initial rates of both lipid and contents mixing decreased mildly
      with increasing ratio. In the context of the "stalk model" for fusion, lipid
      mixing reflects mainly formation of the initial fusion intermediate (stalk),
      while contents mixing reflects conversion of this intermediate either to a second
      intermediate or to a fusion pore. Results with positively curved lipids
      (ganglioside, GM1; lysophosphatidylcholine, LPCs) and negatively curved lipids
      (dioleoylglycerol, DOG, and 1,2-diphytanoyl-sn-glyvero-3-phosphatidylcholine,
      DPhPC) can be taken as supportive of the usual interpretation of the stalk model
      in terms of bending energy, but enhancement of fusion in the presence of long
      chain phospholipids, hexadecane, as well as a mixture of GM1 plus hexadecane
      could not be explained by their curvature alone. We propose that the ability of a
      lipid perturbant to compensate for lipid packing mismatch, that is, to lower
      "void" energy, must be taken into account, along with intrinsic curvature, to
      explain the ability of lipid perturbants to promote pore formation.

PMID- 15035620
TI  - Syntaxin 2 and SNAP-23 are required for regulated surfactant secretion.
AB  - The secretion of lung surfactant in alveolar type II cells is a complex process
      involving the fusion of lamellar bodies with the plasma membrane. This process is
      somewhat different from the exocytosis of hormones and neurotransmitters. For
      example, it is a relatively slower process, and lamellar bodies are very large
      vesicles with a diameter of approximately 1 microm. SNARE proteins are the
      conserved molecular machinery of exocytosis in the majority of secretory cells.
      However, their involvement in surfactant secretion has not been reported. Here,
      we showed that syntaxin 2 and SNAP-23 are expressed in alveolar type II cells.
      Both proteins are associated with the plasma membrane, and to some degree with
      lamellar bodies. An antisense oligonucleotide complementary to syntaxin 2
      decreased its mRNA and protein levels. The same oligonucleotide also inhibited
      surfactant secretion, independent of secretagogues. A peptide derived from the N
      terminus of syntaxin 2 or the C-terminus of SNAP-23 significantly inhibited
      Ca(2+)- and GTPgammaS-stimulated surfactant secretion from permeabilized type II
      cells in a dose-dependent manner. Furthermore, introduction of anti-syntaxin 2 or
      anti-SNAP-23 antibodies into permeabilized type II cells also inhibited
      surfactant release. Our results suggest that syntaxin 2 and SNAP-23 are required
      for regulated surfactant secretion.

PMID- 15035622
TI  - Phospholipid scramblase 1 is imported into the nucleus by a receptor-mediated
      pathway and interacts with DNA.
AB  - Phospholipid scramblase 1 (PLSCR1) is a multiply palmitoylated, Ca(2+)-binding,
      endofacial plasma membrane protein originally identified by its capacity to
      accelerate transbilayer movement of membrane phospholipids. We recently reported
      that when palmitoylation of PLSCR1 does not occur, it is localized to the nucleus
      rather than the plasma membrane. Nuclear localization of PLSCR1 was also observed
      upon induction of its de novo synthesis by cytokines such as interferon alpha
      that activate the PLSCR1 gene. Despite its capacity to enter the nucleus, its
      sequence does not predict a nuclear localization signal. To gain insight into the
      mechanism and potential significance of nuclear PLSCR1, we investigated the
      conditions required for its import and retention in the nucleus. We show that
      nuclear localization of PLSCR1 is dependent on cytosolic factors and energy.
      Furthermore, we show that PLSCR1 is specifically transported into the nucleus by
      the importin alpha/beta import pathway, and binds directly and with high affinity
      to importin alpha. Analysis of deletion mutants suggested that the NLS of PLSCR1
      is between residues 242 and 290 and, furthermore, that a peptide within this
      region encompassing residues (257)GKISKHWTGI(266) is sufficient for nuclear
      import when conjugated to BSA. In addition, in intact cells, mutation of
      positively charged amino acids within this putative NLS in the full-length
      protein completely blocked its entry into the nucleus, consistent with its role
      in targeting PLSCR1 to the nucleus. Release of PLSCR1 from the nucleus was only
      observed after treatment of cells with both detergent and an elevated NaCl
      concentration, or following DNase treatment of the nucleus, suggesting ionic
      interactions of PLSCR1 with a nuclear component bound to genomic DNA or directly
      with genomic DNA. Purified PLSCR1 was also found to bind directly to a genomic
      DNA-cellulose conjugate, and its elution from DNA also required an elevated NaCl
      concentration. These data support a mechanism of receptor-mediated nuclear import
      of PLSCR1 and suggest a potential nuclear function for this plasma membrane
      protein.

PMID- 15035623
TI  - Mapping the electron transfer interface between cytochrome b5 and cytochrome c.
AB  - To characterize the cytochrome b(5) (Cyt b(5))-cytochrome c (Cyt c) interactions
      during electron transfer, variants of Cyt b(5) have been employed to assess the
      contributions of electrostatic interactions (substitution of surface charged
      residues Glu44, Glu48, Glu56, and Asp60 and heme propionate), hydrophobic
      interactions, and the thermodynamic driving forces (substitutions for hydrophobic
      residues in heme pocket residues Phe35, Pro40, Val45, Phe58, and Val61). The
      electrostatic interactions play an important role in maintaining the stability
      and specificity of the Cyt b(5)-Cyt c complex that is formed. There is no
      essential effect on the intraprotein complex electron transfer even if most of
      the involved negatively charged residues on the surface of Cyt b(5) have been
      removed. The results support a dynamic docking paradigm for Cyt b(5)-Cyt c
      interactions. The orientation that is optimal for binding may not be optimal form
      for electron transfer. Substitution of hydrophobic residues does not have a
      significant effect on the binding between Cyt b(5) and Cyt c; rather, it
      regulates the electron transfer rates via changes in the driving force. Combining
      the electron transfer studies of the Cyt b(5)-Cyt c system and the Cyt b(5)-Zn
      Cyt c system, we obtain the reorganization energy (0.6 eV) at an ionic strength
      of 150 mM.

PMID- 15035624
TI  - Effects of sodium ions on DNA duplex oligomers: improved predictions of melting
      temperatures.
AB  - Melting temperatures, T(m), were systematically studied for a set of 92 DNA
      duplex oligomers in a variety of sodium ion concentrations ranging from 69 mM to
      1.02 M. The relationship between T(m) and ln [Na(+)] was nonlinear over this
      range of sodium ion concentrations, and the observed melting temperatures were
      poorly predicted by existing algorithms. A new empirical relationship was derived
      from UV melting data that employs a quadratic function, which better models the
      melting temperatures of DNA duplex oligomers as sodium ion concentration is
      varied. Statistical analysis shows that this improved salt correction is
      significantly more accurate than previously suggested algorithms and predicts
      salt-corrected melting temperatures with an average error of only 1.6 degrees C
      when tested against an independent validation set of T(m) measurements obtained
      from the literature. Differential scanning calorimetry studies demonstrate that
      this T(m) salt correction is insensitive to DNA concentration. The T(m) salt
      correction function was found to be sequence-dependent and varied with the
      fraction of G.C base pairs, in agreement with previous studies of genomic and
      polymeric DNAs. The salt correction function is independent of oligomer length,
      suggesting that end-fraying and other end effects have little influence on the
      amount of sodium counterions released during duplex melting. The results are
      discussed in the context of counterion condensation theory.

PMID- 15035625
TI  - Presenilin modulates Pen-2 levels posttranslationally by protecting it from
      proteasomal degradation.
AB  - The gamma-secretase complex functions to cleave several type I transmembrane
      proteins within their transmembrane domains. These include the amyloid precursor
      protein, which is central to Alzheimer's disease pathogenesis, as well as N
      cadherin and Notch, which regulate transcription. This complex is composed of
      four requisite integral membrane proteins: presenilin 1 (PS1) or presenilin 2
      (PS2), nicastrin, Pen-2, and Aph-1. How these proteins coordinately regulate one
      another and assemble to form a functional complex is not well understood. In this
      report we demonstrate that PS1 selectively enhances the stability of Pen-2
      protein but not that of nicastrin or Aph-1. In the absence of PS1, Pen-2 was
      rapidly degraded by the proteasome. As PS1 levels increased, so too did the half
      life of Pen-2 and therefore its steady-state levels. In addition, Pen-2 protein
      levels correlated with PS1 levels not only in cell culture but in transgenic
      mouse models as well. The genetic absence of PS1 and PS2, and therefore of gamma
      secretase-dependent mediation of transcriptional activity, did not affect Pen-2
      mRNA levels. Rather, presenilin (PS) regulates Pen-2 levels posttranslationally
      by preventing its degradation by the proteasome. Thus, the amount of Pen-2
      protein is effectively titrated by its PS binding partner, and the rapidity with
      which Pen-2 is degraded in the absence of PS interactions could provide a
      mechanism to tightly regulate gamma-secretase complex assembly.

PMID- 15035626
TI  - Determination of the pK for the acid-induced denaturation of ferrocytochrome c.
AB  - Optical absorption spectroscopy was used to characterize the acid-induced
      conformational transition of horse heart ferrocytochrome c in the presence of
      urea. By using linear extrapolation to zero denaturant concentration, an apparent
      pK value for denaturation was found to be 0.86 +/- 0.07 at 25 degrees C. Visible
      absorption spectra in the presence of high urea concentration indicate that the
      dominant population is a high-spin, five-coordinate form under acidic conditions.
      Ferricytochrome c, used as a model reference system, shows a linear dependence of
      pK values versus urea concentration in the range from 0 to 4.1 M. Our data also
      indicate that even at a pH below 2 the iron-sulfur bond in ferrocytochrome c is
      present.

PMID- 15035627
TI  - Correlation between catalytic efficiency and the transcription read-out in
      chemical complementation: a general assay for enzyme catalysis.
AB  - High-throughput assays for enzyme catalysis that can be applied to a broad range
      of chemical reactions are key to advances in directed evolution and proteomics.
      Recently, we reported such a general assay, chemical complementation, which links
      enzyme catalysis to reporter gene transcription in vivo using the yeast three
      hybrid assay. In this proof-of-principle experiment, it was shown that a wild
      type beta-lactamase enzyme could be isolated from a pool of inactive mutants
      using a lacZ screen. Ideally, however, such an assay should be able to
      distinguish enzymes based on their catalytic activity. Thus, here, we set out to
      determine if the catalytic efficiency of an enzyme variant does in fact correlate
      with its level of transcription activation in the chemical complementation assay.
      First, the reaction mechanism for the cleavage of the beta-lactam substrate used
      in the chemical complementation proof-of-principle experiment was determined.
      Then a series of beta-lactamase variants was designed to span several orders of
      magnitude in k(cat)/K(m). The activity of each variant was determined both in
      vitro using purified enzyme and in vivo in the chemical complementation
      transcription assay. Beta-lactamase variants spanning three-orders of magnitude
      in k(cat)/K(m) could be distinguished in the assay, and the catalytic efficiency
      of each variant correlated with its level of transcription activation in vivo.
      These results establish the suitability of chemical complementation for the
      directed evolution of enzymes with improvements in catalytic activity and for
      profiling the relative substrate specificities of a group of enzymes in
      proteomics applications.

PMID- 15035628
TI  - Probing the folding and unfolding dynamics of secondary and tertiary structures
      in a three-helix bundle protein.
AB  - Fast relaxation kinetics studies of the B-domain of staphylococcal protein A were
      performed to characterize the folding and unfolding of this small three-helix
      bundle protein. The relaxation kinetics were initiated using a laser-induced
      temperature jump and probed using time-resolved infrared spectroscopy. The
      kinetics monitored within the amide I' absorbance of the polypeptide backbone
      exhibit two distinct kinetics phases with nanosecond and microsecond relaxation
      times. The fast kinetics relaxation time is close to the diffusion limits placed
      on protein folding reactions. The fast kinetics phase is dominated by the
      relaxation of the solvated helix (nu = 1632 cm(-1)), which reports on the fast
      relaxation of the individual helices. The slow kinetics phase follows the
      cooperative relaxation of the native helical bundle core that is monitored by
      both solvated (nu = 1632 cm(-1)) and buried helical IR bands (nu = 1652 cm(-1)).
      The folding rates of the slow kinetics phase calculated over an extended
      temperature range indicate that the core formation of this protein follows a
      pathway that is energetically downhill. The unfolding rates are much more
      strongly temperature-dependent indicating an activated process with a large
      energy barrier. These results provide significant insight into the primary
      process of protein folding and suggest that fast formation of helices can drive
      the folding of helical proteins.

PMID- 15035629
TI  - Energetics of pore formation induced by membrane active peptides.
AB  - Antimicrobial peptides are known to form pores in cell membranes. We study this
      process in model bilayers of various lipid compositions. We use two of the best
      studied peptides, alamethicin and melittin, to represent peptides making two
      types of pores, that is, barrel-stave pores and toroidal pores. In both cases,
      the key control variable is the concentration of the bound peptides in the lipid
      bilayers (expressed in the peptide-lipid molar ratio, P/L). The method of
      oriented circular dichroism (OCD) was used to monitor the peptide orientation in
      bilayers as a function of P/L. The same samples were scanned by X-ray diffraction
      to measure the bilayer thickness. In all cases, the bilayer thickness decreases
      linearly with P/L and then levels off after P/L exceeds a lipid-dependent
      critical value, (P/L)*. OCD spectra showed that the helical peptides are oriented
      parallel to the bilayers as long as P/L < (P/L)*, but as P/L increases over
      (P/L)*, an increasing fraction of peptides changed orientation to become
      perpendicular to the bilayer. We analyzed the data by assuming an internal
      membrane tension associated with the membrane thinning. The free energy
      containing this tension term leads to a relation explaining the P/L-dependence
      observed in the OCD and X-ray diffraction measurements. We extracted the
      experimental parameters from this thermodynamic relation. We believe that they
      are the quantities that characterize the peptide-lipid interactions related to
      the mechanism of pore formation. We discuss the meaning of these parameters and
      compare their values for different lipids and for the two different types of
      pores. These experimental parameters are useful for further molecular analysis
      and are excellent targets for molecular dynamic simulation studies.

PMID- 15035630
TI  - The alpha-helical domain of liver fatty acid binding protein is responsible for
      the diffusion-mediated transfer of fatty acids to phospholipid membranes.
AB  - Intestinal fatty acid binding protein (IFABP) and liver FABP (LFABP), homologous
      proteins expressed at high levels in intestinal absorptive cells, employ markedly
      different mechanisms for the transfer of fatty acids (FAs) to acceptor membranes.
      Transfer from IFABP occurs during protein-membrane collisional interactions,
      while for LFABP, transfer occurs by diffusion through the aqueous phase. Earlier,
      we had shown that the helical domain of IFABP is critical in determining its
      collisional FA transfer mechanism. In the study presented here, we have
      engineered a pair of chimeric proteins, one with the "body" (ligand binding
      domain) of IFABP and the alpha-helical region of LFABP (alphaLbetaIFABP) and the
      other with the ligand binding pocket of LFABP and the helical domain of IFABP
      (alphaIbetaLFABP). The objective of this work was to determine whether the change
      in the alpha-helical domain of each FABP would alter the rate and mechanism of
      transfer of FA from the chimeric proteins in comparison with those of the wild
      type proteins. The fatty acid transfer properties of the FABP chimeras were
      examined using a fluorescence resonance transfer assay. The results showed a
      significant modification of the absolute rate of FA transfer from the chimeric
      proteins compared to that of the wild type, indicating that the slower rate of FA
      transfer observed for wild-type LFABP relative to that of wild-type IFABP is, in
      part, determined by the helical domain of the proteins. In addition to these
      quantitative changes, it was of great interest to observe that the apparent
      mechanism of FA transfer also changed when the alpha-helical domain was
      exchanged, with transfer from alphaLbetaIFABP occurring by aqueous diffusion and
      transfer from alphaIbetaLFABP occurring via protein-membrane collisional
      interactions. These results demonstrate that the alpha-helical region of LFABP is
      responsible for its diffusional mechanism of fatty acid transfer to membranes.

PMID- 15035631
TI  - Effect of signal peptide on the stability and folding kinetics of maltose binding
      protein.
AB  - While the role of the signal sequence in targeting proteins to specific
      subcellular compartments is well characterized, there are fewer studies that
      characterize its effects on the stability and folding kinetics of the protein. We
      report a detailed characterization of the folding kinetics and thermodynamic
      stabilities of maltose binding protein (MBP) and its precursor form, preMBP.
      Isothermal GdmCl and urea denaturation as a function of temperature and thermal
      denaturation studies have been carried out to compare stabilities of the two
      proteins. preMBP was found to be destabilized by about 2-6 kcal/mol (20-40%) with
      respect to MBP. Rapid cleavage of the signal peptide by various proteases shows
      that the signal peptide is accessible in the native form of preMBP. The observed
      rate constant of the major slow phase in folding was decreased 5-fold in preMBP
      relative to MBP. The rate constants of unfolding were similar at 25 degrees C,
      but preMBP also exhibited a large burst phase change in unfolding that was absent
      in MBP. At 10 degrees C, preMBP exhibited a higher unfolding rate than MBP as
      well as a large burst phase. The appreciable destabilization of MBP by signal
      peptide is functionally relevant, because it enhances the likelihood of finding
      the protein in an unfolded translocation-competent form and may influence the
      interactions of the protein with the translocation machinery. Destabilization is
      likely to result from favorable interactions between the hydrophobic signal
      peptide and other hydrophobic regions that are exposed in the unfolded state.

PMID- 15035632
TI  - Local conformational changes in the Vibrio Na+/galactose cotransporter.
AB  - Na(+) and sugar transport by cotransporters (symporters) is thought to occur as a
      series of ordered ligand-induced conformational changes. To localize these
      conformational changes in a bacterial Na(+)/galactose cotransporter, we have
      employed a combination of cysteine-scanning and fluorescence techniques. Single
      or pairs of cysteine residues were introduced into the external face of a
      cysteine-less Vibrio parahaemolyticus sodium/glucose cotransporter for expression
      in Escherichia coli, and each transporter was purified using affinity
      chromatography. All the mutant proteins retained transport activity in bacteria
      and proteoliposomes. Each mutant was exposed to two different fluorescence
      reagents, ThioGlo3 or pyrene maleimide, that are essentially nonfluorescent until
      they react with a thiol. Fluorescence was recorded as a function of time and
      ligand concentrations. The reagents specifically labeled six of the seven
      cysteine mutants, but only in Cysteine 423 was the fluorescence affected by
      ligands. The rate of labeling of Cys423 by ThioGlo3 or pyrene maleimide was
      reduced by D-galactose in Na(+) buffer. Furthermore, the fluorescence of Thioglo3
      labeled Cys423 was quenched by D-galactose, but only in the presence of Na(+).
      This quench was not accompanied by a Stokes shift and was not produced by
      nontransported sugars, e.g., L-glucose. Reducing the sodium concentration from
      200 to 10 mM decreased the apparent affinity for d-galactose without altering the
      maximum quench with saturating D-galactose. Reducing the galactose concentration
      from 20 to 0.5 mM reduced both the apparent affinity for Na(+) and the maximum
      quench at saturating Na(+). These results suggest an ordered reaction scheme with
      Na(+) binding first. The fluorescence results with ThioGlo3-labeled Cys423
      indicate that conformational changes underlying Na(+)/galactose cotransport occur
      at or near the extracellular domain between transmembrane helices 10 and 11.

PMID- 15035633
TI  - Role of calcineurin B homologous protein in pH regulation by the Na+/H+ exchanger
      1: tightly bound Ca2+ ions as important structural elements.
AB  - We studied the role of the interaction of calcineurin homologous protein 1 (CHP1)
      with the Na(+)/H(+) exchanger 1 (NHE1), particularly its EF-hand Ca(2+) binding
      motifs, in the intracellular pH (pH(i))-dependent regulation of NHE1. We found
      that (45)Ca(2+) binds to two EF-hand motifs (EF3 and 4) of the recombinant CHP1
      proteins with high affinity (apparent K(d) = approximately 90 nM). Complex
      formation between CHP1 and the CHP1 binding domain of NHE1 resulted in a marked
      increase in the Ca(2+) binding affinity (K(d) = approximately 2 nM) by promoting
      a conformational change of the EF-hands toward the tightly Ca(2+)-bound form.
      This suggests that CHP1 always contains two Ca(2+) ions when associated with NHE1
      in cells. Interestingly, overexpression of GFP-tagged CHP1 with mutations in EF3
      or EF4 significantly reduced the exchange activity in the neutral pH(i) range and
      partly impaired the activation of NHE1 in response to various stimuli, such as
      growth factors and osmotic stress. Furthermore, we found that, in addition to
      reducing the activity (V(max)), a CHP1 binding-defective NHE1 mutant had a marked
      reduction in pH(i) sensitivity ( approximately 0.7 pH unit acidic shift), which
      consequently abolished various regulatory responses of NHE1. These observations
      suggest that the association of NHE1 with CHP1 is crucial for maintenance of the
      pH(i) sensitivity of NHE1 and that tightly bound Ca(2+) ions may serve as
      important structural elements in the "pH(i) sensor" of NHE1.

PMID- 15035634
TI  - High-resolution field-cycling NMR studies of a DNA octamer as a probe of
      phosphodiester dynamics and comparison with computer simulation.
AB  - Phosphorus-spin longitudinal relaxation rates of the DNA duplex octamer
      [d(GGAATTCC)](2) have been measured from 0.1 to 17.6 T by means of conventional
      and new field-cycling NMR methods. The high-resolution field-cycling method is
      identical to a conventional relaxation experiment, except that after preparation
      the sample is moved pneumatically from its usual position at the center of the
      high-resolution magnet upward to a lower field above its normal position and then
      returned to the center for readout after it has relaxed for the programmed
      relaxation delay at the low field. This is the first measurement of all
      longitudinal relaxation rates R(1) of a nuclear species in a macromolecule over
      virtually the entire accessible magnetic field range. For detailed analysis,
      three magnetic field regions can be delineated: (i) dipolar relaxation dominates
      at fields below 2 T, (ii) chemical shift anisotropy (CSA) relaxation is roughly
      constant from 2 to 6 T, and (iii) a square-law increasing dependence is seen at
      fields higher than approximately 6 T due to internal motion CSA relaxation. The
      analysis provides a rotational correlation time (tau(r) = 4.1 +/- 0.3 ns) for the
      duplex at both 1.5 and 0.25 mM concentrations (of duplex) at 22 degrees C. For
      comparison, extraction of tau(r) in the conventional way from the ratio of
      T(1)/T(2) at 14 T yields 3.2 ns. The tau(r) discrepancy disappears when we
      exclude the contribution of internal motion from the R(1) in the ratio. The low
      field dipolar relaxation provides a weighted inverse sixth power sum of the
      distances from the phosphorus to the protons responsible for relaxation. This
      average is similar for all phosphates in the octamer and similar to that in
      previous B-DNA structures (its inverse sixth root is about 2.40 A for two
      different concentrations of octamer). The CSA relaxation at intermediate field
      provides an estimate of the order parameter squared, S(c)(2), for each
      phosphorus. S(c)(2) is about 0.7-1, clearly different for different phosphate
      linkages in the octamer duplex. The increasing R(1) at high fields reflects CSA
      relaxation due to internal motions, for which a correlation time, tau(hf), can be
      approximately extracted with the aid of additional measurements at 14.0 and 17.6
      T. We conclude that tau(hf) values are relatively large, in the range of about
      150 ps. Insight into the motions leading to this correlation time was gained by a
      28 ns molecular dynamics simulation of the molecule. S(2) and tau(s)
      (corresponding to tau(hf)) predicted by this simulation were in good agreement
      with the experimental values from the field-cycling data. Both the effect of
      Mg(2+) on the dynamic parameters extracted from (31)P relaxation rates and the
      field dependence of relaxation rates for several protons of the octamer were
      measured. High-resolution field cycling opens up the possibility of monitoring
      residue-specific dipolar interactions and dynamics for the phosphorus nuclei of
      diverse oligonucleotides.

PMID- 15035635
TI  - Synthesis and inhibitory action of novel acetogenin mimics with bovine heart
      mitochondrial complex I.
AB  - Studies on the inhibition mechanism of acetogenins, the most potent inhibitors of
      complex I, are useful to elucidate the structural and functional features of the
      terminal electron-transfer step of this enzyme. We synthesized acetogenin mimics
      that possess two alkyl tails without a gamma-lactone ring, named Deltalac
      acetogenin, and examined their inhibitory action on bovine heart mitochondrial
      complex I. Unexpectedly, the Deltalac-acetogenin carrying two n-undecanyl groups
      (compound 3) elicited very potent inhibition comparable to that of bullatacin.
      The inhibitory potency of compound 3 markedly decreased with shortening the
      length of either or both alkyl tails, indicating that symmetric as well as
      hydrophobic properties of the inhibitor are important for the inhibition. Both
      acetylation and deoxygenation of either or both of two OH groups adjacent to the
      tetrahydrofuran (THF) rings resulted in a significant decrease in inhibitory
      potency. These structural dependencies of the inhibitory action of Deltalac
      acetogenins are in marked contrast to those of ordinary acetogenins. Double
      inhibitor titration of steady-state complex I activity showed that inhibition of
      compound 3 and bullatacin are not additive, though the inhibition site of both
      inhibitors is downstream of iron-sulfur cluster N2. Our results indicate that the
      mode of inhibitory action of Deltalac-acetogenins differs from that of ordinary
      acetogenins. Therefore, Deltalac-acetogenins can be regarded as a novel type of
      inhibitor acting on the terminal electron-transfer step of complex I.

PMID- 15035636
TI  - The biliverdin chromophore binds covalently to a conserved cysteine residue in
      the N-terminus of Agrobacterium phytochrome Agp1.
AB  - Phytochromes are widely distributed biliprotein photoreceptors. Typically, the
      chromophore becomes covalently linked to the protein during an autocatalytic
      lyase reaction. Plant and cyanobacterial phytochromes incorporate bilins with a
      ring A ethylidene side chain, whereas other bacterial phytochromes utilize
      biliverdin as chromophore, which has a vinyl ring A side chain. For Agrobacterium
      phytochrome Agp1, site-directed mutagenesis provided evidence that biliverdin is
      bound to cysteine 20. This cysteine is highly conserved within bacterial
      homologues, but its role as attachment site has as yet not been proven. We
      therefore performed mass spectrometry studies on proteolytic holopeptide
      fragments. For that purpose, an Agp1 expression vector was re-engineered to
      produce a protein with an N-terminal affinity tag. Following proteolysis, the
      chromophore co-purified with a ca. 5 kDa fragment during affinity chromatography,
      showing that the attachment site is located close to the N-terminus. Mass
      spectrometry analyses performed with the purified chromopeptide confirmed the
      role of the cysteine 20 as biliverdin attachment site. We also analyzed the role
      of the highly conserved histidine 250 by site-directed mutagenesis. The
      homologous amino acid plays an important but yet undefined role in plant
      phytochromes and has been proposed as chromophore attachment site of Deinococcus
      phytochrome. We found that in Agp1, this amino acid is dispensable for covalent
      attachment, but required for tight chromophore-protein interaction.

PMID- 15035638
TI  - Effect of variations in the structure of a polyleucine-based alpha-helical
      transmembrane peptide on its interaction with phosphatidylglycerol bilayers.
AB  - High-sensitivity differential scanning calorimetry and Fourier transform infrared
      spectroscopy were used to study the interaction of a cationic alpha-helical
      transmembrane peptide, acetyl-Lys(2)-Leu(24)-Lys(2)-amide (L(24)), and members of
      the homologous series of anionic n-saturated diacyl phosphatidylglycerols (PGs).
      Analogues of L(24), in which the lysine residues were replaced by 2,3
      diaminopropionic acid (L(24)DAP), or in which a leucine residue at each end of
      the polyleucine sequence was replaced by a tryptophan (WL(22)W), were also
      studied to investigate the roles of lysine side-chain snorkeling and aromatic
      side-chain interactions with the interfacial region of phospholipid bilayers. The
      gel/liquid-crystalline phase transition temperature of the host PG bilayers is
      altered by these peptides in a hydrophobic mismatch-dependent manner, as
      previously found with zwitterionic phosphatidylcholine (PC) bilayers. However,
      all three peptides reduce the phase transition temperature and enthalpy to a
      greater extent in anionic PG bilayers than in zwitterionic PC bilayers, with
      WL(22)W having the largest effect. All three peptides form very stable alpha
      helices in PG bilayers, but small conformational changes are induced in response
      to a mismatch between peptide hydrophobic length and gel-state lipid bilayer
      hydrophobic thickness. Moreover, electrostatic and hydrogen-bonding interactions
      occur between the terminal lysine residues of L(24) and L(24)DAP and the polar
      headgroups of PG bilayers. However, such interactions were not observed in
      PG/WL(22)W bilayers, suggesting that the cation-pi interactions between the
      tryptophan and lysine residues predominate. These results indicate that the lipid
      peptide interactions are affected not only by the hydrophobic mismatch between
      these peptides and the host lipid bilayer, but also by the tryptophan-modulated
      electrostatic and hydrogen-bonding interactions between the positively charged
      lysine residues at the termini of these peptides and the negatively charged polar
      headgroups of the PG bilayers.

PMID- 15035637
TI  - Determinants of high-affinity binding and receptor activation in the N-terminus
      of CCL-19 (MIP-3 beta).
AB  - CC chemokine receptor 7 (CCR-7) is expressed on mature dendritic cells and T
      cells. Its ligands, CCL-19 (MIP-3beta) and CCL-21 (SLC), play an important role
      in the migration of these cells to secondary lymphoid organs where they are
      predominantly expressed. For most chemokines, the N-terminal domain preceding the
      first two conserved cysteines is involved in stabilizing the active conformation
      of its cognate receptors. We have chemically synthesized N-terminal analogues of
      CCL-19 with the aid of a native chemical ligation method to investigate structure
      function requirements of this ligand domain by performing ligand binding, GTP
      gammaS binding, and chemotaxis assays. Successive truncations of the N-terminus
      of CCL-19 reduced the affinity of the receptor for the ligand in a size-dependent
      manner. Furthermore, Ala substitutions of Asn(3), Asp(4), and Asp(7) show that
      the side chains of these residues are important for high-affinity binding of CCL
      19 to CCR-7. The effects observed were mirrored in both GTP-gammaS binding and
      chemotaxis assays, highlighting the functional importance of this ligand domain.
      We also describe two partial agonists of CCR-7 ([Nle(72)]CCL-19(6-77) and Ac
      [Nle(72)]CCL-19(7-77)), and identify the first analogue of CCL-19 (Ac
      [Nle(72)]CCL-19(8-77)) that acts as a functional antagonist in vitro (K(B)
      approximately 350 nM for GTP-gammaS binding assays). As mutations of both Glu(6)
      and Asp(7) to Ala did not dissociate effects on ligand binding from receptor
      activation, it is likely that the backbone of these two residues is crucial for
      agonist activity.

PMID- 15035639
TI  - Membrane fusion induced by the catalytic activity of a phospholipase
      C/sphingomyelinase from Listeria monocytogenes.
AB  - Listeria monocytogenes is a bacterium responsible for localized and generalized
      infections in humans and animals. It has the ability to spread from the cytoplasm
      of an infected cell to neighboring cells without becoming exposed to the
      extracellular space. The bacterium secretes a phospholipase C (PLC(LM)) that is
      active on glycerophospholipids, e.g., phosphatidylcholine, and on sphingomyelin;
      thus, PLC(LM) should be described more appropriately as a phospholipase
      C/sphingomyelinase. We have obtained PLC(LM) free from a frequent contaminant,
      listeriolysin O, using an improved purification procedure. PLC(LM) has been
      assayed on large unilamellar liposomes of defined lipid composition. The enzyme
      is activated by K(+) and Mg(2+), and readily degrades phospholipids in bilayer
      form, in the absence of detergents. Enzyme activity is accompanied by important
      changes in the structure of the phospholipid vesicles, namely, vesicle
      aggregation, intervesicular mixing of lipids, and mixing of aqueous contents,
      with very low leakage of vesicular contents. The data are interpreted as
      indicative of PLC(LM)-induced vesicle fusion. This is confirmed by the
      demonstration of intervesicular mixing of inner monolayer lipids, using a novel
      procedure. The observation of PLC(LM)-induced membrane fusion suggests a
      mechanism for the cell-to-cell propagation of the bacterium, which requires
      disruption of a double-membrane vacuole.

PMID- 15035640
TI  - Ionophoric activity of pluronic block copolymers.
AB  - Pluronic block copolymers (triblock copolymers of poly(ethylene oxide) and
      poly(propylene oxide)) exhibit a chemosensitizing effect on multidrug resistant
      cell lines. Changes in membrane permeability are hypothesized to be responsible
      because inhibition of drug transport mediated by both the multidrug-resistance
      associated protein and the P-glycoprotein drug efflux system has been observed.
      To test this hypothesis, we now have studied the ion conductivity mediated by
      Pluronic L61. Besides a detergent-like action, the copolymer was able to form
      regular channels and to exhibit carrier activity. Long living ion channels were
      formed by polymer oligomerization. Aggregate equilibrium was shifted toward L61
      monomers and dimers, which operated as mobile carriers. Copolymer-induced
      membrane permeability for potassium ions (1 M KCl) was less than 10(-8) cm s(-1),
      whereas the permeability for uncharged doxorubicin molecules (1 mM) was equal to
      5 x 10(-4) cm s(-1). The results are consistent with reports about an increased
      doxorubicin accumulation in cells (Venne, Li, S., Mandeville, R., Kabanov, A.,
      and Alakhov, V. Y. (1996) Cancer Res. 56, 3626-3629). However, the increased
      permeability contrasts with the polymer-mediated decrease of drug efflux from
      cells. Preferential polymer binding to membrane proteins may mask the unspecific
      effect of L61 observed on lipid bilayers.

PMID- 15035641
TI  - Phthalocyanine tetrasulfonates affect the amyloid formation and cytotoxicity of
      alpha-synuclein.
AB  - Alpha-synuclein is a pathological component of Parkinson's disease by
      constituting the filamentous component of Lewy bodies. Phthalocyanine (Pc)
      effects on the amyloidosis of alpha-synuclein have been examined. The copper
      complex of phthalocyanine tetrasulfonate (PcTS-Cu(2+)) caused the self
      oligomerization of alpha-synuclein while Pc-Cu(2+) did not affect the protein,
      indicating that introduction of the sulfonate groups was critical for the
      selective protein interaction. The PcTS-Cu(2+) interaction with alpha-synuclein
      has occurred predominantly at the N-terminal region of the protein with a K(d) of
      0.83 microM apart from the hydrophobic NAC (non-Abeta component of Alzheimer's
      disease amyloid) segment. Phthalocyanine tetrasulfonate (PcTS) lacking the
      intercalated copper ion also showed a considerable affinity toward alpha
      synuclein with a K(d) of 3.12 microM, and its binding site, on the other hand,
      was located at the acidic C-terminus. These mutually exclusive interactions
      between PcTS and PcTS-Cu(2+) toward alpha-synuclein resulted in distinctive
      features on the kinetics of protein aggregation, morphologies of the final
      aggregates, and their in vitro cytotoxicities. The PcTS actually suppressed the
      fibrous amyloid formation of alpha-synuclein, but it produced the chopped-wood
      looking protein aggregates. The aggregates showed rather low toxicity (9.5%) on
      human neuroblastoma cells (SH-SY5Y). In fact, the PcTS was shown to effectively
      rescue the cell death of alpha-synuclein overexpressing cells caused by the
      lactacystin treatment as a proteasome inhibitor. The anti-aggregative and anti
      amyloidogenic properties of PcTS were also demonstrated with alcohol
      dehydrogenase, glutathione S-transferase, and amyloid beta/A4 protein under their
      aggregative conditions. The PcTS-Cu(2+), on the other hand, promoted the protein
      aggregation of alpha-synuclein, which gave rise to the fibrillar protein
      aggregates whose cytotoxicity became significant to 35.8%. Taken together, the
      data provided in this study indicate that PcTS/PcTS-Cu(2+) could be considered as
      possible candidates for the development of therapeutic or prophylactic strategies
      against the alpha-synuclein-related neurodegenerative disorders.

PMID- 15035642
TI  - The mipafox-inhibited catalytic domain of human neuropathy target esterase ages
      by reversible proton loss.
AB  - Aging of organophosphorus (OP)-compound-inhibited neuropathy target esterase
      (NTE) is the critical event that initiates OP-compound-induced delayed
      neurotoxicity (OPIDN). Aging has classically been considered to involve side
      group loss from phosphylated NTE, rendering the enzyme refractory to
      reactivation. N,N'-Diisopropylphosphorodiamidofluoridate (mipafox, MIP)-inhibited
      NTE has been thought to age quickly; however, it can be reactivated under acidic
      conditions. The present study was undertaken to determine whether MIP-inhibited
      human recombinant NTE esterase domain (NEST) ages classically by isopropylamine
      loss. Diisopropylphosphorofluoridate (DFP), the oxygen analogue of MIP, was used
      for comparison. Kinetic values for DFP against NEST were as follows: k(i) = 17
      200 +/- 180 M(-1) min(-1); reactivation t(1/2) approximately 90 min at pH 8.0 and
      approximately 60 min at pH 5.2; k(4) = 0.108 +/- 0.041 min(-1) at pH 8.0 and
      0.181 +/- 0.034 min(-1) at pH 5.2. Kinetic values for MIP against NEST were as
      follows: k(i) = 1880 +/- 61 M(-1) min(-1); reactivation t(1/2) = 0 min at pH 8.0
      and approximately 60 min at pH 5.2; aging was complete at all time points tested
      at pH 8.0, but no aging occurred at pH 5.2. Mass spectrometry revealed a mass
      shift of 123.0 +/- 0.6 Da for the active site peptide peak of aged DFP-inhibited
      NEST, corresponding to a monoisopropyl phosphate adduct. In contrast, the
      analogous mass shift for aged MIP-inhibited NEST was 162.8 +/- 0.6 Da,
      corresponding to the intact N,N'-diisopropylphosphorodiamido adduct. Thus, MIP
      inhibited NEST does not age by isopropylamine loss. However, because kinetically
      aged MIP-inhibited NEST yields an intact adduct capable of reversible
      deprotonation, aging could occur by proton loss. Indeed, MIP-inhibited NEST does
      not age at pH 5.2 but ages immediately and completely at pH 8.0. Therefore, we
      conclude that the MIP-NEST conjugate ages by deprotonation rather than classical
      side-group loss.

PMID- 15035643
TI  - Phosphorylated p40PHOX as a negative regulator of NADPH oxidase.
AB  - The leukocyte NADPH oxidase catalyzes the production of O(2)(-) from oxygen at
      the expense of NADPH. Activation of the enzyme requires interaction of the
      cytosolic factors p47(PHOX), p67(PHOX), and Rac2 with the membrane-associated
      cytochrome b(558). Activation of the oxidase in a semirecombinant cell-free
      system in the absence of an amphiphilic activator can be achieved by
      phosphorylation of the cytosolic factor p47(PHOX) by protein kinase C. Another
      cytosolic factor, p40(PHOX), was recently shown to be phosphorylated on serine
      and threonine residues upon activation of NADPH oxidase, but both stimulatory and
      inhibitory roles were reported. In the present study, we demonstrate that the
      addition of phosphorylated p40(PHOX) to the cell-free system inhibits NADPH
      oxidase activated by protein kinase C-phosphorylated p47(PHOX), an effect not
      observed with the unphosphorylated p40(PHOX). Moreover phosphorylated p40(PHOX)
      inhibits the oxidase if added before or after full activation of the enzyme.
      Direct mutagenesis of protein kinase C consensus sites enables us to conclude
      that phosphorylation of threonine 154 is required for the inhibitory effect of
      p40(PHOX) to occur. Although the phosphorylated mutants and nonphosphorylated
      mutants are still able to interact with both p47(PHOX) and p67(PHOX) in pull-down
      assays, their proteolysis pattern upon thrombin treatment suggests a difference
      in conformation between the phosphorylated and nonphosphorylated mutants. We
      postulate that phosphorylation of p40(PHOX) on threonine 154 leads to an
      inhibitory conformation that shifts the balance toward an inhibitory role and
      blocks oxidase activation.

PMID- 15035644
TI  - N-acetyl-p-benzoquinone imine, the toxic metabolite of acetaminophen, is a
      topoisomerase II poison.
AB  - Although acetaminophen is the most widely used analgesic in the world, it is also
      a leading cause of toxic drug overdoses. Beyond normal therapeutic doses, the
      drug is hepatotoxic and genotoxic. All of the harmful effects of acetaminophen
      have been attributed to the production of its toxic metabolite, N-acetyl-p
      benzoquinone imine (NAPQI). Since many of the cytotoxic/genotoxic events
      triggered by NAPQI are consistent with the actions of topoisomerase II-targeted
      drugs, the effects of this metabolite on human topoisomerase IIalpha were
      examined. NAPQI was a strong topoisomerase II poison and increased levels of
      enzyme-mediated DNA cleavage >5-fold at 100 microM. The compound induced scission
      at a number of DNA sites that were similar to those observed in the presence of
      the topoisomerase II-targeted anticancer drug etoposide; however, the relative
      site utilization differed. NAPQI strongly impaired the ability of topoisomerase
      IIalpha to reseal cleaved DNA molecules, suggesting that inhibition of DNA
      religation is the primary mechanism underlying cleavage enhancement. In addition
      to its effects in purified systems, NAPQI appeared to increase levels of DNA
      scission mediated by human topoisomerase IIalpha in cultured CEM leukemia cells.
      In contrast, acetaminophen did not significantly affect the DNA cleavage activity
      of the human enzyme in vitro or in cultured CEM cells. Furthermore, the analgesic
      did not interfere with the actions of etoposide against the type II enzyme. These
      results suggest that at least some of the cytotoxic/genotoxic effects caused by
      acetaminophen overdose may be mediated by the actions of NAPQI as a topoisomerase
      II poison.

PMID- 15035645
TI  - The N-terminus of Drosophila SU(VAR)3-9 mediates dimerization and regulates its
      methyltransferase activity.
AB  - In most eukaryotes, the histone methyltransferase SU(VAR)3-9 and its orthologues
      play a major role in the function of centromeric heterochromatin. Although the
      methyltransferase domain is required for the formation of a fully functional
      centromere, mutations within other regions of the gene such as the N-terminus
      also have a strong impact on its in vivo function. To analyze the contribution of
      the N-terminus on the methyltransferase activity, we have expressed the full
      length Drosophila SU(VAR)3-9 (dSU(VAR)3-9) together with various N-terminal
      deletions in Escherichia coli and analyzed the structural and enzymatic
      properties of the purified recombinant enzymes. Full-length dSU(VAR)3-9
      specifically methylates lysine 9 within histone H3 on peptides, on intact
      histones, and, to a lesser extent, on nucleosomes. A detailed analysis of the
      reaction products shows that dSU(VAR)3-9 adds two methyl groups to an
      unmethylated H3 tail peptide in a nonprocessive manner. The full-length enzyme
      elutes with an apparent molecular weight of 160 kDa from a gel filtration column,
      which indicates the formation of a dimer. This property is dependent on an intact
      N-terminus. In contrast to the full-length enzymes, proteins lacking the N
      terminus fail to dimerize, and show a 10-fold lower specific activity and a
      linear dependence of methyltransferase activity on enzyme concentration. A N
      terminal peptide containing amino acids 1-152 of dSU(VAR)3-9 is sufficient to
      mediate this interaction in vitro. The dimerization of dSU(VAR)3-9 and the
      subsequent increase of its methyltransferase activity provide a starting point to
      understand the molecular details of the formation of heterochromatic structures
      in vivo.

PMID- 15035646
TI  - Subunit proximity in the H+-translocating NADH-quinone oxidoreductase probed by
      zero-length cross-linking.
AB  - The proton-translocating NADH-quinone oxidoreductase (NDH-1) of Paracoccus
      denitrificans is composed of 14 different subunits (designated Nqo1-14), seven of
      which are located in the membrane domain and the other seven in the peripheral
      domain. It has been previously reported that membrane domain subunit Nqo7 (ND3)
      directly interacts with peripheral subunit Nqo6 (PSST) by using a cross-linker, m
      maleimidobenzoyl-N-hydrosuccinimide ester, and heterologous expression [Di
      Bernardo, S., and Yagi, T. (2001) FEBS Lett. 508, 385-388]. To further explore
      the near-neighbor relationship of the subunits, a zero-length cross-linker, 1
      ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), and the Paracoccus membranes
      were used, and the cross-linked products were examined with antibodies specific
      to subunits Nqo1-11. The Nqo6 subunit was cross-linked to subunit Nqo9 (TYKY). In
      addition, a ternary product of Nqo3 (75k), Nqo6, and Nqo7 and binary products of
      Nqo3 and Nqo6 and of Nqo6 and Nqo7 were observed, but a binary product of Nqo3
      and Nqo7 was not detected. The Nqo4 (49k) subunit was found to be associated with
      the Nqo7 subunit. Furthermore, Paracoccus subunits Nqo3, Nqo6, and Nqo7 were
      heterologously coexpressed in Escherichia coli, and EDC cross-linking experiments
      were carried out using the E. coli membranes expressing these three subunits. The
      results were the same as those obtained with Paracoccus membranes. On the basis
      of the data, subunit arrangements of NDH-1 were discussed.

PMID- 15035648
TI  - Neonatal lupus: clinical features and management.
AB  - Neonatal lupus is an uncommon autoimmune disease manifested primarily by
      cutaneous lupus lesions and/or congenital heart block. Maternal autoantibodies of
      the Ro/La family are present in virtually every case, although only approximately
      1% of women who have these autoantibodies will have a baby with neonatal lupus.
      The cutaneous lesions of neonatal lupus may be present at birth, but more often
      develop within the first few weeks of life. Lesions are most common on the face
      and scalp, often in a distinctive periorbital distribution. Lesions tend to
      resolve in a few weeks or months without scarring. The most common cardiac
      manifestation of neonatal lupus is complete heart block. Heart block typically
      begins in utero during the second or third trimester. In some cases, heart block
      begins as first- or second-degree block and then progresses to third-degree
      block. Complete heart block, once established, appears to be irreversible. In
      some cases, cardiomyopathy occurs together with complete heart block. Most cases
      have been noted at birth, but delayed dilated cardiomyopathy has been reported.
      There have been a few cases of endocardial fibroelastosis occurring in the
      absence of congenital heart block. Hepatobiliary disease occurs in about 10% of
      cases. Three types of hepatobiliary disease have been observed: liver failure
      occurring at birth or in utero, transient conjugated hyperbilirubinemia occurring
      in infants, or transient transaminase elevations occurring in infants.
      Hematologic disease, consisting of thrombocytopenia, neutropenia, or anemia,
      occurs in about 10% of cases. It is common for children with neonatal lupus not
      to have the full expression of disease, but rather to have only one or two organ
      systems involved. The diagnosis rests largely on the finding of compatible
      clinical manifestations plus maternal autoantibodies to Ro and/or La, or, in a
      few cases, to U1 ribonuclear protein. Although the pathogenesis has not been
      conclusively established, accumulating evidence, including evidence from animal
      models, implicates autoantibodies in the pathogenesis of the disease. Therapeutic
      interventions include attempts at prevention, early intervention, and treatment
      of well established disease, mainly through the use of systemic corticosteroids.
      Optimal therapy has yet to be determined. The long-term prognosis for children
      who have had neonatal lupus is still under investigation, but some children who
      had neonatal lupus have developed other autoimmune diseases later in childhood.
      About half of the mothers are asymptomatic at the time of presentation of the
      child, but some of these women eventually develop symptoms of autoimmune disease.

PMID- 15035649
TI  - Epidemiology and treatment of juvenile sexual offending.
AB  - The juvenile sex offender is defined as a youth who commits any sexual act with a
      person of any age against the victim's will, or in an aggressive, exploitative,
      or threatening manner. The term 'child molester' refers to those who choose only,
      or primarily, child victims. In this article, we mostly focus on adolescents aged
      between 13 and 18 years. To reduce sex crimes and the risk of adolescent sexual
      re-offending, effective treatment strategies have to be implemented for
      adolescent sexual offenders. Supervision and treatment recommendations for
      juvenile sex offenders initially emerged from the literature on adult sex
      offenders. Treatment must include behavioral therapy, family therapy, and
      psychosocial interventions. Pharmacotherapy is not always a first-line treatment.
      Antidepressants (especially selective serotonin reuptake inhibitors) offer
      promise in the treatment of adolescent sexual offending but further controlled
      studies are needed. In some rare situations, however, especially when severe
      paraphilic behaviors (such as pedophilia) are present, an hormonal intervention
      such as cyproterone acetate treatment may be needed.

PMID- 15035650
TI  - Growth hormone treatment in children: review of safety and efficacy.
AB  - Since the advent of growth hormone (GH), the pediatric applications of GH therapy
      have expanded. Children with a wide variety of growth disorders have received GH
      treatment. The therapeutic effects and safety profile of GH in a number of
      pediatric conditions are reviewed, including GH deficiency (GHD), Turner
      syndrome, chronic renal failure, children born small for gestational age, Prader
      Willi syndrome, juvenile chronic arthritis, and cystic fibrosis. GH therapy has
      been clearly shown to improve height velocity during childhood in a variety of
      pediatric conditions in which growth is compromised. There is now data that
      confirms GH treatment also improves final height in a number of diagnostic
      subgroups. Early initiation and individualization of GH treatment has the
      potential to normalize childhood growth in children with idiopathic GHD and
      enable them to achieve their genetic target height in a cost-effective manner. In
      children in whom GHD is not the main factor compromising growth, supra
      physiological doses of GH have been shown to increase height velocity during
      childhood and final height. The development of predictive models for these
      conditions may allow further improvements in height outcome while maintaining an
      acceptable safety profile. Survivors of childhood malignancy, particularly those
      who have had craniospinal irradiation, represent a particularly challenging
      group. They appear to be less responsive to GH than children with idiopathic GHD
      and have a tendency to enter puberty at an earlier age. Both of these factors
      have a negative impact on their final height. Strategies that combine GH
      treatment with suppression of puberty using a gonadotropin releasing hormone
      analog may result in improved height outcomes. When children with GHD are treated
      with standard doses of GH there is a strong safety record. Adverse events during
      GH therapy are uncommon and often not drug related. Continued surveillance into
      adult life is crucial however, particularly in children receiving supra
      physiological doses of GH or whose underlying condition increases their risk of
      adverse effects.

PMID- 15035653
TI  - Flavor and taste of lansoprazole strawberry-flavored delayed-release oral
      suspension preferred over ranitidine peppermint-flavored oral syrup: in children
      aged between 5-11 years.
AB  - OBJECTIVE: To compare the flavor and taste preference of two acid-inhibitory
      therapies in healthy children aged between 5-11 years. METHODS: A single-site,
      single-blind, taste test trial was conducted in which 111 children participated
      after parental consent. One teaspoonful (5 mL) of lansoprazole delayed-release
      oral suspension (strawberry-flavored) and ranitidine oral syrup (peppermint
      flavored) were provided to each child with a 10-minute break between samples.
      Children tasted the sample, swished it in their mouth for 10 seconds, and then
      expectorated the sample. Spring water and crackers were used to clear the palate
      between samples. After each sampling, children were observed for facial
      expressions and asked to rate their degree of liking of each sample based on a 5
      point facial hedonic scale (5=like it very much, 1=dislike it very much). Likes,
      dislikes, and product preference were recorded. RESULTS: Of the 56 female and 54
      male children who tasted both samples, 95% (105/110) preferred lansoprazole.
      Taste and flavor were the most often cited reasons for preferring lansoprazole
      (61 and 17 children, respectively) while three children preferred the flavor of
      ranitidine oral syrup. Lansoprazole received a higher mean liking rating compared
      with ranitidine (mean liking scores of 4.1 and 2.2, respectively). There was no
      significant difference in the preference for lansoprazole between age groups and
      gender with the degree of liking scores ranging between 3.5-4.4. Forty-two
      children disliked the texture of the lansoprazole oral suspension, citing the
      granules (31/110), thickness (7/110), or consistency/texture (4/110),
      specifically. CONCLUSION: After sampling both products, 95% of children preferred
      the flavor and taste of the strawberry-flavored lansoprazole delayed-release oral
      suspension compared with the peppermint-flavored ranitidine oral syrup.

PMID- 15035652
TI  - Medications that can be fatal for a toddler with one tablet or teaspoonful: a
      2004 update.
AB  - OBJECTIVE: To provide an updated list of the highly toxic medications in North
      America that can kill a 10 kg toddler upon ingestion of 1-2 dose units. METHODS:
      All drugs available in North America were reviewed and their reported lethal
      doses in children or adults (where no pediatric data existed) were identified.
      The dose units of drugs available in North America were subsequently identified,
      followed by those dose units that could kill a toddler upon ingestion of 1-2 dose
      units or teaspoonfuls. RESULTS: Tricyclic antidepressants, antipsychotics,
      quinine derivatives, calcium channel blockers, opioids, and oral hypoglycemics
      can kill a toddler with 1-2 dose units. This list of drugs was responsible for
      40% of toddler fatalities reported to the American Association of Poison Control
      Center Toxic Exposure Surveillance System between 1990-2000. CONCLUSION: Drugs
      that can kill a toddler with 1-2 dose units should be known to clinicians as such
      exposures warrant immediate and intensive management. A new system of special
      labeling of these drugs should be considered.

PMID- 15035651
TI  - Neuroblastoma: evolving therapies for a disease with many faces.
AB  - Neuroblastoma is the most common extra-cranial solid tumor in children and has a
      heterogeneous clinical presentation and course. Clinical and biologic features of
      this disease have been used to develop risk-based therapy. Patients with low-risk
      disease can be treated with surgery alone. Patients with intermediate-risk
      features have an excellent prognosis after treatment with surgery and a
      relatively short course of standard dose chemotherapy. Unfortunately, most
      children with neuroblastoma present with advanced disease. More than 60% of
      patients with high-risk features will succumb to their disease despite intensive
      therapy including a myeloablative consolidation. Research efforts to understand
      the biologic basis of neuroblastoma and to identify new, more effective therapies
      are essential to improve the outcome for these children.

PMID- 15035654
TI  - Hypersensitivity to topiramate sprinkle capsules does not preclude the use of
      topiramate tablets.

PMID- 15035655
TI  - Fluorimetric estimation of the concentration of NADH from human blood samples.
AB  - We report the quantitative fluorimetric estimation of the concentration of NADH
      in human blood samples. To measure both free and bound NADH, the 340-nm-excited
      fluorescence spectra was recorded from blood samples to which SDS was added.
      Diffuse reflectance and the transmittance spectra of the same sample were also
      recorded over the wavelength range 340-650 nm. These measurements were used to
      correct the measured fluorescence spectra for the wavelength-dependent reduction
      in fluorescence due to absorption and scattering in the blood sample. NADH
      concentrations estimated using the corrected fluorescence spectra were found to
      be in reasonable agreement with the concentrations estimated by the biochemical
      method.

PMID- 15035656
TI  - SUT1-promoted sterol uptake involves the ABC transporter Aus1 and the
      mannoprotein Dan1 whose synergistic action is sufficient for this process.
AB  - Efficient sterol influx in the yeast Saccharomyces cerevisiae is restricted to
      anaerobiosis or to haem deficiency resulting from mutations. Constitutive
      expression of SUT1, an hypoxic gene encoding a transcriptional regulator, induces
      sterol uptake in aerobiosis. A genome-wide approach using DNA microarray was used
      to identify the mediators of SUT1 effects on aerobic sterol uptake. A total of
      121 ORFs (open reading frames) were significantly and differentially expressed
      after SUT1 overexpression, 61 down-regulated and 60 up-regulated. Among these
      genes, the role of the putative ABC transporter (ATP-binding-cassette
      transporter) Aus1, and of the cell-wall mannoprotein Dan1, was characterized
      better. These two genes play an essential role in aerobic sterol uptake, since
      their deletion compromised the SUT1 effects, but individual overexpression of
      either of these genes in a wild-type background was not sufficient for this
      process. However, constitutive co-expression of AUS1 and DAN1 in a wild-type
      background resulted in sterol influx in aerobiosis. These results suggest that
      the corresponding proteins may act synergistically in vivo to promote sterol
      uptake.

PMID- 15035657
TI  - Regio- and stereo-chemical oxidation of linoleic acid by human myoglobin and
      hydrogen peroxide: Tyr(103) affects rate and product distribution.
AB  - Mb (myoglobin) plus H2O2 catalyses the oxidation of various substrates via a
      peroxidase-like activity. A Y103F (Tyr103-->Phe) variant of human Mb has been
      constructed to assess the effect of exchanging an electron-rich oxidizable amino
      acid on the peroxidase activity of human Mb. Steady-state analyses of reaction
      mixtures containing Y103F Mb, purified linoleic acid and H2O2 revealed a lower
      total yield of lipid oxidation products than mixtures containing the wild-type
      protein, consistent with the reported decrease in the rate constant for reaction
      of Y103F Mb with H2O2 [Witting, Mauk and Lay (2002) Biochemistry 41, 11495
      11503]. Irrespective of the Mb employed, lipid oxidation yielded 9(R/S)-HODE
      [9(R,S)-hydroxy-10E,12Z-octadecadienoic acid] in preference to 13(R/S)-HODE
      [13(R,S)-hydroxy-9Z,11E-octadecadienoic acid], while 9- and 13-keto
      octadecadienoic acid were formed in trace amounts. However, lipid oxidation by
      the Y103F variant of Mb proceeded with a lower V(max) value and an increased K(m)
      value relative to the wild-type control. Consistent with the increased K(m), the
      product distribution from reactions with Y103F Mb showed decreased selectivity
      compared with the wild-type protein, as judged by the decreased yield of 9(S)
      relative to 9(R)-HODE. Together, these data verify that Tyr103 plays a
      significant role in substrate binding and orientation in the haem pocket of human
      Mb. Also, the midpoint potential for the Fe(III)/(II) one-electron reduction was
      shifted slightly, but significantly, to a higher potential, confirming the
      importance of Tyr103 to the hydrogen-bonding network involving residues that line
      the haem crevice of human Mb.

PMID- 15035658
TI  - Binding of the DNA-dependent protein kinase catalytic subunit to Holliday
      junctions.
AB  - DNA-PK (DNA-dependent protein kinase) is a double-strand break sensor involved in
      DNA repair and signal transduction. In the present study, we constructed site
      directed cross-linking probes to explore the range of DNA discontinuities that
      are recognized by DNA-PK(CS) (DNA-PK catalytic subunit). A comparison between
      different substrate architectures showed that DNA-PK(CS) associates
      preferentially with the crossover region of synthetic Holliday junctions. This
      interaction with four-way junctions was preserved when biotin-streptavidin
      complexes were assembled at the termini to exclude the binding of Ku proteins.
      The association of DNA-PK(CS) with Holliday junctions was salt-labile even in the
      presence of Ku proteins, but this interaction could be stabilized when the DNA
      probes were incubated with the endogenous enzyme in nuclear extracts of human
      cells. Cross-linking of the endogenous enzyme in cellular extracts also
      demonstrated that DNA-PK(CS) binds to DNA ends and four-way junctions with
      similar affinities in the context of a nuclear protein environment. Kinase assays
      using p53 proteins as a substrate showed that, in association with four-way
      structures, DNA-PK(CS) adopts an active conformation different from that in the
      complex with linear DNA. Our results are consistent with a structure-specific,
      but Ku- and DNA end-independent, recruitment of DNA-PK(CS) to Holliday junction
      intermediates. This observation suggests an unexpected functional link between
      the two main pathways that are responsible for the repair of DNA double-strand
      breaks in mammalian cells.

PMID- 15035661
TI  - Biotechnological applications for surface-engineered bacteria.
AB  - Display of heterologous proteins on the surface of micro-organisms, enabled by
      means of recombinant DNA technology, has become an increasingly popular strategy
      in microbiology, biotechnology and vaccinology. Both Gram-negative and Gram
      positive bacteria have been investigated for potential applications. The present
      review will describe the most commonly used systems for bacterial display, with a
      focus on the biotechnology applications. Live bacterial vaccine-delivery vehicles
      have long been investigated through the surface display of foreign antigens and,
      recently, 'second-generation' vaccine-delivery vehicles have been generated by
      the addition of mucosal targeting signals, as a means to increase immune
      responses. Engineered bacteria have also the potential to act as novel microbial
      biocatalysts with heterologous enzymes immobilized as surface exposed on the
      bacterial cell surface. They provide the potential for new types of whole-cell
      diagnostic devices, since single-chain antibodies and other type of tailor-made
      binding proteins can be displayed on bacteria. Bacteria with increased binding
      capacity for certain metal ions can be created, and potential environmental or
      biosensor applications for such recombinant bacteria as biosorbents are being
      explored. Certain bacteria have also been employed to display various polypeptide
      libraries for use as devices in in vitro selection applications. Part of the
      present review has been devoted to a more in-depth description of a promising
      Gram-positive display system, i.e. Staphylococcus carnosus, and its applications.
      The review describes the basic principles of the different bacterial display
      systems and discusses current uses and possible future trends of these emerging
      technologies.

PMID- 15035659
TI  - Enzymic and structural characterization of nepenthesin, a unique member of a
      novel subfamily of aspartic proteinases.
AB  - Carnivorous plants are known to secrete acid proteinases to digest prey, mainly
      insects, for nitrogen uptake. In the present study, we have purified, for the
      first time, to homogeneity two acid proteinases (nepenthesins I and II) from the
      pitcher fluid of Nepenthes distillatoria (a pitcher-plant known locally as
      badura) and investigated their enzymic and structural characteristics. Both
      enzymes were optimally active at pH approx. 2.6 towards acid-denatured
      haemoglobin; the specificity of nepenthesin I towards oxidized insulin B chain
      appears to be similar, but slightly wider than those of other APs (aspartic
      proteinases). Among the enzymic properties, however, the most notable is their
      unusual stability: both enzymes were remarkably stable at or below 50 degrees C,
      especially nepenthesin I was extremely stable over a wide range of pH from 3 to
      10 for over 30 days. This suggests an evolutionary adaptation of the enzymes to
      their specific habitat. We have also cloned the cDNAs and deduced the complete
      amino acid sequences of the precursors of nepenthesins I and II (437 and 438
      residues respectively) from the pitcher tissue of N. gracilis. Although the
      corresponding mature enzymes (each 359 residues) are homologous with ordinary
      pepsin-type APs, both enzymes had a high content of cysteine residues (12
      residues/molecule), which are assumed to form six unique disulphide bonds as
      suggested by computer modelling and are supposed to contribute towards the
      remarkable stability of nepenthesins. Moreover, the amino acid sequence identity
      of nepenthesins with ordinary APs, including plant vacuolar APs, is remarkably
      low (approx. 20%), and phylogenetic comparison shows that nepenthesins are
      distantly related to them to form a novel subfamily of APs with a high content of
      cysteine residues and a characteristic insertion, named 'the nepenthesin-type AP
      specific insertion', that includes a large number of novel, orthologous plant APs
      emerging in the gene/protein databases.

PMID- 15035660
TI  - Intracellular transport of human lysosomal alpha-mannosidase and alpha
      mannosidosis-related mutants.
AB  - Human LAMAN (lysosomal a-mannosidase) was synthesized as a 120 kDa precursor in
      transfected COS cells [African-green-monkey kidney cells], which was partly
      secreted as a single-chain form and partly sorted to the lysosomes being
      subsequently cleaved into three peptides of 70, 40 and 15 kDa respectively. Both
      the secreted and the lysosomal forms contained endo H (endoglucosidase H)
      resistant glycans, suggesting a common pathway through the trans-Golgi network. A
      fraction of LAMAN was retained intracellularly as a single-chain endo H-sensitive
      form, probably in the ER (endoplasmic reticulum). The inherited lack of LAMAN
      causes the autosomal recessive storage disease a-mannosidosis. To understand the
      biochemical consequences of the disease-causing mutations, 11 missense mutations
      and two in-frame deletions were introduced into human LAMAN cDNA by in vitro
      mutagenesis and the resulting proteins were expressed in COS cells. Some selected
      mutants were also expressed in Chinese-hamster ovary cells. T355P (Thr355Pro),
      P356R, W714R, R750W and L809P LAMANs as well as both deletion mutants were
      misfolded and arrested in the ER as inactive single-chain forms. Six of the
      mutants were transported to the lysosomes, either with less than 5% of normal
      specific activity (H72L, D196E/N and R220H LAMANs) or with more than 30% of
      normal specific activity (E402K LAMAN). F320L LAMAN resulted in much lower
      activity in Chinese-hamster ovary cells when compared with COS cells. Modelling
      into the three-dimensional structure revealed that the mutants with highly
      reduced specific activities contained substitutions of amino acids involved in
      the catalysis, either co-ordinating Zn2+ (His72 and Asp196), stabilizing the
      active-site nucleophile (Arg220) or positioning the active-site residue Asp319
      (Phe320).

PMID- 15035664
TI  - Congenital and acquired thrombotic risk factors in lymphoma patients bearing
      upper extremities deep venous thrombosis: a preliminary report.
AB  - BACKGROUND: Congenital thrombotic risk factors, oncological diseases and its
      therapies have been related to an increased occurrence of upper extremities deep
      venous thrombosis (UEDVT). PATIENTS AND METHODS: We studied seven patients
      bearing lymphoma (one Hodgkin's and six non-Hodgkin's) who developed UEDVT, one
      at diagnosis and six during chemotherapy (two of these six cases had implantation
      of a central venous catheter and four received Growth Colony Stimulating Factors
      in addition to chemotherapy). Patients were screened for: factor V G1691A
      (Leiden), prothrombin G20210A, methylene tetrahydrofolate reductase (MTHFR) C677T
      mutations and antithrombin III, proteins C and S plasma activity. RESULTS: All
      patients were wild-type homozygotes for G20210A. One was heterozygote for factor
      V G1691A, the other 6 were wild-type homozygotes. Three of the 7 patients were
      homozygotes and 2 heterozygotes for the MTHFR mutation; the remaining 2 were wild
      type homozygotes. Clotting inhibitor levels were normal in all patients.
      CONCLUSIONS: UEDVT in patients bearing haematological malignancies can occur
      irrespective of congenital thrombophilic alterations. However, in a subgroup of
      patients UEDVT could also depend on congenital thrombophilic alterations. A
      screening for inherited thrombophilia can identify high risk patients that could
      be specifically treated to prevent thrombotic complications.

PMID- 15035663
TI  - Rising statin use and effect on ischemic stroke outcome.
AB  - BACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors)
      have neuroprotective effects in experimental stroke models and are commonly
      prescribed in clinical practice. The aim of this study was to determine if
      patients taking statins before hospital admission for stroke had an improved
      clinical outcome. METHODS: This was an observational study of 436 patients
      admitted to the National Institutes of Health Suburban Hospital Stroke Program
      between July 2000 and December 2002. Self-reported risk factors for stroke were
      obtained on admission. Stroke severity was determined by the admission National
      Institutes of Health Stroke Scale score. Good outcome was defined as a Rankin
      score < 2 at discharge. Statistical analyses used univariate and multivariate
      logistic regression models. RESULTS: There were 436 patients with a final
      diagnosis of ischemic stroke; statin data were available for 433 of them. A total
      of 95/433 (22%) of patients were taking a statin when they were admitted, rising
      from 16% in 2000 to 26% in 2002. Fifty-one percent of patients taking statins had
      a good outcome compared to 38% of patients not taking statins (p = 0.03). After
      adjustment for confounding factors, statin pretreatment was associated with a 2.9
      odds (95% CI: 1.2-6.7) of a good outcome at the time of hospital discharge.
      CONCLUSIONS: The proportion of patients taking statins when they are admitted
      with stroke is rising rapidly. Statin pretreatment was significantly associated
      with an improved functional outcome at discharge. This finding could support the
      early initiation of statin therapy after stroke.

PMID- 15035666
TI  - Concurrent pleomorphic adenoma in parapharyngeal space and submandibular gland.
AB  - BACKGROUND: Pleomorphic adenoma in the parapharyngeal space either occurs de novo
      or as an extension from the deep lobe of the parotid gland. CASE PRESENTATION: A
      rare synchronous occurrence of pleomorphic adenoma in the parapharyngeal space
      and submandibular gland of a 48-year-old Nigerian male is reported. CONCLUSION:
      Pleomorphic adenoma concurrent in the parapharyngeal space and submandibular
      gland is very rare. A complete surgical excision of both tumors is the treatment
      of choice.

PMID- 15035665
TI  - Identification of sperm immunoreactive antigens for immunocontraceptive purposes:
      a review.
AB  - Antisperm antibodies (ASA) may be a reason of infertility in some individuals.
      They may affect pre- as well as post-fertilization stages of the reproductive
      process. There is ongoing progress in the identification of sperm antigens
      related to fertilization. The employed methods for this purpose include
      recombinant DNA technology and the most advanced proteomic analysis. This paper
      enlists the different approaches undertaken in order to identify and characterize
      the immunoreactive sperm antigens. We have mainly focused on those, which have
      been already studied in regard of their immunocontraceptive potential, although
      it has been impossible to include all published data concerning the topic in a
      single article. Few novel sperm auto- and isoantigens, discovered recently, have
      also been reviewed even if their role in fertilization has not been yet
      established.

PMID- 15035669
TI  - Spatial correlations of mapped malaria rates with environmental factors in
      Belize, Central America.
AB  - BACKGROUND: The purposes of this study were to map overall malaria incidence
      rates from 1989 through 1999 for villages in Belize; to assess the seasonal
      distribution of malaria incidence by region; and to correlate malaria incidence
      rates with vegetation cover and rivers in villages, using geographic information
      system technology.Malaria information on 156 villages was obtained from an
      electronic database maintained by the Belize National Malaria Control Program.
      Average annual malaria incidence rates per 1000 population over 10 years were
      calculated for villages using the 1991 population census as a denominator.
      Malaria incidence rates were integrated with vegetation cover from a 1995
      vegetation map, and with river data from a digital data set. RESULTS: Mapping
      malaria incidence over the 10-year period in the study villages indicated the
      existence of a spatial pattern: the southern and western areas of Belize had
      consistently higher rates of malaria than northern areas. Examination of the
      seasonal distribution of malaria incidence by month over 10 years indicated that
      a statistically significant difference existed among districts and among months
      (p < 0.05). Spatial analysis of malaria incidence rates and of vegetation in
      Belize showed villages with high malaria rates having more broadleaf hill
      forests, agricultural land, and wetland vegetation types (i.e. SWF-seasonally
      waterlogged fire-induced shrubland of the plains). Statistical and spatial
      analyses of malaria incidence and of river distributions in Belize determined the
      high 10 percentile malaria incidence villages in western and southern Belize to
      have more rivers within two kilometers of the center of a village and a
      statistically significant correlation between proximity to rivers and villages
      (Spearman's gamma = -0.23; p < 0.05), especially in Stann Creek District
      (Spearman's gamma = -0.82; p < 0.05). CONCLUSIONS: Examination of the
      distribution of malaria during 10 years indicated transmission varied among
      geographic areas and among seasons. Additional studies are needed to examine, in
      more detail, the association between environmental and meteorological factors and
      malaria transmission. Furthermore, the role of An. darlingi in malaria
      transmission in Stann Creek needs further study since, of the three main vectors
      in Belize, An. darlingi has been found strongly associated with rivers.

PMID- 15035670
TI  - Safety assessment of near infrared light emitting diodes for diffuse optical
      measurements.
AB  - BACKGROUND: Near infrared (NIR) light has been used widely to monitor important
      hemodynamic parameters in tissue non-invasively. Pulse oximetry, near infrared
      spectroscopy, and diffuse optical tomography are examples of such NIR light-based
      applications. These and other similar applications employ either lasers or light
      emitting diodes (LED) as the source of the NIR light. Although the hazards of
      laser sources have been addressed in regulations, the risk of LED sources in such
      applications is still unknown. METHODS: Temperature increase of the human skin
      caused by near infrared LED has been measured by means of in-vivo and in-vitro
      experiments. Effects of the conducted and radiated heat in the temperature
      increase have been analyzed separately. RESULTS: Elevations in skin temperature
      up to 10 degrees C have been observed. The effect of radiated heat due to NIR
      absorption is low--less than 0.5 degrees C--since emitted light power is
      comparable to the NIR part of sunlight. The conducted heat due to semiconductor
      junction of the LED can cause temperature increases up to 9 degrees C. It has
      been shown that adjusting operational parameters by amplitude modulating or time
      multiplexing the LED decreases the temperature increase of the skin
      significantly. CONCLUSION: In this study, we demonstrate that the major risk
      source of the LED in direct contact with skin is the conducted heat of the LED
      semiconductor junction, which may cause serious skin burns. Adjusting operational
      parameters by amplitude modulating or time multiplexing the LED can keep the LED
      within safe temperature ranges.

PMID- 15035668
TI  - The proteosome inhibitor MG132 attenuates retinoic acid receptor trans-activation
      and enhances trans-repression of nuclear factor kappaB. Potential relevance to
      chemo-preventive interventions with retinoids.
AB  - BACKGROUND: Nuclear factor kappa B (NFkappaB) is a pro-malignant transcription
      factor with reciprocal effects on pro-metastatic and anti-metastatic gene
      expression. Interestingly, NFkappaB blockade results in the reciprocal induction
      of retinoic acid receptors (RARs). Given the established property of RARs as
      negative regulators of malignant progression, we postulated that reciprocal
      interactions between NFkappaB and RARs constitute a signaling module in
      metastatic gene expression and malignant progression. Using Line 1 tumor cells as
      a model for signal regulation of metastatic gene expression, we investigated the
      reciprocal interactions between NFkappaB and RARs in response to the pan-RAR
      agonist, all-trans retinoic acid (at-RA) and the pan-RAR antagonist, AGN193109.
      RESULTS: At-RA [0.1-1 microM] dose-dependently activated RAR and coordinately
      trans-repressed NFkappaB, while AGN193109 [1-10 microM] dose-dependently
      antagonized the effects of at-RA. At-RA and AGN193109 reciprocally regulate pro
      metastatic matrix metalloprotease 9 (MMP 9) and its endogenous inhibitor, the
      tissue inhibitor of metalloprotease 1 (TIMP 1), in a manner consistent with the
      putative roles of NFkappaB and RAR in malignant progression. Activation of RAR
      concurs with its ubiquitination and proteosomal degradation. Accordingly, the
      proteosome inhibitor, MG132 [5 microM], blocked RAR degradation, quelled RAR
      trans-activation and enhanced RAR trans-repression of NFkappaB. CONCLUSION: We
      conclude that reciprocal interactions between NFkappaB and RARs constitute a
      signaling module in metastatic gene expression and malignant progression and
      propose that the dissociative effect of proteosome inhibitors could be harnessed
      towards enhancing the anticancer activity of retinoids.

PMID- 15035672
TI  - Chemosensitivity assay in mice prostate tumor: Preliminary report of flow
      cytometry, DNA fragmentation, ion ratiometric methods of anti-neoplastic drug
      monitoring.
AB  - Flow cytometry, DNA fragmentation, ion ratiomateric analysis and NMR peaks
      characterized drug chemosensitivity of antineoplastic drugs. Hypotheses were: 1.
      The chemosensitive effect of different cancer cell lines is characteristic; 2.
      DNA fragmentation, ion ratiometric analysis suggest apoptosis status of tumor
      cells. METHODS: PC-3 cell lines were compared with DU-145, LNCaP cell lines in
      culture for the [Na]i and [Ca]i ion sensing dyes, cell death, NMR peaks and
      apoptosis staining for chemotherapeutic action of different drugs. RESULTS: DNA
      fragmentation, ratiometric ions and fluorescence endlabelling plots were
      characteristic for cell lines and drug response. 31P-23Na NMR spectra showed
      characteristic high phospho-choline and sodium peaks. CONCLUSION: Flow cytometry,
      DNA fragmentation, ion ratiometric methods and NMR peaks indicated apoptosis and
      offered in vivo drug monitoring method.

PMID- 15035671
TI  - Low temperature method for the production of calcium phosphate fillers.
AB  - BACKGROUND: Calcium phosphate manufactured samples, prepared with hydroxyapatite,
      are used as either spacers or fillers in orthopedic surgery, but these implants
      have never been used under conditions of mechanical stress. Similar conditions
      also apply with cements. Many authors have postulated that cements are a useful
      substitute material when implanted in vivo. The aim of this research is to
      develop a low cristalline material similar to bone in porosity and cristallinity.
      METHODS: Commercial hydroxyapatite (HAp) and monetite (M) powders are mixed with
      water and compacted to produce cylindrical samples. The material is processed at
      a temperature of 37-120 degrees C in saturated steam to obtain samples that are
      osteoconductive. The samples are studied by X-ray powder diffraction (XRD),
      Vickers hardness test (HV), scanning electron microscopy (SEM), and porosity
      evaluation. RESULTS: The X-ray diffractions of powders from the samples show
      patterns typical of HAp and M powders. After thermal treatment, no new crystal
      phase is formed and no increase of the relative intensity of the peaks is
      obtained. Vicker hardness data do not show any relationship with treatment
      temperature. The total porosity decreases by 50-60% according to the specific
      thermal treatment. Scanning electron microscopy of the surfaces of the samples
      with either HAp 80%-M 20% (c) or Hap 50%-M 50% (f), show cohesion of the powder
      grains. CONCLUSIONS: The dissolution-reprecipitation process is more intesive in
      manufactured samples (c) and (f), according to Vickers hardness data. The process
      occurs in a steam saturated environment between 37 degrees and 120 degrees C. (c)
      (f) manufactured samples show pore dimension distributions useful to cellular
      repopulation in living tissues.

PMID- 15035673
TI  - Genetic analysis of haemophilia A in Bulgaria.
AB  - BACKGROUND: Haemophilias are the most common hereditary severe disorders of blood
      clotting. In families afflicted with heamophilia, genetic analysis provides
      opportunities to prevent recurrence of the disease. This study establishes a
      diagnostical strategy for carriership determination and prenatal diagnostics of
      haemophilia A in Bulgarian haemophilic population. METHODS: A diagnostical
      strategy consisting of screening for most common mutations in the factor VIII
      gene and analysis of a panel of eight linked to the factor VIII gene locus
      polymorphisms was established. RESULTS: Polymorphic analysis for carrier status
      determination of haemophilia A was successful in 30 families out of 32 (94%).
      Carrier status was determined in 25 of a total of 28 women at risk (89%).
      Fourteen prenatal diagnoses in women at high risk of having a haemophilia A -
      affected child were performed, resulting in 6 healthy boys and 5 girls.
      CONCLUSION: The compound approach proves to be a highly informative and cost
      effective strategy for prevention of recurrence of haemophilia A in Bulgaria. DNA
      analysis facilitates carriership determination and subsequent prenatal diagnosis
      in the majority of Bulgarian families affected by haemophilia A.

PMID- 15035667
TI  - Genetic alteration and gene expression modulation during cancer progression.
AB  - Cancer progresses through a series of histopathological stages. Progression is
      thought to be driven by the accumulation of genetic alterations and consequently
      gene expression pattern changes. The identification of genes and pathways
      involved will not only enhance our understanding of the biology of this process,
      it will also provide new targets for early diagnosis and facilitate treatment
      design. Genomic approaches have proven to be effective in detecting chromosomal
      alterations and identifying genes disrupted in cancer. Gene expression profiling
      has led to the subclassification of tumors. In this article, we will describe the
      current technologies used in cancer gene discovery, the model systems used to
      validate the significance of the genes and pathways, and some of the genes and
      pathways implicated in the progression of preneoplastic and early stage cancer.

PMID- 15035674
TI  - Botulinum toxin injection versus lateral internal sphincterotomy in the treatment
      of chronic anal fissure: a non-randomized controlled trial.
AB  - BACKGROUND: Although lateral internal sphincterotomy is the gold-standard
      treatment for chronic anal fissure, intrasphincteric injection of botulinum toxin
      seems to be a reliable new option. The aim of this non-randomized study is to
      compare the effect of lateral internal sphincterotomy and botulinum toxin
      injection treatments on the outcome and reduction of anal sphincter pressures in
      patients with chronic anal fissure. METHODS: Patients with chronic anal fissure
      were treated with either botulinum toxin injection or lateral internal
      sphincterotomy by their own choice. Maximal resting pressure and maximal squeeze
      pressure measurements were performed before and 2 weeks after treatments by anal
      manometry. Patients were followed for fissure relapse during 14 months. RESULTS:
      Twenty-one consecutive outpatients with posterior chronic anal fissure were
      enrolled. Eleven patients underwent surgery and ten patients received botulinum
      toxin injection treatment. Before the treatment, anal pressures were found to be
      similar in both groups. After the treatment, the maximal resting pressures were
      reduced from 104 +/- 22 mmHg to 86 +/- 15 mmHg in the surgery group (p < 0.05)
      and from 101 +/- 23 mmHg to 83 +/- 24 mmHg in the botulinum toxin group (p <
      0.05). The mean maximal squeeze pressures were reduced from 70 +/- 27 mmHg to 61
      +/- 32 mmHg (p > 0.05) in the surgery group, and from 117 +/- 62 mmHg to 76 +/-
      34 (p < 0.01) in the botulinum toxin group. The fissures were healed in 70
      percent of patients in the botulinum group and 82 percent in the surgery group (p
      > 0.05). There were no relapses during the 14 months of follow up. CONCLUSION:
      Lateral internal sphincterotomy and botulinum toxin injection treatments both
      seem to be equally effective in the treatment of chronic anal fissure.

PMID- 15035675
TI  - Library on a slide for bacterial comparative genomics.
AB  - BACKGROUND: We describe a novel application of microarray technology for
      comparative genomics of bacteria in which libraries of entire genomes rather than
      the sequence of a single genome or sets of genes are arrayed on the slide and
      then probed for the presence or absence of specific genes and/or gene alleles.
      RESULTS: We first adopted a 96-well high throughput working protocol to
      efficiently isolate high quality genomic DNA. We then optimized conditions to
      print genomic DNA onto a glass slide with high density (up to 15000 spots) and to
      sensitively detect gene targets in each genome spot using fluorescently labeled
      DNA probe. Finally, we created an E. coli reference collection array and probed
      it for the presence or absence of the hemolysin (hly) gene using a dual channel
      non-competing hybridization strategy. Results from the array hybridization
      matched perfectly with previous tests. CONCLUSIONS: This new form of microarray
      technology, Library on a Slide, is an efficient way for sharing and utilizing
      large strain collections in comparative genomic analyses.

PMID- 15035677
TI  - Calcium and osteoporotic fractures.

PMID- 15035676
TI  - A new spreadsheet method for the analysis of bivariate flow cytometric data.
AB  - BACKGROUND: A useful application of flow cytometry is the investigation of cell
      receptor-ligand interactions. However such analyses are often compromised due to
      problems interpreting changes in ligand binding where the receptor expression is
      not constant. Commonly, problems are encountered due to cell treatments resulting
      in altered receptor expression levels, or when cell lines expressing a
      transfected receptor with variable expression are being compared. To overcome
      this limitation we have developed a Microsoft Excel spreadsheet that aims to
      automatically and effectively simplify flow cytometric data and perform
      statistical tests in order to provide a clearer graphical representation of
      results. RESULTS: To demonstrate the use and advantages of this new spreadsheet
      method we have investigated the binding of the transmembrane adhesion receptor
      CD44 to its ligand hyaluronan. In the first example, phorbol ester treatment of
      cells results in both increased CD44 expression and increased hyaluronan binding.
      By applying the spreadsheet method we effectively demonstrate that this increased
      ligand binding results from receptor activation. In the second example we have
      compared AKR1 cells transfected either with wild type CD44 (WT CD44) or a mutant
      with a truncated cytoplasmic domain (CD44-T). These two populations do not have
      equivalent receptor expression levels but by using the spreadsheet method
      hyaluronan binding could be compared without the need to generate single cell
      clones or FACS sorting the cells for matching CD44 expression. By this method it
      was demonstrated that hyaluronan binding requires a threshold expression of CD44
      and that this threshold is higher for CD44-T. However, at high CD44-T expression,
      binding was equivalent to WT CD44 indicating that the cytoplasmic domain has a
      role in presenting the receptor at the cell surface in a form required for
      efficient hyaluronan binding rather than modulating receptor activity.
      CONCLUSION: Using the attached spreadsheets and instructions, a simple post
      acquisition method for analysing bivariate flow cytometry data is provided. This
      method constitutes a straightforward improvement over the standard graphical
      output of flow cytometric data and has the significant advantage that ligand
      binding can be compared between cell populations irrespective of receptor
      expression levels.

PMID- 15035678
TI  - Evaluation of the protective effects of alpha-tocopherol and retinol against
      ochratoxin A cytotoxicity.
AB  - Ochratoxin A (OTA), a mycotoxin frequently present in food and feedstuffs,
      produces a wide range of toxic effects, including cell death via lipid
      peroxidation. In one human and four animal cell lines we determined the half
      lethal concentration (LC50) of OTA, its effect on reactive oxygen species (ROS)
      production, and its ability to induce cytochrome p450 activity. We also examined
      the protective effect of alpha-tocopherol and all-trans-retinol in the most
      sensitive cell lines (i.e. bovine mammary epithelia, for which LC50 was 0.8
      microg/ml (24 h), and Madin Darby canine kidney, for which LC50 was 4.3 microg/ml
      (48 h)). Pre-incubation for 3 h with either antioxidant significantly (P<0.05)
      ameliorated the OTA-induced reduction in cell viability and significantly
      decreased (P<0.05) ROS production. These findings indicate that oxidative stress
      is an important factor in OTA cytotoxicity. Supplementation with antioxidant
      molecules may counteract the short-term toxicity of this mycotoxin.

PMID- 15035679
TI  - Phyto-oestrogens, their mechanism of action: current evidence for a role in
      breast and prostate cancer.
AB  - The incidence of hormone-dependent cancers, such as those of the breast and
      prostate, is much lower in Eastern countries such as China and Japan in
      comparison with the Western world. Diet is believed to have a major effect on
      disease risk and one group of compounds, the phyto-oestrogens, which are consumed
      in large amounts in Asian populations, have been implicated in cancer protection.
      This view follows the finding that plasma and urinary levels of phyto-oestrogens
      are much higher in areas where cancer incidence is low in comparison with areas
      of high cancer incidence. The phyto-oestrogens are comprised of two main groups;
      the isoflavones and lignans. Of the isoflavones, genistein and daidzein have been
      the most widely studied. These compounds have been shown to possess anticancer
      properties; however their precise mechanism of action remains to be elucidated.
      In comparison, few studies have investigated the effects of lignans in breast and
      prostate cancer. In vitro studies have shown that genistein exerts biphasic
      effects on cancer cell growth, stimulating growth at low concentrations (<10
      microm) and inhibiting growth at high concentrations (>10 microm), which suggests
      that low phyto-oestrogen levels may stimulate cancer growth in vivo. Plasma phyto
      oestrogen concentrations of >10 microm cannot be achieved by dietary intake and
      therefore the timing of exposure to phyto-oestrogens may be of the utmost
      importance in determining their chemopreventive effects. The present paper
      reviews the effects of phyto-oestrogens on breast and prostate cancer in vivo and
      in vitro and discusses possible mechanisms of action via which these compounds
      may exert their effects.

PMID- 15035680
TI  - Bovine lactoferrin reduces plasma triacylglycerol and NEFA accompanied by
      decreased hepatic cholesterol and triacylglycerol contents in rodents.
AB  - In the present study we examined whether oral administration of bovine
      lactoferrin (bLF) reduces plasma or hepatic triacylglycerol and cholesterol in
      mice. When bLF mixed with a standard commercial diet (10 g/kg) was given to mice
      for 4 weeks, plasma triacylglycerol and NEFA decreased, while plasma HDL
      cholesterol levels increased (P<0.01). These changes in plasma lipid profiles
      were accompanied by significant decreases in hepatic cholesterol and
      triacylglycerol contents. When mice were fed a high-fat diet containing 300.0 g
      lard, 10.0 g cholesterol and 2.5 g bovine bile powder/kg for 4 weeks, bovine LF
      did not have any significant effects on plasma or hepatic cholesterol and
      triacylglycerol concentrations. Furthermore, bLF had no significant effects on
      faecal excretion of total bile acids in mice. Interestingly, bLF showed a
      suppressive effect on the lymphatic triacylglycerol absorption in chronically
      treated rats. We conclude that bLF has a beneficial effect on plasma cholesterol
      levels and retards hepatic lipid accumulation in mice fed a standard diet.

PMID- 15035681
TI  - Biohydrogenation of dietary n-3 PUFA and stability of ingested vitamin E in the
      rumen, and their effects on microbial activity in sheep.
AB  - The present study investigated the susceptibility of dietary n-3 PUFA to ruminal
      biohydrogenation, the stability of ingested vitamin E in the rumen and the
      subsequent uptake of PUFA and vitamin E into plasma. Six cannulated sheep were
      assigned to six diets over five 33 d periods, in an incomplete 6x5 Latin square.
      The diets, based on dried grass, were formulated to supply 50 g fatty acids/kg DM
      using three lipid sources: Megalac (calcium soap of palm fatty acid distillate;
      Volac Ltd, Royston, Herts., UK), linseed (formaldehyde-treated; Trouw Nutrition,
      Northwich, Ches., UK) and linseed-fish oil (formaldehyde-treated linseed+fish
      oil). The diets were supplemented with 100 or 500 mg alpha-tocopheryl acetate/kg
      DM. Fat source or level of vitamin E in the diet did not alter microbial activity
      in the rumen. Biohydrogenation of linoleic acid (18 : 3n-6; 85-90 %), linolenic
      acid (18 : 3n-3; 88-93 %), docosahexaenoic acid (22 : 6n-3; 91 %) and EPA (20 :
      5n-3; 92 %) was extensive. Feeding formaldehyde-treated linseed elevated
      concentrations of 18 : 3n-3 in plasma, whilst 22 : 6n-3 and 20 : 5n-3 were only
      increased by feeding the linseed-fish oil blend. Duodenal recovery of ingested
      vitamin E was high (range 0.79-0.92 mg/mg fed). High dietary vitamin E was
      associated with increased plasma alpha-tocopherol (2.57 v. 1.46 microg/ml for 500
      and 100 mg alpha-tocopheryl acetate/kg DM respectively), although all
      concentrations were low. Plasma vitamin E levels, however, tended to decrease as
      the type and quantity of PUFA in the diet increased. The present study
      illustrates that nutritionally beneficial PUFA in both fish and linseed oils are
      highly susceptible to biohydrogenation in the rumen. Although alpha-tocopheryl
      acetate resisted degradation in the rumen, plasma vitamin E status remained
      deficient to borderline, suggesting either that uptake may have been impaired or
      metabolism post-absorption increased.

PMID- 15035682
TI  - Effects of dietary n-3 polyunsaturated fatty acids, breed and dietary vitamin E
      on the fatty acids of lamb muscle, liver and adipose tissue.
AB  - The effect of feeding n-3 PUFA on the fatty acid composition of muscle, adipose
      tissue and liver of lambs was investigated. Groups of eight ram lambs per breed,
      SuffolkxLleyn (24 kg live weight) and Scottish Blackface (18 kg live weight),
      were each fed one of six diets containing one of three fat sources (50 g fatty
      acids/kg DM; Megalac((R)) (calcium soap of palm fatty acid distillate; Volac Ltd,
      Royston, Herts., UK) and formaldehyde-treated whole linseed (Trouw Nutrition UK,
      Northwich, Ches., UK) either alone or with fish oil (1:1, w/w) and either 100 or
      500 mg alpha-tocopheryl acetate/kg DM. Feed was offered ad libitum until
      slaughter at approximately half breed mature live weight. The type of dietary fat
      had no effect on intake, growth rate or feed conversion ratio. The 3.0-fold
      higher concentration of 18 : 3n-3 in the linseed compared with the Megalac((R))
      diet approximately doubled (P<0.001) the concentration in the neutral and polar
      lipid fractions of musculus semimembranosus and liver, and in adipose tissue it
      increased 2.5-fold. Feeding protected linseed also increased (P<0.001)
      concentrations of 20 : 5n-3 and 22 : 5n-3 in muscle polar lipids and both lipid
      fractions of liver. The linseed-fish oil raised the 20 : 5n-3 concentrations
      above those for the linseed diet and also increased 22 : 6n-3. Scottish Blackface
      lambs had lower concentrations of 18 : 3n-3 in all lipids compared with Suffolk x
      Lleyn lambs, but more 20 : 5n-3 in the polar lipids of muscle and liver. High
      levels of dietary vitamin E were associated with small decreases in the
      concentration of monounsaturated fatty acids and increases in PUFA. Linseed
      raised the PUFA : saturated fatty acid ratios in liver and adipose tissue but not
      in muscle, and improved the n-6 : n-3 fatty acid ratio, as did the linseed-fish
      oil. Different combinations of dietary fatty acids and better protection against
      rumen biohydrogenation are required to improve muscle PUFA : saturated fatty
      acids ratios.

PMID- 15035683
TI  - Urinary isoflavone kinetics: the effect of age, gender, food matrix and chemical
      composition.
AB  - Urinary isoflavone excretion is used to monitor compliance and examine biological
      effects. The present study determined if there were alterations in urinary
      isoflavone excretion following the ingestion of different soya foods and if age
      and gender potentially modified profiles. Twenty premenopausal women, seventeen
      post-menopausal women and twenty men received a defined single oral bolus dose
      (0.44 mg isoflavones/kg body weight) of soya milk, textured vegetable protein
      (TVP) or tempeh on three separate occasions. Baseline and four consecutive
      complete 24 h pooled urines were collected during each period. Urinary genistein
      recovery was influenced by gender and food matrix. For women the urinary
      genistein recovery was higher following soya-milk consumption compared with TVP
      (P<0.05). Tempeh consumption also resulted in an increased urinary genistein
      recovery relative to soya milk in premenopausal women (P<0.052). No differences
      in urinary genistein recoveries between soya foods were observed in the men.
      Although urinary daidzein excretion was similar across the foods studied and was
      not affected by age or gender, conversion to its intestinal metabolite, equol,
      resulted in potential matrix and chemical composition effects; urinary equol
      excretion was higher (P<0.01) following tempeh ingestion among equol producers.
      Together these data suggest that the fractional absorption of genistein is
      potentially different in men and women and is influenced by the food matrix and
      chemical composition. Furthermore, the data suggest that the metabolism of
      daidzein may be altered by the chemical composition of the isoflavones ingested.
      Further studies are required to examine the effect of higher intake and define
      the relative influence of these factors in elderly population groups.

PMID- 15035684
TI  - Linoleate supplementation in steers modifies lipid composition of plasma
      lipoproteins but does not alter their fluidity.
AB  - The health value for man of lipids in bovine muscles can be improved by the
      addition of PUFA to the animals' diets, but such treatments can modify fluidity
      of plasma lipoproteins and therefore their metabolic functions. The aim of the
      present study was to analyse whether changes in chemical composition of
      lipoproteins in steers fed sunflower oil-rich diets altered lipoprotein fluidity,
      measured by fluorescence polarization and electron spin resonance. LDL, light HDL
      and heavy HDL fractions were isolated by ultracentrifugation from plasma of
      eighteen crossbred Charolais x Salers steers. For a period of 70 d, animals were
      given a control diet (C, n 6) consisting of hay (540 g/kg) and concentrate
      mixture (460 g/kg) or the same basal diet supplemented with sunflower oil rich in
      n-6 PUFA (40 g/kg diet DM), given either as crushed seeds (S, n 6) or as a free
      oil infused directly into the duodenum (O, n 6), thus avoiding ruminal
      hydrogenation of PUFA. We have shown that in bovine animals: (1) fluidity
      measurements by fluorescence polarization must be made at the bovine
      physiological temperature (38.5 degrees C); (2) heavy HDL always appear as the
      less fluid lipoparticles; (3) electron spin resonance, which does not depend on
      lipoparticle size, is more appropriate to compare the fluidity of LDL with that
      of light HDL. The values for lipoprotein fluidity measured by both methods
      indicated that linoleate-rich diets did not have any effect when compared with
      diet C; however, chemical variables support a fluidification of lipoparticles,
      since in steers given the diet O, n-6 PUFA concentrations increased in polar
      (x1.8) and neutral (x1.6) lipids in lipoparticles (P=0.0001). The
      phospholipid:protein ratio increased in light (+20 %, P=0.019) and heavy (+23 %,
      P=0.06) HDL and especially in LDL (+46 %, P=0.0001); the total
      cholesterol:phospholipid ratio decreased in the three lipoprotein classes (-15 to
      -30 %, NS). Diet S led to similar but less pronounced effects. We concluded that
      linoleate-rich diets modified the chemical composition of plasma lipoproteins in
      steers, but did not alter their fluidity; this probably occurred as a result of
      'homeoviscous adaptation', which ensured their functional capacity.

PMID- 15035685
TI  - Dietary sodium requirement determined for juvenile hybrid tilapia (Oreochromis
      niloticus x O. aureus) reared in fresh water and seawater.
AB  - Two 8-week feeding trials were conducted to determine the dietary Na requirement
      for juvenile hybrid tilapia (Oreochromis niloticus x O. aureus) reared in fresh
      water and seawater. In each experiment, NaCl was added to the basal diet at 0,
      0.5, 1, 2, 3, 5, or 7 g Na/kg diet (fresh water) and at 0, 0.2, 0.5, 0.8, 1.2,
      1.5, 2, or 3 g Na/kg diet (seawater). Each diet was fed to three replicate groups
      of fish, individual fish initially weighing 0.69 (se 0.01) g, in a closed,
      recirculating rearing system. In fresh water, the tilapia fed the diet
      supplemented with 2 g Na/kg diet had significantly (P<0.05) greater weight gain
      than the fish fed the diets supplemented with >/=3 and </=0.5 g Na/kg diet. Feed
      efficiency (FE) in fish generally followed the weight-gain pattern. Gill Na(+)
      K(+) ATPase activity was highest in the fish fed the diets supplemented with 1-3
      g Na/kg diet, followed by the fish fed the diet with 7 g Na/kg diet and lowest in
      the fish fed the unsupplemented control diet. In seawater, the weight gain, FE
      and gill Na(+)-K(+) ATPase activity in fish were not affected by the dietary
      treatment. Analysis by polynomial regression of weight gain, by broken-line
      regression of gill Na(+)-K(+) ATPase activity and by linear regression of whole
      body Na retention of the fish reared in fresh water, indicated that the adequate
      dietary Na concentration for tilapia is about 1.5 g/kg diet. The present study
      also suggests that no dietary Na is required for tilapia reared in seawater.

PMID- 15035686
TI  - Effect of fat replacement by inulin or lupin-kernel fibre on sausage patty
      acceptability, post-meal perceptions of satiety and food intake in men.
AB  - The present study examined whether replacing fat with inulin or lupin-kernel
      fibre influenced palatability, perceptions of satiety, and food intake in thirty
      three healthy men (mean age 52 years, BMI 27.4 kg/m(2)), using a within-subject
      design. On separate occasions, after fasting overnight, the participants consumed
      a breakfast consisting primarily of either a full-fat sausage patty (FFP) or a
      reduced-fat patty containing inulin (INP) or lupin-kernel fibre (LKP). Breakfast
      variants were alike in mass, protein and carbohydrate content; however the INP
      and LKP breakfasts were 36 and 37 % lower in fat and 15 and 17 % lower in energy
      density respectively compared with the FFP breakfast. The participants rated
      their satiety before breakfast then evaluated patty acceptability. Satiety was
      rated immediately after consuming the breakfast, then over the subsequent 4.5 h
      whilst fasting. Food consumed until the end of the following day was recorded.
      All patties were rated above 'neither acceptable or unacceptable', however the
      INP rated lower for general acceptability (P=0.039) and the LKP lower for flavour
      (P=0.023) than the FFP. The LKP breakfast rated more satiating than the INP
      (P=0.010) and FFP (P=0.016) breakfasts. Total fat intake was 18 g lower on the
      day of the INP (P=0.035) and 26 g lower on the day of the LKP breakfast (P=0.013)
      than the FFP breakfast day. Energy intake was lower (1521 kJ) only on the day of
      the INP breakfast (P=0.039). Both inulin and lupin-kernel fibre appear to have
      potential as fat replacers in meat products and for reducing fat and energy
      intake in men.

PMID- 15035687
TI  - Fractional magnesium absorption is significantly lower in human subjects from a
      meal served with an oxalate-rich vegetable, spinach, as compared with a meal
      served with kale, a vegetable with a low oxalate content.
AB  - The aim of the present study was to evaluate Mg absorption from a test meal
      served with an oxalate-rich vegetable, spinach, as compared with a test meal
      served with a vegetable with a low oxalate content, kale. Mg absorption was
      measured by a stable-isotope technique based on extrinsic labelling of the test
      meals and faecal monitoring of the excreted isotope labels. Nine healthy adults
      participated in the study. The test meals were based on 100 g phytate-free white
      bread, served with 300 g spinach (6.6 mmol oxalate; 0.7 mmol (25)Mg label added,
      5.0 mmol total Mg) or 300 g kale (0.1 mmol oxalate; 1.2 mmol (26)Mg label added,
      4.8 mmol total Mg). The test meals were served on days 1 and 3, at breakfast and
      lunch, using a cross-over design. The results from the present study demonstrated
      that apparent Mg absorption was significantly lower from the meal served with
      spinach (26.7 (sd 10.4) %) than the meal served with kale (36.5 (sd 11.8) %)
      (P=0.01). However, the lower fractional apparent Mg absorption from the test meal
      served with spinach can be assumed to be, at least partly, counterbalanced by the
      higher native Mg content of spinach as compared with kale. Although based on
      indirect evidence, i.e. not based on an evaluation of added (or removed) oxalic
      acid, the difference in Mg absorption observed in the present study is attributed
      to the difference in oxalic acid content between the two vegetables.

PMID- 15035688
TI  - Influence of soya-based infant formula consumption on isoflavone and gut
      microflora metabolite concentrations in urine and on faecal microflora
      composition and metabolic activity in infants and children.
AB  - The urinary excretion of soya isoflavones and gut microflora metabolites was
      investigated in infants and children who had been fed soya-based infant formulas
      in early infancy. These infants and children were compared with cows'-milk
      formula-fed controls, to determine at what age gut microflora metabolism of
      daidzein to equol and/or O-desmethylangolensin (O-DMA) was established, and
      whether exposure to isoflavones in early infancy influences their metabolism at a
      later stage of development. Sixty infants and children (aged 4 months-7 years)
      participated in the study; thirty in each of the soya and control groups. There
      were four age groups. These were: 4-6 months (seven in the soya group and seven
      in the control group); 7-12 months (seven in the soya group and nine in the
      control group); 1-3 years (six in the soya group and eight in the control group);
      3-7 years (ten in the soya group and six in the control group). Urine samples
      were collected to measure isoflavonoids by MS, and faecal samples were collected
      to measure gut-health-related bacterial composition, by fluorescent in situ
      hybridisation with oligonucleotide probes, and metabolic activity. A soya
      challenge (typically a soya yoghurt alternative product containing 4.8 g soya
      protein and on average 22 mg total isoflavones) was given to control-group
      infants (>6 months) and children, and also to soya-group children that were no
      longer consuming soya, to determine their ability to produce equol and/or O-DMA.
      Urinary genistein, daidzein and glycitein were detected in all infants (4-6
      months) fed soya-based infant formula; O-DMA was detected in 75 % of infants but
      equol was detected in only 25 %. In the controls (4-6 months), urinary
      isoflavonoids were very low or not detected. In the older age groups (7 months-7
      years), O-DMA was found in the urine samples of 75 % of the soya group and 50 %
      of the controls, after the soya challenge. Equol excretion was detected in 19 %
      of the soya-group infants and children, and in only 5 % of the controls. However,
      in the oldest (3-7 years) children, the proportion excreting O-DMA and equol was
      similar in both groups. Faecal bacterial numbers for bifidobacteria (P<0.001),
      bacteroides and clostridia (P<0.05) were significantly lower for the soya group
      compared with the control group. There appears to be no lasting effect of early
      life isoflavone exposure on isoflavone metabolism.

PMID- 15035690
TI  - Does dietary calcium have a protective effect on bone fractures in women? A meta
      analysis of observational studies.
AB  - It is generally accepted that supplemental Ca and/or vitamin D is effective in
      reducing the incidence of bone fractures; this is supported by numerous
      randomised controlled trials and meta-analyses. However, a question that has
      received much less attention is whether dietary Ca, i.e. Ca in physiological
      doses in normal food intake, also affects bone fracture risk. The present study
      aims to review the effect of dietary Ca on bone fractures at the hip, spine and
      radius in women >35 years old, and to compare these results with previous meta
      analyses. MEDLINE (1966-1999) and reference lists in papers were searched for
      observational dietary Ca studies. Data were extracted in duplicate and
      separately. Heterogeneity and publication bias were tested. Observational studies
      failed to show any association between dietary Ca intake and risk of hip fracture
      (risk ratio 1.01, 95 % CI 0.96, 1.07 for each increment of 300 mg dietary Ca
      intake/d). There is a suggestion that either extremely low Ca intake may increase
      fracture risk, or that East Asian women may respond differently to increasing Ca
      intake.

PMID- 15035689
TI  - Are those in need taking dietary supplements? A survey of 21 923 adults.
AB  - Many people take dietary supplements, but information on characteristics
      associated with their use is lacking. The relationship between lifestyle
      behaviours, morbidity and use of dietary supplements has not been examined and
      earlier studies have limited applicability to a general population. These issues
      were addressed in the current study. Information was obtained by postal
      questionnaire sent to a sample of the general population. The questionnaire was
      completed by 70.5 % of the sample (15 465 from a total sample of 21 923), with at
      least one-third (35.5 %) taking dietary supplements. In adjusted analyses,
      supplement users were more likely to be women, white, home-owners, non-smokers
      and physically active. Use of vitamin, mineral and/or antioxidant supplements was
      associated with eating more fruits and vegetables, and taking fish-oil
      supplements was associated with eating oil-rich fish. A history of CVD or risk
      factors for CVD reduced the risk of taking vitamins, minerals and/or antioxidants
      or fish-oil supplements. Those reporting musculoskeletal disorders such as
      arthritis were more likely to take fish-oil supplements For the first time, we
      have shown that dietary supplement use is related to different types of
      morbidity. In particular, people at risk of primary or secondary CVD seem less
      likely to use dietary supplements, despite possible benefits shown in clinical
      trials. Public health organisations need to develop guidelines for the public and
      health professionals regarding the uncontrolled use of dietary supplements in the
      community.

PMID- 15035691
TI  - Estimated intake of milk fat is negatively associated with cardiovascular risk
      factors and does not increase the risk of a first acute myocardial infarction. A
      prospective case-control study.
AB  - Milk fat is high in saturated fatty acids (SFA) and high intakes of SFA are
      associated with cardiovascular diseases. The aim of the present study was to
      prospectively evaluate the potential risk of a first-ever acute myocardial
      infarction (AMI) in relation to the estimated milk-fat intake, reflected as the
      proportions of pentadecanoic acid (15 : 0) and heptadecanoic acid (17 : 0) in
      serum lipid esters. This was evaluated in a study population selected within the
      Vasterbotten Intervention Program and the northern Sweden 'Monitoring of Trends
      and Determinants in Cardiovascular disease' survey populations. A prospective
      case-control design was used. The proportions of the biomarkers were lower in the
      cases (n 78) than in the controls (n 156), who were matched for age, sex,
      sampling time and geographical region. The standardised odds ratios of becoming
      an AMI case were between 0.7 and 0.8 for the biomarkers. The proportions of 15 :
      0 and 17 : 0 in serum phospholipids were significantly and negatively correlated
      to serum concentrations of plasminogen activator inhibitor-1, tissue-type
      plasminogen activator, triacylglycerols, insulin, specific insulin, pro-insulin
      and leptin (all P<0.0001), suggesting a negative relationship to the insulin
      resistance syndrome and the risk of CHD. Adjustment for BMI did not materially
      change the relationships. Although there seems to be a negative association
      between milk-fat intake as mirrored by the proportions of 15 : 0 and 17 : 0 in
      serum lipid esters and a first-ever AMI, adjustment for clinical risk factors
      removed this relationship.

PMID- 15035692
TI  - Association of adipose tissue arachidonic acid content with BMI and overweight
      status in children from Cyprus and Crete.
AB  - The relationships between n-3 and n-6 fatty acids in subcutaneous fat, BMI and
      overweight status were investigated in eighty-eight children from Crete and
      Cyprus. Overweight status, BMI and serum lipid levels were similar in children at
      both locations, but Cretan children had higher levels of total MUFA than Cypriot
      children (62.2 (sd 2.8) v. 52.2 (sd 2.8) % area, respectively, P<0.001) and
      consequently Cypriot children had higher levels of total saturated,
      polyunsaturated, trans, n-3 and n-6 fatty acids. Cypriot children had also higher
      levels of individual n-3 and n-6 fatty acids, specifically linoleic, alpha
      linolenic and dihomo-gamma-linolenic acids. The variance of BMI was better
      explained (38.2 %) by adipose tissue arachidonic acid content than any other n-3
      and n-6 fatty acids. Mean levels of arachidonic acid, dihomo-gamma-linolenic acid
      and docosahexaenoic acid were higher in overweight and obese subjects. All obese
      subjects fell in the 4th quartile of arachidonic acid levels, whereas 88.9 % of
      overweight subjects fell in the 3rd and 4th quartile of arachidonic acid. These
      results indicate positive associations between adipose tissue arachidonic acid
      and BMI and overweight status. Further research could clarify whether this
      association is causal.

PMID- 15035694
TI  - A pilot study of newer antidepressant concentrations in cord and maternal serum
      and possible effects in the neonate.
AB  - Antidepressants are often used antenatally, and placental transfer may lead to
      adverse effects (toxicity) in the neonate. Pregnant women taking fluoxetine
      (n=4), sertraline (n=4), paroxetine (n=2) or venlafaxine (n=1) in the last
      trimester were studied. Maternal and cord sera were collected at delivery and
      infant serum on day 5 after birth for measurement of antidepressant
      concentrations. Neonatal Abstinence Scores (NAS) were measured in the infants on
      days 13 after birth. In maternal serum, median drug concentrations were:
      fluoxetine (96 microg/l), norfluoxetine (110 microg/l), sertraline (11 microg/l),
      desmethylsertraline (38 microg/l), paroxetine (mean 12 microg/l), venlafaxine
      (220 microg/l), and O-desmethylvenlafaxine (392 microg/l). Corresponding median
      values in cord serum were: fluoxetine (65 microg/l), norfluoxetine (81 microg/l),
      sertraline (10 microg/l), desmethylsertraline (27 microg/l), paroxetine (mean 6
      microg/l), venlafaxine (232 microg/l), and O-desmethylvenlafaxine (406 microg/l).
      Corresponding median cord:maternal concentration ratios were 0.67 for fluoxetine
      and 0.72 for norfluoxetine, 0.67 for sertraline and 0.63 for demethylsertraline,
      0.52 (mean) for paroxetine, and 1.1 and 1.0 for venlafaxine and O
      desmethylvenlafaxine respectively. The neonates of two patients taking fluoxetine
      had high NAS. Only fluoxetine and norfluoxetine were detected in infant serum.
      Our data show substantial placental transfer of antidepressants, but only
      fluoxetine persisted in the infants serum. Neonatal toxicity may be associated
      with serotonin uptake blockade, and also be influenced by neonatal clearance.

PMID- 15035696
TI  - Foxes, green fields and Britishness: on the rhetorical construction of place and
      national identity.
AB  - This paper explores an accepted but under researched feature of national
      categories: their complex relationship with social constructions of place. We
      argue that social psychological work on national identification and mobilization
      would benefit from closer attention to this relationship. In order to develop
      this argument, we analyse a series of newspaper accounts published on behalf of
      the Countryside Alliance, a coalition formed to preserve rural 'ways of life' in
      the UK and, more specifically, to defend extant practices of hunting. Applying a
      discourse analytic method, we show how the Alliance has exploited the rhetoric of
      place in order to portray the preservation of hunting as an issue of national
      significance. By associating British identity with the 'rural idyll' of the
      English countryside, the organization has appealed to a place construction in
      which hunting and its associated activities become cast as essential expressions
      of the national character. Building on relevant work in geography and discursive
      psychology, we trace some wider implications of this process for social
      psychological research on category construction, reification and collective
      mobilization.

PMID- 15035695
TI  - Two traditions of interaction research.
AB  - The paper compares Bales' Interaction Process Analysis (IPA) with Sacks'
      Conversation Analysis (CA), arguing that CA has answered several questions that
      originally motivated the development of IPA, and while doing so, it has re
      specified the phenomena of interaction research. These two research traditions
      are in many ways diametrically opposed: the former is quantitative, theory
      oriented and aims at global characterizations of interactional situations, while
      the latter is qualitative, inductive and aims at characterizing specific layers
      of organization (such as turn taking or sequence organization) that give
      structure to interactional situations. Their primary objects of study are
      different. For the Balesian tradition, it is the functioning and the structure of
      a small group, whereas in the Sacksian tradition, it is the structures and
      practices of human social interaction per se. It is argued, however, that CA has
      radically expanded understanding of the questions IPA was originally developed to
      address. These questions include allocation of resources, control and solidarity.
      Bales' research deals with them in terms of the differentiation of participants
      of a group, whereas CA has re-specified them as emergent aspects of the very
      rules and structures that constitute and regulate interaction sequences. The
      uniqueness of the CA perspective on social interaction is demonstrated by
      exploring the display of emotion as an interactional phenomenon. It is argued
      that the display of emotion is intrinsically embedded in the sequential
      organization of action. Sensitive 'coding and counting' approaches can detect
      emotion displays, but the contribution of CA is to show the specific ways in
      which they are part of the business of interaction.

PMID- 15035697
TI  - The antecedents of identification: a rhetorical analysis of British Muslim
      activists' constructions of community and identity.
AB  - This paper takes as its focus the perception of community. This is analysed
      through reference to the literature concerning the adoption of more inclusive,
      superordinate social categories. Whilst most research tends to focus on the
      consequences of these social categories for self and other perception, we focus
      on their antecedents. These are typically hypothesized to include such issues as
      the perception of the subordinate groups' common fate and factors affecting their
      perceptual differentiation (e.g. their similarity and entitativity). However,
      rather than conceiving of such issues as pre-given antecedent variables, we
      explore how these issues (and others) are actively constructed in and through
      discourse. More specifically, we explore how such issues are sites of
      contestation as activists with different political projects seek to construct
      quite different versions of the relevant superordinate community identity. Our
      data are qualitative and are drawn from contemporary debates amongst British
      Muslims concerning their relations with non-Muslim Britons and non-British
      Muslims across the globe. A key issue in these deliberations concerns the nature
      of British Muslims' identity and the superordinate identifications that best
      facilitate its expression and realization. We suggest that constructions of
      common fate, similarity, entitativity etc., far from being 'givens', are the
      means through which different definitions of Muslim identity are constructed and
      different forms of collective action mobilized.

PMID- 15035698
TI  - Social identity, self-evaluation and in-group bias: the relative importance of
      particular domains of self-esteem to the in-group.
AB  - This investigation sought to assess the link between in-group bias and domain
      specific self-esteem. Two experiments were carried out. Experiment 1 revealed
      that social category members (i.e. Christians), manifested an increase in that
      domain of self-esteem judged to be relatively more important to the in-group
      (i.e. physical self-esteem), following the display of in-group bias. A second
      experiment which sought to examine an alternative explanation for these findings,
      in terms of enhanced social identity salience, produced identical findings.
      Domains of self-esteem relatively less important to the in-group (i.e.
      mathematical self-esteem) were unaffected in each experiment. Consistent with
      recent revisions to the second corollary of the self-esteem hypothesis,
      Experiment 2 further revealed that category members with low public collective
      self-esteem (who believed that Christians were evaluated negatively by Atheists)
      showed more pronounced in-group bias.

PMID- 15035699
TI  - Political identity and the Third Way: some social-psychological implications of
      the current anti-ideological turn.
AB  - This paper considers recent large-scale changes in British politics from the
      standpoint of a detailed examination of the practical dilemmas, concerning
      political identity, faced by local politicians in their talk about politics. It
      seeks to examine the social-psychological significance of a shift which has meant
      that politics, while continuing to be characterized by formal division, has begun
      to extensively reflect the influence of an ideology of anti-ideology.

PMID- 15035700
TI  - Women's collective constructions of embodied practices through memory work:
      Cartesian dualism in memories of sweating and pain.
AB  - The research presented in this paper uses memory work as a method to explore six
      women's collective constructions of two embodied practices, sweating and pain.
      The paper identifies limitations in the ways in which social constructionist
      research has theorized the relationship between discourse and materiality, and it
      proposes an approach to the study of embodiment which enjoins, rather than
      bridges, the discursive and the non-discursive. The paper presents an analysis of
      25 memories of sweating and pain which suggests that Cartesian dualism is central
      to the women's accounts of their experiences. However, such dualism does not
      operate as a stable organizing principle. Rather, it offers two strategies for
      the performance of a split between mind and body. The paper traces the ways in
      which dualism can be both functional and restrictive, and explores the tensions
      between these two forms. The paper concludes by identifiying opportunities and
      limitations associated with memory work as a method for studying embodiment.

PMID- 15035701
TI  - Combining individuality and relatedness: representations of the person among the
      Anglican clergy.
AB  - Representations of the person and their significance for identity and action were
      studied in an interpretative phenomenological analysis of interviews with 42
      Anglican clergymen and clergywomen. Participants portrayed the person as having
      an individual relationship with God and being essentially both unique and related
      to others; the latter themes supported the coexistence among these participants
      of both individualistic and relational values, which might be portrayed as either
      opposing or complementary. The analysis supported theorizing concepts of the
      person as socially constructed themata with broad implications for identity,
      values and action, but did not reflect common assumptions in cross-cultural
      psychology: cultural orientations vary within as well as between nations, and
      individualism and collectivism are not necessarily opposites. We argue for a more
      finely grained approach to the study of culture and personhood.

PMID- 15035702
TI  - Surfing the money tides: understanding the foreign exchange market through
      metaphors.
AB  - This study describes metaphorical conceptualizations of the foreign exchange
      market held by market participants and examines how these metaphors socially
      construct the financial market. Findings are based on 55 semi-structured
      interviews with senior foreign exchange experts at banks and at financial news
      providers in Europe. We analysed interview transcripts by metaphor analysis, a
      method based on cognitive linguistics. Results indicate that market participants'
      understanding of financial markets revolves around seven metaphors, namely the
      market as a bazaar, as a machine, as gambling, as sports, as war, as a living
      being and as an ocean. Each of these metaphors highlights and conceals certain
      aspects of the foreign exchange market and entails a different set of
      implications on crucial market dimensions, such as the role of other market
      participants and market predictability. A correspondence analysis supports our
      assumption that metaphorical thinking corresponds with implicit assumptions about
      market predictability. A comparison of deliberately generated and implicitly used
      metaphors reveals notable differences. In particular, implicit metaphors are
      predominantly organic rather than mechanical. In contrast to academic models,
      interactive and organic metaphors, and not the machine metaphor, dominate the
      market accounts of participants.

PMID- 15035704
TI  - Near-field infrared imaging and spectroscopy of a thin film
      polystyrene/poly(ethyl acrylate) blend.
AB  - The application of broadband, near-field infrared microscopy to the
      characterization of the mesoscale structure of a thin film polymer blend is
      described. Key features of this instrument, which couples the nanoscale spatial
      resolution of scanning probe microscopy with the chemical specificity of
      vibrational spectroscopy, include broad tunability and bandwidth, parallel
      spectral detection for high image acquisition rates, and infrared-transparent
      aperture probes. Nearfield spectral transmission images of a thin film of
      polystyrene/poly(ethyl acrylate) acquired in the C-H stretching region are
      reported. An assessment of the relative importance of transmission image contrast
      mechanisms is a significant aim of this work. Analysis of the near-field infrared
      spectra indicates that the image contrast in the C-H stretching region is largely
      due to near-field coupling and/or scattering effects. Identification and
      differentiation of the operative contrast mechanisms on the basis of their
      relative dependence on wavelength is discussed. Analysis of the contrast
      attributed to absorption is consistent with the chemical morphology of this
      sample derived from previous chemical modification/atomic force microscopy
      studies.

PMID- 15035705
TI  - New indicator for optimal preprocessing and wavelength selection of near-infrared
      spectra.
AB  - Preprocessing of near-infrared spectra to remove unwanted, i.e., non-related
      spectral variation and selection of informative wavelengths is considered to be a
      crucial step prior to the construction of a quantitative calibration model. The
      standard methodology when comparing various preprocessing techniques and
      selecting different wavelengths is to compare prediction statistics computed with
      an independent set of data not used to make the actual calibration model. When
      the errors of reference value are large, no such values are available at all, or
      only a limited number of samples are available, other methods exist to evaluate
      the preprocessing method and wavelength selection. In this work we present a new
      indicator (SE) that only requires blank sample spectra, i.e., spectra of samples
      that are mixtures of the interfering constituents (everything except the
      analyte), a pure analyte spectrum, or alternatively, a sample spectrum where the
      analyte is present. The indicator is based on computing the net analyte signal of
      the analyte and the total error, i.e., instrumental noise and bias. By comparing
      the indicator values when different preprocessing techniques and wavelength
      selections are applied to the spectra, the optimal preprocessing technique and
      the optimal wavelength selection can be determined without knowledge of reference
      values, i.e., it minimizes the non-related spectral variation. The SE indicator
      is compared to two other indicators that also use net analyte signal
      computations. To demonstrate the feasibility of the SE indicator, two near
      infrared spectral data sets from the pharmaceutical industry were used, i.e.,
      diffuse reflectance spectra of powder samples and transmission spectra of
      tablets. Especially in pharmaceutical spectroscopic applications, it is expected
      beforehand that the non-related spectral variation is rather large and it is
      important to remove it. The indicator gave excellent results with respect to
      wavelength selection and optimal preprocessing. The SE indicator performs better
      than the two other indicators, and it is also applicable to other situations
      where the Beer-Lambert law is valid.

PMID- 15035706
TI  - Second-derivative variance minimization method for automated spectral
      subtraction.
AB  - A new second-derivative variance minimization (SDVM) procedure is used to
      automatically extract spectra of a dilute component (solute) from a mixture whose
      spectrum is dominated by a major component (solvent). This procedure involves the
      subtraction of Savitzky-Golay second-derivative preprocessed pure solvent and
      mixture spectra by minimizing the variance of the difference spectrum. The
      resulting undifferentiated output spectra contain primarily features associated
      with the solute and/or solute-induced perturbations of the solvent. The SDVM
      method is found to outperform several related methods, including a previously
      proposed derivative minimization method, as demonstrated using 1000 randomly
      generated solute/solvent synthetic spectral pairs and experimental Raman spectra
      of dilute solutions of benzene in n-hexane and water in acetone. The former
      experimental solution produced SDVM difference spectra containing benzene bands
      with virtually no n-hexane interference, while the latter revealed water-induced
      shifts in acetone spectral features. Several other types of SDVM applications,
      such as the spectroscopic analysis of layered composites, are discussed.

PMID- 15035708
TI  - Ultraviolet-visible and surface-enhanced Raman scattering spectroscopy studies on
      self-assembled metalloporphyrin films on organic monolayer-modified ultra-thin
      silver substrates.
AB  - A self-assembled monolayer (SAM) film of 5,10,15,20-tetra-(para-chlorophenyl)
      porphyrin terbium (or lutetium) hydroxy compound (TbOH/LuOH) fabricated on a
      silver substrate premodified with a SAM of 4-mercaptopyridine (PySH) was studied
      by ultraviolet-visible (UV-Vis) spectroscopy and surface-enhanced Raman
      scattering (SERS) spectroscopy. PySH can modify the substrate and deliver its
      pyridyl group pointing out from the silver surface. Thus, we can investigate the
      effects of the central metals of the metalloporphyrins in the formation of the
      composite films. For the TbOH-PySH composite film, a new absorption band arising
      from TbOH appears at 425 nm, and a band at 512 nm due to the PySH-modified silver
      substrate shifts to a longer wavelength (538 nm). The results suggest that TbOH
      is successfully assembled on the top of PySH-modified silver film and that there
      is an interaction between TbOH and PySH in the film. The frequency shifts and
      relative intensity changes of bands due to PySH in the SERS spectra imply the
      coordination of the pyridyl group on Tb in the SAM. As for the LuOH-PySH
      composite film, its SERS spectrum shows bands arising from both the LuOH and PySH
      moieties, indicating that LuOH is assembled on the PySH-modified silver film.
      Furthermore, a band at 1221 cm(-1) due to the in-plane C-H bending mode of PySH
      disappears, implying that the pyridyl moiety of PySH becomes more parallel to the
      silver surface upon the formation of the LuOH-PySH composite film. Additionally,
      an absorption band at 515 nm shifts to a longer wavelength (541 nm) and becomes
      broad upon the formation of the composite film, suggesting an interaction between
      LuOH and PySH in the film. By comparing the spectral changes between the two self
      assembled composite films, we find that the central metal is crucial in the
      formation of the composite films. The structure and orientation of the composite
      films depend on the central metal of the metalloporphyrin compounds.

PMID- 15035707
TI  - Determination of the molecular orientation of poly(propylene terephthalate)
      fibers using polarized Raman spectroscopy: a comparison of methods.
AB  - For the first time, four different methods to determine the degree of molecular
      orientation from polarized Raman spectroscopy measurements are compared. The
      great influence of molecular orientation on the properties of polymers has driven
      the development of multiple experimental techniques and procedures. This study is
      based on the C(1)-C(4) ring stretching vibration of poly(propylene terephthalate)
      (PPT) at 1614 cm(-1). It is shown that simply ratioing the band intensity
      obtained with the polarization parallel and perpendicular to the unique axis of
      the sample provides a good qualitative method to observe the evolution of
      orientation in a series of similar samples. To quantitatively compare the degree
      of orientation one needs to utilize a more complex method yielding the second-
      and fourth-order parameters of the orientation distribution function (P(2) and
      P(4), respectively). To date, most studies have been based on the assumption of a
      cylindrically symmetric polarizibility tensor. It is shown that this assumption
      is highly questionable although this method has been used fairly successfully in
      the past. This method results in orientation parameters that are clearly
      different from those obtained with the two more complex procedures. The most
      complex method, both theoretically and experimentally, requires the most
      measurements per sample. Major problems have occurred when trying to calculate
      the desired parameters, in particular for samples with high birefringence. These
      problems are related to experimental complexities occurring for measurements when
      the samples are tilted with respect to the polarization direction of the incident
      light. These measurements are replaced by a simple determination of
      depolarization ratio in the third method. This method assumes that the
      depolarization ratio is independent of changes in molecular orientation and
      structure. It was found that this assumption is not correct. Thus, the most
      complex method is the method of choice to quantitatively determine the second-
      and fourth-order parameters of the orientation distribution function, unless one
      has knowledge of the depolarization ratio of each sample being studied. That
      knowledge permits the use of an experimentally simpler method to obtain the
      desired parameters.

PMID- 15035709
TI  - Surface-enhanced-Raman-scattering-inducing nanoprobe for spectrochemical
      analysis.
AB  - This paper describes a new nanoprobe that induces the surface-enhanced Raman
      scattering (SERS) effect when brought into contact with chemicals on any type of
      surface. The SERS-inducing probe was fabricated from an optical fiber that was
      tapered to a tip 100 nm in diameter. A thin layer of silver islands was applied
      to the tip of the tapered fiber via thermal evaporation to induce the SERS
      effect. The small scale of the tip may be amenable to localized, nondestructive
      SERS-based analyses of surfaces with high spatial selectivity. Because the
      contact probe itself induces the SERS effect, no modification of the sample is
      required. Direct analysis at submicrometer spatial selectivity is therefore
      possible for analyte compounds on any type of surface. Various optimization
      studies and preliminary evaluations were performed. A 10-nm silver thickness was
      determined to yield the optimum SERS effect. A 25% relative standard deviation in
      SERS signal was observed for five different probe tips. As a demonstration of the
      SERS-inducing capability of the probe, Raman spectra were recorded for glass
      surfaces coated with brilliant cresyl blue and p-aminobenzoic acid before and
      during contact with the SERS-inducing nanoprobe.

PMID- 15035710
TI  - Infrared absorption enhancement of C60 by overlaying thin silver island films.
AB  - Normal-incidence infrared absorption has been observed for silver overlaid C(60)
      thin films formed on surface-oxidized Si(111) substrates as a function of the
      silver or C(60) film thickness. The absorption spectra exhibit bands at 1429 and
      1180 cm(-1) due, respectively, to the infrared active T(lu) (4) and T(lu) (3)
      modes of C(60) in multi-layers. Additionally, two bands appear at 1442 and 1370
      cm(-1). The former band is caused by activation of the infrared inactive (Raman
      active) A(g) (2) mode via electron transfer from the silver to adsorbed C(60),
      and the latter is assigned to the T(1u) (4) mode red-shifted by the charge
      transfer. These bands are all enhanced in intensity dependent either upon the
      silver or C(60) thickness, i.e., the largest absorption enhancement is obtained
      for 25-monolayers-thick silver and 12-nm-thick C(60). Under atomic force
      microprobe inspection, the average size and height of the islands in the overlaid
      25-monolayers-thick silver change with underlying C(60) film thickness. The
      influence of the C(60) film structure upon the silver film and in turn the
      absorption intensity is strongly suggested.

PMID- 15035711
TI  - Characterization of an optoelectronic polymer, poly(2-phenoxy p-phenylene
      vinylene), and its precursor polymer by dynamic infrared spectroscopy.
AB  - Numerous applications of dynamic infrared spectroscopy to study a variety of
      polymer systems have been described in the literature. Typically, dynamic
      spectral changes are used to determine the molecular and submolecular
      reorientations that give rise to a material's observable mechanical properties.
      In the present study, the normal modes are characterized by their time-dependent
      response to an applied perturbation as an aid to assignment of the observed
      vibrational bands. Characterization of a newly synthesized optoelectronic
      polymer, poly(2-phenoxy p-phenylene vinylene), and its precursor polymer, is
      described. Vibrational modes along the backbone and side chain are expected to
      exhibit significantly different responses to mechanical perturbation due to
      delayed phase response of the phenoxy substituent. In-phase spectra, quadrature
      spectra, and two-dimensional infrared correlation maps are included in this
      characterization. This study has demonstrated that dynamic infrared spectroscopy
      can be used to distinguish backbone phenylene ring stretches from ring stretches
      associated with the phenoxy substituent. Density functional theory calculations
      are applied to confirm infrared spectral assignments. The mechanical properties
      are briefly discussed in light of the dynamic response.

PMID- 15035712
TI  - Analysis of latent fingerprint deposits by infrared microspectroscopy.
AB  - We report the use of infrared (IR) microspectroscopy for the analysis of
      fingerprint residues. The advantage of using an IR microscope lies in the ability
      to visualize and obtain spectra of individual particles and droplets that make up
      fingerprint ridge deposits at a spatial resolution of approximately 10 microm.
      Our initial results suggest that infrared microspectroscopy in reflection
      absorption mode provides reproducible spectral analysis of fingerprint residue.
      Since infrared microspectroscopy is nondestructive to the sample, we will be able
      to study the changes in fingerprint ridge deposits as a function of time. The
      method holds promise for probing the difference between latent fingerprints of
      adults and children.

PMID- 15035713
TI  - Structural changes in the cells of some bacteria during population growth: a
      Fourier transform infrared-attenuated total reflectance study.
AB  - Structural changes occurring in the cells of several bacteria during their growth
      curves have been investigated by Fourier transform infrared (FT-IR) spectroscopy
      using the sampling technique of attenuated total reflectance (ATR). Spectra
      reflect all of the components of the cells, including the cell walls, cell
      membranes, internal structures, and the cytoplasm. The bacteria studied were
      Bacillus stearothermophilus, Halobacterium salinarum, Halococcus morrhuae, and
      Acetobacter aceti. All species showed significant spectral changes during their
      growth curves, indicating structural changes in the cells during increases in
      cell numbers. The major change for B. stearothermophilus was in the lipid
      content, which was at a maximum during the exponential phase of the growth curve.
      For the halophiles H. salinarum and H. morrhuae, the major change was that the
      concentration of sulfate ion in the cells varied during the growth curve and was
      at a maximum during the mid-part of the exponential phase of the growth curve. A.
      aceti cells showed increasing polysaccharide content during the growth curve as
      well as maximum lipid content during the exponential phase of growth.

PMID- 15035714
TI  - Vibrational analysis of structure activity relationships (SAR) in molecular
      binding.
AB  - A novel vibrational spectroscopic approach has been developed to better
      understand the structure activity relationship (SAR) component of the drug
      discovery effort. First, vibrational spectroscopy has been developed as a tool
      for the identification of molecular subcomponents within a compound series, which
      play an active role in binding kinetics. Second, vibrational spectroscopy has
      exhibited utility in uncovering electronic trends within both pendant functional
      groups and within the molecular backbone scaffold, which foster the binding
      process. In this study, three series of compounds (isoflavone, coumarin, and
      benzoxazole) within a human estrogen receptor (ER-beta) study were used to
      explore the feasibility of the technique. In each series, infrared and Raman band
      shifts, which correlated with ER-beta binding activity, were identified. Data
      indicated binding activity to be strongly influenced by electron density in the
      pi-bonding system of the backbone scaffold for each series. The ability to relate
      the physical/electronic state of a molecular subcomponent to activity has far
      reaching implications in the identification and optimization of binding activity.
      The preliminary success of this project opens the door to a much broader
      investigation of the technique using a host of spectroscopic methodologies.

PMID- 15035716
TI  - Application of magnetic resonance imaging to the investigation of the diffusivity
      of 1,1,1,2-tetrafluorethane in two polymers.
AB  - In order to evaluate the suitability of a polymer as a sealing material for
      certain working fluids used in process plants, information about the fluid
      diffusivity into the polymer or the polymer permeability to the fluid is a
      prerequisite. The fluid of interest in the present work is 1,1,1,2
      tetrafluorethane, CH(2)FCF(3), a partly fluorinated hydrocarbon (HFC) commonly
      known as refrigerant R134a. HFCs are increasingly used in refrigeration, air
      conditioning, and heat pump applications as substitutes for the
      chlorofluorocarbons (CFCs) or hydrochlorofluorocarbons (HCFCs) that are believed
      to be responsible for ozone depletion in the stratosphere. The polymers studied
      were FPM, a perfluoroelastomer, and EPDM, an ethylene-propylene-diene rubber. The
      study was carried out using magnetic resonance imaging (MRI). The contact time
      dependence of diffusion of the fluid into the polymer, as well as the spatial
      distributions of spin-lattice, T(1), and spin-spin, T(2), relaxation times, were
      used as indicators of the influence of the EPDM matrix on the mobility of R134a
      molecules.

PMID- 15035715
TI  - Postoperative plasma metabolic consequences of an osseous substitute
      implantation: analysis by fourier transform infrared spectroscopy.
AB  - In this study, we have investigated the postoperative plasma consequences of
      coral implantation into femoral condyle of rabbits. Analyses were performed using
      Fourier transform infrared (FT-IR) spectroscopy, a sensitive and nondestructive
      method, to evaluate plasma modifications one day, one week, one month, and three
      months after surgery. This technique showed that both surgery and implantation
      induced important changes of lipidic compounds one day after surgery, with a body
      lipolysis. Major modifications appeared one week after surgery, with a decrease
      of protein and saccharide contents, and an increase of amino acids accompanied by
      a noticeable inflammatory process. These last changes were revealed by a
      hierarchical classification in the 1430-1295 and 1137-1092 cm(-1) spectral
      regions, leading to two well-separated groups, before and one week after surgery.
      After a delayed time of three months and despite a substantial recovery for
      biomolecules such as proteins and fatty acids, some alterations are always
      observed, such as for amino acids, triglycerides, and glycerol. Moreover,
      molecules implicated in the inflammatory process had not reached their initial
      level.

PMID- 15035718
TI  - Characterization of proton exchange layer profiles in KD2PO4 crystals by micro
      Raman spectroscopy.

PMID- 15035717
TI  - Light emission diode water thermometer: a low-cost and noninvasive strategy for
      monitoring temperature in aqueous solutions.
AB  - A spectroscopic device for monitoring the temperature of aqueous solutions is
      presented. It uses a 950 nm light emission diode as light source and two
      photodiodes as detectors. Temperature is monitored following the thermally
      induced absorbance changes of the water-OH second overtone (approximately 960
      nm). A linear response between the light absorbed by an aqueous solution and its
      temperature is found in the range from 15 to 95 degrees C. A prediction error of
      0.1 degrees C and a precision of 0.07 degrees C in temperature measurement can be
      achieved. Up to 0.1 M of electrolyte concentration can be present in the solution
      without significantly affecting the temperature measurement. Different
      strategies, such as remote (noninvasive) or in situ (using a fiber-optic probe)
      temperature measurement, are shown, and their relative advantages are discussed.

PMID- 15035719
TI  - Rapid dipicolinic acid extraction from Bacillus spores detected by surface
      enhanced Raman spectroscopy.

PMID- 15035720
TI  - Mass treatment of onchocerciasis with ivermectin: should people with epilepsy
      and/or growth-retardation syndromes be excluded?
AB  - In many areas of Africa where human onchocerciasis is endemic there are now
      programmes for mass treatment with ivermectin (Mectizan), to eliminate the
      disease as a public-health problem. To determine whether those with epilepsy
      and/or growth-retardation syndromes (GRS) should be excluded from such mass drug
      administrations, literature searches of the standard biomedical databases were
      performed for all relevant articles published in English or French before January
      2003. Cross-referencing and the retrieving of articles recommended by experts
      completed the search. The literature review revealed that there is insufficient
      evidence for an association between onchocerciasis and epilepsy or GRS. Since
      ivermectin does not normally cross the blood-brain barrier, the drug is unlikely
      to have direct pro- or anti-convulsive activity. Furthermore, an estimated 1-2
      million epileptics in Africa have been treated with ivermectin, in onchocerciasis
      control programmes, without any reports of serious adverse events (SAE) to the
      passive surveillance system for such events. As there are few data on the
      prevalence of GRS in Africa, it is difficult to estimate the number of GRS cases
      who have been treated with ivermectin or the incidence of ivermectin-related SAE
      among such cases. Epileptics should not be excluded from mass treatments with
      ivermectin unless they are actively seizing or postictal. Although those with GRS
      associated with chronic wasting, with or without epilepsy, should be excluded,
      they should be eligible for clinic-based treatment if the diagnosis of
      onchocerciasis is confirmed and the benefits of treatment are deemed to outweigh
      any potential risks.

PMID- 15035721
TI  - Seasonal fluctuations in the carriage of Plasmodium vivax gametocytes in
      Thailand.
AB  - To study the influence of season on Plasmodium vivax gametocyte carriage, the
      relationship between monthly rainfall and the proportion of P. vivax patients
      with detectable gametocytaemia was analysed. Most of the data used came from 6807
      aggregated observations collected, in a refugee camp on the Thai-Burmese border,
      between January 2000 and December 2002. There was a positive correlation between
      rainfall and the incidence of P. vivax infection (Spearman's rho=+0.42; P =0.01)
      but the prevalence of gametocyte carriage among those with P. vivax infection was
      negatively correlated with rainfall (Spearman's rho=-0.58; P <0.001). The latter,
      negative correlation remained significant after controlling for the proportion of
      visitors relative to camp residents (P =0.003). Migrations, changes in
      transmission patterns, seasonal haematological changes, and ultraviolet
      immunosuppression are discussed as potential explanations for these observations.

PMID- 15035722
TI  - Quantitative determination of sporozoites and circumsporozoite antigen in
      mosquitoes infected with Plasmodium falciparum or P. vivax.
AB  - It is essential for malariologists and researchers to have simple and accurate
      means of assessing the threat of Plasmodium parasites. An attempt was therefore
      made to re-standardize one of the circumsporozoite (CS) ELISA that can be used to
      detect and quantify the circumsporozoite antigens of P. falciparum and P. vivax.
      A two-site, 'sandwich' ELISA based on a monoclonal antibody was used to test for
      the CS antigen and sporozoites of each Plasmodium species simultaneously. Using
      the resultant optical-density values, standard curves, that permit the number of
      sporozoites in an infected mosquito to be estimated from the quantification of
      the CS antigen, were constructed. Using these plots and the CS ELISA, the
      presence of just 12.5 sporozoites (i.e. 0.8 pg CS antigen) of P. falciparum, four
      sporozoites (3.2 pg antigen) of P. vivax-210 or 12.5 sporozoites (32.0 pg
      antigen) of P. vivax-247 could be demonstrated.

PMID- 15035723
TI  - A comparative evaluation of amphotericin B and sodium antimony gluconate, as
      first-line drugs in the treatment of Indian visceral leishmaniasis.
AB  - In a study to evaluate the relative efficacies of sodium antimony gluconate (SAG)
      and amphotericin B (AMB), each drug was used to treat 60 Indian cases of visceral
      leishmaniasis (VL). At the time of treatment, each case had recently been
      parasitologically confirmed. The patients received either 20 mg SAG/kg daily, by
      intramuscular injection, for 4 weeks, or 1 mg AMB/kg daily, infused slowly over 2
      h, with no incremental dosage, for 20 days. The response of the patients was
      followed clinically and by the microscopical examination of bone-marrow aspirates
      (BMA). The infected macrophages in subsamples of the BMA collected pre-treatment
      were cultured so that the drug sensitivities of the parasites, to 20 microg SAG
      or 1 microg AMB/ml medium, could be determined in vitro. Other subsamples of the
      BMA were used to set up promastigote cultures that were then used to infect
      BALB/c mice. The responses of the mice to 5 days of treatment with SAG or AMB (at
      the same daily dosages as used in the clinical trials) were subsequently
      explored. SAG only cured 46.6% of the patients given the drug, only cleared
      amastigotes from 38.3% of the macrophage cultures, and only cured 53.3% of the
      infected mice. The corresponding values for AMB - 100%, 100% and 100% - were
      markedly higher (P <0.001 for each comparison). Although nine patients had to be
      withdrawn from the SAG group (all because of cardiac toxicity), all of the
      patients given AMB completed their treatment without any serious adverse effects
      (P <0.01). Two of the patients withdrawn from the SAG arm died shortly after
      their withdrawal; earlier withdrawal may have saved them. At least in the setting
      of the present study, AMB appears far superior to SAG as a first-line drug
      against VL and should replace it.

PMID- 15035724
TI  - Toxicogenetic evaluation of metronidazole in the treatment of women infected with
      Trichomonas vaginalis.
AB  - Samples of peripheral blood were collected once from non-smoking women who were
      healthy (controls) and twice (immediately before and immediately after 7 days of
      treatment with metronidazole at 500 mg/day) from non-smoking women infected with
      Trichomonas vaginalis. Lymphocyte cultures were prepared and used, in
      toxicogenetic studies, to determine the frequency of sister-chromatid exchange
      (SCE), the mitotic index (MI), and the replication index (RI) for each sample.
      MTZ treatment of the infected women led to an increase in the frequency of SCE (P
      <0.001), a decrease in the MI (P <0.003), and a modification in the kinetics of
      cell proliferation, with a decrease in the RI (P <0.0006). The differences seen
      between the results for the controls and those for the infected women, before and
      after MTZ treatment, may be attributed to the presence of the parasite, to the
      treatment itself, and/or to variation in the host's response to infection with T.
      vaginalis.

PMID- 15035725
TI  - The PCR-based detection of Babesia gibsoni infection in dogs (German shepherds)
      reared in South Korea.
AB  - German-shepherd dogs from the South Korean provinces of Gangwon and Gyunggi were
      used in a study exploring both the detection of Babesia gibsoni infection, by use
      of a PCR-based assay, and the nucleotide sequences of part of the P18 gene of the
      parasite. Nine (1.8%) of the 501 dogs checked were found PCR-positive. Although
      the prevalence of the infection appeared slightly higher in the male dogs than in
      the female (2% v. 1.7%), and in the dogs aged <3 years than in the older animals
      (2.7% v. 1.1%), these differences were not statistically significant. In
      addition, the prevalences of infection among the dogs from Gangwon (in the east
      of the country) and those from Gyunggi (in the west) appeared similar. All nine
      PCR-positive dogs were confirmed to have B. gibsoni infection by the
      microscopical examination of thin bloodsmears, which revealed that 0.1%-3%
      (mean=1.5%) of the dog's erythrocytes harboured the parasite. The nucleotide
      sequences of the P18 gene of B. gibsoni from each of the PCR-positive dogs were
      identical to each other and to the corresponding sequence - recorded under
      accession number AB053292 in the DNA Data Bank of Japan (DDBJ) - previously
      determined for isolates of B. gibsoni from Japanese dogs. Although the PCR
      products sequenced in the present study represent only a part of the P18 gene of
      B. gibsoni, it seems that South Korean and Japanese dogs carry a similar strain
      of B. gibsoni. These results may help to clarify the phylogenetic position of the
      B. gibsoni found in South Korea.

PMID- 15035726
TI  - A 26-year follow-up of bancroftian filariasis in two communities in north-eastern
      Tanzania.
AB  - The results of surveys, for human bancroftian filariasis, carried out in 1975 and
      1991 in endemic communities in north-eastern Tanzania have already been reported.
      In 2001, all consenting individuals from two of these communities (Tawalani and
      Kwale) were re-surveyed, and many of the individuals examined in the earlier
      surveys were re-identified. The findings revealed an extraordinarily static
      pattern of infection and disease over the 26 years of follow-up. By 2001, despite
      brief interventions introduced after the first two surveys, the community
      prevalences and mean intensities of microfilaraemia had almost returned to pre
      treatment levels. The majority of re-identified individuals who had been found
      microfilaraemic in 1975 and 1991 were also microfilaraemic in 2001. Being found
      microfilaraemic in the first survey was a highly significant risk factor for
      being found microfilaraemic in the subsequent surveys. These observations
      strongly indicate that re-infection with Wuchereria bancrofti commonly takes
      place, and that, compared with an individual who has never been infected, an
      individual who has been infected in the past has a much higher chance of
      acquiring a new, detectable infection. As most of the re-identified individuals
      who were amicrofilaraemic in 2001 but microfilaraemic in one or both of the
      earlier surveys were still positive for circulating filarial antigens in 2001, it
      seems that, once an infection has been acquired, the chance of ever becoming free
      of infection is small. No relationship between past microfilaraemia and the
      development of chronic filariasis was observed but the number of clinical cases
      seen in 2001, among the re-identified individuals, was low. The significance of
      these findings to our understanding of the natural history of W. bancrofti
      infection is discussed.

PMID- 15035727
TI  - HIV-associated morbidity, mortality and diagnostic testing opportunities among
      inpatients at a referral hospital in northern Tanzania.
AB  - Hospitalized patients with HIV infection are among the most likely to benefit
      from the expanding availability of anti-retroviral therapy in sub-Saharan Africa.
      Between 1990 and 2000, 3667 people known to be HIV-infected were admitted to
      Kilimanjaro Christian Medical Centre (KCMC) in Moshi, northen Tanzania. The level
      of inpatient mortality among these patients varied from 15%-21%, and the
      proportion of the HIV-infected patients admitted who were female increased
      significantly, from 45% at the start of the study period to 52% at the end (P
      <0.001). When the medical records for 1683 of the HIV-infected patients who had
      been admitted between 1996 and 2001 were reviewed, the most prevalent diagnoses
      on admission were found to be pulmonary tuberculosis (21%), malaria (14%) and
      gastro-enteritis/diarrhoea (12%) among the adults, and non-tubercular pulmonary
      infection (21%), pulmonary tuberculosis (19%) and gastro-enteritis/diarrhoea
      (12%) among the children. The crude odds ratios (OR) for inpatient death were
      greatest for adults presenting with meningitis [OR=3.7; 95% confidence interval
      (CI)=2.1-6.7], septicaemia (OR=2.9; CI=1.2-7.3) or renal disease (OR=2.6; CI=1.2
      5.7), and mortality was higher for men than for women (OR=1.4; CI=1.1-1.8). A
      single-day, point-prevalence survey in September 2001, among the KCMC's
      inpatients, identified HIV infection in 21% of those surveyed, many (44%) of the
      patients found positive being previously unaware of their infection. HIV
      infection remains a major cause of hospitalization and mortality in Moshi. A
      policy of routine testing would increase the number of HIV infections detected,
      allowing improvements in case management and in the prevention of infection.

PMID- 15035728
TI  - Prevalence of Helicobacter pylori infection among adult dyspeptic patients in
      Ethiopia.
AB  - In developing countries such as Ethiopia, where chronic gastritis and peptic
      ulcer disease are the most common endoscopic findings, it is important to study
      the association between Helicobacter pylori infection and gastroduodenal
      diseases. Both invasive and non-invasive diagnostic methods were therefore used
      to investigate 300, consecutive, adult patients with dyspepsia, from the
      gastrointestinal clinic of Tikur Anbassa University Hospital, Addis Ababa. The
      apparent overall prevalence of H. pylori infection varied according to the
      detection method employed. Culture revealed H. pylori in only 69% of the patients
      but this pathogen appeared more common when rapid urease tests (71%), PCR
      denaturating gradient gel electrophoresis (91%), histopathology (81%), silver
      staining (75%) or stool-antigen tests (81%) were employed. Antibodies to H.
      pylori were detected, both by enzyme immuno-assay (EIA) and immunoblotting, in
      approximately 80% of the patients, whether the antigens used were of a reference
      strain or from a local isolate of H. pylori. When some of the EIA-positive and
      EIA-negative sera were cross-absorbed with antigens of Campylobacter jejuni and
      re-tested by EIA, the H. pylori-positive sera remained positive and the negative
      sera remained negative. Dyspeptic patients in Ethiopia, like most of those
      previously observed elsewhere in Africa, are often infected with H. pylori. It is
      important that the management of these patients should not be hampered by the
      misinterpretation of the African epidemiology of this pathogen.

PMID- 15035729
TI  - Characteristics of louse-borne relapsing fever in Ethiopian children and adults.
AB  - Louse-borne relapsing fever (LBRF) is endemic in Ethiopia. The epidemiological
      and clinical aspects of LBRF and the differences between the infection in
      children and that in adults were investigated in a rural hospital in Ethiopia.
      During the 5-year study (1997-2002), 197 patients had a confirmed diagnosis of
      LBRF. Most (62.1%) of the cases were children under 15 years of age. The adult
      cases (i.e. those aged > or =15 years) were far more likely to present with
      headache (76.9% v. 40%; P <0.001), musculo-skeletal pains (61.5% v. 30.5%; P
      <0.001), dizziness (64% v. 39%; P =0.002) and bleeding (16.9% v. 3.8%; P =0.005)
      than the paediatric. The overall level of case fatality was 6.4%. Death appeared
      to be significantly associated with adulthood (P =0.01), delay in consultation (P
      =0.026) and the presence of vomiting (P =0.023). LBRF is clearly still a public
      health problem in Ethiopia, where the clinical manifestations of the disease
      differ according to the age of the case.

PMID- 15035730
TI  - A molecular marker for the identification of Simulium squamosum (Diptera:
      Simuliidae).
AB  - All except one of the important groups of West African vectors of Onchocerca
      volvulus that lie within the Simulium damnosum complex can be distinguished from
      each other using morphological characteristics. The exception is S. squamosum,
      which overlaps with other species, and this results in significant levels of
      misidentification. Variation in the untranscribed H3-H4 histone intergenic spacer
      region of flies of the S. damnosum complex has now been investigated. Although a
      CAA/CAG microsatellite was found to be hyper-variable and unsuitable for species
      diagnosis, a 10-bp indel seemed to vary in a species-specific manner. This indel
      was apparently absent from S. squamosum but present in all of the other species
      tested (S. damnosum s.s., S. sirbanum, S yahense, S. sanctipauli and S.
      leonense/konkourense). It should now be possible to identify individual, adult,
      female S. squamosum from the absence of the indel, using a PCR-based
      amplification and agarose- or polyacrylamide-gel electrophoresis, thus removing
      the major barrier to the routine identification of unknown samples.

PMID- 15035735
TI  - Inflammation, reactive oxygen species and cytochrome P450.
AB  - Inflammation may ultimately result from damage to membrane lipids by reactive
      oxygen species (ROS) such as peroxide, superoxide anion, hydroxyl radical and
      singlet oxygen. This study compares some of the methods used to determine ROS
      ethane exhalation, malondialdehyde quantified as thiobarbituric acid-reacting
      materials, and luminol-activated chemiluminescence (LAC)-and explores possible
      relationships with oedema formation in the rat foot-pad model. Iron
      nitrilotriacetate was the most effective of the model compounds tested in
      producing lipid peroxidation and ethane exhalation in mice. In the mouse and the
      rat, iron nitrilotriacetate caused increased ethane exhalation and concomitant
      increases in liver and kidney malondialdehyde. In the rat foot-pad oedema model,
      the challenge with Freund's complete adjuvant produced maximum malondialdehyde
      and maximum LAC in the inflamed paw 8 h after dosing, at which time oedema had
      also reached a high level. These effects were attributed mainly to hydroxyl
      radical and singlet oxygen. The inhibition of oedema by four anti-inflammatory
      drugs correlated well with LAC but less well with inhibition of malondialdehyde
      production. This study shows good agreement between different methods of
      determining ROS formation, and that inhibition of ROS formation in vivo is
      paralleled by a decrease in inflammation.

PMID- 15035734
TI  - Quantitative structure-activity relationships (QSARs) within the cytochrome P450
      system: QSARs describing substrate binding, inhibition and induction of P450s.
AB  - Quantitative structure-activity relationships (QSARs) within substrates, inducers
      and inhibitors of cytochromes P450 involved in xenobiotic metabolism are
      reported, together with QSARs associated with induction, inhibition and metabolic
      rate. The importance of frontier orbitals and shape descriptors, such as
      planarity (estimated by the area/depth(2) parameter) and rectangularity
      (estimated by the length/width parameter) is discussed, particularly in the
      context of the COMPACT system which discriminates between several P450 families
      associated with the activation and detoxication of xenobiotics. The use of
      parameters, particularly those derived from homology modelling of mammalian
      (especially human) P450s that are involved in exogenous metabolism, in generating
      QSARs for P450 substrates is discussed in the context of explaining differences
      in the binding affinities of human P450 substrates which are pharmacologically
      active.

PMID- 15035736
TI  - Multiple organ dysfunction syndrome.
AB  - Multiple organ dysfunction syndrome, including acute respiratory distress
      syndrome (ARDS) and renal failure, is described, its clinical features outlined,
      its origins in tissue oxidative stress following severe infections, surgical
      trauma, ionizing radiation, high-dosage drugs and chemicals, severe hemorrhage,
      etc., are defined, and its prevention and treatment prescribed.

PMID- 15035737
TI  - Treating inflammation: some (needless) difficulties for gaining acceptance of
      effective natural products and traditional medicines.
AB  - The quality of so-called 'natural medicines' is extraordinarily variable. Lack of
      resolute pharmacological assays contributes to this hiatus. More stringent
      evaluation of anti-inflammatory and anti-pyretic activities in rats can help
      resolve some of the uncertainties surrounding (a) preparations of some herbal
      products including so-called 'nature's aspirin' (e.g. willowbark, ginger), cat's
      claw, celery seed, etc., and (b) some animal lipids (e.g. Lyprinol(R) (NZ
      Mussel), emu and fish oils). These animal products can be a remarkable resource
      for supplementing conventional/allopathic therapy for inflammatory disease, e.g.
      providing lipoxygenase inhibitors. Beyond the verifiable science, the healing
      professions and the general public still need to examine more carefully criteria
      for QUALITY(S) in any alternative medicine-to ensure the good (= both reputations
      and products) are not destroyed by the bad-in essence counteracting Gresham's Law
      which states: the bad tends to displace the good.

PMID- 15035733
TI  - Drug-phytochemical interactions.
AB  - Changes in dietary habits favouring diets rich in fruits and vegetables, and a
      meteoric rise in the consumption of dietary supplements and herbal products have
      substantially increased human exposure to phytochemicals. It is, therefore, not
      surprising that diet and herbal remedies can modulate drug-metabolising enzyme
      systems, such as cytochromes P450, leading to clinically relevant drug
      phytochemical interactions. Phytochemicals have the potential to both elevate and
      suppress cytochrome P450 activity. Such effects are more likely to occur in the
      intestine, where high concentrations of phytochemicals may be achieved, and
      alteration in cytochrome P450 activity will influence, in particular, the fate of
      drugs that are subject to extensive first-pass metabolism as a result of
      intestinal cytochrome P450-mediated biotransformation. Moreover, it is becoming
      increasingly apparent that phytochemicals can also influence the pharmacological
      activity of drugs by modifying their absorption characteristics through
      interaction with drug transporters. Clearly, phytochemicals have the potential to
      alter the effectiveness of drugs, either impairing or exaggerating their
      pharmacological activity.

PMID- 15035750
TI  - Heart transplantation.
AB  - Although the number of available donor hearts severely limits the epidemiologic
      impact of heart transplantation on patients with heart failure, patients with end
      stage heart failure unresponsive to medical management currently have no other
      viable alternatives. Destination therapy with a ventricular assist device is the
      closest toward approaching clinical reality but has been plagued with problems of
      infection and stroke. The purpose of this review is to summarize recent
      developments in the field that may broaden the clinical impact of heart
      transplantation. For example, novel methods of cardiac preservation are being
      designed to safely evaluate and utilize "extended criteria" donors. Surgical
      techniques and medical management have reduced the incidence of postoperative
      right heart failure, and immunosuppressive regimens promise to limit chronic
      graft vascular disease.

PMID- 15035751
TI  - Uterine artery embolization for symptomatic myomata.
AB  - Fibroid disease is common and causes significant health problems in women of
      childbearing age. Over the past several years, uterine artery embolization (UAE)
      has emerged as a minimally invasive treatment for symptomatic uterine myomata.
      Embolotherapy is effective in relieving myoma-related symptoms in 80% to 90% of
      patients. It requires shorter hospitalizations than traditional surgical
      therapies for myoma disease and is associated with faster recovery and lower
      complication risks than surgery. Patient selection, the UAE procedure, and post
      UAE management are reviewed.

PMID- 15035752
TI  - Nerve agents: a comprehensive review.
AB  - Nerve agents are perhaps the most feared of potential agents of chemical attack.
      The authors review the history, physical characteristics, pharmacology, clinical
      effects, and treatment of these agents.

PMID- 15035753
TI  - Blood transfusion policy among European pediatric intensive care physicians.
AB  - The objective of this study was to define current blood transfusion practices
      among European pediatric intensive care physicians treating critically ill
      children. A questionnaire of case scenarios was administered to members of the
      European Society of Pediatric and Neonatal Intensive Care (ESPNIC). Of the 258
      members of the ESPNIC, 134 (51.9%) pediatric intensive care physicians completed
      the questionnaire. The suggested blood transfusion thresholds for case scenario 1
      (post-orthopedic surgery child) ranged from <7.0 g/dl to 11 g/dl. A total of
      57.3% suggested 7 g/dl, 33.6% suggested 8 g/dl, and 6.9% suggested 9 g/dl as a
      hemoglobin threshold for transfusion (mean, 7.54 +/- 0.75). For case scenarios 2
      to 4, the suggested hemoglobin thresholds were 7 g/dl to 12 g/dl. For case
      scenario 2 (a child with acute respiratory distress syndrome), 22.4% suggested 8
      g/dl, 15.7% suggested 9 g/dl, and 41% suggested 10 g/dl as a hemoglobin threshold
      for transfusion (mean, 9.40 +/- 1.27 g/dl). For case scenario 3 (a post-cardiac
      surgery infant), 20.1% suggested 7 g/dl, 24.6% suggested 8 g/dl, 21.6% suggested
      9 g/dl, and 23.9% suggested 10 g/dl as a hemoglobin threshold for transfusion
      (mean, 8.72 +/- 1.24 g/dl). For case scenario 4 (a child with septic shock),
      23.1% suggested 8 g/dl, 16.4% suggested 9 g/dl, and 41% suggested 10 g/dl as a
      hemoglobin threshold for transfusion (mean, 9.45 +/- 1.24 g/dl). The threshold
      for transfusion was not statistically different (P >.05) between the physicians
      according to their subspecialty, years of experience, or country of origin. The
      suggested volume of transfused blood was 10 to 15 ml/kg in 427 responses (82.6%)
      and 20 ml/kg in 89 responses (17.2%). Most physicians, 78/128 (60.9%), did not
      consider the age of the transfused blood an important factor in their decision to
      transfuse. Of the 106 (79.1%) physicians who detailed their considerations for
      elevating the threshold for transfusion, 82 (77.3%) gave a general nonspecific
      indication, 47 (44.3%) stated hemodynamic instability and shock, and 40 (37.7%)
      an ongoing bleeding. The hemoglobin threshold for blood transfusion and
      transfusion volume varies among European pediatric intensive care physicians, for
      the same patient.

PMID- 15035754
TI  - Tissue plasminogen activator as an adjuvant therapy for pleural empyema in
      pediatric patients.
AB  - The authors retrospectively review the clinical course and outcome of 6 pediatric
      patients, ranging in age from 2 to 13 years, who were treated with TPA for
      complex empyema. Efficacy was assessed by evaluating pleural fluid drainage for 6
      hours prior to and subsequent to each dose of TPA, as well as by resolution of
      fever and length of hospital stay. The average volume drained for 6 hours before
      infusion of TPA was 22.5 mL +/- 18.4 mL, and the average volume 6 hours after TPA
      therapy was 141.7 mL +/- 28.3 mL, P <.0001. After initiation of TPA therapy, 5
      out of 6 patients became afebrile within 48 hours. The median length of stay
      after initiation of TPA therapy was 6 days, with a range from 4 days to 12 days.
      A discussion of other current therapies for empyema, along with a comparison of
      these therapies to TPA regarding the costs of therapies and risk-benefit ratios,
      is also included.

PMID- 15035755
TI  - Drotrecogin alfa (activated) in an infant with gram-negative septic shock.
AB  - The authors observed the effect of drotrecogin alfa (activated) in a case of
      pediatric severe sepsis. A 4-month-old male infant with Serratia marcescens
      septic shock, multiple organ dysfunction syndrome (MODS), and consumptive
      coagulopathy was admitted. The safety and efficacy of drotrecogin alfa
      (activated) has not yet been established for patients younger than 18 years of
      age. This is the first published report of the use of drotrecogin alfa
      (activated) in an infant with severe sepsis. Within 6 hours of starting therapy,
      there was a significant improvement in hemodynamics, which was not maintained
      after the drotrecogin alfa (activated) infusion was temporarily discontinued. No
      significant bleeding complications occurred during the infusion. A brain MRI on
      day 22 after drotrecogin alfa (activated) infusion showed bilateral small
      occipital hemorrhages. Drotrecogin alfa (activated) in this infant was temporally
      related to significant improvement. It is unknown whether the MRI brain lesions
      are related to severe sepsis with disseminated intravascular coagulation or
      drotrecogin alfa (activated) infusion. The authors believe that drotrecogin alfa
      (activated) should be considered in select children with life-threatening severe
      sepsis.

PMID- 15035756
TI  - Recombinant human-activated protein C (rhAPC) in childhood sepsis.

PMID- 15035758
TI  - Radiology in the intensive care unit (part 2).
AB  - This review of intensive care unit (ICU) radiology has been divided into two
      sections. In Part 1, previously published, the discussion focused on the role of
      the portable radiograph in the evaluation of the critically ill patient and the
      impact of the introduction of digital radiography and picture-archiving
      communications systems on patient care. Part 2 of this review will emphasize the
      role of computed tomography and the increasing contribution of image-guided
      interventional procedures in patient management. The deleterious effects of
      mechanical ventilation due to barotrauma will also be discussed.

PMID- 15035759
TI  - Screening ultrasound in blunt abdominal trauma.
AB  - Ultrasound is used worldwide to evaluate patients with blunt abdominal trauma.
      Sometimes referred to as an extension of the physical exam, ultrasound can
      rapidly help distinguish patients with injury requiring computerized tomography
      (CT) or surgery (typically 5%-10%) from those with no abdominal injury (> 90%).
      Ultrasound has several advantages in the setting of trauma. It is portable,
      integrates easily into the resuscitation of trauma victims without causing delay
      in therapy, is noninvasive, and has no associated morbidity. Limitations of
      ultrasound include its dependence on operator skill and technique, poor image
      quality in patients with morbid obesity or extensive subcutaneous gas, limited
      visualization of the retroperitoneum, and less reliable localization of visceral
      injury compared to CT. Successful use of abdominal ultrasound in the setting of
      trauma can be maximized with adequate sonographer training, appreciation of
      technical limitations, and adherence to an appropriate trauma ultrasound
      protocol.

PMID- 15035760
TI  - Hypogammaglobulinemia in pediatric ICU patients.
AB  - The authors retrospectively review their experience with low immunoglobulin G
      (IgG) levels in a pediatric ICU population over a 12-month period. The total IgG
      level was below the normal for age in 14 of the 20 patients. The 14 patients with
      a low IgG level were younger and weighed less when compared with the 6 patients
      who had a normal IgG level. There was no difference in the risk of mortality
      between the 2 groups. In the 14 patients with an IgG level less than normal for
      age, the IgG level was 33% to 99% of normal, with 4 patients having a level less
      than 50% of normal for their age. Prospective trials are needed to determine the
      incidence of this problem, its impact on survival, and the appropriate therapy in
      the pediatric ICU population.

PMID- 15035761
TI  - Industry-sponsored economic studies in critical and intensive care versus studies
      sponsored by nonprofit organizations.
AB  - The purpose of this analysis of health economic studies in the field of intensive
      and critical care was to investigate whether any relationship could be
      established between type of sponsorship and (1) type of economic analysis, (2)
      health technology assessed, (3) sensitivity analysis performed, (4) publication
      status, and (5) qualitative cost assessment. Using the terms critical care or
      intensive care, all health economics publications in the field of critical and
      intensive care were identified in the Health Economic Evaluations Database (HEED,
      Version 1995-2001) on the basis of sponsorship and comparative studies. This
      search yielded a total of 42 eligible articles. Their evaluations were prepared
      independently by 2 investigators on the basis of specific criteria. When
      evaluators disagreed, a third investigator provided a deciding evaluation. There
      was no statistically demonstrable relationship between types of sponsorship and
      sensitivity analysis performed, publication status, types of economic analysis,
      or qualitative cost assessment.

PMID- 15035762
TI  - Ventilator-associated pneumonia patients who do not reduce bacteria from the
      lungs have a worse prognosis.
AB  - The authors determined the significance of serial semi-quantitative
      bronchoalveolar lavage (BAL) culture results in patients undergoing therapy for
      ventilator-associated pneumonia. A total of 32 patients underwent at least 2
      nonbronchoscopic BAL studies. Fourteen patients had methicillin-resistant
      Staphylococcus aureus (MRSA). Of these, 11 had more than 100 colony-forming units
      (cfu) of MRSA/mL of BAL from the follow-up BAL. Eighteen patients had an organism
      other than MRSA, and 7 of these patients had > 100 cfu of bacteria/mL of BAL from
      the follow-up BAL. Of the 18 patients with > 100 cfu of bacteria/mL of BAL at
      follow-up, 14 (79%) died, whereas only 5 of 14 (36%) patients who cleared their
      bacteria at follow-up died within 28 days. The inability to reduce the bacterial
      burden from the lower respiratory tract within the first few days of therapy for
      ventilator-associated pneumonia was associated with increased mortality.

PMID- 15035763
TI  - A prospective evaluation of the 1-hour decision point for admission versus
      discharge in acute asthma.
AB  - Study objectives were to evaluate the 1-hour decision point for discharge or
      admission for acute asthma; to compare this decision point to the admission
      recommendations of the Expert Panel Report 2 (EPR-2) guidelines; to develop a
      model for predicting need for admission in acute asthma. The design used was a
      prospective preinterventional and postinterventional comparison. The setting was
      a university hospital emergency department. Participants included 50 patients
      seeking care for acute asthma. Patients received standard therapy and were
      randomized to receive albuterol by nebulizer or metered-dose inhaler with spacer
      every 20 minutes up to 2 hours. Symptoms, physical examination, spirometry,
      pulsus paradoxus, medication use, and outcome were evaluated. Based on clinical
      judgment, the attending physician decided to admit or discharge after 1 hour of
      therapy. Outcome was compared to the EPR-2 guidelines. Post hoc statistical
      analyses examined predictors of the need for admission from which a prediction
      model was developed. Maximal accuracy of the admit versus discharge decision
      occurred at 1 hour of therapy. Using FEV(1) alone as an outcome predictor yielded
      suboptimal performance. FEV(1) at 1 hour plus ability to lie flat without dyspnea
      were the best indicators of response and outcome. A model predictive of the need
      for admission was developed. It performed better (P =.0054) than the admission
      algorithm of the EPR-2 guidelines. The decision to admit or discharge acute
      asthmatics from the ED can be made at 1 hour of therapy. No absolute value of
      peak flow or FEV(1) reliably predicts need for hospital admission. The EPR-2
      guideline thresholds for admission are barely adequate as outcome predictors. A
      clinical model is proposed that may allow more accurate outcome prediction.

PMID- 15035764
TI  - Nosocomial pneumonia in the intensive care unit: controversies and dilemmas.
AB  - Nosocomial pneumonia (NP), and its most serious form, ventilator-associated
      pneumonia (VAP), is a major cause of morbidity and mortality in the ICU. Numerous
      controversies exist, from diagnostic criteria to prevention and treatment,
      including the issues of attributable mortality of VAP, differences in the
      approach to early and late VAP, and the best diagnostic methods. Initial,
      accurate therapy is one of the most important factors determining outcome in VAP.
      Antibiotic monotherapy versus combination therapy is not clearly defined, as
      clinicians struggle with the dual risk of inadequate therapy negatively affecting
      outcome and overtreatment promoting antibiotic resistance. The role of airway and
      gastrointestinal colonization and innovative preventive strategies such as
      noninvasive ventilation, antibiotic rotation, and aerosolized antibiotics are
      discussed. No uniform standards exist for the approach to VAP. The authors
      highlight the major controversies and dilemmas in the clinical approach to VAP,
      with recommendations for the bedside management of these patients.

PMID- 15035765
TI  - Non-heartbeating organ donation: a review.
AB  - Organ transplantation is one of the groundbreaking achievements in medicine in
      the 20th century. In the early days of transplantation, organs were obtained from
      non-heartbeating (NHB) cadavers. With time, better options for organ sources
      became available (for example, living-related and "brain dead" donors), and the
      practice of obtaining organs from NHB cadavers fell out of favor. Improvements in
      the field of transplantation have led to an increased demand for organs. Various
      strategies have been employed recently to increase the supply, one of them being
      non-heartbeating organ donation (NHBOD). NHBOD can take place in controlled or
      uncontrolled circumstances. Recently, national organizations have supported and
      proposed guidelines for NHBOD and to aid clinicians in identifying potential
      donors. Outcomes of organs obtained from NHB cadavers are comparable to those
      obtained from heartbeating donors. The practice of NHBOD is increasing and has
      proven that it can contribute to increasing organ availability.

PMID- 15035766
TI  - Radiology in the intensive care unit (Part I).
AB  - The increasing complexity of the intensive care patient combined with the recent
      advances in imaging technology has generated a new perspective on intensive care
      radiology. The purpose of this 2-part review article is to describe the
      contribution of radiology to the management of these critically ill patients. The
      first article will discuss the impact of picture archiving and communication
      system (PACS) on critical care management and utility of the portable chest
      radiograph in the detection and evaluation of pulmonary disease with correlation
      to computed tomography (CT). The second article describes in more detail the
      increasing role of CT in diagnosis and therapeutic procedures. In particular, the
      implementation of CT pulmonary angiography in the evaluation of pulmonary emboli
      and the introduction of the new multislice detector CT scanners that allow even
      the most dyspneic patient to be evaluated. Pleural complications in the intensive
      care unit and image-guided intervention will also be discussed.

PMID- 15035767
TI  - Determination of death by neurological criteria.
AB  - Until 1968, when an ad hoc Harvard Medical School Committee published a landmark
      paper calling for determination of death using neurological rather than
      cardiovascular criteria, death was considered to have occurred when the heart
      irreversibly ceased beating. Since that time, every jurisdiction in the country
      has come to accept through law or court decision neurological criteria to define
      death. The authors review the issue of death by neurological criteria in light of
      current guidelines and recent advances.

PMID- 15035768
TI  - Percutaneous dilatational tracheostomy for emergent airway access.
AB  - The study objective of this article was to evaluate percutaneous dilatational
      tracheostomy (PDT) for emergent airway access. This is a case series of 9
      patients who presented over a 58-month period. All patients were in severe
      respiratory difficulty where intubation by conventional means was unsuccessful.
      All 9 patients were successfully intubated using PDT technique. No technical
      complications were noted, specifically bleeding, extratracheal placement, or
      prolonged procedure time. Six patients ultimately died, 2 from anoxic
      encephalopathy due to failed resuscitation and 4 from comorbid illness. Three
      patients ultimately survived to hospital discharge. The authors conclude that PDT
      can effectively establish a surgical airway in an emergent setting. The major
      advantage of this technique is the ability to gain and maintain competence in an
      elective, controlled environment. The authors believe that PDT may play a role in
      the management of the emergent surgical airway.

PMID- 15035769
TI  - Nosocomial pneumonia: the gorilla in the ICU.

PMID- 15035770
TI  - Digital image compression: pixels n' bits.

PMID- 15035777
TI  - Evaluation of the long-term pancreatic effects of constitutive nitric oxide
      synthase inhibition in dogs.
AB  - Constitutive and inducible isoforms of nitric oxide synthase (NOS) catalyze the
      synthesis of nitric oxide (NO) from L-arginine in various tissues and in
      different pathophysiologic states. Short-term treatment with NOS inhibitors has
      been associated with pancreatic enzyme elevations and pancreatic acinar cell
      degeneration; however, long-term pancreatic effects of NOS inhibition are not
      known. The purpose of this study was to evaluate the subchronic pancreatic
      effects of L-nitro-arginine (LNA), a compound that preferentially inhibits
      constitutive NOS isoforms. LNA was administered orally at doses of 10 and 30
      mg/kg per day to 6 female dogs/group for 4 weeks. To differentiate whether the
      pancreatic effects of LNA may be related to its arginine structure, an additional
      group was given L-arginine (L-Arg) at plasma concentrations similar to the high
      dose of LNA (30 mg/kg per day). Pancreatic effects were monitored by changes in
      serum levels of pancreatic enzymes at regular intervals and by microscopic
      examinations at the end of the study. Both LNA and L-Arg were systematically
      available throughout the 4-week study period. LNA produced dose-related
      elevations (1.3-10-fold above concurrent control) in serum levels of pancreatic
      enzymes (amylase, lipase and trypsin-like immunoreactivity) during the 4-week
      treatment period with peak elevations occurring during the first week. Histologic
      assessments of the pancreas conducted at the end of the 4-week dosing period were
      unremarkable. Additionally, LNA treatment resulted in reduction in heart rate
      (40%), gastric distension and gastric mucosal erosion and ulceration. No
      pancreatic, cardiac, or gastric effects were seen with L-Arg, indicating that
      above effects were likely due to NOS inhibition. Results of this study confirmed
      previous observations of acute pancreatic alterations following the inhibition of
      constitutive NOS isoforms. However, these pancreatic alterations appear to be
      only transient effects as elevations in serum enzymes declined over time and no
      structural acinar cell damage was seen after continuous treatment with LNA for 4
      weeks, suggesting an adaptation to NOS inhibition over time.

PMID- 15035778
TI  - Hepatic acute-phase reaction in histamine-deficient gene targeted mice.
AB  - Histamine is a versatile mediator that, according to in vitro studies, affects
      the synthesis of inflammatory cytokines and acute-phase proteins. The histidine
      decarboxylase knockout (HDC-/-) mouse is a model of in vivo investigation of the
      physiologic and metabolic integration of the acutephase response. These mice do
      not synthesise histamine and feeding them with histamine-poor diet they are
      almost completely histamine-deficient. We compared the serum concentrations of
      representatives of acute-phase plasma proteins, as well as the levels IL-6 and IL
      1alpha in wild type and HDC-/- mice during local (turpentine-induced) or systemic
      (LPS-induced) inflammation. The level of some acute-phase proteins significantly
      differed in wild-type and HDC-/- mice while others remained unaffected. The IL-6
      levels are also differ in the wild-type and histamine-deficient animals,
      suggesting that the effect of histamine is attained through IL-6, although direct
      effect is not disclosed yet.

PMID- 15035776
TI  - Osteoarthritis: symptoms, signs and source of pain.
AB  - Osteoarthritis is the most common form of arthritis. The condition is
      characterised by loss or failure of the functional and/or biochemical integrity
      of the joint. The clinical symptoms include joint stiffness, pain and
      dysfunction, but the principal problem for the majority of patients is the pain.
      Although there are no pain receptors in the cartilage, the origin of the pain is
      thought to be due to stimulation of the A delta mechanoreceptors and the C
      polymodal nerve endings in the synovium and surrounding tissues. However, some of
      the pain experienced in and around the joints is referred pain or sympathetic
      efferent pain. In addition, there is a poor correlation of clinical symptoms with
      radiological or imaging appearance. This lack of correlation of clinical
      evaluation and imaging makes attempts at treatment difficult and compromises
      attempts to design studies and to evaluate the outcome of osteoarthritis in
      clinical trials.

PMID- 15035779
TI  - Effect of selective inhibition of cyclooxygenase-2 on lipopolysaccharide-induced
      hyperalgesia.
AB  - Lipopolysaccharide (LPS) is known to increase the expression and release of
      various pro-inflammatory mediators, including cyclooxygenase-2 (COX-2) and
      produce hyperalgesia. It is also well known that prostaglandins (PGs),
      synthesised both in the periphery and centrally by COX isoforms, play a key role
      in sensitisation of nociceptors and nociceptive processing. To investigate the
      role of COX-2 in LPS-induced hyperalgesia, parecoxib, a selective COX-2
      inhibiting pro-drug, was injected intravenously 30 min before assessing
      hyperalgesia induced by intraperitoneal or subcutaneous administration of LPS (50
      microg/mouse or 25 microg/paw of rat, respectively). Acetic acid-induced writhing
      and tail immersion assay in mice and paw withdrawal response to thermal and
      mechanical stimuli in rats were used to assess the effect of inhibition of COX-2
      on LPSinduced hyperalgesia. Animals showed significant hyperalgesic behavior 8 h
      after LPS injection. Parecoxib (up to 20 mg/kg, i.v.) had no effect in the two
      acute nociceptive assays but showed marked antinociceptive activity in writhing
      and tail immersion assay in LPS-pretreated mice. Similarly, parecoxib reversed
      the hyperalgesia in the LPS-injected paw but not in the contralateral paw of
      rats. Pre-treatment with dexamethasone, an inhibitor of COX-2 expression before
      LPS injection significantly affected the development of hyperalgesia in both mice
      and rats. These findings suggest that inducible COX-2 derived PGs are involved in
      central nociceptive processing, which resulted in hyperalgesic behavior following
      LPS administration and inhibition of COX-2 or its expression attenuated LPS
      induced hyperalgesia.

PMID- 15035780
TI  - Effect of drug release rate on therapeutic outcomes: formulation dependence of
      gastrointestinal toxicity of diclofenac in the rat.
AB  - - The use of the non-steroidal anti-inflammatory drug, diclofenac, is associated
      with occasional serious side effects in the gastrointestinal (GI) tract. We
      examined the effect of altering the site of release of diclofenac sodium on GI
      tract side effects. Dissolution and pharmacokinetic studies were carried out to
      substantiate the sustained-release nature of crushed sustained release tablet.
      Adult male Sprague-Dawley rats were administered diclofenac 10 mg/kg orally as
      either immediate-release or sustained-release preparations. Upper and lower GI
      permeability, as a surrogate marker of toxicity, were measured using sucrose and
      51Cr-EDTA, respectively. Immediate- and sustained-release preparations similarly
      increased upper GI permeability. The induced toxicity in the lower GI tract,
      however, caused by the sustained-release formulation lasted longer than that of
      the immediate release formulation. Since both immediate- and sustained-release
      preparations of diclofenac increased sucrose permeability, the upper GI damage
      caused by diclofenac may be attributable mainly to a systemic mechanism. The
      prolonged lower GI toxicity following the sustained-release preparation may be
      related to a greater residence time therein.

PMID- 15035781
TI  - Time-course evaluation of whole blood phagocytosis in mice treated with the
      neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
AB  - Immunological abnormalities have been described in idiopathic Parkinson's disease
      and in the mouse model of this disorder induced by 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine (MPTP). This investigation was aimed to study the effect of
      MPTP on inflammatory response of whole blood phagocytes at different time
      intervals. C57BL male mice were injected intraperitoneally with either MPTP (30
      mg/kg) or saline (control group) and the blood samples were collected at 4, 24
      and 48 h. 50 microl of a 500-fold diluted blood sample was mixed with 150 microl
      of reaction mixture (0.4 mM luminol + 50 microg opsonized zymosan + 0.1% gelatin,
      in Hanks' balanced salt solution) and the chemiluminescence (CL) signal was
      measured in a luminometer at 37 degrees C. Although the CL response of the whole
      blood from control and MPTP groups was similar at 4 h, a significant increase in
      the CL signal was observed in MPTP-treated mice at 24 h post-treatment, which got
      subsided at 48 h. The findings of this study suggest that in an early stage a pro
      inflammatory response following MPTP might trigger a chain of potentially toxic
      pathways mediated by reactive oxygen species, leading to progressive neuronal
      damage.

PMID- 15035782
TI  - Comparison between plethysmometer and micrometer methods to measure acute paw
      oedema for screening anti-inflammatory activity in mice.
AB  - The present study was undertaken to evaluate the sensitivity of the
      plethysmometer and micrometer, which are the most commonly employed methods to
      measure the paw oedema for screening anti-inflammatory agents. Acute paw swelling
      was induced by s.c. injection of 0.02 ml carrageenan in mice. The maximum paw
      oedema (59.4%) was found to be at 3.5 h after injection of carrageenan in the
      hind paw of mice. Oral indomethacin treatment in the dose of 5 mg/kg 1 h prior to
      the induction of paw oedema, caused a significant (P < 0.05) reduction in paw
      swelling, when the plethysmometer method was used. When the micrometer method was
      used to measure the paw swelling, oral indomethacin at the dose of 1 mg/kg
      resulted in a significant reduction in paw oedema. These findings suggest that
      micrometer method is more sensitive to detect the lowest antiinflammatory dose of
      indomethacin when compared with the plethysmometer method. The possible
      significance of these findings is discussed.

PMID- 15035783
TI  - Giuliano Sclano (1947-2002).

PMID- 15035785
TI  - The impatient patient: a personal view of osteoarthritis.

PMID- 15035787
TI  - Global treatment of osteoarthritis.

PMID- 15035784
TI  - History and current status of osteoarthritis in the population.

PMID- 15035786
TI  - Regulation of bone lysis in inflammatory diseases.
AB  - Focal bone erosion is a major pathological feature of several common inflammatory
      diseases. Over the past decade there have been major advances in our
      understanding of the factors that regulate osteoclast formation and activity. It
      is now apparent that receptor activator for NFkappaB (RANK), its ligand RANKL
      (also known as TRANCE, osteoclast differentiation factor and osteoprotegerin
      (OPG) ligand) and the RANKL inhibitor OPG, are the major factors regulating
      osteoclast formation. These molecules influence normal bone physiology and now
      there is growing evidence that RANK-RANKL interactions also regulate osteoclast
      formation in disease. This paper reviews recent findings showing expression of
      RANK, RANKL and OPG in inflammatory diseases including rheumatoid arthritis,
      periodontal disease and peri-implant loosening. It is emerging that OPG and RANKL
      are key molecules regulating bone loss in disease and therapeutic intervention
      that targets these molecules may be helpful in treating a wide range of diseases.

PMID- 15035788
TI  - Assessment of the safety of selective cyclo-oxygenase-2 inhibitors: where are we
      in 2003?
AB  - Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used
      drugs worldwide despite their well-documented adverse gastrointestinal (GI)
      effects. The risk of developing a severe GI event varies from patient to patient
      and NSAID to NSAID. Selective cyclo-oxygenase-2 inhibitors (coxibs) have been
      designed to have similar efficacy but less GI toxicity than traditional NSAIDs,
      and have been shown to have an improved GI tolerability and less adverse events
      across a range of different GI safety assessments. In clinical trials,
      particularly VIGOR and CLASS, rofecoxib and celecoxib, respectively,
      significantly reduce the risk of ulcers and ulcer complications than nonselective
      NSAID comparators with ulcer rates comparable to placebo. The real benefit of a
      coxib comes from the sparing of the thromboxane and hence preservation of normal
      platelet function. Thus, there is less risk of bleeding with selective inhibition
      of COX-2, which is the most common and serious complication of non-selective
      NSAIDs. Moreover, bleeding can occur anywhere in the GI tract. Although some
      concern has been raised about the cardiovascular safety of coxibs, when used in
      recommended doses, there is no convincing evidence that patients treated with a
      coxib have an increased risk of cardiovascular thrombotic events. Different
      approaches have been advocated to minimize NSAID-related GI toxicity. Choice of
      less harmful NSAIDs such as coxib has been one of the strategies promoted in
      guidelines. The introduction of coxibs with a higher benefit-risk ratio has
      dramatically changed the therapeutic scenario for anti-inflammatory treatment in
      the clinical practice.

PMID- 15035790
TI  - COX-1, COX-2 and the topical effect in NSAID-induced enteropathy.
AB  - The side effects of NSAIDs are equally evident in the stomach and the small
      bowel. The latter is increasingly seen as being clinically significant,
      contributing substantially to the iron-deficiency anaemia that is so common in
      patients with rheumatoid arthritis. Furthermore, NSAID-enteropathy may be
      associated with life-threatening events. The pathogenesis of NSAID-enteropathy is
      uncertain but inhibition of COX-1 is believed to be of pivotal importance.
      However there is increasing evidence that COX-2 inhibition and the topical effect
      may have a synergistic detrimental action. We examined the role of COX-1, COX-2
      and the so called topical effect of acidic NSAIDs. We found that COX-1 or COX-2
      inhibition and the topical effect alone do not damage the GI tract. Dual
      inhibition of COX-1 and COX-2 results in intestinal inflammation similar to that
      caused by Indomethacin. The topical effect may act synergistically in this
      damage. The conventional view that the mechanism of gastrointestinal damage is
      principally caused by COX-1 inhibition needs to be revised in view of recent
      studies using selective inhibitors of the COX enzymes and COX knockout animals.

PMID- 15035789
TI  - Place of OTC analgesics and NSAIDs in osteoarthritis.
AB  - The risk related to the use of non-steroid anti-inflammatory drugs (NSAIDs)
      depends on the dose and duration of their use, in addition to the nature of the
      drug, and patient characteristics. The measures of risk and recent promotion of
      safer drugs have been mostly based on the results of clinical trials using
      continuous full-dose use of NSAIDs for periods up to 12 months which may not
      reflect real-life use and risks of the drugs. To assess this we did two studies
      of the utilisation of NSAIDs, one in a claims database to measure the amount of
      drugs dispensed to OA patients over 9 months, which showed that only a small
      fraction of patients actually bought enough analgesics or NSAIDs to cover the
      whole study period. On average, patients bought enough NSAIDs to cover 60 of 270
      days. The second study was a survey of General Practitioners and rheumatologists
      to assess the number of users of NSAIDs seen over 2 days' consultations, the
      indications for and patterns of NSAIDs use. 11% of GP patients and 26% of
      rheumatologists' patients used NSAIDs, one-third for osteoarthritis (OA), about 8
      10% for rheumatoid arthritis (RA) and the rest for various painful conditions. In
      OA and other conditions patients, more than 70% of patients had been taking their
      NSAIDs for less than 15 days at the time of consultation, whereas 42% of RA
      patients had been taking them for more than 6 months.

PMID- 15035791
TI  - Dexibuprofen: pharmacology, therapeutic uses and safety.
AB  - Dexibuprofen is the single pharmacologically effective enantiomer of rac
      ibuprofen. Racibuprofen and dexibuprofen differ in their physico-chemical
      properties, in terms of their pharmacological properties and their metabolic
      profiles. Several clinical trials and post-marketing surveillance studies were
      performed to broaden the findings on dexibuprofen. In the last 5 years 4836
      patients have been exposed to dexibuprofen in clinical trials and PMS trials.
      Only in 3.7% of patients adverse drug reactions have been reported and 3 serious
      adverse drug reactions (0.06%) were observed. In the dose ratio of 1 : 0.5 (rac
      ibuprofen vs. dexibuprofen) at least equivalent efficacy was proven in acute mild
      to severe somatic and visceral pain models. Dexibuprofen has proven at least
      comparable efficacy to diclofenac, naproxen and celecoxib and has shown a
      favourable tolerability. The results suggest that dexibuprofen processed in a
      special crystal form is a safe and effective treatment for different pain
      conditions.

PMID- 15035792
TI  - Pharmacology of drugs used to treat osteoarthritis in veterinary practice.
AB  - As in humans, pain in animals may be associated with a wide range of conditions
      and circumstances, ranging from acute trauma to joint diseases. Joint diseases
      are common in companion animal medicine (horse, dog, cat) and at least 80% of
      cases are classified as osteoarthritis (OA). Several drug classes are available
      for OA therapy, including corticosteroids, non-steroidal antiinflammatory drugs
      (NSAIDs), agents with potential disease modifying properties and nutraceuticals.
      For long-term maintenance OA treatment, particularly in the horse and dog, NSAIDs
      are routinely and extensively used. This review outlines the pharmacokinetics
      (PK) and pharmacodynamics (PD) of NSAIDs in companion and farm animal species.
      NSAID PK and PD have been studied in models of acute inflammation, which enable
      use of PK-PD modeling to facilitate (a) studies of mechanism of action at the
      molecular level and (b) prediction of dosages for clinical use. The PK-PD
      approach is a powerful but underutilized tool which also facilitates inter
      species comparisons.

PMID- 15035793
TI  - Mechanisms of action of paracetamol and related analgesics.
AB  - Paracetamol and salicylate are weak inhibitors of both isolated cyclooxygenase-1
      (COX-1) and COX-2 but are potent inhibitors of prostaglandin (PG) synthesis in
      intact cells if low concentrations of arachidonic acid are available. The effects
      of both drugs are overcome by increased levels of hydroperoxides. At low
      concentrations of arachidonic acid, COX-2 is the major isoenzyme involved in PG
      synthesis when both COX-1 and COX-2 are present in cells. Therefore, paracetamol
      and salicylate may selectively inhibit PG synthesis involving COX-2 because the
      lower flux through this pathway produces lesser levels of the hydroperoxide,
      PGG(2), than the pathway involving COX-1. Apart from the lack of anti
      inflammatory effect of paracetamol in rheumatoid arthritis, the clinical effects
      of paracetamol and salicylate are very similar and resemble those of the
      selective COX-2 inhibitors. A splice variant of COX-1, termed COX-3, may be a
      site of action of these drugs but, further work, particularly at low
      concentrations of arachidonic acid is required. We suggest that paracetamol,
      salicylate and, possibly, the pyrazolone drugs, such as dipyrone, may represent a
      distinct class of atypical NSAIDs which could be termed peroxide sensitive
      analgesic and antipyretic drugs (PSAADs).

PMID- 15035794
TI  - Nitric oxide and the gut injury induced by non-steroidal anti-inflammatory drugs.
AB  - Nitric oxide (NO) can protect the gastrointestinal tract from injury, including
      that provoked by non-steroidal anti-inflammatory drugs (NSAIDs). This protective
      profile of NO, which predominantly reflects actions on the microcirculation, is
      mimicked by NO donors. Moreover, the NO-donating agents know as the NO-NSAIDs or
      CINODs (cyclo-oxygenase-inhibiting nitric oxide-donating drugs) exhibit reduced
      gut injury in experimental models, which is considered to reflect these local
      beneficial actions of NO. NSAIDs cause chronic inflammatory lesions in the small
      intestine in experimental models. This injury results from initial COX inhibition
      and other local events, with translocation of indigenous luminal bacteria,
      leading to induction of NO synthase isoform, iNOS, and subsequent production of
      the cytotoxic moiety, peroxynitrite from NO and superoxide. Agents that inhibit
      iNOS or superoxide production can attenuate such intestinal injury. In the
      absence of reactive oxygen moieties, NO may play a beneficial role in the
      resolution of inflammatory damage to the gut, thus reconciling the potential
      opposing properties of NO in tissue inflammation and injury.

PMID- 15035795
TI  - COX-inhibiting nitric oxide donators (CINODs) - a new paradigm in the treatment
      of pain and inflammation.
AB  - The clinical utility of non-selective non-steroidal anti-inflammatory drugs
      (NSAIDs) for pain relief is tempered by their propensity to cause
      gastrointestinal toxicity. Cyclooxygenase (COX)-inhibiting nitric oxide donators
      (CINODs) are a new class of drugs designed to provide analgesic efficacy through
      COX inhibition and gastrointestinal safety through the protective effects of
      controlled nitric oxide donation. Pre-clinical studies assessing the
      pharmacology, efficacy and gastrointestinal safety of AZD3582 [4-(nitrooxy)butyl
      (2S)-2-(6-methoxy-2-naphthyl)propanoate] support this concept. Based on these
      studies, AZD3582 was the first CINOD to enter clinical development for the
      treatment of acute and chronic pain. The potential clinical utility of this new
      class is illustrated by a study of AZD3582 in healthy volunteers in which it
      caused significantly less acute gastrointestinal toxicity than an equimolar dose
      of naproxen. The results of the animal studies and the initial clinical study
      warrant long-term tolerability studies of AZD3582 along with evaluation of its
      anti-inflammatory and analgesic effects in humans.

PMID- 15035796
TI  - Nitric oxide: potential role for reducing gastro-enteropathy.
AB  - The pathogenesis of non-steroidal anti-inflammatory drug (NSAID)-induced
      gastroenteropathy may involve a number of key events leading to increased
      intestinal permeability and inflammation (topical effect) and the development of
      ulcers (micro-vascular effects of COX-1 inhibition and prostaglandin deficiency).
      Many strategies have been employed in an attempt to reduce the toxic effects of
      NSAIDs and these have been targeted at the different pathogenic stages of lesion
      development. One of the latest in this long chain of damage limitation has been
      the development of nitric oxide (NO) sequestering NSAIDs (NO-NSAIDs). It is
      suggested that the NO, which is released as the compounds are broken down, may
      counteract the consequences of the NSAID-induced decrease in mucosal
      prostaglandins. Here we examine the proposed mechanisms for NSAID-induced
      gastrointestinal damage together with some of the methods employed to address
      these mechanisms. We also consider the physiologic roles of NO in the gut
      together with how it may be potentially employed as an agent for limiting the
      side effects of NSAIDs in the gastrointestinal tract.

PMID- 15035797
TI  - The CINOD, AZD3582, exhibits an improved gastrointestinal safety profile compared
      with naproxen in healthy volunteers.
AB  - COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs in
      development for the treatment of acute and chronic pain. They comprise a COX
      inhibiting moiety linked to a nitric-oxide-donating component and are designed to
      provide an innovative mechanism of action of balanced COX inhibition and
      controlled nitric oxide donation. Through these pathways, CINODs should provide
      analgesic and anti-inflammatory efficacy, while offering gastrointestinal safety
      through the tissue-protective effects of nitric oxide donation. AZD3582 [4
      (nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is the first agent in
      the CINOD class to enter extensive clinical development. Pre-clinical studies
      demonstrate that AZD3582 has a superior gastrointestinal safety profile to
      naproxen, while demonstrating analgesic and anti-inflammatory efficacy. In
      healthy human volunteers, AZD3582 caused little gastrointestinal damage compared
      with equimolar doses of naproxen. Studies to evaluate the longer-term
      gastrointestinal safety of AZD3582, alongside its efficacy in alleviating chronic
      and acute pain, are ongoing.

PMID- 15035799
TI  - Combination anti-inflammatory therapy: synergism in rats of
      NSAIDs/corticosteroids with some herbal/animal products.
AB  - A useful function of any complementary medicine is to supplement some of the
      benefits from other treatment modalities. In rats, extracts from Indian celery
      seed and the NZ green-lipped mussel are powerful nutraceuticals that (i) amplify
      the potency of salicylates and prednisone for treating pre-established chronic
      inflammation (arthritis, fibrosis) and (ii) reduce the steroid's gastrotoxic and
      lymphopenic side effects. Such combinations might also be useful for treating
      inflammatory components of (a) osteoarthritis caused by microcrystalline
      hydroxyapatite (BCP) and (b) pseudo-gout, associated with calcium pyrophosphate
      crystals; that are usually refractory to monotherapy.

PMID- 15035798
TI  - Potential benefits of ibuprofen in the treatment of viral respiratory infections.

PMID- 15035800
TI  - Arthritic syndromes that defy diagnosis.

PMID- 15035802
TI  - Coronary artery disease, inflammation and the ghost of John Hunter.

PMID- 15035803
TI  - Biochemical aspects and functional role of the copper-containing amine oxidases.
AB  - The copper-containing amine oxidases of the class EC 1.4.3.6 share many
      biochemical similarities. They contain cupric copper and catalyse the same
      general reaction. In mammals, diamine oxidase has a role in the metabolism of
      histamine, some other diamines and spermine oxidase, involved in the metabolism
      of polyamines. However, the functional role of benzylamine oxidase (BAO) and the
      tissue semicarbazide-sensitive amine oxidases (SSAO) is still under
      investigation. Circulating BAO is derived from the tissue SSAO. It has a high
      affinity for benzylamine and its role in the extra-cellular matrix includes the
      maturation of pro-elastin and control of the inflammatory process.

PMID- 15035804
TI  - Budesonide ameliorates early portal hypertension in the rat: possible
      antiexudative splanchnic action.
AB  - Major portal pressure increase occurs on the second day post-stenosing-ligation
      of the portal vein in the rat and it is associated with pancreatic edema,
      intraperitoneal free exudate, hypoalbuminemia and hypoproteinemia. All this
      suggests the development of a regional exudative inflammatory response. In order
      to verify this hypothesis the steroid budesonide, whose antiinflammatory activity
      could prevent these alterations, was administered to rats with prehepatic portal
      hypertension. Wistar male rats were divided into the following groups: Control
      rats that were administered saline solution (CS; n = 10), Control rats that were
      administered budesonide (36 mg/kg per day; CB; n = 10), triple stenosing ligation
      of portal vein (TSLP) with saline solution (n = 10) and triple stenosing ligation
      of portal vein with budesonide (36 mg/kg per day; n = 10). In rats with
      prehepatic portal hypertension at 48 h of postoperative evolution, budesonide
      decreases the incidence of pancreatic edema, of peritoneal free exudate, of
      mesenteric adenopathies and prevents hypoproteinemia, hypoalbuminemia and hyper
      beta-globulinemia. Some of the macroscopic intra-abdominal alterations and some
      of the changes in the electrophoretic pattern found in portal hypertensive rats
      could have an inflammatory etiopathogeny because budesonide shows an effective
      prophylaxis.

PMID- 15035805
TI  - Peroxisome proliferator-activated receptor gamma activation counters the
      detrimental effect of Helicobacter pylori lipopolysaccharide on gastric mucin
      synthesis.
AB  - Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the
      subfamily of ligand-dependent nuclear transcription factors, plays a key role in
      the regulation of the expression of genes associated with inflammation. In this
      study, using gastric mucosal cells in culture, we assess the role of PPARgamma in
      the disturbances in gastric mucin synthesis and apoptotic processes evoked by
      Helicobacter pylori lipopolysaccharide (LPS). Exposure of gastric mucosal cells
      to the LPS led to a concentration-dependent decrease (up to 59.5%) in mucin
      synthesis, and this effect of the LPS was accompanied by a 6.5-fold increase in
      apoptosis, induction of COX-2 and NOS-2 protein expression, and the enhancement
      in PGE(2) generation (18.6-fold) and NOS-2 activity (24.1-fold). However, the
      expression of COX-1 protein was not affected. Activation of PPARgamma with a
      specific synthetic agonist, ciglitazone, countered (up to 90.2%) the LPS-induced
      reduction in mucin synthesis in a concentration-dependent manner, and this effect
      of the agent was reflected in a marked decrease in COX-2 and NOS-2 protein
      expression, reduction (up to 72.4%) in apoptosis and a decline (up to 84.1%) in
      PGE(2) generation and NOS-2 activity (up to 90%). A pronounced prevention (88.2%)
      in the LPS-induced PGE(2) release and the diminished COX-2 protein expression was
      also attained with the COX-2-selective inhibitor NS-398, but the effect was not
      associated with the impedance of the LPS inhibitory effect on mucin synthesis.
      Our findings thus demonstrate that the detrimental influence of H. pylori LPS on
      gastric mucin synthesis is closely linked to the increase in proapoptotic
      processes triggered by NOS-2 upregulation, and that PPARgamma activation obviates
      this detrimental effect. Hence, pharmacological manipulation of PPARgamma
      activation may provide therapeutic benefits in countering the disruptive effects
      of H. pylori on gastric mucosal mucus coat continuity.

PMID- 15035806
TI  - Differential role of platelet-activating factor in gastric mucosal ulcer healing.
AB  - Platelet-activating factor (PAF) is a potent phospholipid-derived messenger
      involved in a number of diverse pathological conditions, including mediation of
      inflammatory cascades associated with wound healing. In this study, we
      investigated the effect of a specific PAF antagonist, BN52020, on the course of
      experimentally induced gastric mucosal ulcer healing by analyzing apoptotic
      processes and the mucosal expression of TNF-alpha, COX-2, and the activity of
      inducible nitric oxide synthase (NOS-2). Groups of rats were intragstrically
      pretreated with BN52020 either 24 and 4 h before acetic acid injury
      (prophylactic) or 24 and 44 h after the injury (therapeutic) and their mucosal
      tissue subjected to assessment of ulcer healing rate and biochemical
      measurements. Compared with the controls, the prophylactic administration of
      BN52020 produced dose-dependent acceleration in ulcer healing, accompanied by an
      increase in COX-2 expression and a marked reduction in the extent of mucosal
      apoptosis, TNF-alpha and NOS-2 activity. A delay in ulcer healing, however,
      occurred with BN52020 administered therapeutically, and this effect of the agent
      was reflected in a decreased COX-2 protein expression and a significant increase
      in the rate of epithelial cell apoptosis, TNF-alpha, and the mucosal NOS-2
      activity. Thus, PAF antagonist, BN52020, when administered prophylactically
      exerts anti-inflammatory effects that accelerate gastric ulcer healing, while
      given therapeutically interferes with COX-2 enzyme expression that leads to a
      protracted inflammatory responses that delay ulcer healing.

PMID- 15035807
TI  - Effect of FK506 (tacrolimus) in animal models of inflammation.
AB  - Inflammation is the response of living tissue to damage. Cytokines play an
      important role in inflammatory processes. FK506 (tacrolimus), an
      immunosuppressant, is known to reduce the activation of microglia in vitro and
      affect the expression of various cytokines like interleukin-1, interleukin-6 and
      tumor necrosis factor. With this background the present study was designed to
      explore the effect of FK506 in animal models of acute inflammation and
      experimental pleurisy. Acute inflammation in rats was induced by intraplantar
      injection of carrageenan (1%, w/v). Experimental pleurisy was induced in rats by
      intrapleural injection of carrageenan (2%, w/v). Pretreatment with FK506 (0.5-3
      mg/kg p.o.) significantly and dose-dependently reduced carrageenan-induced
      increase in paw volume, as well as carrageenan-induced inflammatory nociception.
      FK506 (1 and 3 mg/kg p.o.) inhibits exudate formation and migration of
      polymorhonuclear leukocytes and monocytes in carrageenan-induced experimental
      pleurisy. The myeloperoxidase enzyme level was significantly increased in
      carrageenan-treated animals, which was significantly reversed by FK506 treatment.
      The results of the present study suggest the potential anti-inflammatory
      properties of FK506 against carrageenan-induced acute inflammation and
      experimental pleurisy.

PMID- 15035808
TI  - Localization of COX-2 in the male reproductive tract during sexual maturation.
AB  - Prostaglandins (PGs) are shown to influence sperm motility, contractility of the
      smooth muscle layers surrounding the seminiferous tubules and growth of both the
      seminal vesicle and the ventral prostate. PGs are produced by two distinct
      isoforms of cyclooxygenase (COX), including constitutively expressed COX-1 and
      inducible COX-2. To investigate the potential role of COX-2 in male reproductive
      tract maturation, we evaluated its expression in rats at pre-pubertal (14 days
      old), peri-pubertal (21, 28 and 35 days old) and post-pubertal (62 days old)
      stages. COX-2 was constitutively expressed in the initial segment of the
      epididymis, caput epididymidis and vas deferens at all stages of maturation. Its
      expression was mild in 14-day-old rats but its intensity markedly increased at 28
      days and remained elevated afterwards. There was no COX-2 staining in the testis,
      rete testis, efferent ducts or cauda epididymidis. These data suggest that COX-2
      derived PGs may be involved in the pubertal development of the epididymis, but
      not in the more apical regions of the excurrent duct system, including the rete
      testis and efferent ductules.

PMID- 15035809
TI  - Reduced gingival fluid flow: a peripheral marker of the pharmacological effect of
      roquinimex.
AB  - OBJECTIVE: Roquinimex is a drug with effects on inflammation and tumors. The
      pharmacological effect is not fully understood, and the molecular mechanism most
      characterized in vitro is an increase of plasminogen activator inhibitor type 2
      (PAI-2) in human peripheral blood monocytes. The aims were to investigate
      peripheral pharmacological effects of roquinimex on peripheral blood monocytes
      and dog gingival fluid (GCF). DESIGN: Six dogs were used in a cross-over study.
      The amount of GCF was determined with a Periotron. The PAI-2 concentration in GCF
      was determined with ELISA. Monocytes were isolated from peripheral blood.
      RESULTS: Dogs treated with the drug had significantly lower GCF flow values and
      the PAI-2 concentration in GCF was higher, but no effect was seen on peripheral
      monocytes. CONCLUSION: Roquinimex treatment led to a consistently decreased flow
      rate of GCF and a higher local concentration of PAI-2 in GCF.

PMID- 15035810
TI  - Diclofenac increases the accumulation of kynurenate following tryptophan
      pretreatment in the rat: a possible factor contributing to its antihyperalgesic
      effect.
AB  - Kynurenate, a metabolite of tryptophan formed serially from kynurenine, inhibits
      N-methyl-D-aspartate (NMDA) receptor responses. Non-steroidal anti-inflammatory
      drugs (NSAIDs) may produce anti-hyperalgesic effects by altering tryptophan
      metabolism to increase kynurenate concentrations. We examined whether the NSAID
      diclofenac (40 mg/kg, s.c.) or saline (control) increased kynurenine and
      kynurenate accumulation in tissues following pretreatment with tryptophan (200
      mg/kg, i.p., 150 min before tissue harvesting). Significantly larger increases in
      kynurenine and kynurenate concentrations occurred when diclofenac followed
      tryptophan pretreatment (maximal, 60 min: plasma: by 58% and 49%; kidney: by 205%
      and 203%) when compared to control. Brain and spinal cord kynurenine
      concentrations increased maximally (120 min: by 39% and 95%) when diclofenac
      challenge followed tryptophan pretreatment. In brain, diclofenac increased
      kynurenate concentrations (20 min: by 274%). Diclofenac facilitated kynurenine
      and kynurenate accumulation in plasma and kidney, apparently by inhibiting renal
      elimination. This raises the possibility that (some) NSAIDs could act indirectly,
      with central and/or peripheral NMDA receptors contributing to their
      antihyperalgesic effects.

PMID- 15035811
TI  - Evaluation of the anti-inflammatory property of the extract of Combretum
      micranthum G. Don (Combretaceae).
AB  - A methanol extract of Combretum micranthum leaves was studied for anti
      inflammatory activity in rats and mice using the carrageenan-induced rat paw
      oedema and the acetic acid-induced vascular permeability in mice. The effect of
      the extract on cellular-type inflammation was also investigated in the cotton
      pellet granuloma in rats. The extract (50, 100 mg/kg) significantly (P < 0.05)
      inhibited oedema production induced by carrageenan in rats. Increased vascular
      permeability caused by acetic acid injection was also inhibited by the extract,
      within the same dose range. C. micranthum extract (100 mg/kg) inhibited granuloma
      formation in rats to a similar degree as indomethacin (5 mg/kg). These results
      provide evidence for the anti-inflammatory property of C. micranthum leaves.

PMID- 15035812
TI  - Localization of monoamine oxidase A and B and semicarbazide-sensitive amine
      oxidase in human peripheral tissues.
AB  - Monoamine oxidase (MAO) A and B and semicarbazide-sensitive amine oxidase (SSAO)
      localizations in peripheral human tissues were compared by immunohistochemistry.
      The primary antibodies used were mouse monoclonal anti-human MAO-A (6G11/E1) and
      anti-human MAO-B (3F12/G10/2E3) and a rabbit polyclonal anti-bovine SSAO
      antibody. Immunoreactivities of the samples, obtained from 6 routine autopsy
      cases, showed different distributions in the tissues studied (heart, lung,
      duodenum, liver, pancreas, spleen, thyroid gland, adrenal gland and kidney). The
      relative MAO-A, MAO-B and SSAO distributions indicated a widespread distribution
      of these enzymes in the human body that is characterized by a matching cellular
      pattern in only few tissues. These differences suggest that each amine oxidase
      may play a specific function in, at least some, peripheral tissues.

PMID- 15035814
TI  - Interactions of D-amphetamine with the active site of monoamine oxidase-A.
AB  - Reversible monoamine oxidase A inhibitors (RIMA) are used as antidepressants but
      little is known about how they interact with the active site of the enzyme.
      Heterologous expression of human liver MAO-A in yeast provides sufficient protein
      for molecular studies and direct observation of the changes in the spectrum of
      the FAD co-factor when inhibitors bind. Using the reversible inhibitor, D
      amphetamine, as a model compound, a concentration-dependent change in the
      spectrum with clean isosbestic points was observed. The decrease in absorbance
      between 400 and 500 nm gave a dissociation constant for binding similar to the
      K(i) value. Anaerobic reduction yielded the semiquinone spectrum only and the
      midpoint potential was the same as the free enzyme. Full reduction was not
      possible with dithionite as the reductant, suggesting that the semiquinone
      reduced couple had a much lower midpoint potential than the free enzyme. In
      contrast, with substrate, which reduces the enzyme on an equimolar basis, the
      semiquinone is never seen. In anaerobic stopped-flow experiments, amphetamine
      inhibits completely the reoxidation of the reduced enzyme in contrast to a
      substrate such as 2-phenylethylamine (the desmethyl analogue of amphetamine) that
      accelerates the rate 12-fold. The spectral changes in MAO-A permit the
      examination of inhibitor interaction with the redox co-factor. Stacking of the
      inhibitor and flavin rings constitutes part of the interaction but, taking into
      account other evidence, steric factors may be the clue to the differences between
      substrate and inhibitor.

PMID- 15035813
TI  - Characterization of semicarbazide-sensitive amine oxidase in human subcutaneous
      adipocytes and search for novel functions.
AB  - Numerous studies have characterized semicarbazide-sensitive amine oxidase
      activity (SSAO) in rat fat cells but this oxidase is scarcely documented in human
      adipose tissue. Our aim was to further characterize SSAO in human adipose tissue
      (activity, mRNA and protein abundance) and to investigate whether SSAO activity
      can interplay with glucose and lipid metabolism in human adipocytes via the
      hydrogen peroxide it generates. Polyclonal antibodies directed against bovine
      lung SSAO allowed the detection of a substantial amount of immunoreactive protein
      (apparent molecular mass 100 kDa) in human subcutaneous adipocytes from either
      mammary or abdominal fat depots. A 4-kb mRNA was detected in fat depots using a
      cDNA probe designed from the placenta SSAO sequence. Almost all the oxidation of
      benzylamine found in adipose tissue homogenates was due to fat cells and was
      located in the adipocyte membrane fraction. The oxidation of benzylamine and
      methylamine were similar and totally inhibited by semicarbazide or hydralazine
      but resistant to pargyline. Histamine was poorly oxidized. Benzylamine and
      methylamine dose-dependently stimulated glucose transport in intact adipocytes.
      This insulin-like effect of amines did not increase in the presence of 0.1 mM
      vanadate but was inhibited by semicarbazide and antioxidants. Benzylamine and
      methylamine also exhibited antilipolytic effects, with complete inhibition of
      lipolysis at 1 mM. These results show that fat cells from non-obese subjects
      express a membrane-bound SSAO which readily oxidizes exogenous amines, generates
      hydrogen peroxide and exerts short-term insulin-like actions on glucose and lipid
      metabolism.

PMID- 15035815
TI  - Computer visualisation of the active site of monoamine oxidase-A by means of
      selective inhibitors.
AB  - Computer visualisation of the active site of monoamine oxidase (MAO) is based on
      an assumption that the specific and reversible interaction of a ligand (substrate
      or inhibitor) with the substrate-binding region of the active site requires shape
      complementarity. The size of the ligand must allow its accommodation at the
      substrate-binding region. Analysis of the MAO-inhibitory activity of rigid
      analogues of isatin and pirlindole revealed a dependence between three
      dimensional linear sizes of these molecules and the efficacy of inhibition of
      both MAO-A and MAO-B. However, flexible molecules did not exhibit any dependence
      between linear sizes and MAO-B inhibitory potency, possibly because they folded
      into compact structures could fit into the substrate-binding pocket of MAO-B.
      'Moulding' of the substrate/inhibitor binding region by superposition of
      effective MAO-A inhibitors from various groups of chemicals allowed the shape of
      substrate/inhibitor binding region to be visualised. 'Removal of contents' from
      this mould yielded a cavity, which corresponded to the shape of
      substrate/inhibitor binding region. Such cavity can be used to evaluate the most
      probable positions known inhibitors take in binding to it. The docking procedure
      can also be used for searching molecular databases for new inhibitors. Pilot
      experiments revealed that relatively rigid compounds, which did not fit to this
      cavity, were poor inhibitors of MAO-A.

PMID- 15035816
TI  - Nucleotide sequences of putative cDNAs for guinea-pig monoamine oxidase.
AB  - To study the molecular structure of guinea pig monoamine oxidase (MAO) and its
      phylogenetic relationship with other mammalian MAOs, we determined nucleotide
      sequences of putative MAO cDNAs isolated from guinea pig tissues. Both the 5'-
      and 3'-ends of the cDNAs were amplified using the RACE (rapid amplification of
      cDNA ends) method. The sequence (1924 bp) of a putative guinea-pig MAO-B cDNA
      covers a complete coding region that corresponds to 521 amino acids. We also
      analyzed a partial sequence of a putative guinea-pig MAO-A cDNA, which
      corresponds to 506 amino acids, but have left the region of 66 bp at the 3'-end
      undetermined. The nucleotide and deduced amino-acid sequences of the putative
      guinea-pig MAO cDNAs showed the highest homology with that of human MAO cDNAs
      among the known mammalian MAO sequences. These results suggest that guinea-pig
      MAOs are structurally similar to human MAOs. Our molecular phylogenetic data
      support the idea that guinea pigs and rodents diverged before the separation
      between rodents and other lineage leading to Primates and Artiodactyla.

PMID- 15035817
TI  - Some new functions of amine oxidases.
AB  - Two contrasting topics are examined in this account: the protective actions of
      amine oxidases (AOs) resulting from the elimination and/or modulation of the
      levels of polyamines and some biogenic amines, such as histamine, in anaphylactic
      shock and the cell damaging effect of AOs catabolic products. Other functions of
      the plasma copper-containing amine oxidase are considered; namely the
      modification of some proteins by oxidation of their free amino groups, the auto
      regulation of the catalytic activity of AOs, the protective effect against free
      radicals, and the regulation of K(+)-channels.

PMID- 15035818
TI  - Semicarbazide-sensitive amine oxidase (SSAO): present and future.
AB  - Although the existence of plasma and tissue-bound semicarbazide-sensitive amine
      oxidases (SSAOs) has been recognised for a long time, the physiological relevance
      of these enzymes still remains uncertain. The ability of SSAO to metabolise
      various aliphatic and aromatic monoamines differs between species, which limits
      the predictive value of the animal studies for human tissues. SSAO plays a
      protective role because the oxidative deamination of monoamines reduces their
      pharmacological activities. However, the products of deamination may be toxic.
      Several observations indicated that the plasma and tissue SSAO activities differ
      in certain disease states. It is proposed that selective inhibitors, of low
      toxicity, might be protective, through inhibiting the formation of the toxic
      products and the countering the disease-related elevation of SSAO activity. We
      reported earlier that there was a significant correlation between the serum SSAO
      activity and severity of atherosclerosis, as well as the intima-media thickness
      and serum cholesterol levels. Thus SSAO activity might be a clinical marker in
      the prognostic evaluation of diabetic-vascular complications. Although molecular
      biological studies are providing more and more reliable knowledge about the
      enzyme structure, many more studies should be carried out in different disease
      states are necessary to discover the clinical meaning of the enzyme function.

PMID- 15035819
TI  - Anti-apoptotic function of propargylamine inhibitors of type-B monoamine oxidase.
AB  - In Parkinson's disease and other neurodegenerative diseases, (-)deprenyl, an
      inhibitor of type B monoamine oxidase (MAO-B), has been proposed to protect or
      rescue declining neurons. However, clinical trials failed to confirm the
      neuroprotection, even though in vivo and in vitro studies suggested the
      possibilities. This paper describes the activities of propargylamine MAO-B
      inhibitors against apoptosis induced by an endogenous selective dopaminergic
      neurotoxin, N-methyl(R)salsolinol, in dopaminergic SH-SY5Y cells. A series of
      propargylamines were shown to suppress the apoptotic cascade; preventing collapse
      of mitochondrial membrane potential, activation of caspase 3 and fragmentation of
      nucleosomal DNA. Among propargylamines, (R)-N-propargyl-1-aminoindan (rasagiline)
      was the most potent at preventing cell death. Rasagiline also prevented opening
      of permeability transition pore in insolated mitochondria. These results suggest
      that rasagiline and other propargylamines may regulate the apoptotic machinery in
      mitochondria and rescue or protect deteriorated neurons in neurodegenerative
      disorders.

PMID- 15035820
TI  - Inhibition of human MAO-A and MAO-B by a compound isolated from flue-cured
      tobacco leaves and its neuroprotective properties in the MPTP mouse model of
      neurodegeneration.
AB  - Prompted by the findings that smokers have lowered brain and blood platelet
      monoamine oxidase-A and -B activities compared to non-smokers and that smokers
      have a lowered incidence of Parkinson's disease, we have examined the
      neuroprotective properties of an MAO inhibitor, 2,3,6-trimethyl-1,4
      naphthoquinone (TMN), which is present in the tobacco plant and smoke in the MPTP
      C57BL/6 mouse model of neurodegeneration. Dopamine (DA) levels in the striata of
      mice treated with TMN prior to the administration of MPTP were significantly
      higher than DA levels in the striata of mice receiving MPTP only, thus indicating
      a degree of neuroprotection in this model of Parkinson's disease. The potential
      consequences on MAO activity of long term exposure to this compound need to be
      evaluated. Furthermore, there is evidence for the presence of other inhibitors in
      the tobacco leaf and smoke, including compounds with irreversible MAO inhibitory
      properties. Although there is no evidence to link the lowered activities of MAO
      to the lowered incidence of Parkinson's disease in smokers, the neuroprotective
      effects of TMN in the MPTP mouse model suggest that such a relationship is worthy
      of further evaluation.

PMID- 15035821
TI  - The reduction of food intake induced in mice by benzylamine and its derivatives.
AB  - Characterisation of the pharmacological profile of non-physiological amine
      oxidase substrates could help to identify the endogenous role of this class of
      enzymes. Previous studies have suggested that benzylamine, a common non
      physiological substrate for monoamine and tissue-bound or soluble benzylamine
      oxidases, could behave as a potassium channel blocking agent. Potassium channel
      blockers are known to modify several forms of animal behaviour including food
      consumption. To characterise further the pharmacological profile of benzylamine
      and the role of amine oxidases, we have studied the effect of benzylamine on mice
      food intake. Our results confirm that benzylamine produces a reduction in mice
      feeding in a similar manner to that obtained by amphetamine. The anorectic effect
      of benzylamine and amphetamine in mice was potentiated by pretreatment with amine
      oxidase inhibitors. In addition, the introduction of substituents in the aromatic
      ring of benzylamine did not produce compounds with a higher anorectic potency
      than the one measured with benzylamine.

PMID- 15035822
TI  - Grasping the message: regulated mRNA stability in free radical stress responses.
      Rodriguez-Gabriel MA, Burns G, McDonald WH et al. RNA-binding protein Csx1
      mediates global control of gene expression in response to oxidative stress. EMBO
      J 2003; 22: 6256-6266.

PMID- 15035823
TI  - Role of nitric oxide in pathological responses of the lung to exposure to
      environmental/occupational agents.
AB  - Conflicting evidence exists as to whether nitric oxide expresses
      damaging/inflammatory or antioxidant/anti-inflammatory properties. Data presented
      in this review indicate that in vitro or in vivo exposure to selected
      environmental or occupational agents, such as asbestos, silica, ozone or
      lipopolysaccharide, can result in up-regulation of inducible nitric oxide
      synthase by alveolar macrophages and pulmonary epithelial cells. In the case of
      silica exposure, evidence consistently supports a damaging/inflammatory role of
      nitric oxide and/or peroxynitrite in the pathogenesis of lung disease. Although
      conflicting data have been reported, the majority of published studies suggest
      that nitric oxide plays a damaging role in pulmonary injury resulting from
      exposure to ozone or asbestos. In contrast, most information supports an anti
      inflammatory role of nitric oxide following exposure to lipopolysaccharide.
      Further investigation is required to elucidate fully the mechanisms involved in
      determining the role of nitric oxide in the initiation and progression of various
      pulmonary diseases.

PMID- 15035824
TI  - Attenuation of potassium bromate-induced nephrotoxicity by coumarin (1,2
      benzopyrone) in Wistar rats: chemoprevention against free radical-mediated renal
      oxidative stress and tumor promotion response.
AB  - We report the modulatory effect of coumarin (1,2-benzopyrone) on potassium
      bromate (KBrO(3)) mediated nephrotoxicity in Wistar rats. KBrO(3) (125 mg/kg body
      weight, i.p.) enhances gamma-glutamyl transpeptidase, renal lipid peroxidation,
      xanthine oxidase and hydrogen peroxide (H(2)O(2)) generation with reduction in
      renal glutathione content and antioxidant enzymes. It also enhances blood urea
      nitrogen, serum creatinine, ornithine decarboxylase (ODC) activity and [(3)H]
      thymidine incorporation into renal DNA. Treatment of rats orally with coumarin
      (10 mg/kg body weight and 20 mg/kg body weight) resulted in a significant
      decrease in gamma-glutamyl transpeptidase, lipid peroxidation, xanthine oxidase,
      H(2)O(2) generation, blood urea nitrogen, serum creatinine, renal ODC activity
      and DNA synthesis (P < 0.001). Renal glutathione content (P < 0.01) and
      antioxidant enzymes were also recovered to significant level (P < 0.001). These
      results show that coumarin may be used as an effective chemopreventive agent
      against KBrO(3)-mediated renal oxidative stress, toxicity and tumor promotion
      response in Wistar rats.

PMID- 15035825
TI  - Salt-induced antioxidant metabolism defenses in maize (Zea mays L.) seedlings.
AB  - Salinity alters general metabolic processes and enzymatic activities, causing
      increased production of reactive oxygen species (ROS). Expression of antioxidant
      defense genes would, in turn, be triggered to defend the cell against oxidative
      damage. We report that salt disturbed antioxidant metabolism in maize seedlings,
      causing detrimental effects on the growth and development of maize plantlets,
      increased hydrogen peroxide production and altered antioxidant activities and
      transcripts profiles. Excessive ROS levels were accompanied by increased catalase
      (CAT) activity in photosynthesizing shoots, along with induction of mRNA
      accumulation. Increased accumulation of superoxide dismutase (SOD) transcripts
      was also observed although no significant changes in total SOD enzymatic activity
      and isozyme profiles were detected. Higher salt concentrations (above 0.25 M
      NaCl) were highly detrimental to the plants, causing arrested growth and severe
      wilting, among other effects. Histochemical detection of H(2)O(2) by 3,3
      diaminobenzidine (DAB) staining indicated a collapse of the leaf veins, with
      hydrogen peroxide leaking to neighboring cells. In agreement to these
      observations, Sod1, Sod2, Sod4, Sod4A, as well as all Cat transcripts were
      severely inhibited in plants exposed to high salt concentrations.

PMID- 15035826
TI  - Dose-dependent regulation of superoxide anion on the proliferation,
      differentiation, apoptosis and necrosis of human hepatoma cells: the role of
      intracellular Ca 2+.
AB  - Dose-dependent regulation of cellular processes is one important characteristic
      of signaling molecules. Although recent studies suggest that reactive oxygen
      species (ROS) may act as in vivo signaling molecules, the dose-dependent
      regulation of ROS on cellular processes together in one system needs to be
      evaluated. After treating cells with gradually increased O(2)(-), generated by
      the hypoxanthine-xanthine oxidase system, it was found that: (i) the
      proliferation of hepatoma cells firstly increased at 1-2 microM O(2)(-), then
      decreased markedly as the concentration increased; (2) at 8 or 16 microM O(2)(-),
      re-differentiation of hepatoma cells was induced, as indicated by the indices
      relating to cell malignancy or differentiation, such as cell surface charge,
      alpha-fetoprotein, gamma-glutamyltranspeptidase, tyrosine-alpha-ketoglutarate
      transaminase, cAMP, and the tumor's clonogenic potential; (iii) at 16 microM
      O(2)(-), accompanied by the re-differentiation of cells, cell apoptosis was also
      simultaneously induced as indicated by the appearance of apoptotic bodies,
      detached cells, and other apoptotic morphological features, as well as specific
      DNA fragmentation; (iv) at the highest concentration of O(2)(-) (32 microM) in
      this study, cell necrosis was dramatically induced as shown by Trypan blue
      exclusion; (v), an increase of intracellular Ca(2+) ([Ca(2+)](i)) was observed at
      all concentrations of O(2)(-) treatment, and this [Ca(2+)](i) increase was found
      to be involved in the regulation of O(2)(-) on the cellular processes. In
      conclusion, these results indicate that O(2)(-) could dose-dependently regulate
      the processes of cells, where Ca(2+) is one of its molecular targets, and hence
      provide a direct support for the hypothesis that ROS themselves are important
      signaling molecules.

PMID- 15035827
TI  - Mobilization of intracellular calcium by peroxynitrite in arteriolar smooth
      muscle cells from rats.
AB  - The present study was designed to investigate the possible effects of
      peroxynitrite (ONOO(-)) on the intracellular calcium concentration ([Ca(2+)](i))
      of mesenteric arteriolar smooth muscle cells (ASMCs), and to reveal the
      underlying mechanisms by using fluorescence imaging analysis. The results showed
      that ONOO(-) could exert a concentration- and time-dependent but also a dual
      effect on [Ca(2+)](i). Bolus administration with a low concentration of ONOO(-)
      (25 microM) decreased [Ca(2+)](i), whereas higher concentrations (50 or 100
      microM) increased [Ca(2+)](i) persistently. Further experiments demonstrated that
      pretreatment of ASMCs with calcium-free medium completely abolished [Ca(2+)](i)
      increase by 100 microM ONOO(-). Additionally, nifedipine, an antagonist of
      selective L-type voltage-gated calcium channels (VGCCs), delayed the [Ca(2+)](i)
      response to ONOO(-), and ryanodine, an inhibitor of intracellular calcium release
      from the sarcoplasmic reticulum, effectively antagonized [Ca(2+)](i) increase
      during the late stage of ONOO(-) exposure. Furthermore, [Ca(2+)](i) alteration by
      ONOO(-) appeared to be intimately associated with the subsequent membrane
      potential changes. Although the mechanisms by which ONOO(-) alters [Ca(2+)](i)
      are complex, we conclude that a series of variables such as external calcium
      influx, activation of VGCCs, intracellular calcium release, and membrane
      potential changes are involved. The decrease of [Ca(2+)](i) in ASMCs by a low
      concentration of ONOO(-) may participate in the pathogenesis of low
      vasoreactivity in shock, and the increase of [Ca(2+)](i) by high concentrations
      of ONOO(-) may lead to calcium overload with cellular injury.

PMID- 15035829
TI  - 5th Annual Disease Management Leadership Forum: DMAA State of the Union address.

PMID- 15035828
TI  - Dihydrolipoic acid lowers the redox activity of transition metal ions but does
      not remove them from the active site of enzymes.
AB  - Alpha-lipoic acid (LA) and its reduced form, dihydrolipoic acid (DHLA), have been
      suggested to chelate transition metal ions and, hence, mitigate iron- and copper
      mediated oxidative stress in biological systems. However, it remains unclear
      whether LA and DHLA chelate transition metal ions in a redox-inactive form, and
      whether they remove metal ions from the active site of enzymes. Therefore, we
      investigated the effects of LA and DHLA on iron- or copper-catalyzed oxidation of
      ascorbate, a sensitive assay for the redox activity of these metal ions. We found
      that DHLA, but not LA, significantly inhibited ascorbate oxidation mediated by
      Fe(III)-citrate, suggesting that reduced thiols are required for iron binding.
      DHLA also strongly inhibited Cu(II)(histidine)(2)-mediated ascorbate oxidation in
      a concentration-dependent manner, with complete inhibition at a DHLA:Cu(II) molar
      ratio of 3:1. In contrast, no inhibition of copper-catalyzed ascorbate oxidation
      was observed with LA. To investigate whether LA and DHLA remove copper or iron
      from the active site of enzymes, Cu,Zn superoxide dismutase and the iron
      containing enzyme aconitase were used. We found that neither LA nor DHLA, even at
      high, millimolar concentrations, altered the activity of these enzymes. Our
      results suggest that DHLA chelates and inactivates redox-active transition metal
      ions in small-molecular, biological complexes without affecting iron- or copper
      dependent enzyme activities.

PMID- 15035830
TI  - Estimating the return on investment in disease management programs using a pre
      post analysis.
AB  - Disease management programs have become increasingly popular over the past 5-10
      years. Recent increases in overall medical costs have precipitated new concerns
      about the cost-effectiveness of medical management programs that have extended to
      the program directors for these programs. Initial success of the disease
      management movement is being challenged on the grounds that reported results have
      been the result of the application of faulty, if intuitive, methodologies. This
      paper discusses the use of "pre-post" methodology approaches in the analysis of
      disease management programs, and areas where application of this approach can
      result in spurious results and incorrect financial outcome assessments. The paper
      includes a checklist of these items for use by operational staff working with the
      programs, and a comprehensive bibliography that addresses many of the issues
      discussed.

PMID- 15035831
TI  - Racial comparisons of health care and glycemic control for African American and
      white diabetic adults in an urban managed care organization.
AB  - The excess risk of diabetic complications in African Americans may be due to poor
      glycemic control arising from suboptimal use and/or quality of diabetes-related
      health care. However, little is known about racial differences in these factors,
      particularly in urban populations. We conducted a cross-sectional study using
      medical claims and encounter data on 1,106 adults with diabetes aged > or =30
      years who were members of an urban managed care organization in capitated health
      plans. We examined health care and routine hemoglobin A(1c) (HbA(1c)) testing in
      a biracial cohort for 12 months. We then followed individuals for an additional
      12 months, using a retrospective cohort design, to determine how this health care
      predicted subsequent emergency room visits. On average, compared with their white
      counterparts, African Americans had fewer primary care visits (85% vs. 91% with
      four or more visits) and fewer HbA(1c) tests (56% vs. 68% with two or more
      HbA(1c) tests) (all P < 0.05). Likewise, in the subset who underwent one or more
      HbA(1c) measurement (n = 855), African Americans displayed poorer glycemic
      control (HbA(1c) 9.1 +/- 2.9%) than whites (8.5 +/- 2.2%; P = 0.001). In
      multivariate analyses, racial differences in visit frequency and HbA(1c) testing
      were attenuated by adjustment for age, sex, and type of capitated plan and did
      not remain statistically significant. The relationship of health care to
      subsequent emergency room visits differed by race; in African Americans, fewer
      primary care visits and HbA(1c) tests predicted greater risk of emergency room
      visits. Even in a capitated, managed care setting, urban African Americans with
      diabetes are less likely than their white counterparts to undergo routine primary
      care visits and laboratory testing and are more likely to have suboptimal
      glycemic control. Differences in age, sex, and insurance type seemed to explain
      some of the disparities. Future research should determine the individual
      contributions of physician, patient, and system factors to the racial disparities
      in health care.

PMID- 15035832
TI  - Savings opportunities through Medicaid disease management.
AB  - In their attempts to control spending in Medicaid, a few states have looked
      beyond the obvious reductions in reimbursement, tightened eligibility
      requirements, and institution of copays to disease management outsourcing. While
      the traditional panoply of cutbacks will save money the year they are instituted,
      they tend to have trade-offs. Reducing reimbursement, for example, may encourage
      providers to leave the program. As a result, several states are implementing
      outsourced medical management programs, which together at maturity will, as shown
      below, noticeably reduce Medicaid spending by improving the way health care is
      delivered. These purely voluntary, quality-enhancing outsourced medical
      management programs are also fully guaranteed by a wide variety of vendors to
      save money starting in the first year they are implemented.

PMID- 15035833
TI  - Diabetes disease management in managed care organizations.
AB  - Recent clinical trials and disease management programs sponsored by managed care
      organizations have demonstrated achievements in limiting complications, improving
      health measures, reducing costs, and enhancing the quality of life of the person
      with diabetes. In one managed care organization, Group Health, Inc., persons with
      diabetes received discounted supplies and educational material as encouragement
      to participate in a diabetes disease management program [Disease Management
      Solutions (DMS)]. Health risk appraisals (HRAs) were provided at enrollment, and
      at 6-month intervals thereafter. Over 8,000 persons with diabetes participated in
      the DMS program over a 2 and 1/2-year period. Claims data over a 3-year period
      (pre- and post-enrollment) for 1,368 persons with diabetes demonstrated that
      participation in DMS resulted in greater utilization of primary care services by
      enrolled persons than by non-enrolled, but a lower increase in costs for those
      enrolled. In addition to evaluating the program impact through changes in
      services and costs, HRAs provided self-reported scores on (1) several compliance
      measures and (2) general health impressions and productivity. In the DMS
      population, self-reported compliance with physician-recommended office visits and
      tests (eg, cholesterol screening) improved for persons with diabetes once they
      enrolled in the program. Participants also reported greater productivity (eg,
      fewer missed work days) once enrolled in the program. To validate self-reported
      results, medical claims were used to verify compliance with general office,
      ophthalmologic, and emergency room visits and hospital admissions. A high level
      of validity between self-reported results and claims data recording office and
      emergency room visits and hospital admissions was found.

PMID- 15035834
TI  - Impact of appropriate pharmaceutical therapy for chronic conditions on direct
      medical costs and workplace productivity: a review of the literature.
AB  - This paper presents the findings of a literature review investigating the
      economic impact of appropriate pharmaceutical therapy in treating four prevalent
      chronic conditions - asthma, diabetes, heart failure, and migraine. The goal of
      the review was to identify high-quality studies examining the extent to which
      appropriate pharmaceutical therapy impacts overall medical expenditure (direct
      costs) and workplace productivity (indirect costs). The working hypothesis in
      conducting the review was that the costs of pharmaceuticals for the selected
      chronic conditions are offset by savings in direct and indirect costs in other
      areas. The literature provides evidence that appropriate drug therapy improves
      the health status and quality of life of individuals with chronic illnesses while
      reducing costs associated with utilization of emergency room, inpatient, and
      other medical services. A growing body of evidence also suggests that workers
      whose chronic conditions are effectively controlled with medications are more
      productive. For employers, the evidence translates into potential direct and
      indirect cost savings. The findings also confirm the importance of pharmaceutical
      management as a cornerstone of disease management.

PMID- 15035835
TI  - Do clinical grant payment practices in phase 3 clinical trials influence
      subsequent clinical investigator prescribing behavior?
AB  - The advancement of science requires the cooperation of clinical investigators.
      Recent discourse, which attempts to relate pharmaceutical company grant payments
      to clinical investigators to subsequent preferential prescribing behavior, erodes
      the physician/patient relationship and may lead to an inadequate number of
      investigators. This study was designed to determine why the level of grant
      payments to Phase 3 clinical investigators differs for comparable levels of work
      and whether these differences are related to subsequent prescribing behavior of
      either the study drug or other drugs from the same sponsoring company. From a
      database of 100,000 investigator contracts, 2,108 U.S. physicians participating
      in Phase 3 trials at 2,897 clinical sites for new drugs launched in 1999-2000
      were randomly selected in 10 outpatient indications. The relative grant amounts
      (RGAs) paid to the investigators were compared with their subsequent prescribing
      of the study drug and other sponsor company drugs for a period of six months
      after study drug introduction. The RGA is the payment percentile represented by
      the absolute cost per patient grant paid to any specific investigator compared
      with other similar studies, including such considerations as the number of
      patient visits, the number and types of medical procedures performed, the
      investigator's geographic location, and whether the study was conducted at the
      investigator's office or hospital. Linear regression correlations were calculated
      between study, investigator, and drug characteristics with the RGA, and the
      correlation between the RGA and subsequent prescribing behavior of the study drug
      and other drugs from the sponsor company at three and six months after study drug
      product launch. Five variables were statistically significantly related to the
      RGA received by an investigator: compound therapeutic novelty, the number of
      similar studies being conducted at same time, investigator clinical research
      experience, and the inverse of drug class prescription volume. Most
      significantly, investigators' post-study prescribing behavior was not related to
      RGA. Drug development and market forces explain the RGA, but RGA is not related
      to subsequent sponsor or study drug prescribing.

PMID- 15035836
TI  - Laparoscopic appendectomy in Italy: an appraisal of 26,863 cases.
AB  - OBJECTIVE: To evaluate the practice of laparoscopic appendectomy (LA) in Italy.
      METHODS: On behalf of the Italian Society of Young Surgeons (SPIGC), an audit of
      LA was carried out through a written questionnaire sent to 800 institutions in
      Italy. The questions concerned the diffusion of laparoscopic surgery and LA over
      the period 1990 through 2001, surgery-related morbidity and mortality rates,
      indications for LA, the diagnostic algorithm adopted prior to surgery, and use of
      LA among young surgeons (<40 years). RESULTS: A total of 182 institutions (22.7%)
      participated in the current audit, and accounted for a total number of 26863 LA.
      Laparoscopic surgery is performed in 173 (95%) institutions, with 144 (83.2%)
      routinely performing LA. The mean interval from introduction of laparoscopic
      surgery to inception of LA was 3.4 +/- 2.5 years. There was an emergent basis for
      8809 (32.8%) LA procedures (<6 hours of admission); 10314 (38.4%) procedures were
      performed on an urgent basis (<24 hours of admission); while 7740 (28.8%)
      procedures were elective. The conversion rate was 2.1% (561 cases) and was due to
      intraoperative complications in 197 cases (35.1%). Intraoperative complications
      ranged as high as 0.32%, while postoperative complications were reported in 1.2%
      of successfully completed LA. The mean hospital stay for successfully completed
      LA was 2.5 +/- 1.05 days. The highest rate of intraoperative complications was
      reported as occurring during the learning curve phase of their experience (in
      their first 10 procedures) by 39.7% of the surgeons. LA was indicated for every
      case of suspected acute appendiceal disease by 51.8% of surgeons, and 44.8% order
      abdominal ultrasound (US) prior to surgery. A gynecologic counseling is deemed
      necessary only by 34.5% surgeons, while an abdominal CT scan is required only by
      1.5%. The procedure is completed laparoscopically in the absence of gross
      appendiceal inflammation by 83%; 79.8% try to complete the procedure
      laparoscopically in the presence of concomitant disease; while 10.4% convert to
      open surgery in cases of suspected malignancy. Of responding surgeons aged under
      40, 76.3% can perform LA, compared to 47.3% surgeons of all age categories.
      CONCLUSIONS: The low response rate of the present survey does not allow us to
      assess the diffusion of LA in Italy, but rather to appraise its practice in
      centers routinely performing laparoscopic surgery. In the hands of experienced
      surgeons, LA has morbidity rates comparable to those of international series. The
      higher diagnostic yield of laparoscopy makes it an invaluable tool in the
      management algorithm of women of childbearing age; its advantages in the presence
      of severe peritonitis are less clear-cut. Surgeons remain the main limiting
      factor preventing a wider diffusion of LA in our country, since only 47.3% of
      surgeons from the audited institutions can perform LA on a routine basis.

PMID- 15035837
TI  - Efficacy and cost-effectiveness of the UltraCision harmonic scalpel in thyroid
      surgery: an analysis of 200 cases in a randomized trial.
AB  - BACKGROUND: Thyroid surgery technique has undergone very few changes in the last
      century. The UltraCision harmonic scalpel (UHS) (Smithfield, RI) has been widely
      used in laparoscopic surgery and is documented to be safe and fast for cutting
      and coagulating tissue. We studied whether the use of the UHS could have
      advantages in thyroid surgery in terms of operative time, length of
      hospitalization, morbidity, and general costs. METHOD: Our study was a
      prospective randomized trial of thyroidectomies and lobectomies performed for
      benign thyroid diseases in an endocrine surgery unit between February 2001 and
      July 2002. Patients were randomized in two groups: group A (n=100) underwent
      thyroidectomy using UHS and group B (n=100) with the conventional clamp-and-tie
      technique. Main outcome measures were demographics, operating time, length of
      hospitalization, intra- and postoperative complications, sequelae, and general
      costs. We used the unpaired 2-tailed Student's t test and the chi2 test to
      compare the series. RESULTS: The two groups were similar in age and sex. Mean +/-
      SD operative time was shorter in the UHS group compared with the conventional
      technique group for both lobectomy (61 +/- 06 vs. 78 +/- 10 minutes) and total
      thyroidectomy (86 +/- 20 vs. 101 +/- 16 minutes). Length of hospitalization was
      similar in both groups (1.07 vs. 1.15 days). We did not find statistical
      differences between the two techniques regarding transient postoperative
      complications. There were no deaths, no blood transfusions, no intraoperative
      complications, and no postoperative definitive sequelae. The global charges for
      every patient were significantly less in the UHS group (985.77 +/- 107.08 euro
      vs. 1148.40 +/- 153.25 euro). CONCLUSION: The use of ultrasonically activated
      shears resulted in a reduction of 15-20% in operative time and was cost-effective
      compared to the conventional technique group.

PMID- 15035838
TI  - Esophagectomy via laparoscopy and transmediastinal endodissection.
AB  - An original technique for minimally invasive transmediastinal esophagectomy is
      described. A combined laparoscopic and video-mediastinoscopic approach was
      attempted in a series of patients with high-grade dysplasia or carcinoma of the
      esophagus. Laparoscopy allowed mobilization of the stomach and dissection of the
      distal esophagus at least up to the level of the inferior pulmonary veins.
      Through a left cervicotomy, endodissection of the upper thoracic esophagus was
      accomplished with an operating video-mediastinoscope. After complete upward and
      downward mobilization from the mediastinal bed, the specimen was retrieved
      through the cervical incision and the stomach was guided laparoscopically into
      the posterior mediastinum. Compared to the laparoscopic total esophagectomy, this
      approach provides a more controlled and safer dissection of the upper
      mediastinum.

PMID- 15035839
TI  - Laparoscopic repair of vesicovaginal fistula.
AB  - PURPOSE: To describe a methodology for laparoscopic repair of vesicovaginal
      fistula (VVF), and to provide a comparison of results between a series of
      laparoscopic repairs, a series of transabdominal open repairs (TAORs), a series
      of transvaginal repairs (TVRs), and cases successfully managed without surgery.
      PATIENTS AND METHODS: A total of 16 patients were diagnosed with post
      hysterectomy VVF. All patients were first managed conservatively with continuous
      drainage via a Foley catheter until dry. In 2 of the 16 cases (12.5%) the
      fistulae healed spontaneously with conservative management. After 4-12 weeks, the
      remaining 14 patients underwent surgical repair of their fistulas; 2 (14%) by
      laparoscopy, 6 (43%) by TAOR, and 6 (43%) by TVR. RESULTS: Fistula repair was
      successful in both laparoscopy cases, all 6 TAOR cases, and 5 of 6 TVR cases
      (86%). The failed transvaginal repair was repeated, with a successful outcome.
      Length of hospital stay was 7-10 days (mean, 8.3 days) for the open cases, 3-5
      days (mean, 4.1 days) for the transvaginal cases, and 2-12 days for the
      laparoscopic cases. One patient who underwent laparoscopic repair had a 12-day
      hospital stay due to extended vaginal drainage lasting 3 weeks, which then
      resolved. Three of the 6 patients who underwent TAOR (50%) experienced
      postoperative complications, including 2 cases of ileus and 1 case of fever. One
      of 6 patients who underwent TVR (16%) experienced recurrent urinary tract
      infection. CONCLUSIONS: These data suggest that laparoscopic VVF repair is
      feasible and may result in lower morbidity, shorter hospital stay, and quicker
      recovery than the abdominal or transvaginal approaches. Additional controlled
      studies are warranted. The minimally invasive approach of laparoscopy may be a
      more attractive option for patients who experience VVF following hysterectomy.

PMID- 15035840
TI  - Laparoscopic adrenalectomy: a cost analysis of three approaches.
AB  - Laparoscopic adrenalectomy (LA) is the current standard for treatment of benign
      adrenal disease and is performed more often now in the setting of malignant
      disease. Three surgical approaches, the lateral transperitoneal technique, the
      lateral retroperitoneal technique, and the posterior technique are utilized
      commonly. While advantages of each approach are advocated, a cost analysis is not
      available. This article analyzes the operating costs of the three approaches. The
      operative costs of 51 unilateral LA at the Cleveland Clinic Foundation from 1998
      to 2002 were analyzed for comparison. Patients were grouped according to one of
      the three laparoscopic approaches--transperitoneal (group A), lateral
      retroperitoneal (group B), and posterior (group C). For each group, n=17.
      Perioperative characteristics and operative cost were analyzed. The groups were
      compared using single factor ANOVA analysis. Significance was assigned for
      P<0.05. The average costs of unilateral LA were $2,885, $3,219, and $2,850 for
      groups A, B, and C, respectively (P=0.20). Differences were not statistically
      significant. Six bilateral procedures were performed. There were no significant
      differences for these six cases. However, the cohort was too small for an
      appropriate power analysis. LA is commonly performed utilizing one of three
      surgical approaches. Our data demonstrates no significant difference in operative
      cost between the respective techniques. Operative costs should not be a factor in
      choosing a laparoscopic approach for unilateral adrenal disease.

PMID- 15035841
TI  - A modified transcystic biliary decompression after laparoscopic choledochotomy.
AB  - BACKGROUND: Transcystic biliary decompression (TCBD) has been proposed as an
      alternative to T-tube placement after laparoscopic choledochotomy (LCD). This
      permits safe primary closure of the choledochotomy and eliminates the
      complication associated with T-tubes. The TCBD tube is usually secured by Roeder
      knots and transfixation, and removed 2 to 4 weeks after surgery. This appears to
      reduce the benefits of the minimal access approach. We present a new, secure TCBD
      method after LCD using the ureteral catheter and the Lapro-Clip (David and Geck,
      Danbury, Connecticut). PATIENTS AND METHODS: As of October 2002, in 19 patients
      after LCD, a 5 Fr ureteral catheter were inserted into the common bile duct (CBD)
      via the cystic duct. When in place, the catheter was secured to the cystic duct
      by an absorbable 12 mm Lapro-Clip and the choledochotomy was then primarily
      closed. RESULTS: The average postoperative output of bile via the ureteral
      catheter was 256 mL/day (range, 20-600 mL/day). The median postoperative hospital
      stay was 5 days (range, 3-7 days). The ureteral catheter was removed within 3 to
      7 days after surgery. None of the patients developed early complications such as
      bile leak, slippage of the Lapro-Clip, occlusion, or dislodgment of the ureteral
      catheter. CONCLUSIONS: A modified TCBD after LCD is safe, effective, and easy to
      employ. With this technique, the patients can be discharged within a week without
      any drainage tube. We propose this method as an option for patients with CBD
      stones.

PMID- 15035842
TI  - Intraoperative findings and postoperative complications in laparoscopic
      cholecystectomy: the Greek experience with 5,539 patients in a single center.
AB  - BACKGROUND: This is a retrospective study presenting the experience of a teaching
      oriented laparoendoscopic unit with laparoscopic cholecystectomy (LC) in order to
      add data to the international literature concerning issues such as epidemiology,
      intraoperative findings, conversion and complication rates. PATIENTS AND METHODS:
      In this study 5539 consecutive patients who underwent LC between 1990 and 2000
      were included. Elective (n=4903) or emergent (n=636) LC was performed in all but
      99 patients (who were converted to the open procedure). Conversion rate,
      complication rate, mortality, and length of stay were the main outcome parameters
      in this study. RESULTS: There was no intraoperative or in-hospital mortality in
      our series. The conversion rate was 1.8%. The complication rate was 2.92% (162
      patients). The vast majority of our patients (92%) were discharged from the
      hospital on the first postoperative day. CONCLUSIONS: LC is a safe technique when
      up-to-date equipment and meticulous dissection techniques are employed. A
      specialized laparoscopic unit is important in a general surgery department, to
      have an experienced laparoscopic surgeon in all cases. In our opinion this is the
      only way to minimize common bile duct injuries and the rates of other major
      complications.

PMID- 15035843
TI  - Laparoscopic unroofing of nonparasitic liver cysts within segments VII and VIII:
      technical considerations.
AB  - BACKGROUND: The laparoscopic accessibility of congenital liver cysts located in
      the anterosuperior (VIII) and posterosuperior (VII) segments has been questioned
      for some time. In support of the laparoscopic approach, we here describe our
      minimally invasive technique in two patients with solitary congenital cysts
      located in the apex of liver segments VIII and VII, respectively. METHOD: Both
      patients were placed in the inverted Y position. Four trocars were used, their
      position depending on the location of the cyst. RESULTS: The segment VIII cyst
      was easily reached via this anterior approach, while the segment VII cyst
      required significant mobilization of the right liver lobe. In both cases a
      complete excision of the cystic roof was achieved using the harmonic scalpel.
      Without performing an omentoplasty no recurrences were observed after 20 and 28
      months, respectively. CONCLUSION: Solitary cysts located in segments VII and VIII
      of the liver can be safely treated by laparoscopic unroofing. Cyst recurrences
      may best be prevented by a complete excision of the cystic roof with an adjacent
      rim of hepatic parenchyma.

PMID- 15035844
TI  - Laparoscopic palliative gastrojejunostomy for advanced recurrent gastric cancer
      after Billroth I resection.
AB  - Palliative surgery for advanced gastric cancer has equivocal results. Laparoscopy
      is likely to provide some advantage compared to open procedures. We present a
      case of laparoscopic gastrojejunostomy for advanced gastric cancer, which
      recurred after Billroth I resection. Reproducing the results of the early
      experiences so far reported in the literature, laparoscopy provided us with the
      accurate staging of the disease along with the opportunity, at the same time, to
      perform a palliative procedure, avoiding laparotomy. Operative results were good,
      vomiting was relieved, and the patient was able to cope with his disease until
      death eventually occurred after 6 months.

PMID- 15035845
TI  - Intraoperative catheter management during laparoscopic excision of a giant
      bladder diverticulum.
AB  - BACKGROUND: Massive bladder diverticula present a technical challenge to the
      laparoscopic surgeon. We describe a laparoscopic approach to transperitoneal
      diverticulectomy, using a specific catheter arrangement to allow excellent
      control of the various portions of the procedure. METHODS: A 49-year-old male
      with longstanding frequency was diagnosed with a 1000 cc bladder diverticulum and
      bladder neck outlet obstruction. Laparoscopic transperitoneal diverticulectomy
      was performed using a triple catheter arrangement: endoscopic placement of a
      Councill catheter in the diverticulum, fluoroscopic positioning of an occlusion
      balloon catheter in the renal pelvis, and placement of a Cope loop suprapubic
      tube. Additionally, a transurethral incision of the prostate was performed.
      RESULTS: The procedure was completed laparoscopically using a four port
      transperitoneal approach. During the procedure, the diverticulum could be filled
      and emptied as needed; the catheter across the diverticular neck facilitated
      subsequent closure of the bladder wall defect. The diverticulum was completely
      excised. The remaining defect in the bladder was then closed in 2 layers. The
      patient was discharged on postoperative day 3. CONCLUSION: Careful planning and
      arrangement of catheters in the bladder, ureter, and diverticulum facilitates
      laparoscopic transperitoneal diverticulectomy of even a very large volume
      diverticulum.

PMID- 15035846
TI  - Therapeutic minilaparoscopy for perforated peptic ulcer.
AB  - Laparoscopic repair for perforated peptic ulcer has been demonstrated to be safe
      and effective. We report our initial experience of applying therapeutic
      minilaparoscopy for peptic ulcer perforation. Five patients with perforated
      peptic ulcers managed by a team of surgeons using minilaparoscopy are reported.
      There were no conversions, perioperative morbidity, or mortality. Patients
      experienced minimal wound pain and required minimal parental analgesia. The
      access wound scars were hardly discernable at 3-month followup. Therapeutic
      minilaparoscopy is technically feasible for patients with perforated peptic ulcer
      and is associated with satisfactory clinical and cosmetic outcome.

PMID- 15035847
TI  - Sliding lipoma: an indirect inguinal hernia without a peritoneal sac.
AB  - With the increasing application of endoscopic hernioplasty, surgeons have now
      recognized that the peritoneal sac is sometimes absent in patients who present
      with a reducible inguinal hernia. Sliding lipoma refers to a sliding herniation
      of preperitoneal fat into the inguinal canal forming a reducible indirect
      inguinal hernia in the absence of a peritoneal sac. In this report, we describe a
      patient who underwent bilateral endoscopic totally extraperitoneal inguinal
      hernioplasty (TEP), followed by an early recurrence of left inguinal hernia,
      secondary to a sliding lipoma. Sliding lipoma is a challenging condition specific
      to endoscopic repair of inguinal hernia. All lipomas should be reduced and
      excised whenever feasible. Awareness and appropriate management of the sliding
      lipoma will help to reduce the risk of recurrence after endoscopic hernioplasty.

PMID- 15035849
TI  - Inhibition by interleukin-18 of the growth of Dunn osteosarcoma cells.
AB  - To examine the usefulness of interleukin-18 (IL-18) in the treatment of
      osteosarcomas, the effect of IL-18 on the growth of Dunn osteosarcoma cells was
      investigated. Daily intraperitoneal (i.p.) injection of mouse recombinant IL-18
      (2 microg/mouse) suppressed the growth of Dunn osteosarcoma cells transplanted
      subcutaneously (s.c.) into syngeneic C3H mice. This IL-18-induced suppression was
      not affected by simultaneous treatment with anti-asialo GM1 serum, which
      inactivates natural killer (NK) cells. However, IL-18 failed to suppress the
      growth of Dunn osteosarcoma cells transplanted into BALB/c-nude mice devoid of T
      lymphocytes or C3H-gld/gld mice deficient in functional Fas ligand (FasL). IL-18
      also failed to suppress the growth of Dunn osteosarcoma cells in vitro, although
      expression of IL-18 receptor mRNA and MyD88 mRNA as well as Fas mRNA was detected
      by reverse transcriptase-polymerase chain reaction (RT-PCR). On the other hand,
      antimouse Fas antibody showed cytotoxicity against Dunn osteosarcoma cells in a
      dose-dependent manner in vitro. In addition, treatment of C3H mice with IL-18
      enhanced the cytotoxic activity of CD8(+) T lymphocytes against Dunn osteosarcoma
      cells. These results indicate that IL-18 inhibits the growth of Dunn osteosarcoma
      cells in vivo by enhancing the cytotoxic activity of CD8(+) T lymphocytes through
      the FasL-Fas system.

PMID- 15035850
TI  - Loss of interferon-induced Stat1 phosphorylation in activated T cells.
AB  - Modulation of cytokine responsiveness following T cell activation represents an
      important mechanism that shapes the fate of T cells after encounters with
      antigens. We activated T cells in mice with superantigen and assessed their
      ability to phosphorylate Stat1 in response to interferon-gamma (IFN-gamma) and
      IFN-alpha. After 4 h of activation in vivo, T cells became deficient in their
      ability to phosphorylate Stat1 in response to either cytokine. The loss of IFN
      sensitivity was accompanied by increased mRNA transcription for multiple
      suppressors of cytokine signaling (SOCS) genes (SOCS1, SOCS3, and SOCS7). The
      transcript levels of these SOCS were elevated only during the early hours after
      activation and were at or below normal levels by 60 h. Likewise, the activation
      induced inhibition of IFN-alpha signaling was transient, and sensitivity was
      restored by 3 days postactivation. The loss of sensitivity to IFN-gamma
      persisted, however, and was still evident at 3 days. These data suggest that SOCS
      independent mechanisms specific for inhibition of IFN-gamma signaling may be
      present at later stages of the T cell response. The loss of Stat1 signaling may
      be a factor in differentiation of T cells during and after activation, and it
      could also represent a protective mechanism against the toxic effects of IFN
      gamma during immune responses.

PMID- 15035851
TI  - Synthesis of IFN-beta by virus-infected chicken embryo cells demonstrated with
      specific antisera and a new bioassay.
AB  - Transcripts of interferon-alpha (IFN-alpha) and IFN-beta genes are present in
      virus-infected chicken cells, but because of a lack of appropriate assays and
      reagents, it was unclear if biologically active IFN-beta is secreted. We have
      established a nonviral bioassay for the sensitive detection of chicken IFN
      (ChIFN). This assay is based on a quail cell line that carries a luciferase gene
      that is controlled by the IFN-responsive chicken Mx promoter. Luciferase activity
      was strongly stimulated when the indicator cells were incubated with ChIFN-alpha,
      ChIFN-beta, or ChIFN-gamma but not with chicken interleukin-1beta (ChIL-1beta).
      Unlike the classic antiviral assay that preferentially detects ChIFN-alpha, the
      Mx-luciferase assay detected ChIFN-alpha and ChIFN-beta with similar sensitivity.
      With the help of this novel assay and with rabbit antisera specific for either
      IFN-alpha or IFN-beta, we analyzed the composition of IFN in supernatants of
      virus-infected chicken embryo cells. Virtually all IFN produced in response to
      Newcastle disease virus (NDV) was IFN-alpha. However, IFN produced in response to
      influenza A or vaccinia virus (VV) was a mixture of usually more than 80% IFN
      alpha and up to 20% IFN-beta. Thus, IFN-alpha and IFN-beta both contribute to the
      cytokine activity in supernatants of virus-infected chicken cells. Furthermore,
      the infecting virus appears to determine the IFN subtype composition.

PMID- 15035852
TI  - Transcriptional response of T cells to IFN-alpha: changes induced in IFN-alpha
      sensitive and resistant cutaneous T cell lymphoma.
AB  - Interferon-alpha (IFN-alpha) therapy is commonly used in the treatment of
      neoplastic and autoimmune diseases, including cutaneous T cell lymphoma (CTCL).
      However, the IFN-alpha response is unpredictable, and the IFN-alpha cell targets
      and pathways are only partially understood. To delineate the molecular mechanisms
      of IFN-alpha activity, gene expression profiling was performed in a time-course
      experiment of both IFN-alpha sensitive and IFN-alpha-resistant variants of a CTCL
      cell line. These experiments revealed that IFN-alpha is responsible for the
      regulation of hundreds of genes in both variants and predominantly involves genes
      implicated in signal transduction, cell cycle control, apoptosis, and
      transcription regulation. Specifically, the IFN-alpha response of tumoral T cells
      is due to a combination of induction of apoptosis in which TNFSF10 and HSXIAPAF1
      may play an important role and cell cycle arrest achieved by downregulation of
      CDK4 and CCNG2 and upregulation of CDKN2C and tumor suppressor genes (TSGs).
      Resistance to IFN-alpha appears to be associated with failure to induce IRF1 and
      IRF7 and deregulation of the apoptotic signals of HSXIAPAF1, TRADD, BAD, and
      BNIP3. Additionally, cell cycle progression is heralded by upregulation of CDC25A
      and CDC42. A critical role of NF-kappaB in promoting cell survival in IFN-alpha
      resistant cells is indicated by the upregulation of RELB and LTB.

PMID- 15035855
TI  - A review of the literature examining linkages between organizational factors,
      medical errors, and patient safety.
AB  - The potential role of organizational factors in enhanced patient safety and
      medical error prevention is highlighted in the systems approach advocated for by
      the Institute of Medicine and others. However, little is known about the extent
      to which these factors have been shown empirically to be associated with these
      favorable outcomes. The present study conducted an intensive review of the
      clinical and health services literatures in order to explore this issue. The
      results of this review support the general conclusion that there is little
      evidence for asserting the importance of any individual, group, or structural
      variable in error prevention or enhanced patient safety at the present time. Two
      major issues bearing on the development of future research in this area involve
      strengthening the theoretical foundations of organizational research on patient
      safety and overcoming definitional and observability problems associated with
      error-focused dependent variables.

PMID- 15035853
TI  - Effects of the macrolide antibiotic, midecamycin, on Staphylococcus aureus
      product-induced Th2 cytokine response in patients with atopic dermatitis.
AB  - In the present study, the effects of the macrolide antibiotic, midecamycin (MDM),
      on the Th2 cytokine response induced by the Staphylococcus aureus products,
      staphylococcal enterotoxin B (SEB), lipoteichoic acid (LTA), and peptidoglycan
      (PEG), was investigated in human peripheral blood mononuclear cells (PBMCs) from
      patients with atopic dermatitis (AD). MDM inhibited SEB-induced mRNA expression
      of the Th2 cytokines interleukin-4 (IL-4) and IL-5 in PBMCs from patients with
      AD. Furthermore, MDM also suppressed LTA-induced or PEG-induced IL-5 mRNA
      expression in these patients. Inhibition of mRNA expression by MDM correlated
      with the synthesis of cytokines in PBMCs, indicating that MDM controls Th2
      cytokine production. In addition, S. aureus strains isolated from skin lesions of
      patients with AD were particularly susceptible to MDM compared with gentamicin,
      which is used widely in Japan as an antibiotic ointment combined with steroid for
      topical application in AD. These results suggest that topical administration of
      MDM might be beneficial in AD lesions infected with S. aureus.

PMID- 15035856
TI  - The economies of scale for nursing home care.
AB  - Using a modified hybrid short-term operating cost function and a national sample
      of nursing homes in 1994, the authors examined the scale economies of nursing
      home care. The results show that scale economies exist for Medicare postacute
      care, with an elasticity of -0.15 and an optimal scale of around 4,000 patient
      days annually. However, more than 68 percent of nursing homes in the analytic
      sample produced Medicare days at a level below the optimal scale. The financial
      pressures resulting from the implementation of a prospective payment system for
      Medicare skilled nursing facilities may further reduce the quantity of Medicare
      days served by nursing homes. In addition, the results show that chain-owned
      nursing homes do not have lower short-term operating costs than do independent
      facilities. This indicates that the rationale behind recent increasing horizontal
      integration among nursing homes may not be seeking greater cost efficiency but
      some other consideration.

PMID- 15035857
TI  - Decreased home health use: does it decrease satisfaction?
AB  - This study investigates differences in satisfaction and quality of life for
      Medicare beneficiaries using home health care services before and after
      implementation of the Interim Payment System (IPS) as part of the Balanced Budget
      Act (BBA) of 1997. Data are from surveys conducted pre- and post-BBA.
      Multivariate analyses estimate the effect of being in the post-BBA period
      controlling for beneficiary, agency, and community characteristics. Sixteen
      dependent variables measure satisfaction with the agency, and two measure life
      quality. Despite dramatic utilization decreases, differences were not found for
      overall agency satisfaction, satisfaction with discharge, or with the nursing and
      therapist care received. Decreases in satisfaction were found for some
      interpersonal aspects of staff interaction and, for the group of respondents who
      received services in the agencies that participated in both the pre- and
      postperiods, with the decreased provision of personal care services. A large
      increase was found in staff encouraging independence.

PMID- 15035858
TI  - Nursing homes with persistent high and low quality.
AB  - This article examines the concentration of low- and high-quality care within
      particular nursing facilities over time. The authors explore three different
      explanations for persistent low and high quality over time including the level of
      public reimbursement, the presence of bed constraint policies such as certificate
      of-need and construction moratoria, and the role of consumer information. Using
      1991 through 1999 data from the On-Line Survey, Certification, and Reporting
      system, the authors show that both low- and high-quality nursing home care is
      concentrated in certain facilities over time. Their results further show that
      public reimbursement and asymmetric information are both important factors in
      explaining why low quality persists over time in certain facilities.

PMID- 15035859
TI  - The sensitivity of Medicare billing claims data for monitoring mammography use by
      elderly women.
AB  - Mammography use is monitored through Medicare billing claims; however, the
      sensitivity of this data source has not been previously described. This study
      included 10,852 Colorado women ages 65 and older with a mammogram in 1998 as
      registered by the Colorado Mammography Project who were Medicare fee-for-service
      (FFS) enrollees. These records were matched to Medicare billing data to assess
      the proportion of those mammograms submitted for payment to Medicare. The overall
      sensitivity of the FFS Medicare billing data for screening mammography was 85
      percent. Medicare billing claims were less sensitive for younger women, African
      Americans, women with some college education, and women with supplementary
      private insurance. In Colorado, the Medicare FFS billing claims understates
      mammography usage by 15 percent. Care must be taken when comparing mammography
      use derived from Medicare billing claims, as the sensitivity of billing data can
      vary substantially by age, race, and socioeconomic status.

PMID- 15035860
TI  - Assessing the likelihood of recurrence during RNA evolution in vitro.
AB  - Recurrence is the possibility of resulting in the same endpoint multiple times
      when a living system is allowed to evolve repeatedly starting from a given
      initial point. This concept is of concern to both evolutionary theoreticians and
      molecular biologists who use nucleic acid selection techniques to mimic biotic
      and computorial processes in the test tube. Using the continuous in vitro
      evolution methodology, many replicate experimental evolutionary lineages with
      populations of catalytic RNA were performed to gain insight into the parameters
      that could affect recurrence. The likelihood that the same genotype will result
      in parallel trials of an evolution experiment in vitro depends on several
      factors, including the phenotype under selection, the size and composition of the
      initial diverse pool of nucleic acids used in the experiment, the degree of
      mutation possible during the experiment, the shape of the fitness landscape
      through which the population evolves, and the strategies used to invoke selection
      and to search the landscape, among others. By considering these factors, it can
      be predicted that recurrence is more likely when a small, wild-type-based
      starting pool is used with efficient selection and search strategies involving
      little online mutagenesis within a rugged adaptive landscape with a strong local
      optimum. The recurrence experiments performed here on the 150-nucleotide ligase
      ribozyme demonstrate that it repeatedly jumps from one peak in a fitness
      landscape to another, apparently hurdling a deep fitness valley. These
      predictions can and should be tested by additional multiple replicates of actual
      evolution experiments in the laboratory.

PMID- 15035861
TI  - Folding stabilizes the evolution of catalysts.
AB  - Sequence folding is known to determine the spatial structure and catalytic
      function of proteins and nucleic acids. We show here that folding also plays a
      key role in enhancing the evolutionary stability of the intermolecular
      recognition necessary for the prevalent mode of catalytic action in replication,
      namely, in trans, one molecule catalyzing the replication of another copy, rather
      than itself. This points to a novel aspect of why molecular life is structured as
      it is, in the context of life as it could be: folding allows limited,
      structurally localized recognition to be strongly sensitive to global sequence
      changes, facilitating the evolution of cooperative interactions. RNA secondary
      structure folding, for example is shown to be able to stabilize the evolution of
      prolonged functional sequences, using only a part of this length extension for
      intermolecular recognition, beyond the limits of the (cooperative) error
      threshold. Such folding could facilitate the evolution of polymerases in
      spatially heterogeneous systems. This facilitation is, in fact, vital because
      physical limitations prevent complete sequence-dependent discrimination for any
      significant-size biopolymer substrate. The influence of partial sequence
      recognition between biopolymer catalysts and complex substrates is investigated
      within a stochastic, spatially resolved evolutionary model of trans catalysis. We
      use an analytically tractable nonlinear master equation formulation called PRESS
      (McCaskill et al., Biol. Chem. 382: 1343-1363), which makes use of an
      extrapolation of the spatial dynamics down from infinite dimensional space, and
      compare the results with Monte Carlo simulations.

PMID- 15035862
TI  - Development and the Baldwin effect.
AB  - Baldwin's classic hypothesis states that behavioral plasticity can speed
      evolution by (a) smoothing the fitness landscape and (b) indirect genetic
      assimilation of acquired characteristics. This latter phase demands a strong
      correlation between genotype and phenotype space. But the natural world shows
      signs of this correlation at only a very coarse level, since the intervening
      developmental process greatly complicates the mapping from genetics to physiology
      and ethology. Hence, development appears to preclude a strong Baldwin effect.
      However, by adding a simple developmental mechanism to Hinton and Nowlan's
      classic model of the Baldwin effect, and by allowing evolution to determine the
      proper balance between direct and indirect mapping of genome to phenotype, this
      research reveals several different effects of development on the Baldwin effect,
      some promoting and others inhibiting. Perhaps the most interesting result is an
      evolved cooperation between direct blueprints and indirect developmental recipes
      in searching for unstructured and partially structured target patterns in large,
      needle-in-the-haystack fitness landscapes.

PMID- 15035863
TI  - Learning obstacle avoidance with an operant behavior model.
AB  - Artificial intelligence researchers have been attracted by the idea of having
      robots learn how to accomplish a task, rather than being told explicitly.
      Reinforcement learning has been proposed as an appealing framework to be used in
      controlling mobile agents. Robot learning research, as well as research in
      biological systems, face many similar problems in order to display high
      flexibility in performing a variety of tasks. In this work, the controlling of a
      vehicle in an avoidance task by a previously developed operant learning model (a
      form of animal learning) is studied. An environment in which a mobile robot with
      proximity sensors has to minimize the punishment for colliding against obstacles
      is simulated. The results were compared with the Q-Learning algorithm, and the
      proposed model had better performance. In this way a new artificial intelligence
      agent inspired by neurobiology, psychology, and ethology research is proposed.

PMID- 15035864
TI  - Self-protection and diversity in self-replicating cellular automata.
AB  - The concept of self-protection, a capability of an organism to protect itself
      from exogenous attacks, is introduced into the design of artificial evolutionary
      systems as a possible method to create and maintain diversity in the population.
      Three different mechanisms of self-protection are considered and implemented on a
      cellular-automaton-based evolutionary system, the evoloop. Simulation results
      imply a positive effect of those mechanisms on diversity maintenance, especially
      when the self-protection is moderate so that it conserves both the attacker and
      the attacked. This letter briefly reports the models and the simulation results
      obtained using those models.

PMID- 15035865
TI  - Building artificial life for play.
AB  - Playthings are often engineered to replicate the character of real organisms. In
      the past, inventors lavished great expense on their lifelike automata, their
      constraints being typically related to the mechanical technology they employed
      and the amount of time and effort they were able to commit to the enterprise. The
      devices that are currently produced are usually intended for the mass market. The
      cost of production therefore is a major concern, even though the technology is
      more sophisticated and highly automated than in the past. Consequently, toymakers
      and engineers, as well as artists, of the past and present alike have had to
      think abstractly about living systems in order to construct their simulacra
      economically. This essay examines a number of lifelike toys to discover the
      properties of real organisms that their designers have attempted to recreate.
      That we, as users of these devices, so readily recognize in them a degree of
      lifelikeness demonstrates the extent to which intuition may sway our intellectual
      reasoning about real biology. As a result, an innovative toymaker or artist is
      able to manipulate us to zoomorphize even the most extreme abstractions--at least
      momentarily--despite our rational reluctance to accept the trickery.

PMID- 15035867
TI  - Antineoplastons and the challenges of research in integrative care.

PMID- 15035868
TI  - Cruciferous vegetables: cancer protective mechanisms of glucosinolate hydrolysis
      products and selenium.
AB  - Dietetic professionals urge Americans to increase fruit and vegetable intakes.
      The American Institute of Cancer Research estimates that if the only dietary
      change made was to increase the daily intake of fruits and vegetables to 5
      servings per day, cancer rates could decline by as much as 20%. Among the reasons
      cited for this health benefit are that fruits and vegetables are excellent
      sources of fiber, vitamins, and minerals. They also contain nonnutritive
      components that may provide substantial health benefits beyond basic nutrition.
      Examples of the latter are the glucosinolate hydrolysis products, sulforaphane,
      and indole-3-carbinol. Epidemiological studies provide evidence that the
      consumption of cruciferous vegetables protects against cancer more effectively
      than the total intake of fruits and vegetables. This review describes the
      anticarcinogenic bioactivities of glucosinolate hydrolysis products, the mineral
      selenium derived from crucifers, and the mechanisms by which they protect against
      cancer. These mechanisms include altered estrogen metabolism, protection against
      reactive oxygen species, altered detoxification by induction of phase II enzymes,
      decreased carcinogen activation by inhibition of phase I enzymes, and slowed
      tumor growth and induction of apoptosis.

PMID- 15035869
TI  - The experience of indigenous traditional healing and cancer.
AB  - Indigenous traditional healing is an ancient, deeply rooted, complex holistic
      health care system practiced by indigenous people worldwide. However, scant
      information exists to explain the phenomenon of indigenous medicine and
      indigenous health. Even less is known about how indigenous healing takes place.
      The purpose of this study is to describe the meaning and essence of the lived
      experience of 4 indigenous people who have been diagnosed with cancer and have
      used indigenous traditional healing during their healing journey. The researcher
      used a qualitative phenomenological methodology to collect and analyze interview
      data. Interviews were conducted with 4 self-identified indigenous people, ages 49
      to 61, from diverse tribes. Time since cancer diagnosis varied from 2 to 20
      years; types of cancer included lung, prostate, sarcoma of the leg, and breast.
      Four themes and 2 subthemes emerged (1) receiving the cancer diagnosis (with
      subthemes of knowing something was wrong and hearing something was wrong), (2)
      seeking healing, (3) connecting to indigenous culture, and (4) contemplating
      life's future. This study demonstrates that 4 individuals with cancer integrated
      Western medicine and traditional healing to treat their cancer. This knowledge
      provides necessary data about the phenomena of being healed by indigenous
      healers. Such data may serve as an initial guide for health care professionals
      while interacting with indigenous people diagnosed with cancer. Accordingly,
      traditional healing may be used to decrease health disparities.

PMID- 15035870
TI  - Integrative tumor board: metastatic renal cell carcinoma: case presentation,
      history of present illness, review systems and physical examination.

PMID- 15035871
TI  - Integrative tumor board: metastatic renal cell carcinoma: medical oncology.

PMID- 15035872
TI  - Integrative tumor board: metastatic renal cell carcinoma: medical oncology (II).

PMID- 15035873
TI  - Integrative tumor board: metastatic renal cell carcinoma: naturopathic medicine.

PMID- 15035874
TI  - Integrative tumor board: metastatic renal cell carcinoma: psycho-oncology.

PMID- 15035875
TI  - Integrative tumor board: metastatic renal cell carcinoma: integrative physician's
      perspective.

PMID- 15035876
TI  - The present state of antineoplaston research (1).
AB  - Antineoplastons work as molecular switches, which regulate expression of genes
      p53 and p21 through demethylation of promoter sequences and acetylation of
      histones. They also inhibit the uptake of growth-critical amino acids, such as 1
      glutamine and 1-leucine in neoplastic cells. Phase II trials indicate efficacy of
      antineoplastons in low-grade glioma, brain stem glioma, high-grade glioma,
      adenocarcinoma of the colon, and hepatocellular carcinoma. The best results were
      observed in children with low-grade glioma, where 74% of patients obtained
      objective response, and in patients with adenocarcinoma of the colon with liver
      metastases whose survival rate of more than 5 years is 91% versus 39% in controls
      on chemotherapy. Gene array studies will explain antineoplaston-induced changes
      in gene expression.

PMID- 15035877
TI  - Managing social conflict in complementary and alternative medicine research: the
      case of antineoplastons.
AB  - From December 1991 to December 1995, the National Cancer Institute (NCI)
      initiated phase II clinical trials of A10 and AS2-1 (antineoplastons) infusions
      in patients with diagnosed primary malignant brain tumors. Four years and more
      than a million dollars later, these studies were stopped before it was possible
      to determine the effectiveness of antineoplastons. Both NCI and Dr Burzynski, the
      developer of antineoplastons, accused one another of attempting to undermine the
      project. In an effort to determine why this study failed to be completed, the
      director of the National Institutes of Health Office of Alternative Medicine
      (OAM), who sponsored the study, commissioned a detailed analysis of the conflicts
      that led to the study's closure. The intent was to understand the social dynamics
      surrounding this failed study and to develop a method for managing and possibly
      preventing such failures in the future. This clinical trial was extremely complex
      and comprehensive. It involved hundreds of memoranda, letters, and telephone and
      fax correspondence among a wide number of parties over a 4-year period. All
      correspondence and other documents from the OAM as well as documentation from NCI
      were thoroughly examined. In addition, in-depth interviews with key individuals
      involved in the antineoplaston study were completed and incorporated into the
      analysis. At least 10 areas of conflict emerged from the analysis including
      issues around production, quality, and delivery of antineoplastons; commencement
      of the trial; the role of Dr Burzynski in the trial; types and combinations of
      cancers; choice of clinical investigators; need for communication; criteria for
      patient selection and treatment; and evaluation. Each of these issues clearly
      represented a difference of opinion between the 2 main parties around scientific
      protocols. Yet contention around these substantive, "scientific" disagreements
      reflected conflict in attunement (trust, power, and affiliation) between Dr
      Burzynski and NCI. This article summarizes the findings from this case study.

PMID- 15035878
TI  - Point-counterpoint: using clinical trials for the evaluation of integrative
      cancer therapies.

PMID- 15035879
TI  - One oncologist's view of integrative care: keynote address, comprehensive cancer
      care conference, April 2003.

PMID- 15035880
TI  - I am a health professional, but my loved one has cancer.

PMID- 15035881
TI  - Multiple molecular targets in oncology and integrative care.

PMID- 15035882
TI  - A population-based survey of complementary and alternative medicine use in men
      recently diagnosed with prostate cancer.
AB  - PURPOSE: To determine prevalence and patterns of use of complementary and
      alternative medicine (CAM) among men recently diagnosed with prostate cancer.
      STUDY DESIGN: Men, diagnosed with prostate cancer over a 10-month period in
      British Columbia, Canada, were randomly selected to obtain a population-based
      sample. METHODS: Surveys, addressing patient demographics, types of CAM
      therapies, and CAM information resources utilized, reasons for use, and
      disclosure to physician(s), were mailed to 1108 men newly diagnosed with prostate
      cancer. A 42% response rate was obtained. RESULTS: Thirty-nine percent of
      patients used CAM therapies with the most common being herbal supplements (saw
      palmetto), vitamins (vitamin E), and minerals (selenium). The most common reasons
      given for choosing to use CAM therapies were to (1) boost the immune system and
      (2) prevent recurrence. The majority of men (58%) had told their physician(s)
      about their CAM use, but few utilized either their family physician (15%) or
      their oncologist (7%) as sources of CAM information. CAM users most commonly
      consulted friends or family (39%) or the Internet (19%) for information about
      CAM. CAM users were more likely than nonusers to delay (9%) or decline (4%)
      conventional treatment. Respondents who had never used CAM had typically never
      thought about it or did not have enough information about the treatments.
      CONCLUSIONS: More than one third of recently diagnosed prostate cancer patients
      utilize some form of CAM therapy, and the majority disclose their use to their
      physician(s). However, they tend to rely on anecdotal information for their CAM
      decision making. Dissemination of reliable CAM information is one key to helping
      men navigate this difficult arena.

PMID- 15035883
TI  - Decision-making control: why men decline treatment for prostate cancer.
AB  - The purpose of this study was to conduct a qualitative analysis of decision
      making control by men with prostate cancer who refuse conventional cancer
      therapies. The transcripts for 8 prostate cancer patients from a larger
      qualitative study were analyzed separately to explore in depth the factors
      related to decision-making control. RESULTS: Most men were newly diagnosed when
      they made the decision to forgo conventional cancer treatment in favor of
      alternative approaches. Five areas were identified in which patients took control
      over the treatment process. These include control over (1) the timing of
      treatment, (2) information about conventional treatment and risk assessment, (3)
      designing an alternative treatment plan, (4) coordination of cancer care, and (5)
      monitoring and evaluation of disease progression. Clinicians can support patients
      who delay or forgo treatment for prostate cancer by helping them maintain a sense
      of control over the treatment process. This can be achieved by supporting
      patients' efforts to integrate complementary therapies into their cancer care, by
      addressing fears related to treatment early in the decision-making process, and
      by encouraging open communication about the reasons for seeking alternatives to
      conventional treatment. Findings from this study need to be evaluated in a
      larger, quantitative study.

PMID- 15035885
TI  - Are there differences in breast tissue as a result of hormone replacement
      therapy? Can BEST imaging distinguish these differences?
AB  - Although it has been speculated that estrogen therapy may promote changes in
      breast tissue that could lead to cancer, no information exists as to differences
      in breast tissue for women who do and do not take hormone replacement (HRT)
      therapy. This study seeks to determine if there are differences in the tissue of
      women taking HRT in contrast to those who do not and if these differences are
      apparent in cases of breast cancer, cellular atypia, fibrocystic (FCD) disease
      and normal breasts. A total of 327 non-pregnant, non-lactating, pre-menopausal
      women were enrolled in the study, including 139 women who were actively taking
      HRT and 188 women who never had taken HRT. Using breast enhanced scintigraphy
      test (BEST) imaging, differentiation of breast tissue was determined. The groups
      were then analyzed to determine the effect of hormone therapy within each
      category of breast tissue. Differentiation between normal, FCD, cellular atypia,
      and breast cancer represent statistically significant differences (p.001) in
      metabolic activity and vascularity as demonstrated by differences in both average
      count activity (ACA) and maximal count activity (MCA). The distinction between
      cellular atypia and infiltrating breast cancer was statistically (p.05) different
      when looking at the maximal activity. Normal breast tissue and breasts with FCD
      appear more homogenous with no statistical differences in variability in breast
      tissue. Tissue variability is statistically greater when localized processes,
      such as cellular atypia and breast cancer, are present. Differentiation of
      cellular metabolic activity in breast tissue can be statistically determined when
      looking at the average and maximal metabolic activity. The final distinction
      between cellular atypia and cancer occurs when a focal region of breast tissue
      becomes metabolically more active than the surrounding breast tissue as shown by
      statistical increases in MCA. These findings are confirmed by the increased
      metabolic variability seen in regions of cellular atypia and cancer compared with
      the homogenous metabolic activity present in normal and fibrocystic breasts.

PMID- 15035884
TI  - What effect, if any, does soy protein have on breast tissue?
AB  - Differences in breast tissue can be determined using breast-enhanced scintigraphy
      test (BEST) imaging. Minimal work in vivo has been done previously to determine
      the effects of soy protein on breast tissue. The authors' earlier work
      demonstrated reduction in inflammatory changes in breast tissue. This work was
      conducted to examine the effect of daily soy protein consumption on a larger
      group of women over the course of 1 year. Sixty-four premenopausal women were
      studied after initial BEST imaging evaluation revealed fibrocystic changes of the
      breast. Women were asked to consume a medical-grade soy protein on a daily basis,
      making no other dietary or lifestyle changes during that time. Each woman
      underwent BEST imaging 1 year later with the results compared to the initial
      findings. Women and their physicians reported a subjective reduction in both
      breast tenderness and fibrocystic disease (FCD). There was a nonstatistical
      reduction in both the average and maximal count breast activity following 1 year
      of daily soy consumption. There was a statistically significant reduction ( P <
      .01) in variability of tissue activity following 1 year of soy protein treatment.
      This is the first in vivo study looking at the effect of soy protein on breast
      tissue health. The findings are promising and showed both objective and
      subjective findings consistent with a reduction in fibrocystic disease of the
      breast. Further research is needed to confirm these findings in a greater number
      of women and to determine if soy protein has the same beneficial effect in atypia
      and breast cancer.

PMID- 15035886
TI  - Do women taking hormone replacement therapy (HRT) have a higher incidence of
      breast cancer than women who do not?
AB  - An estimated one third of all American and United Kingdom women take hormone
      therapy. In sharp contrast to these numbers, as many as one half of women
      diagnosed with breast cancer have taken hormones. Little additional information
      is available regarding the risk of breast cancer and even less is known about the
      association between hormone therapy and fibrocystic (FCD) disease or atypia of
      the breast. Three hundred women between 30 and 50 years of age were enrolled in
      this study, including 120 taking hormone replacement (HRT) therapy and 180 women
      who had never taken hormone therapy. These women were divided into four
      categories including those with normal breast tissue, those with FCD disease,
      those with cellular atypia, and those with breast cancer. Another group of women
      were also identified who had breast implants. Using breast enhanced scintigraphy
      (BEST) imaging, changes in breast tissue were determined and compared according
      to the use of HRT. Forty percent (122 of 300) had "normal" breasts, of whom 68.8%
      (84 of 122) did not take HRT. This accounted for 46.7% (84 of 180) of the women
      not taking hormone therapy, while only 31.7% (38 of 120) of the women taking HRT
      had normal breasts. This difference was statistically (p.001) significant. There
      was a greater incidence of breast abnormality in women taking HRT and a lower
      incidence in pathology among women not taking HRT when cumulatively analyzed for
      FCD, cellular atypia, and breast cancer. This difference was statistically
      significant (p.001) for women with breast cancer where 62.5% (10 of 16) were
      women taking HRT. Although the study was relatively small, it is the first such
      study to compare a continuum of changes in breast tissue according to the use of
      HRT. The study suggests that the initial empirical observations regarding higher
      incidence of HRT among women with breast cancer, may have a relationship to
      underlying changes in breast tissue that are associated with differences in
      mitochondrial content and activity. Further investigation is needed.

PMID- 15035887
TI  - Inflammation as cause for scar cancers of the lung.
AB  - The molecular and cellular basis of inflammation has become a topic of great
      interest of late because of the association between mechanisms of inflammation
      and risk for cancer. Inflammatory-mediated events, such as the production of
      reactive oxygen species (ROS), the activation of growth factors (for wound
      repair), and the altering of signal-transduction processes to activate cell
      proliferation (to replace necrotic/apoptotic tissue cells), events that also can
      occur independently of inflammation, are all considered to be components of risk
      for a variety of cancers. Using scar cancer of the lung as an example, mechanisms
      of inflammation associated with recurring infections with Mycobacterium
      tuberculosis are discussed in the context that they may, in fact, be the major or
      sole cause of a cancer. Production of ROS, prostaglandins, leukotrienes, and
      cytokines in pulmonary tissues is greatly enhanced due to a cell-mediated immune
      response against macrophages infected with M. tuberculosis. These responses lead
      to the extensive fibrosis associated with recurring infections, possibly leading
      to decreased clearance of lymph and lymph-associated particles from the infected
      region. They also will enhance rates of cell division by inhibiting synthesis of
      P21, leading to enhanced progression from G0 arrest to G1 phase, from G1 to
      Sphase, and from G2 to M phase of the cell cycle. By increasing rates of
      oxidative DNA damage and inhibiting apoptosis by enhancing synthesis of BCL-2,
      mutagenesis of progeny cells is enhanced, and these effects coupled with enhanced
      angiogenesis stimulated by COX-2 products lead to an environment that is highly
      conducive to tumorigenesis. Based on the evidence, it appears that but for an
      inflammatory response to recurring infections, some cases of scar cancer would
      not exist. By making appropriate lifestyle and dietary changes, a variety of anti
      inflammatory effects can be produced, which should attenuate inflammation-induced
      risk for cancer.

PMID- 15035889
TI  - Integrative tumor board: recurrent breast cancer or new primary? Case
      Presentation.

PMID- 15035888
TI  - Immune system effects of echinacea, ginseng, and astragalus: a review.
AB  - Traditional herbal medicine provides several remedies for strengthening the
      body's resistance to illness through effects on immune system components. This
      review article examines 3 popular herbal immune stimulants that are often of
      interest to cancer patients. Echinacea, a native of North America, is widely used
      to prevent, or provide early treatment for, colds. Preclinical studies lend
      biological plausibility to the idea that echinacea works through immune
      mechanisms. Numerous clinical trials have been carried out on echinacea
      preparations: it appears that the extracts shorten the duration and severity of
      colds and other upper respiratory infections (URIs) when given as soon as
      symptoms become evident. However, trials of long-term use of echinacea as a
      preventive have not shown positive results. Ginseng has been studied in some
      depth as an antifatigue agent, but studies of immune mechanisms have not
      proceeded so far. Preclinical evidence shows some immune-stimulating activity.
      There have been several clinical trials in a variety of different diseases.
      Astragalus is the least-studied agent. There are some preclinical trials that
      show intriguing immune activity. The herbs discussed appear to have satisfactory
      safety profiles. Cancer patients may wish to use these botanicals to inhibit
      tumor growth or to boost resistance to infections. However, passive immunotherapy
      with herbs, with no mechanism to expose tumor antigens, is unlikely to be
      effective in inhibiting tumor growth. Although the margin of safety for these
      herbs is large, more research is needed to demonstrate the clear value of using
      herbs to improve resistance to infections.

PMID- 15035891
TI  - Integrative tumor board: recurrent breast cancer or new primary? Radiation
      oncology.

PMID- 15035890
TI  - Integrative tumor board: recurrent breast cancer or new primary? Medical
      oncology.

PMID- 15035892
TI  - Integrative tumor board: recurrent breast cancer or new primary? Naturopathic
      medicine.

PMID- 15035893
TI  - Integrative tumor board: recurrent breast cancer or new primary? Mind-body-spirit
      medicine.

PMID- 15035894
TI  - Integrative tumor board: recurrent breast cancer or new primary? UCSF Osher
      Center for Integrative Medicine and UCSF Carol Franc Buck Breast Care Center.

PMID- 15035895
TI  - Integrative tumor board: recurrent breast cancer or new primary? Integrative
      physician's perspective.

PMID- 15035896
TI  - Timing is everything.

PMID- 15035897
TI  - Circadian timing in cancer treatment: the biological foundation for an
      integrative approach.
AB  - Despite the many innovations that have occurred in cancer treatment, the age
      specific mortality for most adult tumors has remained stable during the past 30
      years. There have been clinically significant improvements in the outcomes of
      young and middle-aged patients, yet the vast majority of cancer patients are more
      than 50 years of age, among whom we observe few improvements in clinical
      outcomes. Clearly, many of today's cytotoxic agents have been shown to be
      effective in-vitro and in animal model systems; however, few have proved
      efficacious in dramatically improving survival outcomes in adult cancer. There is
      now increasing evidence to suggest that the administration of cytotoxic agents,
      at the appropriate circadian phase, can significantly increase the therapeutic
      index of current cancer therapies.

PMID- 15035898
TI  - Clinical evaluation of "immunoaugmentative therapy (IAT)": an unconventional
      cancer treatment.
AB  - Immunoaugmentative therapy (IAT) is an unconventional therapy used by thousands
      of cancer patients that has not been systematically evaluated for safety and
      efficacy. The authors evaluated the toxicity and effects of this therapy in a
      series of consecutively treated cancer patients. METHODS: A sample of 46
      consecutive patients treated at the Immune Therapy Clinic in Playas, Mexico, from
      April to December 1989 were evaluated for adverse reactions, tumor response,
      quality of life and immune status over 12 weeks of IAT treatment. Patients' blood
      was tested for HIV and hepatitis B antibody before and after treatment.
      Histological confirmation of cancer and staging was obtained in all patients, and
      the results of follow-up radiological examinations were judged in a blinded
      fashion by independent diagnostic radiologists. RESULTS: There were no signs of
      toxicity (SWOG criteria) and no HIV or hepatitis B conversion attributable to
      IAT. None of the 46 patients showed tumor regression. Forty patients (87%) had
      disease progression, and 25 (55%) died within 6 months from disease progression.
      Thirty-five patients (76%) noticed a decline in their quality of life during IAT.
      Thirty-eight patients (83%) opted to continue with the IAT treatment, despite its
      lack of effectiveness. CONCLUSIONS: No indication of toxicity or effectiveness
      was found in an uncontrolled, consecutively selected series of 46 cancer patients
      undergoing IAT treatment. In addition, the therapy did not appear to contribute
      to improved quality of life in most patients. This study does not justify its
      continued use.

PMID- 15035899
TI  - Phytoestrogens in botanical dietary supplements: implications for cancer.
AB  - Phytoestrogens are plant constituents that possess either estrogenic or
      antiestrogenic activity. Although their activities are weak as compared with
      human endogenous estrogens, the consumption of phytoestrogens may have clinically
      significant consequences. A number of botanicals, or the compounds contained
      therein, have been identified as putative estrogenic agents, but consensus in the
      biomedical community has been hampered by conflicting data from various in vitro
      and in vivo models of estrogenic activity. Phytoestrogens may serve as
      chemopreventive agents while at the same time being capable of promoting growth
      in estrogen receptor positive cancer cell lines. Furthermore, they may exert
      their estrogenic influence through receptor-dependent and/or receptor-independent
      mechanisms. These findings have led to speculation that phytoestrogen intake
      might be ill advised for patients at an increased risk for hormone-dependent
      cancers, cancer patients, or cancer survivors. This article will attempt to sort
      out discrepancies between various experimental models and establish whether
      certain herbs possess estrogenic activity. The review will focus on 5 popular
      botanical dietary supplements: Trifolium pratense (red clover), Cimicifuga
      racemosa (black cohosh), Humulus lupulus (hops), Angelica sinensis (dong quai),
      and Glycyrrhiza glabra (licorice). It will address their mechanisms of action,
      clinical evidence bases, and implications for use in cancer.

PMID- 15035900
TI  - Detoxifying cancer causing agents to prevent cancer.
AB  - Different vitamins and other micronutrients in vegetables, fruits, and other
      natural plant products may prevent cancer development (carcinogenesis) by
      interfering with detrimental actions of mutagens, carcinogens, and tumor
      promoters. The goal of current studies in cancer prevention is to determine the
      mechanisms of synergistic action of the natural source compounds known to inhibit
      one or more stages of carcinogenesis, that is, initiation and
      promotion/progression. Many natural cancer preventive agents are effective
      inhibitors of tumor initiation, promotion, and/or progression. The mechanism of
      action is related to their abilities to prevent critical carcinogen metabolism
      and to increase detoxification of carcinogens and tumor promoters. The authors
      review here the potential role of the detoxification system and, in particular,
      the roles of D-glucaric acid and the enzyme beta-glucuronidase in early detection
      and prevention of cancer. There is now growing evidence for the possible control
      of different stages of the cancer induction by inhibiting beta-glucuronidase with
      D-glucaric acid derivatives, especially with its salts (D-glucarates). D-Glucaric
      acid has been found in many vegetables and fruits. Therefore, the consumption of
      fruits and vegetables naturally rich in D-glucaric acid or self-medication with D
      glucaric acid derivatives such as calcium D-glucarate offers a promising cancer
      prevention approach.

PMID- 15035901
TI  - Mega-dose vitamins and breast cancer.

PMID- 15035902
TI  - Vitamin C in alternative cancer treatment: historical background.
AB  - Ascorbic acid is the single-nutrient supplement most commonly used by cancer
      patients, although in most cases this takes place without the physician's
      knowledge or supervision. A comprehensive review of the literature is presented
      on the impact of ascorbic acid on cancer survival. Findings from 6 uncontrolled
      studies suggest that ascorbic acid may increase survival, whereas 2 controlled
      trials have yielded null results. The relative strengths and limitations of these
      studies are discussed. A turning point occurred with the release of the 2
      controlled (null) studies, which influenced many physicians to turn away from
      nutrition in the care of cancer patients. Controversy about these trials still
      persists, however, in the alternative cancer community.

PMID- 15035903
TI  - Comments on "Mega-dose vitamins and minerals in the treatment of nonmetastatic
      breast cancer: an historical cohort study".

PMID- 15035904
TI  - Vitamin C in cancer.

PMID- 15035905
TI  - Clinical testing of supplementation therapy in early stage breast cancer:
      pitfalls and opportunities.

PMID- 15035906
TI  - Mega-dose vitamin and mineral therapy in breast cancer: a clinician's
      perspective.

PMID- 15035907
TI  - Integrative tumor board: colon cancer with liver metastases: case presentation.

PMID- 15035915
TI  - Will lower drug prices jeopardize drug research? A policy fact sheet.

PMID- 15035916
TI  - Human embryo research and the language of moral uncertainty.
AB  - In bioethics as in the sciences, enormous discussions often concern the very
      small. Central to public debate over emerging reproductive and regenerative
      biotechnologies is the question of the moral status of the human embryo. Because
      news media have played a prominent role in framing the vocabulary of the debate,
      this study surveyed the use of language reporting on human embryo research in
      news articles spanning a two-year period. Terminology that devalued moral status
      for example, the descriptors things, property, tissue, or experimental material 
      was found to outnumber fivefold those that affirmed any degree of moral status
      above that of inanimate cellular matter; for example, living, human life, or
      human being. A quarter of the articles failed to note that the embryos under
      discussion were human. These findings confirm that even among scientific and
      philosophical experts a diversity of opinion exists on society's moral
      obligations to nascent human life. The skewed linguistic distribution also
      indicates a distinct bias. Concerned readers should take notice when any category
      of humanity becomes subject to prejudicial and disparaging language and the value
      of vulnerable human life is trivialized alongside sensational assertions of
      anticipated medical cures. The responsibility for holding the media to a higher
      standard of truth and fairness falls to us all.

PMID- 15035917
TI  - When pestilence prevails...physician responsibilities in epidemics.
AB  - The threat of bioterrorism, the emergence of the SARS epidemic, and a recent
      focus on professionalism among physicians, present a timely opportunity for a
      review of, and renewed commitment to, physician obligations to care for patients
      during epidemics. The professional obligation to care for contagious patients is
      part of a larger "duty to treat," which historically became accepted when 1) a
      risk of nosocomial infection was perceived, 2) an organized professional body
      existed to promote the duty, and 3) the public came to rely on the duty.
      Physicians' responses to epidemics from the Hippocratic era to the present
      suggests an evolving acceptance of the professional duty to treat contagious
      patients, reaching a long-held peak between 1847 and the 1950's. There has been
      some professional retrenchment against this duty to treat in the last 40 years
      but, we argue, conditions favoring acceptance of the duty are met today. A
      renewed embrace of physicians' duty to treat patients during epidemics, despite
      conditions of personal risk, might strengthen medicine's relationship with
      society, improve society's capacity to prepare for threats such as bioterrorism
      and new epidemics, and contribute to the development of a more robust and
      meaningful medical professionalism.

PMID- 15035918
TI  - Human embryos and the language of scientific research.

PMID- 15035919
TI  - Embryos, words, and numbers: the ethical treatment of opinion.

PMID- 15035920
TI  - Politics and peer review.

PMID- 15035921
TI  - Human embryo research in the news: scientific versus ethical frames?

PMID- 15035922
TI  - How serve the common weal?

PMID- 15035923
TI  - Human embryo research: from moral uncertainty to death.

PMID- 15035924
TI  - Physicians and strikes: can a walkout over the malpractice crisis be ethically
      justified?
AB  - Malpractice insurance rates have created a crisis in American medicine. Rates are
      rising and reimbursements are not keeping pace. In response, physicians in the
      states hardest hit by this crisis are feeling compelled to take political action,
      and the current action of choice seems to be physician strikes. While the
      malpractice insurance crisis is acknowledged to be severe, does it justify the
      extreme action of a physician walkout? Should physicians engage in this type of
      collective action, and what are the costs to patients and the profession when
      such action is taken? I will offer three related arguments against physician
      strikes that constitute a prima facie prohibition against such action: first,
      strikes are intended to cause harm to patients; second, strikes are an affront to
      the physician-patient relationship; and, third, strikes risk decreasing the
      public's respect for the medical profession. As with any prima facie obligation,
      there are justifying conditions that may override the moral prohibition, but I
      will argue that the current malpractice crisis does not rise to the level of such
      a justifying condition. While the malpractice crisis demands and justifies a
      political response on the part of the nation's physicians, strikes and slow-downs
      are not an ethically justified means to the legitimate end of controlling
      insurance costs.

PMID- 15035925
TI  - Bioethics research and the language of methodological uncertainty.

PMID- 15035926
TI  - Bias in journalistic accounts of embryo research reconsidered.

PMID- 15035927
TI  - The bioethicist as public intellectual.
AB  - Public intellectuals have long played a role in American culture, filling the gap
      between the academic elite and the educated public. According to some
      commentators, the role of the public intellectual has undergone a steady decline
      for the past several decades, being replaced by the academic expert. The most
      notable cause of this decline has been both the growth of the academy in the
      twentieth century,which has served to concentrate intellectual activity within
      its confines, and the changing nature of the media, which has framed the way in
      which information is conveyed to the public. We argue that although bioethics has
      developed primarily within the academic tradition and utilized the role of expert
      when dealing with the public, bioethicists are well suited to don the mantle of
      the public intellectual. Indeed, because they address issues in medicine and
      science of great relevance for the general public, bioethicists have a duty to
      revitalize the tradition of public intellectuals as a necessary complement to the
      important, but narrower role of the expert.

PMID- 15035928
TI  - You say person, I say property: does it really matter what we call an embryo?

PMID- 15035929
TI  - Scientism or luddism: is informed ethical dialogue possible?

PMID- 15035930
TI  - Caveat emptor.

PMID- 15035931
TI  - Bad "Science".

PMID- 15035932
TI  - The language of certainty.

PMID- 15035933
TI  - The human embryo: animal, vegetable, or test-tube "baby"?

PMID- 15035934
TI  - A gower maneuver: the American Society for Bioethics and Humanities' resolution
      of the "Taking Stands" debate.
AB  - The American Society for Bioethics and Humanities debated for several years about
      whether it should adopt positions and, if so, on what range of issues. The
      membership recently approved an amendment to its bylaws permitting the Society to
      adopt positions on matters related to academic freedom and professionalism but
      not on substantive moral and policy issues. This resolution is problematic for a
      number of reasons, including the lack of a categorical difference between these
      types of claims and the Society's inability to speak on behalf of patients and
      research subjects. The implementation of the amendment also raises several
      issues. The Society will need to refrain from speaking too specifically and to
      articulate the responsibilities of its members. If the Society fails to address
      these concerns, it runs the risk of denigrating its public image and that of the
      profession.

PMID- 15035935
TI  - Ethics of research involving mandatory drug testing of high school athletes in
      Oregon.
AB  - There is consensus that children have questionable decisional capacity and,
      therefore, in general a parent or a guardian must give permission to enroll a
      child in a research study. Moreover, freedom from duress and coercion, the
      cardinal rule in research involving adults, is even more important for children.
      This principle is embodied prominently in the Nuremberg Code (1947) and is
      embodied in various federal human research protection regulations. In a program
      named "SATURN" (Student Athletic Testing Using Random Notification), each school
      in the Oregon public-school system may implement a mandatory drug-testing program
      for high school student athletes. A prospective study to identify drug use among
      student-athletes, SATURN is designed both to evaluate the influence of random
      drug testing and to validate the survey data through identification of
      individuals who do not report drug use. The enrollment of students in the drug
      testing study is a requirement for playing a school sport. In addition to the
      coercive nature of this study design, there were ethically questionable practices
      in recruitment, informed consent, and confidentiality. This article concerns the
      question of whether research can be conducted with high school students in
      conjunction with a mandatory drug-testing program, while adhering to prevailing
      ethical standards regarding human-subjects research and specifically the
      participation of children in research.

PMID- 15035936
TI  - Gaming the transplant system.

PMID- 15035937
TI  - A response to commentators on "Ethics of research involving mandatory drug
      testing of high school athletes in Oregon".

PMID- 15035939
TI  - Mandatory drug testing needs controlled evaluation.

PMID- 15035940
TI  - Full court press: a response to "Human embryo research and the language of moral
      uncertainty" by William P. Cheshire.

PMID- 15035941
TI  - Drug-testing research in high school students: is there a will or a way?

PMID- 15035942
TI  - On the origin of species: a response to "Crossing species boundaries" by Jason
      Scott Robert and Francoise Baylis.

PMID- 15035943
TI  - Mandatory drug testing of high school athletes: unethical evaluation, unethical
      policy.

PMID- 15035944
TI  - Students as lab animals.

PMID- 15035945
TI  - Coercion and the SATURN study.

PMID- 15035946
TI  - Omitted considerations and populations: a response to "Should children decide
      whether they are enrolled in nonbeneficial research?" by David Wendler and Seema
      Shah (AJOB 3:4).

PMID- 15035947
TI  - "What is legal is not necessarily ethical": the limits of law and drug-testing
      programs.

PMID- 15035948
TI  - Orbiting SATURN: countering politically-charged misinformation with facts.

PMID- 15035949
TI  - A clinician's perspective.

PMID- 15035950
TI  - Adolescents as doubly-vulnerable research subjects.

PMID- 15035951
TI  - Criticisms of SATURN mirror criticisms of any mandatory student drug-testing
      policy.

PMID- 15035952
TI  - A step toward truly protecting human subjects: reviewing the review boards.

PMID- 15035953
TI  - Required "volunteers" for human investigations--just say no!

PMID- 15035955
TI  - Spinning SATURN.

PMID- 15035958
TI  - Stroke rehabilitation research: time to answer more specific questions?

PMID- 15035954
TI  - Coercion, harm, and complicity in research integrated with mandatory public
      health programs.

PMID- 15035960
TI  - Timing, intensity, and duration of rehabilitation for hip fracture and stroke:
      report of a workshop at the National Center for Medical Rehabilitation Research.
AB  - This article summarizes the proceedings of an NIH workshop on timing, intensity,
      and duration of rehabilitation for acute stroke and hip fracture. Participants
      concentrated on methodological issues facing investigators and suggested
      priorities for future research in this area.

PMID- 15035962
TI  - Gains in distance walking in a 3-month follow-up poststroke: what changes?
AB  - STATEMENT OF PROBLEM: Distance walking remains compromised for many adults
      poststroke. The purpose of this study was to examine if the amelioration of
      stroke-related neuromuscular impairments, improved cardiovascular fitness, or
      better balance contributed to gains in distance walking. METHOD OF STUDY: The
      authors gathered baseline data of 92 adults at an average of 75 days poststroke
      and again 3 months later. Participants performed a bicycle ergometry stress test,
      a 6-min walk, and a Fugl-Meyer assessment for motor control, strength, and
      balance testing. The gain in walk distance was modeled using multiple regression
      with the variables of gains in peak VO2, lower limb control, plantar flexion
      strength, and balance. Separate analyses were done for poor performers, that is,
      participants who walked less than the median distance (213 m) at baseline and
      good performers, that is, participants who walked more than 213 m. RESULTS: For
      poor performers, the gain in balance was the only significant predictor of the
      gain in distance walking and accounted for 16% of the variance. For good
      performers, gains in peak VO2 and the lower limb Fugl-Meyer score were
      significant predictors and accounted for 28% of the variance. DISCUSSION: These
      results suggest that rehabilitation efforts to improve distance walking should
      focus on different factors depending on initial distance walked.

PMID- 15035964
TI  - Effects of sudden, passive muscle shortening according to Grimaldi's method on
      patients suffering from multiple sclerosis: a randomized controlled trial.
AB  - PURPOSE: The purpose of this study was to investigate the short-term effect of a
      therapeutical approach called "Grimaldi's method." The authors hypothesized that
      Grimaldi's method would improve active muscle recruitment. The treatment was
      focused on hip abductors. The authors collected data of hip's active range of
      motion against gravity (AROM), maximum isometric endurance (END), and maximum
      mechanical work (WORK). PARTICIPANTS AND METHODS: Forty patients suffering from
      multiple sclerosis were randomized into 2 groups, 20 were allocated to the
      Grimaldi's group and 20 to the control group. RESULTS: After 3 sessions of
      Grimaldi's treatment parameter, AROM increased from 21.4 degrees to 37.2 degrees
      in the experimental group; the improvement was statistically significant.
      Parameter END did not show any improvement, whereas mechanical work had a sharp
      increase: from 103.9 Nm to 149.6 Nm. CONCLUSION: The findings suggest that
      Grimaldi's method could be useful in increasing muscular recruitment of hip
      abductors, improving active range of motion and mechanical work of the hip in
      patients suffering from multiple sclerosis.

PMID- 15035965
TI  - Earlier management of subjects who are prone to hypertension and diabetes
      mellitus.

PMID- 15035963
TI  - Pulsed magnetic field therapy in refractory neuropathic pain secondary to
      peripheral neuropathy: electrodiagnostic parameters--pilot study.
AB  - CONTEXT: Neuropathic pain (NP) from peripheral neuropathy (PN) arises from
      ectopic firing of unmyelinated C-fibers with accumulation of sodium and calcium
      channels. Because pulsed electromagnetic fields (PEMF) safely induce extremely
      low frequency (ELF) quasirectangular currents that can depolarize, repolarize,
      and hyperpolarize neurons, it was hypothesized that directing this energy into
      the sole of one foot could potentially modulate neuropathic pain. OBJECTIVE: To
      determine if 9 consecutive 1-h treatments in physician's office (excluding
      weekends) of a pulsed signal therapy can reduce NP scores in refractory feet with
      PN. DESIGN/SETTING/PATIENTS: 24 consecutive patients with refractory and
      symptomatic PN from diabetes, chronic inflammatory demyelinating polyneuropathy
      (CIDP), pernicious anemia, mercury poisoning, paraneoplastic syndrome, tarsal
      tunnel, and idiopathic sensory neuropathy were enrolled in this nonplacebo pilot
      study. The most symptomatic foot received therapy. Primary endpoints were
      comparison of VAS scores at the end of 9 days and the end of 30 days follow-up
      compared to baseline pain scores. Additionally, Patients' Global Impression of
      Change (PGIC) questionnaire was tabulated describing response to treatment.
      Subgroup analysis of nerve conduction scores, quantified sensory testing (QST),
      and serial examination changes were also tabulated. Subgroup classification of
      pain (Serlin) was utilized to determine if there were disproportionate responses.
      INTERVENTION: Noninvasive pulsed signal therapy generates a unidirectional
      quasirectangular waveform with strength about 20 gauss and a frequency about 30
      Hz into the soles of the feet for 9 consecutive 1-h treatments (excluding
      weekends). The most symptomatic foot of each patient was treated. RESULTS: All 24
      feet completed 9 days of treatment. 15/24 completed follow-up (62%) with mean
      pain scores decreasing 21% from baseline to end of treatment (P=0.19) but with
      49% reduction of pain scores from baseline to end of follow-up (P<0.01). Of this
      group, self-reported PGIC was improved 67% (n=10) and no change was 33% (n=5). An
      intent-to-treat analysis based on all 24 feet demonstrated a 19% reduction in
      pain scores from baseline to end of treatment (P=0.10) and a 37% decrease from
      baseline to end of follow-up (P<0.01). Subgroup analysis revealed 5 patients with
      mild pain with nonsignificant reduction at end of follow-up. Of the 19 feet with
      moderate to severe pain, there was a 28% reduction from baseline to end of
      treatment (P<0.05) and a 39% decrease from baseline to end of follow-up (P<0.01).
      Benefit was better in those patients with axonal changes and advanced CPT
      baseline scores. The clinical examination did not change. There were no adverse
      events or safety issues. CONCLUSIONS: These pilot data demonstrate that directing
      PEMF to refractory feet can provide unexpected shortterm analgesic effects in
      more than 50% of individuals. The role of placebo is not known and was not
      tested. The precise mechanism is unclear yet suggests that severe and advanced
      cases are more magnetically sensitive. Future studies are needed with randomized
      placebo-controlled design and longer treatment periods.

PMID- 15035966
TI  - Trials of immunotherapy to preserve beta-cell function of prediabetic and new
      onset patient trials.

PMID- 15035967
TI  - T-cell epitopes in type 1 diabetes.
AB  - Type 1 diabetes (TID) results from T-cell-mediated destruction of pancreatic b
      cells in genetically predisposed individuals. Autoreactive CD4(+) T helper cells
      and CD8(+) cytotoxic T lymphocytes (CTLs) recognize b-cell-derived peptides in
      the context of major histocompatibility complex class II and I molecules,
      respectively, in a process that terminates in b-cell death. Many peptide epitopes
      derived from b-cell proteins have been described for both humans and the nonobese
      diabetic (NOD) mouse, but their relative importance in disease pathogenesis is
      unclear. The significance of identifying key b-cell epitopes is underscored by a
      study showing that in the NOD mouse monitoring of a single population of b-cell
      specific CTLs in the peripheral blood using a high-avidity analogue of the
      endogenous peptide may be used to accurately predict diabetes occurrence. Future
      studies focused on the discovery of immunodominant b-cell epitopes and their high
      avidity analogues should have considerable implications for prediction and
      immunotherapy of TID.

PMID- 15035970
TI  - Practical, practice, and policy relevant trials.
AB  - There is a well-documented gap between research and practice in diabetes and many
      other chronic illnesses. This gap is due, in part, to limitations of the research
      database. Different types of clinical trials have recently been called for that
      address issues central to clinicians, administrative decision makers, and policy
      makers. Such "practical clinical trials" that are conducted in multiple
      heterogeneous settings offer great potential. They include diverse patient
      populations, study clinically relevant and feasible interventions, and assess
      multiple outcomes. In this article, examples of these trials are provided, and
      design features that will facilitate clinical and policy decision making are
      summarized.

PMID- 15035968
TI  - Continuous glucose monitoring in type 1 diabetes.
AB  - Continuous glucose monitoring is becoming increasingly more widespread for the
      routine care of people with type 1 diabetes mellitus and may eventually be used
      in closed-loop artificial beta-cell systems. The current "state of the art" of
      this technology, including accuracy, performance in clinical trials, limitations,
      and recommendations for use, is discussed for the two currently approved
      continuous glucose monitoring devices.

PMID- 15035969
TI  - Peripheral antigen-expressing cells in type 1 diabetes.
AB  - Studies in both humans and rodent models provide new insight into key mechanisms
      regulating tolerance to self-molecules. There is evidence that tissue-specific
      molecules are expressed in the thymus and peripheral lymphoid tissues (PLTs) by
      specialized antigen-presenting cells (APCs), and that such expression is critical
      for self-tolerance. Insulin, a key hormone exclusively produced by pancreatic
      beta cells and a critical autoantigen in type 1 diabetes, provides an excellent
      example of a molecule with tissue-restricted expression that is ectopically
      expressed by APCs in both thymus and PLTs. APCs may play a role in insulin
      presentation in both the central and peripheral immune system. Functional data
      from several transgenic and knockout mouse models, some specific for the
      expression of insulin, help dissect the significance of self-molecule
      presentation by APCs and its role in autoimmune diabetes.

PMID- 15035971
TI  - Lifestyle intervention for the prevention of type 2 diabetes: translation and
      future recommendations.
AB  - The effectiveness of lifestyle intervention for the prevention of type 2 diabetes
      has recently been demonstrated. Four clinical trials using lifestyle
      interventions comprised of weight loss, physical activity, and diet have
      successfully prevented or delayed the onset of diabetes development in high-risk
      individuals. As we attempt to translate these results from the clinical trial to
      the community, it is important to understand the various components of the
      lifestyle intervention efforts used. After a description of the key lifestyle
      components of these clinical trials is provided, a discussion of possible
      suggestions for implementing these findings in the broader community setting is
      presented.

PMID- 15035972
TI  - Recognizing and treating depression in patients with diabetes.
AB  - Diabetes doubles the risk for depression, which in turn may interfere with
      effective diabetes self-management, and is associated with hyperglycemia and with
      increased risk for diabetes complications. Despite its relevance to the course of
      diabetes and its chronic character, depression is recognized and treated
      appropriately in fewer than 25% of depressed diabetic patients. The authors
      discuss the use of screening tools to assist primary care providers in
      identifying depressed diabetic patients, as well as the application of a chronic
      care model of depression management. Data from controlled trials are limited but
      promising. They suggest that pharmacologic and psychological approaches are
      effective in the face of diabetes, and that successful treatment also produces
      improvements in glycemic control, overall functioning, and quality of life.

PMID- 15035973
TI  - Coping skills training and problem solving in diabetes.
AB  - Diabetes requires a substantial degree of patient involvement for effective self
      management. Although diabetes education has been the standard of care, it is
      clear that provision of knowledge alone does not change behavior. Coping skills
      training is a cognitive-behavioral intervention that focuses on improving
      competence and mastery by retraining inappropriate or nonconstructive coping
      styles and patterns of behavior into more constructive behavior. Children,
      adolescents, and parents caring for children with type 1 diabetes demonstrated
      improved metabolic and psychosocial outcomes after coping skills training.
      Similar results have been found in adults with type 2 diabetes. Principles of
      this technique can be applied in practice to assist patients with diabetes to
      improve their self-management.

PMID- 15035974
TI  - New autoimmune genes and the pathogenesis of type 1 diabetes.
AB  - Type 1 diabetes is an autoimmune disease with a complex polygenic inheritance.
      Until recently, only three susceptibility genes had been reproducibly identified,
      namely HLA, INS-VNTR, and CTLA4. During the past 7 years, a number of new
      putative susceptibility genes have been isolated from both human and animal
      models of the disease. We present eight genes implicated in type 1 diabetes
      etiology and discuss them in relation to the pathogenesis of the disease: VDR,
      IL6, IL12B, AIRE, FOXP3, B2m, Cblb, and Lyp/Ian4l1.

PMID- 15035977
TI  - From tough nuts to touch-me-nots.
AB  - An intricate arrangement of different cell types is required for the spring
      loaded mechanism of spontaneous seed dispersal typical for many fruits. Liljegren
      and colleagues (2004 [this issue of Cell]) describe a nonlinear network of
      transcription factor genes controlling this process.

PMID- 15035975
TI  - What have rare genetic syndromes taught us about the pathophysiology of the
      common forms of obesity?
AB  - Obesity is a central feature for several congenital syndromes, including Prader
      Willi, Angelman, Bardet-Biedl, Cohen, Alstrom, and Borjeson-Forssman-Lehmann
      syndromes, and Albright's hereditary osteodystrophy. Although a role for the
      central nervous system, including the hypothalamus-pituitary axis, has been
      suggested for the etiology of obesity in these syndromes, the pathophysiologic
      pathways are as yet not well defined, and in many cases may identify currently
      unknown mechanisms. Nevertheless, many of the causative genes and unusual
      mechanisms, including parental imprinting of genes and complex patterns of
      inheritance, have been identified. We review the latest advances in understanding
      congenital syndromes in which obesity is purely genetic, drawing on comparisons
      to genetic studies of obesity in the human population as well as to those in
      experimental and agricultural animal models. An understanding of the genetic
      basis for these syndromes will provide a more comprehensive picture of the
      mechanisms that control food intake and energy balance in humans.

PMID- 15035976
TI  - Animal models of spontaneous autoimmune diabetes: notes on their relevance to the
      human disease.
AB  - The spontaneous autoimmune diabetes of the nonobese diabetic mouse and the
      BioBreeding diabetes-prone rat bears a striking similarity to human type 1
      diabetes. For this reason it comes as a disappointment that interventions known
      to prevent the disease in the animal models proved ineffective in human trials.
      For an explanation I propose that, although the mechanism of beta-cell
      destruction is the same in the three species, this common mechanism may be the
      end point of different loss-of-tolerance pathways in different human patients,
      only two of which are represented by the two animal models. Research strategies
      to address this problem will require more attention to immune subphenotypes or
      their corresponding subgenotypes in the human and, possibly, the generation of
      additional mouse models of spontaneous disease.

PMID- 15035978
TI  - Oncogenic mutations in B-Raf: some losses yield gains.
AB  - A study by Wan et al. in this issue of Cell demonstrates that the majority of
      oncogenic mutations in the B-Raf protein kinase result in increased catalytic
      activity, through disruption of the autoinhibited state of the kinase domain.
      Surprisingly, several mutations lead to impaired B-Raf kinase activity, yet these
      mutants are nevertheless capable of stimulating downstream signaling through
      transactivation of C-Raf.

PMID- 15035979
TI  - Obedient and wayward synaptic behavior.
AB  - Synapse formation is a complex process that culminates in the linking up and
      locking in of pre- and postsynaptic membranes. Shen at al. (2004 [this issue of
      Cell]) begin to dissect the molecular instructions that govern target selection
      of pre- and postsynaptic membrane interactions.

PMID- 15035980
TI  - Socializing with the neighbors: stem cells and their niche.
AB  - The potential of stem cells in regenerative medicine relies upon removing them
      from their natural habitat, propagating them in culture, and placing them into a
      foreign tissue environment. To do so, it is essential to understand how stem
      cells interact with their microenvironment, the so-called stem cell niche, to
      establish and maintain their properties. In this review, we examine adult stem
      cell niches and their impact on stem cell biology.

PMID- 15035981
TI  - A small modulatory dsRNA specifies the fate of adult neural stem cells.
AB  - Discovering the molecular mechanisms that regulate neuron-specific gene
      expression remains a central challenge for CNS research. Here, we report that
      small, noncoding double-stranded (ds) RNAs play a critical role in mediating
      neuronal differentiation. The sequence defined by this dsRNA is NRSE/RE1, which
      is recognized by NRSF/REST, known primarily as a negative transcriptional
      regulator that restricts neuronal gene expression to neurons. The NRSE dsRNA can
      trigger gene expression of neuron-specific genes through interaction with
      NRSF/REST transcriptional machinery, resulting in the transition from neural stem
      cells with neuron-specific genes silenced by NRSF/REST into cells with neuronal
      identity that can express neuronal genes. The mechanism of action appears to be
      mediated through a dsRNA/protein interaction, rather than through siRNA or miRNA.
      The discovery of small modulatory dsRNAs (smRNAs) extends the important
      contribution of noncoding RNAs as key regulators of cell behavior at both
      transcriptional and posttranscriptional levels.

PMID- 15035982
TI  - Imposition of crossover interference through the nonrandom distribution of
      synapsis initiation complexes.
AB  - Meiotic crossovers (COs) are nonrandomly distributed along chromosomes such that
      two COs seldom occur close together, a phenomenon known as CO interference. We
      have used genetic and cytological methods to investigate interference mechanisms
      in budding yeast. Assembly of the synaptonemal complex (SC) initiates at a few
      sites along each chromosome, triggered by a complex of proteins (including Zip2
      and Zip3) called the synapsis initiation complex (SIC). We found that SICs, like
      COs, display interference, supporting the hypothesis that COs occur at synapsis
      initiation sites. Unexpectedly, we found that SICs show interference in mutants
      in which CO interference is abolished; one explanation is that these same
      mutations eliminate the subset of COs that normally occur at SICs. Since SICs are
      assembled in advance of SC and they are properly positioned even in the absence
      of SC formation, these data clearly demonstrate an aspect of interference that is
      independent of synapsis.

PMID- 15035983
TI  - Structures of mismatch replication errors observed in a DNA polymerase.
AB  - Accurate DNA replication is essential for genomic stability. One mechanism by
      which high-fidelity DNA polymerases maintain replication accuracy involves
      stalling of the polymerase in response to covalent incorporation of mismatched
      base pairs, thereby favoring subsequent mismatch excision. Some polymerases
      retain a "short-term memory" of replication errors, responding to mismatches up
      to four base pairs in from the primer terminus. Here we a present a structural
      characterization of all 12 possible mismatches captured at the growing primer
      terminus in the active site of a polymerase. Our observations suggest four
      mechanisms that lead to mismatch-induced stalling of the polymerase. Furthermore,
      we have observed the effects of extending a mismatch up to six base pairs from
      the primer terminus and find that long-range distortions in the DNA transmit the
      presence of the mismatch back to the enzyme active site, suggesting the
      structural basis for the short-term memory of replication errors.

PMID- 15035984
TI  - The Drosophila SDE3 homolog armitage is required for oskar mRNA silencing and
      embryonic axis specification.
AB  - Polarization of the microtubule cytoskeleton during early oogenesis is required
      to specify the posterior of the Drosophila oocyte, which is essential for
      asymmetric mRNA localization during mid-oogenesis and for embryonic axis
      specification. The posterior determinant oskar mRNA is translationally silent
      until mid-oogenesis. We show that mutations in armitage and three components of
      the RNAi pathway disrupt oskar mRNA translational silencing, polarization of the
      microtubule cytoskeleton, and posterior localization of oskar mRNA. armitage
      encodes a homolog of SDE3, a presumptive RNA helicase involved in
      posttranscriptional gene silencing (RNAi) in Arabidopsis, and is required for
      RNAi in Drosophila ovaries. Armitage forms an asymmetric network associated with
      the polarized microtubule cytoskeleton and is concentrated with translationally
      silent oskar mRNA in the oocyte. We conclude that RNA silencing is essential for
      establishment of the cytoskeletal polarity that initiates embryonic axis
      specification and for translational control of oskar mRNA.

PMID- 15035985
TI  - RISC assembly defects in the Drosophila RNAi mutant armitage.
AB  - The putative RNA helicase, Armitage (Armi), is required to repress oskar
      translation in Drosophila oocytes; armi mutant females are sterile and armi
      mutations disrupt anteroposterior and dorsoventral patterning. Here, we show that
      armi is required for RNAi. armi mutant male germ cells fail to silence Stellate,
      a gene regulated endogenously by RNAi, and lysates from armi mutant ovaries are
      defective for RNAi in vitro. Native gel analysis of protein-siRNA complexes in
      wild-type and armi mutant ovary lysates suggests that armi mutants support early
      steps in the RNAi pathway but are defective in the production of active RNA
      induced silencing complex (RISC), which mediates target RNA destruction in RNAi.
      Our results suggest that armi is required for RISC maturation.

PMID- 15035986
TI  - Control of fruit patterning in Arabidopsis by INDEHISCENT.
AB  - The Arabidopsis seedpod opens through a spring-loaded mechanism known as pod
      shatter, which is essential for dispersal of the seeds. Here, we identify
      INDEHISCENT (IND), an atypical bHLH protein, that is necessary for fruit opening
      and is involved in patterning each of the three fruit cell types required for
      seed dispersal. Previous studies suggested that FRUITFULL (FUL), a member of the
      MADS-domain transcription factor family, is required for fruit growth since ful
      mutant fruit fail to undergo the dramatic enlargement that normally occurs after
      fertilization. Here we show, however, that FUL is not directly required for fruit
      elongation and instead is required to prevent ectopic activity of IND. Our
      molecular and genetic studies suggest a model for the regulatory interactions
      among the genes that control fruit development and the mechanism that results in
      the expression of IND in a narrow stripe of cells.

PMID- 15035987
TI  - Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations
      of B-RAF.
AB  - Over 30 mutations of the B-RAF gene associated with human cancers have been
      identified, the majority of which are located within the kinase domain. Here we
      show that of 22 B-RAF mutants analyzed, 18 have elevated kinase activity and
      signal to ERK in vivo. Surprisingly, three mutants have reduced kinase activity
      towards MEK in vitro but, by activating C-RAF in vivo, signal to ERK in cells.
      The structures of wild type and oncogenic V599EB-RAF kinase domains in complex
      with the RAF inhibitor BAY43-9006 show that the activation segment is held in an
      inactive conformation by association with the P loop. The clustering of most
      mutations to these two regions suggests that disruption of this interaction
      converts B-RAF into its active conformation. The high activity mutants signal to
      ERK by directly phosphorylating MEK, whereas the impaired activity mutants
      stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or
      transphosphorylation mechanism.

PMID- 15035990
TI  - Heterocyclic aromatic amines--still a challenge for scientists.

PMID- 15035989
TI  - Vascular development in the retina and inner ear: control by Norrin and Frizzled
      4, a high-affinity ligand-receptor pair.
AB  - Incomplete retinal vascularization occurs in both Norrie disease and familial
      exudative vitreoretinopathy (FEVR). Norrin, the protein product of the Norrie
      disease gene, is a secreted protein of unknown biochemical function. One form of
      FEVR is caused by defects in Frizzled-4 (Fz4), a presumptive Wnt receptor. We
      show here that Norrin and Fz4 function as a ligand-receptor pair based on (1) the
      similarity in vascular phenotypes caused by Norrin and Fz4 mutations in humans
      and mice, (2) the specificity and high affinity of Norrin-Fz4 binding, (3) the
      high efficiency with which Norrin induces Fz4- and Lrp-dependent activation of
      the classical Wnt pathway, and (4) the signaling defects displayed by disease
      associated variants of Norrin and Fz4. These data define a Norrin-Fz4 signaling
      system that plays a central role in vascular development in the eye and ear, and
      they indicate that ligands unrelated to Wnts can act through Fz receptors.

PMID- 15035991
TI  - Formation of heterocyclic aromatic amines in model systems.
AB  - Heterocyclic aromatic amines (HAs) are mutagenic and carcinogenic substances that
      are formed in significant amounts during heating of meat or fish at temperatures
      of at least 150 degrees C. To investigate the chemistry lying behind the
      formation of these harmful substances model systems were established. The first
      aim was to identify the naturally occurring precursors, namely creatinine, amino
      acids and carbohydrates. Later these model systems were used to develop
      strategies for a reduction of the content of the heterocyclic aromatic amines and
      for the evaluation of the reaction mechanisms that lead to the formation of these
      substances. All these aspects are discussed in this review.

PMID- 15035988
TI  - Synaptic specificity is generated by the synaptic guidepost protein SYG-2 and its
      receptor, SYG-1.
AB  - Synaptic connections in the nervous system are directed onto specific cellular
      and subcellular targets. Synaptic guidepost cells in the C. elegans vulval
      epithelium drive synapses from the HSNL motor neuron onto adjacent target neurons
      and muscles. Here, we show that the transmembrane immunoglobulin superfamily
      protein SYG-2 is a central component of the synaptic guidepost signal. SYG-2 is
      expressed transiently by primary vulval epithelial cells during synapse
      formation. SYG-2 binds SYG-1, the receptor on HSNL, and directs SYG-1
      accumulation and synapse formation to adjacent regions of HSNL. syg-1 and syg-2
      mutants have defects in synaptic specificity; the HSNL neuron forms fewer
      synapses onto its normal targets and forms ectopic synapses onto inappropriate
      targets. Misexpression of SYG-2 in secondary epithelial cells causes aberrant
      accumulation of SYG-1 and synaptic markers in HSNL adjacent to the SYG-2
      expressing cells. Our results indicate that local interactions between
      immunoglobulin superfamily proteins can determine specificity during synapse
      formation.

PMID- 15035992
TI  - Formation and stability of heterocyclic amines in a meat flavour model system.
      Effect of temperature, time and precursors.
AB  - A model system based on a commercial meat flavour was used to evaluate the
      formation of heterocyclic amines, simulating the application of this seasoning in
      household cooking. The effects of different treatments in both dry and aqueous
      conditions were studied. The lyophilized meat flavour extract was heated at
      temperatures ranging between 100 and 200 degrees C for times ranging from 10 min
      to 2 h. Similarly, an aqueous suspension of the extract was heated at 175 degrees
      C for 1, 2 and 3 h. Precursors of HAs, such as creatinine, glucose, and the amino
      acids glycine, alanine and phenylalanine were added to the meat extract and their
      effect was tested by heating the mixture at 200 degrees C for 30 min, when dry
      conditions were used, and at 175 degrees C for 2 h in wet systems. All conditions
      led to the formation of HAs, PhIP being the amine that was detected at the
      highest level of concentration in most model systems (i.e. 173 ng g(-1) at 200
      degrees C, 30 min). Moreover, the addition of creatinine and amino acids to the
      meat extract flavour produced an important increase in IQ and MeIQx content.

PMID- 15035994
TI  - Effects of heating time and antioxidants on the formation of heterocyclic amines
      in marinated foods.
AB  - The effect of heating time and antioxidants on the heterocyclic amine (HAs)
      formation in marinated foods were studied. Food samples were cooked at 98 +/- 2
      degrees C for 1, 2, 4, 8, 16 and 32 h in a closed pan in the presence of water,
      soy sauce and rock candy with or without antioxidants. The various HAs in
      marinated food samples and juice were analyzed by HPLC with photodiode-array
      detection. Results showed that the amount of HAs formed during heating followed
      an increased order for each increasing heating time. A larger variety and higher
      amount of HAs were generated in marinated pork when compared to marinated eggs
      and bean cake. In marinated juice, the levels of HAs were present in greater
      amount than in marinated foods. The incorporation of antioxidants Vitamin C,
      Vitamin E and BHT were found to be effective towards HAs inhibition, however, the
      effect was minor.

PMID- 15035993
TI  - Evaluation of a new model system for studying the formation of heterocyclic
      amines.
AB  - Heterocyclic amines (HAs) are an important class of food mutagens and
      carcinogens, which can be found in cooked meat and fish. Increasing heating
      temperatures and times usually increase mutagenic activity in meat and meat
      extracts during cooking. We developed a model system, which allows to examine the
      effects of precursor composition and heating conditions (time and temperature) on
      the formation of HAs in meat. Homogenized and freeze dried meat samples (beef,
      pork chops, chicken breast and turkey breast) are heated with diethylene glycol
      in closed vials under stirring in a thermostated heating block. After an
      appropriate sample preparation (extraction and clean-up) ten different HAs were
      measured by HPLC analyses with gradient elution and mass selective detection. The
      time courses of HA-formation in the different kinds of meat at varying heating
      temperatures were determined up to heating times of 30 min. 2-amino-1-methyl-6
      phenylimidazo[4,5-b]pyridine (PhIP) was the most abundant HA in these experiments
      and reached the highest concentrations in the beef meat samples, as did the other
      HAs (MeIQ, AalphaC) at 220 degrees C in the heating block under stirred
      conditions. Additionally the influence of the antioxidant TBHQ (t
      butylhydroquinone) on the formation of HAs in the model system was tested.
      However TBHQ effected only slight reductions of HA formation in all kinds of
      meat.

PMID- 15035995
TI  - Blue cotton, Blue Rayon and Blue Chitin in the analysis of heterocyclic aromatic
      amines--a review.
AB  - Heterocyclic amines (HCAs) are a group of compounds formed when protein-rich
      foods, such as meat or fish, are prepared under normal cooking conditions, such
      as frying, grilling, or broiling. To evaluate and estimate the risks associated
      with HCAs contained in the diet, it is important to determine the levels in
      cooked foods, and the levels of HCAs and metabolites in the body. HCAs are
      normally found at low amounts in a complex matrix, which necessitates a good
      purification method and a sensitive detection system. The objective of this
      review was to briefly present the current knowledge on the use of Blue Cotton,
      Blue Rayon and Blue Chitin in the analysis of HCAs.

PMID- 15035996
TI  - Evaluation of reversed-phase columns for the analysis of heterocyclic aromatic
      amines by liquid chromatography-electrospray mass spectrometry.
AB  - Liquid chromatography coupled to mass spectrometry (LC-MS), especially by the use
      of electrospray ionisation source (ESI), is currently used for the analysis of
      heterocyclic aromatic amines (HAs) in complex samples. The present paper
      describes the study of the performance of different narrow-bore reversed-phase
      columns to achieve the best chromatographic separation for the determination of
      16 HAs by LC-ESI-MS in food samples. Different parameters such as peak symmetry,
      resolution and number of theoretical plates have been evaluated for each column,
      using different chromatographic conditions. The column that provided the best
      results was TSK Gel Semi-Micro ODS-80TS of Tosohaas. Quality parameters have been
      established, obtaining good short-term precision in all cases (relative standard
      deviation (R.S.D.) lower than 7.7%) and low limits of detection (<13 pg injected
      in MS and <16 pg injected in MS/MS). The content of HAs in two beef extracts have
      been determined.

PMID- 15035997
TI  - Preparation of a beef-extract as a laboratory reference material for the
      determination of heterocyclic amines.
AB  - The present paper describes the preparation of a suitable laboratory reference
      material (LRM) to validate analytical methods for the determination of
      heterocyclic amines (HAs) in foods. Three different lots of reference material
      were prepared using a beef extract which was contaminated with a well-known
      quantity of amines at different levels ranging from 10 to 75 ng/g. These
      materials were then lyophilised under determined conditions and, after grinding
      and sieving, homogenised and, finally, bottled and labelled. Homogeneity and
      stability studies were performed and no statistical differences were observed in
      the analysis of variances for within- and between-bottle results, thus
      demonstrating the homogeneity of the material. Stability at different storage
      temperatures (-18, +4, +25 and +40 degrees C) and times (1, 2, 3 and 6 months)
      was also tested. Therefore, the material can be considered homogeneous and stable
      and can be proposed for use in inter-comparison exercises for the determination
      of HAs.

PMID- 15035998
TI  - Analysis of heterocyclic amines in food products: interlaboratory studies.
AB  - A feasibility study and two interlaboratory exercises on the determination of
      selected heterocyclic amines (HAs) in beef extract, organised in the framework of
      a European project, are presented. The aim of these exercises was to improve the
      quality of the laboratories and to evaluate the performance of a standardised
      analytical method and also the methods currently used by each of the participants
      for the analysis of these compounds. Three lyophilised portions of a commercial
      beef material previously spiked with HAs at different concentration levels
      ranging from 10 to 75 ng g(-1) were used as laboratory reference materials (lot
      A, B and C). Firstly, a feasibility study was carried out using a test standard
      solution and the beef extract (lot A), which contained only five HAs. Then, two
      interlaboratory exercises were carried out using the laboratory reference
      materials lot B and lot C, containing 10 selected HAs at two different
      concentration levels, 75 and 10 ng/g, respectively. The results obtained by all
      participant laboratories using the proposed method showed satisfactory agreement
      and the CV(%) between-laboratories obtained were from 8.3 to 24.1% for lot B and
      from 8.7 to 44.5% for lot C. The standardised method evaluated in these
      collaborative studies is therefore proposed for the analysis of HAs in food
      material. Moreover, LC-MS is recommended as the most suitable technique for the
      analysis of a large number of HAs in food samples.

PMID- 15035999
TI  - Occurrence of heterocyclic amines in several home-cooked meat dishes of the
      Spanish diet.
AB  - Heterocyclic amines (HAs) were determined in several of the most frequently eaten
      meat dishes in Spain such as fried beef hamburger, fried pork loin, fried chicken
      breast, fried pork sausages, griddled chicken breast, griddled lamb steak and
      griddled beef steak. All of the products tested were household cooked. The HAs
      were analysed in the selected meat dishes using an analytical method based on
      solid-phase extraction followed by liquid chromatography coupled to tandem mass
      spectrometry. DMIP, MeIQx, 4,8-DiMeIQx, Norharman, Harman, PhIP, Trp-P-1, AalphaC
      and MeAalphaC were the amines most frequently found at concentrations of up to 47
      ng g(-1) of cooked meat. Glu-P-2, IQ, MeIQ, Glu-P-1, 7,8-DiMeIQx and Trp-P-2 were
      only found in a few of the meat dishes and their concentrations were lower than 1
      ng g(-1) of cooked meat. The highest amounts of HAs, especially PhIP and DMIP,
      were formed in fried chicken breast and the lowest were formed in fried beef
      hamburger and in fried pork sausages. Daily intake of HAs in Spain was estimated
      at 606 ng of mutagenic HAs per capita and day, DMIP and PhIP being the main
      contributors.

PMID- 15036000
TI  - Determination of less polar heterocyclic aromatic amines in standardised beef
      extracts and cooked meat consumed in Austria by liquid chromatography and
      fluorescence detection.
AB  - An analysis method was developed for the determination of trace levels of less
      polar heterocyclic aromatic amines (HAs) in food samples. The development started
      from a frequently used sample pre-treatment scheme which was slightly improved to
      make it applicable with high-performance liquid chromatography (HPLC) with
      fluorescence detection. The method was applied for the analysis of a standardised
      beef extract containing 5-15 ng/g of HAs and the results are compared with those
      of the other participants in the same European project. In addition, the method
      was used for the analysis of less polar HAs in cooked meat consumed in Austria.

PMID- 15036001
TI  - Determination of heterocyclic aromatic amines (HAs) content in samples of
      household-prepared meat dishes.
AB  - Aminoazaarene content was investigated in 10 meat samples (including pork, beef,
      turey and chicken) thermally processed at home according to common recipes used
      by residents of Upper Silesia region in Poland. The clean-up procedure included
      tandem solid-phase extraction (SPE) using Extrelut-type columns filled with
      diatomaceous earth, propylsulphonic acid and chemically bounded phase-C18.
      Identification and quantitative analysis of HAs fraction was carried out using a
      HPLC system with DAD-type detector. Separation was achieved using TSK-gel ODS 80
      TM column and a mixture of 5% acetonitrile and 95% triethylamine phosphate buffer
      (pH 3.3) as a mobile phase. The results of qualitative determinations were
      confirmed by GC-MS method. To achieve this, HAs fractions were derivatized to
      pentafluoropropionic acid (PFPA) amide derivatives. The summary content of five
      aminoazaarenes determined in investigated meat samples, i.e. 2-amino-3
      methylimidazo [4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5
      f]quinoxaline (MeIQx), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2
      amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), 2-amino-1-methyl-6
      phenyl-imidazo[4,5-b]pyridine (PhIP) falls within the range of 1.9-77.4 ng/g of
      sample. The calculated values of theoretically daily human exposure to five
      determined HAs were in the range of 0.2-7.7 microg per day per person.

PMID- 15036002
TI  - Determination of heterocyclic aromatic amines in beef extract, cooked meat and
      rat urine by liquid chromatography with coulometric electrode array detection.
AB  - This paper describes a method for the determination of heterocyclic aromatic
      amines (HAs; DMIP, IQ, MeIQ, MeIQx, 4,8-DiMeIQx, 7,8-DiMeIQx, AalphaC, PhIP) by
      high-performance liquid chromatography (HPLC) with coulometric electrode array
      detection. The compounds are separated on reversed phase columns (LiChroCart
      Superspher 60 RP-select B, 250 mm x 2 mm, 4 microm and LiChrospher 60 RP-select
      B, 250 mm x 4 mm, 5 microm) using mobile phases consisting of
      acetonitrile/buffer/distilled water and detected at eight working electrodes at
      potentials between +190 and +680 mV against modified palladium electrodes. In the
      context of an EU-interlaboratory exercise, the method was applied to analyse a
      standardised test solution and--after isolation of the analytes by several clean
      up steps--for the analysis of standardised beef extract and grilled meat.
      Further, the method could be applied for the analysis of HAs in suspensions of
      bacteria and rat urine without any sample preparation step beyond sample
      dilution. The data obtained show that HPLC with coulometric electrode array
      detection gives accurate results.

PMID- 15036003
TI  - Exposure to beta-carbolines norharman and harman.
AB  - The aromatic beta-carbolines norharman and harman have been implicated in a
      number of human diseases including Parkinson's disease, tremor, addiction and
      cancer. It has been shown that these compounds are normal body constituents
      formed endogenously but external sources have been identified. Here, we summarise
      literature data on levels of norharman and harman in fried meat and fish, meat
      extracts, alcoholic drinks, and coffee brews. Other sources include edible and
      medicinal plants but tobacco smoke has been identified as a major source.
      Exposure levels from these different dietary sources are estimated to a maximum
      of 4 microg norharman per kg body weight (bw) per day and 1 microg harman per kg
      bw per day. Exposure via tobacco smoke depends on smoking habits and type of
      cigarettes but can be estimated to 1.1 microg/kg bw for norharman and 0.6
      microg/kg bw for harman per package of cigarettes smoked. Studies on
      toxicokinetics indicate that inhalative exposure leads to a rapid increase in
      plasma levels and high bioavailability of norharman and harman. Oral
      bioavailability is lower but there are indications that sublingual absorption may
      increase dietary uptake of beta-carbolines. Endogenous formation can be estimated
      to be 50-100 ng/kg bw per day for norharman and about 20 ng/kg bw per day for
      harman but these rates may increase with high intake of precursors. Biomarker
      studies on plasma levels of beta-carbolines reported on elevated levels of
      norharman, harman or both in diseased patients, alcoholics and following tobacco
      smoking or consumption of beta-carboline-containing food. Cigarette smoking has
      been identified as major influence but dietary exposure may contribute to
      exposure.

PMID- 15036004
TI  - Estimates of heterocyclic amine intake in the US population.
AB  - HA-specific meat concentration estimates using a method that combines laboratory
      data to predict HA concentrations from meat type, cooking method and meat
      doneness were used with national dietary data to estimate daily HA intake for
      segments of the US population. PhIP was found to comprise approximately 70% of US
      mean dietary intake of total HAs, with pan-frying and chicken being the single
      cooking method and meat type contributing the greatest to total estimated HA
      exposures. This analysis demonstrated significantly higher concentrations in
      grilled/barbecued meats than in other cooked meats. African-American males were
      estimated to consume nearly twofold and approximately 35 to 40% more PhIP (and
      total HAs) than white males at ages <16 and >30 years, respectively.

PMID- 15036005
TI  - Mutagens formed from beta-carbolines with aromatic amines.
AB  - Norharman, widely distributed in our environment such as cigarette smoke and
      cooked foods, is not mutagenic to Salmonella strains, but becomes mutagenic to
      Salmonella typhimurium TA98 and YG1024 with S9 mix in the presence of aromatic
      amines, including aniline and o-toluidine. Therefore, we have designated
      norharman as a "co-mutagen". Since, humans are simultaneously exposed to
      norharman and aromatic amines in daily life, it is important to clarify the
      mechanisms of its co-mutagenic action to further understanding of the potential
      genotoxic effects in humans. Regarding the mechanisms of this action of norharman
      with aniline, a mutagenic compound, 9-(4'-aminophenyl)-9H-pyrido[3,4
      b]indole[aminophenylnorharman (APNH)] is produced by their interaction, and
      converted to the hydroxyamino derivative which eventually forms the DNA adduct,
      dG-C8-APNH through possible ultimate reactive forms with esterification, and this
      induces mutations. Also other aminophenyl-beta-carboline compounds, such as 9-(4'
      amino-3'-methylphenyl)-9H-pyrido[3,4-b]indole[amino-3'-methylphenylnorharman (3'
      AMPNH)], 9-(4'-amino-2'-methylphenyl)-9H-pyrido[3,4-b]indole [amino-2'
      methylphenylnorharman (2'-AMPNH)], 9-(4'-aminophenyl)-1-methyl-9H-pyrido[3,4
      b]indole[aminophenylharman (APH)] and 9-(4'-amino-3'-methylphenyl)-1-methyl-9H
      pyrido[3,4-b]indole[amino-3'-methylphenylharman (AMPH)], have been found on
      reaction of norharman or harman with aniline or toluidine isomers. These
      compounds showed mutagenic and clastogenic actions in bacterial and mammalian
      cells. Among them, APNH demonstrated the most potent activity, and it was most
      extensively studied. When APNH was administered as a single dose to F344 rats,
      severe testicular toxicity was observed after 6 days. Moreover, liver
      preneoplastic lesions (GST-P-positive foci) in the liver clearly developed in
      animals fed 10-50 ppm of APNH in the diet for 4 weeks. Since, APNH was detected
      in 24 h urine of rats upon simultaneous administration with norharman and aniline
      by gavage, it is likely to be also produced from norharman and aniline in the
      human body. From these findings, it is suggested that aminophenyl-beta-carboline
      derivatives may be classified as one of the novel types of endogenous mutagens
      and carcinogens.

PMID- 15036006
TI  - PhIP metabolites in human urine after consumption of well-cooked chicken.
AB  - We devised an assay to quantify the metabolites of 2-amino-1-methyl-6
      phenylimidazo[4,5-b]pyridine (PhIP) in human urine following a single exposure to
      well-cooked meat. Our method uses LC/MS/MS to detect four metabolites and four
      deuterated internal standard peaks in a single chromatographic run. N2-OH-PhIP-N2
      glucuronide was the most abundant urinary metabolite excreted by the 12
      individuals who participated in our study. N2-PhIP glucuronide was the second
      most abundant metabolite for 8 of the 12 volunteers. The stability of PhIP
      metabolism over time was studied in three of the volunteers who repeated the
      assay eight times over a 2.5 year-period. PhIP metabolite excretion varied in
      each subject over time, although the rate of excretion was more constant. Our
      results suggest that quantifying PhIP metabolites should make future studies of
      individual susceptibility and dietary interventions possible.

PMID- 15036007
TI  - Formation and analysis of heterocyclic aromatic amine-DNA adducts in vitro and in
      vivo.
AB  - The detection and quantification of heterocyclic aromatic amine (HAA)-DNA
      adducts, critical biomarkers in interspecies extrapolation of toxicity data for
      human risk assessment, remains a challenging analytical problem. The two main
      analytical methods currently in use to screen for HAA-DNA adducts are the 32P
      postlabeling assay and mass spectrometry, using either accelerated mass
      spectrometry (AMS) or liquid chromatography and electrospray ionization mass
      spectrometry (LC-ESI-MS). In this review, the principal methods to synthesize and
      characterize DNA adducts, and the methods applied to measure HAA-DNA adduct in
      vitro and vivo are discussed.

PMID- 15036008
TI  - Investigation of the genotoxic effects of 2-amino-9H-pyrido[2,3-b]indole in
      different organs of rodents and in human derived cells.
AB  - Aim of the present study was the investigation of the genotoxicity of amino-alpha
      carboline (AalphaC) in human derived cells and of its organ-specific effects in
      laboratory rodents. This heterocyclic amine (HA) is contained in fried meat and
      fish in higher concentrations than most other cooked food mutagens. In the
      present experiments, AalphaC caused dose-dependent induction of micronuclei in
      the human derived hepatoma cell line HepG2 at concentrations > or =50 microM. In
      contrast, no significant effects were seen in Hep3B, another human hepatoma cell
      line, which may be explained by the concurrent lower activity of sulfotransferase
      (SULT), an enzyme playing a key role in the activation of AalphaC. A positive
      result was also obtained in the single cell gel electrophoresis (SCGE) assay in
      peripheral human lymphocytes, but the effect was only significant at the highest
      concentration (1000 microM). In Fischer F344 rats and ICR mice, the liver was the
      main target organ for the formation of DNA adducts (at > or =50 mg/kg bw), and in
      lungs and colon substantially lower levels were detected. Identical organ
      specificity as in the DNA adduct measurements was seen in SCGE assays with rats,
      whereas in mice the most pronounced induction of DNA migration was observed in
      the colon. Comparison of our results with data from earlier experiments indicate
      that the genotoxic potency of AalphaC is equal to that of other HAs, which are
      contained in human foods in much smaller amounts. Therefore, our findings can be
      taken as an indication that the human health risk caused by exposure to AalphaC
      is higher than that of other HAs that are formed during the cooking of meat and
      fish.

PMID- 15036009
TI  - Enzyme polymorphisms influencing the metabolism of heterocyclic aromatic amines.
AB  - Heterocyclic aromatic amines are dietary carcinogens possibly involved in human
      carcinogenesis, DNA-adduct formation being an obligatory step in this multistage
      process. Heterocyclic amine binding to DNA largely depends on the balance between
      metabolic activation and detoxification pathways and DNA repair efficiency.
      Several genes coding for metabolic enzymes are polymorphic, which affects gene
      expression and/or enzyme activity. This paper briefly reviews the effect of
      polymorphisms of activating/detoxifying enzymes on the metabolism of heterocyclic
      amines. Despite some epidemiological evidence of an association between genetic
      polymorphisms and susceptibility to cancer possibly resulting from dietary
      exposure to heterocyclic aromatic amines (HA), the genetic polymorphisms had only
      slight effects on biomarker levels, suggesting the existence of further unknown
      factors.

PMID- 15036010
TI  - Role of p53 and mismatch repair in PhIP-induced perturbations of the cell cycle.
AB  - Heterocyclic amines, found ubiquitously in our diet, are carcinogenic and
      mutagenic. Among this class of compounds, 2-amino-1-methyl-6-phenylimidazo [4,5
      b]pyridine (PhIP) is the most abundant. To further understand the carcinogenesis
      of this compound, we studied the effects of PhIP on the progression of human
      lymphoblastoid cells through the cell-cycle. Cells differing in p53 or mismatch
      repair status were used to evaluate the role of those proteins. Following PhIP
      treatment, a dose and time-dependent accumulation of p53 was found in cells
      containing functional p53. The augmentation of the p53 protein, accompanied by
      increases in p21-WAF1, confirms that the p53 is activated. The increase in p53
      was independent of the mismatch repair status of the cells. Perturbations in the
      cell-cycle were also observed. Twenty-four hours after PhIP treatment, the
      activation of the G2-M checkpoint was evident. Functional p53 and mismatch repair
      were not required for the PhIP-induced G2-M arrest. The G2-M arrests were
      reversible and are interpreted as necessary for the repair of the PhIP-DNA
      lesions. Under treatment conditions where less than 5% of the cells survived, the
      G2-M arrests were absent.

PMID- 15036011
TI  - Use of antioxidants to minimize the human health risk associated to
      mutagenic/carcinogenic heterocyclic amines in food.
AB  - Heterocyclic amines (HAs) are mutagenic/carcinogenic compounds formed in meat
      during cooking. Several efforts have been made to minimize the risk associated to
      HA human exposure. Supplementation with antioxidants is considered a promising
      measure to reduce HA exposure because of their ability as inhibitors of HA
      formation or as blocking/suppressing agents on HA biotransformation/metabolism.
      The aim of this review is to present the current knowledge on the capability of
      synthetic and natural antioxidants to modulate HA-induced
      mutagenicity/carcinogenicity. Data show a general trend towards a reduction of HA
      formation both in model systems and in real foods as well as an effective
      modulation of biotransformation and metabolism. Phenolic compounds, particularly
      those from tea and olive oil, seem to be the most effective, although a great
      variability is observed because of the concentration-dependent pro- and
      antioxidant effects.

PMID- 15036012
TI  - Mechanisms by which resistant starches and non-starch polysaccharide sources
      affect the metabolism and disposition of the food carcinogen, 2-amino-3
      methylimidazo[4,5-f]quinoline.
AB  - Although both non-starch polysaccharides (NSP) and resistant starches (RS) are
      included in current definitions of dietary fibre, our previous work has suggested
      fundamental differences in the way in which these two classes of material affect
      the disposition and absorption of a dietary carcinogen. The present studies
      explore whether different effects on carcinogen metabolism could play a role in
      the contrasting patterns seen previously. Groups of female Wistar rats were pre
      fed for 4 weeks one of five types of defined diet (AIN-76). The control diet
      contained 35% maize starch and no dietary fibre. The RS-containing diets had all
      the maize starch substituted with either Hi-maize or potato starch. In the NSP
      containing diets, 10% of the maize starch was substituted with dietary fibre in
      the form of either lignified plant cell walls (wheat straw) or soluble dietary
      fibre (apple pectin). Pre-fed rats were gavaged with the food carcinogen, [2-14C]
      2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and plasma and urinary metabolites
      characterized using HPLC at various time intervals after administration. After 4
      h gavage, plasma from rats on both RS-containing diets contained significantly
      higher levels of intact IQ and lower levels of the major metabolites, IQ-5-O
      glucuronide and IQ-5-sulfate, as compared with plasma from the negative control
      group at this time. In contrast, plasma from animals on the NSP-containing wheat
      straw diet (and to a lesser extent the apple pectin diet) showed significantly
      lower levels of intact IQ, and significantly higher levels of the two major
      metabolites, as compared with those from the control rats. These different
      metabolite profiles were also reflected in different urinary excretion profiles.
      Urine from rats pre-fed RS-containing diets revealed significantly slower
      metabolite excretion as compared with urine from rats that had been given the NSP
      containing diets. Western blotting methodologies also profiled differences
      between the effects of these two types of dietary fibre in the expression of
      xenobiotic metabolizing enzymes. We conclude that changes in activity and
      expression of xenobiotic metabolising enzymes could play a role in the
      contrasting effects of these two types of dietary fibre on carcinogen uptake and
      disposition.

PMID- 15036013
TI  - Effect of intestinal microfloras from vegetarians and meat eaters on the
      genotoxicity of 2-amino-3-methylimidazo[4,5-f]quinoline, a carcinogenic
      heterocyclic amine.
AB  - Aim of this study was to investigate the impact of intestinal microfloras from
      vegetarians and non-vegetarians on the DNA-damaging activity of 2-amino-3-methyl
      3H-imidazo[4,5-f]quinoline (IQ), a carcinogenic heterocyclic amine that is found
      in fried meats. Floras from four vegetarians (Seventh Day Adventists) and from
      four individuals who consumed high amounts of meats were collected and inoculated
      into germfree F344 rats. The rats were kept on isocaloric diets that either
      contained animal derived protein and fat (meat consumers group) or proteins and
      fat of plant origin (vegetarian groups). IQ (90 mg/kg bw) was administered
      orally, after 4 h the extent of DNA-damage in colon and liver cells was
      determined in single cell gel electrophoresis assays. In all groups, the IQ
      induced DNA-migration was in the liver substantially higher than in the colon. In
      animals harbouring floras of vegetarians, the extent of damage was in both organs
      significantly (69.2% in the liver, P<0.016 and 64.7%, P<0.042 in the colon,
      respectively) lower than in the meat consumer groups. Our findings show that diet
      related differences in the microfloras have a strong impact on the genotoxic
      effects of IQ and suggest that heterocyclic amines are less genotoxic and
      carcinogenic in individuals that consume mainly plant derived foods.

PMID- 15036014
TI  - Phytoalexin resveratrol attenuates the mutagenicity of the heterocyclic amines 2
      amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5
      f]quinoxaline.
AB  - Resveratrol is a phytoalexin, that belongs to a family of naturally occurring
      stilbenes. It has been reported that resveratrol can inhibit chemical
      carcinogenesis in experimental animals and although the mechanisms involved are
      unknown, an anti-mutagen mechanism has been proposed. We have explored this
      hypothesis using mutagenicity assays based on bacterial (Salmonella typhimurium)
      and eukaryotic cells (Chinese hamster V79 cells). We found resveratrol to be
      potent in both systems, blocking the mutagenicity of the food-derived
      heterocyclic amines (HA) 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)
      and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) at micromolar
      concentrations. Furthermore, in cells capable of activating 2-amino-1-methyl-6
      phenylimidazo[4,5-b]pyridine to cytotoxic derivatives, resveratrol was able to
      attenuate cytotoxicity. Paradoxically, in cells lacking the ability to activate
      PhIP, resveratrol itself was toxic and co-incubation with PhIP reduced this
      toxicity. Our data confirm the potent anti-mutagenic activity of resveratrol and
      support its potential as a chemopreventative.

PMID- 15036015
TI  - Effect of common Brassica vegetables (Brussels sprouts and red cabbage) on the
      development of preneoplastic lesions induced by 2-amino-3-methylimidazo[4,5
      f]quinoline (IQ) in liver and colon of Fischer 344 rats.
AB  - Aim of the present study was the investigation of effects of juices from commonly
      consumed Brassica vegetables (two cultivars of Brussels sprouts and two cultivars
      of red cabbage) on formation and development of preneoplastic lesions in colons
      (aberrant crypt foci, ACF) and livers (glutathione-S-transferase placental form,
      GST-P+) in male F344 rats. The foci were induced by 2-amino-3-methylimidazo[4,5
      f]quinoline (IQ), a widespread carcinogenic heterocyclic aromatic amine which is
      found in fried meats. Recently, we reported on pronounced protective effects in
      the two-organ foci model when the vegetable juices were given during the
      carcinogen treatment but several findings by other groups indicated that
      breakdown products of glucosinolates contained in Brassica vegetables cause
      tumour promotion in various organs of laboratory rodents. In the present study,
      the animals received the juices in the drinking water (5%) over a period of 20
      days after treatment with IQ (100 mg/kg bw on 10 alternate days). To increase the
      foci yield (which facilitates the detection of modifying effects), the animals
      were fed with a modified (high fat, fibre free) AIN-76 diet. With exception of
      the sprout variety "Cyrus", all juices lowered the number of GST-P+ foci as well
      as the foci area in the liver, but none of these effects was statistically
      significant. In the colon, none of the juices had an impact on crypt multiplicity
      (number of crypts/focus), whereas the number of ACF was decreased; only with the
      sprout variety Maximus the protective effect was significant (reduction 49%). The
      present findings show that administration of vegetable juices to the animals
      after the carcinogen does not increase the number and size of IQ-induced
      preneoplastic lesions in liver and colon.

PMID- 15036017
TI  - Role of echocardiography in acute coronary syndromes.

PMID- 15036016
TI  - Protective effects of Brussels sprouts, oligosaccharides and fermented milk
      towards 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced genotoxicity in the
      human flora associated F344 rat: role of xenobiotic metabolising enzymes and
      intestinal microflora.
AB  - We investigated the chemoprotective effects of four common constituents of the
      human diet, i.e. a fermented milk, inulin, oligofructose and Brussels sprouts,
      towards 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced genotoxicity in male
      Fischer 344 rats harbouring a human intestinal microflora. We found that the four
      dietary components significantly reduced IQ-induced DNA damage in hepatocytes
      (reduction ranged from 74% with inulin to 39% with Brussels sprouts) and
      colonocytes (reduction ranged from 68% with inulin to 56% with Brussels sprouts).
      This chemoprotective effect correlated with the induction of hepatic UDP
      glucuronosyl transferase following Brussels sprouts consumption, and with
      alterations of bacterial metabolism in the distal gut (acidification, increase of
      butyrate proportion, decrease of beta-glucuronidase activity) following inulin
      consumption.

PMID- 15036018
TI  - Right ventricular function: the comeback of echocardiography?

PMID- 15036019
TI  - RE: Harmonic vs fundamental echocardiography for the estimation of left
      ventricular mass.

PMID- 15036021
TI  - Enhanced visualisation of the right ventricle by contrast echocardiography in
      congenital heart disease.
AB  - BACKGROUND: Contrast echocardiography improves endocardial border detection of
      the left ventricle. Whether this is also true for the right ventricle (RV) is
      unknown. The aim of this study is to assess whether the use of contrast (Sonovue)
      echocardiography has additional value in RV endocardial border visualisation
      (EBV), and whether it has impact on the echocardiographic judgement of RV
      function. METHODS: Twenty adult patients with congenital heart disease were
      imaged using second harmonic two-dimensional echocardiography with and without
      contrast. Two independent observers analysed EBV of 13 RV wall segments in each
      patient. EBV was graded for each wall segment from 0 to 3 ( 0 = not visible, 3 =
      optimal visible). RESULTS: EBV improved in all patients with contrast
      echocardiography compared to second harmonic imaging (mean EBV 1.00 +/- 0.77 with
      second harmonics, 2.13 +/- 0.75 with contrast, P < 0.0001). The benefit was most
      evident in the near-field images. In 55% of the patients visual estimation of RV
      function changed with contrast echocardiography. CONCLUSION: The use of contrast
      echocardiography is superior to second harmonic imaging for RV EBV. Improved EBV
      may allow more accurate assessment of RV dimensions and function.

PMID- 15036022
TI  - Usefulness of Blalock-Taussig shunt Doppler flow velocity profiles in the
      assessment of pulmonary artery pressure and flow.
AB  - AIM: To assess the utility of continuous wave Doppler evaluation of velocity
      profiles across a Blalock-Taussig (BT) shunt in the evaluation of pulmonary
      artery pressure and pulmonary blood flow. METHODS AND RESULTS: Eleven children
      with complex congenital heart disease with a BT shunt as the sole source of
      pulmonary blood supply were studied prospectively (median age 5 (0.3-21) months).
      Doppler evaluations of shunt flow velocity profile and cardiac catheterization
      were carried out simultaneously. Pulmonary artery pressure and flow were
      estimated using the modified Bernoulli equation and velocity time integral of
      shunt flow. There was a positive correlation between (1) the Doppler estimates
      for mean pulmonary artery pressure, using the diastolic flow velocity, and the
      mean pulmonary venous wedge pressure ( r = 0.93, SEE = 1.0 mmHG; P<0.001 ) and
      (2) the Doppler derived and calculated pulmonary blood flow ( r = 0.9, SEE = 0.19
      l/min; P<0.001). In contrast, the Doppler estimates for mean pulmonary artery
      pressure using the peak or mean Doppler gradients were poor. CONCLUSION: The
      diastolic BT shunt flow velocity can be used reliably to predict mean pulmonary
      artery pressure when a BT shunt is the sole source of pulmonary artery flow.
      There was agreement between Doppler predicted pulmonary blood flow and catheter
      based calculations. These findings may prove a useful tool for perioperative
      management.

PMID- 15036023
TI  - Contrast harmonic imaging improves the evaluation of left ventricular function in
      ventilated patients: comparison with transesophageal echocardiography.
AB  - AIMS: The study examined the value of contrast echocardiography (CE) in the
      assessment of left ventricular (LV) wall motion in ventilated patients in
      comparison with transesophageal (TOE) and standard fundamental transthoracic
      imaging (SE). METHODS: Transthoracic echocardiograms were done in 40 ventilated
      patients. Wall motion was evaluated using the recommendations of the American
      Society of Echocardiography on SE, CE and TOE. A visualization score was assigned
      on a scale of 2-0 for each of 16 segments. The segment was assigned a value of 2
      if the segment was seen in both systole and diastole, 1 if seen only in systole
      or diastole, and 0 if not seen at all. A confidence score was also given for each
      segment with each technique (unable to evaluate; not sure; sure). The ejection
      fraction (EF) was estimated visually for each technique, and a confidence score
      was also applied to the EF. RESULTS: Visualization score 0 was present in 6.2
      segments/patient on SE, 1.2 on CE (P<0.0001) and 1.1 on TOE (P<0.0001). An
      average of 6.5 segments were read with surety on SE, 11.5 on CE (P<0.0001) and
      12.3 on TOE ( P<0.0001 ). There was no significant difference for CE vs TOE. EF
      was uninterpretable in 32% on SE, 0% on CE (P<0.001 and 0% on TOE (P<0.001). The
      EF was read with surety in 53% of patients on SE, 88% on CE (P < 0.0001) and 93%
      with TOE (P<0.0001) with no difference for CE vs TOE. Thus, wall motion was seen
      with more confidence on CE and TOE. CONCLUSIONS: In the ventilated patients with
      suboptimal transthoracic echocardiograms for the evaluation of the LV function,
      CE provides image quality of regional and global LV function similar to that
      achieved with TOE echocardiography.

PMID- 15036025
TI  - Myocardial contrast echocardiography demonstrates myocardial hypoperfusion in the
      LAD territory in patients with acute chest pain at rest--a prospective study
      using power Doppler harmonic imaging with intravenous bolus application.
AB  - AIMS: Using a previously published algorithm we hypothesize that myocardial
      contrast echocardiography (MCE) with power Doppler harmonic imaging (PDHI) is
      able to detect regional hypoperfusion within the territory of the left anterior
      descending artery (LAD) using intravenous (i.v.) injection of contrast in
      patients (pts) with coronary syndrome at rest. METHODS AND RESULTS: Forty-seven
      consecutive patients (pts) were prospectively evaluated using a standardized i.v.
      bolus application of OPTISON. MCE data were acquired within 2 h before
      angiography. Cut-off Doppler intensity (DI)-values determined in the apical, mid,
      and basal septum were distinguished between normal and hypoperfused myocardium
      (e.g. 23.5 and 22.5 dB for maximum DI of the apical or mid-septum triggering on
      every third heart cycle). Seventeen of 42 pts were classified as normal and the
      remaining 25 pts as pathologic (10 of these 25 pts had elevated troponines).
      Angiography detected open vessels or TIMI-III-flow in 15 pts of the normal MCE
      group, significant stenosis (>70%) or reduced TIMI-flow in 22 pts of the
      pathologic MCE group. The highest sensitivities (83-92%) were found in the apical
      septum. CONCLUSION: Assessment of the myocardial perfusion deficits in the LAD
      territory of pts with acute coronary syndrome is feasible with MCE with PDHI
      using an i.v. bolus protocol.

PMID- 15036024
TI  - Right ventricular myocardial activation delay in adult patients with right bundle
      branch block late after repair of Tetralogy of Fallot.
AB  - Electromechanical interaction, with prolonged QRS duration due to right
      ventricular (RV) overload, has been described as a predictor of unfavorable
      outcome in patients late after correction of Tetralogy of Fallot (TOF). Aim of
      our study was to evaluate myocardial function and activation delay of both left
      and right ventricles in TOF patients. Doppler echo, treadmill test and pulsed
      Tissue Doppler (TD) were performed in 25 healthy subjects and in 30 adult
      patients who had undergone surgery for TOF, all with right bundle branch block on
      ECG. Exclusion criteria were evidence of residual pulmonary either stenosis or
      regurgitation. By use of TD, the level of both LV mitral and RV tricuspid annulus
      were measured: systolic (Sm), early- and late-diastolic (Em and Am) regional peak
      velocities. The indexes of myocardial systolic activation were calculated:
      precontraction time (PCTm) and interventricular activation delay (InterV-del)
      (difference of PCTm between RV and LV segments). The two groups were comparable
      for LV diameters and for Doppler indexes, while QRS duration was prolonged and RV
      end-diastolic diameter was increased in TOF. By TD analysis, only at the level of
      tricuspid annulus TOF patients had lower Sm and Em, and increased RV PCTm (
      p<0.001 ) and InterV-del ( p<0.0001 ), even after adjustment for heart rate (HR)
      and QRS duration. By treadmill test, TOF showed reduced cardiac functional
      reserve. In seven patients non-sustained ventricular tachycardia was documented
      during physical effort. By multivariate analysis, RV Em ( p<0.001 ), and InterV
      del ( p<0.01 ) were independently associated to maximal workload at peak effort.
      The same InterV-del was an independent determinant of risk of ventricular
      arrhythmias during effort ( p<0.01 ). A cut-off point of Em peak velocity of
      tricuspid annulus <0.13 m/s at rest showed a sensitivity of 91% and a specificity
      of 88% in identifying TOF patients with submaximal exercise test. A cut-off point
      of InterV-del >55 ms showed 87% sensitivity and 88% specificity to detect
      increased risk of ventricular arrhythmias during effort. In TOF patients, TD
      analysis at rest may be taken into account as a non-invasive and easy-repeatable
      tool to predict cardiac performance during physical effort, and to select
      subgroups of patients at increased risk of ventricular arrhythmias.

PMID- 15036027
TI  - The incremental value of myocardial contrast echocardiography (MCE) as a bedside
      decision-making tool in the coronary care unit.

PMID- 15036026
TI  - Wall thickening assessment with tissue harmonic echocardiography results in
      improved risk stratification for patients with non-ST-segment elevation acute
      chest pain.
AB  - OBJECTIVES: To demonstrate whether the improved imaging quality gained by using
      tissue harmonic echocardiography in place of fundamental echocardiography results
      in the improved risk stratification of patients presenting with non-ST-elevation
      acute chest pain. METHODS AND RESULTS: Eighty patients with over 30 min of non-ST
      elevation chest pain that had lasted less than 6 h were recruited. All patients
      underwent resting tissue harmonic and fundamental echocardiographic scans.
      Diagnosis for acute myocardial infarction was made on a 24 h creatine kinase-MB
      sample. Echocardiographic images were reported by two experienced blinded
      observers. Patients were followed up at least 4 months after admission. Endpoints
      included all-cause mortality, non-fatal myocardial infarction and
      revascularisation procedures. Tissue harmonic echocardiography allowed assessment
      of all myocardial segments in all patients compared to 43/78 patients ( p<0.001 )
      with fundamental echocardiography. A wall thickening abnormality demonstrated on
      tissue harmonic echocardiography and not fundamental echocardiography was a
      significant predictor of index myocardial infarction on admission ( p<0.007 ) and
      for an adverse cardiac event during follow up ( p=0.002 ). CONCLUSIONS: Tissue
      harmonic echocardiography is superior to fundamental echocardiography for
      accurate assessment of systolic wall thickening and hence risk stratification for
      patients presenting with acute chest pain and non-diagnostic electrocardiogram
      changes.

PMID- 15036028
TI  - Native aortic valve vegetative endocarditis with Cunninghamella.
AB  - Cunninghamella bertholletiae is a rare Mucor species that is seldom the cause for
      endocarditis of prosthetic heart valves. It is even a more uncommon cause of
      endocarditis of native heart valves. We present a case of Cunninghamella
      endocarditis of a native aortic valve in an immuno-compromised patient, diagnosed
      from tissue culture obtained at the time of surgery. There have only been two
      other reported cases of native valve endocarditis with a Mucor species, and in
      those cases, the diagnoses were made post-mortem.

PMID- 15036029
TI  - Africanized honeybees have unique tolerance to Varroa mites.

PMID- 15036030
TI  - Free-living endohelminths: the influence of multiple factors.

PMID- 15036032
TI  - Antigenic variation in African trypanosomes: monitoring progress.
AB  - Antigenic variation is central to the success of African trypanosomes and other
      eukaryotic, bacterial and viral pathogens. Our understanding of the control and
      execution of this immune evasion strategy in trypanosomes is incomplete, despite
      the molecular basis of antigenic variation being first described over 20 years
      ago. Recent research progress in this field is highlighted here and some of the
      unresolved questions raised.

PMID- 15036033
TI  - Plasmodium falciparum and the permeation pathway of the host red blood cell.
AB  - Invasion of red blood cells by malaria parasites leads to a huge increase in
      solute traffic across the membrane of a normally tight cell. Recent
      electrophysiological investigations strongly support earlier evidence from
      transport and pharmacological studies that the permeability pathway, which the
      parasite induces in the host cell membrane, is an anion-selective channel. This
      article analyzes the evidence and controversies concerning the nature of this
      channel, surveys the main open questions and suggests directions for future
      research in this area.

PMID- 15036034
TI  - Alternatively activated macrophages during parasite infections.
AB  - Depending on the cytokine environment, macrophages can differentiate into
      distinct subsets that perform specific immunological roles. In this regard, the
      functions of macrophages activated by interferon gamma, referred to as
      classically activated macrophages, have been extensively documented, particularly
      during immune responses to infection. Recently, it was recognized that
      macrophages exposed to cytokines generated by T helper cell type 2 (Th2) cells
      exert an alternative activation program. However, the nature and functions of
      alternatively activated macrophages are ill defined. Evidence for the presence of
      alternatively activated macrophages and their possible influence in the outcome
      of several parasite diseases are discussed here.

PMID- 15036035
TI  - Getting to the roots of parasitism by nematodes.
AB  - Most phytoparasitic nematodes infect plant roots and some species have evolved
      sophisticated interactive relationships with host cells to sustain a sedentary
      parasitic habit. The recent isolation of multiple 'parasitism genes' expressed
      specifically within the esophageal gland cells of sedentary phytonematodes
      suggests that an arsenal of different secreted parasitism proteins from the
      nematode might have direct effects on recipient host cells. These include cell
      wall modifications and potential interactions with signal transduction receptors
      in the extracellular space, as well as direct introduction of proteins into host
      cells that might influence cellular metabolism, the cell cycle, selective protein
      degradation, a localized defense response and regulatory activity within the host
      cell nucleus.

PMID- 15036036
TI  - The Anopheles gambiae genome: next steps for malaria vector control.
AB  - Malaria remains a major public health problem that is made worse by poor
      implementation of control measures, and by the spread of drug- and insecticide
      resistant parasites and vectors, respectively. Availability of the Anopheles
      gambiae genome sequence will accelerate identification and exploitation of new
      target genes in this insect vector. This provides unique opportunities to improve
      on existing vector control tools and to generate new tools within a global
      partnership. However, significant capacity needs to be built for investigators in
      disease-endemic countries to exploit the genome data. When integrated with
      existing strategies, the new tools will form an effective package for selective
      vector control in an effort to prevent mortality and morbidity due to malaria.

PMID- 15036037
TI  - Getting organized: a simple database solution to replace laboratory notebooks.

PMID- 15036038
TI  - Teaching tired T cells to fight HIV: time to test IL-15 for immunotherapy?

PMID- 15036039
TI  - How DCs control cross-regulation between lymphocytes.

PMID- 15036040
TI  - The CD4-Th1 model for multiple sclerosis: a critical [correction of crucial] re
      appraisal.

PMID- 15036041
TI  - CTL ontogeny and viral escape: implications for HIV-1 vaccine design.

PMID- 15036042
TI  - The innate immune response to pneumococcal lung infection: the untold story.

PMID- 15036043
TI  - Transcriptional regulation of the mucosal IgA system.

PMID- 15036044
TI  - Complement function in mAb-mediated cancer immunotherapy.

PMID- 15036045
TI  - Ultrasound of nerve and muscle.
AB  - Over the last two decades, ultrasound has developed into a useful technology for
      the evaluation of diseases of nerve and muscle. Since it is currently not used at
      by the majority of clinicians involved in diagnosis or care of patients with
      neuromuscular disorders, this review briefly describes the technical aspects of
      ultrasound and its physical principles. It relates normal muscle anatomy and
      movement to ultrasound images in the axial and sagittal planes and follows with a
      discussion of ultrasound findings in chronic muscle disease. These include
      evident atrophy and the loss of the hypoechoic architecture of normal muscle
      tissue. It highlights evolving uses of the technique to measure other pathologic
      changes in disease including altered muscle dynamics. With high-resolution
      instruments nerve imaging has now become standard, and the relationships of
      median nerve anatomy and observations of static and dynamic images from
      ultrasound are reviewed. Changes seen in carpal tunnel syndrome include
      significant increases in the cross-sectional area of the nerve just proximal to
      the site of compression, loss of hyperechoic intensities within nerve, and
      reduced mobility. Preliminary use of the technique for the study of other nerves
      is reviewed as well. Ultrasound is an ideal tool for the clinical and research
      investigation of normal and diseased nerve and muscle complementary to existing
      diagnostic techniques. As the technology continues to evolve, it will likely
      assume a more significant role in these areas as those most able to exploit its
      potential, clinical neurophysiologists and neuromuscular clinicians, incorporate
      its use at the bedside.

PMID- 15036046
TI  - Automated interictal spike detection and source localization in
      magnetoencephalography using independent components analysis and spatio-temporal
      clustering.
AB  - OBJECTIVE: Magnetoencephalography (MEG) dipole localization of epileptic spikes
      is useful in epilepsy surgery for mapping the extent of abnormal cortex and to
      focus intracranial electrodes. Visually analyzing large amounts of data produces
      fatigue and error. Most automated techniques are based on matching of interictal
      spike templates or predictive filtering of the data and do not explicitly include
      source localization as part of the analysis. This leads to poor sensitivity
      versus specificity characteristics. We describe a fully automated method that
      combines time-series analysis with source localization to detect clusters of
      focal neuronal current generators within the brain that produce interictal spike
      activity. METHODS: We first use an ICA (independent components analysis) method
      to decompose the multichannel MEG data and identify those components that exhibit
      spike-like characteristics. From these detected spikes we then find those whose
      spatial topographies across the array are consistent with focal neural sources,
      and determine the foci of equivalent current dipoles and their associated time
      courses. We then perform a clustering of the localized dipoles based on distance
      metrics that takes into consideration both their locations and time courses. The
      final step of refinement consists of retaining only those clusters that are
      statistically significant. The average locations and time series from significant
      clusters comprise the final output of our method. RESULTS AND SIGNIFICANCE: Data
      were processed from 4 patients with partial focal epilepsy. In all three subjects
      for whom surgical resection was performed, clusters were found in the vicinity of
      the resectioned area. CONCLUSIONS: The presented procedure is promising and
      likely to be useful to the physician as a more sensitive, automated and objective
      method to help in the localization of the interictal spike zone of intractable
      partial seizures. The final output can be visually verified by neurologists in
      terms of both the location and distribution of the dipole clusters and their
      associated time series. Due to the clinical relevance and demonstrated promise of
      this method, further investigation of this approach is warranted.

PMID- 15036047
TI  - Contribution of different EEG frequencies to auditory evoked potential
      abnormalities in schizophrenia.
AB  - OBJECTIVE: We have shown previously [Clin Neurophysiol 2003;114:79] that phase
      reorganization of the ongoing electroencephalogram (EEG) plays an important role
      in the generation of auditory evoked potential (EP) components with a latency
      between 50 and 200 ms. In the present study, we investigate whether schizophrenia
      patients suffer from phase synchronization deficits as compared to normal
      subjects. METHODS: The auditory EPs from 20 normal subjects and 19 schizophrenia
      patients were analyzed. EPs were obtained using a double stimulus paradigm, in
      which two identical tone bursts (S1 and S2) were delivered with an average inter
      stimulus interval of 500 ms and an inter-pair interval of 8 s. The Piecewise
      Prony Method (PPM) was used to decompose single trial auditory evoked potentials
      into different frequency bands. Pre- and post-stimulus phase histograms were
      compared for each frequency band to determine the degree of phase synchronization
      produced by auditory stimulation in the two populations. RESULTS: The S1 stimulus
      produced significantly less (P < 0.05) phase synchronization in schizophrenia
      patients than in normal subjects in the 2-12 Hz frequency range. Far fewer and
      smaller inter-population phase synchronization differences were seen for the S2
      stimulus. Both populations showed more phase synchronization for S1 than S2. A
      significant correlation (P < 0.01) between N100 amplitude and phase
      synchronization 100 ms post S1 was observed for the normal population but not for
      the schizophrenia group. The correlation between P200 amplitude and phase
      synchronization 200 ms post S1 was significant for the normal group (P < 0.01)
      and the schizophrenia group (P < 0.03). CONCLUSIONS: Schizophrenia patients have
      a phase synchronization deficiency, as compared to a normal control group,
      especially for the first stimulus, in the 2-12 Hz frequency range. This
      deficiency explains the lower EP amplitudes and may be a significant factor
      contributing to reduced sensory gating reported in schizophrenic subjects.
      SIGNIFICANCE: The research presented here contributes to the understanding of the
      mechanism underlying sensory gating in health and gating deficiencies in
      schizophrenia.

PMID- 15036048
TI  - EEG minimum-norm estimation compared with MEG dipole fitting in the localization
      of somatosensory sources at S1.
AB  - OBJECTIVE: Dipole models, which are frequently used in attempts to solve the
      electromagnetic inverse problem, require explicit a priori assumptions about the
      cerebral current sources. This is not the case for solutions based on minimum
      norm estimates. In the present study, we evaluated the spatial accuracy of the L2
      minimum-norm estimate (MNE) in realistic noise conditions by assessing its
      ability to localize sources of evoked responses at the primary somatosensory
      cortex (SI). METHODS: Multichannel somatosensory evoked potentials (SEPs) and
      magnetic fields (SEFs) were recorded in 5 subjects while stimulating the median
      and ulnar nerves at the left wrist. A Tikhonov-regularized L2-MNE, constructed on
      a spherical surface from the SEP signals, was compared with an equivalent current
      dipole (ECD) solution obtained from the SEFs. RESULTS: Primarily tangential
      current sources accounted for both SEP and SEF distributions at around 20 ms
      (N20/N20m) and 70 ms (P70/P70m), which deflections were chosen for comparative
      analysis. The distances between the locations of the maximum current densities
      obtained from MNE and the locations of ECDs were on the average 12-13 mm for both
      deflections and nerves stimulated. In accordance with the somatotopical order of
      SI, both the MNE and ECD tended to localize median nerve activation more
      laterally than ulnar nerve activation for the N20/N20m deflection. Simulation
      experiments further indicated that, with a proper estimate of the source depth
      and with a good fit of the head model, the MNE can reach a mean accuracy of 5 mm
      in 0.2-microV root-mean-square noise. CONCLUSIONS: When compared with previously
      reported localizations based on dipole modelling of SEPs, it appears that equally
      accurate localization of S1 can be obtained with the MNE. SIGNIFICANCE: MNE can
      be used to verify parametric source modelling results. Having a relatively good
      localization accuracy and requiring minimal assumptions, the MNE may be useful
      for the localization of poorly known activity distributions and for tracking
      activity changes between brain areas as a function of time.

PMID- 15036049
TI  - Modeling studies on irregular motor unit potentials.
AB  - OBJECTIVE: The aim of these modeling studies on the generation of motor unit
      potentials (MUPs) was to establish the influence of MU parameters and recording
      conditions on the shape irregularity of MUPs. The focus was on the dependence of
      the irregularity of MUPs on fiber density, fiber diameters and the recording
      distance from the end-plate zone. METHODS: The study was performed using the 'EMG
      Simulator' software for modeling of MUP and our own software for calculations.
      RESULTS: The results indicate that the irregularity of a MUP increases with
      increased recording distance from the end-plate zone and decreases with increased
      fiber diameter and/or with increased fiber density. The quantitative relationship
      between these factors has been derived. CONCLUSIONS: The relationships determine
      the structural conditions in which irregular potential may be generated and
      therefore may be helpful in the interpretation of atypical MUPs.

PMID- 15036050
TI  - Number of Edb motor units estimated using an adapted multiple point stimulation
      method: normal values and longitudinal studies in ALS and peripheral
      neuropathies.
AB  - OBJECTIVE: To validate the adapted multiple point stimulation (AMPS) method to
      estimate the number of motor units (MUNE) from the extensor digitorum brevis
      (Edb) muscle. METHODS: Twenty controls (10 young and 10 old) were examined on
      both sides and 10 patients with amyotrophic lateral sclerosis (ALS) and 5 with
      acute peripheral neuropathy (PN) were examined longitudinally on one side during
      a series of repeated electrophysiological sessions. RESULTS: In the controls, the
      median MUNE and size of the motor unit action potentials (S-MUAPs) were found to
      be age-related (411 and 70 microVms in the young group; 164 and 142 microVms in
      the old group; P < 0.01), with a coefficient of variation of MUNE values of 27%
      and 20%, respectively. In the ALS group, the median MUNE value at diagnosis was
      31 (P < 0.05 vs. controls), and during a mean follow-up period of 11.5 months a
      continuous decrease in the MUNE value was seen, together with an initial
      increase, followed by a later decrease in 4 cases, in S-MUAP size. In the PN
      group, the MUNE value was initially similar to that in controls, but then
      decreased, accompanied by an increase in S-MUAP size, and then showed a
      progressive increase, together with a decrease in S-MUAP size. CONCLUSIONS: AMPS,
      a MUNE method developed in the upper extremity, also appears to be a useful
      procedure for quantifying changes in the MUNE value in the Edb muscle without
      specific software in order to study age-related changes or changes in patients
      with ALS or PN.

PMID- 15036051
TI  - Comparison of conventional and decomposition-enhanced spike triggered averaging
      techniques.
AB  - OBJECTIVE: Spike triggered averaging (STA) is a technique to extract an estimate
      of a recurring motor unit potential from a complex electromyographic (EMG)
      signal. In conventional STA (C-STA), potentials related to the discharges of
      single intramuscular motor units are isolated and used to trigger an averager to
      obtain an individual surface-detected motor unit potential (S-MUP) from an EMG
      signal. In decomposition-enhanced STA (DE-STA), EMG signal decomposition
      algorithms determine discharges of a number of different motor units (4 to 10)
      that can be used to trigger an averager to obtain their corresponding S-MUPs. We
      tested the accuracy of extracting and averaging S-MUPs using DE-STA compared to C
      STA for the same EMG signals. METHODS: We compared the intramuscular potentials
      used for triggering and the resultant averaged S-MUPs that were common in both
      techniques. RESULTS: We found no statistically significant differences in the
      metrics used to describe the triggering potentials and S-MUPs. CONCLUSIONS: We
      conclude that DE-STA is an accurate and efficient method to obtain a large number
      of intramuscular motor unit potentials and their corresponding S-MUP in proximal
      and distal muscles.

PMID- 15036052
TI  - Impact of different stimulation types on orthostatic tremor.
AB  - OBJECTIVE: Primary orthostatic tremor (OT) is thought to be generated by a unique
      supraspinal tremor generator. Here we studied the effect of ipsi- and
      contralateral stimulation of the central and peripheral nervous system on OT.
      METHODS: In 7 patients with primary OT, surface EMG was recorded from both
      tibialis anterior muscles. We performed transcranial magnetic stimulation (TMS)
      over the vertex, and lumbar magnetic stimulation (LMS) over the lumbar spine.
      Supramaximal electrical nerve stimuli were applied to the tibial or peroneal
      nerve at the knee. Proprioceptive input was evoked by rhythmical submaximal
      stimulation of the tibial, peroneal or sural nerve at the ankle. RESULTS: TMS
      reset OT significantly in the contralateral as well as the ipsilateral tibialis
      anterior muscle. The resetting in both muscles was identical. In contrast,
      peripheral input by means of LMS, supra- or submaximal nerve stimulation had no
      impact on OT. CONCLUSIONS: Transcranial magnetic stimulation of one cortical leg
      area resets OT in both legs whereas OT is not modified by any peripheral stimuli
      applied in this study. SIGNIFICANCE: Our results support the hypothesis of n
      unique supraspinal OT generator. This generator receives a modulating input from
      the motor cortex.

PMID- 15036053
TI  - Intraoperative neurophysiologic discovery of uncrossed sensory and motor pathways
      in a patient with horizontal gaze palsy and scoliosis.
AB  - OBJECTIVE: To report the intraoperative neurophysiologic discovery of clinically
      unsuspected non-decussation of the somatosensory and motor pathways. METHODS: We
      performed somatosensory evoked potential (SEP) and transcranial electric
      stimulation (TES) muscle motor evoked potential (MEP) monitoring during scoliosis
      surgery for a 16 year old patient with familial horizontal gaze palsy and
      progressive scoliosis. Our routine procedures included optimizing tibial cortical
      SEP monitoring derivations through saggital and coronal (C4', C2', Cz', C1', C3'
      mastoid) P37 mapping, which surprisingly indicated non-decussation. Consequently,
      we also obtained coronal median nerve SEPs and simultaneous bilateral muscle
      recordings to lateralized TES (C3-Cz, C4-Cz) intraoperatively and focal hand area
      transcranial magnetic stimulation (TMS) postoperatively. RESULTS: For each nerve,
      tibial P37/N37 distribution was contralateral/ipsilateral and median N20
      ipsilateral. For each hemisphere, ipsilateral TES MEPs had lower thresholds and
      TMS MEPs were exclusively ipsilateral. Accurate monitoring required reversed
      montages. Reevaluation of an MRI (previously reported normal) disclosed a ventral
      midline cleft of the medulla. CONCLUSIONS: The results indicate uncrossed dorsal
      column-medial lemniscal and corticospinal pathways due to brain-stem malformation
      with absent internal arcuate and pyramidal decussations. SIGNIFICANCE:
      Simultaneous bilateral recording to unilateral stimulation demonstrates SEP/MEP
      hemispheric origin and is important for accurate interpretation and monitoring
      because decussation anomalies exist.

PMID- 15036054
TI  - Distinct differences in cortical reactivity of motor and prefrontal cortices to
      magnetic stimulation.
AB  - OBJECTIVE: The stimulus intensity of prefrontal transcranial magnetic stimulation
      (TMS) is usually determined with respect to the motor threshold (MT). However,
      the association between the excitability of the prefrontal and motor cortices is
      unknown. METHODS: Magnetic pulses to the left motor and prefrontal cortices were
      delivered at the MT of the right abductor digiti minimi muscle for 9 subjects and
      at 4 different stimulus intensities (60, 80, 100, and 120% of MT) for two
      subjects. Simultaneously, EEG was recorded with 60 scalp electrodes. RESULTS:
      Global mean field amplitudes of the TMS-evoked responses were significantly (32%)
      smaller after prefrontal than after motor cortex TMS, but they correlated
      positively. CONCLUSIONS: The reactivity to TMS is different between the motor and
      prefrontal cortices. However, an association between these reactivities suggests
      that MT may be used for determining the stimulus intensity of prefrontal TMS.

PMID- 15036055
TI  - Electric field and stimulating influence generated by deep brain stimulation of
      the subthalamic nucleus.
AB  - OBJECTIVE: The goal of this project was to develop a quantitative understanding
      of the volume of axonal tissue directly activated by deep brain stimulation (DBS)
      of the subthalamic nucleus (STN). METHODS: The 3-dimensionally inhomogeneous and
      anisotropic tissue medium surrounding DBS electrodes complicates our
      understanding of the electric field and tissue response generated by the
      stimulation. We developed finite element computer models to address the effects
      of DBS in a homogeneous isotropic medium, and a medium with tissue conductivity
      properties derived from human diffusion tensor magnetic resonance data. The
      second difference of the potential distribution generated in the tissue medium
      was used as a predictor of the volume of tissue supra-threshold for axonal
      activation. RESULTS: The model predicts that clinically effective stimulation
      parameters (-3 V; 0.1 ms; 150 Hz) result in activation of large diameter (5.7
      microm) myelinated axons over a volume that spreads outside the borders of the
      STN. The shape of the activation volume was dependent on the strong dorsal
      ventral anisotropy of the internal capsule, and the moderate anterior-posterior
      anisotropy of the region around zona incerta. CONCLUSIONS: Small deviations (
      approximately 1 mm) in the electrode position within STN can substantially alter
      the shape of the activation volume as well as its spread to neighboring
      structures. SIGNIFICANCE: STN DBS represents an effective treatment for medically
      refractory movement disorders such as Parkinson's disease. However, stimulation
      induced side effects such as tetanic muscle contraction, speech disturbance and
      ocular deviation are not uncommon. Quantitative characterization of the spread of
      stimulation will aid in the development of techniques to maximize the efficacy of
      DBS.

PMID- 15036056
TI  - Effects of hand posture on preparatory control processes and sensory modulations
      in tactile-spatial attention.
AB  - OBJECTIVE: Event-related brain potentials (ERPs) were measured to investigate
      spatial coordinate systems involved in the control of preparatory tactile-spatial
      orienting, and in subsequent attentional modulations of somatosensory processing.
      METHODS: On each trial, a visual precue directed attention to the left or right
      hand, where infrequent tactile targets had to be detected. Hands were positioned
      either close together or wide apart. ERPs were recorded in the cue-target
      interval and in response to attended and unattended tactile non-targets. RESULTS:
      A frontal anterior directing attention negativity (ADAN) and a posterior late
      directing attention positivity (LDAP) were elicited in the cue-target interval
      contralateral to the direction of an attentional shift. The ADAN was unaffected
      by hand posture, but the LDAP was attenuated when hands were close together. N140
      amplitudes were enhanced in response to tactile stimuli presented to the attended
      hand, and this effect was more pronounced when hands were wide apart.
      CONCLUSIONS: ADAN and LDAP are linked to separable anterior and posterior
      attentional control systems, which use coordinate systems based on somatotopic
      and external space, respectively. Effects of spatial attention on somatosensory
      stimulus processing are affected by variations in body posture. SIGNIFICANCE: Our
      results demonstrate that representations of body locations in external space play
      a central role in the control of tactile attention.

PMID- 15036057
TI  - Principal component analysis for reduction of ocular artefacts in event-related
      potentials of normal and dyslexic children.
AB  - OBJECTIVE: The aim of this study was to reduce ocular artefacts in single trial
      event-related potentials (ERPs) recorded in normal and in dyslexic children.
      METHODS: ERPs were recorded during passive and active reading of centrally
      presented alphabetic letters and non alphabetic symbols. EEG was recorded from 10
      EEG locations using the 10-20 system. Diagonal EOG from the right eye was also
      recorded. Principal component analysis (PCA) was applied in order to reduce
      ocular artefacts: the first or the second principal component (PC) was subtracted
      when the correlation coefficient between the component and EOG was greater or
      equal to 0.9 or 0.95, respectively. Performance of the method was tested on
      simulated and real data, on both single and averaged trials, varying EOG
      amplitude and artefact transmission characteristics. RESULTS: Applying the method
      to real recordings from normal and dyslexic children, we obtained a significant
      increase in the number of useful trials. In normal children we retrieved 41.0% of
      the rejected trials in passive and 39.1% in active reading. In dyslexic children
      36.7 and 32.2% of the rejected trials in passive and active reading could be
      included in the respective averages. CONCLUSIONS: The method allows an increase
      in the number of trials suitable for averaging, a great improvement in ERP
      quality and a reduction in the recording time.

PMID- 15036059
TI  - Automatic processing of self-regulation of slow cortical potentials: evidence
      from brain-computer communication in paralysed patients.
AB  - OBJECTIVE: Direct brain-computer communication utilizes self-regulation of brain
      potentials to select letters, words or symbols from a computer menu. Selection of
      letters or words with brain potentials requires simultaneous processing of
      several tasks such as production of certain brain potentials at predefined time
      points simultaneously with processing of presented letter strings. This study
      addresses the question of whether the self-regulation of slow cortical potentials
      (SCP) automatizes with practice and can thus be considered as a skill comparable
      to motor or cognitive skills. METHODS: Two nearly completely paralysed patients
      learned over several months to produce electrocortically negative and positive
      SCP by means of visual feedback. Improved performance and a reduction in
      performance variability were regarded as behavioural indicators for automaticity,
      while the topographic focalization of cortical activation was considered as a
      neurophysiological indicator for automaticity. Different indicators of
      automaticity were expected to covary along with practice. RESULTS: In patient 1,
      performance measured as the percentage of correct SCP shifts increased
      simultaneously with the topographic focalization of cortical activation. His
      performance became more stable with practice. For this patient the criteria for
      automaticity were all met. In patient 2, performance also improved, but his
      cortical activity became topographically less focal. His performance was less
      stable than that of patient 1. CONCLUSIONS: The present findings, albeit on only
      two subjects, provide preliminary evidence that SCP self-regulation may
      automatize with long-term practice and can therefore be considered a skill.

PMID- 15036058
TI  - Auditory event-related potential indices of increased distractibility in children
      with major depression.
AB  - OBJECTIVE: Children with major depression (MD) exhibit short-term memory and
      concentration deficits. Using auditory event-related potentials (ERPs), we aimed
      to determine whether these problems could be caused by a dysfunction in auditory
      sensory memory, attentional orienting, or both. METHODS: The subjects were 10
      treatment-naive children with MD and 10 controls. Sound sequences, consisting of
      frequent stimuli (syllable /ka/, P = 0.08), infrequent deviant stimuli (/ta/, P =
      0.01 ), and novel sounds ( P = 0.01 ) were played through loudspeakers while the
      children watched silent videos and ignored the sound stimuli. Auditory sensory
      memory was studied by eliciting the ERPs mismatch negativity (MMN) and late
      discriminative negativity (LDN), and the P3a was used as an index of involuntary
      attention switch. RESULTS: The children with MD had shorter MMN and LDN latencies
      than the controls. The late component of the P3a (lP3a) was enhanced in amplitude
      in the patients as compared with that in the controls. CONCLUSIONS: Auditory
      sensory memory appears to function normally in children with MD. However, the ERP
      findings indicated enhanced sensory sensitivity and attentional distractibility
      in these children. This increased distractibility might underlie the
      concentration difficulties that compromise school performance in children with
      MD.

PMID- 15036060
TI  - Effects of distraction on magnetoencephalographic responses ascending through C
      fibers in humans.
AB  - OBJECTIVE: Using magnetoencephalography (MEG), we evaluated the cerebral regions
      relating to second pain perception ascending through C-fibers and investigated
      the effect of distraction on each region. METHODS: Thirteen normal subjects
      participated in this study. CO2 laser pulses were delivered to the dorsum of the
      left hand to selectively activate C-fibers. The MEG responses were analyzed using
      a multi-dipole model. RESULTS: (1) primary somatosensory cortex (SI), and (2)
      secondary somatosensory cortex (SII)--insula were the main generators for the
      primary component, 1M, whose mean peak latency was 744 ms. In addition to (1) and
      (2), (3) cingulate cortex and (4) medial temporal area (MT) were also activated
      for the subsequent component, 2M, whose mean peak latency was 947 ms. During a
      mental calculation task (Distraction), all 6 sources were significantly reduced
      in amplitude, but the SII-insula (P < 0.01) and cingulate cortex (P < 0.001) were
      more sensitive than the SI (P < 0.05) and MT (P < 0.05). CONCLUSIONS: We
      confirmed that SI in the contralateral hemisphere and SII-insula, cingulate
      cortex and MT in bilateral hemispheres play a major role in second pain
      perception, and all sites were much affected by a change of attention, indicating
      that these regions are related to the cognitive aspect of second pain perception.
      SIGNIFICANCE: The SI, SII, cingulate and MT were activated during the C-fiber
      related MEG response, and responses in these regions were significantly
      diminished during mental distraction.

PMID- 15036061
TI  - Parietal generators of low- and high-frequency MN (median nerve) SEPs: data from
      intracortical human recordings.
AB  - OBJECTIVE: To identify low and high-frequency median nerve (MN) somatosensory
      evoked potential (SEP) generators by means of chronically implanted electrodes in
      the parietal lobe (SI and neighbouring areas) of two epileptic patients. METHODS:
      Wide-pass short-latency and long-latency SEPs to electrical MN stimulation were
      recorded in two epileptic patients by stereotactically chronically implanted
      electrodes in the parietal lobe (SI and neighbouring areas). To study high
      frequency responses (HFOs) an off-line digital filtering of depth short-latency
      SEPs was performed (500-800 Hz, 24 dB roll-off). Spectral analysis was performed
      by fast Fourier transform. RESULTS: In both patients we recorded a N20/P30
      potential followed by a biphasic N50/P70 response. A little negative response in
      the 100 ms latency range was the last detectable wide-pass SEP in both patients.
      Two HFOs components (called iP1 and iP2) were detected by mere visual analysis
      and spectral analysis, and were supposed to be originated within the parietal
      cortex. CONCLUSIONS: This was the very first study that recorded wide bandpass
      and high frequency SEPs by electrodes, exploring both the lateral and the mesial
      part of the parietal lobe and particularly that of the post-central gyrus.

PMID- 15036062
TI  - Modifications of sleep EEG induced by chronic vagus nerve stimulation in patients
      affected by refractory epilepsy.
AB  - OBJECTIVE: The aim of this study was to evaluate the impact of chronic vagus
      nerve stimulation (VNS) on sleep/wake background EEG and interictal epileptiform
      activity (IEA) of patients with medically refractory epilepsy. METHODS: From a
      broader sample of 10 patients subjected to baseline and treatment
      polysomnographies, spectral analysis and IEA count have been performed on 6
      subjects' recordings, comparing the results by means of statistical analysis.
      RESULTS: An overall increase in EEG total power after VNS has been observed, more
      marked in NREM sleep; collapsing EEG power spectra into 5 frequency bands, we
      have found a statistically significant increase in delta and theta in NREM sleep,
      and of alpha in wakefulness and REM sleep. The incidence of IEA is diminished,
      although not significantly; only the duration of discharges is significantly
      diminished. CONCLUSIONS AND SIGNIFICANCE: Long-term VNS produces an enhancement
      in sleep EEG power of medically refractory epileptic patients. These results may
      be related to a better structured composition of EEG, and it is possible that
      chronic VNS may have a major role in enhancing the brain's ability to generate an
      electrical activity.

PMID- 15036063
TI  - EEG background activity described by a large computerized database.
AB  - OBJECTIVE: To show how our newly developed software for classification and
      storage of visually routinely assessed EEGs are used to evaluate the general
      background activity (GBA) and the alpha rhythm (AR) in a large number of
      prospective EEGs. METHODS: EEGs from 4651 consecutive patients were visually
      assessed using a computerized description system connected to an EEG database.
      The AR and the GBA apart from the AR were described separately for frequency and
      amplitude. RESULTS: AR frequencies declined from the age of 45 years and slowed
      with increasing age independently of non-AR pathology and gender. Females had
      higher AR frequencies than males. EEGs with non-GBA pathology had lower GBA
      frequencies and higher GBA amplitudes. Higher GBA amplitudes were associated with
      lower GBA frequencies in normal EEGs for all age groups. EEG interpretations by 4
      independent electroencephalographers showed the same trends, but differed in
      exact assessment of frequencies and amplitudes. CONCLUSIONS: EEG interpretations
      stored in a categorized database with easy access to data have successfully been
      used to evaluate interobserver variation and other quality control measurements.
      Statistical analysis of the data has at the same time produced new information
      regarding the development of AR and GBA throughout life.

PMID- 15036064
TI  - The interplay of lorazepam-induced brain oscillations: microstructural
      electromagnetic study.
AB  - OBJECTIVE: The effects on cortical rhythms of a single-dose (30 microg/kg)
      administration of the GABAA agonist lorazepam were examined in a randomized,
      double-blind, cross-over, placebo-controlled study with 8 healthy volunteers
      using simultaneous electroencephalography (EEG) and magnetoencephalography (MEG).
      METHODS: The oscillations were assessed by means of adaptive classification of
      short-term spectral patterns. RESULTS: Lorazepam (a) decreased the percentage of
      EEG/MEG segments with fast-theta, delta-alpha, fast-theta-alpha and alpha
      activity and increased percentage of EEG/MEG segments with delta, delta-slow
      theta, delta-beta, slow-theta and polyrhythmic activity; (b) decreased diversity
      of EEG/MEG signals (in terms of spectral patterns) and increased the general
      instability of the signal; (c) increased stabilization periods of the spectral
      patterns (reduced brain information processing); (d) maintained larger maximum
      periods of temporal stabilization for delta, slow-theta, delta-slow-theta, delta
      beta and polyrhythmic activity (in terms of spectral patterns); (e) did not
      increase power in the independent beta rhythm. CONCLUSIONS: Lorazepam caused
      significant reorganization of the EEG/MEG microstructure. These results suggest
      also that adaptive classification analysis of single short-term spectral patterns
      may provide additional information to conventional spectral analyses.

PMID- 15036066
TI  - Potentials evoked by chirp-modulated tones: a new technique to evaluate
      oscillatory activity in the auditory pathway.
AB  - OBJECTIVE: Steady-state potentials are oscillatory responses generated by a
      rhythmic stimulation of a sensory pathway. The frequency of the response, which
      follows the frequency of stimulation, is maximal at a stimulus rate of 40 Hz for
      auditory stimuli. The exact cause of these maximal responses is not known,
      although some authors have suggested that they might be related to the 'working
      frequency' of the auditory cortex. Testing of the responses to different
      frequencies of stimulation may be lengthy if a single frequency is studied at a
      time. Our aim was to develop a fast technique to explore the oscillatory response
      to auditory stimuli, using a tone modulated in amplitude by a sinusoid whose
      frequency increases linearly in frequency ('chirp') from 1 to 120 Hz. METHODS:
      Time-frequency transforms were used for the analysis of the evoked responses in
      10 subjects. Also, we analyzed whether the peaks in these responses were due to
      increases of amplitude or to phase-locking phenomena, using single-sweep time
      frequency transforms and inter-trial phase analysis. RESULTS: The pattern
      observed in the time-frequency transform of the chirp-evoked potential was very
      similar in all subjects: a diagonal band of energy was observed, corresponding to
      the frequency of modulation at each time instant. Two components were present in
      the band, one around 45 Hz (30-60 Hz) and a smaller one between 80 and 120 Hz.
      Inter-trial phase analysis showed that these components were mainly due to phase
      locking phenomena. CONCLUSIONS: A simultaneous testing of the amplitude
      modulation-following oscillatory responses to auditory stimulation is feasible
      using a tone modulated in amplitude at increasing frequencies. The maximal
      energies found at stimulation frequencies around 40 Hz are probably due to
      increased phase-locking of the individual responses.

PMID- 15036065
TI  - Co-registration of magnetoencephalography with magnetic resonance imaging using
      bite-bar-based fiducials and surface-matching.
AB  - OBJECTIVE: To introduce a new technique for co-registration of
      Magnetoencephalography (MEG) with magnetic resonance imaging (MRI). We compare
      the accuracy of a new bite-bar with fixed fiducials to a previous technique
      whereby fiducial coils were attached proximal to landmarks on the skull. METHODS:
      A bite-bar with fixed fiducial coils is used to determine the position of the
      head in the MEG co-ordinate system. Co-registration is performed by a surface
      matching technique. The advantage of fixing the coils is that the co-ordinate
      system is not based upon arbitrary and operator dependent fiducial points that
      are attached to landmarks (e.g. nasion and the preauricular points), but rather
      on those that are permanently fixed in relation to the skull. RESULTS: As a
      consequence of minimizing coil movement during digitization, errors in
      localization of the coils are significantly reduced, as shown by a randomization
      test. Displacement of the bite-bar caused by removal and repositioning between
      MEG recordings is minimal ( approximately 0.5 mm), and dipole localization
      accuracy of a somatosensory mapping paradigm shows a repeatability of
      approximately 5 mm. The overall accuracy of the new procedure is greatly improved
      compared to the previous technique. CONCLUSIONS: The test-retest reliability and
      accuracy of target localization with the new design is superior to techniques
      that incorporate anatomical-based fiducial points or coils placed on the
      circumference of the head.

PMID- 15036067
TI  - Effects of electrode density and electrolyte spreading in dense array
      electroencephalographic recording.
AB  - OBJECTIVE: High-density EEG recording offers increased spatial resolution but
      requires careful consideration of how the density of electrodes affects the
      potentials being measured. Power differences as a function of electrode density
      and electrolyte spreading were examined and a method for correcting these
      differences was tested. METHODS: Separate EEG recordings from 8 participants were
      made using a high-density electrode net, first with 6 of 128 electrodes active
      followed by recordings with all electrodes active. For a subset of 4 participants
      measurements were counterbalanced with recordings made in the reversed order by
      drying the hair after the high-density recordings and using a fresh dry electrode
      net of the same size for the low-density recordings. Mean power values over 6
      resting eyes open/closed EEG recordings at the 6 active electrodes common to both
      recording conditions were compared. Evidence for possible electrolyte spreading
      or bridging between electrodes was acquired by computing Hjorth electrical
      distances. Spherical spline interpolation was tested for correcting power values
      at electrodes affected by electrolyte spreading for these participants and for a
      subset of participants from a larger previous study. RESULTS: For both the
      complete set and the counterbalanced subset, significant decreases in power at
      the 6 common electrodes for the high-density recordings were observed across the
      range of the standard EEG bands (1-44 Hz). The number of bridges or amount of
      electrolyte spreading towards the reference electrode as evidenced by small
      Hjorth electrical distances served as a predictor of this power decrease.
      Spherical spline interpolation increased the power values at electrodes affected
      by electrolyte spreading and by a significant amount for the larger number of
      participants in the second group. CONCLUSIONS: Understanding signal effects
      caused by closely spaced electrodes, detecting electrolyte spreading and
      correcting its effects are important considerations for high-density EEG
      recordings. A combination of scalp maps of power density and plots of small
      Hjorth electrical distances can be used to identify electrodes affected by
      electrolyte spreading. Interpolation using spherical splines offers a method for
      correcting the potentials measured at these electrodes.

PMID- 15036068
TI  - Cost-effectiveness of ribavirin plus interferon alpha-2b for either interferon
      relapsers or non-responders in chronic hepatitis C: a Japanese trial.
AB  - The aim of this study was to examine the cost-effectiveness of combination
      therapy with ribavirin plus interferon alpha-2b compared with interferon
      monotherapy for hepatitis C-infected Japanese patients who had either temporarily
      responded or not responded to initial interferon treatment. Data from a recent
      randomized clinical trial among relapsed or non-responding patients comparing
      combination therapy to interferon alone were applied to a computer cohort
      simulation Markov process model to project lifelong clinical and economic
      outcomes. Combination therapy for 24 weeks should increase life expectancy by 1.6
      quality-adjusted life years and should reduce discounted (3% per year) lifetime
      costs by yen 121,000 when compared to retreatment with interferon alone. For the
      subgroup of patients with genotype 1b and high viral load, combination therapy
      should be cost-effective ( yen 187,000 per QALY gained with a 3% annual discount
      rate) by well-accepted international standards. These results were robust with
      combination therapy remaining cost-effective or cost saving in sensitivity
      analysis involving reasonable variation in all parameters. For patients similar
      to those enrolled in the interferon alpha-2b and ribavirin trials in Japan,
      combination therapy should be considered cost-effective with the higher drug
      treatment costs nearly completely offset by future savings through reductions in
      future liver complications from hepatitis C.

PMID- 15036069
TI  - High frequency of anti-ribosomal P antibody in patients with systemic lupus
      erythematosus-associated hepatitis.
AB  - Hepatic manifestations are a common phenomenon in patients with systemic lupus
      erythematosus (SLE). However, their cause may be difficult clinically to
      determine. A significantly increased frequency of anti-ribosomal P antibody has
      recently been found in patients with SLE-associated hepatitis. Thus, we examined
      the prevalence of anti-ribosomal P antibody and clinical differences between anti
      ribosomal P antibody positive and negative SLE patients with liver dysfunction
      using ELISA kits against recombinant ribosomal P0 protein. Sera of 61 patients
      with SLE and 20 patients with autoimmune hepatitis (AIH) were assayed. Of 34 SLE
      patients with liver dysfunction, anti-ribosomal P antibody was detected in 15
      (44.1%), consisting of 11 (68.8%) of 16 patients with SLE-associated hepatitis, 2
      (28.6%) of 7 patients with fatty liver, 1 (16.7%) of 6 patients with drug-induced
      hepatitis, and 1 (20.0%) of 5 patients with SLE complicated by AIH. This antibody
      was not detected in patients with AIH. Except for those with SLE-associated
      hepatitis, anti-ribosomal P antibody positive patients were complicated by renal
      dysfunction and CNS lupus. The positive rate of anti-ribosomal P antibody was
      significantly higher in patients with SLE-associated hepatitis (68.8%) than in
      patients with SLE complicated by AIH (20%) ( [Formula: see text] ) and AIH (0%) (
      [Formula: see text] ). These findings suggest that anti-ribosomal P antibody may
      be a useful marker of SLE-associated hepatitis to differentiate it from AIH and
      other liver dysfunctions in SLE patients without renal dysfunction or CNS lupus.

PMID- 15036070
TI  - Expression of cytosolic and membrane associated tissue transglutaminase in rat
      hepatic stellate cells and its upregulation during transdifferentiation to
      myofibroblasts in culture.
AB  - Transdifferentiation of hepatic stellate cells (HSC) to collagen producing
      myofibroblasts (MFB) is a principal event in liver fibrogenesis. In our studies
      we investigated if tissue transglutaminase (tTG) from these cell types may play a
      role in liver fibrosis. Separation of cytosol and membrane components showed
      membrane associated tTG and during transdifferentiation an upregulation of total
      tTG on mRNA and protein level was found, but no modulation during stimulation
      with TGF-beta1. In HSC and fully differentiated MFB a significant amount of the
      total tTG synthesised during transdifferentiation is found to be membrane
      associated whereas the remaining portion is cytosol-associated and only very
      little is found within the extracellular matrix (ECM). The data implicate that
      tTG in this cell type seems to play an important role in liver fibrogenesis.

PMID- 15036071
TI  - Cotreatment with interferon-alpha and -gamma reduces liver fibrosis in a rat
      model.
AB  - Background/Aims: Interferon-alpha is used widely to treat viral hepatitis.
      Interferon-gamma modulates a system attacking infected cells and also has an anti
      fibrotic effect. A treatment with interferon-alpha and -gamma has undergone
      trials in eliminating hepatitis C virus. We investigated effects of cotreatment
      in a liver fibrosis model to explore anti-fibrotic effects. Methods: Rats were
      assigned to groups including normal controls (NC), CCl(4) controls, rat
      interferon-alpha treatment, rat interferon-gamma treatment, and cotreatment. All
      groups except normal controls received CCl(4) orally for 8 weeks. At the
      beginning of the third week of exposure, 6 weeks of treatment were initiated
      according to interferon group. Digitally analyzed immunohistochemistry,
      biochemical assays, and Northern analysis were performed. Results: Pixels
      (x10(5)) per field containing immunoreactive type III collagen (fibrotic density)
      in CCl(4) controls, interferon-alpha, interferon-gamma, and cotreatment groups
      respectively were [Formula: see text], [Formula: see text], [Formula: see text]
      and [Formula: see text]. Liver hydroxyproline content correlated with fibrotic
      density, and was significantly low in the cotreatment group. Plasma hyaluronate
      and transaminase were significantly low in cotreatment and interferon-alpha
      groups. Northern blotting showed lowest mRNA expression for type I collagen,
      desmin, transforming growth factor (TGF)-beta1, and matrix metalloproteinase-2
      mRNA in the cotreatment group; tissue inhibitor of metalloproteinase-1 and -2
      mRNAs were significantly low in the interferon-gamma group. Conclusions:
      Cotreatment can suppress collagen and transforming growth factor-beta1 and has an
      overall anti-fibrotic effect without exacerbating inflammation.

PMID- 15036072
TI  - Endotoxinemia and benzodiazepine-like substances in compensated cirrhotic
      patients: a randomized study comparing the effect of rifaximine alone and in
      association with a symbiotic preparation.
AB  - Aim: The aim of the present investigation was to test study benzodiazepines
      (BZDs) profile in patients with viral cirrhosis under different combinations of
      rifaximine and of a novel symbiotic. Methods: Our study groups consisted of 30
      patients with a confirmed diagnosis of HCV-related Child B liver cirrhosis.
      Patients were randomly allocated into three groups: rifaximine 400mg t.i.d. for 2
      weeks; (B) SCM-III (Lactobacillus acidophilus, Lactobacillus helveticus and
      Bifidobacteria in a ion- and vitamin-enriched medium, Named srl, Italy) 10ml
      t.i.d. for 2 weeks; (C) rifaximine 400mg t.i.d. for 1 week followed by SCM-III
      10ml t.i.d. for 5 weeks. At weekly interval, blood samples were withdrawn to test
      BZD-like substances, ammonia and endotoxin. Results: Rifaximine treatment brought
      about a significant early drop of BZDs ( [Formula: see text] versus pre-treatment
      and versus control) till fourth week of observation when a gradual increase took
      place with return to pre-treatment values at the sixth week. Symbiotic treatment
      was comparably effective while given to patients but significantly elevated BZDs
      level were noted starting from the third week. Similar phenomena were noted for
      endotoxin and ammonia although symbiotic seemed more effective against endotoxin
      and rifaximine against ammonia increase. However, the sequential treatment
      rifaximine-symbiotic brought about a sustained normalization of BZDs, ammonia and
      endotoxin throughout the 6-week study. Conclusion: The present pilot study
      suggests that a rifaximine-symbiotic regimen could be an effective tool in
      compensated liver cirrhosis to limit some triggering factors of hepatic
      encephalopathy while being amenable to long-term use and devoid of significant
      side effects.

PMID- 15036073
TI  - A case of severe acute hepatitis of unknown etiology treated with the Chinese
      herbal medicine Inchinko-to.
AB  - A prolonged severe hepatitis of unknown etiology was treated with Inchinko-to, a
      Chinese herbal medicine, and this case is herein described. Inchinko-to was given
      with ursodeoxycholic acid (UDCA) and glycyrrhizin. The improvement in the
      patient's liver function seemed to be accelerated after the treatment, especially
      after stopping the administration of kanamycin sulfate which might possibly
      inhibit the conversion of geniposide, one of the constituents of Inchinko-to, to
      an active ingredient through the suppression of the bacterial growth in
      intestinal flora, suggesting the usefulness of Inchinko-to for treatment of
      severe hepatitis.

PMID- 15036074
TI  - A case of latent primary biliary cirrhosis.
AB  - A 53-year-old housewife was the donor when living-related donor liver
      transplantation (LRLT) was performed in her younger sister (49-year-old) with
      terminal primary biliary cirrhosis (PBC). The donor's liver histology was
      diagnostic and compatible with PBC, although she was negative for
      antimitochondrial antibody (AMA: a specific marker of PBC) by immunofluorescence
      and had normal liver function tests as well as no symptoms of liver disease. In
      this patient with latent PBC, AMA was eventually detected by immunoblotting,
      although it was not detected by ELISA. These findings indicate that a family
      history of PBC is a risk factor for the development of this disease. Our patient
      was diagnosed before the advent of any clinical or biochemical indicators and
      before or at the onset of AMA positivity, so her liver histology revealed the
      earliest stage of PBC.

PMID- 15036075
TI  - A review of content-based image retrieval systems in medical applications
      clinical benefits and future directions.
AB  - Content-based visual information retrieval (CBVIR) or content-based image
      retrieval (CBIR) has been one on the most vivid research areas in the field of
      computer vision over the last 10 years. The availability of large and steadily
      growing amounts of visual and multimedia data, and the development of the
      Internet underline the need to create thematic access methods that offer more
      than simple text-based queries or requests based on matching exact database
      fields. Many programs and tools have been developed to formulate and execute
      queries based on the visual or audio content and to help browsing large
      multimedia repositories. Still, no general breakthrough has been achieved with
      respect to large varied databases with documents of differing sorts and with
      varying characteristics. Answers to many questions with respect to speed,
      semantic descriptors or objective image interpretations are still unanswered. In
      the medical field, images, and especially digital images, are produced in ever
      increasing quantities and used for diagnostics and therapy. The Radiology
      Department of the University Hospital of Geneva alone produced more than 12,000
      images a day in 2002. The cardiology is currently the second largest producer of
      digital images, especially with videos of cardiac catheterization ( approximately
      1800 exams per year containing almost 2000 images each). The total amount of
      cardiologic image data produced in the Geneva University Hospital was around 1 TB
      in 2002. Endoscopic videos can equally produce enormous amounts of data. With
      digital imaging and communications in medicine (DICOM), a standard for image
      communication has been set and patient information can be stored with the actual
      image(s), although still a few problems prevail with respect to the
      standardization. In several articles, content-based access to medical images for
      supporting clinical decision-making has been proposed that would ease the
      management of clinical data and scenarios for the integration of content-based
      access methods into picture archiving and communication systems (PACS) have been
      created. This article gives an overview of available literature in the field of
      content-based access to medical image data and on the technologies used in the
      field. Section 1 gives an introduction into generic content-based image retrieval
      and the technologies used. Section 2 explains the propositions for the use of
      image retrieval in medical practice and the various approaches. Example systems
      and application areas are described. Section 3 describes the techniques used in
      the implemented systems, their datasets and evaluations. Section 4 identifies
      possible clinical benefits of image retrieval systems in clinical practice as
      well as in research and education. New research directions are being defined that
      can prove to be useful. This article also identifies explanations to some of the
      outlined problems in the field as it looks like many propositions for systems are
      made from the medical domain and research prototypes are developed in computer
      science departments using medical datasets. Still, there are very few systems
      that seem to be used in clinical practice. It needs to be stated as well that the
      goal is not, in general, to replace text-based retrieval methods as they exist at
      the moment but to complement them with visual search tools.

PMID- 15036076
TI  - Assessing medical residents' usage and perceived needs for personal digital
      assistants.
AB  - Health care professionals need information delivery tools for accessing
      information at the point of patient care. Personal digital assistants (PDAs), or
      hand-held devices demonstrate great promise as point of care information devices.
      An earlier study [The Constellation Project: experience and evaluation of
      personal digital assistants in the clinical environment, in: Proceedings of the
      19th Annual Symposium on Computer Applications in Medical Care, 1995, 678] on the
      use of PDAs at the point of care found that hardware constraints, such as memory
      capability limited their usefulness, however, they were used frequently for
      accessing medical references and drug information [The Constellation Project:
      experience and evaluation of personal digital assistants in the clinical
      environment, in: Proceedings of the 19th Annual Symposium on Computer
      Applications in Medical Care, 1995, 678]. Since this study was completed in 1995,
      hand-held computer technology has advanced rapidly, and between 26 and 50% of
      physicians currently use PDAs [Physician's use of hand-helds increases from 15%
      in 1999 to 26% in 2001: Harris interactive poll results, Harris Poll. 8-24-2002
      (electronic citation); ACP-ASIM survey finds nearly half of U.S. members use hand
      held computers: ACP-ASIM press release, American College of Physicians, 9-3-2002
      (electronic citation)]. This use appears higher among residents, with one recent
      study finding that over two-thirds of family practice residencies use hand-held
      computers in their training programs [J. Am. Med. Inform. Assoc. 9 (1) (2002)
      80]. In this study, we systematically evaluate PDA usage by residents in our
      institution using quantitative and qualitative methods. Our evaluation included a
      brief on-line survey of 88 residents in seven residency programs including
      primary care and specialty practices. The surveys were completed between 26
      October 2001 and 30 April 2002. Follow-up interviews with 15 of the surveyed
      residents were then conducted between 24 April 2002 and 13 May 2002. The original
      contributions of this study are the evaluation of residents in primary and
      specialty programs and evaluation of both medical application software and the
      conventional personal organizational software (such as calendars and to-do
      lists). This evaluation was also conducted using significantly advanced hardware
      and software compared with previous studies [The Constellation Project:
      experience and evaluation of personal digital assistants in the clinical
      environment, in: Proceedings of the 19th Annual Symposium on Computer
      Applications in Medical Care, 1995, 678]. Results of our survey and follow-up
      interviews of residents showed most residents use PDAs daily, regardless of
      practice or whether their program encourages PDAs. Uses include commercial
      medical references and personal organization software, such as calendars and
      address books. Concerns and drawbacks mentioned by these residents included
      physical size of the PDA and the potential for catastrophic data loss. Another
      issue raised by our results suggests that security and Health Information
      Portability and Accountability Act (HIPAA) compliance need to be addressed, in
      part by resident education about securing patient data on PDAs. Overall, PDAs may
      become even more widely used if two issues can be addressed: (a) providing secure
      clinical data for the current patients of a given resident, and (b) allaying
      concerns of catastrophic data loss from their PDAs (e.g. by educating residents
      about procedures to recover information from PDA backup files).

PMID- 15036077
TI  - A categorization and analysis of the criticisms of Evidence-Based Medicine.
AB  - The major criticisms and limitations of Evidence-Based Medicine (EBM) appearing
      in the literature over the past decade can be summarized and categorized into
      five recurring themes. The themes include: reliance on empiricism, narrow
      definition of evidence, lack of evidence of efficacy, limited usefulness for
      individual patients, and threats to the autonomy of the doctor/patient
      relationship. Analysis of EBM according to these themes leads to the conclusion
      that EBM can be a useful tool, but has severe drawbacks when used in isolation in
      the practice of individual patient care. Modern medicine must strive to balance
      an extremely complex set of priorities. To be an effective aid in achieving this
      balance, the theory and practice of EBM must expand to include new methods of
      study design and integration, and must adapt to the needs of both patients and
      the health care system in order to provide patients with the best care at the
      lowest cost.

PMID- 15036078
TI  - Positive attitudes and failed queries: an exploration of the conundrums of
      consumer health information retrieval.
AB  - Several studies have found that consumers report a high level of satisfaction
      with the Internet as a health information resource. Belied by this positive
      attitude, however, are other studies reporting that consumers were often
      unsuccessful in searching for health information. In this paper, we present an
      interview and observation study in which we asked health consumers to search for
      health information on the Internet after first stating their search goals. Upon
      the conclusion of the session they were asked to evaluate their searches. We
      found that many consumers were unable to find satisfactory information when
      performing a specific query, while in general the group viewed health information
      retrieval (HIR) on the Internet in a positive light. We analyzed the observed
      search sessions to determine what factors accounted for the failure of specific
      searches and positive attitudes, and also discussed potential informatics
      solutions.

PMID- 15036079
TI  - Using CISMeF MeSH "Encapsulated" terminology and a categorization algorithm for
      health resources.
AB  - INTRODUCTION: CISMeF is a Quality Controlled Health Gateway using a terminology
      based on the Medical Subject Headings (MeSH) thesaurus that displays medical
      specialties (metaterms) and the relationships existing between them and MeSH
      terms. OBJECTIVE: The need to classify the resources within the catalogue has led
      us to combine this type of semantic information with domain expert knowledge for
      health resources categorization purposes. MATERIAL AND METHODS: A two-step
      categorization process consisting of mapping resource keywords to CISMeF
      metaterms and ranking metaterms by decreasing coverage in the resource has been
      developed. We evaluate this algorithm on a random set of 123 resources extracted
      from the CISMeF catalogue. Our gold standard for this evaluation is the manual
      classification provided by a domain expert, viz. a librarian of the team.
      RESULTS: The CISMeF algorithm shows 81% precision and 93% recall, and 62% of the
      resources were assigned a "fully relevant" or "fairly relevant" categorization
      according to strict standards. DISCUSSION: A thorough analysis of the results has
      enabled us to find gaps in the knowledge modeling of the CISMeF terminology. The
      necessary adjustments having been made, the algorithm is currently used in CISMeF
      for resource categorization.

PMID- 15036080
TI  - Diagnostic accuracy of chest X-rays acquired using a digital camera for low-cost
      teleradiology.
AB  - Store-and-forward telemedicine, using e-mail to send clinical data and digital
      images, offers a low-cost alternative for physicians in developing countries to
      obtain second opinions from specialists. To explore the potential usefulness of
      this technique, 91 chest X-ray images were photographed using a digital camera
      and a view box. Four independent readers (three radiologists and one
      pulmonologist) read two types of digital (JPEG and JPEG2000) and original film
      images and indicated their confidence in the presence of eight features known to
      be radiological indicators of tuberculosis (TB). The results were compared to a
      "gold standard" established by two different radiologists, and assessed using
      receiver operating characteristic (ROC) curve analysis. There was no statistical
      difference in the overall performance between the readings from the original
      films and both types of digital images. The size of JPEG2000 images was
      approximately 120KB, making this technique feasible for slow internet
      connections. Our preliminary results show the potential usefulness of this
      technique particularly for tuberculosis and lung disease, but further studies are
      required to refine its potential.

PMID- 15036081
TI  - Towards a continuous evolution and adaptation of information systems in
      healthcare.
AB  - OBJECTIVES: To address the problem of alignment of health information systems to
      healthcare processes, which is a major challenge in healthcare organizations; to
      present a layered approach for system evolution and adaptation based on an
      application framework and rapid application development; to accomplish a demand
      driven system evolution by embedding the software engineering process in business
      process optimization projects and by closely involving end users to improve their
      own work practices. METHODS: We have used a holistic health information system as
      a core application framework. System functionality is incrementally improved
      using an integrated "generator tool" for rapid application development. We have
      developed an iterative and participatory software engineering process, adapted to
      the conditions of the generator tool. The documentation techniques provided by
      the Unified Modeling Language (UML) were modified to achieve a straight forward
      documentation covering the whole development cycle from the business process
      model to generator-based computer applications. RESULTS AND CONCLUSION: The
      layered approach for system evolution did provide an environment in which a
      flexible and participatory software development process could be established.
      Today, generator-based applications are used in all clinical departments of our
      1200-bed University Hospital. We expect that tools for rapid application
      development will be further improved and will play an increasingly important role
      to establish responsive IT-infrastructures where the application developer can
      concentrate on business process alignment instead of coding and debugging.

PMID- 15036082
TI  - EPR and susceptibility studies of Zn1-xMnxTe crystals at room temperature.
AB  - Single crystals of Zn1-xMnxTe for x = 0.1, 0.25, 0.45, 0.5 and 0.6 were prepared
      using vertical Bridgman technique. EPR (electron paramagnetic resonance) spectra
      were recorded at room temperature (303 K) between 0 and 6 kG magnetic field and
      range of frequency 8.8-9.6 GHz. As the concentration of Mn increases the line
      width (DeltaH) and the number of spins (Ns) were increased. Susceptibility
      studies were carried out at room temperature in the range of dc magnetic field 0
      10 kG using vibrating sample magnetometer (VSM). Non-linear variation in
      susceptibility as a function of concentration (x) was observed and was explained
      on the basis of sp-d and d-d exchange interactions between Mn2+ ions and ZnTe
      lattice ions. Both EPR and susceptibility studies confirm the paramagnetic state
      of Zn1-xMnxTe system at RT.

PMID- 15036083
TI  - Quantitative determination of proteins at nanogram levels by the resonance light
      scattering technique with macromolecules nanoparticles of PS-AA.
AB  - The polystyrene-acrylic acid (PS-AA) nanoparticles have been prepared by
      ultrasonic polymerization, characterized by FT-IR and TEM. It is the first report
      on the determination of proteins with macromolecules nanoparticles of PS-AA by
      resonance light-scattering (RLS). At pH 6.9, the RLS of macromolecules
      nanoparticles of PS-AA can be enhanced by proteins. Based on this, a novel
      quantitative assay of proteins at the nanogram levels has been proposed. At pH
      6.9, the RLS signals of PS-AA were greatly enhanced by proteins in the region of
      250-700 nm characterized by the peak at 342 nm. Under optimal conditions, the
      linear ranges of the calibration curves were 0.02-11.0 microgml-1, 0.04-10.0
      microgml-1 and 0.03-10.0 microgml-1 for gamma-globulin (gamma-IgG), bovine serum
      albumin (BSA) and human serum albumin (HSA), respectively. The detection limits
      were 16.0 ngml-1, 19.0 ngml-1, and 15.0 ngml-1 for gamma-IgG, BSA and HSA,
      respectively. The method has been applied to the analysis of total proteins in
      human serum samples collected from the hospital and the results were in good
      agreement with those reported by the hospital, which indicates that the method
      presented here is not only sensitive, simple, but also reliable and suitable for
      practical application.

PMID- 15036084
TI  - Studies on the spectroscopic behavior of cryptotanshinone, tanshinone IIA, and
      tanshinone I.
AB  - A comparative study on the spectroscopic behavior of cryptotanshinone (CTan),
      tanshinone IIA (Tan IIA), and tanshinone I (Tan I) has been investigated,
      including UV-Vis absorption, low temperature phosphorescence (LTP), low
      temperature fluorescence (LTF), paper substrate-room temperature phosphorescence
      (PS-RTP), paper substrate-room temperature fluorescence (PS-RTF) and fluorescence
      in liquid (LF). The effect of pH on the luminescence intensity is discussed.
      Lifetime and polarization of the LTP and RTP have been examined with
      phosphorescence lifetime in the range of 0.6-0.9s and polarization in the range
      of 0.10-0.27. Analytical characteristics of LF, PS-RTF and PS-RTP of CTan, Tan
      IIA, and Tan I have been studied.

PMID- 15036085
TI  - Fluorescence quenching of coumarins by halide ions.
AB  - Fluorescence quenching of 4-methyl-7-methoxy coumarin (1) and 4-methyl-5-ethoxy-7
      methoxy coumarin (2) in aqueous solutions have been studied at different
      concentrations of halide ions (Cl-, Br-, I-), at room temperature approximately
      20 degrees C. It is observed that the fluorescence intensity of both the coumarin
      compounds (1 and 2) decrease with increase in the concentration of Br- and I-
      ions but remains almost constant in case of Cl- ion. It is observed that the
      quenching due to halide ions proceeds via both a diffusional and static quenching
      processes. The rate constants for diffusional as well as static component of
      quenching process have been calculated using modified Stern-Volmer relation. It
      is further observed, that I- ion has very high quenching ability than Br- ion and
      Cl) ion almost behaves as a non-quencher. It is explained in terms of the sphere
      of action model by showing that the value of radius of sphere of action of the
      halide quencher is greater than the sum of the radii of the respective coumarin
      and quencher. Further, pattern of the quenching ability of the halide quenchers
      is found to be as I- > Br- > Cl- and interestingly this is in the same order as
      of their ionization energy. Finally, the present quenching process has been
      attributed to the electron transfer resulting between colliding species.

PMID- 15036086
TI  - Sensitive indirect spectrophotometric determination of isoniazid.
AB  - A simple, rapid, sensitive and accurate indirect spectrophotometric method for
      the microdetermination of isoniazid (INH) in pure form and pharmaceutical
      formulations is developed. The procedure is based on the reaction of copper(II)
      with isoniazid in the presence of neocuproine (NC). In the presence of
      neocuproine, copper(II) is reduced easily by isoniazid to a Cu(I)-neocuproine
      complex, which shows an absorption maximum at 454 nm. By measuring the absorbance
      of the complex at this wavelength, isoniazid can be determined in the range 0.3
      3.5 microgml-1. This method was applied to the determination of isoniazid in
      pharmaceutical formulation and enabled the determination of the isoniazid in
      microgram quantities (0.3-3.5 microgml-1). The results obtained for the assay of
      pharmaceutical preparations compared well with those obtained by the official
      method and demonstrated good accuracy and precision.

PMID- 15036087
TI  - Spectrophotometric and fluorimetric determination of diazepam, bromazepam and
      clonazepam in pharmaceutical and urine samples.
AB  - New spectrophotometric and fluorimetric methods have been developed to determine
      diazepam, bromazepam and clonazepam (1,4-benzodiazepines) in pure forms,
      pharmaceutical preparations and biological fluid. The new methods are based on
      measuring absorption or emission spectra in methanolic potassium hydroxide
      solution. Fluorimetric methods have proved selective with low detection limits,
      whereas photometric methods showed relatively high detection limits. Successive
      applications of developed methods for drugs determination in pharmaceutical
      preparations and urine samples were performed. Photometric methods gave linear
      calibration graphs in the ranges of 2.85-28.5, 0.316-3.16, and 0.316-3.16
      microgml-1 with detection limits of 1.27, 0.08 and 0.13 microgml-1 for diazepam,
      bromazepam and clonazepam, respectively. Corresponding average errors of 2.60,
      5.26 and 3.93 and relative standard deviations (R.S.D.s) of 2.79, 2.12 and 2.83,
      respectively, were obtained. Fluorimetric methods gave linear calibration graphs
      in the ranges of 0.03-0.34, 0.03-0.32 and 0.03-0.38 microgml-1 with detection
      limits of 7.13, 5.67 and 16.47 ngml-1 for diazepam, bromazepam and clonazepam,
      respectively. Corresponding average errors of 0.29, 4.33 and 5.42 and R.S.D.s of
      1.27, 1.96 and 1.14 were obtained, respectively. Statistical Students t-test and
      F-test have been used and satisfactory results were obtained.

PMID- 15036088
TI  - Spectroscopy study of 5-amino-1,10-phenanthroline.
AB  - Acidity constants for the 5-amino-1,10-phenanthroline (5-Aphen) were determined
      in aqueous media, using SQUAD and SUPERQUAD programs. Spectrophotometry and
      potentiometry data were fitted to the best model to enable correlation of the
      following acidity equilibria: 5-AphenH = 5-Aphen + H+ (-log K = 5.78 +/= 0.03)
      and 5-AphenH2 = 5-AphenH2 = 5-Aphen + 2H+ (-log K = 6.89 +/= 0.07). UV
      absorptivity coefficients obtained suggest that the first protonation takes place
      on the nitrogens of the heterocycle ring and the second protonation could take
      place on the amino group. As expected, the electrochemical evidence of the 5
      Aphen species depends on the degree of protonation.

PMID- 15036089
TI  - Spectroscopic and XRD characterisation of zeolite catalysts active for the
      oxidative methylation of benzene with methane.
AB  - The benzene methylation with methane over zeolite catalysts was previously shown
      in our laboratory to require the presence of oxygen. Thus, a two-step mechanism
      involving the intermediate formation of methanol by partial oxidation of methane
      followed by the methylation of benzene with methanol in the second step, was
      postulated. This paper now reports the results of the characterisation of the
      zeolite catalysts used for the oxidative benzene methylation reaction in order to
      provide some information about their composition, structure, properties and their
      behaviour before and after the reaction. The catalysts were characterised by X
      ray diffraction (XRD), inductively coupled plasma atomic emission spectroscopy
      (ICP-AES), X-ray fluorescence (XRF), FT-IR and solid state NMR. XRD results
      indicate that the crystalline structures of all the ZSM-5 and H-beta catalysts
      remained unchanged after batch reaction of benzene with methane over the
      catalysts in agreement with the observation that the catalysts recovered from the
      reactor could be reused without loss of activity. Elemental analyses and FT-IR
      data show that as the level of metal ion exchange increases, the Bronsted acid
      concentration decreases but this metal ion exchange does not totally remove
      Bronsted acidity. FT-IR results further show that only a small amount of acid
      sites is actually necessary for a catalyst to be active since used catalysts
      containing highly reduced Bronsted acidity are found to be reusable without any
      loss of their activity. 29Si and 27Al magic angle spinning (MAS) NMR together
      with FT-IR spectra also show that all the active zeolites catalysts contain some
      extra-framework octahedral aluminium in addition to the normal tetrahedral
      framework aluminium. The presence of this extra-lattice aluminium does not,
      however, have any adverse effect on the crystallinity of the catalysts both
      before and after oxidative benzene methylation reaction. There appears also to be
      no significant dealumination of the zeolite catalysts during reaction since their
      catalytic performance was retained after use.

PMID- 15036090
TI  - Probing the structure of the silylene complex (Cy3P)2Pt=SiMes2.; UV-Vis and pre
      resonance Raman investigations.
AB  - The UV-Vis, pre-resonance Raman and IR spectra of the complex (Cy3P)2Pt=SiMes2
      (1) were obtained as well as Raman spectra of some model compounds. The
      experimental data and the results of normal coordinate calculations show that the
      stretching vibration of the Si?Pt bond in 1 is not localized, the nuSi=Pt
      internal coordinate makes significant contribution to two normal modes with
      frequencies at 465 and 612cm-1, whose Raman intensity is enhanced by pre
      resonance.

PMID- 15036091
TI  - Proton transfer reaction of a new orthohydroxy Schiff base at room temperature
      and 77 K.
AB  - One new orthohydroxy Schiff base, 2-(N-benzyl-alpha-iminoethyl)naphthol (BEIN)
      has been synthesized. The proton transfer reaction of BEIN has been investigated
      by means of absorption, steady state and time resolved fluorescence spectroscopy
      in different solvents at room temperature and 77K. The behavior of BEIN in
      ethanol and water, has been studied in neutral, acidic and basic conditions.
      Excited state intramolecular proton transfer (ESIPT) is evidenced by a large
      Stokes shifted ( approximately 11,000 cm-1) fluorescence in solid crystalline
      media at room temperature. We present the observation of phosphorescence both in
      non-polar and protic solvents at 77K. The observed decay dynamics of the
      phosphorescence and delayed fluorescence indicates that the triplet state can be
      attributed to the cis-keto form. The molecular structures are determined by
      B3LYP/6-31G** calculation. From theoretical study it is suggested that the
      strengthening of hydrogen bond result from the steric repulsion of the phenyl
      ring. The presence of benzene ring increases the proton transfer barrier in case
      of BEIN compared to previously studied 7-ethylsalicylidenebenzylamine (ESBA).

PMID- 15036092
TI  - Study of the inclusion processes of styrene and alpha-methyl-styrene in beta
      cyclodextrin.
AB  - The inclusion complexes of styrene and alpha-methyl-styrene with beta
      cyclodextrin (beta-CD) were investigated by using [1H] NMR titration in solution
      and X-ray diffraction (XRD) analysis, thermo-gravimetric analysis (TGA),
      elemental analysis (EA) in the solid state. The inclusion process has been
      studied by using PM3 quantum-mechanical semi-empirical method. The calculated
      results are in agreed with the experimental data. All results show that alpha
      methyl-styrene has stronger interaction with beta-cyclodextrin than styrene does,
      so the complex of beta-CD-alpha-methyl-styrene is more stable.

PMID- 15036093
TI  - Absorption of formaldehyde (H2CO) in the A1A2 <-- X1A1 band system at elevated
      temperatures and pressures.
AB  - The electronic A1A2 <-- X1A1 absorption spectra of formaldehyde vapour were
      studied at temperatures varying from 423 to 770 K with variable pressures from
      less than 0.1 to 1 MPa. Broadband vibronic and partially rotationally resolved
      4(0)(1) rovibronic spectra of formaldehyde showed considerable sensitivity to
      temperature. The high resolution spectra showed collision-induced broadening as
      the pressure was increased. The results show that the absorption efficiency of
      the laser radiation from the third harmonic of Nd:YAG lasers is sensitive to the
      spectral properties of the laser, such as line position and shape. Promising
      results were obtained from the comparison between theoretical and measured
      absorption spectra.

PMID- 15036094
TI  - Infrared and Raman spectra, conformational stability, ab initio calculations and
      vibrational assignment of 2-fluorobutane.
AB  - The infrared spectra (3500-50 cm-1) of gas and solid and the Raman spectrum (3500
      50 cm-1) of liquid 2-fluorobutane, CH3CHFCH2CH3, have been recorded. Variable
      temperature studies over the range -105 to -150 degrees C of the infrared spectra
      (3500-400 cm-1) of the sample dissolved in liquid krypton have also been
      recorded. By utilizing the relative intensities of six conformer pairs each for
      both Me-trans/F-trans and Me-trans/H-trans, the Me-trans conformer is found to be
      the lowest energy form with an enthalpy difference to the F-trans conformer of
      102 +/- 10 cm-1 ( 1.21+/- 0.12 kJmol-1) whereas the H-trans conformer is the
      highest energy form with an enthalpy difference of 208 +/- 21 cm-1 ( 2.49 +/-
      0.25 kJmol-1) higher than the Me-trans form. At ambient temperature, it is
      estimated that there is 50 +/- 2% of the Me-trans form, 31 +/- 1% of the F-trans
      form, and 19 +/- 1% of the H-trans conformer present. Equilibrium geometries and
      total energies of the three conformers have been determined by ab initio
      calculations with full electron correlation by the perturbation method to second
      order using a number of basis sets. A complete vibrational assignment is proposed
      for the Me-trans conformer and many of the fundamentals have been identified for
      the other two forms based on the force constants, relative infrared and Raman
      intensities, and depolarization ratios obtained from MP2/6-31Gd ab initio
      calculations. The spectroscopic and theoretical results are compared to the
      corresponding properties for some similar molecules.

PMID- 15036095
TI  - The vibrational spectra and conformations of ethylbenzene.
AB  - Infrared spectra (4000-250 cm-1) of the liquid, amorphous, crystalline solids and
      solutions in liquid krypton and Raman spectra (2500-20 cm-1) of the liquid as
      well as the amorphous and crystalline solids of ethylbenzene and its deuterated
      analogue-ethylbenzene-d(10) have been recorded. The spectra indicate that in the
      liquid and amorphous solids a small amount of a second conformer is present,
      whereas only one conformer remains in the crystalline phases. Assignments of the
      observed band wave numbers are discussed by comparison with normal mode wave
      numbers and IR and RS intensities calculated from ab initio 6-31G force fields
      and optimised geometries for both conformers for two species. All of the normal
      modes of conformers have been assigned.

PMID- 15036096
TI  - Linear-dichroic infrared spectral analysis of Cu(I)-homocysteine complex.
AB  - The interaction between homocysteine (HCysSH) and Cu(II) leads to the formation
      of a yellow complex [Cu(I)(HCysS-SCysH)2]Cl (1) after redox processes in the
      Cu(II)-homocysteine system resulting in dimerization of the ligand and formation
      of a mononuclear Cu(I) complex with two dimers. The structure of (1) was obtained
      by IR-LD spectral analysis of a solid amorphous sample oriented in nematic liquid
      crystal medium. The original technique for orientation developed here and the
      polarized IR spectra thus obtained, permit the determination of the complexation
      sites and coordination mode of diamagnetic complexes. In the complex (1), Cu(I)
      is coordinated through the two O atoms of one COO- group of each of the ligands
      and the metal ion coordination sphere represents a distorted tetrahedron.

PMID- 15036097
TI  - Investigation of the optimum optical design for pulsed-laser crossed-beam thermal
      lens spectrometry in infinite and finite samples.
AB  - Optimization of the optical design for pulsed-laser crossed-beam thermal lens
      (PLCBTL) spectrometry has been investigated. Experiments have been carried out
      with large samples as well as for very small samples in a microchannel and using
      different lens combinations to focus the probe and excitation beams. The results
      have been interpreted in terms of the influence of the excitation beam size as
      well as the degree of mode-mismatching of the excitation and probe beams on the
      optimum sample position and on the amplitude and decay of the photothermal
      signal. A semi-empirical formula that describes the influence of the sample
      position with respect to the probe beam waist has been established. We have shown
      that the optimum signal is inversely proportional to the waist of the excitation
      beam and is independent of the sample size as long as the size of the excitation
      beam is smaller than the microchannel. Time-resolved experiments have also shown
      that when the excitation beam is smaller than the sample, the signal decay
      depends not only on the size of the excitation beam but also on the mode
      mismatching factor. Otherwise, the temporal characteristics are closely related
      to the size of the microchannel.

PMID- 15036098
TI  - Optical absorption and NMR spectroscopic studies on paramagnetic trivalent
      lanthanide complexes with 2,2'-bipyridine.; The solvent effect on 4f-4f
      hypersensitive transitions.
AB  - The optical absorption and NMR studies of trivalent lanthanide chloride complexes
      with 2,2'-bipyridine (bpy) are presented and discussed. The NMR spectra of
      paramagnetic complexes exhibit lower as well as higher field shifts of bpy
      resonances that reflect change in geometry and reveals importance of the factor
      (3 cos2 theta - 1 ) in changing sign of the shift. The paramagnetic shifts
      recorded have been analyzed and the intramolecular shift ratios suggest that the
      paramagnetic shift is predominantly dipolar in origin. Electronic spectral
      studies of the Pr, Nd, Ho, Er and Dy complexes in different solvents (viz.
      methanol, pyridine, DMSO and DMF), which differ with respect to donor atoms,
      reveal that the chemical environment around the lanthanide ion has great impact
      on f-f transitions and any change in the environment results in modifications of
      the spectra. The oscillator strength for the hypersensitive and non
      hypersensitive transitions have been determined and changes in the oscillator
      strength and band shape with respect to solvent type is rationalized in terms of
      ligand (solvent) structure and coordination properties.

PMID- 15036099
TI  - Photoinduced electron transfer studies of Nile red in the presence of TiO2
      colloidal nanoparticles.
AB  - Photoinduced electron transfers between Nile red (NR) with TiO2 colloidal
      nanoparticles are studied using picosecond transient absorption and time resolved
      fluorescence spectroscopy. The dynamics of electron transfer from the dye
      molecule to the semiconductor were understood from the transient, and also the
      formation of conduction band electron and Nile red cation radical were detected.

PMID- 15036100
TI  - Contribution to the analysis of the predissociated rovibronic structure of the
      symmetric isotopomers 16O3 and 18O3 of ozone near 10,400 cm-1): [3A2(3(2)(0)) <--
      X1A1(0(0)(0))] and 3B2 <-- X1A1.
AB  - The absorption spectrum of ozone was recorded at low temperatures (down to -135
      degrees C) by high resolution Fourier transform spectrometry and intra cavity
      laser absorption spectroscopy (ICLAS) near 10,400 cm-1. A preliminary analysis of
      the rotational structure of the absorption spectra of 16O3 and 18O3 shows that
      this spectral region corresponds to a superposition of two different electronic
      transitions, one with a very broad rotational structure, showing for the first
      time the asymmetric stretching frequency mode nu3 of the electronic state 3A2,
      the other formed by a completely diffuse band, probably the 2(1)(0) band of a new
      transition due to the triplet electronic state 3B2. Predissociation effects
      induce large broadening of the rotational lines for the transition centered at
      10,473 cm-1 identified as the 3(2)(0) band of the 3A2 <-- X1A1 electronic
      transition. The rotational structure cannot be analyzed directly but instead the
      band contour method was used to confirm the symmetry of the transition and to
      estimate the spectroscopic constants for the 16O isotopomer. The origin of the
      band is at 10,473 +/- 3 cm-1 and the value of the 16O3(3A2) antisymmetric
      stretching frequency mode is equal to 460 +/- 2 cm-1. We believe that the diffuse
      band is due to the 3B2 state and is located at about 10,363 +/- 3 cm-1 for 16O3
      and 10,354 +/- 3 cm-1 for 18O3. The isotopic rules confirm the different results
      obtained for 18O3 and 16O3.

PMID- 15036101
TI  - Determination of urea, glucose, and phosphate in dialysate with Fourier transform
      infrared spectroscopy.
AB  - Individual control and quantification of phosphate removal is desirable in
      dialysis treatment. Currently, no on-line method exists to quantify phosphate
      removal. We demonstrate that a multivariate calibration model based on infrared
      transmission spectra is capable of predicting phosphate, urea, and glucose
      concentrations at clinically relevant levels. The on-line monitoring of these
      components by infrared spectroscopy is therefore feasible.

PMID- 15036102
TI  - Vibrational analysis for multi-channel decomposition reactions of o-pyridyl
      radical based on DFT methods.
AB  - The decomposition reaction pathways of o-pyridyl were investigated extensively at
      the B3LYP/6-311G** level. With the relative energies after zero-point energy
      correction, the potential energy surface was drawn out. The vibrational
      frequencies for all species were predicted and the reaction mechanism was
      elucidated utilizing vibrational frequencies and vibrational mode analysis. The
      primary products of o-pyridyl decomposition reactions are acetylene and
      cyanoacetylene.

PMID- 15036103
TI  - Synthesis, spectroscopy and redox behaviors of 4,6-di-t-Bu-, 4-Me-6-t-Bu- and 4-t
      Bu-2-nitrosophenolato copper(II) complexes; Characterization of radical species
      generated by PPh3.
AB  - The synthesis, spectroscopy (IR, UV-Vis, ESR), magnetic and thermal behaviors, as
      well electrochemistry and reactivity towards PPh3 of alkyl-substituted bis(2
      nitrosophenolato)copper(II) complexes, CuLx2, where Lx = 4,6-di-t-Bu-2
      nitrosophenolato (L1), 4-CH3-6-t-Bu-2-nitrosophenolato (L2), 4-t-Bu-2
      nitrosophenolato (L3) mono-anion ligands, are presented. The solid-state and
      solution ESR spectra showed an axially symmetric g-tensors with gII > g 2.03
      indicating that the unpaired electron is located in the dx2 - y2orbital. When
      CuLx2 complexes were treated with an excess of PPh3 in air or under vacuum in
      toluene (or other solutions) at 300K, as confirmed by UV-Vis and ESR examination,
      without formation of PPh3 adduct of the complexes, the immediately generation of
      semiquinone type radical species and reduction of Cu(II) to Cu(I) were observed.
      In the case of CuL(1)(2) the further conversion of the generated primary radical
      species to secondary bis(PPh3)2(phenoxazinolato)Cu(I) semiquinone type radical
      was detected. The cyclic voltammetry (CV) of CuLx2 exhibited two successive quasi
      reversible ligand centered reductions and two irreversible metal and ligand
      centered oxidation processes. Electrochemical behaviors were interpreted in terms
      of the existence two-valence tautomeric nitroso and oximato isomers of CuLx2 in
      solution.

PMID- 15036104
TI  - Highly sensitive detection of optical discrete absorption and resonance
      fluorescence of fused silica in the far ultraviolet.
AB  - Ultraviolet light induced high resolution optical absorption spectra and
      resonance fluorescence of spectroscopically pure fused silica have been studied,
      due to its potential applications in optoelectronics and flash (laser flash
      spectroscopy laboratory use), for optical fibers and power optics and lasers. An
      ultraviolet discrete absorption spectra and resonance coherent fluorescence were
      recorded photographically between 200 and 260 nm. Resonance discrete and coherent
      fluorescence were observed at 250-255 and 220-225 nm bands at room temperature by
      flash photolysis technique.

PMID- 15036105
TI  - Vibrational spectroscopic studies in the hydrolysis and condensation of
      chlorotrimethylsilane.
AB  - Raman and infrared spectroscopy were used to study the hydrolysis and
      condensation of chlorotrimethylsilane (CTMC) in aqueous organic solvents. From
      the recorded spectra and their intensity variation with time, we were able to
      identify trimethylsilanol as the reaction intermediate or the hydrolysis product
      as well as hexamethyldisiloxane (HMDS) as the final condensation product. The
      measured Raman intensity of CTMS at different time revealed that hydrolysis of
      CTMS is first order in terms of the CTMS concentration. From the Raman spectra
      collected under different conditions, it was noted that condensation reaction
      rates is faster in neutral condition than in acidic condition.

PMID- 15036106
TI  - Laser photoacoustic spectra of Sm3+ ion in Sm2O3 and SmCl3.6H2O in the spectral
      profile 484-542 nm.
AB  - Microphone based photoacoustic (PA) spectrometer to study solids in powder form
      was designed and fabricated. Laser PA spectra of Sm3+ ion in Sm2O3 and SmCl3.6H2O
      microcrystalline powders were recorded first time in 484-542 nm spectral region
      at room temperature. Analysis of these PA spectra shows new information on the
      Stark components of ground and excited states of Sm3+ ion. A comparison of Stark
      energy levels of Sm3+ ion in both oxide and hexahydrated chloride hosts is
      presented here.

PMID- 15036107
TI  - Normal coordinate analyses and barrier to internal rotation of nitroso- and
      nitroazides.
AB  - The conformational and structural stability of nitrosoazide NNN-N=O and
      nitroazide NNN-NO2 were investigated by DFT-B3LYP and ab initio MP2 calculations
      with 6-311++G** basis set. From the calculations, nitrosoazide was predicted to
      exist predominantly in the planar trans (NNN and N=O groups are trans to each
      other) structure with high trans-cis rotational barrier of about 11 kcal mol-1 as
      a result of pronounced conjugation between the azide group and the N=O bond. The
      NO2 rotational barrier in nitroazide was predicted from the symmetric potential
      function to be of about 7 kcal mol-1. The vibrational frequencies were calculated
      at the DFT-B3LYP level and the infrared and Raman spectra of the cis-trans
      mixture were plotted. Complete vibrational assignments were made on the basis of
      normal coordinate calculations for the stable conformers of both molecules. For
      nitrosoazide, the calculated wavenumbers were compared to the corresponding
      experimental values obtained from early reported Raman spectrum of the molecule.

PMID- 15036108
TI  - Preferential solvation of Brooker's merocyanine in binary solvent mixtures
      composed of formamides and hydroxylic solvents.
AB  - The ET polarity values of 4-[(1-methyl-4(1H)-pyridinylidene)-ethylidene]-2,5
      cyclohexadien-1-one (Brooker's merocyanine) were collected in mixed-solvent
      systems comprising a formamide [N,N-dimethylformamide (DMF), N-methylformamide
      (NMF) or formamide (FA)] and a hydroxylic (water, methanol, ethanol, propan-2-ol
      or butan-1-ol) solvent. Binary mixtures involving DMF and the other formamides
      (NMF and FA) as well as NMF and FA were also studied. These data were employed in
      the investigation of the preferential solvation (PS) of the probe. Each solvent
      system was analyzed in terms of both solute-solvent and solvent-solvent
      interactions. These latter interactions were responsible for the synergism
      observed in many binary mixtures. This synergistic behaviour was observed for DMF
      propan-2-ol, DMF-butan-1-ol, FA-methanol, FA-ethanol and for the mixtures of the
      alcohols with NMF. All data were successfully fitted to a model based on solvent
      exchange equilibria, which allowed the separation of the different contributions
      of the solvent species in the solvation shell of the dye. The results suggest
      that both hydrogen bonding and solvophobic interactions contribute to the
      formation of the solvent complexes responsible for the observed synergistic
      effects in the PS of the dye.

PMID- 15036109
TI  - Determination of nucleic acids with tetra-(N-hexadecylpyridiniumyl) porphyrin
      sensitized by cetyltrimethylammonium bromide (CTMAB) using a Rayleigh light
      scattering technique.
AB  - Using a common spectrofluorometer to measure the intensity of Rayleigh light
      scattering (RLS), a method for determination of nucleic acids has been developed.
      At pH 10.24 and ionic strength 0.01 mol l-1 (NaCl), the Rayleigh light-scattering
      of the tetra-(N-hexadecylpyridiniumyl) porphyrin (TC16PyP) is greatly enhanced by
      nucleic acids in the presence of cetyltrimethylammonium bromide (CTMAB), with the
      scattering peak located at 311.8 nm. The enhanced RLS intensity is in proportion
      to the concentration of calf thymus DNA (ctDNA) in the range 0.2-6.0 microg ml-1
      and to that of fish sperm DNA (fsDNA) in the range 0.05-3.0microg ml-1. The
      limits of detection are 0.016 microg ml-1 for calf thymus DNA and 0.023 microg ml
      1 for fish sperm DNA when the concentration of TPP was chosen 2.0 x 10(-6) mol l
      1. Four synthetic samples were determined satisfactorily.

PMID- 15036110
TI  - Stereochemistry of new nitrogen containing heterocyclic compounds.; X.
      Supramolecular structures and stereochemical versatility of polymeric complexes.
AB  - New polymeric complexes of Cu(II), Co(II), Ni(II) and UO2(II) with 5-(2(1)
      carboxyphenylazo)-8-hydroxyquinoline (LH2) have been prepared and characterized
      on the basis of analytical, magnetic, 1H NMR, EPR and electronic spectral
      studies. Tentative structures for the polymeric complexes are proposed. The
      important infrared (IR) bands and the main 1H NMR signals are assigned and
      discussed relative to the molecular structure. EPR spectrum of copper(II) complex
      has been studied with a view to assigning their stereochemistries. Various EPR
      parameters have been calculated. Each metal has six-coordinates in an octahedral
      environment. The ligand acts as a dibasic (bis-bidentate chelating agent
      coordinating through CN, N=N, COOH and OH groups by replacement of a proton from
      the two latter groups. Considerable interest has also been focused on the
      synthesis of the azo compounds and its polymeric metal complex due to its wide
      potential applications. The thermal decomposition behavior of the complexes is
      also discussed.

PMID- 15036111
TI  - Atomic absorption spectroscopic, conductometric and colorimetric methods for
      determination of fluoroquinolone antibiotics using ammonium reineckate ion-pair
      complex formation.
AB  - Three accurate, rapid and simple atomic absorption spectrometric, conductometric
      and colorimetric methods were developed for the determination of norfloxacin
      (NRF), ciprofloxacin (CIP), ofloxacin (OFL) and enrofloxacin (ENF). The proposed
      methods depend upon the reaction of ammonium reineckate with the studied drugs to
      form stable precipitate of ion-pair complexes, which was dissolved in acetone.
      The pink coloured complexes were determined either by AAS or colorimetrically at
      lambdmax 525 nm directly using the dissolved complex. Using conductometric
      titration, the studied drugs could be evaluated in 50% (v/v) acetone in the range
      5.0-65, 4.0-48, 5.0-56 and 6.0-72 microg ml-1 of NRF, CPF, OFL and ENF,
      respectively. The optimizations of various experimental conditions were
      described. The results obtained showed good recoveries of 99.15 +/- 1.15, 99.30
      +/- 1.40, 99.60 +/- 1.50, and 99.00 +/- 1.25% with relative standard deviations
      of 0.81, 1.06, 0.97, and 0.69% for NRF, CPF, OFL, and ENF, respectively.
      Applications of the proposed methods to representative pharmaceutical
      formulations are successfully presented.

PMID- 15036112
TI  - Optical studies of Eu3+ doped oxyfluoroborate glass.
AB  - Rare earth doped oxyfluoroborate glasses have been prepared with different
      concentration of Eu3+. The UV-Vis/NIR optical absorption, laser induced
      fluorescence and photoacoustic spectra of Eu3+ in this host have been studied.
      Different optical parameters such as oscillator strength, Judd-Ofelt intensity
      parameter, stimulated emission cross-section, transition probability, branching
      ratio and radiative lifetime, etc. have been calculated. Lifetime of the 5D0
      level at various concentrations of Eu3+ have been used to explain the
      concentration dependent fluorescence quenching. The mechanism of quenching was
      found to be dipole-dipole. Energy transfer have also been studied from Eu3+ to
      Pr3+ in sample with 1 mol% (Eu3+) + 1 mol% Pr3+.

PMID- 15036113
TI  - Development of a new fluorescent probe: 1,3,5,7-tetramethyl-8-(4'-aminophenyl)
      4,4-difluoro-4-bora-3a,4a-diaza-s-indacence for the determination of trace
      nitrite.
AB  - A new fluorescent probe, 1,3,5,7-tetramethyl-8-(4'-aminophenyl)-4,4-difluoro-4
      bora-3a,4a-diaza-s-indacence (TMABODIPY) has been developed for the determination
      of trace nitrite in terms of the reaction of nitrite with TMABODIPY first in
      acidic solution and then in alkaline solution to form diazotate, a stable and
      highly fluorescent reagent. The method offered the advantage of specificity,
      sensitivity and simplicity. The linear calibration range for nitrite was 8-300
      nmol l-1s with a 3 sigma detection limit of 0.65 nmol l-1. The proposed method
      has been applied to monitor the trace nitrite in drinking water and vegetable
      without extraction.

PMID- 15036114
TI  - The effects of seasonal weather on the genotoxicity, cytokinetic properties,
      cytotoxicity and organochemical content of extracts of airborne particulates in
      Mexico City.
AB  - Extracted organic material (EOM) from PM10 airborne particles collected during
      three distinct seasons in Mexico City was assayed for genotoxicity, cytokinetic
      effects and cytotoxicity. Using sister chromatid exchange (SCE) for genotoxicity,
      replication index (RI) and mitotic index (MI) for cytokinetics, and microscopic
      evaluation (cell death) for cytotoxicity on human lymphocytes exposed to
      increasing concentrations of EOM, this study showed that the extent of genotoxic,
      cytokinetic, and cytotoxic change caused by pollutants depended at least in part
      on the seasonal weather. Bioactivated extracts of samplings in April (warm and
      dry), August (warm and rainy) and November (cool and dry) produced the highest
      rate of genotoxicity (SCE) in November and the lowest rate in April. Without
      bioactivation the rates were still highest in November but equally low in April
      and August. Thus, almost all of the genotoxic responses in the bioactivation
      experiments during these latter months were from promutagens. However, in
      November equally large amounts of mutagens and promutagens were present.
      Cytokinetics (RI and MI) showed steady decreases as the concentration of EOM was
      increased, independent of bioactivation and weather. Cytotoxicity (cell death)
      occurred when higher concentrations of EOM were used. EOM was the least cytotoxic
      in April and most cytotoxic in November. Bioactivation was not required for
      cytokinetic change and cytotoxicity, suggesting that the agents involved may be
      different from the genotoxic agents. Using gas chromatography/mass spectroscopy
      (GC/MS) it could be shown that the type of pollutant chemicals in the EOM also
      depended on the weather. In particular, all 15 polycyclic aromatic hydrocarbons
      (PAH) studied were present in November EOM whereas four different PAH were absent
      in the other 2 months. Generally the amounts were less in the EOM collected in
      April and August. Conversely, nitro-PAH compounds were greater in number in April
      EOM but higher in amount in November EOM. The significance of these findings is
      discussed.

PMID- 15036115
TI  - Increased radiation toxicity by enhanced apoptotic clearance of HL-60 cells in
      the presence of the pentapeptide thymopentin, which selectively binds to
      apoptotic cells.
AB  - Radiotoxic insult to cells is associated with genetic instability and heritable
      damage [Mutat. Res. 517 (2002) 173]. A strengthened response to such insult by
      enhanced apoptotic clearance, which would be associated with anti-inflammatory
      [Nature 390 (1997) 350; Nature 407 (2000) 784] and anti-necrotic intercellular
      signaling [Nature 418 (2002) 191], has been previously reported. The pentapeptide
      thymopentin (TP5) improves immunological parameters in cancer patients following
      radiotherapy without clinically observable side effects. We assessed the effects
      of TP5 on human promyeloid leukemia HL-60 cells exposed to therapeutic (2Gy)
      doses of X-rays. We observed an increased accumulation of cells in the G2/M phase
      of the cell cycle after irradiation when treated with TP5. However, TP5 had no
      effect on the cell cycle distribution of non-irradiated HL-60 cells.
      Additionally, TP5 treatment of irradiated cells increased the number of cells
      undergoing apoptosis. Furthermore, TP5 was found to selectively bind to apoptotic
      cells. These findings represent a promising and novel approach employing TP5
      mediated modulation of cellular radiation response to augment both clinical gain
      in radiation oncology and safety measures for radiation protection.

PMID- 15036116
TI  - DNA damage in frog erythrocytes after in vitro exposure to a high peak-power
      pulsed electromagnetic field.
AB  - Till the present time, the genotoxic effects of high peak-power pulsed
      electromagnetic fields (HPPP EMF) on cultured cells have not been studied. We
      investigated possible genotoxic effects of HPPP EMF (8.8 GHz, 180 ns pulse width,
      peak power 65 kW, repetition rate 50 Hz) on erythrocytes of the frog Xenopus
      laevis. We used the alkaline comet assay, which is a highly sensitive method to
      assess DNA single-strand breaks and alkali-labile lesions. Blood samples were
      exposed to HPPP EMF for 40 min in rectangular wave guide. The specific absorption
      rate (SAR) calculated from temperature kinetics was about 1.6 kW/kg (peak SAR was
      about 300 MW/kg). The temperature rise in the blood samples at steady state was
      3.5 +/- 0.1 degrees C. The data show that the increase in DNA damage after
      exposure of erythrocytes to HPPP EMF was induced by the rise in temperature in
      the exposed cell suspension. This was confirmed in experiments in which cells
      were incubated for 40 min under the corresponding temperature conditions. The
      results allow us to conclude that HPPP EMF-exposure at the given modality did not
      cause any a-thermal genotoxic effect on frog erythrocytes in vitro.

PMID- 15036117
TI  - Proteomic analysis of plasma proteins of workers exposed to benzene.
AB  - In this study, we analyzed the proteins in plasma of workers exposed to benzene
      by two-dimensional gel electrophoresis, in the hope of finding a specific protein
      suitable for the biomonitoring of benzene exposure. Comet assays were also
      carried out to evaluate lymphocytes DNA damage. Fifty workers from a printing
      company and 38 matched unexposed healthy subjects were enrolled in the study. DNA
      damage was found to be significantly higher in the exposed workers than in the
      controls. The tail moments of the two groups were 2.07 +/- 0.35 and 1.48 +/-
      0.41, respectively (P < 0.0001). The mean values of trans, trans-muconic acid
      (t,t-MA) in workers exposed to benzene and in unexposed subjects were 1.011 +/-
      0.249 and 0.026 +/- 0.028 mg/g creatinine, respectively. Protein profiles were
      significantly different (P < 0.05) in the two groups, as identified by matrix
      assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry
      and confirmed by Western blot. T cell receptor beta chain (TCR beta), FK506
      binding protein (FKBP51) and matrix metalloproteinase-13 (MMP13) were found to be
      up-regulated in the benzene-exposed workers. In addition, the correlation between
      TCR beta and the tail moments of lymphocytes was statistically significant (r
      value, 0.428). We conclude that TCR beta in plasma could be used for the early
      detection of exposure to benzene.

PMID- 15036118
TI  - Stereochemical effects in the metabolic activation of nitrosopiperidines:
      correlations with genotoxicity.
AB  - The genotoxicity of nitrosopiperidine and six alkyl derivatives was studied by
      use of the Ames tester strains TA100 and TA1535 in the pre-incubation method.
      Among the compounds investigated, those exhibiting genotoxic activity under the
      experimental conditions employed were only genotoxic in the presence of S9 mix
      (10%). The results obtained were correlated with models of the metabolic
      activation of nitrosamines in an attempt to rationalize the genotoxicity of these
      compounds. The results show that the presence of substituents in the
      nitrosopiperidine molecule may be one of the modulating factors affecting the
      genotoxicity of these cyclic nitrosamines, and may help provide some chemical
      clues for the identification of risk compounds from among a large group of
      structurally related molecules.

PMID- 15036119
TI  - GSTM1 null genotype as a risk factor for anti-BPDE-DNA adduct formation in
      mononuclear white blood cells of coke-oven workers.
AB  - The influence of the genetic deletion polymorphism of glutathione S-transferase
      micro 1 (GSTM1 *0/*0) on levels of anti (+/-)-r-7,t-8-dihydroxy-t-9,10-oxy
      7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE-DNA) adduct in the peripheral blood
      lymphocyte plus monocyte fraction (LMF) of coke-oven workers was investigated. A
      total of 95 male Polish coke-oven workers (60% current smokers) from two
      different plants comprised the sample population. Polycyclic aromatic
      hydrocarbons (PAH) exposure was assessed by means of the individual post-shift
      urinary excretion of 1-pyrenol (mean +/- S.D.: 6.93 +/- 7.20 micromol/mol
      creatinine; 70% of the subjects exceeded the proposed biological exposure index
      (BEI) 2.28 micromol/mol creatinine). Anti-BPDE-DNA adduct levels were detected by
      high performance liquid chromatography (HPLC)/fluorescence analysis of the anti
      BPDE tetrol I-1 released after acid hydrolysis of DNA samples. Genotypes were
      determined by polymerase chain reaction (PCR) on the genomic DNA of each subject.
      Coke-oven workers without active GSTM1 (GSTM1 *0/*0, 33%) had significantly
      higher adduct levels than those with active GSTM1 (GSTM1*1/*1 and *1/*0) (5.90 +/
      5.59 versus 3.25 +/- 2.01 adducts/10(8) bases, Mann-Whitney U-test, z = 2.53, P
      = 0.011), PAH exposure in the two subgroups being similar (7.06 +/- 6.83 versus
      6.67 +/- 8.00 1-pyrenol micromol/mol creatinine). The highest number of GSTM1
      null subjects (12/23, 39%) belonged to the quartile with the highest adduct
      levels (i.e., >4.67 adducts/10(8) nucleotides). That is, coke-oven workers with
      GSTM1 *0/*0 genotype had a significantly higher risk of having high adduct levels
      than individuals with active GSTM1 genotype (Fisher exact test P = 0.0355; odds
      ratio (OR) = 4.145, 95% CI 1.0-18.8). Multiple linear regression analysis showed
      that the increase in anti-BPDE-DNA adduct levels in LMF was significantly related
      to the high occupational exposure to PAHs (benzo[a]pyrene (BaP)) of coke-oven
      workers (t = 3.087, P < 0.01) and to the lack of GSTM1 activity (t = 3.512, P <
      0.001), rather than to the two other confounding factors of PAH intake, i.e.
      charcoal-broiled meat consumption and smoking habits. In conclusion, our results
      indicate the clear influence of the GSTM1 detoxifying genotype on anti-BPDE-DNA
      adduct formation in the LMF of coke-oven workers. This is invaluable for future
      environmental-occupational studies using this biomarker of PAH exposure.

PMID- 15036121
TI  - Assessment of DNA damage by comet assay on frozen total blood: method and
      evaluation in smokers and non-smokers.
AB  - This study was undertaken with the aim to develop an optimised protocol for the
      evaluation of DNA damage in frozen whole blood. This was achieved by use of the
      single-cell gel electrophoresis (SCGE) or comet assay in its alkaline version.
      After collection of blood, the total blood sample was mixed with dimethyl
      sulfoxide (DMSO), a cryoprotectant commonly used for prevention of freezing
      induced damage to living cells, and then stored at -80 degrees C. We observed no
      statistically significant differences in the level of DNA damage between fresh
      blood samples and frozen blood samples, as assessed by the comet assay.
      Considering the absence of effects of the freezing step, a frozen blood sample
      was included as a control sample in subsequent experiments. Thus the protocol was
      applied to blood samples of twenty healthy subjects including smokers and non
      smokers. The comparative analysis indicated that the level of DNA damage was 56%
      higher in smokers than in non-smokers (P = 0.01). Altogether, this study strongly
      suggests that frozen whole blood could be utilised in association with the comet
      assay in human epidemiological bio-monitoring for the assessment of genetic
      damage in populations at risk.

PMID- 15036120
TI  - Lack of increased genetic damage in 1,3-butadiene-exposed Chinese workers studied
      in relation to EPHX1 and GST genotypes.
AB  - 1,3-Butadiene (BD) is an important industrial chemical and pollutant. Its ability
      to induce genetic damage and cause hematological malignancies in humans is
      controversial. We have examined chromosome damage by fluorescence in situ
      hybridization (FISH) and mutations in the HPRT gene in the blood of Chinese
      workers exposed to BD. Peripheral blood samples were collected and cultured from
      39 workers exposed to BD (median level 2 ppm, 6 h time-weighted average) and 38
      matched controls in Yanshan, China. No difference in the level of aneuploidy or
      structural changes in chromosomes 1, 7, 8, and 12 was detected in metaphase cells
      from exposed subjects in comparison with matched controls, nor was there an
      increase in the frequency of HPRT mutations in the BD-exposed workers. Because
      genetic polymorphisms in glutathione S-transferase (GST) enzymes and microsomal
      epoxide hydrolase (EPHX1) may affect the genotoxic effects of BD and its
      metabolites, we also related chromosome alterations and gene mutations to GSTT1,
      GSTM1 and EPHX1 genotypes. Overall, there was no effect of variants in these
      genotypes on numerical or structural changes in chromosomes 1, 7, 8 and 12 or on
      HPRT mutant frequency in relation to BD exposure, but the GST genotypes did
      influence background levels of both hyperdiploidy and HPRT mutant frequency. In
      conclusion, our data show no increase in chromosomal aberrations or HPRT
      mutations among workers exposed to BD, even in potentially susceptible genetic
      subgroups. The study is, however, quite small and the levels of BD exposure are
      not extremely high, but our findings in China do support those from a similar
      study conducted in the Czech Republic. Together, these studies suggest that low
      levels of occupational BD exposure do not pose a significant risk of genetic
      damage.

PMID- 15036122
TI  - Effects of asbestos on initiation of DNA damage, induction of DNA-strand breaks,
      P53-expression and apoptosis in primary, SV40-transformed and malignant human
      mesothelial cells.
AB  - Human mesothelial cells (HMC), the progenitor cells of asbestos-induced
      mesothelioma, are particularly sensitive to the genotoxic effects of asbestos,
      although the molecular mechanisms by which asbestos induces injury in HMC are not
      well known. The high susceptibility of HMC to simian virus 40 (SV40)-mediated
      transformation is assumed to play a causative role in the pathogenesis of
      mesothelioma. The aim of this study was to investigate the asbestos-induced DNA
      damage in cultured HMC and SV40-transformed HMC (MeT-5A) compared with their
      malignant counterparts, i.e. human mesothelioma cells (MSTO). The time-dependent
      initiation of DNA-strand breaks as well as the induction of oxidative DNA base
      modifications were key factors for investigation. HMC, MeT-5A and MSTO cells were
      exposed to chrysotile and crocidolite asbestos (3 microg/cm2) during different
      time periods (1-72 h). DNA damage was investigated by use of the Comet assay and
      alkaline unwinding, the latter in combination with the Fpg protein. The P53 level
      was analyzed by immunofluorescence, and measurement of apoptosis was conducted by
      flow cytometry. We found a significant induction of DNA damage in asbestos
      treated HMC already after an exposure time of 1.5 h. This effect could not be
      observed in treated MeT-5A and MSTO cells. Also, a time-dependent significant
      increase in DNA-strand breaks was observed by alkaline unwinding in asbestos
      treated HMC, but not in treated MeT-5A and MSTO cells. In none of the three cell
      lines we could detect oxidative DNA damage recognized by the Fpg protein (e.g. 8
      oxo-guanine), up to 24 h after exposure to asbestos. In contrast to what was
      found in HMC, P53 was over-expressed in untreated MeT-5A and MSTO. The induction
      of apoptosis by asbestos fibers was suppressed in MeT-5A and MSTO cells.
      Crocidolite fibers induced the higher genotoxic effects and chrysotile the more
      pronounced apoptotic effects. We conclude that asbestos induces DNA damage in HMC
      already after a very short exposure time in the absence of 8-oxo-guanine
      formation. The presence of SV40-Tag in MeT-5A and MSTO cells results in an
      increased expression of P53, but not in additive genotoxic effects after exposure
      to asbestos. The deregulation of the apoptotic pathway may lead to proliferation
      of genomically damaged cells and finally to the development of mesothelioma.

PMID- 15036123
TI  - Evaluation of the genotoxicity of cis-bis(3-aminoflavone)dichloroplatinum(II) in
      comparison with cis-DDP.
AB  - Short-term tests that detect genetic damage have provided information needed for
      evaluating carcinogenic risks of chemicals to man. The mutagenicity of cis-bis(3
      aminoflavone)dichloroplatinum(II) (cis-[Pt(AF)2Cl2]) in comparison with cis
      diamminedichloroplatinum(II) (cis-DDP) was evaluated in the standard plate
      incorporation assay in four strains of Salmonella typhimurium: TA97a, TA98, TA100
      and TA102, in experiments with and without metabolic activation. It was shown
      that cis-[Pt(AF)2Cl2] acts directly and is mutagenic for three strains of S.
      typhimurium: TA97a, TA98 and TA100. In comparison with cis-DDP this compound
      showed a weaker genotoxicity. Contrary to cis-DDP it has not shown toxic
      properties in the tester bacteria. The genotoxicity of both tested compounds was
      evaluated using chromosomal aberration, sister chromatid exchange and
      micronucleus assays, without and with metabolic activation, in human lymphocytes
      in vitro. The inhibitory effects of both compounds on mitotic activity, cell
      proliferation kinetics and nuclear division index were also compared. In all test
      systems applied, cis-[Pt(AF)2Cl2] was a less effective clastogen and a weaker
      inducer of both sister chromatid exchanges and micronuclei in comparison with cis
      DDP, with and without metabolic activation. cis-[Pt(AF)2Cl2] has a direct
      mechanism of action and is less cytostatic and cytotoxic than the other compound.
      These results provide important data on the genotoxicity of cis-[Pt(AF)2Cl2] and
      indicate its beneficial properties as a potential anticancer drug, especially in
      comparison with cis-DDP.

PMID- 15036124
TI  - Metal-mediated oxidative damage to cellular and isolated DNA by gallic acid, a
      metabolite of antioxidant propyl gallate.
AB  - Propyl gallate (PG), widely used as an antioxidant in foods, is carcinogenic to
      mice and rats. PG increased the amount of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8
      oxodG), a characteristic oxidative DNA lesion, in human leukemia cell line HL-60,
      but not in HP100, which is hydrogen peroxide (H2O2)-resistant cell line derived
      from HL-60. Although PG induced no or little damage to 32P-5'-end-labeled DNA
      fragments obtained from genes that are relevant to human cancer, DNA damage was
      observed with treatment of esterase. HPLC analysis of the products generated from
      PG incubated with esterase revealed that PG converted into gallic acid (GA). GA
      induced DNA damage in a dose-dependent manner in the presence of Fe(III)EDTA or
      Cu(II). In the presence of Fe(III) complex such as Fe(III)EDTA or Fe(III)ADP, GA
      caused DNA damage at every nucleotide. Fe(III) complex-mediated DNA damage by GA
      was inhibited by free hydroxy radical (*OH) scavengers, catalase and an iron
      chelating agent. These results suggested that the Fe(III) complex-mediated DNA
      damage caused by GA is mainly due to *OH generated via the Fenton reaction. In
      the presence of Cu(II), DNA damage induced by GA occurred at thymine and
      cytosine. Although *OH scavengers did not prevent the DNA damage, methional
      inhibited the DNA damage. Cu(II)-mediated DNA damage was inhibited by catalase
      and a Cu(I) chelator. These results indicated that reactive oxygen species formed
      by the interaction of Cu(I) and H2O2 participates in the DNA damage. GA increased
      8-oxodG content in calf thymus DNA in the presence of Cu(II), Fe(III)EDTA or
      Fe(III)ADP. This study suggested that metal-mediated DNA damage caused by GA
      plays an important role in the carcinogenicity of PG.

PMID- 15036126
TI  - Susceptibility of male and female medaka (Oryzias latipes) fish to spontaneous
      and X-ray induced micronucleus formation in gill cells.
AB  - The frequency of micronucleated cells (MNCs) was measured in acridine-orange (AO)
      stained RNA-rich gill cells from male and female medaka (Oryzias latipes) fish of
      known body weight. Spontaneous MNC frequencies were not significantly correlated
      with body weight, despite the fact that the heaviest of the 30 fish used
      outweighed the lightest by a factor of 3. Average MNC frequencies were identical
      in males and females at 0.8 per thousand. An X-ray dose of 4 Gy increased the
      frequency of MNCs over the spontaneous level in all 30 of the fish used, reaching
      a level of 7.2 per thousand on average when assayed 24 h after exposure. In X-ray
      treated fish, MNC frequency and body weight were not significantly correlated,
      nor was there any difference between the sexes. These and other results support
      our primary conclusion that AO-staining is suitable for the medaka micronucleus
      assay in gill cells, and indicate that male and female medaka fish are similarly
      and size-independently susceptible to both spontaneous and X-ray induced
      micronucleus formation in gill cells.

PMID- 15036125
TI  - Influence of GSTT1, mEH, CYP2E1 and RAD51 polymorphisms on diepoxybutane-induced
      SCE frequency in cultured human lymphocytes.
AB  - 1,3-Butadiene (BD) is a common chemical in the human environment. Diepoxybutane
      (DEB) is the most reactive epoxide metabolite of BD. The aim of the present study
      was to evaluate the influence of polymorphisms in enzymes operating in DEB
      metabolism (epoxide hydrolase mEH, CYP2E1 and GSTT1), as well as in the DNA
      repair enzyme RAD51, on the frequency of sister chromatid exchange (SCE) induced
      by DEB in lymphocyte cultures from 63 healthy donors. Their genotypes were
      determined using PCR and restriction fragment length polymorphism (RFLP)-PCR
      techniques. The analysis of xenobiotic-metabolizing genes revealed that GSTT1 and
      CYP2E1 polymorphisms have an influence on DEB-induced SCE frequency. Individuals
      with the GSTT1 null genotype and CYP2E1 c2 variant allele heterozygotes were
      observed to have significantly higher SCE frequency than individuals with more
      common genotypes. A correlation between sensitivity to DEB and GSTT1 null
      genotype indicates that this pathway is a major detoxification step in DEB
      metabolism in whole-blood lymphocyte cultures, which has been shown in many
      studies. The analysis of combined polymorphisms indicated that, in the presence
      of GSTT1, a significantly higher DEB-induced SCE frequency is observed in the
      CYP2E1 c2 variant allele heterozygotes than in individuals with the most common
      CYP2E1 genotype. In the absence of GSTT1, however, the CYP2E1 polymorphism has no
      influence on DEB-induced SCEs. A significant difference was also observed between
      individuals characterized by low and high mEH activity, but only in subjects with
      the GSTT1 null genotype. Lack of GSTT1 resulted in higher SCE frequency in
      individuals with mEH high-activity genotypes than in individuals with mEH low
      activity genotype. In the present study no statistically significant difference
      in DEB-induced SCEs was observed for the RAD51 polymorphism. The influence of
      GSTT1 genotype on SCE-frequency in RAD51 variant allele carriers was not analysed
      as all individuals in this group (except one person) had the GSTT1 gene present.
      Our study shows that the combined analysis of polymorphisms in metabolizing
      enzymes may lead to a better understanding of their contribution to an
      individual's susceptibility to DEB.

PMID- 15036127
TI  - Clastogenicity of selective serotonin-reuptake inhibitors.
AB  - OBJECTIVE: Selective serotonin-reuptake inhibitors (SSRIs) are used in the
      treatment of various forms of psychiatric disorders. Preclinical studies in
      laboratory animals have indicated that SSRIs were not genotoxic, but clear
      results from in vitro testing of SSRIs in a human cell system are currently
      scarce. The purpose of this study was to investigate whether SSRIs might be
      genotoxic. Sertraline was chosen as model SSRI, since it appears to be at least
      as well-tolerated as other SSRIs and may even have a more favourable side-effect
      profile. Unlike fluoxetine, fluvoxamine and paroxetine, sertraline has low
      potential for pharmacokinetic drug interactions. So, sertraline would be
      considered first in the treatment of psychiatric disorders requiring SSRI therapy
      in the future. We therefore examined peripheral lymphocytes from sertraline
      treated patients for both sister chromatid exchanges (SCEs), cells with a high
      frequency of SCEs (HFC) and chromosome aberrations (CA) to evaluate the
      clastogenicity of SSRIs. METHOD: Ten sertraline-treated patients meeting
      'Structured Clinical Interview for DSM-IV' criteria for both generalized anxiety
      disorder and major depression were compared with 18 healthy volunteers and 18 non
      treated patients with similar psychopathology. Sertraline hydrochloride was
      administered orally at 50 mg daily for 10 months to 1 year. The participants were
      selected on the basis of similar responses to a questionnaire assessing risk of
      genotoxicity related to other aspects of life. All participants had very similar
      lifestyles, medical histories, biological and dietary factors. All subjects were
      non-smokers. RESULT: A statistically significant difference between patients with
      both generalized anxiety disorder and major depression (sertraline-treated or non
      treated) and healthy volunteer groups was found by both SCE frequencies and HFC
      percentages. Both patient groups showed higher frequencies of SCEs than the
      healthy controls. No statistically significant difference was found between SCE
      frequencies or HFC percentages observed in sertraline-treated and non-treated
      patient groups. No statistical difference was found between groups with respect
      to the frequency of CA. CONCLUSION: There are no adequate studies analysing the
      clastogenicity of SSRIs, in particular of sertraline. The SCE frequency, the
      percentage HFC and the frequency of CA in patients with both generalized anxiety
      disorder and major depression exposed to daily doses of sertraline do not
      indicate a possible clastogenic hazard. The increased SCE frequencies in patients
      with both generalized anxiety disorder and major depression in our study
      irrespective of sertraline treatment-indicate a possible genotoxic effect.
      However, our observations were based on a limited number of patients; the results
      may be explained by psychogenic stress.

PMID- 15036128
TI  - Ex vivo modulation of chemical-induced mutagenesis by subcellular liver fractions
      of rats treated with rooibos (Aspalathus linearis) tea, honeybush (Cyclopia
      intermedia) tea, as well as green and black (Camellia sinensis) teas.
AB  - Male Fischer rats were given unprocessed (not oxidized) and processed (oxidized)
      rooibos and honeybush teas as well as green and black teas as a sole source of
      drinking fluid for 10 weeks, and sub cellular liver fractions were prepared.
      Cytosolic fractions of rats consuming the unprocessed herbal teas, green and
      black teas significantly (P < 0.05) protected against 2-acetylaminofluorene (2
      AAF)-induced mutagenesis in the Salmonella mutagenicity test with strain TA 98,
      using Aroclor 1254-induced microsomes. A marginal or no protection was obtained
      with the processed herbal teas. The mutagenic response of aflatoxin B1 (AFB1)
      against Salmonella strain TA 100 was significantly (P < 0.05) inhibited by
      cytosolic fractions from rats treated with processed and unprocessed herbal teas,
      while no effect was obtained with the green and black teas. Microsomal fractions
      prepared from livers of rats treated with both the processed and unprocessed
      rooibos teas and the unprocessed honeybush tea, significantly (P < 0.05) reduced
      the activation of AFB1 while no protection was observed against 2-AAF-induced
      mutagenesis. In contrast, microsomal fractions from rats treated with the green,
      black and unprocessed honeybush teas significantly (P < 0.05) enhanced the
      mutagenic response of 2-AAF. None of the tea treatments significantly affected
      the concentration of the microsomal liver cytochrome P450.

PMID- 15036129
TI  - Genotoxic and mutagenic activity of environmental air samples in Flanders,
      Belgium.
AB  - Atmospheric pollution is assumed to play a role in the incidence of respiratory
      diseases and cancers. Airborne particles are able to penetrate deep into the lung
      and are composed of complex chemical mixtures, including mutagens and carcinogens
      such as polycyclic aromatic compounds (PACs). The present study reports mutagenic
      and genotoxic activities associated with ambient air collected near a busy street
      in Borgerhout, at an industrial site in Hoboken and in Peer, a rural community 70
      km east of Antwerp in Flanders, Belgium. Airborne particulates (PM10) and semi
      volatile organic compounds were sampled during winter and summer. Samples were
      collected with a high-volume sampler using quartz filters (QF) and polyurethane
      foam (PUF) cartridges. The mutagenic and genotoxic activity of the organic
      extracts was determined using the Salmonella test/standard plate-incorporation
      assay and the Vitotox assay. Concentrations of 16 polycyclic aromatic
      hydrocarbons (PAHs) in the extracts were determined by reversed-phase high
      performance liquid chromatography (HPLC). The mutagenicity assay, using
      Salmonella typhimurium strain TA98, demonstrated direct mutagenicity of up to 58
      revertants/m3 for the QF extracts and low or no mutagenic activity in the PUF
      extracts. Metabolic activation of the samples resulted in high indirect
      mutagenicity for both QF and PUF extracts: up to 96 revertants/m3 were found in
      QF samples and 62 revertants/m3 in PUF samples. Genotoxic effects of the filter
      extracts were assessed with the Vitotox assay: some direct genotoxic effects were
      noted, i.e. without metabolic activation, but almost no effects were observed
      after metabolic activation. Without activation, most PUF extracts were
      bacteriotoxic. With metabolic activation this toxicity disappeared, but genotoxic
      effects were not observed. Statistical analysis showed that the observed
      biological effects correlated well with the PAH concentrations.

PMID- 15036130
TI  - Induction of apoptosis and necrosis in lymphocytes by the cis-Pt(II) complex of 3
      aminoflavone in comparison with cis-DDP.
AB  - cis-Diamminedichloroplatinum(II) (cis-DDP) is one of the most widely
      administrated antitumor drugs. However, the use of cis-DDP is severely limited
      because of its toxic side effects. Therefore, efforts are concentrated on the
      development of improved platinum compounds with a broader activity spectrum and
      effectiveness in chemotherapy, but lower toxicity. Beneficial properties of
      flavonoids, e.g. their antitumor activity, encouraged scientists to synthesize
      cis-bis(3-aminoflavone)dichloroplatinum(II). Abilities of these compounds to
      induce apoptosis and necrosis were compared by use of trypan blue, fluorochrome
      staining (Hoechst 33258/propidium iodide double staining) and TUNEL assays. The
      cytotoxicity was evaluated by MTT. The results obtained show that the cis-Pt(II)
      complex of 3-aminoflavone is less toxic than cis-DDP. However, the former
      compound has a faster rate of apoptosis induction in lymphocytes than the latter.
      The cis-Pt(II) complex of 3-aminoflavone induces apoptosis in normal lymphocytes
      to a lesser degree and could be a potential antitumor drug.

PMID- 15036131
TI  - Assessment of the performance of the Ames II assay: a collaborative study with 19
      coded compounds.
AB  - Nineteen coded chemicals were tested in an international collaborative study for
      their mutagenic activity. The assay system employed was the Ames II Mutagenicity
      Assay, using the tester strains TA98 and TAMix (TA7001-7006). The test compounds
      were selected from a published study with a large data set from the standard Ames
      plate-incorporation test. The following test compounds including matched pairs
      were investigated: cyclophoshamide, 2-naphthylamine, benzo(a)pyrene, pyrene, 2
      acetylaminofluorene, 4,4'-methylene-bis(2-chloroaniline), 9,10
      dimethylanthracene, anthracene, 4-nitroquinoline-N-oxide, diphenylnitrosamine,
      urethane, isopropyl-N(3-chlorophenyl)carbamate, benzidine, 3,3'-5,5'
      tetramethylbenzidine, azoxybenzene, 3-aminotriazole, diethylstilbestrol, sucrose
      and methionine. The results of both assay systems were compared, and the inter
      laboratory consistency of the Ames II test was assessed. Of the eight mutagens
      selected, six were correctly identified with the Ames II assay by all
      laboratories, one compound was judged positive by five of six investigators and
      one by four of six laboratories. All seven non-mutagenic samples were
      consistently negative in the Ames II assay. Of the four chemicals that gave
      inconsistent results in the traditional Ames test, three were uniformly
      classified as either positive or negative in the present study, whereas one
      compound gave equivocal results. A comparison of the test outcome of the
      different investigators resulted in an inter-laboratory consistency of 89.5%.
      Owing to the high concordance between the two test systems, and the low inter
      laboratory variability in the Ames II assay results, the Ames II is an effective
      screening alternative to the standard Ames test, requiring less test material and
      labor.

PMID- 15036133
TI  - Bacterial subversion of lipid rafts.
AB  - Bacteria rely on numerous basic cellular functions of their target cells to reach
      successful infection. The recent discovery that the plasma membrane contains
      specialized microdomains, called lipid rafts, with many specific functions but in
      particular with the ability to concentrate signaling molecules, has therefore
      attracted the attention of cellular microbiologists. Since then an increasing
      number of bacteria and their products have been shown to interact with lipid
      rafts to promote infection or intoxication. Here we review why certain bacteria
      and/or their products are attracted toward these lipid microdomains.

PMID- 15036134
TI  - Wake of the flood: ascribing functions to the wave of type III effector proteins
      of phytopathogenic bacteria.
AB  - Plant pathogenic bacteria use waves of type III effector proteins, delivered into
      the eukaryotic host cell, to modulate the host cell for the pathogen's benefit.
      This is evidenced by the flood of effector genes that have recently been
      uncovered from the genome sequence of several plant pathogenic bacteria. However,
      pathogens are unwilling to easily reveal the mechanisms by which these effectors
      function. Nevertheless, persistent scrutiny has led to the successful
      characterization of a handful of effectors and it is beginning to provide
      insights into how phytopathogenic bacteria cause disease on their hosts.

PMID- 15036135
TI  - The roles of anthrax toxin in pathogenesis.
AB  - Anthrax lethal toxin is a multi-functional virulence factor that has evolved to
      target multiple host functions to allow for optimal establishment of Bacillus
      anthracis infection. The toxin appears to play a role in all stages of infection,
      from germination to the induction of vascular collapse leading to host death.
      Early in infection, at sublethal doses, it acts to suppress immune cell and
      cytokine responses, thereby promoting bacterial outgrowth. Later in the disease,
      lethal levels of toxin induce the cytokine-independent shock-like death
      associated with anthrax. The understanding of the molecular events induced by
      anthrax toxin in different target cells at each stage of infection will aid in
      deciphering the pathogenesis of this bacterium and developing therapies.

PMID- 15036136
TI  - Innate immunity via Toll-like receptors and Nod proteins.
AB  - Host defense against microbes requires the development of an efficient immune
      response aimed to eradicate the source of infection. Through the expression of a
      battery of germ-line encoded receptors, including the Toll-like receptors and Nod
      proteins, the innate immune system, which is a prerequisite to the adaptive
      immune response, detects microbial motifs and initiates pro-inflammatory
      signaling. Current research into innate immune function focuses on the nature of
      the ligands detected by this system, the cell signaling that occurs downstream of
      receptor activation and finally, how these signals culminate into a tailored
      adaptive immune response directed to eradicate a specific infection.

PMID- 15036137
TI  - Proteomic and gene profiling approaches to study host responses to bacterial
      infection.
AB  - Infectious disease is the result of an intimate relationship between the pathogen
      and host, which involves cross-talk. After an initial flood of mainly descriptive
      reports on the influence of acute bacterial infection on cells, transcriptome and
      proteome studies are now becoming more refined in their approach, and are
      shedding light on the role of pathogen-specific mechanisms/structures in
      pathogenesis. In addition, studies of gene expression in vivo have shed new light
      on how the host influences the niche occupied by bacteria. Elegant refinements to
      proteomics using beads coated with bacterial invasins, or purifying subcellular
      fractions are producing a picture of invasion specific processes. Such approaches
      combined with modern functional genomics technologies such as RNAi represent the
      next phase in understanding host-bacteria interactions.

PMID- 15036138
TI  - Analysis of regulatory networks in Pseudomonas aeruginosa by genomewide
      transcriptional profiling.
AB  - Transcriptional profiling using DNA microarrays has proved to be a valuable tool
      for dissecting bacterial adaptation to various environments, including human
      hosts. Analysis of genomes and transcriptomes of Pseudomonas aeruginosa shows
      that this bacterium possesses and expresses a core set of genes, including
      virulence factors, which allow it to thrive in a range of environments.
      Transcriptional regulators previously thought to control single virulence traits
      are now shown to regulate complex global signaling networks. Microarray-based
      research has led to the discovery of upstream regulators and downstream
      components of these pathways, as well as probed the response to antibiotics,
      environmental stresses and other bacteria. Independent studies have highlighted
      the role of media composition, the makeup of the physical environment and
      experimental methods in the outcome of microarray analyses. A compilation of all
      the published data clearly shows transcriptional regulation of genes in all
      functional classes. Under conditions examined to date, slightly more than a
      quarter of the genome is regulated, suggesting that P. aeruginosa may use much of
      its genome for conditions unexplored in the laboratory.

PMID- 15036139
TI  - T cell responses to Listeria monocytogenes.
AB  - Owing to its unique intracellular biology that allows it to gain access to the
      host cell cytosol, Listeria monocytogenes induces potent, protective CD8
      responses. The study of these responses has served as a paradigm to understand
      cell-mediated immunity to microbial pathogens. The availability of mutants
      specifically defective in unique aspects of the intracellular biology of this
      pathogen has greatly aided these studies. During the past few years, progress has
      been made to understand the contribution of the innate immune system and CD4 T
      cells in the generation of robust, long lasting CD8 responses to L.
      monocytogenes.

PMID- 15036140
TI  - Living in the danger zone: innate immunity to Salmonella.
AB  - Phagocytic cells, including macrophages, neutrophils and dendritic cells, are
      critical components of the innate immune response to bacterial pathogens such as
      Salmonella typhimurium. These cells can have several roles during the early stage
      of an infection including controlling bacterial replication and producing
      cytokines and chemokines that activate and recruit additional cells. Macrophages,
      neutrophils and dendritic cells increase in number early after oral Salmonella
      infection and produce cytokines important in host survival such as tumor necrosis
      factor alpha (TNF-alpha). All three phagocytic cell types also harbor bacteria
      during infection. Natural killer cells, natural killer T cells and T cell
      receptor alpha beta T cells also respond rapidly to infection and are early
      sources of interferon-gamma during infection with Salmonella. Studies using
      infection models with Salmonella are providing a picture of the innate response
      to bacteria and insight into the role of defined cell types and cytokines
      important in the transition from innate to adaptive immunity.

PMID- 15036141
TI  - Adaptive immunity to mycobacteria.
AB  - Advances are now being made in terms of understanding both the initiation of the
      adaptive or acquired response to tuberculosis infection and its interface with
      elements of the innate response, as well as much later events in terms of the
      chronic disease state where reactivation can potentially occur. Despite this,
      there are still several elements of the adaptive response that remain poorly
      understood.

PMID- 15036142
TI  - How do neutrophils and pathogens interact?
AB  - Many pathogens can manipulate macrophages after phagocytosis yet are efficiently
      killed by neutrophils. This poses the question of whether neutrophils have
      mechanisms that enable them to specifically recognise pathogens and have
      pathogens evolved mechanisms to modulate neutrophil function? Here, we review
      recent work on neutrophils and their interaction with four different bacteria:
      Staphylococcus aureus, Helicobacter pylori, Anaplasma phagocytophilum and members
      of the Enterobacteriae family.

PMID- 15036143
TI  - Wolbachia pipientis: intracellular infection and pathogenesis in Drosophila.
AB  - Wolbachia pipientis is a vertically transmitted, obligate intracellular symbiont
      of arthropods. The bacterium is best known for its ability to manipulate host
      reproductive biology where it can induce cytoplasmic incompatibility,
      parthenogenesis, feminization and male-killing. In addition to the various
      reproductive phenotypes it generates through interaction with host reproductive
      tissue it is also known to infect somatic tissues. However, relatively little is
      known about the consequences of infection of these tissues with the exception
      that in some hosts Wolbachia acts as a classical mutualist and in others a
      pathogen, dramatically shortening adult insect lifespan. Manipulation experiments
      have demonstrated that the severity of Wolbachia-induced effects on the host is
      determined by a combination of host genotype, Wolbachia strain, host tissue
      localization, and interaction with the environment. The recent completion of the
      whole genome sequence of Wolbachia pipientis wMel strain indicates that it is
      likely to use a type IV secretion system to establish and maintain infection in
      its host. Moreover, an unusual abundance of genes encoding proteins with
      eukaryotic-like ankyrin repeat domains suggest a function in the various
      described phenotypic effects in hosts.

PMID- 15036145
TI  - Salmonella redirects phagosomal maturation.
AB  - Following invasion of host cells, Salmonella occupies an intracellular vacuole
      that superficially resembles a phagosome. However, unlike bona fide phagosomes
      that undergo a maturation process to become microbicidal phago-lysosomes,
      Salmonella avoid killing by arresting and diverting the maturation program of the
      invasion vacuole. As a result of this re-routing, the bacteria generate a
      protected niche where they survive and replicate.

PMID- 15036144
TI  - A tale of two lipids: Mycobacterium tuberculosis phagosome maturation arrest.
AB  - Mycobacterium tuberculosis persistence in human populations relies on its ability
      to inhibit phagosomal maturation. M. tuberculosis resides in a pathogen-friendly
      phagosome escaping lysosomal bactericidal mechanisms and efficient antigen
      presentation in the host phagocytic cell. M. tuberculosis phagosome maturation
      arrest includes the action of mycobacterial lipid products, which mimic mammalian
      phosphatidylinositols, targeting host cell membrane trafficking processes. These
      products interfere with membrane trafficking and organelle biogenesis processes
      initiated by Ca(2+) fluxes, and ending with host cell Rab GTP-binding proteins
      and their effectors. The block includes phosphatidylinositol 3-kinase and
      membrane tethering molecules that prepare phagosomes for fusion with other
      organelles. Understanding these processes could provide new targets for
      pharmacological intervention in tuberculosis.

PMID- 15036147
TI  - Organelle robbery: Brucella interactions with the endoplasmic reticulum.
AB  - Brucella is an intracellular pathogen that survives and multiplies inside host
      macrophages to cause brucellosis. The underlying mechanisms of intracellular
      survival, including the bacterial and the host determinants remain relatively
      unknown. Recent advances have helped to decipher how Brucella controls the
      biogenesis of its intramacrophagic replicative organelle. Brucella initially
      avoids or escapes the endocytic pathway to ensure its intracellular survival,
      which is then further secured via the biogenesis of an endoplasmic reticulum
      derived replicative organelle. A major virulence factor, the VirB type IV
      secretion system, is required for sustained interactions and fusion with the host
      endoplasmic reticulum.

PMID- 15036146
TI  - Chlamydia: five years A.G. (after genome).
AB  - The obligate intracellular pathogens Chlamydiaceae are the agents of several
      human diseases. They cannot be genetically manipulated and they survive and
      replicate in a unique intracellular organelle called the inclusion. In the past
      five years, publications of the genome sequences of several strains have opened
      new areas of research. Some of these new advances are presented here.

PMID- 15036149
TI  - Searching for functional sites in protein structures.
AB  - An ability to assign protein function from protein structure is important for
      structural genomics consortia. The complex relationship between protein fold and
      function highlights the necessity of looking beyond the global fold of a protein
      to specific functional sites. Many computational methods have been developed that
      address this issue. These include evolutionary trace methods, methods that
      involve the calculation and assessment of maximal superpositions, methods based
      on graph theory, and methods that apply machine learning techniques. Such
      function prediction techniques have been applied to the identification of enzyme
      catalytic triads and DNA-binding motifs.

PMID- 15036151
TI  - Exploring the range of protein flexibility, from a structural proteomics
      perspective.
AB  - Changes in protein conformation play a vital role in biochemical processes, from
      biopolymer synthesis to membrane transport. Initial systematizations of protein
      flexibility, in a database framework, concentrated on the movement of domains and
      linkers. Movements were described in terms of simple sliding and hinging
      mechanisms of individual secondary structural elements. Recently, the accelerated
      pace and sophistication of methods for structural characterization of proteins
      has allowed high-resolution studies of increasingly complex assemblies and
      conformational changes. New data emphasize a breadth of possible structural
      mechanisms, particularly the ability to drastically alter protein architecture
      and the native flexibility of many structures.

PMID- 15036150
TI  - Functional protein microarrays: ripe for discovery.
AB  - The manufacture and use of protein microarrays with correctly folded and
      functional content presents significant challenges. Despite this, the feasibility
      and utility of such undertakings are now clear, and exciting progress has
      recently been demonstrated in the areas of content generation, printing
      strategies and protein immobilization. More importantly, we are now beginning to
      enjoy the fruits of these efforts as functional protein microarrays are being
      increasingly employed for biological discovery purposes. Recent examples of this
      include the characterization of autoantibody responses, antibody specificity
      profiling, protein-protein domain interaction profiling and a comprehensive
      characterization of coiled-coil interactions. The best, however, is yet to come.

PMID- 15036152
TI  - ORFeome projects: gateway between genomics and omics.
AB  - The availability of entire genome sequences is expected to revolutionize the way
      in which biology and medicine are conducted for years to come. However, achieving
      this promise still requires significant effort in the areas of gene annotation,
      cloning and expression of thousands of known and heretofore unknown protein
      encoding genes. Traditional technologies of manipulating genes are too cumbersome
      and inefficient when one is dealing with more than a few genes at a time. Entire
      libraries composed of all protein-encoding open reading frames (ORFs) cloned in
      highly flexible vectors will be needed to take full advantage of the information
      found in any genome sequence. The creation of such ORFeome resources using novel
      technologies for cloning and expressing entire proteomes constitutes an effective
      gateway from whole genome sequencing efforts to downstream 'omics' applications.

PMID- 15036153
TI  - Tagged library approach to chemical genomics and proteomics.
AB  - Proteomics and chemical genomics face great challenges in the form of molecular
      libraries of ever increasing size and diversity requiring rapid screening,
      coupled with a growing number of target proteins for which complimentary
      molecular ligands are sought. Proteomics and chemical genomics are at a stage
      that requires techniques which can dramatically accelerate the discovery process.
      One technique that has shown great promise in accomplishing this is the tagged
      library approach. It entails the synthetic inclusion of an internal tag from the
      beginning of the synthesis. This tag adds another degree of functionality to the
      molecule, in addition to mere ligation, that eliminates the need for time
      consuming steps downstream in the process. The tag's functional possibilities
      span a variety of uses including internal fluorophores, intrinsic binding motifs
      that enable compound identification, functionalities that play the major role in
      the synthesis of the ligand itself, and internal linkers that eliminate the need
      for lengthy 'tether effect' structure-activity relationship studies.

PMID- 15036154
TI  - Modification-specific proteomics: characterization of post-translational
      modifications by mass spectrometry.
AB  - Post-translational modifications generate tremendous diversity, complexity and
      heterogeneity of gene products, and their determination is one of the main
      challenges in proteomics research. Recent developments in mass spectrometry based
      approaches for systematic, qualitative and quantitative determination of modified
      proteins promise to bring new insights on the dynamics and spatio-temporal
      control of protein activities by post-translational modifications, and reveal
      their roles in biological processes and pathogenic conditions. Combinations of
      affinity-based enrichment and extraction methods, multidimensional separation
      technologies and mass spectrometry are particularly attractive for systematic
      investigation of post-translationally modified proteins in proteomics.

PMID- 15036155
TI  - Structural proteomics: a tool for genome annotation.
AB  - In any newly sequenced genome, 30% to 50% of genes encode proteins with unknown
      molecular or cellular function. Fortunately, structural genomics is emerging as a
      powerful approach of functional annotation. Because of recent developments in
      high-throughput technologies, ongoing structural genomics projects are generating
      new structures at an unprecedented rate. In the past year, structural studies
      have identified many new structural motifs involved in enzymatic catalysis or in
      binding ligands or other macromolecules (DNA, RNA, protein). The efficiency by
      which function is deduced from structure can be further improved by the
      integration of structure with bioinformatics and other experimental approaches,
      such as screening for enzymatic activity or ligand binding.

PMID- 15036156
TI  - Protein localization in proteomics.
AB  - A global analysis of the localization of 4156 yeast proteins has just been
      accomplished. Smaller scale analyses have been performed in a variety of
      organisms. These studies typically use green fluorescent protein as a tag for
      proteins in living cells. Improvements in the yellow and sapphire color variants
      will increase their utility. Reengineering of the red fluorescent protein has
      produced faster maturing tetrameric and monomeric variants not prone to
      aggregation. Techniques for high-throughput tagging of proteins include
      integration by homologous recombination, integration using mobile elements or
      recombinational cloning to produce plasmids expressing fusion proteins.
      Alternatives to localizing tagged proteins are to use antibodies or aptamers to
      detect the untagged protein.

PMID- 15036158
TI  - Structural change in response to ligand binding.
AB  - The minutiae of subtle changes that occur in response to ligand binding in
      multiprotein complexes are often difficult to assess without resource to high
      resolution X-ray analysis. Recent developments in mass spectrometry, however, are
      providing insight into dynamic changes within components. In this article we
      review recent applications of MS for selection of ligands and definition of their
      binding characteristics for individual protein targets through to macromolecular
      complexes such as ribosomes.

PMID- 15036157
TI  - The development and application of methods for activity-based protein profiling.
AB  - Recent advances in genomic and proteomic technologies have begun to address the
      challenge of assigning molecular and cellular functions to the numerous protein
      products encoded by prokaryotic and eukaryotic genomes. In particular, chemical
      strategies for proteome analysis have emerged that enable profiling of protein
      activity on a global scale. Herein, we highlight these chemical proteomic methods
      and their application to the discovery and characterization of disease-related
      enzyme activities.

PMID- 15036159
TI  - Chemical probes and tandem mass spectrometry: a strategy for the quantitative
      analysis of proteomes and subproteomes.
AB  - Quantitative proteome profiling using mass spectrometry and stable isotope
      dilution is being widely applied for the functional analysis of biological
      systems and for the detection of clinical, diagnostic or prognostic marker
      proteins. Because of the enormous complexity of proteomes, their comprehensive
      analysis is unlikely to be routinely achieved in the near future. However, in
      recent years, significant progress has been achieved focusing quantitative
      proteomic analyses on specific protein classes or subproteomes that are rich in
      biologically or clinically important information. Such projects typically combine
      the use of chemical probes that are specific for a targeted group of proteins and
      may contain stable isotope signatures for accurate quantification with automated
      tandem mass spectrometry and bioinformatics tools for data analysis. In this
      review, we summarize technical and conceptual advances in quantitative
      subproteome profiling based on tandem mass spectrometry and chemical probes.

PMID- 15036160
TI  - Protein sequence databases.
AB  - A variety of protein sequence databases exist, ranging from simple sequence
      repositories, which store data with little or no manual intervention in the
      creation of the records, to expertly curated universal databases that cover all
      species and in which the original sequence data are enhanced by the manual
      addition of further information in each sequence record. As the focus of
      researchers moves from the genome to the proteins encoded by it, these databases
      will play an even more important role as central comprehensive resources of
      protein information. Several the leading protein sequence databases are discussed
      here, with special emphasis on the databases now provided by the Universal
      Protein Knowledgebase (UniProt) consortium.

PMID- 15036161
TI  - From large networks to small molecules.
AB  - Large-scale analysis of genetic and physical interaction networks has begun to
      reveal the global organization of the cell. Cellular phenotypes observed at the
      macroscopic level depend on the collective characteristics of protein and genetic
      interaction networks, which exhibit scale-free properties and are highly
      resistant to perturbation of a single node. The nascent field of chemical
      genetics promises a host of small-molecule probes to explore these emerging
      networks. Although the robust nature of cellular networks usually resists the
      action of single agents, they may be susceptible to rationally designed
      combinations of small molecules able to collectively shift network behavior.

PMID- 15036162
TI  - Computational design of protein-protein interactions.
AB  - Computational protein design strategies have been developed to reengineer protein
      protein interfaces in an automated, generalizable fashion. In the past two years,
      these methods have been successfully applied to generate chimeric proteins and
      protein pairs with specificities different from naturally occurring protein
      protein interactions. Although there are shortcomings in current approaches, both
      in the way conformational space is sampled and in the energy functions used to
      evaluate designed conformations, the successes suggest we are now entering an era
      in which computational methods can be used to modulate, reengineer and design
      protein-protein interaction networks in living cells.

PMID- 15036163
TI  - Protein expression clone repositories for functional proteomics.
AB  - The information generated from the sequence of the human genome has inspired
      efforts to systematically develop organized collections of human cDNA clones for
      use in expression screens in mammalian cells. These high-throughput cloning
      initiatives offer significant advantages over the cDNA libraries that have been
      used in the past, including greater experimental flexibility, immediate
      identification of hits, information regarding all tested proteins (even for those
      giving no response) and eventually more comprehensive coverage. Some of the
      lessons learned and the considerations that underlie the creation of genome-wide
      cDNA repositories are discussed here. Although still inchoate, these resources
      are already impacting the manner in which high-throughput functional screens are
      performed.

PMID- 15036164
TI  - Professor Melvin David Yahr 1917-2004.

PMID- 15036165
TI  - Uncovering the hidden placebo effect in deep-brain stimulation for Parkinson's
      disease.
AB  - OBJECTIVE: To determine the magnitude of the placebo effect in deep-brain
      stimulation (DBS) for Parkinson's disease (PD). BACKGROUND: The placebo effect in
      PD is related to the expectation of clinical benefit. Changes in expectation
      occurring in DBS crossover studies can be used to estimate the associated placebo
      effect. For example, the response to active-DBS is predicted to be greater in
      patients who have previously experienced the effect of placebo-DBS than in those
      without such an experience. METHODS: Data were obtained by searches of Medline
      and PubMed using three keywords: Parkinson's disease, deep-brain stimulation, and
      crossover study. Between-group comparisons of the effect of active-DBS were
      performed by t-test and analysis of covariance. RESULTS: Data on 126 PD patients
      were available for analysis. These patients participated in a multicenter, two
      period, placebo-controlled crossover study on the efficacy of DBS for PD. As
      predicted, active-DBS was found to be more effective when preceded by placebo-DBS
      (i.e. in the high expectation group) than when not (i.e. in the lower expectation
      group). The estimated magnitude of the placebo effect in DBS was equivalent to
      39% of the magnitude of the effect of active-DBS. CONCLUSIONS: There is a
      prominent placebo effect associated with DBS in PD. Crossover studies may be
      useful for estimating the placebo effect in other medical conditions.

PMID- 15036166
TI  - Quality of life and pain in Parkinson's disease: a controlled cross-sectional
      study.
AB  - PURPOSE: To compare health-related quality of life (HRQL) and pain symptoms in
      patients with PD with a matched control group. To our knowledge, controlled
      studies of Parkinson's disease (PD) patients within this area are rare. SCOPE:
      Fifty-seven patients and 95 controls took part in a self-administered
      questionnaire study. The instruments were the SF-36, visual analogue scales, pain
      drawing and pain-specific questions. CONCLUSIONS: Pain problems are common in PD
      patients but also to a large extent in the normal population. HRQL was reduced (p
      < or = 0.001) for the PD patients on all the scales on the SF-36 and consequently
      also in the pain dimension. The study indicates that even PD patients, who are
      optimally diagnosed and treated by a neurologist, might require additional
      rehabilitation treatment to improve their HRQL and pain problems.

PMID- 15036167
TI  - The effects of a normal protein diet on levodopa plasma kinetics in advanced
      Parkinson's disease.
AB  - LevoDOPA given orally may compete with the neutral aminoacids contained in food
      for its absorption in the small intestine. LevoDOPA plasma kinetics of the
      morning intake with 'french' breakfast (low protein content) were compared with
      those of the noon intake with lunch (normal protein content) in 20 advanced
      parkinsonian patients (mean disease duration: 10 years). The galenic form and the
      dosage of levoDOPA were strictly the same for morning and noon intakes in each
      patient. Blood samplings were collected at T0 (just before intake) and
      successively at 15, 30, 45, 60, 90, 120, 150 and 180 min after intake. LevoDOPA
      plasma levels were further measured with HPLC method, then giving the following
      variables: Cmax (peak concentration), Tmax (time corresponding to Cmax), AUC
      (area under curve). The results showed no significant difference for Cmax and
      Tmax whereas the AUC was significantly (P < 0.001) increased for the noon intake,
      due to the trough concentration effect. These data suggest that, since rich
      protein diet has been shown to impair the clinical effect of LevoDOPA, this
      protein effect is probably not due to competitive intestinal absorption of
      LevoDOPA.

PMID- 15036168
TI  - Hand rhythmic tapping and timing in Parkinson's disease.
AB  - BACKGROUND: Dysrhythmia is one of the features frequently associated with the
      motor disturbance in Parkinson's disease (PD). The mechanism responsible for this
      phenomenon is not known. OBJECTIVES: To assess the rhythmic movements of the hand
      in PD patients in general and in parkinsonian subtypes. METHODS: Fifty-one PD
      patients (32 males) with mean age 66.3 +/- 9.1 years (6.6 years of symptoms) and
      36 healthy controls (age 64.9 +/- 13.2, range 40-85) were studied. Subjects were
      asked to tap with their dominant or less affected arm on a digitized switch board
      at their most comfortable pace (16 s), fastest tapping speed (12 s), and at
      different frequencies provided by a metronome. The mean rhythm and the tap-to-tap
      variation were compared. Performance of the PD patients and control subjects were
      compared, as there were different subtypes of PD patients. Patients were
      subclassified into: tremor predominant (TP) (14 patients), freezing predominant
      (FP) (11 patients), akinetic-rigid (AR) (12 patients) and an unclassified group
      (UC) (14 patients). Results. There was no significance difference between
      patients and controls in the self-chosen, most comfortable tapping rate or in the
      tap-to-tap variation of the self-paced task. PD patients tapped at a
      significantly slower rate than controls when asked to tap at their fastest rate
      (4.39 +/- 1.32 vs. 5.14 +/- 1.31 Hz; p < 0.01). This difference was the result of
      an especially slow performance of the TP and AR subgroups (3.85+/-1.20 and 3.88+/
      1.46, respectively; p < 0.01 compared to the control group). TP was the only
      subgroup to show an increased tap-to-tap variation at their fastest tapping rate
      compared to the control group (0.070 +/- 0.057 vs. 0.029 +/- 0.025 s,
      respectively, p < 0.05). The TP subgroup also showed hastening when they followed
      an externally given rhythm of 2.5 Hz and they tapped at 2.73 +/- 0.36 Hz p <
      0.05). CONCLUSIONS: Externally driven and self-paced tapping are preserved in
      patients with PD, when examined at their best 'on' state. The tremor predominant
      subgroup seems to have specific pacing disturbances.

PMID- 15036169
TI  - Restless legs symptoms in thyroid disorders.
AB  - Dopaminergic dysfunction is associated with thyroid disorders and restless legs
      syndrome (RLS). In a 'face-to-face' interview, we evaluated for RLS using the
      diagnostic criteria of the International Restless Legs Syndrome Study Group
      (IRLSSG) in patients diagnosed biochemically with either hyper- or
      hypothyroidism, and in controls without thyroid disorders. Amongst 146
      consecutive patients with biochemically confirmed thyroid disorders, none
      satisfied all the IRLSSG criteria of RLS, similar to the control population
      (0.2%, 1/434). However, we found 8.2% (12/146) with RLS-like symptoms (satisfied
      the first 3 IRLSSG criteria) compared to 0.9% (4/434) in the controls (p <
      0.0001). Four (33.3%) of these patients reported complete resolution of these
      symptoms after treatment for their thyroid condition. In conclusion, while RLS
      like symptoms were observed in some patients with thyroid disorders, our study
      demonstrates no significant difference of RLS prevalence between patients with
      thyroid disorders and euthyroid controls.

PMID- 15036170
TI  - Mechanical failure of the electrode wire in deep brain stimulation.
AB  - The feasibility and efficacy of deep brain stimulation (DBS) has offered new
      possibilities for treatment of movement disorders. Mechanical failure of the DBS
      system is a potential complication. Here we report five patients who presented
      with mechanical failure of the DBS system. Radiographs of the skull and cervical
      spine were analyzed for disruptions. Seven instances of lead breakage near the
      connection of the DBS electrode with the extension wire were identified. In one
      patient this was in the paramastoid area over the skull, while in all others were
      in the supraclavicular location. The patients consisted of three men and two
      women ranging in age from 24 to 78 (at the time of first operation), one person
      suffering three breakages. The length of spanned time from implantation to
      presentation ranged from 8 to 32 months. Palpation of the electrode lead wire in
      the neck for breakage proved unreliable. Radiography localized the site of
      breakage in all but one patient who required intraoperative exploration, which
      revealed that although the lead wire was disrupted, the two ends remained in
      contact. The fact that all breakages occurred near the connection wire suggests
      that to-and-fro motion of the DBS electrode with repeated head turning leads to
      fatigue and eventual disruption.

PMID- 15036171
TI  - Nocturnal sleep disturbances and daytime dysfunction in patients with Parkinson's
      disease and in their caregivers.
AB  - BACKGROUND: The role of aging, disease, medications, and mood disturbances in
      sleep disturbances (SD) in patients with Parkinson's disease (PD) is poorly
      understood, and the impact of SD on the quality of life of their caregivers (CG)
      largely undocumented. OBJECTIVES: To evaluate the pattern and determinants of
      disturbed sleep in PD patients complaining of SD, and in their primary CG.
      METHODS: A prospective evaluation of 40 non-demented patients with PD complaining
      of SD and 23 of their primary CG (all were spouses) was conducted using
      Pittsburgh Sleep Quality Index, Zung's self-rating depression and anxiety scales,
      Parkinson's Impact Scale (PIMS) (only for PD), and an additional sleep
      questionnaire. RESULTS: Eighty-four percent of patients were 'poor sleepers' with
      global sleep scores (GLSc) > 5. Other abnormalities were: excessive daytime
      sleepiness-57.5%, excessive daytime fatigue-72.5%, depression-51.5%, anxiety
      63.1%, and abnormal PIMS score-83.8%. There was no correlation between the degree
      of sleep dysfunction and the age, severity, duration of PD or its treatment.
      Several component sleep scores correlated with anxiety scores, PIMS score with
      depression, and, subjects with GLSc > or = 10 had higher mean anxiety index.
      Daytime dysfunction (97.5%) was mainly associated with reduced enthusiasm, rather
      than excessive sleepiness. Among CG, 40% had a GLSc > 5, 21% had depression, and
      10.5% had anxiety. Their depression, anxiety and sleep scores correlated with
      those of their spouses. CONCLUSIONS: PD patients with significant SD may
      represent a subset of patients with early, progressive degeneration of sleep
      centres, rather than an enhanced aging process. They are more susceptible mood
      disturbances, which correlate with the severity of sleep dysfunction. Sleep and
      mood disturbances also adversely affect the quality of life of spousal
      caregivers.

PMID- 15036172
TI  - Blepharospasm associated with multiple system atrophy: a case report and review
      of the literature.
AB  - Although blepharospasm has been occasionally associated with parkinsonism, it has
      rarely been reported in patients with multiple system atrophy (MSA). We report a
      65-year-old woman with MSA who developed blepharospasm seven years after onset,
      rendering her functionally blind. Clinical course and the findings of magnetic
      resonance imaging indicated cerebellar type MSA. The blink reflex studies showed
      prolonged R2 response and enhanced recovery cycle, indicating an increased
      excitability of the brainstem interneurons. These results suggest that
      pathophysiology of blepharospasm in MSA is similar to that of essential
      blepharospasm. Recognition of blepharospasm in MSA patients is important, as
      blepharospasm is a treatable feature in this otherwise intractable disorder.

PMID- 15036173
TI  - Post-encephalitic segmental dystonia with apraxia of eyelid opening.
AB  - We describe a 34 year old woman presenting with a 25 year history of segmental
      dystonia with apraxia of eyelid opening, orofacial and focal upper limb dystonia
      following an episode of meningoencephalitis. Post-encephalitic apraxia of eyelid
      opening has not been previously reported in the absence of parkinsonian features.

PMID- 15036174
TI  - Stereotyped behaviors or punding after quetiapine administration in Parkinson's
      disease.
AB  - Quetiapine has been suggested to be useful for the treatment of psychosis in
      patients with Parkinson's disease without prominent deterioration of motor
      functions. We present two patients with Parkinson's disease in whom
      administration of quetiapine for drug-induced psychosis caused characteristic
      stereotyped behaviors or punding. Since stereotyped behaviors are usually
      associated with excessive dopaminergic activity, it is clinically important to
      note that stereotyped behaviors or punding may be induced by an atypical
      antipsychotic drug for the treatment of psychosis in patients with Parkinson's
      disease.

PMID- 15036176
TI  - Drugs of anesthesia, central nicotinic receptors and Parkinson's disease.

PMID- 15036175
TI  - Effects of pergolide on nocturia in Parkinson's disease: three female cases
      selected from over 400 patients.
AB  - We started the subject screening from over 400 patients with Parkinson's disease
      using strict selection criteria to identify the patients with nocturia who would
      allow accurate and efficient evaluation of the pergolide effects. The subjects
      were confined to female patients to exclude patients with potential prostate
      hypertrophy. The patients treated with bromocriptine at 7.5-15 mg/day adjunctive
      to l-dopa were selected to replace bromocriptine with pergolide of the equivalent
      dosage approved in Japan. The nocturia was defined as having more than two
      episodes of urination during sleep per night on average. The subjects received
      the urinary sediment test before and during the study for screening urinary tract
      infection and the study was discontinued when urinary tract infection was found.
      As a result, we identified total 11 patients with nocturia and three of those
      completed the 12-week study of switching dopamine agonist from bromocriptine to
      pergolide. We observed a decrease in nocturia frequency in all three patients, a
      decrease in irritative urinary symptoms in two and an improvement of sleep QOL in
      two. The effect of pergolide on nocturia was independent of improvement of
      parkinsonian symptoms, suggesting a distinct mechanism from that of anti
      parkinsonian effects. Our study also suggests that switching from bromocriptine
      to pergolide improves nocturia, thereby improving sleep status of patients with
      Parkinson's disease.

PMID- 15036177
TI  - Finite element analysis of a femoral retrograde intramedullary nail subject to
      gait loading.
AB  - Intramedullary nails are routinely used in the treatment of fractures of the
      femur. While their effectiveness has been demonstrated clinically, a number of
      complications, including bone refracture and implant failure, persist. This paper
      presents novel three-dimensional finite element (FE) models, at four stages of
      gait, of: (i) a realistic femur analogue known as third generation composite
      bone, and (ii) a system consisting of an intramedullary nail implanted in the
      femur of (i). A comparison of experimentally measured strains on the surface of
      the femur with those predicted by the FE model revealed good agreement. The
      models were then used to identify implant/bone load sharing patterns, and areas
      of stress concentration in both the intramedullary nail and the bone, when
      statically locked by one or two screws at either end. The results of this study
      can be used to guide future implant design and surgical procedure.

PMID- 15036178
TI  - Finite element growth analysis for the craniofacial skeleton in patients with
      cleft lip and palate.
AB  - The purpose of this study was to clarify the differences in the nature of
      craniofacial growth between subjects with normal occlusion and patients with
      unilateral cleft lip and palate (CLP) in terms of the size, shape and principal
      growth direction of craniofacial skeleton using finite element method (FEM).
      Lateral cephalograms were taken of 40 subjects as normal group and 178 patients
      as CLP group. These subjects were divided into seven developmental ages of 4-, 6
      , 8-, 10-, 12-, 14- and 18-year-old. For the finite element analysis, the
      craniofacial complex was discretized into seven structures or elements with three
      nodal points in each after tracing each lateral cephalogram on acetate paper. For
      each stage, the growth parameters in CLP group were compared to those in normal
      group. The growth of upper facial skeleton and maxillary complex was more
      remarkably inhibited in CLP than in normal group. Especially, the growth
      inhibition of posterior maxillary complex in a vertical direction was remarkable
      in CLP group at any ages. Difference in the size and shape of entire mandibular
      skeleton between CLP and normal groups was not apparent. It is suggested that
      grow timing and peak velocity, an essential and key determinant to the success in
      orthodontic treatment, have been clarified in this study more clearly than in
      previous studies. It is hopefully anticipated to explore some key determinants to
      predict individual growth of the craniofacial skeleton near future.

PMID- 15036179
TI  - Comparison of the trabecular architecture and the isostatic stress flow in the
      human calcaneus.
AB  - It is a common theory that the architecture of trabecular bone follows the
      principal stress trajectories, as suggested by Wolff's pioneering studies of the
      proximal femur. Since first published in the late 19th-century, this observation
      (popularized as "Wolff's law") has been supported by numerous studies, but nearly
      all of them have been focused on the femoral head and neck. In this study, the
      manifestation of Wolff's law in the human calcaneus has been analyzed. For this
      purpose, finite element (FE) analysis of the entire complex of the foot during
      standing was undertaken. Orientation of the principal stress flow through the
      calcaneus was compared with the trabecular alignment in a single cadaveric
      calcaneal specimen, by fitting second-order polynomials to real trabecular paths
      and FE-predicted isostatics and calculating their angle of inclination with the
      calcaneal cortex at their insertion points. Four dominant trabecular patterns
      were identified in the cadaveric sagittal section of the specimen of the
      calcaneus: one directed primarily in the dorsal-plantar direction, one aligned
      anteriorly-posteriorly, and two that are strongly oblique. Subsequent numerical
      simulations showed that the dorsal-plantar oriented and posterior oblique
      trabecular paths are aimed to support compressive stresses, while the antero
      posteriorly directed and anterior oblique groups act to bear tension. Insertion
      angles of real trabecular paths into the calcaneal cortex were similar to those
      of the isostatics that were computed under musculoskeletal loading conditions of
      standing (maximum absolute local difference 13 degrees, maximum local error 60%).
      This suggests that the trabecular patterns of the calcaneus are mainly shaped by
      isostatics (static principal stress flow) that are characteristic of the standing
      posture. The present modeling approach can be utilized to explore effects of
      abnormal alterations in the isostatic flow on the microarchitecture of the
      calcaneal trabeculae, as well as for better understanding of the mechanisms of
      calcaneal fractures.

PMID- 15036180
TI  - Minimal haemodynamic system model including ventricular interaction and valve
      dynamics.
AB  - Characterising circulatory dysfunction and choosing a suitable treatment is often
      difficult and time consuming, and can result in a deterioration in patient
      condition, or unsuitable therapy choices. A stable minimal model of the human
      cardiovascular system (CVS) is developed with the ultimate specific aim of
      assisting medical staff for rapid, on site modelling to assist in diagnosis and
      treatment. Models found in the literature simulate specific areas of the CVS with
      limited direct usefulness to medical staff. Others model the full CVS as a closed
      loop system, but they were found to be very complex, difficult to solve, or
      unstable. This paper develops a model that uses a minimal number of governing
      equations with the primary goal of accurately capturing trends in the CVS
      dynamics in a simple, easily solved, robust model. The model is shown to have
      long term stability and consistency with non-specific initial conditions as a
      result. An "open on pressure close on flow" valve law is created to capture the
      effects of inertia and the resulting dynamics of blood flow through the cardiac
      valves. An accurate, stable solution is performed using a method that varies the
      number of states in the model depending on the specific phase of the cardiac
      cycle, better matching the real physiological conditions. Examples of results
      include a 9% drop in cardiac output when increasing the thoracic pressure from -4
      to 0 mmHg, and an increase in blood pressure from 120/80 to 165/130 mmHg when the
      systemic resistance is doubled. These results show that the model adequately
      provides appropriate magnitudes and trends that are in agreement with existing
      data for a variety of physiologically verified test cases simulating human CVS
      function.

PMID- 15036181
TI  - Quantitative assessment of osteoporosis from the tibia shaft by ultrasound
      techniques.
AB  - Bone mineral density (BMD) is used as a clinical estimate of the risk of
      fracture. Ultrasound provides an alternative or complement to X-ray based methods
      of bone densitometry for determining BMD. Among ultrasonic characteristics, the
      speed of sound (SOS) is a useful tool for assessment of osteoporosis because, as
      recently reported, it represents a combination of density and compressibility of
      bone tissue. Thus, it might provide better information on bone quality to
      estimate the fracture risk. In this paper, a dual-transducer ultrasound technique
      was employed to measure the mean ultrasound propagation speed of the cortical
      layer as well as the cancellous layer at the tibia shaft. Encouraging results
      from 18 outpatients showed a high correlation (r = 0.93) between measurements of
      BMD and those from dual energy X-ray absorptiometry (DEXA).

PMID- 15036182
TI  - Exponential taper in arteries: an exact solution of its effect on blood flow
      velocity waveforms and impedance.
AB  - The dimensions and wall elasticity commonly taper along the length of mammalian
      arteries. The effects of taper on flow velocity waveforms can be included by
      either of two methods; to theoretically divide the artery into short sections
      wherein the properties are assumed constant (the approximate solution); or to
      find an exact solution incorporating the effects of taper. In this paper, an
      exact solution to the resulting, and previously unsolved nonlinear Ricatti
      equation for the impedance, is obtained by a process of substitutions. This
      solution is utilised to develop an exact expression for the flow velocity in the
      artery. The transmission line equations are then combined into a single integral
      expression for the entire artery and an exact solution to this is evaluated. This
      is the first solution to simultaneously account for both geometric and elastic
      taper, and it has been validated by comparing simulations of flow in the aorta of
      a dog to those using an infinitesimal approximate solution. The Pulsatility Index
      of the approximate solution requires at least 10 segments to converge to within
      5% of that using the exact solution. The exact solution thus accurately accounts
      for the effects of exponential taper, and may be used to improve existing
      arterial models, which use the less accurate and more computationally cumbersome
      approximate solution.

PMID- 15036184
TI  - A structural fingertip model for simulating of the biomechanics of tactile
      sensation.
AB  - Tactile performance of human fingertips is associated with activity of the nerve
      endings and sensitivity of the soft tissue within the fingertip to the static and
      dynamic skin indentation. The nerve endings in the fingertips sense the
      stress/strain states developed within the soft tissue, which are affected by the
      material properties of the tissues. The vibrotactile sensation and tactile
      performance are thus believed to be strongly influenced by the nonlinear and time
      dependent properties of the soft tissues. The purpose of the present research is
      to simulate the biomechanics of tactile sensation. A two-dimensional model, which
      incorporates the essential anatomical structures of a finger (i.e. skin,
      subcutaneous tissue, bone, and nail), has been used for the analysis. The skin
      tissue is assumed to be hyperelastic and viscoelastic. The subcutaneous tissue is
      considered to be a nonlinear, biphasic material composed of a hyperelastic solid
      and an inviscid fluid phase. The nail and bone are considered to be linearly
      elastic. The advantages of the proposed fingertip model over the previous
      "waterbed" and "continuum" fingertip models include its ability to predict the
      deflection profile of the fingertip surface, the stress and strain distributions
      within the soft tissue, and most importantly, the dynamic response of the
      fingertip to mechanical stimuli. The proposed model is applied to simulate the
      mechanical responses of a fingertip under a line load, and in one-point (1PT) and
      two-point (2PT) tactile discrimination tests. The model's predictions of the
      deflection profiles of a fingertip surface under a line load agree well with the
      reported experimental data. Assuming that the mechanoreceptors in the dermis
      sense the stimuli associated with normal strains (the vertical and horizontal
      strains) and strain energy density, our numerical results suggest that the
      threshold of 2PT discrimination may lie between 2.0 and 3.0 mm, which is
      consistent with the published experimental data. The present study represents an
      effort to develop a structural model of the fingertip that incorporates its
      anatomical structure, and the nonlinear and time-dependent properties of the soft
      tissues.

PMID- 15036183
TI  - Distinct cell-to-fiber junctions are critical for the establishment of
      cardiotypical phenotype in a 3D bioartificial environment.
AB  - The first step toward improving the cell-matrix interactions that occur in
      bioartificial myocardial tissue is an understanding of the ultrastructural links
      between cells and host fibers. Here, we identify a distinct type of junction that
      helps the cells to find anchorage in the three-dimensional environment, and we
      evaluate the phenotype of the resulting tissue. Neonatal rat cardiomyocytes were
      seeded in two different collagen scaffolds after pre-hydration of the scaffold.
      Conventional and electron microscopy were used to analyze the tissue
      microstructure. Viability was assessed by life/dead assay and physical properties
      of the resulting tissue were evaluated. The resulting tissue displayed high
      cellular viability, spontaneous contractions over 12 weeks, and responded to
      passive stretch similar to native rat myocardium. Contractile force responded
      physiologically to calcium (Ca), adrenaline, and stretch administration.
      Ultrastructural studies revealed a cell-to-fiber junction, as well as a
      background matrix configuration, which has not been described before in this
      context. The cells aligned along collagen fibers and engaged in complex
      intercalations. The cell-to-fiber affinity is essential for the phenotypical
      performance of bioartificial myocardial tissue equivalents. Moreover, given the
      appropriate porosity of the scaffold, pre-hydration promotes migration and
      affinity of cells to host structures.

PMID- 15036185
TI  - Interface pressure sensor for IVRA and other biomedical applications.
AB  - The fabrication and testing of a minimally intrusive (2 mm high, 10 mm diameter)
      biomedical interface pressure sensor are described. Such sensors are needed for
      the implementation of improved safety features in the next generation of
      automated intravenous regional anaesthesia (IVRA) systems. The sensor utilizes a
      structured elastomer as a deflection element sandwiched between the plates of a
      parallel plate capacitor device. Simple mechanical modifications allow
      sensitivity and zero offset adjustment. The sensor is housed in a package
      machined from an engineering polymer. The device is easily calibrated using
      either a bench-top or an on-body calibration procedure. The device is
      particularly sensitive to cuff artefacts arising from variations in cuff-wrap
      tightness and folding of the cuff. As such, it offers some promise for detecting
      potential hazard conditions which can occur during conventional IVRA procedures.
      For the purpose of unit conversion, 1 Pa = 1 N/m2, 1 MPA = 1 N/mm2 and 40 kPa
      approximately equal to 300 mmHg.

PMID- 15036187
TI  - The Pancreas Club, Inc.: fellowship and shared interests.

PMID- 15036188
TI  - A 35-year summary of Pancreas Club program content.

PMID- 15036190
TI  - Clinical risk score correlates with yield of PET scan in patients with colorectal
      hepatic metastases.
AB  - Although positron emission tomography (PET) detects occult metastatic disease in
      approximately 20% of patients with isolated hepatic colorectal metastases, it is
      associated with false negative results in up to 16%. We hypothesized that
      patients with a poorer prognosis (as defined by clinical risk score [CRS]) would
      have a higher yield from PET. All patients with colorectal liver metastases who
      were imaged by means of PET between 1998 and 2002 were identified from a
      prospective PET database. All patients were assigned a CRS, with one point added
      for each of five preoperative factors (disease-free interval <1 year, tumor size
      >5 cm, tumor number >1, carcinoembryonic antigen >200, and node-positive primary
      lesion). A total of 85 PET scans were reviewed. In half the patients (53%), PET
      provided no additional information over conventional imaging. Occult extrahepatic
      disease was detected or questionable findings seen on conventional imaging were
      confirmed in 20% of PET scans, whereas PET readings were inaccurate in 27%. PET
      findings were correlated with CRS in a subset of 63 patients presenting with a
      first occurrence of hepatic colorectal metastases. Among patients with a CRS of
      0, no patient had extrahepatic disease detected by PET and 57% had false positive
      readings, whereas among patients with a CRS of 1 or more, 14% were found to have
      additional disease that was detected only by PET, and there were no false
      positive readings (P<0.001, Fisher's exact test). Patients with isolated hepatic
      colorectal metastases and a CRS of 0 should undergo conventional imaging alone
      prior to surgical exploration.

PMID- 15036191
TI  - Extensive preoperative testing is not necessary in morbidly obese patients
      undergoing gastric bypass.
AB  - Morbidly obese patients are considered at high risk for perioperative
      complications and often undergo extensive testing for preoperative clearance. We
      analyzed prospectively collected data from 193 patients undergoing weight loss
      surgery between November 2000 and November 2002. Preoperative chest x-ray
      examination, pulmonary function tests, noninvasive cardiac testing, and blood
      work were performed routinely. Preoperative testing identified abnormalities on
      eight chest x-ray films (4%) and 29 electrocardiograms (15%), none of which
      required preoperative intervention. Spirometry was abnormal in 41 patients (21%);
      logistic regression identified preexisting asthma as predictive of obstructive
      physiology (odds ratio [OR] 3.3; 95% confidence interval [CI] 1.2 to 8.9), and
      body mass index as predictive of restrictive physiology (OR 1.1; 95% CI 1.01 to
      1.2). Arterial blood gases identified only one case of severe hypoxemia requiring
      intervention. Mild hypoxemia was associated with increasing age (OR 14.5; 95% CI
      1.8 to 114). Echocardiography demonstrated four abnormalities (2%); previous
      history of cardiac disease was the only risk factor (OR 14.5; 95% CI 1.8 to 114).
      Complete blood count did not identify 84% and 50% of the patients with iron
      (n=31) and vitamin B(12) (n=12) deficiencies, respectively. Age, body mass index,
      and history of asthma were associated with abnormal pulmonary function tests and
      previous cardiac disease with abnormal cardiac testing. These tests are not
      mandatory as a routine preoperative evaluation and can be used selectively on the
      basis of medical history.

PMID- 15036189
TI  - Management of rectal cancer.

PMID- 15036192
TI  - Kupffer cell-derived Fas ligand plays a role in liver injury and hepatocyte
      death.
AB  - Liver injury is an important prognostic indicator during acute pancreatitis. The
      aim of this study was to determine the role of Fas ligand (FasL) in hepatocyte
      injury. Liver parenchymal enzymes were measured in cocultures of hepatocytes and
      Kupffer cells treated with elastase. FasL and FasL mRNA were measured in elastase
      treated Kupffer cells. Hepatocytes were treated with FasL and their viability was
      assessed by monotetrazolium (MTT), apoptosis by flow cytometry, as well as
      caspase-3 and p38-mitogen-activated protein kinase (MAPK) by immunoblotting.
      Elastase increased aspartate aminotransferase and lactate dehydrogenase in
      cocultures of hepatocyte and Kupffer cells (P<0.040). Elastase increased FasL
      production from Kupffer cells (P=0.02) and upregulated FasL mRNA (FasL/beta-2
      microglobulin (BMG): 0.23+/-0.03 vs. 0.11+/-0.003; P=0.04). FasL increased
      alanine aminotransferase and lactate dehydrogenase (P<0.03) and reduced
      hepatocyte viability by 45% (P=0.01). FasL increased the number of dually labeled
      cells with AnnexinV/7AAD (P=0.03) while upregulating cleavage of caspase-3 and
      the phosphorylation of p38-MAPK. FasL antibody attenuated the FasL-related
      increase in dually labeled cells (P=0.02), the cleavage of caspase-3, and
      phosphorylation of p38-MAPK. Pancreatic elastase upregulates FasL within Kupffer
      cells. FasL induces hepatocyte injury and death and upregulates p38-MAPK and
      caspase-3 within hepatocytes. The ability to manipulate interactions between
      Kupffer cells and hepatocytes may have important therapeutic implications.

PMID- 15036193
TI  - Dendritic cells pulsed with pancreatic cancer total tumor RNA generate specific
      antipancreatic cancer T cells.
AB  - RNA-based dendritic cell immunotherapy with the use of total tumor RNA provides
      the potential to generate a polyclonal immune response to multiple known and
      unknown tumor antigens without HLA restriction. Our study evaluated this approach
      as potential immunotherapy for patients with pancreatic cancer. Dendritic cells
      were generated using adherent monocytes isolated from peripheral blood of
      patients with pancreatic cancer and evaluated phenotypically by flow cytometry to
      determine whether dendritic cells could be generated from the blood of patients
      with pancreatic cancer. Immature dendritic cells were transfected with mRNA
      encoding full-length carcinoembryonic antigen (CEA) or pancreatic cancer total
      tumor messenger RNA, and then matured. Matured dendritic cell phenotypes were
      also analyzed by flow cytometry. Transfected, matured dendritic cells were used
      to stimulate autologous T cells, and the resultant antigen-specific effector T
      cells were analyzed by interferon-gamma Elispot assay. Immature dendritic cells
      with characteristic phenotypic markers CD40, CD80, and CD86 were successfully
      isolated from the blood of patients with pancreatic cancer. Incubation with
      maturation agents increased expression of CD80 and CD83, demonstrating the
      induction of a mature antigen-presenting phenotype. Dendritic cells transfected
      with a pancreatic cancer-associated antigen (CEA) generated antigen-specific T
      cells (P<0.05). Dendritic cells transfected with autologous total tumor
      pancreatic cancer RNA generated T cells that specifically recognized HLA-matched
      pancreatic cancer cell lines (P<0.05 compared to control cell lines). Dendritic
      cells from patients with pancreatic cancer maintain the ability to translate and
      process transfected RNA and serve as mature antigen-presenting cells. These RNA
      transfected dendritic cells from pancreatic cancer patients successfully generate
      specific T cells against the pancreatic cancer-associated antigen CEA as well as
      T cells that specifically recognize pancreatic cancer cells. These data suggest
      that total tumor RNA-pulsed dendritic cells may have potential as an adjuvant
      immunotherapy for patients with pancreatic cancer.

PMID- 15036194
TI  - Treatment outcomes associated with surgery for gallbladder cancer: a 20-year
      experience.
AB  - The aim of this study was to evaluate contemporary outcomes associated with the
      management of gallbladder cancer. The medical records of 48 consecutive patients
      with gallbladder cancer treated at our institution from January 1981 through
      November 2001 were reviewed. Survival was analyzed using the Kaplan-Meier method
      (mean follow-up period 24 months) and the log-rank test. Prognostic factors were
      analyzed using Cox regression. Mean patient age was 68 years. Sixty percent of
      patients were female. Thirty-nine patients (81%) underwent laparotomy or
      laparoscopy. Eighteen patients (38%) underwent complete resection (10 simple
      cholecystectomies and 8 radical cholecystectomies). There were no procedure
      related deaths. The overall 5-year survival rate was 13%. Patients who underwent
      complete resection had a higher 5-year survival rate (31%) than patients who
      underwent palliative surgery or no surgery (0%; P<0.05). For patients who
      underwent radical cholecystectomy, the 5-year survival rate was 60%. For the 18
      patients who underwent curative resection, positive lymph node metastasis and
      patient age over 65 were factors predictive of significantly worse survival.
      Overall survival rates for patients with gallbladder cancer remain poor. Although
      radical surgery can be performed safely, it is associated with long-term survival
      only in a highly select subset of patients with gallbladder cancer.

PMID- 15036195
TI  - Management of complex biliary tract calculi with a holmium laser.
AB  - The difficulty in managing complex biliary tract calculi is exemplified in
      patients with primary intrahepatic calculi. Standard surgical and endoscopic
      approaches often fail to clear calculi in these patients who have recurrent
      episodes of cholangitis. The success of the holmium laser for urologic calculi
      led us to adapt treatment strategies for primary and secondary biliary tract
      calculi where standard treatments had been unsuccessful. Our goals were to remove
      all calculi, prevent recurrent sepsis, and preserve hepatic parenchyma. Thirty
      six patients with complex biliary calculi were treated. After sepsis was
      controlled and the extent of calculi was evaluated, appropriate access to and
      drainage of the biliary tract was achieved. Holmium laser lithotripsy was
      performed under video guidance using flexible choledochoscopes and a 200 micro
      laser fiber generating 0.6 to 1.0 joules at frequencies of 6 to 10 Hz.
      Lithotripsy procedures were repeated until cholangiography and cholangioscopy
      confirmed the clearance of calculi. Twenty-two patients of Asian descent with
      primary intrahepatic calculi and 14 patients with secondary intrahepatic calculi
      were treated. Access to the biliary tract could be accomplished through
      percutaneous catheter tracts, T-tube tracts, or the cystic duct during
      laparoscopic cholecystectomy. Biliary drainage was by biliary enteric anastomosis
      or endoscopic sphincterotomy. Complete stone clearance required an average of 3.9
      procedures (range 1 to 15) for patients with primary intrahepatic calculi and 2.6
      procedures (range 1 to 10) for patients with secondary intrahepatic calculi
      regardless of stone composition. No patient required hepatic resection and no
      complications or deaths were attributed to the holmium laser. Clearance of
      calculi can reliably and safely be achieved with a holmium laser regardless of
      stone composition or location while preserving hepatic parenchyma and preventing
      recurrent sepsis.

PMID- 15036196
TI  - Treatment of patients with unresectable primary hepatic malignancies using
      hyperthermic isolated hepatic perfusion.
AB  - Primary hepatocellular carcinoma is one of the most common malignancies
      worldwide. Isolated hepatic perfusion (IHP) is a regional treatment technique
      that isolates the organ to allow delivery of high-dose chemotherapy, biological
      agents, and hyperthermia directly to unresectable cancers confined to the liver.
      This study presents our experience using IHP with melphalan with or without tumor
      necrosis factor (TNF) to treat patients with hepatocellular carcinoma or
      adenocarcinoma of hepatobiliary origin. Nine patients with unresectable primary
      hepatic malignancies underwent a 60-minute IHP with 1.5 mg/kg melphalan with or
      without 1.0 mg TNF. Four patients failed one or more previous treatment regimens,
      and the mean hepatic replacement by tumor was 41% (range 10% to 75%). Patients
      were monitored for response, toxicity, time to recurrence, and survival. Six
      (67%) of nine patients experienced greater than 50% regression of tumor by
      objective radiographic imaging and an additional patient had a 45% reduction in
      tumor burden. Mean time to progression was 7.7 months for those who responded to
      treatment. Patients who had a response to therapy had an average overall survival
      of 16.3 months. IHP can be performed safely and has significant antitumor
      activity in patients with unresectable primary hepatic malignancies. Hepatic
      progression continues to be the dominant factor influencing survival in this
      group of patients.

PMID- 15036198
TI  - Laparoscopic right hepatectomy: surgical technique.
AB  - The objective of this study was to demonstrate the safety of laparoscopic right
      hepatectomy for benign or malignant disease. Many reports document the success of
      minor or segmental liver resections performed laparoscopically. Major hepatic
      resection has rarely been reported. This report documents our experience with 12
      laparoscopic right hepatectomies. Ten patients had suspected malignancy, but all
      had lesions well clear of the midplane of the liver. The surgery followed three
      distinct phases: (1). Portal dissection during which diathermy and harmonic
      shears are used, clips are applied to the right hepatic duct and right hepatic
      artery, and a vascular stapler is used to divide the right portal vein; (2).
      dissection of the vena cava, which is usually done by tunneling below the liver
      using harmonic shears, clips, and a linear stapler to divide the right hepatic
      vein; and (3). parenchymal division during which harmonic shears and multiple
      firings of linear staplers are used to divide the liver substance. In five
      patients the procedure was completed totally laparoscopically, five patients had
      a laparoscopic-assisted procedure, and two patients had to be converted to formal
      open hepatectomy. Four patients required blood transfusion. There were no deaths
      and two cases of major morbidity-bile leakage in one and wound dehiscence in one.
      The average hospital stay was 8 days, but for those whose operations were
      completed totally laparoscopically, 4 days was the average. Two of the nine
      patients with documented cancer have since died-one with widespread intrahepatic
      hepatocellular carcinoma and another with widespread metastatic melanoma after
      resection of a colorectal metastasis. Seven patients with colorectal cancer are
      alive and disease free with follow-up of 6 to 24 months. Laparoscopic right
      hepatectomy is feasible in selected patients. It is technically demanding but can
      be safely accomplished by surgeons who have experience in advanced laparoscopic
      procedures and open hepatic surgery.

PMID- 15036197
TI  - Liver transplantation for neuroendocrine tumors.
AB  - Liver transplantation for the treatment of metastatic neuroendocrine tumors
      (NETs) is radical. Although cure is not impossible, it is improbable. The
      reported experience with transplantation for NETs is limited to less than 150
      cases with widely varying results and few 5-year disease-free survivors. We
      reviewed our experience with transplantation for patients with NETs. Fourteen
      symptomatic patients with unresectable NET liver metastases who had failed
      medical management were listed for transplantation. Two patients listed for
      transplantation underwent prior right lobectomies. Three patients were listed but
      did not undergo transplantation: one was lost to follow-up, one died 14 months
      after listing, and one remains waiting over 4 years. Eleven patients underwent
      liver transplantation, three with living donor grafts. There were four men
      (36.4%) and seven women (63.6%) who had a mean age of 51.2+/-6.3 years. Three
      patients had distal pancreatectomies and one patient had a Whipple procedure at
      the time of transplantation. There were six nonfunctioning tumors (54.6%), three
      carcinoid tumors (27.3%), and two (18.2%) Vipomas. In one patient, with fulminant
      hepatic failure, the NET was an incidental finding in the explant. The 1- and 5
      year survival among transplanted patients is 73% and 36%, respectively, with a
      mean follow-up of 34+/-40 months (range 0 to 119 months). Of the three patients
      surviving more than 5 years, only one was disease free. In carefully selected
      patients with metastatic NETs, liver transplantation may be an appropriate
      option.

PMID- 15036199
TI  - Intrahepatic cholangiocarcinoma masked as fever of unknown origin.
AB  - Intrahepatic cholangiocarcinoma is a rare malignancy that often presents in an
      advanced stage. For many patients, early diagnosis is often delayed, secondary to
      vague symptoms and a lack of physical findings. Herein, we report an unusual case
      of fever of unknown origin secondary to intrahepatic cholangiocarcinoma.

PMID- 15036200
TI  - A duodenum-preserving and bile duct-preserving total pancreatic head resection
      with associated pancreatic duct-to-duct anastomosis.
AB  - A duodenum-preserving pancreatic head resection technique was first reported in
      1980, but the indications have been limited to benign pancreatic disease as it
      involves a subtotal pancreatic head resection. In 1988 we detailed a duodenum
      preserving total pancreatic head resection (DPTPHR) technique. This procedure
      involved a total pancreatic head resection and as such expanded the indications
      for this approach to include tumorigenic masses. The original method involved
      closure of the proximal pancreatic duct and an anastomosis of the pancreatic duct
      of the distal pancreas to a newly created small hole in the duodenum (we termed
      this a "pancreatoduodenostomy"). Our current technique involves a duct-to-duct
      anastomosis of the proximal pancreatic duct and the distal pancreas to better
      preserve anatomic structure. DPTPHR was performed in 26 patients from 1988 to
      2002, including 12 cases of DPTPHR with pancreatoduodenostomy and 14 cases of
      DPTPHR with pancreatic duct-to-duct anastomosis. No differences were observed
      between the two methods with respect to operative time or blood loss during
      surgery. Postoperatively, there was one case of cholecystitis and one case of
      pancreatitis in a patient who underwent a pancreatoduodenostomy; both of these
      patients were treated conservatively with curative intent. No complications were
      observed in the group undergoing duct-to-duct anastomosis. The advantage of duct
      to-duct anastomosis is that the pancreatic head is totally resected, thus
      allowing removal of neoplastic disease such as an intraductal papillary mucinous
      tumor and also therapy for chronic pancreatitis. A key benefit of this procedure
      is that sphincter function of the duodenal papilla is preserved permitting
      drainage of pancreatic/bile juice into the duodenum, preserving a more
      physiologic state than is the case after a pancreatoduodenostomy.

PMID- 15036201
TI  - The attention of researchers on the biological process of protein folding has
      turned to the formation and properties of aggregates.

PMID- 15036202
TI  - Principles of protein folding, misfolding and aggregation.
AB  - This review summarises our current understanding of the underlying and universal
      mechanism by which newly synthesised proteins achieve their biologically
      functional states. Protein molecules, however, all have a finite tendency either
      to misfold, or to fail to maintain their correctly folded states, under some
      circumstances. This article describes some of the consequences of such behaviour,
      particularly in the context of the aggregation events that are frequently
      associated with aberrant folding. It focuses in particular on the emerging links
      between protein aggregation and the increasingly prevalent forms of debilitating
      disease with which it is now known to be associated.

PMID- 15036203
TI  - Roles of molecular chaperones in protein misfolding diseases.
AB  - Human misfolding diseases result from the failure of proteins to reach their
      active state or from the accumulation of aberrantly folded proteins. The
      mechanisms by which molecular chaperones influence the development of these
      diseases is beginning to be understood. Mutations that compromise the activity of
      chaperones lead to several rare syndromes. In contrast, the more frequent amyloid
      related neurodegenerative diseases are caused by a gain of toxic function of
      misfolded proteins. Toxicity in these disorders may result from an imbalance
      between normal chaperone capacity and production of dangerous protein species.
      Increased chaperone expression can suppress the neurotoxicity of these molecules,
      suggesting possible therapeutic strategies.

PMID- 15036204
TI  - Role of quality control pathways in human diseases involving protein misfolding.
AB  - Advances in connecting phenotype to genotype have led to new insights regarding
      the basis of human disease. Many inherited diseases are now known to arise due to
      specific mutations within a gene that then lead to a protein product unable to
      assume a stable conformation within the cell. Cellular machineries serving as
      "quality control monitors" recognize and target such abnormally folded proteins
      for rapid destruction. As a consequence, specific biochemical pathways requiring
      the protein of interest are adversely affected and lead to the disease phenotype.
      Yet in other cases, upon its misfolding the particular protein quickly
      aggregates, leading to the formation of inclusion bodies that eventually lead to
      cell demise. In what follows I discuss some classic examples of human diseases
      known to arise due to mutations that lead to altered protein folding, abnormal
      protein maturation and/or protein aggregation. In many cases simply altering the
      protein folding environment within the cell, via molecular or pharmacological
      approaches, can effectively rescue the maturation and stability of the mutant
      protein and thereby reduce the onset and/or progression of the disease phenotype.
      These new insights regarding the mechanisms underlying the disease phenotype, as
      well as new approaches to correct the protein folding defect, will undoubtedly
      prove to have a tremendous impact on clinical medicine.

PMID- 15036205
TI  - Amyloidosis: a clinico-pathophysiological synopsis.
AB  - Amyloidosis encompasses a spectrum of diseases in which there is disordered
      folding of certain proteins that leads to them being deposited as insoluble
      fibrils in the extracellular space. The result of this process is impaired tissue
      structure and function. Amyloidosis may be acquired or hereditary and local or
      systemic, and is defined according to the identity of the fibril precursor
      protein. Over 20 unrelated proteins can form amyloid fibrils in vivo, which all
      share a lamellar cross-beta-sheet structure composed of non-covalently associated
      protein or peptide subunits. Glycosaminoglycans and the pentraxin protein, serum
      amyloid P component, are universal non-fibrillar constituents of amyloid deposits
      that are believed to play a role in fibrillogenesis and fibril persistence.
      Greater understanding of the processes underlying amyloidogenesis, at all levels
      from cellular to clinical, has led to improvements in diagnosis, monitoring and
      treatment of this group of diseases, as well as pointing to possible future
      therapies.

PMID- 15036206
TI  - Tau protein and neurodegeneration.
AB  - Tau protein is the major component of the intracellular filamentous deposits that
      define a number of neurodegenerative diseases. They include the largely sporadic
      Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal
      degeneration (CBD), Pick's disease (PiD), argyrophilic grain disease, as well as
      the inherited frontotemporal dementia and parkinsonism linked to chromosome 17
      (FTDP-17). The identification of mutations in Tau as the cause of FTDP-17
      established that dysfunction or misregulation of tau protein is sufficient to
      cause neurodegeneration and dementia. At an experimental level, the new
      understanding is leading to the development of good transgenic animal models of
      the tauopathies.

PMID- 15036209
TI  - Cell-intrinsic regulators of proliferation in vertebrate retinal progenitors.
AB  - The proliferative expansion of retinal progenitor cells (RPCs) is a fundamental
      mechanism of growth during vertebrate retinal development. Over the past couple
      of years, significant progress has been made in identifying genes expressed in
      RPCs that are essential for their proliferation, and the molecular mechanisms are
      beginning to be resolved. In this review, we highlight recent studies that have
      identified regulatory components of the RPC cell cycle machinery and implicate a
      set of homeobox genes as key regulators of proliferative expansion in the retina.

PMID- 15036208
TI  - Neural stem cells in the mammalian eye: types and regulation.
AB  - Neural stem cells/progenitors that give rise to neurons and glia have been
      identified in different regions of the brain, including the embryonic retina.
      Recently, such cells have been reported to be present, in a mitotically quiescent
      state, in the ciliary epithelium of the adult mammalian eye. The retinal and
      ciliary epithelium stem cells/progenitors appear to share similar signaling
      pathways that are emerging as important regulators of stem cells in general. Yet,
      they are different in certain respects, such as in the potential to self-renew.
      These two neural stem cell/progenitor populations not only will serve as models
      for investigating stem cell biology but also will help explain the relationships
      between embryonic and adult neural stem cells/progenitors.

PMID- 15036210
TI  - Cell-cycle regulation and cell-type specification in the developing Drosophila
      compound eye.
AB  - During nervous system development stem cell daughters must exit the proliferative
      cycle to adopt specific neural and glial fates and they must do so in the correct
      positions. Cell proliferation in the central nervous system occurs in
      neuroepithelia such as the neural retina and the ventricular zones. As cells are
      assigned specific fates they migrate out of the plane of the epithelium to form
      higher layers. Recent evidence from the Drosophila compound eye suggests that a
      novel mode of Ras pathway regulation may be crucial in both cell-cycle exit and
      neural patterning: "MAP Kinase cytoplasmic hold".

PMID- 15036211
TI  - Retinal cell fate determination and bHLH factors.
AB  - Retinal development is controlled antagonistically by multiple basic helix-loop
      helix (bHLH) transcriptional activators and repressors. bHLH repressors suppress
      bHLH activators and promote maintenance of progenitors and generation of glial
      cells. In contrast, bHLH activators override activities of bHLH repressors and
      promote neuronal differentiation. However, bHLH activators alone are not
      sufficient but homeodomain factors are additionally required for neuronal subtype
      specification. It is likely that homeodomain factors regulate the layer
      specificity but not the neuronal fate while bHLH activators determine the
      neuronal fate within the homedomain factor-specified layers. Thus, combinations
      of proper bHLH and homeodomain factors are required for neuronal subtype
      specification.

PMID- 15036212
TI  - Roles of cell-extrinsic growth factors in vertebrate eye pattern formation and
      retinogenesis.
AB  - Formation of the vertebrate visual system involves complex interplays of cell
      extrinsic cues and cell-intrinsic determinants. Studies in several vertebrate
      species demonstrate that multiple classes of signaling molecules participate in
      pattern formation of the eye and neurogenesis of the retina. Certain signals,
      such as hedgehog, BMP, and FGF molecules, are repeatedly deployed at varying
      concentration thresholds and in different cellular contexts. Accumulating
      evidence reveals a striking conservation of molecular mechanisms regulating the
      neurogenic process between Drosophila and vertebrate retinas. The remaining
      challenge is to understand how these well-characterized signaling pathways are
      activated and integrated to impact eye morphogenesis and retinal progenitor cell
      fate determination.

PMID- 15036213
TI  - Retinal pattern and the genetic basis of its formation in zebrafish.
AB  - The vertebrate nervous system contains an immense diversity of distinct cellular
      components that are organized into precise spatial patterns. The importance of
      accurate neuronal architecture is particularly obvious in the retina, where it is
      necessary for the formation of visual images. The retina is structured in a
      distinct layered pattern that is remarkably conserved in evolution, including
      phyla as diverse as primates and teleost fish. Genetic analysis in zebrafish
      reveals mechanisms that are essential for the formation of this architecture.

PMID- 15036214
TI  - A gene regulatory hierarchy for retinal ganglion cell specification and
      differentiation.
AB  - Retinal ganglion cells (RGCs) are the first cell type to be specified during
      vertebrate retinogenesis. Specification and differentiation of the RGC lineage
      are a stepwise process involving a hierarchical gene regulatory network. During
      the past decade, a framework of the network has emerged and key transcriptional
      regulators have been identified. Pax6, Notch, Ath5, and the Brn3 (Pou4f) factors
      act at different levels of the regulatory hierarchy. In this review, we summarize
      the current understanding of the functions of these and other transcriptional
      factors in the specification and differentiation of the RGC lineage. We emphasize
      the regulatory relationships among transcription factors at different steps of
      RGC development. We discuss critical issues that need to be addressed before a
      complete understanding of the gene regulatory network for RGC development can be
      achieved. Future directions in RGC development will inevitably rely on combined
      genetic and genomics approaches.

PMID- 15036215
TI  - Ganglion cell axon pathfinding in the retina and optic nerve.
AB  - The eye is a highly specialized structure that gathers and converts light
      information into neuronal signals. These signals are relayed along axons of
      retinal ganglion cells (RGCs) to visual centers in the brain for processing. In
      this review, we discuss the pathfinding tasks RGC axons face during development
      and the molecular mechanisms known to be involved. The data at hand support the
      presence of multiple axon guidance mechanisms concentrically organized around the
      optic nerve head, each of which appears to involve both growth-promoting and
      growth-inhibitory guidance molecules. Together, these strategies ensure proper
      optic nerve formation and establish the anatomical pathway for faithful
      transmission of information between the retina and the brain.

PMID- 15036216
TI  - Building a projection map for photoreceptor neurons in the Drosophila optic
      lobes.
AB  - The sensory tasks performed by the eye are diverse and complex. In Drosophila,
      the eye performs motion detection for navigation as well as detection of the
      quality of light (color and polarized light). Both types of inputs are processed
      separately, as different photoreceptors are specialized in these tasks and
      contact different target cell layers in the optic lobe. However, their respective
      outputs are likely to be integrated in higher brain centers. Here, we discuss the
      cell diversity and potential role of the several ganglia that form the fly optic
      lobe. We also discuss the power of modern genetic tools to provide the potential
      to trace the visual neural networks.

PMID- 15036217
TI  - Concurrent sexual partnerships among African Americans in the rural south.
AB  - PURPOSE: To investigate concurrent sexual partnerships among heterosexual African
      Americans, 18 to 59 years old, in rural North Carolina. METHODS: Household
      interviews with persons randomly selected from the NC driver's license file were
      conducted to identify overlap among the 3 most recent sexual partnerships.
      RESULTS: Concurrency prevalence in the past 5 years was 53% (men) and 31%
      (women). Most (61%) respondents believed that a recent partner had had a
      concurrent partnership. Multivariate analysis revealed strong associations
      between concurrency and male gender, being unmarried, age of sexual debut, and
      incarceration of a sex partner. CONCLUSIONS: Concurrent partnerships may increase
      rates of heterosexual HIV among blacks in the rural Southeastern United States.
      Future research should examine the context that supports this network pattern.

PMID- 15036218
TI  - Trends in use of inhaled corticosteroids for asthma management: 1994-1998.
AB  - PURPOSE: To evaluate trends in prescribing of inhaled corticosteroids for asthma
      between 1994 and 1998 and patterns of prescribing in relation to selected
      physician characteristics. METHODS: Using a HMO database, a physician sample (N =
      335) was linked to patient encounter data and pharmacy claims (N = 51,345) for
      asthma patients ages 5 to 45 years (N = 6,944). Longitudinal and cross-sectional
      analytic methods were used to examine physician prescribing patterns across the
      study period. RESULTS: The percent of physicians prescribing an inhaled
      corticosteroid increased over time with consistently greater prescribing among
      specialists. Annual comparisons by specialty groups revealed that specialists
      (allergy and pulmonary) prescribed inhaled steroids to a larger proportion of
      their patients than generalists (family practice, internal medicine, pediatrics,
      pediatric emergency department); (range: 0.61-0.69 vs. 0.31-0.39, p < .01). The
      lowest proportions were found among pediatric emergency department physicians
      (range: 0.00-0.10) and pediatricians (range: 0.17-0.27). CONCLUSIONS: Significant
      linear trends in either physician group were not observed during this 5-year
      period. Differences across physician groups were evident.

PMID- 15036219
TI  - Occupational asbestos exposure and the incidence of non-Hodgkin lymphoma of the
      gastrointestinal tract: an ecologic study.
AB  - PURPOSE: A previous case-control study observed a strong association between
      occupational exposure to asbestos and the incidence of non-Hodgkin lymphoma of
      the gastrointestinal tract (GINHL). To test this hypothesis, we sought to
      determine whether the geographic pattern of the incidence of GINHL in the US has
      paralleled that of mesothelioma. METHODS: Using data obtained from the nine US
      regions participating in the National Cancer Institute's Surveillance,
      Epidemiology and End Results program, we examined the incidence of malignancies
      among men ages 50 to 84 years between 1973 and 1984. RESULTS: The rates of
      mesothelioma, but not of GINHL, were about two times higher in the areas of
      Seattle and San Francisco, than in the other regions. Overall, there was no
      correlation between the rates of mesothelioma and of GIHNL (Pearson correlation
      coefficient-0.12, p = 0.77). CONCLUSIONS: This ecologic study finds no support
      for the hypothesis that occupational asbestos exposure is related to the
      subsequent incidence of GINHL.

PMID- 15036220
TI  - Estimation of cumulative odds ratios.
AB  - PURPOSE: Standard estimation of ordered odds ratios requires the constraint that
      the etiologic effects of exposure are homogenous across thresholds of the ordered
      response. We present a method to relax this often-unrealistic constraint.
      METHODS: The kernel of the proposed method is the expansion of observed data into
      "person-thresholds." Using standard statistical software, for each subject we
      create a separate record for each response threshold and then apply binary
      logistic regression to estimate generalized cumulative odds ratios for one or
      more exposures. RESULTS: Two examples demonstrate that the proposed method
      provides increased flexibility in assessing the etiologic effects of exposures. A
      Monte Carlo simulation study supports the proposed approach by suggesting the
      estimated cumulative odds ratios are unbiased with proper confidence interval
      coverage attained by use of generalized estimating equations. CONCLUSION: The
      proposed method provides simple estimates of ordered odds ratios that allow the
      etiologic effects of exposure to vary across levels of the ordered response.

PMID- 15036221
TI  - Characteristics of pubertal development in a multi-ethnic population of nine-year
      old girls.
AB  - PURPOSE: Early age at menarche increases future disease risk. Secular decline in
      age at menarche has been attributed to body size characteristics, diet, and
      energy expenditure. Risk factors for puberty have been less frequently explored.
      METHODS: A cross-sectional study of 186 New York Metropolitan Area, 9-year-old
      girls (54 African-American, 70 Hispanic, 62 Caucasians) used interviewer
      administered questionnaires to assess exposures. Height and weight were measured.
      Pediatricians assessed pubertal development according to Tanner stages. RESULTS:
      African-Americans were more likely than Caucasians to have achieved puberty as
      determined by breast or hair development (stage 2 or higher) [age-adjusted odds
      ratios and 95% confidence intervals = 4.91 (2.15-11.19) and 4.25 (1.85-9.77),
      respectively]. Pubertal development was similar among Hispanics and Caucasians.
      Adiposity and height were significantly positively associated with breast or hair
      development. More sedentary activity hours non-significantly increased the
      likelihood of hair development. Lower energy, but higher polyunsaturated fat,
      consumption were suggestive of an association with breast development. Vitamin C
      and hair development were inversely related. No other nutrients or physical
      activity measures were related to pubertal development. CONCLUSIONS: Results are
      consistent with height and adiposity being associated with pubertal development.
      Sedentary activity or diet might possibly influence maturation.

PMID- 15036222
TI  - The association between educational status and risk factors related to
      cardiovascular disease in healthy individuals: The ATTICA study.
AB  - PURPOSE: The object of this work was to study the associations between education
      status and several cardiovascular risk factors in 2271 randomly selected male and
      female adults. METHODS: The formal education level was used as proxy for socio
      economic status; the distribution of the risk factors and the prevalence of risk
      conditions were analyzed by the different levels of education-"low", "medium",
      and "high." The association between education level and the investigated
      measurements was tested by the application of multiple regression analysis.
      RESULTS: Two hundred and twenty (19.8%) males and 292 (25.3%) females were
      classified as "low", 471 (42.4%) males and 476 (41.3%) females as "medium", and
      421 (37.8%) males and 386 (33.4%) females as "high" educated. Compared with those
      with "low" education, individuals who reported "high" education had 8% lower
      systolic (p < 0.001) and 4% lower diastolic (p < 0.001) blood pressure levels, 6%
      lower blood glucose levels (p < 0.001), 7% lower serum total cholesterol (p <
      0.001), 6% higher HDL-cholesterol (p < 0.001), 22% lower lipoprotein-a levels (p
      < 0.001), 11% lower apoliprotein-B levels (p < 0.001), 15% lower triglycerides (p
      < 0.001), 45% lower hs-CRP (p < 0.001), 8% lower fibrinogen levels (p < 0.01),
      and 7% lower white blood cell count (p < 0.001). The associations regarding
      inflammation markers remained statistically significant even after adjustment for
      several potential confounders. CONCLUSIONS: Our findings suggest that in primary
      prevention it is important to focus our attention, especially, on people with low
      education, since they seem to be rather unprotected against the prevalence of
      several cardiovascular risk factors.

PMID- 15036223
TI  - Serum iron, copper and zinc concentrations and risk of cancer mortality in US
      adults.
AB  - PURPOSE: To examine the prospective association of serum iron, copper, and zinc
      with cancer mortality. METHODS: The study sample included 3000 men and 3244 women
      free from cancer at baseline who participated in the Second National Health and
      Nutrition Examination Survey. Vital status at follow-up was identified by the
      Social Security Administration's death file and the National Death Index. Iron,
      transferrin saturation (TS), copper, and zinc were categorized into 4 levels
      using the 10th, 50th, and 90th percentiles for cutoffs. Relative risks (RRs) were
      derived from the proportional hazard models after adjustment for a number of
      potential confounders. RESULTS: Three hundred seven cancer deaths (ICD-9 140-195,
      199-208) were identified during 83,664.4 person-years of follow-up. Cancer
      mortality per 1000 person-years was 3.7 (4.7 for men and 2.8 for women). For men
      and women combined, the adjusted RRs (95% confidence intervals, CI) for the four
      levels were 0.96 (0.57-1.61), 1.00 (reference), 1.12 (0.80-1.58), 1.86 (1.07
      3.22) for iron; 0.97 (0.56-1.70), 1.00 (reference), 1.36 (0.99-1.87), 1.82 (1.10
      3.02) for TS; 0.76 (0.44-1.31), 1.00 (reference), 1.10 (0.77-1.58), 1.89 (1.07
      3.32) for copper; and 0.75 (0.50-1.13), 1.00 (reference), 0.64 (0.47-0.88), 0.84
      (0.53-1.33) for zinc. When the exposures were analyzed as continuous variables,
      the adjusted RRs (CI) were 1.66 (1.03-2.68) for 100 microg/dl iron increase, 1.17
      (1.01-1.36) for 10% TS increase, 1.98 (1.12-3.50) for 100 microg/dl copper
      increase, and 0.57 (0.16-1.96) for 100 microg/dl zinc increase. Sex differences
      in the adjusted RRs for iron, TS, and copper were suggestive. CONCLUSION: People
      with higher serum iron, TS, or copper concentrations had an increased risk of
      dying from cancer.

PMID- 15036224
TI  - Sex steroids and age-related macular degeneration in older French women: the POLA
      study.
AB  - PURPOSE: Postmenopausal women are reported to be at higher risk of eye diseases
      than men. The purpose of our study is to determine the relationships between
      endocrine status, specially plasma sex hormones levels, and the severity of age
      related macular degeneration (AMD) in a large community-based sample of older
      French women. METHODS: The POLA (Pathologies Oculaires Liees a l'Age) Study is a
      population-based study on age-related eye diseases and their risk factors. The
      study enrolled 2584 residents of Southern France, among whom 1451 women aged 60
      years or older were recruited between June 1995 and July 1997. A standardized
      international classification and grading system for AMD was used. Circulating sex
      hormones levels were measured from fasting blood samples. RESULTS: No association
      of hormone replacement therapy (HRT), hysterectomy, or oophorectomy was found
      with soft drusen, pigmentary abnormalities, or late AMD. After multivariate
      adjustment, higher plasma levels of dehydroepiandrosterone sulfate (DHEAS) were
      associated with a higher prevalence of soft drusen (OR = 1.21; 95% CI = 1.01
      1.44). CONCLUSION: These results may indicate no beneficial effect of HRT on AMD.
      The positive association of DHEAS with AMD requires further investigation.

PMID- 15036226
TI  - Racial differences in the treatment of colorectal cancer: a comparison of
      surgical and radiation therapy between Whites and Blacks.
AB  - PURPOSE: To evaluate black to white differences in treatment for colorectal
      cancer. METHODS: Only whites or blacks diagnosed with colon or rectal cancer
      between 1988 and 1997 were identified from SEER database. RESULTS: A total of
      106,377 (91.3% white, 50.5% male) patients formed the study population. The vast
      majority of these patients received standard cancer treatment. Although the
      number of subjects who did not receive such treatment was small, their proportion
      was higher among blacks than among whites. The odds of non-receipt of surgical
      treatment was higher among blacks than whites for stage I (OR = 2.08, 95% CI,
      1.41, 3.03 among males; OR = 2.38, 95% CI, 1.69, 3.45 among females) and stage IV
      colon cancer (OR = 1.25, 95% CI, 1.01, 1.56 among males; OR = 1.41; 95% CI, 1.14,
      1.72 among females). A similar pattern was also seen for most stages of rectal
      cancer. CONCLUSIONS: Most black and white colorectal cancer patients received
      standard treatment. Although the number of subjects without standard treatment
      was small, their proportion was higher among blacks than among whites. Blacks
      were also more likely to refuse recommended treatment. Efforts in educating black
      patients about the benefits of treatment may help to eliminate the remaining
      racial disparity.

PMID- 15036225
TI  - Alcohol consumption and insulin resistance syndrome parameters: associations and
      evolutions in a longitudinal analysis of the French DESIR cohort.
AB  - PURPOSE: To determine the effects of average alcohol consumption and changes in
      alcohol intake on the insulin resistance syndrome parameters in a 3-year follow
      up study. METHODS: Longitudinal study of 1856 and 1529 alcohol drinking men and
      women in the French DESIR study (Data from an Epidemiological Study on the
      Insulin Resistance syndrome), aged 30 to 64 years. RESULTS: In men, fasting
      glucose, body mass index, waist circumference, systolic blood pressure, and HDL
      cholesterol were positively associated with average alcohol consumption while
      there was no association with insulin or triglycerides concentrations. A change
      in alcohol intake was positively associated with HDL-cholesterol concentration
      and systolic blood pressure at follow-up. These effects of alcohol could not be
      attributed specifically to the intake of wine. In women, while the alcohol HDL
      cholesterol relation was similar to that found in the men, the only significant
      effect of average alcohol intake was an increase in systolic blood pressure, with
      a spurious decrease in blood pressure related to a 3-year increase in alcohol
      intake. CONCLUSIONS: Alcohol only provided a beneficial effect on HDL
      cholesterol. The beneficial effect seen by other authors of moderate alcohol
      drinking on diabetes and cardiovascular risk may be due to effects on parameters
      other than those included in the current definitions of the insulin resistance
      syndrome.

PMID- 15036227
TI  - History of kidney stones as a possible risk factor for chronic kidney disease.
AB  - PURPOSE: The incidence of treated end-stage renal disease has increased
      progressively in the United States over the past several decades. It has been
      suggested that kidney stones may be a contributing factor for a small percentage
      of these patients. METHODS: We conducted a case-control study utilizing 548
      hospital cases and 514 age, race and gender-matched community controls. The main
      outcome measure was diagnosis of chronic kidney disease, assessed by
      comprehensive chart review. History of kidney stones and other co-variables were
      obtained during telephone interviews. RESULTS: This study revealed 16.8% of cases
      and 6.4% of controls with reported history of kidney stones. The odds ratios
      (adjusted for confounding variables) for chronic kidney disease (overall),
      diabetic nephropathy and interstitial nephritis for patients with kidney stones
      were 1.9 (95% CI: 1.1, 3.3), 2.5 (95% CI: 0.87, 7.0) and 3.4 (95% CI: 1.5, 7.4),
      respectively. After stratifying by hypertensive status this increased risk
      persisted only for study participants reporting no history of hypertension.
      CONCLUSION: Kidney stones may play a role in the development of chronic kidney
      disease. Our study suggests that the prevention of kidney stones may be a means
      of delaying the onset of chronic kidney disease, however, further studies are
      needed to make conclusive recommendations.

PMID- 15036228
TI  - Distribution of total serum homocysteine and its association with parental
      history and cardiovascular risk factors at ages 12-16 years: the Third National
      Health And Nutrition Examination Survey.
AB  - PURPOSE: To describe the distribution and to assess the association of serum
      total homocysteine (tHcy) concentration with variables associated with insulin
      resistance syndrome in adolescent boys and girls. METHODS: In the Third National
      Health and Nutrition Examination Survey, adolescents aged 12 to 16 years (n =
      941) had parental medical history ascertained and glycated hemoglobin, systolic
      blood pressure, body mass index (BMI), body fat distribution, HDL cholesterol,
      and serum tHcy concentrations were measured. RESULTS: Cumulative distribution of
      serum tHcy in boys was shifted to the right compared with that in girls. A
      parental history of high blood pressure or stroke before age 50 was significantly
      positively associated with the subjects' log serum tHcy after adjustment for
      confounders (beta 0.156, p = 0.003). Log serum tHcy was significantly positively
      associated with systolic blood pressure in boys after adjustment for confounders
      (beta = 0.21, p = 0.03). Log serum tHcy was not significantly associated with
      glycated hemoglobin percent or most other risk factors other than age. Log serum
      tHcy concentration showed borderline significant (r = -0.15, p = 0.044) inverse
      association with BMI in girls. CONCLUSION: tHcy was associated with parental
      history of high blood pressure or stroke before age 50 and with systolic blood
      pressure in adolescent boys.

PMID- 15036229
TI  - Regulatory T cells. Introduction.

PMID- 15036230
TI  - Molecular aspects of regulatory T cell development.
AB  - Naturally arising CD4(+) regulatory T cells are critical mediators of peripheral
      self tolerance and immune homeostasis. Emerging evidence suggests that these
      cells are a dedicated T cell lineage constitutively acting in a dominant, cell
      extrinsic manner to regulate immune function. These observations are driving a
      reevaluation of our understanding of the regulation of immune homeostasis and
      peripheral tolerance. But despite a growing body of phenomenological data, an
      understanding of the molecular mechanisms underlying CD4(+) regulatory T cell
      development has only recently begun to emerge. This review highlights the major
      molecular pathways that have been implicated to date in the development of this T
      cell lineage.

PMID- 15036231
TI  - Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the
      arena of peripheral tolerance.
AB  - Self/non-self discrimination is a complex process that involves maintaining
      tolerance to autoantigens while preserving the potential to generate an effective
      humoral and cellular immune responses against invading pathogens. In the last
      decade, there has been a remarkable resurgence in research on suppressor or
      regulatory T cells. Few areas have captivated the attention of immunologists so
      vividly and entertained so many passionate debates. Indeed, CD4(+)CD25(+) Treg,
      which are at the very center of this fascination, have emerged as a dominant T
      cell population capable of mediating peripheral tolerance to autoantigens, but
      whose functions have now been extended to regulation of T cell responses directed
      to foreign antigens. However, a number of fundamental questions concerning the
      origin, phenotypic nature and mechanism of action of CD4(+)CD25(+) Treg cells
      remain elusive and misunderstood. We propose the existence of two general subsets
      of CD4(+)CD25(+) Treg cells, naturally-occurring and induced, that differ in
      their origin, developmental and activation requirements, and mechanism of action.

PMID- 15036232
TI  - Human CD4+CD25+ regulatory T cells.
AB  - In this report, we review studies of human CD4+CD25+ regulatory T cells (T-reg).
      Although lagging a few years behind the discovery of these cells in the mouse,
      the equivalent population of CD4+CD25+ regulatory T cells has also been isolated
      from human peripheral blood, thymus, lymph nodes and cord blood. In general, the
      characteristics of this T cell subset are strikingly similar between mouse and
      man. In the recent explosion of research reports on human CD4+CD25+ cells,
      although the majority of the characteristics ascribed to these cells appear to be
      consistent, contrasting results have been found primarily in regards to potential
      involvement of TGFbeta and production of IL-10. One explanation for this
      variability may reside in the fact that markedly different techniques are used to
      isolate human CD4+CD25+ T-reg cells and thus may result in the comparison of T
      reg populations that differ in cellular composition and/or activation state.
      Another potential explanation for differences in human T-reg function may rest on
      the extreme variability of the culture conditions and TCR stimuli that have been
      used to test the functional properties of these cells in vitro. The strength of
      the TCR signal provided to the culture greatly affects the functional outcome of
      the co-culture and can result in the difference between suppression and full
      activation. Surprisingly, it appears that stronger stimulation has a greater and
      more rapid effect on the T-resp cell than on the T-reg cell as it causes T-resp
      cells to quickly become resistant to suppression. Thus, the details of in vitro
      culture conditions may at least partially account for disparate findings in
      regard to the functional characterization of human CD4+CD25+ cells. Here we
      review the evidence regarding the identification of human CD4+CD25+ regulatory T
      cells and their possible mechanism(s) of function.

PMID- 15036233
TI  - Role of dendritic cells in the generation of regulatory T cells.
AB  - The induction of antigen-specific T-cell tolerance in the thymus and its
      maintenance in the periphery is crucial for the prevention of autoimmunity. It
      was recently proposed that cells of the dendritic family not only control
      immunity but also maintain tolerance to self-antigens, two complementary
      functions that would ensure the integrity of the organism in an environment full
      of pathogens. The tolerogenic function of dendritic cells has been shown to be
      dependent on certain maturation stages and subsets of different ontogenies, and
      can be influenced by immunomodulatory agents. Here we discuss the current
      knowledge of these tolerogenic dendritic cells and how might the understanding of
      the function and characterization of tolerance-inducing dendritic cells be
      relevant to therapeutic applications.

PMID- 15036234
TI  - Antigen-specific regulatory T cells--their induction and role in infection.
AB  - In addition to the well-established role of natural CD4(+)CD25(+) regulatory T
      (Tr) cells in the maintenance of tolerance to self-antigens, there is
      accumulating evidence for distinct populations of Tr cells induced in the
      periphery after encounter with pathogens and foreign antigens. These antigen
      specific T cells, termed Tr1 or Th3 cells, secrete IL-10 and or TGF-beta, but no
      IL-4 and little or no IFN-gamma, and are induced by semi-mature dendritic cells
      under the influence of regulatory cytokines, including IL-10, TGF-beta and IL-4.
      Tr1 or Th3 cells are capable of suppressing Th1 and Th2 responses and function in
      infection to limit pathogen-induced immunopathology, but can also be exploited in
      therapies for immune-mediated diseases.

PMID- 15036235
TI  - Regulatory T cells and organ transplantation.
AB  - Empirical studies attempting to explain tolerance to transplanted tissues have
      demonstrated a regulatory role for CD4+ T-cells. We here propose that regulatory
      T-cells mediating transplantion tolerance comprise two sets which can
      functionally complement each other. The CD4+CD25+ "natural regulator" arises in
      the thymus, and is preoccupied with self-antigens expressed at sites of
      inflammation. The second, comprising both CD4+CD25+ (FoxP3+) and CD4+CD25- Tr1
      like cells are induced by persistent danger-free antigen in the periphery. The
      role of these cells is to moderate immune responses to prevent tissue destruction
      while allowing microbial elimination.

PMID- 15036236
TI  - Pharmacological induction of tolerogenic dendritic cells and regulatory T cells.
AB  - Immunosuppressive and anti-inflammatory agents are able to generate tolerogenic
      DCs, leading, in some cases, to induction or enhancement of regulatory T cells
      with suppressive activity. This novel mechanism of action, shared by several
      immunosuppressive and anti-inflammatory agents, is becoming firmly established
      and contributes to explain their functional properties. The possibility to
      manipulate DCs in vivo using more or less conventional low molecular weight
      drugs, enabling them to exert tolerogenic activities, could be exploited to
      better control a variety of chronic inflammatory conditions, from autoimmune
      diseases to allograft rejection.

PMID- 15036237
TI  - Regulatory T cells generated ex vivo as an approach for the therapy of autoimmune
      disease.
AB  - Regulatory T cells control the reactivity of potentially harmful, self-reactive T
      cells and prevent autoimmune diseases. Significant progress has been made in the
      identification, derivation, and mechanism of action of T regulatory cells,
      previously called suppressor T cells. Heterogeneous T regulatory subsets can be
      grouped into naturally occurring and those induced in the periphery. Here, we
      consider whether we can harness T regulatory cells to function as a therapeutic
      agent for patients with established autoimmune diseases. Since the principal
      function of thymus-derived, natural CD4+CD25+ cells is to prevent autoimmunity,
      this subset would be an obvious choice. Besides their contact-dependent, cytokine
      independent mechanism of action, they can also induce other CD4+ cells to become
      suppressor cells. However, only few natural CD4+CD25+ cells circulate in human
      peripheral blood. Alternatively, one can use IL-2 and TGF-beta to generate large
      numbers of CD4+CD25+ regulatory T cells ex vivo from naive T cells. These cells
      have the phenotypic and functional properties similar to natural CD4+CD25+ cells,
      including the capacity to induce CD4+CD25- cells to develop suppressive activity.
      These natural-like CD4+CD25+ regulatory T cells are the product of separate
      effects of IL-2 and TGF-beta on both natural CD4+CD25+ and CD4+CD25- cells. The
      ability of natural-like CD4+CD25+ cells to induce other CD4+CD25- cells to
      develop suppressive activity is both contact-dependent and cytokine-dependent.
      Thus, the effects of IL-2 and TGF-beta on both natural CD4+CD25+ cells and
      CD4+CD25- cells may trigger a continuous loop which results in the renewal of
      antigen-specific CD4+ regulatory T cells. These studies suggest that the adoptive
      transfer of CD4+ T regulatory cells generated ex vivo with IL-2 and TGF-beta as a
      treatment for autoimmune diseases may have sustained, long-term beneficial
      effects.

PMID- 15036238
TI  - LIX: a chemokine with a role in hematopoietic stem cells maintenance.
AB  - LIX is a chemokine usually associated with cell migration and activation in
      neutrophil. While using a microarray approach to dissect the hematopoietic
      microenvironment, we have discovered that LIX is also expressed in the
      hematopoietic stromal cells and its expression is associated with hematopoietic
      supportive phenotypes. LIX microarray profiles were verified using reverse
      transcription and semi-quantitative polymerase chain reaction. We subsequently
      tested the effects of LIX on the primary bone marrow derived lineage depleted
      (Lin(-)) cells. LIX was found to increase the number of long-term culture
      initiating cells by 34% (from 1 in 342 to 1 in 255 of Lin(-) cells). LIX also
      increased the clonogenicity of the long-term culture Lin(-) cells by 2-fold
      (p=0.029 ). When compared to untreated EML hematopoietic progenitor cell line,
      LIX was found to increase the level of DNA synthesis in EML cells significantly
      (1.63-fold; 0.010p=), with a corresponding increase in viable cell number by 1.11
      fold 96 h after seeding. Similar effect was not observed with the M1 mature
      myeloid leukemia cell line or with the MS5.1 and AFT024 stromal cell lines. This
      suggested that the proliferative effect of LIX is specific towards the primitive
      hematopoietic cells.

PMID- 15036239
TI  - Gene expression in the elicitation phase of guinea pig DTH and CHS reactions.
AB  - Delayed-type hypersensitivity (DTH) reactions are divided into classical DTH
      induced by protein antigens and contact hypersensitivity (CHS) induced by
      haptens. It has been reported that different cytokines and T cell subsets are
      involved in the induction of each DTH reaction. We previously isolated many genes
      whose expression is elevated during elicitation of skin DTH reaction in guinea
      pigs. In this study, we focused on the expression of tryptophanyl-tRNA synthetase
      (WRS), ferritin heavy chain and major histocompatibility complex (MHC) class II
      genes to investigate the different regulatory mechanisms in classical DTH and
      CHS. Furthermore, the expression of various cytokines and chemokines was
      examined. WRS expression in classical DTH was higher than that in CHS, and the
      expression of interferon-gamma but not that of transforming growth factor-beta
      showed similar patterns. MHC class II mRNA increased only in classical DTH. The
      differential expression of WRS and MHC class II genes in classical DTH might be
      caused by the differential expression of interferon-gamma and/or the involvement
      of CD4(+) T cells in classical DTH, respectively. In contrast, the expression of
      ferritin heavy chain and interleukin-1beta was elevated in CHS, and also by
      treatment with dinitrochlorobenzene in unsensitized guinea pigs, and expression
      of both was correlated.

PMID- 15036240
TI  - Effects of amoxicillin on cytokine and osteocalcin expression in bone tissue
      during experimental acute otitis media.
AB  - There are indications that bone regulatory and immune systems are closely
      related. Of special interest in this context is the acute otitis media (AOM),
      which mainly affects immunologically immature patients and, when complicated,
      involves bone tissue. To explore host responses in bone tissue during Haemophilus
      influenzae-induced AOM modified by amoxicillin, a rat model and PCR techniques
      were used. The treatment eradicated the bacteria and induced changes in the
      expression profile of osteocalcin, a bone formation marker. The maximum levels of
      osteocalcin transcripts in the treatment group were delayed by about a week. The
      mRNA levels never reached the same high levels as in the untreated animal group,
      but the downregulation was slow and entailed higher osteocalcin mRNA levels for a
      longer time period in the treated animals. The expression of IL-6 and TNF-alpha,
      two cytokines associated with bone resorption, remained unaffected by the
      amoxicillin treatment, whereas the downregulation of IL-10, with suppressive
      effects on bone resorption, was slower than that during the natural course. By
      comparing the host responses on the molecular level in different tissues during
      treated and untreated AOM, new approaches to how to minimize the risks of severe
      AOM complications may evolve.

PMID- 15036241
TI  - Construction of a soluble human GH-receptor/EGF-receptor hybrid and its
      activation by GH.
AB  - To develop a cell-free system that can be used to measure cytokine bioactivity we
      have designed a soluble hybrid molecule consisting of the extracellular domain of
      the GH-receptor (GHR) and the intracellular domain of the epidermal growth factor
      receptor (EGFR). A DNA construct encoding this hybrid-receptor was inserted into
      a baculoviral expression vector and expressed in Sf9-cells. Activation of the
      hybrid-receptor by ligand-induced dimerization can be measured as the
      incorporation of radiolabeled phosphate into a biotinylated tyrosine kinase
      peptide substrate. The kinase activity in samples stimulated with GH (10 ng/ml)
      increased 5-fold compared to samples without addition of GH. This is the first
      example of a functional hybrid-receptor where the transmembrane domain has been
      deleted. Our results suggest that such hybrid-receptors may be used for detection
      of GH and other cytokine-receptor activating substances in biological fluids.

PMID- 15036242
TI  - Possible vascular-bed-specific role of interleukin-6 in young women with a
      history of myocardial infarction, lacunar cerebral infarction and deep vein
      thrombosis.
AB  - The level of interleukin-6 (IL-6), a cytokine with prothrombotic properties, and
      its associations with metabolic, coagulation and fibrinolytic parameters were
      investigated in 68 young women (23-49 years, mean 40 years old) six months to six
      years after myocardial infarction (MI, N=22), lacunar cerebral infarction (LACI,
      N=16) and deep vein thrombosis (VT, N=30); all women were in the reproductive
      period, aged <45 years at the time of acute thrombotic event. Forty-seven age
      matched women comprised a control group. Basic and multivariate analysis
      disclosed different patterns of IL-6 increase in all three groups of patients. In
      the MI group IL-6 was significantly elevated independently of factors known to
      increase IL-6 levels; the increase was most pronounced in patients with high
      lipoprotein(a). This result suggests a prothrombotic association of
      lipoprotein(a) with IL-6. In the whole LACI group IL-6 was not significantly
      increased. However, patients with elevated levels of IL-6 had abdominal obesity
      and elevated fibrinogen, suggesting the possibility that this combination might
      represent a specific risk profile. In VT group elevated IL-6 level was found in
      the group of previous users of oral contraceptives (OC). This might be relevant,
      since it is known that OC could importantly increase (previously elevated) IL-6
      level in selected women. Our results suggest the hypothesis that the role of IL-6
      might be vascular-bed-specific and further propose that increased IL-6 level
      might represent a novel, non-classical risk factor for development of MI, LACI
      and VT in specific subgroups of young women, which have to be clarified in
      further studies.

PMID- 15036243
TI  - Interleukin 12 (IL-12) is increased in tumour bearing human liver and expands
      CD8(+) and CD56(+) T cells in vitro but not in vivo.
AB  - Human liver is enriched with CD8(+)T- and CD3(+)CD56(+) natural T (NT)
      lymphocytes, important anti-tumour effectors, similar to murine NKTs. IL-12
      promotes anti-tumour functions of NKTs. We quantified IL-12 and CD56(+)/CD8(+)T
      lymphocytes in normal and tumour bearing liver. We also examined the effect of IL
      12 on the expansion/activation of peripheral blood cells in vitro. IL-12 was
      detected in normal (n=13, median 2032 pg/100 mg protein) and increased in tumour
      bearing liver (n=9, 3678 pg, p< 0.01). Infiltrating monocytes appear to be the
      principal producers. Culture with IL-12 selectively expanded CD8(+)T and
      CD3(+)CD56(+)NT cells and polarised their cytokine responses to Th1-type.
      However, there was no in vivo expansion of these cells in tumour bearing liver.
      Changes observed in culture required addition of IL-2. We therefore quantified IL
      2 in hepatic tissue. IL-2 was detected in normal liver (median 4700 pg/100 mg
      protein). Surprisingly, there was no increase in tumour-infiltrated liver (4910
      pg). The presence of IL-12 may create an environment in healthy liver that
      promotes the accumulation of CD8(+)T and CD56(+)NT cells. Therefore, the
      development of metastases in the presence of high levels of IL-12 may be due to
      an insufficient IL-12 response. Alternatively, lack of IL-2 rather than a defect
      in IL-12, may be responsible for insufficient expansion/activation of tumour
      specific cytotoxic T lymphocytes.

PMID- 15036244
TI  - Interleukin-15 modulates interferon-gamma and beta-chemokine production in
      patients with HIV infection: implications for immune-based therapy.
AB  - Interleukin (IL)-15 is a cytokine that has lymphocyte stimulatory activity
      similar to that of IL-2, and plays important immunoregulatory functions during
      HIV disease. To evaluate the role of IL-15 in HIV infection the following
      patients were studied: 18 antiretroviral-naive patients with advanced disease; 19
      patients with continuous viral suppression and immunological response after 48
      120 weeks of highly active antiretroviral therapy (HAART); and 12 patients with
      evidence of virological and immunological HAART treatment failure. Nineteen
      healthy blood donors were included as controls. The production of IL-15 by human
      peripheral blood monocytes stimulated with lipopolysaccharide and Mycobacterium
      avium complex, the priming effect of IL-15 on IFN-gamma production from purified
      CD4(+) and CD8(+) T cells, and the ability of IL-15 to stimulate the beta
      chemokine release from purified CD4(+) and CD8(+) T cells were analyzed. In the
      present work IL-15 production by human peripheral blood monocytes was
      significantly increased in HIV-infected patients with long-term virological and
      immunological response to HAART. IL-15 enhanced the in vitro priming of CD4(+)
      and CD8(+) T cells for IFN-gamma production, also in patients receiving HAART.
      Finally, IL-15 had positive effects on RANTES, MIP-1alpha, and MIP-1beta release
      by CD4(+) and CD8(+) T cells. In conclusion IL-15 could affect the immune
      response of HIV-infected patients by augmenting and/or modulating IFN-gamma
      production and beta-chemokine release. These data about functional properties of
      IL-15 could provide new implications for immune-based therapies in HIV infection.

PMID- 15036245
TI  - Production of intracellular IL-1alpha, IL-1beta, and IL-1Ra isoforms by activated
      human dermal and synovial fibroblasts: phenotypic differences between human
      dermal and synovial fibroblasts.
AB  - We compared the production of IL-1alpha, IL-1beta, and of IL-1Ra isoforms by
      cultured human dermal (HDF) and synovial fibroblasts (HSF) in response to IL
      1alpha, TNF-alpha, or direct T cell membrane contact. IL-1Ra was constitutively
      present in the cell lysates of cultured HDF and its synthesis increased in
      stimulated cells, whereas IL-1Ra was present in low amounts in the supernatants.
      Secreted IL-1Ra (sIL-1Ra) and intracellular IL-1Ra type 1 (icIL-1Ra1) mRNA levels
      followed the same pattern. In stimulated HDF, IL-1alpha and IL-1beta were
      increased intracellularly but remained undetectable in the supernatants. In HSF,
      IL-1Ra levels increased in both cell lysates and supernatants upon stimulation.
      IL-1beta was only present in HSF cell lysates after stimulation, whereas IL
      1alpha was undetectable. Both sIL-1Ra and icIL-1Ra1 mRNAs were detected in
      stimulated HSF. icIL-1Ra1 was the predominant intracellular isoform in both cell
      types. In conclusion, stimulated HDF produce high amounts of intracellular IL
      1Ra, IL-1alpha, and IL-1beta. In contrast, HSF synthesized both intracellular and
      secreted IL-1Ra, whereas IL-1beta was present only in cell lysates. The presence
      of high amounts of icIL-1Ra1 and intracellular IL-1alpha in HDF suggests that
      these cytokines may carry out important function inside cells.

PMID- 15036246
TI  - Interferon-alpha reduces the development of experimental necrotizing
      enterocolitis.
AB  - Cytokines had important role in the pathogenesis of necrotizing enterocolitis
      (NEC). The aim of this study is to investigate if IFN-alpha has a prophylaxic
      effect on experimental NEC development in newborn rat pups. Twenty eight Wistar
      Albino newborn rat pups were divided into three groups. Control group rats were
      breast-fed, NEC group and interferon (IFN) group rat pups were hand-fed with
      premature newborn formula. IFN-alpha was administered subcutaneously at a dose of
      50,000 IU/rat/day in IFN group. NEC was induced experimentally by cold stress
      twice a day in IFN and NEC groups. On the fourth day, the rats were killed, and
      all the intestine were removed to determine the tissue level of malonaldehyde
      (MDA) and histologic changes. The microscopic lesions in the NEC group rats were
      virtually the same as those seen in neonatal NEC, with severe separation of
      submucosa and/or lamina propria, loss of villi and in some cases necrosis to
      extention the muscularis. In contrast, in the rats treated with IFN, lesions were
      moderate separation of submucosa and/or lamina propria, edema in submucosal and
      muscular layers. Intestinal injury score and MDA levels in NEC group were
      significantly higher than in the IFN group (P<0.05). In conclusion it was
      suggested that IFN-alpha was effective in reducing the severity of NEC in rat
      pups.

PMID- 15036247
TI  - Cytokine gene promoter polymorphisms and mortality in acute renal failure.
AB  - BACKGROUND: Although cytokines play a pivotal role in the inflammatory responses
      that mediate the severity of acute renal failure (ARF), the importance of pro-
      and anti-inflammatory cytokine gene promoter polymorphisms has been unexplored.
      METHODS: We prospectively evaluated the relationship of single nucleotide
      polymorphism in the promoter region of tumor necrosis factor alpha (TNF-alpha)
      and interleukin-10 (IL-10) to mortality in 61 patients with ARF requiring
      intermittent hemodialysis. Cytokine genotyping was performed on leukocytes using
      PCR techniques. Cox proportional-hazards regression analysis was used to explore
      these relationships. RESULTS: The mean (+/-SD) APACHE II score was 24 +/- 7, MOF
      score 2 +/- 1, and 64% had sepsis. The TNF-alpha high producer genotype (-308 A
      allele carrier) was associated with a higher risk of death after adjustment for
      the APACHE II score (HR=2.5; P=0.04), and the IL-10 intermediate/high producer
      genotype (-1082 G-allele carrier) was associated with a lower risk of death after
      adjustment for the MOF score (HR=0.36; P=0.03). Considering combinations of
      genotypes, the TNF-alpha high and IL-10 low producer genotype combination was
      associated with a approximately 6-fold increased risk of death compared to the
      TNF-alpha-low and IL-10 intermediate/high producer genotype combination, after
      adjustment for either APACHE II (P=0.004), MOF score (P=0.004) or sepsis
      (P=0.006). CONCLUSIONS: TNF-alpha and IL-10 gene polymorphisms are related to the
      risk of death among patients with ARF who require dialysis. Larger studies are
      needed to confirm these relationships.

PMID- 15036248
TI  - Increased aberrance of cytokine expression in plasma of patients with more
      advanced squamous cell carcinoma of the head and neck.
AB  - Patients with head and neck squamous cell carcinoma (HNSCC) are biased toward the
      Th2 phenotype as they have increased levels of the Th2 cytokines IL-4, IL-6 and
      IL-10 and diminished levels of the Th1 cytokine IFN-gamma. However, this bias is
      incomplete since levels of the Th1 cytokines IL-2 and GM-CSF are increased. This
      study examined the interrelationship among the plasma levels of Th1 and Th2
      cytokines in 101 HNSCC patients and 40 age-matched controls without a known
      malignancy. Control subjects showed extensive interrelationships among levels of
      IL-1, IL-2, IL-4, and IFN-gamma, as well as between GM-CSF and TGF-beta. HNSCC
      patients showed an interrelationship in levels of IL-2, IL-4, IFN-gamma and GM
      CSF, but to a less significant degree. What was prominent was a decline in
      correlation among cytokine levels with increased disease burden, such that there
      were no relationships among any of the cytokines in stage T4 patients. Nodal
      involvement also was associated with cytokine levels being more independent of
      each other, although the impact of nodal disease was less prominent than tumor
      burden. These results show a partial Th2 cytokine bias in HNSCC patients and a
      progressively more aberrant expression of cytokines with more advanced disease.

PMID- 15036249
TI  - Aspirin inhibits TNFalpha- and IL-1-induced NF-kappaB activation and sensitizes
      HeLa cells to apoptosis.
AB  - Rel/nuclear factor-kappa B (NF-kappaB) transcription factors are involved in
      transcription of several target genes that modulate proliferation, apoptosis and
      cell growth. TNFalpha- and IL-1-induced NF-kappaB activation pathways mainly
      involve the phosphorylation and degradation of IkappaBalpha by a signalsome
      complex followed by nuclear translocation of NF-kappaB and target gene
      expression. NF-kappaB mediates the balance between cell death and survival as
      most cancer cells that have rather constitutive or inducible activation of NF
      kappaB are resistant to apoptosis even by strong apoptotic agents such as
      TNFalpha. In this study we demonstrate that proinflammatory cytokines TNFalpha
      and IL-1 induced NF-kappaB activation in human cervical carcinoma HeLa cells. Our
      studies reveal that acetylsalicylic acid (aspirin) prevents TNFalpha- and IL-1
      induced NF-kappaB activation in a dose-dependent manner through inhibition of
      phosphorylation and degradation of IkappaBalpha and IkappaBbeta. Moreover,
      aspirin sensitizes HeLa cells to TNFalpha-induced apoptosis. These results
      suggest that aspirin could be used to potentiate the effectiveness of TNFalpha
      based therapeutic interventions in cancer treatment.

PMID- 15036250
TI  - The HPA axis and the genesis of chronic fatigue syndrome.
AB  - Many studies of patients with long-standing chronic fatigue syndrome (CFS) have
      found alterations to the hypothalamo-pituitary-adrenal (HPA) axis, including mild
      hypocortisolism, heightened negative feedback and blunted responses to challenge.
      However, recent prospective studies of high-risk cohorts suggest that there are
      no HPA axis changes present during the early stages of the genesis of fatiguing
      illnesses. Moreover, HPA axis changes can be reversed by modifying behavioural
      features of the illness, such as inactivity, deconditioning and sleep
      disturbance. Nevertheless, raising levels of cortisol pharmacologically can
      temporarily alleviate symptoms of fatigue. This article presents the case that
      there is no specific change to the HPA axis in CFS and that the observed changes
      are of multifactorial aetiology, with some factors occurring as a consequence of
      the illness. Nevertheless, the HPA axis might play a role in exacerbating or
      perpetuating symptoms late on in the course of the illness.

PMID- 15036251
TI  - Parathyroid hormone: a double-edged sword for bone metabolism.
AB  - Parathyroid hormone (PTH) is the major hormone regulating calcium metabolism. It
      is also the only FDA-approved drug for osteoporosis treatment that stimulates
      bone formation when injected daily. However, continuous infusion of PTH causes
      severe bone loss in line with its known catabolic effects. Many studies to
      understand the dual effects of PTH have been carried out, and in recent years a
      growing number of molecular and cellular mechanisms underlying these effects have
      emerged. Here, we outline the present knowledge and conclude that the kinetics of
      administration and subsequent signaling probably account for the divergent
      actions of the hormone.

PMID- 15036252
TI  - Estrogen, inflammation and cardiovascular risk in women: a critical appraisal.
AB  - The widely shared enthusiasm about the cardioprotective potential of estrogenic
      compounds has come to an abrupt halt since randomized trials failed to show a
      cardiovascular risk reduction in postmenopausal women. This was unexpected
      because observational studies had strongly suggested that hormone replacement
      therapy would reduce the incidence of cardiovascular disease. Inflammatory
      activity is considered central in atherogenesis and atherosclerosis progression.
      Thus, parts of the striking discrepancy between observational and randomized data
      have been attributed to an estrogen-mediated adverse effect on inflammation.
      Here, we review the current clinical evidence with respect to the inflammation
      modulating effects of different estrogenic compounds as one potential explanatory
      factor for these divergent findings. We conclude that it is still unclear whether
      estrogen-modulated inflammation is an important biological factor determining
      clinical outcome or a mere epiphenomenon.

PMID- 15036253
TI  - Anatomy of the estrogen response element.
AB  - Estrogens exert their regulatory potential on gene expression through different
      nuclear and non-nuclear mechanisms. A direct nuclear approach is the interaction
      of estrogen with specific target sequences of DNA, estrogen response elements
      (ERE) or units. EREs can be grouped into perfect and imperfect palindromic
      sequences with the imperfect sequences differing from the consensus sequence in
      one or more nucleotides and being less responsive to the activated estrogen
      estrogen receptor (ER) complex. Differences in the ERE sequence and the ER
      subtype involved can substantially alter ER-ERE interaction. In addition, cross
      talk between ERs and other nuclear transcription factors profoundly influences
      gene expression. Here, we focus on the recent advances in the understanding of
      the structure of EREs and how ERs are recruited to these. Identifying known
      target genes for estrogen action could help us to understand the potential risks
      and benefits of the administration of this steroid to humans.

PMID- 15036254
TI  - X chromosomes, retrogenes and their role in male reproduction.
AB  - Retrogenes originate from their progenitor genes by retroposition. Several
      retrogenes reported in recent studies are autosomal, originating from X-linked
      progenitor genes, and have evolved a testis-specific expression pattern. During
      male meiosis, sex chromosomes are segregated into a so-called 'XY' body and are
      silenced transcriptionally. It has been widely hypothesized that the silencing of
      the X chromosome during male meiosis is the driving force behind the
      retroposition of X-linked genes to autosomes during evolution. With the advent of
      sequenced genomes of many species, many retrogenes can be identified and
      characterized. The testis-specific retrogenes might be associated with human male
      infertility. My goal here is to integrate recent findings, highlight
      controversies in the field and identify areas for further study.

PMID- 15036255
TI  - Reproductive biology and IVF: ovarian stimulation and endometrial receptivity.
AB  - The influence of ovarian stimulation on endometrium receptivity has been
      inadequately addressed in medical literature. Hormonal effects of ovarian
      stimulation on endometrial changes as compared with the natural cycle should be
      elucidated and correlated with the potential of the embryo to implant. It is
      important to distinguish between the endometrial effect of induction of ovulation
      in anovulatory women and those of ovarian (super)ovulation in ovulatory women.
      Induction of ovulation leads to in vivo conception whereas ovarian stimulation
      results in in vitro fertilization. The available data in the field indicate that
      endometrial changes have an impressive negative influence on the potential of
      embryonic implantation. The aim of this review is to analyse the effects of
      gonadotropin, GnRH-agonist and GnRH-antagonist administration on endometrial
      behaviour, to highlight the gaps in current knowledge and to propose areas in
      which research is needed.

PMID- 15036256
TI  - Stromal reaction and tumour growth.

PMID- 15036257
TI  - Introduction: stroma reaction and cancer progression.

PMID- 15036258
TI  - Tumour invasion and matrix metalloproteinases.
AB  - Matrix metalloproteinases (MMPs) are proteolytic enzymes which play a major role
      in tumour invasion. They are mainly produced by host stromal cells in most
      carcinomas and their expression implies a close co-operation between tumour and
      stromal cells. Increasing data also demonstrate that, in association with a
      process of epithelial-to-mesenchymal transition, many MMPs can be expressed by
      tumour cell themselves. Their most well-known role is the degradation of extra
      cellular matrix macromolecules which in turn may regulate tumour invasion in some
      conditions. This ECM degradation generates some matrikins which are also
      implicated in tumour invasion and angiogenesis. Moreover, MMPs are also
      implicated in the degradation of cell adhesion molecules and release and
      activation of growth factors.

PMID- 15036259
TI  - TIMPs as multifacial proteins.
AB  - Tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of matrix
      metalloproteinases (MMPs) found in most tissues and body fluids. By inhibiting
      MMPs activities, they participate in tissue remodeling of the extracellular
      matrix (ECM). The balance between MMPs and TIMPs activities is involved in both
      normal and pathological events such as wound healing, tissue remodeling,
      angiogenesis, invasion, tumorigenesis and metastasis. The intracellular
      signalling controlling both TIMPs and MMPs expression begins to be elucidated and
      gaining insights into the molecular mechanisms regulated by TIMPs and MMPs could
      represent a new approach in the development of potential therapeutics. Numerous
      investigations have pointed out that TIMPs exhibit multifunctional activities
      distinct from MMP inhibition. In this review, we detailed the multiple activities
      of TIMPs in vivo and in vitro and we reported their implication in physiological
      and pathological processes. Further, we documented recent studies of their role
      in hematopoiesis and we itemized the different signalling pathways they induced.

PMID- 15036260
TI  - An introduction to matrikines: extracellular matrix-derived peptides which
      regulate cell activity. Implication in tumor invasion.
AB  - The term of "matrikines" was coined for designating peptides liberated by partial
      proteolysis of extracellular matrix macromolecules, which are able to regulate
      cell activities. Among these peptides, some of them may modulate proliferation,
      migration, protease production, or apoptosis, which suggest that they can play a
      significant role in the control of tumor progression. In this introduction, we
      present the best characterized matrikines, derived from elastin, connective
      tissue glycoproteins, or collagens.

PMID- 15036261
TI  - Matrix metalloproteinases and matrikines in angiogenesis.
AB  - Neoangiogenesis, the formation of new blood capillaries from pre-existing
      vessels, plays an important role in a number of physiological and pathological
      processes, particularly in tumor growth and metastasis. Extracellular proteolysis
      by matrix metalloproteinases or other neutral proteinases is an absolute
      requirement for initiating tumor invasion and angiogenesis. Cryptic segments or
      pre-existing domains within larger proteins, most of them belonging to the
      extracellular matrix, can be exposed by conformational changes and/or generated
      by partial enzymatic hydrolysis. They can positively or negatively regulate
      important functions of endothelial cells including adhesion, migration,
      proliferation, cell survival and cell-cell interactions. Such regulations by
      cryptic segments and proteolytic fragments led to the concept of matricryptins
      and matrikines, respectively. Matrix metalloproteinases and matrikines in
      conjunction with other pro- or anti-angiogenic factors might act in concert at
      any step of the angiogenesis process. A number of matrikines have been identified
      as potent anti-angiogenic factors, which could provide a new alternative to anti
      proteolytic strategies for the development of anti-angiogenic therapeutic
      molecules aimed at inhibiting tumor growth and metastasis. Some of them are
      currently being investigated in clinical trials.

PMID- 15036262
TI  - Control of melanoma progression by various matrikines from basement membrane
      macromolecules.
AB  - Many biological processes such as cell differentiation, cell migration or gene
      expression are tightly controlled by cell-cell interactions or by various
      cytokines. During tumor progression, cancer cells are in contact with
      extracellular matrix (ECM) macromolecules involving specific receptors such as
      integrins. The different stages of tumor progression, and mainly the proteolytic
      cascades implicated in extracellular matrix degradation and cell migration, may
      be controlled by the extracellular matrix macromolecules or by domains released
      by directed and limited proteolysis of these molecules. In this review, we
      summarise the biological effects of various peptides, named matrikines, derived
      from basement membranes (BM) components, such as laminins (LN), proteoglycans or
      collagens. These peptides may control tumor progression by regulating the
      proteolytic cascades leading to cancer cell dissemination and metastasis.

PMID- 15036263
TI  - Elastin as a matrikine.
AB  - The fact that elastin peptides, the degradation products of the extracellular
      matrix protein elastin, are chemotactic for numerous cell types, promote cell
      cycle progression and induce release of proteolytic enzymes by stromal and cancer
      cells, strongly suggests that their presence in tissues could contribute to
      tumour progression. Thus, elastin peptides qualify as matrikines, i.e. peptides
      originating from the fragmentation of matrix proteins and presenting biological
      activities. After a brief description of their origin, the biological activities
      of these peptides are reviewed, emphasising their potential role in cancer. The
      nature of their receptor and the signalling events it controls are also
      discussed. Finally, the structural selectivity of the elastin complex receptor is
      presented, leading to the concept of elastokine (matrikine originating from
      elastin fragmentation) and morpho-elastokine, i.e. peptides presenting a
      conformation similar to that of bioactive elastin peptides and mimicking their
      effects.

PMID- 15036264
TI  - Thrombospondin 1: a multifunctional protein implicated in the regulation of tumor
      growth.
AB  - Thrombospondins belong to a family of extracellular matrix (ECM) proteins widely
      found from embryonic to adult tissues. The modular structure of thrombospondins
      contains a series of peptide sequences implicated in a multiplicity of biological
      functions. Extracellular matrix undergoes important alterations under proteolysis
      that occurs in pathological processes like tumorigenesis. An elevated secretion
      of thrombospondin 1 (TSP1) is often observed in tumors and is sometimes
      considered as a predictive factor. However, the role of TSP1 in cancer
      progression remains controversial and must be carefully apprehended. The
      regulation of cell adhesion, proliferation, apoptosis by TSP1 is examined in the
      present review and it is clear from the literature and from our investigations
      that TSP1 presents both stimulatory and inhibitory effects. The exposition of
      cryptic sites upon conformational changes can partially explain this
      contradiction. More interestingly, the analysis of TSP1-directed intracellular
      signaling pathways activated through specific receptors or supramolecular
      receptors docking systems may be useful to discriminate the precise function of
      TSP1 in tumor progression. The central role played by TSP1 in the control of
      matrix-degrading enzyme activation and catabolism reveals attractive tracks of
      research and highlights the involvement of the lipoprotein receptor-related
      protein (LRP) receptor in these events. Therefore, TSP1-derived peptides
      constitute a source of potentially active matrikins which could provide essential
      tools in cancer therapy.

PMID- 15036265
TI  - Involvement of stromal proteoglycans in tumour progression.
AB  - Glycosaminoglycans (GAGs) and proteoglycans (PGs) belong to a class of
      extracellular macromolecules necessary for the growth of any multicellular
      structures, including tumours. Transformed cells induce stromal reaction either
      per se or by activation of the mesenchymal cells. Tumour stroma contains several
      chondroitin sulphate and heparan sulphate proteoglycans. These proteoglycans and
      their glycosaminoglycan chains modify cell behaviour by interacting with
      different molecules such as growth factors, cytokines, chemokines, proteinases
      and their inhibitors. This review describes the main proteoglycans of tumour
      stoma and discusses their implication in the regulation of the activity of
      extracellular proteins and peptides.

PMID- 15036266
TI  - Stromal reaction in cutaneous melanoma.
AB  - Cutaneous melanoma is a highly malignant tumor type which is characterized by its
      tendency to give rise to metastases. Stromal relationships are essential for
      growth and metastasis of solid tumors. In cutaneous melanoma, microscopic level
      of invasion (Breslow index), overall architecture of cells (horizontal or
      vertical growth phase), angiogenesis, vessel invasion are morphological features
      which may carry prognostic significance. As demonstrated by in vivo studies,
      stromal reaction in melanoma is mainly characterized by collagen and elastin
      proteolysis preferentially localized around the tumor at the invasive front along
      with variable angiogenesis and lymphocyte infiltration. On the basis of recent
      findings, it becomes increasingly evident that resident stromal cells
      (fibroblasts, endothelial cells) are implicated in the metastatic process,
      including proliferation, matrix degradation, or migration of melanoma cells
      through cell-cell cross-talk by soluble factors (proteases, cytokines, growth
      factors) or by direct contact.

PMID- 15036267
TI  - A novel strategy for designing specific gelatinase A inhibitors: potential use to
      control tumor progression.
AB  - Matrix metalloproteases (MMPs) are zinc endopeptidases deeply implicated in tumor
      progression. MMP inhibitors are attractive potential anti-cancer agent.
      Unfortunately, until now, clinical trials remain disappointing, that could be the
      result of a lack of selectivity. We propose second generation selective MMPs,
      directed toward gelatinase A (MMP-2), based on a non-hydroxamate Zn-ligand
      grafted on the galardin (ilomastat) skeleton.

PMID- 15036269
TI  - The role of telomeres in skin aging/photoaging.
AB  - Recent work has substantially elucidated the mechanisms of skin aging and
      photoaging. In particular, a central role for telomere-based signaling can be
      inferred. Intrinsic aging is largely controlled by progressive telomere
      shortening, compounded by low grade oxidative damage to telomeres and other
      cellular constituents, the consequence of aerobic cellular metabolism. In sun
      exposed skin, UV irradiation also damages DNA and accelerates telomere
      shortening. Aging and photodamage appear to share a common final pathway that
      involves signaling through p53 following disruption of the telomere. These
      telomere-initiated responses, in combination with UV-induced damage to critical
      regulatory genes, lead to the familiar picture of "photoaging." These and other
      insights into the molecular basis for skin aging/photoaging may lead to enhanced
      management options.

PMID- 15036270
TI  - The ageing of the blood supply and the lymphatic drainage of the skin.
AB  - The anatomy and functions of the blood and lymph vessels of human skin are
      described. Variation in these due to site, ageing and events during life
      consequent to exposure to a threatening environment are emphasised. Gradual
      atrophy and greater heterogeneity are features of ageing. Responses to injury and
      repair are complex and the interaction of mechanical signals distorting skin
      cells with numerous chemical signals are referred to. The lymphatics are part of
      an immunosurveillance system to monitor skin barrier penetration. The review
      attempts to draw attention to key recent advances in our understanding of the
      cytokine and growth factor production of the skin in the context of previous
      mainly physiological reviews especially influenced by 50 years of clinical
      practice as a dermatologist with an eye on both the skin and the fields of
      microcirculation and lymphology.

PMID- 15036271
TI  - The role of collagen and elastin in aged skin: an image processing approach.

PMID- 15036272
TI  - A mechanistic model for the aging of human skin.
AB  - The microinflammatory model of skin aging is described. This model accounts for
      the loss of elasticity, resiliene and flexibility of the dermis, as well as for
      the appearance of wrinkles and for the thinning of the epidermis which are
      associated with aging. The lack of appropriate apparatuses for the correct
      measurements of skin hydration does not allow one to test this model for its
      predictive capability of the appearance of dry skin with age. The micro
      inflammatory model of skin aging fails to predict the appearance of age spots on
      the surface of the skin.

PMID- 15036273
TI  - Skin aging and natural photoprotection.
AB  - Aging of skin is a continuous process that may be enhanced by sun exposure.
      Photoaging may provoke changes different from aging. Epidermal changes involve
      thinning of stratum spinosum and flattening of the dermo-epidermal junction. The
      senescent keratinocytes becomes resistant to apoptosis and may survive for a long
      time giving time for DNA and protein damage to accumulate with possible
      implication for carcinogenesis. The numbers of melanocytes decrease with age with
      dysregulation of melanocyte density resulting in freckles, guttate hypo
      melanosis, lentigines and nevi. The number of dendritic Langerhans cells also
      decreases with age and the cells get less dendrites and have reduced antigen
      trapping capacity. Aging involves dermal changes such as damage to elastic and
      collagen fibers giving thickened, tangled, and degraded non-functional fibers.
      Collagen intermolecular cross-links are stable and essential for stability and
      tensile strength. Cross-links increase with age converting divalent cross-links
      into mature trivalent cross-links of, e.g. histidinohydroxylysinonorleucine. Two
      mechanisms are involved; an enzyme-controlled process of maturation and a non
      enzymatic glycosylation, the Maillard reaction leading to cross-links in proteins
      such as in collagen between arginine and lysine. Such may be seen with age and in
      diabetes mellitus. However, autofluorescence studies have shown that UVR reduces
      collagen cross-links. Natural photoprotection involves thickening of stratum
      corneum by sunlight and increased pigmentation. This leads to a factor 2 increase
      in photoprotection from spring until after-summer. The constitutive pigmentation
      is independent of age and thickness of stratum corneum is likewise independent of
      age. The minimal erythema dose is thus the same through life, when corrected for
      pigmentation or measured in areas with constitutive pigmentation.

PMID- 15036274
TI  - Hair cycle and hair pigmentation: dynamic interactions and changes associated
      with aging.
AB  - The tight coupling of hair follicle melanogenesis to the hair growth cycle
      dramatically distinguishes follicular melanogenesis from the continuous
      melanogenesis of the epidermis. Cyclic re-construction of an intact hair follicle
      pigmentary unit occurs optimally in all scalp hair follicles during only the
      first 10 hair cycles, i.e. by approximately 40 years of age. Thereafter there
      appears to be a genetically regulated exhaustion of the pigmentary potential of
      each individual hair follicle leading to the formation of true gray and white
      hair. Pigment dilution results primarily from a reduction in tyrosinase activity
      within hair bulbar melanocytes. Thereafter, sub-optimal melanocyte-cortical
      keratinocyte interactions, and defective migration of melanocytes from a
      reservoir in the upper outer root sheath to the pigment-permitting
      microenvironment close to the follicular papilla of the hair bulb, will all
      disrupt normal function of the pigmentary unit. Evidence from studies on
      epidermal melanocyte aging suggest that reactive oxygen species-mediated damage
      to nuclear and mitochondrial DNA may lead to mutation accumulation in bulbar
      melanocytes. Parallel dysregulation of anti-oxidant mechanisms or pro/anti
      apoptotic factors is also likely to occur within the cells. Pigment loss in
      canities may also affect keratinocyte proliferation and differentiation,
      providing the tantalizing suggestion that melanocytes in the hair follicle
      contribute far more that packages of pigment alone. Here, we review the current
      state of knowledge of the development, regulation and control of the aging human
      hair follicle pigmentary system in relation with hair cycling. The exploitation
      of recently available methodologies to manipulate hair follicle melanocytes in
      vitro, and the observations that melanocytes remain in senile white hair
      follicles that can be induced to pigment in culture, raises the possibility of
      someday reversing canities. The perspective of rejuvenation of the whole hair
      follicle apparatus are still part of the dream but optimising its functional
      properties is clinically relevant and is close to reality. Finally as hair color
      influences its visibility when optical methods such as scalp photography are used
      to count hair fibers, the attention is drawn to possible interpretations of
      statistically significant changes in visible hair. Such changes may not
      exclusively be related to improved hair growth itself but also to changes in
      natural hair color that makes the hair more visible with the method used to count
      hairs.

PMID- 15036275
TI  - The wrinkle and its measurement--a skin surface Profilometric method.
AB  - This study outlines a simple 'Profilometric' method for measuring the size and
      function of the wrinkles. Wrinkle size was measured in relaxed conditions and the
      representative parameters were considered to be the mean 'Wrinkle Depth', the
      mean 'Wrinkle Area', the mean 'Wrinkle Volume', and the mean 'Wrinkle Tissue
      Reservoir Volume' (WTRV). These parameters were measured in the wrinkle profiles
      under relaxed conditions. The mean 'Wrinkle to Wrinkle Distance', which measures
      the distance between two adjacent wrinkles, is an accurate indicator of the
      muscle relaxation level during replication. This parameter, identified as the
      'Muscle Relaxation Level Marker', and its reduction are related to increased
      muscle tone or contraction and vice versa. The mean Wrinkle to Wrinkle Distance
      is very important in experiments where the effectiveness of an anti-wrinkle
      preparation is tested. Thus, the correlative wrinkles' replicas, taken during
      follow up in different periods, are only those that show the same mean Wrinkle to
      Wrinkle Distance. The wrinkles' functions were revealed by studying the
      morphological changes of the wrinkles and their behavior during relaxed
      conditions, under slight increase of muscle tone and under maximum wrinkling.
      Facial wrinkles are not a single groove, but comprise an anatomical and
      functional unit (the 'Wrinkle Unit') along with the surrounding skin. This
      Wrinkle Unit participates in the functions of a central neuro-muscular system of
      the face responsible for protection, expression, and communication. Thus, the
      Wrinkle Unit, the superficial musculoaponeurotic system (superficial fascia of
      the face), the underlying muscles controlled by the CNS and Psyche, are
      considered to be a 'Functional Psycho-Neuro-Muscular System of the Face for
      Protection, Expression and Communication'. The three major functions of this
      system exerted in the central part of the face and around the eyes are: (1) to
      open and close the orifices (eyes, nose, and mouth), contributing to their
      functions; (2) to protect the eyes from sun, foreign bodies, etc.; (3) to
      contribute to facial expression, reflecting emotions (real, pretended, or
      theatrical) during social communication. These functions are exercised
      immediately and easily, without any opposition ('Wrinkling Ability') because of
      the presence of the Wrinkle Unit that gives (a) the site of refolding (the
      wrinkle is a waiting fold, ready to respond quickly at any moment for any skin
      mobility need) and (b) the appropriate skin tissue for extension or compression
      (this reservoir of tissue is measured by the parameter of WTRV). The Wrinkling
      Ability of a skin area is linked to the wrinkle's functions and can be measured
      by the parameter of 'Skin Tissue Volume Compressed around the Wrinkle' in mm(3)
      per 30 mm wrinkle during maximum wrinkling. The presence of wrinkles is a sign
      that the skin's 'Recovery Ability' has declined progressively with age. The
      skin's Recovery Ability is linked to undesirable cosmetic effects of ageing and
      wrinkling. This new Profilometric method can be applied in studies where the
      effectiveness of anti-wrinkle preparations or the cosmetic results of surgery
      modalities are tested, as well as in studies focused on the functional physiology
      of the Wrinkle Unit.

PMID- 15036276
TI  - Aged skin: detection of alterations of major collagen types ratio by image
      processing of electron-optical data.
AB  - Automated algorithms are developed in this paper based on digital signal
      processing to correlate electron-optical data from skin collagen fibrils with
      known sequence data. In particular, they detect alterations on the ratio of major
      collagen types in skin upon age.

PMID- 15036278
TI  - The Ghiretti lecture: commemoration of Francesco Ghiretti.

PMID- 15036279
TI  - Modeling techniques for analysing conformational transitions in hemocyanins by
      small-angle scattering of X-rays and neutrons.

PMID- 15036280
TI  - Tarantula hemocyanins imaged by atomic force microscopy.
AB  - Individual 4 x 6-meric tarantula hemocyanins and dissociation products were
      imaged by AFM in the non-contact mode. Although the resolution was low, the
      hexamers and topological arrangement within the oligomers can be seen. However,
      the relative humidity seems to affect the height profiles.

PMID- 15036281
TI  - Model building of a molluscan hemocyanin from X-ray solution scattering.
AB  - Molluscan hemocyanins are proteins of a truly enormous size. Because of this,
      determination of their quaternary structure at high resolution cannot easily be
      obtained by standard methods such as X-ray crystallography and NMR. Therefore,
      different approaches, using several low-resolution techniques are currently
      necessary to understand hemocyanin structure. In this work a model of the Rapana
      venosa hemocyanin has been obtained from a template model and small angle X-ray
      scattering (SAXS) data. The template model was built from the electron density of
      the closely related Haliotis tuberculata hemocyanin and a computer program was
      written to fit this model to the SAXS data using the simulated annealing
      algorithm.

PMID- 15036282
TI  - Structural subunit organization of molluscan hemocyanins.
AB  - The quaternary structure of Molluscan hemocyanins is not still defined, in
      particular the spatial distribution and the structural subunits. It is important
      to establish the number and the nature of interations between functional units.
      Here we present two non-proteolytic methods for the depolymerization of
      hemocyanins. The results suggest that the carbohydrate moieties apparently play a
      basic role in the organization of the structural subunits.

PMID- 15036283
TI  - 3D reconstruction of the hemocyanin subunit dimer from the chiton Acanthochiton
      fascicularis.
AB  - Procedures are presented for the purification of the subunit dimer from
      Acanthochiton fasicularis hemocyanin. Electron microscopy of negatively stained
      specimens revealed a uniform population of macromolecules possessing the
      characteristic "boat shape". A 3D reconstruction from this EM data generated a
      approximately 3 nm resolution model that correlates well with earlier data of the
      purported subunit dimer, extracted from the 3D reconstruction of the didecamer of
      Haliotis tuberculata hemocyanin type 1.

PMID- 15036284
TI  - Respiratory adaptations of a deep-sea hydrothermal vent crab.

PMID- 15036285
TI  - Respiratory adaptations to the deep-sea hydrothermal vent environment: the case
      of Segonzacia mesatlantica, a crab from the Mid-Atlantic Ridge.
AB  - Segonzacia mesatlantica (Crustacea; Decapoda; Brachyura) is the only endemic crab
      species known from the Mid-Atlantic Ridge (MAR) hydrothermal vents. Known from
      all explored sites in the Atlantic, its wide distribution makes this species a
      model to study physiological adaptation, and specifically respiratory strategies.
      Native haemocyanin (Hc) comprises four non-covalent associations in equilibrium
      formed by monomers, hexamers, dodecamers and octadecamers made up of
      approximately 75 kDa polypeptide chains. Four different amino acid chains are
      observed with a molecular mass ranging from 75,234 to 75,972 Da. Experiments
      carried-out under pressure suggested that the percentage of monomer increased in
      the haemolymph under hypoxic condition. We have also observed a shift of the
      proportion of the two dodecamer series, suggesting a rapid modification of the Hc
      phenotype between hypoxic and hyperoxic conditions. Native Hc possesses a high
      oxygen affinity ( P50 = 2.2 Torr at 15 degrees C and pH 7.5), a large Bohr effect
      (Deltalog P50 / DeltapH approximately -2.7) and a slightly reverse temperature
      effect (DeltaH = +17.19 kJ mol(-1). The composition of Segonzacia haemolymph is
      similar to that of other littoral species except for the large enrichment in free
      copper and zinc. As for other species from hydrothermal vent sites, Segonzacia
      haemolymph possesses a higher buffer capacity than littoral species. Moreover,
      species from the hydrothermal vent decapods from Pacific hydrothermal vent that
      encounter higher CO2 content in their environment have a higher buffer capacity
      than Atlantic vent species. The results presented are discussed in relation with
      the physico-chemical characteristics of the hydrothermal vent environment.

PMID- 15036286
TI  - Structural role of the copper ions in the dinuclear active site of Carcinus
      aestuarii hemocyanin.
AB  - In this work we show, by a combination of biochemical and biophysical approaches,
      that the copper ions bound in the binuclear active site of Carcinus aestuarii
      hemocyanin play a stabilizing role on the tertiary structure of the protein. Upon
      removal of copper, the monomeric hemocyanin, but not the hexameric oligomer,
      undergoes changes at the level of tertiary structure while the secondary
      structure is almost unaffected. By Small-Angle X-Ray Scattering, supported by gel
      chromatography measurements, it can be concluded that the apo-monomer, but not
      the holo form or the hexameric form, undergoes a slow time-dependent
      oligomerization process.

PMID- 15036288
TI  - Molecular adaptation of Daphnia magna hemoglobin.
AB  - Daphnia magna responds to changing environmental conditions impeding aerobic
      metabolism by synthesizing hemoglobin of adequate quantity and quality to
      maintain oxygen supply of the tissues. Hemoglobin subunit composition and its
      oxygen affinity were analyzed as a function of temperature as well as depending
      on the oxygen partial pressure of the medium. Additionally, the time course of
      acclimation to hypoxia was studied. Correlating structural and functional
      changes, the role of individual subunits for the increase in oxygen affinity is
      discussed.

PMID- 15036289
TI  - Comparative analysis of structural properties of Portunid Crab Hemocyanin.
AB  - In order to explore the hemocyanin adaptative potential and evolutive dynamics,
      we have analyzed the structural properties of this oxygen-carrier protein, in
      some species of portunid Crabs, (Brachyura, Portunida). We have compared the
      intra- and interspecific subunits patterns, in native and denaturant conditions,
      to estimate the phenetic relationships and the different stabilities of the
      protein.

PMID- 15036287
TI  - 'Novel' factors that regulate oxygen binding in vertebrate hemoglobins.

PMID- 15036290
TI  - Structural properties, conformational stability and oxygen binding properties of
      Penaeus monodon hemocyanin.
AB  - Hemocyanin sequences allineament shows the presence of highly invariant regions
      especially in the active site and in the tight intersubunits interaction sites.
      Comparing the aminoacids in contact regions between monomers is possible to
      interpret the stability of hexamers.

PMID- 15036291
TI  - Resistance to stress and Hc functional modulation in Liocarcinus sp.
AB  - This study is included in a project aimed to study the alterations on the
      structure of the Northern Adriatic Sea ecosystem produced by fishing activity.
      The indirect or secondary effects of fishery such as the changes of the structure
      and trophic relationships of the ecosystem are under investigation and we have
      particularly considered the effects on species such as Liocarcinus depurator that
      are captured and then rejected because devoid of commercial value. The objective
      of this study is the Liocarcinus sp. adaptative resistance to stress and the
      effects of biochemical parameters (allosteric effectors) on Hc functional
      modulation.

PMID- 15036292
TI  - Coupling of the heme and an internal disulfide bond in human neuroglobin.
AB  - Neuroglobin displays a hexacoordination His-Fe-His in the absence of external
      ligands such as oxygen. The observed oxygen affinity therefore depends on the
      binding rates of both oxygen and the competing distal histidine. Furthermore, the
      binding properties depend on the presence of an internal disulfide bond. In the
      case of human neuroglobin, cysteines at positions CD7 and D5 are sufficiently
      close to form an internal disulfide bond. For cytoglobin, the cysteine residues
      at positions A7 and GH4 may also form a disulfide bond. Mass spectrometry, ligand
      binding, and thiol accessibility studies were used to study the role influence of
      these disulfide bonds. Mutation of specific cysteines, or reduction to break the
      S-S bond, led to a large decrease in the observed oxygen affinity of human
      neuroglobin, mainly due to a decrease in the histidine dissociation rate. This
      suggests a novel mechanism for the oxygen binding; reduction of the disulfide
      bond would provoke the release of oxygen.

PMID- 15036293
TI  - The human brain hexacoordinated neuroglobin three-dimensional structure.
AB  - Neuroglobin, mainly expressed in vertebrate brain and retina, is a recently
      identified member of the globin superfamily. Augmenting O2 supply, neuroglobin
      promotes survival of neurons upon hypoxic injury, potentially limiting brain
      damage. In the absence of exogenous ligands, neuroglobin displays a six
      coordinated heme. O2 and CO bind to the heme-iron, displacing the endogenous
      HisE7 heme distal ligand. Hexacoordinated human neuroglobin displays a classical
      globin fold, adapted to host the reversible bis-histidyl heme complex, and an
      elongated protein matrix cavity, held to facilitate O2 diffusion to the heme. The
      structure of neuroglobin suggests that the classical globin fold is endowed with
      striking adaptability, indicating that hemoglobin and myoglobin are just two
      examples within a wide and functionally diversified protein homology superfamily.

PMID- 15036294
TI  - The effect of protein internal cavities on ligand migration and binding in
      myoglobin.
AB  - Using Fourier Transform Infrared Spectroscopy at cryogenic temperatures, we have
      studied carbon monoxide (CO) migration in the interior of sperm whale myoglobin
      and binding to teh heme iron. The effect of protein internal cavities was
      examined by comparing the wild-type protein with mutants in which the cavities
      were blocked by bulky amino acid sidechains. After photodissociation at 3 K, CO
      ligands reside in the primary docking site (B) from where they can migrate to
      other sites (C, D) that were identified as the Xe4 and Xe1 cavities. These
      studies were complemented by flash photolysis experiments at room temperature,
      which revealed that the protein cavities enable efficient excape of ligands from
      the protein after dissociation from the heme iron.

PMID- 15036295
TI  - Structural properties of cyanobacterial hemoglobins: the unusual heme-protein
      cross-link of Synechocystis sp. PCC 6803 Hb and Synechococcus sp. PCC 7002 Hb.
AB  - The truncated hemoglobins from Synechocystis sp. PCC 6803 and Synechococcus sp.
      PCC 7002 ligate the heme iron with two axial histidines (HisF8 and HisE10). In
      addition, these two proteins are able to form a heme-protein cross-link between a
      vinyl substituent and a histidine at position 16 of the H helix. The product is a
      protein with improved resistance to thermal and acid denaturation.

PMID- 15036296
TI  - The Root effect--a physiological perspective.

PMID- 15036297
TI  - Developmental regulation of the allosteric effector pattern of avian embryonic
      hemoglobin.

PMID- 15036298
TI  - Structure/function and phylogeny of hemoglobins of polar fishes.
AB  - The northern and southern polar oceans have very different oceanographic
      features. Taking advantage of the information available on haemoglobin structure
      and function, we analysed the evolutionary history of the alpha and beta globins
      of Antarctic and Arctic haemoglobins as a basis for reconstructing the
      phylogenetic relationships among species.

PMID- 15036299
TI  - Structural quantitative information on the active sites of hemocyanins and
      related model compounds by the XAS approach: the role of multiple-scattering
      calculations.
AB  - In this contribution, we will present an overview of the role of the multiple
      scattering (MS) calculations in the X-ray absorption spectroscopy (XAS) approach
      in order to extract from experimental data quantitative structural information on
      the active sites of the hemocyanin derivatives and of the related model compounds
      considered.

PMID- 15036300
TI  - Oxygen as a morphogenic factor in sponges: expression of a tyrosinase gene in the
      sponge Suberites domuncula.
AB  - Sponges live in a symbiotic relationship with microorganisms, especially
      bacteria. Here we show, using the demosponge Suberites domuncula as a model, that
      the sponge expresses the enzyme tyrosinase which synthesizes diphenols from
      monophenolic compounds. It is assumed that these products serve as carbon source
      for symbiotic bacteria to grow.

PMID- 15036301
TI  - Conversion of crustacean hemocyanin to catecholoxidase.
AB  - Crustacean hemocyanin as oxygen carrier and catecholoxidase as enzymes belong to
      the same protein family (type 3 copper proteins) sharing very similar active
      sites. Treatment with SDS of these hemocyanins results in an opening of the
      entrance to the active site for bulky phenolic compounds. This demonstrates, that
      almost all hemocyanin subunits possess the ability of catecholoxidase activity.

PMID- 15036302
TI  - Intrinsic and induced o-diphenoloxidase activity of beta-hemocyanin of Helix
      pomatia.

PMID- 15036303
TI  - Laccases: structure, reactions, distribution.
AB  - Laccases (EC 1.10.3.2, p-diphenol: dioxygen oxidoreductases) are multi-copper
      proteins that use molecular oxygen to oxidize various aromatic and non-aromatic
      compounds by a radical-catalyzed reaction mechanism. The enzymes are involved in
      the pathogenicity, immunity and morphogenesis of organisms and in the metabolic
      turnover of complex organic substances such as lignin or humic matter. Owing to
      their high non-specific oxidation capacity, laccases are useful biocatalysts for
      diverse biotechnological applications. Until recently, laccases were only found
      in eukaryotes (fungi, higher plants, insects), but now there is strong evidence
      for their widespread distribution in prokaryotes and the first crystal structure
      of a bacterial laccase is already available. Phylogenetically, laccases are
      members of the multi-copper protein family including ascorbate oxidase,
      ceruloplasmin and bilirubin oxidase.

PMID- 15036304
TI  - Homology modelling of hemocyanins and tyrosinases: pitfalls in automated
      approaches.

PMID- 15036305
TI  - Glycosylation sites of hemocyanins of Helix pomatia and Sepia officinalis.
AB  - Glycopeptides were isolated from functional units of two molluscan hemocyanins
      (Hcs). They were analyzed and localized in the sequences. A comparison with
      potential N-glycosylation sites of two other molluscan Hcs was made. An
      immunological cross-reactivity was observed between the beta-Hc and the alpha
      macroglobulin of Helix pomotia. ELISA experiments with glycopeptide fractions
      indicated a competition.

PMID- 15036306
TI  - Carbohydrate moieties of molluscan Rapana venosa hemocyanin.
AB  - Using Zn2+ ions as new method, several FUs have been isolated from molluscan Hc
      Rapana venosa without formation of non-functional proteolytic side products. N
      terminal sequences of these fragments in comparison with FUS from other
      gastropodan Hcs show a very high degree of structural identity. Four Fus,
      purified from enzyme-treated structural subunits RvH1 and RvH2 (RvH1-a, RvH1-f,
      RvH2-a and RvH2-e) show identical N-terminal sequences compared to fragments
      isolated after treatment with Zn2+ ions. However, in some cases trypsin cleaves
      RvH chains at different positions if compared to the Zn2+ treatment. To analyze
      the oligosaccharide composition of two FUS from the first structural subunit of
      Rapana Hc, RvH1-a and RvH1-f, several techniques were applied: capillary
      electrophoresis, MALDI-MS, ESI-MS in combination with glycosidase digestions. On
      basis of these results and the determined amino acid sequence two N-linkage sites
      were identified in the FU RvH1-a, but only one in the FU RvH1-f.

PMID- 15036307
TI  - Characterization of keyhole limpet hemocyanin (KLH) glycans sharing a
      carbohydrate epitope with Schistosoma mansoni glycoconjugates.
AB  - Keyhole limpet hemocyanin (KLH) is known to share carbohydrate epitopes with
      Schistosoma mansoni. In order to define the structural basis for the observed
      serological cross-reactivity, KLH glycans were released either by enzyme
      treatment or by hydrazinolysis and probed with a rabbit hyperimmune serum
      directed against S. mansoni egg antigen. Both major, non-reacting oligosaccharide
      species as well as the minor compounds recognized were isolated by two
      dimensional high performance liquid chromatography and in part by lectin affinity
      chromatography, and characterized by mass spectrometry. The results revealed that
      KLH carries predominantly high mannose-type glycans as well as short sugar
      chains. As a characteristic feature, a number of the latter glycans contained a
      Gal(beta1-6)Man-unit, which has not yet been found in glycoprotein-N-glycans.
      Oligosaccharides cross-reacting with schistosomal glycans comprised a terminal
      Fuc(alpha1-3)GalNAc-motif, which appears to represent the main carbohydrate
      epitope mediating cross-reactivity of KLH with glycoconjugates from S. mansoni.

PMID- 15036308
TI  - Immobilization of Scapharca HbI crystals improves data quality in time-resolved
      crystallographic experiments.
AB  - Time-resolved crystallography is a powerful technique that allows structural
      transitions to be followed in real time during the course of a chemical reaction.
      The extension of the time resolution of this technique to nanosecond and
      picosecond time scales require a short laser pulse to initiate the transition and
      a rapid polychromatic X-ray pulse to probe the structural perturbations.
      Unfortunately, polychromatic diffraction patterns are quite sensitive to subtle
      crystal movements that can occur from laser pulses used to trigger the structural
      transition. The immobilization of crystals within capillary tubes dramatically
      improves data quality and allows the utilization of more intense laser pulses for
      the initiation step. This leads to an increase in the signal to noise present in
      the electron density maps.

PMID- 15036309
TI  - Urate as effector for crustacean hemocyanins.

PMID- 15036310
TI  - Toward oxygen binding curves of single respiratory proteins.
AB  - Oxygen binding curves of single molecules promise to discriminate between
      different models describing cooperativity because load distributions are
      accessible. Individual tarantula hemocyanins could be detected by fluorescence
      correlation spectroscopy using intrinsic tryptophan fluorescence as sensor of
      bound oxygen. However, imaging of immobilized proteins was not possible due to
      fast photo-bleaching. It is shown that tetra-methyl-carboxy-rhodamine (TAMRA),
      commonly used as a fluorescence label in single-molecule spectroscopy, can also
      be applied to monitor bound oxygen. The dye's fluorescence is quenched due to
      Forster energy transfer to the oxygenated active sites of hemocyanin.

PMID- 15036311
TI  - Blood cells and the biosynthesis of hemocyanin in Sepia embryos.

PMID- 15036312
TI  - Evolution of molluscan hemocyanins as deduced from DNA sequencing.

PMID- 15036313
TI  - Evolutionary history and diversity of arthropod hemocyanins.
AB  - Hemocyanins are copper-containing, multi-subunit proteins that transport oxygen
      in the hemolymph of many molluscs and arthropods [Markl and Decher, Adv. Comp.
      Environ. Physiol. 13 (1992) 325; 15563]. Arthropod hemocyanins originated more
      than 550 million years ago from oxygen-consuming phenoloxidases. Hemocyanins are
      present in various Onychophora, Chelicerata, Myriapoda, Crustacea, and Hexapoda,
      but subunit evolution differs striking in these arthropod subphyla. Hemocyanins
      also gave rise to non-respiratory proteins (crustacean pseudo-hemocyanins, insect
      hexamerins, and hexamerin receptors), which most likely have storage functions.

PMID- 15036314
TI  - Leech hemoglobin: primary structures of four kinds of globins from Haemadipsa
      zeylanica var. japonica.

PMID- 15036315
TI  - The stoichiometry of the four linker subunits of Lumbricus terrestris hemoglobin
      suggests an asymmetric distribution.
AB  - The extracellular, giant ( approximately 3.6 MDa) hexagonal bilayer hemoglobin of
      the earthworm Lumbricus terrestris consists of 12 dodecamers of globin chains
      tethered to a central complex of 36 non-globin, linker chains (24-32 kDa). Four
      types of linker chains L1-L4 have been detected by electrospray ionization (ESI)
      and by matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS)
      and isolated by reversed phase high pressure liquid chromatography (HPLC).
      Deconvolution of the HPLC elution profile and of the MS spectra provided the
      following individual linker contents, expressed as percent of the sum of the four
      linker peak areas: HPLC-21% L1, 37% L2, 23% L3 and 19% L4, MALDI-47% L1, 29% L2,
      16% L3 and 8% L4; ESI-24% L1, 16% L2, 40% L3 and 20% L4; respectively. Comparison
      with electrophoretic results revealed a surprising lack of overall agreement
      between all the methods. The calculated mean values of the available linker
      contents were found to be 32+/-12% L1, 28+/-9% L2, 27+/-10% L3 and 13+/-7% L4,
      suggesting the following relative stoichiometry: L1: L2: L3: L4 approximately 1:
      1: 1: 0.5. With a total of 36 linkers, a hexagonally symmetric distribution of
      each of the four linker chains is impossible. Thus, the asymmetric linker
      distribution provides an explanation for the existence of a large dipole moment
      of Lumbricus terrestris hemoglobin, 17,300+/-2300 Da (Takashima et al., 1999).

PMID- 15036316
TI  - On the molecular mass of Lumbricus erythrocruorin.
AB  - A critical examination of the published molecular mass of erythrocruorin (Ec)
      from Lumbricus and related earthworm species reveals that the results do cluster,
      not at one, but at two values of the molecular mass. One cluster corresponds to
      approximately 3.6 MDa as predicted from the Vinogradov model for the hexagonal
      bilayer (HBL) assembly of Lumbricus terrestris EC and as estimated from the
      crystal structure of HBL at 5.5 A resolution. The other cluster corresponds to
      approximately 4.4 MDa. However, in contrast to the controversy over the molecular
      mass, there is a consensus that the sedimentation coefficient of intact L.
      terrestris Ec is approximately 60S. Drawing on the occurrence of central subunits
      in Ec of Oenone fulgida and few other annelid species, we propose for the 4.4 MDa
      molecule a model of HBL supplemented by a central mass. The proposed model abides
      by D6 symmetry and is a suitable candidate to represent 60S Lumbricus terrestris
      Ec.

PMID- 15036317
TI  - Dicopper and heteronuclear iron-copper peroxo complex formation: kinetics and
      thermodynamics.
AB  - Quasireversible adducts of dioxygen with Cu(I) complexes are of interest as
      models for dioxygen transport proteins, for oxygen-dependent copper redox
      enzymes, and for low-molecular oxidation and oxygenation catalysts. Depending on
      ligand denticity and structural factors dioxygen binds in various geometries and
      metal:O2 ratios to the reduced copper centers. Kinetic investigations produce
      detailed mechanistic insight into the nature of coppers-dioxygen interaction.
      Heteronuclear FeO2Cu complexes with stabilities far beyond statistical
      expectation are obtained when 1:1 mixtures of suitable copper(I) complexes and
      appropriate Fe(II) porphyrins are treated with O2.

PMID- 15036318
TI  - Dicopper peroxo complexes: low temperature stopped-flow reaction kinetics of
      [(BQPA)CuI]+ and [(Me2-TMPA)CuI]+.
AB  - In the last 20 years, the reaction of many different CuI complexes and with
      dioxygen has been described. There is quite a big variety in their coordination
      geometry and most of them have been characterized by X-ray crystallography.
      Beyond structural information, stopped-flow kinetics experiments have provided
      additional mechanistic insights. In the particular systems [(BQPA)CuI]+ and [(Me2
      TMPA)CuI]+ a new equilibrium between the two species trans-mu-1,2-peroxo and bis
      mu-oxo is demonstrated. In the case of [(BQPA)CuI]+ the two species are in an
      equilibrium, presumably via the transient superoxo species. The reaction of [(Me2
      TMPA)CuI]+ with dioxygen leads to the parallel formation of both species. The
      kinetically preferred trans-mu-peroxo species is then isomerised to the
      thermodynamically more stable bis-mu-oxo species.

PMID- 15036319
TI  - New aspects of the reactivity of tyrosinase.
AB  - Tyrosinase was found to be active in the sulfoxidation of thioanisol, producing
      the (R)-sulfoxide with high enantiomeric excess. The activity of the enzyme with
      phenolic and diphenolic substrates in a mixed aqueous Hepes buffer pH 6.8
      methanol-glycerol solvent was also investigated over a range of temperatures.
      These experiments enabled us to deduce the thermodynamic parameters associated
      with substrate binding to the enzyme and the activation parameters associated
      with the rate determining step of the enzymatic reaction.

PMID- 15036320
TI  - What are the structural features of the active site that define binuclear copper
      proteins function?
AB  - The structural basis that define the physiological functions of binuclear copper
      enzymes is discussed in the frame of the data generated by a broad spectroscopic
      approach, spanning from paramagnetic NMR and pulsed EPR to x-ray absorption
      spectroscopies. The structural features discussed for the different oxidation and
      ligation states accessible to a binuclear copper sites are the coordination
      geometry for the first and second shell, the metal-metal distance and the role of
      the bridging exogenous ligand(s). A structural model will be presented to
      rationalize both the differentiation in function within the protein families and
      the reaction mechanism of those proteins that are enzymatically active.

PMID- 15036321
TI  - Multiple mechanisms of bipA gene regulation by the Bordetella BvgAS phosphorelay
      system.

PMID- 15036322
TI  - Bacterial programmed cell death systems as targets for antibiotics.
AB  - Growing experimental evidence has revealed the existence of programmed cell death
      (PCD) systems in bacteria. Among these is the mazEF system, which is a regulable
      suicide module located on the chromosome of E. coli and of some other bacteria,
      including pathogens. Several well-known antibiotics have recently been found to
      cause cell death in E. coli by indirectly activating this built-in suicide
      module. These antibiotics belong to two groups: (i) inhibitors of transcription
      and/or translation; and (ii) inhibitors of folic acid metabolism resulting in
      thymine starvation. These data, together with the recent elucidation of the
      crystal structure of mazEF-directed components, hold promise for a rational
      chemical design of a new class of antibiotics that directly activate chromosomal
      suicide modules by interacting with their components. Because multi-drug
      resistance among bacterial pathogens is becoming more widespread, the results
      obtained might be useful as a basis for producing alternative drugs.

PMID- 15036323
TI  - Strategies of microbial cheater control.
AB  - The potential benefits of cooperation in microorganisms can be undermined by
      genetic conflict within social groups, which can take the form of 'cheating'. For
      cooperation to succeed as an evolutionary strategy, the negative effects of such
      conflict must somehow be either prevented or mitigated. To generate an
      interpretive framework for future research in microbial behavioural ecology, here
      we outline a wide range of hypothetical mechanisms by which cheaters might be
      constrained.

PMID- 15036324
TI  - Dendritic cells: the host Achille's heel for mucosal pathogens?
AB  - Mucosal surfaces represent the main sites of interaction with environmental
      microorganisms and antigens. Sentinel cells, including epithelial cells and
      dendritic cells (DCs), continuously sense the environment and coordinate defenses
      for the protection of mucosal tissues. DCs play a central role in the control of
      adaptive immune responses owing to their capacity to internalize foreign
      materials, to migrate into lymph nodes and to present antigens to naive
      lymphocytes. Some pathogenic microorganisms trigger epithelial responses that
      result in the recruitment of DCs. These pathogens hijack the recruited DCs to
      enable them to infect the host, escape the host's defense mechanisms and
      establish niches at remote sites.

PMID- 15036325
TI  - The biology of Gram-positive sortase enzymes.
AB  - Surface proteins of Gram-positive pathogens play various key roles in
      pathogenicity. Therefore, these proteins are of great interest in terms of
      understanding the infection process and have potential as targets for therapy. A
      major mechanism for the surface display of proteins by Gram-positive bacteria is
      sortase-mediated covalent attachment to the cell wall. The importance of sortase
      enzymes in the virulence of several pathogens is now becoming apparent, as are
      some of the more detailed workings of the enzyme and anchoring pathway. These
      recent advances are discussed.

PMID- 15036326
TI  - Pathophysiology of hepatitis C virus infection and related liver disease.
AB  - Hepatitis C virus (HCV) infects over 170 million people worldwide. Chronic
      infection occurs in 50-80% of cases and eventually leads to cirrhosis and
      hepatocellular carcinoma. The HCV lifecycle is only partly understood owing to
      the lack of a productive cell culture system. Several molecules have been
      implicated in the receptor complex at the surface of target cells, but the mode
      of HCV entry remains unknown. Persistent infection appears to be due to weak
      CD4+and CD8+ T-cell responses during acute infection, which fail to control viral
      replication. When chronic infection is established, HCV does not appear to be
      cytopathic. Liver lesions appear to result from locally driven immune responses,
      which are mainly non-specific. Local inflammation triggers fibrogenesis, in which
      hepatic stellate cells play a major role. Cirrhosis is facilitated by external
      factors, such as chronic alcohol consumption and viral co-infections. Patients
      with cirrhosis are at high risk of developing hepatocellular carcinoma. The role
      of HCV proteins in hepatocarcinogenesis is unknown. Further progress in our
      understanding of HCV infection and pathogenesis awaits the advent of new model
      systems and technologies.

PMID- 15036327
TI  - Linkage to two separate loci in a family with a novel distal myopathy phenotype
      (MPD3).
AB  - We recently described a new type of adult onset distal myopathy (MPD3) with
      autosomal dominant inheritance. The onset of symptoms is around the age of 30 and
      the characteristic first symptoms include clumsiness of the hands and stumbling.
      The thenar and hypothenar muscles are involved at the onset. The disease
      progressed to the intrinsic muscles of the hands, both anterior and posterior
      muscle compartments of the lower legs, the forearm muscles, and later to the
      proximal muscles. Dystrophic changes with rimmed vacuoles were observed in the
      muscle biopsy. We have performed a genome wide scan here in order to identify the
      MPD3 locus. Unexpectedly, markers on two distinct chromosomal regions 8p22-q11
      and 12q13-q22, provided significant evidence for linkage in this family.
      Multipoint linkage analyses produced equal maximum multipoint LOD score of 3.01
      for both chromosomal regions and haplotype analysis showed a specific haplotype
      segregating with the disease for both loci. It is thus impossible to distinguish
      between two loci without additional family material. Two obvious regional
      candidate genes, encoding muscular proteins became subjects for sequence
      analyses, the gene for myosin light chain 1 slow-twitch muscle A on 12q13 and the
      muscle specific exons of ankyrin 1 on 8p11. No mutations were identified in the
      coding sequence.

PMID- 15036328
TI  - Subclinical cardiac involvement in myotonic dystrophy manifesting as decreased
      myocardial Doppler velocities.
AB  - To assess subendocardial (long-axis) and mid-wall (short-axis) left ventricular
      (LV) function in patients with type 1 myotonic dystrophy (MD1), with no symptoms
      or clinical signs of heart disease, to investigate if they have subclinical
      cardiac involvement, 28 subjects (14 with MD1, and 14 age- and sex-matched
      normals) had conventional and tissue Doppler echocardiography. Myocardial
      velocities and timings to peak systolic contractions were measured. LV wall
      thickness, diameters, and ejection fraction were not different between the
      groups. 4/14 of the MD1 patients (29%) had global diastolic dysfunction. Both
      long-axis and short-axis systolic and early diastolic myocardial velocities were
      lower in patients with MD1, whereas time-to-peak myocardial contraction was
      longer; mean longitudinal systolic velocity was 5.5+/-1.7 cm/s in patients with
      MD1, compared with 7.8+/-1.3 cm/s in normal subjects (P<0.001) 10/14 of the
      patients (71%) had reduced longitudinal systolic function. Longitudinal systolic
      and diastolic velocities were inversely related to the duration of the QRS
      complex ( r=-0.86 and r=-0.63 respectively, both P<0.01), but they did not
      correlate with the CTG-repeat size. Patients with MD1 have subclinical cardiac
      impairment revealed by measurement of myocardial velocities using tissue Doppler
      echocardiography.

PMID- 15036329
TI  - Different tissue distribution of a mitochondrial DNA duplication and the
      corresponding deletion in a patient with a mild mitochondrial encephalomyopathy:
      deletion in muscle, duplication in blood.
AB  - Large-scale heteroplasmic mtDNA rearrangements were identified in a 57-year-old
      woman with chronic depressive disorder, hearing-loss, diabetes mellitus and a
      slowly progressive encephalomyopathy. A high percentage of a 24.2 kb duplicated
      molecule was found in lymphocytes whereas the corresponding deletion dimer
      dominated in muscle. PCR and Southern blot analyses were used to identify a 7658
      bp duplication/deletion fragment. The duplicated mtDNA disrupted the cytochrome
      oxidase subunit I and cytochrome b genes at a position where there were no direct
      repeats. Duplicated mtDNA was not observed in the mother and brother of the
      patient. Histochemical analysis of skeletal muscle demonstrated pathological
      accumulation of mitochondria in cytochrome c oxidase negative fibers. In situ
      hybridization demonstrated only deleted mtDNA in cytochrome c oxidase negative
      fibres. We conclude that occurrence of deleted mtDNA correlates with phenotypic
      expression and that the duplicated mtDNA might serve as a generator of deletions,
      but is not directly pathogenic.

PMID- 15036330
TI  - Novel truncating RAPSN mutations causing congenital myasthenic syndrome
      responsive to 3,4-diaminopyridine.
AB  - Rapsyn is essential for clustering the acetylcholine receptor at the postsynaptic
      membrane of the neuromuscular junction. Direct sequencing of RAPSN in two
      children with congenital myasthenic syndromes with no mutation in any of the AChR
      subunits identified two heterozygous recessive mutations in each: a previously
      characterized N88K mutation in both, and a second frameshifting mutation in
      Patient (Pt) 1 and a nonsense mutation in Pt 2. An intercostal muscle biopsy in
      Pt 1 revealed decreased AChRs per endplate and decreased amplitude of the
      miniature endplate potential, predicted consequences of rapsyn deficiency.
      Clinically, both children manifested with hypomotility in utero, fatigable ocular
      and limb weakness since birth, decreased strength during viral illness,
      decremental response on electromyography, and absence of AChR antibodies. Pt 1,
      however, had a more severe clinical course with recurrent episodes of respiratory
      failure, contractures, and craniofacial malformations. In both patients,
      treatment with pyridostigmine was of some benefit, but the addition of 3,4
      diaminopyridine led to significant clinical improvement. Thus, rapsyn deficiency
      predicting similar consequences at the cellular level can result in phenotypes
      with marked differences in severity of symptoms, risk of respiratory failure, and
      presence of contractures and craniofacial malformations.

PMID- 15036331
TI  - Tubular aggregates are from whole sarcoplasmic reticulum origin: alterations in
      calcium binding protein expression in mouse skeletal muscle during aging.
AB  - Tubular aggregates are observed in various muscle disorders and appear as densely
      packed tubules believed to arise from sarcoplasmic reticulum of striated muscle.
      They are found both in human skeletal muscle, especially from patients suffering
      from 'tubular aggregate myopathy' and in fast twitch skeletal muscle of the male
      inbred mouse during aging. In this work, we studied tubular aggregates present in
      inbred male mouse skeletal muscle using electron microscopy as well as
      histochemistry and Western blotting with the main markers of the sarcoplasmic
      reticulum. We show that mouse tubular aggregates include the proteins SERCA 1,
      sarcalumenin (longitudinal sarcoplasmic reticulum), calsequestrin (terminal
      cisternae) and RyR1 (junctional sarcoplasmic reticulum). We demonstrate also that
      95 and 51 kDa triadin isoforms are present in mouse skeletal muscle and are both
      components of tubular aggregates. These results support the hypothesis that
      tubular aggregates form a tubular arrangement of a complete sarcoplasmic
      reticulum containing the junctional, cisternae and longitudinal components of
      sarcoplasmic reticulum implicated in calcium homeostasis. During mouse skeletal
      muscle aging, however, densitometry of Western blots reveals a persistent
      decrease in the expression of the calcium binding protein calreticulin as well as
      a continuous increase in calsequestrin-like protein expression which both appear
      unrelated to the tubular aggregate formation.

PMID- 15036332
TI  - Molecular phenotyping of the mouse ky mutant reveals UCP1 upregulation at the
      neuromuscular junctions of dystrophic soleus muscle.
AB  - The ky mutant mouse displays a muscular dystrophy that affects almost exclusively
      slow type muscles in which persistent muscle regeneration, neuromuscular junction
      instability and an absence of the hypertrophic response are prominent features.
      In order to gain insights into the pathogenesis of this muscular dystrophy we
      have undertaken RNA profiling of the extensor digitorum longus, a fast unaffected
      muscle, and the highly pathological soleus slow muscle, followed by further
      expression studies to validate the results. In dystrophic soleus, there is a
      coordinated change in the expression level of genes encoding energy transducing
      mitochondrial proteins and an increase in the expression of stretch response
      genes. Upregulation of uncoupling proteins 1 and 2 is a unique molecular
      signature of the ky muscular dystrophy and was further characterised at the
      protein level. Our results show a spatial and temporal association between
      disorganisation of acetylcholine receptor clusters and upregulation of uncoupling
      protein 1. There is also evidence of a breakdown of neuromuscular junction muscle
      specific kinase-dependent signalling in adult mutant soleus. Sarcolemma
      associated proteins implicated in muscular dystrophies revealed no differences on
      microarrays and were confirmed as normally distributed by immunofluorescence.
      Altogether, the data presented suggest that the ky muscular dystrophy develops by
      a distinctive pathogenic mechanism.

PMID- 15036333
TI  - A novel mutation, Thr65Ala, in the MPZ gene in a patient with Charcot-Marie-Tooth
      type 1B disease with focally folded myelin.
AB  - Charcot-Marie-Tooth type 1B disease is a demyelinating neuropathy caused by
      mutations in the Myelin Protein Zero gene. It is inherited in an autosomal
      dominant fashion. So far only a few patients with a focally folded myelin
      phenotype on nerve biopsy have been shown to have mutations in the Myelin Protein
      Zero gene. In this report we describe a Polish patient with Charcot-Marie-Tooth
      type 1B disease. Sural nerve biopsy demonstrated focally folded myelin. Molecular
      genetic analysis of the coding region of the Myelin Protein Zero gene revealed a
      novel mutation, Thr65Ala, in exon 2 of the Myelin Protein Zero gene.

PMID- 15036334
TI  - A computational model of spatio-temporal dynamics in depth filling-in.
AB  - We present a computational model based on the heat conduction equation, which can
      well explain human performance of depth interpolation. The model assumes that the
      depth information is locally represented and spatial integration is made by
      iterative processing of mutual interaction of neighbors. It reconstructs a
      dynamically transforming surface which is in good agreement with the results of
      psychophysical experiments on depth perception of untextured (uniform-colored)
      surface moving in depth. The model can also explain a temporal-frequency property
      of human percept. We conclude that the local ambiguity, which is quite common in
      everyday visual scenes, is solved by an interpolation mechanism based on
      iterative local interaction of locally represented visual information.

PMID- 15036335
TI  - Predicting spike timings of current-injected neurons.
AB  - Typical neurospiking models were examined on the ability to reproduce and predict
      the spike sequences of a biological neuron for a variety of fluctuating currents,
      using a fixed set of parameter values. The predicting accuracy was found to be
      particularly good for the Hodgkin-Huxley models augmented with the Ca(2+)
      dependent potassium current generating slow afterhyper-polarization and/or the
      muscarine-sensitive potassium current. In the successful parameter determination
      method, the effective membrane time constant is estimated very short, typically
      about 5 ms. The biological neurons we examined were distinctly classified into
      two types according to the estimated percent contents of those ionic channels.

PMID- 15036336
TI  - Configural representations in transverse patterning with a hippocampal model.
AB  - The hippocampus is necessary in both humans and rats for learning configural
      representations in tasks such as transverse patterning. The transverse patterning
      task, (A+B-, B+C-, C+A-), requires representing individual stimuli in the context
      of other stimuli. This paper extends a previous application to rat data [INNS
      World Congress on Neural Networks, 1995; Biol Cybern 6 (1998a) 203] by applying a
      model of the CA3 region of the hippocampus to human data. A decision function is
      also added that enables the system to choose among training items. Analysis of
      the simulations show that configural representations are formed by unique neural
      codes that depend on temporal and stimuli context. Based on the simulations, we
      hypothesize that configural representations in biological networks depend on a
      proper balance of input and context representations. Furthermore, the division of
      labor between functions in the model is a specific working hypothesis that in
      learning this task the hippocampus specializes in sequence prediction and the
      decision function evaluates the predictions.

PMID- 15036338
TI  - Information processing in a neuron ensemble with the multiplicative correlation
      structure.
AB  - The present study investigates the performance of population codes when the
      fluctuations in neural activity have mutual correlation with strength being
      proportional to the neuronal firing rate (multiplicative noise). The neural field
      is used to calculate the Fisher information, which is decomposed in two parts,
      one due to the tuning function and spatial correlation, and the other due to the
      multiplicative structure. Their different characteristics are studied. The paper
      also investigates three types of maximum likelihood method, namely, decoding by
      using faithful and unfaithful models and the Center of Mass strategy, and
      compares their performances in terms of decoding accuracy and computational
      complexity.

PMID- 15036337
TI  - Clustering behavior in a three-layer system mimicking olivo-cerebellar dynamics.
AB  - A model is presented that simulates the process of neuronal synchronization,
      formation of coherent activity clusters and their dynamic reorganization in the
      olivo-cerebellar system. Three coupled 2D lattices dealing with the main cellular
      groups in this neuronal circuit are used to model the dynamics of the excitatory
      feedforward loop linking the inferior olive (IO) neurons to the cerebellar nuclei
      (CN) via collateral axons that also proceed to terminate as climbing fiber
      afferents to Purkinje cells (PC). Inhibitory feedback from the CN-lattice fosters
      decoupling of units in a vicinity of a given IO neuron. It is shown that noise
      sustained oscillations in the IO-lattice are capable to synchronize and generate
      coherent firing clusters in the layer accounting for the excitable collateral
      axons. The model also provides phase resetting of the oscillations in the IO
      lattices with transient silent behavior. It is also shown that the CN-IO feedback
      leads to transient patterns of couplings in the IO and to a dynamic control of
      the size of clusters.

PMID- 15036340
TI  - Bifurcating neuron: computation and learning.
AB  - The ability of bifurcating processing units and their networks to rapidly switch
      between different dynamic modes has been used in recent research efforts to model
      new computational properties of neural systems. In this spirit, we devise a
      bifurcating neuron based on control of chaos collapsing to a period-3 orbit in
      the dynamics of a quadratic logistic map (QLM). Proposed QLM3 neuron is
      constructed with the third iterate of QLM and uses an external input, which
      governs its dynamics. The input shifts the neuron's dynamics from chaos to one of
      the stable fixed points. This way the inputs from certain ranges (clusters) are
      mapped to stable fixed points, while the rest of the inputs is mapped to chaotic
      or periodic output dynamics. It has been shown that QLM3 neuron is able to learn
      a specific mapping by adaptively adjusting its bifurcation parameter, the idea of
      which is based on the principles of parametric control of logistic maps
      [Proceedings of the International Symposium on Nonlinear Theory and its
      Applications (NOLTA'97), Honolulu, HI, 1997; Proceedings of SPIE, 2000]. Learning
      algorithm for the bifurcation parameter is proposed, which employs the error
      gradient descent method.

PMID- 15036339
TI  - On-line learning through simple perceptron learning with a margin.
AB  - We analyze a learning method that uses a margin kappa a la Gardner for simple
      perceptron learning. This method corresponds to the perceptron learning when
      kappa = 0 and to the Hebbian learning when kappa = infinity. Nevertheless, we
      found that the generalization ability of the method was superior to that of the
      perceptron and the Hebbian methods at an early stage of learning. We analyzed the
      asymptotic property of the learning curve of this method through computer
      simulation and found that it was the same as for perceptron learning. We also
      investigated an adaptive margin control method.

PMID- 15036341
TI  - Generalized neural networks for spectral analysis: dynamics and Liapunov
      functions.
AB  - This paper analyzes local and global behavior of several dynamical systems which
      generalize some artificial neural network (ANN) semilinear models originally
      designed for principal component analysis (PCA) in the characterization of random
      vectors. These systems implicitly performed the spectral analysis of correlation
      (i.e. symmetric positive definite) matrices. Here, the proposed generalizations
      cover both nonsymmetric matrices as well as fully nonlinear models. Local
      stability analysis is performed via linearization and global behavior is analyzed
      by constructing several Liapunov functions.

PMID- 15036342
TI  - Regularising neural networks using flexible multivariate activation function.
AB  - This paper presents a new general neural structure based on nonlinear flexible
      multivariate function that can be viewed in the framework of the generalised
      regularisation networks theory. The proposed architecture is based on multi
      dimensional adaptive cubic spline basis activation function that collects
      information from the previous network layer in aggregate form. In other words,
      each activation function represents a spline function of a subset of previous
      layer outputs so the number of network connections (structural complexity) can be
      very low with respect to the problem complexity. A specific learning algorithm,
      based on the adaptation of local parameters of the activation function, is
      derived. This fact improve the network generalisation capabilities and speed up
      the convergence of the learning process. At last, some experimental results
      demonstrating the effectiveness of the proposed architecture, are presented.

PMID- 15036343
TI  - A principal components analysis self-organizing map.
AB  - We propose a new self-organizing neural model that performs principal components
      analysis. It is also related to the adaptive subspace self-organizing map (ASSOM)
      network, but its training equations are simpler. Experimental results are
      reported, which show that the new model has better performance than the ASSOM
      network.

PMID- 15036344
TI  - Neural networks for nonlinear and mixed complementarity problems and their
      applications.
AB  - This paper presents two feedback neural networks for solving a nonlinear and
      mixed complementarity problem. The first feedback neural network is designed to
      solve the strictly monotone problem. This one has no parameter and possesses a
      very simple structure for implementation in hardware. Based on a new idea, the
      second feedback neural network for solving the monotone problem is constructed by
      using the first one as a subnetwork. This feedback neural network has the least
      number of state variables. The stability of a solution of the problem is proved.
      When the problem is strictly monotone, the unique solution is uniformly and
      asymptotically stable in the large. When the problem has many solutions, it is
      guaranteed that, for any initial point, the trajectory of the network does
      converge to an exact solution of the problem. Feasibility and efficiency of the
      proposed neural networks are supported by simulation experiments. Moreover, the
      feedback neural network can also be applied to solve general nonlinear convex
      programming and nonlinear monotone variational inequalities problems with convex
      constraints.

PMID- 15036345
TI  - A canonical correlation neural network for multicollinearity and functional data.
AB  - We review a recent neural implementation of Canonical Correlation Analysis and
      show, using ideas suggested by Ridge Regression, how to make the algorithm
      robust. The network is shown to operate on data sets which exhibit
      multicollinearity. We develop a second model which not only performs as well on
      multicollinear data but also on general data sets. This model allows us to vary a
      single parameter so that the network is capable of performing Partial Least
      Squares regression (at one extreme) to Canonical Correlation Analysis (at the
      other)and every intermediate operation between the two. On multicollinear data,
      the parameter setting is shown to be important but on more general data no
      particular parameter setting is required. Finally, we develop a second penalty
      term which acts on such data as a smoother in that the resulting weight vectors
      are much smoother and more interpretable than the weights without the
      robustification term. We illustrate our algorithms on both artificial and real
      data.

PMID- 15036346
TI  - Nitric oxide and superoxide impair human placental amino acid uptake and increase
      Na+ permeability: implications for fetal growth.
AB  - Based on evidence that thiol and tyrosine reagents inhibit some amino acid
      transporters, we tested the hypothesis that NO- and O2- -derived free radicals
      would impair nutrient uptake by the human placenta. Syncytiotrophoblast
      microvillous plasma membrane vesicles (MVM) and placental villous fragments were
      exposed to the drug SIN-1 in the presence or absence of superoxide dismutase
      (SOD) and hemoglobin (Hb). The uptake of [3H]arginine, [3H]taurine, and
      [3H]leucine; [14C]MeAIB; and 22Na was studied in MVM, whereas the uptake of
      [3H]taurine was examined in villous fragments. Nitrotyrosine formation was
      assessed by Western blotting and quantified by ELISA. In MVM, SIN-1 caused an
      inhibition of [3H]arginine, [3H]taurine, and [14C]MeAIB uptake but had no
      significant effect on equilibrium [3H]leucine uptake. These effects were
      prevented by SOD or Hb, implying that both NO and O2- radicals were essential. In
      contrast, 22Na+ uptake was significantly increased, and this effect was prevented
      by SOD. In villous fragments, SIN-1 impaired Na+-dependent [3H]taurine uptake,
      with no effect on Na+-independent uptake. Increased nitrotyrosine formation was
      observed in MVM after SIN-1 treatment. Endogenous NO- and O2- -derived free
      radicals may alter human placental nutrient transfer in vivo, with implications
      for fetal growth.

PMID- 15036347
TI  - Coelenterazine: a two-stage antioxidant in lipid micelles.
AB  - Coelenterazine is a luciferin found in many marine bioluminescent organisms. This
      luciferin also possesses high antioxidant properties and an exceptional ability
      to protect cells exposed to oxidative stress. It has been suggested that
      coelenterazine's antioxidative mechanisms include the formation of an oxidation
      product, coelenteramine, also endowed with chain-breaking properties. In this
      work, coelenterazine analogs were shown to delay the onset of lipid peroxidation
      in a linoleate micellar solution exposed to free radical initiators. Their
      consumption was accompanied by the concomitant formation of coelenteramine. This
      was followed by a reduction in the peroxidation rate coinciding with the
      consumption of coelenterazine's oxidation product coelenteramine. The addition of
      coelenteramine to micelles reduced the propagation rate of the oxidative process.
      When coelenterazine analogs oxidizing into an inactive analog of coelenteramine
      were applied, the delaying effect but not the reduced peroxidation rate nor the
      consumption of the aminopyrazine was observed. These results demonstrate the role
      of the oxidation product coelenteramine in the chain-breaking properties of
      coelenterazine and analogs.

PMID- 15036348
TI  - Ergothioneine rescues PC12 cells from beta-amyloid-induced apoptotic death.
AB  - Beta-amyloid (Abeta) peptide is the major component of senile plaques and
      considered to have a causal role in the development and progression of
      Alzheimer's disease. There has been compelling evidence that Abeta-induced
      cytotoxicity is mediated through oxidative and/or nitrosative stress. Recently,
      considerable attention has been focused on dietary manipulation of oxidative
      and/or nitrosative damage. l-Ergothioneine (EGT; 2-mercaptohistidine
      trimethylbetaine) is a low-molecular-weight naturally occurring thiol compound of
      dietary origin that exists in the brain, liver, kidney, erythrocytes, ocular
      tissues, and seminal fluids of mammals. This water-soluble antioxidant has the
      ability to scavenge hydroxyl and peroxynitrite radicals as well as activated
      oxygen species, such as singlet oxygen. In this study, we investigated the
      effects of EGT on Abeta-induced oxidative and/or nitrosative cell death. Rat
      pheochromocytoma (PC12) cells treated with Abeta underwent apoptotic death as
      determined by positive in situ terminal end-labeling (TUNEL staining), decreased
      mitochondrial transmembrane potential, increased ratio of proapoptotic Bax to
      antiapoptotic Bcl-XL, elevated caspase-3 activity, and cleavage of poly(ADP
      ribose) polymerase. EGT pretreatment attenuated Abeta-induced apoptosis in PC12
      cells. Compared to N-acetyl-l-cysteine, which mainly scavenges reactive oxygen
      species, EGT effectively inhibited Abeta-induced cell death by suppressing
      peroxynitrite formation and subsequent nitration of protein tyrosine residues.
      The effects of EGT on the cytotoxicity induced by the nitric oxide donor sodium
      nitroprusside (SNP) and the peroxynitrite-generating 3-morpholinosydnonimine
      chlorhydrate (SIN-1) were compared. Whereas EGT significantly protected against
      SIN-1-mediated cell death, it barely affected the cytotoxicity induced by SNP.
      Thus EGT may attenuate apoptosis caused by Abeta, preferentially by eliminating
      peroxynitrite derived from the neurotoxic peptide. The importance of diet-derived
      antioxidants in the management of Alzheimer's disease and other neurodegenerative
      disorders is discussed.

PMID- 15036349
TI  - Urinary excretion of 8-hydroxydeoxyguanosine and malondialdehyde after high dose
      radiochemotherapy preceding stem cell transplantation.
AB  - The urinary excretion of the hydroxylated DNA base 8-hydroxydeoxyguanosine (8
      OHdG) and the lipid peroxidation product malondialdehyde (MDA) was monitored in
      11 patients with hematological malignancies undergoing total body irradiation and
      high-dose chemotherapy preceding bone marrow transplantation. Nine patients
      showed a prompt increase in urinary 8-OHdG (8-25 times the initial baseline
      level) on days 0-7 after irradiation onset; the excretion then decreased during
      the aplastic period and increased again when engraftment took place (in 7
      patients). A significant positive correlation was found between urinary 8-OHdG
      and whole blood leukocyte count, both on day 5 (p =.04, r =.72) and on day 22 (p
      =.009, r =.80) after irradiation onset. One patient who lacked the first peak of
      8-OHdG excretion showed low blood leukocyte counts (less than 2 x 10(9)/l) before
      therapy onset; this patient, however, later had a successful engraftment and then
      also showed considerable increases in both 8-OHdG excretion and leukocyte count.
      These observations suggest leukocytes play a part in the excretion of 8-OHdG
      after conditioning therapy preceding bone marrow transplantation. As opposed to
      the biphasic 8-OHdG excretion, the excretion of MDA showed a single peak
      appearing on days 11-19 after radiochemotherapy onset, i.e., during the period in
      which the patients suffered from cytopenia, mucositis, and other side effects of
      the treatment. It is suggested, therefore, that these clinical manifestations are
      associated with increased lipid peroxidation. Altogether, these findings
      illustrate the utility of serial urinary samples for monitoring oxidative stress
      due to conditioning therapy in clinical practice. They also demonstrate that
      different oxidative stress markers may behave quite differently regarding their
      appearance in the urine after whole-body oxidative stress.

PMID- 15036350
TI  - Heme oxygenase-1 protects HepG2 cells against cytochrome P450 2E1-dependent
      toxicity.
AB  - The inducible form of heme oxygenase (HO-1) is increased during oxidative injury
      and HO-1 is believed to be an important defense mechanism against such injury.
      Arachidonic acid (AA) and l-buthionine-(S,R)-sulfoximine (BSO), which lowers GSH
      levels, cause cytochrome P450 2E1 (CYP2E1)-dependent oxidative injuries in HepG2
      cells (E47 cells). Treatment of E47 cells with 50 microM AA or 100 microM BSO for
      48 h was recently shown to increase HO-1 mRNA, protein, and activity. The
      possible functional significance of this increase in protecting against CYP2E1
      dependent toxicity was evaluated in the current study. The treatment with AA and
      BSO caused loss of cell viability (40 and 50%, respectively) in E47 cells.
      Chromium mesoporphyrin (CrMP), an inhibitor of HO activity, significantly
      potentiated this cytotoxicity. ROS production, lipid peroxidation, and the
      decline in mitochondrial membrane potential produced by AA and BSO were also
      enhanced in the presence of CrMP in E47 cells. Infection with an adenovirus
      expressing rat HO-1 protected E47 cells from AA toxicity, increasing cell
      viability and reducing LDH release. HO catalyzes formation of CO, bilirubin, and
      iron from the oxidation of heme. Bilirubin was not protective whereas iron
      catalyzed the AA toxicity. The carbon monoxide (CO) scavenger hemoglobin enhanced
      AA toxicity in E47 cells analogous to CrMP, whereas exposure to exogenous CO
      partially reduced AA toxicity and the enhanced AA toxicity by CrMP. Addition of
      exogenous CO to the cells inhibited CYP2E1 catalytic activity, as did
      overexpression of the rat HO-1 adenovirus. These results suggest that induction
      of HO-1 protects against CYP2E1-dependent toxicity and this protection may be
      mediated in part via production of CO and CO inhibition of CYP2E1 activity.

PMID- 15036352
TI  - Effects of nerve graft on nitric oxide synthase, NAD(P)H oxidase, and antioxidant
      enzymes in chronic spinal cord injury.
AB  - Oxidative stress and nitrosative stress play important roles in the pathogenesis
      of secondary spinal cord injury. Recently, we demonstrated that peripheral nerve
      grafts (PNG) with acidic fibroblast growth factor (aFGF) partially restore hind
      limb locomotion in adult rats with completely transected spinal cords. This study
      investigated the protein abundances of the superoxide (O2*)-generating enzyme
      nicotinamide adenine dinucleotide (phosphate) oxidase (NAD(P)H oxidase; gp91phox
      subunit), nitric oxide synthases (NOS), antioxidant enzymes, superoxide
      dismutases (Cu Zn SOD, Mn SOD), catalase, and glutathione peroxidase (GPX) as
      well as nitrotyrosine in the spinal cord tissue 4 months after spinal cord
      transection in rats with and without PNG and aFGF. The protein abundances of the
      gp91phox subunit of NAD(P)H oxidase, Mn SOD, catalase, GPX, eNOS, and
      nitrotyrosine were significantly upregulated, whereas Cu Zn SOD and nNOS were
      unchanged in the injury group compared to the sham controls. The nerve graft with
      aFGF treated group showed significantly better hind limb locomotion recovery than
      the injury group. Although the protein abundances of gp91phox, nitrotyrosine, and
      Cu Zn SOD were similar in the treated group (nerve graft with aFGF) compared to
      the injury group, Mn SOD, GPX, catalase, and eNOS protein abundances were
      significantly higher, whereas nNOS was markedly lower in the treated group. We
      conclude that the combination of nerve graft and aFGF enhances the local
      antioxidant defense system after spinal cord transection in rats.

PMID- 15036351
TI  - Downregulation of nitric oxide formation by cytosolic phospholipase A2-released
      arachidonic acid.
AB  - Exposure of PC12 cells to A23187 or thapsigargin caused a concentration-dependent
      release of arachidonic acid (AA) mediated by cytosolic phospholipase A2 (PLA2).
      Under the same conditions, however, analysis of nitric oxide (NO) formation
      revealed that activation of NO synthase (NOS) is best described by a bell-shaped
      curve. Reduced detection of NO observed at increasing A23187 or thapsigargin
      concentrations was not due to formation of peroxynitrite or to activation of NO
      consuming processes, but rather to AA-dependent inhibition of NOS activity.
      Furthermore, NO formation observed under optimal conditions for NOS activity was
      suppressed by AA as well as by the PLA2 activator melittin. Finally, the effects
      of AA were not the consequence of direct enzyme inhibition, because this lipid
      messenger failed to inhibit formation of NO by purified neuronal NOS, but were
      mediated by an AA-dependent signaling and not by downstream products of the
      cyclooxygenase and lipoxygenase pathways. In conclusion, the present study
      underscores a novel mechanism whereby endogenous, or exogenous, AA promotes
      inhibition of NOS activity. Because AA is generated in response to various
      agonists acting on membrane receptors and extensively released in inflammatory
      conditions, these findings have important physiopathological implications.

PMID- 15036353
TI  - Cupric-amyloid beta peptide complex stimulates oxidation of ascorbate and
      generation of hydroxyl radical.
AB  - A growing body of evidence supports an important role for oxidative stress in the
      pathogenesis of Alzheimer's disease. Recently, a number of papers have shown a
      synergistic neurotoxicity of amyloid beta peptide and cupric ions. We
      hypothesized that complexes of cupric ions with neurotoxic amyloid beta peptides
      (Abeta) can stimulate copper-mediated free radical formation. We found that
      neurotoxic Abeta (1-42), Abeta (1-40), and Abeta (25-35) stimulated copper
      mediated oxidation of ascorbate, whereas nontoxic Abeta (40-1) did not. Formation
      of ascorbate free radical was significantly increased by Abeta (1-42) in the
      presence of ceruloplasmin. Once cupric ion is reduced to cuprous ion, it can be
      oxidized by oxygen to generate superoxide radical or it can react with hydrogen
      peroxide to form hydroxyl radical. Hydrogen peroxide greatly increased the
      oxidation of cyclic hydroxylamines and ascorbate by cupric-amyloid beta peptide
      complexes, implying redox cycling of copper ions. Using the spin-trapping
      technique, we have shown that toxic amyloid beta peptides led to a 4-fold
      increase in copper-mediated hydroxyl radical formation. We conclude that toxic
      Abeta peptides do indeed stimulate copper-mediated oxidation of ascorbate and
      generation of hydroxyl radicals. Therefore, cupric-amyloid beta peptide
      stimulated free radical generation may be involved in the pathogenesis of
      Alzheimer's disease.

PMID- 15036354
TI  - Effect of cold-induced hyperthyroidism on H2O2 production and susceptibility to
      stress conditions of rat liver mitochondria.
AB  - Previous studies have shown that T3 treatment and cold exposure induce similar
      biochemical changes predisposing rat liver to oxidative stress. This suggests
      that the liver oxidative damage observed in experimental and functional
      hyperthyroidism is mediated by thyroid hormone. To support this hypothesis we
      investigated whether middle-term cold exposure (2 and 10 days), like T3
      treatment, also increases H2O2 release by liver mitochondria. We found that the
      rate of H2O2 release increased only during State 4 respiration, but faster flow
      of reactive oxygen species (ROS) from mitochondria to the cytosolic compartment
      was ensured by the concomitant increase in tissue mitochondrial proteins. Cold
      exposure also increased the capacity of mitochondria to remove H2O2. This
      indicates that cold causes accelerated H2O2 production, which might depend on
      enhanced autoxidizable carrier content and should lead to increased mitochondrial
      damage. Accordingly, mitochondrial levels of hydroperoxides and protein-bound
      carbonyls were higher after cold exposure. Levels of low-molecular weight
      antioxidants were not related to the extent of oxidative damage, but
      susceptibility to both in vitro oxidative challenge and Ca2+-induced swelling
      increased in mitochondria from cold exposed rats. The cold-induced changes in
      several parameters, including susceptibility to swelling, were time dependent,
      because they were apparent or greater after 10 days cold exposure. The cold
      induced increase in swelling may be a feedback mechanism to limit tissue
      oxidative stress, purifying the mitochondrial population from ROS-overproducing
      mitochondria, and the time course for such change is consistent with the gradual
      development of cold adaptation.

PMID- 15036356
TI  - Protective mechanisms during ischemic tolerance in skeletal muscle.
AB  - The purpose of this study was to test specific mechanisms of protection afforded
      the rat extensor digitorum longus (EDL) muscle during ischemic tolerance. Two
      days following five cycles of 10 min ischemia and 10 min reperfusion, heme
      oxygenase (HO) and calcium-dependent nitric oxide synthase (cNOS) activities were
      increased 2- and 2.5-fold (p <.05), respectively. Interestingly, calcium
      independent NOS (iNOS) activity was completely downregulated (p <.05). The levels
      of superoxide dismutase (SOD) and catalase were increased 2-fold (p <.05), while
      glutathione peroxidase activity remained unchanged from non-preconditioned
      controls. Using intravital microscopy combined with chromium mesoporphyrin
      (CrMP), a selective HO inhibitor, and l-NAME, a NOS inhibitor, the roles of HO
      and cNOS were evaluated. Ischemic tolerance in the EDL muscle, 48 h after the
      preconditioning stimulus, was characterized by complete protection from both
      microvascular perfusion deficits and tissue injury after a 2-h period of
      ischemia. Removal of NOS activity completely removed the benefit afforded
      microvascular perfusion, while inhibition of HO activity prevented the
      parenchymal protection. These data suggest that ischemic tolerance within
      skeletal muscle is associated with the upregulation of specific cytoprotective
      proteins and that the benefits afforded by cNOS and HO activity are spatially
      discrete to the microvasculature and parenchyma, respectively.

PMID- 15036355
TI  - Green tea polyphenol epigallocatechin-3-gallate protects HepG2 cells against
      CYP2E1-dependent toxicity.
AB  - Chronic ethanol consumption causes oxidative damage in the liver, and induction
      of cytochrome P450 2E1 (CYP2E1) is one pathway involved in oxidative stress
      produced by ethanol. The hepatic accumulation of iron and polyunsaturated fatty
      acids significantly contributes to ethanol hepatotoxicity in the intragastric
      infusion model of ethanol treatment. The objective of this study was to analyze
      the effect of the green tea flavanol epigallocatechin-3-gallate (EGCG), which has
      been shown to prevent alcohol-induced liver damage, on CYP2E1-mediated toxicity
      in HepG2 cells overexpressing CYP2E1 (E47 cells). Treatment of E47 cells with
      arachidonic acid plus iron (AA + Fe) was previously reported to produce
      synergistic toxicity in E47 cells by a mechanism dependent on CYP2E1 activity and
      involving oxidative stress and lipid peroxidation. EGCG protected E47 cells
      against toxicity and loss of viability induced by AA+Fe; EGCG had no effect on
      CYP2E1 activity. Prevention of this toxicity was associated with a reduction in
      oxidative damage as reflected by decreased generation of reactive oxygen species,
      a decrease in lipid peroxidation, and maintenance of intracellular glutathione in
      cells challenged by AA+Fe in the presence of EGCG. AA+Fe treatment caused a
      decline in the mitochondrial membrane potential, which was also blocked by EGCG.
      In conclusion, EGCG exerts a protective action on CYP2E1-dependent oxidative
      stress and toxicity that may contribute to preventing alcohol-induced liver
      injury, and may be useful in preventing toxicity by various hepatotoxins
      activated by CYP2E1 to reactive intermediates.

PMID- 15036357
TI  - The pro-oxidant activity of aluminum.
AB  - Aluminum, a non-redox-active metal is, nevertheless, a pro-oxidant both in in
      vitro preparations and in vivo. It facilitates both superoxide- and iron-driven
      biological oxidation by mechanisms that remain to be resolved. More than 10 years
      ago Fridovich and colleagues suggested that the facilitation of superoxide-driven
      biological oxidation by aluminum was due to an interaction between the metal and
      the superoxide radical anion (Free Radic. Biol. Med. 13: 79-81; 1992). This
      thesis has been examined herein and it is concluded that much, if not all, of the
      pro-oxidant activity of aluminum might be explained by the formation of an
      aluminum superoxide semireduced radical ion.

PMID- 15036358
TI  - Neuronal nitric oxide synthase immunoreactivity in ependymal cells during early
      postnatal development.
AB  - Neuronal nitric oxide synthase (nNOS) immunoreactivity was observed in ependymal
      cell layer of the central canal of spinal cord of neonatal rats (2-20 days old).
      Neuronal nitric oxide synthase immunoreactivity was present in postnatal day 2
      and this immunoreactivity gradually disappeared by postnatal day 16. The
      progressive decrease in nNOS staining with the increasing postnatal age may
      suggest that nNOS staining paralleled the maturation of the central canal and may
      also suggest that nNOS activity plays a role in the development of the ependymal
      cells.

PMID- 15036359
TI  - Reelin immunoreactivity in the adult sea lamprey brain.
AB  - The expression of reelin, a large extracellular matrix glycoprotein, was studied
      in the brain of pre-spawning adult sea lampreys by immunohistochemistry using two
      monoclonal antibodies against this protein. Reelin immunoreactive (reln-ir)
      neurons were observed in the olfactory bulb, and pallial and subpallial regions
      in the telencephalon. In the diencephalon, reln-ir cells were observed in some
      hypothalamic nuclei, in the nucleus of Bellonci, and in the habenula. In the
      mesencephalon, this protein was detected in several nuclei related with the
      centrifugal visual system, although the optic tectum was devoid of
      immunoreactivity. The hindbrain showed several nuclei with immunopositive
      neurons, including the branchiomeric nerve motor nuclei and also some groups of
      non-giant cells of the reticular formation. The rostral spinal cord showed some
      immunopositive neurons mainly located in lateral and ventral positions. Overall,
      the pattern of distribution of reelin in the adult sea lamprey correlates with
      the previously reported in other adult vertebrates. Furthermore, the wide
      distribution of reelin in the adult lamprey brain is consistent with a possible
      existence of different roles for this protein not related with development in the
      central nervous system (CNS) of vertebrates (i.e. neuronal plasticity and/or
      maintenance).

PMID- 15036360
TI  - Nitroglycerin enhances cGMP expression in specific neuronal and cerebrovascular
      structures of the rat brain.
AB  - Although the involvement of nitric oxide (NO) in mediating pain and neurovascular
      coupling is well established, the precise mechanisms sustaining these effects are
      still unclear. Cyclic GMP (cGMP) probably represents the main effector of the
      biological effects of NO at the vascular and neuronal levels. Nitroglycerin is a
      NO donor, which easily crosses the blood brain barrier. Several reports have
      suggested that the study of nitroglycerin effects upon neuronal and
      cerebrovascular elements is a useful animal model for investigating the
      pathophysiological mechanisms underlying migraine. In this study, the anatomic
      distribution of cGMP in the rat brain was evaluated at serial time-points after
      systemic administration of nitroglycerin or vehicle. The results show an increase
      in cGMP immunoreactivity in the nucleus trigeminalis caudalis and in the
      superficial cortical arterioles 2, 3 and 4h after the drug administration. The
      data obtained sustains the idea that cGMP is an important mediator of
      nitroglycerin effect in vascular and neuronal structures that are critical
      elements for the transmission of cephalic pain.

PMID- 15036361
TI  - Co-expression pattern of neuronal nitric oxide synthase and two variants of
      choline acetyltransferase in myenteric neurons of porcine ileum.
AB  - Cholinergic enteric neurons were demonstrated immunohistochemically so far by
      using antibodies staining the common choline acetyltransferase (cChAT) in neurons
      of the central nervous system. The results of staining in the enteric nervous
      system of various species were, however, not satisfactory. We describe here
      findings obtained with a newly raised antibody against a peripheral variant of
      choline acetyltransferase (pChAT) in myenteric neurons of the pig small
      intestine. Triple labelling for pChAT/cChAT/neuronal nitric oxide synthase (nNOS)
      revealed 19.7% of 1664 neurons (within 40 ganglia) to be immunoreactive
      exclusively for pChAT whereas 29.6% were positive for cChAT alone and 18.8% were
      reactive only for nNOS. Colocalization of pChAT and cChAT was found in 22.4%, of
      pChAT and nNOS in 8.1% and of cChAT and nNOS in 1.4%. All three markers were
      simultaneously found in only 1 of 1664 neurons. To investigate the presence and
      possible colocalization of the above markers within morphologically defined
      neuron types, triple labelling of cChAT or nNOS with pChAT and a neurofilament
      (NF) antibody pool was applied and the coexpression patterns of pChAT and cChAT
      as well as of pChAT and nNOS in 120 neurons of each type were recorded. All type
      I, II, IV and V neurons displayed immunoreactivity either for one or both
      cholinergic markers. These neuron types were considered to be cholinergic. All
      type VI neurons, a descending neuron population, were negative for cChAT but
      positive for nNOS. However, 95% were immunoreactive for both pChAT and nNOS. The
      physiological significance of the possible co-existence of acetylcholine and
      nitric oxide within type VI neurons remains to be clarified. It is concluded that
      the pChAT and cChAT antibodies used here recognize partly different populations
      of enteric neurons in the pig. Thus, for total immunohistochemical
      characterization of cholinergic enteric neurons both forms of choline
      acetyltransferase have to be considered.

PMID- 15036362
TI  - Premotor nitric oxide synthase immunoreactive pathway connecting lumbar segments
      with the ventral motor nucleus of the cervical enlargement in the dog.
AB  - In this study we investigate the occurrence and origin of punctate nitric oxide
      synthase immunoreactivity in the neuropil of the ventral motor nucleus in C7-Th1
      segments of the dog spine, which are supposed to be the terminal field of an
      ascending premotor propriospinal nitric oxide synthase-immunoreactive pathway. As
      the first step, nitric oxide synthase immunohistochemistry was used to
      distinguish nitric oxide synthase-immunoreactive staining of the ventral motor
      nucleus. Dense, punctate nitric oxide synthase immunoreactivity was found on
      control sections in the neuropil of the ventral motor nucleus. After hemisection
      at Th10-11, axotomy-induced retrograde changes consisting in a strong
      upregulation of nitric oxide synthase-containing neurons were found mostly
      unilaterally in lamina VIII, the medial part of lamina VII and in the pericentral
      region in all segments of the lumbosacral enlargement. Concurrently, a strong
      depletion of the punctate nitric oxide synthase immunopositivity in the neuropil
      of the ventral motor nucleus ipsilaterally with the hemisection was detected,
      thus revealing that an uncrossed ascending premotor propriospinal pathway
      containing a fairly high number of nitric oxide synthase-immunoreactive fibers
      terminates in the ventral motor nucleus. Application of the retrograde
      fluorescent tracer Fluorogold injected into the ventral motor nucleus and
      analysis of alternate sections processed for nitric oxide synthase
      immunocytochemistry revealed the presence of Fluorogold-labeled and nitric oxide
      synthase-immunoreactive axons in the ventrolateral funiculus and in the lateral
      and medial portions of the ventral column throughout the thoracic and upper
      lumbar segments. A noticeable number of Fluorogold-labeled and nitric oxide
      synthase-immunoreactive somata detected on consecutive sections were found in the
      lumbosacral enlargement, mainly in laminae VIII-IX, the medial part of lamina VII
      and in the pericentral region (lamina X), ipsilaterally with the injection of
      Fluorogold into the ventral motor nucleus. In summary, the present study provides
      evidence for a hitherto unknown ascending premotor propriospinal nitric oxide
      synthase-immunoreactive pathway connecting the lumbosacral enlargement with the
      motoneurons of the ventral motor nucleus in the dog.

PMID- 15036363
TI  - Neuropeptide Y in the olfactory system, forebrain and pituitary of the teleost,
      Clarias batrachus.
AB  - Distribution of neuropeptide Y (NPY)-like immunoreactivity in the forebrain of
      catfish Clarias batrachus was examined with immunocytochemistry. Conspicuous
      immunoreactivity was seen in the olfactory receptor neurons (ORNs), their
      projections in the olfactory nerve, fascicles of the olfactory nerve layer in the
      periphery of bulb and in the medial olfactory tracts as they extend to the
      telencephalic lobes. Ablation of the olfactory organ resulted in loss of
      immunoreactivity in the olfactory nerve layer of the bulb and also in the
      fascicles of the medial olfactory tracts. This evidence suggests that NPY may
      serve as a neurotransmitter in the ORNs and convey chemosensory information to
      the olfactory bulb, and also to the telencephalon over the extrabulbar
      projections. In addition, network of beaded immunoreactive fibers was noticed
      throughout the olfactory bulb, which did not respond to ablation experiment.
      These fibers may represent centrifugal innervation of the bulb. Strong
      immunoreactivity was encountered in some ganglion cells of nervus terminalis.
      Immunoreactive fibers and terminal fields were widely distributed in the
      telencephalon. Several neurons of nucleus entopeduncularis were moderately
      immunoreactive; and a small population of neurons in nucleus preopticus
      periventricularis was also labeled. Immunoreactive terminal fields were
      particularly conspicuous in the preoptic, the tuberal areas, and the
      periventricular zone around the third ventricle and inferior lobes. NPY
      immunoreactive cells and fibers were detected in all the lobes of the pituitary
      gland. Present results describing the localization of NPY in the forebrain of C.
      batrachus are in concurrence with the pattern of the immunoreactivity encountered
      in other teleosts. However, NPY in olfactory system of C. batrachus is a novel
      feature that suggests a role for the peptide in processing of chemosensory
      information.

PMID- 15036364
TI  - Advances in developing molecular-diagnostic tools for strongyloid nematodes of
      equids: fundamental and applied implications.
AB  - Infections of equids with parasitic nematodes of the order Strongylida
      (subfamilies Strongylinae and Cyathostominae) are of major veterinary importance.
      In last decades, the widespread use of drugs against these parasites has led to
      problems of resistance within the Cyathostominae, and to an increase in their
      prevalence and intensity of infection. Novel control strategies, based on
      improved knowledge of parasite biology and epidemiology, have thus become
      important. However, there are substantial limitations in the understanding of
      fundamental biological and systematic aspects of these parasites, which have been
      due largely to limitations in their specific identification and diagnosis using
      traditional, morphological approaches. Recently, there has been progress in the
      development of DNA-based approaches for the specific identification of
      strongyloids of equids for systematic studies and disease diagnosis. The present
      article briefly reviews information on the classification, biology, pathogenesis,
      epidemiology of equine strongyloids and the diagnosis of infections, highlights
      knowledge gaps in these areas, describes recent advances in the use of molecular
      techniques for the genetic characterisation, specific identification and
      differentiation of strongyloids of equids as a basis for fundamental
      investigations of the systematics, population biology and ecology.

PMID- 15036365
TI  - Chemiluminescent detection of genetic polymorphisms based on mismatch
      hybridization: application to cytochrome P4501A1.
AB  - An assay that makes use of differences in thermal stability between perfectly and
      imperfectly matched hybrids in combination with a sensitive chemiluminescence
      detection system was developed and applied to the identification of CYP1A1
      polymorphisms. In this assay, two oligonucleotide probes for each polymorphic
      site were designed: one perfectly matching the wild type allele, the other
      perfectly matching the mutant allele. The genotypes were determined by
      calculating the ratio of signals obtained from the two probes. The method
      described here allows for the rapid, simple and cost-effective detection of DNA
      polymorphisms. Compared with fluorescence- and microarray-based assays, this
      method provides an alternative for genotyping where costly equipment or
      specialized reagents are not available.

PMID- 15036366
TI  - Quantification of virulence-associated gene transcripts in epidemic methicillin
      resistant Staphylococcus aureus by real-time PCR.
AB  - The control of Staphylococcus aureus virulence gene expression is complex and few
      data are available for the epidemic methicillin resistant S. aureus clones
      circulating in the UK. Quantitative real-time PCRs were developed for key gene
      transcripts involved in S. aureus infection (RNAIII, hla and spa) and for the 16S
      rRNA. These assays were applied to log and stationary phase cultures of the
      important EMRSA strains. To correct for inconsistencies in extract yield, results
      were calculated as ratios using the 16S rRNA values as denominator. The
      quantitative assays were sensitive and reproducible. The number of copies of each
      transcript present differed greatly between the EMRSA strains tested. Strains
      within an EMRSA clone or type gave similar results. High levels of RNAIII
      transcripts were not consistently linked to elevated levels of hla transcripts or
      to low levels of the spa transcript. In addition, strains showed significant
      variations in their patterns of induction (or repression) of all three
      transcripts. A complex interplay exists between the regulatory factors that
      control the expression of proteins required for colonisation and survival in the
      host. The transcript level data suggest that this pattern shows great diversity
      among the currently important EMRSA strains.

PMID- 15036367
TI  - Primer extension assay for prion protein genotype determination in sheep.
AB  - Scrapie is a transmissible spongiform encephalopathy (TSE) which affects sheep
      and goats. TSEs are characterised by the conversion of the cellular prion protein
      (PrP(C)) into the pathological form PrP(Sc). The occurrence of scrapie in sheep
      is influenced by polymorphisms in the PrP gene; in particular, three codons (136,
      154 and 171) are important in conditioning the susceptibility/resistance of sheep
      to the disease, with the Val/Val(136) Arg/Arg(154) Gln/Gln(171) genotype being
      the most susceptible and the Ala/Ala(136) Arg/Arg(154) Arg/Arg(171), the most
      resistant one. The latter genotype seems to confer, in sheep, resistance to the
      oral infection with bovine spongiform encephalopathy, as well. The selection of
      genetically resistant sheep populations represents the basis of the recent
      strategies against ovine TSE in the European Union (EU). Herein, we describe a
      rapid and simple method, based on the primer extension technique, for PrP
      genotype determination at codons 136, 154 and 171. Intra-laboratory validation of
      the method showed accuracy levels comparable to those of sequencing analysis.
      Such method could be used for both the application of the EU policies requiring
      PrP genotype analysis in all ovine TSE cases, and the large-scale genotyping
      claimed by the implementation of breeding programmes for genetic resistance to
      TSE in sheep.

PMID- 15036368
TI  - Characterization of a new SNP c767A/T (Arg222Trp) in the candidate TSG FUS2 on
      human chromosome 3p21.3: prevalence in Asian populations and analysis of
      association with nasopharyngeal cancer.
AB  - The FUS2 gene, encoding a novel cytoplasmic acetyltransferase, resides in the
      tumor suppressor gene region on human chromosome 3p21.3 and is considered a
      promising candidate tumor suppressor gene. We have identified a new single
      nucleotide polymorphism (SNP), c767A/T, in the coding region of the gene. The
      polymorphism leads to a non-conservative amino acid change (R222W) located
      between the acetyltransferase (GNAT) and the proline-rich domains of the protein.
      We have analyzed 254 subjects included in 14 sub-populations. The occurrence of
      the SNP varies with the ethnicity of the population, suggesting that this SNP
      could be a valuable biomarker for population genetics. It is most prevalent in
      various Asian populations (T allele frequency>0.54), followed by the Canadian
      polar Inuit (T allele frequency=0.3), African American (T allele frequency=0.17),
      and Caucasian population (T allele frequency=0.1). Since nasopharyngeal carcinoma
      (NPC) is frequent in Southern China, Taiwan, Borneo and polar Canada, we further
      tested for the possible association of the FUS2 SNP with this form of endemic
      cancer. Our analysis, albeit limited, suggests no likely association between NPC
      and the FUS2 gene polymorphism. Further large-scale case-control studies are
      necessary and warranted to prove the strength of this contention.

PMID- 15036369
TI  - Inhibition of real-time RT-PCR quantification due to tissue-specific
      contaminants.
AB  - Real-time reverse transcription-polymerase chain reaction (RT-PCR) is currently
      considered the most sensitive method to study low abundance gene expression.
      Since comparison of gene expression levels in various tissues is often the
      purpose of an experiment, we studied a tissue-linked effect on nucleic acid
      amplification. Based on the raw data generated by a LightCycler instrument, we
      propose a descriptive mathematical model of PCR amplification. This model allowed
      us to study amplification kinetics of four common housekeeping genes in total RNA
      samples derived from various bovine tissues. We observed that unknown tissue
      specific factors can influence amplification kinetics but this affect can be
      ameliorated, in part, by appropriate primer selection.

PMID- 15036370
TI  - Twelve hour real-time PCR technique for the sensitive and specific detection of
      Salmonella in raw and ready-to-eat meat products.
AB  - Rapid pathogen testing is vital to the food industry. Enzyme immunoassays (EIA)
      provide reliable negative results in 48 h, but a presumptive positive (suspect)
      EIA result must be confirmed by traditional culture methods, requiring an
      additional 72 h. Polymerase chain reaction (PCR) testing technology is accepted
      as an accurate diagnostic tool. However, traditional PCR techniques can require
      several days. We sought to develop a rapid, real-time quantitative PCR technique
      for detecting Salmonella spp. in food products. Salmonella spp. was inoculated
      into raw and ready-to-eat beef products. Total DNA was extracted and used as
      template for PCR amplification in the LightCycler (Roche Diagnostics Corp., Idaho
      Technology Inc., Idaho Falls, ID) PCR instrument. Salmonella-specific PCR primers
      were designed to amplify a 251 base pair product from the junction of SipB and
      SipC. Fluorescently-labeled hybridization probes were designed to anneal to SipB
      and SipC. Salmonella was detected down to 1 colony forming unit/ml in food
      products. The results of real-time PCR correlated 100% to those of visual
      immunoprecipitate and culture. PCR methods using the LightCycler can detect and
      confirm the presence or absence of Salmonella spp. in raw and ready-to-eat beef
      products within 12 h with increased sensitivity compared to traditional culture
      and EIA methods.

PMID- 15036371
TI  - Different molecular methods for the identification of rarely isolated non
      tuberculous mycobacteria and description of new hsp65 restriction fragment length
      polymorphism patterns.
AB  - Analysis of heat shock protein 65 (hsp65) gene restriction fragment length
      polymorphism (RFLP) is done frequently to identify non-tuberculous mycobacteria
      (NTM) on a genetic basis. Here we report the results of analysing the hsp65
      patterns of some rarely isolated NTM for which patterns have not been published
      before (Mycobacterium bohemicum, Mycobacterium hassiacum, Mycobacterium
      heckeshornense, Mycobacterium monacense, and Mycobacterium triplex). Furthermore
      new hsp65-variants for Mycobacterium interjectum (type II), Mycobacterium
      mucogenicum (type V), Mycobacterium gordonae (type VIII) and Mycobacterium
      paraffinicum (perhaps synonymous to Mycobacterium scrofulaceum) are described.
      All species were characterised by hsp65-RFLP, sequencing a 441-bp fragment of the
      hsp65 gene and sequencing the hypervariable region of the 16S rDNA. Additional
      data for less frequently isolated mycobacteria are provided and the hitherto
      described data for the Mycobacterium gordonae complex are summarised. Although
      the hsp65-RFLP analysis turned out to be a useful method a number of restraints
      (lack of standardisation, slight variability in fragment length) limits its
      broader use. Reliable identification of NTM needs, however, more than one
      molecular method. Identification results obtained by applying different methods
      yielded conflicting results. Confusion may be caused by older data base entries
      which are not updated and not longer reflect the actual systematic and taxonomy
      of the genus Mycobacterium.

PMID- 15036372
TI  - Real-time PCR assays for genus-specific detection and quantification of
      culturable and non-culturable mycobacteria and pseudomonads in metalworking
      fluids.
AB  - Genus-specific real-time PCR assays were developed and optimized for the direct
      culture-independent detection and quantification of Mycobacteria and Pseudomonads
      in contaminated metalworking fluids (MWF) and the results were compared with
      conventional culturing using selective media. It included optimization of the
      direct DNA isolation from the fluid matrix and the amplification conditions using
      genus-specific primers. Mycobacterium-specific primers based on 65-kDa heat shock
      protein (hsp) gene, and Pseudomonas-specific primers based on 16S rRNA gene were
      used. A standard curve was developed each for the two model bacterial species
      Mycobacterium immunogenum and Pseudomonas fluorescens, representing two important
      genera frequently isolated from MWF. A minimum quantification limit of 10
      cells/ml was achieved although as low as 1 cell/ml yielded a detectable amplicon
      signal. Of the twenty MWF field samples contaminated with mixed microflora, only
      two samples yielded putative colonies of Mycobacteria and Pseudomonads by
      culturing method, while seven samples responded to the genus-specific real-time
      PCR detection and quantification for each genus. In contrast to the low
      culturable counts, the real-time PCR based cell counts ranged from 1.3 x 10(2) to
      5.5 x 10(5)cells/ml and 5.2 x 10(2) to 7.0 x 10(5)cells/ml for Mycobacteria and
      Pseudomonads, respectively, indicating a significant non-culturable fraction in
      the fluids, for the two genera. This is the first application of real-time PCR
      protocol to MWF samples for detection and quantification of total (culturable and
      non-culturable) Mycobacteria and Pseudomonads without culturing.

PMID- 15036373
TI  - Rapid suppressing action of insulin-like growth factor-I (IGF-I) on GH release
      from anterior pituitary cells of goats.
AB  - Goat anterior pituitary cells were cultured to investigate the effects of insulin
      like growth factor-I (IGF-I), insulin, and growth hormone (GH) on basal and GH
      releasing hormone (GHRH)-induced GH release. Changes in cellular Ca2+
      concentrations were also assessed to enable discussion of the cellular mechanisms
      of IGF-I. The cells were cultured for 48 h, and then stimulated with GHRH (10
      nmol/l) for 30 min, with or without each test substance. In the control cells,
      IGF-I (10 and 100 ng/ml) significantly raised the basal, but did not change GHRH
      induced GH release, resulting in the abolishment of GH release induced by GHRH in
      the presence of 100 ng/ml IGF-I. However, there was no significant effect of
      insulin (10, 100, and 1000 microU/ml) on basal and GHRH-induced GH release. In
      the cells cultured for 48 h with each test substance but stimulated for 30 min
      without the test substance, no significant change in the basal and GHRH
      stimulated GH release was observed. Regardless of treatment, there was no
      significant effect on intra-cellular GH content. Analysis with a confocal laser
      microscope revealed that IGF-I (100 ng/ml) significantly increased the basal, but
      significantly reduced GHRH (10 nmol/l)-induced increase in cellular Ca2+
      concentrations. From these findings we conclude that IGF-I exerts an acute
      suppressing action on the GHRH-induced GH release, which partly involves changes
      in cellular Ca2+ metabolism in goat somatotrophs.

PMID- 15036374
TI  - Leptin attenuates the acute effects of centrally administered neuropeptide Y on
      somatotropin but not gonadotropin secretion in ovariectomized cows.
AB  - We tested the hypothesis that recombinant ovine leptin would attenuate the acute
      effects of neuropeptide Y (NPY) on secretion of GH and gonadotropins (LH and FSH)
      in cows. Ovariectomized cows (n=6) fitted with third ventricle guide cannulas
      were assigned randomly to each of three groups in a Latin square arrangement: (1)
      control; saline treatment only, (2) NPY; saline followed by NPY, and (3) L-NPY;
      leptin pretreatment followed by NPY. Treatments were: s.c. injection of saline or
      leptin (30 microg/kg BW) at time 0, i.v. injection of saline or leptin (30
      microg/kg BW) at 70 min, and intracerebroventricular (i.c.v.) injection of saline
      or NPY (500 microg) at 90 min. Plasma leptin was elevated (P<0.01) at least four
      fold throughout the experiment in the L-NPY group. Mean plasma concentrations of
      LH declined within 1 h and were lower (P<0.03) than controls in both the NPY and
      L-NPY groups beginning 2 h after NPY injection. An acute increase in plasma
      concentrations of GH was observed within 1 h after NPY in the NPY group and mean
      values were greater (P<0.01) than controls. However, in the L-NPY group, leptin
      pretreatment attenuated the NPY effect on GH. Treatments had no effect on FSH
      secretion. Results confirm suppressive and stimulatory effects of NPY on LH and
      GH secretion, respectively, and indicate that leptin can attenuate the acute
      effects of NPY on GH secretion in cattle.

PMID- 15036375
TI  - Role of leptin in modulating the hypothalamic-pituitary axis and luteinizing
      hormone secretion in the prepuberal gilt.
AB  - Three experiments (EXP) were conducted to test the hypothesis that leptin
      modulates LH, GnRH, and neuropeptide Y (NPY) secretion. In EXP I, prepuberal
      gilts received intracerebroventricular (i.c.v.) leptin injections and blood
      samples were collected. In EXP II, anterior pituitary cells from prepuberal gilts
      in primary culture were challenged with 10(-14), 10(-13), 10(-12), 10(-11), 10(
      10), 10(-9), 10(-8), 10(-7), or 10(-6) M leptin individually or in combinations
      with 10(-10), 10(-9), and 10(-8) M GnRH. In EXP III, hypothalamic-preoptic area
      (HYP-POA) explants were placed in perfusion system and exposed to 0 (n=5), 10(
      12) M (n=4), 10(-10) M (n=4), 10(-8) M (n=4), or 10(-6) M (n=5) human recombinant
      leptin (LEP) for 30 min. In EXP I, serum LH concentrations were unaffected by
      leptin treatment. In EXP II, all doses of leptin increased LH secretion except
      for 10(-12) and 10(-7) M. Only 10(-7), or 10(-13) M leptin in combination with
      10(-8) or 10(-9) M GnRH, respectively, suppressed LH secretion. In EXP III, prior
      to leptin, media GnRH concentrations were similar across treatments. Media GnRH
      concentrations increased after 10(-12), 10(-10), and 10(-8) M leptin compared to
      control. Leptin treatment failed to influence NPY secretion across treatments.
      These results indicate that components of the neuroendocrine axis that regulate
      GnRH and LH secretion are functional and leptin sensitive before the onset of
      puberty. Other neural peptides in addition to NPY may mediate the acute effects
      of leptin on the GnRH-LH system and lastly, the inability of i.c.v. leptin
      treatment to increase LH secretion may in part be related to stage of sexual
      maturation and associated change in negative feedback action of estradiol on LH
      secretion.

PMID- 15036376
TI  - Expression of messenger ribonucleic acid encoding for steroidogenic acute
      regulatory protein and enzymes, and luteinizing hormone receptor during the
      spring transitional season in equine follicles.
AB  - The period of spring transition, from the anovulatory to the ovulatory season, is
      characterized in many mares by cyclical growth and regression of large dominant
      follicles. These follicles produce only low concentrations of estradiol and it is
      thought that acquisition of steroidogenic competence by large follicles during
      spring transition is prerequisite in stimulating LH prior to first ovulation. In
      situ hybridization was used to localize and quantify expression of factors that
      play a key role in follicular steroidogenesis: StAR, P450scc (CYP11A1), P450c17
      (CYP17), P450arom (CYP19), and LH receptor (LHr). One ovary was obtained from
      mares on the day after detection of an actively growing 30 mm transitional
      anovulatory follicle (defined as the transitional follicle), and the remaining
      ovary was removed at the third estrus of the breeding season on the day after the
      preovulatory follicle reached 30 mm in diameter (defined as the preovulatory
      follicle). Messenger RNAs encoding StAR, CYP11A1, and CYP17 were detected only in
      theca cells and CYP19 mRNA was confined to the granulosa layer. There was
      significantly lower expression of mRNAs for the steroidogenic enzymes, StAR
      (P<0.001) and LHr (P<0.05) in transitional follicles than in preovulatory
      follicles. In conclusion, large equine follicles during spring transition have
      low levels of mRNA encoding steroidogenic enzymes, StAR and LHr which will
      contribute to the steroidogenic incompetence of dominant follicles during spring
      transition and their subsequent regression.

PMID- 15036377
TI  - Effects of fasting on circulating IGF-binding proteins, glucose, and cortisol in
      channel catfish (Ictalurus punctatus).
AB  - The effects of fasting on IGF-binding proteins (IGFBPs), glucose, and cortisol in
      channel catfish were examined. Fed fish (controls) were compared to 14-, 30-, and
      45-day fasted fish and 45-day fasted fish refed for 15 additional days. Body
      length and weight changes, condition factor (CF), hepatosomatic index (HSI), and
      plasma glucose and cortisol were assessed to determine growth and metabolic
      status. Body length and growth rates were inhibited (P<0.05) after 14, 30, and 45
      days of fasting. The 14-, 30-, and 45-day fasted fish exhibited hypoglycemia and
      reduced CF and HSI. Cortisol levels were increased (22.8 +/- 15.2 ng/ml versus
      4.7 +/- 3.9 ng/ml) in 30-day fasted fish compared to fed controls (P<0.05).
      Associated with the increase in cortisol in fasted fish was a concomitant
      increase in plasma levels of a 20-kDa IGFBP through day 45. A 35- and a 45-kDa
      IGFBP were also identified but were similar between fed and unfed fish throughout
      the experiment. At the end of 15 days of refeeding, 20-kDa IGFBP, glucose, and
      cortisol levels were similar to fed controls. Refeeding also caused an increase
      in growth rates. These results suggest the existence of a catfish counter part to
      mammalian IGFBP-1, similar to lower molecular mass IGFBPs reported in other
      species of fish. These results also suggest that a 20-kDa IGFBP is upregulated
      during fasting-induced growth inhibition of channel catfish and provide
      additional evidence of the conserved nature of the IGF-IGFBP-growth axis in fish.

PMID- 15036378
TI  - Quantification of insulin-like growth factor binding protein mRNA using real-time
      PCR in bovine granulosa and theca cells: effect of estradiol, insulin, and
      gonadotropins.
AB  - The effects of estradiol, insulin, and gonadotropins on levels of insulin-like
      growth factor binding protein (IGFBP)-2, -3, -4, and -5 mRNA levels in bovine
      granulosa and theca cells were evaluated in vitro using serum-free medium
      containing various hormone treatments arranged in four different experiments.
      Amounts of IGFBP-2, -3, -4 and -5 mRNA were quantitated using fluorescent
      quantitative real-time RT-PCR. In small-follicle (1-5 mm) granulosa cells,
      follicle-stimulating hormone (FSH) in the presence or absence of insulin
      increased (P<0.05) IGFBP-3 mRNA but did not change IGFBP-2, -4, or -5 mRNA
      levels; estradiol was without effect on IGFBP-2, -3, -4, or -5 mRNA levels in the
      absence of insulin but increased (P<0.05) IGFBP-2 mRNA levels in the presence of
      insulin. Luteinizing hormone (LH) in the absence (but not presence) of insulin
      increased (P<0.05) small-follicle granulosa cell IGFBP-3 mRNA levels. In large
      follicle (>7.9 mm) granulosa cells, insulin alone increased (P<0.05) IGFBP-2 gene
      expression while LH, FSH, and estradiol were without effect (P>0.10). Estradiol
      (3 and 300 ng/ml) decreased (P<0.05) IGFBP-5 mRNA levels in large-follicle
      granulosa cells. In theca cells, insulin decreased (P<0.05) IGFBP-4 expression,
      but had no effect (P>0.10) on IGFBP-2, -3, or -5 mRNA levels. Estradiol decreased
      (P<0.05) IGFBP-2, -3, and -4 mRNA levels but had no effect on IGFBP-5 mRNA levels
      in theca cells. LH had no effect on levels of IGFBP-2, -3, -4, or -5 mRNA in
      theca cells. These results indicate that expression of IGFBP-2, -3, -4, and -5
      mRNA by granulosa and theca cells are differentially regulated by estradiol,
      insulin and gonadotropins, therefore discretely modulating the amount of
      bioavailable IGFs to these cells depending upon the specific hormonal stimuli. In
      particular, these studies are the first in cattle to show that estradiol
      selectively inhibits IGFBP-2, -3, and -4 gene expression in theca cells, inhibits
      IGFBP-5 gene expression in large-follicle granulosa cells, and stimulates IGFBP-2
      gene expression in small-follicle granulosa cells.

PMID- 15036379
TI  - Plasma inhibin A determination at start superovulatory FSH treatments is
      predictive for embryo outcome in goats.
AB  - To test whether inhibin A assays can be used for the prediction of yields in
      embryo programmes in goats, 50 does were treated with 45 mg FGA sponges
      (Chronogest) for 16 days plus a single dose of 100 microg i.m. cloprostenol on
      Day 14, just before the start of administration of eight doses of 1.25 ml of
      Ovagen twice daily for 4 days. At first FSH injection, the number and size of all
      follicles > or =2 mm was assessed by transrectal ultrasound and plasma inhibin A
      levels were measured by specific dimeric assay. There was a positive correlation
      between number of follicles > or =6 mm (8.8 +/- 0.5) and inhibin A levels at
      first FSH dose (193.2 +/- 14.5 pg/ml, P<0.05). The mean number of corpora lutea
      on Day 7 after sponge removal was related to the total number of follicles with a
      diameter of 2-6 mm at the onset of the FSH treatment (15.3 +/- 0.7, P<0.05). The
      total number of embryos recovered was related to the number of follicles with 4-6
      mm in size (6.2 +/- 0.5, P<0.05) and to the inhibin A levels at first FSH dose
      (P<0.05). These results suggest that follicles > or =4 mm are the source of
      inhibin prior to FSH stimulation and are the main source of oocytes resulting in
      the number of viable embryos recovered after a superovulatory treatment. Hence,
      the response to superovulatory treatments in goats in terms of the number of
      embryos can be predicted from either the population of follicles determined by
      ultrasound or the plasma inhibin A levels at start of the superovulatory FSH
      treatment.

PMID- 15036380
TI  - Re-expression of NR2B-containing NMDA receptors in vitro by suppression of
      neuronal activity.
AB  - N-methyl-D-aspartate receptors (NMDARs) are known to play critical roles in the
      development of the nervous system, and their expression is regulated in an
      activity-dependent fashion during development. However, the regulation of NMDAR
      expression after circuit formation is less well understood. To examine this, we
      performed patch-clamp recordings from chick cerebral neurons in an activity
      controlled culture. Analysis of NMDAR channels from neurons before synapse
      formation showed that there are two components in channel open kinetics. The
      major slow component is clearly blocked by ifenprodil, a specific inhibitor of
      NR2B-containing NMDARs. In contrast, slow component of NMDAR channel opening from
      neurons after synapse formation became minor and ifenprodil had little effect on
      the NMDAR channel openings. Furthermore, this change is reversibly regulated by
      neuronal activity, in that suppression induces the re-expression of NR2B
      containing NMDARs, even after circuit formation.

PMID- 15036381
TI  - Effects of histidine and imidazolelactic acid on various parameters of the
      oxidative stress in cerebral cortex of young rats.
AB  - Histidinemia is an inherited metabolic disorder caused by deficiency of histidase
      activity, which leads to tissue accumulation of histidine and its derivatives.
      Affected patients usually present with speech delay and mental retardation,
      although asymptomatic patients have been reported. Considering that the
      pathophysiology of the neurological dysfunction of histidinemia is not yet
      understood and since histidine has been considered a pro-oxidant agent, in the
      present study we investigated the effect of histidine and one of its derivatives,
      l-beta-imidazolelactic acid, at concentrations ranging from 0.1 to 10 mM, on
      various parameters of oxidative stress in cerebral cortex of 30-day-old Wistar
      rats. Chemiluminescence, total radical-trapping antioxidant potential (TRAP),
      thiobarbituric acid reactive substances (TBA-RS), and the activities of the
      antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione
      peroxidase (GSH-Px) were measured in tissue homogenates in the presence of l
      histidine or l-beta-imidazolelactic acid. We observed that l-histidine provoked
      an increase of chemiluminescence and a reduction of TRAP at concentrations of 2.5
      mM and higher, while TBA-RS measurement, GSH-Px, CAT and SOD activities were not
      affected. Furthermore, l-beta-imidazolelactic acid provoked antioxidant effects
      at high concentrations (5-10 mM) as observed by the reduction of
      chemiluminescence, although this compound enhanced chemiluminescence at low
      concentrations (0.5-1 mM). These results suggest that in vitro oxidative stress
      is elicited by histidine but only at supraphysiological concentrations.

PMID- 15036382
TI  - Maturation of astrocyte morphology and the establishment of astrocyte domains
      during postnatal hippocampal development.
AB  - Mature protoplasmic astrocytes exhibit an extremely dense ramification of fine
      processes, yielding a 'spongiform' morphology. This complex morphology enables
      protoplasmic astrocytes to maintain intimate relationships with many elements of
      the brain parenchyma, most notably synapses. Recently, it has been demonstrated
      that astrocytes establish individual cellular-level domains within the neuropil,
      with limited overlap occurring between the extents of neighboring astrocytes. The
      highly ramified nature of protoplasmic astrocytes is closely associated with
      their ability to create such domains. This study was an attempt to characterize
      the development of spongiform processes and the establishment of astrocyte
      domains. A combination of immunolabeling for the astrocyte-specific markers glial
      fibrillary acidic protein and S100beta with intracellular dye labeling in fixed
      tissue slices allowed for the identification of immature astrocytes and the
      elucidation of their complete, well-preserved morphologies. We find that during
      the first two postnatal weeks astrocytes extend stringy, filopodial processes.
      Fine, spongiform processes appear during the third week. Protoplasmic astrocytes
      are quite heterogeneous in morphology at 1-week postnatum, but there is a
      remarkable consistency in morphology by 2 weeks of age. Finally, protoplasmic
      astrocytes initially extend long, overlapping processes during the first two
      postnatal weeks. The subsequent elaboration of spongiform processes results in
      the development of boundaries between neighboring astrocyte domains. Stray
      processes that encroach on neighboring domains are eventually pruned by 1 month
      of age. These observations suggest that domain formation is largely the
      consequence of competition between astrocyte processes, similar to the well
      studied competitive interactions between certain neuronal dendritic fields.

PMID- 15036384
TI  - Tryptophan reduces creatine kinase activity in the brain cortex of rats.
AB  - Hypertryptophanemia is a rare inherited metabolic disorder probably caused by a
      blockage in the conversion of tryptophan to kynurenine, resulting in the
      accumulation of tryptophan and some of its metabolites in plasma and tissues of
      affected patients. The patients present mild-to-moderate mental retardation with
      exaggerated affective responses, periodic mood swings, and apparent hypersexual
      behavior. Creatine kinase plays a key role in energy metabolism of tissues with
      intermittently high and fluctuating energy requirements, such as nervous tissue.
      The main objective of the present study was to investigate the effect of acute
      administration of tryptophan on creatine kinase activity in brain cortex of
      Wistar rats. We also studied the in vitro effect of this amino acid on creatine
      kinase activity in the brain cortex of non-treated rats. The results indicated
      that tryptophan inhibits creatine kinase in vitro and in vivo. We also observed
      that the in vitro inhibition was fully prevented but not reversed by pre
      incubation with reduced glutathione, suggesting that the inhibitory effect of
      tryptophan on CK activity is possibly mediated by oxidation of essential thiol
      groups of the enzyme and/or long-lasting adduct formation. Considering the
      importance of creatine kinase for the maintenance of energy homeostasis in the
      brain, it is conceivable that an inhibition of this enzyme activity in the brain
      may be one of the mechanisms by which tryptophan might be neurotoxic.

PMID- 15036383
TI  - Role of maternal adrenal glands on the developing serotoninergic and
      aminoacidergic systems of the postnatal rat brain.
AB  - Serotonin, gamma-aminobutyric acid and glutamate, which are regulated by
      glucocorticoids in the central nervous system, are involved in neuroendocrine
      functions and the development of the brain. The present study investigates the
      effect of maternal adrenalectomy on the developing serotoninergic, GABAergic and
      glutamatergic systems. Neurotransmitter levels were measured in four brain areas
      of both male and female offspring on postnatal days 1, 8, 12 and 22. At postnatal
      day 1 and 8, the pups of adrenalectomized dams showed higher concentrations of
      serotonin than controls in all the brain areas studied. Serotonin levels
      decreased significantly in males at postnatal day 22 in the hippocampus and
      cortex. During the first 2 weeks of postnatal life, the lack of maternal
      corticosterone produced an increase in glutamate and a reduction in gamma
      aminobutyric acid concentrations, mainly in males. Further, on postnatal day 1,
      increased serotonin and glutamate levels and lower levels of gamma-aminobutyric
      were observed in the hypothalamus of male pups born to adrenalectomized dams. The
      absence of maternal corticosterone affects the pattern of development of the
      serotoninergic system, especially in the hippocampus and cortex, and particularly
      in males. A delay in the maturation of the aminoacidergic systems, mainly of the
      GABAergic system and in males, was also seen. A sexually dimorphic response to
      the removal of maternal glucocorticoids was seen in terms of neurotransmitter
      levels, mainly in the hippocampus and hypothalamus.

PMID- 15036385
TI  - Neonatal ventral hippocampus lesion alters the dopamine content in the limbic
      regions in postpubertal rats.
AB  - The neonatal ventral Hippocampus (nVH) lesion in rats has been used as a model to
      test the hypothesis that early neurodevelopmental abnormalities lead to
      behavioral changes putatively linked to schizophrenia. The schizophrenic patients
      tend to social isolation. In addition, considerable evidence from behavioral and
      neurochemistry studies strongly implicate the dopamine (DA) system and the medial
      part of the prefrontal cortex (mPFC) in the pathophysiology of the social
      isolation syndrome. In order to assess effects of the postweaning social
      isolation (pwSI) on the DA system of the nVH lesions, we investigated the DA
      content and its metabolite, DOPAC in different limbic subregions in rats
      postpubertally at postnatal day (P) 78 following nVH lesions at P7 with and
      without pwSI for 8 weeks. The DA and DOPAC were measured by HPLC with
      electrochemical detection. The nVH lesion induces increase in the DA content in
      the hippocampus with no effect in the mPFC, nucleus accumbens and caudate
      putamen, while the pwSI induces major increase in the DA content in limbic
      subregions such as the mPFC, nucleus accumbens and hipocampus with opposite
      effect in the caudate-putamen. These results suggest that while pwSI has an
      effect in the postpubertal content of DA in both sham and nVH lesions in rats,
      the nVH-lesioned rats appear to be affected to a greater extent than the sham
      animals underscoring the influence of pwSI differences in the development of
      behaviors in the nVH-lesioned animals.

PMID- 15036386
TI  - Neurotrophins and extracellular matrix molecules modulate sensory axon outgrowth.
AB  - Neurotrophins have been known to play a pivotal role in axonal guidance. Recent
      research has implicated the role of extracelluar matrix molecules in co
      ordinating axonal movement. In this study, we examined the influence of
      neurotrophins (nerve growth factor (NGF) and neurotrophin-3 (NT-3)) and
      extracellular matrix molecules (laminin, fibronectin, and poly-l-lysin) on
      sensory neurite outgrowth in thoracic dorsal root ganglia (DRG) dissected from
      rats at embryonic day 13. Adjacent DRG were embedded in a collagen gel matrix and
      supplemented with NGF or NT-3. Under NT-3 conditions, DRG axons extended towards
      each other and intermingled, while neurites from NGF-treated DRG demonstrated a
      strong repellent effect, resulting in turning responses and growth cone collapse.
      This effect was not observed on a collagen culture surface. Interestingly, the
      composition of the extracellular matrix strongly influenced the observed
      repellent effect. Sensory neurites from NGF-stimulated DRG again demonstrated a
      repellent effect when plated on a laminin surface, but showed intermingling
      behavior when plated on poly-l-lysin or fibronectin. This observation suggests
      that a factor secreted by NGF-treated DRG axons interacts with laminin, enabling
      repulsion. This factor and its interaction with the extracellular matrix play an
      important role in the mechanism of sensory axonal pathfinding.

PMID- 15036387
TI  - Methods to detect mitochondrial function.
AB  - The bioenergetic function of mitochondria can be investigated in intact cells by
      a variety of methods. A simple biochemical method to compare mitochondrial
      oxidative phosphorylation with glycolytic ATP synthesis takes advantage of the
      Pasteur effect, since the amount of lactate produced under basal conditions is an
      indication of glycolytic ATP, while the Delta-lactate (the difference between
      excess lactate produced after inhibition of respiration and basal lactate)
      represents ATP produced anaerobically in order to compensate for decreased
      oxidative phosphorylation after respiratory chain inhibition. The system has been
      validated in a series of cells, including human platelets and lymphocytes and
      lines cultured in vitro. Measurement of KCN-sensitive oxygen consumption by the
      cells and its sensitivity to uncouplers can be good supplementary indication of
      mitochondrial phosphorylative capacity.

PMID- 15036388
TI  - The effect of aging and caloric restriction on mitochondrial protein density and
      oxygen consumption.
AB  - It has been proposed that part of the anti-aging mechanism of caloric restriction
      (CR) involves changes in mitochondrial function. To investigate this hypothesis,
      mitochondria from various tissues of male Brown Norway rats (fully fed and CR)
      were isolated and respiration rates determined. In mitochondria from liver,
      heart, brain and kidney, there were no significant effects of CR on state 4
      mitochondrial respiration rate. Further experiments using liver mitochondria
      under a variety of incubation conditions confirmed that CR does not alter
      mitochondrial respiration rate in this tissue. However, the respiration rate of
      mitochondria from brown adipose tissue (BAT) of CR animals was approximately
      three-fold higher compared to mitochondria from fully fed controls. Mitochondrial
      protein density was significantly higher in liver tissue of CR animals; it was
      significantly lower in heart and unchanged in BAT. It is concluded that whilst CR
      results in tissue-specific changes in mitochondrial respiration rate, these
      effects do not explain the CR-induced changes in free radical production reported
      previously for these organelles.

PMID- 15036389
TI  - Calorie restriction attenuates age-related alterations in the plasma membrane
      antioxidant system in rat liver.
AB  - Aging is associated with increased production of reactive oxygen species and
      oxidation-induced damage to intracellular structures and membranes. Caloric
      restriction (CR) is the only non-genetic method proven to extend lifespan in
      mammals. Although the mechanisms of CR remain to be clearly elucidated,
      reductions in oxidative stress have been shown to increase lifespan in several
      model systems. Oxidative stress can be attenuated by CR. Mitochondria and plasma
      membrane (PM) are normal sources of free radicals. The PM has a trans-membrane
      redox system that provides electrons to recycle lipophilic antioxidants, such as
      alpha-tocopherol and coenzyme Q (CoQ). The idea developed in this study is that
      the PM is intimately involved in cellular physiology controlling the relationship
      of the cell to its environment. PM is the key for protecting cellular integrity
      during aging. Specifically, we have investigated age-related alterations and the
      effects of CR in the trans-PM redox (antioxidant) system in rat liver. We found
      that age-related declines in the ratio of CoQ(10)/CoQ(9) and alpha-tocopherol in
      liver PM were attenuated by CR compared to those fed ad libitum (AL). CoQ
      dependent NAD(P)H dehydrogenases were increased in CR old rat liver PMs. As a
      consequence, the liver PM of CR old rats was more resistant to oxidative stress
      induced lipid peroxidation than AL rats. Thus, our results suggest that CR
      induces a higher capacity to oxidize NAD(P)H in the PM of old rat livers and as a
      result, a higher resistance to oxidative stress-induced damage.

PMID- 15036390
TI  - Body weight is not always a good predictor of longevity in mice.
AB  - There have been some observations that low body weight and a low level of some
      hormones (e.g. IGF-1) during the first half of life are predictors of longer life
      in mice. However, contradictions in the available data on the biomarkers of aging
      and predictors of longevity have shown that the research in these fields has
      become a controversial pursuit. In our study we addressed the following
      questions: (i) Can particular physiological parameters (body weight, food intake,
      estrus function, body temperature, incidence of chromosome aberrations in bone
      marrow cells) measured at the age of 3 and 12 months be a predictor of longevity
      and the rate of tumor development in five strains of mice? (ii) Can a heavy body
      weight at the age of 3 and 12 months be a predictor of longevity and high tumor
      risk in five strains of mice? Mice of five strains-CBA, SHR, SAMR, SAMP and
      transgenic HER-2/neu (FVB/N)-were under observation from the age of 2-3 months
      until natural death. Body weight and temperature, food consumption, and estrous
      cycle were longitudinally studied in all animals. Tumors discovered at autopsy
      were studied morphologically. We calculated the life span's parameters (mean,
      maximum, mortality rate, mortality rate doubling time) as well as their
      correlation with other parameters studied. The longest living CBA mice have the
      lowest body weight at the ages of 3 and 12 months, the lowest food consumption,
      body temperature, incidence of chromosome aberrations and spontaneous tumor
      incidence. In comparison with all other mouse strains they also have the latest
      disturbances in estrus function and highest body weight gain. The shortest living
      transgenic HER-2/neu mice have the lowest weight at the ages of 12 months, the
      lowest body weight gain, maximal body temperature, the most rapid disturbances in
      estrus function and the highest incidence of chromosome aberrations and tumor
      incidence in comparison to all other mouse strains. Our findings have shown that
      heavier body weight at the age of 12 months is a predictor of longevity in female
      CBA and SAMP mice but not in SHR, SAMR and HER-2/neu mice. Excessive body weight
      at the ages of 3 or 12 months is not a predictor of increased tumor risk in the
      strains studied. In general, the existence and direction of a significant
      correlation between body weight and life span depends upon the animals' age and
      genotype.

PMID- 15036392
TI  - 1,25(OH)2D3 inhibits bone marrow adipogenesis in senescence accelerated mice (SAM
      P/6) by decreasing the expression of peroxisome proliferator-activated receptor
      gamma 2 (PPARgamma2).
AB  - Senile osteoporosis is the endpoint of a continuum that starts after the third
      decade of life when peak bone mass is attained and then is followed by a
      progressive and irreversible decline in bone mass. One of the mechanisms that
      could explain this is the increasing levels of adipogenesis in bone marrow seen
      with increasing age, probably due to alterations in the differentiation of
      mesenchymal stem cells (MSC). Senescence accelerated mice (SAM-P/6) constitute an
      accepted model for senile osteoporosis since their loss of bone mineral density
      is clearly due to high levels of adipogenesis and a deficit in
      osteoblastogenesis. It is known that MSC expressing a ligand-activated
      transcription factor known as peroxisome proliferators-activated receptor gamma 2
      (PPARgamma2) are committed to differentiate into adipocytes. The regulation of
      PPARgamma2 activation may play a role in the control of adipogenic
      differentiation of MSC and thus contribute to their differentiation into
      osteoblasts in order to form new bone. Our previous studies have shown that the
      active form of vitamin D (1,25(OH)(2)D(3)) plays a role as a bone forming agent
      because it induces osteoblastogenesis and inhibits adipogenesis in bone marrow of
      SAM-P/6 mice. To elucidate the role of 1,25(OH)(2)D(3) on the expression of
      PPARgamma2 we treated 4-month old SAM-P/6 mice with 1,25(OH)(2)D(3) (18pmol/24 h)
      or vehicle during 6 weeks. Initially we found that with aging the levels of
      PPARgamma2 expression increase in bone marrow of SAM-P/6 (P<0.001) We then
      measured the changes in the expression of PPARgamma2 by semi-quantitative reverse
      transcription-polymerase chain reaction and immunofluorescence. We found a
      significant reduction of PPARgamma2-expressing cells in 1,25(OH)(2)D(3)-treated
      (32% +/-6) as compared to vehicle (76% +/-5) treated mice (p<0.01) In summary,
      this study shows that the administration of 1,25(OH)(2)D(3) in an in vivo model
      of senile osteoporosis is associated with reduction in PPARgamma2 a key
      transcription factor for the adipose differentiation of MSC.

PMID- 15036391
TI  - Dehydroepiandrosterone sulfate (DHEAS) and health: does the relationship differ
      by sex?
AB  - This study uses data from a large, nationally representative sample of older
      Taiwanese (aged 54 and older in 2000) to investigate sex differences in the
      relationship between DHEAS and various health outcomes. Data collection included
      an individual interview, a physical examination, and samples of blood and (12-h)
      urine. Regression models of health outcomes on DHEAS are estimated in two steps:
      first, including only controls for age and sex as well as an interaction between
      DHEAS and sex; and second, adding covariates likely to be related to both DHEAS
      and health outcomes (e.g. smoking). Results reveal that higher levels of DHEAS
      are associated with fewer mobility limitations (especially for women), better
      cognitive function (among women but not men), and better self-rated health
      (significant only for men but of similar magnitude for women). These findings are
      in contrast to previous studies conducted in the US and Europe that generally
      find stronger associations for men than women. Also unlike previous studies,
      which often demonstrate a negative relationship between DHEAS and depressive
      symptoms at least for women, we find little evidence of such a relationship for
      either sex.

PMID- 15036393
TI  - Regulation of dendritic cell expansion in aged athymic nude mice by FLT3 ligand.
AB  - This report describes age-related alterations of dendritic cells (DC)
      distribution in nude athymic mice in vivo and reversal of certain age-dependent
      defects by an in vivo administration of hematopoietic growth factor FLT3 ligand
      (FLT3L). There are decreased percentages of CD11c(+) DC in the bone marrow and
      spleen and a reduced expression of MHC class II and CD86 molecules on DC in old
      nude mice. The decreased levels of CD11c(+) DC were due to the CD8alpha(-) DC
      subset. The distribution of CD11c(+) CD8alpha(+) DC in the lymphoid tissues was
      not different in young and old mice. The effect of in vivo administration of
      FLT3L on the generation and distribution of DC in the lymphoid tissues in young
      and old nude mice was also evaluated. Although, FLT3L had a higher inductive
      potential on the expansion of DC from the bone marrow in the elderly mice, the
      total level of CD11c(+) DC in the young animals was still significantly higher as
      compared to the old animals. Interestingly, FLT3L induced a pronounced
      redistribution and accumulation of MHC class II(+) DC in the lymphoid tissues in
      old mice, markedly increased the accumulation of CD8alpha(-) DC in the bone
      marrow in both young and old nude mice, and elevated both CD8alpha(-) and
      CD8alpha(+) DC in the spleen in young mice. However, only the level of
      CD8alpha(+) DC was up regulated in the spleen in old athymic mice after FLT3L
      based therapy. In summary, abnormalities in DC generation and distribution in old
      athymic mice could be, in part, circumvented by the in vivo administration of
      FLT3L.

PMID- 15036394
TI  - Changes in mechanical properties of human plantar flexor muscles in ageing.
AB  - Changes in contractile and elastic properties of human plantar flexor muscles in
      ageing, were investigated in 12 young (19-24 years, YG) and 11 old (61-74 year,
      OG) men. Maximal isometric and concentric voluntary torques, at several angular
      velocities, were measured to construct torque-angular velocity relationship. This
      led to the calculation of an index of maximal shorting velocity (VImax) at low
      torque. Two methods were then used to calculate musculotendinous (MT, quick
      release movements) and musculoarticular (MA, sinusoidal perturbations) stiffness.
      In both cases, stiffness was linearly related to torque, leading to the
      calculation of a stiffness index (SI) as the slope of the stiffness-torque
      relationship: SI(MT) and SI(MA), respectively. MA stiffness under passive
      conditions (Kp) was also determined. Surface electromyograms were useful to
      control agonist and antagonist myoelectrical activities. As expected, maximal
      isometric (P<0.005) and concentric torques (P<0.05) as well as VImax(p<0.05) were
      lower in OG compared to YG. SI(MT) values were higher for OG compared to YG
      (P<0.05) leading to a mean difference of 55%, whereas SI(MA) and Kp were not
      significantly different between the two groups. Thus, older men were weaker and
      exhibited higher SI(MT) values. These impairments seem to be principally due to
      muscular atrophy and modifications in both muscle fibre-type distribution and
      fibre composition, in ageing. Invariance of SI(MA) and Kp would suggest an
      adaptive mechanism in articular structures to avoid the continuous integration of
      the ankle joint stiffness by the central nervous system, what may simplify most
      daily motor tasks.

PMID- 15036395
TI  - Effects of eccentric training on torque-angular velocity-power characteristics of
      elbow flexor muscles in older women.
AB  - The purpose of this study was to investigate the potential of eccentric training
      to improve elbow flexor muscle power in elderly subjects. Fourteen older female
      volunteers (age range 60-78 years) were randomly assigned into either a training
      group (TG) or a control group (CG). For the TG, the 21-session 7-week eccentric
      training program consisted of 5x6 eccentric muscle actions at 60-100% of
      concentric three maximal repetitions. Before and after training, maximal elbow
      flexions were performed against increasing inertia. Maximal isokinetic elbow
      flexions at four angular velocities (eccentric actions, -60 degrees s(-1), -30
      degrees rads(-1); concentric actions, 30, 60 degrees s(-1)) and maximal isometric
      actions were also performed. Maximal power (Pmax) and an index of maximal
      shortening velocity (VImax)were determined. For all action conditions, the
      myoelectric activities of the biceps and the triceps brachii muscles were
      recorded and quantified as a root mean square (RMS) value. In the TG, maximal
      torque developed under isometric, isokinetic and inertial conditions increased
      significantly after training (ranging from 11 to 19%). Pmax and VImax also
      increased significantly (31.3 and 25.9%, respectively). These parameters remained
      unchanged in the CG. The RMS activity of the biceps and triceps muscles was not
      affected by eccentric training for all action conditions excepting the eccentric
      condition at -30 degrees s(-1) where the RMS activity of the biceps increased
      significantly. The gains in maximal torque, Pmax and VImax observed after
      training would result more from intramuscular modifications than from changes in
      muscular activity, except for eccentric condition at -30 degrees s(-1) where the
      torque gains could also be partly explained by a reduction in inhibition of the
      motor unit pool.

PMID- 15036396
TI  - Skeletal muscle gene expression profiles in 20-29 year old and 65-71 year old
      women.
AB  - Gene expression profiling may provide leads for investigations of the molecular
      basis of functional declines associated with aging. In this study, high-density
      oligonucleotide arrays were used to probe the patterns of gene expression in
      skeletal muscle of seven young women (20-29 years old) and eight healthy older
      women (65-71 years old). The older subjects had reduced muscle mass, strength,
      and peak oxygen consumption relative to young women. There were approximately
      1000 probe sets that suggested differential gene expression in younger and older
      muscle according to statistical criteria. The most highly overexpressed genes (>3
      fold) in older muscle were p21 (cyclin-dependent kinase inhibitor 1A), which
      might reflect increased DNA damage, perinatal myosin heavy chain, which might
      reflect increased muscle fiber regeneration, and tomoregulin, which does not have
      a defined function in muscle. More than 40 genes encoding proteins that bind to
      pre-mRNAs or mRNAs were expressed at higher levels in older muscle. More than 100
      genes involved in energy metabolism were expressed at lower levels in older
      muscle. In general, these results support previous observations on the
      differences in gene expression profiles between younger and older men.

PMID- 15036398
TI  - Exaggerated production of nitric oxide (NO) and increases in inducible NO
      synthase mRNA levels induced by the pro-inflammatory cytokine interleukin-1beta
      in vascular smooth muscle cells of elderly rats.
AB  - Nitric oxide (NO) is produced at high levels by inducible nitric oxide synthase
      (iNOS) during inflammation and other pathological conditions, contributing to
      development of cardiovascular diseases. The present study determined if aging
      affects the ability of interleukin-1beta (IL-1beta), a pro-inflammatory cytokine,
      to induce increased NO production (assessed by Griess reaction) and iNOS mRNA
      levels (assessed by RT-PCR/agarose gel electrophoresis) in vascular smooth muscle
      cells (VSMCs) from young (3-month-old) and elderly (20-22-month-old) rats. The
      VSMCs cells were used only in early passages (passages 0 and 1) to avoid
      phenotypic modulation. To uncover subtle differences in basal iNOS mRNA levels in
      VSMCs of young and elderly rats, RT-PCR products were also analyzed by a new
      ultrasensitive technique using capillary electrophoresis with laser-induced
      fluorescence detector (CE-LIF). IL-1beta (5 ng/ml) significantly (P < 0.05)
      increased NO production 3.7-fold in elderly female VSMCs and 6.7-fold in elderly
      male VSMCs, but had no detectable effect in young female and male VSMCs. Basal
      iNOS mRNA levels (assessed by RT-PCR/CE-LIF) were dramatically higher in VSMCs of
      elderly male rats compared to young ones. In general, VSMCs of elderly rats
      showed much greater sensitively to iNOS-inducing actions of IL-1beta. These data
      give new insight into effects of aging on iNOS expression in VSMCs, showing
      dramatic increases in both basal and stimulated iNOS mRNA levels, which may
      contribute to the development of vascular diseases in the elderly.

PMID- 15036397
TI  - Effects of aerobic exercise training on the protein kinase B (PKB)/mammalian
      target of rapamycin (mTOR) signaling pathway in aged skeletal muscle.
AB  - The protein kinase B (PKB)/mammalian target of rapamycin (mTOR) signaling pathway
      is thought to play a critical role in the regulation of protein synthesis and
      skeletal muscle mass. The purpose of the present study was to determine the
      effects of voluntary wheel running on the PKB/mTOR signaling pathway in muscles
      from aged mice (20-22 months). The total levels of mTOR were 65% higher in
      gastrocnemius muscles from aged mice subjected to wheel running compared to aged
      sedentary mice (p-0.002) PKB phosphorlation on Ser473 was 45% higher in
      gastrocnemius muscles from aged mice subjected to wheel running compared to aged
      sedentary mice (p=0.01) The total abundance of PKB was 50% higher in
      gastrocnemius muscles from wheel running mice compared to aged controls
      (p=0.005). Three months of wheel running did not alter the total amount of p70
      S6K in gastrocnemius muscle. Protein synthesis, as assessed by
      [(14)C]phenylalanine incorporation into protein was significantly higher in
      soleus muscles from aged mice subjected to wheel running compared to aged
      sedentary mice (p-0.001) These findings indicate the aerobic exercise training
      may attenuate the age-related decline in protein synthesis, a process that
      appears to be due, in part, to increases in mTOR and PKB.

PMID- 15036399
TI  - Molecular and morphological modifications occurring in rat heart exposed to
      intermittent hypoxia: role for protein kinase C alpha.
AB  - Exposure of rats to intermittent hypoxia determines different responses at tissue
      and cell level. Heart mainly undergoes the effects of hypoxic injury and its
      response is determined both by the relationship between oxygen supply and demand
      and by its functional state. Since molecular mechanisms mediate cells sensing and
      response to low O(2) concentration, here we explore the role played by Protein
      Kinase C alpha (PKC alpha) in the signal transduction mechanisms leading to the
      occurrence of morphological responses in rat neonatal, young and old heart
      subjected to intermittent hypoxia. Along with a key role for hypoxia inducible
      factor and vascular endothelial growth factor in the occurrence of continuous
      state of dynamic adaptation of vasculature, PKC alpha presumably phosphorylates
      IkBalpha in rat normoxic and hypoxic neonatal hearts, supporting the hypothesis
      of a rescue strategy carried out against hypoxia, together with an hypertrophic
      response. In hypoxic young heart PKC alpha activation, paralleled by sustained
      Bax homodimerization and caspase-3 activation, along with reduced p-IKBalpha and
      Inhibiting Apoptosis Protein (IAP) expression, suggests that the young early and
      deeply undergoes the effects of lowered oxygen tension. In addition, since no
      modifications concerning PKC alpha driven signalling system are evidenced in both
      the experimental conditions, we suggest an oxygen impaired sensing during ageing.

PMID- 15036400
TI  - Age associated changes of AGE-receptor expression: RAGE upregulation is
      associated with human heart dysfunction.
AB  - The binding of advanced glycation endproducts (AGEs) to their receptors is known
      to cause changes in cell function during normal ageing and is implicated in the
      pathogenesis of cardiovascular disease. In this study, expression of the AGE
      receptor 3 (AGE-R3) and the receptor for AGEs (RAGE) was compared on the mRNA and
      protein level in the ageing human heart. Western blot and RT-PCR analysis of the
      AGE receptors from the cardiac auricles in senescent and adult patients was
      performed and compared with young controls. Whereas the expressions of AGE-R3 as
      well as RAGE protein were significantly upregulated in the senescent population,
      only the upregulation of RAGE is associated with reduced heart function.
      Therefore, our results support a pathophysiological function for RAGE in the
      ageing human heart.

PMID- 15036401
TI  - mRNA level of alpha-2-macroglobulin as an aging biomarker of human fibroblasts in
      culture.
AB  - Cellular senescence is a well-established model system for studying the molecular
      basis of aging. To identify a reliable biomarker for cellular age and further
      study the gene expression of aging, we profiled the gene expression difference
      between aged and young cultured human embryonic lung fibroblasts by high-density
      complementary deoxyribonucleic acid (cDNA) arrays. Among the differentially
      expressed genes, alpha-2-macroglobulin (alpha(2)M) was selected for further
      study. Its gene expression level as a function of population doubling level (PDL)
      in cultured fibroblasts was determined by RT-PCR and northern hybridization. mRNA
      level of alpha(2)M showed a positive linear-correlation with cumulative PDL.
      Additional assays revealed that the levels of alpha(2)M increased in irreversible
      growth arrest induced by sublethal H(2)O(2), but not in quiescent state of
      cultured fibroblasts induced by serum-deprivation, and remained stable in Hela
      cells. These results suggest that mRNA level of alpha(2)M can be used as a
      biomarker of aging in cultured fibroblasts. mRNA level of alpha(2)M showed
      significant difference between newborn and old human leucocytes, which suggest
      that the mRNA level of alpha(2)M may be used as a biomarker of aging in vivo.

PMID- 15036402
TI  - Proteasome inhibition increases HuR level, restores heat-inducible HSP72
      expression and thermotolerance in WI-38 senescent human fibroblasts.
AB  - At the end of their replicative potential in vitro, late passage WI-38 human
      diploid fibroblasts (HDF) have a low basal expression of heat shock protein 72
      (HSP72) and an attenuated ability to induce it in response to heat shock. The
      transient exposure to the specific and reversible proteasome inhibitor MG132
      during a mild heat shock induced late passage HDF to synthesize and accumulate
      high levels of HSP72. This HSP72 expression was long-lasting and appeared to
      result from both increased cytoplasmic levels and enhanced translation of HSP72
      mRNA. The level of HuR, a stabilizing mRNA-binding protein, increased following
      the MG132 treatment. This result is consistent with the proposed role of HuR in
      assisting mRNA export to the cytoplasm and in antagonizing its degradation.
      Furthermore, the previous exposure of late passage HDF to a mild heat shock in
      the presence of MG132 protected these cells against the otherwise lethal effect
      of a subsequent severe heat shock. This acquisition of thermotolerance appeared
      to be correlated with the level of HSP72.

PMID- 15036403
TI  - Differences between recognition memory and remote memory for olfactory and visual
      stimuli in nondemented elderly individuals genetically at risk for Alzheimer's
      disease.
AB  - Recognition and remote memory for olfactory and visual stimuli were assessed in
      nondemented elderly individuals positive for the apolipoprotein E 4 allele and in
      4 negative controls to examine whether the 4 allele differentially affects
      recognition and/or remote memory depending on the modality of stimulus to be
      remembered. Compared to controls, 4 positive individuals committed more false
      positive recognition memory errors for olfactory but not visual stimuli
      suggesting that 4 positive individuals may show false positive errors for
      olfactory stimuli before deficits for other stimuli are detectable. There were no
      significant differences in familiarity ratings (a proposed measure of remote
      memory) suggesting that brain areas involved in remote memory are not affected in
      nondemented 4 positive individuals. The results suggest that neuropathological
      changes in nondemented individuals genetically at risk for Alzheimer's disease
      may differentially affect memory processes.

PMID- 15036405
TI  - Rules of evidence for models on trial.

PMID- 15036404
TI  - Plasma homocysteine and inflammation in elderly patients with cardiovascular
      disease and dementia.
AB  - Increased levels of plasma total homocysteine (tHcy) may play a role in both
      cardiovascular diseases (CVD) and old-age dementias via enhancement of vascular
      inflammation. However, the association between plasma tHcy and serum C-reactive
      protein (sCRP), taken as a marker of low-grade inflammation, is still uncertain.
      We investigated this association in normal aging, CVD, and dementia, and examined
      whether it was modified by the presence of two major comorbid diseases of older
      age: chronic obstructive pulmonary disease (CPOD) and peptic ulcer (PU). Six
      hundred-twenty-seven individuals aged > or = 65 yr (74+/-7 yr) were selected for
      this study: 373 healthy controls; 160 patients with CVD but no evidence of
      comorbid diseases (CVD+/comorbidity-); 46 patients with CVD and concurrent CPOD
      and/or PU (CVD+/comorbidity+); and 48 patients with dementia. A positive
      association between plasma tHcy and serum CRP, independent of several confounders
      (socio-demographic status, known tHcy and sCRP determinants, inflammation
      markers, traditional vascular risk factors), was found for CVD+/comorbidity+
      (p=0.001; not affected by dementia type) and dementia (p=0.001; not affected by
      dementia type), but not for CVD+/comorbidity- and controls. The results suggest
      that the association between plasma tHcy and sCRP is more an aspecific reflection
      of poor health than a specific correlate of vascular inflammation.

PMID- 15036407
TI  - Einstein's Institute for Aging Research: collaborative and programmatic
      approaches in the search for successful aging.
AB  - While aging research has been progressing rapidly recently, the involvement of
      multiple organs and systems in the aging process has hampered a comprehensive
      assessment of some of aging's basic features. In response to this problem, the
      Institute for Aging Research at Einstein did not emerge out of the traditional
      geriatric programs, but through enhanced collaborations between basic and
      clinical scientists who had successful careers in the research of a specific
      organ or system. The strength of the Center derives from three specific programs
      focused on a specific area of aging research. The programs focus on the Biology
      of Aging, Genetics of Aging and the Aging Brain. Each programmatic area is
      characterized by collaboration between basic and clinical scientists. In addition
      to addressing the traditional questions about the mechanisms of involution, the
      programs also examine the mechanisms for exceptional and healthy longevity. The
      mechanisms favoring longevity are being examined in models of caloric restriction
      (biological nutrient sensing pathways), in human centenarians (longevity genes),
      and in longitudinal studies identifying humans who maintain excellent cognitive
      function (protection from Alzheimer's). Each programmatic area is enhanced by
      common research core laboratory and by the creation of a scientific training
      program for new investigators. In addition to the investigators involved in the
      program project, the Institute for Aging Research includes other investigators
      with funded aging research who participate in journal clubs, seminars, and in
      specific collaborations. We suggest that this Institute serve as a model that
      gerontologists at other institutions should consider as they evaluate
      opportunities for collaborative, multi-disciplinary approaches to enhance aging
      research.

PMID- 15036408
TI  - Life expectancy in Germany until 2050.
AB  - The expected demographic shifts-already having commenced in many countries-have
      their origin primarily in decreasing birth rates and increased life expectancy.
      This paper will show possible development paths for life expectancy at birth up
      until the year 2050. We will distinguish between traditional period life tables
      and cohort life tables, the latter leading to more realistic values for life
      expectancy. It will be shown that a marked increase in life expectancy up to over
      90 years is to be expected.

PMID- 15036409
TI  - AT-hook proteins stimulate induction of senescence markers triggered by 5
      bromodeoxyuridine in mammalian cells.
AB  - 5-Bromodeoxyuridine (BrdU) induces a phenomenon similar to cellular senescence in
      mammalian cells. To address an underlying molecular mechanism in this phenomenon,
      we assessed the role of AT-hook proteins that bind to the minor grooves of
      specific AT-rich sequences. We expressed DsRed-tagged HMGI, MATH2, and MATH20
      proteins in HeLa cells in a doxycycline dependent manner. Modest expression of
      these proteins revealed no apparent effect on the cells although high levels of
      expression were toxic to the cells. In contrast, their modest expression in the
      presence of low concentrations of BrdU similarly and dose-dependently induced
      senescence markers examined, although the same concentrations of BrdU alone
      showed no obvious effect. In both cases, DsRed fluorescence was mainly observed
      as foci or intense dots on Hoechst 33342-staining regions. These distribution
      patterns were not changed by addition of BrdU. Since AT-hook domains can displace
      chromatin compacting proteins pre-bound on AT-rich sequences, these results
      suggest that chromatin unpacking is one of the factors stimulating expression of
      the senescence markers in human cells.

PMID- 15036410
TI  - Detection of the 4977 bp deletion of mitochondrial DNA in different human blood
      cells.
AB  - As recently reported, it is possible to detect and quantify the amount of the
      deleted human mitochondrial DNA (mtDNA) in whole blood, platelets and peripheral
      blood mononuclear cells using real-time PCR. The aim of this study was to
      identify the cell types in human blood carrying the 4977 bp deleted mtDNA and
      their accumulation with regard to donor age. Whole blood from 10 healthy donors
      (five individuals aged from 19 to 22 years, five aged from 57 to 61 years) was
      separated in various cell populations such as granulocytes, B cells/monocytes and
      T cells. Purity of the cell isolates was determined by flow cytometry. Total DNA
      was extracted and 250 ng DNA of each cell type was subjected to PCR using
      fluorescent-labelled primer pairs. The specific PCR product of the 4977 bp
      deletion was quantified using an automated detection system. The accumulation of
      the 4977 bp deletion was more pronounced in T lymphocytes and granulocytes in
      comparison to B lymphocytes/monocytes. The amount of the 4977 bp deletion in
      whole blood varied from 0 to 0.00018%, in T lymphocytes from 0.00009 to 0.00160%,
      in granulocytes from 0 to 0.00162% and in the B lymphocyte/monocyte fraction from
      0 to 0.00025%. The higher amount of the deletion in T lymphocytes may be due to a
      subset of lymphocytes with a longer lifespan thus facilitating the accumulation
      of mitochondrial damage. The higher amount in granulocytes could have the
      explanation in the higher release of free radicals for prevention of infectious
      diseases, because free radicals are supposed to damage the macromolecules of this
      cell type. The 10 donors displayed differences in the pattern of the accumulation
      with regard to the different cell types, but no age-dependent accumulation was
      observed. Differences of the accumulation pattern may be due to actual individual
      living behaviour or environmental factors.

PMID- 15036411
TI  - Coenzyme Q supplementation protects from age-related DNA double-strand breaks and
      increases lifespan in rats fed on a PUFA-rich diet.
AB  - This study investigates the usefulness of a long-term supplementation with
      coenzyme Q(10) in rats from the point of view of lifespan, DNA double-strand
      breaks and to assess whether this supplementation might attenuate oxidative
      alterations related to PUFA-rich diets, which would allow to preserve beneficial
      aspects of PUFA on health avoiding their deleterious aspects. Supplemented
      animals showed higher concentration of coenzyme Q(10) in liver mitochondria,
      lower levels of DNA double-strand breaks in peripheral blood lymphocytes. Animals
      supplemented on coenzyme Q reached a significantly higher mean life span (11,7%
      higher, i.e. 2,5 months) and a significantly higher maximum life span (24%
      higher, i.e. 6 months) than non-supplemented animals. These results suggest that
      a long-term supplementation with a small dosage of coenzyme Q(10) might represent
      a good anti-aging therapy in rats fed on a PUFA-based diet.

PMID- 15036412
TI  - Aging increases DNase gamma, an apoptosis-related endonuclease, in rat liver
      nuclei: effect of dietary restriction.
AB  - Organ-specific endonuclease might play a role in the age-related increase in
      apoptosis in laboratory rodent tissues. In nuclear extracts from liver tissues of
      male F344 rats, the DNase activity gel system identified DNase gamma,
      Ca(2+)/Mg(2+)-dependent endonuclease. The enzyme activity, which was measured at
      3, 6, 16, and 24 months (mo) of age, was significantly increased between 16 and
      24mo in control rats fed ad libitum (AL). The expression level of DNase gamma
      mRNA, estimated by a semi-quantitative reverse transcription-polymerase chain
      reaction method, was also increased at 24mo in group AL. The proportion of
      immunohistochemically DNase gamma-positive cells, most of which were light
      microscopically confined to apoptotic cells, was also significantly increased
      between 16 and 24mo. Dietary restriction, a powerful anti-aging intervention,
      which was achieved by providing 70% of the mean food intake in group AL from 6
      weeks of age, inhibited the age-related increase in the enzyme activity and the
      proportion of immunostained cells; for the mRNA level, statistical significance
      was not obtained. The present study suggests that DNase gamma is involved in an
      age-related increase in the apoptosis of rat liver, and that CR inhibits the
      increase as it minimized the age-related increase in the fraction of DNA-damaged
      hepatocytes susceptible to apoptosis.

PMID- 15036413
TI  - Age-related changes in glutathione availability and skeletal muscle carbonyl
      content in healthy rats.
AB  - The free radical theory of aging proposes that oxidative stress plays a key role
      in the aging process. By altering muscle protein degradation rates, it could
      accelerate the age-related loss of muscle proteins. Glutathione (GSH), one of the
      main body antioxidants, could prevent this phenomenon, but its concentration
      decreases during aging. Our aims were to have a better understanding of the
      mechanisms of the age-related decrease in glutathione availability and of the
      links with sarcopenia. Male Wistar rats aged 6, 9, 12, 15, 19, 22, 25 and 28
      months (n = 6 per age) were used to measure plasma and skeletal muscle protein
      carbonyl content, plasma total and free cyst(e)ine content, liver and muscle
      glutathione content as well as liver GSSG reductase, GSH peroxidase, GSH
      transferase and gamma glutamyl cysteine synthetase (GCS) activities. Although
      tissue glutathione content decreased with age, the other markers of oxidative
      stress were little changed during aging. In particular, muscle protein carbonyl
      content was unchanged. Variations in glutathione availability were not explained
      by cyst(e)ine availability but depended on gamma GCS activity. The stability of
      skeletal muscle carbonyl content during aging suggests a very efficient
      degradation of oxidized proteins in muscle.

PMID- 15036414
TI  - Changes in glucose-6-phosphate dehydrogenase, copper, zinc-superoxide dismutase
      and catalase activities, glutathione and its metabolizing enzymes, and lipid
      peroxidation in rat erythrocytes with age.
AB  - We have studied the activities of enzymes (glucose-6-phosphate dehydrogenase (G-6
      PD), copper, zinc-superoxide dismutase (Cu,Zn-SOD), catalase (CAT), selenium
      dependent glutathione peroxidase (Se-GSH-Px) and glutathione-S-transferase
      (GST)), and the levels of reduced glutathione (GSH), oxidized glutathione (GSSG)
      and thiobarbituric acid-reactive substances (TBARS) in rat erythrocytes and
      estimated the ratio of GSH/GSSG and the redox index. Male Wistar rats at ages of
      1, 6 and 12 months were used. The activities of G-6-PD and Cu,Zn-SOD, the levels
      of GSSG and TBARS were increased, while the activity of Se-GSH-Px and the level
      of GSH were decreased with age. GSH/GSSG ratio was significantly decreased with
      age. We found a positive correlation between age and G-6-PD (r=0.476, p<0.01),
      Cu,Zn-SOD (r=0.291, p<0.01), CAT (r=0.254, p<0.01) and GST activities (r=0.250,
      p<0.05), and GSSG (r=0.708, p<0.05) and TBARS levels (r=0.802, p<0.01), whereas
      the correlation between age and Se-GSH-Px activity (r=-0.376, p<0.05), GSH level
      (r=-0.603, p<0.01) and GSH/GSSG ratio (r=-0.685, p<0.05) were negative. We found
      age-related differences in erythrocyte antioxidant enzyme activities, GSH, GSSG,
      total GSH and TBARS levels, GSH/GSSG ratio and the redox index.

PMID- 15036415
TI  - Age-related changes of muscarinic cholinergic receptor subtypes in the striatum
      of Fisher 344 rats.
AB  - Striatum expresses a cholinergic system involved in the regulation of its
      activity and changes in striatal cholinergic receptors may be related to
      cognitive impairment. This study has investigated muscarinic cholinergic M1-M5
      receptor subtype expression in striatum of Fischer 344 rats aged 6 (young), 15
      (adult) and 22 months (senescent) to assess the contribution of different
      muscarinic cholinergic receptor subtypes in age-related changes of striatal
      cholinergic neurotransmission. Western blot analysis revealed the expression of
      the M1-M5 muscarinic receptor subtytpes in the striatum of rats of the three age
      groups investigated. Both radioligand binding assay and light microscope
      autoradiography showed in young rats a M4>M1>M2>M3>M5 rank order of receptor
      density. With the exception of M1 receptor, the density of which is similar in
      the dorsal (motor) and ventral (limbic) striatum, other receptor subtypes were
      more abundant in ventral than in dorsal striatum. M1 receptor expression was
      unchanged between young and adult rats and decreased in senescent animals both in
      dorsal and ventral striatum. In dorsal striatum M2 and M5 receptor expression did
      not show age-related changes, whereas in ventral striatum it was slightly
      decreased in adult rats compared to young or senescent cohorts. M3 receptor
      expression did not show age-related modifications, whereas a progressive age
      related decrease of M4 receptor was found, both in dorsal and ventral striatum.
      These data indicate a heterogeneous response to age of different muscarinic
      receptor subtypes. Striatal cholinergic markers are thought to correlate with
      cognitive impairment in aged rats. In view of this, the identification of age
      related changes of striatal muscarinic receptor subtypes may contribute to
      develop cholinergic strategies to counter cholinergic neurotransmission changes
      occurring with aging.

PMID- 15036416
TI  - Cellular defense against oxidized low density lipoproteins and fibrillar amyloid
      beta in murine cells of monocyte origin with possible susceptibility to the
      oxidative stress induction.
AB  - Reactive oxygen species (ROS) are associated with aging and the correlation
      between Alzheimer's disease and atherosclerosis is a subject of the discussion.
      The aim of this study was to determine whether genetic factors affect cellular
      defense against cytotoxic beta-amyloid (Abeta) which is considered to be the
      source of ROS. Low levels of Abeta (1-10 microM) led to a significant suppression
      of redox potential as measured by MTT assay in bone marrow-derived cell lines.
      The atherosclerosis-resistant cells (GG2EE) were less affected than the
      susceptible cells (ANA1) in the time-, dose-, and Abeta species-dependent manner.
      Cell death in amyloid treated resident susceptible macrophages (C57BL/6J),
      measured by lactate dehydrogenase release, was induced during prolonged
      incubation and increased when compared with the resistant macrophages (C3H/HeJ, P
      = 0.005). SDS-PAGE showed that Abeta persisted intracellularly during this
      period. The cytotoxicity of oxidized low density lipoproteins (oxLDLs)
      significantly affected only the susceptible cells which actually lowered this
      cytotoxicity, thus, implying that the harmful effect of the oxLDLs was diminished
      when compared to that of Abeta. This fact demonstrates that in vitro the defense
      by cells of monocyte origin against Abeta may be determined in part genetically
      whereas the reaction to oxLDLs could be fully underlined by genetic
      susceptibility.

PMID- 15036417
TI  - Age-related effects on genital reflexes induced by paradoxical sleep deprivation
      and cocaine in rats.
AB  - Although sexual function often decreases with age, a recent study demonstrated
      that paradoxical sleep deprivation (PSD) was effective in inducing penile
      erection (PE) in 60% of 22-month-old PSD rats after acute cocaine injection,
      whereas this behavior was absent in non-PSD control rats. The present study
      sought to compare alterations in genital reflexes (PE and ejaculation-EJ) induced
      by PSD followed by acute cocaine or saline at different points in the life span
      of male rats. Rats of different ages (3, 6, 10, 12, 18, 22 and 28 months), were
      given a single injection of either saline or cocaine (7 mg/kg, i.p.) after a 4
      day period of PSD, and then evaluated for genital reflexes. Results indicated
      that genital reflexes in PSD rats given saline become less frequent with age and
      disappear after the age of 18 months. However, cocaine potentiated and prolonged
      these behaviors until the age of 22 months. Although a number of factors are
      involved in such a complex phenomenon as PE, we suggest that the previously
      documented dopamine receptor supersensitivity induced by PSD may be an important
      contributor to the potentiation by cocaine of genital reflexes after sleep
      deprivation.

PMID- 15036418
TI  - In vivo visualization of aging-associated gene transcription: evidence for free
      radical theory of aging.
AB  - The expression of a variety of proteins is elevated with aging through unknown
      mechanisms. The free radical theory of aging promulgates that reactive oxygen
      species (ROS) promote the aging process. However, the mechanisms as to how ROS
      contribute to the aging process are not clear. We present data here that
      demonstrate that aging induced ROS promote aging-associated interleukin-6 (IL-6)
      gene transcription in mice that are transgenic for the murine IL-6 promoter
      driving a luciferase reporter cDNA. N-acetylcysteine (NAC), an antioxidant,
      completely reverses the increased endogenous IL-6 promoter activity in the old
      mice determined by real-time bioluminescence imaging (BLI). We conclude that
      ability of ROS to act as secondary messengers and induce gene expression may
      contribute to the aging process.

PMID- 15036419
TI  - Age-related changes in the glycation of human aortic elastin.
AB  - Non-enzymatic glycation of proteins is a consequence of hyperglycemia in diabetes
      and correlates with aging. The aim of the study was to investigate age-related
      changes in the glycation of human aortic elastin in healthy subjects by two
      approaches: (1) assessment by fluorescence method of formed in vivo advanced
      glycation end products (AGEs) of elastins, purified from human aortas, obtained
      from different age groups; (2) in vitro glycation of elastins from different age
      groups and investigation of their capacity to form early (by colorimetric
      nitroblue tetrazolium method) and AGEs (fluorescence method). Human insoluble
      elastins were prepared from macro- and microscopic unaltered regions of thoracic
      aortas, obtained from 68 accident victims, distributed in 15 age-groups, using
      the method of Starcher and Galione. Soluble alpha-elastins were obtained by the
      method of Partridge et al. The direct assessment of Maillard reaction related
      fluorescence in the age groups showed increase of the fluorescence with age. The
      'young' elastin had the highest capacity to form both fructosamine and AGEs under
      glycation in vitro. The glycation of 'old' elastin did not increase markedly
      during the incubation. These results are consistent with the interpretation that
      because of its long biological half-life, elastin is susceptible to the slow
      process of glycation and the following modifications would contribute to the age
      related changes of connective tissue.

PMID- 15036420
TI  - The IL-6 -174G>C polymorphism is associated with cardiovascular diseases and
      mortality in 80-year-old humans.
AB  - Chronic low-grade elevations in circulating levels of interleukin (IL)-6 act as a
      marker of subclinical cardiovascular diseases (CVD) and provide an independent
      predictor of increased mortality in elderly populations. The purpose of the
      present study was to test the hypothesis that the IL-6 -174G>C promoter
      polymorphism was associated with a high prevalence of CVD and acted as an
      independent predictor of mortality in a longitudinal study of 324 relatively
      healthy 80-year-old people with a history of CVD in 18% of the cases. The C
      allele was associated with elevated serum levels of IL-6 at baseline and the CC
      genotype had a high prevalence of CVD. A Cox regression model was used to explore
      the effect of the polymorphism on survival in the following six years. A
      significant interaction was found between smoking status and the polymorphism.
      Thus, C allele carrier status was associated with increased all-cause mortality
      risk in non-smokers independently of sex, body mass index, co-morbidity, and low
      grade elevations in serum levels of IL-6. This effect was not detected among
      smokers. We conclude that the IL-6 -174G>C polymorphism was an independent
      predictor of all-cause mortality in octogenarians but the effect was complex and
      interacted with the smoking status.

PMID- 15036421
TI  - Variation in the SHC1 gene and longevity in humans.
AB  - Mice in which the p66(SHC) specific region of the SHC gene is deleted live 30%
      longer without apparent disease. These mice have lower levels of oxidative stress
      and apoptosis, both of which have been linked to old age survival in man. This
      makes SHC1 an important candidate gene for longevity in humans. We found no
      variations in the p66 specific region of the SHC1 gene in 30 young and 30 extreme
      long-lived subjects. Thus in man, no common sequence variations occur in p66
      specific region of the SHC1 gene. In two independent cohorts of respectively 730
      and 563 subjects aged 85 and over, we tested the only known non-synonymous
      polymorphism, Met(410)Val, for association with longevity using a prospective
      follow-up design. In the first cohort, we found increasing valine allele
      frequency in three strata of increasing age at death (2.8-5.2%). Moreover,
      compared to Met/Met carriers, mortality rate was a factor of 0.71 (95% CI 0.45
      1.13) reduced for Met/Val carriers in the combined cohorts, with similar risk
      estimates in both cohorts. Low valine allele frequency resulted, however, in low
      power to detect statistical significance. These data suggest that an association
      between the Met(410)Val polymorphism and longevity in humans may exist.

PMID- 15036422
TI  - A transgenic dwarf rat model as a tool for the study of calorie restriction and
      aging.
AB  - We have previously reported a long-lived transgenic dwarf rat model, in which the
      growth hormone (GH)-insulin like growth factor (IGF)-1 axis was selectively
      suppressed by overexpression of antisense GH transgene. Rats heterozygous for the
      transgene (tg/-) manifest phenotypes similar to those in calorie-restricted (CR)
      rats. To further characterize the transgenic rat in comparison with CR rats, the
      present study evaluated glucose and insulin tolerance in tg/- and control Wistar
      (-/-) rats at 6-9 months of age. Rats were fed ad libitum (AL) or 30% CR from 6
      weeks of age. In CR rats, glucose disposal after glucose load was facilitated
      without any significant surge of serum insulin, and insulin tolerance test also
      indicated increased insulin sensitivity. In transgenic rats, similar findings
      were observed after glucose and insulin load, and CR in tg/- rats further
      facilitated glucose disposal during glucose and insulin tolerance tests. These
      findings suggest the presence of both common and separate mechanisms regulating
      the glucose-insulin system between CR and the reduced GH-IGF-1 axis paradigms.
      The transgenic rat model is, therefore, a useful one for studies of CR and aging.

PMID- 15036423
TI  - Drop of connexins: a possible link between aging and cancer?
AB  - The incidence of cancer increases with age but we do not know why. As a working
      hypothesis we propose here that cells somehow initiated in vivo in the course of
      life and finally engaged in the aging program, which involves a drop of connexins
      with loss of cell-to-cell communication (equivalent to the promotion phase in the
      multistep process of carcinogenesis), may recover their growth potential, thus
      allowing cancer to progress. This is supported by evidence that: (i) connexin 43
      (Cx43) acts as a tumor suppressor; (ii) cx43 and gap junction intercellular
      communication drop in precancerous lesions and in tumors of various origins, as
      well as in aging cells; (iii) telomerase is activated in cancerous somatic cells.

PMID- 15036424
TI  - Founders of child neurology in Japan--Shunsuke Ohtahara.

PMID- 15036425
TI  - Clinical disorders of brain plasticity.
AB  - Clinical disorders of brain plasticity are common in the practice of child
      neurology. Children have an enhanced capacity for brain plasticity compared to
      adults as demonstrated by their superior ability to learn a second language or
      their capacity to recover from brain injuries or radical surgery such as
      hemispherectomy for epilepsy. Basic mechanisms that support plasticity during
      development include persistence of neurogenesis in some parts of the brain,
      elimination of neurons through apoptosis or programmed cell death, postnatal
      proliferation and pruning of synapses, and activity-dependent refinement of
      neuronal connections. Brain plasticity in children can be divided into four
      types: adaptive plasticity that enhances skill development or recovery from brain
      injury; impaired plasticity associated with cognitive impairment; excessive
      plasticity leading to maladaptive brain circuits; and plasticity that becomes the
      brain's 'Achilles' Heel' because makes it vulnerable to injury. A broad group of
      pediatric neurologic disorders can be understood in terms of their impact on
      fundamental mechanisms for brain plasticity. These include neurofibromatosis,
      tuberous sclerosis, Fragile X syndrome, other inherited forms of mental
      retardation, cretinism, Coffin-Lowry syndrome, lead poisoning, Rett syndrome,
      epilepsy, hypoxic-ischemic encephalopathy and cerebral palsy.

PMID- 15036426
TI  - The dissociation of perception and cognition in children with early brain damage.
AB  - Reduced non-verbal compared to verbal intelligence is used in many outcome
      studies of perinatal complications as an indication of visual perceptual
      impairment. To investigate whether this is justified, we re-examined data sets
      from two previous studies, both of which used the visual perceptual battery L94.
      The first study comprised 47 children at risk for cerebral visual impairment due
      to prematurity or birth asphyxia, who had been administered the McCarthy Scales
      of Children's abilities. The second study evaluated visual perceptual abilities
      in 82 children with a physical disability. These children's intellectual ability
      had been assessed with the Wechsler Intelligence Scale for Children-Revised
      and/or Wechsler Pre-school and Primary Scale of Intelligence-Revised. No
      significant association was found between visual perceptual impairment and (1)
      reduced non-verbal to verbal intelligence; (2) increased non-verbal subtest
      scatter; or (3) non-verbal subtest profile deviation, for any of the intelligence
      scales. This result suggests that non-verbal intelligence subtests assess a
      complex of cognitive skills that are distinct from visual perceptual abilities,
      and that this assessment is not hampered by deficits in perceptual abilities as
      manifested in these children.

PMID- 15036427
TI  - Subtle brain dysfunction in treated 6-pyruvoyl-tetrahydropterin synthase
      deficiency: relationship to motor tasks and neurophysiological tests.
AB  - 6-Pyruvoyl-tetrahydropterin synthase (6PTPS) deficiency is a major cause of
      biopterin deficiency. 6PTPS patients usually have an elevated serum phenylalanine
      level, a deficiency of neurotransmitters (serotonin and dopamine), and
      neurological symptoms, if without treatment. We herein investigated the
      possibility of neurological dysfunction in early-treated patients. In the study,
      12 early-treated 6PTPS patients were studied. Their auditory simple reaction
      time, movement rhythm variation (MRV), somatosensory evoked potentials to median
      nerve stimulation, and hand muscle responses to transcranial magnetic
      stimulation, were measured. MRV is a test of repetitive voluntary movements, and
      was used with and without auditory cues at 0.3 Hz. The 6PTPS patients had an
      increased motor threshold but normal motor and sensory central conduction times.
      They performed very well in simple reactions (6PTPS 208.4+/-16.7 ms, control
      200.3+/-11.7 ms, p=0.18), but not in continuous tasks. The continuous performance
      tests showed that MRV had increased in the 6PTPS patients (with cues: 6PTPS
      7.35+/-0.94, control 5.47+/-0.80, p<0.0001; without cues: 6PTPS 9.87+/-1.44,
      control 6.59+/-0.68, p<0.0001). Without cues, MRV had increased in both the 6PTPS
      and control groups, but more significantly in the 6PTPS patients (6PTPS 2.51+/
      0.97, control 1.25+/-0.42; p=0.0001). Our findings indicate that early-treated
      6PTPS patients have subtle neurological dysfunctions. They may not maintain
      movement rhythm as well as normal subjects, even with external cues. Hence, MRV
      is a good method to assess motor control.

PMID- 15036428
TI  - Somatosensory evoked potentials in Arnold-Chiari malformation.
AB  - Nearly all patients with repaired myelomeningoceles have an Arnold-Chiari (AC)
      malformation and about 20% of these patients develop clinical signs of brainstem
      dysfunction. The management of symptomatic AC malformation is still controversial
      and techniques are needed to provide an objective assessment of brainstem
      function. We recorded somatosensory evoked potentials (SEPs) in 52 patients aged
      between 8 months and 20 years (median 7.3 years) with AC malformation, to
      determine whether the SEPs discriminate patients with symptomatic AC malformation
      from those without symptoms. The subcortical far-field components P13, P14 and
      N18, which are generated within the brainstem, were recorded with non-cephalic
      reference electrodes and the cortical N20 with a frontal reference. Fourteen
      patients (27%) had signs and symptoms of brainstem dysfunction, which were
      related to the AC malformation. Abnormal SEPs were mainly recorded in symptomatic
      patients (sensitivity 0.7, specificity 0.9). The SEPs were particularly useful in
      patients from 4 years of age (sensitivity 0.9, specificity 0.9), but not in the
      younger age group. Abnormal somatosensory conduction reflects dysfunction of the
      brainstem or the upper cervical cord and may be clinically useful to assess
      patients with late onset symptomatic AC malformation.

PMID- 15036429
TI  - A study of spike-density on EEG in West syndrome.
AB  - To elucidate the pathophysiology of spasms in series, the distribution and
      density of spikes on hypsarrhythmia were studied in 13 patients with West
      syndrome by excluding slow waves from EEG using a digital filter. (1) Interictal
      spikes were mostly multifocal and dominant over the bilateral posterior head area
      with very few diffuse discharges. Therefore, spikes on hypsarrhythmia were
      demonstrated to occur actually depending on the brain regions although they
      appeared random. (2) The dominant region of interictal spikes did not correspond
      to the underlying focal cortical lesion in many patients, and was indicated to
      reflect the general process of cerebral maturation in infancy. (3) There were far
      fewer inter-spasm spikes, especially during the middle phase of a series of
      spasms, than interictal spikes. It was implied that the cortical activity of
      hypsarrhythmia was interfered with by the abnormal subcortical function, which
      might be related to the generation of spasms. (4) The dominant region of inter
      spasm spikes tended to coincide with a focal cortical lesion shown by MRI and the
      focus of associated partial seizures.

PMID- 15036430
TI  - Post-traumatic syndrome after minor head injury cannot be predicted by
      neurological investigations.
AB  - The aim of this study is to investigate predictive factors of post-traumatic
      syndrome in children with minor head injury. Prospective neurological,
      electroencephalographic and psychological investigations were performed in 98
      children aged 3-13 years within 24 h after the trauma and 4-6 weeks later.
      Inclusion criteria for mild head injury were unconsciousness <10 min or none at
      all, lack of overt neurological symptoms and other complications requiring
      intensive care. Twenty-six of the children had been unconscious for a short
      period. Ten had suffered a skull fracture. Within the first 24 h, nearly all
      children reported acute symptoms of concussion and 64 of 98 showed abnormal EEG
      findings. After 4-6 weeks, 23 of 98 still exhibited post-traumatic complaints
      with headache, fatigue, sleep disturbances, anxiety and affect instability. Such
      post-traumatic symptoms did not correlate with somatic, neurological or
      electroencephalographic findings observed immediately after the injury or at the
      follow-up investigation. As opposed to the situation in more severe head trauma,
      post-traumatic syndrome after minor head injury in children is apparently not due
      to central nervous injury detectable by neurological examination or
      electroencephalography. Irrespective of the necessity of neuroradiological
      investigations and repeated EEGs in more severe and complicated head trauma, we
      discourage the routine EEG examination in very slight head injury and instead
      rather recommend parent and patient counselling.

PMID- 15036431
TI  - Motor outcome differences between two groups of children with spastic diplegia
      who received different intensities of early onset physiotherapy followed for 5
      years.
AB  - The objective of this study is to determine the clinical effectiveness of early
      onset long-term intensive physiotherapy on motor development in children with
      spastic diplegic cerebral palsy (CP). The study was a non-randomized cohort study
      with 62 months (mean) follow-up. The participants were ten infants who were first
      examined before 3 months of age corrected for prematurity. All had a gestational
      age of less than 33 weeks and a birth weight of less than 2000 g. Brain magnetic
      resonance imaging revealed periventricular white matter injury in nine subjects
      and moderate grade bilateral porencephaly in one. Five completed a full course of
      training of 52 months (mean), two did not receive therapy, and three received an
      insufficient course of therapy. The study was conducted at the Regional Center
      for Children with Disabilities including outpatient clinics and a school for
      children with special needs. The Vojta Method was used, which is an extensive
      family oriented physiotherapy program which uses isometric strengthening of
      muscles with tactile stimulation. Subjects were evaluated for the highest motor
      developmental level at the outcome evaluation 59 months (mean) after initiation
      of therapy. Four of the five who completed training could either stand still for
      5 s or walk at the time of the outcome evaluation 52 months after the beginning
      of the therapy program. None of the five subjects with no training or
      insufficient training could accomplish this task when evaluated 64 months
      following therapy initiation. This was a statistically significant difference (P
      = 0.0278). A consistently applied physiotherapy program resulted in better motor
      outcomes in this group of children at risk for developing spastic diplegic CP.

PMID- 15036433
TI  - Startle epilepsy complicating aspartylglucosaminuria.
AB  - A 21-year-old right-handed man with definite diagnosis of aspartylglucosaminuria
      (AGU) presented with a 5-year history of progressive severe gait disturbance with
      frequent falls and generalized epileptic seizures triggered by unexpected
      stimuli. At one time, he was confined to a wheelchair because of the frequent
      falls. Electromyogram recording showed a large, excessive and not habituating
      motor startle response, with the classical and stereotyped order of muscle
      recruitment. During video-polygraphic recording, we recorded a reflex generalized
      tonic seizure triggered by a loud, unexpected acoustic stimulus. Brain magnetic
      resonance (MR) revealed no structural abnormality. A diagnosis of abnormal
      startle and startle epilepsy (SE) was made. The addition of clonazepam to
      valproate and phenobarbital led to a dramatic improvement in his abnormal startle
      and SE, and the patient was able to walk alone unaided. This report illustrates,
      for the first time, that abnormal startle and SE may occur in AGU and complicate
      its clinical picture. Recognition of this entity in AGU is important, as
      progressive gait disorder with frequent falls could be easily misinterpreted as
      an additional irreversible manifestation of the ongoing neurological
      deterioration characteristic of AGU.

PMID- 15036432
TI  - Use of developmental language scales in Chinese children.
AB  - The Reynell Developmental Language Scale (RDLS) and Symbolic Play Test (SPT) have
      been useful language tests for assessing the language age of children. Both tests
      have been validated in English-speaking children. However, there have been no
      studies conducted for Chinese children, whether Mandarin (Northerners) or
      Cantonese (Southerners) is used as the main dialect. As the Chinese population is
      the largest ethnic group in the world, and Chinese emigration occurred to nearly
      all parts of the world, it is essential to test whether these language tools can
      be applied for this ethnic group. The objective of this research was to study
      whether RDLS and SPT are useful in assessing the language age of Chinese
      children. Both RDLS (Chinese version) and SPT are conducted for 116 Chinese
      (Cantonese-speaking) children, aged 13-59 months, in Hong Kong. There is a
      significant positive correlation of the language age using RDLS and SPT with the
      chronological age of Chinese children. Both RDLS and SPT can be adopted in
      determining the language/mental age of Chinese (Cantonese-speaking) children.

PMID- 15036434
TI  - Right thalamic hemorrhage resulting from high-voltage electrical injury: a case
      report.
AB  - A 12-year-old boy was admitted with electrical burn and loss of consciousness. On
      physical examination his general condition was poor. Extensive burn areas, second
      and third degree, were present on his face, scalp, bilateral auricles, right
      cervical region, shoulders, right axilla, upper region of the thorax, and
      proximal region of the upper extremities. The total burned surface area was about
      25%. Pupils were isocoric, but response to light was bilateral poor. He was
      stuporous and responsive only to pain. Deep tendon reflexes were exaggerated and
      plantar responses were bilateral extensor. Bilateral decorticate rigidity was
      noted. Computerized tomography of brain revealed brain edema and right thalamic
      hemorrhage. Magnetic resonance imaging of brain, examined 25 days after
      admission, revealed right thalamic hemorrhage and mild right subdural effusion.
      He was discharged form hospital 40 days after admission. However, spastic
      quadriplegia and severe mental retardation remained as sequela. On the 4th month
      of follow-up, no improvement was noted in his neurological examination. On the
      9th month of follow-up, his clinical condition was better, but bilateral electric
      cataract was diagnosed. Both eyes were operated on and intraocular lenses were
      implanted with good results. Now he is 16th month of follow-up: neurological
      examination revealed only mild hemiparesis on the left side and mild articulation
      disorder. His school performance was moderate and intelligence quotient was 71.
      Magnetic resonance imaging of brain showed markedly improvement of the
      hemorrhage. To our best knowledge thalamic hemorrhage resulting from high-voltage
      electrical injury has not previously been reported in the literature.

PMID- 15036435
TI  - Severe congenital factor X deficiency with intracranial bleeding in two siblings.
AB  - Congenital factor X deficiency is a rare autosomal recessive disorder that
      usually presents with variable bleeding tendency, prolonged prothrombin time and
      partial thromboplastin time. Therefore, it may be misdiagnosed as hemorrhagic
      disease of the newborn. Factor X level should be investigated for the definite
      diagnosis. We first report a new family whose two infants presented with severe
      intracranial bleeding at different times and were found to have congenital factor
      X deficiency. Plasma replacement therapy was not found to be efficacious in these
      infants. In conclusion, a possible factor X deficiency should be considered when
      a newborn presents with intracranial bleeding.

PMID- 15036436
TI  - Forensic analysis of hallucinogenic fungi: a DNA-based approach.
AB  - Hallucinogenic fungi synthesize two controlled substances, psilocin and
      psilocybin. Possession of the fungal species that contain these compounds is a
      criminal offence in North America. Some related species that are morphologically
      similar, do not contain the controlled substances. Therefore, unambiguous
      identification of fungi to the species level is critical in determining if a
      mushroom is illegal. We investigate a phylogenetic approach for the
      identification of species that contain the psychoactive compounds. We analyzed 35
      North American specimens representing seven different genera of hallucinogenic
      and non-hallucinogenic mushrooms. We amplified and sequenced the internal
      transcribed spacer region of the rDNA (ITS-1) and a 5' portion of the nuclear
      large ribosomal subunit of rRNA (nLSU rRNA or 28S). ITS-1 locus sequence data was
      highly variable and produced a phylogenetic resolution that was not consistent
      with morphological identifications. In contrast, the nLSU rRNA data clustered
      isolates from the same species and separated hallucinogen containing and non
      hallucinogen containing isolates into distinct clades. With this information, we
      propose an approach that combines the specificity of PCR detection and the
      resolving power of phylogenetic analysis to efficiently and unambiguously
      identify hallucinogenic fungal specimens for legal purposes.

PMID- 15036437
TI  - Particle size analysis of soils under simulated scene of crime conditions: the
      interest of multivariate analyses.
AB  - Two simulated scenes of crime have been studied. Soil traces adhering to boots,
      sport shoes and tissues have been compared with control samples using particle
      size analysis. Comparisons of percentage of particles per class interval and
      multivariate analyses were used to determine how the size distribution of each
      suspect sample varied compared to the original distribution. A loss of coarse
      fractions characterized most of the suspect samples even though they were derived
      from soils having different distributional patterns. However, the differences
      between control and suspect samples were found to be more important for soils
      dominated by extreme size classes than for soils rich in medium size particles.
      The differences among soil samples from the same source were found to be
      restricted to the extreme size classes. The finding of significant differences
      within size classes ranging from 1 to 0.063 mm should be then considered as a
      dissimilarity sign between trace sample and hypothetic control soil.

PMID- 15036438
TI  - A cross-sectional study on expression of anger and factors associated with
      criminal recidivism in prisoners with prior offences.
AB  - OBJECTIVE: The purpose of this study is to determine demographical
      characteristics leading to crime recidivism and define anger levels and anger
      expression manners for those who re-commit crime. METHOD: All the literate
      inmates in Izmit Closed Penitentiary were included in this cross-sectional study.
      The prisoners were asked to respond to State-Trait Anger Expression Inventory.
      Their socio-demographic data were collected and a questionnaire was given to them
      to determine their state of imprisonment, sentence, nature of the crime in which
      they were involved, their criminal history, their relationship with inmates and
      prison staff and substance and alcohol use. RESULTS: Of the 438 prisoners, 302
      (68.9%) responded to the questionnaires. Crime recidivism among the study cohort
      was observed to be 37.4%. Mean trait anger, anger out and anger in scores were
      significantly higher in prisoners with criminal recidivism in comparison with
      those who did not have prior criminal records. However, mean anger control scores
      for prisoners with or without criminal recidivism were similar. Unemployment,
      education level completed at secondary school or below, having committed a crime
      under the influence of alcohol or narcotics, having been involved in prison
      fights, having resisted police officers, caused damage in their vicinity when
      angry and violent crimes were all found to be possible causes of criminal
      recidivism. Educational level completed at secondary school or below, getting
      into fights with other prisoners, unemployment and resisting police officers were
      determined to be the strongest indicators to predict criminal recidivism when all
      variables were considered according to a logistic regression model. CONCLUSION:
      It can be proposed that those who have problems with officials or hostile towards
      others constitute a risk group for criminal recidivism. If prisoners with
      criminal recidivism can be helped to identify and control their anger, their risk
      of committing a new crime can be minimised.

PMID- 15036441
TI  - The designer drug situation in Ibiza.
AB  - A total of 137 urine samples and 46 serum samples, corresponding to 154 self
      confessed designer drugs consumers in Ibiza island, were analyzed for the
      presence of designer drugs: amphetamine and amphetamine derivatives
      (methamphetamine, methylenedioxymethamphetamine (MDMA),
      methylenedioxyethylamphetamine (MDEA), methylenedioxyamphetamine (MDA), p
      methoxymethylamphetamine (PMMA), p-methoxyamphetamine (PMA), etc.), ketamine and
      gamma-hydroxybutyric acid. Among this population, coming both from the forensic
      clinic and from the emergency room of a hospital, a total of 99 cases were found
      positive for some designer drug. This study shows the prevalence of
      methylenedioxymethamphetamine (MDMA) among designer drug users, sole or in
      association with other drugs. Also, the mixture of MDMA with other designer
      drugs, ethanol and/or cocaine is shown to be more likely to produce toxic
      symptoms requiring clinical attendance in a hospital emergency room. These
      findings along with the consumption history, the concentrations of drugs and
      metabolites in urine and serum and the toxicological significance for the
      interpretation of some MDMA metabolites such as 4-hydroxy-3
      methoxymethamphetamine (HMMA) are discussed in this study.

PMID- 15036439
TI  - The GC-MS detection and characterization of reticuline as a marker of opium use.
AB  - Reticuline (a precursor of opium alkaloids) was detected and characterised as its
      trimethylsilyl ethers, acetyl esters and methyl ethers by GC-EIMS and GC-CIMS in
      opium and the urine of opium users after hydrolysis by acid or beta-glucuronidase
      as coextractive of morphine. Because this compound cannot be detected in heroin
      and poppy seeds, it is suggested as a differentiating marker between opium and
      heroin use, opium and poppy seeds use, or opium and "pharmaceutical" codeine use
      in cases when opiate use has been confirmed by detection of morphine and codeine
      in the urine. As well as being a constituent of opium, reticuline in the urine of
      opium users may also result from the metabolic demethylation of the three other
      benzyltetrahydroisoquinoline opium alkaloids: codamine, laudanosine and
      laudanine.

PMID- 15036442
TI  - Reference ballistic imaging database performance.
AB  - Ballistic imaging databases allow law enforcement to link recovered cartridge
      cases to other crime scenes and to firearms. The success of these databases has
      led many to propose that all firearms in circulation be entered into a reference
      ballistic image database (RBID). To assess the performance of an RBID, we fired
      4200 cartridge cases from 600 9mm Para Sig Sauer model P226 series pistols. Each
      pistol fired two Remington cartridges, one of which was imaged in the RBID, and
      five additional cartridges, consisting of Federal, Speer, Winchester, Wolf, and
      CCI brands. Randomly selected samples from the second series of Remington
      cartridge cases and from the five additional brands were then correlated against
      the RBID. Of the 32 cartridges of the same make correlated against the RBID, 72%
      ranked in the top 10 positions. Likewise, of the 160 cartridges of the five
      different brands correlated against the database, 21% ranked in the top 10
      positions. Generally, the ranking position increased as the size of the RBID
      increased. We obtained similar results when we expanded the RBID to include
      firearms with the same class characteristics for breech face marks, firing pin
      impressions, and extractor marks. The results of our six queries against the RBID
      indicate that a reference ballistics image database of new guns is currently
      fraught with too many difficulties to be an effective and efficient law
      enforcement tool.

PMID- 15036443
TI  - Multi-resolution image fusion technique and its application to forensic science.
AB  - Image fusion is a process of combining two or more images into an image. It can
      extract features from source images, and provide more information than one image
      can. Multi-resolution analysis plays an important role in image processing, it
      provides a technique to decompose an image and extract information from coarse to
      fine scales. In some practical forensic examinations (such as the cartridge image
      check), we cannot obtain all information from just one image; on the contrary, we
      need information from images with difference light sources (or light ways). In
      this paper, we apply an image fusion method based on multi-resolution analysis to
      forensic science. Synthetic and real images (such as images from closed-up
      photography and flash photography) are used to show the capability of the multi
      resolution image fusion technique.

PMID- 15036444
TI  - Three dimensional visualization and comparison of impressions on fired bullets.
AB  - Currently, optical devices, such as microscopes and CCD cameras, are utilized for
      identification of bullets and tool marks in the field of forensic science. While
      these optical methods are easily manageable and effective, they are under great
      influence of illumination condition. In other words, appearances of striations
      through these optical devices have possibility to be changed by lighting
      condition. Besides these appearance-based approaches, we can utilize three
      dimensional (3D) geometric data of tool marks that are free from lighting
      condition. In this study, we focused on 3D geometric data of landmark impressions
      on fired bullets for identification. We obtained the 3D surface data of tool
      marks by a confocal microscope and reconstructed virtual impressions on a PC
      monitor from the geometric data. Furthermore, the 3D data are exploited to
      numerical matching of two surface shapes. We also visualized the difference of
      two shapes. In order to do this, two surface models are aligned automatically. In
      this process, pairings of correspondent points on both surfaces are determined.
      Distance analysis between these pairs leads to a shape comparison. Since
      comparison results are visualized, they are intuitive and easily perceptive.

PMID- 15036445
TI  - Duplications of the Y-chromosome specific loci P25 and 92R7 and forensic
      implications.
AB  - In the present study, we demonstrate that two commonly used Y-chromosome single
      nucleotide polymorphisms (SNPs), P25 and 92R7, are paralogous sequence variants
      (PSVs) originating from segmental duplications and that at least one of the
      sequence variants in each group of loci is polymorphic. Several methodologies
      were used in order to detect the SNP alleles and the PSVs of the loci. All
      results obtained with the various typing techniques supported the conclusion. The
      allele distributions of the binary markers were analysed in more than 600 males
      with seven different haplogroups. For P25, the ancestral allele C was found in
      several samples from different haplogroups. The derived allele A was always
      present with an additional C variant. Haplogroup P was defined by the derived
      allele A at the 92R7 locus. However, the ancestral allele G was always associated
      with an A variant due to the duplication.

PMID- 15036446
TI  - Typing of mitochondrial DNA coding region SNPs of forensic and anthropological
      interest using SNaPshot minisequencing.
AB  - The development of new methodologies for high-throughput SNP analysis is one of
      the most stimulating areas in genetic research. Here, we describe a rapid and
      robust assay to simultaneously genotype 17 mitochondrial DNA (mtDNA) coding
      region SNPs by minisequencing using SNaPshot. SNaPshot is a methodology based on
      a single base extension of an unlabeled oligonucleotide with labeled dideoxy
      terminators. The set of SNPs implemented in this multiplexed SNaPshot reaction
      allow us to allocate common mitochondrial West Eurasian haplotypes into their
      corresponding branch in the mtDNA skeleton, with special focus on those
      haplogroups lacking unambiguous diagnostic positions in the first and second
      hypervariable regions (HVS-I/II; by far, the most common segments analyzed by
      sequencing). Particularly interesting is the set of SNPs that subdivide
      haplogroup H; the most frequent haplogroup in Europe (40-50%) and one of the most
      poorly characterized phylogenetically in the HVS-I/II region. In addition, the
      polymorphic positions selected for this multiplex reaction increase considerably
      the discrimination power of current mitochondrial analysis in the forensic field
      and can also be used as a rapid screening tool prior to full sequencing analysis.
      The method has been validated in a sample of 266 individuals and shows high
      accuracy and robustness avoiding both the use of alternative time-consuming
      classical strategies (i.e. RFLP typing) and the need for high quantities of DNA
      template.

PMID- 15036459
TI  - Immune cell stimulating activity of mucopolysaccharide isolated from yam
      (Dioscorea batatas).
AB  - Mucopolysaccharide (YMP) of yam (Dioscorea batatas Decne) was tested for
      immunomodulatory activity in vitro. We examined the effect of YMP on the
      viability, cell-mediated cytotoxicity and IFN-gamma secretion of splenic
      lymphocytes. The cytotoxic activity of mouse splenocyte against leukemia cell was
      increased in the presence of YMP (10 microg/ml). However, YMP (10 microg/ml) did
      not affect the viability of splenocytes. The production of IFN-gamma was
      significantly increased in the YMP treated splenocytes, suggesting that YMP may
      induce cell-mediated immune responses. The effects of YMP on phagocytic activity
      were studied in relation to uptaking capacity and lysosomal phosphatase activity
      of the mouse peritoneal macrophages in vitro. YMP (50 microg/ml) was found to
      increase uptaking capacity and lysosomal phosphatase activity of peritoneal
      macrophages. In addition, YMP (10-100 microg/ml) significantly increased the
      viability of peritoneal macrophages (P<0.05). The data obtained demonstrate that
      the YMP may be used as sources of immunoactive polysaccharides.

PMID- 15036460
TI  - Efficacy of Myrsine africana, Albizia anthelmintica and Hilderbrantia sepalosa
      herbal remedies against mixed natural sheep helminthosis in Samburu district,
      Kenya.
AB  - Traditional livestock healers from Samburu and Turkana communities in Samburu
      District of Kenya were identified and recruited for participation in this study.
      Sheep with mixed gastrointestinal helminthosis were purchased from nomadic
      livestock owners in the area. Three herbal anthelmintic remedies, viz. Myrsine
      africana, Albizia anthelmintica and Hilderbrantia sepalosa were administered in
      the traditional way by the healers and their efficacy determined using percent
      fecal egg count reduction (percent FECR) test. The results indicate that all the
      herbal remedies had some efficacy against both nematodes and Monezia species of
      helminths. The group effect against nematodes was significantly different
      (P=0.002). Compared to an untreated control group, the efficacy against nematodes
      was 77, 89.8 and 90% for Myrsine afriacana, Albizia antihelmintica and
      Hilderbrantia sepalosa, respectively, while albendazole had 100% efficacy. The
      main nematodes encountered included Haemonchus spp., Trichostrogylus spp. and
      Oesophagostomum spp. With regard to Monezia species herbal remedies performed
      better than albendazole with an efficacy of 100% compared to 63% for albendazole.
      The group of sheep treated with Albizia anthelmintica showed a significant
      increase (P=0.003) in packed cell volume (PCV).

PMID- 15036461
TI  - Cytoprotection by Achyrocline satureioides (Lam) D.C. and some of its main
      flavonoids against oxidative stress.
AB  - Epidemiological studies indicate that dietary antioxidants can influence the
      incidence of neurodegenerative diseases. Among them flavonoids have been proposed
      to be effective cytoprotectors. Consequently, herbs with a high concentration of
      these compounds such as Achyrocline satureioides, Ginkgo biloba and Epilobium
      parviflorum are of special interest. In this context a comparative study of the
      cytoprotective capacity of infusions from the three plants against an oxidative
      insult was performed. Hence, the cytoprotective activity of each infusion against
      H2O2 injury to PC12 cells was tested and the antioxidant capacity was assessed by
      the ABTS*+ radical bleaching assay. Free and glycosylated flavonoids contained in
      the infusions were identified by HPLC and the cytoprotective effect of some of
      these individual flavonoids was tested. The analysis of the flavonoid content of
      the infusions revealed different profiles. Epilobium parviflorum infusion showed
      the highest antioxidant capacity but only Achyrocline satureioides infusion
      proved to be cytoprotective. Moreover, the free flavonoids quercetin and luteolin
      contained in this infusion were also cytoprotective. In conclusion, the free
      radical scavenger capacity did not correlate with the cytoprotective profile of
      the infusions. The special mixture of unglycosylated Achyrocline satureioides
      flavonoids could be a clue to explain the unique effect of this plant.

PMID- 15036462
TI  - Antidermatophytic activity of extracts from Psoralea corylifolia (Fabaceae)
      correlated with the presence of a flavonoid compound.
AB  - Extracts obtained from seeds of Psoralea corylifolia showed several degrees of
      antifungal activity against Trichophyton rubrum, Trichophyton mentagrophytes,
      Epidermophyton floccosum and Microsporum gypseum by the disc diffusion method on
      a Sabouraud dextrose agar (SDA) medium. Methanol extract of the seeds at 250
      microg exhibited the maximum inhibition with a halo of 28 mm diameter. Six
      different bands were obtained when the methanol extract was subjected to TLC. 13C
      NMR and Mass spectra revealed that the active compound would be a flavonoid, 4'
      methoxy flavone. MIC of the active compound along with standard miconazole was
      carried out using tube dilution technique.

PMID- 15036463
TI  - Effects of ethanol extract of propolis (EEP) and its flavones on inducible gene
      expression in J774A.1 macrophages.
AB  - Propolis, a bee-hive product, has been used in folk medicine for centuries, and
      recently in modern medicine as an anti-inflammatory and immunomodulatory agent.
      These activities would be mainly due to phenolic compounds such as flavonoids,
      especially flavone derivatives. The present study examined the effect of ethanol
      extract of propolis (EEP) and selected flavone derivatives (chrysin, galangin,
      kaempferol and quercetin) on interleukin-1beta (IL-1beta) and inducible nitric
      oxide synthase (iNOS) gene expression in lipopolysaccharide (LPS)-induced J774A.1
      macrophages. Treatment of cells with EEP significantly suppressed both IL-1beta
      mRNA (P<0.02) and iNOS mRNA (P<0.001) expression. The concentrations of cytokine
      in cell culture supernatants and cell lysates and nitric oxide (NO) generation
      were reduced in a dose-dependent manner. The tested phenolic compounds
      significantly decreased the IL-1beta mRNA level and IL-1beta protein
      concentration (P<0.05) (excluding galangin), iNOS mRNA level and NO production
      (P<0.001). The most potent inhibitor of the IL-1beta synthesis and NO generation
      was chrysin. These results indicate that EEP exerts its inhibitory effect on the
      IL-1beta and iNOS gene expression in J774A.1 macrophages at the transcriptional
      level. Tested flavone derivatives contribute to the anti-inflammatory activity of
      propolis.

PMID- 15036465
TI  - In vitro antitrypanosomal activity of ethnopharmacologically selected Beninese
      plants.
AB  - The in vitro antitrypanosomal activity of methylene chloride, methanol and
      aqueous extracts of the leaves and twigs of five plant species traditionally used
      in Benin for the treatment of sleeping sickness were evaluated on Trypanosoma
      brucei brucei and their selectivity was analysed on Leishmania mexicana mexicana
      and J774 macrophage-like murine cells. The results showed that the four most
      active extracts had MIC values < or =19 microg/ml (Hymenocardia acida twig and
      leaf, Strychnos spinosa leaf, Trichilia emetica leaf methylene chloride
      extracts). All these extracts had a lower activity on L. m. mexicana and J774
      cells. Determination of the IC50 values of the methylene chloride leaf extracts
      on two strains of trypanosomes (T. b. brucei and T. b. rhodesiense) and two
      mammalian cell lines (L6 and J774 cells) showed that all extracts possessed some
      antitrypanosomal activity with IC50's ranging from 1.5 to 39 microg/ml. All were
      also toxic to the mammalian cells, but usually with higher IC50's. The only
      exception was the S. spinosa methylene chloride leaf extract which had no
      toxicity on J774 cells. Although tannins have been identified in most of the
      species studied, they could not be detected in the most active extracts, just as
      alkaloids. The presence of flavonoids and quinones may at least in part explain
      the observed activities of some of the active extracts.

PMID- 15036464
TI  - In vivo topical anti-inflammatory and in vitro antioxidant activities of two
      extracts of Thymus satureioides leaves.
AB  - Four extracts at increasing polarity were prepared from the leaves of Thymus
      satureioides Coss. (Labiatae) and assayed for the in vivo topical anti
      inflammatory effect using the croton oil ear test in mice, and for in vitro both
      antioxidant (DPPH degrees test) and anti-bacterial (broth microdilution method)
      activities. The chloroform extract showed a topical anti-inflammatory activity
      (ID50=282 microg cm(-2)), only three times lower than that of the reference drug
      indomethacin (ID50=93 microg cm(-2)) and its active components were identified as
      ursolic and oleanolic acids. The methanol extract, showing a significant radical
      scavenging effect (SC50=14.54 microg), was characterized by the isolation and
      identification of some flavonoids. On the contrary, the extracts did not show any
      anti-bacterial effect against four standard aerobial bacteria strains.

PMID- 15036466
TI  - Acute and chronic toxicological studies of Ajuga iva in experimental animals.
AB  - Ajuga iva (L.) Schreber (AI), is widely used in the Moroccan pharmacopoeia as a
      panacea (cure-all), and specifically for gastrointestinal disorders and diabetes,
      and as an anthelmintic. No toxicological investigations have been carried out on
      this plant. We have previously observed that single oral doses (2-14 g/kg) of a
      lyophilised aqueous extract of AI (AI-extract) in mice or daily oral
      administration of 10 mg/kg of AI-extract in rats for 2 weeks did not result in
      any adverse effects. We have now evaluated AI-extract for its behavioural and
      pharmaco-toxicological effects after acute and chronic administration by the oral
      and intraperitoneal routes in rats and mice. No toxicity was observed in mice
      after single oral doses of as high as 14 g/kg of the AI-extract. However, single
      intraperitoneal injections of the AI-extract (1500-5500 mg/kg BW) produced a dose
      dependent increase in adverse effects in the general behaviour and the mortality
      rate; the LD50 of acute intraperitoneal dose was 3.6 g/kg. In chronic
      toxicological studies in rats, the AI-extract (administered orally at daily doses
      of 100, 300 and 600 mg/kg for 3 months), did not cause any changes in
      haematological and biochemical parameters, with the exception of a transient rise
      in platelet counts and a short-term decrease in serum glucose levels.
      Histopathological examination of the brain, liver and the kidneys at the end of
      the study (3 months) showed normal architecture suggesting no morphological
      disturbances.

PMID- 15036467
TI  - Effects of bulbus Fritillaria water extract on blood pressure and renal functions
      in the L-NAME-induced hypertensive rats.
AB  - A pharmacological inhibition of nitric oxide synthase (NOS) in rats produces
      renal vasoconstriction, renal dysfunction, and hypertension. The present study
      was aimed at investigating whether Bulbus Fritillaria water extract (BFWE)
      ameliorates NG-nitro-L-arginine methylester (L-NAME)-induced hypertension.
      Treatment of rats with L-NAME (60 mg/l drinking water, 4 weeks) caused a
      sustained increase in systolic blood pressure (SBP). The NO concentration in
      plasma and NO productions in the vascular tissues of the L-NAME-treated group
      were significantly reduced as compared with those in the control, whereas the
      expressions of NOS proteins were not altered. BFWE restored SBP to normal level
      in the L-NAME-treated hypertensive rats. Moreover, BFWE was able to preserve the
      vascular NO production and plasma NO metabolites concentration without changes of
      the expression NOS proteins. The renal functional parameters including urinary
      volume, sodium excretion, and creatinine clearance (Ccr) were significantly
      restored in rats co-treated with BFWE and L-NAME compared to the L-NAME-treated
      group. Taken together, these results suggest that BFWE prevents the increase of
      SBP in the L-NAME-induced hypertension that may have been caused by enhanced
      generation of vascular NO and amelioration of renal functions.

PMID- 15036468
TI  - Acetylcholinesterase and butyrylcholinesterase inhibitory activity of some
      Turkish medicinal plants.
AB  - The chloroform:medianol (1:1) extracts of a number of the plant species belonging
      to eight families, namely Corydalis solida (L.) Swartz subsp. solida and Glaucium
      corniculatum (L.) J. H. Rudolph (Papaveraceae), Rhododendron ponticum L. subsp.
      ponticum and Rhododendron luteum Sweet. (Ericaceae), Buxus sempervirens L.
      (Buxaceae), Vicia faba L. (Fabaceae), Robinia pseudoacacia L. (Caeselpiniaceae),
      Tribulus terrestris L. and Zygophyllum fabago L. (Zygophyllaceae), Lycopodium
      clavatum L. (Lycopodiaceae), Fumaria vaillantii Lois., Fumaria capreolata L.,
      Fumaria kralikii Jordan, Fumaria asepala Boiss., Fumaria densiflora DC., Fumaria
      flabellata L., Fumaria petteri Reichb. subsp. thuretii (Boiss.) Pugsley, Fumaria
      macrocarpa Boiss. ex Hausskn., Fumaria cilicica Hauskkn., Fumaria parviflora Lam.
      and Fumaria judaica Boiss. (Fumariaceae) were screened for their
      anticholinesterase activity on acetylcholinesterase (AChE) and
      butyrylcholinesterase (BChE) enzymes by in vitro Ellman method at 10 microg/ml
      and 1 mg/ml concentrations. The extracts did not show any noticeable inhibitory
      activity against both of the enzymes at 10 microg/ml. The extracts of
      Rhododendron ponticum subsp. ponticum, Rhododendron luteum, Corydalis solida
      subsp. solida, Glaucium corniculatum, and Buxus sempervirens showed remarkable
      inhibitory activity above 50% inhibition rate on AChE at 1 mg/ml. Among them,
      Rhododendron ponticum subsp. ponticum, Corydalis solida subsp. solida and Buxus
      sempervirens were the most active extracts against BChE having 95.46 +/- 1.03%,
      93.08 +/- 0.97%, and 93.45 +/- 0.88% inhibition rates, respectively. Among the
      extracts screened, all of the Fumaria extracts displayed highly potent inhibition
      against both of the enzymes at 1 mg/ml concentration compared to the standard.

PMID- 15036469
TI  - Antihepatotoxic effect of Nymphaea stellata willd., against carbon tetrachloride
      induced hepatic damage in albino rats.
AB  - Nymphaea stellata willd., a medicinal plant mentioned in Ayurveda for the
      treatment of liver disorders, has not been subjected to systematic scientific
      investigations to asses its hepatoprotective effects. Therefore, the present
      study was undertaken to investigate the hepatoprotective activity of extract of
      Nymphaea stellata willd., flower against carbon tetrachloride-induced hepatic
      damage in albino rats. The oral administration of varying dosage of extract of
      Nymphaea stellata willd., flower to rats for 10 days afforded the good
      hepatoprotection against carbon tetrachloride-induced elevation in serum marker
      enzymes, serum bilirubin, liver lipid peroxidation and reduction in liver
      glutathione, liver glutathione peroxidase, glycogen, superoxide dismutase and
      catalase activity.

PMID- 15036470
TI  - Cytotoxic activities of flavonoids from two Scutellaria plants in Chinese
      medicine.
AB  - The effects of 17 flavonoids, isolated from two flavonoid-rich Scutellaria
      species (Scutellaria baicalensis Georgi and Scutellaria rivularis Wall) used in
      traditional Chinese medicine, on HL-60 cells were assessed by WST-8. Ten of the
      flavonoids inhibited the proliferation of HL-60, as shown by IC50 values used as
      indexes of the inhibition. 2',3',5,7-tetrahydroxy flavone (IC50=9.5 microM),
      apigenin (15.0 microM), viscidulin III (17.4 microM), wogonin (17.4 microM) and
      luteolin (18.4 microM) were more effective than baicalein (23.0 microM) which
      reportedly inhibits the proliferation of some cancer cell lines. Others were less
      effective, and oroxylin A stimulated the proliferation. Scutellaria rivularis,
      used for the treatment of tumors in the clinic, contained flavonoids that were
      more inhibitive than those in Scutellaria baicalensis. These results are
      demonstrative of some reasons for the use of Scutellaria rivularis as a crude
      antitumor drug.

PMID- 15036471
TI  - Antinociceptive and anti-inflammatory effect of the aqueous extract from leaves
      of Pimenta racemosa var. ozua (Mirtaceae).
AB  - The leaves of Pimenta racemosa var. ozua (Urban & Ekman) Landrum L. (Myrtaceae)
      are used against the pain and the inflammation in popular medicine of the Caribe
      area. In the present work, the antinociceptive, anti-inflammatory effect, and
      acute toxicity of the aqueous extract from leaves of Pimenta racemosa have been
      investigated. The antinociceptive action was assayed in several experimental
      models in mice: acetic acid, formalin, and hot plate tests. The aqueous extract
      (125 and 250 mg/kg) significantly and in a dose-dependent manner reduced the
      nociception induced by the acetic acid intraperitoneal injection (P<0.001). In
      the formalin test, the extract also significantly reduced the painful stimulus in
      both phases of the test (P<0.001). On the contrary, the extract neither
      significantly increased the latency time of licking nor jumping in the hot plate
      test. In the anti-inflammatory study, the plant also showed an interesting
      effect. Aqueous extract (125 and 250 mg/kg) orally administered, significantly
      reduced the carrageenan-induced edema in rat paw at 1, 3, and 5 h (P<0.001). In
      the TPA test the edema was dose-dependent and significantly reduced by the
      extract (0.5, 1, and 3 mg per ear) when it was topically applied (P<0.01;
      P<0.001). The levels of myeloperoxidase enzyme also were reduced in the inflamed
      tissue by the extract. Acute toxicity also was investigated and the results
      indicated a moderate toxicity (LD50: 287 +/- 12.9 mg residue/kg; 1.854 +/- 0.083
      g plant/kg). These results revealed that the extract from leaves of Pimenta
      racemosa var. ozua exerts an important antinociceptive activity, associated to an
      anti-inflammatory effect which to appear be markedly influenced by the inhibition
      of neutrophil migration into inflamed tissue and that lack of toxic effects at
      usual doses.

PMID- 15036472
TI  - Anti-diarrheal and spasmolytic activities and acute toxicity study of
      Soonkijangquebo, a herbal anti-diarrheal formula.
AB  - The anti-diarrheal and spasmolytic activities of Soonkijangquebo (SKJQB), a
      Korean herbal anti-diarrheal formulation, were subjected to pharmacological
      evaluation. SKJQB, at a dose of 50-200 mg/kg, inhibited castor oil-induced
      diarrhea in mice. The median effective dose (ED50) for the anti-diarrheal effect
      was 93 mg/kg. In isolated rabbit jejunum preparations, SKJQB produced a
      spasmolytic effect by the relaxation of spontaneous contractions in a dose
      dependent manner. The median effective concentration (EC50) for the spasmolytic
      effect was 3.6 mg/ml. In isolated guinea pig ileum preparations, SKJQB also
      produced a spasmolytic effect by reduction of acetylcholine-induced contractions.
      When tested against calcium channel blockade in rabbit jejunum, SKJQB caused a
      dose-dependent rightward shift in the Ca2+ dose-response curves, similar to that
      produced by verapamil, a well-known calcium antagonist. In an acute toxicity
      study in Sprague-Dawley rats, the median lethal dose (LD50) of SKJQB was greater
      than 2000 mg/kg, and no pathological changes were noticed in macroscopic
      examination by necropsy of rats treated with SKJQB. Thus, SKJQB may be safely
      used as a spasmolytic as well as an anti-diarrheal agent.

PMID- 15036473
TI  - Inhibitory effects of Caesalpinia sappan on growth and invasion of methicillin
      resistant Staphylococcus aureus.
AB  - In the present study, we investigated antimicrobial activity of Caesalpinia
      sappan against clinical isolates of methicillin-resistant Staphylococcus aureus
      (MRSA) and effect of Caesalpinia sappan extract on the invasion of MRSA to human
      mucosal fibroblasts (HMFs). Chloroform, n-butanol, methanol, and aqueous extracts
      of the Caesalpinia sappan showed antimicrobial activity against standard
      methicillin-sensitive Staphylococcus aureus (MSSA) as well as MRSA. Methanol
      extract of Caesalpinia sappan demonstrated a higher inhibitory activity than n
      butanol, chloroform, and aqueous extracts. In the checkerboard dilution method,
      methanol extract of Caesalpinia sappan markedly lowered the minimal inhibitory
      concentrations (MICs) of ampicillin and oxacillin against MRSA. To determine
      whether methanol extract of Caesalpinia sappan inhibits the MRSA invasion to
      HMFs, the cells were treated with various sub-MIC concentrations of methanol
      extract and bacterial invasion was assayed. MRSA invasion was notably decreased
      in the presence of 20-80 microg/ml of Caesalpinia sappan extract compared to the
      control group. The effect of Caesalpinia sappan extract on MRSA invasion appeared
      dose-dependent. These results suggest that methanol extract of Caesalpinia sappan
      may have antimicrobial activity and the potential to restore the effectiveness of
      beta-lactam antibiotics against MRSA, and inhibit the MRSA invasion to HMFs.

PMID- 15036474
TI  - Evaluation of Rhubarb using antioxidative activity as an index of pharmacological
      usefulness.
AB  - We attempted to estimate the pharmacological activity by measuring the
      concentrations of a composition ingredient using a multivariate statistical
      analysis method. Medicinal herb of Rhubarb has been many largely unrecognized
      biochemical and pharmacological effect components. Therefore, we attempted to
      estimate the antioxidative activity of Rhubarb on low-density lipoprotein (LDL)
      of its components. Thirty specimens of Rhubarb from various origins were used,
      chose nine components of anthraquinones, two components of anthrones, two
      components of flavan-3-ols, one component of procyanidin, one component of
      naphthalene, two components of phenylbutanones and one component of stilbene.
      Quantitative analysis of 18 components was performed with high-performance liquid
      chromatography (HPLC) and antioxidative activities were measured with plasma
      taken from spontaneous familial hypercholesterolemia model rabbits. There was
      considerable variation among the specimens in the concentration of components and
      antioxidative activities on LDL. As a result of multiple regression analysis,
      significant multiple correlation coefficient for antioxidative activities on LDL
      (R=0.914, P<0.01) was found in relation to the concentrations of five components:
      aloe-emodin, chrysophanol, emodin 1-O-beta-D-glucoside, lindleyin and 6
      hydroxymusizin 8-O-beta-D-glucoside. Three of the five components were not active
      in promoting antioxidative activity and there was no significant correlation
      between the concentrations of the most active component and the activity. We
      consider this a useful method for selecting of Rhubarb and propose a new
      scientific approach for the selection of natural medicines.

PMID- 15036475
TI  - Evaluation of hypoglycemic and antihyperglycemic effects of Datura metel (Linn.)
      seeds in normal and alloxan-induced diabetic rats.
AB  - The seed powder of Datura metel was tested for its hypoglycemic activity in
      normal and alloxan-induced diabetic rats. Graded doses (25, 50 and 75 mg/kg,
      p.o.) of the seed powder when given to both normal and diabetic rats produced
      significant reduction in blood glucose at the 8 h. The effect was found to be
      dose dependent with all treatments at the doses administered.

PMID- 15036476
TI  - Preliminary evaluation of the antihepatotoxic activity of Kamilari, a polyherbal
      formulation.
AB  - Hepatoprotective efficacy of Kamilari, a polyherbal preparation was studied in
      carbon tetrachloride (CCl4)-induced liver dysfunction in albino rats by
      determining different biochemical parameters in serum and tissues. In serum, the
      activities of enzymes like aspartate aminotransferase (AST), alanine
      aminotransferase (ALT), alkaline phosphatase (ALP) and the concentrations of
      protein and bilirubin were evaluated. The concentrations of total lipids,
      cholesterol, triglycerides (TG) and phospholipids were studied in serum and
      different tissues. Here, a dose-dependent study was conducted and oral
      administration of Kamilari at a dose of 750 mg/kg body weight significantly
      reduced the toxic effects of CCl4. From the observations, the conclusion drawn is
      that Kamilari stabilized the hepatic frame against the toxicity of CCl4.

PMID- 15036477
TI  - Antibacterial and antifungal activity of Syzygium jambolanum seeds.
AB  - The water and methanolic extracts of Syzygium jambolanum seeds were examined for
      antibacterial and antifungal activity in vitro using the disc diffusion method,
      minimum inhibitory concentration, minimum bactericidal concentration and minimum
      fungicidal concentration. Activity against gram positive bacteria (Bacillus
      subtilis, Staphylococcus aureus), gram negative bacteria (Salmonella typhimurium,
      Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli) and fungal
      strains (Candida albicans, Cryptococcus neoformans, Aspergillus flavus,
      Aspergillus fumigatus, Aspergillus niger, Rhizopus sp., Trichophyton rubrum,
      Trichophyton mentagrophytes and Microsporum gypseum) is discussed.

PMID- 15036478
TI  - Antidiabetic activity of Boerhaavia diffusa L.: effect on hepatic key enzymes in
      experimental diabetes.
AB  - The purpose of this study was to investigate the effects of daily oral
      administration of aqueous solution of Boerhaavia diffusa L. leaf extract (BLEt)
      (200 mg/kg) for 4 weeks on blood glucose concentration and hepatic enzymes in
      normal and alloxan induced diabetic rats. A significant decrease in blood glucose
      and significant increase in plasma insulin levels were observed in normal and
      diabetic rats treated with BLEt. Treatment with BLEt resulted in a significant
      reduction of glycosylated haemoglobin and an increase in total haemoglobin level.
      The activities of the hepatic enzymes such as hexokinase was significantly
      increased and glucose-6-phosphatase, fructose-1,6-bisphosphatase were
      significantly decreased by the administration of BLEt in normal and diabetic
      rats. An oral glucose tolerance test (OGTT) was also performed in the same
      groups, in which there was a significant improvement in glucose tolerance in rats
      treated with BLEt. A comparison was made between the action of BLEt and
      antidiabetic drug-glibenclamide (600 microg/kg). The effect of BLEt was more
      prominent when compared to glibenclamide.

PMID- 15036479
TI  - Medicinal plants used by the Criollos of Northwestern Argentine Chaco.
AB  - Medicinal remedies of herbal origin employed by Criollos herdsmen of northwestern
      Chaco were studied through collections of plant specimens and by interviewing 83
      local informants from several villages. A total of 619 medicinal uses were
      recorded for 163 plant species during field work. For each plant species the
      scientific and vernacular names, the parts of the plant used, specific medicinal
      uses, modes of preparation and administration and way of obtaining them were
      listed. Most species are collected in the wild (78%), they account for the
      seventy nine percent of the total recorded medicinal uses; the rest are obtained
      through cultivation or bought in markets. Plants are used mainly for diseases of
      the digestive tract (26.5% of total uses); skin affections (14.6%); respiratory
      disorders (9.1%); reproductive disorders (8.4%) and affections of the circulatory
      system (7.7%); and as antipyretics (7.5% of total uses).

PMID- 15036480
TI  - Effect and putative mechanism of action of ginseng on the formation of glycated
      hemoglobin in vitro.
AB  - As a non-enzymatic, covalent binding between glucose and protein, glycation is a
      well-known cause of various forms of diabetic complications. This study was
      undertaken to determine the effect and mechanism of action of ginseng on the
      formation of glycated protein. A solution containing hemoglobin and glucose was
      incubated for 5 days by adding ginseng extract or glutathione. The quantitative
      measurement of glycated hemoglobin was determined using the ion capture component
      set. The anti-oxidative effect of ginseng and quercetin was determined through
      the TBA method. The amount of glycated hemoglobin (%GHb) significantly increased
      with the addition of glucose (27.8 mM) compared to the non-addition group.
      Nonetheless, this significantly decreased when ginseng extract (2 g/dl) was added
      and further dropped when glutathione (50 mM) was added. The amount of hemoglobin
      A1c (%HbA1c), a sub-fraction of glycated hemoglobin, was lower than that of
      glycated hemoglobin, but it showed a similar tendency. Compared to a non-addition
      group, the optical density of the organic layer that was separated through the
      addition of chloroform in oxidized linoleic acid significantly and dose
      dependently decreased when ginseng extract or quercetin was added. These results
      suggest that the inhibitory effect of ginseng on the formation of glycated
      hemoglobin could be attributed to the anti-oxidative activity of ginseng.

PMID- 15036481
TI  - Isolation, partial characterisation and immunomodulating activities of
      polysaccharides from Vernonia kotschyana Sch. Bip. ex Walp.
AB  - The roots from Vernonia kotschyana Sch. Bip. ex Walp. (Baccharoides adoensis var.
      kotschyana (Sch. Bip. ex Walp.) M.A. Isawumi, G.El-Ghazaly & B. Nordenstam)
      (Asteraceae) are used in Malian folk medicine for the treatment of gastritis,
      gastro duodenal ulcers, as an aid to ameliorate digestion and as a wound healing
      remedy. Since a common feature among these conditions is related to immune
      responses, immunomodulating activities of fractions isolated from both the 50
      degrees C and the 100 degrees C water extracts from Vernonia kotschyana were
      investigated in this study. The active principles were identified as acidic
      polysaccharide fractions, containing pectic arabinogalactan type II structures,
      which showed both complement fixing ability and T-cell independent induction of B
      cell proliferation in vitro. Some activity was also observed on macrophages. The
      present study may provide additional support for the popular use of this plant to
      improve intestinal health.

PMID- 15036482
TI  - Inhibition of mast cell-dependent immediate-type hypersensitivity reactions by
      purple bamboo salt.
AB  - Purple bamboo salt is a specially processed salt according to the traditional
      recipe using normal salt and bamboo etc. It has been used as a folk medicine for
      the purpose of prevention and treatment of various diseases in Korea. This report
      describes an inhibitory effect of purple bamboo salt on mast cell-mediated
      immediate-type allergic reactions. Purple bamboo salt (0.01-1 microg per site)
      significantly inhibited the ear swelling response induced by intradermal
      injection of compound 48/80 in mice. Purple bamboo salt (0.01-1 mg/ml) dose
      dependently inhibited the histamine release from the rat peritoneal mast cells
      (RPMCs) by compound 48/80. Purple bamboo salt (0.01-1 g/kg) also dose-dependently
      inhibited the passive cutaneous anaphylaxis (PCA) by oral administration. Our
      results provide evidence that purple bamboo salt will be beneficial in the
      regulation of immediate-type of allergic reactions.

PMID- 15036483
TI  - In vitro effects of aqueous seeds extract of Acacia cyanophylla on the opsonized
      zymosan-induced superoxide anions production by rat polymorphonuclear leukocytes.
AB  - In vitro studies were carried out in rat pleural polymorphonuclear leukocytes
      (PMNs) activated by opsonized zymosan (OZ) to investigate the effects of aqueous
      extract from Acacia cyanophylla seeds on superoxide anions generation. PMNs were
      collected, after induction of an acute inflammatory reaction, by injection in the
      rat pleural cavity, of a suspension of calcium pyrophosphate (CaPP) crystals
      (pleurisy with CaPP) or serum (pleurisy with serum). The results obtained
      indicate that Acacia cyanophylla aqueous seeds extract had, in vitro, a
      significant stimulatory effect, in a dose dependent manner, on the PMN superoxide
      anions generation. It also corrected the diminution of superoxide anions
      production induced by diclofenac pre-treated PMNs. It could be concluded from the
      results of this study that the stimulatory properties of Acacia cyanophylla seeds
      aqueous extract may at least be due to the presence of polyphenols such tannins
      and/or lignins. Further investigations are needed to determine clearly the
      mechanisms mediating the generation of superoxide radicals in this phenomenon.

PMID- 15036484
TI  - Antinociceptive effects of Zataria multiflora Boiss fractions in mice.
AB  - Activity-guided fractionation of methanol:chloroform (1:1) extract of Zataria
      multiflora Boiss was performed in order to investigate the active component(s)
      responsible for antinociceptive activity. Antinociceptive activity was evaluated
      using hot-plate and writhing tests. Morphine (10 mg/kg, i.p.) and diclofenac (10
      mg/kg, i.p.) were used as positive controls. The methanol-chloroform (1:1)
      extract of the aerial parts of the plants was prepared and partitioned between
      methanol-water (9:1) and n-hexane. The more active hydroalcoholic fraction was
      concentrated and further partitioned between methanol-water (3:2) and chloroform.
      The hydroalcoholic layer showed a dose-dependent and significant activity
      compared to morphine and diclofenac. Further fractionation of the hydroalcoholic
      fraction on silica gel gave six fractions. Three fractions at 100 mg/kg showed
      activity comparable to those of morphine.

PMID- 15036485
TI  - Antidiabetic activity of aqueous leaf extract of Annona squamosa in
      streptozotocin-nicotinamide type 2 diabetic rats.
AB  - The claim by some tribal populations in parts of Northern India that the young
      leaves of the custard apple tree, Annona squamosa L. (Annonaceae) has
      antidiabetic properties was investigated. Diabetes mellitus was induced with
      streptozotocin-nicotinamide and graded doses of the aqueous leaf extracts were
      then administered in drinking water to normal and experimental diabetic rats for
      12 days. Fasting plasma glucose levels, serum insulin levels, serum lipid
      profiles and changes in body weight were evaluated in normal rats while liver
      glycogen levels and pancreatic TBARS levels were evaluated additionally in
      diabetic rats. The diabetic groups treated with the aqueous leaf extract were
      compared with standard glibenclamide. The findings of the study support the
      antidiabetic claims of Annona squamosa.

PMID- 15036486
TI  - Current treatment of dysfunctional uterine bleeding.
AB  - OBJECTIVES: We performed a review of the treatment modalities for dysfunctional
      uterine bleeding. METHODS: Dysfunctional uterine bleeding can be treated
      medically or surgically. Medical treatment consists of anti-fibrinolytic
      tranexamic acid, non-steroidal anti-inflammatory drugs, the combined
      contraception pill, progestogen, danazol, or analogues of gonadotrophin releasing
      hormone. The levonorgestrel releasing intra uterine device is developed for
      contraception, but is also effective in the treatment of dysfunctional uterine
      bleeding. Surgical treatment includes endometrial ablation of the first and
      second-generation, and hysterectomy. This review contains current available
      evidence on the effectiveness of these therapies. RESULTS: Antifibrinolytic
      tranexamic acid is the most effective medical therapy to treat dysfunctional
      uterine bleeding. In general medical therapy is not as effective as endometrial
      resection in terms of patient satisfaction and health related quality of life.
      The levonorgestrel releasing intra uterine device is an effective treatment for
      dysfunctional uterine bleeding. No difference in quality of life was observed in
      patients treated with a levonorgestrel releasing intra uterine device as compared
      to hysterectomy. Ablation techniques of the first generation are effective and
      safe when used by trained surgeons, but have a learning curve. Ablation
      techniques of the second generation are effective, but long-term follow-up data
      are not available. Similarly, there are no large randomised controlled trials
      comparing the levonorgestrel releasing intra uterine device to first and second
      generation ablation techniques. Hysterectomy, the traditional standard of care,
      has a relatively high complication rate, but it generates a high satisfaction
      rate and good health related quality of life scores. CONCLUSION: Since none of
      the treatments for dysfunctional bleeding is superior to one of the others, and
      since all treatments have their advantages and disadvantages, counselling of
      patients with dysfunctional bleeding should incorporate medical approach,
      levonorgestrel releasing IUD, endometrial ablation and hysterectomy.

PMID- 15036487
TI  - Variability of breast cancer risk in observational studies of hormone replacement
      therapy: a meta-regression analysis.
AB  - OBJECTIVES: A re-analysis of data from 51 epidemiological studies reported a
      significant 14% increase in the risk of breast cancer associated with the use of
      hormone replacement therapy (HRT). Unlike randomized trials, these observational
      studies varied in design and methods. This study was conducted to explore the
      impact of study design factors on the rate ratio. METHODS: We performed a meta
      regression analysis of 39 epidemiological studies of HRT and breast cancer. The
      rate ratio of breast cancer associated with ever use of HRT was evaluated in
      relation to study design, study period, country, primary study objective, method
      of exposure measurement, age control, adjustment factors related to reproduction
      and menopause, and the presence of breast cancer surveillance. We used stepwise
      multiple regression analysis, weighted by the inverse of the variance of the
      logarithm of the rate ratio, to estimate ratios of rate ratios for these factors.
      RESULTS: Exposure measured by personal interview and/or medical record review was
      associated with a 14% lower rate ratio estimate as compared with telephone
      interview or self-administered questionnaire (P = 0.018). Among studies that did
      not adjust for age at menopause, the rate ratio was 12% lower if the primary
      objective was HRT effect than not (P = 0.016), while it was 43% higher among
      studies that adjusted for age at menopause (P = 0.042). An index that included as
      six desirable design features, breast cancer surveillance, matching of controls,
      more reliable exposure information, adjustment for age at menopause and
      reproductive risk factors, and as primary objective the effect of HRT suggests
      that studies with none of these properties would lead to a rate ratio estimate of
      1.14 (95% CI: 1.00-1.29) while studies with all six properties would produce a
      rate ratio of 0.98 (95% CI: 0.83-1.15). CONCLUSIONS: Design factors of
      epidemiological studies could be an alternative explanation for the reported 14%
      increase in the risk of breast cancer associated with the use of HRT.

PMID- 15036488
TI  - Body mass index (BMI) and parameters of bone formation and resorption in
      postmenopausal women.
AB  - OBJECTIVES: Aim of this study was to evaluate increased body mass index (BMI) as
      an anthropometric factor, predisposing to lower rates of bone turnover or changes
      in bone balance after menopause. MATERIAL AND METHODS: For this purpose, we
      calculated BMI, and measured spinal (BMD(SP)) and femoral bone mineral density
      (BMD(FN)) and biochemical markers of bone formation (serum osteocalcin (S-OC),
      serum procollagen type I C propeptide (S-PICP), serum bone-specific alkaline
      phosphatase (S-B-ALP)) and resorption (urine N- and C-terminal cross-linking
      telopeptide of type I collagen (U-NTX-I and U-CTX-I), pyridinoline (U-PYD) and
      deoxypyridinoline (U-DPD)) in 130 healthy postmenopausal women, aged 46-85 years.
      Bone balance indices were calculated by subtracting z-scores of resorption
      markers from z-scores of formation markers, to evaluate bone balance. RESULTS: S
      PICP ( r = -0.297, P = 0.002), S-OC ( r = -0.173, P = 0.05) and bone balance
      indices (zPICP-zDPD) and (zPICP-zPYD) were negatively correlated with BMI (r = 
      0.25, P = 0.01 and r = -0.25, P = 0.01 and r = -0.21, P = 0.037) and with BMD(SP)
      (r = -0.196, P = 0.032 and r = -0.275 and P = 0.022). Women were grouped
      according to their BMI, in normals (BMI < 25 kg/m2), overweight (BMI = 25-30
      kg/m2, and obese (BMI > 30 kg/m2). Overweight and obese women had approximately
      30% lower levels of S-PICP compared to normals (68.11 +/- 24.85 and 66.41 ng/ml
      versus 97.47 +/- 23.36 ng/ml, respectively; P = 0.0001). zPICP-zDPD, zPICP-zCTX-I
      and zPICP-zPYD were significantly declined in obese women compared to normals (P
      = 0.0072, 0.02 and 0.0028). CONCLUSIONS: We conclude that in postmenopausal
      women, BMI is inversely associated with levels of collagen I formation marker,
      serum PICP. In obesity formation of collagen I was reduced, in favor of
      degradation, but since this finding is not followed by simultaneous decrease in
      bone mineral density, it seems that increased body weight may have different
      effects on mature estrogen-deficient bone and extraskeletal tissues containing
      collagen I.

PMID- 15036490
TI  - Effects of estrogen replacement therapy on natriuretic peptides and blood
      pressure.
AB  - OBJECTIVE: Estrogen replacement therapy (ERT) has been reported to affect blood
      pressure. Since natriuretic peptides have natriuretic and vasodilatory activity
      and also inhibit the renin-angiotensin-aldosterone system and lower blood
      pressure, it was hypothesized that the changes in blood pressure effected by ERT
      might be mediated via changes in natriuretic peptides. METHODS: Fifty-eight
      postmenopausal hysterectomized women were randomized in a double-blind, double
      dummy study to receive either peroral estradiol valerate 2 mg/day or transdermal
      estradiol gel containing 1 mg estradiol/day for 6 months. Blood pressure was
      measured by using an automatic, oscillometric device. Plasma atrial natriuretic
      peptide (ANP), N-terminal fragment of proANP (NT-proANP), B-type natriuretic
      peptide (BNP), aldosterone, and renin were determined by radioimmunoassay.
      RESULTS: The mean decrease in diastolic blood pressure was -6 mmHg both in the
      peroral group (n = 26) (P = 0.002) and in the gel group (n = 27) (P = 0.001), and
      the corresponding decreases in systolic blood pressure were -4 mmHg (P = 0.070)
      and -7 mmHg (P = 0.028) in the sitting position. Plasma NT-proANP rose from 212
      to 264 pmol/l (P = 0.001) on peroral ERT and from 240 to 292 pmol/l (P = 0.008)
      on transdermal ERT. No significant changes were observed in the plasma ANP, BNP,
      aldosterone, and renin levels. CONCLUSIONS: Both peroral and transdermal ERT
      result in elevated plasma levels of NT-proANP, indicating an activation of the
      natriuretic peptide system. This could explain, at least in part, the lowering of
      blood pressure during ERT.

PMID- 15036489
TI  - Raloxifene therapy does not affect uterine blood flow in postmenopausal women: a
      transvaginal Doppler study.
AB  - OBJECTIVE: To monitor the effects of raloxifene therapy on the uterus of
      postmenopausal women by transvaginal ultrasonography and color flow Doppler.
      METHODS: Twenty-five healthy postmenopausal women were enrolled in this
      prospective longitudinal study performed at Department of Gynecology and
      Obstetrics, Faculty of Medicine of Ribeirao Preto. The patients were treated with
      raloxifene hydrochloride (60 mg per day) for 6 months. All were submitted to
      transvaginal ultrasound examination with color flow Doppler (ATL-HDI 3000
      equipment) before the beginning and after 1, 3 and 6 months of treatment.
      Resistance index (RI) and pulsatility index (PI) of the uterine arteries were
      determined by the Doppler method, being considered as indicators of uterine
      perfusion. The following variables were analyzed: endometrial thickness, uterine
      volume, RI, and PI. Data were analyzed statistically by repeated-measures
      analysis of variance. RESULTS: Before treatment, endometrial thickness was 3.38
      +/- 0.73 mm, and similar values were observed after 1, 3 and 6 months of
      treatment (3.04 +/- 0.82; 3.3 +/- 0.83; and 3.37 +/- 0.79, respectively) (P >
      0.05). No significant differences in uterine volume were observed between the pre
      and post-treatment periods. Uterine artery perfusion as indicated by RI and PI
      measured by Doppler also showed no significant variation, with a high impedance
      flow being maintained throughout treatment. CONCLUSIONS: In the group studied
      here, raloxifene treatment at the dose of 60 mg per day for 6 months did not
      induce significant changes in endometrial thickness, uterine volume or uterine
      artery perfusion, confirming that short-term raloxifene treatment does not affect
      the uterus of postmenopausal women.

PMID- 15036491
TI  - Pharmacokinetics of estradiol valerate and medroxyprogesterone acetate in
      different age groups of postmenopausal women.
AB  - OBJECTIVES: To study whether ageing affects the pharmacokinetics of estradiol
      valerate (E2V) or medroxyprogesterone acetate (MPA) in postmenopausal women.
      METHODS: Forty-six postmenopausal women from two essentially similar
      pharmacokinetic studies were divided into three age categories: under 60 years (n
      = 15), between 60 and 65 years (n = 18) and over 65 years (n = 13). They all were
      treated for 12 days or 14 days with four galenically identical tablets containing
      combinations of 1 mg or 2 mg E2V and 2.5 mg or 5 mg MPA. The studies followed an
      open, randomised cross-over design with no washout between the periods. Serum
      estradiol and MPA concentrations were measured at steady state on study day 12 or
      14 of each period. RESULTS: No statistically significant differences were
      observed in the peak concentration (Cmax), time to peak (t(max)), AUC or
      elimination half-life for estradiol or MPA between the different age groups. In
      spite of the lack of statistical significance the AUC was on an average 1.6-fold
      and Cmax 1.40-fold higher in the oldest group of women than in the youngest group
      and age was found significant as a continuous variable for AUC and Cmax for MPA
      but not for estradiol. CONCLUSIONS: The results suggest that there would be no
      significant changes in the pharmacokinetics of estradiol between women under 60
      and over 65 years of age. However, a significant trend towards higher MPA
      concentrations and bioavailability was observed with increasing age. The results
      suggest that from the pharmacokinetic point of view the relationship between
      estradiol and MPA dose to be used in elderly could be different from that in
      younger postmenopausal women, while no pharmacokinetic reasons to use lower
      estradiol doses in the elderly were observed.

PMID- 15036492
TI  - Factors associated with intention to use hormone replacement therapy among Thai
      middle-aged women.
AB  - OBJECTIVES: To examine the differences among those who express their intentions
      to use hormone replacement therapy (intenders), those who express their
      intentions not to use hormone replacement therapy (non-intenders), and those who
      are undecided, and to examine the factors associated with hormone replacement
      therapy (HRT) intention among Thai middle-aged women. METHODS: A total of 420
      women aged 40-59 years, recruited from one hospital in Bangkok were asked to
      complete a self-administered questionnaire. RESULTS: Compared to intenders and
      non-intenders, the undecided were significantly less knowledgeable about
      menopause and HRT, and perceived the highest level of decisional uncertainty.
      Being inadequately informed was the most important factor that distinguished the
      undecided from intenders and non-intenders. When looking at intenders and non
      intenders, no significant differences in perceived information inadequacy, level
      of knowledge, and perceived risks of HRT were found. However, it was found that
      intenders perceived higher benefit over risk of HRT (OR = 1.05, 95% CI = 1.02,
      1.07), held more negative beliefs towards menopause (OR = 1.61, 95% CI = 1.03,
      2.53), and were approximately two times more likely to have ever used oral
      contraceptives (OR = 1.99, 95% CI = 1.13, 3.47) than non-intenders. CONCLUSION:
      The findings reveal the importance of being informed about menopause and HRT in
      making decision about HRT use. Changes in knowledge, and beliefs are promising
      avenues to study to see how these impacts HRT use.

PMID- 15036494
TI  - Does heterogeneity in menopausal ages reflect heterogeneity in oocyte depletion
      rates?

PMID- 15036493
TI  - The effect of tibolone on bone mineral density in postmenopausal women with
      osteopenia or osteoporosis--8 years follow-up.
AB  - OBJECTIVES: This longitudinal observational study evaluated the effect of 8 years
      of uninterrupted treatment of tibolone on bone mineral density (BMD) in
      postmenopausal women with significant osteopenia or osteoporosis. MATERIAL AND
      METHODS: Subjects were 66 postmenopausal women (29 with moderate or severe
      osteopenia and 37 with osteoporosis) who took tibolone (2.5 mg nocte)
      uninterruptedly for over 8 years and who attended for annual BMD assessments.
      Their mean age was 66.7 (0.86) years (range 50-86 years). BMD measurements at the
      lumbar spine and proximal femur were performed annually by dual-energy X-ray
      absorptiometry (DEXA). RESULTS: During the 8 years of treatment with tibolone
      there was a significant increase in BMD at the spine (P < 0.001) and at the hip
      (P < 0.001). Women who did not have previous oestrogen therapy had significantly
      greater response to tibolone than those who had previous treatment with
      conventional hormone replacement therapy (HRT). CONCLUSION: This long-term
      observational study provides evidence of the effectiveness of tibolone in
      postmenopausal women with moderate/severe osteopenia and osteoporosis in terms of
      a significant increase in BMD.

PMID- 15036496
TI  - A method to reduce the invasiveness of fetal catheterization in the cow.
AB  - Surgical intervention in general anesthesia (GA) of the cow in late gestation is
      a stressful condition for both mother and fetus, potentially leading to premature
      delivery or fetal death. The present study hypothesized that fetal
      catheterization at days 246-253 (90% of gestation) is done with less physical and
      metabolic stress for the mother and fetus, when the surgery is performed on a
      standing cow and local anesthesia (LA) rather than on a recumbent cow in general
      anesthesia. Fetal and uterine maternal intra-vascular catheters were implanted
      during general anesthesia (GA, n=24) or local analgesia (LA, n=7). Blood gases
      and metabolite levels in the fetal calves and their mothers were measured during
      surgery and for 5 days post-operatively. During surgery, venous blood pH was
      higher (7.44 +/- 0.01 versus 7.39 +/- 0.01, P<0.05) and hemoglobin and oxygen
      contents lower in LA cows compared with GA cows (9.3 +/- 0.3 mg/dl versus 11.8 +/
      0.2 mg/dl, P<0.001 and 10.0 +/- 0.3 ml/dl versus 12.6 +/- 0.6 ml/dl, P<0.05).
      The differences between the two groups of fetuses reflected those of their dams
      in that LA fetuses showed lower arterial oxygen pressure (18.3 +/- 1.4 mmHg
      versus 24.8 +/- 1.4 mmHg, P<0.05) and hemoglobin (7.81 +/- 0.30 mg/dl versus 9.22
      +/- 0.21 mg/dl P<0.01) and furthermore, they also showed higher blood glucose
      (2.4 +/- 0.2 mM versus 1.4 +/- 0.1 mM, P<0.01). During the 5 days post-surgery,
      10 GA fetuses (42%) and 1 LA fetus (14%) died in utero. Bacterial contamination
      was implicated in six of the GA deaths and in the one LA death. In the dams with
      surviving calves, differences in hemoglobin (9.49 +/- 0.21 mg/dl versus 11.17 +/-
      0.23 mg/dl P<0.001) and O2ct (10.9 +/- 0.3 ml/dl versus 12.5 +/- 0.5 ml/dl,
      P<0.05) were still present, and in addition, blood glucose was higher in LA
      versus GA cows (4.3 +/- 0.2 mM versus 3.8 +/- 0.1 mM, P<0.05). The choice of
      surgical method did not affect post-surgery blood chemistry in the surviving
      fetuses, except that the higher blood glucose in the LA fetuses at surgery tended
      to be maintained also post-operatively (2.0 +/- 0.2 mM versus 1.5 +/- 0.1 mM,
      P=0.07). The observed differences in blood chemistry parameters between the two
      methods of surgery and possibly in the fetal death may be explained by
      differences in catheterization method and the associated differences in physical
      and metabolic stress during and after surgery. Thus, surgery upon a standing cow
      in local anesthesia should be considered as an alternative to surgery in
      universal anesthesia for fetal catheterization in the cow in late gestation.

PMID- 15036497
TI  - Metabolite and ionic composition of follicular fluid from different-sized
      follicles and their relationship to serum concentrations in dairy cows.
AB  - Metabolic changes in blood serum may be reflected in the biochemical composition
      of follicular fluid and could indirectly influence oocyte quality. The purpose of
      this study was to examine the biochemical composition of follicular fluid
      harvested from different-sized follicles and its relationship with that of blood
      serum in dairy cattle. Following slaughter, blood samples were collected from
      dairy cows n=30 and follicular fluid aspirated from three size classes of non
      atretic follicles (<4 mm, 6-8 mm and >10 mm diameter). Samples remained
      independent between cows and between size classes within cows. Serum and
      follicular fluid samples were assayed using commercial clinical and photometric
      chemistry assays for ions (sodium, potassium and chloride) and metabolites
      (glucose, beta-hydroxybutyrate (beta-OHB), lactate, urea, total protein,
      triglycerides, non-esterified fatty acids (NEFA) and total cholesterol). Results
      showed that follicular fluid concentrations of glucose, beta-OHB and total
      cholesterol increased from small to large follicles and decreased for potassium,
      chloride, lactate, urea and triglycerides. There was a significant concentration
      gradient for all variables between their levels in serum and follicular fluid
      (P<0.05). Significant correlations were observed for chloride (r=0.40), glucose
      (r=0.56), beta-OHB (r=0.85), urea (r=0.95) and total protein (r=0.60) for all
      three follicle size classes and for triglycerides (r=0.43), NEFA (r=0.50) and
      total cholesterol (r=0.42) for large follicles (P<0.05). The results from the
      present study suggest that the oocyte and the granulosa cells of dairy cows grow
      and mature in a biochemical environment that changes from small to large
      follicles. Furthermore, the significant correlation between the composition of
      serum and follicular fluid for the above-mentioned metabolites suggests that
      metabolic changes in serum levels will be reflected in the follicular fluid and,
      therefore, may affect the quality of both the oocyte and the granulosa cells.

PMID- 15036498
TI  - Use of oxytocin and cloprostenol to facilitate semen collection by
      electroejaculation or transrectal massage in bulls.
AB  - Two experiments were conducted with 24 bulls in which semen collection was
      attempted by transrectal massage (RM) and electroejaculation (EE). In experiment
      1, bulls received the following treatments on successive semen collection days:
      saline 10 min prior to electroejaculation (control); saline 10 min prior to 2 min
      of transrectal massage followed by electroejaculation; cloprostenol (CLO) 10 min
      prior to 2 min of transrectal massage followed by electroejaculation; oxytocin
      (OXY) 10 min prior to 2 min of transrectal massage followed by
      electroejaculation. Transrectal massage consisted of general, back and forth
      motion over the ampullae, prostate and urethra with a flattened hand. In
      experiment 2, bulls received saline (control), oxytocin, or cloprostenol 10 min
      before attempting semen collection by transrectal massage. Massage was applied
      specifically to the ampullae for a maximum of 5 min or until a semen sample was
      obtained. Electroejaculation was attempted in all bulls following transrectal
      massage. In experiment 1, semen was obtained in <1% of bulls by transrectal
      massage. However, by using an improved massage technique in experiment 2, semen
      was obtained in 97.2% of attempts. Semen was obtained in 96.9 and 98.9% of
      attempts by electroejaculation in experiments 1 and 2, respectively. Oxytocin
      treatment increased the time to penile protrusion during electroejaculation in
      experiment 1 and during massage in experiment 2. In experiment 1, oxytocin
      decreased the time to semen emission and tended to decrease the number of
      electroejaculation stimuli to semen emission. Cloprostenol treatment, in
      experiment 1, resulted in an increased number of electroejaculation stimuli to
      penile protrusion, but did not affect the number of stimuli required for semen
      emission. Massage of the ampullae prior to electroejaculation reduced both the
      time to semen emission and the number of electroejaculation stimuli required for
      semen emission. Transrectal massage of the ampullae was very effective in this
      experiment for producing semen emission, but quantity of semen samples was less
      than for electroejaculation. The usefulness of transrectal massage for semen
      collection in breeding soundness evaluations needs to be investigated further
      under field conditions.

PMID- 15036499
TI  - Changes in plasma membrane and acrosome integrity of frozen-thawed bovine
      spermatozoa during a 4 h incubation as measured by multicolor flow cytometry.
AB  - Cryopreservation of bull semen is sub-optimal, causing cell death of a majority
      of spermatozoa. Even the surviving cells are affected post-thaw, either
      structurally or functionally. The aim of this study was to investigate the
      sequence of events that take place when sperm plasma membrane and acrosome
      deteriorate during a 4 h incubation period post-thaw, with special attention paid
      to the acrosome status of dying cells. Frozen-thawed semen of six AI dairy bulls
      was used. Three straws per batch were pooled and incubated at 37 degrees C. Sub
      samples were taken at 30 min intervals and stained with SYBR 14, propidium iodide
      (PI) and phycoerythrin-conjugated peanut agglutinin (PE-PNA). Plasma membrane and
      acrosome integrity were measured by flow cytometry. The experiment was repeated
      three times. Immediately after thawing, only 3.45% of the dying cells showed
      acrosomal exocytosis. This number increased dramatically during incubation,
      reaching 67% after 4 h. Within the intact cell population, the overall decrease
      in viability and acrosome integrity was kept at five percentage points. Flow
      cytometry and the triple fluorochrome combination presented a detailed picture of
      the time course in plasma membrane and acrosome deterioration of frozen-thawed
      bull semen. The results are expected to be useful for monitoring new
      cryopreservation protocols.

PMID- 15036501
TI  - Ewe effect: endocrine and testicular changes in experienced adult and
      inexperienced young Corriedale rams used for the ram effect.
AB  - Changes in LH, FSH, and testosterone concentrations, testicular firmness and
      resilience, and scrotal circumference were monitored in 16 Corriedale rams (8
      experienced adult and 8 inexperienced young) for 20 days during which they were
      used to stimulate ewes. The experiment was conducted during November (mid-non
      breeding season). Increases (P<0.05) were observed in LH and testosterone
      concentrations and in testicular firmness and resilience during the first 4 days
      when rams were in permanent contact with estrual ewes. During the following 13
      days, when rams were in contact with non-estrual ewes (i.e. initially estrual
      ewes were no longer in estrus), LH and testosterone concentrations decreased.
      When initially anestrous ewes exhibited estrus 17 to 20 days later,
      concentrations of testosterone increased. Testicular firmness and resilience
      remained high throughout the period. We conclude that: (1) rams used to stimulate
      anestrous ewes show an increase in LH and testosterone concentrations beginning
      at 12 h after joining, and greater concentrations are maintained while estrual
      ewes and mating are allowed; and (2) estrous and mating activity are probably the
      most important stimuli for the increase in hormone concentrations.

PMID- 15036500
TI  - Coincident increases in oxytocin receptor expression and EMG responsiveness to
      oxytocin in the ovine cervix at oestrus.
AB  - This study has localised oxytocin receptor (OTR) mRNA expression within the
      cervix of non-pregnant ewes and related this to changes in the sensitivity of the
      cervical musculature to administered oxytocin (OT) during the oestrous cycle by
      recording electromyographic (EMG) activity. Cervices were collected from 34 ewes
      at specified time points throughout the cycle. OTR mRNA expression was localised
      by in situ hybridisation and results were expressed as optical density
      measurements from autoradiographs in each of four different cervical regions. EMG
      recordings were made for up to 8 h per day from four non-pregnant ewes undergoing
      seasonal oestrous cycles between Days -3 and +3 relative to oestrus (Day 0). The
      highest concentrations of OTR mRNA were detectable within the luminal epithelium
      (LE) of the cervix, with values increasing from Day 15 of the cycle, peaking
      during the follicular phase (P<0.001, compared to the mid-luteal phase) and
      returning to basal by Day 2. There was a small but significant increase in OTR
      mRNA hybridisation (above basal/luteal phase values) within the stromal cells
      (STR) adjacent to the lumen (P<0.05) during the same time period, but no
      differences from basal values were detectable in the dense collagenous annular
      ring or in tissue superficial to this. Analysis of pooled EMG activity recorded
      daily from the cervix indicated that endogenous contractile activity was higher
      on Day 0 than on the Days +1 (P<0.05), -2, +2 and +3 (P<0.001). The response to
      bolus intravenous (i.v.) injections of 25 mU OT (25 mU) varied with day of the
      cycle. This dose produced a measurable and significant response on Days 0
      (P<0.001) and +1 (P<0.001), but not on any of the other days, indicating that the
      sensitivity of the cervical musculature to OT peaked on these days. These data
      show that the cervix is highly responsive to OT at oestrus. This coincides with
      an increase in OTR mRNA expression in the luminal epithelial cells, suggesting
      the likely production of an intermediary messenger between the epithelial and
      smooth muscle cells.

PMID- 15036502
TI  - Ultrasonic characteristics of preovulatory follicle and ovulation in Caspian
      mares.
AB  - The Caspian breed of horses is believed to be the direct descendant of the
      earliest equine animals. Some special characteristics of Caspian horse
      differentiate this breed of horses from other breeds. In the current study the
      ultrasonically observed characteristics of a preovulatory dominant follicle and
      the lengths of estrus, diestrus as well as some related parameters were studied
      during 42 interovulatory intervals in 11 healthy Caspian mares. The preovulatory
      dominant follicle deviated from subordinate follicles and became the largest
      follicle in the ovaries at Day -8.7 +/- 0.53 (Day 0=ovulation). Every mare was a
      single ovulator with ovulations more frequent from the left ovary than from the
      right (65% versus 35%). Mean length of estrus, diestrus, and interovulatory
      interval were 8.3 +/- 0.86, 13.8 +/- 0.59, and 22.1 +/- 0.40 days, respectively.
      The time interval from ovulation until the time in which the mares were no longer
      in estrus was 1.9 +/- 0.42 days.

PMID- 15036503
TI  - Effect of growth hormone and insulin-like growth factor-I on spontaneous
      apoptosis in cultured luteal cells collected from early, mature, and regressing
      porcine corpora lutea.
AB  - The aim of the present study was to test the hypothesis that growth hormone (GH)
      and insulin-like growth factor-I (IGF-I) act at a local level to inhibit luteal
      cell apoptosis. Luteal cells collected from the corpora lutea at different stages
      of the luteal phase were cultured for 24 h in M 199 medium supplemented with 5%
      of calf serum to cause attachment cells to the plastic. After 24 h, the media
      were changed and various concentrations of GH (10, 100 or 200 ng/ml) or IGF-I
      (30, 50 or 100 ng/ml) were added to the culture medium. Twenty-four hours later,
      cells were fixed for morphological assessment of apoptotic cells utilising a
      Hoechst staining technique. To support morphological observations, measurements
      of caspase-3 activity in cultured porcine luteal cells were performed. Increased
      incidence of apoptotic bodies and caspase-3 activity accompanied luteal
      regression and was associated with a decreased progesterone (P4) secretion by
      luteal cells. GH stimulated P4 secretion by luteal cells collected from
      developing (ELP) and mature (MLP) corpora lutea but had no effect on its
      secretion by cells collected from regressing corpora lutea (LLP). Moreover, it
      had no effect on the incidence of apoptotic bodies in all types of corpora lutea.
      However, suppression of caspase-3 activity was observed with 100 and 200 ng of
      GH/ml in all types of corpora lutea. IGF-I had a stimulatory effect on P4
      secretion by ELP and MLP, decreased the incidence of apoptotic bodies and
      suppressed caspase-3 activity in cultures treated with all doses used. In
      conclusion, our results indicate that both GH and IGF-1 trigger anti-apoptotic
      effects either indirectly, by increasing progesterone secretion, or directly,
      through the inhibition of caspase-3 activity and subsequent prevention of
      apoptotic body formation.

PMID- 15036504
TI  - The effect of season on the properties of wild boar (Sus scrofa L.) semen.
AB  - The objective of the study was to determine the properties of wild boar semen and
      their changes in annual cycle. During a 14-month study period, 167 ejaculates
      were sampled from 3 mature boars. In each ejaculate the volume of liquid
      fraction, percentage of spermatozoa motility, spermatozoa concentration and the
      total number of spermatozoa were determined. The activity of acid and alkaline
      phosphatase, and aspartate aminotransferase in the fresh semen plasma was also
      measured. It was shown that wild boar ejaculates did not differ from those of
      domestic boars, and the semen of the highest volume, concentration and number of
      spermatozoa was produced in late autumn. The spermatozoa motility was the lowest
      in summer. The activity of aspartate aminotransferase and alkaline phosphatase in
      the semen plasma increased with shortening of the light period.

PMID- 15036505
TI  - Reproductive performance of gilts and sows in temperate versus subarctic and
      arctic zones of Norway.
AB  - The reproductive performance of gilts and sows from two regions in Norway was
      investigated in a retrospective analysis of data from the litter recording
      system. In the Northern region (North; between 65 degrees N and 71 degrees N),
      there are extreme shifts in natural photoperiod between winter and summer. In the
      Southern region (South; between 59 degrees N and 60 degrees 30'N), photoperiodic
      changes are less dramatic. Gilts were 8 days older at first mating or
      insemination in the North than in the South (P<0.01). A significantly lower
      proportion of sows in the North were mated or inseminated within 5 days post
      weaning than in the South, a difference present both among primiparous and
      multiparous sows (P<0.01). Overall farrowing rate in the North was lower than in
      the South, but litter size (total number born) among those pigs that farrowed was
      larger. After correction for year, month, breed and age at first service, there
      were still lower odds of farrowing for gilts in North than in South. Neither for
      primiparous nor multiparous sows were regional differences in farrowing
      probability significant when year, month, breed and weaning to service interval
      were included in the model. Gilts and primiparous sows had a lower probability of
      farrowing following insemination during summer or autumn months, but service
      month was not significantly related to the farrowing probability of multiparous
      sows. For gilts, litter size was positively related to age at first service. For
      sows, litter size was lowest at weaning to service intervals between 6 and 10
      days. Total numbers of piglets born per litter were estimated to be 0.36, 0.38
      and 0.55 larger in the North than in the South (differences in least square
      means; gilts, primiparous sows and multiparous sows, respectively) (P<0.01).
      Litter size was lower after service during natural long photoperiod than during
      the rest of the year.

PMID- 15036506
TI  - Expression of Smad2 and Smad4, transforming growth factor-beta signal transducers
      in rat endometrium during the estrous cycle, pre-, and peri-implantation.
AB  - SMADs are intracellular signaling molecules that transmit signals elicited by
      members of transforming growth factor-beta (TGF-beta) superfamily. To decipher
      the mechanism of TGF-beta signaling during the estrous cycle and implantation, we
      performed in situ hybridization to investigate the expression patterns of mRNAs
      for Smad2 and Smad4 in rat endometrium during the estrous cycle and on Days 0.5,
      1.5, 2.5, 3.5, 4.5, 5.5, and 6.5 of pregnancy. Intense epithelial expression of
      Smad2 mRNA at diestrus and proestrus was reduced at estrus and metaestrus, while
      Smad4 maintained its constitutive expression during the estrous cycle. During pre
      implantation, both Smads were accumulated in the luminal epithelium and the
      glandular epithelium. Contrary to the dramatic Smad4 expression, Smad2 was highly
      down-regulated on Day 2.5 and was increased on Day 3.5. During peri-implantation,
      both Smads were expressed in the luminal epithelium, subepithelial stroma, and
      the primary decidual zone. Smad4 was down-modulated on Day 5.5. These results
      suggest that (a) both Smads are involved in the tissue remodeling of cycling and
      pregnant rat uteri; (b) TGF-beta signaling functions mainly in the epithelium
      during pre-implantation and Smad2 is involved in the endometrial switch from the
      neutral phase to the receptive phase; (c) TGF-beta signaling is down-regulated at
      the time when trophoblast invasion begins and both Smads are involved in the
      formation of the primary decidual zone.

PMID- 15036507
TI  - Resumption of follicle growth in gilts after ovarian autografting.
AB  - The aims of the study were to evaluate autografting of porcine ovarian tissue in
      terms of establishment of a blood supply, follicle survival and development,
      commencement of oestrous cycles and endocrine patterns in this polyovular
      species. Experiment 1, a preliminary study on four gilts, showed that ovarian
      tissue slices survived the grafting procedure and re-vascularised. In Experiment
      2, a further six pre-pubertal gilts had both ovaries surgically removed and two
      thin cortical slices of each ovary were immediately reattached to each of the
      ovarian pedicles. Blood samples were taken at surgery and then weekly. Two gilts
      were slaughtered 2 weeks after surgery and ovarian tissue recovered. The
      remaining four gilts underwent daily checks for behavioural oestrus until
      slaughter 24 weeks after surgery. All four gilts showed standing heat at least
      once prior to slaughter. Plasma LH and FSH concentrations increased significantly
      (P<0.01) by 3 days after surgery, then fell gradually, but did not return to pre
      surgery levels. Progesterone concentrations showed some evidence of cyclicity in
      all animals. In the grafted tissue, re-vascularisation of the tissue was apparent
      by 2 weeks post-grafting, although no preantral or antral follicles were
      observed. The tissue recovered after 24 weeks contained healthy preantral and
      antral follicles, luteal tissue and some large cystic follicles. It is unclear
      whether these cysts were the result of ovarian or hypothalamic/pituitary
      disturbance. In conclusion, the results of this study have shown that follicle
      growth and resumption of cyclicity can be achieved following ovarian autografting
      in pigs and indicate that this will be a useful model for investigating the
      mechanisms that control the early stages of follicular growth and ultimately
      ovulation rate in this multiovular species.

PMID- 15036508
TI  - Liquid storage of Asian elephant (Elephas maximus) sperm at 4 degrees C.
AB  - The Asian elephant (Elephas maximus) population in the wild has been in decline
      for several decades and breeding in captivity has not been self-sustaining. The
      use of artificial insemination (AI) can help overcome many of the difficulties
      associated with breeding elephants in captivity; however, the ability to store
      semen for extended periods of time is critical to the successful application of
      AI to elephants. The objective of the present study was to assess the effects of
      four different semen extenders and the presence of egg yolk on the viability and
      motility of Asian elephant semen stored at 4 degrees C. High quality ejaculates
      (n=4) were collected from two Asian elephant bulls by rectal massage. Aliquots of
      each ejaculate were extended in four different diluents (Beltsville thawing
      solution (BTS); Tris-citric acid (TCA)/fructose-based; Beltsville F5 (BF5);
      dextrose-supplemented phosphate-buffered saline (PBS)) with or without egg yolk
      then cooled and stored at 4 degrees C. The percentages of viable (viability) and
      motile (motility) sperm were evaluated at 8, 24 and 48 h following collection.
      The addition of egg yolk significantly reduced the percentage loss in viability
      from initial collection to 48 h compared to extenders without egg yolk (17.0 +/-
      8.2 versus 32.6 +/- 8.9 decline in percent viable sperm in the population,
      respectively; P<0.05). Extender and egg yolk affected (P<0.005) total motility
      and percent progressively motile sperm at all evaluation times during incubation.
      TCA + egg yolk maintained higher (P<0.05) levels of progressive motility compared
      to other extenders supplemented with egg yolk. These results indicate that Asian
      elephant semen extended in TCA diluent supplemented with egg yolk can maintain at
      least 50% viability and motility when stored at 4 degrees C for 48 h.

PMID- 15036509
TI  - Changes in feeding level during early pregnancy affect fertility in gilts.
AB  - Modified feeding combining the benefits of restricted feeding after ovulation and
      abundant feeding during implantation in autumn was tested. Three groups of eight
      gilts were housed with individual feeding stalls and fed 40 MJ per day of a
      commercial ration. Following insemination gilts were fed 27 MJ per day (LLL) or
      54 MJ per day (HHH) for 34 days or 27 MJ per day for 10 days, 54 MJ per day for 7
      days followed by 27 MJ per day until day 34 (LHL). Blood for progesterone
      analysis was collected daily during the week of ovulation and then twice a week
      until the end of the study. For LH assay, blood was collected from five gilts
      from each group at 15 min interval for 10 h on the day 15 of pregnancy. Gilts
      were weighed three times at intervals of 4 weeks. The effect of dietary treatment
      was significant (P<0.05) on body weight gain from days 0 to 30 of pregnancy,
      1201, 287 and 438 g per day for groups HHH, LLL and LHL respectively. The
      pregnancy rate at day 34 was significantly higher (P<0.005) in HHH-group (100%)
      compared with LLL (25%) and LHL (38%) although HHH group had significantly lower
      (P<0.05) progesterone concentration on days 9 and 12. The basal LH level was
      significantly higher (P<0.01) in HHH group compared to LHL group (mean +/- S.D.)
      (0.98 +/- 0.22 and 0.60 +/- 0.08, respectively). Gilts in HHH group had a
      significantly higher mean LH concentration (1.18 +/- 0.24) than those in group
      LHL (0.7 +/- 0.07) (P<0.05), but not in group LLL (0.93 +/- 0.15) (P=0.09). There
      was a tendency (P=0.058) for amplitude to be higher for gilts in HHH group. The
      LHL feeding strategy did not provide the benefits anticipated. Instead, it was
      the HHH feeding strategy that provided a distinct advantage in pregnancy rate.
      The mechanism mediating supportive effect of high feeding level on the
      maintenance of early pregnancy is yet to be determined.

PMID- 15036510
TI  - Ovarian follicular wave characteristics in alpacas.
AB  - The objectives were to describe in detail ovarian follicular growth
      characteristics and to establish the interval between successive large follicles
      in unmated alpacas. The ovarian follicular status of 16 non-pregnant, non
      lactating mature alpacas was recorded using ultrasound every second day for
      between 46 and 100 days. An inverse relationship was observed between the
      diameter of the largest follicle and the total number of follicles indicating
      that follicular growth in alpacas occurs in waves. There were 15/38 (39%) inter
      wave intervals of 12 days and 12/38 (32%) intervals of 16 days. The maximum
      follicular diameter in each follicular wave was 8.8 +/- 0.3 mm (n=38). Inter-wave
      intervals of longer duration were associated with a larger maximum follicle
      diameter (P<0.001). However, the growth rate of dominant follicles was consistent
      over the first 10 days after emergence. They reached a diameter capable of
      ovulation by this time, regardless of subsequent inter-wave interval. The latter
      observation suggested that the optimal time of mating might be predicted in
      alpacas, provided that the emergence of ovarian follicular waves was controlled.

PMID- 15036512
TI  - Ultrasonographic evaluation of the pre-pubertal development of the reproductive
      tract in beef heifers.
AB  - To study the development of the reproductive tract in heifers, the ovaries,
      uterus, cervix and vagina were examined by transrectal ultrasonography every 2
      weeks, from 2 to 60 weeks after birth. First ovulation occurred at 63.7 +/- 1.1
      weeks of age. Ovarian dimensions increased rapidly from 2 to 14 weeks of age, and
      increased again after 34 weeks of age (P<0.05). The size of the largest ovarian
      follicles increased from 8 to 14 weeks of age, from 38 to 42 weeks of age, and
      finally from 52 to 60 weeks of age (P<0.05). The number of follicles > or =3 mm
      in diameter tended to increase from 6 to 14 weeks of age (P<0.10) and increased
      significantly from 6 to 60 weeks of age (P<0.05). Mean numerical pixel values of
      the ovarian images decreased from 4 to 26 weeks of age, and then rose to 44 weeks
      of age (P<0.05). Diameter of the uterine body, cervix and vagina increased from 2
      to 20-24 weeks of age, and again after 32 weeks of age (P<0.05). Mean numerical
      pixel values for the uterus and vagina decreased initially (uterus: 4-8 weeks and
      vagina: 6-22 weeks of age) and then increased (uterus: 14-42 weeks and vagina: 22
      32 weeks of age; P<0.05). Pixel heterogeneity showed a consistent peak at 20-22
      weeks of age for the uterus, cervix and vagina (P<0.05). In summary, in the
      heifer calf, the marked growth of the reproductive tract in the first few months
      of age, and prior to first ovulation, reflects phases of increased ovarian
      follicle (> or =3 mm in diameter) numbers and size. Ultrasonographic image
      analysis revealed patterns of numerical pixel values and heterogeneity that may
      be useful in determining important stages of growth and differentiation of the
      reproductive system.

PMID- 15036511
TI  - Follicular growth and ovulation in postpartum beef cows following calf removal
      and GnRH treatment.
AB  - This study investigated the effects of calf removal (CR) and gonadotrophin
      releasing hormone (GnRH) administration on the duration of the postpartum
      anoestrous period in suckled beef cows. Experiment 1 involved 20 multiparous
      suckled cows that were assigned to each of two treatments on Day 61 postpartum:
      (i) unlimited access to their calves (C; n=10) and (ii) calf removal for a period
      of 96 h (CR96, n=10). Experiment 2 involved 24 multiparous cows that were
      assigned to each of two treatments on Day 63 postpartum: (i) CR96 (n=12); and
      (ii) CR96 plus 250 microg of GnRH administered on the day before calf return
      (CR96+GnRH, n=12). Experiment 3 was a 3x2 factorial experiment, involving 48
      multiparous cows assigned to the experiment on Day 58 postpartum. The factors
      were C, CR96 and calf removal for 144 h (CR144), and 0 or 250 microg GnRH
      administered on the day prior calf return. In Experiment 1, the number of cows
      that ovulated within 12 days of calf removal was higher (P<0.05) in CR96 group
      (3/9) compared to the C group (0/10). In Experiment 2, all 12 cows in the
      CR96+GnRH group ovulated. In contrast only 4/12 cows in the CR96 group ovulated
      in response to calf removal. The diameter of the ovulatory follicle tended
      (P=0.06) to be smaller in CR96+GnRH cows (9.8 +/- 0.3 mm) than in CR96 cows (11.3
      +/- 0.9 mm). The maximum diameter attained by the corpus luteum (CL) also tended
      (P=0.08) to be smaller for cows in the CR96+GnRH than for cows in the CR96 group
      (12.1 +/- 2.4 mm versus 16.7 +/- 7.5 mm, respectively). Plasma progesterone
      concentrations 12 days after calf removal tended (P=0.06) to be lower in
      CR96+GnRH cows than in CR96 cows (0.66 +/- 0.1 ng/ml versus 2.00 +/- 1.1 ng/ml,
      respectively). Few cows in the CR96+GnRH group regained normal cyclical activity
      and the interval from onset of calf removal to conception was longer (P<0.05)
      compared to cows in the CR group (52.2 +/- 5.7 days versus 20.0 +/- 6.6 days). In
      Experiment 3, 5/8 cows on the CR144 group and all 8 cows in the CR144+GnRH group
      ovulated. However, the interval from CR to conception was similar for all
      treatments. Temporary (96-144 h) calf removal, particularly in combination with
      GnRH treatment, can induce a high proportion of beef cows to ovulate, but the
      restoration of oestrous cycles may not be achieved.

PMID- 15036513
TI  - Effect of timing of first clinical mastitis occurrence on lactational and
      reproductive performance of Holstein dairy cows.
AB  - Objectives of this study were to determine the influence of timing of first
      clinical mastitis case occurrence on lactational and reproductive performance in
      high producing lactating dairy cows during the first 320 days in milk (DIM).
      Holstein cows, 1001, from two commercial dairy farms in California were
      retrospectively divided into four treatment groups according to timing of first
      clinical mastitis case caused by environmental pathogens: control with no
      recorded clinical cases of mastitis (C; n=501); first clinical mastitis prior to
      first postpartum AI (MG1; n=250); first clinical mastitis between first
      postpartum AI and pregnancy diagnosis (MG2; n=147); and first clinical mastitis
      after diagnosed pregnant (MG3; n=103). Clinical cases of mastitis were identified
      at every milking by the herd personnel based on abnormal milk or swelling of the
      mammary gland. A fore sample of milk was aseptically collected from every
      clinical case for microbiological culture. Mastitis decreased yields of milk,
      3.5% fat-corrected milk, and milk components, but the effect was only observed
      for MG1 and MG2. Cows in the control group had lower linear somatic cell count
      (SCC) score throughout the lactation. Culling was increased by mastitis, and cows
      in the mastitis groups left the study earlier than controls. Conception rate at
      first postpartum AI and pregnancy rate at the end of the study were both
      decreased by mastitis prior to or after first AI, and MG1 and MG2 cows had
      extended days open. Furthermore, cows experiencing mastitis during lactation had
      a higher incidence of abortions. The negative effects of mastitis on reproduction
      were observed regardless of clinical case being caused by either Gram positive or
      negative bacteria. Mastitis either prior to or after first postpartum AI impairs
      lactation performance, increases culling, and decreases reproductive efficiency
      in high producing Holstein dairy cows.

PMID- 15036514
TI  - Induction of a new follicular wave in holstein heifers synchronized with
      norgestomet.
AB  - Treatments with progestin to synchronize the bovine estrous cycle in the absence
      of the corpus luteum, induces persistence of a dominant follicle and a reduction
      of fertility at doses commonly utilized. The objective of the present research
      was to induce a new wave of ovarian follicular development in heifers in which
      stage of the estrous cycle was synchronized with norgestomet. Holstein heifers
      (n=30) were used, in which estrus was synchronized using two doses of PGF2alpha
      i.m. (25 mg each) 11 days apart. Six days after estrus (day 0=day of estrus)
      heifers received a norgestomet implant (6 mg of norgestomet). On day 12, heifers
      were injected with 25 mg of PGF2alpha i.m. and assigned to treatments (T1 to T4)
      as follows: treatment 1, heifers received a second norgestomet implant (T1: N+N,
      n=6), treatment 2, received 100 microg of GnRH i.m. (T2: N+GnRH, n=6), treatment
      3, 200 mg of progesterone i.m. (T3: N+P4, n=6), treatment 4, control treatment
      with saline solution i.m. (T4: N+SS); in the four treatments (T1 to T4) implants
      were removed on day 14. For treatment 5, heifers received 100 microg of GnRH i.m.
      on day 9 and 25 mg of PGF2alpha i.m. (T5: N+GnRH+PGF2alpha) at the time of
      implant removal (day 16). Ovarian evaluations using ultrasonographic techniques
      were performed every 48 h from days 3 to 11 and every 24 h from days 11 to 21.
      Blood samples were collected every 48 h to analyze for progesterone
      concentration. A new wave of ovarian follicular development was induced in 3/6,
      6/6, 3/6, 1/6 and 6/6, and onset of estrus in 6/6, 0/6, 6/6, 6/6 and 6/6 for T1,
      T2, T3, T4 and T5, respectively. Heifers from T1, T3 and T4 that ovulated from a
      persistent follicle, showed estrus 37.5 +/- 12.10 h after implant removal and
      heifers that developed a new wave of ovarian follicular development showed it at
      120.28 +/- 22.81 h (P<0.01). Ovulation occurred at 5.92 +/- 1.72 and 2.22 +/-
      1.00 days (P<0.01), respectively. Progesterone concentration was <1 ng/ml from
      days 7 to 15 in T1, T2 and T4; for T3 progesterone concentration was 2.25 +/-
      0.50 ng/ml on day 13 and decreased on day 15 to 0.34 +/- 0.12 ng/ml (P<0.01). For
      T5, progesterone concentration was 1.66 +/- 0.58 ng/ml on day 15. The more
      desirable results were obtained with T5, in which 100% of heifers had a new wave
      of ovarian follicular development induced, with onset of estrus and ovulation
      synchronized in a short time period.

PMID- 15036515
TI  - Oestrogen and progesterone concentrations in plasma and oviductal tissue of ewes
      exhibiting a natural or induced oestrus.
AB  - Synchronisation of oestrus in Karagouniki ewes by administration of the standard
      dose of progesterone results in lower fertility than observed when these ewes
      ovulate naturally. This suggests that the optimum dose of progesterone may be
      breed dependent. The exogenous progesterone may perturb the concentrations of
      oestradiol-17beta and progesterone in blood plasma and the oviductal wall. This
      possibility was investigated using Karagouniki ewes allocated at random to three
      treatments (n=4 per treatment). Ewes were allowed to exhibit natural oestrus (N)
      or oestrus was synchronised by administration of 250 mg (LP) or 375 mg (HP)
      progesterone (subcutaneous implants) followed by PMSG at 8 mg/kg live weight i.m.
      14 days later. Oestrus was observed using teaser rams. Blood samples were
      collected for plasma oestradiol-17beta and progesterone assay from the onset to
      the end of oestrus at 2 h intervals. The uterus of each ewe was recovered at the
      end of oestrus and samples of the oviductal wall were taken from both oviducts
      and prepared, separately, for progesterone and oestradiol-17beta assay.
      Statistical analysis was performed using univariate analysis of variance. Plasma
      oestradiol-17beta concentrations from the onset to the end of oestrus were
      highest for N ewes and lowest for HP ewes with the values for LP ewes occupying
      an intermediate position. The differences were significant (P<0.05) between HP
      and the other two treatments from 4 to 12 h after the onset of oestrus and then
      between all treatments until the end of oestrus. Plasma progesterone levels were
      similar and fairly constant from the onset to the end of oestrus for N and LP.
      The plasma progesterone levels for HP were significantly (P<0.05) higher than for
      the other two treatments throughout oestrus. In oviductal wall samples, the
      oestradiol-17beta concentration was significantly (P<0.05) higher for N ewes than
      for synchronised ewes and the levels were similar for LP and HP ewes. The
      concentration of oestradiol-17beta differed (P<0.05) between right and left
      oviducts for N ewes but not for ewes of either of the synchronised oestrus
      treatments. Progesterone concentrations in oviductal wall samples were highest
      (P<0.05) for HP ewes and the values for N and LP ewes were similar. The
      concentration of progesterone did not differ between right and left oviductal
      wall samples within treatments. It was concluded that the higher dose of
      exogenous progesterone perturbed the levels of oestradiol-17beta and progesterone
      in blood plasma and the oviductal wall, and this could explain the lower levels
      of fertility (relative to naturally occurring oestrus) observed when this
      protocol is used for Karagouniki ewes in practice.

PMID- 15036516
TI  - Accuracy of evaluation of ovarian structures by transrectal ultrasonography in
      ewes.
AB  - The objective of this study was to assess the accuracy of estimating the size and
      number of corpora lutea (CL) and ovarian follicles by ultrasonography (US) of the
      ewe in standing position. US observations were compared with those made at
      subsequent postmortem examination of the ovaries. Corriedale ewes (n=50) of
      unknown reproductive history and at random stages of the oestrus cycle were used
      for the study. Transrectal US was performed using a 7.5 MHz transducer with the
      ewe in standing position. The ewes were slaughtered 12 h after the US examination
      and the ovaries collected, dissected and the number and size of the CL and
      follicles evaluated. CL were classified as functional or non-functional on the
      basis of their colour and follicles were classified by size (2, 3, 4 and > or =5
      mm). Accuracy of US was assessed by calculating its positive predictive value and
      sensitivity. The data were evaluated by Pearson correlation and linear regression
      analysis. The predictive value and sensitivity of US was 100% for the presence
      and 96% for the absence of CL. In four out of five ewes with double ovulations,
      the presence of both CL was correctly diagnosed by US. For functional CL, the
      sensitivity of US was 100%. The regression coefficient for CL diameter was
      significant (P< or =0.001; r2=0.4; n=35). The size of 85 of 117 follicles was
      accurately determined. The correlation between numbers of follicles counted by US
      and postmortem increased with size of follicle from r=0.44 (P< or =0.01) for 2 mm
      to r=0.85 (P< or =0.001) for >or =5 mm diameter follicles. The regression between
      the diameter of follicles determined by the two methods was significant (P< or
      =0.001; r2=0.8; n=117). The predictive value of US for the number of follicles
      was high (98-100%) for all follicle sizes except for 3 mm diameter follicles
      (predictive value 71%). Similarly, the sensitivity was high for all sizes of
      follicles (90-95%) except for those of 2 mm diameter (62%). It was concluded that
      ultrasound scanning provides a highly accurate method for determining the number
      of CL and follicles > or =4 mm diameter but that its predictive value and
      sensitivity are lower for smaller diameter follicles. The regression equation for
      diameter measured by US on that evaluated postmortem explained more of the
      variation for follicles than for CL.

PMID- 15036517
TI  - Effects of a single injection of hCG or GnRH agonist on day 12 post mating on
      fetal growth and reproductive performance of sheep.
AB  - Reproductive performance and fetal growth were determined when hCG (150 i.u.
      Pregnyl; n=44), GnRH (4 microg synthetic GnRH agonist, buserelin, Receptal; n=43)
      or saline (control, n=45) was administered (i.m.) to ewes on day 12 post mating
      during the breeding season. A total of 12 ewes was slaughtered on day 45 of
      pregnancy (four from each treatment group). Non-return rate and lambing rate were
      higher for ewes in the hCG (0.89 and 84%) and GnRH treated groups (0.86 and 79%)
      than for ewes in the control (0.69 and 62%) group (P<0.05). The ewes in the hCG
      and GnRH groups also had more twins (P<0.05). Birth weights of these twin lambs
      in the hCG and GnRH groups were heavier than those in the control group (P<0.05),
      but this difference had disappeared at weaning 60 days later. Lamb mortality was
      similar among treatment groups resulting in a higher number of lambs weaned in
      the hCG and GnRH groups. The ovarian weights and the number of corpora lutea (CL)
      and luteal weights of ewes slaughtered on day 45 of pregnancy were greater
      (P<0.05) in the hCG and GnRH treated groups than those measured in the control
      group. Administration of hCG on day 12 post mating increased gravid uterus
      weight, crown-rump-length (CRL), chorioallantois weight and total cotyledon
      weight (P<0.05) of conceptuses recovered on day 45 of pregnancy compared to the
      control group. The weights of caruncules (P<0.05) and placenta (P<0.01) were
      higher in conceptuses of both the hCG and GnRH groups. The weights of fetuses in
      the hCG group were higher than those in both the GnRH and control groups
      (P<0.05). In conclusion, both hCG and GnRH administration improved reproductive
      performance of ewes when administered on day 12 post mating. However, hCG and
      GnRH appeared to act differently on embryo survival because only hCG
      administration increased fetal growth.

PMID- 15036518
TI  - Expression of alphav, alpha4, alpha5 and beta3 integrin subunits, fibronectin and
      vitronectin in goat peri-implantation.
AB  - Integrins are glycoprotein heterodimers located in the cell membranes that
      stimulate intercellular adhesion and act as extracellular matrix (ECM) protein
      receptors. Although integrins have been detected in the implantation sites of
      various species, little is known about their participation in ruminant non
      invasive placentation. The objective of this study was the detection of alphav,
      alpha4, alpha5, beta1 and beta3 integrin subunits and of two of their ligands,
      fibronectin and vitronectin, to determine their participation in the caprine peri
      implantation process. On Day 21 post-coitum (pc), endometrial epithelium and
      trophoblastic cells showed an intense alphav and beta3 integrin subunits
      expression and moderate staining for alpha4 and alpha5. On Day 23 pc, integrin
      expression decreased noticeably and only a weak staining of alpha4 and beta3
      integrin subunits were observed. No beta1 integrin subunit expression was
      detected on either of the days studied. Fibronectin (FN) expression in
      trophectodermic and endometrial epithelium was weak or moderate on the days
      studied while vitronectin (VN) expression in the same tissues was moderate or
      strong on Day 21 pc but decreased on Day 23 pc. These results suggest that
      alphavbeta3 integrin, alpha4 and alpha5 subunits, VN and FN are expressed in
      caprine endometrium and blastocyst and may play a role in the cascade of the
      implantation process.

PMID- 15036520
TI  - Prostaglandin F2alpha supplemented semen improves reproductive performance in
      artificially inseminated sows.
AB  - The objective of this study was to assess the effects of the addition of
      prostaglandin F2alpha (PGF2alpha) to semen, to increase reproductive performance
      in sows. Sows in 11 large production units, were inseminated (AI) either with
      PGF2alpha enriched fresh semen (group 1, n=1258) or with untreated fresh semen
      (group 2, n=1101). Conception rate, regular return to estrus, farrowing rate,
      subsequent total and live-born litter size, subsequent weaning to estrus
      intervals, pigs born and pigs weaned per sow per year were evaluated. Conception
      and farrowing rates, as well as regular returns to estrus were altered
      beneficially (P<0.001) with PGF2alpha supplemented semen. Subsequent total-born
      (P<0.06) and subsequent live-born (P<0.15) litter size, as well as subsequent
      weaning to estrus intervals (P<0.22), were not affected to the same extent. Total
      pigs born (P<0.05) and pigs weaned (P<0.04) per sow per year were increased by
      using PGF2alpha supplemented semen.

PMID- 15036519
TI  - Activation and development of porcine oocytes matured in vitro following
      injection of inositol 1,4,5-trisphosphate.
AB  - Inositol 1,4,5-trisphosphate (IP3) is considered to be important for activation
      of mammalian oocytes at the time of fertilization, and activation induces a rise
      in intracellular Ca2+ concentration ([Ca2+]i) by release from the Ca2+ stores in
      the oocytes. Therefore, IP3 could act as an artificial activator of porcine
      oocytes. Activation and development, and rise in [Ca2+]i in matured oocytes
      injected with various concentrations of IP3 were investigated in this study.
      Porcine oocytes were recovered from the ovaries of prepubertal gilts, matured for
      46-48 h and cultured in vitro for 7 days in following treatments as non-injected
      oocytes (NI), injected with carrier buffer, 2.5, 5 and 500 microM of IP3. The
      result showed that IP3 activated porcine oocytes matured in vitro (NI 3.8%,
      buffer 7.1%, 2.5 microM IP3 73.5%, 5 microM IP3 76.2%, 500 microM IP3 85.2%).
      There was a slight but not significant increase in the proportion of oocytes
      activated as the level of IP3 increased. The rate of development to the cleavage
      stage increased remarkably when the concentration of IP3 increased (NI 4.9%,
      buffer 5.7%, 2.5 microM IP3 30.3%, 5 microM IP3 47.1%, 500 microM IP3 78.1%).
      Blastocyst development was only observed in oocytes that had been injected with a
      higher concentration of IP3 (5 microM IP3 6.1% and 500 microM IP3 5.3%). Both the
      peak value and duration of [Ca2+]i rise also increased as the concentration of
      IP3 increased. Baseline values (ratio value, R) for [Ca2+]i ranged from 1.51 to
      1.57 and was not affected by the buffer treatment. The peak value of [Ca2+]i rose
      significantly with increasing level of IP3 treatment (2.5 microM IP3, 3.54 +/-
      0.32; 5 microM IP3, 7.50 +/- 0.37; 500 microM IP3, 8.54 +/- 0.33). Similarly, the
      duration of the [Ca2+]i rise increased as the level of IP3 increased (2.5 microM
      IP3, 43.7+/- 7.00 s; 5 microM IP3, 93.5 +/- 9.17 s; 500 microM IP3, 160.6 +/-
      18.9 s). It was concluded that injected IP3 promotes the development of porcine
      matured oocytes and that their developmental ability is positively correlated
      with the rise in [Ca2+]i induced by IP3.

PMID- 15036521
TI  - Differences among breeds and manifestation of heterosis in AI boar sperm output.
AB  - A total of 271,547 records of semen collections were utilized to appraise sperm
      characteristics of 3319 boars belonging to eight breeds: Czech Large White (CLW),
      Czech Landrace (CLA), Prestice Black-Pied (PBP), Czech Meat Pig (CM), Hampshire
      (HA), Duroc (DC), Pietrain (PN), Large White (LW), and various crosses of these
      breeds. The data was collected over 8 years (1990-1997) from insemination
      stations for boars in the Czech Republic. The assessment of sperm output was
      based on semen volume, number of total spermatozoa and number of viable
      spermatozoa. A linear model was used for statistical analysis included fixed
      effects of breed or crossbred combinations, boar within breed or crossbred
      combinations, year-season, and linear and quadratic regression on age of boars at
      collection and on interval between collections. The average semen volume of boars
      ranged from 161 to 349 ml, number of total spermatozoa from 81x10(9) to 119x10(9)
      and number of viable spermatozoa from 60x10(9) to 86x10(9). The lowest values
      were detected in DC while the highest were observed in LW. In general, sperm
      output significantly differed across breeds and their crossbreeds. The highest
      heterosis effect for semen volume was 30.6% (HA x PN), for number of total
      spermatozoa 18.2% (HA x PN) and 10.4% for number of viable spermatozoa (CLA x
      DC). Sperm output varied with season, including high values in autumn and winter
      and low ones in spring and summer.

PMID- 15036522
TI  - Sperm capacitation in the porcine oviduct.
AB  - In vitro studies suggests that sperm capacitation occurs in the sperm reservoir
      (SR) of the pig, with spermatozoa progressing towards the ampullary-isthmic
      junction (AIJ) around ovulation as a consequence of capacitation/hyperactivation.
      In contrast, in vivo studies are scarce. Consequently, we determined the degree
      of capacitation in boar spermatozoa that were retrieved from the SR of sows at
      well-defined periods of spontaneous standing oestrus, namely pre-, peri- and post
      ovulation, using flow cytometry of Merocyanine-540/Yo-Pro-1-loaded spermatozoa.
      SR-spermatozoa retrieved and incubated in non-capacitating medium (bicarbonate
      free mBO [mBO-]) were largely viable (70-85%) and uncapacitated (69-73%),
      irrespective of the stage of oestrus considered. Those undergoing capacitation
      were a minor proportion (1-5%) during pre- and peri-ovulation, but they
      significantly increased (14%) in post-ovulation oestrus. To clarify whether these
      SR-spermatozoa were able to undergo capacitation under stimuli, sperm aliquots
      were challenged in vitro either by incubation in a bicarbonate-rich medium
      (capacitation medium, mBO+), then further in mBO+ with 20% (v/v) of in vivo
      collected homologous pre-ovulatory isthmic oviductal fluid (IOF), or incubation
      with hyaluronan (HA, 500 microg/ml). Exposure to mBO+ significantly increased the
      sub-population of capacitated spermatozoa from the pre- and peri-ovulation SR,
      indicating that the uncapacitated SR-spermatozoa were responsive to the
      effector/inducer bicarbonate at levels recorded in peri-ovulatory AIJ/ampulla in
      vivo. While addition of IOF or HA to SR-spermatozoa incubated in capacitating
      medium (mBO+) maintained sperm viability without obviously inducing capacitation
      in pre- or peri-ovulatory SR-spermatozoa, they significantly increased these
      percentages during post-ovulation, when compared to baseline values of control
      incubations (mBO-). The results suggest that massive sperm capacitation does not
      occur in vivo in the porcine SR under spontaneous standing oestrus, particularly
      during pre- and peri-ovulation, unless spermatozoa are exposed to the effector
      bicarbonate. Exposure to IOF (and its component HA) under the present
      experimental conditions, reversed bicarbonate influence during pre- and peri
      ovulation and further increased capacitation in post-ovulation, calling for an
      active role of the intratubal fluid. Furthermore, HA appears to have an active
      role in the functionality of the SR.

PMID- 15036524
TI  - Sexual behavior of male New Zealand white rabbits in an intensive production
      unit.
AB  - Sexual behavior in the male white New Zealand rabbit in intensive production
      units is not fully documented. Therefore, the objective of this work was to
      provide further information about the sexual behavior of this species in
      intensive production systems. Fourteen 6- to 12-month-old rabbits were studied
      for 6 months (July/December) when housed individually under natural photoperiod
      (19 degrees latitude north). They were mated once a week. When mated they were
      exposed at 6-min intervals to five oestrous females. The number of mounts, time
      between mounts, time and number of ejaculations, time between ejaculations, and
      also enuresis, grasping and kicking were recorded. Mounts (n=222) were observed
      and recorded. Males mated one to five times during each evaluative session.
      Enuresis was present only in one observation. Sexual aggressiveness such as
      grasping and kicking was present during 142 and 133 matings. Time for mounting
      and ejaculation in accumulated means (minutes, seconds, tenths) from the first to
      the fifth mount were noted and an accumulative average of 4.20 min for the fifth
      mounting was noted. Minimum times for ejaculation and next mating was 00:17:00
      min and maximum was 05:33:03 min. It was concluded that sexual behavior in white
      New Zealand male rabbits remained unchanged through the duration of the period of
      study.

PMID- 15036523
TI  - Effect of estrogen formulation and its site of deposition on serum PGFM
      concentrations, uterine contractility, and time of ovulation in artificially
      inseminated weaned sows.
AB  - At the time of artificial insemination, 48 mixed parity sows were assigned by
      parity to receive 25 microg estradiol-17beta either in oil deposited onto the
      vaginal mucosa (E-oil), or dissolved in extended semen (E-semen), or received no
      estrogen and served as controls. All sows were inseminated transcervically 24 h
      after detection of estrus. The time of ovulation was determined in 15 sows per
      treatment by transrectal ultrasonography. Concentrations of prostaglandin F2alpha
      metabolite (PGFM) were determined in blood samples obtained from eight sows per
      treatment at 1 h intervals from 1 h pre-treatment until 7 h post-treatment. The
      remaining eight sows per treatment were fitted with a transducer to allow
      determination of intrauterine pressure changes during 1 h pre-treatment until 5 h
      post-treatment. There were no differences among treatments for wean to estrus
      interval, size of ovarian follicles at the time of treatment or the estrus
      detection to ovulation interval. In all treatments, plasma PGFM concentrations
      were increased from 1 h after treatment. However, the increase was greater and of
      longer duration in the E-oil sows (P=0.03) supporting the suggestion that this
      formulation and route of administration enhanced uterine PGF2alpha release.
      Compared to controls, both estradiol treatments were associated with myometrial
      contractions of increased amplitude and duration, supporting a causal link
      between estradiol treatment, increased uterine PGF2alpha release, and enhanced
      myometrial contractility.

PMID- 15036525
TI  - Attempts on freezing the Greylag (Anser anser L.) gander semen.
AB  - Semen of Greylag (Anser anser L.) ganders was frozen according to a method
      previously elaborated by the authors for freezing the White Koluda gander semen.
      Semen was collected from five to eight Greylag ganders, twice a week during three
      succeeding reproductive cycles, by dorso-abdominal massage. Semen samples were
      diluted in the ratio of 1:1 or 2:1 (two parts semen: one part diluent) with EK
      diluent, supplemented by 6% DMF, equilibrated and pre-frozen to -140 degrees C at
      a rate 60 degrees C/min, before being transferred into liquid nitrogen container.
      Semen samples thawed in a water bath of 60 degrees C were used for twice a week
      insemination in a volume of 200 microl. Three Greylag and three White Koluda
      geese were involved in frozen-thawed semen fertilizing ability test. The
      reproductive cycle of wild geese lasts usually about 6-7 weeks. The ejaculate
      volume (30-140 microl) and sperm concentration (10x10(6) to 150x10(6) ml(-1)) are
      much lower than these of domestic ganders, but spermatozoa morphology is similar,
      particularly while compared to 1-year-old White Koluda ganders semen. There are
      about 90% of live spermatozoa and about 30% of live morphologically normal cells
      in Greylag gander fresh semen. The Greylag gander spermatozoa susceptibility to
      cryopreservation procedure is as high as in domestic ganders. Dilution ratio 2:1
      resulted in higher number of live spermatozoa, which withstood cryoinjury stress.
      In relation to fresh semen about 60% of spermatozoa remained intact (on the basis
      of light microscope examination) in the frozen-thawed semen. Insemination of
      frozen-thawed semen resulted in 37.5% of fertile eggs in Greylag and 25.0% in
      White Koluda geese. Low fertility rate was caused by an insufficient number of
      live normal spermatozoa used for insemination (about three million in every
      dose).

PMID- 15036526
TI  - Influence of Griseofulvin treatment on semen quality in the dog.
AB  - Griseofulvin is used to treat dermatomycosis in many species and causes
      oligospermia in supra-pharmacological doses. The aim of the present study was to
      evaluate the effect of Griseofulvin administered at therapeutic doses upon semen
      quality in dogs. Four dogs were treated with Griseofulvin (25 mg/kg per day) for
      30 days. Semen collections and analyses were performed before, during and for 100
      days after treatment for the Griseofulvin group and 10 untreated control dogs.
      Semen analyses included mean percentage of forward progressively motile sperm,
      total sperm output, normal live sperm and normal dead sperm. There was no
      significant difference between control and treated dogs for each of the semen
      quality parameters. Therapeutic dosage of Griseofulvin had no deleterious effect
      upon semen quality in dogs, although this does not preclude potential embryotoxic
      and teratogenic effects.

PMID- 15036527
TI  - Intrapreputial infection of young bulls with bovine herpesvirus type 1.2 (BHV
      1.2): acute balanoposthitis, latent infection and detection of viral DNA in
      regional neural and non-neural tissues 50 days after experimental reactivation.
AB  - Venereal infection of bulls with bovine herpesvirus type 1.2 (BHV-1.2) may result
      in acute balanoposthitis followed by the establishment of latent infection,
      presumably in dorsal root nerve ganglia. We herein report the characterization of
      the acute and latent infection of young bulls with a Brazilian BHV-1.2 isolate
      and the investigation of neural and non-neural sites in which viral DNA persists
      during latent infection, i.e. 110 days after inoculation and 50 days after
      experimental reactivation. Intrapreputial inoculation of BHV-1.2 isolate SV-56/90
      (10(6.5)pfu per animal) resulted in severe balanoposthitis, characterized by
      redness of the penis and preputial mucosa, coalescent vesicles and fibrinous
      exsudate in all four infected bulls. Virus shedding was detected in preputial
      secretions and semen up to days 14 and 13 pi, respectively. Dexamethasone
      administration at day 60 pi led to reactivation of the infection in all animals,
      resulting in virus shedding in preputial secretions and/or in semen. At day 50
      post-reactivation (pr), the animals were euthanized and regional tissues were
      collected for PCR and virus isolation. Viral DNA was consistently detected in the
      dorsal root ganglia of nerves genito-femoral (4/4) and obturator (4/4);
      frequently in the pudendal (3/4), sciatic (3/4) and rectal caudal nerve ganglia
      (2/3). In addition, viral DNA was detected in the pelvic sympathetic plexus of
      one bull and in regional lymph nodes (deep inguinal (2/4); sacral (1/4); medial
      iliac (1/4)) of two bulls. No infectious virus could be recovered from
      homogenates of DNA positive tissues, indicating the absence of actively
      replicating virus. These results demonstrate that BHV-1.2 DNA may persist in
      several sacral nerve ganglia and in regional lymph nodes as well during latent
      infection, i.e. 50 days after experimental reactivation. These findings may help
      in understanding the pathogenesis of acute and latent genital infection by BHV
      1.2.

PMID- 15036528
TI  - Influenza surveillance in birds in Italian wetlands (1992-1998): is there a host
      restricted circulation of influenza viruses in sympatric ducks and coots?
AB  - We report the results of a 6-year serological and virological monitoring
      performed in ducks and coots in Italy, in order to assess the degree of influenza
      A virus circulation in these birds during wintering. A total of 1039 sera
      collected from 1992 to 1998 was screened by a double antibody sandwich blocking
      ELISA (NP-ELISA): seroprevalence of antibodies to influenza A viruses was
      significantly higher in ducks compared to coots (52.2% vs. 7.1%, respectively).
      The hemagglutination-inhibition (HI) assay, performed on NP-ELISA positive sera,
      showed that 16.9% of these duck sera and 33.3% of these coot sera had antibodies
      to at least one influenza virus HA subtype: ducks showed HI antibodies against
      most of the HA subtypes, except for the H3, H4, H7, and H12; coots were
      seropositive to the H3 and H10 subtypes, only. From 1993 to 1998, 22 virus
      strains were obtained from 802 cloacal swabs, with an overall virus isolation
      frequency of 2.7%. Viruses belonging to the H1N1 subtype were by far the most
      commonly circulating strains (18/22) and were isolated mainly from ducks (17/18).
      The remaining viruses were representative of the H10N8, H5N2 and H3N8 subtypes.
      Our data indicate some differences between influenza A virus circulation in
      sympatric ducks and coots and a significant antigenic diversity between some
      reference strains and viruses recently isolated in Italy.

PMID- 15036529
TI  - Effect of porcine parvovirus vaccination on the development of PMWS in segregated
      early weaned pigs coinfected with type 2 porcine circovirus and porcine
      parvovirus.
AB  - The objectives of this study were to determine if coinfection of segregated early
      weaned (SEW) pigs with porcine circovirus type 2 (PCV2) and porcine parvovirus
      (PPV) induces an increase in the incidence of post-weaning multisystemic wasting
      syndrome (PMWS) compared to singular PCV2 infection, and to determine if
      vaccination against PPV protects pigs against PMWS associated with PCV2/PPV
      coinfection in SEW pigs. Seventy, 3-week-old, SEW pigs were randomly assigned to
      one of the five groups. Pigs in group 1 (n = 14) served as the negative controls,
      group 2 pigs (n = 14) were inoculated with PCV2, group 3 pigs (n = 12) were
      inoculated with PPV, groups 4 (n = 16) and 5 (n = 14) pigs were inoculated with
      both PCV2 and PPV. Pigs in groups 1-3 and 5 were vaccinated with two doses of a
      killed parvovirus-leptospira-erysipelothrix (PLE) vaccine prior to inoculation.
      The PCV2/PPV-coinfected pigs (groups 4 and 5) had significantly (P < 0.05) higher
      and more persistent fevers than the singular PCV2-infected pigs. One pig in each
      of the coinfected groups developed clinical disease (fever, respiratory disease,
      jaundice, weight loss) consistent with PMWS. Lymphoid depletion was significantly
      (P < 0.05) more severe in the dually-infected pigs at 42 days post-inoculation
      (DPI). Vaccinated, coinfected pigs (group 5) remained viremic significantly (P <
      0.05) longer and had higher copy numbers of genomic PCV2 DNA in sera at 28, 35,
      and 42 DPI compared to the unvaccinated coinfected pigs (group 4). PPV-viremia
      was detected only in the unvaccinated group 4 pigs. PLE-vaccination prevented PPV
      viremia but did not prevent clinical PMWS or reduce the severity of lymphoid
      depletion in PCV2/PPV-coinfected pigs. Evidence of increased incidence of
      clinical PMWS due to vaccination was not observed in this model.

PMID- 15036530
TI  - Experimental dual infection of pigs with an H1N1 swine influenza virus
      (A/Sw/Hok/2/81) and Mycoplasma hyopneumoniae.
AB  - Dual infection of pigs with swine influenza virus (SIV) and Mycoplasma
      hyopneumoniae was carried out to compare the clinical and pathological effects of
      dual infection in caesarian derived and colostrums deprived (CDCD) pigs, with
      that of a single infection with M. hyopneumoniae. In Experiment 1, 40-day-old
      CDCD pigs were inoculated only with SIV (A/Sw/Hok/2/81, H1N1). The virus was
      isolated from nasal swabs for 5-6 days. None of these pigs showed clinical signs
      of infection throughout the experimental period. These results suggested that
      this strain can infect pigs but is only slightly pathogenic when it is inoculated
      singly to a CDCD pig. In Experiment 2, 60-day-old CDCD pigs were inoculated with
      M. hyopneumoniae and then were inoculated with SIV (A/Sw/Hok/2/81) at 1 week
      (MHYO-7d-SIV-7d group) or 3 weeks (MHYO-21d-SIV-7d group) after M. hyopneumoniae
      inoculation. Macroscopically, dark red-to-purple lung lesions were observed in
      all of pigs at 14 or 28 days post-inoculation. Percentages of dark red-to-purple
      lung lesions in dual infection groups (MHYO-7d-SIV-7d group: 18.7 +/- 4.2%, MHYO
      21d-SIV-7d group: 23.0 +/- 8.0%) were significantly (P < 0.05) increased compared
      to those of each control group in which pigs were inoculated only with M.
      hyopneumoniae (MHYO-14d group: 4.7 +/- 2.9%, MHYO-28 group: 3.3 +/- 2.4%).
      Microscopically, bronchial epithelial lesions (epithelial disruption,
      degeneration, hyperplasia and formation of microabscess) were frequently observed
      in dark red-to-purple lung lesions of only the dual infection groups. These
      results demonstrate that the lung lesion of pigs inoculated with M. hyopneumoniae
      and SIV is more severe than that of pigs inoculated only with M. hyopneumoniae.

PMID- 15036531
TI  - Contagious bovine pleuropneumonia (CBPP) caused by vaccine strain T1/44 of
      Mycoplasma mycoides subsp. mycoides SC.
AB  - A study was carried out on four adult cattle to assess the pathogenicity of
      Mycoplasma mycoides subsp. mycoides SC strain T1/44, currently used as a vaccine
      for the control of contagious bovine pleuropneumonia (CBPP) in Namibia. Post
      mortem examination 9 weeks after endobronchial inoculation of the vaccine strain
      to three of the four animals revealed unilateral pleuropneumonic lesions,
      pleuritis and well-developed sequesters in two of the three inoculated animals
      and several small sequesters surrounded by pleuropneumonic lesions in the
      diaphragmatic and apical lobes in one animal. The fourth animal, which was not
      directly inoculated but was in close contact with the inoculated animals,
      revealed only an adhesion area of the lung to the ribcage. Serological
      examination carried out using the complement fixation test (CFT) detected
      positive titres in all three intubated animals and the indirect CBPP-LppQ-ELISA
      was positive for two of the three inoculated animals. The contact animal showed
      no seroconversion. M. mycoides subsp. mycoides SC was isolated from the
      sequesters of two of the inoculated animals. Isolation of mycoplasmas was not
      possible from the third inoculated animal due to heavy contamination of the
      samples by other bacteria, but the presence of M. mycoides subsp. mycoides SC
      could be evidenced by PCR from clinical samples. The identity of the T1/44
      vaccine strain isolated from the sequesters of two animals was confirmed by T1/44
      specific PCR analysis and by IS1296 typing using Southern blot. These results
      clearly show that inoculation of T1/44 vaccine via the endobronchial route can
      lead to CBPP.

PMID- 15036532
TI  - Molecular characterisation of chlamydial isolates from birds.
AB  - Fifty-one chlamydial isolates from birds collected in Switzerland were classified
      by amplification and restriction analysis of the 16S-23S rRNA intergenic spacer
      region as Chlamydophila psittaci. The aim was to characterise a broad panel of
      chlamydial strains from birds and to apply and verify the methods of
      classification and differentiation described for chlamydial organisms. Two of the
      six known avian chlamydial serovars (A and B) were found by serotyping with
      monoclonal antibodies. One isolate was not typable. Digestion of ompA-PCR
      amplicons by AluI generated four distinct restriction patterns (genotypes A, B, F
      and G). Genotypes A and B correlated in most cases to serovars A and B,
      respectively. One serovar A isolate was verified as genotype B instead of A and
      one serovar B isolate belonged to genotype A. The non-serotypable isolate was of
      genotype F and one serovar A generated genotype G. OmpA sequences of one strain
      of each genotype were determined and compared to data bank entries. Amino acid
      sequences of genotype A and B strains corresponded well, showing more than 98.0%
      homology. The homologies of genotypes F and G sequences to genotype A strain were
      82.0 and 83.0% respectively.

PMID- 15036533
TI  - Demonstration of airborne transmission of Actinobacillus pleuropneumoniae
      serotype 2 between simulated pig units located at close range.
AB  - Airborne transmission of Actinobacillus pleuropneumoniae was studied as the
      percentage of air needed to establish airborne transmission from an infected pig
      unit into a neighbouring non-infected pig unit. The experiment was carried out in
      two containers constructed as pig units, placed 1m apart and connected by pipes.
      By manipulating the air pressure in the two units, the amount of ventilation air
      transferred from the infected pigs (unit A) to the non-infected pigs (unit B) was
      controlled and measured. In three experiments, between 48 and 50 specific
      pathogen free-pigs were randomly assigned to each of the two units. In unit A,
      five pigs (experiment 1) or eight pigs (experiments 2 and 3) were inoculated with
      A. pleuropneumoniae serotype 2. In experiments 1 and 3, 10% of the air was
      transferred from unit A to B; in experiment 2, 70% of the air was transferred. In
      the non-infected unit (B), 36% of the pigs seroconverted during experiment 2 (70%
      air transfer), whereas none of the pigs seroconverted in experiments 1 and 3 (10%
      air transfer). As air transmission between closely located pig units has been
      estimated to be less than 2% under field conditions, these results indicate that
      airborne transmission of A. pleuropneumoniae serotype 2 between closely located
      pig units is rare.

PMID- 15036534
TI  - tRNA-intergenic spacer PCR for the identification of Pasteurella and Mannheimia
      spp.
AB  - tRNA-intergenic spacer PCR (tDNA-PCR) was evaluated for its effectiveness in
      differentiating Pasteurella and Mannheimia (sub)species predominantly of ruminant
      origin. For this purpose, 38 reference strains and 13 field isolates belonging to
      both genera were investigated. tDNA-PCR enabled discrimination of all Pasteurella
      species tested (Pasteurella (P.) aerogenes, P. avium, P. canis, P.
      lymphangitidis, P. multocida, P. trehalosi). For the differentiation of the
      subspecies of P. multocida, an additional dulcitol reaction was required. Two of
      the five so far-defined Mannheimia species, M. granulomatis and M. varigena, had
      a distinct fingerprinting profile. The remaining three phylogenetically highly
      related species (M. haemolytica, M. glucosida, and M. ruminalis) clustered
      together. Nevertheless, M. ruminalis is non-haemolytic, and M. haemolytica and M.
      glucosida can be differentiated on the basis of two additional phenotypic
      characteristics (beta-glucosidase and aesculin hydrolysis). In conclusion, tDNA
      PCR is a useful tool in differentiating organisms belonging to the genera
      Pasteurella and Mannheimia.

PMID- 15036535
TI  - Differential expression of the msp1alpha gene of Anaplasma marginale occurs in
      bovine erythrocytes and tick cells.
AB  - Major surface proteins (MSP) 1a and 1b of the tick-borne pathogen Anaplasma
      marginale (Rickettsiales: Anaplasmataceae) are conserved on A. marginale derived
      from bovine erythrocytes and tick cells. MSP1a and MSP1b form the MSP1 complex
      and are adhesins involved in infection of host cells. While both MSP1a and MSP1b
      are adhesins for bovine erythrocytes, only MSP1a is an adhesin for cultured and
      native tick cells. These studies were initiated because antibody responses to
      MSP1a and MSP1b differed in cattle immunized with killed A. marginale derived
      from bovine erythrocytes or cultured tick cells. A strong antibody response to
      MSP1a was observed in cattle immunized with erythrocyte-derived A. marginale,
      whereas cattle immunized with tick cell culture-derived A. marginale produced
      antibodies preferentially to MSP1b. The molecular basis of this differential
      antibody response was then studied using Western blot, confocal microscopy and
      reverse transcriptase (RT)-PCR. Whereas expression of MSP1b by A. marginale
      derived from both bovine and tick host cells was similar at the protein and RNA
      levels, expression of MSP1a by A. marginale in these cells differed. Low levels
      of MSP1a were observed in cultured tick cells and tick salivary glands, but high
      expression of MSP1a occurred on A. marginale derived from bovine erythrocytes.
      The analysis of the expression of the msp1alpha gene by RT-PCR suggests that the
      differential expression of MSP1a is regulated at the transcriptional level and
      may influence the infectivity of A. marginale for host cells. Variation in the
      expression of MSP1a may also contribute to phenotypic and antigenic changes in
      the pathogen.

PMID- 15036536
TI  - Resistance of broiler chickens to Escherichia coli respiratory tract infection
      induced by passively transferred egg-yolk antibodies.
AB  - Egg-yolk antibodies induced by immunizing hens with selected Escherichia coli
      antigens were evaluated for their ability to protect broiler chickens against
      respiratory/septicemic disease caused by avian pathogenic E. coli (APEC). Seven
      groups of broiler breeder hens were vaccinated three times, 1 week apart with
      live E. coli, killed E. coli, E. coli antigens [lipopolysaccharide (LPS), type 1
      pilus adhesin (FimH), P pilus adhesin (PapG), aerobactin outer membrane receptor
      (IutA)] or phosphate buffered saline (PBS). An O78 APEC strain was used for
      preparation of all the antigens. Egg yolk immunoglobulins (IgY) were purified
      from eggs of each group and antibody activity in serum and purified IgY was
      determined by enzyme-linked immunosorbent assay (ELISA). IgY (100mg) was injected
      intramuscularly into 11-day-old broiler chickens, which were challenged 3 days
      later with homologous (O78) or heterologous (O1 or O2) E. coli by the intra-air
      sac route. Mortality was recorded and surviving chickens were euthanized 1 week
      after the challenge and examined for macroscopic lesions. Passive antibodies
      against all antigens except FimH were protective (90-100%) against the homologous
      challenge, but only anti-PapG and anti-IutA were effective against heterologous
      challenge. Anti-PapG IgY provided the greatest protection against the three
      serogroups of E. coli used for challenge. Hence vaccination of broiler breeders
      to induce anti-PapG and anti-IutA antibodies may provide passive protection of
      progeny chicks against respiratory/septicemic disease caused by APEC.

PMID- 15036537
TI  - Isolation and identification of mycobacteria in New World primates maintained in
      captivity.
AB  - The presence of several Mycobacterium species was determined in 68 New World
      monkeys kept captive in the Cali Zoo. One hundred and thirty-three gastric lavage
      and blood samples were evaluated for mycobacterial presence by Ziehl-Neelsen (ZN)
      staining, culture and PCR amplification of the Mycobacterium tuberculosis Mtp40
      species-specific gene. Mycobacteria other than tuberculosis (MOTT) were
      identified by PCR restriction fragment length polymorphism (RFLP). Different
      species of mycobacteria were detected in 65% of the primate population studied by
      Alpha Antigen PCR. Eleven percent were positive for Mtp40 PCR amplification,
      being diagnosed as having M. tuberculosis, and acid-fast bacilli were observed in
      23% by ZN staining. MOTT were isolated from samples taken from 37 primates by
      culturing; according to the RFLP analysis, three strains were classified as
      belonging to the MAISS complex (Mycobacterium avium-intracellulare-scrofulaceum
      simiae) and eight more, isolated from soil inside the cages, were categorized as
      environmental contaminants. Mycobacterium spp. were detected in 13 different New
      World primate species showing that PCR amplification of the Mtp40 gene is a
      better tool than culture for M. tuberculosis detection in captive animals and
      that RFLP is a useful technique for MOTT identification.

PMID- 15036538
TI  - A novel IS element, ISMpa1, in Mycobacterium avium subsp. paratuberculosis.
AB  - A novel insertion element belonging to the IS110 family was identified in
      Mycobacterium avium subsp. paratuberculosis. The IS element, ISMpa1, is 1500 bp
      and has one ORF encoding a putative transposase. Three copies of ISMpa1 were
      identified in the M. avium subsp. paratuberculosis genome. The element had
      inserted into the 3' end of the highly conserved mycobacterial genes prrB and a
      homologue of M. tuberculosis Rv1593c, and between a putative cytochrome p450
      oxygenase and a putative hydrolase. The IS element was present in all (n = 11) M.
      avium subsp. paratuberculosis strains but not detected in most other
      mycobacterial species examined, including 10 M. avium subsp. avium isolates of
      human, avian and porcine origin. However two porcine isolates of M. avium subsp.
      avium and the reference strain IWGMT49 did harbour ISMpa1. These three strains
      belong to a previously described subgroup of M. avium subsp. avium based on
      IS1245 restriction fragment length polymorphism (RFLP) pattern and serovars. All
      of the M. avium subsp. paratuberculosis strains examined had an identical RFLP
      pattern when probed with sequences corresponding to the 5' end of ISMpa1, whereas
      a different pattern was seen in the positive M. avium subsp. avium strains. This
      novel IS element might be a useful tool in strain classification of M. avium
      subsp. avium and also for the identification of M. avium subsp. paratuberculosis
      when used in combination with IS900.

PMID- 15036539
TI  - Intracellular trafficking study of a RB51 B. abortus vaccinal strain isolated
      from cow milk.
AB  - Brucella is responsible for one of the major worldwide zoonoses. Over the last
      century, several vaccines have been used against brucellosis. Among these, the
      rough vaccine Brucella abortus RB51 was introduced with the idea that it would
      not interfere with the diagnosis of brucellosis. Recently, RB51 has been isolated
      from milk and vaginal exudates from vaccinated cows, thus raising the possibility
      of extensive bacterial replication in these animals. We hypothesized that
      shedding of RB51 might be related to a change in its intracellular cell cycle.
      Therefore, we have compared the intracellular trafficking in CHO cells of the
      virulent B. abortus 2308 and two RB51 strains, the vaccinal strain and the one
      isolated from cow milk. Both RB51 strains were transiently observed in phagosomes
      characterized by the presence of the early endosomal marker EEA1 and then were
      found in cathepsin D-enriched lysosomal compartments, in which they eventually
      underwent degradation at later post-infection times. In contrast, the virulent
      2308 strain replicated within the endoplasmic reticulum. These results suggest
      that a change in intracellular trafficking cannot account for Brucella shedding
      in adult vaccinated cows.

PMID- 15036540
TI  - Adhesion of outer membrane proteins containing tandem repeats of Anaplasma and
      Ehrlichia species (Rickettsiales: Anaplasmataceae) to tick cells.
AB  - Infection of cells by tick-borne rickettsiae appears to be mediated by outer
      membrane proteins that allow pathogens to adhere to host cells. Major surface
      protein (MSP) 1a of Anaplasma marginale, the type species for the genus
      Anaplasma, was shown previously to be an adhesin for tick cells. The A. marginale
      MSP1a has a variable number of tandem 28 or 29 amino acid repeats located in the
      amino terminal region of the protein that contains an adhesion domain that is
      necessary and sufficient for infection of tick cells. The MSP1a studies
      demonstrated the importance of combining structural and functional
      characteristics for identification of adhesive proteins. In the present study
      other outer membrane proteins containing tandem repeats were selected from
      organisms of the family Anaplasmataceae and studied for their adhesive properties
      to tick cells. The adhesive properties and protein characteristics were then
      analyzed in order to provide a predictor of the adhesion function of proteins
      identified from genome sequences. Proteins selected included the A. marginale
      MSP1a, A. phagocytophilum 100 and 130 kDa, Ehrlichia chaffeensis 120 kDa, E.
      canis 140 kDa and E. ruminantium "mucin", which were all cloned and expressed in
      Escherichia coli and then tested as adhesins for cultured IDE8 cells. Of the
      proteins studied, the A. marginale MSP1a and the E. ruminantium "mucin" were
      found to be adhesins for tick cells. Although all of these recombinant outer
      membrane proteins were glycosylated, the A. marginale MSP1a and E. ruminantium
      "mucin" adhesins shared a common feature of having a high Ser/Thr content in the
      tandem repeats. The results reported herein provide new information on the role
      of E. ruminantium "mucin" as an adhesin for tick cells and also suggest a role of
      glycans in adhesin molecules.

PMID- 15036541
TI  - Occurrence and characteristics of enterohemorrhagic Escherichia coli O157 in
      calves associated with diarrhoea.
AB  - Little is known of the association of enterohemorrhagic Escherichia coli
      O157:H7/NM (EHEC O157) with disease in naturally infected calves, although cattle
      have been known as a major source for EHEC O157 outbreaks in humans. In this
      study, we investigated the occurrence of EHEC O157 in calves associated
      with/without diarrhoea to examine if EHEC O157 is involved in calf diarrhoea and
      to characterize the isolates. Four hundred and ninety eight diarrhoeic and non
      diarrhoeic young calves from 115 different farms were examined. Of 244 diarrhoeic
      calves, 24 (9.8%) were positive for EHEC O157, and of 254 non-diarrhoeic calves,
      7 (2.8%) were positive. EHEC O157 was recovered from 12/76 (15.79%) of diarrhoeic
      calves less than 2-week-old, and no EHEC O157 was detected in this age group of
      non-diarrhoeic calves. This implicates EHEC O157 as a possible cause of the
      disease in naturally infected neonatal calves. The occurrence of EHEC O157 was
      relatively lower in the older calves (aged older than 8 weeks) and no significant
      difference was found in the occurrence rates between these diarrhoeic and non
      diarrhoeic calves. PCR analysis of virulence markers revealed that the isolates
      carried various virulence genes such as Ehly, eae, stx1 and stx2, which
      underlines the potential importance of these attributes for the infection,
      colonization and possible pathogenesis of calf diarrhoea.

PMID- 15036542
TI  - Influence of sampling time on bacteriological diagnosis of goat intramammary
      infection.
AB  - Intramammary infection in seven commercial goat herds was studied using
      premilking and postmilking samples for purposes as bacteriological diagnosis.
      Using a positive result on both premilking and postmilking samples as the
      definitive diagnosis, we compared the efficacy of single samples collected either
      premilking or postmilking. With this aim, 2268 bacteriological culture results
      were compared. The kappa values (0.60) showed moderate agreement between the two
      samples. Specificity and positive predictive value were higher for postmilking
      samples than for premilking samples. Specificity of postmilking samples was 99.4%
      for coagulase-negative staphylococci, 99.9% for Gram-negative bacilli, 100% for
      streptococci, 99.9% for corynebacteria and 100% for mixed cultures. Premilking
      samples specificity was 96.6, 99.5, 99.7, 99.8 and 99.8%, respectively. False
      positive diagnoses were more frequent for premilking samples. The results suggest
      that postmilking samples should be used to diagnosis of goat intramammary
      infection.

PMID- 15036543
TI  - Cochrane systematic reviews: time for an introduction and appraisal.

PMID- 15036544
TI  - Effectiveness of interventions on opiate withdrawal treatment: an overview of
      systematic reviews.
AB  - AIM: To provide an overview of 5 Cochrane reviews of different approaches for
      treating opioid withdrawal. DESIGN: Narrative and quantitative summary of review
      findings. PARTICIPANTS: There were 46 studies included in the original reviews
      with a total of 3350 participants (range 18-300). INTERVENTION: The 5 reviews
      considered 46 studies covering seven different comparisons, the major ones being
      methadone compared with alpha2-adrenergic agonists and other opioid agonists,
      different alpha2-adrenergic agonists compared with each other and to antagonist
      induced withdrawal and buprenorphine. MEASUREMENTS: The outcomes considered were
      signs and symptoms of withdrawal, retention in treatment, completion rate,
      relapse rate and side effects. FINDINGS: Methadone detoxification results in
      higher retention in treatment, lower relapse rate and fewer side effects when
      compared with adrenergic agonists. No difference was observed when comparing
      different adrenergic agonists; buprenorphine appears to have an advantage over
      adrenergic agonists on withdrawal symptoms and side effects. CONCLUSIONS: Despite
      the considerable number of trials that have been carried out on this topic, they
      are very heterogeneous as far as the comparisons and outcomes considered. This
      prevented many of them from being incorporated into a quantitative meta-analysis.
      Consensus in measurements and results should be reached among researchers
      involved in the evaluation of the effectiveness of treatments for opiate
      addiction in order to produce consistent outcomes in the measuring and reporting
      of results from clinical trials.

PMID- 15036546
TI  - Drug test feasibility in a general population household survey.
AB  - Drug testing was used as an adjunct to a general population household drug use
      survey administered via audio computer assisted self-interview. Participants,
      ages 18-40 years residing in Chicago, were recruited to participate in three
      different biological tests (hair, oral fluid, and urine) presented in random
      order subsequent to completing an interview. Subjects had the option of
      participating in zero to three different tests. We examined participation/refusal
      in tests, reaction to testing requests, as well as variables associated with
      participation and reaction. Subjects were randomly assigned to a low (US$ 10 per
      test) or high (US$ 20 per test) incentive condition. Over 90% of the sample
      participated in at least one test, usually the oral fluid test. Associations
      between refusal status and two variables, socioeconomic status (SES) and presence
      of children in the household, provided partial support for the notion that drug
      test participation parallels the survey response process in general. Incentive
      level did not directly increase drug test participation. Reporting of recent
      illicit drug use was associated with participation in only one procedure, hair
      testing. Type of test offered and individual differences in willingness to be
      drug tested were important predictors of drug test refusal and subject reaction
      to testing requests. Compared with urine and hair testing, oral fluid testing had
      lower refusal rates and was generally more acceptable to respondents in a general
      population survey. The findings support the feasibility of incorporating multiple
      drug tests with modest incentives into general population household surveys on
      drug abuse.

PMID- 15036545
TI  - A comparison of HCV antibody testing in drug-free and methadone maintenance
      treatment programs in the United States.
AB  - Drug treatment programs are uniquely situated to screen patients for antibodies
      for hepatitis C virus (HCV), an infectious disease that has reached epidemic
      proportions among drug users. This paper compares the accessibility and patients'
      use of opportunities for HCV antibody testing in a large sample of methadone and
      drug-free treatment programs (N=256) in the US, and reports programs' recent
      changes and future plans concerning it. Results indicate that almost all
      methadone and about two-thirds of drug-free programs in the sample provided HCV
      antibody screening to at least some patients in 2001. While about two-thirds of
      the methadone and close to one-third of the drug-free programs offered this
      service to all patients, these programs report that only about 3/5 of their
      patients actually provided specimens for testing for HCV antibodies. Some drug
      treatment programs were planning to increase the availability and accessibility
      of HCV antibody screening, but others were planning to cut back on these
      services, primarily due to limited resources. These results can inform
      policymakers who advocate for increased HCV antibody screening in drug treatment
      programs about the current level and future plans for implementing these
      services, illuminating where resources and motivational efforts need to be
      targeted.

PMID- 15036547
TI  - Cannabis use, sport practice and other leisure activities at the end of
      adolescence.
AB  - PURPOSE: To study the relationship between cannabis use, sports practice and
      other leisure activities during adolescence, as a test for the sociological
      theory of deviant opportunities. METHODS: A sample of 12,512 French adolescents
      aged 18 responded to an anonymous self-reported questionnaire in March 2001.
      Three logistic models (for occasional, recent and regular cannabis use) were
      estimated for girls and boys separately. RESULTS: Outings and other peer-oriented
      activities were strongly correlated with cannabis use but this relationship
      depended on which levels of use were considered. Occasional use was more common
      among respondents who participated in many different outdoor activities. Regular
      use was associated with a more selective lifestyle, focusing on music-oriented
      outings and time spent at a friend's home in the evening. CONCLUSIONS: Our
      results provided empirical support for the theory of deviant opportunities.
      Changing patterns of lifestyle associated with transition from initiation to
      higher levels of use may reveal a shift from opportunities of cannabis use
      provided by a wide range of activities to specific activities chosen for their
      convenience to cannabis use. Further research will need to investigate how drug
      use is shaped by lifestyle, and conversely, how drug use reshapes lifestyle.

PMID- 15036548
TI  - Effects of 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) on the self
      administration of cocaine, heroin, and cocaine/heroin combinations in rats.
AB  - Pharmacotherapies utilizing long-acting agonists and mixed function agonists
      antagonists have been successful in the treatment of opiate addiction but no
      comparable treatment exists for cocaine abuse. Long-acting tropane analogues have
      been synthesized that could be candidates for such pharmacotherapies. 2beta
      propanoyl-3beta-(4-tolyl)-tropane (PTT) is one such compound that is a relatively
      selective dopamine (DA) transporter blocker that has a significantly longer
      duration of action than cocaine. The purpose of this study was to assess the
      effects of PTT on the intravenous self-administration of cocaine, heroin, or
      cocaine/heroin combinations. Groups of rats were trained to self-administer
      cocaine, heroin, or cocaine/heroin combinations using a within session dosing
      procedure in which three doses were available each session. PTT pretreatment
      reduced cocaine and cocaine/heroin combinations intake in a dose-dependent manner
      while having only minor effects on heroin intake. These results suggest that the
      neurobiological substrates of cocaine and heroin self-administration are
      different, and that these cocaine/heroin combinations may function more like
      cocaine alone, even when the dose of heroin in the mixture will function
      independently as a reinforcer. These results further support the potential use of
      long-acting dopamine reuptake inhibitors as pharmacotherapeutic adjuncts to a
      comprehensive treatment program for cocaine and cocaine/heroin abuse.

PMID- 15036549
TI  - Prospective examination of effects of smoking abstinence on cortisol and
      withdrawal symptoms as predictors of early smoking relapse.
AB  - This study addressed the hypothesis that exaggerated mood and cortisol changes
      during the first 24h of smoking abstinence are associated with early relapse.
      Salivary cortisol levels and mood reports were measured during 24-h ad libitum
      smoking and the first 24-h abstinence period of a quit attempt. Seventy-two
      habitual smokers (34 women and 38 men) who were interested in smoking cessation
      participated. Cotinine concentrations in saliva and expired carbon monoxide were
      measured before and after abstinence and 1 week after the quit date to verify
      smoking status. Abstinence produced significant withdrawal symptoms in all
      participants and reduced cotinine and carbon monoxide levels. While participants
      showed the expected diurnal changes in cortisol levels, those who relapsed within
      the first week post quitting exhibited a greater drop in morning cortisol
      concentrations during abstinence relative to their ad libitum smoking levels.
      Participants who relapsed reported greater withdrawal symptoms, craving for
      cigarettes, and distress, and they also reported greater reduction in positive
      affect during the first 24-h period of abstinence than those who maintained
      abstinence. These results support the hypothesis that early relapse is associated
      with exaggerated mood and adrenocortical perturbations observed during the first
      day of abstinence.

PMID- 15036550
TI  - Gabapentin maintenance decreases smoked cocaine-related subjective effects, but
      not self-administration by humans.
AB  - Data from research with laboratory animals indicate that cocaine self
      administration can be reduced by lambda-aminobutyric acid (GABA) agonists. Yet,
      the effectiveness of GABA agonists to decrease human cocaine self-administration
      has not been investigated under controlled laboratory conditions. The purpose of
      this study was to assess the effects of gabapentin, a GABA agonist, on cocaine
      related behaviors, including self-administration, in human research participants
      under controlled laboratory conditions. During this 48-day double-blind,
      crossover design study, the effects of gabapentin (0, 600, and 1200 mg/d)
      maintenance on response to cocaine (0, 12, 25, and 50 mg) were investigated in
      seven cocaine abusers. Active cocaine significantly increased choice to self
      administer cocaine, subjective-effect ratings (e.g., "Good Drug Effect"), blood
      pressure and heart rate (HR). Gabapentin did not reduce cocaine choice or
      cardiovascular measures, but it did decrease some subjective effects of cocaine
      (e.g., "Good Drug Effect" and "Anxious"). These data suggest that the cocaine
      gabapentin combination was well-tolerated, and because some cocaine-related
      subjective effects were reduced by maintenance on relatively low gabapentin
      doses, future studies should test higher gabapentin doses.

PMID- 15036551
TI  - Typologies of drug dependence: comparative validity of a multivariate and four
      univariate models.
AB  - Data from a longitudinal cohort study were used to directly compare the
      concurrent and predictive validity of four univariate typologic approaches with a
      multivariate approach in subtyping drug dependence. The four univariate
      typologies were based upon: (a) age-of-onset of drug abuse/dependence, (b)
      presence of drug abuse in first-degree relatives, (c) presence of antisocial
      personality disorder, and (d) sex. The multivariate typologic approach was based
      on indices of vulnerability, chronicity, consequences, and psychopathology,
      yielding the Type A/B dichotomy first demonstrated in alcohol dependence.
      Subtypes generated from the univariate typologies were then each compared with
      the multivariate typology on measures of concurrent and predictive validity, and
      the strength of association was compared statistically. There was evidence of
      significantly greater concurrent validity of the Type A/B typology compared with
      the univariate typologies across all the domains of validation (risk, substance
      use, psychopathology, personality, and overall functioning). The multivariate
      typology also fared better than the univariate ones in all three domains on which
      predictive validity was evaluated: substance use, psychopathology, and overall
      functioning, as well as the degree of change in several composite scores (drug,
      medical, legal, and psychiatric) and the global psychiatric symptom index. This
      direct method of comparison seemed to demonstrate the superior validity of the
      multivariate cluster-analytic approach over the univariate approaches to
      classifying subjects with drug dependence.

PMID- 15036552
TI  - Convergent and concurrent validity of the Contemplation Ladder and URICA scales.
AB  - This study examined the convergent and concurrent validity of the Contemplation
      Ladder and the University of Rhode Island Change Assessment (URICA). Intake data
      of participants recruited into two concurrent studies were analyzed. One group
      (n=77) had no plans to quit smoking within the next 6 months, while a second
      group (n=106) had definite plans to quit. The groups did not differ on any
      demographic variables except employment status. Contemplation Ladder scores for
      the entire sample (n=183) correlated positively with the URICA Contemplation and
      Action subscale scores but negatively with Precontemplation subscale scores. The
      Contemplation Ladder also correlated positively with the URICA Composite score.
      Additionally, participants seeking to quit within the next 6 months had
      significantly higher Contemplation Ladder and URICA Contemplation, Action, and
      Composite scores, but lower Precontemplation scores than participants not seeking
      to quit. Controlling for employment status did not change the pattern of results.
      Our findings provide support for the convergent and concurrent validity of these
      two measures and suggest that the single-item Contemplation Ladder may be a
      practical alternative to the URICA in certain situations.

PMID- 15036554
TI  - Proceedings of the First International Riverwalk Symposium: Neuroprotection and
      the Eye. San Antonio, Texas, USA, February 2000.

PMID- 15036553
TI  - A satisfaction survey of opioid-dependent clients at methadone treatment centres
      in Spain.
AB  - A survey was carried out to evaluate the satisfaction with methadone treatment
      centres of methadone-maintained opioid-dependent patients from Spain. Independent
      interviewers asked 505 consecutively arriving clients from 20 randomly selected
      centres (14 conventional centres, two bus units, and four prisons) to
      participate; 370 (73.3%) clients agreed to fill out the questionnaire, and 351
      (69.5%) completed it. Satisfaction was assessed using the Verona Service
      Satisfaction Scale for methadone treatment (VSSS-MT). The prison sub-sample
      (n=43) was excluded from overall analysis because survey acceptance and
      satisfaction was very different in prisons than in the other centres. Mean
      overall satisfaction in the non-prison sub-sample (n=308) was 3.5 (S.D.=0.6) on a
      1-5 point scale (1=terrible; 5=excellent). The percentage of these clients who
      felt dissatisfied (VSSS-MT scores: < or =3) and satisfied (VSSS-MT scores: >3)
      was, by category: overall satisfaction, 15.9% dissatisfied, 84.1% satisfied;
      basic interventions, 16.0% versus 84.0%; specific interventions, 45.4% versus
      54.6%; social worker skills, 33.8% versus 66.2%; psychologist skills, 38.5%
      versus 61.5%. The number of hours per week that the centre dispensed methadone
      was the only variable able to predict satisfaction. This regression model
      accounted for only 2.5% of the variance in VSSS-MT overall scores. These results
      show that Spanish clients are slightly satisfied with conventional centres and
      bus units, although they fail to detect specific variables that are strongly
      related to that satisfaction.

PMID- 15036555
TI  - The molecular biology of retinal ganglion cell death: caveats and controversies.
AB  - Understanding the molecular pathways activated in dying retinal ganglion cells
      may lead to the development of therapies aimed at blocking the cell death
      process. As we learn more about ganglion cell death, it is becoming clear that
      several new hurdles must be overcome before preventing this process can be a
      realistic therapy. This review details three caveats about retinal ganglion cell
      death that should be considered. The first caveat centers on a critical step in
      the cell death pathway involving mitochondria. Blocking biochemical events after
      mitochondrial dysfunction, such as the caspase cascade, may provide only a
      transient effect on survival, since the cell has already sustained lethal damage.
      The second caveat is that blocking one cell death pathway may be ineffective
      because alternate pathways can become active. This caveat seems to be
      particularly relevant in neurons exposed to excitotoxic insults. The third caveat
      is that although it is possible to block cell death, this does not guarantee that
      the cell will be able to function normally. Consequently, it may be important to
      provide additional treatment to restore normal cell function in conjunction with
      therapies aimed at preventing their death.

PMID- 15036556
TI  - Neuroprotection in ophthalmology: a review.
AB  - Evidence has accumulated that damaged neural cells may not inevitably degenerate,
      and that in vivo cells which are not directly injured by an insult may be
      adversely affected by adjacent dying cells. Neuroprotection is a strategy which
      aims to maximize recovery of injured neural cells and minimize secondary damage
      to neighboring cells. In this work, we review the current knowledge from
      neuroprotection research using in vitro and animal models of eye diseases, and
      clinical data.

PMID- 15036557
TI  - Pharmacologic neuroprotection with an inhibitor of nitric oxide synthase for the
      treatment of glaucoma.
AB  - Excessive nitric oxide, generated by inducible NOS-2 in astrocytes and microglia
      in the optic nerve head of patients with glaucoma, may contribute to the optic
      neuropathy associated with the disease. A rat model of glaucoma, in which there
      is chronic, moderately elevated IOP and slow loss of retinal ganglion cells, has
      been established to study pharmacological agents that have the potential to be
      neuroprotective. In this model, the pharmacological use of an inhibitor of NOS-2,
      aminoguanidine, significantly prevents the loss of retinal ganglion cells. A well
      tolerated pharmacological inhibitor of NOS-2, perhaps orally or locally
      delivered, is a reasonable candidate for a neuroprotective agent for treating
      glaucoma.

PMID- 15036558
TI  - Endogenous neuroprotection in the retina.
AB  - Ischemic preconditioning (IPC) protects the rat retina against the injury that
      ordinarily follows severe ischemia. The retina is protected against the damage
      following severe ischemia for up to 72h after the application of IPC. However,
      there is no early preconditioning, i.e. protective effects starting within hours
      of preconditioning. The IPC stimulus consists of a brief, non-damaging period of
      ischemia. It results in complete preservation of retinal structure and function
      following ischemia, and is thus the most robust neuroprotection demonstrated in
      the retina to date. Release of adenosine, de novo protein synthesis, and
      mediators such as protein kinase C and K(+) ATP channels are required for IPC
      protection. Both the adenosine A1 and A2a receptors are involved. However, the
      molecular mechanisms for neuroprotection have not been completely described. It
      appears that both increased expression of protective proteins and decreased
      expression of pro-apoptotic proteins are involved. In addition, IPC prevents
      hypoperfusion following severe ischemia. Further study of the IPC phenomenon
      could lead to an enhanced understanding of the mechanisms of ischemic damage and
      its prevention in the retina.

PMID- 15036559
TI  - Optic nerve crush: protection and regeneration.
AB  - In neurodegenerative disorders, as well as in acute central nervous system (CNS)
      injuries, the initial impairment triggers a cascade of destructive events,
      collectively termed secondary degeneration, which eventually cause much more
      extensive damage. To investigate the process of secondary degeneration and ways
      to prevent it, we designed a well-calibrated model of optic nerve crush injury.
      Until recently, the main purpose of the immune system was thought to be
      protection of the body against alien pathogens. Since mechanical or biochemical
      insults do not involve exogenous pathogens, recruitment of the adaptive immune
      system was not considered relevant in such cases. We recently demonstrated,
      however, that a T-cell-mediated immune response directed against self-antigens
      residing in the site of damage can be beneficial for the injured optic nerve or
      spinal cord. This protective autoimmune response was found to be spontaneously
      evoked in some individuals, but not strongly enough to significantly affect
      recovery. Our aim was to boost this protective response in those individuals
      capable of spontaneously manifesting it, and to induce it in those incapable of
      manifesting it spontaneously. Optimal functional recovery requires the
      application of a proper combination of neuroprotection and neuroregeneration.

PMID- 15036560
TI  - Heat shock proteins, immunity and glaucoma.
AB  - Glaucoma is no longer viewed simply as elevated intraocular pressure (IOP) that
      damages the optic nerve. In addition to high IOP, evidence is rapidly
      accumulating that suggests damage to the optic nerve may be initiated or
      sustained by any number of factors including ischemia, excitotoxicity,
      neurotrophin insufficiency, peroxynitrite damage or others not yet defined. These
      different harmful influences then likely act through common final pathways that
      eventually activate the cellular proteases that accompany neuronal programmed
      cell death. We believe aberrant immune signal processing may also result in
      retinal ganglion cell death. We hypothesized that one form of glaucoma may be an
      autoimmune neuropathy in which an individual's immune system is not only
      inappropriately regulated, but a cytotoxic effect is rendered by the very system
      which normally serves to protect it against stress. We propose that the family of
      proteins termed "heat shock proteins" are critical modulators of both the
      homeostatic/cytoprotective as well as pathogenic/neurodegenerative arms of the
      immune system in retinal ganglion cells or glial cells and are thus integral to
      glaucomatous neurodegeneration.

PMID- 15036561
TI  - Vaccination for glaucoma: dream or reality?
AB  - Glaucoma is a neurodegenerative disease of the optic nerve, which continues to
      progress even if the primary cause of degeneration is identified and alleviated.
      At any given time the affected optic nerve contains fibers that are amenable to
      neuroprotection, and will escape degeneration provided that the proper
      pharmacological or other intervention is applied. Autoimmunity has long been
      viewed as a deleterious phenomenon that should be terminated or at least
      minimized in order to preserve health. We recently demonstrated, however, that T
      cells specific to self-proteins residing in the site of CNS insult can be
      protective. With the aim of boosting autoimmunity for neuroprotection without
      risking the induction of an autoimmune disease, we developed the use of Cop-1 (an
      FDA-approved drug for the treatment of multiple sclerosis) as an active
      vaccination for neuroprotection. Cop-1 is a synthetic polymer that weakly cross
      reacts with a wide range of self-reacting T cells. Vaccination with Cop-1
      resulted in significant neuroprotection in rat models of optic nerve crush and
      chronic glaucoma. Thus, boosting of a T cell-based mechanism, which we have
      termed 'protective autoimmunity', promotes recovery of the damaged optic nerve.
      Current studies in our laboratory are aimed at translating this treatment into a
      clinical therapy.

PMID- 15036562
TI  - Effects of axonal injury on ganglion cell survival and glutamate homeostasis.
AB  - Axonal trauma leads to a series of pathologic events that can culminate in
      neuronal death. Optic nerve crush can be used to explore histologic and molecular
      changes in traumatic central nervous system malfunction. Although the precise
      mechanisms of retinal ganglion cell death after optic nerve crush have not been
      elucidated, glutamate antagonists can protect retinal ganglion cells after
      axotomy. We, therefore, evaluated the effect of optic nerve crush on levels of
      extracellular glutamate. Ganglion cell survival and extracellular glutamate
      levels were assessed from 1 to 28 days after optic nerve crush in Long-Evans
      rats. Optic nerve crush led to a rise in extracellular glutamate; this rise was
      blocked by treatment with memantine, riluzole, and nimodipine. Partial optic
      nerve crush leads to an increase in vitreal glutamate, perhaps through release of
      intracellular contents. This released glutamate can contribute to additional
      ganglion cell loss. Future work will help to additionally unravel the steps by
      which axotomy induces excitotoxic damage to ganglion cells, and perhaps indicate
      protective interventions.

PMID- 15036563
TI  - Alpha-fodrin is cleaved by caspase-3 in a chronic ocular hypertensive (COH) rat
      model of glaucoma.
AB  - PURPOSE: alpha-Fodrin is a neuronal cytoskeletal protein and a known caspase-3
      target. We sought to determine whether caspase-3 cleaves alpha-fodrin in COH rat
      retinas and whether this process is reduced by adeno-associated virus (AAV)
      induced retinal ganglion cell expression of baculovirus inhibitory repeat
      containing 4 (BIRC4), a potent caspase-3 inhibitor. METHODS: Ocular hypertension
      was induced unilaterally in five rat eyes by limbal injection of hypertonic
      saline. In a similar experiment, ocular hypertension was induced in four eyes pre
      treated with an intravitreal injection of AAV-BIRC4 to assess alpha-fodrin
      cleavage. Western immunoblotting was performed on all retinas. RESULTS: Caspase-3
      cleavage of alpha-fodrin yields a specific 120kDa protein fragment. COH retina
      immunoblots indicated significantly more caspase-3 cleavage of alpha-fodrin than
      controls (P < 0.01, paired t-test). Inhibition of retinal caspase-3 activity with
      BIRC4 reduced caspase-3-mediated alpha-fodrin cleavage compared to controls.
      CONCLUSIONS: This confirms our previous finding of caspase-3 cleavage of alpha
      fodrin in COH retinas and parallels pathology seen in Alzheimer's disease, in
      which neurons undergo chronic caspase activation, slow build-up of cleavage
      products, and delayed apoptosis. If caspase activation in glaucoma leads to
      protracted rather than rapid retinal ganglion cell apoptosis, a much longer
      therapeutic window exists for apoptosis inhibition with caspase inhibitors such
      as BIRC4.

PMID- 15036564
TI  - Oxidative stress-induced apoptosis is associated with alterations in
      mitochondrial caspase activity and Bcl-2-dependent alterations in mitochondrial
      pH (pHm).
AB  - Oxidative stress, the result of cellular production of reactive oxygen species
      (ROS), has been implicated in a number of diseases of the eye. Exposure of eye
      tissues (e.g. the cornea and retina) to oxidative stress over time has been
      hypothesized to underlie the development of age-related macular degeneration
      (AMD) and maturity onset cataract formation. Light-induced free radicals can
      damage the eye, and alterations in the antioxidant defenses of the eye have been
      suggested to play a role in the etiology of glaucoma. Mitochondria are both a
      major endogenous source and target of ROS, and oxidative stress has been shown to
      induce apoptotic cell death by targeting the mitochondria directly. Mitochondrial
      dependent apoptosis has been shown to require release of cytochrome c from
      mitochondria and subsequent activation of a specific class of cytoplasmic
      proteases known as caspases. Bcl-2, an anti-apoptotic protein localized to
      mitochondria, has been shown to inhibit cytochrome c release and protect against
      oxidative stress-induced apoptosis. Here we demonstrate that oxidative stress
      causes activation of mitochondrial matrix caspase-2 and -9 activity that is
      associated with Bcl-2-inhibitable acidification of mitochondrial pH (pH(m)). In
      conjunction with recent reports that caspase activation is maximal at acidic pH,
      these findings have led us to hypothesize that Bcl-2 may modulate cytochrome c
      release following oxidative stress by modifying the pH-dependent activation of
      mitochondrial caspase activity. These studies provide an increased understanding
      of the mechanism(s) by which oxidative stress damages tissues, and may have
      important therapeutic implications for treatment of opthamological diseases.

PMID- 15036565
TI  - Regulation of nitric oxide and soluble guanylyl cyclase.
AB  - Since the discoveries that have verified nitric oxide (NO) as an endogenously
      produced cell signaling molecule, research surrounding its production and
      mechanisms of action have been studied at an exponentially increasing rate. NO is
      produced by a family of enzymes termed the NO synthases (NOS), which are
      regulated independently by various stimuli. Once produced, NO can solicit
      numerous biological events by reacting with various metals, thiols, and oxygen
      species to modify proteins, DNA and lipids. One of the most biologically relevant
      actions of NO is its binding to the heme moiety in the heterodimeric enzyme,
      soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production
      of the second messenger molecule, 3',5'-cyclic guanosine monophosphate (cGMP),
      which can regulate numerous physiological events such as vasodilatation and
      neurotransmission. Here we will review the synthesis and fate of NO, and discuss
      the activation and regulation of the NO receptor, sGC.

PMID- 15036567
TI  - Effectiveness of levobetaxolol and timolol at blunting retinal ischaemia is
      related to their calcium and sodium blocking activities: relevance to glaucoma.
AB  - Glaucoma is a chronic optic neuropathy in which retinal ganglion cells die over a
      number of years. The initiation of the disease and its progression may involve an
      ischaemic-like insult to the ganglion cell axons caused by an alteration in the
      quality of blood flow. Thus, to effectively treat glaucoma it may be necessary to
      counteract the ischaemic-like insult to the region of the optic nerve head.
      Studies on the isolated optic nerve suggest that substances that reduce the
      influx of sodium would be particularly effective neuroprotectants. Significantly,
      of the presently used antiglaucoma substances, only beta-blockers can reduce
      sodium influx into cells. Moreover, they also reduce the influx of calcium and
      this would be expected to benefit the survival of insulted neurones. Betaxolol is
      the most effective antiglaucoma drug at reducing sodium/calcium influx. Our
      electroretinographic data indicated that topical application of levobetaxolol to
      rats attenuated the effects of ischaemia/reperfusion injury. Timolol was also
      effective but to a lesser extent. Based on these data we conclude that beta
      blockers may be able to blunt ganglion cell death in glaucoma, and that
      levobetaxolol may be a more effective neuroprotectant than timolol because of its
      greater capacity to block sodium and calcium influx.

PMID- 15036566
TI  - Pathogenetic aspects of the glaucomatous optic neuropathy: fluorescein
      angiographic findings in patients with primary open angle glaucoma.
AB  - PURPOSE: To identify and quantify the role of retinal circulation, capillary
      leakage and/or nonperfusion of the optic nerve head in digital fluorescein
      angiography in normal subjects and patients with open angle glaucoma. METHODS:
      Eighteen patients with primary open angle glaucoma (POAG) and 18 healthy age
      matched subjects were included. Fluorescein angiograms were performed using the
      scanning laser ophthalmoscope. The arteriovenous passage time (AVP) was assessed
      by dye dilution technique and describes the shortest passage through a retinal
      vascular segment. Optic nerve head nonperfusion was marked manually in early
      angiographic images and is given as percentage of the optic disk area. The
      fluorescence of the optic nerve head (as measure of the disruption of the blood
      brain barrier) and the surrounding retina (ratio of leakage) was measured using
      digital imaging analysis in the late phases of the angiogram (9-10min). RESULTS:
      The AVP time was significantly prolonged ( P=0.001) in patients with open angle
      glaucoma (AVP 2.29+/-0.32 s) compared to healthy subjects (AVP 1.37+/-0.42 s).
      The mean percentage of the optic nerve head nonperfusion was 16%. The ratio of
      optic nerve head fluorescence compared to retinal reference loci was
      significantly increased (P = 0.02) in patients with glaucoma (1.32+/-0.25)
      compared with normal subjects (1.32+/-0.19). CONCLUSIONS: Fluorescein angiography
      revealed altered retinal perfusion along with optic nerve head nonperfusion and
      increased vascular leakage in open angle glaucoma patients. These factors appear
      to influence each other, with ultrastructural changes of the lamina cribrosa
      accompanying changes in the vasculature and nerve fibers. Longitudinal and
      interventive studies should help better elucidate the relationship between
      circulatory and neural loss, adding vasoprotective therapeutic approaches to
      interfere with the glaucomatous neurodegenerative chain of events.

PMID- 15036568
TI  - Sustained perimacular vascular and visual response to topical beta blockers in
      normal human eyes.
AB  - PURPOSE: To assess visual and circulatory responses to treatment with topical
      beta adrenergic antagonists. DESIGN: Institutional prospective randomized
      clinical trial in normal adults. METHODS: Twenty adults (36 (mean) +/- 8 (S.D.)
      years) underwent repeated baseline perimetry (Humphrey 30-2), contrast
      sensitivity (Vector Vision), perimacular microcirculatory studies (Oculix blue
      field entoptic simulator), intraocular pressure (IOP), heart rate (HR), and blood
      pressure (BP) testing. Subjects commenced either timolol 0.5% or betaxolol 0.5%
      twice daily on day 1, were retested on days 3 and 35, discontinued treatment for
      21 days, whereupon repeated tests were performed. Treatment responses were
      compared by paired t-test. RESULTS: Timolol-treated eyes showed improvement in
      contrast sensitivity (P=0.03) and pericentral perimetric thresholds (P=0.01), but
      corresponding increases among betaxolol-treated eyes were significantly higher
      (P=0.03 and 0.04, respectively, relative to timolol-treated eyes). Leukocyte
      velocity increased with both drugs, each with post-withdrawal carryover (P< or
      =0.03). Significant IOP reduction (approximately 2.5 mmHg) occurred in both
      groups, BP fell 2.8 mmHg among betaxolol-treated subjects (P=0.02), and HR was 2
      bpm slower among timolol-treated subjects (P=0.03), but all reverted to baseline
      values after washout. CONCLUSIONS: Both treatment groups demonstrated significant
      changes in visual function and perimacular hemodynamics, sustained after the
      terminal 3-week washout period.

PMID- 15036569
TI  - Vascular change of hippocampal capillary is associated with vascular change of
      retinal capillary in aging.
AB  - Vascular deficiency, such as deleterious change of endothelial cells, becomes the
      prominent feature of hippocampal microvessels during the processes of aging in
      rodents and it seems to be associated with deficiency of intellectual behavior in
      aged subjects. The hippocampal microvessels and hippocampal pyramidal neurons
      form and accumulate intermediates of advanced Maillard reaction (glycation) end
      products, specifically N()-carboxymethyl lysine (CML) and CML in rodents during
      the processes of aging. CML facilitates proliferation of endothelial cells in
      culture. However, further conjugation of CML with the substance(s) seems to occur
      in the microvessels and pyramidal neurons of hippocampus and it brings about
      deleterious change of endothelial cells and pyramidal neuron death. This would
      cause deficiency of recognition and reference memory in rodents during the
      processes of aging. In man in Alzheimer's disease (AD), one might speculate that
      formation and accumulation of CML in the hippocampal microvessels initiate the
      accumulation of amyloid to produce cerebral amyloid angiopathy and it brings
      about hypoglycemia and hypoxia in the hippocampal pyramidal neurons. Furthermore,
      formation and accumulation of CML in the hippocampal pyramidal neurons initiate
      the deposition of neurofibrillary tangles and senile plaques which cause neuronal
      death. In this way, vascular deficiency of hippocampal microvessels seems to be
      associated with the demented disease, the atrophic process of the brain and
      accumulation of amyloid in the brain in man. In terms of vascular deficiency
      concerns, the vascular change of the retinal capillaries becomes also a prominent
      feature during the processes of aging and it has a positive correlation with the
      vascular change of hippocampal capillary. In man during senescence, one might
      also speculate that vascular change of eye capillaries would become the early
      market for diagnosis of dementia in AD.

PMID- 15036570
TI  - Possible therapy for age-related macular degeneration using human telomerase.
AB  - Age-related macular degeneration (AMD) is the leading cause of irreversible
      blindness in people over 60 years of age in the US and many other developed
      countries. Increasingly sophisticated methods for the diagnosis and treatment of
      macular degeneration are not effective for the majority of patients in whom late
      stage disease is present at the time of diagnosis. Research to elucidate the
      changes in RPE cell biology during aging has stimulated interest in preventive
      and prophylactic therapies for earlier intervention in the degenerative process.
      In the normal retina, the RPE performs the functions of barrier, macrophage, and
      neuroprotective cell layer. During aging and in the presence of disease the
      robustness of each of these functions diminishes. The utility of telomerase
      mediated cell and gene therapy to prevent the decline in function of RPE cells
      during aging is evaluated.

PMID- 15036571
TI  - Cattle infestation by Hyalomma ticks and prevalence of Theileria in Hyalomma
      species in the east of Turkey.
AB  - A total of 2388 cattle and 442 shelters, from two provinces (Elazig and Malatya)
      endemic for tropical theileriosis in the east of Turkey, were studied for
      Hyalomma tick populations from July 1993 to July 1995 in Elazig and from May 1998
      to January 1999 in Malatya. Four thousand five hundred and eighty one of 7455
      Hyalomma ticks were collected from cattle, the other ticks (2874) were collected
      from shelters. All of the ticks collected from shelters were Hyalomma anatolicum
      anatolicum. Two thousand eight hundred and ninety five (63.1%) of 4581 Hyalomma
      ticks collected from cattle were H.a. anatolicum. 23.8% (1047/4581), 11.7%
      (536/4581) and 0.6% (3/4581) of Hyalomma ticks were Hyalomma anatolicum
      excavatum, Hyalomma detritum and Hyalomma marginatum marginatum, respectively. A
      total of 5909 Hyalomma adult ticks collected from cattle (3362/5909) and shelters
      (2447/5909) were dissected and salivary glands were stained with
      Methylgreen/Pyronin method. Thousand one hundred and fifty (46.9%) of 2447 H.a.
      anatolicum collected from shelters and 412 (19.1%) of 2147 H.a. anatolicum
      collected from cattle were positive for Theileria infection. Twenty (2.4%) of 820
      H.a. excavatum and 23 (4.6%) of 495 H. detritum collected from cattle were
      positive. The mean number of infected acini per infected male and female ticks
      collected from cattle were 11.3 and 22.4 in H.a. anatolicum, 4 and 6.8 in H.a.
      excavatum, 17.9 and 18.3 in H. detritum, respectively. In H.a. anatolicum
      collected from shelters, the above rates were 11.8 and 17.6 in male and female
      ticks, respectively. The prevalence and intensity of Theileria infection was
      greater in female ticks than in males.

PMID- 15036572
TI  - Mechanical transmission of Trypanosoma vivax in cattle by the African tabanid
      Atylotus fuscipes.
AB  - An experiment was carried out in Burkina Faso to evaluate the potential for
      mechanical transmission of Trypanosoma vivax by the African tabanid Atylotus
      fuscipes. The experiment was carried out in a corral (10 m x 10 m) completely
      covered by a mosquito net (12 m x 12 m and 2.5m high). Eight heifers (cross-bred
      Zebu X Baoule), free of trypanosome infection, were kept together with two
      heifers experimentally infected with a local stock of T. vivax. An average of 539
      A. fuscipes per day, freshly captured with two Nzi traps, were introduced into
      the mosquito net from Day 1 to 20, to allow mechanical transmission of the
      parasites among cattle. Daily parasitological examinations (BCM) of cattle blood
      samples indicated that six of the eight receiver heifers were positive from days
      9, 10, 15, 16, 19 and 29. Mechanical transmission of T. vivax by A. fuscipes was
      demonstrated unequivocally in close to natural conditions, at a high rate (75%
      incidence over a 20-day period) under a mean challenge of 54 insects per heifer
      per day. These results, in addition to previous demonstration of mechanical
      transmission of T. vivax by Atylotus agrestis, confirm that mechanical
      transmission can be a significant route of infection.

PMID- 15036573
TI  - A serosurvey of Hepatozoon canis and Ehrlichia canis antibodies in wild red foxes
      (Vulpes vulpes) from Israel.
AB  - A seroepidemiological survey was conducted to investigate the prevalence of
      antibodies reactive with Ehrlichia canis and Hepatozoon canis antigens in free
      ranging red foxes (Vulpes vulpes) in Israel. Of 84 fox sera assayed, 36% were
      seropositive for E. canis by the indirect fluorescent antibody (IFA) test and 24%
      were positive for H. canis using an enzyme-linked immunosrbent assay (ELISA).
      Canine ehrlichiosis and hepatozoonosis appear to be endemic in the wild red fox
      populations in Israel, and foxes may serve as a reservoir for infection of
      domestic dogs and other wild canine species.

PMID- 15036574
TI  - Base line prevalence and spatial distribution of Echinococcus multilocularis in a
      newly recognized endemic area in the Netherlands.
AB  - The base line prevalence of Echinococcus multilocularis in foxes was determined
      in the eastern part of the province of Groningen in the Netherlands adjacent to
      the German border. This region has been identified in a previous study in 1998 as
      one of the westernmost border areas of E. multilocularis. Base line prevalence
      data are important for a better insight in the possible spread of the parasite
      and its changes in time. As fox feces containing E. multilocularis eggs are an
      important source for human exposure this base line prevalence is also an
      indicator for the potential risk for public health. The base line prevalence was
      estimated at 9.4% (95% CI: 5.2-16.5%). These results confirm previous findings of
      E. multilocularis in the same region. The spatial distribution of the infected
      foxes has been analyzed as a spatial gradient using a logistic model. The
      prevalence appeared to change strongest in east-western direction and was highest
      near the German border, adjacent to a German endemic area. These results suggest
      that the border areas in the Netherlands are the most margin of E. multilocularis
      territory.

PMID- 15036575
TI  - Local and systemic immune responses to Echinococcus granulosus in experimentally
      infected dogs.
AB  - Local and systemic immune responses were studied in six dogs experimentally
      infected with the dog/sheep tapeworm Echinococcus granulosus. All dogs developed
      similar IgG antibody response to parasite antigens. In contrast, IgE and IgA
      responses differed widely. No relationship between IgA responses and parasite
      burden at the end of the infection were observed. Further, clear differences in
      the anti-parasite IgA response in serum as compared with specific IgA forming
      cells in mesenteric lymph nodes were observed within the same dog. An inverse
      association of anti-parasite IgE and parasite load seemed to be present, with the
      strongest IgE response in the one dog that had no worms in the intestine at the
      end of the experiment. No differences were observed in the numbers of intestinal
      mast cells and goblet cells among all infected dogs. However, the dog with no
      detectable parasite load had a marked reduction of detected mast cells in the
      submuscular and muscular layer of the mucosa. Our data give new insight into the
      immune response of dogs during E. granulosus infection and provide information
      that may be useful for the rational design of vaccines for the control of hydatid
      disease.

PMID- 15036576
TI  - High genetic correlation between resistance to Haemonchus contortus and to
      Trichostrongylus colubriformis in INRA 401 sheep.
AB  - To compare the protection acquired by infection with Haemonchus contortus or
      Trichostrongylus colubriformis, successive cross infections with the two species
      were conducted in two genetically similar groups of 150 ewe lambs from 30 sires
      of INRA 401 breed. At 6 and 7.5 months of age, each group received two doses of
      10000 L3 separated by a treatment of one of the species, followed by a similar
      infection with the second species at 9 and 11.5 months. Faecal egg counts (FECs)
      were done 28 and 35 days after each dose. There were very high genetic
      correlation within and between species suggesting that the environmental
      conditions were very similar. The heritability of FEC of H. contortus ranged from
      0.39 to 0.48 and the genetic correlations between FEC after the first and second
      infections with the same or different species were all near 1. Selection against
      this species could be done on the response to only one dose. For T.
      colubriformis, only the response to challenge infection had a similar
      heritability (0.47); the genetic correlations within and among species were also
      near one. These results will assist the selection of sheep resistant to nematode
      parasites.

PMID- 15036577
TI  - Presence of immunoglobulins and antigens in serum, lung and small intestine in
      Ascaris suum infected and immunised pigs.
AB  - The immunodetection of local Ascaris suum antigens and local and systemic
      antibodies were analysed in pigs reinfected with eggs or immunized with the 14,
      42 and 97 kilodalton (kDa) fractions from A. suum. Twenty-one Iberian pigs were
      divided in 7 groups of 3 pigs. Groups 1 and 2 were uninfected and challenge
      control groups, respectively. Groups 3 and 4 were infected weekly with increasing
      doses of A. suum eggs and Group 4 was additionally treated with pyrantel pamoate.
      Groups 5, 6 and 7 were immunised with the 14, 42 or 97 kDa fractions from adult
      worms, respectively. Groups 2-7 were challenged with 10,000 infective eggs.
      Animals of Groups 3 and 4 showed a pulmonary granulomatous reaction with moderate
      number of eosinophils and leukocytes, while Groups 5-7 presented higher number of
      cells, especially in animals immunized with the 42 kDa fraction. These immunized
      groups presented abundant deposition of Ascaris body fluid (BF) and body wall
      (BW) antigens as well as the 14 and 42 kDa fractions in the pulmonary and
      intestinal tissues, while lower deposition of antigens was observed in animals of
      Groups 3 and 4. The immunized pigs of Groups 5 and 6 showed the highest systemic
      IgG titres in serum and these antibodies were negatively correlated with the
      number of larvae recovered in the lungs, suggesting that the IgG response may
      have a protective function against the ascariosis. The highest concentrations of
      IgA-bearing cells were observed in animals of Groups 3 and 4 compared to the
      immunised pigs (Groups 5-7), suggesting that local IgA production may be involved
      in the protection against migrating larvae. The main localisations of IgA-bearing
      cells were the bronchial and peribronchial areas of lungs and the lamina propia
      of duodenum. Low numbers of local IgG-bearing cells were observed in all animals
      and no IgM-bearing cells were detected in the local tissues.

PMID- 15036578
TI  - Experimental acute canine monocytic ehrlichiosis: clinicopathological and
      immunopathological findings.
AB  - Clinical signs, humoral and cellular immune responses, and microscopic and gross
      tissue alterations resulting from acute experimental Ehrlichia canis infection in
      dogs were studied. Four dogs were inoculated with E. canis and four were used as
      uninfected controls. After a 10-14-day incubation period, infected dogs developed
      pyrexia up to 41 degrees C for 6-8 days. Antibody titers to E. canis antigen were
      demonstrable in all inoculated dogs at 30 days post-infection. Necropsy of
      infected animals revealed pale mucous membranes, generalized lymphadenopathy,
      splenomegaly, edema and ascites. Microcopically, the main lesions were:
      lymphoreticular hyperplasia in cortical areas of lymph nodes and spleenic white
      pulp, periportal accumulation of mononuclear cells and centrolobular fatty
      degeneration of the liver. Kidneys presented with glomerulonephritis
      characterized by interstitial mononuclear infiltration. Immunophenotyping of
      lymphocytes from lymph nodes and spleen sections displayed alterations in IgG,
      IgM, CD3+ and CD8+ cells population in infected dogs.

PMID- 15036579
TI  - Multiple binge alcohol consumption during rat adolescence increases anxiety but
      does not impair retention in the passive avoidance task.
AB  - We investigated the effect of binge alcohol consumption on anxiety-related
      behavior and memory in adolescent male Wistar rats. Three consecutive daily
      sessions of ethanol administration (5 g/kg) were repeated weekly for 4 weeks. The
      retention of passive avoidance was measured weekly, 48 h following the treatment.
      Three days after the last memory test a novel object exploration test was done.
      There was no significant difference in step-through latency between the groups,
      but the ethanol-treated group displayed a significantly higher incidence of
      defecation, and an increased number of boluses during the passive avoidance test.
      The latency to explore a novel object was also higher, while the duration of
      exploration was significantly lower. Together, these data suggest that binge
      alcohol consumption in adolescent rats does not impair their memory in passive
      avoidance tasks, but may significantly increase their anxiety.

PMID- 15036580
TI  - Thiol redox state (TRS) and oxidative stress in the mouse hippocampus after
      pentylenetetrazol-induced epileptic seizure.
AB  - In this study we evaluated oxidative stress (lipid peroxidation and protein
      oxidation) and thiol redox state [TRS: glutathione (GSH), glutathione disulfide
      (GSSG), cysteine (CSH), protein (P) thiols (PSH) and protein and non-protein (NP)
      mixed/symmetric disulfides (PSSR, NPSSR, NPSSC, PSSP)] in hippocampus after
      pentylenetetrazol (PTZ) administration at convulsive and subconvulsive dose. The
      significant decrease in PSH, CSH and NPSSC, as well as the increase in PSSP,
      NPSSR, lipid peroxidation and protein oxidation levels after PTZ-induced seizure
      indicate increased oxidative damage in hippocampus, although the levels of GSH
      and GSSG do not change significantly.

PMID- 15036581
TI  - Characterization of NMDA induced depression in rat hippocampus: involvement of
      AMPA and NMDA receptors.
AB  - The involvement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
      (AMPA) vs. N-methyl-d-aspartate (NMDA) receptor mediated changes in NMDA-induced
      long-term depression (LTD) was assessed by monitoring isolated AMPA, isolated
      NMDA and composite field excitatory postsynaptic potentials (EPSP) in the CA1
      area of acute rat hippocampal slices. Application of NMDA (20-50 microM) for 3-5
      min led to LTD of both AMPA and NMDA receptor mediated EPSPs with near equal
      changes of the responses. However, AMPA EPSPs displayed a faster initial recovery
      than NMDA EPSPs. In addition, during the first 15-25 min after NMDA application,
      there was a superimposed potentiation of the later, but not early, part of AMPA
      EPSPs, implying a prolongation of waveform. In contrast, the NMDA EPSP waveform
      remained unaltered throughout the experiments. While it has been maintained that
      NMDA-induced depression is equivalent to stimulus-induced LTD, our results reveal
      additional complexity, suggesting a multitude of changes, most likely at the
      postsynaptic receptor level.

PMID- 15036582
TI  - Milnacipran, a serotonin and noradrenaline reuptake inhibitor, suppresses long
      term potentiation in the rat hippocampal CA1 field via 5-HT1A receptors and alpha
      1-adrenoceptors.
AB  - Pharmacological characteristics of a serotonin (5-HT) and noradrenaline reuptake
      inhibitor (SNRI), milnacipran, in modulation of the synaptic plasticity were
      investigated. Milnacipran (30 mg/kg, i.p.) suppressed the long-term potentiation
      (LTP) in the hippocampal CA1 field of anesthetized rats. Milnacipran-induced
      suppression was reversed by pretreatment with the selective 5-HT1A receptor
      antagonist WAY 100635 (0.1 mg/kg, i.v.) or the alpha1-adrenoceptor antagonist
      prazosin (1 and 10 microg/rat, i.c.v.). The alpha2-adrenoceptor antagonist
      idazoxan (5 mg/kg, i.p.) did not influence the milnacipran-induced synaptic
      responses. These data suggest that the inhibitory effects of milnacipran on LTP
      induction are mediated via both 5-HT1A receptors and alpha1-adrenoceptors. In
      other words, functional interaction between the serotonergic and noradrenergic
      neuronal systems is involved in alteration of the hippocampal synaptic
      plasticity, which may be implicated in the SNRI-induced therapeutic effect on
      psychiatric disorders.

PMID- 15036583
TI  - Brief seizure activity alters Ca2+/calmodulin dependent protein kinase II
      dephosphorylation and subcellular distribution in rat brain for several hours.
AB  - The effect of a brief pentylenetetrazol (PTZ) convulsive seizure on rat cerebral
      cortical Ca2+/calmodulin dependent protein kinase II (CaMKII) was investigated.
      By immunoblot, it was found that a single PTZ seizure, lasting less than a
      minute, caused translocation of CaMKII alpha-subunit (alpha-CaMKII) from the
      particulate to the soluble fraction for several hours, paralleled by a dramatic
      loss of alpha-CaMKII Thr286 phosphorylation. The reduced alpha-CaMKII Thr286
      phosphorylation apparently resulted from enhanced phosphatase activity following
      PTZ seizure, especially in the particulate fraction. CaMKII translocation and
      phosphatase activation following a brief seizure episode can both contribute to
      long-lasting CaMKII regulation far outlasting the immediate effects of the
      seizure on neuronal function.

PMID- 15036585
TI  - Expression of astrocytic nestin in the rat hippocampus during trimethyltin
      induced neurodegeneration.
AB  - In this study we used an immunocytochemical approach to study nestin expression
      in the rat hippocampus during trimethyltin-induced neurodegeneration at different
      time points (5, 10, 15, 21 and 50 days) after intoxication. Nestin is transiently
      expressed by a subpopulation of astroglial cells strictly associated with
      pyramidal neurons in those hippocampal areas severely affected by degeneration.
      This observation shows that cerebral tissue re-expresses this developmental
      protein during neurodegenerative diseases in early stages of astroglial
      activation.

PMID- 15036584
TI  - Effects of the immunophilin ligand FK506 on nerve regeneration in collagen guides
      seeded with Schwann cells in rats.
AB  - We assessed the effects of FK506 administration on regeneration after 5-mm gap
      repair with a collagen guide seeded with syngeneic Schwann cells in the rat
      sciatic nerve. Functional reinnervation was evaluated by non-invasive methods to
      determine recovery of motor and sensory functions in the hindpaw over 4 months
      postoperation. Histological analysis of the regenerated nerves was performed at
      the end of follow-up. Treatment with FK506 (1 mg/kg for the first 2 months)
      resulted in significant improvement of the onset and the degree of reinnervation.
      The numbers of myelinated fibers in the distal regenerated nerve were similar
      between treated and control groups. In conclusion, FK506 improves functional
      recovery after repair with collagen guides seeded with syngeneic Schwann cells.

PMID- 15036586
TI  - Cholecystokinin-B receptor gene expression in cerebellum, pre-frontal cortex and
      cingulate gyrus and its association with suicide.
AB  - Suicide is a complex behaviour. Genetic and environmental factors are implicated
      in suicide. Both factors require genes to exert their effects. One gene
      hypothesized to be involved in the pathophysiology of suicide is cholecystokinin.
      Alterations in cholecystokinin receptor binding have been reported to be
      significant in young suicide victims as compared to matched controls in the
      frontal and cingulate cortex. In this study we report the Cholecystokinin-B gene
      expression using RT-PCR, between suicide completers [(N = 10); mean age 37.2+/-12
      years] and control subjects [(N = 10); mean age 37.6+/-11.9 years].
      Cholecystokinin-B gene expression was significantly higher in the cerebellum (P =
      0.006), cingulate gyrus (P = 0.024) and pre-frontal cortex (P = 0.017) of suicide
      completers when compared to their age and sex-matched controls.

PMID- 15036587
TI  - Region-specific analysis of mitochondrial DNA deletions in neurodegenerative
      disorders in humans.
AB  - Mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) aberrations has
      been implicated in the neuronal death in neurodegenerative disorders. Significant
      neuronal damage can occur if the percentage of mtDNA mutations may reach a
      critical threshold. mtDNA mutations also accumulate during normal aging. Here we
      quantified the 5 kB common mtDNA deletion (CD) using real-time PCR in various
      brain regions from neurodegenerative disorders and controls. We confirmed
      previous results that the CD levels increase with age, reaching highest levels in
      the basal ganglia. High CD levels were also found in affected regions in
      frontotemporal dementia, Parkinson's disease, and dementia with Lewy bodies, but
      not in Alzheimer's disease. This suggests that mtDNA damage may occur in a region
      specific distribution in neurodegenerative disorders.

PMID- 15036588
TI  - Peripherally administered amitriptyline derivatives have differential anti
      allodynic effects in a rat model of neuropathic pain.
AB  - We assessed if derivatives of amitriptyline could alleviate mechanical allodynia
      in a rat model of neuropathic pain. N-methyl amitriptyline (NMA), and
      amitriptyline HCl (AHC) were compared to evaluate the antiallodynic effects
      produced by systemic and peripheral administration. Under general anesthesia with
      halothane, neuropathic injury was produced in rats by tightly ligating the left
      L5 and L6 spinal nerves. All animals developed neuropathic pain behaviors within
      7 days after the surgery. For systemic delivery, three groups of rats were
      injected intraperitoneally with NMA (15 mg/kg), AHC (12.5 mg/kg), or saline. For
      peripheral routes of injection, rats were divided into 3 x 3 groups and injected
      with 100, 330, and 1000 nmol/kg doses of each NMA, AHC and 0.9% normal saline.
      NMA and AHC suppressed mechanical allodynia following peripheral administration
      but not following intraperitoneal injection. NMA was less potent but showed a
      longer-acting response than AHC. This study shows that NMA can be used to relieve
      mechanical allodynia and is a longer-acting agent than AHC.

PMID- 15036589
TI  - Auditory-visual temporal integration as a function of distance: no compensation
      for sound-transmission time in human perception.
AB  - In a psychophysical outdoor experiment with human subjects, the point of
      subjective simultaneity (PSS) of auditory and visual stimuli was measured for
      distances from 1 to 50 m. Repetitive sound and light pulses were presented with
      various stimulus-onset asynchronies, and subjects judged which modality came
      first. With increasing distance of the stimuli the PSS shifted in a linear
      relation toward delays of the light behind the sound. The slope of the regression
      line (3 ms/m) almost exactly corresponded to that of the temporal disparities
      resulting from the lower velocity of sound compared to light. These data refute
      the hypothesis proposed recently that there could be an 'implicit estimation' of
      sound-arrival time. The brain seems to eliminate such crossmodal temporal
      disparities by the integration of auditory and visual stimuli that fall into a
      time window, but not by specific compensatory processes that use an estimate of
      the sound delay.

PMID- 15036590
TI  - The vanilloid receptor-1 is expressed in rat spinal dorsal horn astrocytes.
AB  - The vanilloid receptor-1 (TRPV1), expressed by nociceptive fibers, is a
      transducer of thermal and chemical nociceptive messages. However, endogenous
      ligands excite TRPV1 receptors localized on central nociceptive terminals and
      interneurons. Using immunocytochemistry at the ultrastructural level, we show
      that TRPV1 is also expressed in spinal glial cells characterized as astrocyte by
      double labeling with glial fibrillary acid protein. Quantification of the
      labeling shows that the most numerous labeling is neuronal and that 7% of the
      total TRPV1 labeling is localized in astrocytes. The total absence of staining in
      TRPV1 knock out mice strongly suggests that true TRPV1 protein is present in
      astrocytes. The localization of TRPV1-containing astrocytes apposed to
      nociceptive C-terminals suggests that they may be involved in the control of pain
      transmission.

PMID- 15036591
TI  - Apoptosis induced by endoplasmic reticulum stress depends on activation of
      caspase-3 via caspase-12.
AB  - Recently, endoplasmic reticulum (ER) dysfunction has been implicated in neuronal
      death in patients with Alzheimer's disease. Treatment of human neuroblastoma
      cells with ER stress inducers causes apoptotic death. We confirmed that ER stress
      inducers specifically targeted the ER to cause apoptotic morphological changes.
      We also found that caspase-3, and not caspase-9 (a known mitochondrial apoptotic
      mediator), was mainly activated by ER stress. We generated the neuroblastoma
      cells that stably expressed caspase-12 and analyzed its influence on caspase-3
      activation and vulnerability to ER stress. Cells expressing caspase-12 were more
      vulnerable to ER stress than cells expressing the empty vector, concomitant with
      increased activation of caspase-3. These findings suggested that activation of ER
      resident caspase-12 indirectly activates cytoplasmic caspase-3 and might be
      important in ER stress-induced neuronal apoptosis.

PMID- 15036593
TI  - Postural sway increase in low back pain subjects is not related to reduced spine
      range of motion.
AB  - This study questioned whether postural sway increase in low back pain subjects
      was related to impaired spine mobility, and especially to a decrease in the range
      of motion, which was assumed to represent structural spine stiffness. Ten low
      back pain subjects and ten healthy control subjects performed spine flexion
      extension and spine side bending tests, and standing posturographic examination
      in different experimental conditions. Low back pain subjects showed increased
      postural sway along the antero-posterior axis and reduced side bending, i.e.
      posturographic and range of motion parameters varied in the opposite direction.
      Moreover, no correlation was found between these two types of parameters.
      Although significant, the slight decrease in spine side bending did not seem
      sufficiently great to disturb the low amplitude movements that maintain postural
      equilibrium. Hence, it was concluded that postural sway increase in low back pain
      is not related to a reduced spine range of motion, but might be linked to an
      increase in muscular active tension, which reduces dynamic mobility capacity.

PMID- 15036592
TI  - Reduced facilitation effect of collinear flankers on contrast detection reveals
      impaired lateral connectivity in the visual cortex of schizophrenia patients.
AB  - The aim of this study was to investigate lateral connectivity in early visual
      cortex of schizophrenia patients. Contrast thresholds were measured for centrally
      presented Gabor patches which were surrounded by two collinear or orthogonal
      flankers. The healthy subjects (n = 15) showed lower contrast thresholds for
      central Gabor patches when collinear flankers were presented. This effect was
      significantly reduced in unmedicated highly functioning schizophrenia patients (n
      = 20) who performed normally on the continuous performance test. The performance
      of the patients did not correlate with the positive and negative symptoms. The
      facilitation effect of collinear flankers is believed to reflect lateral
      interactions between feature-specific units in early visual cortex (V1). Our
      results therefore suggest abnormal lateral interactions in early visual cortex of
      schizophrenia patients.

PMID- 15036595
TI  - Zeta 14-3-3 protein favours the formation of human tau fibrillar polymers.
AB  - Tau protein can aggregate, in an aberrant way, in Alzheimer's disease and other
      tauopathies. The formation of those aggregates could take place in vitro by the
      addition of different compounds like polyanions or fatty acids and their
      derivates. Now, we found that a protein, zeta 14-3-3, facilitates the assembly of
      tau as well as a tau peptide containing the self-assembly region of tau molecule
      and a site for PKA phosphorylation. Also, we have found that tau and tau peptide
      polymerization are reduced, but not abolished upon PKA phosphorylation. The
      involvement of a scaffolding protein like 14-3-3 in the generation of tau
      filaments in tauopathies, like AD, is suggested.

PMID- 15036596
TI  - Immunohistochemical localization of phospholipase D2 in embryonic rat brain.
AB  - The present study has characterized the cellular and temporal localization of the
      phospholipase D2 (PLD2) protein in the embryonic rat brain, using
      immunohistochemistry. PLD2 immunoreactivity was first observed in the choroid
      plexus and in the most ventricular zone of the lateral and third ventricles at
      embryonic day 15 (E15), followed by gradual restriction to the limited zone of
      ventricles at E20. In addition, PLD2 expression was high in the developing
      cerebral cortex and hippocampus. In the cortex, PLD2 expression was observed in
      the marginal zone from the earliest stage (E15) and then declined and had
      completely disappeared by E20. Double-labelling studies demonstrated co
      expression of the anti-class III beta-tubulin antibody in most of the PLD2
      immunoreactive cells. Therefore, our findings suggest that PLD2 may be involved
      in early developmental processes of some neuronal progenitors.

PMID- 15036594
TI  - Endomorphin 1- and endomorphin 2-like immunoreactive neurons in the hypothalamus
      send axons to the parabrachial nucleus in the rat.
AB  - Endomorphin 1 (EM1) and endomorphin 2 (EM2) are the endogenous peptides with high
      affinity and selectivity for the mu-opioid receptor (MOR). We examined whether or
      not EM1- and EM2-expressing hypothalamic neurons might send their axons to the
      parabrachial nucleus (PBN), where many MOR-expressing neurons have been observed.
      Immunofluorescence histochemistry was combined with fluorescent retrograde tract
      tracing method. In the rats injected with Fluoro-Gold (FG) into the PBN, some of
      EM1- and EM2-immunoreactive hypothalamic neurons were labeled retrogradely with
      FG. The majority of the EM1/FG and EM2/FG double-labeled neurons were distributed
      in the dorsomedial hypothalamus nucleus, centromedial hypothalamic region, and
      arcuate nucleus; a few of them were also seen in the periventricular hypothalamic
      nucleus and posterior hypothalamic nucleus. Endomorphins released from PBN
      projecting hypothalamic neurons may modulate the gustatory, autonomic and
      nociceptive functions through MOR-expressing PBN neurons.

PMID- 15036597
TI  - An association study of the cholesteryl ester transfer protein TaqI B
      polymorphism with late onset Alzheimer's disease.
AB  - Cholesteryl ester transfer protein (CETP) is reportedly able to affect the amount
      of cholesterol available for deposition and/or removal from peripheral tissues,
      in its capacity to mediate the transfer of cholesterol from high density
      lipoprotein (HDL) to very low density lipoprotein, in exchange for
      triacylglycerols from the latter. The TaqI B polymorphism of the human CETP gene
      has been associated with decreased CETP mass and an increase in HDL-cholesterol.
      While many studies have addressed the atherogenic or anti-atherogenic potential
      of this polymorphism, little is known about its effect on neurodegeneration,
      despite the fact that CETP is expressed in the brain and the disturbance of
      cholesterol homeostasis appears to be an important factor in the pathogenesis of
      Alzheimer's disease (AD). In this report, we have compared the distribution of
      the TaqI B polymorphism in an independent population of 102 clinically diagnosed
      late onset AD patients and a spousal control group of 97 individuals. We have
      also examined the possible interaction between this polymorphism and two other
      polymorphisms suspected of affecting cholesterol flux, namely apolipoprotein E
      APOE epsilon4, and lipoprotein lipase LPLS447X. No statistically significant
      differences have emerged with respect to either genotype or allele frequencies
      between the AD and control populations. CETP TaqI B did not interact
      significantly with either APOE epsilon4 or LPLS447X, in this study.

PMID- 15036598
TI  - Patch clamp study of mouse glomus cells using a whole carotid body.
AB  - Some electrophysiological characteristics of mouse glomus cells (DBA/2J strain)
      were investigated using an undissociated carotid body. The carotid body with
      major carotid arteries was placed in a recording chamber, and glomus cells were
      visualized with a water immersion lens combined with an infrared differential
      interference video camera. Patch clamp experiments revealed that voltage-gated
      outward current, but not inward current, was easily observed in glomus cells.
      Pharmacological experiments and the kinetics of the current suggest that outward
      current is via delayed rectifier, A type, and large conductance calcium-activated
      K channels. Furthermore, K current was reversibly attenuated by mild hypoxia. The
      results suggest electrophysiological similarities of glomus cells among the cat,
      the rat, and the DBA/2J mouse. The method appears useful for physiological
      experiments.

PMID- 15036599
TI  - Sympathetic nervous system mediates cold stress-induced suppression of natural
      killer cytotoxicity in rats.
AB  - The aim of the present study is to investigate the mechanisms of suppression of
      splenic natural killer (NK) cytotoxicity caused by cold stress, using 6
      hydroxydopamine (6-OHDA) as chemical sympathectomy. The NK activity was measured
      by (51)chromium release assay. Central sympathectomy with intracerebroventricular
      (i.c.v.) injection of 6-OHDA reduced significantly the elevation of plasma
      corticosterone level, the expression of Fos in hypothalamic paraventricular
      nucleus and in locus coeruleus, as well as the suppression of NK activity induced
      by cold stress at 4 degrees C for 4 h. Peripheral sympathectomy with
      intraperitoneal (i.p.) injection of 6-OHDA and blockade of beta-adrenergic
      receptor with i.p. injection of propranolol also reversed the cold stress-induced
      suppression of NK cytotoxicity, but without significant effect on Fos expression
      in brain. The results suggest that the activation of hypothalamic-pituitary
      adrenal axis induced by cold stress might be mediated, at least partially, by
      central noradrenergic system, and that the cold stress-induced suppression of NK
      cytotoxicity might be mediated by the activation of peripheral sympathetic nerve.

PMID- 15036600
TI  - Tyrosine augments clozapine-induced dopamine release in the medial prefrontal
      cortex of the rat in vivo: effects of access to food.
AB  - It has been reported that tyrosine administration augments clozapine-induced
      dopamine (DA) release in the medial prefrontal cortex (MPFC). To characterize
      this effect and exclude possible confounds, we conducted a series of studies in
      which microdialysate collection started 24 h after probe implantation, a time at
      which most collected DA is thought to be impulse mediated. Tyrosine (25 or 50
      mg/kg IP) administered 30 min after clozapine (10 mg/kg IP) augmented clozapine
      induced MPFC but not striatal DA release. While tyrosine potentiation was also
      evident in both fasted animals and those with free access to food, the effective
      doses of tyrosine varied. We confirm that tyrosine administration can potentiate
      clozapine-induced MPFC DA release but note that the effect is not evident across
      all doses and conditions.

PMID- 15036602
TI  - Activation of ERK5 is mediated by N-methyl-D-aspartate receptor and L-type
      voltage-gated calcium channel via Src involving oxidative stress after cerebral
      ischemia in rat hippocampus.
AB  - Activation (phosphorylation) and the possible mechanism of extracellular signal
      regulated kinase 5 (ERK5) were evaluated after cerebral ischemia-reperfusion
      (I/R) in the hippocampus in a four-vessel occlusion model of Sprague-Dawley rats.
      Western blotting showed that ERK5 was strongly activated from 10 min to 1 day and
      peaked at 30 min of reperfusion after 15 min ischemia. Pretreatment with N
      acetylcysteine, a free radical scavenger, effectively inhibited ERK5 activation
      in a dose-dependent manner. Consistently, ERK5 activation was significantly
      suppressed by genistein (protein-tyrosine kinase inhibitor), PP2 (specific
      inhibitor of Src family kinases), nifedipine (L-VGCC blocker) and
      dextromethorphan (NMDA receptor antagonist), but not 6,7-dinitroquinoxaline-2,
      3(1H, 4H)-dione (AMPA receptor antagonist). These results suggested that ERK5
      could be significantly activated by I/R, which might be mediated by NMDA receptor
      and L-VGCC through Src kinase pathway involving oxidative stress in rat
      hippocampus.

PMID- 15036601
TI  - alpha-Sialylcholesterol enhances the depolarization-induced release of
      acetylcholine and glutamate in rat hippocampus: in vivo microdialysis study.
AB  - The effects of alpha-sialylcholesterol (alpha-SC), a synthetic ganglioside
      analogue, on synaptic neurotransmission were studied using in vivo microdialysis
      technique. Application of alpha-SC through a microdialysis probe enhanced high
      potassium-evoked release of acetylcholine and glutamate in the hippocampal CA3
      region of Wistar rats. The experiments using synaptosomes and FM1-43, a
      fluorescent styryl dye used for studies of neurotransmitter release mechanisms,
      showed that alpha-SC increased depolarization-induced loss of dye but it did not
      evoke the dye loss at resting condition. These results indicate that alpha-SC
      promotes a depolarization-induced exocytotic neurotransmitter release in the
      brain under in vivo conditions. Application of alpha-SC increased the level of
      glutamate but not that of acetylcholine, suggesting that alpha-SC affects
      spontaneous glutamate release and/or transport system at the brain region.

PMID- 15036603
TI  - Delayed moderate hypothermia reduces calpain activity and breakdown of its
      substrate in experimental focal cerebral ischemia in rats.
AB  - Calpains, intracellular proteases, are involved in various cerebral disorders. To
      determine the effect of moderate hypothermia on calpain activity, transient
      middle cerebral artery occlusion in rats was performed. For the reperfusion
      period normothermic temperature was compared to post-ischemic hypothermia (32
      degrees C). Calpain expression was measured by Western blot analysis and
      immunohistochemistry. The loss of calpain substrate was determined by
      immunohistochemistry against the anti-microtubule-associated protein-2 (MAP-2).
      The increase of calpains in the ischemic as compared to the non-ischemic
      contralateral hemisphere and the loss of MAP-2 were reduced by hypothermia. These
      data indicate that calpain activity and calpain-induced proteolysis play an
      important role in the network of events following cerebral ischemia and can be
      reduced by hypothermia. Moderate hypothermia may be a useful tool to limit
      secondary injury induced by intracellular calpain degradation.

PMID- 15036604
TI  - Pattern of cerebral edema and hemorrhage in a mice model of diffuse brain injury.
AB  - This study aims to examine the time course of the brain edema formation in
      relation with blood-brain barrier (BBB) disruption and cerebral hemorrhage in a
      murine model of diffuse brain injury. Brain water content increased at 1 h post
      injury and persisted up to 7 days. This event was associated with electrolyte
      imbalance such as Na(+) increase within 24 h. Prominent Evans blue extravasation
      was also observed from 1 to 6 h post-injury. Concurrently, hemoglobin increased
      markedly by 1 h, reached a peak at 4 h and declined progressively within a week
      in association with a rise of parenchyma iron content between 24 h and 7 days.
      These results suggest that brain edema is vasogenic and that the hemorrhage
      process is involved in the BBB disruption and edema, both leading to post
      traumatic secondary events.

PMID- 15036605
TI  - Comparing human reaches across three viewing conditions in a step and reach task.
AB  - The effects of gaze and step direction on a step and reach task were studied to
      gain insight to possible motor control strategies used in goal-directed whole
      body movements. Head, foot and arm positions were monitored while subjects
      reached to nine targets in space. In dim light, subjects looked at and reached to
      actual targets or remembered targets, or reached to remembered targets initially
      located eccentric to gaze orientation. Final reaching errors were influenced by
      step and gaze orientations, but gaze direction variables were the largest
      contributors found to predict reach errors. While spatial memory of target
      location was initially encoded in eye-centered coordinates, memory of eccentric
      target location was not updated when subjects stepped and reached. Thus, control
      strategies were dependent on gaze direction in the dim light conditions.

PMID- 15036606
TI  - Shifts in the retinal image of a visual scene during saccades contribute to the
      perception of reached gaze direction in humans.
AB  - We tested whether the perception of gaze direction is affected by the shifts in
      the retinal image of the visual scene during eye movements. To do so, we
      displaced the visual scene during saccadic eye movements and measured whether
      these unconsciously-detected shifts altered subjects' perception of the reached
      gaze direction. While facing a visual environment composed of light-emitting
      diodes, subjects first performed a rightward saccade of a great amplitude before
      producing a leftward saccade towards a target that appeared in the environment.
      During the primary saccade, the visual environment could be shifted by 4.5
      degrees on either side. Subjects overestimated the target by 3.69 degrees and
      underestimated it by 2.45 degrees when the shift of the retinal image of the
      environment was greater and smaller than the extent of eye deviation,
      respectively. This suggests that the perception of gaze direction is largely
      based on the processing of retinal excitation both before and after the eye
      movements.

PMID- 15036607
TI  - Susceptibility for ischemic stroke in Korean population is associated with
      polymorphisms of the interleukin-1 receptor antagonist and tumor necrosis factor
      alpha genes, but not the interleukin-1beta gene.
AB  - Enhanced release of proinflammatory cytokines may contribute to the pathogenesis
      of ischemic stroke. Interleukin-1 receptor antagonist (IL-1Ra) is an anti
      inflammatory cytokine, and tumor necrosis factor (TNF)-alpha and IL-1beta are
      proinflammatory cytokine. To determine the role of cytokines in genetic
      susceptibility to ischemic stroke, we genotyped ischemic stroke patients (n =
      152) and the healthy control subjects (n = 165) for IL-1Ra, TNF-alpha and IL
      1beta polymorphism by polymerase chain reaction-restriction fragment length
      polymorphism methods. The analysis shown the association of IL1RN*1, IL1RN*2
      allele (IL1RN*1, OR=0.44, P = 0.0206 IL1RN*2, OR=2.90, P = 0.0141) and TNF1, TNF2
      allele (TNF1, OR=2.16, P = 0.0225; TNF2, OR=2.16, P = 0.0225) to ischemic stroke.
      However, the genetic polymorphism of IL-1beta was not associated with ischemic
      stroke. Our results suggest that IL-1Ra and TNF-alpha gene polymorphism is
      associated with the susceptibility to ischemic stroke.

PMID- 15036608
TI  - Effect of paroxetine on a model of posttraumatic stress disorder in rats.
AB  - To better understand neurochemical and psychopharmacological aspects of post
      traumatic stress disorder (PTSD), it is necessary to establish an animal model of
      PTSD in which behavioral changes persist after the initial traumatization. We
      administered inescapable electric foot-shock (IS) to male Wistar rats in a
      shuttle-box with the gate closed. With or without paroxetine (PRX; belonging to
      selective serotonin reuptake inhibitors) treatment for 2 weeks after IS, we
      performed an avoidance/escape task session in the shuttle-box using signal lights
      as non-specific anxiogenic stimulants. Locomotor activity decreased before the
      task session and avoidance behavior increased during the session. Two weeks of
      PRX administration reduced hypervigilant behavior during the task session. We
      considered these behavioral changes as representative of numbing/avoidance and
      hypervigilance, referred to as bi-directional changes in PTSD.

PMID- 15036609
TI  - Involvement of serotonergic systems in the lateral parabrachial nucleus in sodium
      and water intake: a microdialysis study in the rat.
AB  - The present study was carried out to investigate whether 0.3 M NaCl and water
      intake alters the release of serotonin (5-hydoxytryptamine, 5-HT) in the region
      of the lateral parabrachial nucleus (LPBN) in freely moving rats. The ingestion
      of 0.3 M NaCl and water was induced by subcutaneous injections of the diuretic
      furosemide (FURO, 10 mg/kg) and the angiotensin converting enzyme inhibitor
      captopril (CAP, 5 mg/kg), and extracellular concentrations of 5-HT and its
      metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured using intracerebral
      microdialysis techniques. The intake of 0.3 M NaCl and water significantly
      enhanced the 5-HT and 5-HIAA levels in the LPBN area. The combined treatment with
      FURO and CAP elicited significant decreases in the 5-HT and 5-HIAA concentrations
      in the LPBN area under the condition that 0.3 M NaCl and water are not available
      for drinking. These results suggest that the serotonergic system in the LPBN area
      may play an important role in the modulation of sodium appetite and thirst.

PMID- 15036610
TI  - Apolipoprotein(a) null phenotype is related to a delayed age at onset of
      Alzheimer's disease.
AB  - Apolipoprotein(a) [apo(a)] is a highly polymorphic glycoprotein which has been
      suggested to play a role in Alzheimer's disease (AD). Plasma lipoprotein(a)
      [Lp(a)] levels and the differential expression of apo(a) isoforms were analyzed
      in 73 sporadic AD patients compared with 73 age- and gender-matched healthy
      controls. The distribution of apo(a) isoforms and Lp(a) concentrations were
      similar in the two groups. However, we observed that AD patients with no apo(a)
      isoform from immunoblots (subjects with the 'null phenotype') had a mean age at
      onset of 76.8+/-8.8 versus 66.9+/-9.6 years of those who expressed at least one
      apo(a) band (P = 0.010). Multivariate analysis showed that this effect was
      independent of apolipoproteinE epsilon4 allele. We conclude that the expression
      of at least one apo(a) isoform may interact with other pathogenic mechanisms
      involved in controlling the age at onset of AD.

PMID- 15036611
TI  - Cyclosporin-A inhibits inducible nitric oxide synthase activity and expression
      after spinal cord injury in rats.
AB  - Nitric oxide is generated from l-arginine by a family of three distinct nitric
      oxide synthase (NOS) enzymes playing a crucial role in the physiopathology of
      spinal cord injury (SCI). Cyclosporin-A (CsA), an immunosupressive agent, may be
      used to inhibit the activity of iNOS and perhaps to protect against neural tissue
      destruction. Rats were submitted to SCI by contusion, and killed 4, 24 and 72 h
      after lesion. Results showed an increase in the activity of iNOS at 72 h after
      the SCI, inhibited by CsA (2.5 mg/kg) administered 12 h after trauma. iNOS
      Western blot assay showed an increase in the expression of iNOS after trauma,
      also antagonized by CsA administration.

PMID- 15036612
TI  - Antipsychotics regulate cyclic AMP-dependent protein kinase and phosphorylated
      cyclic AMP response element-binding protein in striatal and cortical brain
      regions in mice.
AB  - Adenosine 3',5'-monophosphate (cAMP) and cAMP-dependent protein kinase (PKA)
      signaling have been implicated in antipsychotic drug action. This study examines
      the effects of acute antipsychotic treatment using typical (haloperidol) and
      atypical (olanzapine) agents on cAMP signaling in dorsal striatum, nucleus
      accumbens and medial prefrontal cortex in mice. PKA catalytic subunit (PKA-c) and
      phosphorylated cAMP response element-binding protein (pCREB) levels were measured
      to evaluate antipsychotic drug effects. Nuclear PKA-c levels increased in the
      dorsal striatum after haloperidol and olanzapine treatment. In medial prefrontal
      cortex, olanzapine produced dose-dependent decreases in PKA-c and pCREB levels.
      The differential effects of typical versus atypical antipsychotic agents on PKA
      and pCREB in striatal and cortical regions illustrate the diverging actions of
      these agents on cAMP pathways.

PMID- 15036613
TI  - Inhibition of rostral medullary raphe neurons prevents cold-induced activity in
      sympathetic nerves to rat tail and rabbit ear arteries.
AB  - Sympathetically-mediated vasoconstriction of cutaneous vessels is critical for
      thermoregulation in the cold. We determined whether cold-induced sympathetic
      discharge depends on activity of neurons in the rostral medullary raphe. In
      urethane-anesthetized rats and rabbits, cooling the trunk skin by a water jacket
      reproducibly increased cutaneous sympathetic discharge recorded in the tail
      (rats) and the ear pinna (rabbits). When neurons in the rostral medullary raphe
      were inhibited by microinjection of glycine (30-100 nmol in 60-200 nl in rats),
      or muscimol (1 nmol in 100 nl in rabbits), cutaneous sympathetic activity was
      silenced and no longer responded to cooling (7+/-3 and 5+/-2% of pre-injection
      increase in rats and rabbits, respectively, P < 0.01). Our data demonstrate that
      activity of rostral medullary raphe neurons is important for the CNS mediation of
      cold-induced increases in sympathetic cutaneous vasomotor nerves.

PMID- 15036614
TI  - Alzheimer's disease-associated amyloid beta interacts with the human serine
      protease HtrA2/Omi.
AB  - Amyloid beta (Abeta), a principle component of the cerebral plaques found in the
      brains of patients with Alzheimer's disease (AD), is a pivotal factor implicated
      in the pathogenesis of AD. Recent reports show that not only extracellular Abeta
      but also intracellular Abeta induces neuronal apoptosis; however, the mechanism
      remains to be elucidated. Using yeast two-hybrid assays, we found that Abeta
      interacts with HtrA2/Omi, an essential human serine protease with proapoptotic
      activity. Additionally, we mapped the C-terminal region containing the PDZ domain
      of HtrA2/Omi as the binding determinant for Abeta? The interaction of Abeta with
      HtrA2/Omi was further confirmed through in vivo co-immunoprecipitation assay in
      HEK293 cells. This study suggests the possibility that the accumulation of
      intracellular Abeta and a function of proapoptotic protease, HtrA2/Omi are
      correlated.

PMID- 15036615
TI  - Preparative activities in posterior parietal cortex for self-paced movement in
      monkeys.
AB  - Cortical field potentials were recorded by electrodes implanted chronically on
      the surface and at a 2.0-3.0 mm depth in various cortices in monkeys performing
      self-paced finger, toe, mouth, hand or trunk movements. Surface-negative, depth
      positive potentials (readiness potential) appeared in the posterior parietal
      cortex about 1.0 s before onset of every self-paced movement, as well as in the
      premotor, motor and somatosensory cortices. Somatotopical distribution was seen
      in the readiness potential in the posterior parietal cortex, although it was not
      so distinct as that in the motor or somatosensory cortex. This suggests that the
      posterior parietal cortex is involved in preparation for self-paced movement of
      any body part. This study contributes to the investigation of central nervous
      mechanisms of voluntary movements initiated by internal stimulus.

PMID- 15036616
TI  - Calcineurin-mediated BAD Ser155 dephosphorylation in ammonia-induced apoptosis of
      cultured rat hippocampal neurons.
AB  - We previously reported that ammonia induced apoptosis in cultured rat hippocampal
      neurons with moderate increases in the intracellular calcium concentration and
      decreases in phospho-BAD levels. Since this suggested the involvement of
      calcineurin in the apoptosis, the effects of calcineurin inhibitors, 1 microM
      cyclosporin A and 1 microM FK506, on the ammonia-induced neuronal apoptosis were
      tested. Both of the inhibitors abolished the neuronal apoptosis assessed by
      double staining with Hoechst 33258 and anti-neurofilament antibody, and the
      ammonia-induced decrease in phospho-BAD Ser(155) level. Thus, calcineurin
      appeared to be involved in the dephosphorylation of BAD at the sites including
      Ser(155) in ammonia-induced apoptosis.

PMID- 15036617
TI  - Loss of an individual proteasome subunit alters motor function but not cognitive
      function or ambulation in mice.
AB  - The proteasome is a large intracellular protease, composed of multiple subunits,
      that is present in all cells. In the present study we examined motor function,
      cognitive function, and ambulation in transgenic mice that lack the low molecular
      protein 2 (LMP2) proteasome subunit. Comparison of LMP2 knock out (LMP2 KO) mice
      and non-transgenic mice of the same background demonstrate that LMP2 KO mice
      exhibit a higher degree of motor function, but possess a similar level of
      cognitive function and ambulation, as compared to non-transgenic control mice.
      Interestingly, LMP2 KO mice also exhibited increased body weight as compared to
      non-transgenic mice. These data demonstrate for the first time that specific
      proteasome subunits may play a role in regulating both brain function and body
      weight.

PMID- 15036618
TI  - 4-Hydroxynonenal oxidatively modifies histones: implications for Alzheimer's
      disease.
AB  - There is increasing evidence of DNA oxidation and altered DNA repair mechanisms
      in Alzheimer's disease (AD) brain. Histones, which interact with DNA, conceivably
      could provide a protective shield for DNA against oxidative stress. However,
      because of their abundant lysine residues, histones may be a target for 4
      hydroxynonenal (HNE) modification. In this study, we have shown that HNE binds to
      histones and that this binding affects the conformation of the histone, measured
      by electron paramagnetic resonance in conjunction with a protein-specific spin
      label. The covalent modification to the histone by HNE affects the ability of the
      histone to bind DNA. Interestingly, acetylated histones appear to be more
      susceptible to HNE modifications than control histones. Conceivably, altered DNA
      histone interactions, subsequent to oxidative modification of histones by the
      lipid peroxidation product HNE, may contribute to the vulnerability of DNA to
      oxidation in AD brain.

PMID- 15036619
TI  - Mushroom body structural change is associated with division of labor in eusocial
      wasp workers (Polybia aequatorialis, Hymenoptera: Vespidae).
AB  - Highly eusocial insect workers exhibit age-related division of labor. Adults
      begin working inside the nest, moving to the nest periphery and later to
      foraging. Passage through this task sequence is associated with neuroanatomical
      changes in the mushroom bodies (MB) of honey bee (Apis) and ant (Camponotus)
      workers. We asked whether eusocial wasp workers (Polybia aequatorialis) exhibit
      similar changes in adult neuroanatomy. Wasps were identified as working in-nest,
      on-nest, or foraging. The volumes of the somata of workers' MB intrinsic neurons
      (Kenyon cells), and of the neuropils containing the Kenyon cell dendritic arbors
      (calyces), were estimated using stereological methods. In-nest workers had
      significantly smaller calyx to Kenyon cell volume ratios than on-nest and
      foraging workers. Age-related task specializations in Polybia workers are
      associated with major neuroanatomical reorganization in the mushroom bodies.

PMID- 15036620
TI  - Subcellular distribution of Bcl-2 family proteins and 14-3-3 within the
      hippocampus during seizure-induced neuronal death in the rat.
AB  - The molecular regulation of seizure-induced neuronal death may involve
      interactions between proteins of the Bcl-2 and 14-3-3 families. To further
      examine these pathways we performed subcellular fractionation on hippocampi
      obtained following a brief period of status epilepticus in the rat. Western
      blotting determined seizures induced caspase-8 cleavage and increased Bcl-w
      levels within the cytoplasm. Bax, Bad and Bid were largely present within the
      cytoplasm before and after seizures, although some Bax and, following seizures,
      truncated Bid was detected in mitochondria. Levels of 14-3-3 were significantly
      reduced in the cytoplasm and microsomal fractions. These data establish the
      expression and distribution profile of key Bcl-2 family proteins and the
      signaling chaperone 14-3-3 in the rat and provide additional evidence for the
      activation of programmed cell death pathways by seizures.

PMID- 15036621
TI  - APOE and modulation of Alzheimer's and frontotemporal dementia.
AB  - To investigate the difference in the morphologic expression of frontotemporal
      dementia (FTD) and Alzheimer's disease (AD) in patients carrying and not carrying
      the epsilon4 allele of APOE, MR images of 26 controls, 18 AD patients (11
      carrying the epsilon4 allele, seven non-carriers), and eight FTD (two carriers,
      six non-carriers) were compared using voxel by voxel analysis. Greater atrophy
      was found in the disease-specific regions of the epsilon4 carriers vs the non
      carriers at P < 0.05 corrected: medial temporal atrophy was greater in the AD
      carrying the epsilon4 allele, right ventral striatal atrophy in the FTD carrying
      the allele. The non-carriers did not have atrophic regions compared to the
      carriers. The epsilon4 allele of the APOE might modulate the expression of
      degenerative dementias by enhancing the specific effects of neurodegenerative
      diseases on the brain.

PMID- 15036622
TI  - Altered taste function in mice deficient in the 65-kDa isoform of glutamate
      decarboxylase.
AB  - The 65-kDa isoform of glutamate decarboxylase (GAD65) is considered to play an
      important role for GABA synthesis in the central nervous system. Using mice with
      targeted ablation of the GAD65 gene (GAD65(-/-) mice) we investigated a possible
      involvement of GABAergic neurotransmission in several taste functions.
      Preference/aversion responses to four basic tastes were not different between
      GAD65(-/-) and wild-type mice during a 48-h two-bottle choice test. GAD65(-/-)
      mice consumed less sucrose-quinine mixtures than did wild-type mice. The
      injection of midazolam (5 mg/kg), a benzodiazepine agonist, significantly
      increased the consumption of 100 mM sucrose in the wild-type mice. The same
      injection, however, failed to increase intake of the 100 mM sucrose in GAD65(-/-)
      mice. These results suggest that GAD65-generated GABA is not implicated in basic
      taste functions such as simple detection and discrimination. Rather, more complex
      processing of taste information including taste mixtures and palatability may be
      finely tuned by GAD65-mediated GABA synthesis.

PMID- 15036623
TI  - Blockade of Gi/o proteins modifies electrical activity of S-myenteric neurons
      from guinea-pig ileum.
AB  - We have investigated the effect of blockade of G(i/o) proteins on the electrical
      activity of S-myenteric neurons from guinea-pig ileum longitudinal muscle
      myenteric plexus preparations. Intracellular recordings were made from either
      control or pertussis toxin (PTX) treated tissues. PTX is known to disrupt the
      function of G(i/o) proteins. Incubation with PTX (300 ng/ml) induced three main
      changes in the electrophysiological characteristics of S-neurons: (1) resting
      membrane potential was more depolarised; (2) fast excitatory postsynaptic
      potentials (EPSPs) were faster and narrower; and (3) spontaneous fast EPSPs and
      action potentials were more frequent. Amplitude of slow EPSPs was not modified.
      This general increase in excitability after blockade of G(i/o) proteins shares
      characteristics with the slow depolarisation induced by long-lasting trains of
      low-frequency electrical stimulation and could be mediated by similar mechanisms.
      Electrophysiological activity of S-myenteric neurons could be modulated by an
      inhibitory tone, which PTX could modify by either pre- or post-synaptic
      mechanisms, such as inhibition of the tonic release of inhibitory
      neurotransmitters and/or intracellular signal transduction involving PTX
      sensitive G(i/o) proteins.

PMID- 15036624
TI  - Dense serotonergic innervation of principal nuclei of the superior olivary
      complex in mouse.
AB  - To evaluate species differences in the serotonergic innervation of the superior
      olivary complex, serotonergic fibers and varicosities were labeled with
      immunohistochemistry in mouse. Many immunoreactive fibers and varicosities were
      observed in two of the three principal nuclei, in addition to some periolivary
      nuclei. This pattern of staining differs greatly from that observed in other
      mammals in which periolivary, but not principal nuclei are richly innervated by
      serotonin (5-HT). These results indicate a functional relationship between the 5
      HT system and both the ascending and descending auditory systems in the mouse.

PMID- 15036626
TI  - Differential regulation of inducible nitric oxide synthase and cytokine gene
      expression by forskolin and dibutyryl-cAMP in lipopolysaccharide-stimulated
      murine BV2 microglial cells.
AB  - This study shows that two cAMP elevating agents, dibutyryl-cAMP (dbcAMP) and
      forskolin, regulate the expression of several cytokines and inducible nitric
      oxide synthase (iNOS) in a different manner. Both dbcAMP and forskolin repressed
      lipopolysaccharide (LPS)-induced TNF-alpha expression and enhanced anti
      inflammatory cytokine IL-10 level in the BV2 microglia. In contrast, they
      differentially regulated the iNOS, IL-6 and IL-1beta expression levels. DbcAMP
      increased the IL-1beta level without affecting either the IL-6 or iNOS
      expression, whereas forskolin repressed the IL-6 and iNOS expression level
      without affecting IL-1beta in the LPS-stimulated microglia. Treatment with H89, a
      specific inhibitor of protein kinase A (PKA), revealed that an enhancement in the
      IL-10 and IL-1beta levels by dbcAMP or forskolin totally depends on the PKA
      pathway, while changes in the other cytokines and iNOS are independent or only
      partially dependent on the PKA pathway. These results suggest the diverse
      regulation of the inflammatory reactions depending on different cAMP elevating
      agents.

PMID- 15036625
TI  - Inducible nitric oxide synthase is involved in the mechanisms of cocaine enhanced
      neuronal apoptosis induced by HIV-1 gp120 in the neocortex of rat.
AB  - Cocaine, often abused by human immunodeficiency virus (HIV) infected patients,
      has been suggested to worsen the HIV associated dementia via unknown mechanisms.
      Here we report that subchronic treatment with a dose of cocaine (30 mg/kg i.p.),
      unable per se to cause neuronal death, increases the number of apoptotic cells
      typically observed in the neocortex of rats treated with HIV-1 gp120 (100 ng
      given i.c.v.). A pre-treatment with MK801 (0.3 mg/kg i.p.), a NMDA receptor
      antagonist, L-NAME (10 mg/kg i.p.) and 7-nitroindazole (50 mg/kg i.p.), two
      specific inhibitors of NOS, or with 1400 W (1 mg/kg s.c.), a selective inhibitor
      of inducible NOS (iNOS), minimized neurotoxicity by combined administration of
      cocaine and gp120 thus implicating iNOS. This conclusion is supported by the
      evidence that cocaine increases brain neocortical citrulline, the co-product of
      NO synthesis.

PMID- 15036627
TI  - Perirhinal N-methyl-D-aspartate and muscarinic systems participate in object
      recognition in rats.
AB  - To determine the possible involvement of N-methyl-d-aspartate (NMDA) and
      muscarinic activation of the perirhinal cortex in object recognition, an NMDA
      antagonist (d,l-2-amino-5-phosphonopentanoic acid (AP5)) and a muscarinic
      antagonist (scopolamine) were injected into the perirhinal cortex of rats. A high
      dose of AP5 (60 mM) and two doses of scopolamine (20 and 80 mM), but not a low
      dose of AP5 (30 mM) alone, significantly impaired discrimination between novel
      and familiar objects in a spontaneous object recognition task, which is one of
      the recognition memory tasks. These results suggest that activation of both NMDA
      and muscarinic receptors in the perirhinal cortex contributes to object
      recognition.

PMID- 15036628
TI  - V1a receptor knockout mice exhibit impairment of spatial memory in an eight-arm
      radial maze.
AB  - In this study, we examined the performance of vasopressin V1a receptor (V1aR) and
      vasopressin V1b receptor (V1bR) knockout (KO) mice compared to wild-type (WT)
      mice in an eight-arm radial maze. V1aR KO mice exhibited an impairment of spatial
      memory in comparison to WT mice. By contrast, we did not observe any significant
      differences between the V1bR KO mice and the WT mice in the eight-arm radial
      maze. Moreover, OPC-21268, a selective V1aR antagonist, impaired spatial memory
      in the eight-arm radial maze in WT mice characterized by an increased number of
      errors. These results suggest that the V1aR controls spatial memory in mice.

PMID- 15036629
TI  - Choline pivaloyl esters improve in rats cognitive and memory performances
      impaired by scopolamine treatment or lesions of the nucleus basalis of Meynert.
AB  - The effects of two choline pivaloyl esters, [2-(2,2
      dimethylpropionyloxy)ethyl]trimethylammonium iodide (1) and [2-(2,2
      dimethylpropionyloxy)ethyl]trimethylammonium 2,2-dimethylpropionate (2), on
      learning and memory impairments induced in rats by scopolamine or lesions of
      nucleus basalis magnocellularis (NBM) have been evaluated by object recognition
      and Morris water maze tests in comparison with Tacrine (THA). Both 1 and 2
      restored discrimination in object recognition test for assessing working-episodic
      memory and improved spatial memory in scopolamine or NBM-lesioned rats as well.
      The positive effects produced by 1 and 2 on cognitive and memory deficits were
      well comparable with those evoked by THA, used as reference compound.

PMID- 15036630
TI  - A rapid presentation event-related functional magnetic resonance imaging study of
      response inhibition in macaque monkeys.
AB  - Rapid presentation event-related functional magnetic resonance imaging was
      applied to macaque monkeys performing a symmetrically rewarded go/no-go task, to
      investigate neural correlate of response inhibition. Sensorimotor activation
      related to the task performance was observed predominantly in the hemisphere
      contralateral to the response forelimb. Furthermore, no-go dominant activation
      possibly related to response inhibition, was observed in the ventral prefrontal
      cortex, in accordance with previous electrophysiological studies. These results
      show the feasibility of rapid presentation event-related functional magnetic
      resonance imaging in behaving monkeys.

PMID- 15036632
TI  - Effects of spinally administered adenine on dorsal horn neuronal responses in a
      rat model of inflammation.
AB  - A novel G-protein-coupled receptor with adenine identified as the endogenous
      ligand has recently been described. In vivo electrophysiological techniques in
      the rat were used to record the response of dorsal horn neurones in response to
      transcutaneous electrical stimulation to the hindpaw receptive field. Spinal
      adenine (1-1000 microg) exerted facilitatory effects on the electrically-evoked
      neuronal responses, in a mildly dose-related manner. After establishment of
      carrageenan-induced inflammation to the hindpaw this excitatory effect of adenine
      was still apparent, yet reduced. C-fibre-evoked responses and other nociceptive
      related measures were most susceptible to the effects of adenine, whereas non
      nociceptive Abeta-fibre evoked activity remained unaffected. Thus, activation of
      the adenine receptor site, via spinally applied adenine, suggests a
      pronociceptive role in nociceptive sensory transmission.

PMID- 15036631
TI  - Long-term effect of intra-striatal glial cell line-derived neurotrophic factor
      releasing microspheres in a partial rat model of Parkinson's disease.
AB  - Glial cell line-derived neurotrophic factor (GDNF) offers the possibility to
      stimulate axonal regeneration of mesencephalic dopaminergic neurons, which are
      affected in Parkinson's disease. Nevertheless, a safe and efficient GDNF delivery
      system that may be used in clinical trials is still lacking. In a previous study,
      we showed that GDNF-releasing microspheres can deliver the neurotrophic factor
      for 2 months, allowing in a partial rat model of Parkinson's disease a sprouting
      of the preserved dopaminergic fibers and functional improvement 8 weeks after the
      treatment. The present study confirms these previous observations and shows that
      the amphetamine-induced rotation score is still decreased 24 weeks after the end
      of GDNF delivery. Nevertheless, the improvement was not statistically significant
      at the latest time point due to the spontaneous reinnervation observed in the
      model used.

PMID- 15036633
TI  - Brain-derived neurotrophic factor (BDNF) gene delivery into the CNS using bone
      marrow cells as vehicles in mice.
AB  - Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is
      protective in animal models of neurodegenerative diseases. However, BDNF has a
      short half-life and its efficacy in the CNS when delivered peripherally is
      limited due to the blood-brain barrier. In the present study, bone marrow cells
      were used as vehicles to deliver the BDNF gene into the CNS. Marrow cells
      obtained from 6 to 8 week-old SJL/J mice were transduced with BDNF expressing pro
      virus. RT-PCR analysis revealed that BDNF mRNA was expressed in transduced but
      not in non-transduced marrow cells. Additionally, virus transduced marrow cells
      expressed the BDNF protein (296+/-1.2 unit/ml). BDNF-transduced marrow cells were
      then transplanted into irradiated mice through the tail vein. Three months post
      transplantation, significant increases in BDNF as well as glutamic acid
      decarboxylase (GAD(67)) mRNA were detected in the brains of BDNF transplanted
      mice compared to untransplanted animals, indicating biological activity of the
      BDNF transgene. Thus, bone marrow cells can be used as vehicles to deliver the
      BDNF gene into the brain with implications for the treatment of neurological
      diseases.

PMID- 15036634
TI  - Quantitative autoradiography of dopamine receptors in the brains of micro-opioid
      receptor knockout mice.
AB  - Given the existence of functional interactions between opioidergic and
      dopaminergic systems, we have analyzed by quantitative autoradiography the
      possible long-term adaptive changes in the expression of D(1)- and D(2)-like
      dopamine receptors in the brains of mice lacking the micro-opioid receptor gene.
      An overall significant increase in D(1) and D(2) receptors (7.4 and 12.6%,
      respectively) across all cerebral regions examined was obtained in mutant mice
      relative to wild-type mice. However, region by region comparisons failed to reach
      significance in any individual brain area. These results indicate that only
      moderate changes in D(1)- and D(2)-like dopamine receptors densities occur in the
      brains of micro-opioid receptor knockout mice.

PMID- 15036636
TI  - Effects of different jaw relations on postural stability in human subjects.
AB  - Authors investigated the effects of different jaws relations on body posture in a
      sample of 95 subjects. All subjects underwent a posturometric and stabilometric
      analysis using a computerized footboard. Tests were performed in three mandibular
      positions: centric occlusion, rest position and myocentric position, respectively
      determined by teeth engagement, joints position, and muscles contraction. All
      subjects showed variations of body posture in the different mandibular positions.
      Statistical analysis (analysis of variance for repeated measures) confirmed that
      postural variations in different jaws relations were significant: in particular,
      the SKN multiple comparison test showed that myocentric position improved
      postural balance on frontal plane with respect to the other jaw positions
      considered.

PMID- 15036635
TI  - Evidence of caspase-3 activation in hyposmotic stress-induced necrosis.
AB  - Primary culture of dentate gyrus was submitted to a hyposmotic stress that
      induces a rapid cell death that is necrosis morphologically. Surprisingly, we
      observed a rapid and dramatic upregulation of the active form of caspase-3
      (caspase-3(a)) in both neurons and glial cells. Caspase-3(a) immunoreactivity
      appears as early as 1 min after hyposmotic treatment, when some neurons are still
      alive, suggesting that caspase-3(a) may contribute to further necrotic cell
      death.

PMID- 15036638
TI  - Comparison of hypothetical LNG and fuel oil fires on water.
AB  - Large spills of refined petroleum products have been an occasional occurrence
      over the past few decades. This has not been true for large spills of liquefied
      natural gas (LNG). This paper compares the likely similarities and differences
      between accidental releases from a ship of sizable quantities of these different
      hydrocarbon fuels, their subsequent spreading, and possible pool-fire behavior.
      Quantitative estimates are made of the spread rate and maximum slick size, burn
      rate, and duration; effective thermal radiation; and subsequent soot generation.

PMID- 15036639
TI  - Estimation of potential impacts and natural resource damages of oil.
AB  - Methods were developed to estimate the potential impacts and natural resource
      damages resulting from oil spills using probabilistic modeling techniques. The
      oil fates model uses wind data, current data, and transport and weathering
      algorithms to calculate mass balance of fuel components in various environmental
      compartments (water surface, shoreline, water column, atmosphere, sediments,
      etc.), oil pathway over time (trajectory), surface distribution, shoreline
      oiling, and concentrations of the fuel components in water and sediments.
      Exposure of aquatic habitats and organisms to whole oil and toxic components is
      estimated in the biological model, followed by estimation of resulting acute
      mortality and ecological losses. Natural resource damages are based on estimated
      costs to restore equivalent resources and/or ecological services, using Habitat
      Equivalency Analysis (HEA) and Resource Equivalency Analysis (REA) methods. Oil
      spill modeling was performed for two spill sites in central San Francisco Bay,
      three spill sizes (20th, 50th, and 95th percentile volumes from tankers and
      larger freight vessels, based on an analysis of likely spill volumes given a
      spill has occurred) and four oil types (gasoline, diesel, heavy fuel oil, and
      crude oil). The scenarios were run in stochastic mode to determine the frequency
      distribution, mean and standard deviation of fates, impacts, and damages. This
      work is significant as it demonstrates a statistically quantifiable method for
      estimating potential impacts and financial consequences that may be used in
      ecological risk assessment and cost-benefit analyses. The statistically-defined
      spill volumes and consequences provide an objective measure of the magnitude,
      range and variability of impacts to wildlife, aquatic organisms and shorelines
      for potential spills of four oil/fuel types, each having distinct environmental
      fates and effects.

PMID- 15036640
TI  - Modeling evaporation using models that are not boundary-layer regulated.
AB  - Experimentation shows that oil is not strictly air boundary-layer regulated. The
      fact that oil evaporation is not strictly boundary-layer regulated implies that a
      simplistic evaporation equation suffices to describe the process. The following
      processes do not require consideration: wind velocity, turbulence level, area,
      thickness, and scale size. The factors important to evaporation are time and
      temperature. The equation parameters found experimentally for the evaporation of
      oils can be related to commonly available distillation data for the oil.
      Specifically, it has been found that the distillation percentage at 180 degrees C
      correlates well with the equation parameters. Relationships have been developed
      enabling calculation of evaporation equations directly from distillation data:
      percentage evaporated = 0.165 (%D)ln(t) where %D is the percentage (by weight)
      distilled at 180 degrees C and t is the time in minutes. These equations were
      combined with the equations generated to account for the temperature variations:
      percentage evaporated = [0.165(%D)+0.045(T-15))ln(t) The results have application
      in oil spill prediction and modeling. The simple equations can be applied using
      readily available data such as sea temperature and time. Old equations required
      oil vapour pressure, specialized distillation data, spill area, wind speed, and
      mass transfer coefficients, all of which are difficult to obtain.

PMID- 15036641
TI  - Formation of water-in-oil emulsions and application to oil spill modelling.
AB  - Water-in-oil mixtures were grouped into four states or classes: stable,
      mesostable, unstable, and entrained water. Of these, only stable and mesostable
      states can be characterized as emulsions. These states were established according
      to lifetime, visual appearance, complex modulus, and differences in viscosity.
      Water content at formation was not an important factor. Water-in-oil emulsions
      made from crude oils have different classes of stability as a result of the
      asphaltene and resin contents, as well as differences in the viscosity of the
      starting oil. The different types of water-in-oil classes are readily
      distinguished simply by appearance, as well as by rheological properties. A
      review of past modelling efforts to predict emulsion formation showed that these
      older schemes were based on first-order rate equations that were developed before
      extensive work on emulsion physics took place. These results do not correspond to
      either laboratory or field results. The present authors suggest that both the
      formation and characteristics of emulsions could be predicted using empirical
      data. If the same oil type as already studied is to be modelled, the laboratory
      data on the state and properties can be used directly. In this paper, a new
      numerical modelling scheme is proposed and is based on empirical data and the
      corresponding physical knowledge of emulsion formation. The density, viscosity,
      saturate, asphaltene and resin contents are used to compute a class index which
      yields either an unstable or entrained water-in-oil state or a mesostable or
      stable emulsion. A prediction scheme is given to estimate the water content and
      viscosity of the resulting water-in-oil state and the time to formation with
      input of wave height.

PMID- 15036642
TI  - A high-level synthesis of oil spill response equipment and countermeasures.
AB  - This paper presents an operational synthesis of major oil spill response methods
      (mechanical, chemical, etc.) and the corresponding oil response equipment for sea
      context (booms, skimmers, etc.). We focus on important features of oil spill
      response, in order to formulate a decision-based database, capable of supporting
      the development of a complete oil spill response operation. Moreover, we classify
      these findings and introduce simple formatting and standards to supply predictive
      tools for oil spill models. The actual goal of this paper is to come up with a
      decision-driven process, which can provide for a realistic choice of oil spill
      response equipment in the design of the primary oil response phase. This is
      intended to lead to a prompt, logical, and well-prepared oil spill response
      operation satisfying time and cost criteria and protecting the marine
      environment.

PMID- 15036643
TI  - Spill accident modeling: a critical survey of the event-decision network in the
      context of IMO's formal safety assessment.
AB  - In this paper, we present the relationship between an oil spill-assessing
      approach, namely the event-decision network (EDN) and the formal safety
      assessment (FSA) of the International Maritime Organization (IMO). We focus on
      various points at which the Network incorporates basic features of the FSA in
      order to formulate a state-of-the-art, original strategic tool. In keeping with a
      safety-friendly effort, we developed the EDN, which implements a scenario-driven,
      generic tree framework. Moreover, the IMO, under the umbrella of decision-making,
      has introduced FSA, which is a systematic methodology for enhanced maritime
      safety by using risk and cost/benefit criteria. It is of interest to describe the
      introduced spill-scenario analysis/simulation and to pinpoint its
      interconnections with the aforementioned official instrument. Among other things,
      the goal of such a task is the enhancement of marine safety and the subsequent
      protection of seas from oil spills.

PMID- 15036644
TI  - Two-dimensional electrophoretic protein profile analysis following exposure of
      human uroepithelial cells to occupational bladder carcinogens.
AB  - Protein biomarkers to occupational carcinogens were investigated using a
      transformable human uroepithelial cell system, SV-HUC.PC. SV-HUC.PC was treated
      with N-hydroxy-4,4'-methylene bis (2-chloroaniline) (N-OH-MOCA) or N-hydroxy-4
      aminobiphenyl (N-OH-ABP). Two-dimensional gel electrophoresis of cell lysates
      compared protein changes across treatments. Increasing N-OH-MOCA resulted in a
      dose-related increase in protein spots altered. Comparing cell profiles treated
      with either carcinogen revealed alterations in the expression of nine proteins,
      identified using the TagIdent database. These demonstrated isoelectric point
      shift (1) or quantity change (8). Our investigation may be useful in identifying
      biomarkers of effects of exposure to bladder carcinogens.

PMID- 15036646
TI  - Inhibition of human B-cell lymphoma by an anti-CD20 antibody and its chimeric
      F(ab')2 fragment via induction of apoptosis.
AB  - Monoclonal antibodies (mAb) directed against CD20, either unmodified or in
      radiolabeled forms, have been successfully used in clinic as effective
      therapeutic agents in the management of non-Hodgkin's B-cell lymphoma. Despite
      all clinical success the exact mechanisms of action of various anti-CD20
      antibodies remains mostly unclear. Several mechanisms have been proposed to be
      responsible for the therapeutic activity of anti-CD20 antibodies, including
      antibody-dependent cell-mediated cytotoxicity, complement-mediated cytotoxicity,
      and direct inhibition of tumor growth via induction of apoptosis. We previously
      produced an anti-CD20 mAb, HI47, and showed that the antibody effectively blocked
      human B-cell proliferation in vitro and inhibited xenografted B-cell lymphoma in
      nude mice. In this study, we engineered the chimeric versions of both the Fab and
      F(ab)'2 fragments of HI47 and produced the fragments in E. coli. Both fragments
      competed efficiently with HI47 for binding to CD20+ B cells, and inhibited
      proliferation of B-lymphoma cells in a dose-dependent manner. Mechanistic studies
      revealed that both antibody fragments induced significant degree of B-cell
      apoptosis that is independent of any cross-linking agents. Further, both the
      F(ab)'2 and Fab fragments when administered in vivo significantly inhibited the
      growth of human B-cell lymphoma xenografts in nude mice. The bivalent F(ab)'2
      fragment showed consistently better efficacy compared to its monovalent Fab
      counterpart in inducing apoptosis and inhibiting B-cell lymphoma growth both in
      vitro and in vivo. Taken together, these observations suggest that HI47 and its
      fragments most likely exert their antitumor activity through induction of cell
      apoptosis, and cross-linking/dimerization of CD20 molecules on B- cell surface is
      an important, but not essential, process for therapeutic efficacy of HI47 and its
      fragments.

PMID- 15036645
TI  - The modifying effect of Peucedanum japonicum, a herb in the Ryukyu Islands, on
      azoxymethane-induced colon preneoplastic lesions in male F344 rats.
AB  - The modifying effect of dietary Peucedanum japonicum (PJ), which is a traditional
      herb in the Ryukyu Islands and is an anti-oxidant, on azoxymethane (AOM)-induced
      rat colon carcinogenesis was examined. Male F344 rats were divided into six
      groups: rats in groups 1-4 were given subcutaneous injection of AOM (20 mg/kg
      body weight) once a week for 2 weeks. Rats in groups 2, 3 and 4 were fed the
      diets containing 0.2 and 1% PJ and 0.025% chlorogenic acid, respectively. We
      observed modification of the preneoplastic lesions of both aberrant crypt foci
      (ACF) and beta-catenin accumulated crypts (BCAC) in colon carcinogenesis,
      microscopically and immunohistochemically. The numbers of ACF consisting of more
      than four aberrant crypts per rat in groups 2 (3.2+/-1.7) and 3 (3.0+/-3.2) were
      significantly lower than that of group 1 (10.8+/-4.9; P<0.05, respectively). The
      mean number of BCAC in both groups 2 (0.88+/-0.48/cm2/rat) and 3 (0.81+/
      0.34/cm2/rat) was significantly lower than that in group 1 (2.13+/-0.54/cm2/rat;
      P < 0.0001, respectively). In addition, proliferating cell nuclear antigen
      labeling indices in group 2 (10.98+/-2.03) and group 3 (9.85+/-2.62) were
      significantly lower than that in group 1 (14.87+/-3.93; P < 0.001 and P < 0.0001,
      respectively). These findings indicate that PJ inhibits both ACF formation and
      accumulation of beta-catenin, and that PJ also reduces the cell proliferation
      activity, suggesting that PJ may have chemopreventive potential for colon
      carcinogenesis.

PMID- 15036647
TI  - Radiosensitization of human and rodent cell lines by INO-1001, a novel inhibitor
      of poly(ADP-ribose) polymerase.
AB  - Inhibition of poly(ADP-ribose) polymerase (PARP) by a novel, potent inhibitor,
      INO-1001, was examined in two rodent and one human fibroblast cell lines, after
      single and fractionated radiation treatments. Since PARP plays a role in the
      early events following DNA damage and influences the effectiveness of DNA repair,
      its inhibition has been proposed to constitute a drug target for the development
      of novel radiosensitizers. We found that INO-1001 effectively inhibited PARP
      activity at non-cytotoxic concentrations. Combination treatment of 10 microM INO
      1001 and a single dose of radiation resulted in significant radiosensitization of
      all three cells lines (enhancement ratios 1.4-1.6). This radioenhancement was
      even greater when the drug and radiation were given as fractionated treatments
      (enhancement ratio 8.0). Apoptosis (as evaluated by TUNEL staining) was not
      enhanced by the treatments, suggesting that inhibiting PARP enzyme activity by
      INO-1001 enhanced radiation-induced cell killing by interfering with DNA repair
      mechanisms, resulting in necrotic cell death. INO-1001 therefore, appears to have
      potential as a potent enhancer of radiation sensitivity, without any intrinsic
      cytotoxicity from the drug alone.

PMID- 15036648
TI  - Cytotoxicity of human prostate cancer cell lines in vitro and induction of
      apoptosis using 213Bi-Herceptin alpha-conjugate.
AB  - HER-2 has been implicated in the oncogenesis of human prostate cancer (CaP) and
      is the target of a new treatment for metastatic breast cancer using the humanised
      monoclonal antibody (MAb) trastuzumab (Herceptin). In this study, a novel alpha
      particle emitting [213Bi]Herceptin construct, which targets the HER-2
      extracellular domain on CaP cells, was prepared and evaluated in vitro. We used
      immunocytochemistry, flow cytometry and Western blot analysis to examine the
      expression of HER-2 in a panel of established human CaP cell lines, used the MTS
      assay to evaluate the cytotoxicity of 213Bi-Herceptin on these cell lines and the
      TUNEL assay to document apoptosis. The results indicate that LNCaP-LN3 cells
      express high levels of HER-2 protein, in contrast, DU 145 cells express low to
      medium levels, and PC-3 cells express an undetectable level of HER-2 protein.
      213Bi-Herceptin was specifically cytotoxic to LNCaP-LN3 cells in a concentration
      dependent fashion, cause the cells to undergo apoptosis, whereas DU 145 showed an
      HER-2 level-dependent response to 213Bi-Herceptin cytotoxicity. In contrast, PC-3
      cells were resistant to 213Bi-Herceptin-induced cytotoxicity. The 213Bi-Herceptin
      induced apoptosis in LNCaP-LN3 cells could be inhibited by incubation with
      unlabeled Herceptin. Our results suggest that 213Bi-Herceptin alpha-conjugate
      might be a promising new agent for the treatment of preangiogenic cancer cell
      clusters or micro-metastases with high levels of HER-2 expression.

PMID- 15036649
TI  - Increased cell-free DNA in plasma of patients with metastatic spread in prostate
      cancer.
AB  - We compared the plasma DNA concentrations in patients with different prostate
      cancer (PCa) stages and with benign prostate hyperplasia (BPH) and in healthy
      persons. Patients with localized cancer had DNA plasma within the reference
      interval. Increased plasma DNA was found in patients with lymph node and distant
      metastases and also in BPH. The association between plasma DNA and the survival
      time was similarly strong as with prostate-specific antigen. It can be concluded
      that plasma DNA has a limited validity as metastatic marker in PCa patients but
      follow-up studies combined with the investigation of tumor-related
      characteristics of plasma DNA would be reasonable.

PMID- 15036650
TI  - A survey of gene-specific methylation in human prostate cancer among black and
      white men.
AB  - Gene methylation is an important molecular event in prostate carcinogenesis that
      may have diagnostic and prognostic significance. We evaluated the methylation
      status of eight genes implicated in prostate carcinogenesis. DNA was extracted
      from archived paraffin-embedded tumor blocks from 90 prostate cancer patients.
      Gene methylation status of eight genes (GSTP1, RASSF1A, RARbeta2, CD44, EDNRB, E
      cadherin, Annexin-2, and Caveolin-1) was determined using real-time methylation
      sensitive PCR techniques. Differences in gene methylation among race, tumor grade
      and disease stage were evaluated by chi-square test. Of the eight genes, GSTP1,
      RASSF1A, and RARbeta2 methylation was highly prevalent across tumors (>60% for
      all three genes) whereas CD44, E-cadherin and EDNRB methylation was less
      prevalent (33, 24 and 29%, respectively). Annexin-2 and Caveolin-1 were not
      methylated in any of the tumors examined. Methylation of RARbeta2, CD44 and E
      cadherin was correlated with tumor grade but not stage. Interestingly,
      methylation of EDNRB, a gene involved in angiogenesis, was correlated with stage
      of disease but not tumor grade. With the possible exception of CD44, we did not
      observe differences in gene methylation between racial categories for the genes
      under study. In summary, our data suggest that evaluation of the methylation of a
      panel of genes may have diagnostic and prognostic utility in prostate cancer.

PMID- 15036651
TI  - PACAP expression and distribution in human breast cancer and healthy tissue.
AB  - Pituitary adenylate cyclase-activating peptide (PACAP) is involved in various
      biological processes including cell growth, proliferation and differentiation.
      Here, we demonstrate for the first time the presence of both PACAP mRNA and PACAP
      immunoreactivity in human normal breast and breast carcinoma. Control,
      peritumoral and tumoral tissue pieces expressed preproPACAP mRNA since reverse
      transcription-polymerase chain reaction analysis gave an amplification product of
      the expected size (226 bp), which was further identified by analysis of the
      sequence. A main 19.9-kDa product (preproPACAP protein) was identified by Western
      blot in the three classes of breast tissue together with a small amount of a 14.6
      kDa product (conceivably a result of partial processing by proprotein
      convertases). However, the mature peptide PACAP-38 was absent. The levels of both
      PACAP mRNA and PACAP immunoreactivity increased from normal to peritumoral and
      tumoral breast tissues but more patients must be considered to reinforce this
      feature. Immunohistochemistry showed the localization of PACAP immunoreactivity
      in alveolar epithelial cells in normal and carcinomatous tissues but also, at
      high density, in duct-like structures and in leucocytes in the connective tissue
      from breast cancer pieces. The results suggest that PACAP may play a role by
      autocrine/paracrine mechanisms in both normal human breast physiology and breast
      tumorigenesis.

PMID- 15036652
TI  - The truncation of Ku86 in human lymphocytes.
AB  - The Ku heterodimer, which consists of Ku70 and Ku86 subunits, is a major sensor
      of DNA breaks. A truncated form of Ku86 lacking its C-terminus, termed Ku86
      variant, has been detected in extracts from different human cells. Here we report
      that in human lymphocytes the Ku86 variant is not present in vivo but is
      generated in vitro upon cell lysis by a trypsin-like protease. The resulting Ku86
      variant exists exclusively in complexes with Ku70, which possess strong affinity
      to DNA double strand termini. In different blood donors the levels of Ku86
      variant correlated with the magnitude of radiation induced DNA breaks.

PMID- 15036653
TI  - Serum interleukin-12 and interleukin-18 levels as a tumor marker in patients with
      esophageal carcinoma.
AB  - Interleukin (IL)-12 and IL-18 participate in tumor immunology. Serum IL-12 and IL
      18 levels were determined in patients with esophageal carcinoma, and the
      relationship between clinicopathologic factors and prognosis was investigated.
      Peripheral blood samples were obtained from 15 healthy volunteers and from 70
      patients with esophageal carcinoma before curative surgery. IL-12 and IL-18
      levels were determined in each serum sample by enzyme-linked immunosorbent assay.
      Mean serum IL-12 and IL-18 levels were significantly higher in patients with
      esophageal carcinoma compared with healthy volunteers (P < 0.05) and mean serum
      IL-12 and IL-18 levels increased in patients as the pathologic stage progressed.
      A positive correlation was observed between serum IL-12 and IL-18 levels (P <
      0.01). In patients with esophageal carcinoma, increasing serum IL-12 and IL-18
      levels correlated with tumor growth and progression. The function of these two
      interleukin in the host immune response remains unclear. However, this part of
      the host immune response did not appear to contribute to the postoperative
      prognosis. Serum IL-12 and IL-18 levels might correlate with a certain depth of
      invasion and might be useful tumor markers in patients with esophageal carcinoma.

PMID- 15036654
TI  - Expression and functional characterization of the system L amino acid transporter
      in KB human oral epidermoid carcinoma cells.
AB  - We have examined the expression and function of system l amino acid transporter
      in KB human oral epidermoid carcinoma cells. The KB cells express l-type amino
      acid transporter 1 (LAT1) in plasma membrane, but not l-type amino acid
      transporter 2 (LAT2). The [14C]l-leucine uptake by KB cells is inhibited by
      system l selective inhibitor BCH. The majority of [14C]l-leucine uptake is,
      therefore, mediated by LAT1. These results suggest that the transport of neutral
      amino acids including several essential amino acids into the KB cells mediated by
      LAT1 and the specific inhibition of LAT1 in oral cancer cells will be a new
      rationale for anti-cancer therapy.

PMID- 15036655
TI  - Cancer chemopreventive effects of polyunsaturated fatty acids.
AB  - The inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation
      induced by the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), in
      Raji cells as a primary screening test for anti-tumor promoters, for 22 fatty
      acids (as free and esterified forms), including 10 di- and polyunsaturated acids,
      and the inhibitory effects on activation of (+/-)-(E)-methtyl-2-[(E)-hydroxy
      imino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitric oxide (NO) donor, as a
      primary screening test for anti-tumor initiators, for 17 fatty acids (as methyl
      ester forms), were evaluated. Among the fatty acids tested, three n-3
      polyunsaturated acids, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA),
      and docosahexaenoic acid (DHA), exhibited potent inhibitory effects both on EBV
      EA and NOR 1 activation. Furthermore, DHA methyl ester exhibited remarkable anti
      tumor-promoting activity on an in vivo two-stage carcinogenesis test of mouse
      tumor using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a
      promoter.

PMID- 15036656
TI  - Effects of Schistosoma haematobium infection on drug-metabolizing enzymes in
      human bladder cancer tissues.
AB  - The mixed function oxidase system includes the phase I drug oxidation proteins
      e.g. aryl hydrocarbon hydroxylase (AHH), N-nitrosodimethylamine-N-demethylase I
      (NDMA-dI) and cytochrome b5 which metabolize most carcinogens and xenobiotics
      into less and/or more active intermediates. These were determined in human
      bladder tissues diagnosed as bladder cancer only (10 samples) and bladder cancer
      associated with Schistosoma haematobium (12 samples) and normal bladder tissues
      (12 samples). In addition to the above enzymes, agents involved in Phase II drug
      metabolism e.g. glutathione and glutathione S-transferase as well as free
      radicals (detected as thiobarbituric acid-reactive substances, TBARS) were also
      determined in these tissues samples. AAH and NDMA-dI, cytochrome b5, and
      glutathione S-transferase activity decreased by 42, 28, 47 and 32%, respectively,
      in human bladder cancer tissues. In bladder cancer tissues associated with S.
      haematobium infection NDMA-dI and GST activity decreased further by 65 and 56%,
      respectively, whereas AHH activity increased by 50% and levels of reduced
      glutathione also increased by 43% in cancer tissue and by 29% in schistocome
      infected bladder cancer tissue. The level of free radicals also increased
      significantly (by 57%) in infected bladder cancer tissue but not at all in non
      infected cancer tissue. Alterations in the activity of phase I and II of drug
      metabolizing enzymes in human bladder tissues as a result of S. haematobium
      infection may therefore change the bladder's capacity to detoxify many endogenous
      compounds and may also potentiate the deleterious effects of bladder carcinogens,
      (e.g. N-nitrosamines) which are known to be present in relatively large
      quantities in the bladder of patients with schistosomiasis. The present study
      thus provides new insights into mechanisms for the genesis of bladder cancer
      initiated in association with schistosomiasis.

PMID- 15036657
TI  - 20(S)-Protopanaxatriol, one of ginsenoside metabolites, inhibits inducible nitric
      oxide synthase and cyclooxygenase-2 expressions through inactivation of nuclear
      factor-kappaB in RAW 264.7 macrophages stimulated with lipopolysaccharide.
AB  - Ginsenosides from Panax ginseng are metabolized by human intestinal bacteria
      after oral administration of ginseng extract. 20(S)-Protopanaxatriol (PPT) is one
      of the major metabolites of ginsenosides. Inducible nitric oxide synthase (iNOS)
      and cyclooxygenase-2 (COX-2) are important enzymes that mediate inflammatory
      processes. Improper up-regulation of iNOS and/or COX-2 has been associated with
      the pathogenesis of inflammatory diseases and certain types of human cancers.
      Here, we investigated whether PPT could modulate iNOS and COX-2 expressions in
      RAW 264.7 macrophages stimulated with the endotoxin lipopolysaccharide (LPS). We
      found that PPT blocked the increase in LPS-induced iNOS and COX-2 expressions
      through inactivation of nuclear factor-kappaB by preventing I-kappaBalpha
      phosphorylation and degradation. Thus, it may be possible to develop PPT as a
      useful agent for chemoprevention of cancer or inflammatory diseases.

PMID- 15036658
TI  - Induction of the apoptosis of HL-60 promyelocytic leukemia cells by Eurya
      emarginata.
AB  - This study examined the inhibitory effect of Eurya emarginata extracts on the
      growth of cancer cells. The ethylacetate (EtOAc) fraction of the E. emarginata
      leaves markedly inhibited the growth of leukemia cells including HL-60. When the
      HL-60 cells were treated with its EtOAc fraction, DNA fragmentation and sub-G1
      hypodiploid cells were observed. Moreover, the EtOAc fraction of E. emarginata
      reduced the c-Myc and Bcl-2 protein and mRNA levels in a time-dependent manner,
      whereas the Bax protein and mRNA expression levels were slightly increased. The
      results suggest that the inhibitory effect of E. emarginata on the growth of HL
      60 appears to arise from the induction of apoptosis via the down-regulation of
      Bcl-2 and c-Myc expression with an increase in the Bax expression level.

PMID- 15036659
TI  - Antiangiogenic photodynamic therapy (PDT) using Visudyne causes effective
      suppression of tumor growth.
AB  - We previously observed that antiangiogenic photodynamic therapy (PDT), namely,
      laser irradiation at 15 min after administration of photosensitizer, by using
      stable liposomal benzoporphyrin derivative monoacid ring A (BPD-MA), in which the
      liposomes were composed of dipalmitoylphosphatidylcholine,
      palmitoyloleoylphosphatidylcholine, cholesterol, and
      dipalmitoylphosphatidylglycerol (10:10:10:2.5 as a molar ratio), was quite
      effective for cancer treatment. On the other hand, Visudyne, a commercialized
      liposomal formulation of BPD-MA, is based on more fluid lipids, namely,
      dimyristoylphosphatidylcholine and egg yolk phosphatidylglycerol, and is thought
      to be less stable in the presence of serum. The data of spin column
      chromatography indicated a little faster transfer of BPD-MA from Visudyne to
      lipoprotein fraction when Visudyne was incubated with serum than when the stable
      liposomal BPD-MA was used. The phototoxicity of Visudyne against a human
      endothelial cell line, ECV304, was almost the same as that of stable liposomal
      BPD-MA after PDT treatment. Therefore, we examined the antiangiogenic scheduling
      of PDT with Visudyne. Tumor growth of Meth-A sarcoma-bearing mice was strongly
      suppressed when the antiangiogenic scheduling was performed with Visudyne,
      namely, irradiation at 15 min after injection of the drug, in comparison with the
      conventional scheduling in which laser irradiation is done at 3 h post-injection.
      This greater effectiveness of PDT at 15 min was suggested to be caused by
      hemostasis, based on observations made in a dorsal air sac angiogenesis model.
      Visudyne-mediated antiangiogenic PDT cured 40 or 60% of Meth-A-bearing mice
      completely when 0.25 or 0.5 mg/kg BPD-MA, respectively, was used. These data
      suggest that the antiangiogenic scheduling is effective in Visudyne-mediated
      cancer PDT despite the transferring of BPD-MA from the liposomal fraction to
      lipoproteins in the bloodstream.

PMID- 15036660
TI  - MCF-7 breast cancer cell line grown in agarose culture for study of COX-2
      inhibitors in three-dimensional growth system.
AB  - Herein we report a method for studying slow acting pharmaceutical COX-2
      inhibitors in the MCF-7 breast cancer cell line where cells are grown in a three
      dimensional format within an agarose matrix. The cancer cells are suspended in
      agarose and plated in a cell culture dish, where they will form small
      multicellular 'tumors' in the agarose. The time frame for conducting experiments
      is up to 2.5 weeks, and gives ample time for COX-2 inhibitors to induce cell
      death. Etodolac was used for these experiments, and was found to induce cell
      death in a time dependent manner over a 2.5-week period. This is in contrast to
      the cell line grown in monolayer and treated with the same concentrations of
      etodolac. This method is appropriate for determining mechanisms of cell death
      caused by COX-2 inhibition.

PMID- 15036661
TI  - Genetic polymorphisms of p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro and the
      risk of cervical cancer in Japanese.
AB  - To examine the possible association between cervical cancer and p73 G4C14-to
      A4T14 in exon 2 and p53 Arg72Pro polymorphisms, an incident case-control study
      was conducted in Japanese. The cases were 112 cervical cancer patients. Controls
      were 320 healthy women and 122 non-cancer female outpatients. Risk estimation for
      each genotype by an unconditional logistic model demonstrated a possible
      association between the p73 A4T14 variant and the risk of cervical cancer in our
      Japanese population (OR = 1.57; 95%CI, 0.99-2.48, P = 0.053). There was no
      significant difference in the p53 Arg72Pro genotype frequency between the
      controls and cases.

PMID- 15036662
TI  - Influences of lifestyle habits and p53 codon 72 and p21 codon 31 polymorphisms on
      gastric cancer risk in Taiwan.
AB  - Influences of lifestyle habits and p53 codon 72 and p21 codon 31 polymorphisms on
      the risk for developing primary gastric cancer were examined in 89 gastric
      adenocarcinoma cases (51 males, 38 females) and 192 controls (106 males, 86
      females) in a hospital-based, case-control study in Taiwan. In the final
      regression model, Helicobacter pylori infection and substance use (cigarette
      smoking, areca chewing) were significant predictors of risk for developing
      gastric cancer. Compared with subjects negative for H. pylori infection, positive
      subjects were 3.65-fold (95% CI = 2.07-6.42) more likely to develop gastric
      cancer. Compared with non-smokers or non-chewers, subjects with more than a 15
      pack-year history or more than a 498 betel-year history (about 20 betel quids/day
      for 25 years) were 2.27- and 4.86-fold more at risk (95% CI = 1.06-4.84 and 1.20
      19.74), respectively. Frequencies of arg/arg, arg/pro and pro/pro in p53 were 11
      (12.4%), 53 (59.5%) and 25 (28.1%) in carcinoma cases and 40 (20.8%), 95 (49.5%)
      and 57 (29.7%) in control cases, respectively. Frequencies of arg/arg, ser/arg
      and ser/ser in p21 were 26 (29.2%), 36 (40.5%) and 27 (30.3%) in carcinoma cases
      and 49 (25.5%), 94 (49.0%) and 49 (25.5%) in control cases, respectively. Neither
      p53, nor p21 polymorphisms were significantly different in cases and controls ( P
      = 0.16 and P = 0.41, respectively). Results remained insignificant after
      dichotomizing with respect to cigarette smoking, areca chewing and H. pylori
      infection. In summary, our data indicate that in Taiwan, H. pylori infection,
      smoking and areca chewing are significant risk predictors for developing gastric
      cancer. p53 codon 72 and p21 codon 31 genotypes did not modify these risks.

PMID- 15036663
TI  - Investigation of intracellular signalling events mediating the mechanism of
      action of 7-hydroxycoumarin and 6-nitro-7-hdroxycoumarin in human renal cells.
AB  - Previously, 7-hydroxycoumarin (7-OHC) and 6-nitro-7-hydroxycoumarin (6-NO2-7-OHC)
      have been shown to be potent and selective anti-proliferative agents to the human
      renal cell carcinoma (RCC) cell line, A-498. Their effect on mitogen-activated
      protein kinases (MAPK's) was investigated. 6-NO2-7-OHC was shown to alter the
      phosphorylation status of ERK1/ERK2, p38 and SAPK, while 7-OHC activated
      ERK1/ERK2 but had no effect on p38 and SAPK. Also, 7-OHC inhibited topoisomerase
      II mediated relaxation of DNA, while neither compound was a substrate for P
      glycoprotein (P-gp) mediated multi-drug resistance (MDR). Therefore, 6-NO2-7-OHC,
      rather than 7-OHC, modulated signalling events associated with cellular
      differentiation and apoptosis, suggesting its mechanism of action may be the
      promotion of cellular maturation and/or death. Consequently, 6-NO2-7-OHC may
      represent a novel therapeutic agent for the treatment of RCC's.

PMID- 15036664
TI  - Resistance to apoptosis of HPV 16-infected laryngeal cancer cells is associated
      with decreased Bak and increased Bcl-2 expression.
AB  - Human papillomavirus type 16 (HPV 16) plays an etiological role in human
      laryngeal carcinoma. Apoptosis is closely associated with various biological
      processes including oncogenesis. This study investigated how HPV 16 oncoproteins
      E6 and E7 affect apoptosis in human laryngeal cancer cells. We established two
      human laryngeal cancer cell lines that expressed HPV 16 E6 and E7, respectively.
      Using these two cell lines, we found that both E6 and E7 exhibited an inhibitive
      effect on apoptosis induced by tumor necrosis factor alpha and cycloheximide. In
      both transfected cell lines, the expression of pro-apoptotic Bak was reduced and
      that of anti-apoptotic Bcl-2 was over-expressed. However, the expression of
      caspase-3 and caspase-8 was not significantly different between the E6- and E7
      transfected cells and the control cells without HPV 16. p53 Protein was not
      detected in either the transfected or the non-transfected cells. Our study
      indicates that: (1) HPV 16 E6 and E7 oncoproteins are capable of inhibiting
      apoptosis in laryngeal squamous carcinoma cells; (2) the mechanism modulated by
      E6 and E7 involves the over-expression of Bcl-2 and the down-regulation of Bak;
      (3) the anti-apoptotic pathway is not related to the level of p53, caspase-3, or
      caspase-8. These results suggest that the dysregulation of apoptotic molecules
      Bak and Bcl-2 by HPV 16 E6 and E7 plays a role in the prolongation of cell
      survival, which may subsequently contribute to the development of human laryngeal
      cancer.

PMID- 15036665
TI  - Identification of critical residues required for the mutation avoidance function
      of human MutY (hMYH) and implications in colorectal cancer.
AB  - Mutations found in human tumors often include transversions of GC to TA that may
      result from the mis-pairing of 8-oxoG with adenine during DNA replication. The
      human MutY (hMYH) enzyme, an adenine-specific DNA glycosylase, initiates repair
      at this mismatch. It has recently been demonstrated that inherited variants of
      hMYH may predispose individuals to multiple colorectal adenomas and carcinoma
      [Nat. Genet. 30 (2002) 227]. In this study, we demonstrate that two of these
      cancer-associated hMYH mutants, Y165C and G382D, are devoid of glycosylase
      activity directed towards 8-oxoG:A mispairs. These findings implicate a total
      loss of hMYH function associated with colorectal cancers.

PMID- 15036666
TI  - Cathepsin B and cathepsin D expression in the progression of colorectal adenoma
      to carcinoma.
AB  - Lysosomal proteinases, cathepsin B (CB) and cathepsin D (CD) have been implicated
      in the progression of several human tumors. In the present study, the antigen
      levels of CB and CD, and their immunohistochemical staining were compared in
      paired colorectal tumors (n =64) and background colon tissue of the same patients
      with clinicopathological staging. The antigen levels, were found to be
      significantly higher in cancer tissue (mean 35.79 ng/mg protein for CB and 3.97
      ng/mg protein for CD) than in corresponding normal mucosa (24.62 ng/mg protein
      for CB and 2.69 ng/mg protein for CD). CB antigen levels were positively
      correlated with differentiation grade and Duke's stage (P < 0.001 and P = 0.041,
      respectively), but not correlated with nodal status. CD antigen levels were not
      correlated with the previous parameters. Staining intensity for both antigens
      increased from adenoma to adenocarcinoma. The degree of staining for CB and CD
      was associated with differentiation grade (P = 0.004 and 0.001, respectively),
      Dukes' stage (P = 0.002 and 0.001, respectively) and lymph node involvement (P =
      0.002 and P < 0.001, respectively).

PMID- 15036667
TI  - Rifampicin and verapamil induce the expression of P-glycoprotein in vivo in
      Ehrlich ascites tumor cells.
AB  - The effect of an in vivo treatment with two commonly employed drugs that are P
      glycoprotein substrates, verapamil and rifampicin, on Ehrlich ascites carcinoma
      cells, was evaluated. Ehrlich ascites carcinoma cells were inoculated i.p. in CD
      1 mice and animals were orally treated for 10 days with rifampicin (60 mg/kg/day)
      or verapamil (6 mg/kg/day). In the harvested cells the transcripts for mdr1a and
      mrp1, but not those for mdr1b, mrp2 and CYP3A, were detected, and treatment with
      verapamil or rifampicin did not modify the levels of the transcripts. On the
      contrary, an increased expression of P-glycoprotein was observed at the protein
      level with Western blot. The intracellular uptake of doxorubicin, a P
      glycoprotein and MRP substrate, was significantly lower in cells obtained from
      treated animals in comparison with cells obtained from controls; in addition, the
      uptake was increased by a pretreatment with verapamil. The survival time of
      control animals implanted with untreated cells was similar to that of animals
      inoculated with cells obtained from rifampicin treated animals, however, the
      antineoplastic effect of doxorubicin was significanly higher in control animals.
      A treatment with rifampicin or verapamil in Ehrlich ascites tumor confers
      resistance to the antineoplastic drug doxorubicin, probably through an increased
      expression of P-glycoprotein.

PMID- 15036668
TI  - Handling and pathology reporting of specimens with carcinoma of the urinary
      bladder, ureter, and renal pelvis.
AB  - OBJECTIVE: Pathologists play a pivotal role in the diagnosis and in the report of
      the pathological features related to prognosis. METHODS: To meet these endpoints,
      the following issues must be accomplished: adequate information about the patient
      history, proper handling of the specimens, identification of the reliable
      histopathological techniques necessary to reach the more detailed diagnostic
      information and evaluate the prognostic variables, and a standardized
      pathological report. RESULTS: Recent efforts to standardize the histopathological
      evaluation have generated significant confusion among the urological and
      pathological communities as well. No consensus has been achieved about the
      optimal pathological grading of urothelial tumors, to date. CONCLUSION: A
      proposal for standardization of sampling and reporting of the urothelial tissues
      achieved within Uropathology follows. The urologists have a great role in
      assisting pathologists in the proper examination by providing them with clinical
      information.

PMID- 15036669
TI  - Prospective randomized trial comparing flutamide as adjuvant treatment versus
      observation after radical prostatectomy for locally advanced, lymph node-negative
      prostate cancer.
AB  - OBJECTIVE: To assess the efficacy and the tolerability of flutamide as adjuvant
      treatment after radical prostatectomy for locally advanced, lymph node-negative
      prostate cancer. METHODS: Men with locally advanced, lymph node-negative prostate
      cancer were randomized after radical prostatectomy to receive either flutamide
      750mg daily or no adjuvant treatment. Recurrence-free and overall survival were
      the study end points. Recurrence was defined as a PSA value greater than 5ng/ml
      or two values greater than 2ng/ml more than three months apart with increasing
      tendency or three values greater than 1ng/ml more than three months apart with
      increasing tendency or any clinical recurrence. RESULTS: 309 patients (157 in the
      control arm and 152 in the flutamide arm) were eligible for efficacy analysis.
      The median follow-up was 6.1 years. Recurrence-free survival was better in the
      flutamide group ( P=0.0041), there was, however, no detectable difference in
      overall survival ( p=0.92 ). Moreover, there was a considerable toxicity reported
      in the flutamide group. CONCLUSION: Although having some effect on disease
      recurrence, adjuvant flutamide treatment does not improve median-term overall
      survival after radical prostatectomy for locally advanced, lymph node-negative
      prostate cancer.

PMID- 15036670
TI  - A multicountry ecologic study of risk and risk reduction factors for prostate
      cancer mortality.
AB  - OBJECTIVE: The objective of this research is to identify and determine the
      relative importance of dietary and environmental risk and risk reduction factors
      for prostate cancer mortality. MATERIALS AND METHODS: A multicountry ecologic
      approach was used in multivariate regression analyses with prostate cancer
      mortality rates and dietary factors and solar ultraviolet-B (UV-B) radiation.
      Prostate cancer mortality rates for 32 predominantly Caucasian countries for the
      late 1990s were obtained from the World Health Organization. Dietary supply data
      were obtained from the Food and Agriculture Organization. Annual solar UV-B dose
      data were obtained from European ground stations and used to estimate values
      elsewhere. Linear and multiple linear regression analyses were conducted for all
      32 countries as well as the 20 European countries. RESULTS: The strongest risk
      factor for prostate cancer mortality was animal products, with the nonfat portion
      of milk and alcohol being somewhat weaker; the strongest risk reduction factors
      were onions, other protective vegetable products (excluding alcohol, oils, and
      sweeteners), and solar UV-B radiation. Dietary data for 1979-81 yielded the
      highest correlations. CONCLUSIONS: These results are consistent with insulin-like
      growth factor-I (IGF-I), being an important risk factor for prostate cancer, with
      alcohol and calcium being less important risk factors, and with allium family
      vegetables, and, to a lesser extent, vitamin D being important risk reduction
      factors. These results should provide guidance for additional studies on dietary
      and environmental links to prostate cancer.

PMID- 15036671
TI  - Adherence to an annual PSA screening program over 3 years for brothers and sons
      of men with prostate cancer.
AB  - OBJECTIVE: To assess the adherence to an annual PSA screening program conducted
      over 3 years in first-degree relatives of a sample of men with prostate cancer,
      and to identify characteristics of men who failed to undergo the full screening
      process. PATIENTS AND METHODS: Out of 747 candidates that were eligible for the
      screening program (asymptomatic brothers and sons aged between 40 and 70 years of
      men diagnosed with prostate cancer) 640 were contacted. The screening program
      entailed annual serum PSA testing over a 3-year period, during which every
      candidates attendance was recorded. At the outset, each candidate was requested
      to complete a questionnaire regarding their socio-professional characteristics,
      their level of anxiety and their attitude towards genetic susceptibility.
      RESULTS: 442 (69%) candidates agreed to enter the study and 420 filled out the
      questionnaire. During the 3-year period, 50 candidates (12%) who had accepted the
      first year screening refused to undergo subsequent PSA tests. These men were
      younger ( p=0.015), more anxious (p=0.037 ) and to have more than one affected
      first-degree relative ( p=0.028 ). CONCLUSIONS: The crucial and challenging step
      in the adherence to a screening program was the initial recruitment. Once
      recruited, adherence rate after 3 years was very high (88%). Identifying factors
      that help predict men who might leave the screening process may provide us means
      of improving their compliance in the future.

PMID- 15036672
TI  - The long core needle with an end-cut technique for prostate biopsy: does it
      really have advantages when compared with standard needles?
AB  - OBJECTIVE: To evaluate the failure rate, core length and fragmentation rate for
      each different stroke length of the end-cut (BioPince) needle in order to show
      the performance of the needle for different stroke lengths and compare these with
      the standard side-notch needle. METHODS: TRUS guided biopsy of the prostate was
      performed on 86 consecutive men between June 2002 and May 2003. The patients were
      randomized into two groups with 43 men in each group. Patients in group A
      underwent 8 core biopsy with the end-cut needle in different stroke lengths; 13,
      23 and 33mm respectively. Patients in group B underwent 8 core biopsy with the
      side-notch needle. The cores have been evaluated and compared for failure rates,
      core lengths, number of core lengths under 5mm and fragmentation rates. RESULTS:
      When the end-cut needle was used, a significant number of failure rates was
      noted; with an overall failure rate of 16%. The failure rates were 26% for 13mm
      stroke length, 18% for 23mm stroke length and 10% for 33mm stroke length
      respectively. These failure rates showed statistically significant difference
      from standard needle for overall and for every separate stroke length ( p<0.001
      for all). Standard needle and the cores taken with 33mm stroke length of the end
      cut needle had similar low fragmentation rates while 13 and 23mm stroke lengths
      had higher rates. Of the overall cores taken by BioPince needle, 46/344 (13%) of
      the cores were shorter than 5mm and this was significantly higher than the
      standard needle with 3/344 cores less than 5mm ( p<0.001). The end-cut needle
      when used with the 33mm stroke length has improved the core length by 68%
      according to the standard side-notch needle. CONCLUSIONS: Our results showed that
      the performance of the end-cut needle worsens with decreased stroke lengths. The
      end-cut needle showed high failure rates which necessitates new punctures for
      taking a core. Additionally, the fragmentation rates are not lower than the
      standard needle and it has higher rates of taking small core samples. The only
      significant advantage of this needle over the standard needle is taking longer
      cores when it has been used at 33mm stroke lengths.

PMID- 15036673
TI  - Prognosis of muscle-invasive bladder cancer: difference between primary and
      progressive tumours and implications for therapy.
AB  - OBJECTIVE: To evaluate the difference in prognosis between progressive and
      primary muscle-invasive bladder cancer. MATERIALS AND METHODS: From 1986 to 2000,
      74 patients with progressive muscle-invasive bladder cancer were identified.
      Eighty-nine patients with primary muscle-invasive bladder cancer were frequency
      matched for stage to these patients with progressive disease. Baseline data
      including patient and tumour characteristics were collected at the time of
      diagnosis of the muscle-invasive tumour. Duration of survival was defined as time
      from muscle-invasive bladder cancer diagnosis until disease-specific death.
      Kaplan-Meier curves were drawn to determine the difference in prognosis between
      the two study groups. To adjust for potential residual confounding due to
      differences in treatment, 4 subgroups (T2/3, T4, N+ and M+) were constructed
      according to the TNM classification. In order to see whether age and gender had
      any effect on outcome, the four stage groups, age and gender were entered in a
      Cox's proportional hazard regression model. RESULTS: The 3-year bladder cancer
      specific survival was 67% in the primary group and 37% in the progressive group
      (log rank p=0.0015). Kaplan-Meier curves comparing the different stage groups
      showed a better prognosis for the patients with primary, i.e. pT2/3 or N+,
      tumours at baseline. Cox regression analysis demonstrated that age and gender had
      no influence on bladder cancer-specific survival. CONCLUSIONS: Patients with
      muscle-invasive bladder cancer and a history of superficial bladder cancer have a
      worse prognosis than patients with primary muscle-invasive bladder cancer.

PMID- 15036675
TI  - Risk stratification for bladder tumor recurrence, stage and grade by urinary
      nuclear matrix protein 22 and cytology.
AB  - PURPOSE: To test the hypothesis that voided urinary levels of nuclear matrix
      protein 22 (NMP22) would add to the predictive ability of urine cytology in the
      diagnosis, staging and grading of bladder transitional cell carcinoma (TCC), and
      to evaluate the diagnostic performance of different NMP22 cut-points. MATERIALS:
      NMP22 level and barbotage cytology were evaluated in voided urine specimens
      collected before cystoscopy from 302 subjects with a history of TCC, 32 subjects
      with benign urologic pathologies, and 10 healthy volunteers. RESULTS: 180
      patients (52%) had bladder TCC. Higher levels of NMP22 and positive cytology were
      independently associated with an increased risk of TCC, invasive stage, and high
      grade. The NMP22 value with equal sensitivity and specificity for prediction of
      bladder cancer was 6.5U/ml; for prediction of grade 3 TCC it was 13.5U/ml; and
      for prediction of invasive tumor stage it was 17.4U/ml. The NMP22 cut-point of
      6.5U/ml outperformed the 10U/ml cut-point in all pathologic stages and grades.
      The diagnostic sensitivity of the cytology and NMP22 combined was superior across
      all pathologic stages and grades to that of either marker alone. NMP22 and
      cytology stratified patients into groups with significantly different risk for
      TCC presence, invasive stage, and high grade. CONCLUSIONS: 6.5U/ml is a robust
      NMP22 cut-point for bladder cancer surveillance. The diagnostic sensitivities of
      the combined NMP22 and cytology for TCC presence, stage, and grade were
      significantly higher than those of single marker alone. The combination of urine
      cytology and NMP22 could be used to tailor the frequency of cystoscopic follow
      up.

PMID- 15036674
TI  - Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive
      bladder cancer: a combined analysis of two Nordic studies.
AB  - OBJECTIVES: A Nordic collaborative group assessed the effectiveness of
      cisplatinum based combination chemotherapy prior to cystectomy in two consecutive
      trials. We analyzed overall survival in all patients and in prespecified
      subgroups defined by preoperative T-stage, gender and age. METHODS: The studies
      included in 1985-1997 620 patients with clinically T1G3, T2-T4aNXM0 urothelial
      bladder cancer and WHO performance </=2. Platinum was combined with adriamycin in
      the first and with methotrexate in the second trial. In the first of the studies,
      preoperative radiotherapy was used in both arms. Individual patient data were
      used. No patients were lost to follow-up. The median follow-up was 4.7 years. A
      fixed effect model was used to combine the results of the two trials. Subgroup
      analyses were performed for T-stages, gender and age groups. All analyses were
      done according to intention to treat. RESULTS: The combined study results showed
      a hazard ratio of 0.80 (95% confidence interval 0.64-0.99) for overall survival
      in favor of neoadjuvant treatment. Survival was 56% at five years in the
      experimental group versus 48% in the control group, thus corresponding to an
      eight percent absolute risk reduction after neoadjuvant chemotherapy. We could
      not substantiate any differences in effect by subgroup. CONCLUSIONS: In a
      combined analysis of two trials within the same study organization and the same
      clinical and biological domain, neoadjuvant platinum based combination
      chemotherapy was associated with a 20% reduction in the relative hazard in
      probability of death.

PMID- 15036676
TI  - Detection of occult tumor cells in lymph nodes from bladder cancer patients by
      MUC7 nested RT-PCR.
AB  - OBJECTIVE: Systemic progression is the prevalent form of bladder tumor recurrence
      after radical cystectomy. The detection of occult bladder tumor cells in
      histopathologically normal lymph nodes could be of prognostic value. We examined
      the possibility that mucin 7 (MUC7) RNA might reflect the presence of occult
      tumor cells in lymph nodes from bladder cancer patients. We used the polymerase
      chain reaction (RT-PCR), a highly sensitive assay, to monitor MUC7 RNA. METHODS:
      We collected 240 pelvic lymph nodes from 25 bladder cancer patients undergoing
      radical cystectomy. We also obtained 20 lymph nodes from patients with prostate
      cancer and interstitial cystitis to use as negative controls. Each lymph node was
      divided in two parts to provide tissue for both histopathological and PCR
      analysis. RESULTS: 166/240 lymph nodes from bladder cancer patients were usable
      for MUC7 RT-PCR. By conventional histopathology, six of these nodes contained
      metastases. MUC7 RT-PCR analysis was positive for five of the six histologically
      proven lymph node metastases. Histopathological reevaluation of the sixth node
      revealed tumor in an adjacent vein, not in the lymph node, itself. In contrast,
      46/160 (29%) histologically classified normal lymph nodes (pN0) from 17 bladder
      cancer patients were positive for MUC7. All 20 lymph nodes from control patients
      were MUC7-negative. CONCLUSION: MUC7 RT-PCR is a specific and sensitive method
      for the detection of occult tumor cells in lymph nodes from bladder cancer
      patients. Long-term observation will be necessary to evaluate the clinical value
      of MUC7 as a prognostic indicator of lymph node metastasis and disease
      progression.

PMID- 15036677
TI  - Genetic profile of bone metastases in renal cell carcinoma.
AB  - OBJECTIVE: The aim of this study was to define specific genetic alterations which
      are common in bone metastases in renal cancer patients. METHODS: Tumor DNA from
      31 metastases and 13 related primary tumors was extracted from paraffin embedded
      tissue sections. DOP-PCR was performed to amplify the whole DNA. After labelling
      by PCR, CGH was performed according to standard protocols. RESULTS: The mean
      number of aberrations per metastasis was 6.3 (1-13). Losses of chromosomes 3p
      (76%), 6 (20%), 8p (20%), 9 (34%), 14q (27%) and 18 (20%) as well as gains of
      chromosomes 5 (45%), 8q (34%) and 17 (27%) were detected frequently. Thirteen
      related primary tumors were also investigated. In 7 cases, at least one identical
      alteration was found in both primary tumor and metastases. In these cases, the
      number of alterations was mostly higher in primary tumors than in metastases
      without statistical significance. However, in general, the frequency of
      alterations was higher in metastases. CONCLUSIONS: Bone metastases from renal
      cell carcinoma are characterized by typical genetic alterations. Changes leading
      to metastasizing happen early in tumor pathogenesis. However, further
      accumulation of genetic changes occurs in metastases leading to a more complex
      genetic pattern which might be necessary for progression to clinically relevant
      metastases.

PMID- 15036678
TI  - The role of alpha-blockers in the management of acute urinary retention caused by
      benign prostatic obstruction.
AB  - OBJECTIVES: To consider theories concerning the etiology of acute urinary
      retention (AUR), which may influence the outcome of a trial without catheter
      (TWOC), and to discuss evidence regarding the use of medical therapy in the
      management and secondary prevention of AUR. METHODS AND MATERIALS: A search of
      the literature discussing measurable parameters that may identify patients at
      risk for AUR and who require further intervention after initial treatment was
      undertaken. Studies of the effect of medical interventions for benign prostatic
      hyperplasia (BPH) and AUR were also identified. RESULTS: The etiology of acute
      urinary retention remains unknown in many cases, which are often described as
      spontaneous, but catheterization remains standard management followed by a TWOC
      and bladder outlet surgery in those who do not void satisfactorily. Alpha
      blockers (alpha(1)-adrenoreceptor antagonists) effectively reduce the symptoms
      associated with BPH and improve the urodynamic parameters of obstruction, without
      the sexual adverse events associated with the 5alpha-reductase inhibitors. They
      may diminish the incidence of AUR and the need for surgical intervention in
      symptomatic men. There is now good evidence that alfuzosin, in particular,
      improves the success rate of a TWOC, although other uroselective alpha-blockers
      have also been shown to improve the success rates of TWOC. CONCLUSIONS: The
      proven effects of alpha-blockers support the hypothesis that they will increase
      the chances of a successful TWOC following AUR, which has now been proven in
      several well-designed and conducted studies. However, it is not yet clear whether
      these or other medical therapies have a role to play in the secondary prevention
      of further AUR or the need for further surgery. It is clear that certain
      measurable parameters may be used to identify patients at highest risk of a
      further episode of AUR following a successful TWOC; these patients may then be
      offered urgent surgical intervention.

PMID- 15036679
TI  - Clinical correlation of prostatic lithiasis with chronic pelvic pain syndromes in
      young adults.
AB  - OBJECTIVE: To investigate the incidence, morphology and clinical presentation of
      prostatic calculi in a selected population of young adults and to examine any
      possible correlation with chronic prostatitis/chronic pelvic pain syndromes
      (CP/CPPS). METHODS: A population of 1374 young adults was screened with
      ultrasound imaging of the prostate and 101 cases with prostatic lithiasis were
      selected. Patients were divided in two groups, according to the type of prostatic
      calculi (type A: small, multiple or type B: larger, coarser calculi). Further
      evaluation included history and physical examination, recording of lower urinary
      tract symptoms and the Meares-Stamey test. RESULTS: Calculi were type A in 71.3%
      and type B in 28.7% of cases. Localization (central/periurethral) was not
      correlated with other parameters. Age was closely related to calculus burden ( p
      =0.034 ). Type B calculi were more often associated with symptoms and chronic
      prostatitis/CPPS (chi(2)-test, p=0.007 and 0.018 respectively). CONCLUSIONS:
      Small, multiple calcifications are a normal, often incidental ultrasonographic
      finding in the prostate and represent a result of age rather than a pathologic
      entity. However, larger prostatic calculi may be related to underlying
      inflammation and require further evaluation and possibly, treatment.

PMID- 15036681
TI  - Acquiring surgical skills: a comparative study of open versus laparoscopic
      surgery.
AB  - OBJECTIVES: A preliminary study to evaluate the feasibility of a protocol for
      comparing the learning curves for open and laparoscopic surgical procedures.
      PARTICIPANTS AND METHODS: Thirteen pre-clinical medical students with no previous
      surgical training were given intensive coaching in open and laparoscopic surgical
      techniques for 12 weeks. At the end of this period, their open and laparoscopic
      skills were assessed by three independent examiners. Individual and aggregate
      ability scores in various aspects of open and laparoscopic surgery and the time
      taken to perform the procedures were compared using Student's t-test. RESULTS:
      There was no statistically significant difference in the overall scores by the
      two different techniques ( p=0.057 ). However, differences between the two
      techniques were significant in certain criteria including tissue dissection
      (p=0.024), tidiness of gall bladder (p=0.034 ) and liver ( p=0.016 ) specimens
      and the time taken for the two techniques ( p < or = 0.001 ). CONCLUSIONS: This
      study suggests that when inexperienced subjects are given equal training in
      laparoscopy and open surgery, the overall skills acquired were similar by both
      methods when assessed after 6 weeks. However, on detailed analysis of the
      different components of surgery, the laparoscopic skills were deficient in finer
      dissection, identification of correct planes and two-dimensional perception when
      compared to open surgery and required more operative time. Our study group
      perceived that laparoscopy was more difficult to learn than open surgery even
      after the training. The study group also felt that the training in basic surgical
      skills during their undergraduate careers would make them more interested in
      studying surgery and choosing it as a career.

PMID- 15036680
TI  - Long-term safety and tolerability of tadalafil in the treatment of erectile
      dysfunction.
AB  - OBJECTIVE: To assess the long-term safety and tolerability of tadalafil for
      patients with erectile dysfunction (ED). PATIENTS AND METHODS: This was a
      multicentre, open-label, 24-month extension trial involving 1173 men with ED. The
      mean age was 57 (range 23-83) years and 74.8% of patients were taking concomitant
      medications for comorbid conditions, including diabetes mellitus in 30.5% of men
      and hypertension in 29.5%. These patients had participated in 1 of 5 previous 8
      week or 12-week randomised, double-blind, placebo-controlled tadalafil studies.
      In the present trial, the starting 10mg dose of tadalafil could be increased to
      20mg if the patient could not achieve satisfactory intercourse or reduced to 5mg
      for an adverse event that was persistent, intolerable and judged by the
      investigator to be related to tadalafil. RESULTS: Four hundred ninety-three
      (42.0%) men completed 24 months of treatment. In addition, a further 234 (19.9%)
      completed 18 months of treatment due to a sponsor decision to reduce the study
      duration. The total tadalafil exposure was 1676.0 patient-years. Tadalafil was
      safe and well tolerated. Headache (15.8%), dyspepsia (11.8%), nasopharyngitis
      (11.4%), and back pain (8.2%) were the most common treatment-emergent adverse
      events. The rate of discontinuations due to adverse events for this 18-24-month
      study was 6.3% and the rate for any individual event was <1%. Serious adverse
      events occurred in 8.6% of patients. No consistent pattern of serious adverse
      events assessed as causally associated with tadalafil administration was
      observed. None of the four deaths that occurred during the study was assessed as
      tadalafil related. There were no clinically significant laboratory or
      electrocardiographic findings or changes in vital signs in mean baseline-to
      endpoint analysis attributable to tadalafil. Tadalafil administration was not
      causally associated with drug-induced hepatotoxicity, neutropenia,
      thrombocytopenia, or renal dysfunction. CONCLUSION: Tadalafil at doses of 5, 10,
      or 20mg taken as needed up to once daily for 18 to 24 months was safe and well
      tolerated. These findings support the long-term use of tadalafil in the clinical
      management of erectile dysfunction.

PMID- 15036682
TI  - A simple position to provide better imaging of upper ureteral stones close to the
      crista iliaca during extracorporeal shock wave lithotripsy using the Siemens
      Lithostar.
AB  - OBJECTIVE: The fluoroscopic image from the second plan (oblique) tube of an upper
      ureteral stone close to the crista iliaca may be superimposed on the pelvic bones
      during SWL using the Siemens Lithostar with the patient in the prone position.
      This creates difficulty in imaging and targeting of the stone and can necessitate
      using ureteral catheters before treatment and/or intravenous contrast injection
      during SWL. We describe a very simple, yet effective method for easier
      visualization of the stone under this circumstance. METHODS: Between March 1992
      and February 2003, we treated 1561 patients with ureteral stones by SWL with the
      Siemens Lithostar. The stones were localized in the upper ureter in 841. The
      image of the stone from the second plan (oblique) tube was superimposed on the
      pelvic bones in 221 in whom visualization of the stone was hardly possible with
      the standard prone position. By simply rotating the patient 180 degrees on the
      table, the superimposition of the image of the stone on the pelvic bone was
      obviated. This resulted in easier and better imaging of the stone during SWL. It
      also allowed for a clear and superior image to the treating physician during SWL.
      The energy and shock waves, utilization of anesthesia, number of treatment
      sessions, auxiliary measures, and complications were noted. Stone load was
      recorded in square centimeters (cm(2)). Patients were evaluated by intravenous
      urogram or KUB and ultrasonography when stone-free or CIRF (nonobstructive and
      noninfectious insignificant fragments < or =4mm) status was noted at the
      fluoroscopic control 2 to 4 weeks after the last session. Final CIRF decision was
      made 10-12 weeks after the last session. SWL was regarded as failure if no
      fragmentation was noted after the 3rd session. Therapy was continued if
      fragmentation was noted. RESULTS: The median age was 40 (range 5-85). The mean
      stone burden was 0.8 (range 0.24-2.9) cm(2). No indwelling ureteral stents were
      placed in any patients before and during treatment. The mean number of shock
      waves and energy used for the entire patient population was 2007 and 17.5kV,
      respectively. The median and average treatment session was 1 and 1.7,
      respectively. A total of 196 patients (89%) were rendered stone-free. Clinically
      insignificant residual fragments were present in 18 (8%). SWL was unsuccessful in
      7 (3%) patients. These stones were removed by ureterorenoscopy. Intravenous
      contrast administration was not used to facilitate stone targeting during SWL.
      Anesthesia, in the form of analgesic sedation, was used in 7 (3%) patients. We
      did not observe any complications and adverse effects. CONCLUSIONS: The technique
      described hereby does not have an affect on coupling; it only provides a superior
      image of the stone to the treating physician. We advocate its application in all
      patients with upper ureteral stones close to the crista iliaca when the
      fluoroscopic image of the stone from the second plan (oblique) tube is
      superimposed on pelvic bones during SWL in prone position.

PMID- 15036683
TI  - Tension-free vaginal tape and associated procedures: a case control study.
AB  - OBJECTIVES: We compare objective and subjective cure rates after tension-free
      vaginal tape procedures performed alone or in conjunction with vaginal
      procedures. METHODS: One hundred eighty-six women underwent a tension-free
      vaginal tape procedure for stress or mixed urinary incontinence. One hundred
      women treated with tension-free vaginal tape alone (group 1) were compared with
      40 women treated with tension-free vaginal tape and concomitant vaginal
      hysterectomy (group 2), and 46 patients treated with tension-free vaginal tape
      and pelvic floor reconstruction (group 3). Patient outcomes, surgical
      difficulties and complications are reported. Postoperative voiding diaries,
      standing stress-test results, and patient satisfaction were compared. RESULTS:
      There were no significant differences among the three groups in terms of age,
      menopausal status, BMI, previous incontinence surgery, or the type and degree of
      incontinence. Parity was significantly higher in the group treated with tension
      free vaginal tape and pelvic floor reconstruction ( p=0.04 ). The overall
      perioperative complication rate was 15.6%. Women treated with tension-free
      vaginal tape and hysterectomy (group 2), and those treated with tension-free
      vaginal tape and pelvic floor reconstruction (group 3) had a significantly higher
      incidence of bladder injury (17.9% and 13%, respectively, versus 5% in group 1;
      p=0.05 ). Estimated blood loss and the frequencies of postoperative urgency and
      voiding disorders did differ significantly between women treated with tension
      free vaginal tape alone and those who underwent associated procedures. The mean
      follow-up time was 24.5+/-2.6 months. No difference in the objective cure rate
      was found between the tension-free vaginal tape group and the other two groups
      (93% versus 97.5% and 91.1%; p=0.3 ). No difference in the subjective cure rate
      was found between the tension-free vaginal tape group and the groups undergoing
      associated procedures (72% versus 72.5% and 68.8%; p=0.4). CONCLUSION: Pelvic
      floor defects, benign uterine disorders and stress urinary incontinence can be
      safely treated with tension-free vaginal tape and vaginal procedures during the
      same surgical procedure.

PMID- 15036684
TI  - Sequential assessment of urodynamic findings before and after tension-free
      vaginal tape (TVT) operation for female genuine stress incontinence.
AB  - OBJECTIVES: To sequentially compare the urodynamic findings in patients with
      genuine stress incontinence (GSI) before and after tension-free vaginal tape
      (TVT) operation. PATIENTS AND METHODS: Between January 2001 and January 2002, 24
      consecutive patients with GSI who completed multi-channel urodynamic study and 20
      minute pad test before operation and at 3, 6, and 12 months after operation were
      enrolled. The sequential urodynamic findings of each case were compared and
      analyzed. RESULTS: The mean age of the 24 patients was 60.6+/-10.7 years with the
      parity of 3.5+/-1.4. No statistical differences in voiding and storage functions
      before and after TVT operation were noted. In contrast, significant changes of
      stress urethral pressure profile (sUPP) including maximal urethral pressure,
      maximal urethral closure pressure, functional urethral length, urethral closure
      area and continence area were observed at 6 and 12 months postoperatively (
      p<0.03 ). The median pad weight test decreased from 72g (range 10-220) to 0g 3
      months after operation and remained unchanged at 6 and 12 months postoperatively.
      CONCLUSIONS: This prospective study demonstrates that TVT operation, if done
      properly, does not significantly impair voiding and storage functions. The
      significantly increased sUPP parameters may contribute, at least in part, to the
      high cure rate of TVT operation.

PMID- 15036685
TI  - The effect of nitric oxide on the resting tone and the contractile behaviour of
      the external urethral sphincter: a functional urodynamic study in healthy humans.
AB  - AIMS: This functional urodynamic study assessed the effect of the nitric oxide
      donor isosorbide dinitrate on the external urethral sphincter and hypothesised
      first that nitric oxide could lower the resting sphincter pressure, second that
      nitric oxide could influence the sphincter contractility during magnetic
      stimulation, and third that nitric oxide could induce a faster external urethral
      sphincter fatigue during continuous magnetic stimulation. METHODS: Eight healthy
      males gave their written informed consent and were included. A 2-channel microtip
      pressure transducer catheter was inserted into the urethra measuring the bladder
      and the external urethral sphincter pressure. Magnetic stimulation of the sacral
      roots was performed to evoke reproducible contractions of the external urethral
      sphincter. The baseline protocol included six single pulse stimulations and three
      stimulations 10sec in duration each for two frequencies 5Hz and 50Hz with
      intensities at the motor threshold of the pelvic floor. Then the subjects
      received 10 mg of isosorbide nitrate sublingually and the protocol was repeated
      5min, 20min, 40min and 60min after drug administration. RESULTS: The sublingual
      administration of isosorbide dinitrate could significantly reduce the resting
      pressure of the external urethral sphincter for at least one hour. The maximal
      contractile strength measured as the maximal urethral pressure during single
      pulse and continuous magnetic stimulation of the sacral roots also decreased
      significantly. Nitric oxide did not induce a significantly faster fatigue of the
      external urethral sphincter during continuous magnetic stimulation of the sacral
      roots. CONCLUSIONS: This study shows a functionally relevant effect of nitric
      oxide on the resting tone and the contractile behaviour of the human external
      urethral sphincter in vivo while the fatigue properties did not changed
      significantly. Nitric oxide donors could offer a new pharmacological approach to
      treat urinary retention due to overactive or non-relaxing external urethral
      sphincter.

PMID- 15036686
TI  - Characterization of an animal model of spontaneous congenital unilateral
      obstructive uropathy by cDNA microarray analysis.
AB  - INTRODUCTION: The pathophysiology of congenital obstructive uropathy has been
      studied intensively in several animal models. A reliable parameter for early
      detection of relevant obstruction is not yet identified. For further
      investigation of the complex regulatory events of obstructive uropathy, we used a
      cDNA microarray technology for a parallel differential expression analysis of
      about 15000 different genes of obstructed, contralateral and healthy kidneys of
      rats with spontaneous congenital obstructive uropathy. METHODS: Total cellular
      RNA of obstructed, contralateral and healthy control kidneys of 32-35 days old
      rats was extracted and pooled. RNA quality and quantity was assessed using a
      Bioanalyzer 2100. mRNA expression for selected marker genes was assessed by real
      time PCR. High throughput gene expression profiling was performed with cDNA
      microarrays with differentially labeled cDNA targets. RESULTS: Beside expected
      typical alterations of several growth factors such as TGF-beta, EGF, IGF-1, PDGF,
      we observed overexpression of extracellular matrix proteins and a decreased
      activity of antioxidant enzymes. Additionally, NFkappaB, a nuclear transcription
      factor involved in the development of interstitial fibrosis, was slightly up
      regulated in the obstructed kidneys. Down-regulation of genes involved in tubular
      sodium transport indicated impaired concentration ability of the obstructed
      kidneys. Furthermore, we found up-regulation of pro-apoptotic genes including
      transcripts for the proapoptotic protein Siva. Interestingly, TNFalpha, another
      factor involved in the pathophysiology of congenital obstructive uropathy, was
      not differentially regulated. CONCLUSIONS: The alterations of the genes for
      growth factors, extracellular matrix proteins, antioxidant enzymes, sodium
      transport and genes involved in apoptosis support the representative character of
      this animal model for congenital obstructive uropathy. In the rather advanced
      stage of congenital renal obstruction a possible explanation of the lacking
      differential regulation of TNFalpha highlights it as a possible marker of earlier
      stages of obstruction. Furthermore, the possible involvement of the Siva/CD27
      pathway in the apoptotic cascade also offers a new possibility to find a
      sensitive marker to detect renal obstruction already in an earlier stage.

PMID- 15036687
TI  - Nuclear accumulation of histone deacetylase 4 (HDAC4) coincides with the loss of
      androgen sensitivity in hormone refractory cancer of the prostate.
AB  - OBJECTIVES: To examine the effect of androgen treatment upon histone deacetylase
      4 (HDAC4) localisation and, thus, enzymatic function in androgen sensitive
      prostate cancer (CaP) models. To study HDAC4 expression in benign prostatic
      hyperplasia, primary and hormone refractory (HR) CaP and to investigate the
      involvement of histone deacetylase activity in the development of the androgen
      insensitive phenotype. METHODS: Immunohistochemical staining of prostate sections
      of both benign tissue and primary and hormone relapsed prostate cancer, as well
      as of the CWR22 mouse xenograft model, and indirect quantitative
      immunofluorescence staining of endogenous HDAC4 in LNCaP cells. RESULTS: HDAC4 is
      recruited to the nuclei of HR cancer cells, where it may exert an inhibitory
      effect on differentiation and contribute to the development of the aggressive
      phenotype of late stage CaP. The above may result from the loss of androgen
      responsiveness characterising HR CaP, since HDAC4 nuclear localisation is
      regulated by androgens in androgen responsive systems (i.e. LNCaP, CWR22)
      reflecting earlier phase disease. CONCLUSIONS: HDAC4 may contribute to the
      development of HR CaP and, therefore, constitute a potential therapeutic target,
      particularly in the most lethal phase of androgen independence.

PMID- 15036688
TI  - FSH in testis cancer. Re: Nord C, Bjoro T, Ellingsen D, Mykletun A, Dahl O, Klepp
      O, Bremnes RM, Wist E, Fossa SD. Gonadal hormones in long-term survivors 10 years
      after treatment for unilateral testicular cancer. Eur Urol 2003;44:322-8.

PMID- 15036690
TI  - Re: Leroy X, Rigot J-M, Aubert S, Ballereau C, Gosselin B. Value of frozen
      section examination for the management of nonpalpable incidental testicular
      tumors. Eur. Urol. 2003;44:458-60.

PMID- 15036692
TI  - Reply to J. Bharadwa and V.H. Nargund; Re: Leroy X, Rigot JM, Aubert S, Ballereau
      C, Gosselin B. Value of frozen section examination for the management of
      nonpalpable incidental testicular tumors. Eur. Urol. 2003;44:458-60.

PMID- 15036694
TI  - Laboratory stabilization/solidification of tank sludges: GAAT, OHF, and combined
      tank sets.
AB  - Highly radioactive, mixed-waste sludges that have been collected at Oak Ridge
      over several decades are being combined for treatment and disposal. Stabilization
      of the sludges in the different tank sets was tested prior to the proposed
      combination and treatment. This paper, which follows a previous article on the
      Melton Valley Storage Tank/Bethel Valley Evaporator Storage Tank set, documents
      the testing of the Gunite and Associated Tank and Old Hydrofracture Facility tank
      sets, as well as the combined sludges of all the Oak Ridge National Laboratory
      tank sets; the third paper on this subject will discuss efforts to maximize the
      sludge loading. The grout formulations were tested in the laboratory with
      surrogates. A wet-sludge loading of 60wt% resulted in strong wasteforms with no
      free water and gave a volume increase of about 30-40vol%. The Resource
      Conservation and Recovery Act metals included in the surrogate testing were
      silver, cadmium, chromium, lead, selenium, thallium, zinc, and mercury. The grout
      formulations stabilized these metals within the Universal Treatment Standards
      limits. In addition, a grout leachability index of about 10.0-12.0 was measured
      for both (85)Sr and (137)Cs, meeting the recommended requirement of >6.0.

PMID- 15036693
TI  - Laboratory stabilizations/solidification of tank sludges: MVST/BVEST.
AB  - Oak Ridge tank sludges that have been collected over several decades are being
      combined for treatment and disposal. Stabilization of the highly radioactive,
      mixed-waste sludges in the different tank sets has been evaluated prior to the
      proposed combination and treatment. This paper documents the testing of a Melton
      Valley Storage Tank (MVST)/Bethel Valley Evaporator Storage Tank set. Subsequent
      papers will discuss continued work on other tank sets and efforts to maximize the
      sludge loading. Grout formulations were tested in the laboratory both with a
      surrogate and with a sample of an actual mixed waste tank sludge from MVST W-25.
      Wet-sludge loadings of 50-60wt% resulted in strong wasteforms with no free water
      and gave a volume increase of about 40-50vol%. Resource Conservation and Recovery
      Act (RCRA) metals included in the surrogate testing were cadmium, chromium, lead,
      selenium, thallium, and mercury. The actual sludge sample was only
      characteristically hazardous for mercury by the Toxic Characteristic Leaching
      Procedure but exceeded the Universal Treatment Standard (UTS) limit for chromium.
      The grout formulations stabilized these two RCRA metals within UTS limits. In
      addition, a grout leachability index of about 9.0-10.0 was measured for both
      (85)Sr and (137)Cs, meeting the recommended requirement of >6.0.

PMID- 15036695
TI  - Laboratory stabilization/solidification of tank sludges: maximizing sludge
      loading.
AB  - Highly radioactive, mixed-waste sludges that have been collected in tanks at Oak
      Ridge over several decades are being combined for treatment and disposal.
      Stabilization of the sludges in the different tank sets was tested prior to the
      proposed combination and treatment. This paper is the third one in a series on
      the laboratory stabilization/solidification of these tank sludges. It discusses
      efforts to maximize the sludge loading with no strength criterion for the grout
      formulation. Grout formulations were tested in the laboratory both with
      surrogates and with actual samples of tank sludge. Hydrogels eliminated free
      water generation, even at sludge loadings of >90wt%, albeit strong monoliths did
      not form at such high loadings. Correlations established the dependence of the
      chromium and mercury performance in the Toxicity Characteristic Leach Procedure
      for the surrogates on the slag content of the grout while the lead performance
      depended on the extract pH. The surrogate sludge loading was limited by the
      chromate content to about 90wt%, meeting Universal Treatment Standard limits.
      However, tests with actual sludges at such high loadings revealed problems with
      lead and silver stabilization that were not experienced with the surrogate
      testing.

PMID- 15036696
TI  - Climate change policies and capital vintage effects: the cases of US pulp and
      paper, iron and steel, and ethylene.
AB  - Changes in material use, energy use and emissions profiles of industry are the
      result of complex interrelationships among a multitude of technological and
      economic drivers. To better understand and guide such changes requires that
      attention is paid to the time-varying consequences that technology and economic
      influences have on an industry's choice of inputs and its associated (desired and
      undesired) outputs. This paper lays out an approach to improving our
      understanding of the dynamics of large industrial systems. The approach combines
      engineering and econometric analysis with a detailed representation of an
      industry's capital stock structure. A transparent dynamic computer modeling
      approach is chosen to integrate information from these analyses in ways that
      foster participation of stakeholders from industry and government agencies in all
      stages of the modeling process-from problem definition and determination of
      system boundaries to generation of scenarios and interpretation of results. Three
      case studies of industrial energy use in the USA are presented-one each for the
      iron and steel, pulp and paper, and ethylene industry. Dynamic models of these
      industries are described and then used to investigate alternative carbon
      emissions and investment-led policies. A comparison of results clearly points
      towards two key issues: the need for industry specific policy approaches in order
      to effectively influence industrial energy use, fuel mix and carbon emissions,
      and the need for longer time horizons than have typically been chosen for the
      analysis of industrial responses to climate change policies.

PMID- 15036698
TI  - Incorporating community objectives in improved wetland management: the use of the
      analytic hierarchy process.
AB  - Wetlands in Australia provide considerable ecological, economic, environmental
      and social benefits. However, the use of wetlands has been indiscriminate and
      significant damage to many Australian wetlands has occurred. During the last 150
      years one third of the wetlands in Victoria have been lost. A conspicuous problem
      in wetland management is the paucity of involvement by stakeholders. This paper
      uses the Analytic Hierarchy Process (AHP) to incorporate stakeholder objectives
      in the 'Wonga Wetlands' on the Murray River. The study shows that the AHP can
      explicitly incorporate stakeholder preferences and multiple objectives to
      evaluate management options. The AHP also provides several approaches for policy
      makers to arrive at policy decisions.

PMID- 15036697
TI  - Probe into the method of regional ecological risk assessment-a case study of
      wetland in the Yellow River Delta in China.
AB  - Ecological risk assessment (ERA) is a new field of study for evaluating the risks
      associated with a possible eco-environmental hazard under uncertainty. Regional
      ERA is more complex than general ERA, as it requires that risk receptors, risk
      sources, risk exposure, uncertainty and especially spatial heterogeneity all be
      taken into account. In this paper, a five-step process of regional ERA is
      developed and tested through a wetland case study in the Yellow River Delta in
      China. First, indices and formulas are established for measuring degrees of
      ecological risk and damage to ecosystems. Using a combination of remote sensing
      data, historical records and survey data, and with the assistance of GIS
      techniques, the indices and formulas are then applied to the wetland in the study
      area. On the basis of the assessment results, we propose a number of
      countermeasures for the various risk zones in the Yellow River Delta.

PMID- 15036699
TI  - The history and evaluation of saltwater intrusion into a coastal aquifer in
      Mersin, Turkey.
AB  - The Mersin-Kazanli region is a densely industrialized region. The factories and
      towns cover their water demand from groundwater. With the increased water demand,
      saltwater intrusion has occurred. The chloride concentration of the water samples
      from some wells has been analysed periodically since these wells were drilled.
      The results of these analyses and electrical conductivity measurements were used
      to show the history and development of saltwater intrusion up to the year 2000.
      The Cl(-) concentration of the water within the alluvial aquifer increased to
      over 3000 mg/l in 1999 and the wells were closed completely. In 2001 new wells
      were drilled more than 1 km away from the sea and old well field. With the
      results of the analyses conducted in 2001, the current groundwater quality was
      determined. The ground water is of the magnesium-calcium-bicarbonate type and
      this composition is controlled by the interaction of the water with the sediments
      of alluvial deposits.

PMID- 15036701
TI  - The Million Women Study: a licence to kill other investigations?
AB  - The Million Women Study (MWS), published in the summer of 2003, has suggested
      unexpected high risks for invasive breast cancer in women using postmenopausal
      hormone therapy (PHT). Recent reports from randomised controlled trials (RCTs)
      have demonstrated that long-term combined PHT is associated with a small risk
      increase for invasive breast cancer, but not for death due to breast cancer. The
      observational design of the MWS has made this study subject to several biases,
      that can easily explain the discrepancy with the observations done in RCTs and
      several other large observational studies. It is concluded that the hormone fear
      that was caused by the MWS, and augmented by some professionals and the media,
      was unjustifiable.

PMID- 15036702
TI  - Domestic violence: prevalence in pregnant women and associations with physical
      and psychological health.
AB  - OBJECTIVES: To examine the prevalence of domestic violence (DV) and its
      associations with obstetric complications and psychological health in women on
      antenatal and postnatal wards. STUDY DESIGN: A cross-sectional survey conducted
      in an inner-London teaching hospital. Two hundred English-speaking women aged 16
      and over, were interviewed between July 2001 and April 2002. The Abuse Assessment
      Screen was used to assess for experiences of DV. Depression was assessed using
      the Edinburgh Postnatal Depression Scale (EPDS). The analysis of predictors of
      obstetric complications grouped together those known to be associated with DV.
      RESULTS: 23.5% of women had lifetime experience of DV, 3% during the current
      pregnancy. Women with a history of DV were significantly more likely to be
      single, separated or in non-cohabiting relationship and to have smoked in the
      year prior to and/or during pregnancy. Higher EPDS scores were significantly
      associated with DV, single, separated or non-cohabiting status, and obstetric
      complications. Both a history of DV and increased EPDS scores were significantly
      associated with obstetric complications after controlling for other known risk
      factors. CONCLUSIONS: Domestic violence is regarded as an important risk marker
      for the development of obstetric complications and depressive symptomatology.
      This finding of itself justifies training and education of maternity health
      professionals to raise awareness.

PMID- 15036703
TI  - Gestational diabetes and preeclampsia.
AB  - OBJECTIVE: To determine whether gestational diabetes mellitus (GDM) increases the
      risk for preeclampsia independent of other risk factors. STUDY DESIGN: The
      association between GDM and preeclampsia was analyzed in a population of women
      who had given birth to singletons registered in Swedish Medical Birth Register
      from 1992 through 1996 (n=430,852). RESULTS: GDM occurred in 0.8% and
      preeclampsia in 2.9% of all pregnancies. The rate of preeclampsia was higher in
      the GDM than in the non-GDM group (6.1% versus 2.8%). High age, nullipara,
      chronic hypertension, kidney disease, and high body mass index (BMI) were all
      independently associated with increased risk for preeclampsia. Smoking was
      associated with decreased risk. Adjusted odds ratio for GDM as a risk factor for
      preeclampsia was 1.61 (95% confidence interval (CI) 1.39-1.86) when prepregnancy
      BMI, which was a true confounder, was included in the last step of the multiple
      logistic regression analysis. CONCLUSIONS: There is an independent and
      significant association between GDM and preeclampsia. Obesity is a major
      confounding factor but could not explain the total excess risk.

PMID- 15036704
TI  - Amniotic vascular endothelial growth factor (VEGF) and nitric oxide (NO) in women
      with subsequent preeclampsia.
AB  - OBJECTIVE: To assess whether amniotic fluid concentrations of nitric oxide (NO)
      and vascular endothelial growth factor (VEGF) in early pregnancy correlate to
      subsequent preeclampsia. STUDY DESIGN: We performed a retrospective study to
      assess VEGF and NO on the second trimester amniotic fluid of 15 healthy women,
      and 15 women who subsequently developed preeclampsia. RESULTS: In women with
      subsequent preeclampsia, both VEGF (213.19+/-78.42 pg/ml) and NO concentrations
      (4.31+/-1.02 micromol/mg creatinine) were significantly lower than healthy
      controls (VEGF 255.05+/-88.66 pg/ml; NO 5.02+/-1.57 microg/mg creatinine;
      P<0.05). CONCLUSIONS: Our findings suggest that reduced VEGF may be responsible,
      at least in part, for the impaired vascular development which occurs in
      preeclampsia. Low concentrations of VEGF and NO in the second trimester may
      represent an impaired stimulus to vascular formation and endothelial regulation
      that induce placental disease and preeclampsia.

PMID- 15036705
TI  - Plasma malondialdehyde, superoxide dismutase, sE-selectin, fibronectin,
      endothelin-1 and nitric oxide levels in women with preeclampsia.
AB  - OBJECTIVE: The purpose of this study was to determine plasma malondialdehyde
      (MDA), superoxide dismutase (SOD), soluble E-selectin (sE-selectin), fibronectin,
      endothelin-1 (ET-1) and nitric oxide (NO) levels in women with preeclampsia and
      to find out the relations of diastolic blood pressure with these variables. STUDY
      DESIGN: We performed a case-control study consisting of randomly selected 34
      healthy pregnant women and 35 patients diagnosed as preeclampsia.
      Lipoperoxidation was ascertained by the formation of MDA. SOD activity was
      determined by the method of Sun et al. Plasma concentration of NO was estimated
      using colorimetric assay. Plasma ET-1 and sE-selectin were measured by enzyme
      linked immunosorbent assay (ELISA). A nephelometric method for fibronectin
      quantitation was used. RESULTS: The mean plasma level of MDA was significantly
      higher and SOD was significantly lower in preeclamptic pregnancies (P<0.001).
      Plasma concentrations of fibronectin, sE-selectin and ET-1 were significantly
      increased, whereas NO was significantly decreased in women with preeclampsia than
      normotensive women (P<0.001). CONCLUSION: Increased plasma levels of MDA,
      fibronectin, sE-selectin, ET-1, and decreased plasma levels of NO and SOD in
      preeclamptic patients suggest that poorly perfused fetoplacental unit is the
      origin of oxygen free radicals and lipid peroxides.

PMID- 15036706
TI  - Performance of a novel test to quantify activated protein C resistance in women
      with a history of pre-eclampsia.
AB  - OBJECTIVE: We determined the performance of a functional test for activated
      protein C (APC) resistance in formerly pre-eclamptic women and matched controls.
      STUDY DESIGN: In our university medical center, we assessed the response to APC
      in plasma in 118 formerly pre-eclamptic women and in 57 healthy controls, we
      measured plasma levels of thrombophilic factors and we performed statistical
      analysis. RESULTS: The incidence of APC resistance was significantly higher in
      formerly pre-eclamptics than in controls. Formerly APC resistant pre-eclamptics
      more often experienced intra-uterine growth restriction (IUGR) than their non-APC
      resistant counterparts. CONCLUSION: APC resistance determined by this functional
      test is present in a large subgroup of formerly pre-eclamptics. A higher
      incidence of IUGR in this group suggests a more severe course of the experienced
      pregnancy complications. Additional study is needed to determine whether this
      test is sensitive in predicting recurrence of pre-eclampsia or IUGR.

PMID- 15036707
TI  - Fetal inherited thrombophilias influence the severity of preeclampsia, IUGR and
      placental abruption.
AB  - OBJECTIVE: To determine whether common inherited thrombophilias in the fetus
      influence the severity of severe preeclampsia, IUGR and placental abruption.
      DESIGN: A case-control study among patients with complicated pregnancies. Cases
      were defined as fetuses with thrombophilia. SETTING: A university hospital with
      3700 deliveries per year. POPULATION: Seventy cases with severe preeclampsia,
      IUGR or placental abruption. METHODS: Mothers and neonates were tested for
      mutation of factor V Leiden, prothrombin gene and methylenetetrahydrofolate
      reductase. MAIN OUTCOME MEASURES: Gestational age at delivery, birth weight and
      early neonatal complications. RESULTS: Gestational age at delivery and birth
      weight were significantly lower in fetuses with factor V Leiden or prothrombin
      gene mutation compared to control fetuses. CONCLUSIONS: Fetal factor V Leiden
      mutation and prothrombin gene mutation may influence the course of severe
      preeclampsia, IUGR and placental abruption. These thrombophilic changes may cause
      an earlier appearance or lead to a late pregnancy complication of a greater
      severity.

PMID- 15036708
TI  - Thrombophilia and fetal growth restriction.
AB  - OBJECTIVE: Genetic thrombophilia may represent a new risk factor for obstetrical
      complications. The aim of the study was to determine which subgroups may be
      associated with genetic thrombophilia for small for gestational age infants
      (SGA). METHODS: A case-control study was performed in three different maternity
      wards in Normandy. Cases (n=203) were women who had pregnancies complicated by
      unexplained SGA infants defined as a birth weight below the 3rd centile and
      control subjects (n=203) were women who had infants with birth weight > or =10th
      centile. Patients were tested in the immediate postpartum period and 2 months
      later for factor V Leiden mutation, and prothrombin 20210A mutation. Frequencies
      of these mutations were observed in different subgroups of SGA infants depending
      on pregnancy or neonatal outcomes usually associated with intrauterine growth
      restriction (IUGR), and were then compared with the overall prevalence for these
      mutations detected in the control group. RESULTS: Prevalences for factor V Leiden
      mutation (or=2.58; 95% confidence interval: 0.83-8.04), prothrombin 20210A
      mutation (or=2.03; 95% confidence interval: 0.51-8.01), were comparable between
      cases and controls (4.9% versus 1.9% and 2.9% versus 1.4%, respectively).
      Frequencies for these two polymorphisms significantly increased in subgroups of
      SGA infants with a normal Pourcelot index (13/133 versus 7/203; P=0.04), a
      gestational age > or =37 weeks of gestation (15/143 versus 7/203; P=0.01), a
      vaginal delivery (11/117 versus 7/203; P=0.04), a birth weight > or =2000 g
      (12/121 versus 7/203; P=0.03), no admission to paediatric ward (11/116 versus
      7/203; P=0.01), a low Ponderal index <2.5(e) centile (6/45 versus 7/203; P=0.04),
      and normal head circumference >10th centile (7/53 versus 7/203; P=0.01) in
      comparison with the control group. CONCLUSIONS: An association was found between
      polymorphisms for factor V Leiden and prothrombin, and asymmetrical intrauterine
      growth restriction with immediate favourable neonatal outcomes.

PMID- 15036709
TI  - Induction of labor with 50 and 100 microg of misoprostol: comparison of maternal
      and fetal outcomes.
AB  - OBJECTIVE: The aim of this randomized controlled study was to compare the
      efficacy and the safety of different regimens of misoprostol for labor induction.
      MATERIALS AND METHODS Eligible women received intravaginal 100 microg, every 6 h
      or 50 microg every 4 h. Treatment continued until: (1) dilatation >3 cm; (2)
      rupture of membranes (artificial); (3) signs of uterine hyperstimulation; (4)
      adequate contraction pattern (three contraction/10 min). Managing clinician might
      use oxytocin during labor. Cesarean section rate was the main outcome that was
      considered variably. Other outcome measures were neonatal outcome (Apgar scores,
      meconium staining, and umbilical artery pH) and induction to delivery interval.
      RESULTS: A total number of 72 women received either misoprostol 100 microg
      (n=37), or 50 microg (n=35) randomly. The two groups had similar mean Bishops
      scores at induction (4.10+/-2.4 versus 4.2+/-2.1; P=0.85), rates of nulliparity,
      use of epidural anesthesia, and oxytocin augmentation. In two groups the number
      of doses of misoprostol used was similar (1.6+/-0.5 versus 1.7+/-0.3) CONCLUSION:
      There was not any difference between the two groups in the mean+/-S.D. time to
      delivery (h) and cesarean rate. Likewise, there was not a significance between
      two groups in the rates of 5 min Apgar score, and of meconium passage.

PMID- 15036710
TI  - Uterine rupture associated with misoprostol labor induction in women with
      previous cesarean delivery.
AB  - OBJECTIVE: To review our experience with uterine rupture in patients undergoing a
      trial of labor with a history of previous cesarean delivery in which labor was
      induced with misoprostol. STUDY DESIGN: A retrospective chart review was used to
      select patients who underwent induction of labor with misoprostol during the
      period from February 1999 to June 2002. Women with a history of cesarean delivery
      were retrospectively compared with those without uterine scarring. RESULTS:
      Uterine rupture occurred in 4 of 41 patients with previous cesarean delivery who
      had labor induced with misoprostol. The rate of uterine rupture (9.7%) was
      significantly higher in patients with a previous cesarean delivery (P<0.001). No
      uterine rupture occurred in 50 patients without uterine scarring. Women with a
      history of cesarean delivery were more likely to have oxytocin augmentation than
      those without uterine scarring (41% versus 20%; P=0.037). CONCLUSION: Misoprostol
      induction of labor increases the risk of uterine rupture in women with a history
      of cesarean delivery.

PMID- 15036711
TI  - Influence of vasopressin in the pathogenesis of oligohydramnios-polyhydramnios in
      monochorionic twins.
AB  - OBJECTIVES: The pathophysiology of oligohydramnios-polyhydramnios in
      monochorionic (MC) twins complicated by chronic twin-twin transfusion syndrome
      (TTTS) is poorly understood. We hypothesise that oliguria and oligohydramnios in
      the donor twin of chronic TTTS, occurs due to antidiuretic and vasoconstrictive
      activity of vasopressin (AVP). METHODS: We measured AVP levels in maternal, fetal
      and amniotic fluid samples obtained in utero and at birth from 44 MC twins with
      (n=27) or without chronic TTTS (n=17). Concentrations of AVP in pg/ml were
      determined by immuno-radiometry assay. RESULTS: In donor fetuses, plasma and
      amniotic fluid AVP levels were higher than those of the recipient twins in utero
      (P<0.001) and at birth (P<0.001). No such differences were found between the non
      TTTS twins. The plasma AVP concentrations were higher in the recipient fetuses
      with severe hydrops than those without hydrops (2.8+/-0.7 pg/ml versus 0.3+/-0.3
      pg/ml; P<0.05). Maternal AVP levels were comparable between the TTTS and non-TTTS
      groups. In the non-TTTS twins, both plasma and amniotic fluid AVP levels were
      higher than those of the recipient twins (P<0.001) but lower than those of the
      donor twins (P<0.001). There was a significant association between amniotic fluid
      and plasma AVP levels both in the TTTS (r=0.78; P<0.001) and non-TTTS (r=0.70;
      P<0.01) infants. CONCLUSIONS: Vasopressin concentrations in the donor twins were
      three times higher than their co-twins which suggests that oligohydramnios may
      occur as a consequence of AVP mediated reduction in fetal urine output.

PMID- 15036712
TI  - Induction of hepatic hematopoiesis with tenascin-C expression during the second
      trimester of development.
AB  - OBJECTIVE: To determine the role of tenascin-C in fetal hepatic hematopoietic
      proliferation and differentiation in different stages of development. STUDY
      DESIGN: We examined and compared the immunohistochemical expression of tenascin-C
      in the hepatic stromal portal fields in the first, second, and third trimester of
      gestation respectively, in relation to the appearance of CD34 progenitor
      hematopoietic, stromal progenitor and vascular endothelial positive cells.
      RESULTS: Our results demonstrated a quantitative difference in the second
      trimester of gestation concerning the expression of tenascin-C in the connective
      tissue stroma of the hepatic portal fields over the equivalent expression of the
      protein in the first (P<0.0001, t-test) and third trimester (P<0.0001, t-test).
      Similar changes in the above period were found concerning the expression of CD34
      over the first (P<0.0001, t-test) and third trimesters (P<0.0001, t-test),
      suggesting a direct involvement of tenascin-C in the sustaining of hematopoietic
      activity. CONCLUSIONS: Our data provide evidence that an ECM glycoprotein
      component, tenascin-C, plays a relevant role in hematopoiesis through interaction
      between stromal cells and hematopoietic progenitor cells.

PMID- 15036714
TI  - Association of progesterone receptor polymorphism with recurrent abortions.
AB  - OBJECTIVE: The current study sought for polymorphisms within the progesterone
      receptor (PR) gene. Allele and genotype frequencies of patients with repeated
      abortions were compared to a control group. DESIGN: All exons of the PR of 42
      women with repeated abortions and 40 controls were screened for single nucleotide
      polymorphisms (SNP). Determination of the DNA-sequences was performed. RESULTS:
      Three SNPs were detected (exon 1: G1031C Ser344Thr; exon 4: G1978T Leu660Val,
      exon 5: C2310T His770His). These SNPs are linked. The more frequent wildtype (*1)
      allele and the rarer (*2) allele were found in the control group and in the study
      group at different frequencies (control group: *1/*1: 78%, *1/*2: 22%, *2/*2: 0%;
      patient group: *1/*1: 50%, *1/*2: 43%, *2/*2: 7%). The genotypes distributions
      differed significantly from each other (P=0.019, chi2=7.879). CONCLUSIONS: The
      data suggest that the rarer PR allele may be associated with an increased
      likelihood of repeated miscarriages contributing to its multi-factorial causes.

PMID- 15036715
TI  - Increased frequency of sister-chromatid exchange and altered alkaline comet assay
      scores in superovulation cycles for unexplained infertility.
AB  - OBJECTIVE: Sister-chromatid exchange analysis (SCE) and alkaline comet assay
      measure and analyze DNA damage in mammalian cells. This study assesses whether
      ovulation induction agents increase DNA damage in the lymphocytes of infertile
      women undergoing superovulation. STUDY DESIGN: Prospective case control study in
      a university based hospital. Baseline and hCG day peripheral blood samples were
      withdrawn from 20 women with undergoing superovulation for unexplained
      infertility and baseline and luteinizing hormone (LH) peak day samples were also
      withdrawn from another 20 infertile women with unexplained infertility. RESULTS:
      There was increased SCE frequency and DNA damage determined by comet assay on the
      hCG day compared to the basal state. The SCE increase was correlated with the hCG
      day estradiol (E2) but not with ampoules of follicular stimulating hormone (FSH).
      The SCE frequency was also increased naturally ovulating women; however this was
      significantly less than that in FSH receiving women. CONCLUSION: Increased DNA
      damage may indicate for increased potential for malignancies after
      superovulation.

PMID- 15036713
TI  - Perinatal outcome prediction by maternal homocysteine and uterine artery Doppler
      velocimetry.
AB  - OBJECTIVES: (a) To evaluate the predictive value of uterine Doppler velocimetry
      for pregnancy complications, (b) to study the relationship between abnormal
      uterine Doppler velocimetry and plasma homocysteine, and (c) to determine whether
      homocysteine measurement improves the predictive value of uterine Doppler
      screening. STUDY DESIGN: Prospective study including 94 pregnant women without
      previous risk factors. Total homocysteine, folate and Vitamin B(12) were
      analysed. Uterine Doppler velocimetry at weeks 24-25 was performed. RESULTS: The
      presence of any uterine Doppler alteration had a sensitivity of 66.7%, and a
      specificity of 81.2%, in predicting obstetric complications. The likelihood ratio
      was 3.6. The positive and negative predictive values were 27.3 and 95.8%,
      respectively. The global efficiency was 83.0%. The addition of
      hyperhomocysteinemia to Doppler alterations increased the sensitivity from 66.7
      to 77.8%. CONCLUSIONS: The addition of homocysteine determination to uterine
      Doppler evaluation in the second trimester does not usefully improve its
      predictive value.

PMID- 15036716
TI  - Follow-up study on the effectiveness of transcervical myoma resection (TCRM).
AB  - STUDY OBJECTIVE: To measure the efficacy of transcervical hysteroscopic fibroid
      resection (TCRM) among the authors' patients. STUDY DESIGN: In one department, 73
      transcervical hysteroscopic fibroid resections were performed on 68 patients over
      a 6-year period. Using a computerized database and mailed questionnaires, 58
      patients were followed up. RESULTS: Thirty-six of the 58 patients showed no
      symptoms after the procedure; in 15 cases subsequent fibroid was detected, while
      in seven cases other types of complaints occurred, not related to the myoma.
      During the procedures complications happened in four cases; one perforation and
      three bleeding episodes occurred. CONCLUSION: Our data indicate that TCRM is a
      safe and successful method of treating submucosal fibroids.

PMID- 15036717
TI  - The prevalence of the HPV 16 genome, integrated viral status and p53 genotype in
      cervical cancer population of north-eastern Hungary, the correlation with the
      established markers of tumour progression.
AB  - OBJECTIVES: To evaluate the prevalence of the HPV 16 integrated status and the
      p53 genotype in cervical cancer in north-eastern Hungary and their correlation
      with the established prognostic factors. STUDY DESIGN: Parallel with the routine
      histological examination, Southern blot hybridisation and multiplex PCRs were
      used to detect type/physical state of HPV DNA in primary tumours and in regional
      lymph nodes combined with p53 genotyping of 83 patients. RESULTS: 46.9% (39/83)
      prevalence rate of HPV 16 genome was found. The frequency of viral integration
      (76.9% in primary tumours and 95.2% in regional lymph nodes) and that of the
      p53Arg homozygous genotype (64.1%) proved to be higher than reported from other
      parts of the world. The HPV 16 integration and the p53 genotype, failed to
      correlate with the FIGO stage and lymphatic spread. CONCLUSION: The prevalence of
      the integrated status of the HPV 16 genome combined with homozygous p53Arg
      genotype is relatively high in Hungary. These factors however failed to show a
      strong correlation with the established markers of tumour progression.

PMID- 15036718
TI  - Increased prevalence of p53 overexpression from typical endometriosis to atypical
      endometriosis and ovarian cancer associated with endometriosis.
AB  - OBJECTIVE: To evaluate the expression of p53, c-erb-B-2, MIB1 and Bcl-2 in normal
      endometrium, endometriosis, atypical endometriosis and ovarian cancer associated
      with endometriosis, looking for immunohistochemical markers that may help
      determine endometriosis with premalignant potential. STUDY DESIGN: Between 1948
      and 1999, 410 epithelial ovarian cancers and 521 cases of endometriosis were
      surgically treated at Fundacion Jimenez Diaz. Pathology reports and slides were
      reviewed. Four groups were defined: (1) endometriosis/cancer (n=17); (2) atypical
      endometriosis (n=6); (3) endometriosis (n=17); (4) endometrium (n=7). Tumors and
      controls were immunostained and evaluated for expression of p53, c-erb-B-2, MIB1
      and Bcl-2. Statistical analysis was performed using Chi-square for linear trends,
      Fisher exact and Kruskal-Wallis tests. RESULTS: Of the 410 cancers, 17 (4.1%) had
      associated endometriosis and of the 521 endometriosis, 6 (1.2 %) had atypical
      changes. Fourteen of 17 (82.4%) cancers associated with endometriosis and all
      atypical endometriosis had p53 overexpression. Only 2 of 17 (11.8%) endometriosis
      and none of the endometriums had mutant p53 (P<0.01). We found a trend towards
      increased expression of MIB1 (0.073) in the cancer and atypical endometriosis
      groups, and no differences in expression of Bcl-2 or c-erb-B-2. The sensitivity
      and specificity of p53 as a marker for the diagnosis of atypical endometriosis
      and cancer associated with endometriosis were 87%; CI 95% (73.2-100%) and 92%
      (80.6-100%), respectively. When comparing all groups, the mean positive p53 and
      MIB1 cell count was statistically significant (P=0.01). CONCLUSIONS:
      Overexpression of p53 in atypical endometriosis and cancer associated with
      endometriosis is a common finding and may be used to identify endometriosis with
      premalignant potential.

PMID- 15036719
TI  - Does increasing the steroid dose enhance the efficacy of the antiemetic
      combination of granisetron and methylprednisolone in gynecologic cancer patients-
      a randomized study.
AB  - OBJECTIVE: The authors administered two doses of oral methylprednisolone in
      combination with 3mg granisetron intravenously for the prophylaxis of cisplatin
      induced emesis in gynecologic cancer patients. MATERIALS AND METHODS: Thirty-nine
      patients received 100mg (group A) and 25 received 200mg (group B)
      methylprednisolone in the antiemetic combination in a randomized prospective
      trial. RESULTS: No vomiting in 90.2 and 96.7%, one emetic episode in 3 and 1.1%
      and two episodes in 3 and 2.2% were detected in groups A and B, respectively.
      More than two emetic episodes were considered to be a failure and were observed
      only in group A (3.8%). There was no significant difference between the two
      treatment groups (P=0.3160). CONCLUSIONS: There was no evidence for enhanced
      antiemetic effect of elevated steroidal dose in combination with granisetron.

PMID- 15036720
TI  - Acute pulmonary oedema during nicardipine therapy for premature labour; Report of
      five cases.
AB  - We report five maternal cases of acute pulmonary oedema which occurred during
      treatment with nicardipine for tocolysis.

PMID- 15036722
TI  - Early ultrasonographic diagnosis and laparoscopic treatment of abdominal
      pregnancy.
AB  - An early, pre-operative, ultrasonographic diagnosis of an abdominal pregnancy was
      made and successfully treated by laparoscopy in an asymptomatic woman with a 8
      weeks abdominal pregnancy. The early, ultrasonographic diagnosis allowed an easy,
      mini-invasive, endoscopic treatment of the potentially life threatening
      pregnancy.

PMID- 15036723
TI  - Laparoscopic management of pregnancies occurring in non-communicating accessory
      uterine horns.
AB  - A non-communicating rudimentary uterine horn is a rare Mullerian duct
      abnormality. A pregnancy conceived in a non-communicating horn has a 70% chance
      of rupturing and the maternal mortality is approximately 0.5%. We describe two
      cases of the initial medical management of pregnancies conceived in non
      communicating accessory uterine horns, which were then subsequently excised
      laparoscopically.

PMID- 15036721
TI  - A case of primary Addison's disease with hyperemesis gravidarum and successful
      pregnancy.
AB  - We followed up a pregnant woman with Addison's disease diagnosed before
      conception. She presented with hyperemesis gravidarum. Throughout pregnancy, she
      received prednisone and the basic disease did not deteriorate during pregnancy.
      She was delivered by caesarean section due to breech presentation. The fetal
      prognosis was good.

PMID- 15036724
TI  - Metastasis of choriocarcinoma to lumbar and sacral column.
AB  - We describe the case of a patient who reported a 4-month history of edema in the
      lower right limb, which was accompanied by pain and paresthesia and which
      progressed to flaccid paraplegia. Two years earlier she had undergone a uterine
      curettage for hydatidiform mole. Metastases of a choriocarcinoma to the lumbar
      and sacral segments of the column were diagnosed.

PMID- 15036726
TI  - Specialist life--Gian Carlo Di Renzo.

PMID- 15036725
TI  - Rapid recurrence of endometrioma after transvaginal ultrasound-guided aspiration.

PMID- 15036728
TI  - Robert Hooke and the origins of artificial respiration.

PMID- 15036729
TI  - Do textbooks of clinical examination contain information regarding the assessment
      of critically ill patients?
AB  - We postulated that some of the reported deficiencies in trainee doctors'
      knowledge of acute care might be due to the quantity and quality of available
      information about the examination and clinical assessment of critically ill
      patients in commonly used medical textbooks. Using an agreed assessment system,
      30 routinely available texts of clinical examination were reviewed. None of these
      contained a section devoted specifically to "assessing the critically ill
      patient" and few could be regarded as giving a comprehensive, systematic
      description of an assessment system suitable for use with the acutely ill. In
      general, descriptions of how to assess airway patency were rare, with only one
      describing how to differentiate partial from complete airway obstruction. Only
      four of the texts mentioned that measuring the respiratory rate would be useful
      in critically ill patients and the assessment of capillary refill time was poorly
      covered. Use of the AVPU scale to describe neurological status was found in only
      3% of texts, and there was poor description of the clinical significance of
      hypotension, tachycardia, oliguria, hypothermia and pyrexia. We conclude that the
      current texts available to medical students and junior doctors do not provide
      sufficient information regarding the assessment of critically ill patients.

PMID- 15036730
TI  - Improving the rate of return of spontaneous circulation for out-of-hospital
      cardiac arrests with a formal, structured emergency resuscitation team.
AB  - OBJECTIVE: To assess the impact of a formal, structured resuscitation team in the
      emergency department (ED) on the success rate of cardiopulmonary resuscitation
      (CPR) for out-of-hospital cardiac arrest (OHCA) patients. METHODS: This is a
      "three-phase" (organized, transitional, and re-organized), prospective study in
      which medical records of all OHCA patients who needed resuscitation in the ED
      during the three 6-month periods were reviewed and data were coded in out-of
      hospital Utstein style formats. An organized resuscitation team existed in the
      organized and re-organized phases but not in the transitional phase. The study
      population consisted of adult patients with non-traumatic cardiac arrest (>18
      years of age). RESULTS: The rates of return of spontaneous circulation (ROSC)
      were 51.3% for the organized phase, 31.0% for the transitional phase, and 53.1%
      for the re-organized phase ( P=0.013 ). The rates of ROSC from pulseless
      electrical activity (PEA)/asystole were significantly higher in periods with
      organized and re-organized teams ( P=0.007 ). The rates of ROSC for the
      ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT) sub
      groups were not significantly different in all three periods ( P=0.406 ). The
      chance of survival-to-discharge was 9.2% in the organized period, 11.2% in the
      transitional period, and 15.6% in the re-organized period ( P=0.496 ). The
      existence of a formal, structured emergency resuscitation team in the ED (odds
      ratio: 2.56, 95% confidence interval: 1.35-4.80) and witness at the scene (odds
      ratio: 2.45, 95% confidence interval: 1.34-4.45) were the only independent
      predictors of successful ROSC of OHCA patients by multiple logistic regression
      analysis. CONCLUSION: The establishment of a formal and structured emergency
      resuscitation team in the ED is associated with an increased rate of ROSC for
      OHCA patients.

PMID- 15036731
TI  - Non-traumatic aortic dissection or rupture as cause of cardiac arrest:
      presentation and outcome.
AB  - OBJECTIVE: To evaluate the frequency, presentation and outcome of non-traumatic
      aortic dissection/rupture as a cause of cardiac arrest. DESIGN: Retrospective
      analysis of a cardiac arrest registry in a tertiary care hospital emergency
      department. RESULTS: Over 11.5 years, aortic dissection/rupture was identified as
      the immediate cause of cardiac arrest in 46 (2,3%) out of 1990 patients with
      sudden cardiac arrest, primarily affecting the abdominal aorta in 25 and the
      thoracic aorta in 21 cases. The characteristics of the 46 patients were as
      follows: male gender (74%), median age 71 years (IQR 59-76), high co-morbidity
      (89%), previously known aortic aneurysm (33%), pulseless electric activity (70%)
      as initial cardiac rhythm. When performed, bedside abdominal sonography or
      echocardiography was almost always diagnostic. Patients with abdominal aortic
      dissection/rupture had abdominal (52%) and/or flank pain (32%). Patients with
      thoracic aortic dissection/rupture complained of chest pain (48%) or dyspnoea
      (19%). Return of spontaneous circulation occurred in 12 (26%) of 46 patients,
      emergency surgery was performed in eight of these patients, 2 (4%) survived to
      discharge in good neurological condition. CONCLUSIONS: Cardiac arrest caused by
      aortic dissection/rupture is rare, and mortality remains very high, even when
      circulation can be restored initially. Common features such as previously known
      aortic aneurysm, old age, male gender and pulseless electrical activity as
      initial cardiac rhythm should increase suspicion of the condition.

PMID- 15036732
TI  - Risk factors for intraoperative hypotension in traumatic intracranial hematoma.
AB  - Patients suffering from traumatic intracranial hemorrhage (TICH) may experience
      an episode of catastrophic intraoperative hypotension (IHT), after decompression
      of the brain. The aim of this study was to investigate the risk factors for IHT
      during emergency craniotomy A total of 67 patients, who underwent emergency
      craniotomy due to TICH, were divided into two groups: IHT ( n=31 ) or without IHT
      ( n=36 ). Data concerning (1) age; (2) gender; (3) mechanism of injury; (4)
      Glasgow Coma Scale (GCS) on admission; (5) abnormality of the pupils (anisocoria
      or mydriasis); (6) mean arterial blood pressure; (7) heart rate; (8) time elapsed
      before craniotomy from injury; (9) initial brain CT scans; (10) duration of
      craniotomy; and (11) total infusion or urine volume until craniotomy were
      collected prospectively as IHT risk factors. Low GCS score (<5), tachycardia
      (heart rate >112min(-1)) and hypertension (mean blood pressure >131mmHg) before
      emergency craniotomy were strongly ( P<0.05 ) associated with IHT. Delayed
      surgery (>173min until craniotomy) also had a significant ( P<0.005 ) effect on
      IHT. The risk factors for IHT were considered as a low GCS score on admission,
      tachycardia, hypertension before emergency craniotomy and delayed surgery. These
      results suggested the patients with IHT had a high sympathetic tone before
      emergency craniotomy A sudden reduction in sympathetic tone after surgical
      decompression of the brain might cause IHT. We concluded that an important factor
      in the occurrence of IHT was not only the injury severity, but also the balance
      between sympathetic and parasympathetic activity before decompression surgery.

PMID- 15036733
TI  - Frequency of rib and sternum fractures associated with out-of-hospital
      cardiopulmonary resuscitation is underestimated by conventional chest X-ray.
AB  - OBJECTIVE: Fractured ribs and sternum are frequent complications of thoracic
      compression during CPR in adults. This study was conducted to determine whether
      findings of plain chest radiography (CXR) correlate with post-mortem findings in
      patients who underwent cardiopulmonary resuscitation (CPR) after out-of-hospital
      cardiac arrest. METHODS: CXR findings and autopsy results of CPR-related chest
      injuries comprising rib and sternum fractures were compared prospectively in 19
      patients. RESULTS: Fractures were diagnosed in nine of 19 patients by means of
      radiology and in 18 of 19 patients by autopsy (rib fractures in 6/19 versus
      17/19, P=0.002; sternum fractures in 5/19 versus in 9/19, P=0.227. The total
      number of isolated bone fractures detected by CXR was 18 (12 rib and six sternum
      fractures) and by autopsy 92 (83 rib and nine sternum fractures). The majority of
      rib fractures was located in the anterior part of the thoracic cage. Sternum
      fractures predominantly occurred in the lower third. Eight of 19 patients
      received either thrombolytic or antithrombotic treatment during CPR but no major
      bleeding complication associated with CPR was detected by autopsy. CONCLUSIONS:
      The findings of this study indicate that fractures associated with CPR are
      underreported in conventional radiographic investigations. No major bleeding
      complications related to CPR-associated fractures was detected.

PMID- 15036735
TI  - Differential contribution of skin impedance and thoracic volume to transthoracic
      impedance during external defibrillation.
AB  - BACKGROUND: Two mechanisms by which firm external paddle force decreases
      transthoracic impedance (TTI) have been proposed. Decreased impedance at the
      paddle-skin interface has been assumed to be the primary mechanism, but expulsion
      of air from the lungs, reducing lung volume is also likely to contribute. The
      relative contribution of each mechanism is unknown. METHODS AND RESULTS: Thirty
      five intubated patients undergoing general anaesthesia for cardiac surgery were
      studied. TTI across external defibrillation paddles was measured as paddle force
      was increased to 12kgf. Measurements were performed twice; once allowing the
      volume of the lungs to change and once with lung volume held at functional
      residual capacity. TTI with constant lung volume was significantly higher at (P<
      0.001), confirming that a reduction in lung volume contributes to the decrease in
      TTI. At an optimal paddle force of 8kg, the reduction in lung volume contributed
      to 16.2% of the overall decrease in TTI. CONCLUSION: The decrease in TTI seen
      with increasing external paddle force is due primarily to improved electrical
      contact at the paddle-skin interface, with a decrease in thoracic volume
      accounting for no more than 16% of the overall decrease at forces used
      clinically.

PMID- 15036734
TI  - What do we know about patients dying in the emergency department?
AB  - OBJECTIVE: To determine our knowledge in terms of cause of death and quality of
      death certification about patients who die in the emergency department. To
      establish the role of autopsy in this matter. METHODS: Retrospective chart review
      of all patients dying in an academic emergency department (ED) of a tertiary
      hospital over a period of 1 year. RESULTS: One hundred and ninety-six patients
      died in the ED in 1998. In 141/196 patients the cause of death could be
      determined on clinical grounds. In 53/196 patients, the antemortem clinical
      diagnosis was unknown. Twenty-nine out of 53 patients underwent autopsy. In all
      but one patient autopsy revealed the cause of death. After retrospective analysis
      of all patient data (notes, biology, radiology and pathological investigation),
      the major causes of death were cardiac (19.4%), cerebral (non-traumatic) (16.8%),
      trauma (15.3%) and unknown (13.3%). In the patient group with sudden cardiac
      arrest of unclear origin, the postmortem cause of death was identified as cardiac
      (51.7%), non-traumatic bleeding (10.3%), infectious (10.3%) and pulmonary
      embolism (3.4%). In the group of patients with a clinically clear cause of death,
      who underwent autopsy, 14 class II findings according to the Goldman's
      classification of autopsy diagnoses (i.e. major diagnosis whose detection would
      not have altered therapy nor outcome) were found in 16 patients. No class I
      findings (i.e. major diagnosis whose detection would have altered therapy or
      outcome) were noted. Altogether, major discrepancies between the antemortem
      presumed cause of death according to the notes and the real cause of death was
      found in 15.3%. CONCLUSIONS: Autopsy remains a very important tool to establish
      the cause of death in patients dying in ED. The concordance between the
      antemortem presumed cause of death recorded in the patient notes and the real
      cause (all patient data) is poor.

PMID- 15036736
TI  - The perspective of paramedics about on-scene termination of resuscitation efforts
      for pediatric patients.
AB  - OBJECTIVES: The purpose of this study was to assess the attitude of paramedics to
      on-scene termination of cardiopulmonary resuscitation (T-CPR) efforts in children
      prior to developing a pediatric T-CPR policy. METHODS: A 26-item anonymous survey
      was conducted of all of the active paramedics in a large urban EMS system where T
      CPR had been practiced routinely for adults. Questions addressed paramedic
      demographics, training level, experience with adult and pediatric advanced
      cardiac life support (ACLS), experience with T-CPR in adults, T-CPR case
      scenarios, and T-CPR in children. RESULTS: All 201 paramedics in the system (mean
      age=34.2 years; mean years as paramedic = 8.5 ) completed all relevant items of
      the survey (100% compliance). Two-thirds had provided ACLS for cardiac arrest to
      >50 adults (93% >10 adults) and more than one-third had performed ACLS on >20
      children (72% >5 children). In addition, 90% had participated in T-CPR for
      adults. The majority of paramedics reported at least occasional (pre-defined)
      difficulty with adult T-CPR including family confrontation, 43%; personal
      discomfort, 13%; disagreement with physician decision to continue efforts, 11%;
      and fear of liability, 10%. Paramedic self ratings of comfort with terminating
      CPR on a scale from 1 to 10 (1: very comfortable; 10: uncomfortable) for adults
      and children were 1 and 9, respectively (P<0.001). In addition, the clear
      majority (72%) responded that children deserve more aggressive resuscitative
      efforts than adults. CONCLUSIONS: Paramedics feel relatively uncomfortable with
      the concept of terminating resuscitation efforts in children in the pre-hospital
      setting.

PMID- 15036737
TI  - Long-term subjective memory function in ventricular fibrillation out-of-hospital
      cardiac arrest survivors resuscitated by early defibrillation.
AB  - BACKGROUND: Brain injury after a cardiac arrest remains a major cause of
      morbidity. Programs focusing on early defibrillation have yielded improved
      survival of patients after hospital discharge following ventricular fibrillation
      (VF) out-of-hospital cardiac arrest (OHCA). Early defibrillation that promptly
      restores a circulating rhythm should decrease the hypoxic period and subsequent
      organ injury. Therefore this study was designed to determine if long-term memory
      complaints persist in VF OHCA survivors resuscitated in an early defibrillation
      program when compared with a healthy control population not experiencing cardiac
      arrest. METHODS: All patients with an OHCA between November 1990 and January 2001
      who received defibrillation by emergency medical services personnel in Olmsted
      County, MN, USA, were included. The memory function questionnaire (MFQ), a 64
      item, 7-point Likert-scaled instrument to evaluate the perception of everyday
      memory functioning was sent to all survivors. The MFQ comprises four scales:
      general frequency of forgetting (rates general forgetting), retrospective
      functioning (compares current memory with past ability), seriousness of
      forgetting (rates how memory impairment impacts daily life), and mnemonics usage
      (measures adaptation). The MFQ is scaled so that high scores reflect less severe
      memory complaints. The comparison population comprised members of the Mayo Older
      Americans Normative Studies (MOANS) cohort. Quality of life was ascertained with
      a short form (SF)-36 survey. RESULTS: Seventy-nine of the 200 VF OHCA patients
      (40%) were discharged. Twenty-two patients have died since dismissal, with an
      overall average length of follow-up of 4.9+/-3.0 years. Thirty-eight (67%) of the
      survivors completed the MFQ. Compared with the normal, there was a significant
      decrease in the general frequency of forgetting score of 144.2+/-37.4 versus
      168.1+/-27.3 ( P<0.001) and the seriousness of forgetting score of 84.8 +/-26.7
      versus 95.2+/-19.7 (P=0.004). The retrospective function-scale scores were not
      significantly different ( 18.4+/-6.8 versus 18.7+/- 5.0 (P=0.74). Younger
      patients (lesser than 65 years of age) reported an increase in general forgetting
      and the seriousness of forgetting compared with older survivors. A comparison
      with SF-36 scores suggested an association between general forgetting and
      decreased vitality (P=0.03) and the seriousness of forgetting with a decreased
      general health (P=0.005), mental health (P=0.009), physical functioning ( P=0.02
      ), and vitality ( P=0.05). CONCLUSION: In a cohort of VF OHCA patients, survivors
      report more memory complaints in comparison with a general healthy older
      population. There were more long-term-memory complaints in younger patients.
      Patients with higher long-term quality-of-life score have fewer memory
      complaints.

PMID- 15036738
TI  - Is female sex associated with increased survival after out-of-hospital cardiac
      arrest?
AB  - AIM: To evaluate survival after out-of-hospital cardiac arrest in relation to
      sex. METHODS: All patients with out-of-hospital cardiac arrest included in the
      Swedish Cardiac Arrest Registry between 1990 and 2000 in whom cardiopulmonary
      resuscitation (CPR) was attempted and who did not have a crew witnessed arrest
      were included. The registry covers 85% of the inhabitants of Sweden
      (approximately 8 million inhabitants). P-values were adjusted to differences in
      age. Survival was defined as patients being hospitalised alive and being alive
      one month after cardiac arrest. In all, 23,797 patients participated in the
      survey of which 27.9% were women. RESULTS: Among women 16.4% were hospitalised
      alive versus 13.2% among men ( P<0.001). After one month 3.0% among women were
      alive versus 3.4% among men (NS). In a multivariate analysis considering
      differences in age and various factors at resuscitation female sex was an
      independent predictor for patients being hospitalised alive (odds ratio 1.66; 95%
      confidence limits 1.49-1.84) and for being alive after one month (odds ratio
      1.27; 95% confidence limits 1.03-1.56). Women differed from men as they were
      older ( P<0.001 ), had a lower prevalence of witnessed cardiac arrest ( P=0.01),
      a lower occurrence of bystander CPR (P<0.001), a lower occurrence of ventricular
      fibrillation as initial arrhythmia (P<0.001) and a lower occurrence of cardiac
      disease judged to be the cause of cardiac arrest ( P<0.0001 ). On the other hand
      they had a cardiac arrest at home more frequently ( P<0.001 ). CONCLUSION: Among
      patients suffering out-of-hospital cardiac arrest in Sweden which was not crew
      witnessed and in whom resuscitation efforts were attempted, female sex was
      associated with an increased survival.

PMID- 15036739
TI  - Automated speech recognition for time recording in out-of-hospital emergency
      medicine-an experimental approach.
AB  - Precise documentation of medical treatment in emergency medical missions and for
      resuscitation is essential from a medical, legal and quality assurance point of
      view [Anasthesiologie und Intensivmedizin, 41 (2000) 737]. All conventional
      methods of time recording are either too inaccurate or elaborate for routine
      application. Automated speech recognition may offer a solution. A special erase
      programme for the documentation of all time events was developed. Standard speech
      recognition software (IBM ViaVoice 7.0) was adapted and installed on two
      different computer systems. One was a stationary PC (500MHz Pentium III, 128MB
      RAM, Soundblaster PCI 128 Soundcard, Win NT 4.0), the other was a mobile pen-PC
      that had already proven its value during emergency missions [Der Notarzt 16, p.
      177] (Fujitsu Stylistic 2300, 230Mhz MMX Processor, 160MB RAM, embedded soundcard
      ESS 1879 chipset, Win98 2nd ed.). On both computers two different microphones
      were tested. One was a standard headset that came with the recognition software,
      the other was a small microphone (Lavalier-Kondensatormikrofon EM 116 from
      Vivanco), that could be attached to the operators collar. Seven women and 15 men
      spoke a text with 29 phrases to be recognised. Two emergency physicians tested
      the system in a simulated emergency setting using the collar microphone and the
      pen-PC with an analogue wireless connection. Overall recognition was best for the
      PC with a headset (89%) followed by the pen-PC with a headset (85%), the PC with
      a microphone (84%) and the pen-PC with a microphone (80%). Nevertheless, the
      difference was not statistically significant. Recognition became significantly
      worse (89.5% versus 82.3%, P<0.0001 ) when numbers had to be recognised. The
      gender of speaker and the number of words in a sentence had no influence. Average
      recognition in the simulated emergency setting was 75%. At no time did false
      recognition appear. Time recording with automated speech recognition seems to be
      possible in emergency medical missions. Although results show an average
      recognition of only 75%, it is possible that missing elements may be
      reconstructed more precisely. Future technology should integrate a secure
      wireless connection between microphone and mobile computer. The system could then
      prove its value for real out-of-hospital emergencies.

PMID- 15036740
TI  - Determination of heart rate in the baby at birth.
AB  - The International Liaison Committee on Resuscitation (ILCOR) publishes guidelines
      on neonatal resuscitation, which are evidence-based where possible. Initial
      assessment of heart rate, breathing and colour is an essential part of newborn
      resuscitation and the guidelines state that heart rate may be assessed using a
      stethoscope, or palpating the umbilical, brachial or femoral pulse. This study
      aimed to assess the most effective method(s) of heart rate assessment in the
      newborn baby. Healthy term newborn babies were randomised to femoral, brachial or
      cord pulse assessment, within 5min of birth. The heart rate (beats per minute
      (bpm)) was categorised as either not detectable, <60, 60-100 or >100bpm. In all
      cases, the heart rate was >100bpm when assessed using a stethoscope. The femoral
      pulse identified the heart rate as >100bpm in 20%, <100bpm in 35% and
      undetectable in 45%. The brachial pulse identified the heart rate >100bpm in 25%,
      <100bpm in 15% and undetectable in 60%. Umbilical cord palpation was more
      reliable with 55% identified as >100bpm, 25% <100bpm and 20% undetectable. This
      data suggests that in healthy newborn babies, brachial and femoral pulses are not
      reliable for determining heart rate. Umbilical pulsations must not be relied upon
      if low or absent. In assessing heart rate in newborn resuscitation only the
      stethoscope is likely to be completely reliable. In the absence of a stethoscope
      only the umbilical pulse should be used with an awareness of its limitations.

PMID- 15036741
TI  - A randomized controlled trial of sodium bicarbonate in neonatal resuscitation
      effect on immediate outcome.
AB  - Very little evidence is available that supports or disproves the use of
      medications in neonatal resuscitation. In this randomized controlled trial, we
      evaluated the effect of sodium bicarbonate given during neonatal resuscitation,
      on survival and neurological outcome at discharge. SUBJECTS AND METHODS:
      Consecutively born asphyxiated neonates continuing to need positive pressure
      ventilation at 5min of life received either sodium bicarbonate or 5% dextrose.
      The study group was given intravenous sodium bicarbonate solution 4ml/kg
      (1.8meq./kg) over 3-5min. This solution was prepared by diluting 7.5% sodium
      bicarbonate (0.9meq./ml) with distilled water in a 1:1 ratio. The placebo group
      received 4ml/kg of undiluted 5% dextrose at a similar rate. The surviving
      neonates were evaluated for their neurological status at discharge. Primary
      outcome variable: Death or abnormal neurological examination at discharge.
      Secondary outcome variables: Encephalopathy, multi-organ dysfunction,
      intraventricular haemorrhage (IVH) and arterial pH at 6h. RESULTS: Twenty-seven
      babies were randomized to receive sodium bicarbonate (bicarb group) and 28 to
      receive 5% dextrose. Eighteen of the 27 (66.7%) babies in the bicarb group and 19
      of the 28 babies (68%) in the dextrose group survived to discharge ( P=0.84 ).
      Twenty-eight percent of the survivors in the bicarb group and 32% of the
      survivors in the dextrose group were neurologically abnormal at discharge (
      P=0.10 ). The composite primary outcome of death or abnormal neurological
      examination at discharge was similar in both groups (52% versus 54%, P=0.88 ).
      The incidence of encephalopathy (74% versus 63%), cerebral oedema (52% versus
      30%), need for inotropic support (44% versus 29%), intraventricular haemorrhage
      (IVH) and the mean arterial pH at 6hrs were similar between the two groups.
      CONCLUSION: Administration of sodium bicarbonate during neonatal resuscitation
      did not help to improve survival or immediate neurological outcome.

PMID- 15036743
TI  - Advantages of longer compression intervals during Basic Life Support.

PMID- 15036742
TI  - Biphasic concentration change during continuous midazolam administration in brain
      injured patients undergoing therapeutic moderate hypothermia.
AB  - OBJECTIVE: To define the pharmacokinetics of midazolam, a probe for monitoring
      cytochrome (CYP) 3A 4 activity, during moderate hypothermic therapy. DESIGN: A
      prospective randomized study. SETTING: The intensive care unit of a medical
      university hospital. PATIENTS AND INTERVENTIONS: In 15 consecutive brain-injured
      patients, midazolam concentrations were measured serially using high-performance
      liquid chromatography (HPLC). Under continuous administration of the agent, eight
      patients underwent moderate hypothermia of 32-34 degrees C (hypothermia group)
      and seven received normothermic therapy (normothermia group). A one-compartment
      model was selected for pharmacokinetic analyses for the continuous
      administration. Data represent +/-S.D. Statistical analysis was performed using
      ANOVA followed by Scheffe's F-test or the Mann-Whitney U-test ( P<0.05 ).
      MEASUREMENT AND MAIN RESULTS: Serum midazolam concentrations in the hypothermia
      group increased linearly until the body temperature (BT) reached 35 degrees C
      without plateauing, even during continuous administration, after which the levels
      decreased remarkably when BT rose to 36 degrees C. However, the concentrations in
      the normothermia group remained on a plateau, which lasted until the end of the
      study. In the hypothermia group, elimination rate constant (k(e)) and clearance
      (CL) in the phase below 35 degrees C BT were much lesser than those above 35
      degrees C BT, whereas distribution volume (V(d)) during the hypothermic phase was
      greater than that during the period above 35 degrees C BT. CONCLUSION: This study
      has demonstrated for the first time that midazolum concentration changes
      biphasically even during continuous infusion in hypothermic therapy. The
      mechanisms for the change are unclear. Thus, further studies including
      confirmation of cytochrome 3A 4 activity are required, while monitoring for the
      development of undesirable effects from over-dosing is also needed.

PMID- 15036744
TI  - Evaluation of immunotoxicity induced by diazinon in C57bl/6 mice.
AB  - Diazinon (DZN), an organophosphate insecticide, has been used in agriculture for
      several years. It is possible the residue of this compound to be recycled in the
      biological system. There is no report on DZN immunotoxicity potential. In the
      present study, we examined the immunotoxic effects of intraperitoneally
      administered DZN in the C57bl/6 female mice. Diazinon was administered at doses
      of 25, 2, and 0.2 mg/kg for 28 days (five injections per week). Animals were then
      sacrificed to observe the cellularity or histopathological changes in thymus,
      spleen, bone marrow, and peripheral blood. Furthermore, humoral and cellular
      functional responses such as Hemagglutination titration (HA), IgM-Plaque Forming
      Colony Assay (PFC), Delayed-Type-Hypersensitivity (DTH) to SRBC, and T cell
      subtyping (CD4/CD8) were determined. The results showed that DZN at 25 mg/kg not
      only could produce gross histopathological changes in thymus and spleen but also
      could suppress both humoral and cellular activity of the immune system. At lower
      doses (0.2 and 2 mg/kg) there were no observable alteration in cellularity or
      histology of immune tissues. However, DZN at medium dose (2 mg/kg per day) could
      inhibit RBC-cholinesterase and showed a mild decrease (P < 0.1) in thymus/body
      weight ratio and DTH response. At dose of 0.2 mg/kg no histopathological or
      functional disturbances were detectable. These results indicate that DZN has
      immunosuppressive effects in the C57bl/6 mice at doses more than 2 mg/kg. The
      present results however indicate that under recommended Allowed Daily Intake
      (ADI) limit (<0.02 mg/kg), no observable immunotoxicity effect is expected.

PMID- 15036745
TI  - Pesticide mixtures potentiate the toxicity in murine thymocytes.
AB  - The immunotoxic risks of multiple pesticide exposure were evaluated. C57BL/6
      mouse thymocytes were exposed to lindane, malathion, and permethrin, either
      separately or in mixtures of two pesticides, in vitro. These pesticide exposures
      caused both apoptotic and necrotic cell death in thymocytes as evaluated by flow
      cytometric analysis in combination with 7-aminoactinomycin-D (7-AAD), Annexin
      V/propidium iodide (PI) staining assays and lactate dehydrogenase release assays.
      When cells exposed to mixtures of two pesticides, a significantly greater than
      additive interaction was observed in both apoptotic and necrotic populations of
      cells. The gel electrophoresis of DNA of cells showed DNA ladder formation with
      limited genomic DNA and increased laddering in mixture exposures. Based on these
      findings, it is suggested that these pesticides are potent immunotoxicants, in
      vitro, and that the mechanism of cytotoxicity observed upon exposure to these
      pesticides may, at least in part, be due to induction of apoptosis. We also
      provided evidence that induction of drug metabolizing mixed function oxidase
      system with lindane may, in part, be responsible for the potentiation of
      cytotoxicity in the combined exposures. As more information is obtained on the
      potential immunotoxic effects of pesticides, further insights will be gained for
      the risk assessment of these environmental pollutants.

PMID- 15036746
TI  - Short- and long-term effects of T-cell modulating agents in experimental
      autoimmunity.
AB  - Due to the easy and reliable induction of a disease condition with many of the
      features present in human autoimmunity, mercury-induced autoimmunity (mHgAI) in
      rodents is a favourable autoimmune model. Genetically susceptible (H-2(s)) mice
      develop in response to mercury (Hg) a systemic autoimmune condition with
      antinucleolar antibodies (ANoA) targeting the protein fibrillarin, transient
      polyclonal B-cell activation, hyperimmunoglobulinemia, and systemic immune
      complex (IC) deposits. In order to study the short- and long-term effects of
      treatment with immunomodulating agents on the disease parameters in HgAI, groups
      of B10.S (H-2(s)) mice were given 6 mg HgCl(2)/l drinking water for 22 weeks.
      Three weeks initial treatment with cyclosporin A (CyA), a high dose of tacrolimus
      (HD tacrolimus), or anti-CD4 monoclonal antibody (a-CD4) inhibited induction of
      ANoA and IC deposit by Hg. This effect persisted for the subsequent 19 weeks when
      the mice were only treated with Hg. Initial treatment with anti-IL-4 monoclonal
      antibody (a-IL-4) for 3 weeks inhibited induction of IgE and IC deposits by Hg,
      but not ANoA. However, subsequent treatment with Hg without a-IL-4 for 19 weeks
      induced IC deposits. The T-cell modulating agents aggravated some of the HgAI
      disease parameters: a-CD4 stimulated the polyclonal B-cell activation, a-IL-4
      increased the IgG antichromatin antibody response, and a low dose of tacrolimus
      (LD tacrolimus) enhanced the ANoA, the polyclonal B-cell activation, and the IC
      deposits. We conclude that a short initial treatment with a-CD4 or CyA
      efficiently protects against induction of systemic autoimmunity for an extended
      period of time. However, some of the T-cell modulating agents, especially a low
      dose of tacrolimus, aggravate autoimmune manifestations not only during ongoing
      treatment, but also after treatment with these agents has ceased.

PMID- 15036747
TI  - Autoimmunity, environmental exposure and vaccination: is there a link?
AB  - Although the wide clinical experience shows that vaccines are generally safe,
      concern has been expressed for a causal link between vaccines and autoimmune
      diseases. Even though the mechanisms of autoimmunity are ill-elucidated, the role
      of pre-existing risk factors including genetic predisposition and environmental
      factors is largely accepted. The present study was undertaken to test the
      hypothesis that vaccines can promote autoimmunity in genetically-prone
      individuals when simultaneously exposed to a chemical known to induce autoimmune
      reactions. Female lupus-prone (NZB x NZW) F(1) mice were given 1 microg or 10
      microg of a hepatitis B vaccine at 2-week intervals in conjunction with 40 microg
      of mercuric chloride three times per week for 6 weeks. A marked increase in serum
      IgG levels and a slight increase in anti-nuclear autoantibody (ANA) levels were
      seen in the mice given 10 microg of the vaccine plus mercuric chloride. No
      straightforward conclusion can be drawn from these results because of the extreme
      experimental conditions of this study. Nevertheless, the results tend to support
      the hypothesis that vaccination could enhance the risk of autoimmunity in
      genetically susceptible individuals when exposed to certain environmental
      chemicals.

PMID- 15036748
TI  - Ozone exposure enhances antigen-presenting activity of interstitial lung cells in
      rats.
AB  - Ozone (O(3)) as a major component of photochemical air pollutants can increase
      the levels of allergen-specific antibody and may aggravate allergic symptoms.
      Antigen presentation is one of the factors contributing to allergic symptoms. Our
      present study is designed to clarify whether O(3) may increase the antigen
      presenting (AP) activity of whole lung cells and its mechanisms. Male Wistar rats
      were exposed to 1 ppm O(3) for 3 days. The AP activity of whole lung cells and
      dendritic cells (DC) was measured by proliferation of T-cells. The expression of
      Ia and costimulatory molecules (B7.1, B7.2, CD11b/c) in lung cells was measured
      by flow cytometry, and the number of Ia-bearing cells, DC, macrophages, and B
      cells in lung interstitum was examined immunohistochemically. The results show
      that O(3) increases AP activity of whole lung cells and DC, the expression of
      molecules associated with antigen presentation, and the number of AP cells (APC)
      in lung. Our results suggest that O(3) may enhance AP activity of lung cells
      caused by increases in the expression of cell-surface molecules and the number of
      APC in lung. The increase in the AP activity might contribute to subsequent
      antibody production, airway hyperresponsiveness and aggravation of allergic
      responses.

PMID- 15036749
TI  - Immunotoxicological effects of piperine in mice.
AB  - The immunotoxicological effects of piperine were investigated in Swiss male mice,
      gavaged at a dose of 1.12, 2.25 or 4.5 mg/kg body weight for five consecutive
      days. All the dose levels had no overt toxic effect and the liver gained weight
      normally. Treatment at highest dose, however, resulted in significant decrease in
      the weight of spleen, thymus and mesenteric lymph nodes, but not of peripheral
      lymph nodes. All the dose levels suppressed the cellular population of lymphoid
      organs, except for the spleen, where the doses of 1.12 and 2.25 caused an
      increase. Haematologically, doses of 2.25 and 4.5 mg/kg caused a significant
      reduction in total leucocyte counts and differential leucocyte counts showed an
      increase in the percentage of neutrophils. The higher doses of 2.25 and 4.5 mg/kg
      suppressed the mitogenic response of B-lymphocyte to lipopolysaccharide. The
      number of primary antibody (IgM) forming cells in the spleen and the level of
      primary antibody in serum, was decreased. The doses of 1.12 and 2.25 mg/kg
      suppressed the mitogenic response of T-lymphocytes to phytohaemagglutinin and the
      nitroblue tetrazolium (NBT) dye reducing activity of peritoneal exudate cells
      (PECs). Since the lowest dose of 1.12 mg of piperine per kg body weight had no
      immunotoxic effect, it may be considered as immunologically safe "no observed
      adverse effect level (NOAEL)" dose.

PMID- 15036750
TI  - Nonylphenol alters the activity of splenic NK cells and the numbers of leukocyte
      subpopulations in Sprague-Dawley rats: a two-generation feeding study.
AB  - Nonylphenol (NP) has been identified at low levels in surface waters throughout
      North America. This industrial chemical is primarily used for the production of
      certain non-ionic surfactants, and has been reported to have weak estrogen-like
      activity. As estrogen has immunoregulatory properties and is crucial for normal
      fetal development, it was hypothesized that adult and developmental exposures to
      NP had the potential to adversely affect the immune system. Furthermore,
      developmental exposure to NP might also produce differential immunomodulation in
      F(1) male and female rats. Thus, a two-generation feeding study was conducted to
      evaluate the potential for NP to modulate certain immune parameters. Pregnant
      female Sprague-Dawley rats were exposed to NP (0, 25, 500, and 2000 ppm) in their
      feed for 65 days, beginning 7 days into gestation. The F(1) generation male and
      female offspring were exposed in utero at the respective treatment levels,
      commencing the 7th day of gestation, and continuing through to 64 days of age.
      Changes in splenic antibody-forming cell response, natural killer cell activity,
      and leukocyte numbers were used to evaluate NP immunotoxicity. The results from
      the present study indicate that dietary exposure to NP can increase splenic
      natural killer (NK) cell activity and splenocyte subpopulation numbers in the
      F(1) generation rats, without similar changes to the F(0) generation. The
      immunological changes that were observed in the F(1) generation also appeared to
      be gender-specific.

PMID- 15036751
TI  - An oral Brown Norway rat model for food allergy: comparison of age, sex, dosing
      volume, and allergen preparation.
AB  - The purpose of the presented experiments was to study the possibility of using
      the Brown Norway rat as a model for food allergy in our laboratory. Specific
      serum IgE against ovalbumin (OVA) was induced after dosing male and female Brown
      Norway rats daily by gavage for 35 days. The influence of various preparations of
      allergen: OVA grade II, OVA grade V, and fresh egg white, age (4 versus 8 weeks),
      dosing volumes, and animal suppliers was studied. A general finding was that
      females had statistically significantly higher specific IgE and IgG titres and
      number of responders than males. Egg white preparation, age, dosing volume, and
      animal supplier did not statistically significantly influence the median IgE and
      IgG titres and number of responders. The difference between immune responses in
      males and females could not be attributed to variations in daily intake of OVA or
      exposure via the lung. In our hands, the oral Brown rat food allergy model gives
      rise to a moderate number of IgE responders, 13-38 and 38-75% in males and
      females, respectively. For further experiments with this model in our laboratory,
      females seem the sex of choice.

PMID- 15036752
TI  - Failure of the standard battery of short-term tests in detecting some rodent and
      human genotoxic carcinogens.
AB  - Theoretical reasons and experimental evidence indicate that a no-effect level
      generally cannot be expected for genotoxic carcinogens; as a consequence, in
      quantitative risk assessment the capability of distinguishing genotoxic from non
      genotoxic carcinogens is of fundamental importance in order to identify relevant
      levels of human exposure. According to generally accepted guidelines, the
      standard three-test battery for the detection of genotoxic compounds consists of:
      (i) an in vitro test for gene mutation in bacteria; (ii) an in vitro test in
      mammalian cells with cytogenetic evaluation of chromosomal damage and/or a test
      that detects gene mutations; (iii) an in vivo test for chromosomal damage using
      rodent hematopoietic cells. This test battery is designed to avoid the risk of
      false negative results for compounds with genotoxic potential, but it cannot be
      taken for granted that the risk is completely eliminated. As a matter of fact
      there are some chemicals, classified by the International Agency for Research on
      Cancer (IARC) as probably or possibly carcinogenic to humans, which gave
      consistent negative results in this test battery, and in contrast provided
      positive results in other not routinely employed genotoxicity assays. The failure
      of the standard test battery in detecting some genotoxic carcinogens is
      attributable to several causes, but the principal of them are the following ones:
      in vitro, the artificial metabolic activity of the liver S9-mix, and the
      different biotransformation of chemicals in cells of different type and from
      different animal species; in vivo, the pharmacokinetic behaviour of the test
      compound, and its possible species-, sex- and tissue-specificity.

PMID- 15036753
TI  - Sub-chronic exposure to toluene at 40 ppm alters the monoamine biosynthesis rate
      in discrete brain areas.
AB  - Effects of long-term exposure to a sub-toxic concentration of toluene (40 ppm,
      104 h per week, 16 weeks) have been studied on monoamine biosynthesis rate in
      rat. The activities of the rate limiting enzymes in catecholamine and 5
      hydroxytryptamine biosynthesis tyrosine and tryptophan hydroxylase, respectively,
      were estimated in vivo by measuring the accumulation of l-dihydroxyphenylalanine
      and 5-hydroxytryptophan after pharmacological blockade of l-aromatic acid
      decarboxylases by NSD-1015 (100 mg kg(-1) ip). The sub-chronic exposure to
      toluene led to a significant and gender dependent alteration in both
      catecholamine and 5-hydroxytryptamine biosynthesis rate in brainstem
      catecholaminergic cell groups and hypothalamus. In females exposed to toluene,
      changes in tryptophan hydroxylation were found in rostral subset of A2C2 (+41%)
      and in A1C1 (+41%) while a decrease in A5 (-44%) and an increase in A2C2 (+28%)
      were found in tyrosine hydroxylation. In males, an increase in tryptophane
      hydroxylation was observed in rostral subset of A2C2 (+35%) while a decrease was
      observed in ventro-median hypothalamus (-17%). These results suggest that toluene
      exposure to a dose generally recognized as sub-toxic (40 ppm, no observed adverse
      effect level) leads to adverse effects on monoaminergic systems. Therefore, the
      neurotoxicity of toluene should be carefully re-evaluated taking into account not
      only the exposure level but also the duration.

PMID- 15036754
TI  - Organophosphate-induced convulsions and prevention of neuropathological damages.
AB  - Such organophosphorus (OP) compounds as diisopropylfluorophosphate (DFP), sarin
      and soman are potent inhibitors of acetylcholinesterases (AChEs) and
      butyrylcholinesterases (BChEs). The acute toxicity of OPs is the result of their
      irreversible binding with AChEs in the central nervous system (CNS), which
      elevates acetylcholine (ACh) levels. The protective action of subcutaneously (SC)
      administered antidotes or their combinations in DFP (2.0 mg/kg BW) intoxication
      was studied in 9-10-weeks-old Han-Wistar male rats. The rats received AChE
      reactivator pralidoxime-2-chloride (2PAM) (30.0 mg/kg BW), anticonvulsant
      diazepam (2.0 mg/kg BW), A(1)-adenosine receptor agonist N(6)-cyclopentyl
      adenosine (CPA) (2.0 mg/kg BW), NMDA-receptor antagonist dizocilpine maleate (+
      MK801 hydrogen maleate) (2.0 mg/kg BW) or their combinations with cholinolytic
      drug atropine sulfate (50.0 mg/kg BW) immediately or 30 min after the single SC
      injection of DFP. The control rats received atropine sulfate, but also saline and
      olive oil instead of other antidotes and DFP, respectively. All rats were
      terminated either 24 h or 3 weeks after the DFP injection. The rats treated with
      DFP-atropine showed severe typical OP-induced toxicity signs. When CPA, diazepam
      or 2PAM was given immediately after DFP-atropine, these treatments prevented,
      delayed or shortened the occurrence of serious signs of poisoning. Atropine-MK801
      did not offer any additional protection against DFP toxicity. In conclusion, CPA,
      diazepam and 2PAM in combination with atropine prevented the occurrence of
      serious signs of poisoning and thus reduced the toxicity of DFP in rat.

PMID- 15036755
TI  - Effects of human pharmaceuticals on cytotoxicity, EROD activity and ROS
      production in fish hepatocytes.
AB  - Pharmaceuticals are found in the aquatic environment but their potential effects
      on non-target species like fish remain unknown. This in vitro study is a first
      approach in the toxicity assessment of human drugs on fish. Nine pharmaceuticals
      were tested on two fish hepatocyte models: primary cultures of rainbow trout
      hepatocytes (PRTH) and PLHC-1 fish cell line. Cell viability, interaction with
      cytochrome P450 1A (CYP1A) enzyme and oxidative stress were assessed by using 3
      (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrasodium bromide tetrazolium (MTT), 7
      ethoxyresorufin-o-deethylase (EROD) and dichlorofluorescein (DCFH-DA) assays,
      respectively. The tested drugs were clofibrate (CF), fenofibrate (FF),
      carbamazepine (CBZ), fluoxetine (FX), diclofenac (DiCF), propranolol (POH),
      sulfamethoxazole (SFX), amoxicillin (AMX) and gadolinium chloride (GdCl(3)). All
      substances were cytotoxic, except AMX at concentration up to 500 microM. The
      calculated MTT EC(50) values ranged from 2 microM (CF) to 651 microM (CBZ) in
      PLHC-1, and from 53 microM (FF) to 962 microM (GdCl(3)) in PRTH. CF, FF, and FX
      were the most cytotoxic drugs and induced oxidative stress before being
      cytotoxic. Compared to hepatocytes from human and dog, fish hepatocytes seemed to
      be more susceptible to the peroxisome proliferators (PPs) CF and FF. In PLHC-1
      cells none of the tested drugs induced the EROD activity whereas POH appeared as
      a weak EROD inducer in PRTH. Moreover, in PRTH, SFX, DiCF, CBZ and to a lesser
      extend, FF and CF inhibited the basal EROD activity at clearly sublethal
      concentrations which may be of concern at the biological and chemical levels in a
      multipollution context.

PMID- 15036756
TI  - Copper-induced formation of reactive oxygen species causes cell death and
      disruption of calcium homeostasis in trout hepatocytes.
AB  - We have previously shown that copper is acutely toxic for trout hepatocytes,
      inducing enhanced influx of Ca(2+) and a loss of cell viability. The aim of the
      present study was to elucidate the pathways of Ca(2+) entry into the cells, the
      hypothetical role of reactive oxygen species (ROS) in copper toxicity, and the
      interaction of ROS formation and the disruption of Ca(2+) homeostasis. We found
      that, acutely, copper-induced cell death occurred independently from an increase
      of intracellular free Ca(2+) (Ca(2+)i), but could be prevented by addition of
      agents interfering with ROS production. Addition of the Ca(2+) channel blocker
      verapamil did not affect the Ca(2+)i increase evoked by copper, whereas in the
      presence of LaCl(3), an inhibitor of both Ca(2+) channels and Na(+)/Ca(2+)
      exchange, this increase was significantly delayed. ROS formation, estimated by
      use of the fluorescence indicator 2',7'-dichlorofluorescin diacetate, was
      significantly enhanced by copper. Omission of extracellular Ca(2+) or addition of
      either verapamil or LaCl(3) did not diminish ROS formation induced by copper. In
      contrast, the hydroxyl radical scavenger dimethyl sulfoxide and the ferric ion
      chelator deferoxamine inhibited radical production. In addition, these agents
      either partially (dimethyl sulfoxide) or completely (deferoxamine) prevented an
      increase of Ca(2+)i. Altogether our results indicate that ROS formation is the
      crucial event leading to cell death during acute exposure to copper, whereas the
      increase of Ca(2+)i is a secondary, acutely less toxic, phenomenon. Furthermore,
      these findings suggest that Ca(2+) entry occurs via a LaCl(3)-sensitive pathway,
      presumably representing Na(+)/Ca(2+)-exchange, and non-specific membrane leaks
      induced by lipid peroxidation in the presence of copper.

PMID- 15036757
TI  - Percutaneous penetration and genotoxicity of 4,4'-methylenedianiline through rat
      and human skin in vitro.
AB  - 4,4'-Methylenedianiline (MDA) is a primary aromatic amine used in the plastics
      industry and is classified by the International Agency for Research on Cancer as
      an animal carcinogen and possible human carcinogen. In order to estimate human
      exposure it is useful to determine percutaneous penetration. Previous studies
      have suggested that both rat and human skin were permeable to MDA, with greater
      penetration being seen through human skin. In this study no significant
      difference was seen between the percutaneous penetration of MDA through human or
      rat skin for three different treatment levels: 0.01, 0.1 and 1mg per skin
      membrane (0.32 cm(2)). The apparent dermal flux was calculated as 0.7 +/- 0.3 and
      10.1 +/- 2.0 microg/cm(2)/h for the 0.01 and 0.1mg treatments, respectively. The
      permeability constant K(p) was estimated at 1.8 x 10(-3) cm/h and the lag time at
      3.5 +/- 0.5 h. MDA absorbed into the skin was found to be bioavailable.
      Experiments also showed that after application of 0.1mg MDA, 4% penetrated
      through latex and nitrile gloves, respectively. The potential genotoxicity of MDA
      in human skin was assessed by DNA (32)P-postlabelling; levels of DNA adducts were
      detected, following the treatment and penetration of 1mg MDA.

PMID- 15036758
TI  - Effects of prenatal exposure to the environmental pollutant 2-bromopropane on
      embryo-fetal development in rats.
AB  - 2-Bromopropane (2-BP), a halogenated propane analogue, is a substitute for
      chlorofluorocarbones. The present study was carried out to investigate the
      potential adverse effects of 2-BP on pregnant dams and embryo-fetal development
      after maternal exposure on gestational days (GD) 6 through 19 in Sprague-Dawley
      rats. The test chemical was administered subcutaneously to pregnant rats at dose
      levels of 0, 250, 500, and 1000 mg/kg per day. All dams were subjected to
      caesarean section on GD 20 and their fetuses were examined for external, visceral
      and skeletal abnormalities. In the 1000 mg/kg group, maternal toxicity included
      an increase in the incidence of abnormal clinical signs, a suppression in the
      body weight and body weight gain, and a decrease in the food intake.
      Developmental toxicity included an increase in the fetal deaths, a decrease in
      the litter size, and a reduction in the fetal body weight. In addition, an
      increase in the incidence of fetal external, visceral, and skeletal abnormalities
      was seen. In the 500 mg/kg group, minimal developmental toxicity including
      decreased fetal body weight and increased fetal ossification delay was observed.
      There were no adverse effects on either pregnant dams or embryo-fetal development
      in the 250 mg/kg group. These findings suggest that a 14-day subcutaneous dose of
      2-BP is embryotoxic and teratogenic at a maternally toxic dose (i.e., 1000 mg/kg
      per day) and is minimally embryotoxic at a nonmaternally toxic dose (i.e., 500
      mg/kg per day) in Sprague-Dawley rats. In the present experimental conditions,
      the no-observed-adverse-effect level (NOAEL) of 2-BP is considered to be 500
      mg/kg per day for dams and 250 mg/kg per day for embryo-fetal development.

PMID- 15036759
TI  - Antioxidative natural product protect against econazole-induced liver injuries.
AB  - The study objective of this research is in order to investigate the
      hepatoprotective and therapeutic effects of propolis ethanol extract (PEE) on
      acute econazole-induced liver injury. Positive control of various concentrations
      of PEE on liver function and the dose-response relationship of liver injury
      induced by various doses of econazole were firstly observed from biochemical
      assay of serum level of aspartate transaminase (SGOT) and serum alanine
      transaminase (SGPT) and histopathological microscopic examination. The
      hepatoprotective effects of various concentration of PEE on liver damage induced
      by hepatotoxic dose (300 mg/kg) of econazole were observed by the obvious
      decrement of SGOT and SGPT level and further confirmed by hepatohistological
      microscopic examination. The inhibitory effects of PEE on FeCl(2)-induced (in
      vitro) or econazole-induced (in vivo) lipid peroxidation were investigated from
      the measurement of the formed malonic dialdehyde (MDA) level in the rat liver
      homogenate. The IC(50) (microM) of various concentrations of PEE in the
      superoxide scavenging activity in econazole (300 mg/kg)-damaged rat liver
      homogenate were assessed by cytochrome c reduction method and compared with that
      of (+)-alpha-tocopherol. It could be postulated that the hepatoprotective effect
      of PEE may be, at least in part, due to their inhibitory ability on membrane
      lipid peroxidation and free radical formation or due to their free radical
      scavenging ability.

PMID- 15036760
TI  - The reproductive toxicology of ammonium perfluorooctanoate (APFO) in the rat.
AB  - Ammonium perfluorooctanoate (APFO) is a surfactant used primarily as an aid in
      processing various fluoropolymers. Many toxicology and epidemiological studies
      have been conducted with APFO; however, no specific information regarding
      functional reproduction was previously available. Therefore, the potential
      reproductive toxicity of APFO across two generations of offspring was studied
      using current EPA OPPTS 870.3800 guidelines. Male and female Sprague-Dawley rats
      were dosed orally with 0, 1, 3, 10, or 30 mg/kg APFO. Parental (P) generation
      rats ( approximately 6 weeks old) were dosed at least 70 days prior to mating and
      until sacrificed (after mating for male rats; after weaning for female rats).
      F(1)-generation rats were dosed similarly, beginning at weaning. The F(2)
      generation pups were maintained through 22 days of lactation. Reproductive
      parameters evaluated in P- and F(1)-generation rats included estrous cycling,
      sperm number and quality, mating, fertility, natural delivery, and litter
      viability and growth. Age at sexual maturation in F(1), anogenital distance in
      F(2), and presence of nipples (males) in F(2)-generation pups were also
      determined. Feed consumption, body-weight gain, selected organ-weights, gross
      pathology and appropriate histopathology were evaluated. Reproductive endpoints
      including mating, fertility, and natural delivery were not affected in either
      generation. P- and F(1)-generation male rats showed decreased body weight, and
      liver and kidney weight increases at all doses. The 30 mg/kg F(1)-generation pups
      had decreased birth weight. Viability was reduced in the 30 mg/kg F(1)-generation
      pups in apparent relationship to reduced body weight at birth and weaning;
      however, F(2)-generation pups at 30 mg/kg, although somewhat lighter, did not
      show a loss in viability. Preputial separation and vaginal opening were somewhat
      delayed at 30 mg/kg, but these rats went on to show normal reproductive
      performance. No-observed-adverse-effect-levels were >30 mg/kg for reproductive
      function of P- and F(1)-generation rats, 10 mg/kg for F(1)-generation pup
      mortality, birth weight, and sexual maturation, and less than 1mg/kg for male
      body-weight and organ-weight changes.

PMID- 15036761
TI  - Effects of chlorophyllin on transport of dibenzo(a, l)pyrene, 2-amino-1-methyl-6
      phenylimidazo-[4,5-b]pyridine, and aflatoxin B(1) across Caco-2 cell monolayers.
AB  - Chlorophyllin (CHL) is a sodium copper derivative of chlorophyll that is capable
      of forming strong non-covalent complexes with several known carcinogens.
      Antimutagenic and anticarcinogenic effects, including reduced DNA adduct and
      tumor formation have been demonstrated for CHL against aflatoxin B(1) (AFB(1)),
      dibenzo(a,l)pyrene (DBP) and 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine
      (PhIP). Alterations in uptake and/or metabolism of planar molecules with at least
      partial ring structure have been proposed as mechanisms of action for CHL
      chemoprevention. The Caco-2 cell model of intestinal epithelial transport was
      used to evaluate the absorption of 1 microM DBP, AFB(1) and PhIP across cell
      monolayers in the presence of 0, 1, 10, and 100 microM CHL. No significant
      differences were observed in the permeability (P(e)) of DBP and AFB(1) from the
      basolateral-to-apical (BL --> AP) compared to apical-to-basolateral (AP --> BL)
      compartments for DBP and AFB(1), however, the P(e) of PhIP from BL --> AP, 1.26 x
      10(5) +/- 2.10 x 10(6) cm/s, was significantly higher than AP --> BL, 5.83 x
      10(6) +/- 7.56 x 10(7) cm/s, (P<0.001) suggesting an active efflux pathway.
      Transport of DBP from AP --> BL compartments was significantly reduced at all CHL
      concentrations (P<0.05). AP --> BL transport of AFB(1) was significantly reduced
      by the addition of 100 microM CHL (P<0.05) while 1 microM or 10 microM CHL had no
      effect. Complexation studies revealed a higher binding affinity (K(b)) for DBP to
      CHL compared to AFB(1) to CHL in transport buffer. AP --> BL transport of PhIP,
      which has a lower binding affinity for CHL than AFB(1) or DBP, was not
      significantly altered by the addition of CHL. These data suggest that the
      transport of AFB(1) and DBP can be inhibited by CHL, which supports a model of
      direct binding in the intestinal tract of CHL to these carcinogens with resultant
      reduction of bioavailability as one mechanism of action as a cancer
      chemopreventive agent.

PMID- 15036762
TI  - Hypomethylation of DNA and the insulin-like growth factor-II gene in
      dichloroacetic and trichloroacetic acid-promoted mouse liver tumors.
AB  - Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are mouse liver
      carcinogens. DNA hypomethylation is a common molecular event in cancer that is
      induced by DCA and TCA. Hypomethylation of DNA and the insulin-like growth factor
      II (IGF-II) gene was determined in DCA- and TCA-promoted liver tumors. Mouse
      liver tumors were initiated by N-methyl-N-nitrosourea and promoted by either DCA
      or TCA. By dot-blot analysis using an antibody for 5-methylcytosine, the DNA in
      DCA- and TCA-promoted tumors was demonstrated to be hypomethylated. The
      methylation status of 28 CpG sites in the differentially methylated region-2 (DMR
      2) of mouse IGF-II gene was determined. In liver, 79.3 +/- 1.7% of the sites were
      methylated, while in DCA- and TCA-treated mice, only 46.4 +/- 2.1% and 58.0 +/-
      1.7% of them were methylated and 8.7 +/- 2.6% and 10.7 +/- 7.4% were methylated
      in tumors. The decreased methylation found in liver from mice exposed to DCA or
      TCA occurred only in the upstream region of DMR-2, while in tumors it occurred
      throughout the probed region. mRNA expression of the IGF-II gene was increased in
      DCA- and TCA-promoted liver tumors but not in non-involved liver from DCA- and
      TCA-exposed mice. The results support the hypothesis that DNA hypomethylation is
      involved in the mechanism for the tumorigenicity of DCA and TCA.

PMID- 15036763
TI  - Effects of phytoestrogens and environmental estrogens on osteoblastic
      differentiation in MC3T3-E1 cells.
AB  - Phytoestrogens and environmental estrogens, which have in part some structural
      similarity to 17beta-estradiol, are reported to act as agonists/antagonists of
      estrogen in animals and humans. Estrogen is known to play an important role in
      maintaining bone mass, since the concentration of serum estrogen decreases after
      menopause and the estrogen deficiency results in bone loss. In this study, we
      report the effects of phytoestrogens (genistein, daidzein, and coumestrol) and
      environmental estrogens (bisphenol A (BPA), p-n-nonylphenol (NP) and bis(2
      ethylhexyl)phthalate (DEHP)) on osteoblast differentiation using MC3T3-E1 cells,
      a mouse calvaria osteoblast-like cell line. Coumestrol (10(-10) to 10(-6)M)
      slightly enhanced cell proliferation, while neither the other phytoestrogens
      (daidzein, genistein) nor environmental estrogens increased cell proliferation.
      Alkaline phosphatase (ALP) activity and cellular calcium (Ca) and phosphorus (P)
      contents were increased by phytoestrogens and BPA; however, neither NP nor DEHP
      affected those osteoblastic indicators. The effects of estrogenic potency, using
      the cell proliferation of MCF-7 cells, an estrogen receptor (ER)-positive human
      breast cancer cell line, indicate that coumestrol has the highest estrogenic
      potency among those phytoestrogens and environmental estrogens. The estrogenic
      potency of NP and DEHP were lower than the others. In conclusion, phytoestrogens,
      such as coumestrol, genistein and daidzein, and BPA increased ALP activity and
      enhanced bone mineralization in MC3T3-E1 cells, suggesting that not only
      phytoestrogen but also BPA, an environmental estrogen, is implicated in bone
      metabolism.

PMID- 15036765
TI  - Histological and lipid peroxidation changes after administration of 2
      acetylaminofluorene in a rat liver injury model following selective periportal
      and pericentral damage.
AB  - Administration of 2-acetylaminofluorene (2-AAF) suppresses mature hepatocyte
      proliferation following selective periportal or pericentral damage induced by
      allyl-alcohol (AA) or carbon tetrachloride (CCl(4)) administration, respectively.
      The aim of the present study was to investigate the histological and the lipid
      peroxidation changes after 2-AAF administration following CCl(4) and AA
      treatment. The study comprised 108 male Wistar rats that were assigned in four
      groups: Group A: a placebo pellet was implanted in their neck and on 7th day
      single dosages of AA and CCl(4) were administrated. Group B: 28-day release 2-AAF
      pellets (7 0mg-2.5mg per day) were implanted on the neck and on 7th day received
      a single dose of CCl(4). Group C: 28-day release 2-AAF pellets (70-2.5mg per day)
      were implanted on the neck and on 7th day a single dose of AA and CCl(4) were
      administrated. Group D: Sham-operated. Rats of each group were sacrificed on the
      9th, 11th, 13th and 21st day. Liver tissue was obtained for histological
      examination and blood was collected for lipid peroxidation evaluation by
      measuring malondialdehyde (MDA) and for liver enzymes. On the 9th and 21st day
      the histological score of liver necrosis was statistically higher on Groups B and
      C compared to Group A. Concentration of MDA in Group A was significantly higher
      than in Groups B and C on 9th and 11th days. Transaminase levels, however, were
      significantly higher in Group A on 9th day compare to the Groups B and C. In
      conclusion, it appears that oxidative stress was correlated with liver necrosis
      and with liver regeneration. Suppression of liver regeneration after 2-AAF
      administration leads to lower malondialdehyde concentrations.

PMID- 15036766
TI  - Nephrotoxicity of third-generation, intravenous bisphosphonates.

PMID- 15036776
TI  - The future of research on appetitive behavior: 30th Anniversary of the Columbia
      University Seminar on Appetitive Behavior.
AB  - The first 30 years of Columbia's Appetitive Seminar were celebrated by speakers
      extrapolating from the past to the future for six areas of research on appetite.
      This editorial introduces reviews of three of the selected topics and briefly
      summarizes the other three presentations-on the sensing of glucose utilization,
      gastrointestinal controls of satiety and mechanisms of learning and conditioning.

PMID- 15036764
TI  - Parenteral sesame oil attenuates oxidative stress after endotoxin intoxication in
      rats.
AB  - Sesame oil is regarded as a daily nutritional supplement to increase cell
      resistance to lipid peroxidation. The aims of this study were to examine the
      effects of parenteral sesame oil on oxidative stress and hepatic disorder induced
      by lipopolysaccharide and to determine the defense mechanisms involved in sesame
      oil-associated anti-oxidative effects in rats. Oxidative stress was induced by
      lipopolysaccharide (5 mg/kg, intraperitoneally) and assessed by determination of
      lipid peroxidation. Sesame oil (8 ml/kg, subcutaneously) was given 3 h after
      lipopolysaccharide, and lipid peroxide levels, hydroxyl radical, superoxide
      anion, the enzyme activities of superoxide dismutase and catalase as well as the
      levels of glutathione and nitrite were examined 6 h after lipopolysaccharide.
      Hepatic function was assessed by determining the activities of serum aspartate
      aminotransferase and alkaline phosphatase. Sesame oil reduced lipid peroxidation
      and hydroxyl radical, but failed to affect superoxide anion. Superoxide dismutase
      and catalase were increased, but glutathione was not affected, and the levels of
      nitrite were reduced. Further, sesame oil-treated groups showed attenuated
      hepatic disorder in lipopolysaccharide-treated rats. Thus, parenteral sesame oil
      can be used to attenuate oxidative stress and relieve hepatic disorder after
      lipopolysaccharide intoxication in rats.

PMID- 15036777
TI  - The future of research on eating disorders.
AB  - In the last several decades, research on the eating disorders has yielded
      important new knowledge, especially regarding the clinical characteristics and
      the treatment of individuals with Bulimia Nervosa. Challenging issues now
      confronting the field include how the eating disorders should be categorized,
      what factors underlie their development and persistence, and how they are best
      treated. New efforts based on the analysis of genetic factors, on the use of
      brain imaging and on the detailed analysis of behavioral disturbances hold
      promise for significantly advancing our understanding of these disorders in the
      next decade.

PMID- 15036778
TI  - The future of genetic research on appetitive behavior.
AB  - The risk for developing obesity has a significant genetic component. Several
      quantitative trait loci and candidate genes have been identified using current
      methodological approaches however the information gained thus far is insufficient
      to adequately explain the genetics underlying human obesity. The completion of a
      draft of the human genome sequence, the potential benefit of single nucleotide
      polymorphisms association studies for identifying risk conferring alleles, and
      developing functional genomics technologies promise to accelerate obesity gene
      discovery. These advances, used with current evaluative tools (murine molecular
      genetic techniques), may increase our understanding of human obesity, and
      ultimately provide better approaches to diagnosis and treatment.

PMID- 15036779
TI  - The future of research on thirst and salt appetite.
AB  - Substantial progress has been made over the last 50 years in studies examining
      the neural and hormonal basis of thirst and salt appetite. We now understand much
      about the physiological systems that are engaged in response to perturbations of
      water and electrolyte balance, including the brain areas that are activated to
      elicit the appropriate behavioral responses as well as some of the
      neurotransmitters and hormones that are important in these behaviors. A brief
      summary of some of the critical and key findings associated with studies of
      thirst and salt appetite will be reviewed, followed by a discussion of three
      critical areas of research that have not been fully examined and represent viable
      future directions of this field.

PMID- 15036781
TI  - Anticipatory effects of food exposure in women diagnosed with bulimia nervosa.
AB  - OBJECTIVE: To investigate cephalic phase responses (CPRs) in women diagnosed with
      bulimia nervosa and to test the assumption that eating disordered individuals
      respond with more marked CPRs and higher increases in psychophysiological arousal
      to the presentation of food cues. METHOD: Thirteen female inpatients diagnosed
      with bulimia nervosa were compared to 15 non-eating disordered female volunteers.
      Participants were exposed to their preferred binge food in a single laboratory
      session with the possibility to eat immediately after the exposure trial.
      RESULTS: The results show greater salivation responses to food exposure and lower
      sympathetic arousal in patients diagnosed with bulimia nervosa than in non-eating
      disordered participants. Distress and feelings of tension and insecurity during
      food exposure were higher in patients compared to controls. DISCUSSION: These
      results support the hypothesis that anticipatory cephalic phase responses are
      more marked in eating disordered individuals and may therefore play a role in the
      maintenance of binge eating behavior.

PMID- 15036780
TI  - Trust in food in the age of mad cow disease: a comparative study of consumers'
      evaluation of food safety in Belgium, Britain and Norway.
AB  - How do food scandals like dioxines in food in Belgium (summer 1999) and the
      detection of mad cow disease (BSE) in Britain affect consumers' confidence in
      food safety? In this paper, based on three thousand telephone interviews during
      the last quarter of 1999, consumers in Belgium and Britain are compared with
      consumers in Norway, where there has been no such serious food scandal in recent
      years. 'Trust' is a diffuse and complex concept to measure. In this article a
      consumer trust typology is developed and operationalised. Combining a trust
      distrust dimension and a reflexivity dimension, it is possible to differentiate
      between four main consumer types, which are called 'sensible', 'sceptical',
      'naive' and 'denying' consumers, respectively. Does the distribution of these
      consumer types vary in our selected countries? Are there gender differences
      across national borders? Four hypotheses of how consumers could respond to food
      scares are investigated: the Reflexivity hypothesis, the Risk-reducing
      hypothesis, the Complexity-reducing hypothesis and finally the Don't worry, be
      happy hypothesis.

PMID- 15036782
TI  - Mutual exposure or close peer relationships do not seem to foster increased
      similarity in food, music or television program preferences.
AB  - We know very little about either the mechanisms through which preferences are
      created in humans, or the contributions of particular developmental forces: e.g.
      genetics, parental influence, peer influence, the media. Prior work has indicated
      surprisingly low correlations (averaging about 0.15) between the food or music
      preferences of young adult and the mid-point of the biological and rearing
      parents preferences for the same items. A likely candidate for a substantial
      influence is peers. In one study, we show that freshman college roommates,
      randomly assigned, do not become significantly more similar in their food or
      music preferences over the course of about seven months of mutual exposure. In a
      second study, we show that in three suburban third grade classrooms, the
      preferences for food or TV programs in children is not more similar to those of
      their best friends in the school, than it is to randomly selected other children
      of the same gender, in their classes. Although our findings are negative (lack of
      influence), in light of very strong expectations for positive findings, we take
      them to be notable. These findings add further mystery and puzzlement to the
      question of: where do preferences come from? The focus in this study is on
      individual differences among peers and forces that lead to preference similarity.
      The study does not speak to the influence of general peer norms.

PMID- 15036783
TI  - Metabolic and cognitive coefficients in the development of hunger sensations
      after pure macronutrient ingestion in the morning.
AB  - The effect of pure carbohydrate, protein and fat ingestion on different aspects
      of short-term satiety and their relation to metabolic and cognitive performance
      indices were studied in 15 healthy male students. Subjects were tested in three
      sessions for short-term changes in blood indices, indirect calorimetry, different
      aspects of hunger sensations as well as mood and objective cognitive performance
      using a repeated-measures, counterbalanced cross-over design. Measurements were
      made after an overnight fast before and hourly during 3 h after macronutrient
      ingestion. Preloads were isoenergetic (1670 kJ) spoonable creams with similar
      sensory properties of either pure carbohydrates, protein or fat. Overall 'desire
      to eat' and 'gastric emptiness' represented principal components for overall
      'hunger' ratings, which were larger after fat and carbohydrate compared with
      protein ingestion. In the first hour, the hunger suppression of carbohydrates was
      similar to that of protein and related to changes in beta-hydroxybutyrate and
      insulin concentrations accompanied with a preference for carbohydrate-rich food.
      In the third hour, it was similar to the low satiating power of fat and related
      to diet-induced thermogenesis together with a preference for protein-rich food.
      For all macronutrients feelings of 'energy' were negatively related to hunger
      sensations, whereas objective cognitive performance was positively related. Our
      findings suggest that the subjective satiating effect of carbohydrates seems to
      change with time in relation to postprandial metabolic changes, presumably mainly
      dependent on the glycemic response and diet-induced thermogenesis.

PMID- 15036784
TI  - Increasing the portion size of a packaged snack increases energy intake in men
      and women.
AB  - The objective of this study was to determine how the portion size of a packaged
      snack affects energy intake of the snack and of the subsequent meal. On five
      separate days, 60 subjects (34 women and 26 men) ate an afternoon snack and
      dinner in individual cubicles. For each snack, subjects were served one of five
      packages of potato chips (28, 42, 85, 128, or 170 g), which they consumed ad
      libitum directly from the unlabelled, opaque package. Subjects returned to the
      lab three hours later for a standard dinner, which was also consumed ad libitum.
      Results showed that snack intake increased significantly as the package size
      increased for both males and females (p < 0.001). The combined energy intake from
      snack and dinner also increased as the package size increased. On average, when
      served the largest snack package compared to the smallest, subjects consumed an
      additional 596 kJ (143 kcal) at snack and dinner combined. Results from this
      study demonstrate that short-term energy intake increases with increasing package
      size of a snack. These data suggest that the availability of large packages of
      energy-dense snacks may be one of the environmental influences associated with
      excess energy intake.

PMID- 15036785
TI  - Ambivalence towards meat.
AB  - The purpose of the present study was to examine whether differences in
      ambivalence between meat eaters affect their attitude towards eating meat, the
      belief structure underlying these attitudes, meat consumption, and intentions to
      reduce consumption in the future. Not surprisingly, more ambivalent meat eaters
      held a less positive attitude towards meat as compared to less ambivalent meat
      eaters. Moreover, the belief structure of the two groups also differed: More
      ambivalent persons associated the consumption of meat with slightly negative
      feelings, morally unacceptable issues, and risks for both their health and the
      environment. In contrast, less ambivalent meat eaters reported positive affective
      beliefs, did not emphasize moral issues, and perceived less risk. Results
      highlight the role of affective beliefs as a predictor of both attitude and
      ambivalence. Ambivalence, in turn, was a predictor of actual meat consumption;
      i.e. increased ambivalence was related to reduced meat consumption. Moreover,
      more ambivalent meat eaters intended to further reduce their meat consumption in
      the future. Practical and theoretical implications of these results are
      discussed.

PMID- 15036786
TI  - Impressions of functional food consumers.
AB  - Functional foods provide a new way of expressing healthiness in food choices. The
      objective of this study was to apply an indirect measure to explore what kind of
      impressions people form of users of functional foods. Respondents (n=350)
      received one of eight versions of a shopping list and rated the buyer of the
      foods on 66 bipolar attributes on 7-point scales. The shopping lists had either
      healthy or neutral background items, conventional or functional target items and
      the buyer was described either as a 40-year-old woman or man. The attribute
      ratings revealed three factors: disciplined, innovative and gentle. Buyers with
      healthy background items were perceived as more disciplined than those having
      neutral items on the list, users of functional foods were rated as more
      disciplined than users of conventional target items only when the background list
      consisted of neutral items. Buyers of functional foods were regarded as more
      innovative and less gentle, but gender affected the ratings on gentle dimension.
      The impressions of functional food users clearly differ from those formed of
      users of conventional foods with a healthy image. The shopping list method
      performed well as an indirect method, but further studies are required to test
      its feasibility in measuring other food-related impressions.

PMID- 15036787
TI  - Fat-depleted CLA-treated mice enter torpor after a short period of fasting.
AB  - Resting energy expenditure (Resting-EE), EE with treadmill exercise, and post
      prandial thermogenesis were continuously monitored by indirect calorimetry during
      a 24 h recording session in control (CT) and CLA-treated (CLA) (1% CLA in the
      food, by weight) C57Bl/6 male mice. After 15 days of CLA treatment, the fat
      content of CLA mice had fallen to 20% of that in CT mice. CLA mice were able to
      face the energy challenge of exercise but used less lipid than CT mice. Resting
      EE values fell during the post-exercise period. The thermogenic response to a
      calibrated test meal given 5 h after the run abolished the differences in EE and
      substrate oxidation between CT and CLA mice. However, 2.5 h after ingestion of
      the test meal onward, CT mice gradually increased their lipid oxidation to
      sustain resting-EE levels. In contrast, CLA mice did not increase their lipid
      oxidation and their resting-EE levels fell significantly until they entered into
      torpor. Blood leptin was low but similar in CT and CLA-treated mice suggesting
      that leptin is not critical to induce torpor. We suggest that the durable
      inhibition of lipid oxidation in fasting CLA mice was an adaptive behaviour
      devoted at sparing the residual adipose deposits.

PMID- 15036788
TI  - Investigation into the role of cephalic stimulation of acid secretion on gastric
      emptying and appetite following a soup meal using the gastric acid inhibitor
      omeprazole.
AB  - We previously showed that oral administration of a liquid soup preload was
      associated with a slower rate of gastric emptying and suppressed appetite more
      compared with intragastric administration of the same soup [Appetite
      31(1998)377]. The present study was designed to investigate whether these results
      could be explained by the cephalic stimulation of acid secretion induced by oral
      administration. Eight healthy male subjects took part in a double-blind placebo
      controlled study comparing the effects of omeprazole and placebo on gastric
      emptying, appetite ratings and subsequent food intake following the ingestion of
      a liquid soup. Subjects were administered with a single oral dose of 80 mg
      omeprazole or placebo 3 h prior to ingesting the radiolabelled soup preload (400
      kcal; 425 ml) over 15 min. Ratings of hunger, desire to eat and fullness were
      recorded over 135 min and gastric emptying was measured by scintigraphy. Food
      intake was evaluated from a test meal (yoghurt drink) given 120 min after the end
      of the soup ingestion. Analysis of data showed that there was no significant
      difference between omeprazole and placebo in gastric emptying, appetite or
      subsequent energy intake from the test meal. The results suggest that gastric
      acid secretion is not responsible for the differences in gastric emptying and
      appetite observed between intragastrically infused and orally administered soup
      preloads.

PMID- 15036789
TI  - Genetic and biobehavioral analysis of the controls of meal size in mice.
AB  - Transgenic mice are a powerful and much used tool in the field of feeding
      behavior. However, much of the biobehavioral characterization of the controls of
      feeding has been done in rats. The present presentation describes our efforts to
      adapt techniques traditionally used in rats to the analysis of feeding behavior
      in mice. This has been done within Smith's theoretical framework of positive and
      negative feedback controls of meal size. We show that mice are sensitive to
      increases and decreases of post-ingestive negative feedback, as they reduce
      intake in response to intragastric nutrient preloads and CCK, while they increase
      their intake in a sham-feeding preparation. Finally, we discuss our initial
      attempts to characterize the controls of feeding in a transgenic mouse model, the
      NSE-RB mouse.

PMID- 15036790
TI  - Television viewing is associated with an increase in meal frequency in humans.
AB  - In sample of 76 undergraduate students (mostly female) in the USA, television
      viewing was associated with increased meal frequency and as a result with
      increased daily intake of energy.

PMID- 15036791
TI  - Effects of social interaction, physical environment and food choice freedom on
      consumption in a meal-testing environment.
AB  - Consumption of pizza, salad and iced tea was assessed in four separate tests at a
      central location. Three aspects of context were added in successive tests-social
      interaction during consumption, the physical environment in which the food was
      consumed and choice among foods-so that the fourth test had all effects present.
      The proportion consumed averaged from 79 to 82% of the food presented and
      increased significantly in the presence of one or more of the context
      manipulations. Salad consumption was higher when there was a choice of dressings
      in an enhanced environment. Pizza and tea consumption were higher in an enhanced
      restaurant-like environment. Social interaction alone has no detectable impact on
      food consumption. It is concluded that people eat more in enhanced contexts and
      careful consideration should be given to the environment in studies of food
      consumption.

PMID- 15036792
TI  - Chocolate craving and the menstrual cycle.
AB  - Spanish and American female chocolate cravers reported the usual times when they
      craved chocolate by answering an open-ended question. They also were asked
      directly if they craved chocolate perimenstrually. American women (40% open
      ended, 60% direct) were more likely than were Spanish women (4% open-ended, 24%
      direct) to report that their chocolate cravings occurred perimenstrually when
      responding to both questions. The most frequently reported times (other than
      perimenstrually) that chocolate was craved were the same for Spanish men and
      women (after eating, studying) and for American men and women (evening),
      differing cross-culturally but not across gender. The results suggest a cultural
      origin rather than a physiological basis for chocolate craving.

PMID- 15036794
TI  - Identification of Serratia marcescens populations of nosocomial origin by RAPD
      PCR.
AB  - BACKGROUND: Serratia marcescens has been increasingly identified as a cause of
      infection in the immunocompromised host and in high-mortality-rate nosocomial
      outbreaks. It is thus important to use identification methods that allow study of
      the dynamics and evolution of nosocomial S. marcescens strains. The aim of this
      study was to identify S. marcescens strains isolated from nosocomial outbreaks in
      two pediatric hospitals by random amplification polymorphic DNA polymerase chain
      reaction (RAPD-PCR). METHODS: RAPD-PCR was used to study five S. marcescens
      populations isolated from four different nosocomial outbreaks that occurred in
      two pediatric hospitals. This method was compared with the widely used biotyping
      system described by Grimont and Grimont. RESULTS: The combination of
      biotypification and RAPD-PCR allowed accurate identification of S. marcescens
      strains isolated in nosocomial outbreaks at pediatric hospitals; by RAPD-PCR, we
      were able to analyze clonal variations in S. marcescens populations. We
      established bacterial dissemination patterns in hospital environments according
      to hospital administration of medical services and compared changes in bacterial
      DNA amplification patterns in each hospital related with clonal variations by
      selective pressures. CONCLUSIONS: RAPD-PCR is a useful method to identify S.
      marcescens strains associated with nosocomial outbreaks.

PMID- 15036793
TI  - Nitric oxide, an iceberg in cardiovascular physiology: far beyond vessel tone
      control.
AB  - The endothelium is now recognized not only as a physical barrier between blood
      and vascular wall, but also as an important and strategically located organ with
      multiple endocrine and paracrine functions. By releasing vasoactive substances,
      the endothelium acts as an inhibitory regulator of vascular contraction,
      leukocyte adhesion, vascular smooth muscle cell growth, and platelet aggregation.
      This review intends to demonstrate how much the picture of the biological
      functions of nitric oxide has changed in cardiovascular physiology, extending
      beyond its vessel-relaxing activity, as well as to highlight new insights into
      the factors affecting its bioavailability and regulation in relation with many
      cardiovascular diseases.

PMID- 15036795
TI  - Degradation of pro-insulin-receptor proteins by proteasomes.
AB  - BACKGROUND: Type-2 diabetes is characterized by hyperinsulinemia, peripheral
      insulin resistance, and diminished tyrosine phosphorylation activity. It has been
      recently shown that proteasomes are implicated in the degradation of the insulin
      receptor substrate-1 (IRS-1) but not in that of the insulin receptor (IR).
      However, it is unknown whether proteasomes are involved in pro-IR degradation.
      METHODS: We used CHO-IR and the 3T3-L1 cells treated with insulin at different
      concentrations and compared the proteasome activity of IRS-1, IR, and pro-IR
      degradation either in presence or in absence of lactacystin. RESULTS: A total of
      100 nM of insulin allowed degradation of IRS-1 after 6 h of incubation. At 1,000
      nM of insulin, pro-IR degradation began at 1 h of incubation, similar to IRS-1
      degradation. Surprisingly, at a higher concentration (10 microM) of insulin, a
      drastic decrease of proteins was observed from the first minute of incubation.
      This activity was blocked by lactacystin, a specific proteasome inhibitor.
      CONCLUSIONS: According to these results, we propose that pro-IR is degraded by
      proteasomes.

PMID- 15036796
TI  - Evaluation of equipment performance, patient dose, imaging quality, and
      diagnostic coincidence in five Mexico City mammography services.
AB  - BACKGROUND: Regulations concerning the use of x-rays in medical diagnoses were
      published in Mexico in 1997. In this work, we evaluate technical aspects of
      mammography services in the Mexico City area and radiation dose and coincidence
      between the radiological interpretation by the institution radiologist and by a
      panel of experts. METHODS: Following methodology proposed by the American College
      of Radiology and the European Community among others, we have evaluated the
      performance of six mammography systems in Mexico City public and private
      services. The studied services carry out approximately one half of the
      mammography studies in the capital's metropolitan area. RESULTS: The systems
      comply with 53-82% of a total of 31 applied quality control tests and
      measurements, which include the mammography unit, x-ray generation, collimation,
      automatic exposure control, compression devices, grid and image receptor, film
      processing, darkroom, viewboxes, dose, film rejection, and image quality. The
      elements that most frequently fail are film processing, darkroom, and light
      boxes; average ACR phantom score is 11.2 (9.5, 12.0); mean average glandular dose
      measured with the phantom is 1.00 (0.71-1.15) mGy, and measured in patients is
      1.75 (0.3, 4.9) mGy; coincidence between radiologic reports (BI-RADS) by the
      institution radiologist and a panel of experts is obtained in 35% of studied
      cases. CONCLUSIONS: Statistical analysis of results indicated that the level of
      equipment performance is correlated with image quality, image quality estimated
      by the panel of radiologists is correlated with phantom score, and coincidence in
      clinical mammography reports is not correlated with equipment performance and
      appears to depend on the radiologist's experience.

PMID- 15036797
TI  - Down syndrome: clinical profile from India.
AB  - BACKGROUND: Our objective was to study demographic features, clinical features,
      and karyotype analyses of patients with Down syndrome (DS). Our study design was
      a retrospective analysis, while the study was conducted in the Genetic Clinic of
      a tertiary-care teaching hospital. METHODS: Retrospective analysis of cases
      referred to the Genetic Clinic was performed. Case proformas of the patients
      presenting with phenotypic features of DS were analyzed. The following
      information was recorded from the proformas: age at presentation; sex; maternal
      age; craniofacial and other physical features; presence and type of congenital
      heart disease; gastrointestinal abnormalities, and results of cytogenetic
      evaluation. Clinical features in neonates with DS were separately analyzed.
      RESULTS: Analysis included cases of DS presenting over a period of 7.5 years; a
      total of 524 patients were studied (303 males and 221 females; M:F ratio 1.37:1).
      Average age at presentation was 19.4 months (range: 1 day-26 years). Average
      maternal age at birth of the affected child was 26.8 years (range: 16-45 years).
      Craniofacial features noted in >50% of the cases included mongoloid slant
      (83.9%), ear abnormalities (66.9%), epicanthic folds (56.9%), and flat facial
      profile (50.9%). A total of 76.3% cases had hypotonia. Characteristic limb and
      dermatoglyphic anomalies were seen in less than one half of cases. These included
      sandle sign (46.2%), unilateral or bilateral simian crease (33.2%), clinodactyly
      (36.1%), and brachydactyly (11.1%). Ophthalmologic abnormalities included
      hypertelorism (33.9%), nystagmus (3.2%), Brushfield spots (3.2%), squint (2.7%),
      and cataracts (1.9%). Congenital heart disease was clinically diagnosed in 96
      cases (18.3%). The nature of the cardiac defect was ascertained by color Doppler
      examination and/or 2D-echocardiography in 58 cases. The most common cardiac
      anomalies were ventricular septal defect (25.8%), tetralogy of Fallot (15.5%),
      and atrial septal defect (12.1%). Gastrointestinal anomalies were noted in seven
      cases and included three cases with imperforate anus, two with Hirschsprung
      disease, and one each with duodenal atresia and Morgagni hernia. Results of
      cytogenetic abnormalities were available in 42.2%. Free trisomy (non-dysjunction)
      was present in 95%, 3.2% had translocation, and 1.8% were mosaics. In neonates,
      common features noted were mongoloid slant, ear abnormalities, flat facial
      profile, hypotonia, sandle sign, and clinodactyly+/-brachydactyly. CONCLUSIONS:
      All characteristic craniofacial and physical features of DS need not be present
      in every case. Major features noted in the present study were mongoloid slant,
      ear abnormalities, epicanthic folds, flat facies, and hypotonia. Congenital heart
      disease was present in 18.3% of cases, with ventricular septal defect being the
      most common type of defect. Non-dysjunction was the most common cause of the
      chromosomal anomaly.

PMID- 15036799
TI  - Comparison of three rating scales for measuring subjective phenomena in clinical
      research. I. Use of experimentally controlled auditory stimuli.
AB  - BACKGROUND: An interest in measuring subjective phenomena such as pain, nausea,
      anxiety, etc. has led clinicians to develop three types of ratings: the visual
      analog scale (VAS); the verbal rating scale (VRS), and the numeric rating score
      (NRS). These ratings are regarded as global scales because they lack criteria to
      demarcate diverse dimensions or categories that comprise each scale. The purpose
      of this study was to evaluate validity and consistency of usage for these scales.
      Criterion for validity consisted of an experimentally controlled intensity for
      auditory stimuli. METHODS: We conducted a prospective, experimentally controlled,
      clinimetric study at the Audiology Department at the Hospital of Puebla
      Autonomous University (in Puebla State, Mexico). Participants included 25 medical
      students, two psychology students, and three practicing physicians. Interventions
      consisted of pure 1,000 Hz tones in five different intensities applied for 3 sec
      with a 1-min interval between stimuli at three sessions for each observer. Main
      outcome measure was validity and consistency of usage for VAS, VRS, and NRS
      scales. RESULTS: Correlation coefficients between scale results and standard
      stimuli were 0.818 for VAS, 0.735 for NRS, and 0.796 for VRS. Mean weighted kappa
      indices for intraobserver agreement were 0.70, 0.59, and 0.65, respectively, for
      scales with five categories each. Mean weighted kappa indices for inter-observer
      variability were 0.61, 0.48, and 0.54 for VAS, NRS, and VRS again with five
      categories each. CONCLUSIONS: The three instruments appeared reasonably accurate,
      with VAS having highest scores. VRS appeared sufficiently consistent to be
      regarded as providing reliable scientific information.

PMID- 15036798
TI  - A randomized, double-blind, multicenter, controlled clinical trial of
      cyclosporine plus chloroquine vs. cyclosporine plus placebo in early-onset
      rheumatoid arthritis.
AB  - BACKGROUND: Our objective was to assess the efficacy and safety of cyclosporine-A
      (CsA) plus chloroquine (Clq) in early-onset rheumatoid arthritis (RA) compared to
      CsA plus placebo. METHODS: We conducted a prospective, 12-month follow-up,
      multicenter, double-blind, placebo-controlled study of CsA (2.5-5 mg/kg/day[d])
      plus Clq (150 mg/d) vs. CsA plus placebo in active RA of <2 years of evolution.
      RESULTS: A total of 149 patients were included; 111 patients (74.4%) completed
      the 12-month follow-up period. Evaluation at 6 and 12 months showed improvement
      for all clinical disease parameters. In both groups there was a decrease in
      tender joint count, swollen joint count, pain, assessment of efficacy by both
      investigator and patient, functional assessment, and morning stiffness, all
      differences statistically significant. With an intention-to-treat analysis, there
      was 64% in the CsA plus Clq group (CsA/Clq) and 63% in the CsA plus placebo group
      (CsA/Plac) at 12 months in the American College of Rheumatology (ACR)-20 criteria
      of improvement. Response rate for ACR-50 was 48 and 47%, and for ACR-70 it was
      29% in both groups; the difference was not statistically significant between
      study groups. Gastrointestinal complaints were common in both groups. Four
      patients in CsA/Clq group and five patients in CsA/placebo group increased
      creatinine levels; two patients in each group discontinued treatment due to this
      reason. CONCLUSIONS: There was no advantage to adding chloroquine to cyclosporine
      in patients with RA.

PMID- 15036800
TI  - HIV-encephalopathy as initial manifestation of acquired immunodeficiency syndrome
      in Yucatan State, Mexico.
AB  - BACKGROUND: The frequency of neurologic manifestations of the central nervous
      system (CNS) as a defining disease of acquired immunodeficiency syndrome (AIDS)
      (neurologic manifestation defining disease [NMDD-AIDS]) varies according to
      geographic region. The aim of this study was to determine its prevalence among
      patients with AIDS diagnosed in the state of Yucatan, Mexico. METHODS: We carried
      out a retrospective study in which AIDS cases reported at the Health Department
      in the state of Yucatan, Mexico from January 1983 to July 2001 were analyzed.
      Frequency of NMDD-AIDS and other pathologies were obtained. Frequency of other
      pathologies between patients with NMDD-AIDS and those without NMDD-AIDS was
      compared using chi2 and/or Fisher exact test. RESULTS: A total of 1,175 subjects
      (1,054 [90%] men and 121 [10%] women) were included in the study. In 186 (16%),
      NMDD-AIDS were observed. The most common NMDD-AIDS was HIV-encephalopathy in 101
      (54%) patients, CNS toxoplasmosis in 65 (35%), meningeal cryptococosis in 16
      (8.6%), primary lymphoma of the brain in two (1%), and one (0.5%) case of
      progressive multifocal leukoencephalopathy. CD4 lymphocytes were statistically
      different between patients with NMDD-AIDS (n=47) and without (n=312) (mean:
      65/microL (33-500) vs. 189/microL (2-989), p<0.005). Higher frequency of
      oropharyngeal candidiasis, pulmonary tuberculosis, herpetic stomatitis, and
      mortality was observed in patients with initial neurologic disease. CONCLUSIONS:
      Frequency of NMDD-AIDS was similar to some reports from the U.S. but lower than
      others from Mexico. HIV-encephalopathy was the most frequent manifestation. NMDD
      AIDS were associated with advanced stage of immunodeficiency and influenced
      morbidity and mortality associated with AIDS.

PMID- 15036801
TI  - Sympathetic activity and response to ACE inhibitor (enalapril) in normotensive
      obese and non-obese subjects.
AB  - BACKGROUND: Angiotensinogen has been proposed as a possible link between obesity
      and hypertension because the adipocyte produces angiotensinogen and contains the
      enzymes required for its conversion. Moreover, sympathetic overactivity has been
      reported in obese subjects. The aim of this study was to compare heart
      sympathetic activation and serum angiotensinogen levels in obese and non-obese
      normotensive subjects, their relationship, and the effect of a drug that modifies
      the renin-angiotensin system. METHODS: Serum angiotensinogen, leptin, lipids,
      glucose, and insulin levels were measured and 24-h electrocardiograph monitoring
      was carried out in 41 (20 non-obese and 21 obese) volunteers before and after
      administration of 5 mg enalapril twice/day for 7 days. RESULTS: Obese subjects
      had higher values than non-obese subjects for % body fat (35.1+/-4.6 vs. 30.5+/
      5.2; p=0.005), triglycerides (1.93+/-0.9 vs. 1.25+/-0.7 g/L, p=0.002), insulin
      (114.8+/-82.5 vs. 45.9+/-22.2 pmol/L), leptin (31.4+/-20.4 vs. 14.1+/-11.2 ng/mL,
      p=0.002), and LF/HFn index (4.3+/-2.9 vs. 2.2+/-1.3, p<0.005). Enalapril
      increased angiotensinogen levels only in the non-obese group (4.2+/-3.9 vs. 9.7+/
      5.4 ng/mL, p=0.001) and diminished the LF/HFn index (4.3+/-2.9 vs. 3.0+/-1.4,
      p=0.007) in the group of obese subjects. There was no association between
      angiotensinogen levels and sympathetic activity. CONCLUSIONS: Higher level of
      sympathetic activity was found in normotensive obese as compared with non-obese
      subjects. Enalapril treatment reduced heart sympathetic activity in obese
      subjects but did not change angiotensinogen levels.

PMID- 15036803
TI  - Ethics and communication between physicians and their patients with cancer,
      HIV/AIDS, and rheumatoid arthritis in Mexico.
AB  - BACKGROUND: Despite evidence that open communication concerning diagnosis of a
      disease substantially improves the doctor-patient relationship, in developing
      countries physicians often provide partial information. METHODS: We carried out a
      cross-sectional study with 379 physicians practicing at 11 hospitals in Mexico
      City and in the central Mexican state of Morelos to quantify their communication
      patterns with patients with cancer, HIV/AIDS, and rheumatoid arthritis.
      Communication patterns were defined as physician self-reported communication with
      patients with regard to their diagnosis, prognosis, and treatment. Logistic,
      ordinal, multivariate models were constructed for analysis. RESULTS: Assigning a
      high level of value to communication (odds ratio [OR] 5.5, 95% confidence
      interval [95% CI] 2.1-14.8), and bioethics training (OR 1.5, 95% CI 1.0-2.3) were
      principal predictors of explicit communication with cancer patients. We found a
      very strong association between explicit communication with HIV/AIDS patients and
      an accepting attitude of the physician toward death (OR 34.6, 95% CI 8.5-141.0).
      As for communication with rheumatoid arthritis patients, we observed an
      association between a very paternalistic attitude on the part of the physician
      (OR 6.8, 95% CI 1.9-24.1) and complete communication. CONCLUSIONS: In Mexico,
      physicians exercise power and authority over patients in an effort that they
      perceive as beneficial or preventing harm. In most cases, physicians do not seem
      to recognize or respect their patients' autonomy; therefore, communication is
      generally partial and vague. Our study established the need among physicians for
      bioethics and communication training. A discussion of this topic is necessary to
      transform the doctor-patient relationship and to establish a consensus for
      policies and norms for communication that benefits patients.

PMID- 15036802
TI  - Effects of smoking and lead exposure on proximal tubular integrity among Egyptian
      industrial workers.
AB  - BACKGROUND: The hazards of occupational lead exposure are well documented. Tissue
      damage produced by lead is slow and progressive. The renal system is one of the
      systems primarily affected by lead. The present study aimed to evaluate renal
      proximal tubular functional and structural integrity among lead-exposed and
      cigarette-smoking male Egyptian workers. This study was extended to investigate
      the effect of lead exposure and cigarette smoking on urinary excretion of copper
      (Cu) and zinc (Zn). METHODS: Participants included in the present study were 156
      male workers grouped as follows: i) 75 lead non-exposed workers subgrouped into
      G1 that consisted of 36 non-smokers (age, 39.08+/-6.65 years) and G2, which
      included 39 smokers (age, 43.87+/-9.93 years); ii) 45 lead-exposed workers (work
      duration <20 years) subgrouped into G3 that consisted of 25 non-smokers (age,
      37.40+/-3.76 years) and G4, which included 20 smokers (age, 38.40+/-4.95 years),
      and iii) 36 lead-exposed workers (work duration > or =20 years) subgrouped into
      G5 that consisted of 16 non-smokers (age, 45.94+/-4.19 years) and G6 which
      included 20 smokers (age, 45.70+/-2.25 years). Functional integrity of proximal
      tubules was studied by determining urinary level of low-molecular-weight protein
      alpha1-microglobulin (alpha1M), and structural integrity was investigated by
      measuring urinary activities of the lysosomal enzyme N-acetyl-beta-D
      glucosaminidase (NAG) and the cytoplasmic enzyme glutathione S-transferase (GST).
      Urinary concentrations of Pb, Cu, Zn, and creatinine were also determined.
      RESULTS: Data of the present investigation showed increased urinary excretion of
      all measured urinary parameters among lead-exposed workers in comparison with non
      exposed workers whether they were non-smokers or smokers (G3 vs. G1, G5 vs. G1,
      G4 vs. G2, and G6 vs. G2), with greater elevation among lead-exposed smokers than
      among lead-exposed non-smokers (G4 vs. G3, G6 vs. G5). In addition, there was a
      greater increase in levels of all urinary parameters among workers with work
      duration > or =20 years than in those with <20 years' work duration (G6 vs. G4,
      G5 vs. G3). CONCLUSIONS: Lead exposure in Egyptian workers causes damage to renal
      proximal tubules and results in its dysfunction. Cigarette smoking has a
      nephrotoxic effect and also is synergistic to lead nephrotoxicity on urinary
      excretion of GST and NAG, as well as Pb.

PMID- 15036804
TI  - High prevalence of metabolic syndrome in Mexico.
AB  - BACKGROUND: Our objective was to describe the prevalence of the metabolic
      syndrome using World Health Organization (WHO) and National Cholesterol Education
      Program (NCEP-III) definitions in a population-based survey. METHODS: We
      performed an analysis of data from a Mexican nationwide, population-based study.
      The population was composed of 2,158 men and women aged 20-69 years sampled after
      a 9-12 h fasting period. Prevalence of the metabolic syndrome as defined by the
      NCEP-III definition and WHO criteria was estimated and case characteristics were
      assessed. RESULTS: Age-adjusted prevalence was 13.61% for WHO criteria and 26.6%
      for the NCEP-III definition. Prevalence was 9.2 and 21.4%, respectively, in
      subjects without diabetes. Thirty five percent of affected cases were <40 years
      of age. In addition to criteria used for diagnosis, ca. 90% were either
      overweight or obese. In cases detected using WHO criteria, antihypertensive
      treatment or blood pressure reading >140/90 was found in 61.8%. The proportion of
      subjects who qualified for hypolipemiant treatment was lower: lifestyle
      modifications were needed in 42.1% and drug therapy was required in 18.9%. The
      same trends were found for cases detected using the NCEP definition. CONCLUSIONS:
      Prevalence of the metabolic syndrome in Mexico is high. A large proportion of
      affected cases qualify for preventive actions for complications of the metabolic
      syndrome (i.e., weight loss, antihypertensive or hypolipemiant treatment). These
      results provide data for planning therapeutic programs for Mexican patients with
      the metabolic syndrome.

PMID- 15036805
TI  - Patient ratings of care at a rheumatology out-patient unit.
AB  - BACKGROUND: Our objective was to determine patient satisfaction with services
      rendered by health care personnel at the rheumatology out-patient consultation.
      METHODS: We carried out a cross-sectional survey at a tertiary-level care
      hospital in Mexico City. A questionnaire on satisfaction with quality of medical
      care was applied to 347 adult patients who attended the out-patient rheumatology
      clinic at least twice and who agreed to participate. Questions in the instrument
      covered three aspects of quality of care, including structure, process, and
      results. RESULTS: In overall assessment, 83.5% of patients reported satisfaction
      with care. Structure received worst score and process, the best. Outcomes (e.g.,
      disease improvement) received intermediate scores. Correlations within these
      areas were strong but correlation with overall satisfaction was not high. The
      majority of patients stated that physician competence was the most valuable
      aspect of the visit; the least valuable was waiting time. CONCLUSIONS: Specific
      strategies need to be implemented to improve certain areas. Overall satisfaction
      as a measurement renders no specific and useful information due to complexity
      with regard to different dimensions of satisfaction.

PMID- 15036806
TI  - Normal reference value of hemoglobin of infant girls and altitude in China.
AB  - BACKGROUND: The aim of this study was to supply a scientific basis for uniting
      the normal reference value standard of hemoglobin of Chinese infant girls.
      METHODS: A research study was carried out concerning the relationship between the
      normal reference value of 3,771 examples of hemoglobin of infant girls and
      altitude in 40 areas of China. Normal reference values of hemoglobin of infant
      girls were determined by hemoglobincyanide method. RESULTS: It was found that
      correlation of normal reference value of hemoglobin of infant girls and altitude
      was quite significant (r=0.545). By using method of univariate linear regression
      analysis, the following regression equation is inferred: Y = 112.9 + 0.008978X +/
      20.8. CONCLUSIONS: If altitude values are obtained in certain areas, normal
      reference value of hemoglobin of infant girls of this area can be reckoned by
      using the regression equation. Furthermore, depending on altitude, China can be
      divided into three districts as follows: Qingzang District, Central District, and
      Eastern District.

PMID- 15036807
TI  - Human genetics, animal models and computer simulations for studying hypertension.
AB  - Essential hypertension is probably caused by combinations of small quantitative
      changes in the expression of many genes together with environmental factors. In
      this article, strategies for studying hypertension using animal models are
      summarized with emphasis on the combined use of mouse models and computer
      simulations. We have chosen the rennin-angiotensin system as our main example.
      Future directions of hypertension research using gene targeting are also
      discussed.

PMID- 15036809
TI  - Vertebrate floor-plate specification: variations on common themes.
AB  - Situated at the ventral-most part of the vertebrate neural tube, the floor plate
      (FP) is an important signalling centre that controls the regional differentiation
      of neurons in the nervous system. It secretes guidance molecules that direct
      ventrally navigating axons crucial for the correct wiring of neuronal circuits.
      Although the function of the FP is well-conserved from fish to humans,
      discrepancies exists with respect to both the signalling system involved in FP
      induction, and the origin of the FP in various vertebrate species. Recent
      findings from the embryos of zebrafish, chicken and mouse provide insights that
      reconcile previous results and suggest common themes in vertebrate FP
      specification.

PMID- 15036808
TI  - Huntingtin-protein interactions and the pathogenesis of Huntington's disease.
AB  - At least nine inherited neurodegenerative diseases share a polyglutamine
      expansion in their respective disease proteins. These diseases show distinct
      neuropathological changes, suggesting that protein environment and protein
      protein interactions play an important role in the specific neuropathology. A
      gain of toxic function as a result of an expanded polyglutamine tract can cause
      the protein huntingtin to interact abnormally with a variety of proteins,
      resulting in the complex of neuropathological changes seen in Huntington's
      disease. Recent studies have identified several huntingtin-interacting proteins
      that might be associated with the normal function of huntingtin and/or involved
      in the pathology of Huntington's disease. In this article, we focus on the
      potential roles of huntingtin-protein interactions in the pathogenesis of
      Huntington's disease.

PMID- 15036810
TI  - The genetics and genomics of insecticide resistance.
AB  - The past ten years have seen the elucidation of the molecular basis of insect
      resistance to many chemical insecticides. Target genes, mostly in the nervous
      system, have been identified and cloned from Drosophila melanogaster and
      resistance-associated mutations have been examined in a range of pest insects.
      More recently, with the advent of annotated insect genomes, resistance mediated
      by complex multi-gene enzyme systems such as esterases, cytochrome p450s and
      glutathione-S-transferases has also been elucidated. In this article, we review
      the impact of Drosophila genetics on the field of insect resistance and focus on
      the current and future impact of genomics. These studies enable us to address
      three fundamental questions in the evolution of resistance. How many genes are
      involved? How many mutations are there within these genes? How often do these
      mutations arise in natural populations?

PMID- 15036811
TI  - 1978: a good year, but a vintage past its best.
AB  - This article is intended to stimulate debate. Where does public health planning
      in developing countries need to go if it is to focus on the challenges of meeting
      the health needs of the poor and increasing the accountability and performance of
      health services? The article concludes that Alma Ata vintage public health
      planning has frozen many health ministries in a non-monetarised world. The
      effects, are systematic obstacles to using many technologies available in other
      sectors to improve accountability and performance through better business
      planning and control. High time for an Alma Ata II Conference.

PMID- 15036812
TI  - Globalisation and local power: influences on health matters in South Africa.
AB  - This paper reviews some of the multiple influences on health issues in South
      Africa, placing them in the context of globalisation. By examining the complexity
      of factors, both domestic and global, which impact on these issues, it questions
      the extent to which global patterns in areas such as health policy, HIV/AIDS,
      health care pluralism, and neo-liberal macroeconomic policy have played out in
      South Africa. The identification of some of the multiple and complex forces in
      each case reveals a relatively consistent story of global pressures interacting
      with domestic realities, with some recognizably local results. There is no doubt
      that a full and nuanced understanding of health in South Africa requires an
      appreciation of developments in the global political economy, international
      organizations such as the WHO and World Bank, and forces which operate outside of
      institutions. In each case, however, the specific opportunities available to
      actors within the country, as well as the relative power of those actors, should
      be given their due consideration in analysing their potential impact on health
      matters.

PMID- 15036813
TI  - Use of deceptive tactics in physician practices: are there differences between
      international and US medical graduates?
AB  - Concerns have been raised about the medical practices of international medical
      graduates (IMGs) in the United States. This study examined the differences
      between IMGs and US-trained medical graduates (USMGs) in their attitude toward
      and utilization of deception in medical practices. A random sample of physicians
      practicing in the US was surveyed by mail in 1998. The dependent variables of
      interest included 11 attitudinal and behavioral indicators of deceptive tactics
      in medical practice. IMGs and USMGs displayed limited difference in their
      attitudes but some differences in their self-reported use of deceptive tactics in
      medical practice. IMGs were less likely than USMGs to change the patient's
      official diagnosis (OR, 0.557; 95% CI, 0.344-0.902) or to withhold a useful
      service because of utilization rules (OR, 0.612; 95% CI, 0.382-0.979). The
      hypothesis that IMGs have less appropriate professional standards than USMGs is
      not supported by this study. Alternative hypotheses, such as IMG familiarity with
      US health care and legal systems, warrant investigation.

PMID- 15036815
TI  - Equity in resource allocation in the Irish health service. A policy Delphi study.
AB  - Resource allocation in the Irish health service, based on historical allocations
      with incremental increases, is widely believed to be inequitable. Using a three
      round policy Delphi survey, which seeks to explore both consensus and
      disagreement surrounding policy issues, the views of 52 senior health service
      personnel were sought in order to determine ways to improve equity in resource
      allocation. Panelists provided several reasons why the current method of resource
      allocation is inequitable and several suggestions for improving equity. The level
      of consensus on views was determined by calculating the percentage of ratings in
      each category based on a series of rating scales. The main suggestion centred
      around the development and implementation of a needs based resource allocation
      formula. Panelists reached a high consensus in favour of this but only reached a
      low consensus as to its feasibility. Potential obstacles identified included
      methodological difficulties, insufficient resources and resistance from potential
      losers. These findings highlight concerns about the lack of transparency in the
      resource allocation process and openness to the development of a more equitable
      needs based resource allocation model, a move which is becoming more common
      internationally. Feasibility concerns should not preclude an attempt to begin
      this process.

PMID- 15036814
TI  - Prevalence of anti-HAV and anti-HEV antibodies in Konya, Turkey.
AB  - OBJECTIVE: To determine the prevalence of antibodies to hepatitis A (HAV) and E
      (HEV) viruses in the different areas of Konya. METHODS: Anti-HAV and anti-HEV
      antibodies were investigated in 210 healthy children randomly selected (100 from
      rural areas and 110 from urban areas of Konya). None gave a history of previous
      icterus nor other signs of hepatitis, had received blood transfusion and HAV
      vaccine, or had been on hemodialysis. RESULTS: Evidence of HAV infection occurred
      in children under the age of 6 years. The seroprevalence rate was 67.8% in rural
      areas and 25.8% in urban areas. This increased rapidly with age and became
      universal after 11 years of age in both areas. In contrast, HEV infections were
      not detected until children were 6-11 year olds, and the 5.2% seroprevalence rate
      in urban areas and 8.5% seroprevalence rate in rural areas in this age group did
      not significantly increase in older age group. The prevalence of anti-HAV as well
      as anti-HEV was significantly higher in children with poor socio-economic
      conditions in both areas. CONCLUSIONS: These results suggest that HAV infection
      in rural areas of Konya is widespread and that environmental and socio-economic
      factors play a major role in its transmission. In contrast, hepatitis E is not a
      public health problem in Konya.

PMID- 15036816
TI  - Financing and planning of public and private not-for-profit hospitals in the
      European Union.
AB  - While much has been written about health care financing in Europe in recent
      years, discussion has almost entirely focused on revenue. In contrast, there has
      been remarkably little written on financing of capital investment in European
      health care systems. Yet major changes are underway in several countries, in
      particular involving new forms of public-private partnerships (PPP). At the same
      time, there is growing recognition of the way in which the inherited structure of
      the health care delivery system constrains the system's ability to adapt to
      changing circumstances. This paper reports the results of a survey undertaken
      among key informants in the member states of the European Union to begin to
      ascertain existing practices and future plans in relation to hospital planning
      and financing amongst public and private not-for-profit hospitals. The locus of
      hospital planning decisions reflect the constitutional framework of the country
      involved, and thus the emphasis on national or local plans. There has been an
      expansion of private sector involvement, with four basic models identified:
      private loans direct to the hospital; private loans to a regional health body; a
      PPP where the private sector's role is to build, design and operate the non
      clinical functions of the hospital; and, finally, a PPP, where the private
      sector's involvement also includes management of the clinical functions of the
      hospital. It is too early to say whether these approaches will be more successful
      than the models they are replacing.

PMID- 15036817
TI  - Comparing systems for costing hospital treatments. The case of stable angina
      pectoris.
AB  - This paper demonstrates the basic properties in the systems most commonly
      considered for costing treatments in the Danish hospitals. The differences
      between the traditional charge system, the DRG system and the ABC system are
      analysed, and difficulties encountered in comparing these systems are discussed.
      A sample of patients diagnosed with stable angina pectoris (SAP) at Odense
      University Hospital was used to compare the three systems when costing an entire
      treatment path, costing single hospitalisations and studying the effects of
      length of stay. Furthermore, it is illustrated that the main idea behind each
      system is reflected in how the systems over- or underestimate costs. Implications
      when managing the hospitals, particularly reimbursement, are discussed.

PMID- 15036818
TI  - Inequities in access to medical care in five countries: findings from the 2001
      Commonwealth Fund International Health Policy Survey.
AB  - OBJECTIVE: To examine across five countries inequities in access to health care
      and quality of care experiences associated with income, and to determine whether
      these inequities persist after controlling for the effect of insurance coverage,
      minority and immigration status, health and other important co-factors. DESIGN:
      Multivariate analysis of a cross-sectional 2001 random survey of 1400 adults in
      five countries: Australia, Canada, New Zealand, United Kingdom, and United
      States. MAIN OUTCOME MEASURES: Access difficulties and waiting times, cost
      related access problems, and ratings of physicians and quality of care. RESULTS:
      The study finds wide and significant disparities in access and care experience
      between US adults with above and below-average incomes that persist after
      controlling for insurance coverage, race/ethnicity, immigration status, and other
      important factors. In contrast, differences in UK by income were rare. There were
      also few significant access differences by income in Australia; yet, compared to
      UK, Australians were more likely to report out of pocket costs. New Zealand and
      Canada results fell in the mid-range of the five nations, with income gaps most
      pronounced on services less well covered by national systems. In the four
      countries with universal coverage, adults with above-average income were more
      likely to have private supplemental insurance. Having private insurance in
      Australia, Canada, and New Zealand protects adults from cost-related access
      problems. In contrast, in UK having supplemental coverage makes little
      significant difference for access measures. Being uninsured in US has significant
      negative consequences for access and quality ratings. CONCLUSIONS: For policy
      leaders, the five-nation survey demonstrates that some health systems are better
      able to minimize among low income adults financial barriers to access and quality
      care. However, the reliance on private coverage to supplement public coverage in
      Australia, Canada, and New Zealand can result in access inequities even within
      health systems that provide basic health coverage for all. If private insurance
      can circumvent queues or waiting times, low income adults may also be at higher
      risks for non-financial barriers since they are less likely to have supplemental
      coverage. Furthermore, greater inequality in care experiences by income is
      associated with more divided public views of the need for system reform. This
      finding was particularly striking in Canada where an increased incidence of
      disparities by income in 2001 compared to a 1998 survey was associated with
      diverging views in 2001.

PMID- 15036819
TI  - MMR mass vaccination campaigns, vaccine-related adverse events, and the limits of
      the decision making process, in Brazil.
AB  - Vaccination is unquestionably a very important tool for disease control. However,
      vaccines can cause adverse events that may damage the public trust. In recent
      experience in Brazil, the implementation of mass campaigns with MMR (measles,
      mumps, rubella) vaccine was associated with outbreaks of vaccine adverse events.
      The decision-making process regarding the continuation of the use of this vaccine
      proceeded in the context of uncertainties, fears and contradictions between
      information from the scientific literature and data generated by a post-licensure
      monitoring. This experience showed how important is to have a critical view of
      previous recommendations and to get local data addressing questions to guide the
      decision making process.

PMID- 15036820
TI  - Changing health in China: re-evaluating the epidemiological transition model.
AB  - This paper reviews the changing health situation in China, which has shown
      remarkable improvement in the 50 years since the founding of the People's
      Republic of China (PRC) in 1949. At first sight this improving health situation
      follows the classical epidemiological transition model. Just three decades ago
      health in China was characterised by high rates of infectious disease and early
      mortality (diseases of poverty) in a mainly peasant society. More recently
      infectious disease rates have decreased, with corresponding and extended
      morbidity and mortality associated with an aging population in a rapidly
      urbanising society. This process has given rise to new health problems, including
      chronic and degenerative diseases (diseases of affluence). Nonetheless, while
      there is some validity in the application of the epidemiological transition
      concept, further analysis demonstrates that China faces a new epidemiological
      phase, characterised by increasing life expectancy and diseases of affluence
      coupled with the emergence and re-emergence of infectious diseases. We
      demonstrate that China's state policy plays a major role in defining the
      parameters of health in a Chinese context. We conclude that, today, China is
      faced with a new set of health issues, including the impact of smoking,
      hypertension, the health effects of environmental pollution and the rise of
      HIV/AIDS; however, state policy remains vital to the health of China's vast
      population. The challenge for policy is to maintain health reform whilst tackling
      the problems associated with rapid urbanisation, widening social and spatial
      inequalities and the emergence of HIV/AIDS and other infectious diseases.

PMID- 15036821
TI  - p22phox-derived superoxide mediates enhanced proliferative capacity of diabetic
      vascular smooth muscle cells.
AB  - To investigate the mechanisms that contribute to the acceleration of
      atherosclerosis in diabetes, the role of NAD(P)H oxidase in the enhanced
      proliferative capacity of diabetic vascular smooth muscle cells (VSMC) was
      studied. VSMC from streptozotocin (STZ)-induced diabetic rat aorta had increased
      proliferative capacity and generated higher levels of superoxide in comparison
      with cells from control rats. Both the enhanced proliferation and superoxide
      generation in diabetic VSMC were significantly attenuated not only by tiron
      (1mM), a superoxide scavenger but also by diphenyleneiodonium (DPI; 10microM), an
      NAD(P)H oxidase inhibitor. Both the activity of NAD(P)H oxidase and p22phox
      expression were significantly increased in diabetic VSMC. Furthermore, inhibition
      of p22phox expression by transfection of antisense p22phox oligonucleotides into
      diabetic VSMC resulted in a decrease in superoxide generation, which was
      accompanied by a significant attenuation of cell proliferation. Based on these
      results, it is suggested that diabetes-associated increase in NAD(P)H oxidase
      activity via enhanced expression of p22phox contributes to augmented VSMC
      proliferation in diabetic rats.

PMID- 15036822
TI  - Effects of a 4-week 70% high carbohydrate/15% low fat diet on glucose tolerance
      and on lipid profiles.
AB  - In order to investigate the effect of high carbohydrate/low fat diet on glucose
      tolerance and on lipid profiles, we performed a 4-week crossover study. Japanese
      subjects (30 patients with type 2 diabetes mellitus, 15 subjects with impaired
      glucose tolerance and 8 subjects with normal glucose tolerance) were allocated
      either 55% standard carbohydrate/30% fat (sc) or 70% high carbohydrate/15% low
      fat (hc) diet for four weeks, and evaluated by OGTT and various parameters. Then,
      the diet was crossed over to another diet, and identical parameters were re
      evaluated after four weeks. Area under the glucose concentration-time curve (AUG)
      or triglyceride did not show significant changes between the two diets. HDL
      Cholesterol and body mass index decreased significantly by hc diet. Free fatty
      acids and homeostasis model assessment insulin resistance index showed a tendency
      to be decreased by hc diet. AUG hc/sc ratio was inversely correlated with AUG or
      free fatty acids on standard carbohydrate diet. In conclusion, the present 4-week
      high carbohydrate/low fat diet may be useful to reduce body weight and insulin
      resistance. The 4-week high carbohydrate/low fat diet did not affect glucose
      tolerance as a whole. Although the 4-week high carbohydrate/low fat diet
      decreased HDL-Chol, it did not increase triglyceride.

PMID- 15036823
TI  - A quality-of-life assessment of intensive insulin therapy using insulin lispro
      switched from short-acting insulin and measured by an ITR-QOL questionnaire: a
      prospective comparison of multiple daily insulin injections and continuous
      subcutaneous insulin infusion.
AB  - We examined quality-of-life (QOL) of patients with a prospective comparison of
      multiple daily insulin injections therapy (16 patients in MDI group) and
      continuous subcutaneous insulin infusion therapy (12 patients in CSII group)
      using insulin lispro (LP), which was switched from short-acting insulin on the
      basis of a questionnaire about insulin-therapy-related QOL measure (ITR-QOL). The
      overall score of ITR-QOL before using LP in the CSII group was significantly
      higher (P<0.02) than the MDI group. In four subscales of ITR-QOL, the scores of
      social and daily activities and of therapy-related feelings in the CSII group
      were significantly higher (P<0.02) than those in the MDI group, respectively,
      while there was no significant difference in the score of physical function
      between the two groups. Three months after using LP, the score of daily
      activities in the MDI group was significantly higher (P<0.02) than that before
      using LP, while there were no significant differences in other scores of the two
      groups. There were no significant differences in HbA1c between two groups before
      and after using LP. The frequency of hypoglycemic events in the MDI group before
      using LP was higher than that in the CSII group and decreased after using LP.
      These results show that QOL of patients treated by CSII is superior to that
      treated by MDI and demonstrate that insulin lispro has a more beneficial effect
      on daily activities in patients treated by MDI than short-acting insulin.

PMID- 15036824
TI  - Transient elevation of liver transaminase after starting insulin therapy for
      diabetic ketosis or ketoacidosis in newly diagnosed type 1 diabetes mellitus.
AB  - A mild increase of AST and/or ALT is sometimes observed among patients with
      diabetic ketosis or diabetic ketoacidosis (DKA) after initial insulin treatment,
      and the exact mechanism is still undefined. Therefore, we compared the clinical
      background between patients with and without transient elevation of liver
      transaminase (TELT) at the onset of type 1 diabetes mellitus with diabetic
      ketosis or DKA. Among 50 patients, 13 patients showed TELT. The TELT group was
      characterized by higher plasma glucose (P<0.05), higher HbA1c (P<0.05), and
      higher triglyceride (P<0.01) before insulin therapy than those without TELT. The
      TELT group needed significantly more insulin (P<0.05) for the treatment. In echo
      histogram analysis of three patients with TELT, the increase of liver-kidney
      contrast after insulin treatment suggested fat deposition to the liver. The fat
      deposition to the liver might be one of the causes of the mild increase of AST
      and/or ALT after initial treatment of insulin in diabetic ketosis or DKA.

PMID- 15036825
TI  - Dose titration of repaglinide in patients with inadequately controlled type 2
      diabetes.
AB  - A total of 385 drug-therapy naive patients, with inadequately controlled type 2
      diabetes, were randomised into a multinational, parallel-group study to compare
      two strategies for dose titration of the oral hypoglycaemic agent repaglinide.
      Patients were allocated to either a fasting blood glucose (FBG) monitoring group
      with titration target 4.4-6.1 mmol/l or to a post-prandial blood glucose (PPBG)
      monitoring group with titration target 4.4-8.0 mmol/l. An initial titration
      period of up to 8 weeks was followed by a 12-week treatment period. Glycaemic
      control and hypoglycaemic outcomes were compared for the respective groups.
      HbA(1c) decreased significantly more in the FBG monitoring group by a mean of
      1.38% compared to the PPBG group by a mean of 1.22% (P=0.03). The glycaemic
      control targets were met by fewer patients in the FBG group than in the PPBG
      group (57% versus 86% (P<0.001)) despite a higher mean dose of repaglinide in the
      FBG group. The within-patient blood glucose variability was significantly lower
      in the FBG group than in the PPBG group (P<0.001). In conclusion, repaglinide
      lowered the HbA(1c) effectively and safely in both groups and self-monitored FBG
      is a suitable parameter for titration of repaglinide. Whether a lower PPBG target
      might be as good a guide as FBG for titration of repaglinide should be addressed
      in a future study.

PMID- 15036826
TI  - ACE gene polymorphism, left ventricular geometry, and mortality in diabetic
      patients with end-stage renal disease.
AB  - The objectives of this study were to determine the association between
      angiotensin converting enzyme (ACE) gene polymorphism and left ventricular (LV)
      geometry, and to clarify independent effects of ACE genotype on mortality after
      commencing dialysis in diabetic patients with end-stage renal disease (ESRD). A
      total of 106 diabetic patients, 71 men and 35 women, 11 type 1 and 95 type 2
      diabetic, 57 +/- 12 (mean +/- standard deviation (S.D.)) years of age, who
      started dialysis were studied. Patients with cardiac diseases and those treated
      with ACE inhibitors were excluded because of potential effects on LV performance.
      Echocardiographic examination was performed within +/-2 months of the start of
      dialysis. Relation between ACE genotype and LV mass index (LVMI) or relative wall
      thickness (RWT) at onset of dialysis, and impact of ACE genotype on survival
      after commencing dialysis were evaluated. There were no significant differences
      in LVMI or RWT in the three ACE genotype groups at onset of dialysis. However,
      mortality of patients with the ACE-DD genotype was significantly higher than
      patients with the DI and II genotypes (hazard ratio, 2.318; P=0.043), based on a
      survival analysis with a mean follow-up duration of 60 months. The higher
      mortality in patients with the DD genotype was confirmed to be independent of LV
      hypertrophy and increases in RWT. In diabetic patients with ESRD, ACE genotype
      has no association with LV mass or RWT at the start of dialysis, but does have an
      independent impact on patient survival thereafter.

PMID- 15036827
TI  - Low heart rate variability is a risk factor for sudden cardiac death in type 2
      diabetes.
AB  - The purpose of this study is to examine the association between sudden cardiac
      death (SCD) and heart rate variability (HRV) in subjects with and without type 2
      diabetes and to determine whether low HRV can predict SCD in type 2 diabetes.
      Subjects were 8917 consecutively examined persons (3089 diabetic, and 5828
      nondiabetic subjects) aged 35-69 years who underwent a 75 g oral glucose
      tolerance test (OGTT) together with electrocardiography (ECG). HRV was calculated
      from the 12-lead ECG as the coefficient of variance for 100 R-R intervals (CV(R
      R)). During a median observation period of 5.2 years, SCD occurred in 56 subjects
      (33 diabetic, and 23 nondiabetic). Among diabetic subjects, mortality from SCD
      tended to be higher in subjects with a low CV(R-R) (P=0.004). After adjustment
      for age, gender, systolic blood pressure, total cholesterol (TC), triglycerides
      (TG), BMI, ischemic ECG change, and smoking history, relative risk (RR) of SCD
      was 2.07 (95% CI 1.02-4.17) in diabetic subjects with a CV(R-R) <2.2% compared
      with those with a CV(R-R) > or =2.2%. Diabetic subjects with a CV(R-R) <2.2% had
      significantly higher cumulative mortality from SCD than those with a CV(R-R) > or
      =2.2% (P=0.007). In type 2 diabetes, a low CV(R-R) carried an increased risk of
      SCD.

PMID- 15036829
TI  - Sandostatin LAR for cystoid diabetic macular edema: a 1-year experience.
AB  - We report the clinical outcome of a 46-year-old diabetic patient with cystoid
      macular edema treated with Sandostatin long-acting release (LAR). Because cystoid
      changes in both eyes were refractive to conventional treatment (i.e., vitrectomy
      and periocular steroids), the patient was treated with Sandostatin LAR 20 mg
      every four weeks. One year later the patient maintained corrected visual acuity
      of 20/40 in the right eye and 20/100 in the left eye, the cystoid changes had
      disappeared in the right eye and had greatly decreased in the left eye. In
      addition, the intraocular pressure had declined and no other complications were
      found. Thus, Sandostatin LAR may be considered for the treatment of diabetic
      patients with cystoid macular edema.

PMID- 15036828
TI  - Components of the metabolic syndrome as predictors of cardiovascular disease and
      type 2 diabetes in middle-aged Japanese men.
AB  - To determine whether the clustered features of the metabolic syndrome precede the
      7 year incidence of cardiovascular disease (CVD) and type 2 diabetes, we examined
      6182 Japanese male office workers aged 35-59 years without any history of CVD.
      The 5588 subjects without type 2 diabetes also constituted the nondiabetic
      cohort, and were re-examined over seven successive years. Components of the
      metabolic syndrome included glycemic disorder (type 2 diabetes for the risk of
      CVD and impaired fasting glucose for the risk of type 2 diabetes), systemic
      obesity, hypertension, dyslipidemia, proteinuria, and elevated white blood cell
      (WBC) count. After controlling for age, family history of diabetes, alcohol
      intake, and cigarette smoking, the multivariate-adjusted relative risk of
      incidence of CVD compared with absence of components was 3.18, 3.48, 12.55, and
      14.15 (P for trend <0.001), for the presence of 1,2,3, and > or =4 components,
      respectively. The corresponding relative risks of incidence of type 2 diabetes
      were 1.92, 4.36, 6.44, and 15.08 (P for trend <0.001). In both non-smokers and
      current smokers, the multivariate-adjusted relative risks of incidence of CVD and
      type 2 diabetes increased as the number of components increased (P for trend
      <0.001 for all). Our findings indicate that clustered features of the metabolic
      syndrome are closely associated with development of CVD and type 2 diabetes in
      middle-aged Japanese.

PMID- 15036830
TI  - Outcomes of diabetes patients attending a hospital diabetes clinic.

PMID- 15036832
TI  - Using epidemiological information to develop effective integrated virus disease
      management strategies.
AB  - Virus diseases cause serious losses in yield and quality of cultivated plants
      worldwide. These losses and the resulting financial damage can be limited by
      controlling epidemics using measures that minimise virus infection sources or
      suppress virus spread. For each combination of virus, cultivated plant and
      production system, there is an 'economic threshold' above which the financial
      damage is sufficient to justify using such measures. However, individual measures
      used alone may bring only small benefits and they may become ineffective,
      especially over the long term. When diverse control measures that act in
      different ways are combined and used together, their effects are complementary
      resulting in far more effective overall control. Such experiences have led to the
      development of integrated management concepts for virus diseases that combine
      available host resistance, cultural, chemical and biological control measures.
      Selecting the ideal mix of measures for each pathosystem and production situation
      requires detailed knowledge of the epidemiology of the causal virus and the mode
      of action of each individual control measure so that diverse responses can be
      devised to meet the unique features of each of the different scenarios
      considered. The strategies developed must be robust and necessitate minimal extra
      expense, labour demands and disruption to standard practices. Examples of how
      epidemiological information can be used to develop effective integrated disease
      management (IDM) strategies for diverse situations are described. They involve
      circumstances where virus transmission from plant-to-plant occurs in four
      different ways: by contact, non-persistently or persistently by insect vectors,
      and by root-infecting fungi. The examples are: Subterranean clover mottle virus
      (SCMoV) (contact-transmitted) and Bean yellow mosaic virus (BYMV) (non
      persistently aphid-transmitted) in annually self-regenerating clover pasture;
      three seed-borne viruses (all non-persistently aphid-transmitted) plots of
      pasture legume improvement programmes; Tomato spotted wilt virus (TSWV)
      (persistently thrips-transmitted) in vegetables in seedling nurseries, protected
      cropping or field systems; and lettuce big-vein disease (fungus-transmitted) in
      lettuce in seedling nursery, hydroponic, infested field or uninfested field
      situations. By describing the kinds of approaches required, this article is
      intended to help future research and extension programmes devise integrated
      disease management strategies that not only function effectively to diminish the
      losses caused by economically important plant virus diseases but also fulfill the
      requirement of being environmentally and socially responsible.

PMID- 15036833
TI  - Durable virus resistance in plants through conventional approaches: a challenge.
AB  - Breeding for virus resistance is often considered the most efficient and simplest
      way to avoid the losses due to plant virus diseases. Resistance mechanisms are
      very diverse and interact with various stages of the virus cycle in the host
      plant. Resistances may also differ in their specificity, stability and
      durability. Breeding for resistance is a long and costly process, therefore to be
      cost effective it should provide durable protection. Three pathosystems are
      discussed to illustrate some of the field and laboratory approaches that can be
      used to assess resistance durability: Cucumber mosaic virus-specific resistance
      in melon, Zucchini yellow mosaic virus tolerance in zucchini squash, and extreme
      resistance to Potato virus X in potato. The possibility of predicting resistance
      durability is discussed in relation to the nature of the resistance, the genetic
      changes required for a virus to overcome the resistance and the effects of such
      changes on virus fitness.

PMID- 15036834
TI  - Pathogen-derived resistance in potato to Potato virus Y-aspects of stability and
      biosafety under field conditions.
AB  - Plants of three different potato cultivars/lines were transformed via
      Agrobacterium tumefaciens with a truncated NIb gene of a necrotic strain of
      Potato virus Y (PVY(N)) which had been C-terminally fused to enhanced blue
      fluorescing protein. Resistance of the resulting transgenic clones was evaluated
      under glass house conditions using an NTN-strain of PVY. Four clones with the
      highest levels of resistance were chosen for further experiments. Their type of
      resistance was either recovery or extreme resistance. These clones and their
      resistance types were also characterised at the molecular level. Mechanisms other
      than post-transcriptional gene silencing seemed to be involved in the resistance
      which was not dependent on sequence homology between transgene and challenging
      virus. Stability of resistance was tested under field conditions. The plants
      usually became infected with PVY. Tubers of the clone with extreme resistance did
      not recover from infection whereas those from clones with the recovery type did.
      No influence of transgenic potatoes was apparent on aphid population numbers in
      test plots. Recombination events could not be detected at the RNA level between
      transgene and challenging virus.

PMID- 15036835
TI  - Banana streak virus is very diverse in Uganda.
AB  - Banana streak virus (BSV) is a badnavirus that causes a viral leaf streak disease
      of banana and plantain (Musa spp.). Identified in essentially all Musa growing
      areas of the world, it has a deleterious effect on the productivity of infected
      plants as well as being a major constraint to Musa breeding programmes and
      germplasm dissemination. Banana is a staple food in Uganda which is, per capita,
      one of the worlds largest banana producers and consumers. BSV was isolated from
      infected plants sampled across the Ugandan Musa growing area and the isolates
      were analysed using molecular and serological techniques. These analyses showed
      that BSV is very highly variable in Uganda. They suggest that the variability is,
      in part, due to a series of introductions of banana into Uganda, each with a
      different complement of infecting viruses.

PMID- 15036836
TI  - The ecology and epidemiology of whitefly-transmitted viruses in Latin America.
AB  - Whitefly-transmitted geminiviruses are the most important constraint to the
      production of common bean and vegetable crops in the tropical lowlands and mid
      altitude valleys of Latin America. Currently, over 30 distinct species of
      geminiviruses that are transmitted by the whitefly Bemisia tabaci infect common
      bean, tomato, pepper, cucurbits and other horticultural crops. A climate
      probability model (using FloraMap) was obtained using data from 304 geo
      referenced locations where B. tabaci and geminiviruses cause significant damage.
      Clustering of the 304 points produced a simple model with two climatic variables:
      a dry season of at least 4 months each with less than 80 mm of rain and a mean
      temperature of the hottest month exceeding 21 degrees C. A modified Koeppen
      climate classification showed that 55% of the geminivirus-affected localities are
      in the tropical wet/dry region, 22% in the tropical and subtropical dry/humid
      climates and the remaining locations belonged to the wet equatorial and trade
      wind litoral climates. These findings contribute to understanding
      whitefly/geminivirus epidemics and implementation of sustainable integrated pest
      and disease management practices.

PMID- 15036837
TI  - Forecasting aphid outbreaks and epidemics of Cucumber mosaic virus in lupin crops
      in a Mediterranean-type environment.
AB  - Cucumber mosaic virus (CMV) causes a serious disease of narrow-leafed lupin
      (Lupinus angustifolius). It is seed-borne in lupin and seed-infected plants act
      as the primary virus source for secondary spread by aphid vectors within crops.
      Infection with CMV causes yield losses of up to 60% in epidemic years, but has
      little impact on yield in years when spread is limited. Aphids also cause
      sporadic yield losses due to direct feeding damage. A simulation model was
      developed to forecast aphid outbreaks and epidemics of CMV in lupin crops growing
      in the 'grainbelt' of south-west Australia, which has a Mediterranean-type
      climate. The model uses rainfall during summer and early autumn to calculate an
      index of aphid build-up on weeds, crop volunteers and self-regenerating annual
      pastures in each 'grainbelt' locality before the growing season commences in late
      autumn. The index is used to forecast the timing of aphid immigration into crops.
      The subsequent aphid build-up and movement within the crop, spread of CMV from
      virus-infected source plants within the crop, yield losses and percentage of
      harvested seed-infected are then calculated. The model evaluates the effects of
      different sowing dates, percentages of CMV infection in seed sown and plant
      population densities on virus spread. The model simulations were validated with
      14 years' field data from six different sites in the 'grainbelt', representing a
      wide range of pre-growing season rainfall scenarios, sowing dates, percentages of
      infection in seed sown and plant population densities. The model was incorporated
      into a decision support system (DSS) for use by lupin farmers and agricultural
      consultants in planning CMV management and targeting sprays against aphids to
      prevent direct feeding damage. The inputs required from the user are lupin
      cultivar, anticipated emergence date, percentage CMV infection in seed sown,
      plant density and location. The output consists of a personalised risk forecast
      for the user and includes predictions for date of first aphid arrival, aphid
      numbers, CMV spread, final virus incidence, yield loss due to infection and
      percentage infection in harvested seed. Predictions from the DSS are accessible
      via an Internet site and from other information sources. The model can serve as a
      template for modelling similar virus/aphid vector pathosystems in other regions
      of the world, especially those with Mediterranean-type climates.

PMID- 15036838
TI  - Activity of aphids associated with lettuce and broccoli in Spain and their
      efficiency as vectors of Lettuce mosaic virus.
AB  - This research sought to identify the aphid virus vector species associated with
      lettuce and broccoli crops in Spain, and to determine their population dynamics
      and ability to transmit Lettuce mosaic virus (LMV). Green tile traps and Moericke
      yellow water-pan traps were used to monitor aphid flights during the spring and
      autumn growing seasons of 2001. Aphid species feeding on lettuce were counted
      weekly. The transmission efficiencies of LMV were determined for the aphid
      species caught most frequently. The Moericke traps generally caught more aphid
      species than the tile trap, but the latter was the most suitable to estimate
      flight activity of species involved in virus spread. Spring aphid catches
      indicated that the main aphid species landing on lettuce in the regions of Madrid
      and Murcia was Hyperomyzus lactucae, but Brachycaudus helichrysi was also
      abundant in both regions. In broccoli in the Navarra region, the most abundant
      species in spring were Aphis fabae, B. helichrysi and H. lactucae. In autumn-sown
      crops, the main species landing on lettuce in the Madrid region were Hyadaphis
      coriandri and Aphis spiraecola. In Murcia, A. spiraecola and Myzus persicae were
      the most abundant, while in Navarra, Therioaphis trifolii, and various Aphis spp.
      were the most numerous landing on broccoli. The main aphid species colonising
      lettuce was Nasonovia ribisnigri, but other less abundant colonising species were
      Aulacorthum solani and Macrosiphum euphorbiae. The most efficient vectors of LMV
      were M. persicae, Aphis gossypii and M. euphorbiae, while A. fabae and H.
      lactucae transmitted with low efficiency, and Rhopalosiphum padi and N.
      ribisnigri did not transmit. Occurrence of LMV epidemics in central Spain in
      relation to aphid flights and the role of weeds as virus reservoirs is discussed.

PMID- 15036839
TI  - Carrot virus Y: symptoms, losses, incidence, epidemiology and control.
AB  - Carrot virus Y (CarVY) is a newly described potyvirus that causes a foliar and
      root disease in carrots which seriously diminishes yield and quality. It infects
      crops in most commercial carrot producing areas of Australia. Infection sometimes
      reaches very high incidences within individual crops resulting in their being
      abandoned due to unmarketability of the roots. A range of commonly grown carrot
      cultivars were all susceptible. CarVY symptoms in carrot foliage are chlorotic
      mottle, marginal necrosis or reddening and generalised chlorosis of leaves,
      increased subdivision of leaflets giving a 'feathery' appearance and plant
      stunting. Roots from plants infected early are stubby showing severe distortion
      and knobliness, while those from plants infected late are thin with little
      distortion. The known host range of CarVY is narrow and the key infection sources
      for spread by aphid vectors to newly sown crops are infected 'volunteer' carrots
      and adjacent infected carrot crops. Continuous irrigated carrot production in
      sequential plantings on the same farm all-year-round results in massive infection
      with the virus, while discontinuous production results in low incidences.
      Exposure of young carrot plants to peak aphid populations initiates early
      epidemics. Case histories showing how control measures affected CarVY incidence
      are described for one farm that deployed them compared with one that did not. An
      integrated control strategy devised for sustainable management of CarVY in carrot
      crops is described. Preliminary tests indicate that seed transmission of CarVY
      may occur at low levels in carrot, so introduction of the virus to isolated sites
      may be from inadvertent sowings of contaminated carrot seed.

PMID- 15036840
TI  - Estimation of the number of aphids carrying Citrus tristeza virus that visit
      adult citrus trees.
AB  - Aphid species were counted on citrus trees in orchards in Valencia, Spain, in the
      spring and autumn of 1997, 1998 and 1999. Moericke yellow water traps, the
      'sticky shoot' method and counts of established colonies were used in extensive
      surveys in which 29,502 aphids were recorded and identified. Aphis spiraecola and
      Aphis gossypii were the most abundant aphid species. The numbers of aphid species
      landing on mature trees of grapefruit, sweet orange, lemon and clementine and
      satsuma mandarins, were estimated by counting the numbers of young shoots/tree
      and aphids trapped on sticky shoots. The proportions of the different aphid
      species captured were: A. gossypii (53%), A. spiraecola (32%), Toxoptera aurantii
      (11%), Myzus persicae (1%), Aphis craccivora (1%) and other species (2%).
      Clementine was the most visited species with 266,700 aphids landing/tree in
      spring 2000, followed by lemon (147,000), sweet orange (129,150), grapefruit
      (103,200), and satsuma (92,400). The numbers and relative percentages of aphids
      carrying Citrus tristeza virus (CTV) were assessed by nested RT-PCR in single
      closed tubes and analysed by extraction of RNA-CTV targets from trapped aphids.
      An average of 37,190 CTV-carrying aphids visited each tree in spring 2000 (29 per
      shoot). The percentage detection of viral RNA in the aphid species that landed
      were 27% for A. gossypii, 23% for A. spiraecola and 19% for T. aurantii. This
      high incidence of aphids carrying CTV is consistent with the high prevalence and
      rapid spread of CTV in sweet orange, clementine, and satsuma mandarins in recent
      years in the region. The infection rate was proportional to the number of aphids
      landing/tree.

PMID- 15036841
TI  - The epidemiology of Wheat dwarf virus in relation to occurrence of the leafhopper
      Psammotettix alienus in Middle-Germany.
AB  - Occurrence of the leafhopper Psammotettix alienus Dahlb. and its infectivity with
      Wheat dwarf virus (WDV) were studied in cereal crops in Saxony-Anhalt (Middle
      Germany) in 2000 and 2001. The leafhoppers were collected with a sweep net and/or
      a cage trap and their WDV infectivity was determined by transmission to test
      plants. In 2000, adult leafhoppers were caught from the second week of May to the
      third week of December, whereas in 2001 they were trapped from the fourth week of
      May to the second week of December. Nymphs and adults were caught in spring in
      young actively growing crops and in summer in maturing crops and also in self
      sown cereal stands. However, only adults were found in autumn in newly sown
      crops. The peak population density of adult leafhoppers was in self-sown cereal
      plants in September when there were 25 individuals per m(2) in 2000 and 15 in
      2001. The proportion of leafhoppers that were infective with WDV when transferred
      to barley test plants ranged from 5 to 79% in 2000 and from 0 to 56% in 2001. Two
      leafhoppers collected in June 2000 in a crop of maturing winter barley each
      infected both barley and wheat plants with WDV. It is concluded that the same
      leafhoppers are able to acquire both virus strains and transmit them to cereals.

PMID- 15036842
TI  - Control strategies for sweet potato virus disease in Africa.
AB  - Sweet potato virus disease (SPVD), caused by dual infection with the whitefly
      borne Sweet potato chlorotic stunt virus (SPCSV) and the aphid-borne Sweet potato
      feathery mottle virus (SPFMV), is the most serious disease of sweet potato in
      Africa. SPVD has been known there since at least the 1940s, although it took
      several decades to elucidate its aetiology. It occurs throughout Africa and is
      particularly prevalent in the Great Lakes region. Production of sweet potato is
      largely by resource-poor farmers, growing mostly local landraces and for home
      consumption and so control strategies need to be appropriate to these
      circumstances. Most high yielding and/or early maturing landraces in Uganda are
      susceptible to SPVD and most resistant landraces are low-yielding, forcing
      farmers to compromise between the conflicting requirements of large and/or early
      yields, and food security. Accordingly, two strategies were tested to avoid the
      disadvantages associated with such compromises. These were deploying high
      yielding SPVD-resistant cultivars and phytosanitation practices to enable
      susceptible landraces to be grown successfully. In on-farm trials in Masaka and
      Rakai Districts of Uganda, some SPVD-resistant cultivars bred at Namulonge
      Agricultural and Animal Research Station (NAARI), in Wakiso District, out-yielded
      local landraces. Other trials at NAARI and at nearby farms showed that roguing
      diseased cuttings within 1 month of planting and isolation from diseased crops,
      even by as little as 15m, can considerably decrease spread of SPVD to susceptible
      cultivars. This indicates that phytosanitation can protect desirable susceptible
      cultivars, even if adopted only locally. A dual approach of deploying both
      resistant varieties and phytosanitation provides farmers with a valuable increase
      in their choice of control strategies for SPVD.

PMID- 15036843
TI  - Whitefly transmission of sweet potato viruses.
AB  - Three genera of plant viruses, Begomovirus (Geminiviridae), Crinivirus
      (Closteroviridae) and Ipomovirus (Potyviridae), contain members that infect sweet
      potato (Ipomoea batatas) and are transmitted by whiteflies. The begomoviruses,
      Sweet potato leaf curl virus (SPLCV) and Ipomoea leaf curl virus (ILCV), and the
      ipomovirus Sweet potato mild mottle virus are transmitted by Bemisia tabaci, the
      sweet potato whitefly. The crinivirus, Sweet potato chlorotic stunt virus
      (SPCSV), is transmitted by B. tabaci and Trialeurodes abutilonea, the
      bandedwinged whitefly. Transmission experiments were done with three of these
      viruses using laboratory-reared whiteflies and 2-day acquisition and transmission
      feeding periods. SPLCV and ILCV were transmitted from single and double
      infections by B. tabaci at rates of 5-10%. Transmission rates for SPLCV by B.
      tabaci were 15-20%. T. abutilonea transmitted SPCSV at a rate of ca. 3% but did
      not transmit ILCV or SPLCV.

PMID- 15036844
TI  - Methods of surveying the incidence and severity of cassava mosaic disease and
      whitefly vector populations on cassava in Africa: a review.
AB  - Field surveys in many cassava growing areas of Africa have assessed the incidence
      and severity of cassava mosaic disease (CMD), populations of the whitefly vector
      (Bemisia tabaci), and the distribution of cassava mosaic begomoviruses (CMBs).
      The methods employed differ greatly between countries and attempts at
      standardization were made in recent CMD surveys in East and Central Africa,
      notably in the systemwide Whitefly IPM Project, which provides a paradigm for
      future work on CMBs and whiteflies on cassava in Africa and also elsewhere.
      However, there is a need for greater standardization so as to assess the
      continued expansion of the current CMD pandemic in eastern Africa. Standardized
      methods will facilitate the collection of reliable data, which can be used to
      predict future disease spread, develop appropriate management strategies and
      compare disease development between seasons and locations. In this review, the
      methods used and the problems encountered during such surveys are discussed and
      recommendations made on future procedure.

PMID- 15036845
TI  - Tospovirus transmission depends on thrips ontogeny.
AB  - The acquisition of tospoviruses by thrips vectors is restricted to a well defined
      time period during the first and early second larval stages, when there is a
      temporary association between mid-gut, visceral muscles and salivary glands. This
      association is the result of a displacement of the brain into the prothoracic
      region by enlarged cibarial muscles. The subsequent loss of this association
      leads to a strong input of virus particles into the malpighian tubules via the
      haemocoel. Mechanical transmission through excrement and oviposition by adults is
      a possible alternative mode of virus transmission that requires investigation.

PMID- 15036846
TI  - Clinical implementation of dynamic and step-and-shoot IMRT to treat prostate
      cancer with high risk of pelvic lymph node involvement.
AB  - BACKGROUND AND PURPOSE: Two systems have been developed for treating patients
      with locally advanced prostate cancer using intensity-modulated radiotherapy
      (IMRT): one using dynamic multi-leaf collimator delivery and the other using step
      and-shoot. This paper describes the clinical implementation of these two
      techniques, and presents results from the first 14 patients treated in a clinical
      setting (nine dynamic, five step-and-shoot). PATIENTS AND METHODS: Dynamic
      treatments were planned using Corvus, and step-and-shoot using Helax-TMS; all
      were delivered using Elekta accelerators. Prior to the first clinical treatments,
      validation measurements were carried out for each system, including measurements
      for a complete IMRT treatment. The reproducibility of dynamic delivery and the
      characteristics of the accelerator for low-monitor-unit (MU) deliveries were also
      assessed. An extensive quality assurance (QA) program was performed for each of
      the patients. Additionally, timing measurements were carried out to assess the
      practicalities of the technique. RESULTS: The planning objectives were met in
      most cases. Absolute doses for complete IMRT treatments were within 2%, on
      average, with dose distributions generally showing agreement within 3% or 3 mm.
      Beam modulation measurements made throughout each patient's treatment indicated
      that both delivery methods were reproducible. The dynamic plans required an
      average of 765 MU per beam, with a treatment delivery time of 14 min;
      corresponding results for step-and-shoot plans were 105 MU and 10 min.
      CONCLUSIONS: Two IMRT techniques for this group of patients have been
      successfully implemented in the clinic. The more complex dynamic treatments
      showed no advantages over the step-and-shoot approach. QA results have shown
      accurate and reproducible delivery for both techniques, giving increased
      confidence in the techniques and allowing a reduction in the QA program.

PMID- 15036847
TI  - On the use of margins for geometrical uncertainties around the rectum in
      radiotherapy planning.
AB  - BACKGROUND AND PURPOSE: To derive planning organ at risk volume (PRV) margins for
      the rectum and to analyse the impact of such margins on rectum dose volume
      histograms (DVHs). PATIENTS AND METHODS: Weekly repeat computer tomography (CT)
      scans of 19 bladder cancer patients acquired during a conformal radiotherapy
      course were registered with the corresponding planning CT scans. From these
      scans, the internal rectal motion was quantified, and the margins that had to be
      added to the rectum contour in the planning scan to encompass the observed span
      of rectum motion were determined. These margins were compared to the margins
      derived using a recent PRV margin recipe. To illustrate the impact of margins on
      rectum DVHs, the margins were applied in treatment plans of six prostate cancer
      patients. RESULTS: Altogether 141 CT scans were analysed. On average 24% of the
      repeat scan rectum volume was displaced outside the planning scan contours, and
      wall movements of up to 30 mm were observed. Margins of 16 mm anterior and 11 mm
      posterior encompassed all rectal motion except for the two most displaced rectum
      walls in each of these directions, in 89% of the patients. Using a recently
      published statistics-based recipe, margins of 6 mm anterior and 5 mm posterior
      accounted for the systematic rectum variation, i.e. the average wall position, in
      90% of the patients. Adding anterior margin only caused consistent increases (up
      to 20%) in the fraction of the volume inside the high-dose region (40-70 Gy)
      compared to the DVH of rectum only. When using both anterior and posterior
      margins only small shifts (<5%) in the volume fractions were observed.
      CONCLUSIONS: Rectum PRV margins of 5-6 mm will encompass the systematic component
      of rectum motion, while margins up to 16 mm are required to also account for most
      of the random variation. Use of anterior margins only caused large shifts in the
      DVHs in the clinically significant dose range, while only minor shifts were seen
      when using both anterior and posterior margins.

PMID- 15036848
TI  - Quantification of local rectal wall displacements by virtual rectum unfolding.
AB  - BACKGROUND AND PURPOSE: To develop a method to project surface elements of a bent
      tubular organ, e.g. the rectum, in order to create a two-dimensional (2D) map and
      to use this method to quantify on a local scale shape and position variations of
      the rectum. PATIENTS AND METHODS: For this study we used data of 19 patients, who
      each received a planning CT scan and 9-13 repeat CT scans that were considered
      representative for the radiotherapy course. We combined maps from multiple CT
      scans of the same patient to quantify local rectal wall displacements. To make a
      map we first computed a central axis through the rectum and divided it into
      segments of equal length assuming that the length of these segments was invariant
      under rectum shape and position changes. Next, we constructed for each segment a
      planar cross section through the rectum, which was oriented orthogonally to that
      segment. The amount of rectal wall tissue was assumed to be constant in all
      orthogonal cross sections throughout the entire rectum. We unfolded the cross
      sected rectal wall at the dorsal side and projected either the associated dose or
      the coordinates onto the map. RESULTS: The largest variation in the position of
      the rectal wall during the treatment course occurred at the upper anterior, left
      and right side (1 SD=5-7 mm). Near the anus the variation was <3 mm (1 SD) and at
      the posterior side of the rectum <4 mm (1 SD). The anterior-posterior (AP) and
      left-right displacements between the rectum in the planning CT scan and the mean
      rectum shape during the treatment were localized between 40 and 80% of the
      central axis. At the upper anterior, left, and right side the displacements were
      5-8 mm (1 SD). These rectal wall displacements correlated with the rectum volume
      in the planning CT scan. At the upper anterior side the correlation coefficient
      between the AP displacements and the planning rectum volume was 0.85.
      CONCLUSIONS: We quantified variations in rectum shape and in dose in the rectal
      wall. The systematic error in rectal wall position was found to be larger than
      the random shape and position variations. We successfully developed a method to
      virtually unfold a rectum and to project the dose onto a 2D map. The spatial
      information of the dose distribution can be used in the analysis of rectum
      complications.

PMID- 15036849
TI  - Stereotactic boost irradiation for targets in the abdomen and pelvis.
AB  - Based on the experience of stereotactic irradiation of lung and liver tumors the
      feasibility of stereotactic boost irradiation to abdominal and pelvic tumors was
      evaluated. Twenty-one patients with inoperable tumors received a stereotactic
      boost of 2-3 x 5Gy/PTV-enclosing-100% isodose with normalization to 150% at the
      isocenter after normofractionated irradiation of 45-50.4Gy. Actuarial local
      control (16/21 targets) was 96/70% after 12 and 24 months. Treatment was feasible
      and well tolerated.

PMID- 15036850
TI  - A randomized trial of supine vs. prone positioning in patients undergoing
      escalated dose conformal radiotherapy for prostate cancer.
AB  - BACKGROUND AND PURPOSE: The optimal treatment position for patients receiving
      radical radiation therapy for prostate cancer has been a source of controversy.
      To resolve this issue, we conducted a randomized trial to evaluate the effects of
      supine and prone positioning on organ motion, positioning errors, and dose to
      critical organs during escalated dose conformal irradiation for localized
      prostate cancer and patient and therapist satisfaction with setup technique.
      PATIENTS AND METHODS: Twenty eight patients were randomized to commence treatment
      immobilized in the supine or prone position and were subsequently changed to the
      alternate positioning for the latter half of their treatment. Patients underwent
      CT simulation and conformal radiotherapy planning and treatment in both
      positions. The clinical target volume encompassed the prostate gland. Alternate
      day lateral port films were compared to corresponding simulator radiographs to
      measure the isocentre positioning errors (IPE). Prostate motion (PM) and total
      positioning error (TPE) were measured from the same films by the displacements of
      three implanted fiducial markers. Dose volume histograms (DVHs) for the two
      treatment positions were compared at the 95, 80 and 50% dose (D%) levels. The
      patients and radiation therapists completed weekly questionnaires regarding
      patient comfort and ease of setup. RESULTS: Seven patients, who started in the
      supine position, subsequently refused prone position and received their whole
      treatment supine. Small bowel in the treatment volume, not present in the supine
      position, prevented one patient from being treated prone. PM in anterior
      posterior direction was statistically significantly less in the supine position
      (P<0.05). There was no significant difference in superior inferior PM for the two
      treatment positions. No statistically significant difference between supine and
      prone positioning was observed in isocentre positioning error (IPE) or total
      positioning error (TPE) due to a policy of daily pre-treatment correction.
      However, more pre-treatment corrections were required for patients in the prone
      position. The DVH analysis demonstrated larger volumes of the bladder wall,
      rectal wall and small bowel within the D95, D80 and D50% when comparing the
      planning target volumes (PTVs) actually treated for prone positioning. When the
      prone PTV was expanded to account for the greater PM encountered in that
      position, a statistically significant difference (P<0.007) was observed in favour
      of the supine position at all dose levels. In the prone position, four patients
      had small bowel within the 60 Gray (Gy) isodose and in the supine position, no
      patients had small bowel in the 60 or 38Gy volumes. Supine position was
      significantly more comfortable for the patients and setup was significantly
      easier for the radiation therapists. The median patient comfort score was 0.79
      (Standard deviation (SD) 0.03) supine and 0.45 (SD 0.05) prone (P<0.001) The
      therapist convenience of setup was 0.80 (SD 0.016) supine and 0.54 (SD 0.025)
      prone (P<0.005). No statistically significant difference was seen for the other
      parameters studied. CONCLUSIONS: We demonstrated significantly less PM in the
      supine treatment position. There was no difference for either treatment position
      in IPE or TPE, however, more pre-treatment corrections were required in the prone
      position. Prone position required a larger PTV with resulting increased dose to
      critical organs. There were statistically significant improvements at all dose
      levels for small bowel, rectal wall and bladder wall doses in the supine position
      once corrections were made for differences in organ motion. Linear analogue
      scores of patient comfort and radiation therapist convenience demonstrated
      statistically significant improvement in favour of the supine position. Supine
      positioning has been adopted as the standard for conformal prostatic irradiation
      at our centre.

PMID- 15036851
TI  - Measurement of beam-axis displacement from the isocenter during three-dimensional
      conformal radiosurgery with a micro-multileaf collimator.
AB  - We describe the displacement of the beam-axis from the planning isocenter in
      clinical situations during three-dimensional conformal radiosurgery using an
      Acculeaf bi-directional micro-multileaf collimator. The displacements were
      recorded for 64 ports using a video imaging system and a stereotactic arc. The
      mean displacement was 0.41+/-0.25 mm.

PMID- 15036852
TI  - Effect of tertiary multileaf collimator (MLC) on foetal dose during three
      dimensional conformal radiation therapy (3DCRT) of a brain tumour during
      pregnancy.
AB  - BACKGROUND AND PURPOSE: The aim of this work was to measure the dose to foetus
      both in vivo and in vitro during three-dimensional conformal radiation therapy
      (3DCRT) in a pregnant patient with a pituitary adenoma. The study was then
      extended to assess the components contributing to the foetal dose such as
      collimator scatter, internal scatter, head leakage, wedge scatter and multileaf
      collimator (MLC) effect. PATIENTS AND METHODS: A 30-year-old pregnant woman with
      a non-functioning pituitary macroadenoma was planned for 3DCRT with 6MV X-ray
      using four equally weighted MLC-shaped non-coplanar wedged portals. In vivo
      dosimetry was carried out using thermoluminescent (TL) phosphor powder, which was
      placed at different positions on the patient, corresponding to different
      locations in the uterus and also at external os. In vitro measurements were also
      performed on a simulated phantom using the same set-up parameters and beam
      arrangement to verify the in vivo measured dose. Experiments were carried out to
      measure the respective contributions of different components towards peripheral
      dose. RESULTS: In vitro measured dose to foetus was found to be slightly more
      than that of in vivo measurement with a maximum of 0.044% of the prescribed dose
      of 45Gy, which corresponded to 0.0199+/-0.0008Gy. Thermoluminescence dosimeter
      (TLD) kept at the external os of the patient showed a dose of 0.031% of the
      prescribed dose. Among the various components of the peripheral dose (foetal
      dose) measured, head leakage was found to be the leading cause contributing 52%,
      followed by wedge scatter (31%), collimator scatter (14%) and internal scatter
      (13%). The use of MLC reduced not only the volume of normal brain irradiation as
      compared to open fields but also the peripheral dose by 10%. CONCLUSION:
      Radiotherapy of brain tumours during pregnancy poses a unique clinical situation
      and decisions to deliver radiotherapy should be taken after detailed in vitro and
      in vivo dosimetric measurements. Our findings suggest that the beam arrangement
      using 3-4-fields generally used for 3DCRT of brain tumour with MLC for optimal
      coverage can be employed for pregnant patients even in early trimester. A
      possible increase in foetal dose from wedges to a large extent can be compensated
      with the use of MLC.

PMID- 15036853
TI  - Role of 2'-2' difluorodeoxycytidine (gemcitabine)-induced cell cycle
      dysregulation in radio-enhancement of human head and neck squamous cell
      carcinomas.
AB  - BACKGROUND AND PURPOSE: To try to get a better insight on the interaction between
      dFdC and ionizing radiation at the cellular level, we examined in vitro the
      effect of dFdC on the cell cycle of two human head and neck squamous cell
      carcinoma cell lines (SQD9 and SCC61). PATIENTS AND METHODS: Experimental
      conditions yielding radio-enhancement were used. Confluent cells were incubated
      with dFdC (5 microM) for different incubation times, washed, pulse-labeled with
      BrdUrd (10 microM), fixed and then processed for flow cytometry analysis.
      Alternatively, cells preincubated or not with dFdC were irradiated (5Gy) in drug
      free medium, incubated at 37 degrees C for various times and then processed for
      flow cytometry analysis. RESULTS: In both cell lines, dFdC incubated between 1
      and 6 h induced a DNA synthesis inhibition with accumulation of cells in the G1-S
      boundary followed, when DNA reinitiated, by a synchronous progression of cells
      throughout the cycle. A slightly different kinetics was observed in the two cell
      lines. A weak correlation between dFdC radio-enhancement and distribution of
      cells in the cell cycle was observed. It was also observed that for longer dFdC
      incubation times, DNA synthesis could reinitiate while cells were still incubated
      with dFdC. This reinitiation could be correlated with a decrease in the
      intracellular dFdCTP pool to non-inhibitory levels. Finally in both cell lines,
      dFdC modified neither the importance nor the kinetics of the radiation-induced G1
      delay. CONCLUSIONS: This study provides evidence that gemcitabine used at radio
      enhancing concentration induces alteration of cell kinetics and cell
      redistribution throughout the cell cycle. This effect is cell line-dependent.
      However, the weak correlation between dFdC radio-enhancement and cell cycle
      distribution suggests that the cell cycle effect does not constitute the most
      important mechanism of interaction with ionizing radiation. Our study also
      indicated that in the two cell lines studied, a modulation of the G1-S checkpoint
      was not implicated in enhancement of radiation response by dFdC.

PMID- 15036855
TI  - Intraoperative HDR brachytherapy for rectal cancer using a flexible
      intraoperative template: standard plans versus individual planning.
AB  - HDR intraoperative brachytherapy (IOBT) is applied to locally advanced rectal
      tumors using a 5 mm thick flexible intraoperative template (FIT). To reduce the
      procedure time, treatment planning is performed using standard plans that neglect
      the curvature of the FIT. We have calculated the individual treatment plan, based
      on the real geometry of the FIT, and the dose at clips placed during surgery. A
      mean treatment dose of 9.55+/-0.21 Gy was found for the individual plan, compared
      to the prescribed 10 Gy (P<0.0001) The mean central dose was 10.03+/-0.10 Gy in
      the standard plan and 9.20+/-0.32 Gy in the individual plan (P<0.0001) The mean
      dose at the corners of the FIT was 10.3 Gy in the standard plan and ranged
      between 10.3 and 10.5 Gy in the individual plan. In 63% of the clips, the dose
      was larger than 15.0 Gy, which is equivalent to a gap between the FIT and the
      target smaller than 5 mm. In 18% of the clips, the dose was smaller than 13.0 Gy
      indicating that locally the gap was larger than 5 mm. Clinical practice will have
      to prove if these small dose deviations influence the clinical outcome.

PMID- 15036856
TI  - Multi-channel intracavitary vaginal brachytherapy using three-dimensional
      optimization of source geometry.
AB  - BACKGROUND AND PURPOSE: A new multi-channel vaginal cylinder has been
      constructed. The dose distribution is compared to that of a central channel
      cylinder. PATIENTS AND METHODS: The source channels of the multi-channel cylinder
      are placed close to the treatment volume, which means that the dose gradient in
      the radial direction is steep. Therefore the dose is enhanced close to the
      cylinder surface and lowered at larger distances as compared to the central
      channel cylinder. Three patients were each CT-scanned twice with a vaginal
      cylinder in situ. CT-based 3D dose-planning studies were used to calculate the
      dose distribution. Dose-volume histograms (DVHs) were generated for rectum and
      bladder, and a quantification of high dose volumes was calculated from the DVHs.
      Dose to the vaginal mucosa was calculated. RESULTS: The dose to the critical
      organs depends on the depth of normalization. When the dose is normalized on the
      cylinder surface the hot spot dose to bladder and rectum is reduced by 16 and
      17%, respectively, whereas mucosal dose remains the same. When the dose is
      normalized at 5 mm depth the hot spot dose to bladder and rectum is reduced by 1
      and 3%, respectively, whereas mucosal dose is enhanced by 17%. CONCLUSIONS: The
      multi-channel cylinder makes it possible to spare the rectum and the bladder at
      the expense of enhanced mucosal dose.

PMID- 15036854
TI  - Compensation for changes in dose-rate in radical low-dose-rate brachytherapy: a
      radiobiological analysis of a randomised clinical trial.
AB  - BACKGROUND AND PURPOSE: This study reanalysed the results of the Cs-137 low-dose
      rate brachytherapy trials for stage I and II cervix carcinoma at the Christie
      Hospital, Manchester, UK, in order to quantify the clinical outcome as a function
      of dose, and to extract radiobiological parameter values by modelling the data
      for local control and morbidity. PATIENTS AND METHODS: Kaplan-Meier survival
      curves and Cox regression analyses were used to analyse the time to event data.
      Linear-quadratic (LQ) analysis was also used in a mixture model, incorporating a
      half-time for repair, a time factor, and a heterogeneity function between
      patients. Full 5-year follow-up data were available for 339 patients receiving Cs
      137 doses between 60 and 75 Gy delivered at 1.4-1.8 Gy/h, and 178 patients
      receiving a Ra-226 dose of 75 Gy at 0.5 Gy/h, using two insertions 7-10 days
      apart. RESULTS: With the increased dose-rate, a dose reduction between 20 and 25%
      was required to achieve a similar morbidity rate. This reduction had a
      detrimental effect on tumour control, by about 15% points. Unexpectedly, this
      loss in local control did not lead to a decrease in cancer-specific survival. For
      both tumour control and complications a high alpha/beta and short half-time for
      repair best fitted the data, suggesting that consequential late reactions may be
      responsible for much of the bowel and urinary morbidity after these short
      treatments. The variability in response between patients was greater (CV 40%) for
      morbidity than for tumour control (CV 17%), probably reflecting the greater
      variation in dose at the target tissue. There was no significant dependence on
      overall treatment time detected over the 7-10-day range of these treatments.
      CONCLUSIONS: The therapeutic ratio was somewhat less for the higher dose-rate, in
      agreement with radiobiological expectations, although cancer-specific survival
      was inexplicably unchanged. The LQ-parameter analysis suggests that high
      alpha/beta ratios and/or short repair half-times are applicable for both tumour
      and normal tissue responses in these treatments.

PMID- 15036857
TI  - Cranial nerve palsies in metastatic prostate cancer--results of base of skull
      radiotherapy.
AB  - We studied the rate of response to palliative external beam radiation therapy (20
      Gy/5 or 30 Gy/10 fractions) to the base of skull in 32 prostate cancer patients
      with cranial nerve dysfunction. Sixteen patients (50%; 95% CI, 34-66%) had a
      useful response to therapy. The median survival post-therapy was 3 months.

PMID- 15036858
TI  - Differentiation-associated staining with anti-pimonidazole antibodies in head and
      neck tumors.
AB  - BACKGROUND AND PURPOSE: Hypoxia is a strong negative prognostic factor for all
      three major treatment modalities for cancer. The bioreductive drug pimonidazole
      is currently under clinical investigation as a hypoxia marker. In human head and
      neck tumors, in addition to staining patterns typical of chronic hypoxia,
      staining was seen specifically around areas of keratinization, raising the
      question of whether this is hypoxia-related. This could influence quantitative
      hypoxia estimates using this marker. We investigated here whether the
      differentiation-related staining was caused by locally high reductive enzyme
      levels. PATIENTS AND METHODS: The nitrotetrazolium compound NBT was used, which
      is reduced by nitroreductases to yield a blue color. The assay was validated on
      three genetically related MDA231 human mammary carcinoma cell lines: wildtype,
      overexpressing DT-diaphorase (DT1), and overexpressing cytochrome p450 reductase
      (R4). Increased NBT staining under normoxia was indeed seen for both R4 and DT1
      lines. Pimonidazole staining under normoxia was only seen in the R4 line.
      RESULTS: Frozen tumor sections from 20 patients with head and neck cancer
      injected with pimonidazole were incubated with NBT. Parallel sections were
      stained for pimonidazole. Staining patterns were then compared on matched images,
      and areas of keratinization scored for the presence or absence of pimonidazole
      and NBT. Pimonidazole staining was seen in 56% of keratinized areas, and of
      these, 78% showed increased NBT staining, indicating that high reductase levels
      are not a necessary requirement for differentiation-associated pimonidazole
      staining. In a second series, frozen sections of tumors from 15 patients not
      receiving pimonidazole were incubated with NBT and compared with staining after
      incubation with pimonidazole under both oxic and hypoxic conditions. Pimonidazole
      staining of some keratinizing areas under oxic conditions was seen. Of these
      areas, only a proportion (70%) showed increased NBT staining, confirming the lack
      of correspondence between keratin-associated pimonidazole staining and reductase
      levels. CONCLUSION: Hypoxia-independent pimonidazole staining can occur in more
      differentiated head and neck tumors, necessitating caution in hypoxia
      quantification. These data argue against a causative role for locally high
      reductase levels in differentiation-associated staining. DT-diaphorase appears to
      play no role in pimonidazole reduction.

PMID- 15036859
TI  - Survey on the prophylactic as well as symptomatic treatment of intervention sites
      of malignant pleural mesothelioma in the Netherlands and Belgium.

PMID- 15036860
TI  - Protein-protein docking: is the glass half-full or half-empty?
AB  - Are current docking methods capable of building complexes from putative component
      protein structures? Results of recent computational studies, including those of
      the CAPRI (Critical Assessment of Protein Interactions) competition, were used to
      determine the key properties for successful docking and introduce a
      classification of protein complexes based on docking difficulty. Enzyme-inhibitor
      complexes could be determined with reasonable accuracy - possibly to within a few
      alternative structures. Results for antigen-antibody pairs are less predictable,
      and data for small signaling complexes are generally poor. However, moderate
      amounts of experimental data can remove uncertainty and the methodology is
      rapidly improving. Transient complexes with large interface areas undergo
      substantial conformational change and are beyond the reach of current docking
      methods. The docking of such complexes might therefore require fundamentally new
      approaches.

PMID- 15036861
TI  - Protein nanocrystallography: a new approach to structural proteomics.
AB  - This article describes a new approach to structural proteomics that can produce
      and characterize diffracting, stable and radiation-resistant crystals of
      miniscule dimensions using nanotechnology. We believe that the protein
      microcrystals obtained by nanotechnology-based protein thin-film template
      crystallization, as well as groundbreaking technology, such as atomic force
      microscopy, nanogravimetry and synchrotron microfocus, have enabled protein
      nanocrystallography to be defined as a unique technology capable of forming and
      characterizing stable protein microcrystals down to atomic resolution. A new
      route from art to science and technology has, therefore, been opened in protein
      crystallography, and it could be used to unravel the mysteries of many systems
      that remain unsolved.

PMID- 15036862
TI  - Fungal epoxide hydrolases: new landmarks in sequence-activity space.
AB  - Epoxide hydrolases are useful catalysts for the hydrolytic kinetic resolution of
      epoxides, which are sought after intermediates for the synthesis of enantiopure
      fine chemicals. The epoxide hydrolases from Aspergillus niger and from the
      basidiomycetous yeasts Rhodotorula glutinis and Rhodosporidium toruloides have
      demonstrated potential as versatile, user friendly biocatalysts for organic
      synthesis. A recombinant A. niger epoxide hydrolase, produced by an overproducing
      A. niger strain, is already commercially available and recombinant yeast epoxide
      hydrolases expressed in Escherichia coli have shown excellent results. Within the
      vast body of activity information on the one hand and gene sequence information
      on the other hand, the epoxide hydrolases from the Rhodotorula spp. and A. niger
      stand out because we have sequence information as well as activity information
      for both the wild-type and recombinant forms of these enzymes.

PMID- 15036863
TI  - Chemoenzymatic dynamic kinetic resolution.
AB  - During the past decade a new concept has appeared in asymmetric catalysis
      involving the combination of a biocatalyst and a chemocatalyst in one 'pot'
      leading to efficient deracemization via dynamic kinetic resolution (DKR). Here,
      we outline the different strategies that have been developed for efficient
      chemoenzymatic DKR, in particular the powerful combination of an enzyme and a
      metal catalyst.

PMID- 15036864
TI  - The immunogenicity of human embryonic stem-derived cells.
AB  - Human embryonic stem cells have excellent potential for being the ultimate source
      of transplantable cells for many different tissues. To enable their clinical use,
      differentiation protocols should be developed and safety standards must be met.
      The cells should improve symptoms without generating side effects and their
      immune rejection must be overcome. Profiling of the immune antigens expressed on
      the cells has revealed that upon differentiation the cells express molecules of
      the major histocompatibility complex. Here, we propose ways of overcoming the
      rejection of human embryonic stem cells after transplantation.

PMID- 15036865
TI  - Potential applications of microbial surfactants in biomedical sciences.
AB  - The main commercial use of biosurfactants is in pollution remediation because of
      their ability to stabilize emulsions. This enhances the solubility and
      availability of hydrophobic pollutants, thus increasing their potential for
      biodegradation. One useful property of many biosurfactants that has not been
      reviewed extensively is their antimicrobial activity. Several biosurfactants have
      strong antibacterial, antifungal and antiviral activity. Other medically relevant
      uses of biosurfactants include their role as anti-adhesive agents to pathogens,
      making them useful for treating many diseases and as therapeutic and probiotic
      agents. Here, we discuss some of the new and exciting applications and related
      developments of various microbial surfactants in the field of biomedical
      sciences.

PMID- 15036866
TI  - Potato glycoalkaloids: true safety or false sense of security?
AB  - As one of the major agricultural crops, the cultivated potato is consumed each
      day by millions of people from diverse cultural backgrounds. A product of global
      importance, the potato tuber contains toxic glycoalkaloids (GAs) that cause
      sporadic outbreaks of poisoning in humans, as well as many livestock deaths. This
      article will discuss some aspects of the potato GAs, including their toxic
      effects and risk factors, methods of detection of GAs and biotechnological
      aspects of potato breeding. An attempt has been made to answer a question of
      vital importance - are potato GAs dangerous to humans and animals and, if so, to
      what extent?

PMID- 15036867
TI  - Cloning and characterization of metallothionein gene in ayu Plecoglossus
      altivelis.
AB  - Metallothionein (MT) has been used widely as a potential molecular marker to
      detect the deleterious effects of heavy metals in aquatic ecosystem. Here we
      exposed ayu, Plecoglossus altivelis, to zinc (Zn) and tested the distribution as
      well as the induction of MT in various tissues such as liver, kidney, intestine
      and stomach. MT induction was significant in liver tissue, followed by kidney and
      intestine, whereas no induction was detected in stomach. The gene encoding ayu MT
      was successfully cloned and characterized. Complete nucleotide sequencing and
      analysis of the 4.5 kb DNA fragment containing the ayu MT gene revealed that the
      gene has three exons interrupted by two introns, a 5'-flanking region of about
      2.5 kb and about 1.6 kb of 3'-flanking region. In grouper heart and kidney cells,
      the 2.5 kb promoter containing eight metal responsive elements (MREs), two
      hepatic nuclear factor 5 responsive elements (HNF5REs) and one cAMP responsive
      element (CRE) had the highest reporter activity.

PMID- 15036868
TI  - Role of B-esterases in assessing toxicity of organophosphorus (chlorpyrifos,
      malathion) and carbamate (carbofuran) pesticides to Daphnia magna.
AB  - In this study, the cladoceran Daphnia magna was exposed to two model
      organophosphorous and one carbamate pesticides including malathion, chlorpyrifos
      and carbofuran to assess acetylcholinesterase (AChE) and carboxylesterase (CbE)
      inhibition and recovery patterns and relate those responses with individual level
      effects. Our results revealed differences in enzyme inhibition and recovery
      patterns among the studied esterase enzymes and pesticides. CbE was more
      sensitive to organophosphorous than AChE, whereas both CbE and AChE showed
      equivalent sensitivities to the carbamate carbofuran. Recovery patterns of AChE
      and CbE activities following exposure to the studied pesticides were similar with
      80-100% recoveries taking place 12 and 96 h after exposure to organophosphorous
      and carbamates pesticides, respectively. The physiological role of AChE and CbE
      inhibition patterns in Daphnia was examined by using organophosphorous and
      carbamate compounds alone and with specific inhibitors of CbE. Under exposure to
      organophosphorous pesticides, survival of Daphnia juveniles was impaired at AChE
      inhibition levels higher than 50% whereas under exposure to the carbamate
      carbofuran low levels of AChE inhibition affected mortality. Inhibition of CbE by
      80-90% increased toxicity to organophosphorous and carbamate pesticides by up to
      two- and four-fold, respectively. Our results suggest that both AChE and CbE
      enzymes are involved in determining toxicity of Daphnia to the studied chemicals
      and that AChE inhibition levels higher than 50% can be considered of
      environmental concern to Daphnia species.

PMID- 15036869
TI  - Hydrophytes lack potential to exhibit cadmium stress induced enhancement in lipid
      peroxidation and accumulation of proline.
AB  - Investigations were carried out to evaluate if hydrophytes (viz. Ceratophyllum,
      Wolffia, and Hydrilla) can be used as markers to assess the level of heavy metal
      pollution in aquatic bodies. The potential of these hydrophytes for lipid
      peroxidation and accumulation of proline in response to cadmium (Cd2+) pollution
      was studied. Hydrophytes were raised in artificial pond water (APW) supplemented
      with various levels of Cd2+. Interestingly, unlike mesophytes none of the
      hydrophytes showed ability to accumulate proline. Infact, in response to Cd2+
      pollution hydrophytes exhibited a decline in proline levels in comparison to
      controls but mesophytes (viz. Brassica juncea, Vigna radiata and Triticum
      aestivum) showed progressive increase in the level of proline with increase in
      the extent of Cd2+ pollution. Mesophytes showed six to nine-fold increase in the
      level of proline in response to 1 mM Cd2+. The potential of the above hydrophytes
      for lipid peroxidation was also low under Cd2+ stress. In contrast, as expected a
      significant enhancement in the lipid peroxidation was observed in all three
      mesophytes in response to their exposure to Cd2+. About two-fold increase in
      production of malondialdehyde (a cytotoxic product of lipid peroxidation) was
      recorded in mesophytes exposed to 1 mM Cd2+. However, a decline in chlorophyll
      (Chl a and Chl b) levels was recorded in response to Cd2+pollution both in
      hydrophytes as well as mesophytes. In summary, hydrophytes neither have potential
      to accumulate proline nor have ability to accelerate lipid peroxidation under
      heavy metal stress. This suggests that the adaptive mechanism(s) existing in
      hydrophytes to tackle heavy metal stress is distinct from that in mesophytes.

PMID- 15036870
TI  - Roles of uptake, biotransformation, and target site sensitivity in determining
      the differential toxicity of chlorpyrifos to second to fourth instar Chironomous
      riparius (Meigen).
AB  - Early life stages of aquatic organisms tend to be more sensitive to various
      chemical contaminants than later life stages. This research attempted to identify
      the key biological factors that determined sensitivity differences among life
      stages of the aquatic insect Chironomous riparius. Specifically, second to fourth
      instar larvae were exposed in vivo to both low and high waterborne concentrations
      of chlorpyrifos to examine differences in accumulation rates, chlorpyrifos
      biotransformation, and overall sensitivity among instars. In vitro
      acetylcholinesterase (AChE) assays were performed with chlorpyrifos and the
      metabolite, chlorpyrifos-oxon, to investigate potential target site sensitivity
      differences among instars. Earlier instars accumulated chlorpyrifos more rapidly
      than later instars. There were no major differences among instars in the
      biotransformation rates of chlorpyrifos to the more polar metabolites,
      chlorpyrifos-oxon, and chlorpyridinol (TCP). Homogenate AChE activities from
      second to fourth instar larvae were refractory to chlorpyrifos, even at high
      concentrations. In contrast, homogenate AChE activities were responsive in a dose
      dependent manner to chlorpyrifos-oxon. In general, it appeared that chlorpyrifos
      sensitivity differences among second to fourth instar C. riparius were largely
      determined by differences in uptake rates. In terms of AChE depression, fourth
      instar homogenates were more sensitive to chlorpyrifos and chlorpyrifos-oxon than
      earlier instars. However, basal AChE activity in fourth instar larvae was
      significantly higher than basal AChE activity in second to third instar larvae,
      which could potentially offset the apparent increased sensitivity to the oxon.

PMID- 15036871
TI  - Morphological abnormalities and sensorimotor deficits in larval fish exposed to
      dissolved saxitoxin.
AB  - The dietary uptake of one suite of dinoflagellate-produced neurotoxins, that are
      commonly called paralytic shellfish poisoning (PSP) toxins, is known to cause
      acute fish kills. However, little is known about the effects of dissolved phase
      exposure and the potential sublethal effects of this route of exposure on early
      developmental stages of fish. Toxin exposure during early development is of
      particular concern because the embryos and larvae of some marine fish species may
      be unable to actively avoid the dissolved toxins that algal cells release into
      the water column during harmful algal blooms. Here we use the zebrafish (Danio
      rerio) as a model experimental system to explore the sublethal effects of a
      dissolved PSP toxin, saxitoxin (STX), on early development in fish, including
      sensorimotor function, morphology, and long-term growth and survival. Aqueous
      phase exposures of 229 +/- 7 microg STX eq. l(-1) caused reductions in
      sensorimotor function as early as 48 h postfertilization (hpf) and paralysis in
      all larvae by 4 days postfertilization (dpf). Rohon-Beard mechanosensory neurons
      appeared to be more sensitive to STX than dorsal root ganglion neurons at this
      dose. Additionally, exposure to 481 +/- 40 microg STX eq. l(-1) resulted in
      severe edema of the eye, pericardium, and yolk sac in all exposed larvae by 6
      dpf. The onset of paralysis in STX-exposed larvae was stage-specific, with older
      larvae becoming paralyzed more quickly than younger larvae (5 h at 6 dpf as
      compared to 8 and 46 h for 4 and 2 dpf larvae, respectively). When transferred to
      clean water, many larvae recovered from the morphological and sensorimotor
      effects of STX. Thus, the sublethal effects of the toxin on larval morphology and
      behavior were reversible. However, zebrafish exposed to STX transiently during
      larval development (from 2 to 4 dpf) had significantly reduced growth and
      survival at 18 and 30 days of age. Collectively, these data show that (1)
      dissolved phase STX is bioavailable to fish embryos and larvae, (2) the toxin is
      a paralytic with potencies that are stage-specific for fish larvae, (3) the
      observed toxicological effects of STX exposure are reversible, and (4) a short
      term toxin exposure can negatively impact the survival of fish several weeks
      later. Dissolved algal toxins may therefore have important sublethal effects on
      vulnerable species of fish.

PMID- 15036872
TI  - Species-specific responses of developing anurans to coal combustion wastes.
AB  - Field surveys and field experiments have previously documented adverse effects of
      solid byproducts from coal incineration (coal combustion wastes (CCW)) on larval
      amphibians inhabiting aquatic habitats. However, a definitive link between CCW
      exposure and developmental abnormalities has not been established because no
      studies have addressed the direct effects of prolonged exposure to CCW on larval
      amphibian development under controlled laboratory conditions. In the laboratory
      we exposed green frog (Rana clamitans) and wood frog (Rana sylvatica) larvae to
      either clean sand or CCW-contaminated sediment to investigate the direct effects
      of CCW exposure on trace element accumulation, growth, developmental rate,
      malformations, survival, and metamorphic success. While both species accumulated
      significant (P < 0.05) concentrations of at least six trace elements (As, Cd, Fe,
      Se, Sr, and V), effects of exposure to CCW varied between species, with R.
      clamitans larvae experiencing more severe effects including a 26% reduction in
      survival and a 45% reduction in metamorphic success. Furthermore, exposure to CCW
      decreased growth and developmental rates among larvae of both species that
      successfully completed metamorphosis. Larval period duration was increased by 10
      and 11%, and size at metamorphosis was decreased by 10 and 39% in R. clamitans
      and R. sylvatica exposed to CCW, respectively. Rates of malformations were </=
      4%, and were not dependent on species or sediment treatment. Our results confirm
      the direct effects of CCW on aquatic amphibian larvae suggested by previous field
      studies, and indicate that considerable variation may exist in sensitivity among
      species exposed to CCW. These findings have important implications for the
      management of CCW since > 50 million t are discharged annually to surface
      impoundments in the US, which are often used by breeding amphibians.

PMID- 15036873
TI  - Comparative study on the in vitro/in vivo estrogenic potencies of 17beta
      estradiol, estrone, 17alpha-ethynylestradiol and nonylphenol.
AB  - The estrogenic activity of compounds was evaluated in a comparative approach both
      with in vitro and in vivo assays. By comparing simultaneously obtained
      experimental data, we evaluated the differences in response sensitivity (by EC10)
      and concentration-response relationships (including EC50) in order to get an idea
      about the predictive value of in vitro assays for in vivo estrogenic potencies or
      effects in fish. Two human estrogen receptor-based assays, the MVLN-assay
      (transformed MCF-7 human breast cancer cell line) and the yeast estrogen screen
      (YES-screen) were used for the in vitro evaluation of the estrogenic potencies.
      An in vivo model with the female zebrafish (Danio rerio) with plasma vitellogenin
      (VTG) as a biomarker for exposure and the ovarian somatic index (OSI) as an
      effect endpoint was used for the in vivo work. Compounds tested were 17beta
      estradiol (E2), estrone (E1), 17alpha-ethynylestradiol (EE2) and the
      alkylphenolic compound nonylphenol (NP). All compounds were found to be
      estrogenic in both in vitro assays and were able to induce VTG and to reduce the
      ovarian somatic index in female zebrafish. The MVLN-assay appeared up to 15 times
      more sensitive than the YES-screen. Concentration-response relationships,
      determined by EC10 and EC50 (concentration of test compound causing 10% or 50%
      effect compared to control) for VTG and OSI were of the same order of magnitude,
      indicating that VTG induction as an exposure biomarker can be predictive for
      effects on ovaries in females. We further demonstrated that for E1 and NP, the in
      vitro observed estrogenic potencies, based on EC50 values, were of the same order
      of magnitude as the in vivo estrogenic potencies. For EE2, a difference between
      in vitro and in vivo relative estrogenic potency was observed, being about 25
      times more potent in vivo than could be expected based on the in vitro results.
      These experimental results showed the suitability of in vitro assays for
      screening purposes with qualitative assessment of estrogenicity, but they
      meanwhile point to the need of in vivo tests for an accurate hazard assessment
      for wildlife.

PMID- 15036874
TI  - Mercury- and copper-induced lysosomal membrane destabilisation depends on [Ca2+]i
      dependent phospholipase A2 activation.
AB  - Heavy metals are environmental pollutants able to produce different cellular
      effects, such as an alteration of Ca2+ homeostasis and lysosomal membrane
      destabilisation. The latter is one of the most used stress indices in
      biomonitoring programs. Recently, it has been demonstrated that cytosolic calcium
      increase can modulate lysosomal membrane destabilisation via activation of Ca(2+)
      dependent phospholipase A2 (cPLA2). The aim of this work was to investigate the
      possible involvement of Ca(2+)-activated PLA2 in lysosomal membrane
      destabilisation induced by heavy metals in mussel haemolymph cells. We have
      studied the effects of Hg2+ and Cu2+ on free cytosolic calcium using Fura2/AM
      loaded cells and lysosomal membrane destabilisation using neutral red (NR)
      staining. Hg2+ induced a [Ca2+]i rise from 100 to 780 nM in 30 min, and a
      lysosome destaining of 70% after 60 min that indicates destabilisation of
      lysosomal membranes. Both effects were reduced in a Ca(2+)-free medium,
      suggesting a cause-effect relationship. Exposure to Cu2+ produced the same
      effects, but with an intensity of about 50% respect to Hg2+. Metal-induced
      lysosomal destabilisation was also reduced in cells pre-exposed to a specific
      Ca(2+)-dependent cPLA2 inhibitor (AACOCF3). Conversely, haemocyte pretreatment
      with a Ca(2+)-independent PLA2 inhibitor (bromoenol-lactone (BEL)) did not
      prevent the destabilizing effect of heavy metals on lysosomes. Exposure to heavy
      metals also produced an increase in lysosomal volume of 1.8-2-folds, that was
      prevented by pre-incubation with AACOCF3 but not with BEL. These data indicate an
      involvement of cPLA2 in lysosomal membrane destabilisation induced by heavy
      metals.

PMID- 15036875
TI  - How does Parkinson's disease begin? The role of compensatory mechanisms.

PMID- 15036877
TI  - More than just two peas in a pod: common amyloidogenic properties of tau and
      alpha-synuclein in neurodegenerative diseases.
AB  - Intracytoplasmic filamentous aggregates, such as neurofibrillary tangles in
      Alzheimer's disease and Lewy bodies in Parkinson's disease, are composed of the
      proteins tau and alpha-synuclein, respectively. These pathological inclusions are
      linked directly to the etiology and mechanisms of disease in a wide spectrum of
      neurodegenerative disorders, termed 'tauopathies' and 'synucleinopathies'.
      Emerging evidence indicates that there is frequent overlap of the pathological
      and clinical features of patients with tauopathies and synucleinopathies, thereby
      re-enforcing the notion that these disorders might be linked mechanistically.
      Indeed, several lines of investigation suggest that tau and alpha-synuclein might
      constitute a unique class of unstructured proteins that assemble predominantly
      into homopolymeric (rather than heteropolymeric) fibrils, which deposit mainly in
      separate amyloid inclusions, but occasionally deposit together. Thus, the ability
      of tau and alpha-synuclein to affect each other directly or indirectly might
      contribute to the overlap in the clinical and pathological features of
      tauopathies and synucleinopathies.

PMID- 15036878
TI  - Interneuron Diversity series: Interneuronal neuropeptides--endogenous regulators
      of neuronal excitability.
AB  - Interneurons are often classified according to neuropeptide content. However, it
      is becoming increasingly clear that neuropeptides are more than convenient
      neurochemical markers and can act as important modulators of neuronal activity.
      Recent advances in understanding neuropeptide release and physiological actions
      suggest that the interneuronal system of neuropeptides is crucial for maintaining
      appropriate brain function under normal and pathophysiological conditions. In
      particular, interneuronal neuropeptides appear to play roles in cognition and as
      endogenous anti-epileptic agents. This article describes current understanding of
      the conditions under which neuropeptides are released from interneurons, their
      specific effects on neuronal excitability and synaptic transmission, and the
      consequences of their loss of function.

PMID- 15036879
TI  - Orchestrating development and function: retrograde BMP signaling in the
      Drosophila nervous system.
AB  - Recent work has shown that bone morphogenetic protein (BMP) growth factors
      regulate development of the larval neuromuscular junction (NMJ) of Drosophila.
      Intriguingly, the same BMP growth factors also influence the expression of
      circulating hormones that modulate the physiological properties of NMJs.
      Together, the results suggest that retrograde growth factor signaling by BMPs
      integrates neuromuscular development and function at both local and global levels
      in the animal.

PMID- 15036880
TI  - The complex identity of brain tumors: emerging concerns regarding origin,
      diversity and plasticity.
AB  - Elucidation of genetic and epigenetic mechanisms underlying neoplasia is one of
      the great success stories of modern science, but this success has not been
      associated with parallel improvements in the treatment of malignant tumors. One
      possible explanation for this failure is that the most important variables that
      support growth of malignancies are not yet identified. Another possible
      explanation, however, is that multiple variables important in neoplastic
      progression combine to create a level of disease complexity not taken into
      account by current therapeutic approaches. The study of development and neoplasia
      in the CNS provides some of the strongest support for the latter view--a view
      that, if correct, would suggest that a radical rethinking of the biology of
      malignancy is required if we are to make progress in the treatment of this
      important medical condition.

PMID- 15036881
TI  - Equivocal roles of tissue-type plasminogen activator in stroke-induced injury.
AB  - Stroke represents a major health problem in the ever-ageing population of
      industrialized nations. Each year, over three million people in the USA alone
      suffer from this affliction. Stroke, which results from the obstruction of an
      intra- or extra-cerebral artery, induces irreversible neuronal damage. The clot
      busting drug tissue-type plasminogen activator (tPA) is the only FDA-approved
      therapy for acute stroke. Although tPA has been successfully used to treat
      myocardial infarction due to clot formation, its use in the treatment of
      occlusive cerebrovascular diseases remains controversial. Indeed, tPA is clearly
      beneficial as a thrombolytic agent. However, increasing evidence suggests that
      tPA could have direct and deleterious effects on neurons and glial cells.

PMID- 15036882
TI  - Psychology and neurobiology of simple decisions.
AB  - Patterns of neural firing linked to eye movement decisions show that behavioral
      decisions are predicted by the differential firing rates of cells coding selected
      and nonselected stimulus alternatives. These results can be interpreted using
      models developed in mathematical psychology to model behavioral decisions.
      Current models assume that decisions are made by accumulating noisy stimulus
      information until sufficient information for a response is obtained. Here, the
      models, and the techniques used to test them against response-time distribution
      and accuracy data, are described. Such models provide a quantitative link between
      the time-course of behavioral decisions and the growth of stimulus information in
      neural firing data.

PMID- 15036883
TI  - Cytogenetic investigation of testicular carcinoma in situ and early seminoma by
      high-resolution comparative genomic hybridization analysis of subpopulations flow
      sorted according to DNA content.
AB  - Interpretation of data from comparative genomic hybridization (CGH) analysis of
      testicular neoplasms located within normal parenchyma is complicated, because the
      results may be influenced by a heterogeneity of subpopulations with different
      chromosomal aberrations and ploidy. In this study, therefore, early stages of
      testicular germ cell neoplasia were cytogenetically analyzed after flow sorting
      of nuclei according to their DNA ploidy. DNA from subpopulations with different
      ploidy was globally amplified by means of degenerate oligonucleotide primed
      polymerase chain reaction, labeled with FITC-dCTP and -dUTP by nick translation,
      and analyzed with high resolution CGH. A characteristic pattern of chromosomal
      abnormalities associated with testicular germ cell cancer (gains in 1q, 7, 8, 12,
      14, 21, X; losses from 4, 5, 9, 11, 13, 18, Y) was observed in the tri- to
      hexaploid but not in the hyperdiploid or in pure tetraploid subpopulations. Our
      data suggest that subpopulations with a triploid to hexaploid DNA content
      purified from testes with germ cell neoplasia harbor a mixture of overt tumor and
      carcinoma-in-situ cells (CIS) and DNA content of CIS cells being in the triploid
      to hypotetraploid range, supporting the current theory of polyploidization as one
      of the first events of malignant transformation.

PMID- 15036884
TI  - Differentially expressed genes in nonsmall cell lung cancer: expression profiling
      of cancer-related genes in squamous cell lung cancer.
AB  - The expression patterns of cancer-related genes in 13 cases of squamous cell lung
      cancer (SCC) were characterized and compared with those in normal lung tissue and
      13 adenocarcinomas (AC), the other major type of nonsmall cell lung cancer
      (NSCLC). cDNA array was used to screen the gene expression levels and the array
      results were verified using a real-time reverse-transcriptase-polymerase chain
      reaction (RT-PCR). Thirty-nine percent of the 25 most upregulated and the 25 most
      downregulated genes were common to SCC and AC. Of these genes, DSP, HMGA1 (alias
      HMGIY), TIMP1, MIF, CCNB1, TN, MMP11, and MMP12 were upregulated and COPEB (alias
      CPBP), TYROBP, BENE, BMPR2, SOCS3, TIMP3, CAV1, and CAV2 were downregulated. The
      expression levels of several genes from distinct protein families (cytokeratins
      and hemidesmosomal proteins) were markedly increased in SCC compared with AC and
      normal lung. In addition, several genes, overexpressed in SCC, such as HMGA1,
      CDK4, IGFBP3, MMP9, MMP11, MMP12, and MMP14, fell into distinct chromosomal loci,
      which we have detected as gained regions on the basis of comparative genomic
      hybridization data. Our study revealed new candidate genes involved in NSCLC.

PMID- 15036885
TI  - Detection of genetic alterations in primary bladder carcinoma with dual-color and
      multiplex fluorescence in situ hybridization.
AB  - Cytogenetic studies of bladder cancer have shown several nonrandom aberrations.
      Numerical aberrations of both sex chromosomes were investigated in 32 primary
      bladder tumors with bicolor fluorescence in situ hybridization (FISH). Loss of
      chromosome Y and overrepresentation of chromosome X were observed in subgroups of
      male patients. Chromosome X was represented normally in female patients. Two of
      the above primary bladder tumors, a transitional cell carcinoma (TCC) and an
      adenocarcinoma, were further analyzed with both multiplex FISH (24-color M-FISH)
      and G-banding. Both cases exhibited 1) common breakpoints on 5q11 approximately
      q12 and 15q24; 2) involvement of the pericentromeric area of chromosome 13; 3)
      structural abnormalities of chromosomes 8 and 17, with loss of material on the
      short arm; 4) structural abnormalities involving chromosome 11; and 5) loss of
      chromosome Y. The TCC case also exhibited structural abnormalities of chromosome
      9, resulting in loss of 9q. The combined G-banding and M-FISH findings could help
      reveal regions potentially involved in bladder tumorigenesis.

PMID- 15036886
TI  - Renal oncocytomas with 11q13 rearrangements: cytogenetic, molecular, and
      immunohistochemical analysis of cyclin D1.
AB  - Two groups of renal oncocytomas have been cytogenetically defined by the loss of
      one or both of chromosomes Y and 1 or by structural rearrangement involving
      11q12~q13. We report five renal oncocytomas with structural chromosomal
      rearrangements involving 11q13 with previously unreported partner chromosomes
      (namely, 1, 6, and 7). For two of the five cases, a t(6;11)(p21;q13)
      translocation was revealed; the others had t(1;11)(p13;q13), t(7;11)(q11.2;q13),
      and t(5;11)(q35; q13). Fluorescence in situ hybridization confirmed translocation
      of CCND1 at 11q13 to partner chromosomes 5, 6, and 7. Overexpression of cyclin
      D1, the protein product of CCND1, was detected in three of the five cases (60%)
      by means of immunohistochemical staining of formalin-fixed, paraffin-embedded
      tumor sections. In three cases for which fresh tissue was available, Southern
      blot analysis using the MDL-5 probe for the BCL1 breakpoint did not reveal
      rearrangement of BCL1. In addition, six consecutive renal oncocytomas diagnosed
      at our institution between 1999 and 2002 whose karyotypes did not show 11q13
      translocations were all negative for cyclin D1 overexpression under
      immunohistochemical analysis. The findings of CCND1 rearrangement with FISH and
      correlation with cyclin D1 overexpression under immunohistochemical analysis
      suggest that cyclin D1 alterations play a role in the subset of renal oncocytomas
      with 11q translocations, although other genes may also be involved.

PMID- 15036887
TI  - Renal oncocytomas with rearrangements involving 11q13 contain breakpoints near
      CCND1.
AB  - Oncocytomas are typically benign epithelial tumors whose predominant feature is a
      massive accumulation of mitochondria in the cytoplasm. With the goal of
      identifying genes controlling mitochondrial proliferation, we studied three
      oncocytomas belonging to the cytogenetic subgroup with 11q13 rearrangements.
      Fluorescence in situ hybridization using bacterial artificial chromosome (BAC)
      clones showed that the 11q13 breakpoints in all three tumors were near the CCND1
      (previously BCL1) gene and did not disrupt any other known gene. The
      rearrangement in one tumor consisted of a segmental duplication that included
      11q13, suggesting that known mitochondrially targeted genes immediately distal to
      CCND1 may be involved in oncocytic proliferation.

PMID- 15036888
TI  - Constitutional t(5;7)(q11;p15) rearranged to acquire monosomy 7q and trisomy 1q
      in a patient with myelodysplastic syndrome transforming to acute myelocytic
      leukemia.
AB  - We report the case of a 61-year-old woman who presented with a myelodysplastic
      syndrome (MDS) and a t(5;7)(q11.2;p15) in her bone marrow cells. Subsequent
      analysis of phytohemagglutinin-stimulated peripheral blood lymphocytes and
      cultured skin fibroblasts showed that the translocation was constitutional.
      Disruption of chromosome bands 5q11.2 and 7p15 has been described recurrently in
      MDS and acute myelocytic leukemia (AML) and, although the age of onset was not
      earlier than usual, it is nonetheless possible that genes interrupted by this
      translocation may been a predisposing factor for her condition. With progression
      to AML, a further rearrangement of the constitutional der(7)t(5;7) occurred,
      involving chromosome arm 1q. Fluorescence in situ hybridization (FISH) with whole
      chromosome paints showed that the result of the second rearrangement, a
      t(1;7)(q32.1;q32), was observed, leading to trisomy of the segment 1q32.1
      approximately qter and monosomy of the segment 7q32.1 approximately qter. The
      acquired imbalances, particularly loss of 7q, are commonly associated with
      MDS/AML and a poor prognosis; however, this patient remained in remission after
      treatment for more than two years before AML relapse, perhaps because the
      affected regions fall outside of the critical regions of imbalance.

PMID- 15036890
TI  - Constitutional chromosome aberrations as pathogenetic events in hematologic
      malignancies.
AB  - A predisposition to tumor development is associated with some constitutional
      chromosomal abnormalities. Investigations of families with an apparent hereditary
      cancer and constitutional chromosome rearrangements have led to the molecular
      identification of tumor suppressor genes. Under the somatic mutation theory for
      the development of cancer, two mutational events are required. The first step may
      be a constitutional event and the second an acquired genetic mutation.
      Cytogenetic studies were performed on 5633 bone marrow specimens from patients
      with hematologic malignancies from a single institution. Fifty cases of
      constitutional chromosome aberrations were detected. Data collected from the
      literature and from our series are reviewed and compared with the incidence of
      specific constitutional chromosome aberrations in the newborn population.
      Possible mechanisms that may predispose individuals with constitutional
      chromosome aberrations to the development of a hematologic malignancy are
      reviewed.

PMID- 15036889
TI  - Secondary near-tetraploidy with double der(15)t(15;17) in acute promyelocytic
      leukemia in relapse.
AB  - Tetraploidy or near-tetraploidy is a rare cytogenetic abnormality in acute
      myelocytic leukemia. We report here a case of acute promyelocytic leukemia that
      showed near-tetraploidy with double der(15)t(15;17) the leukemia relapsed. At
      diagnosis, cytogenetic analysis failed to reveal any karyotypic abnormality;
      however, a promyelocytic leukemia-retinoic acid receptor alpha (PML/RARA) fusion
      transcript of the bcr3-type was detected with reverse transcriptase-polymerase
      chain reaction analysis, and a single PML/RARA fusion signal was observed with
      fluorescence in situ hybridization analysis. At the first relapse, the majority
      of leukemic cells showed pseudodiploid karyotypes with der(15)t(15;17), as well
      as additional chromosomal abnormalities, and exhibited a single PML/RARA fusion
      signal. A small fraction of leukemic cells, however, showed near-tetraploid
      karyotypes with double der(15)t(15;17), as well as some additional chromosomal
      abnormalities in common with the pseudodiploid clones, and exhibited double
      PML/RARA fusion signals. At the second and third relapses, leukemic cells with
      near-tetraploidy and double PML/RARA fusion signals became predominant. The
      PML/RARA fusion transcript of the bcr3 type was also observed at each relapse. In
      addition, Southern blot analysis of the RARA gene at diagnosis and at the second
      relapse showed a common rearranged band. Notably, giant, bizarre, and
      hypogranular promyelocytes expressing CD2, CD34, and HLA-DR appeared at the first
      relapse and became predominant at the second and third relapses. These
      observations indicate that the APL cells with near-tetraploidy and double
      der(15)t(15;17) clonally evolved from the pseudodiploid leukemic cells and
      exhibited the bizarre morphology and aberrant surface immunophenotypes.

PMID- 15036891
TI  - Molecular cytogenetic parameters in fibroblasts from patients and carriers of
      xeroderma pigmentosum.
AB  - Xeroderma pigmentosum (XP) is a rare autosomal recessive syndrome. Laboratory
      investigations have failed to detect any consistent anomaly in cells from XP
      heterozygotic subjects, although examples of behavior intermediate between normal
      and XP cells have been reported. To estimate random aneuploidy we applied
      fluorescence in situ hybridization (FISH) with alpha-satellite probes for
      chromosomes 8 and 9 and replication pattern for TP53 (p53), ERBB2 (HER-2/neu),
      and MYCN (N-MYC) loci and for the imprinted SNRPN locus. A significantly higher
      rate of aneuploidy rate was observed in XP patients and carriers than in
      controls. The asynchrony pattern was significantly higher in XP carriers and
      patients with all three coding loci analyzed and significantly lower in XP
      patients and carriers with the imprinted locus SNRPN than in the control group.
      Molecular cytogenetic parameters such as random aneuploidy and replication
      pattern, which are known to reflect chromosomal instability, may be part of the
      tumorigenesis process. In XP patients and carriers, this genetic instability may
      represent a potential for developing malignancies.

PMID- 15036892
TI  - Translocation (2;11)(q31;q12) is recurrent in collagenous fibroma (desmoplastic
      fibroblastoma).
AB  - Collagenous fibroma (desmoplastic fibroblastoma) is a rare, benign tumor composed
      of spindle and stellate-shaped fibroblasts and myofibroblasts in a densely
      collagenous background. A t(2;11)(q31;q12) has been reported in one case of
      collagenous fibroma and a rearrangement of the 11q12 breakpoint in a second case.
      In the present study, we detected a t(2;11) identical to that previously
      described in a collagenous fibroma arising in the supraclavicular fossa of a 55
      year-old man. This finding confirms the nonrandom association of t(2;11)(q31;q12)
      with collagenous fibroma.

PMID- 15036893
TI  - A t(11;20)(p15;q11) may identify a subset of nontherapy-related acute myelocytic
      leukemia.
AB  - A t(11;20)(p15;q11) is a rare but recurrent chromosomal aberration, reported in
      one case of polycythemia vera and a few cases of de novo acute myelocytic
      leukemia (AML) and therapy-related myelodysplastic syndrome (t-MDS). In t-MDS
      cases, the translocation resulted in the NUP98/TOP1 fusion transcript. The NUP98
      gene has been suggested as the target for therapy-related malignancies. The
      reciprocal TOP1/NUP98 chimera, however, has not yet been encountered. We report a
      further case of de novo AML, subtype M2 in the French-American-British (FAB)
      classification, in which the reverse-transcriptase polymerase chain reaction (RT
      PCR) revealed the NUP98/TOP1 chimera and also, for the first time, its reciprocal
      TOP1/NUP98. The literature review disclosed that, among six cases of de novo AML
      with t(11;20), the NUP98 gene was shown to be involved in one case and the
      NUP98/TOP1 chimera was detected in another. The translocation seems to be
      frequently associated with the FAB M2 subtype, younger age, hyperleukocytosis,
      and poor prognosis; thus, this translocation may identify a subset of not-therapy
      related AML patients with shared clinical features.

PMID- 15036894
TI  - Low frequency of FLT3 gene internal tandem duplication and activating loop
      mutation in therapy-related acute myelocyticleukemia and myelodysplastic
      syndrome.
AB  - FLT3 gene internal tandem duplication (ITD) and activating loop mutations (D835)
      were determined in 22 cases of therapy-related acute myelocytic
      leukemia/myelodysplastic syndrome (t-AML/MDS) and 102 cases of de novo AML/MDS.
      In t-AML/MDS, FLT3 ITD was absent, and D835 was found in only one case of therapy
      related acute promyelocytic leukemia (APL). In de novo AML/MDS, however, FLT3 ITD
      and D835 were significantly more frequent (28 of 102 cases, P=0.024) and were
      associated with high peripheral blood and marrow blast counts. Our results
      suggest that different pathogenetic pathways might be involved in t-AML/MDS and
      de novo AML/MDS.

PMID- 15036895
TI  - Cytogenetic differences and neuroblastoma cell interconversion.

PMID- 15036897
TI  - A rapidly progressive chronic myeloproliferative disease with isolated trisomy 6.

PMID- 15036898
TI  - An intragenic rearrangement of HMGA2 is not necessary for lipoma formation.

PMID- 15036900
TI  - From interception to incorporation: degeneracy and promiscuous recognition as
      precursors of a paradigm shift in immunology.
AB  - The paper evaluates the role of the concept of degeneracy in current immunology.
      The historical background of the notion is considered, as well as that of related
      concepts like 'cross-reactivity' and 'promiscuity'. A distinction is made between
      degeneracy, as a property of a system and promiscuity, as a property of
      antibodies and lymphocytes, followed by a discussion of the relation of
      degeneracy to the clonal selection theory (CST). Attempts to accommodate the
      notion of degeneracy with the CST theory are critically reviewed. The notion of
      specific agency is identified as central for this debate, and an alternative
      conception of the immune response, focused on incorporation rather than
      interception, is discussed.

PMID- 15036901
TI  - Antigen-receptor degeneracy and immunological paradigms.
AB  - This paper discusses some consequences of the discovery that antigen receptors
      are degenerate: Immune specificity, in contrast to the tenets of the clonal
      selection paradigm, must be generated by the immune response down-stream of
      initial antigen recognition; and specificity is a property of a collective of
      cells and not of single clones.

PMID- 15036902
TI  - T-cell receptor degeneracy: the dog that did not bark. Adaptation of the self
      reactive T-cell response to limit autoimmune disease.
AB  - T-cells provide antigen specific focus to the adaptive immune response. However,
      the receptors that initiate functional responses are not in themselves specific,
      as they can recognise many different ligands. In this paper, we propose that the
      immune system deals with TCR degeneracy by an adaptive process that effects both
      T-cell activation and T-cell function, and exploits TCR degeneracy to limit
      pathogenic autoimmune disease.

PMID- 15036903
TI  - Recognition and function in a degenerate immune system.
AB  - Degeneracy in the immune system not only refers to the recognition by its
      specific receptors, but also at the level of functional degeneracy of reactivity
      by its lymphocytes. Features of the immune system such as dominance and
      competition occur at each of these two levels. Another characteristic of the
      immune system as a fuzzy system, is its continuum of states, where difficult
      choices lead to the emergence of unpredictable phenotypes.

PMID- 15036904
TI  - T cell receptor crossreactivity as a general property of T cell recognition.
AB  - TCR recognition of MHC/peptide complexes directs many aspects of T cell biology,
      including thymic selection, survival of naive T cells and differentiation into
      effector and memory T cells. It was widely thought that TCR recognition is highly
      specific, with an individual T cell being capable of only recognizing a
      particular peptide and closely related sequence variants. By considering the
      structural requirements for peptide binding to MHC molecules and TCR recognition
      of MHC/peptide complexes, we demonstrated that T cell clones could recognize a
      number of peptides from different organisms that are remarkably distinct in their
      primary sequence. These peptides are particularly diverse at those sequence
      positions buried in pockets of the MHC binding site, while a higher degree of
      similarity is present at a limited number of peptide residues that create the
      interface with the TCR. Many examples have now been documented for human and
      murine T cells, indicating that TCR crossreactivity represents a general feature
      of TCR recognition.

PMID- 15036905
TI  - Degenerate recognition of T cell epitopes: impact of T cell receptor reserve and
      stability of peptide:MHC complexes.
AB  - The concept of molecular mimicry suggests that microbial pathogens might activate
      antigen-specific T cells that then cross-react with endogenous antigens and
      result in the generation of autoimmunity. Here we discuss several under
      represented factors impacting the ability of TCRs to recognize a wide spectrum of
      related peptide:MHC (pMHC) ligands. Two of these factors include the affinity of
      the peptide for MHC and the level of TCR expression. Thymocytes that recognize
      peptides with low affinity for MHC avoid negative selection, but mature T cells,
      by virtue of increased TCR expression, will proliferate in response to these same
      unstable pMHC complexes. While the expression of a reserve of antigen receptors
      expands the potential number of epitopes for which a T cell can cross-react,
      phosphatase activity provides a tuning mechanism to increase the threshold level
      of activation. Thus, degenerate recognition of T cell epitopes involves the
      stability of the peptide:MHC complex, the number of TCR expressed, and the level
      of phosphatase activity.

PMID- 15036906
TI  - T cell receptors: affinities, cross-reactivities, and a conformer model.
AB  - Based on findings with the T cell receptor from mouse CTL clone 2C, and other
      TCRs, we propose a model that could account for degeneracy of T cell recognition.
      This "conformer model" holds that a single TCR exists in multiple conformations
      that are in equilibrium. The model is consistent with (1) the characterization of
      multiple ligands that bind to the 2C TCR, and other TCRs, (2) the binding
      properties and predicted structural features of various 2C TCR mutants, including
      higher affinity variants isolated by directed evolution, and (3) the three
      dimensional structures of TCRs and antibodies, with emphasis on the
      conformational diversity exhibited by proteins with the same primary amino acid
      sequence. We propose that the advantages of multiple conformers (e.g. ability of
      a single T cell to recognize many different ligands) outweigh the disadvantages
      (e.g. lower TCR affinity and possibly T cell sensitivity; detrimental cross
      reactivity with structurally unrelated self-ligands).

PMID- 15036907
TI  - Peptide register shifting within the MHC groove: theory becomes reality.
AB  - Degeneracy in immune recognition is usually thought of in terms of the
      astonishing ability of the T cell receptor to recognize an enormously diverse
      array of peptides bound to major histocompatibility complex (MHC) molecules.
      However, in this essay we discuss an alternative aspect of degeneracy in T cell
      recognition: the notion that peptides can assume different "registers" in the
      groove of a single MHC molecule, as first suggested and demonstrated by Sercarz
      and co-workers (reviewed in [J. autoimmun. 16 (2001) 201]). There is now abundant
      evidence, derived from functional, biochemical and structural studies, that
      single peptides can assume alternative, unpredictable binding registers by
      frameshifting within the MHC groove [Nat. Immunol. 3 (2002) 175;; J. Exp. Med.
      187 (1998) 1505; J. Mol. Biol. 304 (2000) 177; Biochemistry 38 (1999) 16663; J.
      Exp. Med. 197 (2003) 1391; Eur. J. Immunol. 19 (1989) 681]. Hence, register
      shifting adds an additional dimension to the concept of degeneracy. In fact, the
      possibility of register shifting multiplies the universe of peptide-MHC (pMHC)
      surfaces that a TCR must recognize by an unknown, perhaps enormous factor.
      Register shifting also has profound implication for autoimmunity: (1) as a
      mechanism to "mask" autoantigenic epitopes during thymic education [Immunol. Rev.
      169 (1999) 147; Immunity 17 (2002) 83]; and (2) as a possible source for pMHC
      complexes capable of molecular mimicry.

PMID- 15036908
TI  - T cells are not as degenerate as you think, once you get to know them.
AB  - In this review, we dissect two different antigen systems which represent the
      apparent extremes of T cell receptor (TCR) recognition. In the hemoglobin (Hb)
      system, a minor change in a single MHC anchor residue disrupts TCR recognition.
      In the KRN system, a single TCR shows strong reactivity to two peptides from
      unrelated proteins, presented by different MHC molecules. Upon closer analysis,
      both turn out to be specific recognition events, following set rules of
      engagement. Thus, although a TCR can recognize multiple ligands sharing minimal
      sequence homology, this recognition is still highly specific and is constrained
      by the same structural requirements. TCR degeneracy is therefore limited and is
      unlikely to be a major mechanism for autoimmunity.

PMID- 15036909
TI  - Specificity and degeneracy of T cells.
AB  - The extent of T cell cross-reactivity is significant, even to the point where the
      terms "promiscuous" and "degenerate" apply. Degeneracy is an important feature of
      the immune response mechanism that permits effective T cell responses to a vast
      number of potential peptide sequences complexed to MHC molecules with specificity
      sufficient to distinguish between self and foreign peptides and thus to avoid
      autoimmune disease. Degeneracy at the clonal level of T cells also permits the
      use of very large combinatorial peptide libraries to identify and optimize
      peptide sequences that might be used for the treatment of T cell mediated
      autoimmune disease and for the design of vaccines for treatment of infectious
      diseases and cancer. Here we explore some recent findings derived from studies
      involving library scans of T cell lines and clones having clinically relevant
      specificities. In particular, we discuss two new insights: degeneracy among CD8 T
      cells appears to be substantially less than among CD4 T cells, and T cell clones
      characterized by a high affinity TCR interaction with a given pMHC complex are
      less degenerate than lower avidity T cells that require higher levels of pMHC
      complex for their activation.

PMID- 15036910
TI  - Specificity and degeneracy: T cell recognition in CNS autoimmunity.
AB  - T cells play a crucial role in the pathogenesis of most autoimmune disorders.
      However, target antigens and pathomechanisms leading to human autoimmune diseases
      are still largely unknown. Cross-recognition of T cells between self and foreign
      antigens has been considered as a driving force in generating autoimmunity. Here,
      we discuss the extent of degeneracy in T cell antigen recognition and hypothesize
      on the role of degenerate recognition in the pathogenesis of multiple sclerosis
      (MS), a candidate autoimmune disease of the central nervous system (CNS).

PMID- 15036911
TI  - A powerful combination: the use of positional scanning libraries and biometrical
      analysis to identify cross-reactive T cell epitopes.
AB  - Studies on the elucidation of the specificity of the T cell receptor (TCR) at the
      antigen and peptide level have contributed to the current understanding of T cell
      cross-reactivity. Historically, most studies of T cell specificity and degeneracy
      have relied on the determination of the effects on T cell recognition of amino
      acid changes at individual positions or MHC binding residues, and thus they have
      been limited to a small set of possible ligands. Synthetic combinatorial
      libraries (SCLs), and in particular positional scanning synthetic combinatorial
      libraries (PS-SCLs) represent collections of millions to trillions of peptides
      which allow the unbiased elucidation of T cell ligands that stimulate clones of
      both known and unknown specificity. PS-SCLs have been used successfully to study
      T cell recognition and to identify and optimize T cell clone (TCC) epitopes in
      infectious diseases, autoimmune disorders and tumor antigens. PS-SCL-based
      biometrical analysis represents a further refinement in the analysis of the data
      derived from the screening of a library with a TCC. It combines this data with
      information derived from protein sequence databases to identify natural peptide
      ligands. PS-SCL-based biometrical analysis provides a method for the
      determination of new microbial antigen and autoantigen sequences based solely on
      functional data rather than sequence homology or motifs, making the method
      ideally suited for the prediction and identification of both native and cross
      reactive epitopes by virtue of its ability to integrate the examination of
      trillions of peptides in a systematic manner with all of the protein sequences in
      a given database. We review here the application of PS-SCLs and biometrical
      analysis to identify cross-reactive T cell epitopes, as well as the current
      efforts to refine this strategy.

PMID- 15036913
TI  - Degenerate recognition and response of human CD4+ Th cell clones: implications
      for basic and applied immunology.
AB  - It was once considered that the T cell response is an all or nothing type event,
      but recent studies have clearly indicated that T cells show many different types
      of activation in recognition of altered ligands for T cell receptors (TCR). In
      this review, we summarize our recent findings on the response of human CD4+
      helper T (Th) cell clones to altered peptide ligands (APL); peptides carrying
      single or multiple residue substitutions in antigenic peptides. The extensive
      analyses revealed that TCR-antagonism and partial agonism are frequently observed
      by the stimulation with APLs substituted at particular amino acid residues of
      antigenic peptides. We observed unique partially agonistic APLs inducing
      prolongation of T cell survival without cell proliferation. Superagonistic APLs
      stimulated enhanced proliferation and production of cytokines in Th cell clones
      reactive to tumor-associated antigens. The other APL induced enhanced production
      of interleukin-12 by antigen presenting cells and subsequent enhancement of IFN
      gamma production by T cells reactive to allergens. By utilizing an HLA-DR
      restricted T cell epitope library generated by mutated invariant chain genes, it
      was revealed that human Th cell clones recognize a more diverse array of peptides
      with multiple and simultaneous amino acid substitutions in an antigenic peptide.
      APLs also induced altered intracellular signaling events including intracellular
      calcium increase and phosphorylation of signaling molecules. This information
      provides basic knowledge regarding the characteristics of antigen recognition by
      human Th cells and the subsequent activation, and a novel method for manipulation
      of human Th cell responses by APLs, as a possible candidate for antigen-specific
      immuno-potentiating or immunosuppressive therapy.

PMID- 15036912
TI  - Peptidic complex mixtures as therapeutic agents in CNS autoimmunity.
AB  - Limited success with antigen-specific immunotherapies has led to the
      identification of novel approaches which consider the degeneracy of the T cell
      response, i.e. their ability to respond to multiple antigenic peptides. Random
      complex mixtures of polypeptides such as glatiramer acetate (GA) were among the
      first to be applied as immunodulators that take into account T cell degeneracy.
      While the mechanisms of action are not completely understood, the immunogenicity
      of GA, its strong major histocompatability complex (MHC) binding, immune
      deviation and bystander suppression all appear to be important. In the present
      study we have designed peptidic complex mixtures (CM) of varied lengths and
      compositions to test their potential as immunomodulating agents. CM were
      synthesized that had defined lengths and contained aa corresponding to binding
      motifs of MHC class II molecules relevant in multiple sclerosis (MS) and its
      animal model, experimental autoimmune encephalomyelitis (EAE), specifically HLA
      DRB1*1501 and HLA-DRB5*0101, which are related to MS, and H2-IA(s) associated
      with EAE in SJL mice. Additional CM were designed based on specificity profiles
      derived from positional scanning synthetic combinatorial library (PS-SCL) testing
      of a GA-specific T cell clone (TCC). Several mixtures were strongly stimulatory
      for peripheral blood mononuclear cells (PBMC) from MS patients and healthy donors
      suggesting a high degree of cross-reactivity with other peptide antigens. A
      subset of these mixtures exhibited cross-reactivity to myelin antigens and
      prophylactic efficacy in reducing the severity of EAE. Based on these
      observations we envision mixture-based peptidic compounds can be developed not
      only for immunotherapeutic purposes in autoimmune diseases and cancer, but also
      in vaccine development.

PMID- 15036914
TI  - The elusive case for a role of mimicry in autoimmune diseases.
AB  - The notion that mimicry between a self and a microbial peptide antigen can
      trigger or aggravate autoimmune pathology remains a popular hypothesis in
      autoimmunity research. Tremendous recent progress in our understanding of the
      interface between the T cell receptor (TCR) and peptide/MHC complexes has
      revealed a vast potential for degenerate recognition of numerous structurally
      similar pMHC complexes by each T lymphocyte. Moreover, functional and structural
      studies have confirmed that structural similarity between unrelated pMHC
      complexes is frequently sufficient for recognition by a single TCR. However,
      despite clear evidence that vaccination with mimetic microbial antigens has the
      potential to activate autoreactive T cells, crucial evidence for triggering of
      autoimmunity by mimetic sequences in natural pathogens is wanting. Antigen
      spreading, i.e. the fact that the number of self antigens targeted by a chronic
      autoimmune response tends to increase with its duration, does not facilitate the
      task of proving initial triggering, or subsequent acceleration, of autoimmune
      conditions by mimetic microbial antigens. Moreover, considering that activation
      rather than presence of autoreactive T cells is the hallmark of autoimmune
      disease, the creation of an environment resulting in failure of tolerance and
      regulatory mechanisms, rather than emergence of novel microbial antigenic
      determinants, may well be at the root of autoimmunity. Based on these
      considerations, we contend that the mimicry concept remains largely hypothetical,
      and that novel carefully designed animal models are needed to make a convincing
      case for a role of mimicry in autoimmune diseases.

PMID- 15036915
TI  - Innate and adaptive immune requirements for induction of autoimmune demyelinating
      disease by molecular mimicry.
AB  - Molecular mimicry is the main postulated mechanism by which infectious agents
      induce autoimmune disease. A number of animal models have been utilized to
      establish a link between molecular mimicry and autoimmunity. However, a model of
      infectious disease whereby a natural pathogen expressing a known mimic epitope
      can induce autoimmunity to a known self-antigen leading to clinical autoimmune
      disease is still lacking. We have engineered a recombinant Theiler's murine
      encephalomyelitis virus (TMEV) to express an encephalitogenic myelin proteolipid
      protein PLP139-151 epitope (PLP-TMEV) and a PLP139-151 mimic peptide naturally
      expressed by Haemophilus influenzae (HI-TMEV). Infection of mice with either PLP
      TMEV or HI-TMEV induces early-onset disease that is associated with the
      activation of cross-reactive PLP139-151-specific immunopathologic CD4+ Th1 cells.
      Based on results from this model, we hypothesize, due to the considerable
      degeneracy in the T cell repertoire, that induction of full-blown autoimmune
      disease via molecular mimicry is a tightly regulated process requiring multiple
      factors related to the pathogen expressing the potential mimic epitope. In this
      review, we will discuss how various factors related to the infectious environment
      control whether or not autoimmune disease is initiated. Contributing factors
      include the nature of the innate immune response to the pathogen which determines
      the immunopathologic potential of the induced cross-reactive T cells, the
      capacity of the mimic epitope to be processed and presented from its natural
      flanking sequences in the pathogen-encoded protein, the site(s) of the primary
      infection in the host and the ability of the pathogen to persist, and the
      potential requirement for multiple infections with the same or different
      pathogens.

PMID- 15036916
TI  - Strong attraction may be dangerous: parameters for the development of long term
      commitment.

PMID- 15036917
TI  - Induction, acceleration or prevention of autoimmunity by molecular mimicry.
AB  - The hypothesis that cross-reactivity between microbial and self determinants
      recognized by the adaptive immune system could induce autoimmune diseases is very
      intriguing. However, definite proof in humans is very difficult to achieve and
      evidence is frequently circumstantial. Therefore, animal models are instrumental
      for understanding, how and when mimicry could be involved in the pathogenesis of
      autoimmunity. In this article, we will discuss experimental scenarios, where
      mimicry between foreign and self determinants does not cause disease per se, but
      rather aggravates a pre-existing yet sub-clinical autoimmune condition. We would
      like to propose that molecular mimicry is more likely to impact on an already
      existing autoimmune process rather than precipitate novel disease by breaking of
      tolerance from the beginning. Already activated autoreactive cells might be
      easier re-activated and primed for effector functions by cross-reactive ligands
      than naive lymphocytes.

PMID- 15036918
TI  - T cell mimicry in inflammatory heart disease.
AB  - Inflammatory heart diseases such as myocarditis and rheumatic heart disease
      result from the infiltration of the myocardium or valve with T cells and
      macrophages that result in scarring of the myocardium or valve and alteration in
      cardiac function. Our studies of T cells from these diseases have identified
      cardiac myosin in both rheumatic carditis and myocarditis as an important
      autoantigen. In rheumatic heart disease, streptococcal M protein specific T cells
      migrate to valves. By investigating streptococcal M protein and cardiac myosin in
      the Lewis rat model of myocarditis and valvulitis, T cell mimicry is supported as
      a potential mechanism in disease. Structural and immunological mimicry between
      the streptococcal M protein and cardiac myosin is shown directly in the Lewis rat
      model. Rat T cell lines demonstrate mimicry between cardiac myosin and M protein,
      and T cells isolated directly from inflammatory lesions in myocarditis respond to
      streptococcal M protein peptides. Studies in BALB/c mice also support the
      immunological crossreactivity of T cells primed against cardiac myosin with
      streptococcal M protein peptides containing cardiac myosin homologies. T cell
      lines produced from the Lewis rat specific to the cardiac myosin like sequences
      of streptococcal M protein migrated to the valves after passive transfer of the M
      protein specific T cell lines. In coxsackieviral myocarditis in the MRL mouse
      strain, cardiac myosin mimicking M protein peptide NT4 was found to induce
      tolerance and prevent coxsackieviral induced myocarditis, suggesting T cell
      mimicry between coxsackievirus and streptococcal M protein, both of which are
      associated with inflammatory heart disease. T cell mimicry between cardiac myosin
      and microbial antigens such as the streptococcal M protein may prime the immune
      system for inflammatory heart disease.

PMID- 15036919
TI  - Heart infiltrating T cell clones from a rheumatic heart disease patient display a
      common TCR usage and a degenerate antigen recognition pattern.
AB  - CD4+ T cells are most likely the ultimate effectors of chronic heart lesions in
      rheumatic heart disease (RHD). We have demonstrated that infiltrating CD4+ T cell
      clones were able to recognize several heart tissue and streptococcal antigens by
      molecular mimicry. Clonality analysis of the mitral valve and myocardium
      infiltrating T cell lines showed several oligoclonal expansions, some of which
      were found in both sites of the lesions. The results presented in this study
      showed a degenerate pattern of reactivity of intralesional T cell clones from one
      RHD patient. Four mitral valve and one papillar muscle-derived T cell clones,
      presenting the same TCR-BV13 BJ2S7 with same sequences of the CDR3 region
      recognized different antigens. They expressed two alpha chains at the RNA level
      and the AV AJ segments were the same for mitral valve T cell clones, but not for
      the papillar muscle-derived T cell clone. Two other intralesional T cell clones
      using the same TCR-BV3 JB2S1 segments with identical CDR3 sequences also
      recognized different antigens. These results indicate that intralesional T cell
      clones with common TCR usage can recognize several epitopes that probably amplify
      the deleterious immune reaction. These data, allow us to hypothesize that
      degenerate T cell recognition may lead to intramolecular degenerate reactivity
      against epitopes with low homology. This can be a novel mechanism of epitope
      spreading, of relevance in the increase of epitopes targets that can activate
      cross-reactive autoimmune T cells.

PMID- 15036921
TI  - HIV comes of age.

PMID- 15036920
TI  - Prevention and control of reciprocal T-B cell diversification: implications for
      lupus-like autoimmunity.
AB  - Autoimmunity is fundamentally a continuously evolving process. The autoimmune
      responses shift, drift and diversify with time not only to other epitopes in the
      original antigen but also to other related and sometimes to unrelated antigens.
      We have described a form of immune diversification--reciprocal T-B epitope
      spreading--where the activation of first T cells by epitopes from an autoantibody
      molecule could lead to help provided to a variety of B cells displaying a cross
      reactive version of the original epitope. The response spreads in this way until
      large cohorts of T and B cells have expanded in lupus-prone mice. Such reciprocal
      T-B cell response can also be induced in normal animals, its extent is limited by
      the emergence of inhibitory T cells. The induction of such inhibitory T cells is
      generally impaired in lupus mice. The delivery of T cell epitopes via plasmid DNA
      vectors, however, can overcome this impairment in lupus mice. The inhibitory T
      cells thus induced can suppress autoantibody production and lupus disease by
      ablating or inhibiting autoreactive B cells. Thus, T-B diversification that
      develops spontaneously in lupus mice could be curtailed in normal animals by
      inhibitory T cells that emerge whenever there is an impending 'danger' of
      pathologic autoimmunity. We have successfully exploited this regulatory potential
      of the normal immune response to inhibit clinical autoimmunity. Understanding the
      mechanisms of autoimmune diversification in lupus mice and of its down-regulation
      in normal animals may pave the way for developing novel treatments for
      autoantibody-mediated diseases such as lupus.

PMID- 15036922
TI  - Looking at J.B.S. Haldane.
AB  - J.B.S. Haldane's photographs reveal that this eminent geneticist was also a
      militant political agitator. Deeply engaged in left-wing British politics,
      Haldane eventually joined the Communist party, but found it increasingly
      difficult to reconcile his scientific beliefs with his Marxist commitments.
      During the controversy over Stalin's rejection of genetics in favour of Trofim
      Lysenko's agricultural reforms, Haldane's activities were critically interpreted
      from various different perspectives.

PMID- 15036923
TI  - Resisting insects: shifting strategies in chemical control.
AB  - Throughout the 20th century, scientists developed a variety of chemical compounds
      to kill insects and other menaces of agriculture and public health. Yet, in many
      cases, the target insects outmaneuvered the scientists by developing resistance
      to insecticides--in much the same way as some bacteria can tolerate antibiotics.
      Insecticide resistance research has involved scientists from a range of
      disciplines and a variety of institutional contexts that have often guided
      research strategy. For example, entomologists working at agricultural stations
      and universities concentrated on insect physiology and evolutionary genetics,
      while industrial chemists continued the development of novel compounds capable of
      killing resistant pests. Collaboration between the two groups beginning in the
      1940s did not provide a solution to the resistance, but did lead to a strategic
      shift from pest control to pest management that continues to the present.

PMID- 15036924
TI  - Astronomers against Newton.
AB  - Francis Baily's publication of the manuscripts of John Flamsteed, the first
      Astronomer Royal, provoked a furious response. Flamsteed had quarrelled with
      Isaac Newton, and described him in terms unforgivable to those who claimed him as
      a paragon of all virtues, both moral and scientific. Baily was condemned for
      putting Flamsteed's complaints in the public sphere. However, his supporters saw
      his work as a critique of the excessive hero-worship accorded to Newton. Written
      when the word 'scientist' had been newly coined, this work and the debates it
      provoked gives us an insight into contemporary views of the role of the man of
      science and of the use of science to back political, religious and moral
      positions.

PMID- 15036925
TI  - The crystallization of enzymes and virus proteins: laying to rest the colloidal
      concept of living systems.
AB  - In 1946 three Americans shared the Nobel Prize for Chemistry--James Sumner 'for
      his discovery that enzymes can be crystallized', and John Northrop and Wendell
      Stanley 'for their preparation of enzymes and virus proteins in a pure form'. The
      award made history as the first time that the Chemistry Prize was shared by three
      individuals. It also doubled the number of Americans that had received the
      Chemistry award since its inception in 1901.

PMID- 15036926
TI  - I got rhythm: Gershwin and birth control in the 1930s.
AB  - Gershwin's song 'I Got Rhythm' serves here as a backdrop representing the social
      context of the inter-war years. On center stage is a particular aspect of the
      history of birth control--the application of a new theory of ovulation to
      contraception. Starting in 1928, a series of experiments revealed a biochemical
      rhythm in the female reproductive cycle, which contradicted the widespread idea
      that ovulation and pregnancy could occur at any time. This discovery was applied
      to a new contraceptive method, the rhythm method, which enjoyed significant
      popularity during the 1930s, especially among Catholics. For a short period,
      women could join Ethel Merman in the refrain 'I got rhythm, I got my man, who
      could ask for anything more?' But the rhythm method has not lived to its promise,
      and the play goes on em leader

PMID- 15036927
TI  - Mary Boole and curve stitching: a look into heaven.
AB  - Mary Everest Boole had a lifelong interest in the unconscious mind, the
      psychology of learning, and how these relate to the teaching of mathematics and
      science. She recommended many practical exercises and teaching aids, one of which
      was the technique of curve stitching, which she had invented while still a child
      herself.

PMID- 15036928
TI  - The city as a context for scientific activity: creating the Mediziner-Viertel in
      fin-de-siecle Vienna.
AB  - At the turn of the 19th century, a surprisingly dense network of academic
      institutes and medical facilities developed on the margins of Ringstrasse, the
      impressive boulevard that surrounded the old city of Vienna. Enmeshed, socially
      and culturally in the life of the city, that area known as the Mediziner-Viertel
      grew out of the needs of natural scientists and physicians as much as it was
      shaped by the liberal ideology, feminists' petitions for women's acceptance to
      university studies, Vienna's intellectuals and Kaffeehaus culture. Recovering the
      city behind the structure of modern academic institutes tells us a good deal
      about the context in which intellectual work was developed and its impact on the
      production of scientific knowledge.

PMID- 15036929
TI  - Adaptations or pathologies? Long-term changes in brain and behavior after a
      single exposure to severe threat.
AB  - The experience of a single threatening situation may alter the behavior of an
      animal in a long-lasting way. Long-lasting changes in behavior have been induced
      in laboratory animals to model and investigate the development and neural
      substrate of human psychopathologies. Under natural conditions, however, changes
      in behavior after an aversive experience may be adaptive because behavioral
      modifications allow animals to adjust to a threat for extended periods of time.
      In the laboratory setting, properties of the aversive situation and the potential
      of the animal to respond to the threat may be altered and lead to extensive,
      prolonged changes, indicating a failure in behavioral regulation. Such long-term
      changes seem to be mediated by neuronal alterations in components of the fear
      pathway. To understand psychopathologies, determinants of exaggerated
      responsivity and the underlying molecular and neural processes have to be
      analyzed in a comparative way under conditions that produce normal and abnormal
      fear and anxiety.

PMID- 15036930
TI  - Behavioural state affects saccades elicited electrically from neocortex.
AB  - Reviewed is how behavioural context influences saccadic eye movements elicited
      electrically from the neocortex of monkeys. Factors found to affect stimulation
      evoked saccades include (1) motor state, i.e. whether stimulation is delivered
      during free-viewing, or during or after active fixation, or before an animal is
      about to execute a saccade to a target location, and (2) reward delivery, i.e.
      the characteristics and timing of reward, which can promote or inhibit the
      evocation of saccades. We conclude that anyone using electrical stimulation in
      neocortex to study sensory and cognitive processes must control for the
      possibility that stimulation of cortex is merely generating a saccade vector
      whose expression is being obscured by the behavioural paradigm in use. Areas of
      neocortex from which saccades can be evoked using low currents (<100 microA) are
      surprisingly widespread and include regions traditionally considered within the
      sensory domain (e.g. V1, V2, V4, and MT), in addition to visuomotor regions such
      as the lateral intraparietal area, the dorsomedial frontal cortex, the frontal
      eye fields, and the prefrontal cortex. This is especially true once the
      behavioural state of a stimulated animal is put under experimental control.

PMID- 15036931
TI  - Rewards and punishments, goal-directed behavior and consciousness.
AB  - A parsimonious account of consciousness is given in which it emerges as a direct
      consequence of basic neural processes without the necessity of any higher order
      system. In this model, pleasant or unpleasant conscious feelings of various
      stimuli in the environment stem from their higher order associations to innate
      rewards or punishments. When a conditioned stimulus (CS) is associated with a
      reward, it acquires pleasant feelings due to the temporal correlation of the
      activations representing its sensory features with those representing innate
      visceral reward acquisition processes. When the CS is associated with the
      punishment, it acquires unpleasant feelings due to the correlation of its sensory
      features with the innate visceral inhibition of punishment acquisition processes.
      The correlations involve coherent activity between the sensory cortex, the limbic
      system, the orbital and medial prefrontal cortex, and more lateral prefrontal
      areas where stimuli can be incorporated into working memory. A conscious act
      involves responses (or attempts to improve the environment) made on the basis of
      the feelings of such stimuli. Covert memory scans, in which comparisons are made
      of the reward and punishment associations of the outcomes of previous responses,
      are related to the motivations and attention behind the conscious selection of a
      current response. This model appears to fit together various empirical
      observations. Its relations to some higher or more abstract mental processes, and
      some evolutionary implications are discussed.

PMID- 15036932
TI  - Schizophrenia-an evolutionary enigma?
AB  - The term 'schizophrenia' refers to a group of disorders that have been described
      in every human culture. Two apparently well established findings have
      corroborated the need for an evolutionary explanation of these disorders: (1)
      cross-culturally stable incidence rates and (2) decreased fecundity of the
      affected individuals. The rationale behind this relates to the evolutionary
      paradox that susceptibility genes for schizophrenia are obviously preserved in
      the human genepool, despite fundamental reproductive disadvantages associated
      with the disorders. Some researchers have therefore proposed that a compensatory
      advantage must exist in people who are carriers of these genes or in their first
      degree relatives. Such advantages were hypothesised to be outside the brain (e.g.
      greater resistance against toxins or infectious diseases), or within the social
      domain (e.g. schizotypal shamans, creativity). More specifically, T.J. Crow has
      suggested an evolutionary theory of schizophrenia that relates the disorders to
      an extreme of variation of hemispheric specialisation and the evolution of
      language due to a single gene mutation located on homologous regions of the sex
      chromosomes. None of the evolutionary scenarios does, however, fully account for
      the diversity of the symptomatology, nor does any one hypothesis acknowledge the
      objection that the mere prevalence of a disorder must not be confused with
      adaptation. In the present article, I therefore discuss the evolutionary
      hypotheses of schizophrenia, arguing that a symptom-based approach to psychotic
      disorders in evolutionary perspective may improve upon the existing models of
      schizophrenia.

PMID- 15036933
TI  - Estrogens and non-reproductive behaviors related to activity and fear.
AB  - Estrogens affect a variety of behaviors in addition to sexual responses, some of
      them related to motor activity and emotional reactivity. This is true in
      experimental animals and in humans. The literatures on these subjects are
      confusing because not all of the experimental results point in the same
      direction. Here we propose the following theoretical suggestion, hoping to
      account for the variety of reports extant: following the generally arousing
      effects of estrogens, their hormonal actions on motor activity and fear depend on
      context. In a safe environment, estrogen treatment causes increased activity. But
      in a novel environment or in contexts otherwise perceived as threatening,
      activity is reduced by estrogen, due to the hormone's arousing action, which
      heightens fear. Many hormone-dependent neural circuits involving several
      neuropeptides could provide mechanisms for this dynamic. We suggest a causal
      route could involve the activation of corticotropin releasing hormone gene
      expression in the brain. In sum, estrogenic effects on arousal states, as
      manifest differently according to details of the environmental context during
      behavioral test, could account for some of the discrepancies in the literature.

PMID- 15036934
TI  - Adaptive and maladaptive psychobiological responses to severe psychological
      stress: implications for the discovery of novel pharmacotherapy.
AB  - Post-traumatic stress disorder (PTSD) is one of the few DSM-IV diagnoses
      contingent upon a psychosocial stressor. In this context, there is an urgent need
      to acquire a better understanding of both the adaptive and maladaptive
      psychobiological responses to traumatic stress. Preclinical investigators have
      utilized a variety of animal models to identify the behavioral and
      neurobiological features of the organism's response to stress. However, given the
      complexity of the healthy and pathological human response to physiological and
      psychological stress, the extent to which the animal data is immediately
      transferable to human remains to be fully determined. This review draws upon
      preclinical and clinical literature to examine the transformation of an adaptive
      human stress response into a maladaptive and debilitating mental disorder. An
      integrative psychobiological model for PTSD is presented, linking psychological
      processes and behavioral patterns with current findings in neurocircuitry,
      neurochemistry and psychophysiology. The implications of this model for the
      discovery of novel pharmacological approaches to the treatment of severe
      psychological distress are discussed.

PMID- 15036936
TI  - Clinical results with imatinib in chronic myeloid leukaemia.
AB  - Since its introduction 5 years ago, imatinib mesylate has shown remarkable
      efficacy in treating patients with chronic myeloid leukaemia. Here we shall
      review the clinical results seen with imatinib at all stages of the disease,
      current views on the best way to monitor patients' responses and potential ways
      of predicting response to treatment. We shall also briefly cover the reasons why
      quiescent stem cells pose a theoretical threat to successful treatment.

PMID- 15036937
TI  - Targeting c-Kit mutations: basic science to novel therapies.
AB  - The Kit receptor tyrosine kinase is a transmembrane receptor that is expressed in
      a variety of different tissues and mediates pleiotropic biological effects
      through its ligand stem cell factor (SCF). Sporadic mutations of Kit as well as
      autocrine/paracrine activation mechanisms of the SCF/Kit pathway have been
      implicated in a variety of malignancies, where its primary contribution to
      metastases is in enhancing tumor growth and reducing apoptosis. For example, Kit
      is frequently mutated and activated in gastrointestinal stromal tumors (GISTs)
      and there is ligand-mediated activation of Kit in some lung cancers. Kit is a
      convenient target in Kit-induced tumors and inhibition of this receptor with the
      small molecule drug Gleevec (imatinib mesylate, STI571) in GIST has shown
      dramatic efficacy. Unfortunately, past experience has demonstrated that
      chemotherapy of cancers with a single drug often leads to resistance of the
      cancer. Further understanding of the molecular mechanisms underlying Kit-mediated
      transformation is therefore important and may lead to the identification of
      further novel drug targets. These Kit-specific signaling pathways may then be
      targeted to overcome potential drug resistance. This review will focus on our
      understanding of the molecular mechanisms involved in transformation by Kit. The
      potential mechanisms by which Kit induces cellular transformation are described.
      We will also discuss the role and expression of Kit in various malignancies.
      Ultimately, the understanding of c-Kit biology, biochemistry, and mutational
      analysis will lead to better therapeutics.

PMID- 15036938
TI  - Mechanisms of transformation by the BCR-ABL oncogene: new perspectives in the
      post-imatinib era.
AB  - Since its introduction less than 3 years ago, imatinib mesylate (STI571) has
      altered the entire approach to the therapy of patients with chronic myeloid
      leukemia (CML). In addition to its impact on clinical practice, imatinib has also
      increased the focus of basic and translational CML research on enhancing the
      cellular effects of imatinib and preventing and overcoming resistance to the
      drug. Here, I summarize some recent advances in our understanding of the
      regulatory and signaling mechanisms of Bcr-Abl, with an emphasis on therapeutic
      implications.

PMID- 15036939
TI  - Lessons learned from the development of imatinib.

PMID- 15036941
TI  - Imatinib therapy for hypereosinophilic syndrome and eosinophilia-associated
      myeloproliferative disorders.
AB  - A pathogenetic mutation, FIP1L1-PDGFRA, that results from an interstitial
      chromosome 4q12 deletion, leads to a constitutive activation of the platelet
      derived growth factor receptor-alpha (PDGFRA) tyrosine kinase as well as a
      disease phenotype that mimics both the hypereosinophilic syndrome (HES) and
      systemic mast cell disease associated with eosinophilia (SMCD-eos). Complete
      remissions, in response to treatment with low-dose imatinib mesylate (100 mg/day
      or less) have now been documented in all cases of FIP1L1-PDGFRA(+) eosinophilic
      disorder as well as other eosinophilic disorders that carry activation mutations
      of the PDGFRB gene that is located on chromosome 5q33. Furthermore, response to
      therapy has been rapid (within days) and durable. Interestingly, imatinib
      mesylate treatment, at a higher dose level (400 mg/day), might induce either
      partial or short-lived complete remissions in HES that is not associated with the
      aforementioned PDGFR mutations. These observations make it necessary to re
      examine current disease classification and treatment algorithms in eosinophilic
      disorders.

PMID- 15036940
TI  - Molecular mechanisms of resistance of leukemia to imatinib mesylate.
AB  - Despite high rates of hematologic and cytogenetic responses to imatinib therapy,
      the emergence of resistance to imatinib has been recognized as a major problem in
      the treatment of Ph-positive leukemia. The high frequency of BCR-ABL mutations
      and amplifications represents the high degree of heterogeneity in patients with
      advanced phase of CML, in whom multiple leukemic clones may exist. Therefore, a
      single inhibitor is unlikely to able to block all mutants.

PMID- 15036942
TI  - Imatinib mesylate (STI571) for myeloid malignancies other than CML.
AB  - Imatinib mesylate, a small molecule tyrosine kinase inhibitor, has had a major
      impact on the treatment of Philadelphia chromosome positive chronic myelogenous
      leukemia. This review will explore its potential in the treatment of other
      myeloid neoplasms, based on its ability to inhibit Kit and PDGFR kinases in
      addition to Bcr-Abl. Imatinib's potential role in the treatment of Philadelphia
      chromosome negative chronic myelogenous leukemia, systemic mastocytosis with
      associated hematologic neoplasms, chronic myelomonocytic leukemia, specific
      subtypes of acute myelogenous leukemia, myelofibrosis/myeloid metaplasia, and
      polycythemia vera is discussed.

PMID- 15036943
TI  - Sweet's syndrome with CML cell infiltration of the skin in a patient with chronic
      phase CML while taking Imatinib Mesylate.
AB  - Sweet's syndrome (acute febrile neutrophilic dermatosis) is characterized by an
      acute onset of erythematous plaques, fever, and leukocytosis. This syndrome has
      been reported to be associated with leukemia including chronic myelogenous
      leukemia (CML). Sweet's syndrome seen in patients with leukemia is usually
      associated with active and/or refractory disease. Imatinib Mesylate (STI-571,
      Gleevec) is widely used for therapy of CML. In this case report, CML cell
      infiltration of the skin was documented by fluorescence in situ hybridization
      (FISH) analysis in a patient with chronic-phase CML on Imatinib Mesylate (STI
      571, Gleevec), who was at the time in molecular remission.

PMID- 15036944
TI  - A 2-year-old with atypical CML with a t(5;12)(q33;p13) treated successfully with
      imatinib mesylate.
AB  - Atypical chronic myelogenous leukemia (aCML) is a
      myelodysplastic/myeloproliferative disorder that usually occurs in older adults.
      Here we report a pediatric patient with aCML and a t(5;12)(q33;p13) with a
      corresponding fusion gene ETV6-PDGFRB. Because the PDGFRB tyrosine kinase is one
      of the known targets of tyrosine kinase inhibitors, this patient achieved
      cytogenetic and molecular remission with treatment with imatinib mesylate
      (formerly STI571; now Gleevec in the United States and Glivec in Europe). This
      case illustrates one of many myelodysplastic/myeloproliferative disorders that
      can be treated with this particular tyrosine kinase inhibitor.

PMID- 15036945
TI  - Divergent clinical outcome in two CML patients who discontinued imatinib therapy
      after achieving a molecular remission.
AB  - Imatinib mesylate therapy leads to major or complete cytogenetic response in the
      majority of patients with CML in the chronic phase. A subset of these patients
      also achieves remission at a molecular level. It is not known if such patients
      will require continuous therapy, or whether imatinib could be safely
      discontinued. This report describes divergent clinical outcomes in two patients
      with chronic phase CML who discontinued imatinib therapy after obtaining a
      molecular remission; one patient who maintained a complete molecular response
      throughout a period of interruption, and a second patient with overt relapse,
      highlighting the uncertainty of discontinuing imatinib therapy.

PMID- 15036946
TI  - Lymphoid transformation in a CML patient in complete cytogenetic remission
      following treatment with imatinib.
AB  - We describe here a patient with Philadelphia (Ph) chromosome-positive chronic
      myeloid leukemia who achieved a complete cytogenetic response following treatment
      with imatinib and then progressed abruptly to lymphoid blastic transformation.
      The sequence of events suggests that at least in some cases patients who respond
      well to imatinib may still harbor residual leukemia progenitor or 'stem' cells
      that are susceptible to acquisition of molecular events that underlie progression
      to advanced phase disease. The case highlights the need for molecular monitoring
      of responders and the need to develop strategies for reducing to a minimum or
      totally eradicating leukemia cells.

PMID- 15036947
TI  - Successful treatment with imatinib mesylate of hypereosinophilic syndrome
      (chronic eosinophilic leukemia) with myelofibrosis.

PMID- 15036948
TI  - Effects of 50 Hz electromagnetic fields on voltage-gated Ca2+ channels and their
      role in modulation of neuroendocrine cell proliferation and death.
AB  - Possible correlation between the effects of electromagnetic fields (EFs) on
      voltage-gated Ca(2+) channels, cell proliferation and apoptosis was investigated
      in neural and neuroendocrine cells. Exposure to 50 Hz EFs significantly enhanced
      proliferation in human neuroblastoma IMR32 (+40%) and rat pituitary GH3 cells
      (+38%). In IMR32 cells EF stimulation also inhibited puromycin- and H(2)O(2)
      induced apoptosis (-22 and -33%, respectively). EF effects on proliferation and
      apoptosis were counteracted by Ca(2+) channel blockade. In whole-cell patch-clamp
      experiments 24-72 h exposure to EFs increased macroscopic Ba(2+)-current density
      in both GH3 (+67%) and IMR32 cells (+40%). Single-channel recordings showed that
      gating of L and N channels was instead unaffected, thus suggesting that the
      observed enhancement of current density was due to increased number of voltage
      gated Ca(2+) channels. Western blot analysis of plasma membrane-enriched
      microsomal fractions of GH3 and IMR32 cells confirmed enhanced expression of
      Ca(2+) channel subunit alpha(1) following exposure to EFs. These data provide the
      first direct evidence that EFs enhance the expression of voltage-gated Ca(2+)
      channels on plasma membrane of the exposed cells. The consequent increase in
      Ca(2+) influx is likely responsible for the EF-induced modulation of neuronal
      cell proliferation and apoptosis.

PMID- 15036950
TI  - Contribution of the cytoskeleton and the phospholipase C signaling pathway to
      fluid stream-induced membrane currents.
AB  - A fluid stream induced by a concentration clamp system evokes in Xenopus oocytes
      a deformation of the membrane which results in transient chloride currents of
      high amplitude (stream-evoked inward current, I(i,st)) during calcium-activated
      chloride current oscillations. The involvement of cytoskeleton elements and of
      components of the phospholipase C-dependent signaling pathway on the generation
      of the I(i,st) were investigated. Incubation of the oocytes with cytoskeleton
      disrupting agents exerted no effects on generation of the I(i,st), suggesting
      that the mechanotransduction is not mediated by these structures. The fluid
      stream induced an elevation of the submembraneous calcium concentration, as
      measured by an increase of Fluo-4-mediated fluorescence after the stimulus.
      Lowering the intracellular calcium concentration by injection of calcium
      chelators or depleting inositol 1,4,5-triphosphate (InsP(3))-sensitive calcium
      stores by blockers of the calcium pumps suppressed the generation of the I(i,st)
      in most cases. Furthermore, the phospholipase C inhibitor U73122 reversibly
      blocked the I(i,st). The results suggest that the fluid stream leads to a
      membrane stretch which modulates directly or indirectly the activity of a
      membrane-bound phospholipase C. The phospholipase C transiently elevates the
      InsP(3) concentration, in turn releasing calcium from InsP(3)-sensitive internal
      calcium stores, thus evoking an enhanced calcium-sensitive chloride current.

PMID- 15036949
TI  - Evaluation, using targeted aequorins, of the roles of the endoplasmic reticulum
      and its (Ca2++Mg2+)ATP-ases in the activation of store-operated Ca2+ channels in
      liver cells.
AB  - The process by which store-operated Ca2+ channels (SOCs) deliver Ca2+ to the
      endoplasmic reticulum (ER) and the role of (Ca2++Mg2+)ATP-ases of the ER in the
      activation of SOCs in H4-IIE liver cells were investigated using cell lines
      stably transfected with apo-aequorin targeted to the cytoplasmic space or the ER.
      In order to measure the concentration of Ca2+ in the ER ([Ca2+]er), cells were
      pre-treated with 2,5-di-tert-butylhydroquinone (DBHQ) to deplete Ca2+ in the ER
      before reconstitution of holo-aequorin. The addition of extracellular Ca2+
      (Cao2+) to Ca2+-depleted cells induced refilling of the ER, which was complete
      within 5 min. This was associated with a sharp transient increase in the
      cytoplasmic Ca2+ concentration ([Ca2+]cyt) of about 15 s duration (a Cao2+
      induced [Ca2+]cyt spike) after which [Ca2+]cyt remained elevated slightly above
      the basal value for a period of about 2 min (low [Ca2+]cyt plateau). The Cao2+
      induced [Ca2+]cyt spike was inhibited by Gd3+, not affected by tetrakis-(2
      pyridymethyl) ethylenediamine (TPEN), and broadened by ionomycin and the
      intracellular Ca2+ chelators BAPTA and EGTA. Refilling of the ER was inhibited by
      caffeine. Neither thapsigargin nor DBHQ caused a detectable inhibition or change
      in shape of the Cao2+-induced [Ca2+]cyt spike or the low [Ca2+]cyt plateau
      whereas each inhibited the inflow of Ca2+ to the ER by about 80%. Experiments
      conducted with carbonyl cyanide m-chlorophenyl-hydrazone (CCCP) indicated that
      thapsigargin did not alter the amount of Ca2+ accumulated in mitochondria. The
      changes in [Ca2+]cyt reported by aequorin were compared with those reported by
      fura-2. It is concluded that (i) there are significant quantitative differences
      between the manner in which aequorin and fura-2 sense changes in [Ca2+]cyt and
      (ii) thapsigargin and DBHQ inhibit the uptake of Ca2+ to the bulk of the ER but
      this is not associated with inhibition of the activation of SOCs. The possible
      involvement of a small sub-region of the ER (or another intracellular Ca2+
      store), which contains thapsigargin-insensitive (Ca2++Mg2+)ATP-ases, in the
      activation of SOCs is briefly discussed.

PMID- 15036951
TI  - Role of FKBP12.6 in hypoxia- and norepinephrine-induced Ca2+ release and
      contraction in pulmonary artery myocytes.
AB  - The cellular and molecular processes underlying the regulation of ryanodine
      receptor (RyR) Ca(2+) release in smooth muscle cells (SMCs) are incompletely
      understood. Here we show that FKBP12.6 proteins are expressed in pulmonary artery
      (PA) smooth muscle and associated with type-2 RyRs (RyR2), but not RyR1, RyR3, or
      IP(3) receptors (IP(3)Rs) in PA sarcoplasmic reticulum. Application of FK506,
      which binds to FKBPs and dissociates these proteins from RyRs, induced an
      increase in [Ca(2+)](i) and Ca(2+)-activated Cl(-) and K(+) currents in freshly
      isolated PASMCs, whereas cyclosporin, an agent known to inhibit calcineurin but
      not to interact with FKBPs, failed to induce an increase in [Ca(2+)](i). FK506
      induced [Ca(2+)](i) increase was completely blocked by the RyR antagonist
      ruthenium red and ryanodine, but not the IP(3)R antagonist heparin. Hypoxic
      Ca(2+) response and hypoxic vasoconstriction were significantly enhanced in
      FKBP12.6 knockout mouse PASMCs. FK506 or rapamycin pretreatment also enhanced
      hypoxic increase [Ca(2+)](i), but did not alter caffeine-induced Ca(2+) release
      (SR Ca(2+) content) in PASMCs. Norepinephrine-induced Ca(2+) release and force
      generation were also markedly enhanced in PASMCs from FKBP12.6 null mice. These
      findings suggest that FKBP12.6 plays an important role in hypoxia- and
      neurotransmitter-induced Ca(2+) and contractile responses by regulating the
      activity of RyRs in PASMCs.

PMID- 15036952
TI  - A store-operated mechanism determines the activity of the electrically excitable
      glucagon-secreting pancreatic alpha-cell.
AB  - The glucagon-releasing pancreatic alpha-cells are electrically excitable cells
      but the signal transduction leading to depolarization and secretion is not well
      understood. To clarify the mechanisms we studied [Ca(2+)](i) and membrane
      potential in individual mouse pancreatic alpha-cells using fluorescent
      indicators. The physiological secretagogue l-adrenaline increased [Ca(2+)](i)
      causing a peak, which was often followed by maintained oscillations or sustained
      elevation. The early effect was due to mobilization of Ca(2+) from the
      endoplasmic reticulum (ER) and the late one to activation of store-operated
      influx of the ion resulting in depolarization and Ca(2+) influx through voltage
      dependent L-type channels. Consistent with such mechanisms, the effects of
      adrenaline on [Ca(2+)](i) and membrane potential were mimicked by inhibitors of
      the sarco(endo)plasmic reticulum Ca(2+) ATPase. The alpha-cells express ATP
      regulated K(+) (K(ATP)) channels, whose activation by diazoxide leads to
      hyperpolarization. The resulting inhibition of the voltage-dependent [Ca(2+)](i)
      response to adrenaline was reversed when the K(ATP) channels were inhibited by
      tolbutamide. However, tolbutamide alone rarely affected [Ca(2+)](i), indicating
      that the K(ATP) channels are normally closed in mouse alpha-cells. Glucose, which
      is the major physiological inhibitor of glucagon secretion, hyperpolarized the
      alpha-cells and inhibited the late [Ca(2+)](i) response to adrenaline. At
      concentrations as low as 3mM, glucose had a pronounced stimulatory effect on
      Ca(2+) sequestration in the ER amplifying the early [Ca(2+)](i) response to
      adrenaline. We propose that adrenaline stimulation and glucose inhibition of the
      alpha-cell involve modulation of a store-operated current, which controls a
      depolarizing cascade leading to opening of L-type Ca(2+) channels. Such a control
      mechanism may be unique among excitable cells.

PMID- 15036953
TI  - Morphological and functional changes of dissociated single pancreatic acinar
      cells: testing the suitability of the single cell as a model for exocytosis and
      calcium signaling.
AB  - Isolated single pancreatic acinar cells have long been used as a model for
      studying many kinds of signaling processes due to their structural and functional
      polarities, but without significant validation. In this study, we examined the
      morphological and functional changes of dissociated single pancreatic acinar
      cells. Acutely isolated single cells showed a collapsed membrane potential and a
      much reduced secretion of zymogen granules in response to acetylcholine (ACh)
      stimulation, whereas clustered cells showed a much more negative membrane
      potential and potent exocytotic secretion. The isolated single cells became
      vertically flattened due to the loss of supporting adhesions with nearby cells,
      and the granule-attached luminal membrane was severely reduced versus that of
      clustered cells. However, polarized Ca(2+) signals and mitochondrial
      localizations were relatively well preserved in the isolated single cells, in
      that Ca(2+) release by ACh commenced at the indented luminal membrane. In
      clusters, the Ca(2+) release site was closest to the lumen where more than three
      cells met or at the tips of conical regions of the luminal membrane. These
      findings suggest that the dissociated single pancreatic acinar cells preserve an
      intact Ca(2+) signaling machinery but alter in shape and have impaired exocytotic
      functions and resting membrane potentials.

PMID- 15036955
TI  - Atresia ani with diphallus and separate scrota in a calf: a case report.
AB  - Atresia ani, a common genetic defect in animals, is often accompanied by
      urogenital defects in calves. This paper reports a case of atresia ani with
      diphallus and separate scrota in a calf. The calf was born with atresia ani;
      surgery (to open the anus) was performed 3 days after birth. No urogenital
      abnormalities were noticed until 4 months after birth. At that time, two separate
      scrota (each containing a testis) and a sac-like structure in the middle of two
      scrota, were visible. The gait was abnormal, with abduction of the hind limbs
      while walking. Additionally, the hind legs appeared wider than usual at the hip
      joints. Two weeks later, two peni (diphallia) was observed, each in a separate
      preputial sheath. The calf had a normal karyotype on cytogenetic examination.
      Plasma concentrations of testosterone at 5.5, 6, and 7 months of age were 3.5,
      1.9, and 1.7 ng/ml, respectively. At necropsy (7 months of age), the prepuce was
      thick and the glans of the right penis was adhered to the prepuce. The left penis
      did not have a urethra or retractor penis muscles. The sac-like structure in the
      middle of the two scrota contained the urinary bladder and a loop of small
      intestine. The pubic bone had failed to fuse at the pelvic symphysis. In
      conclusion, this is the first reported case of atresia ani with diphallus,
      separate scrota, and pubic bone separation in a calf.

PMID- 15036954
TI  - Separation of fluorescence signals from Ca2+ and NADH during cardioplegic arrest
      and cardiac ischemia.
AB  - Determinations of intracellular [Ca(2+)](i) during ischemia using fluorescent
      indicators are hampered by overlapping cellular autofluorescence (AF), which
      largely depends on NADH. If Ca(2+) is to be determined under different kinds of
      ischemia, signal separation merits special attention. We used triple wavelength
      excitation fluorescence to separate autofluorescence from [Ca(2+)]-dependent fura
      2 fluorescence. Excitation at 360 nm served as third, Ca(2+)-insensitive
      wavelength. Using an appropriate evaluation procedure, we separated Ca(2+)
      dependent signals from autofluorescence which is semiquantitatively associated
      with NADH, an indicator of the cellular redox state. We compared changes of
      [Ca(2+)](i) in isolated hearts during ischemia following cardioplegic arrest with
      those after transient stop of nutritive perfusion. We observed [Ca(2+)]
      transients in spontaneously beating hearts, persisting during ischemic episodes,
      and an increase of mean [Ca(2+)](i). In contrast, cardioplegic arrest stopped
      periodical [Ca(2+)](i) transients and heart beats simultaneously. [Ca(2+)](i)
      remained at diastolic values, tended to decrease during the first minutes of
      cardioplegic arrest and then increased slowly. Autofluorescence increased under
      both conditions. During ischemia, this increase was faster than in cardioplegia
      experiments. It started after the last heart beat despite persisting perfusion.
      Our measurements demonstrate that rhythmical heart beat is essential for
      sufficient perfusion. Reduced [Ca(2+)](i) under cardioplegic arrest may influence
      metabolism.

PMID- 15036956
TI  - In vitro maturation and transfer of equine oocytes after transport of ovaries at
      12 or 22 degrees C.
AB  - Transportation of equine ovaries would allow shipment of oocytes for research
      purposes or transfer after the death of a valuable mare. The objective of this
      study was to compare two temperatures for maintaining ovaries during a transport
      interval of 18-24 h. The goal was to obtain pregnancies after transport of
      ovaries, maturation of oocytes in vitro, and transfer of oocytes. Each shipment
      was composed of ovaries four to seven mares collected from an abattoir. From each
      mare, one ovary was packaged at approximately 12 degrees C, and the other was
      packaged at approximately 22 degrees C. Upon arrival at our laboratory, oocytes
      were collected and cultured for 24 h. For each transfer, between 9 and 15 oocytes
      from each group were placed into the oviducts of estrous mares through standing
      flank laparotomies. Recipients received human chorionic gonadotropin (hCG; 2000
      IU, i.v.) 30-36 h before transfer (to synchronize ovulation). Recipients were
      inseminated 18-20 h before transfers with 2 x 10(9) progressively motile sperm.
      Uteri of recipients were examined with ultrasound to determine the number of
      developing embryos. On Day 16 ( ovulation = day 0), developing embryos were
      recovered by uterine lavage. Parentage verification was performed on recovered
      vesicles. Pregnancy rates were analyzed by Chi-square. The percentage of oocytes
      that developed into embryonic vesicles on Day 16 was not different between
      transport temperatures (22 degrees C, 13/73, 18% versus 12 degrees C, 11/73,
      15%). In conclusion, pregnancies were obtained from in vitro matured oocytes that
      were recovered from ovaries transported for 18-24h at 12 or 22 degrees C.

PMID- 15036958
TI  - Effect of grazing system on fetal development in Nellore cattle.
AB  - Intensive grazing systems for beef females, based on abundant availability of
      high quality forages and supplementary concentrates, may affect fetal
      development. The objective of this study was to determine the effect of grazing
      system on length of gestation, fetal development, and characteristics of the calf
      at birth. Twenty-four pregnant (bred to Nellore bulls) Nellore females were
      allocated into two groups. The control group (G1) grazed Brachiaria decumbens
      (signal grass) in a traditional (extensive) grazing system and the second group
      (G2) were managed on Panicum maximumcv. Tanzania 1 (Tanzania grass) in an
      intensive grazing system. Fetal development was evaluated by ultrasonography on
      days 31, 45, 59, 94, 122, 220, and 255 of gestation. The diameter of the amniotic
      and allantoic cavities, crown-rump length, circumference, and diameter of the
      head and ocular orbit were determined. At birth, calves were weighed and height,
      length, thoracic circumference, and ocular orbit and bi-parietal diameters were
      measured. There were no differences (P > 0.05) in fetal development. The G1 cows
      had a longer gestation period (4.5 days; P<0.05) and their calves had greater
      (P<0.05) weight, height, length, and thoracic circumference at birth. In
      conclusion, Nellore females raised under intensive pasture management conditions,
      had significantly shorter gestation and smaller calves at birth than those raised
      under extensive pasture management conditions. Therefore, adoption of new
      management practices (e.g. intensive pasture management), should take into
      consideration animal behavior and productivity.

PMID- 15036957
TI  - Attempts to enhance production of porcine chimeras from embryonic germ cells and
      preimplantation embryos.
AB  - Porcine embryonic germ (EG) cells share common features with porcine embryonic
      stem (ES) cells, including morphology, alkaline phosphatase activity and capacity
      for in vitro differentiation. Porcine EG cells are also capable of in vivo
      development by producing chimeras after blastocyst injection; however, the
      proportion of injected embryos that yield a chimera and the proportion of cells
      contributed by the cultured cells in each chimera are too low for practical use
      in genetic manipulation. Moreover, somatic, but not germ-line chimerism, has been
      reported from blastocyst injection using porcine ES or EG cells. To test whether
      efficiency of chimera production from blastocyst injection can be improved upon
      by changing the host embryo, we used as host embryos four groups according to
      developmental stage or length in culture: fresh 4-cell and 8-cell stage embryos
      subsequently cultured into blastocysts, fresh morulae, fresh blastocysts, and
      cultured blastocysts. Injection and embryo transfer of fresh and cultured
      blastocysts produced similar percentages of live piglets (17% versus 19%). Four
      piglets were judged to have a small degree of pigmentation chimerism, but
      microsatellite analysis failed to confirm chimerism in these or other piglets.
      Polymerase chain reaction analysis for detection of the porcine SRY gene in
      female piglets born from embryos injected with male EG cells identified six
      chimeras, at least one, but not more than two, from each treatment. Chimerism was
      confirmed in two putative pigmentation chimeras and in four piglets without overt
      signs of chimerism. The low percentage of injected embryos that yielded a chimera
      and the small contribution by EG cells to development of each confirmed chimera
      indicated that procedural changes in how EG cells were combined with host embryos
      were unsuccessful in increasing the likelihood that porcine EG cells will
      participate in embryonic development. Alternatively, our results suggested that
      improvements are needed in EG cell isolation and culture procedures to ensure in
      vitro maintenance of EG cell developmental capacity.

PMID- 15036959
TI  - Effects of dietary L-carnitine supplementation on semen characteristics in boars.
AB  - In some species, dietary supplementation with L-carnitine has been reported to
      increase sperm concentration and sperm motility. The objective of these
      experiments was to test the hypothesis that L-carnitine supplementation improves
      the semen characteristics of boars. In Experiment 1, boars (258 days of age) were
      fed daily a control diet (n = 9) or the control diet plus L-carnitine (500mg per
      day; n = 9 ). Semen was collected weekly from Weeks 0 to 15 and on 4 consecutive
      days during Week 16. Experiment 2 was similar to Experiment 1 except boars ( n =
      10 per treatment) were 504 days of age. For the weekly and intensive collections
      there were no consistently positive effects of treatment on semen volume, sperm
      concentration, total spermatozoa, or sperm motility. Spermatozoa from L-carnitine
      treated boars did not display an enhanced ability to maintain motility during 7
      day liquid storage. In conclusion, indicators of semen quality were not enhanced
      by dietary supplementation of L-carnitine in boars.

PMID- 15036960
TI  - Canine pyometra: a study of the urinary proteins by SDS-PAGE and Western blot.
AB  - Canine pyometra often causes glomerulonephritis by immune complex deposition in
      the glomeruli. Proteinuria, ranging from moderate to severe, may be present
      secondary to renal damage. To determine urinary protein excretion due to
      pyometra, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE)
      was conducted on urine from 15 bitches with pyometra and 10 healthy bitches. To
      characterize urinary immunoglobin excretion, Western blot analysis of the urine
      samples using antibodies to canine IgG and IgA was also performed. Nine bands
      were detected by electrophoresis in bitches with pyometra, while only four were
      detected in the healthy animals. The urinary proteins from bitches with pyometra
      were primarily of glomerular origin; 58% were of medium-high molecular weight
      (MW), and the remainder were low MW. None of the healthy dogs had IgG or IgA in
      their urine, whereas three bitches with pyometra had IgG in their urine and
      another bitch with pyometra had both IgG and IgA. The low proportion of bitches
      with urinary immunoglobins was probably be due to early diagnosis of the disease.
      Although only a limited number of dogs was used, this study is apparently the
      first to characterize the electrophoretic pattern of urinary proteins and to
      quantify urinary excretion of IgG and IgA in bitches with pyometra.

PMID- 15036961
TI  - Seasonal variation in the endocrine-testicular function of captive jaguars
      (Panthera onca).
AB  - Captive adult male jaguars (Panthera onca) from two locations in southeast Brazil
      were studied to evaluate the effects of season on endocrine and testicular
      function. For assessment of testicular steroidogenic activity, androgen
      metabolite concentrations were measured in fecal samples collected one to three
      times per week over 14 ( n=14 ), 9 ( n=1 ) or 7 months ( n=1 ). To assess
      seasonality, data were grouped by season (summer: December-February; autumn:
      March-May; winter: June-August; spring: September-November). Additionally,
      samples collected in the dry season (March-August) were compared with those
      collected in the wet season (September-February). There were no differences (
      P>0.05 ) in fecal androgen concentrations in samples collected in spring, summer,
      autumn, and winter ( 480.8+/-50.4 ng/g, 486.4+/-42.0 ng/g, 335.4+/-37.7 ng/g, and
      418.6+/-40.4 ng/g dry feces). However, there were differences ( P<0.05 ) in fecal
      androgen concentrations between the dry and wet seasons ( 380.5+/-28.0 ng/g
      versus 483.9+/-32.3 ng/g dry feces). Sperm samples, collected from all males
      twice (approximately 6 months apart) were similar; mean (+/-S.E.M.) motility,
      concentration and morphology were 57.0 %4.5%, 6.3+/-2.4 x 10(6) ml(-1), and
      60.8+/-3.1 %, respectively. In conclusion, androgen metabolite concentrations in
      the captive male jaguar were not affected by season, but there was a difference
      between the wet and dry periods. Further research is needed to verify these
      results.

PMID- 15036962
TI  - Do high progesterone concentrations decrease pregnancy rates in embryo recipients
      synchronized with PGF2alpha and eCG?
AB  - The objective of this study was to evaluate the effects of equine chorionic
      gonadotropin (eCG) treatment on the number of induced accessory corpora lutea
      (CL), plasma progesterone concentrations and pregnancy rate in cross-bred heifers
      after transfer of frozen-thawed (1.5M ethylene glycol) embryos. All recipients
      received 500 microg PGF2alpha (dl-cloprostenol, i.m.) at random stages of the
      estrous cycle (Day 0) and were observed for estrus for 7 days. On Day 14, heifers
      detected in estrus between 2 and 7 days after PGF2alpha treatment were randomly
      allocated to four groups ( n=83 per group) and given 0 (control), 200, 400, or
      600 IU of eCG. Two days later (Day 16), these recipients were given PGF2alpha and
      observed for estrus. Six to eight days after detection of estrus, plasma samples
      were collected to determine progesterone concentration and ultrasonography was
      performed to observe ovarian structures. Heifers with multiple CL or a single CL
      >15 mm in diameter received an embryo by direct transfer. Embryos of excellent
      and good quality were thawed and transferred to the recipients by the same
      veterinarian. Pregnancy was diagnosed by ultrasonography and confirmed by
      transrectal palpation 21 and 83 days after embryo transfer (ET), respectively.
      Plasma progesterone concentrations on the day of transfer (Day 7 of the estrous
      cycle) were 3.9+/-0.7, 4.2+/-0.4,6.0+/-0.4 and 7.8+/-0.6 ng/ml for groups
      Control, 200, 400, and 600, respectively (Control versus treated groups P=0.009;
      200 versus 400 and 600 groups P=0.0001; and 400 versus 600 P=0.012 ). Conception
      rates 83 days after ET were 41.9, 50.0, 25.0, and 20.9% for groups Control, 200,
      400, and 600, respectively (200 versus 400 and 600 groups P=0.0036 ). In
      conclusion, an increase in progesterone concentration, induced by eCG treatment,
      did not improve pregnancy rates in ET recipients. Conversely, there was a decline
      in conception rates in the animals with the highest plasma progesterone
      concentrations.

PMID- 15036963
TI  - Accuracy of transrectal ultrasonography for determination of pregnancy in sheep:
      effect of fasting and handling of the animals.
AB  - The present study was performed to investigate the effect of previous fasting and
      lifting of the abdomen of the ewes during transrectal ultrasonographic scanning
      on the results of early pregnancy diagnosis. Ewes of four flocks (A, B, C and D;
      all Awassi x Merino ewes, n = 1247 ) aged 0.7-10 years were used in this study.
      These ewes were estrus synchronized and artificially inseminated. From 2 weeks
      later onwards, fertile rams were kept with the ewes of flocks A, B and C ( n=949
      ) for natural breeding, while ewes of flock D ( n=298 ) were re-inseminated 17
      days later. Transrectal ultrasonography (5 MHz) was carried out in ewes of flocks
      A, B and C on four separate occasions but only once in ewes of flock D. For final
      analysis, animals were divided over two groups: ewes of Group 1 ( n=949 scans)
      were scanned in a standing position within the milking parlor. Animals of Group 2
      ( n=764 scans) were scanned by the same operator and with the same scanning
      technique, but these ewes were fasted for 12h prior to scanning and the abdominal
      wall was lifted, just in front of the udder during scanning. The sensitivity of
      the test for diagnosing pregnancy at Days 18-24, 25-30, 31-40 and 41-50 was 21.8,
      32.3, 63.3 and 50% in Group 1, and 46, 92.5, 92.3 and 96.8% in Group 2,
      respectively. Only within Group 1, the sensitivity of the test was higher in
      young ewes (0.7-2 years) than in older ones (>2-10 years). Significant
      differences were observed at scan periods Days 18-24 and Days 41-50 of gestation.
      It is concluded that, fasting prior to scanning and lifting the abdomen during
      scanning significantly improve the accuracy of transrectal ultrasonographic
      pregnancy diagnosis in Awassi x Merino ewes.

PMID- 15036965
TI  - Body and organ weight, sperm acrosomal status and reproduction after genistein
      and diethylstilbestrol treatment of CD1 mice in a multigenerational study.
AB  - The effect of genistein (GEN) and diethylstilbestrol (DES) on body weight, weight
      of different organs, sperm acrosomal status and in vivo fertility of CD1 mice was
      tested in a multigenerational study. The adult parental generation of mice and F1
      and F2 generations were exposed to selected drugs for all their life. GEN had
      effect on different body parameters of 30-day-old mice, but not of adult mice in
      the first generation. Contrary to that, treatment by DES had a strong effect on
      body weight, other body parameters and on the levels of serum hormones. In the
      first generation only sterile pairs of mice were observed. Monoclonal antibody
      against mouse intra-acrosomal sperm protein was used for analysis of the acrosome
      state and as biomarkers of sperm damage. In the control groups, about 93% of
      acrosome-reacted sperm was found, acrosome staining decreased to 78-84% (P<0.01).
      However, the GEN had no effect on fertility of CD1 mice. On the other hand, the
      fertility of mice exposed to DES was disrupted, especially in the first
      generation.

PMID- 15036964
TI  - Fixed-time artificial insemination of postpartum beef cows at 72 or 80 h after
      treatment with the MGA Select protocol.
AB  - The objective was to determine the appropriate timing of fixed-time artificial
      insemination (AI) following administration of the MGA Select protocol. Cows at
      two locations (Location 1, n=114; Location 2, n=97 ) were assigned to fixed-time
      AI at 72 or 80 h by age, body condition score (BCS), days postpartum (DPP), AI
      technician, and sire. All cows were synchronized with the MGA Select protocol,
      consisting of oral administration of melengestrol acetate (MGA; 0.5mg/hd per day)
      for 14 days, GnRH (Cysotrelin, 100 microg, i.m.; Day 26) 12 days after MGA
      withdrawal, followed in 7 days with PGF(2alpha) (PG; Lutalyse, 25mg i.m.; Day
      33). Cows were inseminated at 72 h ( n=108 ) or 80 h ( n=103 ) after PG and GnRH
      (100 microg) was given at insemination. Location was not significant and,
      therefore, was removed from the model. Mean BCS ( 5.2+/-0.1, 72 h; 5.3+/-0.1, 80
      h) and DPP ( 34+/-2, 72 h; 35+/-2, 80 h) did not differ ( P>0.1 ) between
      treatments. Serum progesterone concentrations 7 and 1 day prior to MGA were used
      to determine pre-treatment cyclicity: cows with at least one sample with
      progesterone > or =1 ng/ml were defined as cyclic (33/108, 31%, 72 h, versus
      32/103, 31%, 80 h; P>0.1). Cows with serum progesterone concentrations > or =1
      ng/ml on the day of PG were defined as responding to the synchronization protocol
      (74/108 (69%), 72 h versus 69/103 (67%), 80 h; P>0.1 ). Although pregnancy rates
      were higher ( P<0.05 ) for cows inseminated at 72 h (69/108, 64%) versus 80 h
      (52/103, 50%) after PG, pregnancy rates at the end of the breeding season did not
      differ ( P>0.1 ) between treatments (98/108 (91%), 72 h; 88/103 (85%), 80 h). In
      conclusion, pregnancy rates were higher when postpartum beef cows synchronized
      with the MGA Select protocol were inseminated at 72 h versus 80 h after PG.

PMID- 15036966
TI  - Effect of tamoxifen citrate on reproductive parameters of male dogs.
AB  - Tamoxifen is a synthetic, nonsteroidal Type I antiestrogenic compound that
      competitively blocks estrogen receptors with a mixed antagonist-agonist effect.
      The manifestation of these different actions depends on each species, organ,
      tissue and cell type considered. Very little is known about the effect of
      antiestrogens in dogs. The objectives of this study were to determine the effects
      of tamoxifen citrate on some testis, prostate, hormone, and semen parameters in
      seven Beagle dogs with uncomplicated spontaneous benign prostatic hyperplasia.
      Two dogs were normospermic, four were oligozoospermic, and one was azoospermic.
      The dogs were allocated to a control pre-treatment period, followed by a
      treatment period, and five post-treatment periods (the duration of each period
      was 4 weeks). During the treatment period, 2.5mg tamoxifen citrate was given p.o.
      daily for 28 days to all the dogs. Maximum scrotal width, testicular consistency,
      libido semen parameters, prostatic volume, serum testosterone concentrations, and
      side effects were assessed. Tamoxifen negatively affected testis size and libido
      (P<0.01), and decreased prostatic volume (P<0.01) and testosterone concentrations
      during treatment. Semen quality deteriorated to nadir values (P<0.01)
      approximately one spermatic cycle after treatment and returned to pre-treatment
      values on the second cycle after treatment in all the dogs, except one young
      oligoazoospermic dog, in which the sperm count was higher ( P<0.01 ) at that
      time. No side effects were observed and fertility was conserved at the end of the
      study. Tamoxifen acted more like an agonist than antagonist on the gonadal axis
      and, therefore, upon both the prostate and testis. Therefore, tamoxifen may have
      therapeutic applications in dogs.

PMID- 15036967
TI  - Ovarian follicular dynamics and hormonal profiles in heifer and mixed-parity
      Mediterranean Italian buffaloes (Bubalus bubalis) following an estrus
      synchronization protocol.
AB  - The primary objective was to elucidate ovarian follicular dynamics and hormonal
      profiles in nulliparous heifer (HE; n = 11 ) and mixed-parity (MP; n=10 )
      Mediterranean Italian water buffaloes (Bubalus bubalis) following an estrus
      synchronization protocol. Both groups received a progesterone releasing
      intravaginal device (PRID) implant for 10 days; a luteolytic dose of synthetic
      prostaglandin was given 7 days after PRID insertion. Daily ultrasound monitoring
      and collection of blood to determine plasma concentrations estradiol and
      progesterone started 1 day after PRID removal and lasted for 55 and 65 days in HE
      and MP buffaloes, respectively. Data analysis was restricted to the first 5 days
      after PRID removal and to one estrus cycle following induced ovulation. The HE
      buffaloes were not inseminated and only one ovulated within 5 days after PRID
      removal; the remainder ovulated between 8 and 48 days after PRID removal (except
      one in which ovulation was never detected). All HP buffaloes were inseminated 72,
      96 and 120 h after PRID removal; seven buffaloes ovulated within 5 days after
      PRID removal and two were pregnant. Mean diameter of the largest follicle was
      significantly smaller in HE than MP buffaloes the first 4 days after PRID
      removal. There was a parity by time interaction ( P=0.0047 ) for plasma
      progesterone concentrations; progesterone was higher in HE than MP buffaloes 1
      day after PRID removal, but the converse was true 2 days after PRID removal.
      After induced ovulation, HE buffaloes exhibited a one-wave ( n=5; length of
      cycle, 8-12 days), two-wave ( n=4; range: 20-26 days) or three-wave cycle ( n=1;
      25 days). In contrast, all non-pregnant MP buffaloes ( n=8 ) had a two-wave cycle
      (range: 19-25 days). For buffaloes with two-wave cycles, the growth rate and
      diameter of the largest follicle was significantly smaller in HE than MP
      buffaloes for both the first follicular wave (1.3mm versus 1.7 mm per day and
      10.5 mm versus 13.3 mm, respectively) and the second follicular wave (1.0 mm
      versus 1.3 mm per day and 11.0 mm versus 13.8 mm). In conclusion, there were many
      significant morphological and endocrine differences between HE and MP buffaloes.

PMID- 15036968
TI  - Study of fertilising capacity of spermatozoa after heterospermic insemination in
      rabbit using DNA markers.
AB  - The aim of this study was to evaluate the fertilising capacity of males belonging
      to a rabbit line selected for growth rate using heterospermic insemination and
      genetic markers. Semen from five males was used to make pools of three of them,
      and to perform homospermic insemination. Insemination was carried out in
      receptive multiparous lactating does with 6 million spermatozoa per insemination
      dose. DNA from 360 young rabbits born from heterospermic insemination, 5 sires
      and 42 does were amplified to nine microsatellite loci for determination of the
      offspring rate per male. Although each female was inseminated with the same
      number of spermatozoa from each male (2 million from a total dose of 6 million),
      sperm from one male was always dominant, notable differences being observed in
      the offspring among the males with similar semen quality (83-68% from dominant
      male versus 31-0% from non-dominant, P<0.05 ).

PMID- 15036969
TI  - Effect of a vitrification protocol on the lactate dehydrogenase and glucose-6
      phosphate dehydrogenase activities and the hatching rates of Zebrafish (Danio
      rerio) and Turbot (Scophthalmus maximus) embryos.
AB  - Vitrification, is the most promising option for the cryopreservation of fish
      embryos but requires high concentrations of potentially toxic cryoprotectants. In
      this study, embryos from Turbot and Zebrafish, each in two developmental stages,
      were submitted to a four stepwise cryoprotectant incorporation protocol. After
      incubation in the vitrificant solution (5M dimethyl sulfoxide, 2M methanol, 1M
      ethylen-glycol and 10% sucrose) embryos were loaded in straws and plunged into
      liquid nitrogen. The activity of two cytoplasmic enzymes, LDH and G6PDH, and the
      hatching rates were analyzed in control embryos, those subjected to the
      cryoprotectant solutions and in frozen/thawed embryos. Results showed that the
      cryoprotectants incorporation protocol did not have important effects on the
      analyzed enzymatic activities, which remained at similar levels to that in
      control embryos but significantly reduced the hatching rates. Turbot was less
      sensitive than Zebrafish to the toxic effect of the cryoprotectants, achieving
      hatching rates of 74.8% in comparison with fresh control embryos at G stage,
      whereas in Zebrafish only 17.7% of hatching was reported with five somites
      treated embryos. In Turbot, G stage was more resistant to the cryoprotectants and
      thus more convenient for further vitrification studies. After vitrification no
      survival was recorded and enzymatic activities dropped significantly,
      particularly in Zebrafish, indicating cell damage and loss of cytoplasmic
      enzymes. Nevertheless, total cell lysis was not produced, and once again Turbot
      was more resistant to the effect of vitrification, particularly at the later
      stage. In that stage, Turbot embryos showed around 50% of G6PDH activity after
      vitrification, in comparison with the control, indicating the preservation of
      some cellular activity after freezing-thawing, despite the loss of developmental
      ability.

PMID- 15036971
TI  - Interrelationships of estradiol, inhibin, and gonadotropins during follicle
      deviation in pony mares.
AB  - The changes in circulating concentrations of FSH, LH, estradiol, and total
      inhibin associated with the beginning of follicle diameter deviation were
      compared among the last anovulatory follicular wave of the year and the first and
      second ovulatory waves in pony mares ( n=7 ). Follicle diameters and circulating
      hormone concentrations for each wave were normalized to the observed beginning of
      deviation (Day 0). Follicle deviation was demonstrated during the anovulatory
      wave as well as during the ovulatory waves, and the diameter of the future
      dominant follicle at the beginning of deviation was similar for the three waves
      (overall mean: 23.7+/-0.6 mm). Circulating estradiol concentrations did not
      increase during the last anovulatory wave but increased similarly for the two
      ovulatory waves, beginning near the onset of deviation. There were no differences
      among waves in concentrations of inhibin encompassing deviation. The FSH
      concentrations for the wave-stimulating FSH surge did not differ significantly
      among the three waves; combined for the three waves, concentrations decreased
      between Days -3 and 7. Circulating LH did not increase during the last
      anovulatory wave but increased during the first and second ovulatory waves
      beginning on Days 6 and -2, respectively. Results indicated that the increase in
      circulating estradiol at the beginning of deviation was not required for
      suppression of the wave-stimulating FSH surge and the initiation of deviation,
      based on an estradiol increase in association with deviation during the ovulatory
      waves but not during the anovulatory wave. Concentrations of inhibin were similar
      among waves and, therefore on a temporal basis, the similar suppression of FSH
      was attributable to inhibin. The later increase in LH before the first ovulation
      was not attributable to estradiol, based on the similarity between the two
      ovulatory waves in the increasing estradiol concentrations.

PMID- 15036970
TI  - Improved in vitro development of porcine embryos with different energy substrates
      and serum.
AB  - The effect of replacing 5.5 mM glucose in North Carolina State University (NCSU)
      23 medium with 0.5 mM pyruvate/5.0 mM lactate on porcine IVF embryo development
      was investigated in Experiment 1. Culturing embryos with pyruvate/lactate for 7
      days or with pyruvate/lactate from Days 0 to 2, and then glucose from Days 2 to 7
      improved cleavage rates. In Experiment 2, embryos were cultured for 7 days in
      pyruvate/lactate containing NCSU-23 medium supplemented with 0.05% PVA, 0.4% BSA
      or 10% fetal bovine serum (FBS). The BSA supplement increased the rates of
      cleavage, blastocyst formation, and the number of total cells in blastocysts. In
      Experiment 3, embryos were cultured in pyruvate/lactate containing NCSU-23 medium
      supplemented with 0.4% BSA for 7 days (BSA-PL), 0.4% BSA from Days 0 to 4 and
      then 10% FBS from Days 4 to 7 (BSA-PL-->F ) or 0.4% BSA from Days 0 to 7 with
      addition of 10% FBS (BSA-PL + F ) at Day 4. More blastocysts in BSA-PL--> F and
      hatching or hatched blastocysts in BSA-PL-->F and BSA-PL+F were obtained. Total
      cell number in blastocysts derived from BSA-PL-->F and BSA-PL+F were increased.
      Our results demonstrated that supplementing pyruvate/lactate containing NCSU-23
      medium with 0.4% BSA for 4 days and replacing it with 10% FBS for another 3 days
      improved porcine IVF embryo development.

PMID- 15036972
TI  - Ultrasonographic characterization of the ovaries in non-pregnant first served
      sows and gilts.
AB  - This study was aimed firstly, to examine the ovaries in non-pregnant first served
      sows and gilts by transcutaneous ultrasonography and secondly, to evaluate the
      suitability for this procedure to be performed routinely on farms. Two thousand
      five hundred and twenty-three females on a 1250-sow unit, synchronized with
      Regumate (gilts only) and/or gonadotropins (sows and gilts) not detected as
      returned to estrus by daily boar contact prior to scanning were
      ultrasonographically tested for pregnancy between days 20 and 114
      postinsemination (p.i.). Of 256 sows (S) and 130 gilts (G) found to be non
      pregnant the ovaries were visualized in 87.1 and 80.0% of them, respectively.
      Ovarian findings were: corpora lutea (CL); follicles of 2-6mm (F(2-6)); peri
      ovulatory ovarian structures (POS; comprising follicles of 7-8mm and corpora
      haemorrhagica); single cysts (SC); oligocystic ovarian degeneration (OOD) and
      polycystic ovarian degeneration (POD). Their incidence was: CL>F2-6>POS>POD (
      P<0.05 ) in both S and G. POD and SC plus OOD were more frequently in S ( P<0.05
      ). The ovarian findings were related to the intervals of regular (days 18-25 p.i.
      (R1), 38-46 p.i. (R2)) and irregular service returns (days 26-37 p.i. (IR1), 47
      114 p.i. (IR2)). Comparison within intervals: CL tended to be more frequently
      with P<0.05 only at IR2 in S. Comparison among intervals (R1 to IR2): The
      percentage of females (1) with CL tended to increase (S and G) and (2) with F2-6
      plus POS decreased significantly (S; P<0.05 ) or tendentiously (G). SC plus OOD
      was higher before R2, POD after IR1 (S and G; P<0.05 ). In conclusion, the
      results indicate a high heterogeneity of ovarian structures in non-pregnant first
      served sows and gilts up to day 114 after service and suggest CL as an important
      cause for a delayed and, rather than POD, a failed service return. The results
      further demonstrate that transcutaneous ultrasonography is an appropriate and
      recommended method for examining the ovaries on farm in female pigs with
      reproductive failures.

PMID- 15036973
TI  - In situ oviduct and uterine pH in cattle.
AB  - Knowledge of oviduct and uterine pH in cattle is lacking mainly because of the
      difficulty of accessing these reproductive tissues, which for the oviduct at
      least necessitates anesthesia. Because halothane anesthesia is known to depress
      respiratory function and thus increase blood CO2 and decrease pH, oviduct and
      uterine pH was measured both in the presence and absence of halothane. Using
      short-term anesthesia with thiopentone only, oviduct pH was measured on days 2-4
      of the estrous cycle and uterine pH on days 6 and 8; there was no significant
      effect of day of the cycle but oviduct pH ( 7.60+/-0.010 ) was greater ( P<0.001
      ) than uterine pH ( 6.96+/-0.009 ). Oviduct pH was higher ( P<0.001 ) and uterine
      pH lower ( P<0.001 ) than venous blood pH ( 7.41+/-0.007 ). Using
      thiopentone/halothane anesthesia, oviduct pH was measured on days 0, 2, 3, 4 and
      6, and uterine pH on days 6, 8 and 14; there was no effect of day of cycle but
      oviduct pH values were generally higher than uterine values and significantly so
      ( P<0.001 ) on day 6 where direct comparison was possible. To our knowledge these
      are the first published in situ measurements of oviduct pH in cattle.

PMID- 15036975
TI  - Efficiency of transgenic rat production is independent of transgene-construct and
      overnight embryo culture.
AB  - The aim of the present work was to study factors affecting the efficiency of
      transgenic technology in rats. We investigated the possible effects of pronuclear
      microinjection of buffer or different DNA-constructs on survival and development
      of rat zygotes in vitro and in vivo as well as the influence of overnight culture
      of these embryos before transfer into pseudopregnant foster mothers. The survival
      rate of zygotes and their development to the two-cell and morula stage was not
      affected by pronuclear microinjection with different DNA-constructs or buffer.
      However, the development to the blastocyst stage was impaired. Nevertheless,
      there was no difference in blastocyst development between zygotes injected with
      DNA-constructs or with buffer. Neither was there a difference in cell number in
      in vitro cultured blastocysts resulting from pronuclear microinjection of a
      transgene compared with non-injected controls. The survival rate to term was
      about 30% irrespective of whether microinjected embryos were transferred
      immediately after microinjection or after overnight culture in vitro. However, a
      reduction in the survival to term was observed for non-injected zygotes when they
      were developed in vitro to the two-cell stage before transfer to a pseudopregnant
      female. The percentage of transgenic rats that resulted from microinjected
      zygotes was similar in all groups regardless of the DNA-construct used (2.7
      10.0%). In conclusion, the main detrimental factor in the microinjection of rat
      zygotes is the introduction of solution in the pronucleus. Overnight culture of
      zygotes between microinjection and oviduct transfer does not decrease the
      efficiency of transgenic rat generation.

PMID- 15036974
TI  - Post-warming hatching and birth of live calves following transfer of in vitro
      derived vitrified water buffalo (Bubalus bubalis) embryos.
AB  - Viability of in vitro-derived vitrified-warmed preimplantation stage buffalo
      embryos were assessed in vitro and in vivo. Oocytes were collected from ovaries
      of slaughtered riverine buffaloes, matured and fertilized in vitro with frozen
      semen from riverine buffalo bull and cultured on cumulus cell monolayers.
      Resultant preimplantation stage embryos were cryopreserved by vitrification with
      ethylene glycol, ficoll and sucrose. Seventy-one frozen embryos were warmed in
      0.5M sucrose and were further cultured in vitro for 72 h to assess hatching rate.
      On the other hand, 95 embryos were transferred non-surgically to riverine buffalo
      recipients to assess development competence in vivo through detection of
      pregnancy and birth of live calves. Hatching rate of 83.10% (59/71) was noted
      among embryos cultured in vitro. Pregnancy rate was 16.36% (9/55) while calving
      rate was 10.91% (6/55) after transfer of in vitro-derived vitrified-warmed
      embryos to recipient animals. Six healthy and normal calves with average birth
      weight of 38.75+/-3.55 kg were born from the transferred embryos. These results
      indicate the viability of vitrified in vitro-derived buffalo embryos and the
      potential application of in vitro embryo production and vitrification techniques
      for production and transport of buffalo embryos from germplasm-rich sources to
      guarantee genetic improvement in many parts of the world.

PMID- 15036976
TI  - Room temperature storage of mouse epididymal spermatozoa: exploration of factors
      affecting sperm survival.
AB  - To explore optimal conditions for in vitro sperm survival, we examined the
      effects of several media used for murine egg culture and in vitro fertilization
      (IVF; including M16, M2, PB1, TYH, and CZB) on motility of murine spermatozoa
      stored at 22 degrees C under paraffin oil. Of media tested, M2 medium, that had
      been adjusted to pH 7.2 by adding N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic
      acid (HEPES), was found to be the best. Addition of various concentrations of
      HEPES to TYH did not improve sperm survival, suggesting that HEPES (and probably
      neutral pH) do not enhance survival of murine sperm. Since M16 has higher amounts
      of bicarbonate than M2 (25 mM versus 4.15 mM), four variations of M16 media
      containing 4.15, 8.30, 16.60, or 33.20 mM bicarbonate were prepared and tested.
      The modified M16 media with 4.15-16.60 mM bicarbonate yielded good sperm survival
      (comparable to M2 medium), while relatively high concentrations of bicarbonate
      (ranging from 16.60 to 33.20 mM) were deleterious to isolated sperm, suggesting
      the need for a minimum level of residual bicarbonate. However, the mechanism by
      which the lifespan of spermatozoa is extended remains unknown. The in vitro
      fertilizing abilities of spermatozoa left in M2 medium for 1, 3, and 5 days at 22
      degrees C were 52.5, 21.8, and 7.0%, respectively, when the cleavage rate to the
      two-cell stage was examined. Transfer of two-cell embryos produced in vitro with
      spermatozoa stored for 1, 3, and 5 days at 22 degrees C resulted in production of
      fetuses with efficiencies of 42.5, 23.4, and 12.5%, respectively, which were
      lower than that of embryos derived from in vitro fertilization with fresh
      spermatozoa (68.1%). In conclusion, spermatozoa kept in M2 medium for up to 5
      days at 22 degrees C can fertilize oocytes.

PMID- 15036977
TI  - Induction of abortion in queens by administration of cabergoline (Galastop)
      solely or in combination with the PGF2alpha analogue Alfaprostol (Gabbrostim).
AB  - The efficacy of cabergoline solely or combined with a PGF2alpha analogue in
      inducing abortion at different stages of pregnancy was investigated in 18 queens.
      The queens were assigned to two treatments: Group I ( n=10 )-cabergoline (15
      microg/kg; daily, orally) and Group II ( n=8 )-cabergoline (15 microg/kg; daily,
      orally) combined with alfaprostol (10 microg/kg; every other day,
      subcutaneously). Each group was divided into two subgroups according to the
      duration of pregnancy when treatments started: Group IA ( n=8 ) included queens
      from Days 34 to 42 after mating. Group IB cats ( n=2 ) started treatments on Day
      45 post-mating. Similarly, the combination of cabergoline and PGF2alpha analogue
      was first given to Group IIA ( n=6 ) from Days 25 to 40 of pregnancy and to Group
      IIB ( n=2 ) on Days 45 and 47, respectively. Termination of pregnancies was
      successful in all cats of Group IA, while treatments failed in both cats of Group
      IB, even though seven and eight treatments, respectively, were given. Mean (+/
      S.D.) plasma progesterone concentrations before the start of treatments were
      85.0+/-12.3 nmol/l and decreased within 3 days to 8 nmol/l and subsequently to
      basal values, when the queens aborted (Group IIA, n=6 ) or gave birth prematurely
      (Group IIB, n=2 ). When abortions failed (Group IB, n=2 ), progesterone
      concentrations remained elevated (16.9 and 9.8 nmol/l). Duration of combined
      therapy during late pregnancy in Group IIB ( n=2 ) lasted about 10 days. In both
      cases, premature birth occurred and the kittens died within 16 h after birth.
      Overall, treatments starting on Days 25-42 of pregnancy (Groups IA and IIA) had
      abortion rates of 100%. The average duration of treatments was 5.6+/-1.5 days
      (range, 3-8). Side effects seen were vomiting and occurred in 6 of the 109 (5.5%)
      treatments. In conclusion, pregnancies were successfully terminated in the second
      trimester of feline pregnancy by daily application of cabergoline solely or
      combined with the PGF2alpha analogue alfaprostol (given every other day).
      Cabergoline alone was ineffective in inducing abortion at later stages of
      pregnancy.

PMID- 15036978
TI  - FSH different regimes affect the developmental capacity and cryotolerance of
      embryos derived from oocytes collected by ovum pick-up in donor sheep.
AB  - The objective of the present study was to compare the developmental capacity of
      sheep oocytes obtained by OPU after two different ovarian stimulations, and
      cryotolerance to vitrification procedures of in vitro derived embryos after in
      vitro maturation, fertilisation and culture of these oocytes. Sheep were divided
      into three groups: (A) no treatment (control); (B) constant doses of FSH (FSH-c);
      (C) decreasing doses of FSH (FSH-d). Ovine groups FSH-c and FSH-d were
      synchronised by the insertion of intravaginal sponges left in situ for 7 days;
      FSH (total dose: 96IU) was administered in four doses given every 12h starting on
      Day 5. Twelve hours after the last FSH administration oocytes were collected by
      OPU technique. The control group showed a significantly lower number ( P<0.05 )
      of follicles (166) than FSH-c (294) and FSH-d (317) groups, while the number of
      follicles >5mm was significantly higher ( P<0.01 ) in FSH-d group, showing that
      this protocol stimulates the growth of a different follicle population compared
      to FSH-c group. The control group showed a higher number of <2mm follicles (
      P<0.01 ). We did not find any difference in oocyte quality between the three
      groups and therefore the percentage of discarded oocytes was similar. No
      significant differences were found between control, FSH-c and FSH-d groups in
      terms of maturation (90.9, 85.7 and 87.7%, respectively) and fertilisation rates
      (75.2, 80.9 and 83.7%, respectively) while a significantly higher ( P<0.01 )
      blastocyst rate was observed in the FSH-c group than in the FSH-d and control
      groups (20.4% versus 11.8 and 13.7%, respectively). After vitrification, warming
      and 72 h in vitro culture, the hatching rate was significantly higher ( P<0.01 )
      in the control (87.5%) and FSH-c (90.5%) groups than in the FSH-d group (66.7%).
      Control and FSH-c groups showed a significantly higher ( P<0.001 ) number of
      total cells than FSH-d group ( 217.6+/-26.5 and 203.0+/-33.2 versus 147.5+/-20.2
      ), while no differences were observed in ICM cell rates in the control ( 35.6+/
      3.8 ), FSH-c ( 37.1+/-4.6 ) and FSH-d ( 36.6+/-6.7 ) groups. These results
      indicate that donor sheep stimulated with FSH-c produced better quality oocytes
      and blastocysts showing better cryotolerance than ewes given the decreasing doses
      treatment.

PMID- 15036979
TI  - Activation of sperm motility in striped bass via a cAMP-independent pathway.
AB  - The objective of the present study was to identify the effect of osmolality, ions
      (K+, H+, Ca2+, Mg2+) and cAMP on the initiation of sperm motility in striped bass
      (Morone saxatilis). Striped bass spermatozoa remained motile in solutions
      isotonic to seminal plasma (350 mOsm/kg) until osmolality reached 600 mOsm/kg. K+
      (0-100 mM) had no effect ( p>0.05 ) on sperm motility, and sperm displayed a high
      percentage of motility over a wide range of pH (6.0-8.5). Sperm motility could be
      initiated in Ca2+-free solutions. In contrast, sperm motility was inhibited
      (P<0.01) by solutions containing > or =10 mM Ca2+, and sperm could not be
      reactivated by a Ca2+-free solution. This Ca2+ inhibition was not affected by
      verapamil, a Ca2+ channel blocker. However, if sperm motility was first initiated
      in a Ca2+-free solution, the addition of Ca2+ solutions, up to 80 mM, failed to
      inhibit sperm motility, suggesting that Ca2+ inhibited the initiation of
      motility, but had no control of motile spermatozoa. Mg2+ solutions had similar
      inhibitory effects on sperm motility as Ca2+ solutions. Therefore, initiation of
      motility in striped bass sperm may be related to voltage-gated channels across
      the cell's plasma membrane. Membrane permeable cAMP did not initiate motility of
      quiescent, intact striped bass spermatozoa, and motility of demembranated sperm
      could be activated in the absence of cAMP.

PMID- 15036980
TI  - Developmental capacity of bovine cumulus oocyte complexes after transcriptional
      inhibition of germinal vesicle breakdown.
AB  - Oocytes cultured in the presence of FSH and the transcriptional inhibitor, 5,6
      dichloro-1-beta-d-ribofuranosylbenzimidazole (DRB), remain in meiotic arrest at
      the germinal vesicle (GV) stage. The objectives of this study were to assess the
      kinetics of maturation and the developmental capacity of bovine cumulus oocyte
      complexes (COC) following release from prolonged meiotic arrest by DRB. In
      Experiment I, COC were cultured for 20 h in Tissue culture medium (TCM)-199
      supplemented with 10% estrus cow serum (ECS), 5 microg/ml FSH and 1 microg/ml
      estradiol in the presence of 120 microM DRB. COC were then released from meiotic
      arrest and cultured for 20 h in DRB-free medium. CONTROL COC were cultured for 20
      h in DRB-free medium, with culture initiated concomitant to the release of DRB
      treated COC from meiotic arrest. Nuclear maturation was assessed after 0, 5, 10,
      15, and 20 h of culture in DRB-free medium. The proportion of DRB-arrested
      oocytes reaching metaphase II (MII) following 20 h culture in DRB-free medium was
      not significantly different from controls ( 96+/-4% versus 99+/-4%). In
      Experiment II, COC were cultured for 20 h in TCM-199 supplemented with 10% ECS,
      10 microg/ml LH, 5 microg/ml FSH, and 1 microg/ml estradiol in the presence or
      absence of 120 microM DRB. COC in the DRB-treated group were then washed and
      matured coincident with a second group of control COC for 20 h in DRB-free
      medium. COC in both groups were fertilized and then randomly assigned to one of
      two culture systems: TCM-199 + 10%ECS or mSOF + 0.6% fatty acid-free BSA.
      Development was assessed at 72 h post insemination (hpi), 168 hpi (Day 7) and 216
      hpi (Day 9). In this experiment, culture with DRB-arrested oocyte maturation at
      the GV stage (DRB, 85+/-3% GV; CONTROL, 2+/-3% GV; P<0.001 ). Following release
      from arrest, maturation and fertilization, the proportion of COC that cleaved by
      72 hpi was decreased by treatment with DRB (DRB: 78+/-3% versus CONTROL: 90+/-3%;
      P<0.05). However, no effect of DRB was found on the proportion of cleaved zygotes
      that reached the blastocyst stage on either Day 7 or Day 9 of culture (Day 7: DRB
      16+/-2% versus CONTROL, 21+/-2%; Day 9: DRB 23+/-3% versus CONTROL, 31+/-3%).
      More embryos reached the blastocyst stage in the TCM-199/serum culture system
      compared to the mSOF/BSA system on both Days 7 and 9 (Day 7: TCM-199, 23+/-2%
      versus mSOF, 13+/-2%, P<0.05; Day 9: TCM-199, 32+/-3% versus mSOF, 22+/-3%,
      P<0.05 ). In summary, bovine COC maintained in meiotic arrest for 20 h by culture
      in the presence of the transcriptional inhibitor DRB retained their capacity to
      develop to the blastocyst stage after fertilization in vitro.

PMID- 15036981
TI  - Effect of post-insemination supplementation with PRID on pregnancy in repeat
      breeder Holstein cows.
AB  - Embryonic mortality contributes to repeat-breeding in dairy cows; luteal
      insufficiency is a known cause of embryonic mortality. The objective of this
      study was to assess the efficacy of supplementation with exogenous progesterone
      for 14 days on pregnancy maintenance in inseminated repeat-breeder dairy cows. On
      Day 5 after insemination, treated cows ( n=143 ) received a modified PRID (i.e.
      without estradiol capsule), which was removed on Day 19. Control cows ( n=148 )
      did not receive any treatment. Overall there was no effect of PRID
      supplementation on pregnancy rates. However, when the study population was
      stratified by parity and stage of lactation, PRID supplementation significantly
      improved pregnancy rate in first and second parity late lactation cows (risk
      ratio = 3.26; 95% CI 1.22, 8.69). Pregnancy rates did not differ between PRID
      treated cows with ( n=81 ) and without vaginitis. Control cows tended ( P=0.077 )
      to have a higher proportion of abortions than PRID-treated cows (7/50 versus
      2/51, respectively). In conclusion, young late lactation repeat-breeder cows
      benefited from progesterone supplementation, in terms of maintaining pregnancy
      until traditional time of pregnancy diagnosis.

PMID- 15036982
TI  - Effect of biostimulation on uterine involution, early ovarian activity and first
      postpartum estrous cycle in beef cows.
AB  - The objective was to determine the effect of biostimulation (bull-exposure) on
      uterine involution (UI), plasma progesterone concentration (P4), size of largest
      follicle (LF), number of follicles larger than 5 mm ( F > or = 5 ), presence of
      fluid in uterine lumen (PF), presence of luteal tissue (LT), and length of the
      first estrous cycle postpartum (LEC). Ninety Angus cows with calves were
      allocated by parity and body frame into three groups (30 per group) 1 week
      postpartum. Two groups were exposed to bulls (BE) and one non-exposed group (NE)
      served as a control. Data were collected during weekly sessions of palpation per
      rectum, ultrasonography and bleeding on a subgroup of 30 cows (10 cows per group)
      for 6 weeks, and permanent surveillance of estrus with HeatWatch on all 90 cows.
      There were no significant differences between BE and NE cows for UI ( 17.1+/-1.1
      days versus 20.1+/-1.6 days), LF ( 9.5+/-1.7 mm versus 11.0+/-2.4 mm), F > or = 5
      ( 1.20+/-0.3 versus 1.47+/-0.09 ), and PF. However, LT was detected in more BE
      than NE cows (13 versus 2; P<0.001 ). Overall differences in P4 were found
      between BE and NE cows with detected LT ( 2.00+/-0.3 ng/ml versus 1.05+/-0.4
      ng/ml, respectively; P<0.05 ). More BE cows resumed reproductive cyclicity with
      estrous cycles normal in length compared with NE cows (16/30, 53%; 16/30, 53%;
      and 8/30, 26.6%, for the two BE groups and the NE group, respectively; P<0.01 ).
      In conclusion, BE hastened luteal function but did not affect uterine involution.

PMID- 15036983
TI  - Farrowing rates and litter size following transfer of vitrified porcine embryos
      into a commercial swine herd.
AB  - The objective was to determine farrowing rates and litter sizes that could be
      achieved in a typical farm-to-farm porcine embryo transfer program using
      vitrified blastocysts that were zona pellucida intact when cryopreserved. The
      embryos were transferred surgically on-farm into recipient sows that were managed
      throughout gestation and farrowing under the same conditions as other sows in the
      herd. Twenty recipient sows (mean parity 2.1) received a total of 568 embryos;
      seven received 203 embryos derived from donor sows, five received 139 embryos
      from gilts and eight received a mixture of 161 embryos from sows and 65 from
      gilts. Sixteen sows (80%) were confirmed pregnant at approximately 35 days
      gestation, 15 farrowed at full term (farrowing rate 75%). One sow died during
      gestation (with a total of 18 fetuses in utero). A total of 123 piglets were born
      (mean, 8.2), of which 115 were born alive (mean, 7.7). Of the 568 embryos
      transferred to all 20 sows, 21.6% resulted in piglets born and 29.0% survived to
      produce piglets in sows that farrowed. There were no significant differences in
      embryo survival among sow, gilt or mixed sow and gilt embryos. The ratio of males
      to females was 71/52 and the mean birth weight was 1.6 kg (range 0.6-2.6 kg). In
      conclusion, vitrified zona pellucida intact embryos can be used to transfer
      genetic material from farm-to-farm with acceptable reproductive performance.

PMID- 15036985
TI  - Effects of abnormal ovarian cycles during pre-service period postpartum on
      subsequent reproductive performance of high-producing Holstein cows.
AB  - The primary objective of this study was to investigate the effects of abnormal
      ovarian cycles during the pre-service postpartum period on subsequent
      reproductive performance of high-producing Holstein cows. The study was conducted
      in a commercial dairy farm with approximately 150 lactating cows, in a
      subtropical region of Japan. Animals were kept in free-stall barn, and fed a
      total mixed ration. Cows that calved from June 2001 to July 2002 were included in
      the study. Milk samples were collected twice weekly from 2 to 11 weeks
      postpartum, and progesterone concentrations in skim milk were determined by
      ELISA. After a voluntary waiting period of 40 days, cows detected in estrus were
      bred by artificial insemination (AI). Pregnancy was confirmed by palpation per
      rectum 40-70 days after AI. Out of a total of 91 cases, 39 (42.9%) had normal
      ovarian cycles (ovulation within 45 days after calving, followed by normal
      ovarian cycles), 32 (35.2%) had prolonged luteal phase (i.e. luteal activity for
      >20 days), and 12 (13.2%) had anovulation or delayed first ovulation (i.e. first
      ovulation did not occur until >45 days after calving). The remaining (8.8%) had
      other types of abnormalities. When compared with cows with a normal ovarian
      cycle, prolonged luteal phase cows had a lower 100 days AI submission rate,
      conception rate and pregnancy rate (84.2% versus 56.3%; P<0.05, 50% versus 16.7%;
      P<0.05 and 42.1% versus 9.4%; P<0.01, respectively), and longer intervals to
      first AI and to conception ( 67+/-6 days versus 98+/-7 days and 95+/-9 days
      versus 136+/-11 days; P<0.01 for each). Similarly, when compared with cows with
      normal ovarian cycles, those with anovulation had lower 100 days conception rate
      and pregnancy rate (50% versus 0%; P<0.05 and 42.1% versus 0%; P<0.01,
      respectively), and longer intervals to first AI and to conception ( 67+/-6 days
      versus 93+/-12 days; P<0.05 and 95+/-9 days versus 155+/-14 days; P<0.01,
      respectively). Survival analysis of the data for calving to conception interval
      showed that cows with prolonged luteal phase or anovulation were getting pregnant
      at a slower rate, and took longer to get pregnant than the cows with normal
      resumption of ovarian cyclicity postpartum. In conclusion, abnormal ovarian
      cycles during the pre-service period postpartum adversely affected reproductive
      performance, including AI submission rate, pregnancy rate, interval to first AI,
      and calving to conception interval in high-producing Holstein cows.

PMID- 15036986
TI  - Estrous cycle characteristics, luteal function, secretion of oxytocin (OT) and
      plasma concentrations of 15-keto-13,14-dihydro-PGF2alpha (PGF2alpha-metabolite)
      after administration of low doses of prostaglandin F2alpha (PGF2alpha) in pony
      mares.
AB  - In the present study, the kinetics of the prostaglandin F2alpha (PGF2alpha)
      metabolite 15-keto-13,14-dihydro-PGF2alpha after a single intramuscular
      application of various doses of the natural PGF2alpha dinoprost at Day 7 of the
      cycle in the mare were investigated. Effects of low doses on estrous cycle length
      and life span of corpus luteum were examined, because release of PGF2alpha is
      still under discussion to have detrimental influence on success rates of
      transcervical transfer of equine embryos. Eight Shetland pony mares were each
      randomly assigned to each of four treatments: (a) 0.8 mg/100 kg (group T1), (b)
      0.4 mg/100 kg (group T2), (c) 0.2 mg/100 kg BM dinoprost i.m. (group T3), and (d)
      1 ml physiological saline i.m. (group CO). Treatments were administered as single
      doses on Day 7 of the estrous cycle. Administration of dinoprost caused dose
      dependent rises of plasma concentrations of PGF2alpha-metabolite, although values
      of individual mares showed great variation within groups. Prostaglandin
      treatments resulted in a distinct decrease of plasma progesterone concentrations
      to values between 1.6 and 7.9 ng/ml within 24 h. Treatment groups had
      significantly lower progesterone area under the curve (AUC: T1 942.8+/-175.9, T2
      1050+/-181.2 and T3 1117+/-179.8 ng/ml/h) when compared with controls (CO
      1601.9+/-227.6; t-test, P<0.05 ). There was a small, but significant negative
      correlation between AUC of progesterone and of PGF2alpha-metabolite ( R=-0.4;
      P=0.05 ). Administration of PGF2alpha caused secretion of oxytocin in three (T1,
      T2) and two (T3) mares out of eight ranging from 19.3 to 63.1 pg/ml. The AUC of
      oxytocin was positively correlated with AUC of PGF2alpha-metabolite ( R=0.4,
      P<0.05) and negatively correlated with AUC of progesterone ( R=-0.4, P<0.05).
      Administration of dinoprost yielded significantly shorter intervals from
      treatment to estrus and ovulation (values in parentheses), respectively, when
      compared with controls: T1 3.9+/-0.7 days ( 12.1+/-0.7 days), T2 4.5+/-0.6 (
      12.3+/-0.6 ), T3 4.9+/-0.5 ( 12.3+/-0.6 ), and CO 8.9+/-0.6 days ( 16.5+/-0.8
      days) (t-test, P<0.01 ) (Fig. 2). Different doses of PGF2alpha caused similar
      effects. Data suggest that progesterone concentrations at applications influence
      efficacy of treatments more than doses administered, as demonstrated by their
      high correlation with estrous cycle patterns. It is important to note that
      differences we achieved are gradual and that all mares responded to treatment by
      luteolysis and premature estrus, regardless of doses applied.

PMID- 15036984
TI  - Identification and partial characterization of alpha-1,4-glucosidase activity in
      equine epididymal fluid.
AB  - The expression of alpha-1,4-glucosidase activity was fluorometrically and
      electrophoretically assessed in the epididymal fluid and seminal plasma of
      stallions. alpha-Glucosidase specific activity in the epididymis increased
      significantly from the proximal caput to the cauda. Stallion epididymal
      glucosidase maintained activity in a wide range of pH, with two distinct peaks
      (around pH 4.0 and 6.0, respectively). Enzyme activities at different pH,
      inhibition assays with sodium dodecyl sulfate (SDS) and maltotriose (MTT,
      selective inhibitors of alpha-glucosidases "acidic" and "neutral" isoforms,
      described in other tissues) and the electrophoretic analysis in native and
      native/SDS-PAGE conditions, indicated that stallion epididymal glucosidase was
      due to two catalytically active forms. These forms, analyzed by non-denaturing
      electrophoresis, exhibited different electrophoretic mobility and molecular
      weight. Samples from the proximal caput of the epididymis were rich in Form II or
      "neutral" form, whereas the "acid" or Form I seemed to be predominate in the
      cauda epididymal region. At physiological pH, Form II was predominant in the
      seminal plasma. The physiological role(s) of these forms is uncertain, but based
      on their ability to hydrolyze glucosidic linkage, they probably are involved in
      degradation/modifications of epididymal fluid and/or spermatozoa glycoconjugates,
      thereby participating in plasma membrane remodeling associated with sperm
      maturation.

PMID- 15036987
TI  - Effect of insemination with doses of 2 or 15 million frozen-thawed spermatozoa
      and semen deposition site on pregnancy rate in dairy cows.
AB  - The effects of low-dose artificial insemination (AI) on pregnancy rates have
      seldom been studied in lactating dairy cows. We evaluated the pregnancy results
      after AI with doses of 2 and 15 million frozen-thawed spermatozoa and the effect
      of semen deposition in lactating dairy cows. A total of 284 first inseminations
      with 2 million spermatozoa and 312 first inseminations with 15 million
      spermatozoa were performed on 480 dairy farms. Low-dose inseminations (2 million
      spermatozoa) under field conditions in commercial dairy herds, without estrus
      synchronization, generally resulted in significantly reduced pregnancy rates
      compared with normal doses (15 million spermatozoa). The bull x technician effect
      on fertility was statistically significant. This finding indicates that there is
      a high variability in fertility among bulls using 2 million spermatozoa per dose.
      The semen deposition site did not influence pregnancy rates. It is concluded that
      a dose of 2 million frozen-thawed spermatozoa is probably too low for most bulls
      to achieve acceptable pregnancy rates in dairy cows.

PMID- 15036988
TI  - Effect of blood admixture on in vitro survival of chilled and frozen-thawed
      canine spermatozoa.
AB  - Hematospermia in the dog usually occurs secondary to benign prostatic hypertrophy
      or trauma of the penis or prepuce during semen collection. Regarding the
      difficulty of removing blood cells from a hematospermic sample, the present study
      was performed to determine whether blood contaminated ejaculates can still be
      chilled (4 degrees C) or frozen (-196 degrees C) without an additional decrease
      in sperm quality. In the first experiment, blood additions of up to 10% exerted
      no negative effects on the functional characteristics of canine spermatozoa
      cooled (4 degrees C) and stored for 4 days in an egg-yolk-Tris extender. In
      contrast, in experiment 2, blood admixtures of 4% or more clearly caused negative
      effects on cryopreserved (-196 degrees C) spermatozoa, mainly on the motility
      parameters, on the membrane integrity and on the acrosomal status of the
      spermatozoa. In experiment 3, we showed that these negative effects of blood
      admixture on cryopreserved spermatozoa were mainly associated with the red blood
      cells (RBCs) whereas the addition of plasma, serum or inactivated serum exerted
      little or no negative effect. Moreover, in experiment 4, we showed that 58.3+/
      11.6% of the RBCs hemolysed after a freeze-thaw process. In experiment 5, a clear
      and negative effect of hemoglobin on cryopreserved canine spermatozoa was
      observed. We conclude that the presence of up to 10% blood is not detrimental for
      the storage of chilled canine spermatozoa and that the detrimental effects of
      blood on cryopreserved spermatozoa are at least partly attributable to the high
      amount of hemoglobin originating from the RBC hemolysis observed after freezing
      and thawing.

PMID- 15036990
TI  - Calving and calving management of beef cows and heifers on cow-calf operations in
      the United States.
AB  - A national sample of cow-calf producers was contacted to participate in a study
      to describe selected calving management practices on operations throughout the
      United States. Information was gathered on calving season, frequency of dystocia,
      frequency of observation, timing of assistance, and calving facilities. Regional
      and herd size differences existed in all parameters evaluated. Most calves
      (63.9%) were born in the months of February, March, and April. Overall, 16.7% of
      heifers and 2.7% of cows required some level of assistance in calving. Heifers
      and cows were checked an average of only 3.6 and 2.5 times per 24 h period during
      the calving season. Producers allowed heifers to labor for an average of 2.8h
      prior to lending assistance in calving while cows were allowed an average of 3.5h
      before providing assistance. In addition, only 39.6% of calvings took place in
      specialized calving areas presumably to allow increased observation frequency,
      timely intervention and protection from the elements. Collectively, these
      management practices illustrate that opportunities exist to improve calf
      survivability and increase reproductive efficiency in many cow herds.

PMID- 15036989
TI  - The use of cytological examination of vaginal smears (CEVS) in the selection of
      rabbits for superovulation.
AB  - In the present study, we examined two factors associated with the reproduction of
      rabbit does, cytology of vaginal smears and color of vulva, as potential
      predictors of the success of superovulation treatment. Vulval color and vaginal
      smear cytology were assessed in 55 young New Zealand does. Superovulation was
      then induced by a single administration of eCG (20 IU/kg BW i.m.). Does were
      artificially inseminated 3 days later, followed by intravenous administration of
      hCG (120 IU per animal). Does were classified with regard to vulval color (white,
      rose, red, purple), and the predominant cell type in the vaginal smear (i.e.
      parabasal, intermediate, superficial, or anuclear). Furthermore, we categorized
      cells into two groups because we usually observed parabasal and intermediate
      cells (Group A), and superficial and anuclear cell (Group B) in the same smear.
      Does were humanely killed 19 h after administration of hCG and the total numbers
      of corpora lutea (CLs), oocytes, and zygotes (i.e. 1-cell embryos) were
      determined. The zygotes were assessed by morphological appearance and classified
      as normal or abnormal. The color of the vulva at the time of eCG treatment did
      not predict the success of superovulation in terms of the number of CLs, oocytes
      or zygotes. Does with predominantly superficial cells in vaginal smears yielded
      significantly fewer CLs and oocytes-zygotes (OZ) compared to does with
      predominantly parabasal, intermediate, or anuclear cells (P<0.05). Does with
      predominantly superficial cells in vaginal smears tended to yield fewer normal
      zygotes (nZ), but this reached significance only when compared to does with
      predominantly parabasal cells (P<0.05). Does in Group A yielded significantly
      more (P<0.05) CLs, OZ and nZ compared to does in Group B. Does with predominantly
      parabasal and intermediate cells in vaginal smears and rose color vulva tended to
      yield more OZ and nZ (P<0.05). These results suggest that the cytology of vaginal
      smears may help identify does with a significantly higher likelihood of yielding
      low numbers of CLs, oocytes, or nZ.

PMID- 15036991
TI  - Cryopreservation of caprine ovarian tissue using glycerol and ethylene glycol.
AB  - Cryopreservation of ovarian tissue may be a potential alternative for the
      conservation of genetically superior animals, including high milk- and meat
      producing goat breeds. However, until now, no information was available
      concerning the cryopreservation of preantral follicles (PF) enclosed in caprine
      ovarian tissue. The objective of the present study was to evaluate the structural
      and ultrastructural characteristics of caprine PF after exposure to and
      cryopreservation of ovarian tissue in 1.5 and 3M glycerol (GLY) and ethylene
      glycol (EG). At the slaughterhouse, each ovarian pair from five adult mixed breed
      goats was divided into nine fragments and randomly distributed into treatment
      groups. One fragment was immediately fixed for histological examination and
      ultrastructural analysis, after slaughter (control). Four of the ovarian
      fragments were equilibrated at 20 degrees C for 20 min in 1.8 ml of MEM
      containing 1.5 or 3M GLY or EG for a toxicity test and the final four fragments
      were slowly frozen using these cryoprotectants at the concentrations above. After
      toxicity testing and freezing/thawing, the ovarian fragments were fixed for
      histological examination. Histological analysis showed that after toxicity
      testing and cryopreservation of the ovarian tissue in GLY or EG at both
      concentrations, the percentage of normal PF was significantly lower than
      controls. Ultrastructural analysis of PF frozen in 1.5 and 3M GLY, as well as 3M
      EG demonstrated that these follicles remained morphologically normal. In
      conclusion, we demonstrated cryopreservation of caprine PF in ovarian tissue.

PMID- 15036992
TI  - A novel approach to intrauterine viral inoculation of swine using PCV type 2 as a
      model.
AB  - Experimentally intrauterine (IU) viral inoculation has been commonly used to
      circumvent maternal interference with transplacental infection of fetuses and to
      assess the effect of viral infection on fetal development or reproductive
      parameters. However, IU inoculation requires surgical procedures such as
      laparatomy and surgical incision of the uterus. Post-surgical complications, that
      frequently result in abortion or fetal death, have been a major disadvantage. An
      animal trial was conducted to evaluate the non-surgical procedure of ultrasound
      needle-guided transabdominal injection for IU inoculation of porcine circovirus
      type 2 (PCV2) since this virus has been reported to cause reproductive failure in
      pigs. Two groups of seven pregnant sows at mid- and late-gestation, respectively,
      were inoculated with PCV2 using an ultrasound needle-guided technique that
      delivered PCV2 directly into one of the fluid-filled fetal compartments. The
      effect of transabdominal in utero virus challenge on fetuses and sows was
      assessed until term. While five of six sham-inoculated control sows had no or
      minimal adverse affects from in utero injection, 10 of 14 virus-inoculated sows
      had dead and/or stillborn piglets and PCV2 infection was evident by polymerase
      chain reaction and/or immunohistochemistry. These results supported previous
      field and experimental observations that PCV2 may cause reproductive failure. In
      conclusion, ultrasound needle-guided transabdominal injection was a safe and
      efficient method for IU inoculation of virus in pigs.

PMID- 15036994
TI  - LH and testosterone responses to five doses of a GnRH analogue (buserelin
      acetate) in 12-month-old Thoroughbred colts.
AB  - To determine the responsiveness of the pituitary-gonadal axis of peri-pubertal
      colts to GnRH, buserelin (0.5, 1, 5, 10 and 40 microg) was given to 13 male
      Thoroughbred yearlings ( n=3-8 colts per dose). Jugular venous blood samples were
      taken at -10, 0, 10, 20, 30, 40, 60, 120 and 180 min relative to buserelin
      administration. Increases (P < 0.05) in LH concentrations occurred in colts that
      received 5, 10, or 40 microg buserelin, but not in those that received 0.5 or 1
      microg. Peak LH concentrations and mean area under the curve were higher (P <
      0.05) in colts receiving 40 microg buserelin than in those that received 0.5 or 1
      microg. Increases ( P< 0.05) in testosterone concentrations occurred in some, but
      not all, colts that received 1, 5, 10, or 40 microg buserelin. Neither peak
      concentration nor area under the curve of testosterone differed significantly
      among doses of buserelin. The percentage of horses that responded to the
      buserelin increased with increasing dose, with only the highest dose eliciting LH
      and testosterone responses in all colts. In conclusion, peri-pubertal colts
      exhibited a dose-response release of LH following buserelin treatment, but
      individual colts responded in an "all or nothing" manner, such that each either
      had an LH response or did not. Some colts that exhibited a significant LH
      response had no subsequent increase in plasma testosterone concentrations;
      perhaps the pituitary LH response may not have been great enough to stimulate the
      Leydig cells in these individuals.

PMID- 15036993
TI  - Efficacy of animal anti-fertility compounds against sea lamprey (Petromyzon
      marinus) spermatozoa.
AB  - Sterile-male-release technique is currently used to control the sea lamprey
      (Petromyzon marinus) population in the Great Lakes. The chemosterilant (bisazir)
      used in this program is extremely hazardous; special safety measures are
      necessary when handling this chemical. Therefore, replacement of bisazir with
      safer agents is desirable. In this study, we examined the effects of low-toxicity
      compounds with previously described spermicidal activity (mainly against
      mammalian sperm) on motility and fertilizing ability of sea lamprey spermatozoa.
      Nonoxynol-9, benzalkonium chloride, zinc acetate, cupric chloride, cysteamine,
      tannic acid and propranolol were able to inhibit both sperm motility and
      fertilizing ability. Effective concentrations of these spermicides ranged from
      0.15 to 1%. Therefore, they can be potentially used in further study directed at
      in vivo sterilization of male sea lampreys.

PMID- 15036995
TI  - Influence of oral melatonin on natural and gonadotropin-induced ovarian function
      in the domestic cat.
AB  - Ovarian hyperstimulation after exogenous gonadotropin stimulation is believed to
      be a cause of poor success after artificial insemination (AI) in felids. The
      objectives of this study were to assess the effect of oral melatonin on
      endogenous ovarian activity in the domestic cat and subsequent eCG/hCG-induced
      ovarian activity. Serum melatonin concentrations peaked approximately 1h after a
      single oral dose of 30 mg melatonin and remained elevated above endogenous day
      time concentrations for >8h. The calculated circulating half-life (mean +/-
      S.E.M) of oral melatonin was 45.4+/-3.5 min, and the elimination rate constant
      (k(10)) was 55.2+/-4.2 min(-1). Oral melatonin (30 mg per day) administered 3h
      before lights-off effectively and reversibly suppressed estrous elevations in
      fecal estrogens after 25 days of treatment. There was a progressive decrease in
      baseline estrogen concentrations from inter-estrous concentrations after 25 days
      of treatment to below inter-estrous concentrations after 35 days of treatment.
      Oral melatonin treatment (30 mg per day for 30 days) prior to eCG/hCG
      administration only marginally reduced ancillary follicle development and had no
      significant effect on the quantity or quality of embryos produced by AI. Thus,
      oral melatonin effectively inhibited endogenous ovarian activity and had no
      adverse impact on embryo quality after AI in the domestic cat; however, this
      treatment was only marginally effective in minimizing eCG/hCG-induced ovarian
      hyperstimulation.

PMID- 15036996
TI  - Improved cleavage of bovine ICSI ova cultured in heparin-containing medium.
AB  - Although heparin plays an important role in bovine sperm capacitation, there is
      no direct evidence for a role in embryonic development. The present study was
      designed to examine the effect of heparin on early development of bovine zygotes
      obtained by intracytoplasmic sperm injection (ICSI). Spermatozoa were treated
      with or without heparin, and the ICSI ova were cultured in a chemically defined
      medium + BSA, with or without heparin. Treatment of spermatozoa with heparin
      before ICSI or heparin in post-ICSI culture medium for 18 or 24h had a beneficial
      effect on pronuclear formation, cleavage rate (63% versus 76-83%), and number of
      cells in blastocysts (68 cells versus 82-109 cells; P < 0.05).

PMID- 15036997
TI  - Effect of bovine viral diarrhea virus infection on fertility of dairy heifers.
AB  - A prospective field study in heifers from birth to first breeding was undertaken
      on two commercial dairies to assess the effect of bovine viral diarrhea virus
      (BVDV) congenital and post-natal infection (PNI) on fertility. A high BVDV Type 2
      antibody titer (1:4096) at 10 months of age was associated with 32 more days to
      conceive, compared with a low titer (1:128). Conversely, infection with BVDV by 5
      6 months of age and high BVDV Type 2 titers 1 month before conception or breeding
      was associated with improved fertility. Heifers with evidence of congenital BVDV
      infection had lower fertility than non-infected heifers (15-42 days longer time
      to-first AI), which depended on BVDV Type 2 titers at 10 months of age. Neospora
      caninum infection was associated with additional services per conception (SPC)
      and Leptospira interrogans infection was associated with a delay in the time-to
      first breeding. It appears that under field conditions, the effect of subclinical
      BVDV infection on subsequent heifer fertility may be due to a complex of
      interrelationships among multiple BVDV infections that depend on the type and
      timing of infection relative to reproductive development and events.

PMID- 15036998
TI  - Effect of different cryoprotectants on the structural preservation of follicles
      in frozen zebu bovine (Bos indicus) ovarian tissue.
AB  - Cryopreservation of ovarian tissue is a new and promising technique for germ-line
      storage. The objective of this study was to evaluate the effect of four
      cryoprotectants (at two concentrations each) on the preservation of zebu bovine
      preantral follicles after ovarian cryostorage. Strips of ovarian cortex were
      cryopreserved using glycerol (GLY; 10 or 20%), ethylene glycol (EG), propanediol
      (PROH) or dimethylsulphoxide (DMSO; 1.5 or 3M). In addition, a toxicity test was
      performed for each cryoprotectant by exposing the ovarian tissue to them without
      freezing. Tissues were analyzed by histology and transmission electron
      microscopy. Ovarian tissue frozen in either concentration of DMSO or PROH or in
      10% GLY retained a higher percentage of morphologically normal follicles (73-88%)
      than tissue frozen in 20% GLY or in either concentration of EG (16-52%). In the
      toxicity test, exposure of tissues to DMSO, PROH or GLY resulted in higher
      percentages of normal follicles (80-97%) than exposure to EG (49%). Electron
      microscopy revealed damage to the ultrastructure of follicles frozen in 10% GLY,
      while follicles cryopreserved in DMSO and PROH at either concentration exhibited
      normal ultrastructure. In conclusion, DMSO and PROH were the most effective
      cryoprotectants for zebu ovarian tissue, preserving the structural integrity of
      somatic and reproductive cells within the ovary.

PMID- 15036999
TI  - Fertility following fixed-time AI in CIDR-treated beef heifers given GnRH or
      estradiol cypionate and fed diets supplemented with flax seed or sunflower seed.
AB  - The objectives were to determine pregnancy rates following fixed-time AI (FTAI)
      in heifers: (1). given GnRH or estradiol cypionate (ECP) to synchronize
      follicular wave emergence and ovulation in a CIDR-based protocol; and (2). fed
      diets supplemented with flax or sunflower seeds. At two locations, Angus and
      crossbred Angus heifers (n=983) were examined ultrasonically to confirm
      reproductive maturity and randomly allocated to six synchronization groups in a 2
      x 3 factorial design. On Day 0 (start of synchronization treatments), heifers
      received a CIDR and either 100 microg GnRH i.m. (n=492) or 1mg ECP plus 50 mg
      progesterone i.m. (n=491); in these groups, CIDR removal and PGF treatment were
      done concurrently on Days 7 and 8.5, respectively. Heifers were re-randomized to
      receive 0.5 mg ECP i.m. at CIDR removal or 24 h later (with FTAI 58-60 h after
      CIDR removal in both groups), or 100 microg GnRH i.m. concurrent with FTAI (52-54
      h after CIDR removal). The heifers were fed a barley silage-based diet for 50
      days (from Day -25 to 25) supplemented with 1kg/heifer per day of flax seed
      (n=321), sunflower seed (n=324), or no oilseed (n=338). Pregnancy rate to FTAI
      (overall, 56.2%) was not affected by treatment at CIDR insertion (P = 0.96) but
      was higher (P < 0.05) in heifers given ECP 24h after CIDR removal (216/330,
      65.4%) than in those given either ECP at CIDR removal (168/322, 52.1%) or GnRH at
      AI (169/331, 51.1%). Overall, there was no effect of diet on pregnancy rates (P =
      0.46). In summary, pregnancy rate to FTAI was not significantly affected by
      treatment at CIDR insertion to synchronize follicular wave emergence, but 0.5mg
      ECP 24h after CIDR removal (to synchronize ovulation) resulted in the highest
      pregnancy rate.

PMID- 15037001
TI  - The effect of exogenous estradiol benzoate and altrenogest on uterine and ovarian
      blood flow during the estrous cycle in mares.
AB  - In recent years, a positive relationship between genital perfusion and fertility
      has been established; in species other than horses, uterine and ovarian perfusion
      was improved by exogenous estrogen but impaired by exogenous progestin. The goal
      of the present study was to investigate the effect of exogenous estrogen and
      progestin on uterine and ovarian blood flow in cycling mares. Five Trotter mares
      were examined daily during three estrous cycles. Mares were given no treatment,
      altrenogest (0.044 mg/kg BW) orally from Day 0 (ovulation) to Day 14 and
      estradiol benzoate (5mg i.m.) on Days 0, 5, and 10, in three cycles,
      respectively. There was no difference ( P > 0.05 ) in the length of untreated
      versus estrogen-treated cycles ( 22.8 +/-1.3 days and 23.2 +/= 1.5 days,
      respectively), but cycle length was increased (P < 0.05) in progestin-treated
      cycles (26.0 +/- 1.2). To facilitate comparisons among cycles with different
      lengths, data from Days 0 to 15 (diestrus) and from Days -6 to -1 (estrus) were
      analyzed. Transrectal Doppler sonography was used to evaluate blood flow in both
      uterine arteries and in the ovarian artery ipsilateral to the preovulatory
      follicle during estrus and ipsilateral to the corpus luteum during diestrus.
      Blood flow was assessed semiquantitatively using the pulsatility index (PI); high
      PI values indicated high resistance and a low perfusion and vice versa. An
      immediate effect of treatments occurred only after the administration of
      estradiol benzoate on Day 0; uterine PI values decreased (P < 0.05) between Days
      0 and 1 and estrogen-treated mares but increased (P < 0.05) at the corresponding
      time in untreated cycles. Mean PI values for the uterine and ovarian arteries
      during both diestrus and estrus were higher (P < 0.05) in estrogen-treated versus
      untreated mares. Furthermore, mean uterine PI values during diestrus and estrus
      were higher (P< 0.05) in altrenogest-treated versus untreated mares. Neither
      estrogen nor altrenogest treatments had a significant immediate effect on ovarian
      PI values. Compared to untreated cycles, mean ovarian PI values were elevated (P
      < 0.05) only in the estrus following altrenogest administration. In conclusion,
      exogenous estrogen and progestin both decreased genital perfusion in cycling
      mares.

PMID- 15037000
TI  - In vitro development of preimplantation porcine nuclear transfer embryos cultured
      in different media and gas atmospheres.
AB  - This study investigated the effect of culture media and gas atmospheres on the
      development of porcine nuclear transfer embryos. Oocytes derived from a local
      abattoir were matured for 42-44 h and enucleated. Fetal fibroblasts were prepared
      from a Day 35 porcine fetus. Confluent stage fetal fibroblasts were introduced
      into the perivitelline space of enucleated oocytes. Fusion and activation were
      induced simultaneously with two direct current (1.2 kV/cm for 30 micros) in 0.3 M
      mannitol medium. For parthenogenetic activation, the same pulses were used. In
      Experiment 1, parthenogenetically activated oocytes were cultured in North
      Carolina State University-23 (NCSU-23), Porcine Zygote Medium-3 (PZM-3), or
      Beltsville Embryo Culture Medium-3 (BECM-3). Parthenogenetically activated
      oocytes cultured in PZM-3 had a higher (P < 0.05) developmental rate to the
      blastocyst stage (15.2% versus 3.7-9.6%) as compared to BECM-3 or NCSU-23. The
      number of nuclei in Day 6 blastocysts was higher (P < 0.05) in PZM-3 (23.6) and
      NCSU-23 (21.4) than BECM-3 (14.2). In Experiment 2, parthenogenetically activated
      oocytes were cultured in NCSU-23 under a gas atmosphere of 5% CO(2) in air for 6
      days (T1), 5% CO(2), 5% O(2), 90% N(2) for 6 days (T2), 5% CO(2) in air for 3
      days, then 5% CO(2), 5% O(2), 90% N(2) for 3 days (T3), or 5% CO(2), 5% O(2), 90%
      N(2) for 3 days, then 5% CO(2) in air for 3 days (T4). Blastocyst formation rates
      were not different among treatments (12.9 =/-3.6 %, 13.5 +/- 4.2%, 10.8+/-2.4%,
      and 12.6+/-2.7%, respectively). However, T2 (36.7+/-2.9) and T3 (33.8+/-3.0)
      resulted in more nuclei per blastocyst than T1 (23.2+/-2.1) or T4 (26.0+/-2.1 ).
      In Experiment 3, reconstructed porcine nuclear transfer (NT) embryos were
      cultured in NCSU-23 or PZM-3 under a gas atmosphere of 5% CO(2) in air or 5%
      CO(2), 5% O(2), 90% N(2). Developmental rates to blastocyst stage for porcine NT
      embryos cultured in NCSU-23 under a gas atmosphere of 5% CO(2) in air or 5%
      CO(2), 5% O(2), 90% N(2) were 7.2+/-1.4% and 12.3+/-1.4%, and the number of
      nuclei was 12.2=/-0.8% and 19.4+/-1.0, respectively. NT embryos cultured in PZM-3
      under a gas atmosphere of 5% CO(2) in air or 5% CO(2), 5% O(2), 90% N(2) had
      developmental rates to blastocyst stage of 18.8+/-1.9 %, and 17.8+/-3.8% the
      nuclei number was 20.9 +/- 1.9 and 21.9+/-3.3, respectively. NT embryos cultured
      in NCSU-23 had a higher developmental rate to the blastocyst stage in 5% CO(2),
      5% O(2), 90% N(2) than in 5% CO(2) in air (P < 0.05). Regardless of gas
      atmospheres, NT embryos cultured in PZM-3 had a higher developmental rate (18.3
      =/- 1.7% versus 16.9 +/- 1.2%) and nuclei number (21.4 +/-1.8 versus 16.9 +/-
      1.2) than in NCSU-23 (P < 0.05). In conclusion, a gas atmosphere of 5% CO(2), 5%
      O(2), 90% N(2) supported a higher development rate of porcine NT embryos than 5%
      CO(2) in air when the porcine NT embryos were cultured in NCSU-23. Furthermore,
      regardless of atmosphere, PZM-3 supported a higher development rate of porcine
      nuclear transfer embryos than NCSU-23.

PMID- 15037002
TI  - Reproductive traits in the spur-thighed tortoise (Testudo graeca terrestris): new
      tools for the enhancement of reproductive success and survivorship.
AB  - The Mediterranean tortoise (Testudo graeca) is listed as "Vulnerable" on the IUCN
      Red List. Reproductive characteristics and means to increase offspring production
      were studied in T. graeca terrestris in a semi-natural environment. Courtship and
      mating occurred during early spring for about 4 weeks, followed by a laying
      season of approximately 2 months, with a second, shorter mating period in the
      fall. During the first mating, calcified eggs were already present in the uterus;
      we inferred that sperm from both mating seasons were stored in the oviduct for
      fertilization of eggs of the second laying cycle and of the following year.
      Average egg production was 3.8+/-0.3 eggs/year. Most females laid all of their
      eggs in a single clutch, but 18% laid in a second clutch, 11-21 days later. X-ray
      radiography revealed calcified eggs in the uterus about 4 weeks before
      oviposition. All eggs in the uterus were calcified simultaneously and were laid
      in a single clutch; if a second clutch developed, those eggs were also calcified
      simultaneously. Based on endoscopic examinations, ovaries were active throughout
      the entire year. Plasma progesterone concentrations in females were very low and
      were detected only soon after oviposition ( 440 +/-141 pg/ml). Plasma estradiol
      concentrations in females varied from 4.1 +/-1.5 pg/ml to 70.2 +/-29.4 pg/ml,
      with no clear seasonal pattern. Maintaining tortoises at a low environmental
      temperature (9 +/-1 degrees C versus 28 +/- 1 degrees C) reduced plasma estradiol
      concentrations. Giving 2mg/kg tamoxifen (TAM) increased plasma estradiol to 220
      +/-33 pg/ml when treatment was given in September but not in late October, winter
      or spring. Treatment with TAM increased the number of eggs laid during the
      following laying season to 7.3 +/- 1.0 eggs/year, laid in one to three clutches.
      In males, plasma testosterone concentrations had a seasonal pattern with the
      onset of a rise in July from 2 to >4ng/ml, a continued increase to a peak of
      12.8+/-5.3 ng/ml during November and a decline thereafter. Artificial incubation
      in sand at 29 +/-1 degrees C shortened the natural incubation time of 103+/-3.1
      days to 83.5 +/- 1.3 days, increased hatching rate from 28 to 53%, and increased
      survival rate from 51 to 71% at 40 weeks of age. In summary, this study provides
      options for increasing reproductive performance, hatchability and offspring
      survival in captive Mediterranean tortoises, and may offer new tools for
      conservation of animals that are on the verge of extinction.

PMID- 15037004
TI  - Reversibility of the reproductive toxicity of gossypol in peripubertal bulls.
AB  - Gossypol has been shown to impair sperm production in male ruminants. The purpose
      of this study was to determine if the adverse effects of gossypol on
      spermatogenesis in peripubertal bulls were reversible. Twenty-eight crossbred
      Angus bulls were allocated into treated and control groups at 11 months of age.
      For 8 weeks, treated bulls were fed a ration containing 8 mg of free gossypol per
      kilogram of body weight per day while control bulls were fed a soybean meal
      ration free of gossypol. At 28-days intervals, scrotal circumference was measured
      and semen collected to assess sperm motility and morphology. Seven control and
      seven treated animals were castrated 56 days after the start of the experiment
      and the testes were examined histologically. The remaining bulls were fed a
      gossypol-free diet for 210 days prior to castration. There were significant
      increases in primary and secondary sperm abnormalities in treated bulls 28 and 56
      days after gossypol feeding. The number of sperm with proximal droplets was
      significantly higher in gossypol-treated bulls, suggesting testicular
      degeneration. There was no significant effect on the sperm motility, scrotal
      circumference, or histopathological characteristics of the testes. Four weeks
      after the end of gossypol feeding, primary and secondary abnormalities were still
      increased in gossypol-treated bulls, however in subsequent collection periods the
      percentage of abnormalities were similar between groups. At 210 days, there was
      no treatment effect on scrotal circumference, and histological characteristics of
      the testes were not different between groups. The deleterious effects of gossypol
      on the morphological characteristics of spermatozoa were reversible. Gossypol (8
      mg/kg per day for 56 days) increased sperm abnormalities but the effects were
      reversible.

PMID- 15037003
TI  - Evidence that bears are induced ovulators.
AB  - The objective of this study was to determine if black bears are induced
      ovulators. We conducted a single experiment with two replicates; each replicate
      was divided into two arms: females exposed to male bears and females without male
      exposure. We used laparoscopy to examine ovaries for corpora lutea and measured
      serum progesterone concentrations. Six of the seven isolated females failed to
      ovulate, while seven of the eight females exposed to males produced one to four
      corpora lutea. Furthermore, isolated females had significantly lower progesterone
      concentrations than females exposed to males. Thus, our data suggest that the
      American black bear is an induced ovulator. These results may aid biologists in
      their efforts to reproduce ursids in controlled environments.

PMID- 15037005
TI  - Efficient production of sex-identified and cryosurvived bovine in-vitro produced
      blastocysts.
AB  - To establish a protocol for production of bovine in-vitro produced (IVP)
      blastocysts that were sex-identified and cryopreserved, we examined the sexing
      efficiency and accuracy of Day-3 and Day-4 embryos by polymerase chain reaction
      (PCR), the development of the biopsied embryos into Day-7 blastocysts and the
      freezability of these blastocysts by vitrification in gel-loading tips. One or
      two blastomeres were isolated from IVP embryos at either the 8-cell or 16-cell
      stage (Days 3 and 4, respectively) by a pressing-out method, and were then
      subjected to primer extension preamplification (PEP)-PCR. The successful sex
      identification rate of biopsied samples amplified, purified and analyzed for sex
      by a second PCR (88.9%) was higher than that of those amplified and analyzed
      without purification (32.0%). Developmental rates into Day-7 blastocysts of
      biopsied embryos (Day-3, 65.5%; Day-4, 70.8%) were similar to those of non
      biopsied control embryos (Day-3, 74.5%; Day-4, 65.1%). Total cell numbers and the
      inner cell mass (ICM) ratio of blastocysts derived from biopsied embryos were
      also comparable with those of control embryos. Blastocysts were vitrified-warmed
      in the presence of 20% DMSO, 20% ethylene glycol and 0.6M sucrose using gel
      loading tips as containers. The proportions of biopsied blastocysts that were
      hatched or hatching rates after warming were high, regardless of the biopsy time
      (Day-3, 94.1%; Day-4, 91.9%), similar to the rates for control blastocysts (Day
      3, 97.5%; Day-4, 96.9%). In conclusion, a protocol that allows sexing of Day-3
      and Day-4 bovine embryos without compromising either the developmental ability to
      the blastocyst stage or freezability of Day-7 blastocysts was developed.

PMID- 15037006
TI  - Effects of varying the holding temperature and interval from collection to
      freezing on post-thaw development of bovine embryos in vitro.
AB  - The objective of this study was to evaluate the in vitro development of frozen
      thawed bovine embryos held at room temperature or refrigerated for 2, 6 or 12 h
      prior to freezing. After recovery, embryos were randomly assigned to be placed in
      holding media for 2 h (n=131), 6 h (n=136) or 12h (n=133) prior to freezing.
      Approximately one-half of the embryos were refrigerated (5 degrees C; n=203)
      while the remaining half were held at room temperature (22 degrees C; n = 197)
      until freezing. Embryos were frozen in 10% ethylene glycol and stored in liquid
      nitrogen. After thawing, embryos were cultured for 72 h in Ham's F-10 media
      supplemented with 4% fetal bovine serum. Embryos were evaluated for quality and
      stage of development prior to freezing and after culture. At the end of culture,
      it was determined if each embryo had developed beyond the stage recorded prior to
      freezing and if the embryo had hatched from the zona pellucida. The percentage of
      embryos that developed during culture was greater (P < 0.001) for Grade 1 (81%)
      than for either Grade 2 (65%) or Grade 3 (48%) embryos. Likewise, a greater
      proportion (P < 0.001) of Grade 1 embryos developed to hatched blastocysts (60%)
      than either Grade 2 (40%) or Grade 3 (24%) embryos. The holding temperature from
      collection to freezing did not influence embryo development, regardless of the
      interval from embryo collection to freezing. The proportion of embryos that
      developed to expanded blastocysts and hatched was greater (P < 0.005) for embryos
      held 2 h prior to freezing (64%) than for embryos held for 12 h (33%). Hatching
      rate of embryos held 6 h prior to freezing (54%) tended (P < 0.08) to be lower
      than the hatching percentage for embryos held for 2 h. Thus, post-thaw embryonic
      development was impaired the longer embryos were held prior to freezing and
      temperature during the interval from collection to freezing did not affect post
      thaw development.

PMID- 15037008
TI  - Biological and social predictors of immune senescence in the aged primate.
AB  - The transition to geriatric status occurs at around 20 years of age in monkeys
      after which there is typically a decline in immune responses. However, the loss
      in immune vigor may be quite dissociated from chronological age in some of these
      long-lived animals. The degree to which natural killer (NK) cell activity is
      sustained in aged monkeys has proven to be a valuable prognostic of ultimate
      health and longevity. Another useful biomarker of cellular aging in the monkey is
      interleukin-6 (IL-6) release. For example, when endothelial cell cultures were
      generated from cerebral blood vessels, those derived from aged donors produced
      significantly more IL-6 in response to IL-1, LPS, and hypoxia. Despite this
      evidence of intrinsic aging, we have found that immune responses in old animals
      are quite responsive to contemporaneous conditions, including changes in housing
      or the first onset of illness. Indeed, these changes, especially the pathological
      processes associated with disease, may promote many age-related immune
      alterations at the end of the life span.

PMID- 15037009
TI  - A role of inhibitor of apoptosis (IAP) proteins in increased lymphocyte apoptosis
      in aged humans.
AB  - Lymphocytes from aged humans show increased death-receptor-mediated apoptosis,
      which is associated with an increased and early activation of caspases. Inhibitor
      of apoptosis (IAP) proteins inhibit apoptosis by inhibiting activation and
      activity of caspases. Therefore, we examine the expression of two of the IAPs,
      the cIAP-2 and XIAP in lymphocytes from young and aged subjects by Western
      blotting. Lymphocytes from aged expressed significantly less cIAP2 whereas no
      difference was observed in XIAP expression between young and aged subjects. These
      data may suggest that decreased cIAP2 may play a role in increased apoptosis in
      aged humans. Possible mechanisms for the regulation of IAPs in aging are
      discussed.

PMID- 15037010
TI  - Impact of the Hayflick Limit on T cell responses to infection: lessons from aging
      and HIV disease.
AB  - Aging and HIV disease show certain immunological similarities. In both
      situations, control over viral infection is diminished, and there is an increase
      in certain types of cancer. The immune cell type responsible for controlling
      viral infections and cancer is the so-called CD8 or cytotoxic T cell. In elderly
      persons and individuals chronically infected with HIV, there are high proportions
      of CD8 T cells that resemble cells that reach the end stage of replicative
      senescence in cell culture after repeated rounds of antigen-driven proliferation.
      Senescent cultures are characterized by irreversible cell cycle arrest, shortened
      telomeres, inability to upregulate telomerase, loss of CD28 expression, and
      apoptosis resistance. Strategies that retard replicative senescence may,
      therefore, provide novel approaches to enhancing immune function during aging and
      HIV disease.

PMID- 15037011
TI  - The immunoregulatory effects of homocysteine and its intermediates on T
      lymphocyte function.
AB  - Elevated levels of homocysteine (Hcy) have been identified as independent risk
      identifiers for cardiovascular disease, cerebrovascular disease as well as for
      all-cause mortality. Despite the potential importance of these observations, a
      definitive pathological role for Hcy or its various metabolites in any of these
      conditions has not been established. Particularly deficient is a description of
      the effects of elevated levels of homocysteine on immune function. Folic acid and
      vitamin B12 deficiency have been independently associated with decreased immune
      function, the apoptosis of bone marrow hematopoietic progenitor cells and the
      appearance of leukocytes with hypomethylated DNA in the peripheral circulation. A
      specific role for Hcy or its metabolites in these processes has not been
      described. We have examined the effects of Hcy and its various derivatives on T
      cell activation, differentiation and cell viability. Our results have
      demonstrated that Hcy is a potent concentration-dependent T cell activator
      promoting cellular activation and differentiation as well as potentiating
      activation-induced cell death (AICD) and cellular apoptosis. Overall, Hcy appears
      to exert diverse effects on immune function in the circulation and within the
      tissue microenvironment possibly contributing to age-related immune dysfunction
      and disease pathology.

PMID- 15037012
TI  - Effects of aging on DNA-binding activity of the E47 transcription factor in
      splenic B cells.
AB  - In the present paper, we have investigated the DNA-binding activity of the E2A
      encoded transcription factor E47 in LPS-activated splenic B cells from young and
      old BALB/c mice. E47 is a key regulator of B cell differentiation and function:
      it binds to the E-box site, found in the regulatory regions of several B cell
      specific genes (immunoglobulin (Ig), mb-1, and lambda5), promotes cell survival
      of early pre-B cells, helps to initiate Ig rearrangements, promotes class switch
      and is perhaps involved in somatic mutation in mature splenic and lymph node B
      cells. Results show that LPS-stimulated splenic B cells from old mice display
      decreased E47 DNA-binding activity as compared to young mice and that in splenic
      activated B cells only E47 homodimers bind DNA.

PMID- 15037013
TI  - Thymosin beta4 promotes angiogenesis, wound healing, and hair follicle
      development.
AB  - New blood vessel formation is important in many physiological process, including
      development, wound repair, and tumor growth. In aged animals, angiogenesis is
      reduced resulting in poor wound healing. We have identified a novel small
      molecule, thymosin beta(4), that promotes angiogenesis and wound repair in both
      normal and aged rodents. It also promotes hair growth in normal and aged rodents.
      It acts by increasing angiogenesis and cell migration and is currently in
      clinical trials for wound repair.

PMID- 15037014
TI  - Determinants of plasma leptin concentration in postmenopausal women.
AB  - This investigation examined the influence of hormone replacement therapy on
      plasma leptin concentrations in postmenopausal women and sought to determine if a
      relationship existed between plasma leptin, the thermoregulatory cytokine
      interleukin-1 (IL-1), and basal body temperature. Twenty-two women (54-71 years
      of age) were studied: eight were not taking hormone replacement, seven took oral
      estrogen only, and seven took oral estrogen plus progestin. Morning oral
      temperature, plasma leptin concentration, and mononuclear cell secretion of IL
      1beta, IL-1 receptor antagonist (IL-1Ra), and soluble IL-1 receptor type II (sIL
      1RII) were measured. Plasma leptin concentrations were not affected by hormone
      replacement therapy, but were inversely related to years since menopause (R = 
      0.48, P = 0.02) and were proportional to IL-1 activity (the balance of IL
      1beta/IL-1Ra secretion, R = 0.69, P = 0.001). Moreover, morning oral temperature
      was positively related to plasma leptin (P = 0.03), after stratifying by
      progestin intake. These results support the concept that basal body temperature
      is regulated by a network of endocrine and immune mediators that are
      significantly influenced by age.

PMID- 15037015
TI  - Immunosuppression after injury in aged mice is associated with a TH1-TH2 shift,
      which can be restored by estrogen treatment.
AB  - Aged mice are less likely to survive following traumatic injury and are more
      immunosuppressed than young mice who sustain comparable injuries.
      Immunosuppression in severely injured patients is associated with a TH1-TH2
      shift. Young mice had robust delayed-type hypersensitivity (DTH) responses after
      receiving scald or sham injury, whereas the response was diminished in aged sham
      injured mice (P < 0.05), and completely absent in aged burn-injured mice (P <
      0.01). Production of interferon-gamma (IFN-gamma) did not differ between
      splenocytes from sham-injured young and aged mice. Splenocytes from burn-injured
      young and aged mice yielded similar (63-68%) decreases in IFN-gamma, relative to
      sham-injured mice (P < 0.05). In the absence of injury, cells from aged mice
      produced 2-fold more interleukin-4 (IL-4) than cells from young (P < 0.01).
      Interestingly, after burn, less IL-4 was produced by cell from young and aged
      mice, when compared to age-matched sham-injured animals (P < 0.05). Further
      studies revealed that estrogen replacement in aged mice restored the post-injury
      DTH responses (P < 0.05). Interestingly, this restoration paralleled a recovery
      in IFN-gamma production by splenocytes, but not IL-4 production. Additional
      studies will be required to determine if age-specific therapies are needed for
      the treatment of all trauma patients.

PMID- 15037016
TI  - The usefulness of mouse breast tumor models for testing and optimization of
      breast cancer vaccines at old age.
AB  - Cancer is an age-related disease and with the graying of the society, there is an
      increasing need to optimize cancer management and therapy for application in
      elderly patients. Cancer vaccines that can be applied in both prevention and
      therapy are potentially less toxic than chemotherapy or radiation and could,
      therefore, be especially suitable for older more frail cancer patients. In this
      study, we used syngeneic metastatic (4TO7) and non-metastatic (64pT) breast tumor
      models to obtain valuable information on the potential usefulness of MAGE
      encoding cancer vaccines in metastatic and non-metastatic breast cancer at old
      age. First, we tested a mouse Mage-b DNA vaccine in young mice and found a
      significant preventive effect on the development of metastases. However, little
      effect was observed on primary breast tumors. Second, we studied tumor
      progression in relation to aging and found significant smaller tumors in old
      compared to young mice. This was associated with an increase in the percentage of
      CD8(+) T cells in the inguinal lymph nodes at the site of the tumor at old age.
      These findings suggest that breast cancer immunotherapeutic approaches could be a
      valid strategy even in elderly patients.

PMID- 15037017
TI  - Protection of the elderly from pneumococcal pneumonia with a protein-based
      vaccine?
AB  - Vaccines exist to protect children and adults from pneumococcal infection. The
      adult vaccine contains capsular polysaccharides from those pneumococci causing
      the vast majority of pneumococcal infection around the world. This vaccine is,
      however, poorly immunogenic and not as protective as would be desired. The
      vaccine for children is a seven-valent conjugate vaccine, which is highly
      protective against invasive infection and offers some protection against otitis
      media and pneumococcal carriage. The capsular types in the vaccine are not all
      appropriate for the developing world and the vaccine is too expensive for use in
      the developing world. As a result of these problems there have been extensive
      efforts to develop pneumococcal vaccines for adults and children based on cross
      reactive protein antigens. The molecules used are in general virulence factors
      and the antibodies to them neutralize their function, thus reducing the virulence
      of the infecting bacteria. Studies in humans have revealed that the proteins
      studied are invariably immunogenic in humans, as at least low levels of antibody
      are seen following colonization or infection. Studies in mice have demonstrated
      that vaccines containing more than one of these virulence proteins are generally
      more protective than those involving just one. Proteins that have been studied
      the most in mice are pneumococcal surface protein A (PspA), PspC, PsaA, and
      pneumolysin. PspA has been used in human safety trials and was shown to elicit
      antibodies that can protect mice from otherwise fatal pneumococcal infections.

PMID- 15037018
TI  - Research on aging in Iceland: future potentials.
AB  - Iceland is a small but prototypic western society strategically located between
      mainland Europe and North America. Through private and public funding, Iceland is
      a model in the making for opportunities in research on aging. Its ethnically and
      socioeconomically homogenous population served by an advanced health care system
      has historically been exceptionally supportive and willing to participate in both
      trans-sectional and cohort studies. Interdisciplinary geriatric care is well
      established and Iceland was on of the first countries to adapt from the US, the
      resident assessment instrument (RAI), which makes comparison of long-term care
      between countries very feasible. Among a number of biotech companies recently
      established in Iceland is Deocode, a leading company in the field of linking
      genetic variation to diseases. A major population study on interactions between
      age, genes and environment (AGES) was launched by the Icelandic Heart Association
      in 2002 through support from the NIA and the Icelandic government. Ultimately,
      one may expect that a cutting edge aging research in Iceland will contribute to
      our understanding of how to maintain a better health, independence and active
      participation in later life.

PMID- 15037020
TI  - Resistance to silica-induced lung fibrosis in senescent rats: role of alveolar
      macrophages and tumor necrosis factor-alpha (TNF).
AB  - The purpose of the present study was to investigate the effect of aging on silica
      induced lung toxicity. In young animals silica induced a significant increase in
      bronchoalveolar lavage tumor necrosis factor-alpha (TNF), lactate dehydrogenase
      as well as in cell numbers, which correlate with increased collagen deposition
      and silicotic nodules formations. In old rats, however, no changes in
      bronchoalveolar lavage or lung parameters were observed following silica
      instillation. These in vivo results were also confirmed in vitro, where silica
      failed to induce TNF release in alveolar macrophages obtained from old animals.
      This defective response to silica could be explained with defective protein
      kinase C translocation, due to a reduction in its anchoring protein RACK-1 with
      aging. Overall, these data indicate that the understanding of the molecular
      mechanisms undelaying toxicity is crucial to define the influence of age on the
      toxic response and progression of the disease.

PMID- 15037019
TI  - Macrophage hypo-responsiveness to interferon-gamma in aged mice is associated
      with impaired signaling through Jak-STAT.
AB  - Since macrophages (Mphis) are a first line of defense against pathogens, and are
      involved in both innate and adaptive immunity, understanding the impact of aging
      on Mphi function is important. In the past studies, we and others have shown that
      aging decreases Mphi responsiveness to classical activating signals (e.g. IFN
      gamma and lipopolysaccharide, LPS). In this study, we examined the impact of
      aging on Mphi signaling through the IFN-gamma receptor pathway. Mphis from male
      Balb/c mice aged 2 (young) and 18-24 (old) months were purified and then
      stimulated with IFN-gamma. Western blotting revealed a significant reduction (
      approximately 50%) in IFN-gamma-stimulated tyrosine phosphorylation of signal
      transducer and activator of transcription-1 (STAT-1) alpha and beta in Mphis from
      aged, when compared with young mice. This reduction in phospho-STAT-1 was
      associated with a significant constitutive reduction ( approximately 80%) in
      total STAT-1alpha protein and a complete inhibition of STAT-1 gene expression in
      response to IFN-gamma in old compared to young mice. These data may, in part,
      explain why classical Mphi responses like reactive nitrogen and oxygen species
      generation, tumor killing and microbicidal activity are lower in Mphis from aged
      subjects. We conclude that peritoneal Mphis from aged mice have an intrinsic
      defect in Jak-STAT signaling which prevents them from fully responding to IFN
      gamma.

PMID- 15037021
TI  - Post-marketing effectiveness of Prevnar [pneumococcal 7-valent conjugate vaccine
      (diphtheria CRM197 protein)] and implications for adult immunization.
AB  - Pneumococcal pneumonia is a significant health concern for pediatric, healthy
      adult, and elderly populations. The newly licensed pneumococcal 7-valent
      conjugate (diphtheria CRM197 protein) vaccine, Prevnar, and a second generation
      experimental 9-valent product have demonstrated, for the first time, a clear and
      significant impact on pneumococcal pneumonia in children. The potential for
      saccharide-conjugate vaccines to help prevent pneumococcal pneumonia in adult and
      elderly populations and potential barriers to the introduction of a conjugate
      vaccine in adults are discussed.

PMID- 15037022
TI  - Alzheimer's Abeta vaccination of rhesus monkeys (Macaca mulatta).
AB  - Recent preliminary data suggest that vaccination with Alzheimer's Abeta might
      reduce senile plaque load and stabilize cognitive decline in human Alzheimer's
      disease. To examine the mechanisms and consequences of anti-Abeta-antibody
      formation in a species more closely related to humans, rhesus monkeys (Macaca
      mulatta) were vaccinated with aggregated Abeta(1-42). Immunized monkeys developed
      anti-Abeta titers exceeding 1:1000, and their plasma Abeta levels were 5-10-fold
      higher than the plasma Abeta levels observed in monkeys vaccinated with
      aggregated amylin. These data support the use of non-human primates to model
      certain phenomena associated with vaccination of humans with aggregated
      Alzheimer's Abeta.

PMID- 15037023
TI  - Isolation of pectenotoxin-2 from Dinophysis acuta and its conversion to
      pectenotoxin-2 seco acid, and preliminary assessment of their acute toxicities.
AB  - We have developed a simple and effective method for isolating pectenotoxin-2 (PTX
      2) from Dinophysis cells collected from a natural bloom. A two-step extraction
      procedure followed by two column chromatography steps produced PTX-2 in high
      purity suitable for use as an analytical standard and for toxicological studies.
      Incubation of purified PTX-2 with the supernatant from ultracentrifuged blue
      (Mytilus edulis) or Greenshell (Perna canaliculus) mussel hepatopancreas
      homogenate caused rapid conversion to pectenotoxin-2 seco acid (PTX-2 SA).
      Purification of PTX-2 SA was achieved by solvent extraction followed by column
      chromatography. PTX-2 and PTX-2 SA were fully characterized by LC-MS and NMR, and
      full (1)H and (13)C NMR assignments were obtained. Okadaic acid C(8)-diol ester
      was isolated during the purification of PTX-2, and its identity confirmed by NMR
      and LC-MS analyses. Pectenotoxin-2 seco acid methyl ester, identified by LC-MS,
      was also produced during the hydrolytic procedure due to the presence of
      methanol. PTX-2 was acutely toxic to mice by i.p. injection (LD(50)=219
      microg/kg) but no effects were seen with PTX-2 SA at 5000 microg/kg. Neither PTX
      2 nor PTX-2 SA was overtly toxic to mice by the oral route at doses up to 5000
      microg/kg. No diarrhea was observed in mice dosed with either compound,
      suggesting that pectenotoxins do not belong in the diarrhetic shellfish poison
      group.

PMID- 15037024
TI  - Differential susceptibility of osteosarcoma cells and primary osteoblasts to cell
      detachment caused by snake venom metalloproteinase protein.
AB  - The interaction of extracellular matrix with cells plays a key role in the
      regulation of cell adhesion, migration, proliferation as well as differentiation.
      Transformed cells express a different profile of adhesion molecules, which may
      mediate metastasis under specific matrix microenvironment. We here found that ROS
      17/2.8 osteosarcoma cells and osteoblasts have different expression of alpha5
      integrin, executing different fibronectin fibrillogenesis. As compared with ROS
      17/2.8 cells, osteoblasts have higher expression of fibronectin, collagen,
      alpha5, beta1, alpha2 integrins and focal adhesion kinase as examined by
      immunostaining and flow cytometry. Crovidisin, a PIII snake venom
      metalloproteinase (SVMP) purified from venom of Crotalus viridis, exhibits
      collagen-binding activity and matrix metalloproteinase activity. Crovidisin
      selectively caused the detachment of ROS 17/2.8 osteosarcoma cells but not of
      primary cultured osteoblasts. On the other hand, triflavin, an RGD-dependent
      disintegrin purified from venom of Trimeresurus flavoviridis, did not cause the
      detachment of both osteoblasts and ROS 17/2.8 cells. Although ROS 17/2.8 cells
      detached from substratum after crovidisin treatment for 24 h, the loss of
      mitochondrial membrane potential was not observed unless a prolonged treatment
      for longer than 36 h. These results suggest that cultured primary rat osteoblasts
      and ROS 17/2.8 osteosarcoma cells possess different expression of integrins and
      matrix environment, and ROS 17/2.8 is much more susceptible to be detached by
      crovidisin. The matrix degradation by crovidisin may be responsible for the
      preferential detachment of ROS 17/2.8 osteosarcoma cells.

PMID- 15037025
TI  - Identification of palytoxin as a principle which causes morphological changes in
      rat 3Y1 cells in the zoanthid Palythoa aff. margaritae.
AB  - A very potent cell-bursting principle was isolated from the extract of the
      zoanthid Palythoa aff. margaritae. The compound was identified as palytoxin by
      comparing the spectral data and HPLC profile with those of an authentic sample.

PMID- 15037026
TI  - A highly sensitive immuno-polymerase chain reaction assay for Clostridium
      botulinum neurotoxin type A.
AB  - Our goal was to develop a sensitive method for detecting Clostridium botulinum
      neurotoxin type A (BoNT/A). We were able to detect BoNT/A in the femtogram (10(
      15)g) range using an indirect immuno-polymerase chain reaction (immuno-PCR) assay
      and an indirect sandwich immuno-PCR assay. For the indirect immuno-PCR assay,
      enzyme-linked immunosorbent assay (ELISA) plates were coated with BoNT/A that was
      recognized by anti-BoNT/A monoclonal antibody. For the indirect sandwich immuno
      PCR assay, the monoclonal antibody was immobilized on ELISA plates for detecting
      BoNT/A that was recognized by its polyclonal antibodies. Reporter DNA was
      prepared by PCR amplification using biotinylated 5'-primers, and it was coupled
      with biotinylated antibodies through streptavidin. In order to increase
      sensitivity and reduce background noise, the amounts of reporter DNA (ranging
      from 50 fg to 50 ng) and streptavidin (ranging from 0.125 ng to 8 ng) were
      optimized. Using the optimized concentration of reporter DNA and streptavidin,
      both indirect and indirect sandwich immuno-PCR assays detected BoNT/A as low as
      50 fg. These results are a 10(5)-fold improvement over conventional indirect
      ELISA and indirect sandwich ELISA methods. The assays we developed are currently
      the most sensitive methods for detecting BoNT/A.

PMID- 15037027
TI  - Cyclosporin A attenuates skeletal muscle damage induced by crotoxin in rats.
AB  - This work was undertaken to determine the role of the calcineurin pathway on the
      necrosis of skeletal muscle induced by crotoxin, the major component of the venom
      of Crotalus durissus terrificus. Rats were treated with cyclosporin A (CsA), a
      calcineurin inhibitor, for 5 days and, in the 6th day, received an intramuscular
      injection of crotoxin into the tibialis anterior muscle. Rats were also treated
      with diclofenac, a non-steroidal anti-inflammatory drug, for 5 days and, on the
      6th day, injected with crotoxin. All treated groups were sacrificed 24 h after
      injection of crotoxin. Tibialis anterior and soleus muscles were removed, frozen
      and stored in liquid nitrogen. Histological sections were stained with Toluidine
      Blue and assayed for acid phosphatase. The results show that CsA, but not
      diclofenac, is able to significantly minimize myonecrosis promoted by crotoxin.
      In conclusion, CsA attenuates skeletal muscle necrosis induced by crotoxin,
      indicating that the calcineurin pathway is essential for crotoxin myotoxic
      activity. The myoprotective effect of CsA is not related to its anti-inflammatory
      effect since diclofenac, a cyclo-oxygenase inhibitor, was not able to produce
      myoprotection.

PMID- 15037028
TI  - Bacterial expression, purification and functional characterization of a
      recombinant chimeric Fab derived from murine mAb BCF2 that neutralizes the venom
      of the scorpion Centruroides noxius hoffmann.
AB  - The murine monoclonal antibody BCF2 is able to neutralize the venom of the
      scorpion Centruroides noxius Hoffmann. A chimeric Fab of BCF2 (chFab-BCF2)
      comprising the variable regions of murine BCF2 and human constant regions was
      assembled. chFab-BCF2 was expressed as a soluble and functional protein in the
      periplasmic space of Escherichia coli. An expression yield of 1 mg/l was reached
      by combination of late-log-phase induction, rich culture medium, low expression
      temperature and addition of sucrose (0.3 M) to the culture medium. The addition
      of sucrose induced secretion of 60% of the protein into the medium. After
      expression for 23 h, a novel process was used to release the remaining
      periplasmic protein in situ consisting in the addition of lysozyme and sucrose up
      to 0.6 M (20%) directly to the culture medium. chFab-BCF2 was recovered by
      ammonium sulfate precipitation and purified in a single step by affinity
      chromatography using anti-human anti-F(ab')(2) IgG coupled to Sepharose-proteinG.
      Pure chFab-BCF2 maintained a similar nanomolar affinity as BCF2 to its cognate
      antigen, the Na(+)-channel-affecting toxin Cn2. Recombinant chFab-BCF2 was able
      to neutralize Cn2 in vivo even at a molar ratio of 1:1, as well as the whole
      venom of C. noxius. Thus, it is a promising candidate to be used as a specific
      and efficient recombinant antidote against scorpion stings.

PMID- 15037029
TI  - Catalpol inhibits apoptosis in hydrogen peroxide-induced PC12 cells by preventing
      cytochrome c release and inactivating of caspase cascade.
AB  - In the present study, using a rat pheochromocytoma (PC12) cell line, the effect
      of catalpol on H2O2-induced apoptosis was studied. The apoptosis in H2O2-induced
      PC12 cells was accompanied by down-regulation of Bcl-2, up-regulation of Bax, the
      release of mitochondrial cytochrome c to cytosol and sequential activation of
      caspase-1 and caspase-3 then leading to cleavage of poly-ADP-ribose polymerase
      (PARP). Catalpol not only suppressed the down-regulation of Bcl-2, up-regulation
      of Bax and the release of mitochondrial cytochrome c to cytosol, but also
      attenuated caspase-3 activation, PARP cleavage, and eventually protected against
      H2O2-induced apoptosis. Taken together, these results suggest that treatment of
      PC12 cells with catalpol can block H2O2-induced apoptosis by the regulation of
      Bcl-2 family members, as well as suppression of cytochrome c release and caspase
      cascade activation.

PMID- 15037030
TI  - Role of Ca2+ in vascular smooth muscle contractions induced by Phoneutria
      nigriventer spider venom.
AB  - Phoneutria nigriventer venom (PNV) contracts vascular tissues and increases
      arterial blood pressure. This study aimed to investigate the mechanisms involved
      on PNV-induced contractions of rabbit mesenteric and celiac arteries. Strips of
      mesenteric and celiac arteries were suspended in a cascade system and superfused
      with warmed and oxygenated Krebs solution. PNV was dialyzed in order to exclude
      the participation of biogenic amines in the contractions elicited by the venom.
      Noradrenaline (NA, 30-300 pmol), PNV (1-10 microg), Bay K-8644 (0.3-3 nmol) and
      KCl (10-100 micromol) dose-dependently contracted the preparations. Ca(2+)-free
      solution reduced by 38 and 83% the PNV-induced contractions of mesenteric and
      celiac arteries, respectively. Subsequent infusion of EGTA (0.2 mM) suppressed
      the residual contractions. Nifedipine (1 microM) and verapamil (10 microM)
      abolished PNV- and Bay K-8644-evoked contractions, whereas those induced by NA
      were reduced to a lesser extent. Lanthanum chloride (0.2 mM) inhibited by 75-90%
      the mesenteric and celiac contractions mediated by PNV. Caffeine (2 mM) fully
      blocked contractions induced by NA (95% mean inhibition), but only partly reduced
      those induced by PNV (35% mean inhibition). Ryanodine (10 microM) inhibited by
      50% the contractions evoked by NA, but had no effect on the PNV-induced
      contractions in both tissues. Our findings indicate that PNV contracts vascular
      smooth muscle mainly due to increased influx of Ca(2+) from extracellular
      sources.

PMID- 15037031
TI  - Purification, cloning and biological characterization of a novel disintegrin from
      Trimeresurus jerdonii venom.
AB  - A novel disintegrin, jerdonin, was purified from the Trimeresurus jerdonii venom
      by means of gel filtration and reverse phase high pressure liquid chromatography.
      Its coding cDNA was also isolated from the venom gland. The jerdonin coding cDNA
      is part of a precursor composed of proprotein, metalloproteinase, and disintegrin
      domains. From the deduced amino acid sequence, jerdonin is composed of 71 amino
      acid residues including 12 cysteines and the tripeptide sequence Arg-Gly-Asp
      (RGD), a well-known characteristic of the disintegrin family. Molecular mass of
      jerdonin was determined to be 7483Da by matrix-assisted laser desorption
      ionization time of flight mass spectrometry. Jerdonin inhibited ADP- and collagen
      induced human platelet aggregation with IC(50) of 220 and 240 nM, respectively.
      In vivo, jerdonin inhibited the growth of subcutaneously inoculated B16 solid
      tumor in C57BL/6 mice and improved the survival time of the tumor-bearing mice.

PMID- 15037032
TI  - Effects of ACL myotoxin, a Lys49 phospholipase A(2) from Agkistrodon contortrix
      laticinctus snake venom, on water transport in the isolated toad urinary bladder.
AB  - ACL myotoxin (ACLMT) is a Lys49 phospholipase A(2)-like protein isolated from the
      venom of the snake Agkistrodon contortrix laticinctus. The aim of this work was
      to study the effect of ACLMT on water transport in the toad bladder. Water flow
      through the membrane was measured gravimetrically in bag preparations of the
      bladder. ACLMT (20 nM) increased the baseline water flow and partially inhibited
      arginine-vasopressin (AVP), 8-chlorophenylthio-cAMP (8-CPT-cAMP) and forskolin
      stimulated water flow. The effect of ACLMT on baseline or AVP-stimulated water
      flow was prevented by lanthanum (0.1 mM) indicating that the effect of ACLMT on
      water transport may be mediated through an increase in intracellular calcium. The
      effect of ACLMT on baseline water flow was also prevented by nifedipine (0.1 mM)
      indicating the participation of exogenous calcium in this effect. Carbachol (0.1
      mM) has been shown to enhance baseline water flow while inhibiting AVP-stimulated
      water flow. The effects of ACLMT and carbachol on baseline water flow and AVP
      stimulated water flow were not additive, suggesting that both agents alter water
      transport by a similar mechanism. Indomethacin (10 microM) reduced the effect of
      ACLMT on forskolin-stimulated water flow, suggesting an increase in prostaglandin
      biosynthesis. These results suggest that the effects of ACLMT on water transport
      may be mediated by increasing intracellular calcium and stimulation prostaglandin
      biosynthesis.

PMID- 15037033
TI  - The role of microcystin-LR in the induction of apoptosis and oxidative stress in
      CaCo2 cells.
AB  - The increasing presence of toxic cyanobacteria in drinking and recreational water
      bodies, and their potential to impact on human and animal health is cause for
      concern. Recent work suggests that apoptosis plays a major role in the toxic
      effects induced by microcystin-LR (MCLR) in the gastrointestinal tract; however,
      the biochemical pathway remains elusive. Exposure of CaCo2, a human colon
      carcinoma cell line, and MCF-7, a cell line deficient in pro-caspase-3, cells to
      50 microM MCLR induced similar reductions in cell viability as measured by MTT
      and LDH leakage. The role of MCLR induced oxidative stress in the initiation of
      apoptosis was investigated over a 2-hr period, and it was found that there was an
      increase in the release of H(2)O(2) in the first 30 min of exposure for both cell
      lines. Both cell lines exhibited a dose-dependent increase in both micro- and
      millicalpain after 24 h exposure to MCLR suggesting a role for protease
      activation in MCLR-induced apoptosis in non-hepatic human derived cell lines.

PMID- 15037034
TI  - Caspase-3 and heat shock protein-70 in rat liver treated with aflatoxin B1:
      effect of melatonin.
AB  - In the present study, caspase-3 enzyme activity (apoptotic marker) and heat shock
      protein-70 (HSP70) expression in male rat liver after aflatoxin B1 (AFB1)
      treatment and the effect of melatonin (MEL) were investigated. Four groups of 20
      rats each were used: controls, MEL-treated rats (MEL dose, 5 mg/kg body wt), AFB1
      treated rats (50 microg/kg body wt) and MEL+AFB1-treated rats. After 8 weeks of
      daily treatment, biochemical assays in liver homogenates were done. The caspase-3
      enzyme activity was measured using colorimetric method while the level of HSP70
      expression was determined using dot blot analysis. In addition, the tissue levels
      of lipid peroxides (LPO), nitric oxide (NO), glutathione (GSH) and the enzyme
      activities of glutathione reductase (GR) and glutathione peroxidase (GSPx) were
      determined using colorimetric methods. The levels of caspase-3 activities and
      HSP70 level in AFB1 group were significantly higher than control group.
      Concomitantly, the levels of oxidative stress indices, LPO and NO, were
      significantly increased while the levels of antioxidants, GSH, GSPx and GR in
      AFB1 group were significantly decreased compared to their levels in controls.
      Caspase-3 activity was positively correlated with LPO while negatively correlated
      with GSH in rat livers treated with AFB1. The levels of caspase-3 activity, LPO,
      NO and HSP70 expression were significantly lower while the levels of GSH, GSPx
      and GR activities were significantly higher in MEL+AFB1 group than AFB1 group. In
      conclusion, higher levels of caspase-3 activity and HSP70 expression were
      associated with oxidative stress in rat liver treated with AFB1. The increased
      HSP70 expression in liver of AFB1 group may be due to a compensatory defense
      mechanism. MEL may effectively normalize the impaired antioxidants status, which
      consequently reduce both expression of HSP70 and apoptotic dysregulation in the
      liver. Thus, clinical application of MEL as therapy may benefit in cases of
      aflatoxicosis.

PMID- 15037035
TI  - High affinity for the rat brain sodium channel of newly discovered
      hydroxybenzoate saxitoxin analogues from the dinoflagellate Gymnodinium
      catenatum.
AB  - The paralytic shellfish poison family has been recently extended by the discovery
      of several analogues possessing a hydoxybenzoate moiety instead of the carbamoyl
      group one finds in saxitoxin, the parent molecule of this toxin family. We have
      investigated the potency of these new analogues on a representative isoform of
      the pharmacological target of these toxins, the voltage gated sodium channel.
      These toxins were found to have K1's in the low nanomolar range, only slightly
      less potent than saxitoxin. The hydroxybenzoate group may increase the
      lipophilicity of these toxins and improve their ability to pass through epithelia
      and therefore its uptake and elimination in both intoxication victims and animals
      that bioaccumulate paralytic shellfish toxins.

PMID- 15037036
TI  - A postcard from Brighton.

PMID- 15037037
TI  - Youth risk behaviour in a Chinese population: a territory-wide youth risk
      behavioural surveillance in Hong Kong.
AB  - This cross-sectional study investigated the prevalence rates of different
      categories of youth risk behaviour by age, sex and parental education. The study
      population consisted of 26,111 Hong Kong students, aged 10-19 years, recruited
      from 48 primary (primary grades 4-6) and secondary schools (secondary grades 1
      7). Less than one-third of subjects participated in vigorous exercise regularly,
      about one-third consumed an unhealthy diet frequently, 18% had tried smoking, and
      14.5% had seriously considered attempting suicide. Although only 3.4% of students
      reported experience of sexual intercourse, less than half used a contraceptive
      device. Older students had higher prevalence rates of health-compromising
      behaviours than younger students. Female students were more likely to report
      suicide-related behaviour, attempting weight loss, and non-participation in
      vigorous physical activities. Students with parents of a lower educational
      background were more likely to report rarely or never wearing seat belts and
      bicycle helmets, suicide-related behaviour, smoking, sexual intercourse before 13
      years of age, and attempting weight loss. The availability of data on youth
      health risk behaviours would enable health educators, public health practitioners
      and clinicians to plan appropriate screening and counselling for risk behaviours
      in early adolescents.

PMID- 15037038
TI  - What's said and what's done: the reality of sexually transmitted disease
      consultations.
AB  - OBJECTIVE: Indirect data collection methods, or approaches which disturb usual
      practice, are generally used in health care evaluation. We have compared what
      doctors report at interview what is observed by an identified researcher with an
      unobtrusive measure of their usual practice. DESIGN: Private practitioners who
      provide a service to sexually transmitted disease (STD) patients were interviewed
      regarding their usual case management. An identified researcher carried out
      structured observations of consultations between physicians and patients.
      Simulated clients then sought consultations, presenting a standardised history
      and symptom profile. Structured reporting of the history taking, examination,
      treatment and counselling aspects of these consultations was undertaken.
      SUBJECTS: Eighteen private practitioners in Madras (now Chennai), India. MAIN
      OUTCOME MEASURES: Comparisons between interviews, observations by identified
      researchers and the experiences of simulated clients were carried out. RESULTS:
      Interviews with physicians and observations by identified researchers indicated
      more favourable practice than was seen during simulated client visits. These
      differences were substantial and would lead to a severe misrepresentation of the
      actual situation-and thus of intervention needs, if data from interviews or
      observations were relied upon. CONCLUSIONS: The usual methods used in the
      evaluation of medical services and in carrying out medical audit may produce
      highly unreliable findings. STD services in the study area are failing to realise
      their potential of improving the sexual health of populations. The methodological
      and substantive findings of this study could be combined through the introduction
      of simulated client visits in the monitoring, improvement and licensing of STD
      (and perhaps other medical) services.

PMID- 15037039
TI  - Sexual differences in oral health behaviour and factors associated with oral
      health behaviour in Japanese young adults.
AB  - The aim of this study is to compare the state of oral health behaviour between
      genders and to analyse factors associated with oral health behaviour by gender in
      young adults. Anonymous questionnaire data were collected from 527 adults (245
      men and 282 women) aged 20-29 years who consulted dentists in Chiba City. The Chi
      square test, Mann-Whitney analysis, and logistic regression analysis were used to
      examine the differences in oral health behaviour and determinants of oral health
      behaviour between young men and young women. The rate of good behaviour among
      women were significantly higher than those among men in each oral health
      behaviour item (toothbrushing frequency p < 0.001; using dental floss p = 0.042;
      dental check-ups p < 0.001). In women, factors associated with each oral health
      behaviour were as follows: toothbrushing frequency (family composition p =
      0.030); using dental floss (dental health knowledge p = 0.025, employment status
      p = 0.031), and dental check-ups (age group p = 0.024). In men, a significant
      relationship was seen only between using dental floss and age group p = 0.025).
      This study indicated that young women had better oral health behaviour and that
      more factors were associated with their oral health behaviour in comparison with
      young men.

PMID- 15037040
TI  - Road-traffic-related mortality in Iran: a descriptive study.
AB  - Road traffic accidents are considered to be the second highest cause of mortality
      in Iran. A study was conducted to describe road-traffic-related mortality data in
      Iran in a given period. All Iranian mortality data on road traffic accidents
      between March 1999 and 2000 (one complete Iranian calendar year) were obtained.
      The main variables studied were deceased's gender, age, education level, status
      (i.e. driver, car occupant, etc.), cause and place of death. A total of 15?482
      individuals died from road traffic accidents in Iran in the study period. A
      disproportionate number of deceased individuals were male (79%), mostly aged 40
      years or less (65%), and who were pedestrians or car occupants (62%). Head injury
      was the most common cause of road-traffic-related mortality (66%) in males and
      females of all ages. Following road traffic accidents, 57% of deaths occurred pre
      hospital. Head injury is the most common single cause of mortality attributable
      to road traffic accidents in Iran, and since most deaths occur pre-hospital, it
      seems many are preventable. To overcome this major public health problem, there
      is an urgent need to develop a comprehensive injury control policy and strategy
      in Iran.

PMID- 15037041
TI  - Injuries among children in Karachi, Pakistan--what, where and how.
AB  - OBJECTIVES: To describe the epidemiology of injuries among children in Karachi,
      Pakistan. STUDY DESIGN: Retrospective case series. METHODS: Data on children aged
      < or =15 years who were injured between October 1993 and January 1996 were
      extracted from the logs of the main provider of emergency medical transportation,
      and were classified according to the World Health Organization's basic data set
      for information on injuries. RESULTS: We identified 1320 cases of injuries in
      children < or =15 years old. The major causes were: motor vehicle crashes (MVC)
      (80%), falls other than from vehicles (5%), burns (5%) and drowning (3%). One in
      six of these children (15%) died either at the scene of the accident or during
      transportation to the hospital. The majority of deaths were either due to MVCs
      (67%) or drowning (18%) Large vehicles (buses, minibuses and trucks) were
      involved in 54% of all childhood road traffic injuries. Almost one-third (33%) of
      burns took place in the kitchen at home, and half (51%) of all drowning cases
      occurred in the sea. CONCLUSIONS: The majority of children transported by the
      ambulance service were male and were victims of MVCs. Prevention efforts aimed at
      stricter enforcement of driving laws and family/child education geared towards
      pedestrian safety could potentially reduce morbidity and mortality. This study
      also highlights the role of the prehospital transport system in injury
      surveillance.

PMID- 15037042
TI  - Knowledge and beliefs about elephantiasis and hydrocele of lymphatic filariasis
      and some socio-demographic determinants in an endemic community of Eastern India.
AB  - This study reports the knowledge and beliefs about filarial elephantiasis and
      hydrocele of people from an endemic area of Orissa, India. Both qualitative and
      quantitative data were collected from 12 villages, sampled from four blocks in
      the Khurda district of Orissa. This study found that people were aware of
      different manifestations of filariasis, and perceived them as problems in their
      community. A high proportion of people knew that mosquitoes are the reason for
      the spread of elephantiasis, but less people were aware of the cause of hydrocele
      and the association between elephantiasis and hydrocele. Only half of the
      respondents believed that elephantiasis is curable by modern medicines, and about
      84% of respondents thought that surgery is the only method to cure hydrocele.
      About two-thirds of people know that avoiding mosquitoes can prevent
      elephantiasis. Age, gender, educational level and caste affiliation were
      identified as factors influencing awareness and knowledge. These findings may be
      used in the development of group-specific health education programmes to change
      health behaviour and to achieve higher involvement of the community in annual
      mass drug administration to eliminate lymphatic filariasis.

PMID- 15037043
TI  - Onchocerciasis in Imo State, Nigeria. Community knowledge and beliefs about
      transmission, treatment and prevention.

PMID- 15037044
TI  - Palestinian refugee conditions associated with intestinal parasites and
      diarrhoea: Nuseirat refugee camp as a case study.
AB  - OBJECTIVE: To assess the socioeconomic-demographic, environmental health and
      hygiene conditions associated with intestinal parasites and diarrhoea in Nuseirat
      Refugee Camp of Gaza Strip. METHODS: A cross-section of 1625 households were
      surveyed. A stratified sample was used and drawn from the eight Blocks. Face-to
      face interviews were administered for data collection. Piloted and validated
      questionnaires along with specific checklists were used as instruments. RESULTS:
      A total of 485 women interviewed (29.8%) reported intestinal parasites among
      their household members; 223 (13.7%) admitted cases of diarrhoea. The highest
      prevalence of intestinal parasites (24.1%) was found among children aged 1-4
      years; the highest prevalence of diarrhoea (10.6%) was found among children
      younger than 1 year. Intestinal parasites were strongly associated with crowding,
      source of drinking water and the cleaning of water tanks, and were significantly
      higher among families with unclean homes. Diarrhoea was strongly associated with
      source of drinking water, a full-day water supply and cleaning of water tanks,
      and was significantly higher among families with a presence of mosquitoes and
      garbage around their homes. CONCLUSIONS: Poor socioeconomic-demographic,
      environmental health and hygiene conditions play a major role in the occurrence
      of intestinal parasites and diarrhoea. Children younger than 5 years are at high
      risk. Real interventions, such as health education, environmental awareness,
      community involvement and raising funds for infrastructural development are
      urgently needed.

PMID- 15037046
TI  - The roles and responsibilities of primary care trusts in emergency planning: a
      report of a major incident in Sunderland, UK.

PMID- 15037045
TI  - Nutritional risk following a major disaster in a previously well-nourished
      population: who is vulnerable?

PMID- 15037047
TI  - Demographic and socio-economic factors affecting the physical development,
      haemoglobin and parasitic infection status of schoolchildren in Sanliurfa
      province, Turkey.
AB  - A cross-sectional population-based survey was undertaken to evaluate the
      relationship between nutritional status and parasitic infections of
      schoolchildren and demographic, socio-economic factors in Sanliurfa province,
      southern Turkey. Nine hundred and eight schoolchildren took part in the survey:
      57.2% boys and 42.7% girls. The children's mean z scores were as follows: height
      for age-0.8 (+/-1.0) and weight for age-1.0 (+/-0.9). The mean haemoglobin
      concentration was 123 g/l (+/-2.1) and the prevalence of parasitic infections was
      55.1%. In total, 50.2% of children were hungry when they arrived at school and
      13.4% worked after school. Over 70% (70.4%) of mothers and 18.1% of fathers were
      illiterate, 16.1% of fathers were unemployed and 46.3% of fathers were engaged in
      low-income labour. The mean number of children in each family was 5.4 (+/-2.5),
      and the mean number of children from each family who attended school was 2.1 (+/
      1.1). The school-attendance ratio was 0.4 (+/-1.0). Data indicated that older
      children had significantly lower mean z scores of height (P < 0.0001) and weight
      for age (P < 0.0001) than younger children, and boys had significantly lower mean
      z scores of height for age than girls (P < 0.0001). Children living in shantytown
      areas had significantly lower mean z scores of height for age (P < 0.0001) and
      weight for age (P < 0.0001), lower mean haemoglobin concentrations (P : 0.003)and
      a worse parasitic infection status (P < 0.0001) than those living in apartment
      areas. Children who were hungry when they arrived at school had significantly
      lower mean haemoglobin concentrations than those who had eaten (P : 0.04).
      Multiple regression analyses indicated that mean z scores of height for age were
      significantly related to maternal (multiple R = 0.183; P < 0.0001) and paternal
      illiteracy (multiple R = 0.216; P : 0.004). Mean z scores of weight for age were
      significantly related to maternal illiteracy (multiple R = 0.154; P < 0.0001), as
      was parasitic infection status (multiple R = 0.261; P < 0.0001 ) and the number
      of children in the family (multiple R = 0.267; P : 0.005). Hunger status was
      significantly related to maternal (multiple R = 0.095; P : 0.016) and paternal
      illiteracy (multiple R = 0.104; P : 0.005), as was belonging to a large family
      (multiple R = 0.104; p: 0.009). These findings indicate that school health
      programmes may improve the nutritional and health status of schoolchildren. The
      participation of the local community, which such a programme would entail, may
      help to increase maternal awareness regarding the feeding of their children
      before sending them to school. School health programmes may also motivate parents
      to send their daughters to school, thus increasing maternal literacy in the
      future. In turn, better levels of maternal literacy will positively affect the
      socio-economic development of society.

PMID- 15037048
TI  - Comments on "Education for health: case studies of two multidisciplinary MPH/MSc
      public health programmes in the UK" by El Ansari et al.

PMID- 15037050
TI  - Haptic face recognition and prosopagnosia.
AB  - Cases of cross-modal influence have been observed since the beginning of
      psychological science. Yet some abilities like face recognition are traditionally
      only investigated in the visual domain. People with normal visual face
      recognition capacities identify inverted faces more poorly than upright faces. An
      abnormal pattern of performance with inverted faces by prosopagnosic individuals
      is characteristically interpreted as evidence for a deficit in configural
      processing essential for normal face recognition. We investigated whether such
      problems are unique to vision by examining face processing by hand in a
      prosopagnosic individual. We used the haptic equivalent of the visual-inversion
      paradigm to investigate haptic face recognition. If face processing is specific
      to vision, our participant should not show difficulty processing faces haptically
      and should perform with the same ease as normal controls. Instead, we show that a
      prosopagnosic individual cannot haptically recognize faces. Moreover, he shows
      similar abnormal inversion effects by hand and eye. These results suggest that
      face-processing deficits can be found across different input modalities. Our
      findings also extend the notion of configural processing to haptic face and
      object recognition.

PMID- 15037051
TI  - Hemispheric differences between left and right number representations: effects of
      conscious and unconscious priming.
AB  - The contribution of each hemisphere to the generation of number representations
      was investigated by two lateralized priming experiments in which participants had
      to compare Arabic digits to a fixed standard of four. In Experiment 1, unmasked
      primes (Arabic digits or word numerals) were used. In Experiment 2, masked primes
      were presented consciously or subconsciously. In both experiments similar priming
      effects were found in the left (LH) and the right hemisphere (RH) when the prime
      was presented consciously. However, asymmetries emerged when the primes were
      presented subconsciously: while the priming effects of digits and word numbers
      were equally large in the right visual half field (RVF-LH), the influence of the
      word prime on the semantic and the response stage of the left visual half field
      (LVF-RH) was absent, indicating that a word prime was no longer processed when it
      was presented subconsciously in LVF-RH. We believe that the origin of the latter
      effect can be attributed to a failure to transfer word number primes from the RH
      to the LH when attentional resources are restricted.

PMID- 15037052
TI  - Wishful reality distortions in confabulation: a case report.
AB  - Several theories have been proposed to account for the complex cognitive
      mechanisms underlying the various forms and manifestations of confabulation. As
      regards the content of confabulations, deficit accounts explain what is lacking
      in the confabulations, but accounts of the positive features of the content may
      also be required to explain what remains. There is reason to believe that the
      content of confabulations is not motivationally neutral; in particular, they
      appear to "improve" the world experienced by the patient, making it more pleasant
      than the reality of the situation demands. The present study investigated the
      content of the confabulations of a neurological patient, ES: a 56-year-old man,
      who developed a striking confabulatory syndrome following removal of a meningioma
      in the pituitary and suprasellar region. ES's cognitive abilities were severely
      compromised, and he confabulated continuously and bizarrely. Raters presented
      with transcriptions of ES's confabulations found them to represent significantly
      more pleasant experiences than their corresponding, misrepresented realities.
      This finding suggests that confabulations include motivated (or "wishful")
      content. The influence of this motivational feature of confabulation must be
      considered in parallel with the memory and executive deficits which contribute to
      the mechanism of confabulation.

PMID- 15037053
TI  - Priming illusory words: an ERP approach.
AB  - Repetition blindness (RB) was used to investigate whether illusory words emerge
      at a lexical-perceptual or a semantic-reconstructional level. Illusory words were
      evoked by the rapid serial visual presentation (RSVP) of two real words and a
      word fragment. The initial words share the same string of letters ("CREEP"
      "SHEEP"), producing a free-floating word fragment ("SH"). This fragment is likely
      to be linked to a subsequently presented fragment ("IFT") if both combine to a
      meaningful word ("SHIFT"). The processing level of the illusions was probed by
      prime words preceding the RSVP sequence which were semantically related or
      unrelated to the second real word or to the illusion. Behavioural and
      electrophysiological correlates of the semantic priming effect were recorded in
      14 subjects. Real words related to the prime were perceived more frequently, and
      evoked widespread N400-like effect in the event-related brain potentials (ERPs).
      An ERP effect of the same polarity was obtained for illusory words, however, its
      latency was delayed and the topographical distribution was restricted to left
      posterior electrode positions. These differences suggest that priming might
      affect real and illusory words at different levels of word processing: access to
      real words is facilitated at a semantic level, whereas lexical activation
      apparently accompanies the generation of illusory words.

PMID- 15037054
TI  - On the role of the cerebellum in exploiting temporal contingencies:; evidence
      from response times and preparatory EEG potentials in patients with cerebellar
      atrophy.
AB  - Patients with degenerative cerebellar disease were compared to healthy controls
      in their ability to adapt behaviour to temporal contingencies, both according to
      instructions and according to acquired experience. Participants had to press the
      cued key whenever the inside of a clock face changed its colour, which could
      occur when the pointer, rotating once every 4s, was at "10h" or at "12h" or at
      "2h". Probabilities varied between blocks at which of these three time points the
      colour change occurred, with participants being instructed accordingly. Response
      times correlated intraindividually with these instructed "a priori" probabilities
      in control participants only. Subjectively, at any moment, probabilities of
      occurrence depend on whether the imperative colour change had occurred before,
      thus may be better described by conditional ("a posteriori") probabilities.
      Indeed, when response times were correlated to a posteriori rather than a priori
      probabilities, correlations increased in both groups equally from their different
      a priori levels. The amplitudes of preparatory EEG negativity before responding
      tended to obey to the same relationships, suggesting that the difference between
      groups was not due to pure motor impairment. Thus, these data suggest that
      patients with cerebellar atrophy are more impaired in implementing and using task
      relevant information in a top-down manner than in learning to modify task
      relevant contingencies.

PMID- 15037055
TI  - Developmental amnesia: a new pattern of dissociation with intact episodic memory.
AB  - A case of developmental amnesia is reported for a child, CL, of normal
      intelligence, who has intact episodic memory but impaired semantic memory for
      both semantic knowledge of facts and semantic knowledge of words, including
      general world knowledge, knowledge of word meanings and superordinate knowledge
      of words. In contrast to the deficits in semantic memory, there are no
      impairments in episodic memory for verbal or visual material, assessed by recall
      or recognition. Lexical decision was also intact, indicating impairment in
      semantic knowledge of vocabulary rather than absence of lexical representations.
      The case forms a double dissociation to the cases of Vargha-Khadem et al.
      [Science 277 (1997) 376; Episodic memory: new directions in research (2002) 153];
      Gadian et al. [Brain 123 (2000) 499] for whom semantic memory was intact but
      episodic memory was impaired. This double dissociation suggests that semantic
      memory and episodic memory have the capacity to develop separately and supports
      models of modularity within memory development and a functional architecture for
      the developmental disorders within which there is residual normality rather than
      pervasive abnormality. Knowledge of arithmetical facts is also spared for CL,
      consistent with adult studies arguing for numeracy knowledge distinct from other
      semantics. Reading was characterised by difficulty with irregular words and
      homophones but intact reading of nonwords. CL has surface dyslexia with poor
      lexico-semantic reading skills but good phonological reading skills. The case was
      identified following screening from a population of normal schoolchildren
      suggesting that developmental amnesias may be more pervasive than has been
      recognised previously.

PMID- 15037056
TI  - The relationship of male testosterone to components of mental rotation.
AB  - Studies suggest that higher levels of testosterone (T) in males contribute to
      their advantage over females in tests of spatial ability. However, the mechanisms
      that underlie the effects of T on spatial ability are not understood. We
      investigated the relationship of salivary T in men to performance on a
      computerized version of the mental rotation task (MRT) developed by [Science 171
      (3972) (1971) 701]. We studied whether T is associated specifically with the
      ability to mentally rotate objects or with other aspects of the task. We
      collected hormonal and cognitive data from 27 college-age men on 2 days of
      testing. Subjects evaluated whether two block objects presented at different
      orientations were the same or different. We recorded each subject's mean response
      time (RT) and error rate (ER) and computed the slopes and intercepts of the
      functions relating performance to angular disparity. T level was negatively
      correlated with ER and RT; these effects arose from correlations with the
      intercepts but not the slopes of the rotation functions. These results suggest
      that T may facilitate male performance on MRTs by affecting cognitive processes
      unrelated to changing the orientation of imagined objects; including encoding
      stimuli, initiating the transformation processes, making a comparison and
      decision, or producing a response.

PMID- 15037058
TI  - Qualitative aspects of verbal fluency in HIV-associated dementia: a deficit in
      rule-guided lexical-semantic search processes?
AB  - HIV-associated dementia (HAD) is widely considered a "subcortical" dementia that
      involves a disruption of frontal-basal ganglia circuits. Deficits in verbal
      fluency are common in HAD; however, the cognitive underpinnings of these deficits
      are not well understood. To elucidate the cognitive mechanisms underlying the
      diminished verbal fluency output in HAD, we examined several qualitative aspects
      of letter fluency in 21 individuals with HAD, 51 nondemented persons with HIV
      infection (HIV+), and 30 healthy controls (HC) who were comparable for age,
      education, sex, ethnicity, and estimated premorbid verbal intelligence. The
      verbal fluency protocols were scored to obtain the total number of correct words,
      average phonemic cluster size, total number of switches between phonemic
      clusters, and the proportion of error responses (i.e., intrusions,
      perseverations, and variants). Consistent with prior research, HAD participants
      produced significantly fewer total correct words relative to the HC and
      nondemented HIV+ groups. The HAD group also demonstrated fewer switches and a
      higher proportion of response errors (especially intrusion errors), but no
      differences were observed in average cluster size. Findings are interpreted as
      reflecting a disruption of rule-guided lexical-semantic search strategies in HAD,
      perhaps mediated by prefrontal-striatal circuit dysfunction, rather than depleted
      lexical-semantic memory stores.

PMID- 15037059
TI  - One good turn deserves another: an event-related brain potential study of rotated
      mirror-normal letter discriminations.
AB  - The time to decide if a letter is normal or backwards (mirror-reversed) increases
      as the letter is rotated away from the upright. It is widely accepted that this
      increase in time reflects the mental rotation of the stimulus to the upright
      orientation in order to determine the mirror-normal status of the stimulus.
      Although response times tend to be longer for mirrored stimuli than for normal
      stimuli, the difference is constant across orientation. Little work has been
      focused on why mirror-image stimuli produce longer response times than normal
      stimuli. This study examines the question of whether or not mirrored stimuli are
      rotated in the picture plane at the same time as normal stimuli, and if so, why
      response times to mirrored stimuli are longer than that for normal stimuli. Both
      the behavioural and electrophysiological findings suggest that the mirrored
      stimuli are not only rotated in the picture plane, but that they are subsequently
      rotated to the normal view. It is this additional rotation that produces, at
      least in part, the delayed response times for mirror-image stimuli.

PMID- 15037057
TI  - Effects of Alzheimer disease on memory for verbal emotional information.
AB  - In healthy young and older adults, emotional information is often better
      remembered than neutral information. It is an open question, however, whether
      emotional memory enhancement is blunted or preserved in Alzheimer disease (AD).
      Prior studies of emotional memory in AD have included small samples of patients.
      In addition, studies that failed to find an enhancement effect in AD used stimuli
      lacking semantic coherence (e.g. lists of unrelated words, some that were
      emotional and others that were neutral). To circumvent these limitations, the
      present study examined a large number of AD patients (N=80) and investigated
      whether AD patients would show better memory for a verbal description of an
      emotional event as compared to a neutral one. AD patients were equivalent to
      young and older control participants in rating the emotional descriptions for
      valence and arousal. Unlike the control groups, however, memory in AD patients
      did not benefit from the emotional narratives. We conclude that AD disrupts
      memory enhancement for at least some types of verbal emotional information.

PMID- 15037060
TI  - Chromatic edges, surfaces and constancies in cerebral achromatopsia.
AB  - We tested achromatopsic observer, MS, on a number of tasks to establish the
      extent to which he can process chromatic contour. Stimuli, specified in terms of
      cone-contrast, were presented in a three-choice oddity paradigm. First we show
      that MS is able to discriminate the magnitude of chromatic and luminance
      contrast, but performance is inferior to that of normal observers. Moreover, MS
      can discriminate isoluminant borders of different chromatic composition. These
      abilities are not the result of unintended luminance differences and are
      abolished when chromatic borders are masked by sharp luminance change. In simple
      displays, local cone-contrast signals can make a significant contribution to
      surface colour appearance in normal observers. In more complex displays, the
      perception of a surface's colour becomes largely independent of the local
      contrast to its background, via processes presumed to be similar to the edge
      integration and anchoring stages of Land's Retinex algorithm. We show that in
      simple displays the percepts of both MS and normal observers are dominated by
      local chromatic-contrast. But, although the percepts of normal observers change
      in line with the predictions of retinex theory in more complex displays, those of
      MS do not, remaining dominated by local contrast signals. We conclude that MS has
      lost the ability to perform edge integration and that this loss is closely
      related to his absence of colour experience.

PMID- 15037061
TI  - Spatial attention speeds discrimination without awareness in blindsight.
AB  - An intimate relationship is often assumed between visual attention and visual
      awareness. Using a subject, patient GY, with the neurological condition of
      "blindsight" we show that although attention may be a necessary precursor to
      visual awareness it is not a sufficient one. Using a Posner endogenous spatial
      cueing paradigm we showed that the time our subject needed to discriminate the
      orientation of a stimulus was reduced if he was cued to the location of the
      stimulus. This reaction-time advantage was obtained without any decrease in
      discrimination accuracy and cannot therefore be attributed to speed-error trade
      off or differences in bias between cued and uncued locations. As a result of his
      condition GY was not aware of the stimuli to which processing was attentionally
      facilitated. Attention cannot, therefore be a sufficient condition for awareness.

PMID- 15037062
TI  - Auditory extinction: the effect of stimulus similarity and task requirements.
AB  - Auditory extinction was examined in six patients with right hemisphere lesions,
      using an auditory double simultaneous stimulation task using letters spoken in
      male and female voices. Patients had to detect where the stimuli were located,
      and identify either the letter or the voice (the task-relevant dimension).
      Auditory extinction was greatest when the two stimuli were the same on the task
      relevant dimension, paralleling previous studies of visual extinction.
      Furthermore, we found that errors of omission were much less frequent in the
      contralesional field if the patients were not required to report both identity
      and the location of stimuli. These results are consistent with the notion that
      auditory extinction may be due in part to a failure to bind together identity and
      location.

PMID- 15037063
TI  - Salt-bridges can stabilize but do not accelerate the folding of the homodimeric
      coiled-coil peptide GCN4-p1.
AB  - Double mutant cycle analysis was employed to ascertain the role of intra- and
      interchain salt-bridges in the folding and stability of the dimeric coiled-coil
      peptide, GCN4-p1, the 33-residue leucine zipper domain of the transcriptional
      activator GCN4. Equilibrium circular dichroism studies of the urea-induced
      unfolding reaction at neutral pH revealed that both types of ionic interactions,
      localized primarily in the N-terminal portion of the molecule, enhance the
      stability of the native coiled-coil. By contrast, comparable stopped-flow
      circular dichroism studies indicate that the salt-bridge interactions, with one
      possible exception, are not well formed in the transition state for folding.
      Although the E22Q/R25A double mutant failed to fold, fragmentation studies
      suggest that the E22/R25 intramolecular salt-bridge may play a critical role in
      stabilizing C-terminal nascent helices that drive the association reaction. The
      remaining salt-bridges appear to stabilize the parallel-stranded coiled-coil
      architecture of GCN4-p1 only after the peptide traverses the rate-limiting,
      dimeric transition state.

PMID- 15037064
TI  - Membrane binding of ribosomes occurs at SecYE-based sites in the Archaea
      Haloferax volcanii.
AB  - Whereas ribosomes bind to membranes at eukaryal Sec61alphabetagamma and bacterial
      SecYEG sites, ribosomal membrane binding has yet to be studied in Archaea.
      Accordingly, functional ribosomes and inverted membrane vesicles were prepared
      from the halophilic archaea Haloferax volcanii. The ability of the ribosomes to
      bind to the membranes was determined using a flotation approach. Proteolytic
      pretreatment of the vesicles, as well as quantitative analyses, revealed the
      existence of a proteinaceous ribosome receptor, with the affinity of binding
      being comparable to that found in Eukarya and Bacteria. Inverted membrane
      vesicles prepared from cells expressing chimeras of SecE or SecY fused to a
      cytoplasmically oriented cellulose-binding domain displayed reduced ribosome
      binding due to steric hindrance. Pretreatment with cellulose drastically reduced
      ribosome binding to chimera-containing but not wild-type vesicles. Thus, as in
      Eukarya and Bacteria, ribosome binding in Archaea occurs at Sec-based sites.
      However, unlike the situation in the other domains of Life, ribosome binding in
      haloarchaea requires molar concentrations of salt. Structural information on
      ribosome-Sec complexes may provide insight into this high salt-dependent binding.

PMID- 15037065
TI  - Interaction of helix D of elongation factor Tu with helices 4 and 5 of protein
      L7/12 on the ribosome.
AB  - Elongation factor Tu (EF-Tu) promotes binding of aminoacyl-tRNA to the A site of
      the ribosome. Here, we report the effects of mutations in helix D of EF-Tu and in
      the C-terminal domain of L7/12 on the kinetics of A-site binding. Reaction rates
      were measured by stopped-flow and quench-flow techniques. The rates of A-site
      binding were decreased by mutations at positions 144, 145, 148, and 152 in helix
      D of EF-Tu as well as at positions 65, 66, 69, 70, 73, and 84 in helices 4 and 5
      of L7/12. The effect was due primarily to the lower association rate constant of
      ternary complex binding to the ribosome. These results suggest that helix D of EF
      Tu is involved in an initial transient contact with helices 4 and 5 of L7/12 that
      promotes ternary complex binding to the ribosome. By analogy to the interaction
      of helix D of EF-Tu with the N-terminal domain of EF-Ts, the contact area is
      likely to consist of a hydrophobic patch flanked by two salt-bridges.

PMID- 15037066
TI  - Inactivation of the 3'-5' exonuclease of the replicative T4 DNA polymerase allows
      translesion DNA synthesis at an abasic site.
AB  - Here, we have investigated the consequences of the loss of proof-reading
      exonuclease function on the ability of the replicative T4 DNA polymerase (gp43)
      to elongate past a single abasic site located on model DNA substrates. Our
      results show that wild-type T4 DNA polymerase stopped at the base preceding the
      lesion on two linear substrates having different sequences, whereas the gp43
      D219A exonuclease-deficient mutant was capable of efficient bypass when
      replicating the same substrates. The structure of the DNA template did not
      influence the behavior of the exonuclease-proficient or deficient T4 DNA
      polymerases. In fact, when replicating a damaged "minicircle" DNA substrate
      constructed by circularizing one of the linear DNA, elongation by wild-type
      enzyme was still completely blocked by the abasic site, while the D219A mutant
      was capable of bypass. During DNA replication, the T4 DNA polymerase associates
      with accessory factors whose combined action increases the polymerase-binding
      capacity and processivity, and could modulate the behavior of the enzyme towards
      an abasic site. We thus performed experiments measuring the ability of wild-type
      and exonuclease-deficient T4 DNA polymerases, in conjunction with these
      replicative accessory proteins, to perform translesion DNA replication on linear
      or circular damaged DNA substrates. We found no evidence of either stimulation or
      inhibition of the bypass activities of the wild-type and exonuclease-deficient
      forms of T4 DNA polymerase following addition of the accessory factors,
      indicating that the presence or absence of the proof-reading activity is the
      major determinant in dictating translesion synthesis of an abasic site by T4 DNA
      polymerase.

PMID- 15037067
TI  - Footprint of the retrotransposon R2Bm protein on its target site before and after
      cleavage.
AB  - R2 elements are non-long terminal repeat (non-LTR) retrotransposons that
      specifically integrate into the 28 S rRNA genes of their host. These elements
      encode a single open reading frame with a genome-specific endonuclease and a
      reverse transcriptase that uses the cleaved chromosomal target site to prime
      reverse transcription. Cleavage of the DNA strand that is used to prime reverse
      transcription is an efficient process that occurs in the presence or absence of
      RNA. Cleavage of the second DNA strand is much less efficient and requires RNA.
      Reverse transcription occurs before second strand cleavage and only if the RNA
      bound to the protein contains the 3' untranslated region of the R2 element. Thus
      a complex series of protein interactions with the DNA and conformational changes
      in the protein are likely to occur during this retrotransposition reaction. Here,
      we conduct electrophoretic mobility-shift assays and DNase I footprint studies on
      the binding of the R2 protein to the DNA target in the presence and absence of
      RNA both before and after first strand cleavage. While the total expanse of the
      protein footprint on the DNA eventually covers five helical turns, before
      cleavage the footprint only extends from 17 bp to 40 bp upstream of the cleavage
      site. This footprint is the same in the presence and absence of RNA. We
      hypothesize that the active site of the endonuclease domain is analogous to type
      IIS restriction enzymes in that it is located on a flexible domain that is not
      tightly bound to the cleavage site. After first strand cleavage the protein
      footprint extends beyond the cleavage site. We suggest that this increased
      protection after cleavage is the RT domain that is positioned over the free DNA
      end to begin reverse transcription on the nicked DNA substrate.

PMID- 15037068
TI  - Fluorescence measurements on the E.coli DNA polymerase clamp loader: implications
      for conformational changes during ATP and clamp binding.
AB  - Sliding clamps are ring-shaped proteins that tether DNA polymerases to their
      templates during processive DNA replication. The action of ATP-dependent clamp
      loader complexes is required to open the circular clamps and to load them onto
      DNA. The crystal structure of the pentameric clamp loader complex from
      Escherichia coli (the gamma complex), determined in the absence of nucleotides,
      revealed a highly asymmetric and extended form of the clamp loader. Consideration
      of this structure suggested that a compact and more symmetrical inactive form may
      predominate in solution in the absence of crystal packing forces. This model has
      the N-terminal domains of the delta and delta' subunits of the clamp loader close
      to each other in the inactive state, with the clamp loader opening in a crab-claw
      like fashion upon ATP-binding. We have used fluorescence resonance energy
      transfer (FRET) to investigate the structural changes in the E.coli clamp loader
      complex that result from ATP-binding and interactions between the clamp loader
      and the beta clamp. FRET measurements using fluorophores placed in the N-terminal
      domains of the delta and delta' subunits indicate that the distances between
      these subunits in solution are consistent with the previously crystallized
      extended form of the clamp loader. Furthermore, the addition of nucleotide and
      clamp to the labeled clamp loader does not appreciably alter these FRET
      distances. Our results suggest that the changes that occur in the relative
      positioning of the delta and delta' subunits when ATP binds to and activates the
      complex are subtle, and that crab-claw-like movements are not a significant
      component of the clamp loader mechanism.

PMID- 15037069
TI  - A member of a repeat family is the source of an insertion-deletion polymorphism
      inside a developmentally eliminated sequence of Tetrahymena thermophila.
AB  - In Tetrahymena thermophila, the development of a transcriptionally active
      macronucleus from a transcriptionally inert micronucleus is accompanied by the
      elimination of numerous DNA segments, called internally eliminated sequences
      (IESs), many of which belong to dispersed repetitive sequence families. To
      examine the relationship between the insertion and deletion events expected to
      occur during evolution of the repeats and the developmental elimination process,
      IESs were compared among different Tetrahymena strains. A 600 base-pair DNA
      segment, the R Indel, was discovered inside the R IES, one of the ten sequenced
      IESs out of an estimated 6000 total in the Tetrahymena genome. The R Indel was
      found in strains B3 and C2 but not in several other strains examined, indicating
      that the Indel was probably present in a progenitor of strains B3 and C2. The R
      Indel was found to belong to a moderately large sequence family of about 200
      members; however, BLAST searches did not reveal meaningful similarities with
      other mobile elements. Sequence comparisons revealed that a 300 base-pair
      stretch, very closely related to the first half of the R Indel, was present
      inside the previously described B IES, another of the ten sequenced IESs. This is
      the first example of shared sequences between two of the known IESs.

PMID- 15037070
TI  - Modular structure in developmentally eliminated DNA in Tetrahymena may be a
      consequence of frequent insertions and deletions.
AB  - The work reported here describes insertion-deletion (Indel) polymorphisms in two
      internally eliminated sequences (IESs, that are deleted during development in
      Tetrahymena): a 1.8 kb Indel at one end of the 1.1 kb H1 IES and a 0.5 kb Indel
      inside the 1.4 kb calmodulin (C) IES. These two IESs are located in the proximity
      of the H1 histone and calmodulin genes, respectively, and are among the ten IESs
      that have been fully sequenced out of an estimated total of 6000. Three hundred
      base-pairs of the 1.8 kb H1 Indel are retained in the macronucleus. Both the
      +Indel and the -Indel variants of the H1 and C IESs that occur in different
      strains are eliminated during development. Thus, a drastic change involving over
      half of the deleted sequence and 300 bp of flanking sequence does not disable
      developmental elimination of the H1 IES, which may indicate a lack of requirement
      for specific sequences on the Indel side of the IES. The H1 Indel is a composite
      of three sequence elements: a unique segment and two other sections containing
      members of different repeat families. One of these, a 0.5 kb repetitive
      component, is 75% similar to another 0.5 kb sequence that constitutes the C
      Indel, a sequence present in the middle of the calmodulin IES in some strains,
      but not in others. Therefore, the C Indel sequence is likely to have been part of
      a mobile unit, even though it has no obvious features of a transposon. However,
      sequences similar to the C Indel are present in about 100 copies in the genome.
      The results suggest that IESs may consist, at least in part, of relatively short
      modules of repeated sequences that are the source of insertion-deletion
      polymorphisms among strains of Tetrahymena thermophila.

PMID- 15037071
TI  - Analysis of chemical and enzymatic cleavage frequencies in supercoiled DNA.
AB  - Chemical and enzymatic probing methods are powerful techniques for examining
      details of sequence-dependent structure in DNA and RNA. Reagents that cleave
      nucleic acid molecules in a structure-specific, but relatively sequence-non
      specific manner, such as hydroxyl radical or DNase I, have been used widely to
      probe helical geometry in nucleic acid structures, nucleic acid-drug complexes,
      and in nucleoprotein assemblies. Application of cleavage-based techniques to
      structures present in superhelical DNA has been hindered by the fact that the
      cleavage pattern attributable to supercoiling-dependent structures is heavily
      mixed with non-specific cleavage signals that are inevitable products of multiple
      cleavage events. We present a rigorous mathematical procedure for extracting the
      cleavage pattern specific to supercoiled DNA and use this method to investigate
      the hydroxyl radical cleavage pattern in a cruciform DNA structure formed by a 60
      bp inverted repeat sequence embedded in a negatively supercoiled plasmid. Our
      results support the presence of a stem-loop structure in the expected location
      and suggest that the helical geometry of the cruciform stem differs from that of
      the normal duplex form.

PMID- 15037072
TI  - The 2.0 A crystal structure and substrate specificity of the KDEL-tailed cysteine
      endopeptidase functioning in programmed cell death of Ricinus communis endosperm.
AB  - In the senescing endosperm of germinating castor bean (Ricinus communis) a
      special organelle (the ricinosome) releases a papain-type cysteine endopeptidase
      (CysEP) during the final stages of cellular disintegration. Protein cleavage
      sites for the Ricinus CysEP were determined with fluorogenic peptides (Abz-Xaa
      Arg-/-Gln-Gln-Tyr(NO2)-Asp). The highest kcat/Km values were obtained with
      neutral amino acid residues with large aliphatic and non-polar (Leu, Val, Ile,
      Met) or aromatic (Phe, Tyr, Trp) side-chains. A second series (Abz-Leu-Xaa-/Gln
      Pro-Tyr(NO2)-Asp) was evaluated. Based on these results, the covalent binding
      inhibitor H-D-Val-Leu-Lys-chloromethylketone (CMK) was chosen as substrate
      analogue for replacement in the catalytic site. Unusually, CysEP cleaved beta
      casein N and C-terminal to the amino acid proline. CysEP was crystallized, its
      structure was solved by molecular replacement at 2.0 A resolution and refined to
      a R-factor of 18.1% (Rfree=22.6%). The polypeptide chain folds as in papain into
      two domains divided by the active site cleft, an elongated surface depression
      harboring the active site. The non-primed specificity subsites of the proteinase
      are clearly defined by the H-D-Val-Leu-Lys-CMK-inhibitor covalently bound to the
      active site. The absence of the occluding loop, which blocks the active site of
      exopeptidases at the C-terminal side of the scissile bond, identifies CysEP as an
      endopeptidase. The more open pocket of the Ricinus CysEP correlates with the
      extended variety of substrate amino acid residues accommodated by this enzyme,
      including even proline at the P1 and P1' positions. This may allow the enzyme to
      attack a greater variety of proteins during programmed cell death.

PMID- 15037073
TI  - A synthetic peptide bearing the HIV-1 integrase 161-173 amino acid residues
      mediates active nuclear import and binding to importin alpha: characterization of
      a functional nuclear localization signal.
AB  - In spite of recent efforts to elucidate the nuclear import pathway of the human
      immunodeficiency virus type 1 (HIV-1) integrase protein (IN), its exact route as
      well as the domains that mediate its import are still unknown. Here, we show that
      a synthetic peptide bearing the amino acid residues 161-173 of the HIV-1 IN is
      able to mediate active import of covalently attached bovine serum albumin
      molecules into nuclei of permeabilized cells and therefore was designated as
      nuclear localization signal-IN (NLS(IN)). A peptide bearing residues 161-173 in
      the reversed order showed low karyophilic properties. Active nuclear import was
      demonstrated by using fluorescence microscopy and a quantitative ELISA-based
      assay system. Nuclear import was blocked by addition of the NLS(IN) peptide, as
      well as by a peptide bearing the NLS of the simian virus 40 T-antigen (NLS-SV40).
      The NLS(IN) peptide partially inhibited nuclear import mediated by the full
      length recombinant HIV-1 IN protein, indicating that the sequence of the NLS(IN)
      is involved in mediating nuclear import of the IN protein. The NLS(IN) as well as
      the full-length IN protein interacted specifically with importin alpha, binding
      of which was blocked by the NLS(IN) peptide itself as well as by the NLS-SV40.

PMID- 15037074
TI  - NMR solution structure of the mitochondrial F1beta presequence from Nicotiana
      plumbaginifolia.
AB  - We have isolated, characterized and determined the three-dimensional NMR solution
      structure of the presequence of ATPsynthase F1beta subunit from Nicotiana
      plumbaginifolia. A general method for purification of presequences is presented.
      The method is based on overexpression of a mutant precursor containing a
      methionine residue introduced at the processing site, followed by CNBr-cleavage
      and purification of the presequence on a cation-exchange column. The F1beta
      presequence, 53 amino acid residues long, retained its native properties as
      evidenced by inhibition of in vitro mitochondrial import and processing at
      micromolar concentrations. CD spectroscopy revealed that the F1beta presequence
      formed an alpha-helical structure in membrane mimetic environments such as SDS
      and DPC micelles (approximately 50% alpha-helix), and in acidic phospholipid
      bicelles (approximately 60% alpha-helix). The NMR solution structure of the
      F1beta presequence in SDS micelles was determined on the basis of 518 distance
      and 21 torsion angle constraints. The structure was found to contain two helices,
      an N-terminal amphipathic alpha-helix (residues 4-15) and a C-terminal alpha
      helix (residues 43-53), separated by a largely unstructured 27 residue long
      internal domain. The N-terminal amphipathic alpha-helix forms the putative Tom20
      receptor binding site, whereas the C-terminal alpha-helix is located upstream of
      the mitochondrial processing peptidase cleavage site.

PMID- 15037076
TI  - Kinetic analysis of site-specific photoaptamer-protein cross-linking.
AB  - ssDNA oligonucleotides containing bromodeoxyuridine, BrdU-photoaptamers, are
      rapidly emerging as specific protein capture reagents in protein microarray
      technologies. A mathematical model for the kinetic analysis of photoaptamer
      protein photocross-linking reactions is presented. The model is based on specific
      aptamer/protein binding followed by laser excitation that can lead to either
      covalent cross-linking of the photoaptamer and protein in the complex or
      irreversible photodamage to the aptamer. Two distinct kinetic regimes, (1) frozen
      and (2) rapid equilibrium, are developed analytically to model binding kinetics
      between laser pulses. The models are used to characterize the photocross-linking
      between three photoaptamers and their cognate protein targets; photoaptamers 0650
      and 0615 cross-link human basic fibroblast growth factor and 0518 cross-links HIV
      MN envelope glycoprotein. Data for cross-linking reaction yields as a function of
      both laser energy dose and target protein concentration are analyzed for affinity
      constants and cross-link reaction rates. The binding dissociation constants
      derived from the cross-linking data are in good accord with independent
      measurements; the rapid equilibrium model appears to produce results more
      consistent with the experimental observations, although there is significant
      overlap between the two models for most conditions explored here. The rate of
      photodamage for 0615 and 0518 is 3.5 and 2.5 times that of the specific cross
      link, giving low maximum reaction yields of approximately 20% and approximately
      30%, whereas 0650 cross-links with a rate over five times higher than its
      photodamage rate and has a maximum reaction yield exceeding 80%. Quantum yields
      for the three systems are estimated from the data; photoaptamer 0650 has a
      reasonably high quantum yield of approximately 0.2 for protein cross-linking,
      while 0518 and 0615 have quantum yields of 0.07 and 0.02. The work presented here
      provides a useful set of metrics that allow for refinement of photoaptamer
      properties.

PMID- 15037075
TI  - Solution structure, dynamics, and hydrodynamics of the calcium-bound cross
      reactive birch pollen allergen Bet v 4 reveal a canonical monomeric two EF-hand
      assembly with a regulatory function.
AB  - Birch pollinosis is one of the prevailing allergic diseases. In all, 5-20% of
      birch pollinotics mount IgE antibodies against the minor birch pollen allergen
      Bet v 4, a Ca2+-binding polcalcin. Due to IgE cross-reactivity among the
      polcalcins these patients are polysensitized to various plant pollens.
      Determination of the high-resolution structure of holo Bet v 4 by heteronuclear
      NMR spectroscopy reveals a canonical two EF-hand assembly in the open
      conformation with interhelical angles closely resembling holo calmodulin. The
      polcalcin-specific amphipathic COOH-terminal alpha-helix covers only a part of
      the hydrophobic groove on the molecular surface. Unlike the polcalcin Phl p 7
      from timothy grass, which was recently shown to form a domain-swapped dimer, the
      hydrodynamic parameters from NMR relaxation, NMR translational diffusion, and
      analytical ultracentrifugation indicate that both apo and holo Bet v 4 are
      predominantly monomeric, raising the question of the physiological and
      immunological significance of the dimeric form of these polcalcins, whose
      physiological function is still unknown. The reduced helicity and heat stability
      in the CD spectra, the poor chemical shift dispersion of the NMR spectra, and the
      slightly increased hydrodynamic radius of apo Bet v 4 indicate a reversible
      structural transition upon Ca2+ binding, which explains the reduced IgE binding
      capacity of apo Bet v 4. The remarkable structural similarity of holo Bet v 4 and
      holo Phl p 7 in spite of different oligomerization states explains the IgE cross
      reactivity and indicates that canonical monomers and domain-swapped dimers may be
      of similar allergenicity. Together with the close structural homology to
      calmodulin and the hydrophobic ligand binding groove this transition suggests a
      regulatory function for Bet v 4.

PMID- 15037077
TI  - The crystal structure of the globular domain of sheep prion protein.
AB  - The prion protein PrP is a naturally occurring polypeptide that becomes
      transformed from a normal conformation to that of an aggregated form,
      characteristic of pathological states in fatal transmissible spongiform
      conditions such as Creutzfeld-Jacob Disease and Bovine Spongiform Encephalopathy.
      We report the crystal structure, at 2 A resolution, of residues 123-230 of the C
      terminal globular domain of the ARQ allele of sheep prion protein (PrP). The
      asymmetric unit contains a single molecule whose secondary structure and overall
      organisation correspond to those structures of PrPs from various mammalian
      species determined by NMR. The globular domain shows a close association of helix
      1, the C-terminal portion of helix-2 and the N-terminal portion of helix-3,
      bounded by the intramolecular disulphide bond, 179-214. The loop 164-177, between
      beta2 and helix-2 is relatively well structured compared to the human PrP NMR
      structure. Analysis of the sheep PrP structure identifies two possible loci for
      the initiation of beta-sheet mediated polymerisation. One of these comprises the
      beta-strand, residues 129-131 that forms an intra-molecular beta-sheet with
      residues 161-163. This strand is involved in lattice contacts about a crystal
      dyad to generate a four-stranded intermolecular beta-sheet between neighbouring
      molecules. The second locus involves the region 188-204, which modelling suggests
      is able to undergo a partial alpha-->beta switch within the monomer. These loci
      provide sites within the PrPc monomer that could readily give rise to early
      intermediate species on the pathway to the formation of aggregated PrPSc
      containing additional intermolecular beta-structure.

PMID- 15037078
TI  - Structural changes in alpha-crystallin and whole eye lens during heating,
      observed by low-angle X-ray diffraction.
AB  - Whole eye lens and alpha-crystallin gels and solutions were investigated using X
      ray scattering techniques at temperatures ranging from 20 degrees C to 70 degrees
      C. In whole lens isolated in phosphate-buffered saline, the spacing of the
      dominant X-ray reflection seen with low-angle scattering was constant from 20
      degrees C to 45 degrees C but increased at 50 degrees C from 15.2 nm to 16.5 nm.
      At room temperature, the small-angle X-ray diffraction pattern of the intact lens
      was very similar to the pattern of alpha-crystallin gels at near-physiological
      concentration (approximately 300 mg/ml), so it is reasonable to assume that the
      alpha-crystallin pattern dominates the pattern of the intact lens. Our results
      therefore indicate that in whole lens alpha-crystallin is capable of maintaining
      its structural properties over a wide range of temperature. This property would
      be useful in providing protection for other lens proteins super-aggregating. In
      the alpha-crystallin gels, a moderate increase in both the spacing and intensity
      of the reflection was observed from 20 degrees C to 45 degrees C, followed by an
      accelerated increase from 45 degrees C to 70 degrees C. Upon cooling, this effect
      was found to be irreversible over 11 hours. Qualitatively similar results were
      observed for alpha-crystallin solutions at a variety of lower concentrations.

PMID- 15037079
TI  - Insight into molecular interactions between two PB1 domains.
AB  - Specific protein-protein interactions play crucial roles in the regulation of any
      biological process. Recently, a new protein-protein interaction domain termed PB1
      (Phox and Bem1) was identified, which is conserved throughout evolution and
      present in diverse proteins functioning in signal transduction, cell polarity and
      survival. Here, we investigated the structure and molecular interactions of the
      PB1 heterodimer complex composed of the PB1 domains of the yeast proteins Bem1
      and Cdc24. A structural model of the Cdc24 PB1 was built by homology modeling and
      molecular dynamics simulations, and experimentally validated by 15N nuclear
      Overhauser effect spectroscopy (NOESY)-heteronuclear single quantum coherence
      (HSQC) analysis. Residues at the interface of the complex for both proteins were
      identified by NMR titration experiments. A model of the heterodimer was obtained
      by docking of the two PB1 domains with HADDOCK, which applies ambiguous
      interaction restraints on residues at the interface to drive the docking
      procedure. The refined model was validated by site-directed mutagenesis on both
      Bem1 and Cdc24. Finally, the docking was repeated from the newly published NMR
      structure of Cdc24, allowing us to assess the performance of homology-based
      docking. Our results provide insight into the molecular structure of the Bem1
      Cdc24 PB1-mediated heterodimer, which allowed identification of critical residues
      at the binding interface.

PMID- 15037080
TI  - NMR structure of the integral membrane protein OmpX.
AB  - The structure of the integral membrane protein OmpX from Escherichia coli
      reconstituted in 60 kDa DHPC micelles (OmpX/DHPC) was calculated from 526 NOE
      upper limit distance constraints. The structure determination was based on
      complete sequence-specific assignments for the amide protons and the Val, Leu,
      and Ile(delta1) methyl groups in OmpX, which were selectively protonated on a
      perdeuterated background. The solution structure of OmpX in the DHPC micelles
      consists of a well-defined, eight-stranded antiparallel beta-barrel, with
      successive pairs of beta-strands connected by mobile loops. Several long-range
      NOEs observed outside of the transmembrane barrel characterize an extension of a
      four-stranded beta-sheet beyond the height of the barrel. This protruding beta
      sheet is believed to be involved in intermolecular interactions responsible for
      the biological functions of OmpX. The present approach for de novo structure
      determination should be quite widely applicable to membrane proteins
      reconstituted in mixed micelles with overall molecular masses up to about 100
      kDa, and may also provide a platform for additional functional studies.

PMID- 15037081
TI  - Can contact potentials reliably predict stability of proteins?
AB  - The simplest approximation of interaction potential between amino acid residues
      in proteins is the contact potential, which defines the effective free energy of
      a protein conformation by a set of amino acid contacts formed in this
      conformation. Finding a contact potential capable of predicting free energies of
      protein states across a variety of protein families will aid protein folding and
      engineering in silico on a computationally tractable time-scale. We test the
      ability of contact potentials to accurately and transferably (across various
      protein families) predict stability changes of proteins upon mutations. We
      develop a new methodology to determine the contact potentials in proteins from
      experimental measurements of changes in protein's thermodynamic stabilities
      (DeltaDeltaG) upon mutations. We apply our methodology to derive sets of contact
      interaction parameters for a hierarchy of interaction models including solvation
      and multi-body contact parameters. We test how well our models reproduce
      experimental measurements by statistical tests. We evaluate the maximum accuracy
      of predictions obtained by using contact potentials and the correlation between
      parameters derived from different data-sets of experimental (DeltaDeltaG) values.
      We argue that it is impossible to reach experimental accuracy and derive fully
      transferable contact parameters using the contact models of potentials. However,
      contact parameters may yield reliable predictions of DeltaDeltaG for datasets of
      mutations confined to the same amino acid positions in the sequence of a single
      protein.

PMID- 15037082
TI  - Fucose depletion from human IgG1 oligosaccharide enhances binding enthalpy and
      association rate between IgG1 and FcgammaRIIIa.
AB  - Depletion of fucose from human IgG1 oligosaccharide improves its affinity for
      Fcgamma receptor IIIa (FcgammaRIIIa). This is the first case where a glycoform
      modification is shown to improve glycoprotein affinity for the receptors without
      carbohydrate-binding capacity, suggesting a novel glyco-engineering strategy to
      improve ligand-receptor binding. To address the mechanisms of affinity
      improvement by the fucose depletion, we used isothermal titration calorimetry
      (ITC) and biosensor analysis with surface plasmon resonance. ITC demonstrated
      that IgG1-FcgammaRIIIa binding was driven by favorable binding enthalpy (DeltaH)
      but opposed by unfavorable binding entropy change (DeltaS). Fucose depletion from
      IgG1 enhanced the favorable DeltaH, leading to the increase in the binding
      constant of IgG1 for the receptor by a factor of 20-30. The increase in the
      affinity was mainly attributed to an enhanced association rate. A triple amino
      acid substitution in IgG1, S298A/E333A/K334A, is also known to improve IgG1
      affinity for FcgammaRIIIa. ITC demonstrated that the amino acid substitution
      attenuated the unfavorable DeltaS resulting in a three- to fourfold increase in
      the binding constant. The affinity enhancement by the amino acid substitution was
      due to a reduced dissociation rate. These results indicate that the mechanism of
      affinity improvement by the fucose depletion is quite distinct from that by the
      amino acid substitution. Defucosylated IgG1 exhibited higher antibody-dependent
      cellular cytotoxicity (ADCC) than S298A/E333A/K334A-IgG1, showing a correlation
      between IgG1 affinity for FcgammaRIIIa and ADCC. We also examined the effect of
      FcgammaRIIIa polymorphism (Val158/Phe158) on IgG1-FcgammaRIIIa binding. The Phe
      to Val substitution increased FcgammaRIIIa affinity for IgG1 in an enthalpy
      driven manner with the reduced dissociation rate. These results together
      highlight the distinctive functional improvement of affinity by IgG1
      defucosylation and suggest that engineering of non-interfacial monosaccharides
      can improve glycoprotein affinity for receptors via an enthalpy-driven and
      association rate-assisted mechanism.

PMID- 15037083
TI  - Equilibrium and kinetic folding of rabbit muscle triosephosphate isomerase by
      hydrogen exchange mass spectrometry.
AB  - Unfolding and refolding of rabbit muscle triosephosphate isomerase (TIM), a model
      for (betaalpha)8-barrel proteins, has been studied by amide hydrogen
      exchange/mass spectrometry. Unfolding was studied by destabilizing the protein in
      guanidine hydrochloride (GdHCl) or urea, pulse-labeling with 2H2O and analyzing
      the intact protein by HPLC electrospray ionization mass spectrometry. Bimodal
      isotope patterns were found in the mass spectra of the labeled protein,
      indicating two-state unfolding behavior. Refolding experiments were performed by
      diluting solutions of TIM unfolded in GdHCl or urea and pulse-labeling with 2H2O
      at different times. Mass spectra of the intact protein labeled after one to two
      minutes had three envelopes of isotope peaks, indicating population of an
      intermediate. Kinetic modeling indicates that the stability of the folding
      intermediate in water is only 1.5 kcal/mol. Failure to detect the intermediate in
      the unfolding experiments was attributed to its low stability and the high
      concentrations of denaturant required for unfolding experiments. The folding
      status of each segment of the polypeptide backbone was determined from the
      deuterium levels found in peptic fragments of the labeled protein. Analysis of
      these spectra showed that the C-terminal half folds to form the intermediate,
      which then forms native TIM with folding of the N-terminal half. These results
      show that TIM folding fits the (4+4) model for folding of (betaalpha)8-barrel
      proteins. Results of a double-jump experiment indicate that proline isomerization
      does not contribute to the rate-limiting step in the folding of TIM.

PMID- 15037084
TI  - A family of evolution-entropy hybrid methods for ranking protein residues by
      importance.
AB  - In order to identify the amino acids that determine protein structure and
      function it is useful to rank them by their relative importance. Previous
      approaches belong to two groups; those that rely on statistical inference, and
      those that focus on phylogenetic analysis. Here, we introduce a class of hybrid
      methods that combine evolutionary and entropic information from multiple sequence
      alignments. A detailed analysis in insulin receptor kinase domain and tests on
      proteins that are well-characterized experimentally show the hybrids' greater
      robustness with respect to the input choice of sequences, as well as improved
      sensitivity and specificity of prediction. This is a further step toward proteome
      scale analysis of protein structure and function.

PMID- 15037085
TI  - Allosteric inhibition through core disruption.
AB  - Although inhibitors typically bind pre-formed sites on proteins, it is
      theoretically possible to inhibit by disrupting the folded structure of a protein
      or, in the limit, to bind preferentially to the unfolded state. Equilibria
      defining how such molecules act are well understood, but structural models for
      such binding are unknown. Two novel inhibitors of beta-lactamase were found to
      destabilize the enzyme at high temperatures, but at lower temperatures showed no
      preference for destabilized mutant enzymes versus stabilized mutants. X-ray
      crystal structures showed that both inhibitors bound to a cryptic site in beta
      lactamase, which the inhibitors themselves created by forcing apart helixes 11
      and 12. This opened up a portion of the hydrophobic core of the protein, into
      which these two inhibitors bind. Although this binding site is 16 A from the
      center of the active site, the conformational changes were transmitted through a
      sequence of linked motions to a key catalytic residue, Arg244, which in the
      complex adopts conformations very different from those in catalytically competent
      enzyme conformations. These structures offer a detailed view of what has
      heretofore been a theoretical construct, and suggest the possibility for further
      design against this novel site.

PMID- 15037086
TI  - Letter to the editors: does cockroach sensitivity to odors vary ten fold with
      circadian rhythm?

PMID- 15037088
TI  - The importance of cuticular permeability, osmolyte production and body size for
      the desiccation resistance of nine species of Collembola.
AB  - Euedaphic collembolans have recently been shown to actively regulate internal
      osmotic pressure by means of sugars and polyols in response to desiccation. In
      contrast, studies of cuticular permeability have shown that some, especially
      epedaphic, species of collembolans may primarily rely on a low cuticular
      permeability to survive desiccation. To elucidate to what extent these strategies
      are important for desiccation resistance, the survival of 7-day acute desiccation
      stress (LRH(50)), the cuticular water conductance constant and osmolyte
      production were investigated in nine species of collembolans, covering euedaphic,
      hemiedaphic and epedaphic species. The LRH(50) values ranging from 98.8% to 95.2%
      RH showed no correlation with the vertical distribution of species, since both
      the highest and lowest values were found in epedaphic species. The water
      conductance varied from 698+/-141 to 41+/-13 microg h(-1) cm(-2) mmHg(-1) and
      showed good agreement with the vertical distribution of species in their natural
      habitats. Modelling the drying curves showed that, in addition to cuticular
      permeability and osmolyte production, body size also plays an important role in
      the survival of short-term severe desiccation stress. Furthermore, the model
      pointed to the need for behavioural responses to desiccation, particularly in
      epedaphic species. Thus, in keeping with expected humidity regimes in their
      respective microhabitats, euedaphic species rely on small body size, high
      cuticular permeability and the ability to actively regulate the osmotic pressure
      of their body fluids, hemiedaphic species have similar strategies but with
      reduced cuticular permeability, whereas in epedaphic species, active regulation
      of osmotic pressure is replaced by combinations of greatly reduced cuticular
      permeability or greatly reduced surface area to volume ratio combined with
      behavioural responses to desiccation.

PMID- 15037089
TI  - The effects of dopamine agonists and antagonists on the secretory responses in
      the salivary glands of the locust (Locusta migratoria).
AB  - A study has been made on the effect of dopamine on salivary gland secretion rates
      from isolated locust salivary glands. Application of dopamine induced a
      concentration-dependent secretion with an IC(50) of approximately 0.3 microM. We
      investigated the pharmacological profile of this receptor using dopaminergic
      agonists and antagonists. The effects of dopamine could be mimicked by the
      selective D1 agonist SKF82958, but not by the D2 agonist TNPA-HCl. The receptor
      also showed selectively towards certain D1 agonists. SKF82958 was more potent at
      inducing secretion than SKF81297. We found that dopamine-induced salivary
      secretions were blocked by the selective D1 antagonist SCH23390, whereas the D2
      antagonist sulpiride was relatively ineffective. The cAMP analogue 8-Bromo cAMP
      also increased secretion rates from isolated salivary glands. These data and the
      rank order of potency of the agonists and antagonists in this screen suggest that
      this receptor is a D1-type receptor.

PMID- 15037090
TI  - Cloning and expression of the cDNA encoding the FXPRL family of peptides and a
      functional analysis of their effect on breaking pupal diapause in Helicoverpa
      armigera.
AB  - Diapause hormone (DH) and pheromone biosynthesis activating neuropeptide (PBAN)
      are encoded by a single mRNA in the suboesophegeal ganglion (SG) and are
      responsible for induction of embryonic diapause in Bombyx mori and sex pheromone
      biosynthesis in lepidopteran insects. PBAN cDNA analyses revealed that the DH
      like peptide is present in several species that have a pupal diapause. However,
      the function of the DH-like peptide remains unknown. In the present study, we
      cloned the cDNA encoding DH-PBAN in Helicoverpa armigera utilizing the rapid
      amplification of the cDNA ends method. The nucleotide se quence analysis revealed
      that the longest open reading frame of this cDNA encodes a 194-amino acid
      precursor protein that con tains a 33-aa PBAN, a 24-aa DH-like peptide, and three
      other neuropeptides, all of which have a common C-terminal pentapeptide motif
      FXPR/KL ( X=G, T, S). A homology search showed that H. armigera DH-like and PBAN
      are highly homologous to those from other insects. Northern blot analysis
      demonstrated a single message RNA corresponding to the size of Har-DH-PBAN cDNA
      from pupal SG with significantly higher expression in the SG of nondiapause pupae
      than diapausing pupae. Western blot analysis showed DH-like peptide expression
      from SG of both males and females. When DH-like peptide was injected into
      nondiapause larvae and pupae, it did not induce diapause, but rather efficiently
      broke pupal diapause in H. armigera. The ED(50) of DH to terminate pupal diapause
      is 20 pmol/pupae. The other four FXPRLamide neuropeptides from the DH-PBAN
      polyprotein precursor have cross activity for diapause termination. These
      observations therefore suggest a potential role for these FXPRL family peptides
      in promoting continuous development in several noctuid species. The high
      expression of this gene in pharate adults and adults indicates that the FXPRL
      family peptides may have multiple physiological functions.

PMID- 15037091
TI  - Expression of cytochrome c oxidase subunit 1 gene in the brain at an early stage
      in the termination of pupal diapause in the sweet potato hornworm, Agrius
      convolvuli.
AB  - Suppression-subtractive hybridization was used to isolate cDNAs specifically
      expressed in the brain at the termination of pupal diapause in Agrius convolvuli.
      One of the isolated clones shows similarity to the cytochrome c oxidase subunit 1
      (COX1) gene. The full-length cDNA was obtained from brain mRNA by rapid
      amplification of cDNA ends (RACE). The insert is 1.65 kb in length and has an
      open reading frame of 1.46 kb which encodes a putative protein of 486 amino acid
      residues. RT-PCR reveals that the mRNA increases dramatically at an early stage
      of diapause termination. Activity of cytochrome c oxidase in the brain also
      increases at the same time. The up-regulation of this gene suggests that
      expression of the COX1 gene and ATP synthesis are initiated in the brain in
      association with diapause termination.

PMID- 15037092
TI  - Tsetse flies are attracted to the invasive plant Lantana camara.
AB  - In tsetse both sexes feed exclusively on the blood of vertebrates for a few
      minutes every 2-3 days. Tsetse flies seek cover from high temperatures to
      conserve energy and plants provide shelter for tsetse in all the biotopes they
      occupy. Recently, tsetse have taken cover in plantations and under the invasive
      bush Lantana camara that has invaded large areas of the tsetse fly belt of
      Africa. Flies from such refugia are implicated in sleeping sickness epidemics. In
      a wind tunnel we show that both foliage and an extract of volatiles from foliage
      of L. camara attract three tsetse spp. from different habitats: Glossina fuscipes
      fuscipes (riverine), G. brevipalpis (sylvatic) and G. pallidipes (savannah). Gas
      chromatography analysis of volatiles extracted from leaves and flowers of L.
      camara coupled to electroantennograme recordings show that 1-octen-3-ol and beta
      caryophyllene are the major chemostimuli for the antennal receptor cells of the
      three tsetse spp. studied. A binary mixture of these products attracted these
      flies in the wind tunnel. The gas chromatography linked electroantennograme
      analysis of the L. camara extracts also show that the antennal receptor cells of
      the three tsetse spp. respond similarly to groups of volatiles derived from the
      major biosynthetic and catabolic pathways of plants, i.e. to mono- and
      sesquiterpenes, to lipoxidation products and to aromatics. Mixtures of these
      plant volatiles also attracted tsetse in the wind tunnel. These findings show
      that tsetse flies have conserved a strong sensitivity to volatile secondary
      products of plants, underlining the fundamental role of vegetation in tsetse
      survival.

PMID- 15037093
TI  - The MRJP/YELLOW protein family of Apis mellifera: identification of new members
      in the EST library.
AB  - Major royal jelly proteins (named MRJP1-5) of honeybee (Apis mellifera), yellow
      proteins of Drosophila, together with putative proteins found in several
      bacteria, form a protein family termed the MRJP/yellow family. Members of the
      family exert diverse physiological functions and amongst eukaryotes appear to be
      restricted to the order Insecta. MRJPs constitute about 90% of total protein of
      royal jelly, which is secreted by nurse bees to feed the queen and growing
      larvae. We looked for mrjp and yellow homologues in a honeybee brain expressed
      sequence tags (EST) library. In addition to the five mrjp cDNAs previously
      characterized, we found three additional cDNAs encoding novel MRJPs and
      importantly, two cDNAs coding for orthologues of Drosophila yellow proteins. One
      yellow cDNA and all three cDNAs coding for the novel MRJPs were assembled
      completely, the sequence of the other yellow homologue was partially assembled.
      The data we present here supports the view that repeated duplications and
      functional divergence occurred during the evolution of MRJPs in honeybees, with
      even closely related MRJPs appearing to perform diverse physiological functions.
      Conversely, yellow protein orthologues appear to be conserved and thus candidates
      for maintaining the former function(s) of yellow proteins.

PMID- 15037094
TI  - Fusion proteins containing insect-specific toxins as pest control agents:
      snowdrop lectin delivers fused insecticidal spider venom toxin to insect
      haemolymph following oral ingestion.
AB  - The mannose-specific snowdrop lectin (Galanthus nivalis agglutinin: GNA), when
      fed to insects, binds to the gut epithelium and passes into the haemolymph. The
      ability of GNA to act as a carrier protein to deliver an insecticidal spider
      venom neurotoxin (Segestria florentina toxin 1: SFI1) to the haemolymph of
      lepidopteran larvae was investigated. Constructs encoding SFI1 and an SFI1/GNA
      fusion protein were expressed in Pichia pastoris. The insecticidal activity of
      purified recombinant proteins on injection was found to be comparable to
      published values for SfI1 purified from spider venom [Toxicon 40 (2002) 125].
      Whereas neither GNA nor SFI1 alone showed acute toxicity when fed to larvae of
      tomato moth (Lacanobia oleracea), feeding SFI1/GNA fusion at 2.5% of dietary
      proteins was insecticidal to first stadium larvae, causing 100% mortality after 6
      days. The protein also showed a significant, dose dependent, toxicity towards
      fourth and fifth stadium larvae, with growth reduced by up to approximately 90%
      over a 4-day assay period compared to controls. Delivery of intact SFI1/GNA to
      the haemolymph in these insects was shown by western blotting; haemolymph samples
      from fusion-fed larvae contained a GNA-immunoreactive protein of the same
      molecular weight as the SFI1/GNA fusion. SFI1/GNA and similar fusion proteins
      offer a novel and effective approach for delivering haemolymph active toxins by
      oral administration, which could be used in crop protection by expression in
      transgenic plants.

PMID- 15037095
TI  - Variation in cuticular hydrocarbon signatures, hormonal correlates and
      establishment of reproductive dominance in a polistine wasp.
AB  - In many social insects the relationship between reproductive dominance and
      physiological correlates is poorly understood. Recent evidence now strongly
      suggests that cuticular hydrocarbons are important in reproductive
      differentiation in these societies where they are used as signals of ovarian
      activity in reproductive females. In this study we investigated the relationship
      between reproductive dominance, size of the corpora allata (CA, producer of
      Juvenile Hormone, JH) and the proportions of cuticular hydrocarbons present on
      the cuticle in overwintering foundresses and both associative (polygynous) and
      solitary (monogynous) pre-emergence colonies of the social wasp Polistes
      dominulus. Size of the CA was positively correlated with ovarian development in
      polygynous colonies. In contrast, solitary foundresses possessed significantly
      smaller CAs than dominant foundresses from polygynous nests, yet ovarian activity
      was similar for both female types. CA size variation was associated with
      variation in cuticular hydrocarbon proportions. Overwintering, solitary, dominant
      and subordinate (from associative nests) females all possessed distinctive
      cuticular chemical profiles revealed by multivariate discriminant analyses. Our
      data indicate that the social environment strongly affects reproductive
      physiology in this wasp, and we discuss the role of cuticular hydrocarbons in
      reproductive signaling in P. dominulus and other social insects.

PMID- 15037096
TI  - Male courtship song in circadian rhythm mutants of Bactrocera cucurbitae
      (Tephritidae: Diptera).
AB  - Pulse train intervals (PTI) of courtship song were differentiated between
      circadian clock mutants of the melon fly, Bactrocera cucurbitae (Coquillett)
      (Tephritidae: Diptera). We analysed the male mating song of B. cucurbitae flies
      of two mutant strains that differed in circadian locomotor rhythm by a LabVIEW
      programming system. Flies with a short circadian rhythm (S-strain) had shorter
      PTI than those with a long circadian rhythm (L-strain) in the two age groups
      tested, young and old. Young flies showed longer PTI than old flies, but no
      interaction between strain and age was found in PTI. There was a significant
      interaction between strain and age for pulse train duration (PTD), whereas no
      stable difference was found in PTD between S- and L-strains. These results
      suggest a positive correlation between the length of the circadian locomotor
      rhythm and PTI of courtship song sounds in B. cucurbitae.

PMID- 15037097
TI  - The hemolymph JH titer exhibits a large-amplitude, morph-dependent, diurnal cycle
      in the wing-polymorphic cricket, Gryllus firmus.
AB  - The hemolymph juvenile hormone (JH) titer was measured in over 500 flight-capable
      and flightless, adult female Gryllus firmus at 3-6 h intervals during each of
      days 2-8 of adulthood. The flight-capable morph exhibited a large-amplitude daily
      cycle in the hemolymph JH titer, while the flightless morph exhibited a barely
      perceptible cycle. The JH titer cycle was observed on all days in the flight
      capable morph, but the large amplitude cycle (>15-20 fold increase in mean titer;
      >100-fold increase in some individuals), began on day 5. For both the large and
      small amplitude cycles, the JH titer peaked near the end of the photophase
      beginning of the scotophase. The hemolymph ecdysteroid titer did not exhibit a
      corresponding large amplitude daily cycle, although a low amplitude cycle (1-3
      fold change) was seen in both morphs. The large magnitude rise in the JH titer in
      the flight-capable morph during the photophase was not due to decreased hemolymph
      volume or JH degradation. Daily cycles in the JH titer may be common, but may
      have gone unnoticed in other insect species due to restricted temporal sampling.
      Failure to identify these cycles can result in substantial errors in inferring
      biological roles for JH. Because JH regulates flight behaviors, morph-specific
      daily cycles in the JH titer may be especially common in dispersal-polymorphic
      insects, in which flight is restricted to one morph during a limited period of
      the day or night. However, because JH regulates numerous biological traits,
      analogous cycles may be common in insects exhibiting other types of complex (e.g.
      caste or phase) polymorphism, in which morphs differ in a biological
      characteristic that is restricted to a specific period of the photophase or
      scotophase.

PMID- 15037098
TI  - Low cost of reproduction in female stalk-eyed flies, Cyrtodiopsis dalmanni.
AB  - We investigated the effect of exposure to males on female longevity and egg
      production in the stalk-eyed fly, Cyrtodiopsis dalmanni. In this species, females
      typically mate several times each morning over a lifetime that can span several
      months. We hypothesised that high costs of mating with males would be
      incompatible with the life history of this species. We predicted that 1) female
      longevity costs of exposure to males would be low, and 2) that the magnitude of
      mating-induced fecundity increases in C. dalmanni, if present, would also be low.
      We tested the predictions by comparing the longevity and lifetime fecundity of
      virgin and mated females. In line with prediction 1), the longevity difference
      between virgin and fully reproductive females was small and of borderline
      significance. In line with prediction 2), egg production was not significantly
      higher in females continually exposed to males than for virgin females. Our
      results suggest that costs of reproduction resulting from exposure to males are
      low in species that mate promiscuously at high rates.

PMID- 15037099
TI  - Living on the edge: parasite taxonomy in Australia.
AB  - The way in which the huge Australian parasite fauna is described (discovery and
      naming) is the subject of this address. The approach to the task has never been
      well-organised so that a few groups of parasites are now relatively well-known
      because of the efforts of small groups of workers who have made sustained efforts
      in these groups, but equally some host-parasite systems have been almost
      completely ignored in that no worker has ever given them sustained attention. A
      high proportion of Australian parasites have been described by international
      workers. The sustaining of interest in a group of parasites over a long period is
      the key to real progress being made. The nature of the organisation of Australian
      science presently means that few positions are available for parasite taxonomists
      and funding for taxonomic research is scarce. Thus, parasite taxonomy (like the
      taxonomy of many groups of Australian plants and animals) can only be considered
      to be in crisis.

PMID- 15037100
TI  - Molecular biology of reproduction and development in parasitic nematodes:
      progress and opportunities.
AB  - Molecular biological research on the development and reproduction of parasites is
      of major significance for many fundamental and applied areas of medical and
      veterinary parasitology. Together with knowledge of parasite biology and
      epidemiology, the application of molecular tools and technologies provides unique
      opportunities for elucidating developmental and reproductive processes in
      helminths. This article focuses specifically on recent progress in studying the
      molecular mechanisms of development, sexual differentiation and reproduction in
      parasitic nematodes of socio-economic importance and comparative analyses, where
      appropriate, with the free-living nematode Caenorhabditis elegans. It also
      describes the implications of such work for understanding reproduction, tissue
      migration, hypobiosis, signal transduction and host-parasite interactions at the
      molecular level, and for seeking new means of parasite intervention.

PMID- 15037101
TI  - Technological advances and genomics in metazoan parasites.
AB  - Molecular biology has provided the means to identify parasite proteins, to define
      their function, patterns of expression and the means to produce them in quantity
      for subsequent functional analyses. Whole genome and expressed sequence tag
      programmes, and the parallel development of powerful bioinformatics tools, allow
      the execution of genome-wide between stage or species comparisons and meaningful
      gene-expression profiling. The latter can be undertaken with several new
      technologies such as DNA microarray and serial analysis of gene expression.
      Proteome analysis has come to the fore in recent years providing a crucial link
      between the gene and its protein product. RNA interference and ballistic gene
      transfer are exciting developments which can provide the means to precisely
      define the function of individual genes and, of importance in devising novel
      parasite control strategies, the effect that gene knockdown will have on parasite
      survival.

PMID- 15037102
TI  - Genomics of parasitic flatworms.
AB  - Although we live in what is often touted as the 'post-genomic era', this term is
      hardly appropriate when we consider the paucity of knowledge of the genomic
      biology of parasitic flatworms. The situation is, however, changing-at least for
      two species of Schistosoma. Recent transcriptome analysis of Schistosoma mansoni
      and of Schistosoma japonicum has identified novel genes and genes not previously
      reported for schistosomes, as well as the identification of the molecular
      mechanisms for host-dependent maturation, immune evasion, development, signalling
      and sexual dimorphism. The analyses also identify potential vaccine candidates
      and drug targets. Here, the current state of knowledge is reviewed for
      mitochondrial and nuclear genomes of parasitic flatworms. We highlight the
      remarkable recent progress in gene discovery for schistosomes and the goal of
      sequencing complete schistosome genomes.

PMID- 15037103
TI  - Coyotes (Canis latrans) are definitive hosts of Neospora caninum.
AB  - Four captive-raised coyote pups consumed tissues from Neospora caninum-infected
      calves. Faeces were examined from 4 days before to 28 days after infection. One
      pup shed N. caninum-like oocysts, which tested positive for N. caninum and
      negative for Hammondia heydorni using PCR tests. Coyotes are the second
      discovered definitive host of N. caninum, after dogs. In North America, the
      expanding coyote ranges and population increase the probability of contact with
      domestic livestock. To reduce the risk of transmission of N. caninum to
      intensively farmed cattle, we recommend protection of feedstuffs using canid
      proof fences, and careful disposal of dead stock.

PMID- 15037104
TI  - Oxidative stress in malaria parasite-infected erythrocytes: host-parasite
      interactions.
AB  - Experimenta naturae, like the glucose-6-phosphate dehydrogenase deficiency,
      indicate that malaria parasites are highly susceptible to alterations in the
      redox equilibrium. This offers a great potential for the development of urgently
      required novel chemotherapeutic strategies. However, the relationship between the
      redox status of malarial parasites and that of their host is complex. In this
      review article we summarise the presently available knowledge on sources and
      detoxification pathways of reactive oxygen species in malaria parasite-infected
      red cells, on clinical aspects of redox metabolism and redox-related mechanisms
      of drug action as well as future prospects for drug development. As delineated
      below, alterations in redox status contribute to disease manifestation including
      sequestration, cerebral pathology, anaemia, respiratory distress, and placental
      malaria. Studying haemoglobinopathies, like thalassemias and sickle cell disease,
      and other red cell defects that provide protection against malaria allows
      insights into this fine balance of redox interactions. The host immune response
      to malaria involves phagocytosis as well as the production of nitric oxide and
      oxygen radicals that form part of the host defence system and also contribute to
      the pathology of the disease. Haemoglobin degradation by the malarial parasite
      produces the redox active by-products, free haem and H(2)O(2), conferring
      oxidative insult on the host cell. However, the parasite also supplies
      antioxidant moieties to the host and possesses an efficient enzymatic antioxidant
      defence system including glutathione- and thioredoxin-dependent proteins.
      Mechanistic and structural work on these enzymes might provide a basis for
      targeting the parasite. Indeed, a number of currently used drugs, especially the
      endoperoxide antimalarials, appear to act by increasing oxidant stress, and novel
      drugs such as peroxidic compounds and anthroquinones are being developed.

PMID- 15037105
TI  - Mapping the presence of Wolbachia pipientis on the phylogeny of filarial
      nematodes: evidence for symbiont loss during evolution.
AB  - Wolbachia pipientis is a bacterial endosymbiont associated with arthropods and
      filarial nematodes. In filarial nematodes, W. pipientis has been shown to play an
      important role in the biology of the host and in the immuno-pathology of
      filariasis. Several species of filariae, including the most important parasites
      of humans and animals (e.g. Onchocerca volvulus, Wuchereria bancrofti and
      Dirofilaria immitis) have been shown to harbour these bacteria. Other filarial
      species, including an important rodent species (Acanthocheilonema viteae), which
      has been used as a model for the study of filariasis, do not appear to harbour
      these symbionts. There are still several open questions about the distribution of
      W. pipientis in filarial nematodes. Firstly the number of species examined is
      still limited. Secondly, it is not clear whether the absence of W. pipientis in
      negative species could represent an ancestral characteristic or the result of a
      secondary loss. Thirdly, several aspects of the phylogeny of filarial nematodes
      are still unclear and it is thus difficult to overlay the presence/absence of W.
      pipientis on a tree representing filarial evolution. Here we present the results
      of a PCR screening for W. pipientis in 16 species of filariae and related
      nematodes, representing different families/subfamilies. Evidence for the presence
      of W. pipientis is reported for five species examined for the first time
      (representing the genera Litomosoides, Litomosa and Dipetalonema); original
      results on the absence of this bacterium are reported for nine species; for the
      remaining two species, we have confirmed the absence of W. pipientis recently
      reported by other authors. In the positive species, the infecting W. pipientis
      bacteria have been identified through 16S rDNA gene sequence analysis. In
      addition to the screening for W. pipientis in 16 species, we have generated
      phylogenetic reconstructions based on mitochondrial gene sequences (12S rDNA;
      COI), including a total of 28 filarial species and related spirurid nematodes.
      The mapping of the presence/absence of W. pipientis on the trees generated
      indicates that these bacteria have possibly been lost during evolution along some
      lineages of filarial nematodes.

PMID- 15037106
TI  - Generation of Leishmania donovani axenic amastigotes: their growth and biological
      characteristics.
AB  - In this report, we describe an in vitro culture system for the generation and
      propagation of axenic amastigotes from the well characterised 1S-CL2D line of
      Leishmania donovani. Fine structure analyses of these in vitro-grown amastigotes
      demonstrated that they possessed morphological features characteristic of L.
      donovani tissue-derived amastigotes. Further, these axenic amastigotes (LdAxAm)
      were shown to synthesise and release a secretory acid phosphatase isoform similar
      to that produced by intracellular amastigotes. Such LdAxAm also expressed surface
      membrane 3'-nucleotidase enzyme activity similar to that of tissue-derived
      amastigotes. Moreover, LdAxAm, in contrast to promastigotes, expressed
      significant levels of the amastigote-specific A2 proteins. In addition, LdAxAm,
      derived from long term cultures of Ld 1S-CL2D promastigotes, had significant
      infectivity for both human macrophages in vitro and for hamsters in vivo. Thus,
      the in vitro culture system described herein provides a useful tool for the
      generation of large quantities of uniform populations of axenic amastigotes of
      the L. donovani 1S-CL2D line. The availability of such material should greatly
      facilitate studies concerning the cell and molecular biology of this parasite
      developmental stage.

PMID- 15037107
TI  - Uptake of bovine IgG by first instars of the common cattle grub, Hypoderma
      lineatum.
AB  - The midgut of first instar Hypoderma lineatum (De Vill.) (Diptera: Oestridae) was
      examined for the presence of bovine immunoglobulin using immuno-gold staining in
      conjunction with image analysis. Newly hatched larvae, unexposed to fluids or
      tissues of the host, showed little or no deposit of colloidal gold particles.
      Midgut lumen, microvillar border, epithelial cell bodies and basement membrane of
      first instars, 6-7 months of age, recovered from the host oesophagus, all showed
      colloidal gold staining. This indicates that immuno-reactive portions of bovine
      immunoglobulin survive exposure to extracorporeal larval enzymes, as well as
      transit of the midgut, and pass through epithelial cells to enter the larval
      haemocoel.

PMID- 15037108
TI  - Systematic relationships among Lutzomyia sand flies (Diptera: Psychodidae) of
      Peru and Colombia based on the analysis of 12S and 28S ribosomal DNA sequences.
AB  - Lutzomyia spp. are New World phlebotomine sand flies, many of which are involved
      in the transmission of human diseases, such as leishmaniases and bartonellosis.
      The systematic classification of the approximately 400 species in the genus has
      been based on morphological characters, but the relationships within the genus
      are still very much in question. We have inferred phylogenies of 32 species of
      phlebotomine sand flies belonging to seven sub-genera and two species groups, by
      using fragments of the mitochondrial small subunit (12SrRNA) and of the nuclear
      large subunit (28SrRNA) ribosomal gene sequences. The subgenus Helcocyrtomyia and
      the Verrucarum species group, prominent representatives of the Peruvian sand fly
      fauna, were represented by 11 and 7 species, respectively. Although based on a
      limited number of taxa, the resulting phylogenies, based on 837 characters,
      provide an initial phylogenetic backbone for the progressive reconstruction of
      infrageneric relationships within Lutzomyia.

PMID- 15037109
TI  - Invasion success of Fibrillanosema crangonycis, n.sp., n.g.: a novel vertically
      transmitted microsporidian parasite from the invasive amphipod host Crangonyx
      pseudogracilis.
AB  - Parasitism is known to be an important factor in determining the success of
      biological invasions. Here we examine Crangonyx pseudogracilis, a North American
      amphipod invasive in the United Kingdom and describe a novel microsporidium,
      Fibrillanosema crangonycis n.sp., n.g. The primary site of infection is the
      female gonad and the parasite is transovarially transmitted to the eggs. PCR
      screening reveals a female bias in the distribution of parasites (96.6% of
      females, N=29; 22.2% of males, N=27), which is indicative of host sex ratio
      distortion. The morphological and molecular characterisations of this new
      microsporidium place it outside all currently established genera. On the basis of
      these differences, we erect the new genus Fibrillanosema n.g. While F.
      crangonycis is morphologically identical to uncharacterised microsporidia from
      populations of North American amphipods, it is distinct from microsporidia found
      in European populations of amphipods. These data support the hypothesis that
      vertically transmitted parasites may be selectively retained during invasion
      events. Furthermore where vertical transmission is combined with host sex ratio
      distortion these parasites may directly enhance host invasion success through
      increased rates of population growth.

PMID- 15037110
TI  - Studies on ocular inflammation and development of a prostaglandin analogue for
      glaucoma treatment.
AB  - This review summarizes the Ernst H. Barany Prize Lecture given at the meeting of
      the International Society of Eye Research in Geneva 2002. In the paper the path
      from the author's early studies on neurogenic inflammation in the eye to the
      search for a suitable prostaglandin analogue for glaucoma treatment, and the
      development of latanoprost are described. In particular the solution to the
      nociceptive and hyperemic side-effects of naturally occurring prostaglandins in
      the eye, the mechanism of action of FP prostanoid receptor agonists as well as
      the selection of dose for glaucoma treatment are discussed. In addition,
      pharmacokinetical aspects of latanoprost, and the melanogenic side-effect of
      prostaglandins in the iris are addressed. The paper is primarily focused on
      studies performed by the author and complete reference to other previous, or
      contemporary studies is therefore not always given as the purpose is not to
      present a comprehensive review article.

PMID- 15037111
TI  - Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP
      receptor agonist, as an ocular hypotensive drug.
AB  - To evaluate the pharmacological characteristics of AFP-168 (tafluprost), a new
      prostaglandin (PG) F(2alpha) derivative, we examined its receptor-binding
      affinities, intraocular pressure (IOP)-lowering effect, effects on aqueous humor
      dynamics, and stimulating effect on melanogenesis. The receptor-binding profile
      for AFP-172, a carboxylic acid of AFP-168, was determined by measuring muscle
      contractions in an organ bath, inhibition of platelet aggregation, and
      competitive binding of a radio-labelled ligand. For the IOP-measurement study,
      ocular normotensive and laser-induced ocular hypertensive cynomolgus monkeys were
      used, and IOP was measured using a pneumatonograph. For the studies of aqueous
      humor dynamics, IOP (Goldmann applanation tonometry), fluorophotometry, two-level
      constant pressure perfusion, and isotope dilution and accumulation techniques
      were used in ocular normotensive monkeys. The melanin contents in the medium and
      in the cell bodies of cultured B16-F0 melanoma cells were measured. The affinity
      for the FP receptor shown by AFP-172 (Ki : 0.4 nm) was 12 times that of PhXA85 (
      Ki : 4.7 nm), a carboxylic acid of latanoprost. A single application of AFP-168
      at 0.0025% significantly lowered IOP in both ocular normotensive and hypertensive
      monkeys (3.1 and 11.8 mmHg, respectively, p < 0.01) and latanoprost at 0.005%
      significantly lowered IOP (2.1 mmHg, p < 0.01 and 9.5 mmHg, p = 0.059
      respectively). Once daily instillation of AFP-168 at 0.001, 0.0025, or 0.005% for
      5 days in normotensive monkeys significantly reduced IOP not only for a few
      hours, but also at the drug-trough time 24hr after application. Latanoprost at
      0.005% also reduced IOP, but not at the drug-trough time. AFP-168 decreased IOP
      mainly by increasing uveoscleral outflow by 65% (p < 0.05) and, as sometimes seen
      with other prostanoids, also increased total outflow facility (33% increase, p <
      0.05). In cultured B16-F0 melanoma cells, AFP-172 (100 microM) did not stimulate
      melanogenesis, but PhXA85 (100 microM) did. These findings indicate that AFP-168
      has a high affinity for the prostanoid FP receptor, has potent IOP-lowering
      effects in both ocular normotensive and hypertensive monkeys that exceed those of
      latanoprost, and has less stimulating effect on melanogenesis in melanoma cells.

PMID- 15037112
TI  - Developmental analyses of 5A11/Basigin, 5A11/Basigin-2 and their putative binding
      partner MCT1 in the mouse eye.
AB  - Recent reports by this laboratory and others have demonstrated an association
      between 5A11/Basigin, a member of the immunoglobulin gene superfamily, and
      monocarboxylate transporter-1 (MCT1), a lactose transporter. Indeed, it was
      determined in the 5A11/Basigin null mouse retina that MCT1 does not properly
      integrate into the cell membranes of Muller cells (MCs) or the retinal-pigmented
      epithelium, where the two are colocalized. The purpose of this study was to
      elucidate the association of 5A11/Basigin and MCT1 in the developing mouse
      retina. Immunocytochemical localization and real-time RT-PCR were used to
      evaluate the expression and localization of 5A11/Basigin and MCT1 at embryonic
      days 12, 15, and 18, as well as post-natal days 1, 7, 14, and 21. Expression of
      both proteins progressed from a more generalized distribution throughout the
      undifferentiated neural retina to specific staining of retina-pigmented
      epithilia, the MCs, photoreceptor cells and the ciliary apparatus. Although these
      two membrane glycoproteins were often colocalized, distinct differences in the
      location and magnitude of their expression over time was observed. These findings
      suggest that although 5A11/Basigin and MCT1 can associate within the cell
      membrane, their expression is not always associated and colocalized.

PMID- 15037113
TI  - Fluid transport across cultured layers of corneal endothelium from aquaporin-1
      null mice.
AB  - We explored the role of AQP1, the only known aquaporin in corneal endothelium, on
      active fluid transport and passive osmotic water movements across corneal
      endothelial layers cultured from AQP1 null mice and wildtype mice. AQP1 null mice
      had grossly transparent corneas, just as wildtype mice. Endothelial cell layers
      grown on permeable supports transported fluid at rates of (in microl h(-1) cm(
      2), n = 9 mean+/-s.e.): 4.3+/-0.6, wildtype mice (MCE); 3.5+/-0.6, AQP1 null mice
      (KMCE; difference not significant). The osmotic water flow (also in microl h(-1)
      cm(-2)) induced by a 100 mOsm sucrose gradient across MCE cell layers (8.7+/-0.6,
      n = 8) was significantly greater than that across KMCE (5.7+/-0.7, n = 6, p =
      0.007). When plated on glass coverslips, plasma membrane osmotic water
      permeability determined by light scattering was significantly higher for cells
      from wildtype vs. AQP1 null mice (in microm sec(-1): 74+/-4, n = 19 vs. 44+/-4
      microm sec(-1), n = 11, p < 0.001). Unexpectedly, after 10% hypo-osmotic
      challenge, the extent of the regulatory volume recovery was significantly reduced
      for AQP1 null mice cells (in%: MCE controls, 99+/-1, n = 19 vs. KMCE: 64+/-5, n =
      11, p < 0.001). Thus, as in other 'low rate' fluid transporting epithelia,
      deletion of AQP1 in mice corneal endothelium reduces osmotic water permeability
      but not active transendothelial fluid transport. However, that deletion impaired
      the extent of regulatory volume decrease after a hypo-osmotic challenge,
      suggesting a novel role for AQP1 in corneal endothelium.

PMID- 15037114
TI  - Tonopen measurement of intraocular pressure in mice.
AB  - PURPOSE: To standardize a method of non-invasive measurement of intraocular
      pressure (IOP) in mice. METHODS: Cannulated-eye study: IOP was measured
      simultaneously with a Tonopen and by direct cannulation of the vitreous
      compartment while pressure was manipulated in steps between 10 and 45 mmHg by a
      saline reservoir via a second vitreal cannula (five mice, one rat). Non
      cannulated-eye study: Tonopen and servo-null measurements were performed in
      independent groups (48 mice) to verify Tonopen measurements in non-cannulated
      eyes. Topical brimonidine (0.15%) was used to decrease IOP. RESULTS: In the rat,
      there was a similar relationship between Tonopen readings and direct measurements
      via cannulation of the eye as previously reported. Although readings from mice
      eyes were higher in variability than those obtained from the rat, the
      measurements were reproducible and the correlation between the invasive and the
      non-invasive methods was good (r = 0.97). The IOP lowering effect of brimonidine
      was detected with Tonopen as well as servo-null measurements (p < 0.001) and the
      results with both techniques were similar. CONCLUSION: The Tonopen can be used
      for rapid and reproducible measurements of IOP in mice. The method is easy to
      apply and can provide a useful means for IOP measurement in mouse models of
      induced ocular hypertension, in knock-out and transgenic mice, or in
      pharmacological studies.

PMID- 15037115
TI  - Pharmacological vascular reactivity in isolated hypercholesterolemic rabbit
      ciliary artery.
AB  - We have investigated functional and morphological changes occurring in the wall
      of the hypercholesterolemic rabbit ciliary artery. A mutant rabbit with
      hypercholesterolemia and atherosclerosis was created by serial breeding. Ciliary
      arteries from hypercholesterolemic, age-matched control and young control
      rabbits' eyes were mounted in a myograph system. The effects of phenylephrine
      (PE), carbachol and electrical field stimulation on this artery were investigated
      using isometric tension recording methods. The arteries were also examined
      morphologically. PE caused dose-dependent contraction in young control, age
      matched control and hypercholesterolemic rabbits. The EC(50) values were 1.0
      microm (0.2-2.1, n = 6), 1.4 microm (0.4-2.4, n = 6) and 4.7 microm (1.8-7.7, n =
      8) in the young, age-matched controls and in the Kurosawa and Kusanagi
      hypercholesterolemic (KHC) rabbits, respectively. The EC(50) values of the KHC
      rabbit were significantly different from those of control. Electrical field
      stimulation evoked contraction only in the control rabbits. On the other hand,
      electrical field stimulation evoked relaxation when the ciliary artery was pre
      contracted by 10 microm histamine in each type of rabbit equally. Carbachol also
      induced approximately equal dose-dependent relaxation after pre-contraction. The
      morphological findings of KHC rabbit ciliary artery revealed irregular contours
      on the internal elastic lamina and deformation of the shape of the medial smooth
      muscle cells with irregularity in size and widening of the intercellular spaces.
      However, the endothelial cells were well preserved. Compared with the ciliary
      artery, typical atherosclerotic changes existed in the intima, not the media, in
      the KHC rabbit aorta. In the hypercholesterolemic rabbit ciliary artery, the
      vasoconstricting function was reduced but vasodilatation was well preserved.
      Morphological findings supported this. The pharmacological vascular reactivity in
      the hypercholesterolemic rabbit ciliary artery is quite different from that of
      the large arteries.

PMID- 15037116
TI  - Mechanism of a model dipeptide transport across blood-ocular barriers following
      systemic administration.
AB  - The purposes of this study were to provide functional evidence for the presence
      of a peptide transporter on blood-ocular barriers and to elucidate the mechanism
      of a dipeptide transport across these barriers following systemic administration.
      Glycylsarcosine was chosen as a model dipeptide and [(3)H] glycylsarcosine was
      administered through the marginal ear vein of New Zealand white rabbits. At the
      end of an experimental period, vitreous humor, retina and aqueous humor were
      collected. Time dependent uptake of glycylsarcosine into ocular tissues was
      studied at 5, 10, 15 and 30 min. Competitive inhibition studies were performed by
      intravenous administration of [(3)H] glycylsarcosine with and without various
      inhibitors. Concentration-dependent ocular uptake of glycylsarcosine was carried
      out by administration of various concentrations of unlabelled glycylsarcosine
      spiked with a fixed amount of [(3)H] glycylsarcosine. Time-dependent uptake of
      glycylsarcosine into vitreous humor, retina and aqueous humor for a period of 30
      min following systemic administration was linear. Ocular uptake of
      glycylsarcosine was inhibited by peptide transporter substrates such as
      dipeptides (glycylproline and carnosine) and captopril but not by non-substrates
      such as amino acids. Concentration-dependent self-inhibition of glycylsarcosine
      ocular uptake was also observed. The results indicate that model dipeptide is
      transported across blood-ocular barriers via a carrier-mediated process. In
      conclusion, an oligopeptide transport system is involved in the transport of
      glycylsarcosine across blood-ocular barriers. This information may be utilized to
      design transporter/receptor targeted drug delivery systems for efficient ocular
      uptake from systemic administration.

PMID- 15037117
TI  - ICAM-1 expression predisposes ocular tissues to immune-based inflammation in dry
      eye patients and Sjogrens syndrome-like MRL/lpr mice.
AB  - PURPOSE: We previously reported that immune-based inflammation occurs on the
      ocular surface of humans as well as canines with keratoconjunctivitis sicca
      (KCS). Intercellular adhesion molecule-1 (ICAM-1) was found to be upregulated on
      lymphocytes and/or vascular endothelial cells resulting in lymphocytic diapedesis
      to the lacrimal and conjunctival tissues. The purpose of the current study was to
      demonstrate the role of ICAM-1 in (1) resident epithelial cell response during
      ocular inflammation, (2) local and/or peripheral lymphocyte activation or
      accumulation in the ocular tissues, and (3) whether anti-ICAM-1 is effective to
      attenuate immune-mediated ocular inflammation. METHODS: ICAM-1 levels in various
      ocular tissues of human with KCS and/or MRL/lpr mouse were evaluated by
      immunohistochemistry and in situ hybridization for protein and messenger RNA
      (mRNA) expression, respectively. Soluble ICAM-1 concentrations in MRL/lpr mouse
      plasma over the course of disease development were measured by ELISA. Cell
      proliferation within ocular tissues was assessed by bromodeoxyuridine (BrdU)
      incorporation and immunohistochemical detection. The level of T cell activation
      was determined by IL-2 receptor (CD25, a marker of T cell activation and
      proliferation) and CD69 (a marker of T cell activation) immunoreactivity using
      FACS analysis. To examine the effectiveness of anti-ICAM-1/LFA-1 in elimination
      of lacrimal gland inflammation, MRL/lpr mice were injected intraperitoneally
      (i.p.) with or without monoclonal antibodies against ICAM-1 and LFA-1 at three or
      eight weeks of age. RESULTS: Increased endogenous ICAM-1 expression at the level
      of protein and mRNA was detected in the epithelial cells present in the
      conjunctival and accessory lacrimal tissues in dry eye patients. In MRL/lpr mice,
      ICAM-1 expression by lacrimal acinar epithelial cells and conjunctival epithelial
      cells were detected in addition to inflammatory infiltrates and vascular
      endothelial cells at 16 weeks of age. Soluble ICAM-1 levels were markedly
      increased concomitantly with disease progression over time as compared with the
      controls. No significant lymphocytic proliferation (a lack of BrdU and CD25
      immunoreactivities) was detected within lacrimal glands of MRL/lpr mice at the
      disease onset. However, a population of the infiltrated T cells were CD69
      positive, indicating the activation stage of a T cell subset. Treatment using
      monoclonal antibodies against murine ICAM-1 and LFA-1 resulted in a decrease in
      the number of inflammatory infiltrates in MRL/lpr mice. CONCLUSIONS: Our findings
      suggest that ICAM-1 upregulation locally and systemically promote lymphocyte
      activation and migration to the ocular surface (OS). Ocular resident epithelium
      is an active component of ocular surface and is capable of interacting with
      invasive lymphocytes by ICAM-1 production in response to immune activation and
      inflammation. ICAM-1 synthesized by epithelial cells may serve as a signaling
      molecule for predisposition of ocular surface inflammation and facilitate
      potential antigen presentation by epithelial cells. Lymphocytic infiltrates in
      the lacrimal gland of the MRL/lpr mouse appeared to be the result of the
      accumulation, but not proliferation of circulating lymphocytes diapodesed from
      the vasculature that had migrated into the local ocular tissues. The potential
      use of anti-ICAM-1 therapy in treating immune-based inflammatory diseases such as
      dry eye deserves further investigation.

PMID- 15037119
TI  - Influence of interleukin-1 beta induction and mitogen-activated protein kinase
      phosphorylation on optic nerve ligation-induced matrix metalloproteinase-9
      activation in the retina.
AB  - Ischemic damage to the retina is a multifaceted process that results in
      irreversible loss of ganglion cells and blinding disease. Although the mechanisms
      underlying ischemia-induced ganglion cell death in the retina are not clearly
      understood, we have recently reported that retinal damage induced by ligation of
      the optic nerve results in increased matrix metalloproteinase-9 (MMP-9) synthesis
      and promotes ganglion cell loss. In this study, we have investigated the roles of
      IL-1beta and mitogen activated protein kinases in MMP-9 induction in the retina.
      Optic nerve ligation led to a transient increase in IL-1beta and MMP-9 levels and
      phosphorylation of p42/p44 mitogen activated protein kinases (extracellular
      signal-regulated kinases, ERK1 and ERK2) in the retina. We found no significant
      increase in phosphorylation of p38 MAP kinase or c-jun N-terminal kinases
      indicating that ERK1/2 plays a major role in MMP-9 induction. Intravitreal
      injection of IL-1 receptor antagonist (IL-1Ra) or MAP kinase inhibitor U0126
      significantly decreased both ERK1/2 phosphorylation and MMP-9 induction
      suggesting that interruption of this cascade might attenuate retinal damage. In
      support of this, intravitreal injection of IL-1Ra and U0126 offered significant
      protection against optic nerve-induced retinal damage. These results suggest that
      optic nerve ligation-induced IL-1beta promotes retinal damage by increasing MMP-9
      synthesis in the retina.

PMID- 15037118
TI  - Electroretinographic assessment of retinal function in microphthalmia mutant
      mice.
AB  - The purpose of this study was to examine the effects of mutations in the mouse
      (Mus musculus) multi-allelic microphthalmia transcription factor (Mitf) gene on
      retinal function. Mitf mice provide a rare opportunity to assess retinal
      degeneration caused by defective retinal pigment epithelium (RPE).
      Electroretinography (ERG) was used to evaluate the functional state of the retina
      and to determine the role of the Mitf gene in visual function. Corneal ERGs were
      recorded with a steel wire in response to white flashes of light. Homozygous
      Mitf(Mi-wh)/Mitf(Mi-wh), Mitf(mi-sp)/Mitf(mi-sp) Mitf(mi-bws)/Mitf(mi-bws) and
      wild type mice in addition to Mitf(Mi-wh)/Mitf(mi-sp) compound heterozygous
      mutants were studied at 16 weeks of age. Although each animal was only tested
      once, multiple animals of each genotype were tested. The ERGs of Mitf(mi
      sp)/Mitf(mi-sp) were found to be normal. All components of the ERGs of Mitf(mi
      bws)/Mitf(mi-bws) mice were normal except the photopic b-wave and the scotopic c
      wave, which were reduced in amplitude. The ERGs of Mitf(Mi-wh)/Mitf(Mi-wh) mice
      suggest they are probably blind. On the other hand, ERGs from Mitf(Mi-wh)/Mitf(mi
      sp) mice were reduced in amplitude and delayed, indicating an RPE/photoreceptor
      defect. At 16 weeks post partum, Mitf(Mi-wh)/Mitf(mi-sp) mutants show evidence of
      rod-cone dystrophy. Surprisingly, Mitf(mi-bws)/Mitf(mi-bws) mice, which have a
      similar phenotype as Mitf(mi-vit) mice with respect to coat color and eye
      development, show mostly normal ERGs. The reduced scotopic c-wave in Mitf(mi
      bws)/Mitf(mi-bws) mice, without reduction in the scotopic a-wave indicates an RPE
      defect without photoreceptor involvement in these mice.

PMID- 15037120
TI  - Subcellular distribution of native estrogen receptor alpha and beta subtypes in
      cultured human lens epithelial cells.
AB  - The expression and intracellular localization of the estrogen receptor (ER)
      subtypes, ERalpha and ERbeta were examined in cultured human lens epithelial
      cells (HLE-B3). ERalpha and ERbeta mRNA expression was evaluated by coupled
      reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot
      analysis. Subcellular localization of ERalpha and ERbeta was determined on
      formaldehyde-fixed, Saponin-permeabilized cells using conventional
      immunofluorescence techniques, as well as immunodetection of differential
      cellular components after subjecting the cultured cells to fractionation by
      sucrose gradient centrifugation. Using RT-PCR, ER species specific primers
      distinguished mRNA from total RNA extracted from HLE-B3 cells, as well as from
      human breast adenocarcinoma cells (MCF-7), which provided a positive control. The
      286-bp (ERalpha) and 167-bp (ERbeta) PCR products were verified by sequence
      analysis. Southern blot analysis using internal oligonucleotides directed to
      specific primer pairs for ERalpha and ERbeta, respectively, further confirmed the
      authenticity of the PCR products. HLE-B3 cells expressed ERalpha and ERbeta in
      association with the nucleus and ERbeta in the mitochondria. That the
      mitochondrial-enriched subfraction correlated with the presence of the ERbeta
      subtype was confirmed by Western blot analysis. The differential subcellular
      partitioning of ERalpha and ERbeta subtypes lends a new aspect to the estrogen
      signalling system wherein mitochondrial stabilization, possibly through ER
      binding, may play a causal role in the maintenance of cellular integrity. The
      occurrence of ER subtypes in human lens epithelial cells suggests that estrogen
      plays a role in the physiology of the lens. The comparative nuclear and
      mitochondrial distribution of ERalpha and ERbeta raises the interesting
      probability that the two receptors, dependent upon subcellular localization, may
      have differential cytoprotective potential, and by inference, disparity in their
      mechanisms of action.

PMID- 15037121
TI  - Bfsp2 mutation found in mouse 129 strains causes the loss of CP49' and induces
      vimentin-dependent changes in the lens fibre cell cytoskeleton.
AB  - Here we report the first natural mutation in the mouse Bfsp2 gene.
      Characterisation of mouse Bfsp2 in the 129X1/SvJ revealed a mutation that deleted
      the acceptor site of exon 2. This results in exon 1 being erroneously spliced to
      exon 3 causing a frameshift in the reading frame and the introduction of a stop
      codon at position 2 of exon 3 in the Bfsp2 transcript. RT-PCR studies of lens RNA
      isolated from 129S1/SvImJ, 129S2/SvPas and 129S4/SvJae strains confirmed the
      presence of this mutation in these diverse 129 strains and similar mutations were
      found in both CBA and 101 strains, but not in C3H or C57BL/6J mouse strains. This
      mutation is predicted to result in a severely truncated protein product called
      CP49, comprising essentially only exon 1, but polyclonal antibodies to CP49
      failed to detect either full length or fragments of CP49 in extracts made from
      either 129S1/SvImJ or 129S4/SvJae suggesting that these 129 strains lack CP49
      protein. Like the knockout of Bfsp2 reported recently, filensin protein levels
      and its proteolytic processing were altered also in the 129S1/SvImJ and
      129S4/SvJae strains compared to C57BL/6J. Electron microscopy of the lens
      cytoskeleton from 129S2/SvPas revealed similar morphological changes in the
      cytoskeleton as compared to the CP49 knockout, with beaded and intermediate
      filaments being apparently replaced by poorly defined filament-like material.
      Vimentin was a key component of this residual material as shown by immunoelectron
      microscopy and by the generation of a CP49/vimentin double knockout mouse. This
      report of a natural mutation in Bfsp2 in the 129 and other mouse strains also has
      important implications for lens studies that have used the 129X1/SvJ strain in
      knockout strategies.

PMID- 15037122
TI  - Inhibition of nitric oxide synthesis in corneas in storage media.
AB  - The nitrate/nitrite content in storage media was determined after nitric oxide
      synthase inhibition by adding 400 microl of 100 mm N(G)-monomethyl-l-arginine
      (LMMA) to four chambers of Optisol GS corneal storage media, each containing one
      viable human cornea. The companion corneas in storage media without LMMA served
      as controls. Four hundred microlitre aliquots obtained at baseline (day 0) and at
      one-day intervals for 20 more days for both groups were analyzed for nitrate and
      nitrite (breakdown products of nitric oxide) concentration levels using a
      spectrophotometric method based on the Greiss reaction. Average nitrate/nitrite
      concentrations, statistically analyzed using a polynomial random coefficients
      model, showed a statistically significant marked reduction in the levels of
      nitrate and nitrite accumulation in the study chambers as compared to control
      chambers for days 1-20(P < 0.001) There was also a reduction in the accumulation
      rate of nitrate and nitrite concentrations, as compared to controls (P < 0.05)
      until around day 8 when the differences in rates were no longer statistically
      significant. The progressive increase in nitrate and nitrite accumulation in
      corneal storage media can be blunted by the addition of a nitric oxide synthase
      inhibitor. Given the toxic free radical properties of nitric oxide, corneas in
      storage awaiting transplantation may benefit from having a nitric oxide synthase
      inhibitor added to storage media.

PMID- 15037123
TI  - Observation of A2E oxidation products in human retinal lipofuscin.
AB  - Several retinal dystrophies are associated with the accumulation of lipofuscin in
      the retinal pigment epithelium (RPE). The only structurally characterized
      component of human retinal lipofuscin is the bis-retinoid pyridinium compound
      A2E. We report here on the observation of a monooxygenated product of A2E in the
      organic soluble portion of human retinal lipofuscin and in the organic extract of
      bovine RPE cells that have been fed A2E and irradiated. Liquid chromatography
      mass spectrometry confirms that the products are identical. This is the first
      observation of a photoproduct of A2E in human retinal lipofuscin.

PMID- 15037124
TI  - Towards a new functional anatomy of language.
AB  - The classical brain-language model derived from the work of Broca, Wernicke,
      Lichtheim, Geschwind, and others has been useful as a heuristic model that
      stimulates research and as a clinical model that guides diagnosis. However, it is
      now uncontroversial that the classical model is (i) empirically wrong in that it
      cannot account for the range of aphasic syndromes, (ii) linguistically
      underspecified to an extent that prohibits contact with the language sciences,
      and (iii) anatomically underspecified. We briefly summarize some of the central
      issues that motivate why a new functional anatomy of language is necessary, in
      the context of introducing a collection of articles that describe systematic new
      attempts at specifying the new functional anatomy. The major convergent
      observations are highlighted and the emergent conceptual and empirical trends are
      identified.

PMID- 15037125
TI  - The functional neuroanatomy of prelexical processing in speech perception.
AB  - In this paper we attempt to relate the prelexical processing of speech, with
      particular emphasis on functional neuroimaging studies, to the study of auditory
      perceptual systems by disciplines in the speech and hearing sciences. The
      elaboration of the sound-to-meaning pathways in the human brain enables their
      integration into models of the human language system and the definition of
      potential auditory processing differences between the two cerebral hemispheres.
      Further, it facilitates comparison with recent developments in the study of the
      anatomy of non-human primate auditory cortex, which has very precisely revealed
      architectonically distinct regions, connectivity, and functional specialization.

PMID- 15037126
TI  - Cortical bases of speech perception: evidence from functional lesion studies.
AB  - Functional lesion studies have yielded new information about the cortical
      organization of speech perception in the human brain. We will review a number of
      recent findings, focusing on studies of speech perception that use the techniques
      of electrocortical mapping by cortical stimulation and hemispheric
      anesthetization by intracarotid amobarbital. Implications for recent developments
      in neuroimaging studies of speech perception will be discussed. This discussion
      will provide the framework for a developing model of the cortical circuitry
      critical for speech perception.

PMID- 15037127
TI  - Dorsal and ventral streams: a framework for understanding aspects of the
      functional anatomy of language.
AB  - Despite intensive work on language-brain relations, and a fairly impressive
      accumulation of knowledge over the last several decades, there has been little
      progress in developing large-scale models of the functional anatomy of language
      that integrate neuropsychological, neuroimaging, and psycholinguistic data.
      Drawing on relatively recent developments in the cortical organization of vision,
      and on data from a variety of sources, we propose a new framework for
      understanding aspects of the functional anatomy of language which moves towards
      remedying this situation. The framework posits that early cortical stages of
      speech perception involve auditory fields in the superior temporal gyrus
      bilaterally (although asymmetrically). This cortical processing system then
      diverges into two broad processing streams, a ventral stream, which is involved
      in mapping sound onto meaning, and a dorsal stream, which is involved in mapping
      sound onto articulatory-based representations. The ventral stream projects ventro
      laterally toward inferior posterior temporal cortex (posterior middle temporal
      gyrus) which serves as an interface between sound-based representations of speech
      in the superior temporal gyrus (again bilaterally) and widely distributed
      conceptual representations. The dorsal stream projects dorso-posteriorly
      involving a region in the posterior Sylvian fissure at the parietal-temporal
      boundary (area Spt), and ultimately projecting to frontal regions. This network
      provides a mechanism for the development and maintenance of "parity" between
      auditory and motor representations of speech. Although the proposed dorsal stream
      represents a very tight connection between processes involved in speech
      perception and speech production, it does not appear to be a critical component
      of the speech perception process under normal (ecologically natural) listening
      conditions, that is, when speech input is mapped onto a conceptual
      representation. We also propose some degree of bi-directionality in both the
      dorsal and ventral pathways. We discuss some recent empirical tests of this
      framework that utilize a range of methods. We also show how damage to different
      components of this framework can account for the major symptom clusters of the
      fluent aphasias, and discuss some recent evidence concerning how sentence-level
      processing might be integrated into the framework.

PMID- 15037128
TI  - The spatial and temporal signatures of word production components.
AB  - This paper presents the results of a comprehensive meta-analysis of the relevant
      imaging literature on word production (82 experiments). In addition to the
      spatial overlap of activated regions, we also analyzed the available data on the
      time course of activations. The analysis specified regions and time windows of
      activation for the core processes of word production: lexical selection,
      phonological code retrieval, syllabification, and phonetic/articulatory
      preparation. A comparison of the word production results with studies on auditory
      word/non-word perception and reading showed that the time course of activations
      in word production is, on the whole, compatible with the temporal constraints
      that perception processes impose on the production processes they affect in
      picture/word interference paradigms.

PMID- 15037129
TI  - Lesion analysis of the brain areas involved in language comprehension.
AB  - The cortical regions of the brain traditionally associated with the comprehension
      of language are Wernicke's area and Broca's area. However, recent evidence
      suggests that other brain regions might also be involved in this complex process.
      This paper describes the opportunity to evaluate a large number of brain-injured
      patients to determine which lesioned brain areas might affect language
      comprehension. Sixty-four chronic left hemisphere stroke patients were evaluated
      on 11 subtests of the Curtiss-Yamada Comprehensive Language Evaluation -
      Receptive (CYCLE-R; Curtiss, S., & Yamada, J. (1988). Curtiss-Yamada
      Comprehensive Language Evaluation. Unpublished test, UCLA). Eight right
      hemisphere stroke patients and 15 neurologically normal older controls also
      participated. Patients were required to select a single line drawing from an
      array of three or four choices that best depicted the content of an auditorily
      presented sentence. Patients' lesions obtained from structural neuroimaging were
      reconstructed onto templates and entered into a voxel-based lesion-symptom
      mapping (VLSM; Bates, E., Wilson, S., Saygin, A. P., Dick, F., Sereno, M.,
      Knight, R. T., & Dronkers, N. F. (2003). Voxel-based lesion-symptom mapping.
      Nature Neuroscience, 6(5), 448-450.) analysis along with the behavioral data.
      VLSM is a brain-behavior mapping technique that evaluates the relationships
      between areas of injury and behavioral performance in all patients on a voxel-by
      voxel basis, similar to the analysis of functional neuroimaging data. Results
      indicated that lesions to five left hemisphere brain regions affected performance
      on the CYCLE-R, including the posterior middle temporal gyrus and underlying
      white matter, the anterior superior temporal gyrus, the superior temporal sulcus
      and angular gyrus, mid-frontal cortex in Brodmann's area 46, and Brodmann's area
      47 of the inferior frontal gyrus. Lesions to Broca's and Wernicke's areas were
      not found to significantly alter language comprehension on this particular
      measure. Further analysis suggested that the middle temporal gyrus may be more
      important for comprehension at the word level, while the other regions may play a
      greater role at the level of the sentence. These results are consistent with
      those seen in recent functional neuroimaging studies and offer complementary data
      in the effort to understand the brain areas underlying language comprehension.

PMID- 15037130
TI  - Neural systems behind word and concept retrieval.
AB  - Using both the lesion method and functional imaging (positron emission
      tomography) in large cohorts of subjects investigated with the same experimental
      tasks, we tested the following hypotheses: (A) that the retrieval of words which
      denote concrete entities belonging to distinct conceptual categories depends upon
      partially segregated regions in higher-order cortices of the left temporal lobe;
      and (B) that the retrieval of conceptual knowledge pertaining to the same
      concrete entities also depends on partially segregated regions; however, those
      regions will be different from those postulated in hypothesis A, and located
      predominantly in the right hemisphere (the second hypothesis tested only with the
      lesion method). The analyses provide support for hypothesis A in that several
      regions outside the classical Broca and Wernicke language areas are involved in
      name retrieval of concrete entities, and that there is a partial segregation in
      the temporal lobe with respect to the conceptual category to which the entities
      belong, and partial support for hypothesis B in that retrieval of conceptual
      knowledge is partially segregated from name retrieval in the lesion study. Those
      regions identified here are seen as parts of flexible, multi-component systems
      serving concept and word retrieval for concrete entities belonging to different
      conceptual categories. By comparing different approaches the article also
      addresses a number of method issues that have surfaced in recent studies in this
      field.

PMID- 15037131
TI  - Contributions of memory circuits to language: the declarative/procedural model.
AB  - The structure of the brain and the nature of evolution suggest that, despite its
      uniqueness, language likely depends on brain systems that also subserve other
      functions. The declarative/procedural (DP) model claims that the mental lexicon
      of memorized word-specific knowledge depends on the largely temporal-lobe
      substrates of declarative memory, which underlies the storage and use of
      knowledge of facts and events. The mental grammar, which subserves the rule
      governed combination of lexical items into complex representations, depends on a
      distinct neural system. This system, which is composed of a network of specific
      frontal, basal-ganglia, parietal and cerebellar structures, underlies procedural
      memory, which supports the learning and execution of motor and cognitive skills,
      especially those involving sequences. The functions of the two brain systems,
      together with their anatomical, physiological and biochemical substrates, lead to
      specific claims and predictions regarding their roles in language. These
      predictions are compared with those of other neurocognitive models of language.
      Empirical evidence is presented from neuroimaging studies of normal language
      processing, and from developmental and adult-onset disorders. It is argued that
      this evidence supports the DP model. It is additionally proposed that "language"
      disorders, such as specific language impairment and non-fluent and fluent
      aphasia, may be profitably viewed as impairments primarily affecting one or the
      other brain system. Overall, the data suggest a new neurocognitive framework for
      the study of lexicon and grammar.

PMID- 15037132
TI  - Local radiological staging of rectal cancer.

PMID- 15037133
TI  - Local radiological staging of rectal cancer.
AB  - Rectal cancer is a common malignancy with a highly variable outcome. Local
      recurrence is dependent upon tumour stage and surgical technique. The role of pre
      operative imaging is to determine which patients may be safely managed by surgery
      alone and which need additional therapy in order to facilitate surgery and
      improve outcome. This decision depends on the distinction between those with
      early and advanced disease. While trans-rectal ultrasound has traditionally been
      used to answer this question, a role for magnetic resonance imaging (MRI) is
      increasingly argued. This review will focus on the treatment options for rectal
      cancer and the clinical questions that subsequently arise for the radiologist to
      answer.

PMID- 15037134
TI  - Technical aspects and complications of laparoscopic banding for morbid obesity--a
      radiological perspective.
AB  - Morbid obesity is a significant clinical problem in the western world. Various
      surgical restrictive procedures have been described as an aid to weight reduction
      when conservative treatments fail. Adjustable laparoscopic gastric banding
      (LAPBAND) has been popularized as an effective, safe, minimally invasive, yet
      reversible technique for the treatment of morbid obesity. Radiological input is
      necessary in the follow-up of these patients and the diagnosis of complications
      peculiar to this type of surgery. In this review we will highlight the technical
      aspects of radiological follow-up and the lessons learnt over the last 5 years.

PMID- 15037135
TI  - Masticator space masses and pseudomasses.
AB  - We review the anatomy of the masticator space and the localization of masticator
      space lesions on cross-sectional imaging. The magnetic resonance imaging and
      computed tomography appearances of inflammatory, neoplastic, developmental and
      vascular masticator space lesions are discussed and illustrated. Benign processes
      and normal variations, which mimic masticator space pathology, are also
      considered.

PMID- 15037136
TI  - The consent process in interventional radiology: the role of specialist nurses.
AB  - AIMS: To evaluate the impact of patient education by specialist nurses on
      patients' understanding of interventional procedures, their anxiety levels and
      satisfaction with the given information. MATERIALS AND METHODS: Sixty patients
      attending the radiology department for gastrointestinal interventional procedures
      were interviewed. Patients were assessed using a combination of categorical and
      visual analogue scales. Parameters were assessed on admission and after
      additional information had been given by specialist nurses. After the procedure
      patients were asked to rate the quality of information given and their overall
      satisfaction. RESULTS: Four of the 60 patients were excluded due to a Mini Mental
      Test score of <7. Only 35 (62.5%) claimed to have been given information by the
      referring consultant. Fifty-three patients received additional information before
      formally giving consent, 50 (96.2%) from the specialist nurses. Patient anxiety
      before and after information did not significantly change (p=0.52) but there was
      significant improvement in levels of satisfaction (p=0.001) and perceived
      understanding (p<0.001). Patients rated overall quality of information at an
      average of 9.2/10 and overall satisfaction was high (median=9.1/10). CONCLUSION:
      The use of specialist nurses to educate patients greatly increases patient
      understanding. The process of informed consent is improved and patient
      satisfaction is increased.

PMID- 15037137
TI  - Percutaneous nephrostomy insertion: outcome data from a prospective multi
      operator study at a UK training centre.

PMID- 15037138
TI  - Percutaneous nephrostomy insertion: outcome data from a prospective multi
      operator study at a UK training centre.
AB  - AIM: To determine the success and complication rates of percutaneous
      nephrostomies (PCNs) performed at a UK training centre over a one-year period by
      different groups of operators. MATERIALS AND METHODS: During 2002, a total of 276
      PCNs were performed in 190 patients by operators of varying experience. We
      employed two different techniques: (1) a "Seldinger" technique (ultrasound-guided
      puncture with a 19G sheathed needle followed by guide-wire insertion and track
      dilatation to accommodate 8-12F nephrostomy catheters), with or without
      fluoroscopic guidance, and (2) an ultrasound-guided "one-stab" technique using a
      6F Bonanno catheter. Selection of technique was according to configuration of the
      collecting system and whether the procedure was performed out of hours. RESULTS:
      There were 218 procedures using the Seldinger technique and 62 using the one-stab
      technique. The Seldinger technique and one-stab technique were compared: primary
      technical success rate was 98 versus 93%, the major complication rate was 4.1
      versus 3.2%, the minor complication rate was 5 versus 13%, and tube
      complications, such as drainage catheter dislodgement and blockage, were 29.5
      versus 17.7%, respectively. The 30-day mortality was 4.3%, none of which were
      procedure related. CONCLUSION: Based on data from the USA, proposed targets for
      primary technical success rates are 88-99%, major complications 4-8%, and minor
      complications 3-15%, and the results were within these target ranges. The
      ultrasound-guided one-stab technique is a quick and safe procedure in selected
      cases, and we recommend this method for temporary urinary diversion in cases with
      moderate to severe degrees of pelvicalyceal system dilatation. These data may
      help to form a baseline for outcome targets in the UK.

PMID- 15037139
TI  - Diagnostic value of CT-guided biopsy of indeterminate renal masses.
AB  - AIM: To evaluate the role of percutaneous core biopsies in the diagnosis of renal
      masses that could not be classified as benign or malignant based upon imaging
      alone. MATERIALS AND METHODS: We retrospectively analysed core biopsies of
      indeterminate renal masses of 23 patients who were referred to us for computed
      tomography (CT)-guided biopsy from 1996-2001. Follow-up ranged from 1-5 years.
      Analysis was based on indications for biopsy, size and characteristics of the
      lesion and accuracy of biopsy results. RESULTS: There was one technical failure
      in 22 patients included in the analysis. Fifteen core biopsies revealed
      malignancies that were confirmed either clinically or surgically. Seven were
      benign, one of which was false-negative. The sensitivity was 93%, specificity
      100%, positive predictive value 100% and negative predictive value 75%. The
      results in tumours <==3 cm were similar to those in larger lesions. CONCLUSIONS:
      We recommend the use of core biopsy as a diagnostic tool for indeterminate renal
      masses, regardless of mass size. Renal core biopsy can influence the management
      of lesions: primary renal lesions are resected, while treatment for metastatic
      disease is tailored to the primary tumour. Tumours with benign biopsy results
      should be re-evaluated and either referred for resection of the mass or followed
      up closely with clinical observation and of imaging studies.

PMID- 15037140
TI  - Dedifferentiated chondrosarcoma: use of MRI to guide needle biopsy.
AB  - AIM: To describe the use of MRI to identify and biopsy areas of dedifferentiation
      in patients with a suspected diagnosis of dedifferentiated chondrosarcoma.
      MATERIALS AND METHODS: Low-grade chondrosarcoma is characterized at magnetic
      resonance imaging (MRI) as having a lobulate, hyperintense appearance on T2
      weighted spin-echo sequences. T2-weighted MR images were assessed in 15 patients
      with a final pathological diagnosis of dedifferentiated chondrosarcoma for
      regions of atypical reduced signal intensity. Information regarding the site of
      ultrasound or computed tomography (CT)-guided biopsy was available in 10 cases.
      RESULTS: Nine patients were male and six female with a mean age of 60 years
      (range 25-77 years). The sites involved were the distal femur (n+4) pelvis (n=3)
      proximal femur (n=4) femoral diaphysis (n=1) proximal humerus (n=2) and proximal
      tibia (n=1). The dedifferentiated component consisted of osteosarcoma (n=5)
      malignant fibrous histiocytoma (n=6) spindle cell sarcoma (n=1) leiomyosarcoma
      (n=1) and pleomorphic sarcoma (n=1). In 14 of the 15 cases, areas of lower signal
      intensity lacking in lobulation were identified. In nine of the 10 cases, biopsy
      site included such areas and yielded high-grade sarcoma. CONCLUSIONS:
      Dedifferentiation within chondrosarcoma may be identified on T2-weighted MRI as
      areas of reduced signal intensity. These areas should be the preferred site of
      biopsy.

PMID- 15037141
TI  - Cutaneous haemangioma: prevalence and sonographic characteristics of associated
      hepatic haemangioma.
AB  - AIMS: To determine the prevalence of hepatic haemangiomas (HH) occurring with
      multiple or large cutaneous haemangiomas (CH), and compare the ultrasound (US)
      characteristics of HH with morphology of concurrent CH. MATERIALS AND METHODS:
      Retrospective and prospective sonographic and clinical analysis was undertaken on
      69 patients referred for US to exclude silent HH. This comprised 62 patients
      referred over 6 years with six or more CH or one large CH (#10878;5 cm) and seven
      patients referred over 1 year with three to five small CH. RESULTS: HH occurred
      in 45% miliary CH and 40% mixed small and large CH, but also in 12-14% of
      patients with one large or three or more small CH. None had HH progression. There
      was association between HH sonographic characteristics and CH number and
      morphology. CONCLUSION: Clinically silent HH occurred in nearly one in four of
      infants presenting overall with six or more small CH or large CH. Previous
      studies have documented HH mortality between 18 and 80%, although this was not
      shown in our study. Therefore, if clinical suspicion exists, US is indicated to
      enable early steroid treatment if significant HH are present.

PMID- 15037142
TI  - Computed tomography of odontogenic myxoma.
AB  - AIM: The aim of this study was to determine the computed tomography (CT)
      presentation of odontogenic myxoma (OM) in a Chinese population and to compare
      them with those observed on the accompanying conventional radiographs (CR).
      MATERIALS AND METHODS: The files of the Department of Oral and Maxillofacial
      Surgery of the University of Hong Kong between 1989 and 2000 were reviewed for
      myxoma cases. RESULTS: Ten cases of OM were found of which eight had been
      investigated by CT. The formatted hard copy was found in seven cases, four in the
      maxilla and three in the mandible. Most of the OMs had a round shape but one was
      fusiform. CT was more likely to display a cortex and its perforation. All OMs had
      perforated cortices on CT with soft tissue appearing outside the bony contour in
      two cases. Contrast enhancement was apparent in six cases. Both CR and CT
      displayed septae, but the latter method revealed that most septae were situated
      at the periphery, presenting as "sunray" type spicules in one case. Tooth
      displacement and root resorption were more reliably observed on CR. CONCLUSION:
      The likelihood of perforation and pattern of septa of OM is better displayed by
      CT. CR should also allow a better assessment of the degree of definition of the
      lesion's margins with adjacent normal bone. Therefore, both CT and CR should be
      used in an investigation of an OM.

PMID- 15037143
TI  - The use of SMARTeR stents in patients with biliary obstruction.
AB  - AIM: The purpose of the study was to evaluate the percutaneous use of the new
      nitinol SMARTeR stents in patients with biliary obstruction. MATERIALS AND
      METHODS: Four stents were placed in three patients percutaneously under
      ultrasound and fluoroscopic guidance. RESULTS: The deployment of the stents was
      successful in all three patients. All stents maintained their patency and
      position after short-term follow-up. CONCLUSION: The nitinol SMARTeR stent is
      useful in the management of patients with biliary obstruction although accurate
      placement across the ampulla was found to be technically more difficult than with
      the Wallstent. Larger, long-term follow-up studies are required to evaluate the
      long-term patency of these new devices.

PMID- 15037144
TI  - Retroperitoneal fibrosis mimicking retrocrural lymphadenopathy.

PMID- 15037145
TI  - Oculomotor nerve root enhancement in meningovascular syphilis.

PMID- 15037146
TI  - Neuroimaging for non-accidental head injury in childhood: a proposed protocol.

PMID- 15037147
TI  - Contrast nephrotoxicity and iso-osmolar contrast agents: implications of nephric.

PMID- 15037149
TI  - Recent advances in the stereoselective synthesis of isoprostanes and
      neuroprostanes.
AB  - This review delineates several reported methods for the synthesis of isoprostanes
      and neuroprostanes with particular emphasis on the stereocontrolled construction
      of a suitably functionalized cyclopentane core. The alpha- and omega-side chains
      of these PG-like molecules are typically assembled by Wittig-type olefination
      reactions, standard transformations in the PG synthesis. The synthetic strategies
      include free radical cyclizations, a palladium-promoted coupling of three
      different components, an intramolecular cyclopropanation reaction-ring-opening
      sequence, a [2+2] photocycloaddition-ring-opening metathesis approach, and an
      intramolecular cross-coupling reaction of an alkyl iodide and a tethered
      alkenylsiloxane.

PMID- 15037150
TI  - Total syntheses of iso-, neuro- and phytoprostanes: new insight in lipid
      chemistry.
AB  - Isoprostanes (IsoPs) are a complex family of compounds produced, in vivo, from
      peroxidation of polyunsaturated fatty acids (AA, DHA, EPA, alpha-linolenic) via a
      free-radical-catalyzed mechanism. Carbocyclic annulations are extremely important
      reactions and the stereocontrolled intramolecular free-radical cyclization has
      emerged as a powerful tool for carbon-carbon bond formation in synthetic
      chemistry. The hex-5-enyl radical cyclization is the most well-known for the
      synthesis of cyclopentane rings. After a short review of the literature,
      concerning the total synthesis of isoprostanes and intermediates, we will present
      our own contributions on the preparation of chiral cyclopentane rings from
      glucose leading to new isoprostanes. This study allowed us to control the
      cyclization outcome to yield the all-syn and/or syn-anti-syn precursors which
      permit us to the total synthesis of a large set of iso-, neuro-, and
      phytoprostanes.

PMID- 15037151
TI  - Total synthesis of isoprostanes: discovery and quantitation in biological
      systems.
AB  - Isoprostanes (iP's), a new class of natural products isomeric with
      prostaglandins, are formed as the result of free radical oxygenation of
      polyunsaturated fatty acids. We have identified these iP's and developed
      analytical methodology to measure them in biological fluids. The approach we
      took, which led to the discovery and measurement of iP's, is as follows: (1)
      based on some biochemical and chemical considerations, we proposed possible
      structures for these isoprostanes; (2) we performed the total syntheses of some
      of these iP's, in particular Groups III through VI, and used them as markers for
      their discovery in biological fluids and developed a GC/MS and an LC/MS
      methodologies based on iPF2alpha-III, iPF2alpha-VI, and 8,12-iso-iPF2alpha-VI;
      (3) with the help of these assays, we measured elevated levels of iP's in
      Alzheimer's disease and atherosclerosis.

PMID- 15037153
TI  - Molecular pharmacology of isoprostanes in vascular smooth muscle.
AB  - Isoprostanes are marker of lipid peroxidation and are produced after free-radical
      attack of membrane lipids. In addition, they are biologically active and are
      essentially vaso- and broncho-constrictor. Their smooth muscle constrictor
      actions are closely linked to the activation of the thromboxane A(2) receptor,
      but also involve a distinct receptor not yet identified. The response of vascular
      smooth muscle to isoprostanes is subclass-specific (F-series versus E-series
      isoprostanes) and cell- and species-related. In this review, we will address the
      vascular actions of isoprostanes and their possible role in vascular physiology
      and pathophysiology.

PMID- 15037152
TI  - The diazo ketone approach to the isoprostanes.
AB  - A general synthetic approach to the isoprostanes has been established, based on
      intermolecular aldol condensation of a diazo ketone with an unsaturated aldehyde,
      followed by cyclization of the resulting diazo ketone to the cyclopropane.
      Subsequent kinetic opening with thiophenol followed by further elaboration then
      leads to the isoprostane. The history of this approach and the details of its
      development are discussed.

PMID- 15037154
TI  - Isoprostanes: an emerging role in vascular physiology and disease?
AB  - Among the isoprostanes, the 15-series F2-isoprostanes and 15-E2t-IsoP mediate
      vasoconstriction in different vascular beds and species. In addition, 15-F2t-IsoP
      induces smooth muscle cells mitogenesis and monocyte adhesion to endothelial
      cells. In clinical studies, 15-F2t-IsoP levels are increased in some vascular
      disorders involving atherosclerosis, ischemia-reperfusion and inflammation.
      Whether the same effects observed in vitro are observed consistently in vivo at
      physiological concentrations and whether these effects contribute to pathological
      states in vivo is still debated.

PMID- 15037155
TI  - Isoketals: highly reactive gamma-ketoaldehydes formed from the H2-isoprostane
      pathway.
AB  - Oxidation of arachidonic acid leads to the formation of highly reactive gamma
      ketoaldehydes now termed isoketals. Isoketals react with proteins at a rate that
      far exceeds other well studied products of lipid peroxidation such as 4
      hydroxynonenal and demonstrate a remarkable proclivity to crosslink these
      proteins. For these reasons, isoketals have the potential to significantly alter
      protein function and contribute to disease processes. This article reviews the
      chemistry of isoketal formation, of their adduction to proteins, and of their
      proclivity to crosslink proteins, as well as their effects on protein function,
      and their potential role in diseases associated with oxidative injury.

PMID- 15037156
TI  - The pulmonary biology of isoprostanes.
AB  - Isoprostanes are widely recognized as useful markers of membrane lipid
      peroxidation. It seems to be less well appreciated, however, that they also
      elicit important biological responses, even though this was first shown at the
      same time that they were introduced as markers of oxidative stress. The past
      several years have seen the list of cells/tissues which are sensitive to
      isoprostanes grow considerably: in fact, as we summarize here, there is now
      evidence that essentially every cell type in the lung responds in some
      pathologically relevant way to isoprostanes. In this sense, they might well be
      considered as not just markers of oxidative stress and inflammation, but also as
      a novel group of inflammatory mediators. Moreover, in addition to their
      pathological effects, we summarize here the evidence which has led us to
      hypothesize that isoprostanes could play an important role in vascular smooth
      muscle physiology as "endothelium-derived hyperpolarizing factors."

PMID- 15037157
TI  - Isoprostanes and related products of lipid peroxidation in neurodegenerative
      diseases.
AB  - Lipid peroxidation is a major outcome of free radical-mediated injury to brain,
      where it directly damages membranes and generates a number of oxidized products.
      Some of the chemically and metabolically stable oxidation products are useful in
      vivo biomarkers of lipid peroxidation. These include the isoprostanes (IsoPs) and
      isofurans (IsoFs), derived from arachidonic acid (AA), and neuroprostanes
      (NeuroPs), derived from docosahexaenoic acid (DHA). We have shown increased
      levels of IsoPs, NeuroPs, and IsoFs in diseased regions of brain from patients
      who died from advanced Alzheimer's disease (AD) or Parkinson's disease (PD).
      Increased cerebrospinal fluid (CSF) levels of IsoPs are present in patients with
      AD or Huntington's disease (HD) early in the course of their illness, and CSF
      IsoPs may improve the laboratory diagnostic accuracy for AD. In contrast,
      quantification of IsoPs in plasma and urine of AD patients has yielded
      inconsistent results. These results indicate that brain lipid peroxidation is a
      potential therapeutic target early in the course of AD and HD, that CSF IsoPs may
      aid in the assessment of anti-oxidant experimental therapeutics and laboratory
      diagnosis of AD.

PMID- 15037158
TI  - Isoprostanes and the liver.
AB  - The liver has been central to our understanding of the physiology and biology of
      the F2-isoprostanes. The discovery of F2-IsoPs and the initial demonstration that
      they could be used to localize oxidative stress was first demonstrated in a rat
      model of oxidative liver injury (carbon tetrachloride), and the first
      demonstration that plasma concentrations are increased in a human disease was in
      patients with liver failure and the hepatorenal syndrome [J. Clin. Invest. 90 (6)
      (1992b) 2502; J. Lipid Mediat. 6 (1/3) (1993) 417]. This article will cover the
      measurement of F2-IsoPs as markers of lipid peroxidation in vivo in liver
      disease, and review their biological activity as mediators of disease.

PMID- 15037159
TI  - The isoprostanoid pathway in plants.
AB  - Higher plants are generally unable to synthesize arachidonic acid, and thus, do
      neither form prostaglandins nor C20-isoprostanes. Instead, plants utilize
      linolenic acid for the synthesis of prostaglandin-like compounds of the jasmonate
      type via the lipoxygenase/allene oxide synthase pathway and C18-isoprostanoids,
      termed phytoprostanes, via a nonenzymatic, free radical catalyzed pathway
      analogous to the isoprostane pathway in animals. Both pathways are constitutively
      present in many if not all plants. Formation of jasmonates can be triggered by
      specific stimuli interacting with membrane receptors while phytoprostane
      synthesis can be induced by ROS and heavy metals. Jasmonates are established
      plant signal compounds that induce defense responses including accumulation of
      antimicrobial secondary metabolites (phytoalexins). Preliminary data indicates
      that phytoprostanes also induce phytoalexins in a variety of plant species
      suggesting a possible function of phytoprostanes as mediators of defense
      reactions in response to oxidative stress in plants.

PMID- 15037160
TI  - Determinants of F2-isoprostane biosynthesis and inhibition in man.
AB  - Several cardiovascular risk factors are characterized by the coexistence of low
      grade inflammation, enhanced oxidative stress and lipid peroxidation. It has been
      hypothesized that F2-isoprostanes, a product of in vivo lipid peroxidation, may
      transduce the effects of metabolic and hemodynamic abnormalities into increased
      cardiovascular risk. Thus, the formation of these compounds, including urinary 8
      iso-Prostaglandin (PG) F2alpha, has been investigated in clinical settings
      putatively associated with oxidant stress. Enhanced lipid peroxidation together
      with increased in vivo platelet activation have been found in association with
      the major cardiovascular risk factors. Thus, F2-isoprostanes may transduce the
      effects of oxidant stress associated with complex metabolic disorders into
      specialized forms of cellular activation. In particular, the low-grade
      inflammatory state characterizing metabolic disorders such as obesity,
      hypercholesterolemia, type 2 diabetes mellitus, and homozygous homocystinuria may
      be the primary trigger of thromboxane-dependent platelet activation mediated, at
      least in part, through enhanced lipid peroxidation. Moreover, oxidative stress
      may promote endothelial dysfunction through increased production of reactive
      oxygen species that inactivate nitric oxide. Accumulation and activation of
      leukocytes plays a key role in atherosclerosis and its complications.
      Interestingly, neutrophil adhesion induced by minimally modified low-density
      lipoproteins is mainly mediated by F2-isoprostanes. Although epidemiological
      studies suggest an inverse relationship between antioxidant vitamin intake and
      cardiovascular disease, several clinical trials have obtained conflicting results
      on the effects of vitamin E supplementation on the risk of cardiovascular events.
      On the other hand, the use of F2-isoprostane formation as a biochemical end-point
      for dose-finding studies of vitamin E supplementation has helped clarifying the
      unique features of its pharmacodynamic effects on lipid peroxidation. This
      information could be extremely valuable in the selection of the appropriate
      patient subgroups that may benefit from antioxidant interventions.

PMID- 15037161
TI  - F2-isoprostanes as indices of lipid peroxidation in inflammatory diseases.
AB  - Isoprostanes are a new class of lipids, isomers of conventional enzymatically
      derived prostaglandins, which are produced in vivo primarily by a free radical
      catalyzed peroxidation of polyunsaturated fatty acids. F2-isoprostanes, isomers
      of the enzyme-derived prostaglandin F2alpha, are the most studied species.
      Because of their mechanisms of formation, specific structural features that
      distinguish them from other free radical-generated products and chemical
      stability, they provide a reliable index of the oxidative component of several
      diseases in vivo. Consistent data suggest that formation of F2-isoprostanes is
      indeed altered in a variety of clinical settings associated with inflammation and
      oxidant stress. Moreover, measurement of F2-isoprostanes might provide a
      sensitive biochemical basis of dose-selection in studies of natural and synthetic
      antioxidants.

PMID- 15037163
TI  - Five years of sentinel node biopsy for melanoma: the St George's Melanoma Unit
      experience.
AB  - Sentinel node biopsy has become an integral part of the management of malignant
      melanoma. Here, the authors describe the technique that is used at the St
      George's Hospital Melanoma Unit. Results obtained over the past 5 years on a
      cohort of patients are presented. Three hundred and forty seven patients were
      entered in the study. Population demographics were analysed for both the primary
      melanoma and for sentinel node positive status. Histological features of the
      primary, particularly regression were noted and, in addition to metastatic
      disease, the presence of capsular naevus cells within the node also recorded.
      Complications associated with the procedure have been presented along with the
      specificity and sensitivity of the technique. The relative influence of both
      Breslow thickness and sentinel node positivity were analysed statistically and
      Kaplan-Meier survival curves produced for the cohort as a whole. This confirmed
      the accuracy of sentinel node biopsy and its role as a prognostic indicator.

PMID- 15037162
TI  - The biochemistry of the isoprostane, neuroprostane, and isofuran pathways of
      lipid peroxidation.
AB  - F2-isoprostanes are prostaglandin F2-like compounds that are formed
      nonenzymatically by free radical mediated peroxidation of arachidonic acid.
      Intermediate in the pathway of the formation of isoprostanes are labile
      prostaglandin H2-like bicyclic endoperoxides (H2-isoprostanes), which are reduced
      to F2-isoprostanes and also undergo rearrangement in vivo to form E-ring and D
      ring isoprostanes, isothromboxanes, and highly reactive acyclic gamma
      ketoaldehdyes (isoketals). Docosahexaenoic acid (C22:6omega3) is highly enriched
      in neurons in the brain and is highly susceptible to oxidation. Free radical
      mediated oxidation of docosahexaenoic acid results in the formation of
      isoprostane-like compounds (neuroprostanes). F4- and E4/D4-neuroprostanes as well
      as neuroketals have been shown to be produced in vivo. Finally, we recently
      discovered a new pathway of lipid peroxidation that forms compounds with a
      substituted tetrahydrofuran ring (isofurans). Oxygen concentrations
      differentially modulate the formation of isoprostanes and isofurans; at elevated
      oxygen concentrations, the formation of isofurans is favored whereas the
      formation of isoprostanes is disfavored.

PMID- 15037164
TI  - Use of an early-detection strategy to improve disease control in melanoma
      patients.
AB  - In order to assess whether early detection might lead to improvement in disease
      control for patients with melanoma, a rapid access pigmented lesion clinic (PLC)
      was set up at Mount Vernon Hospital, UK in 1993. Previously we have shown that
      thinner melanomas were detected via the PLC compared with those presenting prior
      to its establishment and with those referred via existing routes of referral. The
      aim of this study was to investigate whether both rates of disease recurrence and
      disease-free interval were improved via a rapid access PLC. A retrospective case
      notes audit was performed on three patient groups: those diagnosed with melanoma
      1991-1992, those diagnosed via the PLC (1993-1996) and those diagnosed with
      melanoma through existing routes of referral after establishment of the PLC (1993
      1996). There was a significantly improved disease-free interval for patients with
      regional recurrences diagnosed via the pigmented lesion clinic (PLC) when
      compared with pre-PLC, non-PLC groups (chi2=13.8487, p=0.0002; chi2=17.0164,
      p<0.0001, respectively), and when compared with all melanoma patients diagnosed
      after the establishment of the PLC, irrespective of route of referral
      (chi2=5.2773, p=0.0216). Local recurrences developed later in patients in the PLC
      group compared with the pre-PLC group (chi2=6.4883, p=0.0109), and the non-PLC
      group (chi2=18.49, p<0.0001). In addition there was a reduction in the proportion
      of regional and local recurrences in the PLC group when compared with the pre-PLC
      group (chi2=13.92, P<0.001; chi2=2.85, P=0.09 respectively) and non-PLC group
      (chi2=17.15, P<0.001; chi2=7.73, P=0.005, respectively). These results support
      the use of rapid access PLCs as a means of improving disease control for melanoma
      patients.

PMID- 15037165
TI  - The development of the male genitourinary system: II. The origin and formation of
      the urethral plate.
AB  - The origin, extent and topographical relationships of the urethral plate and its
      role in the pathogenesis of developmental anomalies (bladder extrophy, epispadias
      and hypospadias) remain incompletely resolved. The commonly held view that the
      urethral plate (the forerunner of the urethra) arises through distal
      proliferation of the cells of the anterior wall of the cloaca cannot explain
      these anomalies. Given this and its newfound implications for hypospadias repair
      the development of the urethral plate is presented in detail. New insights into
      the origin of associated congenital defects are revealed.

PMID- 15037166
TI  - Description of site-specific morphology of keloid phenotypes in an Afrocaribbean
      population.
AB  - By examining the keloid scars of 211 Afrocaribbean patients presenting to the
      Plastic Surgery unit in Kingston, Jamaica, we have described site-specific
      morphologies of scarring; keloid disease is not a homogenous biological entity.
      All cases conformed to clinical criteria for diagnosis of keloid scarring: 369
      keloid scars were present in 137 females (2-83 years; mean 29.6 years; SD+/-14.9
      years) and 74 males (5-90 years, mean 29.5 years; SD+/-15.0 years). Morphologies
      were specific to each anatomical site: trunk scars (n=45,12.1%) were
      geometrically shaped with clear margins or irregular in outline, surface and
      margin; back single scars were well-demarcated botryoid but multiple scars were
      butterfly-shaped, spheroidal and irregular; chest scars (n=72,20.1%) were
      butterfly or nonbutterfly shaped found most commonly in the midsternal line;
      upper limb scars (n=57,15.3%) mostly in the deltoid region (propeller shaped) or
      elsewhere nodular, linear to irregular; ear (n=85,23%) commonest site being the
      lobe, having reniform to bulbous shape; face and neck (n=60,16.2%) scars were
      firm nodular to hard; posterior auricular scars were either horizontal and oblong
      shaped or vertical and reniform in outline; scalp scars (n=11,2.8%) were
      commonest in the occipital area varying from small papules to large plaques;
      lower limb scars (n=39,10.5%) varied from propeller, butterfly, petalloid to dum
      bell-shaped. Three plantar and eight pubic keloids were rare findings.
      Recognition of different morphological phenotypes is necessary in understanding
      genotypic predisposition and aiding diagnosis, treatment and prognosis of keloid
      scars.

PMID- 15037167
TI  - Audit of plastic surgeons' understanding of pathology reports of skin neoplasia.
AB  - This audit was set up to investigate Plastic Surgeons' perception of minimum
      standards of reporting of skin neoplasia at the time of publication of the Royal
      College of Pathologists' guidelines. Eight histopathology case reports of skin
      neoplasia were formulated; four had the minimum information required and four had
      vital information omitted. Surgeons were asked to evaluate and suggest
      management. Marks were allocated for awareness of substandard reporting and for
      patient management. Forty-three out of 60 questionnaires were returned.
      Consultants had a significantly higher total score compared to the other grades
      (p<0.05) A high knowledge score was correlated with a high management score.
      However, awareness of minimum data was relatively poor across all grades. The
      majority of participants themselves were unaware of the new guidelines (38/43).
      Awareness of the guidelines and increased understanding of basic pathology should
      correct these weaknesses.

PMID- 15037168
TI  - Plastic surgery senior house officers in the UK and Ireland: academic background,
      publication rates and research plans.
AB  - Academic achievements by surgical trainees may vary according to the
      competitiveness of the subspecialty and desirability of the consultant post.
      Plastic and reconstructive surgery is a competitive specialty. In order to assess
      the level of achievement of current trainees, we investigated the academic
      qualifications, publication rates and future research plans of 100 senior house
      officers in plastic surgery working in units in the United Kingdom and Ireland.
      Selected results from our survey show that 30% had intercalated degrees, 6% had
      higher degrees, 58% of trainees had MRCS, 37% had previous plastic surgery
      experience and 57% had published (range 1-13). We believe this study provides
      interesting information concerning the current crop of plastic surgery trainees
      in the United Kingdom and Ireland. This survey may provide a benchmark for
      consultants to refer to when shortlisting for SHO posts. We also believe it will
      be of interest to those junior trainees hoping to pursue a career in plastic
      surgery.

PMID- 15037169
TI  - Routine histological examination of the mastectomy scar at the time of breast
      reconstruction: important oncological surveillance?
AB  - This retrospective study assesses whether the routine submission of mastectomy
      scars for histological examination at the time of delayed breast reconstruction
      is useful.

PMID- 15037170
TI  - The inframammary fold: contents, clinical significance and implications for
      immediate breast reconstruction.
AB  - The amount of breast tissue within the inframammary fold (IMF) is controversial.
      Preservation of the IMF during mastectomy facilitates breast reconstruction and
      led some surgeons to practice conservation of the IMF, contrary to traditional
      descriptions of total mastectomy. The aim of this study was to analyse the
      clinical significance of IMF tissue content. A total of 50 IMF specimens were
      studied from 42 patients who underwent mastectomy between January 2001 and
      December 2002. The amount of breast tissue within each IMF was evaluated. The
      median patient age was 46 (range 33-86) years. The median body mass index was
      23.4 (18.1-38.3)kg/m(2). The median IMF volume resected was 2 (0.2-9.7)cm(3)
      which was 0.6 (0.1-2.0)% of the breast volume. Ten specimens (20%) contained
      breast tissue and one (2%) contained breast tissue and an inframammary lymph
      node. Three specimens (6%) containing fibrofatty tissue without breast parenchyma
      had intramammary lymph nodes within the IMF. One patient (2%) who had a
      mastectomy for invasive ductal carcinoma had IMF tissue containing a lymph node
      within the IMF with breast cancer metastasis. The presence of breast tissue or
      lymph nodes within the IMF was unrelated to patient age, body mass index, the
      amount of IMF tissue in relation to breast volume and absolute breast size. Our
      finding that breast tissue and intramammary lymph nodes are present in 28% of IMF
      specimens requires re-consideration of the safety of preserving the IMF at
      mastectomy. If IMF tissue is resected and the immediate breast reconstruction is
      performed, the superficial fascial system should be reconstructed after excision
      of the IMF tissue in order to recreate the inframammary crease.

PMID- 15037171
TI  - Oral functional outcome after intraoral reconstruction with nasolabial flaps.
AB  - In this study, the functional and aesthetic outcome of patients with nasolabial
      flaps in the floor of the mouth was examined. Sixteen patients underwent
      reconstruction of the floor of the mouth with 19 nasolabial flaps after resection
      of a squamous cell carcinoma. Eight patients received postoperative radiotherapy.
      The patients were questioned concerning oral disabilities. Speech, mastication,
      deglutition, oral continence and the aesthetic result were evaluated. Two-point
      discrimination, temperature sensation and blunt-sharp discrimination of the
      intraoral flaps were tested. Speech and the wearing of dentures were hardly
      affected. Consumption of solid foods caused moderate problems in half of the
      patients. No sensibility problems were found. The aesthetic deformity was
      minimal. The use of nasolabial flaps in patients with limited defects of the
      anterior floor of the mouth after tumor resection showed adequate functional and
      aesthetic results.

PMID- 15037172
TI  - Double lateral osteotomy in aesthetic rhinoplasty.
AB  - Lateral osteotomy is a very important step in a cosmetic rhinoplasty; it allows
      the surgeon to narrow the nose, to close the open roof created after hump
      removal, and to achieve symmetry of an asymmetrical nasal bony framework. In most
      patients a single lateral osteotomy reaches the expected result, with excellent
      cosmetic outcome, good stability, and rapid healing. We find that double lateral
      osteotomy is useful in managing severe asymmetry of nasal walls in patients with
      too prominent and thick maxillary processes that join asymmetrically together
      with nasal bones. It is also valuable in correcting very large and wide noses. We
      review our experience of about 1660 rhinoplasties with more than one year follow
      up. Two hundred and ten cases (12.65%) had been treated with monolateral, or
      bilateral double osteotomy. We evaluate postoperative aesthetic and functional
      results.

PMID- 15037173
TI  - Free dermis-fat graft to correct the whistle deformity in patients with cleft
      lip.
AB  - Vermilion notching or 'whistle deformity' is a common secondary deformity of the
      vermilion in patients with cleft lip. The free border of the lip is a composite
      structure consisting of the orbicularis oris and the overlying tissues, namely
      subcutaneous fat, vermilion and mucosa. A deficiency of all or one of these
      structures is responsible for the vermilion notch. An absolute shortage of the
      muscle or subcutaneous tissue necessitates the use of tissue from another source
      to correct the deformity. Dermis fat grafts have been used to augment the free
      border of the lip and correct this deformity. The technique is simple and
      reliable. The tissue is available in plenty, easy to harvest and could be
      repeated if necessary, i.e. in case of resorption. From June 1996 until January
      2000 the technique was used in 10 patients. Of these 10, one was a bilateral
      cleft and nine were unilateral cleft lip deformities. A degree of graft
      resorption was seen in one patient, one had a partial graft loss due to
      ulceration and exposure. The first patient had a further augmentation.

PMID- 15037174
TI  - Congenital internal and external jugular venous aneurysms in a child.
AB  - A 2-year-old boy presented with varices and a neck mass. Imaging studies revealed
      internal jugular vein aneurysm. Gradual increasing of the mass, potential
      thrombus formation and cosmetical considerations were indications for surgery. At
      surgery aneurysms of both the external and internal jugular veins were found and
      resected.

PMID- 15037175
TI  - Vincristine as a treatment for a large haemangioma threatening vital functions.
AB  - We report the use of vincristine to treat a large steroid resistant haemangioma
      of the lower face and neck. At the time of treatment the lesion had shown no
      signs of involution. The haemangioma was not life threatening but extension
      within the mouth was associated with bleeding and ulceration, which was impairing
      feeding and speech development. A significant improvement was seen with
      vincristine treatment.

PMID- 15037176
TI  - A case of squamous cell carcinoma associated with plasmacytoma.

PMID- 15037177
TI  - Imaging to guide amputation of necrotic limbs in paediatric patients with
      meningococcal septicaemia.

PMID- 15037178
TI  - Vascular endothelial growth factor (VEGF) expression and the effect of exogenous
      VEGF on survival of a random flap in the rat.

PMID- 15037179
TI  - Earlobe vs. ear lobule.

PMID- 15037180
TI  - How soft are Soft Touch breast implants?

PMID- 15037181
TI  - Post-irradiation angiosarcoma of the breast.

PMID- 15037183
TI  - Therapeutic angiogenesis.

PMID- 15037184
TI  - Post-operative splinting to maintain full extension of the PIPJ after
      fasciectomy.

PMID- 15037182
TI  - Personal mastopexy technique for breast stabilisation: update.

PMID- 15037185
TI  - Tissue protection when using K-wires in the hand.

PMID- 15037186
TI  - Photosensitivity reaction in a longstanding scar.

PMID- 15037187
TI  - Prevention of torsion when insetting vein grafts.

PMID- 15037188
TI  - The 'two finger' sign. Clinical examination of palmaris longus (PL) tendon.

PMID- 15037189
TI  - Professional tattooing--alternative method to nipple reconstruction.

PMID- 15037190
TI  - Comparative breaking strength of non-permanent sutures.

PMID- 15037191
TI  - The two-state model of antagonist-AT1 receptor interaction: an hypothesis
      defended but not tested.
AB  - A correlation between insurmountable antagonism and slow dissociation has been
      observed for the non-peptidic AT1 receptor antagonists. This commentary examines
      the validity of conclusions regarding a two stage binding mechanism that has been
      proposed in order to account for both the slow dissociation and insurmountable
      antagonism. Support for that hypothetical mechanism is in the form of the
      goodness of fit between experimental data and modelled data in a number of papers
      from the same laboratory. We challenge the idea that a simple match of model and
      data is an adequate test of an hypothesis by showing that a simpler model matches
      the data equally well. We conclude that two stage binding is not necessary to
      explain the behaviour of AT1 receptor antagonists.

PMID- 15037192
TI  - Binding of hybrid molecules containing pyrrolo [2,1-c][1,4]benzodiazepine (PBD)
      and oligopyrrole carriers to the human immunodeficiency type 1 virus TAR-RNA.
AB  - The binding properties of a set of four hybrids, prepared combining from one to
      four polypyrrole minor groove binders and pyrrolo [2,1-c][1,4]benzodiazepine
      (PBD), have been studied using as target molecule the HIV-1 TAR-RNA. We found
      that these hybrids bind to TAR-RNA and inhibit TAR/protein(s) interactions. The
      anti-proliferative activity of the hybrids has been tested in vitro on HL3T1
      cells and compared to the anti-proliferative effects of the natural product
      distamycin A and PBD. The effects on HIV-1 LTR directed transcription were
      studied using the chloramphenicol-acetyltransferase gene reporter system, and
      structure-activity relationships are discussed. The results obtained demonstrate
      that the hybrids 22-25 exhibit different TAR-RNA binding activity with respect to
      both distamycin A and PBD. In addition, a direct relationship was found between
      number of pyrrole rings present in the hybrids 22-25 and anti-proliferative
      effects. It was found that increased length of the polypyrrole backbone leads to
      an increased in vitro anti-proliferative effect, i.e. the hybrid 25, containing
      the four pyrroles distamycin analogous, is more active than 22, 23 and 24 against
      cell proliferation. With respect to inhibition of HIV-1 LTR-driven transcription,
      it was found that the hybrids 23-25 containing two-four pyrroles are active.
      Therefore, when anti-proliferative effects are considered together with the
      inhibitory effects of HIV-1 LTR driven transcription, our results suggest that
      the hybrid 23 is the more interesting, since it exhibits low anti-proliferative
      activity and inhibits HIV-1 LTR driven transcription both in vitro and in ex vivo
      experiments.

PMID- 15037193
TI  - Stimulation of CD36 and the key effector of reverse cholesterol transport ATP
      binding cassette A1 in monocytoid cells by niacin.
AB  - Niacin, the first lipid lowering drug shown to improve survival after myocardial
      infarction, decreases LDL and increases HDL cholesterol levels. These effects
      cannot fully be explained by its suspected mechanism of action, inhibition of
      lipolysis and hepatic VLDL synthesis. Niacin has also been shown to interfere
      with the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and massively stimulate
      prostaglandin D2 (PGD2) formation. The major metabolite of PGD2, 15-deoxy
      Delta(12,14)-prostaglandin J2 (15d-PGJ2), was recently identified as the most
      potent endogenous PPARgamma activator. We, therefore, studied the effects of
      niacin on the PPARgamma- and cAMP-dependent expression of receptors promoting
      reverse cholesterol transport. The transcription of PPARgamma-, HDL-, LDL- and
      scavenger-receptors and the sterol exporter ABCA1, were measured by quantitative
      RT-PCR and cellular cholesterol efflux and PPARgamma activation studied in
      macrophage and hepatocyte models. Niacin stimulated the translocation of
      PPARgamma and the transcription of PPARgamma, CD36 and ABCA1 in monocytoid cells,
      whereas the LDL-receptor (LDL-R) was unchanged. Thereby niacin enhanced HDL
      mediated cholesterol efflux from the cells resulting in a reduced cellular
      cholesterol content. The niacin effect on CD36 but not on ABCA1 was prevented by
      cyclooxygenase inhibition, whereas the niacin effect on ABCA1 but not on CD36 was
      prevented by PKA inhibition, suggesting mediation by the 15d-PGJ2/PPARgamma and
      the cAMP/PKA pathways, respectively. These new actions of niacin on several key
      effectors of reverse cholesterol transport out of the vessel wall provide a
      rational to expect regression of atherosclerosis and test the combination of
      niacin with statins for an overadditive clinical benefit.

PMID- 15037194
TI  - Chronic hypoxia up-regulates expression of adenosine A1 receptors in DDT1-MF2
      cells.
AB  - As the first step to understand how chronic hypoxia might regulate smooth muscle
      function in health and disease, we have employed an established immortalised cell
      model of smooth muscle, DDT1-MF2 cells, to address the hypothesis that adenosine
      A1 receptor density is modulated by O2 availability. Maximal specific binding
      (Bmax) of the selective adenosine A1 receptor antagonist, [3H]-DPCPX, to cell
      membranes increased 3.5-fold from 0.48 +/- 0.02 pmol/mg to 1.7 +/- 0.5 pmol/mg
      protein after 16 hr of hypoxia and this effect was not accompanied by any
      statistically significant changes in either binding affinity (0.84 +/- 0.2 nM vs.
      1.2 +/- 0.3 nM) or Hill coefficient (1.1 +/- 0.1 vs. 0.99 +/- 0.03). Hypoxia
      evoked increases in membrane receptor density were paralleled in intact DDT1-MF2
      cells. In addition, the increase in [3H]-DPCPX binding to intact cells was
      inhibited by co-incubation during hypoxia with the translational inhibitor
      cycloheximide, the transcriptional blocker actinomycin D and the NFkappaB
      inhibitor sulphasalazine. Together, these data show that adenosine A1 receptor
      density is modulated, at least in part, by O2-dependent activation of the
      transcription factor NFkappaB and adds to the list of processes dynamically
      regulated by ambient oxygen availability. Since hypoxia is an initiating factor
      in acute renal failure, similar changes in transcription may account for up
      regulation of adenosine A1 receptors noted previously in the renal vasculature of
      rats with acute renal failure.

PMID- 15037195
TI  - Determination of cytochrome P450 1A2 and cytochrome P450 3A4 induction in
      cryopreserved human hepatocytes.
AB  - Freshly prepared human hepatocytes are considered as the 'gold standard' for in
      vitro testing of drug candidates. However, several disadvantages are associated
      with the use of this model system. The availability of hepatocytes is often low
      and consequently the planning of the experiments rendered difficult. In addition,
      the quality of the available cells is in some cases poor. As an alternative,
      cryopreserved human hepatocytes were validated as a model to study cytochrome
      P450 1A2 (CYP1A2) and cytochrome P450 3A4 (CYP3A4) induction. In a single blinded
      experiment, hepatocytes from three separate lots were incubated with three
      concentrations of different compounds, and compared to non-treated cells and
      cells incubated with omeprazole or rifampicin. CYP1A2 and CYP3A4 induction was
      determined by measuring 7-ethoxyresorufin-O-deethylation activity and 6beta
      hydroxytestosterone formation, respectively. CYP1A2 and CYP3A4 mRNA and protein
      expression were analyzed by TaqMan QRT-PCR and immunodetection. Cells responded
      well to the prototypical inducers with a mean 38.8- and 6.2-fold induction of
      CYP1A2 and CYP3A4 activity, respectively. Similar as with fresh human
      hepatocytes, high batch-to-batch variation of CYP1A2 and CYP3A4 induction was
      observed. Except for 1 and 10 microM rosiglitazone, the glitazones did not
      significantly affect CYP1A2. A similar result was observed for CYP3A4 activity
      although CYP3A4 mRNA and protein expression were dose-dependently upregulated. In
      conclusion, cryopreserved human hepatocytes may be a good alternative to fresh
      hepatocytes to study CYP1A and 3A induction.

PMID- 15037196
TI  - Usnic acid-induced necrosis of cultured mouse hepatocytes: inhibition of
      mitochondrial function and oxidative stress.
AB  - Usnic acid, a lichen acid, is a compound found in crude medicines and dietary
      supplements, including Lipokinetix, a supplement marketed as a weight loss agent
      that caused hepatotoxicity and acute liver failure in patients. In this study, we
      examined the toxicity of usnic acid and assessed whether usnic acid may be
      contributing to hepatotoxicity caused by Lipokinetix. In primary cultured murine
      hepatocytes, usnic acid treatment (5 microM) resulted in 98% necrosis within 16
      hr (no apoptosis was detected). Usnic acid treatment was associated with early
      inhibition and uncoupling of the electron transport chain in mitochondria of
      cultured hepatocytes. This inhibition of mitochondria by usnic acid corresponded
      with a fall in ATP levels in hepatocytes. In isolated liver mitochondria, usnic
      acid was observed to directly inhibit and uncouple oxidative phosphorylation.
      Oxidative stress appears to be central in usnic acid-induced hepatotoxicity based
      on the following findings: (1) pretreatment with antioxidants (butylated
      hydroxytoluene+Vitamin E) decreased usnic acid-induced necrosis by nearly 70%;
      (2) depletion of mitochondrial GSH with diethylmaleate increased susceptibility
      of hepatocytes to usnic acid; (3) usnic acid treatment was associated with
      increase free radical generation, measured using the fluorescent probe,
      dichlorodihydrofluorescin. The source of reactive oxygen species after usnic acid
      treatment include autoxidation of usnic acid and increased hydrogen peroxide
      generation by mitochondria caused by usnic acid inhibition of the respiratory
      chain, with the latter playing a more prominent role. Taken together, our results
      suggest that usnic acid is a strong hepatotoxic agent that triggers oxidative
      stress and disrupts the normal metabolic processes of cells. Usnic acid therefore
      may contribute to the hepatotoxic effects of Lipokinetix and its use in any
      supplement must come into question.

PMID- 15037197
TI  - Glycine 154 of the equilibrative nucleoside transporter, hENT1, is important for
      nucleoside transport and for conferring sensitivity to the inhibitors
      nitrobenzylthioinosine, dipyridamole, and dilazep.
AB  - hENT1 and hENT2 are members of the human equilibrative nucleoside transporter
      family. hENT1 is ubiquitously expressed and plays an important role in the
      disposition and pharmacological activity of nucleoside drugs and nucleosides,
      such as adenosine. hENT2 is expressed in only a few tissues (e.g. muscle). hENT1
      and hENT2 differ in their affinity for nucleoside substrates and in their
      sensitivity to inhibitors, such as nitrobenzylthioinosine (NBMPR). hENT1 has
      higher (or equal) affinity to hENT2 for all natural nucleosides except inosine.
      hENT1 is also more sensitive to NBMPR inhibition (IC50 approximately 0.4-8 nM)
      when compared with hENT2 (IC50 approximately 2.8 microM). This difference in
      inhibition potency is substantially dependent on the difference in amino acid at
      position 154 in hENT1 (glycine) and hENT2 (serine). Since NBMPR competitively
      inhibits nucleoside transporter activity, we hypothesized that G154 may also play
      a role in the transport of natural nucleosides and in the inhibition by other
      hENT1 inhibitors, dipyridamole (DP), and dilazep (DZ). Our results, using a yeast
      expression system, demonstrate that substituting glycine 154 of hENT1 with serine
      of hENT2 converts hENT1 to a transporter that exhibits partial characteristics of
      hENT2. For example, this conversion reduces sensitivity of hENT1 to the
      inhibitors NBMPR, DP, and DZ and reduces its transport affinity for the natural
      nucleosides cytidine and adenosine. However, this conversion renders hENT1 less
      sensitive to inhibition by anti-HIV drugs azidothymidine, dideoxyinosine, and the
      nucleobase, hypoxanthine. Collectively, these results suggest that glycine 154
      plays an important role in the transport of nucleosides and in sensitivity to the
      inhibitors NBMPR, DP, and DZ.

PMID- 15037198
TI  - Interaction of substituted hexose analogues with the Trypanosoma brucei hexose
      transporter.
AB  - Glucose metabolism is essential for survival of bloodstream form Trypanosoma
      brucei subspecies which cause human African trypanosomiasis (sleeping sickness).
      Hexose analogues may represent good compounds to inhibit glucose metabolism in
      these cells. Delivery of such compounds to the parasite is a major consideration
      in drug development. A series of D-glucose and D-fructose analogues were
      developed to explore the limits of the structure-activity relationship of the
      THT1 hexose transporter of bloodstream form African trypanosomes, a portal that
      might be exploited for drug uptake. D-glucose analogues with substituents at the
      C2 and C6 position continued to interact with the exofacial hexose binding site
      of the transporter. There was a limit to the size at C6 which still permitted
      recognition, although compounds carrying large groups at position C2 were still
      recognised. However, radiolabelled N-acetyl-D-[1-14C] glucosamine was not
      internalised by trypanosomes, in spite of the ability of this compound to inhibit
      glucose uptake, indicating that there is a limit to the size of C2 substituent
      that allows translocation. Addition of an alkylating group (bromoacetyl) at
      position C2 in the D-glucose series and at position 6 in the D-fructose set,
      created two analogues which interact with the transporter and kill trypanosomes
      in vitro. This indicates that inhibition of the transporter may be a good means
      of killing trypanosomes.

PMID- 15037199
TI  - Cloning, characterisation and identification of several polymorphisms in the
      promoter region of the human alpha2B-adrenergic receptor gene.
AB  - Screening of a foetal brain genomic DNA library allowed to isolate a 10-kb
      fragment of the gene encoding the human alpha2B-adrenergic receptor, that
      contained 5.5 kb of the 5'-flanking region, the open reading frame and 2.9 kb of
      the 3'-flanking region. The 1-kb fragment upstream from the start codon was rich
      in GC, lacked consensus TATA or CAAT box, but contained several Sp1-binding
      sites. Other potential cis-regulatory elements found in the 5'-flanking region
      included AP2, USF, Stat-6, NFkappaB and Olf-1. A single canonical polyadenylation
      signal (AATAAA) was found at position +3252/+3257 and the polyadenylation site
      was 3274 nucleotides downstream from ATG. Transfection experiments with chimeric
      luciferase constructs containing various truncated fragments of the 5'-region
      showed that the fragment -3160/+3 exhibited promoter activity in all tested cell
      lines and permitted the definition of a minimal 200-bp promoter (-603/-411)
      containing three putative Sp1-binding sites and two initiator elements.
      Transcriptional activity of this region was inhibited by the addition of
      mithramycin, a specific inhibitor of Sp1 binding to GC-rich sequences. The search
      for sequence variants within a fragment covering 1.7 kb of 5'-flanking region and
      the coding region allowed us to identify five novel single nucleotide
      polymorphisms. Interestingly, the G/C substitution at position -98 relative to
      the start codon was common and in complete linkage with a previously identified
      insertion/deletion polymorphism in the coding region which was showed to affect
      alpha2B-adrenergic receptor function. Based on transfection data and computer
      assisted sequence analysis, the -98 G/C single nucleotide polymorphism was
      located within a portion of the 5'-UTR (-127/+3) affecting luciferase activity
      and it created additional putative binding site for Sp1. However, G/C
      substitution had no significant incidence on promoter activity in BHK-21 or HeLa
      cells.

PMID- 15037200
TI  - Pharmacology of polymorphic variants of the human 5-HT1A receptor.
AB  - The 5-HT1A receptor is a critical mediator of serotonergic (5-HT) function. We
      have identified 13 potential single nucleotide polymorphisms resulting in amino
      acid changes throughout the human 5-HT1A receptor. The pharmacological profiles
      of these 13 polymorphic variants were then characterized using a high-throughput
      assay based on ligand-dependent transformation of NIH/3T3 cells. The majority of
      the polymorphic variants displayed wild-type pharmacological profiles in response
      to a panel of well-established agonists at the 5-HT1A receptor. However, the A50V
      polymorphic variant, which had an alanine to valine substitution in transmembrane
      1, exhibited a loss of detectable response to 5-HT. Interestingly, all other
      agonists tested, including buspirone, lisuride, and (+)8-OH-DPAT, exhibited
      efficacies similar to that of the wild-type receptor. The competitive antagonist,
      methiothepin, also displayed a 19-fold decrease in potency at the A50V variant
      receptor. However, both 5-HT and methiothepin were able to compete for [3H]WAY
      100635 binding to the A50V variant with affinities similar to the wild-type
      receptor. Moreover, the Bmax of [3H]WAY-100635 binding was 14-fold lower for the
      A50V variant than for the wild-type receptor. Thus, the A50V receptor variant
      exhibited ligand-specific functional alterations in addition to lower expression
      levels. These data suggest a previously unappreciated role for transmembrane 1 in
      mediating 5-HT response at the 5-HT1A receptor. Furthermore, individuals that
      potentially harbor the A50V polymorphism might display aberrant affective
      behaviors and altered responses to drugs targeting the 5-HT1A receptor.

PMID- 15037201
TI  - Effect of hydrogen peroxide on Ca2+ mobilisation in human platelets through
      sulphydryl oxidation dependent and independent mechanisms.
AB  - Using Fura-2-loaded human platelets we studied the nature of the mechanisms
      involved in Ca2+ signalling mediated by H2O2. In a Ca2+-free medium, H2O2 (10
      microM-100 mM) induced a concentration-dependent increase in [Ca2+]i. Depletion
      of either agonist-sensitive or mitochondrial Ca2+ pools reduced this effect while
      depletion of both stores abolished it. Xestospongin C, an inositol 1,3,5
      trisphosphate (IP3) receptor inhibitor, reduced Ca2+ release evoked by 1 mM H2O2
      by 45%, indicating that H2O2-induced Ca2+ release involves interaction with IP3
      receptors. Blockade of the IP3 turnover by lithium or treatment with U-73122 did
      not modify H2O2-induced Ca2+ release from the agonist-sensitive pool, suggesting
      the involvement of a mechanism independent of IP3 generation. H2O2 inhibited Ca2+
      reuptake into the agonist-sensitive stores mediated by the sarcoendoplasmic
      reticulum Ca2+ ATPase (SERCA). Thimerosal (5 microM), a sulphydryl reagent,
      induced Ca2+ release from the agonist-sensitive stores. This event was impaired
      by treatment with 2 mM DTT, which also inhibited H2O2-induced Ca2+ release from
      the agonist-sensitive pool but not from mitochondria. H2O2 reduced the ability of
      the plasma membrane Ca2+ ATPase (PMCA) to extrude Ca2+ by 75%, an effect that was
      unaffected by DTT. Consistent with this, thimerosal did not modify the PMCA
      activity. Finally, exposure to H2O2 triggered platelet aggregation, which was
      slower than that observed after agonist stimulation. We conclude that H2O2
      induced Ca2+ release from agonist-sensitive stores by oxidation of sulphydryl
      groups in SERCA and the IP3 receptors independently of IP3 generation. In
      addition, H2O2 induced Ca2+ release from mitochondria and inhibited the PMCA
      activity by different mechanisms in human platelets.

PMID- 15037202
TI  - Antiproliferative activity and mechanism of action of fatty acid derivatives of
      arabinofuranosylcytosine in leukemia and solid tumor cell lines.
AB  - 1-beta-D-arabinofuranosylcytosine (ara-C) is a deoxycytidine analog with activity
      in leukemia, which requires phosphorylation by deoxycytidine kinase (dCK) to
      allow formation of its active phosphate 1-beta-D-arabinofuranosylcytosine
      triphosphate, but can be deaminated by deoxycytidine deaminase. Altered membrane
      transport is also a mechanism of drug resistance. In order to facilitate ara-C
      uptake and prolong retention in the cell, lipophilic prodrugs were synthesized.
      Fatty acid groups with a varying acyl chain length and number of double bonds
      were esterified at the 5' position on the sugar moiety of ara-C. The compounds
      were tested in two pairs of ara-C resistant leukemic cell lines (murine L1210 and
      rat BCLO and their resistant variants L4A6 and Bara-C, respectively) and two
      pairs of cell lines with a resistance to gemcitabine, another deoxycytidine
      analog (human ovarian cancer A2780 and murine colon cancer C26-A and their
      resistant variants AG6000 and C26-G, respectively). L4A6, Bara-C and AG6000 have
      varying degrees of decreased dCK activity, while the mechanism for C26-G is not
      yet clear. In the parent cell lines, ara-C was more active, but in the resistant
      variants several of the analogs were more active, while the degree of cross
      resistance varied. In AG6000 with a total dCK deficiency, all compounds were
      inactive. Structure-activity relation analysis showed that ara-C derivatives with
      shorter acyl chains and more double bonds were more active in the parental and
      drug resistant cells. Further mechanistic studies were performed with the elaidic
      acid derivative of ara-C (CP-4055). CP-4055 inhibited deamination of dCyd partly
      and induced DNA synthesis inhibition effectively in C26-A and C26-G cells, but
      the retention of inhibition was much longer for CP-4055 than for ara-C. In
      contrast to ara-C, CP-4055 inhibited RNA synthesis for 60% after drug exposure.
      In conclusion, CP-4055 seems to be a promising prodrug, whose effects were
      different and longer lasting than for the parent drug.

PMID- 15037203
TI  - Selenite-induced apoptosis in doxorubicin-resistant cells and effects on the
      thioredoxin system.
AB  - Selenium treatment of the doxorubicin-resistant cell line, U-1285dox, derived
      from human small cell carcinoma of the lung, resulted in massive apoptosis. This
      effect appeared maximal at 2 days after addition of selenite. The apoptosis was
      caspase-3 independent as revealed by Western blot analysis, activity measurement
      and by using caspase inhibitors. Induction of apoptosis was significantly more
      pronounced and occurred after addition of lower concentrations of selenite in the
      doxorubicin-resistant cells compared to the parental doxorubicin-sensitive cells.
      High levels of selenite caused necrosis in the doxorubicin-sensitive cells.
      Analysis of enzymatic activity (insulin reduction) of thioredoxin reductase
      (TrxR) and TrxR protein concentration, measured by ELISA, revealed increasing
      activity and protein levels after treatment with increasing concentrations of
      selenium. Maximum relative increase was induced up to 1 microM in both sublines
      and at this selenium level the concentrations of TrxR measured as insulin
      reducing activity or ELISA immunoreactivity were nearly identical. Increasing
      concentrations of selenite up to 10 microM resulted in increased activity and
      concentration of TrxR in the sensitive subline but decreasing levels in the
      resistant subline. The level of truncated Trx (tTrx) was higher in the resistant
      U-1285dox cells but the level did not change with increasing selenite
      concentrations. Our results demonstrate pronounced selective selenium-mediated
      apoptosis in therapy-resistant cells and suggest that redox regulation through
      the thioredoxin system is an important target for cancer therapy.

PMID- 15037204
TI  - Synthetic 1,4-anthracenedione analogs induce cytochrome c release, caspase-9, -3,
      and -8 activities, poly(ADP-ribose) polymerase-1 cleavage and internucleosomal
      DNA fragmentation in HL-60 cells by a mechanism which involves caspase-2
      activation but not Fas signaling.
AB  - Synthetic analogs of 1,4-anthraquinone (AQ code number), a compound that mimics
      the antiproliferative effects of daunorubicin (daunomycin) in the nanomolar range
      in vitro but has the advantage of blocking nucleoside transport and retaining its
      efficacy in multidrug-resistant tumor cells, were tested for their ability to
      induce apoptosis in the HL-60 cell system. AQ10 and, especially, the new lead
      antiproliferative compounds AQ8 and AQ9 reduce the growth and integrity of wild
      type, drug-sensitive, HL-60-S cells more effectively than AQ1, suggesting that
      various methyl group substituents at C6 may enhance the bioactivity of the parent
      compound. Internucleosomal DNA fragmentation, a late marker of apoptosis, is
      similarly induced in a biphasic manner by increasing concentrations of AQ8 and
      AQ9 at 24 hr. Poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, an early event
      required for cells committed to apoptosis, is detected within 3-6 hr in HL-60-S
      cells treated with AQ9. In accord with the fact that the caspases 9 and 3 cascade
      is responsible for PARP-1 cleavage, the activities of initiator caspase-9 and
      effector caspase-3 are induced by AQ9 in the same time- and concentration
      dependent manners and to the same maximal degrees in both the HL-60-S and
      multidrug-resistant HL-60-RV cell lines. Interestingly, a 1-hr pulse treatment is
      sufficient for AQ8 and AQ9 to maximally induce caspase-9 and -3 activities at 6
      hr. The release of mitochondrial cytochrome c (Cyt c) is also detected within 3
      6hr in HL-60-S cells treated with AQ9, a finding consistent with the fact that
      Cyt c is the apoptotic trigger that activates caspase-9. Moreover, AQ analogs
      induce Cyt c release, caspase-9 and -3 activities and PARP-1 cleavage in relation
      with their abilities to decrease tumor cell growth and integrity, AQ8 and AQ9
      being consistently the most effective. Since apical caspases 2 and 8 may both act
      upstream of mitochondria to promote Cyt c release, it is significant to show that
      AQ9 maximally induces caspase-2 and -8 activities at 6 and 9 hr, respectively.
      During AQ8 treatment, the caspase-2 inhibitor benzyloxycarbonyl (z)-Val-Asp-Val
      Ala-Asp (VDVAD)-fluoromethyl ketone (fmk) totally blocks caspase-9, -3, and -8
      activations, whereas the caspase-8 inhibitor z-Ile-Glu-Thr-Asp-(IETD)-fmk does
      not prevent caspase-2, -9, and -3 activations, suggesting that AQ-induced caspase
      2 activity is an upstream event critical for the activation of the downstream
      caspases 9 and 3 cascade, including the mitochondrial amplification loop through
      caspase-8. However, these caspase-2 and -8 inhibitors fail to alter AQ8-induced
      Cyt c release, suggesting that AQs might also target mitochondria independently
      from caspase activation. Furthermore, the antagonistic anti-Fas DX2 and ZB4
      monoclonal antibodies (mAbs), which block the induction of Cyt c release and
      caspase-2, -8, and -9 activities by the agonistic anti-Fas CH11 mAb, and the
      neutralizing anti-Fas ligand (FasL) NOK-1 mAb all fail to inhibit AQ9-induced Cyt
      c release and caspase-2, -8, and -9 activities, suggesting that the FasL/Fas
      signaling pathway is not involved in the mechanism by which antiproliferative AQ
      analogs trigger apoptosis in HL-60 cells.

PMID- 15037206
TI  - Methioninase and selenomethionine but not Se-methylselenocysteine generate
      methylselenol and superoxide in an in vitro chemiluminescent assay: implications
      for the nutritional carcinostatic activity of selenoamino acids.
AB  - Methylselenol from selenium metabolism is postulated to be and most experimental
      evidence now indicates that it is the selenium metabolite responsible for the
      dietary chemoprevention of cancers. Using the recombinant enzyme methioninase,
      methylselenol-generating chemiluminesence by superoxide (O2*-) is shown to be
      catalytically produced from L-selenomethionine and D,L-selenoethionine, but not
      from methionine or L-Se-methylselenocysteine (SeMC). Methylselenol enzymaticaly
      generated by methioninase activity from the substrate selenomethionine arises
      from an initial putative selenium radical as measured by chemiluminesence in the
      absence of glutathione (GSH). In the presence of GSH, superoxide was generated as
      measured by chemiluminesence and superoxide dismutase inhibition of
      chemiluminescence. Ascorbic acid also quenched the chemiluminesence from the
      activity of methioninase with selenomethionine. Methylselenol and other redox
      cycling selenium compounds are almost assuredly accountable for inducing cell
      cycle arrest and apoptosis in cancer cells in vitro and in vivo. Methylselenol
      generated from selenomethionine by methioninase is catalytic alone in oxidizing
      thiols, i.e. GSH, generating superoxide and inducing oxidative stress in direct
      proportion to its concentration. Se-methylselenocysteine in vivo is very likely
      carcinostatic in like manner to selenomethionine by generating methylselenol from
      other enzymatic activity, i.e. beta-lyase or amino acid oxidases.

PMID- 15037207
TI  - Comparison of gene expression profiles between white and brown adipose tissues of
      rat by microarray analysis.
AB  - To characterize the energy metabolism in brown adipose tissue (BAT), the
      differences in gene expression profiles between BAT and white adipose tissue
      (WAT) were analyzed using a high-density cDNA microarray. RNAs isolated from two
      adipose tissues were hybridized to an Agilent rat cDNA Microarray that contained
      about 14,500 cDNA probe sets. The expression levels of 499 cDNA/ESTs were found
      to be at least 5-fold higher or lower in BAT than in WAT. Consistent with our
      previous findings, high expression levels of genes encoding uncoupling protein 1,
      muscle-type carnitine palmitoyltransferase and some other proteins involved in
      energy metabolism in BAT were found. Most of the genes encoding mitochondrial
      proteins, such as subunits of ATP synthase, cytochrome c oxidase, and NADH
      dehydrogenase, were highly expressed, reflecting possible differences in the
      cellular content of mitochondria between BAT and WAT. However, the expression
      levels of several genes encoding mitochondrial protein, such as liver
      mitochondrial aldehyde dehydrogenase and dicarboxylate carrier, were remarkably
      lower in BAT. These results may give important clues to understand the unique
      energy metabolism in BAT.

PMID- 15037205
TI  - The p38 pathway partially mediates caspase-3 activation induced by reactive
      oxygen species in Fanconi anemia C cells.
AB  - Because Fanconi anemia (FA) cells display hypersensitivity to oxidative stress
      and reactive oxygen species (ROS) that act as second messengers in cellular
      signaling, we investigated c-Jun N-terminal kinase (JNK) and p38 mitogen
      activated protein kinase (MAPK) activation in two FA-C lymphocyte cell lines
      (HSC536/N and PD149L) and one FA-A cell line (HSC99) exposed to interferon (IFN)
      gamma or H2O2. IFN-gamma induced accumulation of ROS and activation of JNK and
      p38 in HSC536/N and PD149L but not in HSC99 cells. Higher concentrations of H2O2
      were needed to induce moderate intracellular levels of ROS and phosphorylation of
      MAPKs in FA-A than in FA-C cells. Pre-incubation with dehydroascorbic acid
      resulted in reduced intracellular ROS levels and inhibition of MAPK activation
      induced by the above treatments. To define the functional role of JNK and p38 in
      IFN-gamma signaling, the effects of pharmacological inhibition of the MAPKs on
      induction of IFN-gamma and anti-Fas antibody responses were determined. Treatment
      of HSC536/N cells with p38-specific inhibitors partially inhibited caspase-3
      activation while pre-incubation with specific inhibitors of JNK had no effect.
      Altogether, these results suggest that FA-C cells are hypersensitive to IFN-gamma
      and are more sensitive to oxidative stress than FA-A cells and that IFN-gamma and
      anti-Fas antibody mediate signals for apoptosis in FA-C cells via p38 but not JNK
      pathways.

PMID- 15037208
TI  - Preservation of mitochondrial function during ischemia as a possible mechanism
      for cardioprotection of diltiazem against ischemia/reperfusion injury.
AB  - A possible mechanism for D-cis-diltiazem (diltiazem)-mediated improvement of the
      contractile function of ischemic/reperfused hearts was examined. Thirty-five-min
      ischemia/60-min reperfusion recovered little the left ventricular developed
      pressure (LVDP) and decreased myocardial high-energy phosphates (HEPs). Ischemia
      induced an accumulation of tissue Na+ content, an increase in cytochrome c in the
      cytosolic fraction, and a decrease in the oxygen consumption rate (OCR) in
      perfused hearts. Treatment of the heart with 1 microM diltiazem for the last 3
      min of pre-ischemia did not affect the decrease in HEPs during ischemia, whereas
      that with 3 microM partially attenuated the decrease in ATP, suggesting that 3
      microM diltiazem exerted energy-sparing effect. Treatment with 1 microM diltiazem
      enhanced the post-ischemic recovery of LVDP associated with attenuation of the
      ischemia-induced accumulation of tissue Na+, increase in cytochrome c in the
      cytosolic fraction, and decrease in myocardial OCR, and restoration of the
      myocardial HEPs during reperfusion. Combined treatment with diltiazem and a
      Na+/H+ exchange inhibitor, but not a Na+ channel blocker, facilitated the
      attenuation of Na+ accumulation in the ischemic heart and the enhancement of the
      post-ischemic recovery of LVDP. Sodium lactate, a possible metabolite in ischemic
      hearts, and sodium chloride increased the Na+ concentration in mitochondria,
      released cytochrome c into incubation medium, and reduced the mitochondrial
      respiration. Treatment of isolated mitochondria with diltiazem failed to
      attenuate the sodium lactate- and sodium chloride-induced alterations. These
      results suggest that the cardioprotection of diltiazem may be exerted via
      attenuating cytosolic Na+ overload through Na+ channels in the ischemic heart,
      leading to preservation of mitochondrial functional ability during ischemia,
      followed by improvement of post-ischemic energy production and contractile
      recovery.

PMID- 15037209
TI  - Role of direct cytotoxic effects of NSAIDs in the induction of gastric lesions.
AB  - A major clinical problem encountered with the use of non-steroidal anti
      inflammatory drugs (NSAIDs), is gastrointestinal complications. We previously
      reported that NSAIDs induce both necrosis and apoptosis in vitro. We here
      examined the cyclooxygenase (COX) dependency of this cytotoxic effect of NSAIDs
      and its involvement in NSAID-induced gastric lesions. Necrosis and apoptosis by
      NSAIDs was observed with all selective COX-2 inhibitors except rofecoxib and was
      not inhibited by exogenously added prostaglandin E2, suggesting that cytotoxicity
      of NSAIDs seems to be independent of the inhibition of COX. Intravenously
      administered indomethacin, which completely inhibited COX activity at gastric
      mucosa, did not produce gastric lesions. Orally administered selective COX-2
      inhibitors, which did not inhibit COX at gastric mucosa, also did not produce
      gastric lesions. Interestingly, a combination of the oral administration of each
      of all selective COX-2 inhibitors except rofecoxib with the intravenous
      administration of indomethacin clearly produced gastric lesions. These results
      suggest that in addition to COX inhibition by NSAIDs, direct cytotoxicity of
      NSAIDs may be involved in NSAID-induced gastric lesions.

PMID- 15037210
TI  - Indomethacin-induced renal damage: role of oxygen free radicals.
AB  - Nonsteroidal anti-inflammatory drugs are used extensively in clinical medicine.
      In spite of their therapeutic utility, however, they are known to cause
      significant gastrointestinal and renal toxicities, circumstances that limit their
      use. The side effects produced in these organs have been attributed mainly to the
      inhibitory effect of these drugs on the activity of cyclooxygenase, a key enzyme
      in prostaglandin synthesis. In addition to this, in the small intestine it is
      known that reactive oxygen species also contribute to the enteropathy seen in
      response to these drugs. In the kidney, however, there is little information
      whether other mechanisms contribute to the renal toxicity. This study was
      designed to look at the possible biochemical mechanisms involved in indomethacin
      induced renal damage. Rats fasted overnight were dosed with indomethacin (20
      mg/kg) by gavage and sacrificed 24 hr later. Histology of the kidney showed
      abnormalities in the mitochondria in the proximal tubules. Evidence of oxidative
      stress was found in the kidney associated with mitochondrial dysfunction and
      neutrophil infiltration. The lipid composition in the mitochondria was also
      altered. Such effects were abolished by the prior administration of arginine, a
      donor of nitric oxide. This study, thus, suggests that one of the mechanisms by
      which nonsteroidal anti-inflammatory drugs induce renal damage is through oxygen
      free radicals possibly generated by activated neutrophils and mitochondrial
      dysfunction.

PMID- 15037212
TI  - Cetirizine and allopurinol as novel weapons against cellular autoimmune
      disorders.
AB  - Type 1, or cellular, immune response is characterized by overproduction of TNF
      alpha, IFN-gamma, IL-1, IL-2 and IL-8 and is the underlying immune mechanism of
      psoriasis, alopecia areata, rheumatoid arthritis, Crohn's disease, multiple
      sclerosis, insulin-dependent diabetes mellitus and experimental autoimmune
      uveitis (EAU). Type 2 immune response is seen in antibody-mediated autoimmune
      diseases. Based on the pharmacokinetic effects of cetirizine and allopurinol,
      this paper introduces these two safe and inexpensive drugs as novel potential
      agents against cell-mediated autoimmune disorders. Cetirizine, supposed to
      inhibit DNA binding activity of NF-kappa B, inhibits the expression of adhesion
      molecules on immunocytes and endothelial cells and the production of IL-8 and
      LTB4, two potent chemoattractants, by immune cells. It induces the release of
      PGE2, a suppressor of antigen presentation and MHC class II expression, from
      monocyte/macrophages and reduces the number of tryptase positive mast cells in
      inflammation sites. Tryptase is a chemoattractant, generates kinins from
      kininogen, activates mast cells, triggers maturation of dendritic cells and
      stimulates the release of IL-8 from endothelial cells and the production of Th1
      lymphokines by mononuclear immunocytes. Allopurinol is a free radical scavenger,
      suppresses the production of TNF-alpha and downregulates the expression of ICAM-1
      and P2X(7) receptors on monocyte/macrophages. ICAM-1 serves as a ligand for LFA-1
      (on T lymphocytes), allowing proper antigen presentation. P2X(7) receptors are
      thought to be involved in IL-1beta release, mitogenic stimulation of T
      lymphocytes and the probable cytoplasmic communication between macrophages and
      lymphocytes at inflammation sites. Allopurinol was markedly more effective than
      prednisolone in treating experimental autoimmune uveitis and in combination with
      cyclosporine suppressed the inflammatory reaction of this condition more
      effectively than either agent alone. As allopurinol is a competitive inhibitor of
      xanthine oxidase and decreases serum levels of uric acid, which is protective
      against multiple sclerosis, it should preferably be coadministered with uric acid
      precursors in the treatment of this condition. Cetirizine and allopurinol may
      prove of benefit in the treatment of various cellular autoimmune disorders.

PMID- 15037211
TI  - Immune cells: free radicals and antioxidants in sepsis.
AB  - The excessive production of reactive oxygen species (ROS), associated with
      inflammation, leads to a condition of oxidative stress. Oxidative stress is a
      major contributing factor to the high mortality rates associated with several
      diseases such as endotoxic shock. This condition can be controlled to a certain
      degree by antioxidant therapies. Immune cells use ROS in order to support their
      functions and therefore need adequate levels of antioxidant defenses in order to
      avoid the harmful effect of an excessive production of ROS. This review discusses
      the toxic effects of endotoxin, paying particular attention to immune function.
      It continues by analyzing the mechanism to which specific cells of the immune
      system recognize endotoxin, and the resulting pathways leading to nuclear factor
      kappaB activation and proinflammatory gene transcription. We also focus on the
      involvement of reactive oxygen and nitric oxide (NO) and the protective role of
      antioxidants. The potential clinical use of antioxidants in the treatment of
      sepsis and the effects on the redox state of the immune cells are discussed.

PMID- 15037213
TI  - Neem (Azadirachta indica) leaf mediated immune activation causes prophylactic
      growth inhibition of murine Ehrlich carcinoma and B16 melanoma.
AB  - Conditional growth inhibition of murine Ehrlich carcinoma (EC) and B16 melanoma
      (B16Mel) was observed, following treatment of mice (Swiss and C57BL/6) with
      aqueous extract of neem (Azadirachta indica) (1 unit/mice/week for 4 weeks)
      either before or after inoculation of 1 x 10(6) tumor cells. Tumor inoculation
      after weekly injections for 4 weeks with neem leaf preparation (NLP) induced
      significant reduction of tumor growth (both EC and B16Mel) and increased
      survivability of mice. On the other hand, NLP treatment after tumor inoculation
      demonstrated no tumor growth inhibition in the NLP treated group in comparison to
      the PBS treated control. No direct cytotoxic effect of NLP towards EC and B16Mel
      tumor cells was observed in vitro. The spleen cells of NLP treated mice when
      mixed with inoculum of B16Mel tumor cells and injected into a group of mice,
      tumor growth was found to be significantly reduced and survivability of the tumor
      hosts increased remarkably in comparison to mice inoculated with tumor along with
      normal spleen cells. Concanavalin A (ConA) induced proliferation of lymphocytes
      from NLP treated mice was significantly higher than the lymphocytes of untreated
      mice. In in vitro, NLP by itself had no proliferative effects on lymphocytes but
      it co-stimulated ConA induced mitogenesis. NLP induced lymphocytosis as evidenced
      by increased lymphocyte count in blood as well as spleen. Flow cytometric
      evidence suggested that increase in CD4+ and CD8+ T cells accounted for
      lymphocytosis. The conditional tumor growth retardation, observed in mice treated
      with NLP before tumor inoculation, may be regulated by NLP mediated immune
      activation, having prominent role in the cellular immune function of the tumor
      host.

PMID- 15037214
TI  - The effects of fexofenadine on eosinophilia and systemic anaphylaxis in mice
      infected with Trichinella spiralis.
AB  - BACKGROUND: The effects of the non-impairing, H(1)-receptor antagonist
      fexofenadine were investigated in in vivo mouse models of eosinophilia and
      systemic anaphylaxis. METHODS: Eosinophilia was investigated in C57BL/6 mice (n=5
      per group) infected with Trichinella spiralis, with and without administration of
      fexofenadine HCl (5, 10 and 20 mg/kg/day). Eosinophilia was also studied, with
      and without fexofenadine administration, in mice with a congenital mast-cell
      deficiency (W/W(v)) and controls (+/+). The effect of fexofenadine HCl (20
      mg/kg/day) on IL-5 and eotaxin blood levels was also investigated in C57BL/6
      mice. In a separate model, systemic anaphylaxis was induced in C57BL/6 mice using
      T. spiralis antigen. Fexofenadine HCl (5, 10 and 20 mg/kg) or vehicle was
      administered 20 min before antigen challenge (n=5 per group). The effect of
      fexofenadine on systemic anaphylaxis caused by IgE and anti-IgE was also examined
      in CBF1 mice injected with serum from NC/Nga mice with high IgE levels. Rectal
      temperature was measured as an indicator of anaphylaxis. RESULTS: In C57BL/6
      mice, repetitive oral administration of fexofenadine HCl (5, 10 and 20 mg/kg/day)
      resulted in dose-dependent suppression of eosinophilia (p<0.05-0.0001). No
      suppression was observed in mast-cell deficient W/W(v) mice. In addition, single
      oral administration of fexofenadine HCl (10 and 20 mg/kg) significantly
      suppressed the decrease in rectal temperature (p<0.01), a marker for systemic
      anaphylaxis, in C57BL/6 mice. In CBF1 mice injected with serum from NC/Nga mice
      with high IgE levels, the decrease in rectal temperature was suppressed by single
      administration of fexofenadine HCl (10 and 20 mg/kg; p<0.01 and p<0.001,
      respectively). Fexofenadine had no effect on peripheral IL-5 and eotaxin levels.
      CONCLUSION: These results indicate that fexofenadine suppresses both eosinophilia
      and systemic anaphylaxis, both of which are fundamental reactions in allergic
      diseases.

PMID- 15037215
TI  - Penta-O-galloyl-beta-D-glucose inhibits phorbol myristate acetate-induced
      interleukin-8 [correction of intereukin-8] gene expression in human monocytic
      U937 cells through its inactivation of nuclear factor-kappaB.
AB  - We investigated the effects of the gallotannin penta-O-galloyl-beta-d-glucose
      (PGG) on interleukin (IL)-8 gene expression and nuclear factor (NF)-kappaB
      activation. PGG inhibited IL-8 production and gene expression in human monocytic
      U937 cells stimulated with phorbol myristate acetate (PMA), as measured by enzyme
      linked immunosorbent assay and reverse transcription-polymerase chain reaction
      analysis, respectively. PGG also inhibited PMA-mediated NF-kappaB activation, as
      measured by electromobility shift assay. Furthermore, PGG prevented PMA-mediated
      degradation of the NF-kappaB inhibitory protein I-kappaBalpha, as measured by
      Western blot analysis. PGG also inhibited both IL-8 production and NF-kappaB
      activation in the U937 cells stimulated with tumor necrosis factor-alpha. These
      results suggest that PGG, a major constituent of the root cortex of Paeonia
      suffruticosa ANDREWS, can inhibit IL-8 gene expression by a mechanism involving
      its inhibition of NF-kappaB activation, which is dependent on I-kappaBalpha
      degradation.

PMID- 15037217
TI  - Coimmunization of Agaricus blazei Murill extract with hepatitis B virus core
      protein through DNA vaccine enhances cellular and humoral immune responses.
AB  - DNA vaccines induce protective humoral and cell-mediated immune responses in
      several animal models. Agaricus blazei Murill (ABM) is particularly rich in
      polysaccharides, and has shown particularly strong results in treating and
      preventing cancers. The goal of this study was to investigate whether co
      immunization of the fungus ABM with hepatitis B virus (HBV) core DNA vaccine
      could increase the immune responses. Compared with the control mice which
      received hepatitis B virus core antigen (HBcAg) alone, significant increase in
      not only the HBcAg-specific antibody response but also T cell proliferation was
      observed in mice which received HBcAg DNA vaccine plus ABM extract. These results
      suggest that ABM extract might represent an adjuvant to improve the efficacy of
      DNA vaccines in vivo.

PMID- 15037216
TI  - DNA array analysis of altered gene expression in human leukocytes stimulated with
      soluble and particulate forms of Candida cell wall beta-glucan.
AB  - We previously reported that 1,3-beta-d-glucan derived from Candida albicans, a
      pathogenic fungus was obtained by oxidation of the cell wall with sodium
      hypochlorite (NaClO). It could be solubilized by treatment with dimethylsulfoxide
      (DMSO). We found that OX-CA and CSBG showed significantly different levels of
      activity toward leukocytes. Here, we have used cDNA microarrays to analyze the
      mRNA expression of 1176 genes in PBMCs stimulated with Candida cell wall glucan
      and considered the difference in the activation mechanism of OX-CA and CSBG.
      Total mRNA showed a significant change for 147 out of 1176 arrayed genes on
      stimulation with OX-CA and CSBG for 4 h. Among those genes, 62 were common, 26
      were OX-CA-specific and 59 were CSBG-specific. Many of these up-regulated genes
      encode effectors with well-characterized proinflammatory properties. The
      expression of genes related with signal transduction differed in the particulate
      and soluble glucans derived from C. albicans having exactly the same primary
      structure. This fact suggested that each glucan induced specific biological
      activity through a different activation mechanism. This study using cDNA
      microarrays to analyze a broad spectrum of mRNA expression provides information
      on the biological activity of Candida cell wall glucan as a potential pathogenic
      factor.

PMID- 15037218
TI  - Mannan from Aloe saponaria inhibits tumoral cell activation and proliferation.
AB  - In this study, we tested the antiproliferative effects of mannan from Aloe
      saponaria using normal murine (SpMC) and human cells (PBMC) and several tumoral
      cell lines. Employing flow cytometry, it could be determined that mannan inhibits
      the proliferative response in normal and tumoral cells. Mannan affects the
      expression of CD3(+) SpMC indicating that mannan inhibits mainly T lymphocyte
      proliferative response. Also in SpMC cultured with or without mitogen mannan
      produces an increase of an activation marker (CD25). On C1498 cell line, mannan
      reduces CD3 expression and abolishes the CD25 expression. In conclusion, mannan
      has a dual beneficial effect when applied to normal and tumoral cells at the same
      time by inhibiting the activation of cancer cells and improving that of normal
      ones.

PMID- 15037219
TI  - Buprenorphine produces naltrexone reversible alterations of immune status.
AB  - Substantial evidence demonstrates that administration of high efficacy mu opioid
      agonists such as morphine modulate the immune response in a dose-dependent and
      pharmacologically specific manner, indicating functional interactions between the
      opioid and immune systems. In contrast to the well-characterized immunomodulatory
      effects of high efficacy mu opioids, little is known about how these effects
      generalize to other clinically employed opioids and agonists of varying degrees
      of mu opioid receptor stimulation. Buprenorphine is a mu opioid agonist of
      intermediate efficacy that is used clinically for pain management and has
      recently been approved for the treatment of opioid dependence. Recent evidence
      indicates pharmacological and mechanistic differences between buprenorphine and
      morphine. Therefore, the aim of the present study was to investigate whether
      buprenorphine also possesses immunomodulatory properties. The results demonstrate
      that buprenorphine dose-dependently suppresses splenic natural killer cell
      activity, lymphocyte proliferation and IFN-gamma production in rats in a
      naltrexone reversible manner, demonstrating pharmacological specificity of
      buprenorphine-induced immune alterations.

PMID- 15037221
TI  - Sulfur mustard primes phagocytosis and degranulation in human polymorphonuclear
      leukocytes.
AB  - Sulfur mustard (2,2'-bis-chloroethyl-sulfide; SM) is a chemical warfare vesicant
      that causes debilitating skin lesions. Although a great deal of work has focused
      on the direct effects of SM exposure on the epithelium, it is unclear how much
      the inflammatory response, induced by exposure, contributes to lesion
      pathogenesis. Keratinocytes exposed to SM express a number of inflammatory
      mediators and elicit a cellular infiltrate consisting largely of
      polymorphonuclear leukocytes (PMN). PMN infiltration into SM lesions occurs as
      early as 30 min and peaks after several hours postexposure, and, despite the
      relatively short half-life of SM, PMN infiltrating a lesion could be exposed to
      micromolar concentrations of the agent. Previously, we have shown that exposure
      to low doses of sulfur mustard prime oxidative function in human PMN. The current
      study was undertaken to evaluate the effects of low-dose SM exposure on PMN
      phagocytosis, degranualtion and chemotaxis. PMN exposed to low doses of SM (50
      200 microM) showed a dose-dependent enhancement of phagocytic function.
      Exocytosis of PMN azurophilic and specific granules [determined by analysis of
      granule-specific intravesicular receptors, Interleukin 10 receptor (IL-10R) and
      CD63] was also enhanced by SM exposure. Finally, we examined the effect of SM as
      a chemoattractant for PMN and show that SM is not itself a chemotaxin. These
      results suggest that SM injury may, in part, be caused by normal inflammatory
      function, and that therapeutic strategies aimed at down-regulating PMN activation
      could lessen the severity of SM injury and the time required for its resolution.

PMID- 15037220
TI  - Immunomodulatory effect of caffeic acid phenethyl ester in Balb/c mice.
AB  - Caffeic acid phenethyl ester (CAPE), an the active component of propolis, is
      known to have anticarcinogenic, antiviral and various biological activities;
      however, the effect of CAPE on the immunomodulatory activity in vivo remains
      unknown. We have investigated the effect of CAPE on the immune system in female
      Balb/c mice. CAPE (0, 5, 10, 20 mg/kg) was given to mice orally for 14 days.
      Immunomodulatory activity was evaluated by assessment of body and organ weight,
      lymphocyte blastogenesis, plaque-forming cell (PFC) assay, lymphocyte
      subpopulation by flow cytometry and cytokine production. Even though the change
      of body weight was not observed in CAPE-administered group, thymus weight and/or
      cellularity of thymus and spleen are decreased at the all dose groups of CAPE (5,
      10, 20 mg/kg). On the other hand, CAPE had no effect on B lymphocyte
      proliferation induced by lipopolysaccharide (LPS) but increased T lymphocyte
      blastogenesis induced by concanavalin A (Con A) at the dose of 20 mg/kg. In the
      case of lymphocyte subpopulation, the population of T and B cells was not changed
      but CD4(+) T cell subsets are significantly increased in exposure to CAPE. The
      antibody responses to T lymphocyte dependent antigen, sheep red blood cell and
      keyhole limpet hemocyanin (KLH) were increased more than 10 mg/kg in CAPE-treated
      group. Likewise, the cytokine, IL-2, IL-4 and IFN-gamma were significantly
      increased at the dose of 20 mg/kg CAPE group. These results suggest that CAPE
      could have immunomodulatory effects in vivo.

PMID- 15037222
TI  - Deferoxamine administration in septic animals: improved survival and altered
      apoptotic gene expression.
AB  - BACKGROUND: Oxidative damage is one of the major factors that lead to cell
      damage, organ dysfunction and death in sepsis. Thus, an attractive candidate for
      the pharmacologic treatment of the septic syndrome is desferoxamine (DFX), an
      antioxidant iron chelator used for the removal of iron and a potential free
      radical scavenger. OBJECTIVE: The impact of DFX administration on the survival of
      septic animals. The effect on cell integrity and cycle of vital organs. METHODS:
      Sepsis was induced in 40 rats using the cecal ligation and puncture method (CLP)
      and 20 rats randomly received twice subcutaneously DFX (total dose: 40 mg/kg).
      Rats were monitored for 36 h and all vital organs were harvested for pathology
      examination and immunohistochemical detection of Bax, Bcl-2, cytochrome c and
      caspase-8 apoptosis regulating proteins. RESULTS: Mean survival in the DFX group
      was 34.2 h (median 36.0, S.D. 4.4) and 30.2 h (median 36.0, S.D. 9.1) in the
      control group (p=0.04), while 36 h after follow up 85% of the DFX-treated rats
      and 55% of placebo rats were alive (p=0.04). Expression of pro-apoptotic bax
      protein was significantly increased in the heart, liver and kidney of animals in
      the DFX group compared to the control group. CONCLUSIONS: Treatment with the
      polymeric iron chelator DFX significantly increases survival of septic subjects
      and alters the expression of bax, an apoptosis regulating protein in certain
      organs (heart, liver and kidney).

PMID- 15037223
TI  - Effects of Chinese medicinal fungus water extract on tumor metastasis and some
      parameters of immune function.
AB  - The effects of the immunomodulation and antitumor metastasis of the Chinese
      medicinal fungus water extract (FWE) were investigated. After B16 melanoma cells
      were implanted in C57BL/6 mice through their tail veins, the mice were orally
      administered by FWE at low dose (160 mg/kg/day) and high dose (400 mg/kg/day) for
      14 days. The tumor metastatic foci on the lung surface were observed under
      dissecting microscope. Phagocytosis of peritoneal macrophages was detected
      through ingesting chicken red blood cells (CRBC) test. Lymphocyte proliferation
      and the natural killer (NK) cell activity were determined by MTT method and
      lactate-dehydrogenase (LDH)-release assay, respectively. The expressions of bcl-2
      and p53 of livers and lungs were assayed by immunohistochemical method. The
      results showed that FWE could increase body weights of mice dose dependently. The
      lung metastasis inhibition rates (MIR) of B16 melanoma cells by low dose and high
      dose of FWE were 15.5% and 72.7%, respectively. FWE at the two doses enhanced
      significantly (p<0.05) the phagocytosis, which was evaluated using the phagocytic
      rate (PR) and phagocytic index (PI). FWE had significantly promoted mice' NK
      activity at high dose (p<0.001). Lymphocyte proliferation was not significantly
      elevated in both of low- and high-dose groups. FWE depressed the levels of bcl-2
      and p53 protein in the liver and lung cells at both of the two doses. These
      results indicate that FWE not only promoted the mouse's immunity, but also
      inhibited tumor metastasis.

PMID- 15037224
TI  - Cyclosporine reduces hepatic antioxidant capacity: protective roles of
      antioxidants.
AB  - The immunosuppressive agent cyclosporine A (CsA) has been reported to exert
      measurable hepatotoxic effects. One of the causes leading to hepatotoxicity is
      thought to be reactive oxygen radical formation. Therefore, this study was
      designed to elucidate possible relation between cyclosporine A treatment and
      antioxidant capacity (AOC) of hepatic tissue and, to determine if antioxidant
      supplementation is beneficial. Cyclosporine A was given to 20 rabbits orally for
      10 days. Vitamins E and C combination were given intramuscularly. Vitamin therapy
      was started 3 days before cyclosporine A treatment and continued for 10 days. In
      each group (control, cyclosporine A, cyclosporine A+vitamin, and vitamin only)
      there were five animals. After the animals were sacrificed, their livers were
      removed to be used in the AOC measurement. AOC was found to be lower in
      cyclosporine A group compared to control and vitamin groups. Results suggest that
      reduced antioxidant capacity may play part in the cyclosporine A-induced
      hepatotoxicity and use of some antioxidants may give beneficial results.

PMID- 15037225
TI  - Improving drug discovery output--starting with the early discovery enterprise.

PMID- 15037226
TI  - Stuart Schreiber: biology from a chemist's perspective. Interview by Joanna
      Owens.
AB  - Stuart L. Schreiber is Morris Loeb Professor and Chair of the Department of
      Chemistry and Chemical Biology at Harvard University, and an Investigator at the
      Howard Hughes Medical Institute. He founded Harvard's ICCB and directs the NIH
      funded Initiative for Chemical Genetics (ICG). He is also a faculty member of the
      Broad Institute, a joint initiative by Harvard University and MIT that is
      'dedicated to leveraging different disciplines to create a new toolkit for
      genomic medicine'. Following doctoral studies at Harvard University in the
      laboratory of R. B. Woodward and Y. Kishi, he joined the faculty at Yale
      University in 1981, where he was promoted to Full Professor in 1986. In 1988, he
      returned to Harvard, where, in addition to his main roles described above, he is
      an affiliate of both the Harvard Department of Molecular and Cellular Biology and
      Harvard Medical School Department of Cell Biology. He is also a member of the
      Graduate Programs in Biophysics at Harvard University and in Immunology at the
      Harvard Medical School. In keeping with his multiple roles at Harvard, Schreiber
      is renowned for taking an integrative and systematic approach to exploring
      biology. His pioneering work in the field of chemical biology has resulted in the
      characterisation of many cellular pathways, including (in collaboration with
      researchers at Stanford University) the identification of the calcium-calcineurin
      NFAT signalling pathway. His lab has developed several methodologies including
      diversity-oriented synthesis (DOS) and in 2003 launched the Chembank public
      database (), a suite of informatic tools and databases to promote the use of
      chemical genetics. Schreiber has received many awards and honours including the
      Tetrahedron Prize for Creativity in Organic Chemistry (1997) and most recently
      the Society for Biomolecular Screening Achievement Award (2004). He has founded
      several successful biotechnology firms, including Vertex Pharmaceuticals in 1989,
      ARIAD Pharmaceuticals in 1991, and Infinity Pharmaceuticals in 2001. He was also
      founding editor of the journal Chemistry & Biology, which is now in its tenth
      year of publication.

PMID- 15037227
TI  - Getting more mileage out of a tankful of new molecular entities?

PMID- 15037228
TI  - Multidimensional separation and hyphenated techniques in pharmaceutical research:
      practical considerations.

PMID- 15037229
TI  - RNAi and siRNA in target validation.

PMID- 15037231
TI  - Strategies for dealing with metabolite elucidation in drug discovery and
      development.
AB  - Structural information on metabolites can be a considerable asset for enhancing
      and streamlining the process of developing new drug candidates. Modern approaches
      that generate and use metabolite structural information can accelerate the drug
      discovery and development process by eliminating potentially harmful candidates
      earlier in the process and improving the safety of new drugs. This review
      examines the relative merits of current and potential strategies for dealing with
      metabolite characterization.

PMID- 15037230
TI  - Revival of the regulatory T cell: new targets for drug development.
AB  - Compelling new evidence supports the idea that regulatory T cells play a major
      role in our immune system. Several subsets of these regulators have been
      identified recently. Differences in the phenotypical and functional
      characteristics of these subsets have immunological implications. From our
      growing knowledge of the field of immunology, we could potentially generate a new
      class of therapeutic agents that target immune-related diseases.

PMID- 15037232
TI  - Proceedings of the 5th International Conference on AAA+ Proteins. June, 2003.
      Warrenton, Virginia, USA.

PMID- 15037233
TI  - Phylogenetic analysis of AAA proteins.
AB  - AAA ATPases form a large protein family with manifold cellular roles. They belong
      to the AAA+ superfamily of ringshaped P-loop NTPases, which exert their activity
      through the energy-dependent unfolding of macromolecules. Phylogenetic analyses
      have suggested the existence of five major clades of AAA domains (proteasome
      subunits, metalloproteases, domains D1 and D2 of ATPases with two AAA domains,
      and the MSP1/katanin/spastin group), as well as a number of deeply branching
      minor clades. These analyses however have been characterized by a lack of
      consistency in defining the boundaries of the AAA family. We have used cluster
      analysis to delineate unambiguously the group of AAA sequences within the AAA+
      superfamily. Phylogenetic and cluster analysis of this sequence set revealed the
      existence of a sixth major AAA clade, comprising the mitochondrial, membrane
      bound protein BCS1 and its homologues. In addition, we identified several deep
      branches consisting mainly of hypothetical proteins resulting from genomic
      projects. Analysis of the AAA N-domains provided direct support for the obtained
      phylogeny for most branches, but revealed some deep splits that had not been
      apparent from phylogenetic analysis and some unexpected similarities between
      distant clades. It also revealed highly degenerate D1 domains in plant MSP1
      sequences and in at least one deeply branching group of hypothetical proteins
      (YC46), showing that AAA proteins with two ATPase domains arose at least three
      times independently.

PMID- 15037234
TI  - Evolutionary history and higher order classification of AAA+ ATPases.
AB  - The AAA+ ATPases are enzymes containing a P-loop NTPase domain, and function as
      molecular chaperones, ATPase subunits of proteases, helicases or nucleic-acid
      stimulated ATPases. All available sequences and structures of AAA+ protein
      domains were compared with the aim of identifying the definitive sequence and
      structure features of these domains and inferring the principal events in their
      evolution. An evolutionary classification of the AAA+ class was developed using
      standard phylogenetic methods, analysis of shared sequence and structural
      signatures, and similarity-based clustering. This analysis resulted in the
      identification of 26 major families within the AAA+ ATPase class. We also
      describe the position of the AAA+ ATPases with respect to the RecA/F1, helicase
      superfamilies I/II, PilT, and ABC classes of P-loop NTPases. The AAA+ class
      appears to have undergone an early radiation into the clamp-loader,
      DnaA/Orc/Cdc6, classic AAA, and "pre-sensor 1 beta-hairpin" (PS1BH) clades.
      Within the PS1BH clade, chelatases, MoxR, YifB, McrB, Dynein-midasin, NtrC, and
      MCMs form a monophyletic assembly defined by a distinct insert in helix-2 of the
      conserved ATPase core, and additional helical segment between the core ATPase
      domain and the C-terminal alpha-helical bundle. At least 6 distinct AAA+
      proteins, which represent the different major clades, are traceable to the last
      universal common ancestor (LUCA) of extant cellular life. Additionally,
      superfamily III helicases, which belong to the PS1BH assemblage, were probably
      present at this stage in virus-like "selfish" replicons. The next major
      radiation, at the base of the two prokaryotic kingdoms, bacteria and archaea,
      gave rise to several distinct chaperones, ATPase subunits of proteases, DNA
      helicases, and transcription factors. The third major radiation, at the outset of
      eukaryotic evolution, contributed to the origin of several eukaryote-specific
      adaptations related to nuclear and cytoskeletal functions. The new relationships
      and previously undetected domains reported here might provide new leads for
      investigating the biology of AAA+ ATPases.

PMID- 15037235
TI  - Multiple binding proteins suggest diverse functions for the N-ethylmaleimide
      sensitive factor.
AB  - The hexameric ATPase, N-ethylmaleimide sensitive factor (NSF), is essential to
      vesicular transport and membrane fusion because it affects the conformations and
      associations of the soluble NSF attachment protein receptor (SNARE) proteins. NSF
      binds SNAREs through adaptors called soluble NSF attachment proteins (alpha- or
      beta-SNAP) and disassembles SNARE complexes to recycle the monomers. NSF contains
      three domains, two nucleotide-binding domains (NSF-D1 and -D2) and an amino
      terminal domain (NSF-N) that is required for SNAP-SNARE complex binding.
      Mutagenesis studies indicate that a cleft between the two sub-domains of NSF-N is
      critical for binding. The structural conservation of N domains in NSF, p97/VCP,
      and VAT suggests that a similar type of binding site could mediate substrate
      recognition by other AAA proteins. In addition to SNAP-SNARE complexes, NSF also
      binds other proteins and protein complexes such as AMPA receptor subunits
      (GluR2), beta2-adrenergic receptor, beta-Arrestin1, GATE-16, LMA1, rabs, and rab
      containing complexes. The potential for these interactions indicates a broader
      role for NSF in the assembly/disassembly cycles of several cellular complexes and
      suggests that NSF may have specific regulatory effects on the functions of the
      proteins involved in these complexes. The structural requirements for these
      interactions and their physiological significance will be discussed.

PMID- 15037236
TI  - Molecular perspectives on p97-VCP: progress in understanding its structure and
      diverse biological functions.
AB  - The 97-kDa valosin-containing protein (p97 or VCP) is a type-II AAA ( ATPases
      associated with a variety of activities) ATPases, which are characterized by
      possessing two conserved ATPase domains. VCP forms a stable homo-hexameric
      structure, and this two-tier ring-shaped complex acts as a molecular chaperone
      that mediates many seemingly unrelated cellular activities. The involvement of
      VCP in the ubiquitin-proteasome degradation pathway and the identification of VCP
      cofactors provided us important clues to the understanding of how this molecular
      chaperone works. In this review, we summarize the reported biological functions
      of VCP and explore the molecular mechanisms underlying the diverse cellular
      functions. We discuss the structural and biochemical studies, and elucidate how
      this sophisticated enzymatic machine converts chemical energy into the mechanical
      forces required for the chaperone activity.

PMID- 15037237
TI  - Design and regulation of the AAA+ microtubule motor dynein.
AB  - Dyneins are highly complex molecular motors that transport their attached cargo
      towards the minus end of microtubules. These enzymes are required for many
      essential motile activities within the cytoplasm and also power eukaryotic cilia
      and flagella. Each dynein contains one or more heavy chain motor units that
      consist of an N-terminal stem domain that is involved in cargo attachment, and
      six AAA+ domains (AAA1-6) plus a C-terminal globular segment that are arranged in
      a heptameric ring. At least one AAA+ domain (AAA1) is capable of ATP binding and
      hydrolysis, and the available data suggest that one or more additional domains
      also may bind nucleotide. The ATP-sensitive microtubule binding site is located
      at the tip of a 10nm coiled coil stalk that emanates from between AAA4 and AAA5.
      The function of this motor both in the cytoplasm and the flagellum must be
      tightly regulated in order to result in useful work. Consequently, dyneins also
      contain a series of additional components that serve to define the cargo-binding
      properties of the enzyme and which act as sensors to transmit regulatory inputs
      to the motor units. Here we describe the two basic dynein designs and detail the
      various regulatory systems that impinge on this motor within the eukaryotic
      flagellum.

PMID- 15037238
TI  - Recruitment of host ATP-dependent proteases by bacteriophage lambda.
AB  - Upon infection of a bacterial cell, the temperate bacteriophage lambda executes a
      regulated temporal program with two possible outcomes: (1) Cell lysis and virion
      production or (2) establishment of a dormant state, lysogeny, in which the phage
      genome (prophage) is integrated into the host chromosome. The prophage is
      replicated passively as part of the host chromosome until it is induced to resume
      the lytic cycle. In this review, we summarize the evidence that implicates every
      known ATP-dependent protease in the regulation of specific steps in the phage
      life cycle. The proteolysis of specific regulatory proteins appears to fine-tune
      phage gene expression. The bacteriophage utilizes multiple proteases to
      irreversibly inactivate specific regulators resulting in a temporally regulated
      program of gene expression. Evolutionary forces may have favored the utilization
      of overlapping protease specificities for differential proteolysis of phage
      regulators according to different phage life styles.

PMID- 15037239
TI  - Chaperone networks in bacteria: analysis of protein homeostasis in minimal cells.
AB  - The prevention of aberrant behavior of proteins is fundamental to cellular life.
      Protein homeostatic processes are present in cells to stabilize protein
      conformations, refold misfolded proteins, and degrade proteins that might be
      detrimental to the cell. Molecular chaperones and proteases perform a major role
      in these processes. In bacteria, the main cytoplasmic components involved in
      protein homeostasis include the chaperones trigger factor, DnaK/DnaJ/GrpE,
      GroEL/GroES, HtpG, as well as ClpB and the proteases ClpXP, ClpAP, HslUV, Lon,
      and FtsH. Based on recent genome sequencing efforts, it was surprising to find
      that the Mycoplasma, a genus proposed to include a minimal form of cellular life,
      do not contain certain major members of the protein homeostatic network,
      including GroEL/GroES. We propose that, in mycoplasmas, there has been a
      fundamental shift towards favoring processes that promote protein degradation
      rather than protein folding. The arguments are based on two different premises:
      (1) the regulation of stress response in Mycoplasma and (2) the unique
      characteristics of the Mycoplasma proteome.

PMID- 15037240
TI  - Broad yet high substrate specificity: the challenge of AAA+ proteins.
AB  - AAA+ proteins remodel target substrates in an ATP-dependent manner, an activity
      that is of central importance for a plethora of cellular processes. While sharing
      a similar hexameric structure AAA+ proteins must exhibit differences in substrate
      recognition to fulfil their diverse biological functions. Here we describe
      strategies of AAA+ proteins to ensure substrate specificity. AAA domains can
      directly mediate substrate recognition, however, in general extra domains, added
      to the core AAA domain, control substrate interaction. Such extra domains may
      either directly recognize substrates or serve as a platform for adaptor proteins,
      which transfer bound substrates to their AAA+ partner proteins. The positioning
      of adaptor proteins in substrate recognition can enable them to control the
      activity of their partner proteins by coupling AAA+ protein activation to
      substrate availability.

PMID- 15037241
TI  - The ClpB/Hsp104 molecular chaperone-a protein disaggregating machine.
AB  - ClpB and Hsp104 (ClpB/Hsp104) are essential proteins of the heat-shock response
      and belong to the class 1 family of Clp/Hsp100 AAA+ ATPases. Members of this
      family form large ring structures and contain two AAA+ modules, which consist of
      a RecA-like nucleotide-binding domain (NBD) and an alpha-helical domain.
      Furthermore, ClpB/Hsp104 has a longer middle region, the ClpB/Hsp104-linker,
      which is essential for chaperone activity. Unlike other Clp/Hsp100 proteins,
      however, ClpB/Hsp104 neither associates with a cellular protease nor directs the
      degradation of its substrate proteins. Rather, ClpB/Hsp104 is a bona fide
      molecular chaperone, which has the remarkable ability to rescue proteins from an
      aggregated state. The full recovery of these proteins requires the assistance of
      the cognate DnaK/Hsp70 chaperone system. The mechanism of this "bi-chaperone"
      network, however, remains elusive. Here we review the current understanding of
      the structure-function relationship of the ClpB/Hsp104 molecular chaperone and
      its role in protein disaggregation.

PMID- 15037242
TI  - Crystal structure of the AAA+ alpha domain of E. coli Lon protease at 1.9A
      resolution.
AB  - The crystal structure of the small, mostly helical alpha domain of the AAA+
      module of the Escherichia coli ATP-dependent protease Lon has been solved by
      single isomorphous replacement combined with anomalous scattering and refined at
      1.9A resolution to a crystallographic R factor of 17.9%. This domain, comprising
      residues 491-584, was obtained by chymotrypsin digestion of the recombinant full
      length protease. The alpha domain of Lon contains four alpha helices and two
      parallel strands and resembles similar domains found in a variety of ATPases and
      helicases, including the oligomeric proteases HslVU and ClpAP. The highly
      conserved "sensor-2" Arg residue is located at the beginning of the third helix.
      Detailed comparison with the structures of 11 similar domains established the
      putative location of the nucleotide-binding site in this first fragment of Lon
      for which a crystal structure has become available.

PMID- 15037243
TI  - FtsH exists as an exceptionally large complex containing HflKC in the plasma
      membrane of Escherichia coli.
AB  - FtsH is an ATP-dependent and membrane-associated protease, which exerts
      processive proteolysis against membrane-embedded and soluble substrate proteins.
      Although previous studies suggested that it functions as a homo-oligomer and it
      also interacts with HflK-HflC membrane protein complex (HflKC), it is still
      important to address the question of what kind of supramolecular assembly FtsH
      forms in wild-type cells. Now we show that FtsH in wild-type Escherichia coli
      cells exists exclusively as a large complex, termed FtsH holo-enzyme, which can
      be separated from bulk of membrane proteins after detergent solubilization and
      velocity sedimentation. This complex appears to have molecular mass of around
      1000 kDa. A tentative model is presented that it is composed of hexamers of FtsH
      and of HflKC, with an ability to bind one or a few substrate molecules.

PMID- 15037244
TI  - Effects of local protein stability and the geometric position of the substrate
      degradation tag on the efficiency of ClpXP denaturation and degradation.
AB  - ClpX and related AAA+ ATPases of the Clp/Hsp100 family are able to denature
      native proteins. Here, we explore the role of protein stability in ClpX
      denaturation and subsequent ClpP degradation of model substrates bearing ssrA
      degradation tags at different positions. ClpXP degraded T. thermophilus RNase-H*
      with a C-terminal ssrA tag very efficiently, despite the very high global
      stability of this thermophilic protein. In fact, global thermodynamic stability
      appears to play little role in susceptibility to degradation, as a far less
      stable RNase-H*-ssrA mutant was degraded more slowly than wild type by ClpXP and
      a completely unfolded mutant variant was degraded less than twice as fast as the
      wild-type parent. When ssrA peptide tags were covalently linked to surface
      cysteines at positions 114 or 140 of RNase-H*, the conjugates were proteolyzed
      very slowly. This resistance to degradation was not caused by inaccessibility of
      the ssrA tag or an inability of ClpXP to degrade proteins with side-chain linked
      ssrA tags. Our results support a model in which ClpX denatures proteins by
      initially unfolding structural elements attached to the degradation tag, suggest
      an important role for the position of the degradation tag and direction of force
      application, and correlate well with the mapping of local protein stability
      within RNase-H* by native-state hydrogen exchange.

PMID- 15037245
TI  - Kinetics of protein substrate degradation by HslUV.
AB  - The HslUV protease-chaperone complex degrades specific protein substrates in an
      ATP-dependent reaction. Current models propose that the HslU chaperone, a AAA
      protein of the Clp/Hsp100 family, binds and unfolds substrates and translocates
      the polypeptide into the catalytic cavity of the HslV protease. These processes
      are being characterized using substrates that are targeted to HslUV with a
      carboxy-terminal fusion of the natural substrate SulA or the carboxy-terminal 11
      amino acid residues thereof. In a tandem fusion of green fluorescent protein with
      SulA, HslUV degrades the SulA moiety but not green fluorescent protein. Wild type
      and mutant Arc repressor variants are degraded; over a range of substrate
      stabilities, the specific rate of degradation and its dependence on substrate
      stability is similar to that of ClpXP. For a hyperstable Arc variant having an
      intermolecular disulfide bond, the rate of degradation by HslUV is an order of
      magnitude slower than by ClpXP. Similarity in degradation rates for a subset of
      substrates by HslUV and ClpXP suggests a similarity in mechanism of the apparent
      rate-limiting steps of unfolding and translocation by the chaperone components
      HslU and ClpX. The fall-off in degradation by HslUV for the more stable
      substrates that are degraded by ClpXP is consistent with the two systems acting
      on different spectra of biological substrates.

PMID- 15037246
TI  - Spectrometric analysis of degradation of a physiological substrate sigma32 by
      Escherichia coli AAA protease FtsH.
AB  - We have established a fluorescence polarization assay system by which degradation
      of sigma32, a physiological substrate, by FtsH can be monitored
      spectrometrically. Using the system, it was found that an FtsH hexamer degrades
      approximately 0.5 molecules of Cy3-sigma32 per min at 42 degrees C and hydrolyzes
      approximately 140 ATP molecules during the degradation of a single molecule of
      Cy3-sigma32. Evidence also suggests that degradation of sigma32 proceeds from the
      N-terminus to the C-terminus. Although FtsH does not have a robust enough
      unfoldase activity to unfold a tightly folded proteins such as green fluorescent
      protein, it can unfold proteins with lower T(m)s such as glutathione S
      transferase (T(m) = 52 degrees C).

PMID- 15037247
TI  - The N-terminal coiled coil of the Rhodococcus erythropolis ARC AAA ATPase is
      neither necessary for oligomerization nor nucleotide hydrolysis.
AB  - Deletion mutants of the Rhodococcus erythropolis ARC AAA ATPase were generated
      and characterized by biochemical analysis and electron microscopy. Based on
      sequence comparisons the ARC protein was divided into three consecutive regions,
      the N-terminal coiled coil, the central ARC-specific inter domain and the C
      terminal AAA domain. When the ARC AAA domain was expressed separately it formed
      aggregates of undefined structure. However, when the AAA domain was expressed in
      conjunction with the preceeding inter domain, but without the N-terminal coiled
      coil, high-molecular weight-complexes were formed (ARC-DeltaCC) which showed an N
      ethylmaleimide-sensitive ATPase activity. In 2D crystallization experiments the
      ARC-DeltaCC particles yielded crystals nearly identical to those formed by the
      wild-type ARC complexes. Thus, the N-terminal coiled coil, which was proposed to
      have a role in the assembly of and/or interaction between the eukaryotic AAA
      ATPases in the 26S proteasome, is neither essential for assembly nor for ATP
      hydrolysis of the ARC ATPase. The N-terminal domain of related AAA ATPases
      mediates the interaction with substrates or co-factors, suggesting a regulatory
      function for the N-terminal coiled coil of the ARC ATPase. Surprisingly, the
      mutant ARC protein ARC-DeltaAAA consisting of the N-terminal coiled coil and the
      central inter domain, but deleted for the C-terminal AAA domain, was shown to
      form a dodecameric complex with sixfold symmetry. This suggests an important role
      of the inter domain for the ordered assembly of the ARC ATPase.

PMID- 15037248
TI  - Crystallographic investigation of peptide binding sites in the N-domain of the
      ClpA chaperone.
AB  - Escherichia coli ClpA, an Hsp100/Clp chaperone and an integral component of the
      ATP-dependent ClpAP protease, participates in the dissolution and degradation of
      regulatory proteins and protein aggregates. ClpA consists of three functional
      domains: an N-terminal domain and two ATPase domains, D1 and D2. The N-domain is
      attached to D1 by a mobile linker and is made up of two tightly bound,
      identically folded alpha-helical bundles related by a pseudo 2-fold symmetry.
      Between the halves of the pseudo-dimer is a large flexible acidic loop that
      becomes better ordered upon binding of the small adaptor protein, ClpS. We have
      identified a number of structural features in the N-domain, including a Zn(++)
      binding motif, several interfaces for binding to ClpS, and a prominent
      hydrophobic surface area that binds peptides in different configurations. These
      structural motifs may contribute to binding of protein or peptide substrates with
      weak affinity and broad specificity. Kinetic studies comparing wild-type ClpA to
      a mutant ClpA with its N-domain deleted show that the N-domains contribute to the
      binding of a non-specific protein substrate but not of a folded substrate with
      the specific SsrA recognition tag. A functional model is proposed in which the N
      domains in ClpA function as tentacles to weakly hold on to proteins thereby
      enhancing local substrate concentration.

PMID- 15037250
TI  - A link between sequence conservation and domain motion within the AAA+ family.
AB  - The AAA+ family of proteins play fundamental roles in all three kingdoms of life.
      It is thought that they act as molecular chaperones in aiding the assembly or
      disassembly of proteins or protein complexes. Recent structural studies on a
      number of AAA+ family proteins have revealed that they share similar structural
      elements. These structures provide a possible link between nucleotide
      binding/hydrolysis and the conformational changes which are then amplified to
      generate mechanical forces for their specific functions. However, from these
      individual studies it is far from clear whether AAA+ proteins in general share
      properties in terms of nucleotide induced conformational changes. In this study,
      we analyze sequence conservation within the AAA+ family and identify two
      subfamilies, each with a distinct conserved linker sequence that may transfer
      conformational changes upon ATP binding/release to movements between subdomains
      and attached domains. To investigate the relation of these linker sequences to
      conformational changes, molecular dynamics (MD) simulations on X-ray structures
      of AAA+ proteins from each subfamily have been performed. These simulations show
      differences in both the N-linker peptide, subdomain motion, and cooperativity
      between elements of quaternary structure. Extrapolation of subdomain movements
      from one MD simulation enables us to produce a structure in close agreement with
      cryo-EM experiments.

PMID- 15037249
TI  - The N-terminal substrate-binding domain of ClpA unfoldase is highly mobile and
      extends axially from the distal surface of ClpAP protease.
AB  - ClpAP is a barrel-like complex consisting of hexameric rings of the ClpA ATPase
      stacked on the double heptameric ring of ClpP peptidase. ClpA has two AAA+
      domains (Dl and D2) and a 153-residue N-domain. Substrate proteins bind to the
      distal surface of ClpA and are unfolded and translocated axially into ClpP. To
      gain insight into the functional architecture of ClpA in the ATPgammaS state, we
      have determined its structure at 12A resolution by cryo-electron microscopy. The
      resulting model has two tiers, corresponding to rings of Dl and D2 domains:
      oddly, there is no sign of the N-domains in the density map. However, they were
      detected as faint diffuse density distal to the Dl tier in a difference image
      between wild-type ClpAP and a mutant lacking the N-domain. This region is also
      accentuated in a variance map of ClpAP and in a difference imaging experiment
      with ClpAP complexed with ClpS, a 12kDa protein that binds to the N-domain. These
      observations demonstrate that the N-domains are highly mobile. From molecular
      modeling, we identify their median position and estimate that they undergo
      fluctuations of at least 30A. We discuss the implications of these observations
      for the role of N-domains in substrate binding: either they effect an initial
      transient binding, relaying substrate to a second site on the Dl tier where
      unfolding ensues, or they may serve as an entropic brush to clear the latter site
      of non-specifically bound ligands or substrates bound in non-productive
      complexes.

PMID- 15037251
TI  - The structure of dynein-c by negative stain electron microscopy.
AB  - Dynein ATPases contain six concatenated AAA modules within the motor region of
      their heavy chains. Additional regions of sequence are required to form a
      functional ATPase, which a previous study suggested forms seven or eight
      subdomains arranged in either a ring or hollow sphere. A more recent homology
      model of the six AAA modules suggests that these form a ring. Therefore both the
      number and arrangement of subdomains remain uncertain. We show two-dimensional
      projection images of dynein-c in negative stain which reveal new details of its
      structure. Initial electron cryomicroscopy shows a similar overall morphology.
      The molecule consists of three domains: stem, head, and stalk. In the absence of
      nucleotide the head has seven lobes of density forming an asymmetric ring. An
      eighth lobe protrudes from one side of this heptameric ring and appears to join
      the elongated cargo-binding stem. The proximal stem is flexible, as is the stalk,
      suggesting that they act as compliant elements within the motor. A new analysis
      of pre- and post-power stroke conformations shows the combined effect of their
      flexibility on the spatial distribution of the microtubule-binding domain and
      therefore the potential range of power stroke sizes. We present and compare two
      alternative models of the structure of dynein.

PMID- 15037252
TI  - ClpA and ClpX ATPases bind simultaneously to opposite ends of ClpP peptidase to
      form active hybrid complexes.
AB  - The Escherichia coli ATP-dependent ClpAP and ClpXP proteases are composed of a
      single proteolytic component, ClpP, complexed with either of the two related
      chaperones, ClpA or ClpX. ClpXP and ClpAP complexes interact with different
      specific substrates and catalyze ATP-dependent protein unfolding and degradation.
      In vitro in the presence of ATP or ATPgammaS, ClpA and ClpX form homomeric rings
      of six subunits, which bind to one or both ends of the double heptameric rings of
      ClpP. We have observed that, when equimolar amounts of ClpA and ClpX hexamers are
      added to ClpP in vitro in the presence of ATP or ATPgammaS, hybrid complexes in
      which ClpX and ClpA are bound to opposite ends of the same ClpP are readily
      formed. The distribution of homomeric and heteromeric complexes was consistent
      with random binding of ClpA and ClpX to the ends of ClpP. Direct demonstration of
      the functionality of the heteromeric complexes was obtained by electron
      microscopy, which allowed us to visualize substrate translocation into
      proteolytically inactive ClpP chambers. Starting with hybrid complexes to which
      protein substrates specific to ClpX or ClpA were bound, translocation of both
      types of substrates was shown to occur without significant redistribution of ClpA
      or ClpX. The stoichiometric ratios of the ClpA, ClpX, and ClpP oligomeric
      complexes in vivo are consistent with the predominance of heteromeric complexes
      in growing cells. Thus, ClpXAP is a bifunctional protease whose two ends can
      independently target different classes of substrates.

PMID- 15037253
TI  - EM single particle analysis of the ATP-dependent BchI complex of magnesium
      chelatase: an AAA+ hexamer.
AB  - BchI, belonging to the AAA+ -protein family, forms the enzyme magnesium chelatase
      together with BchD and BchH. This enzyme catalyses the insertion of Mg2+ into
      protoporphyrin IX upon ATP hydrolysis. Previous studies have indicated that BchI
      forms ATP-dependent complexes and it is a member of the AAA+ -protein family
      (ATPases associated with various cellular activities) and it was suggested based
      on structural homology that the BchI formed hexameric complexes. AAA+ -proteins
      are Mg2+ -dependent ATPases that normally form oligomeric ring complexes in the
      presence of ATP. Single particle analysis of fully formed ring complexes of BchI
      observed by negative staining EM indicate that the BchI has strong 6- and 2-fold
      rotational symmetries and a weaker 4-fold rotational symmetry which are
      reminiscent of DNA helicase. A 2D average of the fully formed BchI-ATP ring
      complex is presented here from images of the complex obtained from negative
      staining EM. Other complexes are also observed in the EM micrographs and the
      class averages of these are indicative of the fragility and dynamic nature of the
      BchI complex which has been reported and they are suggestive of partially
      circular complexes with six or less protomers per particle. The resolution of the
      average circular complex is estimated at approximately 30A and it is similar in
      shape and size to an atomic resolution hexameric model of BchI rendered at 30A.

PMID- 15037254
TI  - Levels of MCM4 phosphorylation and DNA synthesis in DNA replication block
      checkpoint control.
AB  - Blockage of a DNA replication fork movement not only stabilizes the fork
      structure but also prevents initiation of DNA replication. We reported that MCM4,
      a subunit of a putative replicative DNA helicase, is extensively phosphorylated
      in the presence of hydroxyurea (HU) or after exposure to UV irradiation. Here we
      examined the relationship between levels of MCM4 phosphorylation and DNA
      synthesis during DNA replication checkpoint control and after release of the
      control. The results suggest that there is roughly inverse correlation between
      these two levels; namely the higher the level of MCM4 phosphorylation, the lower
      the level of DNA synthesis. The presence of HU or UV irradiation can stimulate
      phosphorylation at several cyclin-dependent kinase (CDK) sites in MCM4, which can
      lead to inhibition of MCM4/6/7 helicase activity. These results are consistent
      with the notion that the phosphorylation of MCM4 is involved in regulation of DNA
      synthesis in the checkpoint control.

PMID- 15037255
TI  - Analysis of the two p97/VCP/Cdc48p proteins of Caenorhabditis elegans and their
      suppression of polyglutamine-induced protein aggregation.
AB  - A class of inherited neurodegenerative diseases including Huntington's disease is
      caused by polyglutamine (polyQ) expansion in the responsible proteins. Pathology
      is typically associated with polyQ expansions of greater than 40 residues, and
      the longer the length of the expansion, the earlier the onset of disease. It has
      been reported that p97/VCP/Cdc48p, a member of AAA family of proteins, can bind
      to longer polyQ tracts. In Caenorhabditis elegans, two p97/VCP/Cdc48p homologues,
      C41C4.8 and C06A1.1, have been identified. Our results indicate that these
      p97/VCP/Cdc48p homologues have essential but redundant functions in C. elegans.
      To provide a model system for investigating the molecular basis of pathogenesis,
      we have expressed polyQ expansions fused to green fluorescent protein in the body
      wall muscle cells of C. elegans. When the repeats are longer than 40, discrete
      cytoplasmic aggregates are formed and these appear at an early stage of
      embryogenesis. The formation of aggregates was partially suppressed by co
      expression of either C41C4.8 or C06A1.1. These results suggest that these
      p97/VCP/Cdc48p homologues, AAA chaperones, may play a protective role in polyQ
      aggregation.

PMID- 15037256
TI  - Werner syndrome protein directly binds to the AAA ATPase p97/VCP in an ATP
      dependent fashion.
AB  - We have previously shown that the Werner syndrome helicase, WRNp, a member of the
      RecQ helicase family, forms a tight molecular complex with the p97/Valosin
      containing protein (VCP), a member of the AAA (ATPases associated with diverse
      cellular activities) family of proteins. This interaction is disrupted by
      chemical agents that confer DNA damage, suggesting that VCP plays an important
      role in the signal-dependent release of WRNp from its nucleolar sequestration
      site. Here, we characterized the structural requirements for interactions between
      WRNp and VCP and for the nuclear localization of VCP. We discovered that VCP
      directly binds to the RQC (RecQ conserved) domain of WRNp, which is a highly
      conserved motif common to the RecQ helicase family. This interaction is ATP
      dependent, suggesting that VCP plays a mechanistic role in releasing WRNp from
      the nucleolus. Immunohistochemical analysis of various VCP domains and mutated
      proteins expressed in vitro demonstrated that VCP may contain several
      hierarchical cellular localization motifs within its domain structure.

PMID- 15037257
TI  - Primary esophageal repair for Boerhaave's syndrome whatever the free interval
      between perforation and treatment.
AB  - OBJECTIVES: Boerhaave's syndrome is the most sinister cause of esophageal
      perforation responsible with mortality rate ranging from 20 to 30%. Combination
      of mediastinal contamination with microorganisms, gastric acid and digestives
      enzymes, long free interval between injury and initiation of treatment causes
      severe mediastinitis which is fatal in most untreated cases. The aim of this
      paper is to emphasize primary esophageal repair and resuscitation whatever the
      free interval from rupture and repair. METHODS: A retrospective review of
      patients treated for Boerhaave's syndrome in our department from January 1980 to
      February 2003 was performed. The principle of treatment was surgical treatment
      and avoidance of esophageal exclusion or esophagectomy whichever was possible.
      RESULTS: There were 25 patients (17 males and 8 females). All patients were
      operated on by primary esophageal repair, except for three who underwent
      immediate exclusion of the esophagus and one patient who deceased on arrival
      before being operated. Patients were classified according to free interval
      between perforation and treatment: group 1 (n=9; 36%) within the 24 h (range from
      12 to 24 h) and group 2 (n=16; 64%) more than 24 h (range from 2 to 17 days).
      Altogether 6 patients deceased (24%). In hospital mortality rate for groups 1 and
      2 was, respectively, 44% (four patients) and 13% (two patients), not
      significantly different. Mean hospital stay was 63 days. Two patients developed
      anastomotic leakage needing esophagectomy and retrosternal coloplasty in one or
      more steps. One patient developed pleural abscess treated by percutaneous
      drainage. Three patients presented temporary symptomatic esophageal stenosis, of
      whom one underwent dilation. CONCLUSIONS: Long free interval before treatment
      does not preclude primary esophageal repair in Boerhaave's syndrome. Esophageal
      exclusion may be more often than not avoided in most cases.

PMID- 15037258
TI  - Functional assessment of the cervical esophagus after gastric transposition and
      cervical esophagogastrostomy.
AB  - OBJECTIVES: The aim of this exploratory study was to investigate swallowing and
      function of the cervical esophagus after esophageal resection and reconstruction.
      METHODS: Nine patients (8 males, 1 female; median age 63 years), who underwent
      esophageal resection for adenocarcinoma, were studied from 6 to 40 months (median
      18 months) postoperatively. For all patients, the upper gastrointestinal tract
      was reconstructed by transposing a narrow gastric tube through the posterior
      mediastinum to the left neck, where a semi-mechanical anastomosis to the cervical
      esophagus was performed. No patient had an anatomic obstruction to swallowing or
      stricture. The oral and pharyngeal phases of deglutition and function of the
      cervical esophagus were evaluated objectively by video barium swallow,
      esophagogastroscopy, velopharyngeal examination, manometry and balloon inflation
      in the cervical esophagus. RESULTS: The median length of the cervical esophagus
      was 5 cm (range 3-7 cm). Mild reflux laryngopharyngitis was seen in all patients.
      Although all patients had an objective functional dysphagia measurement (American
      Speech-Language-Hearing Association) of 7 (normal), five reported subjective
      dysphagia. Four (of the five symptomatic) patients were found to have high
      pressure peristalitic activity (mean >100 mmHg) following balloon distention (10
      30 ml) of the cervical esophagus, which was painful in three cases. CONCLUSIONS:
      We conclude that in the absence of an anatomic cause for dysphagia after cervical
      esophagogastrostomy, a functional etiology may be explained by hypertensive
      peristalsis resulting from distention of the remaining cervical esophageal
      remnant. These findings may further explain anecdotal reports of the efficacy of
      empiric dilation after upper gastrointestinal reconstruction when no stricture is
      seen.

PMID- 15037259
TI  - Should cervical ultrasonography be a routine staging investigation for lung
      cancer patients with impalpable cervical lymph nodes?
AB  - OBJECTIVES: Detection of cervical N3 lymph nodes is currently not a routine
      preoperative investigation for lung cancer patients. We designed a study to
      assess if the frequency and accuracy of detection of metastatic cervical lymph
      nodes using cervical ultrasonography (US) and fine needle aspiration (FNA)
      justify their routine use in all lung cancer patients with impalpable cervical
      lymph nodes. METHODS: Fifty patients with suspected and potentially operable non
      small cell lung cancer were enrolled. Patients with palpable cervical lymph nodes
      were excluded. In addition to routine preoperative investigations, all patients
      received cervical US to determine the presence of cervical lymph nodes. Nodes
      suspicious of harboring malignancy according to a specific set of sonographic
      criteria (which include shape, echogenicity, nodal architecture, and vascular
      patterns) were subjected to biopsy by ultrasound-guided FNA. RESULTS: Normal
      cervical lymph nodes were detected by cervical US in 30 patients (60%). Cervical
      lymph nodes suspicious of harboring malignancy were detected in 10 patients
      (20%). FNA confirmed cervical nodal metastasis in four of these patients (8%).
      The TNM staging of two patients (4%) was revised up to stage IIIb as a result,
      excluding them from further surgery. Cost analysis suggests this technique to be
      cost-effective when used as a routine preoperative investigation to exclude
      patients from unnecessary surgical intervention. No mortality or complications
      were encountered in all patients. CONCLUSIONS: Cervical US and FNA is a safe and
      cost-effective method of evaluating the status of impalpable cervical lymph nodes
      in lung cancer patients. Further study is warranted to establish the role of
      cervical US and FNA in lung cancer staging algorithms.

PMID- 15037260
TI  - Re-evaluation of non-palpable scalene lymph node biopsy for the staging of non
      small cell lung cancer.
AB  - OBJECTIVES: The purpose of this study was to determine the most suitable
      candidates for scalene lymph node biopsy to detect non-palpable scalene lymph
      node metastasis (N(3)-scalene) in non-small cell lung cancer patients. METHODS:
      Standard cervical mediastioscopies and ipsilateral scalene lymph node biopsies
      were performed preoperatively by a single surgeon on 121 consecutive patients
      with non-small cell lung cancer scheduled to have surgical resection between
      January 1997 and August 2002, who had neither evidence of distant metastasis on
      imaging diagnosis nor palpable supraclavicular lymph nodes. RESULTS: N(3)-scalene
      was detected in six patients (5.0%), who all had non-squamous cell carcinoma,
      including one (1.0%) out of 98 patients with negative standard cervical
      mediastinoscopy and five (21.7%) out of the remaining 23 patients with positive
      mediastinal lymph node involvement. There was a significant difference in the
      incidence of the N(3)-scalene between the two groups (P<0.01). Five patients with
      N(3)-scalene had metastatic lesions in the multilevel mediastinal lymph node
      station on the same side as the cancer (multilevel N(2)), and accounted for 31.3%
      of 16 patients with multilevel N(2) disease. The N(3)-scalene was detected in 5
      (45.5%) of 11 patients with lung cancer classified as non-squamous cell carcinoma
      with multilevel N(2) disease. CONCLUSIONS: The results of the present study
      suggest that non-palpable scalene lymph node biopsy is indicated for lung cancer
      patients diagnosed as having non-squamous cell carcinoma with mediastinoscopic
      multilevel N(2) disease.

PMID- 15037261
TI  - The case for routine cervical mediastinoscopy prior to radical surgery for
      malignant pleural mesothelioma.
AB  - OBJECTIVES: To assess whether cervical mediastinoscopy is necessary before
      radical resection of malignant pleural mesothelioma (MPM). METHODS: Patients who
      underwent radical excision of MPM in a 48-month period were prospectively
      followed for evidence of disease recurrence and death. Histological evidence of
      extra pleural lymph node metastases was correlated with survival. Lymph node size
      at intraoperative lymphadenectomy was correlated with the presence of metastatic
      tumour. RESULTS: The 55 patients who underwent radical resection (51 extra
      pleural pneumonectomies and 4 radical pleurectomies) comprised 50 men and 5 women
      with a median age of 58 years, range 41-70. Histological examination revealed 50
      epithelioid, four biphasic and one sarcomatoid histology. Postoperative IMIG T
      stage was stage I 4, II 11, III 30 and IV 10. Postoperatively the 17 patients
      with metastases to the extra pleural lymph nodes had significantly shorter
      survival (median 4.4 months, 95% CI 3.2-5.4) than those without (median survival
      16.3 months, 95% CI 11.6-21.0) P=0.012 Kaplan-Meier analysis. Seventy-seven extra
      pleural lymph nodes without metastases were measured with a mean long axis
      diameter of 16.9 mm (range 4-55); 22 positive nodes had a mean long axis diameter
      of 15.2 mm (range 6-30). In 15 of the 17 patients with positive extra pleural
      nodes, the nodes could have been biopsied at cervical mediastinoscopy.
      CONCLUSIONS: This study confirms that extra pleural nodal metastases are related
      to poor survival. Pathological nodal involvement cannot be predicted from nodal
      dimensions. These data suggest that all patients being considered for radical
      resection of MPM should preferentially undergo preoperative cervical
      mediastinoscopy irrespective of radiological findings.

PMID- 15037262
TI  - Skip metastases: analysis of their clinical significance and prognosis in the
      IIIA stage of non-small cell lung cancer.
AB  - OBJECTIVE: To determine the clinical significance of skip metastases (pN2/S) in
      patients with resected pIIIA/N2 NSCLC. The incidence of pN2/S after mediastinal
      lymph node dissection (MLD) and sampling (MLS) were compared. METHOD: From 1997
      to 2000, 580 lung resections for NSCLC performed at our department. The 151
      patients (26.5%) at stage IIIA/N2 (pN2+) were grouped according to their skip
      metastases status. Group A included the ordinary pN2 (pN2/O) cases (71%) and
      group B the pN2/S (29%). Age, gender, type of resection, right or left lesion,
      histology, tumor lobe predilection, MLD or MLS pathologic results, the level and
      the number of node stations involved and survival were analyzed. RESULTS: In 44
      patients (29%) pN2/S disease was present. Statistical analysis revealed
      significant difference between pN2/O and pN2/S for the following: (1) pN2/S was
      more common for right-sided lesions (P=0.007); (2) Squamous carcinoma was the
      main type of pN2/S (P=0.007) and (3) pN2/S was more frequently detected after MLD
      than after MLS (P=0.001). Although pN2/S involved more often upper mediastinal
      lymph nodes (Nos. 2, 3) and one station level (pN2/S: 41 vs. pN2/O: 19.6%,
      P=0.228) was not found statistically significant. pN2/O was more common after
      right upper lobectomy and pN2/S after right lower lobectomy. The 3-year survival
      was more favorable for the pN2/S group (A: 24 vs. B: 36%, P=0.07). CONCLUSION:
      (1) MLD was found to be more reliable for pN2/S detection than MLS. (2) The
      presence of pN2/S proved to be a less aggressive form of lymphatic spread that
      should be taken into account in the future. (3) Strong correlation between right
      lower lobe tumors and pN2/S was demonstrated. (4) Different routes of cancer
      lymphatic spread between pN2/S and pN2/O are suggested.

PMID- 15037263
TI  - One step removal of dumb-bell tumors by postero-lateral thoracotomy and extended
      foraminectomy.
AB  - OBJECTIVE: Thoracic dumb-bell tumors are rare, usually benign tumors in the
      posterior mediastinum, consisting of intrathoracic and intraspinal parts.
      Surgical removal is the treatment of choice, performed by two teams -
      neurosurgeons and thoracic surgeons operating in a prescribed order. METHODS:
      Between 1994 and 1997 five patients had dumb-bell tumors removed in a one-step
      operation involving postero-lateral thoracotomy and extended foraminectomy. This
      operating method, rarely described in the medical literature, consists of
      intrathoracic and intraspinal parts being performed by a thoracic team
      independently or with the assistance of a neurosurgeon. Initially the
      intrathoracic part is resected, followed by an extensive widening of the
      intervertebral foramen to an appropriate extension and the removal of the
      remaining intraspinal part of the tumor. RESULTS: Four postero-lateral
      thoracotomies and one incision over a huge tumor in the thoraco-lumbal region,
      without entering the pleural cavity, were performed. In one patient
      postoperative, transient leakage of the cerebral fluid was observed. No form of
      late complications or neurologic sequelae have been reported within a 5-year
      follow-up. CONCLUSIONS: One-step removal of a dumb-bell tumor by postero-lateral
      thoracotomy and extended foraminectomy is a safe surgical procedure that can be
      performed by the thoracic team alone. Early and late surgical results confirm the
      appropriateness and usefulness of the method.

PMID- 15037264
TI  - Causes of death within 1 year of resection for lung cancer. Early mortality after
      resection.
AB  - OBJECTIVES: Some of the lung cancer patients who are treated surgically with
      curative intent ultimately die in the early postoperative period. The aim of this
      study is to analyze the causes of death within 1 year of resection for lung
      cancer in our patients. METHODS: Six hundred and twenty patients, who underwent
      resection for lung cancer with a curative intent were reviewed retrospectively.
      Eighteen patients (2.9%) died due to postoperative complications or within the
      first month and 51 (8.4%) patients (group 1) died within the first year after
      operation. Fifty-one patients (group 1) were compared with the survivors (group
      2) in terms of age, gender, preoperative FEV 1, pathological tumor node
      metastasis (TNM), histopathological subtypes, type of resection, completeness of
      the resection, preoperative Karnofsky performance status and application of
      postoperative radiotherapy. RESULTS: Pathological TNM (P<0.001) type of resection
      (P<0.01) histopathological subtype (P<0.001) completeness of the resection
      (P<0.05) and postoperative radiotherapy (P<0.001) were determined to be
      significant factors in mortality within 1 year after resection for lung cancer.
      CONCLUSIONS: The patients with pathological stage 3 disease, with large cell
      histology or who had undergone pneumonectomy have a higher risk of mortality
      within 1 year. These patients require detailed preoperative work up in terms of
      metastatic disease and cardiopulmonary physiological status.

PMID- 15037265
TI  - Carcinoembryonic antigen as a predictive factor for postoperative tumor relapse
      in early-stage lung adenocarcinoma.
AB  - OBJECTIVES: To clarify the usefulness of measuring serum carcinoembryonic antigen
      (CEA) preoperatively to detect patients who will have a poor outcome after
      surgery, and who cannot be selected by conventional staging modalities. METHODS:
      One hundred patients with adenocarcinoma of the lung underwent standard surgical
      procedures between 1994 and April 2001 at our institution. Preoperative staging
      was assessed according to the TNM classification of the International Union
      Against Cancer. The associations between preoperative serum CEA level and the
      postoperative recurrence or lymph node metastasis were examined. The serum CEA
      level was classified into two groups according to concentration of CEA level: low
      (normal) CEA (<or=5.0 ng/ml) and high CEA (>5.0 ng/ml). RESULTS: The high CEA
      level was associated with tumor relapse (P=0.01). According to the preoperative
      staging, the increased CEA was associated with tumor relapse only in stage C-IA
      (P=0.001). Stage C-IB and more advanced stages did not show an association
      between increased CEA and tumor relapse. In C-IA, risk for lymph node involvement
      was significantly higher in the high CEA group (4/9; 44.4%) than in the low CEA
      group (6/47; 12.8%, P=0.03). Furthermore, the rate of tumor relapse in C-IA-pN0
      was significantly higher in the high CEA group (4 of the 5, 80%) than in the low
      CEA group (9 of the 41, 22.0%, P=0.018). The 5-year disease-free survival rate
      for patients with a high serum CEA level (N=9) was 22.2%, and 75.0% for patients
      with a normal CEA (N=47) level (P=0.0004). CONCLUSIONS: Increased serum CEA is an
      important predictive factor for poor outcome after surgery in early-stage (C-IA)
      lung adenocarcinoma.

PMID- 15037266
TI  - Ultrastructural changes in pneumocyte type II cells following traumatic brain
      injury in rats.
AB  - OBJECTIVE: We aimed to demonstrate the time-dependent ultrastructural changes in
      pneumocyte type II cells following brain injury, and to propose an electron
      microscopic scoring model for the damage. METHODS: Forty Wistar-Albino female
      rats weighing 170-200 g were used. The rats were allocated into five groups. The
      first group was the control and the second was the craniotomy without trauma. The
      others were trauma groups. Weight-drop method was used for achieving head trauma.
      Samples were obtained from the right and left pulmonary lobes at 2-, 8-, and 24-h
      intervals after transcardiac perfusion. An electron microscopic scoring model was
      used to reveal the changes. RESULTS: There were no ultrastructural pathological
      findings pointing to lung injury in any rat of the control groups. There was
      intense intracellular oedema in type II pneumocyte and interstitial oedema in the
      adjacent tissue in trauma groups. Oedema in mitochondria and dilatation in both
      smooth endoplasmic reticulum and Golgi apparatus was more evident in the 8- and
      24-h trauma groups. The chromatin dispersion was disintegrated in the nucleus in
      all trauma groups. Scores of all trauma groups were significantly different from
      the controls (P<0.05). All trauma groups were different from each other at
      significant levels (P<0.05 for each trauma groups). CONCLUSIONS: The data
      suggested that ultrastructural damage is obvious at 2 h and deteriorates with
      time. The electron microscopic scoring model worked well in depicting the
      traumatic changes, which were supported by lipid peroxidation. Further
      experiments are needed to determine the exact outcome after brain death model.

PMID- 15037267
TI  - Protective effects of preischemic treatment with pioglitazone, a peroxisome
      proliferator-activated receptor-gamma ligand, on lung ischemia-reperfusion injury
      in rats.
AB  - OBJECTIVES: Lung injury induced by ischemia-reperfusion is the main cause of
      early graft failure after lung transplantation, which may result from oxygen-free
      radicals, inflammatory cytokine production, and polymorphonuclear leukocyte
      accumulation into the interstitium, resulting in severe lung edema. Peroxisome
      proliferator-activated receptor-gamma (PPAR-gamma) belongs to the nuclear
      receptor superfamily and has an anti-inflammatory effect by preventing the
      activation of transcription factors such as nuclear factor-kappaB (NF-kappaB). NF
      kappaB regulates the expression of many genes of early response products in the
      development of acute inflammation. We examined the effects of pioglitazone, a
      synthetic ligand of PPAR-gamma, against lung ischemia-reperfusion injury in rats.
      METHODS: The left lungs of male Wistar rats were rendered ischemic for 90 min and
      then reperfused for 2 h. Treated animals received pioglitazone (10 mg/kg) 2 h
      before induction of ischemia. Lung injury was quantified in terms of lung
      microvascular permeability (Evans blue dye extravasation), tissue lipid
      peroxidation (thiobarbituric acid reactive substances), and tissue
      polymorphonuclear leukocyte accumulation (myeloperoxidase activity). The tissue
      concentrations of tumor necrosis factor-alpha (TNF-alpha) and cytokine-induced
      neutrophil chemoattractant-1 (CINC-1) were also measured. Statistical analyses
      were performed by one-way analysis of variance, followed by Sheffe's multiple
      comparison test. RESULTS: The lung vascular permeability in pioglitazone-treated
      animals was reduced by 55% of the increase of Evans blue dye extravasation
      relative to control animals (P=0.003). The protective effects of pioglitazone
      treatment were correlated with the reduction by 79% of the increase of
      thiobarbituric acid reactive substances (P=0.045) and the reduction by 58% of
      myeloperoxidase activity increase (P<0.001). The production of TNF-alpha was
      reduced by 63% of the increase (P<0.001) and the reduction of CINC-1 was 45%
      (P<0.001). Pioglitazone did not affect the lung in the sham animals. CONCLUSIONS:
      Pioglitazone treatment before ischemia attenuated lung ischemia-reperfusion
      injury in rats. The mechanism of these protective effects involves inhibition of
      the production of proinflammatory cytokines, polymorphonuclear leukocyte
      accumulation, and tissue lipid peroxidation, resulting in reduced lung edema.

PMID- 15037268
TI  - Cardiac operations in patients with hematologic malignancies.
AB  - OBJECTIVES: Patients with hematologic malignancies are frequently in need of
      major cardiac operations. Previous reports suggest an increased risk for
      perioperative complications in these immunodeficient patients. METHODS: Patients
      diagnosed with any type of hematologic malignancy who underwent open-heart
      surgery at our institution between 7/1996 and 6/2002 were identified. Their
      hospital charts were reviewed; demographics, perioperative data and outcomes were
      recorded. RESULTS: There were 24 patients (20 men, 4 women); mean age was 68+/-13
      years (range 31-84 years). Ten patients had chronic lymphocytic leukemia, seven
      non-Hodgkin lymphomas, three multiple myeloma and one Hodgkin's disease, chronic
      myelocytic leukemia, hairy cell leukemia and cutaneous T-cell lymphoma each. The
      mean pre-operative duration of the hematologic disease was 6.6 years. Twenty-two
      patients underwent coronary artery bypass grafting (with valve replacement in
      three patients) and two patients had isolated valve replacement. There was one in
      hospital death (4.1%). Twelve patients (50%) had a minor or major complication.
      Seven reoperations were required-five during the same admission (one for
      mediastinal bleeding, one for an expanding femoral pseudoaneurysm, one for acute
      cholecystitis and two for IACD/pacer insertion) and two within 30 days (one for
      deep sternal wound infection and one for leg wound infection). Mean post
      operative stay was 8.2+/-5.8 days and mean ICU stay was 1.6+/-1.1 days. There
      were three late deaths-two were due to progression of the hematologic disease.
      The 3-year actuarial survival was 83%. CONCLUSIONS: Cardiac operations can be
      performed with acceptable mortality but significant morbidity rates in patients
      with hematologic malignancies. Bleeding and infectious complications are most
      frequently seen and usually lead to reoperations. These findings warrant caution
      during patient selection.

PMID- 15037270
TI  - Long-term outcome and quality of life of patients requiring prolonged mechanical
      ventilation after cardiac surgery.
AB  - OBJECTIVES: To study the long-term survival and quality of life of patients with
      a complicated post-operative course after cardiac surgery requiring prolonged
      (>or=7 days) mechanical ventilation (MV), since they represent a heavy burden on
      hospital resources and their outcome has never been adequately evaluated.
      METHODS: Out of 4827 consecutive cardiac surgical patients, 148 (3%) required
      prolonged post-operative MV: their hospital course was analysed and factors
      affecting prolonged MV and mortality were identified using multivariate analysis.
      Long-term survival was assessed using Cox proportional hazard method. Long-term
      (36+/-12 months) follow-up information was collected and quality of life was
      assessed by an ad hoc questionnaire. RESULTS: Overall mortality in the study
      group was 45.3 versus 2% in the control population (P<0.0001). Predictors of
      death in the prolonged MV group were age (odds ratio, OR 1.049) and diabetes (OR
      3.459). Long-term survival was significantly worse in those patients who were
      extubated after 21 days: 88.9 versus 70.9% at 1 year (P=0.03) and 80.9 versus
      64.5% at 5 years (P=0.05). Mild or no limitation in daily living was referred by
      69% of the survivors. CONCLUSIONS: The hospital mortality of patients requiring
      prolonged MV is high. The long-term survival of patients who are weaned from MV
      after 21 days is significantly lower. The great majority of the survivors can
      enjoy a good quality of life.

PMID- 15037269
TI  - Weaning from ventilator after cardiac operation using the Ciaglia percutaneous
      tracheostomy.
AB  - OBJECTIVE: To determine the predictors of weaning from mechanical ventilation
      after cardiac operation with the Ciaglia percutaneous dilatational tracheostomy
      (PDT) in our preliminary experience in the use of this technique. METHODS: We
      prospectively analysed 33 consecutive patients (mean age 70.9+/-12.7 years) who
      underwent PDT in our intensive care unit after cardiac operation. The
      investigation involved preoperative and postoperative clinical status, operative
      procedure, indication and timing for PDT. RESULTS: PDT was performed after a mean
      time of 7.7+/-5.0 consecutive days of translaryngeal intubation. Twenty-four
      (73%) patients were weaned from ventilator after a mean time of mechanical
      ventilation of 15.8+/-9.1 days. Time point of PDT was the only predictor of
      ventilator weaning (P=0.0029): there was significant association between PDT
      performed before the seventh consecutive day of translaryngeal intubation (early
      PDT) and successful weaning from ventilator (P=0.01; odds ratio=11.2, 95%
      confidence interval=1.2-104.3). Among the patients weaned from ventilator, those
      who underwent early PDT had significantly shorter times of mechanical
      ventilation, and intensive care unit and hospital stays than patients with later
      PDT (P=0.035, 0.011 and 0.0073, respectively). Nine (27%) patients died of their
      underlying disease while still being mechanically ventilated; another six (18%)
      spontaneously breathing but still incannulated patients died afterward. No major
      PDT-related complications were observed. Two minor peristomal bleedings and one
      self-resolving subcutaneous emphysema were recorded. CONCLUSIONS: Early PDT was a
      safe and effective method to wean from mechanical ventilation the cardiosurgical
      patients of this series.

PMID- 15037272
TI  - Arterial endothelial denudation by intraluminal use of papaverine-NaCl solution
      in coronary bypass surgery.
AB  - OBJECTIVES: Preservation of endothelial integrity during coronary artery bypass
      grafting is considered important for short- and long-term patency of the graft.
      In current literature there are controversial data about the safety of
      papaverine, a vasorelaxant widely used in coronary artery bypass grafting.
      Accordingly, we examined the immediate effects of papaverine on the endothelial
      morphology of arterial grafts and on viability of cultured human coronary artery
      endothelial cells. METHODS: Totally 22 segments of the radial artery were
      collected from 11 patients undergoing coronary artery bypass grafting. The
      segments were cut from the distal redundant parts of the arteries, which were not
      required for bypass grafting. A small distal segment of the artery was excised
      and placed into autologous heparinized whole blood (control segment). The rest of
      the graft, still remaining proximally attached to the circulation, was treated
      intraluminally with papaverine-NaCl solution (pH 4.2) for 5 min, after which
      another small distal segment was excised for the study (papaverine-treated
      segment). Segments were then perfusion-fixed and the endothelial surface was
      examined by scanning electron microscopy. Endothelial denudation was assessed and
      its severity graded. Additionally, viability of cultured human coronary artery
      endothelial cells after treatment with papaverine was assessed with trypan blue
      staining. RESULTS: Treatment with papaverine solution markedly increased the
      endothelial denudation (grades from 6.2+/-1.7 to 10.0+/-3.5; mean+/-SD; P=0.004).
      Papaverine-treatment increased trypan blue staining of cultured human coronary
      artery endothelial cells regardless of papaverine diluent (normal saline of pH
      4.5 or 7.4 or blood). CONCLUSIONS: Treatment of arterial grafts with papaverine
      solutions apparently damages endothelial cells. Thus, the clinical practice of
      dilating arterial bypass grafts with papaverine should be reassessed, and
      alternative methods of vasodilatation should be considered.

PMID- 15037271
TI  - Diltiazem provides higher internal mammary artery flow than nitroglycerin during
      coronary artery bypass grafting surgery.
AB  - OBJECTIVES: Perioperative internal mammary artery (IMA) vasospasm in patients
      undergoing coronary artery bypass grafting (CABG) surgery may lead to morbidity
      and mortality. Surgical stimulus is one of the common causes of IMA vasospasm.
      Preventive measures, beside treatment should be taken into consideration to
      obtain vasospasm free IMA. The effect of a pharmacologic agent on IMA flow when
      it is administered before harvesting the artery has not been documented. We
      designed a prospective randomized clinical study to compare the IMA free blood
      flows in patients receiving either diltiazem or nitroglycerin, starting infusion
      of study drugs before a surgical stimulus was applied to the IMA region and
      continuing throughout the isolation period. METHODS: Sixty patients undergoing
      elective CABG surgery with the left IMA received diltiazem (n=30, 0.05-0.1 mg/kg
      per hour) or nitroglycerin (n=30, 0.25-2.5 microg/kg per minute) in a randomized
      manner. Infusions of study drugs were started before applying a surgical stimulus
      to the IMA region and continued throughout the harvesting period. The first free
      flow was measured after IMA was cut above its bifurcation and the second after
      its distal segment was resected. Heart rate, temperature, mean arterial and
      central venous pressures were recorded. Data were analyzed with Student's t-test
      and Fischer's exact test. RESULTS: Preoperative and hemodynamic data were similar
      between the groups. The means of first and second IMA flows in patients treated
      with diltiazem (53.8+/-30.1 and 72.3+/-35.4 ml/min) were significantly higher
      than in those treated with nitroglycerin (25.7+/-16.2 and 48.9+/-23.8 ml/min;
      P=0.000, 0.004, respectively). IMA flows significantly increased after distal
      segment resection both in diltiazem (34%) and nitroglycerin groups (90%; P=
      0.000, 0.000, respectively). CONCLUSIONS: Diltiazem infusion which started prior
      to harvesting provided higher IMA blood flow compared to nitroglycerin infusion.
      Considering the percentage of increases in flows after resection of distal
      segment, the most prone part to vasospasm, we assume that a certain amount of
      spasm occurred in IMA in spite of infusion of study drugs, such that less with
      diltiazem and more with nitroglycerin. Diltiazem plays more important role than
      nitroglycerin in the prevention of vasospasm.

PMID- 15037273
TI  - Isolated high-grade lesion of the proximal LAD: a stent or off-pump LIMA?
AB  - OBJECTIVES: The objective of this study was to compare the long-term outcome of
      patients with an isolated high-grade stenosis of the left anterior descending
      (LAD) coronary artery randomized to percutaneous transluminal coronary
      angioplasty with stenting (PCI, stenting) or to off-pump coronary artery bypass
      grafting (surgery). METHODS: Patients with an isolated high-grade stenosis
      (American College of Cardiology/American Heart Association classification type
      B2/C) of the proximal LAD were randomly assigned to stenting (n=51) or to surgery
      (n=51) and were followed for 3-5 years (mean 4 years). Primary composite endpoint
      was freedom from major adverse cardiac and cerebrovascular events (MACCEs),
      including cardiac death, myocardial infarction, stroke and repeat target vessel
      revascularization. Secondary endpoints were angina pectoris status and need for
      anti-anginal medication at follow-up. Analysis was by intention to treat.
      RESULTS: MACCEs occurred in 27.5% after stenting and 9.8% after surgery (P=0.02;
      absolute risk reduction 17.7%). Freedom from angina pectoris was 67% after
      stenting and 85% after surgery (P=0.036). Need for anti-anginal medication was
      significantly lower after surgery compared to stenting (P=0.002). CONCLUSION:
      Patients with an isolated high-grade lesion of the proximal LAD have a
      significantly better 4-year clinical outcome after off-pump coronary bypass
      grafting than after PCI.

PMID- 15037274
TI  - Change in right ventricular function during off-pump coronary artery bypass graft
      surgery.
AB  - OBJECTIVES: Hemodynamic derangement during displacement of beating heart in off
      pump coronary artery bypass graft (OPCAB) surgery might be related with right
      ventricular (RV) dysfunction. We evaluated RV function and hemodynamic
      alterations using a thermodilution pulmonary artery catheter. METHODS: The study
      included 30 patients undergoing OPCAB, using single pericardial suture and tissue
      stabilizer. A thermodilution pulmonary artery catheter for continuous monitoring
      of the cardiac output (CO), right ventricular ejection fraction (RVEF) and RV
      volume was inserted before anesthesia. The hemodynamic variables were measured
      after the induction of anesthesia, 5 min after the heart was positioned for each
      coronary anastomosis and after the sternum was closed. RESULTS: There was no
      significant change in the RVEF and cardiac index during anastomosis of the left
      anterior descending artery and right coronary artery. However, the significantly
      reduced RVEF accompanied by an increase in RV afterload and decrease in the CO
      was observed during anastomosis of the obtuse marginal (OM) artery. RV volumes
      did not significantly change during anastomoses, though the right atrial pressure
      increased during anastomoses of all coronary arteries. CONCLUSIONS: The
      displacement of beating heart for positioning during anastomosis of the graft to
      OM artery caused significant derangement of RV function and decrease in CO. A
      thermodilution catheter continuously measuring the CO and RVEF was useful to
      monitor the change in RV function and volume during OPCAB.

PMID- 15037275
TI  - Arterial conduit shear stress following bypass grafting for intermediate coronary
      artery stenosis: a comparative study with saphenous vein grafts.
AB  - OBJECTIVES: Graft failure has been reported when the arterial conduit, such as
      the internal thoracic artery (ITA) or the right gastroepiploic artery (GEA), is
      grafted to a lower grade coronary artery stenosis. The shear stress as a
      significant factor affecting graft patency was compared between the arterial
      conduit and the saphenous vein graft (SVG) after surgery. METHODS: In 101
      patients, 40 ITAs, 27 GEAs and 34 SVGs were examined using a Doppler-tipped guide
      wire during postoperative angiography. The graft flow volume and shear stress
      were calculated from velocity and diameter data. The study grafts were classified
      according to the grade of native coronary artery stenosis: group L had more than
      50 up to 75% stenosis, and group H had more than 75% stenosis. Group H consisted
      of 25 ITAs, 17 GEAs and 21 SVGs, while group L consisted of 15 ITAs, 10 GEAs and
      13 SVGs. RESULTS: In group H, graft flow volume did not significantly differ
      among the ITA (34+/-11 ml/min), GEA (36+/-16 ml/min) and SVG (41+/-15 ml/min),
      and graft shear stress significantly (ITA vs. GEA P<0.0001; GEA vs. SVG P<0.01)
      differed among the ITA (16.0+/-4.8dyn/cm(2)), GEA (9.1+/-3.2dyn/cm(2)) and SVG
      (4.8+/-1.6dyn/cm(2)). In group L, flow volume was lower (P<0.001) in the ITA
      (18+/-6 ml/min) and GEA (13+/-8 ml/min) than in the SVG (35+/-16 ml/min), and
      shear stress was significantly (P<0.001) greater in the ITA (13.7+/-4.9dyn/cm(2))
      than the GEA (5.6+/-2.0dyn/cm(2)) or SVG (4.6+/-2.0dyn/cm(2)). CONCLUSIONS: These
      data suggest that shear stress of the ITA is superior and maintained despite the
      flow volume being reduced by flow competition. Lower shear stress of the GEA for
      intermediate stenosis may be associated with the development of conduit failure.

PMID- 15037276
TI  - Perivascular application of C-type natriuretic peptide attenuates neointimal
      hyperplasia in experimental vein grafts.
AB  - OBJECTIVE: C-type natriuretic peptide (CNP), which is produced by vascular
      endothelial cells, exhibits anti-proliferative and anti-inflammatory effects.
      Cytotoxic T-lymphocytes may be involved in vein graft disease. Attenuation of
      vein graft disease necessitates a remodelling of the arterialized vein towards a
      more contractile phenotype which is characterized, among other factors, by the
      calponin amount. We investigated the effects of perivascularly applied CNP in a
      mouse model of vein graft disease. METHODS: C57BL6J mice underwent interposition
      of the inferior vena cava from isogenic donor mice into the common carotid artery
      using a previously described cuff technique. In the treatment group, 10(-6)mol/l
      of CNP were applied locally in pluronic gel. The control group did not receive
      local treatment. Grafts were harvested at 1, 2, 4, and 8 weeks and underwent
      morphometric analysis as well as immunohistochemical analysis. RESULTS: In
      grafted veins without treatment (controls) median intimal thickness was 10 (6
      29), 12 (8-40)microm, was 47 (12-58), and 79 (62-146)microm after 1, 2, 4 and 8
      weeks, respectively. In the treatment groups, which received 10(-6)mol/l of CNP,
      the intimal thickness was 5 (3-6), 6 (4-15), 32 (5-54), and 43 (39-70)microm
      after 1, 2, 4 and 8 weeks, respectively. This reduction of intimal thickness was
      significant at 1, 2 and 8 weeks. Immunohistochemically, the reduction of intimal
      thickness was associated with a decreased infiltration of CD-8 positive cells and
      an increased amount of calponin in the CNP-treated grafts. CONCLUSION: We
      conclude that perivascular application of CNP inhibits neointimal hyperplasia of
      vein grafts in a mouse model. These results suggest that CNP may have a
      therapeutic potential for the prevention of vein graft disease.

PMID- 15037277
TI  - Effect of training on outcomes following coronary artery bypass graft surgery.
AB  - OBJECTIVE: We examined our coronary artery bypass surgery (CABG) experience to
      assess the effect of training on mortality and morbidity outcomes. METHODS:
      Between April 1997 and September 2002, 5678 consecutive patients underwent
      isolated CABG. Five hundred and fifty-five (9.9%) were performed by trainee
      surgeons. Multivariate logistic regression was used to assess the effect of
      training on adverse outcomes, while adjusting for patient and disease
      characteristics (treatment selection bias). Cox proportional hazards analysis was
      used to adjust Kaplan-Meier survival curves. Treatment selection bias was
      controlled for by constructing a propensity score from core patient
      characteristics including the additive EuroSCORE. The propensity score was the
      probability of CABG performed by trainee, with a C-statistic of 0.79, and was
      included along with the comparison variable (trainee vs Consultant) in a
      multivariable analysis of outcome. The propensity score is used as the sole
      variable for adjustment due to the low number of events, providing a more
      complete risk adjustment. RESULTS: CABG procedures performed by trainee surgeons
      were less likely to be female, hypertensive, obese, triple-vessel disease, redo
      and emergency cases. Also, trainee surgeons were less likely to operate on
      patients with cerebrovascular disease, renal dysfunction, and previous myocardial
      infarctions, prior gastrointestinal surgery, and poor left ventricular ejection
      fraction. The additive EuroSCORE was 2.9 in trainee cases compared to 3.5 in
      Consultant led cases (P<0.001) Crude outcomes were significantly better in
      trainee CABGs due to selection bias. In-hospital results were no longer
      significantly different between both groups after adjusting for the propensity
      score. The adjusted freedom from death in the trainee cases at 30 days, 1, 2, 3,
      and 4 years was 98.1, 96.2, 94.7, 93.2 and 91.8%, respectively, compared to 97.9,
      95.7, 94.1, 92.3 and 90.8% for the Consultant led cases (P=0.53). CONCLUSIONS:
      After adjusting for case-mix, with careful case selection, training does not
      adversely affect the early and mid-term outcomes of CABG.

PMID- 15037278
TI  - Renal dysfunction after myocardial revascularization.
AB  - OBJECTIVES: In this study, we evaluate the incidence of and analyse the pre and
      intraoperative risk factors for the development of postoperative renal
      dysfunction (PRD), and the impact of such an event on perioperative mortality and
      on hospital length of stay. In addition, we sought to investigate the influence
      of a mildly increased serum creatinine (1.3-2.0 mg/dl) on perioperative mortality
      and morbidity. METHODS: The study included 2445 consecutive patients who had no
      pre-existing renal disease (creatinine <or=2.0 mg/dl, without dialysis) and who
      underwent isolated coronary surgery under cardiopulmonary bypass between July
      1996 and December 2001. The main outcome measure was PRD, defined as a
      postoperative serum creatinine level >or=2.1 mg/dl with a preoperative-to
      postoperative increase >or=0.9 mg/dl. Univariate and multivariate analyses were
      performed where appropriate. RESULTS: Global 30-day mortality was 0.7%. The
      incidence of PRD was 5.6% (136 patients). Mortality for patients who experienced
      PRD was 8.8 vs. 0.1% for patients who did not (P<0.001). PRD increased the length
      of hospital stay by 3.4 days (7.6 vs. 11.0 days; P<0.001), and patients who
      needed haemodialysis (11%) had a perioperative mortality of 33.3% and a mean
      hospital length of stay of 16 days. Multivariable logistic regression identified
      the following variables as independent predictors of PRD: age (P=0.017; odds
      ratio (OR) 1.3 per 10 years), angina class III/IV (P=0.003; OR 1.7);
      cardiopulmonary bypass time (P=0.007; OR 1.01 per minute); preoperative serum
      creatinine levels: group 1 (1.3-1.6 mg/dl (P<0.001; OR 5.5)) and group 2 (1.7-2.0
      mg/dl (P<0.001; OR 14.2)). Finally, a mild elevation of the preoperative
      creatinine level (1.3-2.0 mg/dl) increased significantly the probability of
      perioperative mortality, low cardiac output, haemodialysis and prolonged hospital
      stay. CONCLUSIONS: Although the likelihood of PRD in patients without pre
      existing renal dysfunction is relatively low, it dramatically increases
      mortality, morbidity and length of stay after CABG. Mildly elevated (>1.2 mg/dl)
      preoperative serum creatinine level significantly increases the perioperative
      mortality and morbidity.

PMID- 15037279
TI  - Mechanical versus medical bridge to transplantation in children. What is the best
      timing for mechanical bridge?
AB  - OBJECTIVE: Precise timing of mechanical circulatory support as a bridge to
      transplantation is crucial for successful outcome. In our practice, increasing
      metabolic injury resulting from third organ (renal/gut) dysfunction is an
      indication for mechanical circulatory support. It is not known how metabolic
      injury would influence the outcomes in these patients. In this study we compared
      biochemical and clinical parameters between children who received mechanical
      circulatory support and those who were treated with medical management alone as a
      bridge to transplantation. METHODS: Data from 24 patients were retrospectively
      analysed from their records. There were 11 patients in the mechanical group. In
      this group, five patients received biventricular assist device, five received
      veno arterial extra corporeal membrane oxygenation and one received left
      ventricular assist device. In the medical group, there were 13 patients who
      received various levels of inotropic support before transplantation. Five
      clinical and three biochemical parameters were identified and compared between
      the mechanical and medical groups. Mortality prior to transplantation was also
      compared between the two groups. Transplantation was the end point of the study.
      RESULTS: Serum creatinine and serum lactate levels were significantly higher in
      the mechanical group (P=0.006 and 0.001, respectively), reflecting advanced
      metabolic injury in these patients. Mean fractional shortening in the mechanical
      group was 8.4%, compared to 14.5% in the medical group which was statistically
      significant (P=0.02). All of the 11 patients in the mechanical group were
      ventilated compared to 7 of the 13 (53.8%) in the medical group. Need for renal
      support was higher in the mechanical group (83.3%) in comparison to none in the
      medical group (P=0.023). Mortality in both groups was comparable with two
      patients in each group. 11 patients in the medical group (84.6%) and 9 in the
      mechanical group (81.8%) reached transplantation. CONCLUSION: This study
      confirmed that patients in the mechanical group were considerably worse in
      metabolic terms when compared to the medical group. Final outcome of bridging
      them to transplantation was comparable. This study seem to support the
      justification of reserving the mechanical circulatory support to those who are
      metabolically more injured without adversely affecting their outcomes.

PMID- 15037280
TI  - Permanent mechanical circulatory support in patients of advanced age.
AB  - OBJECTIVE: This study details our initial results of long-term left ventricular
      assist device (LVAD) support in patients suffering from catecholamine-dependent
      end-stage heart failure or cardiogenic shock with age above 65 years or age above
      60 and contraindications to cardiac transplantation. METHODS: Between September
      2000 and July 2002, 27 patients received implantation of left ventricular assist
      devices (Micromed DeBakey (n=15), Berlin Heart Excor (n=6), Arrow Lion Heart
      (n=4) and Novacor N100 (n=2)). The mean age of this group was 66.2+/-4.1 (60-77)
      years. The patients presented with the following features by the time of LVAD
      implantation: failure of weaning from inotropic support (78%), either profound
      cardiogenic shock (37%) or instable hemodynamic status (22%), high-dose inotropic
      (52%) or intraaortic balloon pump support (11%), dialysis (15%), artificial
      ventilation (15%), and at least one previous cardiac procedure (44%). RESULTS:
      The cumulative survival rate for the whole group was 63% at 30 days, 30% at 180
      days, and 22% at 2 years. The presence of preoperative cardiogenic shock was
      associated with a higher perioperative mortality rate. Late complications (n=7)
      included replacement of two thrombosed DeBakey LVADs and five late deaths
      secondary to thrombembolism/intracranial hemorrhage (DeBakey LVAD, n=3) or
      septicemia (n=2). As of May 15, 2003, six patients remain on LVAD support for an
      average of 653 (339-953) days, three patients now for more than 2 years. Ten
      patients were discharged home to spend 73% of their life span on out-of-hospital
      long-term LVAD support. CONCLUSION: This study reports the first single-center
      experience of permanent LVAD support in patients of advanced age. For this
      initial experience, many patients with critical circulatory status and previous
      cardiac operations were included and a high postoperative mortality rate was
      encountered among them. Older age and associated multimorbidity are the key
      determinants rendering the conditions of LVAD therapy for this patient cohort to
      be different from the bridge-to-transplant experience. The LVADs employed in this
      study showed different capabilities with regard to long-term support. Our
      experience shows that permanent mechanical circulatory support does have the
      potential to evolve as a treatment option in selected elderly patients with end
      stage heart failure.

PMID- 15037281
TI  - Peripheral blood dendritic cells in human end-stage heart failure and the early
      post-transplant period: evidence for systemic Th1 immune responses.
AB  - OBJECTIVES: Dendritic cells (DCs) are antigen presenting cells that play a
      central role in inflammation, allograft rejection and immune tolerance. Myeloid
      (mDC) and plasmacytoid (pDC) subsets regulate immune reactions by polarising
      naive T-helper cells into a Th1 or Th2 response, respectively. In this study we
      examined total peripheral blood DCs, mDC and pDC subsets in chronic heart failure
      (CHF) and clinical heart transplantation (HTx). METHODS: We compared 16 heart
      transplant patients before and after HTx to 14 healthy controls. Whole blood was
      collected pre-HTx and 1-week post-HTx from patients and at corresponding time
      points from controls. All patients received induction and maintenance
      immunosuppression post-HTx. mDCs and pDCs were measured by flow cytometry and
      were further characterised for maturation and homing potential to the secondary
      lymphoid organs with CD83 and CCR7, respectively. Data were expressed as absolute
      numbers/microl whole blood, percentage (%) mDC or pDC of total blood DCs and %
      positive DCs for CD83 and CCR7. RESULTS: CHF patients had more peripheral blood
      DCs compared to controls (P<0.01) while only the mDC fraction was increased
      compared to controls (P=0.01). Percentage CD83(+) and CCR7(+) mDCs was also
      higher than control levels (P<0.05). One week post-HTx, total DCs, mDCs and pDCs
      decreased below controls (P<0.001). At the same time % mDCs in peripheral blood
      increased markedly compared to CHF and control levels (P<0.001). The %CD83(+)
      mDC, %CD83(+) pDC and %CCR7(+) mDC also returned to control levels and only
      %CCR7(+) pDC decreased below control levels (P=0.005). CONCLUSIONS: Total
      peripheral blood DCs are elevated during CHF due to an increase in the mature
      fraction of the mDC subset suggesting a possible Th1 response in end-stage heart
      failure. The decrease in total DCs and mature mDCs and pDCs seen post-HTx,
      probably reflects immunological quiescence through adequate immunosuppression.
      Peripheral blood DC monitoring may provide a new insight into mechanisms of heart
      failure and allograft rejection by safe weaning from immunosuppression after
      clinical HTx.

PMID- 15037282
TI  - Combined transplantation of skeletal myoblasts and bone marrow stem cells for
      myocardial repair in rats.
AB  - OBJECTIVES: To prove whether intramyocardial transplantation of combined skeletal
      myoblasts (SM) and mononuclear bone marrow stem cells is superior to the isolated
      transplantation of these cell types after myocardial infarction in rats. METHODS:
      In 67 male Fischer rats myocardial infarction was induced by direct ligature of
      the LAD. Seven days postinfarction baseline echocardiography and intramyocardial
      cell transplantation were performed. Via lateral thoracotomy 200 microl
      containing either 10(7) SMs or 10(7) bone marrow-derived mononuclear cells (BM
      MNC) or a combination of 5x10(6) of both cell types (MB) were injected in 10-15
      sites in and around the infarct zone. In controls (C) 200 microl of cell-free
      medium were injected in the same manner. Before injection both cell types were
      stained using a fluorescent cell linker kit (PKH, Sigma). In addition, SMs were
      transfected with green fluorescent protein. Nine weeks postinfarction follow-up
      echocardiography was performed and animals were sacrificed for further analysis.
      RESULTS: At baseline echocardiography there was no difference in left ventricular
      ejection fraction (LVEF; C, SM, BM-MNC, MB: 60.1+/-3.2, 53.3+/-10.2, 53.1+/-8.7,
      49+/-9.0%) and left ventricular end diastolic diameter (LVEDD; C, SM, BM-MNC, MB:
      6.5+/-0.8, 5.17+/-0.8, 5.77+/-1.4, 6.25+/-0.8 mm) between the different
      therapeutic groups. Eight weeks after cell transplantation LVEDD was
      significantly increased in all animals except those that received a combination
      of myoblasts and bone marrow stem cells (MB; C, SM, BM-MNC, MB: 7.7+/-0.6 mm,
      P=0.001; 7.7+/-1.5 mm, P<0.001; 7.7+/-1.1 mm, P=0.005; 6.6+/-1.7 mm, P=0.397. At
      the same time LVEF decreased significantly in the control group (C), stayed
      unchanged in animals that received bone marrow stem cells (BM-MNC) and increased
      in animals that received myoblasts (SM) and a combination of both cell types (MB;
      C, SM, BM-MNC, MB: 45.3+/-7.0%, P=0.05; 63.9+/-15.4%, P=0.044; 54.3+/-6.3%,
      P=0.607; 63.0+/-11.5%, P=0.039). CONCLUSIONS: The present data show that the
      concept of combining SMs with bone marrow-derived stem cells may be of clinical
      relevance by merging the beneficial effects of each cell line and potentially
      reducing the required cell quantity. Further studies are required to identify the
      exact mechanisms underlying this synergy and to allow full exploitation of its
      therapeutic potential.

PMID- 15037284
TI  - Late dehiscence of a mitral annuloplasty band in an asymptomatic patient: the
      value of follow-up with echocardiography.

PMID- 15037285
TI  - Myocardial infarction and ventricular septal rupture caused by myocardial
      bridging.

PMID- 15037283
TI  - Human umbilical cord cells for cardiovascular tissue engineering: a comparative
      study.
AB  - OBJECTIVE: Tissue engineering of viable, autologous cardiovascular replacements
      with the potential to grow, repair and remodel represents an attractive approach
      to overcome the shortcomings of available replacements for the repair of
      congenital cardiac defects. Currently, vascular myofibroblast cells represent an
      established cell source for cardiovascular tissue engineering. Cell isolation
      requires the invasive harvesting of venous or arterial vessel segments prior to
      scaffold seeding, a technique which may not be preferable, especially in
      pediatric patients. This study evaluates cells isolated from human umbilical cord
      artery, umbilical cord vein and whole cord as alternative autologous cell sources
      for cardiovascular tissue engineering. METHODS: Cells were isolated from human
      umbilical cord artery (UCA), umbilical cord vein (UCV), whole umbilical cord
      (UCC) and saphenous vein segments (VC), and were expanded in culture. All three
      expanded cell groups were seeded on bioabsorbable copolymer strips and grown in
      vitro for 28 days. Isolated cells were characterized by flow cytometry,
      histology, immunohistochemistry, proliferation assays and compared to VC.
      Morphological analysis of the seeded polymer strips included histology,
      immunohistochemistry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis,
      transmission electron microscopy (TEM), scanning electron microscopy (SEM) and
      uniaxial stress testing. RESULTS: UCA, UCV and UCC demonstrated excellent cell
      growth properties comparable to VC. Following isolation, all three cell groups
      showed myofibroblast-like morphology and characteristics by staining positive for
      alpha-smooth muscle actin (ASMA) and vimentin. Histology and immunohistochemistry
      of seeded polymers showed good tissue and extracellular matrix formation
      containing collagen I, III and elastin. TEM showed viable myofibroblasts and the
      deposition of collagen fibrils and progressive growing tissue formation, with a
      confluent surface, was observed in SEM. No difference was found among the
      mechanical properties of UCA, UCV, UCC and VC tissue engineered constructs.
      CONCLUSIONS: Tissue engineering of cardiovascular constructs by using UCA, UCV
      and UCC is feasible in an in vitro environment. Cell growth, morphology,
      characteristics and tissue formation were comparable between UCA, UCV, UCC and
      VC. UCC represent an attractive, readily available autologous cell source for
      cardiovascular tissue engineering offering the additional benefits of utilizing
      juvenile cells and avoiding the invasive harvesting of intact vascular
      structures.

PMID- 15037286
TI  - A rare case of a large right ventricular aneurysm.

PMID- 15037287
TI  - Concomitant aneurysms of the coronary arteries with a fistula draining into the
      right ventricular intramural hemangioma.

PMID- 15037288
TI  - Surgical emergency due to coronary stent migration.

PMID- 15037289
TI  - Giant pulmonary arteriovenous malformation.

PMID- 15037290
TI  - Osteoblastic chondrosarcoma with cardiac and pulmonary arterial extension.

PMID- 15037291
TI  - Recurrent laryngeal nerve paralysis resulting from a metastatic lymphadenopathy
      caused by a right-sided lung cancer.

PMID- 15037292
TI  - A rare cause of hemoptysis: benign sugar (clear) cell tumor of the lung.
AB  - A case of benign sugar (clear) cell tumor of the lung with an unusual clinical
      presentation and its evaluation with computed tomography are reported. A 48-year
      old man presented with one episode of hemoptysis. Chest radiographs revealed a
      round nodule in the lower left lung lobe, and fiberoptic bronchoscopy was normal.
      On the computed tomography scans, the nodule showed intense post-contrast
      enhancement (74.7 Hounsfield units). The patient underwent a left thoracotomy,
      and a segmentectomy was performed. Pathologic examination showed a benign sugar
      cell tumor of the lung. The patient is alive and has remained free of disease for
      the last 2 years. To the best of our knowledge, this is the first case report of
      sugar cell tumor located in lung parenchyma that presented with hemoptysis and
      the second report of the contrast-enhanced computed tomography findings in this
      neoplasm.

PMID- 15037293
TI  - Inferior laryngeal paraganglioma presenting as plunging goiter.
AB  - Paragangliomas are uncommon slow-growing neuroendocrine tumors that may arise
      from the extra-adrenal paraganglia. Paragangliomas of the inferior and superior
      laryngeal paraganglia are known as laryngeal paraganglioma. Inferior laryngeal
      paraganglioma, which is also called subglottic paraganglioma, is very seldomly
      observed. To our knowledge only 24 patients with subglottic paraganglioma have
      been found. We present a 77-year-old male patient who has been previously
      followed-up for cervical goiter, which has a progressive enlargement into the
      mediastinum, causing severe tracheal obstruction. The tumor was completely and
      easily resected via median sternotomy with collar incision and finally diagnosed
      as inferior laryngeal paraganglioma. The present case is the first subglottic
      laryngeal paraganglioma descending into the visceral compartment of the
      mediastinum in the literature.

PMID- 15037295
TI  - Surgery for T4 non-small cell lung cancer.

PMID- 15037294
TI  - Thoracic aneurysm expansion secondary to collateral supplies via thyrocervical
      trunk and intercostal arteries in a patient after thromboexclusion.
AB  - A case of thoraco-abdominal aortic aneurysm complicated after permanent clamping
      of the descending aorta (thromboexclusion) is reported. Angiographic and
      operative findings were: (1) a pseudo-aneurysm right at the distal anastomosis of
      previous intrathoracic bypass for pseudo-coarctation of the aorta filled by left
      ninth intercostal artery, which was supplied by the left internal thoracic
      artery; and (2) the cervical and thoracic spinal cord were supplied by the left
      vertebral artery and the mediastinal branch of the left thyrocervical trunk. This
      rare cause of a thoraco-abdominal aortic aneurysm and the significance of the
      subclavian artery as a source of spinal cord blood supply are discussed.

PMID- 15037296
TI  - Coronary artery tourniquet and shunting: acute effects and wall damage.

PMID- 15037299
TI  - Making all the right moves: chemotaxis in neutrophils and Dictyostelium.
AB  - Neutrophils and Dictyostelium discoideum share the ability to migrate
      directionally in response to external chemoattractant gradients. The binding of
      chemoattractants to specific receptors that are coupled to heterotrimeric G
      proteins leads to a wide range of biochemical responses that become highly
      localized as cells polarize and migrate by chemotaxis. The signaling mechanisms
      that lead to the predominant polymerization of F-actin at the front of cells for
      propulsion and to myosin II assembly at the sides to suppress lateral pseudopod
      formation and at the back for retraction are now beginning to emerge.

PMID- 15037300
TI  - Prespecification and plasticity: shifting mechanisms of cell migration.
AB  - Cell migration is a universal process involving different morphologies and
      mechanisms in different cell types and tissue environments. Prespecified cell
      type-specific patterns of cell migration can be classified into single cell
      migration (amoeboid, mesenchymal) and collective migration modes (cell sheets,
      strands, tubes, clusters). These intrinsic molecular programs are associated with
      a characteristic structure of the actin cytoskeleton, as well as the cell-type
      specific use of integrins, matrix-degrading enzymes (matrix metalloproteinases
      and serine proteases), cell-cell adhesion molecules (cadherins and activated
      leukocyte adhesion molecule), and signaling towards the cytoskeleton (carried out
      by RHO GTPases). In response to the gain or loss of these key molecular
      determinants, significant adaptation reactions can modify the cell's shape,
      pattern, and migration mechanism; examples of this include the epithelial
      mesenchymal transition, mesenchymal-amoeboid transition and collective-amoeboid
      transition.

PMID- 15037301
TI  - Structural/functional homology between the bacterial and eukaryotic
      cytoskeletons.
AB  - Structural proteins are now known to be as necessary for controlling cell
      division and cell shape in prokaryotes as they are in eukaryotes. Bacterial ParM
      and MreB not only have atomic structures that resemble eukaryotic actin and form
      similar filaments, but they are also equivalent in function: the assembly of ParM
      drives intracellular motility and MreB maintains the shape of the cell. FtsZ
      resembles tubulin in structure and in its dynamic assembly, and is similarly
      controlled by accessory proteins. Bacterial MinD and eukaryotic dynamin appear to
      have similar functions in membrane control. In dividing eukaryotic organelles of
      bacterial origin, bacterial and eukaryotic proteins work together.

PMID- 15037302
TI  - Toxoplasma as a novel system for motility.
AB  - Motility is a characteristic of most living organisms and often requires
      specialized structures like cilia or flagella. An alternative is amoeboid
      movement, where the polymerization/depolymerization of actin leads to the
      formation of pseudopodia, filopodia and/or lamellipodia that enable the cell to
      crawl along a surface. Despite their lack of locomotive organelles and in absence
      of cell deformation, members of the apicomplexan parasites employ a unique form
      of locomotion called gliding motility to promote their migration across
      biological barriers and to power host-cell invasion and egress. Detailed studies
      in Toxoplasma gondii and Plasmodium species have revealed that this unique mode
      of movement is dependent on a myosin of class XIV and necessitates actin dynamics
      and the concerted discharge and processing of adhesive proteins. Gliding is
      essential for the survival and infectivity of these obligate intracellular
      parasites, which cause severe disease in humans and animals.

PMID- 15037303
TI  - Linked for life: temporal and spatial coordination of late mitotic events.
AB  - Establishing the temporal order of mitotic events is critical to ensure that each
      daughter cell receives a complete DNA complement. The spatial co-ordination of
      the cytokinetic ring site with the axis of chromosome segregation is likewise
      crucial. Recent studies in fungi indicate that regulators of chromosome
      segregation also participate in promoting mitotic exit and that the proteins that
      initiate mitotic exit, in turn, additionally regulate cytokinesis. These findings
      suggest that late mitotic events are coupled by employing one pathway to control
      multiple events. The regulatory mechanisms that ensure the spatial co-ordination
      of the mitotic spindle apparatus with the division site have also been elucidated
      recently in the asymmetrically dividing budding yeast. Interestingly, the spatial
      co-ordination of late mitotic events seems also to be important in higher
      eukaryotes.

PMID- 15037304
TI  - The good, the bad and the ugly: the practical consequences of centrosome
      amplification.
AB  - Centrosome amplification (the presence of more than two centrosomes at mitosis)
      is characteristic of many human cancers. Extra centrosomes can cause the assembly
      of multipolar spindles, which unequally distribute chromosomes to daughter cells;
      the resulting genetic imbalances may contribute to cellular transformation.
      However, this raises the question of how a population of cells with centrosome
      amplification can survive such chaotic mitoses without soon becoming non-viable
      as a result of chromosome loss. Recent observations indicate that a variety of
      mechanisms partially mute the practical consequences of centrosome amplification.
      Consequently, populations of cells propagate with good efficiency, despite
      centrosome amplification, yet have an elevated mitotic error rate that can fuel
      the evolution of the transformed state.

PMID- 15037305
TI  - Variations on a theme: the many modes of cytokinesis.
AB  - Animal cell division is believed to be mediated primarily by the 'purse-string'
      mechanism, which entails furrowing of the equatorial region, driven by the
      interaction of actin and myosin II filaments within contractile rings. However,
      myosin II-null Dictyostelium cells on substrates divide efficiently in a cell
      cycle-coupled manner. This process, termed cytokinesis B, appears to be driven by
      polar traction forces. Data in the literature can be interpreted as suggesting
      that adherent higher animal cells also use a cytokinesis B-like mechanism for
      cytokinesis. An additional chemotaxis-based cytokinesis that involves a 'midwife'
      cell has also been reported. Collectively, these findings demonstrate an
      unexpected diversity of mechanisms by which animal cells carry out cytokinesis.

PMID- 15037306
TI  - Relating biochemistry and function in the myosin superfamily.
AB  - All characterized myosins share a common ATPase mechanism. However, detailed
      kinetic analyses suggest that modulation of the rate and equilibrium constants
      that define the ATPase cycle confers specific properties to these motor proteins,
      suiting them to specific physiological tasks. Understanding the kinetic
      mechanisms allows potential cellular functions of the different myosin classes
      and isoforms to be better defined.

PMID- 15037307
TI  - Cytoplasmic streaming in plants.
AB  - Plant cells are surrounded by a cell wall composed of polysaccharides and hence
      can change neither their form nor their position. However, active movement of
      organelles (cytoplasmic streaming or protoplasmic streaming) is observed in plant
      cells, and involvement of the actin/myosin system in these processes has been
      suggested. Successful biochemical and biophysical approaches to studying myosins
      have extensively promoted the understanding of the molecular mechanism underlying
      these phenomena.

PMID- 15037309
TI  - mRNA localization and the cytoskeleton.
AB  - mRNA localization is a widespread post-transcriptional mechanism for targeting
      protein synthesis to specific cellular sites. It is involved in the generation of
      cell polarity, asymmetric segregation of cell fate determinants and germ cell
      specification. Actin and microtubule filaments have key functions during RNA
      localization, especially during transport of mRNAs and anchoring at target sites.
      Recent advances in understanding the role of motors and filament systems have
      mainly resulted from the contribution of live imaging of mRNA movement and from
      the purification of putative localization ribonucleoproteins. There have also
      been new findings on the role of centrosomes in RNA localization.

PMID- 15037308
TI  - Multiple and surprising new functions for emerin, a nuclear membrane protein.
AB  - Emerin is an integral protein of the nuclear inner membrane. Emerin is not
      essential, but its loss of function causes Emery-Dreifuss muscular dystrophy. We
      summarize significant recent progress in understanding emerin, which was
      previously known to interact with barrier-to-autointegration factor and lamins.
      New partners include transcription repressors, an mRNA splicing regulator, a
      nuclear membrane protein named nesprin, nuclear myosin I and F-actin. These
      interactors imply multiple roles for emerin in the nucleus, some of which overlap
      with related LEM-domain proteins.

PMID- 15037311
TI  - Talin: an emerging focal point of adhesion dynamics.
AB  - The adhesion protein talin and the phosphoinositide PIP2 are emerging as key
      modulators of adhesion dynamics. Recent genetic studies on talin demonstrate its
      physiological role in organizing adhesions, stabilizing integrin-actin linkages
      and mediating integrin signaling in vivo. Biophysical force measurements provide
      further evidence that it is required for the reinforcement of the extracellular
      matrix-integrin-actin connection. Knockdown data along with structural analyses
      establish a major role for talin in 'inside-out' integrin activation through its
      direct interaction with integrin cytoplasmic domains. A recently uncovered role
      for talin is the recruitment of a PIPKI gamma isoform to adhesions. This
      introduces a novel connection between talin and PIP2 generation. Finally, PIP2
      also stimulates the transient, direct binding interaction of the Arp2/3 complex
      with vinculin and thus may couple adhesion to actin assembly.

PMID- 15037310
TI  - Breaking into the epithelial apical-junctional complex--news from pathogen
      hackers.
AB  - The epithelial apical-junctional complex is a key regulator of cellular
      functions. In addition, it is an important target for microbial pathogens that
      manipulate the cell to survive, proliferate and sometimes persist within a host.
      Out of a myriad of potential molecular targets, some bacterial and viral
      pathogens have selected a subset of protein targets at the apical-junctional
      complex of epithelial cells. Studying how microbes use these targets also teaches
      us about the inherent physiological properties of host molecules in the context
      of normal junctional structure and function. Thus, we have learned that three
      recently uncovered components of the apical-junctional complex of the Ig
      superfamily--junctional adhesion molecule, Nectin and the coxsackievirus and
      adenovirus receptor--are important regulators of junction structure and function
      and represent critical targets of microbial virulence gene products.

PMID- 15037312
TI  - Formin-induced nucleation of actin filaments.
AB  - Formins are proteins best defined by the presence of the unique, highly conserved
      formin homology domain 2 (FH2). FH2 is necessary and sufficient to nucleate an
      actin filament in vitro. The FH2 domain also binds to the filament's barbed end,
      modulating its elongation and protecting it from capping proteins. FH2 itself
      appears to be a processive cap that walks with the barbed end as it elongates.

PMID- 15037313
TI  - Cortical control of microtubule stability and polarization.
AB  - In both dividing and interphase cells, microtubules are remodeled in response to
      signal transduction pathways triggered by a variety of stimuli. Members of the
      Rho family of small GTPases have emerged as key intermediates in transmitting
      signals to cortical factors that mediate capture of dynamic microtubules at
      specific sites. The specificity of cortical capture appears to be controlled by
      microtubule tip proteins and cortical receptors that bind these proteins. Recent
      studies suggest that some of the proteins interacting with microtubule tips
      behave as bridging proteins between the microtubule tip proteins and their
      cortical receptors. Such bridging proteins may enhance cortical capture of
      microtubules directly or indirectly through interactions with the actin
      cytoskeleton.

PMID- 15037314
TI  - Involvement of Wingless/Armadillo signaling in the posterior sequential
      segmentation in the cricket, Gryllus bimaculatus (Orthoptera), as revealed by
      RNAi analysis.
AB  - In insects, there are two different modes of segmentation. In the higher dipteran
      insects (like Drosophila), their segmentation takes place almost simultaneously
      in the syncytial blastoderm. By contrast, in the orthopteran insects (like
      Schistocerca (grasshopper)), the anterior segments form almost simultaneously in
      the cellular blastoderm and then the remaining posterior part elongates to form
      segments sequentially from the posterior proliferative zone. Although most of
      their orthologues of the Drosophila segmentation genes may be involved in their
      segmentation, little is known about their roles. We have investigated
      segmentation processes of Gryllus bimaculatus, focusing on its orthologues of the
      Drosophila segment-polarity genes, G. bimaculatus wingless (Gbwg), armadillo
      (Gbarm) and hedgehog (Gbhh). Gbhh and Gbwg were observed to be expressed in the
      each anterior segment and the posterior proliferative zone. In order to know
      their roles, we used RNA interference (RNAi). We could not observed any
      significant effects of RNAi for Gbwg and Gbhh on segmentation, probably due to
      functional replacement by another member of the corresponding gene families.
      Embryos obtained by RNAi for Gbarm exhibited abnormal anterior segments and lack
      of the abdomen. Our results suggest that GbWg/GbArm signaling is involved in the
      posterior sequential segmentation in the G. bimaculatus embryos, while Gbwg,
      Gbarm and Gbhh are likely to act as the segment-polarity genes in the anterior
      segmentation similarly as in Drosophila.

PMID- 15037315
TI  - Ectopic expression and knockdown of a zebrafish sox21 reveal its role as a
      transcriptional repressor in early development.
AB  - Sox proteins are DNA-binding proteins belonging to the HMG box superfamily and
      they play key roles in animal embryonic development. Zebrafish Sox21a is part of
      group B Sox proteins and its chicken and mouse orthologs have been described as
      transcriptional repressor and activator, respectively, in two different target
      gene contexts. Zebrafish sox21a is present as a maternal transcript in the oocyte
      and is mainly expressed at the developing midbrain-hindbrain boundary from the
      onset of neurulation. In order to understand its role in vivo, we ectopically
      expressed sox21a by microinjection. Ectopic expression of full length sox21a
      leads to dorsalization of the embryos. A subset of the dorsalized embryos shows a
      partial axis splitting, and hence an ectopic neural tube, as an additional
      phenotype. At gastrulation, injected embryos show expansion of the expression
      domains of organizer-specific genes, such as chordin and goosecoid. Molecular
      markers used in somitogenesis highlight that sox21a-injected embryos have
      shortened AP axis, undulating axial structures, enlarged or even radialized
      paraxial territory. The developmental abnormalities caused by ectopic expression
      of sox21a are suggestive of defects in convergence-extension morphogenetic
      movements. Antisense morpholino oligonucleotides, designed to functionally
      knockdown sox21a, cause ventralization of the embryos. Moreover, gain-of-function
      experiments with chimeric constructs, where Sox21a DNA-binding domain is fused to
      a transcriptional activator (VP16) or repressor (EnR) domain, suggests that
      zebrafish Sox21a acts as a repressor in dorso-ventral patterning.

PMID- 15037316
TI  - Local inhibition guides the trajectory of early longitudinal tracts in the
      developing chick brain.
AB  - During development of the chick central nervous system, the trajectories of the
      descending medial and lateral longitudinal fascicles (MLF and LLF) are pioneered
      by axons originating from the interstitial nucleus of Cajal (INC) and the
      mesencephalic trigeminal nucleus (MTN), respectively. Both tracts cross
      rhombomere 1 at two specific locations in the basal plate. In this study, we have
      investigated the molecular properties of these crossing points and find that they
      are permissive regions situated in an otherwise inhibitory boundary region. We
      show that the dorsal part of rhombomere 1 is inhibitory for the growth of both
      MTN and INC axons. Ventrally, MLF and LLF axons are repelled from the midline by
      Slit proteins. Our results reveal the existence of a new repulsive/inhibitory
      mechanism for axons in the alar plate in addition to the ventral repulsion by
      Slit proteins. This suggests a model where MLF and LLF axons are channeled
      longitudinally within the neural tube by both dorsal and ventral constraints.

PMID- 15037317
TI  - Distinct Wnt members regulate the hierarchical morphogenesis of skin regions
      (spinal tract) and individual feathers.
AB  - Skin morphogenesis occurs in successive stages. First, the skin forms distinct
      regions (macropatterning). Then skin appendages with particular shapes and sizes
      form within each region (micropatterning). Ectopic DKK expression inhibited
      dermis formation in feather tracts and individual buds, implying the importance
      of Wnts, and prompted the assessment of individual Wnt functions at different
      morphogenetic levels using the feather model. Wnt 1, 3a, 5a and 11 initially were
      expressed moderately throughout the feather tract then were up-regulated in
      restricted regions following two modes: Wnt 1 and 3a became restricted to the
      placodal epithelium, then to the elongated distal bud epidermis; Wnt 5a and 11
      intensified in the inter-tract region and interprimordia epidermis or dermis,
      respectively, then appeared in the elongated distal bud dermis. Their role in
      feather tract formation was determined using RCAS mediated misexpression in ovo
      at E2/E3. Their function in periodic feather patterning was examined by
      misexpression in vitro using reconstituted E7 skin explant cultures. Wnt 1
      reduced spinal tract size, but enhanced feather primordia size. Wnt 3a increased
      dermal thickness, expanded the spinal tract size, reduced interbud domain
      spacing, and produced non-tapering "giant buds". Wnt 11 and dominant negative Wnt
      1 enhanced interbud spacing, and generated thinner buds. In cultured dermal
      fibroblasts, Wnt 1 and 3a stimulated cell proliferation and activated the
      canonical beta-catenin pathway. Wnt 11 inhibited proliferation but stimulated
      migration. Wnt 5a and 11 triggered the JNK pathway. Thus distinctive Wnts have
      positive and negative roles in forming the dermis, tracts, interbud spacing and
      the growth and shaping of individual buds.

PMID- 15037319
TI  - WNT5A signaling affects pituitary gland shape.
AB  - Wnt signaling is important in organogenesis, and aberrant signaling in mature
      cells is associated with tumorigenesis. Several members of the Wnt family of
      signaling molecules are expressed in the developing pituitary gland. Wnt5a is
      expressed in the neuroectoderm that induces pituitary gland development and has
      been proposed to influence pituitary cell specification. We discovered that mice
      deficient in Wnt5a display abnormal morphology in the dorsal part of the
      developing pituitary. The expression of downstream effectors of the canonical Wnt
      pathway is not altered, and expression of genes in other signaling pathways such
      as Shh, Fgf8, Fgf10 and Fgfr2b is intact. Prop1 and Hesx1 are also important for
      normal shape of the pituitary primordium, but their expression is unaltered in
      the Wnt5a mutants. Specification of the hormone-producing cell types of the
      mature anterior pituitary gland occurs appropriately. This study suggests that
      the primary role of Wnt5a in the developing pituitary gland is in establishment
      of the shape of the gland.

PMID- 15037318
TI  - Craniofacial defects in mice lacking BMP type I receptor Alk2 in neural crest
      cells.
AB  - Neural crest cells (NCCs) are pluripotent migratory cells that contribute to the
      development of various craniofacial structures. Many signaling molecules have
      been implicated in the formation, migration and differentiation of NCCs including
      bone morphogenetic proteins (BMPs). BMPs signal through a receptor complex
      composed of type I and type II receptors. Type I receptors (Alk2, Alk3 and Alk6)
      are the primary determinants of signaling specificity and therefore understanding
      their function is important in revealing the developmental roles of molecular
      pathways regulated by BMPs. Here we used a Cre/loxP system for neural crest
      specific deletion of Alk2. Our results show that mice lacking Alk2 in the neural
      crest display multiple craniofacial defects including cleft palate and a
      hypotrophic mandible. Based on the present results we conclude that signaling via
      Alk2 receptors is non-redundant and regulates normal development of a restricted
      set of structures derived from the cranial neural crest.

PMID- 15037320
TI  - Control of foot differentiation in Hydra: in vitro evidence that the NK-2
      homeobox factor CnNK-2 autoregulates its own expression and uses pedibin as
      target gene.
AB  - The foot of the simple metazoan Hydra is a highly dynamic body region of constant
      tissue movement, cell proliferation, determination and differentiation.
      Previously, two genes have been shown to participate in the development and
      differentiation of this body region: homeodomain factor CnNK-2 and signal peptide
      pedibin [Dev. Biol. 180 (1996) 473; Development 126 (1999) 517; Development 122
      (1996) 1941; Mech. Dev. 106 (2001) 37]. CnNk-2 functions as transcriptional
      regulator and is responsive to changes in the positional value while the secreted
      peptide pedibin serves as "extrinsic" positional signal. Exposure of polyps to
      pedibin increases the spatial domain of CnNK-2 expression towards the gastric
      region, indicating that positional signals are integrated at the cis-regulatory
      region of CnNK-2. In the present study, to elucidate the molecular basis of the
      interaction of CnNK-2 and pedibin, we characterized the 5' regulatory regions of
      both genes. Within the CnNK-2 5' upstream region, electrophoretic mobility shift
      assays showed that putative NK-2 binding motifs are specifically bound by both
      nuclear protein from Hydra foot and by recombinant CnNK-2, suggesting that CnNK-2
      might autoregulate its own expression. This is the first indication for an
      autoregulatory circuit in Hydra. In addition, we also identified NK-2 binding
      sites in the cis-regulatory region of the pedibin gene, indicating that this gene
      is one of the targets of the transcription factor CnNK-2. On the basis of these
      results, we present a model for the regulatory interactions required for
      patterning the basal end of the single axis in Hydra which postulates that CnNK-2
      together with pedibin orchestrates foot specific differentiation.

PMID- 15037322
TI  - Etiology and susceptibility of urinary tract isolates in Kosova.
AB  - Urinary tract infections are amongst the most common pathogenic infections with
      an increasing resistance to antimicrobials. The objective of this study was to
      determine the etiology and antimicrobial susceptibility patterns of urinary tract
      infection pathogens isolated in Kosovo. A retrospective study was carried from
      urine samples of both inpatients and outpatients that were received in our
      laboratory throughout 2001. During the study period, 16500 urine samples were
      analysed, of which 4260 (25.8%) had significant bacteriuria obtained from 1420
      patients. Of this, 1059 (74.6%) were collected from females and 361 (25.4%) from
      males. Urine samples processed from outpatients were 72.5% (1029), whereas 27.5%
      (391) were from hospitalised patients. Escherichia coli was the most common
      aetiologic agent isolated (80.5%), followed by Proteus spp. (6.1%), Klebsiella
      spp. (5.9%), Citrobacter (5.1%) and Mycobacterium tuberculosis (0.8%). Gram
      positive bacteria accounted for only 0.3%. Pseudomonas aeruginosa was only
      isolated from inpatients and was responsible for 0.6% of infections. Amoxicillin,
      ampicillin and trimethoprim-sulphamethoxazole resistance rates were 48.7, 46.5
      and 32.1%, respectively. Nitrofurantoin, cefalexin and ciprofloxacin expressed
      the highest susceptibility among these isolates. E. coli isolates from inpatients
      and outpatients showed more than 25% resistance to trimethoprim
      sulphamethoxazole. Of all isolates, 16% (225) were resistant to three or more
      agents and considered multi-drug resistant. Current data on the prevalence of
      multidrug resistance among urinary tract isolates should be a consideration to
      change the current empiric treatment of urinary tract infections.

PMID- 15037323
TI  - Urinary bactericidal activity, urinary excretion and plasma concentrations of
      gatifloxacin (400 mg) versus ciprofloxacin (500 mg) in healthy volunteers after a
      single oral dose.
AB  - In an open randomised double-crossover study 12 volunteers (six men, six women)
      received a single oral dose of gatifloxacin (400 mg) or ciprofloxacin (500 mg) to
      assess urinary bactericidal activity (in eight intervals up to 120 h) and
      pharmacokinetic (PK) parameters (up to 36 h). Plasma concentrations and urinary
      excretion were determined by HPLC with fluorescence detection, and urinary
      bactericidal titers (UBT) by microdilution-method, using antibiotic-free urine of
      each volunteer. The mean maximum plasma concentration of gatifloxacin was 3.35
      mg/l and that of ciprofloxacin 2.12 mg/l. The mean (median) cumulative renal
      excretion of the parent drug was for gatifloxacin 81 (83)% of the administered
      dose within 120 h and for ciprofloxacin 43 (45)%. The UBTs, i.e. the highest two
      fold dilution (antibiotic-free urine as diluent) of urine still being
      bactericidal, were determined for an Escherichia coli ATCC reference strain and
      nine clinical uropathogens with the following MICs (mg/l) for
      gatifloxacin/ciprofloxacin (microdilution, MHB): E. coli ATCC 25922
      (0.008/0.008); E. coli 523 (0.06/0.06); Klebsiella pneumoniae 1058 (0.03/0.016);
      Proteus mirabilis 524 (0.125/0.016); Pseudomonas aeruginosa 561 (1/0.125);
      Enterococcus faecalis strains 60 an 55 (0.5/1 and 8/32); Staphylococcus aureus
      strains 248 and 596 (both 0.03/0.125) and S. saprophyticus Ho94 (0.125/0.25). The
      median UBTs measured within the first 6h for gatifloxacin were between 1:16 and
      1:>or=1024 for the Gram-negative strains including P. aeruginosa and between 1:8
      and 1:>or=1024 for the five Gram-positive strains. The median UBTs for
      ciprofloxacin were between 1:64 and 1:>or=1024 for the Gram-negative strains
      (incl P. aeruginosa) and between 1:1.5 and 1:768 for the five Gram-positive
      strains. The UBTs up to 12 < 0.05 h showed no difference (P<0.05 ) for both E.
      coli strains, but ciprofloxacin was superior to gatifloxacin against Klebsiella,
      Proteus and Pseudomonas strains and gatifloxacin was superior to ciprofloxacin
      against all Gram-positive strains. For the UBTs at 12-24 h, gatifloxacin was
      generally superior to ciprofloxacin, but showed no difference in the Proteus and
      Pseudomonas strains. The areas under the UBT-time-curve (AUBT) up to 120 h showed
      statistically significant (P ) differences between both quinolones in favour of
      gatifloxacin against 8 of 10 strains tested, no difference for P. mirabilis and
      significantly higher activity of ciprofloxacin against P. aeruginosa. In
      conclusion, gatifloxacin and ciprofloxacin had overall comparable initial urinary
      bactericidal activity with some differences for specific pathogens, some times in
      favour of gatifloxacin (Gram-positives) and some times of ciprofloxacin (usually
      Gram-negatives), suggesting that for empiric therapy a single oral dose of
      gatifloxacin (400mg) would be clinically equivalent to ciprofloxacin (500 mg)
      twice daily-in agreement with the results of a clinical study in complicated UTI
      performed previously [Int. J. Antimicrob. Agents (2004)].

PMID- 15037324
TI  - Controversies in antibiotic prophylaxis in urology.
AB  - Antibiotic prophylaxis in urologic surgery remains controversial. However,
      progress has been made and some of the controversies have been answered. Firstly,
      it is important to underline that urologic diagnostic and therapeutic procedures
      can induce surgical site infections (SSIs), bacteriuria, pyelonephritis and
      septicaemia in a substantial number of patients, too great to be neglected.
      Secondly, as patients are different and have various risk factors, a careful
      assessment of the patient and its individual risk is crucial. Thirdly, the same
      procedure may be totally different from one individual to another and they can
      rarely be grouped as standard procedures. A floating level of invasiveness is
      followed by a variation of the risk of infection. Fourthly, the pathogens and
      their susceptibility pattern vary extensively in Europe so that no clear-cut
      recommendations as for the choice of antibiotics can be given. Basic principles
      of antibiotic prophylaxis in terms of timing, mode of administration and length
      of regiment apply for urologic interventions. Thus, clean operations will usually
      not require antimicrobial prophylaxis except for those including the implant of a
      prosthetic device, while clean-contaminated will benefit from preventive
      antimicrobials. It is the task of the urologists to carefully assess each
      individual patient and procedure to opt for an optimal prophylaxis.

PMID- 15037325
TI  - Emergence of antibiotic resistance and prudent use of antibiotic therapy in
      nosocomially acquired urinary tract infections.
AB  - Nosocomially acquired urinary tract infections (NAUTI) are common. The reported
      rates, however, depend very much on the definitions used and the number of
      investigations requested. In a prospective study on a surgical intensive care
      unit and adhering closely to the CDC criteria, NAUTI was diagnosed in about 17%
      of the patients. The urinary catheter associated UTI rate per 1000 catheter days
      was 14.5 much higher than otherwise reported. Whereas the rates of symptomatic
      NAUTI and other nosocomially acquired infections were similar, the main
      difference was found for asymptomatic UTI which depends very much on the effort
      to search for it systematically. In a prospective study on a urological ward it
      could be demonstrated that cross-transmission probably plays a much greater role
      than so far suggested. Continuous surveillance of the bacterial spectrum and
      resistance is necessary not only on a global but also on a local level. Selection
      of an appropriate agent for empirical antibacterial therapy can be better
      tailored if not only the total bacterial spectrum is considered but if all
      information already available during the identification process is used, such as
      Gram stain and other simple and rapid tests for stratification of the pathogens.
      Since in NAUTI usually some kind of biofilm infection is involved, the
      fluoroquinolones can be considered agents of choice. Only those substances with
      high antibacterial activity, good bioavailability and those that are mainly
      excreted by the kidneys should be chosen and they have to be administered at
      sufficiently high doses.

PMID- 15037326
TI  - Nosocomially acquired urinary tract infections in urology departments. Why an
      international prevalence study is needed in urology.
AB  - Nosocomially acquired urinary tract infection (NAUTI) is the most frequent
      nosocomial infection and a particular problem in urology departments. The
      incidence of NAUTI has become an important quality parameter and a legal issue.
      Several characteristics related to the health care provider, the patient and the
      procedures are known to increase the risk of NAUTI. The single most important
      risk factor for NAUTI is an indwelling catheter. NAUTI may be prevented by good
      health care facilities, evidence-based practice, wise patient selection and
      surgical skill. But the most important factors are tailored antibiotic
      prophylaxis and continuous monitoring of the incidence and pathogens causing
      NAUTI in each institution. Raising antimicrobial resistance in some countries
      calls for a closer monitoring of NAUTI on international level within urology.
      There is room for improvement in urinary catheter care in many hospitals, and the
      importance of patient and urological risk factors for development of NAUTI is not
      fully known. In order to meet these challenges the European Society for
      Infections in Urology is planning a prevalence study combined with a quality
      improvement initiative related to NAUTI.

PMID- 15037327
TI  - Rapid resolution of symptoms with ciprofloxacin therapy in 3859 hospitalised
      patients with urinary tract infection.
AB  - This post-marketing surveillance study including 3859 hospitalised patients with
      urinary tract infection (UTI) was conducted to evaluate the efficacy and
      tolerability of treatment with intravenous or orally administered ciprofloxacin.
      The most frequent initial doses of ciprofloxacin were a total daily dose of 400
      mg intravenously and 500 mg orally. After 4 days of therapy, 75.6% of patients
      were asymptomatic and, 92.0% after 7 days. 93.9% of patients were rated as having
      improved or have been cured at the end of the observation period. Improvement and
      cure were independent of the severity of infection. The tolerability of the
      treatment was rated by physicians as good or very good for 96.9% of patients.
      Adverse events were reported in 3.5% of patients.

PMID- 15037328
TI  - Gatifloxacin 200 mg or 400 mg once daily is as effective as ciprofloxacin 500 mg
      twice daily for the treatment of patients with acute pyelonephritis or
      complicated urinary tract infections.
AB  - The efficacy and safety of two oral dosing regimens of gatifloxacin were compared
      to ciprofloxacin in the treatment of complicated urinary tract infection in a
      randomised, double-blind multi-centre trial. One thousand one hundred and twenty
      three adult patients with complicated urinary tract infection (70%) or
      pyelonephritis (30%) were initially enrolled, 1122 were treated. Of these, 824
      were included in a modified ITT population: gatifloxacin 200 mg (274 patients) or
      400 mg (280 patients) once daily or ciprofloxacin 500 mg twice daily for 5-14
      days (269 patients). Bacteriological and clinical responses were assessed 7-9
      days after the end of treatment (EOT) and 4-6 weeks post-treatment (end of study
      visit, EOS). The bacteriological response rates per patient at EOT in the
      gatifloxacin 400 mg, gatifloxacin 200 mg and ciprofloxacin groups were 77%
      (207/269), 78% (208/268) and 73% (190/259), respectively. At EOS they were
      slightly lower: 70% (184/262), 71% (176/248) and 69% (174/252), respectively. The
      clinical responses at EOT were 69% (190/277), 70% (190/273) and 65% (174/266). At
      EOS they were 71% (193/273), 70% (182/259) and 74% (190/258). The overall
      eradication rates of initial pathogens at EOT and EOS were 85.3% and 88.4% in the
      gatifloxacin 400 mg group; 84.1 and 90.1% in the gatifloxacin 200 mg group and
      85.1 and 91.4% in the ciprofloxacin group. Both oral regimens of gatifloxacin
      were as effective as that of ciprofloxacin. All treatment groups showed a similar
      safety profile, nausea being the most frequently reported adverse event.

PMID- 15037329
TI  - Extended-release ciprofloxacin (Cipro XR) for treatment of urinary tract
      infections.
AB  - Symptomatic urinary tract infections (UTIs) constitute a major health problem
      throughout the Western world. In the USA, UTIs are responsible for 7-8 million
      outpatient visits each year and for over one-third of all hospital-acquired
      infections. Empiric antimicrobial therapy for UTIs, which are primarily caused by
      Escherichia coli, is increasingly being complicated by the emergence of
      resistance to the most widely used agents. Recent studies indicate that the
      prevalence of E. coli resistance to trimethoprim/sulphamethoxazole (TMP/SMX), the
      current first-line therapy for UTIs, exceeds 20% in many North American regions.
      Importantly, antibiotic resistance often translates into clinical failure. The
      use of antibiotics with favourable pharmacokinetic/pharmacodynamic profiles and
      convenient dosing schedules, which effectively increase bacterial eradication and
      patient compliance, can help to curb the current epidemic of resistance and
      reduce the rate of clinical failure associated with resistance. Fluoroquinolones
      have well-established efficacy in the treatment of multiple bacterial infections
      and, over the years, the rates of resistance to these antibiotics have remained
      very low. Fluoroquinolones are currently recommended for therapy of uncomplicated
      UTIs when the local incidence of TMP/SMX resistance is >or=10-20%, as well as for
      the treatment of complicated UTIs and acute pyelonephritis. Ciprofloxacin, one of
      the most widely used fluoroquinolones, has a potent bactericidal effect across
      the full spectrum of uropathogens, as well as a long and excellent efficacy and
      safety record in the management of UTI and other infections. A recently developed
      extended (modified)-release formulation of ciprofloxacin (Cipro XR or Cipro XL)
      provides higher maximum plasma concentrations with lower inter-patient
      variability than the conventional, immediate-release, twice-daily formulation.
      Additionally, therapeutic drug levels with extended-release ciprofloxacin are
      achieved rapidly and maintained over the course of 24 h, allowing once-daily
      dosing. Clinical trials in patients with cystitis and those with complicated UTIs
      or acute uncomplicated pyelonephritis indicate that extended-release
      ciprofloxacin is at least as effective as the immediate-release formulation.
      These studies have also confirmed good tolerability and safety of extended
      release ciprofloxacin, similar to the immediate-release formulation. Therefore,
      extended-release ciprofloxacin is a convenient, well-tolerated and effective
      therapy for UTIs that may improve patients' compliance with treatment and thus
      decrease the risk of treatment failure and the spread of antibiotic resistance.

PMID- 15037330
TI  - Bacterial biofilm formation on urologic devices and heparin coating as preventive
      strategy.
AB  - In the process of endourological development a variety of foreign bodies have
      been invented besides urinary catheters, on which biofilm can be formed. Bacteria
      in the biofilm are less susceptible to antibiotics. An additional problem of
      medical biomaterials in the urinary tract environment is the development of
      encrustation and consecutive obstruction. The most promising prevention strategy
      for bacterial biofilms is the production of materials with anti-adhesive surfaces
      such as heparin. Although heparin-coated ureteral stents are expensive, they
      justify their cost. Our studies show that such devices are protected against
      incrustation and biofilm formation for a longer period of time: 6-12 months, both
      in vitro and in vivo.

PMID- 15037331
TI  - Prevention of catheter-related infections: the potential of a new nano-silver
      impregnated catheter.
AB  - Contaminated or infected catheters are a major source of nosocomial infections
      responsible for >40% of all episodes of nosocomial sepsis in acute-care
      hospitals. Antibiotics as well as surface modifications with, for example,
      hydrogels proved to be of little value in preventing the contamination of
      indwelling catheters. The even distribution of 10(12-13) activated silver
      nanoparticles per gram in various polymers, e.g. polyurethane and silicone,
      results in an excellent antimicrobial activity against a broad spectrum of
      organisms in vitro. Substantial reduction of incrustation of these catheters was
      also observed. These preliminary experimental data warrant clinical studies.

PMID- 15037332
TI  - Azithromycin treatment follow-up: antibacterial susceptibility of Chlamydia
      trachomatis in patients with chronic prostatitis.
AB  - The antibacterial susceptibility of Chlamydia trachomatis in 138 patients with
      chronic prostatitis (CP) and clinical failures after antibacterial treatment with
      azithromycin (AZI) were investigated. Azithromycin was not found to be top-of-the
      line drug in the follow-up treatment, showing only average results in vitro. The
      investigation of the susceptibility of chlamydia to antibiotics in causes of
      chronic prostatitis is highly recommended.

PMID- 15037335
TI  - The relationship of neuropsychological test performance with the PANSS in
      antipsychotic naive, first-episode psychosis patients.
AB  - BACKGROUND: Chronic schizophrenia patients have been sampled for factor analytic
      studies to identify the factor structure of the Positive and Negative Syndrome
      Scale (PANSS). Many of these studies have identified a cognitive factor, which
      may provide useful information about patients for whom formal neuropsychological
      testing is unavailable. However, the relationship between the clinically rated
      cognitive factor and performance-based cognitive test scores has not been
      thoroughly examined, particularly in patients who are early in the course of
      illness. OBJECTIVES: The validity of the PANSS cognitive factor was examined in a
      sample of antipsychotic naive, first-episode psychosis patients and the PANSS
      items that best predicted cognitive functioning were identified. METHOD: PANSS
      scores and performance on a battery of cognitive tests from the baseline
      assessment of a clinical trial of 167 neuroleptic naive patients with
      schizophrenia-like illnesses were analyzed. RESULTS: Factor analysis revealed a
      five-factor model that was consistent with previously described factor models
      from samples of chronically treated patients. There were modest correlations
      (less than r=0.44) between the derived cognitive factor and six of the
      neuropsychological test variables (Wisconsin Card Sorting Test total errors and
      number of categories correctly sorted, WMS-R immediate and delayed recall scores,
      Category Fluency total score, and WAIS-R digit symbol). Five PANSS items (P6, N5,
      N6, G2, and G10) were identified that predicted global cognitive functioning;
      however, 66% of the variance in cognitive functioning remained unexplained.
      CONCLUSIONS: A PANSS cognitive factor can be identified in first-episode,
      neuroleptic naive patients. However, clinical ratings of cognitive deficits lack
      sensitivity and specificity and thus should not be relied upon fully.

PMID- 15037334
TI  - Correlates of cognitive deficits in first episode schizophrenia.
AB  - OBJECTIVE: The presence of cognitive dysfunction in schizophrenia has been well
      documented, but questions remain about whether there are relationships between
      this dysfunction and clinical symptomatology. If present, such relationships
      should be most clearly observable in patients with first episode schizophrenia;
      that is, before the effects of chronic illness, institutionalization, or
      treatment might confound them. METHOD: 307 schizophrenia subjects in their first
      episode of illness were recruited to participate in a clinical trial comparing
      the long-term efficacy of haloperidol and risperidone. The psychopathology,
      cognitive functioning, early treatment history, and duration of untreated
      psychosis of these subjects were assessed prior to their assignment to
      randomized, double-blind treatment. Approximately two-thirds of the subjects were
      receiving antipsychotic treatment at the time of assessment; however, the
      duration of treatment was limited to 12 weeks or less. RESULTS: The severity of
      negative symptoms at the time of assessment was associated with deficits in
      memory, verbal fluency, psychomotor speed and executive function. Positive
      symptoms were not associated with cognitive deficits. Also, the duration of
      untreated illness (DUI) prior to assessment was not significantly associated with
      cognitive impairment. CONCLUSIONS: The results of this study of first episode
      schizophrenia patients suggest that a relationship exists between negative
      symptoms and cognitive dysfunction. However, that relationship accounts for only
      a minor portion of the variance (i.e., 10-15%) in the severity of cognitive
      dysfunction after controlling for a number of potentially confounding factors.
      This finding provides support for the theory that the neurobiological processes
      that give rise to symptomatology and cognitive dysfunction in schizophrenia are
      partially overlapping.

PMID- 15037333
TI  - Single-drug or combined antibacterial therapy in the treatment of patients with
      chronic prostatitis and Chlamydia trachomatis?
AB  - The efficacy of antibacterial combinations as compared with single-drug treatment
      in 57 patients with chronic prostatitis and Chlamydia trachomatis was
      investigated in this study.

PMID- 15037336
TI  - Neuropsychological functioning in early onset psychotic disorders.
AB  - This paper examines whether neuropsychological profiles of youth with early onset
      psychotic disorders predicted diagnostic or clinical status. Youth with
      schizophrenia (n=27), bipolar disorder (n=22), and psychosis NOS (n=20) were
      included. Subjects received an extensive neuropsychological evaluation, including
      measures of general cognition, attention, memory, and executive functioning.
      Medication status was not controlled. No statistically significant neurocognitive
      differences across diagnostic groups were found. Compared to standardized norms,
      youth with schizophrenia demonstrated deficits in general cognition, verbal
      learning, recall, sustained effort, and social knowledge. Subjects with bipolar
      disorder and psychosis NOS exhibited deficits on measures of verbal learning,
      recall, and sustained effort similar to those of youth with schizophrenia.
      Neurocognitive deficits in memory and attention appeared to be common among youth
      with psychotic illnesses, regardless of diagnosis. Those with schizophrenia may
      have greater global cognitive deficits and problems with social knowledge. Across
      diagnoses, subjects demonstrated relative strengths on tests that provided them
      with immediate feedback, and performed most poorly on tests requiring delayed
      recall.

PMID- 15037337
TI  - Facial recognition deficits and cognition in schizophrenia.
AB  - Previous investigations have found impaired recognition of facial affect and
      cognition in schizophrenia. We compared patients with schizophrenia and healthy
      control volunteers on computerized tasks of emotion recognition, to determine
      whether emotion processing deficits were correlated with neurocognitive
      performance. A Computerized Neuropsychological Test Battery (CNP) was
      administered to 40 patients (25 male, 15 female, mean age+/-S.D. 30.4+/-8.1) with
      schizophrenia (DSM-IV, 15 first episode and 25 chronically ill patients) treated
      with atypical neuroleptics and 43 healthy volunteers. A German version of the
      PENN Facial Discrimination, Differentiation and Memory Test, including happy, sad
      and neutral faces was used. Additionally, all patients were tested with a
      standard neuropsychological battery and rated for positive and negative symptoms.
      Patients with schizophrenia performed worse than control subjects on all emotion
      recognition tasks (p<0.01). We found higher error rates for discrimination of
      emotion in happy (p<0.02) and happy female faces (p<0.01), for differentiation of
      sad versus happy faces (p<0.001) and for facial memory (p<0.04). Poorer
      performance in emotion discrimination and facial memory correlated with severity
      of negative symptoms, abstraction-flexibility (p<0.001), verbal memory (p<0.01)
      and language processing (p<0.001). The study did not reveal a specific deficit
      for emotion recognition in schizophrenia. These findings lend support to the
      notion that difficulties in emotion recognition are associated in schizophrenia
      with key cognitive deficits.

PMID- 15037338
TI  - Nonspecific and attenuated negative symptoms in patients at clinical high-risk
      for schizophrenia.
AB  - BACKGROUND: Retrospective studies have shown that nonspecific psychopathology and
      negative symptoms, including social isolation and academic dysfunction, tend to
      precede onset of psychosis. The present report describes the baseline
      psychopathology of subjects in the Hillside Recognition and Prevention (RAP)
      Program, and presents an operationalized classification algorithm for the
      prospective study of both positive and negative symptoms of clinical high-risk
      (CHR) for schizophrenia. METHODS: Eighty-two adolescent and young adult patients
      were characterized using semi-structured interviews of both a parent informant
      and the patient. The Scale of Prodromal Symptoms (SOPS) was utilized to derive a
      three-part classification scheme: CHR- subjects (n=20) were defined as having at
      least one attenuated negative symptom with no positive symptoms; CHR+ subjects
      (n=42) were defined as having one or more attenuated positive symptoms without
      psychosis; schizophrenia-like psychosis (SLP) subjects (n=20) were defined as
      having a psychotic symptom, but without meeting criterion A, B, or C of DSM-IV
      schizophrenia. RESULTS: Social isolation was the most common presenting symptom.
      The three RAP subgroups did not significantly differ in levels of attenuated
      negative and disorganized symptoms, despite the fact that these were not required
      for inclusion in the CHR+ and SLP groups. Common co-morbid diagnoses included
      major depression, attention deficit hyperactivity disorder, avoidant personality
      disorder, and Cluster A personality disorders. CONCLUSIONS: Negative symptoms and
      other nonspecific behavioral abnormalities represent clinically important
      phenomena in prodromal patients, and may provide insight into pathophysiologic
      mechanisms in schizophrenia and possible preventive interventions.

PMID- 15037339
TI  - Pretreatment and longitudinal studies of neuropsychological deficits in
      antipsychotic-naive patients with schizophrenia.
AB  - The early course of neuropsychological dysfunction in schizophrenia and the
      impact of treatment on these deficits need to be better specified. A sample of 45
      patients with schizophrenia underwent five neuropsychological evaluations from
      prior to treatment with antipsychotic treatment through a 2-year follow-up
      period. A comparison sample of 33 matched healthy individuals underwent
      neuropsychological evaluations at similar time points. At baseline, a generalized
      deficit across cognitive domains was evident for the schizophrenia sample. After
      6 weeks of treatment, patients showed modest improvements in visual memory and
      visual perception, but a decline in verbal memory. Verbal memory performance
      returned to baseline levels by the 6-month follow-up while deficits in other
      neuropsychological domains persisted throughout the 2-year period. Relatively
      static and generalized neuropsychological dysfunction, evident from illness
      onset, is consistent with neurodevelopmental rather than neurodegenerative models
      of schizophrenia.

PMID- 15037340
TI  - Neurocognitive measures of prefrontal cortical dysfunction in schizophrenia.
AB  - Frontal lobe dysfunction in individuals with schizophrenia has frequently been
      detected using both neuroimaging and neuropsychological testing. Results from
      previous studies vary in the findings of regional specificity vs. generalized
      frontal cortical dysfunction. We sought to examine potential regional differences
      in frontal cortical functioning among patients with schizophrenia vs. a
      comparison group using two different neurocognitive tasks: the Gambling Task (GT)
      and the Wisconsin Card Sorting Test (WCST). In general, the GT is thought to
      reflect function of the ventromedial prefrontal cortex (VMPFC), while the WCST
      reflects function of the dorsolateral prefrontal cortex (DLPFC). Twenty
      individuals with schizophrenia or schizoaffective disorder and 15
      nonpsychiatrically ill comparison subjects underwent an assessment battery
      consisting of the GT, WCST, and positive and negative symptom ratings. Patients
      with schizophrenia performed worse on the GT with respect to total monetary gain
      (p=0.05) and total monetary loss (p<0.05). They also preferred disadvantaged vs.
      advantaged cards (p<0.04). Surprisingly, WCST performance was poor in both groups
      and was not significantly different between groups. These findings are at some
      variance with those in the previously reported literature, but nonetheless
      support the idea that prefrontal cortical areas mediating different cognitive
      tasks may be distinguished by specific neurocognitive assessments.

PMID- 15037342
TI  - Neurocognitive deficits and history of childhood abuse in schizophrenia spectrum
      disorders: associations with Cluster B personality traits.
AB  - Cluster B personality traits have been detected in persons with schizophrenia, at
      a rate exceeding that of the general population. Unclear, however, is how to
      account for such high rates of Cluster B traits. Accordingly, this study explored
      the hypothesis that the presence of these traits may be linked to impairments in
      neurocognition, and childhood abuse history. To test this, we simultaneously
      obtained an assessment of Cluster B traits using the Millon Clinical Multiaxial
      Inventory III, along with measures of attention, verbal memory, affect
      recognition, executive function and childhood abuse history among 37 persons with
      schizophrenia spectrum disorders in a post acute phases of illness. Pearson
      correlation coefficients revealed that higher levels of histrionic and
      narcissistic traits were related to poorer neurocognition while higher levels of
      narcissistic traits were negatively correlated with childhood physical abuse.
      Higher levels of borderline traits were uniquely related to the report of
      childhood sexual abuse while higher levels of antisocial traits were related to
      higher levels of childhood physical abuse. Theoretical and clinical implications
      are discussed.

PMID- 15037341
TI  - Lexical competition and spoken word identification in schizophrenia.
AB  - Schizophrenia (SZ) is a disorder associated with dysfunction of the neural
      substrate involved in lexical processing, the superior temporal lobe (STL). We
      examined whether the detrimental effects of lexical competition on word
      identification are exaggerated in SZ. The results showed that SZ patients were
      less able than controls to identify words coming from high lexical competitor
      environments (i.e., high density and high frequency lexical neighborhoods). They
      did not differ from controls, however, in identifying words coming from low
      lexical competitor environments (i.e., low density and low frequency lexical
      neighborhoods). Further, when SZ patients misidentified high competitor words,
      the erroneously reported words were of a significantly higher frequency than
      those reported by controls when they misidentified high competitor words (i.e.,
      the HF misidentification bias). Identification accuracy for high competitor words
      negatively correlated with amount of thought disorder, and the HF
      misidentification bias positively correlated with the lifetime frequency and
      severity of auditory hallucinations, the latter of which serving as presumed
      independent measures of STL dysfunction in SZ.

PMID- 15037343
TI  - The Penn Conditional Exclusion Test (PCET): relationship to the Wisconsin Card
      Sorting Test and work function in patients with schizophrenia.
AB  - Performance on the Penn Conditional Exclusion Test (PCET), a new computerized
      measure of executive function with alternate forms, was compared with performance
      on the Wisconsin Card Sorting Test (WCST) in a sample of 32 patients with
      schizophrenia. In Analysis 1, the PCET and WCST were administered with several
      other standard neuropsychological measures to assess convergent and divergent
      validity. Results revealed that categories achieved and total errors on the PCET
      were closely related to analogous measures from the WCST. Divergent validity was
      supported through nonsignificant correlations between the PCET and measures of
      speeded visual sequencing, verbal learning and psychomotor speed. In Analysis 2,
      the relationship between the PCET, WCST and a detailed measure of vocational
      function, the Work Behavior Inventory (WBI), was compared. Results revealed that
      both executive-function measures were related to specific dimensions of work
      function as measured in a vocational setting. More specifically, categories
      achieved and total errors on both the WCST and PCET were related to measures of
      cooperativeness on the job. Errors on the PCET were also related to measurements
      of work quality and general impressions of work. These results provide the first
      evidence of criterion-related validity for the PCET and are part of a growing
      literature suggesting a relationship between performance on measures of executive
      function and work skills.

PMID- 15037344
TI  - Dementia praecox studies.

PMID- 15037346
TI  - Emotion Management Training (EMT) in persons with treatment-resistant
      schizophrenia: first results.

PMID- 15037345
TI  - A process approach to verbal fluency in patients with schizophrenia.

PMID- 15037347
TI  - Selective attention in schizoaffective disorder: pilot data.

PMID- 15037348
TI  - Reinforcement learning with via-point representation.
AB  - In this paper, we propose a new learning framework for motor control. This
      framework consists of two components: reinforcement learning and via-point
      representation. In the field of motor control, conventional reinforcement
      learning has been used to acquire control sequences such as cart-pole or stand-up
      robot control. Recently, researchers have become interested in hierarchical
      architecture, such as multiple levels, and multiple temporal and spatial scales.
      Our new framework contains two levels of hierarchical architecture. The higher
      level is implemented using via-point representation, which corresponds to macro
      actions or multiple time scales. The lower level is implemented using a
      trajectory generator that produces primitive actions. Our framework can modify
      the ongoing movement by means of temporally localized via-points and trajectory
      generation. Successful results are obtained in computer simulation of the cart
      pole swing up task.

PMID- 15037349
TI  - Self-organized two-state membrane potential transitions in a network of
      realistically modeled cortical neurons.
AB  - Recent studies have revealed that in vivo cortical neurons show spontaneous
      transitions between two subthreshold levels of the membrane potentials, 'up' and
      'down' states. The neural mechanism of generating those spontaneous states
      transitions, however, remains unclear. Recent electrophysiological studies have
      suggested that those state transitions may occur through activation of a
      hyperpolarization-activated cation current (H-current), possibly by inhibitory
      synaptic inputs. Here, we demonstrate that two-state membrane potential
      fluctuations similar to those exhibited by in vivo neurons can be generated
      through a spike-timing-dependent self-organizing process in a network of
      inhibitory neurons and excitatory neurons expressing the H-current.

PMID- 15037350
TI  - A robust method for distinguishing between learned and spurious attractors.
AB  - Hopfield/constraint satisfaction type networks can be used to learn
      (autoassociate) patterns. Random inputs to the network will sometimes converge on
      states which are learned patterns, and sometimes converge on states which are
      unlearned/spurious. It would be useful for many reasons to be able to tell
      whether or not a given state was learned or spurious. In this paper we present a
      robust and general method, based on 'energy profiles', which allows us to make
      this distinction. We briefly describe related research, and note links with the
      study of recall, recognition and familiarity in the psychological literature.

PMID- 15037351
TI  - Investigation of color constancy with a neural network.
AB  - The perceptual stability of an object's color under different illuminants is
      called color constancy. We created a neural network to investigate this
      phenomenon. The net consisted of one input channel for the background and one for
      the test object. Each channel had a set of three (L, M, and S) receptors that
      were transmitting to three opponent neurons. The signals from the opponent
      neurons were passed to hidden neurons, which were connected to the output
      neurons. The output signal was generated from the three components of a color
      vector. The neural net was trained to identify the color of Munsell samples under
      various illuminants using the back-propagation algorithm. Our study investigated
      the properties of a successfully trained neural network. Based on the cross
      neuron weight analysis, we report that the successfully trained neural net
      calculates color differences between the test object and the background. By
      comparing the human visual system to the neural net, we conclude that to satisfy
      the color constancy phenomenon, the human visual system has to contain two
      separate components: one to approximate the background color and the other to
      estimate the color difference between the object and the background.

PMID- 15037352
TI  - Models of MT and MST areas using wake-sleep algorithm.
AB  - We present two-layered neural network models with Q (> or =2)-states neurons for
      a system with middle temporal (MT) neurons and medial superior temporal (MST)
      neurons by using a wake-sleep algorithm proposed by Hinton et al.; we notice that
      the wake-sleep algorithm consists of local learning rules. We first investigate a
      model with binary neurons for response properties of the MST neurons to optical
      flows as for various types of motion. We next extend the model with binary
      neurons to a model with Q (> or =3)-states neurons and investigate the response
      properties of the MST neurons for various values of Q (> or =3). We obtain better
      response properties for the model with Q (> or =3)-states neurons than for the
      one with binary neurons.

PMID- 15037353
TI  - A via-point time optimization algorithm for complex sequential trajectory
      formation.
AB  - In our previous research, we proposed a method for the reproduction of complex
      movement trajectories and robot arm control that could mimic fast, skilled human
      movements. That method is based on bi-directional theory and uses a
      representation of a set of via-points as boundary conditions or control variables
      to perform robot arm trajectory control. The via-points are extracted from human
      movement data and the resultant via-point representation is able to regenerate
      handwritten characters, control a Kendama toy, and perform a tennis serve. The
      via-point information contains both spatial and temporal information, that is,
      the position on the trajectory and the time of passing through the via-point
      position, respectively. Trajectory generation is performed using the trajectory
      formation model based on the optimal criterion, namely, the smoothness criterion,
      for which the boundary conditions are both the position and the timing of the via
      point information. However, generating a smooth trajectory at different movement
      speeds is quite difficult if the time of passing through the via-point position
      is unknown or different from the extracted via-point time. In this paper, we
      therefore propose a new algorithm which can determine temporal via-point
      information. Our proposed algorithm can generate roughly the same trajectory as
      the measured human trajectory from only the spatial information of via-point
      locations. The optimality and the convergence of the new algorithm are
      investigated theoretically, and the trajectory generated by the algorithm is
      shown in numerical experiments. It is shown that starting from arbitrary temporal
      information the proposed algorithm can produce an appropriate trajectory.

PMID- 15037354
TI  - Marginal median SOM for document organization and retrieval.
AB  - The self-organizing map algorithm has been used successfully in document
      organization. We now propose using the same algorithm for document retrieval.
      Moreover, we test the performance of the self-organizing map by replacing the
      linear Least Mean Squares adaptation rule with the marginal median. We present
      two implementations of the latter variant of the self-organizing map by either
      quantifying the real valued feature vectors to integer valued ones or not.
      Experiments performed using both implementations demonstrate a superior
      performance against the self-organizing map based method in terms of the number
      of training iterations needed so that the mean square error (i.e. the average
      distortion) drops to the e(-1) = 36.788% of its initial value. Furthermore, the
      performance of a document organization and retrieval system employing the self
      organizing map architecture and its variant is assessed using the average recall
      precision curves evaluated on two corpora; the first comprises of manually
      selected web pages over the Internet having touristic content and the second one
      is the Reuters-21578, Distribution 1.0.

PMID- 15037355
TI  - Absolute exponential stability of recurrent neural networks with Lipschitz
      continuous activation functions and time delays.
AB  - This paper investigates the absolute exponential stability of a general class of
      delayed neural networks, which require the activation functions to be partially
      Lipschitz continuous and monotone nondecreasing only, but not necessarily
      differentiable or bounded. Three new sufficient conditions are derived to
      ascertain whether or not the equilibrium points of the delayed neural networks
      with additively diagonally stable interconnection matrices are absolutely
      exponentially stable by using delay Halanay-type inequality and Lyapunov
      function. The stability criteria are also suitable for delayed optimization
      neural networks and delayed cellular neural networks whose activation functions
      are often nondifferentiable or unbounded. The results herein answer a question:
      if a neural network without any delay is absolutely exponentially stable, then
      under what additional conditions, the neural networks with delay is also
      absolutely exponentially stable.

PMID- 15037356
TI  - Absolutely exponential stability of a class of neural networks with unbounded
      delay.
AB  - In this paper, the existence and uniqueness of the equilibrium point and absolute
      stability of a class of neural networks with partially Lipschitz continuous
      activation functions are investigated. The neural networks contain both variable
      and unbounded delays. Using the matrix property, a necessary and sufficient
      condition for the existence and uniqueness of the equilibrium point of the neural
      networks is obtained. By constructing proper vector Liapunov functions and
      nonlinear integro-differential inequalities involving both variable delays and
      unbounded delay, using M-matrix theory, sufficient conditions for absolutely
      exponential stability are obtained.

PMID- 15037357
TI  - Twinned principal curves.
AB  - Principal Curves are extensions of Principal Component Analysis and are smooth
      curves, which pass through the middle of a data set. We extend the method so
      that, on pairs of data sets which have underlying non-linear correlations, we
      have pairs of curves which go through the 'centre' of data sets in such a way
      that the non-linear correlations between the data sets are captured. The core of
      the method is to iteratively average the current local projections of the data
      points which produces an increasingly sparsified set of nodes. The Twinned
      Principal Curves are generated in three ways: by joining up the nodes in order,
      by performing Local Canonical Correlation Analysis and by performing Local
      Exploratory Correlation Analysis (Koetsier et al., 2002). The latter two are
      shown to improve the forecasting capability of the method but at an increased
      computational load. We show that it is crucial to terminate the algorithm after a
      small number of iterations for the first method and investigate several criteria
      for doing so.

PMID- 15037358
TI  - Massively parallel networks for edge localization and contour integration-
      adaptable relaxation approach.
AB  - The paper describes a new adaptive neural network for edge-based pattern
      extraction problems. In the model, each neuron represents an edge with continuous
      state variables describing its location and orientation. The post-synaptic
      distribution is dependent on the state variables. Each neuron adjusts its state
      to increase its membrane potential, which results in highly adaptive dynamics of
      the synaptic weight distribution. The network allocates multiple neurons with
      different orientation modes for each edge. The strategy allows accurate modeling
      of multi-modal distributions at key-points such as corners and junctions. As a
      result, the network delineates edges at sub-pixel accuracy while preserving key
      points. It is also capable of processing a sequence of images and following
      moving objects. The network is extended for contour integration and key-point
      detection tasks. The paper presents experiments conducted on both synthetic and
      non-synthetic data to demonstrate the effectiveness of the technique.

PMID- 15037359
TI  - A neural network controller for hydronic heating systems of solar buildings.
AB  - An artificial neural network (ANN)-based controller for hydronic heating plants
      of buildings is presented. The controller has forecasting capabilities: it
      includes a meteorological module, forecasting the ambient temperature and solar
      irradiance, an indoor temperature predictor module, a supply temperature
      predictor module and an optimizing module for the water supply temperature. All
      ANN modules are based on the Feed Forward Back Propagation (FFBP) model. The
      operation of the controller has been tested experimentally, on a real-scale
      office building during real operating conditions. The operation results were
      compared to those of a conventional controller. The performance was also assessed
      via numerical simulation. The detailed thermal simulation tool for solar systems
      and buildings TRNSYS was used. Both experimental and numerical results showed
      that the expected percentage of energy savings with respect to a conventional
      controller is of about 15% under North European weather conditions.

PMID- 15037360
TI  - A high performance k-NN approach using binary neural networks.
AB  - This paper evaluates a novel k-nearest neighbour (k-NN) classifier built from
      binary neural networks. The binary neural approach uses robust encoding to map
      standard ordinal, categorical and numeric data sets onto a binary neural network.
      The binary neural network uses high speed pattern matching to recall a candidate
      set of matching records, which are then processed by a conventional k-NN approach
      to determine the k-best matches. We compare various configurations of the binary
      approach to a conventional approach for memory overheads, training speed,
      retrieval speed and retrieval accuracy. We demonstrate the superior performance
      with respect to speed and memory requirements of the binary approach compared to
      the standard approach and we pinpoint the optimal configurations.

PMID- 15037361
TI  - Biology of fibrocartilage cells.
AB  - Fibrocartilage is an avascular tissue that is best documented in menisci,
      intervertebral discs, tendons, ligaments, and the temporomandibular joint.
      Several of these sites are of particular interest to those in the emerging field
      of tissue engineering. Fibrocartilage cells frequently resemble chondrocytes in
      having prominent rough endoplasmic reticulum, many glycogen granules, and lipid
      droplets, and intermediate filaments together with and actin stress fibers that
      help to determine cell organization in the intervertebral disc. Fibrocartilage
      cells can synthesize a variety of matrix molecules including collagens,
      proteoglycans, and noncollagenous proteins. All the fibrillar collagens (types I,
      II, III, V, and XI) have been reported, together with FACIT (types IX and XII)
      and network-forming collagens (types VI and X). The proteoglycans include large,
      aggregating types (aggrecan and versican) and small, leucine-rich types (decorin,
      biglycan, lumican, and fibromodulin). Less attention has been paid to
      noncollagenous proteins, although tenascin-C expression may be modulated by
      mechanical strain. As in hyaline cartilage, matrix metalloproteinases are
      important in matrix turnover and fibrocartilage cells are capable of apoptosis.

PMID- 15037362
TI  - Cellular deflagellation.
AB  - Deciliation, also known as deflagellation, flagellar autotomy, flagellar
      excision, or flagellar shedding, refers to the process whereby eukaryotic cells
      shed their cilia or flagella, often in response to stress. Used for many decades
      as a tool for scientists interested in the structure, function, and genesis of
      cilia, deciliation itself is a process worthy of scientific investigation.
      Deciliation has numerous direct medical implications, but more profoundly,
      intriguing relationships between deciliation, ciliogenesis, and the cell cycle
      indicate that understanding the mechanism of deciliation will contribute to a
      deeper understanding of broad aspects of cell biology. This review provides a
      critical examination of diverse data bearing on this problem. It also highlights
      current deficiencies in our understanding of the mechanism of deciliation.

PMID- 15037363
TI  - The bacterial flagellar motor: structure and function of a complex molecular
      machine.
AB  - The bacterial flagellar motor harnesses ion flow to drive rotary motion, at
      speeds reaching 100000 rpm and with apparently tight coupling. The functional
      properties of the motor are quite well understood, but its molecular mechanism
      remains unknown. Studies of motor physiology, together with mutational and
      biochemical studies of the components, place significant constraints on the
      mechanism. Rotation is probably driven by conformational changes in membrane
      protein complexes that form the stator. These conformational changes occur as
      protons move on and off a critical aspartate residue in the stator protein MotB,
      and the resulting forces are applied to the rotor protein FliG. The bacterial
      flagellum is a complex structure built from about two dozen proteins. Its
      construction requires an apparatus at the base that exports many flagellar
      components to their sites of installation by way of an axial channel through the
      structure. The sequence of events in assembly is understood in general terms, but
      not yet at the molecular level. A fuller understanding of motor rotation and
      flagellar assembly will require more data on the structures and organization of
      the constituent proteins.

PMID- 15037364
TI  - Apoptosis in plants: specific features of plant apoptotic cells and effect of
      various factors and agents.
AB  - Apoptosis is an integral part of plant ontogenesis; it is controlled by cellular
      oxidative status, phytohormones, and DNA methylation. In wheat plants apoptosis
      appears at early stages of development in coleoptile and initial leaf of 5- to 6
      day-old seedlings. Distinct ultrastructural features of apoptosis observed are
      (1). compaction and vacuolization of cytoplasm in the apoptotic cell, (2).
      specific fragmentation of cytoplasm and appearance in the vacuole of unique
      single-membrane vesicles containing active organelles, (3). cessation of nuclear
      DNA synthesis, (4). condensation and margination of chromatin in the nucleus,
      (5). internucleosomal fragmentation of nuclear DNA, and (6). intensive synthesis
      of mitochondrial DNA in vacuolar vesicles. Peroxides, abscisic acid, ethylene
      releaser ethrel, and DNA methylation inhibitor 5-azacytidine induce and stimulate
      apoptosis. Modulation of the reactive oxygen species (ROS) level in seedling by
      antioxidants and peroxides results in tissue-specific changes in the target date
      for the appearance and the intensity of apoptosis. Antioxidant butylated
      hydroxytoluene (BHT) reduces the amount of ROS and prevents apoptosis in
      etiolated seedlings, prolongs coleoptile life span, and prevents the appearance
      of all apoptotic features mentioned. Besides, BHT induces large structural
      changes in the organization of all cellular organelles and the formation of new
      unusual membrane structures in the cytoplasm. BHT distorts mitosis and this
      results in the appearance of multiblade polyploid nuclei and multinuclear cells.
      In roots of etiolated wheat seedlings, BHT induces differentiation of plastids
      with the formation of chloro(chromo)plasts. Therefore, ROS controlled by BHT
      seems to regulate mitosis, trigger apoptosis, and control plastid differentiation
      and the organization of various cellular structures formed by endocytoplasmic
      reticulum.

PMID- 15037365
TI  - Cell biology of Leydig cells in the testis.
AB  - This article reviews results on differentiation, structure, and regulation of
      Leydig cells in the testes of rodents and men. Two different populations-fetal
      and adult Leydig cells-can be recognized in rodents. The cells in these two
      populations are different in ultrastructure, life span, capacity for androgen
      synthesis, and mechanisms of regulation. A brief survey on the origin,
      ontogenesis, characterization of precursors, ultrastructure, and functional
      markers of fetal and adult Leydig cells is presented, followed by an analysis of
      genes in Leydig cells and the role of luteinizing hormone and its receptor,
      steroidogenic acute regulatory protein, hydroxysteroid dehydrogenases, androgen
      and its receptor, anti-Mullerian hormone, estrogens, and thyroid hormones.
      Various growth factors modulate Leydig cell differentiation, regeneration, and
      steroidogenic capacity, for example, interleukin 1alpha, transforming growth
      factor beta, inhibin, insulin-like growth factors I and II, vascular endothelial
      growth factor, and relaxin-like growth factor. Retinol and retinoic acid increase
      basal testosterone secretion in adult Leydig cells, but decrease it in fetal
      Leydig cells. Resident macrophages in the interstitial tissue of the testis are
      important for differentiation and function of Leydig cells. Apoptosis of Leydig
      cells is involved in the regulation of Leydig cell number and can be induced by
      cytotoxins. Characteristics of aging Leydig cells in rodents seem to be species
      specific. 11beta-hydroxysteroid dehydrogenase protects testosterone synthesis in
      the Leydig cells of stressed rats. Last, the following aspects of human Leydig
      cells are briefly described: origin, differentiation, triphasic development,
      aging changes, pathological changes, and gene mutations leading to infertility.

PMID- 15037367
TI  - Striking a balance, finding the theme.

PMID- 15037366
TI  - The exocyst complex in polarized exocytosis.
AB  - Exocytosis is an essential membrane traffic event mediating the secretion of
      intracellular protein contents such as hormones and neurotransmitters as well as
      the incorporation of membrane proteins and lipids to specific domains of the
      plasma membrane. As a fundamental cell biological process, exocytosis is crucial
      for cell growth, cell-cell communication, and cell polarity establishment. For
      most eukaryotic cells exocytosis is polarized. A multiprotein complex, named the
      exocyst, is required for polarized exocytosis from yeast to mammals. The exocyst
      consists of eight components: Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70, and
      Exo84. They are localized to sites of active exocytosis, where they mediate the
      targeting and tethering of post-Golgi secretory vesicles for subsequent membrane
      fusion. Here we review the progress made in the understanding of the exocyst and
      its role in polarized exocytosis.

PMID- 15037368
TI  - Current trends in the management of frontal sinus fractures.
AB  - The majority of frontal sinus fractures are sustained by young male adults
      involved in vehicle accidents. Treatment of these fractures is of paramount
      importance because of the anatomical relationship of the sinus with the brain and
      the delicate periorbital region. The optimal treatment of frontal sinus fractures
      remains controversial. However, most authors would accept an open exploration and
      obliteration of the sinus in the presence of a depressed or displaced anterior
      wall fracture or injury to the nasofrontal duct. A successful obliteration
      requires meticulous extirpation of the frontal sinus mucosa, removal of the inner
      cortex of bone and permanent occlusion of the nasofrontal duct. If the posterior
      wall is involved, a concomitant dural tear is a common phenomenon. The main goal
      in this case is the restoration of the dural integrity and the isolation of the
      intracranial contents from the outer environment. Devastating complications such
      as meningitis, encephalitis or brain abscess are quite uncommon nowadays.
      Nevertheless, late development of invasive mucoceles is not a rarity and
      therefore long-term follow-up is mandatory.

PMID- 15037369
TI  - Predicting outcome after multiple trauma: which scoring system?
AB  - We have undertaken a review of the commonly used scoring systems to identify
      advantages and possible pitfalls involved in their use. Currently, there is a
      variety of systems available for scoring trauma severity. Some of them are based
      on the anatomical description of the injuries, whilst others are based on
      physiological parameters. The most widely used systems for the purpose of
      predicting outcome after trauma are based on combined anatomical and
      physiological parameters. Systems such as the Injury Severity Score (ISS) and the
      Trauma Injury Severity Score (TRISS) have served some useful purposes and have
      proved popular over time, but it now seems that there is no ideal scoring system
      available. The task of incorporating various factors such as pre-existing
      morbidity, age, immunological differences and different genetic predispositions
      has made the prospect of creating a universally acceptable and applicable trauma
      scoring system extremely arduous, if not impossible. Therefore caution should be
      exercised when using any of the existing scoring systems until an ideal one
      becomes available.

PMID- 15037370
TI  - Barotrauma.
AB  - Barotrauma is pressure-induced injury. The application of direct pressure to the
      body may cause trauma, including positive pressure from artificial ventilation.
      Trauma may also be caused by the effects of pressure changes on gas-containing
      body spaces, not in communication with the environment. This can include the
      external ear, the middle ear (and, indirectly, the inner ear), the para-nasal
      sinuses, the lungs, the gut, and abscess cavities (for example, in the teeth).
      Gas may penetrate tissues adjoining the affected space (such as the anterior
      cranial fossa, via the ethmoid sinus), or may embolise via the blood stream. The
      most severe expression of this is cerebral arterial gas embolism, which may
      present as a stroke. The management of these problems includes prevention, the
      use of pressure-equalizing techniques, vasoconstrictor drugs, surgery, and
      hyperbaric oxygen therapy.

PMID- 15037371
TI  - Pharyngeal and oesophageal injuries.
AB  - OBJECTIVES: (1) To determine the actual incidence of transmural pharyngeal and
      oesophageal injuries (POI); (2) to reveal the main causes and character of
      infectious complications following transmural POI; (3) to evaluate the
      effectiveness of different types of urgent surgical intervention for complicated
      transmural POI. METHODS: A detailed retrospective analysis was completed on 15
      years (1987-2001) of clinical experience, involving 84 cases of POI, caused by
      neck or chest injuries, foreign bodies, tracheal intubation, oesophagogastroscopy
      and oesophageal dilation (bougienage). RESULTS: Transmural (perforating) and
      superficial (non-perforating) POI were revealed in 58 and 26 cases, respectively.
      Transmural POI was diagnosed within 24h in 38 of the 58 patients. Fourteen
      patients with uncomplicated transmural POI were treated conservatively; all
      recovered uneventfully. Forty-two patients with complicated transmural POI
      underwent urgent surgical intervention. Hospital stay was shorter in patients who
      underwent primary repair of the perforated pharyngeal or oesophageal wall than in
      those who had only irrigational drainage ( 22.4 +/- 5.3 days versus 31.7 +/- 8.4
      days). Overall post-operative morbidity and mortality were 42.8 and 19.0%,
      respectively. CONCLUSIONS: (1) Transmural injuries occurred in approximately two
      third of the total number of POI; (2) underlying pathology, location of injury,
      time to accurate diagnosis and, eventually, urgent surgical intervention
      constituted statistically significant influences ( P < 0.05) relevant to
      development of complications following transmural POI; (3) urgent surgical
      intervention is the main part of the combined treatment of complicated transmural
      POI.

PMID- 15037372
TI  - Longitudinal trends in trauma mortality and survival in Stoke-on-Trent 1992-1998.
AB  - OBJECTIVES: To identify factors related to mortality and to test the null
      hypothesis of no longitudinal trend in mortality in patients admitted to the
      North Staffordshire Hospital (NSH) with an Injury Severity Score (ISS) greater
      than 15, between April 1992 and March 1998. DESIGN: Longitudinal prospective
      study of 18 factors, including age, sex, mechanism of injury, anatomical injury
      scores and year of admission. Outcome, based on mortality at discharge, was
      analysed in two ways: alive or dead at discharge (mortality) and time to death or
      discharge (survival). RESULTS: A decreasing trend (P < 0.01 ) in mortality with
      year of admission was detected on the log-odds scale. The trend could not be
      explained by a case-mix analysis, which allowed for the 17 other factors. Using
      multiple logistic regression analysis (mortality) and Cox proportional hazards
      analysis (survival), eight factors were identified as determinants of outcome:
      age, head AIS score, chest AIS score, abdominal AIS score, calendar year of
      admission, external injury AIS score, mechanism of the injury and primary
      receiving hospital. CONCLUSIONS: The observed improvement in survival in severely
      injured patients must result from the interplay of factors not controlled in this
      analysis or improvements in patient care or both.

PMID- 15037374
TI  - Epidemiology of major injury in the population of Friuli Venezia Giulia-Italy.
AB  - OBJECTIVE: To provide reliable and comparable information on major injury (MIJ)
      (Injury Severity Score (ISS) > 15) by establishing a comprehensive and Utstein
      style compliant registry of all occurrences in a defined geographical area.
      METHODS: Prospective, population-based, 12-month study targeting the 1,200,000
      inhabitants of the Italian region Friuli Venezia Giulia (FVG). Deliberate self
      harm was excluded. RESULTS: The total number of MIJ cases was 627, the resulting
      incidence 522 per million per year. Trauma was mostly blunt (98.4%). Young (15-44
      years) adults (54.8%) and males (78.6%) were most affected. Leading mechanisms of
      injury were traffic accidents (81%) and falls (9.1%). Most events occurred in
      rural (80.9%) areas despite one third of the regional population living in major
      urban centres. Summer and weekends carried the highest frequency. The mean ISS (
      n = 455 ) was 30.0, median 25. On-scene vital parameters were often subnormal,
      e.g. 53.9%, GCS < 14. The Emergency Medical System was nearly always activated
      (98.4%). The time intervals were within standards although in part susceptible of
      improvement. The percentage of direct triage to the definitive hospital was
      79.8%. Overall mortality was 45.6% or 238 per million per year. Most fatalities
      were found already dead (171/300) and no trimodal distribution was verified. Only
      1.5% of the patients found alive died outside hospital. Mean GOS was 4.4 +/- 1
      (S.D.), median 5. CONCLUSION: A considerable amount of information on MIJ in FVG
      has been gathered, of both local and general interest because it can help to
      assess the local trauma system and also, given the relative scarcity of
      prospective, population-based information on MIJ, contribute to scientific
      research.

PMID- 15037373
TI  - Measuring trauma outcomes in India: an analysis based on TRISS methodology in a
      Mumbai university hospital.
AB  - BACKGROUND: In this prospective study, the TRISS methodology is used to compare
      trauma care at a university hospital (Lokmanya Tilak Municipal General (LTMG)
      Hospital) in Mumbai, India, with the standards reported in the Major Trauma
      Outcome Study (MTOS). METHODS: Between 1 August 2001 and 31 May 2002, 1074
      severely injured patients were included in the study. Survival analysis was
      completed for 98.3% of the patients. RESULTS: The majority of the patients were
      men (84%) and the average age was 31 years. 90.4% were blunt injuries, with road
      traffic crashes (39.2%) being the most common cause. The predicted mortality was
      10.89% and the observed mortality was 21.26%. The mean Revised Trauma Score (RTS)
      was 6.61 +/- 1.65 and the mean Injury Severity Score (ISS) was 16.7 +/- 10.67.
      The average probability of survival (Ps) was 89.14. The M and Z statistics were
      0.84 and -14.1593, respectively. CONCLUSION: The injured in India were found to
      be older, the injuries more severe and with poorer outcomes, than in the MTOS
      study.

PMID- 15037375
TI  - Musculo skeletal trauma in an East African public hospital.
AB  - The contribution of musculo skeletal trauma to morbidity and disability in
      developing countries is often underestimated. As Head of Department of Surgery
      and Orthopaedics for 3 years at a non-paying hospital in Malawi/East Africa (one
      of the least developed countries according to UNDP), I analysed my operation log
      book of 658 cases. Although there are many specific and local factors influencing
      the picture, the main problems of trauma care in rural Africa become evident.
      Based on personal experience views on non-operative versus operative fracture
      treatment, indications, quality control and training are presented. First world
      standards, equipment and implants of yesterday are often the only ones available
      but they scarcely meet the demands of clinical practice in developing countries.
      Contemporary state-of-the-art knowledge lacks most of its material basis to be
      successfully introduced. However, transforming it into "appropriate technologies"
      is most rewarding not only for the individual trauma surgeon, but for the wider
      community within orthopaedics.

PMID- 15037376
TI  - Missed injury in major trauma patients.
AB  - OBJECTIVES: To determine the incidence, aetiology and contributing factors to
      injuries being missed during the primary and secondary surveys in patients with
      major trauma managed on a general Adult Intensive Care Unit (AICU). METHODS: The
      records for patients admitted to the AICU following severe injury (defined as
      injury severity score (ISS) >16) over a 1-year period were reviewed. Diagnostic
      imaging performed during the resuscitation was reviewed in cases where missed
      injuries were discovered. RESULTS: Forty-five patients with a median injury
      severity score of 26 were included in the study. Twelve missed injuries were
      discovered in 10 patients during the intensive care admission; three required an
      additional surgical procedure. There was no significant difference in Glasgow
      Coma Score, revised trauma score, ISS or admission systolic blood pressure
      between patients with missed injuries and those patients where all injures were
      found at resuscitation (P > 0.05). Three quarters of the undetected injuries were
      orthopaedic. CONCLUSIONS: Significant injuries can be missed during the primary
      and secondary surveys in severely injured patients. A tertiary survey should be
      completed in all trauma patients admitted to an intensive care unit.

PMID- 15037377
TI  - Delayed presentation is no barrier to satisfactory outcome in the management of
      open tibial fractures.
AB  - The management of open tibial fractures is a challenge to all orthopaedic trauma
      surgeons. The major goals are fracture union, uncomplicated soft tissue healing
      and return to pre-injury level of function. The geographical isolation and
      vastness of the Northern Territory of Australia complicates the management of
      these injuries by adding a significant delay to treatment. Forty-five patients
      sustained 48 open tibial fractures over the 30-month period of the study. Twelve
      received primary surgical treatment within 6h of injury but 33 were treated more
      than 6h after injury. The mean time to treatment in this latter group was 12h
      15min (median 9h 45min, range 6-37h). The majority of injuries were high energy,
      with 23 patients having multiple injuries and 29 fractures (60%) being classified
      as AO C3 with 35 (73%) having Gustilo III soft tissue injuries. There was a mean
      time to union of 7.5 months and an overall complication rate of 42.2%. Thirteen
      patients (29%) required additional (late) surgical procedures subsequent to
      definitive fracture and soft tissue management. The zone of injury infection rate
      was 12.5%. The high incidence of open tibial fractures places a large financial
      burden on the state. However, despite the absence of a plastic surgical service
      and delays in presentation, satisfactory outcomes can be obtained by the
      application of the established surgical principles of thorough debridement, soft
      tissue management and fracture stabilisation.

PMID- 15037378
TI  - Influence of fall height and impact surface on biomechanics of feet-first free
      falls in children.
AB  - OBJECTIVE: The objectives of our study were to assess biomechanics associated
      with feet-first free falls in 3-year-old children and to investigate the
      influence of impact surface type and fall height on key biomechanical measures
      associated with injury risk. METHODS: Repeatable feet-first free fall experiments
      were conducted in a laboratory mock-up environment using an instrumented Hybrid
      II 3-year-old test dummy. Impact surface type and fall height were varied to
      examine their influence on biomechanical measures. RESULTS: Feet-first falls from
      short distances (27 in.) (0.69 m) were found to have a low risk of contact-type
      head injury, regardless of impact surface type. When comparing different types of
      impact surfaces in a 27 in. (0.69 m) fall, head acceleration associated with
      falls onto playground foam was significantly less than that associated with falls
      onto wood, linoleum or padded carpet. For falls onto playground foam, femoral
      compressive loads and bending moments were found to significantly increase as
      fall height increased. CONCLUSIONS: Impact surface type and fall height were
      found to influence biomechanics associated with injury risk in feet-first free
      falls as assessed through experimental mock-ups using an instrumented child test
      dummy. Feet-first falls from short distances (27 in.) (0.69 m) were associated
      with a low risk of contact-type head injury as assessed using HIC, irrespective
      of impact surface type.

PMID- 15037379
TI  - Falls from flat-roofed houses: a surgical experience of 1643 patients.
AB  - PURPOSE: High falls from flat-roofed houses are a common cause of death and
      disability in the south-east part of Turkey; the aim of this study was to
      describe our experience of such falls seen over a 4-year period in Diyarbakir.
      METHODS: One thousand six hundred and forty-three patients (570 females and 1073
      males) who sustained injuries after an accidental fall from a flat-roofed house
      were entered into the study. RESULTS: The mean age was 18 (1-95) years; 49.4% of
      patients were under 10 years old; 81.5% were under 30 years old. The mean fall
      height was 4.5m (1-20 m). The mortality rate was 5.8% (96 patients). The mean
      fall height in children under the age of 15 years who died from the fall was 4m
      (67 patients) and in patients over the age of 15 years, 9m (29 patients). The
      most common injuries were to the head (45.1%) and 93.75% of those (n = 90) who
      died had a head injury. One hundred patients (6%) were followed because of
      abdominal bleeding: one of these had fallen from 2m, the reminder from 4 to 9 m;
      12 were operated on and 88 treated conservatively. CONCLUSION: Craniocerebral
      trauma is the most common injury in fatal falls from flat roofs and blunt
      abdominal trauma is an uncommon injury after falling from less than 4m.

PMID- 15037380
TI  - Ladder fall injuries: patterns and cost of morbidity.
AB  - Ladder fall injuries are associated with a wide spectrum of injury patterns.
      However, the healthcare cost of these injuries is unknown. The aim of this study
      was to determine the healthcare cost and duration of the morbidity associated
      with ladder fall injuries. A retrospective observational study involving patients
      with ladder injuries who presented to a Level 1 Trauma Centre over a 3-year
      period was performed. Patients then underwent a structured telephone interview to
      provide information about the duration of their disability and unemployment.
      There were 72 patients in the study, of whom 89% were male. Thirteen patients
      (18%) required hospital admission. The median length and cost of hospital stay
      was 1 week and 3555 (US$ 3950), respectively. The median duration of disability
      and unemployment was 6 weeks. The longest duration of disability was associated
      with foot fractures. The majority of patients fell between 5 and 10ft, and fell
      at work. The upper extremity was the most commonly injured anatomical region.
      There were no fatalities. Ladder injury falls are expensive to the health service
      and may warrant investment in their prevention.

PMID- 15037381
TI  - A novel solution for the notorious long-leg cylinder cast.
AB  - Although the long-leg cylinder cast is an effective means of immobilization, it
      is prone to distal migration which commonly results in skin compromise. Described
      here is a simple technique that involves using adhesive tape as a suspension
      mechanism. This technique is clinically effective, has a low complication rate
      and requires only a small diversion from standard practice.

PMID- 15037382
TI  - Superselective embolization for control of facial haemorrhage.
AB  - A case on the successful management of acute facial bleeding from the maxillary
      artery by superselective embolization is described. A 26-year-old male sustained
      a gunshot wound (GSW) to the face leading to profuse bleeding from the site of
      bullet entry, the nose and the mouth. Local measures failed to arrest the
      bleeding. The patient was stabilised haemodynamically, then the source of
      bleeding was located by angiography and the bleeding was arrested by
      superselective embolization.

PMID- 15037383
TI  - Necrosis of femoral head after fixation of trochanteric fractures with Gamma
      Locking Nail: a cause of late mechanical failure.

PMID- 15037385
TI  - Dall-Miles plates for periprosthetic femoral fractures a critical review of 16
      cases.

PMID- 15037386
TI  - A novel solution for the notorious long-leg cylinder case-commentary.

PMID- 15037387
TI  - Hormonal suppressive therapy for endometriosis may not improve patient health.
AB  - OBJECTIVE: To critically examine the possible association between hormonal
      treatment of endometriosis and ovarian cancer. RESULT(S): The malignant potential
      of endometriosis has been suggested by several clinical studies. Although
      controversial, ovarian carcinoma of the endometrioid and clear cell subtypes has
      been associated with endometriosis, particularly among subjects with a
      longstanding disease. Furthermore, a significantly higher frequency of
      endometriosis has been found in patients undergoing surgery for endometrioid,
      clear cell, and mixed subtypes of ovarian carcinoma, as compared with the other
      subtypes. Changes in the genomic material in endometriotic implants were observed
      by many investigators in chromosomes 1, 5, 6, 7, 16, and 22 by several methods
      (fluorescent in situ hybridization, comparative genomic hybridization, and
      others). Because hormonal ablative treatments may suppress the normal, eukaryotic
      cells more than the aneuploid cells bearing chromosomal aberrations, it may
      increase the rate of dyskaryotic cells in the endometriotic implants, possibly
      augmenting the risk of malignant transformation. A recent published association
      between Danazol and ovarian cancer suggests that such a theoretical risk may
      occur. CONCLUSION(S): The hormonal ablative treatment of endometriosis may
      increase the risk of malignant transformation in the endometriotic implants by
      causing a negative selection and increasing the rate of dyskaryosis and loss of
      heterozygosity.

PMID- 15037388
TI  - The potential danger of COX-2 inhibitors.
AB  - Cyclooxygenase (COX)-2 inhibitors have a major effect on ovulation and may impair
      fertilization, decidualization, implantation, and parturition, as well as female
      fertility. Women attempting to become pregnant need to pay more attention to
      their use of COX-2 inhibitors.

PMID- 15037389
TI  - George Washington's infertility: why was the father of our country never a
      father?
AB  - George Washington was the single most important figure in the founding of the
      United States of America. Numerous biographies of Washington have been written
      and his name is honored in countless ways, including as the name of the United
      States' capital. Washington has become so idealized in U.S. consciousness that it
      is easy to lose sight of his failings and disappointments. Undoubtedly, one of
      his most personal sorrows was his inability to have a child with his wife Martha.
      As the historian W.S. Randall puts it, "He was content with Martha, but mystified
      why, year after year, he and Martha could produce no Washington heir." In this
      article, George and Martha Washington's inability to have children is discussed,
      and it is suggested that George was the likely source of the couple's
      infertility. The author also speculates as to the cause of Washington's
      infertility and its effect on the course of American history. Frank discussion of
      Washington's infertility might provide some comfort to men struggling with
      infertility today.

PMID- 15037390
TI  - The desire of infertile patients for multiple births.
AB  - OBJECTIVE: To determine the proportion of infertile women who prefer a multiple
      birth over a singleton, patient characteristics associated with this desire, and
      patient knowledge about the risks of multiple births. DESIGN: Prospective
      analysis. SETTING: Academic university hospital-based infertility center and
      private general gynecology clinic. PATIENT(S): Four hundred sixty-four female
      patients with infertility who presented for their initial visit. MAIN OUTCOME
      MEASURE(S): Demographic characteristics, infertility history, desire regarding
      multiple births, knowledge of the risks of multiple births, and goals of
      infertility evaluation and treatment were determined by using a 41-question
      survey. Univariate analysis was performed to assess patient characteristics
      associated with the desire for multiple births. Independent factors associated
      with this desire were assessed by multivariable logistic regression analysis.
      RESULT(S): 20.3% of women desired multiples over a singleton gestation.
      Nulliparity, lower family income, younger patient age, prior evaluation for
      infertility, longer duration of infertility, and lack of knowledge regarding
      risks of twin gestations were associated with this desire. Only nulliparity and
      lower family income were independently associated. CONCLUSION(S): A sizable
      minority of infertility patients prefers a multiple birth as their treatment
      outcome. Patient education may be an effective strategy to reduce the incidence
      of twin and higher-order multiple pregnancies.

PMID- 15037392
TI  - Damaged babies from assisted reproductive technologies: focus on the BESST (birth
      emphasizing a successful singleton at term) outcome.
AB  - The BESST (birth emphasizing a successful singleton at term) statistic per
      assisted reproductive technolgies (ART) cycle commenced is proposed to help
      minimize multiple births.

PMID- 15037391
TI  - Parenting stress in first-time mothers of twins and triplets conceived after in
      vitro fertilization.
AB  - OBJECTIVE: To examine psychosocial and obstetric outcomes at 1 year postpartum in
      first-time mothers who conceived after IVF. DESIGN: Prospective cohort study.
      SETTING: University medical center in the United Kingdom. PATIENT(S): One hundred
      twenty-nine mothers with a single naturally conceived birth, 95 mothers with a
      single IVF birth, and 36 mothers with a twin or triplet IVF birth. MAIN OUTCOME
      MEASURE(S): General Health Questionnaire and Parenting Stress Index. RESULT(S):
      Twenty-two percent of mothers of multiples had Parenting Stress Index scores
      indicating severe parenting stress, compared with 5% of mothers of IVF singletons
      (odds ratio, 5.14 [95% confidence interval (CI), 1.55-16.99]) and 9% of mothers
      of naturally conceived singletons (odds ratio, 2.76 [95% CI, 1.03-7.4]). Mothers
      of multiple children conceived by IVF did not have poorer mental health but were
      less likely to be in paid employment at follow-up than were mothers of singletons
      conceived by IVF (odds ratio, 0.3 [95% CI, 0.13-0.67]) or naturally (odds ratio,
      0.27 [95% CI, 0.12-0.59]). Multiple births were more premature, had lower birth
      weights, and had more medical complications. They were more likely to have been
      admitted to special care than were singletons conceived by IVF (odds ratio, 14.6
      [95% CI, 5.1-42.0)] or those conceived naturally (odds ratio, 10.59 [95% CI, 3.67
      30.57]) CONCLUSION(S): Clinicians should ensure that couples making decisions
      about embryo transfer have considered the potential psychosocial burden of a
      multiple birth.

PMID- 15037393
TI  - In vitro fertilization outcomes: why doesn't anyone get it?
AB  - It is not only patients who frequently do not understand the implications of
      multiple pregnancies and IVF outcomes in general. Physicians, insurers, and
      governments must share the responsibility for failing to properly address both
      overall and multiple pregnancy rates after IVF.

PMID- 15037394
TI  - Multiple births from assisted reproductive technologies: a challenge that must be
      met.
AB  - The success of assisted reproductive technologies (ART) has been accompanied by
      dramatic increases in multiple births and their associated costs. Physicians who
      perform ART must develop effective treatment paradigms to reduce multiple births
      or risk regulatory intervention.

PMID- 15037395
TI  - Infertility and the desire for multiple births.
AB  - Increased physician and patient awareness of the risks of multiple births may be
      an important strategy to reduce the incidence of multiple gestation associated
      with assisted reproductive technologies.

PMID- 15037397
TI  - Informing offspring of their conception by gamete donation.
AB  - The Ethics Committee supports disclosure from parents to offspring about the use
      of donor gametes in their conception. The merits of further disclosure are
      discussed, and suggestions are made for policies for programs and sperm banks.

PMID- 15037398
TI  - A multimedia psychosocial support program for couples receiving infertility
      treatment: a feasibility study.
AB  - OBJECTIVE: To develop and test the feasibility of a theory-driven, psychosocial
      support CD-ROM prototype for couples in infertility treatment. DESIGN: Focus
      group meetings with reproductive health experts, semistructured interviews with
      infertility patients, and content analysis of an infertility message board to
      determine content domains of the CD-ROM. Usability and acceptance testing of
      prototype CD-ROM based on predetermined feasibility criteria. SETTING: Private
      offices and fertility centers. PATIENT(S): Expert panel of 5 reproductive health
      specialists; interviews with 62 individuals with infertility (35 women, 27 men);
      feasibility study with 12 patients and 12 experts in reproductive medicine and
      infertility support. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Product
      usability/acceptance test. RESULT(S): Participant feedback and content analysis
      informed the development of a prototype patient education CD-ROM that uses audio,
      video, interactive tasks, and personalized feedback. Over 80% of participants
      successfully completed usability tasks, and over 90% rated prototype satisfaction
      as "good" to "excellent." Some areas were noted for improvement in navigation and
      refinement in delivery of instructions. Results strongly indicate an interest in
      an infertility multimedia support tool. CONCLUSION(S): Multimedia methods may
      serve as an effective, innovative psychosocial intervention for infertility
      patients and overcome barriers of limited local access to educational and support
      services.

PMID- 15037399
TI  - Body composition characteristics and fat distribution patterns in young infertile
      women.
AB  - OBJECTIVE: To document body composition and fat patterning characteristics in
      normal and underweight infertile women. DESIGN: Status quo method. SETTING:
      University clinics. PATIENT(S): Fifteen amenorrheic women with anorexia nervosa,
      16 women with polycystic ovary syndrome (PCO2), 10 women with primary amenorrhea
      and 19 healthy controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S):
      Determination of body mass index, body composition parameters such as fat mass,
      lean body mass, bone mass using dual-energy x-ray absorptiometry (DEXA), fat
      distribution patterns, 17beta-estradiol, FSH, LH, prolactin, progesterone,
      testosterone, DHEA-S, and androstenedione levels. RESULT(S): A statistically
      significant difference was found comparing all proband groups with healthy
      controls for the majority of body fat and bone mineral content parameters but not
      for lean body mass. Infertile women of normal weight, with PCOS, and with primary
      amenorrhea exhibited an extraordinarily high amount of fat tissue and a tendency
      toward android fat patterning. In contrast, patients with anorexia nervosa and
      the healthy controls showed predominantly gynoid fat patterning. According to
      logistic regression analyses, anorexia nervosa was characterized by reduced fat
      tissue and PCOS was characterized by android fat patterning and an increased fat
      percentage. Patients with primary amenorrhea were characterized by reduced bone
      mass. CONCLUSION(S): Infertile young women showed characteristic differences in
      body composition and fat distribution patterns when compared with healthy,
      fertile, age-matched counterparts.

PMID- 15037400
TI  - Clomiphene citrate intrauterine insemination (IUI) before gonadotropin IUI
      affects the pregnancy rate and the rate of high-order multiple pregnancies.
AB  - OBJECTIVE: To determine if previous treatment with clomiphene citrate
      intrauterine insemination (CC-IUI) affects pregnancy and high-order multiple
      pregnancy (HOMP) rates in subsequent hMG-IUI or FSH-IUI cycles. DESIGN:
      Retrospective cohort study. SETTING: Private infertility clinic. PATIENT(S): Five
      hundred fifty-one patients (age <38 years) without tubal factor infertility,
      treated with 918 cycles of hMG/FSH-IUI after one or more unsuccessful cycles of
      CC-IUI; 908 patients treated with 1459 cycles of hMG/FSH-IUI without prior CC
      IUI. INTERVENTION(S): CC-IUI, hMG-IUI, FSH-IUI. MAIN OUTCOME MEASURE(S):
      Pregnancy rate per cycle, HOMP (three or more gestational sacs). RESULT(S):
      Pregnancy rates during the first three hMG-IUI or FSH-IUI cycles averaged 21.8 +/
      1.1% without previous CC-IUI, 19.6 +/- 1.3% after one to four cycles of CC-IUI,
      and 3.6 +/- 2.6% after >or= five previous CC-IUI cycles. The HOMP rates were 8.8%
      without previous CC-IUI, 7.5% after one, 5.7% after two and <2.6% (0 out of 38)
      after >or= three previous CC-IUI cycles. CONCLUSION(S): Pregnancy rates in
      hMG/FSH-IUI cycles are significantly reduced after four unsuccessful CC-IUI
      cycles. High-order multiple pregnancies due to hMG/HMG-IUI are reduced following
      previous unsuccessful CC-IUI cycles.

PMID- 15037401
TI  - Single blastocyst transfer: a prospective randomized trial.
AB  - OBJECTIVE: To determine the efficacy of single blastocyst transfer. DESIGN:
      Prospective randomized trial. SETTING: Private assisted reproductive technology
      unit. PATIENT(S): Forty-eight women undergoing IVF-embryo transfer with day 3 FSH
      <or=10 mIU/mL and at least 10 follicles >12 mm in diameter on day of hCG
      administration. INTERVENTION(S): Embryo culture to the blastocyst stage in
      sequential media G1/G2 followed by transfer of either one or two blastocysts.
      MAIN OUTCOME MEASURE(S): Implantation rate, ongoing pregnancy rate, and twinning.
      RESULT(S): The transfer of a single blastocyst resulted in an implantation and
      ongoing pregnancy rate of 60.9% with no twins. The transfer of two blastocysts
      resulted in an implantation rate of 56%, an ongoing pregnancy rate of 76% with a
      47.4% incidence of twins. CONCLUSION(S): Single blastocyst transfer is an
      effective method of eliminating multiple births while maintaining high pregnancy
      rates in this selected group of patients.

PMID- 15037402
TI  - Adjuvant low-dose aspirin therapy in poor responders undergoing in vitro
      fertilization: a prospective, randomized, double-blind, placebo-controlled trial.
AB  - OBJECTIVE: To evaluate the effect of adjuvant low-dose aspirin on utero-ovarian
      blood flow and ovarian responsiveness in poor responders undergoing IVF. DESIGN:
      Prospective randomized, double-blind, placebo-controlled study. SETTING:
      University-affiliated teaching hospital. PATIENT(S): Sixty patients classified as
      poor responders undergoing IVF. INTERVENTION(S): Supplementation with low-dose
      aspirin (80 mg daily) or placebo to a long down-regulation protocol. MAIN OUTCOME
      MEASURE(S): Doppler measurement of intraovarian and uterine pulsatility index was
      performed before (baseline) and after ovarian stimulation (day of hCG
      administration). Duration of use and dose of gonadotropins, cycle cancellation
      rate, number of mature follicles recruited, and oocytes retrieved were also
      measured. RESULT(S): High cancellation rates were found in both groups (33.3% vs.
      26.7%, placebo vs. treatment). There were no significant differences in total
      dose of hMG used (66 vs. 57 hMG, 75 IU ampules), median number of mature
      follicles recruited (3.5 vs. 3.0), or median number of oocytes retrieved (4 vs.
      3). No significant differences were found in either intraovarian or uterine
      artery pulsatility index measured at baseline or on the day of hCG
      administration. CONCLUSION(S): Supplementation with low-dose aspirin failed to
      improve either ovarian and uterine blood flow or ovarian responsiveness in poor
      responders undergoing IVF.

PMID- 15037404
TI  - Blastocyst-stage embryo transfer in patients who failed to conceive in three or
      more day 2-3 embryo transfer cycles: a prospective, randomized study.
AB  - OBJECTIVE: To compare blastocyst-stage embryo transfers (ETs) with day 2-3 ETs in
      patients who failed to conceive in three or more day 2-3 IVF/ET cycles. DESIGN:
      Prospective, randomized. SETTING: Fertility unit in a university medical center.
      PATIENT(S): Fifty-four patients with an adequate ovarian response underwent
      oocyte retrievals. The patients were prospectively and randomly divided into
      blastocyst-stage and day 2-3 ET groups. INTERVENTION(S): Ovarian down-regulation
      was obtained using GnRH agonist, and controlled ovarian hyperstimulation was
      achieved using daily administration of gonadotropins. MAIN OUTCOME MEASURE(S):
      The rate of blastocyst formation, ET cancellations, pregnancies, implantation,
      multiple gestation, and live births. RESULT(S): The clinical pregnancy rates per
      oocyte retrieval were 21.7% and 12.9% per blastocyst and day 2-3 ETs,
      respectively. Although there was a significantly higher implantation rate for
      blastocyst embryos (21.2%) as compared with 48- to 72-hour embryos (6%), the
      multiple-pregnancy rate was not significantly different between both groups. An
      ET cancellation rate of 26% and 6.4% for blastocyst and day 2-3 ETs,
      respectively, was observed. The presence of two or more 8-cell embryos on day 3
      in culture carried a high probability of obtaining blastocysts for transfer.
      CONCLUSION(S): This prospective randomized study suggests that in patients with
      an adequate ovarian response who failed to conceive in at least three IVF/ET
      cycles [1]. transfer of blastocyst-stage embryos carries a significantly higher
      implantation rate; [2]. the pregnancy rate per oocyte retrieval and ET are higher
      in the blastocyst-stage group, even if it did not reach statistical significance;
      [3]. a higher ET cancellation rate was observed in the whole blastocyst-stage
      group; [4]. the ET cancellation rate was reduced significantly if the decision to
      proceed to blastocyst transfer was made on day 3 after oocyte retrieval, which is
      a post hoc conclusion.

PMID- 15037403
TI  - Comparison of two different starting multiple dose gonadotropin-releasing hormone
      antagonist protocols in a selected group of in vitro fertilization-embryo
      transfer patients.
AB  - OBJECTIVE: To compare the efficacy of two starting protocols of multiple dose
      GnRH antagonists (GnRH-a). DESIGN: Prospective randomized controlled study.
      SETTING: In vitro fertilization-embryo transfer program at the Instituto
      Valenciano de Infertilidad, Valencia, Spain. PATIENT(S): One hundred nine
      patients undergoing controlled ovarian hyperstimulation (COH) with recombinant
      gonadotropins and GnRH-a (0.25 mg/d). INTERVENTION(S): Patients started GnRH-a
      administration on stimulation day 6 (group 1) or when the leading follicle
      reached a mean diameter of 14 mm (group 2). MAIN OUTCOME MEASURE(S): Implantation
      and pregnancy rates; serum E(2) and LH levels during ovarian stimulation; days of
      stimulation and GnRH-a administration. RESULT(S): Days needed for ovarian
      stimulation were similar in both groups but there was a significant difference
      when comparing days of GnRH-a administration. Serum E(2) and LH followed similar
      curves in both groups. Implantation and pregnancy rates were 23.7% and 44.4 % in
      group 1 and 28.6% and 50.9 % in group 2 (P=not significant [NS]). CONCLUSION(S):
      The efficacy of the two starting protocols of the multiple dose GnRH-a evaluated
      in this study is similar; however, this remark can only be drawn for a selected
      group of patients.

PMID- 15037405
TI  - Assisted reproduction may change birth intentions.
AB  - OBJECTIVE: To determine whether the development and expansion of assisted
      reproductive technology (ART) between 1982 and 1995 raised the birth intentions
      of subfecund people relative to fecund people. DESIGN: Comparison of birth
      intention rates among fecund and subfecund women in the 1982, 1988, and 1995
      rounds of the National Survey of Family Growth, standardized by age, parity, and
      education. SETTING: No clinical setting. PARTICIPANT(S): Nationally
      representative samples of married women who were 20 to 44 years old.
      INTERVENTION(S): None. RESULT(S): Between 1982 and 1995, birth intentions rose at
      least 2.5 times faster among subfecund women than among fecund women. This rise
      was not due to increasing average age at maternity over the period.
      CONCLUSION(S): The development of ART and expansion of services may well have
      increased birth intentions among subfecund women between 1982 and 1995.

PMID- 15037406
TI  - Impact of subserosal and intramural uterine fibroids that do not distort the
      endometrial cavity on the outcome of in vitro fertilization-intracytoplasmic
      sperm injection.
AB  - OBJECTIVE: To further evaluate the effects of intramural and subserosal uterine
      fibroids on the outcome of IVF-ET, when there is no compression of the
      endometrial cavity. DESIGN: Retrospective, matched-control study from January
      2000 to October 2001. SETTING: Private IVF center. PATIENT(S): Two hundred forty
      five women with subserosal and/or intramural fibroids that did not compress the
      uterine cavity (fibroid group) and 245 women with no evidence of fibroids
      anywhere in the uterus (control group). INTERVENTION(S): In vitro fertilization
      intracytoplasmic sperm injection (IVF-ICSI) cycles. MAIN OUTCOME MEASURE(S): The
      type of fibroid (intramural, subserosal), number, size (cm), and location of
      intramural leiomyomas (fundal, corpus) were recorded. Outcomes of IVF-ICSI cycles
      were compared between the two groups. RESULT(S): There was no correlation between
      location and number of uterine fibroids and the outcomes of IVF-ICSI. Patients
      with subserosal or intramural fibroids <4 cm had IVF-ICSI outcomes (pregnancy,
      implantation, and abortion rates) similar to those of controls. Patients with
      intramural fibroids >4.0 cm had lower pregnancy rates than patients with
      intramural fibroids <or=4.0 cm. There were no statistical differences related to
      delivery rates (31.5% vs. 32%, respectively) between all patients with fibroids
      and controls. Premature delivery rates for singleton gestations were 10% vs. 8%,
      respectively, in all patients with fibroid and controls. CONCLUSION(S): Patients
      having subserosal or intramural leiomyomas of <4 cm not encroaching on the
      uterine cavity have IVF-ICSI outcomes comparable to those of patients without
      such leiomyomas. Therefore, they might not require myomectomy before being
      scheduled for assisted reproduction cycles. However, we recommend caution for
      patients with fibroids >4 cm and that such patients be submitted to treatment
      before they are enrolled in IVF-ICSI cycles. Whether or not women with fibroids >
      4 cm would benefit from fibroid treatment remains to be determined.

PMID- 15037407
TI  - Role of cholesterol, calcium, and mitochondrial activity in the susceptibility
      for cryodamage after a cycle of freezing and thawing.
AB  - OBJECTIVE: To correlate the levels of two concrete sperm markers, cholesterol and
      Ca(+2), together with mitochondrial activity on raw semen samples with the post
      thaw recovery of spermatozoa with progressive motility on human sperm samples as
      the first step to improve sperm cryostorage protocols. DESIGN: Controlled
      prospective research project. SETTING: Private and university-affiliated setting.
      PATIENT(S): Semen samples from 122 males attending our center for infertility (n
      = 47) or semen donation (n = 75) were studied. INTERVENTION(S): The mean basic
      semen parameters of the 122 semen samples studied before and after the freezing
      and thawing process. MAIN OUTCOME MEASURE(S): We determined Ca(+2) and
      cholesterol concentrations on seminal plasma by enzymoimmunoanalysis techniques,
      intracellular Ca(+2) concentrations, cholesterol concentrations in the sperm
      plasma membrane and mitochondrial activity by fluorometry. RESULT(S): Cholesterol
      concentration in seminal plasma and cholesterol contents in the sperm membrane
      and mitochondrial activity were studied. No correlations were initially found to
      be of statistical significance. Regarding seminal plasma and intracellular sperm
      Ca(+2) concentrations, a statistically significant negative correlation was found
      (P=.036 and P=.016). CONCLUSION(S): Higher cholesterol contents do not appear to
      protect sperm against cryodamage. Conversely, Ca(+2) equilibrium appears to be
      essential for a good post-thaw recovery. Mitochondrial activity is not reflecting
      the possibilities of sperm survival and is probably not a good indicator of the
      sperm metabolism.

PMID- 15037408
TI  - Pharmacokinetics of dehydroepiandrosterone and its metabolites after long-term
      daily oral administration to healthy young men.
AB  - OBJECTIVE: To determine the effects of dehydroepiandrosterone (DHEA)
      supplementation on the pharmacokinetics of DHEA and its metabolites and the
      reproductive axis of healthy young men. DESIGN: A prospective, randomized, double
      blind, placebo-controlled pharmacokinetic study. SETTING: General Clinical
      Research Center and laboratories at the Keck School of Medicine of the University
      of Southern California, Los Angeles, California. PATIENT(S): Fourteen healthy
      men, ages 18-42 years. INTERVENTION(S): Daily oral administration of placebo (n =
      5), 50 mg DHEA (n = 4), or 200 mg DHEA (n = 5) for 6 months. Blood samples were
      collected at frequent intervals on day 1 and at months 3 and 6 of treatment. MAIN
      OUTCOME MEASURE(S): Quantification of DHEA, DHEA sulfate (DHEAS),
      androstenedione, T, E(2), dihydrotestosterone (DHT), and 5alpha-androstane-3alpha
      17beta-diol glucuronide (ADG). Physical examination, semen analysis, serum LH,
      FSH, prostate-specific antigen, and general chemistries were carried out.
      RESULT(S): Baseline DHEA, DHEAS, and ADG levels increased significantly from day
      1 to months 3 and 6 in the DHEA treatment groups but not in the placebo group. No
      significant changes were observed in pharmacokinetic values. Clinical parameters
      were not affected. CONCLUSION(S): DHEA, DHEAS, and ADG increased significantly
      during 6 months of daily DHEA supplementation. Although the pharmacokinetics of
      DHEA and its metabolites are not altered, sustained baseline elevation of ADG, a
      distal DHT metabolite, raises concerns about the potential negative impact of
      DHEA supplementation on the prostate gland.

PMID- 15037409
TI  - Human spermatozoa capacitated with progesterone or a long incubation show
      accelerated internalization by an alkyl ether lysophospholipid.
AB  - OBJECTIVE: To evaluate changes that occur in sperm plasma membranes during
      capacitation, the internalization of [(3)H]lyso-platelet activating factor
      ([(3)H]lyso-PAF) across the plasma membrane of human spermatozoa was measured as
      a function of incubation time or exposure to progesterone (P). DESIGN: In vitro
      cell culture study using human spermatozoa. SETTING: Department of Obstetrics and
      Gynecology, School of Medicine, the University of Tokushima, Japan. PATIENT(S):
      Semen were obtained from three fertile healthy volunteers. INTERVENTION(S): The
      internalization of [(3)H]lyso-PAF across the plasma membranes of human
      spermatozoa that were incubated for an extended period or exposed to P was
      measured at 5, 20, 60, and 120 minutes after the addition of the phospholipid
      probe using the modified albumin back-exchange method. MAIN OUTCOME MEASURE(S):
      The percentage of capacitated and acrosome-reacted sperm and the proportion of
      internalization of lyso-PAF across the plasma membrane. RESULT(S): A 6-hour
      incubation period significantly increased the percentage of capacitated
      spermatozoa and the proportion of internalization of [(3)H]lyso-PAF across the
      plasma membrane of human spermatozoa compared with controls (capacitated
      spermatozoa, 20.3 +/- 10.6% vs. 8.5 +/- 1.8%; internalization 120 minutes after
      the addition of the phospholipid probe, 25.6 +/- 2.5% vs. 11.6 +/- 3.0%) (mean +/
      SEM). Exposure to P significantly increased the percentage of capacitated
      spermatozoa compared with controls (19.6 +/- 6.8% vs. 11.0 +/- 2.4%) and also
      significantly accelerated the internalization of [(3)H]lyso-PAF compared with
      controls (internalization 120 minutes after the addition of the phospholipid
      probe, 26.2 +/- 1.8% vs. 21.4 +/- 1.1%). CONCLUSION(S): The administration of P
      or a long incubation increased the proportion of internalization and consequently
      induced capacitation in human spermatozoa.

PMID- 15037410
TI  - Age at natural menopause is not linked with the follicle-stimulating hormone
      receptor region: a sib-pair study.
AB  - OBJECTIVE: Studies have shown that age at natural menopause is heritable.
      Mutations in the FSH-receptor have been identified in women with premature
      ovarian failure (POF) and the FSH-receptor gene may, therefore, be considered a
      candidate gene for (early) menopausal age. This study investigates whether there
      is linkage between genetic markers in the FSH-receptor region and (early) age at
      menopause using a sib-pair design. DESIGN: Sib-pair based linkage analysis.
      SETTING: Sister pairs and their first-degree family members from The Netherlands.
      PATIENT(S): The inclusion criteria for a family were natural menopause in upper
      or lower tail of the distribution of menopausal age in at least two sisters. A
      total of 126 families with at least one sib-pair were included in this study. Six
      polymorphic markers encompassing the FSH-receptor gene were genotyped.
      INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Single point and multipoint
      logarithm of the odds (LOD) scores. RESULT(S): None of the markers showed
      evidence in favor of linkage with overall age at natural menopause or early age
      at natural menopause. CONCLUSION(S): Possibly, age at natural menopause in the
      more or less normal range is not part of the spectrum of phenotypes determined by
      mutations in the FSH-receptor gene. Alternatively, our results might be explained
      by genetic heterogeneity in the left tail of the distribution of menopausal age.
      This can limit the chance of finding a genetic locus, especially if this factor
      has a modest contribution to the phenotype.

PMID- 15037411
TI  - Effects of tibolone and continuous combined hormone therapy on mammographic
      breast density and breast histochemical markers in postmenopausal women.
AB  - OBJECTIVE: To compare changes in mammographic density and the expression of
      markers of proliferation (Ki67) and apoptosis (Bcl-2) after 1 year of treatment
      with tibolone and continuous conjugated equine estrogens combined with
      medroxyprogesterone acetate (CEE-MPA). DESIGN: Comparative, randomized, evaluator
      blinded study. SETTING: City research hospital. PATIENT(S): Thirty-seven
      postmenopausal women. INTERVENTION(S): Tibolone (2.5 mg; n = 18) or continuous
      conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (5 mg;
      n = 19) for 1 year. MAIN OUTCOME MEASURE(S): Mammographic density (BI-RADS
      density score), expression of immunohistochemical markers Ki67 and Bcl-2.
      RESULT(S): Mean breast density score decreased significantly from 2.22 to 1.67 in
      the tibolone group, compared with a significant increase in the CEE-MPA-treated
      group from 1.84 to 2.63. Ki67 expression decreased in 12 of 15, increased in 2 of
      15, and remained unchanged in 1 of 15 subjects in the tibolone group, compared
      with 1 of 19, 15 of 19, and 3 of 19 subjects, respectively, in the CEE-MPA group.
      Bcl-2 expression decreased in 12 of 15, increased in 2 of 15, and remained
      unchanged in 1 of 15 subjects in the tibolone group, compared with 5 of 19, 9 of
      19, and 5 of 19 subjects, respectively, in the CEE-MPA group. CONCLUSION(S): One
      year treatment with tibolone induced a decrease in breast density, with a
      reduction in proliferation and a stimulation of apoptosis, whereas 1-year
      treatment with CEE-MPA induced an increase in breast density, with stimulation of
      proliferation and inhibition of apoptosis, indicating that tibolone effects on
      the breast are different from those of CEE-MPA.

PMID- 15037412
TI  - Effect of rosiglitazone on insulin resistance, growth factors, and reproductive
      disturbances in women with polycystic ovary syndrome.
AB  - OBJECTIVE: To evaluate the effects of rosiglitazone on insulin resistance, growth
      factors, and reproductive disturbances in women with polycystic ovary syndrome
      (PCOS). DESIGN: Prospective study. SETTING: Women with PCOS attending as
      outpatients of the Endocrine Division, Hospital Durand, Buenos Aires. PATIENT(S):
      Twenty-four insulin-resistant women with PCOS. INTERVENTION(S): Hormonal
      evaluations and a standardized oral glucose tolerance test before and after a 3
      month trial of 4 mg of rosiglitazone daily. MAIN OUTCOME MEASURE(S): Serum LH,
      FSH, T, IGF-1, IGFBP-1, IGFBP-3, leptin, 17alpha-hydroxyprogesterone, insulin,
      and glucose concentrations. The area under insulin curve (AUC-insulin), the HOMA
      index (insulin resistance), the QUICKI index (insulin sensitivity), and the beta
      cell function were calculated. Body mass index (BMI) and the waist/hip ratio were
      evaluated. RESULT(S): A significant decrease was observed in serum fasting
      insulin, AUC insulin, HOMA index, beta-cell function, IGF-1, LH, and waist/hip
      ratio. The QUICKI index and IGFBP-1 increased significantly. Serum sex hormone
      binding globulin, androgens, leptin, IGFBP-3, and BMI remained unchanged. Twenty
      two of 23 females had their menses restored, and three patients became pregnant.
      One patient was excluded because she became pregnant at the second month.
      CONCLUSION(S): Associated with the decrease in LH, rosiglitazone improved insulin
      resistance parameters and normalized the menstrual cycle, which suggests that
      this drug could improve the endocrine-reproductive condition in insulin-resistant
      women with PCOS.

PMID- 15037413
TI  - A randomized trial of the effects of two types of short-term hypocaloric diets on
      weight loss in women with polycystic ovary syndrome.
AB  - OBJECTIVE: We performed this study as a pilot experiment to investigate the short
      term effects of two diets of varying composition on weight loss as the primary
      outcome in obese women with polycystic ovary syndrome (PCOS) seeking fertility.
      DESIGN: Randomized clinical trial. SETTING: Academic medical center. PATIENT(S):
      Thirty-five obese women with PCOS. INTERVENTION(S): We examined the effects of a
      1-month dietary intervention on the PCOS phenotype. Participants were randomized
      to one of two energy-restricted diets; high protein (HP: 30% protein, 40%
      carbohydrate, and 30% fat) or high carbohydrate (HC: 15% protein, 55%
      carbohydrate, and 30% fat). The fat content was held constant in both diets. MAIN
      OUTCOME MEASURE(S): Primary - change in body weight; Secondary - biometric,
      hormonal, lipid and lipoprotein, and markers of glucose homeostasis and energy
      metabolism. RESULT(S): Twenty-six women completed the study. Both the HP (-3.7 +/
      1.9 kg) and HC (-4.4 +/- 1.5 kg) diets resulted in significant weight loss, but
      there was no significant difference in mean weight loss between the two groups.
      There were also no differences between diets on a variety of measures including
      circulating androgens, measures of glucose metabolism, and leptin. However, the
      effects of a hypocaloric diet per se on improving metabolic and reproductive
      abnormalities in a group of PCOS women were marked by a decline in circulating
      androgens (P=.03), fasting and area under the curve (AUC) insulins (P<.05) on a 3
      hour oral glucose tolerance test (OGTT), and fasting and AUC leptin levels
      (P<.0001). There was a high prevalence of menstrual bleeding during the trial (14
      out of 26 patients). CONCLUSION(S): Those who completed the short-term
      hypocaloric diet had a significant weight loss and a significant improvement in
      their reproductive and metabolic abnormalities. There was no increased benefit to
      a high-protein diet. Future diet studies evaluating the ideal composition of a
      hypocaloric diet in women with PCOS will require a large study population, and
      will most likely require a multicenter trial.

PMID- 15037414
TI  - Cell-free fetal DNA levels in maternal plasma after elective first-trimester
      termination of pregnancy.
AB  - OBJECTIVE: To determine if first-trimester elective termination of pregnancy
      affects cell-free fetal DNA (fDNA) levels in maternal plasma. DESIGN: Prospective
      cohort study. SETTING: Clinical and academic research centers. PATIENT(S): One
      hundred thirty-four women who underwent first-trimester elective termination
      procedures. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Real-time polymerase
      chain reaction (PCR) amplification and measurement of DYS1, a Y-chromosome
      sequence, was used as a marker of fDNA. RESULT(S): We detected fDNA in
      pretermination samples from 27 out of 71 patients in the surgical arm, and 29 out
      of 63 patients in the medical arm. Based on confirmation of male gender in
      placental tissue, the sensitivity of fDNA detection is 92.6%. We detected fDNA as
      early as 32 days of gestation, which increased 4.2 genome equivalents/mL/week. In
      the surgical arm, the mean level of posttermination fDNA, adjusted for the
      clearance of fDNA in maternal blood, was higher than projected based on an
      expected increase with gestational age. In the medical arm, six patients had
      increased fDNA levels up to 11 days following termination. CONCLUSION(S): We
      found that fDNA can be reliably quantified in the early first trimester; fDNA
      elevation that occurs shortly after surgical termination may reflect fetomaternal
      hemorrhage or destruction of trophoblastic villi. Continued elevation of fDNA for
      several days may occur following medical termination.

PMID- 15037416
TI  - Differential macrophage infiltration in early and advanced endometriosis and
      adjacent peritoneum.
AB  - OBJECTIVE: To investigate the distribution of macrophage (Mphi) infiltration in
      eutopic and ectopic endometrium throughout the menstrual cycle. DESIGN:
      Controlled clinical study using intact tissue. SETTING: Nagasaki University
      School of Medicine, Nagasaki, Japan. PATIENT(S): Twenty infertile women with
      pelvic endometriosis and 20 women without endometriosis. INTERVENTION(S): Biopsy
      specimens from peritoneal lesions and corresponding eutopic endometrium were
      collected from women with or without endometriosis. Adjacent peritoneal biopsies
      were also obtained from a fraction of these women. The activated Mphi marker
      CD68, mitogenic marker hepatocyte growth factor (HGF), and endothelial cell
      surface marker von Willebrand factor were immunolocalized and quantitated by
      light microscopy and Q-H score. MAIN OUTCOME MEASURE(S): Tissue infiltration of
      Mphi in eutopic endometrium, ectopic endometrium, and adjacent peritoneum was
      examined, and its relationship with the immunoreaction of HGF and microvessel
      number was analyzed. The possible production of HGF by the isolated basal Mphi
      was also examined. RESULT(S): Tissue infiltration of Mphi in the eutopic and
      ectopic endometrium of women with stage I-II endometriosis was significantly
      higher than with stage III-IV endometriosis or in control women. Red peritoneal
      lesions and their adjacent peritoneum had the greatest Mphi concentration,
      compared with black or white lesions. These inflammatory cells showed a higher
      distribution in the secretory phase of the menstrual cycle. The Mphi density in
      the eutopic endometrium and corresponding red lesions showed a significant
      correlation with both Q-H score of HGF and microvessel density. A substantial
      amount of HGF was also produced by the isolated basal Mphi from women with
      endometriosis. CONCLUSION(S): These results suggest that the peritoneal lesions
      of early and active endometriosis and their adjacent peritoneum harbor abundant
      Mphi that could be involved in the growth of endometriosis.

PMID- 15037415
TI  - Psychological effect of the oral contraceptive formulation containing 3 mg of
      drospirenone plus 30 microg of ethinyl estradiol.
AB  - OBJECTIVE: To investigate in healthy eumenorrheic young women whether an oral
      contraceptive (OC) containing drospirenone (DRSP) (3 mg) + ethinyl estradiol (EE)
      (30 microg) (DRSP + EE) could modify psychological symptoms and whether it could
      modify steroids interfering with the gamma-aminobutyric acid (GABA)-A receptors.
      DESIGN: Clinical study of treated subjects and nontreated controls. SETTING:
      Healthy volunteers in the Department of Obstetrics and Gynecology at Cagliari
      University. PATIENT(S): Control group (n = 12) and OC group (n = 10) women with
      similar age, body mass index, and main outcome measures. INTERVENTION(S): The
      control group was studied during the first menstrual cycle at the follicular
      phase (FP) and at the luteal phase (LP) and during the third cycle at the LP; the
      OC group was studied during the first cycle, as described above, and on day 16-18
      of the third cycle of treatment with DRSP + EE. MAIN OUTCOME MEASURE(S):
      Psychometric scale (SCL-90), DHEAS, P, allopregnanolone (AP), and
      allotetrahydrodeoxy-corticosterone (THDOC). RESULT(S): SCL-90 and DHEAS did not
      vary throughout the menstrual cycle. P, AP, and THDOC values were higher during
      the LP than the FP. At the third cycle, in the control group the main outcome
      measures were similar to those at LP. In the OC group, the SCL-90 global score,
      the intensity of anxiety and phobic anxiety, the levels of anxiolytic steroids
      (P, AP, THDOC) and the anxiety-inducing steroid DHEAS were reduced.
      CONCLUSION(S): The results suggest beneficial effects of DRSP + EE on
      psychological symptoms by decreasing DHEAS.

PMID- 15037418
TI  - Synchronous sperm retrieval and sperm washing in an intracytoplasmic sperm
      injection cycle in an azoospermic man who was positive for human immunodeficiency
      virus.
AB  - OBJECTIVE: To present the first reported case of synchronous sperm retrieval
      followed by sperm washing before an intracytoplasmic sperm injection (ICSI) cycle
      in an HIV-positive azoospermic man. DESIGN: Case report. SETTING: Assisted
      reproduction center. PATIENT(S): A 40-year-old HIV-positive man with obstructive
      azoospermia due to vasal aplasia. INTERVENTION(S): Synchronous sperm retrieval,
      sperm washing, nucleic acid-based sequence amplification testing, and
      intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Successful sperm
      retrieval sufficient for sperm washing and fertilization. RESULT(S): Sufficient
      quantity of spermatozoa for washing was obtained at epididymal aspiration. After
      the wash, HIV ribonucleic acid (RNA) was undetectable with nucleic acid-based
      sequence amplification testing, enabling injection of oocytes collected after
      routine gonadotropin superovulation. Of seven oocytes collected from the 39-year
      old woman partner, six were injected and five fertilized (83%). Three embryos
      were transferred on day 2. The pregnancy test was negative on this occasion.
      CONCLUSION(S): This case demonstrates that sperm washing can be applied in cases
      of sperm retrieval where sperm volume and density is low, allowing the treatment
      of azoospermic HIV-positive men.

PMID- 15037417
TI  - Possible role of bacterial and viral infections in miscarriages.
AB  - OBJECTIVE: To determine the role of infections in miscarriages. Chorionic villi
      from aborted material were subjected to cytogenetic evaluation and analyzed for
      the presence of Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma
      hominis, human cytomegalovirus (HCMV), adeno-associated virus (AAV), and human
      papillomaviruses (HPV). DESIGN: Retrospective study. SETTING: University hospital
      and academic research institution. MAIN OUTCOME MEASURE(S): Karyotyping and
      detection of bacterial and viral DNA by means of polymerase chain reaction (PCR)
      in placenta specimens. RESULT(S): In 54 (50%) of 108 samples the karyotype was
      normal, in 38 (35%) samples it was abnormal, and in 16 (15%) samples karyotype
      was undetermined. No U. urealyticum, M. hominis, HCMV, or AAV-2 DNA was detected,
      while C. trachomatis DNA was detected in one (1%) and HPV DNA in eight (7%)
      samples. No significant correlation of HPV-positive findings with karyotype
      status was established. CONCLUSION(S): Our findings do not support a role of C.
      trachomatis, U. urealyticum, M. hominis, HCMV, or AAV infections in miscarriages
      during the first trimester of pregnancy. However, further investigation should be
      made to determine a possible involvement of HPVs in the development of genetic
      abnormalities of the fetus and in miscarriages.

PMID- 15037419
TI  - Hyperandrogenism in a postmenopausal woman presenting with a metastatic ileum
      endocrine tumor.
AB  - OBJECTIVE: To elucidate the mechanism of the hyperandrogenism found in a
      postmenopausal woman presenting an ileum endocrine tumor with ovarian metastases.
      DESIGN: Case report. SETTING: University hospital. PATIENT(S): A postmenopausal
      woman was referred for hirsutism. Basal plasma testosterone was high, 6.6 nM/L
      (normal, <or=0.7 nM/L). Pelvic magnetic resonance imaging revealed a 6-cm left
      ovarian mass. INTERVENTION(S): Bilateral salpingo-oophorectomy was performed.
      Pathological examination found a bilateral metastatic endocrine ovarian tumor,
      associated with a functional stroma. A primary ileum endocrine tumor was
      discovered and resected. MAIN OUTCOME MEASURE(S): Immunohistochemical study of
      the expression of steroidogenic enzymes and beta and alpha subunits of hCG.
      RESULT(S): Immunohistochemical expression of steroidogenic enzymes was found in
      the ovarian stromal tissue surrounding the tumor but not in the metastatic
      tumoral cells. A substantial percentage of the metastatic tumoral cells was
      immunopositive for the beta and alpha subunit of hCG but not the ileal cells.
      CONCLUSION(S): These data suggest an hCG paracrine effect of the ovarian
      metastases tumor on the adjacent interstitial cells, resulting in the
      virilization of the patient.

PMID- 15037420
TI  - Two successful spontaneous pregnancies in a patient with a primary primitive
      neuroectodermal tumor of the ovary.
AB  - OBJECTIVE: To describe a patient with primary primitive neuroectodermal tumor of
      the ovary with two successful spontaneous pregnancies. DESIGN: Case report.
      SETTING: Tertiary center for gynecologic oncology. PATIENT(S): A 25-year-old
      woman with two spontaneous pregnancies 5 months after and 2 years after
      conservative treatment of International Federation of Gynecology and Obstetrics
      stage IC primary primitive neuroectodermal tumor of the ovary. INTERVENTION(S):
      Assessment of extraovarian spread with staging laparotomy. Four courses of BEP
      (bleomysin, etoposide, cisplatin) and, for recurrent disease, six courses of
      salvage VIP (vinblastin, iphosphamide, mesna, cisplatin) chemotherapy. MAIN
      OUTCOME MEASURE(S): Two successful deliveries and no residual ovarian cancer.
      RESULTS(S): A healthy, normal female infant weighing 3600 g was delivered by
      cesarean section at 38 weeks' gestation. Sixteen months later another infant, a
      healthy, normal male weighing 3500 g, was delivered by cesarean section at 38
      weeks' gestation. No residual cancer was detected at follow-up 12 months after
      the last delivery. CONCLUSION(S): Conservative fertility-preserving treatment
      might be considered in patients with primary primitive neuroectodermal tumor of
      the ovary. Without any assisted reproductive technologies, spontaneous
      pregnancies might occur.

PMID- 15037421
TI  - Meiotic segregation of a t(7;8)(q11.21;cen) translocation in two carrier
      brothers.
AB  - OBJECTIVE: To determine the meiotic segregation of a t(7;8)(q11.21;cen)
      translocation in two carrier brothers. DESIGN: Analysis of sperm nuclei by
      fluorescence in situ hybridization (FISH). SETTING: Franche-Comte University
      Fertility Center in Besancon, France. PATIENT(S): Two oligospermic brothers with
      a (7;8) translocation. INTERVENTION(S): Dual FISH for chromosomes 7 and 8, and
      multicolor FISH for chromosomes X, Y, 15, and 18 were performed. MAIN OUTCOME
      MEASURE(S): Meiotic segregation differences between both brothers and controls.
      RESULT(S): In dual FISH 7-8, a total of 34527 (older brother) and 10023 (younger
      brother) spermatozoa were analyzed. The frequencies of alternate, adjacent 1,
      adjacent 2, and 3:1 segregations and diploidies were 56.7%, 25.1%, 11.1%, 7.06%,
      and 0.04%, respectively, in the older brother and 62.84%, 17.61%, 12.8%, 6.47%,
      and 0.28% in the younger. Also, the disomy rates of some chromosomes not
      implicated in the translocation would suggest a possible interchromosomal effect.
      CONCLUSION(S): The similar segregation profiles for the same translocation,
      compared with those very divergent profiles of the other cases of studied
      translocations that were published in the literature, confirm that the risks of
      meiotic imbalances vary primarily according to the characteristics of the
      chromosomes involved in the rearrangement and the breakpoint position.

PMID- 15037422
TI  - Pregnancy from intracytoplasmic sperm injection of a sperm head and detached
      tail.
AB  - OBJECTIVE: To evaluate sperm ultrastructure and the efficacy of intracytoplasmic
      sperm injection (ICSI) with careful positioning of the sperm midpiece next to the
      sperm head in a patient with easily decapitated sperm syndrome. DESIGN: In vitro
      fertilization case report with retrospective sperm ultrastructure analysis.
      SETTING: In vitro fertilization clinic and andrology laboratory. PATIENT(S): A
      couple seeking treatment for diminished ovarian reserve and male factor
      infertility using donor oocyte IVF. INTERVENTION(S): Motile sperm inadvertently
      decapitated during micromanipulation were used for a modified ICSI procedure in
      which the midpiece was carefully positioned proximal to the sperm head. Sperm
      were also analyzed by transmission electron microscopy (TEM). MAIN OUTCOME
      MEASURE(S): Fertilization rate, embryo development, pregnancy, and the incidence
      of normal sperm ultrastructure. RESULT(S): The ICSI resulted in a fertilization
      rate of 63% and embryo development of good to moderate quality of 36% of the
      embryos. Transfer of two embryos resulted in a pregnancy and birth of a healthy
      child. Normal sperm centrosomes were identified retrospectively. CONCLUSION(S):
      Pregnancy can result in patients where the sperm are decapitated during
      immobilization before ICSI if normal centrosomes are present and the head and
      midpiece are positioned closely together.

PMID- 15037423
TI  - Bilateral ovarian agenesis and the presence of the testis-specific protein 1-Y
      linked gene: two new features of Mayer-Rokitansky-Kuster-Hauser syndrome.
AB  - OBJECTIVE: To describe the clinical and laboratory features of Mayer-Rokitansky
      Kuster-Hauser syndrome (MRKH) and to provide evidence for its etiology. DESIGN:
      Case report. SETTING: General hospital. PATIENT(S): Six consecutive cases of MRKH
      over a period of 12 months. INTERVENTION(S): Endocrine evaluation was performed.
      Genital system abnormalities were studied by pelvic ultrasound, magnetic
      resonance imaging, and laparoscopy; associated congenital anomalies by bone
      studies and intravenous pyelogram; and presence of Y chromosome material by
      karyotype and polymerase chain reaction (PCR and nested PCR). MAIN OUTCOME
      MEASURE(S): Clinical and laboratory features of MRKH and presence of Y chromosome
      genes. RESULT(S): Endocrine evaluation was normal in five patients. One woman
      revealed hypergonadotropic hypogonadism due to bilateral absence of gonads. Four
      patients had symmetric (type A) and two had asymmetric uterine remnants and
      fallopian tubes (type B). Renal and skeletal malformations were present in both
      types of MRKH. Karyotype was 46,XX in all patients. Although PCR was negative,
      nested PCR revealed the testis specific protein 1-Y-linked (TSPY) gene in two
      women. CONCLUSION(S): Skeletal and renal malformations may be present in both
      MRKH subtypes. Gonadal absence may coexist with the syndrome. This is the first
      report that detects Y-chromosome genes in patients with MRKH.

PMID- 15037424
TI  - Apparent primary follicle-stimulating hormone deficiency is a rare cause of
      treatable male infertility.
AB  - OBJECTIVE: To find the underlying defect in a case of primary FSH deficiency and
      to estimate the beneficial effect of FSH treatment. DESIGN: Case report. SETTING:
      University hospital fertility clinic. PATIENT(S): Normal, healthy, 37-year-old
      male patient with severe oligoteratozoospermia. INTERVENTION(S): Levels of FSH,
      LH, LHRH provocation test, karyotyping, genomic analysis on the Y-chromosomal AZF
      region and sequencing of the FSHB gene, FSH treatment. MAIN OUTCOME MEASURE(S):
      We compiled detailed clinical and molecular data on four pregnancies. We compare
      this case with a similar case published recently. RESULT(S): There were
      detectable but very low FSH levels after LHRH provocation; the LH response was
      not entirely normal, and no genomic abnormalities were found in the FSHB gene.
      The FSH treatment resulted in four pregnancies, two of which ended in abortion;
      the other two resulted in the birth of two healthy children. Both our case and
      the published case had detectable but abnormally low FSH levels on some
      occasions, but normal or highly normal inhibin B levels that differed from the
      expected low levels. Both patients had a normal male phenotype and no detectable
      mutation in the FSHB gene. The published case differed from our patient in that
      the published case was azoospermic whereas ours was extremely
      oligoteratozoospermic. The beneficial effect of FSH treatment was only shown in
      our patient. CONCLUSION(S): The published case and ours may have a common, as yet
      unidentified, underlying defect. The dramatic and immediate effect of FSH
      treatment on our patient's fertility was clearly demonstrated.

PMID- 15037425
TI  - Expression failure of the Notch signaling system is associated with the
      pathogenesis of maturation arrest in male infertility patients.
AB  - The receptor or ligand of the Notch signaling system fails to express in the germ
      cells of maturation arrest patients, indicating that this signaling system is
      associated with for the pathogenesis of maturation arrest.

PMID- 15037426
TI  - Lack of association between smoking behavior and the sex ratio of offspring in
      the avon longitudinal study of parents and children.
AB  - In a population-based prospective cohort study, we found no evidence of an
      association between smoking behavior around the time of conception and the sex of
      the resulting offspring.

PMID- 15037427
TI  - Sharing of oocytes from infertile versus paid donors results in similar pregnancy
      and implantation rates.
AB  - Addition of infertile donors to the recipient program would increase availability
      of donor eggs and reduce long waiting times. Furthermore, it may allow some
      patients (i.e., the donors) to have IVF services even though they do not have
      adequate finances.

PMID- 15037428
TI  - Treatment of sexual dysfunctions secondary to male infertility with sildenafil
      citrate.
AB  - With the assumption that infertility and related diagnostic and therapeutic
      processes are stressful, an uncontrolled pilot study was designed to evaluate the
      effect of sildenafil citrate on sexual compliance and reproductive outcome. A
      group of sexually healthy men were studied after the administration of 50 mg
      sildenafil before semen collection for intrauterine artificial insemination (n =
      25) or planned intercourse for a postcoital test (n = 12). We demonstrated that
      sexual dysfunction is highly prevalent in patients undergoing diagnostic
      procedures for infertility, and that sildenafil is effective in reversing stress
      induced transitory impotence. Furthermore, sildenafil improved some seminal
      parameters, such as the percentage of spermatozoa with linear progressive
      motility, as well as the number of spermatozoa penetrating the cervical mucus.
      Two pregnancies were obtained after sildenafil administration.

PMID- 15037430
TI  - Selecting cryopreserved semen for assisted reproductive techniques based on the
      level of sperm nuclear DNA fragmentation resulted in pregnancy.
AB  - A cryopreserved sperm sample with a low level of DNA fragmentation was used for
      intracytoplasmic sperm injection and resulted in a twin birth from a couple with
      a 10-year history of idiopathic infertility.

PMID- 15037429
TI  - Role of CO(2) pneumoperitoneum-induced acidosis in CO(2) pneumoperitoneum
      enhanced adhesion formation in mice.
AB  - The effect of assisted ventilation and CO(2) pneumoperitoneum during laparoscopic
      surgery upon blood gases and adhesion formation were evaluated in mice. We
      confirmed that the CO(2) pneumoperitoneum induces acidosis and enhances adhesion
      formation, and an association between both effects was demonstrated, together
      with its modulation by the assisted ventilation.

PMID- 15037431
TI  - Initiation of the gonadotropin-releasing hormone antagonist ganirelix for in
      vitro fertilization cycles in which the lead follicle is >14 mm.
AB  - The initiation of GnRH antagonists when the lead follicle is >14 mm does not
      adversely affect IVF success rates and leads to a shortened duration of GnRH
      antagonist administration.

PMID- 15037432
TI  - Survival of frozen-thawed human ovarian fetal follicles in long-term organ
      culture.
AB  - Ovarian follicles obtained from second and third-trimester human fetuses survived
      4 weeks in organ culture and secreted 17-beta estradiol (E(2)).

PMID- 15037433
TI  - Effect of cryoprotectants on the ultrastructure of cooled human pronuclear
      oocytes.
AB  - Ultrastructural changes in human pronuclear oocytes were evaluated after cooling
      in the presence or absence of cryoprotectant.

PMID- 15037434
TI  - Developmental potential and chromosomal constitution of embryos derived from
      larger single pronuclei of human zygotes used in in vitro fertilization.
AB  - Blastocysts that develop from larger 1 pronuclear zygotes are suspected to be
      diploid and are comparable in development potential to 2 pronuclear zygotes.

PMID- 15037435
TI  - Is there a better match than yourself?

PMID- 15037437
TI  - Is there a better match than yourself?

PMID- 15037438
TI  - BMI--the fragility of fertility.

PMID- 15037440
TI  - More than one fertile ovulation per cycle?

PMID- 15037441
TI  - More than one fertile ovulation per cycle?

PMID- 15037442
TI  - More than one fertile ovulation per cycle?

PMID- 15037443
TI  - More than one fertile ovulation per cycle?

PMID- 15037444
TI  - Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor
      alpha blockers in ankylosing spondylitis.
AB  - BACKGROUND: TNFalpha blockers have been shown to be highly efficacious in
      patients with active ankylosing spondylitis (AS). OBJECTIVE: To identify
      parameters predicting the clinical response to TNF blockers in AS. METHODS:
      Patients with active AS participated in two placebo controlled, randomised trials
      conducted in Germany with infliximab (n = 69) and etanercept (n = 30),
      respectively. For inclusion in either trial patients had to have high disease
      activity (BASDAI >or=4) and a spinal pain score (numerical rating scale 0-10)
      >or=4 despite treatment with NSAIDs. A major clinical response was defined as a
      50% improvement of the initial BASDAI (BASDAI 50) after 12 weeks' treatment with
      active drug. Logistic regression likelihood ratio tests (univariate and
      multivariate), Student's t test, and chi(2) tests were performed. RESULTS:
      Univariate analysis showed the following to be predictors of a major response
      (BASDAI 50) to treatment: shorter disease duration (p = 0.003); lower BASFI (p =
      0.007); younger age (p = 0.009); raised ESR (p = 0.033); raised CRP (p = 0.035).
      After adjustment for disease duration, BASFI, ESR, and CRP, but not age, remained
      significantly associated. After adjustment for disease duration and for BASFI,
      ESR, CRP, and in addition, a higher BASDAI were significantly associated with
      response. The best multivariate model built by stepwise regression contained the
      covariables disease duration, BASFI, BASDAI, and CRP. CONCLUSION: A shorter
      disease duration, younger age, and a lower BASFI are predictors of a major
      clinical response to TNF blockers in active AS. Raised CRP and a higher BASDAI
      may also be valuable predictors. These data need to be confirmed in further
      studies.

PMID- 15037446
TI  - Does the 'old bag' make a good 'wind bag'?: Comparison of four fabrics commonly
      used as exclusion bags in studies of pollination and reproductive biology.
AB  - BACKGROUND AND AIMS: Fabrics used in pollination bags may exclude pollen carried
      by biotic vectors, but have varying degrees of permeability to wind-borne pollen.
      The permeability of bags to wind-borne pollen may have important consequences in
      studies of pollination and reproductive biology. The permeability of four fabrics
      commonly used in the construction of pollination bags was examined. METHODS:
      Deposition of wind-borne pollen on horizontally and vertically oriented
      microscope slides was assessed on slides enclosed in pollination bags, as well as
      on control slides. KEY RESULTS: It was found that the permeability of fabrics to
      wind-borne pollen, as measured by deposition on both horizontally and vertically
      oriented slides, decreased with pore size. However, deposition on horizontal
      slides was always greater than on vertical slides for a given fabric; this could
      manifest itself as differential success of pollination of flowers in bags
      dependent on flower orientation. CONCLUSIONS: Obviously, bags with mesh size
      smaller than most pollen grains are impermeable to pollen. However, material for
      such bags is very expensive. In addition, it was also observed that bags with
      even moderately small pore size, such as pores (approx. 200 microm) in twisted
      fibre cotton muslin, offered highly significant barriers to passage of wind-borne
      pollen. Such bags are sufficiently effective in most large-sample-size
      reproductive biology studies.

PMID- 15037445
TI  - Radiography as primary outcome in rheumatoid arthritis: acceptable sample sizes
      for trials with 3 months' follow up.
AB  - OBJECTIVES: To investigate whether plain radiographs can show changes in joint
      damage due to rheumatoid arthritis (RA) within 3 months. METHODS: 188 film pairs
      taken with a 3 month interval were evaluated. They were scored with
      (chronological) and without (paired) knowledge of the sequence of the films
      according to the Sharp/van der Heijde method. Changes in joint damage were
      analysed on a group and an individual level for different subsets of patients.
      Sample sizes required to detect statistically and clinically significant
      differences were estimated based on the percentages of patients with progression
      larger than the smallest detectable change (SDC). RESULTS: Changes in joint
      damage were seen by both the chronological and the paired scoring method. The
      percentage of patients with progression of joint damage larger than the
      corresponding SDCs (1.7 and 2.4) varied in the subsets from 18% to 64% if based
      on the chronological change-scores and from 9% to 36% using paired change-scores.
      Acceptable sample size estimates were seen in several subsets, depending on (a)
      how the investigated drug would reduce the individual risk of progression of
      joint damage (by an absolute or a relative risk reduction model); (b) how damage
      was scored (chronological or paired); (c) the baseline risk; and (d) whether a
      two sided or one sided test would be used. CONCLUSIONS: Changes in joint damage
      due to RA can be detected reliably already within 3 months. This finding can be
      used to plan short term, randomised controlled trials with radiographic
      progression as primary outcome.

PMID- 15037447
TI  - The north-east-Brazilian Liana, Adenocalymna dichilum (Bignoniaceae) pollinated
      by bats.
AB  - BACKGROUND AND AIMS: Of the set of syndromes displayed by specialized (euphilic)
      flowers, adaptation to pollination by bats (chiropterophily) is the least known.
      Accumulated new evidence reveals that this pollination mode plays a considerable
      role in tropical communities, especially in the neotropics. One family in which
      bat-pollinated species are known in several genera is the Bignoniaceae. Here is
      reported, for the first time, bat pollination and floral ecology in Adenocalymna
      dichilum (tribe Bignonieae). METHODS: Floral features of this species growing in
      Bahia (north-east Brazil) indicated possible chiropterophily, which was
      subsequently confirmed by direct observation and from photographs of bat visits.
      Timing of anthesis and nectar parameters were monitored in the field, and floral
      morphology was investigated with fixed flowers. KEY RESULTS: One to two flowers
      open per night on the upright, simple racemes of A. dichilum during several weeks
      in a 'steady state' mode. The bilabiate, cream-coloured corollas are functional
      for only a single night and wilt during the following day. A stout corolla, with
      a musky odour, and a large nectary disc with large quantities of watery nectar
      also conform to the syndrome. Glossophaga soricina (Glossophaginae) visited and
      pollinated the flowers in a trap-lining manner. Whilst hovering, the bats put
      their heads into the corolla mouth for less than 1 s to feed, thereby effecting
      the transfer of pollen which is deposited on their backs. CONCLUSIONS:
      Adenocalymna, a New World genus comprising approx. 50 species, exhibits floral
      adaptive radiation including species pollinated by bees, birds and possibly
      moths. The discovery of chiropterophily in A. dichilum adds another facet to the
      array of floral syndromes represented in the genus.

PMID- 15037449
TI  - Comparative ITS and AFLP analysis of diploid Cardamine (Brassicaceae) taxa from
      closely related polyploid complexes.
AB  - BACKGROUND AND AIMS: Diploid representatives from the related polyploid complexes
      of Cardamine amara, C. pratensis and C. raphanifolia (Brassicaceae), were studied
      to elucidate phylogenetic relationships among the complexes and among the
      individual taxa included. METHODS: Two independent molecular data sets were used:
      nucleotide sequences from the internal transcribed spacers (ITS) of nrDNA, and
      amplified fragment length polymorphism (AFLP) markers. Seventeen diploid taxa
      from the studied groups were sampled. KEY RESULTS: Both ITS and AFLP analyses
      provided congruent results in inferred relationships, and revealed two main
      lineages. While the C. amara group, consisting of C. wiedemanniana and four
      subspecies of C. amara, was resolved as a well-supported monophyletic group, taxa
      from the C. pratensis and C. tenera groups (the latter representing diploid taxa
      of the complex of C. raphanifolia) all appeared together in a single
      clade/cluster with no support for the recognition of either of the groups. Intra
      individual polymorphisms and patterns of nucleotide variation in the ITS region
      in C. uliginosa and C. tenera, together with the distribution of AFLP bands,
      indicate ancient hybridization and introgression among these Caucasian diploids.
      CONCLUSIONS: The lack of supported hierarchical structure suggests that extensive
      reticulate evolution between these groups, even at the diploid level, has
      occurred (although an alternative explanation, namely ancestral polymorphism in
      ITS data, cannot be completely excluded). Several implications for the
      investigation of the polyploid complexes of concern are drawn. When tracing
      origins of polyploid taxa, a much more complex scenario should be expected,
      taking into account all relatives as potential parents, irrespective of the group
      in which they are classified.

PMID- 15037450
TI  - Analysis of the spatial expression pattern of seven Kip related proteins (KRPs)
      in the shoot apex of Arabidopsis thaliana.
AB  - BACKGROUND AND AIMS: Kip-related-proteins (KRPs), negative regulators of cell
      division, have recently been discovered in plants but their in planta function is
      as yet unclear. In this study the spatial expression of all seven KRP genes in
      shoot apices of Arabidopsis thaliana were compared. METHODS: In situ
      hybridization analyses were performed on longitudinal sections of shoot apices
      from 2-month-old Arabidopsis plants. KEY RESULTS: The study provides evidence for
      different expression pattern groups. KRP1 and KRP2 expression is restricted to
      the endoreduplicating tissues. In contrast, KRP4 and KRP5 expression is mainly
      restricted to mitotically dividing cells. KRP3, KRP6 and KRP7 can be found in
      both mitotically dividing and endoreduplicating cells. CONCLUSION: The results
      suggest differential roles for the distinct KRPs. KRP1 and KRP2 might
      specifically be involved in the establishment of polyploidy. In contrast, KRP4
      and KRP5 might be involved in regulating the progression through the mitotic cell
      cycle. KRP3, KRP6 and KRP7 might have a function in both types of cell cycle.

PMID- 15037451
TI  - The role of staminate flowers in the breeding system of Olea europaea (Oleaceae):
      an andromonoecious, wind-pollinated taxon.
AB  - BACKGROUND AND AIMS: Andromonoecy, as a breeding system, has generated a
      considerable body of theory in terms of sexual selection, but extended records
      comparing the performance of pollen grains from staminate versus hermaphrodite
      flowers are still sparse. The objective in this study was to elucidate the role
      of staminate flowers in the andromonoecious breeding system of olive (Olea
      europaea). METHODS: To determine the meaning of staminate flowers, an evaluation
      was made of resource allocation to, and phenology of, staminate and hermaphrodite
      flowers in the cultivar 'Mission', and a comparison was made of the male function
      between both kinds of flowers. KEY RESULTS: Dry weight of hermaphrodite flowers
      was 19 % greater than dry weight of staminate flowers arising in comparable
      positions of the panicle. This difference was mainly due to pistil and petal
      weight; there were no significant differences in stamen weight. There were no
      significant differences between staminate and hermaphrodite flowers in either
      amount of pollen per anther, or pollen quality as determined by pollen viability,
      germinability or ability to fertilize other flowers. There was no significant
      link between gender and time of anthesis. However, position of the flower within
      the panicle correlated with time of anthesis and gender. Flowers at the apex and
      at primary pedicels tended to be hermaphrodite and open earlier, whereas flowers
      arising in secondary pedicels were mainly staminate and were commonly the last to
      reach anthesis. CONCLUSIONS: It is proposed that the main advantage provided by
      production of staminate flowers in olive is to enhance male fitness by increasing
      pollen output at the whole plant level, although a relict function of attracting
      pollinators cannot be completely discarded.

PMID- 15037453
TI  - Susac's syndrome.

PMID- 15037448
TI  - A post-genomic approach to understanding sphingolipid metabolism in Arabidopsis
      thaliana.
AB  - AIMS: To highlight the importance of sphingolipids and their metabolites in plant
      biology. SCOPE: The completion of the arabidopsis genome provides a platform for
      the identification and functional characterization of genes involved in
      sphingolipid biosynthesis. Using the yeast Saccharomyces cerevisiae as an
      experimental model, this review annotates arabidopsis open reading frames likely
      to be involved in sphingolipid metabolism. A number of these open reading frames
      have already been subject to functional characterization, though the majority
      still awaits investigation. Plant-specific aspects of sphingolipid biology (such
      as enhanced long chain base heterogeneity) are considered in the context of the
      emerging roles for these lipids in plant form and function. CONCLUSIONS:
      Arabidopsis provides an excellent genetic and post-genomic model for the
      characterization of the roles of sphingolipids in higher plants.

PMID- 15037452
TI  - Seed coat microsculpturing changes during seed development in diploid and
      amphidiploid Brassica species.
AB  - BACKGROUND AND AIMS: Seed coat morphology is known to be an excellent character
      for taxonomic and evolutionary studies, thus understanding its structure and
      development has been an important goal for biologists. This research aimed to
      identify the developmental differences of seed coats between amphidiploids and
      their putative parents in Brassica. METHODS: Scanning electron microscope (SEM)
      studies were carried out on six species (12 accessions), three amphidiploids and
      their three diploid parents. KEY RESULTS: Twelve types of basic ornamentation
      patterns were recognized during the whole developmental process of the seed coat.
      Six types of seed coat patterns appeared in three accessions of Brassica rapa,
      five types in B. oleracea, B. nigra and B. carinata, seven types in B. napus, and
      eight types in B. juncea. There was less difference among seed coat patterns of
      the three accessions of B. rapa. The reticulate and blister types were two of the
      most common patterns during the development of seeds in the six species, the
      blister-pimple and the pimple-foveate patterns were characteristic of B. rapa,
      and the ruminate of B. oleracea and B. nigra. The development of seed coat
      pattern in amphidiploids varied complicatedly. Some accessions showed
      intermediate patterns between the two putative parents, while others resembled
      only one of the two parents. CONCLUSIONS: The variation in the patterns of seed
      coat development could be used to provide a new and more effective way to analyse
      the close relationship among amphidiploids and their ancestral parents.

PMID- 15037454
TI  - Peripheral nerve imaging and the magic angle.

PMID- 15037455
TI  - Back surgery begets back surgery.

PMID- 15037456
TI  - Diffusion tensor imaging of cerebral white matter: a pictorial review of physics,
      fiber tract anatomy, and tumor imaging patterns.

PMID- 15037458
TI  - Quantitative assessment of parenchymal and ventricular readjustment to
      intracranial pressure relief.
AB  - A 26-year-old patient underwent endoscopic third ventriculostomy for the
      treatment of obstructive hydrocephalus. 3D volume data sets were obtained at 3 T
      before surgery and three times after surgery. Off-line analysis of individual
      imaging data (initial linear registration, intensity adjustment, and final
      nonlinear registration of pre- to postoperative MR images) yielded 3D
      displacement fields representing the postoperative structural brain change. In
      principle, such an analysis technique can be used in any clinical follow-up for
      which careful observation of tissue readjustment is of particular importance.

PMID- 15037457
TI  - Diffusion tensor imaging as potential biomarker of white matter injury in diffuse
      axonal injury.
AB  - BACKGROUND AND PURPOSE: Multiple biomarkers are used to quantify the severity of
      traumatic brain injury (TBI) and to predict outcome. Few are satisfactory. CT and
      conventional MR imaging underestimate injury and correlate poorly with outcome.
      New MR imaging techniques, including diffusion tensor imaging (DTI), can provide
      information about brain ultrastructure by quantifying isotropic and anisotropic
      water diffusion. Our objective was to determine if changes in anisotropic
      diffusion in TBI correlate with acute Glasgow coma scale (GCS) and/or Rankin
      scores at discharge. METHODS: Twenty patients (15 male, five Female; mean age, 31
      years) were evaluated. Apparent diffusion coefficients (ADCs) and fractional
      anisotropy (FA) values were measured at multiple locations and correlated with
      clinical scores. Results were compared with those of 15 healthy control subjects.
      RESULTS: ADC values were significantly reduced within the splenium (Delta18%, P
      =.001). FA values were significantly reduced in the internal capsule (Delta14%; P
      <.001) and splenium (Delta16%; P =.002). FA values were significantly correlated
      with GCS (r = 0.65-0.74; P <.001) and Rankin (r = 0.68-0.71; P <.001) scores for
      the internal capsule and splenium. The correlation between FA and clinical
      markers was better than for the corresponding ADC values. No correlation was
      found between ADC of the internal capsule and GCS/Rankin scores. CONCLUSION: DTI
      reveals changes in the white matter that are correlated with both acute GCS and
      Rankin scores at discharge. DTI may be a valuable biomarker for the severity of
      tissue injury and a predictor for outcome.

PMID- 15037459
TI  - Susac syndrome: report of four cases and review of the literature.
AB  - Susac syndrome is a rare disease of unknown pathogenesis. It is caused by a
      microangiopathy affecting the arterioles of the brain, retina, and cochlea,
      giving the classic clinical triad of subacute encephalopathy, visual loss
      secondary to retinal branch occlusions, and sensorineural hearing loss. The
      features of four cases of this syndrome are presented. MR imaging, retinal
      fluorescein angiography, and audiography findings enable diagnosis. Early therapy
      may reduce sequelae and improve recovery.

PMID- 15037460
TI  - Increased anterior temporal lobe T2 times in cases of hippocampal sclerosis: a
      multi-echo T2 relaxometry study at 3 T.
AB  - BACKGROUND AND PURPOSE: Increased T2 relaxation times in the ipsilateral
      hippocampus are present in patients with hippocampal sclerosis. Visual assessment
      of T2-weighted images of these patients suggests increased signal intensity in
      the anterior temporal lobe as well. Our aim was to assess hippocampal and
      anterior temporal T2 relaxation times in patients with partial epilepsy by using
      a new T2-relaxometry sequence implemented by using a 3-T General Electric imaging
      unit. METHODS: Coronal view T2 maps were generated by using an eight-echo Carr
      Purcell-Meiboom-Gill sequence (TE, 28-231) with an acquisition time of 7 min on a
      3-T General Electric Signa Horizon LX imaging unit. T2 relaxation times were
      measured in the hippocampus and anterior temporal lobe of 30 healthy control
      volunteers and 20 patients with partial epilepsy. RESULTS: For the 30 control
      volunteers, the mean hippocampal T2 relaxation time was 98 +/- 2.8 ms. In all
      measured areas, the asymmetry index was small (<0.01). For the 15 patients with
      independent evidence of hippocampal sclerosis established by visual, volumetric,
      and, when available, pathologic criteria, mean hippocampal T2 relaxation times
      were 118 +/- 7 ms (P <.0001) on the ipsilateral side and 101 +/- 4 ms (P =.005)
      on the contralateral side. The T2 values were also increased in the anterior
      temporal lobe (ipsilateral: 82 +/- 6 ms, P <.0001; contralateral: 79 +/- 6 ms, P
      =.01) as compared with the values for the control volunteers (75 +/- 3 ms). The
      five patients with focal cortical dysplasia had hippocampal T2 relaxation times
      that were not different from control values. CONCLUSION: T2 relaxometry at 3 T is
      feasible and useful and confirmed marked ipsilateral hippocampal signal intensity
      increase in patients with hippocampal sclerosis. Importantly, definite signal
      intensity change was also present in the anterior temporal lobe. T2 relaxometry
      is a sensitive means of identifying abnormalities in the hippocampus and other
      brain structures.

PMID- 15037461
TI  - Neurobrucellosis: clinical and neuroimaging correlation.
AB  - BACKGROUND AND PURPOSE: Manifestation of nervous system involvement by
      neurobrucellosis, a treatable infection, is not well documented. We investigated
      patterns of nervous system involvement and determined if neuroimaging
      abnormalities correlated with clinical manifestations of neurobrucellosis.
      METHODS: We reviewed 23 MR imaging studies (17 of brain, six of spine) and seven
      CT scans of brain in 23 patients (14 male and nine female patients; age range 17
      71 years) with positive Brucella titers in their serum and CSF. RESULTS: Twelve
      patients had central nervous system (CNS) involvement, four had peripheral
      nervous system (PNS) involvement, two had combined PNS and CNS involvement, and
      five had isolated hearing loss. Imaging findings were variable: five of seven
      brain CT studies were normal, and 10 of 23 MR studies were normal (eight brain,
      one thoracic, one lumbar). One brain CT study showed subthalamic hemorrhage, mild
      perivascular enhancement, left caudate lacunae, and diffuse white matter changes.
      One other brain CT study showed enhancement of the tentorium in addition to white
      matter changes. Abnormal MR findings were basal meningeal enhancement (n = 3),
      lumbar nerve root enhancement (n = 3), granuloma of the suprasellar region (n =
      1), diffuse white matter changes (n = 7), and spinal cord atrophy (n = 1). All
      patients improved after treatment with three antimicrobial drugs for 3-12 months.
      Seven patients had follow-up imaging; the enhancement disappeared but the white
      matter and ischemic changes persisted despite almost complete clinical recovery.
      CONCLUSION: Clinical-radiologic correlation in neurobrucellosis varies from a
      normal imaging study despite positive clinical findings, to a variety of imaging
      abnormalities that reflect either an inflammatory process, an immune-mediated
      process, or a vascular insult.

PMID- 15037462
TI  - Prediction of neurologic deterioration in patients with lacunar infarction in the
      territory of the lenticulostriate artery using perfusion CT.
AB  - BACKGROUND AND PURPOSE: A significant proportion of patients with lacunar
      infarctions experience neurologic deterioration after onset. However, no clinical
      examination has been established for prediction of the progress of symptoms. To
      determine the hemodynamic predictors of such progression, we performed perfusion
      CT to quantitatively assess cerebral blood flow (CBF), cerebral blood volume
      (CBV), and mean transit time (MTT) of patients with lacunar infarctions in the
      territory of the lenticulostriate artery. METHODS: We performed MR imaging and
      perfusion CT of 26 patients with lacunar infarction within 24 hr after onset. On
      the CBF map on perfusion CT scans, a round small region of interest was set at
      the region, with decreased CBF in the territory of the lenticulostriate artery
      (region of interest 1). Another region of interest was set in the mirror position
      to region of interest 1 in the contralateral hemisphere (region of interest 2).
      Using these two regions of interest, CBF, CBV, and MTT were measured. All
      patients underwent neurologic and MR imaging follow-up while receiving equivalent
      medical treatment. RESULTS: Neurologic deterioration after onset was shown in 13
      patients (progress group), whereas no neurologic deterioration was shown in the
      other 13 patients (control group). In the progress group, lacunar infarctions
      were enlarged on follow-up MR images. The ratio of region of interest 1/region of
      interest 2 showed significantly lower CBF and higher MTT in the progress group
      than in the control group. CONCLUSIONS: These results suggest that progressive
      lacunar infarction in the territory of the lenticulostriate artery could be
      predicted with a higher MTT ratio (>1.26) and a lower CBF ratio (<0.76) on
      perfusion CT scans obtained within 24 hr after onset.

PMID- 15037463
TI  - Imaging features of calvarial tuberculosis: a study of 42 cases.
AB  - BACKGROUND AND PURPOSE: Tuberculosis of the calvaria is a rare entity, and only
      anecdotal reports describing its imaging features have been previously published
      in the literature. We report the role of conventional radiography and CT findings
      on in the evaluation of calvarial tuberculosis in 42 cases. METHODS: Forty-two
      cases of pathologically verified calvarial tuberculosis were analyzed
      retrospectively by using conventional radiography and CT imaging. The patients
      included 28 male and 14 female subjects ranging in age from 5 to 48 years (mean
      age, 16 years). Surgery was performed in 28 patients, and the remaining 14
      patients underwent fine needle aspiration cytology. The histologic findings were
      consistent with the diagnosis of tuberculosis. At follow-up after 2 years, all
      patients had completely recovered. RESULTS: The male-to-female ratio was 2:1 (28
      male and 14 female). The maximum number of patients affected by calvarial
      tuberculosis ranged in age from 11 to 20 years (61.2%). The average duration of
      symptoms was 2.5 months. Thirty-nine (92.8%) patients had subgaleal soft tissue
      swelling, whereas 31(73.8%) patients had a well-defined lytic lesion in the
      calvaria. The parietal bone was most commonly affected site of the calvaria (ie,
      in 22 patients [52.4%]). These lesions were detected at conventional radiography
      in 34 (80.95%) patients. CT depicted bone destruction in 36 patients (85.7%)
      cases. Extradural lesions and intraparenchymal pathologies were detected in 22
      (52.3%) patients and 5 (11.9%) patients, respectively. CONCLUSION: In calvarial
      tuberculosis, conventional radiographs of the skull show focal bone destruction
      often with accompanying soft tissue opacity. CT helps in assessing the extent of
      bone destruction, scalp swelling, and degree of intracranial involvement. Surgery
      involving bone debridement is resorted to only in cases where bone destruction is
      extensive.

PMID- 15037464
TI  - Disappearing calvarium in Gorham disease: MR imaging characteristics with
      pathologic correlation.
AB  - Gorham disease is a rare condition characterized by intraosseous neoplastic
      proliferation of hemangiomatous tissue with progressive, massive osteolysis. We
      present a pathologically proved case of Gorham disease that involved the left
      parietal bone in a 23-year-old man. Imaging studies including conventional
      radiography of the skull, CT, MR imaging, and Technetium-99 m (Tc-99 m)
      scintigraphy demonstrated a large skull defect without associated soft tissue
      mass over the left parietal skull. Contrast enhancement and increased isotope
      uptake along the margin of the defect were shown at gadolinium-enhanced T1
      weighted MR imaging and Tc-99 m methylene diphosphate (Tc-99 m MDP) bone
      scintigraphy. Pathologic study revealed intraosseous angiomatosis at the
      periphery of the osteolytic skull lesion.

PMID- 15037465
TI  - Alexia without agraphia in a postpartum eclamptic patient with factor V Leiden
      deficiency.
AB  - We present a case of eclampsia complicated by alexia without agraphia. To our
      knowledge, this syndrome has never before been described in the literature.

PMID- 15037466
TI  - Pseudofenestration of the cervical internal carotid artery: a pathologic process
      that simulates an anatomic variant.
AB  - Fenestration of the cervical segment of the internal carotid artery (ICA) is
      considered an extremely rare anatomic variant, with, to the best of our
      knowledge, only four cases reported in the literature. We report six angiographic
      observations of apparent fenestration of the cervical ICA, which we believe are
      secondary to arterial dissection. We discuss the angiographic appearance of these
      pseudofenestrations and their potential clinical implications.

PMID- 15037467
TI  - Double origin of the posterior inferior cerebellar artery.
AB  - Double origin of the posterior inferior cerebellar artery (PICA) has rarely been
      demonstrated by angiography in the peer-reviewed literature. Of the three
      previous reports, this PICA variant arose from the left vertebral artery. We
      report a right-sided, double-origin PICA.

PMID- 15037468
TI  - A small pulmonary arteriovenous malformation as a cause of recurrent brain
      embolism.
AB  - We report a case of recurrent paradoxical brain embolism mediated through a small
      pulmonary arteriovenous malformation (PAVM) with a 1.8-mm-diameter feeding
      artery. In this case, the further recurrent stroke was prevented successfully by
      PAVM embolization. Although embolization therapy is currently recommended only
      for PAVMs with feeding arteries greater than 3 mm in diameter, the therapy may be
      needed also in the smaller PAVMs.

PMID- 15037469
TI  - Magic angle effects in MR neurography.
AB  - BACKGROUND AND PURPOSE: Magic angle effects are well recognized in MR imaging of
      tendons and ligaments, but have received virtually no attention in MR
      neurography. We investigated the hypothesis that signal intensity from peripheral
      nerves is increased when the nerve's orientation to the constant magnetic
      induction field (B(0)) approaches 55 degrees (the magic angle). METHODS: Ten
      volunteers were examined with their peripheral nerves at different orientations
      to B(0) to detect any changes in signal intensity and provide data to estimate
      T2. Two patients with rheumatoid arthritis also had their median nerves examined
      at 0 degrees and 55 degrees. RESULTS: When examined with a short TI inversion
      recovery sequence with different TEs, the median nerve showed a 46-175% increase
      in signal intensity between 0 degrees and 55 degrees and an increase in mean T2
      from 47.2 to 65.8 msec. When examined in 5 degrees to 10 degrees increments from
      0 degrees to 90 degrees, the median nerve signal intensity changed in a manner
      consistent with the magic angle effect. No significant change was observed in
      skeletal muscle. Ulnar and sciatic nerves also showed changes in signal intensity
      depending on their orientation to B(0). Components of the brachial plexus were
      orientated at about 55 degrees to B(0) and showed a higher signal intensity than
      that of nerves in the upper arm that were nearly parallel to B(0). A reduction in
      the change in signal intensity in the median nerve with orientation was observed
      in the two patients with rheumatoid arthritis. CONCLUSION: Signal intensity of
      peripheral nerves changes with orientation to B(0). This is probably the result
      of the magic angle effect from the highly ordered, linearly orientated collagen
      within them. Differences in signal intensity with orientation may simulate
      disease and be a source of diagnostic confusion.

PMID- 15037470
TI  - Cervical radiculopathy: open study on percutaneous periradicular foraminal
      steroid infiltration performed under CT control in 30 patients.
AB  - BACKGROUND AND PURPOSE: Cervical radiculopathy is a common entity that can become
      unremitting, seriously disrupting the patient's work and social activities. The
      purpose of our study was to evaluate the feasibility, tolerance, and efficacy of
      transforaminal periganglionic steroid infiltration under CT control. METHODS:
      Thirty patients with cervical radiculopathy, despite at least 1 month of
      appropriate medical treatment, underwent percutaneous periradicular foraminal
      steroid infiltration under CT control. Sixteen patients had foraminal
      degenerative stenosis, and 14 patients had disk herniation. The intensity of
      radicular pain was scored on an analogic visual scale (AVS). Pain relief was
      classified as excellent when the pain had diminished by 75% or more; good, by 50%
      74%; fair by 25%-49%; or poor, by less than 25%. The patients were followed up at
      2 weeks and at 6 months. RESULTS: No local complications occurred after the
      procedure. The mean AVS pain scores were 6.5 points before the procedure and 3.3
      points 2 weeks after, with significant pain relief (P <.001). Pain relief was
      excellent in 11 patients (37%) and good in seven patients (23%). There was no
      rebound of pain at the 6-month follow-up. The duration of symptoms before
      infiltration and the intensity and cause of radiculalgia were not predictive of
      radicular pain relief. CONCLUSION: Intraforaminal cervical infiltration produced
      substantial sustained pain relief, whatever the cause of the radiculalgia. The CT
      approach ensures the safety of vital structures and allows the precise injection
      of a steroid specifically targeted to the ganglia.

PMID- 15037471
TI  - MR imaging findings in cerebrospinal gnathostomiasis.
AB  - Human gnathostomiasis is an infection caused mainly by Gnathostoma spinigerum, a
      nematode. Infected humans can present with various clinical manifestations.
      Serology is the criterion standard for diagnosing gnathostomiasis, whereas MR
      imaging represents a complementary tool for assessing severity and extent of
      disease. We report two definite cases of gnathostomiasis that were confirmed by
      the immunoblotting technique. MR imaging of the cervical cords showed cord
      enlargement and diffuse high signal intensity, mainly of the gray-white matter
      regions. MR imaging of the brain showed hemorrhagic tract and scattered deep
      intracerebral hemorrhage with diffuse, fuzzy white matter lesions with nodular
      enhancement. Severe gnathostomiasis was unresponsive to treatment.

PMID- 15037472
TI  - MR imaging and spectroscopic study of epileptogenic hypothalamic hamartomas:
      analysis of 72 cases.
AB  - BACKGROUND AND PURPOSE: Reports of MR imaging in hypothalamic hamartomas
      associated with epilepsy are few, and the number of patients studied is small. We
      aimed to detail the relationship of hypothalamic hamartomas to surrounding
      structures, to determine the frequency and nature of associated abnormalities,
      and to gain insight into mechanisms of epileptogenesis. METHODS: We
      systematically examined MR imaging studies of 72 patients with hypothalamic
      hamartoma and refractory epilepsy (patient age, 22 months to 31 years). A
      dedicated imaging protocol was used in 38 cases. Proton MR spectroscopy of the
      hypothalamic hamartoma was performed for 19 patients and compared with the
      metabolite profile of the thalamus in 10 normal children and the frontal lobe in
      10 normal adults. RESULTS: Compared with normal gray matter, hypothalamic
      hamartomas were hyperintense on T2-weighted images (93%), hypointense on T1
      weighted images (74%), and had reduced N-acetylaspartate and increased
      myoinositol content shown by MR spectroscopy. Hypothalamic hamartomas always
      involved the mammillary region of the hypothalamus, with attachment to one or
      both mammillary bodies. Intrahypothalamic extension (noted in 97%) tended to
      displace the postcommissural fornix and hypothalamic gray matter anterolaterally,
      such that the hypothalamic hamartomas nestled between the fornix, the mammillary
      body, and the mammillothalamic tract. Larger hamartoma size was associated with
      central precocious puberty. Associated findings of questionable epileptic
      significance included anterior temporal white matter signal intensity
      abnormalities (16%) and arachnoid cysts (6%). Malformations of cortical
      development were observed in only two patients, and hippocampal sclerosis was not
      observed. CONCLUSIONS: Hypothalamic hamartomas can be readily distinguished from
      normal hypothalamic gray and adjacent myelinated fiber tracts, best appreciated
      on thin T2-weighted images. MR imaging and spectroscopy suggest reduced neuronal
      density and relative gliosis compared with normal gray matter. Associated
      epileptogenic lesions are rare, supporting the view that the hypothalamic
      hamartoma alone is responsible for the typical clinical features of the syndrome.
      The intimate relationship to the mammillary body, fornix, and mammillothalamic
      tract suggests a role for these structures in epileptogenesis associated with
      hypothalamic hamartomas.

PMID- 15037474
TI  - Spontaneous superficial parenchymal and leptomeningeal hemorrhage in term
      neonates.
AB  - BACKGROUND AND PURPOSE: Intracranial hemorrhage in term neonates often results
      from asphyxia, obvious birth trauma, blood dyscrasia, or vascular malformation
      but may occur without an obvious inciting event. In this study, we review the
      clinical and neuroimaging features of healthy term neonates presenting with
      spontaneous superficial parenchymal and leptomeningeal (ie, subpial or
      subarachnoid) hemorrhage. METHODS: The clinical records and neuroimaging studies
      of seven term neonates with spontaneous superficial parenchymal and
      leptomeningeal hemorrhage were retrospectively reviewed. All underwent diffusion
      weighted MR imaging and 6 underwent CT within 72 hours of birth. Magnetic
      susceptibility-weighted imaging was performed in five, MR angiography in two, and
      MR venography in two. Follow-up MR imaging was performed in one infant. Clinical
      follow-up was done in four patients. RESULTS: All neonates had normal birth
      weights and high 5-minute APGAR scores. All were delivered vaginally (one with
      forceps assistance, and one with vacuum assistance). No blood dyscrasias were
      noted. Within 36 hours after delivery, all neonates presented with apnea or
      seizures or both. Neuroimaging subsequently revealed superficial parenchymal and
      leptomeningeal hemorrhage. Four occurred in the anterior-inferior-lateral
      temporal lobe adjacent to the pterion. The remaining three were located in the
      parietal lobe, frontal lobe, and lateral temporal lobe under the squamosal
      suture. Decreased diffusion in parenchyma adjacent to the hemorrhage and
      overlying subcutaneous soft-tissue swelling were apparent in five patients.
      Susceptibility-weighted imaging showed no additional lesions. MR angiography and
      MR venography findings were normal. Follow-up MR imaging in one patient
      demonstrated encephalomalacia. Four patients with short-term clinical follow-up
      were neurologically normal. CONCLUSION: Spontaneous superficial parenchymal and
      leptomeningeal hemorrhage occurs in otherwise healthy term neonates. The
      hemorrhage is most often in the temporal lobe and in proximity to sutures,
      accompanied by overlying soft-tissue swelling and adjacent decreased diffusion.
      This pattern leads us to implicate local trauma with contusion or venous
      compression or occlusion in the development of these hemorrhages.

PMID- 15037473
TI  - MR imaging quantification of cerebellar growth following hypoxic-ischemic injury
      to the neonatal brain.
AB  - BACKGROUND AND PURPOSE: Cerebellar atrophy may occur as a result of a primary
      injury, such as infarction or hemorrhage. Impaired growth of a non-injured
      cerebellum may be seen as a secondary effect related to damage in other remote
      but connected areas of the brain, or so-called diaschisis. We sought to determine
      whether perinatal hypoxic-ischemic injury leads to poor cerebellar growth and
      whether such impairment occurs asymmetrically in infants with predominantly
      unilateral brain injury. METHODS: We used a computerized quantification program
      to measure cerebellar size by using serial MR images. Term-born infants
      presenting with encephalopathy and/or seizures presumed due to a hypoxic-ischemic
      insult within 48 hours of delivery were included if they had two or more volume
      acquisition images obtained at least 3 months apart but within the first 15
      months of delivery. RESULTS: When data were grouped by MR appearances,
      significant differences in total cerebellum growth were seen between infants with
      focal infarction and those with basal ganglia and thalamic injury (P <.001).
      Unilateral forebrain lesions shown on MR imaging were not predictive of
      asymmetric cerebellar growth. CONCLUSION: Infants with focal infarction of the
      cerebral hemisphere had an apparently normal pattern of growth in both cerebellar
      hemispheres. However, in infants with severe basal ganglia and thalamic lesions,
      cerebellar growth was reduced, and the vermis showed little or no growth during
      the first year after birth.

PMID- 15037475
TI  - Imaging findings of CNS atypical teratoid/rhabdoid tumors.
AB  - Four patients with brain tumors were diagnosed with atypical teratoid/rhabdoid
      tumors and underwent CT and MR imaging. For all tumors, aggressive features were
      shown by imaging studies and included hydrocephalus, apparent invasion of the
      adjacent brain and dura, and marked mass effect. The striking heterogeneity of
      the atypical teratoid/rhabdoid tumor shown by imaging studies reflects the
      histopathologic complexity of these tumors, and awareness of atypical
      teratoid/rhabdoid tumor is important in making the correct diagnosis of this
      uncommon but probably underdiagnosed entity.

PMID- 15037477
TI  - In vivo proton MR spectroscopy of primary and nodal nasopharyngeal carcinoma.
AB  - BACKGROUND AND PURPOSE: The aim of this study was to determine the feasibility of
      performing in vivo proton ((1)H) MR spectroscopy of nasopharyngeal carcinoma
      (NPC) and to document the (1)H spectrum of this cancer. METHODS: Twenty-seven
      patients with NPC lesions >1 cm(3) underwent localized (1)H MR spectroscopy
      performed at 1.5 T. Water-suppressed spectra from both primary tumors (nine
      cases) and metastatic nodes (18 cases) were obtained at TE 136 and 272. Spectra
      were analyzed in the time domain by using a nonlinear least squares fitting
      algorithm with incorporation of previous knowledge. Choline (Cho)/creatine (Cr)
      ratios for primary NPC and metastatic nodes were calculated and compared. Spectra
      from normal neck muscle of five volunteers were acquired as control data.
      RESULTS: (1)H MR spectroscopy was successfully obtained in seven (78%) of nine
      primary tumors and 16 (89%) of 18 metastatic nodes. Intense lipid signals in the
      range of 0.89 to 2.02 ppm were observed in 95% of spectra at TE 136 and 91% of
      spectra at TE 272. At TE 136, Cho/Cr for metastatic nodes (5.3 +/- 1.6) was
      significantly higher than the ratio for primary (2.6 +/- 0.5) NPC lesions (P
      =.02). Cho/Cr ratios for NPC lesions were higher than those for normal neck
      muscles, for which values ranged from 0 to 0.97 and 0 to 1.1 at TE 136 and 272,
      respectively. CONCLUSION: (1)H MR spectroscopy is a feasible technique for the
      evaluation of NPC tumors >1 cm(3). Cho/Cr ratios for the lesions were high
      compared with those for normal neck muscle.

PMID- 15037476
TI  - Atypical teratoid/rhabdoid tumor of the cerebellum: report of two infantile
      cases.
AB  - Atypical teratoid/rhabdoid tumor of the CNS is an aggressive infantile neoplasm
      of uncertain origin. In our two infantile cases, this tumor presented as a bulky
      cerebellar hemispheric mass with significant mass effect to the fourth ventricle
      and brain stem. Although the attenuation on CT and signal intensity
      characteristics at MR imaging of this tumor were similar to those of vermian
      medulloblastoma, cerebellar hemispheric location and aggressive growth pattern
      could be considered as different gross morphologic characteristics of this tumor.
      Despite intensive chemotherapy and radiation therapy, both of our two patients
      died within 8 months of pathologic diagnosis.

PMID- 15037478
TI  - Progressive calvarial and upper cervical pneumatization associated with habitual
      valsalva maneuver in a 70-year-old man.
AB  - A 70-year old man with a 15-year-history of chronic daily Valsalva maneuvers for
      left ear congestion presented with worsening vertigo and calvarial
      (occipitoparietal) and upper cervical hyperpneumatization. With continued
      frequent Valsalva maneuvers, subsequent studies demonstrated increased
      pneumatization with extension of air into the epidural space, causing mass effect
      on the left parietal lobe. Four months after discontinuing the habitual Valsalva
      maneuvers, CT demonstrated resorption of the epidural air and partial regression
      of the calvarial pneumatization.

PMID- 15037479
TI  - Charcot-Marie-Tooth disease: extensive cranial nerve involvement on CT and MR
      imaging.
AB  - We report a case of genetically verified Charcot-Marie-Tooth disease in which the
      patient had cranial nerve symptoms. CT and MR imaging demonstrated enlargement of
      several cranial nerves, as well as their skull-base foramina, with faint contrast
      material enhancement identified.

PMID- 15037480
TI  - Lacrimal location of sinus histiocytosis (Rosai-Dorfman-Destombes disease).
AB  - A 7-year-old West African male patient presented with recurrence of multiple
      cervical lymphadenopathy. Cervical node biopsy disclosed a sinus histiocytosis
      with massive lymphadenopathy (Rosai-Dorfman-Destombes disease). During follow-up,
      the patient developed a left orbital mass corresponding to an enlarged lacrimal
      gland shown by CT. The histologic features of the gland were consistent with the
      diagnosis, and with steroid treatment, the gland decreased in size. Although
      rare, the diagnosis of sinus histiocytosis with massive lymphadenopathy has to be
      considered in cases of lacrimal gland enlargement.

PMID- 15037481
TI  - Endovascular management of the traumatic cerebral aneurysms associated with
      traumatic carotid cavernous fistulas.
AB  - BACKGROUND AND PURPOSE: Simultaneous traumatic carotid-cavernous fistulas(TCCFs)
      and traumatic cerebral aneurysms (TCAs) of the internal carotid artery (ICA) are
      rare. We describe the pitfalls of detecting a TCA before TCCF occlusion and the
      endovascular management of the TCA and TCCF. METHODS: Over 12 years, 156 patients
      with TCCFs were treated at our institute. In four men (mean age, 34 years),
      associated TCAs were detected before (n = 1) or after (n = 3) endovascular
      occlusion of the TCCFs. Causes for the missed detection of the TCA before TCCF
      occlusion were masking by a parent artery and fistula drains (n = 1), steal
      phenomenon (n = 1), and a latent period (n = 1). The TCAs were in the
      supraclinoid ICA (n = 3) or the paraophthalmic artery (n = 1). Three TCAs were
      treated with the endosaccular placement of electrodetachable coils. RESULTS: Two
      TCCFs and associated TCAs were successfully occluded with preservation of the
      ICA. The paraophthalmic TCA was treated with coil occlusion of the TCA and TCCF.
      Spontaneous fatal rupture of the TCA occurred in one patient after subtotal TCCF
      occlusion. No notable procedure-related complication was observed in the other
      three patients. CONCLUSION: TCAs may be difficult to detect before treatment of
      the TCCF because it may be overlooked, a latent period may occur, flow may be
      shunted, or they may be masked by a nearby parent artery or fistula drains. As
      soon as a TCA is found, endovascular management should be initiated promptly.

PMID- 15037483
TI  - A novel endovascular treatment of a wide-necked basilar apex aneurysm by using a
      Y-configuration, double-stent technique.
AB  - Wide-necked bifurcation aneurysms remain a formidable challenge to the
      neuroendovascular surgeon. A 36-year-old woman with a wide-necked basilar
      bifurcation aneurysm was unsuccessfully treated by endovascular methods, despite
      the use of the balloon-remodeling technique. Successful coiling was ultimately
      achieved by use of a Y-configuration double stent-assisted technique. This novel
      method of using self-expanding stents may represent a significant advance in the
      management of basilar apex and other bifurcation aneurysms.

PMID- 15037482
TI  - Postembolization hemorrhage of a large and necrotic meningioma.
AB  - Microparticulate embolization of meningiomas is a useful preoperative measure,
      but the potential risk of hemorrhagic complications should be recognized and
      balanced against the benefits. We report a case of subarachnoid hemorrhage
      occurring immediately after the embolization of a meningioma. Techniques for
      early diagnosis, such as CT, and early surgical intervention are crucial to a
      promising outcome. Large-size and necrotic or cystic components of a meningioma
      are probable risk factors that demand special consideration.

PMID- 15037484
TI  - Hyperacute stroke: experience essential when reading unenhanced CT scans.

PMID- 15037485
TI  - Establishing an optimal therapeutic range for coumarins: filling in the gaps.

PMID- 15037486
TI  - The costs of denying scarcity.

PMID- 15037487
TI  - Deception in the pursuit of science.

PMID- 15037488
TI  - Clinical considerations in premenopausal osteoporosis.
AB  - Osteoporosis can occur at any age. In premenopausal osteoporosis, full
      achievement of peak bone mass may be curtailed, and accelerated bone loss may
      occur in young adulthood. Premenopausal osteoporosis may be associated with
      chronic glucocorticoid therapy, prolonged amenorrhea, anorexia nervosa,
      rheumatoid arthritis, and diseases that affect calcium and vitamin D metabolism.
      Lesser degrees of bone loss may be associated with common conditions such as
      dieting, low calcium intake, smoking, and oligomenorrhea. Owing to a paucity of
      prospective studies on screening and treatment in younger age groups, few
      practice recommendations exist to guide the management of osteoporosis in young
      adults. We review the most important clinical concerns in premenopausal
      osteoporosis, including measurement of bone mass, normal bone accrual, risk
      factors for premature bone loss, clinical outcomes, and management issues. We
      emphasize clinically relevant information for primary care physicians, who are
      usually the first to encounter premenopausal patients with risk factors for early
      bone loss.

PMID- 15037489
TI  - Leukotriene modifier use and asthma severity: how is a new medication being used
      by adults with asthma?
AB  - BACKGROUND: The introduction of leukotriene modifiers, the first novel class of
      medications for asthma in more than 2 decades, provided an opportunity to
      evaluate the clinical context in which patients receive new treatments. Because
      milder asthma is usually controllable with more familiar medications, we
      hypothesized that adults with asthma would receive leukotriene modifiers for more
      severe disease. METHODS: We conducted a prospective, longitudinal, 18-month
      cohort study of 349 patients with asthma. We evaluated the association of
      baseline self-reported medication use and measures of asthma severity. We also
      examined the impact of baseline measurement of asthma severity on incident
      leukotriene modifier use at follow-up. RESULTS: At baseline, 39 (11%) of 349
      patients reported leukotriene modifier use during the previous 2 weeks (95%
      confidence interval [CI], 8%-15%). Adults with asthma who reported recent use of
      leukotriene modifiers were more likely to indicate use of other long-term
      controller medications for asthma, such as inhaled corticosteroids (80% vs 57%;P
      =.007). Leukotriene modifier use was also associated with poorer severity-of
      asthma scores (mean score difference, 3.6 points; 95% CI, 1.7-5.2 points) and
      asthma-specific health-related quality of life (mean score difference, 8.1
      points; 95% CI, 3.4-12.8 points). Leukotriene modifier users were also more
      likely to indicate a recent emergency department visit (odds ratio [OR], 2.3; 95%
      CI, 0.9-5.6) or hospitalization for asthma (OR, 4.1; 95% CI, 1.4-11.4). Greater
      baseline asthma severity was associated with an increased probability of new
      onset leukotriene modifier use during 18-month follow-up. Poorer baseline
      severity-of-asthma scores and asthma-specific quality-of-life scores were related
      to a greater likelihood of leukotriene modifier use at follow-up (OR per SD-sized
      score increment, 2.0; 95% CI, 1.4-2.7; OR, 1.8; 95% CI, 1.3-2.5; respectively).
      Recent hospitalization for asthma at baseline was also associated with a greater
      likelihood of leukotriene modifier use at follow-up (OR, 4.9; 95% CI, 1.6-14.8).
      CONCLUSIONS: Adults with asthma who receive leukotriene modifiers have more
      severe asthma.

PMID- 15037490
TI  - Alcohol consumption and cardiovascular disease mortality in hypertensive men.
AB  - BACKGROUND: Heavy alcohol drinking is associated with a dose-dependent increase
      in blood pressure, but data on the relation between alcohol consumption and
      mortality in hypertensive patients are sparse. OBJECTIVE: To assess the relation
      between light to moderate alcohol consumption and total mortality from
      cardiovascular disease (CVD) among men with hypertension. PARTICIPANTS AND
      DESIGN: From the Physicians' Health Study enrollment cohort of 88,882 men who
      provided self-reported information on alcohol intake, we identified a group of
      14,125 men with a history of current or past treatment for hypertension who were
      free of myocardial infarction, stroke, cancer, or liver disease at baseline. Main
      Outcome Measure Comparison of total and CVD mortality among men with hypertension
      who had reported to be either nondrinkers or rare drinkers, or light to moderate
      drinkers. RESULTS: During 75,710 person-years of follow-up, there were 1018
      deaths, including 579 from CVD. Compared with individuals who rarely or never
      drank alcoholic beverages, those who reported monthly, weekly, and daily alcohol
      consumption, respectively, had multivariate adjusted relative risks (RRs) for CVD
      mortality of 0.83 (95% confidence interval [CI], 0.62-1.13), 0.61 (CI, 0.49
      0.77), and 0.56 (CI, 0.44-0.71) (P<.001 for linear trend). In the same groups,
      RRs for total mortality were respectively 0.86 (CI, 0.67-1.10), 0.72 (CI, 0.60
      0.86), and 0.73 (CI, 0.61-0.87) (P<.001 for linear trend). Among men with a
      systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of
      90 mm Hg or higher, the RRs for CVD mortality were, respectively, 1.00
      (referent), 0.82 (CI, 0.56-1.21), 0.64 (CI, 0.48-0.85), and 0.56 (CI, 0.42-0.75)
      (P<.001 for linear trend). On the other hand, we found no significant association
      between moderate alcohol consumption and cancer mortality (P =.8 for linear
      trend). CONCLUSION: These results, which require confirmation in other large
      scale studies, suggest that light to moderate alcohol consumption is associated
      with a reduction in risk of total and CVD mortality in hypertensive men.

PMID- 15037491
TI  - Incidence and severity of potential drug-dietary supplement interactions in
      primary care patients: an exploratory study of 2 outpatient practices.
AB  - BACKGROUND: To explore the incidence and severity of potential interactions
      between prescription medications and dietary supplements. METHODS: A survey was
      conducted on dietary supplement use in 458 veteran outpatients currently taking
      prescription medications. Self-reported dietary supplement use was cross
      referenced with each patient's prescription medication list, and potential
      interactions were identified from several tertiary sources and medical literature
      searches. RESULTS: One hundred ninety-seven patients (43%) were currently taking
      at least 1 dietary supplement with prescription medication(s). The most common
      products included vitamins and minerals, garlic, Ginkgo biloba, saw palmetto, and
      ginseng. Among these, 89 (45%) had a potential for drug-dietary supplement
      interactions of any significance. Most of these interactions (n = 84 [94%]) were
      not serious based on limited available evidence, giving an incidence of 6% (5/89)
      of potentially severe interactions among patients taking interacting drugs and
      dietary supplements and 3% (5/197) among patients taking coincident dietary
      supplements and medications. CONCLUSIONS: Although the use of dietary supplements
      appears to be very common among patients who also take prescription medications,
      most potential drug-dietary supplement interactions found were not serious.
      However, literature support was sparse at best. Health care providers should
      continue to inquire about dietary supplement use and consider the potential for
      interactions, regardless of their severity.

PMID- 15037492
TI  - Timing of antibiotic administration and outcomes for Medicare patients
      hospitalized with community-acquired pneumonia.
AB  - BACKGROUND: Pneumonia accounts for more than 600 000 Medicare hospitalizations
      yearly. Guidelines have recommended antibiotic treatment within 8 hours of
      arrival at the hospital. METHODS: We performed a retrospective study using
      medical records from a national random sample of 18 209 Medicare patients older
      than 65 years who were hospitalized with community-acquired pneumonia from July
      1998 through March 1999. Outcomes were severity-adjusted mortality, readmission
      within 30 days of discharge, and length of stay (LOS). RESULTS: Among 13 771
      (75.6%) patients who had not received outpatient antibiotic agents, antibiotic
      administration within 4 hours of arrival at the hospital was associated with
      reduced in-hospital mortality (6.8% vs 7.4%; adjusted odds ratio [AOR], 0.85; 95%
      confidence interval [CI], 0.74-0.98), mortality within 30 days of admission
      (11.6% vs 12.7%; AOR, 0.85; 95% CI, 0.76-0.95), and LOS exceeding the 5-day
      median (42.1% vs 45.1%; AOR, 0.90; 95% CI, 0.83-0.96). Mean LOS was 0.4 days
      shorter with antibiotic administration within 4 hours than with later
      administration. Timing was not associated with readmission. Antibiotic
      administration within 4 hours of arrival was documented for 60.9% of all patients
      and for more than 50% of patients regardless of hospital characteristics.
      CONCLUSIONS: Antibiotic administration within 4 hours of arrival was associated
      with decreased mortality and LOS among a random sample of older inpatients with
      community-acquired pneumonia who had not received antibiotics as outpatients.
      Administration within 4 hours can prevent deaths in the Medicare population,
      offers cost savings for hospitals, and is feasible for most inpatients.

PMID- 15037493
TI  - Effects of health maintenance organization coverage of self-monitoring devices on
      diabetes self-care and glycemic control.
AB  - BACKGROUND: Increasingly, government mandates require insurance coverage of blood
      glucose monitors and test strips for patients with type 1 and type 2 diabetes. No
      data exist on the effects of such coverage on self-monitoring of blood glucose
      (SMBG), medication compliance, or blood glucose control. We evaluated whether a
      policy providing free blood glucose monitors increased SMBG and whether
      initiating SMBG was associated with increased regularity of medication use and
      improved glucose control (hemoglobin A(1c) [HbA(1c)] level). METHODS: Using
      interrupted time-series analysis and controlling for preintervention trends, we
      determined changes in rates of SMBG 2 years before and after the policy among
      3219 continuously enrolled patients with diabetes receiving drug therapy within a
      multispecialty medical group (part of a health maintenance organization) serving
      approximately 300 000 patients. We also compared changes over time in regularity
      of medication use (mean days between dispensings) and mean HbA(1c) level among
      initiators and noninitiators of SMBG. RESULTS: The policy resulted in a small,
      significant increase in SMBG among insulin-treated patients (n = 1428). Among
      sulfonylurea-treated patients (n = 1791), the monthly initiation rate of SMBG
      increased by 14 new patients per 1000 (95% confidence interval [CI], 10 to 17), a
      doubling of the expected initiation rate. Test strip consumption increased during
      the first 6 months after the policy by 17.9 strips per cohort member (75%
      relative increase by 6 months; 95% CI, 50% to 101%). Compared with noninitiators
      of SMBG, initiators (n = 593) showed sudden, significant improvements in
      regularity of medication use by 6 months after initiation (-19.5 days between
      dispensings among those with low refill regularity [95% CI, -27.7 to -11.3]; -9.7
      days among those with moderate regularity [95% CI, -12.3 to -7.1]), and in
      glucose control (-0.63% mean HbA(1c) level [as percentage of total hemoglobin]
      among those with poor baseline glycemic control [HbA(1c) >10%; 95% CI, -1.14% to 
      0.12%]). CONCLUSIONS: Providing free glucose monitors improved rates of self
      monitoring in this health maintenance organization population, possibly by
      offering an initial incentive for patients to engage in more desirable patterns
      of care. Initiating SMBG was associated with increased regularity of medication
      use and a reduction in high blood glucose levels.

PMID- 15037494
TI  - Characteristics associated with physician discipline: a case-control study.
AB  - BACKGROUND: There has been increasing attention devoted to patient safety.
      However, the focus has been on system improvements rather than individual
      physician performance issues. The purpose of this study was to determine if there
      is an association between certain physician characteristics and the likelihood of
      medical board-imposed discipline. METHODS: Unmatched, case-control study of 890
      physicians disciplined by the Medical Board of California between July 1, 1998,
      and June 30, 2001, compared with 2981 randomly selected, nondisciplined controls.
      Odds ratios (ORs) were calculated for physician discipline with respect to age,
      sex, board certification, international medical school education, and specialty.
      RESULTS: Male sex (OR, 2.76; P<.001), lack of board certification (OR, 2.22;
      P<.001), increasing age (OR, 1.64; P<.001), and international medical school
      education (OR, 1.36; P<.001) were associated with an elevated risk for
      disciplinary action that included license revocation, practice suspension,
      probation, and public reprimand. The following specialties had an increased risk
      for discipline compared with internal medicine: family practice (OR, 1.68; P
      =.002); general practice (OR, 1.97, P =.001); obstetrics and gynecology (OR,
      2.25; P<.001); and psychiatry (OR, 1.87; P<.001). Physicians in pediatrics (OR,
      0.62; P =.001) and radiology (OR, 0.36; P<.001) were less likely to receive
      discipline compared with those in internal medicine. CONCLUSION: Certain
      physician characteristics and medical specialties are associated with an
      increased likelihood of discipline.

PMID- 15037495
TI  - Longitudinal follow-up and outcomes among a population with chronic kidney
      disease in a large managed care organization.
AB  - BACKGROUND: Chronic kidney disease is the primary cause of end-stage renal
      disease in the United States. The purpose of this study was to understand the
      natural history of chronic kidney disease with regard to progression to renal
      replacement therapy (transplant or dialysis) and death in a representative
      patient population. METHODS: In 1996 we identified 27 998 patients in our health
      plan who had estimated glomerular filtration rates of less than 90 mL/min per
      1.73 m(2) on 2 separate measurements at least 90 days apart. We followed up
      patients from the index date of the first glomerular filtration rates of less
      than 90 mL/min per 1.73 m(2) until renal replacement therapy, death,
      disenrollment from the health plan, or June 30, 2001. We extracted from the
      computerized medical records the prevalence of the following comorbidities at the
      index date and end point: hypertension, diabetes mellitus, coronary artery
      disease, congestive heart failure, hyperlipidemia, and renal anemia. RESULTS: Our
      data showed that the rate of renal replacement therapy over the 5-year
      observation period was 1.1%, 1.3%, and 19.9%, respectively, for the National
      Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) stages 2,
      3, and 4, but that the mortality rate was 19.5%, 24.3%, and 45.7%. Thus, death
      was far more common than dialysis at all stages. In addition, congestive heart
      failure, coronary artery disease, diabetes, and anemia were more prevalent in the
      patients who died but hypertension prevalence was similar across all stages.
      CONCLUSION: Our data suggest that efforts to reduce mortality in this population
      should be focused on treatment and prevention of coronary artery disease,
      congestive heart failure, diabetes mellitus, and anemia.

PMID- 15037496
TI  - Lack of physician concordance with guidelines on the perioperative use of beta
      blockers.
AB  - BACKGROUND: The American College of Physicians recommends perioperative use of
      beta-blockers for certain patients to improve outcomes after surgery. Study of
      physician behavior with respect to guidelines and recommended practices have
      shown that beta-blockers have been underutilized after myocardial infarction. We
      evaluated physician concordance with the perioperative use of beta-blockers along
      with a specialty-related difference in the frequency of perioperative beta
      blocker use. METHODS: To determine perioperative use of beta-blockers, we
      retrospectively analyzed the medical charts of adult patients who underwent open
      cholecystectomy at a tertiary care medical center from December 1997 through
      December 2001. Patients met criteria for perioperative beta-blocker use if they
      had a history of coronary artery disease or if they had the presence of 2 or more
      of the following risk factors: 65 years or older; history of hypertension,
      diabetes mellitus, or hypercholesterolemia; or current smoking. RESULTS: Among
      the 336 cases of cholecystectomy reviewed, criteria for beta-blocker use were met
      in 146 patients (43%) who did not have emergency operations and/or
      contraindications to beta-blocker use. Of these 146 patients, 123 (84%) had a
      documented preoperative medical evaluation by a physician in the medical chart.
      There were 44 patients (30%) receiving beta-blockers prior to admission, and 102
      patients (70%) were not receiving beta-blockers. Of those 102 patients not
      receiving beta-blockers at admission but who meet criteria for their use, 94
      (92%) were not started on beta-blocker therapy preoperatively. Of the 18 patients
      evaluated by a cardiologist, 4 (22%) were started on beta-blocker therapy
      compared with 3 (6%) of 47 patients evaluated by a noncardiologist physician (P
      =.08). CONCLUSION: Perioperative beta-blocker therapy is underutilized in
      patients with risk factors for coronary artery disease despite evidence that its
      use in appropriate individuals may be lifesaving.

PMID- 15037497
TI  - Lowering the intensity of oral anticoagulant therapy: effects on the risk of
      hemorrhage and thromboembolism.
AB  - BACKGROUND: Oral anticoagulation is effective in the prevention of arterial
      thromboembolism. The major drawback of coumarin therapy is the increased risk of
      hemorrhage. Implementing the optimal intensity of oral anticoagulation, ie, the
      level at which thromboembolic events are prevented without introducing an
      excessive bleeding risk, is an important step to improve the safety of oral
      anticoagulant therapy. METHODS: We observed all patients of the Leiden
      Anticoagulation Clinic who were treated because of a mechanical heart valve or
      atrial fibrillation between January 1, 1995, and January 1, 1998, or because of
      cerebral ischemia between January 1, 1994, and January 1, 1998. In 1996, at the
      halfway point of follow-up, the target intensity for patients with a mechanical
      heart valve was lowered from 4.0 (range, 3.6-4.8) to 3.5 (range, 3.0-4.0)
      international normalized ratio, and for atrial fibrillation and cerebral
      ischemia, from 3.5 (range, 3.0-4.5) to 3.0 (range, 2.5-3.5) international
      normalized ratio. We compared incidence rates of hemorrhage and thromboembolism
      before and after the introduction of lower target intensities. RESULTS: Higher
      target treatments were given to 2341 patients (2863 patient-years) and lower
      target treatments to 2256 patients (2260 patient-years). After introduction of
      the lower target ranges, the overall incidence rate of major untoward events
      declined from 5.7 (95% confidence interval [CI], 4.9-6.7) to 3.6 (95% CI, 2.8
      4.4) per 100 patient-years. The incidence of major bleeding fell from 3.6 (95%
      CI, 2.9-4.4) to 2.7 (95% CI, 2.1-3.5) and the incidence of major thromboembolism
      from 2.0 (95% CI, 1.5-2.5) to 0.8 (95% CI, 0.5-1.3) per 100 patient-years.
      CONCLUSION: Implementation of lower target intensities for coumarin therapy
      decreased the complication risk.

PMID- 15037498
TI  - Differentiating inhalational anthrax from other influenza-like illnesses in the
      setting of a national or regional anthrax outbreak.
AB  - The workup of a febrile patient who presents with an influenza-like illness in
      the setting of a national or regional anthrax outbreak presents a unique
      challenge to the physicians who initially evaluate this patient, and the
      diagnostic challenge can be even more profound during the influenza season. Based
      on information gathered from the recent inhalational anthrax cases, we have
      developed an algorithm to be used by physicians in the emergency department to
      evaluate patients with influenza-like illnesses during a national or regional
      anthrax outbreak. The algorithm necessitates stays no longer than 24 hours in the
      emergency department or hospital.

PMID- 15037499
TI  - Solutions to the undertreatment of osteoporosis-related fractures.

PMID- 15037500
TI  - People are fatter than they think.

PMID- 15037501
TI  - Role of steroids in tendon rupture or disintegration known for decades.

PMID- 15037502
TI  - Increased prevalence of acquired vascular abnormalities of the gastrointestinal
      tract associated with aortic stenosis and other cardiac, pulmonary, and vascular
      diseases.

PMID- 15037503
TI  - Aortic stenosis and unexplained gastrointestinal bleeding.

PMID- 15037504
TI  - Screening for primary human immunodeficiency virus infection.

PMID- 15037505
TI  - Omic space: coordinate-based integration and analysis of genomic phenomic
      interactions.
AB  - MOTIVATION: With the recent progress in genomics, various data sets of omic
      interactions describing networks of omic elements have become available. In order
      to obtain reliable hypotheses from the data, it is effective to integrate
      interactions from different sorts of data sets. In order to facilitate a
      coordinate-based integration and analysis of omic interactions, we introduce the
      concept of an omic space comprising a comprehensive set of omic planes. Genomic,
      transcriptomic, proteomic, metabolomic, phenomic and other omic planes are
      defined by two orthogonal genomic-coordinate axes. RESULTS: We show that the omic
      space concept helps us to assimilate biological findings comprehensively into
      hypotheses or models combining higher-order phenomena and lower-order mechanisms
      by demonstrating that a comprehensive ranking of correspondences among
      interactions in the space can be used effectively for estimating candidates of
      responsible gene pairs for epistatic interacting loci of tumors in mice. We also
      show that the omic space offers a convenient framework for database integration,
      by presenting a system named the 'Genome <==> Phenome Superhighway' (GPS) that
      serves as a framework for integration and visualization of omic interactions
      based on omic spaces of some model species including Homo sapiens, Mus musculus,
      Caenorhabditis elegans and Arabidopsis thaliana. AVAILABILITY: For the GPS web
      site, see http://omicspace.riken.jp/gps/.

PMID- 15037506
TI  - Decomposition of metabolic network into functional modules based on the global
      connectivity structure of reaction graph.
AB  - MOTIVATION: Metabolic networks are organized in a modular, hierarchical manner.
      Methods for a rational decomposition of the metabolic network into relatively
      independent functional subsets are essential to better understand the modularity
      and organization principle of a large-scale, genome-wide network. Network
      decomposition is also necessary for functional analysis of metabolism by pathway
      analysis methods that are often hampered by the problem of combinatorial
      explosion due to the complexity of metabolic network. Decomposition methods
      proposed in literature are mainly based on the connection degree of metabolites.
      To obtain a more reasonable decomposition, the global connectivity structure of
      metabolic networks should be taken into account. RESULTS: In this work, we use a
      reaction graph representation of a metabolic network for the identification of
      its global connectivity structure and for decomposition. A bow-tie connectivity
      structure similar to that previously discovered for metabolite graph is found
      also to exist in the reaction graph. Based on this bow-tie structure, a new
      decomposition method is proposed, which uses a distance definition derived from
      the path length between two reactions. An hierarchical classification tree is
      first constructed from the distance matrix among the reactions in the giant
      strong component of the bow-tie structure. These reactions are then grouped into
      different subsets based on the hierarchical tree. Reactions in the IN and OUT
      subsets of the bow-tie structure are subsequently placed in the corresponding
      subsets according to a 'majority rule'. Compared with the decomposition methods
      proposed in literature, ours is based on combined properties of the global
      network structure and local reaction connectivity rather than, primarily, on the
      connection degree of metabolites. The method is applied to decompose the
      metabolic network of Escherichia coli. Eleven subsets are obtained. More detailed
      investigations of the subsets show that reactions in the same subset are really
      functionally related. The rational decomposition of metabolic networks, and
      subsequent studies of the subsets, make it more amenable to understand the
      inherent organization and functionality of metabolic networks at the modular
      level. SUPPLEMENTARY INFORMATION: http://genome.gbf.de/bioinformatics/

PMID- 15037507
TI  - Non-linear conversion between genetic and physical chromosomal distances.
AB  - A supervised nonlinear interpolation significantly improves the reliability of
      conversions from genetic distances to physical distances as compared with the
      linear ones. A webaccessible application was created that addresses this question
      with a graphical presentation that may be wrapped by local installations.
      MOTIVATION: Genetic linkage maps and radiation hybrid (RH) maps are based on the
      rate of uncoupling between linked genetic markers. These are usually measured in
      centiMorgan (cM) when uncoupling is originated by natural recombination or in
      centiRay (cR) for chromosomes that are irradiated artificially to separate the
      markers. Physical maps arise from genome-wide DNA sequencing and are measured in
      bp. This work was originally motivated as an extension of the software
      application Expressionview (Fischer et al., 2003), exploring its spectrum of
      appliance combining different mapping systems. The relationship between physical
      and genetic maps is known to be not always linear (Yu et al., 2001). The shift
      from the linear model seems to depend on local idiosyncrasies of the chromosomes
      and the kind of genetic map used. The present application addresses this problem
      for the first time. AVAILABILITY: http://qtl.pzr.uni-rostock.de/cartographer.php

PMID- 15037508
TI  - Normalization of single-channel DNA array data by principal component analysis.
AB  - MOTIVATION: Detailed comparison and analysis of the output of DNA gene expression
      arrays from multiple samples require global normalization of the measured
      individual gene intensities from the different hybridizations. This is needed for
      accounting for variations in array preparation and sample hybridization
      conditions. RESULTS: Here, we present a simple, robust and accurate procedure for
      the global normalization of datasets generated with single-channel DNA arrays
      based on principal component analysis. The procedure makes minimal assumptions
      about the data and performs well in cases where other standard procedures
      produced biased estimates. It is also insensitive to data transformation,
      filtering (thresholding) and pre-screening.

PMID- 15037510
TI  - BLAST2GENE: a comprehensive conversion of BLAST output into independent genes and
      gene fragments.
AB  - SUMMARY: BLAST2GENE is a program that allows a detailed analysis of genomic
      regions containing completely or partially duplicated genes. From a BLAST (or
      BL2SEQ) comparison of a protein or nucleotide query sequence with any genomic
      region of interest, BLAST2GENE processes all high scoring pairwise alignments
      (HSPs) and provides the disposition of all independent copies along the genomic
      fragment. The results are provided in text and PostScript formats to allow an
      automatic and visual evaluation of the respective region. AVAILABILITY: The
      program is available upon request from the authors. A web server of BLAST2GENE is
      maintained at http://www.bork.embl.de/blast2gene

PMID- 15037509
TI  - MITOPRED: a genome-scale method for prediction of nucleus-encoded mitochondrial
      proteins.
AB  - MOTIVATION: Currently available methods for the prediction of subcellular
      location of mitochondrial proteins rely largely on the presence of mitochondrial
      targeting signals in the protein sequences. However, a large fraction of
      mitochondrial proteins lack such signals, making those tools ineffective for
      genome-scale prediction of mitochondria-targeted proteins. Here, we propose a
      method for genome-scale prediction of nucleus-encoded mitochondrial proteins. The
      new method, MITOPRED, is based on the Pfam domain occurrence patterns and the
      amino acid compositional differences between mitochondrial and non-mitochondrial
      proteins. RESULTS: MITOPRED could predict mitochondrial proteins with 100%
      specificity at a 44% sensitivity rate and with 67% specificity at 99%
      sensitivity. Additionally, it was sufficiently robust to predict mitochondrial
      proteins across different eukaryotic species with similar accuracy. Based on
      Matthews correlation coefficient measure, the prediction performance of MITOPRED
      is clearly superior (0.73) to those of the two popular methods TargetP (0.51) and
      PSORT (0.53). Using this method, we predicted the nucleus-encoded mitochondrial
      proteins from six complete genomes (three invertebrate, two vertebrate and one
      plant species) and estimated the total number in each genome. In human, our
      method estimated the existence of 1362 mitochondrial proteins corresponding to
      4.8% of the total proteome. AVAILABILITY: MITOPRED program is freely accessible
      at http://mitopred.sdsc.edu. Source code is available on request from the
      authors. SUPPLEMENTARY INFORMATION: Training data sets are also available at
      http://mitopred.sdsc.edu

PMID- 15037511
TI  - Inferring dynamic architecture of cellular networks using time series of gene
      expression, protein and metabolite data.
AB  - MOTIVATION: High-throughput technologies have facilitated the acquisition of
      large genomics and proteomics datasets. However, these data provide snapshots of
      cellular behavior, rather than help us reveal causal relations. Here, we propose
      how these technologies can be utilized to infer the topology and strengths of
      connections among genes, proteins and metabolites by monitoring time-dependent
      responses of cellular networks to experimental interventions. RESULTS: We
      demonstrate that all connections leading to a given network node, e.g. to a
      particular gene, can be deduced from responses to perturbations none of which
      directly influences that node, e.g. using strains with knock-outs to other genes.
      To infer all interactions from stationary data, each node should be perturbed
      separately or in combination with other nodes. Monitoring time series provides
      richer information and does not require perturbations to all nodes. Overall, the
      methods we propose are capable of deducing and quantifying functional
      interactions within and across cellular gene, signaling and metabolic networks.
      SUPPLEMENTARY INFORMATION: Supplementary material is available at
      http://www.dbi.tju.edu/bioinformatics2004.pdf

PMID- 15037512
TI  - Vascular hyper-reactivity following arterial balloon injury: distant and delayed
      effects.
AB  - The adverse functional effects of balloon angioplasty include simple procedure
      failure, compromise of vessel lumen (rupture), and restenosis. A much less well
      defined repercussion of balloon injury to arteries is a paradoxical alteration in
      vascular reactivity at an anatomically distant site. The paper by Accorsi
      Mendonca in the current issue presents new data showing that, following balloon
      injury to the rat left common carotid artery, there is a delayed hyperreactivity
      to both phenylephrine and angiotensin II in the contralateral artery. The
      pharmacological basis of these effects is unknown, although the authors
      demonstrate that products of cyclooxygenase (COX) 1 or 2 are responsible for the
      hyperreactivity to angiotensin II and phenylephrine, respectively. The absence of
      delayed hyperreactivity to these agents in the aorta of injured rats would
      suggest that a humoral factor is not involved.

PMID- 15037513
TI  - Comparison of functional profiles at human recombinant somatostatin sst2
      receptor: simultaneous determination of intracellular Ca2+ and luciferase
      expression in CHO-K1 cells.
AB  - 1. Somatostatin (somatotropin release inhibiting factor; SRIF) acts via five G
      protein-coupled receptors (sst(1)-sst(5)) that modulate multiple cellular
      effectors. The aim of this study was to compare two functional effects of the
      human sst(2) receptor stably expressed in CHO-K1 cells in a single experiment
      using a duplex assay for intracellular calcium and serum response element (SRE)
      driven luciferase expression. 2. Intracellular calcium was measured using a
      fluorometric imaging plate reader II (FLIPR II). SRIF-14 rapidly and transiently
      increased intracellular calcium with a pEC(50) of 8.74+/-0.03 (n=52). At 5 h
      after FLIPR II measurements, luciferase expression was determined. SRIF-14
      concentration-dependently increased luciferase expression (pEC(50)=9.06+/-0.03,
      n=52). 3. Natural and synthetic agonist/antagonist ligands for SRIF receptors
      were tested in the duplex assay. Correlation of agonist potencies and efficacies
      between the two responses were significant (r(2)=0.83 and 0.90, pEC(50) and
      E(max), respectively). 4. Pertussis toxin pretreatment reduced SRIF-14/octreotide
      mediated intracellular calcium increases by 45-47% and luciferase expression by
      95-98%. 5. Thapsigargin pretreatment abolished the SRIF-14/octreotide-mediated
      intracellular calcium increase but had no effect on luciferase expression. 6. In
      conclusion, SRIF stimulates an increase in intracellular calcium and SRE
      luciferase expression via human sst(2) receptors in CHO-K1 cells. The increase in
      luciferase is mediated via G(i)/G(o) while intracellular calcium increase is
      mediated by both G(i)/G(o) proteins and pertussis toxin-insensitive G proteins,
      and is mainly via release of calcium from intracellular stores. SRIF ligands
      display a similar recognition profile suggesting that the ligand/receptor/G
      protein/effector interaction is similar for the two parameters.

PMID- 15037514
TI  - Effect of acute and chronic lamotrigine on basal and stimulated extracellular 5
      hydroxytryptamine and dopamine in the hippocampus of the freely moving rat.
AB  - 1. We have studied the effects of acute and chronic treatment with the
      anticonvulsant lamotrigine (LTG) on basal and stimulated extracellular 5
      hydroxytryptamine (5-HT), dopamine (DA) and their metabolites in the hippocampus
      of freely moving rats using in vivo microdialysis. 2. Acute LTG (10 and 20 mg kg(
      1)) decreased extracellular 5-HT, but had no effect on its metabolite 5
      hydroxyindoleacetic acid (5-HIAA). Dialysate DA was also decreased by LTG as were
      its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).
      When transmitter release was stimulated by either 50 microm veratridine or 100 mm
      K(+), marked increases in the release of both transmitters occurred, but LTG was
      entirely without effect on this. 3. In chronic experiments, rats were dialysed
      after 2, 4, 7, 14 and 21 days of LTG treatment (5 mg kg(-1), twice daily). During
      this period a progressively different response to the drug was seen. After 2
      days, basal extracellular 5-HT was significantly greater in treated rats than
      control rats. This effect persisted up to 14 days, but by 21 days 5-HT levels had
      returned to control values. 5-HIAA levels were unaltered and there was no effect
      of LTG on veratridine or K(+) stimulated 5-HT release. 4. Similarly, DA
      concentrations significantly increased after 2-7 days of LTG treatment, but
      returned and remained at basal values thereafter. During the treatment period LTG
      had no effect on extracellular DOPAC, but HVA followed a similar pattern to its
      parent transmitter. As with 5-HT, at no time point did LTG have any effect on
      stimulated DA release. 5. These neurochemical findings observed in these
      experiments are considered in relation to the use of LTG in bipolar disorder.

PMID- 15037515
TI  - R-citalopram functionally antagonises escitalopram in vivo and in vitro: evidence
      for kinetic interaction at the serotonin transporter.
AB  - 1. Clinical observations with the selective serotonin reuptake inhibitor (SSRI),
      S-citalopram, indicate that S-citalopram is more efficacious and produces earlier
      symptom relief than RS-citalopram. Since R-citalopram is at least 20-fold weaker
      than S-citalopram as inhibitor of the 5-HT transporter (SERT) in preclinical
      studies, the clinical data suggest an unexpected antagonistic interaction between
      the two enantiomers. We therefore characterised the interaction of R- and S
      citalopram with the SERT in in vivo and in vitro assays. 2. In both behavioural
      (potentiation of 5-hydroxytryptophan (5-HTP)-induced behaviour) and
      electrophysiological studies (inhibition of 5-HT-elicited ion currents in Xenopus
      oocytes expressing the human SERT (hSERT) R-citalopram inhibited the effects of S
      citalopram in a dose-dependent manner. With S-citalopram : R-citalopram ratios of
      1 : 2 and 1 : 4, 5-HTP potentiation was significantly smaller than with S
      citalopram alone. 3. R-citalopram did not antagonise the effects of another SSRI
      (fluoxetine) in either behavioural or electrophysiological studies. 4. In
      oocytes, inhibition of hSERT-mediated currents by R-citalopram was almost
      completely reversible and characterised by fast on- and off-sets of action. In
      contrast, the off-set for S-citalopram was 35-fold slower than for R-citalopram.
      5. Kinetic analysis of the oocyte experiments suggests that S-citalopram binding
      to SERT induces a long-lasting, inhibited state of the transporter and that
      coapplication of R-citalopram partially relieves SERT of this persistent
      inhibition. 6. We propose that the kinetic interaction of R- and S-citalopram
      with SERT is a critical factor contributing to the antagonistic effects of R
      citalopram on S-citalopram in vitro and in vivo.

PMID- 15037516
TI  - Cardioprotective efficacy of zoniporide, a potent and selective inhibitor of
      Na+/H+ exchanger isoform 1, in an experimental model of cardiopulmonary bypass.
AB  - 1. We determined (1) the inhibitory potency of zoniporide against the native
      Na(+)/H(+) exchanger isoform 1 (NHE1) that is expressed in adult rat ventricular
      myocytes and platelets, and (2) the cardioprotective efficacy of zoniporide in
      isolated, blood-perfused adult rat hearts subjected to cardioplegic arrest,
      hypothermic ischaemia (150 min at 25 degrees C) and normothermic reperfusion (60
      min at 37 degrees C). 2. In isolated myocytes, in which NHE1 activity was
      determined directly by measurement of H(+) efflux rate following intracellular
      acidification, zoniporide produced a dose-dependent inhibition of such activity
      (IC(50) 73 nm at 25 degrees C). A comparable NHE1-inhibitory potency was retained
      at 37 degrees C. 3. In platelets, in which the rate of cell swelling was used as
      a surrogate index of NHE1 activity, this was again inhibited by zoniporide
      (IC(50) 67 nm at 25 degrees C). 4. In the isolated heart model, administration of
      zoniporide (loading bolus of 1 mg kg(-1) i.v. plus continuous infusion at 1.98 mg
      kg(-1) h(-1) i.v.) to the support animal achieved a free plasma drug
      concentration of >/=1 microm. At this dose, zoniporide afforded significant
      cardioprotective benefit relative to vehicle treatment, with improved
      preservation of left ventricular end-diastolic and developed pressures and
      coronary perfusion pressure during reperfusion. Myocardial myeloperoxidase
      activity was also attenuated by zoniporide treatment, indicating reduced
      neutrophil accumulation. 5. These data show that zoniporide (1) is a potent
      inhibitor of native NHE1 activity in ventricular myocytes and platelets, and (2)
      affords significant cardioprotective benefit during ischaemia and reperfusion in
      an experimental model that mimics several distinctive features of human
      cardioplegic arrest with cardiopulmonary bypass.

PMID- 15037517
TI  - Markedly reduced effects of (-)-isoprenaline but not of (-)-CGP12177 and
      unchanged affinity of beta-blockers at Gly389-beta1-adrenoceptors compared to
      Arg389-beta1-adrenoceptors.
AB  - 1. Substitution of arginine by glycine at position 389, a frequent beta(1)
      adrenoceptor polymorphism, reduces adenylyl cyclase stimulation by (-)
      isoprenaline. beta(1)-Adrenoceptors mediate the effects of catecholamines and
      nonconventional partial agonists ((-)-CGP12177) through different sites. We
      investigated the influence of the 389 polymorphism on beta blocker affinity, as
      well as on the responses to (-)-isoprenaline and the nonconventional partial
      agonist (-)-CGP12177 on cyclic AMP levels in CHO cells expressing recombinant
      Arg389-beta(1)-adrenoceptors (101 fmol mg(-1) protein) or Gly389-beta(1)
      adrenoceptors (94 fmol mg(-1)). 2. The affinity of beta-blockers and partial
      agonists, estimated from competition binding with (-)-[(125)I]-cyanopindolol, was
      not different for Arg389-beta(1)-adrenoceptors and Gly389-beta(1)-adrenoceptors.
      3. The maximum cAMP increases by (-)-isoprenaline and (-)-CGP12177 at Gly389
      beta(1)-adrenoceptors were reduced by 97 and 46%, but the potencies enhanced 2
      and 0.5 log units, respectively, compared to Arg389-beta(1)-adrenoceptors. The
      intrinsic activity of (-)-CGP12177 with respect to the (-)-isoprenaline was 0.057
      at Arg389-beta(1)-adrenoceptors and 1.05 at Gly389-beta(1)-adrenoceptors. 4. We
      confirm in intact CHO cells that responses to (-)-isoprenaline are markedly
      reduced at Gly389-beta(1)-adrenoceptors compared to Arg389-beta(1)-adrenoceptors.
      However, the 389 polymorphism reduces considerably less the agonist responses to
      (-)-CGP12177, indicating that coupling to G(s) protein is different for beta(1)
      adrenoceptors activated by catecholamines than for receptors activated by
      nonconventional partial agonists. The affinity of beta-blockers is conserved
      across the Arg389Gly polymorphism.

PMID- 15037518
TI  - Suppression of insulin signalling by a synthetic peptide KIFMK suggests the
      cytoplasmic linker between DIII-S6 and DIV-S1 as a local anaesthetic binding site
      on the sodium channel.
AB  - 1. Acetyl-KIFMK-amide (KIFMK) restores fast inactivation to mutant sodium
      channels having a defective inactivation gate. Its binding site with sodium
      channels could be considered to be the cytoplasmic linker (III-IV linker)
      connecting domains III and IV of the sodium channel alpha subunit. There is a
      close resemblance of the amino-acid sequences between the III-IV linker and the
      activation loop of the insulin receptor (IR). This resemblance of the amino-acid
      sequences suggests that KIFMK may also modulate insulin signalling. In order to
      test this assumption, we studied the effects of KIFMK and its related (KIYEK,
      KIQMK, and DIYET) and unrelated (LPFFD) peptides on tyrosine phosphorylation or
      dephosphorylation of IR in vitro. 2. Purified IR was phosphorylated in vitro with
      insulin in the presence of various synthetic peptides and lignocaine. The
      phosphorylation level of IR was then evaluated after SDS-PAGE separation,
      followed by Western blot analysis with antiphosphotyrosine antibody. 3. KIFMK and
      KIYEK inhibited insulin-stimulated autophosphorylation of IR. Lignocaine showed
      similar effects, but at a higher order of concentration. KIYEK and DIYET, but not
      KIFMK, dephosphorylated the phosphorylated tyrosine residues. The structurally
      unrelated peptide LPFFD had no effect either on phosphorylation or
      dephosphorylation of IR. 4. These results indicate that KIFMK, KIYEK, and
      lignocaine bind with the autophosphorylation sites of IR. 5. The present findings
      also suggest that KIFMK and lignocaine bind with the III-IV linker of sodium
      channel alpha subunit.

PMID- 15037519
TI  - Vascular relaxation response to hydrogen peroxide is impaired in hypertension.
AB  - 1. In phenylephrine (1 microm)-precontracted rat superior mesenteric arteries
      (MA), hydrogen peroxide (H(2)O(2), 0.3 and 1 mm) caused a biphasic response: a
      transient contraction followed by a relaxation. In the presence of thromboxane
      A(2)/prostaglandin H(2) (TP) receptor antagonist (SQ 29548), the contractile
      component of the biphasic response was abolished. The relaxation response to
      H(2)O(2) was smaller in spontaneously hypertensive rats (SHR) when compared with
      normotensive Wistar-Kyoto rats (WKY). 2. The mechanisms for the attenuated
      relaxation to H(2)O(2) in the SHR were studied. KCl (40 mm) prevented the
      relaxation response. Calcium-dependent K(+) channel (K(Ca)) blockers
      (tetraethylammonium chloride, TEA; iberiotoxin, and charybdotoxin) showed a
      greater inhibition of H(2)O(2) relaxation in SHR than in WKY, whereas voltage
      dependent K(+)-channel (K(v)) blocker 4-aminopyridine was more effective in
      inhibiting the relaxation in WKY than in SHR. 3. H(2)O(2) (1 mm) greatly enhanced
      the frequency and intensity of the spontaneous transient outward K(+) currents in
      SHR MA, and the effects of H(2)O(2) were inhibited by iberiotoxin, while in WKY
      MA the K(+) currents induced by H(2)O(2) were mainly of the K(v) type. The
      consequence of the activation of different types of K(+) channel was that the net
      increase in mean outward K(+) current density in response to H(2)O(2) was smaller
      in SHR than in WKY, which may account for the attenuated relaxation response to
      H(2)O(2) in the SHR. 4. The contractile responses of MA to TEA, iberiotoxin, and
      charybdotoxin were greater in SHR than in WKY. 5. In summary, an attenuated
      relaxation response to H(2)O(2) was found in SHR MA when compared to WKY. In
      contrast to the activation of K(v) channels in WKY, H(2)O(2) markedly enhanced
      K(Ca) activity in SHR, resulting in an attenuation of the increase in mean
      outward K(+) current density in response to H(2)O(2). These results suggest that
      alteration in K(+) channel activation by reactive oxygen species may play a role
      in the development of hypertension in SHR.

PMID- 15037520
TI  - The balloon catheter induces an increase in contralateral carotid artery
      reactivity to angiotensin II and phenylephrine.
AB  - 1. The effects of balloon injury on the reactivity of ipsilateral and
      contralateral carotid arteries were compared to those observed in arteries from
      intact animals (control arteries). 2. Carotid arteries were obtained from Wistar
      rats 2, 4, 7, 15, 30 or 45 days after injury and mounted in an isolated organ
      bath. Reactivity to angiotensin II (Ang II), phenylephrine (Phe) and bradykinin
      (BK) was studied. Curves were constructed in the absence or presence of
      endothelium or after incubation with 10 microm indomethacin, 500 microm valeryl
      salicylate or 0.1 microm celecoxib. 3. Phe, Ang II and BK maximum effects (Emax)
      were decreased in ipsilateral arteries when compared to control arteries. No
      differences were observed among pD2 or Hill coefficient. 4. Emax to Phe (4 and 7
      days) and to Ang II (15 and 30 days) increased in the contralateral artery. In
      addition, Phe or Ang II reactivity was not significantly different in aorta rings
      from control or carotid-injured animals. 5. The increased responsiveness of
      contralateral artery was not due to changes in carotid blood flow or resting
      membrane potential. The endothelium-dependent inhibitory component is not present
      in the contraction of contralateral arteries and it is not related to superoxide
      anion production. 6. Indomethacin decreased contralateral artery responsiveness
      to Phe and Ang II. Valeryl salicylate reduced the Ang II response in
      contralateral and control arteries. Celecoxib decreased the Phe Emax of
      contralateral artery. 7. In conclusion, decreased endothelium-derived factors and
      increased prostanoids appear to be responsible for the increased reactivity of
      contralateral arteries after injury.

PMID- 15037523
TI  - Role of p53 and p38 MAP kinase in nitric oxide-induced G2/M arrest and apoptosis
      in the human lung carcinoma cells.

PMID- 15037521
TI  - Treating irritable bowel syndrome: overview, perspective and future therapies.
AB  - This article summarizes the ongoing challenges in irritable bowel syndrome and
      the exciting opportunities for development of novel therapies for this common,
      enigmatic condition. The challenges include insufficient understanding of
      mechanisms, lack of specificity of symptoms, differentiation from other
      conditions, and lack of availability of noninvasive tests to identify
      dysfunctions. However, significant opportunities are reflected by the advances in
      clinical trial design and, particularly, clinically relevant end points for such
      trials, and the increasing understanding of basic neuroenteric science. The
      latter has delivered two new medications to the practice (alosetron and
      tegaserod), and other candidate therapies (other serotonergic, tachykininergic,
      opioid, cannabinoid modulators) are being carefully appraised as potential drugs
      for the future.

PMID- 15037524
TI  - Effects of acute mental stress and exercise on T-wave alternans in patients with
      implantable cardioverter defibrillators and controls.
AB  - BACKGROUND: Malignant cardiac arrhythmias can be triggered by exercise and by
      mental stress in vulnerable patients. Exercise-induced T-wave alternans (TWA) is
      an established marker of cardiac electrical instability. However, the effects of
      acute mental stress on TWA have not been investigated as a vulnerability marker
      in humans. METHODS AND RESULTS: TWA responses to mental stress (anger recall and
      mental arithmetic) and bicycle ergometry were evaluated in patients with
      implantable cardioverter defibrillators (ICDs) and documented coronary artery
      disease (n=23, age 62.1+/-12.3 years) and controls (n=17, age 54.2+/-12.1 years).
      TWA was assessed from digitized ECGs by modified moving average analysis. Dual
      isotope single photon emission computed tomography was used to assess myocardial
      ischemia. TWA increased during mental stress and exercise (P values <0.001), and
      TWA responses were higher in ICD patients than in controls (arithmetic
      Delta=8.9+/-1.4 versus 4.3+/-2.2 microV, P=0.043; exercise Delta=21.4+/-2.8
      versus 13.8+/-3.2 microV, P=0.038). TWA increases with mental stress occurred at
      substantially lower heart rates (anger recall Delta=9.7+/-7.7 bpm, arithmetic
      Delta=14.3+/-13.3 bpm) versus exercise (Delta=53.7+/-22.7 bpm; P values <0.001).
      After adjustment for heart rate increases, mental stress and exercise provoked
      increased TWA in ICD patients (P values <0.05), but not in controls (P values
      >0.2). Ejection fraction and stress-induced myocardial ischemia were not
      associated with TWA. CONCLUSIONS: Mental stress can induce cardiac electrical
      instability, as assessed via TWA, among patients with arrhythmic vulnerability
      and occurs at lower heart rates than with exercise. Pathophysiological mechanisms
      of mental stress-induced arrhythmias may therefore involve central and autonomic
      nervous system pathways that differ from exercise-induced arrhythmias.

PMID- 15037525
TI  - Association of type 2 diabetes with cyclooxygenase-mediated inflammation and
      oxidative stress in an elderly population.
AB  - BACKGROUND: Involvement of cyclooxygenase (COX)-mediated inflammation in type 2
      diabetes has not been studied, and the association between cytokine-mediated
      inflammation and diabetes is not fully clarified. METHODS AND RESULTS: 15-Keto
      dihydro-prostaglandin F2alpha (a metabolite of prostaglandin F2alpha and an
      indicator of COX-mediated inflammation), high-sensitivity C-reactive protein
      (CRP), serum amyloid protein A (SAA), 8-iso-PGF2alpha (a nonenzymatic, free
      radical product of arachidonic acid and an indicator of oxidative stress), and
      alpha-tocopherol were measured in a population-based sample of 77-year-old men
      (n=765), in which 112 men had type 2 diabetes. The inflammatory indicators were
      increased in men with diabetes (urinary 15-keto-dihydro-PGF2alpha, P<0.001, CRP
      and SAA, P<0.05). However, when adjusted for body mass index, waist
      circumference, or fasting insulin, no association was found between diabetes and
      CRP or SAA. The oxidative stress indicator 8-iso-PGF2alpha in urine was increased
      (P<0.01) in men with diabetes. Patients who were newly diagnosed with diabetes
      (<7 years since diagnosis) had increased urinary 15-keto-dihydro-PGF2alpha and
      decreased alpha-tocopherol, but 8-iso-PGF2alpha was unaltered. CONCLUSIONS: This
      is the first study to show that type 2 diabetes in elderly men is related to COX
      mediated inflammation, reflected by enhanced prostaglandin formation. The high
      levels of cytokine-mediated acute-phase proteins observed in men with diabetes
      appear to be related to obesity and increased fasting insulin. The results
      further suggest that the appearance of chronic inflammation is an early process
      in the pathogenesis of diabetes, whereas oxidative injury may be a later process,
      possibly related to inflammation.

PMID- 15037522
TI  - Tachykinin NK2 receptor antagonists for the treatment of irritable bowel
      syndrome.
AB  - Tachykinin NK2 receptors are expressed in the gastrointestinal tract of both
      laboratory animals and humans. Experimental data indicate a role for these
      receptors in the regulation of intestinal motor functions (both excitatory and
      inhibitory), secretions, inflammation and visceral sensitivity. In particular,
      NK2 receptor stimulation inhibits intestinal motility by activating sympathetic
      extrinsic pathways or NANC intramural inhibitory components, whereas a modulatory
      effect on cholinergic nerves or a direct effect on smooth muscle account for the
      NK2 receptor-mediated increase in intestinal motility. Accordingly, selective NK2
      receptor antagonists can reactivate inhibited motility or decrease inflammation-
      or stress-associated hypermotility. Intraluminal secretion of water is increased
      by NK2 receptor agonists via a direct effect on epithelial cells, and this
      mechanism is active in models of diarrhoea since selective antagonists reverse
      the increase in faecal water content in these models. Hyperalgesia in response to
      intraluminal volume signals is possibly mediated through the stimulation of NK2
      receptors located on peripheral branches of primary afferent neurones. NK2
      receptor antagonists reduce the hyper-responsiveness that occurs following
      intestinal inflammation or application of stressful stimuli to animals. Likewise,
      NK2 receptor antagonists reduce intestinal tissue damage induced by chemical
      irritation of the intestinal wall or lumen. In healthy volunteers, the selective
      NK2 antagonist nepadutant reduced the motility-stimulating effects and irritable
      bowel syndrome-like symptoms triggered by intravenous infusion of neurokinin A,
      and displayed other characteristics that could support its use in patients. It is
      concluded that blockade of peripheral tachykinin NK2 receptors should be
      considered as a viable mechanism for decreasing the painful symptoms and altered
      bowel habits of irritable bowel syndrome patients.

PMID- 15037526
TI  - Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase
      inhibition by naproxen and low-dose aspirin in healthy subjects.
AB  - BACKGROUND: The current controversy on the potential cardioprotective effect of
      naproxen prompted us to evaluate the extent and duration of platelet, monocyte,
      and vascular cyclooxygenase (COX) inhibition by naproxen compared with low-dose
      aspirin. METHODS AND RESULTS: We performed a crossover, open-label study of low
      dose aspirin (100 mg/d) or naproxen (500 mg BID) administered to 9 healthy
      subjects for 6 days. The effects on thromboxane (TX) and prostacyclin
      biosynthesis were assessed up to 24 hours after oral dosing. Serum TXB2, plasma
      prostaglandin (PG) E2, and urinary 11-dehydro-TXB2 and 2,3-dinor-6-keto
      PGF(1alpha) were measured by previously validated radioimmunoassays. The
      administration of naproxen or aspirin caused a similar suppression of whole-blood
      TXB2 production, an index of platelet COX-1 activity ex vivo, by 94+/-3% and 99+/
      0.3% (mean+/-SD), respectively, and of the urinary excretion of 11-dehydro-TXB2,
      an index of systemic biosynthesis of TXA2 in vivo, by 85+/-8% and 78+/-7%,
      respectively, that persisted throughout the dosing interval. Naproxen, in
      contrast to aspirin, significantly reduced systemic prostacyclin biosynthesis by
      77+/-19%, consistent with differential inhibition of monocyte COX-2 activity
      measured ex vivo. CONCLUSIONS: The regular administration of naproxen 500 mg BID
      can mimic the antiplatelet COX-1 effect of low-dose aspirin. Naproxen, unlike
      aspirin, decreased prostacyclin biosynthesis in vivo.

PMID- 15037527
TI  - Profoundly reduced neovascularization capacity of bone marrow mononuclear cells
      derived from patients with chronic ischemic heart disease.
AB  - BACKGROUND: Cell therapy with bone marrow-derived stem/progenitor cells is a
      novel option for improving neovascularization and cardiac function in ischemic
      heart disease. Circulating endothelial progenitor cells in patients with coronary
      heart disease are impaired with respect to number and functional activity.
      However, whether this impairment also extends to bone marrow-derived mononuclear
      cells (BM-MNCs) in patients with chronic ischemic cardiomyopathy (ICMP) is
      unclear. METHODS AND RESULTS: BM-MNCs were isolated from bone marrow aspirates in
      18 patients with ICMP (ejection fraction, 38+/-11%) and 8 healthy control
      subjects (controls). The number of hematopoietic stem/progenitor cells
      (CD34+/CD133+), CD49d(+) (VLA-4) cells, and CXCR4+ cells did not differ between
      the 2 groups. However, the colony-forming capacity of BM-MNCs from patients with
      ICMP was significantly lower compared with BM-MNCs from healthy controls (37.3+/
      25.0 versus 113.8+/-70.4 granulocyte-macrophage colony-forming units; P=0.009).
      Likewise, the migratory response to stromal cell-derived factor 1 (SDF-1) and
      vascular endothelial growth factor (VEGF) was significantly reduced in BM-MNCs
      derived from patients with ICMP compared with BM-MNCs from healthy controls (SDF
      1, 46.3+/-26.2 versus 108.6+/-40.4 cells/microscopic field, P<0.001; VEGF, 34+/
      24.2 versus 54.8+/-29.3 cells/microscopic field, P=0.027). To assess the in vivo
      relevance of these findings, we tested the functional activity of BM-MNCs to
      improve neovascularization in a hindlimb animal model using nude mice. Two weeks
      after ligation of the femoral artery and intravenous injection of 5x10(5) BM
      MNCs, laser Doppler-derived relative limb blood flow in mice treated with BM-MNCs
      from patients with ICMP was significantly lower compared with mice treated with
      BM-MNCs from healthy controls (0.45+/-0.14 versus 0.68+/-0.15; P<0.001). The in
      vivo neovascularization capacity of BM-MNCs closely correlated with the in vitro
      assessment of SDF-1-induced migration (r=0.78; P<0.001) and colony-forming
      capacity (r=0.74; P<0.001). CONCLUSIONS: BM-MNCs isolated from patients with ICMP
      have a significantly reduced migratory and colony-forming activity in vitro and a
      reduced neovascularization capacity in vivo despite similar content of
      hematopoietic stem cells. This functional impairment of BM-MNCs from patients
      with ICMP may limit their therapeutic potential for clinical cell therapy.

PMID- 15037528
TI  - Myocyte nitric oxide synthase 2 contributes to blunted beta-adrenergic response
      in failing human hearts by decreasing Ca2+ transients.
AB  - BACKGROUND: Human heart failure (HF) usually exhibits blunted response to beta
      adrenergic receptor (AR) stimulation. Here, we examined whether expression of
      nitric oxide synthase-2 (NOS2, or inducible NOS) contributes to this loss of
      inotropic reserve in human HF. METHODS AND RESULTS: Failing human hearts were
      obtained at transplantation. Contraction and [Ca2+]i measurements were performed
      in isolated cardiac myocytes and trabeculae. In HF myocytes and muscle,
      isoproterenol (ISO), a beta-AR agonist, led to small inotropic and lusitropic
      responses. Specific inhibition of NOS2 by aminoguanidine (AG) or L-NIL
      dramatically increased the ISO-induced inotropy and lusitropy, such that the
      ISO+AG response in HF approached that seen with ISO alone in nonfailing human
      myocytes or muscles. Ca2+ transient data directly paralleled these results,
      indicating that altered cellular Ca2+ handling is responsible. In nonfailing
      human hearts, NOS2 inhibition had no effects. In addition, NOS2 inhibition also
      had no effect in 30% of failing hearts, but in these myocytes and muscles, the
      ISO response alone was similar to that of nonfailing hearts. In line with these
      functional findings, NOS2 protein expression measured by Western blotting was
      induced in HF when AG/L-NIL had a functional effect but not when AG/L-NIL had no
      effect on contractility and Ca2+ transients. CONCLUSIONS: NOS2 expression
      strongly limited ISO-induced increases in contraction, twitch Delta[Ca2+]i, and
      lusitropy in trabeculae and isolated myocytes from failing human hearts. Thus,
      the beta-AR hyporesponsiveness in human HF is mediated in large part by NO (or
      related congeners) produced within cardiac myocytes via NOS2.

PMID- 15037530
TI  - Taurine supplementation reduces oxidative stress and improves cardiovascular
      function in an iron-overload murine model.
AB  - BACKGROUND: Iron overload has an increasing worldwide prevalence and is
      associated with significant cardiovascular morbidity and mortality. Elevated iron
      levels in the myocardium lead to impaired systolic and diastolic function and
      elevated oxidative stress. Taurine accounts for 25% to 50% of the amino acid pool
      in myocardium, possesses antioxidant properties, and can inhibit L-type Ca2+
      channels. Thus, we hypothesized that this agent would reduce the cardiovascular
      effects of iron overload. METHODS AND RESULTS: Iron-overloaded mice were
      generated by intraperitoneal injection of iron either chronically (5 days per
      week for 13 weeks) or subacutely (5 days per week for 4 weeks). Iron overload
      causes increased mortality, elevated oxidative stress, systolic and diastolic
      dysfunction, hypotension, and bradycardia. Taurine supplementation increased
      myocardial taurine levels by 45% and led to reductions in mortality and improved
      cardiac function, heart rate, and blood pressure in iron-overloaded mice.
      Histological examination of the myocardium revealed reduced apoptosis and
      interstitial fibrosis in iron-overloaded mice supplemented with taurine. Taurine
      mediated reduced oxidative stress in iron-overloaded mice along with attenuation
      of myocardial lipid peroxidation and protection of reduced glutathione level.
      CONCLUSIONS: These results demonstrate that treatment with taurine reduces iron
      mediated myocardial oxidative stress, preserves cardiovascular function, and
      improves survival in iron-overloaded mice. The role of taurine in protecting
      reduced glutathione levels provides an important mechanism by which oxidative
      stress-induced myocardial damage can be curtailed. Taurine, as a dietary
      supplement, represents a potential new therapeutic agent to reduce the
      cardiovascular burden from iron-overload conditions.

PMID- 15037529
TI  - Constitutive cardiac overexpression of sarcoplasmic/endoplasmic reticulum Ca2+
      ATPase delays myocardial failure after myocardial infarction in rats at a cost of
      increased acute arrhythmias.
AB  - BACKGROUND: Heart failure often complicates myocardial infarction (MI), and
      sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a) is underexpressed in the
      failing myocardium. We examined the effect of preexisting cardiac SERCA2a protein
      overexpression on rat survival and left ventricular (LV) remodeling after MI.
      METHODS AND RESULTS: Baseline myocardial SERCA2a expression was 37% higher in
      transgenic (TG) rats than in their wild-type (WT) controls, consistent with
      enhanced myocardial function. The mortality rate of TG rats during the 24 hours
      after surgical MI was higher than that of WT rats (71% versus 35%, P<0.001),
      associated with a higher frequency of ventricular arrhythmias, and was normalized
      by lidocaine treatment. The increased acute-phase mortality in TG rats was not
      accompanied by increased 6-month mortality. Function of the noninfarcted
      myocardium, as assessed by tissue Doppler imaging, was higher in TG rats than in
      WT rats for up to 1 month after MI, a beneficial effect no longer observed at 3
      months. LV remodeling and global function were similar in TG and WT rats. No
      difference in papillary muscle function was found at 6 months. CONCLUSIONS:
      Constitutive cardiac SERCA2a overexpression has a transient beneficial effect on
      remote myocardium function in rat MI, with no improvement in LV global function
      or prevention of LV remodeling and failure. This benefit is associated with a
      higher risk of acute mortality, which is prevented by lidocaine treatment.

PMID- 15037531
TI  - Possible protective role for C-reactive protein in atherogenesis: complement
      activation by modified lipoproteins halts before detrimental terminal sequence.
AB  - BACKGROUND: Previous work indicated that enzymatically remodeled LDL (E-LDL)
      might activate complement in atherosclerotic lesions via a C-reactive protein
      (CRP)-dependent and CRP-independent pathway. We sought to substantiate this
      contention and determine whether both pathways drive the sequence to completion.
      METHODS AND RESULTS: E-LDL was prepared by sequential treatment of LDL with a
      protease and cholesteryl esterase. Trypsin, proteinase K, cathepsin H, or plasmin
      was used with similar results. Functional tests were used to assess total
      complement hemolytic activity, and immunoassays were used to demonstrate C3
      cleavage and to quantify C3a, C4a, C5a, and C5b-9. E-LDL preparations activated
      complement to completion, independent of CRP, when present above a threshold
      concentration (100 to 200 microg/mL in 5% serum). Below the threshold, all E-LDL
      preparations activated complement in dependence of CRP, but the pathway then
      halted before the terminal sequence. Native LDL and oxidized LDL did not activate
      complement under any circumstances tested. Immunohistological analyses
      corroborated the concept that CRP-dependent complement activation inefficiently
      generates C5b-9. CONCLUSIONS: Binding of CRP to E-LDL is the first trigger for
      complement activation in the atherosclerotic lesion, but the terminal sequence is
      thereby spared. This putatively protective function of CRP is overrun at higher E
      LDL concentrations, so that potentially harmful C5b-9 complexes are generated.

PMID- 15037532
TI  - Sinoatrial node dysfunction and early unexpected death of mice with a defect of
      klotho gene expression.
AB  - BACKGROUND: Homozygous mutant mice with a defect of klotho gene expression
      (kl/kl) show multiple age-related disorders and premature death from unknown
      causes. METHODS AND RESULTS: The kl/kl mice subjected to 20-hour restraint stress
      showed a high rate (20/30) of sudden death, which was associated with sinoatrial
      node dysfunction (conduction block or arrest). Heart rate and plasma
      norepinephrine of kl/kl mice, unlike those of wild-type (WT) mice, failed to
      increase during the stress. Intrinsic heart rate after pharmacological blockade
      of autonomic nerves in kl/kl mice was significantly lower than that in WT mice
      (380+/-33 versus 470+/-44 bpm; n=7). The sinus node recovery time after an
      overdrive pacing (600 bpm, 30 seconds) in kl/kl mice was significantly longer
      than in WT mice (392+/-37 versus 233+/-24 ms; n=6). In isolated sinoatrial node
      preparations, the positive chronotropic effect of isoproterenol was significantly
      less, whereas the negative chronotropic effect of acetylcholine was significantly
      greater in kl/kl than in WT mice. There was no degenerative structural change in
      the sinoatrial node of kl/kl mice. The precise localization of klotho was
      analyzed in newly prepared klotho-null mice with a reporter gene system (kl(
      geo)). Homozygous kl(-geo) mice showed characteristic age-associated phenotypes
      that were almost identical to those of kl/kl mice. In the kl(-geo) mice, klotho
      expression was recognized exclusively in the sinoatrial node region in the heart
      in addition to parathyroid, kidney, and choroid plexus. CONCLUSIONS: In the
      heart, klotho is expressed solely at the sinoatrial node. klotho gene expression
      is essential for the sinoatrial node to function as a dependable pacemaker under
      conditions of stress.

PMID- 15037534
TI  - Lower loop reentry as a mechanism of clockwise right atrial flutter.
AB  - BACKGROUND: Right atrial reentrant tachycardia resulting from lower loop reentry
      (LLR) around the inferior vena cava (IVC) has been described recently. However,
      all reported cases of LLR in the literature have negative flutter waves on the
      inferior surface ECG leads similar to that of counterclockwise typical atrial
      flutter around the tricuspid annulus (TA). Right atrial flutter with positive
      flutter waves in the inferior ECG leads has been assumed to rotate as a single
      reentrant activation wave front around the TA, and the role of LLR in those
      patients is not known. METHODS AND RESULTS: Twelve consecutive patients with
      flutter wave morphology on surface ECG consistent with clockwise atrial flutter
      were studied. The endocardial activation pattern recorded from conventional
      multipolar electrode catheters was characteristic of clockwise atrial flutter
      around the TA. Entrainment pacing in all 12 patients and 3D activation sequence
      mapping in 7 patients, however, revealed clockwise LLR involving the lower right
      atrium around the IVC in 7 patients, figure-of-8 double-loop reentry around both
      the IVC and TA in 4, and single reentrant loop around the TA in 1. Linear
      radiofrequency ablation in the isthmus between the TA and IVC (TI isthmus)
      terminated the tachycardia in all patients. CONCLUSIONS: Surface ECG flutter wave
      morphology and limited recording intracardiac sites proved insufficient to
      delineate the precise mechanism of the TI isthmus-dependent clockwise right
      atrial flutters. Most right atrial flutters with positive flutter wave on surface
      ECG may be supported by a reentrant circuit around the IVC or a figure-of-8
      double-loop reentry involving both the IVC and TA.

PMID- 15037533
TI  - gp91phox-containing NADPH oxidase mediates endothelial dysfunction in
      renovascular hypertension.
AB  - BACKGROUND: Isoforms of the NADPH oxidase contribute to vascular superoxide anion
      (*O2-) formation and limit NO bioavailability. We hypothesized that the
      endothelial gp91phox-containing NADPH oxidase is predominant in generating the O2
      to scavenge endothelial NO and thus is responsible for the development of
      endothelial dysfunction. METHODS AND RESULTS: Endothelial dysfunction was studied
      in aortic rings from wild-type (WT) and gp91phox-knockout (gp91phox-/-) mice with
      and without renovascular hypertension induced by renal artery clipping (2K1C).
      Hypertension induced by 2K1C was more severe in WT than in gp91phox-/- mice
      (158+/-2 versus 149+/-2 mm Hg; P<0.05). Endothelium-dependent relaxation to
      acetylcholine (ACh) was attenuated in rings from clipped WT but not from clipped
      gp91phox-/- mice. The reactive oxygen species (ROS) scavenger Tiron, PEG
      superoxide dismutase, and the NADPH oxidase inhibitory peptide gp91ds-tat
      enhanced ACh-induced relaxation in aortae of clipped WT mice. Inhibition of
      protein kinase C, Rac, and the epidermal growth factor receptor kinase, elements
      involved in the activation of the NADPH oxidase, restored normal endothelium
      dependent relaxation in vessels from clipped WT mice but had no effect on
      relaxations in those from gp91phox-/- mice. Relaxations to exogenous NO were
      attenuated in vessels from clipped WT but not clipped gp91phox-/- mice. After
      removal of the endothelium or treatment with PEG-superoxide dismutase, NO-induced
      relaxations were identical in vessels from clipped and sham-operated WT and
      gp91phox mice. CONCLUSIONS: These data indicate that the formation of O2- by the
      endothelial gp91phox-containing NADPH oxidase accounts for the reduced NO
      bioavailability in the 2K1C model and contributes to the development of
      renovascular hypertension and endothelial dysfunction.

PMID- 15037535
TI  - A walnut diet improves endothelial function in hypercholesterolemic subjects: a
      randomized crossover trial.
AB  - BACKGROUND: Epidemiological studies suggest that nut intake decreases coronary
      artery disease (CAD) risk. Nuts have a cholesterol-lowering effect that partly
      explains this benefit. Endothelial dysfunction is associated with CAD and its
      risk factors and is reversed by antioxidants and marine n-3 fatty acids. Walnuts
      are a rich source of both antioxidants and alpha-linolenic acid, a plant n-3
      fatty acid. METHODS AND RESULTS: To test the hypothesis that walnut intake will
      reverse endothelial dysfunction, we randomized in a crossover design 21
      hypercholesterolemic men and women to a cholesterol-lowering Mediterranean diet
      and a diet of similar energy and fat content in which walnuts replaced
      approximately 32% of the energy from monounsaturated fat. Participants followed
      each diet for 4 weeks. After each intervention, we obtained fasting blood and
      performed ultrasound measurements of brachial artery vasomotor function. Eighteen
      subjects completing the protocol had suitable ultrasound studies. Compared with
      the Mediterranean diet, the walnut diet improved endothelium-dependent
      vasodilation and reduced levels of vascular cell adhesion molecule-1 (P<0.05 for
      both). Endothelium-independent vasodilation and levels of intercellular adhesion
      molecule-1, C-reactive protein, homocysteine, and oxidation biomarkers were
      similar after each diet. The walnut diet significantly reduced total cholesterol
      (-4.4+/-7.4%) and LDL cholesterol (-6.4+/-10.0%) (P<0.05 for both). Cholesterol
      reductions correlated with increases of both dietary alpha-linolenic acid and LDL
      gamma-tocopherol content, and changes of endothelium-dependent vasodilation
      correlated with those of cholesterol-to-HDL ratios (P<0.05 for all). CONCLUSIONS:
      Substituting walnuts for monounsaturated fat in a Mediterranean diet improves
      endothelium-dependent vasodilation in hypercholesterolemic subjects. This finding
      might explain the cardioprotective effect of nut intake beyond cholesterol
      lowering.

PMID- 15037536
TI  - Infliximab improves endothelial dysfunction in systemic vasculitis: a model of
      vascular inflammation.
AB  - BACKGROUND: Endothelial vasomotor dysfunction and markers of systemic
      inflammation are independent determinants of cardiovascular risk. However, the
      link between clinical inflammation and endothelial dysfunction is unclear. The
      aim of this study was to use anti-neutrophil cytoplasmic antibody-associated
      systemic vasculitis (AASV) as a model of systemic inflammation in which to test
      the hypothesis that inflammation is associated with endothelial dysfunction and
      can be reversed with anti-tumor necrosis factor-alpha (TNF-alpha) therapy.
      METHODS AND RESULTS: Fourteen patients with active AASV and 21 age-matched
      control subjects were studied. Endothelial function was assessed through the use
      of forearm plethysmography and related to clinical disease activity: Birmingham
      Vasculitis Activity Score (BVAS) and serum levels of C-reactive protein (CRP),
      interleukin-6 (IL-6), and TNF-alpha. The effects of anti-TNF-alpha therapy
      (infliximab), either alone (n=6) or in combination with standard treatment (n=4),
      on endothelial function were subsequently determined. Patients had a mean BVAS of
      11+/-1, and CRP and IL-6 were higher in the AASV group than in control subjects
      (34.8+/-10.5 versus 1.6+/-0.2 pg/mL, P<0.001; 9.0+/-0.7 versus 6.7+/-0.6 pg/mL,
      P=0.02). Forearm blood flow response to acetylcholine (ACh) was reduced in the
      patients compared with control subjects (P=0.002), but sodium nitroprusside (SNP)
      responses were not (P=0.3). The response to ACh improved with infliximab
      treatment (P=0.004) in particular, with infliximab alone (P=0.03). CONCLUSIONS:
      AASV is associated with endothelial dysfunction. Anti-TNF-alpha therapy, alone or
      in combination with standard treatment, results in clinical remission, reduced
      inflammation, and improved endothelium-dependent vasomotor responses.

PMID- 15037539
TI  - Role of cardiac magnetic resonance imaging in the assessment of myocardial
      viability.

PMID- 15037537
TI  - Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques
      in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase
      activity.
AB  - BACKGROUND: Clinical trials have demonstrated that agents that inhibit the
      angiotensin II pathway confer benefit beyond the reduction of blood pressure
      alone. However, the molecular mechanism underlying this effect has yet to be
      investigated. Recently, we have demonstrated enhanced expression of inducible
      cyclooxygenase (COX) and prostaglandin (PG)E2-dependent synthase (COX-2/mPGES-1)
      in human symptomatic plaques and provided evidence that it is associated with
      metalloproteinase (MMP)-induced plaque rupture. Thus, the aim of this study was
      to characterize the effect of the angiotensin II type 1 (AT1) receptor antagonist
      irbesartan on the inflammatory infiltration and expression of COX-2/mPGES-1 and
      MMPs in human carotid plaques. METHODS AND RESULTS: Seventy patients with
      symptomatic carotid artery stenosis were randomized to irbesartan (300 mg/d) or
      chlorthalidone (50 mg/d) for 4 months before endarterectomy. Plaques were
      subjected to analysis of COX-1, COX-2, mPGES-1, MMP-2, and MMP-9, angiotensin II,
      AT(1), AT2, and collagen content by immunocytochemistry, Western blot, and
      reverse-transcriptase polymerase chain reaction, whereas zymography was used to
      detect MMP activity. Immunohistochemistry was also used to identify CD68+
      macrophages, CD3+ T lymphocytes, smooth muscle cells (SMCs), and HLA-DR+
      inflammatory cells. Plaques from the irbesartan group had fewer (P<0.0001)
      macrophages, T lymphocytes, and HLA-DR+ cells; less (P<0.0001) immunoreactivity
      for COX-2/mPGES-1 and MMPs; reduced (P<0.0001) gelatinolytic activity; and
      increased (P<0.0001) collagen content. It is worth noting that COX-2/mPGES-1
      inhibition was observed after incubation in vitro with irbesartan but not with
      the selective AT2 blockade PD123,319. CONCLUSIONS: This study demonstrates that
      irbesartan decreases inflammation and inhibits COX-2/mPGES-1 expression in plaque
      macrophages, and this effect may in turn contribute to plaque stabilization by
      inhibition of MMP-induced plaque rupture.

PMID- 15037540
TI  - Images in cardiovascular medicine. Human atherosclerotic plaques contain gamma
      glutamyl transpeptidase enzyme activity.

PMID- 15037538
TI  - Early predictors of in-hospital death in infective endocarditis.
AB  - BACKGROUND: Data on early determinants of outcome in infective endocarditis (IE)
      are limited. We evaluated the prognostic significance of early clinical
      characteristics in a large, prospective cohort of patients with IE. METHODS AND
      RESULTS: Two hundred sixty-seven consecutive patients with definite or possible
      IE by modified Duke criteria and echocardiography performed within 7 days of
      presentation were evaluated. Acute physiology was assessed by the Acute
      Physiology, Age, Chronic Health Evaluation II (APACHE II) score at the time of
      presentation, and early heart failure was diagnosed by Framingham criteria. In
      hospital mortality rate in the cohort was 19% and similar for patients with
      definite or possible IE (20% versus 16%, respectively; P=0.464). Independent
      predictors of death determined by logistic regression modeling were diabetes
      mellitus (OR 2.48; 95% CI, 1.24 to 4.96), Staphylococcus aureus as causative
      organism (OR, 2.06; 95% CI, 1.01 to 4.20), APACHE II score (OR, 1.07; 95% CI,
      1.01 to 1.12), and embolic event (OR, 2.79; 95% CI, 1.15 to 6.80). Early
      echocardiographic findings of the Duke criteria were not predictive of death.
      CONCLUSIONS: Early in the course of IE, readily available clinical
      characteristics that reflect the host-pathogen interaction are predictive of in
      hospital death. These factors may identify those patients with IE for more
      aggressive treatment.

PMID- 15037541
TI  - Cardiology patient pages. Innocent murmurs: a parent's guide.

PMID- 15037542
TI  - Images in cardiovascular medicine. Pulmonary vein ablation using a 3D catheter
      tracking system.

PMID- 15037543
TI  - Stenosis and the drug-eluting stent.

PMID- 15037544
TI  - p63 and the epithelial stem cell: more than status quo?

PMID- 15037545
TI  - Prions: proteins as genes and infectious entities.

PMID- 15037546
TI  - Glucocorticoid receptor function in hepatocytes is essential to promote postnatal
      body growth.
AB  - Mice carrying a hepatocyte-specific inactivation of the glucorticoid receptor
      (GR) gene show a dramatic reduction in body size. Growth hormone signaling
      mediated by the Stat5 transcription factors is impaired. We show that Stat5
      proteins physically interact with GR and GR is present in vivo on Stat5-dependent
      IGF-I and ALS regulatory regions. Interestingly, mice with a DNA-binding
      deficient GR but an unaltered ability to interact with STAT5 (GR(dim/dim)) have a
      normal body size and normal levels of Stat5-dependent mRNAs. These findings
      strongly support the model in which GR acts as a coactivator for Stat5-dependent
      transcription upon GH stimulation and reveal an essential role of hepatic GR in
      the control of body growth.

PMID- 15037547
TI  - Local chromatin structure at the ribosomal DNA causes replication fork pausing
      and genome instability in the absence of the S. cerevisiae DNA helicase Rrm3p.
AB  - Lack of the yeast Rrm3p DNA helicase causes replication defects at multiple sites
      within ribosomal DNA (rDNA), including at the replication fork barrier (RFB).
      These defects were unaltered in rrm3 sir2 cells. When the RFB binding Fob1p was
      deleted, rrm3-generated defects at the RFB were eliminated, but defects at other
      rDNA sites were not affected. Thus, specific protein-DNA complexes make
      replication Rrm3p-dependent. Because rrm3-induced increases in recombination and
      cell cycle length were only partially suppressed in rrm3 fob1 cells, which still
      required checkpoint and fork restart activities for viability, non-RFB rrm3
      induced defects contribute to rDNA fragility and genome instability.

PMID- 15037548
TI  - PPAR gamma signaling exacerbates mammary gland tumor development.
AB  - Breast cancer cell lines that express the nuclear peroxisome proliferator
      activated receptor gamma (PPAR gamma) can be prompted to undergo growth arrest
      and differentiation when treated with synthetic PPAR gamma ligands. To evaluate
      the therapeutic potential of increased PPAR gamma signaling in vivo, we generated
      transgenic mice that express a constitutively active form of PPAR gamma in
      mammary gland. These mice are indistinguishable from their wild-type littermates.
      However, when bred to a transgenic strain prone to mammary gland cancer, bigenic
      animals develop tumors with greatly accelerated kinetics. Surprisingly, in spite
      of their more malignant nature, bigenic tumors are more secretory and
      differentiated. The molecular basis of this tumor-promoting effect may be an
      increase in Wnt signaling, as ligand activation of PPAR gamma potentiates Wnt
      function in an in vivo model of this pathway. These results suggest that once an
      initiating event has taken place, increased PPAR gamma signaling serves as a
      tumor promoter in the mammary gland.

PMID- 15037549
TI  - Loss of cell polarity causes severe brain dysplasia in Lgl1 knockout mice.
AB  - Disruption of cell polarity is seen in many cancers; however, it is generally
      considered a late event in tumor progression. Lethal giant larvae (Lgl) has been
      implicated in maintenance of cell polarity in Drosophila and cultured mammalian
      cells. We now show that loss of Lgl1 in mice results in formation of
      neuroepithelial rosette-like structures, similar to the neuroblastic rosettes in
      human primitive neuroectodermal tumors. The newborn Lgl1(-/-) pups develop severe
      hydrocephalus and die neonatally. A large proportion of Lgl1(-/-) neural
      progenitor cells fail to exit the cell cycle and differentiate, and, instead,
      continue to proliferate and die by apoptosis. Dividing Lgl1(-/-) cells are unable
      to asymmetrically localize the Notch inhibitor Numb, and the resulting failure of
      asymmetric cell divisions may be responsible for the hyperproliferation and the
      lack of differentiation. These results reveal a critical role for mammalian Lgl1
      in regulating of proliferation, differentiation, and tissue organization and
      demonstrate a potential causative role of disruption of cell polarity in
      neoplastic transformation of neuroepithelial cells.

PMID- 15037550
TI  - Ephrin-B1 forward and reverse signaling are required during mouse development.
AB  - Eph receptors and ephrin ligands are key players in many developmental processes
      including embryo patterning, angiogenesis, and axon guidance. Eph/ephrin
      interactions lead to the generation of a bidirectional signal, in which both the
      Eph receptors and the ephrins activate downstream signaling cascades
      simultaneously. To understand the role of ephrin-B1 and the importance of ephrin
      B1-induced reverse signaling during embryonic development, we have generated
      mouse lines carrying mutations in the efnb1 gene. Complete ablation of ephrin-B1
      resulted in perinatal lethality associated with a range of phenotypes, including
      defects in neural crest cell (NCC)-derived tissues, incomplete body wall closure,
      and abnormal skeletal patterning. Conditional deletion of ephrin-B1 demonstrated
      that ephrin-B1 acts autonomously in NCCs, and controls their migration. Last, a
      mutation in the PDZ binding domain indicated that ephrin-B1-induced reverse
      signaling is required in NCCs. Our results demonstrate that ephrin-B1 acts both
      as a ligand and as a receptor in a tissue-specific manner during embryogenesis.

PMID- 15037552
TI  - Prevalence, detection, management, and control of hypertension in Ashanti, West
      Africa.
AB  - Hypertension and stroke are important threats to the health of adults in sub
      Saharan Africa. Nevertheless, detection of hypertension is haphazard and stroke
      prevention targets are currently unattainable. Prevalence, detection, management,
      and control of hypertension were assessed in 1013 men (n=385) and women (n=628),
      both aged 55 [SD 11] years, living in 12 villages in Ashanti, Ghana. Five hundred
      thirty two lived in semi-urban and 481 in rural villages. The participants
      underwent measurements of height, weight, and blood pressure (BP) and answered a
      detailed questionnaire. Hypertension was defined as BP > or =140 and/or > or =90
      mm Hg or being on drug therapy. Women were heavier than men. Participants in semi
      urban areas were heavier and had higher BP (129/76 [26/14] versus 121/72 [25/13]
      mm Hg; P<0.001 for both) than in rural areas. Prevalence of hypertension was
      28.7% overall and comparable in men and women, but higher in semi-urban villages
      (32.9% [95% CI 28.9 to 37.1] versus 24.1% [20.4 to 28.2]), and increased with
      age. Detection rate was lower in men than women (13.9% versus 27.3%; P=0.007).
      Treatment and control rates were low in both groups (7.8% and 4.4% versus 13.6%
      and 1.7%). Detection, treatment, and control rates were higher in semi-urban
      (25.7%, 14.3%, and 3.4%) than in rural villages (16.4%, 6.9%, and 1.7%).
      Hypertension is common in adults in central Ghana, particularly in urban areas.
      Detection rates are suboptimal in both men and women, especially in rural areas.
      Adequate treatment of high BP is at a very low level. There is an urgent need for
      preventive strategies on hypertension control in Ghana.

PMID- 15037551
TI  - Targeting of TAK1 by the NF-kappa B protein Relish regulates the JNK-mediated
      immune response in Drosophila.
AB  - The molecular circuitry underlying innate immunity is constructed of multiple,
      evolutionarily conserved signaling modules with distinct regulatory targets. The
      MAP kinases and the IKK-NF-kappa B molecules play important roles in the
      initiation of immune effector responses. We have found that the Drosophila NF
      kappa B protein Relish plays a crucial role in limiting the duration of JNK
      activation and output in response to Gram-negative infections. Relish activation
      is linked to proteasomal degradation of TAK1, the upstream MAP kinase kinase
      kinase required for JNK activation. Degradation of TAK1 leads to a rapid
      termination of JNK signaling, resulting in a transient JNK-dependent response
      that precedes the sustained induction of Relish-dependent innate immune loci.
      Because the IKK-NF-kappa B module also negatively regulates JNK activation in
      mammals, thereby controlling inflammation-induced apoptosis, the regulatory cross
      talk between the JNK and NF-kappa B pathways appears to be broadly conserved.

PMID- 15037553
TI  - Prolyl oligopeptidase is involved in release of the antifibrotic peptide Ac-SDKP.
AB  - N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a ubiquitous tetrapeptide
      hydrolyzed almost exclusively by angiotensin-converting enzyme (ACE). Chronic
      treatment with Ac-SDKP decreases cardiac and renal fibrosis and inflammatory cell
      infiltration in hypertensive rats. However, very little is known about endogenous
      synthesis of Ac-SDKP, except that thymosin-beta4 may be the most likely
      precursor. Two enzymes are potentially able to release Ac-SDKP from thymosin
      beta4: prolyl oligopeptidase (POP) and endoproteinase asp-N. POP is widely
      present and active in several tissues and biological fluids, whereas
      endoproteinase asp-N appears to be lacking in mammals. Therefore, we hypothesized
      that POP is the main enzyme involved in synthesizing the antifibrotic peptide Ac
      SDKP. We investigated in vitro and in vivo production of Ac-SDKP. Using kidney
      cortex homogenates, we observed that Ac-SDKP was generated in a time-dependent
      manner in the presence of exogenous thymosin-beta4, and this generation was
      significantly inhibited by several POP inhibitors (POPi), Z-prolyl-prolinal, Fmoc
      prolyl-pyrrolidine-2-nitrile, and S17092. Long-term administration of S17092 in
      rats significantly decreased endogenous levels of Ac-SDKP in the plasma (from
      1.76+/-0.2 to 1.01+/-0.1 nM), heart (from 2.31+/-0.21 to 0.83+/-0.09 pmol/mg
      protein), and kidneys (from 5.62+/-0.34 to 2.86+/-0.76 pmol/mg protein). As
      expected, ACE inhibitors significantly increased endogenous levels of Ac-SDKP in
      the plasma, heart, and kidney, whereas coadministration of POPi prevented this
      increase. We concluded that POP is the main enzyme responsible for synthesis of
      the antifibrotic peptide Ac-SDKP.

PMID- 15037554
TI  - Nitric oxide and cardiac muscarinic control in humans.
AB  - Cardiac parasympathetic activity reduces susceptibility to potentially lethal
      ventricular arrhythmias in heart failure and ischemic heart disease. This
      influence is mediated in large part by antagonism of the adverse cardiac effects
      of sympathetic overactivity ("indirect" parasympathetic activity) in addition to
      the "direct" effects of muscarinic stimulation. Nitric oxide modulates
      parasympathetic cardiac signaling in some animal models, but human data are
      lacking. We have investigated the influence of endogenous nitric oxide on cardiac
      responses to parasympathetic stimulation in healthy humans. In 18 volunteers, we
      studied chronotropic and inotropic responses to muscarinic stimulation, both
      before and after prestimulation with isoproterenol. Cardiac muscarinic
      stimulation was achieved using an intravenous bolus of the short-acting
      cholinesterase inhibitor, edrophonium. Responses were assessed during a
      background infusion of a nitric oxide synthase inhibitor (N(G)-monomethyl-L
      arginine [L-NMMA]), placebo (saline), or phenylephrine (vasoconstrictor control)
      in a single-blind, random order, crossover protocol. L-NMMA did not affect
      chronotropic responses to edrophonium alone (direct parasympathetic activity).
      The decrease in heart rate attributable to "indirect" parasympathetic activity
      (derived by comparison with the effect of edrophonium during concurrent
      adrenergic stimulation) was substantially attenuated by L-NMMA in comparison to
      both control infusions. No modification of muscarinic inotropic responses by L
      NMMA was apparent in comparison to the vasoconstrictor control. Nitric oxide
      exerts a powerful facilitating influence on indirect (antiadrenergic) but not
      direct human cardiac parasympathetic control. Stimulation of the endogenous
      nitric oxide pathway might enhance parasympathetic protection against the adverse
      influences of cardiac sympathetic overactivity.

PMID- 15037555
TI  - Alpha-2 adrenergic transmission and human baroreflex regulation.
AB  - We observed earlier that central alpha-2 adrenoceptor stimulation in mice greatly
      augments parasympathetic tone. To test the effects in humans, we assessed
      autonomic vasomotor tone and baroreflex regulation in 9 normal young adults on 2
      occasions, once with and once without clonidine. We determined heart rate (HR),
      beat-by-beat blood pressure (BP), and muscle sympathetic nerve activity. HR
      variability was analyzed in the time and frequency domain. Pharmacological
      baroreflex slopes were determined using incremental phenylephrine and
      nitroprusside infusions. Clonidine lowered resting BP (122+/-4/73+/-3 versus
      100+/-7/55+/-3 mm Hg, P<0.01), muscle sympathetic nerve activity (18+/-3 versus
      4+/-2 bursts/min, P<0.01), and HR (62+/-3 versus 56+/-3 bpm, P<0.05). The
      baroreflex heart rate curve was reset to much lower HR values and showed no
      saturation at low HR. HR variability profoundly increased during clonidine plus
      phenylephrine (total power: 3224+/-843 versus 8943+/-2329 ms2, P<0.05). High
      frequency power was 1451+/-520 at baseline and 6720+/-2475 ms2 during
      baroreceptor loading (P<0.05). The low-frequency/high-frequency ratio decreased
      (1.94+/-0.41 versus 0.69+/-0.10, P<0.05). In contrast, clonidine reduced resting
      sympathetic vasomotor tone and shifted the operating point of the sympathetic
      baroreflex to a flat part of the sympathetic baroreflex curve. The shift
      decreased the ability of the baroreflex to withdraw sympathetic vasomotor tone
      during baroreflex loading. These baroreflex changes were associated with a
      moderate increase in phenylephrine responsiveness. We conclude that alpha-2
      adrenoceptor stimulation has a differential effect on baroreflex HR and vasomotor
      regulation. alpha-2 Adrenoceptor stimulation greatly augments baroreflex-mediated
      bradycardia, most likely by parasympathetic activation.

PMID- 15037556
TI  - When does new onset diabetes resulting from antihypertensive therapy increase
      cardiovascular risk.

PMID- 15037557
TI  - Adverse prognostic significance of new diabetes in treated hypertensive subjects.
AB  - Diabetes may develop in nondiabetic hypertensive subjects during treatment, but
      the long-term cardiovascular implications of this phenomenon are not clear. We
      determined the prognostic value of new diabetes in hypertensive subjects. In a
      long-term cohort study, 795 initially untreated hypertensive subjects, 6.5% of
      whom with type 2 diabetes, underwent diagnostic procedures including 24-hour
      ambulatory blood pressure (BP) monitoring and electrocardiography (ECG).
      Procedures were repeated after a median of 3.1 years in the absence of
      cardiovascular events. Follow-up duration was 1 to 16 years (median 6.0). New
      diabetes occurred in 5.8% of subjects initially without diabetes.
      Antihypertensive treatment included a diuretic in 53.5% of these subjects, versus
      30.4% of those in whom diabetes did not develop (P=0.002). Plasma glucose at
      entry (P=0.0001) and diuretic treatment on follow-up (P=0.004) were independent
      predictors of new diabetes. Subsequent to the follow-up visit, a first
      cardiovascular event occurred in 63 subjects. Event rate in nondiabetic subjects
      at both visits, new diabetes, and diabetes at entry were 0.97, 3.90, and 4.70x100
      person-years, respectively (P=0.0001). After adjustment for several confounders,
      including 24-hour ambulatory BP, the relative risk of events was 2.92 (95% CI:
      1.33 to 6.41; P=0.007) in the group with new diabetes and 3.57 (95% CI: 1.65 to
      7.73; P=0.001) in the group with previous diabetes, when compared with the group
      persistently free of diabetes. In treated hypertensive subjects, occurrence of
      new diabetes portends a risk for subsequent cardiovascular disease that is not
      dissimilar from that of previously known diabetes.

PMID- 15037559
TI  - The JNC-7 guidelines and the optimal target for systolic blood pressure.

PMID- 15037560
TI  - QRS duration and QT interval predict mortality in hypertensive patients with left
      ventricular hypertrophy: the Losartan Intervention for Endpoint Reduction in
      Hypertension Study.
AB  - Left ventricular hypertrophy is a risk factor for cardiovascular mortality,
      including sudden cardiac death. Experimentally, left ventricular hypertrophy
      delays ventricular conduction and prolongs action potential duration.
      Electrocardiographic QRS duration and QT interval measures reflect these changes,
      but whether these measures can further stratify risk in patients with
      electrocardiographic left ventricular hypertrophy is unknown. We measured the QRS
      duration and QT intervals from the baseline 12-lead electrocardiograms in the
      Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, which
      included hypertensive patients with electrocardiographic evidence of left
      ventricular hypertrophy randomized to either losartan-based or atenolol-based
      treatment to lower blood pressure. In the present study, we related study
      baseline electrocardiographic measures to cardiovascular and all-cause mortality.
      There were 5429 patients (male 45.8%; mean age 66+/-7 years) included in the
      present analyses. After a mean follow-up of 4.9+/-0.8 years, there were 417
      deaths from all causes, including 214 cardiovascular deaths. In separate
      univariate Cox regression analyses, QRS duration and several QT measures were
      significant predictors of cardiovascular mortality and all-cause mortality.
      However, in multivariate Cox analyses including all electrocardiographic measures
      and adjusting for other risk factors as well as treatment strategy, only QRS
      duration and maximum rate-adjusted QT(apex) interval remained as significant
      independent predictors of cardiovascular (P=0.022 and P=0.037, respectively) and
      all-cause mortality (P=0.038 and P=0.002, respectively). In conclusion, in a
      hypertensive risk population identified by electrocardiographic left ventricular
      hypertrophy, increased QRS duration and maximum QT(apex) interval can further
      stratify mortality risk even in the setting of effective blood pressure-lowering
      treatment.

PMID- 15037561
TI  - Adjacent expression of renin and angiotensinogen in the rostral ventrolateral
      medulla using a dual-reporter transgenic model.
AB  - All components of the renin-angiotensin system are localized in the brain.
      However, because renin is present in very low concentrations, the mechanism by
      which angiotensin II is formed in the brain remains unclear. We previously
      reported the development of 2 transgenic mouse models using sensitive reporters,
      enhanced green fluorescent protein (eGFP) and beta-galactosidase (beta-Gal), to
      examine the cellular localization of renin and angiotensinogen in the mouse
      brain. To determine whether renin and angiotensinogen are coexpressed or present
      in neighboring cells in the rostral ventrolateral medulla (RVLM) and other
      cardiovascular control regions of the brain, we produced and examined double
      transgenic mice, which express eGFP driven by the renin promoter (REN-1c/eGFP)
      and beta-gal driven by the human angiotensinogen promoter (hAGT/beta-gal). Using
      these reporter transgenes as sensitive markers for renin and angiotensinogen
      expression, we conclude that both proteins are coexpressed in the parabrachial
      nucleus and central nucleus of the amygdala and are in adjacent cells in the
      RVLM, reticular formation, bed nucleus of the stria terminalis, subfornical
      organ, and CA1-3 region. These data suggests that, in these areas, both renin and
      angiotensinogen are in close proximity providing the potential for the local
      formation of angiotensin I either intracellularly, when there is colocalization,
      or in the interstitium, when they are in juxtaposed cells.

PMID- 15037563
TI  - Glucose-cholesterol interaction magnifies coronary heart disease risk for
      hypertensive patients.
AB  - Elevated cholesterol and glucose are known independent risk factors for coronary
      heart disease. This study examines whether an adverse synergistic interaction of
      cholesterol and glucose magnifies coronary heart disease risk among treated
      hypertensive patients. Subjects were hypertensive patients (n=6672) in a worksite
      treatment program, with entry fasting glucose <6.99 mmol/L (126 mg/dL) and total
      cholesterol <6.72 mmol/L (260 mg/dL) observed for mean 5.6+/-4.5 years follow-up
      (range 0.5 to 21.7 years). Outcome events were incident hospitalization or death
      due to coronary heart disease. Cox proportional hazard models were constructed
      for the whole sample to assess interaction and then stratified by fasting glucose
      categories with thresholds defined either at impaired fasting glucose (> or =6.11
      mmol/L [110 mg/dL]) or upper quartile (> or =5.72 mmol/L [103 mg/dL]). An
      interaction product term of total cholesterol and fasting glucose as continuous
      variables significantly (P=0.009) improved a Cox proportional hazards model,
      adjusting for total cholesterol, fasting glucose, and other coronary heart
      disease risk factors. Adjusted hazard ratios for 3 upper total cholesterol
      categories (with total cholesterol <5.17 mmol/L [200 mg/dL] as reference) in the
      higher fasting glucose stratum were more than double the corresponding hazard
      ratios in the lower stratum, whether using impaired fasting glucose or upper
      quartile fasting glucose as the cut point. These results suggest that an adverse
      synergistic interaction between glucose and cholesterol magnifies coronary heart
      disease risk associated with total cholesterol among hypertensive patients,
      raising the possibility that coronary heart disease prevention might be enhanced
      if cholesterol intervention criteria were modified by glucose status.

PMID- 15037562
TI  - Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in
      skeletal muscles of diabetic mice.
AB  - Angiotensin II has been shown to contribute to the pathogenesis of insulin
      resistance; however, the mechanism is not well understood. The present study was
      undertaken to investigate the potential effect of an angiotensin II type-1 (AT1)
      receptor blocker, valsartan, to improve insulin resistance and to explore the
      signaling basis of cross-talk of the AT1 receptor- and insulin-mediated signaling
      in type 2 diabetic KK-Ay mice. Treatment of KK-Ay mice with valsartan at a dose
      of 1 mg/kg per day, which did not influence systolic blood pressure,
      significantly increased insulin-mediated 2-[3H]deoxy-d-glucose (2-[3H]DG) uptake
      into skeletal muscle and attenuated the increase in plasma glucose concentration
      after a glucose load and plasma concentrations of glucose and insulin. In
      contrast, insulin-mediated 2-[3H]DG uptake into skeletal muscle was not
      influenced in AT2 receptor null mice, and an AT2 receptor blocker, PD123319, did
      not affect 2-[3H]DG uptake and superoxide production in skeletal muscle of KK-Ay
      mice. Moreover, we observed that valsartan treatment exaggerated the insulin
      induced phosphorylation of IRS-1, the association of IRS-1 with the p85
      regulatory subunit of phosphoinositide 3 kinase (PI 3-K), PI 3-K activity, and
      translocation of GLUT4 to the plasma membrane. It also reduced tumor necrosis
      factor-alpha (TNF-alpha) expression and superoxide production in skeletal muscle
      of KK-Ay mice. Specific AT1 receptor blockade increases insulin sensitivity and
      glucose uptake in skeletal muscle of KK-Ay mice via stimulating the insulin
      signaling cascade and consequent enhancement of GLUT4 translocation to the plasma
      membrane.

PMID- 15037564
TI  - Sphingosine-1-phosphate inhibits C-type natriuretic peptide activation of
      guanylyl cyclase B (GC-B/NPR-B).
AB  - C-type natriuretic peptide (CNP) binds and activates the transmembrane guanylyl
      cyclase B receptor (NPR-B), which decreases vascular tone and inhibits cell
      proliferation and migration. In contrast, the bioactive lipid sphingosine-1
      phosphate (S1P) elicits the opposite physiological effects. Here, we demonstrate
      a potent acute inhibitory effect of S1P on NPR-B activity in NIH3T3 fibroblasts
      and A10 vascular smooth muscle cells. In fibroblasts, S1P reduced CNP-dependent
      cGMP elevations to the same levels as 10% fetal bovine serum, the most potent NPR
      B desensitizing agent known. The reduction was dose-dependent (IC50=0.08
      micromol/L) and due to decreased NPR-B activity because CNP-dependent guanylyl
      cyclase activities were markedly diminished in membranes prepared from S1P
      treated cells. Similarly, in A10 cells, S1P inhibition was rapid (t1/2=2 to 5
      minutes), dose-dependent (IC50=0.3 micromol/L S1P), and mediated by a cell
      surface receptor. The mechanism of the S1P-dependent desensitization in A10 cells
      did not require NPR-B degradation or protein kinase C activation, but did require
      elevated calcium concentrations because a nonspecific calcium ionophore also
      inhibited NPR-B and an intracellular calcium chelator blocked a significant
      portion of the S1P response. These are the first data demonstrating cross-talk
      between the natriuretic peptide and S1P signaling systems. They suggest that the
      effects of S1P on vascular disease and wound healing may be mediated in part
      through inhibition of NPR-B.

PMID- 15037566
TI  - Age-related changes on the surface of vitreous collagen fibrils.
AB  - PURPOSE: To determine whether aging vitreous collagen fibrils undergo
      ultrastructural changes that might underlie vitreous liquefaction and posterior
      vitreous detachment. METHODS: Vitreous collagen fibrils from 21 human subjects
      (age range, 3-89 years) and from bovine eyes were isolated on electron microscopy
      grids. Cupromeronic blue labeling in the presence of 0.3 M MgCl(2) and immunogold
      labeling for collagen types II and IX were analyzed by transmission electron
      microscopy. RESULTS: Aging was associated with marked changes on the surface of
      human vitreous collagen fibrils, including an exponential loss of type IX
      collagen along with its chondroitin sulfate side-chains (half-life, 11 years) and
      a fourfold increase in the exposure of type II collagen. CONCLUSIONS: Despite
      being a minor component of vitreous collagen fibrils, type IX collagen, probably
      by virtue of its chondroitin sulfate side-chains, shields type II collagen from
      exposure on the fibril surface. With aging, this shielding diminishes, resulting
      in the surface exposure of "sticky" type II collagen and thus predisposing the
      vitreous collagen fibrils to fusion. These changes could underlie vitreous
      liquefaction and weakening of vitreoretinal adhesion.

PMID- 15037565
TI  - AT1 receptor mediated augmentation of intrarenal angiotensinogen in angiotensin
      II-dependent hypertension.
AB  - Angiotensin (Ang) II-infused hypertensive rats exhibit increases in renal
      angiotensinogen mRNA and protein, as well as urinary angiotensinogen excretion in
      association with increased intrarenal Ang II content. The present study was
      performed to determine if the augmentation of intrarenal angiotensinogen requires
      activation of Ang II type 1 (AT1) receptors. Male Sprague-Dawley rats (200 to 220
      g) were divided into 3 groups: sham surgery (n=10), subcutaneous infusion of Ang
      II (80 ng/min, n=11), and Ang II infusion plus AT1 blocker (ARB), olmesartan (5
      mg/d, n=12). Ang II infusion progressively increased systolic blood pressure
      (SBP) compared with sham (178+/-8 mm Hg versus 119+/-4 at day 11). ARB treatment
      prevented hypertension (113+/-6 at day 11). Twenty-four-hour urine collections
      were taken at day 12, and plasma and tissue samples were harvested at day 13. The
      Ang II+ARB group had a significant increase in plasma Ang II compared with Ang II
      and sham groups (365+/-46 fmol/mL versus 76+/-9 and 45+/-14, respectively).
      Nevertheless, ARB treatment markedly limited the enhancement of kidney Ang II by
      Ang II infusion (65+/-17 fmol/g in sham, 606+/-147 in Ang II group, and 288+/-28
      in Ang II+ARB group). Ang II infusion significantly increased kidney
      angiotensinogen compared with sham (1.69+/-0.21 densitometric units versus 1.00+/
      0.17). This change was reflected by increased angiotensinogen immunostaining in
      proximal tubules. ARB treatment prevented this increase (1.14+/-0.12). Urinary
      angiotensinogen excretion rates were enhanced 4.7x in Ang II group (4.67+/-0.41
      densitometric units versus 1.00+/-0.21) but ARB treatment prevented the
      augmentation of urinary angiotensinogen (0.96+/-0.23). These data demonstrate
      that augmentation of intrarenal angiotensinogen in Ang II-infused rats is AT1
      dependent and provide further evidence that urinary angiotensinogen is closely
      linked to intrarenal Ang II in Ang II-dependent hypertension.

PMID- 15037567
TI  - Demonstration of systematic variation in human intraorbital optic nerve size by
      quantitative magnetic resonance imaging and histology.
AB  - PURPOSE: To use magnetic resonance imaging (MRI) to measure the diameter along
      the course of the intraorbital optic nerve in living subjects and cadaveric
      specimens, and to validate measurements histologically in the same specimens.
      METHODS: Measurements of the intraorbital optic nerve were made in 23 living
      human subjects and in three formalin-fixed orbits using high-resolution, surface
      coil MRI in the coronal plane. Fixed orbits were then serially sectioned in the
      same plane, and stained by Masson's trichrome for digital morphometry of nerve
      diameter and densitometry of connective tissue constituents. RESULTS: In
      cadaveric specimens, MRI and histologic measurements of optic nerve dimensions
      were in close quantitative agreement, showing significant decrease in the average
      optic nerve diameter along its retrobulbar course. This finding was confirmed by
      MRI in living subjects, with average optic nerve diameter declining from 3.99 +/-
      0.04 mm (SEM) just posterior to the globe, to 3.50 +/- 0.04 mm at 10 mm further
      to the posterior (P < 0.0001). Color densitometry demonstrated a consistent cross
      sectional area of nervous tissue, but decreasing amounts of collagen posteriorly.
      CONCLUSIONS: There is a significant decrease in normal optic nerve diameter along
      its length in normal subjects, reflecting reduction in connective tissue. High
      resolution MRI is a valid and sensitive method of detecting subtle changes in
      retrobulbar optic nerve size and can be useful in the investigation of structural
      optic nerve lesions. Optic nerve diameters must be measured, however, at similar
      distances posterior to the globe to allow meaningful comparisons.

PMID- 15037568
TI  - Age-related changes in the photoreactivity of retinal lipofuscin granules: role
      of chloroform-insoluble components.
AB  - PURPOSE: Lipofuscin accumulates in human retinal pigment epithelium (RPE) cells
      with age and may be the main factor responsible for the increasing susceptibility
      of RPE to photo-oxidation with age. As the composition, absorption, and
      fluorescence of lipofuscin undergo age-related changes, the purpose of this study
      was to determine whether photoreactivity of lipofuscin granules also changes with
      the donor age. METHODS: To determine whether the photoreactivity of lipofuscin
      itself is age related, lipofuscin granules were isolated from human RPE and
      pooled into age groups. Photoreactivity was assessed by measuring action spectra
      of photo-induced oxygen uptake and photogeneration of reactive oxygen species.
      Separation of chloroform-soluble (ChS) and -insoluble (ChNS) components by
      Folch's extraction was used to determine the factors responsible for the age
      related increase in lipofuscin photoreactivity. RESULTS: The observed rates of
      photo-induced oxygen uptake and photo-induced accumulation of superoxide-derived
      spin adducts indicated that when normalized to equal numbers of lipofuscin
      granules, aerobic photoreactivity of lipofuscin increased with age. Both ChS and
      ChNS mediated photogeneration of singlet oxygen, superoxide radical anion, and
      photo-oxidation of added lipids and proteins. Although both ChS and ChNS
      exhibited substantial photoreactivities, neither exhibited significant age
      related changes when normalized to equal dry mass. In contrast, ChNS contents in
      lipofuscin granules significantly increased with aging. CONCLUSIONS: Aerobic
      photoreactivity of RPE lipofuscin substantially increases with aging. This effect
      may be ascribed to the increased content of insoluble components.

PMID- 15037569
TI  - Decreased visual field sensitivity measured 1 day, then 1 week, after migraine.
AB  - PURPOSE: To determine whether perimetric performance is worse the day after a
      migraine than prior interictal measurements, and if so, to determine whether
      differences have resolved by 1 week after migraine. METHODS: Twenty-two
      nonheadache control subjects (aged 18-45 years) and 22 migraineurs (aged 18-45
      years: 10 migraine with visual aura, 12 migraine without aura) participated.
      Standard automated perimetry (SAP) and temporal modulation perimetry (TMP) were
      measured by perimeter (model M-700; Medmont, Pty Ltd., Camberwell, Victoria,
      Australia). Control subjects attended two test visits: baseline and retest.
      Migraineurs attended three times: baseline (>or=4 days after migraine), the day
      after the offset of the next migraine, and 7 days later. Groups were compared
      using the global indices of the perimeter: Average Defect (AD) and Pattern Defect
      (PD), in addition to point-wise comparisons. RESULTS: Group migraineur TMP
      performance was significantly worse the day after a migraine, showing decreased
      general sensitivity and increased localized loss. Performance measured 7 days
      later was not significantly different from that measured the day after a
      migraine. Group migraineur SAP performance was not significantly worse after
      migraine; however, a subgroup of six eyes from five patients had 10 or more
      visual field locations with decreases in sensitivity greater than control test
      retest 95% confidence limits. CONCLUSIONS: Decreased visual field performance was
      present after migraine, as well as greater test-retest variability in the
      migraine group compared with control subjects. As migraineurs constitute 10% to
      15% of the general population, the presence of this subgroup of patients with
      periodic prolonged decreased visual field sensitivity after migraine has
      implications for differential clinical diagnosis, and for clinical research using
      perimetry.

PMID- 15037570
TI  - Prevalence, incidence, and progression of myopia of school children in Hong Kong.
AB  - PURPOSE: To determine the prevalence, incidence, and progression of myopia of
      Chinese children in Hong Kong. METHODS: A cross-sectional survey was initially
      conducted. A longitudinal follow-up study was then conducted 12 months later.
      RESULTS: A total of 7560 children of mean age 9.33 (95% confidence interval [CI]
      = 9.11-9.45; range, 5-16) participated in the study. Mean spherical equivalent
      refraction (SER) was -0.33 D (SD = 11.56; range, -13.13 to +14.25 D). Myopia (SER
      <or= -0.50 D) was the most common refractive error and was found in 36.71% +/-
      2.87% (SD) of children. Prevalence of myopia correlated positively with older
      age. Children aged 11 years were almost 15 times more likely to have myopia than
      were children younger than 7 years (Odds ratio [OR] = 14.81; 95% CI = 14.17
      15.48). Incidence of myopia was 144.1 +/- 2.31 (SD) per 1000 primary school
      children per annum. Increasing age was correlated with increased incidence of
      myopia, with highest risk in children ages 11 years (OR = 2.27; 95% CI = 2.11
      2.44). The average annual change in SER for children with myopia (SER <or= -0.50
      D) was -0.63 D (SD = 3.44) compared with -0.29 D (SD = 2.96) for those who were
      not myopic at the beginning of the study (P < 0.001). CONCLUSIONS: The results
      show that the prevalence and progression of myopia in Hong Kong children was much
      higher than those previously reported in Western countries. The long-term
      socioeconomic impact of these findings warrants further studies.

PMID- 15037571
TI  - The effect of optical defocus on the test-retest variability of visual acuity
      measurements.
AB  - PURPOSE: To determine the effect of optical defocus on the test-retest
      variability (TRV) of visual acuity measurements in normal subjects. METHODS:
      Normal subjects underwent repeated visual acuity measurement with optical defocus
      of 0, 0.50, and 1.00 D. All measurements were taken using the Early Treatment
      Diabetic Retinopathy Study (ETDRS) version of the Bailey-Lovie logMAR chart. TRV
      was quantified in terms of its 95% range, both empirically and using the approach
      of Bland and Altman. RESULTS: According to the Bland and Altman approach, the
      estimated 95% TRV ranges were +/-0.11 logarithm of the minimum angle of
      resolution (logMAR) for 0-D defocus, +/-0.18 logMAR for 0.50-D defocus, and +/
      0.25 logMAR for 1.00-D defocus. CONCLUSIONS: Optical defocus has a considerable
      effect on the TRV of visual acuity measurements. These findings have important
      implications for both clinical practice and clinical research. Uncorrected
      refractive errors as small as 0.50 D may compromise the detection of visual
      change in individuals, and contribute to unnecessarily large sample sizes in
      clinical trials in which visual acuity is used as a primary outcome measure.

PMID- 15037572
TI  - Regulation of involucrin expression in normal human corneal epithelial cells: a
      role for activator protein one.
AB  - PURPOSE: Understanding the mechanisms that regulate gene expression in the human
      cornea is an important goal. In the present study, the involucrin gene was used
      as a model to study this regulation. Human involucrin (hINV) is a structural
      protein that is selectively expressed in surface epithelia, including corneal
      epithelial cells. METHODS: Regulation of involucrin gene expression was monitored
      in cultures of normal human primary corneal epithelial cells. RESULTS: The
      studies revealed that an activator protein (AP)-1 DNA-binding site is essential
      for appropriate basal and stimulus-dependent hINV promoter activity. Mutation of
      this site, AP1-1, results in a loss of hINV promoter activity. A gel mobility
      supershift analysis revealed interaction of the AP1 factors, Fra-1, Fra-2, and
      JunB, with this element. Inhibition of AP1 function with a dominant-negative form
      of AP1 also inhibited expression. Treatment with 12-O-tetradecanoylphorbol-13
      acetate (TPA), a protein kinase C activator, increased hINV gene expression, a
      response that correlates with increased nuclear AP1 factor level and binding to
      the hINV gene AP1-1 response element. Expression of the endogenous hINV gene is
      also increased by TPA treatment. CONCLUSIONS: These findings point to an
      important role for AP1 transcription factors in the regulation of human corneal
      epithelial cell involucrin gene expression.

PMID- 15037574
TI  - Thymosin-beta4 inhibits corneal epithelial cell apoptosis after ethanol exposure
      in vitro.
AB  - PURPOSE: The purpose of this study was to determine the effect of thymosin beta 4
      (Tbeta(4)) treatment on human corneal epithelial cells exposed to ethanol in
      vitro. The efficacy of Tbeta(4) in preventing mitochondrial disruption and in
      inhibiting caspase-mediated apoptosis was examined. METHODS: Nontransformed human
      corneal epithelial cells (HCECs) at passage 4 were untreated or treated with
      ethanol (20% for 20 seconds) or a combination of ethanol and Tbeta(4). The cells
      were allowed to recover from ethanol treatment for 24 hours. Mitochondrial
      membrane integrity and the release of cytochrome c to the cytoplasm were assessed
      using microscopy, Western blot, and ELISA. Bcl-2 expression and cell
      proliferation were measured using ELISA. Colorimetric activity assays were
      completed for caspase-2, -3, -8, and -9. RESULTS: Tbeta(4) treatment decreased
      deleterious mitochondrial alterations, significantly decreased cytochrome c
      release from mitochondria, and increased Bcl-2 expression in ethanol-exposed
      human corneal epithelial cells. In ethanol-exposed corneal epithelium Tbeta(4)
      treatment inhibited caspase-2, -3, -8, and -9 activity, with caspase-8 showing
      the most significant inhibition. Tbeta(4) treatment resulted in no significant
      effect on the proliferation of human corneal epithelial cells after ethanol
      exposure. CONCLUSIONS: Tbeta(4) plays an antiapoptotic role under conditions of
      epithelial cell challenge with an external stress such as exposure to ethanol.
      Tbeta(4) may function as an antiapoptotic agent by inhibiting the release of
      cytochrome c from mitochondria and by suppressing the activation of caspases.

PMID- 15037573
TI  - Insulin, not leptin, promotes in vitro cell migration to heal monolayer wounds in
      human corneal epithelium.
AB  - PURPOSE: To investigate the effects of insulin and leptin on in vitro wound
      healing of transformed human corneal epithelial cell monolayers and to identify
      cellular (migration versus proliferation) and intracellular signaling mechanisms.
      METHODS: Scratch wounds were created in monolayers of an immortalized human
      corneal epithelial cell (HCEC) line. The wounded monolayers were exposed to
      insulin and leptin. Wound areas were measured every hour after wounding for up to
      8 hours. Phosphoinositide 3-kinase (PI3-kinase) and mitogen-activated protein
      (MAP)-kinase signaling was analyzed with Western blot. The actions of insulin
      were also examined after incubation with inhibitors to extracellular signal
      regulated kinase (ERK 1/2) and PI3-kinase. RESULTS: The presence of insulin, but
      not leptin facilitated closure of wounds created in corneal epithelial cell
      monolayers. Phosphorylation of ERK 1/2 and Akt was stimulated after exposure of
      the monolayers to insulin. Inhibitors of PI3-kinase and ERK 1/2 prevented or
      reduced insulin-induced corneal wound healing, respectively. CONCLUSIONS:
      Exposure of corneal epithelium to insulin facilitated closure of in vitro small
      wounds through enhanced cell migration instead of proliferation, which depended
      on ERK 1/2 and PI3-kinase signaling. These data suggest a mechanism by which
      insulin may influence corneal wound healing in vitro. In vivo, disruptions to the
      insulin signaling pathway observed in diseases such as diabetes might account for
      the delayed wound healing and corneal defects.

PMID- 15037576
TI  - Involvement of CTGF in TGF-beta1-stimulation of myofibroblast differentiation and
      collagen matrix contraction in the presence of mechanical stress.
AB  - PURPOSE: This study was undertaken to investigate the role of connective tissue
      growth factor (CTGF) in fibroblast-to-myofibroblast differentiation and
      fibroblast-mediated collagen matrix contraction in the presence of mechanical
      stress. METHODS: An in vitro three-dimensional contraction model of human corneal
      fibroblast-seeded collagen lattices (FSCLs) in the presence of mechanical stress
      generated by attaching the lattices to the culture well was used to measure FSCL
      contraction. FSCLs were treated with CTGF; TGF-beta1; serum-free (SF) control
      medium; or TGF-beta1 plus antisense oligodeoxynucleotides to CTGF; TGF-beta1 plus
      scrambled-sequence oligodeoxynucleotide to CTGF; or TGF-beta antibody. Expression
      of alpha-smooth muscle actin (alpha-SMA) by fibroblasts in FSCLs was detected by
      immunostaining and confocal microscopy, whereas ELISA was used for the
      fibroblasts cultured on plastic. The conditioned media were analyzed by ELISA for
      CTGF production. RESULTS: Exogenous CTGF stimulated significantly less collagen
      matrix contraction and myofibroblast differentiation than TGF-beta1, but similar
      to that stimulated by SF. TGF-beta1 stimulated fibroblasts to express CTGF. CTGF
      antisense oligodeoxynucleotide inhibited TGF-beta1-stimulated myofibroblast
      differentiation and FSCL contraction. Exogenous CTGF circumvented the inhibitory
      effects of CTGF antisense on FSCL contraction. TGF-beta antibody significantly
      inhibited FSCL contraction and myofibroblast differentiation under mechanical
      stress and SF control conditions. CONCLUSIONS: In the presence of mechanical
      stress, CTGF is necessary for TGF-beta1-stimulation of myofibroblast
      differentiation and subsequent collagen matrix contraction, but CTGF alone is not
      sufficient to induce myofibroblast differentiation and collagen matrix
      contraction. Thus, TGF-beta1 appears to regulate multiple genes that are
      essential for fibroblast-mediated contraction of stressed matrix, one of which is
      CTGF.

PMID- 15037575
TI  - Corneal development, limbal stem cell function, and corneal epithelial cell
      migration in the Pax6(+/-) mouse.
AB  - PURPOSE: To investigate the etiology of corneal dysfunction in the Pax6(+/-)
      mouse model of aniridia-related keratopathy. METHODS: Mosaic patterns of X-gal
      staining were compared in the corneal and limbal epithelia of female Pax6(+/-)
      and Pax6(+/+) littermates, age 3 to 28 weeks, hemizygous for an X-linked LacZ
      transgene, and Pax6(+/+), LacZ(-)<-->Pax6(+/+), LacZ(+) and Pax6(+/+), LacZ(-)<-
      >Pax6(+/-), LacZ(+) chimeras. Histologic examination of chimeric corneas was
      performed. RESULTS: Disrupted patterns of X-gal staining showed that
      heterozygosity for Pax6 perturbed clonal patterns of growth and development in
      the corneal and limbal epithelium. Centripetal migration of Pax6(+/-) corneal
      epithelial cells was diverted. Normal patterns of centripetal Pax6(+/-) cell
      migration and epithelial morphology were restored in Pax6(+/+)<-->Pax6(+/-)
      chimeras. Fewer, larger clones of limbal stem cells were present in Pax6(+/-)
      eyes, compared with wild-type. In the chimeras, Pax6(+/-) limbal stem cells were
      cell-autonomously depleted or less efficient than wild-type cells at producing
      progeny to populate the corneal epithelium. CONCLUSIONS: The correct Pax6 dosage
      is necessary for normal clonal growth during corneal development, normal limbal
      stem cell activity, and correct corneal epithelial cell migration. Disruption of
      normal cell movement in heterozygotes may be the consequence of failure of
      nonautonomous guidance cues. Degeneration of the corneal surface in aniridia
      related keratopathy relates to both a deficiency within the limbal stem cell
      niche and nonautonomous diversion of corneal epithelial cell migration.

PMID- 15037577
TI  - Roles of thrombospondin-1 and -2 in regulating corneal and iris angiogenesis.
AB  - PURPOSE: Thrombospondin (TSP)-1 and -2 are important antiangiogenic factors
      thought to be involved in maintaining corneal avascularity (angiogenic
      privilege). This study was undertaken to investigate whether deficiencies of
      these factors altered developmental and inflammation-induced angiogenesis in the
      cornea and developmental angiogenesis of the iris of mice. METHODS: Expression of
      TSP-1 and -2 mRNA and protein was assayed in cornea and iris stroma by RT-PCR and
      Western blot. Corneas and irides of TSP-1(-/-), TSP-2(-/-), and TSP-1,2(-/-) mice
      aged 2, 3, and 6 months, and wild-type control mice, were analyzed for
      spontaneous angiogenesis biomicroscopically, histologically, and with CD31
      immunohistochemistry. The mouse model of suture-induced, inflammatory corneal
      neovascularization was used to evaluate the lack of TSP-1,2 and both TSPs on
      induced-corneal angiogenesis. Seven days after intrastromal placement of three 11
      0 sutures, vascularized areas were analyzed morphometrically on CD31-stained
      corneal flatmounts. RESULTS: Corneas and irises from normal mouse eyes
      constitutively expressed TSP-1 and -2 mRNAs and proteins. Corneas of TSP-1(-/-), 
      2(-/-), and -1,2(-/-) mice displayed no evidence of spontaneous developmental
      postnatal angiogenesis, although irises of these mice contained significantly
      increased iris vessel density compared with wild-type animals (P < 0.01). One
      week after suturing, corneas of all TSP(-/-) mice had significantly greater
      corneal angiogenesis than those of control mice (P < 0.05). TSP-1(-/-) had a
      significantly greater effect on induced corneal neovascularization than did TSP
      2(-/-), with the opposite being the case in developmental iris angiogenesis (P <
      0.01). CONCLUSIONS: Corneal avascularity during development is redundantly
      regulated, shown by the fact that lack of the antiangiogenic factors TSP-1 and/or
      -2 resulted in no spontaneous corneal angiogenesis. By contrast, TSP-1, more than
      TSP-2, helps to suppress inflammation-induced corneal angiogenesis postnatally,
      implying that angiogenic privilege in the cornea is actively maintained.

PMID- 15037578
TI  - Role of the C domain of IGFs in synergistic promotion, with a substance P-derived
      peptide, of rabbit corneal epithelial wound healing.
AB  - PURPOSE: Insulin-like growth factors (IGFs) and either substance P (SP) or an SP
      derived peptide (FGLM-amide) synergistically facilitate corneal epithelial wound
      healing in vitro and in vivo. The mechanism of this synergism and the clinical
      potential of these agents were further investigated by determination of the
      relevant functional domain of IGFs. METHODS: The effects of IGF-derived peptides
      on corneal epithelial cell migration were evaluated with the rabbit cornea in an
      organ culture system. Corneal epithelial wound closure in vivo was also evaluated
      in rabbits after epithelial debridement with n-heptanol. RESULTS: In the presence
      of FGLM-amide, peptides corresponding to the C domain of IGF-1 or -2
      significantly promoted corneal epithelial migration in vitro to an extent similar
      to that apparent with the full-length molecules. In contrast, peptides
      corresponding to the D domain of these growth factors had no such effect.
      Mutation of serine-34 in the C domain of IGF-1 to alanine abolished the
      synergistic effect with FGLM-amide on corneal epithelial migration. The C peptide
      of proinsulin did not affect corneal epithelial migration in the absence or
      presence of FGLM-amide. The administration of eye drops containing both the C
      domain peptide of IGF-1 and FGLM-amide significantly promoted corneal epithelial
      wound closure in vivo. CONCLUSIONS: The C domain of IGF-1 or -2, for which no
      biological function has previously been identified, is essential for the
      synergistic effect of these growth factors with SP on corneal epithelial
      migration.

PMID- 15037580
TI  - Extended slow phase in latent/manifest latent nystagmus.
AB  - PURPOSE: To investigate the slow phase in latent/manifest latent nystagmus (LMLN)
      by producing long eye-drift intervals devoid of fast phases (extended slow phases
      [ESPs]) and to relate ESP metrics to clinical findings. METHODS: Ten patients
      with LMLN had eye movements recorded while attending to paired visual and
      auditory cues presented to their left or right. Patients compared location of the
      visual target with that of the subsequently heard tone. The auditory cue and the
      comparison task directed attention away from vision and delayed the fast-phase
      onset to obtain ESPs. ESP metrics were analyzed with regard to patients' clinical
      characteristics. Five patients' data were further explored by isolating slow
      phase components. RESULTS: All patients exhibited ESPs that resembled the usual
      slow phase but lasted two to three times longer. Five patients maintained
      alignment, whereas the other five made vergence movements. Greater eye velocity,
      excursion, and convergence during an ESP were associated with poor vision and
      large uncorrected esotropia. These metrics decreased when the viewing eye was in
      adduction, compared with primary position or abduction. Slow-phase components
      found in five patients consisted of a dominant decreasing-velocity or linear
      drift and a low-amplitude periodic oscillation. CONCLUSIONS: Shifting attention
      away from vision reliably delays the fast phase, revealing long intervals of slow
      phase, which can facilitate nystagmus investigation. ESP analysis in five
      patients with LMLN demonstrated two slow-phase components. ESP characteristics
      suggest that better ocular alignment is associated with improved stability in
      LMLN and provide metrics of eye drift that correlate with vision.

PMID- 15037579
TI  - Central and peripheral visual interactions in disparity-induced vergence eye
      movements: I. Spatial interaction.
AB  - PURPOSE: To evaluate the interaction between central and peripheral disparities
      in the initiation of vergence eye movements. METHODS: Eye movements were recorded
      in eight normal subjects using an infrared limbus tracker. Three-dimensional
      visual stimuli were back projected onto a tangent screen by using two liquid
      crystal display (LCD) projectors through crossed polarizers. The central target
      was a vertical bar, which always jumped from 2 to 1 m. The peripheral target was
      a random-dot pattern that jumped from 2 to 0.75, 1, or 1.5 m (near planes), 2 m
      (no change), or 3 m (far plane) simultaneously with the central target jump.
      Latency, amplitude at 150 ms, and average amplitude over 1 to 2 seconds after
      vergence onset; peak velocity; and the main-sequence relationship of the initial
      vergence response were calculated. How far the central target appeared to jump
      was scored subjectively. RESULTS: In half of the subjects, there was a clear
      effect of the peripheral disparity on the dynamics of the vergence response to
      the central disparity. The amplitude of vergence at 150 ms, as an index of open
      loop gain, was significantly greater when the peripheral target moved closer, but
      steady state amplitude (average during 1-2 seconds) did not change, and the
      vergence latency was significantly greater when the peripheral target jumped
      away. There was no obvious relationship between the perceived amount of movement
      of the central target and the parameters of the dynamic properties of the
      vergence response. CONCLUSIONS: Peripheral disparity can modulate the dynamics of
      the initial vergence response to a central disparity and is probably independent
      of the perception of motion in depth.

PMID- 15037581
TI  - Correlations of genotype with phenotype in Indian patients with primary
      congenital glaucoma.
AB  - PURPOSE: To establish the genotype-phenotype correlations of various CYP1B1
      (human cytochrome P450) mutations in patients in India with primary congenital
      glaucoma (PCG). METHODS: The study cohort comprised 146 patients with PCG from
      138 pedigrees. Patients were analyzed for six distinct CYP1B1 mutations by
      sequencing and polymerase chain reaction-restriction fragment length polymorphism
      (PCR-RFLP) methods. A severity index for grading various PCG phenotypes was
      constructed based on clinical parameters. RESULTS: Six mutations were identified
      in 45 patients analyzed and genotype-phenotype correlations were established for
      43 of them. The percentages of severe phenotypes associated with various
      mutations in at least one eye were: frameshift, 100%; G61E, 66.7%; P193L, 62.5%;
      E229K, 80%; R368H, 72%; R390C, 83.3%. The frameshift mutation resulted in
      blindness. Based on the severity index, the disease severity was graded from
      normal to severe and the prognosis from good to very poor (blind). De novo
      mutation was identified in one family. CONCLUSIONS: This is the first study to
      attempt to devise a severity index for grading various PCG phenotypes and to use
      genotype as an indicator to predict the prognoses of the disorder. This index may
      help guide therapy and counseling of the afflicted family regarding the
      progression of the disorder. All patients with severe phenotypes showed poor
      prognoses (r = 0.976; P < 0.0001). The data derived from this study could be used
      as an added clinical tool in disease management. Integrated management of PCG
      that makes use of a genetic approach could yield better results than medical,
      surgical, and rehabilitation interventions alone.

PMID- 15037582
TI  - Susceptibility of retinal vascular endothelium to infection with Toxoplasma
      gondii tachyzoites.
AB  - PURPOSE: Retinochoroidal infection with the protozoan parasite Toxoplasma gondii
      is the most common cause of posterior uveitis worldwide. Tachyzoites spread
      throughout the body through the blood stream and lymphatics, but preferentially
      encyst in the eye and other parts of the central nervous system (CNS). It is
      unknown whether T. gondii penetrates the CNS selectively or whether these sites
      of immune privilege have limited capacity to eradicate the parasite. METHODS:
      Human vascular endothelial cell lines, including retinal (three lines from three
      different donors), aortic, umbilical vein, and dermal microvascular endothelium,
      as well as human foreskin fibroblasts, were grown to confluence in 24-well
      plates. Cells were incubated with RH-strain T. gondii tachyzoites in the presence
      of [(3)H]-uracil. Trichloroacetic acid-insoluble radioactivity was measured as an
      index of T. gondii proliferation, because tachyzoites, but not human cells,
      incorporate uracil directly through pyrimidine salvage. RESULTS: Tachyzoites
      showed higher [(3)H]-uracil incorporation after incubation with retinal vascular
      endothelial cells in comparison with aortic (55% more), umbilical vein (33% more)
      and dermal (34% more) endothelial cells. In eight separate assays, significantly
      greater radioactivity was measured for tachyzoites cultured with retinal versus
      other cell subtypes (P < 0.05), except for one assay in which differences reached
      only borderline significance (P <or= 0.07). In contrast, experiments comparing
      different retinal endothelial lines revealed no difference between any pair.
      Growth of the tachyzoites was approximately 2.8-fold higher in retinal
      endothelium than in foreskin fibroblasts, the cell subtype often used to
      investigate processes of T. gondii infection. CONCLUSIONS: Enhanced
      susceptibility of retinal vascular endothelium to infection by T. gondii
      tachyzoites may explain, at least in part, preferential localization of T. gondii
      to the retina. Susceptibility may relate to preferential binding of tachyzoites
      to the retinal vascular endothelial surface, relative ease of penetration into
      the cell, rate of replication within the cell and/or cell response to infection.

PMID- 15037583
TI  - Uveal melanoma expression of tumor necrosis factor-related apoptosis-inducing
      ligand (TRAIL) receptors and susceptibility to TRAIL-induced apoptosis.
AB  - PURPOSE: The study had two purposes: to examine the expression of tumor necrosis
      factor-related apoptosis-inducing ligand (TRAIL) receptors on uveal melanoma
      cells and metastases arising from uveal melanoma and to determine the
      susceptibility of uveal melanoma cells to TRAIL-induced apoptosis. METHODS: Nine
      human uveal melanoma cell lines and three cell lines derived from uveal melanoma
      metastases were examined for TRAIL receptor expression by flow cytometry. In
      vitro apoptosis assays were performed to determine the relative susceptibility of
      uveal melanoma cells to TRAIL-induced apoptosis. Annexin V staining was also used
      to determine the capacity of either cycloheximide or interferon-beta to enhance
      TRAIL-induced apoptosis. RESULTS: Five of the nine uveal melanoma cell lines
      expressed TRAIL-R2 on more than 60% of the cells. All three of the cell lines
      derived from uveal melanoma metastases expressed TRAIL-R2 on more than 50% of the
      cells. Cycloheximide exerted a profound effect in enhancing TRAIL-induced
      apoptosis in all but two of the uveal melanoma cell lines and in all three of the
      metastases cell lines. Interferon-beta produced a similar enhancement of TRAIL
      induced apoptosis, even in cell lines that were previously shown to be resistant.
      CONCLUSIONS: TRAIL is a potentially useful therapeutic modality for the
      management of uveal melanomas and their metastases. Moreover, pharmacological
      agents and biological response modifiers that independently display
      antineoplastic properties can enhance TRAIL-induced apoptosis in resistant uveal
      melanoma cells.

PMID- 15037584
TI  - Effect of metalloprotease inhibitors on corneal allograft survival.
AB  - PURPOSE: The expression of Fas ligand (FasL) in the cornea is essential for
      corneal allograft acceptance in mice. Because the expression of FasL on the
      surface of cells is sensitive to cleavage with matrix metalloproteases (MMPs),
      this study examined whether inhibitors of MMPs would lead to increased FasL
      expression and improved corneal allograft survival. METHODS: Corneal endothelia
      derived from mice and humans were treated with MMP inhibitors, and FasL
      expression was examined. BALB/c mice were engrafted with C57BL/6 or C57BL/6-gld
      corneas and treated with an ointment containing the MMP inhibitor, doxycycline.
      Corneal allograft survival was monitored for 50 days. RESULTS: Corneal
      endothelial cells from both mice and humans displayed increased surface
      expression of FasL after treatment with MMP inhibitors. The increase in surface
      expression was further evidenced by the ability of these cells to kill Fas
      expressing target cells. Mice treated with doxycycline after corneal allograft
      transplantation showed significantly prolonged allograft survival and an increase
      in the overall acceptance rate. CONCLUSIONS: MMP inhibitor treatment of cornea
      derived endothelial cells results in increased FasL expression and function. MMP
      inhibitor treatment prolongs corneal allograft survival and results in a modest
      increase in corneal allograft acceptance.

PMID- 15037585
TI  - Role of macrophage migration inhibitory factor in conjunctival pathology in
      ocular cicatricial pemphigoid.
AB  - PURPOSE: Macrophage migration inhibitory factor (MIF) is a pleiotropic,
      proinflammatory cytokine that mediates various immunoinflammatory processes.
      Ocular cicatricial pemphigoid (OCP) is an autoimmune disease in which affected
      conjunctivae show features of an immunoinflammatory disease. In this study, the
      role of MIF in the pathogenesis of OCP was examined. METHODS: The expression of
      MIF in conjunctival tissues of patients with OCP (n = 10) and normal subjects (n
      = 5) was studied by quantitative real-time PCR and immunohistochemistry. The
      production of MIF by conjunctival fibroblasts of normal control subjects and
      patients with OCP was determined, by using quantitative real-time PCR and enzyme
      linked immunosorbent assay (ELISA). In addition, the effects of interleukin (IL)
      1, tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta1
      on the induction of MIF by conjunctival fibroblasts were studied by quantitative
      real-time PCR. To determine the relationship between conjunctival expression of
      MIF and accumulation of macrophages, in patients with OCP, a correlation study
      was performed. RESULTS: An increased conjunctival expression of MIF was detected
      in patients with OCP, both at the mRNA (by real-time PCR) and protein level (by
      immunohistochemistry), compared with normal control patients. The expression of
      MIF was detected in the epithelial cells and occasionally in the stromal cells in
      control conjunctival tissues, by immunohistochemistry. In contrast, a
      statistically significant increase (P < 0.0001) in the expression of MIF was
      detected in the stromal cells of conjunctival tissues obtained from patients with
      OCP (control: 4.89 +/- 0.5; OCP: 19.82 +/- 1.34). By quantitative real-time PCR,
      compared with control conjunctiva, an increase in the expression of MIF was
      detected in the conjunctiva obtained from patients with OCP. A similar increase
      in the expression of MIF was also detected in conjunctival fibroblasts of
      patients with OCP, compared with control fibroblasts, by quantitative real-time
      PCR. A significantly increased (P < 0.001) level of MIF was also detected in
      supernatant collected from conjunctival fibroblasts of patients with OCP (186 +/-
      5.4), compared with supernatant collected from control fibroblasts (9.3 +/- 7.6).
      Moreover, IL-1, TNF-alpha, and TGF-beta1, known factors involved in the
      pathogenesis of OCP, were found to induce the expression of MIF by conjunctival
      fibroblasts. A statistically significant correlation (P < 0.0001, r(2) = 0.4465)
      was observed between the expression of MIF and accumulation of CD68-positive
      macrophages in conjunctiva of patients with OCP. CONCLUSIONS: This study
      demonstrated an increased conjunctival expression of MIF in patients with OCP.
      MIF may be actively involved in the pathogenesis of OCP, possibly regulating the
      inflammatory events of the disease process.

PMID- 15037586
TI  - Murine ocular heparanase expression before and during infection with Pseudomonas
      aeruginosa.
AB  - PURPOSE: To demonstrate the constitutive expression and regulation of heparanase
      (heparan sulfate endoglycosidase) in the normal mouse eye and in mice
      intracorneally infected with Pseudomonas aeruginosa. METHODS: Naive (unimmunized)
      and immunized C57BL/6J mice were infected with P. aeruginosa, and corneal
      heparanase gene and protein expression were detected by semiquantitative RT-PCR
      and immunoblot analysis. Immunohistochemistry was also applied to characterize
      corneal heparanase in naive mice. RESULTS: Heparanase mRNA and protein expression
      were detected in uninfected corneas of C57BL/6J mice. Immunohistochemical studies
      indicated heparanase protein expression was primarily in the corneal epithelium
      before corneal infection and was also in the corneal stroma after infection.
      Immunohistochemical studies of uninfected and infected whole eyes of naive mice
      indicated heparanase protein expression in most layers of the retina, but the
      expression did not appear to be upregulated during corneal infection. Staining
      was most intense in the inner photoreceptor layer of the retina. CONCLUSIONS:
      Heparanase was constitutively expressed in both the corneal epithelium and
      several retinal layers before intracorneal infection with P. aeruginosa. Temporal
      upregulation of corneal heparanase protein expression was detected in naive mice
      during infection, most likely due to heparanase positive infiltrating cells, but
      the protein was not upregulated in corneas from immunized mice because they had a
      lower inflammatory response, associated with the restoration of corneal clarity.
      There did not appear to be temporal upregulation of heparanase expression in the
      retina of infected mice, as determined by immunohistochemistry.

PMID- 15037587
TI  - Fate of MHC-matched corneal allografts in Th1-deficient hosts.
AB  - PURPOSE: To determine whether the Th1 cytokine, interferon (IFN)-gamma, is
      necessary for corneal graft rejection. METHODS: Full-thickness penetrating
      keratoplasties were performed in normal mice and in IFN-gamma knockout (KO) mice.
      RESULTS: Sixty-four percent of the MHC-mismatched corneal allografts were
      rejected in IFN-gamma KO mice. By contrast, MHC-matched corneal allografts were
      rejected in 50% to 77% of the wild-type hosts, but were not rejected in any of
      the IFN-gamma KO mice or the wild-type mice treated with anti-IFN-gamma
      monoclonal antibody. Corneal graft rejection in IFN-gamma-deficient hosts was
      characterized by an eosinophilic infiltrate compared with a mononuclear
      inflammatory infiltrate in normal mice. CONCLUSIONS: IFN-gamma is not necessary
      for the rejection of MHC-mismatched corneal grafts. However, IFN-gamma and Th1
      immune mechanisms are necessary for the rejection of MHC-matched corneal
      allografts that confront the host with foreign minor histocompatibility antigens.
      The immune response in atopic patients, as in IFN-gamma KO mice, is characterized
      by cross-regulation of Th1 cytokines, such as IFN-gamma. The present results
      indicate that MHC matching dramatically reduces the risk of corneal graft
      rejection when IFN-gamma is depressed or absent. Thus, MHC matching may reduce
      the risk of corneal graft rejection in patients with atopic keratoconus.

PMID- 15037589
TI  - Genetic and allelic heterogeneity of Cryg mutations in eight distinct forms of
      dominant cataract in the mouse.
AB  - PURPOSE: The purpose of this study was the characterization of eight new dominant
      cataract mutations. METHODS: Lenses of mutant mice were described morphologically
      and histologically. Each mutation was mapped by linkage studies. The candidate
      genes (the Cryg gene cluster and the closely linked Cryba2 gene) were sequenced.
      RESULTS: Molecular analysis confirmed all mutations in Cryg genes. Five mutations
      lead to amino acid exchanges, two are due to premature stop codons, and one is a
      10-bp deletion in the Cryge gene. Morphologically, mutant carriers expressed
      nonsyndromic cataracts, ranging from diffuse lenticular opacities (Crygd(ENU910)
      and Cryge(ENU449)), to dense nuclear and subcortical opacity (Crygd(K10),
      Crygc(MNU8), Cryge(Z2), Crygd(ENU4011), and Cryge(ADD15306)), to dense nuclear
      opacity and ruptured lenses (Cryga(ENU469)). Results of histologic analyses
      correlate well with the severity of lens opacity, ranging from alterations in the
      process of secondary fiber nucleus degradation to lens vacuoles, fiber
      degeneration, and disruption of the lens capsule. CONCLUSIONS: In total, 20
      mutations have been described that affect the Cryg gene cluster: Nine mutations
      affect the Cryge gene, but only one affects the Crygb or Crygf genes. No mutation
      was observed in the closely linked Cryba2. Two mutations occur at the same site
      in the Crygd and Cryge genes (Leu45-->Pro). The unequal distribution of mutations
      suggests hot spots in the Cryg genes. The overall high number of mutations in
      these genes demonstrates their central role in the maintenance of lens
      transparency.

PMID- 15037590
TI  - Characterization of a bradykinin-hydrolyzing protease from the bovine lens.
AB  - PURPOSE: To isolate and characterize bovine lens endopeptidase activity that
      cleaves the Phe-Ser bond in peptide substrates. METHODS: The protease activity in
      young bovine lens homogenate was measured using the Mca-(Ala(7),Lys(Dnp)(9))
      bradykinin substrate. Degradation of bradykinin and other unlabeled peptide
      substrates was monitored by reversed-phase HPLC on a C18 column. The protease was
      purified by means of several chromatography steps. An in-gel tryptic digest of
      the purified protease was analyzed by using matrix-assisted desorption ionization
      time of flight mass spectrometry (MALDI-ToF-MS and nanospray quadrupole time of
      flight mass spectrometry (QqToF MS). The specificity of the protease was
      determined with bradykinin and its analogues. Crystallin fragments isolated from
      aged bovine lenses were tested for their susceptibility to degradation by a newly
      identified endopeptidase. RESULTS: Bradykinin hydrolyzing endopeptidase activity
      was localized mainly in the outer cortex of the lens. A characterization study
      showed that the purified protease was thiol and metal dependent. Peptide mass
      fingerprinting and tandem mass spectrometry (MS/MS) analysis of an in-gel tryptic
      digest matched the protein sequence of thimet oligopeptidase (TOP). The purified
      protease cleaved bradykinin specifically at Phe(5)-Ser(6) and neurotensin at
      Arg(8)-Arg(9). Basic or hydrophobic amino acids at P1 and P1' positions in the
      substrate were preferred over acidic residues. Enzyme activity was also inhibited
      by physiological levels of adenosine triphosphate (1 mM; ATP) and glutathione (3
      mM; GSH). The crystallin fragments obtained from aged bovine lenses were cleaved
      by the purified enzyme. CONCLUSIONS: This study shows the presence of TOP in the
      bovine lens. Its unique substrate specificity and regulation of its activity by
      ATP and GSH suggest that TOP has an important role in peptide hydrolysis in the
      lens.

PMID- 15037588
TI  - Differential regulation of components of the ubiquitin-proteasome pathway during
      lens cell differentiation.
AB  - PURPOSE: To investigate the role for the ubiquitin-proteasome pathway in
      controlling lens cell proliferation and differentiation and the regulation of the
      ubiquitin conjugation machinery during the differentiation process. METHODS: bFGF
      induced lens cell proliferation and differentiation was monitored in rat lens
      epithelial explants by bromodeoxyuridine (BrdU) incorporation and expression of
      crystallins and other differentiation markers. Levels of typical substrates for
      the ubiquitin-proteasome pathway, p21(WAF) and p27(Kip), were monitored during
      the differentiation process, as were levels and activities of the enzymes
      involved in ubiquitin conjugation. RESULTS: Explants treated with bFGF initially
      underwent enhanced proliferation as indicated by BrdU incorporation. Then they
      withdrew from the cell cycle as indicated by diminished BrdU incorporation and
      accumulation of p21(WAF) and p27(Kip). bFGF-induced cell proliferation was
      prohibited or delayed by proteasome inhibitors. Lens epithelial explants treated
      with bFGF for 7 days displayed characteristics of lens fibers, including
      expression of large quantities of crystallins. Whereas levels of E1 remained
      constant during the differentiation process, the levels of ubiquitin-conjugating
      enzyme (Ubc)-1 increased approximately twofold, and the thiol ester form of Ubc1
      increased approximately threefold on 7 days of bFGF treatment. Levels of Ubc2
      increased moderately on bFGF treatment, and most of the Ubc2 was found in the
      thiol ester form. Although levels of total Ubc3 and -7 remained unchanged, the
      proportions of Ubc3 and -7 in the thiol ester form were significantly higher in
      the bFGF-treated explants. Levels of Ubc4/5 and -9 also increased significantly
      on treatment with bFGF, and more than 90% of Ubc9 was found in the thiol ester
      form in the bFGF-treated explants. In contrast, levels of Cul1, the backbone of
      the SCF type of E3s, decreased 50% to 70% in bFGF-treated explants. CONCLUSIONS:
      The data show that proteolysis through the ubiquitin-proteasome pathway is
      required for bFGF-induced lens cell proliferation and differentiation. Various
      components of the ubiquitin-proteasome pathway are differentially regulated
      during lens cell differentiation. The downregulation of Cul1 appears to
      contribute to the accumulation of p21(WAF) and p27(Kip), which play an important
      role in establishing a differentiated phenotype.

PMID- 15037591
TI  - Magnetic resonance imaging study of current and ion delivery into the eye during
      transscleral and transcorneal iontophoresis.
AB  - PURPOSE: The objectives were to determine by nuclear magnetic resonance imaging
      (MRI) the target sites of ion delivery in the eye during iontophoresis, compare
      transscleral and transcorneal ocular iontophoresis, and monitor the distribution
      of a probe ion in the anterior chamber and vitreous after iontophoretic delivery.
      METHODS: Thirty-minute 2-mA anodal constant current transscleral and transcorneal
      iontophoresis (current density, 10 mA/cm(2)) was performed on three New Zealand
      White rabbits in vivo. Intravitreal injection and passive delivery were the
      controls. Transscleral and transcorneal iontophoresis experiments were conducted
      with the electrode device placed in the superior cul-de-sac away from the limbus
      and on the cornea adjacent to the limbus, respectively. During iontophoresis, the
      current delivered into the eye was monitored using a probe ion (Mn(2+)) with MRI.
      The distributions of the ion in the aqueous and vitreous humor after
      iontophoresis, passive delivery, and intravitreal injection were also determined
      by MRI. RESULTS: With the short application time, passive diffusion did not
      deliver a significant amount of the ion into the eye. Whereas transscleral
      iontophoresis delivered the ion into the vitreous, transcorneal iontophoresis
      delivered the ion into the anterior chamber. The current pathways during
      iontophoresis were mainly from the electrode into the eye, perpendicular to the
      electrode-eye interface beneath the electrode. Electric current along the surface
      of the globe was relatively minimal. With the present transscleral iontophoresis
      protocol, the ion penetrated the sclera and traveled as far as 1.5 mm from the
      electrode-conjunctiva interface into the vitreous. For transcorneal
      iontophoresis, the ion penetrated the cornea and filled the entire anterior
      chamber. CONCLUSIONS: MRI can be a useful technique in the study of the
      penetration of probe compounds in the eye during and after iontophoresis, such as
      in iontophoresis protocol and device testing. Ocular pharmacokinetic studies
      using MRI are noninvasive and provide real-time data without perturbation and
      compound redistribution that can occur during dissection and assay in traditional
      pharmacokinetic studies. With MRI, it was shown that transscleral iontophoresis,
      transcorneal iontophoresis, and intravitreal injection deliver ions to different
      parts of the eye.

PMID- 15037592
TI  - Vitamin C transport in oxidized form across the rat blood-retinal barrier.
AB  - PURPOSE: To elucidate the mechanisms of vitamin C transport across the blood
      retinal barrier (BRB) in vivo and in vitro. METHODS. [(14)C]Dehydroascorbic acid
      (DHA) and [(14)C]ascorbic acid (AA) transport in the retina across the BRB were
      examined using in vivo integration plot analysis in rats, and the transport
      mechanism was characterized using a conditionally immortalized rat retinal
      capillary endothelial cell line (TR-iBRB2) as an in vitro model of the inner BRB.
      RESULTS: The apparent influx permeability clearance (K(in)) per gram of retina of
      [(14)C]DHA and [(14)C]AA was found to be 2.44 x 10(3) microL/(min x g retina) and
      65.4 microL/(min x g retina), respectively. In the retina and brain, the K(in) of
      [(14)C]DHA was approximately 38 times greater than that of [(14)C]AA, whereas
      there was no major difference in the heart. The K(in) of [(14)C]DHA in the retina
      was eight times greater than that in the brain. HPLC analysis revealed that most
      of the vitamin C accumulated in AA form in the retina. These results suggest that
      vitamin C is mainly transported in DHA form across the BRB and accumulates in AA
      form in the rat retina. In an in vitro uptake study in TR-iBRB2 cells, the
      initial uptake rate of [(14)C]DHA was 37 times greater than that of [(14)C]AA,
      which is in agreement with the results of the in vivo study. [(14)C]DHA uptake by
      TR-iBRB2 cells took place in an Na(+)-independent and concentration-dependent
      manner with a K(m) of 93.4 microM. This process was inhibited by substrates and
      inhibitors of glucose transporters. [(14)C]DHA uptake was inhibited by D-glucose
      in a concentration-dependent manner with a 50% inhibition concentration of 5.56
      mM. Quantitative real-time PCR and immunostaining analyses revealed that
      expression of GLUT1 and -3 was greater than that of the Na(+)-dependent L
      ascorbic acid transporter (SVCT)-2 in TR-iBRB2 cells. CONCLUSIONS: Vitamin C is
      mainly transported across the BRB as DHA mediated through facilitative glucose
      transporters and accumulates as AA in the rat retina.

PMID- 15037593
TI  - Expression of neurturin, glial cell line-derived neurotrophic factor, and their
      receptor components in light-induced retinal degeneration.
AB  - PURPOSE: Dysregulation of neurturin (NTN) expression has been linked to
      photoreceptor apoptosis in a mouse model of inherited retinal degeneration. To
      investigate the extent to which any such dysregulation depends on the nature of
      the apoptotic trigger, the expression of NTN, glial cell line-derived
      neurotrophic factor (GDNF), and their corresponding receptor components were
      compared in a rat model of light-induced retinal degeneration. METHODS: Retinal
      expression of NTN, GDNF, their corresponding receptors GFRalpha-2 and -1, the
      transmembrane receptor tyrosine kinase (Ret), and cSrc-p60, a member of the
      cytoplasmic protein-tyrosine kinases family, were analyzed by Western blot
      analysis and immunocytochemistry in cyclic light- and dark-reared rats in the
      presence and absence of intense light exposure. RESULTS: All components for NTN
      mediated signaling activation are present in rat photoreceptors and retinal
      pigment epithelium, the cells primarily affected by light-induced damage. The
      expression levels of GDNF, its receptor components, and NTN, were not affected by
      light-induced stress. However, GFRalpha-2 expression strikingly increased with
      the extent of retinal damage, especially at the photoreceptors, in contrast to
      decreased levels that were observed previously in an inherited degeneration
      model. CONCLUSIONS: The present study indicates that the expression of receptors
      of the GDNF family is independently regulated in normal and light-damaged rat
      retina, and in conjunction with previous work, suggests that the pattern of
      modulation of these genes during photoreceptor degeneration is determined by the
      nature of the apoptotic trigger. Such differential responses to different modes
      of retinal degeneration may reflect influences of the neurotrophic system on
      photoreceptor survival or in the regulation of neuronal plasticity.

PMID- 15037594
TI  - Microarray analysis of changes in mRNA levels in the rat retina after
      experimental elevation of intraocular pressure.
AB  - PURPOSE: The goal of this study was to identify altered patterns of retinal mRNA
      expression after experimental elevation of intraocular pressure (IOP) in a rat
      glaucoma model. METHODS: Brown Norway rats (N = 16) received unilateral
      episcleral vein injection of hypertonic saline to elevate IOP. IOP was monitored
      daily by handheld tonometer, and retinas were collected 8 days and 5 weeks after
      surgery. Comparison of mRNA levels between experimental and fellow retinas was
      made using gene microarrays (rat U34A rat arrays; Affymetrix, Santa Clara, CA).
      Semiquantitative RT-PCR was used to confirm selected results from array analysis
      and to compare with alterations after optic nerve transection. RESULTS: IOP
      elevation for 5 weeks resulted in reproducible changes in levels of 81 mRNAs. Of
      these, 74 increased, whereas only 7 decreased. The expression levels of 27 of
      these same messages were changed after 8 days of IOP elevation. In addition, four
      other genes demonstrated altered expression after the shorter period of elevated
      IOP exposure. Approximately half of the mRNAs with altered expression were
      associated with either neuroinflammatory responses or apoptosis. For 25 of the
      selected functionally relevant messages altered by array analysis, the
      alterations were confirmed by semiquantitative RT-PCR. The levels of 24 of 25
      selected messages were also changed after optic nerve transection. CONCLUSIONS:
      The activation of glia and the complement system after IOP elevation, which is
      similar to that described in several neurodegenerative diseases and after optic
      nerve transection, suggests that this rat glaucoma model could be used to
      evaluate the neuroprotective potential of therapeutic agents that target these
      processes.

PMID- 15037595
TI  - Impairment of the transient pupillary light reflex in Rpe65(-/-) mice and humans
      with leber congenital amaurosis.
AB  - PURPOSE: To determine the impairment of the transient pupillary light reflex
      (TPLR) due to severe retinal dysfunction and degeneration in a murine model of
      Leber congenital amaurosis (LCA) and in patients with the disease. METHODS:
      Direct TPLR was elicited in anesthetized, dark-adapted Rpe65(-/-) and control
      mice with full-field light stimuli (0.1 second duration) of increasing
      intensities (-6.6 to +2.3 log scot-cd. m(-2)). 9-cis-Retinal was administered
      orally to a subset of Rpe65(-/-) mice, and TPLR was recorded 48 hours after the
      treatment. TPLR was also measured in a group of patients with LCA. RESULTS:
      Baseline pupillary diameters in Rpe65(-/-) and control mice were similar. TPLR
      thresholds of Rpe65(-/-) mice were elevated by 5 log units compared with those of
      control animals. The waveform of the TPLR in Rpe65(-/-) mice was similar to that
      evoked by 4.8-log-unit dimmer stimuli in control mice. Treatment of Rpe65(-/-)
      mice with 9-cis-retinal lowered the TPLR threshold by 2.1 log units. Patients
      with LCA had baseline pupillary diameters similar to normal, but the TPLR was
      abnormal, with thresholds elevated by 3 to more than 6 log units. When adjusted
      to the elevation of TPLR threshold, pupillary constriction kinetics in most
      patients were similar to those in normal subjects. CONCLUSIONS: Pupillometry was
      used to quantify visual impairment and to probe transmission of retinal signals
      to higher nervous centers in a murine model of LCA and in patients with LCA.
      Mouse results were consistent with a dominant role of image-forming
      photoreceptors driving the early phase of the TPLR when elicited by short
      duration stimuli. The objective and noninvasive nature of the TPLR measurement,
      and the observed post-treatment change toward normal in the animal model supports
      the notion that this may be a useful outcome measure in future therapeutic trials
      of LCA.

PMID- 15037596
TI  - Energy substrate requirements of rat retinal pigmented epithelial cells in
      culture: relative importance of glucose, amino acids, and monocarboxylates.
AB  - PURPOSE: To determine the metabolic conditions that provide maintenance of
      viability for cultured rat RPE cells and to determine whether monocarboxylates
      such as lactate or pyruvate, which are known to exist at high concentrations in
      the subretinal space, can provide an alternative energy source to maintain cells
      when other nutritive supplies are limited. METHODS: Cultured rat RPE cells
      (passage 2-4), in the absence of serum, were subjected to different metabolic
      challenges relating to glucose, amino acid, or oxygen deprivation. Lactate or
      pyruvate was added to some cells in each instance to determine whether cells
      could be maintained by using these substances as fuel sources for metabolic
      reactions. Cell viability was assessed after treatments, and in some cases
      proliferation rates and appearance of apoptosis-like DNA cleavage were also
      investigated by terminal deoxynucleotidyl-transferase UTP-linked nick-end
      labeling (TUNEL). Western blot analysis was used to determine the expression of
      transporters for glucose and monocarboxylates in these cells. RESULTS: RPE cell
      viability was partially reduced in the absence of glucose or with glycolytic
      inhibition. Lactate or pyruvate did not prevent these reductions. Inhibition of
      transaminase reactions with aminooxyacetic acid (AOAA) in the absence of glucose
      caused a complete loss of viability that was reversed by pyruvate or lactate. MCT
      inhibition was detrimental to RPE cell viability only at high concentrations (500
      microM) in the presence of glucose but blocked the protective effect of pyruvate
      lactate in the presence of AOAA at 1 microM. CONCLUSIONS: Rat RPE cells require
      glucose as their primary metabolic substrate in culture, but can metabolize
      glutamine in its absence. When glucose and glutamine are limiting, RPE cells can
      metabolize monocarboxylates such as lactate or pyruvate. These data provide
      evidence that such cells are able to withstand various types of insult brought
      about by nutrient deprivation, by altering their pathways of energy production.

PMID- 15037597
TI  - Benefit and timing of second transplantations in multiple myeloma: clinical
      findings and methodological limitations in a European Group for Blood and Marrow
      Transplantation registry study.
AB  - PURPOSE: To use European Group for Blood and Marrow Transplantation registry data
      to assess the benefit and optimal timing of a double-autologous transplantation
      strategy for patients with myeloma. PATIENTS AND METHODS: 7,452 transplantation
      patients described as being either in a multiple graft program ("planned") or
      not, were analyzed on an intention-to-treat basis. Subsequent multivariate
      analyses concentrated on the real occurrence of second transplantation, survival,
      relapse, and transplant-related mortality. RESULTS: Although the transplantation
      rate in the planned group failed to reach 60%, the median survival from
      transplantation is 60 months for the planned, compared with 51 months for the
      remainder group. While the hazard ratio of the planned group is 0.89 (95% CI,
      0.79 to 1.00; P =.05) before approximately 70 months, this "effect" is reversed
      after 70 months, with the hazard ratio estimated as 3.01 (95% CI, 1.07 to 8.46; P
      =.04). A time-dependent multivariate Cox analysis shows that, taking patients
      without a second transplantation as a reference group, those receiving a second
      transplantation in first remission (ie, before relapse) show an increased
      probability of transplant-related mortality, especially if the transplantation is
      performed more than 12 months after the first, and the reduction of the risk of
      relapse is less than when the transplantation is performed earlier. Performing a
      second transplantation after relapse does not seem to prolong survival, though a
      second transplantation before relapse is associated with a higher probability of
      mortality. CONCLUSION: To improve survival of tandem autologous transplantation
      in multiple myeloma, the second transplantation should preferably be performed
      before relapse and within 6 to 12 months of the first transplantation.

PMID- 15037598
TI  - Nerve-independent formation of a topologically complex postsynaptic apparatus.
AB  - As the mammalian neuromuscular junction matures, its acetylcholine receptor
      (AChR)-rich postsynaptic apparatus is transformed from an oval plaque into a
      pretzel-shaped array of branches that precisely mirrors the branching pattern of
      the motor nerve terminal. Although the nerve has been believed to direct
      postsynaptic maturation, we report here that myotubes cultured aneurally on
      matrix-coated substrates form elaborately branched AChR-rich domains remarkably
      similar to those seen in vivo. These domains share several characteristics with
      the mature postsynaptic apparatus, including colocalization of multiple
      postsynaptic markers, clustering of subjacent myonuclei, and dependence on the
      muscle-specific kinase and rapsyn for their formation. Time-lapse imaging showed
      that branched structures arise from plaques by formation and fusion of AChR-poor
      perforations through a series of steps mirroring that seen in vivo. Multiple
      fluorophore imaging showed that growth occurs by circumferential, asymmetric
      addition of AChRs. Analysis in vivo revealed similar patterns of AChR addition
      during normal development. These results reveal the sequence of steps by which a
      topologically complex domain forms on a cell and suggest an unexpected nerve
      independent role for the postsynaptic cell in generating this topological
      complexity.

PMID- 15037599
TI  - Laminin: the crux of basement membrane assembly.
AB  - Laminin-1 is emerging as the key molecule in early embryonic basement membrane
      assembly. Here we review recent insights into its functions gained from the
      synergistic application of genetic and structural methods.

PMID- 15037600
TI  - VCIP135 acts as a deubiquitinating enzyme during p97-p47-mediated reassembly of
      mitotic Golgi fragments.
AB  - The AAA-ATPase p97/Cdc48 functions in different cellular pathways using distinct
      sets of adapters and other cofactors. Together with its adaptor Ufd1-Npl4, it
      extracts ubiquitylated substrates from the membrane for subsequent delivery to
      the proteasome during ER-associated degradation. Together with its adaptor p47,
      on the other hand, it regulates several membrane fusion events, including
      reassembly of Golgi cisternae after mitosis. The finding of a ubiquitin-binding
      domain in p47 raises the question as to whether the ubiquitin-proteasome system
      is also involved in membrane fusion events. Here, we show that p97-p47-mediated
      reassembly of Golgi cisternae requires ubiquitin, but is not dependent on
      proteasome-mediated proteolysis. Instead, it requires the deubiquitinating
      activity of one of its cofactors, VCIP135, which reverses a ubiquitylation event
      that occurs during mitotic disassembly. Together, these data reveal a cycle of
      ubiquitylation and deubiquitination that regulates Golgi membrane dynamics during
      mitosis. Furthermore, they represent the first evidence for a proteasome
      independent function of p97/Cdc48.

PMID- 15037601
TI  - YSK1 is activated by the Golgi matrix protein GM130 and plays a role in cell
      migration through its substrate 14-3-3zeta.
AB  - The Golgi apparatus has long been suggested to be important for directing
      secretion to specific sites on the plasma membrane in response to extracellular
      signaling events. However, the mechanisms by which signaling events are
      coordinated with Golgi apparatus function remain poorly understood. Here, we
      identify a scaffolding function for the Golgi matrix protein GM130 that sheds
      light on how such signaling events may be regulated. We show that the mammalian
      Ste20 kinases YSK1 and MST4 target to the Golgi apparatus via the Golgi matrix
      protein GM130. In addition, GM130 binding activates these kinases by promoting
      autophosphorylation of a conserved threonine within the T-loop. Interference with
      YSK1 function perturbs perinuclear Golgi organization, cell migration, and
      invasion into type I collagen. A biochemical screen identifies 14-3-3zeta as a
      specific substrate for YSK1 that localizes to the Golgi apparatus, and
      potentially links YSK1 signaling at the Golgi apparatus with protein transport
      events, cell adhesion, and polarity complexes important for cell migration.

PMID- 15037602
TI  - RanGAP1*SUMO1 is phosphorylated at the onset of mitosis and remains associated
      with RanBP2 upon NPC disassembly.
AB  - The RanGTPase activating protein RanGAP1 has essential functions in both
      nucleocytoplasmic transport and mitosis. In interphase, a significant fraction of
      vertebrate SUMO1-modified RanGAP1 forms a stable complex with the nucleoporin
      RanBP2/Nup358 at nuclear pore complexes. RanBP2 not only acts in the RanGTPase
      cycle but also is a SUMO1 E3 ligase. Here, we show that RanGAP1 is phosphorylated
      on residues T409, S428, and S442. Phosphorylation occurs before nuclear envelope
      breakdown and is maintained throughout mitosis. Nocodazole arrest leads to
      quantitative phosphorylation. The M-phase kinase cyclin B/Cdk1 phosphorylates
      RanGAP1 efficiently in vitro, and T409 phosphorylation correlates with nuclear
      accumulation of cyclin B1 in vivo. We find that phosphorylated RanGAP1 remains
      associated with RanBP2/Nup358 and the SUMO E2-conjugating enzyme Ubc9 in mitosis,
      hence mitotic phosphorylation may have functional consequences for the RanGTPase
      cycle and/or for RanBP2-dependent sumoylation.

PMID- 15037603
TI  - Conformational control of Bax localization and apoptotic activity by Pro168.
AB  - In healthy cells, Bax resides inactive in the cytosol because its COOH-terminal
      transmembrane region (TMB) is tucked into a hydrophobic pocket. During apoptosis,
      Bax undergoes a conformational change involving NH2-terminal exposure and
      translocates to mitochondria to release apoptogenic factors. How this process is
      regulated remains unknown. We show that the TMB of Bax is both necessary and
      sufficient for mitochondrial targeting. However, its availability for targeting
      depends on Pro168 located within the preceding loop region. Pro168 mutants of Bax
      lack apoptotic activity, cannot rescue the apoptosis-resistant phenotype of
      Bax/Bak double knockout cells, and are retained in the cytosol even in response
      to apoptotic stimuli. Moreover, the mutants have their NH2 termini exposed. We
      propose that Pro168 links the NH2 and the COOH terminus of Bax and is required
      for COOH-terminal release and mitochondrial targeting once this link is broken.

PMID- 15037604
TI  - Phosphoprotein of the rinderpest virus forms a tetramer through a coiled coil
      region important for biological function. A structural insight.
AB  - Phosphoprotein (P) of negative sense RNA viruses functions as a transcriptional
      transactivator of the viral polymerase (L). We report here the characterization
      of oligomeric P protein of rinderpest virus (RPV) and provide a structural basis
      for its multimerization. By size exclusion chromatography and dynamic light
      scattering analyses we show that bacterially expressed P protein exists as an
      oligomer, thus excluding the role of phosphorylation in P protein
      oligomerization. Gel filtration analyses of various parts of the P protein, also
      expressed in Escherichia coli, revealed that the predicted coiled coil region in
      the C-terminal domain is responsible for P protein oligomerization. Dynamic light
      scattering analysis confirmed the oligomeric nature of the coiled coil region of
      P. Chemical cross-linking analysis suggested that the C-terminal coiled coil
      region exists as a tetramer. The tetramer is formed by coiled coil interaction as
      shown by circular dichroism spectral analysis. Based on sequence homology, we
      propose a three-dimensional structure of the multimerization domain of RPV P
      using the crystal structure for multimerization domain of sendai virus (SeV) P as
      a template. Four-stranded coiled coil structure of the model is stabilized by a
      series of interactions predominantly between short nonpolar side chains emerging
      from different strands. In an in vivo replication/transcription system using a
      synthetic minigenome of RPV, we show that multimerization is essential for P
      protein function(s), and the multimerization domain is highly conserved between
      two morbilliviruses namely RPV and peste de petits ruminants virus. These results
      are discussed in the context of biological functions of P protein among various
      negative-stranded RNA viruses.

PMID- 15037605
TI  - Protein kinase C (PKC) betaII induces cell invasion through a Ras/Mek-, PKC
      iota/Rac 1-dependent signaling pathway.
AB  - Protein kinase C betaII (PKCbetaII) promotes colon carcinogenesis. Expression of
      PKCbetaII in the colon of transgenic mice induces hyperproliferation and
      increased susceptibility to colon cancer. To determine molecular mechanisms by
      which PKCbetaII promotes colon cancer, we established rat intestinal epithelial
      (RIE) cells stably expressing PKCbetaII. Here we show that RIE/PKCbetaII cells
      acquire an invasive phenotype that is blocked by the PKCbeta inhibitor LY379196.
      Invasion is not observed in RIE cells expressing a kinase-deficient PKCbetaII,
      indicating that PKCbetaII activity is required for the invasive phenotype.
      PKCbetaII induces activation of K-Ras and the Ras effector, Rac1, in
      RIE/PKCbetaII cells. PKCbetaII-mediated invasion is blocked by the Mek inhibitor,
      U0126, and by expression of either dominant negative Rac1 or kinase-deficient
      atypical PKCiota. Expression of constitutively active Rac1 induces Mek activation
      and invasion in RIE cells, indicating that Rac1 is the critical downstream
      effector of PKCbetaII-mediated invasion. Taken together, our results define a
      novel PKCbetaII --> Ras --> PKCiota /Rac1 --> Mek signaling pathway that induces
      invasion in intestinal epithelial cells. This pathway provides a plausible
      mechanism by which PKCbetaII promotes colon carcinogenesis.

PMID- 15037606
TI  - The broad spectrum antiviral nucleoside ribavirin as a substrate for a viral RNA
      capping enzyme.
AB  - The broad spectrum antiviral nucleoside ribavirin displays activity against a
      variety of RNA and DNA viruses. A number of possible mechanisms have been
      proposed during the past 30 years to account for the antiviral activity of
      ribavirin, including the possibility that ribavirin might have a negative effect
      on the synthesis of the RNA cap structure of viral RNA transcripts. In the
      present study, we investigated the possibility that ribavirin can directly serve
      as a substrate for the vaccinia virus RNA capping enzyme. We demonstrate that
      ribavirin triphosphate can be used as a substrate by the capping enzyme and can
      form a covalent ribavirin monophosphate-enzyme intermediate reminiscent of the
      classical GMP-enzyme intermediate. Furthermore, our data indicate that ribavirin
      monophosphate can be transferred to the diphosphate end of an RNA transcript to
      form the unusual RpppN structure. Finally, we provide evidence that RNA
      transcripts that possess ribavirin as the blocking nucleoside are more stable
      than unblocked transcripts. However, in vitro translation assays indicate that
      RNA transcripts blocked with ribavirin are not translated efficiently. Our study
      provides the first biochemical evidences that ribavirin can directly interact
      with a viral capping enzyme. The ability of a purified RNA capping enzyme to
      utilize ribavirin as a substrate has not been previously documented and has
      implications for our understanding of the catalytic mechanisms of RNA capping
      enzymes. The biological implications of these findings for the proposed ribavirin
      mediated inhibition of capping are discussed.

PMID- 15037608
TI  - Mutational Analysis of Hepatitis C Virus NS5B in the Subgenomic Replicon Cell
      Culture.
AB  - The hepatitis C virus (HCV) NS5B is an RNA-dependent RNA polymerase (RdRP), a
      central catalytic enzyme of HCV RNA replication. We previously identified five
      novel residues of NS5B in a JK-1 isolate indispensable for RdRP activity in vitro
      (Qin, W., Yamashita, T., Shirota, Y., Lin, Y., Wei, W., and Murakami, S. (2001)
      Hepatology 33, 728-737). We addressed the role of these residues in HCV RNA
      replication using a HCV replicon system derived from an M1LE isolate (Kishine,
      H., Sugiyama, K., Hijikata, M., Kato, N., Takahashi, H., Noshi, T., Nio, Y.,
      Hosaka, M., Miyanari, Y., and Shimotohno, K. (2002) Biochem. Biophys. Res.
      Commun. 293, 993-999). The five residues of NS5B in M1LE were found to be
      critical for HCV replication in vivo and also indispensable for RdRP activity in
      vitro along with purified bacterial recombinant proteins. We also found a
      chimeric replicon of JK-1 and M1LE in which only the NS5B sequence derived from
      JK-1 could not replicate in Huh-7 cells. The residues responsible for the
      phenomenon were mapped by several chimeric and substituted forms of NS5B M1LE
      and/or JK-1 isolates in the HCV RNA replicon. Two residues, amino acids 220 and
      288, were critical, and two residues, amino acids 213 and 231, were important for
      efficient HCV replication. Mutant JK-1 NS5B harboring all four residues of M1LE
      was replication-competent in the chimeric replicon and was as efficient as the
      original M1LE replicon. By comparing the replication competence in vivo and RdRP
      activity in vitro with various chimeric and mutated versions of NS5B, the HCV
      replication ability was found to correlate well with the RdRP activity. However,
      heat- and dilution-sensitive NS5Bs exhibiting weaker RdRP activity in vitro were
      found to be replication-incompetent, suggesting that HCV replication requires
      RdRP activity higher than a certain critical threshold.

PMID- 15037607
TI  - The human CYP1A1 gene is regulated in a developmental and tissue-specific fashion
      in transgenic mice.
AB  - Regulation and expression of human CYP1A1 is demonstrated in transgenic mice. We
      have developed two transgenic mouse lines. One mouse strain (CYPLucR) carries a
      functional human CYP1A1 promoter (-1612 to +293)-luciferase reporter gene, and
      the other strain (CYP1A1N) expresses CYP1A1 under control of the full-length
      human CYP1A1 gene and 9 kb of flanking regulatory DNA. With CYPLucR(+/-) mice,
      2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) and several other aryl hydrocarbon
      receptor ligands induced hepatocyte-specific luciferase activity. When other
      tissues were examined, TCDD induced luciferase activity in brain with limited
      induction in lung and no detectable luciferase activity in kidney. Treatment of
      CYP1A1N(+/-) mice with TCDD resulted in induction of human CYP1A1 in liver and
      lung, while mouse Cyp1a1 was induced in liver, lung, and kidney. Although induced
      CYP1A1/Cyp1a1 could not be detected by Western blot analysis in brains from
      CYP1A1N(+/-) mice, induction in brain was verified by detection of CYP1A1/Cyp1a1
      RNA. The administration of TCDD to nursing mothers to examine the effect of
      lactational exposure via milk demonstrated prominent induction of luciferase
      activity in livers of CYPLucR(+/-) newborn pups with limited induction in brain.
      However, TCDD treatment of adult CYPLucR(+/-) mice led to a 7-10-fold induction
      of brain luciferase activity. Combined these results indicate that tissue
      specific and developmental factors are controlling aryl hydrocarbon receptor
      mediated induction of human CYP1A1.

PMID- 15037609
TI  - Two exoribonucleases act sequentially to process mature 3'-ends of atp9 mRNAs in
      Arabidopsis mitochondria.
AB  - In plant mitochondria, transcription proceeds well beyond the region that will
      become mature 3' extremities of mRNAs, and the mechanisms of 3' maturation are
      largely unknown. Here, we show the involvement of two exoribonucleases,
      AtmtPNPase and AtmtRNaseII, in the 3' processing of atp9 mRNAs in Arabidopsis
      thaliana mitochondria. Down-regulation of AtmtPNPase results in the accumulation
      of pretranscripts of several times the size of mature atp9 mRNAs, indicating that
      3' processing of these transcripts is performed mainly exonucleolytically by
      AtmtPNPase. This enzyme is however not sufficient to completely process atp9
      mRNAs, because with down-regulation of another mitochondrial exoribonuclease,
      AtmtRNaseII, about half of atp9 transcripts exhibit short 3' nucleotide
      extensions compared with mature mRNAs. These short extensions can be efficiently
      removed by AtmtRNaseII in vitro. Taken together, these results show that 3'
      processing of atp9 mRNAs in Arabidopsis mitochondria is, at least, a two-step
      phenomenon. First, AtmtPNPase is involved in removing 3' extensions that may
      reach several kilobases. Second, AtmtRNaseII degrades short nucleotidic
      extensions to generate the mature 3'-ends.

PMID- 15037610
TI  - Interaction interface of human flap endonuclease-1 with its DNA substrates.
AB  - Flap endonuclease-1 or FEN-1 is a structure-specific and multifunctional nuclease
      critical for DNA replication, repair, and recombination; however, its interaction
      with DNA substrates has not been fully understood. In the current study, we have
      defined the borders of the interaction between the FEN-1 protein and its DNA
      substrates and identified six clusters of conserved positively charged amino acid
      residues, which are in direct contact with DNA substrate. To map further the
      corresponding interactions between FEN-1 residues and DNA substrates, we
      performed biochemical assays employing a series of flap DNA substrates lacking
      some structural components and a series of binding-deficient point mutants of FEN
      1. It was revealed that Arg(47), Arg(70), and Lys(326)-Arg(327) of FEN-1 interact
      with the upstream duplex of DNA substrates, whereas Lys(244)-Arg(245) interact
      with the downstream duplex. This result indicates the orientation of the FEN-1
      DNA interaction. Moreover, Arg(70) and Arg(47) were determined to interact with
      the sites around the 2nd nucleotide (Arg(70)) or the 5th/6th nucleotide (Arg(47))
      of the template strand in the upstream duplex portion counting from the nick
      point of the flap substrate. Together with previously published data and the
      crystallographic ainformation from the FEN-1.DNA complex that we published
      recently (Chapados, B. R., Hosfield, D. J., Han, S., Qiu, J., Yelent, B., Shen,
      B., Tainer, J. A. (2004) Cell 116, 39-50) we are able to propose a reasonable
      model for how the human FEN-1 protein interacts with its DNA substrates.

PMID- 15037611
TI  - Substrate-induced conformational change in bacterial complex I.
AB  - The mechanism coupling electron transfer and proton pumping in respiratory
      complex I (NADH-ubiquinone oxidoreductase) has not been established, but it has
      been suggested that it involves conformational changes. Here, the influence of
      substrates on the conformation of purified complex I from Escherichia coli was
      studied by cross-linking and electron microscopy. When a zero-length cross
      linking reagent was used, the presence of NAD(P)H, in contrast to that of NAD+,
      prevented the formation of cross-links between the hydrophilic subunits of the
      complex, including NuoB, NuoI, and NuoCD. Comparisons using different cross
      linkers suggested that NuoB, which is likely to coordinate the key iron-sulfur
      cluster N2, is the most mobile subunit. The presence of NAD(P)H led also to
      enhanced proteolysis of subunit NuoG. These data indicate that upon NAD(P)H
      binding, the peripheral arm of the complex adopts a more open conformation, with
      increased distances between subunits. Single particle analysis showed the nature
      of this conformational change. The enzyme retains its L-shape in the presence of
      NADH, but exhibits a significantly more open or expanded structure both in the
      peripheral arm and, unexpectedly, in the membrane domain also.

PMID- 15037612
TI  - Adenylylation and catalytic properties of Mycobacterium tuberculosis glutamine
      synthetase expressed in Escherichia coli versus mycobacteria.
AB  - Bacterial glutamine synthetases (GSs) are complex dodecameric oligomers that play
      a critical role in nitrogen metabolism, converting ammonia and glutamate to
      glutamine. Recently published reports suggest that GS from Mycobacterium
      tuberculosis (MTb) may be a therapeutic target (Harth, G., and Horwitz, M. A.
      (2003) Infect. Immun. 71, 456-464). In some bacteria, GS is regulated via
      adenylylation of some or all of the subunits within the aggregate; catalytic
      activity is inversely proportional to the extent of adenylylation. The
      adenylylation and deadenylylation of GS are catalyzed by adenylyl transferase
      (ATase). Here, we demonstrate via electrospray ionization mass spectrometry that
      GS from pathogenic M. tuberculosis is adenylylated by the Escherichia coli ATase.
      The adenylyl group can be hydrolyzed by snake venom phosphodiesterase to afford
      the unmodified enzyme. The site of adenylylation of MTb GS by the E. coli ATase
      is Tyr-406, as indicated by the lack of adenylylation of the Y406F mutant, and,
      as expected, is based on amino acid sequence alignments. Using electrospray
      ionization mass spectroscopy methodology, we found that GS is not adenylylated
      when obtained directly from MTb cultures that are not supplemented with
      glutamine. Under these conditions, the highly related but non-pathogenic
      Mycobacterium bovis BCG yields partially ( approximately 25%) adenylylated
      enzyme. Upon the addition of glutamine to the cultures, the MTb GS becomes
      significantly adenylylated ( approximately 30%), whereas the adenylylation of M.
      bovis BCG GS does not change. Collectively, the results demonstrate that MTb GS
      is a substrate for E. coli ATase, but only low adenylylation states are
      accessible. This parallels the low adenylylation states observed for GS from
      mycobacteria and suggests the intriguing possibility that adenylylation in the
      pathogenic versus non-pathogenic mycobacteria is differentially regulated.

PMID- 15037613
TI  - Substrate specificity for 4-thiouridine modification in Escherichia coli.
AB  - The biosynthesis of 4-thiouridine (s4U) in Escherichia coli tRNA requires the
      action of both the thiamin pathway enzyme ThiI and the cysteine desulfurase IscS.
      IscS catalyzes sulfur transfer from l-cysteine to ThiI, which utilizes Mg-ATP to
      activate uridine 8 in tRNA and transfers sulfur to give s4U. In this work, we
      show through deletion analysis of unmodified E. coli tRNA(Phe) that the minimum
      substrate for s4U modification is a mini-helix comprising the stacked acceptor
      and T stems containing an internal bulged region. The size of the bulged loop
      must be at least 4 nucleotides and contain the target uridine as the first
      nucleotide. Replacement of the T loop sequence with a tetraloop in the deletion
      substrate increases activity and shows that the TpsiC primary sequence is not a
      recognition element. An unmodified tRNA(Phe) transcript in which the 3'-terminal
      ACCA sequence is removed to give a blunt terminus has <0.1% activity, although
      the addition of a single overhanging base essentially restores activity. In
      addition, reducing the distance of the 3' terminus relative to U8 by as little as
      1 bp severely impairs activity. By dissecting a minimal RNA substrate in the T
      loop region, a two-piece system consisting of a substrate RNA and a "guide" RNA
      is efficiently modified. Our results indicate that outside of the modified U8,
      there is no primary sequence requirement for substrate recognition. However, the
      secondary and tertiary structure restrictions appear sufficient to explain why
      s4U modification is limited in the cell to tRNA.

PMID- 15037614
TI  - Coordinated metabolism of Alcadein and amyloid beta-protein precursor regulates
      FE65-dependent gene transactivation.
AB  - The Alcadeins (Alcs)/calsyntenins and the amyloid beta-protein precursor (APP)
      associate with each other in the brain by binding via their cytoplasmic domains
      to X11L (the X11-like protein). We previously reported that the formation of this
      APP-X11L-Alc tripartite complex suppresses the metabolic cleavages of APP. We
      show here that the metabolism of the Alcs markedly resembles that of APP. The
      Alcs are subjected to a primary cleavage event that releases their extracellular
      domain. Alcs then undergo a secondary presenilin-dependent gamma-cleavage that
      leads to the secretion of the amyloid beta-protein-like peptide and the
      liberation of an intracellular domain fragment (AlcICD). However, when Alc is in
      the tripartite complex, it escapes from these cleavages, as does APP. We also
      found that AlcICD suppressed the FE65-dependent gene transactivation activity of
      the APP intracellular domain fragment, probably because AlcICD competes with the
      APP intracellular domain fragment for binding to FE65. We propose that the Alcs
      and APP are coordinately metabolized in neurons and that their cleaved
      cytoplasmic fragments are reciprocally involved in the regulation of FE65
      dependent gene transactivation. Any imbalance in the metabolism of Alcs and APP
      may influence the FE65-dependent gene transactivation, which together with
      increased secretion of amyloid beta-protein may contribute to neural disorders.

PMID- 15037615
TI  - The ORF3 protein of hepatitis E virus interacts with liver-specific alpha1
      microglobulin and its precursor alpha1-microglobulin/bikunin precursor (AMBP) and
      expedites their export from the hepatocyte.
AB  - Hepatitis E virus (HEV), a plus-stranded RNA virus contains three open reading
      frames. Of these, ORF1 encodes the viral nonstructural polyprotein; ORF2 encodes
      the major capsid protein and ORF3 codes for a phosphoprotein of undefined
      function. Using the yeast two-hybrid system to screen a human cDNA liver library
      we have isolated, an N-terminal deleted protein, alpha(1) -microglobulin/bikunin
      precursor (AMBP) that specifically interacts with the ORF3 protein of HEV.
      Independently cloned, full-length AMBP was obtained and tested positive for
      interaction with ORF3 using a variety of in vivo and in vitro techniques. AMBP, a
      liver-specific precursor protein codes for two different unrelated proteins
      alpha(1)-microglobulin (alpha(1)m) and bikunin. alpha(1) m individually
      interacted with ORF3. The above findings were validated by COS-1 cell
      immunoprecipitation, His(6) pull-down experiments, and co-localization
      experiments followed by fluorescence resonance energy transfer analysis. Human
      liver cells showing co-localization of ORF3 with endogenously expressing alpha(1)
      m showed a distinct disappearance of the protein from the Golgi compartment,
      suggesting that ORF3 enhances the secretion of alpha(1)m out of the hepatocyte.
      Using drugs to block the secretory pathway, we showed that alpha m was not
      degraded in the presence of ORF3. Finally, (1)pulse labeling of alpha(1)m showed
      that its secretion was expedited out of the liver cell at faster rates in the
      presence of the ORF3 protein. Hence, ORF3 has a direct biological role in
      enhancing alpha(1)m export from the hepatocyte.

PMID- 15037616
TI  - XRCC3 ATPase activity is required for normal XRCC3-Rad51C complex dynamics and
      homologous recombination.
AB  - Homologous recombinational repair preserves chromosomal integrity by removing
      double-strand breaks, cross-links, and other DNA damage. In eukaryotic cells, the
      Rad51 paralogs (XRCC2/3, Rad51B/C/D) are involved in this process, although their
      exact functions are largely undetermined. All five paralogs contain ATPase
      motifs, and XRCC3 exists in a single complex with Rad51C. To examine the function
      of this Rad51C-XRCC3 complex, we generated mammalian expression vectors that
      produce human wild-type XRCC3 or mutant XRCC3 with either a nonconservative
      mutation (K113A) or a conservative mutation (K113R) in the GKT Walker A box of
      the ATPase motif. The three vectors were independently transfected into Xrcc3
      deficient irs1SF Chinese hamster ovary cells. Wild-type XRCC3 complemented irs1SF
      cells, albeit to varying degrees, whereas ATPase mutants had no complementing
      activity, even when the mutant protein was expressed at comparable levels to that
      in wild-type-complemented clones. Because of dysfunction of the mutants, we
      propose that ATP binding and hydrolyzing activities of XRCC3 are essential. We
      tested in vitro complex formation by wild-type and mutant XRCC3 with His6-tagged
      Rad51C upon co-expression in bacteria, nickel-affinity purification, and Western
      blotting. Wild-type and K113A mutant XRCC3 formed stable complexes with Rad51C
      and co-purified with Rad51C, whereas the K113R mutant did not and was
      predominantly insoluble. The addition of 5 mm ATP but not ADP also abolished
      complex formation by the wild-type proteins. These results suggest that XRCC3
      probably regulates the dissociation and formation of Rad51C-XRCC3 complex through
      ATP binding and hydrolysis with both processes being essential for the ability of
      the complex to participate in homologous recombinational repair.

PMID- 15037617
TI  - Regulation of NDR2 protein kinase by multi-site phosphorylation and the S100B
      calcium-binding protein.
AB  - Nuclear Dbf2-related (NDR) protein kinases are a family of AGC group kinases that
      are involved in the regulation of cell division and cell morphology. We describe
      the cloning and characterization of the human and mouse NDR2, a second mammalian
      isoform of NDR protein kinase. NDR1 and NDR2 share 86% amino acid identity and
      are highly conserved between human and mouse. However, they differ in expression
      pattern; mouse Ndr1 is expressed mainly in spleen, lung and thymus, whereas mouse
      Ndr2 shows highest expression in the gastrointestinal tract. NDR2 is potently
      activated in cells following treatment with the protein phosphatase 2A inhibitor
      okadaic acid, which also results in phosphorylation on the activation segment
      residue Ser-282 and the hydrophobic motif residue Thr-442. We show that Ser-282
      becomes autophosphorylated in vivo, whereas Thr-442 is targeted by an upstream
      kinase. This phosphorylation can be mimicked by replacing the hydrophobic motif
      of NDR2 with a PRK2-derived sequence, resulting in a constitutively active
      kinase. Similar to NDR1, the autophosphorylation of NDR2 protein kinase was
      stimulated in vitro by S100B, an EF-hand Ca(2+)-binding protein of the S100
      family, suggesting that the two isoforms are regulated by the same mechanisms.
      Further we show a predominant cytoplasmic localization of ectopically expressed
      NDR2.

PMID- 15037618
TI  - Nicotine induces multi-site phosphorylation of Bad in association with
      suppression of apoptosis.
AB  - Nicotine is an important component in cigarette smoke that can activate the
      growth-promoting pathways to facilitate the development of lung cancer. However,
      the intracellular mechanism(s) by which nicotine promotes survival of lung cancer
      cells remains enigmatic. Bad is a proapoptotic BH3-only member of the Bcl2 family
      and is expressed in both small cell lung cancer and non-small cell lung cancer
      cells. Here we report that nicotine potently induces Bad phosphorylation at
      Ser112, Ser136, and Ser155 in a mechanism involving activation of MAPKs ERK1/2,
      PI3K/AKT, and PKA in human lung cancer cells. Nicotine-induced multi-site
      phosphorylation of Bad results in sequestering Bad from mitochondria and
      subsequently interacting with 14-3-3 in the cytosol. Treatment of cells with PKC
      inhibitor (staurosporine), MEK-specific inhibitor (PD98059), PI3 kinase inhibitor
      (LY294002), or PKA inhibitor (H89) blocks the nicotine-induced Bad
      phosphorylation that is associated with enhanced apoptotic cell death. The fact
      that beta-adrenergic receptor inhibitor (propranolol) blocks nicotine-induced
      activation of ERK1/2, AKT, PKA, Bad phosphorylation, and cell survival suggests
      that nicotine-induced Bad phosphorylation may occur through the upstream beta
      adrenergic receptors. The fact that specific knockdown of Bad expression by RNA
      interference using short interfering RNA enhances cell survival and that nicotine
      has no additional survival effect on these cells suggests that Bad may act as a
      required target of nicotine. Thus, nicotine-induced survival may occur in a
      mechanism through multi-site phosphorylation of Bad, which may lead to
      development of human lung cancer and/or chemoresistance.

PMID- 15037619
TI  - TDAG51 mediates the effects of insulin-like growth factor I (IGF-I) on cell
      survival.
AB  - Insulin-like growth factor-I (IGF-I) receptors and insulin receptors belong to
      the same subfamily of receptor tyrosine kinases and share a similar set of
      intracellular signaling pathways, despite their distinct biological actions. In
      the present study, we evaluated T cell death-associated gene 51 (TDAG51), which
      we previously identified by cDNA microarray analysis as a gene specifically
      induced by IGF-I. We characterized the signaling pathways by which IGF-I induces
      TDAG51 gene expression and the functional role of TDAG51 in IGF-I signaling in
      NIH-3T3 (NWTb3) cells, which overexpress the human IGF-I receptor. Treatment with
      IGF-I increased TDAG51 mRNA and protein levels in NWTb3 cells. This effect of IGF
      I was specifically mediated by the IGF-IR, because IGF-I did not induce TDAG51
      expression in NIH-3T3 cells overexpressing a dominant-negative IGF-I receptor.
      Through the use of specific inhibitors of various protein kinases, we found that
      IGF-I induced TDAG51 expression via the p38 MAPK pathway. The ERK, JNK, and
      phosphatidylinositol 3-kinase pathways were not involved in IGF-I-induced
      regulation of TDAG51. To assess the role of TDAG51 in IGF-I signaling, we used
      small interfering RNA (siRNA) expression vectors directed at two different target
      sites to reduce the level of TDAG51 protein. In cells expressing these siRNA
      vectors, TDAG51 protein levels were decreased by 75-80%. Furthermore, TDAG51
      siRNA expression abolished the ability of IGF-I to rescue cells from serum
      starvation-induced apoptosis. These findings suggest that TDAG51 plays an
      important role in the anti-apoptotic effects of IGF-I.

PMID- 15037620
TI  - Structural and functional characterization of the dimerization region of soluble
      guanylyl cyclase.
AB  - Soluble guanylyl cyclase (sGC) is a ubiquitous enzyme that functions as a
      receptor for nitric oxide. Despite the obligate heterodimeric nature of sGC, the
      sequence segments mediating subunit association have remained elusive. Our
      initial screening for relevant interaction site(s) in the most common sGC
      isoenzyme, alpha(1) beta(1), identified two regions in each subunit, i.e. the
      regulatory domains and the central regions, contributing to heterodimer
      formation. To map the relevant segments in the beta(1) subunit precisely, we
      constructed multiple N- and C-terminal deletion variants and cotransfected them
      with full-length alpha(1) in COS cells. Immunoprecipitation revealed that a
      sequence segment spanning positions 204-408 mediates binding of beta(1) to
      alpha(1) The same region of beta(1)[204-408] was found to promote beta /beta(1)
      homodimerization. Fusion of [204 beta(1)-408] to enhanced green fluorescent
      protein conferred binding activity to the recipient protein. Coexpression of
      beta(1)[204-408] with alpha(1) or beta(1) targeted the sGC subunits for
      proteasomal degradation, suggesting that beta(1)[204-408] forms structurally
      deficient complexes with alpha(1) and beta(1). Analysis of deletion constructs
      lacking portions of the beta(1) dimerization region identified two distinct
      segments contributing to alpha(1) binding, i.e. an N-terminal site covering
      positions 204-244 and a C-terminal site at 379-408. Both sites are crucial for
      sGC function because deletion of either site rendered sGC dimerization-deficient
      and thus functionally inactive. We conclude that the dimerization region of
      beta(1) extends over 205 residues of its regulatory and central domains and that
      two discontinuous sites of 41 and 30 residues, respectively, facilitate binding
      of beta(1) to the alpha(1) subunit of sGC.

PMID- 15037621
TI  - The NADPH-cytochrome P450 reductase gene from Gibberella fujikuroi is essential
      for gibberellin biosynthesis.
AB  - The fungus Gibberella fujikuroi is used for the commercial production of
      gibberellins (GAs), which it produces in very large quantities. Four of the seven
      GA biosynthetic genes in this species encode cytochrome P450 monooxygenases,
      which function in association with NADPH-cytochrome P450 reductases (CPRs) that
      mediate the transfer of electrons from NADPH to the P450 monooxygenases. Only one
      cpr gene (cpr-Gf) was found in G. fujikuroi and cloned by a PCR approach. The
      encoded protein contains the conserved CPR functional domains, including the FAD,
      FMN, and NADPH binding motifs. cpr-Gf disruption mutants were viable but showed a
      reduced growth rate. Furthermore, disruption resulted in total loss of GA(3),
      GA(4), and GA(7) production, but low levels of non-hydroxylated C(20)-GAs (GA(15)
      and GA(24)) were still detected. In addition, the knock-out mutants were much
      more sensitive to benzoate than the wild type due to loss of activity of another
      P450 monooxygenase, the detoxifying enzyme, benzoate p-hydroxylase. The UV
      induced mutant of G. fujikuroi, SG138, which was shown to be blocked at most of
      the GA biosynthetic steps catalyzed by P450 monooxygenases, displayed the same
      phenotype. Sequence analysis of the mutant cpr allele in SG138 revealed a
      nonsense mutation at amino acid position 627. The mutant was complemented with
      the cpr-Gf and the Aspergillus niger cprA genes, both genes fully restoring the
      ability to produce GAs. Northern blot analysis revealed co-regulated expression
      of the cpr-Gf gene and the GA biosynthetic genes P450-1, P450-2, P450-4 under GA
      production conditions (nitrogen starvation). In addition, expression of cpr-Gf is
      induced by benzoate. These results indicate that CPR-Gf is the main but not the
      only electron donor for several P450 monooxygenases from primary and secondary
      metabolism.

PMID- 15037622
TI  - Differential roles of tau class glutathione S-transferases in oxidative stress.
AB  - The plant glutathione S-transferase BI-GST has been identified as a potent
      inhibitor of Bax lethality in yeast, a phenotype associated with oxidative stress
      and disruption of mitochondrial functions. Screening of a tomato two-hybrid
      library for BI-GST interacting proteins identified five homologous Tau class
      GSTs, which readily form heterodimers between them and BI-GST. All six LeGSTUs
      were found to be able to protect yeast cells from prooxidant-induced cell death.
      The efficiency of each LeGSTU was prooxidant-specific, indicating a different
      role for each LeGSTU in the oxidative stress-response mechanism. The prooxidant
      protective effect of all six proteins was suppressed in the absence of YAP1, a
      transcription factor that regulates hydroperoxide homeostasis in Saccharomyces
      cerevisiae, suggesting a role for the LeGSTUs in the context of the YAP1
      dependent stress-responsive machinery. The different LeGSTUs exhibited varied
      substrate specificity and showed activity against oxidative stress by-products,
      indicating that their prooxidant protective function is likely related to the
      minimization of oxidative damage. Taken together, these results indicate that Tau
      class GSTs participate in a broad network of catalytic and regulatory functions
      involved in the oxidative stress response.

PMID- 15037624
TI  - A mutation in human topoisomerase II alpha whose expression is lethal in DNA
      repair-deficient yeast cells.
AB  - Type II DNA topoisomerases are ATP-dependent enzymes that catalyze alterations in
      DNA topology. These enzymes are important targets of a variety of anti-bacterial
      and anti-cancer agents. We identified a mutation in human topoisomerase II alpha,
      changing aspartic acid 48 to asparagine, that has the unique property of failing
      to transform yeast cells deficient in recombinational repair. In repair
      proficient yeast strains, the Asp-48 --> Asn mutant can be expressed and
      complements a temperature-sensitive top2 mutation. Purified Asp-48 --> Asn
      Top2alpha has relaxation and decatenation activity similar to the wild type
      enzyme, but the purified protein exhibits several biochemical alterations
      compared with the wild type enzyme. The mutant enzyme binds both covalently
      closed and linear DNA with greater avidity than the wild type enzyme.
      hTop2alpha(Asp-48 --> Asn) also exhibited elevated levels of drug-independent
      cleavage compared with the wild type enzyme. The enzyme did not show altered
      sensitivity to bisdioxopiperazines nor did it form stable closed clamps in the
      absence of ATP, although the enzyme did form elevated levels of closed clamps in
      the presence of a non-hydrolyzable ATP analog compared with the wild type enzyme.
      We suggest that the lethality exhibited by the mutant is likely because of its
      enhanced drug-independent cleavage, and we propose that alterations in the ATP
      binding domain of the enzyme are capable of altering the interactions of the
      enzyme with DNA. This mutant enzyme also serves as a new model for understanding
      the action of drugs targeting topoisomerase II.

PMID- 15037623
TI  - Dissection study on the severe acute respiratory syndrome 3C-like protease
      reveals the critical role of the extra domain in dimerization of the enzyme:
      defining the extra domain as a new target for design of highly specific protease
      inhibitors.
AB  - The severe acute respiratory syndrome (SARS) 3C-like protease consists of two
      distinct folds, namely the N-terminal chymotrypsin fold containing the domains I
      and II hosting the complete catalytic machinery and the C-terminal extra helical
      domain III unique for the coronavirus 3CL proteases. Previously the functional
      role of this extra domain has been completely unknown, and it was believed that
      the coronavirus 3CL proteases share the same enzymatic mechanism with
      picornavirus 3C proteases, which contain the chymotrypsin fold but have no extra
      domain. To understand the functional role of the extra domain and to characterize
      the enzyme-substrate interactions by use of the dynamic light scattering,
      circular dichroism, and NMR spectroscopy, we 1) dissected the full-length SARS
      3CL protease into two distinct folds and subsequently investigated their
      structural and dimerization properties and 2) studied the structural and binding
      interactions of three substrate peptides with the entire enzyme and its two
      dissected folds. The results lead to several findings; 1) although two dissected
      parts folded into the native-like structures, the chymotrypsin fold only had weak
      activity as compared with the entire enzyme, and 2) although the chymotrypsin
      fold remained a monomer within a wide range of protein concentrations, the extra
      domain existed as a stable dimer even at a very low concentration. This
      observation strongly indicates that the extra domain contributes to the
      dimerization of the SARS 3CL protease, thus, switching the enzyme from the
      inactive form (monomer) to the active form (dimer). This discovery not only
      separates the coronavirus 3CL protease from the picornavirus 3C protease in terms
      of the enzymatic mechanism but also defines the dimerization interface on the
      extra helical domain as a new target for design of the specific protease
      inhibitors. Furthermore, the determination of the preferred solution conformation
      of the substrate peptide S1 together with the NMR differential line-broadening
      and transferred nuclear Overhauser enhancement study allows us to pinpoint the
      bound structure of the S1 peptide.

PMID- 15037625
TI  - The pleckstrin homology domain of phosphoinositide-specific phospholipase Cdelta4
      is not a critical determinant of the membrane localization of the enzyme.
AB  - The inositol lipid and phosphate binding properties and the cellular localization
      of phospholipase Cdelta(4) (PLCdelta(4)) and its isolated pleckstrin homology
      (PH) domain were analyzed in comparison with the similar features of the
      PLCdelta(1) protein. The isolated PH domains of both proteins showed plasma
      membrane localization when expressed in the form of a green fluorescent protein
      fusion construct in various cells, although a significantly lower proportion of
      the PLCdelta(4) PH domain was membrane-bound than in the case of PLCdelta(1)PH
      GFP. Both PH domains selectively recognized phosphatidylinositol 4,5-bisphosphate
      (PI(4,5)P(2)), but a lower binding of PLCdelta(4)PH to lipid vesicles containing
      PI(4,5)P(2) was observed. Also, higher concentrations of inositol 1,4,5
      trisphosphate (Ins(1,4,5)P(3)) were required to displace the PLCdelta(4)PH from
      the lipid vesicles, and a lower Ins(1,4,5)P(3) affinity of PLCdelta(4)PH was
      found in direct Ins(1,4,5)P(3) binding assays. In sharp contrast to the
      localization of its PH domain, the full-length PLCdelta(4) protein localized
      primarily to intracellular membranes mostly to the endoplasmic reticulum (ER).
      This ER localization was in striking contrast to the well documented PH domain
      dependent plasma membrane localization of PLCdelta(1). A truncated PLCdelta(4)
      protein lacking the entire PH domain still showed the same ER localization as the
      full-length protein, indicating that the PH domain is not a critical determinant
      of the localization of this protein. Most important, the full-length PLCdelta(4)
      enzyme still showed binding to PI(4,5)P(2)-containing micelles, but
      Ins(1,4,5)P(3) was significantly less potent in displacing the enzyme from the
      lipid than with the PLCdelta(1) protein. These data suggest that although
      structurally related, PLCdelta(1) and PLCdelta(4) are probably differentially
      regulated in distinct cellular compartments by PI(4,5)P(2) and that the PH domain
      of PLCdelta(4) does not act as a localization signal.

PMID- 15037626
TI  - Identification of a novel A-kinase anchoring protein 18 isoform and evidence for
      its role in the vasopressin-induced aquaporin-2 shuttle in renal principal cells.
AB  - Arginine vasopressin (AVP) increases the water permeability of renal collecting
      duct principal cells by inducing the fusion of vesicles containing the water
      channel aquaporin-2 (AQP2) with the plasma membrane (AQP2 shuttle). This event is
      initiated by activation of vasopressin V2 receptors, followed by an elevation of
      cAMP and the activation of protein kinase A (PKA). The tethering of PKA to
      subcellular compartments by protein kinase A anchoring proteins (AKAPs) is a
      prerequisite for the AQP2 shuttle. During the search for AKAP(s) involved in the
      shuttle, a new splice variant of AKAP18, AKAP18delta, was identified. AKAP18delta
      functions as an AKAP in vitro and in vivo. In the kidney, it is mainly expressed
      in principal cells of the inner medullary collecting duct, closely resembling the
      distribution of AQP2. It is present in both the soluble and particulate fractions
      derived from renal inner medullary tissue. Within the particulate fraction,
      AKAP18delta was identified on the same intracellular vesicles as AQP2 and PKA.
      AVP not only recruited AQP2, but also AKAP18delta to the plasma membrane. The
      elevation of cAMP caused the dissociation of AKAP18delta and PKA. The data
      suggest that AKAP18delta is involved in the AQP2 shuttle.

PMID- 15037627
TI  - Coordination of membrane excitability through a GIRK1 signaling complex in the
      atria.
AB  - Control of heart rate is a complex process that integrates the function of
      multiple G protein-coupled receptors and ion channels. Among them, the G protein
      regulated inwardly rectifying K+ (GIRK or KACh) channels of sinoatrial node and
      atria play a major role in beat-to-beat regulation of the heart rate. The atrial
      KACh channels are heterotetrameric proteins that consist of two pore-forming
      subunits, GIRK1 and GIRK4. Following m2-muscarinic acetylcholine receptor (M2R)
      stimulation, KACh channel activation is conferred by the direct binding of G
      protein betagamma subunits (Gbetagamma) to the channel. Here we show that atrial
      KACh channels are assembled in a signaling complex with Gbetagamma, G protein
      coupled receptor kinase, cyclic adenosine monophosphate-dependent protein kinase,
      two protein phosphatases, PP1 and PP2A, receptor for activated C kinase 1, and
      actin. This complex would enable the KACh channels to rapidly integrate beta
      adrenergic and M2R signaling in the membrane, and it provides insight into
      general principles governing spatial integration of different transduction
      pathways. Furthermore, the same complex might recruit protein kinase C (PKC) to
      the KACh channel following alpha-adrenergic receptor stimulation. Our electro
      physiological recordings from single atrial KACh channels revealed a potent
      inhibition of Gbetagamma-induced channel activity by PKC, thus validating the
      physiological significance of the observed complex as interconnecting site where
      signaling molecules congregate to execute a coordinated control of membrane
      excitability.

PMID- 15037629
TI  - Triplet repeat expansion generated by DNA slippage is suppressed by human flap
      endonuclease 1.
AB  - Human flap endonuclease 1 (h-FEN1) mutations have dramatic effects on repeat
      instability. Current models for repeat expansion predict that h-FEN1 protein
      prevents mutations by removing 5'-flaps generated at ends of Okazaki fragments by
      strand displacement synthesis. The models propose that hairpin formations within
      flaps containing repeats enable them to escape h-FEN1 cleavage. Friedreich's
      ataxia is caused by expansion mutations in a d(GAA)n repeat tract. Single
      stranded d(GAA)n repeat tracts, however, do not form stable hairpins until the
      repeat tracts are quite long. Therefore, to understand how d(GAA)n repeat
      expansions survive h-FEN1 activity, we determined the effects of h-FEN1 on
      d(GAA)n repeat expansion during replication of a d(TTC)n repeat template.
      Replication initiated within the repeat tract generated significant expansion
      that was suppressed by the addition of h-FEN1 at the start of replication. The
      ability of h-FEN1 to suppress expansion implies that DNA slippage generates a 5'
      flap in the nascent strand independent of strand displacement synthesis by an
      upstream polymerase. Delaying the addition of h-FEN1 to the replication reaction
      abolished the ability of h-FEN1 ability to suppress d(GAA)n repeat expansion
      products of all sizes, including sizes unable to hairpin. Use of model substrates
      demonstrated that h-FEN1 cleaves d(GAA)n 5'-flaps joined to double-stranded
      nonrepeat sequences but not those joined to double-stranded repeat tracts. The
      results provide evidence that, given the opportunity, short d(GAA)n repeat
      expansion products rearrange from 5'-flaps to stable internal loops inside the
      repeat tract. Long expansion products are predicted to form hairpinned flaps and
      internal loops. Once formed, these DNA conformations resist h-FEN1. The
      biological implications of the results are discussed.

PMID- 15037628
TI  - High osmolarity glycerol (HOG) pathway-induced phosphorylation and activation of
      6-phosphofructo-2-kinase are essential for glycerol accumulation and yeast cell
      proliferation under hyperosmotic stress.
AB  - In response to changes in the environment, yeast cells coordinate intracellular
      activities to optimize survival and proliferation. The transductions of diverse
      extracellular stimuli are exerted through multiple mitogen-activated protein
      kinase (MAPK) cascades. The high osmolarity glycerol (HOG) MAPK pathway is
      activated by increased environmental osmolarity and results in a rise of the
      cellular glycerol concentration to adapt the intracellular osmotic pressure. We
      studied the importance of the short time regulation of glycolysis under
      hyperosmotic stress for the survival and proliferation of yeast cells. A
      stimulation of the HOG-MAPK pathway by increasing the medium osmolarity through
      addition of salt or glucose to cultivated yeast leads to an activation of 6
      phosphofructo-2-kinase (PFK2), which is accompanied by a complex phosphorylation
      pattern of the enzyme. An increase in medium osmolarity with 5% NaCl activates
      PFK2 3-fold over the initial value. This change in the activity is the result of
      a 4-fold phosphorylation of the enzyme mediated by protein kinases from the HOG
      MAPK pathway. In the case of hyperosmolar glucose a 5-fold PFK2 activation was
      achieved by a single phosphorylation with protein kinase A near the carboxyl
      terminus of the protein on Ser(644) and an additional 5-fold phosphorylation
      within the same amino-terminal fragment as in the presence of salt. The effect of
      hyperosmolar glucose is the result of an activation of the Ras-cAMP pathway
      together with the HOG-MAPK pathway. The activation of PFK2 leads to an activation
      of the upper part of glycolysis, which is a precondition for glycerol
      accumulation. Yeast cells containing PFK2 accumulate three times more glycerol
      than cells lacking PFK2, which are not able to grow under hypertonic stress.

PMID- 15037630
TI  - Stimulation by parathyroid hormone of a NHERF-1-assembled complex consisting of
      the parathyroid hormone I receptor, phospholipase Cbeta, and actin increases
      intracellular calcium in opossum kidney cells.
AB  - Parathyroid hormone (PTH) binds its cognate G-protein-coupled receptor (PTH1R)
      and signals through both adenylyl cyclase and phospholipase C (PLC). C-terminal
      determinants of the PTH1R interact with the Na+/H+ exchanger regulatory factor 1
      (NHERF-1) by binding the first of two PDZ (psd95, discs-large, ZO-1) domains.
      Compared with wild-type opossum kidney (OK) cells, OKH cells, a sub-clone, do not
      display PTH-mediated increases of [Ca2+]i and express NHERF-1 at markedly lower
      levels. Stable expression of NHERF-1 in the OKH parent (OKH-N1) restores the PTH
      mediated increase of [Ca2+]i that arises from an influx of extracellular calcium
      and is both PLC-dependent and pertussis toxin-sensitive. From a morphological
      perspective, NHERF-1 and the PTH1R co-localize to apical patches of OKH-N1 cells,
      an expression pattern that is absent in OKH cells and depends on a direct NHERF-1
      PTH1R interaction in OKH-N1 cells. Actin and PLCbeta1 and -beta3 co-localize with
      NHERF-1 and the PTH1R in OKH-N1 cell apical patches. Actin is also an integral
      component of the NHERF-1-assembled complex because cytochalasin D disrupts apical
      localization of both NHERF-1 and the PTH1R and inhibits the PTH-mediated increase
      of [Ca2+]i. Expression of the first PDZ domain of NHERF-1 acts as a dominant
      negative interactor by blocking apical localization of the PTH1R and inhibiting
      PTH-elicited increases of [Ca2+]i. Thus, NHERF-1 assembles a signaling complex in
      the apical domains of OK cells that contains the PTH1R, PLCbeta, and the actin
      cytoskeleton. Disruption of this complex blocks the PTH mediated increases of
      intracellular calcium.

PMID- 15037631
TI  - p38 MAPK activation selectively induces cell death in K-ras-mutated human colon
      cancer cells through regulation of vitamin D receptor.
AB  - Ras is the most characterized oncogene in human cancer, and yet there are no
      effective therapeutics to selectively target this oncogene. Our previous work
      demonstrated the inhibitory activity of the p38 pathway in Ras proliferative
      signaling in experimental NIH 3T3 cells (Chen, G., Hitomi, M., Han, J., and
      Stacey, D. W. (2000) J. Biol. Chem. 275, 38973-38980). Here we explore the
      therapeutic potential of p38 kinase activation in human colon cancer cells with
      and without endogenous K-ras activation. p38 activation by both adenovirus
      mediated gene delivery of constitutively active p38 activator MKK6 and by
      arsenite selectively induces cell death in K-ras-activated human colon cancer
      HCT116 cells but not in the K-ras-disrupted HCT116-derived sublines. The cell
      death-inducing effect of MKK6 is not because of its selective activation of p38
      kinase or its downstream transcription factor substrates, ATF-2 or c-Jun, in K
      ras-activated cells. Rather, cell death in K-ras-activated cells is linked to the
      down-regulation of vitamin D receptor (VDR) by an AP-1-dependent mechanism.
      Forced VDR expression in K-ras-activated cells inhibits p38 activation-induced
      cell death, and inhibition of endogenous VDR protein expression in K-ras
      disrupted cells increased the arsenite-induced toxicity. Analysis of an
      additional two human colon cancer cell lines with and without K-ras mutation also
      showed a K-ras- and VDR-dependent toxicity of MKK6. Hence, p38 pathway activation
      selectively induces cell death in K-ras-mutated human colon cancer cells by
      mechanisms involving the suppression of VDR activity.

PMID- 15037632
TI  - Transforming acidic coiled-coil protein 3 (TACC3) controls friend of GATA-1 (FOG
      1) subcellular localization and regulates the association between GATA-1 and FOG
      1 during hematopoiesis.
AB  - Physical association between the transcription factor GATA-1 and the cofactor,
      Friend of GATA-1 (FOG-1), is essential for the differentiation of two blood cell
      types, erythroid cells and megakaryocytes. However, little is known regarding the
      mechanisms that modulate their interaction within cells. In the present study, we
      have identified TACC3 as a FOG-1-interacting protein. Transforming acidic coiled
      coil protein 3 (TACC3), a protein that is highly expressed in hematopoietic
      cells, has been reported to have a critical role in the expansion of immature
      hematopoietic progenitors. We show that TACC3 affects FOG-1 nuclear localization,
      altering the interaction between GATA-1 and FOG-1. However, GATA-1 competes with
      TACC3 in the interaction with FOG-1. We observe that high levels of TACC3 inhibit
      the function of FOG-1 as a transcriptional cofactor of GATA-1. Furthermore,
      forced expression of TACC3 to levels similar to those found in progenitor cells
      delays terminal maturation of MEL and G1ER cells, two cell models of erythroid
      cell development. We suggest a role for TACC3 in regulating the cellular
      distribution of FOG-1 and thus the direct interaction of GATA-1 and FOG-1 as a
      mechanism to control the transition between expansion of multipotential
      progenitor cell populations and final stages of erythroid maturation.

PMID- 15037633
TI  - Identification of a G protein-coupled receptor specifically responsive to beta
      alanine.
AB  - We isolated a cDNA encoding an orphan G protein-coupled receptor, TGR7, which has
      been recently reported to correspond to MrgD. To search for ligands for TGR7, we
      screened a series of small molecule compounds by detecting the Ca2+ influx in
      Chinese hamster ovary cells expressing TGR7. Through this screening, we found
      that beta-alanine at micromolar doses specifically evoked Ca2+ influx in cells
      expressing human, rat, or mouse TGR7. A structural analogue, gamma-aminobutyric
      acid, weakly stimulated cells expressing human or rat TGR7, but another analogue,
      glycine, did not. In addition, beta-alanine decreased forskolin-stimulated cAMP
      production in cells expressing TGR7, suggesting that TGR7 couples with G proteins
      Gq and Gi. In guanosine 5'-O-3-thiotriphosphate binding assays conducted using a
      membrane fraction of cells expressing TGR7, beta-alanine specifically increased
      the binding of guanosine 5'-O-3-thiotriphosphate. When a fusion protein composed
      of TGR7 and green fluorescent protein was expressed in cells, it localized at the
      plasma membrane but internalized into the cytoplasm after treatment with beta
      alanine. In addition, we found that beta-[3H]alanine more efficiently bound to
      TGR7-expressing cells than to control cells. From these results, we concluded
      that TGR7 functioned as a specific membrane receptor for beta-alanine.
      Quantitative PCR analysis revealed that TGR7 mRNA was predominantly expressed in
      the dorsal root ganglia in rats. By in situ hybridization and immunostaining, we
      confirmed that TGR7 mRNA was co-expressed in the small diameter neurons with P2X3
      and VR1, both in rat and monkey dorsal root ganglia. Our results suggest that
      TGR7 participates in the modulation of neuropathic pain.

PMID- 15037634
TI  - Activation of syntaxin 1C, an alternative splice variant of HPC-1/syntaxin 1A, by
      phorbol 12-myristate 13-acetate (PMA) suppresses glucose transport into
      astroglioma cells via the glucose transporter-1 (GLUT-1).
AB  - Syntaxin 1C is an alternative splice variant lacking the transmembrane domain of
      HPC-1/syntaxin 1A. We found previously that syntaxin 1C is expressed as a soluble
      protein in human astroglioma (T98G) cells, and syntaxin 1C expression is enhanced
      by stimulation with phorbol 12-myristate 13-acetate (PMA). However, the
      physiological function of syntaxin 1C is not known. In this study, we examined
      the relationship between syntaxin 1C and glucose transport. First, we discovered
      that glucose transporter-1 (GLUT-1) was the primary isoform in T98G cells.
      Second, we demonstrated that glucose uptake in T98G cells was suppressed
      following an increase in endogenous syntaxin 1C after stimulation with PMA, which
      did not alter the expression levels of other plasma membrane syntaxins. We
      further examined glucose uptake and intracellular localization of GLUT-1 in cells
      that overexpressed exogenous syntaxin 1C; glucose uptake via GLUT-1 was inhibited
      without affecting sodium-dependent glucose transport. The value of Vmax for the
      dose-dependent uptake of glucose was reduced in syntaxin 1C-expressing cells,
      whereas there was no change in Km. Immunofluorescence studies revealed a
      reduction in the amount of GLUT-1 in the plasma membrane in cells that expressed
      syntaxin 1C. Based on these results, we postulate that syntaxin 1C regulates
      glucose transport in astroglioma cells by changing the intracellular trafficking
      of GLUT-1. This is the first report to indicate that a syntaxin isoform that
      lacks a transmembrane domain can regulate the intracellular transport of a plasma
      membrane protein.

PMID- 15037637
TI  - Transition in organ function during the evolution of air-breathing; insights from
      Arapaima gigas, an obligate air-breathing teleost from the Amazon.
AB  - The transition from aquatic to aerial respiration is associated with dramatic
      physiological changes in relation to gas exchange, ion regulation, acid-base
      balance and nitrogenous waste excretion. Arapaima gigas is one of the most
      obligate extant air-breathing fishes, representing a remarkable model system to
      investigate (1) how the transition from aquatic to aerial respiration affects
      gill design and (2) the relocation of physiological processes from the gills to
      the kidney during the evolution of air-breathing. Arapaima gigas undergoes a
      transition from water- to air-breathing during development, resulting in striking
      changes in gill morphology. In small fish (10 g), the gills are qualitatively
      similar in appearance to another closely related water-breathing fish
      (Osteoglossum bicirrhosum); however, as fish grow (100-1000 g), the inter
      lamellar spaces become filled with cells, including mitochondria-rich (MR) cells,
      leaving only column-shaped filaments. At this stage, there is a high density of
      MR cells and strong immunolocalization of Na(+)/K(+)-ATPase along the outer cell
      layer of the gill filament. Despite the greatly reduced overall gill surface
      area, which is typical of obligate air-breathing fish, the gills may remain an
      important site for ionoregulation and acid-base regulation. The kidney is greatly
      enlarged in A. gigas relative to that in O. bicirrhosum and may comprise a
      significant pathway for nitrogenous waste excretion. Quantification of the
      physiological role of the gill and the kidney in A. gigas during development and
      in adults will yield important insights into developmental physiology and the
      evolution of air-breathing.

PMID- 15037635
TI  - Adipocyte determination- and differentiation-dependent factor 1/sterol regulatory
      element-binding protein 1c regulates mouse adiponectin expression.
AB  - Adiponectin is exclusively expressed in differentiated adipocytes and plays an
      important role in regulating energy homeostasis, including the glucose and lipid
      metabolism associated with increased insulin sensitivity. However, the control of
      adiponectin gene expression in adipocytes is poorly understood. We show here that
      levels of adiponectin mRNA and protein are reduced in the white adipose tissue of
      ob/ob and db/db mice and that there is a concomitant reduction of the adipocyte
      determination- and differentiation-dependent factor 1 (ADD1)/sterol regulatory
      element-binding protein 1c (SREBP1c) transcription factor. To determine whether
      ADD1/SREBP1c regulates adiponectin gene expression, we isolated and characterized
      the mouse adiponectin promoter. Analysis of the adiponectin promoter revealed
      putative binding sites for the adipogenic transcription factors ADD1/SREBP1c,
      peroxisomal proliferator-activated receptor gamma and CCAAT enhancer-binding
      proteins. DNase I footprinting and chromatin immunoprecipitation analyses
      revealed that ADD1/SREBP1c binds in vitro and in vivo to the proximal promoter
      containing sterol regulatory element (SRE) motifs. A luciferase reporter
      containing the promoter was transactivated by ADD1/SREBP1c, and introduction of
      SRE mutations into the construct abolished transactivation. Adenoviral
      overexpression of ADD1/SREBP1c also elevated adiponectin mRNA and protein levels
      in 3T3-L1 adipocytes. Furthermore, insulin stimulated adiponectin mRNA expression
      in adipocytes and augmented transactivation of the adiponectin promoter by
      ADD1/SREBP1c. Taken together, these data indicate that ADD1/SREBP1c controls
      adiponectin gene expression in differentiated adipocytes.

PMID- 15037638
TI  - The mechanism of sodium chloride uptake in hyperregulating aquatic animals.
AB  - The emphasis in this review will be on Na(+) absorption across the skin and gills
      of vertebrates and the gills of crustaceans. However, some recent studies of Cl(
      ) uptake, especially in crustaceans, will also be described.

PMID- 15037639
TI  - The crayfish Procambarus clarkii CRY shows daily and circadian variation.
AB  - The circadian rhythms of crayfish are entrained by blue light, through putative
      extra retinal photoreceptors. We investigated the presence and daily variation of
      CRY, a protein photosensitive to blue light spectra and ubiquitous in animals and
      plants, in the putative pacemakers of Procambarus clarkii, namely the eyestalk
      and brain, at different times of the 24 h light:dark cycles. Using different
      experimental light protocols and by means of qualitative/quantitative
      immunofluorescence anatomical and biochemical methods, we identified CRY
      immunoreactivity in cells located in the medulla-terminalis-hemiellipsoidal
      complex (MT-HB) and the anterior margin of the median protocerebrum (PR). The
      immunoreaction varied with the time of day and the two neural structures showed a
      semi-mirror image. The results of the biochemical analysis matched these
      variations. Western blotting demonstrated statistically significant circadian
      rhythms in brain CRY abundance, but no daily circadian CRY abundance oscillations
      in the eyestalk. These immunocytochemical and biochemical results link a specific
      photoreceptor molecule to circadian rhythmicity. We propose that CRY may be
      linked to the photoreception of the clock and to the generation of circadian
      rhythmicity.

PMID- 15037641
TI  - The cardiovascular responses of the freshwater turtle Trachemys scripta to
      warming and cooling.
AB  - Seven freshwater turtles Trachemys scripta were instrumented with flow probes and
      cannulated for blood pressure measurements. The turtles were warmed from 24 to 34
      degrees C, and cooled down to 24 degrees C, with and without atropine. Animals
      exhibited a hysteresis of heart rate and blood flow to both the pulmonary and
      systemic circulations, which was not cholinergically mediated. Blood pressure
      remained constant during both warming and cooling, while systemic resistance
      decreased during heating and increased during cooling, indicating a barostatic
      response. There was a large right-to-left (R-L) shunt during warming and cooling
      in untreated animals, which remained relatively constant. Atropinisation resulted
      in a large L-R shunt, which decreased during warming and increased during
      cooling. Nevertheless, heating rates were the same in untreated and atropinised
      animals, and cooling rates were significantly longer in atropinised animals,
      indicating that shunt patterns contribute little to heat exchange.

PMID- 15037640
TI  - Interactions between zooplankton feeding, photosynthesis and skeletal growth in
      the scleractinian coral Stylophora pistillata.
AB  - We investigated the effect of zooplankton feeding on tissue and skeletal growth
      of the scleractinian coral Stylophora pistillata. Microcolonies were divided into
      two groups: starved corals (SC), which were not fed during the experiment, and
      fed corals (FC), which were abundantly fed with Artemia salina nauplii and
      freshly collected zooplankton. Changes in tissue growth, photosynthesis and
      calcification rates were measured after 3 and 8 weeks of incubation.
      Calcification is the deposition of both an organic matrix and a calcium carbonate
      layer, so we measured the effect of feeding on both these parameters, using
      incorporation of (14)C-aspartic acid and (45)Ca, respectively. Aspartic acid is
      one of the major components of the organic matrix in scleractinian corals. For
      both sampling times, protein concentrations were twice as high in FC than in SC
      (0.73 vs 0.42 mg P(-1) cm(-2) skeleton) and chlorophyll c(2) concentrations were
      3-4 times higher in fed corals (2.1+/-0.3 micro g cm(-2)). Cell specific density
      (CSD), which corresponds to the number of algal cells inside a host cell, was
      also significantly higher in FC (1.416+/-0.028) than in SC (1.316+/-0.015). Fed
      corals therefore displayed a higher rate of photosynthesis per unit area
      (P(g)(max)= 570+/-60 nmol O(2) cm(-2) h(-1) and I(k)=403+/-27 micro mol photons
      m(-2) s(-1)). After 8 weeks, both light and dark calcification rates were twofold
      greater in FC (3323+/-508 and 416+/-58 nmol Ca(2+) 2 h(-1) g(-1) dry skeletal
      mass) compared to SC (1560+/-217 and 225+/-35 nmol Ca(2+) 2 h(-1) g(-1) dry
      skeletal mass, respectively, under light and dark conditions). Aspartic acid
      incorporation rates were also significantly higher in FC (10.44+/-0.69 and 1.36+/
      0.26%RAV 2 h(-1) g(-1) dry skeletal mass, where RAV is total radioactivity
      initially present in the external medium) than in SC (6.51+/-0.45 and 0.44+/
      0.02%RAV 2 h(-1) g(-1) dry skeletal mass under dark and light conditions,
      respectively). Rates of dark aspartic acid incorporation were lower than the
      rates measured in the light. Our results suggest that the increase in the rates
      of calcification in fed corals might be induced by a feeding-stimulation of
      organic matrix synthesis.

PMID- 15037642
TI  - Immunohistochemical localization of Papilio RBP in the eye of butterflies.
AB  - We recently identified a novel retinoid binding protein, Papilio RBP, in the
      soluble fraction of the eye homogenate of the butterfly Papilio xuthus, and
      demonstrated that the protein is involved in the visual cycle. We now have
      localized the protein in the Papilio eye by light and electron microscopic
      immunohistochemistry using a monospecific antiserum produced against artificially
      expressed Papilio RBP. We found strong immunoreactivity in the primary as well as
      secondary pigment cells and in the tracheal cells. The pigment cells have long
      been regarded as an important site of the visual cycle, and this view is further
      supported by the present result. Interestingly, the cytoplasm and nuclei of these
      cells were equally labeled, indicating that the protein exists in both the
      cytoplasm and the nucleus. We conducted a survey for the existence of the Papilio
      RBP-like proteins in other insects including several species of butterflies,
      dragonflies, cicadas, grasshoppers and honeybees. Anti-Papilio RBP
      immunoreactivity was confirmed in the proteins isolated only from butterflies
      belonging to the superfamily Papilionoidea and not from other species. In all
      insects tested, however, fluorescing proteins were clearly detected, suggesting
      that these insects also have similar retinol-binding proteins.

PMID- 15037643
TI  - Ventricular diastolic filling characteristics in stage-24 chick embryos after
      extra-embryonic venous obstruction.
AB  - Alteration of extra-embryonic venous blood flow in stage-17 chick embryos results
      in well-defined cardiovascular malformations. We hypothesize that the decreased
      dorsal aortic blood volume flow observed after venous obstruction results in
      altered ventricular diastolic function in stage-24 chick embryos. A microclip was
      placed at the right lateral vitelline vein in a stage-17 (52-64 h of incubation)
      chick embryo. At stage 24 (4.5 days of incubation), we measured simultaneously
      dorsal aortic and atrioventricular blood flow velocities with a 20-MHz pulsed
      Doppler velocity meter. The fraction of passive and active filling was integrated
      and multiplied by dorsal aortic blood flow to obtain the relative passive and
      active ventricular filling volumes. Data were summarized as means +/- S.E.M. and
      analyzed by t-test. At similar cycle lengths ranging from 557 ms to 635 ms
      (P>0.60), dorsal aortic blood flow and stroke volume measured in the dorsal aorta
      were similar in stage-24 clipped and normal embryos. Passive filling volume
      (0.07+/-0.01 mm(3)) was decreased, and active filling volume (0.40+/-0.02 mm(3))
      was increased in the clipped embryo when compared with the normal embryo (0.15+/
      0.01 mm(3), 0.30+/-0.01 mm(3), respectively) (P<0.003). In the clipped embryos,
      the passive/active ratio was decreased compared with that in normal embryos
      (P<0.001). Ventricular filling components changed after partially obstructing the
      extra-embryonic venous circulation. These results suggest that material
      properties of the embryonic ventricle are modified after temporarily reduced
      hemodynamic load.

PMID- 15037644
TI  - Resetting the path integrator: a basic condition for route-based navigation.
AB  - During short excursions away from home, some mammals are known to update their
      position with respect to their point of departure through path integration (dead
      reckoning) by processing internal (idiothetic) signals generated by rotations and
      translations. Path integration (PI) is a continuously ongoing process in which
      errors accumulate. To remain functional over longer excursions, PI needs to be
      reset through position information from stable external references. We tested the
      homing behaviour of golden hamsters (Mesocricetus auratus W.) during hoarding
      excursions following a rotation of the arena and nest. In continuous darkness,
      the hamsters returned to their point of departure at the rotated nest, and
      therefore depended on PI only. In other trials, the animals were briefly
      presented with visual room cues during or at the end of the outward trip, visual
      cues being pitted by 67 degrees or 98 degrees against the animal's current self
      generated position vector. After a fix, the animals headed for the usual
      (unrotated) nest location, as defined by room cues, independent of the timing of
      the fix. These results were obtained in two different geometrical settings and
      showed that, after the fix, the animals update their position, and not merely
      their head direction or internal compass, in a new reference frame. Thus,
      episodic fixes on familiar external references reset the PI and therefore greatly
      enhance the functional signification of navigation that is based on feedback
      information from locomotion.

PMID- 15037645
TI  - On the nature of pre-freeze mortality in insects: water balance, ion homeostasis
      and energy charge in the adults of Pyrrhocoris apterus.
AB  - Three acclimation groups [i.e. non-diapause (LD), diapause (SD) and diapause,
      cold-acclimated (SDA)] of the adult bugs Pyrrhocoris apterus differed markedly in
      their levels of chill tolerance. Survival time at a sub-zero, but non-freezing,
      temperature of -5 degrees C (Lt50) extended from 7.6 days, through 35.6 days, to
      >60 days in the LD, SD and SDA insects, respectively. The time necessary for
      recovery after chill-coma increased linearly with the increasing time of exposure
      to -5 degrees C, and the steepness of the slope of linear regression decreased in
      the order LD>SD>SDA. The capacity to prevent/counteract leakage of Na(+) down the
      electrochemical gradient (from haemolymph to tissues) during the exposure to -5
      degrees C increased in the order LD<SD<SDA. As a result, the rates of
      counteractive outward movement of K(+), and of the E(K) dissipation, decreased in
      the same order. The least chill-tolerant insects (LD) showed the highest rate of
      body-water loss. Most of the water was lost from the haemolymph compartment. The
      ability to regulate a certain fraction of ion pools into the hindgut fluid was
      the highest in the SDA group, medium in the SD group and missing in the LD group.
      The adenylate energy charge in the fat body cells was constant in all three
      groups. The total pools of ATP, ADP and AMP, however, decreased in the SD and SDA
      groups but remained constant in the LD group. The inability of insects to
      maintain ion gradients at sub-zero temperature is discussed as an important cause
      of pre-freeze mortality.

PMID- 15037646
TI  - In vitro delayed senescence of extirpated buds from zooids of the colonial
      tunicate Botryllus schlosseri.
AB  - In the colonial growth of botryllid ascidians, blastogenesis (bud formation) is a
      cyclical and synchronized developmental process characterized by a weekly rhythm
      of budding and apoptotic events. Very little is known about this cycle regulation
      and its control. In this study, the in vitro fate of developing buds and
      regressing zooids extirpated from Botryllus schlosseri colonies at different
      blastogenic stages were examined, revealing that stages 'B' to 'D' buds (but not
      stage 'A' buds) developed new structures under in vitro conditions. These were
      mainly spheres (up to 1 mm in diameter) and epithelial monolayers around the
      attached buds. We also found that: (1) when attached spheres and epithelial
      monolayers appeared, the life expectancy of an isolated bud in vitro reached 50
      60 days, five times the life expectancy of intact, in vivo developing zooids; (2)
      the life expectancy of in vitro buds that remained unattached to the substrates
      was at least 150 days; (3) after attaching to the substrates, buds obeyed a newly
      imposed developmental clock dictating up to 35 survival days for spheres and up
      to 14 days for epithelial monolayers; (4) the prevailing mode of death in vitro
      was necrotic, in contrast to the apoptotic mode of zooidal deterioration at the
      takeover phase of blastogenesis; (5) under in vitro conditions, degenerating
      zooids surprisingly produced epithelial monolayers within 3 weeks of culturing.
      Monolayers survived for up to 10 additional days, extending the lifespan of the
      degenerating zooids from a few hours to up to 1 month. We conclude that under in
      vitro conditions, not only are the underlying colonial growth mechanisms replaced
      by different developmental pathways, but also the internal colonial-level clocks
      programming death, are replaced by a new biological mechanism with different
      timetables.

PMID- 15037648
TI  - Acclimation to hypothermic incubation in developing chicken embryos (Gallus
      domesticus): I. Developmental effects and chronic and acute metabolic
      adjustments.
AB  - Chronic exposure to a low incubation temperature clearly slows the development of
      poikilothemic chicken embryos (or any other poikilotherms), but little is known
      about the more subtle developmental effects of temperature, especially on
      physiological regulatory systems. Consequently, two populations of chicken
      embryos were incubated at 38 degrees C and 35 degrees C. When compared at the
      same development stage, incubation temperature had no significant impact on
      embryonic survival or growth. Moreover, the relative timing of major
      developmental landmarks (e.g. internal pipping), expressed as a percentage of
      development, was unaffected by temperature. The ability to maintain the rate of
      oxygen consumption ((O(2))) during an acute drop in ambient temperature (T(a))
      improved from Hamburger-Hamilton (HH) stages 39-40 to 43-44 in the 38 degrees C
      but not the 35 degrees C populations. Late stage (HH43-44) embryos incubated at
      38 degrees C could maintain (O(2)) (approximately 27-33 micro l g(-1) min(-1))
      during an acute drop in T(a) to approximately 30 degrees C. However, at the same
      stage 35 degrees C embryos acutely measured at 38 degrees C were unable to
      similarly maintain their (O(2)), which fell as soon as T(a) reached 36 degrees C.
      Thus, while hypothermic incubation does not affect gross development (other than
      would be predicted from a simple effect of Q(10)), there is a significant delay
      in the relative timing of the onset of thermoregulatory ability induced by
      hypothermic incubation.

PMID- 15037647
TI  - beta-naphthoflavone induction of CYP1A in brain of juvenile lake trout
      (Salvelinus namaycush Walbaum).
AB  - Many environmental pollutants induce expression of the cytochrome P450 (CYP) 1A
      subfamily of genes. We integrated cellular and molecular biological techniques to
      examine the effects of beta-naphthoflavone (BNF) exposure in lake trout brain
      CYP1A distribution and dynamics. Over a 32-day time-course, real time
      quantitative reverse transcription polymerase chain reaction (Q-RT-PCR) results
      showed that CYP1A mRNA induction in response to BNF exposure occurred rapidly and
      continued to rise in the BNF-treated lake trout after 4 h, with a peak at or
      after 2 days. Messenger RNA levels fell after 4 days, and this trend continued
      after 16 days of exposure. In situ hybridization indicated that CYP1A mRNA was
      universally elevated in the brain of BNF-exposed fish and was mainly expressed in
      the endothelia and occasionally in the glial cells. CYP1A immunoreactivity was
      induced in the olfactory bulb and valvula cerebelli of BNF-treated fish. Other
      brain areas showed constitutive CYP1A immunoreactivity in both control and BNF
      treated fish. Some BNF-treated fish contained multifocal hemorrhages in the brain
      tissue, and these fish had overall depressed CYP1A immunoreactivity in the brain.
      The relationship between transcriptional and translational effects of BNF
      exposure in the brain of juvenile lake trout is discussed.

PMID- 15037649
TI  - Acclimation to hypothermic incubation in developing chicken embryos (Gallus
      domesticus): II. Hematology and blood O2 transport.
AB  - Hypothermic incubation reduces the ability of the late-stage chicken embryo to
      mount endothermic heat production. This study investigates whether blood O(2)
      transport is similarly limited by cooler incubation temperatures. Two populations
      of chicken embryos were incubated at 38 degrees C and 35 degrees C. At Hamilton
      Hamburger (HH) developmental stage 41-42, hypothermic incubation had no
      significant effect on hematocrit ( approximately 26%) or [Hb] (7 g%). However, in
      the final stages of incubation (stage 43-44), hypothermic incubation reduced
      hematocrit from approximately 31% at 38 degrees C to approximately 27.5% at 35
      degrees C. Hypothermic incubation similarly caused a reduced [Hb] from 8.5 g% (38
      degrees C) to 6.25 g% (35 degrees C), indicating a reduction in blood O(2)
      carrying capacity in embryos. Incubation temperature had a strong effect on blood
      O(2) affinity in late development (stage 43-44), with P(50) at 38 degrees C
      falling significantly from approximately 6 kPa in 38 degrees C embryos to
      approximately 4 kPa in 35 degrees C embryos. P(O(2)) values in chorioallantoic
      arterial blood at HH 41-42 were 4.3 kPa at pH 7.46 (38 degrees C) and 3.4 kPa at
      pH 7.39 (35 degrees C). In chorioallantoic venous blood these values were 9.1 kPa
      at pH 7.34 (38 degrees C) and 8.1 kPa at pH 7.42 (35 degrees C). With further
      development to HH 43-44, chorioallantoic arterial blood oxygenation fell to 2.4
      kPa at pH 7.54 (38 degrees C) and 2.8 kPa at pH 7.52 (35 degrees C). Similarly,
      P(O(2)) in chorioallantoic venous blood fell slightly to 7.7 kPa at pH 7.42 (38
      degrees C) and 7.4 kPa at pH 7.48 (35 degrees C). Collectively, these data reveal
      that beyond HH 41-42, 35 degrees C embryos experience retarded hematological
      development, and the findings that support the observed delayed metabolic
      response to acute temperature changes.

PMID- 15037650
TI  - Locomotory behaviour and post-exercise physiology in relation to swimming speed,
      gait transition and metabolism in free-swimming smallmouth bass (Micropterus
      dolomieu).
AB  - We examined swimming behaviour, gait recruitment and post-exercise muscle
      glycogen, muscle lactate, plasma lactate and oxygen consumption in smallmouth
      bass (Micropterus dolomieu; 24-38 cm fork length) that voluntarily ascended a 25
      m raceway against water velocities ranging from 40 to 120 cm s(-1). Physiological
      parameters were referenced to additional measurements made following exhaustive
      exercise in a static tank and aerobic exercise in a swim tunnel. Maximum speeds
      maintained exclusively using a steady gait in the raceway ranged from 53.6 to
      97.3 cm s(-1) and scaled positively with fish length. Minimum swimming speeds
      maintained exclusively through recruitment of an unsteady gait were also
      positively correlated to fish length and ranged from 81.4 to 122.9 cm s(-1). Fish
      switched between steady and unsteady swimming at intermediate speeds. Smallmouth
      bass always maintained a positive ground speed in the raceway; however, those
      that primarily swam using a steady gait to overcome low to moderate water
      velocities (20-50 cm s(-1)) maintained mean ground speeds of approximately 20 cm
      s(-1). By contrast, mean ground speeds of fish that primarily recruited an
      unsteady locomotory gait increased significantly with water velocity, which
      resulted in an inverse relationship between exercise intensity and duration. We
      interpret this behaviour as evidence that unsteady swimming was being fuelled by
      the limited supply of anaerobic substrates in the white muscle. This hypothesis
      is supported by the fact that unsteady swimming fish showed significantly lower
      muscle glycogen levels, higher lactate concentrations (muscle and plasma) and
      higher post-exercise oxygen consumption rates compared with fish that used a
      steady gait. The reduction in passage time achieved by fish using an unsteady
      gait allowed them to ascend the raceway with relatively minor post-exercise
      metabolic imbalances, relative to individuals chased to exhaustion.

PMID- 15037651
TI  - On the scaling of mammalian long bones.
AB  - Although there is much data available on mammalian long-bone allometry, a theory
      explaining these data is still lacking. We show that bending and axial
      compression are the relevant loading modes and elucidate why the elastic
      similarity model failed to explain the experimental data. Our analysis provides
      scaling relations connecting bone diameter and length to the axial and transverse
      components of the force, in good agreement with experimental data. The model also
      accounts for other important features of long-bone allometry.

PMID- 15037652
TI  - The hydrodynamic trails of Lepomis gibbosus (Centrarchidae), Colomesus psittacus
      (Tetraodontidae) and Thysochromis ansorgii (Cichlidae) investigated with scanning
      particle image velocimetry.
AB  - The hydrodynamic trails of fish belonging to the families Centrarchidae,
      Tetraodontidae and Cichlidae were investigated. Water movements were measured in
      six horizontal planes, spaced 10-12 mm apart, for up to 5 min after the passage
      of a fish, using a computer controlled array of modulated laser diodes. We
      measured continuously and non-continuously swimming fish. Water velocities
      decayed rapidly in the leading seconds after the passage of a fish, but could
      still be measured for a period considerably longer than that. In still water
      (median water velocity <0.5 mm s(-1)), the hydrodynamic trails of Lepomis
      gibbosus lasted for more than 5 min. The trails of Colomesus psittacus and
      Thysochromis ansorgii could be detected for more than 30 s and more than 3 min,
      respectively. The water disturbance left behind by these fish was sufficient to
      be sensed by a piscivorous predator at a distance where vision or hearing
      frequently fail. Acoustic stimuli estimated from a dipole model in a distance
      that would be covered by the tested fish in 1 min (4-25 m) were 1.5 x 10(-7) to
      3.1 x 10(-10) m s(-2), while the hearing threshold of a perch is three orders of
      magnitude above that. By contrast, the fish wakes after 1 min (except for one
      Colomesus wake) contained water velocities between 0.95 and 2.05 mm s(-1), which
      are within the detection range of hydrodynamic sensory systems. The three species
      differed with respect to water velocities, the spatial extent of the fish
      generated water disturbances and the structure of the wake.

PMID- 15037653
TI  - Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors.
AB  - Bone Morphogenetic Protein-2 (BMP-2) is highly overexpressed in the majority of
      patient-derived lung carcinomas. However, a mechanism revealing its role in
      cancer has not been established. Here we report that BMP-2 enhances the
      neovascularization of developing tumors. Recombinant BMP-2 stimulated blood
      vessel formation in tumors formed from A549 cells injected s.c. into thymic nude
      mice. Recombinant BMP-2 also enhanced angiogenesis in Matrigel plugs containing
      A549 cells in nude mice. The BMP-2 antagonist noggin abrogated BMP-2-induced
      angiogenic response. Furthermore, antisense transfection of BMP-2 cDNA resulted
      in a decrease in blood vessel formation in the Matrigel assays. BMP-2 induced
      tube formation in both human aortic endothelial cells (HAEC) and umbilical vein
      endothelial cells. BMP-2 also stimulated proliferation of HAEC. The ability of
      BMP-2 to activate endothelial cells was further demonstrated by its ability to
      phosphorylate Smad 1/5/8 and ERK-1/2 and to increase expression of Id1. This
      study reveals that BMP-2 enhanced the angiogenic response in developing tumors.
      Furthermore, these data suggest that BMP-2 stimulation of angiogenesis may
      involve the activation of endothelial cells.

PMID- 15037654
TI  - Thombospondin-1 disrupts estrogen-induced endothelial cell proliferation and
      migration and its expression is suppressed by estradiol.
AB  - The natural hormone 17beta-estradiol (17beta-E2) is known to induce tumor
      angiogenesis in various target organs by activating positive regulators of
      angiogenesis. In this study, we show for the first time that in human umbilical
      vein endothelial cells (HUVECs), 17beta-E2 transiently down-regulates the
      expression and secretion of a potent negative regulator of angiogenesis,
      thrombospondin-1 (TSP-1). This inhibitory effect of 17beta-E2 is mediated through
      nongenomic estrogen receptor (ER)/mitogen-activated protein kinase
      (MAPK)/extracellular-regulated kinase (ERK) 1/2 and c-Jun NH(2)-terminal kinase
      (JNK)/stress-activated protein kinase (SAPK) signaling pathways, because this
      effect can be abolished by a pure ER antagonist (ICI 182,780) and inhibitors of
      downstream signaling proteins of MAPK signaling cascades, including MAPK kinase
      1/2 and ERK1/2 inhibitor and JNK/SAPK inhibitor. To understand the functional
      role(s) of TSP-1 during estradiol-induced angiogenesis, we examined the growth
      and migration of endothelial cells in different experimental environments. Using
      a recombinant protein, we show that increments of TSP-1 protein concentration in
      culture medium significantly reduce the migration and proliferation of HUVECs
      stimulated by 17beta-E2. Together, these studies suggest that TSP-1 can be
      considered an important negative factor in understanding the increased
      angiogenesis in response to estrogens.

PMID- 15037655
TI  - Mitotic aberration coupled with centrosome amplification is induced by hepatitis
      B virus X oncoprotein via the Ras-mitogen-activated protein/extracellular signal
      regulated kinase-mitogen-activated protein pathway.
AB  - Multinucleated cells have been noted in pathophysiological states of the liver
      including infection with hepatitis B virus (HBV), the status of which is also
      closely associated with genomic instability in liver cancer. Here, we showed that
      hepatitis B virus X oncoprotein (HBx) expression in Chang cells results in a
      multinuclear phenotype and an abnormal number of centrosomes (n >or=3).
      Regulation of centrosome duplication in HBx-expressing ChangX-34 cells was
      defective and uncoupled from the cell cycle. HBx induced amplification of
      centrosomes, multipolar spindle formation, and chromosomal missegregation during
      mitosis and subsequently increased the generation of multinucleated cells and
      micronuclei formation. Treatment with PD98059, a mitogen-activated
      protein/extracellular signal-regulated kinase (MEK) 1/2 inhibitor, significantly
      reduced the number of cells with hyperamplified centrosomes and decreased the
      multinucleated cells and micronuclei formation. Consistently, the phospho-ERK
      level during cell progression was substantially higher in ChangX-34 cells than
      that of Chang cells. In contrast, neither wortmannin, an inhibitor of
      phosphoinositide-3 kinase, nor SB203589, an inhibitor of p38 mitogen-activated
      protein kinase (MAPK), showed any effects. Introduction of Ras dominant-negative
      (D/N) and MEK2 D/N genes into ChangX-34 cells significantly alleviated centrosome
      amplification, whereas introduction of the PKC D/N and PKB D/N genes did not.
      Thus, our results demonstrate that the HBx induced centrosome hyperamplification
      and mitotic aberration by activation of the Ras-MEK-MAPK. Intervention of this
      signaling pathway could suppress the centrosome amplification as well as mitotic
      aberration. These findings may provide a possible mechanism by which HBx promotes
      phenotypic progression by predisposing chromosomal alteration in HBV-infected
      liver.

PMID- 15037656
TI  - The interaction of specific peptide aptamers with the DNA binding domain and the
      dimerization domain of the transcription factor Stat3 inhibits transactivation
      and induces apoptosis in tumor cells.
AB  - The transcription factor signal transducer and activator of transcription (Stat)
      3 is activated through the interleukin-6 family of cytokines and by binding of
      growth factors to the epidermal growth factor (EGF) receptor. It plays an
      essential role in embryonic development and assumes specialized tasks in many
      differentiated tissues. Constitutively activated Stat3 has been found in tumor
      cell lines and primary tumors and plays a crucial role in tumor cell survival and
      proliferation. To inhibit the oncogenic action of Stat3 in tumor cells, we have
      selected short peptides, so-called peptide aptamers, which specifically interact
      with defined functional domains of this transcription factor. The peptide
      aptamers were selected from a peptide library of high complexity by an adaptation
      of the yeast two-hybrid procedure. Peptide aptamers specifically interacting with
      the Stat3 dimerization domain caused inhibition of DNA binding activity and
      suppression of transactivation by Stat3 in EGF-responsive cells. Similarly, a
      peptide aptamer selected for its ability to recognize the Stat3 DNA binding
      domain inhibited DNA binding and transactivation by Stat3 following EGF
      stimulation of cells. Peptide aptamers were expressed in bacteria as fusion
      proteins with a protein transduction domain and introduced into human myeloma
      cells. This resulted in dose-dependent growth inhibition, down-regulation of Bcl
      x(L) expression, and induction of apoptosis. The inhibition of Stat3 functions
      through the interaction with peptide aptamers counteracts the transformed
      phenotype and could become useful in targeted tumor therapy.

PMID- 15037657
TI  - Cystatin C antagonizes transforming growth factor beta signaling in normal and
      cancer cells.
AB  - Cystatin C (CystC) is a secreted cysteine protease inhibitor that regulates bone
      resorption, neutrophil chemotaxis, and tissue inflammation, as well as resistance
      to bacterial and viral infections. CystC is ubiquitously expressed and present in
      most bodily fluids where it inhibits the activities of cathepsins, a family of
      cysteine proteases that can promote cancer cell invasion and metastasis.
      Transforming growth factor beta (TGF-beta) is a multifunctional cytokine endowed
      with both tumor-suppressing and tumor-promoting activities. We show herein that
      TGF-beta treatment up-regulated CystC transcript and protein in murine 3T3-L1
      fibroblasts. Moreover, CystC mRNA expression was down-regulated in approximately
      50% of human malignancies, particularly cancers of the stomach, uterus, colon,
      and kidney. Overexpression of CystC in human HT1080 fibrosarcoma cells
      antagonized their invasion through synthetic basement membranes in part via a
      cathepsin-dependent pathway. Independent of effects on cathepsin activity, CystC
      also reduced HT1080 cell gene expression stimulated by TGF-beta. Invasion of 3T3
      L1 cells occurred through both cathepsin- and TGF-beta-dependent pathways. Both
      pathways were blocked by CystC, but only the TGF-beta-dependent pathway was
      blocked by a CystC mutant (i.e., delta14CystC) that is impaired in its ability to
      inhibit cathepsin activity. Moreover, CystC and delta14CystC both inhibited 3T3
      L1 cell gene expression stimulated by TGF-beta. We further show that CystC
      antagonized TGF-beta binding to its cell surface receptors, doing so by
      interacting physically with the TGF-beta type II receptor and antagonizing its
      binding of TGF-beta. Collectively, our findings have identified CystC as a novel
      TGF-beta receptor antagonist, as well as a novel CystC-mediated feedback loop
      that inhibits TGF-beta signaling.

PMID- 15037658
TI  - A simple epigenetic method for the diagnosis and classification of brain tumors.
AB  - The new, simple, and reliable method for the diagnosis of brain tumors is
      described. It is based on a TLC quantitative determination of 5-methylcytosine
      (m(5)C) in relation to its damage products of DNA from tumor tissue. Currently,
      there is evidence that oxidative stress through reactive oxygen species (ROS)
      plays an important role in the etiology and progression of several human
      diseases. Oxidative damage of DNA, lipids, and proteins is deleterious for the
      cell. m(5)C, along with other basic components of DNA, is the target for ROS,
      which results in the appearance of new modified nucleic acid bases. If so, m(5)C
      residue constitutes a mutational hotspot position, whether it occurs within a
      nucleotide sequence of a structural gene or a regulatory region. Here, we show
      the results of the analysis of 82 DNA samples taken from brain tumor tissues. DNA
      was isolated and hydrolyzed into nucleotides, which, after labeling with [gamma
      (32)P]ATP, were separated on TLC. Chromatograms were evaluated using
      PhosphorImager and the amounts of 5-methyldeoxycytosine (m(5)dC) were calculated
      as a ratio (R) of m(5)dC to m(5)dC + deoxycytosine + deoxythymidine spot
      intensities. The R value could not only be a good diagnostic marker for brain
      tumors but also a factor differentiating low-grade and high-grade gliomas.
      Therefore, DNA methylation pattern might be a useful tool to give a primary
      diagnosis of a brain tumor or as a marker for the early detection of the relapse
      of the disease. This method has several advantages over those existing nowadays.

PMID- 15037659
TI  - Pronounced instability of tandem IU base pairs in RNA.
AB  - Optical melting was used to determine the stabilities of three series of RNA
      oligomers containing tandem XU base pairs, GGCXUGCC (5'XU3'), GGCUXGCC (5'UX3')
      and GGCXXGGC/CCGUUCCG (5'XX3'), where X is either A, G or I (inosine). The
      helices containing tandem AU base pairs were the most stable in the first two
      series (5'XU3' and 5'UX3'), with an average melting temperature approximately 11
      degrees C higher than the helices with tandem 5'GU3' base pairs and 25 degrees C
      higher than the helices with tandem 5'IU3' base pairs. For the third series
      (5'XX3'), the helix containing tandem GG is the most stable, with an average
      melting temperature approximately 2 degrees C higher than the helix with tandem
      AA base pairs and approximately 24 degrees C higher than the helix with tandem II
      base pairs. The thermodynamic stability of the oligomers with tandem IU base
      pairs was also investigated as a function of magnesium ion concentration. As with
      normal A-U or G-U tandem duplexes, the data could best be interpreted as non
      specific binding of magnesium ions to the inosine-containing RNA
      oligonucleotides.

PMID- 15037660
TI  - A conformational change in TFIIB is required for activator-mediated assembly of
      the preinitiation complex.
AB  - TFIIB plays a pivotal role during assembly of the RNA polymerase II transcription
      preinitiation complex. TFIIB is composed of two domains that engage in an
      intramolecular interaction that can be disrupted by the VP16 activation domain.
      In this study, we describe a novel human TFIIB derivative harbouring two point
      mutations in the highly conserved N-terminal charged cluster domain. This mutant,
      TFIIB R53E:R66E, exhibits an enhanced affinity in its intramolecular interaction
      when compared with wild-type TFIIB. Consistent with this, the mutant displays a
      significantly reduced affinity for VP16. However, its ability to complex with
      TATA-binding protein at a model promoter is equivalent to that of wild-type
      TFIIB. Furthermore, this TFIIB derivative is able to support high order
      preinitiation complex assembly in the absence of an activator. Strikingly though,
      an activator fails to recruit the TFIIB mutant to the promoter. Taken together,
      our results show that a TFIIB conformational change is critical for the formation
      of activator-dependent transcription complexes.

PMID- 15037661
TI  - The CtBP2 co-repressor is regulated by NADH-dependent dimerization and possesses
      a novel N-terminal repression domain.
AB  - The C-terminal binding protein 2 (CtBP2) is a 48 kDa phosphoprotein reported to
      function as a co- repressor for a growing list of transcriptional repressors. It
      was recently demonstrated that CtBP is a dimeric NAD+-regulated d-isomer-specific
      2-hydroxy acid dehydrogenase. However, the specific substrate(s) of CtBP
      enzymatic activity and the relationship of this activity to its co-repression
      function remain unknown. The ability of a human CtBP to bind and serve as a co
      repressor of E1A has been shown to be regulated by nuclear NADH levels. Here we
      extend the functional characterization of CtBP by demonstrating that amino acid
      substitutions at Gly189 in the conserved NAD+-binding fold both abrogate the
      ability of CtBP2 to homodimerize and are associated with a dramatic loss of co
      repressor activity. Consistent with the known enzymatic activity of CtBP2,
      mutations at Arg272 in the substrate-binding domain and at His321 in the
      catalytic domain result in significant loss of CtBP2 transcriptional co-repressor
      activity. High resolution serial C-terminal deletion analysis of CtBP2 also
      revealed a novel N-terminal repression domain that is distinct from its
      dehydrogenase domain. Our results suggest a model in which CtBP2 co-repressor
      function is regulated, at least in part, through the effect of NADH on CtBP2
      homodimerization.

PMID- 15037662
TI  - Quantitative oligonucleotide microarray fingerprinting of Salmonella enterica
      isolates.
AB  - We report on a genome-independent microbial fingerprinting method using nucleic
      acid microarrays for microbial forensics and epidemiology applications and
      demonstrate that the microarray method provides high resolution differentiation
      between closely related microorganisms, using Salmonella enterica strains as the
      test case. In replicate trials we used a simple 192 probe nonamer array to
      construct a fingerprint library of 25 closely related Salmonella isolates.
      Controlling false discovery rate for multiple testing at alpha = 0.05, at least
      295 of 300 pairs of S.enterica isolate fingerprints were found to be
      statistically distinct using a modified Hotelling T2 test. Although most pairs of
      Salmonella fingerprints are found to be distinct, forensic applications will also
      require a protocol for library construction and reliable microbial classification
      against a fingerprint library. We outline additional steps required to produce
      such a protocol.

PMID- 15037664
TI  - Management of motor complications in Parkinson's disease.
AB  - Motor fluctuations in Parkinson's disease (PD) typically develop after 4-6 years
      of therapy, and affect approximately half of all patients. The wearing-off effect
      is the most common type, and "delayed-on," "no-on," and "on-off" effects, as well
      as dyskinesias, may also develop as the disease progresses. Collectively, motor
      fluctuations represent a significant source of disability in advanced PD
      patients, and their mitigation is a major goal of patient management. Adjunctive
      medications, including dopamine agonists, amantadine, MAO-B inhibitors, and COMT
      inhibitors, each may reduce the frequency or duration of "off" periods, but none
      does so completely, and each contributes its own side effects which may limit
      optimal dosing. Surgery is another strategy to reduce "off" time, and both
      pallidotomy and deep brain stimulation of the globus pallidus or the subthalamic
      nucleus have been shown to be highly effective in this regard. However, surgery
      may be contraindicated in elderly advanced patients who could most benefit from
      its effect on "off" time. The unmet need for treatment of "off" episodes suggests
      the potential utility of an agent such as apomorphine injectable, which can
      reliably trigger an "on" response within 10-15 minutes of injection.

PMID- 15037663
TI  - Sensitive and specific detection of K-ras mutations in colon tumors by short
      oligonucleotide mass analysis.
AB  - Short oligonucleotide mass analysis (SOMA) is a technique by which small
      sequences of mutated and wild-type DNA, produced by PCR amplification and
      restriction digestion, are characterized by HPLC-electrospray ionization tandem
      mass spectrometry. We have adapted the method to specifically detect two common
      point mutations at codon 12 of the c-K-ras gene. Mutations in DNA from 121 colon
      tumor samples were identified by SOMA and validated by comparison with
      sequencing. SOMA correctly identified 26 samples containing the 12GAT mutation
      and four samples containing the 12AGT mutation. Sequencing did not reveal mutant
      DNA in three samples out of the 26 samples shown by SOMA to contain the 12GAT
      mutation. In these three samples, the presence of mutant DNA was confirmed by
      SOMA analysis after selective PCR amplification in the presence of BstN1
      restriction enzyme. Additional mutations in codons 12 and 13 were revealed by
      sequencing in 24 additional samples, and their presence did not interfere with
      the correct identification of G to A or G to T mutations in codon 12. These
      results provide the basis for a sensitive and specific method to detect c-K-ras
      codon 12-mutated DNA at levels below 10-12% of wild-type DNA.

PMID- 15037665
TI  - Subcutaneously administered apomorphine: pharmacokinetics and metabolism.
AB  - Apomorphine is a non-narcotic morphine derivative that acts as a potent
      dopaminergic agonist. Its high first-pass hepatic metabolism prevents
      effectiveness by the oral route; instead, subcutaneous injection is the usual
      route, and intranasal, sublingual, rectal, and iontophoretic transdermal delivery
      has been investigated for the treatment of Parkinson's disease (PD). The rate of
      uptake after subcutaneous injection is influenced by factors such as location,
      temperature, depth of injection, and body fat. Studies have shown the latency of
      onset to clinical effect after s.c. injection ranged from 7.3 to 14 minutes.
      Cerebrospinal fluid T(max)lags behind plasma T(max) by 10 to 20 minutes.
      Considerable intersubject variability is found with pharmacokinetic variables; in
      some studies there are five- to tenfold differences in C(max)and area-under-the
      concentration-time-curve seen in PD patients. Apomorphine metabolism occurs
      through several enzymatic pathways, including N-demethylation, sulfation,
      glucuronidation, and catechol-O-methyltransferase as well as by nonenzymatic
      oxidation. The complexities of apomorphine uptake, distribution, and clearance
      probably contribute to its variability of clinical actions.

PMID- 15037666
TI  - Literature review: intermittent subcutaneous apomorphine therapy in Parkinson's
      disease.
AB  - Apomorphine injectable has been used in Europe for more than a decade as a rescue
      therapy for intractable "off" periods in Parkinson's disease (PD). Some studies
      were performed as early as the 1970's. This article reviews double-blind and open
      studies with apomorphine for PD prior to the year 2000. Most were performed in
      Europe. Double-blind studies with injection doses of 1-5 mg have demonstrated
      that onset of clinical benefit typically occurs within 10 minutes, and lasts for
      up to two hours. The magnitude of benefit rivals that of levodopa. Long-term,
      open-label studies have demonstrated the persistent response to apomorphine
      injectable as a rescue therapy for as long as five years. Duration of benefit and
      dose of a single injection remains the same, but a need for increased number of
      doses per day is reported in keeping with disease progression. For many patients,
      the need for concomitant domperidone administration for antiemesis wanes over
      time. Apomorphine has also been shown in smaller studies to be effective for a
      variety of non-motor "off" phenomena, including pain, panic attacks, and a
      variety of gastrointestinal symptoms. Subutaneous intermittent bolus injects are
      also useful in patients post operatively who are unable to take oral medications.

PMID- 15037667
TI  - Apomorphine: North American clinical experience.
AB  - This manuscript reviews North American clinical trials examining subcutaneous
      injection of apomorphine in Parkinson's disease (PD) patients, and the available,
      cumulative apomorphine safety data for the US. These data provide strong
      documentation concerning dosing range (2-6 mg/injection), dosing frequency (1-10
      injections/day), therapeutic response, and duration and onset of benefit. The US
      pivotal trial for subcutaneously injected apomorphine demonstrated robust and
      statistically significant benefit from drug administration when compared to
      subjects receiving placebo. Interestingly, these changes closely mirrored the
      response to levodopa in the same population, as measured by Unified Parkinson's
      Disease Rating Scale and Webster Step Seconds, and suggests that apomorphine may
      have greater potency than other agonists. A study of subjects ranging from early
      to advanced disease, conducted at the NIH, demonstrated a decline in duration of
      response and increased time to response in the advanced group when compared to
      levodopa naive subjects, despite the observation that threshold and optimal
      response dosages did not differ. Pharmacodynamic responses from a single average
      dosage administration of 4.2 mg apomorphine in several studies demonstrated a
      benefit as early as 7.5 minutes with a duration of benefit as long as 90 minutes.
      Serious adverse events occurred in 16% of the subjects in these studies with the
      most common adverse events including dyskinesias (21%), hallucinations (11%), and
      orthostatic hypotension (9%).

PMID- 15037668
TI  - Other formulations and future considerations for apomorphine for subcutaneous
      injection therapy.
AB  - This manuscript reviews apomorphine administration in formulations other than
      intermittent bolus injection, and comments on other potential uses for this
      unique compound. Continuous sc apomorphine therapy has been shown to alter peak
      dose dyskinesia thresholds in advancing patients, and in some instances may
      replace all other anti-parkinson therapies. In general continuous infusion of sc
      apomorphine at a rate of 4 mg/h is well tolerated, and has been postulated to be
      equivalent to approximately 600 mg levodopa/day. This therapy is associated with
      skin complications, particularly nodule formation, and focal panniculitis is seen
      in more than 50% of subjects. Optimal dosages for intranasal apomorphine range
      from 2 to 5 mg per inhalation with benefit seen at 7.5 minutes and duration of
      effect of 45 to 55 minutes. Side effects included nasal irritation, vestibulitis,
      dyskinesias, yawning, and nausea. Comparison of 3 mg sc and 30 mg sublingual
      apomorphine in 9 Parkinson's disease subjects in a blinded cross-over trial found
      that the time to peak benefit was beyond 40 minutes with sl apomorphine, compared
      to 21 minutes in the sc preparation. Chronic use of the sublingual formulation
      was associated with severe stomatitis in half the subjects, and markedly limited
      the treatment. Rectal administration of apomorphine has been evaluated in
      limited, usually post-operative settings. Administration of a 200 mg apomorphine
      rectal suppository resulted in an average time to benefit of 32 minutes with an
      average duration of 195 minutes. Sedation, nausea and faintness were reported as
      side effects. Although the diagnostic confirmation potential of this agent has
      been questioned, the drug may have an important role in evaluating the potential
      for benefit in the deep brain stimulation surgical setting.

PMID- 15037669
TI  - Rapid treatment of "wearing off" in Parkinson's disease.
AB  - Patients with advanced Parkinson's disease (PD) may develop a variety of motor
      complications associated with levodopa therapy. Motor fluctuations, such as early
      morning akinesia and "wearing-off," may respond to individualized medical
      management with titrated combinations of levodopa, dopamine agonists, COMT
      inhibitors and amantadine. Often with disease progression, dyskinesias and
      unpredictable, rapid "off" periods will also emerge. These motor complications
      are less amenable to traditional anti-parkinson therapy manipulation. This
      manuscript reviews approaches for "rescue" therapy in PD patients with "wearing
      off," sudden "offs," early morning akinesia, and variable response to individual
      doses of oral medications. Strategies for preparing and administering liquid
      levodopa are discussed within the context of gastric emptying, intestinal
      absorption, and active transport across the blood brain barrier. In addition
      other levodopa preparations in early development, including the orally
      administered levodopa methyl ester and the potential for a subcutaneously
      administered levodopa ethyl ester are reviewed. Furthermore, practical guidelines
      regarding the dosing, administration, use of the antiemetic trimethobenzamide
      (Tigan), time to "on," duration of benefit, and potential side effects associated
      with subcutaneously injected apomorphine are provided.

PMID- 15037670
TI  - Practical considerations in the use of apomorphine injectable.
AB  - This manuscript provides a practical summary of guidelines for institution of
      apomorphine subcutaneous injectable therapy, including patient education, pre
      treatment issues, dosage titration and side-effect care. The timing of each
      injection is crucial if an impending "off" period is to be averted. Patients need
      to be aware of symptoms of an approaching "off" period, and the injection should
      be administered at the onset or ideally, in anticipation of an "off" episode.
      Patients being considered for apomorphine treatment should undergo pre-treatment
      assessment and optimization of ongoing oral therapy prior to initiation.
      Education and counseling regarding the benefits of apomorphine can often
      alleviate this. In addition, and where available, it is beneficial to provide the
      patient and caregiver(s) with additional written information and videos provided
      by the manufacturer demonstrating the operation of the pump or pen injection
      systems. Once a patient has been assessed as being a suitable candidate for
      apomorphine, an apomorphine challenge is performed to determine responsiveness
      and guide appropriate dosing, establish an individual dose, and to observe for
      side effects, such as nausea, postural hypotension, excessive somnolence, or
      dyskinesia. Three days prior to the challenge, domperidone 20 mg tid or
      trimethobenzamide (Tigan) 300 mg tid is recommended. Potential side effects
      include yawning, dopaminergic side effects, such as dyskinesias, nausea,
      orthostatic hypotension, confusion, hallucinations, somnolence and rarely,
      hypersexuality or other behavioral disturbances, and skin nodule formation.

PMID- 15037671
TI  - Terminology and classification of the cortical dysplasias.
AB  - BACKGROUND: There have been difficulties in achieving a uniform terminology in
      the literature regarding issues of classification with respect to focal cortical
      dysplasias (FCDs) associated with epilepsy. OBJECTIVE: S: To review and refine
      the current terminology and classification issues of potential clinical relevance
      to epileptologists, neuroradiologists, and neuropathologists dealing with FCD.
      METHODS: A panel discussion of epileptologists, neuropathologists, and
      neuroradiologists with special expertise in FCD was held. RESULTS: The panel
      proposed 1) a specific terminology for the different types of abnormal cells
      encountered in the cerebral cortex of patients with FCD; 2) a reappraisal of the
      different histopathologic abnormalities usually subsumed under the term
      "microdysgenesis," and suggested that this terminology be abandoned; and 3) a
      more detailed yet straightforward classification of the various histopathologic
      features that usually are included under the heterogeneous term of "focal
      cortical dysplasia." CONCLUSION: The panel hopes that these proposals will
      stimulate the debate toward more specific clinical, imaging, histopathologic, and
      prognostic correlations in patients with FCD associated with epilepsy.

PMID- 15037672
TI  - Mechanisms of epileptogenicity in cortical dysplasias.
AB  - Cortical dysplasias (CDs) increasingly are recognized as pathologic substrates in
      patients with medically intractable epilepsy. Several studies have demonstrated
      the intrinsic epileptogenicity of these lesions, but the cellular and molecular
      mechanisms responsible for seizure initiation remain unknown. The increased
      availability of surgically resected neocortical tissue has provided the
      opportunity for direct histopathologic and electrocorticographic correlations.
      Moreover, the description of various animal models of CDs allowed the testing of
      various mechanistic hypotheses. It is likely that the mechanisms of
      epileptogenicity in CDs are multifactorial. In this article, the authors
      summarize current knowledge of the molecular and cellular mechanisms of
      epileptogenicity in focal CDs based on human and animal data. In particular, they
      focus on the roles of glutamate (NMDA and alpha-amino-3-hydroxy-5-methylisoxazole
      4-propionic acid) and gamma-aminobutyric acid receptors identified in animal
      models and resected human neocortex.

PMID- 15037673
TI  - Focal malformations of cortical development.

PMID- 15037675
TI  - Neuroimaging of the cortical dysplasias.

PMID- 15037674
TI  - Hemispheric malformations of cortical development.
AB  - The term hemispheric malformations of cortical development (MCDs) is used in this
      article to represent congenital malformations that predominantly or exclusively
      involve complete or substantial portion of one cerebral hemisphere. Hemispheric
      MCDs usually present during early childhood with intractable epilepsy, cognitive
      delay, and contralateral hemiparesis. Early identification and selection of
      children who may be candidates for epilepsy surgery are important during
      diagnostic evaluation of hemispheric MCD. Surgical intervention at an appropriate
      time, whenever possible, offers the best chance for seizure freedom and improved
      cognitive outcome. In addition, making an accurate genetic diagnosis is
      imperative to offer genetic testing and counseling to the family. In this
      article, the authors discuss the developmental and genetic mechanisms, pathologic
      features, diagnosis, and treatment of hemispheric MCD that are substrates of
      catastrophic childhood epilepsy amenable to surgical treatment.

PMID- 15037676
TI  - Surgery for focal cortical dysplasia.

PMID- 15037678
TI  - Pediatric neurology's midlife crisis.

PMID- 15037679
TI  - Diagnosing "undiagnosed" leukodystrophies: The role of molecular genetics.

PMID- 15037680
TI  - Incidental research imaging findings: Pandora's costly box.

PMID- 15037681
TI  - Practice parameter: diagnostic assessment of the child with cerebral palsy:
      report of the Quality Standards Subcommittee of the American Academy of Neurology
      and the Practice Committee of the Child Neurology Society.
AB  - OBJECTIVE: The Quality Standards Subcommittee of the American Academy of
      Neurology and the Practice Committee of the Child Neurology Society develop
      practice parameters as strategies for patient management based on analysis of
      evidence. For this parameter the authors reviewed available evidence on the
      assessment of a child suspected of having cerebral palsy (CP), a nonprogressive
      disorder of posture or movement due to a lesion of the developing brain. METHODS:
      Relevant literature was reviewed, abstracted, and classified. Recommendations
      were based on a four-tiered scheme of evidence classification. RESULTS: CP is a
      common problem, occurring in about 2 to 2.5 per 1,000 live births. In order to
      establish that a brain abnormality exists in children with CP that may, in turn,
      suggest an etiology and prognosis, neuroimaging is recommended with MRI preferred
      to CT (Level A). Metabolic and genetic studies should not be routinely obtained
      in the evaluation of the child with CP (Level B). If the clinical history or
      findings on neuroimaging do not determine a specific structural abnormality or if
      there are additional and atypical features in the history or clinical
      examination, metabolic and genetic testing should be considered (Level C).
      Detection of a brain malformation in a child with CP warrants consideration of an
      underlying genetic or metabolic etiology. Because the incidence of cerebral
      infarction is high in children with hemiplegic CP, diagnostic testing for
      coagulation disorders should be considered (Level B). However, there is
      insufficient evidence at present to be precise as to what studies should be
      ordered. An EEG is not recommended unless there are features suggestive of
      epilepsy or a specific epileptic syndrome (Level A). Because children with CP may
      have associated deficits of mental retardation, ophthalmologic and hearing
      impairments, speech and language disorders, and oral-motor dysfunction, screening
      for these conditions should be part of the initial assessment (Level A).
      CONCLUSIONS: Neuroimaging results in children with CP are commonly abnormal and
      may help determine the etiology. Screening for associated conditions is warranted
      as part of the initial evaluation.

PMID- 15037682
TI  - State of training in child neurology 1997-2002.
AB  - OBJECTIVE: To track growth of child neurology training programs during the past 7
      years and to assess changes in resident demographics, use of different pathways
      for completion of training, and chosen careers after residency. METHODS: Two
      surveys were sent: one in June 2000 (response rate = 92% of active programs) and
      one in May 2001 (response rate = 98%) to the directors of all Accreditation
      Council for Graduate Medical Education-listed child neurology programs. Fifty
      eight programs were consistently active through the survey period. RESULTS: From
      1997 through 2002 there was an average of 80 positions per year with a fill rate
      of 65% and an average of 1.4 positions per program. Fifty-five percent of
      programs completely filled their first-year positions. An average of 47% of
      residents were international medical graduates. In 2001 and 2002, 51.5% of
      trainees were men, and 48.5% were women. Sixteen percent entered their programs
      through an alternative pathway. An equal number of residents entered academic and
      fellowship positions after graduation (41%), and 18% of residents went into
      private practice. Twenty-three percent went into basic research. Residents wrote
      papers in 48% of the programs. CONCLUSIONS: The number of child neurology
      positions and trainees has been stable through recent years but may not meet the
      growing demand for services. The increasing number of international medical
      graduates and women in training programs predicts a change in the demographic
      characteristics of the future child neurology workforce. Many residents are
      pursuing academic careers, and continued support for programs that provide
      avenues for training in research is needed.

PMID- 15037684
TI  - Cognitive side effects of antiepileptic drugs in children.
AB  - Cognitive impairment associated with antiepileptic drug (AED) therapy in children
      is an important concern given the potential negative effects of treatment on
      school learning and performance. Unfortunately, there have been few studies
      examining the cognitive effects of AEDs in this population and no adequate
      studies of newer AEDs. This article will discuss the effects of the traditional
      and newer AEDs on neuropsychological function in children. Because of various
      limitations in the designs of these studies, however, many of the studies report
      inconclusive findings. Although it will be necessary to overcome many
      programmatic and procedural hurdles, well-designed randomized prospective studies
      that are of adequate length to determine how AEDs ultimately relate to school
      performance and social adjustment are needed to firmly establish the cognitive
      and behavioral effects of AEDs in children.

PMID- 15037685
TI  - Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common
      MLC1 mutation.
AB  - BACKGROUND: A distinct clinical syndrome characterized by megalencephaly, mild to
      moderate cognitive decline, slowly progressive spasticity, ataxia, occasional
      seizures, and extensive white matter changes with temporal cysts by imaging
      studies has been described in a particular ethnic group (Agarwals) in India. This
      disorder is very similar to megalencephalic leukoencephalopathy with subcortical
      cysts (MLC), a newly characterized leukodystrophy whose molecular basis was
      recently shown to be mutations in a gene (KIAA0027) that has been renamed MLC1.
      OBJECTIVE: To determine if this disorder among the Agarwals is due to mutations
      in MLC1 by a mutation screening study conducted on affected Agarwal patients.
      METHODS: Genomic DNA from these Indian leukodystrophy patients was screened for
      mutations in the entire coding region, including the exon-intron boundaries, of
      the MLC1 gene. RESULTS: Thirty-three affected individuals whose clinical and
      imaging presentations were consistent with MLC were screened. All were from
      northern India and included 31 known Agarwals, 1 non-Agarwal, and 1 adopted
      patient whose ethnicity is unknown. All 31 Agarwal patients tested positive for a
      homozygous insertion of a cytosine in exon 2. The adopted patient was homozygous
      for A157E. No mutation in the coding region was found in the non-Agarwal patient.
      CONCLUSIONS: Indian patients with megalencephaly and MRI changes that show
      extensive white matter changes with temporal cysts should raise suspicion for
      MLC. Members of the Agarwal ethnic group affected with the disorder present with
      a mildly progressive course and show a common mutation (320insC) in the MLC1
      gene, suggesting a founder effect.

PMID- 15037686
TI  - Nasal sumatriptan is effective in treatment of migraine attacks in children: A
      randomized trial.
AB  - OBJECTIVE: To investigate the efficacy of nasal sumatriptan in migraine attacks
      of children and adolescents. METHODS: A double-blind, placebo-controlled, two-way
      crossover trial was conducted in three hospital outpatient departments, with 8 to
      17 year olds diagnosed with migraine serving as subjects (International Headache
      Society 1988). A single dose of sumatriptan nasal spray and a matching placebo
      were administered at home during two attacks. The sumatriptan dose was 10 mg for
      a body weight of 20 to 39 kg and 20 mg for those with a body weight of >/=="
      BORDER="0">40 kg. The primary efficacy endpoint was headache relief by two grades
      on a 5-grade face scale at 2 hours. RESULTS: Eighty-three patients used both
      treatments and 11 only the first. At 2 hours, the primary endpoint was reached
      nearly twice as often after sumatriptan (n = 53/83; 64%) as after placebo (n =
      32/83; 39%) (p = 0.003). Already at 1 hour, headache relief was seen more often
      after sumatriptan (n = 42/83; 51%) than after placebo (n = 24/83; 29%) (p =
      0.014). The difference was even more obvious in patients who received the 20-mg
      dose as well as in the intention-to-treat analyses (n = 94). Other endpoints,
      including child's preference and using rescue medication, also favored
      sumatriptan. The most common adverse effect was a bad taste after sumatriptan,
      reported in 29% (n = 26/90) of the attacks. No serious adverse effects were
      observed. CONCLUSION: Nasal sumatriptan is an effective and well-tolerated
      treatment for migraine attacks in children over 8 years of age.

PMID- 15037687
TI  - Ethical consideration of incidental findings on adult brain MRI in research.
AB  - OBJECTIVE: To characterize the frequency and severity of incidental findings in
      brain MRIs of young and older adult research volunteers, and to provide an
      evaluation of the ethical challenges posed by the detection of such findings.
      METHODS: The authors reviewed 151 research MRI scans obtained retrospectively
      from subjects recruited to studies as healthy volunteers. Incidental findings
      were classified into four categories: no referral, routine, urgent, or immediate
      referral. p Values for significance were computed from chi(2) tests of
      contingency. RESULTS: Of 151 studies, the authors found an overall occurrence of
      incidental findings having required referral of 6.6%. By age, there were more
      findings in the older cohort (aged >60 years) than in the younger cohort (p <
      0.05) and in more men than women in the older cohort (p < 0.001). Three of four
      (75%) findings in the younger cohort were classified in the urgent referral
      category; 100% of the findings in the older cohort were classified as routine (p
      < 0.05). CONCLUSION: The significant presence but different characteristics of
      incidental findings in young and older subjects presumed to be neurologically
      healthy suggest that standards of practice are needed to guide investigators in
      managing and communicating their discovery.

PMID- 15037688
TI  - Characteristics of intracranial aneurysms in patients with familial subarachnoid
      hemorrhage.
AB  - BACKGROUND: Compared with sporadic aneurysms, familial aneurysms rupture at an
      earlier age and are more often located at the middle cerebral artery. Other
      characteristics of familial aneurysms may also differ from sporadic aneurysms.
      The authors compared the size of ruptured aneurysms and the number of aneurysms
      between patients with familial subarachnoid hemorrhage (SAH) and those with
      sporadic SAH. METHODS: The authors included all patients with familial SAH
      admitted to the University Medical Center Utrecht (UMCU) and their first-degree
      relatives with proven aneurysmal SAH, including admissions elsewhere. As
      reference group the authors used a consecutive series of patients with sporadic
      SAH admitted to the UMCU from December 1995 to March 1997. Criteria for sporadic
      SAH were absence of a positive family history and exclusion of aneurysms in first
      degree relatives by means of MR angiography. The authors dichotomized sizes of
      aneurysms into small (</=10 mm) and large (>10 mm). Size and number of aneurysms
      between patients with familial SAH and sporadic SAH were compared with relative
      risks (RR) with corresponding 95% CI. RESULTS: The authors found 58 patients with
      familial SAH (48 with information on aneurysm size) and 88 patients with sporadic
      SAH. Twenty of 48 patients with familial SAH (41%) had large aneurysms, versus 17
      (19%) with sporadic SAH (RR 2.1, 95% CI 1.2 to 3.6). Fifteen of 58 patients with
      familial SAH (26%) had multiple aneurysms, versus 9 (10%) with sporadic SAH (RR
      2.5, 95% CI 1.2 to 5.4). CONCLUSIONS: Familial aneurysms are generally larger at
      time of rupture and more likely to be multiple than sporadic aneurysms. The
      development of large and multiple aneurysms may be related to genetic factors
      that determine defects of the arterial wall.

PMID- 15037689
TI  - A population-based study of acute stroke and TIA diagnosis.
AB  - BACKGROUND: Acute stroke therapy is heavily dependent on the diagnostic acumen of
      the physician in the emergency department (ED). OBJECTIVE: To determine this
      diagnostic accuracy in a population-based multiethnic stroke study. METHODS: The
      Brain Attack Surveillance in Corpus Christi (BASIC) Project prospectively
      ascertained all acute stroke or TIA cases in an urban Texas county of 313,645
      residents without an academic medical center. Cases were validated by board
      certified neurologists using source documentation. Case validation was used as
      the gold standard to compare the diagnosis given by the ED physician. RESULTS:
      From January 2000 to August 2002, a total of 13,015 patients were screened. Of
      these, 1,800 were validated as stroke/TIA. Overall sensitivity of the emergency
      physician for the BASIC-validated diagnosis was 92%, and positive predictive
      value was 89%. Of the cases that the emergency physician thought were stroke, 11%
      were validated as no stroke. In multivariable modeling, motor symptoms was an
      independent predictor of protection from false-negative ED diagnosis of
      stroke/TIA (odds ratio [OR] = 0.61; 95% CI 0.41 to 0.89). Protection from false
      positive stroke/TIA diagnosis was predicted by sensory symptoms (OR = 0.43; 95%
      CI 0.28 to 0.66), motor symptoms (OR = 0.44; 95% CI 0.32 to 0.62), and severe
      neurologic deficit (OR = 0.33; 95% CI 0.14 to 0.78). History of stroke/TIA
      predicted false-positive stroke diagnosis (OR = 1.72; 95% CI 1.23 to 2.40). The
      majority of disagreements occurred in patients with generalized neurologic or
      acute medical, nonneurologic syndromes. CONCLUSIONS: Physicians practicing in the
      ED are sensitive for stroke/TIA diagnosis. The modest positive predictive value
      argues for a systems approach with neurology support so that proper decisions
      regarding acute stroke therapy can be made.

PMID- 15037690
TI  - Importance of the imaging modality in decision making about carotid
      endarterectomy.
AB  - OBJECTIVE: To determine the influence of all possible imaging strategies on the
      appropriateness ratings for carotid endarterectomy, because less accurate
      noninvasive techniques are replacing contrast angiography, which was used in the
      major efficacy trials. METHODS: An expert panel, using appropriateness
      methodology, rated 203 scenarios where endarterectomy might be performed. Each
      scenario was rated where internal carotid artery stenosis was determined using
      five different imaging sources: 1) conventional angiography, 2) ultrasound
      carotid Doppler only, 3) CT (CTA) or MR (MRA) angiography only, 4) concordant
      results from two noninvasive carotid imaging studies, and 5) discordant results
      from two noninvasive studies. The scenarios deemed appropriate by conventional
      angiography were identified. The effect of the other imaging modalities on these
      results was examined. RESULTS: Thirty-three scenarios were identified as being
      appropriate. Concordant imaging results had no effect on appropriateness ratings
      in symptomatic carotid artery disease when compared with conventional
      angiography. Single noninvasive imaging techniques were deemed appropriate for
      investigation only in the presence of severe symptomatic stenosis. In all other
      scenarios, single noninvasive imaging and discordant results reduced the
      appropriateness rating of scenarios to either uncertain benefit or
      inappropriateness. The single appropriate scenario for asymptomatic carotid
      artery stenosis was where severe stenosis was determined by concordant
      noninvasive imaging or by CTA or MRA alone. CONCLUSION: It is important to take
      into account both the clinical scenario and the imaging modalities utilized to
      determine the degree of internal carotid artery stenosis in the clinical decision
      making surrounding carotid endarterectomy.

PMID- 15037691
TI  - Depressive symptoms after stroke and relationship with dementia: A three-year
      follow-up study.
AB  - OBJECTIVE: To determine frequency, determinants, and time course of poststroke
      depressive symptoms (DS) and their relationship with dementia. METHODS: Two
      hundred two consecutive stroke patients were prospectively evaluated for DS,
      followed up over a 3-year period. Patients with Montgomery and Asberg Depression
      Rating Scale (MADRS) scores of >/==" BORDER="0">7 were considered as having DS.
      The severity of the neurologic deficit, functional outcome, and dementia were
      quantified with the Orgogozo Scale, modified Rankin Scale, Informant
      Questionnaire on Cognitive Decline in the Elderly, and an extensive battery of
      neuropsychological tests. RESULTS: DS were present in 43% of survivors after 6
      months, 36% after 12 months, 24% after 24 months, and 18% after 36 months. The
      severity of the neurologic deficit at admission was the only independent
      predictor of DS at month 6. DS at month 6 were more frequent in patients with
      previous depression, dementia, and right superficial lesions. Younger age and
      right superficial lesions were the two variables independently associated with
      the presence of DS at month 36. The time course of the various DS differed,
      sadness remaining frequent 3 years after stroke (50%), whereas slowness, psychic
      slowness, lack of energy, and concentration difficulties remained frequent at
      month 36 in patients with dementia. CONCLUSION: DS are frequent after stroke.
      Their time course varies and depends on the cognitive status; this variation
      contributes to differences among previous studies on poststroke depression.

PMID- 15037692
TI  - The neuropsychological profile of vascular cognitive impairment in stroke and TIA
      patients.
AB  - OBJECTIVE: To characterize the neuropsychological profile of vascular cognitive
      impairment (VCI) and vascular dementia (VaD). METHODS: The authors examined 170
      patients with stroke or TIA at 3 to 6 months after the vascular event, and 96 age
      matched healthy controls, with detailed neuropsychological and medical
      psychiatric assessments, with a majority (66.7%) undergoing MRI brain scans. The
      subjects were diagnosed as having VaD, VCI, or no cognitive impairment by
      consensus. The neuropsychological tests were classified into cognitive domains,
      and composite z-scores adjusted for age and education. RESULTS: VaD subjects had
      disturbance in all cognitive domains, with verbal memory, especially retention,
      being less affected. VCI subjects had similar but less severe disturbance. The
      domains that best discriminated cognitively impaired from unimpaired patients
      were abstraction, mental flexibility, information processing speed, and working
      memory. Cognitive impairment had a significant correlation with deep white matter
      hyperintensities, but not with volume and number of infarctions, even though the
      VaD subjects had larger infarct volumes than VCI subjects. The MRI variables did
      not provide additional discrimination between subgroups. CONCLUSIONS: The
      cognitive deficits in VaD and VCI are characterized by disturbance of frontal
      functions, with less verbal memory impairment. VaD and VCI differ in severity but
      not pattern of disturbance. The brain lesions that best account for these
      deficits are noninfarct subcortical white matter and gray matter changes due to
      ischemia. The picture of VaD/VCI presented shows subcortical deficits embellished
      by cognitive deficits from cortical infarctions.

PMID- 15037693
TI  - Effect of smoking on global cognitive function in nondemented elderly.
AB  - BACKGROUND: Contrary to early case-control studies that suggested smoking
      protects against Alzheimer disease (AD), recent prospective studies have shown
      that elderly who smoke may be at increased risk for dementia. OBJECTIVE: To
      examine prospectively the effect of smoking on cognition in nondemented elderly.
      METHOD: In a multicenter cohort, the European Community Concerted Action
      Epidemiology of Dementia (EURODEM), including the Odense, Personnes Agees Quid
      (Paquid), Rotterdam, and Medical Research Council: Ageing in Liverpool Project
      Health Aspects (MRC ALPHA) Studies, 17,610 persons aged 65 and over were screened
      and examined for dementia. After an average 2.3 years of follow-up, 11,003
      nondemented participants were retested. Excluding incident dementia cases and
      those without baseline information on smoking gave an analytical sample of 9,209
      persons. Average yearly decline in Mini-Mental State Examination (MMSE) score was
      compared among groups, adjusting for age, sex, baseline MMSE, education, type of
      residence, and history of myocardial infarction or stroke. RESULTS: MMSE score of
      persons who never smoked on average declined 0.03 point/year. The adjusted
      decline of former smokers was 0.03 point greater and of current smokers 0.13
      point greater than never smokers (p < 0.001). Higher rates of decline by smoking
      were found in men and women, persons with and without family history of dementia,
      and in three of four participating studies. Higher cigarette pack-year exposure
      was correlated with a significantly higher rate of decline. CONCLUSION: Smoking
      may accelerate cognitive decline in nondemented elderly.

PMID- 15037694
TI  - Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle
      formation in AD brain.
AB  - BACKGROUND: Pathologic changes in the Alzheimer disease (AD) brain occur in a
      hierarchical neuroanatomical pattern affecting cortical, subcortical, and limbic
      regions. OBJECTIVE: To define the time course of pathologic and biochemical
      changes-amyloid deposition, amyloid beta-peptide (Abeta) accumulation,
      neurofibrillary tangle (NFT) formation, synaptic loss, and gliosis-within the
      temporal association cortex of AD cases of varying disease duration, relative to
      control brains. METHODS: Stereologic assessments of amyloid burden and tangle
      density as well as ELISA-based measurements of Abeta, synaptophysin, and glial
      fibrillary acidic protein (GFAP) were performed in the superior temporal sulcus
      from a cohort of 83 AD and 26 nondemented control brains. RESULTS: Relative to
      control cases, AD brains were characterized by accumulation of NFT and amyloid
      plaques, increase of tris- and formic acid-extractable Abeta species, reduced
      levels of synaptophysin, and elevated levels of GFAP. In AD cases, the duration
      of dementia correlated with the degree of tangle formation, gliosis, and synaptic
      loss but not with any Abeta measures. Accumulation of Abeta, measured both
      neuropathologically and biochemically, was markedly increased in AD brains
      independent of disease duration, even in cases of short duration. CONCLUSIONS:
      These data support distinct processes in the initiation and progression of AD
      pathology within the temporal cortex: Deposition of Abeta reaches a "ceiling"
      early in the disease process, whereas NFT formation, synaptic loss, and gliosis
      continue throughout the course of the illness.

PMID- 15037695
TI  - Essential tremor course and disability: A clinicopathologic study of 20 cases.
AB  - OBJECTIVE: To correlate autopsy findings with the clinical course and disability
      profile in clinically diagnosed longitudinally followed autopsied essential
      tremor (ET) patients. METHODS: All ET patients followed by one neurologist
      between 1970 and 2001 who came to autopsy were included. Clinical features and
      disability were recorded prospectively. Autopsy studies were performed by a
      qualified neuropathologist. RESULTS: Twenty cases (10 men and 10 women) had ET
      onset between childhood and age 68 (median 46.5 years). Six cases had additional
      features of Parkinson syndrome (PS), with presence of bradykinesia, rigidity, and
      rest tremor (RT). These included progressive supranuclear palsy (PSP; n = 2),
      drug-induced parkinsonism (n = 2), idiopathic Parkinson disease (PD; n = 1), and
      basal ganglia status cribrosus (n = 1). Of the remaining 14 ET cases, 6 had
      additional RT but no bradykinesia or rigidity. Ten of these 14 (71%) reported
      physical disability. Eleven of the 14 (79%) had only upper limb (UL) tremor at
      onset, and 8 of these 11 (73%) had subsequent cranial extension of tremor. Two
      patients clinically had mild cerebellar ataxia but no cerebellar histologic
      abnormality. There was no consistent brain pathology in the ET or ET + RT cases.
      CONCLUSIONS: UL tremor was the most common onset, which often progressed to the
      cranial musculature. Functional disability and psychological distress were common
      in these patients. Functional disability was related to the UL tremor. Six of 20
      (30%) had additional features of PS. Six of the remaining 14 (43%) had ET and RT;
      there was no identifiable pathology in these cases. The risk of PD in ET cases
      was comparable with that in the general population. PSP in two cases was
      incidental comorbidity.

PMID- 15037696
TI  - Mortality and Parkinson disease: A community based study.
AB  - OBJECTIVE: To compare the mortality of a community-based cohort of patients with
      carefully diagnosed Parkinson disease (PD) with the mortality in an age-matched
      population from the same study area and to investigate the possible influence of
      clinical features and diagnostic accuracy on survival in PD. METHODS: A total of
      245 patients with PD were identified and included in the study. Patients were
      classified into groups of clinical definite, probable, and possible PD. The study
      period was 8 years. A total of 142 patients died. The mortality rates for the
      Norwegian population, which were available in 1-year intervals for all birth
      cohorts and both sexes during the study period, were used as controls. RESULTS:
      The standardized mortality ratio (SMR) for the total patient group was 1.52. The
      mortality rate was increased for both sexes (male SMR = 1.54, female SMR = 1.49)
      and in all age groups at disease onset (<60 years SMR = 1.92, 60 to 70 years SMR
      = 1.50, >70 years SMR = 1.41). The survival of patients with clinical definite PD
      was only modestly reduced (SMR = 1.35), whereas the SMR for possible PD was as
      high as 1.99. CONCLUSIONS: Our study gives evidence for increased mortality in PD
      despite modern treatment. The increase is not extensive in patients with a high
      probability for idiopathic PD.

PMID- 15037697
TI  - Does magnetoencephalography add to scalp video-EEG as a diagnostic tool in
      epilepsy surgery?
AB  - OBJECTIVE: The authors evaluated the sensitivity and selectivity of interictal
      magnetoencephalography (MEG) versus prolonged ictal and interictal scalp video
      electroencephalography (V-EEG) in order to identify patient groups that would
      benefit from preoperative MEG testing. METHODS: The authors evaluated 113
      consecutive patients with medically refractory epilepsy who underwent surgery.
      The epileptogenic region predicted by interictal and ictal V-EEG and MEG was
      defined in relation to the resected area as perfectly overlapping with the
      resected area, partially overlapping, or nonoverlapping. RESULTS: The sensitivity
      of a 30-minute interictal MEG study for detecting clinically significant
      epileptiform activity was 79.2%. Using MEG, we were able to localize the resected
      region in a greater proportion of patients (72.3%) than with noninvasive V-EEG
      (40%). MEG contributed to the localization of the resected region in 58.8% of the
      patients with a nonlocalizing V-EEG study and 72.8% of the patients for whom V
      EEG only partially identified the resected zone. Overall, MEG and V-EEG results
      were equivalent in 32.3% of the cases, and additional localization information
      was obtained using MEG in 40% of the patients. CONCLUSION: MEG is most useful for
      presurgical planning in patients who have either partially or nonlocalizing V-EEG
      results.

PMID- 15037698
TI  - Acute motor axonal neuropathy after Mycoplasma infection: Evidence of molecular
      mimicry.
AB  - BACKGROUND: Patients with Guillain-Barre syndrome (GBS) after Mycoplasma
      pneumoniae infection often have antibodies to galactocerebroside (GalC).
      Electrodiagnosis may show acute inflammatory demyelinating polyneuropathy (AIDP).
      METHODS: The authors report a patient with acute motor axonal neuropathy (AMAN)
      after Mycoplasma infection and review seven cases of Mycoplasma-associated GBS.
      They investigated anti-GalC serology under various conditions associated with
      Mycoplasma infection. RESULTS: The patient had immunoglobulin (Ig)G and IgM
      antibodies against GM1 and GalC, which cross-reacted. During the acute phase, IgM
      selectively immunostained axons. The cholera toxin B-subunit and rabbit anti-GM1
      IgG stained a band in the lipid extract from M pneumoniae, indicative of the
      presence of a GM1 epitope. Six Mycoplasma-associated GBS patients with anti-GalC
      antibodies had non-AIDP electrodiagnoses, whereas one with Mycoplasma-associated
      AIDP had no anti-GalC antibodies. Anti-GalC antibodies were positive in two of
      five patients who had neurologic diseases other than GBS after Mycoplasma
      infection and in one of 12 who had acute respiratory disease caused by M
      pneumoniae not followed by a neurologic disease. CONCLUSIONS: Anti-GalC
      antibodies in Mycoplasma-associated GBS may be an epiphenomenon. In certain
      cases, anti-GM1 antibodies induced by molecular mimicry with M pneumoniae may
      cause acute motor axonal neuropathy.

PMID- 15037701
TI  - Paraparesis due to capsular hemorrhages.

PMID- 15037700
TI  - The quicksilver prize: Mercury vapor poisoning aboard HMS Triumph and HMS Phipps.
AB  - In 1810, two British ships, HMS Triumph and HMS Phipps, salvaged a large load of
      elemental mercury from a wrecked Spanish vessel near Cadiz, Spain. The bladders
      containing the mercury soon ruptured. The element spread about the ships in
      liquid and vapor forms. The sailors presented with neurologic compromises:
      tremor, paralysis, and excessive salivation as well as tooth loss, skin problems,
      and pulmonary complaints. The events are reviewed in the context of what was
      known about mercury vapor inhalation.

PMID- 15037699
TI  - Neuropsychiatric impact of hepatitis C on advanced HIV.
AB  - OBJECTIVE: To determine whether hepatitis C (HCV) contributes to CNS dysfunction
      among HIV-infected individuals. METHODS: Using a cross-sectional design, the
      neuropsychiatric profile of individuals with advanced HIV coinfected with
      hepatitis C (HIV+/HCV+) was compared to similarly advanced HIV patients without
      HCV coinfection (HIV+/HCV-). Participants were derived from the Manhattan HIV
      Brain Bank and underwent neurocognitive testing and semistructured psychiatric
      interviews. Evidence of HCV infection was determined by serology performed prior
      to study entry. Hepatic function was determined by serum chemistries (bilirubin,
      creatinine, and international normalized ratio) at the time of the cognitive
      assessments. RESULTS: Coinfected (HIV+/HCV+) individuals were significantly more
      likely to have had past opiate or cocaine or stimulant dependence. HIV+/HCV+
      participants also had significantly greater rates of past substance-induced major
      depression. There were no significant differences in rates of primary mental
      disorders. Forty-two percent of both the HIV+/HCV+ and HIV+/HCV- participants met
      criteria for current major depression. There was a trend for HIV+/HCV+ patients
      to perform worse neurocognitively. On tests of executive functioning, HIV+/HCV+
      individuals exhibited a greater rate of impairment and had significantly more
      perseveration. Differences in cognitive functioning were associated with serology
      but did not correlate with indices of liver disease severity. The HCV+ patients
      were also more likely to be diagnosed with HIV-associated dementia. CONCLUSIONS:
      There appears to be a neuropsychiatric impact of HCV that is detectable even
      among an advanced HIV cohort.

PMID- 15037703
TI  - Syndrome resembling PSP after surgical repair of ascending aorta dissection or
      aneurysm.
AB  - Seven patients, after seemingly uncomplicated surgery for ascending aorta
      aneurysm or dissection, with or without aortic valve replacement, developed an
      unusual and fairly stereotyped biphasic neurologic disorder without imaging
      evidence of related cerebral ischemia or infarct. The initial phase was mild,
      nonprogressive, or receding. The latent and progressive phase closely resembled a
      progressive supranuclear palsy phenotype. The disorder may prove to be self
      limiting but leaves the patients with considerable neurologic deficits.

PMID- 15037702
TI  - Statin use and stroke outcomes in the Heart and Estrogen-Progestin Replacement
      Study (HERS).
AB  - The authors investigated the relationship between statin use and the risk of
      stroke in the Heart and Estrogen-Progestin Replacement Study (HERS). Despite
      large reductions in relative risk point estimates, statin use was not associated
      with differences in the risks of all fatal stroke (relative hazard [RH] 0.52, 95%
      CI 0.23 to 1.18, p = 0.12), fatal ischemic stroke (RH 0.51, 95% CI 0.18 to 1.45,
      p = 0.21), fatal hemorrhagic stroke (RH 0.18, 95% CI 0.02 to 1.46, p = 0.11), or
      TIA (RH 1.32, 95% CI 0.84 to 2.09, p = 0.23).

PMID- 15037704
TI  - Acute aphasia in multiple sclerosis: A multicenter study of 22 patients.
AB  - Aphasia is usually considered to be rare in multiple sclerosis (MS). To determine
      the clinical and radiologic characteristics of MS patients with acute aphasia,
      the authors investigated data from 2,700 patients from three MS centers and found
      22 patients with acute aphasia (0.81%). Aphasia was the first clinical
      manifestation of MS in eight patients (36%). Brain MRI showed giant plaques in
      eight cases (40%). A full recovery was observed in 14 patients (64%).
      Furthermore, acute aphasia did not appear to be a criterion for poor prognosis.

PMID- 15037705
TI  - Devic disease and thymoma with anti-central nervous system and antithymus
      antibodies.
AB  - A patient with myasthenia gravis and thymoma developed neuromyelitis optica (NMO)
      and necrotizing myositis 4 months after treatment of the tumor. Antibodies
      reacting with the CNS and thymic epithelial cells were detected in the serum
      during the acute phase of NMO, suggesting that the NMO was linked to the thymoma.

PMID- 15037706
TI  - Reversible diffusion MRI abnormalities and transient mutism after liver
      transplantation.
AB  - Transient mutism was observed in a liver transplant patient under
      immunosuppressant therapy with cyclosporine A and antifungal prophylaxis with
      amphotericin B. Fluid-attenuated inversion recovery and diffusion-weighted images
      revealed reversible bilateral symmetric hyperintensity located in the frontal
      motor cortex and corticospinal tracts. These MRI abnormalities may be caused by
      acute edema, possibly a combination of cytotoxic and vasogenic edema, which
      resolved with a prompt change in therapy.

PMID- 15037708
TI  - Prognostic value of the MIB-1 labeling index for central neurocytomas.
AB  - Although central neurocytomas are generally described as benign CNS lesions,
      malignant behavior including craniospinal dissemination and tumor-related death
      may occur. This meta-analysis was performed to investigate the prognostic value
      of the MIB-1 labeling index. Data were obtained not from the literature alone but
      also from contact with the authors. The data suggested an MIB-1 index score of
      >3% to be associated with a worse prognosis for local control (p < 0.0001) and
      survival (p = 0.0004).

PMID- 15037707
TI  - Rasmussen encephalitis with active inflammation and delayed seizures onset.
AB  - Severe focal epilepsy is regarded as a clinical hallmark of Rasmussen
      encephalitis (RE). The authors report two children with progressive hemiparesis,
      contralateral hemispheric atrophy, and pathologic features characteristic for RE.
      At histologic diagnosis and over several months, neither patient experienced
      seizures. The report enlarges the clinical spectrum of RE and suggests that
      seizures are not an obligatory presenting symptom of the disorder.

PMID- 15037709
TI  - Effectiveness of broadcasting guidelines for photosensitive seizure prevention.
AB  - Emissions from TV programs are a dangerous light source for photosensitive
      individuals, because 48.9% of patients have photosensitive seizures caused by TV
      programs. The authors used a national survey to verify the effectiveness of
      current Japanese guidelines, which are based on neurophysiologic principles of
      photosensitivity. They show that the guidelines successfully control TV images to
      protect many photosensitive persons from harmful TV emissions.

PMID- 15037710
TI  - Mevalonate kinase deficiency: Evidence for a phenotypic continuum.
AB  - Both mevalonic aciduria, characterized by psychomotor retardation, cerebellar
      ataxia, recurrent fever attacks, and death in early childhood, and hyper
      immunoglobulin D (hyper-IgD) syndrome, with recurrent fever attacks without
      neurologic symptoms, are caused by a functional deficiency of mevalonate kinase.
      In a systematic review of known mevalonate kinase-deficient patients, the authors
      identified five adults with phenotypic overlap between these two syndromes, which
      argues for a continuous spectrum of disease. Mevalonate kinase deficiency should
      be considered in adult patients with fitting neurologic symptoms, with or without
      periodic fever attacks.

PMID- 15037711
TI  - Cortical involvement in the generation of "involuntary" movements in restless
      legs syndrome.
AB  - The pathophysiology of the restless legs syndrome (RLS) is poorly understood. One
      index symptom is the urge to move, increasing at night. It is largely accepted
      that movement in RLS is "involuntary" and that the generators are below the level
      of the neocortex. Here the authors provide evidence that characteristic leg
      movements in RLS are preceded by preparatory cortical activation that cannot be
      attributed to sensory processing or to the expectancy of movement.

PMID- 15037712
TI  - SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I.
AB  - Hereditary sensory neuropathy type I (HSN I) is an autosomal dominant
      ulceromutilating disorder of the peripheral nervous system characterized by
      progressive sensory loss. HSN I locus maps to chromosome 9q22.1-22.3 and is
      caused by mutations in the gene coding for serine palmitoyltransferase long-chain
      base subunit 1 (SPTLC1). A novel missense mutation in exon 13 of the SPTLC1 gene
      (c.1160G-->C; p.G387A) in twin sisters with a severe HSN I phenotype is reported.

PMID- 15037713
TI  - Strict bed rest following lumbar puncture in children and adolescents is of no
      benefit.
AB  - The effect of 24-hour bed rest or free mobility on the frequency of complaints
      following diagnostic lumbar puncture was studied in a randomized trial of 111
      patients aged 2 to 17 years. Patients of the bed-rest group encountered
      significantly more head- or backaches (positional headache 15 vs 2%; all
      headaches 39 vs 21%; backaches 42 vs 23%). There were no differences in the
      frequencies of nausea or neck stiffness. Prophylactic bed rest following lumbar
      puncture in children and adolescents is of no benefit and may actually be
      disadvantageous.

PMID- 15037714
TI  - Pilot trial of albuterol in Duchenne and Becker muscular dystrophy.
AB  - The authors conducted a randomized, crossover, double-blind, placebo-controlled
      pilot study of albuterol in nine boys with dystrophinopathies. Primary outcomes
      were 1) isometric knee extensor and flexor strength; and 2) manual muscle testing
      (MMT). Isometric knee extensor strength and MMT scores were significantly higher
      in patients taking albuterol vs placebo. Therefore, 12-week treatment with
      extended-release albuterol may increase strength in patients with
      dystrophinopathies. A larger, double-blind, randomized study is necessary to
      confirm these results.

PMID- 15037715
TI  - POMT1 mutation results in defective glycosylation and loss of laminin-binding
      activity in alpha-DG.
AB  - Walker-Warburg syndrome (WWS) is a congenital muscular dystrophy associated with
      neuronal migration disorder and structural eye abnormalities. The mutations in
      the O-mannosyltransferase 1 gene (POMT1) were identified recently in 20% of
      patients with WWS. The authors report on a patient with WWS and a novel POMT1
      mutation. Their patient expressed alpha-dystroglycan (alpha-DG) core protein, but
      fully glycosylated alpha-DG antibody epitopes were absent, associated with the
      loss of laminin-binding activity.

PMID- 15037716
TI  - Periodic paralysis mutation MiRP2-R83H in controls: Interpretations and general
      recommendation.
AB  - An R83H point mutation in KCNE3-encoded MiRP2 has been reported to cause 2% of
      all cases of familial periodic paralysis. The authors found MiRP2-R83H in 3 of
      321 control subjects and in 5 unaffected related individuals. Provocation of an
      unaffected carrier with glucose or KCl did not induce weakness. The authors
      propose that causality criteria for mutations require exclusion of mutations in n
      = ln(P)/ln(1 - p(1)) ethnically matched control chromosomes (P = acceptable error
      probability; p(1) = mutation prevalence in patient chromosomes).

PMID- 15037717
TI  - Proton MR spectroscopy in succinic semialdehyde dehydrogenase deficiency.
AB  - Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare hereditary
      disorder of the CNS catabolism of gamma-aminobutyric acid (GABA), leading to
      accumulation of the metabolite 4-hydroxybutyrate (GHB). Here the authors report
      on 1.5 and 3.0 T proton MR spectroscopy in a patient with SSADH deficiency. A
      characteristic pattern with clearly elevated GABA levels and traces of GHB was
      found in both the white and the gray matter of the brain. In vivo spectroscopy
      may be useful for diagnosis and monitoring SSADH deficiency.

PMID- 15037718
TI  - Limbic encephalitis: Not a picture to forget.

PMID- 15037719
TI  - Familial occurrence of dysembryoplastic neuroepithelial tumor.

PMID- 15037720
TI  - Focal dystonia caused by Mohr-Tranebjaerg syndrome with complete deletion of the
      DDP1 gene.

PMID- 15037721
TI  - Effects of shunting CSF in superficial siderosis of the CNS.

PMID- 15037722
TI  - Ultrasound image of a single symptomatic carotid stenosis disclosed as
      fibromuscular dysplasia.

PMID- 15037723
TI  - The development of hippocampal sclerosis in a patient with occipital lobe
      epilepsy and migraine.

PMID- 15037724
TI  - Acute motor conduction block neuropathy: Another Guillain-Barre syndrome variant.

PMID- 15037725
TI  - "Economy class" stroke syndrome.

PMID- 15037726
TI  - Occurrence of amyotrophic lateral sclerosis among Gulf War veterans.

PMID- 15037727
TI  - Emergent EEG: Indications and diagnostic yield.

PMID- 15037728
TI  - DHEA treatment of Alzheimer's disease: A randomized, double-blind, placebo
      controlled trial.

PMID- 15037729
TI  - New treatment alternatives for Duchenne and Becker muscular dystrophy.

PMID- 15037731
TI  - Control of male gametophyte development.

PMID- 15037730
TI  - Multiple pathways in the decision to flower: enabling, promoting, and resetting.

PMID- 15037732
TI  - Arabidopsis histone deacetylase HDA6 is required for maintenance of
      transcriptional gene silencing and determines nuclear organization of rDNA
      repeats.
AB  - Histone acetylation and deacetylation are connected with transcriptional
      activation and silencing in many eukaryotic organisms. Gene families for enzymes
      that accomplish these modifications show a surprising multiplicity in sequence
      and expression levels, suggesting a high specificity for different targets. We
      show that mutations in Arabidopsis (Arabidopsis thaliana) HDA6, a putative class
      I histone deacetylase gene, result in loss of transcriptional silencing from
      several repetitive transgenic and endogenous templates. Surprisingly, total
      levels of histone H4 acetylation are only slightly affected, whereas significant
      hyperacetylation is restricted to the nucleolus organizer regions that contain
      the rDNA repeats. This switch coincides with an increase of histone 3 methylation
      at Lys residue 4, a modified DNA methylation pattern, and a concomitant
      decondensation of the chromatin. These results indicate that HDA6 might play a
      role in regulating activity of rRNA genes, and this control might be functionally
      linked to silencing of other repetitive templates and to its previously assigned
      role in RNA-directed DNA methylation.

PMID- 15037734
TI  - Enod40, a short open reading frame-containing mRNA, induces cytoplasmic
      localization of a nuclear RNA binding protein in Medicago truncatula.
AB  - In eukaryotes, diverse mRNAs containing only short open reading frames (sORF
      mRNAs) are induced at specific stages of development. Their mechanisms of action
      may involve the RNA itself and/or sORF-encoded oligopeptides. Enod40 genes code
      for highly structured plant sORF-mRNAs involved in root nodule organogenesis. A
      novel RNA binding protein interacting with the enod40 RNA, MtRBP1 (for Medicago
      truncatula RNA Binding Protein 1), was identified using a yeast three-hybrid
      screening. Immunolocalization studies and use of a MtRBP1-DsRed2 fluorescent
      protein fusion showed that MtRBP1 localized to nuclear speckles in plant cells
      but was exported into the cytoplasm during nodule development in enod40
      expressing cells. Direct involvement of the enod40 RNA in MtRBP1 relocalization
      into cytoplasmic granules was shown using a transient expression assay. Using a
      (green fluorescent protein)/MS2 bacteriophage system to tag the enod40 RNA, we
      detected in vivo colocalization of the enod40 RNA and MtRBP1 in these granules.
      This in vivo approach to monitor RNA-protein interactions allowed us to
      demonstrate that cytoplasmic relocalization of nuclear proteins is an RNA
      mediated cellular function of a sORF-mRNA.

PMID- 15037733
TI  - Composition and structure of the centromeric region of rice chromosome 8.
AB  - Understanding the organization of eukaryotic centromeres has both fundamental and
      applied importance because of their roles in chromosome segregation, karyotypic
      stability, and artificial chromosome-based cloning and expression vectors. Using
      clone-by-clone sequencing methodology, we obtained the complete genomic sequence
      of the centromeric region of rice (Oryza sativa) chromosome 8. Analysis of 1.97
      Mb of contiguous nucleotide sequence revealed three large clusters of CentO
      satellite repeats (68.5 kb of 155-bp repeats) and >220 transposable element (TE)
      related sequences; together, these account for approximately 60% of this
      centromeric region. The 155-bp repeats were tandemly arrayed head to tail within
      the clusters, which had different orientations and were interrupted by TE-related
      sequences. The individual 155-bp CentO satellite repeats showed frequent
      transitions and transversions at eight nucleotide positions. The 40 TE elements
      with highly conserved sequences were mostly gypsy-type retrotransposons.
      Furthermore, 48 genes, showing high BLAST homology to known proteins or to rice
      full-length cDNAs, were predicted within the region; some were close to the CentO
      clusters. We then performed a genome-wide survey of the sequences and
      organization of CentO and RIRE7 families. Our study provides the complete
      sequence of a centromeric region from either plants or animals and likely will
      provide insight into the evolutionary and functional analysis of plant
      centromeres.

PMID- 15037735
TI  - Patterning of virus-infected Glycine max seed coat is associated with suppression
      of endogenous silencing of chalcone synthase genes.
AB  - Most commercial Glycine max (soybean) varieties have yellow seeds because of loss
      of pigmentation in the seed coat. It has been suggested that inhibition of seed
      coat pigmentation in yellow G. max may be controlled by homology-dependent
      silencing of chalcone synthase (CHS) genes. Our analysis of CHS mRNA and short
      interfering RNAs provide clear evidence that the inhibition of seed coat
      pigmentation in yellow G. max results from posttranscriptional rather than
      transcriptional silencing of the CHS genes. Furthermore, we show that mottling
      symptoms present on the seed coat of G. max plants infected with some viruses can
      be caused by suppression of CHS posttranscriptional gene silencing (PTGS) by a
      viral silencing suppressor protein. These results demonstrate that naturally
      occurring PTGS plays a key role in expression of a distinctive phenotype in
      plants and present a simple clear example of the elucidation of the molecular
      mechanism for viral symptom induction.

PMID- 15037737
TI  - Conserved T cell receptor usage in primary and recall responses to an
      immunodominant influenza virus nucleoprotein epitope.
AB  - The CD8+ T cell response to the immunodominant DbNP366 epitope has been analyzed
      sequentially to determine the prevalence and persistence of different T cell
      antigen receptor (TCR)Vbeta8.3 clonotypes after primary and secondary influenza
      virus challenge. Based on the length and amino acid sequences of the
      complementarity-determining region 3 of TCRbeta (CDR3beta) loop and associated
      Jbeta usage, the same dominant TCRbeta signatures were found in the blood, the
      spleen, and the site of virus-induced pathology in the infected respiratory
      tract. Longitudinal analysis demonstrated that TCRbeta prominent in the antigen
      driven phase of response persisted into memory and were again expanded after
      secondary challenge. A proportion of these high-frequency TCRbeta expressed
      "public" CDR3beta sequences that were detected in every mouse sampled, whereas
      others were found more than once but were not invariably present. Analysis of N
      region nucleotide diversity established that as many as 10 different nucleic acid
      sequences (maximum of four "nucleotypes" in any one mouse) could encode a single
      public TCRbeta amino acid sequence. Conversely, whereas some of the unique,
      "private" TCRbeta achieved a substantial clone size, they were always specified
      by a single nucleotype. Although there is a strong stochastic element in this
      response, the public TCRbeta seem to represent a "best fit" for this
      immunodominant epitope, are selected preferentially from the naive TCR
      repertoire, and assume even greater prominence after secondary challenge.

PMID- 15037740
TI  - A global suppressor motif for p53 cancer mutants.
AB  - The transcription factor and tumor suppressor protein p53 is frequently
      inactivated in human cancers. In many cases, p53 gene mutations result in high
      levels of inactive, full-length p53 protein with one amino acid change in the
      core domain that recognizes p53 DNA-binding sites. The ability to endow function
      to mutated p53 proteins would dramatically improve cancer therapy, because it
      would reactivate a central apoptotic pathway. By using genetic strategies and p53
      assays in yeast and mammalian cells, we identified a global suppressor motif
      involving codons 235, 239, and 240. These intragenic suppressor mutations, either
      alone or in combination, restored function to 16 of 30 of the most common p53
      cancer mutants tested. The 235-239-240 suppressor motif establishes that
      manipulation of a small region of the core domain is sufficient to activate a
      large number of p53 cancer mutants. Understanding the structural basis of the
      rescue mechanism will allow the pursuit of small compounds able to achieve a
      similar stabilization of p53 cancer mutants.

PMID- 15037746
TI  - Nuclear protein-coding genes support lungfish and not the coelacanth as the
      closest living relatives of land vertebrates.
AB  - The colonization of land by tetrapod ancestors is one of the major questions in
      the evolution of vertebrates. Despite intense molecular phylogenetic research on
      this problem during the last 15 years, there is, until now, no statistically
      supported answer to the question of whether coelacanths or lungfish are the
      closest living relatives of tetrapods. We determined DNA sequences of the nuclear
      encoded recombination activating genes (Rag1 and Rag2) from all three major
      lungfish groups, the Australian Neoceratodis forsteri, the South American
      Lepidosiren paradoxa and the African lungfish Protopterus dolloi, and the
      Indonesian coelacanth Latimeria menadoensis. Phylogenetic analyses of both the
      single gene and the concatenated data sets of RAG1 and RAG2 found that the
      lungfishes are the closest living relatives of the land vertebrates. These
      results are supported by high bootstrap values, Bayesian posterior probabilities,
      and likelihood ratio tests.

PMID- 15037741
TI  - Structural basis of androgen receptor binding to selective androgen response
      elements.
AB  - Steroid receptors bind as dimers to a degenerate set of response elements
      containing inverted repeats of a hexameric half-site separated by 3 bp of spacer
      (IR3). Naturally occurring selective androgen response elements have recently
      been identified that resemble direct repeats of the hexameric half-site (ADR3).
      The 3D crystal structure of the androgen receptor (AR) DNA-binding domain bound
      to a selective ADR3 reveals an unexpected head-to-head arrangement of the two
      protomers rather than the expected head-to-tail arrangement seen in nuclear
      receptors bound to response elements of similar geometry. Compared with the
      glucocorticoid receptor, the DNA-binding domain dimer interface of the AR has
      additional interactions that stabilize the AR dimer and increase the affinity for
      nonconsensus response elements. This increased interfacial stability compared
      with the other steroid receptors may account for the selective binding of AR to
      ADR3 response elements.

PMID- 15037748
TI  - From paragraph to graph: latent semantic analysis for information visualization.
AB  - Most techniques for relating textual information rely on intellectually created
      links such as author-chosen keywords and titles, authority indexing terms, or
      bibliographic citations. Similarity of the semantic content of whole documents,
      rather than just titles, abstracts, or overlap of keywords, offers an attractive
      alternative. Latent semantic analysis provides an effective dimension reduction
      method for the purpose that reflects synonymy and the sense of arbitrary word
      combinations. However, latent semantic analysis correlations with human text-to
      text similarity judgments are often empirically highest at approximately 300
      dimensions. Thus, two- or three-dimensional visualizations are severely limited
      in what they can show, and the first and/or second automatically discovered
      principal component, or any three such for that matter, rarely capture all of the
      relations that might be of interest. It is our conjecture that linguistic meaning
      is intrinsically and irreducibly very high dimensional. Thus, some method to
      explore a high dimensional similarity space is needed. But the 2.7 x 10(7)
      projections and infinite rotations of, for example, a 300-dimensional pattern are
      impossible to examine. We suggest, however, that the use of a high dimensional
      dynamic viewer with an effective projection pursuit routine and user control,
      coupled with the exquisite abilities of the human visual system to extract
      information about objects and from moving patterns, can often succeed in
      discovering multiple revealing views that are missed by current computational
      algorithms. We show some examples of the use of latent semantic analysis to
      support such visualizations and offer views on future needs.

PMID- 15037749
TI  - A highly conserved candidate chemoreceptor expressed in both olfactory and
      gustatory tissues in the malaria vector Anopheles gambiae.
AB  - Anopheles gambiae is a highly anthropophilic mosquito responsible for the
      majority of malaria transmission in Africa. The biting and host preference
      behavior of this disease vector is largely influenced by its sense of smell,
      which is presumably facilitated by G protein-coupled receptor signaling [Takken,
      W. & Knols, B. (1999) Annu. Rev. Entomol. 44, 131-157]. Because of the importance
      of host preference to the mosquitoes' ability to transmit disease, we have
      initiated studies intended to elucidate the molecular mechanisms underlying
      olfaction in An. gambiae. In the course of these studies, we have identified a
      number of genes potentially involved in signal transduction, including a family
      of candidate odorant receptors. One of these receptors, encoded by GPRor7
      (hereafter referred to as AgOr7), is remarkably similar to an odorant receptor
      that is expressed broadly in olfactory tissues and has been identified in
      Drosophila melanogaster and other insects [Krieger, J., Klink, O., Mohl, C.,
      Raming, K. & Breer, H. (2003) J. Comp. Physiol. A 189, 519-526; Vosshall, L. B.,
      Amrein, H., Morozov, P. S., Rzhetsky, A. & Axel, R. (1999) Cell 96, 725-736]. We
      have observed AgOr7 expression in olfactory and gustatory tissues in adult An.
      gambiae and during several stages of the mosquitoes' development. Within the
      female adult peripheral chemosensory system, antiserum against the AgOR7
      polypeptide labels most sensilla of the antenna and maxillary palp as well as a
      subset of proboscis sensilla. Furthermore, AgOR7 antiserum labeling is observed
      within the larval antenna and maxillary palpus. These results are consistent with
      a role for AgOr7 in both olfaction and gustation in An. gambiae and raise the
      possibility that AgOr7 orthologs may also be of general importance to both
      modalities of chemosensation in other insects.

PMID- 15037750
TI  - Both chemotaxis and net motility greatly influence the infectivity of Vibrio
      cholerae.
AB  - The role of chemotaxis in the virulence of gastrointestinal pathogens is ill
      defined. Counterintuitively, nonchemotactic mutants of the polarly flagellated
      pathogen Vibrio cholerae greatly out-compete the wild-type strain during
      infection of the small intestine. We show that the out-competition phenotype is
      dependent on the direction of flagellar rotation and independent of Toxin Co
      regulated Pilus function. Specifically, the out-competition associated with the
      loss of chemotaxis required the presence of counterclockwise-biased flagellar
      rotation and smooth straight runs by the bacteria. In contrast, a nonchemotactic
      strain with clockwise-biased flagellar rotation was confined to small-scale net
      movement and was attenuated for infection. The significance of the out
      competition phenotype was examined and was shown to correlate with a true
      increase in infectivity. Counterclockwise-biased mutants are aberrantly
      distributed throughout the infant mouse small intestine and we find that the
      expression of virulence factors occurs normally in all segments. Thus, alteration
      of the chemotactic properties of V. cholerae allows it to exploit additional
      niches in the host intestine.

PMID- 15037752
TI  - Catalytic enantioselective intermolecular cycloadditions of 2-diazo-3,6
      diketoester-derived carbonyl ylides with alkene dipolarophiles.
AB  - Catalyzed cascade reactions that generate molecular complexity rapidly and in an
      enantioselective manner are attractive methods for asymmetric synthesis. In the
      present article, chiral rhodium catalysts are shown to effect such a
      transformation by using a range of 2-diazo-3,6-diketoesters with
      bicyclo[2.2.1]alkenes and styrenes as reaction partners. The reactions are likely
      to proceed by formation of a catalyst-complexed carbonyl ylide from the diazo
      compound, followed by intermolecular cycloaddition with the alkene dipolarophile.
      It was possible to obtain high levels of asymmetric induction [up to 89%
      enantiomeric excess (ee) and 92% ee for the two chiral catalysts investigated].
      Enantioselectivity is not highly sensitive to substituent variation at the ketone
      that forms the ylide; however, branching does improve ee. Observations of
      dipolarophile-dependent enantiofacial selectivity in the cycloadditions indicate
      that the dipolarophile can be intimately involved in the enantiodiscrimination
      process.

PMID- 15037753
TI  - Promoter unwinding and promoter clearance by RNA polymerase: detection by single
      molecule DNA nanomanipulation.
AB  - By monitoring the end-to-end extension of a mechanically stretched, supercoiled,
      single DNA molecule, we have been able directly to observe the change in
      extension associated with unwinding of approximately one turn of promoter DNA by
      RNA polymerase (RNAP). By performing parallel experiments with negatively and
      positively supercoiled DNA, we have been able to deconvolute the change in
      extension caused by RNAP-dependent DNA unwinding (with approximately 1-bp
      resolution) and the change in extension caused by RNAP-dependent DNA compaction
      (with approximately 5-nm resolution). We have used this approach to quantify the
      extent of unwinding and compaction, the kinetics of unwinding and compaction, and
      effects of supercoiling, sequence, ppGpp, and nucleotides. We also have used this
      approach to detect promoter clearance and promoter recycling by successive RNAP
      molecules. We find that the rate of formation and the stability of the unwound
      complex depend profoundly on supercoiling and that supercoiling exerts its
      effects mechanically (through torque), and not structurally (through the number
      and position of supercoils). The approach should permit analysis of other nucleic
      acid-processing factors that cause changes in DNA twist and/or DNA compaction.

PMID- 15037754
TI  - The unique insert in myosin VI is a structural calcium-calmodulin binding site.
AB  - Myosin VI contains an inserted sequence that is unique among myosin superfamily
      members and has been suggested to be a determinant of the reverse directionality
      and unusual motility of the motor. It is thought that each head of a two-headed
      myosin VI molecule binds one calmodulin (CaM) by means of a single "IQ motif".
      Using truncations of the myosin VI protein and electrospray ionization(ESI)-MS,
      we demonstrate that in fact each myosin VI head binds two CaMs. One CaM binds to
      a conventional IQ motif either with or without calcium and likely plays a
      regulatory role when calcium binds to its N-terminal lobe. The second CaM binds
      to a unique insertion between the converter region and IQ motif. This unusual CaM
      binding site normally binds CaM with four Ca2+ and can bind only if the C
      terminal lobe of CaM is occupied by calcium. Regions of the MD outside of the
      insert peptide contribute to the Ca(2+)-CaM binding, as truncations that
      eliminate elements of the MD alter CaM binding and allow calcium dissociation. We
      suggest that the Ca(2+)-CaM bound to the unique insert represents a structural
      CaM, and not a calcium sensor or regulatory component of the motor. This
      structure is likely an integral part of the myosin VI "converter" region and
      repositions the myosin VI "lever arm" to allow reverse direction (minus-end)
      motility on actin.

PMID- 15037755
TI  - Impact of isotype-selective estrogen receptor agonists on ovarian function.
AB  - Other isotype-selective estrogen receptor (ER) agonists, the selective ERalpha
      agonist 3,17-dihydroxy-19-nor-17alpha-pregna-1,3,5 (10)-triene-21,16alpha-lactone
      and the selective ERbeta agonist 8-vinylestra-1,3,5 (10)-triene-3,17beta-diol,
      were used in hypophysectomized rats, gonadotropin-releasing hormone antagonist
      treated mice, as well as intact rats to elucidate the effects of isotype
      selective estrogens on the physiology of folliculogenesis and ovulation. In
      hypophysectomized rats and gonadotropin-releasing hormone antagonist-treated
      mice, the ERbeta agonist caused stimulation of early folliculogenesis, a decrease
      in follicular atresia, induction of ovarian gene expression, and stimulation of
      late follicular growth, accompanied by an increase in the number of ovulated
      oocytes similar to 17beta-estradiol (E2). In contrast, the ERalpha agonist had
      little or no effect on these parameters, implying that direct estrogen effects on
      ovarian follicular development are mediated by ERbeta. In intact rats, E2 and the
      ERalpha agonist dose-dependently inhibited ovulation, in contrast to the ERbeta
      agonist. On the other hand, the ERbeta agonist did not stimulate uterine weight
      in intact rats, in contrast to E2 and the ERalpha agonist. This finding is in
      line with the assumption that estrogen mediated ovulation inhibition and
      stimulation of uterine growth are mediated by ERalpha but not by ERbeta

PMID- 15037758
TI  - The yeast cell-cycle network is robustly designed.
AB  - The interactions between proteins, DNA, and RNA in living cells constitute
      molecular networks that govern various cellular functions. To investigate the
      global dynamical properties and stabilities of such networks, we studied the cell
      cycle regulatory network of the budding yeast. With the use of a simple dynamical
      model, it was demonstrated that the cell-cycle network is extremely stable and
      robust for its function. The biological stationary state, the G1 state, is a
      global attractor of the dynamics. The biological pathway, the cell-cycle sequence
      of protein states, is a globally attracting trajectory of the dynamics. These
      properties are largely preserved with respect to small perturbations to the
      network. These results suggest that cellular regulatory networks are robustly
      designed for their functions.

PMID- 15037762
TI  - Coupling morphogenesis to mitotic entry.
AB  - In eukaryotes, cyclin B-bound cyclin-dependent protein kinase 1 promotes mitotic
      entry but is held in check, in part, by Wee1 protein kinase. Timely mitotic entry
      in budding yeast requires inactivation of Swe1 (Wee1 ortholog). Perturbations of
      the septin collar at the bud neck lead to Swe1 stabilization, delaying the G(2)/M
      transition. Swe1 is recruited to the neck and hyperphosphorylated before
      ubiquitin-mediated degradation. Hsl1 kinase (Nim1 ortholog), a negative regulator
      of Wee1, is required for efficient Swe1 localization at the neck but seems not to
      phosphorylate Swe1. Here, we show that two other kinases targeted sequentially to
      the neck, Cla4/PAK and Cdc5/Polo, are responsible for stepwise phosphorylation
      and down-regulation of Swe1. This mechanism links assembly of a cellular
      structure to passage into mitosis.

PMID- 15037763
TI  - Evolutionary resealing of a split RNA: Reversal of gene permutation.

PMID- 15037764
TI  - Mutations in the middle domain of yeast poly(A) polymerase affect interactions
      with RNA but not ATP.
AB  - The eukaryotic poly(A) polymerase (PAP) is responsible for the
      posttranscriptional extension of mRNA 3' ends by the addition of a poly(A) tract.
      The recently published three-dimensional structures of yeast and bovine PAPs have
      made a more directed biochemical analysis of this enzyme possible. Based on these
      structures, the middle domain of PAP was predicted to interact with ATP. However,
      in this study, we show that mutations of conserved residues in this domain of
      yeast PAP, Pap1, do not affect interaction with ATP, but instead disrupt the
      interaction with RNA and affect the enzyme's ability to process substrate lacking
      2' hydroxyls at the 3' end. These results are most consistent with a model in
      which the middle domain of PAP interacts directly with the recently extended RNA
      and pyrophosphate byproduct.

PMID- 15037766
TI  - Two strategically placed base pairs in helix 8 of mammalian signal recognition
      particle RNA are crucial for the SPR19-dependent binding of protein SRP54.
AB  - Signal recognition particle (SRP) guides secretory proteins to biological
      membranes in all organisms. Assembly of the large domain of mammalian SRP
      requires binding of SRP19 prior to the binding of protein SRP54 to SRP RNA. The
      crystal structure of the ternary complex reveals the parallel arrangement of RNA
      helices 6 and 8, a bridging of the helices via a hydrogen bonded A149-A201 pair
      and protein SRP19, and two A minor motifs between the asymmetric loop of helix 8
      (A213 and A214) and helix 6. We investigated which residues in helix 8 are
      responsible for the SRP19-dependent binding of SRP54 by taking advantage of the
      finding that binding of human SRP54 to Methanococcus jannaschii SRP RNA is
      independent of SRP19. Chimeric human/M. jannaschii SRP RNA molecules were
      synthesized containing predominantly human SRP RNA but possessing M. jannaschii
      SRP RNA-derived substitutions. Activities of the chimeric RNAs were measured with
      respect to protein SRP19 and the methionine-rich RNA-binding domain of protein
      SRP54 (SRP54M). Changing A213 and A214 to a uridine has no effect on the SRP19
      dependent binding of SRP54M. Instead, the two base pairs C189-G210 and C190-G209,
      positioned between the conserved binding site of SRP54 and the asymmetric loop,
      are critical for conveying SRP19 dependency. Furthermore, the nucleotide
      composition of five base pairs surrounding the asymmetric loop affects binding of
      SRP54M significantly. These results demonstrate that subtle, and not easily
      perceived, structural differences are of crucial importance in the assembly of
      mammalian SRP.

PMID- 15037765
TI  - Evidence that polyadenylation factor CPSF-73 is the mRNA 3' processing
      endonuclease.
AB  - Generation of the polyadenylated 3' end of an mRNA requires an endonucleolytic
      cleavage followed by synthesis of the poly(A) tail. Despite the seeming
      simplicity of the reaction, more than a dozen polypeptides are required, and
      nearly all appear to be necessary for the cleavage reaction. Because of this
      complexity, the identity of the endonuclease has remained a mystery. Here we
      present evidence that a component of the cleavage-polyadenylation specificity
      factor CPSF-73 is the long-sought endonuclease. We first show, using site
      specific labeling and UV-cross-linking, that a protein with properties of CPSF-73
      is one of only two polypeptides in HeLa nuclear extract to contact the cleavage
      site in an AAUAAA-dependent manner. The recent identification of CPSF-73 as a
      possible member of the metallo-beta-lactamase family of Zn(2+)-dependent
      hydrolytic enzymes suggests that this contact may identify CPSF-73 as the
      nuclease. Supporting the significance of the putative hydrolytic lactamase domain
      in CPSF-73, we show that mutation of key residues predicted to be required for
      activity in the yeast CPSF-73 homolog result in lethality. Furthermore, in
      contrast to long held belief, but consistent with properties of metallo-beta
      lactamases, we show that 3' cleavage is metal-dependent, likely reflecting a
      requirement for tightly protein-bound Zn(2+). Taken together, the available data
      provide strong evidence that CPSF-73 is the 3' processing endonuclease.

PMID- 15037767
TI  - Analysis of the requirement for RNA polymerase II CTD heptapeptide repeats in pre
      mRNA splicing and 3'-end cleavage.
AB  - The carboxyl-terminal domain (CTD) of RNA polymerase II (pol II) plays an
      important role in coupling transcription with precursor messenger RNA (pre-mRNA)
      processing. Efficient capping, splicing, and 3'-end cleavage of pre-mRNA depend
      on the CTD. Moreover, specific processing factors are known to associate with
      this structure. The CTD is therefore thought to act as a platform that
      facilitates the assembly of complexes required for the processing of nascent
      transcripts. The mammalian CTD contains 52 tandemly repeated heptapeptides with
      the consensus sequence YSPTSPS. The C-terminal half of the mammalian CTD contains
      mostly repeats that diverge from this consensus sequence, whereas the N-terminal
      half contains mostly repeats that match the consensus sequence. Here, we
      demonstrate that 22 tandem repeats, from either the conserved or divergent halves
      of the CTD, are sufficient for approximate wild-type levels of transcription,
      splicing, and 3'-end cleavage of two different pre-mRNAs, one containing a
      constitutively spliced intron, and the other containing an intron that depends on
      an exon enhancer for efficient splicing. In contrast, each block of 22 repeats is
      not sufficient for efficient inclusion of an alternatively spliced exon in
      another pre-mRNA. In this case, a longer CTD is important for counteracting the
      negative effect of a splicing silencer element located within the alternative
      exon. Our results indicate that the length, rather than the composition of CTD
      repeats, can be the major determinant in efficient processing of different pre
      mRNA substrates. However, the extent of this length requirement depends on
      specific sequence features within the pre-mRNA substrate.

PMID- 15037768
TI  - Transportins 1 and 2 are redundant nuclear import factors for hnRNP A1 and HuR.
AB  - Several mRNA-binding proteins, including hnRNP A1 and HuR, contain bidirectional
      transport signals that mediate both their nuclear import and export. Previously,
      Transportin 1 (Trn1) was identified as a mediator of hnRNP A1 import, whereas the
      closely related protein Transportin 2 (Trn2) was shown to interact with HuR. Here
      we have investigated the subfamily of transportins that consists of Trn1 (or Kap
      beta2A) and two alternatively spliced Trn2 isoforms (Trn2a and Trn2b), also
      called Trn2 and Kap beta2B. The sequence differences among these proteins could
      alter either their cargo specificity or their response to RanGTP and thus their
      function as import or export receptors. Using in vitro binding assays, we show
      that hnRNP A1 preferentially binds Trn1 and Trn2b versus Trn2a. HuR interacts
      with all three transportins, as well as weakly with Imp beta. The hnRNP A1 and
      HuR shuttling domains, called M9 and HNS, respectively, are sufficient for these
      interactions. Despite small differences in the binding of HuR and hnRNP A1 to the
      three transportins, in vitro interaction studies performed in the presence and
      absence of RanQ69LGTP indicate that all three transportins most likely act as
      import factors for HuR and hnRNP A1. In digitonin-permeabilized HeLa cells, both
      M9 and HNS peptides compete for the import of recombinant hnRNP A1 and HuR,
      indicating that HuR and hnRNP A1 import pathways are at least partially
      overlapping. Possible nucleocytoplasmic shuttling mechanisms for hnRNP A1 and HuR
      are discussed.

PMID- 15037769
TI  - Definition of bases in 23S rRNA essential for ribosomal subunit association.
AB  - The ribosome is a two-subunit molecular machine, sporting a working cycle that
      involves coordinated movements of the subunits. Recent structural studies of the
      70S ribosome describe a rather large number of intersubunit contacts, some of
      which are dynamic during translocation. We set out to determine which
      intersubunit contacts are functionally indispensable for the association of
      ribosome subunits by using a modification interference approach. Modification of
      the N-1 position of A715, A1912, or A1918 in Escherichia coli 50S subunits is
      strongly detrimental to 70S ribosome formation. This result points to 23S rRNA
      helices 34 and 69, and thus bridges B2a and B4, as essential for ensuring
      stability of the 70S ribosome.

PMID- 15037771
TI  - Mitochondrial 3' tRNA editing in the jakobid Seculamonas ecuadoriensis: a novel
      mechanism and implications for tRNA processing.
AB  - The jakobid flagellates are bacteriovorus protists with mitochondrial genomes
      that are the most ancestral identified to date, in that they most resemble the
      genomes of the alpha-proteobacterial ancestors of the mitochondrion. Because of
      the bacterial character of jakobid mitochondrial genomes, it was expected that
      mechanisms for gene expression and RNA structures would be bacterial in nature.
      However, sequencing of the mitochondrial genome of the jakobid Seculamonas
      ecuadoriensis revealed several apparent mismatches in the acceptor stems of two
      predicted tRNAs. To investigate this observation, we determined the cDNA
      sequences of these tRNAs by RT-PCR. Our results show that the last three
      positions of the 3' extremity, plus the discriminator position of seryl and
      glutamyl tRNAs, are altered posttranscriptionally, restoring orthodox base
      pairing and replacing the discriminator with an adenosine residue, in an editing
      process that resembles that of the metazoan Lithobius forficatus. However, the
      most 5' of the edited nucleotides is occasionally left unedited, indicating that
      the editing mechanism proceeds initially by exonucleolytic degradation, followed
      by repair of the degraded region. This 3' tRNA editing mechanism is likely
      distinct from that of L. forficatus, despite the apparent similarities between
      the two systems.

PMID- 15037770
TI  - Loss of the mRNA-like region in mitochondrial tmRNAs of jakobids.
AB  - It has been postulated that a highly reduced form of transfer messenger RNA
      (tmRNA), a bacterial molecule involved in the rescue of stalled ribosomes during
      translation, is expressed in the mitochondrion of the jakobid Reclinomonas
      americana. Here we show that genes encoding both one-piece and two-piece tmRNAs
      are present in six different jakobid mitochondrial DNAs. Mitochondrial tmRNAs
      have retained the highly conserved tRNA(Ala)-like domain, but they apparently
      lack the mRNA-like region present in all bacterial tmRNAs. Comparative analysis
      of jakobid mitochondrial genomes shows that a potential mRNA-like region in R.
      americana (orf64) is located at distant genomic positions in other jakobids. Our
      results strongly suggest that orf64 is a tatA homolog. Through Northern
      hybridization we confirm the postulated reduced size of both a one-piece tmRNA in
      Jakoba libera and a two-piece tmRNA in Seculamonas ecuadoriensis. The J. libera
      tmRNA is post-transcriptionally modified by addition of a 3' CCA tail, processed
      in vitro by RNase P RNA, and specifically charged with alanine in vitro by alanyl
      tRNA synthetase. Our results strongly support the functionality of these reduced
      mitochondrial tmRNAs.

PMID- 15037773
TI  - The Neurospora crassa CYT-18 protein C-terminal RNA-binding domain helps
      stabilize interdomain tertiary interactions in group I introns.
AB  - The Neurospora crassa mitochondrial tyrosyl-tRNA synthetase (CYT-18 protein)
      promotes the splicing of group I introns by stabilizing the catalytically active
      RNA structure. To accomplish this, CYT-18 recognizes conserved structural
      features of group I intron RNAs using regions of the N-terminal nucleotide
      binding fold, intermediate alpha-helical, and C-terminal RNA-binding domains that
      also function in binding tRNA(Tyr). Curiously, whereas the splicing of the N.
      crassa mitochondrial large subunit rRNA intron is completely dependent on CYT
      18's C-terminal RNA-binding domain, all other group I introns tested thus far are
      spliced efficiently by a truncated protein lacking this domain. To investigate
      the function of the C-terminal domain, we used an Escherichia coli genetic assay
      to isolate mutants of the Saccharomyces cerevisiae mitochondrial large subunit
      rRNA and phage T4 td introns that can be spliced in vivo by the wild-type CYT-18
      protein, but not by the C-terminally truncated protein. Mutations that result in
      dependence on CYT-18's C-terminal domain include those disrupting two long-range
      GNRA tetraloop/receptor interactions: L2-P8, which helps position the P1 helix
      containing the 5'-splice site, and L9-P5, which helps establish the correct
      relative orientation of the P4-P6 and P3-P9 domains of the group I intron
      catalytic core. Our results indicate that different structural mutations in group
      I intron RNAs can result in dependence on different regions of CYT-18 for RNA
      splicing.

PMID- 15037774
TI  - Dim2p, a KH-domain protein required for small ribosomal subunit synthesis.
AB  - Recent proteomic analyses are revealing the dynamics of preribosome assembly.
      Following cleavage at processing site A(2), which generates the 20S pre-rRNA (the
      immediate precursor to the 18S rRNA), early RRPs (ribosomal RNA processing
      factors) are released in bulk from the preribosomes, and the resulting pre-40S
      subunits are left associated with a limited set of proteins that we refer to as
      the SSU RRP complex. Dim2p, a core constituent of the SSU RRP complex and
      conserved KH-domain containing protein, is required for pre-rRNA processing and
      is associated with early nucleolar and late cytoplasmic pre-rRNA species.
      Consistently, Dim2p shuttles between the nucle(ol)us and the cytoplasm, a
      trafficking that is tightly regulated by growth. The association of Dim2p with
      the 18S rRNA dimethyltransferase Dim1p, as well as its requirement for pre-rRNA
      processing at cleavage sites A(1) and A(2) and for 18S rRNA dimethylation,
      suggest that Dim2p may recruit Dim1p to nucleolar pre-rRNAs through its KH
      domain.

PMID- 15037772
TI  - In vivo recruitment of exon junction complex proteins to transcription sites in
      mammalian cell nuclei.
AB  - Studies over the past years indicate that there is extensive coupling between
      nuclear export of mRNA and pre-mRNA processing. Here, we visualized the
      distribution of exon junction complex (EJC) proteins and RNA export factors
      relative to sites of abundant pre-mRNA synthesis in the nucleus. We analyzed both
      HeLa cells infected with adenovirus and murine erythroleukemia (MEL) cells stably
      transfected with the human beta-globin gene. Using in situ hybridization and
      confocal microscopy, we observe accumulation of EJC proteins (REF/Aly, Y14,
      SRm160, UAP56, RNPS1, and Magoh) and core spliceosome components (U snRNPs) at
      sites of transcription. This suggests that EJC proteins bind stably to pre-mRNA
      cotranscriptionally. No concentration of the export factors NXF1/TAP, p15, and
      Dbp5 was detected on nascent transcripts, arguing that in mammalian cells these
      proteins bind the mRNA shortly before or after release from the sites of
      transcription. These results also suggest that binding of EJC proteins to the
      mRNA is not sufficient to recruit TAP-p15, consistent with recent findings
      showing that the EJC does not play a crucial role in mRNA export. Contrasting to
      the results obtained in MEL cells expressing normal human beta-globin
      transcripts, mutant pre-mRNAs defective in splicing and 3'end processing do not
      colocalize with SRm160, REF, UAP56, or Sm proteins. This shows that the
      accumulation of EJC proteins at transcription sites requires efficient processing
      of the nascent pre-mRNAs, arguing that transcription per se is not sufficient for
      the stable assembly of the EJC.

PMID- 15037775
TI  - Premature termination codons do not affect the rate of splicing of neighboring
      introns.
AB  - Introduction of a premature termination codon (PTC) into an exon of a gene can
      lead to nonsense-mediated decay of the mRNA, which is best characterized as a
      cytoplasmic event. However, increasing evidence has suggested that PTCs may also
      influence the nuclear processing of an RNA transcript, leading to models of
      nuclear surveillance perhaps involving translating nuclear ribosomes. We used
      quantitative RT-PCR to measure the in vivo steady-state levels of every exon
      intron junction in wild-type, PTC-containing, and missense-containing precursor
      mRNAs of both the nonrearranging dihydrofolate reductase (DHFR) and the
      somatically rearranging Ig- micro genes. We find that each exon-intron junction's
      abundance and, therefore, the rate of intron removal, is not significantly
      affected by the presence of a PTC in a neighboring exon in either the DHFR or Ig-
      micro pre-mRNA. Similarly, the abundance of the uncleaved Ig- micro
      polyadenylation sites does not differ between wild-type and PTC-containing Ig-
      micro pre-mRNAs. Our Ig- micro data were confirmed by RNase protection analyses,
      and multiple cell isolates were examined to resolve differences with previously
      published data on steady-state pre-mRNA levels. We conclude that the presence of
      a PTC affects the rate of neither splicing nor the cleavage step of 3' end
      formation during pre-mRNA processing in the nucleus. Our results are discussed
      with respect to existing evidence for nuclear surveillance mechanisms.

PMID- 15037776
TI  - Functional dissection of hnRNP D suggests that nuclear import is required before
      hnRNP D can modulate mRNA turnover in the cytoplasm.
AB  - Many shuttling proteins not only function in the nucleus but also control mRNA
      fates in the cytoplasm. We test whether a link exists between their nuclear
      association with mRNPs and their cytoplasmic functions using the p37 isoform of
      hnRNP D, which inhibits the rapid cytoplasmic mRNA decay in NIH3T3 cells. We
      showed that p37 shuttles between nucleus and cytoplasm, and narrowed down the
      nuclear import signal to a 50-amino-acid C-terminal domain. A p37 mutant missing
      this domain, still capable of associating with target mRNAs in vitro, was
      confined to the cytoplasm, where it was unable to block cytoplasmic mRNA
      turnover. Introducing heterologous shuttling domains to this mutant, thereby
      restoring its ability to enter the nucleus, concomitantly restored its
      cytoplasmic function. Association of p37 with its target mRNAs can only be
      detected when it can enter the nucleus. Our results suggest that nuclear import
      of hnRNP D is a prerequisite for it to exert its cytoplasmic function. This study
      provides a useful model system to elucidate the mechanisms by which "nuclear
      history" affects cytoplasmic mRNA fates.

PMID- 15037777
TI  - Pseudouridines in and near the branch site recognition region of U2 snRNA are
      required for snRNP biogenesis and pre-mRNA splicing in Xenopus oocytes.
AB  - Virtually all uridines in the branch site recognition region (BSRR) of vertebrate
      U2 are converted into pseudouridines after initial transcription. Here, we report
      a functional analysis of these modified nucleotides using the Xenopus oocyte
      reconstitution system. Using site-specific (32)P-labeling and TLC, we show that
      U2 pseudouridylation occurs much faster in the BSRR than in the 5'-terminal
      region. To functionally dissect the pseudouridines in the BSRR, we replaced each
      uridine with 5-fluorouridine (unmodifiable nucleotide) using site-specific RNase
      H cleavage directed by 2'-O-methyl-RNA-DNA chimeras followed by three-piece
      ligation. Whereas in vitro transcribed U2 containing no 5-fluorouridines rescued
      splicing in U2-depleted oocytes, no rescue was observed with U2 RNA containing 5
      fluorouridines introduced into the BSRR. Additionally, U2 RNA containing 5
      fluorouridines in the BSRR specifically inhibited pseudouridylation in the BSRR
      of in vitro transcribed U2 injected at a later time, although pseudouridylation
      in the 5'-end region was not affected. Our reconstitution results indicated that
      prior injection into U2-depleted oocytes with U2 RNA containing 5-fluorouridines
      in the BSRR almost completely abrogated the ability of in vitro transcribed U2 to
      rescue splicing, whereas full rescue was obtained with either cellular U2 or U2
      containing pseudouridines in the BSRR. Further analyses using glycerol-gradient
      and native gel electrophoresis indicated that U2 RNAs lacking the BSRR
      pseudouridines do not participate in the assembly of the functionally active 17S
      U2 snRNP and the spliceosome. We conclude that the BSRR pseudouridines of
      vertebrate U2 are required for complete snRNP assembly and pre-mRNA splicing in
      Xenopus oocytes.

PMID- 15037779
TI  - A multiprotein complex involved in chloroplast group II intron splicing.
AB  - The psaA gene of the green alga Chlamydomonas reinhardtii consists of three exons
      that are widely separated on the chloroplast genome and transcribed
      independently. The exons are flanked by group II intron sequences. Maturation of
      the psaA mRNA requires two steps of splicing in trans between the transcripts of
      exons 1, 2, and 3. At least 14 nuclear loci and one chloroplast gene (tscA) are
      involved in this process. Recently the genes of three of these nuclear factors
      have been cloned. Raa3 is involved in the first trans-splicing reaction, and Raa1
      and Raa2 are required for the second trans-splicing reaction. Here we show that
      Raa1 and Raa2 can be coimmunoprecipitated and that they are part of a high
      molecular weight complex of 400-500 kD. The size and integrity of the complex are
      affected by mutations in other complementation groups, suggesting that the
      corresponding proteins may also be components of this multiprotein complex or
      required for its assembly. Raa1 is also associated with a larger complex.

PMID- 15037778
TI  - Leaky termination at premature stop codons antagonizes nonsense-mediated mRNA
      decay in S. cerevisiae.
AB  - The Nonsense-Mediated mRNA Decay (NMD) pathway mediates the rapid degradation of
      mRNAs that contain premature stop mutations in eukaryotic organisms. It was
      recently shown that mutations in three yeast genes that encode proteins involved
      in the NMD process, UPF1, UPF2, and UPF3, also reduce the efficiency of
      translation termination. In the current study, we compared the efficiency of
      translation termination in a upf1Delta strain and a [PSI(+)] strain using a
      collection of translation termination reporter constructs. The [PSI(+)] state is
      caused by a prion form of the polypeptide chain release factor eRF3 that limits
      its availability to participate in translation termination. In contrast, the
      mechanism by which Upf1p influences translation termination is poorly understood.
      The efficiency of translation termination is primarily determined by a
      tetranucleotide termination signal consisting of the stop codon and the first
      nucleotide immediately 3' of the stop codon. We found that the upf1Delta
      mutation, like the [PSI(+)] state, decreases the efficiency of translation
      termination over a broad range of tetranucleotide termination signals in a
      unique, context-dependent manner. These results suggest that Upf1p may associate
      with the termination complex prior to polypeptide chain release. We also found
      that the increase in readthrough observed in a [PSI(+)]/upf1Delta strain was
      larger than the readthrough observed in strains carrying either defect alone,
      indicating that the upf1Delta mutation and the [PSI(+)] state influence the
      termination process in distinct ways. Finally, our analysis revealed that the
      mRNA destabilization associated with NMD could be separated into two distinct
      forms that correlated with the extent the premature stop codon was suppressed.
      The minor component of NMD was a 25% decrease in mRNA levels observed when
      readthrough was >/=0.5%, while the major component was represented by a larger
      decrease in mRNA abundance that was observed only when readthrough was </=0.5%.
      This low threshold for the onset of the major component of NMD indicates that
      mRNA surveillance is an ongoing process that occurs throughout the lifetime of an
      mRNA.

PMID- 15037780
TI  - The Saccharomyces cerevisiae TAN1 gene is required for N4-acetylcytidine
      formation in tRNA.
AB  - The biogenesis of transfer RNA is a process that requires many different factors.
      In this study, we describe a genetic screen aimed to identify gene products
      participating in this process. By screening for mutations lethal in combination
      with a sup61-T47:2C allele, coding for a mutant form of, the nonessential TAN1
      gene was identified. We show that the TAN1 gene product is required for formation
      of the modified nucleoside N(4)-acetylcytidine (ac(4)C) in tRNA. In Saccharomyces
      cerevisiae, ac(4)C is present at position 12 in tRNAs specific for leucine and
      serine as well as in 18S ribosomal RNA. Analysis of RNA isolated from a tan1-null
      mutant revealed that ac(4)C was absent in tRNA, but not rRNA. Although no tRNA
      acetyltransferase activity by a GST-Tan1 fusion protein was detected, a gel-shift
      assay revealed that Tan1p binds tRNA, suggesting a direct role in synthesis of
      ac(4)C(12). The absence of the TAN1 gene in the sup61-T47:2C mutant caused a
      decreased level of mature, indicating that ac(4)C(12) and/or Tan1p is important
      for tRNA stability.

PMID- 15037781
TI  - Demonstrating internal ribosome entry sites in eukaryotic mRNAs using stringent
      RNA test procedures.
AB  - The dicistronic assay for internal ribosome entry site (IRES) activity is the
      most widely used method for testing putative sequences that may drive cap
      independent translation initiation. This assay typically involves the
      transfection of cells with dicistronic DNA test constructs. Many of the reports
      describing eukaryotic IRES elements have been criticized for the use of
      inadequate methods for the detection of aberrant RNAs that may form in
      transfected cells using this assay. Here we propose the combined use of a new
      RNAi-based method together with RT-PCR to effectively identify aberrant RNAs. We
      illustrate the use of these methods for analysis of RNAs generated in cells
      transfected with dicistronic test DNAs containing either the hepatitis C virus
      (HCV) IRES or the X-linked inhibitor of apoptosis (XIAP) cellular IRES. Both
      analyses indicated aberrantly spliced transcripts occurred in cells transfected
      with the XIAP dicistronic DNA construct. This contributed to the unusually high
      levels of apparent IRES activity exhibited by the XIAP 5' UTR in vivo. Cells
      transfected directly with dicistronic RNA exhibited much lower levels of XIAP
      IRES activity, resembling the lower levels observed after translation of
      dicistronic RNA in rabbit reticulocyte lysates. No aberrantly spliced transcripts
      could be detected following direct RNA transfection of cells. Interestingly,
      transfection of dicistronic DNA or RNA containing the HCV IRES did not form
      aberrantly spliced transcripts. These observations stress the importance of using
      alternative test procedures (e.g., direct RNA transfection) in conjunction with a
      combination of sensitive RNA analyses for discerning IRES-containing sequences in
      eukaryotic mRNAs.

PMID- 15037784
TI  - Cryopreservation of semen of the Salmonidae with special reference to large-scale
      fertilization.

PMID- 15037782
TI  - Practical and general synthesis of 5'-adenylated RNA (5'-AppRNA).
AB  - A simple strategy is reported for 5'-adenylation of nearly any RNA sequence of
      indefinite length. The 5'-adenylated product (5'-AppRNA) is an activated RNA that
      is structurally similar to 5'-triphosphorylated RNA, which is usually prepared by
      in vitro transcription using T7 RNA polymerase. In the new 5'-adenylation
      strategy, the RNA substrate is first 5'-monophosphorylated either by T4
      polynucleotide kinase, by in vitro transcription in the presence of excess GMP,
      or by appropriate derivatization during solid-phase synthesis. The RNA is then 5'
      adenylated using ATP and T4 RNA ligase, in an interrupted version of the natural
      adenylation-ligation mechanism by which T4 RNA ligase joins two RNA substrates.
      Here, the final ligation step of the mechanism is inhibited with complementary
      DNA blocking oligonucleotide(s) that permit adenylation to occur with good yield.
      The 5'-AppRNA products of this approach should be valuable as activated RNAs for
      in vitro selection experiments as an alternative to 5'-triphosphorylated RNAs,
      among other likely applications. The 5'-terminal nucleotide of an RNA substrate
      to be adenylated using the new method is not restricted to guanosine, in contrast
      to 5'-triphosphorylated RNA prepared by in vitro transcription. Therefore, using
      the new approach, essentially any RNA obtained from solid-phase synthesis or
      other means can be activated by 5'-adenylation in a practical manner.

PMID- 15037785
TI  - Fertilization and sperm chemotaxis in ascidians.

PMID- 15037783
TI  - Selection of AU-rich transiently expressed sequences: reversal of cDNA abundance.
AB  - Study of early and transient response gene expression is important for
      understanding the mechanisms of response to growth stimuli and exogenous agents
      such as microbes, stress, and radiation. Many of the cytokines, proto-oncogenes,
      and other transiently expressed gene products are encoded by mRNAs that contain
      AU-rich elements (AREs) in their 3' untranslated regions (UTRs). In this article,
      we describe an approach to selectively synthesize ARE-containing cDNA (ARE-cDNA)
      using an innovative combination of culture treatment, thermostabilization of
      reverse transcriptase (RT) by the disaccharide trehalose, and use of optimized
      ARE-specific oligomers. The monocytic cell line, THP-1, was treated with
      cycloheximide and endotoxin to enrich for ARE-mediated gene expression followed
      by the RT procedure. Selection of ARE-cDNA with simultaneous suppression of
      abundant cDNA was made possible using the procedure as monitored by the
      preferential expression of IL-8, an ARE-cDNA molecule, over the abundant
      housekeeping cDNA, beta-actin. The use of trehalose dramatically reversed cDNA
      abundance, resulting in almost complete suppression of housekeeping cDNA.
      Finally, construction of specialized ARE-cDNA libraries confirmed the selectivity
      of ARE-cDNAs and the presence of rare genes. The ability to reverse the abundance
      of housekeeping and other highly expressed genes toward ARE genes facilitates the
      discovery and study of rare early response and transiently expressed genes.

PMID- 15037786
TI  - Assays for vertebrate sperm chemotaxis.

PMID- 15037787
TI  - Stallion spermatozoa viability: comparison of flow cytometry with other methods.

PMID- 15037788
TI  - Visualization of sperm accessory structures in the mammalian spermatids,
      spermatozoa, and zygotes by immunofluorescence, confocal, and immunoelectron
      microscopy.

PMID- 15037789
TI  - Localization of zona pellucida receptors on live sperm by fluorophore-conjugated
      solubilized zona pellucida proteins.

PMID- 15037790
TI  - Detection of human papillomavirus DNA in sperm using polymerase chain reaction.

PMID- 15037791
TI  - Spermatogonial stem cells.

PMID- 15037792
TI  - Molecular and cellular approaches for establishment of an in vitro
      spermatogenesis system.

PMID- 15037793
TI  - Acrosin activity assay for the evaluation of mammalian sperm acrosome reaction.

PMID- 15037794
TI  - Isolation of sea urchin sperm plasma membranes.

PMID- 15037795
TI  - Detection of centrosome structure in fertilized and artificially activated sea
      urchin eggs using immunofluorescence microscopy and isolation of centrosomes
      followed by structural characterization with field emission scanning electron
      microscopy.

PMID- 15037797
TI  - Immunocytochemical staining of the metaphase II spindle in mammalian oocytes.

PMID- 15037796
TI  - Microscopic techniques for studying sperm-oocyte interaction during fertilization
      and early embryonic development.

PMID- 15037798
TI  - Spindle imaging in living mammalian oocytes using the liquid-crystal polarized
      light microscope and its practical use.

PMID- 15037799
TI  - In vitro maturation and fertilization of pig oocytes.

PMID- 15037800
TI  - In vitro maturation and in vitro fertilization of human oocytes.

PMID- 15037801
TI  - In vitro maturation and fertilization of canine oocytes.

PMID- 15037802
TI  - Detection and measurement of membrane-bound protein tyrosine kinases in the
      zebrafish egg.

PMID- 15037803
TI  - Single-cell method for estimation of protein tyrosine kinases in the zebrafish
      egg.

PMID- 15037804
TI  - Activity of MAPK/p90rsk during fertilization in mice, rats, and pigs.

PMID- 15037805
TI  - Glutamate signaling system in bone.
AB  - L-glutamate (Glu) has been thought to be an excitatory amino acid
      neurotransmitter in the mammalian central nervous system (CNS). The hypothesis is
      supported by successful cloning of a number of genes encoding different signaling
      molecules, such as Glu receptors for signal input, Glu transporters for signal
      termination, and vesicular Glu transporters for signal output through exocytotic
      release. Limited information is available in the literature with regard to an
      extracellular transmitter role of Glu in peripheral neuronal and non-neuronal
      tissues, whereas recent molecular biological analyses including ours give rise to
      a novel function for Glu as an autocrine and/or paracrine factor in bone
      comprised of osteoblasts, osteoclasts, and osteocytes, in addition to other
      peripheral tissues including pancreas, adrenal, and pituitary glands. Emerging
      evidence suggests that Glu could play a dual role in mechanisms underlying
      maintenance of cellular homeostasis as an excitatory neurotransmitter in the CNS
      and as an extracellular signal mediator in peripheral autocrine and/or paracrine
      tissues. In this review, therefore, we summarized the possible signaling by Glu
      as an extracellular signal mediator in mechanisms underlying maintenance of
      cellular homeostasis with a focus on bone tissues.

PMID- 15037806
TI  - Hypoxia-inducible factor 1-related diseases and prospective therapeutic tools.
AB  - Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a
      master regulator of oxygen homeostasis. HIF-1 regulates the expressions of the
      proteins that increase oxygen delivery, which enables cells to survive in oxygen
      deficient conditions. Based on information as to which types of genes are
      controlled by HIF-1, it appears that HIF-1 provides pathological tissues with
      survival in hypoxic regions or angiogenic activity. Therefore, HIF-1 inhibitors
      could be useful as therapeutic agents for various diseases associated with the
      over-activation of HIF-1, such as cancers, cardiovascular remodeling,
      preeclampsia, and other angiogenesis-related diseases. In this review, we
      summarize the oxygen-dependent and -independent regulation of HIF-1 and introduce
      prospective HIF-1 inhibitors that might be useful in the treatment of HIF-1
      related diseases.

PMID- 15037807
TI  - Protein kinase C activation by Helicobacter pylori in human gastric epithelial
      cells limits interleukin-8 production through suppression of extracellular signal
      regulated kinase.
AB  - Helicobacter pylori (H. pylori) infection of gastric epithelial cells has been
      shown to induce interleukin (IL)-8 production, but the signal transduction
      mechanism leading to IL-8 production has not been clearly defined. Here, we
      investigate the role of protein kinase C (PKC) in the mechanism of induction of
      IL-8 release by H. pylori in human gastric epithelial cells. In MKN45 cells, H.
      pylori-induced IL-8 release was enhanced by treatment with PKC inhibitors
      (GF109203X and calphostin C) and PKC depletion, which completely inhibited PKC
      activity. Moreover, PKC inhibitors and PKC depletion increased extracellular
      signal-regulated kinase (ERK) activity and phosphorylation, but not
      calcium/calmodulin-dependent protein kinase II (CaMK II) activity, in response to
      H. pylori infection. PKC activated by H. pylori inhibited activation of ERK
      induced by H. pylori without affecting the CaMK II activity and negatively
      regulated IL-8 production in human gastric epithelial cells.

PMID- 15037808
TI  - Role of pharmacokinetic effects in the potentiation of morphine analgesia by L
      type calcium channel blockers in mice.
AB  - The present study was designed to investigate the pharmacokinetic interaction of
      morphine with three classes of L-type calcium channel blockers (CCB) and its
      relationship to morphine-induced mechanical antinociception in mice. The CCB
      classes were benzothiazepine (diltiazem), dihydropyridine (nimodipine), and
      phenylalkylamine (verapamil). Each of the three classes of L-type CCB (diltiazem,
      40 and 80 mg/kg; nimodipine, 40 mg/kg; verapamil, 40 mg/kg), when administered
      prior to morphine (4 mg/kg, s.c.), potentiated the analgesic effect of morphine
      and markedly increased the level of morphine in serum. Pretreatment with
      diltiazem (40 and 80 mg/kg) and verapamil (40 mg/kg) also increased morphine
      level in the brain. However, these drugs produced less increase in morphine level
      in the brain than they produced in serum (i.e., they decreased the brain-to-serum
      ratio of morphine). Pretreatment with nimodipine (40 mg/kg) did not affect the
      morphine level in the brain and also decreased the brain-to-serum ratio of
      morphine. When morphine (3.2-100 mg/kg, s.c.) was injected alone, the brain-to
      serum ratio of morphine was constant, regardless of the morphine dose. These
      results suggest that increases in morphine concentration in peripheral blood may
      be, at least in part, involved in the ability of L-type CCBs to potentiate the
      analgesic effect of morphine.

PMID- 15037809
TI  - Electroencephalographic properties of zaleplon, a non-benzodiazepine
      sedative/hypnotic, in rats.
AB  - The encephalographic (EEG) properties of zaleplon were investigated in comparison
      with those of other sedative hypnotics in conscious rats with chronically
      implanted electrodes. The oral administration of zaleplon (0.25-1.0 mg/kg),
      triazolam (0.0625-0.25 mg/kg), zopiclone (1.0-4.0 mg/kg), brotizolam (0.0625-0.25
      mg/kg), and nitrazepam (0.125-0.5 mg/kg) lengthened the total sleep in a dose
      dependent manner. On distribution of sleep-wakefulness stages, zaleplon, in
      particular, increased the slow wave deep sleep (SWDS), whereas triazolam,
      brotizolam, and nitrazepam increased the slow wave light sleep (SWLS) in a dose
      dependent manner. Zopiclone significantly increased the SWDS at a dose of 2 mg/kg
      and both the SWLS and the SWDS at a dose of 4 mg/kg. All tested hypnotics caused
      no influence on fast wave sleep (FWS) at doses tested. The appearance of the
      sleep-inducing activity of zaleplon was more rapid than those of any compounds
      tested, and zaleplon significantly increased the relative EEG power density in
      the delta frequency band over that of triazolam at 20 and 30 min after the
      administration in the spectral analysis. Therefore, the present findings suggest
      that the non-benzodiazepine zaleplon can be expected to exhibit high practical
      potential as a hypnotic and is characterized by an increase in SWDS with rapid
      onset of hypnotic action.

PMID- 15037810
TI  - The inhibitory mechanism of YC-1, a benzyl indazole, on smooth muscle cell
      proliferation: an in vitro and in vivo study.
AB  - The pharmacological mechanisms of a synthetic compound 1-benzyl-3-(5'
      hydroxymethyl-2'-furyl) indazole (YC-1) in preventing smooth muscle cell
      proliferation remains to be elucidated. The present study was aimed to explore
      the effects of YC-1 on certain molecules responsible for cell proliferation,
      including transforming growth factor (TGF)-beta1, soluble guanylyl cyclase (sGC)
      and focal adhesion kinase (FAK). The in vivo assay was correlated to the in vitro
      results of YC-1 on vascular stenosis. YC-1 was applied topically via a pluronic
      gel onto the balloon-injured rat carotid arteries, which were then harvested two
      weeks later for histological analysis. Our in vitro results showed that TGF-beta1
      was suppressed by YC-1 by 50%. The translational level of sGC was threefold
      activated by YC-1 while the transcription level of sGC was increased up to 24
      fold. FAK, the molecule responsible for cell proliferation and migration, was
      suppressed by YC-1 on the translational levels for 72%. These in vitro results
      were in consistent with the in vivo observation that the area ratio of neointima
      to media was reduced by YC-1. This study provides insights into the
      pharmacological mechanisms of YC-1 in preventing abnormal smooth muscle cell
      proliferation and thus supports the use of YC-1 as an adjuvant therapy for
      balloon injury-induced restenosis.

PMID- 15037811
TI  - Possible involvement of p38 in mechanisms underlying acceleration of
      proliferation by 15-deoxy-Delta(12,14)-prostaglandin J2 and the precursors in
      leukemia cell line THP-1.
AB  - 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ2), which is a ligand for
      peroxisome proliferator-activated receptor gamma (PPARgamma), induced apoptosis
      of several human tumors including gastric, lung, colon, prostate, and breast.
      However, the role of PPARgamma signals in other types of cancer cells (e.g.,
      leukemia) except solid cancer cells is still unclear. The aim of this study is to
      evaluate the ability of 15dPGJ2 to modify the proliferation of the human leukemia
      cell line THP-1. 15dPGJ2 at 5 microM stimulated the proliferation in THP-1 at 24
      to 72 h after incubation. In contrast, 15dPGJ2 at concentrations above 10 microM
      inhibited the proliferation through the induction of apoptosis. PGD2, PGJ2, and
      Delta12-PGJ2 (DeltaPGJ2), precursors of 15dPGJ2, had similar proliferative
      effects at lower concentrations, whereas they induced apoptosis at high
      concentrations. 15dPGJ2 and three precursors failed to induce the differentiation
      in THP-1 as assessed by using the differentiation marker CD11b. FACScan analysis
      revealed that PGD2 at 5 microM, PGJ2 at 1 microM, DeltaPGJ2 at 1 microM and
      15dPGJ2 at 5 microM all accelerated cell cycle progression in THP-1.
      Immunoblotting analysis revealed that PGD2 at 5 microM and 15dPGJ2 at 5 microM
      inhibited the expression of phospho-p38, phospho-MKK3/MKK6, and phospho-ATF-2,
      and the expression of Cdk inhibitors including p18, p21, and p27 in THP-1. In
      contrast, PGJ2 at 1 microM and DeltaPGJ2 at 1 microM did not affect their
      expressions. These results suggest that 15dPGJ2 and PGD2 may, through
      inactivation of the p38 mitogen-activated protein kinase pathway, inhibit the
      expression of Cdk inhibitors, leading to acceleration of the THP-1 proliferation.

PMID- 15037812
TI  - The effects of selective serotonin-reuptake inhibitor on visual evoked potential
      in rats.
AB  - The present study was undertaken to clarify the effects of selective serotonin
      reuptake inhibitors (SSRIs) on visual evoked potential (VEP) in rats. To
      elucidate the mechanism of action of SSRIs, some serotonin (5-HT) agonists were
      used. SSRIs, fluvoxamine and paroxetine, caused a reduction in the amplitudes of
      P1-N1, P3-N3, and N3-P4 components of VEP. The amplitude of the P1-N1 component
      was also reduced by the 5-HT1A agonist 8-OH-DPAT and 5-HT1B agonist anpirtoline.
      On the other hand, amplitudes of P3-N3 and N3-P4 components were reduced by
      anpirtoline and the 5-HT2 agonist DOI. These results indicate that the reduction
      in the amplitude of the P1-N1 component of VEP induced by SSRIs may participate
      in 5-HT1A and 5-HT1B receptors, and those of P3-N3 and N3-P4 components induced
      by SSRIs may be closely related with 5-HT1B and 5-HT2 receptors.

PMID- 15037813
TI  - Modulation of capsaicin-evoked visceral pain and referred hyperalgesia by
      protease-activated receptors 1 and 2.
AB  - Protease-activated receptors (PARs) 1 and 2 are expressed in capsaicin-sensitive
      sensory neurons, being anti- and pro-nociceptive, respectively. Given the
      possible cross talk between PAR-2 and capsaicin receptors, we investigated if PAR
      2 activation could facilitate capsaicin-evoked visceral pain and referred
      hyperalgesia in the mouse and also examined the effect of PAR-1 activation in
      this model. Intracolonic (i.col.) administration of capsaicin triggered visceral
      pain-related nociceptive behavior, followed by referred hyperalgesia. The
      capsaicin-evoked visceral nociception was suppressed by intraperitoneal (i.p.)
      TFLLR-NH2, a PAR-1-activating peptide, but not FTLLR-NH2, a control peptide, and
      unaffected by i.col. TFLLR-NH2. SLIGRL-NH2, a PAR-2-activating peptide, but not
      LRGILS-NH2, a control peptide, administered i.col., facilitated the capsaicin
      evoked visceral nociception 6-18 h after administration, while i.p. SLIGRL-NH2
      had no effect. The capsaicin-evoked referred hyperalgesia was augmented by i.col.
      SLIGRL-NH2, but not LRGILS-NH2, 6-18 h after administration, and unaffected by
      i.p. SLIGRL-NH2, and i.p. or i.col. TFLLR-NH2. Our data suggest that PAR-1 is
      antinociceptive in processing of visceral pain, whereas PAR-2 expressed in the
      colonic luminal surface, upon activation, produces delayed sensitization of
      capsaicin receptors, resulting in facilitation of visceral pain and referred
      hyperalgesia.

PMID- 15037814
TI  - Changes of brain endothelin levels and peripheral endothelin receptors by chronic
      cigarette smoke in spontaneously hypertensive rats.
AB  - The present study was conducted to evaluate the contribution of endothelin (ET)
      to the pharmacodynamic response to chronic cigarette smoke in spontaneously
      hypertensive rats (SHR). The contribution of ET was studied consequent to the
      hemodynamic response following 8 weeks of cigarette smoke by determining the
      changes in tissue ET-1 content and ET receptors. The blood pressure (BP) at the
      early phase of smoking and the heart rate (HR) 24 h later were apparently reduced
      in SHR, while the HR at the early phase was transiently elevated in normotensive
      Wistar Kyoto (WKY) rats. Tissue ET-1 levels in the hypothalamus, striatum, and
      cortex of SHR were higher than those in WKY rats, and these higher levels in SHR
      were reduced by exposure to chronic cigarette smoke. The ET-1 contents in the
      medulla oblongata and midbrain of both strains were clearly increased by smoke
      exposure, although the levels of SHR and WKY rats were not different. In
      addition, the immunoreactivity of the ET type A receptor in the adrenal glands
      and type B receptor in the kidneys of SHR showed a different response to smoke
      exposure as compared to WKY rats. Our present findings suggest that the changes
      of ETs may relate to the pharmacodynamic effects of chronic cigarette smoke.

PMID- 15037816
TI  - Disability of development of tolerance to morphine and U-50,488H, a selective
      kappa-opioid receptor agonist, in neuropathic pain model mice.
AB  - We examined the analgesic and anti-allodynic effects of morphine and U-50,488H
      (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)
      benzeneacetamide methanesulfonate salt), a selective kappa-opioid receptor
      agonist, and the development of tolerance to their effects in neuropathic pain
      model mice induced by sciatic nerve ligation (SNL). In the tail-pinch method,
      morphine at 10 mg/kg, s.c. produced a weak analgesic effect in SNL mice; however,
      U-50,488H at 5 mg/kg, s.c. produced an analgesic effect equipotent to that in
      normal mice. In contrast, morphine produced an adequate analgesic effect when
      given either intracerebroventricularly (i.c.v.) or intrathecally (i.t.), but U
      50,488H only produced analgesia when given i.t. Repeated administration of
      morphine (either i.c.v. or i.t.) or U-50,488H (either s.c. or i.t.), did not
      induce tolerance to the effect. In the static allodynia test with an application
      of von Frey filaments, both compounds given s.c. suppressed the allodynic effect,
      but in the dynamic allodynia test involving lightly stroking the plantar surface
      with a cotton bud, only U-50,488H produced an anti-allodynic effect. Repeated
      administrations of both compounds did not develop tolerance to these anti
      allodynic effects. Thus, U-50,488H was found to be a highly effective at blocking
      hyperalgesia and allodynia in nerve injury, and these findings suggest that kappa
      opioid receptor agonists are attractive pharmacological targets for the control
      of patients with neuropathic pain.

PMID- 15037815
TI  - Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate
      exchanger in the proximal tubules.
AB  - Human organic anion transporter OAT4 is expressed in the kidney and placenta and
      mediates high-affinity transport of estrone-3-sulfate (E1S). Because a previous
      study demonstrated no trans-stimulatory effects by E1S, the mode of organic anion
      transport via OAT4 remains still unclear. In the present study, we examined the
      driving force of OAT4 using mouse proximal tubular cells stably expressing OAT4
      (S2 OAT4). OAT4-mediated E1S uptake was inhibited by glutarate (GA) (IC50:1.25
      mM) and [14C]GA uptake via S2 OAT4 was significantly trans-stimulated by
      unlabeled GA (5 mM) (P<0.001). [3H]E1S uptake via S2 OAT4 was significantly trans
      stimulated by preloaded GA (P<0.001) and its [14C]GA efflux was significantly
      trans-stimulated by unlabeled E1S in the medium (P<0.05). In addition, both the
      uptake and efflux of [14C]p-aminohippuric acid (PAH) and [14C]GA via S2 OAT4 were
      significantly trans-stimulated by unlabeled GA or PAH. The immunoreactivities of
      OAT4 were observed in the apical membrane of proximal tubules along with those of
      basolateral organic anion/dicarboxylate exchangers such as hOAT1 and hOAT3 in the
      same tubular population. These results indicate that OAT4 is an apical organic
      anion/dicarboxylate exchanger and mainly functions as an apical pathway for the
      reabsorption of some organic anions in renal proximal tubules driven by an
      outwardly directed dicarboxylate gradient.

PMID- 15037817
TI  - Effects of sasanquasaponin on ischemia and reperfusion injury in mouse hearts.
AB  - We investigated effects of sasanquasaponin (SQS), a traditional Chinese herb's
      effective component, on ischemia and reperfusion injury in mouse hearts and the
      possible role of intracellular Cl- homeostasis on SQS's protective effects during
      ischemia and reperfusion. An in vivo experimental ischemia model was made in mice
      (weight 27-45 g) using ligation of left anterior descending coronary artery, and
      in vitro models were made in perfused hearts by stopping flow or in isolated
      ventricular myocytes by hypoxia. The in vivo results showed that SQS inhibited
      cardiac arrhythmias during ischemia and reperfusion. Incidence of arrhythmias
      during ischemia and reperfusion, including ventricular premature beats and
      ventricular fibrillation, was significantly decreased in the SQS-pretreated group
      (P<0.05). Results in perfused hearts showed that SQS suppressed the arrhythmias,
      prevented against ischemia-induced decrease in contract force and promoted the
      force recovery from reperfusion. Furthermore, intracellular Cl- concentrations
      ([Cl-]i) were measured using a MQAE fluorescence method in isolated ventricular
      myocytes in vitro. SQS slightly decreased [Cl-]i in non-hypoxic myocytes and
      delayed the hypoxia/reoxygenation-induced increase in [Cl-]i during ischemia and
      reperfusion (P<0.05). Our results showed that SQS protected against
      ischemia/reperfusion-induced cardiac injury in mouse hearts and that modulation
      of intracellular Cl- homeostasis by SQS would play a role in its anti-arrhythmia
      effects during ischemia and reperfusion.

PMID- 15037818
TI  - Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression by
      inhibiting activator protein 1 and nuclear factor kappab bindings in BV2
      microglial cells.
AB  - Inflammation is a significant component of chronic neurodegenerative diseases.
      Cyclooxygenase-2 (COX-2) is expressed in activated microglial cells and appears
      to be an important source of prostaglandins during inflammatory conditions. To
      investigate the effect of curcumin on COX-2 gene expression in microglial cells,
      we treated lipopolysaccharide (LPS)-challenged BV2 microglial cells with various
      concentrations of curcumin. Curcumin significantly inhibited LPS-mediated
      induction of COX-2 expression in both mRNA and protein levels in a concentration
      dependent manner. COX-2 enzyme activity was also inhibited in accordance with
      mRNA and protein levels. Furthermore, curcumin markedly inhibited LPS-induced
      nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) DNA bindings.
      These data suggest that curcumin suppresses LPS-induced COX-2 gene expression by
      inhibiting NF-kappaB and AP-1 DNA bindings in BV2 microglial cells.

PMID- 15037819
TI  - The phenoxazine derivative Phx-1 suppresses IgE-mediated degranulation in rat
      basophilic leukemia RBL-2H3 cells.
AB  - Antigen-induced aggregation of the high affinity IgE receptor (FcepsilonRI) on
      mast cells induces degranulation to release chemical mediators, leading to acute
      allergic inflammation. We have demonstrated that the treatment of rat mast cells,
      RBL-2H3, with a phenoxazine derivative Phx-1 (2-amino-4,4alpha-dihydro-4alpha,7
      dimethyl-3H-phenoxazine-3-one) suppresses the antigen-induced degranulation.
      Biochemical analysis reveals that the complementary signaling pathway through
      Gab2 and Akt is inhibited by this compound in mast cells. These findings suggest
      that phenoxazine derivatives may have a therapeutic potential for allergic
      diseases by inhibiting mast cell degranulation.

PMID- 15037820
TI  - Nicotinic acetylcholine receptor alpha7 subunit mediates migration of vascular
      smooth muscle cells toward nicotine.
AB  - GbaSM-4 cells, vascular smooth muscle cells (VSMCs) derived from brain basilar
      arteries, were shown to migrate toward d-nicotine by augmenting the actin
      cytoskeleton in their cell bodies and lamellipodia, and expression of nicotinic
      acetylcholine receptor (alpha7-nAChR) was detected in GbaSM-4 cells. Their
      chemotaxis was antagonized by an alpha7-nAChR antagonist of methyllycaconitine.
      It was also antagonized by inhibiting myosin light chain (MLC) kinase and by down
      regulating MLC kinase. However, the changes in MLC phosphorylation were not
      associated with the nicotine treatment, suggesting the involvement of non-kinase
      activity of MLC kinase as reviewed by Gao et al. (IUBMB Life. 2001;51:337). This
      plot may work to induce arteriosclerosis during cigarette smoking.

PMID- 15037821
TI  - Randomized dose-response study of rosuvastatin in Japanese patients with
      hypercholesterolemia.
AB  - Rosuvastatin is a novel statin that has been shown to produce large dose
      dependent reductions in low-density lipoprotein cholesterol (LDL-C) in Western
      hypercholesterolemic patients. Rosuvastatin dose response was assessed in a
      randomized, double-blind phase II trial in which 112 Japanese patients with
      fasting LDL-C > 160 and < 220 mg/dl and triglycerides < 300 mg/dl received
      placebo or rosuvastatin 1, 2.5, 5, 10, 20, or 40 mg once daily for 6 weeks. LDL-C
      change from baseline showed a linear dose response (p < 0.0001 for slope of
      regression line) over the rosuvastatin dose range, with each doubling of dose
      producing an additional 5.12% reduction. Mean reductions (least-squares mean
      percentage change from baseline from ANOVA) in LDL-C were 35.8% to 66.0% and
      significantly different from placebo at all doses (p < 0.0001). Linear dose
      response was also observed for total cholesterol (TC) and apolipoprotein (apo) B,
      but not for triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), or
      apo A-I or A-II. Mean changes at 6 weeks were - 25.5 to - 45.1% for TC, - 16.0 to
      - 26.2% for TG, + 7.5 to + 12.8% for HDL-C, - 31.9 to - 57.8% for apo B, + 5.5 to
      + 10.0% for apo A-I, and + 0.4 to + 8.1% for apo A-II. Rosuvastatin was well
      tolerated. Although there was some suggestion of increased frequency of treatment
      related adverse events at higher doses, there were no clear dose relationships in
      safety parameters. Only one patient withdrew from the study because of a
      treatment-related adverse event. No patients had clinically significant
      elevations in liver transaminases or creatine kinase. Rosuvastatin produces good
      dose-related reductions in LDL-C and beneficial changes in other lipid fractions
      in Japanese hypercholesterolemic patients and is well tolerated.

PMID- 15037822
TI  - The ratio of serum paraoxonase/arylesterase activity using an improved assay for
      arylesterase activity to discriminate PON1(R192) from PON1(Q192).
AB  - Human serum paraoxonase (PON1) exists in 2 major polymorphic forms: Q (glutamine)
      or R (arginine) at codon 192. The PON1(192) activity polymorphism is substrate
      dependent. The PON1(Q192) isoform has a higher rate of in vitro hydrolysis of
      diazoxon, sarin, and soman, whereas the PON1(R192) isoform has higher activity
      for the hydrolysis of paraoxon and chlorpyrifos oxon. Both isoforms hydrolyze
      phenyl acetate at approximately the same rate. The present study described and
      evaluated a kinetic method of arylesterase activity determination with a modified
      fixed incubation method that used the oxidative coupling of phenol with 4
      aminoantipyrine of phenyl acetate as the substrate. Our improved method shows
      that arylesterase activity is lower with the PON1(R192) isoform than with the
      PON1(Q192) isoform. The average activities of serum of individuals of a specific
      PON1(Q192) genotype showed higher arylesterase and lower paraoxonase activity
      than the PON1(R192) genotype. The ratio of paraoxonase/arylesterase activity
      showed a clear separation of all three PON1(192) genotypes with no overlap
      between the groups (QQ: < 5.0, QR: 5.0-11.0, RR: > 11.0). PCR has suggested that
      the PON1(192) phenotypes correspond to the PON1(192) genotypes. Therefore, when
      conducting epidemiological or mechanistic studies that examine the role of PON1
      in organophosphorus or lipid metabolism, this ratio is more useful and
      informative than a PCR-based genotype alone.

PMID- 15037823
TI  - Fluvastatin increases LDL particle size and reduces oxidative stress in patients
      with hyperlipidemia.
AB  - The effects of fluvastatin on levels of urinary 8-iso-prostaglandin F2alpha
      (iPF2alphaIII), a marker of oxidative stress, and low-density lipoprotein (LDL)
      particle size in serum were investigated in patients with hypercholesterolemia.
      After 6 months of fluvastatin therapy, levels of urinary iPF2alphaIII decreased
      from 1720.1 +/- 392.0 to 539.6 +/- 75.5 pg/mg (p < 0.01), and LDL particle size
      increased from 24.3 +/- 0.3 to 26.5 +/- 0.2 nm (p < 0.001). These changes from
      the treatment of fluvastatin were not correlated with those of the serum LDL
      cholesterol (LDL-C) levels. The results imply that fluvastatin, with its unique
      antioxidant property among statins, reduces oxidative stress and increases LDL
      particle size simultaneously in hyperlipidemic patients.

PMID- 15037825
TI  - [A survey of pain prevalence at Albert-Chenevier Hospital. Comparison of patient,
      caregivers and physician assessments].
AB  - The purpose of this study is to estimate the prevalence of pain in hospitalized
      patients and to compare pain assessments performed by patients, caregivers and
      physicians. This cross-sectional study was based on evaluating pain with three
      questionnaires. Two structured questionnaires explored the patient's and
      physician's points of view about hospital pain management. Caregivers used the
      validated Doloplus-2 scale. The three assessments were considered consistent when
      all three indicated the presence or absence of pain. All inpatients (447) were
      included. The prevalence of pain was 57% when assessment was performed by
      caregivers and 53% when it was performed by physicians. Among patients included
      in the prevalence study, 366 could express themselves and agreed to answer the
      self-assessment questionnaire (82%): 66% of these patients reported pain.
      Patients and physicians often reported leg pain. Assessment of pain produced a
      higher level of pain intensity when performed by patients than when by
      physicians. Furthermore, 88% of patients reporting pain received pain relief
      treatment: nevertheless patients felt that their pain was satisfactorily managed
      in only half of their locations, and they had a less positive appreciation of
      their level of pain management than physicians did. Our study showed that many
      psychiatric patients declared they suffered pain. Full consistency between the
      three assessments was noted for half the cases. One out of ten patients
      experiencing pain was not identified.

PMID- 15037824
TI  - Recovery of platelet function after withdrawal of cilostazol administered orally
      for a long period.
AB  - To clarify the recovery of platelet function after abrupt withdrawal of
      cilostazol, we studied platelet function and cilostazol concentration in elderly
      who received cilostazol, 100 mg twice a day (200 mg/day), for a long period.
      After interviewing the time of final cilostazol intake, platelet aggregability
      was determined with an aggregometer using four different concentrations of
      adenosine-5'-diphosphate as an inducer, which showed the grading curve (GC) type
      and platetet aggregatory threshold index (PATI). Serum cilostazol concentration
      was also determined by high-performance liquid chromatography. The GC type and
      PATI showed suppressed platelet function until 15 hours after withdrawal in half
      of patients. Bleeding time measured by the Simplate method was prolonged within 4
      hours, but recovered by 12 hours after the withdrawal. Some serum cilostazol
      concentrations were still high 15 hours after withdrawal, while platelets were
      inhibited even in patients with low serum concentration of cilostazol. In the
      group receiving the drug for less than 6 months, PATI correlated with serum
      cilostazol concentration, but platelets in the long-term administration group
      (more than 48 months) were suppressed at the low serum cilostazol concentration.
      These findings indicated that platelet function recovered within 12-16 hours
      after withdrawal in these patients.

PMID- 15037826
TI  - [Meteorologic conditions and esophageal varices rupture].
AB  - BACKGROUND: While meteorologic conditions are thought to be related to the
      incidence of certain cardiac and cerebrovascular events, very little information
      is available concerning the onset of variceal bleeding. We undertook this study
      to determine whether there is any correlation between esophageal variceal
      hemorrhage and several meteorologic and astronomic parameters. METHODS: Sixty
      seven episodes of bleeding from ruptured esophageal varices observed in 52
      patients from southern Tunisia during a 7-Year period were studied
      retrospectively. All patients underwent endoscopic examination within 24 hours of
      admission. The date of the event (variceal rupture) was considered--if no
      stigmates of active bleeding were found at endoscopy--as the day of occurrence of
      the hematemesis and the day preceding melena. Meteorologic readings (11
      parameters) plus moon-cycle, circadian and seasonal distribution of the 67 days
      of variceal bleeding in comparison with a control period of days randomly
      selected among 134 days without rupture. RESULTS: No relationship was found
      between variceal bleeding and mean atmospheric pressure, daily hours of sunshine,
      nebulosity, direction and velocity of wind and mean humidity. On the contrary, a
      significant correlation was observed with the mean temperature (18 degrees C vs
      21.16 degrees C; p=0003), rainfall (p<0.01) and stormy weather (p=0.008), the
      latter being the only parameter retained as an independent factor at multivariate
      analysis: OR=13.37 (95% CI=1.5-118.5). Furthermore, a negative correlation was
      found with full moon but only at univariate analysis (p=0.04). The seasonal
      distribution of variceal bleeding episodes showed the highest percentage during
      winter with a significant variation at multivariate analysis: OR=3.2 (95% IC=1.6
      6.54). Occurrence of variceal bleeding also showed a circadian variation with the
      higher prevalence night between 6 and 0 PM (p<0.001).

PMID- 15037827
TI  - [Progress in the management of pyogenic cerebral abscesses in non
      immunocompromised patients].
AB  - Advances in radiological techniques over the last two decades have enabled
      establishing well-defined clinical and radiological signs for the diagnosis of
      cerebral abscess. Conversely, no consensus has been reached on the appropriate
      therapeutic management. To date, there has been no published randomized
      therapeutic trial dedicated to cerebral abscesses, probably because of low
      incidence. Progress in bacterial epidemiology, imaging techniques allowing early
      diagnosis, and antibiotic therapy have however generated a shift towards more
      frequent use of shorter, exclusively medical, treatment. Based on a review of the
      literature, we present and discuss the treatments usually applied in specialized
      departments for non-immunocompromised patients.

PMID- 15037828
TI  - [Lymphoma genesis in the context of HIV infection].
AB  - The incidence of lymphomas is high among HIV infected patients. These lymphomas
      are non-Hodgkin's lymphoma (NHL) in 70% of cases and Hodgkin's disease (HD) in
      30% of cases. Their localization is often extra-nodal with early dissemination. B
      cell high grade NHL predominates. The most frequent histological types are
      diffuse large B-cell lymphoma (30 to 40%) and Burkitt's lymphoma (40 to 50%).
      Other histological types are low-grade B-cell lymphoma, polymorphic B cell
      lymphoma and primary effusion lymphoma. Three main factors are predominant in HIV
      related lymphomagenesis: cellular immunodeficiency, oncogene viruses (Epstein
      Barr and HHV8) and molecular lesions. HIV-related cellular immunodeficiency leads
      to the increase of EBV infected B-cells and to the diminution of antitumor
      immunity. Clonal EBV genome is found in lymphoma cells in 30 to 70% of cases of
      HIV-related NHL. It expresses oncogenic proteins including LMP-1 which behaves
      like an activated CD40. It induces the expression of intra-cellular genes which
      stimulate cell growth and inhibit apoptosis. Cytogenetic and molecular lesions
      are not specific to HIV-related NHL or to histological subtypes. A better
      knowledge of these mechanisms should lead to the development of specific targeted
      treatments (antiviral, cytotoxic anti-EBV lymphocytes, cell cycle regulators).

PMID- 15037829
TI  - [Investigation of the complement system in clinical practice].
AB  - The complement system plays an important role in defence of the host against
      infection and in the clearance of immune complexes. Defects in complement
      proteins are often associated with infections or auto/immune complex diseases.
      Investigation of complement is useful for diagnosis and following of auto-immune
      diseases. The aim of this Article is to provide an overview of important
      applications of complement in medicine, emphasizing the role of complement in
      pathogenesis and the usefulness of measurements of complement proteins in
      diagnosis and assessment of the evolution of disease states. Emphasis has been
      placed on practical applications and understanding basic mechanisms of disease.
      The best screen for complement deficiencies or significant activation is the
      CH50, which measures total classical pathway activity and the measurement of C3
      and C4. The absence or decrease of multiple components is usually due to
      consumption of complement. Complete lack of CH50 associated with normal C3
      antigen is a strong indication for complement deficiency and should be followed
      up with further tests to determine which component is missing.

PMID- 15037830
TI  - [Chronic fever revealing an urachal cyst].
AB  - In the adult, the urachus remains as a non-specific fibrous formation extended
      from the bladder dome to the Retzius space. This urachal remnant is commonly
      asymptomatic or may be revealed by a cyst. This later may also be asymptomatic or
      lead to local inflammation or inflammatory pseudo-tumor. We report an original
      observation of chronic fever revealing an urachal cyst in a 21-Year-old male.

PMID- 15037831
TI  - [Slipped capital femoral epiphysis associated with hyperparathyroidism. A case
      report].
AB  - Slippage of the upper femoral epiphysis can occur in association with multiple
      endocrine imbalances. A case of slipped femoral epiphysis with primary
      hyperparathyroidism is reported. The patient was an adolescent, 16 Years of age,
      who presented bilateral slipped epiphysis. Investigation showed that he had
      hypercalcemia (3.1 mmol/l) related to primary hyperparathyroidism. A parathyroid
      adenoma was removed. Outcome was favorable and the slipped femoral epiphyses did
      not require a specific treatment.

PMID- 15037832
TI  - [Acute "pseudo-angiocholitis" due to colonic adenocarcinoma in a man with primary
      sclerosis cholangitis and ulcerative colitis].
AB  - We report the case of a 49-Year-old-man with primary sclerosis cholangitis (PSC)
      and ulcerative colitis who developed two acute episodes of pseudo-angiocholitis.
      Both episodes were triggered by septic hepatitis translocated from ulcerative
      colonic adenocarcinoma. The biliary MRI did not show any signs of lithiasis or
      cholangiocarcinoma. cholangiocarcinoma, intra-hepatic lithiasis and colonic
      cancer are potential diagnoses in patients with PSC who develop angiocholitis.

PMID- 15037833
TI  - [Bilateral primary non-Hodgkin's lymphomas of the adrenals].
AB  - Bilateral primary non-Hodgkin's lymphomas of the adrenals are rare: only 32 cases
      have been reported to date in the literature. We report a new case and recall the
      contribution of radiography to diagnosis.

PMID- 15037834
TI  - [Necrolytic migratory erythema revealing glucagonoma without diabetes].
AB  - We report a case of glucagonoma syndrome, revealed by a necrolytic migratory
      erythema that had developed for four Years, associated with anorexia, severe
      weight loss, anemia, hypoprotidemia, and hypoaminoacidemia. The fasting blood
      glucose level tended paradoxically to be low (0.6 g/l). Elevated plasma glucagon
      levels confirmed our diagnosis. The absence of diabetes was explained by an
      independent insulin secretion derived from this composite pancreatic tumor,
      authenticated by the histological analysis and the proinsulin level. This level
      was similar to those typically observed in insulinomas. Six Months after a
      complete surgical exeresis, symptoms disappeared and biological results returned
      to normal values.

PMID- 15037835
TI  - Inflammatory pseudotumor of lymph nodes.
AB  - A case of inflammatory pseudotumor in a 22-Year-old man is described. Symptoms
      and signs showed high fever and prominent cervical lymphadenopathy; laboratory
      findings were consistent with an acute inflammatory process. Diagnosis was
      reached through a lymph node biopsy which allowed a definitive diagnosis and
      ruled out several mimicking pathological processes such as malignant lymphoma,
      infectious diseases and autoimmune disorders. Inflammatory pseudotumor should be
      included in the differential diagnosis of patients with persistent fever and
      lymph node enlargement.

PMID- 15037840
TI  - Fou rire prodromique and history of pathological laughter in the XIXth and XXth
      centuries.
AB  - Fou rire prodromique (prodrome of crazy laughter) is a rarely described
      nosological entity. In 1903, Charles Fere, a French neurologist, introduced the
      term fou rire prodromique to describe pathological laughter heralding an
      apoplectic event. He was also among the first to describe gelastic epilepsy. His
      description was influenced by Edouard Brissaud, who supported the existence of a
      thalamic center for laughter regulation and suggested that spasmodic laughter and
      crying were due to lesions of the faisceau psychique (anterior internal capsule)
      or to irritation of the faisceau genicule (corticobulbar tract). One hundred
      Years later, we review the evolution of the theories about pathological laughter
      and crying from Charles Bell in the early XIXth Century, up to the seminal works
      of Kinnier Wilson and James Papez and the era of modern neuroscience.

PMID- 15037836
TI  - Kartagener's syndrome and renal failure.

PMID- 15037841
TI  - [POEMS syndrome (or Crow-Fukase syndrome)].
AB  - POEMS is an acronym for polyneuropathy, organomegaly, endocrinopathy, M-protein
      and skin changes. POEMS syndrome is also called Crow-Fukase syndrome, chiefly in
      Japan. The 5 above mentioned features are not always present at the first
      examination. The minimal criteria to establish the diagnosis are the presence of
      a demyelinating and axonal polyneuropathy associated with an IgA or IgG
      monoclonal gammopathy, the light chain being almost always lambda, and at least 2
      of the 8 other features: sclerosing plasmocytoma, endocrinopathy, skin changes,
      organomegaly, Castleman's disease, anasarca, papillary edema or thrombocytosis.
      Among these features, only cutaneous glomeruloid angioma are specific.
      Ultrastructural identification of uncompacted myelin lamellae on the peripheral
      nerve biopsy is also a strong argument in favor of the diagnosis. An associated
      "osteosclerotic" bone lesion must be carefully searched, because its treatment
      may improve the other features of the syndrome, especially the neuropathy.
      Cytokines and the vascular growth endothelial factor might play a role in the
      pathogenesis of this rare multisystemic disorder.

PMID- 15037843
TI  - [Lateral gaze palsy and progressive scoliosis in 4 Tunisian families].
AB  - In 1975, Sharpe and Silversides described a neurological entity in a Chinese
      family. Clinical picture was characterized by paralysis of horizontal gaze,
      pendular nystagmus and progressive scoliosis. To date, 43 cases have been
      reported. The pathogenesis remains unclear. The Authors report four Tunisian
      families with 12 affected individuals. The age of patients ranges from 6 to 34
      Years. All examined patients have complete lateral gaze palsy, pendular nystagmus
      and progressive scoliosis. Blood routine tests, cerebrospinal fluid (CSF), evoked
      potentials, electromyography (EMG), muscle biopsy, CT scan and cerebral MRI were
      normal. Autosomal recessive (AR) mode of inheritance is the most probable
      pattern.

PMID- 15037842
TI  - [Metabolic stability and physiological adaptation of muscle under conditions of
      exercise].
AB  - The first role played by group III (thin myelinated) and group IV (unmyelinated)
      afferent fibres from skeletal muscle is to transmit nociceptive information from
      muscle to the central nervous system. The second role of these free endings
      located in the interstitium of the muscle is to induce cardiovascular and
      respiratory adjustments during muscular exercise. These respiratory and
      circulatory responses during muscular exercise may be reflexly induced via
      muscular afferents. Indeed, static contraction of hindlimb muscles in
      anaesthetised mammals has been shown to reflexly increase the ventilatory
      function, the myocardial contractility and heart rate. The mechanical muscle
      deformation and the accumulation of metabolites in its intersitium are the cause
      of raised activity in small nerve fibres which in turn induces the physiological
      responses. It is also admitted that the central locomotor areas on the medullary
      and spinal neuronal pools control ventilatory and cardiovascular function during
      exercise. This mechanism is called "central command". Furthermore, adjustments of
      the locomotor activity during exercise is mediated by the thinly myelinated and
      unmyelinated fibres with endings in the working muscle. These fibres, also called
      "metaboreceptor" may be responsible of the coupling between the ventilation and
      the locomotion. Thickly myelinated muscle afferents (i.e. group I and II) appear
      to play little role in causing the reflex autonomic responses to contraction.

PMID- 15037844
TI  - [A prospective epidemiological and aetiological study of strokes in young Afro
      Caribbean patients from Martinique, French West Indies].
AB  - Few data are available regarding stroke among young black patients. We have
      conducted, in Martinique, a prospective study among young Afro-Caribbeans aged 15
      to 45 Years, from June 1994 through May 1999. We identified 60 cerebral infarcts
      (CI) and 20 cases of intracerebral hemorrhage (ICH). Annual incidence and case
      fatality rate at 30 days were 7.6/100000/Year (95p.cent confidence interval, 3.13
      to 11.35) and 8.3p.cent respectively for CI, and 2.42/100000/Year (95p.cent
      confidence interval, 0.06 to 4.7) and 25p.cent for ICH. Hypertension was the most
      prevalent stroke risk factor: 35p.cent in CI and 68p.cent in ICH. According to
      the TOAST criteria, a probable cause of ischemic stroke was identified in
      61.3p.cent. Atherosclerosis, lacunar infarcts and cardioembolism were the main
      causes of CI (13.3p.cent for each etiology). Spontaneous cervical arterial
      dissection was found in only 6.7p.cent. Hypertensive ICH (60p.cent) was the most
      common subtype of ICH. In Martinique, high frequencies of ICH and lacunar
      infarcts are characteristic of stroke in young Afro-Carribeans. These suggest the
      role of the high prevalence of hypertension in the black population. We confirm
      the heterogeneity of stroke etiologies and the low prevalence of cervical
      arterial dissection in black people.

PMID- 15037845
TI  - [Seasonal variation in strokes incidence and the influence of the meteorological
      conditions].
AB  - The aim of this paper was to study the seasonal and Monthly distribution of
      different subtypes of strokes, and also the influence of the most usual
      meteorological factors on their incidence. The study, based on the population
      based data of the Dijon register of stroke (France), involved 3287 patients with
      a cerebrovascular event during the Years 1985-1998. The seasonal distribution
      pointed out a summer decrease for all stroke subtypes. The cerebrovascular risk
      was the highest in autumn for small artery atheroma infarcts and for cerebral
      infarcts and, among these later, for cardioembolic infarcts and large artery
      atheroma infarcts, as well as for subarachnoid hemorrhages and for the total
      number of strokes. It was followed by spring (total number of strokes, small
      artery atheroma infarcts, cerebral infarcts) and/or winter (subarachnoid
      hemorrhages, cerebral infarcts, cardioembolic infarcts and large artery atheroma
      infarcts). For intracerebral hemorrhages, the risk peaked in spring and secondly
      in autumn. But the difference from one season to another was significant only for
      total number of strokes, cerebral infarcts and, among the later, for
      cardioembolic infarcts and large artery atheroma infarcts. As regards the Monthly
      distribution, the difference between Months was significant only for the total
      number of strokes and cerebral infarcts, with a minimum from July to September
      and a maximum in October for the later. Correlations with meteorological data
      were found for the total number of strokes, cerebral infarcts, cardioembolic
      infarcts, large artery atheroma infarcts and small artery atheroma infarcts. They
      showed an influence of temperature and relative humidity of the day of stroke or
      of the one to five days before. Correlations with wind speed, duration of
      sunshine or snow, even if less frequent, could also be found. Such results
      sometimes differ from those of some earlier studies, for which the climate and
      the risk factors were not the same, showing that regional epidemiological studies
      are necessary in order to determine the relations between seasons, meteorological
      factors and strokes.

PMID- 15037847
TI  - [A survey of school teachers' knowledge and behaviour about epilepsy, in a
      developing country such as Senegal].
AB  - Epilepsy is one of the most common disorders encountered in children of
      developing countries. In Senegal, as in many other African countries, the disease
      is enrobed in superstition, discrimination, and stigma. There is a clear-cut lack
      of information programs in the developing world about seizures and epilepsy.
      Academic achievement of children with epilepsy is hampered by social barriers in
      addition to the burden of the disease and its treatment. The aim of this study
      was to evaluate teachers'knowledge, awareness, and current attitudes about
      epilepsy in order to obtain baseline data for the development of a school health
      education program on epilepsy. The study was carried out in Dakar. It was
      conducted by sending self-administered and anonymous questionnaires to 400
      elementary school teachers; the data were randomly mapped, stratified, and chosen
      to produce a statistically representative sample of the teacher population of
      Dakar. The questionnaires contained 22 items related to knowledge of epilepsy,
      the attitude of teachers towards epilepsy, and their ability to provide first aid
      in case of seizures. A total of 373 teachers (93p.cent) completed the
      questionnaires. For 69p.cent, epilepsy arises in the brain, for 28.7p.cent it is
      a subnatural affliction. Epilepsy was considered to be contagious for 24p.cent
      and could be cured for 73p.cent. Although 66p.cent would help an epileptic pupil
      during a seizure, 53p.cent mentioned harmful measures. Eighty-four percent
      noticed that an epileptic child could go to a normal classroom, while 62.5p.cent
      would prefer a special school. Eighty-four percent said their knowledge on
      epilepsy was not sufficient and the majority (99p.cent) desired training on
      epilepsy. For 25.7p.cent, better collaboration between parents, doctors, and
      teachers would b helpful to achieve better management of epileptic children. This
      study demonstrated encouraging knowledge of teachers about epilepsy. However,
      some of their wrong attitudes may be attributed to superstitions and could be
      improved by informative actions and better training about epilepsy. Such
      education might be provided by local health professionals with the collaboration
      of parents, teachers, and non-governmental organizations.

PMID- 15037846
TI  - [Knowledge about stroke in patients admitted in a French Stroke Unit].
AB  - Admission delay remains the main cause for stroke patient exclusion from urgent
      therapeutic protocols. Public lack of knowledge about stroke symptoms may result
      in delay in seeking medical care and late presentation at hospital. Lack of
      knowledge of risk factors for stroke may also hamper compliance with stroke
      prevention practices. The aim of this prospective study using a standardized
      questionnaire was to evaluate the stroke awareness of acute stroke patients in
      France. From July 2, 1998 to July 2, 1999, 166 consecutive stroke patients were
      admitted at our stroke unit. Among the 91 patients who were able to answer the
      questionnaire during the first 48 hours, only 19 patients (21 p.cent) thought
      they were having a stroke before their arrival at the hospital, 38 patients (42
      p.cent) did not know a single sign of stroke and 33 patients (36 p.cent) did not
      know a single risk factor of stroke. The most common risk factors named by the
      patients were smoking and hypercholesterolemia (named by 31 patients (34 p.cent)
      and 19 patients (21 p.cent), respectively). The most common warning signs named
      by the patients were paralysis of one side of body or one limb and speech
      disturbance (named by 40 patients (44 p.cent) and 15 patients (16 p.cent),
      respectively). Female sex and "knowing somebody who had a stroke" were
      significantly associated with awareness of signs of stroke in multivariate
      analysis. Educational public programs regarding stroke awareness are needed in
      France. Educational campaigns must stress the risk factors and symptoms of stroke
      and the appropriate response in the hopes of reducing admission delay and
      improving stroke prevention.

PMID- 15037848
TI  - [Neonatal thrombosis of the jugular veins: long-term repercussions on cerebral
      development (two cases)].
AB  - Bilateral obstruction of the internal jugular veins is rare in the neonatal
      period and no long-term follow-up has been reported yet. We report two cases. The
      first developped an extensive thrombosis of superior veina cava related to a
      central veinous line, the second an unilateral thrombosis of the transverse
      sigmoid sinus associated to a constitutional hypoplasia of the contralateral
      jugular vein. In the latter case, no cause or risk factor was noticeable, except
      for a forceps delivery. In both cases the clinical course was dominated by the
      development of a prominent collateral network of cervico-facial veins and by a
      progressive macrocrania. According to MRImaging, the latter was not related to a
      dilation of CSF spaces, but to a macro-encephaly, either by inflation of the
      vascular veinous compartment inside the parenchyma or by genuine brain's
      overgrowth. Long-term follow-up showed a grossly normal course, both from the
      neurological and the scholar point of view. However, slight neuropsychological
      anomalies were noticed, bringing some shade on the prognosis.

PMID- 15037849
TI  - [Pseudo-dementia as presentation of a dural arteriovenous fistula].
AB  - We describe a case of a 70-Year-old man who presented subacute pseudo-dementia
      due to a dural fistula. Neurological assessment and the reversibility of the
      symptoms after embolization support the originality of this observation.

PMID- 15037850
TI  - [Myoclonic encephalopathy associated with proton pump inhibitors].
AB  - Two men (66 and 73 Years) with a cardiovascular history were hospitalized for
      rapid onset encephalopathy associated with myoclonia and an extrapyramidal
      syndrome. On the basis of the French Pharmacovigilance system, this
      symptomatology has been attributed to the coadministration of a proton pump
      inhibitor, lansoprazole (15mg/day) with levodopa. Lansoprazole withdrawal led to
      a normalisation of the situation.

PMID- 15037851
TI  - [Improvement in swallowing difficulties treated by subcutaneous apomorphine
      infusion after deep brain stimulation in Parkinson's disease].
AB  - In Parkinson's patients, swallowing difficulties may result in inhalation
      pneumonia, with a potentially serious prognosis. They may be revealed by
      withdrawal of L-dopa, especially after deep brain stimulation surgery. The
      following two cases illustrate the usefulness of apomorphine.

PMID- 15037853
TI  - [Reversible posterior leucoencephalopathy syndrome].

PMID- 15037852
TI  - [Multiple neurological complications in a case of anterior pituitary
      insufficiency].
AB  - Neurological manifestations of anterior pituitary deficiency are well known but
      their association remains rare. We report a woman who developed, insidiously over
      ten Years, a complex neurological disorder associating cognitive impairment,
      psychiatric disorder, cerebellar ataxia, demyelinating neuropathy, and myopathy
      with pseudomyotonia. After 18 Months of hormone substitution treatment, the
      patient fully recovered.

PMID- 15037854
TI  - [The diagnosis of acquired sensory neuropathies].
AB  - INTRODUCTION: Peripheral neuropathies usually include a sensory component of
      various causes. The diagnosis approach requires careful a clinical assessment and
      a precise electrophysiological exploration. STATE OF ART: Axonal sensory
      polyneuropathies are classified according to the type of fibers involved (large
      or small fibers). While there is a large number of causes, current emphasis is
      placed on glucose intolerance as a source of small-fiber sensory neuropathies.
      Demyelinating polyneuropathies are often associated with a monoclonal IgM
      gammapathy with anti-MAG activity. Multiple sensory mononeuropathies are
      exceptional and suggest possible early-phase vasculities, sensorymotor neuropathy
      with conduction blocks or leprosy. Sensory neuronopathies can also suggest
      Sjogren's syndrome or a paraneoplastic syndrome. Finally chronic sensory
      polyradiculoneuritis constitute a rare subgroup clearly defined as demyelinating
      inflammatory neuropathy. CONCLUSION: The diagnostic approach to sensory
      neuropathies requires careful nosological electroclinical classification to
      reduce the number of explorations performed for etiological diagnosis.

PMID- 15037856
TI  - Private cord blood banks.

PMID- 15037855
TI  - [The reprints of German neurologists in Professor Charcot's archives].

PMID- 15037857
TI  - Abarelix (Plenaxis) for advanced prostate cancer.

PMID- 15037858
TI  - Olanzapine/Fluoxetine (Symbyax) for bipolar depression.

PMID- 15037859
TI  - Comparison of different isolation techniques prior gene expression profiling of
      blood derived cells: impact on physiological responses, on overall expression and
      the role of different cell types.
AB  - Owing to its clinical accessibility, peripheral blood is probably the best source
      for the assessment of differences or changes in gene expression associated with
      disease or drug response and therapy. Gene expression patterns in peripheral
      blood cells greatly depend on temporal and interindividual variations. However,
      technical aspects of blood sampling, isolation of cellular components, RNA
      isolation techniques and clinical aspects such as time to analysis and
      temperature during processing have been suggested to affect gene expression
      patterns. We therefore assessed gene expression patterns in peripheral blood from
      29 healthy individuals by using Affymetrix microarrays. When RNA isolation was
      delayed for 20-24 h-a typical situation in clinical studies-gene signatures
      related to hypoxia were observed, and downregulation of genes associated with
      metabolism, cell cycle or apoptosis became dominant preventing the assessment of
      gene signatures of interindividual variation. Similarly, gene expression patterns
      were strongly dependent on choice of cell and RNA isolation and preparation
      techniques. We conclude that for large clinical studies, it is crucial to reduce
      maximally the time to RNA isolation. Furthermore, prior to study initiation, the
      cell type of interest should already be defined. Our data therefore will help to
      optimize clinical studies applying gene expression analysis of peripheral blood
      to exploit drug responses and to better understand changes associated with
      disease.

PMID- 15037860
TI  - Can nature's defence against malaria be mimicked by the development of host
      directed therapies?

PMID- 15037861
TI  - Management of community-acquired pneumonia in persons with spinal cord injury.
AB  - STUDY DESIGN: Retrospective case series. OBJECTIVES: Respiratory disorders are
      the leading cause of death in persons with spinal cord injury (SCI), but the
      epidemiology and medical management of pneumonia in persons with chronic SCI is
      not well characterized. We describe the clinical presentation of persons with SCI
      with community-acquired pneumonia (CAP), characterize its management and compare
      practice to recommendations for CAP in the general population. SETTING: Three
      United States Veterans Affairs Medical Centers with specialized SCI services.
      METHODS: Chart abstraction was performed for all persons with chronic SCI seen at
      participating centers for treatment of CAP during a 2-year period. Collected data
      included presenting signs and symptoms, laboratory and imaging results, initial
      antibiotic therapy, secretion mobilization techniques, in-patient vs outpatient
      management, length of stay, and mortality. RESULTS: In all, 41 persons with SCI
      received treatment for CAP during the study period. A total of 32 (78.0%)
      patients were admitted for treatment; two (4.8%) required intubation and
      mechanical ventilation. Initial antibiotic coverage met guideline recommendations
      for only half of inpatients and infrequently provided adequate antipseudomonal
      coverage. Microbiologic testing was performed on 26 cases (63.4%) and
      demonstrated a specific pathogen in only five cases (12.2% of total). Three cases
      (7.3%) died during treatment for CAP, and 16 (42.1%) of 38 CAP survivors died
      within a median follow-up of 3 years. CONCLUSION: The majority of chronic SCI
      patients who present to specialized SCI centers with CAP are admitted for
      treatment. Short-term mortality is comparable to CAP in the general population.

PMID- 15037862
TI  - Spinal shock revisited: a four-phase model.
AB  - Spinal shock has been of interest to clinicians for over two centuries. Advances
      in our understanding of both the neurophysiology of the spinal cord and
      neuroplasticity following spinal cord injury have provided us with additional
      insight into the phenomena of spinal shock. In this review, we provide a
      historical background followed by a description of a novel four-phase model for
      understanding and describing spinal shock. Clinical implications of the model are
      discussed as well.

PMID- 15037863
TI  - Verrucous carcinoma of the foot from chronic pressure ulcer.
AB  - STUDY DESIGN: This is a case report with literature review. OBJECTIVE: To
      describe a case of verrucous carcinoma, a rare histopathologic type, complicating
      a chronic pressure ulcer of duration less than 3 years. SETTING: The department
      of Physical Medicine and Rehabilitation, University of North Carolina at Chapel
      Hill, USA. METHOD: A 24-year-old African-American male with long-standing
      incomplete paraplegia visited the wound clinic due to a pressure ulcer that had
      lasted for more than 1 year on the medial side of the right foot. Despite
      conservative management for almost 2 years after the initial visit, the ulcer is
      suspected to have undergone malignant transformation. Histological study led to
      the diagnosis of verrucous carcinoma that necessitated transtibial amputation on
      the right foot. RESULT: The carcinoma developed within 3 years, which was a
      relatively short time period for a pressure ulcer to have undergone malignant
      transformation. The diagnosis of verrucous carcinoma has never been reported as
      carcinoma complicating a pressure ulcer. No evidence of local recurrence or
      distant metastasis was seen in postoperative 10 months. CONCLUSION: The
      possibility of malignant transformation should be kept in mind in cases of
      pressure ulcers that are unresponsive to treatment or that show morphological
      changes suspected to be cancerous. Furthermore, early detection and intervention
      increases the probability for successful outcome.

PMID- 15037864
TI  - Influence of SERTPR and STin2 in the serotonin transporter gene on the effect of
      selective serotonin reuptake inhibitors in depression: a systematic review.
AB  - Large differences in clinical response to selective serotonin reuptake inhibitors
      (SSRIs) are observed in depressive patients with different genotypes.
      Quantification of these differences is needed to decide if genetic testing prior
      to antidepressant treatment is useful. We conducted a systematic review of the
      literature on the influence of polymorphisms in the serotonin transporter gene
      (SERTPR (or 5-HTTLPR) and STin2) on SSRI response. Studies were identified by the
      use of MEDLINE, EmBase and PsycINFO, references of articles, reviews and
      information from pharmaceutical companies. Nine studies assessing the influence
      of SERTPR or STin2 on treatment response were included. Outcome was expressed as
      the percentage of decrease in depression score (HAM-D or MADRS) or as the
      percentage of responders (> or =50% reduction on the depression scale). Both
      study methodologies and study outcomes showed large heterogeneity. Weighted mean
      decreases in depression score for patients with the s/s, s/l and l/l genotypes
      were 35.4, 46.3 and 48.0% at week 4, respectively, and 53.9, 54.6 and 48.3% at
      week 6. Among Caucasian patients, both mean decrease in depression score and
      response rate were lowest in the s/s group, while among Asian patients, results
      were inconsistent. Weighted response rates were 36.1% for the 10/12 genotype of
      the STin2 polymorphism and 80.7% for the 12/12 genotype (chi2=27.8, P<0.001)
      (only Asians). The available evidence points to a less favourable response to
      SSRI treatment among Caucasian patients with the SERTPR s/s genotype and among
      (Asian) patients with the STin2 10/12 genotype. In view of the scarcity and
      heterogeneity of the studies, however, current information is insufficiently
      reliable as a basis for implementing genetic testing in the diagnostic work-up of
      the depressive patient.

PMID- 15037865
TI  - Binge-eating episodes are not characteristic of carriers of melanocortin-4
      receptor gene mutations.
AB  - Recently, Branson and coworkers reported a strong association between binge
      eating disorder (BED) and variants in the melanocortin-4 receptor gene (MC4R). In
      the current study, we compared the eating behavior of 43 obese probands with
      functionally relevant MC4R mutations and of 35 polymorphism carriers (V103I or
      I251L) with wild-type carriers. The module for eating disorders of the Composite
      International Diagnostic Interview was used to identify binge-eating behavior.
      The Three-Factor Eating Questionnaire and the Leeds Food Frequency Questionnaire
      were used to assess restrained eating, disinhibition, hunger and percent total
      energy intake as fat. No significant differences between carriers of MC4R
      variants and wild-type carriers were detected. In particular, we found no
      evidence for an increased rate of binge-eating behavior in obese carriers of MC4R
      variants. Our findings do not support the strong association between BED and MC4R
      carrier status.

PMID- 15037866
TI  - Pharmacogenetics of antidepressants and antipsychotics: the contribution of
      allelic variations to the phenotype of drug response.
AB  - Genetic factors contribute to the phenotype of drug response. We systematically
      analyzed all available pharmacogenetic data from Medline databases (1970-2003) on
      the impact that genetic polymorphisms have on positive and adverse reactions to
      antidepressants and antipsychotics. Additionally, dose adjustments that would
      compensate for genetically caused differences in blood concentrations were
      calculated. To study pharmacokinetic effects, data for 36 antidepressants were
      screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19
      were found and that in 14 drugs such genetic variation would require at least
      doubling of the dose in extensive metabolizers in comparison to poor
      metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6
      and CYP2C19 genotype was of relevance. To study the effects of genetic
      variability on pharmacodynamic pathways, we reviewed 80 clinical studies on
      polymorphisms in candidate genes, but those did not for the most part reveal
      significant associations between neurotransmitter receptor and transporter
      genotypes and therapy response or adverse drug reactions. In addition
      associations found in one study could not be replicated in other studies. For
      this reason, it is not yet possible to translate pharmacogenetic parameters fully
      into therapeutic recommendations. At present, antidepressant and antipsychotic
      drug responses can best be explained as the combinatorial outcome of complex
      systems that interact at multiple levels. In spite of these limitations,
      combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of
      relevance might contribute to identify genotypes associated with best and worst
      responders and they may also identify susceptibility to adverse drug reactions.

PMID- 15037867
TI  - Inter-relationships of intermediate phenotypes for serotonin function,
      impulsivity, and a 5-HT2A candidate allele: His452Tyr.
AB  - Central serotonin (5-hydroxytryptamine, 5-HT) function has a role in a range of
      genetically influenced psychiatric diagnoses and behaviors. Several human 5-HT
      receptor polymorphisms are 'candidate alleles', altering in vitro function, and
      potentially affecting behavior and drug response. The 5-HT(2A) His452Tyr
      polymorphism alters signal transduction, and has been associated with diminished
      efficacy of clozapine in schizophrenia. Another 5-HT(2A) receptor polymorphism
      consists of the silent thymidine-cytosine substitution (102T>C), which has been
      controversially associated with schizophrenia. We investigated the role of
      His452Tyr and the 102T>C in behavior and in vivo intermediate biochemical
      phenotypes. Intracellular 5-HT-induced Ca(2+) release by platelets and
      fenfluramine-induced prolactin release by pituitary were evaluated in 27
      psychiatrically interviewed subjects (including both impulsive patients and
      controls) stratified by His452Tyr genotype and also genotyped for a second 5
      HT(2A) polymorphism, 102T>C. Subjects with increased measures of impulsivity
      showed decreased postreceptor 5-HT function, as indicated by reduced 5-HT-induced
      Ca(2+) release, but no alteration in net 5-HT function, as measured by
      fenfluramine response. No significant effects of either polymorphism were
      associated with altered 5-HT-induced calcium response or fenfluramine-stimulated
      prolactin release. One available Tyr452/Tyr452 homozygote had diminished Ca(2+)
      release and one of the highest levels of fenfluramine response. Although not
      statistically significant, the effect of the T102C, but not the His452Tyr,
      genotype on prolactin level change over time was associated with a medium to
      large strength of association (treatment magnitude of T(2)=0.10), suggesting that
      further study is warranted.

PMID- 15037868
TI  - Autism as a disorder of neural information processing: directions for research
      and targets for therapy.
AB  - The broad variation in phenotypes and severities within autism spectrum disorders
      suggests the involvement of multiple predisposing factors, interacting in complex
      ways with normal developmental courses and gradients. Identification of these
      factors, and the common developmental path into which they feed, is hampered by
      the large degrees of convergence from causal factors to altered brain
      development, and divergence from abnormal brain development into altered
      cognition and behaviour. Genetic, neurochemical, neuroimaging, and behavioural
      findings on autism, as well as studies of normal development and of genetic
      syndromes that share symptoms with autism, offer hypotheses as to the nature of
      causal factors and their possible effects on the structure and dynamics of neural
      systems. Such alterations in neural properties may in turn perturb activity
      dependent development, giving rise to a complex behavioural syndrome many steps
      removed from the root causes. Animal models based on genetic, neurochemical,
      neurophysiological, and behavioural manipulations offer the possibility of
      exploring these developmental processes in detail, as do human studies addressing
      endophenotypes beyond the diagnosis itself.

PMID- 15037870
TI  - Ethnicity and tracking blood pressure in children.
AB  - There is growing evidence that hypertension, one of the major modifiable risk
      factors for cardiovascular disease (CVD), is established early in life. Given
      this, it is important to discover when hypertension first becomes apparent.
      Further, it is of particular importance to examine the ethnic differences in
      blood pressure (BP) in children, given the variation in rates of CVD morbidity
      and mortality among adults from different ethnic groups.

PMID- 15037869
TI  - Substantial attributable risk related to a functional mu-opioid receptor gene
      polymorphism in association with heroin addiction in central Sweden.

PMID- 15037871
TI  - Do variations in blood pressures of South Asian, African and Chinese descent
      children reflect those of the adult populations in the UK? A review of cross
      sectional data.
AB  - The objective of this study was to assess whether variations in BP in children of
      UK ethnic minority populations correspond to those seen in adults. A systematic
      literature review was carried out using MEDLINE 1966-2003 and EMBASE 1980-2003,
      supplemented by correspondence with expert informants, and citations from
      references. Five studies were identified. There were important differences
      between studies in terms of age and sex of samples, definition of ethnic minority
      children and methods of evaluating BP. Three studies of children of African
      descent reported lower mean SBP in boys from African descent compared to white
      boys, the differences being significant only in one study. In African descent
      girls, the mean SBP was significantly lower in one study, while DBP was
      significantly higher in one study. Four studies included children of South Asian
      origin. The Health Survey for England '99 reported on South Asian groups
      separately. Pakistani boys had a significantly higher age- and height
      standardised mean SBP than the general population. The mean DBP was significantly
      higher in Indian and Pakistani boys than the general population. Pakistani and
      Bangladeshi girls had a significantly higher mean DBP than the general
      population. The other three studies, which combined South Asian subgroups found
      no significant differences in the mean BP between South Asians and white
      subjects. One study included children of Chinese descent and reported
      significantly higher mean DBP in Chinese boys and girls compared to the general
      population. Overall, BP across ethnic groups was similar. These similarities in
      BP patterns particularly in African, Bangladeshi and Pakistani descent children
      contrasts with those in the corresponding adult populations in the UK where BP is
      comparatively high in those of African descent and comparatively low in those of
      Bangladeshi and Pakistani descent.

PMID- 15037872
TI  - Health-related quality of life during treatment of elderly patients with
      hypertension: results from the Study on COgnition and Prognosis in the Elderly
      (SCOPE).
AB  - The Study on COgnition and Prognosis in the Elderly (SCOPE) was a multinational,
      randomised, double-blind study to assess the effects of candesartan 8-16 mg daily
      on cardiovascular events and cognitive function in elderly patients (aged 70-89
      years) with mild to moderate hypertension. A total of 4937 patients were
      randomised to candesartan or placebo with other antihypertensive drugs (mostly
      diuretics, beta-blockers, and calcium antagonists) added as needed to control
      blood pressure. Only 16% of the patients in the control group received placebo
      alone. The mean follow-up was 3.7 years. The aim of this health-related quality
      of life (HRQL) substudy analysis was to investigate changes in HRQL during
      antihypertensive treatment, and possible differences in patients receiving
      candesartan-based or other antihypertensive treatment. Three validated HRQL
      instruments were used: the Psychological General Well-being (PGWB) Index, the
      Subjective Symptoms Assessment Profile (SSA-P), and the EuroQoL Health Utility
      Index (EuroQoL). The HRQL was generally good at baseline and well preserved
      during follow-up in the presence of substantial blood pressure reductions in both
      treatment groups. Several of the observed changes in score from baseline to last
      visit favoured candesartan-based compared to control treatment, particularly the
      changes in PGWB Anxiety (-0.5 vs -1.0, P=0.01), PGWB Positive well-being (-0.8 vs
      -1.1, P=0.04), SSA-P Cardiac symptoms (0.03 vs 0.10, P=0.03), and EuroQoL Current
      health (-3.1 vs -5.3, P=0.008). This favourable result may be related to the
      somewhat lower blood pressure associated with candesartan-based treatment. In
      conclusion, there should be no reason to withhold modern antihypertensive therapy
      in elderly patients due to concerns for a negative effect on HRQL.

PMID- 15037873
TI  - Increased pulse pressure is associated with reduced baroreflex sensitivity.
AB  - Although pulse pressure (PP), heart rate variability (HRV) and baroreflex
      sensitivity (BRS) have been shown to predict cardiovascular events and mortality
      in various populations, their relationships have not been clarified. We examined
      these associations in two separate population-based samples of healthy middle
      aged subjects. In population 1, data were obtained from 149 subjects (71 men and
      78 women) aged 35-64 (mean 47.7) years, and in population 2, from 214 subjects
      (88 men and 126 women) aged 40-62 (mean 50.5) years. Increased 24-h ambulatory PP
      was related to decreased cross-spectral BRS independent of age and gender (beta=
      0.28, P<0.001 for population 1; beta=-0.22, P=0.003 for population 2). This
      association remained significant when 24-h ambulatory diastolic blood pressure,
      body mass index, smoking and alcohol intake were added as covariates in the
      multivariate analysis. Increased ambulatory PP was also associated with increased
      beat-to-beat systolic arterial pressure variability. Associations between
      ambulatory PP and HRV were not significant after controlling for age and gender.
      Our results suggest that elevated PP does not affect overall HRV, but it
      interferes with baroreflex-mediated control of the heart rate. This association
      may be due to a common denominator, such as arterial stiffness, for PP and BRS.

PMID- 15037874
TI  - Factors influencing acute blood pressure values in stroke subtypes.
AB  - The aim of this prospective observational study was to determine the association
      of acute blood pressure values with independent factors (demographic, clinical
      characteristics, early complications) in stroke subgroups of different aetiology.
      We evaluated data of 346 first-ever acute (<24 h) stroke patients treated in our
      stroke unit. Casual and 24-h blood pressure (BP) values were measured. Stroke
      risk factors and stroke severity on admission were documented. Strokes were
      divided into subgroups of different aetiopathogenic mechanism. Patients were
      imaged with CT-scan on admission and 5 days later to determine the presence of
      brain oedema and haemorrhagic transformation. The relationship of different
      factors to 24-h BP values (24-h BP) was evaluated separately in each stroke
      subgroup. In large artery atherosclerotic stroke (n=59), history of hypertension
      and stroke severity correlated with higher 24-h BP respectively. In cardioembolic
      stroke (n=87), history of hypertension, stroke severity, haemorrhagic
      transformation and brain oedema were associated with higher 24-h BP, while heart
      failure with lower 24-h BP. History of hypertension and coronary artery disease
      was related to higher and lower 24-h BP, respectively, in lacunar stroke (n=75).
      In patients with infarct of undetermined (n=57) cause 24-h BP were mainly
      influenced by stroke severity and history of hypertension. An independent
      association between higher 24-h BP and history of hypertension and cerebral
      oedema was documented in intracerebral haemorrhage (n=68). In conclusion,
      different factors influence acute BP values in stroke subtypes of different
      aetiology. If the clinical significance of these observations is verified, a
      differentiated approach in acute BP management based on stroke aetiology may be
      considered.

PMID- 15037875
TI  - End-digit preference in blood pressure recordings of patients with ischaemic
      heart disease in primary care.
AB  - End-digit preference describes the disproportionate selection of specific end
      digits. The rounding of figures might lead to either an under- or over-recording
      of blood pressure (BP) and a lack of accuracy and reliability in treatment
      decisions. A total of 85 000 BP values taken from computerised general practice
      records of ischaemic heart disease patients in England between 2001 and 2003 were
      examined. Zero preference accounts for 64% of systolic and 59% of diastolic
      readings, compared with an expected frequency of 10% (P<0.000001). Even numbers
      are more frequently seen than odd numbers. In all, 64% of nonzero systolic
      recordings and 65% of diastolic recordings ended in even numbers, compared with
      expected proportions of 44% (P<0.0001). Among the nonzero even numbers, eight is
      the most frequently observed: 28% of systolic and 31% of diastolic recordings
      compared with an expected proportion of 25% (P<0.0001). Among the five nonzero
      odd numbers, five is the most frequently observed end digit, representing 59%
      systolic and 62% of diastolic compared with an expected level of 20% (P<0.00001).
      English general practice displays marked end-digit preference. This is strongly
      for the end-digit zero. However, there is more use of other end-digits, notably 8
      and 5. This bias potentially carries important treatment consequences for this
      high-risk population.

PMID- 15037876
TI  - The T-allele of the C825T polymorphism is associated with higher arterial
      stiffness in young healthy males.
AB  - Arterial stiffening is the major cause of increasing systolic blood pressure in
      arterial hypertension. Increased arterial stiffness is one major mechanism
      responsible for morbidity and mortality in hypertension. A C825T polymorphism was
      identified in the gene encoding the G-protein beta3 subunit (GNB3), and an
      association of the T-allele with hypertension was demonstrated in several
      studies. In order to identify a pathogenetic link between hypertension and
      arterial stiffness, we compared two indices of arterial stiffness, pulse wave
      velocity (PWV) and augmentation index, in young, healthy men with and without the
      825T-allele under resting conditions. PWV was determined from pressure tracing
      over carotid and femoral arteries in 99 subjects (CC: n=43; CT&TT: n=56).
      Augmentation index was derived in 72 subjects (CC: n=30; CT&TT: n=42) by pulse
      wave analysis using radial applanation tonometry. Carriers of the 825T-allele
      exhibited a significantly higher PWV compared to subjects with the CC genotype
      (6.0+/-0.1 m/s (TC&TT) vs 5.7+/-0.1 m/s (CC); P=0.0251). There was also a
      significant difference (P = 0.0448) in augmentation index between carriers of the
      T-allele (CT&TT: 3.4+/-2.9%) and controls with the CC -genotype (-5.0+/-4.1 %).
      There was no difference in any other anthropometric (age, height, weight, body
      mass index) or haemodynamic (heart rate, peripheral and central blood pressure).
      In summary, the C825T polymorphism is associated with higher arterial stiffness
      in young, healthy males. Arterial stiffening may pathogenetically contribute to
      the development of hypertension in carriers of the T-allele.

PMID- 15037877
TI  - Improvement of blood pressure control in a hypertension clinic: a 10-year follow
      up study.
AB  - The objective of the study was to assess whether the publication of new
      guidelines, such as JNC VI 1997 and WHO/ISH 1999, and the development of new
      antihypertensive drugs have improved blood pressure (BP) control. A total of 150
      patients (age 29-88, mean 66+/-11 years in 2001) who were followed at our
      hypertension clinic during 1991-2001 were retrospectively investigated. We
      compared the clinical characteristics of the patients in 2001 to those in 1991
      and 1996, using the averaged BP determined at two occasions each year for our
      analysis. The average BP decreased during the 10 years between 1991 and 2001.
      When good BP control was defined as <140/90 mmHg, the rate of patients with good
      BP control increased from 31% in 1991 to 43% in 1996, and to 57% in 2001 (P<0.001
      vs 1991). Both younger (< or =64 years) and older (> or =65 years) patients
      showed similar improvement during these 10 years. In 2001, satisfactory BP
      control (<130/85 mmHg) was achieved in 24% of younger patients, which was
      significantly higher than the achievement in 1991 (10%, P=0.02). This improvement
      occurred at the same time as an increase in the prescription of Ca antagonists
      and angiotensin II antagonist. The patients with improved BP control during these
      10 years (n=50) showed lower body mass index (BMI) and serum total cholesterol
      levels in 2001 compared to persistently uncontrolled patients (n=54).
      Furthermore, the change in BMI during these 10 years was significantly less in
      the patients with improved BP control than in the persistently uncontrolled
      patients. In conclusion, BP control improved in the 10 years studied, and it
      seems to be attributable to the more frequent use of the newer drugs such as
      angiotensin II antagonists and Ca antagonists, to lifestyle modification and also
      to the growth in awareness of the importance of strict BP control.

PMID- 15037878
TI  - Should pulse pressure become part of the Framingham risk score?
AB  - An increased pulse pressure suggests aortic stiffening. New evidence also
      suggests that pulse pressure is a more sensitive measure of risk than other
      indexes of blood pressure in middle-aged and older persons. The objective of the
      study was to relate pulse pressure to the risk of cardiovascular events in the
      general population, and to assess whether pulse pressure could improve the
      Framingham risk prediction. A total of 378 men and 391 women over the age of 50
      years (mean 62.7 years) were followed. Sex-specific Framingham cardiovascular
      risk scores were derived from age, systolic pressure, diastolic pressure, total
      and HDL cholesterol, smoking status and the presence or absence of diabetes
      mellitus. The cutoff points used to develop a pulse pressure score were
      calculated by determining the percentile points corresponding to the blood
      pressure categories in the Framingham risk score. We calculated relative hazard
      rates by multiple Cox regression. After a median follow-up of 7.2 years (range:
      11 months-15 years), a total of 148 cardiovascular events occurred. In Cox
      regression analysis, a 10 mmHg higher pulse pressure was associated with 31%
      (P<0.0001) increase in the risk for cardiovascular events (fatal and nonfatal)
      after adjustment for sex, age, total and HDL cholesterol, smoking and the
      presence of diabetes mellitus. After adjustment for the aforementioned risk
      factors, a one-point increment in the blood pressure and pulse pressure scores
      was associated with a 40 and 48% (both P<0.0001) increase in the risk of fatal
      and nonfatal cardiovascular events, respectively. When both the blood pressure
      and pulse pressure scores were forced into a Cox model, only the pulse pressure
      score remained statistically significant (P<0.0001) with a relative hazard rate
      of 1.37 (CI: 1.16-1.69). These prospective data suggest that pulse pressure may
      improve the Framingham risk prediction among middle-aged and older individuals.
      Further studies, especially in the Framingham cohort, are warranted.

PMID- 15037879
TI  - Recurrent posterior reversible encephalopathy syndrome (PRES).
AB  - Posterior reversible encephalopathy syndrome is a proposed
      cliniconeuroradiological entity characterized by headache, altered mental status,
      cortical blindness, seizures, and other focal neurological signs, and a
      diagnostic magnetic resonance imaging picture. A variety of different etiologies
      have been reported like hypertension, pre-eclampsia/eclampsia, cyclosporin A or
      tacrolimus neurotoxicity, uraemia and porphyria. With early diagnosis and prompt
      treatment, the syndrome is usually fully reversible. We report a case of
      recurrent PRES of unknown aetiology following intensive care unit treatment and
      only moderately elevated blood pressure. Clinicians as well as radiologists must
      be familiar with this clinically frightening, underdiagnosed condition to assure
      timely diagnosis and treatment to prevent persistent deficits.

PMID- 15037880
TI  - Levels of plasma fibrinogen and D-dimer in subjects with white-coat hypertension.

PMID- 15037881
TI  - Tilt test alters accuracy of the oscillometric device Omron HEM-705CP.

PMID- 15037882
TI  - Relationship between changes in food group variety, dietary intake, and weight
      during obesity treatment.
AB  - BACKGROUND: Experimental studies show diets with greater variety in energy-dense
      foods increase consumption and body weight. Reducing variety in energy-dense food
      groups may decrease energy and dietary fat intake, promoting weight loss.
      OBJECTIVE: This study examined changes in food group variety during obesity
      treatment and the relation between changes in food group variety, dietary intake,
      and weight. DESIGN: Overweight men and women (n=202) were randomly assigned to
      one of two standard behavioral treatments with varying exercise prescriptions
      (exercise level of 4186 kJ/week (1000 kcal/week) or 10465 kJ/week (2500
      kcal/week)), but received the same diet. Complete measures were obtained from 122
      participants, of which 70 (58%) were female, with a mean body mass index of 31.3
      kg/m(2) (s.d.=2.5). MEASUREMENTS: Food group variety and diet composition were
      assessed at 0, 6, and 18 months from food-frequency questionnaires. Food group
      variety was calculated as percent of foods consumed on a weekly basis within a
      food group, irrespective of servings consumed. RESULTS: Participants reported
      increased variety (P</=0.001) in low-fat breads (LFB) and vegetables, and
      decreased variety (P</=0.001) in high-fat foods (HFF), and fats, oils, and sweets
      (FOS) over the course of the 18-month study. From 0 to 6 months, decreased HFF
      and FOS variety was associated with reduced energy and percent dietary fat
      intake, and decreased HFF variety was related to weight loss. From 6 to 18
      months, decreased HFF variety and increased LFB variety was associated with
      reduced percent dietary fat consumed and weight loss. CONCLUSION: Changing
      variety in specific food groups may help in adopting and sustaining a diet low in
      energy and fat, producing better weight loss and weight loss maintenance.

PMID- 15037884
TI  - An unusual case of tuberculous dacryocystitis.

PMID- 15037883
TI  - Change in the level of physical activity from adolescence into adulthood and
      obesity at the age of 31 years.
AB  - OBJECTIVE: To evaluate how a change in the level of leisure-time physical
      activity from adolescence into adulthood is associated with overall and abdominal
      obesity at the age of 31 y. DESIGN: Prospective follow-up study of Northern
      Finland birth cohort of 1966. SUBJECTS: In all, a population of 2834 males and
      2872 females aged 31 y was studied. MEASUREMENTS: At the age of 31 y, overweight
      was defined as a body mass index (BMI) of 25.0-29.9 kg/m(2) and obesity as a BMI
      of 30.0 kg/m(2) or more. The cutoff points of waist circumference for mild and
      severe abdominal obesity were 94.0 and 102.0 cm in males and 80.0 and 88.0 cm in
      females. The change in the level of physical activity (at least moderately active
      vs inactive) was evaluated by inquiries conducted at the ages of 14 and 31 y. The
      odds ratios (OR) and their 95% confidence intervals (CI) obtained from logistic
      regression were adjusted for maternal BMI before pregnancy, BMI at the age of 14
      y, alcohol intake, occupational physical activity, smoking, and, in the case of
      females, for parity at age 31 y. RESULTS: Becoming inactive during the transition
      from adolescence to adulthood was associated with overall overweight in males (OR
      1.49, CI 1.18-1.89), overall obesity in males (OR 1.53, CI 0.99-2.37) and females
      (OR 1.51, CI 0.94-2.44), and with severe abdominal obesity in females (OR 1.80,
      CI 1.13-2.86). Being persistently inactive from adolescence to adulthood was
      associated with mild abdominal obesity in males (OR 1.83, CI 1.13-2.95), but not
      with other obesity measures in either gender after adjustment for confounding
      factors. CONCLUSIONS: Becoming inactive during the transition from adolescence to
      adulthood is related to overall obesity in both genders, and to severe abdominal
      obesity in females at the age of 31 y. The results emphasize the role of
      continued physical activity from adolescence into adulthood in the prevention of
      adult obesity.

PMID- 15037885
TI  - Medically unexplained visual loss in adult patients.
AB  - PURPOSE: To evaluate the characteristics of patients with nonorganic or medically
      unexplained visual loss (MUVL) presenting to a neuro-ophthalmology clinic.
      METHODS: A retrospective review of the case notes of patients identified from our
      diagnostic register. All patients had been followed up for at least 18 months and
      investigations (including, in all cases, neuroimaging) had failed to reveal any
      underlying pathology. To be included, patients had to have at least one
      inconsistent feature on visual function testing. RESULTS: : We identified 58
      patients with MUVL. A total of 79% of patients were female and 21% were male. In
      total, 36% of patients had been seen in other medical specialties with
      unexplained symptoms. In all, 60% of patients complained of glare or pain. Of the
      patients with bilateral visual loss, the acuities were frequently the same in
      each eye and the most common pattern of visual field loss was concentric
      contraction. Those with unilateral visual loss had a more variable pattern of
      visual failure. In total, 22% of patients showed some visual recovery though this
      was usually incomplete. In one patient, organic pathology accounting for the
      visual symptoms became apparent after the end of the 18 month follow-up period.
      CONCLUSIONS: Medically unexplained symptoms, in general, form an important part
      of the workload in most medical specialties. Unexplained symptoms in
      ophthalmology have not been well studied. Terminology should be brought into line
      with that used in other medical specialties. Further work may help in the
      identification of positive diagnostic features of MUVL which should not be simply
      a 'diagnosis of exclusion'.

PMID- 15037886
TI  - Pars plana vitrectomy for traumatic cyclodialysis with persistent hypotony.

PMID- 15037887
TI  - Mifepristone treatment in patients with surgically incurable sphenoid-ridge
      meningioma: a long-term follow-up.

PMID- 15037888
TI  - Unusual presentation of dirofilariasis as a lacrimal mass.

PMID- 15037889
TI  - A three-year prospective, randomized and open comparison between latanoprost and
      timolol in Japanese normal-tension glaucoma patients.
AB  - PURPOSE: To compare the longitudinal effects of treatment on intraocular pressure
      (IOP) and visual field performance in Japanese normal-tension glaucoma (NTG)
      between latanoprost and timolol. PATIENTS AND METHODS: This is an open-label,
      randomized, study. A total of 62 NTG patients were prospectively, consecutively
      enrolled. All study subjects were randomly assigned to 0.005% latanoprost
      instillation once daily in the morning or 0.5% timolol instillation twice daily
      for a prospective 3-year follow-up, and underwent a routine ocular examination
      every month. Automated perimetry was performed every 6 months using Humphrey
      field analysers. Stereophotographs of optic discs were also obtained every 6
      months. RESULTS: Percentage of IOP reduction or the magnitude of IOP reduction
      showed no intergroup differences either at any time point (13-15%). In the visual
      field, the estimated rate of change in the MD value (dB/year) was -0.34+/-0.17
      (SE) for the latanoprost group, and -0.10+/-0.18 (SE) for the timolol group. The
      estimated rate of change in MD showed no significant difference from zero in both
      groups, and there were no statistical intergroup differences. No changes in the
      optic nerve head topography in the vertical cup-to-disc ratio and rim area
      measured by image-analysis techniques were observed in either group. There were
      no patients who dropped out due to the side effects of treatment regimens.
      CONCLUSION: Both latanoprost and timolol single treatments reduced IOP by 13-15%
      at their trough effects for 3 years in Japanese NTG patients; both showed similar
      effects on visual field performance.

PMID- 15037890
TI  - Efficacy and safety of the latanoprost/timolol maleate fixed combination vs
      concomitant brimonidine and latanoprost therapy.
AB  - AIMS: To evaluate the efficacy and safety of latanoprost/timolol maleate fixed
      combination (LTFC) given once daily vs the concomitant therapy of brimonidine
      twice daily and latanoprost once daily in primary open-angle glaucoma or ocular
      hypertensive subjects. METHODS: A prospective, double-masked, active-controlled
      comparison in which qualified subjects had all glaucoma medicines discontinued
      for 1 month and then were randomized to either LTFC or brimonidine and
      latanoprost concomitant therapy for 6 weeks. They were then switched to the other
      treatment regimen. The intraocular pressure (IOP) was measured at 0800, 1200, and
      1600 h at baseline and at the end of Periods 1 and Period 2. RESULTS: In 32
      subjects, the diurnal curve of the untreated IOP of 26.0+/-3.4 decreased to
      17.8+/-2.5 on LTFC and 17.2+/-2.8 mmHg on brimonidine and latanoprost (P=0.31).
      At 0800 and 1600 h, the IOPs were statistically similar between the groups
      (P>0.05). At 1200 h the latanoprost and brimonidine treatment IOP was
      statistically lower (16.2+/-3.2) than LTFC (18.0+/-2.8 mmHg). However, the
      reduced IOP from untreated baseline was not statistically different at each time
      point and for the diurnal curve for each therapy (P<0.05). Safety was similar
      between groups for both solicited and unsolicited side effects (P>0.05).
      CONCLUSION: This study suggests that LTFC and concomitant therapy of brimonidine
      and latanoprost provide statistically similar diurnal IOP reduction from an
      untreated baseline.

PMID- 15037892
TI  - Smallanthus sonchifolius and Lepidium meyenii - prospective Andean crops for the
      prevention of chronic diseases.
AB  - Smallanthus sonchifolius (yacon) and Lepidium meyenii (maca) were the traditional
      crops of the original population of Peru where they are also still used in folk
      medicine. These plants are little known in Europe and Northern America although
      at least yacon can be cultivated in the climatic conditions of these regions.
      This article deals with the botany and the composition, the structure of main
      constituents, biological activity of these plants and the cultivation of yacon in
      the Czech Republic. The potential of yacon tubers to treat hyperglycemia, kidney
      problems and for skin rejuvenation and the antihyperglycemic and cytoprotective
      activity of its leaves seems to be related mostly to its oligofructan and
      phenolic content, respectively. Maca alkaloids, steroids, glucosinolates,
      isothicyanates and macamides are probably responsible for its aptitude to act as
      a fertility enhancer, aphrodisiac, adaptogen, immunostimulant, anabolic and to
      influence hormonal balance. Yacon and maca are already on the European market as
      prospective functional foods and dietary supplements, mainly for use in certain
      risk groups of the population, e.g. seniors, diabetics, postmenopausal women etc.

PMID- 15037891
TI  - Giant retinal pigment epithelium rip secondary to subretinal proliferative
      vitreoretinopathy.

PMID- 15037894
TI  - Natural phenolics in the prevention of UV-induced skin damage. A review.
AB  - UV skin exposure induces extensive generation of reactive oxygen species (ROS).
      These can react with DNA, proteins, fatty acids and saccharides causing oxidative
      damage. Such injuries result in a number of harmful effects: disturbed cell
      metabolism, morphological and ultrastructural changes, attack on the regulation
      pathways and, alterations in the differentiation, proliferation and apoptosis of
      skin cells. These processes can lead to photoaging and skin cancer development.
      One approach to protecting human skin against the harmful effects of UV
      irradiation is to use antioxidants as photoprotectives. In recent years naturally
      occurring herbal compounds such as phenolic acids, flavonoids, and high molecular
      weight polyphenols have gained considerable attention as beneficial protective
      agents. In this review, we strive to summarize the findings of studies performed
      to date, regarding the photoprotective effects of plant phenolics on the skin
      damage induced by UV radiation.

PMID- 15037893
TI  - Approaches to messenger RNA detection - comparison of methods.
AB  - Detection of messenger RNA is an important part of current biomedical research,
      although utilized for decades. This communication endeavors to compare three most
      commonly used techniques of mRNA detection, i.e. Northern blot, ribonuclease
      protection assay (RPA), and real-time polymerase chain reaction (RT-PCR).
      Principles and general procedures of these methods are described, and advantages
      and weaknesses of each are discussed in terms of their specificity, sensitivity,
      difficulty, time and material demands as well as health and environmental risks.
      We conclude that choice of any method discussed depends on particular purpose,
      experience of the researcher, and on laboratory equipment and organization.

PMID- 15037895
TI  - Metal-chelating properties, electrochemical behavior, scavenging and
      cytoprotective activities of six natural phenolics.
AB  - Chelation, electrochemical, antioxidant and cytoprotective properties of six
      phenolics - cynarin and caffeic, chlorogenic, ferulic, protocatechuic and
      rosmarinic acids were studied on the following models: (i) chelation of
      transition metals, (ii) quenching of the diphenylpicrylhydrazyl radical (DPPH),
      (iii) determination of half-wave potential, (iv) erythrocytes or mitochondrial
      membranes damaged by tert-butyl hydroperoxide (tBH) and (v) a primary culture of
      rat hepatocytes intoxicated by Cu(II) and Fe(III) or tBH. All phenolics
      suppressed cell membrane damage induced by transition metals or tBH. The
      protectivity correlated with their capacity to bind transition metals, to
      scavenge DPPH radical and with the value of half-wave potentials. In in vitro
      assays, the most promising was rosmarinic acid.

PMID- 15037896
TI  - Minipig as a model for drug metabolism in man: comparison of in vitro and in vivo
      metabolism of propafenone.
AB  - To prove the suitability of minipigs as experimental animal in modeling of the
      drug metabolism and pharmacokine-tics in man, propafenone metabolism in vitro at
      the microsomal level as well as propafenone pharmacokinetics in the minipig was
      studied. The results were compared with those obtained for humans. It can be
      concluded that whereas the microsomal in vitro system of minipig may be a good
      model for drug metabolism in the man, the pharmacokinetics in the whole organism
      is more complex reflecting differences in substrate specificities of many
      enzymatic and transport systems. In this particular case, it has been documented
      that the glucuronidation of propafenone principal metabolite (5
      hydroxypropafenone) is more efficient in the minipig.

PMID- 15037897
TI  - Adiponectin in patients with various stages of coronary heart disease -
      comparison of its concentration in coronary arteries and peripheral venous
      circulation.
AB  - Adiponectin is an adipocytes-produced protein and showing a number of
      antiatherogenic effects. Adiponectin seems to be extensively deposited in the
      intersticium of venous lesions of persons with myocardial infarction. It may
      exhibit antiatherogenic and reparative effects. A decreased adiponectin
      concentration may be a risk factor of the origin and complications of
      atherosclerosis. AIM OF THE STUDY: 1) Do the adiponectin concentrations in venous
      blood of persons with acute coronary syndrome (ACS) differ from those in persons
      with stress angina pectoris? 2) In these persons do adiponectin concentrations in
      venous blood differ from those in main coronary arteries? 3) Do adiponectin
      levels differ in the infarction and non-infarction arteries in persons with STEMI
      (ST Elevation Myocardial Infarct) and delay within 4 hours after the onset? 4) In
      persons with ACS does any correlation exist between venous adiponectin and common
      risk factors of cardiovascular complications? Adiponectin concentration was
      determined in samples of blood collected from the peripheral vein and during
      coronarography in various localizations in 4 groups of examined persons (I. - no
      signs of CAD, II. - stable stress angina pectoris, III. - ACS over 48 hours
      without elevations of ST segment, IV. - STEMI during first 4 hours after its
      origin and proved occlusion of coronary artery at coronarography). Coronary
      angiography, risk factors and anamnestic data were analyzed. The software Medcalc
      was used to perform statistical analysis. We examined 73 probands with signs of
      myocardial ischemia (mean age of 61.5 years, 64 % males), who were subjected to
      coronarography and 21 healthy volunteers. A mean delay (delay from the origin of
      complaints to the performed coronarography) was 3.1 +/- 0.5 hours in individuals
      in the group IV. In patients with ACS we found lower adiponectin concentrations
      in venous blood compared to healthy individuals and persons with stress AP, but
      changes were not statistically significant (I.: -5.9 +/- 2.7 ng/l, II.: -4.9 +/-
      1.2 ng/l, III.: -5.2 +/- 4.1 ng/l, IV.: -4.6 +/- 2.7 ng/l); no differences were
      found also with BMI. No significant difference was recorded between the samples
      of venous blood and those of coronary arteries, nor between the infarction and
      the non-infarction arteries in the group IV. (5.2 +/- 2.6 ng/l vs. 4.8 +/- -2.7
      ng/l). Significant negative correlations were observed between adiponectin
      concentrations and BMI (correlation coefficient -0.29), triacylglycerols
      (correlation coefficient -0.4), AOPP (correlation coefficient -0.39), and
      positive correlations with HDL (correlation coefficient 0.32). No correlation was
      recorded between adiponectin and CRP. Adiponectin concentrations in persons with
      ACS are lower than in healthy persons or patients with stable angina pectoris,
      but differences are not statistically significant. The absence of adiponectin
      differences between the infarction/non-infarction artery may support the
      hypothesis of adiponectin uptake in the ischemic lesion with subsequent decrease
      in blood adiponectin. On the contrary, adiponectin decrease may be a risk factor
      independent of the origin and development of ACS.

PMID- 15037898
TI  - Adiponectin concentrations as a criterion of metabolic control in persons with
      type 2 diabetes mellitus?
AB  - Adiponectin (ADP) is an adipocytokin with many antiatherogenic properties; its
      decreased level is associated with numerous atherogenic diseases and syndromes
      (e.g. diabetes mellitus (DM), dyslipidemia, endothelial dysfunction,
      hypertension, and obesity). Decreased ADP values in blood may be an independent
      risk factor of atherosclerotic (ATS) complications. AIM OF THE STUDY: 1) Do
      persons with type 2 diabetes have lower ADP values than individuals without DM
      but with a high risk of ATS complications? 2) Do ADP values differ between
      persons with well controlled and persons with uncontrolled type 2 diabetes? We
      examined 109 patients of the Metabolic Center of Hospital Sternberk. Out of them,
      58 had type 2 diabetes, others were individuals with variously expressed risk
      factors of early atherosclerosis (obesity, hypertension, age, family history,
      smoking, dyslipidemia, etc.). In all persons under this study the following
      parameters were determined in peripheral venous blood: adiponectin, resistin,
      leptin, ObRe, cholesterol, HDL-cholesterol, triacylglycerols, glucose, HbA1c,
      creatinine, urea, ALT, AST, CRP, homocysteine, thrombocyte aggregation after CPG
      induction. The whole group was divided according to the presence of type 2DM into
      two subgroups; persons with diabetes were divided into the well controlled and
      uncontrolled subgroups. All data obtained were processed statistically using the
      software SPSS for Windows and Medcalc. The adiponectin/BMI index correlated
      negatively with HbA1c value (correlation coefficient -0.37, p = 0.00053),
      triacylglycerols (-0.4, p = 0.000001), P-glucose (-0.3, p = 0.0017), uricemia (
      0.35, p = 0.0007) and positively with HDL-cholesterol value (0.6, p=0.00001).
      Women had higher adiponectin values than men. Persons with hypertension and with
      diabetes mellitus, individuals with atherogenic lipotype or persons with
      inflammation signs had lower values than individuals without these diseases and
      syndromes. Persons with wellcontrolled diabetes mellitus had higher values than
      persons with uncontrolled diabetes (medians of the adiponectin/BMI index 9.7 vs.
      6.7, p < 0.01). Persons with type 2 diabetes mellitus have lower ADP values than
      persons with a high ATS risk without diabetes mellitus. Persons with
      wellcontrolled diabetes mellitus (DM) and with satisfactory compensation have
      significantly higher ADP levels (independently of other metabolic parameters of
      DM control). ADP may be a new marker of metabolic control in persons with a high
      risk of atherosclerotic complications.

PMID- 15037899
TI  - The occurrence of reactive oxygen species in the semen of males from infertile
      couples.
AB  - The aim of this pilot study was to establish a reactive oxygen species (ROS)
      evaluation method as a step in the routine diagnosis of men from infertile
      couples, which attend the Centre of Assisted Reproduction at the Teaching
      Hospital in Olomouc. Standard semen analyses were performed manually according to
      WHO guidelines. The number of peroxidase-positive leukocytes in the semen was
      determined using the Endtz test. The levels of ROS were estimated by
      chemiluminescence assay using luminol (5-amino-2,3 dihydro-1,4 phthalazinedione)
      as a probe. The semen samples were collected from 68 patients. Normospermia was
      found in 15 patients (22.1 %). The semen samples of 3 normospermic patients were
      classified as ROS-positive. Elevated ROS production was recorded in all subgroups
      of patients irrespective of any pathology found. We confirmed that spermatozoa
      might be the source of ROS as well as the seminal leukocytes. Apart from the
      leukocytes, sperm cells with residual cytoplasm and immature spermatozoa are
      considered to be a major source of ROS. Thus it is suggested that sperm
      morphology abnormalities should be evaluated more carefully.

PMID- 15037900
TI  - Use of cystatin C determination in clinical diagnostics.
AB  - This paper presents a current view of the possible clinical uses of cystatin C
      determination. Cystatin C is an inhibitor of cysteine proteases, and relatively
      stable in the systemic circulation it is comparatively easily determined.
      Although in clinical practice it is known primarily as a relatively reliable and
      endogenous marker for glomerular filtration, lately cystatin C analysis has been
      discussed in connection with the diagnostics of a variety of diseases such as
      early atherosclerosis, Alzheimer's dementia, vascular aneurysms,
      hyperhomocysteinaemia and other neurodegenerative diseases.

PMID- 15037901
TI  - Surface artery volume pulse wave measurement - verification of a new method.
AB  - The aim of this paper is to prove the possible reproducibility of measurement
      with a new developed device for artery elasticity monitoring and determining the
      standard of major pulse wave parameters. As a measurement sensor, a conic probe
      with thin convex membrane was used. This technique allows setting an arbitrary
      pressure to a measured surface artery. We measured pulse waves on the radial
      arteries of 108 individuals. We expected similar features in arterial wall
      elasticity. We concentrated primarily on the amount of subcutaneous fat. For the
      measured waves we evaluated five following pulse wave parameters: relative crest
      time, elasticity index, dicrotic wave attenuation, dicrotic wave time and
      interwave distance. There were no significant differences in measured pulse wave
      parameters among the tested groups of subjects.

PMID- 15037902
TI  - Selected indicators of bone metabolism in patients after kidney transplant.
AB  - Bone metabolism defects and skeleton diseases, so called renal osteopathy (RO),
      represent very serious clinical problems in the care of patients with kidney
      dysfunction. Renal osteopathy is a complicated skeletal disorder with a very
      complicated pathogenesis and we can encounter its individual forms in kidney
      transplant patients.

PMID- 15037903
TI  - Protocol biopsy and subclinical rejection in patients after kidney
      transplantation treated by tacrolimus (Prograf).
AB  - The article deals with the contribution of tacrolimus (Prograf) to improvement in
      kidney transplant results. Tacrolimus, in comparison with cyclosporine
      significantly reduces the incidence of acute rejection and improves survival of
      grafts as well as patients. Based on the literature, the primary immunological
      differences between tacrolimus and cyclosporine effects are pointed out. These
      differences explain the better immunosuppressive effectiveness of tacrolimus.
      Based on analysis of the results, subclinical rejection problems and significance
      of protocol biopsy for present-day transplantology are discussed. There is also a
      critical analysis of the questions, which priority, in relationship to the
      expanding availability of immunosuppressive substances currently has high
      interest for nephrologists researching subclinical rejection.

PMID- 15037904
TI  - Effect of various protective solutions on function after kidney transplantation.
AB  - From 1995 to 2002 we monitored a group of 127 patients who had undergone kidney
      transplantations in the Olomouc transplantation centre. The aim of our study was
      to assess the function of the kidneys after the transplantation, which were
      rinsed during the removal from cadaverous donors and afterwards were treated by
      different preservative dilutions. We divided the patients into three groups of
      approximate similar size, according to the used dilution - EC (Eurocollins), HTK
      (Custodiol) and UW (Viaspan). In the first three weeks we assessed in each group,
      the immediate function of the kidneys as primary, belated and afunction. The EC
      group showed the primary function in 51.2 % of cases, belated in 46.8 % of cases
      and afunction in 2.1 % of cases. In the HTK group, primary function was found in
      73.7 %, belated 23.6 % and afunction 2.7 %. The results of the UW group came to
      primary function 71.5 %, belated 26.2 % and afunction 2.3 %. The criteria of the
      immediate but also the long-term function (five year investigation) was a serum
      creatinine figure. The lowest decline of creatinine in three weeks after the
      transplantation was noticed in the EC group (the average figure = 429 micro
      mol/l). In contrast the HTK group (the average figure 279 micro mol/l) and the UW
      group (the average figure 288 micro mol/l) had comparable figures and there was
      no significant difference between them from the statistical point of view. It
      means later in the first, the third and the fifth year after the transplantation
      the figures levelled out: EC 154 micro m/l, HTK 182 micro m/l, and UW 133 micro
      m/l. There was statistically a minimum significant difference between the HTK
      group and the UW group. Another criteria was to determine the amount of
      functional grafts in alive donees. The Assessment was carried out always in each
      year after the transplantation, altogether five years. The amount of the
      functional renal grafts in EC and HTK group was 100 %, in the UW group 76.9 %.
      CONCLUSION: HTK and UW gave better immediate functionality results, but there
      were no differences found among EC, HTK and the UW group from the long-term point
      of view.

PMID- 15037905
TI  - Endovascular treatment of central venous stenoses in patients with dialysis
      shunts.
AB  - OBJECTIVE: Evaluation of long-term results of percutaneous treatment of central
      vein stenoses or occlusions in patients with haemodialysis shunt. MATERIALS AND
      METHODS: In 26 patients with haemodialysis shunts and confirmed central vein
      stenosis or occlusion, 28 primary percutaneous transluminal angioplasties (PTA)
      and 5 repeated PTAs (re-PTA) were performed; in three patients a stent was
      implanted - primary in one patient and due to early restenosis after PTA in two
      patients. To maintain stent patency, 10 re-PTA were performed. RESULTS: The
      technical success rate of primary interventions was 96 % (100 % in stenoses and
      50 % in occlusions). Primary post-PTA patency rate was 70 % at 3 months, 60 % at
      6 months and 30 % at 12 months. CONCLUSION: PTA with possible stent implantation
      is a first-choice method in the treatment of stenoses and occlusions of the
      central venous system. Despite the relatively frequent re-interventions,
      endovascular treatment is capable to preserve long-term function of the dialysis
      shunt.

PMID- 15037906
TI  - The importance of indicators of the initial phase of atherosclerosis in patients
      with microvascular angina.
AB  - Endothelial dysfunction (ED) is generally considered to be the initial step in
      the progression to atherosclerosis but there is still much uncertainty about the
      role of the microvascular form of angina in patients with a normal coronary
      angiogram with regard to ED. The authors investigated the extent of endothelial
      perturbation and thereby whether the microvascular form of angina precedens
      macroscopic atherosclerosis by means of non-invasive ultrasound measurement of
      the intima-media thickening (IMT) in common carotid artery and flow mediated
      dilatation (FMD) in the brachial artery. 28 patients with stable angina with
      positive exercise test and ST segment depression (22 females, 6 males, average
      age 54 years) were compared with a control group consisting of 28 patients with
      no clinical signs of coronary artery disease (18 females, 10 males, average age
      53 years). No significant difference in FMD% (7.3 vs. 10.8, p = 0.07) was found
      between the groups, though specific measurements (average dilatation of the
      brachial artery induced by ischemic insult, peak blood flow and peak hyperemic
      flow) differed considerably. Also IMT did not vary significantly between the
      groups (0.74 vs. 0.65, p = 0.08). In patients with IMT > 0.8 mm (6 patients in
      each group) a significant decrease of FMD was found as compared with patients
      with normal IMT (p < 0.05). It was concluded that in patients with increased IMT
      an inverse relationship between FMD and IMT exists both in patients with
      microvascular angina and in the healthy control subjects whereas in the group of
      patients with normal IMT no ED was demonstrated. This supports the hypothesis
      that the microvascular form of angina is the early stage of coronary artery
      atherosclerosis and this escapes angiographic recognition.

PMID- 15037907
TI  - Changes in mammographic and ultrasound image of the breast of women undergoing
      estrogen replacement therapy.
AB  - OBJECTIVE: Evaluation of changes in mammographic and ultrasound image of the
      breast in female patients undergoing estrogen hormonal replacement therapy (ERT).
      MATERIAL AND METHODS: 126 women with surgical menopause in case of benign disease
      using ERT and a control group of 100 women in menopause with no hormonal
      replacement therapy were selected for the study. Changes in the mammographic
      image were monitored in relation to individual types of breast according to
      Tabar's typology and with regard to the type of ERT application. In 38 women,
      changes in ultrasound image were also monitored together with ERT. RESULTS: In 17
      women (13 %) undergoing ERT, an increase in mammographic image density was found.
      This data was statistically significant in comparison with the control group
      without ERT (chi2 = 21.566, p < 0.0001). In 103 (82 %) women there was no change
      in mammographic density and in 6 women (5 %) decreased density despite using of
      ERT was found. In the group of patients undergoing ERT in peroral form, we found
      a greater percentage of women with an increased mammographic density (17 %) in
      comparison with the group of women with intradermally applied ERT (9 %).
      Increased density of mammographic image was more frequent in women with a
      prevalence of adipose tissue in their breasts (type II according to Tabar). In 8
      patients (21 %) of 38 women with ultrasound examination an enlargement or
      development of new benign formations in the breast was found; this data was
      statistically insignificant in comparison with the control group. CONCLUSION: In
      women with surgical menopause undergoing ERT, a statistically significant
      increase in the density of mammographic image was found (chi2 = 21.566, p <
      0.0001). Increase in density of mammographic image was most frequent in women
      with a predominance of adipose tissue in breasts (a type II according to Tabar)
      and in women undergoing ERT in the peroral form. These data were statistically
      insignificant in 21 % of women with supplementary ultrasound examination
      enlargement and development of new benign lesions in the breasts were found.

PMID- 15037908
TI  - CT-guided stereotaxy: first 10-year experience.
AB  - The authors present an overview on CT-guided stereotaxy performed in the last 10
      years in the University Hospital Olomouc. During this period a total of 811
      stereotactic brain operations were performed. Of these, 710 were done in the
      field of afunctional and 101 in the field of functional stereotaxy. The majority
      of procedures were biopsies of intracranial lesions (n = 464), evacuations of
      intracerebral hematomas with or without drainage and fibrinolysis (n = 147) and
      thalamotomies in patients with Parkinson's disease (n = 88). With the exception
      of the two years at the beginning, the number of yearly performed stereotaxies
      varied between 66-106 (mean, 86.9). Serious complications appeared after three
      procedures (0.37 %).

PMID- 15037909
TI  - Isolated ruptures of the supraspinatus muscle.
AB  - We rarely encounter isolated ruptures of the supraspinatus muscle. At the Clinic
      of Orthopedics at the Faculty Hospital in Olomouc, we encountered only 21 cases
      out of 385 arthroscopic operation cases from October 1998 to October 2003. The
      patients were examined by USG, 5 patients were examined arthrographically and 3
      patients underwent MRI examination. Of these 21 patients, only 3 were operated
      for acute post-injury haemarthrosis of the shoulder joint. During arthroscopic
      operation, an isolated rupture of the supraspinatus muscle was discovered in all
      these patients. The remaining 40 patients were only treated at our clinic for
      problems associated with impingement syndrome after an interval of 3-11 months
      and were indicated for operational therapy for the rupture of the supraspinatus
      muscle, verified sonographically and by MRI. Surgically we performed end to end
      sutures in 12 patients, in 9 cases we performed refixation using 1-2 titanium
      MITEK anchors. We supplemented the work by a detailed anatomical study of the
      supraspinatus muscle on 27 cadaverous anatomical preparations. It was noted that
      the supraspinatus muscle may be divided into three parts, with a superficial and
      deep layer of muscle fascicles. An aponeurotic insertion tendon runs through the
      center, to which part of the superficial muscle fascicles are attached. The
      muscle fascicles, including the central attachment tendon, run across the
      superior margin of the shoulder joint and by broad tendon are attached to the
      superior surface of the greater tubercle of the humerus. Together with the long
      head of the biceps muscle, they act as a significant shoulder stabiliser. The
      authors believe that due to the course of the muscle fascicles, this muscle acts
      as a significant shoulder stabiliser and a powerful abductor and elevator in the
      shoulder joint. The inferior portion of the muscle fascicles acts as an external
      rotator of the shoulder.

PMID- 15037910
TI  - Some peculiarities of the rotator cuff muscles.
AB  - The authors studied the origin, course and insertion as well as some
      peculiarities of RC muscles on 25 cadaverous fixed limbs. They discovered that RC
      muscles exchange muscle bundles and are secured by synovial sheaths. They
      described the articular muscles in all of the observed muscles, including the
      deltoid muscle, which significantly stretch the capsule of the glenohumeral
      joint. They expressed the opinion that the subscapular bursa enhances motions in
      the shoulder joint. Due to the possibilities of arthroscopic diagnostic and
      treatment methods, they are convinced that more attention must directed to this
      issue from both the morphological and functional perspective.

PMID- 15037911
TI  - Analysis of articulation of fricative praealveolar sibilant "S" in control
      population.
AB  - Defective pronunciation of one or more mother language phones, i.e. dyslalia,
      represents the most frequent speech impairment both in children and adult people.
      Cases of persisting speech disorder need professional approach and help. The aim
      of the study was to obtain a model of physiological articulation of the sibilant
      "s" in children. The method of FFT spectral analysis was made use of. Results
      will serve for further use in evaluation of speech impairment.

PMID- 15037912
TI  - The detection of phagocytes involved in executional phase of apoptosis in human
      metanephros.

PMID- 15037913
TI  - Evaluation of speech disorders among children with orthodontic anomaly.

PMID- 15037914
TI  - Quantitative gated SPECT of myocardium in detection of ischemic heart disease:
      validation of findings by means of coronarography.

PMID- 15037917
TI  - The stabilization of L-ascorbic acid in aqueous solution and water-in-oil-in
      water double emulsion by controlling pH and electrolyte concentration.
AB  - This study presents a new approach that can stabilize effectively L-ascorbic acid
      in water-in-oil-in-water (w/o/w) double emulsions. Basically, the behavior of L
      ascorbic acid in the aqueous phase was observed, considering its molecular
      deformation. Then, it was found that the stability determined in the aqueous
      phase by high-performance liquid chromatography (HPLC) showed that the collapse
      of ionization of L-ascorbic acid played a crucial role in protecting the
      molecular deformation. Then, the stable aqueous system was incorporated into the
      internal aqueous phase of the double emulsions. From the HPLC analysis, it was
      observed that the L-ascorbic acid in an appropriate system showed high molecular
      stability for a long time. Moreover, in the measurement of in vitro skin
      permeation, the L-ascorbic acid stabilized in this study showed considerable skin
      permeation ability, indicating its potential applicability in pharmaceutics and
      cosmetics.

PMID- 15037918
TI  - Effects of thermal treatments with a curling iron on hair fiber.
AB  - The effect of curling hair with a curling iron has been investigated.
      Possibilities of thermal damage with repeated curling according to, and in
      violation of, the manufacturer's specifications have been studied. The propensity
      of hair surface to damage depends on the moisture content of the hair, and these
      experiments have been conducted in both wet and dry conditions, with and without
      application of tension, and with short or prolonged times. Scanning electron
      microscopic (SEM) examination revealed that fibers treated under the dry
      condition (50% RH) show radial and axial cracking along with scale edge fusion.
      Similar thermal treatment on wet hair resulted in severe damage of the type
      described above, as well as bubbling and buckling of the cuticle due to the
      formation and escaping of steam from the fiber. Fibers subjected to repeated
      curling in the dry condition show slight increases in tensile mechanical
      properties, characteristic of a crosslinked fiber. Fibers treated with
      conditioners show an improvement in characteristic life, especially in the case
      of low-molecular-weight conditioners, such as CETAB, which can penetrate into the
      hair fiber (shown by TOF-SIMS analysis).

PMID- 15037919
TI  - Optical properties of hair--detailed examination of specular reflection patterns
      in various hair types.
AB  - Details of the specular reflection of curved hair tresses, resulting from
      illumination with a collimated incident light source, were examined both
      qualitatively and quantitatively using high-resolution photography and image
      analysis. The reflections were found to consist of a multitude of light dots
      aligned with the fibers and typically separated by a distance of 81-145 microm.
      The contrast between the dots (specular reflection) and the darker regions
      (diffuse reflection) of the entire reflection band was found to increase with
      increasing pigmentation of hair. Highly pigmented Oriental hair provided more
      contrast within the specular reflection band than unpigmented natural white hair.
      A quantitative description of the light reflection patterns within the specular
      reflection band included two-dimensional distribution of luminosity, histograms
      of the frequency of appearance for peak maxima and minima in luminosity
      distribution plots, and histograms of absolute maxima and minima of luminosity
      along the length of the fibers. Specular reflection from African hair, which
      consists of many curls that provide multiple and randomly distributed reflection
      centers, have also been investigated. Using microscopy software, Image Tool 2.0,
      and a method termed image threshold, the number of reflection sites and their
      shapes could be quantified. For example, treatment of African hair with synthetic
      sebum was shown to significantly affect the reflection patterns, resulting in a
      decrease in the overall hair luster. Comparison of reflection patterns from
      Caucasian frizzy, very curly, and curly hair is also discussed.

PMID- 15037920
TI  - Studies of light scattering from ethnic hair fibers.
AB  - One of the most desirable hair attributes to consumers, irrespective of ethnic
      background, is hair shine. The light reflected from a fiber has two components,
      specular and diffuse. The specular fraction of reflected light from the front
      surface of the fiber is generally recognized as a contributor to high luster. The
      distinction between specular and diffuse reflection is, however, not always
      clearly defined. In this study an attempt has been made to differentiate between
      specular and diffuse reflectance by analyzing mathematically goniophotometric
      curves of light reflected from unaltered single hair fibers from European,
      African, and Asian ethnic groups. The effect of macroscopic characteristics of
      the hair fibers, such as fiber diameter, cross-sectional shape, and curvature on
      luster is demonstrated. Results indicate that broadening of the specular peak
      reduces luster values, and is related to these characteristics. Thus, specular
      peak broadening is one of the important features to take into account when
      evaluating luster. Therefore, a new method for luster evaluation from
      goniophotometric curves is proposed. Additionally, we present the general model
      for light scattering, showing how scattering by surface roughness of different
      origin and magnitudes, and the scattering and absorption processes by the hair's
      interior, affect the position of the specular reflectance peak and its
      broadening.

PMID- 15037921
TI  - Targeted delivery of salicylic acid from acne treatment products into and through
      skin: role of solution and ingredient properties and relationships to irritation.
AB  - Salicylic acid (SA) is a beta hydroxy acid and has multifunctional uses in the
      treatment of various diseases in skin such as acne, psoriasis, and photoaging.
      One problem often cited as associated with salicylic acid is that it can be quite
      irritating at pH 3-4, where it exhibits the highest activity in the treatment of
      skin diseases. We have identified strategies to control the irritation potential
      of salicylic acid formulations and have focused on hydroalcoholic solutions used
      in acne wipes. One strategy is to control the penetration of SA into the skin.
      Penetration of the drug into various layers of skin, i.e., epidermis, dermis, and
      receptor fluid, was measured using a modified Franz in vitro diffusion method
      after various exposure times up to 24 hours. A polyurethane polymer
      (polyolprepolymer-15) was found to be an effective agent in controlling delivery
      of SA. In a dose-dependent fashion it targeted delivery of more SA to the
      epidermis as compared to penetration through the skin into the receptor fluid. It
      also reduced the rapid rate of permeation of a large dose of SA through the skin
      in the first few hours of exposure. A second strategy that proved successful was
      incorporation of known mild nonionic surfactants like isoceteth-20. These
      surfactants cleanse the skin, yet due to their inherent mildness (because of
      their reduced critical micelle concentration and monomer concentration), keep the
      barrier intact. Also, they reduce the rate of salicylic acid penetration,
      presumably through micellar entrapment (either in solution or on the skin surface
      after the alcohol evaporates). Cumulative irritation studies showed that
      targeting delivery of SA to the epidermis and reducing the rapid early rate of
      penetration of large amounts of drug through the skin resulted in a reduced
      irritation potential. In vivo irritation studies also showed that the surfactant
      system is the most important factor controlling irritancy. SA delivery is
      secondary, as formulations with less SA content reduced the rate of delivery to
      the receptor and yet were some of the most irritating formulations tested,
      presumably due to the action of the specific anionic surfactant on the barrier.
      Alcohol content also did not appreciably affect irritation and SA delivery;
      formulations with considerably lower alcohol content but containing anionic
      versus nonionic surfactant systems exhibited considerably higher irritancy. Thus
      the surfactant type was again the predominant factor in those studies, although
      arguably alcohol plays some role (solubilization of SA). Results showed that both
      polymers and mild surfactants work in concert to provide the optimal formulation
      benefits of targeted delivery and reduced irritation. Synergistic relationships
      among hydroalcoholic formulation components will be discussed along with the
      mechanisms likely involved in controlling delivery of SA to skin.

PMID- 15037922
TI  - Analyzing the laser-light reflection from human hair fibers. II. Deriving a
      measure of hair luster.
AB  - Hair shine or luster is perceived as an important, though analytically somewhat
      elusive, attribute of beauty, primarily associated with clean and healthy hair.
      Principles for the assessment of hair luster are developed that are consistent
      with the practical situation. These principles are related to the components of
      light, specularly and diffusely reflected from single hair fibers, as measured by
      laser-based, multiangle goniophotometry, presented in Part I. Considering various
      definitions of gloss, their tradition, practical implementation, and their
      inherent limitations for testing hair, the gloss index as a physically consistent
      measure of hair luster is derived from the ratio of the integral intensities of
      the light components. Changes of the parameter values along hair length, namely
      their decrease, are analyzed for hairs of different color and ethnic origin. The
      correlation with shine evaluations of hair tresses by panels, based on literature
      data, is analyzed and ascertained.

PMID- 15037924
TI  - Evidence and utility of melanin degrading enzymes.
AB  - The biochemical synthesis of human melanin is understood in some detail. However,
      little is known about melanin degradation and catabolism of melanin. We
      hypothesize that human skin contains enzymes that degrade melanin and these
      enzymes can be used to reduce skin color. To test this hypothesis, HaCaT
      keratinocytes and normal human keratinocytes in culture were pulse labeled for
      one hour with radiolabeled synthetic melanin. This melanin was synthesized in
      vitro using tyrosinase enzyme from mushrooms and using radiolabeled [14C]3,4
      dihydroxyphenylalanine (DOPA) as a substrate. After the initial pulse labeling,
      samples of both the cells and media were taken at 2, 4, 6 and 18 hours. Over
      these time periods the counts remaining in the media and cell fraction were
      significantly decreased. This data suggests the need for new protein synthesis
      and the lysosome organelle function for the degradation. Melanin degrading
      extracts isolated from Aspergillus fumigatus and Saccharomyces cerevisiae were
      applied to human skin. These extracts cause significant reduction in UVB induced
      pigmentation. These extracts may be useful in developing new whitening products
      to even skin color and tone.

PMID- 15037923
TI  - Review of the current understanding of the effect of ultraviolet and visible
      radiation on hair structure and options for photoprotection.
AB  - This article describes the current understanding of the effect of ultraviolet
      (UV) radiation and visible light on the structure and integrity of human hair
      fibers; furthermore, it discusses current and past approaches to the protection
      of hair from UV rays. Relevant literature is reviewed.

PMID- 15037925
TI  - A review of systemic retinoid therapy for acne and related conditions.
AB  - Oral isotretinoin, since its introduction more than 20 years ago, has been and
      still is the "gold standard" in the treatment of acne and its variants. This is
      the only approach to acne with the possibility of a permanent "cure" or long term
      remission. The role of isotretinoin has evolved with higher dosage schedules and
      use earlier in the course of the disease. The frequency of laboratory monitoring
      has diminished along with associated costs based on 2 decades of experience.
      Pregnancy-associated safeguards have become a more prominent facet of oral
      retinoid therapy leading to increased safety for its use in females of child
      bearing potential.

PMID- 15037926
TI  - Anticoagulants and blood thinners during cutaneous surgery: always, sometimes or
      never?
AB  - There is no consensus with regard to perioperative blood thinner management in
      patients undergoing cutaneous procedures. The rationale and problems associated
      with blood thinners during cutaneous surgery are examined and the preoperative
      screening and surgical management of patients taking anticoagulant medicines
      discussed. There are many studies that support continuation of blood thinners
      during cutaneous procedures supporting the conclusion that blood thinners should
      not be discontinued for cutaneous procedures.

PMID- 15037927
TI  - Small bowel adenocarcinoma at a strictureplasty site in a patient with Crohn's
      disease: report of a case.

PMID- 15037928
TI  - Mid pouch strictureplasty for Crohn's disease after ileal pouch-anal anastomosis:
      an alternative to pouch excision.
AB  - A 33-year-old female developed an isolated stricture of the mid portion of her
      ileal pouch nine years after proctocolectomy and J-ileal pouch-anal anastomosis
      for ulcerative colitis. Repeated episodes of pouchitis and partial small-bowel
      obstruction led to pouchoscopy and pouchography, which demonstrated pouch
      inflammation and a long, tight, midpouch stricture. Her diagnosis was changed to
      Crohn's disease and she was treated with azathioprine, budesonide, and
      infliximab. Repeat pouchoscopy demonstrated mucosal healing but a persistent
      fibrotic stricture. Pouch reconstruction was performed with a midpouch
      strictureplasty alleviating her obstructive symptoms. One year after surgery, the
      patient has no clinical evidence of obstruction and repeat pouchography
      demonstrates a wider pouch lumen across the strictureplasty site. Strictureplasty
      is an alternative to pouch excision in the management of patients with Crohn's
      disease who have an isolated pouch stricture.

PMID- 15037929
TI  - Uncomplicated pregnancy after formation of antegrade continent enema cecostomies
      for slow-transit constipation.

PMID- 15037930
TI  - A systematic review of hepatic artery chemotherapy after hepatic resection of
      colorectal cancer metastatic to the liver.
AB  - PURPOSE: Colorectal cancer metastatic to the liver, when technically feasible, is
      resected with a moderate chance of cure. The most common site of failure after
      resection is in the remaining liver. To enhance survival, chemotherapy has been
      delivered directly to the liver postresection via the hepatic artery. This study
      was designed to assess the effect of posthepatic resection, hepatic artery
      chemotherapy on overall survival. METHODS: Trials were sought in Medline, the
      Cochrane Controlled Trial Register, The Cochrane Hepatobiliary Group Trials
      Register, and through contact of trial authors and reference lists using key
      words: colorectal, cancer, hepatic metastases, hepatic artery, chemotherapy, and
      randomized. Trials were chosen in which patients having resection of colorectal
      cancer metastatic to the liver were randomized to hepatic artery chemotherapy or
      any alternative treatment. Survival data were obtained principally from
      abstraction from survival curves in published studies using the method of Parmar
      to calculate a study-specific, log-hazard ratio and then combined-effect, log
      hazard ratio, as well as a combined Kaplan-Meier survival probability curve.
      RESULTS: Overall survival at five years in the hepatic artery group was 45
      percent and 40 percent in the control group. Forty-three individuals developed
      recurrent liver metastases in the hepatic artery chemotherapy group, and 97
      developed liver recurrence in the control group. However, no significant
      advantage was found in the meta-analysis for hepatic artery chemotherapy
      measuring overall survival and calculating survival based on "intention to treat"
      (log-hazard ratio = 0.0848, favoring the control group; 95 percent confidence
      interval = +/-0.2037). Adverse events related to hepatic artery therapy were
      common, including five therapy-related deaths. CONCLUSIONS: Although recurrence
      in the remaining liver happened less frequently in the hepatic artery
      chemotherapy group, overall survival was not improved. The log-hazard ratio even
      favored the control group, although not significantly. This added intervention
      for the treatment of metastatic colorectal cancer cannot be recommended at this
      time.

PMID- 15037931
TI  - Long-term results of anterior sphincteroplasty.
AB  - PURPOSE: This study was designed to evaluate the outcome of anterior
      sphincteroplasty in a large series with ten-year follow-up. METHODS: The long
      term results in 191 consecutive patients who were a median of ten years from
      sphincteroplasty were assessed. A questionnaire was administered to assess
      current bowel function, degree of incontinence, and quality of life as measured
      by the Fecal Incontinence Quality of Life Scale. Subjective assessment of early
      outcome was available for most patients at a median follow-up of three years.
      RESULTS: During the follow-up period, three patients died and one developed
      severe dementia. Five patients required further surgery for incontinence and were
      considered failures. Of the remaining 182 patients, 130 (71 percent) returned a
      completed questionnaire. At ten years follow-up, 6 percent had no incontinence,
      16 percent were incontinent of gas only, 19 percent had soiling only, and 57
      percent were incontinent of solid stool. Results worsened significantly between
      the assessments at three and ten years. The only significant predictors of a poor
      outcome were older age and fecal incontinence at three years. Preoperative
      anorectal physiology studies did not predict outcome. Scores on the Fecal
      Incontinence Quality of Life Scale were lower in those with fecal incontinence,
      indicating a poorer disease-specific quality of life. CONCLUSIONS: Only 40
      percent of patients maintain fecal continence long-term after sphincteroplasty.
      Older patients and patients with poorer short-term function are more likely to
      have fecal incontinence at ten years. Incontinence at ten years had a negative
      effect on quality of life. Further research is needed to develop techniques to
      improve long-term continence in these patients.

PMID- 15037932
TI  - Inherited colorectal cancer registries in the United States.
AB  - PURPOSE: The prevalence of familial adenomatous polyposis-associated cancers in
      the United States has been conservatively estimated at 15,000, and that of
      hereditary nonpolyposis colorectal cancer (HNPCC)-associated cancers at 30,000.
      Every blood descendant of each of these patients is at risk of carrying a
      germline mutation predisposing them to early onset colorectal and other cancers.
      Optimal care of these high-risk families involves a center with expertise in the
      syndromes. This study was performed to see how many such centers exist in the
      United States and to learn something of how they work. METHODS: The mailing lists
      of three international societies concerned with inherited colorectal cancer were
      used to send surveys inquiring about the presence of a registry or center, and
      how that center worked. The Collaborative Group of the Americas, the Leeds Castle
      Polyposis Group, and the International Collaborative Group on hereditary
      nonpolyposis colorectal cancer were queried. RESULTS: There were 30 centers in
      the United States: 26 responded, representing 15 states. Eighteen centers that
      responded had registries for inherited colorectal cancer. There were 1,396
      familial adenomatous polyposis families among the 18 registries, 2,058 hereditary
      nonpolyposis colorectal cancer families, 42 with juvenile polyposis, and 216 with
      Peutz-Jehger's syndrome. The 18 registries employed 29 genetic counselors or
      coordinators. Seven used Microsoft Access as a database, five used Progeny, three
      a SQL server-based system, one Filemaker Pro, one Microsoft Excel and one used
      Oracle. Cyrillic was the pedigree-drawing program in 6 registries, Progeny in 12,
      and Ped Draw in 1. Hereditary nonpolyposis colorectal cancer was defined using
      the Amsterdam I criteria by four registries, Amsterdam II by five, both criteria
      by six, Bethesda guidelines by one, and by genotype alone in two registries.
      CONCLUSIONS: The United States is underserved by registries for inherited
      colorectal cancer, having enrolled only a small proportion of the families
      theoretically available. Registries differ in fundamental aspects of function.
      More collaboration and more registries are needed.

PMID- 15037933
TI  - Outcome of patients with indeterminate colitis undergoing a double-stapled ileal
      pouch-anal anastomosis.
AB  - INTRODUCTION: The aim of this study was to assess the outcome of patients with
      indeterminate colitis undergoing double-stapled ileal pouch anal anastomosis.
      METHODS: A retrospective review of demographic, disease-related, and outcome
      variables of all patients undergoing double-stapled ileal pouch anal anastomosis
      from August 1988 to January 2000 was undertaken. All patients were evaluated
      using the validated American Society of Colon and Rectal Surgeons Fecal
      Incontinence Severity Index. Patients with familial adenomatous polyposis, those
      who had undergone pouch revision or had S-configured pouches, and patients with a
      follow-up of less than three months were excluded from analysis. RESULTS: Three
      hundred ninety-five patients underwent the double-stapled ileal pouch anal
      anastomosis; of these 303 patients were included for analysis. The mean duration
      of follow-up was 40 months. Fifty-six (18.1 percent) had a preoperative diagnosis
      of indeterminate colitis. Postoperatively, indeterminate colitis was diagnosed in
      13 (4.3 percent), mucosal ulcerative colitis in 285 (94 percent), and Crohn's
      disease in 5 (1.6 percent). The overall complication rate was 37.7 percent, 60
      percent, and (30.7) percent in patients with mucosal ulcerative colitis, Crohn's
      disease, and indeterminate colitis, respectively. Postoperative hemorrhage,
      abscess, and fistula occurred in 2.4 percent, 6.3 percent, and 3.9 percent,
      respectively, in patients with mucosal ulcerative colitis, and 0 percent, 15.3
      percent, and 7.7 percent, respectively, in patients with indeterminate colitis.
      Small-bowel obstruction occurred in 8.5 percent, 20 percent, and 7.7 percent of
      patients with mucosal ulcerative colitis, Crohn's disease, and indeterminate
      colitis, respectively. Pouchitis occurred in 4.6 percent of patients with mucosal
      ulcerative colitis but in none of the patients with indeterminate colitis.
      Dysplasia of the anal transition zone was seen in one patient each with mucosal
      ulcerative colitis and indeterminate colitis. These patients had consistent
      follow-up and neither showed any sign of evolution to neoplastic disease. None of
      the patients with indeterminate colitis had a postoperative diagnosis of Crohn's
      disease during the follow-up period. Functional outcome was comparable in all
      three patient groups. CONCLUSION: The outcome of the double-stapled ileal pouch
      anal anastomosis in patients with indeterminate colitis is similar to that of
      patients with mucosal ulcerative colitis. Therefore, it is a safe option in
      patients with indeterminate colitis.

PMID- 15037934
TI  - Prevalence of cytomegalovirus infection in inflammatory bowel disease patients.
AB  - PURPOSE: Although there has been an increasing number of case reports on
      inflammatory bowel disease complicated by cytomegalovirus infection, few reports
      have described its prevalence. The aim of this study was to investigate the
      prevalence of cytomegalovirus infection in inflammatory bowel disease and clarify
      the clinicopathologic features of the cases. METHODS: We studied 55 biopsy
      specimens and 39 surgical specimens taken from patients clinically diagnosed as
      having ulcerative colitis, and 49 biopsy specimens and 30 surgical specimens from
      patients clinically diagnosed as having Crohn's disease. In all cases
      cytomegalovirus infection was histopathologically examined by means of
      hematoxylin and eosin and immunohistochemical staining to detect inclusion bodies
      in specimens. RESULTS: Cytomegalovirus infection was confirmed in 1 of 55 biopsy
      specimens and in 8 of 39 surgical specimens obtained from the cases with
      ulcerative colitis. No cytomegalovirus inclusion bodies were exhibited in the 49
      biopsy specimens and 30 surgical specimens taken from patients with Crohn's
      disease. CONCLUSIONS: Cytomegalovirus infection was detected rather frequently
      (21 percent) in the surgical specimens of ulcerative colitis, and all cases were
      steroid resistant. The possibility of cytomegalovirus infection should always be
      taken into account in patients with ulcerative colitis who are resistant to
      steroid therapy.

PMID- 15037935
TI  - Detection of occult metastasis in lymph nodes from colorectal cancer patients: a
      multiple-marker reverse transcriptase-polymerase chain reaction study.
AB  - INTRODUCTION: Lymph node status is a key factor for disease staging and is the
      main determinant for adjuvant therapy of colorectal cancer. The current staging
      procedure is unable to identify occult metastasis in lymph nodes, which is likely
      to be an important cause of treatment failure in some early-stage patients. The
      detection of occult metastasis could identify a patient subgroup at risk for
      disease relapse that would benefit from adjuvant therapy. The purpose of this
      study was to establish and test a multimarker reverse transcriptase-polymerase
      chain reaction assay for the molecular detection of occult metastases in lymph
      nodes. METHODS: Forty-four patients with colorectal cancer and 14 patients with
      benign bowel diseases undergoing colonic resection were enrolled in the study.
      Reverse transcriptase-polymerase chain reaction was used to detect expression of
      three epithelial markers, carcinoembryonic antigen, cytokeratin 20, and guanylyl
      cyclase C, in fresh colorectal lymph node tissue. RESULTS: Forty-six of 47 (97.9
      percent) histologically positive lymph nodes were also positive by reverse
      transcriptase-polymerase chain reaction. Of 221 histologically negative nodes, 97
      (43.9 percent) were positive for at least one of the three markers by reverse
      transcriptase-polymerase chain reaction: 24.9 percent for carcinoembryonic
      antigen, 16.7 percent for cytokeratin 20, and 24.9 percent for guanylyl cyclase
      C. Among these were 13 of 20 stage I and II cases, implying a staging shift to
      stage III by molecular diagnosis of occult metastasis. Fifty-nine additional
      nodes were found to be positive for occult metastases in 22 of 24 stage III and
      IV patients. CONCLUSIONS: These results indicate that occult metastases are
      detectable by reverse transcriptase-polymerase chain reaction in histologically
      negative lymph nodes from colorectal cancer. The use of a panel of three markers
      improves the specificity of the method.

PMID- 15037936
TI  - Clinical use of micronized purified flavonoid fraction for treatment of symptoms
      after hemorrhoidectomy: results of a randomized, controlled, clinical trial.
AB  - PURPOSE: The aim of this study was to evaluate if the combination of micronized
      purified flavonoid fraction with short-term routine antibiotic and anti
      inflammatory therapy was better at reducing the intensity of postoperative
      symptoms and wound bleeding after a Milligan-Morgan's open hemorrhoidectomy than
      antibiotic and anti-inflammatory treatment alone. METHODS: Fifty patients were
      randomly assigned to receive routine antibiotic and anti-inflammatory treatment
      alone (control patients) or a combination of micronized purified flavonoid
      fraction with identical antibiotic and anti-inflammatory treatment (micronized
      purified flavonoid fraction patients). The evolution of symptoms (pain, tenesmus,
      pruritus, and bleeding) during the postoperative period was assessed by means of
      patients' self-questionnaires. Each symptom was scored on a graded severity scale
      from 0 to 3, daily during the first three days of the immediate postoperative
      period, then at regular intervals (about every 14 days) until postoperative day
      60. A global score for evaluation of each postoperative symptom and bleeding was
      used. The global score for each symptom was the sum of scores for each patient
      over the study period. The global score for each symptom was compared between the
      two groups with the Mann-Whitney U test. RESULTS: No significant differences in
      age, gender distribution, and stage of disease between the two groups were
      noticed at baseline. Posthemorrhoidectomy symptoms were relieved more rapidly in
      the micronized purified flavonoid fraction group; during the first three
      postoperative days, the global score for each symptom was significantly more
      reduced in the micronized purified flavonoid fraction group. The global scores
      for each symptom are as follows: pain after 3 days, 6.16 (SD = 1.9) in the
      control group vs. 3.48 (SD = 1.8) in the micronized purified flavonoid fraction
      group (P < 0.0001); tenesmus, 5.36 (SD = 1.8) in the control group vs. 1.48 (SD =
      1.5) in the micronized purified flavonoid fraction group (P < 0.0001); pruritus,
      4.04 (SD = 1.9) in the control group vs. 1.84 (SD = 1.4) in the micronized
      purified flavonoid fraction group (P < 0.0001); bleeding, 4.4 (SD = 2.1) in the
      control group vs. 2.0 (SD = 1.3) in the micronized purified flavonoid fraction
      group (P < 0.0001). A significant difference (P < 0.0001) between groups was also
      shown in favor of micronized purified flavonoid fraction patients when global
      scores were calculated over the entire study period (60 days). CONCLUSION:
      Micronized purified flavonoid fraction used in combination with short-term
      antibiotic and anti-inflammatory treatment can reduce both the duration and
      extent of postoperative symptoms and wound bleeding following hemorrhoidectomy.

PMID- 15037937
TI  - Perioperative topical nitrate and sphincter function in patients undergoing
      transanal stapled anastomosis: a randomized, placebo-controlled, double-blinded
      trial.
AB  - PURPOSE: The use of transanal stapling devices may impair continence because of
      digital dilatation and/or instrumentation. This study assessed the effect of
      pharmacological dilatation of the sphincter prior to stapler insertion. METHODS:
      A randomized, placebo-controlled, double-blinded study of 60 patients undergoing
      transanal stapled anastomosis was undertaken. Consenting patients were randomly
      assigned to receive a single intraoperative dose of topical 0.2 percent
      nitroglycerin (glyceryl trinitrate) ointment or nitroglycerin-free placebo. All
      patients were assessed preoperatively and postoperatively by clinical methods
      (Wexner incontinence scores and examination), anorectal manometry by a station
      pull-through technique, and endoanal ultrasonography. RESULTS: Intraoperative
      mean (+/-SEM) resting pressures (mmHg) were significantly reduced by
      nitroglycerin compared with prenitroglycerin levels (9.9 +/- 0.9 vs. 50.5 +/-
      2.7; P = 0.002) or controls (56.0 +/- 3.2; P = 0.001). Twenty-one of the 28
      controls (75 percent) but only 4 of the 32 patients in the nitroglycerin group
      (12.5 percent) required digital dilatation to insert the stapling instrument ( P
      = 0.003). Squeeze pressures were unaltered by the intervention but mean resting
      pressures were higher in the nitroglycerin group postoperatively (52.9 +/- 3.2 -
      31.6 +/- 1.3 = 21.3 mmHg; 95 percent confidence interval, 14-27). Incontinence
      scores were lower in the nitroglycerin group at the 3-month (1.1 +/- 0.2 vs. 4.6
      +/- 0.3; P = 0.003) and 12-month (0.9 +/- 0.1 vs. 4.4 +/- 0.3; P = 0.002) clinic
      visits. CONCLUSION: Preoperative nitroglycerin dilatation protects sphincter
      function in patients undergoing transanal stapled anastomoses.

PMID- 15037938
TI  - Quality of life in adults diagnosed with familial adenomatous polyposis and
      desmoid tumor.
AB  - PURPOSE: The purpose of this study was to examine the health-related quality of
      life in a sample of Canadian adults diagnosed with familial adenomatous polyposis
      and desmoid tumor. METHODS: The study was conducted in two parts. Seven
      individuals participated in a focus group prior to a mail-out survey. A cross
      sectional mail-out survey was administered to eligible individuals who were
      actively followed at the Familial Gastrointestinal Cancer Registry at Mount Sinai
      Hospital. RESULTS: Forty-one individuals (25 female and 16 male) were available
      to be contacted by the registry coordinator and 23 questionnaire packages were
      completed, resulting in a 56.1 percent participation rate. The results of this
      study demonstrated a reduced health-related quality of life for individuals
      living with familial adenomatous polyposis and desmoid tumor for over 10 years.
      The main predictors of health-related quality of life in this analysis included
      marital status (married vs. not married), prior knowledge of desmoid tumor in the
      family, and current level of hopelessness (R(2) = 0.856, df = 13, F = 26.8, P <
      0.001). The qualitative content analysis of themes from the focus group indicated
      that ongoing medical uncertainty and lack of information from health care
      professionals, isolation, and family communication were the main challenges in
      living with desmoid tumors. CONCLUSIONS: The findings from this study suggest
      that ongoing education of health care professionals is warranted and that
      information and support interventions may be beneficial to this clinical
      population.

PMID- 15037940
TI  - Integrating multiple clinical information systems using the Java Message Service
      framework.
AB  - This article describes an application for capturing, delivering, and tracking
      urgent radiology exam results. Urgent exam findings are entered using a Web form
      embedded within the Picture archiving and communication system (PACS) display
      station. The findings are then accessible via soft copy using the PACS display
      stations, hospital information system (HIS) terminals, or wireless-enabled
      personal digital assistants (PDAs) or via hard copy printouts that are generated
      automatically or on demand. Additionally, quality control is performed on those
      findings entered by radiology residents and fellows, the results of which are
      used for both performance tracking and educational activities. The application
      was developed using Sun Microsystems' Java programming language. The Java Message
      Service (JMS) was used to manage the delivery of findings. JMS provides a robust,
      flexible framework for exchanging messages between disparate applications. The
      application is now used for all urgent exams; completely replacing the original
      paper-based system. The use of JMS provides the necessary level of reliability
      needed by this application.

PMID- 15037941
TI  - Scabies by Kenneth Mellanby.
AB  - BACKGROUND: Epidemics of scabies are often associated with wars or other times of
      social upheaval. This was particularly evident during the Second World War when
      it was estimated that there were one to two million patients with scabies in
      Great Britain. OBJECTIVE: This article reviews the work of the zoologist Kenneth
      Mellanby of England and evaluates his contribution to our knowledge of the
      diagnosis and treatment of scabies in the Second World War. CONCLUSION: Using
      humans, Mellanby studied the transmission and treatment of this disease. Among
      his contributions were knowledge of how many mites the average patient had, and
      where they were located. He clearly noted and described that the scabies rash was
      not limited to the location of the mites on the body; he attributed the rash in
      areas with no mites to "a true sensitization." He found that "fomites were not
      the major method of transmissions.

PMID- 15037942
TI  - Early detection of skin cancer by family physicians: a pilot project.
AB  - BACKGROUND: Malignant melanoma is rising quickly in incidence and mortality
      rates. Family physicians (FPs) have been reported to lack confidence in
      diagnosing skin cancers. OBJECTIVE: The aim of this study was to determine
      whether an educational intervention can improve FPs' abilities to diagnose skin
      cancers. METHODS: The design was a prospective, randomized trial which included a
      skin cancer questionnaire, a video intervention, and a skin biopsy review.
      RESULTS: Pre-intervention, FPs answered 57% of the questions correctly on the
      skin cancer questionnaire. Post-intervention, the video intervention group scored
      higher than did the control group. The video intervention group removed 10% fewer
      benign lesions and almost 3 times more malignant lesions compared with their pre
      intervention biopsy rate. No findings were statistically significant. CONCLUSION:
      An educational intervention may improve FPs' knowledge and diagnosis of skin
      cancer. Our results may guide future studies with larger sample sizes in
      developing a skin cancer continuing medical education (CME) course for FPs.

PMID- 15037945
TI  - Intrathyroidal branchial cleft-like cyst with heterotopic salivary gland-type
      tissue.
AB  - A rare case is described of intrathyroidal branchial cleft-like cyst associated
      with unusual heterotopic tissues including the salivary gland type tissue, fat,
      and cartilage. This coexistence in the thyroid gland has not been described
      previously, to our knowledge. The patient was a 7-year-old girl with a growing
      mass in the left lateral neck. The ultrasonography revealed a cystic lesion in
      the left thyroid. Histologically, the cyst was lined by squamous or respiratory
      type epithelium resting on the fibrous tissue containing lymphoid tissues with
      follicle formation and solid cell nests (SCNs). This cyst was intimately
      associated with heterotopic tissues including lobules of well-differentiated
      seromucinous salivary glands, mature fat tissue, and islands of the cartilage.
      This association of branchial cleft-like cyst with SCNs and unusual heterotopic
      tissues in the normal thyroid suggests a possible origin from the SCN as
      ultimobranchial vestigial structures.

PMID- 15037946
TI  - "Hamartoma" of the spleen (splenoma) in children.
AB  - Hamartomas of the spleen or splenomas, are uncommon benign tumorous growths in
      this organ which have not been well characterized in children. We report four
      patients, 4 to 11 years old, who had splenomegaly and splenic "hamartomas"
      associated with different hematologic conditions (refractory microcytic anemia,
      sickle cell anemia, hereditary spherocytosis, and dyserythropoietic hemolytic
      anemia). All patients had total splenectomy as a primary therapeutic approach or
      to lessen their transfusion requirements. In only one patient was a focal splenic
      mass identified preoperatively with contrasted computed tomography (CT) scans and
      magnetic resonance imaging (MRI). None of the patients showed a mass by
      ultrasonography. Gross examination showed enlarged spleens (315-724 g) which on
      cut surface revealed a single nodule in one and multiple bulging nodules in three
      specimens. The nodules varied from 1.3 to 7 cm and were indistinct from the
      surrounding nonlymphoid splenic (i.e., red pulp) parenchyma. Histology of the
      nodules showed red splenic pulp with variable histiocytic proliferation, focal
      extramedullary hematopoiesis, lympho-plasmacytosis, fibrosis, and siderotic
      calcific deposits. Intranodular small T- and B-cell lymphoid aggregates but no
      organized secondary follicles or periarteriolar sheaths were seen. Proliferation
      antigen Ki-67 (Mib-1) immunostains showed a low (< 5%) proliferation index in the
      nodules and surrounding tissue. Reticulin stains did not show a capsule or border
      between the normal spleen and the nodules. The critical histologic differential
      diagnosis for these lesions is with benign vascular tumors. These can be
      identified by their more disorderly pattern, by immunohistochemistry and by their
      higher proliferation index. It is our contention that these splenic nodules are
      not true hamartomas, as they seem to result from remote ischemic or
      infectious/inflammatory insults, leading to the fibro-inflammatory reaction and
      deposition of calcium and hemosiderin that is better designated with the
      descriptive term of splenoma. Review of the literature and our own experience
      indicates that most children with splenic hamartomas or splenomas as we prefer to
      call them, have an underlying hematologic disorder likely made worse by a state
      of hypersplenism that explains the consistent improvement in the blood values
      after splenectomy.

PMID- 15037951
TI  - Percutaneous femoral closure following stent-graft placement: use of the Perclose
      device.
AB  - PURPOSE: To describe our early clinical experience using the Prostar Perclose
      device for arterial closure after placement of a stent-graft. METHODS: Sixty
      three patients had stent-graft devices placed for iliac (n = 7), abdominal aortic
      (n = 43) or thoracic applications (n = 13). The devices were introduced through
      18 Fr (22 Fr O.D.) (n = 3), 16 Fr (20 Fr O.D.) (n = 15), 14 Fr (18 Fr O.D.) (n =
      44) or 12 Fr (14 Fr O.D.) (n = 38) sheaths. After Perclose deployment, the
      arteriotomies were dilated to the appropriate sizes for the deployment sheaths.
      All patients were anticoagulated during the procedure. After stent-graft
      deployment, hemostasis was achieved by the Perclose sutures that were in place.
      All the femoral sites were followed with physical examination and CT angiography
      (CTA). RESULTS: The follow-up periods have ranged from 2 to 18 months (mean 7.5
      months). All 100 femoral sites were closed without the need for surgical closure.
      In 4% (4/100) of the femoral sites, the Perclose sutures were pulled out while
      securing the knots and these patients required manual compression. In 2% (2/100)
      of the sites, additional manual compression was required after successful
      deployment of the Perclose devices. In 1% (1/100) of the femoral sites, there was
      acute femoral popliteal thrombosis perhaps related to common femoral artery
      narrowing at the site of Perclose deployment. In 5% (5/100) of the femoral sites,
      pseudoaneurysms were seen on follow-up CTA examinations. In 1% (1/100) of
      patients, there was infection at the puncture site requiring surgical bypass. In
      1% (1/100) of patients, there was a stable, asymptomatic intimal dissection at
      the puncture site. By CTA criteria, none of the patients have developed stenotic
      lesions at the sites of Perclose deployment with follow-up periods limited to 6
      months. Fifty-one of 63 patients (81%) patients ambulated within 4-6 hr.
      CONCLUSION: The Perclose device, when placed prior to arterial dilatation, can be
      used to achieve hemostasis for stent-graft procedures. The device used in this
      manner is associated with complications, the most common being pseudoaneurysm
      formation. The long-term effect on the femoral arteries is uncertain.

PMID- 15037952
TI  - Development of a new intravascular low-profile device for exclusion of aortic
      aneurysm: an experimental pilot study.
AB  - PURPOSE: To present a new intravascular device for the treatment of aorto-iliac
      aneurysms. METHODS: This new device was tested in five dogs with abdominal aortic
      aneurysm created experimentally by over-dilation of a balloon-expandable stent
      with a 16 or 18 mm wide PTA balloon catheter. The design of the device is based
      on a self-expanding aortic stent which consists of two stretchable circular
      frames filled with a textile Dacron mesh membrane that is suspended horizontally
      into the infrarenal abdominal aorta proximally to the aneurysm. The frames are
      part of a preshaped double helical structure that is introduced longitudinally
      through a catheter in a parallel fashion and forming the desired shape at the
      vessel site to be occluded. Two iliac stent-grafts are introduced in a low
      profile status through the membrane sealing the aneurysm sac and holding the
      stent-grafts in place. After stent-graft expansion, a new bifurcation located
      more proximally than the natural one is created. The follow-up of the dogs was
      performed clinically and angiographically, and specimens were evaluated
      histomorphologically. RESULTS: The membrane device can be introduced through a 9
      Fr vascular sheath. Technical success was achieved in four of five dogs. Nine of
      ten stent-grafts could be fixed securely within the membrane, thus preventing
      dislocation. Aneurysms were excluded immediately, and blood flow to the external
      iliac arteries was restored by the stent-grafts. At 6-9 months follow-up of
      technically successful implanted devices, there were no endoleaks, no migration,
      no stenoses at contact sites between the implant material and vascular wall, and
      no stenosis or occlusion of the stent-grafts. At microscopic evaluation, the
      interspace between the membranes was filled with thrombotic material, thus
      ensuring exclusion of the aneurysm. CONCLUSION: This new device was found to be
      flexible, low profile and useful in excluding abdominal aortic aneurysm in the
      experimental setting.

PMID- 15037954
TI  - Effectiveness of voluntary habitat stewardship in conserving grassland: case of
      operation burrowing owl in Saskatchewan.
AB  - There have been no published performance evaluations of nongovernmental,
      voluntary habitat stewardship programs. The Operation Burrowing Owl (OBO)
      stewardship program, initiated in 1987, was evaluated for its effectiveness in
      conservation of grassland habitat during 1986-1993. The 108 OBO sites from 1987
      to 88 and 98 randomly selected non-OBO sites that were grassland in 1986 in the
      Regina-Weyburn, Saskatchewan study area were classified by size and agricultural
      soil suitability. By 1993, 41 (38%) of the 108 OBO sites had been withdrawn from
      the program. The 1986 area of grassland was compared with grassland area
      calculated from digitized 1993 LANDSAT imagery. A correction for satellite
      inaccuracies was determined. Grassland retention in 1993 was significantly higher
      at OBO sites (66%) than at random sites (49%), demonstrating that the OBO
      voluntary program effectively conserved habitat. Also, grassland retention was
      significantly lower on sites with better agricultural soils, and for sites <12 ha
      in size. Site type (OBO or random), size and their interaction, followed by
      agricultural soil suitability, had the greatest effects on grassland retention.
      During an era of accelerated grassland loss, OBO strongly and positively
      (statistically significant) affected conservation of grassland sites most at
      risk: sites <12 ha in size and with good to excellent agricultural soils. This
      suggests that grassland conservation efforts focus on vulnerable sites (small
      size and/or good agricultural soils) to provide nesting habitat for burrowing
      owls. Our study demonstrates that a voluntary stewardship program can
      significantly increase conservation of habitat.

PMID- 15037955
TI  - A management-orientated comparative analysis of urban and rural anglers living in
      a metropolis (Berlin, Germany).
AB  - Increased efforts to analyze the human dimensions of anglers are necessary to
      improve freshwater fisheries management. This paper is a comparative analysis of
      urban and rural anglers living in a metropolis, based on n = 1061 anglers
      responding to a mail survey in the German capital of Berlin. More than two thirds
      of the anglers (71%) had spent most (>50%) of their effort outside the city
      borders of Berlin and thus were categorized as rural anglers. Compared to the
      rural anglers, urban anglers (>/=50% of total effort spent inside the city) were
      younger and less educated. Urban anglers were more avid and committed, less
      mobile, and more frequently fished from boats and during weekdays. Rural anglers
      were more experienced, fished for longer times per trip, fished more often at
      weekends and on holidays, were more often members of angling clubs, and more
      frequently caught higher valued fish species. The achievement and fish quantity
      aspects of the angling experience were more important for urban than for rural
      anglers. Concerning management options, urban anglers more frequently suggested
      constraining other stakeholders and reducing regulations, whereas rural anglers
      more often proposed improving physical access to angling sites. Future urban
      fishing programs should offer ease of access, connection to public
      transportation, moderate prices, and diverse piscivorous fish stocks. In contrast
      to rural fisheries, the provision of high ecological and aesthetical quality of
      the angling waters can be regarded as of minor importance in urban fisheries.
      Rural fisheries managers need to consider the needs of stakeholders living in
      Berlin to minimize impacts on the less degraded rural water bodies and potential
      user conflicts with resident anglers. Ecosystem-based management approaches
      should guide rural fisheries policy.

PMID- 15037956
TI  - Integrating strategic environmental assessment with industry planning: a case
      study of the Pasquai-Porcupine forest management plan, Saskatchewan, Canada.
AB  - Strategic environmental assessment (SEA) is gaining widespread recognition as a
      tool for integrating environmental considerations in policy, plan, and program
      development and decision-making. Notwithstanding the potential of SEA to improve
      higher-order decision processes, there has been very little attention given to
      integrating SEA with industry planning practices. As a result, the benefits of
      SEA have yet to be fully realized among industrial proponents. That said, SEA
      practice is ongoing, albeit informally and often under a different label, and is
      proving to be a valuable tool for industry planning and decision-making. Based on
      a case study of the Pasquai-Porcupine forest management plan in Saskatchewan,
      Canada, this paper illustrates how an integrated approach to SEA can contribute
      to industry environmental decision-making and can enhance the quality and
      deliverability of industry plans.

PMID- 15037958
TI  - The concentric medial thigh lift.
AB  - Plastic surgeons often are asked to perform horizontal medial thigh lifts because
      the skin of this area has poor elasticity, inducing excess skin, and also because
      there is upper fat deposit. This excess skin and fat lead to irritation and even
      functional problems. But surgeons dislike this operation because of its justified
      bad reputation. Obviously, this area is difficult to manage because of the many
      possible side effects (e.g., healing difficulty, scar migration, necrosis,
      effusions, pain) and unreliable results. A new way of thinking is proposed to
      lighten this operation and make its more frequent use possible. This horizontal
      technique presents several innovating points: -A new incision line located along
      the labia major in the perineal crease remains at the same height backward. The
      incision never descends into the buttock fold. -No undermining whatsoever occurs
      even in the resection area. Liposuction is the key to avoidance of any
      undermining. It is performed everywhere in the thigh, but most importantly under
      the resection area where all the fat must be eliminated to lighten the flap and
      favor its lifting. -The resection removes only the skin layers (epidermis and
      dermis) and not the liposucted tissue, which is very thin. Consequently, all
      lymphatic and other vessels are preserved, and the healing process is much
      easier. Moreover, there is no dead space after ascension of the flap and no risk
      of effusion. -The resection is realized on demand, depending on the excess of
      skin brought on the incision line by each anchor suture. Therefore, any tension
      on the skin closure is avoided. -The direction of the skin stretching is
      concentric toward the labia minor. Consequently, the length of the scar is
      shortened at both the front and the rear. -Anchor sutures pull a nonundermined
      skin, thus drastically decreasing the risk of necrosis. In the past 2 years, 25
      patients, most of them as outpatients, have undergone surgery using this
      technique, with a real improvement in the quality of the result, as compared with
      the results from the standard technique.

PMID- 15037957
TI  - Secondary rhinoplasty of the Asian nose: correction of the contracted nose.
AB  - The contracted nose is a unique entity that follows primary rhinoplasty in the
      Asian patient. The proposed reasons for this complication are capsular
      contraction from a silicone nasal implant, pressure necrosis of the lower lateral
      cartilage resulting from the nasal implant, and infection after alloplastic
      implantation. The two principal anatomic constituents that must be addressed at
      the time of secondary rhinoplasty are the lower lateral cartilages and the skin
      envelope. The lower lateral cartilages should be derotated, projected, and
      transfixed with an extended spreader graft. Additional onlay grafting may be
      required to provide greater nasal tip derotation and projection. A
      transcolumellar incision situated at the columellar-labial angle permits
      undermining of the upper lip skin to release tension on the incision. If the
      nasal tip retraction is severe, then the skin envelope may be insufficient to
      provide coverage to the new cartilaginous framework. In this case, a paramedian
      forehead flap is recommended to provide adequate tissue coverage. Correction of
      alar-columellar disparity should be undertaken with composite grafting only after
      6 months have transpired to gauge the ultimate relation between the alae and
      columella. Infection that arises after correction of the contracted nose can be
      devastating. It should be treated aggressively, but tailored to the severity of
      the infection. Wound tension along the columella may predispose to skin necrosis
      and consequent cartilage exposure, which should be managed in turn with
      prostaglandin emollients to accelerate wound healing and to prevent infection.

PMID- 15037959
TI  - Collateral vessels in endovascular aneurysm treatment.

PMID- 15037960
TI  - The occurrence of lysogenic bacteria and microbial aggregates in the lakes of the
      McMurdo Dry Valleys, Antarctica.
AB  - The McMurdo Dry Valleys of Antarctica form the coldest and driest ecosystem on
      Earth. Within this region there are a number of perennially ice-covered (3-6 m
      thick) lakes that support active microbial assemblages and have a paucity of
      metazoans. These lakes receive limited allochthonous input of carbon and
      nutrients, and primary productivity is limited to only 6 months per year owing to
      an absence of sunlight during the austral winters. In an effort to establish the
      role that bacteria and their associated viruses play in carbon and nutrient
      cycling in these lakes, indigenous bacteria, free bacteriophage, and lysogen
      abundances were determined. Total bacterial abundances (TDC) ranged from 3.80 x
      10(4) to 2.58 x 10(7) cells mL(-1) and virus-like particle (VLP) abundances
      ranged from 2.26 x 10(5) to 5.56 x 10(7) VLP mL(-1). VLP abundances were
      significantly correlated (P < 0.05) with TDC, bacterial productivity (TdR),
      chlorophyll a (Chl a), and soluble reactive phosphorus (SRP). Lysogenic bacteria,
      determined by induction with mitomycin C, made up between 2.0% and 62.5% of the
      total population of bacteria when using significant decreases and increases in
      TDC and VLP abundances, respectively, and 89.5% when using increases in VLP
      abundances as the sole criterion for a successful induction event. The
      contribution of viruses released from induced lysogens contributed <0.015% to the
      total viral production rate. Carbohydrate and protein based organic aggregates
      were abundant within the water column of the lakes and were heavily colonized by
      bacteria and VLPs. Alkaline phosphatase activity was detected within the matrix
      of the aggregates, implying phosphorus deficiency and consortial nutrient
      exchanges among microorganisms.

PMID- 15037961
TI  - The calculative nature of microbe-mineral interactions.
AB  - Microorganisms continually redefine themselves at many levels, including the
      molecule, cell, and community. Although it was initially assumed that this
      resulted from the genesis of information within DNA alone, it has since been
      shown that innovation originates at multiple levels. This occurs through
      calculative units, each unit consisting of two proliferating structures, one
      nested within the other and each undergoing changes in structural geometry that
      affect the proliferation rate of the other. For example, the recombination of
      genetic structures affects the proliferation of community structures, and the
      recombination of community structures affects the proliferation of genetic
      structures. The proliferation of a nested series of structures (e.g., genes
      proliferating within cells, cells proliferating within communities, communities
      proliferating within ecosystems) results in a logic circuit that calculates the
      form and function of each structural element in the series. In this situation
      each element functions as both a habitat and an inhabitant (environment and
      organism), and it is this dichotomy that determines the balance of nature. Nested
      geological structures, such as minerals and continents, also proliferate and
      redefine themselves in much the same way. Microbe-mineral interactions thus link
      nested biological calculations to an analogous set of nested geological
      calculations. Examples include the microorganisms involved in the nucleation
      (proliferation) of ferric hydroxides, carbonates, silicates, and ice crystals.

PMID- 15037962
TI  - The recent emergence of plague: a process of felonious evolution.
AB  - Yersinia pestis, the causative agent of bubonic plague, evolved from closely
      related Yersinia pseudotuberculosis within the past 20,000 years, an event that
      corresponds to the end of the last ice age and distribution of Homo sapiens
      throughout the world. Y. pseudotuberculosis causes chronic but generally mild
      enteropathogenic infections whereas plague is the most devastating acute disease
      experienced by mankind. The very recent evolution of plague from its progenitor
      assures close genomic homogeneity between the two species and thus high
      probability that disparities in DNA sequence mediate dramatic differences in
      symptoms of infection. The purpose of this minireview is to define salient
      distinctions between the genomes of Y. pestis and Y. pseudotuberculosis and to
      equate unique functions to respective acute and chronic mechanisms of virulence.
      The significance of these processes is then related to the procedures the
      organisms use to survive when between hosts (i.e., the flea vector colonized by
      Y. pestis and natural environments including soil and water in the case of Y.
      pseudotuberculosis). Next, an attempt is made to order the various mutational
      events that caused the recent emergence of Y. pestis as a distinct species.
      Finally, selective pressures such as predatory soil nematodes are considered that
      possibly influenced the early evolution of those yersiniae now pathogenic to
      humans.

PMID- 15037963
TI  - Strong indirect effects of a submersed aquatic macrophyte, Vallisneria americana,
      on bacterioplankton densities in a mesotrophic lake.
AB  - Phytoplankton and allochthonous matter are important sources of dissolved organic
      carbon (DOC) for planktonic bacteria in aquatic ecosystems. But in small
      temperate lakes, aquatic macrophytes may also be an important source of DOC, as
      well as a source or sink for inorganic nutrients. We conducted micro- and
      mesocosm studies to investigate the possible effects of an actively growing
      macrophyte, Vallisneria americana, on bacterial growth and water chemistry in
      mesotrophic Calder Lake. A first microcosm (1 L) study conducted under high
      ambient NH4+ levels (NH4+ > or = 10 microM) demonstrated that macrophytes had a
      positive effect on bacterial densities through release of DOC and P. A second
      microcosm experiment, conducted under NH4+-depleted conditions (NH4+ < 10
      microM), examined inter- active effects of macrophytes and their sediments on
      bacterial growth and water chemistry. Non-rooted macrophytes had negative effects
      on bacterial numbers, while rooted macrophytes had no significant effects,
      despite significant increases in DOC and P. A 70-L mesocosm experiment
      manipulated macrophytes, as well as N and P supply under surplus NH4-+conditions
      (NH4+ > or = 10 gmicro), and measured effects on bacterial growth, Chl a
      concentrations, and water chemistry. Bacterial growth and Chl a concentrations
      declined with macrophyte additions, while bacterial densities increased with P
      addition (with or without N). Results suggest that the submersed macrophyte
      Vallisneria exerts a strong but indirect effect on bacteria by modifying nutrient
      conditions and/or suppressing phytoplankton. Effects of living macrophytes
      differed with ambient nutrient conditions: under NH4+-surplus conditions,
      submersed macrophytes stimulated bacterioplankton through release of DOC or P,
      but in NH4-+depleted conditions, the influence of Vallisneria was negative or
      neutral. Effects of living macrophytes on planktonic bacteria were apparently
      mediated by the macrophytes use and/or release of nutrients, as well as through
      possible effects on phytoplankton production.

PMID- 15037964
TI  - Filamentous fungi: the indeterminate lifestyle and microbial ecology.
AB  - The filamentous fungi have dynamic and variable hyphal structures within which
      cytoplasm can be moved, synthesized, and degraded, in response to changes in
      environmental conditions, resource availability, and resource distribution. Their
      study has gone through several phases. In the first phase, direct observation was
      emphasized without undue concern for interior structures or in the presence of
      cytoplasm. By the mid-1970s, single biochemical proxies (ergosterol, marker fatty
      acids, chitin derivatives, etc.) were being used increasingly. The use of these
      surrogate single measurements continues, in spite of their inability to provide
      information on the physical structure of the filamentous fungi. Molecular
      approaches also are being used, primarily through the use of bulk nucleic acid
      extraction and cloning. Because the sources of the nucleic acids used in such
      studies usually are not known, taxonomic and phylogenetic information derived by
      this approach cannot be linked to specific fungal structures. Recently, a greater
      emphasis has been placed on assessing physical aspects of indeterminate fungal
      growth, involving the assessment of cytoplasm-filled and evacuated (empty)
      hyphae. Both of these parameters are important for describing filamentous fungal
      growth and function. The use of phase contrast microscopy and varied general
      stains, as well as fluorogenic substrates with observation by epifluorescence
      microscopy, has made it possible to provide estimates of cytoplasm-filled hyphal
      lengths. Using this approach, it has been possible to evaluate the responses of
      the indeterminate fungal community to changes in environmental conditions,
      including soil management. It is now possible to obtain molecular information
      from individual bacteria and fungal structures (hyphae, spores, fruiting bodies)
      recovered from environments, making it possible to link individual fungal
      structures with their taxonomic and phylogenetic information. In addition, this
      information can be considered in the context of the indeterminate filamentous
      fungal lifestyle, involving the dynamics of resource allocation to hyphal
      structural development and synthesis of cytoplasm. Use of this approach should
      make it possible to gain a greater appreciation of the indeterminate filamentous
      fungal lifestyle, particularly in the context of microbial ecology.

PMID- 15037965
TI  - Isolation and biodiversity of hitherto undescribed soil bacteria related to
      Bacillus niacini.
AB  - The hitherto largely not described phylogenetic neighborhood of Bacillus niacini
      has been explored by a comprehensive cultivation experiment and genomic variety
      studies. Previous culture-independent studies demonstrated that approximately 15%
      of all Bacillus 16S rDNA directly extracted from soils worldwide was affiliated
      to B. niacini. Seven different media were inoculated with soil suspensions in
      serial dilutions and incubated at different temperatures. Then, bacterial
      colonies were picked and analyzed by sequencing. A mineral medium with acetate as
      carbon source yielded a B. niacini rate of >3% of all picked colonies. Other
      media were less efficient but also successful. Applying this culturing approach,
      we succeeded in obtaining 64 isolates from different Dutch soils. The isolates
      turned out to be diverse, although closely related to B. niacini as revealed by
      16S rDNA sequencing. Close matches with environmental clones were also found,
      thus demonstrating much more diversity beyond previously known 16S rDNA
      sequences. The rep-PCR fingerprinting method revealed a high genomic variety,
      redundancy could not be observed among our isolates. Hence, the hitherto
      neglected B. niacini lineage, apparently among the most abundant soil Bacillus,
      was accessible to our cultivation approach.

PMID- 15037968
TI  - Editorial: microbial ecology.

PMID- 15037966
TI  - Productivity and growth of a natural population of the smallest free-living
      eukaryote under nitrogen deficiency and sufficiency.
AB  - The influence of dissolved inorganic nitrogen (DIN) enrichments on cell
      normalized carbon uptake rate, chlorophyll a content, and apparent cell size of a
      picoeukaryote (<1 microm) ( Ostreococcus tauri, the smallest eukaryotic cell)
      from a natural summer phytoplanktonic assemblage (<200 microm) in a northern
      Mediterranean Lagoon (Thau Lagoon) was studied in 20-L enclosures in June 1995.
      The natural planktonic community was incubated in situ for 24 h with initial
      ammonium and nitrate enrichments and compared to a control without enrichment. O.
      tauri cell-normalized productivity was estimated from the combination of flow
      cytometric (FCM) enumeration and 2-h (radioactive) carbonate incorporation
      measured on post-incubation size fractions (<1microm). No difference between the
      effects of the two DIN sources of enrichment on the studied biological parameters
      was measured during this experiment. Growth of natural O. tauri was perturbed by
      the low DIN availability in the control with drastic changes in cell
      productivity, chlorophyll content, and cell cycle (from the variations in
      apparent cell size) as compared to the DIN sufficiency conditions. On the other
      hand, a very high specific growth rate for natural O. tauri, up to 8 day(-1)
      under DIN enrichments, has been estimated from production and abundance data
      obtained during this experiment. This supports values measured in culture and
      suggests that the yearly high contribution of picophytoplankton to the total
      primary production in Thau Lagoon is likely to be due to their high growth rate
      rather than the previously suggested lack of grazing pressure.

PMID- 15037969
TI  - Interleukin-6, transforming growth factor-beta 1, and bone markers after kidney
      transplantation.
AB  - The aim of this study was to investigate the relationship between interleukin 6
      (IL-6), transforming growth factor (TGF)-beta 1, IL-6 soluble receptors, and
      biochemical parameters of bone turnover after kidney transplantation. Of 64
      patients enrolled in the study, 19 received the kidney transplant 2 to 12 months
      before the study, and 45 within the previous 15 to 175 months. We measured IL-6,
      TGF-beta 1, intact parathyroid hormone (PTH) bone alkaline phosphatase (BALP),
      osteocalcin (OC), and procollagen type I propeptide (P1CP) concentrations in the
      serum, and deoxypyridinoline crosslinks (DPD) in the urine of the patients. In 16
      patients in the first posttransplantation year, the concentrations of IL-6 (P =
      0.02), TGF-beta 1 (P = 0.01), BALP (P = 0.0002), OC (P = 0.001), and DPD (P =
      0.01) were significantly higher than in patients with longer posttranslation
      period. Statistically significant negative correlation was found between post
      transplantation time and IL-6 (P = 0.04), BALP (P = 0.003), OC (P = 0.0009), P1CP
      (P = 0.03), and DPD (P = 0.01) concentrations. Repeated measurements of the
      investigated parameters in the first post-transplantation year showed a
      significant decrease only in TGF-beta I level. In all patients, IL-6 correlated
      positively with PTH (P = 0.0009) and DPD (P = 0.03), and IL-6 soluble receptor
      (IL-6 sR) with DPD (P = 0.03). A decrease in IL-6 and TGF-beta 1 concentrations
      that paralleled the decrease in bone turnover markers in the posttransplantation
      period indicated that IL-6 and TGF-beta 1 were probably involved in the bone
      turnover after kidney transplantation.

PMID- 15037970
TI  - Effects of sex steroid receptor specificity in the regulation of skeletal
      metabolism.
AB  - The interaction between estrogens and androgens, with their protective effects in
      bone, and parathyroid hormone (PTH), a calcitropic peptide hormone, is complex
      but may be better understood with murine models. The purpose of this study was to
      characterize skeletal phenotypes of mice deficient in estrogen receptor alpha
      (ERalpha), androgen receptor (AR, mutant tfm), or both, and determine if ERalpha
      and AR alter osteoblast differentiation and/or PTH response in vitro. Loss of
      ERalpha resulted in increased long bone length in females, but reduced length in
      males, suggesting loss of ERalpha reversed sex steroid-dependent skeletal
      dimorphism. The AR deficient tfm mice (genetically male but phenotypically
      female) had the longest bones and, similar to males, lengths were reduced with
      loss of ERalpha. Loss of AR and/or ERalpha resulted in a reduction in femoral
      bone mineral density (BMD) compared to male wildtype (WT) mice, suggesting tfm
      mice follow the female sex for BMD. In males or tfm mice, but not females, loss
      of AR and/or ERalpha caused a reduction in cortical width of the tibia compared
      to male WT mice. Reduced trabecular bone was found in tibiae of female and tfm
      mice versus male littermates, suggesting that tfm mice follow the female sex for
      trabecular bone but loss of ERalpha did not alter trabecular bone levels. Primary
      calvarial osteoblasts of male WT mice were less responsive to PTH stimulation of
      cAMP than all other genotypes, suggesting the female chromosomal sex and/ or loss
      of ERalpha or AR results in increased sensitivity to PTH. In conclusion, tfm mice
      follow the male pattern of long bone development, but imitate females in bone
      density and trabecular bone. Loss of ERalpha and/or AR results in increased
      osteoblast sensitivity to PTH and may explain actions of PTH noted in hypogonadal
      humans.

PMID- 15037971
TI  - Bisphosphonates induce apoptosis of stromal tumor cells in giant cell tumor of
      bone.
AB  - Giant cell tumour of bone (GCT) is an aggressive primary neoplasm that results in
      the production of osteolytic lesions. Stromal cells, which form the main
      neoplastic component of this tumor, regulate the formation of osleoclast-like
      giant cells that are ultimately responsible for bone destruction. Bisphosphonates
      prevent bone resorption by inhibiting osteoclast activity and promoting
      osteoclast apoptosis, and they have been known to induce apoptosis of primary
      neoplastic cells such as those in breast and prostate cancers. We hypothesized
      that in bisphosphonates may induce apoptosis not only in osteoclast-like giant
      cells but also in neoplastic stromal cells of GCT both in vitro and in vivo.
      Twelve patients with GCT were treated with weekly injections of pamidronate for a
      period of 6 weeks prior to surgery. GCT specimens were collected at the time of
      biopsy and during definitive surgery. TUNEL assay was used to evaluate apoptotic
      DNA fragmentation in cells. In addition, twelve GCT primary cultures from these
      patients were treated with zoledronate, pamidronate, or alendronate for 48 hours
      at different doses (3, 30, or 150 microM) and subjected to apoptosis assay by
      flow cytometry following fluorescent Annexin-V labeling. The results showed that
      pamidronate significantly induced apoptosis in both osteoclast-like giant cells
      and stromal tumor cells, in vivo. All three bisphosphonates caused substantial
      apoptosis of stromal tumor cells in cultures. Zoledronate was the most potent
      reagent, resulting in an average cell death of 27.41% at 150 microM, followed by
      pamidronate (22.23%) and alendronate (15.3%). Our observations suggest that these
      drugs may be considered as potential adjuvants in the treatment of GCT.

PMID- 15037973
TI  - Dual X-ray absorptiometry: cross-calibration of a new fan-beam system.
AB  - The high precision and stable calibration of dual X-ray absorptiometry (DXA)
      scanners have led to their widespread use in longitudinal studies for research
      and the follow-up of individual patients who are receiving treatment for
      osteoporosis. However, difficulties in maintaining the continuity of the bone
      mineral density (BMD) calibration scale can arise when an old DXA system is
      replaced by a newer model. We report the results of an in vivo cross-calibration
      study performed when a GE-Lunar Prodigy fan-beam system replaced a DPX-L pencil
      beam scanner. Lumbar spine and hip DXA scans were performed in 133 patients (104
      female, 29 male) attending long-term BMD monitoring. On average, lumbar spine BMD
      measurements on the two systems agreed closely, with Prodigy values 1% lower than
      those on the DPX-L. However, after allowing for this difference, the root mean
      square error (RMSE) of 0.037 g/cm2 was larger than in previous cross-calibration
      studies reported in the literature, and was 3 times the value expected from the
      precision of the BMD measurements. Mean femoral neck BMD also agreed closely
      between the two systems, although for Prodigy, the spread of measurements was 10%
      smaller than that for the DPX-L. For the trochanter and Ward's triangle regions,
      mean BMD was 4% and 6% lower, respectively, on the Prodigy system, and the
      results were affected by a similar compression of the range of values. RMSE
      values were 0.037 g/cm2, 0.044 g/cm2, and 0.044 g/cm2, respectively, for the
      femoral neck, trochanter, and Ward's triangle sites. When the high value of the
      RMSE was investigated, it was found that for lumbar spine BMD, patient body
      weight and the difference between the two systems in the percentage fat reported
      in the soft tissue reference region explained 40% of the variance. This enabled
      equations to be developed that significantly improved the agreement between scans
      performed on the two systems. Smaller improvements were obtained for the femur
      BMD measurements.

PMID- 15037972
TI  - Technical considerations for microstructural analysis of human trabecular bone
      from specimens excised from various skeletal sites.
AB  - The purpose of this study was to test the effect of repositioning, systematic
      displacements of the region of interest (ROI), and acquisition parameters (scan
      mode and integration time) on quantitative analysis of human trabecular bone
      microstructure at various skeletal sites, using microcomputed tomographic
      (microCT) technology. We investigated 28 cylindrical specimens of human
      trabecular bone (length 14 mm, diameter 8 mm) from four skeletal sites (femoral
      neck, greater trochanter, second lumbar vertebra, and distal radius). These
      specimens were selected from over 200 microCT measurements, in order to cover a
      large range of bone volume fraction (BV/TV) observed at each site. Cylindrical
      ROIs (length 6 mm, diameter 6 mm) were examined twice at an isotropic resolution
      of 26 microm, 8 weeks apart. In addition, comparative analyses were performed for
      displacements of the volumes of interest (VOIs) by 1, 2, 3, and 4 mm (83.4%,
      66.6%, 50%, and 33.3% overlap), respectively. Eventually, comparative
      measurements were obtained at different resolution scan modes and integration
      times. The results show that microCT measurements are highly reproducible (range
      of the root mean square coefficient variation % (RMS CV%) = 0.64% to 1.29% for
      BV/TV at different sites). Displacements of the VOI of up to 4 mm generally led
      to non significant systematic differences in mean values of < 10%. When comparing
      various combinations of resolution scan modes and integration times, the use of
      an integration time of 100 ms was found to be preferable for determining
      microstructural parameters from human samples with this microCT scanner.

PMID- 15037974
TI  - Differential bone turnover in an angulated fracture model in the rat.
AB  - We have developed a simple rat model of angulated tibial fracture which elicits
      substantial differences in bone formation and resorption within the same bone. In
      35 rats the right mid-tibia was manually fractured and fixed with an
      intramedullary 17-gauge cannula needle. Twenty tibias were fixed in anterior
      angulation (27 +/- 5 degrees) and 15 in posterior angulation (31 +/- 5 degrees).
      Serial X-rays were taken over a 12-week period. All fractures healed completely
      within five weeks. In both groups, bone thickness was already significantly
      greater on the concave side than on the convex side at week 3 and remained so
      until the end of the experiment. The thickness on the convex side decreased
      dramatically within 3 to 5 weeks and gradually thereafter. For morphological
      analysis of bone mineralization, 3 rats from each group were given calcein and
      alizarin red injected at different time points up to 14 weeks. Maximum new bone
      formation was noted within the first 3 weeks. Over the ensuing weeks, new bone
      formation remained intense on the concave side, but it was virtually absent on
      the convex side. These results show that angulated fracture deformity
      reproducibly exhibits differential bone turnover, which can be exploited in
      research on local regulatory factors. To exemplify the utility of the model, an
      immunohistochemical study on two local markers was done. Callus tissue of five
      rats in the anterior angulation group at week 3 post-fracture was stained for the
      cytokine IL- 1beta, a stimulator of bone resorption, and the neuropeptide CGRP,
      an inhibitor of resorption, showing clear differences in positive staining
      between the concave and convex sides. Our in-vivo model offers a means of
      analyzing morphologically and quantitatively the differential expression and
      action of factors involved in local bone turnover.

PMID- 15037975
TI  - [A science which hesitates to forget its founders is lost?].

PMID- 15037976
TI  - [Attention-deficit/hyperactivity disorder (ADHS) in adulthood].
AB  - The attention-deficit-/hyperactivity disorders (ADHD) are the most common
      psychiatric disorders in children and adolescents. ADHD persists in 30 - 50 %
      into the adulthood. Attention problems were found to be more persistent than
      hyperactivity and impulsivity. Many of the symptoms classified as ADHD symptoms
      of inattention are actually symptoms of executive function impairments.
      Assessment and differential diagnosis of adult ADD/ADHD may be difficult, because
      of a high rate of comorbidity. This article gives an overview about the
      impairments caused by attention-deficits, the clinical picture, the problems of
      diagnosis, the pharmacotherapy, the psychotherapy and comorbidity of ADHD in
      adults.

PMID- 15037977
TI  - [Fibromyalgia as a dysfunction of the central pain and stress response].
AB  - Fibromyalgia is often understood as a syndrome mainly characterised by widespread
      pain and tenderness and "unexplained" etiology and pathogenesis. In the last
      years evidence is growing that biological as well as psychosocial stress play a
      pathogenetic key-role. Beginning with the general function and development of the
      stress response system the actual knowledge of its relationship with central pain
      processing mechanisms is reviewed. Early adverse childhood experiences can impair
      the function of the stress system all over the lifespan. Subsequently, research
      evidence for the role of stress in the etiopathogenesis of fibromyalgia is
      summarised. Psychological as well as psychobiological consequences are outlined.
      Finally, an integrative model of fibromyalgia is proposed, which may put several
      pieces of a biopsychosocial puzzle together. This model offers an approach for
      the differentiation of subgroups and a clinical orientation for developing an
      adequate therapy for the individual patient.

PMID- 15037978
TI  - [Perceived parental rearing behaviour and adult attachment patterns in intimate
      relationships].
AB  - Based on the assumption that the parental rearing behaviour recalled by adults
      can be conceptualized as a specific mental representation of attachment, the
      study examines the associations between these rearing-related memories and adult
      attachment patterns in intimate relationships. The data for this study were
      obtained from a large community-based sample of the German population (1509
      subjects between the ages of 18 and 50 years). Both, the perceived parental
      rearing behaviour and the adult attachment patterns have been assessed via
      questionnaires (Questionnaire of Recalled Parental Rearing Behaviour [Fragebogen
      zum erinnerten elterlichen Erziehungsverhalten, FEE] and Bielefeld Partnership
      Expectations Questionnaire [Bielefelder Fragebogen zu Partnerschaftserwartungen,
      BFPE]). As the result of the study it could be shown that a secure adult
      attachment pattern in intimate relationships is associated with a parental
      rearing behaviour that has been perceived as positive, while on the other hand
      insecure attachment patterns are rather associated with more negative experiences
      of parental rearing.

PMID- 15037979
TI  - [Patients' perceptions of mental health specialists' professional competence].
AB  - Several studies indicate that the public does not differentiate between
      professional activities provided by psychotherapists, psychiatrists and
      psychologists. 543 psychiatric outpatients completed a questionnaire concerning
      mental health professionals' competence. Patients were least familiar with the
      competence "psychological testing". 35 % respectively 40 % of our patients
      expected that psychologists or psychotherapists could prescribe
      psychopharmacological drugs. 47 % expected counsellors to provide psychotherapy,
      44 % expected diagnostic competence. Physicians' diagnostic and
      psychopharmacological competence was underestimated. Mental health professionals
      should not trust in patients' knowledge concerning their professional activities.
      Especially in the beginning of a diagnostic or therapeutic process patient
      information is of major importance.

PMID- 15037980
TI  - [From applied psychosomatic medicine to integrated medicine - experiences with
      the Steglitz allocated bed model].
AB  - Changes in the German hospital system like the introduction of the DRG
      compensation system suggest the usefulness of considering the modification of
      inpatient psychosomatic treatment options. Patients in a university hospital
      underwent diagnosis-related psychosomatic treatment in the wards of other
      departments after instituting the allocated bed model. The report presented here
      points out chances and risks of such a change. First psychodiagnostic assessments
      indicate a significant improvement of symptoms in these patients. Despite the
      overall positive result obtained thus far, the institutional and administrative
      framework conditions for such a change should be carefully considered and further
      evaluated.

PMID- 15037981
TI  - [Screening and Measurement of Change of Dissociative Psychopathology:
      Psychometric Properties of the Short Version of the Fragebogen zu Dissoziativen
      Symptomen (FDS-20)].
AB  - Given the clinical and scientific relevance of dissociative experiences our study
      aimed to assess the psychometric properties of a short version of the German
      Dissociative Experience Scale (called FDS-20) as well as its ability to measure
      changes in dissociation. In a large sample (N = 1289) the FDS- 20 showed good
      internal consistency. A factor analysis indicated that the scale measures one
      single factor reflecting the general degree of dissociative psychopathology.
      Between-group-comparisons suggested a good discriminant validity between high and
      low dissociators; however, due to high standard deviations the FDS-20 is not well
      suited for an individual diagnosis and therefore, it should be used as a
      screening device. Low effect sizes (d < 0,3) between scores at the beginning and
      the end of inpatient treatment as well as low micro -indices pointed to a
      temporal stable construct and a trait scale, respectively. Alternatively to group
      comparisons, individual parameters of treatment success (statistical and clinical
      significance) were calculated. They proved to be more appropriate in measuring
      changes in dissociation.

PMID- 15037982
TI  - [The clinical emotions list - a procedure for assessing patients' affective
      repertoires].
AB  - Using 20 video-interviews with psychosomatic outpatients we developed a category
      system that should allow a differentiated and complete assessment of a person's
      affective repertoire. In doing so we considered the psychological literature on
      verbal expression of emotions. Semantic construction, distinguishing emotion
      categories from one another, was chosen as the main criterion for coding. The
      final version of the Clinical Emotions List contained 48 items. An exploratory
      analysis of another ten Interviews with patients showed satisfactory reliability
      of the system.

PMID- 15037983
TI  - [Antonovsky's sense of coherence scale and presentation of a psychiatric
      diagnosis].
AB  - Despite a wide reception of Antonovsky's salutogenetic model, only recently
      representative data measuring sense of coherence with the Sense of Coherence
      Scale (SOC) have been collected for Germany. Meanwhile, norms have been published
      for the long (SOC-29) and the short-form (SOC-13) of the scale. Also an
      alternative short-form (SOC-9L) has been developed. Basis of this investigation
      are data from 4002 subjects (70.2 % response rate) from a representative sample
      in the City of Lubeck and the surrounding communities. In addition to a
      comprehensive battery of psychometric instruments, the Munich-Composite
      International Diagnostic Interview (M-CIDI) was used to derive DSM-IV diagnostic
      criteria. In this study, test statistical parameters for SOC-items stemming from
      a representative survey are reported. Internal consistencies (Cronbach's alpha)
      for the three forms are: SOC-29 = 0.91, SOC-13 = 0.86 und SOC-9L = 0.85. Critical
      differences with an alpha of 5 % are ascertained at: SOC-29 = 17.73, SOC-13 =
      11.55 und SOC-9L = 8.61. Arithmetic means (and standard deviations) of the three
      scales for the whole sample are: SOC-29 = 155 (23), SOC-13 = 70 (11), SOC-9L = 51
      (8). Also descriptive values, respecting age and gender for the three forms of
      the SOC are referred. Additionally all three SOC forms for the whole sample are
      contrasted with SOC scores of subjects who a) never fulfilled criteria for a
      psychiatric disorder in their lifetime, b) fulfilled criteria for a psychiatric
      disorder once in their lifetime, and c) fulfilled criteria for a psychiatric
      disorder in the last 12 months. Subjects who never fulfilled criteria showed
      highest scores, those who did so within the last 12 months showed lowest scores.
      The other two group scored in between.

PMID- 15037984
TI  - [The modest challenger].

PMID- 15037986
TI  - The role of pdx1 and HNF6 in proliferation and differentiation of endocrine
      precursors.
AB  - Ex vivo expansion of embryonic stem cells (ES cells) or pancreatic stem cells for
      insulin delivery to diabetic patients provides potential for the restoration of
      islet function in these individuals. Understanding the spatial and temporal
      requirements of crucial factors for endocrine progenitor specification,
      proliferation, and terminal differentiation remains a major challenge in the
      field of pancreas development. Here, we provide speculation as to the role of
      pdx1 and HNF6 in these different stages of pancreatic endocrine cell development.
      At the time when islets begin to form within the pancreas, the expression
      patterns of pdx1 and HNF6 diverge, suggesting distinct functions for each of the
      genes over the course of endocrine cell development. The current body of evidence
      provides support for a role of both factors in early endocrine specification as
      well as a requirement for pdx1 in the generation of mature pancreatic endocrine
      cells. The precise temporal requirement of HNF6 in the production of terminally
      differentiated endocrine cells remains unclear. Future studies in this area will
      rely on conditionally manipulatable systems in combination with lineage-tracing
      studies for a more accurate assessment of pdx1 and HNF6 function at different
      stages along the pathway of endocrine cell development.

PMID- 15037985
TI  - Pharmacological approach to diabetic retinopathy.
AB  - Diabetic retinopathy is the most frequent cause of legal blindness in the
      population of 30-to-70-year olds. Whether retinopathy appears or not depends
      mainly on the duration of the disease and the degree of metabolic control the
      patient maintains. High blood glucose values lead to important changes in
      cellular metabolism and the main effects of these alterations are endothelial
      dysfunction that sets in motion the morphological process of diabetic
      retinopathy. The biochemical lesions caused by prolonged hyperglycemia can be
      positively influenced, but usually not normalized, pharmacologically with some
      groups of drugs, which are now under development. This makes tight control of
      glycemia a key measure in preventing the onset or progression of diabetic
      retinopathy, together with an effective program of ophthalmologic detection and
      follow-up in patients with diabetes. Regarding the role of endothelial
      dysfunction, antiplatelet drugs have been shown to slow some aspects of the
      evolution of diabetic retinopathy in its initial stages, mainly a lower degree of
      microaneurysms. However, a new approach to controlling endothelial dysfunction
      shows promise, mainly through the vascular endothelial growth factor (VEGF)
      inhibitors. These agents may prove to be especially useful in the treatment of
      proliferative diabetic retinopathy. Other encouraging results have been obtained
      in studies of antioxidant drugs and inhibitors of the formation of advanced
      glycation end products. Once retinal lesions appear, preventive measures need to
      be redoubled, with special attention to controlling glycemia; however, it is also
      necessary to resort to laser photocoagulation. This intervention aims to
      eliminate areas of ischemia and to diminish the formation of retinal exudates. If
      this measure fails or if vitreous hemorrhage appears, the only remaining
      therapeutic measure is vitrectomy.

PMID- 15037987
TI  - Evidence for a vicious cycle of exercise and hypoglycemia in type 1 diabetes
      mellitus.
AB  - Exercise is a cornerstone of diabetes management as it aids in glycemic control,
      weight management, reducing blood pressure, and improving the quality of life of
      patients. Unfortunately, owing to the complexity and difficulties of regulating
      exogenous insulin in a physiologic manner during exercise, physical activity
      often results in hypoglycemia in patients with type 1 diabetes mellitus (type 1
      DM). When glucose levels fall below threshold glycemic levels, neuroendocrine,
      autonomic nervous system (ANS), and metabolic glucose counterregulatory
      mechanisms are activated. These hypoglycemic counterregulatory mechanisms in type
      1 DM can be blunted irreversibly by disease duration or by acute episodes of
      prior stress. These reduced (or absent) counterregulatory responses result in a
      threefold increase in severe hypoglycemia when intensive glycemic control is
      implemented in type 1 DM. Much recent work has been focused on determining the in
      vivo mechanisms responsible for causing the increased incidence of severe
      hypoglycemia in type 1 DM. Studies from several laboratories have demonstrated
      the role played by episodes of antecedent hypoglycemia in producing blunted
      glucose counterregulatory responses during subsequent exposures of hypoglycemia.
      Until recently, the mechanisms responsible for exercise related hypoglycemia in
      type 1 DM have been attributed to relative or absolute increases of insulin
      levels or incomplete glycogen repletion after physical activity. Owing to the
      qualitative similarity of neuroendocrine, ANS, and metabolic responses to
      hypoglycemia and exercise, we have hypothesized that neuroendocrine and ANS
      counterregulatory dysfunction may also play an important role in the pathogenesis
      of exercise-related hypoglycemia in type 1 DM. Vicious cycles can be created in
      type 1 DM, where an episode of hypoglycemia or exercise can feed forward to
      downregulate neuroendocrine and ANS responses to a subsequent episode of either
      stress, thereby creating further hypoglycemia. This article will review the
      recent work that has studied the contribution of counterregulatory dysfunction to
      exercise-induced hypoglycemia in type 1 DM.

PMID- 15037988
TI  - Calcium-dependent mitochondrial permeability transition is augmented in the
      kidney of Goto-Kakizaki diabetic rat.
AB  - BACKGROUND: Renal disease associated with diabetes mellitus is a major problem
      among diabetic patients. The role of mitochondria in the pathogenesis of diabetes
      has received a large amount of attention in the last years, but many aspects of
      this subject are still poorly understood. In the present study, we studied the
      susceptibility of the mitochondrial permeability transition (MPT) on kidney
      mitochondria from the Goto-Kakizaki (GK) rat, an animal model featuring
      physiological and pathological alterations characteristic of type 2 diabetes.
      METHODS: Kidney mitochondria were isolated by differential centrifugations;
      mitochondrial electric transmembrane potential and calcium loading capacity were
      evaluated with a TPP+-selective electrode and with a calcium-sensitive
      fluorescent probe. Coenzyme Q9, Q10 and vitamin E were evaluated by high
      performance liquid chromatography (HPLC). RESULTS: Kidney mitochondria from the
      diabetic animals had an increased susceptibility to the induction of the MPT by
      calcium. We observed a loss of calcium-loading capacity and a higher calcium
      induced mitochondrial depolarization. Vitamin E and coenzyme Q9 were also
      increased in kidney mitochondria from GK rats. CONCLUSIONS: The results show an
      enhanced MPT activation in kidney mitochondria from GK rats, which lead us to
      suggest that this condition may be one major alteration triggered by chronic
      diabetes in kidney cells, ultimately leading to cell dysfunction.

PMID- 15037989
TI  - Genetic prediction of type 1 diabetes in a population with low frequency of HLA
      risk genotypes and low incidence of the disease (the DIABFIN study).
AB  - BACKGROUND: To develop a sensitive, specific screening strategy for predicting
      genetic risk for type 1 diabetes mellitus (T1DM) in the low-incidence continental
      Italian population, and to define with this tool, a cohort of high-to-moderate
      risk infants for an immunological follow-up study aimed at identifying
      environmental risk factors for T1DM. METHODS: 4855 newborns in three regions of
      continental Italy were screened for T1DM HLA-DRB1-DQB1 risk genotypes using a
      reverse line blot typing method. Risk classification was based on odds ratios
      (OR) found in a preliminary case-control study (356 T1DM patients, 412 controls).
      Screening efficiency was optimized by allele subtyping. RESULTS: Screening for
      well-known T1DM susceptibility genotypes [DRB1*03/*04-DQB1*0302; DRB1*03/*03;
      DRB1*04/*04-DQB1*0302; DRB1*04-DQB1*0302/X where X is not equal to DRB1*03,
      DRB1*04-DQB1*0302, DQB1*0602 or DQB1*0603] was associated with <60% sensitivity
      due to their low frequencies in the general Italian population. Inclusion of an
      additional genotype from which protective DRB1 and DQB1 alleles had been excluded
      [DRB1*03/X degrees where DQB1 is not equal to *0301, *0503, *0602, or *0603 and X
      degrees not equal DRB1*03, DRB1*04-DQB1*0302 or DRB1*07] increased screening
      sensitivity to 75% (specificity: 85%). Among 4855 newborns, we have found the
      high-risk genotype [DRB1*03/*04-DQB1*0302; estimated absolute risk (AR) 1/23] to
      be present in only 0.9%. The moderate-risk genotypes were found in 13.8% of
      newborns (estimated AR 1/177). CONCLUSIONS: Risk classification must be tailored
      to the characteristics of the individual population, in particular, the allelic
      frequencies in the background population and T1DM prevalence. We have developed a
      screening strategy with good levels of sensitivity that should prove effective
      for use throughout the Italian peninsula.

PMID- 15037990
TI  - A linkage study of 12 IDDM susceptibility loci in the Finnish population.
AB  - BACKGROUND: HLA region is the major locus (IDDM1) of type 1 diabetes (T1D)
      susceptibility. It explains approximately 50% of the genetic background of T1D,
      indicating additional genetic determinants. Genome scans and candidate gene
      studies have generated several chromosomal candidate regions that may have a role
      in T1D development. METHODS: We tested 12 of these loci for linkage in 107
      Finnish T1D multiplex families using 23 microsatellite markers and 2 SNPs.
      Families were stratified according to the HLA status and sharing at the DQB1
      gene. RESULTS: We found no significant or suggestive MLS in our unstratified
      families outside the IDDM1 locus. The highest MLS was seen close to the IDDM9
      region marker D3S3576 at 3q21-q25 (MLS=1.05). This marker also had a global p
      value of 0.0032 (ETDT) in maternal transmissions. IDDM6 and 12q12-q15 region
      showed MLS=1.1 and MLS=1.3 respectively in HLA-DQB1*0302/x (x is not equal to HLA
      DQB1*02) stratified families. IDDM12 showed MLS=2.0 in HLA-DQB1 identical sib
      pairs. Linkage at IDDM12 was supported by a global p-value of 0.0006
      (uncorrected) in ETDT. For IDDM2, p-values of 0.028 and 0.009 were observed in
      ETDT with MspI-2221 SNP in unstratified and HLA-DQB1*0302/x-stratified families
      respectively. CONCLUSIONS: Our results are consistent with previous findings of
      linkage or association to T1D at IDDM2, IDDM6, IDDM9, IDDM12 and 12q12-q15
      regions but do not unambiguously confirm them. A larger sample set is required to
      gain statistical power needed to confirm our findings in the Finnish population.

PMID- 15037991
TI  - Longer breastfeeding is an independent protective factor against development of
      type 1 diabetes mellitus in childhood.
AB  - BACKGROUND: Early weaning diet, early introduction of breast milk substitution
      and cow's milk have been shown to increase the risk of type 1 diabetes later in
      life. It is also shown that older maternal age, maternal education, preeclampsia,
      prematurity, neonatal illness and neonatal icterus caused by blood group
      incompatibility, infections and stress might be risk factors for type 1 diabetes.
      We aimed to determine whether early nutrition is an independent risk factor for
      diabetes despite other life events. METHODS: Data from 517 children (268 boys and
      249 girls) in south-east of Sweden and 286 children (133 boys and 153 girls) in
      Lithuania in the age group of 0 to 15 years with newly diagnosed type 1 diabetes
      mellitus were included into analysis. Three age- and sex-matched healthy controls
      were randomly selected. Response rate in control families in Sweden was 72.9% and
      in Lithuania 94.8%. Information was collected via questionnaires. RESULTS:
      Exclusive breastfeeding longer than five months (odds ratio 0.54, 95% confidence
      interval 0.36-0.81) and total breastfeeding longer than 7 (0.56, 0.38-0.84) or 9
      months (0.61, 0.38-0.84), breastfeeding substitution that started later than the
      third month (0.57, 0.33-0.98) among Swedish children 5 to 9 years old and later
      than the seventh month (0.24, 0.07-0.84) among all Swedish children is protective
      against diabetes when adjusted for all other above-listed risk factors. In
      Lithuania, exclusive breastfeeding longer than two months in the age group of 5
      to 9 years is protective (0.58, 0.34-0.99) when adjusted for other factors.
      CONCLUSIONS: Longer exclusive and total breastfeeding appears as an independent
      protective factor against type 1 diabetes.

PMID- 15037993
TI  - Current literature in diabetes.

PMID- 15037992
TI  - Gender differences in GAD antibody-positive diabetes mellitus in relation to age
      at onset, C-peptide and other endocrine autoimmune diseases.
AB  - BACKGROUND: Females have an increased incidence of autoimmune diseases. However,
      no gender difference in the incidence of type 1 diabetes is found. The frequency
      of antibodies against glutamic acid decarboxylase (GADA) in diabetes mellitus
      depends on age at diagnosis and also gender. Several studies have shown that high
      GADA levels can predict future beta-cell failure and need for insulin treatment.
      The aim of this study was to investigate possible gender differences in relation
      to GADA levels, fasting plasma C-peptide levels and frequency of other autoimmune
      endocrine diseases in GADA-positive patients with different age at diabetes
      diagnosis. METHODS: GADA were screened in 4974 patients from a local diabetes
      registry, and plasma C-peptide was measured and a history of other autoimmune
      endocrine diseases was recorded. Of these patients, 822 were GADA positive and
      were further divided into four groups depending on the age at diagnosis of
      diabetes; Group 1: <20 years, Group 2: 20-39 years, Group 3: 40-59 years and
      Group 4: > or =60 years. RESULTS: Female patients in Group 3 had lower fasting
      plasma C-peptide levels (median 0.21[0.00-0-56] vs. 0.41[0.00-0.73] nmol/L,
      p=0.02), higher GADA levels (median 7 [4-9] vs. 5 [2-7] Arbitrary Unit (AU),
      p=0.0003) and higher frequency of other autoimmune endocrine diseases (22.4 vs.
      5.3%, p=0.0001) than male patients. In a stepwise logistic regression analysis,
      diabetes duration (p<0.000001), high GADA levels (Exp (B) 3.68 CI 1.69-7.98,
      p=0.001) and low BMI (p=0.00002) were associated with total beta-cell failure in
      Group 3. CONCLUSIONS: GADA-positive female diabetic patients with an age at
      diagnosis between 40 and 59 years have higher GADA levels and a more severe loss
      of beta-cell function than male patients with the same age at diagnosis. This
      could be due to the effect of sex steroids and/or GnRH on the regulation of the
      immune system. Female patients with high GADA levels also had a high prevalence
      of other autoimmune endocrine diseases, especially autoimmune thyroid disease,
      which further emphasises the need for screening of thyroid function in female
      patients with high GADA levels.

PMID- 15037994
TI  - A novel response of wild-type duckweed (Lemna paucicostata Hegelm.) to heavy
      metals.
AB  - The responses of wild-type Lemna paucicostata, used as the experimental stock, to
      seven heavy metals were investigated with a hydroponic culture in a culture
      facility. The results showed that six of the metals could induce L. paucicostata
      to release daughter fronds from the mother frond before maturity, resulting in
      breakup of the colony. This phenomenon is novel and has not been reported before.
      Six of the heavy metals investigated-copper, cadmium, nickel, zinc, mercury, and
      chromium-could induce this response, but sensitivity and response of the plant
      varied. When Cu(2+) at a concentration of 0.2 micromol/L was added, the response
      was significantly different from that of the control after a 2-h exposure. The
      response to cadmium (0.8 micromol/L) was significantly different after a 6-h
      exposure; to zinc (10 micromol/L) and nickel (5 micromol/L), after 5 and 7 h,
      respectively. But for lead, even at a concentration of 80 micromol/L for 96 h, no
      colony breakup was induced. The response to heavy metals occurred within 24 h;
      increasing the exposure by another 24 h had nearly no additional effect on the
      colony breakup. When the response was over, the number of colonies with fronds
      varied with the inducement capacity of the metal. Nutrients could affect the
      sensitivity of L. paucicostata to some heavy metals, such as mercury, chromium,
      zinc, and nickel, but not to copper and cadmium. Sensitivity was also changed
      when CuCl(2) was used as the copper source instead of CuSO(4). These results
      indicate that some heavy metals could serve as a toxicant for inducing L.
      paucicostata to release daughter fronds in advance. This change might involve a
      stress response such as ethylene production. Also discussed is the possibility of
      this response as a biomarker in a bioassay.

PMID- 15037995
TI  - Noninvasive assessment of liver detoxification capacity of children, observed in
      children from heavily polluted industrial and clean control areas, together with
      assessments of air pollution and chloro-organic body burden.
AB  - The liver is an important target organ in exposure to foreign substances or their
      metabolites. Early changes in the metabolic capacity of the liver may be a first
      sign of the effect of an exposure and an indication of an early (pre)pathological
      process. For the noninvasive testing of this metabolic capacity, a special
      diagnostic tool has been developed and demonstrated under real exposure
      conditions. The main questions investigated were (1) whether the liver
      detoxification capacity of children is affected by long-term low exposure in a
      highly polluted area and (2) to what extent redevelopment in once heavily
      polluted industrial areas contributes to improvement in the health measured in
      the children from the changed detoxification capacity. Kindergarten children from
      a heavily polluted industrial area and a control area were observed over a
      prolonged period during redevelopment of the industrial area. The liver's
      detoxification capacity was assessed with a stable-isotope-based diagnostic test,
      the [(15)N]methacetin test. In addition, the region-specific external exposure
      (indicator components were chlorinated compounds) and internal load were
      measured. The difference in the children's internal load between the exposed and
      control groups reflected the differences in exposure (exposed children had an
      internal load 2.3 times greater than that of the control children). The exposed
      children showed a 6% lower liver detoxification capacity. A reduction in
      pollution by about 70% as a result of remediation was reflected in improved liver
      detoxification capacity, and the difference between the polluted and control
      areas was no longer significant. Prolonged exposure to low concentrations of
      xenobiotics can disturb hepatic functioning. The proposed test can be used as a
      tool to determine the effects of multicomponent exposure and is well suited for
      bioeffect monitoring.

PMID- 15037996
TI  - Seawater quality along the Adriatic coast, Croatia, based on toxicity data.
AB  - The potential toxicity of organic extracts from 12 seawater samples from each of
      24 sampling sites, collected during 1999-2001 along the Adriatic coast, Croatia,
      was analyzed with the Microtox toxicity bioassay. The results were consistent
      with the usefulness of Microtox for the detection of accidental toxic events. To
      determine the water quality of selected areas, cluster analysis for
      discrimination between groups with similar toxicity load and water quality index
      as a base for the ranking of sampling sites was introduced. Based on our
      experimental data, five classes of the quality index were defined, and so areas
      were ranked in five categories (excellent, good, fair, poor, and very poor)
      according to their potential toxic influence. The water quality of selected sites
      for the potential toxicity of organic extracts could be described as excellent at
      one sampling site, good at 15 sampling sites, and fair at eight sampling sites.
      Poor and very poor seawater quality was not detected.

PMID- 15037997
TI  - Effects of the herbicide hexazinone on nutrient cycling in a low-pH blueberry
      soil.
AB  - The herbicide hexazinone was applied as the commercial formulation Velpar L at
      field-rate (FR) concentrations of FR (14.77 microg ai g(-1)), FRx5 (73.85 microg
      ai g(-1)), FRx10 (147.70 microg ai g(-1)), FRx50 (738.50 microg ai g(-1)), and
      FRx100 (1477.00 microg ai g(-1)) to acidic soil, pH 4.12, taken from a lowbush
      blueberry field. Hexazinone was tested for inhibitory effects on various
      transformations of the nitrogen cycle and soil respiration. Nitrogen fixation was
      unaffected by hexazinone levels up to FRx100 following a 4-week incubation
      period. Ammonification was initially inhibited by all levels of hexazinone, but
      after 4 weeks, ammonification in all treatment systems was equal to or greater
      than the control. Nitrification was more sensitive to hexazinone; however,
      application at a field-rate level caused no inhibition. Inhibitory effects were
      noted above FR after a 2-month endpoint analysis and above FRx5 after a 6-month
      endpoint analysis. Hexazinone concentrations up to and including FRx100
      stimulated denitrification. Soil respiration was also stimulated over a 3-week
      period when applied at a level up to 100 times the recommended field rate. In
      general, it was found that when applied at the recommended field application
      rate, hexazinone does not adversely affect the nitrogen cycle or soil respiration
      in acidic lowbush blueberry soils.

PMID- 15037998
TI  - Marine toxin okadaic acid induces aneuploidy in CHO-K1 cells in presence of rat
      liver postmitochondrial fraction, revealed by cytokinesis-block micronucleus
      assay coupled to FISH.
AB  - Okadaic acid (OA), a major polyether toxin involved in diarrhetic shellfish
      poisoning (DSP), is a potent tumor promoter in rodent skin and glandular stomach
      and a specific inhibitor of the serine/threonine protein phosphatases PP1 and
      PP2A. A previous study, which used the cytokinesis-block micronucleus (CBMN)
      assay in CHO-K1 cells, showed that OA induced chromosome damage in the presence
      of a rat liver metabolic activation system (S9). To support OA biotransformation
      by S9, the same test system was performed, and DNA damage induced by OA was
      measured with and without metabolic activation as well as in the presence of heat
      inactivated S9 fraction. The results showed that only in the presence of active
      S9 did OA significantly increased the frequency of micronucleated binucleated
      (MNBN) cells. After a 4-h treatment a 2- to 5-fold increase of MNBN cells was
      observed at 30 nM and at 50 nM of OA. However, without S9 or in the presence of
      heat-inactivated S9, OA did not induce any chromosome damage. We concluded that
      OA can be metabolically activated in vitro into metabolites that are more
      genotoxic. The CBMN assay coupled with fluorescence in situ hybridization (FISH)
      using a DNA probe for centromere detection was performed to discriminate between
      clastogenic (chromosome breakage) and aneugenic (chromosome loss) effects. FISH
      analysis showed that OA metabolites increased in a dose-dependent manner in
      centromere positive micronuclei (CEN+): 60% of CEN+ at 30 nM and 75% of CEN+ at
      50 nM of OA. The uptake of OA into CHO-K1 cells and the biotransformation of the
      toxin are discussed.

PMID- 15037999
TI  - Cytogenetic effects of leachates from tannery solid waste on the somatic cells of
      Vicia faba.
AB  - The contamination of surface- and groundwater by the leaching of solid wastes
      generated by industrial activities as a result of water runoff and rainfall is a
      matter of great concern. The leachates from tannery solid waste (TSW), a major
      environmental pollutant, were examined for their possible genotoxic effects on
      the somatic cells of Vicia faba. Leachates were prepared from solid wastes
      procured from leather-tanning industrial sites, and V. faba seedlings were
      exposed to three test concentrations, 2.5%, 5%, and 10%, through soil and aqueous
      media for 5 days. The root tips examined for cytogenetic damage revealed that
      leachate of TSW significantly inhibited the mitotic index and induced
      significantly frequent chromosomal and mitotic aberrations (CA/MA) in a dose
      dependent manner. The chemical analysis of TSW samples revealed that the chief
      constituents were chromium and nickel, which may cause genetic abnormalities. The
      frequency of aberrations was found to be higher in the root meristematic cells of
      Vicia faba exposed through the aqueous medium than those exposed through the soil
      medium. The results of the present study indicated that contamination of potable
      water bodies by leachates of TSW may cause genotoxicity. For the biomonitoring of
      complex mixtures of toxicants with the V. faba bioassay, the use of the aqueous
      medium seems to be a more promising method than the use of the soil medium.

PMID- 15038000
TI  - Toxicity of ammonia to three marine fish and three marine invertebrates.
AB  - Laboratory toxicity tests were performed to obtain more data on the toxicity of
      ammonia to saltwater organisms. The standards for in-stream ammonia limits in
      marine environments presently are based on toxicity tests involving both
      freshwater and saltwater organisms. Acute tests (48 and 96 h) were performed at
      20 degrees C, and chronic tests (7 days) were performed at 25 degrees C.
      Synthetic seawater and natural seawater from the Chesapeake Bay were used and
      compared. Included among the organisms tested were sheepshead minnow (14 days
      old), summer flounder (2 months old), Atlantic silverside (14 days old), mysid
      shrimp (less than 2 days old), ghost shrimp (10 days old), and quahog clam (9
      months old). Based on these results, it seems the chronic criterion for ammonia
      in marine environments could be increased from 0.035 to 0.081 mg/L un-ionized
      ammonia, which would, of course, increase the chronic limit for total ammonia
      under typical saltwater conditions by a factor of 2.31. No difference was
      observed in the toxicity of ammonia in natural water compared to synthetic water
      for both the summer flounder and Atlantic silverside. Furthermore, the Atlantic
      silverside became more sensitive to ammonia as the salinity was increased from 14
      to 22 ppt, but exhibited no change in toxicity response from 22 to 30 ppt.

PMID- 15038001
TI  - Heavy-metal and microbial depuration of the clam Ruditapes decussatus and its
      effect on bivalve behavior and physiology.
AB  - The bivalve Ruditapes decussatus was evaluated as a possible biomonitor of heavy
      metal contamination. Concentrations of copper (Cu), cobalt (Co), iron (Fe),
      nickel (Ni), and manganese (Mn) were measured in R. decussatus. Water and
      sediment samples were collected at two stations of Timsah Lake in Ismailia,
      Egypt, from October to November 2002, using atomic absorption spectrophotometry
      (AAS). Results from the heavy-metal and microbial analyses indicated that site II
      was less contaminated than site I. The bivalve showed accumulation of metals,
      with a bioaccumulation factor (BAF) greater than 4. The bioaccumulation of metals
      varied strongly according to the sampling site. After 48 h of depuration, Fe, Ni,
      Co, Cu, and Mn were reduced significantly, to 46.8% and 47.7%, 19.9% and 20.3%,
      27.3% and 27.9%, 35.9% and 36.6%, and 18.2% and 26.6%, compared with the initial
      concentrations, in clam tissue at the two stations. In bivalves from site II the
      counts of total bacteria, fecal coliforms, and bacterial pathogens were reduced
      by more than 90%, whereas phage counts were only reduced by 56% after 4 days of
      depuration. The depuration of bivalves collected from the heavily polluted site
      (I) was not effective, as coliforms were reduced only by 85% after 4 days,
      whereas counts of pathogens and pathogenic indicators such as Vibrio, fecal
      Streptococcus, and coliphage decreased to less than 50% of the initial
      concentration. The time necessary to decrease contamination to 10%, 50%, and 90%
      for clams at both stations was consistently shorter for heavy metals than for
      microorganisms. Investigation of the effects of heavy-metal and microbiological
      depuration on valve movement and physiological rates (oxygen consumption and
      ammonia excretion) was carried out on R. decussatus to test the utility of
      physiological stress indices in assessing the health of depurated animals. Clams
      in the experimental tanks exhibited various states of activity, which were rated
      by identifying and scoring (0-4) the different parameters, including shell gap,
      siphon extension, and foot protrusion. Moreover, an increase in ammonia excretion
      was usually associated with an increase in respiration rate. The oxygen-to
      nitrogen ratio provided a sensitive indicator of bivalve health. It can be
      concluded that shellfish monitoring and depuration data depended on the initial
      concentration of the pollutants. There were differences in the physiological
      responses of clams from the two sites during the periods of pre- and
      postdepuration of the contaminants. There was a significant correlation between
      reduction of metal concentration in clam tissue and enhancement of valve
      movement, as well as activity and increasing respiration rate.

PMID- 15038003
TI  - Negative BOLD in the visual cortex: evidence against blood stealing.
AB  - The positive BOLD (blood oxygen level-dependent) response elicited in human
      visual cortex by a localized visual stimulus is accompanied by a reduction in the
      BOLD response in regions of the visual cortex that represent unstimulated
      locations in the visual field. We have suggested previously that this negative
      BOLD reflects attention-related suppression of neural activity, but it might also
      be explained in terms of "blood stealing," i.e., hemodynamic changes that have no
      neural correlate. We distinguish two possible hemodynamic effects of this type:
      (1). blood flow reduction caused by locally reduced pressure in vessels that
      share their blood supply with nearby dilated vessels; and (2). blood flow
      reduction caused by active constriction of vessels under neural control. The
      first is ruled out as an explanation of negative BOLD by showing that a visual
      stimulus that stimulates primary visual cortex in one hemisphere can cause
      extensive suppression in the other hemisphere i.e., it is not a local phenomenon.
      Negative BOLD most likely reflects suppression of neural activity, but could also
      reflect an active blood flow control system.

PMID- 15038002
TI  - Detoxification of organophosphorus compounds by recombinant carboxylesterase from
      an insecticide-resistant mosquito and oxime-induced amplification of enzyme
      activity.
AB  - Currently, bioremediation is a promising approach to the degradation of
      environmental pollutants. Here we describe the application of the recombinant
      insecticide-resistant mosquito carboxylesterase B1 to detoxify organophosphorous
      compounds. However, this approach has a major limitation: 1:1 stoichiometry of
      the enzyme detoxification of those organophosphorous compounds containing no
      carboxyl ester bonds, such as paraoxon, chlorpyrifos etc. To improve the
      effectiveness of the enzymatic detoxification of organophosphorous compounds, we
      used a combination of carboxylesterase B1 with the uncharged oxime
      diacetylmonoxime. It was demonstrated that the repeated addition of 20 times the
      molar concentration of paraoxon to carboxylesterase B1 every 2 h in the presence
      of 4 mM diacetylmonoxime did not result in significant inhibition of the enzyme.
      The stoichiometry of enzyme detoxification was higher than 45:1 and 20:1 for
      paraoxon and chlorpyrifos, respectively. The kinetic experiments on reactivation
      of organophosphorus compound-inhibited carboxylesterase B1 showed that the half
      life for paraoxon- and chlorpyrifos-inhibited carboxylesterase reactivation is
      0.75 and 0.88 h, respectively. Using the recombinant insecticide-resistant
      mosquito carboxylesterase with oxime is an effective approach for detoxification
      of organophosphorous compounds.

PMID- 15038004
TI  - Recursive penalized least squares solution for dynamical inverse problems of EEG
      generation.
AB  - In the dynamical inverse problem of electroencephalogram (EEG) generation where a
      specific dynamics for the electrical current distribution is assumed, we can
      impose general spatiotemporal constraints onto the solution by casting the
      problem into a state space representation and assuming a specific class of
      parametric models for the dynamics. The Akaike Bayesian Information Criterion
      (ABIC), which is based on the Type II likelihood, was used to estimate the
      parameters and evaluate the model. In addition, dynamic low-resolution brain
      electromagnetic tomography (LORETA), a new approach for estimating the current
      distribution is introduced. A recursive penalized least squares (RPLS) step forms
      the main element of our implementation. To obtain improved inverse solutions,
      dynamic LORETA exploits both spatial and temporal information, whereas LORETA
      uses only spatial information. A considerable improvement in performance compared
      to LORETA was found when dynamic LORETA was applied to simulated EEG data, and
      the new method was applied also to clinical EEG data.

PMID- 15038005
TI  - Neural substrates of tactile object recognition: an fMRI study.
AB  - A functional magnetic resonance imaging (fMRI) study was conducted during which
      seven subjects carried out naturalistic tactile object recognition (TOR) of real
      objects. Activation maps, conjunctions across subjects, were compared between
      tasks involving TOR of common real objects, palpation of "nonsense" objects, and
      rest. The tactile tasks involved similar motor and sensory stimulation, allowing
      higher tactile recognition processes to be isolated. Compared to nonsense object
      palpation, the most prominent activation evoked by TOR was in secondary
      somatosensory areas in the parietal operculum (SII) and insula, confirming a
      modality-specific path for TOR. Prominent activation was also present in medial
      and lateral secondary motor cortices, but not in primary motor areas, supporting
      the high level of sensory and motor integration characteristic of object
      recognition in the tactile modality. Activation in a lateral occipitotemporal
      area associated previously with visual object recognition may support cross-modal
      collateral activation. Finally, activation in medial temporal and prefrontal
      areas may reflect a common final pathway of modality-independent object
      recognition. This study suggests that TOR involves a complex network including
      parietal and insular somatosensory association cortices, as well as
      occipitotemporal visual areas, prefrontal, and medial temporal supramodal areas,
      and medial and lateral secondary motor cortices. It confirms the involvement of
      somatosensory association areas in the recognition component of TOR, and the
      existence of a ventrolateral somatosensory pathway for TOR in intact subjects. It
      challenges the results of previous studies that emphasize the role of visual
      cortex rather than somatosensory association cortices in higher-level
      somatosensory cognition.

PMID- 15038007
TI  - Functional coupling of simultaneous electrical and metabolic activity in the
      human brain.
AB  - The relationships between brain electrical and metabolic activity are being
      uncovered currently in animal models using invasive methods; however, in the
      human brain this relationship remains not well understood. In particular, the
      relationship between noninvasive measurements of electrical activity and
      metabolism remains largely undefined. To understand better these relations,
      cerebral activity was measured simultaneously with electroencephalography (EEG)
      and positron emission tomography using [(18)f]-fluoro-2-deoxy-D-glucose (PET-FDG)
      in 12 normal human subjects during rest. Intracerebral distributions of current
      density were estimated, yielding tomographic maps for seven standard EEG
      frequency bands. The PET and EEG data were registered to the same space and voxel
      dimensions, and correlational maps were created on a voxel-by-voxel basis across
      all subjects. For each band, significant positive and negative correlations were
      found that are generally consistent with extant understanding of EEG band power
      function. With increasing EEG frequency, there was an increase in the number of
      positively correlated voxels, whereas the lower alpha band (8.5-10.0 Hz) was
      associated with the highest number of negative correlations. This work presents a
      method for comparing EEG signals with other more traditionally tomographic
      functional imaging data on a 3-D basis. This method will be useful in the future
      when it is applied to functional imaging methods with faster time resolution,
      such as short half-life PET blood flow tracers and functional magnetic resonance
      imaging.

PMID- 15038006
TI  - Neural correlates of switching set as measured in fast, event-related functional
      magnetic resonance imaging.
AB  - Attentional switching has shown to involve several prefrontal and parietal brain
      regions. Most cognitive paradigms used to measure cognitive switching such as the
      Wisconsin Card Sorting Task (WCST) involve additional cognitive processes besides
      switching, in particular working memory (WM). It is, therefore, questionable
      whether prefrontal brain regions activated in these conditions, especially
      dorsolateral prefrontal cortex (DLPFC), are involved in cognitive switching per
      se, or are related to WM components involved in switching tasks. Functional
      magnetic resonance imaging (fMRI) was used to examine neural correlates of pure
      switching using a paradigm purposely designed to minimize WM functions. The
      switching paradigm required subjects to switch unpredictably between two spatial
      dimensions, clearly indicated throughout the task before each trial. Fast, event
      related fMRI was used to compare neural activation associated with switch trials
      to that related to repeat trials in 20 healthy, right-handed, adult males. A
      large cluster of activation was observed in the right hemisphere, extending from
      inferior prefrontal and pre- and postcentral gyri to superior temporal and
      inferior parietal cortices. A smaller and more caudal cluster of homologous
      activation in the left hemisphere was accompanied by activation of left
      dorsolateral prefrontal cortex (DLPFC). We conclude that left DLPFC activation is
      involved directly in cognitive switching, in conjunction with parietal and
      temporal brain regions. Pre- and postcentral gyrus activation may be related to
      motor components of switching set.

PMID- 15038008
TI  - Passive perception of odors and semantic circuits.
AB  - The sense of smell has been traditionally assumed to be different from other
      sensory modalities in that odors are encoded perceptually, without a semantic
      component. Recent findings of improved odor memory upon encoding with verbal cues
      question this view. Furthermore, familiar odors are easier to remember and
      discriminate than are unfamiliar ones, and odor familiarity is reported to
      predict odor naming. To investigate whether familiar odors are processed by
      different cerebral structures than those that process unfamiliar odors, (15)O
      H(2)O-positron emission tomography (PET) measurements of cerebral blood flow were
      carried out in 14 healthy men. The task was passive, birhinal, smelling of
      familiar odors (FAM), unfamiliar odors (uFAM), and odorless air (AIR).
      Significant activations (P < 0.05) were calculated using the contrasts FAM-AIR,
      uFAM-AIR, and FAM-uFAM, and deactivations running these contrasts in the opposite
      direction. In relation to AIR, both FAM and uFAM activated amygdala, piriform
      cortex, and parts of anterior cingulate cortex. FAM activated, in addition, left
      frontal cortex (Brodmann's areas 44,45,47), left parietal cortex incorporating
      precuneus, and right parahippocampus. Clusters covering parahippocampus and
      precuneus were observed also in FAM-uFAM. The activation of left frontal cortex
      and right parahippocampus was positively correlated with familiarity ratings.
      Smelling of familiar but not unfamiliar odorants seems to engage cerebral
      circuits mediating memory and language functions, in addition to the engagement
      of olfactory cortex. Already the most elemental form of odor processing, passive
      perception thus seems to engage semantic circuits. This is achieved by the
      ability of odorants to immediately elicit associations and judgments of odor
      characteristics.

PMID- 15038009
TI  - Don't think of a white bear: an fMRI investigation of the effects of sequential
      instructional sets on cortical activity in a task-switching paradigm.
AB  - Using functional magnetic resonance imaging (fMRI), we investigated processes
      involved in switching between two ongoing tasks, thought to be paradigmatic of
      executive control processes. Subjects were considerably slower and less accurate
      when switching between two tasks than when repeatedly carrying out one task, so
      called "switch costs." Switch costs, however, generally occur only when more than
      one task is associated with each stimulus type. This has led to the surmise that
      switch costs may be due largely to ongoing interference from previously learned
      stimulus-response (S-R) associations, which are no longer relevant for the task
      at hand. We used a paradigm that specifically assessed this hypothesis and
      investigated three stages. In Stage 1, a single task was carried out with each
      stimulus type; in Stage 2, a second novel task was introduced for each stimulus
      type; and in Stage 3, subjects reverted to carrying out solely the original tasks
      (as in Stage 1). In Stage 1, only one task was associated with each stimulus
      type, whereas two tasks were associated with each stimulus type in Stages 2 and
      3. We compared images obtained during Stage 3 to those obtained during Stage 1
      and show that during Stage 3, there was robust activation in the network of areas
      associated with the Stage 2 tasks, even though these tasks were no longer
      relevant. Our data strongly suggest that switch costs may derive largely from
      continued activation of areas associated with carrying out the now-irrelevant
      task(s). We posit that a large component of executive control processes involves
      resolution of competition between potentially relevant tasks. Our data also
      revealed widespread activation of a frontoparietal network of areas, and we
      discuss how this network might be involved in mediating this competition.

PMID- 15038011
TI  - Roles for journals.

PMID- 15038012
TI  - Structure and organization of a microsurgically oriented plastic surgery unit.

PMID- 15038013
TI  - Risks of allogeneic hand transplantation.
AB  - A patient undergoing allogeneic hand transplantation needs lifelong
      immunosuppression with the risk of serious side effects, including life
      threatening disease. The question remains: does the eventual improvement in
      function justify the risk? To answer this question, we try to assess the risks
      based on a large body of cumulative data derived from more 200,000 kidney
      transplants using the Collaborative Transplantation Study (CTS). Only selective
      data which apply to a patient population aged between 15-40 years were used (n =
      58,310). Data are compared to the literature references and show superiority with
      respect to patient numbers, statistics, actuality, and methodology. The CTS data
      show that the incidence of de novo malignancies is lower than previously
      reported. The risk of developing any form of cancer is approximately 3%, of
      developing a skin cancer 1.1%, and of developing a lymphoma 0.58% within 5 years
      after transplantation. The risk of suffering from a cataract is 11% after 5
      years, which is also lower than previously reported. Although the incidence of
      side effects (particularly malignant disease) is likely to be lower than
      previously thought, the risk-benefit question must be answered by each hand
      surgeon for each individual patient.

PMID- 15038014
TI  - Concept of arteriovenous loupes in high-risk free-tissue transfer: history and
      clinical experiences.
AB  - The present study describes the concepts of arteriovenous (A-V) loupes prior to
      microsurgical free flap transfer in a selected high-risk group of patients. A one
      stage concept was employed in 26 patients; 5 patients underwent two-stage flap
      transfer. Seven thrombotic occlusions of the A-V fistula or flap vessels were
      recorded; 6 patients underwent successful revision. Overall flap survival was
      96.8% and compared favorably to reports in the literature. Defect coverage could
      be achieved in all but one case. It can be concluded from the data that in
      selected high-risk patient groups, i.e., following radiation, compound trauma,
      chronic infection, or multiple comorbidities, the creation of an A-V fistula
      prior to flap transfer may facilitate innovative reconstructive solutions.

PMID- 15038015
TI  - Use of a cross-over arteriovenous fistula for simultaneous microsurgical tissue
      transfer and restoration of blood flow to the lower extremity.
AB  - A new microsurgical concept for simultaneous restoration of peripheral perfusion
      in the lower extremity and microsurgical free-tissue transfer is presented. The
      concept consists of a contralateral cross-over suprapubic arteriovenous (A-V)
      fistula, end-to-side anastomoses of the superficial and deep femoral artery to
      the A-V fistula, and microsurgical flap transfer after division of the A-V loop.
      With this concept, simultaneous restoration of perfusion and defect
      reconstruction were facilitated.

PMID- 15038016
TI  - Clinical application of the retrograde arterialized venous flap.
AB  - Retrograde arterialized venous flaps were applied to skin and soft-tissue defects
      in 13 patients with an average age of 34.4 years. Ten defects were located on the
      hand, and three on the lower leg. All flaps were harvested from the flexor aspect
      of the forearm; they ranged in size from 2 x 1 to 11 x 7 cm. There was venous
      congestion with superficial epidermolysis in six flaps, but not in the other
      seven. Partial skin necrosis in two of the lower-extremity flaps necessitated
      secondary skin grafts. Our results suggest that retrograde perfusion enhances
      blood flow in the periphery of arterialized venous flaps and gives good results
      in terms of flap survival, especially on the upper extremity.

PMID- 15038017
TI  - Preoperative CT angiography for free fibula transfer.
AB  - The role of preoperative imaging prior to free fibula flap harvest remains
      controversial. The standard method of preoperative imaging has been
      arteriography. However, arteriography is associated with known risks and
      potential complications to the patient. Alternatives to traditional angiography
      have been sought to attempt to reduce these risks. CT angiography is a
      noninvasive imaging modality that can accurately assess the arterial and venous
      circulation, while providing images equal to those of traditional angiography. CT
      angiography was used in 7 patients prior to free fibula flap harvest. There were
      no complications from the CT angiogram or the fibula harvest. We describe our use
      of CT angiography for vascular imaging of the lower extremity prior to free
      fibula harvest.

PMID- 15038018
TI  - Versatility of rectus abdominis free flap for reconstruction of soft-tissue
      defects in extremities.
AB  - Rectus abdominis flaps, whose blood supply is mainly provided by superior and
      deep inferior epigastric vessels, are suitable not only for local transfer but
      also as free flaps. Based on abundant anastomoses of deep inferior epigastric
      vessels with other vessels such as superior epigastric vessels, lower intercostal
      vessels, subcostal vessels, lumbar vessels, superficial epigastric vessels, and
      superficial and deep iliac circumflex vessels, the rectus abdominis flap may be
      designed as a vertical flap, transverse flap, or oblique flap. From September
      1995-October 2002, 42 free rectus abdominis flaps were transferred to reconstruct
      a variety of soft-tissue defects. The size of rectus abdominis flaps ranged from
      6-25 cm in length and 5-12 cm in width. The overall success rate was 100% (42 of
      42). The donor area was closed directly in 8-10-cm-wide flaps, leaving an
      inconspicuous scar. Larger flaps required skin grafting. After a mean 7-month
      (range, 3 weeks-18 months) follow-up, all flaps have healed uneventfully, and
      donor abdominal morbidity is minimal.

PMID- 15038019
TI  - Let it be: Salvage of exposed hemodialysis grafts with fasciocutaneous island
      flaps.
AB  - Contaminated and exposed prosthetic implants have traditionally required surgical
      explantation. This has been standard treatment, particularly for implants in the
      central circulation or those bridging major vascular structures, such as
      hemodialysis grafts. We present our experience in salvaging exposed hemodialysis
      grafts utilizing regional fascio- and septo-cutaneous flaps. In 5 of 6 cases,
      graft salvage was achieved, obviating the need for explantation and de novo
      insertion at another location. In selected instances of hemodialysis graft
      exposure, wound coverage and graft function can be obtained with regionally based
      flaps.

PMID- 15038020
TI  - Noradrenaline levels rise significantly in rat arterial grafts at 6 hours
      postoperatively, and take 48 hours to come down.
AB  - The aim of this study was to investigate the rate of disappearance of
      noradrenaline in arterial grafts after their transplanation. Arterial grafts were
      harvested from AO/Ks:OC strain rats. In each rat, a graft was harvested from the
      femoral artery and transplanted into the common carotid artery. A contralateral
      unoperated femoral artery served as control. High-performance liquid
      chromatography (HPLC) with electrochemical detection was used to determine the
      noradrenaline content in grafts and controls. Immediately after grafting, the
      noradrenaline content was 76% of control value, at 6 h 130% of control value, and
      at 48 h 4% of control value. The drop in graft noradrenaline content (from 0-48
      h) was statistically significant (P = 0.005). The difference between 0-h, 12-h,
      and 24-h groups was statistically insignificant. Compared to control specimens,
      grafts contained less noradrenaline after 12 h, and it disappeared almost
      completely from femoral arterial grafts in rats within 48 h.

PMID- 15038021
TI  - Comparative experimental study on treatment outcome of nerve transfer, using
      selective C7 nerve root vs. phrenic nerve.
AB  - The treatment outcome of nerve transfer using the C7 nerve root or phrenic nerve
      was compared in a rat experiment. One hundred and twenty SD rats were divided
      into two groups, one undergoing phrenic nerve transfer to the musculocutaneous
      nerve, and the other partial ipsilateral C7 (anteriolateral fascicles of the
      anterior division) to the musculocutaneous nerve. Neurotization outcomes of the
      two groups were evaluated by comparing the electrophysiologic, histologic, and
      myophysiologic changes of the biceps muscle. No significant differences were
      found between parameters from the phrenic nerve transfer group and those from the
      ipsilateral C7 nerve transfer group. This indicates that the treatment outcome of
      selective ipsilateral C7 transfer is comparable to that of phrenic nerve
      transfer. It is the surgery of choice in treating brachial plexus upper-trunk
      avulsion accompanied by phrenic nerve injury.

PMID- 15038022
TI  - Electrophysiologic study of influence on C7 innervated muscles after transection
      of different C7 fascicles.
AB  - An experimental study was conducted to observe the electrophysiologic changes in
      C7 innervated muscles following transection of different fascicles of C7 nerve
      root in the brachial plexus with already transected C5 and C6. Twenty-four
      Sprague-Dawley rats were randomized into groups A, B, and C. C5 and C6
      transection, C5, C6, and partial C7 (anteriolateral fascicles of the anterior
      division) transection, and C5, C6, and C7 transection were done in group A, B,
      and C, respectively. One month postoperatively, compound muscle action potentials
      of the latissimus dorsi, triceps, and extensor digitorum communis were recorded.
      Decreased amplitude and a prolonged latent period were seen in all three muscles
      of group C. No obvious changes, however, were found in groups A and B. This
      suggests that when the upper trunk of the brachial plexus is injured, partial
      transection of C7 does not obviously impair C7 innervated muscle function.
      Selective ipsilateral C7 transfer is safe for the treatment of upper-trunk
      avulsion.

PMID- 15038023
TI  - Late-phase ischemic preconditioning in skeletal muscle: is the phenomenon
      protective?
AB  - Reports in the literature on the effectiveness of late-phase Ischemic
      preconditioning (IPC) in skeletal muscle are controversial. The purpose of this
      study was to determine in the same muscle flap model the effectiveness of various
      IPC protocols in inducing late-phase protection. Rat latissimus dorsi muscle
      (LDM) flaps were preconditioned with either 30 or 60 min of total ischemia,
      divided as follows: single cycles of either 30 or 60 min, two cycles of 15 or 30
      min, and three cycles of 10 or 20 min. Ischemia cycles were separated by 10 min
      of reperfusion. A day after IPC, flaps were elevated and challenged with 4 h of
      ischemia. Three days later, flaps were assessed for viability. We found that IPC
      protocols of different total durations and comprised of two or three cycles of
      ischemia elicited a protective effect against necrosis. We conclude that IPC
      induces late-phase protection against necrosis in skeletal muscle, and that the
      protection requires more than one ischemia/reperfusion cycle.

PMID- 15038026
TI  - Chemistry in motion--unidirectional rotating molecular motors.

PMID- 15038027
TI  - Bigger DNA: new double helix with expanded size.

PMID- 15038028
TI  - Nanocatalysis: mature science revisited or something really new?
AB  - "Nanomania" has reached the area of heterogeneous catalysis. Nanosized catalyst
      constituents are important for functions that require structural control over
      several scales of dimension. Nanocatalysis may be understood as a redefinition of
      catalyst synthesis: multidimensional structural control is exerted by considering
      catalysts as inorganic polymers rather than as close-packed crystals. Primary,
      secondary, and tertiary structural hierarchies translate into molecular building
      blocks and linkers, the defect structure of crystals, and particle morphology.
      High-throughput techniques and in situ synthetic analysis are the tools required
      to arrive at better defined catalytic materials that can fulfil the high
      expectations created by the incorporation of catalysts into the "nano" research
      field.

PMID- 15038029
TI  - Chemistry and biology of terpene trilactones from Ginkgo biloba.
AB  - Ginkgo biloba, the ginkgo tree, is the oldest living tree, with a long history of
      use in traditional Chinese medicine. In recent years, the leaf extracts have been
      widely sold as phytomedicine in Europe and as a dietary supplement worldwide.
      Effects of Ginkgo biloba extracts have been postulated to include improvement of
      memory, increased blood circulation, as well as beneficial effects to sufferers
      of Alzheimer's disease. The most unique components of the extracts are the
      terpene trilactones, that is, ginkgolides and bilobalide. These structurally
      complex molecules have been attractive targets for total synthesis. Terpene
      trilactones are believed to be partly responsible for the neuromodulatory
      properties of Ginkgo biloba extracts, and several biological effects of the
      terpene trilactones have been discovered in recent years, making them attractive
      pharmacological tools that could provide insight into the effects of Ginkgo
      biloba extracts.

PMID- 15038030
TI  - Proton-assisted ethylene hydration in aqueous solution.

PMID- 15038032
TI  - An electrochemically controlled molecular shuttle.

PMID- 15038031
TI  - Responsive cyclohexane-based low-molecular-weight hydrogelators with modular
      architecture.

PMID- 15038033
TI  - Methotrexate conjugates: a molecular in vivo protein tag.

PMID- 15038035
TI  - Copper(II)-catalyzed highly enantioselective addition of enamides to imines: the
      use of enamides as nucleophiles in asymmetric catalysis.

PMID- 15038034
TI  - Targeted enzyme-responsive drug carriers: studies on the delivery of a
      combination of drugs.

PMID- 15038037
TI  - Heterogeneous enantioselective catalyzed carbonyl- and imino-ene reactions using
      copper bis(oxazoline) zeolite Y.

PMID- 15038036
TI  - Synthetic strategy toward skeletal diversity via solid-supported, otherwise
      unstable reactive intermediates.

PMID- 15038038
TI  - Enantiomeric resolution of a ruffled porphyrinoid.

PMID- 15038039
TI  - HP-RAFT: a free-radical polymerization technique for obtaining living polymers of
      ultrahigh molecular weights.

PMID- 15038041
TI  - High-throughput measurement of the enantiomeric excess of chiral alcohols by
      using two enzymes.

PMID- 15038042
TI  - A tandem semipinacol rearrangement/alkylation of alpha-epoxy alcohols: an
      efficient and stereoselective approach to multifunctional 1,3-diols.

PMID- 15038040
TI  - Let the best ring win: selective macrocycle formation through Pd-catalyzed or Cu
      mediated alkyne homocoupling.

PMID- 15038043
TI  - Infrared spectra of indium hydrides in solid hydrogen and of solid indane.

PMID- 15038044
TI  - Synthesis and crystal structure of [[nBuMg(mu-TMP)]2] and of a homometallic
      inverse crown in tetranuclear [[nBuMg2[mu-N(H)Dipp]2(mu 3-OnBu]2].

PMID- 15038045
TI  - Novel [60]fullerene-assisted ortho-phosphanation on a tetrairidium butterfly
      framework.

PMID- 15038046
TI  - A water-soluble tetranuclear ZrIV compound supported by the Klaui tripodal
      ligand: a model of ZrIV in aqueous media.

PMID- 15038047
TI  - Aqueous supramolecular polymer formed from an amphiphilic perylene derivative.

PMID- 15038048
TI  - Onion-type complexation based on carbon nanorings and a buckminsterfullerene.

PMID- 15038049
TI  - Total synthesis of natural myriaporones.

PMID- 15038050
TI  - Total synthesis and stereochemical assignment of myriaporones 1, 3, and 4.

PMID- 15038051
TI  - Iron-containing nucleoside analogues with pronounced apoptosis-inducing activity.

PMID- 15038052
TI  - Fluorescent imaging of citrate and other intermediates in the citric Acid cycle.

PMID- 15038053
TI  - Regio- and stereoselective tether-directed remote functionalization of C60 with
      derivatives of the Troger base.

PMID- 15038057
TI  - Novel reaction products from thiobarbituric Acid of biological interest.
AB  - The reactions of 1, 2-dihydro-2-thioxo-4, 6(1H, 5H)pyrimidinedione (1) with some
      pi-deficients have led to the formation of unexpected heterocyclic products such
      as anilinomethylenethioxopyrimidinedione, 2, 2'-bis(pyrimidinecarbothioamide),
      allylthioxopyrimidinecarbothioamide, indenopyranopyrimidine and
      benzofuropyrimidine derivatives. A possible mechanism for the formation of these
      products is discussed, and the biological activity is determined.

PMID- 15038056
TI  - 4-Aryl(benzyl)amino-4-heteroarylbut-1-enes as building blocks in heterocyclic
      synthesis. 4. Synthesis of 4, 6-dimethyl-5-nitro(amino)-2-pyridylquinolines and
      their antiparasitic activities.
AB  - New nitro- and aminoquinoline derivatives containing a pyridyl nucleus were
      synthesized from 6, 8-disubstituted 4-methyl-2-pyridylquinolines, which were
      prepared from N-pyridylmethylidenanilines. The anti-chagasic and trichomonacidal
      in vitro activity, as well as the cytotoxic properties towards macrophages of
      some of these compounds were evaluated. Although some of the compounds showed
      only moderate activity it was possible to establish some structure-activity
      relationships.

PMID- 15038058
TI  - Synthesis and antimicrobial evaluation of some novel cholestane heterocyclic
      derivatives.
AB  - This study was performed to investigate the reactivity of 5alpha-cholestan-3-one
      (1) towards various chemical reagents to produce new steroidal heterocyclic
      derivatives. The aminothieno[2, 3:2, 3]cholestane derivative 2 was synthesized
      according to Gewald's conditions. The diazonium salt of compound 2 coupled with
      malononitrile to afford dicyanomethylenhydrazinothieno[2', 3':2, 3]cholestane
      derivative 5. The behavior of compound 5 towards nitrogen nucleophiles and
      several active methylene reagents was investigated. Additionally, a variety of
      steroidal heterocyclic derivatives like compounds 15a, b-22a, b were synthesized
      starting with 5alpha-cholestan-3-one (1). The structures of the compounds were
      established based on the analytical and spectral data. The in vitro antimicrobial
      activity of some newly synthesized compounds against bacteria and fungi was
      studied.

PMID- 15038059
TI  - Synthesis of furoannelated analogues of Emivirine (MKC-442).
AB  - Furoannelated analogues 1-alkoxymethyl-7-phenyl-5, 7-dihydro-1H-furo[3, 4-d]
      pyrimidine-2, 4-diones of Emivirine (3a, b) were synthesized from the primary
      alcohols 1-alkoxymethyl-6-benzyl-5-hydroxymethyl-1H-pyrimidine-2, 4-dione (5a, b)
      using a radical ring closure reaction with Pb(OAc)(4). These analogues are
      conformationally restricted in order to fix the aromatic substituent of Emivirine
      in nearly the same position as it is in the case when the complex of Emivirine is
      bound to HIV-1 RT. However, the anti HIV-1 activities of 3a, b were considerably
      lower than those of the lead Emivirine.

PMID- 15038060
TI  - Total synthesis and in vitro-antifungal activity of (+/-)-2-methoxytetradecanoic
      Acid.
AB  - The marine fatty acid (+/-)-2-methoxytetradecanoic acid was synthesized in two
      steps (71% overall yield) starting from commercially available methyl-2-hydroxy
      tetradecanoate. The title compound was antifungal against Candida albicans (ATCC
      14053) in RPMI medium and Aspergillus niger (ATCC 16404) and Cryptococcus
      neoformans (ATCC 66031) in SDB medium at the minimum inhibitory concentration
      (MIC) of 100 mM, which compares to the fungitoxicity of a 2-iodotetradecanoic
      acid against the same fungi. The title compound was also five to ten times more
      cytotoxic than capric acid to C. albicans and A. niger in the tested medium but
      comparable in cytotoxicity to either capric acid and its 2-methoxylated analog to
      C. neoformans. The antifungal activity of (+/-)-2-methoxytetradecanoic acid is
      explained in terms of inhibition of N-myristoyltransferase.

PMID- 15038062
TI  - Synthesis and biological testing of novel analogues of sydnone as potential
      antibacterial agents.
AB  - Several series of 3-phenylsydnone derivatives conjugated to well-known moieties
      with antibacterial activity were synthesized via several routes. These
      derivatives include 3-cyano-2-oxopyridine, 2-amino-3-cyanopyridine, 2-arylidene-1
      ethylidenehydrazine and 2-aroyl-1-ethylidenehydrazine moieties. Thus, the key
      intermediate 3-(4-acetylphenyl)sydnone (3) was allowed to react with the
      appropriate aldehyde, ethyl cyanoacetate or malononitrile in presence of excess
      ammonium acetate in two steps (method 1) or through a one-pot reaction technique
      (methods 2 and 3) to give the corresponding sydnone derivatives 5 and 6,
      respectively. Moreover, condensation of compound 3 with hydrazine hydrate
      followed by the reaction with the appropriate aldehyde, mono- and dicarboxylic
      acid hydrazide yielded the corresponding sydnone derivatives 8, 9 and 10,
      respectively. Most of the synthesized compounds were screened for their in vitro
      antibacterial activity against various pathogenic organisms of both Gram-positive
      and Gram-negative bacteria. The minimum inhibitory concentrations (MICs) were
      determined using agar dilution method.

PMID- 15038061
TI  - Antiaggregating and antithrombotic activities of new 1, 2, 3
      triazolecarboxamides.
AB  - Twenty five new triazolecarboxamides related to YC-1 were prepared and tested for
      their antiplatelet (in vitro) and antithrombotic (in vivo) activities. Five of
      them inhibited the aggregation of blood platelets (Born test, inducer collagen)
      with IC50 values between 90 and 130 microM. Nine compounds exhibited significant
      antithrombotic properties with an inhibition of thrombus formation between 11 and
      7%. Only one compound (8c) showed both, in vitro and in vivo effects. In vitro,
      the most active compounds were 11c and 12d. They inhibit platelet aggregation
      with IC50 = 90 and 95 microM. In vivo, 10a showed the strongest inhibition of
      thrombus formation with 11% in arterioles (5% in venules) after a single oral
      dose of 60 mg/kg. With serotonin as inducer both, 11c and 12d, showed lower IC50
      values namely 25 or 30 microM, respectively. Additional antiplatelet activities
      were found for 11c against adrenaline (IC50 = 25 microM) and for 12d against
      platelet activating factor (PAF) (IC50 = 15 microM) as inducer.

PMID- 15038063
TI  - Food and health in Europe: a new basis for action.
AB  - Poor nutrition, foodborne disease and lack of secure access to good food make an
      important contribution to the burden of disease and death in the WHO European
      Region. Better diets, food safety and food security will not only reduce or
      prevent suffering to individuals and societies but also help cut costs to health
      care systems and bring social and economic benefits to countries. People's
      chances for a healthy diet depend less on individual choices than on what food is
      available and whether it is affordable. Policies to benefit health through good
      food and nutrition must extend beyond the health sector to include sectors
      ranging from agriculture and food processing, manufacturing and trade to
      transport, retailing, catering and advertising. Food and nutrition policies
      should be coordinated so that public health is given due priority in the making
      of food policies by non-health sectors. This publication discusses in depth the
      components of food and nutrition policies and the evidence supporting them. It
      describes food- and nutrition-related ill health and its costs, shows the need
      for action and describes the steps for decision-makers to take. This book
      highlights the urgent need for integrated, multisectoral food and nutrition
      policies to encourage the sustainable production of food, its safety and the
      provision of food of high nutritional quality for all.

PMID- 15038064
TI  - Cholera, Africa (as at 18 February 2004).

PMID- 15038065
TI  - Nipah virus.

PMID- 15038066
TI  - Recommended composition of influenza virus vaccines for use in the 2004-2005
      influenza season.

PMID- 15038067
TI  - Validity and reliability of the measurement of the quardriceps femoris muscle
      strength with a hand-held dynamometer on the affected side in hemiplegic
      patients.
AB  - The purpose of this study was to investigate validity and reliability of
      measuring the quadriceps femoris muscle strength on the affected side in
      hemiplegic patients with a hand-held dynamometer(HHD) to prepare for a multi
      center cooperative study. Measurements of the known weights(8.972 and 18.665 kg)
      with HHD were 8.98 +/- 0.00 kg and 18.57 +/- 0.00 kg, respectively, and
      measurements with HHD were almost consistent with those with KIN-COM (gold
      standard), because the Pearson's product-moment correlation coefficient was 0.99
      (P < 0.001). There were significant differences in measurements of the quadriceps
      femoris muscle strength on the affected side in a hemiplegic patient between just
      anterior to the face of the ankle and 7 cm proximal to the ankle, and on a chair
      with or without a backrest (t-test, P < 0.05), but no significant difference was
      found between the 90 degrees and 60 degrees flexed position of the knee (t-test,
      0.1 > P > 0.05). There were also no significant differences in muscle strength
      measured by three different examiners and on four trials, but significant
      differences were found among three patients (General Linear Model, P < 0.001).
      Therefore, by using the standardized measuring procedure, the HHD is reliable to
      measure strength of the quadriceps femoris muscle on the affected side in
      hemiplegic patients.

PMID- 15038069
TI  - Male reproductive health in relation to occupational exposure to endocrine
      disrupting and other potent chemicals, a review of the epidemiologic literature.
AB  - The line of research focusing on the human, especially male, reproductive system
      in relation to occupational exposure has diversified since the infiltration of
      the concept of endocrine disrupting chemicals (EDC), early in the 1990s. The main
      stream, until then, was the study of reproductive toxicity caused by single
      albeit relatively heavy exposures to chemicals of limited range (conventional
      scheme). The new and increasingly important stem is the search for a wider range
      of chemicals with endocrine disrupting potential, and health effects due to
      multiple low-dose exposures of potent chemicals (new scheme). There are also
      studies having aspects of both the conventional and new schemes. For studies with
      the new scheme, progress has been made in areas such as adherence to standardized
      techniques in evaluating male reproductive function and more sensitive study
      designs. Indeed, some studies have suggested the presence of EDCs in the
      occupational setting. However, epidemiological findings are still constrained by
      difficulties in the identification of occupationally-exposed populations and
      evaluation of exposure. There is thus a need for convergence of knowledge and a
      widening of the scope of epidemiological research targeting occupationally
      exposed populations under a carefully-designed protocol.

PMID- 15038068
TI  - An effective method for extracting DNA from contaminated soil due to industrial
      waste.
AB  - Recently, labor accidents caused by toxic gas production such as H2S and CH4 have
      happened at some waste disposal sites and illegal dumping sites in Japan. The gas
      production has been known to be end products of bacterial respiration. In order
      to investigate a microbial flora in industrial waste contaminated soil by a DNA
      based detection method, we developed a simple DNA extraction method. The method
      is based on lysis with sodium dodecyl sulfate (SDS) and a high concentration (4.0
      mg/ml) of lysozyme at room temperature. DNA yields increased according to the
      concentration of lysozyme (0-2 mg/ml), although the cell lysis occurred at
      comparable efficiency independent of the lysozyme concentration. Interestingly,
      bovine serum albumin and insulin (4 mg/ml) also contributed high DNA yields. This
      suggests proteins play an important role at high concentration on a DNA
      extraction process, presumably by suppressing DNA degradation or adsorption. DNA
      yields from three contaminated soil samples at 0.3, 1.5 and 3 m in depth by using
      our method were significantly higher than those extracted by using a widely-used
      conventional method which did not contain lysozyme. A novel and simple DNA
      extraction method using high concentration of protein was established for a DNA
      based detection method of microbial flora in soil.

PMID- 15038070
TI  - Medical fitness to return to work for disabled workers.
AB  - Return to work for the disabled worker is one of the critical issues for both the
      person himself and his employer. The early return to work is a manifestation of
      social restoration for the disabled worker as well as an effective way to reduce
      social cost-related disabilities. Several studies on effectiveness of the formal
      return to work program have been reported. This program is one of the workplace
      disability management systems that promote the workplace accommodation for the
      disabled. The purpose of a medical assessment of fitness for return to work in
      this program is to make sure that an individual is fit to perform the task
      involved effectively and without risk to his own or to others' health and safety.
      Decision-making, the process of assessment of medical fitness, and the design for
      a return to work are discussed.

PMID- 15038072
TI  - [Study on lower back pain in home helpers and development of materials for
      occupational health education].
AB  - People who are engaged in home health care services often have to transfer
      clients while in a half standing posture using repetitious movement including
      gravitational changes. Transferring heavy patients at homes for the severely
      mental and physical handicapped is equivalent to the care giving work, listed in
      the "guideline for prevention of lower back pain in work places" (1994/9/6). The
      purpose of this study was to investigate incidences of lower back pain and
      injuries among home helpers as well as to determine the relationship between
      their level of protective knowledge and prevalence of lower back pain. The
      results of the study revealed that home helpers complained of a mild type of
      lower back pain. Although almost all of them had the protective knowledge for
      lower back injuries that was taught in their training courses, they still felt
      the need for more knowledge through continuous education regarding protective
      measures for lower back injuries and pain. Regarding the method of teaching, they
      want to learn by TV programs, books, texts and self-learning materials. Few of
      them wanted to learn by computer assisted instructions or the internet. Based
      upon the results of this study, we have developed new teaching materials for home
      helpers which explain adequate postures in home care through utilizing their
      protective knowledge to avoid lower back pain.

PMID- 15038071
TI  - Acrylamide does not cause apparent changes in genetic expression of creatine
      kinase in rat cerebellum.
AB  - Acrylamide inhibits creatine kinase (CK) activities in the brain of rats or mice.
      However, its effects on genetic expression of CK have not yet been studied. CK
      mRNA and protein level were examined by RT-PCR and Western blotting,
      respectively. Neither cytosolic CK (B subunit) and mitochondrial CK (ubiquitous
      form) mRNA nor B subunit protein was clearly changed in the cerebellum from rats
      intoxicated with acrylamide (50 mg/kg/day i.p. for 8 days) and showing clinical
      neurotoxic signs.

PMID- 15038073
TI  - [Laryngospasm associated with anesthesia: diagnosis and management].
AB  - Securing the airway is the most important part of anesthesia safety. In clinical
      practice there is always the risk of encountering laryngospasm, which is defined
      as the occlusion of the glottis by the action of the intrinsic laryngeal muscles.
      Once laryngospasm occurs, it leads to acute desaturation and subsequent organ
      dysfunction. In spite of such a dramatic deterioration, however, there are no
      systematic reviews that include pathophysiology, clinical incidence, prevention
      and its treatment. In this paper, we have reviewed laryngospasm, according to the
      induction of anesthesia and emergence from it, methods for securing the airway
      using a tracheal tube or a laryngeal mask airway, and the timing of tracheal
      extubation. In addition, we have summarized a prompt diagnosis and adequate
      prevention and management of laryngospasm associated with anesthesia.

PMID- 15038074
TI  - [Mechanism for activation of heparin-binding EGF-like growth factor induced by
      stimuli].
AB  - Heparin-binding epidermal growth factor-like growth factor(HB-EGF), which belongs
      to the EGF family, is a critical growth factor for a number of physiological and
      pathological processes, such as wound healing and cardiac hypertrophy. HB-EGF is
      synthesized as a membrane-anchored form(pro-HB-EGF), and pro-HB-EGF is cleaved at
      the cell surface to yield soluble HB-EGF by a mechanism called "ectodomain
      shedding". Soluble HB-EGF has mitogenic activity. Ectodomain shedding of proHB
      EGF is induced by stimuli, including 12-O-tetradecanoylphorbol-13-acetate(TPA), a
      ligand for seven-transmembrane G protein-coupled receptors(GPCR), stress and
      inflammatory cytokine. Lysophosphatidic acid(LPA), a ligand for GPCR, stimulates
      the shedding of proHB-EGF, which constitutes a GPCR-mediated transactivation of
      the EGF receptor. Ras-Raf-MEK signal and the small GTPase Rac are essential for
      the LPA-induced shedding. On the other hand, protein kinase C and ADAM 9 protease
      are essential for the TPA-induced shedding. Furthermore, p38 MAPK is essential
      for the stress- and IL-1 beta-induced shedding. Finally there is a mechanism for
      activation of HB-EGF regulated by the environment in the living body.

PMID- 15038075
TI  - [Significance of working environment improvement based on determination of source
      of harmful substance--example of an endoscope syringe room using glutaraldehyde].
AB  - Because a worker complained of irritated eyes and throat due to glutaraldehyde
      (GA) in an endoscope syringe room, the automated endoscope washers and GA liquid
      stored in reserve were isolated in a separate room. A ventilation system was
      installed in this room, and the packing of the automated endoscope washers was
      changed. However, since the obnoxious smell of GA still remained in the endoscope
      syringe room, we had to determine the source of the smell. A plastic bucket with
      a cap was found to be filled with GA for disinfection of the endoscope apparatus.
      GA had evaporated when dispersed around the bucket, resulting in the obnoxious
      smell. The plastic bucket was replaced with a different type of container.
      Moreover, GA from the separate room did not affect the concentration of GA in the
      working area because the separate room for the automated endoscope washers had
      twice the ventilation volume proposed by the guidelines of the Society of
      Gastroenterology Nurses and Associates of the USA and the Healthcare Engineering
      Association of Japan. Consequently, we reconfirmed the significance of working
      environment improvement after clarifying the source of the harmful substance.

PMID- 15038076
TI  - [Paradoxical worsening ocular movement in idiopathic carotid-cavernous fistula
      without conjunctival congestion--case report].
AB  - We report a case of carotid-cavernous fistula(CCF) without conjunctival
      congestion and showing radiographically paradoxical worsening ocular movement. A
      71-year-old woman suffered from mild double vision. The first carotid angiogram
      revealed left CCF, which was supplied by dural branches of the internal and
      external carotid arteries and drained out well via only the superior orbital vein
      to the angular vein. We did not perform intravascular intervention because of
      spontaneous improving of her symptom. However, three weeks after her discharge,
      her symptom began worsening and she was readmitted because of left complete
      ophthalmoplegia, but without conjunctival congestion. Contrary to our expectation
      the second left carotid angiogram demonstrated that the shunt flow to the angular
      vein of CCF was much less than that seen previously. After transvenous
      embolization of the left cavernous sinus, her symptom completely improved and CCF
      did not recur.

PMID- 15038077
TI  - [Multiple rectal ulcer developing in a 28-year-old male patient with collagen
      disease].

PMID- 15038078
TI  - Do SSRIs cause gastrointestinal bleeding?
AB  - Selective serotonin re-uptake inhibitor antidepressants (SSRIs) can inhibit
      uptake, and therefore storage, of serotonin by platelets. This is significant
      because release of serotonin from platelets augments their aggregation; so use of
      SSRIs could, in theory, predispose patients to bleeding disorders. Case reports
      have suggested a link between SSRIs and easy bruising, nosebleeds, menorrhagia,
      petechial, ocular, small bowel, rectal and cerebral haemorrhages, and a prolonged
      bleeding time. Also, the summaries of product characteristics (SPCs) for all
      SSRIs include warnings about use in patients with a history of bleeding disorders
      or concomitant use with drugs known to affect platelet function. Here we review
      the risk of gastrointestinal bleeding associated with the use of SSRIs.

PMID- 15038079
TI  - Are Seretide and Symbicort useful in COPD?
AB  - Seretide (fluticasone + salmeterol--Allen & Hanburys) and Symbicort (budesonide +
      formoterol--AstraZeneca) inhalers have recently been licensed in the UK for the
      symptomatic treatment of patients with severe chronic obstructive pulmonary
      disease (COPD) and a history of repeated exacerbations. Advertising for Seretide
      depicts a man and states that the drug "has improved his ability to breathe and
      reduced his risk of exacerbations", while promotional claims for Symbicort
      include benefits in "reducing symptoms" and "improving quality of life". Here we
      assess the place of these fixed-dose combination inhalers containing a
      corticosteroid and a long-acting beta 2 agonist in the management of patients
      with COPD.

PMID- 15038081
TI  - [Clinical characteristics of gastric and duodenal ulcer].

PMID- 15038080
TI  - Epoetins and [symbol: see text] darbepoetin alfa in malignant disease.
AB  - Anaemia is common in people with cancer, and may reduce their quality of life and
      life expectancy. Blood transfusion can increase haemoglobin levels but is usually
      reserved for those with moderate anaemia (haemoglobin level below 10 g/dL). A
      potential alternative is treatment with one of the human recombinant forms of
      erythropoietin, epoetin alfa (Eprex--Janssen-Cilag) or epoetin beta (NeoRecormon-
      Roche), or their hyperglycosylated derivative [symbol: see text] darbepoetin alfa
      (Aranesp--Amgen). These products have improved the management of patients with
      chronic renal failure who are anaemic. Here we assess the place of the epoetins
      and darbepoetin alfa in managing anaemia in patients with cancer.

PMID- 15038082
TI  - [Future for basic and clinical studies on peptic ulcer disease].
AB  - Since the discovery of H. pylori, various causes of peptic ulcer disease is
      reevaluated, and only four factors are now considered most important; H. pylori
      infection, gastric acid, NSAID administration, and mental and physical stress.
      Among them, gastric acid is an aggravating factor, and gastric acid alone can
      hardly develop peptic ulcers. The relationship between H. pylori infection and
      stress has been studied at Hanshin-Awaji great earthquake occurred in 1995.
      Immediately after the earthquake, the number of patients with peptic ulcer
      disease has been greatly increased, and those patients were considered to be
      typical cases of stress ulcers. Interestingly, however, it was found that 83.2%
      of the patients were infected with H. pylori. The data suggested that stress
      ulcer developed in those infected with H. pylori. In contrast, the relationship
      between H. pylori infection and NSAID in the development of ulcer disease is more
      complex. It is still unclear whether H. pylori infection is an additive effect
      for development of peptic ulcer disease by NSAID administration or not.

PMID- 15038083
TI  - [Receptor for VacA toxin and pathogenesis of gastric ulcer].
AB  - The vacuolating cytotoxin VacA produced by Helicobacter pylori causes massive
      cellular vacuolation in vitro, and gastric tissue damage in vivo leading to
      gastric ulcers when administered intragastrically. We found that mice deficient
      in protein tyrosine phosphatase receptor type Z(Ptprz) do not show mucosal damage
      by VacA, although VacA is incorporated into the gastric epithelial cells to the
      same extent as in wild-type mice. Primary cultures of gastric epithelial cells
      from Ptprz+/+ and Ptprz-/- mice showed similar cellular vacuolation, but only
      Ptprz+/+ cells showed marked detachment from a reconstituted basement membrane
      from 24 h after treatment with VacA. VacA bound to Ptprz, and the tyrosine
      phosphorylation level of Git1, a Ptprz substrate, was elevated by VacA,
      indicating that VacA behaves as a ligand for Ptprz. These data indicate that
      erroneous Ptprz signaling by VacA, but not cellular vacuolation, induces gastric
      ulcers.

PMID- 15038084
TI  - [Helicobacter pylori-related cytokines influence gastric acid secretion and
      gastric mucosal inflammation in gastroduodenal ulcers].
AB  - Helicobacter pylori(H. pylori) is an important pathogenic factor for
      gastroduodenal ulcers and gastric cancer. The level of gastric acid output may
      influence the outcome of those diseases. With low acid output, H. pylori can
      spread to the corpus of the stomach, resulting in progression to atrophic
      gastritis. It may cause an increased risk of gastric cancer and ulcer. In
      contrast, with high output, H. pylori is confined in the gastric antrum, which
      develops antrum-predominant gastritis. This may contribute to an increased risk
      of duodenal ulcer. It is well known that inflammatory cytokines including
      interleukin (IL)-1 beta, IL-8 and tumor necrosis factor alpha modulate gastric
      acid secretion. Therefore, the host immune response by the cytokines may cause
      these disparate pathways in gastric acid secretion.

PMID- 15038085
TI  - [Rolipram, a specific type IV phosphodiesterase inhibitor, ameliorates
      indomethacin-induced gastric mucosal injury in rats].
AB  - Inhibition of type IV phosphodiesterase activity is beneficial in various
      inflammation mediated by its function to suppress the production of inflammatory
      cytokines in inflammatory cells. Nonsteroidal anti-inflammatory drugs(NSAIDs)
      such as indomethacin are well known to develop gastric mucosal lesion. As
      pathogenesis of indomethacin induced gastric mucosal lesion, activation of
      neutrophils and inflammatory cytokine production play critical roles. However,
      the effect of phosphodiesterase inhibitors on development of gastric mucosal
      lesion has not been reported. In the present study, we examined the effect of
      specific type IV phosphodiesterase inhibitor(rolipram) on NSAIDs-induced gastric
      mucosal lesion. Also, we examined the effect of rolipram on tissue prostaglandin
      E2 production.

PMID- 15038086
TI  - [Interluekin-1 beta genetic polymorphism influences the impact of cytochrome P
      2C19 genotype on the cure rate of H. pylori eradication therapy].
AB  - Genetic polymorphism of interleukin(IL)-1 beta is associated with differences in
      gastric acid suppression in response to H. pylori infection. Thus, the
      polymorphism might affect H. pylori eradication therapy since antibiotics used in
      treatment regimens may be acid-sensitive. We examined the impact of IL-1 beta
      genetic polymorphism on the cure rate of triple therapy for H. pylori in relation
      to cytochrome P(CYP)2C19 genotype. In the normal acid-secretion IL-1 beta
      genotype group, the cure rate among CYP2C19 poor metabolizers was significantly
      higher than among those in the CYP2C19 extensive metabolizer groups. IL-1 beta
      genetic polymorphism, although not an independent factor in treatment outcome,
      influences the impact of the CYP2C19 genotype on the cure rate of H. pylori
      eradication therapy.

PMID- 15038087
TI  - [Evaluation of diagnostic methods for Helicobacter pylori infection].
AB  - In Japan, the noninvasive diagnostic tests currently approved for health
      insurance by the Ministry of Health are the serology test, the 13C-UBT test and
      the stool antigen test. The serology(antibody detection) test is useful for
      pretreatment screening, but because it reflects an immunologic response, false
      negatives are seen in patients with diseases such as rheumatoid arthritis and
      connective tissue diseases, and in the elderly. Furthermore, the serology test is
      difficult to use in the clinical setting, because 6 months or more is needed for
      the antibody titer to fall, after eradication therapy. For UBT, the expensive 13C
      UBT is used. In view of the anticipated increase in testing, a test that is
      relatively inexpensive, simple, accurate and safe is needed. The stool antigen
      test has become available, and the test has been validated for accuracy. The
      stool antigen test is useful for the diagnosis of H. pylori infection before and
      after treatment in Japanese population.

PMID- 15038088
TI  - [Helicobacter pylori stool antigen test].
AB  - In Japan, Helicobacter pylori stool antigen(HpSA) test was opened for diagnosis
      of H. pylori infection before and after eradication therapy form Nov. 1, 2003. We
      can use two kinds of HpSA kits, Premier Platinum HpSA(Meridian Bioscience, USA)
      and Testmate pylori antigen EIA(Wakamoto Pharmaceutical Co., Ltd., Japan). We
      evaluated the diagnostic accuracy of the HpSA test(Premier Platinum HpSA)
      compared with diagnosis based on endoscopic biopsy-based methods. In 136
      patients, the sensitivity and specificity of the HpSA test before therapy were
      98.3% and 95.0%, respectively. In 54 patients, the sensitivity and specificity of
      the HpSA test after eradication therapy were 90% and 97.7%, respectively.
      Therefore, it is concluded that the HpSA test is a useful method for the
      diagnosis of H. pylori infection before and after eradication therapy.

PMID- 15038090
TI  - [Strategy for peptic ulcer therapy in the era of H. pylori eradication therapy].
AB  - The Japanese guideline for gastric ulcer therapy published 2003 has adopted a
      policy that eradication therapy for H. pylori as the first line therapy on ulcer
      patients with positive H. pylori status. For NSAID-induced gastric ulcer
      patients, cessation should be considered. In patients who cannot stop NSAIDs,
      proton-pump inhibitors or prostaglandin drugs is recommended. Similar strategy
      can be applied for duodenal ulcer patients. Implementation of this basic strategy
      in daily clinical practice, however, require further efforts to wider recognition
      of the new guideline for gastric ulcer therapy as well as to solve several
      barriers caused by discrepant health reimbursement policy.

PMID- 15038089
TI  - [Immunological rapid urease test].
AB  - Immunological rapid urease test for detection of Helicobacter pylori infection,
      composed of a solid-phase tip coated with monoclonal antibody against H. pylori's
      urease and ion-sensitive field transistor (ISFT)-based pH sensor system, was
      developed. The monoclonal antibody against H. pylori's urease was useful to avoid
      the contamination of urease activity in other bacteria. Because ISFTT had high
      ability to detect pH change, the sensitivity and specificity of immunological
      rapid urease test was significantly improved comparing with that of conventional
      rapid urease test. The utility of immunological rapid urease test was evaluated
      in some clinical studies.

PMID- 15038092
TI  - [Second-line eradication therapy for H. pylori infection].
AB  - The widespread use of eradication therapy for Helicobacter pylori has lead to an
      increase in antibiotic-resistant strains and the problem of retreatment in cases
      of eradication failure. Retreatment in cases of eradication failure has achieved
      relatively good results with regimens containing bismuth compounds and
      tetracyclines in the world, but consensus has not been reached in Japan and each
      institution has its own policy. An triple therapy consisted of proton pump
      inhibitor, amoxicillin and metronidazole has been reported to show a good cure
      rate as a second line therapy in Japan, but metronidazole has not been approved
      by the Japanese regulatory authority for use against bacterial infections,
      including H. pylori, despite its worldwide use as an antimicrobial agent in H.
      pylori eradication regimens.

PMID- 15038093
TI  - [Peptic ulcer recurrence after successful eradication of Helicobacter pylori-
      clinical characteristics and management].
AB  - Peptic ulcer recurrence after successful eradication of Helicobacter pylori(H.
      pylori) is not rare. We evaluated the effect of H. pylori eradication on
      prevention of gastric ulcer recurrence. Ulcer recurrence had occurred in 20 of
      256 H. pylori-eradicated patients, and most of ulcer recurrence were found within
      1 year after eradication. NSAIDs and psychological stress, but not sex, smoking
      habit, drinking habit, and past history of ulcer, seem to be associated with
      ulcer recurrence. Intractable ulcers after the eradication of H. pylori
      frequently recurred. Some recurrent ulcers were refractory to treatment with H2
      receptor antagonists or proton pump inhibitors. The mechanism(s) by which healed
      ulcers recur after successful eradication of H. pylori remains unclear.

PMID- 15038091
TI  - [Eradication effect of lansoprazole-based triple therapy against H. pylori].
AB  - Eradication of H. pylori provides a potential cure in the majority of patients
      with gastric ulcer as well as duodenal ulcer. Two proton pump inhibitor(PPI)
      based triple therapy, combining with clarithromycin(CAM), amoxicillin(AMPC) or
      metronidazole have been established as standard regimens worldwide. In Japan,
      lansoprazole(LPZ)-based triple therapy combined with CAM and AMPC for 1 week was
      firstly investigated on eradication effect against H. pylori and determination of
      the optimal dose of CAM in multicenter, double-blind trial. Patients with active
      gastric ulcer or duodenal ulcer were enrolled in this study. The eradication rate
      of H. pylori in patients with gastric ulcer were 0%, 87.5% and 89.2% and those in
      patients with duodenal ulcer were 4.4%, 91.1% and 83.7% in LPZ(60 mg/d) alone,
      LPZ(60 mg/d) with CAM(400 mg/d) and AMPC(1,500 mg/d), LPZ(60 mg/d) with CAM(800
      mg/d) and AMPC(1,500 mg/d), respectively, in the full set analysis. LPZ-based
      triple therapy demonstrated a high eradication rate and was safe. In addition,
      the combination regimens with lower or higher dose of CAM were equivalent in
      Japanese patients.

PMID- 15038094
TI  - [Reflux esophagitis after H. pylori eradication].
AB  - We have reported that prevalence of H. pylori infection and grade of atrophic
      gastritis were significantly lower, while acid secretion was significantly
      greater in the patients with reflux esophagitis than those without it. We have
      also reported that increased gastric acid secretion after H. pylori eradication
      may explain a reason for developing reflux esophagitis. Therefore, H. pylori is
      considered to be a protective factor for the development of reflux esophagitis
      via the induction of gastric hyposecretion. Conversely, according to recent large
      population-based studies, no evidence was obtained that supports the increased
      frequency of heartburn symptoms or reflux oesophagitis after the eradication of
      H. pylori. One reason for the discrepancy may be the difference in the evaluation
      of gastro-esophageal reflux, another reason may be the difference in acid
      secretion before the clearance of H. pylori in individual subjects, because the
      effects of H. pylori on acid secretion vary from patient to patient.

PMID- 15038095
TI  - [NSAID ulcer (H. pylori, treatment, prevention)].
AB  - Although it has been reported that NSAID ulcer has been increasing in western
      countries, the epidemiology and treatment or prevention of this type of peptic
      ulcer have not been fully studied. Recently 'Guideline for the treatment of
      gastric ulcer' has been published in Japan. Based on the data described in the
      guideline, at present it is recommended to use misoprostol, protonpump inhibitor,
      or high dose of H2 receptor in the prevention of NSAID ulcer. In the treatment of
      NSAID ulcer, to stop NSAID and/or to use misoprostol or protonpump inhibitor are
      recommended.

PMID- 15038096
TI  - [Endoscopic hemostasis using high-frequency hemostatic forceps for hemorrhagic
      gastric ulcer].
AB  - Gastric ulcer is a major responsible lesion for upper gastrointestinal bleeding.
      Several methods for endoscopic hemostasis are widely used throughout Japan to
      treat the ulcerative lesion. High-frequency hemostatic forceps is one of the
      endoscopic coagulation devices developed solely for hemostasis. Unlike biopsy
      forceps, it has narrow opening angle, a small cup and a dull edge to make
      pinpoint holding of the target lesion possible. We applied high-frequency
      hemostatic forceps for eleven cases of hemorrhagic gastric ulcer with exposed
      vessels. All of the cases were treated by endoscopic hemostasis with the device.
      Initial hemostasis obtained in all of the cases(100%), and no rebleeding was
      observed. Additional treatment, however, was necessary in four cases(36%). No
      serious complication, like perforation, was observed. We concluded that
      endoscopic hemostasis using high-frequency hemostatic forceps for hemorrhagic
      gastric ulcer is safe and effective method.

PMID- 15038097
TI  - [Laparoscopic surgery for perforated peptic ulcer].
AB  - Laparoscopic surgery has become the treatment of choice for the management of
      perforated peptic ulcer. The advantages of laparoscopic repair for perforated
      peptic ulcer include less pain, a short hospital stay, and an early return to
      normal activity. Although the operation time of laparoscopic surgery is
      significantly longer than that of open surgery, laparoscopic technique is safe,
      feasible, and with morbidity and mortality comparable to that of the conventional
      open technique. To benefit from the advantages offered by minimally invasive
      laparoscopic technique, further study will need to determine whether laparoscopic
      surgery is safe in patients with generalized peritonitis or sepsis.

PMID- 15038098
TI  - [Arteriosclerosis and gastoduodenal ulcer].
AB  - Recent reports suggested an increase in the occurrence of gastroduodenal ulcers
      in old age people. And it was reported that gastroduodenal ulcers in old age
      generation has the characteristics which was different from that in young
      generation. Namiki et al reported that gastric ulcer in old age generation occurs
      often at the gastric corpus and is larger and deeper and more often with bleeding
      comparing with that in young people. Furthermore NSAID ulcer is known to occur
      more often in old age than in young. Although the pathogenesis of the
      gastroduodenal ulcer in old age is not clear, a decrease in gastric mucosal blood
      flow with aging might be related that is possibly due to narrowing of arteries
      based on arteriosclerosis. Since the report by Virchow that suggested the
      importance of vessels as a cause for gastric ulcer, many studies indicated the
      involvement of vessels in the pathogenesis of gastroduodenal ulcer. Until
      recently, however, there were no methods except autopsy to evaluate the severity
      of arteriosclerosis, therefore the involvement of arteriosclerosis in the
      pathogenesis was not clarified. Recently a new device that case evaluate the
      arteriosclerosis by the measuring pulse wave velocity was developed and is now
      widely used. We undertook to clarify the relation between arteriosclerosis and
      gastroduodenal ulcer. The result suggested the involvement of arteriosclerosis in
      the pathogenesis of gastroduodenal ulcer, especially of NSAID ulcer with
      bleeding. In this manuscript, we refer to the previous reports that suggest the
      relation between arteriosclerosis and gastroduodenal ulcer.

PMID- 15038099
TI  - [Peptic ulcer disease complicated with liver cirrhosis].
AB  - A microcirculatory disorder and alterations of humoral factor are important in
      gastric mucosal lesion formation with liver cirrhosis, and degradation of a
      defense factor is important in ex-ulceration in the gastric mucosa. In terms of
      H. pylori infection, the liver cirrhosis which I sanitized when I think about
      consequence may be to be good. It is important that degradation of a gastric
      mucosal defense by liver cirrhosis itself, gastric mucosal atrophy might greatly
      affect the ulcerogenic mechanism in the stomach.

PMID- 15038100
TI  - [GVHD gastro-duodenitis].
AB  - Graft-versus-host disease(GVHD) colitis after allogeneic bone marrow
      transplantation or peripheral blood stem cell transplantation was often
      accompanied with upper gastro-intestinal symptoms such as upper abdominal pain.
      We investigated 7 cases of gastro-duodenal lesions with GVHD colitis. Endoscopic
      features of gastric lesions with GVHD were turbidity(100%), erythema(100%),
      erosions(85.7%), easy bleeding of mucosa(71.4%) and duodenal involvement(71.4%),
      histological findings of those were infiltration of inflammatory cells(100%),
      dilatation of capillaries(100%), hemorrhage(71.4%), stromal edema(85.7%),
      degenerated glands and apoptotic bodies(100%). Those findings resembled with
      endoscopic and histological features of GVHD colitis, so we diagnosed those
      lesions as GVHD gastro-duodenitis. Clinically GVHD colitis with gastro-duodenitis
      was severe compared with colitis without gastro-duodenitis.

PMID- 15038101
TI  - [Peptic ulcer in children].
AB  - H. pylori infection is the main cause of peptic ulcer in children. Japan
      pediatric H. pylori research meeting made the guideline for diagnosis and
      eradication therapy for H. pylori. This guideline showed the methods for diagnose
      and the eradication therapy for children with H. pylori infection. Many pediatric
      patients have been free from some abdominal symptoms after eradication therapy
      for H. pylori. However we need endoscopy for diagnose in spite of children. And
      recently new non-invasive diagnostic devices are developed and some species
      acquired tolerance for clarithromycin. Therefore we hope that a new guideline for
      children will be written soon.

PMID- 15038102
TI  - [Functional analyses of gastric mucosa using mice deficient in both histamine H2
      receptor and CCKB/gastrin receptor].
AB  - Histamine H2 and cholecystokinin (CCK)-B/gastrin receptors are very important in
      both acid secretion and growth and differentiation of the gastric mucosa.
      Generations of mice deficient in each of these receptors have provided
      information on the structure and function of the gastric mucosa, respectively. To
      examine the gastric mucosa in further detail, we generated mice deficient in both
      receptors. This review discusses the roles of histamine H2 and CCK-B/gastrin
      receptors in gastric mucosa based on data from our double-null mice.

PMID- 15038103
TI  - [Effect of proton pump inhibitors (PPIs) on wound healing of gastric mucosal cell
      injury].
AB  - The pH-independent effect of PPI such as lansoprazole(LPZ) on cell restitution
      was shown in vitro. After wounding, addition of LPZ significantly promoted the
      cell restitution rate. While the addition of MEK inhibitor significantly
      attenuated the cell restitution rate in the LPZ groups, suggesting that mechanism
      of cell proliferation and migration promoted by LPZ might involve the activation
      of p44/p42 MAPK.

PMID- 15038104
TI  - [Are COX-2 inhibitors truly able to prevent NSAIDs-associated ulcer?].
AB  - Non-steroidal anti-inflammatory drugs(NSAIDs) have a potential to cause mucosal
      injury in the gastrointestinal tract. Inhibitions of cyclooxygenase, one of the
      targets of NSAIDs and direct cytotoxic effects of NSAIDs, are reported to be
      involved in NSAIDs-related mucosal damage. It is estimated that 15-30% of
      patients taking NSAIDs develop gastroduodenal ulcers, 2% of patients have life
      threatening complications. Normal gastroduodenal mucosa expresses only COX-1, and
      it is reported that NSAIDs are more strongly inhibiting COX-1 are more harmful to
      gastroduodenal mucosa. Therefore, selective COX-2 inhibitors have been developed
      as safer NSAIDs than non-selective NSAIDs. Recent reports have, however, shown
      that COX-2 is expressing in gastroduodenal ulcers and H. pylori infection,
      suggesting that COX-2 plays an important role in mucosal healing. In this
      article, we discuss whether COX-2 selective inhibitors are able to prevent NSAIDs
      associated ulceration.

PMID- 15038105
TI  - [The role of mucoprotective drugs in gastric ulcer treatment: with specifical
      reference to their effects on gastritis mucosa].
AB  - A study group supported by Ministry of Health, Labor and Welfare recently
      reported the Japanese guideline for gastric ulcer treatment which suggests that
      gastric ulcer can be cured by either H. pylori eradication or acid suppression
      therapy by proton pump inhibitors(PPI) and H2-receptor antagonists(H2RA). It also
      suggests that all mucoprotective drugs except sucrafate, misoprostol and
      enprostil can't be recommended for gastric ulcer treatment. However, some
      mucoprotective drugs have been shown to possess anti-inflammatory action, leading
      to the inhibition of leucocyte infiltration in H. pylori gastritis, while long
      term usage of PPI and H2RA might worsen gastritis. Thus, mucoprotective drugs
      should be investigated in terms of long-term effects on H. pylori-gastritis
      rather than the effects on gastric ulceration.

PMID- 15038106
TI  - [The trend of the research on H. pylori eradication and gastric cancer
      prevention].
AB  - The strongest evidence for the association between H. pylori infection and
      gastric cancer(GC) development in the current is provided by the prospective
      study that a large number of patients with H. pylori infection were followed with
      serial endoscopic examinations. Over time, GC was not diagnosed in negative
      patients. In contrast, the risk for GC was highly increased in positive patients.
      It was also revealed that in patients with early GC subjected to endoscopic
      mucosal resection but without eradication therapy, new GC was found in 13% as
      opposed to only 1% on GC relapse during 8 years in patients with eradication.
      These studies indicate that some positive patients should be eradicated to reduce
      the progression of ongoing gastric carcinogenesis.

PMID- 15038107
TI  - [Serum hemopexin: suppressive effect on neutrophil functions and prospect of
      clinical application to autoimmune diseases].
AB  - Hemopexin is a serum glycoprotein with a high binding affinity for heme, and is
      known as a scavenger/transporter of heme. Recent studies indicated that purified
      hemopexin suppresses neutrophil adhesion and phagocytosis by a mechanism
      unrelated to heme-binding, suggesting a novel activity of hemopexin. Unidentified
      serum factor in combination with Ca2+ dampens the effect of hemopexin. So,
      hemopexin in peripheral blood may not act as an inhibitor of neutrophil function.
      However, because hemopexin is synthesized in injured peripheral nerves, it may be
      hypothesized that hemopexin has an anti-inflammatory role in nerve repair by
      suppressing phagocyte accumulation/phagocytosis. Further studies of hemopexin may
      provide new therapeutic strategies aimed at suppressing neutrophil functions to
      control inflammation and tissue injury, especially in autoimmune diseases such as
      rheumatoid arthritis.

PMID- 15038108
TI  - [Environmental chemistry of organotin compounds].

PMID- 15038109
TI  - [Laboratory-performance study of the notified methods to detect genetically
      modified maize (CBH351) and potato (NewLeaf Plus and NewLeaf Y)].
AB  - To investigate the key factors affecting the reliability of the analytical
      results, a laboratory-performance study was attempted for the notified methods to
      detect genetically modified (GM) maize (CBH351) and GM potato (NewLeaf Plus and
      NewLeaf Y). The test samples were designed as three pairs of blind duplicates,
      which included 0%, 0.1% and 1.0% GM maize (CBH351) or GM potato (NewLeaf Plus or
      NewLeaf Y). Fourteen laboratories participated in the study. The test samples
      were sent to the participating laboratories along with the protocol. The data
      were collected from all laboratories and statistically analyzed. For the 0%
      sample of the CBH351 maize, one laboratory reported a false-positive result. It
      was considered that contamination could have occurred via the common use of
      equipment or tools for the test. For the 0.1% samples of the NewLeaf Plus potato
      or NewLeaf Y potato, on the other hand, three laboratories reported false
      negative results. It was presumed that these results were due to changes of the
      conditions of the electrophoresis and agarose-gel staining. The other
      laboratories reported appropriate results. It was considered that the method
      employed in this study was suitable for the assessment of laboratory performance.

PMID- 15038110
TI  - Evaluation of MPN method combined with PCR procedure for detection and
      enumeration of Vibrio parahaemolyticus in seafood.
AB  - Vibrio parahaemolyticus densities in spiked and naturally contaminated seafood
      samples were enumerated by the MPN method combined with a PCR procedure (MPN-PCR
      method) targeting the species-specific thermolabile hemolysin gene (tlh), and by
      the MPN method using subcultivation of alkaline-peptone-water (APW) enrichment
      culture on thiosulfate-citrate-bile-sucrose (TCBS) agar (MPN-TCBS method). In the
      samples spiked with both V. parahaemolyticus and V. alginolyticus, the numbers of
      V. parahaemolyticus enumerated by the MPN-PCR method were similar to, or higher
      than the numbers of spiked cells, whereas those enumerated by the MPN-TCBS method
      were below the numbers of spiked cells. In naturally contaminated seafood
      samples, the numbers of V. parahaemolyticus enumerated by the MPN-PCR method were
      higher than those by the MPN-TCBS method. In the case of the MPN-TCBS method,
      isolation of V. parahaemolyticus from some APW cultures was difficult because of
      the overgrowth of many colonies other than V. parahaemolyticus (e.g., V.
      alginolyticus) on TCBS agar. In contrast, the PCR technique could detect tlh from
      APW culture without isolation of V. parahaemolyticus, so the possibility of
      failing to obtain a positive result in APW culture by the MPN-PCR method was
      considered to be lower than that by the MPN-TCBS method. Furthermore, utilization
      of the PCR technique reduces the time and labor required for the biochemical
      identification tests used in the MPN-TCBS method. For the detection and
      enumeration of V. parahaemolyticus in seafood, especially for samples that show
      many colonies other than V. parahaemolyticus on TCBS agar, the MPN-PCR method may
      be more convenient and reliable than the MPN-TCBS method.

PMID- 15038111
TI  - Levels and congener distributions of PCDDs, PCDFs and Co-PCBs in Japanese retail
      fresh and frozen vegetables.
AB  - To evaluate dioxin contamination in retail vegetables, congener analyses of
      polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs)
      and coplanar polychlorinated biphenyls (Co-PCBs) were performed on sixty
      varieties of fresh vegetables including cereals and mushrooms, obtained from
      Japanese supermarkets in 2002. The toxic equivalent quantity (TEQ) levels for
      dioxins in samples ranged from < 0.001 to 0.089 pg-TEQ/g wet weight, when
      undetected and trace were taken as zero. Among the samples, dioxins were
      generally detected in green leafy vegetables. The highest TEQ value was for
      mulukhiya (0.089 pg-TEQ/g), followed by spinach and komatsuna (Japanese mustard
      spinach) (0.077 and 0.074 pg-TEQ/g, respectively). Additionally, the dioxin
      levels in seventeen varieties of frozen vegetables were also determined, and
      showed TEQ values ranging from < 0.001 to 0.080 pg-TEQ/g. The total TEQ in
      commercial vegetables mainly reflected the levels of 1,2,3,7,8-PeCDD, 2,3,4,7,8
      PeCDF and 3,3',4,4',5-PeCB (#126) (the sum of them represented 63% of the total
      TEQ).

PMID- 15038112
TI  - [Determination of acrylamide in processed foods by column-switching HPLC with UV
      detection].
AB  - A simple and convenient analytical method for the determination of acrylamide in
      processed foods was established. Acrylamide was extracted with water in an
      ultrasonic bath. The extract was passed through an OASIS HLB cartridge and the
      eluate was injected into the HPLC system using a column-switching technique. The
      HPLC system consisted of two pumps, two 6-port-2-position valves, two columns and
      a UV detector. At first, the sample solution was chromatographed on an ODS column
      with a mobile phase of water, then the flow of the mobile phase was switched
      using a 6-port-2-position valve, and the acrylamide peak fraction was introduced
      into an aqueous gel permeation column (analytical column). The fraction was
      chromatographed again on the analytical column with a mobile phase of water, and
      the eluate was monitored with a UV detector (205 nm). The recoveries of
      acrylamide from potato chips, fried potato, croquette and instant noodle
      fortified at levels of 50 to 1,000 micrograms/kg were 93.1 to 101.5% and the
      coefficient of variation was 1.5 to 5.2%. The detection limit corresponded to 10
      micrograms/kg in processed foods. Forty-six samples, potato chips (11), fried
      potato (10), croquette (20) and instant noodle (5), were analyzed by this method.
      The acrylamide level was 67-4,499 micrograms/kg for potato chips, 125-1,183
      micrograms/kg for fried potato, nd-255 micrograms/kg for croquette and nd-151
      micrograms/kg for instant noodle.

PMID- 15038113
TI  - [Determination of low-level pesticide residues in agricultural products by ion
      trap GC/MS/MS].
AB  - The objective of this study was to elucidate the utility of ion-trap GC/MS/MS for
      the analysis of pesticides in extracted matrices from various agricultural
      products. Identification and quantitative analysis of pesticides in matrices were
      performed by quadrupole GC/MS and ion-trap GC/MS/MS. Chlorpyrifos was added to
      the matrix of spinach, soybean in the pod or corn, and aldrin, dieldrin, endrin,
      alpha-BHC, beta-BHC, gamma-BHC, delta-BHC, p,p'-DDD, p,p'-DDE, o,p'-DDT and p,p'
      DDT were added to each matrix of green tea, black tea or oolong tea. Although
      most of the pesticides in the matrix could not be determined by quadrupole GC/MS
      Scan analysis at 0.1 microgram/mL, every pesticide was identified from the mass
      spectrum using ion-trap GC/MS/MS at the same concentration. The quantitation
      limit of every pesticide in each matrix by ion-trap GC/MS/MS analysis was higher
      than that by GC/MS-SIM analysis. The calibration curves obtained by GC/MS/MS were
      linear in the range of 0.01-0.25 microgram/mL of each pesticide. The recoveries
      of each pesticide from four kinds of samples spiked at the levels of 0.01 ppm to
      0.02 ppm in extracts were 61.2-138.3% with SD values in the range from 1.2 to
      15.4%. This study revealed that ion-trap GC/MS/MS was useful for the
      identification and quantitative analysis of low-level pesticides residues in
      matrices of agricultural products.

PMID- 15038114
TI  - Contamination levels and congener distributions of PCDDs, PCDFs and Co-PCBs in
      several fast foods in Japan.
AB  - We determined the concentrations of polychlorinated dibenzo-p-dioxins (PCDDs),
      dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (Co-PCBs) in three
      types of fast foods [(1) seventeen hamburgers and two hot dogs, (2) six portions
      of fried potatoes and (3) three chicken products] obtained from fast food shops
      or convenience stores in Japan. All samples tested showed low toxic equivalent
      quantity (TEQ) levels of dioxins in the range of 0.001-0.083 pg-TEQ/g wet weight
      (0.006-0.053 pg-TEQ/g for hamburgers and hot dogs, 0.001-0.083 pg-TEQ/g for fried
      potatoes and 0.053-0.065 pg-TEQ/g for chicken products). The congener profile in
      hamburgers and hot dogs suggested that the total TEQ was mainly determined by Co
      PCBs, especially by 3,3',4,4',5-PeCB (#126), which accounted for 44% of the total
      TEQ value. Findings for animal foods such as beef and cheese were consistent with
      this result. For fried potatoes, PCDD/Fs accounted for 94% of the total TEQ
      value, and 2,3,4,7,8-PeCDF accounted for 32% of PCDD/Fs. Dioxins in the chicken
      products consisted of 3,3',4,4',5-PeCB (#126) and 1,2,3,7,8-PeCDD, which
      accounted for 23% and 21% of the total TEQ, respectively. If an adult (50 kg
      weight) eats 150 g of hamburger, 100 g of potatoes and 150 g of chicken, the
      daily intake is estimated to be 0.299 pg-TEQ/kg b.w./day using the average values
      (0.022, 0.028 and 0.059 pg-TEQ/g, respectively) obtained in this study. This
      value corresponds to 7.5% of the tolerable daily intake (TDI) for PCDD/Fs and Co
      PCBs in Japan.

PMID- 15038115
TI  - Modification of cleanup methods for dioxin analysis in green leafy vegetables and
      comparison of packing methods for a multi-layer silica gel column.
AB  - To determine polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated
      dibenzofurans (PCDFs) and coplanar polychlorinated biphenyls (Co-PCBs) in green
      leafy vegetables, the cleanup method was modified, and packing methods for a
      multi-layer silica gel column were compared in food samples. First, the
      additional cleanup was examined for a mono-ortho PCBs fraction obtained by
      alumina column chromatography from spinach extract. Small solids such as rough
      crystals that remained after concentration of the mono-ortho PCBs fraction were
      identified as long-chain hydrocarbons from leaf epicuticular wax by GC/MS.
      Cleanup using an activated carbon silica gel column with n-hexane as the washing
      solvent was effective. Next, multi-layer silica gel columns packed by wet packing
      and dry packing were compared using komatsuna, salmon and butter as samples. The
      columns prepared by both methods gave similar values at each isomeric
      concentration level and showed similar efficiency with favorable recoveries.

PMID- 15038116
TI  - [Analysis of constituents in Jamaica quassia extract, a natural bittering agent].
AB  - Jamaica quassia extract, a natural bittering agent, is described as "a substance
      extracted from bark of Jamaica quassia (Quassia excelsa Sw.)" in the List of
      Existing Food Additives in Japan. The constituents in Jamaica quassia extract
      product were investigated as a part of an ongoing study to evaluate its quality
      and safety as a food additive. The main constituents of the extract were
      identified as quassin and two isomers of neoquassin by using LC/MS. The main
      constituent, quassin, was isolated and the structure was determined by spectral
      means. The quantification of their main constituents was performed by HPLC using
      quassin as a standard, and the concentrations of quassin and total of neoquassin
      isomers were 21.4% and 55.5%. In addition, it was confirmed that Jamaica quassia
      extract was different from quassia extract, which is extracted from bark of
      Picrasma quassioides Benn. belonging to the same family as Q. excelsa, by
      comparing their HPLC profiles.

PMID- 15038118
TI  - [Current situation of safety evaluation for mycotoxins].

PMID- 15038119
TI  - [Conditions and treatment of anemia--recent progress].

PMID- 15038117
TI  - [Studies on the analytical method for epichlorohydrin from internal can
      coatings].
AB  - An improved migration test was developed for determination of trace amounts of
      epichlorohydrin from internal can coatings. Eight kinds of sample cans, coated
      mainly with epoxy resin, for foods and beverages were prepared, and both their
      bodies and lids were tested for migration as follows. A body was filled with n
      pentane and soaked for 2 hours at 25 degrees C. A lid was soaked in n-pentane (2
      mL/cm2) for 2 hours at 25 degrees C. The test solution was analyzed by GC-FID and
      GC/MS using two DB-WAX capillary columns with different inside diameters. The
      limits of quantitation were 0.05 microgram/mL by GC-FID and 0.02 microgram/mL by
      GC/MS with selected ion monitoring. Recoveries of spiked epichlorohydrin were
      99.9-104.5% at the level of 0.05 microgram/mL and 0.5 microgram/mL, with high
      precision. In this study, no epichlorohydrin was found to have migrated from any
      of the bodies and lids.

PMID- 15038120
TI  - [Disease condition and treatment of chronic heart failure].

PMID- 15038121
TI  - [Disease condition and the mechanism of the development of type 2 diabetes
      mellitus].

PMID- 15038122
TI  - [Molecular mechanism of hematopoiesis and its clinical presentation].

PMID- 15038123
TI  - [Diffuse panbronchiolitis and new actions of macrolides].

PMID- 15038124
TI  - [From autoimmune hepatitis to immunotherapy of cancer].

PMID- 15038125
TI  - Is the big conversation just a tall tale?

PMID- 15038127
TI  - Expanding respiratory care.

PMID- 15038126
TI  - Should patients choose the sex of their nurses?

PMID- 15038128
TI  - Using teamwork to save lives.

PMID- 15038129
TI  - Making an impact on return to practice.

PMID- 15038130
TI  - 'It's a dedicated service of real benefit to patients'.

PMID- 15038131
TI  - The route back into nursing.

PMID- 15038132
TI  - A guide to your new NHS.

PMID- 15038133
TI  - Balancing life and work.

PMID- 15038134
TI  - Coordination is the key.

PMID- 15038135
TI  - Support systems for returners.

PMID- 15038136
TI  - Time for a change of agenda.

PMID- 15038137
TI  - Measles, mumps and rubella--safety of the combined vaccine.
AB  - Despite the fact that scientific evidence shows no support for a link between the
      combined measles, mumps and rubella vaccine (MMR) and autism or bowel problems,
      many parents remain worried. This article discusses the reasons for the
      introduction of MMR and outlines the debate about its safety and the problems
      associated with using single vaccines.

PMID- 15038139
TI  - Understanding the barriers to multiprofessional collaboration.
AB  - Multiprofessional collaboration is key to delivering quality patient care. Many
      developments in health care such as supplementary prescribing or the single
      assessment process rely on the premise that such collaboration already exists.
      This article focuses on barriers to interprofessional collaboration and explores
      whether 'new ways of working' in health care can survive in an environment with a
      long history of independent disciplines.

PMID- 15038138
TI  - What you need to know about ... bipolar disorder.

PMID- 15038140
TI  - Improving policy and practice in the prevention of pressure ulcers.
AB  - This article reports on a project to update policy and practice in pressure-ulcer
      prevention in a district general hospital. A literature review was undertaken on
      pressure-ulcer prevention to identify the best methods for use in a district
      general hospital and to bring practice in line with current evidence. The
      literature review covered evidence-based tools for risk assessment, treatment
      protocols, policy, and patient information. An analysis of the training and
      educational needs of staff within the trust was also undertaken.

PMID- 15038141
TI  - Inflammatory bowel disease.
AB  - Inflammatory bowel disease (IBD) is a term used to describe ulcerative colitis
      and Crohn's disease. Both are chronic, lifelong conditions characterised by
      periods of exacerbation and remission. The management of IBD is complex for the
      health care team. Following an exploration of the physical, psychological and
      sociological impact of the condition, the medications used to control the
      symptoms are described, together with consideration of the surgical options used
      in the management of IBD. Finally, the role of the nurse in meeting holistically
      the needs of patients with IBD is highlighted.

PMID- 15038142
TI  - Nursing babies in the first weeks of life.

PMID- 15038143
TI  - The production of understanding.
AB  - While there is little doubt that sociological theory and research has had an
      important impact on the way people think about health and health care, mental
      health and medical sociologists are often confronted with challenges concerning
      the utility of the work that they do. Among the doubters are deans, funding
      agencies and family members. We are challenged by the ascendency of biological
      interpretations of human behaviors, by the incompatibility between the contextual
      view we prefer and the very strong individualistic orientation of our culture,
      and by the fact that we do not have an applied arm that trains the professionals
      who treat health and mental-health conditions. How do we respond to this
      challenge? The title of this paper gives a short answer: "The Production of
      Understanding." I propose that a powerful but under-recognized value of our work
      is the generation of explanations about health and mental health matters that
      help people understand the other side of an "us"/"them" divide. We produce
      understanding in a context in which misunderstanding is regularly constructed by
      powerful people who offer victim-blaming explanations for the circumstances
      experienced by people with less power. The production of understanding serves as
      an important counterbalance to this tendency. Our work shapes the way people
      think about problems related to health and mental health, limits the power of
      inaccurate victim-blaming accounts and provides understanding about why health
      and mental health are mal-distributed among people from different social
      circumstances.

PMID- 15038144
TI  - Has the future of marriage arrived? A contemporary examination of gender,
      marriage, and psychological well-being.
AB  - A long tradition of research and theory on gender, marriage, and mental health
      suggests that marital status is more important to men's psychological well-being
      than women's while marital quality is more important to women's well-being than
      men's. These beliefs rest largely on a theoretical and empirical foundation
      established in the 1970s, but, despite changes in gender and family roles, they
      have rarely been questioned. The present analysis of three waves of a nationally
      representative survey indicates that, with few exceptions, the effects of marital
      status, marital transitions, and marital quality on psychological well-being are
      similar for men and women. Further, for men and women, occupying an unsatisfying
      marriage undermines psychological well-being to a similar extent--and, in some
      cases, to a greater extent--than exiting marriage or being continually unmarried.

PMID- 15038145
TI  - Status variations in stress exposure: implications for the interpretation of
      research on race, socioeconomic status, and gender.
AB  - Life events checklists have been the predominant method for estimating variations
      in stress exposure. It is unknown, however, whether such inventories are equally
      meaningful for estimating differences in exposure between men and women, African
      Americans and whites, and those in lower and higher socioeconomic categories. In
      this paper, we employ a wider range of measures of stress--recent life events,
      chronic stressors, lifetime major events, and discrimination stress--to examine
      the extent to which these dimensions collectively yield conclusions about status
      variations in stress exposure that are similar to or different from estimates
      based only on a life events checklist. Our analyses of data collected from 899
      young men and women of African American and non-Hispanic white ancestry suggest
      that status differences in exposure to stress vary considerably by the measure of
      stress that is employed. Although women are more exposed to recent life events
      than men, males report more major events and discrimination stress than females.
      Our results also reveal that life event measures tend to substantially under
      estimate differences between African Americans and non-Hispanic whites in
      exposure to stress. A similar pattern also holds for socioeconomic status. When
      stress is more comprehensively estimated, level of exposure profoundly affects
      ethnic differences in depressive symptomatology, accounting for almost half of
      the difference by socioeconomic status but contributing little to the explanation
      of the gender difference in distress. The implications of these findings for the
      debate over the relative mental health significance of exposure and vulnerability
      to stress are discussed.

PMID- 15038146
TI  - Misgivings of medicine?: African Americans' skepticism of psychiatric medication.
AB  - Research has consistently documented black-white differences in rates of
      voluntary psychiatric treatment that cannot be reduced entirely to differences in
      either need or access. A variety of explanations have been offered for the gap
      that remains, but the empirical testing of alternative propositions has thus far
      been minimal. Using the 1998 General Social Survey's Pressing Issues in Health
      and Medical Care module (n = 1,387), I find consistent and substantial black
      white differences in a variety of beliefs about psychiatric medications, one of
      the most common treatments for mental illness, and the predisposition to use
      them. Specifically, blacks express less willingness to use psychiatric
      medications themselves or to administer them to a child for whom they are
      responsible. Neither socioeconomic status, knowledge, religious involvement, nor
      trust in medicine appears to explain this reluctance. Rather, it stems almost
      entirely from blacks' beliefs about psychiatric medications' efficacy and side
      effects. The results indicate, first, that researchers should not assume that
      African Americans will use psychiatric medications at rates similar to whites if
      offered equal access. Second, the results indicate that blacks' skepticism of
      psychiatric medications may be rooted in specific beliefs about psychiatric
      medications, rather than general ideologies about medical practice. Health
      beliefs about psychiatric treatment, therefore, will continue to play an
      important role in understanding race differences in the use of psychiatric
      medications.

PMID- 15038147
TI  - Social context and adolescent health behavior: does school-level smoking
      prevalence affect students' subsequent smoking behavior?
AB  - This paper examines the links between individual adolescent smoking behavior and
      actual and perceived smoking behavior in the individual's school cohort. We
      hypothesized that students enrolled in schools with higher smoking prevalence
      among students in their grade are more likely to smoke subsequently. We also
      expected perceived school-level prevalence of smoking to have a greater impact
      than actual prevalence because the former is a more direct measure of perceived
      norms. Adjusting for demographics, actual school-level prevalence at baseline
      (grade 7) was strongly associated with smoking frequency one year later. However,
      the association disappeared after adjusting for individual smoking frequency at
      baseline. School-level prevalence did not moderate the association between
      individual's baseline and subsequent smoking frequency. Perceived prevalence of
      smoking among grade 8 students and two measures tapping the behavior of smaller
      peer groups--cigarette offers and exposure to friends and other peers who smoke-
      were associated with increased risk of smoking.

PMID- 15038148
TI  - Financial strain and health among elderly Mexican-origin individuals.
AB  - In this paper we examine the associations among perceived financial strain and
      various health measures--including self-rated health, self-reported functional
      capacity, performance-based mobility, and mortality--in a sample of older Mexican
      origin individuals. We employ the Hispanic Established Population for
      Epidemiological Studies of the Elderly, an eight-year longitudinal survey of over
      3,000 Mexican-origin individuals in five southwestern states who were initially
      interviewed in 1993 and 1994. Although financial strain is associated with actual
      income and poverty, it is also associated with cognitive capacity, depression,
      and self-esteem, and while it is strongly associated with subjective measures, it
      has a weaker association with more objective measures, such as performance-based
      mobility and mortality. Financial strain appears to be part of a package of
      cognitions and emotions indicative of low morale or demoralization that has
      adverse effects on subjective health.

PMID- 15038149
TI  - Moving beyond poverty: neighborhood structure, social processes, and health.
AB  - We investigate the impact of neighborhood structural characteristics, social
      organization, and culture on self-rated health in a large, cross-sectional sample
      of urban adults. Findings indicate that neighborhood affluence is a more powerful
      predictor of health status than poverty, above and beyond individual demographic
      background, socioeconomic status, health behaviors, and insurance coverage.
      Moreover, neighborhood affluence and residential stability interact in their
      association with health. When the prevalence of affluence is low, residential
      stability is negatively associated with health. Neighborhood affluence also
      accounts for a substantial proportion of the racial gap in health status.
      Finally, collective efficacy is a significant positive predictor of health but
      does not mediate the effects of structural factors.

PMID- 15038150
TI  - Microtiter plate assay of yeast cell number using the fluorescent dye calcofluor
      white M2R.

PMID- 15038151
TI  - Human aldehyde reductase promoter allows simultaneous expression of two genes in
      opposite directions.

PMID- 15038153
TI  - Versatile PCR-mediated insertion or deletion mutagenesis.

PMID- 15038152
TI  - Dual regulation of gene expression mediated by tetracycline and Cre recombinase.

PMID- 15038154
TI  - Generation of large deletion mutants from plasmid DNA.

PMID- 15038155
TI  - Rapid screening of microsatellite markers for polymorphisms using SYBR green I
      and a DNA sequencer.

PMID- 15038156
TI  - High-throughput beta-galactosidase assay for bacterial cell-based reporter
      systems.

PMID- 15038157
TI  - Generation of optimized yellow and red fluorescent proteins with distinct
      subcellular localization.
AB  - Fluorescent proteins (FPs) have revolutionized many aspects of cell biology and
      have become indispensable research tools. Today's increasingly complex
      experiments aiming to understand biological systems strongly depend on the
      availability of combinations of multiple FPs, which allow their distinguishable
      simultaneous detection in the same cell or tissue. Recently, the VENUS and DsRed.
      T4 FPs were described as the latest generation of yellow and red FPs. To increase
      the combinatorial possibilities when using these optimized FPs, we have generated
      and successfully tested seven new forms of VENUS and DsRed. T4 proteins with
      distinct subcellular localization. To facilitate their use as markers in
      biological experiments, bicistronic expression constructs, which have been
      optimized for robust expression in almost all mammalian developmental stages and
      cell types, were produced for the new FPs. In addition, several plasmids were
      created, which contain all necessary elements for inserting the reading frames of
      these FPs into specific gene loci in knock-in experiments without disrupting the
      reading frame of the endogenous gene.

PMID- 15038158
TI  - Annealing control primer system for identification of differentially expressed
      genes on agarose gels.
AB  - We developed GeneFishing technology, an improved method for the identification of
      differentially expressed genes (DEGs) using our novel annealing control primer
      (ACP) system. Because of high annealing specificity during PCR using the ACP
      system, the application of the ACP to DEG discovery generates reproducible,
      authentic, and long (100 bp to 2 kb) PCR products that are detectable on agarose
      gels. To demonstrate this method for gene expression profiling, Gene-Fishing
      technology was used to detect genes that are differentially expressed during
      development using total RNAs isolated from mouse conceptus tissues at 4.5-18.5
      days of gestation. Ten DEGs (DEG1-10) were isolated and confirmed by Northern
      blot hybridization. The sequence analysis of these DEGs showed that DEG6 and
      DEG10 are unknown genes.

PMID- 15038159
TI  - New Drosophila transgenic reporters: insulated P-element vectors expressing fast
      maturing RFP.
AB  - In vivo green fluorescent protein (GFP)/red fluorescent protein (RFP) double
      labeling studies have been hampered by several inconvenient properties of DsRed,
      the first described RFP. These disadvantages include a very slow (> 24 h)
      maturation time, emission of contaminating green light, and low solubility. A
      recently developed variant of DsRed, called DsRed.T4, has a much shorter
      maturation time, no significant green emission, and improved solubility. We have
      constructed Drosophila P-element transformation vectors encoding DsRed.T4 for
      promoter/enhancer analysis, labeling of living cells, or RFP tagging of proteins.
      These new vectors have all of the features of the widely used Pelican/Stinger GFP
      vectors, including insulator sequences to reduce position effects, an extensive
      polylinker, and both cytoplasmic and nuclear-localized forms of the reporter. We
      have also constructed an upstream activating sequence (UAS)-DsRed.T4 vector, for
      GAL4 activation of the reporter. We find that DsRed.T4 is very easily detected in
      transgenic flies without contamination of the GFP signal and that it matures to
      its fluorescent form nearly simultaneously with GFP. This advance in Drosophila
      reporter technology makes timed double-labeling experiments in developing
      transgenic animals possible for the first time.

PMID- 15038160
TI  - Silencing of antiapoptotic survivin gene by multiple approaches of RNA
      interference technology.
AB  - Silencing of mammalian gene expression by RNA interference (RNAi) technology can
      be achieved using small interfering RNA (siRNA) or short hairpin RNA (shRNA).
      However, the relative effectiveness of these two approaches is not known. It is
      also not clear whether gene-specific shRNA transcribed from an RNA polymerase II
      (Pol II)-directed promoter in a fusion form can disrupt the targeted gene
      expression. Here, we report that using both luciferase and antiapoptotic survivin
      genes as targets, both siRNA and shRNA approaches significantly silenced the
      targeted gene expression in cancer cells. We further demonstrated that shRNAs
      transcribed from an RNA Pol II-mediated promoter in a green fluorescent protein
      (GFP) fusion form at the 3'-untranslated region silenced luciferase and survivin
      expression as well, suggesting that the extra RNA sequence outside of the shRNA
      hairpin does not disrupt shRNA function. We also showed that silencing of
      survivin expression selectively induces apoptosis in transfected cells. Together,
      we have validated multiple approaches of RNAi technology using both survivin and
      luciferase genes as targets and demonstrated for the first time that GFP-shRNAs
      transcribed from an RNA Pol II-mediated promoter could mediate gene silencing,
      which may lead to new directions for the application of RNAi technology.

PMID- 15038161
TI  - Development of a microarray assay that measures hybridization stoichiometry in
      moles.
AB  - Microarray data is most useful when it can be compared with other genetic
      detection technologies. In this report, we designed a microarray assay format
      that transforms raw data into a defined scientific unit (i.e., moles) by
      measuring the amount of array feature present and the cDNA sequence hybridized.
      This study profiles a mouse reference universal RNA sample on a microarray
      consisting of PCR products. In measuring array features, a labeled DNA sequence
      was designed that hybridizes to a conserved sequence that is present in every
      array feature. To measure the amount of cDNA sample hybridized, the RNA sample
      was processed to ensure consistent dye to DNA ratio for every labeled target cDNA
      molecule, using labeled branched dendrimers rather than by incorporation. A dye
      printing assay was then performed in order to correlate molecules of cyanine dye
      to signal intensity. We demonstrate that by using this microarray assay design,
      raw data can be transformed into defined scientific units, which will facilitate
      interpretation of other experiments, such as data deposited at the Gene
      Expression Omnibus and ArrayExpress.

PMID- 15038162
TI  - Enhanced detection of RNA from paraffin-embedded tissue using a panel of
      truncated gene-specific primers for reverse transcription.

PMID- 15038163
TI  - Removal of template DNA from cRNA preparations by combined oligo (dT) affinity
      chromatography and DNase I digestion.

PMID- 15038164
TI  - Noninvasive method for obtaining RNA from buccal mucosa epithelial cells for gene
      expression profiling.

PMID- 15038165
TI  - Dual-function stem molecular beacons to assess mRNA expression in AT-rich
      transcripts of Plasmodium falciparum.
AB  - The genome of the human malaria parasite Plasmodium falciparum is extremely AT
      rich such that it is particularly difficult to design standard probes to identify
      and quantify specific transcripts. Biased AT genome contents (70%-80%) lead to a
      high proportion of short repetitions and a low free energy of binding between
      target sequences and their specific probes during hybridization. This causes
      nonspecific annealing and high background noise. We constructed molecular beacon
      probes with dual-function stems to avoid nonspecific detection and establish
      identical melting patterns for use with several fluorescent probes for the
      analysis of mRNA expression in P. falciparum in real-time reverse transcription
      PCR (RT-PCR) assays. The method proved highly efficient at detecting low
      transcript levels in P. falciparum microcultures. Conditions were established for
      two types of real-time instruments, demonstrating that molecular beacons with
      dual-function stems are a useful tool for the functional analysis of high AT
      genomes. The procedure could be adapted to high-throughput gene expression
      protocols for the biomolecular screening of the P. falciparum and other AT-rich
      genomes.

PMID- 15038166
TI  - Amplification protocols introduce systematic but reproducible errors into gene
      expression studies.
AB  - The desire to perform microarray experiments with small starting amounts of RNA
      has led to the development of a variety of protocols for preparing and amplifying
      mRNA. This has consequences not only for the standardization of experimental
      design, but also for reproducibility and comparability between experiments. Here
      we investigate the differences between the Affymetrix standard and small sample
      protocols and address the data analysis issues that arise when comparing samples
      and experiments that have been processed in different ways. We show that data
      generated on the same platform using different protocols are not directly
      comparable. Further, protocols introduce systematic biases that can be largely
      accounted for by using the correct data analysis techniques.

PMID- 15038167
TI  - One-step real-time duplex reverse transcription PCRs simultaneously quantify
      analyte and housekeeping gene mRNAs.
AB  - We developed a one-step real-time duplex reverse transcription PCR (RT-PCR)
      method using the LightCycler platform. This method allows simultaneous reverse
      transcription and real-time PCR amplification of two mRNAs of specific genes of
      interest (analyte genes) and mRNA of constantly transcribed genes (housekeeping
      genes) in a single-tube reaction. Specimen total nucleic acids were used because
      eukaryotic cDNA is discriminated from genomic DNA using exon-spanning primers
      and/or fluorescence resonance energy transfer (FRET) probes. Transcripts of
      murine arginase I and hypoxanthine-phosphoribosyl transferase (HPRT; housekeeping
      gene) or murine arginase II analyte and porphobilinogen deaminase (PBGD;
      housekeeping gene) were quantified in such duplex RT-PCRs. Twenty-minute reverse
      transcription reactions at 55 degrees C followed by 18 high-stringency step-down
      thermal cycles and 25 relaxed-stringency fluorescence acquisition cycles produced
      sensitive and accurate RT-PCR results. Fluorescent signal spillover between
      channels was fully compensated. A matrix of duplex PCRs at variable ratios of
      target standards yielded equations for factors that correct PCR-specific target
      ratio-dependent deviations in quantification. The one-step real-time duplex RT
      PCRs reliably and accurately determined 10-10,000 copies of each target over a
      100,000-fold range of target copy ratios (analyte to housekeeping mRNA = 10(-2.5)
      10(2.5)) in a single assay.

PMID- 15038168
TI  - Immune systems biology: immunoprofiling of cells and molecules.
AB  - White blood cells and their secreted products are key elements of immune systems
      biology that are important indicators of patient health and disease. We have
      developed the SurroScan microvolume laser scanning cytometer to immunoprofile
      hundreds of variables, including cell populations, cell surface antigens, and
      intracellular molecules in antibody-based assays on small samples (about 1 mL) of
      whole blood, processed blood, or other fluids without cell purification or
      washing steps. The system enables high-throughput, robust and automated data
      capture and analysis. We demonstrate the utility of this immunoprofiling
      technology platform by surveying patient samples before and after
      glucocorticosteroid administration and show both the expected and novel response
      characteristics. This system complements recent advances in genomic and proteomic
      approaches to disease prediction and monitoring.

PMID- 15038169
TI  - Is Tony Blair listening?

PMID- 15038170
TI  - MP's sign up to campaign.

PMID- 15038171
TI  - Throwing a lifeline.

PMID- 15038172
TI  - A solution to PCT pressure.

PMID- 15038173
TI  - You can learn to change.

PMID- 15038174
TI  - Working to get pay right.

PMID- 15038175
TI  - Pain management in day-case surgery.
AB  - BACKGROUND: Effective pain management following day surgery is a challenging
      issue. For the majority of patients severe pain is uncommon. However, a number of
      patients experience considerable pain following discharge. Uncontrolled pain is
      one of the main causes of re-admission to an inpatient bed following day surgery
      and a leading cause of patient dissatisfaction with it. CONCLUSION: This article
      reviews the literature and there is a discussion of the issues concerning
      effective pain management in day surgery. The drugs commonly used in day surgery
      practice are outlined to demonstrate the constraints that day surgery practices
      can impose on effective pain management. Day surgery is continually expanding and
      hip replacement and cholecystectomy are now being undertaken in day surgery
      facilities (Amarnath et al 2002, Berger 2003). The role of the nurse in effective
      pain management is therefore crucial amid such innovative developments as, even
      when explicitly instructed, the majority of patients still experience some post
      operative pain.

PMID- 15038176
TI  - Using the ventrologluteal site for intramuscular injection.
AB  - The administration of intramuscular injections is a common nursing intervention
      in clinical practice. This article aims to raise awareness of the use of the
      ventrogluteal site for administering intramuscular injections. It describes the
      main reasons for using this site and outlines the complications associated with
      the dorsogluteal site. It is hoped that this review of the literature will shift
      everyday practice in favour of the ventrogluteal site.

PMID- 15038179
TI  - Leadership pearls for NPs.

PMID- 15038177
TI  - Asylum seekers: a health professional perspective.
AB  - The authors examine the situation of asylum seekers and refugees in the UK to
      enable health professionals to provide access to health care, effective
      communication and appropriate assessment and referral for this group.

PMID- 15038181
TI  - Providing testimony.

PMID- 15038180
TI  - Shortness of breath with nonproductive cough and fatigue.

PMID- 15038182
TI  - Overactive bladder. Strategies for better recognition and management.

PMID- 15038183
TI  - Pharmacologic treatment of pediatric asthma. Consider disease severity as well as
      delivery method.

PMID- 15038184
TI  - Broccoli and pixie stix. Profile of a pediatric asthma program.

PMID- 15038185
TI  - Update on COPD. Today's strategies improve quality of life.

PMID- 15038186
TI  - A breath of fresh air. Tired of smoky restaurants and bars, more communities go
      smoke-free.

PMID- 15038187
TI  - Kicking butt. A review of smoking cessation strategies.

PMID- 15038188
TI  - Trivial pursuits? The health implications of snoring.

PMID- 15038189
TI  - Advance directives. Vital to quality care for elderly patients.

PMID- 15038190
TI  - Patient information. The best illness prevention: hand washing.

PMID- 15038191
TI  - Preventing restenosis in CAD patients. Folate therapy reduces homocysteine--and
      risk.

PMID- 15038192
TI  - Recognition of sleep problems in primary care. Crucial to patient health and
      safety.

PMID- 15038193
TI  - Identification of Marfan syndrome in primary care. Prompt referral can reduce
      morbidity and mortality.

PMID- 15038194
TI  - The miracle in the cabinet. A look at the future of aspirin.

PMID- 15038195
TI  - Making sense of syncope. Evaluation in primary care settings.

PMID- 15038196
TI  - Karon's Law.

PMID- 15038197
TI  - [The mammary duct fistula: a persistent problem that can be treated adequately].
AB  - Three female patients, 39, 39 and 46 years old, had recurrent, non-puerperal,
      subareolar abscesses caused by obstructed and dilated lactiferous ducts and
      resulting in paramamillary fistulas. Further recurrence was stopped by surgery.
      Based on the pathogenesis, surgery is the recommended treatment for this chronic
      ailment, i.e. fistulectomy using a radial incision through the centre of the
      nipple and excising the pathological nipple-areolar complex. Only the nipple is
      reconstructed, leaving the remainder of the wound open for healing by secondary
      intention and thus preventing recurrence.

PMID- 15038198
TI  - [Transcranial magnetic stimulation: a fascinating development].
AB  - Transcranial magnetic stimulation is a novel technique for safely stimulating or
      inhibiting cortical brain functions. Its possible role in neurology and
      psychiatry is the subject of a broad field of research. At present, standard
      clinical implementation is not yet warranted. On the other hand, the technique as
      such is quite promising, especially because it can pave the way to a 'bottom-up'
      approach to mental disorder, starting from basic psychobiological concepts and
      then gradually developing in the direction of more complex clinical applications.

PMID- 15038199
TI  - [Repetitive transcranial magnetic stimulation in depression; stimulation of the
      brain in order to cure the psyche].
AB  - Transcranial magnetic stimulation (TMS) is a non-invasive approach to briefly
      stimulate or inhibit cortical brain areas. A novel approach entails the delivery
      of repetitive TMS pulses (rTMS) at a fixed frequency. In rTMS cortical activity
      is altered beyond the period of actual stimulation. The changes occur locally as
      well as at a distance in functionally connected brain areas. These features
      render rTMS a suitable tool to study normal brain functions and the
      pathophysiology of brain diseases. Furthermore, it is expected that rTMS could be
      used as a novel therapy for neurological or psychiatric diseases characterised by
      abnormal cortical activation. This possibility has been studied mostly in
      patients suffering from depression, where rTMS has been used to restore normal
      activity in the hypoactive prefrontal cortex. Despite statistically significant
      therapeutic effects in small sized trials, the clinical implications are still
      limited.

PMID- 15038200
TI  - [Cutaneous reactions to drugs].
AB  - Exact data concerning the incidence of cutaneous drug eruptions are lacking due
      to underreporting. Diagnostics of cutaneous drug eruptions is hampered by the
      fact that one drug may induce different eruptions while the same cutaneous
      eruption can be caused by several drugs. Important steps in the diagnostics of
      cutaneous drug eruptions are: suspicion of the drugs as cause of the eruption,
      precise history-taking with emphasis on medication use and a complete physical
      examination. The 'golden standard' in the diagnostics of a drug eruption is the
      dechallenge-rechallenge procedure, but in severe cutaneous reactions such as
      Stevens-Johnson syndrome, toxic epidermal necrolysis and vasculitis, this
      procedure can cause severe, sometimes life-threatening reactions. Reporting
      suspected adverse drug reactions to pharmaco-vigilance centres is important to
      identify rare drug reactions.

PMID- 15038202
TI  - [Diagnostic image (178). A term pregnant woman with a tumor in the vulva. Extreme
      edematous swelling of the anterior labium of the cervix].
AB  - In a term pregnant woman vaginal blood loss and a protruding tumour in the vulva
      were caused by extreme oedematous swelling of the anterior labium of the cervix.

PMID- 15038201
TI  - [Cross-over transplantation; a new national program for living kidney donations].
AB  - In the Netherlands, cross-over kidney transplantation has been introduced as an
      extra option in the living kidney donation programme. In cross-over
      transplantation, patients who cannot be given their own partner's kidney for
      immunological reasons are given a kidney from the partner of another patient in
      exchange for a kidney from their own partner. There is no difference in the
      medical indications and contraindications between direct and indirect living
      donation. There are no ethical obstacles since the net gain for the two couples
      is no different from that of direct living kidney donation and because the
      exchange takes place on the basis of equality. One should be aware that the extra
      possibilities may result in more psychological pressure on potential donors. It
      is important that the donation procedures start at the same moment and that the
      wishes of patients and donors for anonymity be preserved. A successful cross-over
      kidney transplantation programme requires a large pool of donors and patients.
      Therefore, this has been organised in a national programme. The Dutch
      Transplantation Foundation is responsible for the allocation of cross-over
      kidneys. Organ trade will thus be impossible. The seven Dutch centres for kidney
      transplantation have developed a protocol.

PMID- 15038203
TI  - [Tuberculosis among Trio-Indians in Surinam].
AB  - OBJECTIVE: Evaluation of the extent and possible causes of the increased
      incidence of tuberculosis among Amazonian Indians in Surinam. DESIGN:
      Descriptive. METHOD: In two cross-sectional surveys in 1998 and 2000, the
      inhabitants of Kwamalasamutu, a village of Trio-Indians in Surinam, were examined
      for the presence of active and latent tuberculosis. Previous cases from the
      period 1995-2000 were evaluated retrospectively by consulting individual
      physicians and the archives of the 'Medische Zending' (Medical Mission), the
      'Diakonessenhuis' hospital, the clinic for pulmonary diseases, and the Central
      Laboratory. Family ties and other factors that might be associated with
      tuberculosis were examined. Spoligotyping was done on all patient isolates.
      RESULTS: Between 1995 and 2000, active tuberculosis was diagnosed in 25 Indians
      from Kwamalasamutu, equal to 4.2 cases/1000 person-years (95% CI: 2.7-6.1).
      Tuberculin skin tests were positive in 105/733 Indians (14.3%). Cases of
      tuberculosis were found predominantly within certain families, who were
      genetically related. Spoligotyping of 5 Mycobacterium tuberculosis isolates from
      Trio-Indians showed unique patterns, which were also found in 34 isolates from
      elsewhere in Surinam. CONCLUSION: Tuberculosis was relatively common among Trio
      Indians, clustering in certain families. This isolated tribe may have a genetic
      predisposition for tuberculosis, but their lifestyle and limited access to health
      care certainly play a role as well.

PMID- 15038204
TI  - [Function of tetanus immunoglobulin in case of injury: administration often
      unnecessary].
AB  - OBJECTIVE: To calculate the number of tetanus immunoglobulin (TIG) injections
      given in order to prevent one patient developing tetanus (number needed to treat
      (NNT)) and the accompanying costs. DESIGN: Functional study. METHOD: The risk of
      developing tetanus was calculated from the results of a national study on tetanus
      immunity in the general population of the Netherlands (1995-1996; n = 7715) and
      from official notifications of tetanus in the period 1984-1996 (n = 30 persons
      born before 1945). According to current vaccination policy TIG is advised for
      unvaccinated persons and those with an unclear vaccination status as well as
      those vaccinated more than 15 years ago. RESULTS: The tetanus risk after injury
      was estimated at 0.5-2 per million for unvaccinated individuals. Immunity was
      lowest (< 50%) in men born before 1936 and women born before 1950. The NNT for
      these groups was a minimum of 530.000. With a mortality of 10% and costs of 20
      Euro per TIG injection, the cost of each life saved was found to be a minimum of
      105 million Euro. The NNT and cost per life saved were astronomical for those
      persons born after 1955. CONCLUSION: The current TIG policy is inefficient.
      Thanks to the success of the National Immunisation Programme it is now justified
      to limit the administration of TIG to those who are at the highest risk i.e.
      those who are known to be unvaccinated, women born before 1950 and men born
      before 1936.

PMID- 15038205
TI  - [The central-venous compression syndrome: rare, but adequately treatable with
      endovascular stenting].
AB  - Two patients, women aged 30 and 29, had severe chronic pain in the left leg, and
      a woman aged 36 had pain in the left flank. On the grounds of the clinical
      symptoms, phlebography and venous-duplex ultrasonography, a central-venous
      compression syndrome was diagnosed: compression of the left common iliac vein
      between the crossing right common iliac artery and the body of the fifth lumbar
      vertebra (May-Thurner syndrome). The patient with left flank pain also had
      haematuria. Angiography, computed tomography and phlebography revealed that these
      symptoms were due to compression of the left renal vein between the abdominal
      aorta and the superior mesenteric artery (nutcracker phenomenon). The treatment
      of all 3 patients consisted of venous endovascular stenting. At follow-up after
      12, 30 and 15 months, respectively, the complaints had subsided considerably.

PMID- 15038206
TI  - [A teenager presenting with vomiting, general malaise and weight loss].
AB  - A 16-year-old girl had symptoms of vomiting, malaise and weight loss for two
      months. Blood tests revealed an elevated activity of liver enzymes and
      hyperthyroidism. Although the patient at first denied the possibility of
      pregnancy, a pregnancy was subsequently confirmed. Hyperemesis gravidarum was
      diagnosed based on the combination of the clinical symptoms, pregnancy and
      increased serum human chorionic gonadotrophin and oestradiol. Hyperemesis
      gravidarum also explained the demonstrated biochemical hyperthyroidism and
      elevated liver enzyme levels. Rapid alleviation of all the clinical symptoms was
      seen after termination of this unwanted pregnancy. Although vomiting, malaise and
      weight loss in children can have many different causes, in girls at a sexually
      mature age a pregnancy with possible hyperemesis gravidarum should certainly also
      be considered and a gynaecological examination performed.

PMID- 15038207
TI  - [A cluster of lymphogranuloma venereum among homosexual men in Rotterdam with
      implications for other countries in Western Europe].
AB  - In mid-December 2003, a cluster of 15 cases of lymphogranuloma venereum (LGV)
      among male homosexuals was reported to the Municipal Health Service in Rotterdam
      by the Erasmus Medical Centre's outpatient clinic for sexually transmitted
      infections (STI). Most patients presented with proctitis and some with
      constipation. All were Caucasian and between 26 and 48 years of age. Thirteen of
      them were HIV-positive and eight had a concomitant STI. All men reported having
      had unprotected insertive and receptive anal sexual contact. Many sexual contacts
      were anonymous and were reported to have taken place in Germany, Belgium, the
      United Kingdom and France. This outbreak of LGV may extend through a large part
      of western Europe. In view of the patients' international contacts, international
      warnings and alertness are needed. Concerted action of professionals in
      infectious disease control and curative care is called for.

PMID- 15038208
TI  - [Multiple pregnancies: epidemiology and management].

PMID- 15038210
TI  - [Diseases and the diseased--scientific and alternative medicine].

PMID- 15038209
TI  - [A patient with an extremely severe immunohaemolytic anemia due to diclofenac].

PMID- 15038211
TI  - [Present status of cardiac pacing in Croatia].
AB  - The number of implanted cardiac pacemakers in Croatia has considerably increased
      in the recent years. However, we still have not reached the level of the
      developed European countries. This particularly applies to the number of
      implanted cardioverter-defibrillators, and less so to the proportion of simple
      and sophisticated cardiac pacemakers. Despite this, when indication is
      established our patients receive top quality and most modern devices, because in
      Croatia the products of the most renowned world manufacturers are implanted.

PMID- 15038212
TI  - [Epidemiology of congenital heart diseases in Croatia--a multicenter nationwide
      study, 1995-2000].
AB  - Congenital heart diseases (CHD) comprise a group of different conditions seen in
      0.55-1% of live births. Tendency to classify CHD according to Clark's pathogenic
      classification is based on the assumption that relatively few pathogenic
      mechanisms cause a wide spectrum of phenotypic forms of CHD. The aim of this
      study was to classify CHD according to Clark's classification and to calculate
      the prevalence rates of CHD in the Croatian population. We formed the Registry
      including all children with CHD born between 1995 and 2000 treated in paediatric
      cardiology departments in Croatia. In the study were enrolled 276,565 live
      births, 2,204 of them with CHD, 1.126 males and 1.078 females. Total birth
      prevalence was 8.0@1000. A statistically significant difference was found between
      CHD prevalence rates in several counties. The prevalence of all main pathogenic
      groups of CHD was constant in time, except for cell death defects where a twofold
      increase in the prevalence of muscular ventricular septal defect (VSD) was noted
      (0.6@1000-1.3@1000). The most common diagnosis was perimembranous VSD (19.0%),
      followed by atrial septal defect (ASD) type II (14.4%), muscular VSD (11.1%) and
      pulmonary stenosis (8.5%). This four diagnoses were composing more than 50% of
      all CHD diagnoses. Prevalence and diagnostic possibilities weren't different from
      those presented in the literature. However, differences in prevalence between the
      counties warrant further investigation into the development and aetiology of CHD.

PMID- 15038213
TI  - [Importance of determination of various histologic components in testicular germ
      cell tumors].
AB  - Testicular germ cell tumors represent about 95% of all testicular tumors. They
      are often composed of many different components. Seminoma usually has a favorable
      course but the prognosis of mixed germ cell tumors is depending on the type and
      proportion of different histologic components. The aim of this study was to
      determine the proportion and histologic type of various components of testicular
      germ cell tumors diagnosed in the period 1992-2000. In this period there were 131
      testicular germ cell tumors with 72 (55.0%) nonseminomatous and 59 (45.0%)
      seminomatous tumors. Of all nonseminomatous tumors, 4 were composed of one
      component only, and 68 contained different components. Nonseminomatous tumors
      contained most commonly embryonal carcinoma (91.7%), teratoma (70.8%) and yolk
      sac tumor (33.3%) components. The most frequent combination of mixed germ cell
      tumors was composed of teratoma and embryonal carcinoma in 28 (41.2%) cases.
      Seminoma was found in 59 cases as pure seminoma and in 19 (26.4%) additional
      cases represented a component of testicular mixed germ cell tumor. Analysis of
      deeper sections by means of HE stained slides and immunohistochemistry
      (cytokeratin, CD30, alpha-fetoprotein, beta-HCG, PLAP and hPL) revealed 20 cases
      with components that were not described in original biopsy findings. We may
      conclude that the analysis of many sections using immunohistochemistry is
      necessary to identify all tumor components.

PMID- 15038214
TI  - [Does the suture material and technique have an effect on healing of the
      uterotomy in cesarean section?].
AB  - The aim of the study is to present the influence of different suturing techniques
      and different materials (catgut plain, Dexon and Vicryl) on healing of lower
      transverse uterotomy (in further text uterotomy) in Cesarean section (CS).
      Uterotomies were sutured by four ways: one row interrupted (group A), one row
      continuous (group B), two rows interrupted (group C), two rows interrupted and
      continuous (group D). Uterotomies were classfied according to the material used
      for suturing into the catgut group, Dexon group and Vicryl group. Between January
      1983 and December 2001 out of 7830 CSc 1946 (24.8%) patients had repeat
      deliveries: 1059 (55.0%) had a vaginal delivery and 887 (45.0%) repeat CS. In the
      same period out of 1946 deliveries 15 (0.8%) uterine ruptures-dehiscences (URD)
      were diagnosed. In catgut group out of 302 deliveries 11 (3.6%) URD were
      registered: nine (7.2%) in group D (N = 125) and two (1.7%) in group C (N = 20).
      No URD was diagnosed in group A (N = 57). In Dexon group (N = 226) URD were
      diagnosed regardless of the method of suturing the uterotomy. In Vicryl group out
      of 1486 deliveries four (0.28%) URD were registered: one (0.16%) in group A (N =
      615), one (0.3%) in group B (N = 333), one (0.52%) in group C (N = 190) and one
      (0.35%) in group D (N = 280). The best uterine scar is the one after using one
      layer interrupted Vicryl and Dexon suture. The worst healing results were
      obtained after two-row interrupted and continuous sutures using catgut.

PMID- 15038215
TI  - [Sudden infant death syndrome (SIDS) in Croatia].
AB  - We have analyzed certain epidemiological factors of sudden infant death syndrome
      (sex, age and infant's nationality, geographic and calendar death distribution,
      socio-economic conditions, age, marital status and mother's employment).
      Available statistics reports and death certificates for 22 from the total of 24
      registered cases of sudden infant death syndrome during 2000 and 2001 in the
      Republic of Croatia have been used. There were 11 boys and 11 girls, with a peak
      incidence of SIDS from 2-4 months of age (total of 14 cases), which is consistent
      to the international references. As many as 9 mothers have no education or have
      finished only several grades of primary school, but not a single mother has
      academic degree. A third of the infants were born in the illegitimate families.

PMID- 15038216
TI  - [Is transfusion of a single dose of concentrated erythrocytes poor clinical
      practice?].
AB  - The aim of the study was to determine whether a single unit of red blood cell
      (RBC) transfusion is a true criterion of poor patient care. Medical records of
      148 patients, 76 (51.4%) males, 72 (48.6%) females, mean age 66.88 +/- 14.56
      years who have received a single unit RBC transfusion at the Department of
      Medicine in the period from 1997 to 2000 were retrospectively studied.
      Pretransfusion mean hemoglobin (Hb) value (Hb1) was 85.0 +/- 12.0 (mod 78) g/L,
      increasing to (Hb2) 96.9 +/- 11.8 (mod 90) g/L after transfusion and the last
      measured value (Hb3) was 98.2 +/- 13.4 (mod 102) g/L. Six patients (66.6%) of 9
      with decrease in Hb3 value (group A) died, 13 patients (35.1%) of 37 with raise
      in Hb3 level < 5 g/L (group B) and 5-10 g/L (group C) died during the hospital
      stay vs. 7 patients (6.8%) of 102 with Hb3 level raise > 10 g/L (group D). The
      differences between the Hb2 and Hb1 values were significant considerably from the
      differences between the Hb3 and Hb1 values (p = 0.001), as well as the difference
      in the distribution of differences between Hb2 and Hb1 (p 0.028) and Hb3 and Hb1
      (p = 0.001) according to the disease outcome and the difference in mortality of
      men and women (p = 0.021). 38.4% of the deceased patients were from the group of
      coronary syndrome and/or heart failure. Statistically significant were the
      differences between the arterial oxygen tension (PaO2) at Hb1 and Hb2 (p =
      0.0001), as well as between the arterial oxygen saturation (SaO2) at the Hb1 and
      Hb2 values (p = 0.0001). There is no strict clinical indication for a single unit
      of RBC transfusion. Determinants of the need and amount of RBC transfusion except
      hemoglobin value include the etiology and duration of the anemia, the patient's
      ability to compensate for decreased oxygen carrying capacity and tissue oxygen
      requirements. The majority of a single unit RBC transfusion was appropriate for
      the clinical situation. Our data indicate that the use of smaller volumes of
      allogenic RBC transfusion was not a bad clinical practice.

PMID- 15038217
TI  - [Role of angiogenesis in the growth and progression of tumors. Treatment with
      angiogenesis inhibitors: from promising results in experimental animal models to
      the reality of clinical use].
AB  - The development of new blood vessels (angiogenesis) is necessary to sustain the
      growth of primary tumor as well as a process of tumor metastasis. Cancer cells
      activate the quiescent vasculature to produce new blood vessels via an
      "angiogenic switch". Understanding of molecular mechanisms involved in that
      process is essential for the development of antiangiogenic drugs. Drugs that
      inhibit angiogenesis could offer a treatment that is complementary to traditional
      chemotherapy. Chemotherapy directly targets tumor cells, which are prone to
      develop acquired drug resistance due to genetic instability. Antiangiogenic
      therapy is directed against endothelial cells in tumor stroma, which are
      genetically stabile. First results from animal studies supported the theory that
      endothelial cells do not develop drug resistance and had excellent results in
      inducing tumor quiescence. However, recent clinical trials showed that
      antiangiogenic therapy has limitations but that it can improve conventional
      therapeutic modalities of disseminated disease.

PMID- 15038218
TI  - [Non-arteritic ischemic optic neuropathy].
AB  - An up-to-date review of the concepts on nonarteritic ischemic optic neuropathy
      (NION) is presented with special emphasis on its most common form, nonarteritic
      anterior ischemic optic neuropathy (NAION). Relevant clinical data are presented,
      along with the description of diagnostic and therapeutic algorithms. The methods
      used in clinical diagnosis and validity of expectations from particular methods
      during the clinical course of the disease are elaborated. Controversies of
      medical and surgical approach in the management of this entity are discussed,
      with special references to the use of aspirin and optic nerve sheath
      fenestration.

PMID- 15038219
TI  - [First online continuing tele-education in gastroenterology in Croatia].
AB  - The expansion and popularity of the Internet created the expansion of tele
      medicine, with tele-education as its important part. Such on-line distance
      learning is especially important for diseases being in the focus of public health
      interest, as diseases of the gastrointestinal, hepatobiliary and pancreatic
      system due to their frequency. Therefore, in this study is shown the "TIGEL
      project of tele-interventional gastroenterology" that was launched in May 2001 at
      the Center for Interventional Gastroenterology, Department of Gastroenterology,
      University Department of Medicine, Zagreb University Hospital Center. The project
      includes creation of a web site at the server of the Zagreb University School of
      Medicine (www.mef.hr/edumed/gastro/index.html), and among the most important
      goals of the project is continuous medical tele-education in gastroenterology.
      Beside description of the project, one of the founders of continuous on-line
      medical education in Croatia, this work describes many advantages but also some
      still unsolved questions considering medical tele-education, a very promising but
      still developing way of education.

PMID- 15038221
TI  - The health care battlefront: the enemy is outside.
AB  - As the pressures of managed care and other market forces escalate, physicians and
      hospitals are becoming bedfellows in the battle to find efficiencies, improve
      reimbursement, and redesign the way medical care is delivered. The payers have
      become so onerous that physicians and hospitals are realizing that they are not
      each other's enemies. The health care industry is at a major crossroads.

PMID- 15038220
TI  - The health care continuum: beyond four walls.
AB  - For decades, the individual organs of health care--physicians, hospitals, home
      health agencies, long-term care facilities, and hospice centers--have been
      fragmented, operating independently from one another. Slowly, fragmentation is
      narrowing as hospitals team with physicians, home health agencies, long-term care
      facilities, and other health care providers to form integrated delivery systems.

PMID- 15038222
TI  - Power to the patient. Hospitals make it real.
AB  - Patient-centered care puts individuals in control of decisions about their
      medical treatment and treats patients as people. Hospitals are working to make
      this person-power real. If patient autonomy is the trump principle, how do we
      make it work? For physicians and other health care professionals who practice
      within hospital walls, the task is not easy, but the end results will be worth
      the effort.

PMID- 15038223
TI  - New Jersey Hospital Association Board of Trustees Chair, Richard Oths. The New
      Jersey Medicine interview. Interview by Bill Berlin.

PMID- 15038224
TI  - Raising the curtain on domestic violence.
AB  - In New Jersey, the statistics blare: over the past five years, the number of
      domestic violence victims grew 60 percent. Quietly, intuitively, you realize
      there are more. One study shows that domestic violence may account for as much as
      $1.8 billion in health care services annually in the U.S. But more important than
      the health care costs are the personal and long-term social ramifications of
      domestic violence.

PMID- 15038225
TI  - Health redefined: look it up.
AB  - Health care providers always have shaped their definition of health around one
      single interpretation: absence of disease. In recent years, there has been
      growing recognition that health extends far beyond medical perimeters and walks a
      fine line with societal issues and pressures, for each societal ill bears its own
      unique health care price tag.

PMID- 15038226
TI  - Money makes the hospital go 'round.
AB  - Recent statistics compiled by the New Jersey Hospital Association show that the
      average hospital operating margin in New Jersey is about 0.8 percent, the lowest
      point in a decade. The average total margin, which measures overall profitability
      of a hospital including restricted funds, fell to 2.5 percent in 1997, the lowest
      point since 1992. Nearly 40 percent of the state's hospitals are losing money,
      and the average day's cash on hand--which measures a hospital's reserves--is 40
      days, lower than both the Northeast and national averages. These financial
      realities could signal a difficult crossroads ahead.

PMID- 15038227
TI  - Hospitals on the World Wide Web.
AB  - Currently, 67 percent of the state's hospitals and health systems have web sites,
      representing 70 facilities. While it is true on the World Wide Web that Caveant
      Lector et Viewor (let the reader and viewer beware), New Jersey's hospital web
      sites provide trusted resources that demonstrate the power of the Internet as a
      high-quality medical information tool for patients and professionals.

PMID- 15038228
TI  - Merger mania lures many hospitals. While others still stand alone.
AB  - During the past five years, more hospital affiliations, consolidations, and
      mergers have been announced than ever before. Why the urge to merge? The answer
      is being driven in part by economics and the shift away from inpatient care, in
      part by managed care, and in part by the current regulatory climate.

PMID- 15038230
TI  - Digital devices.

PMID- 15038231
TI  - The 15/30 emergency room guarantee.
AB  - Emergency rooms strive to treat patients as quickly as possible. To ensure timely
      treatment, one New Jersey hospital system invokes a 15/30 guarantee: Evaluation
      by a nurse in 15 minutes and by a physician in 30 minutes. Is such a guarantee of
      emergency medical care working?

PMID- 15038229
TI  - Taking care of legislative business.
AB  - The New Jersey Hospital Association (NJHA) works with legislative leaders to
      shape policy that will benefit the state's 120 hospitals and the people they
      serve. The NJHA "to-do" list includes protecting providers against insolvent
      HMOs; guaranteeing children health care; and making the most of the tobacco
      settlement money. Attention also is being given to the damage caused by the
      Balanced Budget Act.

PMID- 15038232
TI  - Alternative medicine for the clinician.

PMID- 15038233
TI  - 1999 AMNJ honorees. Bernard Robins, MD, and Clark Martin. The New Jersey medicine
      interviews. Interview by Bill Berlin.

PMID- 15038234
TI  - Women and headache pain. Breaking the cycle.
AB  - Hormone-related migraines correspond with a woman's reproductive life cycle.
      Migraines first occur as a girl enters puberty and are rare after menopause. Is
      there medical relief available for this pain?

PMID- 15038236
TI  - Thought out of chaos.

PMID- 15038235
TI  - Hypertension. Silent killer.
AB  - Hypertension is the leading cause of heart disease in the United States. Still,
      this common and potentially life-threatening disease, affecting 25 percent of the
      adult American population, is not well controlled. New research gives the medical
      community the tools needed to fight hypertension.

PMID- 15038237
TI  - Steroids. Building a better you?
AB  - The use of anabolic steroids was first reported in the 1950s among weight lifters
      seeking to gain an edge in strength and muscle size. Since then, anabolic
      steroids have been used to augment strength and appearance. Today, steroids reach
      far beyond the world of professional athletes to high school locker rooms,
      neighborhood gyms, and suburban fitness centers. An estimated one million
      Americans use anabolic steroids for nonmedical purposes, supporting an illicit
      $400 million market.

PMID- 15038239
TI  - Detecting coronary artery disease by electron beam CT.
AB  - Electron beam computed tomography is a sensitive method for detection and
      quantitation of coronary artery calcification. The absence or presence and the
      amount of coronary artery calcification has prognostic significance for the
      existence of occlusive coronary artery disease and the risk of developing angina
      pectoris, myocardial infarction, and sudden death.

PMID- 15038238
TI  - Taking action on arthritis.
AB  - The statistics regarding arthritis are mind boggling: one out of every six
      Americans have arthritis. In New Jersey, more than one million people are
      affected by arthritis diseases. The condition costs the U.S. economy $65 billion
      annually in medical care and lost wages. The Centers for Disease Control and
      Prevention (CDC) projects that in the year 2020, one in five Americans will have
      arthritis--an estimated 59.4 million people. Increasing awareness of this disease
      among physicians is a necessity.

PMID- 15038241
TI  - Changing roles. Physicians and their patients.
AB  - With today's rapid cultural and technological changes, the interaction between
      health care providers and patients is undergoing a dramatic transformation.
      Nearly everyone has to adapt, including physicians, insurers, pharmaceutical
      companies, hospitals, HMOs, government agencies, and patients.

PMID- 15038240
TI  - Anaesthesiology. Current trends.
AB  - Anesthesiology is not just putting patients to sleep anymore. Increased
      regulatory oversight, technological advances, better short-acting drugs, and
      nontraditional approaches to anesthesiology practice are ushering this medical
      specialty into the 21st century.

PMID- 15038242
TI  - The changing face of health care. In search of the perfect solution.
AB  - Managed care has introduced a new accountability to the health care community and
      has challenged many to perform at a higher level--including health plans. Yet no
      one seems to be interested in evaluating the impact of the rules we already have.
      We need to see where we have succeeded, where we have failed, and where we may
      have added costly requirements with no net benefit to the system. Some observers
      seem reluctant to acknowledge that many of our new regulations carry a cost. Some
      regulations are worth the price, but objective analysis and evaluation may
      conclude that others are not.

PMID- 15038243
TI  - NJ Commission on the Physician Workforce recommendations.
AB  - The New Jersey Commission on the Physician Workforce recommendations offer one
      approach to stabilize the state's physician workforce. Regardless of the approach
      used by our state it is imperative that the primary focus be directed to
      patients. Residents of the Garden State deserve to continue to obtain high
      quality medical care throughout their lives.

PMID- 15038244
TI  - Developmental toxicity study of dimethylpiperidone.
AB  - The potential maternal and developmental toxicity of dimethylpiperidone (DMPD)
      was assessed in rats. Groups of 25 mated female Crl:CD (SD)IGS BR rats were
      exposed by inhalation (whole-body exposures) for approximately six hours per day
      over days 7-21 of gestation (G); day 1G was the day of copulation plug detection.
      The exposure levels were 0, 52, 260, or 340 (vapor plus aerosol) mg/m3 DMPD.
      During the in-life portion, body weights, food consumption, and clinical
      observation data were collected. On day 22G, the dams were euthanized and
      examined for gross external and internal alterations. The uterine contents were
      described and the fetuses were weighed and examined for external, visceral, and
      skeletal alterations. Maternal toxicity was seen at both 260 and 340 mg/m3. At
      340 mg/m3, evidence of maternal toxicity included mortality, increased clinical
      observations, and decreased body weight and food consumption. At 260 mg/m3,
      maternal toxicity was limited to increased clinical observations and decreased
      food consumption. Developmental toxicity was also produced at 260 and 340 mg/m3.
      At 340 mg/m3, evidence of developmental toxicity included decreased fetal weight,
      increased embryofetal lethality with concomitant reductions in litter size, and
      increased fetal malformations and variations. At 260 mg/m3, effects in fetuses
      were limited to slightly decreased fetal weight and increased fetal variations;
      additionally, one litter from this level consisted entirely of resorptions. There
      were no compound-related effects in either dams or fetuses at 52 mg/m3. It was,
      therefore, concluded that DMPD was not selectively toxic to the rat conceptus.

PMID- 15038245
TI  - Protective effects of ethanolic neem leaf extract on N-methyl-N'-nitro-N
      nitrosoguanidine-induced genotoxicity and oxidative stress in mice.
AB  - We evaluated the effects of pretreatment with ethanolic neem leaf extract on N
      methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced genotoxicity and oxidative
      stress in male Swiss albino mice. The frequency of micronuclei (MN),
      concentrations of lipid peroxides and the status of the antioxidants, reduced
      glutathione (GSH), glutathione peroxidase (GPx) and glutathione-S-transferase
      (GST) were used as intermediate biomarkers of chemoprotection. Animals were
      divided into four groups of five animals each. Animals in group 1 were given MNNG
      (40 mg/kg body weight) by intragastric intubation. Animals in group 2 received
      intragastric administration of ethanolic neem leaf extract at a concentration of
      200 mg/kg body weight for 5 days followed by MNNG 1.5 h after the final feeding.
      Group 3 animals received ethanolic neem leaf extract alone for five days. Group 4
      received the same volume of normal saline and served as control. The animals were
      sacrificed by cervical dislocation 27 h after the carcinogen exposure. In MNNG
      treated mice, enhanced lipid peroxidation with compromised antioxidant defences
      in the stomach, liver and erythrocytes was accompanied by increase in bone marrow
      micronuclei. Pretreatment with ethanolic neem leaf extract significantly reduced
      MNNG-induced micronuclei and lipid peroxides and enhanced GSH-dependent
      antioxidant activities. The results of the present study demonstrate that
      ethanolic neem leaf extract exerts protective effects against MNNG-induced
      genotoxicity and oxidative stress by augmenting host antioxidant defence
      mechanisms.

PMID- 15038247
TI  - Treatment with antimalarials adversely affects the oxidative energy metabolism in
      rat liver mitochondria.
AB  - Effects of in vivo treatment with the three antimalarials chloroquine, primaquine
      and quinine on rat liver mitochondrial energy transduction functions were
      examined. Treatment with all the three antimalarials decreased the state 3 and
      state 4 respiration rates drastically. The extent of inhibition was higher with
      pyruvate + malate as the substrate than with glutamate. The antimalarials also
      acted as uncouplers. The uncoupling effect was seen on site II and site III of
      phosphorylation; site I was unaffected. As a consequence the ADP phosphorylation
      rates also decreased significantly. Following antimalarials treatment the basal
      and Mg2+ stimulated ATPase activities increased while the DNP-stimulated ATPase
      activity was reduced by half. Treatment with chloroquine resulted in decreased
      contents of cytochromes aa3 and b; primaquine and quinine treatments increased
      the contents of the two cytochromes in 14 day treatment groups.

PMID- 15038246
TI  - Effects of fosphenytoin on nerve agent-induced status epilepticus.
AB  - This study evaluated the effectiveness of fosphenytoin as a single or adjunctive
      anticonvulsant treatment for nerve agent-induced status epilepticus. Guinea pigs,
      implanted with cortical electroencephalographic (EEG) recording electrodes, were
      pretreated with pyridostigmine bromide (0.026 mg/kg, intramuscular (i.m.)) 30 min
      before challenge with 56 micrograms/kg, subcutaneous (s.c.), (2 x LD50) of the
      nerve agent soman. One min after soman, the animals were treated (i.m.) with 2
      mg/kg atropine sulfate admixed with 25 mg/kg of the oxime 2-pralidoxime chloride,
      and the EEG was observed for seizure onset. When administered (intraperitoneal,
      i.p.) therapeutically 5 min after seizure onset, only the highest fosphenytoin
      dose (180 mg/kg) was capable of terminating seizure activity in 50% of the
      animals tested (3 of 6). When fosphenytoin (18-180 mg/kg) was administered as a
      pretreatment, i.p., 30 min before soman challenge, seizures were blocked or
      terminated in a dose-dependent fashion (ED50 = 61.8 mg/kg; 40.5-94.7 mg/kg = 95%
      confidence limits). Combinations of diazepam and fosphenytoin were also tested
      for effectiveness. No dose of fosphenytoin (18-56 mg/kg), given in conjunction
      with a fixed dose of diazepam (4.8 mg/kg, i.m.) 5 min after seizure onset,
      enhanced the anticonvulsant effect of diazepam. When fosphenytoin (18 or 32
      mg/kg, i.p.) was given as a pretreatment and diazepam was given 5 min after
      seizure onset, the 32 mg/kg dose of fosphenytoin significantly reduced the time
      for seizure control. These studies show that fosphenytoin, either alone or in
      combination with diazepam, has little or no therapeutic anticonvulsant
      effectiveness for nerve agent-induced status epilepticus.

PMID- 15038248
TI  - Association of thioacetamide and ethanol treatment: dolichol and retinol in
      isolated rat liver cells.
AB  - Our aim was to study the distribution of dolichol, dolichol isoprenoids, and
      retinol in hepatocytes, Kupffer, sinusoidal endothelial and two subfractions of
      hepatic stellate cells, --Ito-1 and Ito-2--, after chronic treatment of rats for
      2 and 4 months with a low dosage of thioacetamide associated with ethanol. Each
      type of cell responded differently to the two hepatotoxins. Overall, ethanol
      rarely affected the action of thioacetamide. Some new information emerges with
      regard to these hepatotoxins in comparison with the effects exerted by each of
      the drugs separately: treatment with thioacetamide plus ethanol determined an
      early decrease in dolichol in Kupffer cells (about 13% and 50% after 2 and 4
      months, respectively). Moreover, after liver damage, a load of vitamin A
      evidenced altered percentages of the form of dolichol with eighteen isoprene
      units; these percentages were modified by all treatments in all cell types. The
      results confirm that dolichol is the preferred target of oxidative stress and
      suggest a relationship between dolichol and retinol metabolisms, and a possible
      new role of dolichol precursors, of prenyltransferases and of retinol metabolites
      in liver pathology.

PMID- 15038249
TI  - Function of plasma and microsomal enzymes in soman toxicity.
AB  - Such organophosphorous (OP) nerve agents as sarin (isopropyl
      methylphosphonofluoridate) and soman (pinacolyl methylphosphonofluoridate) are
      effective inhibitors of acetylcholinesterases (AChE), butyrylcholinesterases
      (BChE) and carboxylesterases (CaE). The acute toxicity of these compounds in
      mammals is known to be mediated through inhibition of AChEs, which leads to
      increased acetylcholine (ACh) levels. The aim of this study was to compare the
      significance of the plasma CaEs, microsomal CaEs and CYP450 enzymes in
      detoxification of soman with and without physostigmine treatment. The mice
      received physostigmine (0.1 mg/kg body wt) intravenously (i.v.) 10 min prior to
      the intraperitoneal (i.p.) injection of soman (0.400-0.650 mg/kg body wt in olive
      oil). To avoid possible signs of poisoning, the animals received atropine sulfate
      (37.5 mg/kg body wt in saline) subcutaneously (s.c.) immediately after the soman
      administration. In the present study, the inhibitory effect of soman was greater
      in plasma CaE than in hepatic microsomal CaE fraction. In addition, soman or the
      combination of soman-physostigmine had no remarkable effect on the microsomal CaE
      or P4502B activities. In spite of this, however, the microsomal CaEs might offer
      more protection against multiple LD50s of soman.

PMID- 15038250
TI  - The application of the fluoride reactivation process to the detection of sarin
      and soman nerve agent exposures in biological samples.
AB  - The fluoride reactivation process was evaluated for measuring the level of sarin
      or soman nerve agents reactivated from substrates in plasma and tissue from in
      vivo exposed guinea pigs (Cava porcellus), in blood from in vivo exposed rhesus
      monkeys (Macaca mulatta), and in spiked human plasma and purified human albumin.
      Guinea pig exposures ranged from 0.05 to 44 LD50, and reactivated nerve agent
      levels ranged from 1.0 ng/mL in plasma obtained from 0.05 LD50 sarin-exposed
      guinea pigs to an average of 147 ng/g in kidney tissue obtained from two 2.0 LD50
      soman-exposed guinea pigs. Positive dose-response relationships were observed in
      all low-level, 0.05 to 0.4 LD50, exposure studies. An average value of 2.4 ng/mL
      for reactivated soman was determined in plasma obtained from two rhesus monkeys
      three days after a 2 LD50 exposure. Of the five types of guinea pig tissue
      studied, plasma, heart, liver, kidney and lung, the lung and kidney tissue
      yielded the highest amounts of reactivated agent. In similar tissue and with
      similar exposure procedures, reactivated soman levels were greater than
      reactivated sarin levels. Levels of reactivated agents decreased rapidly with
      time while the guinea pig was alive, but decreased much more slowly after death.
      This latter chemical stability should facilitate forensic retrospective
      identification. The high level of reactivated agents in guinea pig samples led to
      the hypothesis that the principal source of reactivated agent came from the agent
      carboxylesterase adduct. However, there could be contributions from adducts of
      the cholinesterases, albumin and fibrous tissue, as well. Quantitative analysis
      was performed with a GC-MS system using selected ion monitoring of the 99 and 125
      ions for sarin and the 99 and 126 ions for soman. Detection levels were as low as
      0.5 ng/mL. The assay was precise and easy to perform, and has potential for
      exposure analysis from organophosphate nerve agents and pesticides in other
      animal species.

PMID- 15038251
TI  - Another cause of hypogonadism.

PMID- 15038252
TI  - Catheter-based treatment of atherosclerosis. Options for effective percutaneous
      intervention are plentiful.
AB  - Percutaneous treatment of atherosclerotic disease has made tremendous progress
      over the past four decades. It is now safe, effective, and widely available in
      the United States. New frontiers and challenges continue to be tackled, and
      application of these procedures continues to expand.

PMID- 15038253
TI  - Lipid-lowering therapy. New and established agents reduce risk of cardiovascular
      events.
AB  - Lipid therapy has come a long way in the past 20 years. In the late 1980s, 3
      hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") were
      introduced, and they have continued to demonstrate benefits in multiple large
      scale primary and secondary prevention trials. A broader understanding of the
      effects of statin medications has led to new therapeutic goals for different
      patient populations. In this article, Dr Smith discusses recent developments in
      statin therapy as well as the introduction of a new class of drugs called
      selective cholesterol absorption inhibitors.

PMID- 15038254
TI  - Practical strategies for cardiac disease prevention. Basic steps to ensure better
      heart health.
AB  - Primary care physicians are deluged with medical information from many sources:
      medical literature, public media and the Internet, the pharmaceutical and medical
      device industries, and patients themselves. How can a physician best deal with
      the volume of data provided by scientific research, medical education, drug
      promotion, popular opinion, government regulation, and payer constraints?

PMID- 15038255
TI  - Abnormal liver test results on routine screening. How to evaluate, when to refer
      for a biopsy.
AB  - Primary care physicians are often the first healthcare professionals to see
      abnormalities that show up in routine serum liver testing--results that may
      indicate liver disease. In this article, Drs Mallory, Lee, and Kowdley offer a
      practical approach to evaluating abnormal levels of markers of hepatocellular
      injury, cholestasis, and liver synthetic function. They also explore the
      considerations that might prompt physicians to request a liver biopsy.

PMID- 15038256
TI  - Acute pericarditis. Evaluation and treatment of infectious and other causes.
AB  - Acute pericarditis is a common disease that typically is diagnosed on the basis
      of its classic chest pain, pericardial friction rub, and changes on ECG. Although
      most cases are idiopathic and self-limited, numerous causes should be considered.
      The diagnostic yield of extensive laboratory evaluation and pericardiocentesis is
      very low, and invasive procedures should be limited to patients in whom
      therapeutic intervention is necessary. Treatment should focus on symptomatic
      relief, usually through use of NSAIDs, and patients should be carefully evaluated
      and monitored for common complications of the disease.

PMID- 15038257
TI  - How useful are new radiographic tools for detecting breast cancer?

PMID- 15038258
TI  - Wireless interference with telemetry equipment?

PMID- 15038260
TI  - Patient notes: quitting smoking.

PMID- 15038259
TI  - Reticulated rash on the thighs. Erythema ab igne.

PMID- 15038261
TI  - [Application of the satellite systems in the management of medical service].

PMID- 15038262
TI  - [The peculiarities of summing-up the work for the treatment and disease
      prophylaxis in military inpatient hospitals].
AB  - It is shown that in a number of cases the summing up of military hospital work
      has the formal character. It consists the following: for the week (30.0 +/-
      5.4%), for the day (18.0 +/- 2.4%), for the month (15.0 +/- 2.1%) and for the
      quarter (12.0 +/- 1.6%); for the education period (5.0 +/- 1.1%) and for the
      school year (3.0 +/- 0.9%). The experts consider that the main causes of chiefs'
      formal attitude to summing-up are the following: lack of sufficient volume of
      necessary information (25%), high official load (20%), low professional level of
      the chiefs dealing with the given problem (15%), other causes (40%).

PMID- 15038264
TI  - [Preventive medicine and healthy life style in the Armed Forces (Report 1)].

PMID- 15038263
TI  - [New approaches to correction of the nutritional status in servicemen with body
      mass deficiency].

PMID- 15038265
TI  - [Optimization of the specialized treatment of wounded with gunshot long-bone
      fractures of extremities].

PMID- 15038266
TI  - [Characteristics of the provision of hemotransfusion materials to the wounded and
      patients during antiterrorist operation].
AB  - The authors analyze the experience of organization of the wounded and patient
      provision with hemotransfusion materials to render assistance during
      antiterrorist operation in Republic of Dagestan and Republic of Chechnya in 1999
      2001. It is shown that supply of military treatment-and-prophylactic institutions
      deployed in the zone of military conflict, of specialized hospitals with
      hemotransfusion materials was the following: with blood preparations (at the
      expense of centralized deliveries), with blood components (91.8%, at the expense
      of centralized deliveries form the district blood transfusion station). The
      volume of stored blood taken from emergency reserve donors in the military
      treatment-and-prophylactic institutions located near the zone of military actions
      constituted 8.2% of the total volume of blood components received.

PMID- 15038267
TI  - [The case of multiple gunshot wounds of the abdominal cavity, femur, and hip].

PMID- 15038268
TI  - [The treatment of thoracic penetrating gunshot wounds].

PMID- 15038269
TI  - [Work capacity of the patients after reconstructive operations on the coronary
      vessels].

PMID- 15038270
TI  - [Simultaneous and combined operations in gynecology].

PMID- 15038271
TI  - [Epidemiological significance of HIV-infections in military personnel].
AB  - The increase in HIV-infection incidence in the RF Armed Forces requires the study
      of modern epidemiology of this infection, the improvement of prophylactic and
      antiepidemic measures to prevent the contamination of units and ships and to
      eliminate the epidemiologic foci in time. The epidemiological situation connected
      with HIV-infection in Russia and the Armed Forces has the general patterns. The
      maximal incidence is registered in servicemen living in HIV unfavorable
      territories of the country. In 2001 the structure of HIV transmission in the
      military collectives was the following: sexual--51%, parenteral (drug addiction)-
      45%, parenteral (use of one shaving set)--1%, parenteral (tattooing)--1%,
      uncertain--2%. The high military epidemiological significance of HIV-infection
      requires the improvement of preventive forms and methods taking into account the
      main causes and factors that determine the epidemiological situation in Army and
      Navy.

PMID- 15038273
TI  - [Psychophysiological approaches to increasing work capacity and fighting
      efficiency of military personnel].

PMID- 15038274
TI  - [Memoirs of I. A. Mitropol'skii, the military physician].

PMID- 15038272
TI  - [Comparative antigenic activity of the hepatitis A inactivated vaccine among
      military personnel].

PMID- 15038275
TI  - [Momentous event of the year].

PMID- 15038276
TI  - Visualization of atomic processes on ruthenium dioxide using scanning tunneling
      microscopy.
AB  - The visualization of surface reactions on the atomic scale provides direct
      insight into the microscopic reaction steps taking place in a catalytic reaction
      at a (model) catalyst's surface. Employing the technique of scanning tunneling
      microscopy (STM), we investigated the CO oxidation reaction over the RuO2(110)
      and RuO2(100) surfaces. For both surfaces the protruding bridging O atoms are
      imaged in STM as bright features. The reaction mechanism is identical on both
      orientations of RuO2. CO molecules adsorb on the undercoordinated surface Ru
      atoms from where they recombine with undercoordinated O atoms to form CO2 at the
      oxide surface. In contrast to the RuO2(110) surface, the RuO2(100) surface
      stabilizes also a catalytically inactive c(2 x 2) surface phase onto which CO is
      not able to adsorb above 100 K. We argue that this inactive RuO2(100)-c(2 x 2)
      phase may play an important role in the deactivation of RuO2 catalysts in the
      electrochemical Cl2 evolution and other heterogeneous reactions.

PMID- 15038277
TI  - Molecular basis of the dynamic strength of the sialyl Lewis X--selectin
      interaction.
AB  - The selectins are Ca(2+)-dependent cell adhesion molecules that facilitate the
      initial attachment of leukocytes to the vascular endothelium by binding to a
      carbohydrate moiety as exemplified by the tetrasaccharide, sialyl Lewis X (sLeX).
      An important property of the selectin-sLeX interaction is its ability to
      withstand the hydrodynamic force of the blood flow. Herein, we used single
      molecule dynamic force spectroscopy (DFS) to identify the molecular determinants
      within sLeX that give rise to the dynamic properties of the selectin/sLeX
      interaction. Our atomic force microscopy (AFM) measurements revealed that the
      unbinding of the selectin/sLeX complexes involves overcoming at least two
      activation barriers. The inner barrier, which determines the dynamic response of
      the complex at high forces, is governed by the interaction between the Fuc
      residue of sLeX and a Ca2+ ion chelated to the lectin domain of the selectin
      molecule, whereas the outer activation barrier can be attributed to interactions
      involving the sialic acid residue of sLeX. Due to their steep inner activation
      barriers, the selectin-sLeX complexes are less sensitive to high pulling forces.
      Hence, besides its contribution to the bond energy, the Ca2+ ion also grants the
      selectin-sLeX complexes a tensile strength that is crucial for the selectin
      mediated rolling of leukocytes.

PMID- 15038278
TI  - The gas-phase hydrogen bond complexes between formic acid with hydroxyl radical:
      a theoretical study.
AB  - We report a theoretical study on seven radical hydrogen bond complexes between
      syn-HCOOH and OH and eight radical hydrogen bond complexes between anti-HCOOH and
      OH, that have been carried out by using the B3LYP, MP2, QCISD, and CCSD(T)
      theoretical approaches with the 6-311 + G(2df,2p) basis set. In all cases, the
      bonding features were analysed using the atoms in molecules (AIM) theory by Bader
      and the natural bond orbital (NBO) partition scheme by Weinhold et al. We have
      found twelve complexes having a single hydrogen bond and three complexes
      presenting a cyclic structure with multiple bonds, pointing out the existence of
      a cooperative effect. One of them presents a bound O...O interaction producing a
      stabilisation effect. The stability of these complexes has been calculated to be
      in the -0.81 and -5.96 kcal mol-1 range and their possible implication in the
      HCOOH plus OH reaction is also discussed. Finally, we also report the computed
      harmonic vibrational frequencies of the two O-H stretching modes and the HOC out
      of-plane wagging mode, along with the frequency red-shifts originated by the
      complex formation and the corresponding computed intensity ratio relative to the
      monomers.

PMID- 15038279
TI  - Manganese, iron, cobalt, and nickel oxo-, peroxo-, and superoxoclusters: a
      density functional theory study.
AB  - The 3d-transition-metal dioxo-, peroxo-, and superoxoclusters with the general
      composition MO2, M(O2), and MOO (M = Mn, Fe, Co, and Ni) were studied by DFT by
      the B1LYP functional. The dioxides in their ground states represent the global
      minima for the M + O2 system. Both ground-state dioxides and the lowest-energy
      peroxides are in their (d-only) highest spin states. The 6A1 state of Co(O2)
      exceeds the d-only spin-multiplicity value (quartet), being nearly isoenergetic
      with the 4A1 state of Co(O2). The energy gain on transforming the peroxides to
      the corresponding dioxides decreases in the order Mn(O2) > Fe(O2) > Co(O2) >
      Ni(O2) and varies in the range 0.27-1.8 eV. The dissociation energy to M + O2 for
      all studied peroxides is less than 1 eV being the lowest (0.47 eV) for Mn(O2).
      The Mn and Fe peroxides need less than 0.3 eV to rupture one of the MO bonds to
      form the corresponding superoxide. Mn and Fe superoxides are less stable than the
      corresponding peroxides; the superoxide of Co is more stable than its peroxide,
      while Ni superoxide is unstable--its energy is above the limit of dissociation to
      Ni + O2. According to the electrostatic potential maps, the oxygen atoms in the
      peroxides are more nucleophilic than those in the dioxides and superoxides, in
      which the terminal oxygen atom is more nucleophilic than the M-bonded oxygen
      atom. This result differs from the expectations based on charge-distribution
      analysis.

PMID- 15038280
TI  - Two- and three-dimensional molecular organization of Schiff-base derivatives.
AB  - We have designed and synthesized a series of Schiff base derivatives, and studied
      their structural features in two-dimensional (2D) and three-dimensional (3D)
      states by combining scanning tunneling microscopy (STM) and X-ray diffraction
      experiments. The Schiff-base derivatives with short alkyl chains crystallize
      easily, which allows a detailed structural analysis by X-ray diffraction. Due to
      the strong adsorbate-substrate interactions, those bases with long alkyl chains
      easily form 2D assemblies on highly oriented pyrolytic graphite (HOPG). The STM
      images indicate also that the introduction of two methoxy groups into the
      molecule can change the structure of these 2D assemblies as a result of the
      increased steric hindrances, for example: the Schiff-base derivative, bearing
      both methoxy groups and C16H33 tails, forms 2D Moire patterns, and an alignment
      of pairing Schiff-base molecules may be easily resolved. Conversely, the Schiff
      base derivative, bearing solely C16H33 tails, forms 2D non-Moire patterns. It is
      demonstrated that the 3D structural features result from the compromise of
      intermolecular interactions of different molecular moieties. However, there is
      one more factor, which also governs the 2D structure: the adsorbate-substrate
      interaction. The 3D crystal structure may thus help to understand many factors
      involved in the formation of 2D structures, and would be helpful for designing
      new molecular assemblies with tailoring functions.

PMID- 15038281
TI  - Improper hydrogen C-H...O bonds cause self-association of alpha, beta
      enaminoketones containing fluorosubstituted alkyl groups.
AB  - Concentration- and temperature-dependent IR, NMR and dipole-moment studies on 4
      N,N-dimethylamino-1,1,1-trifluoro-3-buten-2-one and two of its higher homologues
      showed that these compounds undergo reversible dimerization in nonpolar solvents.
      Antiparallel "closed" dimers are formed with a network of improper intermolecular
      C-H...O hydrogen bonds. Quantitative analysis of the 1H NMR data yielded delta H0
      = -17.6 kJ mol-1 and delta S0 = -46.9 J deg-1 mol-1. The interactions observed
      are the strongest among those involving a C-H group reported so far. The complex
      described here is the first example of a cyclic complex stabilized by two
      improper C-H...O hydrogen bonds. The conclusions drawn from the solution and
      solid-state data were confirmed by ab initio calculations.

PMID- 15038283
TI  - Kinetics and mechanisms for the reactions of phenyl radical with ketene and its
      deuterated isotopomer: an experimental and theoretical study.
AB  - Kinetics and mechanism for the reaction of phenyl radical (C6H5) with ketene (H2C
      beta=C alpha=O) were studied by the cavity ring-down spectrometric (CRDS)
      technique and hybrid DFT and ab initio molecular orbital calculations. The C6H5
      transition at 504.8 nm was used to detect the consumption of the phenyl radical
      in the reaction. The absolute overall rate constants measured, including those
      for the reaction with CD2CO, can be expressed by the Arrhenius equation k = (5.9
      +/- 1.8) x 10(11) exp[-(1160 +/- 100)/T] cm3 mol-1 s-1 over a temperature range
      of 301-474 K. The absence of a kinetic isotope effect suggests that direct
      hydrogen abstraction forming benzene and ketenyl radical is kinetically less
      favorable, in good agreement with the results of quantum chemical calculations at
      the G2MS//B3LYP6-31G(d) level of theory for all accessible product channels,
      including the above abstraction and additions to the C alpha, C beta, and O
      sites. For application to combustion, the rate constants were extrapolated over
      the temperature range of 298-2500 K under atmospheric pressure by using the
      predicted transition-state parameters and the adjusted entrance reaction barriers
      E alpha = E beta = 1.2 kcal mol-1; they can be represented by the following
      expression in units of cm3 mol-1 s-1: k alpha = 6.2 x 10(19)T-23 exp[-7590/T] and
      k beta = 3.2 x 10(4)T2.4 exp[-246/T].

PMID- 15038282
TI  - Functional microdomains of glycolipids with partially fluorinated membrane
      anchors: impact on cell adhesion.
AB  - Functional microdomains of glycolipids were designed by mixing neoglycolipids
      with partially fluorinated alkyl (F-alkyl) chains and matrix lipids with alkyl
      chains. Fluorescence images of the mixed lipid monolayers at the air-water
      interface demonstrated that it is possible to control both size and distribution
      of the microdomains by means of the strong demixing of alkyl and F-alkyl membrane
      anchors, while the carbohydrate head groups seemed to play a rather minor role.
      These microdomains in monolayers could be transferred onto hydrophobized
      substrates and subjected to experiments in a dynamic flow chamber. The results
      obtained here clearly indicated that the dynamic adhesion of Chinese hamster
      ovarial cells expressing E-selectin (CHO-E cells) on a lipid monolayer containing
      microdomains of sialyl Lewisx (sLex) can be both enhanced and reduced by
      controlled demixing of ligands and matrices. Moreover, the same clusters of sLex
      could also be formed in giant lipid vesicles, which can be used as a model cell
      that locally expresses biospecific functions.

PMID- 15038284
TI  - 18O isotope substitution, vibrational coupling and protein structure: a
      theoretical approach.

PMID- 15038285
TI  - Supramolecular architectures of electrostatic self-assembled glucose oxidase
      enzyme electrodes.

PMID- 15038286
TI  - Energy transfer from dye-zeolite L antenna crystals to bulk silicon.

PMID- 15038287
TI  - Molecular insight, through IR spectroscopy, on solvating phenomena occurring in
      CO2-expanded solutions.

PMID- 15038288
TI  - Modelling of the adsorption of C60 on the Au(110) surface.

PMID- 15038289
TI  - Potential energy landscape for conformationally gated secondary ubiquinone
      binding in the photosynthetic reaction center of Rhodobacter sphaeroides.

PMID- 15038290
TI  - Mechanical properties of microtubules explored using the finite elements method.

PMID- 15038291
TI  - A strategy for the measurement of the vibrations of a muoniated radical centre:
      experimental evidence.

PMID- 15038292
TI  - Synthesis of a surface photovoltage sensor using self-ordered tin-modified MCM-41
      films: enhanced NO2 gas sensing.

PMID- 15038293
TI  - Epitaxial growth of pentacene films on metal surfaces.

PMID- 15038294
TI  - 4'-pivaloyl substituted thymidine as a precursor for the thymyl radical: an EPR
      spectroscopic study.

PMID- 15038295
TI  - Electrochemical doping of double-walled carbon nanotubes: an in situ Raman
      spectroelectrochemical study.

PMID- 15038296
TI  - Photophysical and redox NIR-sensitivity enhancement in photorefractive polymer
      composites.

PMID- 15038297
TI  - 'Results' smack of quick fixes.

PMID- 15038298
TI  - Coast to coast. Media friendly.

PMID- 15038299
TI  - First steps of the journey: job evaluation for agenda for change.

PMID- 15038300
TI  - Consultant nurse roles: experiences from an NHS trust.

PMID- 15038301
TI  - Consent to clinical decisions when capacity is absent. Part 1: Making decisions.

PMID- 15038302
TI  - The importance of honesty in clinical supervision. Part 2: The skill of
      challenging.

PMID- 15038303
TI  - Continuing professional development: what do we need?

PMID- 15038304
TI  - The end of paternalism?

PMID- 15038306
TI  - Nurses and bending the rules. Interview by Leah Kinnaird.

PMID- 15038308
TI  - Health care issues. What the presidential candidates are saying.

PMID- 15038307
TI  - Looking through the years: 1925. The soul of the nurse.

PMID- 15038309
TI  - The first MNA. Turning RN into reality.

PMID- 15038310
TI  - Making an IMPACT through active participation.

PMID- 15038312
TI  - As I see it.

PMID- 15038311
TI  - How to be politically active in 2 minutes.

PMID- 15038313
TI  - Cutting deals on the side. Is your employer trying to go through the illegal back
      door?

PMID- 15038314
TI  - Safe patient care.

PMID- 15038315
TI  - Suicides in UK prisons.

PMID- 15038317
TI  - Patients, doctors and the law (1963-2003): a few reflections.

PMID- 15038316
TI  - Jodie and Mary, conjoined twins: a case of judicial moral hubris?

PMID- 15038318
TI  - Claiming for nervous shock due to negligence in the workplace.

PMID- 15038320
TI  - [Esophageal tumors at our outpatient clinic].
AB  - INTRODUCTION: In the 1984-1997 period 1179 tumorous patients presented themselves
      at the oesophagus consultation of the Ist. Department of Surgery of Semmelweis
      University. The authors examined the changes in the characteristic features of
      these patients and the task of supply. OBJECT: The aim of analysis was estimating
      of the place and importance of the therapeutic methods applicable to ambulatory
      patients. METHODS: Essential task of the outpatients service was to summarize the
      diagnostic results and to supply the lacks for the therapeutic plan of the
      patients. Having possession of the results they had to make decisions of the
      necessary and possible method of therapy. From the 1179 patients it was necessary
      the ward admittance of 787 patients, in 512 cases in hope of resective operation,
      and in 275 cases in order to carry out palliative intervention under hospitalized
      circumstances. 392 patients were treated as outpatients. To outpatients in 296
      cases tube endoprosthesis was implanted by endoscopic method for palliative
      purposes, there were made 14 dilating nasogastric tube treatments, in 2 cases
      percutaneous endoscopic gastrostomy, and in the case of 116 patients there were
      collaborations in intraluminal after-loading irradiation treatments. RESULTS: It
      appeared from the age-characteristics of the patients that the incidence in the
      examined period increased in the younger age-groups. The patients' main complaint
      was dysphagia, their average anamnesis-time was 4.03 months and it did not change
      during the 13 years. The incidence of the oesophago-respiratory fistula was 11.1%
      in the patient-population, and the incidence of reflectory dysphagia was 13.2%.
      There was an improvement in respect of the medical check-up of patients and the
      verification by histological examination of the tumorous process. In the case of
      597 patients it was observed dysphagia requiring palliation and in 482 cases it
      succeeded to perform it by implanting endoprosthesis. There were 36 unsuccessful
      implantation attempts and in the case of 79 patients there were no conditions of
      intervention. CONCLUSIONS: In the treatment of oesophageal tumorous patients the
      interventions made in favour of the palliative improvement of agglutination were
      executable within the frame of the outpatient service, from among of which the
      implantation of endoscopic tube appeared to be the method improving the patients'
      quality of life and survival with the best result. In the course of years
      palliative treatments were made more and more in the frame of outpatient service.
      The authors feel it necessary to consider all the condition-ameliorating
      treatment possibilities and applications, which may not be alternatives of each
      other but complementaries.

PMID- 15038319
TI  - [New steroid hormone family: endogenous cardiac glycosides and their role in
      physiologic and pathologic conditions].
AB  - In the last two decades extensive study has been carried out on the isolation,
      identification and biosynthesis of the "endogenous digitalis-like compounds"
      whose physiological and pathophysiological functions are only starting to be
      understood. Besides ouabain (strophanthin) and digoxin, four further endogenous
      cardiac glycosides were isolated and identified so far. These compounds are found
      in almost all mammalian tissues, including blood plasma and urine, but with the
      highest concentrations in the adrenal gland, pituitary and hypothalamus. De novo
      biosynthesis of these glycosides occurs in zona fasciculata cells of adrenal
      glands, precursors such as progesterone, pregnenolone, and rhamnose increase the
      synthesis of the ouabain-like immunoreactive material. The secretion of these
      compounds from the adrenocortical cells are controlled by adrenerg mechanisms, as
      well as via the renin-angiotensin system. The hydrophobic cardiac glycosides are
      transported in blood as complexes bound to specific binding globulins. The
      identified endogenous cardiac glycosides fulfill all the postulated criterions of
      the hormones, so they represent a new class of steroid hormones. The cardiac
      glycosides influence the active sodium pump, indirectly the intracellular free
      calcium concentration and therefore exert a positive inotropic effect on cardiac
      muscle. Furthermore, in physiological concentrations they can regulate the cell
      growth and protein synthesis inducing activation of intracellular signal
      pathways. Under pathological conditions, however, when the concentration of these
      steroids are high, they play a crucial role in the development of different
      serious illnesses such as essential hypertension as well as congestive heart
      failure. Further intensive investigations are needed to clarify some
      contradictory details accumulated during the last few years in this field.

PMID- 15038321
TI  - [Functional imaging in mental disorders].
AB  - Considerable progress has been achieved by functional brain imaging over the past
      20 years in uncovering the biological basis of major psychiatric disorders and to
      more effectively target therapeutics. Radioligand techniques, especially the PET
      (positron emission tomography) method, are specific and sensitive tools for
      quantitative in vivo imaging of molecular pathways and molecular interactions
      within brain tissues. Since 1980s, advances in neuroimaging and
      neurophysiological techniques have provided tremendous merits for investigations
      into different psychiatric disorders. PET and SPECT (single photon emission
      computer tomography) neuroreceptor imaging, especially in schizophrenia has been
      an extremely fruitful area of research. Evidences from these studies suggest that
      schizophrenia affects various cortical and subcortical regions involved in
      cognitive, emotional, and motivational aspects of human behavior. PET and SPECT
      provide useful data in studying the fundamental neurobiology of mood disorders.
      Both techniques are playing a central role in studying patients with new methods
      and ligands for specific receptor subtypes, and are likely to increase the
      application of PET/SPECT in the development of new pharmacotherapies. Nuclear
      medicine plays an important role in studying patients with other psychiatric
      disorders such as obsessive-compulsive disorder (OCD), attention deficit
      hyperactivity disorder (ADHD), anxiety, etc. Some forms of OCD seem to share a
      common genetic etiology with Tourette-syndrome (TS) and to be a facultative part
      of the TS phenotypic spectrum. In conclusion, PET and SPECT methods seem to be
      helpful in the diagnosis and management of patients with different psychiatric
      disorders and may provide a better understanding of clinical symptomatology or
      the relationship of these physiological parameters to the patient's prognosis.
      Additionally, radionuclide techniques may improve medical therapy by
      demonstrating individual biochemical abnormalities of altered brain functions.

PMID- 15038322
TI  - [Endoscopic placement of self-expanding metal stent for malignant colorectal
      obstruction].
AB  - AIM: 15-20% of the patients with colorectal carcinoma is admitted to hospital
      with symptoms of colonic obstruction. If urgent, subtotal colectomy can not be
      done, Hartmann operation is performed, that means diverting colostomy and
      resection followed by a later re-anastomosis. In this article the authors report
      on the placement of a self-expandable stent for decompression of a malignant
      colorectal obstruction, which allows elective one stage resection of the tumour
      affected segment. PATIENTS AND METHODS: A 63-year-old male patient was admitted
      with clinical and radiological symptoms of ileus. A total obstruction was found
      by irrigoscopy at the rectosigmoid transition. An atraumatic guide wire, and a
      balloon catheter were introduced through the stenotic segment and dilated to 15
      mm in diameter. Following that the stenosis was bridged with a SX Ella type, 25
      mm diameter, nitiol stent. RESULTS: After the placement of the metal stent the
      obstruction ceased. Stabilisation of the condition of the patient, proper pre
      operative decompression, definition of the tumour stage, appropriate preparation
      of the patient for the operation became possible. After elective, primary
      resection the patient recovered without complications. DISCUSSION: There are two
      main indications for the application of metal stents in colorectal obstructions.
      One of them is temporary, preoperative decompression in malignant colorectal
      obstruction. The other one is the palliative treatment of inoperable, malignant
      large bowel obstructions. In the latter case more complications have to be
      considered. CONCLUSIONS: Metal stent therapy is an effective and non-invasive,
      alternative method for preoperative or palliative treatment of malignant
      colorectal obstructions.

PMID- 15038324
TI  - ["Secrets" of the Nobel Prize].

PMID- 15038323
TI  - [Treatment of myocardial infarction with ST-segment elevation].

PMID- 15038325
TI  - [On the so-called activity of ulcer disease].

PMID- 15038326
TI  - Nurse's claim for sexual harassment, etc. fails.

PMID- 15038327
TI  - Nurse botches catheterization causing severe urethral stricture. Case on point:
      Tucker v. Community Medical Center, 833 A.2d 217-PA (2003).

PMID- 15038329
TI  - GA: is alleged negligence same as malpractice?: is expert medical testimony
      needed for negligence?

PMID- 15038328
TI  - MO: was association's oral agreement binding?: did statute of frauds apply to
      oral agreement?

PMID- 15038330
TI  - Licensed vocational nurse (LVN) recoils at 'graveyard shift': workers' comp.
      awarded. Case on point: E. & J. Gallo Winery v. Workers' Comp. Appeal Board, 2004
      WL 103535-CA.

PMID- 15038331
TI  - [Not Available].

PMID- 15038332
TI  - Opioids in chronic pain.

PMID- 15038333
TI  - [Not Available].

PMID- 15038334
TI  - [Not Available].

PMID- 15038335
TI  - Treatment of opioid-induced delirium with acetylcholinesterase inhibitors: a case
      report.
AB  - A 55-year-old woman with advanced ovarian cancer and severe pain developed
      hypoactive delirium after an increase in her opioid dosage. Myoclonus and
      delirium improved dramatically with the intravenous injection of the
      acetylcholinesterase inhibitor physostigmine, and this improvement was maintained
      during the administration of donepezil, an oral medication with similar
      pharmacodynamic properties. Evidence for a disorder of cholinergic
      neurotransmission in opioid-induced delirium is discussed, as is the rationale
      for treatment with acetylcholinesterase inhibitors and other cholinomimetic
      agents.

PMID- 15038336
TI  - Hot flashes refractory to HRT and SSRI therapy but responsive to gabapentin
      therapy.
AB  - There is a need for alternative therapies for hot flashes, as hormone replacement
      therapy (HRT) is associated with increased rates of breast cancer and heart
      disease, and some women fail to respond to HRT. A 32-year-old woman with
      surgically-induced menopause experienced 20-30 severe hot flashes per day and
      failed to respond to various formulations of HRT and selective serotonin reuptake
      inhibitor (SSRI) therapy for 17 years. She markedly responded to gabapentin
      therapy. Gabapentin, SSRIs, and estrogen may act at different cellular targets in
      the treatment of hot flashes.

PMID- 15038337
TI  - [Not Available].

PMID- 15038338
TI  - [Acupuncture].

PMID- 15038341
TI  - [Not Available].

PMID- 15038339
TI  - Efficacy of transdermal nitroglycerin combined with etodolac for the treatment of
      chronic post-thoracotomy pain: an open-label prospective clinical trial.
AB  - Chronic post-thoracotomy pain (CPP) is associated with surgical intercostal nerve
      injury. Like other forms of neuropathic pain, there is no ideal treatment.
      Nitroglycerin (NTG) has been found efficacious in acute pain, but has not been
      tested for chronic pain with neuropathic characteristics. The present study
      investigated the efficacy of NTG combined with the nonsteroidal anti-inflammatory
      drug etodolac for the treatment of CPP. Thirty of 129 patients who underwent
      thoracotomy within an 18-month period had moderate to severe pain that did not
      respond to etodolac. NTG, 5 mg/day, was added to the treatment. A significant
      reduction in VAS was observed on day 14 of treatment (from 66.7 +/- 11 to 42.1 +/
      5, P< 0.05). Similar changes were noted in breakthrough pain intensity and and
      sleep efficiency. The only side effect was mild headache, which was self-limited
      to the first few days of NTG administration. We conclude that NTG added to
      etodolac appears to be effective for the treatment of CPP, with minimal side
      effects. Further randomized blinded studies are required.

PMID- 15038340
TI  - [Not Available].

PMID- 15038342
TI  - Palliation of malignant bowel obstruction using a percutaneous cecostomy.
AB  - Bowel obstruction is a common complication of metastatic gastrointestinal and
      ovarian cancers, and can cause distressing symptoms. Along with medical options,
      surgical options should be considered in all patients with bowel obstruction,
      including percutaneous gastrostomy. We report the case of a patient with
      metastatic colon cancer with an obstructing recurrence at the primary site who
      was not eligible for major surgery or percutaneous gastrostomy and was managed
      with a percutaneous cecostomy for symptom control.

PMID- 15038343
TI  - [The constipating effect of the opioids Tilidine-N and Tramadol in comparison
      with codeine". Comment on the article by E. Freye et al].

PMID- 15038345
TI  - [Not Available].

PMID- 15038344
TI  - [Differential diagnosis of migraine attacks].

PMID- 15038346
TI  - [Protein chemistry determines light chain-mediated renal damage in patients with
      plasma cell dyscrasias: a molecular understanding of variable manifestations].

PMID- 15038347
TI  - [Brief introduction to gene transfer technique applied in the study of kidney
      diseases].

PMID- 15038348
TI  - [Advances in paediatric pathology].

PMID- 15038349
TI  - [Not Available].

PMID- 15038350
TI  - [Not Available].

PMID- 15038351
TI  - [Not Available].

PMID- 15038353
TI  - [Not Available].

PMID- 15038352
TI  - [Relaxation procedures for chronic pain patients].

PMID- 15038354
TI  - [The research advance on the pathology and pathogenesis of light chain deposition
      disease].

PMID- 15038355
TI  - [To enhance the study of the diagnosis and treatment of psychoses during
      pregnancy and postpartum stage].

PMID- 15038356
TI  - Neurobiological Background to Rehabilitation: Plasticity, Motor control,
      Spasticity and Pain Modulation. Proceedings of a symposium. September 19-21,
      2002, Goteborg, Sweden.

PMID- 15038357
TI  - Giant cell tumor of the distal fibula: fifteen-year result after en bloc
      resection and fibula reconstruction.
AB  - INTRODUCTION: Giant cell tumor of the distal fibula is a very rare condition. The
      treatment of advanced tumors at this location can be challenging and has been
      described in the literature only in single cases. MATERIALS AND METHODS: We
      report on a patient with a stage III giant cell tumor, according to the
      classification of Campanacci, of the distal fibula after en bloc resection and
      distal fibula reconstruction with a long bone graft from the iliac crest in a
      second procedure. The syndesmosis was reconstructed with a periosteal flap, the
      capsule and ligaments with local scar tissue. RESULTS: Fifteen years after the
      initial treatment the patient is free of local recurrence and demonstrates an
      excellent clinical outcome without any signs of instability, loss of function or
      osteoarthritis of the ankle joint. CONCLUSION: We suggest the method to be
      worthwhile for treatment of this uncommon lesion in terms of recurrence and
      functional outcome.

PMID- 15038358
TI  - [Pain therapy--carte blanche for charlatans? Call for standards].

PMID- 15038359
TI  - [Victory for the pain patient--a pyrrhic victory? Response to the editorial by P.
      Knuth in Schmerz 3/97].

PMID- 15038360
TI  - Proceedings of the 2nd International Symposium on Antioxidants in Nutrition and
      Therapy. 2-4 October 2002, Bali, Indonesia.

PMID- 15038361
TI  - Where are the words to heal?

PMID- 15038363
TI  - A healing truth in puns.

PMID- 15038362
TI  - On reviewing manuscripts.

PMID- 15038364
TI  - The smallest patient.

PMID- 15038365
TI  - The use of generic names.

PMID- 15038366
TI  - Cold comfort.

PMID- 15038367
TI  - Cerebral modeling and dynamic Bayesian networks.
AB  - The understanding and the prediction of the clinical outcomes of focal or
      degenerative cerebral lesions, as well as the assessment of rehabilitation
      procedures, necessitate knowing the cerebral substratum of cognitive or
      sensorimotor functions. This is achieved by activation studies, where subjects
      are asked to perform a specific task while data of their brain functioning are
      obtained through functional neuroimaging techniques. Such studies, as well as
      animal experiments, have shown that sensorimotor or cognitive functions are the
      offspring of the activity of large-scale networks of anatomically connected
      cerebral regions. However, no one-to-one correspondence between activated
      networks adn functions can be found. Our research aims at understanding how the
      activation of large-scale networks derives from cerebral information processing
      mechanisms, which can only explain apparently conflicting activation data. Our
      work falls at the crossroads of neuroimaging interpretation techniques and
      computational neuroscience. Since knowledge in cognitive neuroscience is
      permanently evolving, our research aims more precisely at defining a new modeling
      formalism and at building a flexible simulator, allowing a quick implementation
      of the models, for a better interpretation of cerebral functional images. It also
      aims at providing plausible models, at eht level of large-scale networks, of
      cerebral information processing mechanisms in humans. In this paper, we propose a
      formalism, based on dynamic Bayesian networks (DBNs), that respects the following
      constraints: an oriented, networks architecture, whose nodes (the cerebral
      structures) can all be different, the implementation of causality--the activation
      of the structure is caused by upstream nodes' activation--the explicit
      representation of different time scales (from 1 ms for the cerebral activity to
      many seconds for a PET scan image acquisition), the representation of cerebral
      information at the integrated level of neuronal populations, the imprecision of
      functional neuroimaging data, the nonlinearity and the uncertainty in cerebral
      mechanisms, and brain's plasticity (learning, reorganization, modulation). One of
      the main problems, nonlinearity, has been tackled thanks to new extensions of the
      Kalman filter. The capabilities of the formalism's current version are
      illustrated by the modeling of a phoneme categorization process, explaining the
      different cerebral activations in normal and dyslexic subjects.

PMID- 15038369
TI  - [The 96th annual meeting of the Japanese Society of Animal Reproduction.
      Hokkaido, Japan. September 11-13,2003. Abstracts].

PMID- 15038368
TI  - Automated segmentation of human brain MR images using a multi-agent approach.
AB  - Image interpretation consists in finding a correspondence between radiometric
      information and symbolic labeling with respect to specific spatial constraints.
      It is intrinsically a distributed process in terms of goals to be reached, zones
      in the image to be processed and methods to be applied. To cope the the
      difficulty inherent in this process, several information processing steps are
      required to gradually extract information. In this paper we advocate the use of
      situated cooperative agents as a framework for managing such steps. Dedicated
      agent behaviors are dynamically adapted depending on their position in the image,
      of their topographic relationships and of the radiometric information available.
      The information collected by the agents is gathered, shared via qualitative maps,
      or used as soon as available by acquaintances. Incremental refinement of
      interpretation is obtained through a coarse to fine strategy. Our work is
      essentially focused on radiometry-based tissue interpretation where knowledge is
      introduced or extracted at several levels to estimate models for tissue-intensity
      distribution and to cope with noise, intensity non-uniformity and partial volume
      effect. Several experiments on phantom and real images were performed. A complete
      volume can be segmented in less than 5 min with about 0.84% accuracy of the
      segmented reference. Comparison with other techniques demonstrates the potential
      interest of our approach for magnetic resonance imaging (MRI) brain scan
      interpretation.

PMID- 15038371
TI  - [The 77th annual meeting of the Japanese Society for Bacteriology. Osaka, Japan.
      April 1-3, 2004. Abstracts].

PMID- 15038370
TI  - [The 44th annual meeting of the Japanese Respiratory Society. Tokyo, Japan. March
      31,April 1-2,2004. Program and Abstracts].

PMID- 15038372
TI  - Conditions for psychiatric patients--a report: recommendations.

PMID- 15038373
TI  - Research involving persons with mental disorders that may affect decisionmaking
      capacity--executive summary.

PMID- 15038374
TI  - The bioethical structure of a human being.
AB  - Bioethical debates such as those surrounding the manipulation of human embryos
      are often based on metaphysical assumptions that lack a foundation in the natural
      sciences. In this paper we support a gradualist position whereby the embryo
      progressively takes on the form and associated ethical significance of a human
      being. We support this position by introducing a concept of biological structure
      or form to show how the gradualist position has its metaphysical foundations in
      modern biology. The conceptual basis for form and structure are outlined and
      their compatibility with and basis in current empirical biology is demonstrated
      by some recent advances in our understanding of the processes of development from
      single cell to organism. We then briefly explore the ethical significance of
      accepting a form or structure based conception of biology for the status of the
      early embryo.

PMID- 15038375
TI  - Can it ever be better never to have existed at all? Person-based consequentialism
      and a new repugnant conclusion.
AB  - Broome and others have argued that it makes no sense, or at least that it cannot
      be true, to say that it is better for a given person that he or she exist than
      not. That argument can be understood to suggest that, likewise, it makes no
      sense, or at least that it cannot be true, to say that it is worse for a given
      person that he or she exist than that he or she never have existed at all. This
      argument is of critical importance to the question of whether consequentialist
      theory should take a traditional, aggregative form or a less conventional, person
      affecting, or person-based form. I believe that, potentially, the argument
      represents a far more serious threat to the person-based approach than does, for
      example, Parfit's two medical programmes example. Parfit's example nicely
      illuminates the distinction between aggregative and person-based approaches and
      raises important questions. But the example--though not, I think, by Parfit--is
      sometimes pressed into service as a full-fledged counterexample against the
      person-based approach. As such, I argue, the example is not persuasive. In
      contrast, the Broomeian argument, if correct, is definitive. For that argument
      relies on certain metaphysical assumptions and various uncontroversial normative
      claims--and hence nicely avoids putting into play the controversial normative
      claims that lie at the very heart of the debate. The purpose of the present
      paper, then, is to evaluate the Broomeian argument. I argue that this potentially
      definitive challenge to a person-based approach does not in fact succeed.

PMID- 15038376
TI  - Re: Tunks E. The chronic need to improve the management of pain. Pain Res Manage
      2003;8(4):187-188.

PMID- 15038377
TI  - Response to John Berkman and "Gestating the embryos of others".

PMID- 15038378
TI  - Reply to Tonti-Filippini on "Gestating the embryos of others".

PMID- 15038379
TI  - Holism, determinism, and the developing embryo.

PMID- 15038381
TI  - Ethical decision making for Christian physicians: inspiration from Saint Ignatius
      of Loyola.

PMID- 15038380
TI  - Further discussion: determination of death by neurological criteria.

PMID- 15038382
TI  - Embryonic rights: self-interest and the Thirteenth Amendment.

PMID- 15038384
TI  - Using pluripotent germ cells in regenerative medicine: an ethical alternative.

PMID- 15038383
TI  - The ovulation or pregnancy approach in cases of rape?

PMID- 15038385
TI  - John Paul II on the language empowering the culture of death.

PMID- 15038386
TI  - Artificial hydration and nutrition for the PVS patient: ordinary care or
      extraordinary intervention?

PMID- 15038387
TI  - Caring for homeless persons living with AIDS: compassion in the healing
      relationship.

PMID- 15038388
TI  - Testimony on embryo research and related issues.

PMID- 15038389
TI  - Aging and the endothelium.
AB  - One link between aging and endothelial function is the inflammatory response. On
      one hand, the latter shortens the biological engaged by activated leukocytes
      against invaders or stressing agents. On the other hand, the surveyed tissues
      become targets of the toxicity of reactive oxygen species, ROS. The ensuing
      regeneration is source of transcriptional infidelity, leading to the alteration
      of the repaired tissue. Hence, the toll of inflammatory stress consists in
      premature senescence of cell and tissues. This hypothesis is discussed in the
      present review, which focuses on the molecular targets relevant for cancer and
      degenerative diseases, both tributary to an inflammatory environment and taking
      advantage from the consequences of cell and tissue dysfunctions characteristic of
      aging. Eventually, adaptation to stress, whatever its origin -inflammatory and/or
      psychosocial-is discussed. Basal nitric oxide (NO) release, such as provided
      through moderate exercise, seems to be the most potent guardian against immune,
      nervous and cardiovascular over-stimulation. Tissue regeneration is also obtained
      by circulating endothelial progenitors able to recognize the damaged tissue. To
      avoid post-inflammatory alterations resulting in detrimental changes of tissues
      and organs, the pharmacological protection of endothelium by agents able to
      modulate its activation seems crucial to us.

PMID- 15038391
TI  - European biotech gets personal.

PMID- 15038390
TI  - Dystrophin expression in myofibers of Duchenne muscular dystrophy patients
      following intramuscular injections of normal myogenic cells.
AB  - Three Duchenne muscular dystrophy (DMD) patients received injections of myogenic
      cells obtained from skeletal muscle biopsies of normal donors. The cells (30 x 10
      (6)) were injected in 1 cm3 of the tibialis anterior by 25 parallel injections.
      We performed similar patterns of saline injections in the contralateral muscles
      as controls. The patients received tacrolimus for immunosuppression. Muscle
      biopsies were performed at the injected sites 4 weeks later. We observed
      dystrophin-positive myofibers in the cell-grafted sites amounting to 9 (patient
      1), 6.8 (patient 2), and 11% (patient 3). Since patients 1 and 2 had identified
      dystrophin-gene deletions these results were obtained using monoclonal antibodies
      specific to epitopes coded by the deleted exons. Donor dystrophin was absent in
      the control sites. Patient 3 had exon duplication and thus specific donor
      dystrophin detection was not possible. However, there were fourfold more
      dystrophin-positive myofibers in the cell-grafted than in the control site. Donor
      dystrophin transcripts were detected by RT-PCR (using primers reacting with a
      sequence int eh deleted exons) only in the cell-grafted sites in patients 1 and
      2. Dystrophin transcripts were more abundant in the cell-grafted than in the
      control site in patient 3. Therefore, significant dystrophin expression can be
      obtained in teh skeletal muscles of DMD patients following specific conditions of
      cell delivery and immunosuppression.

PMID- 15038392
TI  - Biotech is the new alchemy.

PMID- 15038393
TI  - Respecting communities allays biopiracy alarm.

PMID- 15038394
TI  - Trends in the development of chiral drugs.

PMID- 15038395
TI  - Benign prostatic hyperplasia: medical management considering sexual function and
      prostate cancer.

PMID- 15038396
TI  - "Alphabet soup" and the prostate: LUTS, BPH, BPE, and BOO.
AB  - The patient described, though not typical, is one among many of those of the
      aging male population in whom their primary care physicians will increasingly
      diagnose diseases affecting the prostate gland. Primary care physicians then will
      offer first-line therapy not only for prostatic diseases but also for concurrent
      sexual and erectile dysfunction. This brief primer for primary care physicians
      "unscrambles" the alphabet in a "soup" of initialisms and acronyms for lower
      urinary tract symptoms, benign prostatic hyperplasia, benign prostatic
      enlargement, and bladder outlet obstruction.

PMID- 15038397
TI  - Benign prostatic hyperplasia, sexual function, and overall evaluation of the male
      patient.
AB  - Erectile dysfunction (ED) and benign prostatic hyperplasia (BPH) are a
      significant problem for a large proportion of men in the United States. Lower
      urinary tract symptoms (LUTS), which are often caused by BPH, and ED are common
      in the aging male population. From numerous epidemiologic studies, it is well
      known that the prevalence of BPH and the loss of erectile function increase with
      advancing age. Men with LUTS have sexual dysfunction, including ejaculatory loss,
      painful ejaculation, and ED. Even though the pathogenic relationship between BPH
      and ED is not completely understood, a direct association between these two
      symptom complexes in aging men is now becoming evident. This presentation reviews
      the role of LUTS and ED in aging men and noninvasive and invasive treatment
      modalities for BPH.

PMID- 15038398
TI  - A current review of medical therapy for benign prostatic hyperplasia.
AB  - Benign prostatic hyperplasia (BPH) is one of the most common diseases of aging
      men. It is estimated that by age 60 years, greater than 50% of men will have
      histologically documented evidence of the disease. Therapy for this disease has
      evolved considerably from its inception. Recent data from long-term population
      based studies have shed new light on the treatment of this common problem in
      aging men. The authors review the current state of diagnosis of BPH and medical
      therapy for this condition in the primary care setting.

PMID- 15038399
TI  - Christian Doppler and the influence of his work on modern medicine.

PMID- 15038400
TI  - [Do we need a new addiction medicine specialty?].

PMID- 15038401
TI  - [Drug interactions with antiepileptic agents].
AB  - Drug interactions with antiepileptic agents are based in large part on
      pharmacokinetic mechanisms. Most prominent are induction or inhibition of enzymes
      of the cytochrome P450 (CYP) system, which is of central importance for metabolic
      elimination of lipophilic xenobiotics. Potent inductors of CYP isoenzymes are
      carbamazepine, phenobarbital, phenytoin, and primidone, thereby decreasing not
      only their own plasma levels and efficacy but also that of other antiepileptics
      and other drugs. Felbamate, oxcarbazepine, and topiramate are weak inductors of
      the CYP isoenzyme 3A4, whereas they inhibit CYP2C19. Valproic acid is a potent
      inhibitor of several CYP isoenzymes and glucuronyltransferases, resulting in an
      increase in plasma concentrations and toxicity of antiepileptics and other drugs.
      Antiepileptics that are not involved in drug interactions include gabapentin,
      levetiracetam, and vigabatrine. The P-glycoprotein may mediate the exit of
      antiepileptics from the brain. This transport mechanism is inhibited by
      carbamazepine, which may explain the enhanced clinical efficacy of a combination
      of carbamazepin with other antiepileptics. Other possible pharmacokinetic
      interactions are precipitation of antiepileptics in the stomach by antacids or
      sucralfate and displacement from plasmaprotein binding of one antiepileptic agent
      by another. Therapeutic drug monitoring (TDM) may be helpful in assessing
      pharmacokinetic drug interactions. Pharmacodynamic interactions appear to be
      responsible for the enhanced efficacy of antiepileptic combination therapy. In
      prescribing drugs, their spectrum of interactions has to be known.

PMID- 15038403
TI  - Anthroposophical medicine: a systematic review of randomised clinical trials.
AB  - The aim of this systematic review was to summarise and critically evaluate all
      randomised clinical trials testing the effectiveness of the whole system of
      anthroposophical medicine either as a sole or as an adjunctive form of treatment.
      Seven independent literature searches were conducted to locate all such studies.
      Trials of single remedies within the wider anthroposophical approach were
      excluded. No language restrictions were applied. Unfortunately not a single study
      was located which met the inclusion/exclusion criteria. It was therefore
      concluded that, at present, the question whether the anthroposophical concept of
      healing generates more good than harm cannot be answered.

PMID- 15038404
TI  - Glutathione S-transferase M1 gene polymorphism is related to COPD in patients
      with non-small-cell lung cancer.
AB  - OBJECTIVE: Oxidative stress contributes to the development of both lung cancer
      and chronic obstructive pulmonary disease (COPD). Antioxidative enzymes may
      protect against such damage. We hypothesized that genetic variations in
      glutathione S-transferase M1 and/or T1 genes (GSTM1 and GSTT1, respectively) may
      influence susceptibility to COPD in patients with non-small-cell lung cancer.
      PATIENTS AND METHODS: The polymorphisms in GSTM1 and GSTT1 genes were examined in
      110 patients (age: 63+/-1 years) with newly diagnosed non-small-cell lung cancer
      using the polymerase chain reaction. Respiratory function was assessed by
      bodyplethysmography. RESULTS: In the GSTM1 null (-/-) genotype, both FEV1 and
      FEV1/FVC were significantly lower than in the GSTM1 plus genotype (GSTM1 -/+ or
      +/+) (75.8+/-2.5 versus 86.6+/-3.6%, p<0.02; 69.1+/-1.6 versus 77.0+/-2.4,
      p<0.01, respectively). Among the patients with GSTM1 null genotype, 49% suffered
      from COPD as opposed to 21% of patients with GSTM1 plus genotype. In contrast, no
      differences were seen in FEV1 or FEV1/FVC when comparing patients with GSTT1 null
      genotype and GSTT1 plus genotype (81.4+/-4.9 versus 79.3+/-2.3, p=NS; 71.1+/-2.9
      versus 72.2+/-1.6, p=NS). Multiple stepwise regression analysis identified the
      GSTM1 genotype (p<0.02) as a significant independent predictor of FEV1 in this
      group of patients. CONCLUSION: The present study suggests that in patients with
      non-small-cell lung cancer the presence of at least one active allele in GSTM1
      has a protective effect against the development of COPD.

PMID- 15038402
TI  - [Current consumer conditions among opioid addicts--implications for maintenance
      treatment programmes provided by ambulatory drug treatment centers and
      physicians].
AB  - BACKGROUND: Anonymous evaluation of the current conditions of drug scene and drug
      consumption, entrance age, personal motives for drug consumption and satisfaction
      among opioid-dependent clients with treatments available within an ambulant
      maintenance treatment setting. METHODS: The questionnaire for the study was based
      on representative studies and covered 112 questions regarding drug consumption.
      In addition, an instrument of the "Hessische Landesstelle gegen die
      Suchtgefahren", which measures satisfaction of opioid clients regarding public
      drug-treatment centers, was used. RESULTS: A total of 158 opioid clients within
      an ambulant maintenance treatment setting were enrolled in the study. The mean
      age at first drug consumption was 15.1 (2.4) years for men and 15.2 (3.5) years
      for women. The Spearman correlation showed a significant positive correlation
      (r=0.284) between age and time of first drug consumption (p=0.019). Cannabis was
      the most frequent entrance drug (55.8%), followed by alcohol (33.8%), opioids
      (17.6%) and nicotine (11.8%). Additional consumption of benzodiazepines was
      observed in 44.7% of men and 39.7% of women, of cannabis in 74.5% of men and
      52.4% of women, and of sustained-release morphine in 41.4% of men and 33.3% of
      women. Within the previous 6-12 months cocaine was consumed significantly less
      (p=0.024) by men (63.8%) than by women (90.5%). 93.3% of the drug users rated a
      follow-up assistance programme after withdrawal and 71.9% special care programmes
      for designer drugs very important. IMPLICATIONS: The present study supports the
      assumption of an earlier age of first drug consumption. In view of our findings
      on entrance age, and on polytoxicomanic consumption patterns and gender-specific
      differences, we believe that the objectives of substitution programmes can only
      be reached if programmes are adequately adapted to the actual conditions of the
      drug scene and are able to cooperate with other public drug-treatment systems.

PMID- 15038406
TI  - Hyperbaric oxygenation combined with streptokinase for treatment of arterial
      thromboembolism of the lower leg.
AB  - Thromboembolic occlusion of peripheral arteries is a common problem in patients
      referred to vascular surgery departments. Standard treatments include catheter
      aspiration techniques, use of fibrinolytic agents and surgical
      thrombendarterectomy. Recent reports have described the use of hyperbaric oxygen
      therapy in patients with limb ischemia, yet their main focus has been on patients
      with chronic disorders. We present the case of a 74-year-old woman with atrial
      fibrillation and acute thromboembolic occlusion of the posterior tibial artery.
      The patient presented with severe pain in the right calf, unresponsive to non
      opioid parenteral analgesia and accompanied by coldness, numbness and partial
      motor palsy of the right foot. After 60 minutes of oxygenation in a hyperbaric
      chamber with a pressure of 2.2 bar, the pain receded, although without signs of
      restored blood flow in the occluded artery. After fibrinolytic therapy with
      streptokinase, patency of the posterior tibial artery was verified by return of
      palpable pulsations and color Doppler ultrasonography. By combining hyperbaric
      oxygenation and streptokinase in the treatment of lower-leg arterial
      thromboembolism we achieved regression of ischemic pain, prolongation of the
      survival time of tissues compromised by ischemia and resolved the cause of the
      ischemia. We believe the use of this therapeutic strategy in selected cases of
      peripheral arterial thromboembolism is justified.

PMID- 15038405
TI  - Bcl-2 expression and other clinicopathologic parameters in uterine
      leiomyosarcoma.
AB  - BACKGROUND: The bcl-2 protein, which is involved in cell-cycle regulation and
      apoptosis, seems to play an important role in the growth of tumors. Until
      recently, only one study described the frequent expression of bcl-2 in uterine
      leiomyosarcomas (LMS) and indicated its important prognostic role. Thus, the aims
      of the present study were to examine bcl-2 expression in patients with uterine
      LMS and to determine if the expression of this protein would influence the
      prognosis. In addition, a possible association between bcl-2 expression and
      various clinicopathologic parameters was evaluated. PATIENTS AND METHODS: Bcl-2
      expression was investigated using immunohistochemical techniques on paraffin
      embedded tissue from 21 patients with uterine LMS. The immunohistochemical
      findings were correlated with different clinicopathologic parameters (FIGO stage,
      age, vascular-space involvement and recurrence of disease) of the patients.
      RESULTS: Bcl-2 was expressed in 57% (12/21) of uterine LMS: 3/12 (25%) stained
      weakly positive, 3/12 (25%) stained moderately positive and 6/12 (50%) stained
      strongly positive. Nine (43%) cases were negative. Evaluation of the correlation
      between bcl-2 expression and several clinicopathologic parameters identified a
      significant negative correlation between vascular-space involvement and bcl-2
      expression (p=0.04). The relationship between bcl-2 expression and FIGO stage,
      age and recurrence of disease did not reach statistical significance. A
      univariate Cox model revealed significantly longer overall survival in women with
      bcl-2-positive LMS compared with women with bcl-2-negative LMS (p=0.03).
      CONCLUSIONS: Significant negative correlation was found between bcl-2 expression
      and vascular-space involvement and improved survival rates in patients with bcl-2
      positive tumors. Though limited by the small number of patients, these data
      indicate the role of bcl-2 expression in uterine LMS.

PMID- 15038407
TI  - [Ruptured abdominal aortic aneurysms: status quo after a quarter century of
      treatment experience].

PMID- 15038408
TI  - Percutaneous aortic valve replacement: more than palliation?

PMID- 15038409
TI  - Levosimendan: first in a new class of inodilator for acute and chronic severe
      heart failure.
AB  - Heart failure is the most common malignant disease in the developed world.
      Levosimendan (Simdax) is a novel intravenous agent that exerts inotropic effects
      through sensitization of myofilaments to calcium and vasodilator effects by
      opening ATP-dependent potassium channels on vascular smooth muscle. Infusion of
      levosimendan increases cardiac output due to an increase in stroke volume and
      heart rate, with a fall in pulmonary capillary wedge pressure. It has an active
      metabolite with a half-life of about 80 h, therefore infusions of 6 to 24 h
      result in hemodynamic effects that persist for 7 to 10 days. Preliminary
      observations suggest that a single infusion of levosimendan lasting 6 to 24 h in
      patients with severe heart failure due to left ventricular systolic dysfunction
      results in hemodynamic changes, symptomatic benefit and a reduction in morbidity
      and mortality over the following 2 to 4 weeks compared with placebo in one study
      and with dobutamine in another. Long-term follow-up suggests no loss of this
      early benefit over 6 months. Levosimendan is licensed for the treatment of
      decompensated heart failure in many countries but not in North America. Further
      large trials are being conducted comparing levosimendan with placebo and with
      dobutamine in patients with severe heart failure and left ventricular systolic
      dysfunction. If these studies confirm the benefits of levosimendan, then it may
      become routine therapy for the management of severe heart failure.

PMID- 15038410
TI  - Skeletal myoblast transplantation for cardiac repair.
AB  - Cell transplantation is gaining interest as a potentially new means of improving
      function of the failing heart through replacement of lost cardiomyocytes with new
      contractile cells. Primarily for practical reasons, autologous skeletal myoblasts
      have been the first to undergo clinical trials but other cell types are also
      being considered, particularly bone marrow stem cells which are credited for a
      plasticity that might allow them to change their phenotype in response to
      environmental cues. Several key issues still need to be addressed including: the
      comparative efficacy of different donor cell lineages in relation to the
      patient's clinical condition (i.e., ischemia vs. heart failure, the mechanism by
      which cell engraftment improves cardiac function, the enhancement of cell
      survival and functional integration within the recipient tissue, and the
      development of minimally invasive cell delivery techniques. In parallel to these
      laboratory studies, clinical trials are now being implemented to generate
      efficacy data. Altogether, these efforts should allow the assessment of whether
      and to what extent cell transplantation may ameliorate function of the failing
      heart.

PMID- 15038412
TI  - Immunomodulatory treatment strategies in inflammatory cardiomyopathy: current
      status and future perspectives.
AB  - Chronic autoimmunity and viral persistence constitute prognostic factors for
      adverse outcome in dilated cardiomyopathy patients. Inflammatory cardiomyopathy
      is a specific cardiomyopathy entity diagnosed in approximately 50% of dilated
      cardiopmyopathy patients by immunohistological quantification of immunocompetent
      infiltrates and cell adhesion molecule abundance. Patients with autoimmune
      inflammatory cardiomyopathy benefit from immunosuppressive treatment and
      immunoadsorption by improvement of left ventricular ejection fraction and heart
      failure symptoms, paralleled by a significant suppression of intramyocardial
      inflammation. However, dilated cardiomyopathy patients with viral persistence do
      not respond favorably to immunosuppression.

PMID- 15038411
TI  - The role of aldosterone in heart failure and the clinical benefits of aldosterone
      blockade.
AB  - Aldosterone has a variety of detrimental effects on the heart and vasculature and
      is increasingly recognized as an important target in chronic heart failure, as
      illustrated by the Randomized Aldactone Evaluation Study. In this article, the
      evidence supporting the cardiovascular effects of aldosterone in humans and the
      proven benefits of aldosterone-receptor antagonists in heart failure shall be
      discussed.

PMID- 15038413
TI  - The role of cardiovascular magnetic resonance in the evaluation of patients with
      heart failure.
AB  - Chronic heart failure is a common disorder placing significant burdens on
      patients and health-care services. Noninvasive imaging plays a central role in
      accurate diagnosis, determination of etiology and prognosis, and in monitoring
      therapy. Advances in technology mean cardiovascular magnetic resonance (CMR)
      imaging has established itself as both a valuable clinical and research tool in
      this arena. Not only is CMR the new gold standard for accurate and reproducible
      assessment of ventricular volumes and mass, but by using gadolinium contrast,
      underlying pathology can often be determined. In ischemic cardiomyopathy a 'one
      stop' assessment can be made of function, perfusion and mass. Continuing advances
      such as myocardial tagging and the increasing availability of CMR mean that it
      will become an increasingly important and useful tool for clinicians looking
      after patients with cardiomyopathy and heart failure.

PMID- 15038414
TI  - Transesophageal echocardiography: a complementary view of the heart.
AB  - Transesophageal echocardiography has been widely used as a diagnostic tool during
      the past two decades to detect cardiac abnormalities that are not visible or
      poorly visible with transthoracic echocardiography. At present, transesophageal
      echocardiography is a cornerstone of modern diagnosis of several cardiac
      diseases, providing diagnostic, prognostic and therapeutic information. In this
      review, the present status of transesophageal echocardiography not only as a
      diagnostic tool, underlining its effects on clinical decision making, but also as
      a monitoring adjunct for many interventional cardiac procedures is examined.

PMID- 15038415
TI  - Stress echocardiography.
AB  - Stress echocardiography is the combination of 2D echocardiography with a
      physical, pharmacological or electrical stress. The diagnostic end point for the
      detection of myocardial ischemia is the induction of a transient worsening in
      regional function during stress. Stress echocardiography provides similar
      diagnostic and prognostic accuracy as radionuclide stress perfusion imaging but
      at a substantially lower cost, without environmental impact and with no
      biohazards for the patient and the physician. In spite of its dependence upon
      operator's training, it is the best possible choice to achieve the still elusive
      target of sustainable cardiac imaging in the field of noninvasive diagnosis of
      coronary artery disease.

PMID- 15038416
TI  - Recent advances in echocardiography.
AB  - Important recent developments have occurred in echocardiography that are already
      being used clinically. Portable ultrasound devices that weigh less than five
      pounds are capable of performing a complete bedside echo exam. An intracardiac
      echocardiographic catheter has recently been introduced that can be placed
      intracardiac via a vein and navigated within right heart chambers to obtain
      detailed anatomical landmarks that guide catheter based interventional procedures
      such as intracardiac ablation and closure of atrial septal defects and patent
      foramen ovale. Tissue Doppler imaging is finding its role in detecting mechanical
      asynchrony in patients with congestive heart failure who might benefit from
      biventricular pacing. The availability of real-time 3D echocardiography has for
      the first time made assessment of complex cardiac anatomy possible. This review
      discusses each of these new developments and their potential impact on the
      practice of echocardiography and cardiology in general.

PMID- 15038417
TI  - Allografts for aortic valve and root replacement: veni vidi vici?
AB  - Allografts were introduced in the early 1960s for the replacement of the aortic
      valve and regarded at the time as a close-to-perfect valve substitute. However,
      over the past 40 years it has become evident that not all of the high
      expectations could be met. This review summarizes the past 40 years of clinical
      experience with allografts for aortic valve replacement, describes the advantages
      and disadvantages of allografts compared with other aortic valve substitutes and
      their impact on patient prognosis, and discusses the future role of allografts
      for the replacement of the aortic valve or root.

PMID- 15038418
TI  - Acquired aortic stenosis.
AB  - Aortic stenosis is the most commonly encountered valvular disease in the elderly,
      with approximately 2-3% of individuals over 65 years of age afflicted. The most
      common cause of acquired aortic stenosis is calcific degeneration, characterized
      by a slowly progressive, asymptomatic period which can last decades. Once
      symptomatic, the clinical manifestation of aortic stenosis is from functional
      obstruction of left ventricular outflow and the additional hemodynamic effects on
      the left ventricle and vasculature. With advances in echocardiography,
      individuals with aortic stenosis are increasingly diagnosed in the asymptomatic
      latent period. However, echocardiographic measures alone cannot identify
      clinically significant outflow obstruction as there is considerable overlap in
      hemodynamic severity between symptomatic and asymptomatic individuals. Current
      clinical guidelines predicate the timing of surgical valve replacement on the
      presence or absence of symptoms. Management for symptomatic, significant stenosis
      is surgical valve replacement as there are no current medical therapies reliably
      proven to decrease aortic stenosis severity or improve long-term outcomes.
      However, recent retrospective studies have demonstrated an association between
      atherosclerotic disease risk factors, such as hyperlipidemia and aortic stenosis.
      Given these findings, there are now advocates for prospective primary prevention
      trials for aortic stenosis in patients with mild or moderate valvular disease.
      The following paper will discuss etiology, diagnostic evaluation and therapeutic
      options of acquired aortic stenosis. This review will discuss etiology,
      diagnostic evaluation, and therapeutic options of acquired aortic stenosis.

PMID- 15038420
TI  - Stentless aortic valve replacement: current status and future trends.
AB  - Stentless aortic xenografts were introduced into clinical practice as aortic
      valve substitutes over a decade ago. Stentless prosthetic valves were expected to
      provide enhanced durability and more physiologic hemodynamic behavior when
      compared with stented bioprostheses. Whilst the former expectation has not been
      fulfilled, partly due to concomitantly improved durability of second-generation
      stented bioprostheses, the latter has consistently been satisfied in early and
      late clinical observation. Evidence is accumulating suggesting improved long-term
      survival due to more timely and thorough regression of ventricular hypertrophy.
      In addition, stentless xenografts have shown extreme versatility when adopted in
      a variety of complex clinical conditions associated with aortic valve disease,
      including small aortic anulus, ascending aortic aneurysm, endocarditis and left
      ventricular dysfunction. Future research in the form of prospective, multicenter,
      randomized trials must address the issues of very long-term durability and
      survival, while simplification in valve design is required to promote wider use
      of stentless valves.

PMID- 15038419
TI  - Radiofrequency applications in congenital heart disease.
AB  - The relatively recent application of radiofrequency technologies in the treatment
      of congenital heart defects has provided a safe and effective alternative to
      conventional therapies in establishing endovascular patency for a variety of
      lesions. Radiofrequency, with typically used frequencies of approximately 500
      kHz, does not cause pain and is unlikely to induce atrial or ventricular
      fibrillation. It can be used either to ablate (higher power (35-50 W); longer
      duration of application (90-120 sec); lower voltage (30-50 V)) or to perforate
      (lower power (5-10 W) shorter duration of application (1-5 sec), higher voltage
      (150-280 V)). In the past, perforating radiofrequency has been applied to
      establish right ventricular outflow tract patency in pulmonary atresia with
      intact septum and with ventricular septal defect. More recently radiofrequency
      has been shown to be effective at recanalizing central and peripheral vasculature
      and has also been applied in establishing percutaneous left heart access. A new
      radiofrequency catheter, dedicated to transseptal left atrial cannulation, has
      been demonstrated to be safe and effective in an animal model and is now ready
      for clinical trials.

PMID- 15038421
TI  - The role of echocardiography in the diagnosis and prognosis of patients with
      heart failure.
AB  - The number of patients with congestive heart failure has increased in epidemic
      proportions. Echocardiography plays an important role in the diagnosis and
      management of these patients. Recent studies have also confirmed the independent
      prognostic information of the echocardiographic findings.

PMID- 15038422
TI  - Cervical spondylomyelopathy (wobbler syndrome) in the Boerboel.
AB  - The Boerboel is a South African large-breed dog resembling a Bullmastiff. The
      records of Onderstepoort Veterinary Academic Hospital were searched for dogs that
      had presented, between 1998 and 2003, with symptoms indicative of wobbler
      syndrome and had undergone survey radiographic and myelographic studies. Ten
      cases fitted the inclusion criteria. Dogs presented within the first 2 years of
      life, often with acute onset of symptoms. All presented with pelvic limb and 6
      with concomitant thoracic limb ataxia or paresis. Treatment varied and included
      none (4), prednisolone (2), and dorsal laminectomy (2). Two dogs were euthanased
      at the time of diagnosis. The breed appears to be affected with a form of
      spondylomyelopathy that comprises bony malformation of cervical and/or thoracic
      vertebrae. In 8 dogs, malformations were evident on survey radiographs and were
      characterised by enlarged, irregular articular facets and associated medial
      deviation of the pedicles. These changes resulted in axial compression of the
      spinal cord best seen on ventrodorsal or dorsoventral myelographic studies.
      Multiple vertebrae were affected in some dogs and lesions were not confined to
      the caudal area of the cervical spine. Three dogs were alive and without symptoms
      at follow-up. Four were euthanased as a result of the disease and 1 died as a
      result of post-operative complications. Two additional dogs presenting with
      wobbler clinical signs are also described. One had medial deviation of the T5 and
      T6 caudal pedicles and 1 dog suffered from multiple cervical articular facet
      synovial cysts.

PMID- 15038423
TI  - The use of dried bakery products in a free-choice feeding method for small-scale
      broiler production.
AB  - Waste material from bakeries is an unconventional energy feed source which is
      available in sufficient quantities for use in small-scale broiler production in
      South Africa. Small-scale broiler producers do not have access to the computer
      programs required to balance home-mixed rations. This investigation confirms that
      the use of dried bakery products (DBP) in a 2-stage, free-choice method can be
      used to compensate for this lack. A total of 570 day-old male broiler chickens
      was assigned to 3 feeding treatments: the control group was fed a 2-stage feeding
      programme using standard commercial starter and grower rations. The 2nd group
      received a commercial starter ration up to Day 7 and was thereafter given a
      choice of a commercial starter ration with normal salt content (0.35%) and DBP.
      The 3rd group was fed a commercial starter ration up to Day 7, then offered a
      choice of commercial starter ration with a lower salt content (0.1%) and DBP. The
      low salt alternative was used to test whether the higher salt percentage in DBP
      influenced the choice of feed by the birds. It was found that the control group
      consumed significantly more feed (P < 0.05) and was significantly heavier (P <
      0.05) than the experimental groups. However, there was no significant difference
      between the 2 experimental groups, which indicated that salt content did not play
      a role in the choice of ration. Feed consumption by both experimental groups was
      about one-third less than the control group, but the profit margin, as calculated
      using gross margin analysis, was approximately 15 % higher. It was therefore
      concluded that dried bakery products can be profitably incorporated as an energy
      feed source, using the free-choice feeding method, in small-scale broiler
      enterprises.

PMID- 15038424
TI  - Distribution and habitats of the snail Lymnaea truncatula, intermediate host of
      the liver fluke Fasciola hepatica, in South Africa.
AB  - This paper focuses on the geographical distribution and habitats of Lymnaea
      truncatula, the intermediate, snail host of the liver fluke, Fasciola hepatica,
      as reflected by the 723 samples in the database of the National Freshwater Snail
      Collection, Potchefstroom, South Africa. The 221 different loci (1/16-degree
      squares) on record reflect an extensive but discontinuous distribution, except in
      Lesotho and in parts of the Mpumalanga, Gauteng and North West provinces of South
      Africa. Although recorded from 12 different types of waterbody, it was mostly
      (42.0%) recovered from swamps. Most samples (45.8%) were collected in habitats
      with slow-flowing water. A muddy substratum was recorded for 62.5% of the
      samples. Most samples (86.3%) were collected in habitats with a mean annual air
      temperature of 10-20 degrees C, and more than 69% came from localities with a
      mean annual rainfall of 600-900 mm. An integrated decision tree constructed from
      the data indicated that temperature and types of waterbody play a decisive role
      in determining the presence of L. truncatula in a given area. A temperature index
      calculated for all mollusc species ranked L. truncatula second in a total of 53
      species according to its association with low temperatures. It remains to be
      established whether its distribution is indeed discontinuous, and whether its
      preference for a particular habitat, amphibious habits and ability to aestivate
      could have resulted in some populations having been overlooked during surveys.

PMID- 15038425
TI  - The efficacy of collars impregnated with flumethrin and propoxur against
      experimental infestations of adult Rhipicephalus sanguineus on dogs.
AB  - The efficacy of 2 sets of collars (Kiltix Collar, Bayer AG), containing different
      plasticisers and impregnated with the acaricides flumethrin (2.25%) and propoxur
      (10%), was compared against adult Rhipicephalus sanguineus on experimentally
      infested, kennelled dogs. Thirty individually penned dogs were infested with 25
      male and 25 female, unfed R. sanguineus. On the following day they were allocated
      to 3 groups of 10 dogs each on the magnitude of their tick burdens. Two days
      after infestation, medicated collars containing 1 of the plasticisers were fitted
      to 10 of the dogs and similar collars containing the other plasticiser were
      fitted to 10 others. The remaining 10 dogs were the untreated controls. Seven and
      28 days after having fitted the collars, all dogs were re-infested with 50 unfed
      adult ticks of both sexes, and again at approximately 28-day intervals up to the
      5th month, and then at approximately 14-day intervals during the 6th month.
      Efficacy was determined by comparing the mean number of live, attached ticks on
      the untreated control group with those on the collared dogs 2 days after each re
      infestation. Immediate efficacy of the collars (Day +2) was > 95%, and residual
      efficacy was > 98% up to and including Day +114, and > 93% up to Day +170 on both
      groups of collared dogs. The mean tick counts on the 2 groups of collared dogs
      did not differ significantly (P < 0.0001) for any of the assessment days.

PMID- 15038426
TI  - Epistaxis related to exercise-induced pulmonary haemorrhage in south African
      Thoroughbreds.
AB  - This study investigated if environmental factors had an effect on the incidence
      of epistaxis related to exercise-induced pulmonary haemorrhage (EIPH) among
      racehorses in southern Africa. Data covering the period 1986-2001 and involving
      778 532 race runs were analysed. This included the following information: date of
      race, age, sex, name of breeder, trainer, distance, jockey, state of going,
      weight carried, racing centre and altitude. Veterinarians employed by the Jockey
      Club suspended officially entered horses that presented with epistaxis (frank
      bleeding from the nostrils) after racing. On-course endoscopy is not performed as
      a standard practice at any southern African racetrack. Epistaxis was identified
      in 1287 horses (0.165%). More horses presented with EIPH-related epistaxis (a) at
      sea level, (b) from May to October, (c) when older (> 3 years), (d) after 1995,
      (e) on Fridays and Sundays, and (f) more in geldings than in mares or entire
      males. No association could be established between epistaxis and breeder,
      trainer, distance run, jockey, state of going and weight carried. It is concluded
      that the frequency of EIPH-related epistaxis is associated with altitude, winter
      and spring, sex and age. It is suggested that racing at lower altitudes may
      increase the probability of exercise-induced pulmonary haemorrhage.

PMID- 15038427
TI  - Mathematics at matriculation level as an indicator of success or failure in the
      1st year of the Veterinary Nursing Diploma at the Faculty of Veterinary Science,
      University of Pretoria.
AB  - Mathematics at matriculation level (Grade 12) is one of the subjects required for
      admission to the Veterinary Nursing Diploma in the Faculty at Veterinary Science
      of the University of Pretoria. The present study shows that there is no
      statistically significant relationship between the grade of mathematics at
      matriculation level and the success or failure in the 1st year of study. There
      is, however, a statistical difference in the adjusted mark obtained for
      mathematics at matriculation level between the groups that passed and failed the
      1st year of the veterinary nursing course. The results of this research are not
      consistent with other research which showed that secondary school mathematics
      results are not a significant factor in tertiary education. It is recommended
      that selection criteria for veterinary nurses should in future still include
      mathematics, but that cognisance should be taken of the mark obtained and
      students with higher marks (above 57%) given preference.

PMID- 15038428
TI  - Pasteurella testudinis associated with respiratory disease and septicaemia in
      leopard (Geochelone pardalis) and other tortoises in South Africa.
AB  - The first recorded isolates of Pasteurella testudinis from South African
      tortoises kept in captivity is presented. P. testudinis was found in association
      with respiratory disease in affected animals.

PMID- 15038429
TI  - Overview of suspected adverse reactions to veterinary medicinal products reported
      in South Africa (March 2002 - February 2003).
AB  - The Veterinary Pharmacovigilance and Medicines Information Centre is responsible
      for the monitoring of veterinary adverse drug reactions in South Africa. An
      overview of reports of suspected adverse drug reactions received by the centre
      during the period March 2002 to February 2003 is given. In total, 40 reports were
      received. This had declined from the previous year. Most reports involved
      suspected adverse reactions that occurred in dogs and cats. Most of the products
      implicated were Stock Remedies. The animal owner predominantly administered these
      products. Only 1 report was received from a veterinary pharmaceutical company.
      Increasing numbers of reports are being received from veterinarians.

PMID- 15038430
TI  - Equine hair analysis: current status and future prospects.

PMID- 15038431
TI  - An epidemiological study of risk factors associated with the recurrence of equine
      grass sickness (dysautonomia) on previously affected premises.
AB  - REASONS FOR PERFORMING STUDY: The reasons why equine grass sickness (EGS) recurs
      on premises are unknown and, consequently, practical methods for reducing the
      risk of recurrence are not available. OBJECTIVES: To identify risk factors
      associated with recurrence of EGS on premises and to gain possible insights into
      the pathogenesis of the disease. METHODS: Data on disease history and risk
      factors were collected by postal questionnaire from premises with EGS cases
      between 1st January 1997 and 31st December 2001. Data on variation in rates of
      recurrence of EGS for different risk factors were analysed using Poisson
      regression analysis. RESULTS: Of 509 premises contacted, 305 (60%) returned
      useable questionnaires and 100 of these (33%) were classified as 'recurrent'
      premises. An overall median incidence rate for EGS of 2.1 EGS incidents/100
      horses/premises/year was recorded. There was an increased rate of recurrence with
      higher numbers of horses, presence of younger animals, stud farms and
      livery/riding establishments, loam and sand soils, rearing of domestic birds and
      mechanical droppings removal. The rate of recurrence decreased with chalk soil,
      cograzing ruminants, grass cutting on pastures and removal of droppings by hand.
      Several statistically significant interactions were identified. CONCLUSIONS: Many
      of the findings are consistent with the theory that EGS is a toxico-infectious
      form of botulism. Several of the significant factors identified may directly or
      indirectly relate to soil disturbance and consequent soil contamination of grass,
      thereby increasing the rate of exposure of grazing horses to Clostridium
      botulinum, which resides in soil. POTENTIAL RELEVANCE: Identification of
      potentially modifiable risk factors may, ideally following validation in
      appropriately designed, controlled and randomised intervention studies, lead to
      practical measures to reduce the incidence of EGS on previously affected
      premises.

PMID- 15038432
TI  - Hair analysis as a novel investigative tool for the detection of historical drug
      use/misuse in the horse: a pilot study.
AB  - REASONS FOR PERFORMING STUDY: Analysis of human hair for drug residues is being
      used increasingly as a diagnostic tool in the investigation of drug use and
      abuse. Hair analysis is complementary to urine/blood testing in that it can
      provide an extensive historical record of drug use, is noninvasive, impersonal
      and can facilitate retesting. However, the technique has not been studied in
      horses. HYPOTHESIS: That the systemic administration of drugs in horses could be
      identified by the detection of drug residues in hair. OBJECTIVE: To evaluate hair
      analysis as a potential retrospective diagnostic test for drug administration in
      horses by studying the deposition of systemically administered drugs in tail
      hair. METHODS: Tail hairs (n = 40-50) from 4 horses with known drug histories
      were washed, chopped into 3-5 mm fragments and extracted overnight, in 0.1 mol/l
      hydrochloric acid, prior to solid-phase extraction and analysis by high
      performance liquid chromatography. Horse 1, a 3-year-old Thoroughbred colt
      (gastric ulcer), was treated for 14 days with omeprazole; Horse 2, a 3-year-old
      Thoroughbred colt (anaerobic infection), was treated for 5 days with
      metronidazole; Horse 3, an 8-year-old Thoroughbred gelding (sinusitis), was
      treated for 10 days with trimethoprim/sulphadiazine; and Horse 4, a 3-year-old
      Thoroughbred colt (respiratory infection), was treated for 5 days with procaine
      benzylpenicillin. RESULTS: Omeprazole was not detected in tail hair.
      Metronidazole was detected in tail hair at a concentration of 0.57 ng/mg,
      trimethoprim and sulphadiazine at concentrations of 9.14 and 2.26 ng/mg,
      respectively, and procaine at a concentration of 1.66 ng/mg. CONCLUSIONS: The
      data presented suggest that hair analysis may become a useable technique for the
      retrospective detection of drug administration in horses. POTENTIAL RELEVANCE:
      This technique could ultimately be used as part of a prepurchase veterinary
      examination to identify misuse of anti-inflammatory and sedative drugs, in an in
      training testing programme to identify use of anabolic agents, or to provide
      evidence to support post race blood or urine test results. Clearly, more
      extensive research will be required to evaluate the effectiveness of the
      technique over a much broader range of drugs.

PMID- 15038433
TI  - The beta-agonist clenbuterol in mane and tail hair of horses.
AB  - REASONS FOR PERFORMING STUDY: The beta2-agonist clenbuterol is commonly
      administered for therapeutic purposes in the horse, but its use an an anabolic
      agent is illegal. Clenbuterol can be detected in blood and urine for a relatively
      short period after administration and detection in hair could enhance the
      analytical range and be used to determine the history of clenbuterol application.
      HYPOTHESIS: That detection in mane or tail hair is possible over an extended
      period. METHODS: Four horses received 0.8 microg clenbuterol hydrochloride/kg bwt
      b.i.d. for 10 days. Four other horses were used as untreated controls. Blood,
      urine, mane and tail hair samples were taken on Day 0 (before) and 5, 10, 30, 35,
      40, 60, 90, 120, 150 and 360 days after start of treatment. Gas
      chromotography/high resolution mass spectrometry (GC/HRMS) was developed for
      clenbuterol analysis: limit of detection was 0.2 pg/mg; intra-assay repeatability
      limit r = 0.06 (confidence level 95%); interassay repeatability limit r = 0.03
      (confidence level 95%). Prior to treatment, clenbuterol was absent from all
      samples analysed. RESULTS: Clenbuterol was detectable as early as Day 5 in tail
      and mane hair of Segment 1 (0-20 mm from the roots) and was maximal on Day 90.
      However, as time progressed, shift into lower 20 mm segments was observed. On Day
      360, the maximum concentration (up to 21 pg/mg) was located in Segment 13, i.e.
      26-28 cm from roots of hair. Clenbuterol was not detectable in blood or urine
      after Day 30. Mane and tail hair results were very similar. CONCLUSIONS: The
      study showed that the beta-agonist clenbuterol can be found in mane and tail hair
      of horses after extended periods. POTENTIAL RELEVANCE: It will be possible to
      detect clenbuterol in breeding and show horses where anabolic drugs have been
      used illegally to improve conformation. This method may also be helpful to
      monitor therapeutic clenbuterol treatment.

PMID- 15038434
TI  - Equine grass sickness is associated with low antibody levels to Clostridium
      botulinum: a matched case-control study.
AB  - REASONS FOR PERFORMING STUDY: Equine grass sickness is a high mortality disease
      which, despite many years of investigation, is of unknown aetiology. Recent
      findings indicating that the disease is associated with Clostridium botulinum
      require support from an epidemiological study that recognises and controls for
      potential confounders, e.g. age, time of year and premises. HYPOTHESIS: EGS is
      associated with low antibody levels to C. botulinum antigens. METHODS: A matched
      case-control study was conducted. Data were collected from 66 histologically
      confirmed cases of EGS and 132 premises-matched control horses. The probability
      of EGS in horses was modelled using conditional logistic regression. RESULTS: EGS
      was significantly associated (age-adjusted P < 0.005) with low antibody levels to
      each of 3 clostridial antigens; C. botulinum type C and C. novyi type A surface
      antigens and a C. botulinum type C toxin complex toxoid. These serological risk
      factors for EGS remained highly significant when entered into multivariable
      models. This study also identified new horse-level risk factors for EGS; feeding
      hay or haylage was associated with a decreased risk of disease, change of feed
      type or quantity during the 14 days prior to disease was associated with
      increased risk, and the use of an ivermectin anthelmintic at both the ultimate
      and penultimate treatments was also associated with a significantly increased
      risk of EGS. CONCLUSIONS: This study provides strong support for the role of C.
      botulinum in the aetiology of EGS and identifies managemental risk factors for
      the disease. POTENTIAL RELEVANCE: Increasing anticlostridial antibody levels by
      vaccination and appropriate managemental interventions may decrease the risk of
      EGS occurring.

PMID- 15038436
TI  - Pharmacokinetics of recombinant hirudin in healthy horses.
AB  - REASONS FOR PERFORMING STUDY: Recombinant (r)-hirudin is a specific inhibitor of
      thrombin that is independent of the activity of antithrombin. OBJECTIVES: To
      evaluate pharmacokinetic properties and coagulatory changes of r-hirudin in
      healthy horses. METHODS: Two clinically healthy horses received a single i.v.
      bolus of 0.4 mg/kg bwt r-hirudin and 6 clinically healthy horses received the
      same dose subcutaneously (subcut.) q. 12 h for 3 days. Coagulation times and r
      hirudin plasma concentration were determined over 720 mins and 3 days after i.v.
      and subcut. administration, respectively. RESULTS: In all horses, treatment with
      r-hirudin was not associated with systemic or local side effects. After i.v.
      injection, the 2 horses showed an elimination half-life of 58 and 80 mins,
      respectively. After subcut. administration, maximum plasma concentration of r
      hirudin occurred at 128 +/- 55 mins and declined with a terminal half-life of 561
      +/- 364 mins. Maximum response of activated partial thromboplastin time (aPTT)
      occurred 1.5 h after administration of r-hirudin. A prolongation of 1.9 +/- 0.2
      times the pretreatment value was noted. CONCLUSIONS: Pharmacokinetics of r
      hirudin in healthy horses were similar to those in man and other animal species.
      POTENTIAL RELEVANCE: The results of this study indicate that r-hirudin can be
      used in horses, but further studies should be performed in order to prove its
      effectiveness in diseased horses.

PMID- 15038435
TI  - Why are certain premises at increased risk of equine grass sickness? A matched
      case-control study.
AB  - REASONS FOR PERFORMING STUDY: Equine grass sickness (EGS) occurs repeatedly on
      certain premises over time. Few studies have sought, or identified, the
      determinants of this phenomenon in order to inform advice on disease prevention
      strategies. HYPOTHESIS: Premises-level risk factors are important determinants of
      whether EGS occurs. METHODS: A matched case-control study was undertaken. Sixty
      premises giving rise to one or more histologically confirmed case of EGS and 120
      time-matched control premises were sampled. Data were collected on pasture
      management, soil nutrient content, pasture nutrient content and local weather
      conditions for 2 weeks prior to the onset of disease. Data were analysed by
      conditional logistic regression. RESULTS: Multivariable modelling identified an
      association between EGS and increased soil nitrogen content, pasture disturbance
      and previous occurrence of EGS on the premises. None of the meteorological
      variables recorded in this study were significantly associated with EGS
      occurrence. No relationship between certain management practices (e.g. harrowing,
      fertilisation, reseeding) and the risk of EGS was detected. CONCLUSIONS AND
      POTENTIAL RELEVANCE: This information is useful in understanding the causal
      pathway of EGS and may be used in the formulation of evidence-based disease
      avoidance strategies.

PMID- 15038437
TI  - Clinical significance of ossification of the cartilages of the front feet based
      on nuclear bone scintigraphy, radiography and lameness examinations in 21
      Finnhorses.
AB  - REASONS FOR PERFORMING STUDY: Research on the clinical significance of
      ossification of the cartilages of the foot has been limited, despite the common
      nature of the condition and conflicting reports in previous literature.
      HYPOTHESIS: Some radiographic features in the ossification of the cartilages,
      such as incomplete fusion lines between separate centres of ossification and the
      ossified base, are of clinical significance. METHODS: The relationships between
      radiopharmaceutical uptake in bone phase nuclear scintigraphy at the heels
      (palmar processes of the distal phalanx, including ossification of the cartilages
      of the foot), radiographic extent and type of ossification of the cartilages and
      clinical lameness were evaluated retrospectively in 21 Finnhorses (age > or = 4
      years) in a total of 36 front feet. RESULTS: No significant relationship between
      height of the ossifications and radiopharmaceutical uptake at the ipsilateral
      heels existed. Clearly separate centres of ossification were not associated with
      increased uptake. Moderately increased uptake was suspected to be associated with
      ossification of the adjacent cartilage in only one foot. Intense uptake was
      present unilaterally in 4 horses, at one medial and 3 lateral heels. In 2 of
      these horses, a unilateral palmar digital nerve block relieved the mild lameness;
      2 horses had no obvious lameness but had a history of being stiff or having
      locomotion problems during high speed trot. At 2 of the lateral heels, an
      incomplete fusion line was present between a large separate centre of
      ossification and the base, and the third horse had a high sidebone with bony
      protrusions, suggestive of chronic entheseopathy in a narrow foot. At the medial
      heel, an oblique radiograph revealed a faint radiolucent line at the base of the
      ossification. In all cartilages with intense radiopharmaceutical uptake at the
      heel and/or lameness, the ossified part of the cartilage was wider and more
      irregular compared to other ossifications of the front feet of the individual.
      CONCLUSIONS: Increased radiopharmaceutical uptake, associated with a different
      radiographic appearance from that of other ossifications of the front feet, was a
      conclusive sign of clinical significance. Obscure locomotion problems were more
      commonly associated with ossification of the cartilages than true lameness.
      POTENTIAL RELEVANCE: This information is useful in lameness and prepurchase
      examinations and is likely also to be applicable to other coldblooded breeds used
      for athletic purposes.

PMID- 15038438
TI  - Weight prediction from linear measures of growing Thoroughbreds.
AB  - REASON FOR PERFORMING STUDY: Monitoring weight of foals is a useful management
      practice to aid in maximising athletic potential while minimising risks
      associated with deviations from normal growth. OBJECTIVE: To develop predictive
      equations for weight, based on linear measurements of growing Thoroughbreds
      (TBs). METHODS: Morphometric equations predicting weight from measurements of the
      trunk and legs were developed from data of 153 foals. The accuracy, precision and
      bias of the best fitting equation were compared to published equations using a
      naive data set of 22 foals. RESULTS: Accuracy and precision were maximised with a
      broken line relating calculated volumes (V(t + l)) to measured weights. Use of
      the broken line is a 2 step process. V(t + l) is calculated from linear measures
      (m) of girth (G), carpus circumference (C), and length of body (B) and left
      forelimb (F). V(t + I) = ([G2 x B] + 4[C2 x F]) 4pi. If V(t + l) < 0.27 m3,
      weight is estimated: Weight (kg) = V(t + l) x 1093. If V(t + l) > or = 0.27 m3:
      Weight (kg) = V(t + l) x 984 + 24. The broken line was more accurate and precise
      than 3 published equations predicting the weight of young TBs. CONCLUSIONS:
      Estimation of weight using morphometric equations requires attention to temporal
      changes in body shape and density; hence, a broken line is needed. Including
      calculated leg volume in the broken line model is another contributing factor to
      improvement in predictive capability. POTENTIAL RELEVANCE: The broken line
      maximises its value to equine professionals through its accuracy, precision and
      convenience.

PMID- 15038439
TI  - The influence of repeated arthrocentesis and exercise on matrix metalloproteinase
      and tumour necrosis factor alpha activities in normal equine joints.
AB  - REASONS FOR PERFORMING STUDY: Matrix metalloproteinases (MMPs) and tumour
      necrosis factor alpha (TNF-alpha) may be useful as biomarkers of joint disease or
      inflammation. However, activity of both MMPs and TNF-alpha in synovial fluid (SF)
      may be influenced by nonpathological factors such as arthrocentesis or exercise.
      OBJECTIVE: To investigate the influence of repeated arthrocentesis and exercise
      on MMP and TNF-alpha activities in SF from normal equine joints. METHODS: SF was
      collected from the left metacarpophalangeal, radiocarpal and tarsocrural joints
      of 16 horses. Eight of these horses were subsequently subjected to an exercise
      programme on a treadmill and 8 were box-rested as controls. Arthrocentesis was
      repeated 14, 145, 17 and 24 days after the start of the exercise programme.
      General MMP and TNF-alpha activities were determined in SF. RESULTS: Repeated
      arthrocentesis caused a gradual increase but the exercise regimen no significant
      increase in MMP activity. There was a significant increase in TNF-alpha activity
      in SF collected from horses 2 h after cessation of the exercise programme.
      CONCLUSIONS AND POTENTIAL RELEVANCE: When using MMPs as biomarkers for joint
      disease, at least 14 days should elapse after previous arthrocentesis before
      subsequent SF collection. Moderate exercise does not increase MMP activity in SF
      from normal joints and it may be possible to ignore this as a source of error in
      evaluating MMP activity in diseased joints.

PMID- 15038440
TI  - Collateral desmitis of the distal interphalangeal joint in 18 horses (2001-2002).
AB  - REASONS FOR PERFORMING STUDY: There have been no previously published case series
      of horses examined using either scintigraphy or MRI to diagnose collateral
      ligament injuries not detectable using ultrasonography or radiography, nor have
      other concurrent soft tissue lesions been described. OBJECTIVES: To describe the
      clinical features of horses with desmitis of the collateral ligaments of the
      distal interphalangeal (DIP) joint and to evaluate the results of radiographic,
      ultrasonographic, scintigraphic and magnetic resonance imaging (MRI)
      examinations. METHODS: Horses were examined between January 2001 and January 2003
      and were selected for inclusion in the study if there was unequivocal evidence of
      collateral desmitis of the DIP joint based on ultrasonography or MRI. Subject
      details, case history, results of clinical examination and responses to local
      analgesic techniques were reviewed. The results of radiographic,
      ultrasonographic, scintigraphic and MRI examinations were assessed. RESULTS:
      Eighteen horses were identified with desmitis of a collateral ligament of the DIP
      joint, 3 horses (Group 1) based on ultrasonography alone, 7 (Group II) with
      positive ultrasonographic and magnetic resonance images and 8 (Group III) with no
      lesion detectable using ultrasonography, but lesions identified using MRI.
      Seventeen horses had forelimb injuries and one a hindlimb injury. The medial
      collateral ligament was injured most frequently (13 horses). In the majority of
      horses, no localising clinical signs were seen. Lameness was invariably worse in
      circles compared with straight lines. Lameness was improved by palmar digital
      analgesia in 16 horses (87%), but only 6 were nonlame. Intra-articular analgesia
      of the DIP joint produced improvement in lameness in 6/15 horses (40%). In 16
      horses, no radiographic abnormality related to the DIP joint or collateral
      ligament attachments was identified. Eight of 14 horses (57%) had focal,
      moderately or intensely increased radiopharmaceutical uptake (IRU) at the site of
      insertion of the injured collateral ligament on the distal phalanx. Alteration in
      size and signal in the injured collateral ligament was identified using MRI. In
      addition, 5 horses had abnormal mineralisation and fluid in the distal phalanx at
      the insertion of the ligament. Eleven horses had concurrent soft tissue injuries
      involving the deep digital flexor tendon, distal sesamoidean impar ligament,
      navicular bursa or collateral ligament of the navicular bone. CONCLUSIONS AND
      POTENTIAL RELEVANCE: Collateral desmitis of the DIP joint should be considered as
      a cause of foot lameness. Although some injuries are detectable
      ultrasonographically, false negative results occur. Focal IRU at the ligament
      insertion on the distal phalanx may be indicative of injury in some horses. MRI
      is useful for both characterisation of the injury and identification of any
      concurrent injuries. Further follow-up information is required to determine
      factors influencing prognosis.

PMID- 15038441
TI  - Descriptive epidemiology of fractures occurring in British Thoroughbred
      racehorses in training.
AB  - REASONS FOR PERFORMING STUDY: Musculoskeletal injury is the major cause of days
      lost from training and wastage in Thoroughbred racehorses. Little scientific
      information is available on the majority of injuries occurring in training.
      OBJECTIVES: To estimate the incidence of fractures in British racehorses in
      training and describe the occurrence of different fracture types and bones
      involved. METHODS: Thirteen UK racehorse trainers participated in a prospective
      study, providing data on horses in their care for 2 years. Details on horses,
      their daily exercise and fracture occurrence were recorded. RESULTS: A total of
      1178 horses provided 12,893 months at risk. Nontraumatic fracture incidence was
      1.15/100 horse months (95% CI = 0.98, 1.35) and 78% of fractures occurred during
      training. A wide variety of fracture types and bones were involved, although at
      least 57% were stress fractures. Pelvic and tibial stress injuries accounted for
      28% of fractures diagnosed. CONCLUSIONS: It is important to study injuries in
      training as well as in racing. The number of stress fractures suggests that
      training regimes for young Thoroughbreds could often be improved to create a more
      robust skeleton, able to withstand injury. POTENTIAL RELEVANCE: Studying injuries
      in racehorses in training can provide a scientific basis for the design of safer
      training regimes.

PMID- 15038442
TI  - Assessment of the efficacy of composite surgery for the treatment of dorsal
      displacement of the soft palate in a group of 53 racing Thoroughbreds (1990
      1996).
AB  - REASONS FOR PERFORMING STUDY: There has been no objectively assessed case-control
      study of the efficacy of surgery to correct dorsal displacement of the soft
      palate (DDSP) previously reported. HYPOTHESIS: Composite surgery has a beneficial
      result on racing performance in horses affected with DDSP as compared to a
      matched control population. METHODS: Race records were obtained for 53 racing
      Thoroughbreds which underwent composite staphylectomy, sternothyrohyoideus
      myectomy and ventriculectomy for correction of idiopathic DDSP at the University
      of Bristol between 1990 and 1996. Each surgical case was matched for age, sex and
      training yard with 2 control horses. The racing performance, based on prize money
      won, of surgical cases and control horses were compared for 3 races run before
      and after the date of surgery. RESULTS: Ninety-two percent of the surgical cases
      returned to racing after surgery. There was a significant increase in earnings of
      the surgical group before and after surgery (P = 0.011), but there was no
      significant difference in earnings of the control group before and after the date
      of surgery (P = 0335). Sixty percent of the surgical group had higher earnings
      after surgery than before, compared to 40% of controls. When horses which
      underwent surgery were ranked relative to their 2 matched controls, surgical
      cases did not significantly change in rank (P = 033), whereas control horses
      significantly decreased in rank (P = 0.012). Additionally, horses within the
      surgical group were more likely (P < 0.01) to start in 3 post operative races
      than those in the control group. CONCLUSIONS AND POTENTIAL RELEVANCE: Composite
      surgery had a beneficial effect on racing performance of horses afflicted with
      idiopathic DDSP, and further studies to evaluate objectively the usefulness of
      other surgical techniques are warranted.

PMID- 15038443
TI  - Study of faecal shedding of Clostridium difficile in horses treated with
      penicillin.

PMID- 15038444
TI  - Prospects for vaccination against equine grass sickness.

PMID- 15038445
TI  - Phenotypic characterization and description of two major O-serotypes in
      Tenacibaculum maritimum strains from marine fishes.
AB  - Tenacibaculum maritimum is the etiological agent of marine flexibacteriosis
      disease, with the potential to cause severe mortalities in various cultured
      marine fishes. The development of effective preventive measures (i.e.
      vaccination) requires biochemical, serological and genetic knowledge of the
      pathogen. With this aim, the biochemical and antigenic characteristics of T.
      maritimum strains isolated from sole, turbot and gilthead sea bream were
      analysed. Rabbit antisera were prepared against sole and turbot strains to
      examine the antigenic relationships between the 29 isolates and 3 reference
      strains. The results of the slide agglutination test, dot-blot assay and
      immunoblotting of lipopolysaccharides (LPS) and membrane proteins were evaluated.
      All bacteria studied were biochemically identical to the T. maritimum reference
      strains. The slide agglutination assays using O-antigens revealed cross-reaction
      for all strains regardless of the host species and serum employed. However, when
      the dot-blot assays were performed, the existence of antigenic heterogeneity was
      demonstrated. This heterogeneity was supported by immunoblot analysis of the LPS,
      which clearly revealed 2 major serological groups that were distinguishable
      without the use of absorbed antiserum: Serotypes O1 and O2. These 2 serotypes
      seem to be host-specfic. In addition, 2 sole isolates and the Japanese reference
      strains displayed cross-reaction with both sera in all serological assays, and
      are considered to constitute a minor serotype, O1/O2. Analysis of total and outer
      membrane proteins revealed that all strains share a considerable number of common
      bands that are antigenically related.

PMID- 15038446
TI  - Ichthyobodo necator (Kinetoplastida)--a complex of sibling species.
AB  - Ichthyobodo necator is a parasitic flagellate that attacks fishes, causing
      disease problems in freshwater worldwide. Findings of similar flagellates in
      strictly marine fishes have indicated that ichthyobodiosis may be caused by more
      than 1 flagellate species. We obtained partial small subunit rDNA (ssu rDNA)
      sequences of 14 Ichthyobodo isolates originating from fishes in Norway, Japan,
      Singapore, South Africa and Brazil, and identified 8 strains or species,
      including 2 species infecting cultured salmon in Norway. An Ichthyobodo species
      isolated from the skin of Atlantic salmon parr in freshwater is suggested to
      represent L. necator sensu stricto, while another species, showing particular
      affinity for the gills, infects salmon in both fresh- and seawater. Atlantic cod
      is infected with a marine Ichthyobodo species unrelated to those infecting
      salmonids; 2 cyprinids originating from different parts of the world had related
      Ichthyobodo strains/species, and 2 isolates from unrelated North and South
      American fishes were also closely related. The phylogenetic relationships of the
      Ichthyobodo isolates is described, and the implications of the molecular findings
      on past and future morphological studies of Ichthyobodo spp. are discussed.

PMID- 15038447
TI  - Effect of Cryptobia salmositica-induced anorexia on feeding behavior and immune
      response in juvenile rainbow trout Oncorhynchus mykiss.
AB  - At 10 degrees C, rainbow trout Oncorhynchus mykiss (n = 13 per group) infected
      with Cryptobia salmositica Katz, 1951 became anorexic at 3 wk post-infection
      (w.p.i.), with feed-intake decreasing significantly from 1.33 to 0.94% body
      weight (b.w.). Anorexia was most severe at 4 w.p.i. (0.80% b.w.), coinciding with
      peak parasitemia (9.2 x 10(6) parasites ml blood(-1)) and anemia. At 8 w.p.i.,
      fish had recovered their appetite although they still had contained detectable
      parasites (6.8 x 10(5) parasites ml(-1)) and were anemic (pack cell volume, PCV,
      of 24.4%). However at 5 degrees C, anorexia occurred at 5 w.p.i. (0.81% b.w.),
      and was most severe at 7 w.p.i. (0.40% b.w.). At 8 w.p.i. (0.43% b.w.), fish
      displayed high parasitemia (4.6 x 10(6) parasites ml(-1)) and low PCV (10.8%).
      Fish at 5 degrees C had lower gastric evacuation (GE) rates (GE48h) than 10
      degrees C fish, however there were no differences between infected and naive fish
      at both temperatures. Before anorexia, there was no significant correlation
      between mean share of meal (MSM, a measure of how food was partitioned within a
      group) and coefficient of variation in feeding but this became significant during
      anorexia (p = 0.02 and p = 0.0002 at 10 and 5 degrees C respectively).
      Significant correlations were detected between b.w. and MSM before onset of
      anorexia at 10 degrees C (p = 0.005) and 5 degrees C (p = 0.02); this was
      maintained at 10 degrees C (p = 0.001) but not at 5 degrees C (p = 0.98). Fish on
      an anorexic diet (0.93% b.w.) responded well at 10 degrees C to a live C.
      salmositica vaccine; this could partly be due to constant antigenic stimulation
      by the live vaccine.

PMID- 15038448
TI  - Comparative susceptibility of Atlantic salmon, lake trout and rainbow trout to
      Myxobolus cerebralis in controlled laboratory exposures.
AB  - The susceptibility of lake trout Salvelinus namaycush, rainbow trout Oncorhynchus
      mykiss and Atlantic salmon Salmo salar to Myxobolus cerebralis, the causative
      agent of whirling disease, was compared in controlled laboratory exposures. A
      total of 450 (225 for each dose) fry for each species were exposed to a low (200
      spores per fish) or high (2000 spores per fish) dose of the infective
      triactinomyxon. At 22 wk post-exposure, 60 fish from each group, as well as
      controls for each species, were examined for clinical signs (whirling behavior,
      blacktail, deformed heads and skeletal deformities), microscopic lesions, and
      presence of spores. Rainbow trout were highly susceptible to infection, with 100%
      being positive for spores and with microscopic pathological changes in both
      exposure groups. Rainbow trout were the only species to show whirling behavior
      and blacktail. Atlantic salmon were less susceptible, with only 44 and 61% being
      positive for spores, respectively, in the low and high dose groups, while 68 and
      75%, respectively, had microscopic pathology associated with cartilage damage.
      Rainbow trout heads contained mean spore concentrations of 2.2 (low dose) or 4.0
      (high dose) x 10(6) spores g tissue(-1). The means for positive Atlantic salmon
      (not including zero values) were 1.7 (low) and 7.4 (high) x 10(4) spores g
      tissue(-1). Lake trout showed no clinical signs of infection, were negative for
      spores in both groups and showed no histopathological signs of M. cerebralis
      infection.

PMID- 15038450
TI  - In vitro development of the fish parasite Hysterothylacium aduncum from the third
      larval stage recovered from a host to the third larval stage hatched from the
      egg.
AB  - Anisakids are parasitic nematodes of fish worldwide, producing economic and human
      health concerns. It is thus important to ascertain their in vitro life cycle in
      laboratory studies. Here we describe the in vitro development of third-stage
      larvae (L3) of Hysterothylacium aduncum isolated from blue whiting Micromesistius
      poutassou, to the hatching of L3 from eggs obtained from H. aduncum worms grown
      in GLIT medium (a modified mixture of Yaeger's LIT [Liver Infusion Tryptose] and
      Grace's media) at pH 4.0, 13 degrees C and with 5% CO2 in air. Under these
      conditions, L3 recovered from fish developed to mature adults (3.4 to 6.2 cm in
      length), with oviposition starting from Day 26 in culture. Fertilized eggs (mean
      size 64 x 52 microm) had a thick, rugose eggshell and were larger than
      unfertilized ones (mean size 49 x 42 microm), whose eggshells were thin and
      smooth. Eggs laid during the first and second week of oviposition, and maintained
      in 2.8% NaCl solution at 13 degrees C, developed to L3. Under these maintenance
      conditions, between 20.6 and 52.5% of the eggs laid during the first week
      developed into larvae. Motile larvae, enclosed in a sheath, hatched from between
      2 and 11% of these eggs. The larvae started to hatch 23 d after deposition. These
      larvae were 144 to 215 microm in length, enclosed in a 237 to 305 microm-long
      sheath. This GLIT culture medium may help to study the biology of this and other
      anisakids.

PMID- 15038449
TI  - Genetic relationship among gill-infecting Myxobolus species (Myxosporea) of
      cyprinids: molecular evidence of importance of tissue-specificity.
AB  - The importance of tissue-specificity was studied in Myxobolus spp. infecting the
      gills of 7 cyprinid species. The 18S rDNA of 10 Myxobolus species was amplified
      by optimised nested-PCR, resulting in approximately 1600 bp PCR products.
      Phylogenetic trees generated by distance matrix and parsimony analyses revealed 4
      main groups. Muscle-infecting species all belonged to the same group, while
      members of 2 gill-infecting groups were clearly distinguishable on the basis of
      tissue-specificity, and were also recognisable by differences in spore
      morphology. On the basis of tissue tropism, phylogenetic relationships among the
      species examined indicate that genetic separation is a more ancient evolutionary
      feature than host-specificity.

PMID- 15038451
TI  - Investigation of Nematopsis spp. oocysts in 7 species of bivalves from Chonburi
      province, Gulf of Thailand.
AB  - This is the first detailed report of Nematopsis spp. in Thai bivalves. A monthly
      survey was conducted on 7 species of commercial bivalves from Chonburi province,
      on the eastern seaboard of Thailand, from November 2000 to November 2001 to
      investigate the prevalence of the apicomplexan parasite Nematopsis Schneider,
      1892. Nematopsis spp. sporozoites were found in the cultivated bivalves Arcuatula
      arcuatula, Anadara granosa and Perna viridis as well as the locally harvested
      Paphia undulata. They were not found in Donax faba, Meretrix meretrix or
      Saccostrea cucullata. Using light microscopy, we were able to identiby 4 oocyst
      morphotypes of the gregarine Nematopsis spp. Prevalence of Nematopsis spp. during
      the 13 mo sampling period was highest in A. arcuatula (91.8%; n = 110) and lowest
      in A. granosa (59.2%; n = 130). The morphology of the oocysts differed between
      hosts, with an average (x +/- SD) length/width of 16.28 +/- 0.64/12.01 +/- 0.35
      microm (n = 50) for A. arcuatula, 16.90 +/- 0.71/12.69 +/- 0.33 microm (n = 50)
      for A. granosa, 17.61 +/- 0.69/12.72 +/- 0.36 microm (n = 50) for P. viridis, and
      11.21 +/- 0.62/8.55 +/- 0.52 microm (n = 50) for P. undulata. Identification of
      oocysts of these apicomplexan gregarines to species was not attempted. The
      prevalence of infection in relation to habitat and time of sampling is discussed.

PMID- 15038452
TI  - Metazoan parasite species in cultured mussel Mytilus galloprovincialis in the
      Thermaikos Gulf (North Aegean Sea, Greece).
AB  - This is the first study on parasites of cultured Mytilus galloprovincialis L. in
      Greek waters, and is based on samples collected every 2 to 3 mo between September
      2000 and November 2001 at 3 stations in the Thermaikos Gulf. Each sample
      comprised 40 mussels. We found 4 metazoan parasite species: hydroid Eugymnanthea
      inquilina, gill turbellarian Urastoma cyprinae, trematode Proctoces maculatus and
      gut copepod Mytilicola intestinalis. Of 840 mussels examined, 406 (48.3%) mussels
      were harbouring hydroids of E. inquilina, 278 (33.1%) were infested with U.
      cyprinae, 94 (11.2%) were infested with M. intestinalis, and only 7 (0.8%) were
      infested with P. maculatus. The prevalence and intensity of these parasites were
      related to temperature and pollution. Mussels infested with these parasites had
      significantly lower condition indices than non-infested mussels; larger mussels
      were more often infested than smaller ones.

PMID- 15038453
TI  - Histopathological effects of trypanorhynch metacestodes in the digestive gland of
      a novel host, Carcinus maenas (Decapoda).
AB  - The green crab Carcinus maenas was introduced to Australian temperate waters in
      the late 1800s, has since become established, and is now considered to be a pest.
      We undertook an extensive parasite survey to find potential natural enemies of C.
      maenas and found it to be infected in Australia by 2 species of larval
      trypanorhynch tapeworm, Trimacracanthus aetobatidis and Dollfusiella martini. We
      describe the gross pathology and histopathology of the parasites' new host (C.
      maenas) and note that the plerocercoid larvae are located in the lumen of the
      digestive gland tubules. The presence of D. martini in C. maenas with low
      population numbers suggests that either D. martini has an impact (direct or
      indirect) on the survival of C. maenas, or that the parasite may be an indicator
      of high predation pressure. If the former were true, this would contribute to the
      control of this introduced pest species.

PMID- 15038454
TI  - Hyperparasitism of the cryptoniscid isopod Liriopsis pygmaea on the lithodid
      Paralomis granulosa from the Beagle Channel, Argentina.
AB  - A total of 29,570 false king crab Paralomis granulosa were sampled from the
      Beagle Channel (54 degrees 51'S, 68 degrees 12'W), Tierra del Fuego, Argentina,
      between July 1996 and August 1998. Crab size varied from 6.8 to 111.2 mm carapace
      length (CL). A few crabs parasitized by the rhizocephalan Briarosaccus callosus
      were found; prevalences of externae (the rhizocephalan reproductive body) and
      scars (the mark left on the host after the death of the parasite) were 0.28 and
      0.16%, respectively. Of 85 externae examined, 55 were non-ovigerous and 30
      ovigerous. The cryptoniscid isopod Liriopsis pygmaea infested 36.5% of the B.
      callosus examined. The most abundant stage was the cryptonicus larva, accounting
      for 208 of the 238 L. pygmaea recovered. Cryptonisci showed a highly aggregated
      distribution. A total of 92.7% of cryptonicsci were recovered inside empty
      externae, suggesting that the latter were attractive to cryptonisci. Early
      subadult females of L. pygmaea were rare; only 3 individuals occurred inside 1
      ovigerous externa. Eight late subadult and 18 adult females were found on 3 and 7
      non-ovigerous externae, respectively; in addition, 1 aberrant late subadult was
      found on 1 ovigerous externa. In the Beagle Channel, the population of P.
      granulosa harbours 3 different parasites: the bopyrid isopod Pseudione
      tuberculata, which reaches highest prevalence at 10 to 20 mm CL, the
      rhizocephalan B. callosus, with highest prevalence at 20 to 40 mm CL, and the
      cryptoniscid isopod L. pygmaea, which mainly infests rhizocephalan on crabs >40
      mm CL.

PMID- 15038455
TI  - Microsporidians in penaeid shrimp along the west coast of Madagascar.
AB  - Three species of penaeid shrimp, Fenneropenaeus indicus, Penaeus monodon and P.
      semisulcatus, found in trawler catches off the west coast of Madagascar were
      infected with microsporidian parasites. The infections were evident as muscular
      lesions with a cottony appearance when abundant. Spore size (2.6 x 1.6 microm)
      and morphology (ovoid) for the parasites infecting both F. indicus and P.
      semisulcatus were not significantly different, suggesting that they might be the
      same microsporidian species. Spore size (1.4 x 1.1 microm) and morphology (sub
      globose to ovoid) in P. monodon infections were significantly different from
      those in the other 2 shrimp species, suggesting that it was a different parasite.
      The presence of microsporidians in this biogeographical zone means that there is
      a potential risk of infections of cultured shrimp in farms situated in the
      vicinity. This must be assessed by increasing current knowledge of the parasites.

PMID- 15038456
TI  - Dot-blot hybridization and RT-PCR detection of extra small virus (XSV) associated
      with white tail disease of prawn Macrobrachium rosenbergii.
AB  - The availability of specific and reliable detection methods is essential for
      monitoring the health status of farmed species, particularly for viral diseases.
      Extra small virus (XSV), a virus-like particle, is associated with Macrobrachium
      rosenbergii Noda virus (MrNV) in white tail disease (WTD) of M. rosenbergii. We
      developed 2 genome-based detection methods for the identification of XSV, namely
      dot-blot hybridization and a single-step RT-PCR. Detection limits were
      established and are ca. 2.5 pg and 5 fg of viral RNA for dot-blot hybridization
      and RT-PCR, respectively. Application of the methods to field samples indicated
      that some animals positively diagnosed with MrNV did not contain XSV, at least
      within the detection limit of the methodology. This raises the question of the
      actual role of XSV and its interactions with MrNV in WTD of M. rosenbergii.

PMID- 15038457
TI  - Pharmacokinetics and tissue distribution of galantamine and galantamine-related
      radioactivity after single intravenous and oral administration in the rat.
AB  - The plasma kinetics and tissue distribution of galantamine hydrobromide [4aS-(4a
      alpha,6beta,8aR*)]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro
      [3a,3,2-ef] [2benzazepin-6-ol hydrobromide, CAS-1953-04-4], a reversible
      acetylcholinesterase inhibitor, were studied in male and female non-pregnant and
      pregnant SPF Wistar rats and in male Fisher x Copenhagen pigmented rats. Most
      studies were performed using 3H-labelled galantamine hydrobromide, measuring
      unchanged drug (UD) and non-volatile radioactivity (NVR) in plasma and tissues by
      high-performance liquid chromatography (HPLC), liquid scintillation counting and
      quantitative whole-body autoradiography (QWBA). Plasma levels after single
      intravenous administration of UD (1.25-2.5 mg/kg) declined bi- or triphasically,
      with an elimination half-life of 3.5 h in male, and 5.1 h in female rats. The
      plasma clearance (Cl) averaged 1.9 l/kg/h (male rats) and 0.9 l/kg/h (female
      rats), and the volume of distribution (VdSS) was about 5 l/kg for both male and
      female rats. Following oral administration (2.5-10 mg/kg), galantamine was
      rapidly absorbed in both sexes, with an absolute oral bioavailability of 77%.
      Distribution studies after oral administration of 3H-galantamine showed an almost
      immediate equilibrium between plasma and tissues, with highest tissue levels of
      NVR and UD in liver, kidney, salivary glands, adrenal glands and, for the female
      rat, spleen, and lowest in white fat. To most tissues and especially to brain,
      the distribution of UD was more pronounced than that of its metabolites. Tissue
      concentrations of UD and NVR declined at a similar rate as plasma, showing no
      undue retention. QWBA in the pigmented rat showed the same distribution and
      elimination pattern of NVR. Only in hair follicles and choroid some retention of
      NVR was seen, but the calculated half-life was less than one day. In the female
      pregnant SPF Wistar rat, maternal tissue distribution of NVR was similar to that
      of the non-pregnant rat. NVR tissue levels in the foetus were similar to those
      found in maternal blood during the whole experiment, indicating a rapid
      equilibrium without accumulation.

PMID- 15038458
TI  - Effects of alpha1-acid glycoprotein in combination with catecholamines on
      hemorrhagic hypovolemic shock in rats.
AB  - To determine whether the beneficial effects of catecholamines on the variables of
      hemorrhagic hypovolemic shock are augmented by coadministration of alpha1-acid
      glycoprotein during resuscitation, alpha1-acid glycoprotein (200 mg/kg), a
      placebo formulation or Ringer's solution was infused in a rat model of
      hemorrhagic hypovolemic shock for 1 h concomitantly with either norepinephrine
      (CAS 51-40-1; 0.1, 0.3, 1 microg x kg(-1) x min(-1)) or dopamine (CAS 62-31-7; 5,
      10, 15 microg x kg(-1) x min(-1)). Resuscitation with norepinephrine or dopamine
      alone was continued for a further 4 h. Mean arterial blood pressure, cardiac
      output, stroke volume, heart rate and total peripheral vascular resistance were
      measured during the entire 5-h period. The combination of dopamine or
      norepinephrine with alpha1-acid glycoprotein more effectively restored mean
      arterial blood pressure and cardiac output than analogous combinations with
      placebo formulation or Ringer's solution. So co-administration with alpha1-acid
      glycoprotein considerably augments the beneficial effects of catecholamines on
      the main variables of hemorrhagic hypovolemic shock.

PMID- 15038459
TI  - Hypolipidemic and antioxidant activity of the novel acyl-CoA:cholesterol
      acyltransferase (ACAT) inhibitor KY-455 in rabbits and hamsters.
AB  - The hypolipidemic and antioxidant effects of N-(4,6-dimethyl-1-pentylindolin-7
      yl)-2,2-dimethylpropanamide (CAS 178469-71-1, KY-455), a novel acyl
      CoA:cholesterol acyltransferase (ACAT) inhibitor, were examined in hyperlipidemic
      rabbits and normolipidemic hamsters. KY-455 inhibited rabbit intestinal, hepatic,
      macrophage and adrenal ACAT with IC50 values of 0.4, 0.9, 2.9 and 4.1 micromol/l,
      respectively. KY-455 also inhibited rabbit plasma and LDL-peroxidation (IC50: 0.4
      and 1.7 micromol/l, respectively). In rabbits fed a high-cholesterol diet,
      treatment with KY-455 (30 mg/kg/day) for 8 days markedly lowered serum
      esterified, free, low-density lipoprotein (LDL)-cholesterol, and hepatic
      esterified cholesterol levels. KY-455 tended to inhibit ex vivo hepatic ACAT
      activity 5 h after the final administration. KY-455 also inhibited ex vivo
      peroxidation of plasma lipids 1 and 5 h after the final administration in
      rabbits. In normolipidemic hamsters fed a regular diet, treatment with KY-455 (30
      mg/kg, twice a day) for 4 days significantly reduced serum esterified, free and
      LDL-cholesterol, and hepatic esterified and free cholesterol levels. A single
      administration of KY-455 (30 mg/kg) significantly inhibited ex vivo hepatic ACAT
      activity in hamsters. In conclusion, KY-455 showed in vitro inhibitory effects on
      LDL-peroxidation and macrophage ACAT activity at similar concentrations, and in
      vivo hypolipidemic and ex vivo antioxidative effects at the same dose. Long-term
      administration of KY-455 is expected to prevent the progress of atherosclerosis
      by lowering plasma lipid levels, inhibiting both LDL-oxidation and accumulation
      of cholesterol in macrophages.

PMID- 15038460
TI  - Study on the influence of silymarin pretreatment on metabolism and disposition of
      metronidazole.
AB  - A clinical study was undertaken in 12 healthy volunteers. At first, subjects
      received metronidazole (CAS 443-48-1; a substrate for cytochrome CYP3A4 and
      CYP2C9) alone at a dose of 400 mg every 8 h for 3 days. On day 4, blood and urine
      were collected at different time points and metronidazole levels were measured.
      After a washout period (> 10 half-lives) of one week silymarin (CAS 22888-70-6)
      was given at a daily dose of 140 mg for 9 days. From day 7 both silymarin (140
      mg/day) and metronidazole (3 x 400 mg/day) were given till the 9th day. On day
      10, blood and urine were collected as above and the levels of metronidazole and
      its metabolite were measured by HPLC. Administration of silymarin increased the
      clearence of metronidazole and its major metabolite, hydroxy-metronidazole (HM)
      by 29.51% and 31.90%, respectively, with a concomitant decrease in half-life,
      Cmax and AUC(0-48). Urinary excretions of acid-metronidazole (AM), HM as well as
      metronidazole in 48 h were decreased. The results indicate that silymarin might
      induce both intestinal P-glycoprotein and CYP3A4 upon multiple dose
      administration.

PMID- 15038461
TI  - Influence of peroral application of a herbal immunomodulator on the antibody
      production of Peyer's patches cells.
AB  - The influence of the peroral administration of the macromolecular components of a
      herbal immunomodulator isolated from an aqueous-ethanolic extract of the mixed
      herbal drugs Thujae summitates, Baptisiae tinctoriae radix, Echinaceae purpureae
      radix and Echinaceae pallidae radix on the function of Peyer's patches cells was
      investigated in mice. Peyer's patches cells isolated from mice which had received
      oral administration of the macromolecular fraction of the plant extract developed
      a significantly enhanced plaque-forming cell (PFC) response to sheep red blood
      cells after incubation with these cells in the presence of lipopolysaccharide or
      the extract fraction for 7 days in vitro. These results show that after oral
      administration of the herbal immunomodulator, the immunologically active
      macromolecules can contact the cells of the gut-associated lymphoid tissue and
      modulate the mucosal immune response.

PMID- 15038462
TI  - Synthesis and preliminary antimicrobial evaluation of new 7-(N-pyrrolyl)
      derivatives of cephalosporins.
AB  - A series of seven new cephalosporins was prepared for preliminary microbiological
      evaluation by N-acylation of 7-aminocephalosporanic acid with substituted N
      pyrrolylcarboxylic acids via mixed anhydrides. The chemical structure of the
      compounds were confirmed by IR, 1H-NMR and mass spectral data. The 7-(N-pyrrolyl)
      cephalosporin derivatives were tested in vitro by the disc diffusion method upon
      3 strains and subsequent determination of the minimal inhibitory concentration
      (MIC) of the most active ones upon 29 strains. The products of the series
      exhibited antibacterial activity. They showed selective potency against gram
      positive and were practically inactive against gram-negative microorganisms. The
      compound 3-[(acetyloxy)methyl]-7-([2-[3-(ethoxycarbonyl)-2-methyl-5-phenyl-1H-1
      pyrrolyl]acetyl]amino)-6-oxo-7,7a-dihydro-2H,6H-aceto[2,1-b][1,3]thiazine-4
      carboxylic acid (4a) was outlined as more active than the reference cefazolin
      (CAS 23325-78-2) in regard to S. pyogenes and some strains of S. aureus, the MIC
      of 4a against S. pyogenes were at least 4-fold lower. The toxicological
      evaluations of the starting N-pyrrolylcarboxylic acids showed no acute toxicity.

PMID- 15038463
TI  - Synthesis of some new 6-methylimidazo[2,1-b]thiazole-5-carbohydrazide derivatives
      and their antimicrobial activities.
AB  - In this study, 14 new compounds having 6-methyl-N2
      (alkylidene/cycloalkylidene)imidazo[2,1-b]thiazole-5-carbohydrazide (3a-g), 3
      [[(6-methylimidazo[2,1-b]thiazole-5-yl)carbonyl]amino]-4-thiazolidinone (4a-d)
      and 4-[[(6-methylimidazo[2,1-b]thiazole-5-yl)carbonyl]amino]-1-thia-4
      azaspiro[4.4]nonan/[4.5]decan-3-one (4e-g) structures were synthesized. The
      structures of the compounds were elucidated by UV, IR, 1H-NMR, 13C-NMR, 1H-13C
      COSY, mass spectra and elemental analysis. All compounds synthesized were tested
      for antimicrobial activity against Staphylococcus aureus ATCC 6538,
      Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella
      pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Salmonella typhi,
      Shigella flexneri, Proteus mirabilis ATCC 14153, Candida albicans ATCC 10231 and
      Mycobacterium tuberculosis H37Rv. Only 4d and 4f demonstrated antimicrobial
      activity against S. epidermidis ATCC 12228 (MIC: 19.5 microg/ml and 39 microg/ml,
      respectively).

PMID- 15038465
TI  - The burden of seizures in children.

PMID- 15038464
TI  - Influenza infection of the embryonated hen's egg/an alternative model for in vivo
      evaluation of antiviral compounds.
AB  - The embryonated hen's egg can be infected with influenza A virus in laboratory
      experiments leading to death of chick embryos within 8 days post infection. This
      model can be used for rapid and reliable in vivo evaluation of potential anti
      influenza inhibitors. It offers a realistic alternative to experiments with small
      laboratory rodents. By an example of treatment with the antiviral drugs
      amantadine (CAS 665-66-7), rimantadine (CAS 1501-84-4) and zanamivir (CAS 139110
      80-8), it could be demonstrated that chick embryos survive a lethal influenza A
      virus infection when these drugs are administered immediately before or after the
      infective agent is inoculated. In conclusion, the use of influenza virus-infected
      chick embryos for evaluation of new antiviral substances can lead to a
      considerable reduction in the number of small laboratory rodents required.

PMID- 15038466
TI  - Industry and academic medicine: a dangerous liaison?

PMID- 15038467
TI  - Progress in clinical neurosciences: Parkinson's disease with dementia and
      dementia with Lewy bodies.
AB  - Dementia occurs in up to 30% of people with Parkinson's disease and is a major
      cause of disability. Pathologically, Parkinson's dementia, where dementia follows
      the onset of parkinsonism by at least one year, overlaps with dementia with Lewy
      bodies. We review the functional impact, definitions, neuropsychology,
      epidemiology and pathophysiology of Parkinson's dementia, dementia with Lewy
      bodies and their overlap. Associated psychiatric and imaging findings are also
      considered. Lastly, current and emerging approaches to assessment and treatment
      in patients with these Lewy body associated dementias are presented.

PMID- 15038468
TI  - Carotid endarterectomy: a review.
AB  - BACKGROUND: Since the validation of carotid endarterectomy (CEA) as an effective
      means of stroke prevention, there has been renewed interest in its best
      indications and methods, as well as in how it compares to carotid angioplasty and
      stenting (CAS). This review examines these topics, as well as the investigation
      of carotid stenosis and the role of auditing and reporting CEA results.
      INVESTIGATION: Brain imaging with CT or MRI should be obtained in patients
      considered for CEA, in order to document infarction and rule out mass lesions.
      Carotid investigation begins with ultrasound and, if results agree with
      subsequent, good-quality MRA or CT angiography, treatment can be planned and
      catheter angiography avoided. An equally acceptable approach is to proceed
      directly from ultrasound to catheter angiography, which is still the gold
      standard in carotid artery assessment. INDICATIONS: Appropriate patients for CEA
      are those symptomatic with transient ischemic attacks or nondisabling stroke due
      to 70-99% carotid stenosis; the maximum allowable stroke and death rate being 6%.
      Uncertain candidates for CEA are those with 50-69% symptomatic stenosis, and
      those with asymptomatic stenosis > or = 60% but, if selected carefully on the
      basis of additional risk factors (related to both the carotid plaque and certain
      patient characteristics), some will benefit from surgery. Asymptomatic patients
      will only benefit if surgery can be provided with exceptionally low major
      complication rates (3% or less). Inappropriate patients are those with less than
      50% symptomatic or 60% asymptomatic stenosis, and those with unstable medical or
      neurological conditions. TECHNIQUES: Carotid endarterectomy can be performed with
      either regional or general anaesthesia and, for the latter, there are a number of
      monitoring techniques available to assess cerebral perfusion during carotid cross
      clamping. While monitoring cannot be considered mandatory and no single
      monitoring technique has emerged as being clearly superior, EEG is most commonly
      used. "Eversion" endarterectomy is a variation in surgical technique, and there
      is some evidence that more widely practiced patch closure may reduce the acute
      risk of operative stroke and the longer-term risk of recurrent stenosis. CAROTID
      ANGIOPLASTY AND STENTING: Experience with this endovascular and less invasive
      procedure grows, and its technology continues to evolve. Some experienced
      therapists have reported excellent results in case series and a number of
      randomized trials are now underway comparing CAS to CEA. However, at this time it
      is premature to incorporate CAS into routine practice replacing CEA. AUDITING: It
      has been shown that auditing of CEA indications and results with regular feed
      back to the operating surgeons can significantly improve the performance of this
      operation. Carotid endarterectomy auditing is recommended on both local and
      regional levels.

PMID- 15038469
TI  - Multiple sclerosis in its European matrix: some aspects of history, mechanisms
      and treatment.
AB  - Susceptibility to multiple sclerosis is influenced by several genes which are
      relatively common in populations of European origin. Their precise identification
      is currently being intensively investigated. The pathophysiology of the main
      clinical features is better understood. Relapse results from abnormalities of
      conduction to which both demyelination and inflammation contribute. At the
      membrane level, remission depends on the formation of new sodium channels which
      restore conduction even in persistently demyelinated axons. Remyelination
      presumably contributes and synaptic reorganisation may also do so. Axonal
      degeneration contributes to irrecoverable deficit and progression of disability.
      These observations suggest new therapeutic strategies. The management of multiple
      sclerosis needs to be improved. Progress requires an ethically based partnership
      between patients, whose needs are paramount, the research and caring communities
      and the pharmaceutical industry.

PMID- 15038470
TI  - The burden of seizures in Manitoba children: a population-based study.
AB  - BACKGROUND: Population-based studies are necessary to better understand the risk
      factors for developing seizure disorders and the impact of these conditions on
      children. We undertook an assessment of the prevalence of seizure disorders in a
      population of children on the basis of health care utilization records. METHODS:
      Using Manitoba's population-based prescription and health care data for 1998/99,
      the prevalence of children with seizure disorders, on the basis of at least one
      physician visit or hospitalization for epilepsy or a prescription for an
      antiepileptic drug, was determined by age, urban/rural region and socioeconomic
      status. The latter was measured as neighbourhoods stratified by income quintiles
      according to Census data. RESULTS: Age-specific prevalence rates for seizure
      disorders in Manitoba children, determined from health care administrative
      records, were similar to published data on the prevalence of epilepsy, with one
      exception. Prevalence rates in adolescents were higher than those reported in the
      literature. No statistically significant differences in prevalence rates were
      observed between urban and rural populations. However, a higher prevalence was
      found among children of all ages living in lower socioeconomic neighbourhoods in
      urban areas, which presented as a gradient of increased prevalence with decreased
      levels of income. CONCLUSIONS: Population-based health care administrative data
      can be used to describe the geographical distribution of seizure disorders. Our
      data suggest that the burden of seizure disorders is not evenly distributed among
      children.

PMID- 15038471
TI  - The endovascular management of superior cerebellar artery aneurysms.
AB  - BACKGROUND: Superior cerebellar artery aneurysms are rare. We present a clinical
      series of twelve of these aneurysms that were treated exclusively with
      endovascular coils. METHOD: A retrospective analysis of a prospectively collected
      database of cerebral aneurysms treated with coil embolization was performed.
      Clinical notes and radiological images were reviewed. RESULTS: Twelve superior
      cerebellar artery aneurysms were treated in eleven patients between 1992 and
      2001. Seven patients presented with subarachnoid hemorrhage, two with neurologic
      deficit, and two had asymptomatic aneurysms. Coiling resulted in complete
      aneurysm obliteration in six patients and incomplete obliteration in the other
      six. No subsequent hemorrhage occurred with follow-up between 6 and 119 months
      (mean follow-up 50 months). Procedural morbidity was one superior cerebellar
      artery infarct with good recovery. Management morbidity was one middle cerebral
      artery embolus during a follow-up angiogram that required thrombolysis with a
      good clinical result. Nine out of 11 patients on follow-up were performing at
      Glasgow Outcome Scale (GOS) 5. One patient with GOS 3 presented with a poor grade
      subarachnoid hemorrhage and the other patient with GOS 4 presented with a
      parenchymal hemorrhage due to an arteriovenous malformation. CONCLUSION:
      Endovascular treatment of superior cerebellar artery aneurysms is an effective
      treatment strategy with low morbidity.

PMID- 15038472
TI  - Lipoatrophy in patients with multiple sclerosis on glatiramer acetate.
AB  - BACKGROUND: Patients with relapsing remitting multiple sclerosis on the disease
      modifying therapy of glatiramer acetate may be experiencing an adverse reaction
      of lipoatrophy at the sites of their subcutaneous injections. The purpose of this
      study was to complete a full examination of the injection site areas for users of
      glatiramer acetate, and to examine the relationship between lipoatrophy and
      patient characteristics. METHODS: Glatiramer acetate users were identified by
      means of chart review. Over six months, during regular clinic appointments,
      assessment included a full examination of injection site areas including visual
      inspection and manual palpation. Additional patient and clinical characteristics
      were obtained by means of chart review and patient questioning. RESULTS: Seventy
      six patients had been or were current users of glatiramer acetate. Of these, 34
      (45%) had evidence of lipoatrophy in at least one injection site area. All were
      female, and five had severe, nine had moderate and 20 had mild lipoatrophy. In
      some cases, lipoatrophy occurred within months of therapy initiation. Case
      reviews are included for five of the 34 patients, along with photographs of the
      lipoatrophy, a magnetic resonance image and comments on skin biopsies.
      CONCLUSIONS: Prevalence of lipoatrophy was much higher than expected. Possible
      reasons for this adverse reaction are explored and suggested treatment
      recommendations are reviewed. Lipoatrophy can be very disfiguring and is thought
      to be permanent, and the psychological impact can be significant. It is,
      therefore, important that patients be aware of the possibility of lipoatrophy, be
      able to identify it and discontinue injecting in areas where it is identified.

PMID- 15038473
TI  - Do general and multiple sclerosis-specific quality of life instruments differ?
AB  - BACKGROUND: Quality of life instruments provide information that traditional
      outcome measures used in studies of multiple sclerosis do not. It is unclear if
      longer, disease-specific instruments provide more useful information than
      shorter, more general instruments, or whether patients prefer one type to
      another. METHODS: We conducted a cross-sectional study of quality of life in a
      multiple sclerosis clinic population using a mailed questionnaire that combined
      three different quality of life instruments; the SF-36, the Multiple Sclerosis
      Quality of Life Instrument-54, and the EuroQol EQ-5D. We assessed the feasability
      of using each instrument and patient preference for each, calculated correlation
      coefficients for the summary scores of each instrument and other measures of
      disease severity, and calculated odds ratios from proportional odds models
      comparing each instrument with the Expanded Disability Status Scale. RESULTS: We
      did not find substantial differences between the three instruments. All were well
      received by patients, and over 75% felt that the combination of the three
      instruments best assessed their quality of life. For each instrument there was
      substantial variability between patients with similar quality of life scores in
      terms of their disability (as assessed by the Expanded Disability Status Scale
      and their own perception of their disease severity and quality of life (on simple
      1-10 scales). CONCLUSIONS: Quality of life instruments are easy to use and well
      received by patients, regardless of their length. There do not appear to be
      clinically important differences between general and disease-specific
      instruments. Each instrument appears to measure something other than a patient's
      disability or perception of their own disease severity or quality of life.

PMID- 15038475
TI  - Jugular bulb oximetry for prediction of vasospasm following subarachnoid
      hemorrhage.
AB  - BACKGROUND: Cerebral vasospasm adversely impacts the outcome of those suffering
      aneurysmal subarachnoid hemorrhage (SAH). Prediction of vasospasm could improve
      outcomes. We hypothesized that preclinical vasospasm would be heralded by an
      increase in cerebral oxygen extractions (AVDO2) which could be detected by
      jugular bulb oximetry. A pilot study was conducted to address this hypothesis.
      METHODS: Fourteen consenting patients with aneurysmal SAH, undergoing early
      surgery, were entered into the study. Four patients were withdrawn from the study
      secondary to failure of catheters or religious belief. At the time of craniotomy,
      a jugular bulb catheter was placed. Post-operatively, arterial and jugular bulb
      blood samples were taken every 12 hours to calculate AVDO2. As this was an
      observational study, no change in management occurred based on measurements.
      RESULTS: Four of 10 patients had clinical vasospasm. These patients had a
      significant rise in AVDO2 approximately one day prior to the onset of neurologic
      deficits (P<0.001). Symptoms resolved along with a significant improvement in
      AVDO2 on instituting hypertensive, hemo-dilutional, and hypervolemic therapy in
      these patients. The six patients who did not exhibit clinical vasospasm did not
      demonstrate significant rise in AVDO2. CONCLUSIONS: Jugular bulb oximetry is
      simple and cost effective. Increases in AVDO2 using this technique were
      predictive of clinically evident vasospasm in the subsequent hours to days. This
      investigation supports a larger study to assess the utility of jugular bulb
      oximetry in predicting vasospasm in aneurysmal SAH.

PMID- 15038474
TI  - Effectiveness of a multidisciplinary treatment program for chronic daily
      headache.
AB  - BACKGROUND: Chronic daily headache (CDH: headache on fifteen days a month or
      more) is one of the most common forms of chronic pain. The relative efficacy of
      different treatment methods for these patients needs to be determined. OBJECTIVE:
      To compare treatment outcomes for patients with CDH treated in a traditional
      office-based pharmacological treatment program with a second group treated in a
      multidisciplinary management program. METHODS: Patient outcomes were measured
      using changes in the Headache Disability Inventory (HDI) and the Short-Form-36
      (SF-36) over the treatment period. Outcomes from seventy patients treated in an
      office setting were compared to thirty-seven patients treated in a
      multidisciplinary headache treatment program. Both groups received similar
      pharmacological treatment. All patients treated in the office setting and the
      majority of patients in the multidisciplinary program had transformed migraine.
      RESULTS: Even though a reduction in headache days per month occurred, mean
      headache related disability (measured by HDI) and mean Health Related Quality of
      Life (HRQoL measured by SF-36) did not improve for the patient group treated in
      the office setting but did improve significantly for the patient group treated in
      the multidisciplinary headache program. CONCLUSION: For patients with CDH,
      headache-related disability and HRQoL is more likely to improve with management
      in a multidisciplinary headache treatment program as compared to the traditional
      specialist consultation-family physician office-based setting.

PMID- 15038476
TI  - Intraspinal transplantation of hNT neurons in the lesioned adult rat spinal cord.
AB  - BACKGROUND: The role of neural transplantation as a restorative strategy for
      spinal cord injury continues to be intensely investigated. Ideally, the tissue
      source for transplantation must be readily available, free of disease and able to
      survive and mature following implantation into the adverse environment created by
      the injury. We have studied the use of a commercially available cell line of
      cultured human neurons (hNT neurons) as a tissue source for neural
      transplantation in spinal cord injury. METHODS: Following a left lateral thoracic
      hemisection, 54 immunosuppressed, female Wistar rats were randomly allocated into
      different treatment groups; hemisection only or hemisection and hNT cell
      transplantation (via a bridge, double or triple graft). Grafting occurred three
      days after spinal cord injury. After thirteen weeks the animals were sacrificed
      and tissue sections were stained with human neuron specific enolase and human
      specific neural cell adhesion molecule. RESULTS: Immunohistochemical evidence of
      graft survival was displayed in 66.7% of the surviving, grafted animals. Fibre
      outgrowth, greatest in the bridge and triple grafts, was observed in both rostral
      and caudal directions essentially bridging the lesion. Double grafts were
      smaller, displaying less fibre outgrowth, which did not cross the lesion. Long
      fibre outgrowth was evident up to 2 cm from the graft as assessed by tracing and
      immunohistochemical studies. CONCLUSIONS: Bridge and triple grafts displayed
      greater growth and enabled the hNT graft to essentially bridge the lesion. This
      suggests that hNT neurons have the potential to structurally reconnect the
      proximal and distal spinal cord across the region of injury.

PMID- 15038477
TI  - Wernicke encephalopathy in a patient with T-cell leukemia and severe
      malnutrition.

PMID- 15038478
TI  - Can rt-PA be administered to the wrong patient? Two patients with somatoform
      disorder.
AB  - BACKGROUND: Intravenous rt-PA (i.v. rt-PA) for acute stroke has raised many
      concerns, including its inadvertent use in patients presenting with acute stroke
      like symptoms as the expression of their somatoform disorder. Diagnosis of the
      somatoform disorder is often delayed, and thrombolytics in these patients for
      their stroke-like presentation subjects them to risk for hemorrhage. METHODS: The
      presentation, neurological findings, and the therapeutic decision making was
      audited in 85 patients who received i.v. rt-PA for a diagnosis of acute stroke.
      All the surviving patients were re-examined neurologically at least three months
      after i.v. rt-PA. Baseline and follow-up brain CT scans were re-reviewed by a
      neuroradiologist who was blinded to clinical presentation and outcome. Patients
      whose clinical presentation, brain CT and neurological outcome did not fit into
      known or expected anatomical and clinical patterns of stroke underwent
      psychological assessment using the Minnesota Multiphasic Personality Inventory-2.
      RESULTS: In two patients three stroke-like presentations of somatoform disorder
      inadvertently were treated with i.v. rt-PA. This was primarily caused by
      abbreviated neurological examination and narrow differential diagnosis.
      INTERPRETATION: Patients with somatoform disorder may present with symptoms
      mimicking acute stroke. Under the time constraints of i.v. rt-PA use, a diagnosis
      of somatoform disorder can be missed, subjecting such patients to the potential
      complications of thrombolytics.

PMID- 15038479
TI  - Bony metastases of anaplastic oligodendroglioma respond to temozolomide.
AB  - BACKGROUND: Fewer than 30 cases of oligodendroglioma or anaplastic
      oligodendroglioma metastatic to bone are reported in the literature. Prolonged
      survival even with therapy is uncommon. METHODS: We report a case of anaplastic
      oligodendroglioma metastatic to bone with a dramatic and durable response to
      temozolomide therapy. A retrospective case review, molecular analysis, and
      literature search were performed. RESULTS: The patient presented with a right
      frontal mass in 1990. Progression led to resection of the lesion in 1995.
      Histology revealed an anaplastic oligodendroglioma and the tumour was found to
      have allelic loss of heterozygosity (LOH) of chromosome 1p (1p-). He received
      standard radiation therapy. In 2000 he developed hip and pelvic pain. A bone scan
      showed multiple skeletal lesions. Magnetic resonance imaging of the brain showed
      stability of intracranial disease. Resection of one lesion found metastatic
      anaplastic oligodendroglioma with identical morphology to the patient's original
      tumour, including glial fibrillary acidic protein expression. The patient was
      started on standard temozolomide chemotherapy and celecoxib with prompt pain
      relief, and rapid normalization of serum alkaline phosphatase. He received a
      total of 12 cycles of combined therapy with no toxicity and no evidence of
      progression until increasing pain marked disease recurrence. The patient
      underwent palliative chemo- and radiation therapy but eventually succumbed.
      DISCUSSION: Loss of heterozygosity 1p- is associated with prolonged survival in
      anaplastic oligodendroglioma and may increase the cumulative risk for development
      of systemic metastases. We speculate that metastases from oligodendroglioma
      harbouring loss of heterozygosity at chromosome 1p- retain the chemosensitivity
      of the initial lesion.

PMID- 15038480
TI  - Lacunar stroke associated with methylphenidate abuse.
AB  - BACKGROUND: Methylphenidate is a central nervous system stimulant used for the
      treatment of attention deficit hyperactivity disorder and narcolepsy and like
      other psychostimulants has a potential for abuse. CASE STUDY: A young man with a
      cerebral lacunar infarction following chronic oral abuse of methylphenidate is
      presented. CONCLUSIONS: The experience of our patient and a review of the
      literature suggest that cerebral infarction is a potential side effect of chronic
      consumption of methylphenidate.

PMID- 15038481
TI  - Fabry's disease presenting as stroke in a young female.
AB  - BACKGROUND: Fabry's disease is an X-linked disorder, caused by a deficiency of
      the lysosomal enzyme alpha-galactosidase A which results in the accumulation of
      the glycosphingolipid, ceramide trihexose in the vascular endothelium and can
      lead to cerebral infarction. Male hemizygotes are generally more severely
      affected than heterozygote females. Clinical disease in females is thought to be
      due to unequal X chromosome inactivation. CASE: A 19-year-old woman, who was
      previously well, presented with neurological deficits secondary to basal ganglia
      and pontine infarction. Extensive cardiac, arterial and hematologic
      investigations did not identify the etiology of her stroke. Muscle biopsy
      revealed endothelial lysosomal aggregates most consistent with a diagnosis of
      Fabry's disease. The diagnosis was confirmed on the basis of molecular genotype
      analysis. DISCUSSION: Inherited causes of stroke such as Fabry's disease should
      be considered in young patients with stroke if an etiologic diagnosis is not
      reached after complete investigations. Muscle biopsy can assist with the
      diagnosis and guide further investigations. This report summarizes the
      biochemical and histological features of Fabry's disease and the associated
      genetic abnormalities.

PMID- 15038482
TI  - Renal cell carcinoma metastatic to the choroid mimicking intraventricular
      meningioma.
AB  - BACKGROUND: Metastatic renal cell carcinoma to the choroid plexus is a rare
      condition and can be easily confused with meningioma. METHODS: A 61-year-old
      female presented with progressive neurologic deterioration and MRI findings of
      obstructive hydrocephalus and a homogeneously contrast enhancing 3 cm oval mass
      in the trigone of the left lateral ventricle. RESULTS: Despite radiologic,
      intraoperative gross features, and frozen pathology all consistent with
      meningioma, the final pathology revealed metastatic renal cell carcinoma.
      CONCLUSION: Renal cell carcinoma metastatic to the choroid plexus can mimic
      intraventricular meningioma. We present a review of the literature and comparison
      of the radiological features of meningiomas and metastatic renal cell carcinoma.
      We also discuss the use of an under-utilized technique, the contralateral
      transcallosal approach, in the surgical treatment of this intraventricular
      lesion.

PMID- 15038483
TI  - Contralateral motor automatisms in neocortical temporal lobe epilepsy.
AB  - BACKGROUND: The lateralizing value of the motor automatisms is generally doubted
      in most patients with temporal lobe epilepsy. However, subgroup analysis of the
      seizures of temporal lobe origin suggests a role for motor automatisms in
      discriminating seizures of neocortical versus mesial temporal lobe origin.
      METHODS: Video-EEG of a patient with well-defined neocortical temporal lobe
      epilepsy was reviewed to assess the localizing value of motor automatisms.
      RESULTS: We report a patient with left upper extremity motor automatisms and
      clonic movements of the proximal left lower extremity with altered awareness as
      the sole manifestations of right temporal neocortical seizures. CONCLUSION: Early
      onset unilateral motor automatisms without dystonic posturing can localize the
      seizure origin to the contralateral temporal lobe neocortex.

PMID- 15038484
TI  - Orthodontic "second opinions": what they sometimes are, what they should be.

PMID- 15038485
TI  - A 2003 update of bone physiology and Wolff's Law for clinicians.
AB  - By 1892, Julius Wolff and others realized that mechanical loads can affect bone
      architecture in living beings, but the mechanisms responsible for this effect
      were unknown, and it had no known clinical applications. In 2003 we know how this
      effect occurs and some of its applications. Our load-bearing bones (LBBs) include
      tibias, femurs, humeri, vertebrae, radii, mandibles, maxillae, wrists, hips, etc
      (so LBBs are not limited to weight-bearing ones). The strength of such bones and
      their trabeculae would represent their most important physiologic feature but in
      the special sense of relative to the size of the typical peak voluntary loads on
      them. The biologic "machinery" that determines whole-bone strength forms a tissue
      level negative feedback system called the mechanostat. Two thresholds make a
      bone's strains determine its strength by switching on and off the biologic
      mechanisms that increase or decrease its strength. Equally, two thermostats can
      determine a room's temperature by switching on and off the room's heating and
      cooling systems. General features show that the largest voluntary loads on LBBs
      determine most of their strength after birth. These loads come from muscle forces
      so muscle strength strongly influences the strength of our LBBs. This process
      affects, in part, the healing of fractures, bone grafts, osteotomies, and
      arthrodeses; the bone's ability to endure load-bearing joint and dental
      endoprostheses; why healthy bones are stronger than the minimum needed to keep
      voluntary loads from breaking them suddenly or from fatigue; some general
      functions and disorders of bone modeling and basic multicellular unit-based bone
      remodeling; some limitations of in vitro data and of pharmaceutical actions; and
      the fact that many bone-active humoral and local agents have permissive roles in
      a bone's adaptations and healing, instead of forcing them to occur.

PMID- 15038486
TI  - Changes in the periodontal ligament after experimental tooth movement using high
      and low continuous forces in beagle dogs.
AB  - The aim of this study was to evaluate histological changes in the periodontal
      structures of beagle dogs after using high and low continuous forces during
      experimental tooth movement. An orthodontic appliance was placed on the second
      premolar and the first molar by exerting a continuous and constant reciprocal
      force of 25 cN on one side and 300 cN on the other side of the mandible. Tooth
      movement was recorded weekly. Dogs were sacrificed after one, four, 20, 40, and
      80 days for histological evaluation. Hematoxylin and eosin (HE) staining was used
      for tissue survey, staining for alkaline phosphatase as a marker was used for
      active osteoblasts, and tartrate-resistant acid phosphatase staining was used for
      osteoclasts. After 24 hours, the remodeling process had already started at the
      pressure and tension side, and in some samples hyalinization was found. In
      contrast to earlier studies, hyalinization was found throughout the entire
      experimental period, both in molars and in premolars. In the periodontal ligament
      of some teeth, small patches of hyalinization were found at the pressure side,
      mostly located buccally or lingually of the mesiodistal plane, whereas others
      showed large areas of necrotic tissue. It is concluded that hyalinization limits
      tooth movement, but there is no relationship with the force level.

PMID- 15038487
TI  - Morphologic characteristics of the dentition and palate in cases of skeletal
      asymmetry.
AB  - The purpose of this study was to clarify the three-dimensional morphological
      characteristics of the dentition and palate in skeletal asymmetry in patients
      with skeletal Class III malocclusion using a newly defined palatal reference
      plane in a dental cast. Twenty patients (5 males and 15 females) who had skeletal
      Class III malocclusion with facial asymmetry were selected. Pretreatment
      posteroanterior cephalometric radiographs and maxillary dental casts were used.
      The lateral deviation of Me was measured as the distance from a line
      perpendicular to Lo-Lo' that passed through CG. The angle between the Lo-Lo'
      plane and the J-J' plane was measured. Each maxillary dental cast was measured
      using a three-dimensional surface-scanning system, and the newly defined palatal
      reference plane was calculated. The right/left difference in the radius of
      curvature of the palate and right/left differences in the vertical and
      mesiodistal positions of the first molars were analyzed. Linear correlation and
      regression techniques were used. Our findings demonstrate that the lateral
      deviation of the mandible is closely related to the morphology of the alveolar
      process and to the vertical height of the dentition. In this study, the three
      dimensional application of a new palatal reference plane is very useful in
      morphological research, and the results provide detailed information on the
      characteristics of facial asymmetry.

PMID- 15038488
TI  - Electromyographic activity of lower lip muscles when chewing with the lips in
      contact and apart.
AB  - Masticatory muscle activity is coordinated with perioral muscle during chewing.
      Subjects with competent lips usually chew with the lips in light contact, whereas
      subjects with incompetent lips possibly have dysfunctional chewing. In this
      study, the electromyographic (EMG) activities of the lower lip and masseter
      muscles were recorded when chewing with the lips in contact and apart. At first,
      37 subjects were divided into an incompetent lip group and competent lip group on
      the basis of EMG activity of the lower lip muscle at rest. The durations of the
      masseter nonactive phase and total phase when chewing with lips in contact were
      shorter in the incompetent lip group than in the competent lip group. In the
      incompetent lip group, when chewing with the lips apart, the EMG activity of
      lower lip in the masseter nonactive phase was significantly (P < .05) higher than
      in the competent lip group, but there was no difference in the EMG activity in
      the masseter active phase between two groups. Our results suggest that subjects
      with incompetent lips have difficulty chewing while their lips are relaxed. We
      conclude that the inability of sealing the lips and lip dysfunction could
      possibly affect masticatory function.

PMID- 15038489
TI  - Soft tissue facial morphology in obese adolescents: a three-dimensional
      noninvasive assessment.
AB  - The number of obese adolescents is increasing in the Western society. For a
      deeper understanding of the mechanisms underlying this pathology, the
      quantitative characteristics of the facial soft tissues should also be
      investigated. The three-dimensional coordinates of 12 soft tissue facial
      landmarks were obtained by computerized digitizers in 11 male and 14 female
      adolescents aged 13-17 years, all with a body mass index larger than 30 kg/m2
      (mean 31.67 kg/m2, SD 1.58). From the landmarks, several facial dimensions were
      calculated. Data were compared with those collected in normal individuals of the
      same age, ethnicity, and sex by computing z scores. Significant (paired Student's
      t-test, P < .05) larger dimensions were found for skull base width (girls),
      mandibular width (both sexes), lower face depth (girls), and mandibular corpus
      length (girls). In the pooled sample (boys plus girls), the faces of obese
      adolescents were significantly wider transversally (skull base width, mandibular
      width), deeper sagittally (mid and lower face depth, mandibular corpus length),
      and shorter vertically (upper facial height) than those of their normal school
      companions. "Borderline" obese adolescents possessed some facial characteristics
      typical of patients with more substantial obesity. The effect of an increased
      body weight-per-height was therefore present also in subjects not already
      referred to a medical control.

PMID- 15038490
TI  - An evaluation of dynamic lip-tooth characteristics during speech and smile in
      adolescents.
AB  - This retrospective study was conducted to measure lip-tooth characteristics of
      adolescents. Pretreatment video clips of 1242 consecutive patients were screened
      for Class-I skeletal and dental patterns. After all inclusion criteria were
      applied, the final sample consisted of 50 patients (27 boys, 23 girls) with a
      mean age of 12.5 years. The raw digital video stream of each patient was edited
      to select a single image frame representing the patient saying the syllable
      "chee" and a second single image representing the patient's posed social smile
      and saved as part of a 12-frame image sequence. Each animation image was analyzed
      using a SmileMesh computer application to measure the smile index (the ratio of
      the intercommissure width divided by the interlabial gap), intercommissure width
      (mm), interlabial gap (mm), percent incisor below the intercommissure line, and
      maximum incisor exposure (mm). The data were analyzed using SAS (version 8.1).
      All recorded differences in linear measures had to be > or = 2 mm. The results
      suggest that anterior tooth display at speech and smile should be recorded
      independently but evaluated as part of a dynamic range. Asking patients to say
      "cheese" and then smile is no longer a valid method to elicit the parameters of
      anterior tooth display. When planning the vertical positions of incisors during
      orthodontic treatment, the orthodontist should view the dynamics of anterior
      tooth display as a continuum delineated by the time points of rest, speech, posed
      social smile, and a Duchenne smile.

PMID- 15038491
TI  - Lip curve changes in females with premolar extraction or nonextraction treatment.
AB  - Changes in lip curvature resulting from treatment have been largely ignored in
      orthodontic literature. The focus instead has been primarily directed at
      retraction of the vermilion border and changes in the nasolabial angle. This
      study, therefore, was designed to retrospectively analyze changes in the upper
      and lower lip curves associated with growth and treatment. The lateral
      cephalometric records of 137 female orthodontic patients were digitized. Sixty
      two were treated with premolar extractions and 75 without extractions. The
      overall extraction group was further divided into subgroups on the basis of the
      chosen extraction sequence, which included extraction of 4/4, 4/5, or 5/5.
      Statistical analysis revealed no significant differences in changes in lip curve
      depth between the two overall samples, relative to either of the two reference
      lines. This would suggest that an appropriately selected plan, whether extraction
      or nonextraction, should allow treatment to be carried out without negative
      effects on the curvature of the lips. Calculation of correlation coefficients and
      regression analysis suggested that the inherent properties and morphology of the
      soft tissues themselves are probably the greatest determinants of lip curve
      behavior with treatment. The midface soft tissues appear to be less dependent on
      changes in the underlying hard tissues than do the lower face soft tissues.
      Pretreatment upper and lower incisor positions and angulations and the underlying
      vertical facial dimension appear to play more significant roles in the behavior
      of the lower lip than the upper lip.

PMID- 15038492
TI  - Comparison between the opinions of Tanzanian parents and their children on dental
      attractiveness.
AB  - The objective was to investigate the opinion of Tanzanian parents on dental
      attractiveness and to compare their opinion with that of their children. A
      prestructured questionnaire with 18 intraoral frontal photographs was given to
      286 parents and their children aged 9-18 years. The photographs represented
      various types of occlusion traits, with the first 10 intraoral photographs
      representing grade 1-10 of the aesthetic component (AC) of the index of
      orthodontic treatment need, and the remaining eight photographs were added to
      represent malocclusions that are often seen in Tanzania. Basic statistical
      techniques were used to analyze the data. Photographs showing severe deviations
      were perceived by both children and parents as the most unattractive. The opinion
      was significantly correlated with children's age (P = .02) and sex (P < .0005),
      with older girls tending to dislike photographs showing severe deviations the
      most. The mean of the opinion for the photographs showing some spacing with
      overbite < or = 2 mm or open bite and overbite > 2 mm fell in the middle of the
      scale, with a tendency toward unattractiveness. Photographs matching 8-10 on the
      AC scale were perceived as the most unattractive, indicating what could be a lay
      person's priority when considering an orthodontic treatment policy in Tanzania.

PMID- 15038493
TI  - Semirapid maxillary expansion--a study of long-term transverse effects in older
      adolescents and adults.
AB  - A new approach, namely, semirapid maxillary expansion (SRME) was introduced with
      the hypothesis that SRME may stimulate the adaptation process in the
      nasomaxillary complex and thus would result in reduction of relapse in the
      postretention period. The aim of this study was therefore to evaluate the short-
      and long-term effects of SRME on dentofacial structures in older adolescents and
      adults. The study sample consisted of 40 individuals, 20 orthodontic patients who
      required maxillary expansion and 20 control cases who received no orthodontic
      treatment. The mean ages were 14.57 and 13.83 years at the start of treatment and
      control periods, respectively, and ranged between MP3cap and Ru hand-and-wrist
      maturation stages. A rigid acrylic maxillary expander was used for SRME (RME of 5
      7 days, followed by slow maxillary expansion). The mean expansion time was 0.34
      years, and the mean follow-up period was 2.68 years after retention. PA
      cephalometric film measurements were performed, and the data were analyzed
      statistically by using paired and Student's t-tests. Lower nasal and maxillary
      base widths, and upper intermolar and incisor interapex widths were significantly
      increased compared with the control group (P < .05, P < .001) and remained
      unchanged during the retention and follow-up stages. Moreover, significant amount
      of increases occurred in zygomatic and lower nasal widths during the follow-up
      period. The findings of this study suggested that the dentoskeletal changes after
      the use of SRME were maintained satisfactorily in the long term in older
      adolescents and adults.

PMID- 15038494
TI  - The treatment effect of mandibular protrusive appliances on the glenoid fossa for
      Class II correction.
AB  - A study was undertaken to determine the contribution of glenoid fossa
      modification in the correction of skeletal Class II malocclusions. Individually
      corrected lateral tomograms of 35 patients (18 boys and 17 girls) between the
      ages of 7.96 and 15.06 years were used. The subjects were selected on the basis
      of the criteria that they were suitable for treatment with a mandibular
      protrusive appliance (activator). The mean duration of activator treatment was
      1.33 years. Tomograms were taken on a pre- and posttreatment basis. The tomograms
      were scanned and digitized on screen using a common software program. Points were
      located on each tomogram and specific linear measurements were used to evaluate
      any changes in glenoid fossa morphology. Paired t-tests were applied for the left
      and right sides separately and between the before and after treatment
      measurements. Paired t-tests were also applied between the left and right sides
      to test for any difference between the sides. The results of this study
      demonstrated that there are no positive radiographically depictable contributions
      from glenoid fossa modification for the correction of skeletal Class II
      malocclusions treated with mandibular protrusive appliances (activators). In
      addition, no statistically significant differences were found between right and
      left sides denoting relative symmetry. It is concluded that, contrary to animal
      research and magnetic resonance findings, it seems possible that glenoid fossa
      modeling is not induced by mandibular protrusive appliances during treatment of
      skeletal Class II problems.

PMID- 15038495
TI  - The effect of continuous bite-jumping in adult rats: a morphological study.
AB  - The aim of this study was to determine the mandibular morphology before, during,
      and after bite-jumping in nongrowing species. Fifty-two adult female Sprague
      Dawley rats were divided into four experimental groups and four control groups.
      The experimental groups were fitted with fixed bite-jumping devices that
      protruded the mandible. The animals were sacrificed on days 3, 14, 30, and 60.
      Right halves of the mandible were harvested and freed of soft tissue. Digital
      pictures were obtained in a standardized manner. Selected linear and angular
      measurements were made. There were no morphological differences between the
      controls and experimental group on days 3 and 14. The length of condylar process
      increased significantly on day 30 and remained so on day 60 in the experimental
      group. The angulation of the condylar process was significantly affected because
      of increased apposition of bone in the middle and especially the posterior parts
      of the condyle. Thus, bite-jumping of the mandible in adult rats affects the size
      and angulation of the condylar process because of differential apposition of bone
      on the condylar head.

PMID- 15038496
TI  - Changes in response properties of periodontal mechanoreceptors after experimental
      orthodontic tooth movement in rats.
AB  - Using an in vitro preparation, we investigated chronological changes in response
      properties of periodontal mechanoreceptors (PMRs) in the rat right mandibular
      first molar (M1) after experimental orthodontic tooth movement. Orthodontic force
      was applied to M1 for 14 days by activating 24.5 mN superelastic titanium-nickel
      alloy closed coil springs anchored to the mandibular incisors. Experiments were
      performed on days 3, 7, 10, and 14 during application of orthodontic force and on
      days 7, 14, 21, and 28 after removal of orthodontic force. The rats without
      application of orthodontic force were used as control group. In each group,
      direct mechanical stimulation using von Frey hairs and electrical stimulation was
      applied to the distal root of M1. Results showed that compared with controls (1)
      the mechanical thresholds were significantly lower during application of
      orthodontic force; however, no significant difference was found after removal of
      force application and (2) conduction velocities were significantly lower from day
      7 during application of orthodontic force to day 14 after removal of orthodontic
      force; however, no significant difference was found on days 21 and 28 after
      removal of orthodontic force. These results suggest that the PMRs, although
      having some of their response properties altered during orthodontic force
      application, were able to recover and adapt to the newly acquired intraoral
      condition after removal of the orthodontic force.

PMID- 15038497
TI  - CD40-CD40L expression during orthodontic tooth movement in rats.
AB  - The aim of this study was to investigate the expression of the costimulatory
      molecules CD40 and CD40L in periodontal and bone cells in orthodontically treated
      and untreated teeth using immunohistochemistry. The upper first molars were moved
      mesially by a fixed appliance. In the experimental group, CD40+ cells were
      detected at both the tension and the resorption sides in fibroblast-, macrophage
      , and dendritic-like cells. The staining was more pronounced on the resorption
      side. The strongest expression was observed on day 3, decreased on day 7, and
      reached a low level on day 10 after application of orthodontic force. In
      contrast, in the treated animals CD40 ligand was expressed on day 3, the
      expression was enhanced on day 7, and was more pronounced on day 10. CD40L
      expressing cells were found predominantly around hyalinized tissue in the
      resorption zone and the tension areas of the distal root. CD40L was expressed in
      the bone marrow cells in the pressure zone. In the tension side, some cells of
      the cellular cementum expressed CD40L. The expression of CD40 and CD40L was low
      in untreated teeth. These results suggest that CD40-CD40L interaction appears to
      be an active process during orthodontic tooth movement and that orthodontic force
      induces T-cell activation. Such activation may be involved in the induction of
      inflammatory mediators and subsequent bone remodeling. In addition, this may lead
      to the generation of anti-inflammatory mediators that support defense mechanisms
      against root resorption, which depend on the type of immune response that is
      induced regarding CD40-CD40L expression.

PMID- 15038498
TI  - Custom base preaging in indirect bonding.
AB  - This in vitro evaluation analyzed the influence of custom base composite age on
      bond strength in indirect bonding. One hundred fifty permanent bovine mandibular
      incisors were randomly divided into 10 groups of 15 specimens each. Stainless
      steel brackets were bonded to the teeth using the Thomas indirect bonding
      technique using two different custom base composite-sealant combinations: (1)
      chemically cured Phase II composite and chemically cured Custom I.Q. sealant, and
      (2) light-cured Transbond XT composite and chemically cured Sondhi Rapid Set
      sealant. The composite custom bases were preaged for 24 hours and for seven, 15,
      30, and 100 days. Shear bond strength tests for the two composite-sealant
      combinations showed no significant differences. Preaging of the custom base
      composite up to 30 days did not affect shear bond strength, and mean bond
      strength values exceeded 15 MPa in these groups. However, bond strength
      measurements for groups with a custom composite base aged for a longer interval
      (100 days) before sealant polymerization were significantly lower. On the basis
      of the results of this study, clinicians can safely use custom base composites
      aged up to 30 days when using the Thomas indirect bonding technique.

PMID- 15038499
TI  - Nonlinear large-deflection analysis of orthodontic wires.
AB  - The purposes of this study were (1) to measure the nonlinear force-deflection
      behavior of selected orthodontic wires using a conventional tensile test, (2) to
      extend a mathematical model for simulating the force system produced by
      orthodontic wires based on the small-deflection linear theory to the large
      deflection nonlinear theory, and (3) to examine the effects of the cross-section
      and mechanical properties of orthodontic wires on nonlinear characteristics. A
      method for extending a mathematical model for simulating the force system
      produced by orthodontic wires based on the small-deflection linear theory to the
      large-deflection nonlinear theory was established, and this can provide a clear
      view of the true nature of orthodontic wires. Furthermore, our results
      demonstrated that the nonlinear properties of orthodontic wires were affected
      more by the cross-sectional shape than by mechanical properties.

PMID- 15038500
TI  - Use of skeletal maturation based on hand-wrist radiographic analysis as a
      predictor of facial growth: a systematic review.
AB  - The purpose of this systematic review was to evaluate the predictive value of
      hand-wrist radiographic assessment of skeletal maturity in estimating facial
      growth timing and velocity. A search of PubMed, Medline, Cochrane Database of
      Systematic Reviews, Embase, Web of Sciences, and Lilacs identified 16 articles
      that met the following inclusion criteria: use of hand-wrist radiographs for
      skeletal maturation determination, facial growth evaluated through cephalometric
      radiographs, and cross-sectional or longitudinal studies. Five articles were
      rejected because of major methodological issues. Most of the remaining articles
      had small sample size, and there was no report of randomization or method error.
      Skeletal maturity determined by hand-wrist radiographic analysis was well related
      to overall facial growth velocity. Maxillary and mandibular growth velocities
      were related to skeletal maturity, but their relationship was less robust than
      that for overall facial growth. The available articles have not adequately
      defined a relationship between cranial base growth velocity and skeletal
      maturity. Hand-wrist radiographic assessment of skeletal maturity for use in
      facial growth prediction should include bone staging as well as ossification
      events. The role of skeletal maturity assessment in clinical and research
      applications is discussed and recommendations are provided.

PMID- 15038501
TI  - Surgical orthodontic correction of acromegaly with mandibular prognathism.
AB  - A male (30 years five months) who complained of mandibular prominence and
      masticatory dysfunction was diagnosed as a mandibular prognathic with acromegaly
      after cephalometric and endocrine examinations. The level of growth hormone (GH)
      subsequent to a transsphenoidal hypophysectomy had been controlled by medicines
      for about five years. Surgical orthodontic correction improved his occlusion and
      profile, but magnetic resonance imaging detected a recurrent adenoma in the
      cranial base during the retention period. The recurrence resulted in slight
      prognathic changes of the patient with a high level of GH. This is a case report
      of the treatment of an acromegalic patient discussing growth considerations that
      could influence the orthodontic treatment plan and long-term stability.

PMID- 15038502
TI  - Orthodontic treatment of an impacted dilacerated maxillary central incisor
      combined with surgical exposure and apicoectomy.
AB  - The impacted incisor was moved into its proper position with surgical exposure
      and orthodontic traction. Although apicoectomy was performed during the
      orthodontic treatment, the incisor showed good stability after the long retention
      period.

PMID- 15038503
TI  - Facial asymmetry case with multiple missing teeth treated by molar
      autotransplantation and orthognathic surgery.
AB  - Autotransplantation is an alternative treatment in cases of missing teeth.
      Autotransplantation of teeth can lead to significantly shorter treatment time and
      an improved treatment result in certain cases of tooth loss, wherever a suitable
      tooth is available and the anatomic circumstances permit it. The presented case
      report, treated successfully with molar autotransplantation and orthognathic
      surgery, had a number of missing teeth and facial asymmetry.

PMID- 15038504
TI  - Psychosocial resource depletion of parents of twins after assisted versus
      spontaneous reproduction.
AB  - OBJECTIVE: To examine the effect of mode of conception (spontaneous versus
      induced) on parenting stress, psychological well-being and marital quality during
      the transition to parenthood among parents of twins. METHODS: The Parenting
      Stress Index was assessed in 37 parents of twins conceived by assisted
      reproductive technologies (ART) and compared to that of 38 controls who conceived
      spontaneously. RESULTS: First-time parents after assisted reproduction
      experienced significantly higher levels of parenting stress than parents who
      conceived spontaneously (89.3 vs 72.8). Primiparas following assisted
      reproduction score lower on psychological well-being than do controls. The two
      study groups did not differ in their perception of marital quality. In addition,
      ART primiparous mothers experience higher levels of parenting stress and lower
      levels of psychological well-being in comparison to primiparous mothers who
      conceived spontaneously. CONCLUSIONS: The transition to parenthood following
      assisted reproduction is demanding for both parents of twins. In particular,
      first-time mothers may require qualified emotional support to facilitate
      adjustment to twin parenthood.

PMID- 15038505
TI  - Embryo disposition: the forgotten "child" of in vitro fertilization.
AB  - Cryopreservation of embryos is frequently employed in in vitro fertilization
      (IVF) practices because transfer of more than 3 embryos per cycle is not
      advantageous, and cryopreserved embryos offer fairly high pregnancy rates upon
      eventual transfer. Unfortunately, frozen embryos accumulate (approximately 4 per
      cycle). Thus, industrialized countries have developed laws or guidelines to
      govern their disposition, which may be disposal, or donation to medical research
      or to a recipient infertile couple. Worldwide, national regulations vary from
      eternal preservation to 10-year and 5-year preservation limits. The attitudes of
      couples who have undergone IVF range from almost parental concern for the embryos
      to regarding them as medical by-products--with little relationship to a couple's
      having a living child, in most studies. This paper describes disposition studies
      in various countries and couples' actions taken at time of disposition, with
      special detail on the problems involved in embryo donation to another couple.

PMID- 15038506
TI  - Emotional distress in infertile women in Kuwait.
AB  - OBJECTIVES: Although previous studies conducted in the Western countries have
      reported that psychological factors are implicated in the experience of
      infertility, no study has assessed this relationship in Arab women. We postulate
      that with all important causal "confounders" such as age, gender, education and
      general health status controlled, any significant difference in psychological
      profile can be attributed to infertility. METHODS: An Arabic version of the
      Hospital Anxiety and Depression Scale (HADS) was used to examine the
      psychological status of 120 Kuwaiti infertile women and an age-matched sample of
      125 healthy pregnant women as a control group. RESULTS: Compared with an age
      matched pregnant control sample, the infertile women exhibited significantly
      higher psychopathology in all HADS parameters in the form of tension, hostility,
      anxiety, depression, self-blame and suicidal ideation. The illiterate group
      attributed the causes of their infertility to supernatural causes, such as evil
      spirits, witchcraft and God's retribution, while the educated group blamed
      nutritional, marital and psychosexual factors for their infertility. Faith and
      traditional healers were the first treatment choice among illiterate women, while
      the educated women opted for an infertility clinic for treatment. Childlessness
      resulted in social stigmatization for infertile women and placed them at risk of
      serious social and emotional consequences. CONCLUSIONS: The prevalence and
      severity of psychological distress in this sample of infertile Kuwaiti women
      indicate the appropriateness of referring these patients for psychological
      evaluation. Programs successful in dealing with infertility in Kuwait need to
      include establishment of a community-based intervention strategy to educate
      people about infertility and to give guidelines for treatment.

PMID- 15038507
TI  - Rationale for new oral contraceptive dosing.
AB  - The evolution of both the type and dose of the estrogen and the progestin in oral
      contraceptives has been complex. Whereas the evolution of the progestin component
      remains dominated by a concern for the metabolic effects of the 19
      nortestosterone derivatives, the evolution of the estrogen component has been
      more of a concern for safety, or perceived safety. By lowering the estrogen dose,
      some side effects, such as breast tenderness, bloating and nausea, have
      decreased. At the same time, others, such as breakthrough bleeding and spotting
      (BTB/BTS), have increased. Indeed, BTB and BTS are the chief reason why women
      discontinue OCs as well as the primary reason clinicians change the dose or brand
      of an OC. During the past few years numerous studies have shown inferior cycle
      control with 20-microgram ethinyl estradiol (EE) OC formulations compared to
      slightly higher dose OCs. Recently marketed OCs containing 25-30 micrograms of EE
      have addressed this issue. The 25-microgram EE OCs combined with desogestrel have
      cycle control equal to a 35-microgram EE OC, whereas the 25-microgram OC combined
      with norgestimate has shown superior cycle control compared to a 20-microgram EE
      OC. The 30-microgram EE OC combined with drospirenone in a non-comparative trial
      is also associated with low rates of BTB/BTS. Our current goal, now that safety
      issues have been put to rest, is that of identifying formulations that will
      enhance adherence and increase successful use of OCs.

PMID- 15038508
TI  - Severity of ovarian hyperstimulation syndrome: its relation to number of
      conceptuses.
AB  - OBJECTIVE: To assess the possibility that number of days of hospital stay
      increases with an increasing number of conceptuses in patients with ovarian
      hyperstimulation syndrome (OHSS). METHODS: We reviewed 100 OHSS patients who were
      treated with a conservative therapeutic approach; 15 patients conceived but
      experienced spontaneous abortion by 8 weeks' gestation (SA group), 24 patients
      conceived a single fetus (singleton group), 16 patients conceived 2 fetuses (n =
      14) or 3 fetuses (n = 2) (multiple group), and 45 patients did not conceive (NC
      group). The number of days of hospital stay, number of days of albumin
      supplementation, and hospital days when patients exhibited a urine volume of > or
      = 1200 mL/day and a hematocrit of > 40% were compared among the four groups.
      RESULTS: The number (SD) of days of hospital stay was 23.6 (9.0) days for the
      multiple group, 16.5 (7.7) days for the singleton group, 13.9 (7.6) days for the
      SA group, and 11.6 (4.8) days for the NC group. The orders of the other three
      variables were the same as that of the number of days of hospital stay, in that a
      larger number of days was observed with an increasing number of conceptuses.
      CONCLUSION: Pregnant women sustained OHSS for a longer time with an increasing
      number of conceived fetuses.

PMID- 15038509
TI  - Psychological aspects of infertility due to various causes--prospective study.
AB  - SUBJECTS AND METHODS: One hundred and twenty infertile couples (30 each among
      unexplained infertility, anovulation, tubal factor, and male factor groups) and
      30 fertile couples as controls were evaluated for psychological assessment by
      different psychological test instruments. Initial evaluation was done at
      recruitment, followed by reassessment at 3, 6, 9 and 12 months during the
      infertility work-up, and at the end when the specific diagnosis and the
      management and prognosis were disclosed. RESULTS: Psychological components were
      found to play a significant role in infertility of unknown etiology, especially
      in the male partner. They affected the personality and social behavior of the
      male partner and caused anxiety, but led to depression in the female partner. In
      cases of organically caused infertility, partners were worried about the other's
      reaction. Anxiety was significantly greater in the partner with the fertility
      problem than in the other partner. Life events were significant in the partner in
      whom the fertility problem was detected. Periodic psychological assessment was
      not affected by infertility work-up on the male partner in any of the groups,
      whereas anovulation and tubal factor infertility showed a significant
      psychological effect on the female partner at the end of work-up. Depression and
      anxiety in the female partner were evident soon after the investigation started.

PMID- 15038511
TI  - Scope and epidemiology of cancer therapy-induced oral and gastrointestinal
      mucositis.
AB  - OBJECTIVE: To discuss the scope and epidemiology of cancer therapy-induced
      mucositis. DATA SOURCE: Peer-reviewed articles and book chapters. CONCLUSION:
      Mucositis is a frequent and costly complication of cancer treatment. The risk of
      cancer therapy-induced mucositis varies depending on a number of patient- and
      treatment-related factors. IMPLICATIONS FOR NURSING PRACTICE: An awareness of the
      risk factors associated with mucositis will allow nurses to identify cancer
      patients at greatest risk and incorporate supportive care measures into their
      management plans.

PMID- 15038512
TI  - Pathobiology of mucositis.
AB  - OBJECTIVE: To describe the pathogenesis of mucositis, summarize the techniques
      used to study the condition, and describe the current five-phase model that
      defines mucositis pathogenesis. DATA SOURCE: Published research articles, ongoing
      laboratory and clinical studies, and clinical experience. CONCLUSION: Defining
      the biological mechanisms associated with mucosal injury is critical for
      effective intervention. Research performed over the past few years has shown that
      the pathobiology of mucositis is complex, and involves all of the cells and
      tissues of the mucosa. IMPLICATIONS FOR NURSING PRACTICE: An understanding of
      this evolving pathobiologic model of mucositis will enable nurses to more
      effectively assess and manage mucositis.

PMID- 15038513
TI  - Clinical consequences of oral mucositis.
AB  - OBJECTIVE: To identify the clinical manifestations, risk factors, secondary
      complications, and assessment and management of oral mucositis. DATA SOURCES:
      Professional journals, websites, and books. CONCLUSION: Secondary consequences of
      oral mucositis include infection, xerostomia, hemorrhage, and nutritional
      deficits. IMPLICATIONS FOR NURSING PRACTICE: Nurses should have an extensive
      knowledge base about the appropriate interventions that can be used to alleviate
      or lessen the consequences often associated with oral mucositis.

PMID- 15038514
TI  - Assessment and measurement of oral mucositis.
AB  - OBJECTIVE: To discuss the assessment and monitoring of mucositis and provide an
      overview of instruments available to assess or measure mucositis. DATA SOURCE:
      Published journal articles, texts, and clinical experience. CONCLUSION: The lack
      of consistent use of valid and reliable instruments for the assessment of
      mucositis have limited progress in the prevention and management of mucositis.
      IMPLICATIONS FOR NURSING PRACTICE: Nurses play a key role in the assessment of
      oral cavity changes. Using valid and reliable measures will foster the ability to
      predict risk for mucositis and to test the effectiveness of protocols for its
      prevention and treatment.

PMID- 15038516
TI  - Gastrointestinal mucositis.
AB  - OBJECTIVE: To review the management of radiotherapy- and chemotherapy-induced
      gastrointestinal mucositis. DATA SOURCE: Articles and research studies.
      CONCLUSION: Gastrointestinal damage is becoming a common dose-limiting toxicity.
      However, there is only limited research into the mechanism and possible treatment
      of this toxicity. IMPLICATIONS FOR NURSING PRACTICE: It is important to document
      the frequency and severity of gastrointestinal mucositis, and to alleviate
      symptoms wherever possible.

PMID- 15038515
TI  - Managing pain in mucositis.
AB  - OBJECTIVE: To discuss pharmacologic and nonpharmacologic approaches available to
      manage pain. DATA SOURCE: Published journal articles, book chapters, clinical
      experience. CONCLUSION: Pain management requires treatment directed at the
      various factors involved in the pain experience. IMPLICATIONS FOR NURSING
      PRACTICE: Nurses need to assess pain daily and follow patients closely until
      mucositis resolves. Management targeted to specific dimensions of pain can
      improve the effectiveness of pain control.

PMID- 15038517
TI  - Educational issues in oral care.
AB  - OBJECTIVE: To discuss the importance of patient, family, and health care
      professional education in enhancing oral care and adherence to treatment
      regimens. DATA SOURCE: Textbooks, review articles, and research studies.
      CONCLUSION: Oral complications of cancer therapy influence both patient outcomes
      and fiscal outcomes. Patient awareness of the importance of oral health improves
      adherence to the oral care standard. However, the lack of knowledge of health
      professionals is a barrier to implementing patient education and oral care
      standards. IMPLICATIONS FOR NURSING PRACTICE: Curriculum should incorporate oral
      assessment and oral hygiene. Training of oncology nurses must include assessment,
      prevention, and treatment of oral mucositis.

PMID- 15038518
TI  - Novel therapies.
AB  - OBJECTIVE: To highlight selected research directed to new drug and device
      technologies to manage mucositis in cancer patients and to illustrate potential
      impact of successful therapies. DATA SOURCES: Published research articles and
      abstracts, clinical experience. CONCLUSION: Advances in molecular modeling of
      mucosal injury in cancer patients have created new opportunities for therapy.
      Research is analyzing the impact of single-agent interventions; varying degrees
      of efficacy are being reported. Once optimal dosing strategies for single-agent
      management are defined, the opportunity for multi-agent therapies will emerge.
      IMPLICATIONS FOR NURSING PRACTICE: The oncology nurse plays a pivotal role in
      assessing and managing mucositis in cancer patients.

PMID- 15038519
TI  - Evidence-based guidelines for managing mucositis.
AB  - OBJECTIVES: To discuss implementation of evidence-based clinical practice
      guidelines for mucositis. DATA SOURCE: Published articles, book chapters, web
      sources, clinical experience, unpublished manuscripts. CONCLUSION: Nurses can
      implement evidence-based guidelines but must include an evaluation component to
      determine effect on clinical outcomes. IMPLICATIONS FOR NURSING PRACTICE: Nurses
      have an integral role implementing and evaluating evidence-based practice
      guidelines for managing mucositis. When evidence is lacking and guidelines have
      gaps, nurses can play important roles in research to overcome these gaps.

PMID- 15038520
TI  - [Asymptomatic carotid stenosis].

PMID- 15038521
TI  - [A critical appraisal of diagnostic imaging techniques in asymptomatic carotid
      stenosis].
AB  - Asymptomatic stenosis of the internal carotid artery requires a non-invasive
      imaging work-up. The objectives include the quantification of the degree of
      stenosis, the analysis of the atherosclerotic plaque and the consequences of this
      stenosis on the brain tissue. Previous studies showed the reliability of MR
      angiography and spiral CT for the assessment of the arterial lumen. However, the
      consensus is based on the association of ultrasonography and MRA because of the
      non-invasive approach of these examinations that allow a complete evaluation of
      both the extracranial and the intracranial vessels. Recent advances in MRI will
      probably allow to simultaneously analyze the arterial wall in order to detect the
      plaques at risk and to optimize the therapeutic approach.

PMID- 15038522
TI  - [Evolution of the management and outcomes of patients admitted for acute
      myocardial infarction in France from 1995 to 2000: data from the USIK 1995 and
      USIC 2000 nationwide registries].
AB  - We assessed the in-hospital management and short- and long-term outcomes of two
      series of patients admitted for acute myocardial infarction, 5 years apart, in
      France. The most recent cohort was younger and with a less frequent history of
      cardiac diseases, but was more often diabetic and with anterior infarcts. Five
      day mortality significantly improved from 7.7% to 6.1% (P < 0.03) and 1-year
      survival was also less in the most recent period (15% versus 19%, P < 0.01).
      Multivariate analyses showed that the period of inclusion (2000 versus 1995) was
      an independent predictor of both short- and long-term mortality. In analyses
      restricted to the patients who were alive by day 5, initial treatment with
      statins was associated with a 38% decrease in the risk of death at 1 year.
      Likewise, in patients with left ventricular ejection fraction < or = 35%, the
      early prescription of ACE inhibitors was associated with a 41% reduction in the
      risk of 1-year mortality. Thus, in the real world setting, a continued decline in
      1-year mortality is observed in patients admitted to intensive care units for
      recent acute myocardial infarction. This goes along with a shift in reperfusion
      therapy towards a broader use of coronary angioplasty and with an increased use
      of the early prescription of recognised secondary prevention medications.

PMID- 15038523
TI  - [Hypertension and age over 70 years are the two most important risk factors for
      stroke in patients with atrial fibrillation].
AB  - In a registry of 250 patients treated for atrial fibrillation (160 recurrent, 90
      permanent forms), we prospectively looked for associated risk factors for
      cerebrovascular complications. After a 4-years follow-up, 19 patients had
      presented a cerebral accident (13 strokes, 4 transient ischemic attacks, 2
      cerebral hemorrhages). Prognostic factors for cerebrovascular complications were
      hypertension, valvular heart disease, and age > or = 70 years. When restricting
      the analysis to stroke and transient ischemic attacks, prognostic factors were
      limited to hypertension and age > or = 70 years. In conclusion, hypertension and
      age > or = 70 years are the main independent risk factors for cerebral ischemic
      attacks in out-of-hospital patients treated for atrial fibrillation.

PMID- 15038524
TI  - [Percutaneous transluminal renal angioplasty in hypertension].
AB  - The aim of our study was assess anatomical and functional results of renal artery
      angioplasty with and without stenting in 25 hypertensive patients (8 female and
      16 male, 42.6 and 61.6 years old respectively) with significative renal artery
      stenosis (RAS) (atherosclerotic: 22; fibrodysplastic: 3). Eleven patients had
      simple angioplasty and 13 had stenting. The rate of angioplasty success was 96%.
      In the stent group, the anatomical result was better: 2% of residual stenosis
      versus 24% in the other group (p < 0.001). Restenosis occurred in 2 patients.
      Immediately after revascularisation arterial blood pressure decreased from
      195/105 +/- to 150/85 +/- mmHg in-group without stent (p < 0.001) and from
      190/100 to 145/85 mmHg in the group (p < 0.001). The value of serum creatinine
      concentration in patient with renal failure didn't change after
      revascularization.

PMID- 15038526
TI  - [Asymptomatic carotid stenosis at high risk of ipsilateral cerebro-vascular
      events].
AB  - The management of asymptomatic carotid stenosis remains unclear in terms of
      screening as well as of treatment. The degree of carotid stenosis is not enough
      to clarify the debate. It seems useful to search among severe carotid stenosis
      parameters indicating higher ipsilateral stroke risk. Duplex ultrasound and
      transcranial Doppler offer this opportunity with a diagnostic battery allowing to
      evaluate hemodynamical risk (degree of stenosis, common carotid flow, MCA signal,
      cerebral vasoreactivity), thrombo-embolic risk (echostructure of the stenosis,
      micro-embolic signals, HITS) and progression of the stenosis.

PMID- 15038527
TI  - [Cervical bruits].

PMID- 15038525
TI  - [Cross over bypasses ilio-femoral and femoro-femoral. Indications and results
      about 60 cases].
AB  - The goal of this retrospective study is to review indications and results of
      cross over bypasses. METHODS AND MATERIAL: between January 1990 and December
      2000, 60 patients (all males with mean age = 60 years) underwent cross over
      bypass for unilateral iliac occlusive disease: femoro-femoral in 48%, ilio
      femoral in 44% and ilio-popliteal in 8%. RESULTS: mortality was 5% while
      complications occurred in 13.3%. Early limb salvage rate was 92%. During follow
      up (mean: 32 months) we noticed 13 late thrombosis. The actuarial patency rate
      being at 83.5%, 74% and 67% at 1 year, 3 years and 5 years respectively.
      CONCLUSION: cross over bypasses are technically simple with low morbidity and
      acceptable results. In addition to widely accepted indications (general or local
      unfavourable conditions to approach abdominal aorta), cross over bypasses may be
      considered as satisfactory challenge even in young patients with how operative
      risk.

PMID- 15038528
TI  - [Is the screening of asymptomatic carotid stenosis worthwhile?].
AB  - Endarteriectomy may be of some benefit for those patients who have asymptomatic
      carotid stenosis above 80%. Duplex echography is a useful non-invasive diagnosis
      method, and the detection of asymptomatic carotid stenosis is questionable.
      Detection in the whole population seems inefficient since most stenosis are found
      in patients who experience other locations of atherosclerosis or who have several
      risk factors. The conditions where detection seems useful are the patients above
      55 years with lower limb occlusive arterial disease or aortic aneurysm, and the
      subjects who have three of the four following conditions: age above 65 years,
      hypercholesterolemia, tobacco, and ischaemic cardiopathy.

PMID- 15038529
TI  - [Duplex surveillance after carotid endarteriectomy: review of the literature].
AB  - Duplex surveillance after carotid endarterectomy is a common practice but no
      consensus has been reached. On one hand, the low rate of restenosis, the low
      probability of post-operative stroke and a poor cost-effectiveness are advocating
      against this strategy. On the other hand, progression of controlateral
      atherosclerostic lesions leads to justify an ultrasound rather than a clinical
      follow-up. Neither literature nor recommendation allows today a validated policy.
      Therefore, it is possible to propose a reasonable strategy in order to balance
      cost and patient's benefit.

PMID- 15038530
TI  - [Treatment of asymptomatic carotid stenoses: evolution of ideas, medical
      treatment, surgical treatment, what about percutaneous transluminal
      angioplasty?].
AB  - Asymptomatic carotid lesions treatment techniques have not greatly evolved over
      the last 15 years. Although there seems to be a consensus to apply only medical
      treatment for lesions less than 60-70%, there is still debate with regards to
      patient cohort suffering from high-grade stenosis (between 70% and 90%). Very
      high-grade lesions seem, however, to benefit from surgery. The most significant
      improvements come from Duplex scan and non-invasive radiology (TDM with injection
      and MRI) allowing a more accurate stenosis measurement and above all, detection
      of potential high-risk lesion (inhomogeneous plaque, haematoma under plaque).
      Medical treatment as well as risk factor balancing is always complementary to
      surgery. The most significant improvement is probably the anaesthesiology
      technique with the wide use of local analgesia allowing an ideal cerebral
      protection. The various surgical techniques: simple endarterectomy or with patch,
      eversion endarterectomy, venous or prosthetic by-pass show no significant
      difference either in the immediate results or in restenosis. These techniques
      enabled a mortality rate of less than 1% (due to a better cardiac check-up) and
      morbidity rate of less than 2%. The development of percutaneous transluminal
      angioplasty with stenting (secured by protection devices) has made indications
      slightly more difficult by adding a non-validated technique which has not proven
      its merits compared to surgery. One of the dangers from this technique is that it
      may lead to abusive indications. In summary, surgery is the most adequate
      treatment for high-grade asymptomatic carotid lesions after a precise
      locoregional check-up, especially a cardiac one. Medico legal implications in
      this asymptomatic situation call for precise and honest patient information.

PMID- 15038531
TI  - [Asymptomatic carotid stenoses. A cardiologist's viewpoint].
AB  - Cardiologist work is undergoing profound changes. He is in charge of the
      prevention and treatment of atherothrombotic disease. Preoperative evaluation of
      global cardiovascular risk is of paramount importance to choose between medical,
      surgical or interventional treatment. Furthermore, because the cardiologist has
      extensive experience with coronary angioplasty, he will have an essential role in
      carotid angioplasty.

PMID- 15038532
TI  - Pool of dust particles over the Asian continent: balloon-borne optical particle
      counter and ground-based lidar measurements at Dunhuang, China.
AB  - Measurements of aerosols were made in 2001 and 2002 at Dunhuang (40 degrees 00'N,
      94 degrees 30'E), China to understand the nature of atmospheric particles over
      the desert areas in the Asian continent. Balloon-borne measurements with an
      optical particle counter suggested that particle size and concentration had
      noticeable peaks in super micron size range not only in the boundary mixing layer
      but also in the free troposphere. Super-micron particle concentration largely
      decreased in the mid tropopause (from 5 to 10 km; above sea level, a.s.l.). Lidar
      measurements made during August 2002 at Dunhuang suggested the possibility that
      mixing of dust particles occurred from near the ground to about 6 km even under
      calm weather conditions, and a large depolarization ratio of particulate matter
      was found in the aerosol layer. The top of the aerosol layer was found at heights
      of nearly 6 km (a.s.l.). It is strongly suggested that nonspherical dust
      particles (Kosa particles) frequently diffused in the free atmosphere over the
      Taklamakan desert through small-scale turbulences and are possible sources of
      dust particles of weak Kosa events that have been identified in the free
      troposphere not only in spring but also in summer over Japanese archipelago.
      Electron microscopic experiments of the particles collected in the free
      troposphere confirmed that coarse and nonspherical particles observed by the
      mineral particle were major components of coarse mode (diameter larger than 1
      microm) below about 5 km over Dunhuang, China.

PMID- 15038533
TI  - Comparison of scan-angle method and convective cloud differential method in
      retrieving tropospheric ozone from TOMS.
AB  - Tropospheric ozone, derived from the Scan-Angle Method (SAM) and the Convective
      Cloud Differential (CCD) method, exhibits a noticeable abundance over the South
      Atlantic, where it is associated with biomass-burning in the austral spring. This
      feature is also seen in the distribution of carbon monoxide observed from
      Measurements Of Pollution In The Troposphere (MOPITT). In the boreal burning
      season, however, the distribution of the results from SAM and MOPITT-CO present
      an enhancement related to the biomass-burning over North Africa that does not
      appear in the CCD results. The relationship of the results from SAM and MOPITT-CO
      is better than those of the results from the CCD and MOPITT-CO for the December
      February period. Conversely, the latter relationship is better than the former
      for the October-November period. The two methods, SAM and CCD, show higher
      correlation in the southern burning season, but lower correlation in the northern
      burning season. The influence of biomass burning on ozone amounts is clearly seen
      in the SAM results of the elevated ozone over northern equatorial Africa during
      the northern burning season, but is not present in the CCD results.

PMID- 15038534
TI  - Global and regional distribution of carbon monoxide from MOPITT: seasonal
      distribution at 700 hPa.
AB  - The Measurement of Pollution in the Troposphere (MOPITT) instrument is an eight
      channel gas correlation radiometer, which was launched on the Earth Observing
      System (EOS) Terra satellite in 1999. Carbon monoxide (CO) is one of the
      important trace gases because its concentration in the troposphere directly
      influences the concentrations of tropospheric hydroxyl (OH), which controls the
      lifetimes of tropospheric trace gases. CO traces the transport of global and
      regional pollutants from industrial activities and large scale biomass burning.
      The global and regional distributions of CO were analyzed using the MOPITT data
      for East Asia, which were compared with the ozone distributions. In general,
      seasonal CO variations are characterized by a peak in the spring, which decrease
      in the summer. This work also revealed that the seasonal cycles for CO are at a
      maximum in the spring and a minimum in the summer, with average concentrations
      ranging from 118 to 170 ppbv. The monthly average for CO shows a similar profile
      to that for O3. This fact clearly indicates that the high concentration of CO in
      the spring is possibly due to one of two causes: the photochemical production of
      CO in the troposphere, or the transport of the CO into East Asia. The seasonal
      cycles for CO and O3 in East Asia are extensively influenced by the seasonal
      exchanges of different air mass types due to the Asian monsoon. The continental
      air masses contain high concentrations of O3 and CO, due to the higher
      continental background concentrations, and sometimes to the contribution from
      regional pollution. In summer this transport pattern is reversed, where the
      Pacific marine air masses that prevail over Korea bring low concentrations of CO
      and O3, which tend to give the apparent summer minimums.

PMID- 15038535
TI  - LIDAR measurements of the vertical aerosol profile and optical depth during the
      ACE-Asia 2001 IOP, at Gosan, Jeju Island, Korea.
AB  - In order to investigate the characteristic of optical properties of Asian dust
      particles, the atmospheric aerosol vertical profile was measured with the multi
      wavelength LIDAR system, at the Gosan super site (33 degrees 17'N, 126 degrees
      10'E) in Jeju Island, Korea, during the ACE-Asia intensive observation period, 11
      March-4 May 2001. An air mass backward trajectory analysis, using Hysplit-4, was
      carried out to track the aerosol plume, with high mass loading, from the Chinese
      desert regions during the period of Asian dust storm events. Vertical atmospheric
      aerosol profiles on three major Asian dust storm event days, 22 March and 13 and
      26 April 2001, have been analyzed. The LIDAR-derived aerosol optical depth values
      were compared with those measured by a collocated sunphotometer.

PMID- 15038536
TI  - Interferometric microwave radiometers for high-resolution imaging of the
      atmosphere brightness temperature based on the adaptive Capon signal processing
      algorithm.
AB  - Passive microwave remote sensing from satellites and ground stations has
      contributed uniquely, and substantially, to the study of atmospheric chemistry,
      meteorology, and environmental monitoring. As user requirements are raised, in
      terms of the accuracy and the spatial resolution, a mechanically scanning
      radiometer, with a real aperture, becomes impractical due to the requirement for
      a very large antenna size. However, an aperture synthesis interferometric
      radiometer presents a valuable alternative. The work presented in this paper was
      devoted to high spatial resolution imaging, using the 37 GHz band interferometric
      radiometer, developed by ourselves. The spatially adaptive Capon beamforming
      method was exploited for the imaging, which outperformed the conventional Fourier
      Transform method. We concluded that the high spatial resolution imaging of the
      brightness temperature of the atmosphere could be accomplished with an
      interferometric radiometer equipped with the developed Capon beamforming imaging
      algorithm.

PMID- 15038537
TI  - Characteristics of ion components and trace elements of fine particles at Gosan,
      Korea in spring time from 2001 to 2002.
AB  - Size-segregated measurements of the composition of an aerosol are used to
      determine the transport of natural and anthropogenic aerosols to the Gosan site
      in springtime from 2001 to 2002. Although the transport of Asian dust is a well
      known phenomenon in springtime, this study shows that not only is soil dust
      transported into Gosan each spring but so are anthropogenic aerosols, including
      sulfur, enriched trace metals such as Pb, Zn, Ni, K, S. This study also combines
      the size- and time-resolved aerosol composition measurements with isentropic,
      backward air-mass trajectories in order to identify some potential source regions
      of the anthropogenic aerosols. Finally, four types of transport episodes were
      identified: (1) anthropogenic pollutants, (2) dust storm mixed with the
      anthropogenic aerosols, (3) typical dust storms, (4) some sea salt with clean air
      mass. Overall, in addition to typical soil dust, a large amount of anthropogenic
      aerosols, whether mixed with the soil dust or not, are transported to Gosan each
      spring.

PMID- 15038538
TI  - Aerosol optical and radiative properties observed at Anmyeon and Jeju, Korea in
      the spring of 2000 and 2001.
AB  - The radiative properties of atmospheric aerosols are determined by their masses,
      chemical characteristics, and optical properties, such as aerosol optical depth
      (AOD), Angstrom parameter (alpha) and single scattering albedo (SSA). In
      particular, the aerosol optical properties determine the surface temperature
      perturbation that may give some information in understanding regional atmospheric
      radiative forcing. To understand the radiative forcing and regional source of an
      aerosol, the present study focused on the analysis of the aerosol optical
      properties based on two different observations in the spring season, during the
      special Asian dust storm period. The Korean Global Atmosphere Watch Observatory
      (KGAWO), at Anmyeon Island, and the ACE-Asia super-site, at Gosan, Jeju Island,
      have measured radiations and aerosols since 2000. The sites are located in the
      mid-west and south of the Korean peninsula, which are strongly affected by the
      Asian dust coming from China every spring. The aerosol optical properties,
      measured by ground-based sun and sky radiometers, over both sites were analyzed
      to gain an understanding of the radiation and climate properties. The probability
      distributions of the aerosol optical depths were rather narrow, with a modal
      value of approximately 0.38 at both sites during 2001 and 2002. The Angstrom
      parameter frequency distributions showed two peaks at Anmyeon GAW, but only one
      peak at the Jeju ACE-Asia super site. One peak, around 0.63, characterizes the
      situation of a day having Asian dust, the second peak, around 1.13, corresponded
      to the relatively dust-free cases. The correlation between the aerosol optical
      depth and the Angstrom exponents resulted in a wide range of the Angstrom
      parameter, alpha, over a wide range of optical depths at Anmyeon, whereas a
      narrow range of alpha, with moderate to low values for the AOD at Jeju. Under
      dust free conditions the single scattering albedo (SSA) decreased with
      wavelength, while in the presence of Asian dust, the SSA either stayed neutral,
      or increased slightly with wavelength at Anmyeon, and showed higher value than
      Jeju. The change in the surface temperature was highly correlated with increases
      in the aerosol optical depth at Anmyeon to a greater extent than at Jeju.

PMID- 15038539
TI  - Adaptive consensus principal component analysis for on-line batch process
      monitoring.
AB  - As the regulations of effluent quality are increasingly stringent, the on-line
      monitoring of wastewater treatment processes becomes very important. Multivariate
      statistical process control such as principal component analysis (PCA) has found
      wide applications in process fault detection and diagnosis using measurement
      data. In this work, we propose a consensus PCA algorithm for adaptive wastewater
      treatment process monitoring. The method overcomes the problem of changing
      operating conditions by updating the covariance structure recursively. The
      algorithm does not require any estimation compared to typical multiway PCA
      models. With this method process disturbances are detected in real time and the
      responsible measurements are directly identified. The presented methodology is
      successfully applied to a pilot-scale sequencing batch reactor for wastewater
      treatment.

PMID- 15038540
TI  - Respirometric evaluation by graphical analysis for microbial systems.
AB  - Analysis of respirometric graphs for system diagnosis has recently drawn much
      attention due to the nature of the test being a fast method with reliable oxygen
      uptake (Ou) data. In this study, a new graphical analysis procedure is proposed,
      using the oxygen uptake rate (OUR) vs. Ou respirogram because of its distinct
      characteristics that provides easy visual inspection. The OUR plot is typically
      divided into two respiration phases, and each one of these phases can be
      simulated by a previously derived analytical equation. Based on the 2-phase
      model, five characteristic parameters (CPs) were derived for the OUR respirogram.
      Mathematically the 5 CPs can be related to the system parameters (SPs), including
      the four Monod kinetic parameters and two operating conditions (initial substrate
      and biomass concentration). Sensitivity analyses were then conducted to assess
      the 5 CPs for the level of effect caused by system parameters (SPs). This study
      also conducted respirometric tests under batch operation to evaluate the
      applicability of the graphical analysis method. Based on the 5 CPs estimated from
      the OUR respirogram of the tests, it can be concluded that respirometric tests
      normally experience the problems associated with initial lag, non-uniform
      seeding, and inadequate mixing.

PMID- 15038541
TI  - Characterization of SnO2 ceramic gas sensor for exhaust gas monitoring of SVE
      process.
AB  - A Figaro-type gas sensor system was investigated for the monitoring of volatile
      organic contaminants (VOC) in the exhaust gas from a soil vapor extraction (SVE)
      process. Benzene, toluene, ethyl benzene and xylene (BTEX), and their mixtures,
      were tested as representative contaminants. Reasonably good correlation factors
      >0.98 were obtained between the GC analyses and the sensor responses for each
      component, and for the total gas concentrations. Although the composition of the
      exhaust gas from SVE process, as well as the amount of each component, change
      with time, the sensor can be used to estimate the residual amount of contaminants
      by measuring the total concentrations in the exhaust gas. The sensor can be
      utilized as a valuable tool for the monitoring of SVE process by indicating when
      the operation to remediate a contaminated site should be stopped. The proposed
      ceramic gas sensor system may be a good alternative to existing methods, because
      it can satisfy the essential monitoring necessities of SVE processes, and has
      many advantages over other fully equipped instrumentation, as a cost-effective
      device, with long-term monitoring stability.

PMID- 15038542
TI  - Determination of Cr(VI) using an ion selective electrode with SLMs containing
      Aliquat336.
AB  - An ion selective electrode (ISE) for the measurement of Cr(VI), using supported
      liquid membranes (SLMs), containing tricaprylmethyl ammonium chloride
      (Aliquat336), was investigated in this study. Aliquat336, as a carrier, had a
      high selectivity for Cr(VI) in the presence of interfering ions, in the order
      SO4(2-) > CO3(2-) > Cl(-) > NO2(-) > NO3(-) > I(-) > SCN(-). The composition of
      the SLM for the detection of Cr(VI) was optimized at 0.169 mL Aliquat336 mL(-1)
      NPOE (o-nitrophenyl octyl ether) 0.5 g Poly (vinyl chloride), for the preparation
      of a 19.6 cm2 sheet. The Cr(VI) concentrations were measured, using the SLM
      prepared in the study, in the range 2.023 x 10(-5) to 0.1 M (1.052 to 5200 ppm).
      It seemed that the Cr(VI) was transported as a negatively charged monovalent ion,
      as indicated by the slope of the electromotive force (emt) response. The
      selectivity coefficients and detection limits for the Cr(VI). against the
      interfering ions, were determined experimentally using the fixed interference
      (FIM) and the separate solution methods (SSM).

PMID- 15038543
TI  - Remediation process monitoring of PAH-contaminated soils using laser-induced
      fluorescence.
AB  - In order to investigate the feasibility of Laser-Induced Fluorescence (LIF) for
      soil remediation process monitoring, the variation in the LIF intensity was
      studied, in relation to the moisture content and soil particle size distribution
      for different soil conditions. For each set of conditions, significant
      correlation was shown between the level of Polycyclic Aromatic Hydrocarbon (PAH)
      and the LIF intensity (R2 > 0.97). Higher fluorescence intensities were measured
      for PAH contaminated soils with higher sand and moisture contents. The results of
      the LIF monitoring for the remediation process were compared with the traditional
      High Pressure Liquid Chromatography (HPLC) results, after applying a surfactant
      enhanced electrokinetic process for the remediation of PAH-contaminated soils. In
      the electrokinetic (EK) process cell. the PAH concentration, and the normalized
      LIF intensity near the anode and cathode, showed somewhat contrary trends with
      respect to the degree of the remediation, even though significantly similar
      trends were observed in the middle of the soil cell. This may be interpreted as
      the EK remediation advances, as the electro osmotic flow induce a different
      moisture and silt/clay, or sand, distribution throughout the soil media, which in
      turn influences the LIF intensity of the soils. Therefore, in order to overcome
      these differences, the corrected LIF intensity, using the diffuse reflectance,
      was applied, which showed a similar remediation trend for the soil specimens in
      the electrokinetic process cell.

PMID- 15038544
TI  - Isolation of humic and non-humic NOM fractions: structural characterization.
AB  - The combination of RO concentration and XAD-8/XAD-4 resin adsorption techniques
      was used to isolate the different constituents of the Natural Organic Matter
      (NOM) from inorganic salts. NOM fractions i.e. colloids, hydrophobic NOM (HPO
      humic substances), transphilic NOM (TPI) and hydrophilic NOM (HPI) fractions
      isolated from different surface waters were characterized using 13C NMR and FT-IR
      spectroscopy and HPLC/Size Exclusion Chromatography coupled with UV and DOC
      detection. Results showed that the isolation procedure was suitable to
      quantitatively isolate the different fractions of NOM.

PMID- 15038545
TI  - Assessment of human health risk of dioxin in Korea.
AB  - This study assessed the daily exposure to dioxin using comparable approach
      methods in order to predict the human health risks of dioxin on the general adult
      population and incinerator workers in Korea. The health risk assessment of dioxin
      involved four scenarios (General-Direct, General-Breast Milk, General-Blood, and
      Worker-Blood). The risks were described in terms of the excess cancer risk and
      the MOEs (Margin-Of-Exposure) for cancer, reproductive dysfunctions,
      endometriosis, and neurobehavioral effects. The adult daily intake (General
      Direct) of dioxin was estimated to be 0.50 pg-TEQ/kg-day based on the dioxin
      concentrations in the environmental media and foods in Korea. The average dioxin
      concentrations in General-Breast Milk, General-Blood, and Worker-Blood were 15.13
      pg-TEQ/g fat, 14.57 pg-TEQ/g lipid, and 22.90 pg-TEQ/g lipid, respectively. The
      lifetime average daily doses (LADDs) of dioxin for General-Breast Milk, General
      Blood, and Worker-Blood were estimated to be 1.35 pg-TEQ/kg day, 0.99 pg-TEQ/kg
      day, and 1.15 pg-TEQ/kg day, respectively. Although the estimated risks of cancer
      and reproductive dysfunctions were not unusually high in any of the four
      scenarios, the MOE values for the neurobehavioral effects on infants were not
      sufficiently high to guarantee the safety against this endpoint.

PMID- 15038546
TI  - Effect of potassium dichromate and fenitrothion on hemoglobins of Chironomus
      riparius Mg. (Diptera, Chironomidae) larvae: potential biomarker of environmental
      monitoring.
AB  - In an attempt to identify Chironomus hemoglobins as biomarkers for environmental
      monitoring, alterations in the hemoglobins in Chironomus riparius Mg. (Diptera:
      Chironomidae) larvae, exposed to potassium dichromate and fenitrothion, were
      investigated under laboratory conditions. The hemoglobins were evaluated in terms
      of their total contents by a cyanomethemoglobin procedure, individual components
      by electrophoresis of isoelectric focusing, and their oxidation by multi
      wavelength rapid-scanning spectrophotometry. The total hemoglobin contents
      increased at the high level of fenitrothion exposure. No variations in the
      individual hemoglobin component levels were found, by exposure to either
      fenitrothion or potassium dichromate. Whereas, the absorption spectra of the
      hemoglobins showed decreases in the peaks corresponding to the oxyhemoglobins by
      exposure to both compounds, but more sensitively by the chromium, which probably
      reflects the increase of the autoxidation of the oxyhemoglobins to methemoglobins
      by these compounds. These results suggest that autoxidation of the hemoglobins in
      Chironomus riparius seems to be a sensitive parameter in response to redox-active
      chemical exposure, and this biochemical parameter could be developed as a
      biomarker in environmental monitoring.

PMID- 15038548
TI  - A yeast DNA microarray for the evaluation of toxicity in environmental water
      containing burned ash.
AB  - Numerous studies on the hazard assessment and epidemiological health responses to
      burned ash have been reported. However, there is little information on the
      potential toxicity of unknown chemical complexes in burned ash. For an overall
      evaluation of the multiple toxicities of burned ash, a DNA microarray was used in
      this study, as a new attempt to assess these toxicities. Using the global gene
      expression on yeast DNA chip to reflect the changes in mRNA levels, our study
      discovered a lot of evidences for the action of cell homeostasis and stress
      response etc., against the toxic effects on yeast cells. On the genes of 5,117
      open reading frames (ORFs), as valid spots in a microarray, 997 were up
      regulated, 1,259 were down-regulated and 2,861 remained unchanged. A detailed
      analysis of the microarray revealed the genes that were dynamically correlated to
      the function of the subcellular localization, energy/metabolism, various stress
      responses/cell homeostasis and detoxification. Significantly, the toxicities,
      caused by reactive oxygen species (ROS), metals and the other xenobiotics, were
      indicated in burned ash. Also, the possibility of mutagenicity of the burned ash
      was suggested on the basis of the DNA repair related genes.

PMID- 15038550
TI  - A flexible RF applicator for heating viscous lossy products such as foods.
AB  - A helical RF industrial applicator was evaluated for heating minced meat flowing
      in a hollow tube. Heating was homogeneous inside the product, although the
      product was highly lossy due to its high electric conductivity. The homogeneity
      was much better than could be obtained with microwave heating. A high power
      density, up to 5 kW/liter, can be deposited inside the product with 95%
      efficiency.

PMID- 15038547
TI  - Construction of transformant reporters carrying fused genes using pcbC promoter
      of Pseudomonas sp DJ-12 for detection of aromatic pollutants.
AB  - Three reporter gene fusions were constructed by a transcriptional fusion method
      using the pcbC promoter of Pseudomonas sp. DJ-12, which can extensively degrade
      biphenyl and 4-chlorobiphenyl by meta-cleavage dioxygenase. The reporter genes
      used for the construction of the fusions were luc, luxCDABE and gfpuv. The
      reporter fusion plasmids were introduced into E. coli XL1-Blue, and the
      transformant reporters examined for the production of fluorescent light by
      exposure to aromatic compounds, such as biphenyl, 4-chlorobiphenyl, 4
      hydroxybiphenyl, 2,3-dihydroxybiphenyl, catechol and 4-chlorocatechol. The
      reporter cells, carrying the respective gene fusions, responded well to the
      aromatics when exposed to a concentration of 0.1 mM for 10 min. In particular,
      the reporter cells carrying the pcbCp::luxCDABE gene fusion produced
      bioluminescence most extensively to the above mentioned aromatics. This means
      that the pcbCp::luxCDABE reporter gene fusion may be useful in bacterial
      biosensors for the detection of aromatic pollutants in the environment, and may
      also be valuable for examining the bioavailability of the inducing pollutants.

PMID- 15038551
TI  - Microwave processing of maple sap to maple syrup and maple syrup products.
AB  - A study of the physical process of concentration of maple sap to maple syrup and
      preparation of maple syrup products by microwave heating is described. Duty
      cycles of 60, 75 and 100% were used for the microwave application. During the
      process, some of the drying kinetics are discussed, including the reduction of
      moisture content with time, the progress of the process in terms of increasing
      sugar concentration and the power absorbed. Obviously, the rate of water removal
      was higher in case of the higher duty cycles. The total time required for
      finishing the syrup was also dependent on the initial mass of the load and the
      initial sugar content. The products obtained were compared with commercial graded
      products for the quality and met the highest standards prescribed by the
      industry. The absence of heat damage or browning of the product was identified as
      a distinct advantage that could be derived from microwave processing of maple
      syrup.

PMID- 15038549
TI  - A slotted waveguide applicator for continuous flow grain drying.
AB  - A slotted waveguide antenna was designed and developed with series slots cut on
      the broad side that constituted a popular means of coupling microwaves with grain
      for drying. The radiating characteristics of the slotted wave guide antenna
      mounted in a setup that simulated the coupling to a grain conveying tube were
      studied at a frequency of 2.45 GHz. The antenna consisted of a WR-340 waveguide
      made of copper. The effect of the slot inclination angle O, moisture content and
      the shape of the slots were investigated. The results indicated 55 degrees as an
      optimum slot angle for slots having a width of 13 mm and a length 58 mm. Slots
      with a width of 6 mm did not exhibit any regular behavior and the effect of O was
      not clearly identified.

PMID- 15038552
TI  - The effects of microwaves on airborne microorganisms.
AB  - This paper reports preliminary results of simple experiments carried out to study
      the effects of microwave irradiation at 2.45 GHz on fungi, yeast and bacteria of
      the type encountered in food processing plants or in enclosures containing
      individuals infected with tuberculosis mycobacterium (TB). The results are
      sufficiently encouraging to justify further multivariable experiments
      particularly with air circulation schemes in which the air can be sterilized in a
      circular cylindrical microwave cavity operating at a higher order mode.

PMID- 15038553
TI  - Radio-frequency and microwave dielectric properties of insects.
AB  - Basic principles and definitions of dielectric properties of materials are
      presented. Data from the literature on the dielectric properties of insects are
      briefly reviewed and discussed in relation to insect control by selective
      dielectric heating. Because early measurements of the dielectric properties of
      insects were taken on bulk samples of insects (insect and air-space dielectric
      mixtures), a means for converting the dielectric properties, or permittivities,
      of bulk samples of particulate materials to those of the solid particles is
      described. The technique uses the Landau & Lifshitz, Looyenga dielectric mixture
      equation and information on the bulk densities of air-insect mixtures used for
      dielectric properties measurements along with the densities of the insects. Such
      converted data for the dielectric constants and loss factors of the insects are
      presented and collected for comparison with other measurements of insect tissues
      and permittivity determinations from more recent microwave measurements of these
      same parameters. Resulting data are presented for reference, and comparisons are
      presented and discussed briefly.

PMID- 15038554
TI  - Derivation of an explicit formula for determining the effective permittivity of a
      three-component composite.
AB  - The author extends the Bergman-Milton formula of the effective permittivity of a
      two-component heterogeneous dielectric mixture to the case of a three-component
      mixture. He validates the introduction of a unique two-variable density function
      which describes the microgeometry. He also supplements the theoretical approach
      by discussing the significance and the forms of the percolation terms. The
      geometrical density functions, which correspond to the well-known Lichtnecker,
      C.R.I.M. and Looyenga formulae are explicitly given as cases for illustrating the
      general approach.

PMID- 15038555
TI  - The AMPERE association and trends in its biennial conferences.
AB  - AMPERE (Association for Microwave Power in Europe for Research and Education) is
      a "European" non-profit association devoted to the promotion of microwave and
      radio frequency heating techniques for research and industrial applications.
      Despite the fact that AMPERE is a European association, it has a world-wide
      membership which comprises industrialists, academics, researchers and
      consultants. This brief paper focuses on the trends in the subject matter and
      activities in the biennial AMPERE conferences held in Europe since 1986.

PMID- 15038556
TI  - European regulations of the radio spectrum, ISM use and safety.
AB  - In Europe, many standards dealing with equipment electromagnetic compatibility
      (EMC) are threatening the ISM use of the radio spectrum. The basis and the
      shortcomings of the standards are discussed and compared with the actual
      electromagnetic environment. The standards for equipment are too strict involving
      higher investment costs. High frequency and microwave power applications are
      therefore likely to slow down. Guidelines and standards for protection of human
      exposure to electromagnetic fields (EMF) are too conservative and have no
      reference to ISM applications. Only a leakage standard for the domestic microwave
      oven and similar equipment exist. Some recommendations are presented for
      improvement.

PMID- 15038557
TI  - EDF involvement in research and development of RF and microwave industrial
      processes in Europe. The "Club Rayonnements".
AB  - In France, RF and microwave techniques are now mature. They are commercialized by
      industries having now reliable references in different fields of manufacturing
      industry. The present situation is the result of many studies and collaborations
      where universities and public technical centers were strongly involved during the
      last three decades. During this period, the "Club Rayonnements" sponsored by EDF
      has been a real "melting pot" for people coming from university, industry and
      technical centers.

PMID- 15038558
TI  - Development of industrial microwave heating of foods in Europe over the past 30
      years.

PMID- 15038559
TI  - Numerical modeling for RF and microwave heating using FE comes of age.
AB  - This paper gives a brief resume of the numerical work carried out over the past
      decade at the Electricity Utilisation Group usingfinite elements for the
      characterization of RF and microwave heating systems. Maxwell's equations are
      solved in 3D while for coronas the Poisson's and particle continuity equations
      are solved in 2D. In addition work on modeling thin films and the use of parallel
      computing describes the latest work to emanate from the group.

PMID- 15038560
TI  - Look at European RF industrial applications.
AB  - The authors review the European RF industrial applications. European RF
      technology produced the 50omega-technology, which has been the basis for many
      successful applications in classical industrial domains such as food tempering
      and defrosting, rubber curing but also in new domains such as RF for curing of
      many car products. These new applications make clear the fundamental advantage of
      fast processing with RF technology.

PMID- 15038561
TI  - [Is coincidence detection emission tomography (CDET) as reliable as positron
      emission tomography (PET) in head and neck cancer?].
AB  - OBJECTIVE: Positron emission tomography (PET) is becoming more and more useful in
      head and neck tumour detection, guiding diagnostic and therapeutic decision.
      However, techniques, similar to PET, but using modified conventional tomography
      equipment, are used. The most commonly used is the dual-head positron emission
      tomography using coincidence detection (CDET). This study was aimed at searching
      if CDET could be as reliable as PET in some of its indications. PATIENTS AND
      METHODS: Between 1997 and 2001, 19 patients, with head and neck cancer, had a
      CDET, for 3 indications. We studied retrospectively sensitivity (Se) and
      specificity (Sp) rates for these 3 indications. RESULTS: 1 degree) Detection of
      unknown primary head and neck cancers with lymph node manifestation: Se = 100%,
      Sp = 66,7%. 2 degrees) Detection of body metastasis: Se = 50%, Sp = 33%. 3
      degrees) Detection of local recurrent cancer: Se = 100%, Sp = 25%. CONCLUSION:
      CDET seems to be useful in finding unknown primary cancers with lymph node
      manifestation but is not reliable to look for metastasis and local recurrences.
      It cannot be used in all indications for PET. If no other tool is available, this
      investigation can be used, keeping in mind its limitations.

PMID- 15038562
TI  - A simple assessment of quality of life in head and neck cancer patients; what can
      it tell us?
AB  - OBJECTIVE: A number of well validated quality of life (QoL) instruments are
      available. Head and neck cancer patients often find these exhaustive
      questionnaires too long or bothersome. The purpose of our study was to evaluate a
      patient self-reported very simple assessment of quality of life and to compare it
      with the well-validated European Organisation for Research and Treatment of
      Cancer (EORTC) QoL questionnaire. METHODS: A departmental simple questionnaire
      was designed consisting of 2 components: 1. A visual analogue scale; 2. A space
      for patients to enter up to 3 specific problems which prevent quality of life
      being better. These may be physical, emotional, social or practical problems. 112
      patients attending the head and neck oncology clinic completed both
      questionnaires (half completed the simple questionnaire first and the other half
      the EORTC questionnaire first). RESULTS: There was a good correlation between the
      global health scores of the EORTC and the visual analogue scale of the simple
      questionnaire. There was poor correlation between specific domains in the EORTC
      questionnaire and the 3 comments mentioned by patients in the simple
      questionnaire. CONCLUSION: A simple patient assessment of quality of life can be
      used as a simple outcome tool in head and neck cancer data bases when specific
      details are not required.

PMID- 15038563
TI  - [Interest of MIBI scintigraphy in the preoperative investigation of primary
      hyperthyroidism].
AB  - OBJECTIVE: The purpose of this study is to show the place of MIBI scintigraphy in
      the preoperative investigation of primary hyperthyroidism, and then to
      demonstrate the extent to which this test allows us to formulate new surgical
      strategies, thus reducing the need for neck exploration in favour of minimally
      invasive techniques. MATERIALS AND METHODS: We have carried out a retrospective
      study related to 118 cases of primary hyperthyroidism. A MIBI scintigraphy has
      been applied on all the patients, so that we have been able to compare its
      results with the surgical and histological findings. RESULTS: Our study shows a
      great accuracy of MIBI scintigraphy, with respect to the localization of
      parathyroid adenoma, which represents the major cause of primary
      hyperparathyroidism. Furthermore, these results prove the reliability of the new
      surgical strategies: unilateral neck exploration and minimally invasive surgery,
      when facing a single scintigraphic site. CONCLUSION: As of now, MIBI scintigraphy
      must be part of preoperative investigation in cases of primary
      hyperparathyroidism, so that by limitating the surgical neck exploration, it
      allows us to decrease operative time and the risks, length and cost of the
      hospital stay.

PMID- 15038564
TI  - [A detailed examination of injuries to the head and neck caused by bullfighting,
      and of their surgical treatment; the role of the cervico-facial surgeon].
AB  - Bullfighting (corrida) dates back to the 13th century in France, especially in
      the Camargue and the South-West, even if this fight between man and wild bull had
      been described before in other countries. The current modern bullfight, as an
      artistic interpretation, was codified in Spain during the 18th century into 3
      tercios (parts): the tercio of the lance, of the bandillera, and of the muletta,
      which end with the death of the bull. Celebrated by our Spanish neighbours as a
      national fiesta, the corrida represents a confrontation between the intelligence
      of man and the power of the bull. Injuries are the heavy cost of this art paid by
      each bullfighter. Most of them have been injured seriously, or even gored to
      death inside the bullring. Goring is a single injury, a mix of wound, burn,
      contusion and infection. Its treatment calls for an expert, which makes this type
      of surgery highly specialised. Head and neck trauma represents 16% of the total
      wounds in bullfighting. Its not very often that this type of injury happens, but
      each time it is serious. This study is based on 1450 case reports, deals with
      causes and accident circumstances, together with the type of injuries and their
      early management in the bullring's infirmary. The seriousness of these wounds
      would justify a head and neck surgeon being part of the medical staff during the
      corrida.

PMID- 15038565
TI  - [Recurrences of pleomorphic adenomas of the parotid: changing attitudes].
AB  - OBJECTIVE: The real issue of parotid surgery for pleomorphic adenoma is its risk
      of recurrence. The aim of this study was to compare the changing attitudes
      towards the pathology and surgical treatment in order to better define prevention
      and management of pleomorphic adenoma recurrences. MATERIAL AND METHOD:
      Histological study was performed after reviewing of slides originating from 100
      patients with pleomorphic adenomas of the parotid gland, treated in our
      institution during the period May 1992 - November 2002. Study of the diagnostic
      value of fine needle cytology aspiration and MRI for pleomorphic adenoma
      diagnosis was performed for 181 patients operated on for parotid tumors. RESULTS:
      Hypocellular pleomorphic adenomas often have a thin capsule and constitute the
      most frequently encountered subtypes of recurrence. Pseudopodia are considered as
      an additional risk of recurrence. In our series, cytological study gave excellent
      diagnostic value with a sensitivity of 92% and a PPV of 96%. MRI study had a
      sensitivity of 83% and a PPV of 89%. CONCLUSIONS: According to these findings,
      enucleation surgery on a pleomorphic adenoma should not be performed any more.
      Parotidectomy techniques (total or superficial) constitute the surgical treatment
      of choice. The management of recurrences is based on surgery, with total
      parotidectomy and facial nerve preservation. The role of radiotherapy is still
      indeterminate.

PMID- 15038566
TI  - [Adenoid cystic carcinoma of the head and neck: a review of 30 cases].
AB  - OBJECTIVES: To evaluate treatment results and identify prognostics factors which
      determine local and regional treatment failure and crude survival in adenoid
      cystic tumours (ACT) in the head and neck. METHODS: A retrospective study (1984
      to 2001) of 30 cases of adenoid cystic tumour. The mean age was 56.9 years, with
      a sex ratio female to male of 2:1. Tumours of all sites were encountered, most
      (26.7%) being in the nose and sinuses and major salivary glands (26.6%). Tumours
      at the T4 stage were found in 14 cases, mainly situated in the nose and sinuses
      (50%). No patient had cervical lymphadenopathy, while two patients (6.7%) had
      bony metastases at the time of diagnosis. Two patients (6.7%) were treated by
      surgery alone, for T1 and T2 tumours; four patients (13%) had radiotherapy alone,
      and 24 patients (80%) had surgery with post-operative radiotherapy with a mean
      dose of 60.3 Grays (56-65 Grays). RESULTS: Local recurrence occurred in 30.8%
      (nine cases) after a mean interval of 43 months (1 to 10 years). Treatment of
      these recurrences was by revision surgery in six cases, leading to local control
      in one case, but in a patient with pulmonary metastases. No cases of lymph node
      recurrence were observed. 30% of patients developed metastases; these were
      pulmonary in 44% and bony in 33.3%. Mean follow-up was five years. Crude survival
      at 3 years was 91%, at 5 years 86%, and at 10 years 50%. The percentage tumour
      free survival was 70% at 3 years, and 57% at 5 years. 22 patients (73.3%) are
      still alive, 17 of them recurrence-free. Analysis of the prognostic factors has
      shown tumour to be more aggressive in the nose and sinuses when they presented at
      an advanced stage (T4); recurrence was more common when excision was incomplete,
      or if there was peri-neural spread. Tumours of "massive" histological type
      carried a poorer prognosis than those of cribrigorm type (60% death compared with
      10%). The development of metastases is independent of local recurrence.
      Metastases to bone appear to be more rapidly aggressive than pulmonary
      metastases, which may remain asymptomatic for some time. CONCLUSION: Combined
      radiotherapy and surgery have allowed improved local control of ACT, but the
      therapeutic challenge remains the multiply recurrent ACT, or those with
      symptomatic metastases, and this despite new research techniques (neutral
      therapy, immuno-histochemistry, molecular biology). ACT are rare tumours, whose
      prognosis remains poor.

PMID- 15038567
TI  - Ectopic ossification in the parotid gland.
AB  - We present a unique report of ectopic ossification with dystrophic calcification
      within an otherwise histologically normal parotid gland. The histopathological
      features of the case are discussed and general pathogenetic explanations for the
      lesion are explored.

PMID- 15038569
TI  - Hearing results in stapes surgery using two different prosthesis.
AB  - AIM OF THE STUDY: Evaluation of hearing results after implantation of a
      fluoroplastic-platinum piston (FP) and of a titanium piston (T) with a shaft
      diameter of respectively 0.6 mm and 0.4 mm, in cases of otosclerosis requiring
      stapedotomy. MATERIAL AND METHODS: Pre-operative and post-operative hearing
      results obtained after primary stapedotomy by implantation of 30 FP and 30 T
      performed by the same expert author (C.Z.) were reviewed. In each patient we
      evaluated pre- and post-operative auditory thresholds, as recommended. RESULTS:
      All patients of both groups showed a significant air-bone gap (ABG) improvement
      for all frequencies after surgery ( P < 0. 001). Post-operative ABG comparison
      between the two groups showed a better ABG for lower frequencies in the FP group
      and for higher frequencies in the T group, but the difference was not
      significant. No post-operative complications, including sensorineural hearing
      loss, were found. Bone conduction improvement was better in the FP group than in
      the T one and this difference was statistically significant at 1000 and 2000 Hz.
      There was no statistically significant difference in the post-operative outcomes
      between the two prosthesis. Better results of FP for lower frequencies suggest
      that an increase in diameter of the prosthesis results in a greater improvement
      in the hearing threshold at low frequencies, while a decrease of diameter results
      in a greater improvement in the hearing threshold at high frequencies, as
      indicated by previous international studies. CONCLUSION: Our data shows that
      titanium piston is a as good as fluoroplastic piston in stapes surgery for
      otosclerosis.

PMID- 15038568
TI  - [Cerebro-spinal fluid otorrhea and a spontaneous defect of the tegmen tympani or
      antri. A report of 3 cases . Role of arachnoid granulations].
AB  - Less than 150 cases of cerebro-spinal fluid leak with spontaneous defect of the
      roof of the temporal bone have been described in the international literature.
      THE AIM OF THIS WORK: Is to define this pathology, to describe the clinical
      features, to suggest a diagnostic strategy, and to clarify the treatment method
      and the hypotheses on causation. MATERIALS AND METHODS: This is a retrospective
      study of 3 cases. RESULTS: At the first medical examination, the most common
      clinical feature is serous otitis media or otorrhea after myringotomy. Rhinorrhea
      is rarely pointed out by the patients but exists in our 3 observations. The
      diagnosis of cerebro-spinal fluid leak with spontaneous defect of the roof of the
      temporal bone needs; cerebro-spinal fluid leakage, absence of an otologic history
      or cranial trauma and a bony defect on CT scan. CT scan with millimeter slices is
      able to show the location and the size of the bony defect(s) of the roof of the
      temporal bone and often shows partial or total opacity of the middle ear
      cavities. MRI is able to show if this opacity exists in conjunction with
      meningeal hernia or cerebro-meningeal hernia. Surgical repair consists of placing
      an autologous graft over the bony defect by the middle fossa approach. The origin
      of a spontaneous defect of the temporal bone is discussed. We study the
      hypothesis in which arachnoid granulations could be responsible for a temporal
      bone defect.

PMID- 15038570
TI  - [When to suspect a perilymphatic fistula?].
AB  - INTRODUCTION: The diagnosis of perilymphatic fistula (PLF) is difficult since no
      single clinical situation gives the diagnosis for sure. The goal of this study is
      to clarify the clinical situations where you must suspect a PLF. METHODS:
      Retrospective study of 20 patients that had an exploratory tympanotomy with a PLF
      confirmed peroperatively. An analysis of the symptoms, signs and complementary
      exams was done. The surgical findings and the postoperative evolution were noted.
      RESULTS: 100% of patients reported a hearing loss, 80% vertigo, 70% a tinnitus
      and 35% equilibrium problems. Every patient had an etiological event to explain
      the PLF (trauma 85%), stapedotomy (10%), other ear surgeries. Five patients had a
      positive fistula or Vasalva test. All patients except one had an hearing loss on
      the audiogram (sensorineural, mixte or conductive). 50% had a CT scan, 70% of
      which were abnormal. A VNG was done on 3 patients. The sites of the PLF were as
      follows: 90% oval window, 5% round window and 5% both windows. The hearing got
      better or was stabilised in 95% of patients after the operation. 64% saw an
      improvement of their tinnitus and 87% of their vertigo. CONCLUSION: The diagnosis
      of PLF is difficult and a high index of suspicion is mandatory. One must look for
      an etiologic situation to explain the PLF. The audiogram is almost always
      modified, a mixte hearing loss being common due to the high incidence of
      ossicular trauma associated with PLF. The clinical clinical situations where you
      must suspect a PLF were identified as follows: An old trauma, a recent trauma, a
      history of otologic surgery particularly on the stapes and a preexisting hearing
      loss that aggravates. A diagnosis scale to evaluate the risk of PLF, based on
      clinical situations, physical exam and complementary exams was done to help the
      clinician in the evaluation of PLF.

PMID- 15038571
TI  - Delayed labyrinthine fistula in canal wall down mastoidectomy.
AB  - PURPOSE OF THE STUDY: This article is a retrospective review of 5 cases of
      delayed labyrinthine fistula in patients with a longstanding canal wall down
      mastoidectomy. MATERIAL: All patients had a long-term postoperative follow up
      with no evidence of complications till they suddenly started to have vertigo. The
      symptoms were caused by a bony erosion of the lateral semicircular canal detected
      on physical examination or by a CT-scan. There was no evidence of a recurrent
      cholesteatoma. RESULTS: The patients underwent surgery in order to close the
      fistula, with a good result. In all cases, a factor such as an infection or
      trauma, seems to have triggered off the bone erosion. CONCLUSION: Late
      complications may occur in the canal wall down mastoidectomy technique, after a
      long period of follow up in the absence of recurrent cholesteatoma. For this
      reason, it is advisable to look for a labyrinthine fistula in patient who develop
      vertigo a long time following mastoid surgery with a resultant radical cavity.

PMID- 15038572
TI  - [Why is allergic rhinitis currently at the centre of a debate?].

PMID- 15038573
TI  - [Proctology].

PMID- 15038574
TI  - [The organisation and carrying-out of proctological examinations].
AB  - Coloproctology, a specialist field requiring specialist knowledge, experience and
      skill, is dealt with only marginally in current further education courses for
      doctors. A thorough anamnesis, and here a questionnaire is of great help in
      procuring rapid and complete information, and examination of the patient in the
      lithotomy position (being the most comfortable for the patient and the most
      practical for the doctor) ar vital. A thorough basic diagnosis, independent of
      the reported symptoms, is always required: 1. Abdominal examination. 2.
      Inspection and palpation of the anal region with and without abdominal muscular
      pressure. 3. Digital examination, including the prostate. 4. Rectosigmoidoscopy.
      5. Proctoscopy, possibly with anal speculum examination. 6. Test for occult blood
      in the faeces. Depending on the anamnesis and findings, this basic diagnosis must
      be supplemented by further tests.

PMID- 15038575
TI  - [Conservative treatment of haemorrhoids].
AB  - Haemorrhoidal symptoms have been known from time immemorial; they are considered
      to be a widespread problem, which is progressive if untreated. Treatment is
      according to the proctological qualification of the doctor and the degree of the
      changes. If possible, it should be carried out from the point of view of causal
      therapy. The most frequently occurring 1st degree haemorrhoids can almost always
      be treated conservatively, i.e. with sclerotherapy. To prevent recurrence, the
      life style and defecation habits should be changed. Regular monitoring by
      specialists aids prevention.

PMID- 15038576
TI  - [Surgical treatment of hemorrhoids].
AB  - The spectrum of procedures for hemorrhoidal disease can deal with all
      developmental stages if carried out in a differential way. Stapled
      hemorrhoidopexy is an effective supplement to actual conventional surgical
      procedures. Hemorrhoidectomies performed with the stapler were compared with
      segmental hemorrhoridectomies according to Milligan-Morgan as well as anoplasty
      according to Fansler-Arnold, and proved to be superior as regards complication
      rate, need for analgesics and operation time, stay in hospital and time off work.
      But despite the justified euphoria about this innovative method, its necessary
      limitations should not be disregarded.

PMID- 15038577
TI  - [The anal fistula disease and abscess].
AB  - There are two forms of anal fistulas arising from its pathogenesis: the acute
      stage is the abscess, whereas the chronic stage is the fistula in ano. The
      classification of the fistula in ano is named after Parks. Pathogenesis and
      classification are explained. For complete cure, every abscess needs precise
      examination to be able to show the course and shape of the fistula. The surgical
      procedure depends on the fistula tract. Most fistulas can be operated by means of
      a fistulotomy or fistulectomy. Recovery depends on locating the total fistula
      tract.

PMID- 15038578
TI  - [Anal fissure].
AB  - Anal fissures are present in about 10-15% of proctological patients. The cause of
      the illness is unknown, but is probably multifactorial. Cardinal symptoms are
      pain during and after defecation, as well as persistent sphincter spasm. In most
      cases an acute anal fissure heals spontaneously or with adequate conservative
      therapy. Chronic anal fissures can be cured in some cases by conservative
      treatment. Where there is treatment resistance, surgical cleansing is necessary.

PMID- 15038579
TI  - [Outpatient surgery in proctology].
AB  - Proctological surgery can be carried out increasingly on an outpatient basis and
      thus more cost-effectively. The reasons for this are, in addition to modern
      anaesthetic procedures, short operation times and low complication rates in
      numerous proctological operations. Fissurectomies, individual
      haemorrhoidectomies, operations on uncomplicated fistulae and benign anal tumours
      only rarely need to be carried out nowadays under inpatient conditions. The
      conditions for successful outpatient surgery are: appropriate diagnosis of the
      indication, selection of the patients with respect to their suitability for
      surgery and standardised follow-up care.

PMID- 15038580
TI  - [Diagnostics and conservative treatment of anal incontinence].
AB  - Anal incontinence is diagnosed primarily by clinical and proctologic examination.
      Etiological factors of the disease are found in 85% of the patients by additional
      examinations. Motility dysfunction of colon and rectum has to be excluded
      (stenosis, dyschezia, internal hernias). Because anal incontinence is a
      multifactorial disease as a rule, the single compounds have to be diagnosed and
      have to undergo therapy. Accordingly, useful investigations are: endorectal
      ultrasound (defect of muscle, inflammatory or tumour infiltration), manometry
      (alteration of either anal resting pressure and/or anal squeezing pressure) and
      surface electromyography (ability of contraction, duration of contraction,
      strength). Neurophysiological examinations are: needle electromyography, pudendal
      nerve latency time measurement (PNLT). The occurrence of nerve damage determines
      the outcome of operative intervention! Conservative treatment is indicated in 80
      to 90% of all patients, even higher when one includes all patients in the
      perioperative period. Possible therapy modalities are: nutrition consultation,
      physiotherapy, pelvic floor training, biofeedback training of pelvic floor and
      sphincter muscles, electrostimulation and the combination of both (EMG-triggered
      electrostimulation). Short-term results are satisfying in up to 85% of patients,
      but later, successful results depend on the patient's willingness or ability to
      continue training, and on his/her age.

PMID- 15038581
TI  - [Fecal incontinence--operative treatment of a complex problem].
AB  - Anal continence is maintained by the controlled synergism of all parts of the
      complex anal sphincter system and the normal functioning of the preposed gut.
      Operative treatment may improve the function of a single part of the system. In
      case of malfunction of more than one element of the anal sphincter, an operation
      may result in partial improvement. In these cases, additional conservative
      treatment is recommended. In a few cases, additional operations are needed. The
      indications for and results of the established operations for the treatment of
      anal incontinence will be discussed here.

PMID- 15038582
TI  - [The diagnosis and treatment of perianal dermatitis].
AB  - Perianal dermatitis is one of the most common proctological disorders. The
      anatomy of the anal region provides suitable conditions for the development of
      dermatitis. In the diagnostic work-up and the management of patients with
      perianal dermatitis, three types need to be distinguished: irritant contact
      dermatitis, atopic dermatitis, and allergic contact dermatitis. Each type has its
      aetiological and pathogenetic factors, which will provide clues to the diagnosis
      and subsequent management of the condition. In the differential diagnosis of the
      condition, consideration should be given to inflammatory diseases of the perianal
      region which may produce eczema-like patterns.

PMID- 15038583
TI  - [When is ileocolonoscopy indicated in chronic inflammatory intestinal diseases?].
AB  - The question frequently arises in proctological practice whether there is an
      indication for ileocolonoscopy in chronic inflammatory intestinal diseases.
      Endoscopy is an essential constituent of the initial diagnosis of ulcerative
      colitis and Crohn's disease. Control colonoscopies are not necessary for
      assessing remission and in renewed acute attacks with confirmed diagnosis are
      without therapeutic consequences. Ileocolonoscopy with stepwise biopsy is
      currently the only accepted monitoring programme for carcinoma prophylaxis in the
      presence of an increased risk of colorectal carcinoma in both diseases.

PMID- 15038584
TI  - When should cholera vaccine be used in cholera-endemic areas?

PMID- 15038585
TI  - Association of vitamin A and zinc status with altered intestinal permeability:
      analyses of cohort data from northeastern Brazil.
AB  - To examine the association of intestinal barrier function with vitamin A
      deficiency and whether supplementation of micronutrients improves intestinal
      function and/or linear growth, height-for-age z-score (HAZ), concentrations of
      serum retinol and zinc, and intestinal permeability were determined in a cross
      sectional sample of 75 children in northeastern Brazil. Effects of vitamin A and
      supplementation of zinc on intestinal permeability and growth were also
      determined comparing results before and after treatment in 20 children and age
      matched controls. Lactulose:mannitol (L/M) permeability ratios inversely
      correlated with serum retinol concentrations (r = -0.55, p < 0.0005). Increased
      L/M permeability ratios with reduced concentrations of serum retinol were
      predominantly attributable to lower absorption of mannitol (r = 0.28, p = 0.02).
      L/M permeability ratios (p = 0.001) and HAZ scores (p = 0.007) improved with
      supplementation. It is concluded that impaired intestinal barrier function and
      linear growth shortfalls improve following supplementation of vitamin A and zinc
      in this setting.

PMID- 15038586
TI  - Factors associated with carriage of penicillin-resistant Streptococcus pneumoniae
      among Vietnamese children: a rural-urban divide.
AB  - This study examined the relationship between antimicrobial resistance in
      Streptococcus pneumoniae and patterns of antimicrobial usage and over-the-counter
      dispensing by pharmacies in urban and rural districts of Vietnam. The
      antimicrobial susceptibility of S. pneumoniae carried by healthy urban and rural
      school children was determined. Questionnaires were distributed to parents to
      describe their healthcare-seeking behaviour. Mock parents presented standardized
      cases of mild respiratory infection and acute watery diarrhoea to pharmacies in
      the district surrounding each school. Penicillin resistance was significantly
      more common in S. pneumoniae carried by urban children compared to rural children
      as was recent antibiotic usage. Both urban and rural pharmacies showed high rates
      of dispensing inadequate antimicrobial regimens. The high level of antimicrobial
      resistance in S. pneumoniae may be related to greater antimicrobial usage. This
      may result from the much easier access to healthcare providers in urban areas and
      may suggest that relying solely on education without limiting access to outlets
      may have only limited impact. The results suggest a greater understanding of the
      subtleties of healthcare-seeking behaviour, and access to healthcare is needed to
      help refine and guide rationale suggestions to reduce the continued spread of
      drug resistance.

PMID- 15038587
TI  - Rice-ORS versus glucose-ORS in management of severe cholera due to Vibrio
      cholerae O139 Bengal: a randomized, controlled clinical trial.
AB  - This study examined the comparative efficacies of rice-based oral rehydration
      solution (R-ORS) and glucose-based oral rehydration solution (G-ORS) in the
      management of severe cholera due to Vibrio cholerae O139 Bengal that causes
      epidemic cholera in many developing countries. Stool culture-proved adult male
      patients with severe cholera due to V. cholerae O139 Bengal were randomly
      assigned in a 1:1 ratio to receive either R-ORS or G-ORS after their initial
      rehydration with intravenous (i.v.) fluid and subsequently four hours of
      observation. They also received the usual hospital diet and tetracycline capsules
      (500 mg 6 hourly for three days) immediately after their enrollment in the study.
      The primary outcomes for observation were stool output during the first 24 hours
      after intervention and treatment failure as measured by the incidence of re
      institution of i.v. fluid after initiation of trial therapy and duration of
      diarrhoea. Of 113 patients finally included in the study, 57 received R-ORS and
      56 G-ORS. The admission characteristics of the two treatment groups were
      comparable. No significant differences in the first 24 hours of median (inter
      quartile range) stool output [179 (67-206) g/kg in R-ORS group vs 193 (80-237)
      g/kg in G-ORS group; p = 0.52], incidences of unscheduled i.v. fluid requirement
      [21% (12/57) in R-ORS group vs 25% (14/56) in G-ORS group; p = 0.78], and median
      (inter-quartile range) duration of diarrhoea [32 (24-48) hours in R-ORS group vs
      32 (24-56) hours in G-ORS group; p = 0.64] were observed. It is concluded that
      rice-based ORS is effective but not superior to standard glucose-based ORS in the
      management of adult males with severe cholera due to V. cholerae O139 Bengal.

PMID- 15038588
TI  - Impact of coffee and other selected factors on general mortality and mortality
      due to cardiovascular disease in Croatia.
AB  - In Croatia, the mortality rate is higher than that in the countries of the
      European Union (EU), and consumption of coffee is moderate compared to the EU
      countries. The study examined the effects of coffee consumption on all-cause
      (general) mortality, mortality due to cardiovascular disease, and survival.
      Analyses were based on data obtained from an epidemiological longitudinal study
      started in 1969 with follow-ups in 1972, including 1,571 men and 1,793 women aged
      35-59 years, and in 1982, including 1,093 men and 1,330 women. The sample was age
      and gender-stratified and included urban and rural populations from three
      coastal and three continental regions of Croatia. During the observation period
      from spring 1972 to the end of 1999, 568 men and 382 women died. In total, 254
      men and 181 women died due to cardiovascular disease. The sample was classified
      in 4 groups: non-drinkers, consumption of coffee sometimes, regularly 1-2 cup(s),
      and regularly more than 2 cups per day. Apart from coffee, the effects of
      diastolic blood pressure, smoking habit, well-being, stomach ulcer, and resident
      status were analyzed. Data on general mortality and mortality due to
      cardiovascular disease were also analyzed. The influence of region and the
      effects of diastolic pressure and smoking habit on general mortality and
      cardiovascular disease-associated mortality were confirmed in both the sexes. No
      significant effects of coffee consumption on general mortality and mortality due
      to cardiovascular disease were found among men. Positive effects of coffee on
      general mortality (p = 0.0089) but not on cardiovascular disease-associated
      mortality were observed among women. Women who regularly drank coffee 1-2 cup(s)
      per day had a significantly lower risk of all-cause death adjusted for age,
      region, smoking, diastolic blood pressure, feeling of well-being, and history of
      stomach ulcer (relative risk = 0.631; p = 0.0033; confidence interval: 0.464
      0.857). The role of coffee consumption on mortality was less relevant than other
      variables. However, it cannot be completely neglected in women.

PMID- 15038589
TI  - Growth charts of heights and weights of male children and adolescents of Isfahan,
      Iran.
AB  - Measurements of height and weight are important data source relating to growth
      and development, puberty, and nutritional status of children and adolescents. In
      clinical setting, the charts of the National Center for Health Statistics (NCHS),
      USA, are used in Iran. A survey identified significant differences in weight- and
      height-for-age across provinces, between urban and rural children. Although the
      percentiles derived from data of the national health survey, in 1990-1992, were
      substantially below the NCHS charts, the growth patterns were parallel to the
      NCHS percentiles. In 1997, an anthropometric assessment of male students aged 6
      18 years was conducted in Isfahan, a centrally-located city in Iran. The goal of
      the study was to establish the normograms of heights and weights in Isfahan for
      use in clinical settings. By a random cluster sample survey, 4,364 of 200,000
      male students aged 6-18 years were selected from all areas of the city. Trained
      health staff measured their heights (cm) and weights (kg), and all the
      percentiles were calculated. A comparison was made with weight and height data
      collected from other parts of the country on several occasions. Findings showed
      that the growth percentiles of 6-18-year male students of Isfahan in 1997 were
      comparable to the NCHS charts. These students were taller and heavier than their
      fellow-citizens 22 years earlier, their compatriots in rural areas of Isfahan
      (1997) and Rasht (1989). They were also taller than those who were living in
      Tehran (1994). A similar study was conducted at the same time on urban Isfahani
      female students aged 6-18 years. All the percentiles of their height and weight
      curves were comparable with those of the NCHS charts. Thus, it is appropriate to
      use the NCHS charts for school-age children and adolescents in Isfahan city. The
      cause of improvement in growth parameters in Isfahan should be evaluated in
      future studies.

PMID- 15038590
TI  - Prevalence of, and factors associated with, HIV/AIDS-related stigma and
      discriminatory attitudes in Botswana.
AB  - Botswana has the highest prevalence of HIV in the world. The epidemic of HIV/AIDS
      is often accompanied by stigma and discrimination that create the circumstances
      for spreading HIV. To facilitate the design of effective programmes to fight the
      high prevalence of HIV/AIDS-related stigma and discriminatory attitudes, this
      study examined survey data on the prevalence of, and factors associated with,
      such attitudes in Botswana. While most respondents showed discriminatory
      attitudes towards a teacher or a shopkeeper with HIV/AIDS, only 11% of 4,147
      respondents reported unwillingness to care for a family member with HIV/AIDS. The
      more tolerant attitudes towards a family member with HIV/AIDS appeared to be
      promoted by the fact that family members have been and continue to care for their
      sick members through a government project called Community Home-based Care aimed
      at relieving public hospitals of HIV/AIDS patients. Since the burden of caring
      for sick relatives rests on the shoulders of women, they portrayed more tolerant
      attitudes towards HIV/AIDS patients. Young people and those who believed a person
      could get HIV infection by sharing a meal with an HIV/AIDS patient had
      discriminatory attitudes towards people with HIV/AIDS. The national information,
      education and communication programme needs to be strengthened to reach more
      people for HIV/AIDS education. Finally, programmes that aim to promote more
      tolerant attitudes towards people with HIV/AIDS may be more effective if the
      human rights of those with HIV/AIDS are promoted and respected.

PMID- 15038591
TI  - Determinants of condom use among monogamous men in Ondo State, Nigeria.
AB  - This study examined the factors that influence condom use among monogamous men in
      Ondo State, Nigeria. Such information can help improve the design of male
      involvement interventions in reproductive health and campaigns to reduce the
      spread of HIV among the general population. Overall, analysis was restricted to
      394 men who were in their first union and reported a monogamous marriage at the
      time of interview. The analysis used logistic regression models for predicting
      the effects of selected socioeconomic background characteristics on ever-use of a
      condom and reasons for its use. Findings showed that 30% of monogamous men had
      ever used a condom, while about 15% of men were currently using the method. The
      findings further showed that prevention of pregnancy was a concern among
      monogamous men, much more than prevention of sexually transmitted infections
      (STIs), including HIV/AIDS. The logistic regression models indicated that ever
      use of a condom was associated with age, education, and having been counselled on
      family planning, while place of residence, frequency of television-watching, and
      exposure to family-planning counselling were factors associated with motivation
      for condom use. Although prevention of pregnancy is a major motivation for condom
      use, many men would use a condom for protection against STIs and prevention of
      pregnancy simultaneously. Therefore, programme interventions aimed at promoting
      the use of condoms among men should convey both pregnancy and STIs/HIV/AIDS
      prevention messages in one programme.

PMID- 15038592
TI  - Acceptability and use of clean home delivery kits in Nepal: a qualitative study.
AB  - This research was carried out in rural Nepal to explore how different categories
      of birth attendants at home deliveries accepted and used clean home delivery kit
      (CHDK) and its contents, including hand-washing practices, during delivery and
      preparations for birth. In-depth interviews were conducted to collect information
      from 51 women-both users and non-users of the kit. The respondents were
      interviewed within one month of their most recent delivery. Results of the
      interviews showed that the attendants who used the kit perceived it as hygienic
      and convenient, affordable, and culturally acceptable. The razor blade and thread
      were the most useful items, and the purpose of the plastic coin was understood.
      Despite its perceived usefulness, awareness and use of the kit were low, and
      common reasons for non-use included not knowing about the kit or difficulty in
      procuring a kit locally. In addition, the kit had limited influence on general
      hygiene practices. The authors explore the importance of evaluating promotional
      efforts re-targeted to individuals who hold decision-making power regarding the
      use of the kit. They recommend that kit promoters emphasize hand-washing and
      single use of the kit.

PMID- 15038593
TI  - Factors influencing the use of maternal healthcare services in Ethiopia.
AB  - This study examined the factors that influence the use of maternal healthcare
      services in Ethiopia and particularly assessed the use of antenatal and delivery
      care services. Data for the study were drawn from the 2000 Ethiopia Demographic
      and Health Survey. Multivariate logistic regression analysis was employed to
      explore the relative importance of a number of demographic and sociocultural
      variables in the likelihood of using these services. Results of the study showed
      that the coverage of maternity-care services was very low in Ethiopia, i.e. about
      27% and 6% of women, respectively, received professionally-assisted antenatal and
      delivery-care services in the five years preceding the survey. The study also
      revealed that demographic and sociocultural factors were the most important
      aspects that influenced the use of maternal healthcare services in Ethiopia. The
      independent factors influencing the use of maternal healthcare services included
      education of mothers, marital status, place of residence, parity, and religion.
      However, this cannot detract from the relevance of service-related factors,
      especially in the rural areas of the country.

PMID- 15038594
TI  - Impact of a community-based comprehensive primary healthcare programme on infant
      and child mortality in Bolivia.
AB  - Community-based comprehensive primary healthcare programmes are a widely-promoted
      strategy for improving child survival in less-developed countries, but limited
      documentation exists concerning their effectiveness in actually reducing child
      mortality. This study examined the impact of a community-based comprehensive
      primary healthcare programme on child survival in Bolivia. Mortality rates from
      two intervention areas where Andean Rural Health Care (ARHC) had been conducting
      child-survival activities for 5-9 years were compared with those from two
      geographically-adjacent comparison areas that lacked such activities and that
      were virtually identical to the intervention areas in socioeconomic
      characteristics. Vital events were registered at the time of regular visit to all
      homes. In the comparison areas, limited services were available which reached
      only a small percentage of the population, while in the intervention areas,
      prenatal care, immunizations, growth monitoring, nutrition rehabilitation, and
      acute curative services were readily available to the entire population. In 1992
      1993, the annual rates of mortality of children, aged less than five years, were
      205.5 per 1,000 and 98.5 per 1,000 in the comparison and intervention areas
      respectively. The absolute difference in mortality of 107.0 deaths per 1,000 (95%
      confidence interval [CI], 72.7-141.3 per 1,000) represented 52.1% (95% CI, 35.2
      68.8%) lower mortality of children aged less than five years in the intervention
      areas compared to the control communities. These results suggest that the
      provision of community-based, integrated health services can significantly
      improve child survival in poor countries. Better-designed and larger field trials
      of community-based comprehensive primary healthcare programmes in multiple
      regions of the world are needed to provide a stronger scientific basis for
      developing this approach further in developing countries.

PMID- 15038595
TI  - Enhanced isolation of Shigella species by extended incubation of primary
      isolation plates.

PMID- 15038596
TI  - Mitochondrial disease: a historical, biochemical, and London perspective.
AB  - Roland Luft is credited with describing the first truly mitochondrial disorder in
      the late 1950s and early 1960s. Cases such as his have proven to be exceptionally
      rare. Some years later, methods of mitochondrial analysis--enzymatic,
      polarographic, and spectroscopic, which had been developed primarily by groups in
      Philadelphia--were applied to the study of mitochondria isolated from skeletal
      muscle biopsies of patients thought to have defects of oxidative phosphorylation.
      In the vanguard of these investigations were groups in New York and London. John
      Clark led the latter group. Application of biochemical studies, more recently
      supplemented by molecular mtDNA and nuclear DNA studies, have revealed that
      mitochondrial disorders are among the most common of all metabolic disorders.

PMID- 15038597
TI  - Mitochondrial dysfunction in neurodegenerative diseases associated with copper
      imbalance.
AB  - Copper is an essential transition metal ion for the function of key metabolic
      enzymes, but its uncontrolled redox reactivity is source of reactive oxygen
      species. Therefore a network of transporters strictly controls the trafficking of
      copper in living systems. Deficit, excess, or aberrant coordination of copper are
      conditions that may be detrimental, especially for neuronal cells, which are
      particularly sensitive to oxidative stress. Indeed, the genetic disturbances of
      copper homeostasis, Menkes' and Wilson's diseases, are associated with
      neurodegeneration. Furthermore, copper interacts with the proteins that are the
      hallmarks of neurodegenerative disorders, such as Alzheimer's disease,
      Parkinson's disease, prion diseases, and familial amyotrophic lateral sclerosis.
      In all cases, copper-mediated oxidative stress is linked to mitochondrial
      dysfunction, which is a common feature of neurodegeneration. In particular we
      recently demonstrated that in copper deficiency, mitochondrial function is
      impaired due to decreased activity of cytochrome c oxidase, leading to production
      of reactive oxygen species, which in turn triggers mitochondria-mediated
      apoptotic neurodegeneration.

PMID- 15038599
TI  - Neurodegeneration or neuroprotection: the pivotal role of astrocytes.
AB  - Formation of nitric oxide (NO), by astrocytes, has been suggested to contribute,
      via impairment of mitochondrial function, to the neurodegnerative process. Thus
      co-culture of neuronal cells with NO-generating astrocytes leads to a loss of
      mitochondrial function, as reflected by diminished activities of complexes IV and
      II+III. However, such damage may in the first instance be limited due to
      upregulation of neuronal glutathione metabolism as a result of metabolic
      trafficking of glutathione from the astrocyte to neurone. Furthermore, exposure
      of astrocytes to NO leads to increased glutathione metabolism resulting in the
      preservation of glutathione precursors for neuronal utilization. Failure of
      glutathione trafficking could render neuronal cells particularly susceptible to
      NO, leading to cell death. In addition, depletion with time of the nitric oxide
      synthase cofactor, tetrahydrobiopterin, may result in the astrocytic generation
      of more potent oxidizing species, which could contribute to the neurodegenerative
      process.

PMID- 15038598
TI  - Neuropathological aspects of mitochondrial DNA disease.
AB  - Mitochondrial DNA disorders are an important cause of neurological disease, yet
      despite our awareness of the importance of these conditions, relatively little is
      known about the neuropathology of these disorders and even less about the
      mechanisms involved in neuronal dysfunction and death. In this review we detail
      important features from neuropathological studies available and highlight
      deficiencies that are currently limiting our understanding of mitochondrial DNA
      disease. We also discuss possible future approaches that might resolve some of
      these outstanding issues. Further study of these disorders is critical because
      mitochondria play a central role in neuronal survival and it is likely that an
      understanding of the mechanisms involved in neuronal dysfunction and cell death
      in mitochondrial DNA disease may have implications for other neurodegenerative
      diseases.

PMID- 15038600
TI  - Mitochondrial function in apoptotic neuronal cell death.
AB  - Apoptosis can be defined as the regulated death of a cell and is conducted by
      conserved pathways. Apoptosis of neurons after injury or disease differs from
      programed cell death, in the sense that neurons in an adult brain are not "meant"
      to die and results in a loss of function. Thus apoptosis is an honorable process
      by a neuron, a cell with limited potential to replace itself, choosing instead to
      commit suicide to save neighboring cells from release of cellular components that
      cause injury directly or trigger secondary injury resulting from inflammatory
      reactions. The excess of apoptosis of neuronal cells underlies the progressive
      loss of neuronal populations in neurodegenerative disorders and thus is harmful.
      Mitochondria are the primary source for energy in neurons but are also poised,
      through the "mitochondrial apoptosis pathway," to signal the demise of cells.
      This duplicity of mitochondria is discussed, with particular attention given to
      the specialized case of pathological neuronal cell death.

PMID- 15038602
TI  - Respiratory complex I in brain development and genetic disease.
AB  - A study is presented on the expression and activity of complex I, as well as of
      other complexes of the respiratory chain, in the course of brain development and
      inherited encephalopathies. Investigations on mouse hippocampal cells show that
      differentiation of these cells both in vivo and in cell cultures is associated
      with the expression of a functional complex I, whose activity markedly increases
      with respect to that of complexes III and IV. Data are presented on genetic
      defects of complex I in six children with inborn encephalopathy associated with
      isolated deficiency of the complex. Mutations have been identified in nuclear and
      mitochondrial genes coding for subunits of the complex. Different mutations were
      found in the nuclear NDUFS4 gene coding for the 18 kD (IP, AQDQ) subunit of
      complex I. All the NDUFS4 mutations resulted in impairment of the assembly of a
      functional complex. The observations presented provide evidence showing a
      critical role of complex I in differentiation and functional activity of brain
      cells.

PMID- 15038603
TI  - Role of oxidative damage in Friedreich's ataxia.
AB  - Plasma malondialdehyde (MDA) levels were raised in Friedreich's ataxia (FRDA)
      patients. These levels correlated with increasing age and disease duration,
      suggesting lipid peroxidation increased with disease progression. Using
      fibroblasts from FRDA patients we observed that GSH levels and aconitase
      activities were normal, suggesting their antioxidant status was unchanged. When
      exposed to various agents to increase free radical generation we observed that
      intracellular superoxide generation induced by paraquat caused enhanced oxidative
      damage. This correlated with the size of the GAA1 expansion, suggesting decreased
      frataxin levels may render the cells more vulnerable to mild oxidative stress.
      More severe oxidative stress induced by hydrogen peroxide caused increased cell
      death in FRDA fibroblasts but was not significantly different from control cells.
      We propose that abnormal respiratory chain function and iron accumulation may
      lead to a progressive increase in oxidative damage, but increased sensitivity to
      free radicals may not require detectable respiratory chain dysfunction.

PMID- 15038601
TI  - The energetics of Huntington's disease.
AB  - Huntington's disease (HD) is a hereditary neurodegenerative disorder that
      gradually robs sufferers of the ability to control movements and induces
      psychological and cognitive impairments. This devastating, lethal disease is one
      of several neurological disorders caused by trinucleotide expansions in affected
      genes, including spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy,
      and spinal bulbar muscular atrophy. HD symptoms are associated with region
      specific neuronal loss within the central nervous system, but to date the
      mechanism of this selective cell death remains unknown. Strong evidence from
      studies in humans and animal models suggests the involvement of energy metabolism
      defects, which may contribute to excitotoxic processes, oxidative dmage, and
      altered gene regulation. The development of transgenic mouse models expressing
      the human HD mutation has provided novel opportunities to explore events
      underlying selective neuronal death in HD, which has hitherto been impossible in
      humans. Here we discuss how animal models are redefining the role of energy
      metabolism in HD etiology.

PMID- 15038605
TI  - Peroxynitrite mediates nitric oxide-induced blood-brain barrier damage.
AB  - Using the in vitro blood-brain barrier (BBB) model ECV304/C6, which consists of
      cocultures of human umbilical vein endothelial-like cells (ECV304) and rat glioma
      cells (C6), the role of peroxynitrite (OONO-) in nitric oxide (NO*)-mediated BBB
      disruption was evaluated. Endothelial cell cultures were exposed to NO* gas, in
      the presence or absence of the OONO- blocker FeTPPS. Separate exposure to NO* and
      OONO- resulted in endothelial cell cytotoxicity and a decline in barrier
      integrity. Unfortunately, FeTPPS induced significant detrimental effects on model
      BBB integrity at a concentration of 300 microM and above. At 250 microM (the
      highest concentration usable), FeTPPS displayed a trend toward prevention of NO*
      elicited perturbation of barrier integrity. Dichlorofluorescein diacetate is
      oxidized to fluorescent dichlorofluorescein by OONO- but only marginally by NO*
      or O2*-. We observed large and rapid increases in fluorescence in ECV304
      preloaded cells following NO* exposure, which were blocked by FeTPPS.
      Furthermore, using an antinitrotyrosine antibody we detected the nitration of
      endothelial cell proteins following NO* exposure and conclude that NO*-mediated
      BBB dysfunction is predominantly elicited by OONO- and not NO*. Proposed
      mechanisms of NO*-mediated OONO- elicited barrier dysfunction and damage are
      discussed.

PMID- 15038604
TI  - Initiation of neuronal damage by complex I deficiency and oxidative stress in
      Parkinson's disease.
AB  - Oxidative stress and partial deficiencies of mitochondrial complex I appear to be
      key factors in the pathogenesis of Parkinson's disease. They are interconnected;
      complex I inhibition results in an enhanced production of reactive oxygen species
      (ROS), which in turn will inhibit complex I. Partial inhibition of complex I in
      nerve terminals is sufficient for in situ mitochondria to generate more ROS. H2O2
      plays a major role in inhibiting complex I as well as a key metabolic enzyme,
      alpha-ketoglutarate dehydrogenase. The vicious cycle resulting from partial
      inhibition of complex I and/or an inherently higher ROS production in
      dopaminergic neurons leads over time to excessive oxidative stress and ATP
      deficit that eventually will result in cell death in the nigro-striatal pathway.

PMID- 15038606
TI  - Mitochondrial disease: mutations and mechanisms.
AB  - The mitochondrial diseases encompass a diverse group of disorders that can
      exhibit various combinations of clinical features. Defects in mitochondrial DNA
      (mtDNA) have been associated with these diseases, and studies have been able to
      assign biochemical defects. Deficiencies in mitochondrial oxidative
      phosphorylation appear to be the main pathogenic factors, although recent studies
      suggest that other mechanisms are involved. Reactive oxygen species (ROS)
      generation has been implicated in a wide variety of neurodegenerative diseases,
      and mitochondrial ROS generation may be an important factor in mitochondrial
      disease pathogenesis. Altered apoptotic signaling as a consequence of defective
      mitochondrial function has also been observed in both in vitro and in vivo
      disease models. Our current understanding of the contribution of these various
      mechanisms to mitochondrial disease pathophysiology will be discussed.

PMID- 15038607
TI  - Astrocyte mitochondrial mechanisms of ischemic brain injury and neuroprotection.
AB  - Research on ischemic brain injury has established a central role of mitochondria
      in neuron death. Astrocytes are also damaged by ischemia, although the
      participation of mitochondria in their injury is ill defined. As astrocytes are
      responsible for neuronal metabolic and trophic support, astrocyte dysfunction
      will compromise postischemic neuronal survival. Ischemic alterations to astrocyte
      energy metabolism and the uptake and metabolism of the excitatory amino acid
      transmitter glutamate may be particularly important. Despite the significance of
      ischemic astrocyte injury, little is known of the mechanisms responsible for
      astrocyte death and dysfunction. This review focuses on differences between
      astrocyte and neuronal metabolism and mitochondrial function, and on neuronal
      glial interactions. The potential for astrocyte mitochondria to serve as targets
      of neuroprotective interventions is also discussed.

PMID- 15038608
TI  - Increased mitochondrial permeability in response to intrastriatal N-methyl-D
      aspartate: detection based on accumulation of radiolabel from [3H]deoxyglucose.
AB  - Induction of the mitochondrial permeability transition has been proposed as an
      important contributor to cell loss in several neurological disorders, but the
      evidence that this change can develop in cells in the intact mature brain is
      largely indirect. In this study, we have tested whether an intrastriatal
      injection of N-methyl-D-aspartate results in increases in inner membrane
      permeability that can be detected from mitochondrial accumulation of metabolites
      of 3H-deoxyglucose previously taken up by brain cells. An increase in
      incorporation of deoxyglucose metabolites was found in mitochondria prepared from
      the striatum but not from cerebral cortex distant from the injection site. This
      change developed more than 8 h after treatment with N-methyl-D-aspartate and is
      consistent with the induction of the permeability transition as a late change in
      the progression to irreversible neuronal damage in response to this excitotoxic
      insult. At earlier times, the restricted permeability of the inner mitochondrial
      membrane was apparently preserved, at least sufficiently to prevent significant
      diffusion of metabolites between the cytoplasm and the matrix.

PMID- 15038609
TI  - Redox control of signal transduction, gene expression and cellular senescence.
AB  - Reactive oxygen species (ROS) act as subcellular messengers in such complex
      cellular processes as mitogenic signal transduction, gene expression, regulation
      of cell proliferation, replicative senescence, and apoptosis. They serve to
      maintain cellular homeostasis and their production is under strict control.
      However, the mechanisms whereby ROS act are still obscure. Here we review recent
      advances in our understanding of signaling mechanisms and recent data about the
      involvement of ROS in: (i) the regulation of the mitogenic transduction elements,
      particularly protein kinases and phosphatases; (ii) the regulation of gene
      expression; and (iii) the induction of replicative senescence and the role, if
      any, in aging and age-related disorders.

PMID- 15038610
TI  - Substantial linkage disequilibrium across the dihydrolipoyl succinyltransferase
      gene region without Alzheimer's disease association.
AB  - Association of the candidate gene DLST with late-onset Alzheimer's disease (LOAD)
      risk has been suggested on the basis of case-control studies. This gene, located
      on chromosome 14q24.3, encodes a subunit of a mitochondrial component known to be
      defective in AD, the alpha-ketoglutarate dehydrogenase complex. Positive reports
      have correlated different DLST alleles with LOAD, whereas other groups have
      failed to find any significant association. We therefore reexamined the
      association of DLST and LOAD in a more ethnically homogeneous series using three
      additional single nucleotide polymorphisms (SNP) located within or closely
      flanking either end of the DLST gene. Pairwise analysis of these SNPs indicated
      there was strong linkage disequilibrium across the DLST locus. Analysis of
      complex genotypes or haplotypes based upon all five SNP loci failed to identify a
      LOAD risk allele, suggesting that further studies of DLST in relation to AD are
      not warranted.

PMID- 15038612
TI  - Mitochondrial heterogeneity within and between different cell types.
AB  - Mitochondrial membrane potentials (MMP) reflect the functional status of
      mitochondria within cells. Our recently published method provides a
      semiquantitative estimate of the MMP of populations of mitochondrial-like
      particles within living cells at 37 degrees C using a combination of conventional
      fluorescence microscopy and three-dimensional deconvolution by exhaustive photon
      reassignment. The current studies demonstrate variations in the mean MMP among
      six different cell types (i.e., human skin fibroblasts, naive and differentiated
      PC12 cells, SH-SY5Y cells, dopaminergic cells, and primary cultured neurons) and
      MMP in different parts of the same cells (i.e., growth cones vs. cell bodies).
      The largest MMP was in nontransformed fibroblasts (mean MMP was -112 +/- 2 mV),
      while the lowest was in transformed neuroblastoma SH-SY5Y cells (-87 +/- 2 mV).
      This method revealed large variations in mean MMP among cells of the same type
      within a single culture dish. The percent area of the cell occupied by
      mitochondrial-like particles differed among different cell types, and ranged from
      4% in SH-SY5Y to 24% in differentiated PC12 cells. The data can also be analyzed
      by calculating the sum potential of all of the pixels in a cell. The sum MMP per
      cell revealed a large range between cell types from -2238 +/- 355 mV/microm2 in
      SH-Y5Y to -15445 +/- 1039 mV/microm2 in PC12 cells. Although biological
      implications of heterogeneity of MMP are not clear, this approach provides a tool
      to address this question.

PMID- 15038614
TI  - High prevalence of human anti-bovine IgG antibodies as the major cause of false
      positive reactions in two-site immunoassays based on monoclonal antibodies.
AB  - A sandwich ELISA for quantification of the endometrial protein PP14 revealed
      false positive reactions in 81% of male sera (n = 54). The PP14 ELISA was based
      on two monoclonal antibodies (Mabs) with different epitope specificities--a
      catcher and a biotinylated indicator. The monoclonal antibodies were purified by
      protein G affinity chromatography from culture supernatant containing 10% (v/v)
      fetal calf serum (FCS). Human anti-animal IgG (bovine, mouse, horse, and swine)
      antibodies and human anti-bovine serum albumin antibodies were measured using an
      ELISA design, with direct bridging of the solid phase and biotinylated antigens.
      The false positive reactions were abolished by addition of 1% (v/v) bovine serum
      to the dilution buffer (DB). Human anti-bovine IgG antibodies (HABIA) were
      detected in 99 out of 104 sera from blood donors (50 females; 54 males). HABIA
      levels in male sera (n = 54) were positively correlated to the false positive
      signals in the PP14 ELISA (r = 0.923; p < 0.0001). Antibodies to IgG from other
      mammalian species (mouse, horse, and swine) were also detected in the donor sera,
      but levels and frequencies were lower compared to that of HABIA. Furthermore,
      HABIA were positively correlated to human anti-bovine serum albumin antibodies in
      the donor sera (r = 0.639; p < 0.0001; n = 103). HABIA (prevalence 95%) cause
      false positive reactions due to crossbinding of contaminating bovine IgG and/or
      crossreaction with mouse IgG in two-site immunoassays. The apparent presence of
      human anti-mouse IgG antibodies (HAMA), described to create false positive
      results, may be due to a crossreacting fraction of the polyclonal circulating
      antibodies against bovine IgG.

PMID- 15038613
TI  - Intra-assay total uncertainty of results in immunoassay techniques.
AB  - Uncertainty is a parameter associated with the result of a measurement; this
      parameter characterizes the dispersion of the values that could reasonably be
      attributed to the sample. Data processing methods do not take into account the
      influence of the imprecision and deviation of the experimental points of the
      calibration system and their impact on the final result of a sample analysis. The
      aim of this work is: (a) to propose, for each run, a simple method to calculate
      the uncertainty due to the calibration system (Uc); and (b) to present a method
      to determine the "intra-assay total uncertainty" (Ut) and evaluate its impact on
      the final result for an analyte. Ten replicates of standards, controls, and two
      serum-male and female samples were measured in the same run with a manual kit for
      determination of testosterone. To calculate Ut, random duplicate responses were
      selected. For controls and samples, Ut was affected by Uc (2.91% to 6.59%) and by
      the uncertainty of the measurement of the sample (Us) (1.01 to 8.73%); this
      allowed us to determine that Ut had values from 3.73% to 9.87%. While Us affects
      the result of a given sample, Uc affects the result of all the samples with a
      similar response (cpm). In the method proposed, Ut involves Us and Uc, both
      factors that introduce variations into the result of a sample by random causes.
      Intraassay total uncertainty includes the most probable result for the analytical
      methodology selected.

PMID- 15038615
TI  - Development of sandwich enzyme-linked immunosorbent assay for determination of
      tetanus toxoid concentration.
AB  - According to the recommendation of the World Health Organization (WHO), the use
      of an in vivo test for measuring of the potency of tetanus toxoid vaccine (TTdV)
      is still unavoidable, but the establishment of a convenient in vitro test would
      significantly improve the work in this field. A sandwich enzyme-linked
      immunosorbent assay (sELISA) was developed for a rapid and sensitive
      quantification of tetanus toxoid (TTd). We produced four monoclonal antibodies
      (MAbs) designated 41, 51, 62, and 71 that reacted with TTd and recognized
      different antigenic determinants on TTd. We also used two of these antibodies for
      developing a sELISA, with MoAb 71 as an immobilized and MoAb 51 as a capture
      antibody. The measurement range of this assay was from 31-1000 ng/mL and the
      minimum detection limit for TTd was 31 ng/mL. This high sensitivity of this
      sELISA and its good reproducibility suggest that the developed method could be
      reliably used to estimate the concentration of TTd, which could be easily
      extrapolated to the estimation of vaccine potency.

PMID- 15038616
TI  - Establishment and primary application of a highly-sensitive orexin-A
      radioimmunoassay.
AB  - Orexin-A was labeled by 125I using the chloramine-T method, and was purified with
      a Sephadex G-25 chromatographic column. The reaction between antigen and antibody
      was carried out by a one-step balance method and was incubated at 4 degrees C for
      24 hours, then bonded and free antigen were separated by PR reagent. The
      detection range of this RIA is 21-2000 pg/mL; the lowest detection level is 21
      pg/mL. The intra-assay and inter-assay variations were 7.8% and 9.7%,
      respectively. Plasma orexin-A levels of 30 normal individuals and 30 patients
      with hyperlipidemia (serum triglyceride > 1.7 mmol/L and serum total cholesterol
      > 5.7 mmol/L) were detected by this RIA, while orexin-A levels of plasma and
      hypothalamus in rat intestinal ischemia-reperfusion injury model were also
      measured. Plasma orexin-A levels of normal individuals was 338.48 +/- 20.24
      pg/mL, while those of patients with hyperlipidemia were 343.51 +/- 15.49 pg/mL;
      there were no significant differences between these two groups t = -0.1976; P =
      0.8441. We also found that orexin-A levels of rat plasma and hypothalamus did not
      express a significant change during the early stages of intestinal ischemia
      reperfusion injury. These results have shown that this orexin-A radioimmunoassay
      is stable, simple, and specific, being sensitive enough to test orexin-A levels
      in human plasma, rat plasma, and hypothalamus.

PMID- 15038611
TI  - Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative
      stress.
AB  - Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta
      (Abeta) peptides. Although the disease undoubtedly reflects the interaction of
      complex multifactorial processes, Abeta itself is toxic to neurons in vitro and
      the load of Abeta in vivo correlates well with the degree of cognitive
      impairment. There has therefore been considerable interest in the mechanism(s) of
      Abeta neurotoxicity. We here review the basic biology of Abeta processing and
      consider some of the major areas of focus of this research. It is clear that both
      AD and Abeta toxicity are characterized by oxidative stress, alterations in the
      activity of enzymes of intermediary metabolism, and mitochondrial dysfunction,
      especially impaired activity of cytochrome c oxidase. Studies in vitro also show
      alterations in cellular calcium signaling. We consider the mechanisms proposed to
      mediate cell injury and explore evidence to indicate which of these many changes
      in function are primary and which secondary.

PMID- 15038617
TI  - Determination of morphine by capillary zone electrophoresis immunoassay combined
      with laser-induced fluorescence detection.
AB  - A competitive immunoassay for detecting morphine in bio-samples was established
      by capillary zone electrophoresis combined with laser-induced fluorescence
      detection (CZE-LIF). The antigen of morphine was labeled with isothiocyano
      fluorescein (FITC) and then incubated with morphine monoclonal antibody and
      samples. The linear range was 50-1000 ng/mL, which was suitable for clinical and
      forensic applications. The detection limit can reach 40 ng/mL, based on S/N = 2.
      The recoveries of morphine from serum were satisfactory.

PMID- 15038618
TI  - Generation of a polyclonal antibody specifically against the p33(ING1b) tumor
      suppressor.
AB  - The p33(ING1b) tumor suppressor protein plays a prominent role in cellular stress
      responses including cell cycle arrest, DNA repair, apoptosis, and chromatin
      remodeling. As the main product of the inhibitor of growth 1 (ING1) gene,
      p33(ING1b) is the most intensively studied protein of the ING family. So far,
      most ING1 antibodies have been raised against full-length proteins. Since all
      ING1 isoforms share an identical carboxyl-terminus, and commercially available
      ING1 antibodies often lack specificity, we sought to develop a polyclonal
      antibody capable of specifically recognizing the p33(ING1b) protein. Here, we
      describe the development and characterization of the p33(ING1b)-specific
      antibody.

PMID- 15038619
TI  - A competitive ELISA for albumin in rat urine.
AB  - Nephropathy is characterized by urinary micro albumin. Rats are usually used in
      experimental studies. But, there was no specific and simple method for detecting
      rat urinary albumin. A specific, easily performed, and sensitive method for
      quantitatively determining rat urinary albumin is needed. Using rabbit anti-rat
      albumin polyclonal antibody, biotinylated goat anti-rabbit IgG, avidin conjugated
      peroxidase, and TMB (3,3',5,5'-tetramethylbenzidine) as substrate, a competitive
      ELISA for rat albumin in urine was developed. With this method, the urinary
      albumin in diabetic and normal rats was detected. This method was sensitive to 30
      ng/mL and reproducibly quantifies rat urinary albumin levels in the range of 0.05
      5 microg/mL. The rabbit anti-rat albumin polyclonal antibody showed no cross
      reaction with bovine and human serum albumins and rat IgG, and showed little
      cross-reaction with mouse albumin. The intra-assay CV was less than 10%. The
      urinary albumin markedly increased in diabetic rats. Since quantifying urinary
      albumin was very important in the experimental study of diabetic nephropathy, the
      results from our experiments indicated that this competitive ELISA could be used
      for quantification of rat urinary albumin.

PMID- 15038620
TI  - Production and characterization of anti-recombinant human erythropoietin (rhEPO)
      monoclonal antibody.
AB  - Anti-rhEPO McAb is valuable for the determination of recombinant human
      erythropoietin (rhEPO) levels for diagnosis of renal anemia and for doping
      control analysis. In this paper, anti-rhEPO hybridoma was prepared by fusion of
      SP2/0 murine myeloma cells with spleen cells isolated from immunized BALB/c
      mouse, using an enzyme-linked immunosorbent assay (ELISA) method to screen the
      positive hybridoma. The purified McAb was characterized by ELISA, SDS-PAGE, and
      Western-blotting. Experimental results showed that the subclass and the light
      chain of anti-rhEPO McAb was IgG1 and kappa light chain. The molecular weight of
      anti-rhEPO McAb was 166,000 Daltons. The affinity constant (K(aff)) of anti-rhEPO
      McAb with coated antigen was 5.0 x 10(5)L/mol.

PMID- 15038621
TI  - Strategies against high blood pressure in the early morning.
AB  - Acute myocardial infarction and cerebrovascular disease reportedly show peak
      onset in the early morning, when blood pressure increases. The increase of blood
      pressure, or morning surge, may result from increased sympathetic activity
      reactive to arousal. The circadian pattern of vascular events is considered to be
      related to the morning surge in blood pressure, sympathetic activity, and
      hypercoagulability. Although there is no direct evidence indicating a causal
      relationship between the morning surge in blood pressure and vascular
      complications, it may be postulated that morning blood pressure surge is a factor
      which affects hypertensive complications. There may be two possible approaches to
      morning blood pressure surge; the pharmacodynamic and pharmacokinetic approach.
      On the basis of pharmacodynamics, drugs with adrenergic alpha-blocking actions
      are usually selected. From a pharmacokinetic view, it is essential to maintain
      blood concentration of a drug at the critical early morning period. On this
      point, use of long acting agents, changes in drug regimen and the development of
      a chronobiological system has been studied, with many studies reporting
      successful results in lowering morning blood pressure. Further study whether such
      kinds of treatments improve long term outcomes in hypertensive patients are
      desired.

PMID- 15038622
TI  - Progress report on the HOMED-BP Study: hypertension objective treatment based on
      measurement by electrical devices of blood pressure study.
AB  - Hypertension Objective treatment based on Measurement by Electrical Devices of
      Blood Pressure Study (HOMED BP Study) is the first large-scale intervention trial
      in Japan using a Prospective Randomized Open Blinded Endpoint (PROBE) design to
      determine an optimal target blood pressure (BP) level on the basis of self
      measured BP at home, and an optimal initial course of antihypertensive
      medication. The registered patients are randomized to either a more intensive BP
      lowering group (home systolic BP < 125 mmHg and diastolic < 80 mmHg) or a less
      intensive group (home systolic/diastolic BP within the range 134-125/84-80 mmHg)
      by host computer via the Internet. The differential effect of three classes of
      initial antihypertensive regimens on the prognosis, i.e., calcium antagonist (Ca
      A), angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor
      antagonist (ARB), which are used most frequently in Japan, are examined. Three
      regimens are also randomly assigned to the host computer via the Internet. A
      pilot study was started in May 2001. In March 2002, the number of participating
      doctors was 461. At the end of March 2002, 546 patients were recruited. Of these,
      412 (202 men and 210 women, aged 58.4 +/- 10.2 y) were randomized. Patients will
      be recruited until February, 2006 and followed for 7 years.

PMID- 15038623
TI  - The effects of physical activity and autonomic nerve tone on the daily
      fluctuation of blood pressure.
AB  - The effects of daily activity and autonomic nerve tone on the fluctuation of
      ambulatory blood pressure were studied in hypertensive patients. The autonomic
      nerve tone was measured by frequency domain analysis of the RR interval. Physical
      activity was evaluated by a walk count, converted to a walk rate (WR), recorded
      using a digital Holter ECG fitted with an accelerometer, with simultaneous
      monitoring of blood pressure (Bp). Average values of the WR, H and L/H components
      were calculated for the 15 min. period just prior to Bp monitoring. The
      relationship between the average WR, H and L/H values and the Bp was determined
      by a linear regression analysis. Hypertension was classified into three types,
      autonomic nerve dominant (AN), exercise dominant (EX), and irregular (IR), based
      on a high correlation coefficient between Bp and either H or L/H (AN type),
      between Bp and WR (EX type), or no significant correlation between Bp and any of
      the parameters (IR type). Of the thirty hypertensive patients studied 11 were
      classified as AN, 12 as EX, and 7 as IR. Patients of the EX type had
      significantly lower Bp than patients in the other two classes. Furthermore, all
      of the IR type patients showed non-dipper type hypertension, suggesting that the
      Bp regulation mechanisms were impaired. The results suggest the significance of
      simultaneous monitoring of physical activity and autonomic nerve function at the
      time of Bp monitoring.

PMID- 15038624
TI  - Cardiac autonomic balance and QT dispersion during head-up tilt testing in
      diabetics with and without sensory neuropathy.
AB  - BACKGROUND: Cardiovascular autonomic dysfunction is associated with higher
      mortality in diabetics. However, detection methods of early cardiac diabetic
      dysautonomia, and its correlation with severity of sensory neuropathy, have not
      been described. METHODS: We analyzed the heart rate variability (HRV) by spectral
      analysis and QT dispersion in 23 diabetics with and without sensory neuropathy,
      and in 5 age-matched controls, in the supine position and during head-up tilt
      testing (HUT). Diabetics were divided into 3 groups according to the degree of
      sensory neuropathy. RESULTS: In the spectral analysis of HRV, the high frequency
      components in the supine position decreased as a function of severity of the
      neuropathy. High frequency in diabetics was significantly decreased in the supine
      position, even in absence of sensory neuropathy. The low/high frequency ratio
      (L/H) in the supine position was similar among controls and the 3 patient groups.
      L/H in diabetics with moderate or severe neuropathy did not increase from the
      supine to the upright position. Baseline QT dispersion increased proportionally
      to the severity of sensory neuropathy and, in patients without apparent sensory
      neuropathy, QT dispersion increased significantly during HUT. CONCLUSIONS: The
      spectral analysis of HRV and measurements of QT dispersion, before and during
      HUT, were reliable detection methods of early abnormalities in autonomic balance
      and may predict a risk of sudden cardiac death in diabetics.

PMID- 15038625
TI  - Relationships between diurnal blood pressure variation, physical activity, and
      health-related QOL.
AB  - The aim of this study is to clarify the associations between diurnal blood
      pressure variation, physical activity and health-related quality of life (HRQOL).
      Ninety-seven volunteers, including 52 hypertensive patients and 45 healthy
      subjects (average age, 48 years) participated in this study. Twenty-four hour
      ambulatory blood pressure and heart rate variability were measured using TM2425
      (A&D Co). Physical activity was measured using actigraphy, and HRQOL was assessed
      by a Medical Outcome Study Short-Forum 36-Item Health Survey (SF-36). Awake mean
      physical activity positively correlated with the nocturnal dip in systolic blood
      pressure (SBP) (r = 0.242, p < 0.02) and diastolic blood pressure (DBP) (r =
      0.219, p < 0.04). The score of physical functioning positively correlated with
      awake mean physical activity (r = 0.265, p < 0.02). The score of role-emotional
      also correlated with awake mean physical activity (r = 0.269, p = 0.01). Using
      multiple regression analysis, the nocturnal dip in SBP was found to be correlated
      with awake and sleep mean physical activities (p < 0.05, p < 0.05, respectively).
      In conclusion, physical activity is associated with the nocturnal dip in blood
      pressure. Moreover, physical activity correlates with some of the factors of
      HRQOL.

PMID- 15038626
TI  - The mean pulse rate pressure (mPRP) is an accurate parameter to assist in the
      efficacy of management of cerebrovascular disease cases with hypertension.
AB  - 1121 cases of patients with cerebrovascular disease (CVD) and non-CVD (NCVD) were
      evaluated by sex and age groups for the clinical differences between mean
      arterial blood pressure (MAP) and it's double product, mean pulse rate pressure
      (mPRP = MAP x pulse rate). Two treatment arms were also compared. One group were
      given antihypertensive agent therapy (AHA), while the others were given lifestyle
      modification (LSM). In the AHA group, the mean values of blood pressure upper
      limit (UL) calculated by MAP and the UL and lower limit (LL) calculated by the
      mPRP in the females and older (> or = 60 years) age groups were significantly
      lower compared to those in the LSM arm of therapy. The same results were found in
      the UL calculated by mPRP in males and the younger (< 60 years) age group. The
      threshold indexes (TI) calculated by MAP and mPRP were never below 1.4 and 2.0
      respectively. We conclude that in managing patients suffering from CVD with
      hypertension, the mPRP produced more detailed information in comparison to the
      MAP.

PMID- 15038627
TI  - Determination of baroreceptor-stroke volume reflex sensitivity by power spectral
      analysis: a quantitative probe of baroreceptor-cardiac reflex.
AB  - Baroreceptor-cardiac reflex, which consists of baroreceptor-induced chronotropic
      and inotropic actions, is a very useful index of cardiac sympathovagal balance.
      Baroreceptor-heart rate reflex sensitivity, which reflects baroreceptor-induced
      chronotropic action, has been used as a marker of baroreceptor-cardiac reflex.
      However, it cannot be used in patients with chronotropic incompetence and/or
      implanted cardiac pacemaker. We hypothesized that baroreceptor-stroke volume (SV)
      reflex sensitivity, which reflects baroreceptor-induced inotropic action, may
      also be a useful method for measurement of baroreceptor-cardiac reflex, similar
      to the baroreceptor-heart rate reflex sensitivity. To test this hypothesis, we
      measured baroreceptor-SV reflex sensitivity expressed as ratio of low frequency
      (LF) power to total power of SV fluctuation (LF/TP(SV): %/mmHg) by spectral
      analysis of mean blood pressure and SV fluctuations, the gain in low-frequency
      band between two signals in supine and 60 degrees upright positions, and compared
      these values to baroreceptor-heart rate reflex sensitivity in 14 healthy
      subjects. Baroreceptor-SV reflex sensitivity correlated significantly with
      baroreceptor-heart rate reflex sensitivity (r = 0.73, p < 0.0001). In addition,
      baroreceptor-SV reflex sensitivity correlated significantly and positively with
      high frequency (HF) power (r = 0.57, p < 0.005) and negatively with LF/HF ratio
      (r = -0.57, p < 0.005) in power spectral analysis of R-R interval variability.
      Moreover, baroreceptor-SV reflex sensitivity in LF/TP(SV) correlated positively
      with the R-R interval (r = 0.70, p < 0.0001) and negatively with diastolic blood
      pressure (r = -0.50, p < 0.01). We conclude that baroreceptor-SV reflex
      sensitivity in LF/TP(SV) can be used as a quantitative probe of baroreceptor
      cardiac reflex, similar to the baroreceptor-heart rate reflex sensitivity in
      healthy subjects, and it may enable us to estimate inotropic aspect in
      baroreceptor-cardiac reflex in patients with chronotropic incompetence and/or
      implanted pacemaker.

PMID- 15038628
TI  - Risers and extreme-dippers of nocturnal blood pressure in hypertension:
      antihypertensive strategy for nocturnal blood pressure.
AB  - There is increasing evidence that disruption of diurnal blood pressure (BP)
      variation is a risk factor for hypertensive target organ damage and
      cardiovascular events. Especially, the risers (extreme non-dippers), who exhibit
      a nocturnal BP increase compared with daytime BP, have the worst cardiovascular
      prognosis, both for stroke and cardiac events. On the other hand, extreme-dippers
      (with marked nocturnal BP falls) are at risk for non-fatal ischemic stroke and
      silent myocardial ischemia, particularly extreme-dippers complicated with
      atherosclerotic arterial stenosis and excessive BP reduction due to
      antihypertensive medication. Extreme-dipping status of nocturnal BP is closely
      associated with excessive morning BP surge and orthostatic hypertension.
      Hypertensive patients who have these conditions and exhibit marked BP variations
      are likely to have silent cerebral infarct and to be at high-risk with regard to
      future stroke. Individualized antihypertensive medication targeting disrupted
      diurnal BP variation might thus be beneficial for such high-risk hypertensive
      patients.

PMID- 15038629
TI  - Dental licensure exams: human subjects and one-shot evaluations.

PMID- 15038631
TI  - Dental students with Hepatitis B: issues to be considered when defining policies.
AB  - Carriers of the Hepatitis B virus represent a significant proportion of the
      world's population. Since the existing policies on how to manage infected dental
      students lack clarity, the issues related to Hepatitis B and a set of
      recommendations for the adoption of a new policy will be presented here. After
      considering the virology, epidemiology, prevention, and treatment of Hepatitis B,
      the current health management policies will be reviewed, and ethical
      considerations, including the issue of disclosure, will be explored. The
      recommendations presented here for a new Canadian policy on infected health care
      workers include universal immunization, assessment of infectivity by measuring
      Hepatitis B DNA levels, and disclosure to patients on the basis of scientific
      evidence. These recommendations are intended to aid Canadian dental schools, and
      dental schools in other nations, with students who are carriers of Hepatitis B.

PMID- 15038630
TI  - If only we all cared.

PMID- 15038632
TI  - Issues to consider when planning and conducting educational research.
AB  - This article is intended to provide students and clinicians aspiring to perform
      educational research with some background information pertaining to many of the
      issues inherent in performing research within this domain. It is not intended to
      provide a comprehensive review of the quantitative methods one might adopt, nor
      will it fully reflect all of the debate that currently exists within the
      educational research community. Rather, it is intended to offer an overview of
      issues and controversies within the field that will hopefully provide a starting
      point from which interested individuals can begin to engage in the study of
      educational effectiveness. Using investigations of the efficacy of problem-based
      learning as background, the article represents an attempt to guide new
      researchers through the process of generating and refining scientific research
      questions, identifying appropriate outcome measures, and selecting or adapting
      the optimal research design for the questions to be addressed. The article
      focuses on quantitative methods in general with particular attention paid to
      experimental designs.

PMID- 15038633
TI  - Mentorship: a critical component for professional growth and academic success.
AB  - Faculty in a twenty-first century school of dentistry face a variety of daily
      challenges. Balancing teaching, research, and scholarship can be an overwhelming
      task for junior faculty and is influenced by the environment and the interactions
      we have with colleagues. Effective mentorship can play a critical role in
      professional growth and development as well as academic success. Excellent
      mentors provide a distinct vision and can guide their proteges to achieve the
      goals associated with these visions. Current literature supports the definitive
      characteristics that potential proteges and effective mentors exhibit and
      delineates how mentoring can enhance productivity, efficiency, and motivation.
      There is also evidence that formal mentoring programs have an overall positive
      impact on junior faculty and may assist in retention of dental school faculty.
      Successful mentors take proteges under their wings for guidance, inspiration, and
      encouragement and in the process create motivated, productive, and successful
      teachers and researchers, thus leaving a legacy. The purpose of this paper is to
      review the literature regarding the importance and benefits of excellent
      mentorship.

PMID- 15038634
TI  - The current status of allied dental faculty: a survey report.
AB  - Allied dental program directors have expressed increasing concerns about possible
      current and future shortages of allied dental educators. As a result, the ADEA
      Board of Directors created a task force to investigate the current status of
      allied dental faculty, including the degree of cultural diversity, and to
      identify whether current and/or potential future shortages of educators exist. A
      survey was sent to all accredited allied dental program directors. Results
      indicated that a current faculty shortage exists for dental assisting and dental
      hygiene programs, with a projected greater future shortage for all allied dental
      education disciplines, primarily as a result of retirement of current faculty
      members. The data collected also revealed a lack of diversity in allied dental
      faculties, especially in dental hygiene and dental assisting programs.
      Recommendations for action steps included investigating: 1) the use of technology
      to provide the faculty expertise necessary to allow more affordable quality
      education in almost any location and to maximize available resources; 2)
      alternative ways to reward faculty; 3) loan forgiveness as an incentive for
      exemplary graduates to pursue educational career goals; 4) an ongoing database to
      monitor the status of allied dental educators; and 5) best practices in higher
      education to attract a more diverse student body and faculty in terms of gender,
      ethnicity, and race.

PMID- 15038635
TI  - The aging and diminishing dental faculty.
AB  - A dire need for additional dental educators is emerging. This article reflects on
      the heavily skewed age groups of our current dental educators and the lack of
      sufficient new faculty to undertake the tasks of faculty members. A literature
      review is presented of previous studies monitoring the current demographics of
      dental faculty, projected trends, and factors that influence an individual's
      career choices concerning dental education involvement. Both intrinsic and
      extrinsic factors are explored to offer potential avenues for interesting,
      recruiting, and retaining qualified individuals as dental faculty. The goal of
      this article is to stimulate thought-provoking discussions and/or solutions
      within academic dentistry in regard to the question: Who will be our dental
      school faculty in the next decade?

PMID- 15038636
TI  - Students' perceived importance of diversity exposure and training in dental
      education.
AB  - Intercultural competence is an important component of the doctor-patient
      relationship in the multicultural climate evolving in the United States. We
      hypothesized that 1) exposure to racial and ethnic diversity in the student body,
      faculty, staff, and patient population in dental school and 2) a dental school
      curriculum that includes presentations on issues concerning racial and ethnic
      diversity will contribute to students' feeling more competent and confident to
      enter the multicultural work environment that is rapidly developing in the United
      States. A Likert-type scale questionnaire was administered to 627 fourth-year
      dental students enrolled in seven dental schools representing geographically
      diverse regions of the United States. Of these, 376 questionnaires were returned
      for a response rate of 60 percent. Results indicated that both the perception of
      diversity in the school environment and the presentation of diversity-specific
      content in the curriculum had moderately positive and significant correlations
      with the students' perception of their competency or ability to serve and work
      with diverse populations. The respective Pearson correlation coefficients for
      diversity in the school environment and diversity curriculum were .497 (p<.001)
      and .459 (p<.001). These results support the hypotheses that diversity exposure
      and training in the dental school environment are important for dental students
      entering a multicultural workplace.

PMID- 15038637
TI  - Development and evaluation of an interactive tobacco cessation CD-ROM educational
      program for dental students.
AB  - Dentists and dental hygienists can be effective in providing advice and brief
      counseling to tobacco-using patients. However, lack of training in effective
      interventions is a barrier to incorporating tobacco cessation interventions into
      routine practice. After we developed and evaluated an interactive CD-ROM tobacco
      cessation training program, we evaluated the effect of using the program on the
      knowledge level and attitudes of forty-seven third-year dental students and
      thirty dental hygiene students and also obtained their opinions of program
      quality and utility. Significant change was observed from pre- to post
      intervention (t (46) = -11.62, p <.001; Cohen's d = 1.36). Program use was
      strongly related to change in the measure of tobacco cessation knowledge,
      attitudes, and beliefs (semi-partial r = .57, p <.001). In addition, participants
      rated the program highly on measures of satisfaction. The results of our
      evaluation provide strong support for the efficacy of the program with dental and
      dental hygiene students. An interactive educational program such as the one
      reported herein could be a useful tool for enabling dental professionals to
      obtain the skills necessary to help their patients quit using tobacco.

PMID- 15038638
TI  - A comparison of health professions student attitudes regarding tobacco curricula
      and interventionist roles.
AB  - Health care providers who feel prepared are more apt to assume tobacco
      interventionist roles; therefore, educational preparation is critical. A
      nonprobability sample of health professions students at an urban academic health
      center were asked to respond to a twenty-two-item survey eliciting demographic,
      behavioral, and tobacco-related attitudinal information. Frequency distributions
      were assessed with Pearson chi-square statistics. The overall response rate was
      76.7 percent, and final sample size was 319. Current use of spit tobacco (ST) was
      2.5 percent and current smoking 5.6 percent. In comparing current smokers to
      nonsmokers and current ST users to nonusers, we found that no differences in
      proportion agreeing with any of the five questions about attitudes and opinions
      were statistically significant at p-value 0.05. At least 70 percent of students
      from each of six health professions programs agreed it was their professional
      responsibility to help smokers quit, and at least 65 percent agreed to the same
      responsibility for helping ST users quit. The proportion agreeing that their
      programs had course content describing their role in helping patients quit
      tobacco use varied widely by program from 100 percent agreement among dental
      hygiene and pharmacy students to 14.6 percent of physical therapy students (p
      value <0.001). When asked whether their program adequately prepared them to help
      smokers quit, agreement ranged from 100 percent among dental hygiene students to
      only 5.5 percent among physical therapy students (p-value <0.001). Almost 90
      percent of dental hygiene students agreed that they were adequately trained to
      help ST users quit, but no other program had a percentage of agreement above 34
      percent (p-value <0.001). Consistent and comprehensive multidisciplinary tobacco
      related curricula could offer desirable standardization.

PMID- 15038639
TI  - A preliminary study in using virtual reality to train dental students.
AB  - This study compared virtual reality simulator-enhanced training with laboratory
      only practice on the development of dental technical skills. Sixty-eight students
      were randomly assigned to practice their skills in either a traditional
      preclinical dentistry laboratory or in combination with a virtual reality
      simulator. The results indicate that students who trained with the virtual
      reality simulator between six and ten hours improved significantly more than did
      the students in the control group from the first examination of the year to the
      final examination of the year. These results indicate that the use of virtual
      reality simulators holds promise for the training of future dentists. Additional
      research is necessary to determine the ideal implementation of virtual reality
      simulators into traditional dentistry curricula.

PMID- 15038640
TI  - Effect of magnification lenses on student operator posture.
AB  - A distinct body of literature supports the association between clinical postures
      of the dental practitioner and work-related musculoskeletal disorders (WRMD).
      Several aids or devices have been tested to improve clinical posture in the
      interest of decreasing WRMD. The use of magnification lenses while performing
      dental procedures may increase the quality of work and decrease the likelihood of
      musculoskeletal problems. To date, only anecdotal and personal opinions had
      existed regarding the benefits of using magnification lenses, and no empirical
      evidence had authenticated the contention that use of magnification lenses exerts
      a positive change in operator posture. The objective of this study was to assess
      the effect magnification lenses had on the posture of dental hygiene students.
      Using a randomized crossover design, researchers videotaped nineteen senior
      dental hygiene students performing an intra-oral procedure with and without the
      use of magnification lenses. The tapes were then evaluated by a panel of five
      dental hygiene educators calibrated in the use of Branson's Posture Assessment
      Instrument (PAI). Results of a paired t-test indicate that the posture of the
      students while wearing magnification lenses was more acceptable (p=.019) than
      when wearing traditional safety glasses. Results of this study indicate a
      quantifiable change in acceptability of posture for clinicians wearing
      magnification lenses and suggest that the use of such lenses in dental education
      may be warranted.

PMID- 15038641
TI  - Report of the ADEA President's Commission on Mentoring.

PMID- 15038642
TI  - [Treatment of biliary lithiasis with the advent of new technologies in Italy in
      the Lazio and Abruzzo regions over the past 15 years. Comparison between the
      patient series in a Roman university hospital and in a number of hospitals in the
      Abruzzo region].
AB  - Biliary lithiasis is a disease with a high incidence in the western world and a
      high social cost. To evaluate the impact of new technologies--mainly laparoscopic
      cholecystectomy and radiological and endoscopic techniques--in the treatment of
      biliary lithiasis, a statistical study was conducted on the surgical
      interventions performed over the past 15 years in Italy in the Lazio and Abruzzo
      regions. From 1985 to 1999, 150,000 cases of hepatobiliary lithiasis were
      hospitalized every year in Italy with a mean hospital stay of 7.8 days (13,000 in
      Lazio and 6,000 in Abruzzo). 100,000 cholecystectomies were performed every year
      in Italy in public hospitals, 30% of which by conventional laparotomy and 70%
      laparoscopically. Ten percent of these operations on average were performed in
      the Lazio region and 3% in the Abruzzo region. 10,615 cases of main bile duct
      stones were treated in 1999, 6,502 of which by ERCP and the others with open
      procedures and radiologically. The mortality was 0-0.1% for laparoscopic
      cholecystectomy as against 0-0.5% in open procedures.

PMID- 15038643
TI  - [Indications and results of the first 100 liver resections in Bolzano].
AB  - The aim of the study was to report on a survey of 100 liver resections performed
      over an 8-year period. Seventy-four patients underwent surgery for primary or
      secondary liver tumours, 15 for benign diseases, and 11 for traumas. The overall
      operative mortality rate was 3.0%, while the operative mortality rate in elective
      resections was 2.3%. Five-year survival was 22% for colorectal metastases and 25%
      for hepatocarcinomas. The expanding role of liver surgery in the treatment of
      hepato-biliary diseases is emphasized and the importance of anatomical surgery,
      guided by intraoperative ultrasonography, with limited blood loss and
      transfusion, is stressed.

PMID- 15038644
TI  - Cancer of the rectum: comparison of two different surgical approaches.
AB  - Surgical treatment of rectal cancer is still controversial as regards the type of
      operation and the extent of lymphadenectomy. Four hundred and fifty-eight
      patients with rectal cancer operated on at two different hospitals (206 patients,
      Surgical Department, S. Martino General Hospital and 252 patients, Surgical
      Department, Galliera General Hospital) in the decade 1980-1989 were studied. None
      of the patients were submitted to adjuvant or neoadjuvant therapy. The operations
      opted for were anterior resection for carcinoma of the upper rectum, anterior
      resection or abdominoperineal resection for carcinoma of the middle rectum, and
      abdominoperineal resection for lower rectal cancer. At the S. Martino General
      Hospital, anterior resection comprised ligation of the inferior mesenteric artery
      at its origin, with subsequent preaortic lymphadenectomy. In abdominoperineal
      resection, the pelvis was left open and was closed later. At the Galliera General
      Hospital, preaortic lymph node dissection was not performed, and abdominoperineal
      resection comprised a one-stage pelvic floor closure. Survival was no different
      in the two patient populations. Extended lymphadenectomy was of no benefit in
      terms of survival in operated rectal cancer patients. Abdominoperineal resection
      may still be useful for selected patients.

PMID- 15038645
TI  - [Conventional colonoscopy versus chromoendoscopy and magnifying endoscopy for the
      diagnosis of colorectal lesions: a comparative prospective study in 995
      patients].
AB  - Early endoscopic diagnosis of colorectal cancers is the best tool for the
      reduction of colorectal cancer mortality, but conventional colonoscopy seems
      unable to detect minor changes in the colorectal mucosa. The authors compare the
      results of conventional colonoscopy and chromoendoscopy plus magnifying endoscopy
      for the detection of colorectal lesions. This prospective study evaluated 995
      consecutive selected patients. All patients with a previous diagnosis of
      colorectal polyps, inflammatory bowel disease, history of colorectal surgery,
      high coagulative risk or poor bowel preparation were excluded from the study. All
      examinations were performed by a single endoscopist. The authors compared the
      results of conventional endoscopy and chromoendoscopy with a 0.4% indigo carmine
      solution and magnifying endoscopy. At the end of each examination, data from
      ordinary and dye-spraying views were carefully recorded. A total of 202
      protruding, 99 flat and 5 depressed lesions were detected. The incidence of high
      grade dysplasia and early carcinoma was 9.9% for protruding lesions, 13.1% for
      flat lesions and 60% for depressed lesions. Chromoendoscopy revealed new
      neoplastic patterns not detectable at conventional endoscopy in 127 patients.
      This prospective study shows the high accuracy rate of chromoendoscopy for the
      detection of non-polypoid lesions. Chromoendoscopy could be used as a routine
      procedure in order to enhance the early diagnosis of colorectal cancers.

PMID- 15038646
TI  - Rare surgical complications of Crohn's disease. Clinical and therapeutic
      considerations.
AB  - We present our clinical experience in the management of rare surgical
      complications in Crohn's disease. Two hundred and eight patients affected by
      Crohn's disease were treated surgically between January 1992 and September 2001,
      at the Department of Surgical and Gastroenterological Sciences of the University
      of Padua. Rare surgical complications were identified in 17 patients (6.2%): 4
      with small intestine adenocarcinoma, 5 with massive gastrointestinal bleeding, 5
      with free peritoneal perforation and 3 with psoas abscesses. The very substantial
      clinical variability of Crohn's disease is a constant challenge to researchers.
      In particular, the high incidence of associated pathologies and complications
      related to Crohn's disease makes this pathology extremely disabling. In addition,
      this disease quite often appears to occur together with a rare complication
      which, though in most cases its course tends to remain unknown, at times may be
      potentially life-threatening. For this reason, it is crucial to suspect the
      occurrence of these pathologies, especially in patients responding poorly to
      therapy or in those whose symptoms suddenly become acute. Early diagnosis and
      treatment are therefore fundamental for the most appropriate treatment to be
      administered.

PMID- 15038647
TI  - [Indications and efficacy of parathyroidectomy in the treatment of secondary
      hyperparathyroidism in patients with chronic renal failure: our experience].
AB  - Although secondary hyperparathyroidism is improved by pharmacological therapy; 10
      30% of patients with chronic renal failure undergo parathyroidectomy. The authors
      report on their experience with 66 cases of secondary hyperparathyroidism
      surgically treated over the period from January 1991 to December 2002. The
      surgical indications included: persistent hypercalcaemia, osteodystrophy with
      bone fractures, joint pain, itching and ectopic calcifications. The median
      preoperative parathyroid hormone level was 400 pg/ml. The operations performed
      were: subtotal parathyroidectomy (PTX 7/8) in 43 cases; total parathyroidectomy
      with autotransplantation (PTXt + At) in 13 cases; total parathyroidectomy (PTXt)
      alone in 6 cases and incomplete parathyroidectomy (PTXi) in 4 cases. The
      immediate results were satisfactory in each group. Calcium levels reverted to
      normal 24-48 hours postoperatively in 37 patients with PTX 7/8, in 11 patients
      with PTXt + At, in 5 patients with PTXt; 4 patients with PTXi showed a reduction,
      but no normalization, of calcium levels. Almost all patients, except those
      undergoing PTXi, showed an acceptable reduction in PTH levels in 25-35 days.
      Secondary hyperparathyroidism relapsed in 3 cases with PTXt + At and in 2 cases
      with PTX 7/8, while it proved persistent in 50% of patients with PTXi and in 7%
      of patients with PTX 7/8. Patients with PTXt mainly showed a substantial
      reduction of calcium levels. Parathyroidectomy is indispensable for the treatment
      of secondary hyper-parathyroidism. In our opinion, PTX 7/8 is the surgical
      treatment of choice because it is the easiest technique to perform and has the
      lowest relapse rate.

PMID- 15038648
TI  - [Thoracic outlet syndrome: clinical staging].
AB  - The clinical and instrumental manifestations of thoracic outlet syndrome are well
      known but the therapeutic choices frequently differ in relation to the
      physician's experience. Thus, there is no univocal opinion regarding the therapy
      of this complex syndrome. To solve this problem we have attempted to bring
      together the clinical and instrumental pictures in a single classification that
      includes the three fundamental aspects of the syndrome, namely nerve, artery and
      vein injury (NAV). Our goal was to achieve a universally accepted therapy
      oriented staging system, as is the case with the TNM system for malignant
      tumours. From 1984 to 2002, in our institution 156 patients with thoracic outlet
      syndrome were evaluated. These were grouped in 4 stages depending on their NAV
      status. Subsequent therapy was in accordance with stage. Our results confirmed
      the accuracy of NAV. On the basis of our preliminary experience, the NAV staging
      system is useful for correct patient grouping. Now a prospective multicentre
      study is needed for universal scientific validation.

PMID- 15038649
TI  - Cushing's syndrome induced by bronchopulmonary carcinoid tumours: a review of 98
      cases and our experience of two cases.
AB  - Bronchopulmonary carcinoids are one of the most common cause of ectopic secretion
      of corticotropin (ACTH) and account for approximately 1% of all the patients in
      whom Cushing's syndrome develops. We reviewed 98 cases described in the World
      Literature and we report on two new cases. A 60-year old woman affected by
      Cushing's syndrome underwent to surgical wedge resection of a peripheral
      pulmonary nodule and a 30-year old woman with similar clinical features underwent
      to middle lobectomy for a small hilar neoplasm. Histopathologic examination of
      the tumours defined them as typical bronchopulmonary carcinoids. The patients are
      asymptomatic and with no sign of recurrence 72 and 30 months after surgery.
      According to our review we found no clear evidence that bronchial carcinoids
      associated with Cushing's syndrome should be considered a more aggressive variant
      or subtype of the typical carcinoid. If Cushing's syndrome does not disappear
      after surgery, the presence of residual disease (often a nodal involvement)
      should be investigated. A long-term relapse of the syndrome requires a careful
      search for local or distant neoplastic recurrence.

PMID- 15038651
TI  - Laparoscopic cholecystectomy with three trocars: 10 years experience.
AB  - Since 1992 we have performed laparoscopic cholecystectomy with 3 trocars (10, 10
      and 5 mm) while most surgeons use 4. In our 10 years of experience a total of
      1,243 cholecystectomies have been performed with the 3-trocar technique. The
      overall conversion rate is 0.75%. In 5.7% of cases we used a fourth trocar in
      order to avoid anatomical difficulties or to perform intraoperative
      cholangiography. All interventions are technically feasible, even in sclerotic
      cholecystitis and in emergency operations. We describe this technique which can
      be considered an economic and cosmetically satisfying alternative, that is safe
      and effective for the patient and easy to perform for the surgeon.

PMID- 15038650
TI  - ["Low-pressure" laparoscopic cholecystectomy in high risk patients (ASA III and
      IV): our experience].
AB  - The insufflation pressure used for laparoscopic cholecystectomy is usually 12-15
      mm Hg, and a pneumoperitoneum with carbon dioxide has a significant effect on
      both cardiovascular and respiratory function. These effects are transient in
      young, healthy patients, but may be dangerous in ASA III and IV patients with a
      poor cardiac reserve. This study was designed to assess the feasibility of
      performing laparoscopic cholecystectomy at 6.5-8 mm Hg insufflation pressure in
      "high-risk" patients. Thirteen patients, 10 ASA III and 3 ASA IV, with
      cholelithiasis, were included in this study The insufflation pressure was 6.5-8
      mm Hg, with a 10 degrees anti-Trendelenburg position. The cardiovascular and
      blood gas variables studied were: mean arterial blood pressure, heart rate,
      respiratory rate, and end-tidal CO2 pressure. The authors reported no conversions
      and no intra- or postoperative complications. During insufflation heart rate and
      mean arterial blood pressure increased minimally if compared with laparoscopic
      cholecystectomy at 12-15 mm Hg. Pa CO2 increased after insufflation (+5 mm Hg),
      and the end-tidal CO2 pressure gradient was moderate (3.5 mm Hg) and unchanged
      during surgery. A low-pressure pneumoperitoneum is feasible for laparoscopic
      cholecystectomy and minimizes the adverse haemodynamic effects of peritoneal
      insufflation.

PMID- 15038652
TI  - [Ergonomic and cosmetic aspects of laparoscopic appendectomy: personal
      technique].
AB  - We analyzed our case series in order to evaluate the evolution of our
      laparoscopic technique in ergonomic and cosmetic terms, leading to the right
      compromise between these aspects. We retrospectively analyzed 136 diagnostic
      laparoscopies for suspected appendicitis, using scheme A in the first 98 cases
      (one 10/12-mm umbilical trocar for the optics and two 5-mm operative trocars
      placed above the pubis on the right and left side) and scheme B in the other 38
      cases (one 10/12-mm umbilical trocar for the optics and two 5-mm operative
      trocars, one placed over the pubis and the other one on the right hip, just on
      the umbilical line). The diagnosis of appendicitis was confirmed in 117 patients,
      while other diseases were present in 19 patients. There were no differences
      between the two groups in mean operative time (45 min), postoperative
      complications (0.7%) and clinical course (hospital stay: 36 hours on average). We
      believe that the right compromise between ergonomic and cosmetic considerations
      is the one shown in scheme B. In this way it is possible to perform all
      diagnostic and therapeutic manoeuvres such as pulling the appendix out through
      the umbilical trocar and using suprapubic trocars as an access route for a
      possible drainage.

PMID- 15038653
TI  - Laparoscopic colorrhaphy, irrigation and drainage in the treatment of complicated
      acute diverticulitis: initial experience.
AB  - The natural history of diverticulosis is worthy of note for its acute, sometimes
      recurrent, attacks of diverticulitis and the significant risk of serious
      complications, such as abscess, fistula and peritonitis. Most mild attacks of
      diverticulitis respond well to medical therapy while surgical treatment is
      indicated in the complicated forms of the disease. We evaluate the results of
      treatment of complicated acute diverticulitis by laparoscopic colorrhaphy,
      irrigation and drainage as a minimal surgical approach in 7 selected patients. We
      retrospectively analyzed all patients admitted to our institute for acute
      diverticulitis from 1996 to 2001. One hundred and thirty-five patients were
      admitted for acute sigmoid diverticulitis. Ninety-eight patients (72%) had their
      diverticular disease completely resolved after medical therapy, while 37 (28%)
      required a surgical approach. Seven patients underwent a laparoscopic colorrhaphy
      with irrigation and drainage. Laparoscopic procedures were completed in 6
      patients. No perioperative morbidity or mortality was observed. All patients were
      discharged with no further re-operation. The technique could be considered a
      valid alternative for the management of complicated and perforated diverticulitis
      in selected patients.

PMID- 15038655
TI  - [Sentinel lymph-node biopsy in breast cancer: five years' experience].
AB  - The authors report on their experience with sentinel lymph-node biopsy in breast
      cancer. Sentinel lymph-node biopsy was performed in 91 patients with T1-T2 N0 M0
      breast cancer using radiocolloid (99mTC radiolabelled colloidal human albumin
      microaggregate) injected perilesionally in 56 cases and by Blu Patent V alone in
      35 cases. The sentinel lymph nodes identified were located in the axilla in 88
      cases, in the internal mammary nodes in 2 cases and in a subclavicular site in 1
      case. The histological examination was negative in 62 cases and positive in 29;
      Axillary lymph-node dissection was carried out in node-positive cases. No
      recurrences were observed in any of the cases treated. Lymphatic mapping and
      sentinel lymphadenectomy in primary breast cancer is now a feasible and useful
      method of avoiding routine axillary lymphadenectomy. However, the role of micro-
      or macrometastases in sentinel lymph nodes and the significance of identification
      of tumour mRNA have yet to be defined.

PMID- 15038654
TI  - Role of transperineal Doppler and ultrasound in evaluating anal sphincter injury
      after stapled haemorrhoidopexy.
AB  - The stapler treatment first described by Longo is considered by some authors to
      be a good technical solution for mucohaemorrhoidectomy. The aim of the present
      prospective study was to assess the function and morphology of the internal and
      external anal sphincters preoperatively and one month after surgery by means of a
      clinical examination, anorectal manometry and transperineal ultrasound. Ten
      patients (6 M, 4 F) underwent rectal mucosal prolapsectomy according to Longo.
      Anoscopy, anorectal manometry and transperineal ultrasound were performed in all
      patients preoperatively and again one month after surgery. The thickness and
      integrity of the internal and external anal sphincters were ascertained and
      colour Doppler was performed to assess the presence, quantity and size of any
      haemorrhoid swellings. All anatomical specimens underwent histological
      examination in search of smooth muscle fibres. Anorectal manometry revealed no
      postoperative sphincter tone defects. Transperineal ultrasound detected no
      postoperative sphincter lesions and the presence of venous swellings (always
      present at preoperative colour Doppler) never persisted at postoperative follow
      up. The mean follow-up was 52.7 days (range: 31-151). Transperineal ultrasound
      proved useful in demonstrating the lifting of the mucohaemorrhoid prolapse within
      the ampulla of the rectum one month after surgery. The Longo procedure, in our
      albeit limited experience, caused no sphincter lesions.

PMID- 15038656
TI  - [Evaluation of complications and long-term results after surgery for
      gynaecomastia].
AB  - In an attempt to evaluate ten years of surgical treatment of gynaecomastia, we
      analysed the incidence of complications and the quality of the results in a group
      of patients classified according to Simon. Over the decade 1992-2002, 107
      patients with gynaecomastia aged from 17 to 79 years were treated. The prevalent
      surgical approach was subcutaneous mastectomy. In 71 patients the surgical
      approach was via a periareolar inferior incision, superior in 15, inferior with
      bilateral extensions in 10; using a complete circumareolar approach (according to
      Padron) in 8 patients and a subcutaneous transareolar mastectomy in 3. No
      immediate complications were observed. Ten patients presented a modest
      postoperative haematoma. Only in one diabetic patient with chronic bronchitis and
      grade III gynaecomastia did partial dehiscence of the surgical wound occur. Most
      patients achieved good results. We judged the results excellent in 94 patients,
      good in 11, and unsatisfactory in 2. On the basis of our experience and in
      agreement with the literature data, we can affirm that the best results were
      obtained by subcutaneous mastectomy with a periareolar incision.

PMID- 15038657
TI  - [Radiofrequency thermoablation in the treatment of primary and secondary liver
      tumours].
AB  - Radiofrequency thermoablation is a locoregional procedure based on the use of
      electromagnetic waves that induce movement and consequently the production of
      heat. This is the basis for the coagulative necrosis produced in the tissues. The
      method, experimented with and developed in the '90s, is today extensively used in
      the treatment of focal hepatic lesions, both primary and secondary. The factors
      that condition the procedure are related essentially to the characteristics of
      the tumours and to the possibility of obtaining a predictable area of necrosis
      that guarantees the radicality of the treatment. As regards primary neoplasms, it
      should be stressed that the treatment for hepatocellular carcinoma is implemented
      only in a small percentage of cases due to both the stage of the cirrhosis and
      because a wide resection is not justified for small-sized lesions or for
      recurrences after resection. As far as liver metastases are concerned,
      particularly those from the colon-rectum, surgery is becoming increasingly
      indicated. Obviously the conditions are decidedly less demanding than those of
      surgery in liver parenchyma with cirrhosis. Radiofrequency thermal ablation, even
      in this condition, has a place as an alternative or in combination with liver
      resection, particularly during recurrences or in cases of multiple metastases
      that require extensive extirpative operations. The authors present their
      experience over the period from February 1999 to December 2002 in 82 patients, 71
      with hepatocellular carcinoma and 11 with metastases, treated with radiofrequency
      thermoablation. Depending upon the site, the number of lesions and the Child-Pugh
      functional classes in patients with cirrhosis, 117 treatments were carried out:
      the percutaneous approach was used in 77 cases and the open procedure in 36,
      while the thermoablation was combined with surgical resection in 4 cases. The
      results are examined on the basis of perioperative morbidity and mortality and
      local recurrence, and the time of hospitalisation is compared in the different
      patient groups. The authors conclude favourably for this procedure, which is
      associated with an extremely low percentage of complications and with an almost
      total lack of perioperative mortality, and in some cases may be a valid
      alternative and in other cases a useful complement to resection treatment.

PMID- 15038658
TI  - [Treatment of inguinal hernia with the Prolene Hernia System (P.H.S.)].
AB  - Among the several techniques available for the treatment of inguinal hernia, the
      Prolene Hernia System (P.H.S.) has gained widespread acceptance over the past few
      years. This is an original prosthetic device that combines, in a single step,
      what other techniques offer separately, namely an underlay patch (preperitoneal
      placement), an onlay patch (subfascial placement) and a connector that joins them
      together and works as a plug. The aims of this study were to specify the
      indications and the technique of this method and to evaluate its efficacy in our
      experience. From January 1999 to July 2003 we performed 156 inguinal
      herniorraphies with the P.H.S. in 152 patients (143 male, 9 female; mean age 62.4
      years). One hundred and thirty-six cases were primary hermias (mainly types III,
      IV and VI according to the Rutkow and Robbins classification) and 18 were
      recurrences (mainly type R3 according to the Campanelli classification). In 56.5%
      of cases the operations were performed in the day surgery setting, 37.5% as
      ordinary admissions and 6% as emergency procedures. Locoregional (62.5%) or local
      (34.2%) anaesthesia were mainly given. Early postoperative complications (7%)
      were 7 haematomas and 4 seromas. In 125 patients with a follow-up of at least 6
      months, the late postoperative complications included 4 cases of persistent
      inguinocrural pain among the primary hernias (3.7%) and a new recurrence among
      the recurring hernias. The Authors believe that hernia repair with the P.H.S. is
      a valid choice comparable to the other common techniques but they suggest its use
      particularly in primary hernias with major relaxation of the posterior inguinal
      wall of the inguinal canal or of the entire myopectineal orifice.

PMID- 15038659
TI  - [Our experience with the treatment of high perianal fistulas with the mucosal
      flap advancement technique].
AB  - The authors present their experience with the treatment of high transphincteric
      anal fistulas with the mucosal flap advancement technique. This technique, though
      by no means easy to perform, allows fistulas to be treated in a single surgical
      session in comparison to the technique in which setone is used or to the less
      well known transposition techniques, given the same long-term results in terms of
      continence and recurrence rate. After a brief overview of the problem, from the
      points of view of both aetiopathogenesis and classification, the principal
      surgical treatment techniques are described, presenting the results and
      complications observed in the authors' own case series.

PMID- 15038660
TI  - Actinomycotic liver abscess. Case report and review of the literature.
AB  - Actinomycosis is a chronic suppurative, granulomatous disease, which is
      characterized clinically by extensive necrosis and abscess formation, and
      histologically by the presence of the so-called "sulphur granules". Actinomycosis
      is generally classified as being of cervicofacial, thoracic or abdominal type.
      The objective of this study is the presentation of a case of actinomycotic liver
      abscess that we encountered in our department 5 years ago, along with a brief
      review of this rare disease. A 39-year-old male non-Greek Caucasian patient
      presented with high fever, malaise, anorexia, vomiting after food ingestion and
      right upper quadrant pain. Leucocytosis with a left shift was present, and
      ultrasonography demonstrated a mass of mixed composition in the anterior part of
      the right hepatic lobe, measuring 6.8 x 4.6 cm, suggestive of an abscess or
      haemangioma. MRI scan confirmed the presence of a space-occupying lesion,
      suggestive of an abscess. The patient was submitted to surgical drainage of the
      hepatic abscess. The culture of the purulent material was found to be sterile,
      while the histochemical examination of the specimen demonstrated the presence of
      actinomycosis. The patient had an uneventful postoperative course and after
      discharge received prolonged chemoprophylaxis. Actinomycotic liver abscess is a
      very rare clinical entity, and only 57 cases have been reported in the English
      literature. Due to the rarity of the disease and the limited number of reported
      cases, we considered it useful to report this case.

PMID- 15038661
TI  - Papillary cystic and solid tumour of the pancreas: description of a clinical case
      in a young woman.
AB  - Papillary cystic and solid tumour of the pancreas is a very rare variant form of
      pancreatic tumour. Such neoplasms have a malignant potential, but their prognosis
      is good if they are diagnosed early and treated by radical surgical resection.
      This paper describes a case of a young woman with papillary cystic and solid
      tumour of the pancreas, localized in the body and tail of the pancreas and
      treated by distal pancreatectomy. The authors discuss the pathogenesis and the
      clinical, histological, radiological and surgical features of this tumour.

PMID- 15038662
TI  - [Acute intestinal bleeding due to Taenia solium infection].
AB  - Parasite infections of the digestive tract are a rare cause of acute haemorrhage
      in Western countries. We report here on a case of acute intestinal bleeding due
      to Taenia solium infection diagnosed at surgery. A 79-year-old white female
      patient was admitted to our institution for instable angina and severe anaemia
      secondary to acute intestinal bleeding. The patient's medical history was
      positive for long-standing microcytic anaemia. A recent diagnostic work-up had
      revealed the presence of chronic erosive antral gastritis and colonic
      diverticular disease without acute bleeding. On admission to our department the
      patient underwent antegrade bowel endoscopy which showed a bleeding site 120 cm
      caudad to the Treitz ligament in the absence of ulcers and/or neoplastic lesions.
      The patient was eventually referred to surgery for suspected intestinal
      angiodysplasia. At surgery no gross lesions of the stomach, bowel or colon were
      observed. We then performed a custom enterotomy 120 cm caudad to the Treitz
      ligament and discovered a 250-cm-long tapeworm. The parasite was removed with the
      aid of a second enterotomy 60 cm cephalad to the previous one and the entire
      bowel was explored with an intraoperative fiberoptic endoscope. Histology of the
      parasite revealed a T. solium species. The postoperative course was uneventful
      and the patient was discharged on postoperative day 10 with a prescription of 2
      g/day niclosamide. No recurrent digestive bleeding has so far been reported after
      a follow-up of 8 months. T. solium infection is a common cause of chronic
      microcytic anaemia in tropical and subtropical areas. In Western countries
      intestinal parasite infections are rarely taken into account in the diagnostic
      work-up of patients affected with chronic anaemia and/or acute digestive
      bleeding. The mechanisms responsible for acute intestinal bleeding in tapeworm
      infections are poorly understood and could be related to parasite-induced
      erosions of the bowel wall or be secondary to manipulations occurring during
      diagnostic manoeuvres.

PMID- 15038663
TI  - Giant condyloma acuminatum of the anorectum (Buschke-Lowenstein tumour): a case
      report of conservative surgery.
AB  - Giant condyloma acuminatum of the anorectum (Buschke-Lowenstein tumour) is a rare
      interesting infectious disease caused by the papillomavirus serotypes 16 and 18.
      In January 2002 a 47-year-old heterosexual male presented with Buschke-Lowenstein
      tumour and reported having had the disease for 12 years. The patient underwent
      thorough screening for sexually-transmitted diseases (which proved negative),
      abdominal CT, transanal US-endoscopy, inguinal ultrasound, chest X-ray and
      anorectal manometry, which revealed only localized disease. He was treated
      conservatively with radical local excision of the lesions. No postoperative
      complications were observed. Twelve months after surgery, there has been no local
      or remote recurrence and faecal continence is normal. The treatment of choice for
      Buschke-Lowenstein tumour is controversial; there is no evidence to support the
      need for demolitive surgery or chemo- and/or radiotherapy. The majority of
      authors prefer abdominoperineal amputation, but in our opinion conservative
      surgery is the best choice, especially in terms of the patient's quality of life.

PMID- 15038664
TI  - Review: Glycosphingolipids in health and disease.
AB  - Glycosphingolipids are ubiquitous membrane constituents that are subdivided in
      neutral or acidic fractions (gangliosides and sulfatides). Their analysis
      requires extraction and separation by thin-layer chromatography or high
      performance liquid chromatography. Ganglioside composition changes occur in
      response to variations in cellular morphology and function. Glycosphingolipids
      are implicated in the pathogenesis of various diseases, including
      glycosphingolipidoses, peripheral neuropathies caused by anti-ganglioside
      antibodies, and secretory diarrhea. Gangliosides play a role in the induction of
      apoptosis. For example, ceramide-induced apoptosis is associated with increased
      synthesis of a ganglioside, GD3. Gangliosides are also potential diagnostic
      markers and therapeutic targets for cancer.

PMID- 15038665
TI  - Review: Metabolic cardiomyopathy and conduction system defects in children.
AB  - Metabolic cardiomyopathies include amino acid, lipid and mitochondrial disorders,
      as well as storage diseases. A number of metabolic disorders are associated with
      both myopathy and cardiomyopathy. These include the glycogen storage diseases,
      ie, acid maltase deficiency (infantile, childhood, and adult onset), McArdle
      disease, and debrancher and brancher deficiencies. Disorders of lipid metabolism
      include systemic carnitine deficiency and abnormalities of carnitine
      palmitoyltransferase (CPT), long-chain acyl-CoA dehydrogenase, and multiple acyl
      CoA dehydrogenase. Disorders of mitochondrial metabolism affect complex I, II,
      III, IV and V, in addition to multiple respiratory chain defects. These may cause
      either hypertrophic or dilated cardiomyopathy. In addition, cardiomyopathy is
      frequently a component part of the storage disorders, including
      mucopolysaccharidosis, mucolipidosis, Fabry disease, gangliosidosis, and neuronal
      ceroid lipofuscinosis. Primary hypertrophic cardiomyopathy is caused by mutations
      in one of the genes that encode proteins of the cardiac sarcomere. Mutations in
      different genes are attended by different prognoses and different risks of sudden
      death. Mutations of the genes for myosin binding protein C (MBPC) and tropomyosin
      have low penetrance and cause mild forms of primary hypertrophic cardiomyopathy,
      while mutations of the troponin T and B-myosin genes carry a worse prognosis.
      Conduction disorders result in cardiac arrhythmias that may be fatal.
      Histiocytoid cardiomyopathy is usually an autosomal recessive disorder that
      results in the presence of abnormal Purkinje cells that interfere with normal
      cardiac conduction. Other conduction defects include arrhythmogenic right
      ventricular dysplasia (ARVD), congenital heart block, noncompaction of the left
      ventricle, and long Q-T syndrome (LQTS). The genetic loci for LQTS reside usually
      in the potassium channel, and, less frequently, in the sodium channel
      (channelopathies). Although the histological appearance of some of these
      disorders may be diagnostic, molecular analysis is necessary to define clearly
      the particular type of cardiomyopathy.

PMID- 15038666
TI  - Effector peptides from glutathione-S-transferase-pi affect the activation of jun
      by jun-N-terminal kinase.
AB  - We have previously found that the pi-isozyme of glutathione-S-transferase (GST
      pi) is a strong and selective inhibitor of the phosphorylation of the
      transcriptional activating protein jun by its activating kinase, jun-N-terminal
      kinase (JNK). We further performed molecular dynamics calculations on the 3
      dimensional structure of GST-pi free and bound to an inhibitor that blocks its
      ability to inhibit the JNK-jun activation. We thus identified 4 putative domains
      that may be involved in the interaction between GST-pi and the JNK-jun complex:
      residues 34-50, 99-121, 165-182 (with 2 overlapping sub-domains 165-175 and 169
      182), and 194-201. We have synthesized each of these domains and tested them for
      their abilities to affect the GST-JNK-jun system, first in a cell-free system. We
      find that peptides corresponding to residues 99-121 and 194-201 strongly inhibit
      the binding of GST to the JNK-jun complex but do not inhibit JNK-induced
      phosphorylation of jun, while peptides corresponding to residues 34-50 and 165
      182 do not inhibit GST binding but, except for the 165-175 subdomain peptide,
      strongly inhibit jun phosphorylation. A control peptide, X13, had no effect on
      either process. Peptide effects on jun phosphorylation appear to be selective for
      the JNK-jun system since the 34-50 peptide has no effect on other kinase systems
      (eg, casein kinase, MAP kinase). Three of the domain peptides, 34-50, 165-175,
      and 194-201 have been attached on their carboxyl-terminal ends to a penetratin
      sequence, enabling transmembrane transport into cells, and have been introduced
      into human astrocytes in which JNK was activated with anisomycin. We find that
      the 34-50-penetratin peptide strongly inhibits intracellular jun phosphorylation
      while the 194-201-penetratin peptide has no effect; the 165-175-penetratin
      peptide has a weak effect on this process. Thus, the effects in cells parallel
      those in the cell-free system. We conclude that all putative domains, identified
      in our prior structural studies, appear to interact with the JNK-jun complex. The
      34-50 peptide may be useful in selectively blocking uncontrolled mitogenic
      signaling involving the JNK-jun pathway and may be a potential agent for blocking
      oncogenic ras-p21-induced cell transformation.

PMID- 15038667
TI  - Quantification of human PPARgamma1 gene expression by competitive PCR using an
      homologous internal standard.
AB  - The polymerase chain reaction (PCR) is useful for amplifying specific mRNAs,
      particularly those present in low copy numbers. However, due to the exponential
      nature of the amplification process, PCR cannot readily be used to quantify gene
      expression. A competitive PCR technique was developed to address this
      shortcoming. An internal standard that is 100% homologous to, but shorter than,
      the target gene was constructed. The practicality of the method was demonstrated
      by determining the expression levels of a human transcription factor, peroxisome
      proliferator-activated receptor gamma 1 (hPPARgamma1) which is normally present
      in low copy numbers in selected cells. A mock system was used to test the
      accuracy and sensitivity of the method, which was subsequently used to determine
      the expression of this receptor in lipopolysaccharide (LPS)-activated monocytes,
      which are known to express hPPARgamma1 differentially during cellular activation.
      Densitometric analysis showed that the competitive PCR method reliably estimated
      the expression levels of hPPARgamma1 at the attomole (10(-18)) level in
      monocytes.

PMID- 15038668
TI  - Oxidative stress and enzymatic antioxidant status in patients with nonalcoholic
      steatohepatitis.
AB  - Oxidative stress is an important pathophysiological mechanism in nonalcoholic
      steatohepatitis (NASH). To assess whether there are relationships between
      oxidative stress and antioxidant enzymes in the development of NASH, we
      investigated oxidative stress by measuring serum malondialdehyde (MDA) and nitric
      oxide (NO) and antioxidant status by measuring serum glutathione (GSH),
      glutathione peroxidase (GSH-Px), glutathione reductase (GR), and superoxide
      dismutase (SOD). The study included 18 patients (13 men, 5 women; mean age 42 yr)
      with biopsy proven NASH and 16 healthy volunteers (10 men, 6 women; mean age 38
      yr). Serum levels of MDA, NO, GSH, GSH-Px, GR and SOD were determined by
      spectrophotometric methods. Serum levels (mean +/- SD) of MDA (6.7 +/- 1.6 vs 2.8
      +/- 1.7 nmol/ml, p 0.0001), NO (135 +/- 28 vs 113 +/- 35 mmol/L, p 0.04), GSH
      (919 +/- 137 vs 770 +/- 128 mmol/L, p 0.003) were increased in patients with NASH
      vs controls. Serum levels of GSH-Px (1063 +/- 152 vs 1000 +/- 94 U/L) and GR (47
      +/- 22 vs 40 +/- 21 U/L) were not singnificantly different in the patients vs
      controls. However, the serum level of SOD (1.24 +/- 0.32 vs 1.51 +/- 0.37 U/ml,
      p: 0.04) was significantly decreased. Impaired antioxidant defense mechanisms may
      be an important factor in the pathogenesis of NASH. Treatment approaches that
      affect the antioxidant enzymes may be beneficial in patients with NASH.

PMID- 15038670
TI  - Development and validation of a third generation allergen-specific IgE assay on
      the continuous random access IMMULITE 2000 analyzer.
AB  - In vitro determination of allergen-specific IgE (sIgE) represents an important
      aid in the diagnosis and treatment of allergy. Improvements in laboratory
      methodology--the development of second, and now third generation assays for sIgE-
      have brought about major advances in speed, convenience, performance, and in the
      standards for judging performance. In this study, following the NCCLS I/LA20-A
      guidelines, we evaluated the analytical performance of a quantitative
      chemiluminescent enzyme immunoassay for sIgE using the continuous random access
      IMMULITE 2000 system. Defining features of this "third generation" sIgE assay
      include a true zero calibrator with a detection limit and functional sensitivity
      of 0.1 and 0.2 kU/L, respectively. The use of liquid allergens allows for
      complete automation, fast binding kinetics between IgE and the natural allergenic
      protein conformations, and a time-to-first-result of 65 min. Stable reagents and
      the low nonspecific signal associated with the liquid allergens and centrifugal
      wash technique permit extension of the measuring range to 0.1-100 kU/L, based on
      lot-specific, factory-calibrated master curves standardized to the WHO 75/502
      reference standard. The assay demonstrated good precision and linearity over its
      measuring range. Relative to a first generation RIA (mRAST, from Hycor), clinical
      sensitivity, specificity, and concordance were 88%, 92%, and 90%, respectively (n
      = 812). Quantitative comparisons to a second generation assay yielded a linear
      regression relationship of IMMULITE 2000 = 0.99 (Pharmacia FEIA) + 1.99 kU/L, r =
      0.859 (n = 169).

PMID- 15038669
TI  - Identification of a novel O allele in the Taiwanese population.
AB  - The ABO system is one of the major blood groups that have significant impact on
      blood transfusion and paternity testing. We have found a new ABO allele by
      analyses of the ABO genotype of the Taiwanese population. Exons 6 and 7 of the
      ABO gene were amplified by the polymerase chain reaction and analyzed by direct
      sequencing. The results indicated that the ABO gene in the Taiwanese population
      consists mainly of the A1, A1v, B, O1, and O1v alleles. In addition, a novel O
      allele designated as OTaiwan was identified that has G --> T substitution at the
      nucleotide 801 of the O1 allele. The OTaiwan allele is inheritable, since it is
      also present in an offspring of the OTaiwan-carrying individual. The information
      presented herein is valuable for population research and for analyses of
      evolutionary lineage.

PMID- 15038671
TI  - Effect of protein on hemoglobin and hematocrit assays with a conductivity-based
      point-of-care testing device: comparison with optical methods.
AB  - Point-of-care testing (POCT) for blood hemoglobin and hematocrit (H/H) levels
      provides rapid patient assessment including the need for transfusion.
      Conductivity-based methods of blood H/H determinations can be influenced by
      plasma protein concentration. To assess this factor, we measured H/H levels at
      varying protein concentrations using two POCT instruments: iSTAT-1 (conductivity
      method) and Hemocue (optical method). These H/H results were compared to results
      obtained by our core laboratory hematology analyzer (GenS). Anticoagulated whole
      blood was centrifuged to sediment the red blood cells; the plasma was removed to
      serve as source of protein for mixing studies. A series of reconstituted samples
      was prepared with varying H/H and protein levels. To mimic hemodilution in
      clinical practice, samples were diluted with saline or lactated Ringer's
      solutions. Following H/H analysis, the samples were centrifuged and protein
      determined in the supernatant plasmas. The H/H results obtained with the Hemocue
      instrument correlated exactly with those of the GenS analyzer at protein
      concentrations from 0.7 to 6.2 g/dl. The correlation was unaffected when
      hemodilution was performed with either saline (r = 0.999) or lactated Ringer's (r
      = 1.000). The H/H results obtained with the iSTAT-1 instrument gave slightly less
      correlation with those of the GenS analyzer (r = 0.978 - 0.980) over this protein
      range. However, the iSTAT-1 results were generally lower than the GenS results,
      with discrepancies up to 2 g/dL for hemoglobin values and up to 4% for
      hematocrits at the lowest protein concentration. Therefore, it is recommended
      that H/H testing in patients with suspected hypoproteinemia or substantial
      hemodilution should be tested with a non-conductivity-based method.

PMID- 15038672
TI  - Evaluation of Vitek system for susceptibility testing of Enterococcus faecium
      isolates.
AB  - Although imipenem is not a first-line drug for treating enterococcal infection,
      it could well become a useful drug for treating mixed infections that include
      enterococci. However, there is no NCCLS guideline for susceptibility testing of
      imipenem versus enterococci. Moreover, there are no statements to indicate that
      in vitro susceptibility results for other antimicrobial agents can be used to
      predict the in vitro activity of imipenem against enterococci. In this study, 52
      Enterococcus faecium isolates were collected from patients hospitalized at
      Kangnam St. Mary's Hospital between March 2002 and December 2002. The sources of
      the isolates were mainly urine specimens and wounds. For ampicillin, the "major"
      and "very major" error rates observed with the Vitek system were 0% and 2.0%,
      respectively. For penicillin, the major and very major error rates observed with
      the Vitek system were both 0%. For imipenem, the major and very major error rates
      observed with the Vitek system were 0% and 36.5%, respectively. The MICs of
      ampicillin and penicillin obtained using the Vitek system were reliable, but that
      of imipenem was unreliable. In the 52 E. faecium isolates, the in vitro activity
      of penicillin and ampicillin versus enterococci accurately predicted that of
      imipenem. Therefore, the MIC of imipenem obtained with the Vitek system must be
      retested by the agar dilution method, when it disagrees with those of penicillin
      and ampicillin.

PMID- 15038673
TI  - The optimal hepatocyte density for a hollow-fiber bioartificial liver.
AB  - A bioartificial liver (BAL) based on viable porcine hepatocytes can serve as a
      bridge to liver transplantation in patients with acute liver failure (ALF). To
      support liver functions, an adequate mass of hepatocytes is needed, which depends
      upon the cell density in the BAL device. This study evaluated the optimal density
      of hepatocytes within BAL devices that were constructed by perfusing porcine
      hepatocyte suspensions mixed with cytodex-3 into polysulfon hollow-fibers. The
      BAL devices were prepared with 6 different cell densities. The mass of
      hepatocytes in each device was evaluated for (a) cell viability, (b) ability to
      degrade diazepam, (c) ability to synthesize urea, (d) incorporation of [3H]
      leucine into protein, (e) glucose-6-phosphatase activity, (f) total RNA content,
      and (g) p53 gene expression. Hepatocyte viability was about 90% in each device.
      With increasing hepatocyte density, the diazepam concentration in the medium
      decreased from 9.26 +/- 0.96 mg/L at 1 x 10(5) cells/ml to a minimum of 5.25 +/-
      1.02 mg/L at 5 x 10(6) cells/ml and thereafter remained at low levels. Urea
      production and [3H]-leucine incorporation into protein increased progressively
      until the cell density reached 5 x 10(6)/ml and thereafter remained at high
      levels. Glucose-6-phosphatase activity and total RNA content stayed at high
      levels until the cell density reached 5 x 10(6)/ml and then progressively
      decreased. p53 gene expression differed from the other parameters, since it
      increased only when the cell density reached 5 x 10(7)/ml. In conclusion, the
      density of 5 x 10(6) cells/ml is a critical inflection point for most of the
      functional parameters, although p53 gene expression is not elevated at this cell
      density. These findings suggest that 5 x 10(6) cells/ml is the optimal hepatocyte
      density in the hollow-fiber BAL device.

PMID- 15038674
TI  - Prevalence of bronchial asthma in patients with endoscopically-documented
      esophagitis.
AB  - The association of gastroesophageal reflux, esophagitis, and asthma has been
      studied for a long time, but the results are often conflicting. The aim of this
      study is to evaluate the prevalence of bronchial asthma and the presence of extra
      esophageal symptoms in subjects with endoscopically-documented reflux
      esophagitis. Forty patients were divided into 2 groups: group A (22 patients)
      affected by endoscopically-documented esophagitis, and group B (18 patients) with
      positive endoscopic examination for other pathologies of the gastroenteric tract.
      All of the patients underwent complete medical examination, skin-prick tests,
      esophageal-gastric-endoscopy, and pulmonary function tests (basal and after
      methacholine). The prevalence of asthma was 30% in group A vs 10% in group B
      (odds ratio = 2.57; confidence interval = 0.75-10.25). Relationships between
      chronic cough and esophagitis (p<0.01) and between chronic cough and asthma
      (p<0.05) were found. No significant relationships were observed between
      esophagitis and the other respiratory symptoms considered (wheezing, chest
      tightness, hoarseness, bronchospasm, and dysphagia). The results confirm the
      increased prevalence of asthma in patients with esophagitis and they emphasize
      the role of gastroesophageal reflux as a trigger factor for asthma. Chronic cough
      represents an important symptom of asthma in subjects with esophagitis.

PMID- 15038675
TI  - Brief communication: Respiratory function is closely associated with basal
      metabolic rate in elderly persons.
AB  - To investigate the association between respiratory function and basal metabolic
      rate (BMR), pulmonary function indices and BMR were measured in 251 elderly
      persons using a spirometer and a body composition analyzer. Forced vital capacity
      (FVC) and forced expiratory volume in one second (FEV1) were more strongly
      correlated with BMR (r = 0.48 and r = 0.43, p < 0.01) than with lean body mass (r
      = 0.36 and r = 0.35, p < 0.01) and waist-to-hip ratio (r = -0.29 and r = -0.32, p
      < 0.01) in elderly men. FVC and FEV1 in elderly men with BMR > or = 1390 kcal/day
      averaged 4.05 +/- 0.56 L and 3.19 +/- 0.45 L, which were significantly above the
      values (3.54 +/- 0.51 L and 2.80 +/- 0.42 L, p < 0.01) in men with BMR < 1390
      kcal/ day. Prevalences of the subjects with elevated FVC or FEV1 were
      significantly higher in the group of men with BMR > or = 1390 kcal/day than in
      those with BMR < 1390 kcal/day (66.0% and 68.0% vs 28.3% and 33.9%, p < 0.01). No
      significant differences were observed between the postmenopausal women with BMR >
      or = 1135 kcal/day and those with BMR < 1135 kcal/day. In summary, respiratory
      function is more closely associated with BMR in elderly persons, compared to lean
      body mass, waist-to-hip ratio, or body fat mass, and these associations are
      stronger in men than in women.

PMID- 15038677
TI  - Case report: Malignant struma ovarii.
AB  - Struma ovarii are specialized teratomas consisting of thyroid tissue with various
      microscopic features, ranging from benign to malignant. We report a rare form of
      malignant struma ovarii, composed exclusively of a follicular variant of
      papillary thyroid carcinoma with capsular invasion, which occurred in a 65-yr-old
      woman.

PMID- 15038676
TI  - Brief communication: Effects of soy-protein diet on elevated brain lipid peroxide
      levels induced by simulated weightlessness.
AB  - The influence of soy-protein diet on brain lipid peroxidation in female rats was
      studied using a tail-suspension model of weightlessness. The study tested the
      efficacy of diets containing 0% or 11.1% soy-protein in 4 groups of female
      Sprague Dawley rats that were maintained with or without tail-suspension for a
      period of 3 weeks. At term, the whole brain was removed, segmented, and analyzed
      for malondialdehyde (MDA) as an index of lipid peroxidation. Brain levels of MDA
      were significantly higher in both tail-suspended groups than in the non-suspended
      control groups on the same diet, (p<0.05). The high soy-protein diet decreased
      MDA levels significantly, compared to the 0% soy-protein groups (p<0.05).
      Furthermore, MDA levels were significantly lower in the tail-suspended group on
      high soy-protein diet, compared to the corresponding 0% soy-protein group. In
      conjunction with previous findings in male rats, these data indicate that tail
      suspension increases brain MDA levels in rats regardless of gender, and that a
      diet rich in soy-protein decreases the brain MDA level in both the non-suspended
      and tail-suspended groups. These observations imply that the soy-protein diet has
      a protective antioxidant effect during both the basal condition and the stressful
      condition.

PMID- 15038679
TI  - The burden of disease in the Asia-Pacific region--challenges to public health.

PMID- 15038678
TI  - A note from history: The first histopathologists.

PMID- 15038680
TI  - Low back pain in Australian adults: the economic burden.
AB  - This paper reports the results of a "cost-of-illness" study of low back pain
      (LBP) in Australian adults. It estimates the direct cost of LBP in 2001 to be AU
      dollars 1.02 billion. Approximately 71% of this amount is for treatment by
      chiropractors, general practitioners, massage therapists, physiotherapists and
      acupuncturists. However, the direct costs are minor compared to the indirect
      costs of AU dollars 8.15 billion giving a total cost of AU dollars 9.17 billion.
      LBP in Australian adults represents a massive health problem with a significant
      economic burden. This burden is so great that it has compelling and urgent
      ramifications for health policy, planning and research. This study identifies
      that research should concentrate on both direct but particularly the indirect
      costs including cost-effective management regimes that encourage an early return
      to duties.

PMID- 15038681
TI  - Caregiving burden is associated with short rather than long duration of care for
      older persons.
AB  - This is a preliminary cross-sectional study of 51 caregivers of older persons
      attending the Geriatric Clinic at an urban hospital in Kuala Lumpur, Malaysia. A
      questionnaire helped determine how the duration of caregiving affects the outcome
      of caregiver burden. The short version of Zarit's Burden Interview (BI) allowed
      the burden level to be grouped as low or high burden. The duration of caregiving
      was also grouped into short (two or less years) or long (more than two years)
      durations. One third of the caregivers, 31% (16 out of 51) reported high burden
      and within this group 81%, (13 out of 16) are short duration caregivers. Majority
      of the longer duration caregivers, 88% (21 out of 24) reported low level of
      burden. This was a significant finding (p-value 0.008). The study also showed
      that a higher proportion of caregivers are employed, working in the private
      sector, and earn less than RM2,000 per month. However, these findings were not
      significantly associated with high burden. It is concluded that although this
      study showed low level of caregiver burden, shorter duration of caregiving is
      associated with higher level of burden and longer duration of caregiving is
      associated with lower level of burden.

PMID- 15038682
TI  - Measuring the impact of hepatitis A virus in Chinese cities: a life table
      approach.
AB  - The infection of hepatitis A virus is an important public health problem in
      China. In 1990, a survey on seroprevalence of anti-hepatitis A was conducted in
      eight large cities of population size between one to four million. The results
      were used to analyze the impact of hepatitis A. In our study, we used life table
      techniques to determine the impact that the hepatitis A virus (HAV) has on these
      eight cities by computing the expected years of life with anti-hepatitis A virus.
      We compared the results from our approach with those from a previous method. The
      expected years of life with anti-hepatitis A virus were 53.82, 54.65, 44.26,
      53.89, 46.18, 55.77, 55.31 and 49.89 for the eight cities (Xi'an, Huhehaote,
      Chongqing, Nanjing, Jinan, Ha'erbin, Fuzhou and Nanchang), respectively. The
      hepatitis A virus had the greatest impact in Ha'erbin in northeastern China;
      whereas, the impact was lowest in Chongqing in southwestern China. However, based
      on the previous indicator, Chongqing was ranked the highest among these cities.
      Through our comparative study of the methods, our approach provides a better
      measure on the burden of the disease than the previous method. It also identifies
      subgroups of the population where the disease has its greatest impact on the
      population.

PMID- 15038683
TI  - Waist circumference as a screening tool for weight management: evaluation using
      receiver operating characteristic curves for Malay subjects.
AB  - Body Mass Index (BMI) is the most established anthropometric indicator used for
      assessment of nutritional status. Other anthropometric indicators which are
      related closely to BMI are waist hip ratio (WHR) and waist circumference. In this
      paper, receiver operating characteristics (ROC) curves were constructed to assess
      the value of waist circumference and waist hip ratio as a screening measure for
      the need of weight management using BMI as the reference test. Sensitivity and
      specificity were calculated at several cut-offs. The areas under the ROC curve
      calculated by comparing waist circumference with BMI were high (0.70 - 0.86)
      while the areas calculated for WHR were low (0.46 - 0.67). Sensitivities of 0.745
      and 0.800 were observed at cut-off points of waist circumference at 90cm and 80cm
      for males and females respectively, while the false positive rates were 0.233 for
      males and 0.250 for females. These cut-off points could be considered as a fair
      trade-off. Therefore it is concluded that waist circumference performed better
      than WHR as a screening test. It is indicative that waist circumference could be
      used as a tool in raising awareness of weight management in this population.

PMID- 15038684
TI  - Socio-demographic risk indicators for tooth mortality in rural Sri Lankans.
AB  - To explore the socio-demographic factors associated with tooth loss in rural
      inhabitants of Sri Lanka, a random sample of 2178 males aged 20-60 years was
      selected using multi-stage cluster sampling procedure. The number of missing and
      present teeth was recorded excluding third molars and the subjects were
      interviewed to elicit socio-demographic information as well as oral hygiene and
      tobacco consumption habits. The mean number of teeth lost in the sample was 5.17
      +/- 5.43. Tooth loss increased significantly with age. Sinhalese had
      significantly fewer lost teeth (5.05 +/- 5.38) compared to Tamils (6.54 +/- 6.18)
      and Muslims (6.02 +/- 5.21) whereas education, income, oral hygiene practices and
      tobacco use were significantly associated with tooth loss in the bivariate
      analysis. A forward stepwise multiple regression analysis revealed that age,
      Muslim ethnicity and quantified tobacco use were positively associated with tooth
      loss while better socio-economic conditions and good oral hygiene habits were
      negatively linked with tooth mortality independent of other factors. Age, Muslim
      ethnicity, quantified tobacco use, income, education, brushing frequency and
      substance used for cleaning had significantly affected tooth loss. Quantified
      tobacco use and oral hygiene may be regarded as modifiable socio-demographic risk
      indicators associated with tooth mortality in Sri Lankans.

PMID- 15038685
TI  - A pilot study of dental caries status in relation to knowledge, attitudes and
      practices in oral health in Myanmar.
AB  - This study was to determine the dental caries prevalence among the Myanmar
      population, and to investigate the correlations between oral clinical indices and
      knowledge, attitudes and practices (KAP) on oral health. Subjects were randomly
      selected from 140,000 people residing in the Kyauktan township in a cross
      sectional community-based study. The present analysis was confined to 739
      subjects (353 males and 386 females) aged 12, 35-44 and 65-74 years, who were
      divided into two specified groups based on urban or rural location. KAP on oral
      health data and social demographic information were collected, while dental
      caries status was assessed by DMFT. The mean number of decayed teeth (DT) in
      rural areas was higher than that in urban areas, while the mean number of filled
      teeth (FT) in rural areas was lower than that in urban areas. Mean knowledge and
      attitude scores for correct answers were also significantly higher for the urban
      than the rural subjects. There were statistically significant correlations
      between the correct/incorrect responses to knowledge and attitude questionnaires
      on oral health and the mean number of DMFT. KAP pertaining to oral health of
      Myanmar population, especially those of rural subjects, might not be satisfactory
      and related to threaten their dental caries status.

PMID- 15038686
TI  - Leaching of bisphenol A from new and old babies' bottles, and new babies' feeding
      teats.
AB  - Bisphenol A is the monomer used in the manufacture of polycarbonate. Bisphenol A
      is also known to mimic the female hormone estrogen. In this study, the
      possibility of the leaching of bisphenol A from polycarbonate babies' bottles and
      feeding teats was investigated. Bisphenol A was extracted from water samples
      exposed to the bottles and teats using liquid-liquid extraction. Bisphenol A was
      analysed by gas chromatograph-mass spectrometer with quadrapole detector in
      selected ion monitoring mode. Mean leaching of bisphenol A from 100 used babies'
      bottles when filled with water at 25 degrees C and 80 degrees C were 0.71 +/-
      1.65 ng/cm2 (mean +/- standard deviation) and 3.37 +/- 5.68 ng/cm2 respectively.
      Mean leaching of bisphenol A from 30 new babies' bottles when filled with water
      at 25 degrees C and 80 degrees C were 0.03 +/- 0.02 ng/cm2 and 0.18 degrees 0.30
      ng/cm2 respectively. Bisphenol A was observed to have leached from babies'
      feeding teats into 37 degrees C water ranged from non-detectable to 22.86 ng/g.
      The technique employed in this study is fast, reliable and economical.

PMID- 15038687
TI  - Secretory IgA level in pharyngeal mucous of infants with different feeding
      methods at the age of four to eight weeks.
AB  - The stimulating effect of human breast milk on the mucosal immunological
      development of recipient infant has been speculated. The objective of this study
      was to clarify the influence of breast feeding on the level of secretory IgA
      (sIgA) of infants. The level of sIgA in pharyngeal mucous among 79 healthy
      infants aged 4-8 weeks with different feeding methods was estimated. The
      concentrations of sIgA and protein were measured after the mucous absorbed by the
      throat swab was emulsified in saline. The level of sIgA was expressed as a
      percentage of the total protein content (sIgA % protein). The difference of the
      mean sIgA % protein was not significant among infants with different feeding
      methods. The results suggest that breast milk does not influence the sIgA levels
      of infant. Breast feeding may promote specific sIgA production without raising
      the total level of sIgA.

PMID- 15038688
TI  - IT usage, perceptions and literacy of medical students.
AB  - A cross-sectional study of medical students using a self-administered
      questionnaire was carried out in the Faculty of Medicine, University of Malaya,
      Malaysia from December 2000 to January 2001 to determine IT usage, perceptions
      and literacy of medical students. 366 of 653 (56.0%) students reported owning
      some type of personal computer. Students mainly used the computer to get onto the
      Internet, do word-processing and make presentations. Junior (Year One and Two)
      students and those who had used computers before entering university were more
      likely to use the Internet. Those who own computers were more likely to feel
      comfortable with software (OR 1.61, 95% CI: 1.09, 2.38). Students who use the
      Internet were more likely to perceive that IT facilitated their studies (OR 4.61,
      95% CI: 2.35, 9.05). The highest self-reported IT skill was e-mailing followed by
      surfing the World Wide Web and word-processing. Male students and junior students
      had significantly higher self-reported IT literacy scores compared to female
      students and senior students. Significant predictors for an IT identifier score
      after adjusting for other variables were self-reported rating of computer
      knowledge, number of siblings, parents' income and gender.

PMID- 15038689
TI  - Quality and disease management.
AB  - Does having a comprehensive list of quality targets as part of the contract
      incentivize vendors to do the right thing? Not necessarily. However, if a vendor
      needs incentives to do the right thing in the quality department, one may have
      picked the wrong vendor and/or negotiated the wrong contract. Conversely, a
      vendor willing to be measured by the most objective measures possible is a vendor
      with enough confidence in its own outcomes to be considered an excellent choice
      as a partner.

PMID- 15038690
TI  - Quality of life in managed care patients with irritable bowel syndrome.
AB  - The relationship between the severity of abdominal discomfort/pain and generic
      and disease-specific quality of life (QoL) was explored in patients with
      irritable bowel syndrome in an MCO. Subjects were stratified into four symptom
      severity groups. Descriptive and multivariate analyses were used to examine the
      relationship of QoL to severity of abdominal discomfort/pain. Generic and disease
      specific QoL scores declined as severity of abdominal discomfort/pain increased.
      The lowest 36-Item Short-Form Health Survey scores for respondents with the most
      severe abdominal discomfort/pain were for role physical (24.2 +/- 35.4) and
      vitality (33.7 +/- 19.2). In multivariate regression models controlling for age,
      sex, work status and education, severity of abdominal discomfort/pain was a
      significant independent predictor of QoL.

PMID- 15038692
TI  - Exploring the effect of the Medicare drug discount card program.

PMID- 15038691
TI  - Assessing patient satisfaction with desloratadine after conversion from
      loratadine, fexofenadine, or cetirizine.
AB  - A number of prescription and nonprescription nonsedating antihistamines are
      available for the treatment of allergic rhinitis. From a managed care
      perspective, determining the extent to which a medication conversion to
      desloratadine from loratadine, fexofenadine, or cetirizine results in maintained
      or increased patient satisfaction with allergy care would be informative for
      formulary decision makers and other budget holders. To that end, a survey was
      undertaken of patient medication assessments after a switch in antihistamines. On
      average, patients who converted to desloratadine from loratadine, fexofenadine,
      or cetirizine reported increased satisfaction with desloratadine treatment.

PMID- 15038693
TI  - The Medicare prescription drug benefit poses opportunities for disease
      management.

PMID- 15038695
TI  - Enantioselective guest binding and dynamic resolution of cationic ruthenium
      complexes by a chiral metal-ligand assembly.
AB  - A supramolecular metal-ligand assembly encapsulates a variety of cationic half
      sandwich ruthenium complexes. Due to the chirality of both host and guest, chiral
      recognition is observed with diastereomeric excesses up to 70%. The chiral cavity
      can be used to carry out a dynamic resolution of the rapidly equilibrating
      enantiomers of the chiral organometallic guest.

PMID- 15038694
TI  - How heme metabolism occurs in heme oxygenase: computational study of oxygen
      donation ability of the oxo and hydroperoxo species.
AB  - We report a density functional theory study on the heme metabolism in heme
      oxygenase using iron-hydroperoxo and -oxo models. The activation energies for
      heme oxidation at the alpha-carbon by the iron-hydroperoxo and -oxo species are
      calculated to be 42.9 and 39.9 kcal/mol, respectively. These high activation
      barriers lead us to reconsider the catalytic mechanism of heme oxygenase

PMID- 15038696
TI  - Facile quantification of enantiomeric excess and concentration with indicator
      displacement assays: an example in the analyses of alpha-hydroxyacids.
AB  - An enantioselective indicator-displacement assay was developed to determine
      enantiomeric excess (ee) and concentration of alpha-hydroxyacid samples with two
      independent absorption measurements. The inherent relationship between the
      absorbance of the indicator-displacement ensemble and the overall concentration
      and ee of the analyte was established through solution equilibria.

PMID- 15038697
TI  - Permanent bubble arrays from a cross-linked poly(para-phenyleneethynylene):
      picoliter holes without microfabrication.
AB  - An azide-substituted poly(para-phenyleneethynylene) (PPE) 4 was prepared by the
      Heck-Cassar-Sonogashira-Hagihara method. Thin films of 4 form self-assembled
      bubble arrays from carbon disulfide solution utilizing the breath figure method.
      The as-formed porous films of 4 are soluble in common solvents, and the air
      bubbles are interconnected. Upon heating to 300 degrees C, 4 cross-links and the
      thin film turn into insoluble matrix with isolated bubbles. The cross-linking
      process has transformed the bubble arrays of 4 into insoluble picoliter beakers
      or picoliter vials, whose diameters are approximately 3.0 and 1.5 mum at the top
      and bottom, respectively.

PMID- 15038698
TI  - Thermochemistry of aqueous hydroxyl radical from advances in photoacoustic
      calorimetry and ab initio continuum solvation theory.
AB  - Photoacoustic signals from dilute ( approximately 30 mM) solutions of H2O2 were
      measured over the temperature range from 10 to 45 degrees C to obtain the
      reaction enthalpy and volume change for H2O2(aq) --> 2 OH(aq) from which we
      ultimately determined DeltafG degrees , DeltafH degrees and partial molal volume,
      v degrees , of OH (aq). We find DeltarH = 46.8 +/- 1.4 kcal/mol, which is 4
      kcal/mol smaller than the gas-phase bond energy, and DeltaVr = 6.5 +/- 0.4
      mL/mol. The v degrees for OH in water is 14.4 +/- 0.4 mL/ml: smaller than the v
      degrees of water. Using ab intio continuum theory, the hydration free energy is
      calculated to be -3.9 +/- 0.3 kcal/mol (for standard states in number density
      concentration units) by a novel approach devised to capture in the definition of
      the solute cavity the strength and specific interactions of the solute with a
      water solvent molecule. The shape of the cavity is defined by "rolling" a three
      dimensional electron density isocontour of water on the ab initio water-OH
      minimum interaction surface. The value of the contour is selected to reproduce
      the volume of OH in water. We obtain for OH(aq): DeltafH degrees = -0.2 +/- 1.4
      and DeltafG degrees = 5.8 +/- 0.4 kcal/mol that are in agreement with literature
      values. The results provide confidence in the pulsed PAC technique for measuring
      aqueous thermochemistry of radicals and open the way to obtaining thermochemistry
      for most radicals that can be formed by reaction of OH with aqueous substrates
      while advancing the field of continuum solvation theory toward ab initio-defined
      solute cavities.

PMID- 15038699
TI  - Sensitivity-enhanced quantitative 13C NMR spectroscopy via cancellation of 1J(CH)
      dependence in DEPT polarization transfers.
AB  - A scheme has been developed to eliminate virtually all signal intensity
      dependence on 1JCH in polarization transfers between 1H and 13C nuclei, reducing
      differences in signal intensity to only 1.5% over the entire natural 1JCH range.
      The scheme relies on the summation of time-domain data acquired with four
      suitably selected Delta delays so that the J dependence is essentially canceled
      in the final, signal-averaged free-induction decay. These Delta delays have been
      incorporated into the DEPT pulse sequence to create sensitivity-enhanced
      experiments for collecting quantitative 13C{1H} spectra. Four experiments, each
      with unique read pulse angles, give quantitative spectra with 200-300% more
      sensitivity than conventional 13C spectra acquired with inverse-gated 1H
      decoupling. The experiments are ideal for recording spectra with improved
      quantitative information or for substantially reducing the long acquisition times
      indicative of quantitative 13C experiments. The ability of the experiments to
      provide quantitative spectra was demonstrated with a simple ethylbenzene
      solution, however, they can easily be adapted to various applications for
      analysis of complex mixtures.

PMID- 15038700
TI  - Formation of pseudorotaxane induced by electrochemical oxidation of ferrocene
      containing axis molecule in the presence of crown ether.
AB  - The electrochemical oxidation of aminomethylferrocenes in the presence of
      dibenzo[24]crown-8 affords pseudorotaxanes containing a ferrocenyl group in its
      axis moiety. The formation of the pseudorotaxanes results from formation of
      secondary ammonium ions by rapid electron transfer from the N atom to the
      initially formed Fe(III) state, followed by hydrogen atom transfer from TEMPOH to
      the N+*.

PMID- 15038701
TI  - Iron-catalyzed cross-coupling of primary and secondary alkyl halides with aryl
      grignard reagents.
AB  - An iron-catalyzed cross-coupling reaction of a primary or secondary alkyl halide
      with an aryl Grignard reagent proceeds under mild conditions to give the
      corresponding coupling product in quantitative yield.

PMID- 15038702
TI  - Catalytic enantioselective hydrostannation of cyclopropenes.
AB  - The first examples of catalytic enantioselective hydrostannation of the C=C
      double bond of cyclopropenes has been demonstrated. This method allows for the
      efficient synthesis of 2,2-disubstituted cyclopropylstannanes with high degrees
      of diastereo- and enantioselectivity. The facial selectivity of this reaction is
      entirely controlled by steric factors. A variety of functional groups at C-3 of
      the cyclopropenes were tolerated.

PMID- 15038704
TI  - Design and use of fluorogenic aldehydes for monitoring the progress of aldehyde
      transformations.
AB  - We describe the first examples of fluorogenic aldehydes useful for monitoring
      many types of reactions including aldol reactions, allylations, and reductions.
      The fluorogenic aldehydes were constructed by covalent combination of a
      fluorophore and an aldehyde moiety via a linker. In the resulting single
      molecule, the aldehyde functioned as a quencher of the fluorophore's
      fluorescence. The reaction product, modified at the aldehyde functionality, no
      longer served as an effective quencher. The reaction products showed up to
      approximately 80-fold higher fluorescence than the aldehyde reactants.

PMID- 15038703
TI  - P-Chirogenic diaminophosphine oxide: a new class of chiral phosphorus ligands for
      asymmetric catalysis.
AB  - We successfully synthesized a novel P-chirogenic diaminophosphine oxide 4, which
      was applied to catalytic enantioselective construction of quaternary carbon
      centers using Pd-catalyzed asymmetric allylic substitution with various beta-keto
      esters (up to 99% yield, 94% ee). Preliminary mechanistic studies indicated that
      two molecules of 8 coordinate to the Pd metal in a monodentate fashion, resulting
      in the formation of Pd complex 9 (Pd:8 = 1:2), which functions as the active
      species.

PMID- 15038705
TI  - Biosynthetic origin of the rare nitroaryl moiety of the polyketide antibiotic
      aureothin: involvement of an unprecedented N-oxygenase.
AB  - The antibiotic aureothin is a rare natural nitroaromatic compound produced by
      Streptomyces thioluteus. By labeling experiments, we demonstrate for the first
      time that p-nitrobenzoate (PNBA) serves as a polyketide synthase starter unit.
      Cloning, heterologous expression, and inactivation experiments reveal that this
      unusual primer is synthesized from p-aminobenzoate (PABA) by means of AurF, a
      novel N-oxygenase.

PMID- 15038706
TI  - Fully extended polyelectrolyte-amphiphile complexes adsorbed on graphite.
AB  - In a polyelectrolyte-amphiphile complex, where the amphiphilic component is known
      to self-assemble on graphite, the polyelectrolyte adsorbs in a predictable way as
      straight, fully extended macromolecule.

PMID- 15038707
TI  - Ligand-dependent scope and divergent mechanistic behavior in nickel-catalyzed
      reductive couplings of aldehydes and alkynes.
AB  - A new procedure for catalytic reductive coupling of aldehydes and alkynes has
      been developed. The procedure uses Ni(COD)2 with an imidazolium carbene ligand as
      the catalyst and triethylsilane as the reducing agent. A crossover deuterium
      labeling experiment illustrated that variants involving trialkyl phosphines and
      imidazolium carbene ligands with a nickel catalyst proceed by different
      mechanisms.

PMID- 15038708
TI  - Platinum-catalyzed intramolecular alkylation of indoles with unactivated olefins.
AB  - Reaction of 1-methy-2-(4-pentenyl)indole (1) with a catalytic amount of PtCl2 (2
      mol %) in dioxane that contained a trace of HCl (5 mol %) at 60 degrees C for 24
      h led to the isolation of 4,9-dimethyl-2,3,4,9-tetrahydro-1H-carbazole (2) in 92%
      yield. Platinum-catalyzed cyclization of 2-(4-pentenyl)indoles tolerated
      substitution at each position of the 4-pentenyl chain. Furthermore, the protocol
      was applicable to the synthesis of tetrahydro-beta-carbolinones and was effective
      for cyclization of unprotected indoles. 2-(3-Butenyl)indoles underwent platinum
      catalyzed cyclization with exclusive 6-endo-trig regioselectivity. Mechanistic
      studies established a mechanism for the platinum-catalyzed cyclization of 2
      alkenyl indoles involving nucleophilic attack of the indole on a platinum
      complexed olefin.

PMID- 15038709
TI  - A one-pot multicomponent coupling reaction for the stereocontrolled synthesis of
      (Z)-trisubstituted allylic alcohols.
AB  - In this Communication, we outline a new one-pot, multicomponent coupling reaction
      that allows easy access to (Z)-trisubstituted allylic alcohols. Our strategy is
      based on E to Z isomerization of the 1-bromo-1-dialkylvinylborane upon reaction
      with dialkylzinc reagents, and subsequent transmetalation to give (Z)
      trisubstituted vinylzinc species. In situ trapping of the reactive vinylzinc
      intermediates with aldehydes furnished a series of (Z)-trisubstituted allylic
      alcohols. This method represents a viable alternative to the Still-Gennari
      modification of the HWE olefination reaction, and it has the advantage that it
      allows coupling of larger fragments.

PMID- 15038710
TI  - Total synthesis and structural revision of (+)-amphidinolide W.
AB  - An enantioselective first total syntheis of amphidinolide W (2) and a revision of
      its C6 absolute stereochemistry (1) are described. Amphidinolide W (1), a 12
      membered macrolide isolated from Amphidinium sp., has shown potent antitumor
      properties against a variety of NCI tumor cell lines. The synthesis is
      convergent, and four of the five chiral centers were derived through asymmetric
      synthesis. The synthesis features Sharpless asymmetric dihydroxylation,
      diastereoselective alkylation, efficient cross metathesis of functionalized
      substrates, and novel functional group transformations using selective lipase
      catalyzed hydrolysis of the primary acetate group. Of particular note, the C6
      absolute stereochemistry of amphidinolide W (1) has now been revised through our
      current synthesis.

PMID- 15038711
TI  - Hydration of nitrosylruthenium bis(alkynyl) complexes with
      hydrotris(pyrazolyl)borate: insertion/hydration and double hydration products.
AB  - Hydration of nitrosylruthenium bis(alkynyl) complex TpRu(CCPh)2(NO) (1) (Tp =
      BH(pyrazol-1-yl)3) was carried out in the presence of HBF4.Et2O in distilled MeOH
      and afforded the metallacycle TpRu{CH=C(Ph)C(O)CH(Ph)}(NO) (2) (39%) and the
      bis(ketonyl) TpRu(CH2C(O)Ph)2(NO) (3) (37%). While double hydration of 1 gave 3,
      2 was produced through a combination of insertion and hydration processes. On the
      other hand, a similar reaction performed in THF instead of MeOH afforded 2 (52%),
      the acyl-ketonyl complex TpRu(C(O)CH2Ph)(CH2C(O)Ph)(NO) (4) (8.9%), and trace
      amounts of 3 and TpRu(CCPh)(CH2C(O)Ph)(NO) (5). Moreover, the 1/HBF4.Et2O/H2O
      reaction system in distilled MeOH at 0 degrees C gave rise to 5 exclusively
      (79%). Treatment of THF solution of isolated 5 with water in the presence of
      protic acid furnished 3 and 4, revealing that 5 is the intermediate in their
      formation.

PMID- 15038712
TI  - Molecular optical gating devices based on polymer nanosheets assemblies.
AB  - We describe here a polymer nanosheet assembly that serves as a molecular
      photoswitching and optical exclusive OR (EXOR) logic gate. Separate polymer
      nanosheets (monolayers) containing phenanthrene, anthracene, and dinitrobenzene
      chromophore were prepared by the Langmuir-Blodgett technique (LB films). A
      bilayer-couple, consisting of phenanthrene (sensitizer) monolayer and
      dinitrobenzene (acceptor) monolayer, and the other couple, of anthracene
      monolayer and dinitrobenzene monolayer, were confirmed to function as a
      photodiode showing current rectification on light irradiation. The two
      photodiodes are connected as each photocurrent direction becomes opposite. In the
      polymer photodiode array (LB films), anodic photocurrent was observed when the
      anthracene was selectively excited. On the other hand, cathodic photocurrent was
      observed by selective excitation of the phenanthrene. Moreover, the output
      photocurrent displayed a very small value when the phenanthrene and anthracene
      were excited simultaneously. The performance is discussed for this gate's
      application to an optical EXOR logic gate.

PMID- 15038713
TI  - Sequence-specific assignments of methyl groups in high-molecular weight proteins.
AB  - A new 3D multiple-quantum (H)CCmHm-TOCSY experiment is proposed to assign methyl
      resonances in high-molecular weight proteins, on the basis of spectral patterns
      and prior backbone assignments. The favorable relaxation properties of the
      multiple-quantum coherences and the slow decays of in-phase methyl 13C
      magnetizations optimize performance of the proposed experiment for application to
      large proteins. The experiment has been demonstrated on an acyl carrier protein
      synthase (trimer, 42 kDa, overall correlation time of 26 ns) at 25 degrees C, and
      63 out of 67 nonmethionine methyl groups have been assigned.

PMID- 15038714
TI  - Ru(II)-catalyzed chemo- and regioselective cyclotrimerization of three
      unsymmetrical alkynes through boron temporary tether. One-pot four-component
      coupling via cyclotrimerization/Suzuki-Miyaura coupling.
AB  - The Ru(II)-catalyzed [2+2+2] cyclotrimerization of alkynylboronates, propargyl
      alcohol, and terminal alkynes proceeded chemo- and regioselectively to give rise
      to arylboronates, which were subjected to Suzuki-Miyaura cross-coupling with
      aryliodides to afford highly substituted biaryls in 53-76% yields.

PMID- 15038715
TI  - Molecular details of urease inhibition by boric acid: insights into the catalytic
      mechanism.
AB  - The structure of the complex of urease, a Ni-containing metalloenzyme, with boric
      acid was determined at 2.10 A resolution. The complex shows the unprecedented
      binding mode of the competitive inhibitor to the dinuclear metal center, with the
      B(OH)3 molecule bridging the Ni ions and leaving in place the bridging hydroxide.
      Boric acid can be considered a substrate analogue of urea, and the structure
      supports the proposal that the Ni-bridging hydroxide acts as the nucleophile in
      the enzymatic process of urea hydrolysis.

PMID- 15038716
TI  - Magnetically ordered (Tc= 200 K) bis(tetracyanopyrazine)vanadium,
      V[TCNP]2.yCH2Cl2.
AB  - A new organic-based magnet, V[TCNP]2.yCH2Cl2 (TCNP = tetracyanopyrazine), has
      been synthesized, and its magnetic properties have been examined. The amorphous
      nature of V[TCNP]2.yCH2Cl2 makes it difficult to determine the structure of the
      material; however, ac and dc magnetic measurements indicate that it is a
      ferrimagnet below 200 K with a small coercive field of 8 Oe at 5 K.

PMID- 15038717
TI  - Interior surface modification of bacteriophage MS2.
AB  - An efficient strategy for the interior surface functionalization of MS2 viral
      capsids is reported, featuring a new hetero-Diels-Alder bioconjugation reaction.
      After virus isolation, the RNA genome was removed from the spherical particles by
      exposure to pH 11.8 conditions for a period of 4 h. Following this, 180 tyrosine
      residues on the interior surface of each "empty" capsid shell were modified by
      using a site-selective diazonium-coupling reaction. To attach additional
      functionality, the azo conjugate was reduced with Na2S2O4 to afford an ortho
      amino tyrosine derivative. Oxidation of this moiety with NaIO4 produced an o
      iminoquinone on the protein surface, which was found to undergo an efficient
      hetero-Diels-Alder reaction with N-(4-aminophenyl)acrylamide. This four-step
      procedure can be carried out in under 4 h, reaches high levels of conversion, and
      yields the desired conjugates in >60% overall yield.

PMID- 15038718
TI  - A new method for rapid characterization of the folding pathways of multidisulfide
      containing proteins.
AB  - Oxidative folding is a composite process that consists of both the conformational
      folding to the native three-dimensional structure and the regeneration of the
      native disulfide bonds of a protein, frequently involving over 100 disulfide
      intermediate species. Understanding the oxidative folding pathways of a multiple
      disulfide-containing protein is a very difficult task that often requires years
      of devoted research due to the high complexity of the process and the very
      similar features of the large number of intermediates. Here we developed a method
      for rapidly delineating the major features of the oxidative folding pathways of a
      protein. The method examines the temperature dependence of the oxidative folding
      rate of the protein in combination with reduction pulses. Reduction pulses expose
      the presence of structured intermediates along the pathways. The correlation
      between the regeneration rate at different temperatures and the stability of the
      structured intermediates reveals the role that the intermediates play in
      determining the pathway. The method was first tested with bovine pancreatic
      ribonuclease A whose folding pathways were defined earlier. Then, it was explored
      to discern some of the major features of the folding pathways of its homologue,
      frog Onconase. The results suggest that the stability of the three-dimensional
      structure of the native protein is a major determinant of the folding rate in
      oxidative folding.

PMID- 15038719
TI  - Stable helical polyguanidines: poly[N-(1-anthryl)-N'-[(R)- and/or (S)-3,7
      dimethyloctyl]guanidines].
AB  - Using chiral catalysts of (R)- and/or (S)-BINOL-Ti, the asymmetrical
      polymerization of achiral monomer, N-(1-anthryl)-N'-n-octadecylcarbodiimide,
      yielded soluble nonregioregular polyguanidines of Poly-R1 and Poly-S1. A
      racemization process occurred when the toluene solution of Poly-R1 was annealed
      at elevated temperatures (70-80 degrees C). Kinetic studies reveal this to be a
      slow process with an activation energy of ca. 36 kcal/mol. On the other hand,
      using titanium(IV) trifluoroethoxide catalyst, the polymerization of N-(1
      anthryl)-N'-[(R)- and/or (S)-3,7-dimethyloctyl]carbodiimides afforded highly
      regioregular polyguanidines of Poly-R2 and Poly-S2. These polymers adopt stable
      helices in various solvents and elevated temperatures, whose kinetically
      controlled conformations and thermodynamically controlled conformations are
      essentially the same.

PMID- 15038720
TI  - Synthesis and electronic properties of donor-acceptor pi-conjugated siloles.
AB  - An efficient method is presented for the synthesis of novel donor-acceptor silole
      chromophores through selective monohalogenation of 2,5-dimetallosiloles followed
      by Negishi alkyne cross-coupling reactions. The electronic properties and crystal
      packing of these new siloles can be controlled through judicious combinations of
      peripheral functional groups.

PMID- 15038721
TI  - Short total synthesis of (+/-)-sceptrin.
AB  - Gifted with novel chemical features and extraordinary biological activity,
      sceptrin has remained a prominent unanswered synthetic challenge since its
      characterization in 1981 by Faulkner and Clardy. A concise and practical solution
      to the myriad of chemical challenges posed by sceptrin is reported in this
      Communication. Thus, through a sequence involving rearrangement of an
      oxaquadricyclane, a new method for chemo- and regioselective halogenation, a mild
      sequence for 2-aminoimidazole formation, and careful synthetic choreography, (+/
      )-sceptrin is obtained in a minimum of steps and in 24% overall yield from
      dimethyl acetylenedicarboxylate without a single use of chromatography.

PMID- 15038722
TI  - trans-Bis(alkynyl) diruthenium(III) tetra(amidinate): an effective facilitator of
      electronic delocalization.
AB  - Insertion of a Ru2(DMBA) unit into 1,4-bisferrocenylbutadiyne drastically
      enhances the electronic coupling between two Fc units.

PMID- 15038723
TI  - Two-dimensional diversity: screening human cDNA phage display libraries with a
      random diversity probe for the display cloning of phosphotyrosine binding
      domains.
AB  - A random phosphopeptide probe (bio-pYZZZ) has been used for the isolation and
      identification of multiple SH2 domains from human cDNA-displaying phage
      libraries. In addition, on-phage analysis and quantification of binding
      affinities for these phage-displayed proteins has shown them to be functional
      domains, retaining the same characteristics as in their native state.

PMID- 15038724
TI  - Asymmetric catalysis with CO2: direct synthesis of optically active propylene
      carbonate from racemic epoxides.
AB  - This communication describes a convenient route to optically active propylene
      carbonate by a catalytic kinetic resolution process resulting from the coupling
      reaction of CO2 and racemic epoxides using simple chiral SalenCo(III)/quaternary
      ammonium halide catalyst systems.

PMID- 15038725
TI  - Ag-catalyzed asymmetric mannich reactions of enol ethers with aryl, alkyl,
      alkenyl, and alkynyl imines.
AB  - An efficient catalytic and enantioselective method (up to >98% ee) for Mannich
      reactions between trimethylsilyl enol ethers derived from acetone and
      acetophenone and aryl, alkenyl, alkynyl, and alkyl imines is disclosed. A large
      variety of beta-amino ketones can be synthesized in the presence of 1-5 mol %
      AgOAc and an inexpensive and readily available amino acid-derived phosphine. All
      Ag-catalyzed asymmetric Mannich reactions can be run in undistilled THF and air.
      The o-anisyl activating groups of product amines can be removed in >70% isolated
      yield through a single vessel operation. The synthetic utility of the catalytic
      asymmetric method is illustrated by a four-pot synthesis of optically pure
      alkaloid (-)-sedamine.

PMID- 15038726
TI  - Solid-phase synthesis of positively charged deoxynucleic guanidine (DNG)
      tethering a Hoechst 33258 analogue: triplex and duplex stabilization by
      simultaneous minor groove binding.
AB  - Deoxynucleic guanidine (DNG), a DNA analogue in which positively charged
      guanidine replaces the phosphodiester linkages, tethering to Hoechst 33258
      fluorophore by varying lengths has been synthesized. A pentameric thymidine DNG
      was synthesized on solid phase in the 3' --> 5' direction that allowed stepwise
      incorporation of straight chain amino acid linkers and a bis-benzimidazole
      (Hoechst 33258) ligand at the 5'-terminus using PyBOP/HOBt chemistry. The
      stability of (DNA)(2).DNG-H triplexes and DNA.DNG-H duplexes formed by DNG and
      DNG-Hoechst 33258 (DNG-H) conjugates with 30-mer double-strand (ds) DNA,
      d(CGCCGCGCGCGCGAAAAACCCGGCGCGCGC)/d(GCGGCGCGCGCGCTTTTTGGGCCGCGCGCG), and single
      strand (ss) DNA, 5'-CGCCGCGCGCGCGAAAAACCCGGCGCGCGC-3', respectively, has been
      evaluated by thermal melting and fluorescence emission experiments. The presence
      of tethered Hoechst ligand in the 5'-terminus of the DNG enhances the
      (DNA)(2).DNG-H triplex stability by a DeltaT(m) of 13 degrees C. The fluorescence
      emission studies of (DNA)(2).DNG-H triplex complexes show that the DNG moiety of
      the conjugates bind in the major groove while the Hoechst ligand resides in the
      A:T rich minor groove of dsDNA. A single G:C base pair mismatch in the target
      site decreases the (DNA)(2).DNG triplex stability by 11 degrees C, whereas
      (DNA)(2).DNG-H triplex stability was decreased by 23 degrees C. Inversion of A:T
      base pair into T:A base pair in the center of the binding site, which provides a
      mismatch selectively for DNG moiety, decreases the triplex stability by only 5-6
      degrees C. Upon hybridization of DNG-Hoechst conjugates with the 30-mer ssDNA,
      the DNA.DNG-H duplex exhibited significant increase in the fluorescence emission
      due to the binding of the tethered Hoechst ligand in the generated DNA.DNG minor
      groove, and the duplex stability was enhanced by DeltaT(m) of 7 degrees C. The
      stability of (DNA)(2).DNG triplexes and DNA.DNG duplexes is independent of pH,
      whereas the stability of (DNA)(2).DNG-H triplexes decreases with increase in pH.

PMID- 15038727
TI  - Chemical genetic control of protein levels: selective in vivo targeted
      degradation.
AB  - Genetic loss of function analysis is a powerful method for the study of protein
      function. However, some cell biological questions are difficult to address using
      traditional genetic strategies often due to the lack of appropriate genetic model
      systems. Here, we present a general strategy for the design and syntheses of
      molecules capable of inducing the degradation of selected proteins in vivo via
      the ubiquitin-proteasome pathway. Western blot and fluorometric analyses
      indicated the loss of two different targets: green fluorescent protein (GFP)
      fused with FK506 binding protein (FKBP12) and GFP fused with the androgen
      receptor (AR), after treatment with PROteolysis TArgeting Chimeric moleculeS
      (PROTACS) incorporating a FKBP12 ligand and dihydrotestosterone, respectively.
      These are the first in vivo examples of direct small molecule-induced recruitment
      of target proteins to the proteasome for degradation upon addition to cultured
      cells. Moreover, PROTAC-mediated protein degradation offers a general strategy to
      create "chemical knockouts," thus opening new possibilities for the control of
      protein function.

PMID- 15038728
TI  - Control of bacteria adhesion by cell-wall engineering.
AB  - UDP-MurNAc-pentapeptide derivative bacterial cell-wall precursors were
      synthesized as effective tools for surface display on living bacteria.
      Lactobacilli were incubated in the ketone-modified precursor-containing medium,
      and the ketone moiety was displayed on the bacterial surface through cell-wall
      biosynthesis. Oligomannose was coupled with the ketone moiety on the bacterial
      surface via a aminooxyl linker, thereby displaying this oligosaccharide on the
      surface of the bacteria. The increase in the adhesion of the sugar-displaying
      bacteria onto a concanavalin A-attached film compared to that of native bacteria
      was confirmed by microscopic observation and surface plasmon resonance
      measurement. The incorporation of the artificial cell-wall precursors was
      enhanced when incubated with fosfomycin, an inhibitor of cell-wall precursor
      biosynthesis.

PMID- 15038729
TI  - The diastereomeric assembly of polylysine is the low-volume pathway for
      preferential formation of beta-sheet aggregates.
AB  - The interaction of left- and right-handed polylysine chains (poly(D-lysine) and
      poly(L-lysine)) results in a dramatic increase in the propensity to form
      aggregated beta-sheet structure (and amyloid-like fibrils), which is reflected by
      an approximately 15 degrees C decrease of temperature of the alpha-helix-to-beta
      sheet transition. While a relative volume expansion of 13-19 mL x mol(-1)
      accompanies the alpha-to-beta-transition in a single enantiomer, this does not
      hold true for the mixture, which, along with substantially more negative heat
      capacity changes, points to a lower solvent-entropy cost of the transition as the
      possible thermodynamic driving force of the diastereomeric aggregation. The
      underlying solvational mechanism may be one of the decisive factors responsible
      for the spontaneous protein aggregation in vivo and, as such, may shed new light
      on the molecular basis of amyloid-associated diseases.

PMID- 15038730
TI  - Probing the transition states of four glucoside hydrolyses with 13C kinetic
      isotope effects measured at natural abundance by NMR spectroscopy.
AB  - Kinetic isotope effects (KIEs) were measured for methyl glucoside (4) hydrolysis
      on unlabeled material by NMR. Twenty-eight (13)C KIEs were measured on the acid
      catalyzed hydrolysis of alpha-4 and beta-4, as well as enzymatic hydrolyses with
      yeast alpha-glucosidase and almond beta-glucosidase. The 1-(13)C KIEs on the acid
      catalyzed reactions of alpha-4 and beta-4, 1.007(2) and 1.010(6), respectively,
      were in excellent agreement with the previously reported values (1.007(1),
      1.011(2): Bennet and Sinnott, J. Am. Chem. Soc. 1986, 108, 7287). Transition
      state analysis of the acid-catalyzed reactions using the (13)C KIEs, along with
      the previously reported (2)H KIEs, confirmed that both reactions proceed with a
      stepwise D(N)A(N) mechanism and showed that the glucosyl oxocarbenium ion
      intermediate exists in an E(3) sofa or (4)H(3) half-chair conformation. (13)C
      KIEs showed that the alpha-glucosidase reaction also proceeded through a
      D(N)*A(N) mechanism, with a 1-(13)C KIE of 1.010(4). The secondary (13)C KIEs
      showed evidence of distortions in the glucosyl ring at the transition state. For
      the beta-glucosidase-catalyzed reaction, the 1-(13)C KIE of 1.032(1) demonstrated
      a concerted A(N)D(N) mechanism. The pattern of secondary (13)C KIEs was similar
      to the acid-catalyzed reaction, showing no signs of distortion. KIE measurement
      at natural abundance makes it possible to determine KIEs much more quickly than
      previously, both by increasing the speed of KIE measurement and by obviating the
      need for synthesis of isotopically labeled compounds.

PMID- 15038731
TI  - Electronic and spectroscopic studies of the non-heme reduced binuclear iron sites
      of two ribonucleotide reductase variants: comparison to reduced methane
      monooxygenase and contributions to O2 reactivity.
AB  - Circular dichroism (CD), magnetic circular dichroism (MCD), and variable
      temperature variable-field (VTVH) MCD have been used to probe the biferrous
      active site of two variants of ribonucleotide reductase. The aspartate to
      glutamate substitution (R2-D84E) at the binuclear iron site modifies the
      endogenous ligand set of ribonucleotide reductase to match that of the binuclear
      center in the hydroxylase component of methane monooxygenase (MMOH). The crystal
      structure of chemically reduced R2-D84E suggests that the active-site structure
      parallels that of MMOH. However, CD, MCD, and VTVH MCD data combined with spin
      Hamiltonian analysis of reduced R2-D84E indicate a different coordination
      environment relative to reduced MMOH, with no mu-(1,1)(eta(1),eta(2)) carboxylate
      bridge. To further understand the variations in geometry of the active site,
      which lead to differences in reactivity, density functional theory (DFT)
      calculations have been carried out to identify active-site structures for R2-wt
      and R2-D84E consistent with these spectroscopic data. The effects of varying the
      ligand set, positions of bound and free waters, and additional protein
      constraints on the geometry and energy of the binuclear site of both R2-wt and
      variant R2s are also explored to identify the contributions to their structural
      differences and their relation to reduced MMOH.

PMID- 15038732
TI  - The role of large conformational changes in efficient ultrafast internal
      conversion: deviations from the energy gap law.
AB  - Conversion of electronic excitation energy into vibrational energy was
      investigated for photochromic spiropyran molecules, using femtosecond UV-mid-IR
      pump-probe spectroscopy. We observe a weaker energy gap dependence than demanded
      by the "energy gap law". We demonstrate that large conformational changes
      accompanying the optical excitation can explain the observed time scale and
      energy gap dependence of ultrafast S(1) --> S(0) internal conversion processes.
      The possibility of dramatic deviations from standard energy gap law behavior is
      predicted. We conclude that controlling molecular conformations by rigid
      environments can have a substantial impact on photophysical and (bio)chemical
      processes.

PMID- 15038733
TI  - Mechanisms of HNO and NO production from Angeli's salt: density functional and
      CBS-QB3 theory predictions.
AB  - The mechanism of decomposition of Angeli's salt, Na(2)N(2)O(3), was explored with
      B3LYP and CBS-QB3 computational methods. Angeli's salt produces both nitroxyl
      (HNO) and nitric oxide (NO), depending upon the pH of the solution. These
      calculations show that protonation on N(2), while less favorable than O
      protonation, leads spontaneously to HNO production, while diprotonation at O(3)
      leads to NO generation. K(a) values for protonation at different centers and rate
      constants have been found which reproduce experimental data satisfactorily.

PMID- 15038734
TI  - Conformational control in the cyclization of hydrogen-bonded supramolecular
      polymers.
AB  - Bifunctional 2-ureido-4[1H]-pyrimidinone (UPy) derivatives can form small cyclic
      oligomers as well as long supramolecular polymers in chloroform solutions using
      the quadruple hydrogen-bonding motif. Ring-chain equilibria of a set of
      supramolecular monomers containing methyl-substituted alkyl linkers between the
      hydrogen-bonding UPy moieties were investigated by (1)H NMR spectroscopy and
      viscometry. The data were characterized in terms of critical concentration (CC,
      denoting the onset of polymerization) and equilibrium cyclic dimer concentration
      (EDC, representing preorganization of the monomer toward selective formation of
      cyclic dimer). Methyl substituents in the monomer were found to promote
      conformations favorable for cyclic dimerization, leading to an increase in both
      the EDC and the CC with respect to unsubstituted monomer. Furthermore, we
      observed an odd-even effect in the CC and EDC with increasing length of the
      linker between the hydrogen-bonding units. The combined results allow tuning of
      the critical concentration over a broad range and offer detailed information on
      the correlation between monomer structure, conformation, and polymerizability
      which may provide new insights for the study and design of other ring-chain
      equilibria or helix-random coil transitions.

PMID- 15038735
TI  - Characterization of a chiral stationary phase by HR/MAS NMR spectroscopy and
      investigation of enantioselective interaction with chiral ligates by transferred
      NOE.
AB  - The surface chemistry of a chiral stationary phase (CSP) with a (tert-butyl
      carbamoyl) quinine selector immobilized on thiol-modified silica has been
      characterized by (1)H HR/MAS NMR and (29)Si CP/MAS NMR spectroscopy. The mostly
      well-resolved (1)H signals could be assigned to stem from the surface-bound
      selector and the latter suggested a bi- and trifunctional silane linkage.
      Suspended-state NMR spectroscopy thus proved a well-characterized surface
      chemistry as proposed. To study chiral recognition phenomena in the presence of
      the CSP, (1)H HR/MAS 2D transfer NOESY investigations in methanol-d(4) have been
      undertaken with various solutes including N-3,5-dinitrobenzoyl derivatives of
      leucine (DNB-Leu) and N-acetyl phenylalanine (Ac-Phe). Both (R)- and (S)
      enantiomers of DNB-Leu and Ac-Phe interacted with the tBuCQN-CSP as indicated by
      negative cross-peaks in the trNOESY spectra, while the 2D NOESY of the dissolved
      solutes in absence of the chiral stationary phase showed positive cross-peaks.
      The intensities of the trNOE cross-peaks were much stronger for the (S)
      enantiomers. This stereoselectivity paralleled the experimental chromatographic
      behavior, where the (S)-enantiomers revealed stronger binding and retention on
      the tBuCQN-CSP as well. Hence, we were able to correlate the retention behavior
      to the trNOE NMR spectroscopic data in a qualitative manner.

PMID- 15038736
TI  - A contrivance for a dynamic porous framework: cooperative guest adsorption based
      on square grids connected by amide-amide hydrogen bonds.
AB  - Flexible porous coordination polymers containing amide groups as a function
      origin have been synthesized and categorized as "Coordination Polymer with Amide
      Groups". Bispyridyl ligands with a spacer of amide group afford two-dimensional
      (2-D) motifs with a deformed square grid, resulting in three-dimensional (3-D)
      frameworks of [Co(NO(3))(2)(3-pna)(2)](n)(1), [Co(Br)(2)(3-pna)(2)](n)(2), and
      [[Co(NCS)(2)(4-peia)(2)].4Me(2)CO](n)(3 subset 4Me(2)CO) (3-pna = N-3
      pyridylnicotinamide, 4-peia = N-(2-pyridin-4-yl-ethyl)-isonicotinamide), where
      the 2-D motifs are bound by complementary hydrogen bond between the amide groups.
      In the case of the 3 subset 4Me(2)CO, the amide groups form a contrivance for a
      dynamic porous framework because of their relevant position and orientation in
      the mutual nearest neighboring motifs. Consequently, 3 subset 4Me(2)CO shows
      amorphous (nonporous)-to-crystal (porous) structural rearrangement in the Me(2)CO
      adsorption and desorption process, where the framework of the 2-D motif is
      maintained. The adsorption isotherm has threshold pressure (P(th)), a sort of
      gate pressure. The heat of Me(2)CO adsorption (DeltaH(ad) = -25 kJ/mol) is
      obtained from the temperature dependence of threshold pressure (P(th)), which is
      close to acetone vaporization enthalpy (DeltaH(vap) = 30.99 kJ/mol).

PMID- 15038737
TI  - Resonance Raman studies of HOO-Co(III)bleomycin and Co(III)bleomycin:
      identification of two important vibrational modes, nu(Co-OOH) and nu(O-OH).
AB  - Bleomycin is an antitumor agent whose cytotoxicity is dependent on its ability to
      bind DNA in the nucleus and effect double-stranded DNA cleavage, which is
      difficult for the cell to repair. In order for this DNA cleavage to occur,
      bleomycin must, through a series of reactions, form a low-spin Fe(III) complex,
      the putative "activated" form of the drug, HOO-Fe(III)bleomycin. The relative
      strengths of the bonds in the Fe(III)-OOH linkage have not been determined due to
      the weakness of the hydroperoxo-to-iron(III) charge-transfer transition. The much
      more stable HOO-Co(III)bleomycin has often been studied as a structural analogue
      of HOO-Fe(III)bleomycin, and hence, an understanding of the relative bond
      strengths in the Co-OOH linkage may serve to enhance our understanding of the
      analogous Fe-OOH linkage. In this report, we present resonance Raman data that
      identify two important vibrational modes in the Co-OOH linkage, the stretching
      modes, nu(Co-OOH) and nu(O-OH). Both of these vibrational modes were found to be
      unperturbed by complexation of the drug with calf thymus DNA. Advantage was also
      taken of the isostructural realtionship between Fe-bleomycin and Co-bleomycin to
      analyze and assign the high-frequency modes for HOO-Co(III)bleomycin and
      Co(III)bleomycin (A(2) and B(2)). These data could be useful for future studies
      of photoactivated Co-bleomycin and Co-bleomycin analogues in an attempt to
      characterize oxygen-independent DNA damage pathways.

PMID- 15038738
TI  - Further studies on the biosynthesis of the manumycin-type antibiotic, asukamycin,
      and the chemical synthesis of protoasukamycin.
AB  - Asukamycin (2), a metabolite of Streptomyces nodosus ssp. asukaensis ATCC 29757
      and a member of the manumycin family of antibiotics, is assembled from three
      components, an "upper" polyketide chain initiated by cyclohexanecarboxylic acid,
      a "lower" polyketide chain initiated by the novel starter unit, 3-amino-4
      hydroxybenzoic acid (3,4-AHBA), and a cyclized 5-aminolevulinic acid moiety, 2
      amino-3-hydroxycyclopent-2-enone (C(5)N unit). To shed light on the order in
      which these components are assembled, we synthesized in labeled form various
      potential intermediates and evaluated their incorporation into 2. The assembly of
      the molecular framework of 2 from 3,4-AHBA and cyclohexanecarboxylic acid
      apparently does not involve free, unactivated intermediates. However,
      protoasukamycin (12), the total synthesis of which is reported, was efficiently
      converted into 2, demonstrating that the modification of the aromatic ring to the
      epoxyquinol structure is the terminal step in the biosynthesis. The results
      suggest that the two polyketide chains are synthesized separately and that the
      "upper" chain must be connected to the "lower" polyketide chain before the C(5)N
      unit.

PMID- 15038739
TI  - Covalent versus electrostatic nature of the strong hydrogen bond: discrimination
      among single, double, and asymmetric single-well hydrogen bonds by variable
      temperature X-ray crystallographic methods in beta-diketone enol RAHB systems.
AB  - Beta-diketone enols are known to form intramolecular...O=C-C=C-OH... resonance
      assisted hydrogen bonds (RAHBs) with O...O distances as short as 2.39-2.44 A.
      However, even the most accurate diffraction studies have not been able to assess
      with certainty whether these very strong hydrogen bonds (H-bonds) are to be
      described as proton-centered O...H...O bonds in a single-well (SW) potential or
      as the dynamic or static mixing of two O-H...O <= => O...H-O tautomers in a
      double-well (DW) one. This contribution reexamines the problem and shows that
      diffraction methods are fairly able to assess the SW or DW nature of the H-bond
      formed and, in the second case, its dynamic or static nature, provided a Bayesian
      approach is used which associates a number of experimental techniques (X-ray
      crystallography at variable temperature, difference Fourier maps, least-squares
      refinement of proton populations, Hirshfeld's rigid-bond test) with a reasonable
      prior, that is the full set of possible proton-transfer (PT) pathways for the O
      H...O system derived from theoretical calculations. The method is first applied
      to three beta-diketone enols, whose crystal structures were determined in the
      interval of temperatures 100-295 K and then generalized to the interpretation of
      a much wider set of beta-diketone enol structures derived from the literature,
      making it possible to establish a general relationship between chemical structure
      (symmetric or dissymmetric substitution, steric compression or stretching,
      increased pi-bond delocalizability), H-bond strength, and the shape of the PT
      barrier. Final results are interpreted in terms of simplified VB theory and state
      correlation (or avoided-crossing) diagrams.

PMID- 15038740
TI  - Liquid-crystalline octopus dendrimers: block molecules with unusual mesophase
      morphologies.
AB  - The synthesis and the mesomorphic properties of several new main-chain liquid
      crystalline dendrimers, thereafter designated as octopus dendrimers in accordance
      with their eight sidearms, are reported. In these dendritic systems, the
      arborescence is ensured by anisotropic segments, acting as branching cells with a
      double multiplicity, which are incorporated at every node of the dendritic
      architecture. In such a way, these compounds radically differ from the classical
      end-functionalized liquid-crystalline dendrimers, the most commonly reported
      systems. Following our previous report on purely homolithic systems, that is, the
      building blocks constituting the dendritic matrix are all identical, several
      heterolithic systems made of different anisotropic blocks have been prepared. The
      dendritic branches and corresponding dendrimers were synthesized using a modular
      construction. Polarized optical microscopy and X-ray diffraction studies showed
      that all of these new octopus dendrimers exhibit either smectic-like or columnar
      phases with novel morphologies, the nature of the mesophases depending on the
      number of terminal chains attached to the peripheral groups. The mesomorphism of
      these heterolithic dendrimers is discussed in terms of their intrinsic
      architecture and compared to the analogous homolithic octopus systems. Models for
      the molecular organizations within both the smectic and the columnar phases are
      proposed on the basis of small Bragg angle X-ray diffraction studies and are
      supported by molecular modelizations. Moreover, this study showed that the
      mesophase stability is very sensitive to the nature and to the mutual arrangement
      (the spatial location) of the mesogenic segments within the dendritic matrix,
      illustrating the intimate relationships existing between the mesomorphic
      properties and the molecular architecture of these dendrimers.

PMID- 15038741
TI  - Photocatalytic synthesis of silver nanoparticles stabilized by TiO2 nanorods: a
      semiconductor/metal nanocomposite in homogeneous nonpolar solution.
AB  - A novel colloidal approach toward semiconductor/metal nanocomposites is
      presented. Organic-soluble anatase TiO(2) nanorods are used for the first time to
      stabilize Ag nanoparticles in optically clear nonpolar solutions in the absence
      of specific ligands for silver. Metallic silver is generated upon UV illumination
      of deaerated TiO(2) solutions containing AgNO(3). The Ag nanoparticles can be
      obtained in different size-morphological regimes as a function of the irradiation
      time, due to light-induced photofragmentation and ripening processes. A mechanism
      for the colloidal stabilization of the silver nanoparticles is tentatively
      suggested, which regards the TiO(2) nanorods as inorganic stabilizers, thus
      acting in the same manner as conventional surfactant molecules. The proposed
      photocatalytic approach offers a convenient method for producing TiO(2)/Ag
      nanocomposite systems with a certain control over the metal particle size without
      the use of surfactants and/or additives. Stable colloidal TiO(2)-nanorod
      stabilized Ag nanoparticles can be potentially available for a number of
      applications that require "clean" metal surfaces, such as homogeneous organic
      catalysis, photocatalysis, and sensing devices.

PMID- 15038742
TI  - Syntheses and spectroscopic and quadratic nonlinear optical properties of
      extended dipolar complexes with ruthenium(II) ammine electron donor and N
      methylpyridinium acceptor groups.
AB  - In this paper, we describe the extremely unusual optical properties of Ru(II)
      based electron donor-acceptor (D-A) polyene and some closely related
      chromophores. For three different polyene series, the intense, visible d-->pi*
      metal-to-ligand charge-transfer bands unexpectedly blue-shift as the number of E
      ethylene units (n) increases from 1 to 3, and the static first
      hyperpolarizabilities beta(0) determined via hyper-Rayleigh scattering and Stark
      spectroscopy maximize at n = 2, in marked contrast to other known D-A polyenes in
      which beta(0) increases steadily with n. Time-dependent density-functional theory
      and finite field calculations verify these empirical trends, which arise from the
      orbital structures of the complexes. This study illustrates that transition metal
      based nonlinear optical chromophores can show very different behavior when
      compared with their more thoroughly studied purely organic counterparts.

PMID- 15038743
TI  - Mechanistic study on the replacement reaction between silver nanostructures and
      chloroauric acid in aqueous medium.
AB  - The replacement reaction between silver nanostructures and an aqueous HAuCl(4)
      solution has recently been demonstrated as a versatile method for generating
      metal nanostructures with hollow interiors. Here we describe the results of a
      systematic study detailing the morphological, structural, compositional, and
      spectral changes involved in such a heterogeneous reaction on the nanoscale. Two
      distinctive steps have been resolved through a combination of microscopic and
      spectroscopic methods. In the first step, silver nanostructure (i.e., the
      template) is dissolved to generate gold atoms that are deposited epitaxially on
      the surface of each template. Silver atoms also diffuse into the gold shell (or
      sheath) to form a seamless, hollow nanostructure with its wall made of Au-Ag
      alloys. The second step involves dealloying, a process that selectively removes
      silver atoms from the alloyed wall, induces morphological reconstruction, and
      finally leads to the formation of pinholes in the walls. Reaction temperature was
      found to play an important role in the replacement reaction because the
      solubility constant of AgCl and the diffusion coefficients of Ag and Au atoms
      were both strongly dependent on this parameter. This work has enabled us to
      prepare metal nanostructures with controllable geometric shapes and structures,
      and thus optical properties (for example, the surface plasmon resonance peaks
      could be readily shifted from 500 to 1200 nm by controlling the ratio between Ag
      and HAuCl(4)).

PMID- 15038745
TI  - Competitive paths for methanol decomposition on Pt(111).
AB  - Periodic, self-consistent, Density Functional Theory (PW91-GGA) calculations are
      used to study competitive paths for the decomposition of methanol on Pt(111).
      Pathways proceeding through initial C-H and C-O bond scission events in methanol
      are considered, and the results are compared to data for a pathway proceeding
      through an initial O-H scission event [Greeley et al. J. Am. Chem. Soc. 2002,
      124, 7193]. The DFT results suggest that methanol decomposition via CH(2)OH and
      either formaldehyde or HCOH intermediates is an energetically feasible pathway; O
      H scission to CH(3)O, followed by sequential dehydrogenation, may be another
      realistic route. Microkinetic modeling based on the first-principles results
      shows that, under realistic reaction conditions, C-H scission in methanol is the
      initial decomposition step with the highest net rate. The elementary steps of all
      reaction pathways (with the exception of C-O scission) follow a linear
      correlation between the transition state and final state energies. Simulated
      HREELS spectra of the intermediates show good agreement with available
      experimental data, and HREELS spectra of experimentally elusive reaction
      intermediates are predicted.

PMID- 15038744
TI  - Molecule-specific imaging with mass spectrometry and a buckminsterfullerene
      probe: application to characterizing solid-phase synthesized combinatorial
      libraries.
AB  - We employ a newly developed buckminsterfullerene (C(60)) primary ion beam with
      time-of-flight secondary ion mass spectrometry to create molecule-specific images
      of resin particles employed in the solid-phase synthesis of peptide combinatorial
      libraries. This new cluster ion source, when operated at an incident energy of 20
      keV, is remarkably effective at desorbing small peptides directly from a polymer
      surface and opens new possibilities for characterizing large arrays of diverse
      sets of molecules. In addition, the C(60) ion beam may be focused to a spot of
      1.5 microm in diameter, enabling molecule-specific images of single 100 microm
      resin particles to be acquired. We report three significant aspects associated
      with utilizing the C(60) projectile that show how this technology can be taken to
      a more advanced level, especially when compared to results obtained with more
      conventional atomic primary ions. First, the useful yield of molecular ions is
      generally observed to be enhanced by at least 3 orders of magnitude over those
      previously possible. Second, the energy dissipation process associated with the
      C(60) impact is most efficient at desorbing molecules on soft substrates such as
      polymer surfaces rather than harder substrates such as metals or semiconductors.
      Third, there is a greatly reduced tendency for insulating surfaces to build up
      excess charge, obviating the need for charge compensation. Using a small five
      member peptide library as a model, we show that by utilizing the focusing
      properties of the C(60) beam, it is possible to assay the surface composition of
      100-microm polymer beads at a rate of up to 10 particles/s. Moreover, even at the
      picomole level, there are enough sequence ions in the mass spectrum to determine
      a unique composition. The results illustrate the ability to quickly assay large
      libraries without the use of tags and suggest the strategy may be applicable to a
      range of high-throughput experiments.

PMID- 15038746
TI  - Chemical activity of the nitrogenase FeMo cofactor with a central nitrogen
      ligand: density functional study.
AB  - We investigate the chemical consequences of a central ligand in the nitrogenase
      FeMo cofactor using density functional calculations. Several studies have shown
      that the central ligand most probably is a nitrogen atom, but the consequences
      for the chemical reactivity of the cofactor are unknown. We investigate several
      possible routes for insertion of the central nitrogen ligand and conclude that
      all routes involve barriers and intermediate states, which are inaccessible at
      ambient conditions. On this basis we suggest that the central nitrogen ligand is
      present at all times during the reaction. Furthermore, we investigate how the
      FeMoco with the central ligand can interact with N(2) and reduce it.

PMID- 15038747
TI  - Electronic structure and solvation of copper and silver ions: a theoretical
      picture of a model aqueous redox reaction.
AB  - Electronic states and solvation of Cu and Ag aqua ions are investigated by
      comparing the Cu(2+) + e(-)--> Cu(+) and Ag(2+) + e(-)--> Ag(+) redox reactions
      using density functional-based computational methods. The coordination number of
      aqueous Cu(2+) is found to fluctuate between 5 and 6 and reduces to 2 for Cu(+),
      which forms a tightly bound linear dihydrate. Reduction of Ag(2+) changes the
      coordination number from 5 to 4. The energetics of the oxidation reactions is
      analyzed by comparing vertical ionization potentials, relaxation energies, and
      vertical electron affinities. The model is validated by a computation of the free
      energy of the full redox reaction Ag(2+) + Cu(+) --> Ag(+) + Cu(2+).
      Investigation of the one-electron states shows that the redox active frontier
      orbitals are confined to the energy gap between occupied and empty states of the
      pure solvent and localized on the metal ion hydration complex. The effect of
      solvent fluctuations on the electronic states is highlighted in a computation of
      the UV absorption spectrum of Cu(+) and Ag(+).

PMID- 15038748
TI  - Molecular view of the anomalous acidities of Sn2+, Pb2+, and Hg2+.
AB  - Experimental results taken from both the condensed and gaseous phase show that,
      when associated with water, the three dications Sn(2+), Pb(2+), and Hg(2+)
      exhibit a facile proton-transfer reaction. In the gas phase, no stable
      [M.(H(2)O)(n)](2+) ions are observed; but instead the cations appear to undergo
      rapid hydrolysis to give ions of the form M(+)OH(H(2)O)(n-1). A series of ab
      initio calculations have been undertaken on the structures and proton-transfer
      reaction profiles associated with the complexes [M.(H(2)O)(2,4)](2+), where M is
      one of Sn, Pb, Hg, and Ca. The latter has been used as a reference point both in
      terms of comparisons with previous calculations, and the fact that Ca(2+) is a
      very weak acid. The calculations show that for Sn(2+), Pb(2+), and Hg(2+), the
      only barriers to proton transfer are those associated with the movement of water
      molecules. In the gas phase, these barriers could be overcome through energy
      gained during ion formation, and in the condensed phase the thermal motion of
      water molecules would be sufficient. In contrast, the calculations show that for
      Ca(2+) it is the proton-transfer step that provides the most significant reaction
      barrier. Proton transfer in Sn(2+) and Pb(2+) is further assisted by distortions
      in the geometries of [M.(H(2)O)(2,4)](2+) complexes due to voids created by the
      5s(2) (6s(2)) inert lone pair. For Hg(2+), ease of proton transfer is derived
      partly from the high degree of covalent bonding found in both the reactants and
      products.

PMID- 15038749
TI  - Protein-induced bonding perturbation of the rhodopsin chromophore detected by
      double-quantum solid-state NMR.
AB  - We have obtained carbon-carbon bond length data for the functional retinylidene
      chromophore of rhodopsin, with a spatial resolution of 3 pm. The very high
      resolution was obtained by performing double-quantum solid-state NMR on a set of
      noncrystalline isotopically labelled bovine rhodopsin samples. We detected
      localized perturbations of the carbon-carbon bond lengths of the retinylidene
      chromophore. The observations are consistent with a model in which the positive
      charge of the protonated Schiff base penetrates into the polyene chain and
      partially concentrates around the C13 position. This coincides with the proximity
      of a water molecule located between the glutamate-181 and serine-186 residues of
      the second extracellular loop, which is folded back into the transmembrane
      region. These measurements support the hypothesis that the polar residues of the
      second extracellular loop and the associated water molecule assist the rapid
      selective photoisomerization of the retinylidene chromophore by stabilizing a
      partial positive charge in the center of the polyene chain.

PMID- 15038750
TI  - The dynamics of noble metal atom penetration through methoxy-terminated
      alkanethiolate monolayers.
AB  - We have studied the interaction of vapor-deposited Al, Cu, Ag, and Au atoms on a
      methoxy-terminated self-assembled monolayer (SAM) of HS(CH(2))(16)OCH(3) on
      polycrystalline Au[111]. Time-of-flight secondary ion mass spectrometry, infrared
      reflection spectroscopy, and X-ray photoelectron spectroscopy measurements at
      increasing coverages of metal show that for Cu and Ag deposition at all coverages
      the metal atoms continuously partition into competitive pathways: penetration
      through the SAM to the S/substrate interface and solvation-like interaction with
      the -OCH(3) terminal groups. Deposited Au atoms, however, undergo only continuous
      penetration, even at high coverages, leaving the SAM "floating" on the Au
      surface. These results contrast with earlier investigations of Al deposition on a
      methyl-terminated SAM where metal atom penetration to the Au/S interface ceases
      abruptly after a approximately 1:1 Al/Au layer has been attained. These
      observations are interpreted in terms of a thermally activated penetration
      mechanism involving dynamic formation of diffusion channels in the SAM via
      hopping of alkanethiolate-metal (RSM-) moieties across the surface. Using
      supporting quantum chemical calculations, we rationalized the results in terms of
      the relative heights of the hopping barriers, RSAl > RSAg, RSCu > RSAu, and the
      magnitudes of the metal-OCH(3) solvation energies.

PMID- 15038751
TI  - Probing slow dynamics in high molecular weight proteins by methyl-TROSY NMR
      spectroscopy: application to a 723-residue enzyme.
AB  - A new CPMG-based multiple quantum relaxation dispersion experiment is presented
      for measuring millisecond dynamic processes at side-chain methyl positions in
      high molecular weight proteins. The experiment benefits from a methyl-TROSY
      effect in which cancellation of intramethyl dipole fields occurs, leading to
      methyl (13)C-(1)H correlation spectra of high sensitivity and resolution
      (Tugarinov, V.; Hwang, P. M.; Ollerenshaw, J. E.; Kay, L. E. J. Am. Chem. Soc.
      2003, 125, 10420-10428). The utility of the methodology is illustrated with an
      application to a highly deuterated, methyl-protonated sample of malate synthase
      G, an 82 kDa enzyme consisting of a single polypeptide chain. A comparison of the
      sensitivity obtained using the present approach relative to existing HSQC-type
      (13)C single quantum dispersion experiments shows a gain of a factor of 5.4 on
      average, significantly increasing the range of applications for this methodology.

PMID- 15038752
TI  - Charge transfer in the electron donor-acceptor complex BH3NH3.
AB  - As a simple yet strongly binding electron donor-acceptor (EDA) complex,
      BH(3)NH(3) serves as a good example to study the electron pair donor-acceptor
      complexes. We employed both the ab initio valence bond (VB) and block-localized
      wave function (BLW) methods to explore the electron transfer from NH(3) to BH(3).
      Conventionally, EDA complexes have been described by two diabatic states: one
      neutral state and one ionic charge-transferred state. Ab initio VB self
      consistent field (VBSCF) computations generate the energy profiles of the two
      diabatic states together with the adiabatic (ground) state. Our calculations
      evidently demonstrated that the electron transfer between NH(3) and BH(3) falls
      in the abnormal regime where the reorganization energy is less than the
      exoergicity of the reaction. The nature of the NH(3)-BH(3) interaction is probed
      by an energy decomposition scheme based on the BLW method. We found that the
      variation of the charge-transfer energy with the donor-acceptor distance is
      insensitive to the computation levels and basis sets, but the estimation of the
      amount of electron transferred heavily depends on the population analysis
      procedures. The recent resurgence of interest in the nature of the rotation
      barrier in ethane prompted us to analyze the conformational change of BH(3)NH(3),
      which is an isoelectronic system with ethane. We found that the preference of the
      staggered structure over the eclipsed structure of BH(3)NH(3) is dominated by the
      Pauli exchange repulsion.

PMID- 15038753
TI  - Perturbation of conjugation in allylic lithium compounds due to stereochemical
      control of internal lithium coordination: crystallography, NMR, and calculational
      studies.
AB  - Several allylic lithium compounds have been prepared with ligands tethered at
      C(2). These are with (CH(3)OCH(2)CH(2))(2)NCH(2)-, 6, 1-TMS 5, 1,3-bis(TMS) 8,
      and 1,1,3-tris(TMS) 9. Allylic lithiums with
      (CH(3)OCH(2)CH(2))(2)NCH(2)C(CH(3))(2)-, are 10, 1-TMS 11, and 1,3-bis(TMS), 12
      compounds with -C(CH(3))(2)CH(2)N-((S)-(2-methoxymethyl)-pyrrolidino) at C(2) 13,
      1-TMS 14, and 1,3-bis(TMS) 15. In the solid state, 8-10 and 12 are monomers, 6
      and 13 are Li-bridged dimers, and 5 and 7 are polymers. In solution (NMR data),
      5, 7-12, 14, and 15 are monmeric, and 6 is a dimer. All samples show lithium to
      be closest to one of the terminal allyl carbons in the crystal structures and to
      exhibit one-bond (13)C-(7)Li or (13)C(1)-(7)Li spin coupling, for the former
      typically ca. 3 Hz and for the latter 6-8 Hz. In every structure, the C(1)-C(2)
      allyl bond is longer than the C(2)-C(3) bond, and both lie between those for
      solvated delocalized and unsolvated localized allylic lithium compounds,
      respectively, as is also the case for the terminal allyl (13)C NMR shifts.
      Lithium lies 40-70 degrees off the axis perpendicular to the allyl plane at C(1).
      These effects are variable, so the trend is that the differences between the C(1)
      C(2) and C(2)-C(3) bond lengths, (13)delta(3)-(13)delta(1) values, and the
      (13)C(1)-(7)Li or (13)C-(6)Li coupling constants all increase with decreasing
      values of the torsional angle that C(1)-Li makes with respect to the allyl plane.

PMID- 15038754
TI  - A theoretical study of the mechanism for the biogenesis of cofactor topaquinone
      in copper amine oxidases.
AB  - In the present quantum chemical study, the biogenesis of the cofactor topaquinone
      (TPQ) has been studied using hybrid density functional theory (B3LYP). The
      suggested mechanism is divided into six steps and incorporates the observation of
      four crystallized intermediates. The experimental suggestion that the formation
      of the Cu(II)-peroxy species is the rate-limiting step is consistent with the
      results of the present study. Before the formation of the Cu(II)-peroxy species,
      dioxygen is suggested to first bind at the equatorial position on the copper
      metal center. A mechanism for the critical O-O bond cleavage is suggested, and
      this step is found to be driven by an unusually large exothermicity. A complex,
      spin-forbidden formation of H(2)O(2) with and without the involvement of the
      copper metal center is discussed. The results are discussed in detail, and
      comparisons are made to experimental findings and suggestions.

PMID- 15038755
TI  - Failure of time-dependent density functional theory for long-range charge
      transfer excited states: the zincbacteriochlorin-bacteriochlorin and
      bacteriochlorophyll-spheroidene complexes.
AB  - It is well-known that time-dependent density functional theory (TDDFT) yields
      substantial errors for the excitation energies of charge-transfer (CT) excited
      states, when approximate standard exchange-correlation (xc) functionals are used,
      for example, SVWN, BLYP, or B3LYP. Also, the correct 1/R asymptotic behavior of
      CT states with respect to a distance coordinate R between the separated charges
      of the CT state is not reproduced by TDDFT employing these xc-functionals. Here,
      we demonstrate by analysis of the TDDFT equations that the first failure is due
      to the self-interaction error in the orbital energies from the ground-state DFT
      calculation, while the latter is a similar self-interaction error in TDDFT
      arising through the electron transfer in the CT state. Possible correction
      schemes, such as inclusion of exact Hartree-Fock or exact Kohn-Sham exchange, as
      well as aspects of the exact xc-functional are discussed in this context.
      Furthermore, a practical approach is proposed which combines the benefits of
      TDDFT and configuration interaction singles (CIS) and which does not suffer from
      electron-transfer self-interaction. The latter approach is applied to a (1,4)
      phenylene-linked zincbacteriochlorin-bacteriochlorin complex and to a
      bacteriochlorophyll-spheroidene complex, in which CT states may play important
      roles in energy and electron-transfer processes. The errors of TDDFT alone for
      the CT states are demonstrated, and reasonable estimates for the true excitation
      energies of these states are given.

PMID- 15038756
TI  - Quantum mechanical/molecular mechanical investigation of the mechanism of C-H
      hydroxylation of camphor by cytochrome P450cam: theory supports a two-state
      rebound mechanism.
AB  - The stereospecific cytochrome P450-catalyzed hydroxylation of the C(5)-H((5-exo))
      bond in camphor has been studied theoretically by a combined quantum
      mechanical/molecular mechanical (QM/MM) approach. Density functional theory is
      employed to treat the electronic structure of the active site (40-100 atoms),
      while the protein and solvent environment (ca. 24,000 atoms) is described by the
      CHARMM force field. The calculated energy profile of the hydrogen-abstraction
      oxygen-rebound mechanism indicates that the reaction takes place in two spin
      states (doublet and quartet), as has been suggested earlier on the basis of
      calculations on simpler models ("two-state reactivity"). While the reaction on
      the doublet potential energy surface is nonsynchronous, yet effectively
      concerted, the quartet pathway is truly stepwise, including formation of a
      distinct intermediate substrate radical and a hydroxo-iron complex. Comparative
      calculations in the gas phase demonstrate the effect of the protein environment
      on the geometry and relative stability of intermediates (in terms of spin states
      and redox electromers) through steric constraints and electronic polarization.

PMID- 15038757
TI  - Structure-dependent charge transport and storage in self-assembled monolayers of
      compounds of interest in molecular electronics: effects of tip material,
      headgroup, and surface concentration.
AB  - The electrical properties of self-assembled monolayers (SAMs) on a gold surface
      have been explored to address the relation between the conductance of a molecule
      and its electronic structure. We probe interfacial electron transfer processes,
      particularly those involving electroactive groups, of SAMs of thiolates on Au by
      using shear force-based scanning probe microscopy (SPM) combined with current
      voltage (i-V) and current-distance (i-d) measurements. Peak-shaped i-V curves
      were obtained for the nitro- and amino-based SAMs studied here. Peak-shaped
      cathodic i-V curves for nitro-based SAMs were observed at negative potentials in
      both forward and reverse scans and were used to define the threshold tip bias,
      V(TH), for electric conduction. For a SAM of 2',5'-dinitro-4,4'
      bis(phenylethynyl)-1-benzenethiolate, VII, V(TH) was nearly independent of the
      tip material [Ir, Pt, Ir-Pt (20-80%), Pd, Ni, Au, Ag, In]. For all of the SAMs
      studied, the current decreased exponentially with increasing distance, d, between
      tip and substrate. The exponential attenuation factors (beta values) were lower
      for the nitro-based SAMs studied here, as compared with alkylthiol-based SAMs.
      Both V(TH) and beta of the nitro-based SAMs also depended strongly on the
      molecular headgroup on the end benzene ring addressed by the tip. Finally, we
      confirmed the "memory" effect observed for nitro-based SAMs. For mixed SAMs of
      VII and hexadecanethiol, I, the fraction of the charge collected in the negative
      tip bias region that can be read out at a positive tip bias on reverse scan (up
      to 38%) depended on the film composition and decreased with an increasing
      fraction of I, suggesting that lateral electron hopping among molecules of VII
      occurs in the vicinity of the tip.

PMID- 15038758
TI  - Electrocatalytic activity of ordered intermetallic phases for fuel cell
      applications.
AB  - The electrocatalytic activities of a wide range of ordered intermetallic phases
      toward a variety of potential fuels have been studied, and results have been
      compared to those of a pure polycrystalline platinum (Pt(pc)) electrode. A
      significant number of the ordered intermetallic phases exhibited enhanced
      electrocatalytic activity when compared to that of Pt, in terms of both oxidation
      onset potential and current density. The PtBi, PtIn, and PtPb ordered
      intermetallic phases appeared to be the most promising electrocatalysts tested
      thus far for fuel cell applications. PtPb, in particular, showed an onset
      potential that was 100 mV less positive and a peak current density approximately
      40 times higher than those observed for Pt in the case of methanol oxidation. The
      ability to control the geometric and electronic structures of the
      electrocatalytic material by using ordered intermetallic phases has been shown to
      be a promising direction of inquiry in the search for superior electrocatalysts
      for fuel cell applications.

PMID- 15038760
TI  - A genome scanning approach to assess the genetic effects of radiation in mice and
      humans.
AB  - We used Restriction Landmark Genome Scanning (RLGS) to assess, on a genome-wide
      basis, the mutation induction rate in mouse germ cells after radiation exposure.
      Analyses of 1,115 autosomal NotI DNA fragments per mouse for reduced spot
      intensity, indicative of loss of one copy, in 506 progeny derived from X
      irradiated spermatogonia (190, 237 and 79 mice in 0-, 3-, and 5-Gy groups,
      respectively), permitted us to identify 16 mutations affecting 23 fragments in 20
      mice. The 16 mutations were composed of eight small changes (1-9 bp) at
      microsatellite sequences, five large deletions (more than 25 kb), and three
      insertions of SINE B2 or LINE1 transposable elements. The maximum induction rate
      of deletion mutations was estimated as (0.17 +/- 0.09) x 10(-5)/locus Gy(-1). The
      estimate is considerably lower than 1 x 10(-5)/locus Gy(-1), the mean induction
      rate of deletion mutations at Russell's 7 loci, which assumed that deletion
      mutations comprise 50% of all mutations. We interpret the results as indicating
      that the mean induction rate of mutations in the whole genome may be
      substantially lower than that at the 7 loci. We also demonstrate the
      applicability of RLGS for detection of human mutations, which allows direct
      comparisons between the two species.

PMID- 15038761
TI  - Human fetuses do not register chromosome damage inflicted by radiation exposure
      in lymphoid precursor cells except for a small but significant effect at low
      doses.
AB  - Human fetuses are thought to be highly sensitive to radiation exposure because
      diagnostic low-dose X rays have been suggested to increase the risk of childhood
      leukemia. However, animal studies generally have not demonstrated a high
      radiosensitivity of fetuses, and the underlying causes for the discrepancy remain
      unidentified. We examined atomic bomb survivors exposed in utero for
      translocation frequencies in blood lymphocytes at 40 years of age. Contrary to
      our expectation of a greater radiosensitivity in fetuses than in adults, the
      frequency did not increase with dose except for a small increase (less than 1%)
      at doses below 0.1 Sv, which was statistically significant. We interpret the
      results as indicating that fetal lymphoid precursor cells comprise two
      subpopulations. One is small in number, sensitive to the induction of both
      translocations and cell killing, but rapidly diminishing above 50 mSv. The other
      is the major fraction but is insensitive to registering damage expressed as
      chromosome aberrations. Our results provide a biological basis for resolving the
      long-standing controversy that a substantial risk of childhood leukemia is
      implicated in human fetuses exposed to low-dose X rays whereas animal studies
      involving mainly high-dose exposures generally do not confirm it.

PMID- 15038762
TI  - A cohort study of thyroid cancer and other thyroid diseases after the Chornobyl
      accident: objectives, design and methods.
AB  - The thyroid gland in children is one of the organs that is most sensitive to
      external exposure to X and gamma rays. However, data on the risk of thyroid
      cancer in children after exposure to radioactive iodines are sparse. The
      Chornobyl accident in Ukraine in 1986 led to the exposure of large populations to
      radioactive iodines, particularly (131)I. This paper describes an ongoing cohort
      study being conducted in Belarus and Ukraine that includes 25,161 subjects under
      the age of 18 years in 1986 who are being screened for thyroid diseases every 2
      years. Individual thyroid doses are being estimated for all study subjects based
      on measurement of the radioactivity of the thyroid gland made in 1986 together
      with a radioecological model and interview data. Approximately 100 histologically
      confirmed thyroid cancers were detected as a consequence of the first round of
      screening. The data will enable fitting appropriate dose-response models, which
      are important in both radiation epidemiology and public health for prediction of
      risks from exposure to radioactive iodines from medical sources and any future
      nuclear accidents. Plans are to continue to follow-up the cohort for at least
      three screening cycles, which will lead to more precise estimates of risk.

PMID- 15038763
TI  - Optimal gamma-ray dose and irradiation conditions for producing low-molecular
      weight chitosan that retains its chemical structure.
AB  - This study focuses on the optimal conditions for gamma irradiation to reduce the
      molecular weight of chitosan but still retain its chemical structure. Chitosan
      was irradiated under various conditions, i.e. flake solid state (condition 1),
      flake dispersed in water (condition 2), flake dispersed in 0.05, 0.1, 1 and 2%
      aqueous K(2)S(2)O(8) solution (conditions 3a, 3b, 3c and 3d, respectively), flake
      dispersed in 0.5, 1 and 2% aqueous H(2)O(2) solution (conditions 4a, 4b and 4c,
      respectively), and chitosan acetic acid solution (condition 5). Comparative
      studies were done using three types of chitosans with molecular weights of the
      order of 10(5) Da with degrees of deacetylation of 0.80, 0.85 and 0.90%. For all
      conditions, after irradiation, there were two regions of molecular weight
      reduction. A severe degradation occurred in the first region with decreases in
      the molecular weight of 80% for radiation doses up to 50 kGy for conditions 1, 2
      and 3 (3a-3c) and 20 kGy for condition 4. In the second region, a slow
      degradation occurred, which resembled a plateau stage. The results for conditions
      3d and 5 were the most dramatic, since the primary structure of chitosan was
      changed after the irradiation. The degradation of chitosan by gamma rays was
      found to be most effective for the amorphous structure. The retention of the
      structure of chitosan after gamma irradiation makes it possible to produce a low
      molecular-weight chitosan that retains its functionality, as demonstrated by its
      activity in the coupling reaction with N,N'-carbonyldiimidazole.

PMID- 15038764
TI  - Ammonium formate, a compound for sensitive EPR dosimetry.
AB  - Alanine EPR dosimetry has been applied successfully when measuring intermediate
      and high radiation doses. Although the performance of alanine dosimetry is being
      improved, the sensitivity of the material is too low for a fast and simple low-
      dose determination. Here we present the results using ammonium formate as an EPR
      dosimeter material. Ammonium formate is seven times more sensitive than alanine,
      using spectrometer settings optimized for the latter. Deuterated ammonium formate
      is found to be more than eight times more sensitive than alanine. Analysis of
      signal stability with time shows that the ammonium formate signal is stable by 5
      min after irradiation and that no change in signal intensity is found during 8
      days. The atomic composition of ammonium formate is closer to that of tissue than
      alanine, and thus the energy dependence is smaller than that of alanine at photon
      energies below 200 keV. Power saturation studies indicate that the energy
      transfer between the spins and the lattice is fast in ammonium formate, which
      gives the possibility of using high microwave power without saturation to further
      increase the sensitivity. These results suggest that ammonium formate has some
      important properties required of an EPR dosimeter for applications in dosimetry
      in the dose range typical for radiation therapy.

PMID- 15038765
TI  - Investigation of gamma-irradiated vegetable seeds with high-resolution solid
      state 13C NMR.
AB  - 13C solid-state NMR was used to investigate the effects of gamma radiation on
      vegetable seeds, Pisum sativum and Latuca sativa, at absorbed doses that inhibit
      their germination. By combining single-pulse excitation and cross-polarization
      experiments under magic angle spinning, both liquid and solid domains of seeds
      can be characterized. We showed that the liquid domains, mostly made of
      triacylglycerols (TAG), of vegetable seeds are not sensitive to radiation. The
      main structural changes have been observed in the embryonic axes of seeds when
      the seeds are water-imbibed before irradiation. These results rule out a starting
      hypothesis concerning the potential role of TAG contained in oil bodies as a
      potential source of aldehydes that could further react with DNA moiety.

PMID- 15038766
TI  - A fast Monte Carlo algorithm to simulate the spectrum of DNA damages formed by
      ionizing radiation.
AB  - Ionizing radiation produces both singly and multiply damaged DNA sites. Multiply
      damaged sites (MDS) have been implicated in radiation-induced cell killing and
      mutagenesis. The spatial distribution of elementary damages (strand breaks and
      base damages) that constitute MDS is of special interest, since the complexity of
      MDS has an impact on damage repair. A fast and easy-to-implement algorithm to
      simulate the local clustering of elementary damages produced by ionizing
      radiation is proposed. This algorithm captures the major trends in the DNA damage
      spectrum predicted using detailed track- structure simulations. An attractive
      feature of the proposed algorithm is that only four adjustable parameters need to
      be identified to simulate the formation of DNA damage. A convenient recipe to
      determine the parameters used in the fast Monte Carlo damage simulation algorithm
      is provided for selected low- and high-LET radiations. The good agreement among
      the damage yields predicted by the fast and detailed damage formation algorithms
      suggests that the small-scale spatial distribution of damage sites is determined
      primarily by independent and purely stochastic events and processes.

PMID- 15038767
TI  - Qualitative and quantitative analyses of the decomposition products that arise
      from the exposure of thymine to monochromatic ultrasoft X rays and 60Co gamma
      rays in the solid state.
AB  - HPLC analyses of condensed thymine irradiated with monochromatic synchrotron
      ultrasoft X rays in the energy region around nitrogen and oxygen K-shell edges
      were performed. Cobalt-60 gamma rays were used as a reference radiation. The
      radiation chemical dose response of each separated thymine decomposition product
      was also determined. Uracil (U), 5-(hydroxymethyl)uracil (HMU), 5,6
      dihydrothymine (DHT), 5-formyluracil (foU) and four main unknown products were
      found in the HPLC chromatogram of the sample irradiated with ultrasoft X rays in
      vacuo. Similar spectra of the products were also found in the gamma-ray
      experiment; however, some unknown products that appeared after elution of the
      thymine peak were significantly larger than those in the ultrasoft X- ray
      experiment. This result indicates the difference in radiation quality. The G
      value of DHT produced by gamma radiation was 10 times larger than those produced
      by the ultrasoft X- ray photons with energies of 395 and 407 eV corresponding to
      below and on the nitrogen K-shell edge, respectively. This result suggests that
      the differences in the photon energy and/ or in the energy spectra of the
      secondary electron between ultrasoft X rays and gamma rays are causing
      differences in the process of the radiation chemistry. Moreover, the yields of
      all the thymine decomposition products induced by 538 eV photons (oxygen K-shell
      edge) were significantly smaller than those induced by photons around the
      nitrogen K-shell edge. The K-shell excitation of oxygen in thymine may
      efficiently promote the production of small thymine fragments susceptible to
      desorption from the sample.

PMID- 15038768
TI  - Ion desorption from DNA components irradiated with 0.5 keV ultrasoft X-ray
      photons.
AB  - Positive ion desorption from thin films of DNA components, 2-deoxy-d-ribose,
      thymine, thymidine (dThd), and thymidine 5'-monophosphate (dTMP) was investigated
      in the oxygen K- shell edge excitation region using synchrotron ultrasoft X rays
      (538 eV). A large number of molecular fragments, H(+), CH(x)(+), C(2)H(x)(+),
      CO(+), CH(x)O(+), C(3)H(x)(+), C(2)H(x)O(+) and C(3)H(x)O(+) (x = 1, 2 and 3),
      were observed as desorbed ions from 2-deoxy-d-ribose. Some of these ions are
      related to simultaneous bond scission at particular C-C and C-O (or C-C) bonds in
      the furanose ring structure in the 2-deoxy-d-ribose molecule, indicating that the
      impact of photons on the oxygen atom and the impact of ejected secondary
      electrons (e.g. Auger electrons) cause an intense destruction of the furanose
      ring structure. In thymine thin films, H(+), CH(x)(+), CO(+), CH(x)O(+),
      C(2)H(x)N(+) and CH(x)NO(+) (x = 1, 2 and 3) fragments were observed. The yields
      of these ions were smaller than the yields from 2-deoxy-d-ribose. The desorption
      of CH(3)(+) from thymine might induce a molecular conversion from thymine to
      uracil. The mass patterns of dThd and dTMP, and especially that of dTMP, were
      similar to that of 2-deoxy-d-ribose, indicating that a number of ions were
      generated at the sugar site, even in the nucleotide molecule. It is therefore
      predicted that the sugar moiety is more fragile than the thymine base.

PMID- 15038769
TI  - Effect of 50 Hz electromagnetic fields on the induction of heat-shock protein
      gene expression in human leukocytes.
AB  - Although evidence is controversial, exposure to environmental power-frequency
      magnetic fields is of public concern. Cells respond to some abnormal
      physiological conditions by producing cytoprotective heat-shock (or stress)
      proteins. In this study, we determined whether exposure to power-frequency
      magnetic fields in the range 0-100 microT rms either alone or concomitant with
      mild heating induced heat-shock protein gene expression in human leukocytes, and
      we compared this response to that induced by heat alone. Samples of human
      peripheral blood were simultaneously exposed to a range of magnetic-field
      amplitudes using a regimen that was designed to allow field effects to be
      distinguished from possible artifacts due to the position of the samples in the
      exposure system. Power-frequency magnetic-field exposure for 4 h at 37 degrees C
      had no detectable effect on expression of the genes encoding HSP27, HSP70A or
      HSP70B, as determined using reverse transcriptase-PCR, whereas 2 h at 42 degrees
      C elicited 10-, 5- and 12-fold increases, respectively, in the expression of
      these genes. Gene expression in cells exposed to power-frequency magnetic fields
      at 40 degrees C was not increased compared to cells incubated at 40 degrees C
      without field exposure. These findings and the extant literature suggest that
      power-frequency electromagnetic fields are not a universal stressor, in contrast
      to physical agents such as heat.

PMID- 15038771
TI  - Expression of the oxidative base excision repair enzymes is not induced in TK6
      human lymphoblastoid cells after low doses of ionizing radiation.
AB  - Most of the DNA damage produced by ionizing radiation is repaired by the base
      excision repair (BER) pathway. To determine whether the BER genes were up
      regulated by low doses of ionizing radiation, we investigated their expression in
      TK6 human lymphoblastoid cells by measuring mRNA levels using real-time
      quantitative PCR. No induction at the transcriptional level of any of the base
      excision repair genes, NTH1 (NTHL1), OGG1, NEIL1, NEIL2, NEIL3, APE1, POLB, or
      accessory protein genes, LIG3, XRCC1 or XPG, was found at gamma-radiation doses
      ranging from 1 cGy to 2 Gy in a 24-h period. As has been measured in other cell
      lines, a dose-dependent induction of CDKN1A (WAF1) mRNA levels was observed in
      TK6 cells in the dose range of 0.5 to 2.0 Gy. We also examined BER enzyme
      activity on 8-oxoguanine-, dihydrouracil- and furan-containing oligonucleotide
      substrates and found no increase in extracts of TK6 cells after gamma-ray doses
      of 0.5-2.0 Gy. These data were corroborated by Western blot analysis of APE1 and
      NTH1, suggesting that the BER enzymes are also not up-regulated at the post
      transcriptional level after ionizing radiation exposure.

PMID- 15038770
TI  - Radiation-induced up-regulation of Mmp2 involves increased mRNA stability, redox
      modulation, and MAPK activation.
AB  - We have previously observed time- and dose-dependent increases in matrix
      metalloproteinase 2 (Mmp2) protein levels in rat tubule epithelial cells (NRK52E)
      after irradiation. However, the mechanism(s) involved remains unclear. In the
      present study, irradiating NRK52E cells with 0-20 Gy gamma rays was associated
      with time- and dose-dependent increases in Mmp2 mRNA. Studies using the
      transcription inhibitor actinomycin D (ActD) added 24 h after irradiation
      revealed the t(1/2) of Mmp2 mRNA to be approximately 8 h in control cells. In
      contrast, the increase in Mmp2 mRNA levels in irradiated cells was essentially
      unchanged after incubation with ActD for up to 12 h. Incubating cells with the
      antioxidants N-acetylcysteine or ebselen or the MEK pathway inhibitors PD98059
      and U0126 prior to irradiation abolished the radiation-induced up-regulation of
      Mmp2. Irradiating NRK52E cells led to reactive oxygen species-mediated Erk1/2
      activation; preincubation with NAC prevented the radiation-induced increase in
      phosphorylated Erk1/2. Transfecting cells with a dominant-negative ERK mutant
      completely inhibited radiation-induced Erk phosphorylation and abolished the
      radiation-induced up-regulation of Mmp2 protein. Thus the radiation-induced up
      regulation of Mmp2 mRNA is due in part to increased mRNA stability and is
      mediated by redox; the ERK MAPK signaling pathway may be involved.

PMID- 15038772
TI  - Hypertonic saline enhances expression of phosphorylated histone H2AX after
      irradiation.
AB  - Phosphorylation of histone H2AX at serine 139 occurs at sites surrounding DNA
      double-strand breaks, producing discrete spots called "foci" that are visible
      with a microscope after antibody staining. This modification is believed to
      create changes in chromatin structure and assemble various repair proteins at
      sites of DNA damage. To examine the role of chromatin structure, human SiHa cells
      were exposed to hypertonic salt solutions that are known to condense chromatin
      and sensitize cells to chromosome damage and killing by ionizing radiation.
      Postirradiation incubation in 0.5 M Na(+) increased gammaH2AX expression about
      fourfold as measured by flow cytometry and immunoblotting, and loss of gammaH2AX
      was inhibited in the presence of high salt. Focus size rather than the number of
      radiation-induced gammaH2AX foci was also increased about fourfold. When high
      salt treatment was delayed for 1 h after irradiation, effects on focus size and
      retention were reduced. The increase in focus size was associated with a decrease
      in the rate of rejoining of double-strand breaks as measured using the neutral
      comet assay. We conclude that gammaH2AX expression after irradiation is sensitive
      to salt-induced changes in chromatin structure during focus formation, and that a
      large focus size may be an indication of a reduced ability to repair DNA damage.

PMID- 15038773
TI  - The bystander response in C3H 10T1/2 cells: the influence of cell-to-cell
      contact.
AB  - Although radiation-induced heritable damage in mammalian cells was thought to
      result from the direct interaction of radiation with DNA, it is now accepted that
      biological effects may occur in cells that were not themselves traversed by
      ionizing radiation but are close to those that were. However, little is known
      about the mechanism underlying such a bystander effect, although cell-to-cell
      communication is thought to be of importance. Previous work using the Columbia
      microbeam demonstrated a significant bystander effect for clonogenic survival and
      oncogenic transformation in C3H 10T(1/2) cells. The present study was undertaken
      to assess the importance of the degree of cell-to-cell contact at the time of
      irradiation on the magnitude of this bystander effect by varying the cell
      density. When 10% of cells were exposed to a range of 2-12 alpha particles, a
      significantly greater number of cells (P < 0.0001) were inactivated when cells
      were irradiated at high density (>90% in contact with neighbors) than at low
      density (<10% in contact). In addition, the oncogenic transformation frequency
      was significantly higher in high-density cultures (P < 0.0004). These results
      suggest that when a cell is hit by radiation, the transmission of the bystander
      signal through cell-to-cell contact is an important mediator of the effect,
      implicating the involvement of intracellular communication through gap junctions.

PMID- 15038774
TI  - A threshold exists in the dose-response relationship for somatic mutation
      frequency induced by X irradiation of Drosophila.
AB  - The dose-response relationship of ionizing radiation and its stochastic effects
      has been thought to be linear without any thresholds. The basic data for this
      model were obtained from mutational assays in the male germ cells of the fruit
      fly Drosophila melanogaster. However, it is more appropriate to examine
      carcinogenic activity in somatic cells than in germ cells. Here the dose-response
      relationship of X irradiation and somatic mutation was examined in Drosophila. A
      threshold at approximately 1 Gy was observed in DNA repair-proficient flies. In
      the repair-deficient siblings, the threshold was smaller and the inclination of
      the dose-response curve was much steeper. These results suggest that the dose
      response relationship between X irradiation and somatic mutation has a threshold
      and that the DNA repair function contributes to its formation.

PMID- 15038775
TI  - Antagonistic effects of simultaneous exposure of ergot alkaloids on kidney
      adenosine triphosphatase system.
AB  - Much of the research on fescue toxicosis has concentrated on evaluating animal
      response to grazing endophyte-infected (E+) versus endophyte-free tall fescue or
      the effects of single toxins such as ergonovine (EN), ergovaline (EV), or
      ergotamine (ET) on animal performance. Such approaches have eliminated the
      opportunity to test the possible additive, synergistic, or antagonistic
      interactions of one or more ergot alkaloids with the other ergot alkaloids found
      in E+ tall fescue. This study was conducted to determine the effects of
      simultaneous exposure of pairs of EN, EV, and ET on the kidney adenosine
      triphosphatase (ATPase) system in vitro. Tests were performed using three
      separate rat kidney homogenates and were repeated four times at concentrations of
      0, 75, and 200 microM. Individually, EN, EV, and ET induced dose-dependent
      inhibitions of kidney Na(+)/K(+) ATPase, with EN being most potent, followed by
      purified EV, and then by ET. The ergot alkaloids inhibited Mg(2+) ATPase to a
      lesser degree than Na(+)/K(+) ATPase, with EN again being the most potent toxin.
      Simultaneous exposure to any combination of the ergot alkaloid pairs tested (EV +
      ET, EV + EN, and ET + EN) resulted in significant interactions (P < 0.05),
      indicating antagonistic effects on the inhibition of Na(+)/K(+) ATPase and Mg(2+)
      ATPase for most concentration combinations. These interactions suggest that in
      studies of the effects of any ergot alkaloid on animal performance, effects of
      other ergot alkaloids may also be present. Effects may not be additive, as was
      the case in this study, and the presence of one toxin may enhance or hinder the
      effectiveness of others.

PMID- 15038777
TI  - Reconstruction of tubular structures in three-dimensional collagen gel culture
      using proximal tubular epithelial cells voided in human urine.
AB  - Human proximal tubular (PT) epithelial cells were isolated from urine and
      monoclonally cultured as monolayers for 1 wk, after which they were subcultured
      between two layers of collagen gel, designated a "collagen gel sandwich." Under
      these culture conditions, PT cells formed three-dimensional tubular structures
      exhibiting distinct polarized cell morphology. Scanning and transmission electron
      microscopic studies showed that they bore numerous microvilli at the apical
      surface and that they closely contacted the collagen gel at the basal surface.
      These studies indicate that PT cells exfoliated in urine still exhibit the
      potential to proliferate and form organized structures mimicking in vivo tubules.
      Because of the current lack of useful culture systems for human tubular
      epithelial cells originating from kidney tissue, we suggest that this unique
      culture system using voided PT cells in urine could open up new avenues to study
      not only the mechanisms of morphogenesis but also the physiology of human PT
      cells.

PMID- 15038776
TI  - Isomers of conjugated linoleic acid modulate human preadipocyte differentiation.
AB  - Conjugated linoleic acids (CLAs) reduce fat deposition in several mammalian
      species. Among the proposed mechanisms for this effect are reduced preadipocyte
      proliferation and differentiation. We measured proliferation and differentiation
      of cultured human preadipocytes treated with CLAs. Preadipocytes were
      differentiated with insulin, hydrocortisone, transferrin, and 10% fetal bovine
      serum, with isobutyl-methylxanthine included for the first 2 d. The
      differentiation medium contained 200 microM oleic acid (C18:1), 50 microM cis
      9,trans-11-CLA (9,11-CLA), or 50 microM trans-10,cis-12-CLA (10,12-CLA); the
      negative control medium contained no added fatty acid, and the cells did not
      differentiate. Cell number increased three to four times during the 17 d of
      differentiation, but was 30-35% lower in the CLA-treated cells than in the
      negative control cells. Compared with the negative control cells, differentiation
      was increased in the cells treated with C18:1 (increased Oil Red O-stained
      material [OROSM], triacylglycerol, glycerol 3-phosphate dehydrogenase activity
      [GPDH], peroxisome proliferator-activated receptor-gamma [PPAR gamma] messenger
      ribonucleic acid [mRNA], and lipoprotein lipase [LPL] mRNA). In effect, the C18:1
      treated cells act as a positive control to demonstrate the differentiation
      capacity of each cell lot. Both 9,11-CLA- and 10,12-CLA-treated cells had
      increased differentiation (increased OROSM, triacylglycerol, GPDH, PPAR gamma,
      and LPL) compared with the negative control cells. The data suggest that early in
      differentiation when de novo fatty acid (FA) synthesis is limited and competition
      for FAs by membrane and triacylglycerol synthetic pathways is great, human
      preadipocytes do not differentiate unless a PPAR gamma ligand is added. Either
      CLA isomer or C18:1 can provide such a ligand.

PMID- 15038778
TI  - Application of inter-simple sequence repeats to insect cell lines: identification
      at the clonal and tissue-specific level.
AB  - Inter-simple sequence repeat (ISSR) primers designed to anneal to microsatellites
      were used to obtain deoxyribonucleic acid (DNA) fingerprint profiles to
      distinguish among 16 established insect cell lines derived from an assortment of
      lepidopteran, dipteran, and coleopteran species. Three different levels of cell
      line comparison were made: (1) between parents and their clones, (2) among cell
      lines derived from different tissues from the same species, and (3) among cell
      lines derived from different insect species. Of the 16 repeat oligonucleotide
      primers used in this study, nine primers generated several unique markers to
      distinguish between parental cell lines and their clones. Four of the 16 primers
      also generated DNA profiles with a number of unique bands, enabling the
      distinction among cell lines derived from specific tissues from the same species.
      In addition, ISSR-generated DNA profiles provided the greatest number of unique
      markers to distinguish easily among insect cell lines derived from different
      species.

PMID- 15038779
TI  - Static magnetic field with a strong magnetic field gradient (41.7 T/m) induces c
      Jun expression in HL-60 cells.
AB  - We investigated the effects of 6- and 10-T static magnetic fields (SMFs) on the
      expression of protooncogenes using Western blot immunohybridization methods. We
      used a SMF exposure system, which can expose cells to a spatially inhomogeneous 6
      T with a strong magnetic field (MF) gradient (41.7 T/m) and a spatially
      homogeneous 10 T of the highest magnetic flux density in this experiment. HL-60
      cells exposed to either 6- or 10-T SMF for periods of 1 to 48 h did not exhibit
      remarkable differences in levels of c-Myc and c-Fos protein expression, as
      compared with sham-exposed cells. In contrast, c-Jun protein expression increased
      in HL-60 cells after exposure to 6-T SMF for 24, 36, 48, and 72 h. These results
      suggest that a homogeneous 10-T SMF does not alter the expression of the c-jun, c
      fos, and c-myc protooncogenes. However, our observation that exposure to a strong
      MF gradient induced c-Jun expression suggests that a strong MF gradient may have
      significant biological effects, particularly regarding processes related to an
      elevation of c-jun gene expression.

PMID- 15038780
TI  - Phenotypic characterization of a human synovial sarcoma cell line, SW982, and its
      response to dexamethasone.
AB  - SW982 cells are characterized by expression of inflammatory cytokine and matrix
      metalloproteinase (MMP) genes and by their response to dexamethasone at different
      cell densities. They express genes encoding interleukin (IL)-1 beta; IL-6;
      transforming growth factor-beta; intercellular adhesion molecule-1; cycloxygenase
      (COX)-2; and MMPs, including MMP-1, MMP-2, MMP-13, and MT1-MMP; tissue inhibitor
      of metalloproteinase-2; and a disintegrin and metalloproteinase with
      thrombospondin motifs-4. Expression of all the genes examined was induced with 2
      ng/ml IL-1 beta at low cell density. The cells, however, failed to express tumor
      necrosis factor-alpha, COX-1, and MMP-9, regardless of the presence of IL-1 beta.
      Dexamethasone significantly reduced IL-1 beta, IL-6, COX-2, and MMP-1 expression
      at high cell density. The results suggest that SW982 cells are a useful tool for
      studying the expression of inflammatory cytokine or MMP genes.

PMID- 15038781
TI  - Evelyn M. Witkin awarded the National Medal of Science.

PMID- 15038782
TI  - ZOBB versus QUACC.

PMID- 15038783
TI  - Anxiety related to dental general anaesthesia: changes in anxiety in children and
      their parents.
AB  - AIM: To examine the anxiety levels of children referred for dental general
      anaesthesia and their parents at various key points of the referral and
      anaesthetic procedure. METHODS: Structured interviews and anxiety measures were
      conducted with 50 children attending the Department of Paediatric Dentistry,
      Leeds Dental Institute, and progressing to general anaesthetic (GA) and their
      parents. Interviews were conducted with parents and children prior to initial
      assessment, following assessment and prior to a GA. Anxiety was measured at each
      interview, using the Visual Analogue Scale for parents and the Venham's Picture
      test for children. A fourth telephone interview was conducted with parents one
      week after the GA when the degree of upset caused to parents and children by the
      procedure was evaluated. RESULTS: Anxiety of children remained constant at each
      interview. Parent and child anxiety were not related. There was a rise in parent
      anxiety following initial assessment in those families attending in response to a
      routine referral and progressing to GA (p<0.05). There was a further rise in
      parent anxiety in these families immediately prior to the GA itself (p<0.001).
      Parent upset was strongly related to their anxiety at each of the three
      interviews prior to the GA (p<0.01, 0.05 and 0.001 respectively) and to the
      distress of their child (p<0.02). Child distress was strongly related to anxiety
      at each of the three interviews prior to the GA. CONCLUSION: The anxiety levels
      of children did not appear to change throughout the whole GA assessment and
      treatment process. Parent anxiety rose significantly following assessment and
      again just prior to the GA. Factors contributing to parent upset post treatment
      were child upset and pre treatment parent anxiety levels. Children who were most
      anxious prior to GA found the procedure most distressing.

PMID- 15038784
TI  - Dental anxiety and behavioural problems: what is their influence on the treatment
      plan?
AB  - AIM: This was to investigate the influence of emotional and behavioural problems
      on the choice of treatment type. In addition, the actual contents of the
      treatment of dentally fearful children was studied in an attempt to develop
      dental treatment protocols for children with such problems. METHODS: The parents
      of 265 children (144 girls, mean age 88.4 months, SD+/-34.2 months), referred to
      a centre for special dental care, were asked to complete the Child Behaviour
      Check List (CBCL) before their first appointment. The CBCL was used to assess
      behavioural problems. All selected children were dentally anxious (score >or=35
      on the Children's Fear Survey Schedule Dental Subscale, CFSS-DS). After
      treatment, the children's records were analysed on treatment type and contents.
      RESULTS: The CBCL score was related to the type of treatment. Children treated
      with the aid of nitrous oxide sedation scored significantly higher on the CBCL
      than children treated with behavioural management or under intravenous
      anaesthesia (IVA). In the IVA group more surfaces were treated than in the other
      groups. The CBCL score was not related to the treatment contents (number of
      surfaces filled, amount of radiographs, sealants, stainless steel crowns or
      pulpotomies), the time spent on the child's treatment or the number of sessions.
      CONCLUSION: Dentally anxious children with behavioural problems as assessed by
      the CBCL have dental treatment (contents and length) comparable with that of
      dentally anxious children without those problems. However, anxious children with
      behavioural problems are more often treated with nitrous oxide sedation.
      Therefore, there seems to be an urgent need for access to nitrous oxide sedation
      for dentists working in special dentistry.

PMID- 15038785
TI  - Dental anxiety in a subpopulation of African children: parents ability to predict
      and its relation to general anxiety and behaviour in the dental chair.
AB  - AIM: This was to investigate the ability of Nigerian parents to predict their
      child's dental anxiety level and the relationship between the child's dental
      anxiety, general anxiety and behaviour in the dental chair. METHODS: A group of
      53 mothers and 35 fathers and their respective children completed schedules that
      measured general and dental anxiety. The child's behaviour on the dental chair
      was also assessed. The child's self report of dental anxiety and general anxiety
      was compared with that of the parents. Dental anxiety ratings by the children and
      parents were correlated with the behaviour assessment of the dentist. Statistical
      significance was determined at <0.05. RESULTS: There was no statistically
      significant difference between the parent's assessment of their child's dental
      anxiety level and the child's self report (t=0.389; p=0.689). However, the
      mothers were able to rate their child's dental anxiety level better than the
      fathers (r=0.497 and p<0.001 for mothers, r=-0.049 and p=0.789 for fathers). Also
      there was a moderate correlation between the child's self reported dental anxiety
      and general anxiety levels (r=0.58, p<0.05) and a low correlation between the
      clinical behaviour ratings and the child's self reported dental anxiety level
      (r=0.10, p>0.05). CONCLUSION: The Nigerian mothers could be relied upon to make
      objective assessment of their child's dental anxiety. General anxiety appears to
      play a significant role in dental anxiety development in Nigerian children who
      appear to behave well in the dental chair despite their reported dental anxiety
      levels.

PMID- 15038786
TI  - Management of obstructive sleep apnoea in children with modified monobloc
      appliances.
AB  - AIM: This was to investigate the effect of the use of an orthodontic appliance in
      the treatment of obstructive sleep apnoea (OSA) in children using
      polysomnographic variables. METHODS: 10 boys and 10 girls with OSA aged between 4
      to 8 years, referred from an otolaryngology clinic because of sleep apnoea, wore
      modified monobloc devices nightly for 6 months. Polysomnography was used for each
      patient for baseline diagnosis of OSA and also for post therapy assessment.
      RESULTS: The median obstructive apnoea- hypopnoea index decreased after 6 months
      of therapy with oral appliances. The mean (+/-SD) number of episodes of OSA was
      7.88+/-1.81 before treatment and 3.66+/-6.80 after 6 months (p<0.001).
      CONCLUSIONS: The modified monobloc appliance is suggested for use in children
      with OSA and may be an effective therapeutic alternative in children with mild to
      moderate OSA.

PMID- 15038787
TI  - Surface quality of Cerec CAD/CAM ceramic veneers treated with four different
      polishing systems.
AB  - AIM: To achieve satisfactory aesthetic appearance of ceramic veneers food debris
      retention and plaque formation, resulting in possible irritation of surrounding
      tissues, should be avoided. It is, therefore, necessary to decrease the roughness
      of ceramic surfaces as much as possible. The aim of this study was to evaluate
      surface roughness of ceramic veneers after polishin15038787 g with four different
      techniques. METHODS: Twenty veneers were fabricated using Cerec 2 CAD/CAM method
      (Sirona AG, Bensheim, Germany) from Cerec VITA MARK II ceramic blocks (Vita
      Zahnfabrik, Bad Sackingen, Germany) and cemented onto prepared extracted teeth.
      Veneers were divided into 4 groups of 5 specimens and polished with 4 different
      techniques: 1. Sof-lex discs grit 150, 360, 600, 1200 (3M, St. Paul, MN, USA); 2.
      Hawe brushes (Hawe Neos Dental, Bioggio, Switzerland); 3. Hawe brushes and
      diamond paste Diabrill (Oralia Dental GmbH, Kostanz, Germany); 4. Politip-P
      rubber cups (Vivadent, Schaan, Liechtenstein). Surface profile was measured using
      Perthometer Perthen S8P 4.5 (Feinpruf Perthen GmbH, Goettingen, Germany)
      profilometer. STATISTICS: Data were analysed using ANOVA with Tukey HSD test.
      RESULTS: Sof-lex discs revealed significant statistical differences for Rz, Ra,
      Rk, Rpk values (p=0.0002) (Rz=2.92 mm; Ra=0.462 mm; Rk=1.098 mm; Rpk=0.472 mm).
      Values for Rvk were statistically significant only for rubber cups with diamond
      paste (p=0,002) (Rvk 4=3.04 mm). Rvk values for all other techniques were not
      statistically significant (Rvk 1=1.148 mm; Rvk 2=1.936 mm; Rvk 3=2.18 mm).
      CONCLUSION: The best surface smoothness was achieved with Sof-lex discs polishing
      system. All other methods are clinically acceptable. Selection of polishing
      technique should be made according to geometric construction of the polishing
      instrument and possibility of reaching various restoration areas with the
      polishing instrument.

PMID- 15038788
TI  - Surgical removal of supernumerary teeth and the fate of incisor eruption.
AB  - AIM: The aims of this study were firstly to determine the fate of unerupted
      permanent maxillary incisor teeth following supernumerary tooth removal and
      secondly to make recommendations regarding the management of such incisor teeth
      following supernumerary tooth extraction. STUDY DESIGN: This is a retrospective
      study. METHODS: Records of children attending the Departments of Paediatric
      Dentistry, Edinburgh Dental Institute, Lothian Primary Care NHS Trust and Dundee
      Dental Hospital, Tayside University Hospitals Trust between 1995 and 2002 were
      examined with regard to non-eruption of one or both maxillary central incisors in
      association with supernumerary teeth requiring surgical removal. Subsequent
      permanent maxillary incisor eruption was recorded and in those cases of incisor
      non-eruption, further surgical interventions were noted. RESULTS: In all 118 sets
      of patient records were included in the study (87 males, 31 females) with a mean
      age at presentation of 8.8 years (range 5.3-11.6 years). Failure of eruption of
      the associated permanent maxillary central incisor teeth occurred in 27% of
      cases, in relation to both conical and tuberculate supernumerary teeth. All
      tuberculate supernumerary teeth associated with non-eruption cases were palatally
      placed and 59% were adjacent to maxillary incisors with near complete apex
      formation. To facilitate incisor eruption in these cases, 41% required surgical
      exposure of the non-erupted incisor tooth and 59% required surgical exposure with
      bonding of an orthodontic bracket and gold chain for orthodontic traction.
      CONCLUSION: Non-erupted permanent maxillary incisor teeth with near complete
      apical formation, associated with palatally placed, tuberculate-shaped
      supernumerary teeth, may benefit from having an orthodontic bracket and gold
      chain placed at the same time as the surgical procedure to remove the
      supernumerary tooth to facilitate future orthodontic traction.

PMID- 15038789
TI  - Fluoride levels in saliva and dental plaque after consumption of snacks prepared
      with fluoridated salt.
AB  - AIM: To determine the concentration of fluoride in saliva and supragingival
      dental plaque at designated time intervals after consumption of snacks prepared
      with a standardised amount of fluoridated salt. STUDY DESIGN: The investigation
      had a single blind prospective crossover design. METHODS: A group of 11 healthy
      young adults volunteered to participate after verbal and written information and
      consent. After a 1-week fluoride depletion period, the subjects consumed popcorn
      prepared with either fluoridated (250 mg/kg) or non-fluoridated salt during 30
      minutes. Unstimulated whole saliva and samples of supragingival plaque were
      collected before consumption (baseline) and at 30, 60 and 120 minutes after the
      intake. Fluoride concentration was determined with a fluoride-specific electrode
      and the post-ingestion levels were compared with baseline by ANOVA. RESULTS: In
      saliva, the mean fluoride concentrations at baseline ranged from 0.021 to 0.027
      mg/L and after the 30 minutes consumption of fluoride prepared snacks a 15-fold
      increase (p<0.001) was found. The same pattern was disclosed in the plaque
      samples. In both saliva and plaque, the fluoride levels remained significantly
      elevated after 2 hours (p<0.001 and p<0.05, respectively). CONCLUSION:
      Consumption of snacks prepared with fluoridated table salt resulted in
      significantly increased fluoride levels in saliva and supragingival plaque for a
      period of at least two hours.

PMID- 15038790
TI  - Subgingival foreign body embedment in a preschool child: management with three
      and a half years follow-up.
AB  - CASE REPORT: This is a case report of diagnosis and management of a foreign body
      embedded in the gingivae of a preschool child. A 3 year-old girl presented with
      pain, mobility and intraoral oedema of the upper left primary canine (#63). An
      angular, diffuse radiolucency on the mesial aspect of the primary canine was
      observed in the periapical radiograph and within this radiolucency, a linear
      radiopacity was noted in contact with the mesial surface of the root. A clinical
      diagnosis of severe localized periodontal involvement due to foreign body
      embedment was made. It was initially attempted unsuccessfully to remove the
      foreign body by subgingival root scaling and planning. The area was then
      surgically exposed. Upon flap elevation, a tubular plastic material similar to
      those used for the insulation of electric wires was found to encircle tightly the
      cervical area of the root of the primary canine, which was removed. Three months
      after the surgery, the gingiva of the affected tooth had attained its normal
      color but had started to recede for about 1 mm. One year post surgery, the
      gingival recession had progressed to 3 mm and a carious lesion had already
      developed at the denuded root surface. Three and a half years post surgery a mild
      inflammation of the buccal gingivae was apparent, but periodontal healing had
      occurred. CONCLUSION: The dentist must always consider the possibility of a
      foreign body embedment in the periodontal tissues of children and be familiar to
      the clinical signs and symptoms as well as the proper treatment procedures.

PMID- 15038794
TI  - Bridging the chasm: a professional college's role in quality.
AB  - OBJECTIVE: To review the role of the Royal Australian and New Zealand College of
      Psychiatry (RANZCP) in ensuring quality and to suggest ways to enhance that role.
      METHODS: Literature relating to medical error and quality of health care was
      reviewed and the performance of the RANZCP assessed against that literature.
      RESULTS: Considerable evidence exists regarding the risk of medical practice to
      health. The 'Quality Chasm' report is a useful analytic framework for planning
      quality improvement. CONCLUSION: The RANZCP is on target with a number of quality
      initiatives. We need to strengthen the partnership with patients and their
      families in the design of initiatives.

PMID- 15038795
TI  - A rounded dozen.
AB  - Welcome to a new series in which we invite distinguished psychiatrists from
      around the world to select the 12 books they have found valuable in shaping their
      ideas and influencing their clinical practice. I must be candid. I was totally
      won over to the intrinsic worth of doing such an exercise when I was invited to
      contribute to the '10 books' series of the British Journal of Psychiatry. I had
      to think long and hard but the effort was exhilarating. I discovered in an odd
      sort of way the figures who have proved central to the development of my career.
      Peter Tyrer, the Editor of the British Journal, graciously encouraged me to
      imitate the 10 books column. Hence the 'rounded dozen' concept. (I had immense
      difficulty confining myself to 10 books when I had to make my selections and
      thought a couple of extra places would not go amiss!) I am delighted that a dear
      friend and mentor, the eminent German psychiatrist, psychoanalyst and family
      therapist, Helm Stierlin, acepted my invitation to launch the new column. His
      'essay' is not only replete with fascinating psychiatric history but also reveals
      a colleague who is able to maintain an eager curiosity about the nature of our
      marvellous profession and a willingness to alter his way of thinking in the light
      of new conceptual and empirical knowledge. I commend his essay to you and hope
      you are as inspired by it as I am. I shall be inviting other eminent
      psychiatrists to prepare a 'rounded dozen' but welcome any suggestions from the
      readership for potential contributors. Sidney Bloch Editor

PMID- 15038793
TI  - Transglutaminase 5 is regulated by guanine-adenine nucleotides.
AB  - Transglutaminases (TGases) are Ca2+-dependent enzymes capable of catalysing
      transamidation of glutamine residues to form intermolecular isopeptide bonds.
      Nine distinct TGases have been described in mammals, and two of them (types 2 and
      3) are regulated by GTP/ATP. TGase2 hydrolyses GTP and is therefore a
      bifunctional enzyme. In the present study, we report that TGase5 is also
      regulated by nucleotides. We have identified the putative TGase5 GTP-binding
      pocket by comparative amino acid sequence alignment and homology-derived three
      dimensional modelling. GTP and ATP inhibit TGase5 cross-linking activity in
      vitro, and Ca2+ is capable of completely reversing this inhibition. In addition,
      TGase5 mRNA is not restricted to epidermal tissue, but is also present in
      different adult and foetal tissues, suggesting a role for TGase5 outside the
      epidermis. These results reveal the reciprocal actions of Ca2+ and nucleotides
      with respect to TGase5 activity. Taken together, these results indicate that
      TGases are a complex family of enzymes regulated by calcium, with at least three
      of them, namely TGase2, TGase3 and TGase5, also being regulated by ATP and GTP.

PMID- 15038791
TI  - Murine cystathionine gamma-lyase: complete cDNA and genomic sequences, promoter
      activity, tissue distribution and developmental expression.
AB  - Cystathionine gamma-lyase (CSE) is the last key enzyme in the trans-sulphuration
      pathway for biosynthesis of cysteine from methionine. Cysteine could be provided
      through diet; however, CSE has been shown to be important for the adequate supply
      of cysteine to synthesize glutathione, a major intracellular antioxidant. With a
      view to determining physiological roles of CSE in mice, we report the sequence of
      a complete mouse CSE cDNA along with its associated genomic structure, generation
      of specific polyclonal antibodies, and the tissue distribution and developmental
      expression patterns of CSE in mice. A 1.8 kb full-length cDNA containing an open
      reading frame of 1197 bp, which encodes a 43.6 kDa protein, was isolated from
      adult mouse kidney. A 35 kb mouse genomic fragment was obtained by lambda genomic
      library screening. It contained promoter regions, 12 exons, ranging in size from
      53 to 579 bp, spanning over 30 kb, and exon/intron boundaries that were conserved
      with rat and human CSE. The GC-rich core promoter contained canonical TATA and
      CAAT motifs, and several transcription factor-binding consensus sequences. The
      CSE transcript, protein and enzymic activity were detected in liver, kidney, and,
      at much lower levels, in small intestine and stomach of both rats and mice. In
      developing mouse liver and kidney, the expression levels of CSE protein and
      activity gradually increased with age until reaching their peak value at 3 weeks
      of age, following which the expression levels in liver remained constant, whereas
      those in kidney decreased significantly. Immunohistochemical analyses revealed
      predominant CSE expression in hepatocytes and kidney cortical tubuli. These
      results suggest important physiological roles for CSE in mice.

PMID- 15038796
TI  - Academic consumer researchers: a bridge between consumers and researchers.
AB  - OBJECTIVE: To describe the contributions that consumers, and academic consumer
      researchers in particular, can make to mental health research. METHOD: A
      literature survey and a systematic consideration of the potential advantages of
      consumer and academic consumer researcher involvement in health research.
      RESULTS: Consumer researchers may contribute to better health outcomes, but there
      are significant barriers to their participation in the research process. To date,
      discussion has focused on the role of nonacademic consumers in the health
      research process. There has been little recognition of the particular
      contributions that consumers with formal academic qualifications and research
      experience can offer. Academic consumer researchers (ACRs) offer many of the
      advantages associated with lay consumer participation, as well as some unique
      advantages. These advantages include acceptance by other researchers as equal
      partners in the research process; skills in research; access to research funding;
      training in disseminating research findings within the scientific community;
      potential to influence research funding and research policy; capacity to
      influence the research culture; and potential to facilitate the involvement of
      lay consumers in the research process. In recognition of the value of a critical
      mass of ACRs in mental health, a new ACR unit (the Depression and Anxiety
      Consumer Research Unit [CRU]) has been established at the Centre for Mental
      Health Research at the Australian National University. CONCLUSIONS: Academic
      consumer researchers have the potential to increase the relevance of mental
      health research to consumers, to bridge the gap between the academic and consumer
      communities and to contribute to the process of destigmatizing mental disorders.

PMID- 15038792
TI  - In vitro synthesis of a crystalline (1-->3,1-->4)-beta-D-glucan by a mutated (1-
      >3,1-->4)-beta-D-glucanase from Bacillus.
AB  - Oligo- and poly-saccharides have a large number of important biological
      functions, and they occur in natural composite materials, such as plant cell
      walls, where they self-assemble during biosynthesis in a poorly understood
      manner. They can also be used for the formation of artificial composite materials
      with industrial applications. Fundamental and applied research in biology and
      nanobiotechnology would benefit from the possibility of synthesizing tailor-made
      oligo-/poly-saccharides. In the present paper, we demonstrate that such syntheses
      are possible using genetically modified glycoside hydrolases, i.e.
      glycosynthases. The ability of the endoglycosynthase derived from Bacillus (1-
      >3,1-->4)-beta-D-glucanase to catalyse self-condensation of sugar donors was
      exploited for the in vitro synthesis of a regular polysaccharide. The specificity
      of the enzyme allowed the polymerization of alpha-laminaribiosyl fluoride via the
      formation of (1-->4)-beta-linkages to yield a new linear crystalline (1-->3,1-
      >4)-beta-D-glucan with a repeating 4betaG3betaG unit. MS and methylation analyses
      indicated that the in vitro product consisted of a mixture of oligosaccharides,
      the one having a degree of polymerization of 12 being the most abundant.
      Morphological characterization revealed that the (1-->3,1-->4)-beta-D-glucan
      forms spherulites which are composed of platelet crystals. X-ray and electron
      diffraction analyses allowed the proposition of a putative crystallographic
      structure which corresponds to a monoclinic unit cell with a =0.834 nm, b =0.825
      nm, c =2.04 nm and gamma=90.5 degrees. The dimensions of the ab plane are similar
      to those of cellulose I(beta), but the length of the c -axis is nearly twice that
      of cellulose I. It is proposed that four glucose residues are present in an
      extended conformation along the c -axis of the unit cell. The data presented show
      that glycosynthases represent promising enzymic systems for the synthesis of
      novel polysaccharides with specific and controlled structures, and for the
      analysis in vitro of the mechanisms of polymerization and crystallization of
      polysaccharides.

PMID- 15038797
TI  - Impact of demographic factors, early family relationships and depressive
      symptomatology in teenage pregnancy.
AB  - AIM: Teenage pregnancy has been well studied from a demographic risk perspective,
      but less data examining the early interpersonal family experiences of teenage
      mothers are available. We aimed to explore the relative impact of demographic,
      early interpersonal family relationships and depressive symptomatology as
      associations for teenage, as compared to non-teenage, childbearing. METHOD: A
      prospective cross-sectional cohort study was undertaken. Institutional ethics
      committee approval and informed consent were obtained. Data from consecutive
      teenage (teenage) and non-teenage (control) subgroups of antenatal women were
      compared. Subjects were interviewed and completed the following questionnaires:
      demographic, drug use and lifestyle; early life experiences; Hospital Anxiety and
      Depression Scale (HADS); and General Health Questionnaire-28. RESULTS: In
      multivariate analysis, the following factors had a significant independent
      association with younger age of motherhood in order of magnitude: a history of
      parental separation/divorce in early childhood; exposure to family violence in
      early childhood; illicit drug use (ever or in pregnancy); idealization of the
      pregnancy; low family income; a positive HADS-A or HADS-D subscale score; and a
      low level of education. CONCLUSIONS: Interventions to reduce the rate of teenage
      births need to be multifocal and should include strategies to address early
      childhood exposure to parental separation and violence, reduce idealization of
      pregnancy, diagnose psychological symptomatology and offer alternative career
      choices to children defaulting in the education system.

PMID- 15038798
TI  - Single and combined psychotropic medication use in a child and adolescent mental
      health service.
AB  - OBJECTIVE: An audit of the extent and effectiveness of medication prescribing in
      a metropolitan child and adolescent mental health service (CAMHS) is presented,
      given the lack of data about medication effectiveness in CAMHS. METHOD: The audit
      involved: (i) determining the rates of prescription of different medications, the
      symptoms, syndromes and diagnoses for which they were used, and the profession of
      the medication prescriber; and (ii) a semistructured interview of clinicians
      using combination pharmacotherapy enquiring about the rationale for its use and
      the outcomes obtained. RESULTS: Two hundred and thirty-five patients using
      medication were included in the study. A range of medications were prescribed,
      both alone and in combination. Indications for combination therapy were a single
      medication being ineffective or associated with adverse effects. They were
      targeted at symptoms and were associated with no increase in adverse effects.
      Trainees did relatively little prescribing. CONCLUSIONS: This study confirms
      earlier findings that medical practitioners are prescribing combination
      pharmacotherapy despite a lack of research to support this practice. Trainees
      working in CAMHS may be receiving inadequate experience in prescribing
      psychotropic medication.

PMID- 15038799
TI  - A comparative evaluation of community treatments for post-partum depression:
      implications for treatment and management practices.
AB  - OBJECTIVE: To compare existing community treatments for post-partum depression
      (PPD), treatment efficacy was evaluated for 146 women seeking treatment for PPD
      in the local community. METHODS: Self-report questionnaires were designed to
      assess clinical depression and anxiety (psychological and physiological), risk
      factors, treatment satisfaction and the impact of social supports. RESULTS:
      Comparison of treated subjects with those on a wait-list demonstrated that
      depression and the psychological component of anxiety decreased significantly
      after treatment. Psychological and pharmacological interventions produced similar
      clinical benefit in the treatment of psychological symptoms, and receiving both
      treatments in combination was of no added clinical benefit in the immediate or
      longer term. Individual treatment was associated with more rapid treatment gains
      initially than group treatment. However, the benefits of group treatment emerged
      during the 6 months following treatment, leading both interventions to be equally
      effective in the longer term. Cognitive behavioural therapy was not superior to
      the combination of non-specific counselling or behavioural strategies, either
      immediately following treatment or 6 months later. CONCLUSIONS: Clinical efficacy
      together with other clinical and financial benefits strongly advocate the
      application of psychological treatment for PPD. Clear parallels between PPD and
      general depression support the application of knowledge about general depression
      to extend understanding of PPD and refine clinical management practices.

PMID- 15038800
TI  - Medication options in the treatment of treatment-resistant depression.
AB  - AIM: Less than half of those suffering major depressive episodes achieve
      remission with the first antidepressant provided and one-third of all patients
      suffering depression have a chronic condition. Clinical experience indicates that
      a substantial proportion of patients suffer treatment-resistant depression (TRD).
      Our aim is to explore the literature reporting the drug treatment of TRD, and to
      present such information as would be of interest to clinical psychiatrists.
      METHOD: Literature searches were conducted using PubMed and entering the words
      antidepressant, augmentation, combined antidepressants, treatment resistant
      depression and the names of individual antidepressant medications. RESULTS: Most
      authors recommended that TRD should be first approached by reassessing the
      diagnosis, adding psychotherapy and attending to psychosocial factors. Details of
      the following pharmacological options were identified: (i) augmentation of the
      currently employed antidepressant with a medication which is not an
      antidepressant; (ii) change of antidepressant; and (iii) addition of a second
      antidepressant to the current antidepressant, or commencement of a combination of
      two antidepressants. CONCLUSIONS: When monotherapy provided at the maximum
      manufacturer-recommended doses for 3-4 weeks has failed to provide remission in
      depression, the diagnosis should be confirmed, psychotherapy added and
      psychosocial factors should receive attention. In the sustained absence of
      remission, a better outcome may be obtained by augmenting the antidepressant,
      changing from a single-action to a double- or multiple-action drug, or by
      combining antidepressants.

PMID- 15038801
TI  - Changes in semantic uses of first person pronouns as possible linguistic markers
      of recovery in psychotherapy.
AB  - OBJECTIVE: To examine changes in linguistic markers in the course of
      psychotherapy, drawing on Frege's logic of relations to define semantic variables
      distinct from syntactic variables. METHOD: From a sample of 73 patients, 10
      patients with the best and 10 patients with the worst outcomes were selected.
      Forty transcribed sessions of each outcome group were compared statistically for
      change between commencement and termination of psychotherapy in: (i) the
      syntactic usage of first person pronouns ('I', 'me', 'we', 'us', 'implied I',
      'implied me'); (ii) semantic usage of first person pronouns (expressing alpha,
      omega, or unclear positions); and (iii) non-pronoun linguistic variables (passive
      voice, negative, copula, auxiliary verbs expressing a sense of obligation).
      RESULTS: There were no significant differences between the best and worst outcome
      groups in the change of either syntactic usage, or of the non-pronoun linguistic
      variables. However, the outcome groups differed significantly in the change of
      their semantic usage (alpha: p = 0.002; omega: p = 0.028): The best outcome group
      showed an increase of alpha positions and a decrease of omega positions, whereas
      the worst outcome group showed the inverse (i.e. decrease of alpha and increase
      of omega positions). CONCLUSIONS: Results suggest only semantic, that is meaning
      driven, usage of first person pronouns marks recovery in the course of
      psychotherapy. If replicated, this finding could be used to monitor treatment
      responses. Replication in other kinds of treatment could mean these semantic
      changes are markers of recovery more generally than in psychotherapy.

PMID- 15038802
TI  - Pre-existing antidepressants and the outcome of group cognitive behaviour therapy
      for social phobia.
AB  - OBJECTIVE: This is a naturalistic treatment outcome study investigating the
      impact of pre-existing antidepressant use on the effectiveness of group cognitive
      behaviour therapy (CBT) for social phobia. METHOD: Of the 133 participants who
      completed the CBT program, 49 reported taking antidepressants (CBT + AD group),
      while 84 reported not taking antidepressants (CBT group). The treatment program
      involves 40 h of structured, group-based CBT over 7 weeks. The dependent measures
      included the Social Phobia Scale and Social Interaction Anxiety Scale, the Fear
      of Negative Evaluation Scale, the Depression, Anxiety and Stress Scale and the
      Short Form-12. RESULTS: Both the CBT + AD group and the CBT group improved
      significantly across treatment on all dependent measures. There were no
      significant differences between the groups on any outcome measure and the rate of
      improvement from pre- to post-treatment for both groups did not differ.
      CONCLUSIONS: Pre-existing antidepressants did not significantly enhance or
      detract from the positive treatment outcome of a structured, group-based CBT
      program for social phobia.

PMID- 15038803
TI  - An audit of outpatient antipsychotic usage in the three health sectors of
      Auckland, New Zealand.
AB  - OBJECTIVE: To examine antipsychotic usage in outpatients in three community
      mental health centres. METHOD: A retrospective chart review was conducted for all
      outpatient files that were active in March 2000 at all community mental health
      services in Auckland (population 1.3 million). All patients prescribed an
      antipsychotic had information entered into a specifically designed computer
      software program. The antipsychotic, dose and route of administration were
      recorded. The diagnosis, number of hospitalizations, ethnicity and gender were
      also collected. RESULTS: 6558 community files were audited and 3254 people were
      prescribed antipsychotics; 3178 (97.6%) files had adequate information for study
      inclusion. The mean antipsychotic daily dose in chlorpromazine equivalents (CPZe)
      was 360 mg. Most of the population (76.6%) was prescribed an oral antipsychotic
      alone, 14.9% were prescribed depot antipsychotic only and 8.4% were on a depot
      and oral antipsychotic. The average daily dose prescribed for people on
      antipsychotic polypharmacy was 601 mg CPZe compared with 312 mg CPZe for those on
      a single antipsychotic. There were 2300 patients with schizophrenia (72.5% of
      cohort) and 585 patients with bipolar affective disorder (18.5%). The mean total
      daily dose in CPZe was significantly higher for schizophrenia than any other
      psychotic diagnoses. Regional analysis showed differences in the doses and type
      of antipsychotics prescribed; one health sector had significantly higher daily
      doses while another was significantly more likely to prescribe atypical
      antipsychotics and correspondingly fewer depot antipsychotics. CONCLUSIONS: There
      is a significant variation in the prescribing of antipsychotics across the three
      Auckland health sectors. The variation relates to dosage used, type of
      antipsychotics prescribed and effect of multiple antipsychotic prescribing.
      Combination therapy of more than one oral antipsychotic or a combination of oral
      and depot antipsychotics leads to a significant trend of higher doses in excess
      of best practice guidelines.

PMID- 15038804
TI  - Enhancing medication adherence: clinician outcomes from the Medication Alliance
      training program.
AB  - OBJECTIVE: Patient nonadherence to psychiatric medication is a key cause of
      relapse but clinicians do not appear to possess specific adherence skills. We
      sought to demonstrate that a brief training program on medication adherence
      strategies could improve the adherence skills, attitudes and knowledge of mental
      health clinicians. METHODS: Twenty-three Tasmanian mental health workers were
      provided a 3 day training workshop on strategies to enhance patient adherence to
      medications (Medication Alliance). Pre- and post-training measures were taken of
      clinician knowledge about adherence strategies, ability to identify predictors of
      nonadherence, attitudes toward working with nonadherent patients, and optimism
      about treatment outcomes for patients. Videotapes of clinicians demonstrating key
      adherence therapy skills were also collected before and after training and blind
      rated by two experienced therapists. RESULTS: A series of paired samples t-tests
      indicated significant improvements in skills, knowledge and attitudes.
      CONCLUSIONS: Compared with similar studies in the UK, Medication Alliance was
      found to be an effective and efficient training program. However, there is a need
      for further research to assess maintenance of training effects over time and
      patient outcomes.

PMID- 15038805
TI  - Violence in male patients with schizophrenia: risk markers in a South African
      population.
AB  - OBJECTIVE: We investigate the role of functional variants in the catecholamine-O
      methyl transferase gene (COMT) and the monoamine oxidase-A gene (MOA-A), as well
      as previously identified non-genetic risk factors in the manifestation of violent
      behaviour in South African male schizophrenia patients. METHOD: A cohort of 70
      acutely relapsed male schizophrenia patients was stratified into violent and non
      violent subsets, based on the presence or absence of previous or current violent
      behaviour. Standardized violence rating scales were also applied and the
      COMT/NlaIII and MAO-A promoter region variable number of tandem repeats (VNTR)
      polymorphisms were genotyped. RESULTS: A multiple logistic regression model based
      on the clinical, genetic and socio-demographic variables indicated that delusions
      of control (OR = 3.7, 95% CI = 1.21-11.61) and the combined use of cannabis and
      alcohol (OR = 6.89, 95% CI = 1.28-37.05) were two significant predictors of
      violent behaviour in this schizophrenia population. No association was found
      between the tested polymorphisms and violent behaviour. CONCLUSIONS: Although the
      sample size may have limited power to exclude a minor role for these specific
      gene variants, such a small contribution would have limited clinical relevance
      given the strong significance of the non-genetic markers. These findings suggest
      that currently proactive management of violent behaviour in this schizophrenia
      population should continue to be based on clinical predictors of violence.

PMID- 15038806
TI  - Knowledge and attitudes about suicide in 25-year-olds.
AB  - OBJECTIVE: To examine knowledge and attitudes about suicide in a New Zealand
      sample of young people aged 25 years. METHOD: The sample was a birth cohort of
      1265 young people born in New Zealand in 1977 who have been followed in a
      longitudinal study for 25 years. At age 25, participants were asked a series of
      questions designed to assess their knowledge and attitudes about suicide.
      RESULTS: Young people had poor knowledge about youth suicide. They overestimated
      the number of youth suicide deaths, with a quarter believing that the number of
      deaths was at least 10x higher than the actual number. They overestimated the
      fraction of all suicides accounted for by youth suicides with two-thirds
      believing that 50% or more of all suicides occurred among young people. The most
      common source of information about suicide was the media. Young people tended to
      hold mixed attitudes toward suicide, having both liberal and conservative views.
      Those with lifetime histories of suicidal ideation or suicide attempt and those
      with family histories of suicide or suicide attempt tended to hold more liberal
      attitudes. Attitudes toward suicide were unrelated to gender and to knowledge
      about suicide. CONCLUSIONS: Young people over-estimate the prevalence of youth
      suicide and the fraction of suicides accounted for by youth deaths, and hold both
      conservative and liberal attitudes toward suicide. Their primary source of
      information about suicide is the media. These findings raise concerns about the
      potential for media coverage of youth suicide issues to normalize suicide as a
      common, and thereby acceptable, response among young people, and suggest the need
      for careful dissemination of accurate information about suicide by knowledgeable,
      respected and reputable sources.

PMID- 15038807
TI  - Olanzapine-induced galactorrhea in a woman with psychotic illness.

PMID- 15038808
TI  - Mirtazapine: not a dual action antidepressant?

PMID- 15038809
TI  - Mechanism of action of mirtazapine: dual action or dual effect?

PMID- 15038811
TI  - Guilt and PTSD.

PMID- 15038817
TI  - 'Accelerated aging': a primrose path to insight?
AB  - Organism envy afflicts most researchers who work on aging in mice; how
      frustrating it is to see the worm and fly biologists nail down milestone after
      milestone, citation after citation! Surely genetic trickery can produce mice that
      age in a comparable jiffy? Alas, our near-total ignorance of what times the aging
      process makes it hard to guess what genes to tweak, if indeed aging can be
      mimicked a presto. Building a case that a given short-lived mutant ages quickly
      is a steep and thorny path, requiring more than just plucking a symptom here and
      there from a list of things that sometimes go wrong in old people or old mice.
      The hallmark of aging is that a lot goes wrong more or less at the same time, in
      2-year-old mice, 10-year-old dogs and 70-year-old people. Finding ways to damage
      one or two systems in a 6-week or 6-month-old mouse is not too hard to do, but
      the implications of such studies for improved understanding of aging per se are
      at best indirect and at worst imaginary and distracting.

PMID- 15038818
TI  - Rebuttal to Hasty and Vijg: 'Accelerating aging by mouse reverse genetics: a
      rational approach to understanding longevity'.

PMID- 15038820
TI  - Rebuttal to Miller: 'Accelerated aging': a primrose path to insight?'.

PMID- 15038819
TI  - Accelerating aging by mouse reverse genetics: a rational approach to
      understanding longevity.
AB  - Investigating the molecular basis of aging has been difficult, primarily owing to
      the pleiotropic and segmental nature of the aging phenotype. There are many often
      interacting symptoms of aging, some of which are obvious and appear to be common
      to every aged individual, whereas others affect only a subset of the elderly
      population. Although at first sight this would suggest multiple molecular
      mechanisms of aging, there now appears to be almost universal consensus that
      aging is ultimately the result of the accumulation of somatic damage in cellular
      macromolecules, with reactive oxygen species likely to be the main damage
      inducing agent. What remains significant is unravelling how such damage can give
      rise to the large variety of aging symptoms and how these can be controlled.
      Although humans, with over a century of clinical observations, remain the obvious
      target of study, the mouse, with a relatively short lifespan, easy genetic
      accessibility and close relatedness to humans, is the tool par excellence to
      model aging-related phenotypes and test strategies of intervention. Here we
      present the argument that mouse models with engineered defects in genome
      maintenance systems are especially important because they often exhibit a
      premature appearance of aging symptoms. Confirming studies on human segmental
      progeroid syndromes, most of which are based on heritable mutations in genes
      involved in genome maintenance, the results thus far obtained with mouse models
      strongly suggest that lifespan and onset of aging are directly related to the
      quality of DNA metabolism. This may be in keeping with the recent discovery of a
      possible 'universal survival' pathway that improves antioxidant defence and
      genome maintenance and simultaneously extends lifespan in the mouse and several
      invertebrate species.

PMID- 15038821
TI  - Folate deficiency and homocysteine induce toxicity in cultured dorsal root
      ganglion neurons via cytosolic calcium accumulation.
AB  - Folate deficiency induces neurotoxicity by multiple routes, including increasing
      cytosolic calcium and oxidative stress via increasing levels of the neurotoxin
      homocysteine (HC), and inducing mitochondrial and DNA damage. Because some of
      these neurotoxic effects overlap with those observed in motor neuron disease, we
      examined the impact of folate deprivation on dorsal root ganglion (DRG) neurons
      in culture. Folate deprivation for 2 h increased cytosolic calcium and reactive
      oxygen species (ROS) and impaired mitochondrial function. Treatment with
      nimodipine [an L voltage-sensitive calcium channel (LVSCC) antagonist], MK-801
      (an NMDA channel antagonist) and thapsigarin (an inhibitor of efflux of calcium
      from internal stores) indicated that folate deprivation initially induced calcium
      influx via the LVSCC, with subsequent additional calcium derived from NMDA
      channels and internal stores. These compounds also reduced ROS and mitochondrial
      degeneration, indicating that calcium influx contributed to these phenomena.
      Calcium influx was prevented by co-treatment with 3-deaza-adenosine, which
      inhibits HC formation, indicating that HC mediated increased cytosolic calcium
      following folate deprivation. Nimodipine, MK-801 and thapsigargin had similar
      effects following direct treatment with HC as they did following folate
      deprivation. These findings support the idea that folate deprivation and HC
      treatment can compromise the health of DRG neurons by perturbing calcium
      homeostasis.

PMID- 15038822
TI  - Mitochondria in homeotherm aging: will detailed mechanisms consistent with the
      evidence now receive attention?

PMID- 15038823
TI  - Commentary on 'Fast anterograde transport of herpes simplex virus: role for the
      amyloid precursor protein of Alzheimer's disease' by Prasanna Satpute-Krishnan et
      al. Aging Cell Vol. 2, Issue 6, 305-318 (2003).

PMID- 15038824
TI  - Perspectives on herpes-APP interactions.

PMID- 15038827
TI  - A comparison of sexual behaviour and attitudes of healthy adolescents in a Danish
      high school in 1982, 1996, and 2001.
AB  - AIM: To assess changes in sexual behaviour among students at a high school in
      Denmark from 1982 to 2001. METHODS: An anonymous self-administered questionnaire
      was used to compare data from three identical cross-sectional surveys performed
      in 1982, 1996, and 2001. RESULTS: Girls: More girls reported their first sexual
      intercourse before their 16th birthday in 2001 (42%) than in 1996 (29%) In 1982
      it was also 42% (Chi-square for trend: p = 0.003). Fewer girls with no regular
      partner used condoms for their personal protection in 2001 (2%) than in 1996 (9%)
      and 1982 (0%) (Chi-square for trend p = 0.016). The proportion of girls with no
      regular partner who considered protection from sexually transmitted disease
      important for their choice of contraception was 39% in 2001 compared with 71% in
      1996 and only 10% in 1982 (Chi-square for trend: p < 0.0001).Boys: More boys
      reported sexual debut before their 16th birthday in 2001 (40%) than in 1996 (37%)
      and 1982 (24%) (Chi-square for trend: p = 0.023). For boys with no regular
      partner, condom was preferred for personal protection by 85% in 2001, 91% in 1996
      and 61% in 1982 (Chi-square for trend p = 0.007). Protection against sexually
      transmitted infection declined, especially among boys with no regular partner,
      from 51% in 2001 to 72% in 1996 and 21% in 1982 Chi-square for trend: p <
      0.0001).The tendency towards earlier sexual debut and less use of safe sex
      practices to protect against sexually transmitted infections (STI) was
      accompanied by a rise in the number of detected STIs during this period.
      CONCLUSIONS: The period from 1982 to 1996 during which sexual attitudes were
      directed toward safer sex seems to have given way to a reverse trend in the
      period from 1996 to 2001. These findings may have significant implications for
      health care authorities organising preventive strategies for healthy adolescents.

PMID- 15038826
TI  - Regulatable systemic production of monoclonal antibodies by in vivo muscle
      electroporation.
AB  - The clinical application of monoclonal antibodies (mAbs) potentially concerns a
      wide range of diseases including, among others, viral infections, cancer and
      autoimmune diseases. Although intravenous infusion appears to be the simplest and
      most obvious mode of administration, it is very often not applicable to long-term
      treatments because of the restrictive cost of mAbs certified for human use and
      the side effects associated with injection of massive doses of antibodies.
      Gene/cell therapies designed for sustained and, possibly, regulatable in vivo
      production and systemic delivery of mAbs might permit to advantageously replace
      it. We have already shown that several such approaches allow month- to year-long
      ectopic antibody production by non-B cells in living organisms. Those include
      grafting of ex vivo genetically modified cells of various types, in vivo
      adenoviral gene transfer and implantation of encapsulated antibody-producing
      cells. Because intramuscular electrotransfer of naked DNA has already been used
      for in vivo production of a variety of proteins, we have wanted to test whether
      it could be adapted to that of ectopic mAbs as well. We report here that this is
      actually the case since both long-term and regulatable production of an ectopic
      mAb could be obtained in the mouse taken as a model animal. Although serum
      antibody concentrations obtained were relatively low, these data are encouraging
      in the perspective of future therapeutical applications of this technology in mAb
      based immunotherapies, especially in developing countries where cost-effective
      and easily implementable technologies would be required for large-scale
      applications in the context of severe chronic viral diseases such as HIV and HCV
      infections.

PMID- 15038828
TI  - Using linked data to calculate summary measures of population health: Health
      adjusted life expectancy of people with Diabetes Mellitus.
AB  - OBJECTIVES: To estimate the health-adjusted life expectancy (HALE) from diabetes
      mellitus (DM) using a population health survey linked to a population-based DM
      registry. METHODS: The 1996/97 Ontario Health Survey (N = 35,517) was linked to
      the Ontario Diabetes Database (N = 487,576). The Health Utilities Index (HUI3)
      was used to estimate health-related quality of life. HALE was estimated using an
      adapted Sullivan method. RESULTS: Life expectancy at birth of people with DM was
      64.7 and 70.7 years for men and women - 12.8 and 12.2 years less than for men and
      women without DM. The HUI3 was lower for physician-diagnosed DM compared to self
      reported DM (0.799 versus 0.872). HALE at birth was 58.3 and 62.8 years for men
      and women - 11.9 and 10.7 years less than that of men and women without DM.
      CONCLUSIONS: The linked data approach demonstrates that DM is an important cause
      of disease burden. This approach reduces assumptions when estimating the
      prevalence and severity of disability from DM compared to methods that rely on
      self-reported disease status or indirect assessment of disability severity.

PMID- 15038830
TI  - Reconsidering the psychometrics of quality of life assessment in light of
      response shift and appraisal.
AB  - The increasing evidence for response shift phenomena in quality of life (QOL)
      assessment points to the necessity to reconsider both the measurement model and
      the application of psychometric analyses. The proposed psychometric model posits
      that the QOL true score is always contingent upon parameters of the appraisal
      process. This new model calls into question existing methods for establishing the
      reliability and validity of QOL assessment tools and suggests several new
      approaches for describing the psychometric properties of these scales.
      Recommendations for integrating the assessment of appraisal into QOL research and
      clinical practice are discussed.

PMID- 15038829
TI  - Reactive oxygen species and sperm cells.
AB  - There is a dynamic interplay between pro- and anti-oxidant substances in human
      ejaculate. Excessive reactive oxygen species (ROS) generation can overwhelm
      protective mechanism and initiate changes in lipid and/or protein layers of sperm
      plasma membranes. Additionally, changes in DNA can be induced. The essential
      steps of lipid peroxidation have been listed as well as antioxidant substances of
      semen. A variety of detection techniques of lipid peroxidation have been
      summarized together with the lipid components of sperm membranes that can be
      subjected to stress. It is unsolved, a threshold for ROS levels that may induce
      functional sperm ability or may lead to male infertility.

PMID- 15038832
TI  - Lymph node removal enhances corneal graft survival in mice at high risk of
      rejection.
AB  - BACKGROUND: As shown previously, the submandibular (SM) lymph node (LN) is
      required for priming the immune response during corneal graft rejection. In this
      study, we wished to determine whether corneal grafts at "high-risk" of rejection
      were also protected after selective SM LN removal and if so to investigate
      whether this improved corneal graft survival was due to induction of specific
      regulatory/suppressor cells or was due to immunological "ignorance". METHODS: Two
      sets of experiments were performed. (1) Adoptive transfer of possible regulatory
      splenocytes from mice with long-term accepted corneal graft after SM LN removal.
      (2) SM LN removal and corneal grafts in "high-risk" hosts, which had been (A)
      subjected to corneal trauma with vascularization or (B) allosensitized by
      previous corneal graft or (C) allosensitized by previous skin graft. RESULTS:
      Adoptive transfer of splenocytes from tolerant mice after SM LN removal did not
      enhance corneal graft survival in naive recipients (p > 0.05). SM LN removal in
      mice with corneal vascularization enhanced corneal allograft survival compared to
      grafted controls with/without vascularization (p < 0.0001). The removal of the SM
      LN in mice, who had already been allosensitized by a previous corneal graft, did
      not statistically prolong corneal graft survival (p > 0.05). SM LN removal
      procedure did not delay rejection of corneal grafts in mice allosensitized by a
      previous skin transplant with the same strain combination (p > 0.05). CONCLUSION:
      The results suggest that removal of the SM LN in "high-risk" mice prevents
      rejection by mechanisms involving immune "ignorance", since prior
      allosensitization prevents graft acceptance after LN removal. In allosensitized
      recipients the stronger the allosensitization (skin- vs. corneal graft
      presensitization) the greater the possibility of priming for rejection at
      alternative draining LN sites.

PMID- 15038833
TI  - Reversibility of stress-echo induced ST-segment depression by long-term oral n-3
      PUFA supplementation in subjects with chest pain syndrome, normal wall motion at
      stress-echo and normal coronary angiogram.
AB  - BACKGROUND: Normal coronary arteries may coexist with abnormal coronary and
      systemic endothelial function in patients with chest pain. Recent work by the
      renowned Pisa echo-group elegantly suggests that isolated ST-segment depression
      during stress-echo (SE) can be used as a marker of coronary endothelial
      dysfunction, in the absence of stress-inducible wall motion abnormalities and in
      the absence of angiographically-significant coronary artery disease (CAD). The
      long chain n-3 polyunsaturated fatty acids (PUFAs) have been reported to possess
      several properties that may positively influence vascular function. The present
      study's hypothesis is that a 4 month-course of oral supplementation with n-3
      PUFAs can reverse endothelial dysfunction. METHODS: Subjects were selected on the
      basis of the following criteria: 1) reported chest pain syndrome, 2) significant
      ST-segment depression during an otherwise normal SE, 3) absence of
      angiographically-significant CAD. Subjects underwent a 4-month course of oral
      supplementation with commercially available n-3 PUFA, 1 g once a day.
      Normalization of endothelial dysfunction was defined, at the end of the
      supplementation period, by the absence of significant ST-segment depression
      during repeat SE. We tested the aforementioned hypothesis in a very small series
      of consecutive subjects, with the intent to produce a hypothesis-generating
      study. RESULTS: Seven out of the total nine subjects enrolled (77.8%) had normal
      ST-segment during repeat SE performed after the 4 month course of therapy.
      CONCLUSIONS: A striking rate of reversion of SE-induced ST-segment depression
      after oral n-3 PUFAs suggests reversion of coronary endothelial dysfunction;
      nonetheless these data need to be validated in larger, placebo-controlled
      studies.

PMID- 15038831
TI  - Intraocular pressure and ocular pulse amplitude using dynamic contour tonometry
      and contact lens tonometry.
AB  - BACKGROUND: The new Ocular Dynamic Contour Tonometer (DCT), investigational
      device supplied by SMT (Swiss Microtechnology AG, Switzerland) allows
      simultaneous recording of intraocular pressure (IOP) and ocular pulse amplitude
      (OPA). It was the aim of this study to compare the IOP results of this new device
      with Goldmann tonometry. Furthermore, IOP and OPA measured with the new slitlamp
      mounted DCT were compared to the IOP and OPA measured with the hand-held
      SmartLens,a gonioscopic contact lens tonometer (ODC Ophthalmic Development
      Company AG, Switzerland). METHODS: Nineteen healthy subjects were included in
      this study. IOP was determined by three consecutive measurements with each of the
      DCT, SmartLens, and Goldmann tonometer. Furthermore, OPA was measured three times
      consecutively by DCT and SmartLens. RESULTS: No difference (P = 0.09) was found
      between the IOP values by means of DCT (mean: 16.6 mm Hg, median: 15.33 mm Hg,
      SD: +/- 4.04 mm Hg) and Goldmann tonometry (mean: 16.17 mm Hg, median: 15.33 mm
      Hg, SD: +/- 4.03 mm Hg). The IOP values of SmartLens (mean: 20.25 mm Hg, median:
      19.00 mm Hg, SD: +/- 4.96 mm Hg) were significantly higher (P = 0.0008) both from
      Goldmann tonometry and DCT. The OPA values of the DCT (mean: 3.08 mm Hg, SD: +/-
      0.92 mm Hg) were significantly lower (P = 0.0003) than those obtained by
      SmartLens (mean: 3.92 mm Hg, SD: +/- 0.83 mm Hg). CONCLUSIONS: DCT was equivalent
      to Goldmann applanation tonometry in measurement of IOP in a small group of
      normal subjects. In contrast, SmartLens (contact lens tonometry) gave IOP
      readings that were significantly higher compared with Goldmann applanation
      tonometer readings. Both devices, DCT and SmartLens provide the measurement of
      OPA which could be helpful e.g. for the management of glaucoma.

PMID- 15038835
TI  - Functional classes of bronchial mucosa genes that are differentially expressed in
      asthma.
AB  - BACKGROUND: Asthma pathogenesis and susceptibility involves a complex interplay
      between genetic and environmental factors. Their interaction modulates the airway
      inflammation and remodelling processes that are present even in mild asthma and
      governs the appearance and severity of symptoms of airway hyperresponsiveness.
      While asthma is felt to develop as the result of interaction among many different
      genes and signalling pathways, only a few genes have been linked to an increased
      risk of developing this condition. RESULTS: We report the results of expression
      microarray studies using tissue obtained from bronchial biopsies of healthy
      controls and of subjects with allergic asthma, both before and following inhaled
      corticotherapy. We identified 79 genes that show significant differences in
      expression (following Bonferroni cutoff using p < 6.6 x 10(-6) to correct for
      multiple testing) in asthmatics compared to controls at significance levels.
      These included 21 genes previously implicated in asthma, such as NOS2A and GPX3,
      as well as new potential candidates, such as ALOX15, CTSC and CX3CR1. The
      expression levels of one third of these transcripts were partially or completely
      corrected following inhaled corticosteroid therapy. CONCLUSION: The study shows
      that bronchial biopsies obtained from healthy and asthmatic subjects display
      distinct expression profiles. These differences provide a global view of
      physiopathologic processes active in the asthmatic lung and may provide
      invaluable help to clarify the natural history of asthma.

PMID- 15038836
TI  - A plant natriuretic peptide-like gene in the bacterial pathogen Xanthomonas
      axonopodis may induce hyper-hydration in the plant host: a hypothesis of
      molecular mimicry.
AB  - BACKGROUND: Plant natriuretic peptides (PNPs) are systemically mobile molecules
      that regulate homeostasis at nanomolar concentrations. PNPs are up-regulated
      under conditions of osmotic stress and PNP-dependent processes include changes in
      ion transport and increases of H2O uptake into protoplasts and whole tissue.
      PRESENTATION OF THE HYPOTHESIS: The bacterial citrus pathogen Xanthomonas
      axonopodis pv. Citri str. 306 contains a gene encoding a PNP-like protein. We
      hypothesise that this bacterial protein can alter plant cell homeostasis and thus
      is likely to represent an example of molecular mimicry that enables the pathogen
      to manipulate plant responses in order to bring about conditions favourable to
      the pathogen such as the induced plant tissue hyper-hydration seen in the wet
      edged lesions associated with Xanthomonas axonopodis infection. TESTING THE
      HYPOTHESIS: We found a Xanthomonas axonopodis PNP-like protein that shares
      significant sequence similarity and identical domain organisation with PNPs. We
      also observed a significant excess of conserved residues between the two proteins
      within the domain previously identified as being sufficient to induce biological
      activity. Structural modelling predicts identical six stranded double-psi beta
      barrel folds for both proteins thus supporting the hypothesis of similar modes of
      action. No significant similarity between the Xanthomonas axonopodis protein and
      other bacterial proteins from GenBank was found. Sequence similarity of the
      Xanthomonas axonopodis PNP-like protein with the Arabidopsis thaliana PNP (AtPNP
      A), shared domain organisation and incongruent phylogeny suggest that the PNP
      gene may have been acquired by the bacteria in an ancient lateral gene transfer
      event. Finally, activity of a recombinant Xanthomonas axonopodis protein in plant
      tissue and changes in symptoms induced by a Xanthomonas axonopodis mutant with a
      knocked-out PNP-like gene will be experimental proof of molecular mimicry.
      IMPLICATION OF THE HYPOTHESIS: If the hypothesis is true, it could at least in
      part explain why the citrus pathogen Xanthomonas campestris that does not contain
      a PNP-like gene produces dry corky lesions while the closely related Xanthomonas
      axonopodis forms lesions with wet edges. It also suggests that genes typically
      found in the host, horizontally transferred or heterologous, can help to explain
      aspects of the physiology of the host-pathogen interactions.

PMID- 15038834
TI  - The extracellular matrix, p53 and estrogen compete to regulate cell-surface
      Fas/Apo-1 suicide receptor expression in proliferating embryonic cerebral
      cortical precursors, and reciprocally, Fas-ligand modifies estrogen control of
      cell-cycle proteins.
AB  - BACKGROUND: Apoptosis is important for normal cerebral cortical development. We
      previously showed that the Fas suicide receptor was expressed within the
      developing cerebral cortex, and that in vitro Fas activation resulted in caspase
      dependent death. Alterations in cell-surface Fas expression may significantly
      influence cortical development. Therefore, in the following studies, we sought to
      identify developmentally relevant cell biological processes that regulate cell
      surface Fas expression and reciprocal consequences of Fas receptor activation.
      RESULTS: Flow-cytometric analyses identified two distinct neural sub-populations
      that expressed Fas on their cell surface at high (FasHi) or moderate (FasMod)
      levels. The anti-apoptotic protein FLIP further delineated a subset of Fas
      expressing cells with potential apoptosis-resistance. FasMod precursors were
      mainly in G0, while FasHi precursors were largely apoptotic. However, birth-date
      analysis indicated that neuroblasts express the highest levels of cell-surface
      Fas at the end of S-phase, or after their final round of mitosis, suggesting that
      Fas expression is induced at cell cycle checkpoints or during interkinetic
      nuclear movements. FasHi expression was associated with loss of cell-matrix
      adhesion and anoikis. Activation of the transcription factor p53 was associated
      with induction of Fas expression, while the gonadal hormone estrogen
      antagonistically suppressed cell-surface Fas expression. Estrogen also induced
      entry into S-phase and decreased the number of Fas-expressing neuroblasts that
      were apoptotic. Concurrent exposure to estrogen and to soluble Fas-ligand (sFasL)
      suppressed p21/waf-1 and PCNA. In contrast, estrogen and sFasL, individually and
      together, induced cyclin-A expression, suggesting activation of compensatory
      survival mechanisms. CONCLUSIONS: Embryonic cortical neuronal precursors are
      intrinsically heterogeneous with respect to Fas suicide-sensitivity. Competing
      intrinsic (p53, cell cycle, FLIP expression), proximal (extra-cellular matrix)
      and extrinsic factors (gonadal hormones) collectively regulate Fas suicide
      sensitivity either during neurogenesis, or possibly during neuronal migration,
      and may ultimately determine which neuroblasts successfully contribute neurons to
      the differentiating cortical plate.

PMID- 15038837
TI  - Metabolic modulation of muscle fiber properties unrelated to mechanical stimuli.
AB  - The effects of chronically increasing (creatine-fed) or decreasing (beta
      guanidinopropionic acid [beta-GPA]-fed) high-energy phosphates for up to 8 weeks
      on daily voluntary activity levels, swimming endurance capacity, electromyogram
      (EMG) activity, and the morphological and metabolic properties of single fibers
      in the soleus and extensor digitorum longus (EDL) muscles in young rats were
      determined. High-energy phosphate, voluntary activity, and soleus-integrated EMG
      levels were lower in beta-GPA-fed rats than in control rats. Endurance capacity
      was higher at a relatively low intensity of swimming and lower at a relatively
      high intensity in beta-GPA-fed rats than in control rats. Muscle mass and fiber
      size were smaller, and the percentage of slow fibers was higher in the soleus and
      EDL of beta-GPA-fed rats than in control rats. Succinate dehydrogenase activity
      was higher in both the fast and slow fibers of the EDL of beta-GPA-fed rats than
      in control rats. Thus, a reduction in high-energy phosphates transformed some
      fast fibers toward a slow phenotype. Creatine supplementation had minimal
      effects: The only significant change was an increase in alpha-glycerophosphate
      dehydrogenase activity in the fast fibers of the EDL. These results indicate that
      the metabolic environment of a muscle fiber can influence the prominence of a
      given muscle fiber independent of the activity level of muscle.

PMID- 15038838
TI  - The influences of L(+)-lactate and pH on contractile performance in rabbit
      glycerinated skeletal muscle.
AB  - To know whether L(+)-lactate directly induces the decrease in muscle contractile
      performance, several parameters of cross-bridge function were measured at various
      concentrations of lactate and pH in glycerinated rabbit psoas and soleus muscles
      at three different temperatures (5, 20, 28 degrees C). At all pHs studied (pH
      7.0, 6.5, 6.0, and 5.5), isometric tension, unloaded velocity of shortening, and
      stiffness of a fiber during active and resting state in the presence of 50 mM
      lactate were not virtually different from those in the absence of lactate, but pH
      had remarkable effects on these parameters. The active stiffness decreased only
      slightly, and the small resting stiffness appeared at low pH; they were not
      affected by the presence of lactate. The present results indicate that the
      lactate anions may not have marked influence on the interaction between actin and
      myosin, and the concomitant change in pH with the production of lactate may
      remarkably affect it, as far as they were examined under the existing conditions
      of the experimental solutions.

PMID- 15038839
TI  - Hyperthyroidism causes mechanical insufficiency of myocardium with possibly
      increased SR Ca2+-ATPase activity.
AB  - Hyperthyroidism is known to affect multiple organ functions, and thyroid hormone
      has been known to improve myocardial function in a failing heart. The purpose of
      this study is to elucidate the functional and metabolic effects of thyroid
      hormone on myocardium in a rat model exposed to long-term excess thyroid hormone,
      particularly focusing on the SR Ca(2+)-ATPase (SERCA2) function. 3,5,3'-Triiodo-L
      thyronine (T3), or the vehicle, was subcutaneously given for 4 weeks (T3 and
      control [C] group). Bolus I.V. Thapsigargin (TG) was used to test the SERCA2
      function (C-TG and T3-TG) in Langendorff perfused heart. Myocardial functions
      such as LV-developed pressure (LVDP; mmHg), +/- dP/dt (mmHg/s), tau (ms), and
      oxygen consumption (MVO(2); ml/min/g wt) were measured. SERCA2 and GLUT4 protein
      level were also evaluated by Western immunoblotting. Left ventricle to body
      weight (LV/BW) ratio was significantly higher in the T3 group. Both negative
      dP/dt and tau were significantly decreased by TG. It is interesting that the
      decrement of negative dP/dt and tau attained by TG was significantly larger in
      the hyperthyroid group (T3-TG) than in a normal heart (C-TG). SERCA2 and GLUT4
      protein levels were not significantly different between control and the T3 group.
      We conclude that prolonged exposure to thyroid hormone causes hypertrophy of the
      myocardium and an augmentation of the SR Ca(2+) ATPase activity. Care must be
      taken in hyperthyroid heart during the ischemia-reperfusion process where the
      SRECA2 function is inhibited.

PMID- 15038840
TI  - Block of recombinant KCNQ1/KCNE1 K+ channels (IKs) by intracellular Na+ and its
      implications on action potential repolarization.
AB  - I(Ks), the slow component of delayed rectifier K+ current, plays an important
      role for the repolarization of ventricular action potential. We investigated the
      block of I(Ks) by intracellular Na+ ([Na+](i)), using a heterologous expression
      system (KCNQ1/KCNE1 expressed in COS7 cells), since this well-known blocking
      action on various K+ channels has not been fully or quantitatively characterized
      in I(Ks) current. The Na+ block of I(Ks) was concentration- and voltage-dependent
      and was described by a conventional binding-site model (Woodhull AM: J Gen
      Physiol 61: 687-708, 1973). In physiological ionic conditions, the blocking
      action was operating noticeably with Delta ("electrical" distance of the block
      site) approximately 0.6 and K(d)(0) (apparent dissociation constant at 0 mV)
      approximately 300 mM. Because K(d)(0) was a function of intra- and extracellular
      K+ concentrations, changes in ionic environments not only of [Na+](i), but also
      of [K+](o), affected the amplitude of I(Ks) through the modulation of the Na+
      block. Based on these experimental data, we analyzed the effects of Na+ block on
      action potentials by a computer simulation study, using the Luo-Rudy model. In a
      physiological ionic environment, the Na+ block of I(Ks) contributed little to
      modifying action potentials. However, when action potential duration (APD) was
      marginally prolonged because of decreased I(Ks), as observed in M cells under the
      conditions of bradycardia and low [K+](o), the Na+ block of I(Ks) may contribute
      to arrhythmogenesis through the facilitation of early afterdepolarizations
      (EADs).

PMID- 15038841
TI  - Effect of skin temperature on the cholinergic sensitivity of the human eccrine
      sweat gland.
AB  - Although sweat gland activity is directly controlled by the central nervous
      system, which detects changes in core body temperature, sweat glands can also be
      influenced by local cutaneous thermal conditions. OBJECTIVE: The present study
      sought to determine the effect of local skin temperature on pilocarpine-induced
      sweating within a range of typical skin temperatures. METHODS: Thirteen subjects
      (30 +/- 6 years; 172 +/- 11 cm; 72.8 +/- 11.0 kg) had forearm sweat rates
      measured at rest following pilocarpine iontophoresis at each of three skin
      temperatures in randomized order: warm (T(warm) = 37.1 +/- 0.9 degrees C),
      control (T(con) = 32.3 +/- 1.4 degrees C), and cool (T(cool) = 26.6 +/- 1.3
      degrees C). T(skin) was raised and lowered with an electric heating pad and gel
      ice pack, respectively. Forearm T(skin) was measured with a skin temperature
      probe. Pilocarpine iontophoresis was used on an approximately 7 cm(2) area of the
      anterior forearm to stimulate localized sweating. Following stimulation, sweat
      was collected from the area for 15 min with a Macroduct Sweat Collection System.
      RESULTS: There was a higher sweat rate at T(warm) (p = 0.001) and T(con) (p =
      0.006) compared to that at T(cool). However, there was no difference between the
      sweat rate at T(warm) and that at T(con) (p = 0.127). CONCLUSION: These results
      indicated that skin temperatures below approximately 32 degrees C affect local
      sweat production primarily by altering glandular sensitivity to the
      neurotransmitter, whereas skin temperatures above approximately 32 degrees C
      predominantly affect neurotransmitter release. Furthermore, sweat glands display
      maximal or near maximal cholinergic sensitivity at resting skin temperature in a
      thermoneutral environment.

PMID- 15038842
TI  - Modulation of intracellular Na+ and Ca2+ induced by the cardiac Na+-Ca2+
      exchanger in guinea pig ventricular myocytes.
AB  - The Na+-Ca2+ exchanger current was measured in single guinea pig ventricular
      myocytes, using the whole-cell voltage-clamp technique, and intracellular free
      calcium concentration ([Ca2+](i)) was monitored simultaneously with the
      fluorescent probe Indo-1 applied intracellularly through a perfused patch
      pipette. In external solutions, which have levels of Ca2+ (approximately 66
      microM Ca2+) thought low enough to inhibit exchanger turnover, the removal of
      external Na+ (by replacement with Li+) induced both an outward shift of the
      holding current and an increase in [Ca2+](i), even though the recording pipette
      contained 30 mM bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA),
      sufficient to completely block phasic contractions. The effects of Na+ removal
      were blocked either by the extracellular application of 2 mM Ni2+ or by chelating
      extracellular Ca2+ with 1 mM EGTA. In the presence of 10 microM Ryanodine, the
      effects of external Na+ substitution with Li(+) on both membrane current and
      [Ca2+](i) were attenuated markedly in amplitude and at a much slower time course.
      Reversal potentials were estimated by using ramp pulses and by defining exchange
      currents as the Ni2+-sensitive components. The experimental values of the
      reversal potential and [Ca2+](i) were used to calculate cytosolic Na+ ([Na+](i))
      by assuming an exchanger stoichiometry of 3Na+ : 1Ca2+. These calculations
      suggested that in the nominal absence of external Ca2+ ( approximately 66 microM
      under our experimental conditions), the exchanger operates at -40 mV as though
      approximately 40 mM Na+ had accumulated in the vicinity of the intracellular
      binding sites. We conclude that under the conditions of low extracellular Ca2+
      and high intracellular Ca2+ buffering, the Na+-Ca2+ exchanger can still generate
      sufficient Ca2+ influx on the removal of external Na+ to markedly increase
      cytosolic free Ca2+.

PMID- 15038843
TI  - High-glucose induced protective effect against hypoxic injury is associated with
      maintenance of mitochondrial membrane potential.
AB  - Our previous report has showed that the treatment of 48 h with 22 mM glucose
      prevents hypoxia-induced cardiac cell death. In the present study, we
      investigated whether high glucose affects the mitochondrial death pathway during
      hypoxia, and if it does, what relates to the high glucose induced
      cardioprotection. Heart-derived H9c2 cells were incubated in low (5.5 mM) or high
      (22 mM) glucose medium for 48 h, then transferred to a normoxic or hypoxic
      condition. The hypoxia-induced reduction of mitochondrial redox potential,
      assessed by MTT assay, was inhibited in high glucose treated cells. The
      mitochondrial membrane potential was significantly decreased by hypoxia in low
      glucose treated cells, but not in high glucose treated cells. The hypoxia-induced
      cytoplasmic accumulation of cytochrome c, released from the mitochondria, was
      blocked by a treatment of high glucose. High glucose did not induce the
      expression of an antiapoptotic protein Bcl-2, nor did it reduce a proapoptotic
      protein Bax, but it did inhibit a hypoxia-induced downregulation of Bcl-2. The
      cellular ATP contents were not changed by the treatment of high glucose for 48 h,
      and the hypoxia-induced decline of intracellular ATP level was observed in high
      glucose treated cells and in low glucose. A glycolytic inhibitor, 2-deoxyglucose,
      did not reverse the high glucose induced reduction of LDH release. The elevation
      of [ROS](i) induced by hypoxia was inhibited in high glucose treated cells. These
      results suggest that high glucose induced cardioprotection may be accounted for
      in part by the preservation of MMP and the maintenance of a basal level of
      [ROS](i) during hypoxia.

PMID- 15038844
TI  - Carotid-sinus baroreflex modulation of core and skin temperatures in rats: an
      open-loop approach.
AB  - The neural mechanisms of the thermoregulatory control of core and skin
      temperatures in response to heat and cold stresses have been well clarified.
      However, it has been unclear whether baroreceptor reflexes are involved in the
      control of core and skin temperatures. To investigate how the arterial
      baroreceptor reflex modulates the body temperatures, we examined the effect of
      pressure changes of carotid sinus baroreceptors on core and skin temperatures in
      halothane-anesthetized rats. To open the baroreflex loop and control arterial
      baroreceptor pressure (BRP), we cut vagal and aortic depressor nerves and
      isolated carotid sinuses. We sequentially altered BRP in 20-mmHg increments from
      60 to 180 mmHg and then in 20-mmHg decrements from 180 to 60 mmHg while measuring
      systemic arterial pressure (SAP), heart rate (HR), and core blood temperature
      (T(core)) at the aortic arch and skin temperature (T(skin)) at the tail. In
      response to the incremental change in BRP by 120 mmHg, SAP, HR, and T(core) fell
      by 90.3 +/- 5.1 mmHg, 60.3 +/- 10.5 beats min(-1), and 0.18 +/- 0.01 degrees C,
      respectively. T(skin) rose by 0.84 +/- 0.10 degrees C. The maximum rate of change
      per unit BRP change was -2.1 +/- 0.2 for SAP, -1.5 +/- 0.4 beats min(-1) mmHg(-1)
      for HR, -0.003 +/- 0.001 degrees C mmHg(-1) for T(core), and 0.011 +/- 0.002
      degrees C mmHg(-1) for T(skin). After the administration of hexamethonium or
      bretylium, these baroreflexogenic responses were completely abolished. We
      concluded that T(core) and T(skin) are modulated by the arterial baroreceptor
      reflex.

PMID- 15038845
TI  - Regional differences in blood volume and blood transit time in resting skeletal
      muscle.
AB  - We examined regional differences in blood volume and transit time along the
      length of a resting skeletal muscle by positron emission tomography. In contrast,
      blood volume didn't change. The blood transit time increased significantly from
      proximal to distal portions, suggesting that blood flow velocity slows even
      though there are no changes in blood volume.

PMID- 15038847
TI  - Relationship between caloric intake, body composition, and physical activity to
      leptin, thyroid hormones, and cortisol in adolescents.
AB  - This study examined the interrelationships between (1) the hormones leptin, TSH,
      free T3, and cortisol, and (2) caloric intake, body composition, and physical
      activity to these select hormones in adolescent boys and girls (n = 125, age =
      13.4 +/- 0.9 years). The data indicate that adolescent boys and girls have some
      common hormonal interrelationships. However, certain hormonal relationships are
      not in agreement with reports for adults, suggesting that researchers should not
      assume that all endocrine findings in adults are automatically applicable to
      adolescents.

PMID- 15038846
TI  - Effects of hydrogen peroxide on contraction of skinned aorta from guinea pigs.
AB  - We examined the effects of hydrogen peroxide (H2O2) on the contractile force of
      cell membrane permeabilized descending thoracic aorta from guinea pigs. H2O2
      enhanced generated force in the Ca2+-induced contraction at any given
      concentration of Ca2+, and maintained force level in the 30 mM Mg2+-induced Ca2+
      independent force maintenance. H2O2 seems to directly enhance the cross-bridge
      interaction of aortic smooth muscles.

PMID- 15038848
TI  - A new quantitative filtration apparatus to evaluate erythrocyte deformability.
AB  - We have developed a quantitative filtration apparatus to evaluate erythrocyte
      deformability, using a precision metal filter which we developed. The test
      material is sucked into the filter through the action of decreasing negative
      pressure. The device automatically gives a liquid level (height)-time relation
      and a pressure-flow rate relation, similar to gravity-based filtration. Unlike
      the gravity-based system, the experimental performance of this system is very
      good and reproducible.

PMID- 15038849
TI  - Retinal circadian clocks and control of retinal physiology.
AB  - Retinas of all classes of vertebrates contain endogenous circadian clocks that
      control many aspects of retinal physiology, including retinal sensitivity to
      light, neurohormone synthesis, and cellular events such as rod disk shedding,
      intracellular signaling pathways, and gene expression. The vertebrate retina is
      an example of a "peripheral" oscillator that is particularly amenable to study
      because this tissue is well characterized, the relationships between the various
      cell types are extensively studied, and many local clock-controlled rhythms are
      known. Although the existence of a photoreceptor clock is well established in
      several species, emerging data are consistent with multiple or dual oscillators
      within the retina that interact to control local physiology. A prominent example
      is the antiphasic regulation of melaton in and dopamine in photoreceptors and
      inner retina, respectively. This review focuses on the similarities and
      differences in the molecular mechanisms of the retinal versus the SCN
      oscillators, as well as on the expression of core components of the circadian
      clockwork in retina. Finally, the interactions between the retinal clock(s) and
      the master clock in the SCN are examined.

PMID- 15038850
TI  - Phase determination of circadian gene expression in Synechococcus elongatus PCC
      7942.
AB  - The authors analyzed the upstream regulatory region of purF, a gene that is
      expressed in a minority phase that peaks at dawn (class 2 circadian phasing) in
      Synechococcus elongatus, to determine whether specific cis elements are
      responsible for this characteristic expression pattern. Fusions of various
      promoter-bearing fragments to luciferase reporter genes showed that normal class
      2 phasing of purF expression was correlated with promoter strength. No specific
      cis element that is separable from the promoter was responsible for determining
      phase. Very weak promoter activity of unstable phasing was mapped to a 50-bp
      segment. Inclusion of sequences that flank this minimal promoter either upstream
      or downstream increased the promoter strength and stabilized the phase in class
      2, but neither segment was individually necessary. Because the data suggested a
      role for the overall promoter context rather than a specific "phase element," the
      authors proposed that DNA topology is important in the phase determination of
      circadian gene expression in S. elongatus. To test this hypothesis, they fused
      the well-characterized DNA topology-dependent Escherichia coli fis promoter to
      luciferase and showed that it acts as a class 2 promoter in S. elongatus.

PMID- 15038851
TI  - Expression of haPer1 and haBmal1 in Syrian hamsters: heterogeneity of transcripts
      and oscillations in the periphery.
AB  - The molecular biology of circadian rhythms has been extensively studied in mice,
      and the widespread expression of canonical circadian clock genes in peripheral
      organs is well established in this species. In contrast, much less information
      about the peripheral expression of haPer1, haPer2, and haBmal1 is available in
      Syrian hamsters despite the fact that this species is widely used for studies of
      circadian organization and photoperiodic responses. Furthermore, examination of
      oscillating expression of these genes in mouse testis has generated discrepant
      results, and little is known about gonadal expression of haPer1 and haBmal1 or
      their environmental control. To address these questions, the authors examined the
      pattern of haPer1 and haBmal1 in heart, kidney, liver, muscle, spleen, and testis
      of hamsters exposed to DD. In most organs, Northern blots suggested the existence
      of single transcripts of each of these messenger RNAs (mRNAs). haPer1 peaked in
      late subjective day and haBmal1 during the late subjective night. Closer
      inspection of SCN and muscle haPer1, however, revealed the existence of two major
      transcripts of similar size, as well as minor transcripts that varied in the 3'
      untranslated region. In hamster testis, two haPer1 transcripts were found, both
      of which are truncated relative to the corresponding mouse transcript and both of
      which contain a sequence homologous to intron 18 of mPer1. Neither testis
      transcript contains a nuclear localization signal, and haPer1 transcripts lacked
      the putative C-terminal CRY1-binding domain. Furthermore, the testis deviated
      from the general pattern in that haPer1 and haBmal1 both peaked in the subjective
      night. In situ hybridization revealed that haPer1, but not haBmal1, showed a
      heterogeneous distribution among seminiferous tubules. Hamster testis also
      expresses 2 haPer2 transcripts, but no circadian variation is evident. In a
      second experiment, long-term exposure to DD sufficient to induce gonadal
      regression was found to eliminate circadian oscillations of both testicular
      haPer1 transcripts. In contrast, gonadal regression was accompanied by a more
      robust rhythm of haBmal1.

PMID- 15038852
TI  - Dec1 and Dec2 expression is disrupted in the suprachiasmatic nuclei of Clock
      mutant mice.
AB  - DEC1 and DEC2 are basic helix-loop-helix transcription factors that functionally
      resemble negative feedback components of the mammalian circadian clock. The genes
      Dec1 and Dec2 are expressed rhythmically in the rat suprachiasmatic nuclei, and
      Dec1 expression is stimulated by light in a time-dependent manner with the
      kinetics of an immediate early gene. DEC1 and DEC2 can inhibit CLOCK:BMAL1
      transactivation of the clock gene Per1, suggesting that these transcription
      factors may help regulate circadian timing. The authors present data on the
      expression pattern of Dec1 and Dec2 in wild-type and homozygous Clock mutant
      mice. In the suprachiasmatic nuclei, the Clock mutation significantly reduces the
      expression of Dec1 and Dec2. Dec1 becomes arrhythmic; Dec2 remains weakly
      rhythmic in a 12L:12D light-dark cycle but is arrhythmic in constant darkness. A
      robust attenuation of the Dec1 and Dec2 signals in Clock mutant mice was detected
      in all brain areas examined. These data point to up-regulation of Dec1 and Dec2
      by Clock in vivo.

PMID- 15038853
TI  - Photoperiodism in Neurospora crassa.
AB  - Plants and animals use day or night length for seasonal control of reproduction
      and other biological functions. Overwhelming evidence suggests that this
      photoperiodic mechanism relies on a functional circadian system. Recent progress
      has defined how flowering time in plants is regulated by photoperiodic control of
      output pathways, but the underlying mechanisms of photoperiodism remain to be
      described. The authors investigate photoperiodism in a genetic model system for
      circadian rhythms research, Neurospora crassa. They find that both propagation
      and reproduction respond systematically to photoperiod. Furthermore, a
      nonreproductive light-regulated function is also enhanced under certain
      photoperiodic conditions. All of these photoperiodic responses require a
      functional circadian clock, in that they are absent in a clock mutant. Night
      break experiments show that measuring night length is one of the mechanisms used
      for photoperiod assessment. This represents the first formal report of
      photoperiodism in the fungi.

PMID- 15038854
TI  - Influence of the corticosterone rhythm on photic entrainment of locomotor
      activity in rats.
AB  - The question of involvement of glucocorticoid hormones as temporal signals for
      the synchronization of the timekeeping system was addressed in rats with
      different corticosterone status. The authors showed that adrenalectomy had no
      effects on the synchronization of wheel-running activity rhythms to a steady
      state LD 12:12 cycle, regardless of whether it was compensated for by a
      corticosterone replacement therapy that either reinstated constant plasma
      concentrations of the hormone or mimicked its natural rhythm. However, after a 12
      h phase shift (daylight reversal), the lack of circulating corticosterone induced
      a significant shortening of the resynchronization rate (less than 3 days vs. 7
      days). Normalization required restoration of a rhythmic corticosterone secretion
      that was synchronized to the new photoperiod. Under constant darkness, the
      corticosterone rhythm did not show any synchronizing effect, providing evidence
      that it participates in entrainment of the locomotor activity rhythm through
      modulation of light effects. It is proposed that, under stable lighting
      conditions, circulating glucocorticoids contribute to stabilizing activity
      rhythms by reinforcing resistance of the circadian timing system to variations of
      the photoperiod. Experimental evidence that serotonergic neurons are involved in
      relaying their modulatory effects to the clock is also presented.

PMID- 15038855
TI  - Relationships between the circadian rhythms of finger temperature, core
      temperature, sleep latency, and subjective sleepiness.
AB  - Skin temperature circadian rhythms have been explored relatively recently. It has
      been suggested that distal and proximal skin temperature changes play a role in
      the regulation of the core temperature circadian rhythm and sleepiness. The
      authors investigated the circadian finger and core temperature rhythms in
      conjunction with the circadian rhythms of subjective and objective sleepiness.
      Fourteen healthy, young, good sleepers participated in a modified constant
      routine procedure in which palmar finger temperature, rectal temperature,
      subjective sleepiness, and objective sleep latency were measured half-hourly
      across a 48-h period of enforced wakeful bed rest. Individual curves were
      adjusted to the group mean temperature minimum time of 0500 h and averaged to
      create the 4 mean curves. The 5 possible cross-correlation curves between these 4
      measures were calculated for half-hourly phase lags from 12 h before to 12 h
      after the group mean core temperature minimum time. Maximum cross-correlations
      for each curve suggested that finger temperature preceded core temperature by 3 h
      (r = -0.22), and subjective sleepiness followed core temperature by 0.5 h (r = 
      0.33) and objective sleepiness by 2 h (r = 0.29). Although these data are
      correlational, they are consistent with the notion that finger temperature
      changes drive core temperature changes, which determine changes of subjective and
      objective sleepiness.

PMID- 15038857
TI  - The mother of all clock genes?

PMID- 15038856
TI  - Local polynomial regression modeling of human plasma melatonin levels.
AB  - Accurate characterization of features of the melatonin production curve is
      important for research in chronobiology. Local polynomial regression is used to
      model the plasma melatonin concentration curve and obtain consistent and
      asymptotically normally distributed estimates of synthesis onset and offset
      times, duration, peak concentration, and area under the curve. A simple
      production-clearance model for melatonin kinetics provides the connection between
      plasma concentrations and the melatonin production curve. This model identifies
      onset and offset times with critical points of derivatives of the concentration
      curve. The method proposed has the advantage of flexibility and ease of
      implementation. Local polynomial regression can be shown to produce consistent
      estimates of the regression curve and parameters of interest. Furthermore, the
      method can be implemented in any software package with weighted least squares
      routines.

PMID- 15038858
TI  - Parallel and overlapping HIV and bloodborne hepatitis epidemics in Africa.
AB  - A world overview of HIV and hepatitis B and C virus (HBV and HCV) infections
      shows strong parallels in the distribution of generalized epidemics. However,
      several recent papers have argued that HCV prevalence in countries and cohorts in
      sub-Saharan Africa is too low to allow parenteral transmission to account for an
      important proportion of HIV infections. This conclusion is unwarranted. The
      transmission efficiencies of HCV and HIV through needlestick accidents are
      similar, while some parenteral exposures - such as intramuscular injections - may
      be more efficient in transmitting HIV than HCV. Much of the data used to show
      current low HCV prevalence in Africa comes from blood samples collected in 1986
      95. For South Africa, the picture of low and stable HCV prevalence in the 1990s
      is based on selected evidence and ignores multiple studies reporting 3-5.4%
      prevalence in the black population. From a literature search, we found 62 cohorts
      in Africa with information on HCV and HIV prevalence. Across these cohorts, there
      is a trend for HCV prevalence to increase with HIV, though much of the variance
      is unexplained. For 25 cohorts with sufficient data, the median relative risk for
      HCV infection for persons with HIV is 1.52.

PMID- 15038859
TI  - Anal cancer, anal squamous intraepithelial lesions and the genitourinary medicine
      specialist.

PMID- 15038860
TI  - The prevalence of rectal chlamydial infection amongst men who have sex with men
      attending the genitourinary medicine clinic in Edinburgh.
AB  - Little is known about the prevalence of rectal chlamydial infection amongst men
      who have sex with men (MSM). Previous studies using culture methods reported this
      to be between 4-6%. The emergence of nucleic acid amplification tests has
      significantly increased the sensitivity and specificity for chlamydial detection,
      making it possible to estimate the prevalence of rectal infection more
      accurately. A prospective cross sectional study involving 443 MSM who were
      screened for sexually transmitted infections (STIs) between May 1999 and January
      2002. Rectal swabs for chlamydiae were obtained in addition to specimens for
      routine STI screening. Rectal chlamydiae were detected by ligase chain reaction
      (LCR) utilizing the Abbott LCX Amplicor with confirmation by COBASE amplicor for
      the majority of cases. Those with rectal chlamydial infection were treated with
      azithromycin. The characteristics of men with rectal chlamydial infection were
      compared with those who were not infected at this site. Rectal chlamydia was
      detected in 32 (7.2%) of 443 patients. Those with rectal chlamydial infection
      were more likely to have rectal symptoms (12/32) or having a partner with
      confirmed chlamydial (2/32) or gonococcal (3/32) urethritis than those MSM
      without rectal chlamydial infection. They were also more likely to have a history
      of receptive anal sex (25/32) in the previous three months compared to those MSM
      without rectal chlamydial infection (263/411). The most common symptoms of
      patients with rectal chlamydial infection were pruritus ani and peri-anal pain.
      Eight (25%) of those with rectal chlamydial infection were known to be HIV
      seropositive. Rectal chlamydial infection is common amongst MSM and is
      effectively diagnosed by LCR. The test should be included in the routine STI
      screening offered to MSM.

PMID- 15038861
TI  - Predictors of maternal HIV infection at the primary care level in inner city
      Ibadan.
AB  - National HIV prevalence rate is derived from the sentinel surveys, which are
      carried out once in two years and remain anonymized. Epidemiological data are
      largely unavailable on the pregnant HIV-positive mothers particularly at the
      grass root level. This information is urgently needed when developing a realistic
      intervention programme. Three hundred and forty-three consenting pregnant women
      attending a randomly selected primary health care clinic in inner city Ibadan
      from April to November 2001 were enrolled at booking and followed up till
      delivery of their babies. Sociodemographic and reproductive health data were
      collected by questionnaire and all mothers were screened for HIV/AIDS using an
      enzyme-linked immunosorbent assay based rapid test. Results showed that about one
      in three teenage mothers screened positive, having the highest HIV rate. HIV
      prevalence rate reduced, though not significantly, in mothers 20-29 years and
      those 30-39 years with mothers in these groups having similar rates. No mother
      over 39 years screened positive. Following logistic regression analysis, young
      age 15-19 years, was associated with a significantly increased risk for infection
      at the primary health care level (P =0.046). Christian religion was associated
      with a lower risk (P =0.038), and mothers who booked late in pregnancy (P =0.025)
      or had husbands in the lower socio-economic class (P =0.001) were less likely to
      be infected. None of the women were aware of their HIV status prior to the study.
      With a predominantly heterosexual mode of HIV transmission, it is necessary to
      identify infected pregnant women early through voluntary counselling and testing
      (VCT), so that they can be given the option to take preventive drugs, which would
      among other benefits reduce mother-to-child transmission, and help infected
      mothers stay healthy and productive for longer.

PMID- 15038862
TI  - General practitioners and the National Strategy on Sexual Health and HIV.
AB  - To determine general practitioners' knowledge of, and opinions on, the National
      Strategy for Sexual Health and HIV and whether they intend to provide Level 1 and
      2 HIV/STI services, a self-administered questionnaire was sent to one partner
      from 155 general practices in Sheffield and North Derbyshire in November 2001.
      Response rate was 57% (88). Forty-eight (55%) GPs aware of strategy but 53 (60%)
      had no knowledge of what it involved. LEVEL 1. Sixty-two (71%) felt confident in
      providing advice on STI prevention and 46 (52%) on HIV. Nine (10%) GPs provide
      HIV testing and 29 (33%) anticipate doing so but 24 (83%) require staff training
      and 20 (70%) increased funding. All Level 1 STI services are provided by 60 (68%)
      practices and 72 (82%) anticipate providing. LEVEL 2. Thirty-nine (45%)
      anticipate testing and treating STIs but only nine (10%) will undertake partner
      notification. Resources required are training, nine (60%) and funding, nine
      (60%). The main reasons for not offering in the future were too busy 58 (72%) and
      lack of demand 25 (31%). Many GPs are unaware of the strategy but most anticipate
      providing Level 1 STI services. Less than half anticipate offering HIV testing.
      Although 45% of GPs may provide Level 2 care, it is unlikely to include partner
      notification. Many GPs are too busy and require extra training and funding. These
      needs must be addressed if the Strategy is to be implemented.

PMID- 15038863
TI  - High resistance to antiretroviral drugs: the Indian experience.
AB  - Effective antiretroviral treatment (ART) has significantly reduced the morbidity
      and mortality among people living with HIV/AIDS. The emergence of drug resistance
      is the major obstacle to the successful implementation of long-term treatment
      strategy of HIV disease. Hence, monitoring the resistance to ART is an essential
      task. The MGM Medical College in Navi Mumbai is the only national facility with
      the capacity to monitor ART resistance using tissue culture technique. The main
      objective of the study was to determine the prevalence of primary and secondary
      resistance between May 1997 and April 2003. Four hundred and sixty viral isolates
      of 74 individuals were tested for ART resistance using tissue culture-based
      protocol (McGill University, Canada). These included 287 primary and 173 follow
      up viral isolates. Following activation of tissue culture, a panel of 12
      antiretroviral drugs in concentrations from 0.038 mg/mL to 0.090 mg/mL was
      tested. The resistance was determined on the basis of the production of p24
      antigen at the end of 72 and 144 hours of incubation. The overall resistance
      against reverse transcriptase inhibitors (RTIs) was 33.7% and that to protease
      inhibitors (PIs) was 21.5%. However, prevalence of primary resistance among ART
      naive to RTIs was 14/208 (6.7%) of isolates and that to (PIs) was 2/79(2.5%) of
      isolates. The incidence of resistance to RTI was 22/500 years (4.4/100 years) and
      that to PIs was 8/253.6 years (3.2/100 years). It is possible that non-B subtypes
      of HIV-1 that are prevalent in most developing countries are likely to develop
      resistance rapidly after ART. However, common factors that influence development
      of resistance such as poor adherence, inadequate 'wild' doses and regimens, and
      poor monitoring were not validated in the study. Unless active surveillance is
      instituted, these factors can pose major challenge for the management of people
      on ART in developing countries.

PMID- 15038864
TI  - A 16-year study of HIV seroprevalence and HIV-related diseases in a teaching
      tertiary care hospital in India.
AB  - A total of 183,912 persons were screened from September 1986 to May 2002 in and
      around Haryana, out of whom 1178 were reactive (0.64%) for anti-HIV antibodies.
      The overall incidence of HIV-1 in the seropositive patients was 98.5%, HIV-2
      alone was 0.8% and 0.7% had a mixed infection with both HIV-1 and 2. High
      seropositivity (22.8%) was observed among the relatives of these HIV-positive
      individuals. The heterosexual route (78%) remained the predominant mode of
      transmission. Among the jail inmates only one individual out of 1306 (1986 to
      1993) was found to be positive. Tuberculosis (46.7%) was the most common
      opportunistic infection in these seropositive patients. Significant titres of
      Venereal Disease Research Laboratory tests were observed in 8.8% seropositive
      patients, 7.9% were positive for hepatitis B surface antigen and only two
      patients were suffering from chancroid. Forty-six of these HIV-seropositive
      patients had already died. In order to cope with this epidemic, new models of
      care and cost-effective preventive measures are needed.

PMID- 15038865
TI  - A multi-district audit of the management of syphilis in genitourinary medicine
      clinics in Yorkshire.
AB  - An audit against standards and guidelines of a representative sample of syphilis
      cases managed in genitourinary medicine clinics in Yorkshire was carried out.
      Satisfactory serological endpoints could be determined for about two-thirds of
      treated early and less than one-third of treated late syphilis cases. HIV
      antibody testing was obtained for less than half of all cases. Recently available
      national guidelines suggest inadequacy of both the dose and duration of
      treatments with procaine penicillin of asymptomatic late syphilis cases where
      lumbar puncture was not carried out. The diagnosis and management of syphilis is
      complex, and this audit demonstrates the importance of the systematic approach
      developed by genitourinary medicine clinic and laboratory services.

PMID- 15038866
TI  - Dual sampling for the detection of female Chlamydia trachomatis infection with a
      polymerase chain reaction test.
AB  - Using a polymerase chain reaction method of detection, the value of taking
      urethral and endocervical specimens to screen for female Chlamydia trachomatis
      infection and to test for cure of that infection was audited. In the population
      of 130 women being screened, 19 (14.6%) had a positive result in either or both
      specimens. Eighteen infections (94.7%) were detected on the urethral sample and
      16 (84.2%) on the endocervical sample. In the population of 40 women being tested
      for cure, C. trachomatis was detected in nine. The urethral sample was positive
      in 9/9 (100%) and the endocervical sample in 7/9 (77.8%). Analysis of those nine
      cases showed that seven had failed to take their treatment properly or had been
      at risk of re-infection.

PMID- 15038867
TI  - Genitourinary medicine: an opportunity to reduce unwanted pregnancy.
AB  - We sought to investigate contraceptive use in women attending a genitourinary
      medicine (GUM) clinic, and to assess the need for a contraceptive service in this
      setting. Female attendees at Nottingham GUM clinic were invited to complete an
      anonymous questionnaire regarding past and present contraceptive use and whether
      a contraceptive service within GUM would be utilized. Four hundred and eighty
      nine questionnaires were analysed. The majority had previously used condoms
      (89.8%) or the combined oral contraceptive pill (COCP) (74.6%), and 46.6% and
      37.4%, respectively were currently using these methods. Contraception was
      frequently used for the dual aims of avoiding both pregnancy and infection
      (48.5%). General practitioners (GPs) and family planning clinics were most
      frequently cited as sources of regular contraceptive advice, 58.1% and 47.2%
      respectively, and emergency contraception 50.8% and 37.3%, respectively. If a
      contraceptive service was available within GUM 56.9% of respondents indicated
      they would use it.

PMID- 15038869
TI  - A case of condyloma acuminata with giant and multiple lesions on the vulva and
      breast: successfully treated with surgical operations.
AB  - We report a case of a 24-year-old female patient with a history of giant and
      multiple lesions of condylomata acuminata on the vulva and breasts which were
      treated by surgical excision.

PMID- 15038868
TI  - Management of sexually acquired reactive arthritis in 19 North Thames GUM
      clinics.
AB  - Our objective was to describe how genitourinary medicine (GUM) clinics in the
      North Thames region manage sexually acquired reactive arthritis (SARA), and to
      compare management with national guidelines. A self-completed questionnaire
      survey and retrospective case note review was conducted between September and
      October 2001. Clinicians in 33 clinics were asked to describe their clinic's
      policy on the management of SARA, and to review the last five cases seen or the
      last cases seen in the preceding two years, if less than five. Nineteen (58%)
      clinics took part. There were inter-clinic variations in the investigation and
      management of patients, with only 63% (12/19) of clinics offering non-steroidal
      anti-inflammatory drugs (NSAIDs) and 58% (11/19) giving doxycycline 1001mg. twice
      daily for two weeks for urethritis - the rest using any of three other antibiotic
      regimens. There was no consistent policy of referral between other specialties
      and GUM for genital screening and partner notification. A total of 36 male and
      female case notes were reviewed. Patients without arthritis or joint swelling
      (5/38, 13%), or with non-typical symptoms such as diarrhoea (5/38, 13%) were
      diagnosed inappropriately with SARA. Only 33 (87%) had evidence of a sexually
      transmitted infection (STI) with at least two (5%) of patients being treated with
      antibiotics despite no apparent indication being present. Only 21 (55%) had
      documented NSAID therapy. Case identification was difficult due to the lack of a
      national disease code (KC60) for SARA. The data suggest that a diagnosis of SARA
      is sometimes being made with no identifiable STI, or where symptoms are more
      suggestive that another route of infection is likely. A clear guideline within
      clinics to standardize prescribing of antibiotics is needed and collaborative
      policies with GUM are needed for other specialties to use when investigating and
      managing patients with seronegative arthritis. GUM should consider re-introducing
      a KC60 code for SARA for better case identification.

PMID- 15038870
TI  - Extensive genital warts associated with HTLV-I infection.
AB  - This is the first report of infection with HTLV-I associated with severe
      condylomatosis. Assessment of atypical or extensive genital warts should include
      testing for this retroviral infection.

PMID- 15038871
TI  - Hepatitis B infection in an HIV-positive man treated with tenofovir: a case of re
      infection or reactivation?
AB  - We report an HIV-positive man who re-acquires hepatitis B with evidence of
      serological protection which then resolves while on anti-retrovirals including
      tenofovir.

PMID- 15038872
TI  - HIV and AIDS, the internet pornography industry and safer sex.

PMID- 15038873
TI  - Impact of bacterial vaginosis on detection of chlamydial infection.

PMID- 15038874
TI  - An outbreak of HIV infection among injection drug users in a small town in
      Pakistan: potential for national implications.

PMID- 15038875
TI  - Condom use among the female sex worker population in Thailand.

PMID- 15038876
TI  - Early detection of lung cancer in high-risk patients with HIV-1 infection.

PMID- 15038877
TI  - Gonorrhoea: test of cure for sensitive bacteria? Use of genotyping to disprove
      treatment failure.

PMID- 15038880
TI  - The characteristics of a geographical sample of convicted rapists: sexual
      victimization and compliance in comparison to child molesters.
AB  - The limited research literature that relates specifically to sexual offenders
      against adults (rapists) would suggest that they are more likely to demonstrate a
      greater criminogenic profile but to have experienced fewer childhood and adult
      psychological difficulties than child molesters. The aim of this study is to
      describe the characteristics of an urban sample of convicted rapists (n =80),
      comparing them to a sample of child molesters (n = 230) on background and offense
      related variables. Although there were a number of similarities between the two
      groups, rapists were less likely to have been sexually victimized as a child. The
      sexual recidivism rate was low (5%) for rapists after an average time at risk of
      3 years despite a trend toward them being less compliant in the community. This
      article comments on the treatment needs of those with a range of psychological
      difficulties and indicates future directions for research.

PMID- 15038881
TI  - Patterns of childhood sexual abuse characteristics and their relationships to
      other childhood abuse and adult health.
AB  - The purpose of this study was twofold: (a) to cluster women who experienced
      childhood sexual abuse (CSA) according to their shared patterns of CSA
      characteristics and (b) to examine differences across clusters on measures of
      other childhood abuse and adult health. Seven CSA characteristic variables were
      used for cluster analysis. The seven-cluster solution that emerged ranged from a
      noncontact extrafamilial CSA cluster that occurred without force only once to the
      most severe clusters in which penetration by an intrafamilial or extrafamilial
      abuser occurred multiple times with force. Significant differences among clusters
      were found for childhood emotional abuse and physical abuse, adult physical and
      psychosocial symptomatology, and depression. There were no significant
      differences for health care utilization. The results promote further
      understanding of which victims of CSA are more likely to have experienced other
      forms of childhood abuse and which victims are more at risk for poor health in
      adulthood.

PMID- 15038882
TI  - Date-rape-supporting and victim-blaming attitudes among high school students in a
      multiethnic society: Israel.
AB  - This study examined the extent to which a multiethnic sample of 900 Israeli high
      school students supported date-rape and victim-blaming attitudes and the
      predictors of such support. Findings indicate wide support for stereotypes
      justifying sexual coercion by time and the location of the date, the victim's
      behavior, and the minimization of the seriousness of date rape. A regression
      analysis indicates that students' gender and age are the strongest predictors of
      rape-tolerant and victim-blaming attitudes. Socioeconomic status and religious
      orientation explain a small proportion of the variance in the support of such
      attitudes. By contrast, no significant relationship is indicated with ethnicity.
      Alternative sex-education and rape-prevention programs must address date-rape and
      victim-blaming attitudes and make students of both genders aware of various
      factors that continue to be misread as an invitation to have sex and put them at
      high risk of experiencing sexual coercion on a date.

PMID- 15038883
TI  - Rape myth acceptance and rape proclivity: expected dominance versus expected
      arousal as mediators in acquaintance-rape situations.
AB  - Individuals who are high in rape myth acceptance (RMA) have been found to report
      a high proclivity to rape. In a series of three studies, the authors examined
      whether the relationship between RMA and self-reported rape proclivity was
      mediated by anticipated sexual arousal or anticipated enjoyment of sexually
      dominating the rape victim. Results of all three studies suggest that the
      anticipated enjoyment of sexual dominance mediates the relationship between RMA
      and rape proclivity, whereas anticipated sexual arousal does not. These findings
      are consistent with the feminist argument that rape and sexual violence may be
      motivated by men's desire to exert power over women. Theoretical and practical
      implications of our findings are discussed.

PMID- 15038884
TI  - Between normality and deviance: the breakdown of batterers' identity following
      police intervention.
AB  - With the transformation of intimate violence from private trouble to social
      problem, police intervention in domestic violence cases became more prevalent.
      Research has focused mainly on battered women's perception of police
      intervention, their evaluations, and their level of satisfaction with the
      intervention. However, there is little research examining the perpetrators'
      subjective perceptions of such interventions. The purpose of this study is to
      describe and analyze battering men's perceptions of police intervention. The
      study is based on semistructured, in-depth interviews with 20 batterers who had
      repeated encounters with police. Findings show a continuum of self-management,
      ranging from attempts to preserve a normative identity in the first encounter to
      struggling against criminalization in the second encounter and adopting a victim
      identity in the third encounter. The findings are discussed in the context of
      gender identity and power relations.

PMID- 15038885
TI  - A survey of online harassment at a university campus.
AB  - This exploratory study of 339 students at the University of New Hampshire found
      that approximately 10% to 15% of students reported receiving repeated e-mail or
      Instant Messenger (I-M) messages that "threatened, insulted, or harassed," and
      more than half of the students received unwanted pornography. Approximately 7% of
      students reported online harassment to an authority. Messages originated from
      strangers, acquaintances, and significant others. No difference in online
      harassment was found based on demographic variables except sexual orientation.
      Sexual minority students were more likely to receive online harassment from
      strangers than were heterosexual students. Implications for further research and
      for policy/program development are discussed.

PMID- 15038886
TI  - Attributions about perpetrators and victims of interpersonal abuse: results from
      an analogue study.
AB  - This analogue study (written vignettes and videotapes) examines the influence of
      victim-perpetrator relationship (spouse or acquaintance), sex of perceiver, and
      type of abuse (psychological vs. physical) on attributions about victims and
      perpetrators of domestic abuse. College student participants (73 men, 108 women)
      were randomly assigned to condition. As expected, type of relationship influenced
      observer perceptions. Specifically, participants rated the victim of marital
      violence as more psychologically damaged and disturbed by the abuse than the
      victim of acquaintance violence. Furthermore, interaction effects showed that
      men, more than women, rated the actions of the married perpetrator as more of a
      victim's rights violation than the actions of the acquaintance perpetrator.
      Second, type of abuse was shown to influence perceptions of the perpetrator but
      not the victim. Sex-of-perceiver effects were also obtained. Women held the
      perpetrator more responsible and assigned less blame to the victim than did men.
      Legal and clinical implications are then discussed.

PMID- 15038888
TI  - The presumption in favour of liberty: a comment on the HFEA's public consultation
      on sex selection.
AB  - In its recently published report 'Sex Selection: Options for Regulation', the
      Human Fertilisation and Embryology Authority (HFEA) concluded that sex selection
      for non-medical reasons should not be permitted in the United Kingdom. The HFEA's
      recommendation to ban sex selection for any but the most serious of medical
      reasons clearly reflects the majority view of UK citizens. Notwithstanding the
      general moral consensus against non-medical sex selection, the HFEA's approach to
      social policy needs to be criticised for betraying the commonly held presumption
      in favour of liberty.

PMID- 15038890
TI  - Sex selection, public policy and the HFEA's role in political decision making -
      response to Edgar Dahl's 'The presumption in favour of liberty'.
AB  - The Human Fertilisation and Embryology Authority's report on sex selection is
      criticized because its recommendation to prohibit all techniques for social
      sexing is based on unsupported allegations. As a body with a scientific status,
      the Authority should allow the application of some methods of sex selection for
      non-medical reasons in a strictly regulated fashion, in order to gather empirical
      evidence about the psychosocial as well as medical consequences for all people
      involved.

PMID- 15038891
TI  - Gender variety as a valid choice: a comment on the HFEA - response to Edgar
      Dahl's 'The presumption in favour of liberty'.
AB  - The Human Fertilisation and Embryology Authority (HFEA) has made several sensible
      recommendations about sperm sorting and preimplantation genetic diagnosis for sex
      selection, but has not provided a convincing case for restricting all non-medical
      uses of sex selection techniques. It relies too much on a public opinion survey
      and speculative fears about bad outcomes for offspring, and overlooks the
      legitimate interest of some families in using such techniques to have offspring
      of different genders.

PMID- 15038893
TI  - Community concerns about sex selection: research as a way forward - response to
      Edgar Dahl's 'The presumption in favour of liberty'.
AB  - This commentary argues that notwithstanding the implicit logic underpinning
      philosophical and moral arguments regarding individual rights to access sex
      selection for non-medical reasons, community concerns about the psychosocial
      impact of the technology cannot be dismissed or ignored. It is true, however,
      that such concerns are often based on unsupported assumptions about the impact of
      the technology on individuals, families and communities and about the propensity
      of scientists, unless restrained, to act in ways that are irresponsible or
      dangerous. The research conducted to date has dispelled many of the myths and
      assumptions about IVF children and their families. Further careful research is
      now needed to test the extent to which fears and assumptions regarding 'designer
      babies' are justified.

PMID- 15038895
TI  - Stem cells today: A. Origin and potential of embryo stem cells.
AB  - The study of embryo stem cells began in 1963, initially using disaggregates of
      cleaving rabbit and mouse embryos. Their differentiation in vitro was modest, and
      usually curtailed at best to the formation of trophectoderm cells, which attached
      to plastic. Rabbit morulae and blastocysts adhered more readily, trophectoderm
      forming a sheet of cells which was overgrown by stem cells from inner cell mass.
      Whole-blastocyst cultures on collagen-coated surfaces produced a pile of cells,
      and its outgrowths included neural, blood, neuronal, phagocytic and many other
      types of cell. When inner cell mass was freed and cultured intact or as cell
      disaggregates, lines of embryo stem cells (ES) were established which possessed
      good rates of cleavage, and immense stability in their secretion of enzymes,
      morphology and chromosomal complement. Developmental capacities of single mouse
      embryo stem cells were measured by injecting one or more into a recipient
      blastocyst, and extent of colonization in resulting chimaeras measured their
      pluripotency. In mouse, cell clumps were termed embryoid bodies, which produced
      similar outgrowths as in rabbit. Component cells again differentiated widely,
      depending to a limited extent on their exposure to various cytokines or
      substrates. Markers for differentiation or pluripotency were established, which
      revealed how neural, cardiac, haematological and other ES lines could be
      established in vitro. These have proved useful to study early differentiation and
      their use in grafting to sick recipients. Displaying similar properties, human ES
      cells emerged in the late 1990s. Models for the clinical use of ES cells showed
      how they colonized rapidly, travelled to target tissues via fetal pathways,
      differentiated and colonized target organs. No signs of inflammation or tissue
      damage were noted; injured tissues could be repaired including remyelination, and
      no cancers were formed. ES cells offer wide therapeutic potentials for humans,
      although extensive clinical trials are still awaited.

PMID- 15038896
TI  - Y chromosome assessment and its implications for the development of ICSI
      children.
AB  - The aetiology of compromised spermatogenesis is often genetic in nature. There
      are only a few reports of father/son cohorts that have been evaluated to assess
      heritability of mutations associated with male factor infertility and the
      psychological well-being of the children. In the present study, multiple tissues
      were sampled from consenting male patients and their sons derived from
      intracytoplasmic sperm injection (ICSI) and underwent chromosomal and genetic
      analyses. Paediatric and psychological examinations were also conducted. In 87
      men and 47 boys, 22 sequence tagged sites (STS) were analysed by multiplex PCR
      and deletion breakpoints were defined with additional loci. In one patient, the
      breakpoints map to the highly unstable palindrome-rich region within AZFb and
      proximal AZFc was investigated. A total of 86 blood, 26 semen, and 73 cheek cells
      samples were collected from adults, and 36 blood samples and 44 cheek cell
      specimens were obtained from the boys. Though all of the fathers had normal
      karyotypes, the incidence of chromosomal abnormalities in the somatic cells of
      male progeny was 8.3% (3/36). The incidence of germ line aneuploidy in these men
      was 0.5-2.8%. A CF mutation (Delta508) was detected in one of 87 men (1.2%) and
      microdeletions in Yq AZF were detected in 3.4% of 87 adults and in 2.1% of their
      sons (n = 47). In conclusion, screening for Y chromosome microdeletions provides
      crucial information in the counselling of couples seeking infertility treatment.
      Moreover, DNA extraction and Y deletion assessments of cheek cells provide a non
      invasive approach. Inheritance of Yq deletions appears not to affect the
      psychological and physical development of children derived from ICSI.

PMID- 15038897
TI  - Benefits of 8-bromo-guanosine 3',5'-cyclic monophosphate (8-br-cGMP) in human
      ovarian cortical tissue culture.
AB  - Guanosine 3',5'-cyclic monophosphate (cGMP) is an important intracellular second
      messenger in many cells of the body; however, its importance in the ovary is only
      now being realized. The effects of the cGMP analogue 8-bromo-guanosine 3',5'
      cyclic monophosphate (8-br-cGMP) were tested on human ovarian follicle
      development and survival using an established tissue culture method. Ovarian
      biopsies were collected from 27 women (mean age 32 years) undergoing Caesarean
      sections or gynaecological operations. Tissue was cut into small pieces and
      cultured in the presence or absence of 5 mmol/l 8-br-cGMP for 7 and 14 days. 8-br
      cGMP enhanced the rate of follicle growth to the secondary stage after both 7 and
      14 days of culture. Furthermore, it significantly improved the proportion of
      viable follicles when compared with control cultures. All cultured follicles
      reaching the secondary stage were smaller than those uncultured. This suggests
      that although granulosa cells were stimulated to proliferate and form a double
      layer, the cells themselves did not become larger as usually occurs with
      maturation and differentiation. Oestradiol production was greater in the 8-br
      cGMP-containing cultures after 12 days compared with control cultures, presumably
      due to the concurrent increase in the proportion of secondary follicles. In the
      early stages of human ovarian tissue culture, 8-br-cGMP may be a necessary
      component as both a growth enhancer and survival factor.

PMID- 15038899
TI  - Expression profiles of individual human oocytes using microarray technology.
AB  - Microarray technology is a relatively new technique that provides the
      investigator with the ability to monitor and quantify the expression of thousands
      of genes simultaneously. This technological breakthrough has the potential to
      provide detailed insight into cellular processes involved in the regulation of
      gene expression. In this study, microarray methods were used to examine the
      expression of linearly amplified RNA from individual and pooled (n = 5) human
      oocytes. The amplification strategy consistently produced a complex
      representative cDNA population. A catalogue of 1361 transcripts expressed in
      human oocytes was identified, of which 406 have been independently confirmed
      using other methods.

PMID- 15038901
TI  - Real-time reverse transcription-polymerase chain reaction analysis of translation
      initiation factor 1A (eIF-1A) in human and mouse preimplantation embryos.
AB  - Fluorescence-monitored real-time reverse transcription-polymerase chain reaction
      (RT-PCR) was used to study steady state concentrations of translation initiation
      factor eIF-1A mRNA in mouse and human preimplantation embryos. Its expression in
      human embryos has not been described previously. Human oocytes, and 2-cell and 4
      cell embryos all showed comparable total concentrations of eIF-1A RNA, indicating
      a gradual decrease in the average concentration per blastomere during these
      developmental stages. A 4-fold increase was observed in the 8-cell embryos. This
      concentration remained at the morula stage, followed by a 7- to 8-fold further
      increase at the blastocyst stage. Mouse preimplantation embryos already showed
      increased concentrations of eIF-1A RNA at the 2-cell stage. Thus, transcription
      levels of the eIF-1A gene are associated with embryonic gene activation (EGA) in
      both species. The method used, real time RT-PCR, proved to be sensitive enough to
      detect quantitative expression in single mouse blastomeres, the observed values
      for steady-state concentrations of mRNA in single blastomeres correlating well
      with the values for whole embryos. The possibility to study gene expression
      quantitatively in single blastomeres may be useful in preimplantation genetic
      diagnosis.

PMID- 15038902
TI  - Cumulative live birth rates after transfer of cryopreserved ICSI embryos.
AB  - A cohort follow-up study was designed to assess the efficacy of an
      intracytoplasmic sperm injection cryopreservation programme through analysis of
      cumulative live birth rates in successive frozen-thawed cycles in a tertiary
      referral centre. There were 2013 patients and they underwent 2680 frozen-thawed
      embryo transfer cycles. The follow-up period was between 1992 and 2001. Only
      frozen-thawed embryo transfer cycles up to the fourth trial were included. Crude
      cumulative live birth rates were calculated in five age subgroups, i.e. <30, 30
      34, 35-37, 38-39 and >/=40 years old and in surgically or non-surgically
      retrieved sperm subgroups. Expected cumulative live birth rates were calculated
      only for the total number of patients. Outcome measure was a live birth occurring
      after 25 weeks of gestation. Overall, the expected cumulative live birth rate was
      as high as 26.7% after four cycles while the crude cumulative delivery rate was
      10.5%. Multiple cryopreserved embryo transfer cycles increase the chance of a
      couple to achieve a live birth.

PMID- 15038905
TI  - Transcriptomes and the analysis of mouse embryo, stem cells and tissue stem
      cells.

PMID- 15038904
TI  - Previous miscarriages influence IVF and intracytoplasmatic sperm injection
      pregnancy outcome.
AB  - Previous conceptions are one predictor for the outcome of assisted reproductive
      technology procedures. Approximately 18-34% of clinical pregnancies following
      assisted reproduction procedures result in spontaneous abortion. The risk of such
      pregnancy loss is believed to increase with women's age, previous miscarriages
      and use of frozen-thawed embryos. This study analyses German IVF Registry data to
      examine the impact of previous miscarriages on the outcome of assisted
      reproduction procedures. The data set consists of a total of 174,909 assisted
      reproduction procedures performed between January 1998 and December 2000.
      Multiple logistic regression is used to assess the correlation between women's
      age, spousal/partner change, and infertility diagnosis. It is demonstrated that
      any previous miscarriage will increase the treatment-dependent miscarriage rate
      in assisted reproduction procedures. A significantly higher impact is shown for
      one previous miscarriage achieved by assisted reproduction procedures compared
      with spontaneous conception. Partner change is shown to have no specific impact
      on the treatment dependent miscarriage rate, whereas a statistically significant
      increase in miscarriages in all assisted reproduction procedures was found among
      women older than 34 years of age. Overall, the highest rate of treatment
      dependent miscarriages was seen in assisted reproduction procedures with
      cryopreserved embryo transfer.

PMID- 15038906
TI  - Routine examination of the newborn: the EMREN study. Evaluation of an extension
      of the midwife role including a randomised controlled trial of appropriately
      trained midwives and paediatric senior house officers.
AB  - OBJECTIVES: To assess the implications and cost-effectiveness of extending the
      role of midwives to include the routine (24-hour) examination of the healthy
      newborn usually carried out by junior doctors. DESIGN: The study included a
      prospective randomised controlled trial (RCT) with mother and baby dyads
      randomised to either senior house officer (SHO) or midwife for the routine
      examination of the newborn. Midwives and SHOs were also videoed while performing
      the examinations and the videos were rated by an independent consultant and
      senior midwife. In addition extensive interviews, surveys, consultations and
      assessments were carried out. SETTING: A District General Hospital (for the RCT),
      a London Teaching Hospital, general practices and mothers' homes (for
      interviews); questionnaires were sent to all maternity units in England (for the
      National Survey). PARTICIPANTS: A total of 826 mother and baby dyads in a
      District General Hospital in south-east England. Midwives and SHOs, as well as
      midwifery managers, paediatric consultants; general practitioners (GPs) and
      representatives of key organisations. INTERVENTIONS: A routine examination of a
      newborn baby was carried out at about 24 hours from birth and a further
      examination for half the babies in each group, at 10-days at home by the
      community midwife. MAIN OUTCOME MEASURES: Referrals assessed as appropriate and
      as major or minor by three independent consultants. Problems identified during
      the first year of life assessed as identifiable at 24 hours. Quality assessment
      by video against an agreed written proforma. Maternal satisfaction. Opinion of
      professionals and mothers about aspects of the examination. RESULTS: There was no
      statistical difference between SHO and midwife examinations in appropriate
      referral rates to hospital or community or in inappropriate referral rates to
      hospital. Videoed assessments were assessed as carried out more appropriately by
      the midwives than by the SHOs. Overall maternal satisfaction was high and higher
      when a midwife rather than an SHO examined. Few new health problems were
      identified at the 10-day examination. From the National Survey, it was estimated
      that about 2% of babies in England are examined by a midwife. If midwives were to
      examine all babies where there were no complications of birth or antenatal
      history, there would be savings of about 2 pounds per baby born, equivalent to
      savings of 1.2 pounds million nationally. Were midwives to examine all babies on
      normal wards savings would increase to about 4.30 pounds per baby born or 2.5
      million pounds nationally. Representatives of the professional bodies were of the
      opinion that having trained midwives carrying out the examination would be
      valuable. CONCLUSIONS: All component aspects of the study were consistent in
      showing benefits or at least no significant barriers to suitably qualified,
      trained midwives carrying out the examinations. Developing the role of the
      midwife to include examination of the newborn is likely to result in improved
      quality of examinations and higher satisfaction from mothers. It would slightly
      reduce overall health service costs, with some increased resources needed by
      midwifery departments, and some decrease in resource needs of paediatric
      departments. There is a need for further research into the value of the
      examination being carried out at home rather than in hospital; the overall
      unsatisfactory quality of the examination of the hips; and appropriate inclusion
      criteria for which babies' midwives should examine.

PMID- 15038907
TI  - Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone
      in the treatment of type 2 diabetes: a systematic review and economic evaluation.
AB  - OBJECTIVES: To evaluate the use of pioglitazone and rosiglitazone, in terms of
      both clinical and cost-effectiveness in the treatment of type 2 diabetes. DATA
      SOURCES: Electronic databases and the reference lists of relevant articles, in
      addition 14 health services research-related resources were consulted via the
      Internet. REVIEW METHODS: A systematic review of the literature, involving a
      range of databases, was performed to identify all papers relating to the
      glitazones. The methodological quality of the included randomised controlled
      trials (RCTs) was assessed using the Jadad method. A generic proforma for the
      critical appraisal of modelling studies in health economics was used in
      systematically reviewing the economic assessment studies identified. This was
      supplemented by a detailed review of the disease-specific factors within the
      studies. Where possible, key outcomes were compared. Readers should note that
      information from the sponsor's submission was submitted in confidence to the
      National Institute for Clinical Excellence (NICE). Such information was made
      available to the NICE Appraisals Committee, but has been removed from this
      version of the report. RESULTS: Of the 1272 studies identified, nine studies met
      the inclusion criteria. The clinical evidence available showed that glitazones
      reduce glycosylated haemoglobin by approximately 1%, and are more effective at
      higher doses than at lower doses. Glitazone treatment is associated with weight
      gain. No published data were available on the long-term effects of glitazone use.
      No prospective RCTs were found comparing pioglitazone to rosiglitazone, but the
      available evidence indicated that the two treatments had similar effects. There
      are no published economic studies on either pioglitazone or rosiglitazone.
      Economic evaluations for both glitazones were provided by the manufacturers.
      Sensitivity analyses undertaken by the assessment team suggest that the cost per
      quality-adjusted life-year (QALY) of rosiglitazone is most sensitive to dosage
      and treatment effect, that is, the effect of rosiglitazone on beta-cell function
      and insulin sensitivity. In the two scenarios where rosiglitazone is compared
      with metformin and sulfonylurea combination therapy, the cost-effectiveness of
      rosiglitazone switches from around 10,000 pounds per QALY to being dominated by
      the comparator strategy. Since the baseline estimate of cost-effectiveness is not
      robust to changes in the treatment effect and is reliant on the many assumptions
      included within the metabolic and long-term economic models, caution should be
      used in interpreting the baseline result. CONCLUSIONS: The clinical evidence
      available showed that glitazones can reduce glycosylated haemoglobin; however
      there were no peer-reviewed data available on the long-term effects of their use
      or any prospective RCTs found comparing pioglitazone with rosiglitazone. No
      published economic studies on either pioglitazone or rosiglitazone were found,
      although sensitivity analyses undertaken by the assessment team suggest that the
      cost per QALY of rosiglitazone is most sensitive to dosage and treatment effect.
      It is suggested that research already undertaken in this area should be
      published, preferably in peer-reviewed journals. Direct head-to-head comparisons
      of the glitazones in combination with metformin or sulfonylurea would be helpful.
      The current licence arrangements do not allow for routine use of the glitazones
      in triple oral combination therapy or in combination with insulin. Evidence is
      emerging of use of the glitazones within such combinations; therefore,
      prospective RCTs would be useful. These studies could examine short-term
      transition strategies and longer term management. The impact of the glitazones in
      delaying transfer to insulin and the impact on long-term outcomes should also be
      considered for investigation.

PMID- 15038909
TI  - Selective serotonin reuptake inhibitor treatment of major depressive disorder in
      children and adolescents.

PMID- 15038910
TI  - Diagnostic interviews.
AB  - This review addresses issues related to the use of structured psychiatric
      diagnostic interviews in children and adolescents. Structured diagnostic
      interviews improve the diagnostic process by better organizing the collection of
      clinical data and eliminating biases when applying diagnostic criteria. Available
      interviews generally fall into two categories. Highly structured (or respondent
      based) measures use a set script and record subject's responses without
      interpretation. Thus, they are useful for epidemiologic surveys or other settings
      in which nonclinical interviewers are used. Semistructured (or interviewer-based)
      tools allow clinical interpretation of responses as well as the incorporation of
      other sources of information, thereby making them more relevant for clinicians.
      Structured diagnostic instruments are currently most often used in research
      settings, but potentially are useful for clinical settings as well. This review
      also addresses challenges in psychiatric diagnosis, a brief history of diagnostic
      standards, and the potential limitations/advantages of using structured
      diagnostic interviews.

PMID- 15038911
TI  - The University of California at Los Angeles Post-traumatic Stress Disorder
      Reaction Index.
AB  - Over the past decade, the University of California at Los Angeles Post-traumatic
      Stress Disorder Reaction Index has been one of the most widely used instruments
      for the assessment of traumatized children and adolescents. This paper reviews
      its development and modifications that have been made as the diagnostic criteria
      for post-traumatic stress disorder have evolved. The paper also provides a
      description of standard methods of administration, procedures for scoring, and
      psychometric properties. The Reaction Index has been extensively used across a
      variety of trauma types, age ranges, settings, and cultures. It has been broadly
      used across the US and around the world after major disasters and catastrophic
      violence as an integral component of public mental health response and recovery
      programs. The Reaction Index forms part of a battery that can be efficiently used
      to conduct needs assessment, surveillance, screening, clinical evaluation, and
      treatment outcome evaluation after mass casualty events.

PMID- 15038912
TI  - Defining and identifying early onset bipolar spectrum disorder.
AB  - Early onset bipolar spectrum disorder (EOBPSD) is difficult to diagnose because
      of symptom overlap with other disorders and nearly ubiquitous comorbidity. A
      thorough assessment of EOBPSD should include the following: 1) a timeline of the
      child's development, from birth to present, showing the episodic nature of
      EOBPSD; 2) a structured clinical interview determining comorbidity and
      differential diagnosis; 3) a family history genogram to ascertain familial
      loading and environmental stressors, which informs case conceptualization; 4)
      depression and mania rating scales to assess symptom severity and track treatment
      outcome; 5) global rating scales to obtain cross-informant data and inform broad
      based treatments; and 6) a current mood log to document baseline functioning and
      track treatment outcome. Examples of a timeline, family history genogram, and
      current mood log are presented. This comprehensive approach to assessing EOBPSD,
      a severe and possibly lifelong disorder, is strongly advocated. No scale,
      instrument, or technique alone is adequate to diagnose EOBPSD.

PMID- 15038913
TI  - A practical guide to using ratings of depression and anxiety in child psychiatric
      practice.
AB  - The objective of this paper is to provide pragmatic information on commonly used
      rating scales of depression and anxiety disorders with established psychometric
      properties. A comprehensive Medline search on the rating scales of depression and
      anxiety was conducted. Relevant research findings were further synthesized where
      possible, with the information on clinical use of the scales from manuals.
      Research findings replicating original studies, strengths, weaknesses, and
      scoring information were summarized for each scale, and psychometric properties
      were tabulated. Several rating scales are available for screening, determining
      the severity, as well as estimating treatment effects in depression and anxiety.
      It is prudent to use more than two scales, especially a combination of self
      rating scale and a clinician rating scale. It is recommended that the depression
      and anxiety scales are used in concert to aid in differentiating these two
      disorders. Several new and improved scales are available, although they await
      further replication.

PMID- 15038914
TI  - Gene-environment interactions and correlations in psychiatric disorders.
AB  - Genetic and environmental risk factors are known to influence many aspects of
      human behavior, including the susceptibility to various psychiatric conditions in
      adult and childhood. Recent evidence suggests that these risk factors interact
      and correlate with each other to influence phenotypic outcomes. Gene-environment
      interactions are expressed through genetic variation in the susceptibility toward
      particular environmental risks, whereas gene-environment correlations are
      genetically mediated propensities in the exposure toward certain environments.
      Recent findings from quantitative and molecular methodologic approaches have
      highlighted their prevalence and importance across several samples and phenotypic
      outcomes. These have important implications in guiding future psychiatric
      research, mental health practice, and policy-making bodies.

PMID- 15038920
TI  - Dynamic transcriptome of mice.
AB  - Life science in the 21st century is developing rapidly through the structural
      analysis of biomolecules, the completion of the human genome sequence and the
      analysis of transcriptomes. The mouse transcriptome has been comprehensively
      analyzed using a gene discovery approach to collect full-length cDNA (FL-cDNA)
      clones. The framework of the transcriptome was then mapped out by an
      international Functional ANnoTation Of Mouse cDNA (FANTOM) effort, and a
      significant new population of noncoding transcripts was discovered. The
      geographical analogy of a second "RNA continent," separate from the "continent"
      of expressed proteins, aids the visualization of this concept. An unexpected
      number of variations was discovered in the mouse transcriptome. The animal
      transcriptome has evolved to produce several transcripts and proteins from a
      single "transcriptional unit". Transcriptome analysis has given rise to the FL
      cDNA database and to the 60 770 FANTOM FL-cDNA clone set, and the DNABook was
      developed as an easier way to distribute these clones. In conjunction with genome
      sequence databases, transcriptome databases and clone banks will be platforms for
      developing advanced databases of gene function (e.g. the Genome Function
      Database). This will enable life science to make rapid progress towards
      understanding life as a system of molecules.

PMID- 15038916
TI  - Pharmacogenetics and psychiatry.
AB  - Genetic factors play a significant role in predicting an individual's response to
      a drug. The response may be the desired therapeutic effect of the drug and also
      may be the undesirable development of adverse effects. This relationship between
      genes and drug response interests the pharmacogeneticist. This article aims to
      give an overview of the exciting discoveries made so far in the field of
      psychiatry, particularly concerning the response to antidepressants and
      antipsychotics, as well as to mention some of the more recent findings. The
      ultimate goal of pharmacogenetics is to provide medication "tailored" to the
      individual based on their genetic profile, and although this may currently seem a
      distant target, it has already begun to raise ethical questions, which also are
      discussed.

PMID- 15038915
TI  - Molecular genetics of Alzheimer's disease.
AB  - Alzheimer disease (AD) is the most common cause of dementia. In the past decade,
      many advances in the understanding of the etiology of AD have been reported.
      Familial early onset AD is a heterogeneous disorder that can be caused by
      mutations in at least three different genes. Current studies are focused on
      identifying genetic risk factors for late onset AD. In this article, the authors
      will review the progress in understanding the pathogenic implications of the
      genes mutated in familial early onset AD and the mapping studies to identify
      additional genes involved in late-onset AD.

PMID- 15038921
TI  - Engineering grapevine for increased resistance to fungal pathogens without
      compromising wine stability.
AB  - The vast majority of wine proteins have recently been identified as pathogenesis
      related (PR) proteins. During the growing season, these proteins are expressed in
      developmentally dependent and inducible manners in grapevine leaves and grape
      berries, in which they are believed to play an important role in protection
      against fungal pathogens and possibly other stresses. Because of their inherent
      resistance to proteolytic attack and to the low pH values characteristic of
      wines, vinification can be seen as a "purification strategy" for grape PR
      proteins. The inevitable consequent accumulation of these proteins in wines
      becomes a technological nuisance because they adversely affect the clarity and
      stability of wines. Genetically modified vines underexpressing PR proteins would
      certainly lead to stable wines but would increase the plant susceptibility to
      fungal attack, and the actual trend seems to be in the opposite direction, that
      is overexpressing these proteins to obtain plants with enhanced resistance to
      pathogens--a trend that will probably augment problems associated with protein
      instability in the resulting wines.

PMID- 15038917
TI  - Recent advances in the genetics of attention deficit hyperactivity disorder.
AB  - In the past few years, interest in the molecular genetics of attention deficit
      hyperactivity disorder (ADHD) has grown enormously, with many groups searching
      for susceptibility genes, often through large collaborative efforts facilitated
      by the International ADHD Genetics Consortium. Association findings for several
      candidate genes within the dopaminergic system, the DRD4 and DRD5 receptor genes
      and the dopamine transporter gene, DAT1, have been well replicated, and the first
      of several ongoing genome linkage scan study results have been published. Current
      challenges in this field are to identify the actual functional variant(s) in
      these genes conferring susceptibility and other genetic and environmental risk
      factors for ADHD.

PMID- 15038922
TI  - Life and death in mammalian cell culture: strategies for apoptosis inhibition.
AB  - Mammalian cell culture is widely used to produce valuable biotherapeutics
      including monoclonal antibodies, vaccines and growth factors. Industrial cell
      lines such as Chinese hamster ovary (CHO), mouse myeloma (NS0), baby hamster
      kidney (BHK) and human embryonic kidney (HEK)-293 retain many molecular
      components of the apoptosis cascade. Consequently, these cells often undergo
      programmed cell death upon exposure to stresses encountered in bioreactors. The
      implementation of strategies to control apoptosis and enhance culture
      productivities represents a major goal of biotechnologists. Fortunately, previous
      research has uncovered many intracellular proteins involved in activating and
      inhibiting apoptosis. Here, we summarize three apoptotic pathways and discuss
      different environmental and genetic methodologies implemented to limit cell death
      for biotechnology applications.

PMID- 15038923
TI  - Progress and recent trends in biotechnological methods for leather processing.
AB  - Global environmental regulations are changing the leather-processing industry.
      Pre-tanning and tanning processes contribute 80-90% of the total pollution in the
      industry and generate noxious gases, such as hydrogen sulfide, as well as solid
      wastes, such as lime and chrome sludge. The use of enzyme-based products is
      currently being explored for many areas of leather making. Furthermore, enzymes
      are gaining increasing importance in the de-hairing process, eliminating the need
      for sodium sulfide. This review discusses emerging novel biotechnological methods
      used in leather processing. One significant achievement is the development of a
      bioprocess-based de-hairing and fiber-opening methodology to reduce toxic waste.

PMID- 15038924
TI  - Milking of microalgae.
AB  - The low productivity of algal cultures in the production of high-value compounds
      is the most significant bottleneck for commercialization of this technology.
      Cultures in which cell mass is reused for continuous production are proposed as a
      solution to overcome this problem. Recently, a method was developed in which beta
      carotene was harvested from the microalga Dunaliella salina grown in a two-phase
      bioreactor. This raises the question of whether this technique could also be used
      in the mass production of secondary metabolites. Understanding the mechanism of
      the milking process and its relationship to the product formation pathway should
      reveal whether other products can be milked from various species of microalgae.

PMID- 15038925
TI  - Microscale tissue engineering using gravity-enforced cell assembly.
AB  - Designing artificial microtissues by reaggregation of monodispersed primary
      cells, neoplastic or engineered cell lines is providing insight into cell-cell
      interactions and underlying regulatory networks. Recent advances in microtissue
      production have highlighted the potential of scaffold-free cell aggregates in
      maintaining tissue-specific functionality, supporting seamless integration of
      implants into host tissues, and providing complex feeder structures for difficult
      to-differentiate cell types. Furthermore, these tissues are amenable to
      therapeutic and phenotype-modulating interventions using latest-generation
      transduction technologies. Microtissues produce therapeutic transgenes at
      increased levels and offer tissue-like assay environments to improve drug
      function correlations in current discovery programs. Here, we outline scaffold
      free microtissue design in liver, heart and cartilage, and discuss how this
      technology could significantly impact regenerative medicine.

PMID- 15038926
TI  - Psychotropic drug versus psychotropic drug-update.
AB  - Psychotropic drugs are not necessarily the drugs of psychiatry. Seventy percent
      of antidepressants, and 90% of anxiolytics are prescribed by nonpsychiatric
      physicians. Since psychotropic medications are so frequently employed by
      nonpsychiatric physicians, e.g., neurologists, primary care physicians,
      internists, and because large numbers of their patients are concurrently on
      medical drugs for somatic reasons, the interactions of psychotropic versus
      medical drugs and psychotropic versus psychotropic drugs as listed below must be
      understood before primary care physicians or psychiatrists prescribe psychotropic
      medications, especially to the medically ill. Seventy commonly prescribed
      psychotropic drugs were examined for their interactions with other psychotropic
      medications using six reference tools: 1) MEDLINE (PubMed) employing the first
      generic psychotropic drug name, the second generic psychotropic drug name, and
      the term "interaction;" 2) Hanston's Drug Interaction Analysis and Management
      Text (quarterly updated version); 3) Drug Interactions Facts (Facts and
      Comparisons) (July 2001 quarterly updated version); 4) Micromedex Drug-dex; 5)
      American Hospital Formulary Service Drug Information; and 6) Food and Drug
      Administration (MedWatch) (Dear Doctor Letters and new labeling) ( for (1999,
      2000, and 2001). The authors recognized that all of the above sources do not
      necessarily cover the entire information database regarding drug-drug
      interactions. (Citations regarding children, reports in foreign languages or
      concerning food, animals, in vitro experiments, analgesics, and naturalistic
      herbal or natural products-treatment interactions were excluded).

PMID- 15038927
TI  - Characteristics, treatment patterns, and outcomes of persistent depression
      despite treatment in primary care.
AB  - We examine the sociodemographic and clinical characteristics of depressed primary
      care patients who receive at least minimal standards of evidence-based treatment,
      comparing those who remain depressed with those who recover; and their subsequent
      treatment patterns and other outcomes. We used observational data from a subset
      of 542 treated patients participating in a group-level randomized controlled
      trial of quality improvement interventions for depression conducted in six
      managed care organizations. Nonresponse to treatment was defined as having at
      least minimally appropriate treatment for at least two of three 6-month periods
      but continuing to have probable depression. Our definitions of depression and
      appropriate treatment are broader than those used in clinical trials, but
      relevant to primary care settings. Many of the factors predictive of treatment
      resistance in clinical trials predict nonresponse to guideline concordant care
      among diverse primary care, depressed patients. The main unique predictors of
      nonresponse to treatment include a clinical factor (suicide ideation) requiring
      clinician assessment and intervention, a social/economic factor (unemployment)
      usually not addressed by medical interventions, and medication nonadherence.
      Nonresponders used more adjunctive therapies and combination medications,
      suggesting clinicians and patients were searching for solutions. High rates of
      service use and poor outcomes emphasize the urgency of new research to find
      solutions for these patients.

PMID- 15038928
TI  - A patient-doctor relationship questionnaire (PDRQ-9) in primary care: development
      and psychometric evaluation.
AB  - In health care research, the patient-doctor relationship as perceived by the
      patient is considered important. Our aim was to develop and validate a
      questionnaire that assesses the Patient-Doctor Relationship, the Patient-Doctor
      Relationship Questionnaire (PDRQ-9). The PDRQ-9 was developed out of the Helping
      Alliance Questionnaire of Luborsky, a scale that measures the therapeutic
      alliance in psychotherapy. Its psychometric qualities and validity in general
      practice were assessed, with the collaboration of 110 general practice patients
      and 55 patients in an Epilepsy Clinic. Principal components analysis demonstrates
      a two-factorial structure, one related to the doctor, and one related to the
      medical symptoms of the patient. Both show high reliability but as the second
      factor explains only 9% of the variance, it is eliminated from the questionnaire.
      The PDRQ-9 provides researchers a brief measure of the therapeutic aspects of the
      patient-doctor relationship in the primary care setting. It is a valuable tool
      for scientific and practical purposes involving the monitoring of the patient
      doctor relationship.

PMID- 15038930
TI  - Suicide attempts and suicidal ideation: links with psychiatric comorbidity in
      eating disorder subjects.
AB  - Additional psychiatric disorders in eating disorders patients may contribute to
      the risk of suicide and suicide attempts. The aim of this study was to examine
      associations between Axes I and II comorbidity and suicidality in a large sample
      of women currently suffering from an eating disorder (ED). In a sample of 288
      women (87 anorexia nervosa, 158 bulimia nervosa, 43 eating disorders not
      otherwise specified) psychiatric comorbidity of Axes I and II was determined
      using the Structured Clinical Interview for DSM-IV. Histories of attempted
      suicide were explored in a structured interview. Suicidal ideation was determined
      by means of the SCL-90. Past suicide attempts were reported by 26%. Subjects with
      a purging type ED more frequently had a history of attempted suicide than
      subjects with a nonpurging type ED. A history of suicide attempts was associated
      with higher levels of Axes I and II comorbidity, in particular with affective
      disorders and Cluster B personality disorders. Current suicidal ideation was
      generally linked with higher levels of all types of Axes I and II comorbidity.
      Eating disorders are serious psychiatric disorders associated with high levels of
      comorbidity and suicidality. Incorporating a comprehensive psychiatric evaluation
      into the clinical assessment of ED patients is important for the assessment of
      suicidality and for the provision of adequate treatments.

PMID- 15038929
TI  - Distress, psychiatric morbidity, and prescriptions for psychotropic medication in
      a breast cancer waiting room sample.
AB  - We examined relationships among psychiatric screening, the prevalence of
      psychiatric morbidity, and prescription rates for psychotropic medication in a
      waiting room sample of breast cancer patients (N=113). Rates of distress (29%),
      major depressive disorder (MDD; 9%), and generalized anxiety disorder (GAD; 6%)
      were low and similar to those found in primary care settings. A substantial
      proportion of patients (52%) had received psychotropic medication during
      treatment, including almost half (48%) of those without a current psychiatric
      diagnosis. Most individuals with MDD received pharmacotherapy during cancer
      treatment (80%), although only half of those with GAD were treated. Overall high
      rates psychotropic medication negatively impacted the efficiency of screening,
      and individuals with elevated distress were about 6 times less likely to
      represent a case of untreated psychiatric morbidity than to be a new case. We
      conclude that the risk of psychiatric morbidity attributable to breast cancer may
      be lower and treatment rates for psychiatric morbidity higher than previously
      believed and that screening is unlikely to provide efficient identification of
      untreated psychiatric morbidity. Adequacy of follow-up care is unclear and
      medication may be prescribed nonspecifically. The low rate of untreated
      psychiatric morbidity may signal a need for multisite collaborations to generate
      adequate numbers of participants in clinical trials.

PMID- 15038931
TI  - Should a suicidal patient with Huntington's disease be hospitalized against her
      will? Attitudes among future physicians and lawyers and discussion of ethical
      issues.
AB  - The issue of rational suicide of a competent patient suffering from a hopeless
      but not terminal disease is controversial. Little is known about how
      psychiatrists, other physicians or judges make decisions about involuntary
      hospitalization of such patients, or about their ethical reasoning. The objective
      of this study was to identify future physicians' and lawyers' views on
      involuntary hospitalization of a suicidal Huntington's disease (HD) patient and
      to evaluate whether they are ethically defendable. Five-hundred and ninety-nine
      law students and advanced medical students reported whether they agree or not to
      involuntary hospitalize a suicidal HD patient (audio/video recording). No
      significant differences were found between medical and law students. Forty-four
      percent of students agreed to hospitalization, 49.3% disagreed. The comments
      indicate that medical and law students had pessimistic views about the quality of
      life of an HD patient. Medical students referred more often than law students to
      patients' autonomy rights and less often to benefits to relatives. Involuntary
      hospitalization of a suicidal but not terminal HD patient is controversial among
      future physicians and lawyers. Students underestimated the need for careful
      evaluation. More open discussion and more ethical teaching on the subject of
      acceptance of rational suicide for hopelessly, but not yet terminally ill
      patients are needed.

PMID- 15038932
TI  - Commentary on Elger and Harding can suicide be rational in persons who are not
      terminally ill?

PMID- 15038933
TI  - INTERMED: a measure of biopsychosocial case complexity: one year stability in
      Multiple Sclerosis patients.
AB  - The 1-year temporal stability of the INTERMED in a sample of patients with
      relatively stable care needs, patients with established Multiple Sclerosis (MS)
      was analyzed. Seventy MS patients underwent an interview to assess the INTERMED
      by a trained nurse, and two examinations of disability, EDSS and GNDS by medical
      doctors. At the following appointment with the nurse, approximately 1 year later,
      a second INTERMED assessment was done. Spearman correlations and change scores
      between the INTERMED assessments were calculated. Correlations between the two
      assessments were considerable: 0.75 for the total score and 0.55-0.74 for the
      domain scores (all P <.05). Median change of all four INTERMED domain scores and
      total score were 0. Changes in INTERMED total scores tended to be associated with
      changes in EDSS scores over time (P = 0.09), but not with changes in GNDS scores
      (P = 0.67). Patients with INTERMED scores above 20 on at least one of the two
      assessments had longer disease duration (P < 0.01), were more frequently
      suffering from a chronic form of MS (P < 0.01), and had more disability on EDSS
      (P < 0.01) and GNDS (P < 0.01) assessments. In a sample of patients with an
      established diagnosis of MS, INTERMED scores remained fairly stable over the
      period of a year. Implementing the INTERMED in routine care of patients with
      chronic conditions may help the clinician to structure interdisciplinary care.

PMID- 15038934
TI  - Hallucinations in Latino psychiatric outpatients: a preliminary investigation.
AB  - Accuracy of diagnosis and efficacy of treatment depend on recognition of cultural
      variation in symptomatology of mental illness. Caribbean Latinos have been
      observed to present in outpatient settings with a higher than expected prevalence
      of hallucinations; however little is known about this phenomenon and whether it
      reflects psychotic illness. This study is a retrospective record review of 54
      Spanish-speaking psychiatric outpatients who were evaluated in their own
      language. Demographic and clinical data were extracted from the records and
      relationships to hallucinations were examined. Of the total sample, 46% reported
      hallucinations, and 84% of these were simple (e.g., hearing one's name called).
      Thought disorder was diagnosed in only 9% of the sample. Caribbean Latinos
      presented to this outpatient mental health setting with a high rate of perceptual
      symptoms in the absence of other signs of psychosis. Since hallucinations are
      known to be nonspecific, the symptoms reported in this patient sample are best
      understood as nonpsychotic hallucinations. Further research is necessary to
      clarify the epidemiological and cultural aspects of this phenomenon, and to guide
      treatment.

PMID- 15038935
TI  - Early detection of postoperative delirium and confusion in a surgical ward using
      the NEECHAM confusion scale.
AB  - The early detection and prevention of postoperative delirium and confusion has
      become an important issue in surgical ward management. With the aim of
      determining an objective technique for early detection of delirium, 64 patients
      admitted to a surgical ward before surgery were examined using the NEECHAM
      confusion scale. On the 2nd postoperative day they were tested again and divided
      into 3 groups on the basis of their NEECHAM scores: high risk, low risk, and no
      risk, for confusion. The trends of the NEECHAM scores in the 3 groups were
      compared, and the relationship between the NEECHAM scores and suspected clinical
      risk factors for delirium was investigated. Use of NEECHAM scaling enabled
      medical staff to identify cases of possible confusion early, indicating that the
      NEECHAM confusion scale should be useful for the detection of postoperative
      delirium and confusion in the surgical ward.

PMID- 15038936
TI  - Diabetes management and borderline personality symptomatology: a pilot study.

PMID- 15038937
TI  - Olanzapine treatment of monosymptomatic hypochondriacal psychosis.

PMID- 15038938
TI  - Hepatitis and HIV screening, education, and treatment for adults with serious
      mental illness.

PMID- 15038939
TI  - The diagnosis of Asperger's syndrome in an adult presenting with an index episode
      of mania by Ng et al.

PMID- 15038941
TI  - Progress with thiazolidinediones in the management of type 2 diabetes mellitus.
AB  - BACKGROUND: Much progress has been made in the field of medicine within the past
      20 years; however, cardiovascular outcomes in patients with diabetes mellitus
      have not improved to a corresponding degree. Although numerous treatments are
      available for the management of type 2 diabetes, current approaches appear to
      address the spectrum of the disease and its complications insufficiently.
      OBJECTIVES: This article reviews evidence for the minimal effects of standard
      antidiabetic treatments on the macrovascular complications associated with type 2
      diabetes, discusses the improvements in markers of cardiovascular risk seen with
      the thiazolidinediones (TZDs), and explores the rationale for their earlier use.
      METHODS: Relevant articles and guidelines on the use of oral antidiabetic agents
      in the treatment of type 2 diabetes were identified through a search of MEDLINE
      for the past 15 years using the terms cardiovascular, insulin resistance,
      metabolic syndrome, metformin, sulfonylurea, type 2 diabetes, and
      thiazolidinediones. The reference lists of selected articles also were searched.
      Articles chosen for review were required to assess clinically important outcomes
      or surrogate markers that have been shown to have a direct link to clinically
      important outcomes. RESULTS: The data reviewed suggest that the sulfonylureas
      and/or metformin are able to reduce microvascular complications associated with
      type 2 diabetes but do not substantially affect macrovascular complications. In
      contrast, the TZDs demonstrate insulin-sensitizing effects attributable to their
      novel mechanism of action on the peroxisome proliferator-activated receptor
      gamma. The resulting reduction in insulin resistance appears to improve many of
      the metabolic and cardiovascular pathways influenced by insulin activity. Blood
      pressure, vascular and coagulation defects, lipid abnormalities, and beta-cell
      function have been found to improve in patients receiving TZD treatment. For
      example, there are reports of significant reductions in levels of C-reactive
      protein (P < 0.01); small, dense low-density lipoprotein cholesterol particles (P
      < 0.05); and circulating free fatty acids (P < 0.003), in addition to
      improvements in the proinsulin-to-insulin ratio (P < 0.05). CONCLUSIONS: In this
      review of the literature, use of TZDs as monotherapy or as part of combination
      therapy has been associated with effective glycemic control and reductions in
      markers of various macrovascular complications of type 2 diabetes. Although
      outcomes trials are ongoing, the preliminary effects of TZD therapy are promising
      and suggest that earlier use of TZDs in the pharmacologic management of type 2
      diabetes has the potential to minimize severe disease sequelae.

PMID- 15038942
TI  - Topical antibacterial therapy for mycobacterial keratitis: potential for surgical
      prophylaxis and treatment.
AB  - BACKGROUND: Mycobacterium chelonae and Mycobacterium fortuitum are the 2 most
      commonly implicated species of nontuberculous mycobacteria in cases of bacterial
      keratitis. OBJECTIVES: This article summarizes available data on the in vitro
      antibacterial activity against M chelonae or M fortuitum of 2 agents-amikacin and
      clarithromycin-that have been used in the treatment of bacterial keratitis. In
      addition, the article reviews the in vitro activity of 5 commercially available
      topical ocular fluoro-quinolones (in order of availability, ciprofloxacin,
      ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin) that may have potential
      in the surgical prophylaxis and treatment of keratitis caused by M chelonae or M
      fortuitum. METHODS: A search of the English-language literature indexed on the
      MEDLINE, Life Sciences, EMBASE, BIOSIS, and Pharmaprojects databases from 1966 to
      October 7, 2003, was conducted using the terms Mycobacterium chelonae,
      Mycobacterium fortuitum, bacterial keratitis, topical antibiotic therapy, ocular
      infection-mycobacteria, and LASIK infections. Data on the minimum concentrations
      at which 90% of isolates were inhibited (MIC(90)s) were reviewed and compared.
      RESULTS: In the literature reviewed, the MIC(90) against M fortuitum was from 1
      to 16 microg/mL for amikacin, from </=2 to >/=8 microg/mL for clarithromycin,
      from 0.1 to 1 microg/mL for ciprofloxacin, from 0.5 to 3.13 microg/mL for
      ofloxacin, and </=2 microg/mL for levofloxacin. The results were similar against
      M chelonae. The fourth-generation fluoroquinolones-gatifloxacin and moxifloxacin
      had similar MIC(90)s against M fortuitum (both, 0.2 to 1 microg/mL); however,
      moxifloxacin had greater activity than gatifloxacin against M chelonae (minimum
      inhibitory concentration range: moxifloxacin, </=1 to 1.6 microg/mL;
      gatifloxacin, 3.2 to 6.25 microg/mL). CONCLUSIONS: Topical fluoroquinolones may
      be beneficial for ocular surgical prophylaxis and for the treatment of keratitis
      caused by M chelonae or M fortuitum. Based on their reported MIC(90)s, none of
      the antibacterials reviewed had greater in vitro activity than moxifloxacin. In
      addition, moxifloxacin had greater in vitro activity than gatifloxacin against M
      chelonae, one of the predominant nontuberculous mycobacterial species involved in
      bacterial keratitis. Pending the conduct of controlled clinical studies, these
      findings suggest that moxifloxacin may have utility in the prevention and
      treatment of atypical mycobacterial keratitis.

PMID- 15038943
TI  - Stress-related mucosal disease: risk factors and prophylactic therapy.
AB  - BACKGROUND: The term stress-related mucosal disease (SRMD) represents a continuum
      of conditions ranging from stress-related injury (superficial mucosal damage) to
      stress ulcers (focal deep mucosal damage). Caused by mucosal ischemia, SRMD is
      most commonly seen in critically ill patients in the intensive care unit (ICU).
      Prophylaxis of stress ulcers may reduce major bleeding but has not yet been shown
      to improve survival. OBJECTIVES: This article reviews currently available agents
      for the prophylaxis of SRMD and discusses their uses and potential adverse
      effects. METHODS: Relevant articles in the English-language literature were
      identified through a MEDLINE search (1968-2003) using the key words stress
      related mucosal disease, stress-related injury, ulcer, prophylaxis, intensive
      care unit, and upper gastrointestinal bleeding. RESULTS: The most widely used
      drugs for stress-related injury are the intravenous histamine(2)-receptor
      antagonists. These drugs raise gastric pH but are associated with the development
      of tolerance and possible drug interactions and neurologic manifestations.
      Sucralfate, which can be administered by the nasogastric route, can protect the
      gastric mucosa without raising pH, but may decrease the absorption of
      concomitantly administered oral medications. The prostaglandin misoprostol has
      not been shown to be of benefit in the prophylaxis of SRMD. Antacids lower the
      risk of gastrointestinal bleeding, but large volumes of antacids are required and
      treatment is labor intensive. Proton pump inhibitors (PPIs) are the most potent
      acid-suppressive pharmacologic agents available. Esomeprazole, lansoprazole,
      omeprazole, pantoprazole, and rabeprazole substantially raise gastric pH for up
      to 24 hours after a single dose. The availability of an intravenous formulation
      of pantoprazole may help improve the treatment of SRMD in ICU patients,
      particularly those receiving mechanical ventilation. Tolerance does not develop,
      and few adverse effects have been reported. CONCLUSIONS: Recent studies of PPIs
      have shown promising results in high-risk patients, making this class of drugs an
      option for the prophylaxis of SRMD.

PMID- 15038945
TI  - Efficacy and tolerability of moxifloxacin in the treatment of acute bacterial
      sinusitis caused by penicillin-resistant Streptococcus pneumoniae: a pooled
      analysis.
AB  - BACKGROUND: Penicillin-resistant Streptococcus pneumoniae (PRSP) has become a
      relatively common pathogen in upper and lower respiratory tract infections,
      including acute bacterial sinusitis (ABS). OBJECTIVE: The goal of this analysis
      was to assess the efficacy and tolerability of moxifloxacin in the treatment of
      ABS caused by penicillin-sensitive S pneumoniae (PSSP) and PRSP METHODS: Two
      prospective, multicenter, open-label, noncomparative US trials of moxifloxacin
      were included in this pooled analysis. All patients received oral moxifloxacin
      400 mg once daily for 7 to 10 days. Minimum inhibitory concentrations (MICs) of
      moxifloxacin and penicillin were determined using the E-test and standard broth
      microdilution methods. The primary end point was clinical success at the test-of
      cure visit (21-37 days after completion of therapy) in patients with a positive
      pretherapy sinus culture. Data are presented for patients with ABS caused by both
      PSSP and PRSP RESULTS: Of 806 patients enrolled in the 2 studies, 146 had
      microbiologically confirmed bacterial infection. Sixty-nine patients had ABS
      caused by S pneumoniae, including 15 confirmed cases of PRSP infection. The
      majority of the 69 clinically evaluable patients were white (n = 63) and female
      (n = 46), and the mean age of this population was 43 years. Investigators
      categorized the episode of ABS as severe in 26 (37.7%) of clinically evaluable
      patients and of moderate severity in the remainder (62.3% [43]); however, most
      patients (78.3% [54/69]) reported >/=1 severe symptom. The episode of ABS was
      classified as severe in 8 (53.3%) of the 15 patients with PRSP infection.
      Clinical and bacteriologic success at the test-of-cure visit was achieved in
      93.3% (14/15) of patients with PRSP infection, compared with 88.4% (61/69) of all
      patients infected with S pneumoniae regardless of penicillin susceptibility.
      Moxifloxacin MICs against the 15 PRSP strains ranged from 0.06 to 0.25 microg/mL.
      Data from 805 patients were available for tolerability analysis. The most
      commonly occurring adverse events were nausea, headache, and diarrhea. Generally,
      adverse events were mild to moderate. None of the 6 serious adverse events
      reported were considered related to moxifloxacin therapy. CONCLUSION: In this
      small cohort of patients, moxifloxacin provided clinical and bacteriologic cures
      in the majority of patients with ABS caused by PRSP, including those with severe
      sinusitis.

PMID- 15038944
TI  - Efficacy and tolerability of sumatriptan tablets in a fast-disintegrating, rapid
      release formulation for the acute treatment of migraine: results of a
      multicenter, randomized, placebo-controlled study.
AB  - BACKGROUND: Sumatriptan tablets have been developed in a fast-disintegrating,
      rapid-release formulation designed to facilitate tablet disintegration and drug
      dispersion and to potentially mitigate the effects of gastric stasis that can
      accompany migraine. OBJECTIVE: This study was conducted to evaluate the efficacy
      and tolerability of sumatriptan 50- and 100-mg tablets in a fast-disintegrating,
      rapid-release formulation compared with those of placebo in patients with
      migraine. METHODS: This clinical trial had a randomized, double-blind, placebo
      controlled, parallel-group design. Exclusion criteria included >6 migraines
      monthly during either of the 2 months before screening; uncontrolled
      hypertension; suspected or confirmed cardiovascular or cerebrovascular disease;
      and ophthalmic, basilar, or hemiplegic migraine. Sumatriptan 50 and 100 mg and
      placebo were taken on an outpatient basis during the mild-pain phase of a single
      migraine attack. Patients recorded details of the treated migraine on a diary
      card and rated pain severity immediately before dosing and 30 minutes, 45
      minutes, 1 hour, and 2 hours after dosing using a 4-point scale (from 0 = none to
      3 = severe). The primary efficacy end point was the proportion of patients who
      were pain free 2 hours after dosing. Additional efficacy end points were the
      proportion of patients who were pain free at 30 minutes, 45 minutes, and 1 hour
      after dosing; the proportion who were migraine free through 2 hours after dosing;
      and the proportion with a sustained pain-free response. RESULTS: Patients' mean
      age ranged from 39.7 to 41.5 years across the 3 groups, and the majority were
      women (79.7%-85.9%) and white (98.7%-100%). One hundred thirty-seven patients
      received sumatriptan 50 mg, 142 sumatriptan 100 mg, and 153 placebo. In the
      intent-to-treat population (n = 432), 51.1% of patients who received sumatriptan
      50 mg and 66.2% of patients who received sumatriptan 100 mg were pain free 2
      hours after dosing, compared with 19.6% of the placebo group (P < 0.001, each
      sumatriptan dose vs placebo). In an exploratory analysis, the 2-hour pain-free
      rate with sumatriptan 100 mg was significantly better than that with sumatriptan
      50 mg (P = 0.007). Significantly more patients who received sumatriptan 100 mg
      were pain free compared with placebo at 30 minutes (P < 0.01), 45 minutes (P <
      0.001), and 1 hour after dosing (P < 0.001); similar pain-free results were
      observed in patients who received sumatriptan 50 mg at 45 minutes (P < 0.05) and
      1 hour (P = 0.01). In the per-protocol population (n = 313), pain-free efficacy 2
      hours after dosing was 52.7% with sumatriptan 50 mg and 74.8% with sumatriptan
      100 mg, compared with 21.0% with placebo (P < 0.001, each sumatriptan dose vs
      placebo). These rates were greater than those in the overall study population,
      approximately 12.0% of whom treated moderate or severe pain. The only drug
      related adverse events reported in >/=3% of patients in any treatment group were
      nausea and vomiting (<1%, 5%, and 2% in the sumatriptan 50 and 100 mg and placebo
      groups, respectively), chest symptoms (2%, 3%, and 0%), and malaise and fatigue
      (1%, 3%, and <1%). No serious adverse events were reported. CONCLUSIONS: In this
      study, sumatriptan tablets in a fast-disintegrating, rapid-release oral
      formulation provided pain-free efficacy in the acute treatment of migraine.
      Efficacy was maximized with the 100-mg dose compared with the 50-mg dose, and by
      treating early when pain was mild. In the intent-to-treat population, 51.1% of
      patients who received sumatriptan 50 mg and 66.2% of those who received
      sumatriptan 100 mg were pain free 2 hours after dosing. In the per-protocol
      population, 3 of 4 patients taking the 100-mg tablets for mild pain within 1 hour
      of its onset were pain free at 2 hours. Sumatriptan tablets were generally well
      tolerated.

PMID- 15038946
TI  - The KARTAN study: a postmarketing assessment of Irbesartan in patients with
      hypertension.
AB  - BACKGROUND: An important purpose of postmarketing surveillance of drugs is to
      better characterize the safety profile of drug therapy in the clinical setting.
      Another goal is to confirm the effectiveness of these drugs in patients who are
      candidates for antihypertensive therapy and who may have been excluded from Phase
      III studies. Irbesartan is a long-acting angiotensin II-receptor blocker specific
      for the angiotensin 1-receptor subtype that, in clinical trials in patients with
      hypertension, reduces blood pressure. OBJECTIVES: The KARTAN (this word was
      derived from the first and last syllables of Karvea [trademark of Bristol-Myers
      Squibb Group, Madrid, Spain] and irbesartan) study was designed to confirm and
      extend the findings from previous clinical trials using data from a large number
      of patients with hypertension treated with irbesartan in routine clinical
      practice. The primary goal was to assess the types and incidences of adverse drug
      reactions (ADRs) occurring at a low frequency (<0.05%) with irbesartan. The
      secondary objectives were to study the effect of irbesartan as an
      antihypertensive agent, to assess the types and incidences of the most frequent
      ADRs (>/=0.05%) occurring in routine clinical practice, and to detect possible
      interactions between irbesartan and other drugs frequently used in the primary
      care setting. METHODS: This 6-month, observational, open-label, uncontrolled,
      national, longitudinal, prospective study was conducted by 852 primary care
      physicians across Spain. Men and women aged >/=18 years with mild to moderate
      hypertension who, in their physicians' opinion, should have been treated with
      irbesartan were included. Each patient was followed up for 6 months, attending
      visits at baseline (ie, the start of treatment) and 1, 3, and 6 months after the
      start of treatment. A sample size of 3219 patients was calculated for the
      detection of >/=1 low-incidence (<0.05%) ADR. After the baseline visit, therapy
      typically was begun with irbesartan 150 mg/d. The initial dose was titrated up,
      at 300-mg increments based on the patient's response, at each visit as needed to
      achieve the treatment goals (systolic blood pressure, <140 mm Hg; diastolic blood
      pressure, <90 mm Hg). Information regarding ADRs was collected on case-report
      forms designed for each visit and analyzed by the scientific committee of the
      study. All recruited patients were included in the tolerability analysis.
      RESULTS: A total of 4887 patients were enrolled (2165 men, 2 772 women; mean [SD]
      age, 61.1 [11.0] years [range, 19-94 years]; 23.3% of patients were aged >70
      years); 4612 were assessable for efficacy. One hundred eight patients (2.2%)
      experienced ADRs over the 6-month treatment period; 3 of these patients (0.1%)
      experienced >1 ADR. Of the total number of clinical manifestations of ADRs, 24
      occurred at an incidence <0.05%. Irbesartan produced reductions in blood pressure
      that were statistically significant from the first visit (all p < 0.001), and
      39.9% of the patients achieved the treatment goal at the end of the follow-up
      period. CONCLUSION: In this postmarketing surveillance study of patients with
      hypertension treated in routine clinical practice, irbesartan showed a
      satisfactory tolerability profile that was consistent with that seen in
      randomized, controlled trials.

PMID- 15038947
TI  - Compliance and satisfaction with raloxifene versus alendronate for the treatment
      of postmenopausal osteoporosis in clinical practice: An open-label, prospective,
      nonrandomized, observational study.
AB  - BACKGROUND: The treatment of osteoporosis among postmenopausal women represents a
      major public health challenge because long-term therapy is needed to prevent
      fractures and chronic disability. Low patient compliance with prescribed
      osteoporosis treatments can severely distort the validity of controlled clinical
      trials. Raloxifene and alendronate have been shown to reduce the incidence of
      osteoporotic fracture in postmenopausal women in well-conducted randomized
      trials, but few data are available on the rate of adherence to these treatments
      in routine clinical practice. OBJECTIVE: The primary aim of this study was to
      assess the compliance of postmenopausal women at risk for osteoporotic fractures
      who were treated with raloxifene hydrochloride (RLX) versus alendronate sodium
      (ALN) during a 12-month observational period in a routine clinical setting.
      Secondary objectives were the assessment of factors that might contribute to
      noncompliance and patient satisfaction. METHODS: This open-label, prospective,
      multicenter, nonrandomized, observational, comparative study was conducted at 154
      centers across Spain. Assignment to either RLX or ALN treatment was determined by
      the physician and was based on each patient's clinical profile. Compliance with
      RLX (60-mg tablet once daily) versus ALN (10-mg tablet once daily) was assessed
      using 3 different compliance assessment tools: the Morisky-Green test, the
      Autocompliance test, and the Compliance Questionnaire. A logistic regression
      model was used to assess different factors affecting compliance. Patient
      satisfaction was also assessed using a questionnaire. Adverse events (AEs) were
      collected as reasons for discontinuation in the Compliance Questionnaire and at
      the discontinuation visit. RESULTS: A total of 902 women (RLX group, n = 476; ALN
      group, n = 426) were included in the study (mean age, 64.4 [6.9] years). Overall,
      patients in the RLX group reported significantly better compliance than patients
      in the ALN group, as collected either by the Morisky-Green test (68.7% vs 54.0%;
      P < 0.001) or the Autocompliance test (94.7% vs 90.6%; P = 0.033). More patients
      discontinued treatment prematurely in the ALN group compared with the RLX group
      (25.8% vs 16.4%; P < 0.001). The age-adjusted relative risk for discontinuation
      was 1.4-fold higher for women treated with ALN than for those treated with RLX
      (95% CI, 1.21-1.61). The main reason for premature discontinuation was due to AEs
      (RLX 4.8% vs ALN 11.0%; P < 0.001). The proportion of patients with
      gastrointestinal AEs was 9.9% in the ALN group and 3.4% in the RLX group (P <
      0.001). Only treatment and type of physician were independent covariates of
      treatment compliance. After 12 months of observation, significantly more patient
      in the RLX group were satisfied or very satisfied with their treatment than
      patients in the ALN group (P < 0.001). CONCLUSION: In this study of
      postmenopausal women at risk for osteoporotic fractures, compliance with 12-month
      treatment with daily RLX was higher than with daily ALN in clinical setting. RLX
      showed significant benefits compared with ALN in terms of compliance assessed by
      means of the Morisky-Green and Autocompliance tests and the patients' self
      reported satisfaction.

PMID- 15038950
TI  - The increasing use of the internet for obtaining medical information.

PMID- 15038948
TI  - A systematic review and meta-analysis of the efficacy and safety of a fixed, low
      dose perindopril-indapamide combination as first-line treatment of hypertension.
AB  - BACKGROUND: A low-dose combination of perindopril and indapamide may effectively
      reduce blood pressure (BP) in hypertensive patients, but some factors related to
      study design might have contributed to the between-group differences in the rate
      of reduction of BP observed in some trials. OBJECTIVE: The aim of this study was
      to systematically assess the efficacy and safety profiles (through review of
      randomized, controlled trials) of the fixed, low-dose combination perindopril 2
      mg and indapamide 0.625 mg given as 1 tablet daily as first-line antihypertensive
      therapy in patients with mild to moderate hypertension. METHODS: We searched
      MEDLINE (1966-April 2003), EMBASE (1980-March 2003), BIOSIS (1999-December 2002),
      and the Cochrane Library, using the medical subject headings with the search
      terms perindopril, indapamide, hypertension, randomized controlled trials,
      randomly, random, randomization, perindopril-indapamide, essential hypertension,
      and primary hypertension. Additional articles were obtained from the reference
      lists of relevant reviews and papers. RESULTS: We reviewed 11 trials (5936
      individuals). In 5 studies of perindopril-indapamide versus placebo, the between
      group weighted mean differences (WMDs) for both systolic and diastolic BP (SBP
      and DBP, respectively) favored perindopril-indapamide (SBP, -9.03 mm Hg [95% CI, 
      9.54 to -8.52]; DBP, -5.09 mm Hg [95% Cl, -5.42 to -4.77]; both P < 0.01 for z
      score for overall effect). In 6 studies of perindopril-indapamide versus routine
      antihypertensives, the between-group WMDs for SBP and DBP favored perindopril
      indapamide (SBP, -3.72 mm Hg [95% CI, -7.11 to 0.33], P = 0.03 for z score for
      overall effect; DBP, -1.71 mm Hg [95% CI, -2.27 to -1.16], P < 0.01 for z score
      for overall effect). Five studies compared perindopril-indapamide and placebo; in
      the remaining 3 studies, which assessed perindopril-indapamide versus routine
      antihypertensives, the between-group WMDs for SBP and DBP favored perindopril
      indapamide (SBP, -4.00 mm Hg [95% CI, -6.54 to -1.47], P < 0.01; DBP, -1.02 mm Hg
      [95% CI, -1.73 to -0.31], P < 0.01). Adverse events and withdrawals were not
      significantly different between perindopril-indapamide, placebo, or routine
      antihypertensive drugs. CONCLUSION: The studies in our analysis consistently
      demonstrated that a fixed, low-dose perindopril-indapamide combination has a
      favorable safety profile and may be efficacious as first-line treatment for
      patients with mild to moderate essential hypertension.

PMID- 15038949
TI  - Effects of blood loss and fluid volume replacement on serum and tissue gentamicin
      concentrations during colorectal surgery.
AB  - BACKGROUND: The prophylactic administration of antimicrobial agents to surgical
      patients has become standard practice to minimize the risk for postsurgical
      infection. During surgery, factors such as renal clearance, fluid administration,
      and blood loss contribute to drug concentrations achieved in the blood and
      tissues. The aminoglycoside gentamicin was chosen to investigate these factors
      because it is used for standard antimicrobial prophylaxis in colorectal surgery.
      OBJECTIVE: The aim of this study was to investigate the effects of surgical blood
      loss and fluid volume replacement on gentamicin concentrations in serum and in 3
      tissue types (subcutaneous fat, epiploic fat, and colonic wall) in patients
      undergoing colorectal surgery. METHODS: This uncontrolled, open-label study was
      conducted at the Aretaieion Hospital (Athens, Greece) between November 2002 and
      March 2003. Patients selected for this study were scheduled to undergo elective
      colorectal surgery of ? 2-hour duration with general and epidural anesthesia and
      to receive gentamicin as major antimicrobial prophylaxis. Blood and tissue
      samples were obtained concurrently at specific times throughout each procedure.
      The effect of intraoperative blood loss on gentamicin concentrations and its
      pharmacokinetic properties was determined. RESULTS: Sixteen patients completed
      the study (11 men, 5 women; white race, 16 patients [100%]; mean [SD] age, 61 [3]
      years [range, 39-80 years]). Mean (SEM) serum gentamicin concentration was found
      to be insufficient; the maximum plasma drug concentration/minimum inhibitory
      concentration (MIC) ratio was <8:1 for pathogens commonly isolated in the
      surgical unit of the hospital (MIC: 1-4 microg/mL). The mean (SEM) concentration
      at first surgical incision was 7.83 (0.82) microg/mL and decreased to 2.60 (0.28)
      microg/mL at skin closure, resulting in borderline effectiveness even for
      susceptible gram-positive microorganisms (MIC approximately 1.0). Initially, mean
      (SEM) tissue gentamicin concentrations in subcutaneous fat, epiploic fat, and
      colonic wall were low (2.02 [0.34] microg/mL, 2.41 [0.42] microg/mL, and 1.93
      [0.38] microg/mL, respectively) and decreased approximately 1.0 microg/mL (
      approximately 50%) by skin closure. Statistically significant positive
      correlations were found between gentamicin concentrations in serum and tissues (P
      </= 0.03). A strong negative correlation was found between the intravenously
      administered fluids and gentamicin concentrations in serum and tissues (P </=
      0.04). CONCLUSIONS: In this study, the administration of a 2-mg/kg dose of
      gentamicin as antimicrobial prophylaxis during colorectal surgery associated with
      significant intraoperative blood loss and therefore requiring significant fluid
      replacement did not achieve concentrations of the drug above MICs for gram
      negative microorganisms throughout the procedures in either serum or tissue
      samples.

PMID- 15038951
TI  - Health care cost of analgesic use in hypertensive patients.
AB  - BACKGROUND: Hypertension is one of the most frequently diagnosed chronic medical
      conditions in the United States and imposes a substantial financial and social
      burden on Americans. OBJECTIVE: The aim of this study was to compare the cost of
      health care resources for hypertensive patients taking analgesics stratified by
      having controlled versus uncontrolled hypertension. METHODS: This was a
      retrospective, database analysis of data for managed-care patients in Maryland
      and Washington, DC, recorded from February 1, 1999, to July 31, 2001.
      Hypertensive patients who were taking analgesics were stratified by their
      hypertension control status using a claims-based algorithm. Annualized costs and
      differences in annualized costs calculated for the periods before and after the
      initiation of analgesics were compared by patient hypertension control status.
      RESULTS: Of the 9805 patients in the study (mean [SD] age, 49.8 [12.04] years),
      2523 (25.73%) were categorized as having uncontrolled hypertension. The mean
      total annualized costs differed significantly between the controlled and
      uncontrolled hypertension groups by 2568 dollars (P < 0.001). The annualized
      costs for emergency-department visits and hospitalizations for uncontrolled
      hypertensive patients exceeded those for controlled hypertensive patients by 9.3%
      and 28.0%, respectively. The differences between the postindex- and preindex
      period costs for health care resources were 1972 dollars with controlled
      hypertension and 2961 dollars with uncontrolled hypertension (P < 0.001). The
      results of linear regression, after adjustments were made for preindex costs and
      other covariates, indicated that patients with uncontrolled hypertension had
      significantly increased billed annualized costs (P < 0.001). CONCLUSIONS: These
      data suggest that the costs of health care resources were significantly higher
      for analgesic users with uncontrolled hypertension than for analgesic users with
      controlled hypertension. A considerable proportion of the cost differential was
      directly attributable to hypertension-related treatment care.

PMID- 15038952
TI  - Evaluation of an algorithm for switching from IV to PO therapy in clinical
      practice in patients with community-acquired pneumonia.
AB  - BACKGROUND: In patients with community-acquired pneumonia (CAP), switching from
      IV to PO antibiotics offers advantages over IV therapy alone, including improved
      cost-effectiveness through reductions in the length of hospital stay and
      treatment costs. OBJECTIVE: The aim of this study was to determine whether a
      method for switching therapy in clinical practice could be used in patients with
      CAP and whether differences were found in the duration of IV treatment and length
      of hospital stay between the 5 risk classes of the Pneumonia Severity Index (PSI)
      after the therapy switch. METHODS: This was a prospective, observational study of
      patients aged >/=18 years presenting with CAP at our teaching hospital between
      December 1998 and November 2000. Microbiological and serological tests were
      performed, and signs and symptoms of CAP, C-reactive protein levels, and white
      blood cell counts were assessed throughout treatment and at the 1-month follow
      up. Patients were stratified by PSI risk class. When the patient's temperature
      had been normalized for 72 hours and respiratory symptoms (dyspnea, coughing, and
      thoracal pain) had improved, patients were switched from IV to PO therapy (same
      drug). RESULTS: The study included 180 patients with CAP Clinical cure was seen
      in 174 (97%) patients. No significant difference between the 5 risk classes was
      found in duration of therapy. Patients in risk class V remained hospitalized for
      a significantly longer period than patients in risk classes I through IV (P <
      0.001). Furthermore, after patients were switched to PO antibiotics, the level of
      C-reactive protein decreased in patients in all risk classes and was normalized
      by follow-up. CONCLUSIONS: In the population studied, use of specific criteria
      (ie, absence of fever for 72 hours and reduction in respiratory symptoms) allowed
      successful switch from IV to PO antibiotic therapy for the treatment of CAP
      Duration of therapy was not affected by PSI risk class, but those in risk class V
      were hospitalized longer than other risk classes.

PMID- 15038953
TI  - Intensive lifestyle changes or metformin in patients with impaired glucose
      tolerance: modeling the long-term health economic implications of the diabetes
      prevention program in Australia, France, Germany, Switzerland, and the United
      Kingdom.
AB  - BACKGROUND: In the Diabetes Prevention Program (DPP), interventions with
      metformin (plus standard lifestyle advice) or intensive lifestyle changes (ILC)
      reduced the risk of developing type 2 diabetes mellitus (DM) by 31% and 58%,
      respectively, versus control (standard lifestyle advice only) in patients with
      impaired glucose tolerance (IGT). OBJECTIVE: The goal of this study was to
      establish whether implementing the active treatments used in the DPP would be
      cost-effective in Australia, France, Germany, Switzerland, and the United
      Kingdom. METHODS: A Markov model simulated 3 states-IGT, type 2 DM, and deceased
      using probabilities from the DPP and published data. Country-specific direct
      costs were used throughout. RESULTS: Assuming only within-trial effects and costs
      of interventions, both metformin and ILC improved life expectancy versus control.
      Mean improvements in nondiscounted life expectancy were 0.11 and 0.22 years for
      metformin and ILC, respectively. Both interventions were associated with cost
      savings versus control in all countries except the United Kingdom, where a small
      increase in costs was observed in both intervention arms. When a lifetime effect
      of interventions was assumed, incremental improvements in life expectancy were
      0.35 and 0.90 years for metformin and ILC, respectively. Results were sensitive
      to probabilities of developing type 2 DM, the projected long-term duration of
      effect of interventions after the 3-year trial period, the relative risk of
      mortality for type 2 DM compared with IGT, and the costs of implementing the
      interventions. CONCLUSIONS: Based on probabilities from the DPP and published
      data, in this model analysis, incorporation of the DPP interventions into
      clinical practice in 5 developed countries was projected to lead to an increase
      in DM-free years of life, improvements in life expectancy, and either cost
      savings or minor increases in costs compared with standard lifestyle advice in a
      population with IGT. Thus, financial constraints should not prevent the
      implementation of DM prevention programs.

PMID- 15038954
TI  - A retrospective data analysis of the impact of the New York triplicate
      prescription program on benzodiazepine use in medicaid patients with chronic
      psychiatric and neurologic disorders.
AB  - BACKGROUND: Benzodiazepines are treatment mainstays for several disorders, but
      there is often concern about dependency and addiction. In January 1989, New York
      implemented regulations requiring physicians to order benzodiazepines using state
      monitored triplicate prescription forms. OBJECTIVE: The purpose of this study was
      to assess the effects of the triplicate prescription program (TPP) on changes in
      use of benzodiazepines and other psychoactive drugs in clinically vulnerable
      Medicaid populations. METHODS: Using an interrupted time series with comparison
      series design, psychoactive medication use was examined in the New York
      (intervention) and New Jersey (control) Medicaid programs before and after
      implementation of the New York benzodiazepine TPP among community-dwelling
      Medicaid beneficiaries aged >/=19 years continuously enrolled from January 1988
      through December 1990 in New York or New Jersey with diagnoses of schizophrenia,
      schizophreniform disorder, schizoaffective disorder, schizoid personality
      disorder, or schizotypal personality disorder; bipolar disorder; epilepsy; and/or
      panic disorder, agoraphobia without history of panic disorder, social phobia, or
      specific phobia. RESULTS: A total of 125,837 New York and 139,405 New Jersey
      Medicaid beneficiaries were continuously enrolled and met the study inclusion
      criteria. Of these, there were 6054 Medicaid enrollees in New York and 6875
      enrollees in New Jersey who were clinically vulnerable patients with >/=1 of the
      specified diagnoses. New York Medicaid patients with any of these diagnoses
      experienced a -48.1% relative change (95% CI, -50.0% to -46.2%) in benzodiazepine
      use at 6 months after TPP implementation, with no decline in use in New Jersey
      patients. The largest reduction in benzodiazepine use was seen among patients
      with seizure disorder (-59.9% at 6 months; 95% CI, -63.9% to -55.9%). Although
      use of substitute drugs increased slightly in New York after the TPP, it did not
      offset reductions in benzodiazepine use. The effects of TPP were sustained for 7
      years of follow-up and had the greatest impact on nonproblematic benzodiazepine
      use. CONCLUSIONS: During the time period studied in this analysis, the New York
      TPP reduced benzodiazepine use among chronically ill patients for whom these
      agents represent effective treatment. Our findings suggest that many patients
      previously receiving benzodiazepines did not receive any pharmacologic
      intervention.

PMID- 15038955
TI  - Investigation of regulatory mechanisms in coenzyme Q metabolism.

PMID- 15038956
TI  - Methods for characterizing TPQ-containing proteins.

PMID- 15038958
TI  - Redox cycling of beta-lapachone and structural analogues in microsomal and
      cytosol liver preparations.

PMID- 15038957
TI  - Aldo-keto reductases and formation of polycyclic aromatic hydrocarbon o-quinones.

PMID- 15038959
TI  - Quinone chemistry and melanogenesis.

PMID- 15038960
TI  - Quinoids formed from estrogens and antiestrogens.

PMID- 15038961
TI  - Ubiquinone and plastoquinone metabolism in plants.

PMID- 15038962
TI  - Extramitochondrial reduction of ubiquinone by flavoenzymes.

PMID- 15038963
TI  - Tissue bioavailability and detection of coenzyme Q.

PMID- 15038964
TI  - Coenzyme Q and vitamin E interactions.

PMID- 15038965
TI  - Preparation of tritium-labeled 3-methyl-3-buten-1[3H]-yl diphosphate (3H
      isopentenyl diphosphate).

PMID- 15038966
TI  - High-performance liquid chromatography-EC assay of mitochondrial coenzyme Q9,
      coenzyme Q9H2, coenzyme Q10, coenzyme Q10H2, and vitamin E with a simplified on
      line solid-phase extraction.

PMID- 15038967
TI  - Simultaneous determination of coenzyme Q10, cholesterol, and major
      cholesterylesters in human blood plasma.

PMID- 15038968
TI  - Assay of coenzyme Q10 in plasma by a single dilution step.

PMID- 15038969
TI  - Quinone oxidoreductases of the plasma membrane.

PMID- 15038970
TI  - Regulation of ceramide signaling by plasma membrane coenzyme Q reductases.

PMID- 15038971
TI  - Stabilization of extracellular ascorbate mediated by coenzyme Q transmembrane
      electron transport.

PMID- 15038972
TI  - Regulation of antioxidant response element-dependent induction of detoxifying
      enzyme synthesis.

PMID- 15038973
TI  - Antioxidant responsive element activation by quinones: antioxidant responsive
      element target genes, role of PI3 kinase in activation.

PMID- 15038974
TI  - Signaling effects of menadione: from tyrosine phosphatase inactivation to
      connexin phosphorylation.

PMID- 15038975
TI  - Unique function of the Nrf2-Keap1 pathway in the inducible expression of
      antioxidant and detoxifying enzymes.

PMID- 15038976
TI  - Role of protein phosphorylation in the regulation of NF-E2-related factor 2
      activity.

PMID- 15038977
TI  - Analysis of transcription factor remodeling in phase II gene expression with
      curcumin.

PMID- 15038978
TI  - Quinones and glutathione metabolism.

PMID- 15038979
TI  - Doxorubicin cardiotoxicity and the control of iron metabolism: quinone-dependent
      and independent mechanisms.

PMID- 15038982
TI  - Detecting autocatalytic, self-sustaining sets in chemical reaction systems.
AB  - The ability of systems of molecular reactions to be simultaneously autocatalylic
      and sustained by some ambient 'food source' of simple molecules may have been an
      essential step in the origin of life. In this paper we first describe a
      polynomial-time algorithm that determines whether any given set of molecules,
      reactions and catalysations contains a subsystem that is both autocatalytic and
      able to be sustained from a given subset of the molecules. We also describe some
      combinatorial properties of this algorithm, and show how it can be used to find
      irreducible auto-catalysing and sustaining subsystems. In the second part of the
      paper we use the algorithm to investigate random catalytic networks-in
      particular, a model described by Kauffman. Using simulations and some analytic
      techniques we investigate the rate of catalysis that is required for the
      emergence of autocatalytic and sustaining subsystems.

PMID- 15038980
TI  - Oxidant-induced iron signaling in Doxorubicin-mediated apoptosis.

PMID- 15038984
TI  - When to parasitize? A dynamic optimization model of reproductive strategies in a
      cooperative breeder.
AB  - We consider a cooperatively breeding group and find the optimal pattern of
      reproductive parasitism by a subordinate helper as a function of its body size,
      and hence the share of reproduction obtained by the subordinate. We develop the
      model for the social system of the cooperatively breeding cichlid fish
      Neolamprologus pulcher but the general framework is also applicable to other
      cooperative systems. In addition to behaving cooperatively by sharing tasks,
      sexually mature male cichlid helpers may directly parasitize the reproduction of
      dominant breeders in the group. We investigate the relative influence of life
      history and behavioural variables including growth, parasitism capacity, future
      reproductive fitness benefits and costs, relatedness and expulsion risk on the
      optimal reproductive strategy of subordinates. In a detailed analysis of the
      parameter space we show that a male helper should base its decision to parasitize
      primarily on an increase in expulsion risk resulting from reproductive parasitism
      (punishment), intra-group relatedness and the parasitism capacity. If expulsion
      risk is high then helpers should not parasitize reproduction at medium body size
      but should parasitize either when small or large.

PMID- 15038983
TI  - The human immune response to Mycobacterium tuberculosis in lung and lymph node.
AB  - A key issue for the study of tuberculosis is to understand why individuals
      infected with Mycobacterium tuberculosis (Mtb) experience different clinical
      outcomes. To better understand the dynamics of Mtb infection and immunity, we
      have previously developed a temporal mathematical model that qualitatively and
      quantitatively characterizes the cellular and cytokine control network during
      infection. In this work we extend that model to a two compartmental model to
      capture the important processes of cellular activation and priming that occur
      between the lung and the nearest draining lymph node. We are able to reproduce
      typical disease progression scenarios including primary infection, latency or
      clearance. Then we use the model to predict key processes determining these
      different disease trajectories (i.e. identify bifurcation parameters), suggesting
      directions for further basic science study and potential new treatment
      strategies.

PMID- 15038985
TI  - Phylogenetics of artificial manuscripts.
AB  - Biological evolution has parallels with the development of natural languages, man
      made artifacts, and manuscript texts. As a result, phylogenetic methods developed
      for evolutionary biology are increasingly being used in linguistics,
      anthropology, archaeology, and textual criticism. Despite this popularity, there
      have been few critical tests of their suitability. Here, we apply phylogenetic
      methods to artificial manuscripts with a known true phylogeny, produced by modern
      'scribes'. Although the survival of ancestral forms and multiple descendants from
      a single ancestor are probably much more common in manuscript evolution than
      biological evolution, we were able to reconstruct most of the true phylogeny.
      This is important because phylogenetic methods are influencing the production of
      critical editions of major written works. We also show that the variation in
      rates of change at different locations in the text follows a gamma distribution,
      as is often the case in DNA sequences.

PMID- 15038986
TI  - A mathematical model for chronic myelogenous leukemia (CML) and T cell
      interaction.
AB  - In this paper, we propose and analyse a mathematical model for chronic
      myelogenous leukemia (CML), a cancer of the blood. We model the interaction
      between naive T cells, effector T cells, and CML cancer cells in the body, using
      a system of ordinary differential equations which gives rates of change of the
      three cell populations. One of the difficulties in modeling CML is the scarcity
      of experimental data which can be used to estimate parameters values. To
      compensate for the resulting uncertainties, we use Latin hypercube sampling (LHS)
      on large ranges of possible parameter values in our analysis. A major goal of
      this work is the determination of parameters which play a critical role in
      remission or clearance of the cancer in the model. Our analysis examines 12
      parameters, and identifies two of these, the growth and death rates of CML, as
      critical to the outcome of the system. Our results indicate that the most
      promising research avenues for treatments of CML should be those that affect
      these two significant parameters (CML growth and death rates), while altering the
      other parameters should have little effect on the outcome.

PMID- 15038987
TI  - Improved approximations to scaling relationships for species, populations, and
      ecosystems across latitudinal and elevational gradients.
AB  - Historically, allometric equations relate organismal traits, such as metabolic
      rate, individual growth rate, and lifespan, to body mass. Similarly, Boltzmann or
      Q(10) factors are used to relate many organismal traits to body temperature.
      Allometric equations and Boltzmann factors are being applied increasingly to
      higher levels of biological organization in an attempt to describe aggregate
      properties of populations and ecosystems. They have been used previously for
      studies that analyse scaling relationships between populations and across
      latitudinal gradients. For these kinds of applications, it is crucial to be aware
      of the "fallacy of the averages", and it is often problematic or incorrect to
      simply substitute the average body mass or temperature for an entire population
      or ecosystem into allometric equations. We derive improved approximations to
      allometric equations and Boltzmann factors in terms of the central moments of
      body size and temperature, and we provide tests for the accuracy of these
      approximations. This framework is necessary for interpreting the predictions of
      scaling theories for large-scale systems and grants insight into which
      characteristics of a given distribution are important. These approximations and
      tests are applied to data for body size for several taxonomic groups, including
      groups with multiple species, and to data for temperature at locations of varying
      latitude, corresponding to ectothermic body temperatures. Based on these results,
      the accuracy and utility of these approximations as applied to biological systems
      are assessed. We conclude that approximations to allometric equations at the
      species level are extremely accurate. However, for systems with a large range in
      body size, evaluating the skewness and kurtosis is often necessary, so it may be
      advantageous to calculate the exact form for the averaged scaling relationships
      instead. Moreover, the improved approximation for the Boltzmann factor, which
      uses the average and standard deviation of temperature, is quite accurate and
      represents a significant improvement over previous approximations.

PMID- 15038988
TI  - Discrete and continuous state population models in a noisy world.
AB  - Simple ecological models operate mostly with population densities using
      continuous variables. However, in reality densities could not change
      continuously, since the population itself consists of integer numbers of
      individuals. At first sight this discrepancy appears to be irrelevant,
      nevertheless, it can cause large deviations between the actual statistical
      behaviour of biological populations and that predicted by the corresponding
      models. We investigate the conditions under which simple models, operating with
      continuous numbers of individuals can be used to approximate the dynamics of
      populations consisting of integer numbers of individuals. Based on our definition
      for the (statistical) distance between the two models we show that the continuous
      approach is acceptable as long as sufficiently high biological noise is present,
      or, the dynamical behaviour is regular (non-chaotic). The concepts are
      illustrated with the Ricker model and tested on the Tribolium castaneum data
      series. Further, we demonstrate with the help of T. castaneum's model that if
      time series are not much larger than the possible population states (as in this
      practical case) the noisy discrete and continuous models can behave temporarily
      differently, almost independently of the noise level. In this case the noisy,
      discrete model is more accurate [OR has to be applied].

PMID- 15038989
TI  - Bacterial shape maintenance: an evaluation of various models.
AB  - In this article, we examine a large number of combinations of growth models, with
      separate attention to cell volume, cylindrical surface-area, polar caps, nascent
      poles, onset of constriction, precision of cell division and interdivision-time
      dispersion, for Escherichia coli cells growing in steady state at various
      doubling times. Our main conclusion is striking, and quite general: exponential
      cylindrical surface-area growth is not possible, irrespective of the behaviour of
      cell volume, the polar regions, the nascent poles, or any other feature of cell
      growth-such cells never reach steady state. The same is true of linear
      cylindrical surface-area growth, regardless of when during the cell cycle the
      doubling in growth rate takes place. Only after the introduction of feedback into
      the surface-area growth law, do the cultures attain steady state, all of them.
      The other components of the models contribute only marginally to the properties
      of the steady state. Thus, whether the feedback applies just to the cylindrical
      portion of the cell or to its entire surface area affects only the coefficient of
      variation of cell radius and the radius-volume correlation. The dynamics of old
      pole maintenance, constant area or constant shape, influences the radius-length
      and radius-volume correlations and, to a much lesser extent, the coefficients of
      variation of cell radius and length; how the nascent poles grow, whether linearly
      or exponentially, does not seem to matter at all. The absolute dimensions of the
      cells are set by the growth rate of the culture and have almost no effect when
      the feedback is taken to apply to the entire cell surface area; when it is
      limited to the cylindrical portion of the cell, however, both radius-length and
      radius-volume correlations increase with increasing doubling time. Comparison
      with published values was inconclusive. The nature of cell surface-area growth
      has therefore been settled, but whether the volume increases by simple
      exponential or by pseudo-exponential growth, or whether the old poles maintain a
      constant shape or a constant area during the cell cycle, can be determined only
      with more precise experimental data. The form of nascent-pole growth is not
      resolvable by present techniques.

PMID- 15038990
TI  - Adaptation and constraint in the evolution of environmental sex determination.
AB  - When environments differentially influence male and female performance,
      environmental sex determination (ESD) might evolve. The conclusion from several
      previous theoretical models was that reaction norms for sex determination should
      have a single, sharp threshold, with only females being produced in some
      environments and only males in others. These reaction norms can be
      disadvantageous in fluctuating environments, however, because they lead to sex
      ratio fluctuations. We analysed the evolution of ESD, looking for equilibrium
      strategies in unconstrained as well as constrained strategy spaces. We identified
      situations where a single-threshold reaction norm is not evolutionarily stable.
      In these cases, we found stable strategies in the form of complex reaction norms,
      showing an oscillatory pattern of sex determination with respect to variation in
      an environmental variable. Considering that constraints could prevent such
      phenotypes from being realized, we found that certain randomized reaction norms,
      with probabilistic sex determination for a range of environments, would achieve
      nearly the same fitness. We also investigated reaction norms constrained to have
      a single threshold and found that genetic polymorphism in the environmental
      threshold value could evolve, producing a similar effect as a randomized reaction
      norm. We argue that the appearance of genetic variation can be regarded as an
      alternative outcome when constraints prevent the evolution of a more complex or a
      randomized strategy.

PMID- 15038991
TI  - Non-stationary time series and the robustness of circadian rhythms.
AB  - Circadian rhythms are regular oscillations in the value of behavioral and
      physiological variables of organisms that recur on a daily basis. The purpose of
      this study was to evaluate the extent of non-stationarity of circadian rhythms
      over several days, to determine how damaging is the violation of the assumption
      of stationarity in the analysis of circadian rhythms, and to formalize the
      concept of "rhythm robustness" as an index of oscillatory ("weak") stationarity.
      Simulated (computer-generated) and experimental data sets (rhythms of body
      temperature and running-wheel activity in several rodent species) were analysed.
      Tests of stationarity based on the variance of the daily means and the variance
      of the daily variances revealed that most experimental data sets are not
      stationary. Analysis of linear trends indicated that significant trends are rare
      in experimental data sets. Although the non-stationarity of the experimental data
      sets reduced the spectral energy of the Enright periodogram used to assess
      rhythmicity, detection of circadian rhythmicity was not prevented in any of the
      rhythmic data sets. The results of the various analyses allow the inference that,
      after high-frequency noise is filtered out, the value of the periodogram's Q(P)
      statistic reflects the extent of stationarity of the time series. Thus, the
      "robustness" of a circadian rhythm (i.e. the magnitude of the empirical Q(P)
      value as compared to the Q(P) value associated with a perfectly rhythmic time
      series) can serve as an index of the stationarity of the rhythm.

PMID- 15038992
TI  - Autoimmunity as an immune defense against degenerative processes: a primary
      mathematical model illustrating the bright side of autoimmunity.
AB  - Self-tolerance, or the ability of the immune system to refrain from destroying
      the organism's own tissues, is a prerequisite for proper immune system operation.
      How such self-tolerance is achieved is still a subject of debate. The belief that
      autoimmunity poses a continuous threat to the organism was challenged by data
      demonstrating that autoimmunity has a protective function after traumatic injury
      to the central nervous system. This finding led us to suggest the 'comprehensive
      immunity' approach by which autoimmunity is viewed as a special case of immunity,
      namely as a defense mechanism that operates by fighting against the threat of
      potential destructive activity originated or mediated within the organism,
      similarly to the immune defense that operates against the threat from exogenous
      pathogens. We present a primary mathematical spatio-temporal model that supports
      this concept. The numerical solutions of this model illustrate the beneficial
      operation of a well-controlled immune response specific to self-antigens residing
      in the site of lesion. The model also explains how the response to self might be
      tolerated on a day-to-day basis. In addition, we demonstrate that the same
      autoimmune response, operating at different levels of regulation, can lead to
      either an autoimmune disease or a degenerative disorder. This preliminary
      qualitative model supports our contention that the way autoimmunity is perceived
      should be revised.

PMID- 15038993
TI  - P50 sensory gating in adolescents from a pacific island isolate with elevated
      risk for schizophrenia.
AB  - BACKGROUND: Gating or inhibition of the P50 auditory evoked potential is a
      heritable neurobiological trait that has shown strong potential to serve as an
      endophenotype for schizophrenia. P50 sensory gating deficits have been found
      repeatedly in schizophrenic patients and in their unaffected first-degree
      relatives. P50 sensory gating has not yet been studied in high-risk (HR)
      offspring nor in prodromal adolescents. METHODS: A paired-stimulus auditory event
      related potential paradigm was used to examine P50 sensory gating in 44
      genetically HR adolescent offspring and 43 clinically HR prodromal adolescents
      with the same low genetic liability as a comparison group of 39 normal
      adolescents. RESULTS: Auditory sensory gating, as measured by the P50 ratio, was
      impaired in both genetically HR offspring and also in the clinically HR prodromal
      adolescents with no close affected relatives. In the genetically HR group,
      abnormal P50 sensory gating was found only in offspring who met criteria for the
      schizophrenia prodrome. CONCLUSIONS: Our findings suggest that P50 deficits are
      associated with the presence of prodromal symptoms, regardless of genetic risk.
      The results are consistent with the hypothesis that genetic liability in HR
      offspring increases risk for prodromal symptoms, and prodromal symptoms, in turn,
      increase risk for impaired sensory gating.

PMID- 15038994
TI  - Impaired hippocampal function during the detection of novel words in
      schizophrenia.
AB  - BACKGROUND: Patients with schizophrenia have smaller hippocampal volumes and
      perform abnormally on most declarative memory tasks. Although these findings are
      likely related, the impact of hippocampal pathology on cognitive performance in
      schizophrenia remains unclear. This study examined this relationship by measuring
      the volume of the hippocampus and its activation during memory task performance.
      METHODS: Participants included 15 patients with schizophrenia and 16 age-matched
      control subjects. Hippocampal volume was determined via three-dimensional
      volumetric analysis of high-resolution magnetic resonance images. Hippocampal
      activity was assessed by measuring changes in blood oxygen level-dependent signal
      during a recognition memory task. RESULTS: Patients with schizophrenia had
      smaller hippocampal volumes bilaterally and demonstrated poorer performance on
      the recognition memory task, largely because of a heightened rate of false alarms
      to novel stimuli. Both groups showed robust hippocampal activity to old and new
      items when compared with a low-level baseline task; however, direct comparison of
      hippocampal activity during recognition task performance revealed that healthy
      control, but not the schizophrenia, subjects showed significant right anterior
      hippocampal activation during the evaluation of novel items. CONCLUSIONS: The
      impaired ability to classify new items as previously not experienced is
      associated with decreased recruitment and smaller volume of the hippocampus in
      schizophrenia.

PMID- 15038995
TI  - Mitochondrial complex I subunits expression is altered in schizophrenia: a
      postmortem study.
AB  - BACKGROUND: Several independent lines of evidence indicate mitochondrial
      dysfunction in schizophrenia in the brain and periphery, including mitochondrial
      hypoplasia, dysfunction of the oxidative phosphorylation system, and altered
      mitochondrial-related gene expression. METHODS: In this study, three subunits of
      mitochondrial complex I were analyzed at the level of mRNA and protein in
      postmortem brain specimens from the prefrontal and the ventral parietooccipital
      cortex of patients with schizophrenia, major depression, bipolar disorder, and
      normal control subjects. RESULTS: Both mRNA and protein levels of the 24-kDa and
      51-kDa subunits of complex I were significantly decreased in the prefrontal
      cortex, but increased in the ventral parietooccipital cortices of schizophrenia
      patients compared with normal control subjects. In the latter region, protein
      levels of both subunits were increased in bipolar patients as well, being in line
      with the significant overlap in clinical symptoms between schizophrenia and
      bipolar patients. No change was observed in the 75-kDa subunit expression in the
      prefrontal cortex. CONCLUSIONS: The schizophrenia-specific reduction in complex I
      subunits in the prefrontal cortex is consistent with one of schizophrenia's most
      prominent deficits, namely, hypofrontality, thus further supporting the
      hypothesis of mitochondrial dysfunction in this disorder. The abnormal,
      bidirectional expression of complex I in various brain regions, rather than in a
      circumscribed area, supports the idea of impaired cerebral circuitry in
      schizophrenia.

PMID- 15038997
TI  - Gender effects on attention-deficit/hyperactivity disorder in adults, revisited.
AB  - BACKGROUND: This study reexamined gender differences in a large sample of adults
      with attention-deficit/hyperactivity disorder (ADHD). METHODS: We assessed the
      effects of ADHD, gender, and their interaction on rates of psychiatric
      comorbidity and cognitive functioning in 219 adults with ADHD who were referred
      to an outpatient psychiatric clinic over the last 7 years compared with 215
      control subjects group-matched to control subjects on age and gender, and
      ascertained from ongoing family genetic case control adults with ADHD. RESULTS:
      There was no evidence that gender moderated the association between ADHD and
      other psychiatric disorders. Attention-deficit/hyperactivity disorder was
      associated with cognitive deficits and higher rates of major depression, anxiety,
      substance use disorders, and antisocial personality disorder. CONCLUSIONS:
      Attention-deficit/hyperactivity disorder in adults is associated with psychiatric
      and cognitive impairment in both genders. These results bear striking
      similarities to findings reported in pediatric samples, supporting the validity
      of ADHD and stressing the importance of identifying and treating the disorder in
      adulthood.

PMID- 15038998
TI  - The effects of early maternal deprivation on auditory information processing in
      adult Wistar rats.
AB  - BACKGROUND: There is now ample evidence that schizophrenia is due to an
      interaction between genetic and (early) environmental factors which disturbs
      normal development of the central nervous system and ultimately leads to the
      development of clinical symptoms. Recently, we showed that a single 24-hour
      period of maternal deprivation of rat pups at postnatal day 9 leads to a
      disturbance in prepulse inhibition, similar to what is seen in schizophrenia. The
      present set of experiments was designed to further characterize the information
      processing deficits of maternally deprived Wistar rats. METHODS: Wistar rats were
      deprived from their mother for 24 hours on postnatal day 9. At adult age, rats
      were tested in the acoustic startle paradigm for prepulse inhibition and startle
      habituation. Rats were also tested in the evoked potentials paradigm for auditory
      sensory gating. RESULTS: The results show that maternal deprivation led to a
      reduction in acoustic startle habituation and auditory sensory gating in adult
      rats. Moreover, maternal deprivation disrupted prepulse inhibition but only when
      the prepulses were given shortly (50-100 milliseconds) before the startle
      stimulus. At longer intervals (250-1000 milliseconds), no effect was seen.
      CONCLUSIONS: The implications for the model and the development of disturbances
      in information processes are discussed.

PMID- 15038999
TI  - Postnatal repeated maternal deprivation produces age-dependent changes of brain
      derived neurotrophic factor expression in selected rat brain regions.
AB  - BACKGROUND: Adverse life events occurring early in development may alter the
      correct program of brain maturation and render the organism more vulnerable to
      psychiatric disorders. Identification of persistent changes associated with these
      events is crucial for the development of novel therapeutic strategies. METHODS:
      We used postnatal repeated maternal deprivation (MD) from postnatal day (PND) 2
      14 to investigate changes in brain-derived neurotrophic factor (BDNF) levels.
      RNase protection assay and enzyme linked immunosorbent assay were employed to
      determine the anatomic profile of neurotrophin expression at different ages
      following MD. RESULTS: We found that MD produces a short-term up-regulation of
      neurotrophin expression in hippocampus and prefrontal cortex, as measured on PND
      17, whereas at adulthood, a selective reduction of BDNF expression was observed
      in prefrontal cortex. When adult animals were challenged with a chronic swim
      stress paradigm, both a reduced expression of BDNF in prefrontal cortex and a
      significant reduction in striatal protein levels were found only in control
      subjects, whereas levels in the MD group were not further decreased. CONCLUSIONS:
      Our data suggest that MD produces a significant reduction of BDNF expression
      within prefrontal cortex and striatum, which may render these structures less
      plastic and more vulnerable under challenging conditions.

PMID- 15039000
TI  - Neurobiological correlates of high (HAB) versus low anxiety-related behavior
      (LAB): differential Fos expression in HAB and LAB rats.
AB  - BACKGROUND: Two Wistar rat lines selectively bred for either high (HAB) or low
      (LAB) anxiety-related behavior were used to identify neurobiological correlates
      of trait anxiety. METHODS: We used Fos expression for mapping of neuronal
      activation patterns in response to mild anxiety-provoking challenges. RESULTS: In
      both lines, exposure to an open field (OF) or the open arm (OA) of an elevated
      plus-maze induced Fos expression in several brain areas of the anxiety/fear
      circuitry. Rats of the HAB type, which showed signs of a hyperanxious phenotype
      and a hyperreactive hypothalamic-pituitary-adrenal axis compared with LAB rats,
      exhibited a higher number of Fos-positive cells in the paraventricular nucleus of
      the hypothalamus, the lateral and anterior hypothalamic area, and the medial
      preoptic area in response to both OA and OF. Less Fos expression was induced in
      the cingulate cortex in HAB than in LAB rats. Differential Fos expression in
      response to either OA or OF was observed in few brain regions, including the
      thalamus and hippocampus. CONCLUSIONS: The present data indicate that the
      divergent anxiety-related behavioral response of HAB versus LAB rats to OF and OA
      exposures is associated with differential neuronal activation in restricted parts
      of the anxiety/fear circuitry. Distinct hypothalamic regions displayed
      hyperexcitability, and the cingulate cortex showed hypoexcitability, which
      suggests that they are main candidate mediators of dysfunctional brain activation
      in pathologic anxiety.

PMID- 15039001
TI  - The role of the endocrine system in baboon maternal behavior.
AB  - BACKGROUND: Human mothers display a wide range of parenting skills, and although
      we have gathered a large body of evidence on a variety of factors affecting
      maternal behavior, we still know relatively little about the physiologic
      correlates of variation in parental behavior in primates. METHODS: Excreted
      gonadal and adrenal steroids were measured across parturition in a large sample
      (n = 89) of group-living female baboons. Maternal behavior data were collected
      during the first 2 months of infants' life. RESULTS: We found that changes in the
      excreted sex steroid hormones and cortisol were associated with baboon mothers'
      infant-directed behaviors. Mothers who displayed more stress-related behaviors,
      who were also prone to maintain less contact with their infants, had higher
      postpartum cortisol levels, higher prepartum pregnanediol-3-glucoronide (PdG)
      levels, and lower postpartum PdG levels. Mothers with higher prepartum cortisol
      levels showed higher levels of infant-directed affiliative behaviors.
      CONCLUSIONS: These results point toward the importance of the whole endocrine
      system as a functional unit in terms of enhancing maternal care in primates. The
      dramatic physiologic changes occurring across parturition may act, in
      coordination with the cognitive-experiential system, to help the mother cope with
      the additional challenges imposed by the newborn.

PMID- 15039002
TI  - Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic
      pituitary-adrenal axis response to stress in infant macaques.
AB  - BACKGROUND: In humans and macaques, a promoter polymorphism that decreases
      transcription of the serotonin transporter gene is associated with anxiety.
      Serotonin transporter gene disruption in rodents produces anxious animals with
      exaggerated limbic-hypothalamic-pituitary-adrenal (LHPA) responses to stress. We
      wanted to determine whether serotonin transporter gene promoter variation (rh
      5HTTLPR) and rearing condition would interact to influence endocrine responses to
      stress in infant rhesus macaques. METHODS: Animals were reared with their mothers
      (MR, n = 141) or in peer-only groups (PR, n = 67). At 6 months of age,
      adrenocorticotropic hormone (ACTH) and cortisol levels were determined at
      baseline and during separation stress. Serotonin transporter genotype (l/l and
      l/s) was determined with polymerase chain reaction followed by gel
      electrophoresis. RESULTS: Cortisol levels increased during separation, and there
      was a main effect of rearing condition, with decreased cortisol levels among PR
      macaques. Animals with l/s rh5-HTTLPR genotypes had higher ACTH levels than did
      l/l animals. Adrenocorticotropic hormone levels increased during separation, and
      there was a separation x rearing x rh5-HTTLPR interaction, such that PR-l/s
      animals had higher ACTH levels during separation than did other animals studied.
      CONCLUSIONS: These data demonstrate that serotonin transporter gene variation
      affects LHPA axis activity and that the influence of rh5-HTTLPR on hormonal
      responses during stress is modulated by early experience.

PMID- 15039003
TI  - Genetics of monoamine metabolites in baboons: overlapping sets of genes influence
      levels of 5-hydroxyindolacetic acid, 3-hydroxy-4-methoxyphenylglycol, and
      homovanillic acid.
AB  - BACKGROUND: Monoamine neurotransmitters (serotonin, dopamine, and norepinephrine)
      are associated with several psychiatric disorders. Limited evidence suggests that
      monoamine levels are heritable, but no information concerning genetic
      relationships among monoamines is available. Further genetic analysis can help
      explain phenotypic correlations among monoamine levels and might eventually help
      identify genes involved in response to therapy or risk of psychopathology.
      METHODS: Levels of the monoamine metabolites homovanillic acid (HVA), 5
      hydroxyindolacetic acid (5-HIAA), and 3-hydroxy-4-methoxyphenylglycol (MHPG) were
      measured in cerebrospinal fluid from 271 baboons (Papio hamadryas). Variance
      components methods were used to estimate heritabilities, and multivariate
      analyses were used to estimate genetic correlations (pleiotropy) and
      environmental correlations between metabolites. RESULTS: Each metabolite
      exhibited significant heritability in baboons (5-HIAA: h(2) =.30 +/-.17; MHPG:
      h(2) =.36 +/-.16; HVA: h(2) =.50 +/-.19). Multivariate analyses revealed genetic
      correlations between 5-HIAA and HVA and between HVA and MHPG. Environmental
      correlations were found between 5-HIAA and HVA and between 5-HIAA and MHPG.
      CONCLUSIONS: Overlapping, nonidentical sets of genes influence individual
      variation in 5-HIAA, MHPG, and HVA levels among baboons. The phenotypic
      correlation between 5-HIAA and HVA observed in nonhuman primates and humans is
      likely due to both shared genetic and environmental factors. Genetic analyses of
      monoamine levels in primates can provide novel information concerning the
      genetics of variation among humans.

PMID- 15039004
TI  - Hypocortisolism and increased glucocorticoid sensitivity of pro-Inflammatory
      cytokine production in Bosnian war refugees with posttraumatic stress disorder.
AB  - BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with dysregulation
      of the hypothalamus pituitary adrenal (HPA) axis. Alterations include various
      responses to HPA axis stimulation, different basal hormone levels, and changes in
      glucocorticoid receptor (GR) numbers on lymphocytes. The functional significance
      of these latter changes remains elusive. METHODS: Twelve Bosnian war refugees
      with PTSD and 13 control subjects were studied. On 2 consecutive days, they
      collected saliva samples after awakening and at 11, 15, and 20 hours.
      Glucocorticoid (GC) sensitivity was measured by dexamethasone (DEX) inhibition of
      lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor
      alpha (TNF-alpha) production in whole blood. RESULTS: The PTSD patients showed no
      cortisol response after awakening and had lower daytime cortisol levels (F =
      14.57, p <.001). Less DEX was required for cytokine suppression in PTSD patients
      (IL-6: t = -2.82, p =.01; TNF-alpha: t = 5.03, p <.001), reflecting higher GC
      sensitivity of pro-inflammatory cytokine production. The LPS-stimulated
      production of IL-6, but not TNF-alpha, was markedly increased in patients (IL-6:
      F = 10.01, p <.004; TNF-alpha: F =.89, p =.34). CONCLUSIONS: In refugees with
      PTSD, hypocortisolism is associated with increased GC sensitivity of immunologic
      tissues. Whether this pattern reflects an adaptive mechanism and whether this is
      sufficient to protect from detrimental effects of low cortisol remains to be
      investigated.

PMID- 15039005
TI  - Pituitary volumes in pediatric maltreatment-related posttraumatic stress
      disorder.
AB  - BACKGROUND: Previous findings suggest that corticotrophin-releasing hormone (CRH)
      is elevated in adults with posttraumatic stress disorder (PTSD), maltreated
      children, and children with maltreatment-related PTSD. METHODS: Magnetic
      resonance imaging was used to measure pituitary volumes in 61 medication-naive
      maltreated subjects with PTSD (31 male and 30 female subjects) and 121
      nontraumatized healthy comparison subjects (62 male and 59 female subjects).
      RESULTS: Overall, no differences were seen between PTSD and control subjects in
      pituitary volumes. There was a significant age-by-group effect for PTSD subjects
      to have greater differences in pituitary volume with age than control subjects.
      Post hoc analyses revealed that pituitary volumes were significantly larger in
      pubertal and postpubertal maltreated subjects with PTSD than control subjects but
      were similar in prepubertal maltreated subjects with PTSD and control subjects.
      Pituitary volumes were larger in the PTSD subjects with history of suicidal
      ideation. CONCLUSIONS: These findings may suggest developmental alterations in
      pituitary volume in maltreatment-related pediatric PTSD. This finding may be
      associated with stress-related differences in CRH and may be more pronounced in
      pediatric patients with PTSD comorbid with suicidal ideation.

PMID- 15039006
TI  - A positron emission tomography study of memories of childhood abuse in borderline
      personality disorder.
AB  - BACKGROUND: Borderline personality disorder (BPD) is a common psychiatric
      disorder, which is linked to early stressors in many cases; however, the impact
      of traumatic events in the etiology of BPD is still unclear. This pilot study was
      conducted to measure the neural correlates of recall of traumatic memories in
      women with and without BPD. METHODS: Twenty women with a history of childhood
      physical or sexual abuse underwent measurement of brain blood flow with positron
      emission tomography imaging while they listened to scripts describing neutral and
      personal traumatic abuse events. Brain blood flow during exposure to trauma and
      neutral scripts was compared between women with and without BPD. RESULTS:
      Memories of trauma were associated with increases in blood flow in right
      dorsolateral prefrontal cortex (Brodmann's area [BA] 44 and 45) and with
      decreased blood flow in left dorsolateral prefrontal cortex (BA 44 and 45) in
      women without BPD. There was also increased blood flow in right anterior
      cingulate (BA 24) and left orbitofrontal cortex (BA 11) in women without BPD.
      Women with BPD failed to activate anterior cingulate gyrus and orbitofrontal
      cortex. Also, no blood flow changes were seen in dorsolateral prefrontal gyrus in
      women with BPD. CONCLUSIONS: Dysfunction of dorsolateral and medial prefrontal
      cortex, including anterior cingulate, seems to be correlated with the recall of
      traumatic memories in women with BPD. These brain areas might mediate trauma
      related symptoms, such as dissociation or affective instability, in patients with
      BPD.

PMID- 15039007
TI  - Positron emission tomography imaging of the serotonin transporter in subjects
      with a history of alcoholism.
AB  - BACKGROUND: Our purpose was to investigate the serotonin transporter (SERT) in
      various brain regions of alcoholics using positron emission tomography and C-11
      McN5652. METHOD: Thirty-two adult subjects were involved, 17 social drinkers as
      control subjects and 15 subjects who were abstinent or recovering alcoholics.
      Concomitant psychiatric diseases were ruled out based on DSM-IV criteria. The
      majority of subjects were men. Radioligand binding in 11 brain areas was
      expressed as the total distribution volume (DV), distribution volume of specific
      binding (DV(spec)), and distribution volume ratio (DVR). The cerebellum was used
      as reference tissue for calculation of DV(spec) and DVR. RESULTS: In subjects
      with a history of alcoholism, DV was lower in all brain regions, with significant
      differences in the midbrain, thalamus, amygdala, pons, cingulate gyrus, frontal
      cortex, and cerebellum. Additionally, DV(spec) was lower in all brain regions,
      but differences were only significant in the midbrain; DVR was lower in nine
      regions but the differences did not reach statistical significance. CONCLUSIONS:
      These studies demonstrate lower binding of [(11)C](+)McN5652 to the SERT in the
      brain of abstinent or recovering alcoholics compared with control subjects.
      Differences in the radioligand distribution volumes are more significant before
      than after correction for nonspecific binding of the radioligand.

PMID- 15039008
TI  - Training of slow cortical potentials in attention-deficit/hyperactivity disorder:
      evidence for positive behavioral and neurophysiological effects.
AB  - BACKGROUND: Learned self-control of slow cortical potentials (SCPs) may lead to
      behavioral improvement in attention-deficit/hyperactivity disorder (ADHD). Hence,
      training effects should also be reflected at the neurophysiological level.
      METHODS: Thirteen children with ADHD, aged 7-13 years, performed 25 SCP training
      sessions within 3 weeks. Before and after training, the German ADHD rating scale
      was completed by parents, and event-related potentials were recorded in a cued
      continuous performance test (CPT). For a waiting-list group of nine children with
      ADHD, the same testing was applied. RESULTS: ADHD symptomatology was reduced by
      approximately 25% after SCP training. Moreover, a decrease of impulsivity errors
      and an increase of the contingent negative variation were observed in the CPT
      task. CONCLUSIONS: This study provides first evidence for both positive
      behavioral and specific neurophysiological effects of SCP training in children
      with ADHD.

PMID- 15039009
TI  - Sources of auditory selective attention and the effects of methylphenidate in
      children with attention-deficit/hyperactivity disorder.
AB  - BACKGROUND: The aim of this study was to determine 1) whether abnormal auditory
      selective attention in children with attention-deficit/hyperactivity disorder
      (ADHD), as reflected in the processing negativity (PN) of the event-related
      potential, is related to impaired frontal functioning; and 2) how methylphenidate
      (MPh) affects attentional functioning in ADHD. METHODS: Sources of electrical
      brain activity were estimated in healthy control children, in ADHD children
      without medication, and in children with ADHD during a placebo-controlled
      medication trial involving MPh. RESULTS: The source models showed that the PN is
      generated in the auditory cortex. Children with ADHD showed less activity related
      to selective attention in this brain region. Administration of MPh resulted in
      more frontally located sources. CONCLUSIONS: The results showed no evidence for
      an important role of the frontal cortex in abnormalities in selective attention
      in children with ADHD. Also, the data did not indicate that MPh normalizes brain
      activity in these children.

PMID- 15039010
TI  - Bioelectrochemistry of red blood cells. Proceedings of the 14th Meeting of the
      European Association for Red Cell Research. Roscoff, France, 24-28 April 2003.

PMID- 15039011
TI  - The cooperative role of membrane skeleton and bilayer in the mechanical behaviour
      of red blood cells.
AB  - Red blood cell (RBC) shape, behaviour and deformability can be consistently
      accounted for by a model for the elastic properties of the RBC membrane that
      includes the elasticity of the membrane skeleton in dilation and shear, and the
      local and nonlocal resistance of the bilayer to bending. The role of the
      corresponding energy terms in different RBC shape and deformation situations is
      analyzed. RBC shape transformations are compared to the shape transformations of
      phospholipid vesicles that are driven by the difference between the equilibrium
      areas of the bilayer leaflets (DeltaA0). It is deduced that the skeleton energy
      contributions play a crucial role in the formation of an echinocyte. The effect
      of a transformation of the natural biconcave RBC shape into an echinocyte on its
      resistance to entry into capillary-sized cylindrical tubes is analyzed. It is
      shown that, during the aspiration of an echinocyte into a pipette, there are two
      competing skeleton deformation effects, which arise due to skeleton density
      changes, one due to spicule formation and the other due to deformation induced by
      micropipette aspiration. Furthermore, the shift of the observed dependence of the
      projection length on the aspiration pressure of more crenated cells towards
      higher aspiration pressures can be accounted for by an increase of the
      equilibrium area difference DeltaA0 and consequent modification of the nonlocal
      contribution to the cell elastic energy.

PMID- 15039012
TI  - Erythrocyte membrane permeability for a series of diols.
AB  - Erythrocyte membrane permeability coefficients for a series of diols have been
      defined by the method developed. The method is based on the physical and
      mathematical modeling of hypotonic hemolysis process. There have been also
      determined membrane permeability coefficients for erythrocytes treated with p
      chloromercuribenzenesulfonic acid monosodium salt (pCMBS), which is known to
      block aqueous protein channels. Permeating process is shown to be conditioned
      both by hydrophilic/hydrophobic properties of the molecules and their geometrical
      parameters. The obtained results propose that, when exceeding the molecules
      diameter over a value of 4 A, the permeability coefficient reduces due to
      decreasing of flow through the aqueous protein pores of a constant size.
      Permeability coefficients for comparatively hydrophobic molecules are almost
      directly proportional to the coefficients of partition between hydrophobic and
      hydrophilic phases, by pointing to a lipid way of permeation of these molecules
      through erythrocyte membranes.

PMID- 15039013
TI  - Estimation of erythrocyte population state by the spherical index distribution.
AB  - The densities of cell distributions by spherical index (SI) in erythrocyte
      populations from healthy adults and donors with endocrine pathologies were
      determined via the developed method. The investigation shows that this
      characteristic varies for different donors, thereby reflecting the erythrocyte
      population state of an individual donor. Individual distribution curves obtained
      from healthy donors are close to Gaussian and are characterized by smooth curve
      plot with one maximum. Cells distribution by SI in donors with endocrine
      pathologies has a polymodal character. Our research shows that the developed
      method for determining erythrocyte distribution density by SI is a sensitive and
      informative test for quantitative evaluation of an erythrocyte population state.
      Moreover, this characteristic has clear physical and physiological significance,
      because an erythrocyte shape is strongly conditioned by the cell age and
      influences the ability to pass through microcapillaries in blood circulation.

PMID- 15039014
TI  - Red blood cell ghosts and intact red blood cells as complementary models in
      photodynamic cell research.
AB  - Recent research on erythrocytes as model cells for photodynamic therapy showed
      differing behaviour of certain photosensitisers in erythrocytes compared to other
      cells. Differences of dye accumulation in the cell membrane were proposed to be
      the reason for the distinct photodynamic effects. Using pheophorbide a as an
      example, the combination of erythrocyte ghosts as models to follow the dye
      accumulation in the cell membrane and intact erythrocytes as model cells to show
      the photodynamic damage is provided. Evidence for the correctness of the
      combination of erythrocyte ghosts and intact erythrocytes as a functioning model
      system in photodynamic cell research is provided using the confocal laser
      scanning microscopy on intact, pheophorbide a loaded erythrocytes.

PMID- 15039015
TI  - Effect of the ionic strength and prostaglandin E2 on the free Ca2+ concentration
      and the Ca2+ influx in human red blood cells.
AB  - Human red blood cells (RBCs) were loaded with the Ca(2+)-sensitive fluorescent
      dye fura-2 to investigate the effects of media ionic strength and prostaglandin
      E2 (PGE2) on the intracellular free Ca2+ concentration ([Ca2+]i). [Ca2+]i of
      intact RBCs in a Ca(2+)-containing physiological (high) ionic strength (HIS)
      solution was 75.1 +/- 8.3 nM after 5 min incubation, increasing to 114.9 +/- 9.6
      nM after 1 h. In Ca(2+)-containing low ionic strength (LIS) solutions, [Ca2+]i
      was significantly lower than in the Ca(2+)-containing HIS solution (p = 0.041 or
      0.0385 for LIS solutions containing 200 or 250 mM sucrose, respectively), but, as
      in HIS solution, an increase of [Ca2+]i was seen after 1 h. In Ca(2+)-free (0
      Ca2+ plus 15 microM EGTA) media, [Ca2+]i decreased (ranging from 15 to 21 nM),
      but were not significantly different in HIS or LIS, and did not change following
      1 h incubation. The effect of the ionic strength and PGE2 on passive Ca2+ influx
      was investigated on ATP-depleted RBCs. Ca2+ influx was faster during the initial
      10 min in comparison with the subsequent time period (10-45 min), both in HIS and
      LIS media, decreasing from 20.3 +/- 1.9 to 12.9 +/- 1.3 micromol/(lcells x h) in
      HIS, and from 36.7 +/- 5.3 to 8.6 +/- 1.2 micromol/(lcells x h) in LIS.
      Prostaglandin E2 (PGE2; 10(-7)-10(-11) M), dissolved in deionised water or in
      ethanol, did not affect [Ca2+]i in either normal or in ATP-depleted RBCs
      suspended in Ca(2+)-containing HIS medium. Finally, the addition of carbachol
      (100 microM) did not affect [Ca2+]i. The present findings suggest that
      stimulation of the Ca(2+)-activated K+ channel by PGE2, reported in [J. Biol.
      Chem. 271 (1996) 18651], cannot be mediated via increased [Ca2+]i.

PMID- 15039016
TI  - Inhibitors of the K+(Na+)/H+ exchanger of human red blood cells.
AB  - The effect of substances as possible inhibitors of the K+(Na+)/H+ exchanger in
      the human red cell membrane has been tested on the (ouabain+bumetanide+EGTA)
      resistant K+ influx in both physiological (HIS) and low ionic strength (LIS)
      solution with tracer kinetic methods. It is demonstrated that high concentrations
      of quinacrine (1 mM) and chloroquine (2 mM) inhibit the residual K+ influx in LIS
      solution to 60% and 85%, respectively, but activate it in HIS solution. Thus,
      chloroquine suppressed the 10-fold LIS-induced activation of the flux nearly
      completely. Amiloride derivatives were able to inhibit the K+ influx in both HIS
      and LIS solution. EIPA (75 microM) reduced the flux by about 20% and 55% in HIS
      and LIS solution, respectively. Newly developed drugs (HOE 642, 1 mM; HOE 694,
      0.5 mM) designed to inhibit Na+/H+ exchanger isoforms showed an inhibition of the
      residual K+ influx of 40% and 33% in HIS and 65% and 44% in LIS solution,
      respectively, without haemolysis. The inhibitory effect of HOE 642 persisted in
      HIS (24%) and LIS (48%) solutions when Cl- was replaced by CH3SO4-. The K(+)-Cl-
      cotransport inhibitor DIOA (100 microM) stimulated the residual K+ influx in both
      solutions. It is, therefore, concluded that the K(+)-Cl- cotransporter does not
      contribute to the residual K+ influx both in HIS and LIS media. Okadaic acid
      decreased the residual K+ influx by 40% and 25% in HIS and LIS solution,
      respectively, showing that the residual K+ influx is affected by phosphatases
      like other ion transport pathways. The results show that the residual K+ influx
      can be decreased further by inhibiting the K+(Na+)/H+ exchanger. It remains still
      unclear to what extent the K+(Na+)/H+ exchanger is inhibited by the different
      substances used. However, the ground state membrane permeability for K+ is much
      smaller than assumed so far.

PMID- 15039017
TI  - Oxygen dependence of K(+)-Cl- cotransport in human red cell ghosts and sickle
      cells.
AB  - KCC activity in normal human red cells (containing haemoglobin A, HbA, and termed
      HbA cells) is O2-dependent, being active in oxygenated cells but inactive in
      deoxygenated ones. The mechanism for O2 dependence is unknown but a role for Hb
      has been suggested. In this paper, we address two main questions. First, do
      membrane ghosts prepared from HbA cells retain an O2-sensitive KCC activity?
      Second, how is the response of KCC to changes in O2 tension altered in sickle
      cell patients heterozygous for HbS and HbC? We found that substantial Cl(-)
      dependent K+ influx, indicative of KCC activity, was present in both pink (5-10%
      normal Hb complement) and white (no measurable Hb) ghosts when equilibrated with
      air. KCC responded to deoxygenation in pink ghosts only (86 +/- 10% inhibition,
      mean+/-S.E.M., n = 3), whilst KCC activity in white ghosts remained high (23 +/-
      8% inhibition). Results indicate that pink ghosts retain an O2-dependent KCC
      activity but that this is lost in white ghosts. Second, HbSC-containing red cells
      showed sickling (88 +/- 3%) when deoxygenated, together with activation of the
      deoxygenation-induced cation pathway (Psickle) and the Gardos channel. KCC
      activity, however, was elevated in oxygenated HbSC cells, but inhibited by
      deoxygenation. Thus Hb polymerisation and sickling could be dissociated from the
      abnormal response of KCC to deoxygenation observed in HbS-containing red cells.
      These preparations provide a useful system with which to study the components
      involved in O2-sensitive membrane transport and why it is perturbed in certain
      pathological conditions (such as sickle cell disease and oxidant toxicity).

PMID- 15039018
TI  - Modulation of Gardos channel activity by oxidants and oxygen tension: effects of
      1-chloro-2,4-dinitrobenzene and phenazine methosulphate.
AB  - We compare the effects of 1-chloro-2,4-dinitrobenzene (CDNB) and phenazine
      methosulphate (PMS) on Gardos channel activity in normal human red cells. Both
      stimulate channel activity, both are dependent on the presence of extracellular
      Ca2+, and neither is affected by inhibitors of protein (de)phosphorylation. Of
      the two, PMS has a considerably greater effect. In addition, a major difference
      is that whilst CDNB has a greater stimulatory effect in oxygenated cells, by
      contrast, PMS is more effective in deoxygenated cells. These actions are
      correlated with ca. 30% inhibition of the plasma membrane Ca2+ pump (PMCA) and an
      increased sensitivity of the Gardos channel to Ca2+ (EC50 falling to about 150
      nM). These findings are important in understanding how oxidants alter red cell
      cation permeability and may be relevant to the abnormal permeability phenotype
      shown by deoxygenated sickle cells.

PMID- 15039019
TI  - Oxygen sensitivity of red cell membrane transporters revisited.
AB  - In this paper, we provide an update on O2-dependent membrane transport in red
      cells. O2-sensitive membrane transport was compared in nucleated (chicken) and
      enucleated (human) red cells, to investigate effects on organic (glucose
      transporter [GLUT]) and inorganic (K(+)-Cl- cotransporter [KCC]/Na(+)-K(+)-2Cl-
      cotransporter [NKCC]) transporters, to study the response of so-called
      "housekeeping" transporters (Na+/K+ pump and anion exchanger [AE]) and, finally,
      to compare O2 sensitivity in normal human red cells with those from sickle cell
      patients. The Na+/K+ pump showed no change in activity between oxygenated and
      deoxygenated cells in any of the samples. KCC in normal human red cells had the
      greatest O2 sensitivity, being stimulated some 20-fold on oxygenation. It was
      more modestly stimulated by O2 in chicken red cells and HbS cells. By contrast,
      NKCC was stimulated by deoxygenation in all cases. GLUT showed little response to
      O2 tension, other than a small stimulation in deoxygenated chicken red cells.
      Finally, AE1 was stimulated by oxygenation in HbA cells, but this stimulation by
      O2 was absent in HbS cells and pink ghosts prepared from HbA cells. The
      significance of these findings is discussed.

PMID- 15039020
TI  - Spherocyte shape transformation and release of tubular nanovesicles in human
      erythrocytes.
AB  - We have studied dodecylmaltoside-induced echinocyte-spheroechincyte-spherocyte
      shape transformation and membrane vesiculation using transmission electron
      microscopy (TEM) on freeze-fracture replicas. It is indicated that spherical
      erythrocyte shape at higher dodecylmaltoside concentration is formed due to loss
      of membrane in the process where small, mostly tubular nanovesicles are released
      predominantly from the top of echinocyte and spheroechinocyte spicules.

PMID- 15039021
TI  - Effect of alkyl-beta,d-glucopyranosides on hypertonic haemolysis of erythrocytes.
AB  - The effect of temperature (5-20 degrees C) and treatment with phenylhydrazine on
      the hypertonic lysis of erythrocytes in the presence of alkyl-beta,d
      glucopyranosides was studied. The results highlight an important role for the
      cytoskeleton-membrane complex, which allows the cells to both withstand
      hypertonic stress within the temperature range studied and facilitate the
      protective effect of alkylglucopyranosides at low temperatures (5 degrees C).

PMID- 15039022
TI  - Phosphotyrosine phosphatases acting on band 3 in human erythrocytes of different
      age: PTP1B processing during cell ageing.
AB  - The phosphorylation of tyrosine residues of human red blood cell (RBC) band 3 is
      regulated in vivo by constitutively active tyrosine-kinases (PTKs) and
      phosphotyrosine-phosphatases (PTPs), identified so far as, respectively, p72(syk)
      and p56/53(lyn), and PTP1B and SHPTP-2. Tyr-phosphorylation of band 3 increases
      upon reduction of cell volume as in hypertonic media or during Ca(2+)-induced
      membrane vesiculation. We show here that old RBCs display higher Tyr
      phosphorylation levels of band 3 than younger cells under hypertonic conditions,
      at least in part due to the reduced cell volume of old RBCs, a condition of
      lowered threshold for activation of volume-sensitive PTKs. We have also analysed
      the membrane-bound PTP activity and the relative abundance of PTP1B (as the main
      membrane-associated PTP) in RBCs of different age. Immunodetection of PTP1B in
      purified ghost membranes revealed that the catalytic, N-terminal domain of the
      PTP is partially cleaved, in an age-dependent manner, from the membrane-bound
      domain, and it is lost during the preparation of ghost membranes. This suggests
      that erythrocytes may undergo in vivo activation of the Ca(2+)-dependent calpain
      system that proteolytically regulates PTP1B activity, as already documented for
      other cell types. On the other hand, the assay of the PTP activity that remains
      associated with the membranes of RBCs of different age indicated that the PTP
      undergoes oxidative inactivation that can be further differentiated into
      reversible and irreversible components.

PMID- 15039023
TI  - Experiences in the measurement of RBC-bound IgG as markers of cell age.
AB  - An immunologically mediated pathway has been largely accepted to be one of the
      mechanisms involved in the clearance of senescent or prematurely damaged RBC.
      According to this pathway, RBC removal is mediated by binding of naturally
      occurring IgG to clustered integral membrane proteins, followed by complement
      deposition. The validation of an immunoenzymatic method for the detection of RBC
      bound autologous IgG is presented. The use of RBC-bound IgG as an index related
      to red cell age was evaluated by measuring IgG binding in RBC treated with the
      clustering agent ZnCl2, in density fractionated RBC and in a selected group of
      patients expected to have an altered RBC life span. The immunoenzymatic method
      for IgG detection resulted to be reproducible (CV = 3.4%). IgG binding to in
      vitro clustered RBC was found to be enhanced to a very great extent, about 20
      times higher with respect to untreated RBC. A slight but significant increase
      (about 1.8-fold) in membrane-bound IgG was observed in the highest density
      fraction of normal RBC, which constituted 1% of the total cells. A significantly
      greater number of RBC-bound IgG was measured in splenectomized beta-thalassemia
      intermedia patients and in subjects with secondary decreases in the C3 complement
      fraction concentration.

PMID- 15039024
TI  - Voltage activation and hysteresis of the non-selective voltage-dependent channel
      in the intact human red cell.
AB  - Suspension of intact human red cells in media with low chloride and sodium
      concentrations (isotonic sucrose substitution) results in strongly inside
      positive membrane potentials, which activate the voltage-dependent non-selective
      cation (NSVDC) channel. By systematic variation of the initial Nernst potentials
      for chloride (degree of ion substitution) as well as the chloride conductance
      (block by NS1652), and by exploiting the interplay between the Ca(2+)-permeable
      NSVDC channel, the Ca(2+)-activated K+ channel (the Gardos channel) and the
      Ca(2+)-pump, a graded activation of the NSVDC channel was achieved. Under these
      conditions, it was shown that the NSVDC channels exist in two states of
      activation depending on the initial conditions for the activation. The hysteretic
      behaviour, which in patch clamp experiments has been found for the individual
      channel unit, is thus retained at the cellular level and can be demonstrated with
      red cells in suspension.

PMID- 15039026
TI  - Activity of membrane-bound NADH-methemoglobin reductase and physical state of
      lipids in erythrocyte membranes.
AB  - The activity of membrane-bound NADH-methemoglobin reductase in erythrocytes and
      the physical state of lipids in erythrocyte membranes under oxidative stress in
      cells were studied. A decrease of the activity of membrane-bound NADH
      methemoglobin reductase and a change of physical state of the lipid bilayer of
      membranes under oxidative stress were found in erythrocytes in vivo and in vitro.

PMID- 15039025
TI  - Temperature-dependent changes in erythrocytes' cytosol state during natural and
      artificial hypobiosis.
AB  - At present, the question of how the structural state of the erythrocyte cytosol
      is arranged to maintain essential permeabilities successfully both at normal
      temperature and during periods with a significant body temperature reduction
      during hypobiosis remains unanswered. In the present work, we performed
      comparative investigations of temperature-dependent changes in the cytosol state
      of erythrocytes from animals subjected to natural (winter hibernating ground
      squirrels) or artificial hypobiosis. The cytosol state was evaluated by the ESR
      method of spin probes (TEMPON) within the temperature range of 0-50 degrees C.
      Erythrocyte resistance to acid hemolysis, which is limited by the permeability of
      membranes for protons and the state of the anion channel, were determined using
      the method described by Terskov and Getelson [Biofizika 2 (1957) 259]. A change
      in cytosol microviscosity of erythrocytes was found as well as a temperature
      dependent increase in acid resistance of erythrocytes. Our investigations allow
      us to conclude that physiological changes occurring in a mammalian organism
      during natural and artificial hypobiosis are accompanied by structural
      modifications of the erythrocyte cytosol. The temperature range where these
      modifications are observed (8, 15, 40 degrees C) suggests that the most probable
      modifying link is spectrin and/or the sites of its interaction with membrane. The
      interaction of cytoskeletal components with the cell membrane plays a key role in
      regulation of membrane permeability, suggesting an important role of this
      interaction in the adaptive reactions of erythrocytes.

PMID- 15039028
TI  - Has the real potential of cloning technology been overlooked?

PMID- 15039027
TI  - Effects of anti-GLUT antibodies on glucose transport into human erythrocyte
      ghosts.
AB  - We have studied the effects of anti-GLUT1 antibodies on the uptake of glucose
      into erythrocytes. Glucose transport into human erythrocyte ghosts was measured
      directly using 3H-2-deoxy-glucose, or indirectly by monitoring associated volume
      changes using light scattering. The uptake of glucose was significantly inhibited
      in ghosts resealed in solutions containing specific antibodies against GLUT1.
      Such an effect was not observed when an antibody against the oestrogen receptor,
      lacking specificity towards GLUT1, was employed instead. The antibodies were also
      without effect on the efflux of preloaded glucose from erythrocyte ghosts. The
      demonstration that anti-GLUT antibodies can inhibit glucose uptake is support for
      the hypothesis that they exaggerate the cytoplasmic barrier to glucose uptake
      created by endofacial segments of GLUT1.

PMID- 15039029
TI  - Fall-out from a possible transfusion-related transmission of vCJD.

PMID- 15039030
TI  - Lifting the burden: The global campaign against headache.

PMID- 15039031
TI  - AIDS and stroke risk.

PMID- 15039032
TI  - Anticysticercal treatment and seizures in neurocysticercosis.

PMID- 15039033
TI  - Monogenic idiopathic epilepsies.
AB  - Major advances have recently been made in our understanding of the genetic bases
      of monogenic inherited epilepsies. Direct molecular diagnosis is now possible in
      numerous inherited symptomatic epilepsies. Progress has also been spectacular
      with respect to several idiopathic epilepsies that are caused by mutations in
      genes encoding subunits of ion channels or neurotransmitter receptors. Although
      these findings concern only a few families and sporadic cases, their potential
      importance is great, because these genes are implicated in a wide range of more
      common epileptic disorders and seizure types as well as some rare syndromes.
      Functional studies of these mutations, while leading to further progress in the
      neurobiology of the epilepsies, will help to refine genotype-phenotype relations
      and increase our understanding of responses to antiepileptic drugs. In this
      article, we review the clinical and genetic data on most of the idiopathic human
      epilepsies and epileptic contexts in which the association of epilepsy and
      febrile convulsions is genetically determined.

PMID- 15039035
TI  - Genetic risk factors for stroke and carotid atherosclerosis: insights into
      pathophysiology from candidate gene approaches.
AB  - Ischaemic stroke is the most common form of stroke and is caused by
      atherosclerosis in most patients. Several genetic determinants contribute to
      stroke risk. Of these, carotid intimal-medial wall thickness (IMT) is
      particularly relevant, because it is a surrogate measure of subclinical
      atherosclerosis and a strong predictor of future ischaemic stroke. Studies of
      twins, siblings, and families have provided significant evidence for
      heritability, but the genes involved have not been identified. Some researchers
      have reported that IMT is high in people with functional variants of genes
      related to matrix deposition (MMP3), inflammation (interleukin 6), and lipid
      metabolism (hepatic lipase, APOE, CETP, and PON1). In this review, we assess the
      robustness of these associations and examine whether there is any evidence of
      risk modification by factors, such as smoking.

PMID- 15039034
TI  - Alzheimer's disease: the two-hit hypothesis.
AB  - There are many lines of evidence showing that oxidative stress and aberrant
      mitogenic changes have important roles in the pathogenesis of Alzheimer's disease
      (AD). However, although both oxidative stress and cell cycle-related
      abnormalities are early events, occurring before any cytopathology, the relation
      between these two events, and their role in pathophysiology was, until recently,
      unclear. However, on the basis of studies of mitogenic and oxidative stress
      signalling pathways in AD, we proposed a "two-hit hypothesis" which states that
      although either oxidative stress or abnormalities in mitotic signalling can
      independently serve as initiators, both processes are necessary to propagate
      disease pathogenesis. In this paper, we summarise evidence for oxidative stress
      and abnormal mitotic alterations in AD and explain the two-hit hypothesis by
      describing how both mechanisms are necessary and invariant features of disease.

PMID- 15039036
TI  - Headache with focal neurological signs or symptoms: a complicated differential
      diagnosis.
AB  - Headache syndromes can be associated with focal neurological symptoms or signs.
      Good knowledge of primary headaches, a detailed history and a thorough clinical
      examination are prerequisites for their differential diagnosis. The neurological
      symptoms produced by the migraine aura are the most characteristic and
      recognisable. However, structural lesions, such as vascular malformations, can
      produce similar symptoms to migraine with aura, which highlights that
      paraclinical investigations are necessary in most patients with headache and
      focal neurological symptoms. In this review, we provide an overview of the
      differential diagnosis of the most common headache disorders with focal
      neurological symptoms or signs to refresh the practising neurologist's
      differential diagnostic knowledge for the clinical situation and to aid the
      teaching of neurology residents.

PMID- 15039037
TI  - Amnestic MCI or prodromal Alzheimer's disease?
AB  - The concept of mild cognitive impairment (MCI) draws attention to cognitive
      changes not severe enough to warrant the diagnosis of dementia. As used today, it
      covers many pathological disorders and characterises a diverse population of
      patients who attend memory clinics. Our concern is the underlying heterogeneity.
      We suggest that it will soon be possible (if it is not already) to identify the
      underlying pathological disorders before the affected patients meet the criteria
      of dementia, thanks to specific neuropsychological assessments, neuroimaging, and
      biomarkers. In particular, patients with Alzheimer's disease (AD), the most
      important subgroup of patients with MCI, can already be identified before
      appearance of the fully developed clinical dementia syndrome. Accordingly, this
      paper proposes diagnostic criteria for "prodromal AD".

PMID- 15039038
TI  - Genetic testing and Huntington's disease: issues of employment.

PMID- 15039039
TI  - The brain-cancer puzzle.

PMID- 15039040
TI  - Outcome of the antibody response: a question of antigen dose and distribution.

PMID- 15039042
TI  - Epithelial metaplasia: an inadequate environment for antitumour immunity?

PMID- 15039043
TI  - Polyreactivity of antibody molecules.

PMID- 15039044
TI  - Lamarckian inheritance by somatically acquired maternal IgG phenotypes.

PMID- 15039045
TI  - Seasonal immune function and sickness responses.

PMID- 15039046
TI  - The intricate interface between immune system and metabolism.
AB  - Increasing experimental evidence indicates that several factors that influence
      metabolism also play a role in the regulation of immune responses. Dissection of
      the interface connecting the metabolic and immune systems has recently gained
      wide interest. Particular focus has been on certain cytokines [interleukin-1 (IL
      1), IL-6, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN
      gamma)], hormones (leptin and insulin), neuropeptides (corticotropin-releasing
      hormone and alpha-melanocyte-stimulating hormone), immune-related proteins (zinc
      alpha2-glycoprotein and attractin and/or mahogany), transcription factors
      (peroxisome-proliferator-activated receptors) and glucose metabolism. A better
      knowledge of the intricate network of interactions among energy regulation,
      immune surveillance and vital organ functions could in the near future lead to
      valuable strategies for therapeutic intervention in several immune-mediated
      diseases.

PMID- 15039047
TI  - CXC chemokines: the regulatory link between inflammation and angiogenesis.

PMID- 15039048
TI  - Setting the stage: an anatomist's view of the immune system.

PMID- 15039049
TI  - Studies on the chronology of third molar mineralization in a Japanese population.
AB  - In Germany, a sharp increase in forensic age estimations of living individuals
      has been observed in recent years. With regard to the relevant age group,
      radiologic assessment of the mineralization stage of the third molars is of
      particular importance. Still, the influence of ethnicity on the pace of
      mineralization has been insufficiently analyzed. A total of 1615
      orthopantomograms of 929 female and 686 male Japanese subjects aged between 12
      and 30 years was examined. The mineralization stages of third molars were
      evaluated on the basis of Demirjian's stages modified in accordance with Mincer's
      model. For the individual mineralization stages, the study presents the means and
      standard deviations for the genders separately. No statistically significant
      differences in the chronology of third molar mineralization between maxilla and
      mandible and between sides were observed. A comparison between genders largely
      did not render significant differences either. Apart from forensic age
      determination in living subjects, the presented reference data can also be used
      for age estimations of unidentified corpses and skeletons.

PMID- 15039050
TI  - A simple Duplex-PCR to evaluate the DNA quality of anthropological and forensic
      samples prior short tandem repeat typing.
AB  - Typing of DNA from ancient or otherwise highly degraded material, e.g. formalin
      fixed tissues, can be difficult, time consuming and costly. Very often, genetic
      typing is not possible at all. We present an inexpensive and easy to use Duplex
      PCR that amplifies a 164 bp fragment specific for nuclear DNA together with a 260
      bp mitochondrial DNA fragment and that can be employed as a pretest prior to
      short tandem repeat (STR) typing. All together, we analyzed DNA from 20 ancient
      bones, 20 formalin fixed tissues and 20 other forensic samples in different
      concentrations. Each sample that failed in the presented Duplex-amplification was
      also negative for STR typing, while samples that showed strong and clear signals
      in the Duplex-PCR led to reproducible genetic profiles using the multiplex kits
      AmpFLSTR Identifiler and Powerplex ES. The Duplex-PCR worked as a reliable
      indicator of DNA quality in the sample.

PMID- 15039051
TI  - Y-chromosome 10 locus short tandem repeat haplotypes in a population sample from
      Sicily Italy.
AB  - This study reports the first data on Y-chromosome-specific short tandem repeat
      (STR) haplotype frequencies, in the population of the island of Sicily (Italy),
      based on the combination of alleles at the following 10 Y-chromosome loci DYS19,
      DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, and DYS439. In
      a total of 117 males, 108 unique haplotypes were observed, with 99 of them being
      singletons. The 10 locus haplotypes generated a diversity value of 0.9987 and
      discriminatory power (DP) of 92.30%. The data on the seven of the 10
      polymorphisms (DYS19; DYS389I; DYS389II; DYS390; DYS391; DYS392 and DYS393) that
      have been most studied in worldwide populations were compared with similar data
      from neighboring Mediterranean populations in order to address the question of
      shared ancestry, gene flow and population affinities. Overall, results indicate
      Sicily is closest genetically to the mainland Italian population but also with
      evidence of a significant African component in the male gene pool. These findings
      are consistent with those obtained from other genetic markers (autosomal and
      mitochondrial DNA as well as the classical blood groups) and also with the
      recorded settlement history (either peaceful or due to invasion) of the island.

PMID- 15039052
TI  - The expression of '150-kDa oxygen regulated protein (ORP-150)' in human brain and
      its relationship with duration time until death.
AB  - The expression of oxygen regulated protein 150-kDa (ORP-150) was strongly induced
      in human brain under the hypoxic conditions. We examined the expression of ORP
      150 in the brain samples, and discussed its significance in forensic practice.
      The cerebral cortexes of 31 cases (asphyxia: 9 cases, hypothermia: 4,
      exsanguinations: 5, CO intoxication (CO): 6, sudden cardiac death (SCD): 7) were
      used for this study. Each tissue section was incubated with anti-ORP-150
      polyclonal antibody and the number of ORP-150 positive cells were counted. In the
      multiple linear regression method, the estimated regression coefficient of ORP
      150 on age was significant (P=0.039) thus, we could find that the ORP-150
      expression level depended on age. Using analysis of covariance, we compared the
      means of ORP-150, LSMEAN, which means hypothetic average value excluding
      influence of age, for each cause of death. The LSMEAN+/-SE was 84.74+/-9.03 in
      hypothermia, 57.52+/-6.34 in asphyxia, 46.68+/-6.70 in CO, 24.84+/-8.05 in
      exsanguinations, and 16.24+/-7.35 in SCD. As a result of the analysis, the LSMEAN
      of the ORP-150 expression level was related to the cause of death. There might be
      differences in the duration of brain ischemia before death. For example, SCD is
      presumed to be instant death, while brain ischemia continues for several minutes
      in asphyxia, CO and exsanguinations, and for several hours in hypothermia cases.
      Therefore, the immunohistochemical and morphometrical analysis of ORP-150 in the
      brain may be very useful to determine the duration of brain ischemia before death
      in forensic autopsy cases.

PMID- 15039053
TI  - Evaluation of the species specificity for six human short tandem repeat loci
      CSF1PO, TPOX, TH01, F13A01, FESFPS and vWA, in the Japanese macaque.
AB  - We examined six human short tandem repeat (STR) loci (c-fms proto-oncogene for
      CSF-1 receptor, CSF1PO; thyroid peroxidase, TPOX; tyrosine hydroxylase, TH01;
      coagulation factor XIII a subunit, F13A01; c-fes/fps proto-oncogene, FESFPS and
      von Willebrand factor, vWA) in the Japanese macaque, Macaca fuscata, using
      commercially available human STR kits. No products were amplified by polymerase
      chain reaction (PCR) using the human CSF1PO, TH01, FESFPS and vWA primers.
      Macaque DNAs were amplified with human TPOX and F13A01 primers. Macaque PCR
      products amplified with the TPOX and F13A01 primers migrated more slowly than
      human ones during electrophoresis. Sequencing results showed that the nucleotide
      sequences of the counterpart of the TPOX and F13A01 STR loci in the Japanese
      macaque were closely similar to those of the human genes except for tandem repeat
      regions. The macaque products amplified with human TPOX and F13A01 primers were
      highly polymorphic, with four variants of the former and 15 variants of the
      latter in the nine samples. These results indicate that the commercially
      available kits can be used to discriminate the Japanese macaque samples from
      human samples.

PMID- 15039054
TI  - The levels of kerosene components in biological samples after repeated dermal
      exposure to kerosene in rats.
AB  - The current study was experimentally investigated using rats whether or not
      kerosene components are accumulated from daily repeated dermal exposure. Rats
      received daily 1h-exposure to kerosene for 5 days (5K), daily 1h-exposure for 4
      days and left for 1 day (4KL), a single 1h-exposure (1K), a single 1h-exposure
      and left for 1 day (1KL), or a single 1h-exposure, sacrificed and left dead for 1
      day (1KLD). Kerosene components, trimethylbenzenes (TMBs) and aliphatic
      hydrocarbons (AHCs) in blood and tissues were determined by GC-MS. In blood,
      almost the same concentrations of TMBs were detected in the rats sacrificed
      immediately after exposure (5K, 1K and 1KLD), and only trace levels were detected
      in the rats sacrificed 1 day after exposure (4 and 1KL). Almost the same levels
      of AHCs in blood were detected among groups except for the rats sacrificed 1 day
      after a single exposure (1KL), in which AHCs were slightly lower. These results
      suggest that (1) AHCs tend to be accumulated from daily exposure, while TMBs do
      not, (2) the proportions of detected kerosene components in blood can be an
      indicator of whether the last exposure occurred just before death or not, (3) the
      kerosene levels last at least 1 day without blood circulation.

PMID- 15039055
TI  - Changes of the cerebral mannitol concentrations in the course of brain death of a
      rodent model.
AB  - Determining the time of brain death is one of the critical issues in forensic
      examinations. Few authors have attempted to determine the time of brain death
      using pharmacokinetic approaches. We investigated cerebral concentrations of
      mannitol of which a single dose (1 g/kg) was administered in the course of brain
      death. The inflation of an epidural balloon was adopted as a rodent model of
      brain death. Brain death was determined using ordinary tests. Specimens were
      collected 4 h after brain death. Brain water content was higher in brain dead
      (BD) groups than those in control groups. Cerebral concentrations of mannitol in
      the BD group were significantly higher than those in the control group (P<0.01).
      In all areas of brain the concentration was the highest at the time when mannitol
      was administered during balloon inflation. Interhemispheric difference in the
      cerebrum was observed, followed by balloon inflation (P<0.05). Significant
      differences were observed in the average concentration of administered mannitol
      before and after brain death in the contralateral hemisphere (P<0.01) and in the
      brainstem (P<0.01). As the concentrations of mannitol in the brain are affected
      by cerebral trauma and brain death follows, mannitol can be used to determine the
      time of brain death at forensic examinations.

PMID- 15039056
TI  - The use of different multiplex PCRs for twin zygosity determination and its
      application in forensic trace analysis.
AB  - STR typing becomes more and more valuable for different approaches of science. It
      revolutionized determining of zygosity in twin research and it is very often the
      only possibility for discrimination in forensic trace analysis. In this study 55
      twin pairs from Denmark were genetically investigated to determine their
      zygosity. For analysis two multiplex PCR kits, the AmpFlSTR Identifiler kit,
      which comprises 15 loci plus the amelogenin gender determination and the
      Powerplex ES kit with eight different loci were employed. For a forensic approach
      every twin pair was regarded as being a forensic trace analysis, i.e. suspect or
      victim/biological trace and then we determined the security and precision with
      that a match of genetic patterns or an exclusion could be observed. Sixty percent
      of the twin pairs were di- and 40% monozygotic. There were no differences in
      zygosity determination between the two multiplex kits. The lowest number of
      exclusions by determining dizygosity was four loci for the Identifiler and three
      for Powerplex ES kit, the highest was 13 (Identifiler) and eight (Powerplex). It
      could be shown that the highly discriminative multiplex PCR kits gave matching
      probabilities of over 99.999999% (calculation based on data for unrelated
      individuals) even when only five or six STRs could be determined (assuming a
      trace analysis with some non-detectable STRs and therefore an incomplete genetic
      pattern). No questionable results regarding zygosity of the twin pairs were
      obtained even when only eight loci (using the Powerplex ES kit) were
      investigated. The simulated forensic results showed that matching probabilities
      should always be handled with care to not possibly come to wrong conclusions
      concerning the origin of the biological trace.

PMID- 15039057
TI  - Simulating irradiation power density on body surface in postmortem cooling.
AB  - Irradiation poses a major problem to determining the time since death by
      temperature-based methods. Neither empirical nor heat-flow postmortem cooling
      models have so far been able to assess irradiation. Heat-flow models seem overall
      better suited to calculate irradiation because of their direct relation to the
      physics of heat transfer. An implementation of irradiation boundary conditions in
      heat-transfer models requires the knowledge of the irradiation power density on
      the body surface. The present study develops formulae and implements them in a
      computer program to simulate the radiation power density on a semi-cylindrical
      body surface coming from irradiation by a rectangular radiant heater nearby or
      from the sun. The formulae are valid for deliberate geometrical arrangements of
      either body and radiant heater or body and sun. In case of the radiant heater
      scenario shading functions for the shading of the semi-cylinder by itself and by
      the rear panel of the radiant heater are developed. In case of the sun scenario
      only the shading by the semi-cylinder is relevant. In examplary analyses of
      typical irradiation scenarios the power density coming from a 2000W radiant
      heater nearby on the body surface amounted to a maximum of 418W/m2, the radiation
      power density originating from sunlight on a clear summer afternoon in middle
      Europe amounted to a maximum of 422W/m2.

PMID- 15039058
TI  - Skeletal maturation and ethnicity.

PMID- 15039059
TI  - Refolding and purification of unprocessed porcine myostatin expressed in
      Escherichia coli.
AB  - Myostatin is a member of the transforming growth factor-beta (TGF-beta)
      superfamily, and it acts as a negative regulator for skeletal muscle growth. Like
      many other TGF-beta family member proteins, the mature form of myostatin is a
      homodimer that is processed post-translationally from a precursor form of
      myostatin. Since the presence of a prodomain is essential for proper folding and
      homodimer assembly for some members of the TGF-beta superfamily, we compared the
      refolding in vitro of porcine unprocessed and mature myostatin over-expressed in
      Escherichia coli as inclusion bodies. A high alkaline buffer solution containing
      a mild anionic detergent and a reducing agent was used to solubilize the
      myostatin inclusion bodies. An optimal condition for refolding was obtained by
      rapid dilution of the solubilized protein in a buffer system containing reduced
      and oxidized glutathione, and subsequent incubation at 4 degrees C for at least 7
      days. The unprocessed porcine myostatin demonstrated reversible disulfide bond
      formation after refolding, a characteristic of the native form of myostatin. In
      contrast, the mature myostatin formed aggregates that did not demonstrate
      reversible disulfide bond formation in the refolding condition used in this
      study. These results demonstrate the importance of the myostatin prodomain in
      facilitating the proper folding of mature myostatin. Reaction of the refolded,
      unprocessed myostatin with furin, an endopeptidase cleaving between paired basic
      residues, yielded prodomain and mature myostatin, demonstrating that the
      unprocessed myostatin is a substrate for furin. The prodomain did not form
      disulfide bond formation but the mature myostatin demonstrated reversible
      disulfide-linked homodimer formation. It is concluded that myostatin prodomain
      facilitates the proper folding of myostatin, and the refolded, native form of
      unprocessed myostatin could be obtained in high yield (15%) after E. coli
      expression as inclusion bodies.

PMID- 15039060
TI  - High-level synthesis of recombinant murine endostatin in Chinese hamster ovary
      cells.
AB  - Endostatin, a carboxy-terminal fragment of collagen XVIII, has been shown to act
      as an anti-angiogenic agent that specifically inhibits proliferation of
      endothelial cells and growth of various primary tumors. Here, we describe the
      expression by Chinese hamster ovary (CHO) cells of murine endostatin and of a
      tagged-fusion protein, (his)6-met-endostatin. A dicistronic mRNA expression
      vector was utilized in which endostatin cDNA was inserted upstream of the
      amplifiable marker gene, dihydrofolate reductase (DHFR). After transfection of
      the expression vectors, stepwise increments in methotrexate levels in the culture
      medium were applied, promoting gene amplification and increasing expression
      levels of the proteins of interest. The expression level of secreted native
      endostatin was about 78 microg/mL while the one for secreted (his)6-met
      endostatin was about 114 microg/mL, for the best expressing clones.
      Characterization of physico-chemical and immunological activities of the proteins
      was performed using SDS-PAGE and Western blotting. The biological activities of
      recombinant endostatins were tested with a cow pulmonary artery endothelial (C
      PAE) cell proliferation assay. Both recombinant endostatin and (his)6-met
      endostatin inhibited, in a dose-dependent fashion, growth of C-PAE cells
      stimulated by basic fibroblast growth factor (bFGF).

PMID- 15039061
TI  - Expression cloned cDNA for 10-deacetylbaccatin III-10-O-acetyltransferase in
      Escherichia coli: a comparative study of three fusion systems.
AB  - 10-Deacetylbaccatin III-10-O-acetyltransferase (10-DABT) catalyzes the formation
      of baccatin III, which is an immediate diterpenoid precursor of Taxol. A cDNA
      encoding 10-DABT was cloned from Taxus baccata by using RT-PCR and screening a
      cDNA library. A study of its heterologous overexpression in Escherichia coli was
      carried out. To get high-level expression of recombinant enzyme, three kinds of
      IPTG inducible fusion expression systems (with glutathione S-transferase (GST),
      hexahistidine (6x His), and biotinylated tag) were used, and results of
      expression were compared. Fusion 10-DABT with different tags was expressed with
      diverse expression levels and solubility in the three systems. Optimum IPTG
      concentration, temperature, and inducing time for producing recombinant enzymes
      were found. Under higher IPTG concentration (up to 1 mM), the highest level of
      expression for fusion protein was obtained in the 6x His fusion system with phage
      T5 promoter, but expressed products were only partially soluble. With lower IPTG
      concentration (less than 0.5 mM), the highest expression was detected in the GST
      fusion system with tac promoter, and the lowest level of expression appeared in
      the biotinylated fusion system. The expression level in the latter system did not
      differ dramatically with a range of different inducer concentrations. GST and 6x
      His fusion proteins were mainly soluble in aqueous solutions and Triton X-100
      improved the solubility of biotinylated fusion proteins (inferring this protein
      is membrane-associated). Fusion proteins could only be partially purified by a
      single affinity chromatography step for all three systems. Glutathione-coupled
      matrix and streptavidin-conjugated resin have higher specificity than Ni-NTA
      resin, and elution conditions were shown to affect enzyme activity. Three kinds
      of recombinant 10-DABT with different tags showed enzyme activity, but total
      enzyme activity was lost as a result of the affinity chromatography step.
      Thrombin and Factor Xa could be used for site-specific cleavage of fusion
      proteins, but the incubation temperature affected enzyme activity of recombinant
      enzymes.

PMID- 15039062
TI  - Bioactive recombinant neuregulin-1, -2, and -3 expressed in Escherichia coli.
AB  - The neuregulins (NRGs) are a family of signaling proteins that are ligands for
      receptor tyrosine kinase of the ErbB family (namely ErbB3 and ErbB4). To date,
      four different neuregulin genes have been identified (neuregulin1-4). While NRG1
      isoforms have been extensively studied, little is yet known about the other genes
      of the family. We report the expression of recombinant NRG1beta1, NRG2alpha,
      NRG2beta, and NRG3 as recombinant fusion proteins in Escherichia coli. The cDNA
      encoding for the EGF-like domain of each protein was cloned from the mouse
      olfactory bulb and inserted into the pET-19b vector allowing for bacterial
      expression of the protein fused to an N-terminal His tag. The recombinant NRGs
      expressed in the inclusion bodies were solubilized under denaturing conditions,
      purified by affinity chromatography, and refolded via dialysis in the presence of
      reducing agents. Purified recombinant NRGs were active as they bound to their
      receptors and induced their phosphorylation. In particular, and in agreement with
      data on the native proteins, all the molecules were able to bind and activate
      ErbB4 while only the rNRG1 and the two rNRG2 (but not rNRG3) bound ErbB3.

PMID- 15039063
TI  - Higher activity of recombinant bovine deoxyhypusine synthase vs. human
      deoxyhypusine synthase.
AB  - Mature eukaryotic initiation factor 5A (eIF5A) is the only known protein in
      eukaryotic cells that contains the unusual amino acid hypusine (Nepsilon-(4-amino
      2(R)-hydroxybutyl)lysine). The synthesis of hypusine is essential for the
      function of eIF5A in eukaryotic cell proliferation and survival. Deoxyhypusine
      synthase is the first of the two enzymes that catalyzes the maturation of eIF5A.
      We have subcloned the cDNA encoding bovine and human deoxyhypusine synthase into
      a pET-11a expression vector, separately. T7-tagged bovine and human deoxyhypusine
      synthase have been overexpressed in Escherichia coli and purified to homogeneity
      using T7 antibody affinity chromatography. Activities of the enzyme from both
      human and bovine have been measured by their ability to convert the eIF5A
      precursor protein to the intermediate, deoxyhypusine form of eIF5A. Our results
      have shown that bovine deoxyhypusine synthase has considerably higher activity
      than human deoxyhypusine synthase in catalyzing the synthesis of deoxyhypusine.

PMID- 15039064
TI  - Optimized expression and refolding of human keratoepithelin in BL21 (DE3).
AB  - Keratoepithelin (KE) is an extracellular protein participating in cell adhesion
      and differentiation. Mutations of the KE gene (on 5q31 in humans) cause
      deposition of abnormal proteins (amyloid and non-amyloid) in corneal stroma and
      lead to several corneal dystrophies in humans. However, further studies on the KE
      protein have been limited by the intrinsic difficulty of purifying this protein.
      A high-expression plasmid containing human KE gene was constructed to generate
      recombinant KE proteins in Escherichia coli. The plasmid was transformed into E.
      coli BL21 (DE3) and the recombinant protein was expressed as an insoluble His
      tagged fusion protein and purified by nickel chelation affinity chromatography
      under denaturing conditions. On average, 12 mg of purified KE was routinely
      obtained from 1L of culture media. The recombinant KE was refolded in arginine
      containing dialysis solutions and the recovery of bioactive KE typically was
      approximately 70%. The procedures developed in this report should enable
      reproducible production of KE and related mutant proteins in large quantities and
      facilitate future studies on biochemical and biophysical properties of KE and the
      pathogenesis of related corneal dystrophies.

PMID- 15039065
TI  - Cloning, expression, and characterization of uracil-DNA glycosylase of Chlamydia
      pneumoniae in Escherichia coli.
AB  - A uracil-DNA glycosylase gene was cloned from Chlamydia pneumoniae AR39 and
      expressed in E. coli strains BL21 (DE3) and BL21 (DE3) pLysS. After purification
      by Ni-NTA His x Bind Resin and DEAE Sepharose Fast Flow column chromatography,
      recombinant CpUDG with a specific activity of 1,000,000 U/mg was obtained. The
      enzymatic activity of the purified CpUDG protein was further characterized using
      oligodeoxyribonucleotides carrying uracil bases as substrates. The base opposite
      to uracil in double strand DNAs affected uracil removal efficiencies in the
      order: U/- > U/T > U/C > U/G > U/A. Free uracil and abasic sites (AP site) could
      inhibit the reaction. The optimal temperature and pH for uracil removal by CpUDG
      were 37 degrees C and pH 8.0, respectively. Site-directed mutagenesis studies
      indicated that amino acids D77, H200, and A205 were important for the catalytic
      activity of CpUDG. Together, these data suggest that CpUDG is a member of the UDG
      family-I protein. This is the first report on cloning, expression, and
      characterization of Chlamydia uracil-DNA glycosylase.

PMID- 15039066
TI  - Comparative analysis of GFP(UV)-beta1,3-N-acetylglucosaminyltransferase 2
      production in two insect-cell-based expression systems.
AB  - Active beta1,3-N-acetylglucosaminyltransferase 2 (beta3GnT2) was produced in the
      baculovirus expression system (BES) and in stably transformed insect Tn-5B1-4
      cells. beta3GnT2 was expressed as a secreted fusion protein with GFP(UV) with
      three different types of signal sequence to enhance the secretion of the fusion
      protein. In the stably transformed cells, the maximal beta3GnT2 activity differed
      between isolates, but their secretion efficiencies were similar. The difference
      between the maximal beta3GnT activities of the isolates studied was considered to
      be due to the presence of a copy number of the fusion gene, as determined on the
      basis of the results of Southern blot analysis. The beta3GnT activities of the
      culture supernatant in BES (Tn-5B1-4 cells) without or with the addition of the
      protease inhibitor, leupeptin, were 0.68 and 2.01 mU/ml, respectively. The stably
      transformed Tn-5B1-4 cells (Tn-pXme11) exhibited a beta3GnT activity of 6.83
      mU/ml, which was 3.4-fold higher than that observed for BES with the leupeptin
      addition. The purity of fusion protein purified from the culture supernatant of
      the Tn-pXme11 was higher than 95% on SDS-PAGE, in contrast with that purified
      from the culture supernatant of the baculovirus-infected cells which contained
      low-molecular-weight fragments of the fusion protein. The stably transformed cell
      line is more suitable than BES for the efficient production of the secretory
      protein, beta3GnT2.

PMID- 15039067
TI  - Expression of the murine leukemia virus protease in fusion with maltose-binding
      protein in Escherichia coli.
AB  - The protease of murine leukemia virus (MLV) was cloned into pMal-c2 vector,
      expressed in fusion with maltose-binding protein (MBP), and purified to
      homogeneity after Factor Xa cleavage of the chimeric protein. Substantial
      degradation of the fusion protein was observed during expression, which severely
      diminished the yield. The degree of degradation of the fusion protein was even
      more pronounced when a single-chain form of the MLV protease was cloned after the
      gene coding for MBP. To increase the yield, a hexahistidine tag with an
      additional Factor Xa cleavage site was cloned after the protease and nickel
      chelate affinity chromatography was used as the first purification step. The
      modified procedure resulted in substantially higher yield as compared to the
      original procedure. The degradation of hexahistidine-tagged active site mutant
      MLV protease was very low and comparable to that obtained with hexahistidine
      tagged MBP, but purified MLV protease alone was not able to degrade purified MBP,
      suggesting that during expression the active MLV protease may activate bacterial
      proteases which appear to be responsible for the degradation of the fusion
      proteins.

PMID- 15039069
TI  - System for the expression of recombinant hemoproteins in Escherichia coli.
AB  - Expression of recombinant hemoproteins in Escherichia coli is often limited
      because a vast majority of the protein produced lacks the heme necessary for
      function. This is compounded by the fact that standard laboratory strains of E.
      coli have a limited capacity to withdraw heme from the extracellular environment.
      We are developing a new tool designed to increase the heme content of our
      proteins of interest by simply supplementing the expression medium with low
      concentrations of hemin. This hemoprotein expression (HPEX) system is based on
      plasmids (pHPEX1-pHPEX3) that encode an outermembrane-bound heme receptor (ChuA)
      from E. coli O157:H7. This heme receptor, and others like it, confers on the host
      the ability to more effectively internalize exogenous heme. Transformation of a
      standard laboratory E. coli protein expression strain (BL-21 [DE3]) with the
      pHPEX plasmid led to the expression of a new protein with the appropriate
      molecular weight for ChuA. The receptor was functional as demonstrated by the
      ability of the transformant to grow on iron-deficient media supplemented with
      hemin, an ability that the unmodified expression strain lacked. Expression of our
      proteins of interest, catalase-peroxidases, using this system led to a dramatic
      and parallel increase in heme content and activity. On a per-heme basis, the
      spectral and kinetic properties of HPEX-derived catalase-peroxidase were the same
      as those observed for catalase-peroxidases expressed in standard E. coli-based
      systems. We suggest that the pHPEX plasmids may be a useful addition to other E.
      coli expression systems and may help address a broad range of problems in
      hemoprotein structure and function.

PMID- 15039068
TI  - Improved production of recombinant tumstatin in stably transformed Trichoplusia
      ni BTI Tn 5B1-4 cells.
AB  - We describe the expression and in vitro activity of recombinant tumstatin from
      stably transformed Trichoplusia ni BTI Tn 5B1-4 cells. Recombinant tumstatin was
      secreted into a culture medium with a molecular weight of 29 kDa. Recombinant
      tumstatin was also purified to homogeneity using a simple one-step Ni2+ affinity
      fractionation. Purified recombinant tumstatin inhibited endothelial cell
      proliferation in a dose-dependent manner. The concentration at half-maximum
      inhibition (ED50) for recombinant tumstatin expressed in stably transformed Tn
      5B1-4 cells was approximately 0.76 microg/ml. A maximum production level of 4.0
      mg/l recombinant tumstatin was obtained in a T-flask culture of Tn 5B1-4 cells, 6
      days after cultivation. We also investigated the individual effects of both
      dimethyl sulfoxide (DMSO) and sodium butyrate on recombinant tumstatin production
      in stably transformed Tn 5B1-4 cells. Supplementing cultures with DMSO and sodium
      butyrate separately increased recombinant tumstatin production in stably
      transformed Tn 5B1-4 cells by 117 and 32%, respectively.

PMID- 15039070
TI  - Cloning, expression, and characterization of single-chain variable fragment
      antibody against mycotoxin deoxynivalenol in recombinant Escherichia coli.
AB  - Deoxynivalenol (DON), a mycotoxin produced by several Fusarium species, is a
      worldwide contaminant of food and feedstuffs. The DON-specific single-chain
      variable fragment (scFv) antibody was produced in recombinant Escherichia coli.
      The variable regions of the heavy chain (V(H)) and light chain (V(L)) cloned from
      the hybridoma 3G7 were connected with a flexible linker using an overlap
      extension polymerase chain reaction. Nucleotide sequence analysis revealed that
      the anti-DON V(H) was a member of the V(H) III gene family IA subgroup and the
      V(L) gene belonged to the Vlambda gene family II subgroup. Extensive efforts to
      express the functional scFv antibody in E. coli have been made by using gene
      fusion and chaperone coexpression. Coexpression of the molecular chaperones (DnaK
      DnaJ-GrpE) allowed soluble expression of the scFv. The scFv antibody fused with
      hexahistidine residues at the C-terminus was purified by immobilized metal
      affinity chromatography (IMAC). Soluble scFv antibody produced in this manner was
      characterized for its antigen-binding characteristics. Its biological affinity as
      antibody was measured by surface plasmon resonance (SPR) analysis and proved to
      be significant but weaker than that of the whole anti-DON mAb.

PMID- 15039071
TI  - Expression of LEKTI domains 6-9' in the baculovirus expression system:
      recombinant LEKTI domains 6-9' inhibit trypsin and subtilisin A.
AB  - The precursor lympho-epithelial Kazal-type-related inhibitor (LEKTI), containing
      two Kazal-type and 13 nonKazal-type domains, is an efficient inhibitor of
      multiple serine proteinases, among them plasmin, subtilisin A, cathepsin G,
      elastase, and trypsin. To gain insight into the structure and function of some of
      these domains, a portion of the cDNA coding for LEKTI domains 6-9' was cloned and
      expressed in Sf9 cells using the baculovirus expression vector system (BEVS).
      Through a single purification step using a Co2+ column, 3-4 mg of purified
      recombinant LEKTI-domains 6-9' (rLEKTI6-9') with the predicted molecular mass of
      34.6 kDa was obtained from the cell pellet of a 1-L culture. Unlike full-length
      LEKTI, rLEKTI6-9' inhibited trypsin and subtilisin A but not plasmin, cathepsin
      G, or elastase. The inhibition of trypsin and subtilisin A by rLEKTI6-9' occurred
      through a noncompetitive mechanism, with inhibitory constants (Ki) of 356 +/- 12
      and 193 +/- 10 nM, respectively. On the basis of the Ki values, rLEKTI6-9' was
      determined to be a more potent trypsin inhibitor and a less potent subtilisin A
      inhibitor than the full-length LEKTI. In contrast to LEKTI domains 6-9',
      recombinant LEKTI domain 6 does not inhibit subtilisin A but competitively
      inhibited trypsin with a Ki of 200 +/- 10 nM. Taking LEKTI6-9' as an example, the
      BEVS should facilitate the structure-function analysis of naturally occurring
      processed LEKTI forms that have physiological relevance.

PMID- 15039072
TI  - Expression and activity of the nucleotide-binding domains of the human ABCA1
      transporter.
AB  - The aim of this study was the expression and production in Escherichia coli of
      the nucleotide-binding domains (NBDs) of the human ABCA1 transporter, in a
      soluble, non-denatured form. To increase the protein solubility, and avoid
      expression in E. coli inclusion bodies, we extended the length of the expressed
      NBD domains, to include proximal domains. The corresponding cDNA constructs were
      used to express the N-terminal His-tagged WT and mutant proteins, which were
      purified by Ni(2+)-affinity chromatography. Optimal expression of soluble
      proteins was obtained for constructs including the NBD, the downstream 80-residue
      domain, and about 20 upstream residues. The size homogeneity of WT and mutant
      NBDs was determined by Dynamic Light Scattering, and ATP-binding constants and
      ATPase activities were measured. The NBD1 and NBD2 domains bound ATP with
      comparable affinity. The ATPase activity of WT His-NBD1 was about three times
      higher than that of NBD2 and amounted to 5913 compared to 1979 nmol Pi/micromol
      NBD/min for WT His-NBD2. All engineered mutants had comparable ATPase activity to
      the corresponding WT protein. The optimisation of the length of the expressed
      proteins, based upon the boundary prediction of NBDs and neighbour domains,
      enables the expression and purification of soluble ABCA1 NBDs, with high ATPase
      activity. This approach should prove useful for the study of the structural and
      functional properties of the NBDs and other domains of the ABC transporters.

PMID- 15039073
TI  - Purification and characterization of two recombinant human glucuronyltransferases
      involved in the biosynthesis of HNK-1 carbohydrate in Escherichia coli.
AB  - Two glucuronyltransferases (GlcAT-P and GlcAT-S) are involved in the biosynthesis
      of HNK-1 carbohydrate, which is spatially and temporally regulated in the nervous
      system. To clarify the enzymatic properties of the respective
      glucuronyltransferases, we established an expression system for producing large
      amounts of soluble forms of flag-tagged human GlcAT-P and GlcAT-S in Escherichia
      coli. Approximately 15 and 6 mg of enzymatically active flag-GlcAT-P and flag
      GlcAT-S were purified from E. coli cells in 5 liters of culture medium,
      respectively. These recombinant enzymes transferred GlcA to a glycoprotein
      acceptor, asialo-orosomucoid (ASOR), as well as a glycolipid acceptor,
      paragloboside. The specific activity of the recombinant GlcAT-P (1100
      nmol/min/mg) toward a glycoprotein acceptor, ASOR, was comparable to that of the
      enzyme (4300 nmol/min/mg) purified from rat brain. Phosphatidylinositol (PI) is
      specifically required for expression of the activity of the recombinant enzymes
      toward a glycolipid acceptor, paragloboside. The recombinant GlcAT-P was highly
      specific for the terminal type II structure, Galbeta1-4GlcNAc, while the
      recombinant GlcAT-S recognized not only the type II structure, Galbeta1-4GlcNAc,
      but also the type I structure, Galbeta1-3GlcNAc. These acceptor specificities
      were similar to those of the native enzymes.

PMID- 15039074
TI  - Purification of the Porcine rubulavirus attachment protein by liquid isoelectric
      focusing.
AB  - Porcine rubulavirus (PoRV) is an emerging virus responsible for
      meningoencephalitis, respiratory distress, and reproductive alterations in pigs.
      The hemagglutinin-neuraminidase (HN) glycoprotein is the most exposed and
      antigenic of the virus proteins. HN plays central roles in PoRV infection; i.e.,
      it recognizes sialic acid-containing cell receptors that mediate virus attachment
      and penetration; in addition, its neuraminidase (sialic acid hydrolysis) activity
      has been proposed to be a virulence factor. So, HN is an ideal target for
      therapeutic treatment and prevention of this viral infection. This work describes
      a simple, fast, and sensitive method to purify the active form of HN protein
      based on its isoelectric point. HN was purified at a pH of 4.4, at which a single
      protein band of 66 kDa was observed on SDS-PAGE. Pure HN showed a maximal
      enzymatic activity at pH 3.5 and 37 degrees C using bovine fetuin as substrate.
      However, it retains circa 80% of its activity at a wide temperature range from 30
      to 55 degrees C. We also describe improvements of neuraminidase determination
      method, which permits analysis in a microplate spectrophotometer, thereby
      increasing the sensitivity and reducing the costs of valuable reagents and
      biological samples.

PMID- 15039075
TI  - Expression and purification of wild type and mutant forms of the yeast
      mitochondrial core RNA polymerase, Rpo41.
AB  - The mitochondrial RNA polymerase (mtRNAP) from Saccharomyces cerevisiae (yeast)
      is composed of two nuclear encoded proteins, the core RNA polymerase (Rpo41) and
      the mitochondrial transcription factor (Mtf1). Although Rpo41 is strikingly
      similar to the single subunit RNAPs from the T7 and T3 bacteriophage (T7RNAP),
      the core mtRNAP requires Mtf1 for accurate transcription from a linear promoter
      containing DNA template, while T7RNAP does not require any other additional
      factors for promoter selectivity. The fact that the mtRNAP requires an additional
      promoter utilization factor makes it an excellent model system for the analysis
      of the transitions that occur during transcription initiation. However, large
      scale purification of the 153 kDa Rpo41 has only been reported from yeast cells,
      or as a recombinant from baculovirus, both sources requiring extensive
      purification with poor yields. We have developed a His-tagged Rpo41 expression
      construct suitable for rapid purification of large amounts of soluble Rpo41 from
      bacterial cells. Transcriptionally active forms of both wild type and point
      mutants of Rpo41 can be purified by a combination of batch ion exchange
      chromatography to remove nucleic acids and nickel affinity chromatography. An
      additional advantage of the isolation of Rpo41 from bacterial cells is the
      absence of its associated specificity factor Mtf1. This allows analysis of
      combinations of mutant forms of both components of the mtRNAP holoenzyme.

PMID- 15039076
TI  - Evidence for a new metal in a known active site: purification and
      characterization of an iron-containing quercetin 2,3-dioxygenase from Bacillus
      subtilis.
AB  - The protein YxaG from Bacillus subtilis, of previously unknown function, was
      found to have quercetin 2,3-dioxygenase activity when overexpressed in
      Escherichia coli. The enzyme converts the flavonol quercetin to 2
      protocatechuoylphloroglucinol carboxylic acid and carbon monoxide, indicating
      that it performs the same reaction and yields the same products as the well
      characterized copper-containing quercetin 2,3-dioxygenase from Aspergillus. In
      contrast to the Aspergillus protein, YxaG contains iron, and the enzyme is
      sensitive to strong Fe(II) chelators, similar to the extensively studied catechol
      dioxygenases. The active site metal was probed by EPR spectroscopy using the
      label nitric oxide to confirm the presence of an Fe(II) atom. The kinetic
      parameters and pH activity profiles are also markedly different from those of the
      copper-containing quercetin 2,3-dioxygenases from Aspergillus. YxaG represents
      the first example of a prokaryotic quercetin 2,3-dioxygenase.

PMID- 15039077
TI  - Purification and characterization of human prolyl dipeptidase DPP8 in Sf9 insect
      cells.
AB  - DPP8 is a new member of the prolyl dipeptidases, many of which have important
      biological functions in vivo. DPP8 catalyzes the cleavage at the carboxyl side of
      the proline residue at the penultimate position. To study its structure and
      biochemical properties, we have overexpressed the human DPP8 protein in
      baculovirus infected Sf9 cells. The protein is soluble and can be purified to
      homogeneity. Using the chromogenic H-Gly-Pro-pNA as the substrate, a kinetic
      study shows that purified DPP8 is active and has a similar kcat value as that of
      DPP-IV, a prolyl dipeptidase that is a drug target for type II diabetes. The
      kinetic constants of DPP8 are also determined for other chromogenic substrates,
      and the results indicate that DPP8 has substrate preference at both the P1 and P2
      sites. The expression system provides means of better understanding the
      structure, catalytic mechanism, and biological function of DPP8 protein.

PMID- 15039078
TI  - An epitope tag derived from human transcription factor IIB that reacts with a
      polyol-responsive monoclonal antibody.
AB  - Polyol-responsive monoclonal antibodies (PR-mAbs) provide a strategy to purify
      active, nondenatured proteins by a single-step immunoaffinity chromatography
      procedure. The high affinity interaction between these antibodies and the antigen
      can be dissociated in the presence of a nonchaotropic salt and a low molecular
      weight polyhydroxylated compound (polyol). The epitope for PR-mAb IIB8 is located
      near the N-terminus of the human transcription factor IIB (TFIIB). The epitope is
      an eight amino acid sequence, TKDPSRVG, that can be fused to a desired protein
      for use as a purification tag. This epitope tag (termed hIIB) was fused to the C
      terminus of green fluorescent protein (GFP). An additional GFP fusion protein
      utilized another version of hIIB containing a point mutation at position two.
      These fusion proteins, expressed in Escherichia coli, allowed successful
      separation of the desired protein in a single chromatographic step. This strategy
      extends PR-mAb gentle-release purification to numerous expressed proteins.

PMID- 15039080
TI  - In vitro analysis of chromatin structure in model systems.

PMID- 15039079
TI  - Characterization of the cAMP-dependent protein kinase catalytic subunit Cgamma
      expressed and purified from sf9 cells.
AB  - The Cgamma and Calpha subunits of the cAMP-dependent protein kinase (PKA) contain
      350 amino acids that are highly homologous (83% amino acid sequence), with 91%
      homology within the catalytic domain (a.a. 40-300). Unlike Cgamma, the Calpha
      subunit has been readily purified and characterized as a recombinant protein in
      vitro, in intact cells, and in vivo. This report describes for the first time the
      expression, purification, and characterization of Cgamma. The expression of
      active Cgamma was eukaryote-specific, from mammalian and insect cells, but not
      bacteria. Active recombinant Cgamma was optimally expressed and purified to
      homogeneity from Sf9 cells with a 273-fold increase in specific activity and a
      21% recovery after sequential CM-Sepharose and Sephacryl S-300 chromatography.
      The specific activity of pure Cgamma was 0.31 and 0.81 U/mg with kemptide and
      histone as substrates, respectively. Physical characterization showed Cgamma had
      a lower apparent molecular weight and Stokes radii than Calpha, suggesting
      differences in tertiary structures. Steady-state kinetics demonstrated that like
      Calpha and Cbeta, Cgamma phosphorylates substrates requiring basic amino acids at
      P-3 and P-2. However, Cgamma generally exhibited a lower Km and Vmax than Calpha
      for peptide substrates tested. Cgamma also exhibited a distinct pseudosubstrate
      specificity showing inhibition by homogeneous preparations of RIalpha and
      RIIalpha-subunits, but not by pure recombinant protein kinase inhibitors PKIalpha
      and PKIbeta, PKA-specific inhibitors. These studies suggest that Cgamma and
      Calpha exhibit differences in structure and function in vitro, supporting the
      hypothesis that functionally different C-subunit isozymes could diversify and/or
      fine-tune cAMP signal transduction downstream of PKA activation.

PMID- 15039081
TI  - Expression and purification of recombinant human histones.
AB  - Nucleosomes reconstituted from bacterially expressed histones are useful for
      functional and structural analyses of histone variants, histone mutants, and
      histone post-translational modifications. In the present study, we developed a
      new method for the expression and purification of recombinant human histones. The
      human histone H2A, H2B, and H3 genes were expressed well in Escherichia coli
      cells, but the human histone H4 gene was poorly expressed. Therefore, we designed
      a new histone H4 gene with codons optimized for the E. coli expression system and
      constructed the H4 gene by chemically synthesized oligodeoxyribonucleotides. The
      recombinant human histones were expressed as hexahistidine-tagged proteins and
      were purified by one-step chromatography with nickel-nitrilotriacetic acid
      agarose in the presence of 6 M urea. The H2A/H2B dimer and the H3/H4 tetramer
      were refolded by dialysis against buffer without urea, and the hexahistidine-tags
      of the histones in the H2A/H2B dimer and the H3/H4 tetramer were removed by
      thrombin protease digestion. The H2A/H2B dimer and the H3/H4 tetramer obtained by
      this method were confirmed to be proficient in nucleosome formation by the salt
      dialysis method. The human CENP-A gene, the centromere-specific histone H3
      variant, contains 28 minor codons for E. coli. A new CENP-A gene optimized for
      the E. coli expression system was also constructed, and we found that the
      purified recombinant CENP-A protein formed a nucleosome-like structure with
      histones H2A, H2B, and H4.

PMID- 15039083
TI  - Construction, analysis, and transcription of model nucleosomal templates.
AB  - Transcription through the nucleosome by Saccharomyces cerevisiae RNA polymerase
      II (Pol II) is characterized by an almost absolute block to transcription at
      physiological ionic strength and displacement of one H2A/H2B dimer to form a
      hexasome [Mol. Cell 9 (2002) 541]. In previous studies of Pol II transcription
      through chromatin, templates containing nucleosomes in multiple positions were
      used. These templates do not allow detailed analysis of the mechanism of
      transcription through chromatin. Here, we describe the development of a new
      template that is only long enough to accommodate a single nucleosome position
      along the DNA so that all of the templates are identical and allow for more in
      depth analysis. After ligation of the nucleosome to promoter DNA or assembled
      elongation complexes, the mechanism of transcription through this uniquely
      positioned nucleosome by various RNA polymerases can be analyzed.

PMID- 15039082
TI  - Methods for chromatin assembly and remodeling.
AB  - Packaging of the DNA in nucleosomes restricts its accessibility to regulatory
      factors and enzymatic complexes, making a local remodeling of the nucleosome
      structure a prerequisite to the establishment of protein-DNA interactions. The
      use of an experimental system in which one nucleosome is reconstituted on a short
      linear DNA fragment allows gel fractionation of nucleosomes according to their
      translational positions, whose locations are dependent on the underlying DNA
      sequence. Nucleosome mobilization by chromatin remodeling factors is easily
      detected by observing band disappearance in gel, which in turn provides evidence
      for histone octamer displacement. Here, we provide methods for chromatin assembly
      that we have been using in our analysis for nucleosome mobilization by chromatin
      remodeling factors. These methods are straightforward and easy to follow. Thus,
      they may provide a good starting assay system for analysis of nucleosome
      movements by other chromatin remodeling machines.

PMID- 15039084
TI  - Large scale preparation of nucleosomes containing site-specifically chemically
      modified histones lacking the core histone tail domains.
AB  - The core histone tail domains are critical regulators of chromatin structure and
      function and modifications such as acetylation of lysine residues within the
      tails are central to this regulation. Studies have shown that the removal of core
      histone tail domains by trypsinization in which one-half to two-thirds of each
      core histone tail domain are removed in gross aspects mimics the acetylation of
      core histone tails. In addition, removal of the tails has been useful in
      understanding general tail function. Thus, removal of native core histone tails
      by trypsinization is a widely used method. In addition, many in vitro studies now
      employ core histones site-specifically modified with photo activatable cross
      linking probes or fluorescent probes. However, in our experience, standard
      methods employing trypsinized donor chromatin for reconstitution of nucleosomes
      containing certain chemically modified histones lacking the core histone tail
      domains are not uniformly applicable. Here, we describe various methods for
      preparing nucleosomes containing a core histone modified with a cross-linking
      agent, APB, and lacking the core histone tail domains.

PMID- 15039085
TI  - Measurement of histone-DNA interaction free energy in nucleosomes.
AB  - Nucleosome positioning DNA sequences are of increasing interest because of their
      proposed roles in gene regulation and other chromosome functions in vivo, and
      because they have revealed new insights into the sequence-dependent structures
      and mechanics of DNA itself. Here, we describe methods to quantify the relative
      affinities of histone-DNA interactions in nucleosomes, i.e., the nucleosome
      positioning power of differing DNA sequences. We review methods developed by
      others and then discuss in detail our own approach to measurement of histone-DNA
      interaction free energies. Compared to earlier methods, our dialysis-based
      approach reduces the possibility that non-equilibrium or irreproducible results
      could be obtained. It facilitates a direct comparison of free energies for many
      sequences at the same time and it allows analysis of DNAs having a wide range of
      relative affinities.

PMID- 15039086
TI  - In vitro analysis of histone acetyltransferase activity.
AB  - Interest in histone acetylation has risen dramatically in recent years. In the
      following report, we present methods for the analysis of histone
      acetyltransferase activity in vitro. Protocols are described for radiolabeling
      histone proteins and N-terminal "tail" peptides, and for the analysis of
      acetylation by immunoblotting. Techniques for acetylating immobilized histone
      peptides are also described.

PMID- 15039087
TI  - Understanding global changes in histone H1 phosphorylation using mass
      spectrometry.
AB  - Histone post-translational modifications have been implicated in a variety of
      biological processes such as gene expression, DNA replication, and chromatin
      assembly. The modifications include methylation, acetylation, phosphorylation,
      ubiquitination, glycosylation, and ADP-ribosylation. For several years, we have
      been investigating the role of histone H1 phosphorylation in transcription using
      the hormone inducible mouse mammary tumor virus (MMTV) promoter. When mouse cells
      were exposed to prolonged treatment with dexamethasone, a significant decrease in
      the level of histone H1 phosphorylation was observed. Traditionally, Western
      analyses with anti-histone H1 and phospho-specific H1 antibodies were performed
      to observe changes in phosphorylation levels of the bulk H1 histones. More
      recently, we have applied electrospray ionization mass spectrometry to the
      analysis of histone H1 isoforms. Utilizing this approach, we have investigated
      the phosphorylation state of the specific H1 isoforms before and after prolonged
      treatment with dexamethasone. Specifically, we could determine that the relative
      phosphorylation levels of the histone H1.3, H1.4, and H1.5 isoforms decrease
      after prolonged hormone exposure. Recent advancements in mass spectrometry have
      proven invaluable toward the analysis of post-translational modifications on
      proteins. The continued developments in the area of mass spectrometry should
      provide new insights into not only the function of proteins but also into the
      basic regulatory mechanisms that control cellular functions.

PMID- 15039088
TI  - Purification and nucleosome mapping analysis of native yeast plasmid chromatin.
AB  - There is much evidence indicating the importance in gene regulation of the
      positions of nucleosomes with respect to DNA sequence. Low resolution chromatin
      structures have been described for many genes, but there is a dearth of detailed
      high resolution chromatin structures. In the cases where they are available, high
      resolution maps have revealed much more complex chromatin structures, with
      multiple alternative nucleosome positions. The discovery that ATP-dependent
      chromatin remodelling machines are recruited to genes, with their ability to
      mobilise nucleosomes on DNA and to alter nucleosomal conformation, emphasises the
      necessity for obtaining high resolution nucleosome maps, so that the details of
      these remodelling reactions can be defined in vivo. Here, we describe protocols
      for purifying plasmid chromatin from cells of the yeast Saccharomyces cerevisiae
      and for mapping nucleosome positions on the plasmid using the monomer extension
      mapping method. This method requires purified chromatin, but is capable of
      mapping relatively long stretches of chromatin in great detail. Typically, it
      reveals very complex chromatin structures.

PMID- 15039090
TI  - Use of bifunctional cross-linking reagents in mapping genomic distribution of
      chromatin remodeling complexes.
AB  - Chromatin remodeling complexes consist of multiple subunits, some of which are in
      intimate contact with DNA while others are not. The ability to effectively cross
      link proteins to DNA with formaldehyde is impacted by the average distance
      between the two species. Productive cross-linking of proteins not in direct
      contact with DNA is greatly facilitated by the inclusion of an initial cross
      linking reaction using bifunctional imidoester cross-linking reagents.

PMID- 15039089
TI  - Mapping chromatin structure in vivo using DNA methyltransferases.
AB  - Cytosine-5 DNA methyltransferases (C5 DMTases) are effective reagents for
      analyzing chromatin and footprinting DNA-bound factors in vivo. Cytosine
      methylation in accessible regions is assayed positively by the PCR-based
      technique of bisulfite sequencing. In this article, we outline two complementary
      uses for the DNA methyltransferase CviPI (M.CviPI, GC specificity) in probing
      chromatin organization. First, we describe the use of the naturally occurring,
      free enzyme as a diffusible probe to map changes in nucleosome structure and to
      footprint factor interactions at cis-regulatory sequences. In a second
      application, termed targeted gene methylation (TAGM), the DMTase is targeted via
      in-frame fusion to a DNA-binding factor. The rapid accumulation of DNA
      methylation enables highly sensitive detection of factor binding. Both strategies
      can be applied with any C5 DMTase, such as M.SssI, which also possesses a short
      recognition specificity (CG). A description of methods for constructing C5 DMTase
      expressing strains of Saccharomyces cerevisiae and analyzing chromatin regions is
      provided. We also include comprehensive protocols for the isolation and bisulfite
      treatment of genomic DNA as well as the subsequent bisulfite sequencing steps.
      Data demonstrating the efficacy of both DMTase probing techniques, theoretical
      considerations, and experimental analyses are presented at GAL1 and PHO5.

PMID- 15039091
TI  - Analysis of chromatin assembled in vivo using exogenous histones in Physarum
      polycephalum.
AB  - Histones are involved in the regulation of almost all events within the
      eukaryotic cell nucleus that utilize DNA as a substrate. We have developed a
      novel approach for examining the function of histone proteins and specific
      domains of these proteins in these various nuclear processes, and in particular
      assembly of chromatin throughout the cell cycle. This approach exploits several
      unique characteristics of the slime mold Physarum polycephalum, including the
      natural synchrony of all (approximately 10(8)) nuclei throughout the cell cycle
      and the ability of this organism to take up exogenous proteins. Here, culture
      techniques and biochemical procedures for the incorporation of exogenous core
      histones into Physarum chromatin in vivo are described. The procedures for
      subsequent verification of the assembly of exogenous proteins into bona fide
      nucleosomes are also described.

PMID- 15039092
TI  - Identification of genomic groups in the genus Stenotrophomonas using gyrB RFLP
      analysis.
AB  - Stenotrophomonas maltophilia isolates have been recovered from various clinical
      samples, including the respiratory tract of cystic fibrosis (CF) patients, but
      this organism is also widespread in nature. Previously it has been shown that
      there is a considerable genomic diversity within S. maltophilia. The aims of our
      study were to determine the taxonomic resolution of restriction fragment length
      polymorphism (RFLP) analysis of the polymerase chain reaction-amplified gyrB gene
      for the genus Stenotrophomonas. Subsequently, we wanted to use this technique to
      screen a set of S. maltophilia isolates (with emphasis on a specific subset,
      isolates recovered from CF patients), to assess the genomic diversity within this
      group. In this study we investigated 191 Stenotrophomonas sp. isolates (including
      40 isolates recovered from CF patients) by means of gyrB RFLP. The taxonomic
      resolution of gyrB RFLP, and hence its potential as an identification tool, was
      confirmed by comparison with results from published and novel DNA-DNA
      hybridisation experiments. Our data also indicate that the majority of CF
      isolates grouped in two clusters. This may indicate that isolates from specific
      genomic groups have an increased potential for colonisation of the respiratory
      tract of CF patients.

PMID- 15039093
TI  - Production of tumor necrosis factor alpha by Treponema pallidum, Borrelia
      burgdorferi s.l., and Leptospira interrogans in isolated rat Kupffer cells.
AB  - Stimulation of isolated rat Kupffer cells by viable Leptospira interrogans,
      Treponema pallidum and Borrelia garinii elicited cellular responses resulting in
      the release of different tumor necrosis factor alpha (TNF-alpha) levels,
      depending on the spirochetes. L. interrogans induced TNF-alpha levels higher than
      those achieved with B. garinii and T. pallidum (in this order), but lower than
      the levels achieved with lipopolysaccharide (LPS). In contrast to L. interrogans,
      pretreatment of borreliae and treponemes with polymyxin B did not substantially
      diminish the ability of B. garinii and T. pallidum to stimulate Kupffer cells.
      Purified T. pallidum lipoproteins TpN47, TmpA, TpN15-TpN17, and B. garinii OspA
      induced TNF-alpha responses comparable to that achieved by LPS. This response was
      almost insensitive to the action of polymyxin B.

PMID- 15039094
TI  - Effect of conjugation methodology on the immunogenicity and protective efficacy
      of meningococcal group C polysaccharide-P64k protein conjugates.
AB  - Neisseria meningitidis serogroup C polysaccharide (CCPS) was conjugated to the
      carrier protein P64k using two different conjugation procedures, condensation
      mediated by carbodiimide with adipic acid dihydrazide as spacer and the reductive
      amination method. BALB/c mice were immunized with the resultant polysaccharide
      protein conjugates and the immune response was evaluated. All conjugates assayed
      generated at least 10-fold higher antibody titers than the free polysaccharide.
      The reductive amination method rendered the best conjugate (CCPS-P64kR) that was
      able to elicit antibody titers statistically higher than the titer elicited by
      the plain CCPS (P<0.001). The sera of the group immunized with CCPS-P64kR showed
      a three-fold higher bactericidal response than the sera of the group immunized
      with the plain CCPS and they were able to protect against challenge with
      meningococci in the infant rat protection model. In addition, three different
      conjugates were obtained from polysaccharides with molecular relative sizes of
      2000-4000 Da, 4000-10,000 Da or 10,000-50,000 Da, but no differences were
      detected in the immune response obtained against the three conjugates. Our
      experiments demonstrate that it is possible to generate a protective, T-cell
      dependent response against CCPS using the P64k protein as carrier.

PMID- 15039095
TI  - Prevention of lethal respiratory vaccinia infections in mice with interferon
      alpha and interferon-gamma.
AB  - The antiviral efficacy of interferons (IFNs) was evaluated using a vaccinia
      intranasal infection model in mice in this study. We provide evidence that
      intranasal administration of IFN-alpha and IFN-gamma (days -1 to +3) resulted in
      100 and 90% survival against a lethal respiratory vaccinia infection (8 LD50) in
      mice, respectively; whereas no animals in the placebo group survived through the
      study period (21 days). The IFN treatment consisted of a single daily dose of
      5x10(3) U per mouse for 5 consecutive days. The efficacy of IFN-gamma was evident
      even when the IFN-gamma treatments started 1-2 days after infection and when a
      lower dose (2x10(3) U per mouse) was used. The treatment of IFN-alpha and IFN
      gamma reduced the virus titers in the lungs of infected mice by 1000-10,000-fold,
      when the administration started 1 day after infection. Our data suggest that IFN
      alpha and IFN-gamma are effective in protecting vaccinia-infected mice from viral
      replication in lungs and mortality, and may be beneficial in other human
      orthopoxvirus infections.

PMID- 15039096
TI  - CD14 gene promoter polymorphism in different clinical forms of tuberculosis.
AB  - Mycobacterium tuberculosis interacts with monocyte-macrophages through cell
      surface molecules including CD14. A soluble form of CD14 (sCD14) exists in human
      serum, and higher amounts of it are found in tuberculosis. A polymorphism on CD14
      gene promoter was associated with increased sCD14 levels in some diseases. To
      evaluate whether this polymorphism associates with tuberculosis, its clinical
      forms, and increased sCD14, genotype/allele frequencies in tuberculosis patients
      were compared with the controls. Results confirmed increased levels of sCD14 in
      patients with tuberculosis, and those with miliary tuberculosis had the highest
      levels. sCD14 decreased to normal levels after anti-tuberculosis treatment. No
      association was found between the CD14 polymorphism and tuberculosis or sCD14
      levels. Results suggest that sCD14 may be involved in anti-tuberculosis immune
      response, but its increase is a consequence of infection rather than a
      predisposed genetic trait. Measuring sCD14 in tuberculosis may help monitor anti
      tuberculosis treatment.

PMID- 15039097
TI  - Cloning and expression of a sialic acid-binding lectin from the snail Cepaea
      hortensis.
AB  - Highly degenerated gene-specific oligonucleotide primers (GSPs) were constructed
      from the amino acid sequence of tryptic fragments produced from the purified
      sialic acid-specific lectin of the garden snail Cepaea hortensis. From the
      albumin glands, the total RNA or the mRNA was prepared. Combination of a
      universal primer with the GSPs delivered gene-specific fragments of about 650,
      620 and 280 bp by polymerase chain reaction (PCR). These fragments were cloned
      into the vector pDrive (Qiagen) and sequenced. The resulting cDNA sequence
      consisted of 744 bp, including an open reading frame of 480 bp. The encoded
      protein consists of 159 amino acids, including the putative signal sequence
      peptide. The mature protein should comprise 141 amino acid residues with a
      calculated molecular mass of 15,529 Da. The expression of the recombinant lectin
      in Escherichia coli resulted in a soluble protein reacting specifically with
      rabbit antiserum raised against the native lectin.

PMID- 15039098
TI  - The probiotic Escherichia coli strain Nissle 1917 interferes with invasion of
      human intestinal epithelial cells by different enteroinvasive bacterial
      pathogens.
AB  - The probiotic Escherichia coli strain Nissle 1917 (Mutaflor) of serotype O6:K5:H1
      was reported to protect gnotobiotic piglets from infection with Salmonella
      enterica serovar Typhimurium. An important virulence property of Salmonella is
      invasion of host epithelial cells. Therefore, we tested for interference of E.
      coli strain Nissle 1917 with Salmonella invasion of INT407 cells. Simultaneous
      administration of E. coli strain Nissle 1917 and Salmonella resulted in up to 70%
      reduction of Salmonella invasion efficiency. Furthermore, invasion of Yersinia
      enterocolitica, Shigella flexneri, Legionella pneumophila and even of Listeria
      monocytogenes were inhibited by the probiotic E. coli strain Nissle 1917 without
      affecting the viability of the invasive bacteria. The observed inhibition of
      invasion was not due to the production of microcins by the Nissle 1917 strain
      because its isogenic microcin-negative mutant SK22D was as effective as the
      parent strain. Reduced invasion rates were also achieved if strain Nissle 1917
      was separated from the invasive bacteria as well as from the INT407 monolayer by
      a membrane non-permeable for bacteria. We conclude E. coli Nissle 1917 to
      interfere with bacterial invasion of INT407 cells via a secreted component and
      not relying on direct physical contact with either the invasive bacteria or the
      epithelial cells.

PMID- 15039099
TI  - Induction of opsonic antibodies to the gamma-D-glutamic acid capsule of Bacillus
      anthracis by immunization with a synthetic peptide-carrier protein conjugate.
AB  - The capsule of Bacillus anthracis, a polymer of gamma-D-glutamic acid, functions
      as a virulence determinant and is a poor immunogen. In this study we show that
      antibodies reactive with the B. anthracis capsule can be elicited in mice by
      immunization with a conjugate consisting of a synthetic gamma-D-glutamic acid
      nonamer peptide (gamma-D-glu9) covalently coupled to keyhole limpet hemocyanin.
      The serum response to gamma-D-glu9 was comprised primarily of IgG antibodies that
      recognized an epitope requiring a minimum of four gamma-linked D-glutamic acid
      residues. Antibodies to (gamma-D-glu9) bound to the surface of encapsulated B.
      anthracis cells and mediated opsonophagoctosis. These findings suggest that anti
      capsular antibodies could mediate the clearance of vegetative B. anthracis cells
      in vivo. Thus, inclusion of an immunogenic capsular component as well as
      protective antigen in new anthrax vaccines would generate immune responses
      targeting both the bacteremic and toxigenic aspects of anthrax infection and thus
      may increase protective efficacy.

PMID- 15039100
TI  - LAAE-14, a new anti-inflammatory drug, increases the survival of Candida albicans
      inoculated mice.
AB  - LAAE-14, a lipidic acid-amido ether derivative, has been recently described as a
      new anti-inflammatory drug. We have studied the effect of treatment with this
      compound on the susceptibility of mice to in vivo experimental Candida albicans
      infection. ICR mice orally treated with LAAE-14 (25 mg kg(-1)) and experimentally
      intravenously infected showed a significantly increased survival as compared to
      control mice. In vitro, the compound did not inhibit the growth of C. albicans
      yeast cells or the yeast-to-hyphal transition. The in vitro production of
      prostaglandin E2 by peritoneal macrophages in response to the yeasts and hyphae
      of C. albicans was significantly decreased upon treatment with LAAE-14, in a dose
      dependent manner. Thus, reduced prostaglandin production during fungal infection
      could be an important factor in controlling fungal colonisation and infection.

PMID- 15039101
TI  - Injury recovery of foodborne pathogens in high hydrostatic pressure treated milk
      during storage.
AB  - Bacteria are expected to be injured or killed by high hydrostatic pressure (HHP).
      This depends on pressure levels, species and strain of the microorganism and
      subsequent storage. Injured bacteria may be repaired which could affect the
      microbiological quality of foodstuffs with an important safety consideration
      especially in low acid food products. In this study two Gram-positive (Listeria
      monocytogenes CA and Staphylococcus aureus 485) and two Gram-negative
      (Escherichia coli O157:H7 933 and Salmonella enteritidis FDA) relatively pressure
      resistant strains of foodborne pathogens were pressurized at 350, 450 and 550 MPa
      in milk (pH 6.65) and stored at 4, 22 and 30 degrees C. The results of shelf life
      studies indicated two types of injury, I1 and I2, for all the pathogens studied.
      It is obvious that I2 type injury is a major injury and after its repair (I2 to
      I1), the cells can form colonies on non-selective but not on selective agar. The
      formation of colonies on both selective and non-selective agar occurs only after
      full recovery of injury (I1 to AC). The results presented in this study show that
      even if injured cells are not detected immediately after HHP treatment, I2 type
      injury could be potentially present in the food system. Therefore, it is
      imperative that shelf life studies must be conducted over a period of time for
      potential repair of I2 type injury either to detectable injury (I1) or to active
      cells (AC) to ascertain microbiological safety of low acid food products.

PMID- 15039102
TI  - Immune response to superoxide dismutase in group A streptococcal infection.
AB  - Extracellular localisation of manganese-dependent superoxide dismutase (SodA) by
      group A streptococcus (GAS) may have a role in protection of this pathogenic
      bacterium from exogenously produced reactive oxygen species. In this study we
      show that SodA is found both in surface protein extracts and in culture
      supernatants of GAS. To investigate whether SodA is a possible vaccine candidate
      outbred Quackenbush mice were subcutaneously vaccinated with recombinant SodA.
      Strong antibody responses which were moderately opsonic were elicited. These
      antibodies were unable to protect mice from intraperitoneal challenge with M1
      GAS. We also show that SodA and p145 (a conserved peptide from the M-protein)
      antibodies are present at significantly higher levels amongst patients with
      rheumatic heart disease than in control subjects from the same endemic region.
      The higher SodA antibody levels in patients may be indicative of a role for this
      protein in pathogenesis of rheumatic heart disease but are more likely to be a
      marker of recent or recurrent streptococcal infection.

PMID- 15039103
TI  - Attenuation of zinc-induced neuronal death by the interaction of growth
      inhibitory factor with Rab3A in rat hippocampal neurons.
AB  - We examined the protective effect of growth inhibitory factor (GIF) against zinc
      induced neuronal death in rat hippocampal neurons. In an in vitro cell culture
      system, 300 microM Zn(2+) readily induced death of hippocampal neuronal cells,
      which was characterized by massive necrosis and a minor degree of apoptosis.
      Neither the addition of recombinant GIF nor Rab3A alone could rescue these cells
      from death. However, the combination of GIF with Rab3A could significantly
      enhance the survival of the hippocampal neurons. This result was supported by
      both Annexin -V FITC/propidium dual staining and chromosomal DNA analysis. These
      findings suggest that GIF may inhibit Zn(2+)-induced neuronal death via its
      interaction with Rab3A.

PMID- 15039104
TI  - Antioxidant effects of a single dose of acetylsalicylic acid and salicylic acid
      in rat brain slices subjected to oxygen-glucose deprivation in relation with its
      antiplatelet effect.
AB  - The aim of the present study was to analyze the relative participation of the
      antiplatelet and the antioxidant effects of acetylsalicylic acid (ASA) and
      salicylic acid (SA) after a single dose (1 or 10 mg/kg i.p.) in an in vitro model
      of anoxia in slices of rat brain. After 20 min of drug administration, blood and
      brain were obtained (n=6 rats per group). We measured: lipid peroxidation,
      glutathione levels and lactate dehydrogenase efflux (LDH), ASA and SA
      concentrations and platelet aggregation in whole blood. An increase in lipid
      peroxidation (80%) and in LDH efflux (520%) and a decrease in glutathione levels
      (35%) were observed after 120 min anoxia in saline-treated rats. SA reduced this
      oxidative stress and LDH efflux, but it did not modify platelet aggregation. ASA
      strongly inhibited platelet aggregation but exerted a poor antioxidant effect.
      ASA was not detectable in brain tissue. We conclude that repeated doses of ASA
      are necessary to obtain a tissular antioxidant effect, probably when liver
      generates enough SA.

PMID- 15039106
TI  - Ca2+ store-independent augmentation of [Ca2+]i responses to G-protein coupled
      receptor activation in recombinantly TRPC5-expressed rat pheochromocytoma (PC12)
      cells.
AB  - Mammalian homologues of the Drosophila canonical transient receptor potential
      (trp) protein (TRPC) have been implicated to function as receptor-operated Ca(2+)
      channels (ROCs) or store-operated Ca(2+) channels (SOCs). To determine the role
      of TRPC5 protein in neural cells, TRPC5 was recombinantly expressed in rat
      pheochromocytoma cells (PC12) and changes in intracellular Ca(2+) concentration
      ([Ca(2+)](i)) and Na(+) concentration ([Na(+)](i)) were analyzed. TRPC1 and TRPC3
      mRNAs were endogenously expressed in PC12 cells. In TRPC5-expressed cells (TRPC5
      cells), the resting [Ca(2+)](i) and [Na(+)](i) were significantly higher than
      those in control cells. The [Ca(2+)](i) increases induced by bradykinin and
      uridine 5'-triphosphate were significantly larger in TRPC5-cells. TRPC5
      expression did not change in store-operated Ca(2+) entry elicited by
      thapsigarigin. TRPC5-cells showed larger inward current and increase of
      [Na(+)](i) in response to BK than control cells. These results suggest that TRPC5
      channels expressed in PC12 cells function as ROCs activated by G
      protein/phospholipase C coupled receptors, but not as SOCs.

PMID- 15039105
TI  - Sox21 is a repressor of neuronal differentiation and is antagonized by YB-1.
AB  - Sox21, a high-mobility group box transcription factor, is expressed throughout
      the immature neural stem/progenitor population in ventricular zone but not in the
      cortical plate in embryonic mouse brain and its expression is restricted to the
      subventricular zone in the adult brain. In undifferentiated PC12 cells,
      endogenous Sox21 expression is detected but its expression ceases during the
      nerve growth factor (NGF)-induced neuronal differentiation. Overexpression of
      Sox21 results in a substantial repression of NGF-induced neurite outgrowth in
      PC12 cells. Further, we biochemically identified a Sox21-associating protein, Y
      box binding protein 1 which not only binds to Sox21 but also partially restores
      NGF-induced neurite outgrowth of PC12 cells inhibited by Sox21. These results
      suggest that Sox21 is a repressor of neuronal differentiation in the developing
      nervous system.

PMID- 15039107
TI  - Wavelet-based analysis of low-frequency fluctuations of blood pressure and
      sympathetic nerve activity in rats.
AB  - Biorthogonal wavelets were employed to quantify the relationship of fluctuations
      between blood pressure (BP) and sympathetic nerve activity (SNA). We forced the
      SNA to fluctuate by electrical stimulation the medulla in anesthetized,
      paralyzed, vagotomized, cardiac sympathetic-blocked, baroreceptor-denervated, and
      angiotensin II-converting enzyme-inhibited rats. Although spectral analysis
      showed a close coupling between fluctuations of BP and SNA at the stimulating
      frequencies, only the fluctuations of SNA in frequencies of 0.25 to approximately
      0.4 Hz were proportional to BP fluctuations over the course of time. The results
      suggest that fluctuations transmitted from SNA to BP were uniform without
      shifting due to the nature of vasculature or the lagging of sympathetic action in
      frequencies of 0.25 to approximately 0.4 Hz, and support the possibility of using
      low-frequency variabilities of BP to quantitatively estimate fluctuations of SNA
      at time domain.

PMID- 15039108
TI  - Female rats living in small cages respond to restraint stress with both
      adrenocortical corticosterone release and acetylcholine release in the
      hippocampus.
AB  - Since we found that the stress response of acetylcholine release in the
      hippocampus was attenuated in male rats living in a small cage, we individually
      housed female rats in a large (diameter=35 cm) or a small (19 cm) cylindrical
      cage for 4 days and examined the response to restraint stress which was applied
      from 12:00 h to 13:00 h. Both groups of rats showed a significant increase in the
      acetylcholine release in the hippocampus, as well as an increase in
      corticosterone release. But neither housing condition affected the expression of
      the 4-day estrous cycle. We surmise that there may be a sex difference in the
      effect of housing condition in the stress response of acetylcholine release in
      the hippocampus.

PMID- 15039109
TI  - Diversity in the circadian periods of single neurons of the rat suprachiasmatic
      nucleus depends on nuclear structure and intrinsic period.
AB  - The circadian periods of single cultured neurons of the hypothalamic
      suprachiasmatic nucleus (SCN) in rats were assessed by means of multi-electrode
      array dish. Although the mean circadian period was not different between the
      dispersed cell culture and organotypic slice culture, the periods distributed in
      a wide range from 20.0 to 30.9 h in the former whereas concentrated in a narrow
      range in the latter. The same difference was also detected within each culture
      dish. There is a significant correlation between the period length and variation
      of circadian rhythm, where the more the mean circadian period in a culture dish
      deviates from the overall mean, the larger the standard deviation of period in a
      dish becomes. Such a correlation was not observed in the organotypic slice
      culture. These findings indicate that the diversity of circadian periods in the
      individual SCN neurons depends on the maintenance of SCN structure and the
      circadian period, suggesting that not only cell-to-cell communication but also
      the intrinsic circadian period plays a significant role in synchronizing the
      constitutional oscillators in the SCN.

PMID- 15039111
TI  - Pointing to a target from an upright standing position: anticipatory postural
      adjustments are modulated by the size of the target in humans.
AB  - To examine the influence of the target size onto postural EMG activity, eight
      subjects performed, from a standing position, rapid and accurate pointings to a
      target located within reach. The target size was varied across blocks of trials.
      Hand movement time increased when the target size was decreased. Interestingly,
      the magnitude of the integrated EMG activity of lower limb muscles (TAi, TFLc,
      RFi) decreased with a decreasing target size, while that of the erector spinae
      increased. The effects were observed as early as 200 ms before the hand movement
      onset. When standing, these early commands could influence the control of the
      hand during the acceleration phase. The target size was specified within the
      postural command before any hand movement took place suggesting the
      characteristics of the pointing task were integrated in a feedforward manner.

PMID- 15039110
TI  - Growth factor-estradiol interaction on DNA labeling and cytoskeletal protein
      expression in cultured rat astrocytes.
AB  - Growth factors are major signaling agents regulating neuron-glia dialogue.
      Epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), insulin
      growth factor-I (IGF-I) and insulin (INS) induce neuronal and astroglial cell
      proliferation and differentiation. This is true also for estrogens that influence
      astrocytes and exert neuroprotectant activity. In this study interactions between
      growth factors and estradiol on DNA labeling and glial fibrillary acidic protein
      (GFAP) and vimentin expression in cultured astrocytes were investigated. DNA
      labeling was significantly stimulated by bFGF pretreatment followed by 24 h
      estradiol and EGF or IGF-I or INS added in the last 12 h. Western blotting showed
      also a modulation of GFAP and vimentin expression in treated astrocytes. This
      suggests the occurrence of a crucial growth factor-estradiol interaction on DNA
      labeling and cytoskeletal protein expression during astrocyte proliferation and
      differentiation in culture.

PMID- 15039112
TI  - Directional sensitivity of dendritic calcium responses to wind stimuli in the
      cricket giant interneuron.
AB  - We examined directional sensitivities in the dendritic activity of the identified
      giant interneurons (GIs) in the cricket, using in vivo Ca(2+) imaging during
      different directional air-current stimuli. Air current stimulus evoked action
      potential burst and quick Ca(2+) increase in GI. The stimulus direction of the
      maximal Ca(2+) responses corresponded to that of the maximal voltage response.
      However, the shapes of the directional tuning curves based on the Ca(2+)
      responses for each dendritic branch were different from the overall tuning curve
      based on spike counts for the cell. Moreover, different dendritic branches
      displayed distinct directional sensitivity profiles to the air-current stimuli.
      We propose that postsynaptic activities will influence the local Ca(2+) signals
      in the distal dendrites, and produce the difference in directional sensitivity of
      the dendritic Ca(2+) response.

PMID- 15039113
TI  - 1,2-bis(2-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid (BAPTA-AM) inhibits
      caffeine-induced apoptosis in human neuroblastoma cells.
AB  - In the present study, it was investigated whether 1,2-bis(2-aminophenoxy)ethane
      N,N,N'N'-tetraacetic acid (BAPTA-AM), an intracellular Ca(2+) chelator, possesses
      protective effect against caffeine-induced apoptosis in the central nervous
      system. Through morphological and biochemical analyses, cells treated with
      caffeine exhibited several apoptotic features. On the other hand, cells treated
      with caffeine and BAPTA-AM, showed decreased occurrence of apoptotic features. In
      addition, it was shown that BAPTA-AM treatment inhibits caffeine-induced increase
      of caspase-3 enzyme activity. These results show that caffeine induces apoptotic
      death in human SK-N-MC neuroblastoma cells and BAPTA-AM prevents apoptosis by
      attenuating caffeine-induced caspase-3 activation.

PMID- 15039114
TI  - Slow repetitive transcranial magnetic stimulation increases somatosensory high
      frequency oscillations in humans.
AB  - Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a
      possible treatment for psychiatric and neurological disorders characterized by
      focal brain excitability, such as major depression and action myoclonus. However,
      the mechanism of modulating excitability by rTMS is unclear. We examined the
      changes in high frequency oscillations (HFOs) of somatosensory evoked potentials
      (SEPs) before and after slow rTMS over the right primary somatosensory cortex
      (0.5 Hz, 50 pulses, 80% motor threshold intensity). The HFOs, which represent a
      localized activity of intracortical inhibitory interneurons, were significantly
      increased after slow rTMS, while the SEPs were not changed. Our results suggest
      that slow rTMS affects cortical excitability by modulating the activity of the
      intracortical inhibitory interneurons beyond the time of the stimulation and that
      rTMS may have therapeutic effects on such disorders.

PMID- 15039115
TI  - Small changes in temporal deviance modulate mismatch negativity amplitude in
      humans.
AB  - The relative sensitivity of mismatch negativity (MMN) amplitude to small changes
      in temporal (i.e. timing) deviance of an ongoing stimulus train was investigated.
      MMN was measured at Fz in response to 3.75-15% decrements of inter-stimulus
      interval from a 400 ms standard with a deviant probability of 1/15. This
      parameter space represents the smallest degree of deviance and the narrowest
      range of variation that has been tested in the context of MMN sensitivity to
      temporal variables. Waveform amplitude was found to significantly increase with
      degree of temporal deviance even within this relatively narrow parameter space.
      This finding is consistent with the view that the MMN corresponds to pre
      attentive neural activity that subsequently allows the conscious perception of
      time during temporal discrimination tasks.

PMID- 15039116
TI  - Differential effects of forced swim-stress on the corticotropin-releasing hormone
      and vasopressin gene transcription in the parvocellular division of the
      paraventricular nucleus of rat hypothalamus.
AB  - Corticotropin-releasing hormone (CRH) and vasopressin (AVP) colocalize in the
      parvocellular division of the paraventricular nucleus of the hypothalamus (PVN).
      We examined the effect of forced swim-stress on the CRH and AVP primary
      transcript (hnRNA) levels in the rat PVN by semi-quantitative in situ
      hybridization. CRH hnRNA increased markedly following 10-min swim-stress and
      returned to the basal level by 2 h. AVP hnRNA in the parvocellular division of
      the PVN, where AVP colocalizes with CRH, did not change significantly immediately
      after the swim-stress, but it did increase significantly 2 h after the stress.
      Pretreatment with dexamethasone abolished the increases in CRH and AVP hnRNA
      levels after the swim-stress. The present results demonstrate the differential
      effects of forced swim-stress on the CRH and AVP gene transcription in the
      parvocellular PVN, confirming the diverse response of the dual peptide-containing
      system in the face of acute stressful events.

PMID- 15039118
TI  - A peptide derived from the C-terminal region of acetylcholinesterase modulates
      extracellular concentrations of acetylcholinesterase in the rat substantia nigra.
AB  - It is well established that acetylcholinesterase (AChE) has 'non-classical'
      functions independent of cholinergic transmission. A region of AChE distinct from
      the catalytic site may be responsible for these actions via a 14-residue peptide
      located between residues 586-599 at the C-terminus of human AChE. This AChE
      peptide possesses a high amino acid sequence homology with a region of amyloid
      precursor protein and shares many biophysical and physiological characteristics.
      In this study, the effect of AChE-peptide (AEFHRWSSYMVHWK) on the extracellular
      levels of endogenous AChE was examined in rat substantia nigra in vitro. A
      chemiluminescent assay was used to continuously measure the soluble AChE
      concentration from tissue punches of the substantia nigra. Application of NMDA
      evoked an increase in extracellular AChE levels consistent with previous results
      obtained from in vivo models. AChE-peptide, when applied alone, had no effect on
      AChE release: however, when co-applied with NMDA, AChE-peptide reduced the
      effectiveness of NMDA to evoke release of AChE. These results indicate, in a
      region of the brain central to the aetiology of Parkinson's disease, that an AChE
      peptide fragment derived from AChE displays a bioactivity that could involve
      regulation of Ca(2+) availability and hence the release of AChE.

PMID- 15039117
TI  - Psychosine-induced apoptosis in a mouse oligodendrocyte progenitor cell line is
      mediated by caspase activation.
AB  - Globoid cell leukodystrophy (GLD) is an inherited neurological disorder caused by
      the deficiency of galactocerebrosidase (GALC) activity resulting in cell death of
      oligodendrocytes and subsequent demyelination. The death of oligodendrocytes is
      accompanied by accumulation of psychosine, which is also a substrate for the GALC
      enzyme. In this report, we investigated the mechanism of the toxic effect of
      psychosine in a mouse-derived oligodendrocyte progenitor cell line (OLP-II), a
      precursor to the cell type most affected in GLD. Psychosine caused cytotoxicity
      in a dose-dependent manner. Lower concentration of psychosine (5 microM) did not
      significantly reduce OLP-II cell numbers. However, 50 microM psychosine induced
      up to 45% cell death. These results were confirmed by the Tunel assay, which is a
      hallmark for the detection of apoptosis. Moreover, psychosine treatment resulted
      in the activation/cleavage of initiator caspase-8 and -9, and effector caspase-3.
      These results support a role for psychosine in OLP-II cell death via an apoptotic
      mechanism, and suggest the involvement of caspases.

PMID- 15039119
TI  - Analysis of strain difference in behavior to Cholecystokinin (CCK) receptor
      mediated drugs in PVG hooded and Sprague-Dawley rats using elevated plus-maze
      test apparatus.
AB  - This study investigated the behavioral mechanisms underlying the anxiogenic, or
      anxiolytic mediated effects of CCK(2) receptor mediated agonist (CCK-4) and
      antagonist drugs (LY225910, LY288513, CR2945) in PVG hooded and Sprague-Dawley
      (SD) rats using the elevated plus maze test apparatus. In addition, the effects
      of a CCK(1) antagonist (CR1409) were investigated for its possible mediation in
      anxiety behavior between PVG hooded and SD rats. PVG hooded rats treated with CCK
      4, decreased the time spent in the open arm and increased the time spent in the
      closed arm and correspondingly showed increase in the number of entries in the
      open arms while the number of entries in closed arm was insignificant, whereas SD
      rats decreased the time spent in the closed arm, while other parameters remained
      insignificant. PVG hooded rats administered with various CCK(2) antagonists
      (LY225910, LY288513, and CR2945) significantly increased the time spent in the
      open arm and correspondingly decreased the time spent in the closed arm, while
      the number of entries in the open or closed arm was insignificant, in contrast,
      SD rats failed to show any reliable significance. PVG hooded rats administered
      with the CCK(1) antagonist (CR1409), failed to show any reliable significance, in
      contrast, SD rats significantly increased the time spent in the open arm. The
      strain differences observed in this study suggests that CCK plays mainly as a
      neuromodulator, in which the various CCK(2) antagonists may not affect baseline
      anxiety state, but instead they modulate heightened states of anxiety through
      differential effects of CCK(1)/CCK(2) receptors.

PMID- 15039120
TI  - Genetic variation in CTNNA3 encoding alpha-3 catenin and Alzheimer's disease.
AB  - Linkage studies have implicated a broad region on chromosome 10q in Alzheimer's
      disease (AD). A recent genetic association study has provided evidence that
      polymorphism in the gene encoding alpha-3 catenin (CTNNA3, referred to previously
      as VR22 and also known as alpha-T catenin) may underlie linkage signals. Here, to
      investigate this finding, markers that previously exhibited maximum evidence of
      association have been tested in Swedish and Scottish AD case-control samples.
      Across models of disease risk and in relation to multiple quantitative indices of
      AD pathology (CSF A beta 42 and tau levels, age-at-onset, MMSE scores, and
      measures of senile plaque density) no evidence was found supporting a role for
      these particular variants in AD. More detailed studies of regional linkage
      disequilibrium structure around CTNNA3 will likely be required to determine
      whether sequence variation in this region impacts AD.

PMID- 15039121
TI  - Facial nerve injury induces facilitation of responses in both trigeminal and
      facial nuclei of rat.
AB  - A study was made of the effects of facial nerve transection on trigeminal
      stimulation- evoked field potentials in the principal trigeminal (Pr5) and facial
      nuclei (7) in rats. Although the transected branch of the facial nerve contains
      pure motoric efferents, it resulted in enhanced responses in both Pr5 and 7.
      These electrophysiological results suggest a functional circuitry involving the
      whiskers, trigeminal nerve, Pr5 and 7 and the facial nerve as efferent. The
      disconnection (opening) of this loop results in enhanced responsiveness of the
      neurons in both Pr5 and 7.

PMID- 15039122
TI  - Molecular genetics of myocardial infarction: many genes, more questions than
      answers.

PMID- 15039123
TI  - Are we making efficient use of clopidogrel?

PMID- 15039125
TI  - Genotypes and haplotypes predisposing to myocardial infarction: a multilocus case
      control study.
AB  - AIM: To identify polymorphisms and haplotypes in candidate genes that predispose
      to myocardial infarction (MI) using a multilocus approach. METHODS AND RESULTS:
      1052 subjects, comprising 547 acute MI cases and 505 controls were studied. The
      association between MI and 58 SNPs in 35 candidate genes (generating 61 016
      individual genotypes), and between MI and estimated haplotypes at 14 loci
      encompassing 16 genes was investigated. Two individual gene variants and
      haplotypes at two loci showed statistical association with MI. The alpha-adducin
      460trp variant (OR 0.73, 95% CI 0.59-0.91, P=0.006) and the cholesteryl ester
      transfer protein -629A variant (OR 0.82, 95% CI 0.68-0.97, P=0.025) were both
      associated with a significant protective effect on MI, as was the paraoxonase
      1/paraoxonase 2 haplotype comprising met55 and gln192 in paraoxonase 1 and cys311
      in paraoxonase 2 (OR 0.52, 95% CI 0.39-0.77, P=0.001). The apolipoprotein C III
      haplotypes CCTTCG and ATCCCG at positions -641*-482*-455*1100*3175*3206 were
      associated with an increased risk of MI, odds ratios 1.41 (95% CI 1.06-1.76,
      P=0.023) and 1.71 (95% CI 1.28-2.14, P=0.038), respectively. CONCLUSIONS: We
      report associations of two polymorphisms and haplotypes at two loci with risk of
      MI that warrants testing in future studies. Furthermore, we demonstrate the
      application of a multilocus assay in the setting of a large association study and
      the additional benefit gained from the study of haplotypes to identify variants
      influencing risk of coronary heart disease.

PMID- 15039124
TI  - A lot more can be done to prevent cardiovascular diseases.

PMID- 15039126
TI  - Cardiovascular risk in healthy men and markers of oxidative stress in diabetic
      men are associated with common variation in the gene for uncoupling protein 2.
AB  - BACKGROUND: Oxidative stress reduces total antioxidant status (TAOS) and is
      implicated in atherogenesis. Mitochondrial uncoupling protein 2 (UCP2) negatively
      regulates reactive oxygen species generation. The UCP2 gene demonstrates a common
      functional promoter variant (-866G>A). METHODS AND RESULTS: Amongst 465 diabetic
      men (age 61.7 +/- 13.3 years), an association of the UCP2-866A allele with
      significantly lower TAOS in those without CHD was even more pronounced in those
      with CHD (TAOS 30.1 +/- 16.1% vs. 41.6 +/- 12.4% for AA vs. GG; P=0.016). In a
      sample of 20 diabetic men selected for homozygosity for the UCP2-866G>A variant,
      matched for baseline characteristics, plasma markers of oxidative stress in those
      with CHD were significantly higher in AA genotype men (TAOS 31.7 +/- 7.3% vs.
      52.6 +/- 6.3%; P=0.001 and F2-isoprostanes 220.6 +/- 37.2 pg ml(-1) vs. 109.9 +/-
      51.1 pg ml(-1); P=0.005 for AA vs. GG). Amongst 2695 healthy men (age 56.1 +/-
      3.5 years) prospectively studied for a median 10.2 years, AA homozygotes had a
      highly significant doubling in CHD risk after adjustment for established risk
      factors (HR 1.99 [1.37-2.90]; P=0.002). Risk associated with this genotype was
      substantially increased by the presence of other risk factors (obesity,
      hypertension and diabetes). CONCLUSIONS: This study provides the first in vivo
      evidence of a role for UCP2 in modifying oxidative stress and CHD risk in humans.

PMID- 15039127
TI  - Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin
      therapy undergoing percutaneous coronary interventions.
AB  - AIM: Our aim was to evaluate the early efficacy and variability of the platelet
      inhibition exerted by 300 mg clopidogrel for the purpose of acute percutaneous
      coronary interventions using platelet function tests. METHODS AND RESULTS:
      Elective percutaneous coronary intervention was used as a timely model in which
      clopidogrel was added to ongoing acetylsalicylic acid (aspirin) (100 mg/day) at
      2.5 h prior to procedure. Blood samples were collected before administration of
      clopidogrel and immediately before the intervention from 50 patients. Platelet
      functions were assessed with traditional aggregation and PFA-100. At baseline, 14
      (28%) patients were poor responders to aspirin according to PFA and 9 (18%)
      continued to show arachidonic acid-induced aggregation. After clopidogrel ADP
      triggered aggregation was only modestly inhibited in 40% of the patients. Eight
      percent of the study population was left without any measurable antiplatelet
      effect. The patients with modest response to clopidogrel had higher levels of c
      peptide (1.5 nmol/L) than the ones responding well (0.9 nmol/L, P<0.05).
      CONCLUSION: Neither ongoing aspirin treatment nor added clopidogrel did reach an
      expected extent of platelet inhibition. This study shows that aspirin-treated
      patients undergoing PCI gain highly variable levels of platelet inhibition with
      short-term clopidogrel 300 mg. At 2 h after adding clopidogrel it failed to
      enhance platelet inhibition in 40% of the patients. In future, targeted platelet
      function tests may be helpful to individually select an effective antiplatelet
      medication for these patients. This study suggests that for acute PTCA
      clopidogrel does not reach the optimal antithrombotic efficacy in all patients.

PMID- 15039128
TI  - Evaluating the impact of population and high-risk strategies for the primary
      prevention of cardiovascular disease.
AB  - AIMS: To estimate the potential effectiveness of different "high-risk" and
      "population" approaches to the primary prevention of cardiovascular disease (CVD)
      in middle-aged British men, after correction for regression dilution bias.
      METHODS AND RESULTS: We used a combination of cohort and randomised controlled
      trial evidence to estimate the effectiveness of high-risk strategies, based on
      the identification of high-risk factors or high absolute risk, and strategies
      based on population-wide reductions in cholesterol and blood pressure. High-risk
      strategies were potentially effective but would need to be used widely to have a
      substantial effect on CVD in the population. Aggressive pharmacological treatment
      (using statins, beta-blockers, ACE-inhibitors and aspirin) in individuals with a
      10-year Framingham event risk of >or=30% (6% of population) would have reduced
      major CVD by at most 11%. This figure increased to 34% at a >or=20% treatment
      threshold (26% of population). In contrast, modest downwards shifts in the
      population distributions of serum total cholesterol and systolic blood pressure
      led to marked expected reductions in major CVD. Taking regression dilution bias
      into account, 10% reductions in long-term mean blood cholesterol and blood
      pressure could have reduced major CVD by 45%. CONCLUSIONS: If high-risk
      strategies are to have a major impact on CVD in the population, they need to be
      more widely used than previously envisaged. Population-wide reduction of major
      risk factors is needed if CVD is to be substantially reduced.

PMID- 15039130
TI  - The natural history of myocardium awaiting revascularisation in patients with
      impaired left ventricular function.
AB  - AIMS: Our aim was to follow changes in myocardial function and physiology in
      patients awaiting coronary artery bypass surgery (CABG) and relate changes to
      post-revascularisation functional response. METHODS AND RESULTS: In 21 patients
      with CAD and LV dysfunction, myocardial glucose utilisation (MGU) and blood flow
      (MBF) were measured with positron emission tomography using F-18
      fluorodeoxyglucose and oxygen-15-labelled water. Left ventricular function, MGU,
      and MBF were re-assessed after one year, immediately prior to CABG. At baseline,
      dysfunctional myocardium displayed a reduction in MGU, hyperaemic MBF, and
      coronary vasodilator reserve (CVR) compared to normally functioning muscle. In
      the year preceding CABG, the overall wall motion score index increased (2.09 +/-
      0.65 vs. 2.3 +/- 0.7, p=0.0001) and the LV ejection fraction decreased (30.6 +/-
      11.1% vs. 27.3 +/- 11.5%, p<0.001). LVEF fell in 14 patients (28.7 +/- 9.4 vs.
      23.8, p<0.0001). Aggregate regional wall motion worsened in 15 patients. In
      contrast to myocardium displaying stable function at echocardiography, myocardium
      with evidence of deterioration showed a parallel decrease in hyperaemic MBF and
      CVR (1.57 +/- 0.67 vs. 1.19 +/- 0.7 ml/min/g, [p=0.004] and 1.9 +/- 0.75 vs. 1.33
      +/- 0.6, [p=0.005], respectively). Such myocardium displayed attenuated recovery
      postoperatively (21/68 [31%] LV segments) versus 'waiting-time' stable myocardium
      (98/169 [58%], p=0.0002). CONCLUSION: Delayed revascularisation in ischaemic left
      ventricular impairment results in declining function and a reduced likelihood of
      contractile improvement.

PMID- 15039129
TI  - Inflammation, coagulation, and depressive symptomatology in cardiovascular
      disease-free people; the ATTICA study.
AB  - BACKGROUND: Depression is associated with an increase in cardiovascular disease,
      but the underlying mechanisms are not well understood. The aim of this study was
      to examine the associations of depressive symptoms with inflammation and
      coagulation factors related to cardiovascular risk in persons free of
      cardiovascular disease. METHODS: A random algorithm was developed and stratified
      by gender-age and multistage sampling was performed during 2001-2002. In this
      study, we analysed data from 453 men (19-89 years old) and 400 women (18-84 years
      old). Inflammation markers were C-reactive protein (CRP), serum amyloid A, white
      blood cell (WBC) and total platelet counts; and coagulation factors including
      homocysteine and fibrinogen. Depression was assessed with the Zung Self-Rating
      Depression Scale (ZDRS range 0-100) after validation for the study population. A
      ZDRS score of 50 or more classified a person as mildly depressive. Statistical
      adjustments were made for risk factors (age, gender, smoking, diabetes mellitus,
      and physical activity level). RESULTS: Women had significantly higher scores on
      the Zung depression scale than men (47 +/- 9 vs. 43 +/- 10, p<0.001). Thus, 21%
      of men and 27% of women had mild depression, while 4% of men and 6% of women had
      severe depressive symptomatology. The depression scale correlated positively with
      C-reactive protein levels (p<0.05), white blood cell count (p<0.05), and
      fibrinogen (p<0.05) in both genders after adjustment for control variables.
      CONCLUSION: This study revealed that depression was associated with inflammation
      and coagulation factors in cardiovascular disease-free people, suggesting a
      possible pathway leading to an increased frequency of events of coronary heart
      disease in depressive individuals.

PMID- 15039131
TI  - Relationship between reduced elasticity of extracardiac vessels and left main
      stem coronary artery disease.
AB  - OBJECTIVES: To investigate the elastic properties of medium-size extracardiac
      arteries and veins between patients with and without left main stem coronary
      artery disease. METHODS: The compliance, distensibility, and incremental elastic
      modulus (iEmod) of the internal thoracic arteries (n=53), long saphenous veins
      (n=38), and radial arteries (n=35) from 74 patients undergoing coronary surgery
      were studied in organ baths. Twenty-four patients had left main stem (LMS)
      disease and 50 non-LMS coronary disease. RESULTS: Internal thoracic arteries from
      patients with LMS presented significantly lower compliance (-17%) and
      distensibility (-18%) and significantly higher iEmod (19%) than internal thoracic
      arteries from patients with non-LMS disease. Radial arteries from patients with
      LMS presented higher iEmod (50%) than radial arteries from patients with non-LMS
      disease. Furthermore, long saphenous veins from patients with LMS had reduced
      compliance (-45%), reduced distensibility (-40%) and increased iEmod (34%)
      compared to those from patients with non-LMS disease. CONCLUSIONS: LMS coronary
      disease is associated with a significantly reduced elasticity of extracardiac
      arteries and veins compared to non-LMS coronary disease. This finding suggests
      that widespread vascular elasticity defects may play a role in the development of
      LMS disease and be responsible for the higher incidence of early and late
      cardiovascular morbidity observed in this condition.

PMID- 15039132
TI  - The amount of calcium-deficient hexagonal hydroxyapatite in aortic valves is
      influenced by gender and associated with genetic polymorphisms in patients with
      severe calcific aortic stenosis.
AB  - AIMS: The study evaluated the relationship between cardiovascular risk factors
      (CRF), gene polymorphism, calcification and fibrosis of stenotic aortic valves.
      METHODS AND RESULTS: The calcium content of 187 excised stenotic aortic valves
      was determined using atomic absorption spectroscopy. Hydroxyproline content was
      quantified. Left-heart catheterization was performed. CRF and genotypes of the
      interleukin 10, connective tissue growth factor (CTGF) and chemokine receptor 5
      (CCR5) polymorphisms were assessed. Calcification consisted of Ca-deficient
      hexagonal hydroxyapatite, Ca(10 - x)(HPO4)x(PO4)(6 - x)(OH)(2 - x); with
      0<or=x<or=1. Calcification (quintiles) was positively associated with the mean
      gradient across the aortic valve (44 +/- 14, 52 +/- 17, 54 +/- 16, 60 +/- 15, 68
      +/- 19 mm Hg; p<0.001). Males (n=101) had a higher degree of calcification (26.1
      +/- 8.9 vs 20.8 +/- 9.2 mass%; p<0.001), despite the same mean gradient across
      the aortic valve (56 +/- 17 vs 56 +/- 19 mm Hg; p=0.958). CRF were not, whereas
      interleukin 10 polymorphisms -1082, -819, and -592 were significantly associated
      with the degree of calcification. Furthermore, if certain allele carriers had
      additionally the rare CCR5 or CTGF allele the degree of calcification was higher.
      CONCLUSION: Calcification of stenotic aortic valves consists of Ca-deficient
      hexagonal hydroxyapatite. Gender and genetic polymorphisms have an impact on the
      degree of aortic valve calcification.

PMID- 15039133
TI  - Relations of plasma homocysteine to left ventricular structure and function: the
      Framingham Heart Study.
AB  - AIMS: Hyperhomocysteinaemia is a risk factor for congestive heart failure,
      especially in women. We investigated if homocysteine promotes left ventricular
      (LV) remodelling. METHODS AND RESULTS: We examined cross-sectional relations of
      plasma total homocysteine to echocardiographic LV structure and function in 2697
      Framingham Heart Study participants (mean age 58 years, 58% women) free of heart
      failure and previous myocardial infarction. Adjusting for age and height, plasma
      homocysteine was positively related to LV mass, wall thickness, and relative wall
      thickness in women (p=0.0004-0.04), but not in men (p=0.28-0.68). Adjusting
      additionally for other clinical covariates, the relations of plasma homocysteine
      to LV mass and wall thickness in women remained statistically significant, but
      the relation to relative wall thickness became of borderline significance (1.92
      g, 0.01 cm, and 0.29% increase, respectively, for a 1-SD increase in
      ln[homocysteine], p=0.01-0.08). LV mass and wall thickness were higher in the
      fourth quartile of plasma homocysteine compared to the lower three in all models
      in women (p=0.0003-0.02), but not in men (p=0.25-0.78). Plasma homocysteine was
      not related to left atrial size or LV fractional shortening in either sex.
      CONCLUSION: In our community-based sample, plasma homocysteine was directly
      related to LV mass and wall thickness in women but not in men.

PMID- 15039134
TI  - Arrhythmogenic right ventricular cardiomyopathy: clinical registry and database,
      evaluation of therapies, pathology registry, DNA banking.

PMID- 15039135
TI  - Interleukin-22: a potential immunomodulatory molecule in the lung.
AB  - Interleukin (IL)-22 is a member of the human type I interferon family, which
      includes IL-10. IL-22 has the potential to interact with IL-10 because it binds
      to the IL-10R2c chain with IL-22R1 in its receptor complex. Binding can be
      blocked by the soluble receptor, IL-22 binding protein (IL-22BP). We hypothesize
      that IL-22 and IL-22BP are involved in inflammatory regulation and its subsequent
      role in the pathogenesis of inflammatory lung disease. We have demonstrated IL-22
      mRNA expression in alveolar macrophages (AM), monocytes, and alveolar epithelial
      (AE) cells. IL-22BP mRNA is expressed in AM, AE cells, and neutrophils. In
      contrast, IL-22R1 is expressed in AE only. Immunohistochemistry on normal and
      interstitial lung disease lung sections has confirmed IL-22 protein expression.
      Western blotting for IL-22 in bronchoalveolar lavage fluid demonstrated that
      lower levels of IL-22 were present in patients with acute respiratory distress
      syndrome and sarcoidosis relative to control subjects (P = 0.0152 and P =
      0.0213). Levels of IL-22 in idiopathic pulmonary fibrosis were not different than
      those of the control subjects (P = 0.5838). IL-22 did not affect IL-10 inhibition
      of tumor necrosis factor-alpha in monocytes, which do not express IL-22R1. By
      contrast, we demonstrated synergy between IL-10 and IL-22 in terms of IL-8
      inhibition in IL-22R1-expressing A549 cells. These data suggest a role for IL-22
      in the regulation of pulmonary inflammation.

PMID- 15039136
TI  - The PAI-1 gene as a direct target of endothelial PAS domain protein-1 in
      adenocarcinoma A549 cells.
AB  - Endothelial PAS domain protein-1 (EPAS1) regulates transcription of the genes
      encoding erythropoietin and vascular endothelial growth factor, which are
      important for maintaining oxygen homeostasis. We have previously shown that
      plasminogen activator inhibitor-1 (PAI-1) gene expression is induced by hypoxia.
      In this study, we sought to determine whether PAI-1 gene expression is directly
      regulated by EPAS1 in cancer cells because activities of proteases and their
      inhibitors are tightly regulated for tumor invasion. Hypoxia increased the PAI-1
      mRNA levels in human adenocarcinoma A549 cells. Overexpression of EPAS1
      significantly increased the PAI-1 mRNA and protein levels. Transient transfection
      assays revealed that EPAS1 increased PAI-1 gene transcription through a sequence
      containing 5'-CACGTACA-3' located at -194 (we refer to it as site HREPAI-1) and
      GT-box located at -78. Electrophoretic gel mobility shift assays revealed that
      HREPAI-1 serves as a binding site for EPAS1, and Sp1 constitutively binds to GT
      box. In conclusion, PAI-1 expression is induced by EPAS1 through HREPAI-1 and
      through an Sp1-binding site. These results indicate that the PAI-1 gene is a
      direct target of EPAS1 and suggest the role of EPAS1 and Sp1 in the hypoxic
      response of cancer cells.

PMID- 15039137
TI  - Complement factors c3a, c4a, and c5a in chronic obstructive pulmonary disease and
      asthma.
AB  - Studies of animal models have shown that the activation of the complement system
      could have a role in chronic obstructive pulmonary disease (COPD) and asthma by
      promoting inflammation and enhancing airway hyperresponsiveness. We sought to
      determine whether the levels of complement factors C3a, C4a, and C5a are elevated
      at the site of inflammation in patients with COPD and patients with asthma. We
      analyzed the induced sputum of seven patients with COPD, ten patients with
      asthma, and twelve healthy nonsmokers. The concentrations of anaphylatoxins in
      the induced sputum were measured by cytometric bead array. We found significantly
      increased C5a/C5a desArg concentrations in supernatants of the induced sputum of
      patients with COPD (P = 0.007) and those with asthma (P = 0.002) compared with
      the control group. In patients with COPD the C5a/C5a desArg concentrations were
      significantly negatively correlated with lung diffusion coefficient (r = -0.71, P
      = 0.035). There was no significant difference in C3a/C3a desArg or C4a/C4a desArg
      measurements between the three groups of subjects. These in vivo results propose
      the involvement of complement factor C5a in the pathogenesis of COPD and asthma.

PMID- 15039138
TI  - Ultrastructural and chromosomal studies on manganese superoxide dismutase in
      malignant mesothelioma.
AB  - Mesothelioma represents an aggressive tumor type with high resistance to all
      treatment modalities. Its pathogenesis is strongly associated with exposure to
      asbestos fibers and probably with free radicals. One of the most important free
      radical scavenging enzymes, mitochondrial manganese superoxide dismutase (MnSOD),
      has been shown to be elevated in mesothelioma (K. Kahlos et al., 1998, Am. J.
      Respir. Cell Mol. Biol. 18:570-580). In the present study, we could detect
      intense ultrastructural accumulation of MnSOD in the mitochondrial compartment of
      malignant mesothelioma cells. There was no association between the
      immunohistochemical reactivity and the most common and functional polymorphic
      variant of MnSOD, the Ala to Val amino acid change at 9 position (16th amino acid
      from the beginning of the signal sequence), in the 31 mesothelioma cases
      investigated. Comparative genomic hybridization and fluorescence in situ
      hybridization did not reveal any changes in chromosome 6, where the MnSOD gene is
      located. Sequencing of the MnSOD promoter region in four mesothelioma cell lines
      showed similar nucleotide variables in the malignant and nonmalignant cells.
      Therefore, the intense expression of MnSOD in the mitochondria of mesothelioma
      cells does not appear be associated with any major chromosomal alterations or the
      polymorphism of MnSOD gene. Association with oxidative/nitrosative stress in
      mesothelioma using nitrotyrosine immunostaining pointed to a tendency for more
      intense reactivity in those mesotheliomas with higher MnSOD expression (P =
      0.069).

PMID- 15039139
TI  - Activation of airway cl- secretion in human subjects by adenosine.
AB  - We investigated cystic fibrosis (CF) transmembrane conductance regulator (CFTR)
      regulation by A2 adenosine (Ado) receptors and beta2 adrenergic receptors in CFTR
      corrected CFBE41o- airway cells and human subjects. CFBE41o- cells stimulated
      with Ado (10 microM), isoproterenol (Iso, 10 microM), or Ado + Iso (10 microM
      each) elevated cyclic AMP (cAMP) above control conditions (P < 0.001), with the
      Iso conditions increasing cAMP approximately 10-fold above that produced by Ado
      alone (P < 0.001). All agonist conditions had similar effects on short circuit
      current at 10 and 25 microM, with no further currents produced by subsequent
      stimulation with forskolin (20 microM). CFTR dependence was demonstrated by
      glybenclamide block of agonist-stimulated currents. Nasal potential difference
      studies in normal (n = 50) subjects demonstrated that Ado (10 microM) and Ado +
      Iso (10 microM each) produced more polarization compared with Iso (10 microM Ado
      increase = 44%, 10 microM Ado + Iso increase = 52%, P < 0.05 for each condition
      compared with Iso alone). Studies completed in patients with CF (n = 10, "severe"
      genotypes) confirmed that Ado-stimulated polarization was CFTR-dependent.
      Together, these results indicate that Ado is a potent Cl- secretagogue in vivo,
      with relatively small effects on cAMP levels despite strong effects on CFTR
      dependent short circuit current and nasal Cl- transport. These findings support
      growing evidence indicating a role for Ado regulation of CFTR-dependent Cl-
      secretion in vivo.

PMID- 15039140
TI  - Oxysterols trigger ABCA1-mediated basolateral surfactant efflux.
AB  - Surfactant is an apically-secreted surface-active material containing primarily
      disaturated phosphatidylcholine (DSPtdCho) that is released from alveolar
      epithelia into the alveolus. Surfactant deficiency is an important aspect of
      inflammatory lung disease and may result from extravasation of serum lipoproteins
      into the alveolus. We investigated whether one bioactive component of modified
      lipoproteins, oxysterols, might reduce surfactant PtdCho availability by altering
      its trafficking. The oxysterol, 22-hydroxycholesterol (22HC), in combination with
      its obligate partner, 9 cis-retinoic acid (RA), decreased surfactant PtdCho
      levels, in part, by stimulating basolateral phospholipid export in murine lung
      epithelia. 22HC/RA stimulated basolateral PtdCho efflux in cells via
      transcriptional activation of the ATP-binding cassette transporter 1 (ABCA1)
      gene. This effect was mediated by a DR-4 locus within the ABCA1 promoter. ABCA1
      knockdown studies using ABCA1 siRNA or the ABCA1 inhibitor, glyburide,
      selectively attenuated 22HC/RA-driven basolateral PtdCho efflux. 22HC/RA
      significantly increased export of PtdCho molecular species containing saturated
      (16:0) fatty-acyl species typical of DSPtdCho. Overexpression of ABCA1 mimicked
      22HC/RA effects by increasing cellular PtdCho efflux, whereas mutagenesis of
      ABCA1 at Trp590 attenuated PtdCho release. The results indicate the existence of
      an oxysterol-activated basolateral exit pathway for surfactant that might impact
      the availability of phospholipid destined for apical secretion.

PMID- 15039141
TI  - Immunolocalization of protein kinase C isoenzymes alpha, beta I, beta II, delta,
      and epsilon in mouse kidney.
AB  - Localization of protein kinase C (PKC) isoenzymes alpha, beta I, beta II, delta,
      and epsilon was studied employing Western blot analysis and immunohistochemical
      methods including confocal laser-scanning microscopy in the kidney of two mice
      strains, namely, C57BL/6 and 129/Sv, which have recently been used as genetic
      backgrounds for respective knockout mice. Immunoblot analysis identified
      immunoreactive bands for each isoenzyme in total kidney cell extracts. Isoenzyme
      expression sites were identical for both strains. Glomeruli expressed PKC-alpha, 
      beta I, and -epsilon. The latter isoenzyme was also detected in apical aspects of
      proximal convoluted but not in proximal straight tubules. In contrast to rats,
      neither PKC-alpha nor PKC-beta I was detectable in the proximal tubule.
      Immunofluorescence was observed in luminal membranes of medullary (MTAL) and
      cortical thick ascending limbs for PKC-beta I and in MTAL for PKC-epsilon. The
      cortical collecting duct expressed PKC-alpha, -beta I, and -delta in intercalated
      cells only. In the outer medullary collecting duct, PKC-alpha and -beta I were
      detectable in principal cells, whereas PKC-delta was found in intercalated cells.
      In the inner medullary collecting duct, PKC-alpha, -beta I, and -beta II were
      detected. As described for the rat, the expression of PKC-beta II was otherwise
      restricted to cortical and medullary interstitial cells. The specificity of all
      labeling was confirmed in respective PKC isoenzyme knockout mice. In summary,
      distinct expression patterns were shown for PKC isoenzymes alpha, beta I, beta
      II, delta, and epsilon in the mouse kidney.

PMID- 15039142
TI  - Evidence for a role of protein kinase C-alpha in urine concentration.
AB  - In mouse kidney, the conventional protein kinase C (PKC) isoenzyme alpha is
      expressed in glomeruli, the cortical collecting duct (intercalated cells only),
      and medullary collecting duct. To get insights on its function, PKC-alpha
      knockout (-/-) and wild-type (+/+) mice were studied. When provided free access
      to water, PKC-alpha -/- mice showed approximately 50% greater urine flow rate and
      lower urinary osmolality in 24-h metabolic cage experiments despite a greater
      urinary vasopressin-to-creatinine ratio vs. PKC-alpha +/+ mice. Renal albumin
      excretion was not different. Clearance experiments under inactin/ketamine
      anesthesia revealed a modestly reduced glomerular filtration rate and showed a
      reduced absolute and fractional renal fluid reabsorption in PKC-alpha -/- mice.
      The sodium-restricting response to a low-sodium diet was unaffected in PKC-alpha 
      /- mice. Urinary osmolality was reduced to similar hypotonic levels in PKC-alpha 
      /- and +/+ mice during acute oral water loading or application of the vasopressin
      V(2)-receptor antagonist SR-121463. In comparison, the lower urinary osmolality
      observed in PKC-alpha -/- mice vs. wild-type mice under basal conditions
      persisted during water restriction for 36 h. In conclusion, PKC-alpha appears not
      to play a major role in renal sodium reabsorption but, consistent with its
      expression in the medullary collecting duct, contributes to urinary concentration
      in mice. Considering that PKC-beta I and -beta II are coexpressed with PKC-alpha
      in mouse medullary collecting duct, the present results indicate that
      conventional PKC isoenzymes cannot fully compensate for each other.

PMID- 15039143
TI  - Regulation of Na+ transport by aldosterone: signaling convergence and cross talk
      between the PI3-K and MAPK1/2 cascades.
AB  - Cross talk between the phosphatidylinositol 3-kinase (PI3-K) and mitogen
      activating protein kinase (MAPK)1/2 signaling cascades in response to aldosterone
      induced K-RasA was investigated in renal A6 epithelial cells. In addition, the
      contribution of these signaling pathways to aldosterone-stimulated Na(+)
      transport was investigated. Aldosterone increased active K-RasA levels in A6
      cells resulting in activation of downstream effectors in both the MAPK1/2 and PI3
      K cascades with K-RasA directly interacting with the catalytic p110 subunit of
      PI3-K in a steroid-dependent manner. Aldosterone-stimulated PI3-K signaling
      impinged on the MAPK1/2 cascade at the level of Akt-mediated phosphorylation of c
      Raf at an established negative regulatory site. Aldosterone also increased Sgk
      levels as well as stimulated phosphorylation of this kinase in a PI3-K- and K
      RasA-dependent manner. Blockade of MAPK1/2 signaling had little effect on Na(+)
      transport. Conversely, inhibition of PI3-K markedly suppressed transport.
      Likewise, suppression of K-RasA induction decreased transport. However, Na(+)
      transport was subsequently stimulated under these conditions with the PLA(2)
      inhibitor aristolochic acid, an established positive modulator of Na(+)
      transport, suggesting that K-RasA signaling through PI3-K does not directly
      affect epithelial sodium channel (ENaC) levels but the activity of this channel.
      Consistent with this possibility, activity of ENaC reconstituted in Chinese
      hamster ovary cells was increased by coexpression of constitutively active PI3-K.
      The current study demonstrates that aldosterone increases Na(+) transport, in
      part, by stimulating PI3-K signaling and that during aldosterone actions, there
      is both signaling convergence between the two aldosterone-induced proteins, K
      RasA and Sgk, as well as cross talk between the PI3-K and MAPK1/2 cascades with
      the prior but not latter cascade enhancing ENaC activity.

PMID- 15039144
TI  - Protection against puromycin aminonucleoside-induced chronic renal disease in the
      Wistar-Furth rat.
AB  - The Wistar-Furth (WF) rat is protected against chronic renal disease (CRD)
      following 5/6th ablation/infarction vs. the Sprague-Dawley (SD) rat, and
      protection was associated with preserved renal nitric oxide (NO) production. This
      study examined CRD induced with repeated administration of puromycin
      aminonucleoside (PAN). SD PAN developed nephrotic range proteinuria (>1 g/24 h),
      and at 15 wk severe renal injury developed and the glomerular filtration rate
      (GFR) was reduced to approximately 10% of sham. Total NO production, renal NO
      synthase (NOS) activity, and renal neuronal (n) and medullary endothelial (e)NOS
      abundance were reduced in the SD PAN. WF PAN exhibited less severe initial
      proteinuria (>400 mg/24 h), which abated within weeks, whereas GFR was normal and
      injury was minimal at 15 wk. Total NO production and renal NOS activity and
      abundance were significantly elevated compared with SD PAN. NOS mRNA (nNOS, eNOS,
      and inducible NOS) was not altered in WF, whereas SD showed significant increases
      in NOS gene expression with PAN. In conclusion, WF showed resistance to a second
      model of CRD with maintained renal NOS activity compared with SD.

PMID- 15039145
TI  - Ablation of calcitonin/calcitonin gene-related peptide-alpha impairs fetal
      magnesium but not calcium homeostasis.
AB  - We used the calcitonin/calcitonin gene-related peptide (CGRP)-alpha gene knockout
      model (Ct/Cgrp null) to determine whether calcitonin and CGRPalpha are required
      for normal fetal mineral homeostasis and placental calcium transfer. Heterozygous
      (Ct/Cgrp(+/-)) and Ct/Cgrp null females were mated to Ct/Cgrp(+/-) males. One or
      two days before term, blood was collected from mothers and fetuses and analyzed
      for ionized Ca, Mg, P, parathyroid hormone (PTH), and calcitonin. Amniotic fluid
      was collected for Ca, Mg, and P. To quantify skeletal mineral content, fetuses
      were reduced to ash, dissolved in nitric acid, and analyzed by atomic absorption
      spectroscopy for total Ca and Mg. Placental transfer of (45)Ca at 5 min was
      assessed. Ct/Cgrp null mothers had significantly fewer viable fetuses in utero
      compared with Ct/Cgrp(+/-) and wild-type mothers. Fetal serum Ca, P, and PTH did
      not differ by genotype, but serum Mg was significantly reduced in null fetuses.
      Placental transfer of (45)Ca at 5 min was normal. The calcium content of the
      fetal skeleton was normal; however, total Mg content was reduced in Ct/Cgrp null
      skeletons obtained from Ct/Cgrp null mothers. In summary, maternal absence of
      calcitonin and CGRPalpha reduced the number of viable fetuses. Fetal absence of
      calcitonin and CGRPalpha selectively reduced serum and skeletal magnesium content
      but did not alter ionized calcium, placental calcium transfer, and skeletal
      calcium content. These findings indicate that calcitonin and CGRPalpha are not
      needed for normal fetal calcium metabolism but may regulate aspects of fetal Mg
      metabolism.

PMID- 15039147
TI  - Assessment of the function of the betaC-subunit of activin in cultured
      hepatocytes.
AB  - We assessed the function of the beta(C)-subunit of activin in hepatocytes. We
      studied the effect of conditioned medium of Chinese hamster ovary (CHO) cell line
      stably expressing the beta(C) gene (CHO-beta(C)) on growth of AML12 hepatocytes.
      We also examined the effect of recombinant activin C and transfection of the
      beta(C) gene by using adenovirus vector. CHO-beta(C) secreted activin C, a
      homodimer of the beta(C), as well as precursors of the beta(C). The conditioned
      medium of CHO-beta(C) increased both [(3)H]thymidine incorporation and the cell
      number in AML12 cells. It also supported survival of AML12 cells in a serum-free
      condition. Recombinant human activin C also increased both [(3)H]thymidine
      incorporation and the number of AML12 cells. Transfection of AML12 cells with the
      beta(C)-subunit led to the stimulation of [(3)H]thymidine incorporation. Analysis
      of the conditioned medium revealed that the beta(C)-subunit formed a heterodimer
      with the endogenous beta(A), the formation of which was dependent on the amount
      of beta(C) expressed. Recombinant activin C did not affect the binding of (125)I
      activin A to its receptor or follistatin. These results indicate that activin C
      stimulates growth of AML12 cells. The beta(C)-subunit modifies the function of
      the beta(A)-subunit by multiple mechanisms.

PMID- 15039146
TI  - Efficacy of a single sequence of intermittent bright light pulses for delaying
      circadian phase in humans.
AB  - It has been shown in animal studies that exposure to brief pulses of bright light
      can phase shift the circadian pacemaker and that the resetting action of light is
      most efficient during the first minutes of light exposure. In humans, multiple
      consecutive days of exposure to brief bright light pulses have been shown to
      phase shift the circadian pacemaker. The aim of the present study was to
      determine whether a single sequence of brief bright light pulses administered
      during the early biological night would phase delay the human circadian
      pacemaker. Twenty-one healthy young subjects underwent a 6.5-h light exposure
      session in one of three randomly assigned conditions: 1) continuous bright light
      of approximately 9,500 lux, 2) intermittent bright light (six 15-min bright light
      pulses of approximately 9,500 lux separated by 60 min of very dim light of <1
      lux), and 3) continuous very dim light of <1 lux. Twenty subjects were included
      in the analysis. Core body temperature (CBT) and melatonin were used as phase
      markers of the circadian pacemaker. Phase delays of CBT and melatonin rhythms in
      response to intermittent bright light pulses were comparable to those measured
      after continuous bright light exposure, even though the total exposure to the
      intermittent bright light represented only 23% of the 6.5-h continuous exposure.
      These results demonstrate that a single sequence of intermittent bright light
      pulses can phase delay the human circadian pacemaker and show that intermittent
      pulses have a greater resetting efficacy on a per minute basis than does
      continuous exposure.

PMID- 15039148
TI  - Glucocorticoids modulate amino acid-induced translation initiation in human
      skeletal muscle.
AB  - Amino acids are unique anabolic agents in that they nutritively signal to mRNA
      translation initiation and serve as substrates for protein synthesis in skeletal
      muscle. Glucocorticoid excess antagonizes the anabolic action of amino acids on
      protein synthesis in laboratory animals. To examine whether excessive
      glucocorticoids modulate mixed amino acid-signaled translation initiation in
      human skeletal muscle, we infused an amino acid mixture (10% Travasol)
      systemically to 16 young healthy male volunteers for 6 h in the absence (n = 8)
      or presence (n = 8) of glucocorticoid excess (dexamethasone 2 mg orally every 6 h
      for 3 days). Vastus lateralis muscles were biopsied before and after amino acid
      infusion, and the phosphorylation of eukaryotic initiation factor (eIF) 4E
      binding protein 1 (4E-BP1), ribosomal protein S6 kinase (p70(S6K)), and eIF2alpha
      and the guanine nucleotide exchange activity of eIF2B were measured. Systemic
      infusion of mixed amino acids significantly stimulated the phosphorylation of 4E
      BP1 (P < 0.04) and p70(S6K) (P < 0.001) and the dephosphorylation of eIF2alpha (P
      < 0.003) in the control group. Dexamethasone treatment did not alter the basal
      phosphorylation state of 4E-BP1, p70(S6K), or eIF2alpha; however, it abrogated
      the stimulatory effect of amino acid infusion on the phosphorylation of 4E-BP1 (P
      = 0.31) without affecting amino acid-induced phosphorylation of p70(S6K) (P =
      0.002) or dephosphorylation of eIF2alpha (P = 0.003). Neither amino acid nor
      dexamethasone treatment altered the guanine nucleotide exchange activity of
      eIF2B. We conclude that changes of amino acid concentrations within the
      physiological range stimulate mRNA translation by enhancing the binding of mRNA
      to the 43S preinitiation complex, and the activity of p70(S6K) and glucocorticoid
      excess blocks the former action in vivo in human skeletal muscle.

PMID- 15039149
TI  - Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily
      without time- and food-related cues.
AB  - Ghrelin is an orexigenic hormone that is implicated in meal initiation, in part
      because circulating levels rise before meals. Because previous human studies have
      examined subjects fed on known schedules, the observed preprandial ghrelin
      increases could have been a secondary consequence of meal anticipation. A causal
      role for ghrelin in meal initiation would be better supported if preprandial
      increases occurred before spontaneously initiated meals not prompted by external
      cues. We measured plasma ghrelin levels among human subjects initiating meals
      voluntarily without cues related to time or food. Samples were drawn every 5 min
      between a scheduled lunch and a freely requested dinner, and hunger scores were
      obtained using visual analog scales. Insulin, glucose, fatty acids, leptin, and
      triglycerides were also measured. Ghrelin levels decreased shortly after the
      first meal in all subjects. A subsequent preprandial increase occurred over a
      wide range of intermeal intervals (IMI; 320-425 min) in all but one subject.
      Hunger scores and ghrelin levels showed similar temporal profiles and similar
      relative differences in magnitude between lunch and dinner. One subject displayed
      no preprandial ghrelin increase and was also the only individual whose insulin
      levels did not return to baseline between meals. This finding, along with a
      correlation between area-under-the-curve values of ghrelin and insulin, suggests
      a role for insulin in ghrelin regulation. The preprandial increase of ghrelin
      levels that we observed among humans initiating meals voluntarily, without time-
      or food-related cues, and the overlap between these levels and hunger scores are
      consistent with a role for ghrelin in meal initiation.

PMID- 15039150
TI  - Earning and maintaining the public trust.

PMID- 15039151
TI  - Strategies for formulating appropriate MDCT techniques when imaging the chest,
      abdomen, and pelvis in pediatric patients.
AB  - OBJECTIVE: Our aim was to formulate appropriate MDCT chest and abdominopelvic CT
      scan protocols for pediatric patients. MATERIALS AND METHODS: Surface radiation
      dose measurements from a set of anthropomorphic phantoms (nominal 1 year old, 5
      year old, and 10 year old) and an adult phantom were compared with standard CT
      dose index measurements. Image-noise values on axial 5-mm-thick anthropomorphic
      phantom images were obtained as a measure of image quality. RESULTS: Peripheral
      CT dose index values obtained with the standard 16-cm acrylic phantom were within
      approximately 10% of the CT surface dose measurements for the pediatric
      anthropomorphic phantoms for both chest and abdominopelvic scan protocols. The
      noise value for the adult phantom image acquired using a typical clinical CT
      technique was identified, and targeting this level of noise for pediatric CT
      examinations resulted in a decrease in dose of 60-90%. Initially, 80 kVp was
      selected for use with very small children; however, beam-hardening artifacts were
      severe enough to cause us to abandon this option. Current pediatric protocols at
      M. D. Anderson Cancer Center rely on 100- and 120-kVp settings. The display field
      of-view parameter can be used as a surrogate for patient size to develop clinical
      pediatric CT protocol charts. CONCLUSION: CT dose index measurements obtained
      using the 16-cm standard acrylic phantom are sufficiently accurate for estimating
      chest and abdominopelvic CT entrance exposures for pediatric patients of the same
      approximate size as the anthropomorphic phantoms used in this study. Image-noise
      measurements can be used to adjust chest and abdominopelvic CT techniques for
      pediatric populations, resulting in a decrease in measured entrance dose by 60
      90%.

PMID- 15039153
TI  - Assessment of vasculature using combined MRI and MR angiography.
AB  - OBJECTIVE: The purpose of this study was to compare combined cine gradient
      recalled echo MRI and MR angiography with conventional angiography in the
      evaluation of the pulmonary vascular supply in patients with pulmonary atresia,
      ventricular septal defect, and major aortopulmonary collateral arteries.
      MATERIALS AND METHODS: Eleven patients who underwent both MRI and conventional
      angiography were retrospectively reviewed. Contiguous 2D cine gradient-recalled
      echo images (TR range/TE, 30-80/4.8; flip angle, 20 degrees or 30 degrees ) and
      3D MR angiographic images (TR range/TE range, 3.8-5.0/1.3-2.0; acquisition time,
      13-32 sec) using gadopentetate meglumine (0.1-0.2 mmol/kg) were obtained. The
      presence, size, and course of the pulmonary arteries (main, right, left) and
      major aortopulmonary collateral arteries (>/= 5 mm) were determined. Presence of
      minor collateral arteries (< 5 mm) was also noted. Results were compared with
      findings at conventional angiography. RESULTS: MRI showed all main (n = 4) and
      branch (n = 17) pulmonary arteries found at conventional angiography and showed
      the pulmonary confluence in five of six cases. MRI showed all major aortic
      collaterals (n = 22) with a highly significant correlation between MRI and
      conventional angiography measurements (r = 0.84, p < 0.001 [95% confidence
      interval, -0.35 to 0.40]). One coronary artery collateral was not shown on MRI
      examination. At MRI, 12 of 14 major and four of seven minor brachiocephalic
      artery collaterals were shown. MRI showed more minor aortic collaterals than
      angiography (22 vs 18 vessels, respectively). CONCLUSION: Combined cine gradient
      recalled echo MRI and MR angiography is a reliable method for imaging pulmonary
      vascular supply in patients with these disorders. Additional prospective studies
      comparing MRI and conventional angiography may determine whether routine
      preoperative conventional angiography is required.

PMID- 15039154
TI  - How many observers are needed in clinical studies of medical imaging?

PMID- 15039156
TI  - Improved teleradiology reporting using fax software.
AB  - OBJECTIVE: In an effort to expedite after-hours teleradiology reports in an
      efficient and accurate manner with minimal usage of manpower, we have for the
      past 4 years used commercially available fax software running on a laptop
      computer placed beside the home-based teleradiology system. The software and
      laptop combination allows the radiologist to make a report rapidly by typing
      brief sentences in a fillable field or by selecting an applicable pretyped report
      from a menu. The report is then electronically faxed to single or multiple sites
      with a single mouse click. CONCLUSION: The system has drastically reduced the
      number of telephone calls between technologists and teleradiologists and has been
      well received by both technologists and emergency department staff and referring
      physicians.

PMID- 15039157
TI  - Abdominal CT angiography before surgery as a predictor of postoperative death in
      acute aortic dissection.
AB  - OBJECTIVE: The purpose of our study was to search for a relationship between
      postoperative death in acute aortic dissection and abdominal helical CT findings
      before surgery. MATERIALS AND METHODS: We retrospectively included 48 patients
      admitted to our institution for emergent surgery of acute aortic dissection
      diagnosed with helical CT angiography. We recorded postoperative deaths and
      analyzed abdominal helical CT vessels and parenchymal abnormalities, including
      the presence of dissected abdominal aortic branches, a compressed aortic lumen,
      and low enhancement of the parenchyma in abdominal organs. RESULTS: Among the 48
      patients, 11 died after surgery. Postoperative death occurred in one of five
      patients with low enhancement of the parenchyma in one abdominal organ and in
      seven of eight patients with low enhancement of the parenchyma in at least two
      abdominal organs. The postoperative death rates strongly correlated with the
      number of low-enhanced abdominal organs per patient (p < 0.00005) but did not
      correlate with the number of dissected abdominal aortic branches. CONCLUSION: The
      rate of abdominal organs with low enhancement of the parenchyma seen on CT before
      surgery is a strong factor in outcome in patients with acute aortic dissection.
      Additional analysis of low enhancement of the parenchyma in abdominal organs on
      CT might be a useful tool to detect, before surgery, patients at risk of
      postoperative death.

PMID- 15039159
TI  - Characterization of lesions missed on interpretation of CT colonography using a
      2D search method.
AB  - OBJECTIVE: We examined potential factors that may cause false-negative results on
      CT colonography examinations. MATERIALS AND METHODS: In this prospective and
      retrospective study, 500 asymptomatic patients at high risk for colorectal cancer
      underwent CT colonography and colonoscopy. Each CT data set was interpreted by
      two independent observers, who were unaware of endoscopic findings, using a
      method of searching through enlarged axial images to detect intraluminal lesions.
      Another observer identified and characterized lesions missed at prospective
      interpretation. Polyps were assessed for size, method of visualization, intrinsic
      and extrinsic features, and examination quality. RESULTS: We found 116 polyps at
      least 5 mm in diameter, 54 (47%) of which were missed by at least one of the
      prospective observers. Polyps seen in only one position were missed more often
      than polyps seen in both supine and prone positions (84% vs 50%, p < 0.01).
      Polyps located in suboptimally prepared colonic segments or along a thickened
      colonic wall were more frequently missed (p = 0.02 and p = 0.05, respectively).
      Endoscopic morphology and irregular surface contour were associated with missed
      lesions of all sizes (p = 0.03 and p = 0.04, respectively). Rounded intraluminal
      lesions were detected more often than other morphologies on CT (p = 0.04).
      CONCLUSION: Factors that influence the likelihood that a polyp may be missed at
      interpretation of CT colonography include being seen only in one position, having
      flat endoscopic or CT morphology, having surface irregularity, and being located
      in a poorly prepared segment or along a thickened colonic wall. Understanding
      these features should lead to improved polyp detection on CT colonography.

PMID- 15039160
TI  - Long-term results of celiac Ganglia block: correlation of grade of tumoral
      invasion and pain relief.
AB  - OBJECTIVE: We evaluated the long-term results and response rates of celiac
      ganglia block to the level of tumor invasion of the celiac region. SUBJECTS AND
      METHODS. Forty-one patients each with an inoperable intraabdominal carcinoma who
      were referred to our department for celiac ganglia block were included in this
      study. Tumor invasion of the celiac ganglia region was graded on a four-point
      scale according to CT features (grade I = no invasion, grade II = invasion < 50%,
      grade III = invasion > 50%, and grade IV = complete invasion). Subjective pain
      levels (0 = no pain, 10 = worst pain) were obtained from the patients, and
      objective criteria (change in daily analgesic doses) were noted before the
      procedure and during the follow-up to determine effectiveness of the celiac
      ganglia block. RESULTS: Celiac ganglia block was successfully performed in all 41
      patients (100%). In 39 (95%) of 41 patients, pain decreased significantly after
      the procedure, and the pain level did not change in the remaining two patients.
      Major complications were not encountered in any of the patients. Minor
      complications were observed in 35 patients (85%). Mean pain intensity and mean
      daily analgesic consumption significantly decreased after the procedure in all
      four groups. The amount of pain decrease for these two parameters was inversely
      related to degree of invasion. Responses of the patients were obtained at the end
      of the first week after the procedure and remained unchanged during long-term
      follow-up. CONCLUSION: Percutaneous celiac ganglia block, particularly when
      performed in earlier stages of ganglia invasion, is an effective, easy, and safe
      procedure with successful long-term results.

PMID- 15039161
TI  - Time interval between abnormalities seen on CT and the clinical diagnosis of
      pancreatic cancer: retrospective review of CT scans obtained before diagnosis.
AB  - OBJECTIVE: Our purpose was to determine whether abdominal CT can detect
      pancreatic cancer before its clinical diagnosis. SUBJECTS AND METHODS: Two
      radiologists interpreted in a blinded manner 62 CT scans in 28 pancreatic cancer
      patients that were obtained before histologic diagnosis and 89 CT scans in 89
      control subjects and noted specific CT findings. The presence of pancreatic
      cancer was characterized as definite, suspicious, low probability, or normal. The
      scans of the pancreatic cancer patients were divided into four groups on the
      basis of the time interval preceding cancer diagnosis (0-2, 2-6, 6-18, or > 18
      months), and one scan (closest to 18 months) was selected per patient per time
      interval. Sensitivity and specificity for pancreatic cancer and interobserver
      agreement for CT findings were calculated. RESULTS: Radiologists agreed that CT
      findings definite or suspicious for pancreatic cancer were present in 50% of the
      scans obtained 2-6 and 6-18 months before the diagnosis of pancreatic cancer (3/6
      and 4/8 scans, respectively), but they noted such CT findings in only 7% (1/15)
      of the scans obtained more than 18 months before diagnosis. Pancreatic duct
      dilatation and cutoff were early CT findings identified by both radiologists and
      were associated with near-perfect and substantial interobserver agreement (kappa
      = 0.84 and 0.76, respectively). Ninety-five percent confidence intervals of
      specificity for tumor absence ranged from 92% to 100%. CONCLUSION: CT can detect
      a significant proportion of asymptomatic incident pancreatic cancers before the
      clinical diagnosis of pancreatic cancer. CT should be considered in screening at
      risk patient populations. Pancreatic duct dilatation and cutoff are early
      findings associated with the development of pancreatic cancer and can be detected
      on CT with a high degree of reproducibility.

PMID- 15039163
TI  - Spectrum of imaging findings after pancreas transplantation with enteric exocrine
      drainage: Part 1, posttransplantation anatomy.

PMID- 15039162
TI  - Frequency and CT patterns of bowel wall thickening proximal to cancer of the
      colon.
AB  - OBJECTIVE: This study was performed to determine the frequency and patterns of
      colon wall thickening seen on CT of patients with adenocarcinoma of the colon.
      MATERIALS AND METHODS: Preoperative abdominal and pelvic CT scans of 185 patients
      with surgically proven adenocarcinoma of the colon were retrospectively evaluated
      by three abdominal radiologists for the presence of colon obstruction and colon
      wall thickening proximal to the colon adenocarcinoma. The distributions and
      patterns of colon wall thickening were categorized by consensus. CT findings were
      compared with pathologic findings. Fisher's exact test was used to determine the
      statistical significance of any associations. RESULTS: Of 185 patients, CT
      findings of 20 (10.8%) showed colon wall thickening. Of these, the adenocarcinoma
      obstructed the colon in 19 patients (p < 0.01). Colon obstruction was partial in
      10 patients (53%) and complete in nine (47%). Colon wall thickening was
      contiguous to the tumor in 14 (70%) patients and noncontiguous in six (30%).
      Segmental and pancolonic, patchy and diffuse, and dependent and nondependent
      colon wall thickening was observed in 10 patients (50%) in each category.
      Associated small-bowel wall thickening was shown in 10 (50%) of the 20 patients.
      Pathologic examination showed colon wall thickening to be due to edema in all
      cases. CONCLUSION: Colon wall edema can occur proximal to colon adenocarcinoma,
      is almost always associated with colon obstruction, and is predominantly
      contiguous with the obstructing adenocarcinoma.

PMID- 15039164
TI  - Spectrum of imaging findings after pancreas transplantation with enteric exocrine
      drainage: Part 2, posttransplantation complications.

PMID- 15039165
TI  - Upper gastrointestinal tract barium examination of postbulbar duodenal ulcers.
AB  - OBJECTIVE: The purpose of our investigation was to review the findings on barium
      studies in a series of eight patients with postbulbar duodenal ulcers in order to
      better characterize the clinical and radiographic features of these ulcers.
      CONCLUSION: Our experience suggests that ulcers in the postbulbar duodenum are
      considerably larger than those in the duodenal bulb and that they constitute a
      greater percentage of all duodenal ulcers than has previously been recognized. It
      is important for radiologists to be familiar with the characteristic radiographic
      features of postbulbar ulcers because of the increased risk of serious upper
      gastrointestinal tract bleeding in patients with this condition.

PMID- 15039166
TI  - Prevalence of meniscal radial tears of the knee revealed by MRI after surgery.
AB  - OBJECTIVE: Meniscal resection decreases the ability of the meniscus to evenly
      distribute forces placed on it. These forces are oriented centrifugally on the
      meniscus by normal weight-bearing and are distributed by circumferentially
      oriented fibers. This alteration may predispose the knee to radial tears after
      surgery. SUBJECTS AND METHODS: One of three musculoskeletal radiologists
      prospectively interpreted 100 consecutive postoperative MRI examinations of the
      knee. A prospective MRI report was generated for the referring orthopedic
      surgeon, and prospective MRI interpretations were correlated with arthroscopic
      findings (n = 63). MRI examinations on those patients who underwent second-look
      arthroscopy were retrospectively reviewed by three musculoskeletal radiologists
      who reached a consensus on the prevalence of new postoperative meniscal radial
      tears. MRI criteria for radial tear diagnosis were used as outlined by Tuckman et
      al.: truncation, abnormal morphology, lack of continuity, absence of the
      meniscus, or any combination of those criteria on one or more MR images. An
      additional criterion used was abnormal increased signal in that area on T2
      weighted images. RESULTS: Thirty-two of the 100 patients had meniscal radial
      tears on prospective MRI interpretations. In 29 of these 32 patients, second-look
      arthroscopy confirmed meniscal radial tears in the areas described on the MRI
      examinations. Five additional radial tears were shown on second-look arthroscopy
      that were not seen on prospective MRI interpretations. Two of those additional
      five radial tears were seen on consensus retrospective MRI review. CONCLUSION: In
      this study, a 32% prevalence of meniscal radial tears in the postoperative knee
      was present on prospective MRI interpretations as opposed to a reported 14%
      prevalence in the nonoperated knee. Meniscal resection decreases the ability of
      the meniscus to evenly distribute forces placed on it. This circumstance may
      increase the prevalence of meniscal radial tears in the postoperative knee. New
      meniscal radial tears are common in patients presenting with pain after knee
      surgery.

PMID- 15039167
TI  - Rheumatoid arthritis of the hand and wrist: comparison of three imaging
      techniques.
AB  - OBJECTIVE: The purpose of this study was to compare the relative results from
      conventional high-field-strength 1.5-T MRI, 0.2-T low-field-strength dedicated
      extremity MRI, and radiography to detect and grade bone erosions, joint-space
      narrowing, and synovitis in the hands and wrists of patients with rheumatoid
      arthritis. SUBJECTS AND METHODS: Eighteen patients with rheumatoid arthritis
      underwent conventional high-field-strength MRI, low-field-strength dedicated
      extremity MRI, and conventional radiography of both hands and wrists. Two
      independent reviewers searched for the presence and extent of bone erosions,
      joint-space narrowing, and synovitis. Bone erosions (E scores) and joint-space
      narrowing (J scores) were evaluated at 14 and 13 sites, respectively, on
      conventional high-field-strength MRI, low-field-strength dedicated extremity MRI,
      and radiography, using the Sharp-Genant scoring system. Synovitis (S scores) were
      evaluated at 13 sites on conventional high-field-strength MRI and low-field
      strength dedicated extremity MRI. RESULTS: For the detection of bone erosions, we
      found no significant difference (p = 0.71) between conventional high-field
      strength MRI (mean +/- SD E score, 27.5 +/- 9.8) and low-field-strength dedicated
      extremity MRI (28.8 +/- 10.0), but a significant difference (p < 0.001) appeared
      between MRI and radiography (13.1 +/- 8.3). J scores derived from MRI
      (conventional high-field-strength MRI, 15.2 +/- 8.3; low-field-strength dedicated
      extremity MRI, 14.5 +/- 10.4) were higher than those derived from radiography
      (12.7 +/- 9.6), although the difference was not significant (p = 0.70).
      Conventional high-field-strength MRI (S score, 35.1 +/- 8.6) and low-field
      strength dedicated extremity MRI (30.8 +/- 10.2) were equivalent (p = 0.14) for
      the evaluation of synovitis. The interobserver agreement for MRI scores was good
      to excellent (intraclass correlation coefficients, 0.83-0.94). CONCLUSION:
      Conventional high-field-strength MRI and low-field-strength dedicated extremity
      MRI showed similar results in terms of cross-sectional grading of bone erosions,
      joint-space narrowing, and synovitis in the hands and wrists of patients with
      rheumatoid arthritis.

PMID- 15039168
TI  - Optimal positioning for MRI of the distal biceps brachii tendon: flexed abducted
      supinated view.

PMID- 15039169
TI  - Percutaneous vertebroplasty in patients with spinal canal compromise.
AB  - OBJECTIVE: The American College of Radiology Standard for Performance of
      Percutaneous Vertebroplasty lists as relative contraindications to the procedure
      conditions causing "significant spinal canal compromise." We believe percutaneous
      vertebroplasty can be performed safely and efficaciously in individuals without
      radicular symptoms who present with canal compromise, with or without cord
      compression. MATERIALS AND METHODS: We reviewed all vertebroplasties performed at
      our institution over the past 4 years. Cases in which vertebroplasty was
      performed at levels showing complete effacement of the epidural space,
      particularly those with cord compression, were included in the review. Follow-up
      data obtained from questionnaires routinely sent to our vertebroplasty patients
      were used to evaluate symptomatic response in this subset of patients as well as
      the occurrence of any complications. RESULTS: Of 686 levels treated over the past
      4 years, 26 levels in 23 patients qualified for our review. Follow-up ranged from
      6 months to 2 years. Patients were asked to rate the degree of their original
      pain as follows: gone, better than, the same as, or worse than before the
      procedure. Of the 23 patients, five (22%) reported complete resolution of pain,
      15 (65%) reported their symptoms to be better, and three (13%) reported no
      appreciable change. No complications with clinical sequelae were encountered.
      CONCLUSION: Percutaneous vertebroplasty can be performed safely at levels showing
      spinal cord compression in patients without radicular signs. Most patients (87%)
      in our series showed some improvement or complete eradication of their symptoms.
      No patient reported worsening symptoms.

PMID- 15039170
TI  - Sonographically guided phenol injection in painful stump neuroma.

PMID- 15039171
TI  - Normal anatomy and pathology of the posterior capsular area of the knee: findings
      in cadaveric specimens and in patients.

PMID- 15039173
TI  - Positron emission tomography of schwannomas: emphasizing its potential in
      preoperative planning.
AB  - OBJECTIVE: In this article, we describe FDG uptake in schwannoma as measured on
      positron emission tomography (PET). FDG uptake is compared with tumor
      cellularity, tumor size, and tumor proliferation rate (Ki-67 index). CONCLUSION:
      Schwannomas generally have a high tumor-to-background ratio on FDG PET.
      Semiquantitative analysis with standardized uptake values (SUVs) reveals a wide
      variation in SUVs that can be explained by variations in the degree of
      cellularity. No correlation was found between FDG uptake and tumor size or tumor
      proliferation rate (Ki-67 index). Because these tumors often have a high level of
      FDG uptake, distinguishing schwannomas from malignant peripheral nerve sheath
      tumors before biopsy or surgery is not possible. Even in cases in which the
      maximum SUV or average SUV is greater than 6.0, schwannomas cannot be excluded.
      Therefore, schwannoma should be included in the differential diagnosis of
      peripheral nerve sheath tumors with low, intermediate, or high SUVs.

PMID- 15039172
TI  - Imaging of vascularized fibula autograft placed inside a massive allograft in
      reconstruction of lower limb bone tumors.
AB  - OBJECTIVE: Bone allografts and vascularized fibula autografts were combined (the
      fibula inside the massive allograft) for skeletal reconstruction in a homogeneous
      group of patients. To verify the biologic behavior of the grafts, we followed the
      series using conventional radiography and CT analysis. MATERIALS AND METHODS:
      Twenty-four patients with bone tumors had intercalary segments of tibia or femur
      reconstructed and were followed up for 36-120 months. Sequential radiographs and
      CT scans were analyzed. RESULTS: Three types of behavior were observed. In 13
      patients, the allograft maintained its architecture without fracture, although a
      regular enlargement of the inlaid fibula led to progressive integration with the
      allograft. A dense line on allograft endosteum was the first sign of bone bridges
      heralding fusion of the two grafts. In eight patients, fracture or nonunion of
      the allograft occurred, and the autograft reacted with rapid appearance of dense
      hypertrophy that again induced bridges to the allograft. In three patients, no
      changes in autograft size and density were followed by fracture with no callus
      formation. This behavior was interpreted as unsuccessful vascularization of the
      autograft. CONCLUSION: Sequential radiography and CT analysis enabled us to
      understand the changes in a combined graft offering an original way to
      revascularize bone allografts.

PMID- 15039174
TI  - FDG positron emission tomography of bone involvement in sarcoidosis.

PMID- 15039176
TI  - False-positive FDG positron emission tomography uptake in nonmalignant chest
      abnormalities.

PMID- 15039175
TI  - Coronal reformations of volumetric expiratory high-resolution CT of the lung.
AB  - OBJECTIVE: The purposes of this study were to evaluate the quality of coronal
      reformatted images obtained from volumetric expiratory high-resolution CT imaging
      and to compare coronal and axial images with regard to their usefulness in
      detecting and characterizing air trapping. SUBJECTS AND METHODS. We studied 40
      consecutive patients with known or suspected diffuse lung diseases with airway
      abnormalities who underwent volumetric expiratory high-resolution CT between May
      and July 2003. Respiratory motion artifacts were evaluated at upper, middle, and
      lower lung areas. Cardiac motion, beam-hardening, and other artifacts were
      evaluated throughout the lung fields. Detectability, clarity of borders, size,
      distribution, and extent of air trapping were compared on axial versus coronal
      end-expiratory high-resolution CT images. RESULTS: Respiratory motion artifacts
      were either imperceptible or not diagnostically limiting in all patients except
      three (7%) with diagnostically limiting image degradation at lower lung areas.
      Other diagnostically limiting image degradation was caused by beam-hardening
      artifacts in two patients (5%) and by quantum noise in two other patients (5%).
      The borders of air trapping were more clearly identified on coronal images than
      on axial images (grade 1 [vague], nine vs three; grade 2 [partially clear], 23 vs
      21; grade 3 [completely clear], eight vs 16; median, two vs two; p = 0.001). The
      coronal reformatted images were as informative as axial images for detecting and
      assessing the classification and extent of air trapping. CONCLUSION: Coronal
      reformations of volumetric expiratory high-resolution CT scans were acceptable in
      image quality and provided additional value by affording clearer visualization of
      the borders of air trapping than was found in contiguous axial images.

PMID- 15039177
TI  - Acute cerebral infarction after radiofrequency ablation of an atypical carcinoid
      pulmonary tumor.

PMID- 15039178
TI  - ECG-gated cardiac CT.

PMID- 15039179
TI  - Pretransplantation diagnosis and staging of hepatocellular carcinoma in patients
      with cirrhosis: value of dual-phase helical CT.
AB  - OBJECTIVE: The objective of our study was to prospectively evaluate the results
      of helical CT in the detection of hepatocellular carcinoma (HCC) in patients with
      cirrhosis undergoing orthotopic liver transplantation. SUBJECTS AND METHODS.
      Eighty-five patients with cirrhosis were studied preoperatively with biphasic
      helical CT. Arterial, portal, and equilibrium phase images were obtained after
      injection of 170 mL of contrast material at 5 mL/sec. The prospective CT
      interpretation was compared with pathologic results on a lesion-by-lesion basis.
      RESULTS: Pathologic examination found 85 cases of HCC in 51 patients. Helical CT
      enabled a correct diagnosis of HCC in 67 of 85 lesions for a sensitivity of
      78.8%. HCC nodules were hypervascular in the arterial phase and hypovascular in
      the equilibrium phase in 63.5% (54/85) of patients. The false-negative rate was
      21% (n = 18), and the positive predictive value was 88%. We had nine false
      positive findings (11.8%) related to hemangiomas, transient hepatic attenuation
      differences, and regenerative nodules. Helical CT detected 61% (23/38) of lesions
      smaller than 2 cm and 93.6% (44/47) of lesions 2 cm or larger. CONCLUSION:
      Helical CT is a useful preoperative imaging technique in cirrhotic patients who
      are candidates for orthotopic liver transplantation, although it is relatively
      insensitive for detection of small lesions (< 2 cm).

PMID- 15039180
TI  - Characterization of hepatic tumors: value of contrast-enhanced coded phase
      inversion harmonic angio.
AB  - OBJECTIVE: Our purpose was to evaluate the value of contrast-enhanced coded phase
      inversion harmonic imaging in showing the characteristic intranodular
      hemodynamics of hepatic tumors. SUBJECTS AND METHODS. Using a microbubble
      contrast agent we performed coded harmonic angio in 163 patients with 192 hepatic
      tumor nodules: 153 hepatocellular carcinomas, 13 metastases, 14 hemangiomas,
      eight dysplastic nodules, and four focal nodular hyperplasias. After injecting
      Levovist, we performed real-time scanning, interval-delay fast low-angle shot
      imaging, and sweep scanning in the early arterial phase, late vascular phase, and
      postvascular phase, respectively. RESULTS: On contrast-enhanced coded harmonic
      angio, the typical hemodynamic pattern of hepatocellular carcinomas was shown as
      abundant tumor vessels supplied from the periphery to the center of the tumor and
      dense parenchymal tumor staining with fast washout (sensitivity, 92.8%;
      specificity, 92.3%). The characteristic hemodynamic pattern of metastases was
      peripheral tumor vessels with a rim parenchymal stain in the vascular phase
      followed by a perfusion defect in the postvascular phase (sensitivity, 69.2%;
      specificity, 100%). Hemangiomas were hypovascular in the early arterial phase
      with gradual spotty or cotton-wool pooling continuing to the late vascular phase
      (sensitivity, 92.9%; specificity, 100%). Dysplastic nodules were shown as having
      no early arterial supply with isovascularity in the late vascular phase
      (sensitivity, 75%; specificity, 100%). Focal nodular hyperplasias were shown to
      have a spoked wheel pattern of blood vessels accompanied by dense staining in
      interval-delay scanning (sensitivity, 100%; specificity, 100%). CONCLUSION:
      Contrast-enhanced coded harmonic angio is a promising method to provide useful
      information for the differential diagnosis of hepatic tumors.

PMID- 15039181
TI  - Frequency and imaging appearance of hepatic angiomyolipomas in pediatric and
      adult patients with tuberous sclerosis.
AB  - OBJECTIVE: This study evaluates the frequency and imaging appearance of hepatic
      angiomyolipomas in pediatric and adult patients with tuberous sclerosis.
      CONCLUSION: Multiple hepatic angiomyolipomas are often found in patients with
      tuberous sclerosis, particularly in those with bilateral diffuse renal
      angiomyolipomas.

PMID- 15039182
TI  - Focal intrahepatic extramedullary hematopoiesis presenting as fatty lesions.

PMID- 15039183
TI  - Changing role of imaging-guided percutaneous biopsy of adrenal masses: evaluation
      of 50 adrenal biopsies.
AB  - OBJECTIVE: Prior series of percutaneous imaging-guided biopsies of adrenal masses
      before the advent of dedicated CT and MRI of the adrenal glands have shown that
      40-57% of adrenal masses biopsied were adenomas-benign lesions requiring no
      further evaluation or treatment. This study was performed to assess the effect of
      dedicated adrenal imaging with CT and MRI on the rate of percutaneous imaging
      guided biopsies of adrenal masses. MATERIALS AND METHODS: We reviewed 50
      consecutive adrenal mass biopsies performed during a 48-month period. The patient
      demographics, technique of biopsy, pathology results, and results of any prior
      dedicated adrenal imaging with MRI or CT protocols were noted. RESULTS: Only six
      (12%) of 50 biopsies were adenomas. Five of these six cases were preceded by
      dedicated adrenal CT or MRI. Thirty-five cases were metastatic disease, four were
      adrenal cortical carcinoma, three were pheochromocytoma, and two biopsies were
      nondiagnostic. Overall, 20 of 50 cases were preceded by a dedicated adrenal CT or
      MRI examination to exclude an adenoma; in 21 of the remaining 30 cases, the
      imaging characteristics before biopsy were inconsistent with the potential
      diagnosis of an adenoma and dedicated adrenal CT or MRI was not recommended.
      CONCLUSION: The number of adrenal adenomas biopsied has declined markedly with
      the introduction of dedicated adrenal CT and MRI for adrenal adenomas.
      Percutaneous imaging-guided biopsy is useful in confirming the presence and
      nature of suspected metastatic deposits to the adrenal gland and in diagnosing or
      excluding adrenal adenomas in patients with equivocal imaging characteristics.

PMID- 15039184
TI  - Normal ureter size on unenhanced helical CT.
AB  - OBJECTIVE: Unenhanced helical CT is the imaging method of choice when evaluating
      patients with acute flank pain and suspected ureterolithiasis. In addition to
      directly identifying stones in the lumen of the ureter, CT secondary signs of
      obstruction such as ureteral dilatation are frequently present and can be helpful
      in establishing a diagnosis. The purposes of this study were to define ureteral
      dilatation on unenhanced helical CT and determine the range of normal ureter
      size. MATERIALS AND METHODS: We retrospectively reviewed the unenhanced helical
      CT studies of 212 consecutive patients with acute flank pain whose CT scans
      showed acute ureterolithiasis. The size of the ureter was determined on the
      asymptomatic side as well as on the obstructed side. Mean ureteral diameter was
      determined as the largest transverse dimension along the course of the ureter
      beginning 1-2 cm below the ureteropelvic junction. RESULTS: The mean size of
      ureters on the asymptomatic side was 1.8 mm with a standard deviation (SD) of 0.9
      mm. The mean size of ureters on the obstructed side was 7 mm with an SD of 3.2
      mm. In 96% of patients, the ureter diameter on the asymptomatic side was 3 mm or
      smaller. CONCLUSION: Three millimeters should be considered the upper limit of
      normal size for nonobstructed ureters on unenhanced helical CT.

PMID- 15039185
TI  - Triple-phase dynamic MRI of intratumoral vessel density and hyalinization grade
      in uterine leiomyomas.
AB  - OBJECTIVE: Our purpose was to clarify the relationship between the tissue
      vascularity shown on triple-phase dynamic MRI and the number of intratumoral
      vessels and degree of hyalinization, which are two histopathologic changes in
      leiomyoma. SUBJECTS AND METHODS. The subjects were 10 premenopausal patients with
      20 leiomyomas who had undergone surgery without preoperative gonadotropin
      releasing hormone analogue treatment. Intratumoral vessel density was determined
      by the mean number of intratumoral vessels with at least one smooth-muscle layer
      in the optic fields magnified 100 times. Hyalinization grade was determined by
      the severity of hyalinization, histopathologically classified in three grades.
      The enhancement index (EI) of the leiomyoma was calculated using the formula
      EI(t) = [S(t) - S(0)] / S(0), where S(0) is the signal intensity on pre-enhanced
      T1-weighted images and S(t) is the signal intensity on each dynamic phase image
      (t = 20, 60, and 180 sec) [corrected]. The histopathologic parameters of
      intratumoral vessel density and hyalinization grade were compared with the
      enhancement indexes obtained from the triple-phase dynamic MRI. RESULTS: We found
      positive correlations between intratumoral vessel density and EI(60) and between
      intratumoral vessel density and EI(180) (in both cases, p = 0.0028 and r = 0.69).
      We found significant differences among the mean enhancement indexes for each
      hyalinization grade at all dynamic phases (p < 0.01). The leiomyomas with lower
      intratumoral vessel densities tended to show greater hyalinization. CONCLUSION:
      Our results showed that leiomyomas with only slight hyalinization or with
      abundant vessels were well enhanced, but the leiomyomas with severe hyalinization
      enhanced poorly.

PMID- 15039186
TI  - Imaging characteristics of cherubism.
AB  - OBJECTIVE: We sought to describe the radiographic and imaging features of
      cherubism. CONCLUSION: Cherubism is a rare osseous disorder of children and
      adolescents. Although the radiologic characteristics of cherubism are not
      pathognomonic, the diagnosis is strongly suggested by bilateral relatively
      symmetric jaw involvement that is limited to the maxilla and mandible. Imaging
      typically shows expansile remodeling of the involved bones, thinning of the
      cortexes, and multilocular radiolucencies with a coarse trabecular pattern.

PMID- 15039187
TI  - Transcatheter embolization of the middle sacral artery: collateral feeder in
      recurrent rectal bleeding.

PMID- 15039188
TI  - Simultaneous bilateral breast and high-resolution axillary MRI of patients with
      breast cancer: preliminary results.
AB  - OBJECTIVE: The aims of this study were to develop a standardized one-step
      procedure for simultaneous high-resolution MRI of the axilla and bilateral breast
      MRI and to identify nodal features suggestive of metastatic involvement. SUBJECTS
      AND METHODS. We studied 16 women undergoing axillary lymph node dissection after
      combined bilateral breast MRI and high-resolution MRI of the axilla with a
      maximum in-plane resolution of 0.6 x 0.4 mm. MRI was performed using a standard
      double breast coil and a 15-cm round flexible surface coil adapted to the axilla.
      High-resolution axillary sequences, including inversion recovery T2- and spin
      echo T1-weighted sequences, were performed before and after gadolinium chelates
      bolus injection. Axillary image analysis focused on nodal morphology including
      size, contour regularity, cortex and hilar appearance, signal intensity, and
      enhancement parameters. Axillary MRI findings were compared with the final
      pathogic results from axillary lymph node dissection in all patients. Patients
      were divided into groups according to the final pathologic axillary status.
      Differences in MRI lymph node features across the groups were tested using a t
      test for quantitative data and the chisquare test or Fisher's exact test for
      binary data. RESULTS: The features of the axilla on high-resolution MRI that best
      discriminated between patients with positive pathologic findings and those with
      negative pathologic findings were the presence of nodes with irregular contours
      (p < 10(-4)), high signal intensity on T2 sequences (p < 10(-3)), marked
      gadolinium enhancement (p < 10(-3)), and round hila and abnormal cortexes (p <
      0.05). CONCLUSION: Breast tissue and axillary lymph nodes both can be analyzed on
      MRI in a one-step process using a bilateral breast coil combined with a surface
      coil. Morphologic features observed on high-resolution MRI of the axilla can
      improve the identification of metastatic nodes.

PMID- 15039189
TI  - Generalized lymphangiomatosis.

PMID- 15039190
TI  - Sonographic appearance of mucinous carcinoma of the breast.
AB  - OBJECTIVE: The aim of this study was to evaluate the sonographic and mammographic
      features of mucinous carcinoma and to correlate the imaging features with two
      histologic classifications. MATERIALS AND METHODS: Two radiologists analyzed the
      mammographic and sonographic features of 33 mucinous carcinomas. Mammographic
      features according to the Breast Imaging Reporting and Data System (BI-RADS) and
      sonographic features were recorded and analyzed. The imaging features of the mass
      were correlated with the nuclear grade and mucin content of these 33 mucinous
      carcinomas. The incidence of axillary lymph nodes metastasis in different
      histologic grades and their detection by imaging were also assessed. RESULTS: As
      many as 21.2% (7/33) of mucinous carcinomas could not be detected
      mammographically. When they were detected mammographically, more than 92% of the
      tumors presented as a mass, either oval or lobular. Microlobulations were present
      in 38.5% of these lesions. The margin of the lesion as seen on mammography can be
      used to predict the histologic grade. A circumscribed margin was associated with
      a favorable histologic grade (p = 0.01), whereas an indistinct margin was more
      commonly associated with the mixed type of lesion (p = 0.05). Sonographically,
      mixed cystic and solid components, distal enhancement, and microlobulated margins
      were commonly found in mucinous carcinomas, with an incidence of 37.5%, 43.8%,
      and 56.3%, respectively. Homogeneity on sonography was associated with the pure
      type of mucinous carcinoma and hence a better prognosis. Sonography showed a
      sensitivity of 50%, specificity of 89%, positive predictive value of 60%,
      negative predictive value of 84%, and accuracy of 79.2% in the detection of
      axillary lymph node metastasis. CONCLUSION: Both sonographic and mammographic
      assessments are important in the correct diagnosis of mucinous carcinoma, the
      prediction of histologic grade, and the prognosis of the tumors.

PMID- 15039191
TI  - MRI-guided breast biopsy: clinical experience with 14-gauge stainless steel core
      biopsy needle.
AB  - OBJECTIVE: Core needle biopsy has proven advantages for wire localization and
      excision; however, MRI-guided core biopsy has been limited by less satisfactory
      sampling efficiency and less availability of MRI-compatible biopsy needles. We
      evaluated the feasibility and diagnostic yield of MRI-guided biopsy using 14
      gauge stainless steel core biopsy needles and MRI-compatible coaxial sheaths in a
      closed 1.5-T scanner. MATERIALS AND METHODS: Thirty-five consecutive breast
      biopsies performed in 29 women between March 2001 and August 2002 were
      retrospectively reviewed. For each procedure, an MRI-compatible sheath was placed
      under MRI guidance using a dedicated breast coil and biopsy guidance system. With
      the patient out of the magnet, a 14-gauge steel core biopsy needle was used to
      obtain multiple samples. Lesion characteristics, including size, morphology, and
      enhancement, were recorded. Histology of all the lesions was obtained; and
      surgical, imaging, or clinical follow-up was performed. RESULTS: Targeted masses
      and enhancing foci ranged from 3 to 17 mm. Regional enhancement ranged from 14 to
      70 mm. Thirty-four of the 35 biopsies were technically successful. Histology
      revealed malignancy in eight lesions (23%), atypical ductal hyperplasia in five
      lesions (14%), and benign entities in 21 lesions (60%). Surgery confirmed all
      eight core biopsies with malignant findings. Two of five lesions with atypical
      ductal hyperplasia were upgraded to malignancy after surgery. CONCLUSION: This
      new method of MRI-guided breast biopsy with a 14-gauge stainless steel core
      biopsy needle and a closed 1.5-T MRI scanner is feasible, safe, and effective and
      produces satisfactory diagnostic yield. This method offers an alternative to MRI
      guided wire localization and to MRI-guided core biopsy with nonferrous needles.

PMID- 15039192
TI  - Breast MRI for cancer detection in a patient with diabetic mastopathy.

PMID- 15039193
TI  - Adenomyosis: MRI of the uterus treated with uterine artery embolization.

PMID- 15039194
TI  - Beware of false claims.

PMID- 15039195
TI  - Aortopulmonary window or angle on the chest radiograph?

PMID- 15039196
TI  - The shading sign in cerebral squamous cell metastases.

PMID- 15039198
TI  - Seminal vesicle hydatid cysts: CT features in two patients.

PMID- 15039197
TI  - CT angiography, sonography, and MRI of aneurysm of the testicular artery.

PMID- 15039199
TI  - Foreign-body granuloma caused by dispersed oil droplets simulating subcutaneous
      fat tissue on MR images.

PMID- 15039201
TI  - Proteases, extracellular matrix, and cancer: a workshop of the path B study
      section.
AB  - The role of the extracellular matrix (ECM) in the tumor microenvironment is not
      limited to being a barrier against tumor invasion. The ECM is a reservoir of cell
      binding proteins and growth factors that affect tumor cell behavior. It is also
      substantially modified by proteases produced by tumor cells or stroma cells. As a
      result of the activity of these proteases, cell-cell and cell-ECM interactions
      are altered, new biologically active ECM molecules are generated, and the
      bioavailability and activity of many growth factors, growth factor receptors, and
      cytokines are modified. ECM-degrading proteases also play a critical role in
      angiogenesis, where they can act as positive as well as negative regulators of
      endothelial cell proliferation and vascular morphogenesis. This review article
      summarizes some of the most relevant findings made over the recent years that
      were discussed at a workshop organized by the Path B Study Section of the
      National Institutes of Health in October 2002.

PMID- 15039202
TI  - It's the matrix! ECM, proteases, and cancer.

PMID- 15039203
TI  - Building a more perfect beast: APP transgenic mice with neuronal loss.

PMID- 15039204
TI  - Epithelial tissue chimerism after human hematopoietic cell transplantation is a
      real phenomenon.
AB  - Bone marrow transplantation in animals has been shown to generate epithelial
      populations, a phenomenon that has also recently been suggested to take place
      after human hematopoietic cell transplantation. However, reports in humans are
      not conclusive because they still leave open the possibility that the identified
      donor-derived cells are not epithelial cells but intraepithelial lymphocytes.
      Here, we demonstrate that donor-derived CD45(+) hematopoietic cells in close
      contact with epithelial tissue may be falsely characterized as donor-derived
      epithelial cells if the three-dimensional structure of the tissue is not
      considered and the hematopoietic markers are not examined. By using a rigorous
      three-dimensional analysis on single sections of colon biopsies triple stained
      with donor-specific, epithelial-specific, and hematopoietic-specific markers we
      demonstrate that chimerism of colon epithelium is a real phenomenon occurring
      constantly after human hematopoietic cell transplantation. We exclude horizontal
      DNA transfer or cell fusion as the underlying mechanism of our findings. Tissue
      damage enhances the engraftment of the donor-derived epithelial cells. The
      physiological and therapeutical role of the donor-derived epithelial cells after
      human hematopoietic cell transplantation needs further investigation. However,
      their identification requires stringent and unequivocal detection systems.

PMID- 15039206
TI  - Oxidized low-density lipoprotein is present in astrocytes surrounding cerebral
      infarcts and stimulates astrocyte interleukin-6 secretion.
AB  - Ischemic injury to brain is associated with both disruption of the blood-brain
      barrier and increased oxidative stress. Given the neurotoxicity associated with
      exposure to oxidized low-density lipoprotein (oxLDL) in vitro, we tested the
      hypothesis that oxLDL may be present in parenchymal cells of cerebrum after
      infarction and that oxLDL may influence the pathophysiology of cerebral
      infarction. Our results showed that the subacute phase of cerebral infarction in
      patients was characterized by the appearance of oxLDL epitopes in astrocytes, but
      not neurons or microglia, in the perinecrotic zone. We further demonstrated that
      minimally oxLDL was most effectively internalized by primary cultures of rat
      astrocytes, and that exposure to minimal oxLDL stimulated astrocyte interleukin-6
      secretion but did not alter nitric oxide production. These results demonstrate
      for the first time that oxLDL is present in brain parenchyma of patients with
      ischemic infarction and suggest a potential mechanism by which oxLDL may activate
      innate immunity and thereby indirectly influence neuronal survival.

PMID- 15039205
TI  - Correlation of acute humoral response with brain virus burden and survival time
      in pig-tailed macaques infected with the neurovirulent simian immunodeficiency
      virus SIVsmmFGb.
AB  - Infection of pig-tailed macaques with the simian immunodeficiency virus (SIV)
      isolate SIVsmmFGb frequently results in SIV encephalitis (SIVE) in addition to
      immunodeficiency and acquired immune deficiency syndrome. We used in situ
      hybridization to quantitate the number of SIV-infected cells in brain parenchyma,
      choroid plexus, and meninges from 17 macaques that developed acquired immune
      deficiency syndrome after infection with SIVsmmFGb. SIV-infected cells and
      histopathological lesions of SIVE were identified in 15 of 17 animals (88.2%),
      including 12 of 12 rapid progressors (RP) and 3 of 5 slow progressors (SP). The
      parenchymal virus burden was much greater in RP macaques than in the three SP
      macaques with SIVE (median values of 24.3 versus 0.3 infected cells/mm(2),
      respectively; P < 0.05). Viral load differences between RP and SP with SIVE were
      less marked in choroid plexus (29.6 versus 12.8 infected cells/mm(2),
      respectively) and meninges (133.0 versus 34.2 infected cells/mm(2),
      respectively). A significant negative correlation was observed between the
      magnitude of the anti-SIV antibody titer at 1 month after inoculation and brain
      virus burden at necropsy (r = -0.614; P < 0.01). The close association between
      immune response and SIVE in this model should prove useful for identifying
      correlates of immune protection against primate lentiviral encephalitis.

PMID- 15039207
TI  - Suppression of tumor growth and angiogenesis in vivo by a truncated form of 24-kd
      fibroblast growth factor (FGF)-2.
AB  - Efforts to treat tumors have routinely depended on disruption of cell
      proliferation by a variety of methods, many involving stimulation of apoptosis.
      We have previously shown that a truncated form of 24-kd basic fibroblast growth
      factor consisting of the amino terminal 86 amino acids inhibits migration of
      tumor and endothelial cells in vitro. In the present study, this peptide was
      tested for its ability to suppress angiogenesis and tumor growth using the murine
      dorsal skin-fold chamber model in vivo. Treatment of MCF-7 breast carcinoma tumor
      spheroids with this peptide resulted in cessation of the angiogenic response and
      a significant reduction in tumor size. Blood vessels that did form were poorly
      developed. In addition to inhibiting angiogenesis, the peptide also inhibited
      migration of Lewis lung carcinoma cells away from the tumor core before onset of
      angiogenesis indicating that the peptide-mediated inhibition of migration affects
      both angiogenesis and tumor growth independently. Despite inhibition of tumor
      cell migration, the peptide had no effect on neutrophil or eosinophil chemotaxis.
      This study demonstrates that the truncated form of 24-kd basic fibroblast growth
      factor is effective in suppressing tumor development in vivo through inhibition
      of angiogenesis as well as inhibition of tumor cell migration without
      compromising other homeostatic events.

PMID- 15039208
TI  - Pericyte-like location of GFP-tagged melanoma cells: ex vivo and in vivo studies
      of extravascular migratory metastasis.
AB  - Previous studies have demonstrated that some tumor cells occupy a pericyte-like
      location in melanoma, forming angio-tumoral complexes. We hypothesized that these
      tumor cells are migrating along the abluminal surface of the endothelium, a
      mechanism termed "extravascular migratory metastasis." In the present study, we
      have used human and murine melanoma cells that stably express enhanced green
      fluorescence protein (GFP) to examine, in an ex vivo co-culture model, melanoma
      cell interactions with vessels that have sprouted from rat aortic rings. We also
      used in vivo tumor growth on the chick chorioallantoic membrane (CAM) to observe
      the dissemination pathway of melanoma cells. In the ex vivo rat aorta system, we
      observed a pericyte-like location of tumor cells that were spreading along the
      vascular channels. For examination of the CAM in vivo, we have used the Lugassy
      preparation, allowing one to obtain striking images of the relationship between
      fluorescent GFP cells and microvessels. Melanoma cells were found cuffing the
      outside of vessels around the tumor. Tumor cells were observed along the vessels
      several centimeters from the tumor. Confocal microscopy and histopathology
      confirmed the pericyte-like location of tumor cells, without any observable
      intravasation. The results indicate that melanoma cells can migrate along the
      abluminal surface of vessels. This study also demonstrates that these models can
      provide quantitation analysis that may prove useful in elucidating the molecular
      interactions involved in extravascular migratory metastasis.

PMID- 15039209
TI  - Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1,
      and ank: an integrated model of the pathogenesis of mineralization disorders.
AB  - Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes the mineralization
      inhibitor inorganic pyrophosphate (PP(i)). Deletion of the TNAP gene (Akp2) in
      mice results in hypophosphatasia characterized by elevated levels of PP(i) and
      poorly mineralized bones, which are rescued by deletion of nucleotide
      pyrophosphatase phosphodiesterase 1 (NPP1) that generates PP(i). Mice deficient
      in NPP1 (Enpp1(-/-)), or defective in the PP(i) channeling function of ANK
      (ank/ank), have decreased levels of extracellular PP(i) and are hypermineralized.
      Given the similarity in function between ANK and NPP1 we crossbred Akp2(-/-) mice
      to ank/ank mice and found a partial normalization of the mineralization
      phenotypes and PP(i) levels. Examination of Enpp1(-/-) and ank/ank mice revealed
      that Enpp1(-/-) mice have a more severe hypermineralized phenotype than ank/ank
      mice and that NPP1 but not ANK localizes to matrix vesicles, suggesting that
      failure of ANK deficiency to correct hypomineralization in Akp2(-/-) mice
      reflects the lack of ANK activity in the matrix vesicle compartment. We also
      found that the mineralization inhibitor osteopontin (OPN) was increased in Akp2(
      /-), and decreased in ank/ank mice. PP(i) and OPN levels were normalized in
      [Akp2(-/-); Enpp1(-/-)] and [Akp2(-/-); ank/ank] mice, at both the mRNA level and
      in serum. Wild-type osteoblasts treated with PP(i) showed an increase in OPN, and
      a decrease in Enpp1 and Ank expression. Thus TNAP, NPP1, and ANK coordinately
      regulate PP(i) and OPN levels. The hypomineralization observed in Akp2(-/-) mice
      arises from the combined inhibitory effects of PP(i) and OPN. In contrast, NPP1
      or ANK deficiencies cause a decrease in the PP(i) and OPN pools that leads to
      hypermineralization.

PMID- 15039211
TI  - Overexpression of pigment epithelium-derived factor decreases angiogenesis and
      inhibits the growth of human malignant melanoma cells in vivo.
AB  - Pigment epithelium-derived factor (PEDF) has recently been shown to be the most
      potent inhibitor of angiogenesis in the mammalian eye, and is involved in the
      pathogenesis of angiogenic eye disease such as proliferative diabetic
      retinopathy. However, a functional role for PEDF in tumor growth and angiogenesis
      remains to be determined. In this study, we have investigated both the in vitro
      and in vivo growth characteristics of human malignant melanoma G361 cell lines,
      stably transfected to overexpress human PEDF. Expression levels of PEDF proteins
      in melanoma cell lines G361 and A375 were comparable with that of human cultured
      melanocytes, whereas vascular endothelial growth factor levels in two tumor cell
      lines were much stronger than that in normal melanocytes. Overexpression of PEDF
      was found to significantly inhibit tumor growth and vessel formation in G361 nude
      mice xenografts. Furthermore, in vitro proliferation rates of G361 cells were
      decreased in PEDF-transfected cells. PEDF proteins showed dose-dependent induced
      growth retardation and apoptotic cell death in nontransfected G361 cells, which
      were completely prevented by treatment with antibodies against the Fas ligand.
      Our present study highlights two beneficial effects of PEDF treatment on melanoma
      growth and expansion; one is the suppression of tumor angiogenesis, and the other
      is induction of Fas ligand-dependent apoptosis in tumor cells. PEDF therefore
      might be a promising novel therapeutic agent for treatment of patients with
      melanoma.

PMID- 15039210
TI  - Assembly and reorientation of stress fibers drives morphological changes to
      endothelial cells exposed to shear stress.
AB  - Fluid shear stress greatly influences the biology of vascular endothelial cells
      and the pathogenesis of atherosclerosis. Endothelial cells undergo profound shape
      change and reorientation in response to physiological levels of fluid shear
      stress. These morphological changes influence cell function; however, the
      processes that produce them are poorly understood. We have examined how actin
      assembly is related to shear-induced endothelial cell shape change. To do so, we
      imposed physiological levels of shear stress on cultured endothelium for up to 96
      hours and then permeabilized the cells and exposed them briefly to fluorescently
      labeled monomeric actin at various time points to assess actin assembly.
      Alternatively, monomeric actin was microinjected into cells to allow continuous
      monitoring of actin distribution. Actin assembly occurred primarily at the ends
      of stress fibers, which simultaneously reoriented to the shear axis, frequently
      fused with neighboring stress fibers, and ultimately drove the poles of the cells
      in the upstream and/or downstream directions. Actin polymerization occurred where
      stress fibers inserted into focal adhesion complexes, but usually only at one end
      of the stress fiber. Neither the upstream nor downstream focal adhesion complex
      was preferred. Changes in actin organization were accompanied by translocation
      and remodeling of cell-substrate adhesion complexes and transient formation of
      punctate cell-cell adherens junctions. These findings indicate that stress fiber
      assembly and realignment provide a novel mode by which cell morphology is altered
      by mechanical signals.

PMID- 15039212
TI  - Retention of the arginine allele in codon 72 of the p53 gene correlates with poor
      apoptosis in head and neck cancer.
AB  - The allele constitution at codon 72 of the p53 gene (CGC-arginine or CCC-proline)
      plays a major role in inducing apoptosis in p53 mutant cells. To verify this, we
      determined GC-status, p53-mutations, and p53-loss of heterozygosity (LOH) in a
      group of 54 squamous cell carcinomas of the head and neck (SCCHN). A novel
      approach, using a one-step real-time PCR analysis with fluorescent hybridization
      probes, was applied to detect the GC status in tumors and corresponding blood
      samples. p53 mutations in exons 4 to 8 were detected by PCR-SSCP-sequencing
      analysis. Apoptosis was determined immunohistochemically using antibodies against
      Fas, FasL, p53, Bcl2, and terminal deoxy-transferase-mediated dUTP nick end
      labeling (TUNEL) staining. The overall frequency of p53-LOH in SCCHN was 45.2%.
      In cases of LOH, there was a preferential loss of the proline allele, which was
      associated with an up-regulation of Bcl2 and lack of co-expression of Fas/FasL
      and, thus, impaired apoptosis (P < 0.001). Apoptosis was not observed in tumors
      carrying the arginine allele. p53 mutations were detected in 29.6% of SCCHN and
      preferentially occurred at the arginine allele (P = 0.01). p53 alterations were
      more frequently observed in tumors of the oral cavity, oropharynx and
      hypopharynx, whereas they were rare in larynx carcinomas (P = 0.07). The p53-LOH
      status was not found to be significantly correlated with sex, age, TNM-status, or
      tumor grading. We conclude that apoptosis is correlated with the allelic status
      of codon 72 in SCCHN. Homozygous proline 72 appears to be an important regulator
      of apoptosis via the Fas/FasL pathway in SCCHN.

PMID- 15039213
TI  - Expression of a truncated form of the c-Kit tyrosine kinase receptor and
      activation of Src kinase in human prostatic cancer.
AB  - A truncated form of the c-Kit tyrosine kinase receptor, originally identified in
      mouse haploid germ cells, is aberrantly expressed in human cancer cell lines of
      various origin. This alternative transcript originates in the 15th intron of the
      human c-kit gene. We have previously demonstrated that sperm-carried mouse
      truncated c-Kit (tr-Kit) is a strong activator of the Src-family tyrosine kinases
      both in transfected cells and in mouse oocytes. In the present work, we report
      that human tr-Kit mRNA and protein are expressed in LNCaP prostatic cancer cells.
      We have identified two regions in the 15th and 16th introns of the human c-kit
      gene that show homology with sequences in the spermatid-specific tr-Kit promoter
      within the 16th intron of mouse c-kit. We also show that nuclear factors present
      in LNCaP cells bind to discrete sequences of the mouse tr-Kit promoter. Moreover,
      Western blot analysis of 23 primary prostate cancers indicated that tr-Kit was
      expressed in approximately 28% of the tumors at less advanced stages (Gleason
      grade 4 to 6) and in 66% of those at more advanced stages (Gleason grade 7 to 9),
      whereas it was not expressed in benign prostatic hypertrophies. Sequencing of the
      cDNA for the truncated c-Kit, amplified from both LNCaP cells and neoplastic
      tissues, confirmed the existence in prostate cancer cells of a transcript arising
      from the 15th intron of human c-kit. We also show that tr-Kit-expressing LNCaP
      cells and prostatic tumors have higher levels of phosphorylated/activated Src
      than tr-Kit-negative PC3 cells or prostatic tumors, and that transfection of tr
      Kit in PC3 cells caused a dramatic increase in Src activity. Interestingly, we
      found that Sam68, a RNA-binding protein phosphorylated by Src in mitosis, is
      phosphorylated only in prostate tumors expressing tr-Kit. Indeed, both activation
      of Src and phosphorylation of Sam68 were observed in all of the three grade 7 to
      9 tumors analyzed that expressed tr-Kit. Our data describe for the first time the
      existence of a truncated c-Kit protein in primary tumors and show a correlation
      between tr-Kit expression and activation of the Src pathway in the advanced
      stages of the disease. Thus, these results might pave the way for the elucidation
      of a novel pathway in neoplastic transformation of prostate cells.

PMID- 15039215
TI  - Inhibition of platelet-derived growth factor promotes pericyte loss and
      angiogenesis in ischemic retinopathy.
AB  - We investigated whether inhibition of platelet-derived growth factor (PDGF)
      receptor tyrosine kinase activity would affect pericyte viability, vascular
      endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2
      (VEGFR-2) expression and angiogenesis in a model of retinopathy of prematurity
      (ROP). ROP was induced in Sprague Dawley rats by exposure to 80% oxygen from
      postnatal (P) days 0 to 11 (with 3 hours/day in room air), and then room air from
      P12-18 (angiogenesis period). Shams were neonatal rats in room air from P0-18.
      STI571, a potent inhibitor of PDGF receptor tyrosine kinase, was administered
      from P12-18 at 50 or 100 mg/kg/day intraperitoneal (i.p.). Electron microscopy
      revealed that pericytes in the inner retina of both sham and ROP rats appeared
      normal; however STI571 induced a selective pericyte and vascular smooth muscle
      degeneration. Immunolabeling for caspase-3 and alpha-smooth muscle cell actin in
      consecutive paraffin sections of retinas confirmed that these degenerating cells
      were apoptotic pericytes. In all groups, VEGF and VEGFR-2 gene expression was
      located in ganglion cells, the inner nuclear layer, and retinal pigment
      epithelium. ROP was associated with an increase in both VEGF and VEGFR-2 gene
      expression and blood vessel profiles in the inner retina compared to sham rats.
      STI571 at both doses increased VEGF and VEGFR-2 mRNA and exacerbated angiogenesis
      in ROP rats, and in sham rats at 100 mg/kg/day. In conclusion, PDGF is required
      for pericyte viability and the subsequent prevention of VEGF/VEGFR-2
      overexpression and angiogenesis in ROP.

PMID- 15039214
TI  - IKK2 inhibitor alleviates kidney and wasting diseases in a murine model of human
      AIDS.
AB  - Wasting and renal diseases are frequent complications of HIV (human
      immunodeficiency virus) infection and are associated with accelerated disease
      progression and increased mortality. Transgenic mice expressing HIV1 under
      control of the CD4 promoter develop an AIDS-like disease and were used in the
      present work to study HIV1-induced wasting and kidney pathology. In this study,
      we reported that disease evolution paralleled increases in serum urea and
      creatinine levels, indicating an early and progressive deterioration of kidney
      function; meanwhile the wasting syndrome characterized by up-regulation of the
      ubiquitine-proteasome pathway and increased level of serum 3-methyl-histidine
      levels occurred at later stages just prior to death. Further examination of
      kidney and muscle pathologies revealed a progressive accumulation of CD45(+)
      cells, first affecting the kidneys. In addition, the onset of disease is
      accompanied by elevated levels of circulating "regulated on activation, normal
      and secreted T cell expressed and secreted" (RANTES). These results prompted us
      to assess the effects of AS602868, a specific small molecule inhibitor of IkappaB
      kinase 2 (IKK2) on disease progression. Inhibition of the NF-kappaB pathway
      indeed resulted in increased lifespan, kidney and lean body mass preservation.
      These beneficial results were associated with a reduction of CD45(+) cells
      infiltrating the kidneys, amelioration of the renal architecture, and reduced
      level of circulating RANTES. Together our data provide evidence that IKK2
      inhibitors have therapeutic relevance in the treatment of HIV1-associated
      disorders.

PMID- 15039216
TI  - Increased expression levels of integrin alphavbeta5 on scleroderma fibroblasts.
AB  - Integrin alphavbeta5 is a receptor for vitronectin, a plasma glycoprotein that is
      also distributed in extracellular matrix of various tissues. Matrix-bound
      vitronectin has the potential to stabilize the active form of plasminogen
      activator inhibitor-1, resulting in the inhibition of the plasmin-mediated
      pericellular proteolytic cascade. In this study, we compared the levels of
      alphavbeta5 and matrix-bound vitronectin between normal and scleroderma
      fibroblasts and investigated the association with fibrosis. We demonstrated that
      alphavbeta5 was up-regulated on scleroderma fibroblasts. The up-regulated
      alphavbeta5 contributed to the increase in vitronectin-binding ability in
      scleroderma fibroblasts, which led to the vitronectin-dependent activation of
      plasminogen activator inhibitor-1. In immunohistochemistry, the alphav and beta5
      subunits were stained strongly on scleroderma fibroblasts and the amount of
      vitronectin was increased in the pericellular matrix of those cells. The
      transient overexpression of alphavbeta5 on normal fibroblasts enhanced the human
      alpha2(I) collagen promoter activity through Sp-1 and Smad3 as well as the
      vitronectin-dependent plasminogen activator inhibitor-1 activity. This effect on
      the promoter activity was also observed in the absence of vitronectin and
      completely disappeared in the presence of anti-alphavbeta5 antibody. These
      results indicate that the up-regulated alphavbeta5 may contribute to the
      phenotypical alteration of scleroderma fibroblasts, while at the same time
      suppressing the plasmin-mediated pericellular proteolytic cascade.

PMID- 15039217
TI  - Activin a in the regulation of corneal neovascularization and vascular
      endothelial growth factor expression.
AB  - Activin A, a dimeric glycoprotein that belongs to the transforming growth factor
      beta superfamily, governs cellular differentiation in a wide variety of models
      and has been implicated in the regulation of angiogenesis. We examined the role
      of activin A and its downstream signaling pathway in a murine model of
      inflammatory corneal neovascularization induced by mechanical injury
      (debridement), and in vitro in corneal epithelial cells. Activin A expression
      increased steadily from day 2 until day 8 after mechanical debridement in vivo,
      paralleling vascular endothelial growth factor (VEGF) expression. Administration
      of recombinant activin A in mice increased the area of neovascularization, VEGF
      expression, and the kinase activities of p38 and p42/44 MAPKs after mechanical
      debridement. Systemic inhibition of activin A in vivo with a neutralizing
      antibody reduced the area of neovascularization, VEGF expression, and p38 and
      p42/44 MAPK activity, whereas administration of an isotype-matched control
      antibody had no effect. In vitro treatment with activin A increased VEGF
      secretion, as well as p38 and p42/44 MAPK activity in corneal epithelial cells,
      whereas concurrent administration of specific inhibitors of p38 or p42/44 MAPK
      abolished the stimulatory effect of activin A on VEGF production. We conclude
      that activin A stimulates inflammatory corneal angiogenesis by increasing VEGF
      levels through a p38 and p42/44 MAPK-dependent mechanism.

PMID- 15039218
TI  - Impairment of skin wound healing in beta-1,4-galactosyltransferase-deficient mice
      with reduced leukocyte recruitment.
AB  - Cell-surface carbohydrate chains are known to contribute to cell migration,
      interactions, and proliferation, but their roles in skin wound healing have not
      been evaluated. We examined the biological roles of beta4-galactosylated
      carbohydrate chains in skin wound healing using mutant mice that lack beta-1,4
      galactosyltransferase-I (beta4GalT-I), which is responsible for the biosynthesis
      of the type 2 chain in N-glycans and the core 2 branch in O-glycans. beta4GalT-I
      deficient mice showed significantly delayed wound healing with reduced re
      epithelialization, collagen synthesis, and angiogenesis, compared with control
      mice. Neutrophil and macrophage recruitment at wound sites was also impaired in
      these mice probably because of selectin-ligand deficiency. In accordance with the
      reduced leukocyte infiltration, the expression levels of macrophage-derived
      chemokines, transforming growth factor-beta1, and vascular endothelial growth
      factor were all reduced in beta4GalT-I(-/-) mice. These results demonstrate that
      beta4-galactosylated carbohydrate chains play a critical role in skin wound
      healing by mediating leukocyte infiltration and epidermal cell growth, which
      affects the production of chemokines and growth factors. This study introduces a
      suitable mouse model for investigating the molecular mechanisms of skin wound
      healing and is the first report showing that carbohydrate chains have a strong
      influence on skin wound healing.

PMID- 15039219
TI  - FIZZ1 stimulation of myofibroblast differentiation.
AB  - Bleomycin-induced pulmonary fibrosis is characterized by inflammation, emergence
      of myofibroblasts, and deposition of extracellular matrix. In an attempt to
      identify genes that may be involved in fibrosis, we used a 10,000 element (10 K)
      rat cDNA microarray to analyze the lung gene expression profiles in this model in
      the rat. Cluster analysis showed 628 genes were more than or equal to twofold up-
      or down-regulated, many of which were known to be involved in fibrosis. However,
      the most dramatic increase was observed with FIZZ1 (found in inflammatory zone;
      also known as RELM-alpha or resistin-like molecule-alpha), which was induced 17
      fold to approximately 25-fold at the peak of expression. In situ hybridization
      analysis revealed FIZZ1 expression to localize primarily to alveolar and airway
      epithelium, which was confirmed in vitro by analysis of isolated type II alveolar
      epithelial cells. However FIZZ1 expression was not detected in isolated lung
      fibroblasts. Co-culture of FIZZ1-expressing type II cells with fibroblasts
      stimulated alpha-smooth muscle actin and type I collagen expression independent
      of transforming growth factor-beta. Transfection of a FIZZ1-expressing plasmid
      into fibroblasts or treatment with glutathione S-transferase-FIZZ1 fusion protein
      stimulated alpha-smooth muscle actin and collagen I production. These results
      suggest a novel role for FIZZ1 in myofibroblast differentiation in pulmonary
      fibrosis.

PMID- 15039220
TI  - Pathological role of large intestinal IL-12p40 for the induction of Th2-type
      allergic diarrhea.
AB  - IL-12 consists of two disulfide-linked subunits, p40 and p35, that form
      functionally active heterodimers for the induction of Th1 cells. In contrast to
      IL-12 heterodimers, p40 monomers and homodimers possess inhibitory effects on Th1
      cells leading to the creation of a Th2 environment. Although it has been shown
      that IL-12p40 acts as antagonist of IL-12p70 in vitro, no evidence is currently
      available whether IL-12p40 is functional in vivo. We now report that IL-12p40
      plays an important pathological role in anintestinal allergic disease. A high
      expression of IL-12p40 protein was demonstrated in epithelial cells, dendritic
      cells, and macrophages in large but not small intestine of allergic diarrhea
      induced mice. Interestingly, neutralization with anti-IL-12p40 mAbs reduced the
      incidence and delayed the onset of disease development. Lower levels of ovalbumin
      (OVA)-specific IgE Abs in serum were detected in anti-IL-12p40 mAb-treated mice
      than in control Ab-treated mice. The secretion of Th2 cytokines and eotaxin by
      the mononuclear cells isolated from the large intestine of anti-IL-12p40 mAb
      treated mice was significantly decreased. Finally, the removal of the IL-12p40
      gene resulted in complete inhibition of disease development. These results show
      that over-expression of IL-12p40 is an important contributing factor for the
      generation of the dominant Th2-type environment in the large intestine of mice
      with allergic diarrhea.

PMID- 15039221
TI  - Pretumor progression: clonal evolution of human stem cell populations.
AB  - Multistep carcinogenesis through sequential cycles of mutation and clonal
      succession is usually described as tumor progression, or the clonal evolution of
      tumor cell populations. However, many mutations found in cancers are also
      compatible with normal appearing phenotypes and therefore genetic progression may
      precede tumor progression. To better characterize such pretumor progression
      (mutations in the absence of visible phenotypic changes), a quantitative model
      was developed that postulates most oncogenic cancer mutations first accumulate in
      normal appearing colon crypt niche stem cells. Each crypt contains multiple stem
      cells, and random niche stem cell loss with replacement eventually leads to the
      loss of all stem cell lineages except one. This niche succession or crypt clonal
      evolution is similar to the clonal succession of tumor progression except it does
      not require selection or change visible phenotype. Mutations may sequentially
      accumulate during stem cell clonal evolution either through drift (passenger
      mutations) or selection. To determine the feasibility of pretumor progression,
      mutation rates sufficient to recreate the epidemiology of colorectal cancer were
      estimated. Pretumor progression may completely substitute for visible tumor
      progression because it is theoretically possible for all cancer mutations to
      first accumulate in normal appearing colon with normal replication fidelity.
      Elevated mutation rates or tumorigenesis may be unnecessary for early
      progression.

PMID- 15039222
TI  - Transit-amplifying ductular (oval) cells and their hepatocytic progeny are
      characterized by a novel and distinctive expression of delta-like
      protein/preadipocyte factor 1/fetal antigen 1.
AB  - Hepatic regeneration from toxic or surgical injury to the adult mammalian liver,
      endorses different cellular responses within the hepatic lineage. The molecular
      mechanisms determining commitment of a cell population at a specific lineage
      level to participate in liver repair as well as the fate of its progeny in the
      hostile environment created by the injury are not well defined. Based on the role
      of the Notch/Delta/Jagged system in cell fate specification and recent reports
      linking Notch signaling with normal bile duct formation in mouse and human liver,
      we examined the expression of Notch1, Notch2, Notch3, Delta1, Delta3, Jagged1,
      and Jagged2, and delta-like protein/preadipocyte factor 1/fetal antigen 1 (dlk)
      in four well-defined experimental rat models of liver injury and regeneration.
      Although Delta3 and Jagged2 were undetectable by reverse transcriptase-polymerase
      chain reaction and Northern blot, we observed the most significant up-regulation
      of all other transcripts in the 2-acetylaminofluorene-70% hepatectomy (AAF/PHx)
      model, in which liver mass is restored by proliferation and differentiation of
      transit-amplifying ductular (oval) cells. The most profound change was observed
      for dlk. Accordingly, immunohistochemical analyses in the AAF/PHx model showed a
      specific expression of dlk in atypical ductular structures composed of oval
      cells. Delta-like protein was not observed in proliferating hepatocytes or bile
      duct cells after partial hepatectomy or ligation of the common bile duct whereas
      clusters of dlk immunoreactive oval cells were found in both the retrorsine and
      the AAF/PHx models. Finally, we used dlk to isolate alpha-fetoprotein-positive
      cells from fetal and adult regenerating rat liver by a novel antibody panning
      technique.

PMID- 15039223
TI  - Interferon-gamma-induced nitric oxide causes intrinsic intestinal denervation in
      Trypanosoma cruzi-infected mice.
AB  - In this study, the role of nitric oxide (NO) in neuronal destruction during acute
      phase Trypanosoma cruzi infection was evaluated in male C57BL/6 (WT, wild-type)
      mice and knockout mice [inducible nitric oxide synthase (iNOS)(-/-) and
      interferon (IFN)(-/-)]. Selected animals were infected by intraperitoneal
      injection of 100 trypomastigote forms of the Y strain of T. cruzi. Others were
      injected intraperitoneally with an equal volume of saline solution and served as
      controls. Our findings support those of previous studies regarding myenteric
      denervation in acute-phase T. cruzi infection. In addition, we clearly
      demonstrate that, despite the fact that parasite nests and similar inflammatory
      infiltrate in the intestinal wall were more pronounced in infected iNOS(-/-) mice
      than in infected WT mice, the former presented no reduction in myenteric plexus
      neuron numbers. Neuronal nerve profile expression, as revealed by the general
      nerve marker PGP 9.5, was preserved in all knockout animals. Infected IFN(-/-)
      mice suffered no significant neuronal loss and there was no inflammatory
      infiltrate in the intestinal wall. On days 5 and 10 after infection, iNOS
      activity was greater in infected WT mice than in controls, whereas iNOS activity
      in infected knockout mice remained unchanged. These findings clearly demonstrate
      that neuronal damage does not occur in NO-impaired infected knockout mice,
      regardless of whether inflammatory infiltrate is present (iNOS(-/-)) or absent
      (IFN(-/-)). In conclusion, our observations strongly indicate that myenteric
      denervation in acute-phase T. cruzi infection is because of IFN-gamma-elicited NO
      production resulting from iNOS activation in the inflammatory foci along the
      intestinal wall.

PMID- 15039224
TI  - Enhanced stem cell survival in familial adenomatous polyposis.
AB  - Individuals with heterozygous germline adenomatous polyposis coli (APC) mutations
      or familial adenomatous polyposis (FAP) are born with normal appearing colons but
      later develop hundreds to thousands of polyps. Tumor progression apparently
      starts after somatic loss of the normal APC allele, but germline APC mutations
      may potentially alter niche stem cell survival through dominant-negative
      interactions or haploinsufficiency. Although morphologically occult, altered stem
      cell turnover or clonal evolution rates may be detected by measuring the
      diversity of crypt sequences, with greater diversity expected with longer lived
      stem cell lineages. Methylation pattern diversity (numbers of unique patterns per
      crypt) was higher in normal appearing crypts from four of five FAP colons
      compared to six non-FAP colons and one attenuated FAP colon. Simulations indicate
      higher FAP crypt diversity is consistent with slower clonal evolution from
      enhanced stem cell survival, either through increased stem cell numbers or
      decreased stem cell lineage extinction, which is predicted to increase
      progression rates to cancer. Enhanced stem cell survival was associated with APC
      mutations that remove some but not all catenin-binding repeats. Therefore, some
      APC mutations may be common in colorectal cancers because they confer occult
      pretumor "caretaker" and "gatekeeper" defects. FAP crypts accumulate more
      alterations from slower stem cell clonal evolution rather than increased error
      rates. In non-FAP crypts, enhanced stem cell survival conferred by somatic
      heterozygous APC mutations would favor fixation through occult clonal niche
      expansions. Heterozygous APC mutations may change stem cell survival during
      colorectal pretumor progression.

PMID- 15039225
TI  - A locus on chromosome 7 determines dramatic up-regulation of osteopontin in
      dystrophic cardiac calcification in mice.
AB  - Calcification of necrotic tissue is frequently observed in chronic inflammation
      and atherosclerosis. A similar response of myocardium to injury, referred to as
      dystrophic cardiac calcinosis (DCC), occurs in certain inbred strains of mice. We
      now examined a putative inhibitor of calcification, osteopontin, in DCC after
      transdiaphragmal myocardial freeze-thaw injury. Strong osteopontin expression was
      found co-localizing with calcification in DCC-susceptible strain C3H/HeNCrlBr,
      which exhibited low osteopontin plasma concentrations otherwise. Osteopontin mRNA
      induction was 20-fold higher than in resistant strain C57BL/6NCrlBr, which
      exhibited fibrous lesions without calcification and little osteopontin
      expression. Sequence analysis identified several polymorphisms in calcium-binding
      and phosphorylation sites in osteopontin cDNA. Their potential relevance for DCC
      was tested in congenic mice, which shared the osteopontin locus with
      C57BL/6NCrlBr, but retained a chromosomal segment from C3H/HeNCrlBr on proximal
      chromosome 7. These mice exhibited strong osteopontin expression and DCC
      comparable to C3H/HeNCrlBr suggesting that a trans-activator of osteopontin
      transcription residing on chromosome 7 and not the osteopontin gene on chromosome
      5 was responsible for the genetic differences in osteopontin expression. A known
      osteopontin activator encoded by a gene on chromosome 7 is the transforming
      growth factor-beta1, which was more induced (3.5x) in C3H/HeNCrlBr than in
      C57BL/6NCrlBr mice.

PMID- 15039227
TI  - Osteoblasts express the inflammatory cytokine interleukin-6 in a murine model of
      Staphylococcus aureus osteomyelitis and infected human bone tissue.
AB  - Staphylococcus aureus is the single most common cause of osteomyelitis in humans.
      Incidences of osteomyelitis caused by S. aureus have increased dramatically in
      recent years, in part due to the appearance of community-acquired antibiotic
      resistant strains. Therefore, understanding the pathogenesis of this organism has
      become imperative. Recently, we have described the surprising ability of bone
      forming osteoblasts to secrete a number of important immune mediators when
      exposed to S. aureus in vitro. In the present study, we provide the first
      evidence for the in vivo production of such molecules by osteoblasts during
      bacterial infection of bone. These studies demonstrate the expression of the key
      inflammatory cytokine interleukin-6 by osteoblasts in organ cultures of neonatal
      mouse calvaria, and in vivo using a mouse model that closely resembles the
      pathology of trauma-induced staphylococcal osteomyelitis, as determined by
      confocal microscopic analysis. Importantly, we have established the clinical
      relevancy of these findings in infected human bone tissue from patients with S.
      aureus-associated osteomyelitis. As such, these studies demonstrate that
      bacterial challenge of osteoblasts during bone diseases, such as osteomyelitis,
      induces cells to produce inflammatory molecules that can direct appropriate host
      responses or contribute to progressive inflammatory damage.

PMID- 15039226
TI  - Advanced glycation end products induce tubular epithelial-myofibroblast
      transition through the RAGE-ERK1/2 MAP kinase signaling pathway.
AB  - Advanced glycation end products (AGEs) have been shown to play a role in tubular
      epithelial-myofibroblast transdifferentiation (TEMT) in diabetic nephropathy, but
      the intracellular signaling pathway remains unknown. We report here that AGEs
      signal through the receptor for AGEs (RAGE) to induce TEMT, as determined by de
      novo expression of a mesenchymal marker (alpha-smooth muscle actin, alpha-SMA)
      and loss of epithelial marker (E-cadherin), directly through the MEK1-ERK1/2 MAP
      kinase pathway, which is TGF-beta independent. This is supported by the following
      findings: AGEs induced de novo alpha-SMA mRNA expression as early as 2 hours
      followed by a loss of E-cadherin before TGF-beta mRNA expression at 24 hours and
      occurred in the absence of TGF-beta and AGE-induced activation of ERK1/2 MAP
      kinase at 15 minutes and TEMT at 24 hours were completely blocked by a
      neutralizing RAGE antibody, a soluble RAGE receptor, an ERK1/2 MAP kinase
      inhibitor (PD98059), and DN-MEK1, but not by a neutralizing TGF-beta antibody.
      Thus, this study demonstrates that AGEs activate the RAGE-ERK1/2 MAP kinase
      pathway to mediate the early TEMT process. The findings from this study suggest
      that targeting the RAGE or the ERK MAP kinase pathway may provide new therapeutic
      strategies for diabetic nephropathy and shed new light on the pathogenesis of
      diabetic nephropathy.

PMID- 15039228
TI  - Antigen location contributes to the pathological features of a transplanted heart
      graft.
AB  - Organ-specific injury after transplantation presents with a variety of clinical
      and pathological phenotypes, yet the factors influencing development of each
      outcome are poorly understood. Because primed T lymphocytes must re-encounter
      their antigen within the target organ to engage effector functions, we postulated
      that the cellular location of antigen within that organ could significantly
      impact the induced pathology. We challenged female Marilyn CD4 T-cell receptor
      transgenic mice, in which all T cells are specific for the male minor
      transplantation antigen, with male heart transplants expressing the relevant
      peptide: major histocompatibility complex on either graft parenchymal/vascular
      cells or alternatively, on graft-infiltrating mononuclear cells. The two
      different graft donors led to equivalent activation of recipient T cells as
      assessed by frequency, cell surface marker expression, cytokine production, and
      the ability to traffic to the graft. Nonetheless, if the target antigen was
      expressed on graft vascular and/or parenchymal cells, the outcome was acute graft
      destruction. In contrast, if the antigen was expressed only on graft-infiltrating
      mononuclear cells the same effector T-cell repertoire caused chronic rejection
      and vasculopathy. This unique result, that target antigen location can influence
      pathological outcome, has significant implications for understanding the
      pathogenesis of chronic allograft injury in humans.

PMID- 15039229
TI  - Differential expression of d-type cyclins in podocytes in vitro and in vivo.
AB  - The proliferative response of podocytes to injury determines the histological
      phenotype. Moreover, an apparent lack of podocyte proliferation may underlie the
      development of glomerulosclerosis. Podocyte proliferation is closely linked with
      its state of differentiation. However, the mechanisms regulating these processes
      are not fully elucidated. Because D-type cyclins have been shown to be important
      in the regulation of proliferation and differentiation, we examined their
      expression in podocytes in vitro and in vivo. The glomerular expression of
      cyclins D1 and D3 was examined in vitro in cultured immortalized podocytes by
      immunostaining and Western blot analysis, and in embryonic mice and rats, the
      passive Heymann nephritis model of experimental membranous nephropathy in rats,
      and human immunodeficiency virus (HIV)-transgenic mice. Kidneys from cyclin D1
      knockout mice were also examined. Cyclin D1 was abundant in cultured
      proliferating podocytes, but not in quiescent differentiated podocytes. In
      contrast, cyclin D3 was abundant in differentiated, but not proliferating
      podocytes. Cyclin D1 was expressed in embryonic mouse and rat glomeruli during
      the S- and comma-shaped stages, and was absent in podocytes at the capillary loop
      stage and in mature rodent glomeruli. Cyclin D1 protein increased after injury in
      passive Heymann nephritis rats and in HIV-transgenic mice. Cyclin D3 was
      constitutively and specifically expressed in podocytes in normal rodent
      glomeruli, and decreases during dedifferentiation and proliferation in HIV
      transgenic mice. Kidneys from cyclin D1-/- mice were normal with the podocytes
      expressing specific differentiation markers. Cyclin D1 is not necessary for the
      terminal differentiation of podocytes, and expression coincides with cell-cycle
      entry. In contrast, cyclin D3 expression coincides with podocyte differentiation
      and quiescence.

PMID- 15039230
TI  - Partial loss-of-function mutations in insulin-degrading enzyme that induce
      diabetes also impair degradation of amyloid beta-protein.
AB  - The causes of cerebral accumulation of amyloid beta-protein (Abeta) in most cases
      of Alzheimer's disease (AD) remain unknown. We recently found that homozygous
      deletion of the insulin-degrading enzyme (IDE) gene in mice results in an early
      and marked elevation of cerebral Abeta. Both genetic linkage and allelic
      association in the IDE region of chromosome 10 have been reported in families
      with late-onset AD. For IDE to remain a valid candidate gene for late-onset AD on
      functional grounds, it must be shown that partial loss of function of IDE can
      still alter Abeta degradation, but without causing early, severe elevation of
      brain Abeta. Here, we show that naturally occurring IDE missense mutations in a
      well-characterized rat model of type 2 diabetes mellitus (DM2) result in
      decreased catalytic efficiency and a significant approximately 15 to 30% deficit
      in the degradation of both insulin and Abeta. Endogenously secreted Abeta(40) and
      Abeta(42) are significantly elevated in primary neuronal cultures from animals
      with the IDE mutations, but there is no increase in steady-state levels of rodent
      Abeta in the brain up to age 14 months. We conclude that naturally occurring,
      partial loss-of-function mutations in IDE sufficient to cause DM2 also impair
      neuronal regulation of Abeta levels, but the brain can apparently compensate for
      the partial deficit during the life span of the rat. Our findings have relevance
      for the emerging genetic evidence suggesting that IDE may be a late-onset AD-risk
      gene, and for the epidemiological relationships among hyperinsulinemia, DM2, and
      AD.

PMID- 15039231
TI  - Disturbed homeostasis of lung intercellular adhesion molecule-1 and vascular cell
      adhesion molecule-1 during sepsis.
AB  - Cecal ligation and puncture (CLP)-induced sepsis in mice was associated with
      perturbations in vascular adhesion molecules. In CLP mice, lung vascular binding
      of (125)I-monoclonal antibodies to intercellular adhesion molecule (ICAM)-1 and
      vascular cell adhesion molecule (VCAM)-1 revealed sharp increases in binding of
      anti-ICAM-1 and significantly reduced binding of anti-VCAM-1. In whole lung
      homogenates, intense ICAM-1 up-regulation was found (both in mRNA and in protein
      levels) during sepsis, whereas very little increase in VCAM-1 could be measured
      although some increased mRNA was found. During CLP soluble VCAM-1 (sVCAM-1) and
      soluble ICAM-1 (sICAM-1) appeared in the serum. When mouse dermal microvascular
      endothelial cells (MDMECs) were incubated with serum from CLP mice, constitutive
      endothelial VCAM-1 fell in association with the appearance of sVCAM-1 in the
      supernatant fluids. Under the same conditions, ICAM-1 cell content increased in
      MDMECs. When MDMECs were evaluated for leukocyte adhesion, exposure to CLP serum
      caused increased adhesion of neutrophils and decreased adhesion of macrophages
      and T cells. The progressive build-up in lung myeloperoxidase after CLP was ICAM
      1-dependent and independent of VLA-4 and VCAM-1. These data suggest that sepsis
      disturbs endothelial homeostasis, greatly favoring neutrophil adhesion in the
      lung microvasculature, thereby putting the lung at increased risk of injury.

PMID- 15039232
TI  - Colorectal pretumor progression before and after loss of DNA mismatch repair.
AB  - A pretumor progression model predicts many oncogenic cancer mutations may first
      accumulate in normal appearing colon. Although direct observations of early
      pretumor mutations are impractical, it may be possible to retrospectively
      reconstruct tumor histories from contemporary cancer mutations. To infer when and
      in what order mutations occur during occult pretumor progression, we examined 14
      cancers from individuals with heterozygous germline mutations in DNA mismatch
      repair (MMR) genes or hereditary nonpolyposis colorectal cancer (HNPCC). Somatic
      inactivation of the normal allele occurs sometime during a lifetime and results
      in loss of MMR, elevated mutation rates, and subsequent widespread somatic
      microsatellite mutations in HNPCC cancers. Patient ages at MMR loss can be
      estimated because intervals between MMR loss and cancer removal can be inferred
      from numbers of microsatellite tumor mutations. The relative order of MMR loss
      during pretumor progression may also be inferred from its collective ages of
      occurrence. Somatic MMR loss preceded cancer removal by an average of 6.1 years,
      occurred relatively late in life (average of 41.6 versus 47.7 years at cancer
      removal), and was a surprisingly late (fifth or sixth) step. Calculations
      indicate five or six oncogenic mutations could accumulate with relatively normal
      replication fidelity in normal appearing colon. HNPCC pretumor progression
      essentially begins from birth and ends with MMR loss, implying elevated mutation
      rates and tumorigenesis may be unnecessary for most progression.

PMID- 15039233
TI  - Targeting experimental autoimmune encephalomyelitis lesions to a predetermined
      axonal tract system allows for refined behavioral testing in an animal model of
      multiple sclerosis.
AB  - In multiple sclerosis (MS) the structural damage to axons determines the
      persistent clinical deficit patients acquire during the course of the disease. It
      is therefore important to test therapeutic strategies that can prevent or reverse
      this structural damage. The conventional animal model of MS, experimental
      autoimmune encephalomyelitis (EAE), typically shows disseminated inflammation in
      the central nervous system, which leads to a clinical deficit that cannot be
      directly attributed to a defined tract system. For this reason we have developed
      a localized EAE model, in which large inflammatory lesions are targeted to the
      dorsal columns of the spinal cord, an area including the corticospinal tract.
      These lesions show the pathological hallmarks of MS plaques and lead to
      reproducible and pronounced deficits in hindlimb locomotion. Because of the
      anatomical specificity of this technique we can now use highly sensitive
      behavioral tests that assess the functional integrity of specific axonal tracts.
      We show that these tests are predictive of the site and extent of a given lesion
      and are more sensitive for assessing the clinical course than the scales commonly
      used for disseminated EAE models. We believe that this targeted EAE model will
      become a helpful new tool for the evaluation of therapeutic approaches for MS
      that attempt to protect axons or support their repair.

PMID- 15039234
TI  - Loss of the nf1 tumor suppressor gene decreases fas antigen expression in myeloid
      cells.
AB  - Genetic loss of surface Fas antigen expression leads to reduced apoptosis of
      myeloid and lymphoid progenitor cells, and a propensity to develop autoimmunity
      and myeloid leukemia in mouse models. Oncogenic p21(ras) decreases surface Fas
      antigen expression and renders fibroblasts resistant to Fas mediated apoptosis.
      Neurofibromin, which is encoded by NF1, is a GTPase activating protein that
      negatively regulates p21(ras) activity. NF1 loss leads to deregulation of
      p21(ras)-effector pathways, which control myeloid cell survival. Heterozygous
      inactivation of Nf1 increases mast cell numbers in Nf1 +/- mice, and enhances
      mast cell survival in response to c-kit ligand (kit-L). Here, we show that Nf1
      deficient mast cells have reduced surface Fas antigen expression in response to
      kit-L and are resistant to Fas ligand-mediated apoptosis. Using genetic
      intercrosses between Nf1 +/- and class I (A)-PI-3K-deficient mice, we demonstrate
      that hyperactivation of the p21(ras)-class I(A) PI-3K pathway is the mechanism
      for this phenotype. Finally, we demonstrate that mast cells from both Fas antigen
      deficient mice and Nf1 +/- mice are resistant to apoptosis following kit-L
      withdrawal in vivo. Thus, therapies designed to decrease p21(ras) activity and up
      regulate Fas antigen expression may limit the pathological accumulation of
      myeloid cells in disease states where p21(ras) is hyperactivated.

PMID- 15039238
TI  - The big blue revisited.

PMID- 15039235
TI  - Characteristic multiorgan pathology of cystic fibrosis in a long-living cystic
      fibrosis transmembrane regulator knockout murine model.
AB  - The lack of an appropriate animal model with multiorgan pathology characteristic
      of the human form of cystic fibrosis has hampered our understanding of the
      pathobiology of the disease. We evaluated multiple organs of congenic C57BL/6J
      cystic fibrosis transmembrane regulator (Cftr)(-/-) and Cftr(+/+) mice maintained
      from weaning on a liquid diet then sacrificed between 1 and 24 months of age. The
      lungs of the Cftr(-/-) animals showed patchy alveolar overdistention,
      interstitial thickening, and fibrosis, with progression up to 6 months of age.
      The proximal and distal airway surface was encased with mucus-like material but
      lacked overt evidence of chronic bacterial infections or inflammation. All Cftr(
      /-) animals showed progressive liver disease, with hepatosteatosis, focal
      cholangitis, inspissated secretions, and bile duct proliferation; after 1 year of
      age there was progression to focal biliary cirrhosis. The intercalated,
      intralobular and interlobular ducts and acinar lumina of the exocrine pancreas,
      the parotid and submaxillary glands of the Cftr(-/-) animals were dilated and
      filled with inspissated material, as well as mild inflammation and acinar cell
      drop out. Quantitative measurements of the pancreas showed significant acinar
      atrophy and increased acinar volume in comparison with age-matched Cftr(+/+)
      littermates. The ileal lumen and crypts were filled with adherent fibrillar
      material. After 3 months of age the vas deferens of the Cftr(-/-) animals could
      not be identified. None of the aforementioned pathological changes were observed
      in the Cftr(+/+) littermates fed the same liquid diet. We show, for the first
      time, that long-lived C578L/6J Cftr(-/-) mice develop manifestations of cystic
      fibrosis-like disease in all pathologically affected organs in the human form of
      cystic fibrosis.

PMID- 15039239
TI  - Rage against the machine.

PMID- 15039236
TI  - Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model
      of Alzheimer's disease.
AB  - According to the "amyloid hypothesis of Alzheimer's disease," beta-amyloid is the
      primary driving force in Alzheimer's disease pathogenesis. Despite the
      development of many transgenic mouse lines developing abundant beta-amyloid
      containing plaques in the brain, the actual link between amyloid plaques and
      neuron loss has not been clearly established, as reports on neuron loss in these
      models have remained controversial. We investigated transgenic mice expressing
      human mutant amyloid precursor protein APP751 (KM670/671NL and V717I) and human
      mutant presenilin-1 (PS-1 M146L). Stereologic and image analyses revealed
      substantial age-related neuron loss in the hippocampal pyramidal cell layer of
      APP/PS-1 double-transgenic mice. The loss of neurons was observed at sites of
      Abeta aggregation and surrounding astrocytes but, most importantly, was also
      clearly observed in areas of the parenchyma distant from plaques. These findings
      point to the potential involvement of more than one mechanism in hippocampal
      neuron loss in this APP/PS-1 double-transgenic mouse model of Alzheimer's
      disease.

PMID- 15039240
TI  - Child protection in sport.

PMID- 15039242
TI  - A longitudinal study on the ammonia threshold in junior cyclists.
AB  - OBJECTIVES: To identify the effect of a one year non-specific training programme
      on the ammonia threshold of a group of junior cyclists and to correlate ammonia
      threshold with other common physiological variables. METHODS: The cyclists
      performed tests at three time points (T1, T2, T3) during the year. Follow up
      tests were conducted every six months after the original test. Ammonia threshold
      was obtained from a graded exercise with four minute steps. RESULTS: The
      relatively non-specific one year training programme was effective in inducing an
      increase in peak VO(2) (60.6 (5.9), 65.9 (7.4), and 64.6 (6.5) ml/min/kg at T1,
      T2, and T3 respectively) and endurance time (18.3 (4.5), 20.1 (5.2), and 27.0
      (6.1) minutes at T1, T2, and T3 respectively), but was not effective for the
      sprint related variables. Ammonia threshold, together with lactate threshold and
      ventilatory threshold, was not significantly different at the three test times.
      Only endurance time correlated significantly with ammonia threshold (r = 0.915, p
      = 0.001). CONCLUSIONS: The findings suggest that a relatively non-specific one
      year training programme does not modify the ammonia threshold of junior cyclists.
      The significant correlation between ammonia threshold and endurance time further
      confirms that ammonia threshold is a measure of the ability to sustain exercise
      at submaximal intensities.

PMID- 15039241
TI  - Negative neurofunctional effects of frequency, depth and environment in
      recreational scuba diving: the Geneva "memory dive" study.
AB  - OBJECTIVES: To explore relationships between scuba diving activity, brain, and
      behaviour, and more specifically between global cerebral blood flow (CBF) or
      cognitive performance and total, annual, or last 6 months' frequencies, for
      standard dives or dives performed below 40 m, in cold water or warm sea
      geographical environments. METHODS: A prospective cohort study was used to
      examine divers from diving clubs around Lac Leman and Geneva University Hospital.
      The subjects were 215 healthy recreational divers (diving with self-contained
      underwater breathing apparatus). Main outcome measures were: measurement of
      global CBF by (133)Xe SPECT (single photon emission computed tomography);
      psychometric and neuropsychological tests to assess perceptual-motor abilities,
      spatial discrimination, attentional resources, executive functioning, and memory;
      evaluation of scuba diving activity by questionnaire focusing on number and
      maximum depth of dives and geographical site of the diving activity (cold water v
      warm water); and body composition analyses (BMI). RESULTS: (1) A negative
      influence of depth of dives on CBF and its combined effect with BMI and age was
      found. (2) A specific diving environment (more than 80% of dives in lakes) had a
      negative effect on CBF. (3) Depth and number of dives had a negative influence on
      cognitive performance (speed, flexibility and inhibition processing in
      attentional tasks). (4) A negative effect of a specific diving environment on
      cognitive performance (flexibility and inhibition components) was found.
      CONCLUSIONS: Scuba diving may have long-term negative neurofunctional effects
      when performed in extreme conditions, namely cold water, with more than 100 dives
      per year, and maximal depth below 40 m.

PMID- 15039243
TI  - Effect of sex on preactivation of the gastrocnemius and hamstring muscles.
AB  - BACKGROUND: The reason for the higher incidence of anterior cruciate ligament
      injury from non-contact mechanisms in female athletes is not known. Stability of
      the joint from dynamic restraints occurs through proprioceptive and kinaesthetic
      mechanisms providing a flexion moment. Reflexive muscle activation is different
      between the sexes, but it is unclear if sex differences exist in the ability to
      dynamically stabilise joints through a neuromuscular feed forward process as
      measured by preactivation of the muscles. OBJECTIVE: To determine if the level of
      preactivation of the gastrocnemius and hamstring muscles during dynamic activity
      is affected by sex. METHODS: Thirty four healthy active subjects, evenly grouped
      by sex, participated in the study. Maximum voluntary contraction normalised
      electromyographic (EMG) activity of the quadriceps, hamstrings, and gastrocnemius
      muscles was recorded during downhill walking (0.92 m/s) and running (2.08 m/s) on
      a 15 degrees declined treadmill. Preactivation of the EMG signal was calculated
      by setting a mark 150 milliseconds before foot strike, as indicated by a
      footswitch. Multiple t tests for sex differences of preactivity mean percentage
      (M-EMG%) during the downhill activities were performed. RESULTS: The female
      subjects had a higher M-EMG% for the medial hamstrings than the male subjects
      (31.73 (9.89) and 23.04 (8.59) respectively; t((2,32)) = 2.732, p = 0.01) during
      walking. No other muscles exhibited a sex difference in M-EMG% during either
      activity. CONCLUSION: The female subjects in this study showed higher medial
      hamstring preactivation. However, this may be because they were not injured,
      indicating their propensity for joint stabilisation. A long term prospective
      study is required to eliminate this potential explanation. No sex difference in
      gastrocnemius preactivation was seen, adding to the controversy about whether
      this muscle contributes to feed forward joint stability. Further research of
      preactivation of the musculature of the leg is required.

PMID- 15039244
TI  - Is risk of fast bowling injury in cricketers greatest in those who bowl most? A
      cohort of young English fast bowlers.
AB  - OBJECTIVES: To determine whether young fast bowlers are exceeding directives
      limiting bowling and how incidence of fast bowling injury varies with amount of
      bowling. METHODS: A prospective cohort study of injuries sustained by 70 fast
      bowlers (mean (SD) age 15.3 (2.4) years) was undertaken. Bowlers were recruited
      from the Centres of Excellence of three "First Class" counties in England in
      January 1998. Details of injuries were collected by telephone questionnaire every
      six weeks for six months from each bowler. The number of balls bowled in matches
      and practices by each bowler was recorded. The cohort was divided into groups
      according to the number of balls bowled in the study period, and bowling injury
      incidences were calculated for each group. MAIN OUTCOME MEASURES: All injuries
      caused by bowling and interfering with bowling. RESULTS: Telephone follow up was
      achieved when planned on 97.9% of occasions. There were 23 bowling injuries
      reported in the study period that met the inclusion criteria. The overall
      incidence of bowling injury in the study period was 32.8 per 100 fast bowlers.
      The incidence of bowling injury for the 15 bowlers who bowled less than 1000
      balls in the study period was 20.0 per 100 fast bowlers. The incidence for the 32
      who bowled 1000-2000 balls was 37.5 per 100 fast bowlers. The incidence for the
      14 who bowled 2000-3000 balls was 35.7 per 100. The incidence for the nine who
      bowled more than 3000 balls was 33.3 per 100. CONCLUSIONS: The expected increased
      incidence of bowling injury in young fast bowlers who bowl most was not observed,
      although more than 12% exceeded the recommended limit.

PMID- 15039245
TI  - Hormonal responses during prolonged exercise are influenced by a selective DA/NA
      reuptake inhibitor.
AB  - OBJECTIVE: A decrease in dopamine activity is thought to lead to a reduction in
      motivation and arousal and therefore to the "central" component of fatigue. The
      purpose of the present study was to investigate the effects of a dopamine (DA)
      noradrenaline (NA) reuptake inhibitor, bupropion (Zyban), on exercise performance
      and on the hormonal response to exercise. METHODS: Eight healthy well trained
      male cyclists (Watt(max) 397+/-15 W) participated in the study. Subjects
      completed one maximal exercise test (to determine maximal power output
      Watt(max)), and two endurance performance tests (time trials) in a double blind
      randomised cross-over design. Subjects took either placebo capsules (lactose) or
      2 x 300 mg bupropion (BUP). Blood samples were collected for adrenocorticotropin
      (ACTH), prolactin, cortisol, growth hormone, beta-endorphins, and catecholamines.
      RESULTS: Performance was not influenced by BUP (placebo: 89+/-1 min; BUP 2 x 300
      mg: 89+/-0.7 min). All hormones increased during exercise in all trials. Cortisol
      plasma concentrations were significantly higher in the BUP trial at rest, at min
      60, and at the end of exercise, while beta-endorphins were higher in the BUP
      trial at the end of exercise and during recovery, and ACTH at the end of
      exercise. CONCLUSION: From the present results, we can conclude that bupropion
      had a more marked central noradrenergic effect (compared to dopaminergic) on the
      hormonal response to exercise, but no effect on the outcome of performance.

PMID- 15039246
TI  - Modification of plasma glycosaminoglycans in long distance runners.
AB  - BACKGROUND: It is well documented that exercise reduces the risk of
      thromboembolic disease, possibly by increasing the plasma concentration of
      anticoagulant-antithrombotic compounds. OBJECTIVES: As plasma glycosaminoglycans
      (GAGs) play a role in the anticoagulant-antithrombotic potential of plasma, to
      examine the concentration and profile of these compounds in well trained, long
      distance runners and sedentary subjects. METHODS: Plasma GAGs were measured in 10
      male, long distance runners and 10 sedentary counterparts before and after
      ergometric tests. GAGs were extracted, purified, and identified by
      electrophoretic and enzymatic methods, and measured as hexosamine. RESULTS:
      Plasma GAGs found in sedentary subjects were slow migrating heparan sulphates I
      and II, keratan sulphate I, and chondroitin 4-6-sulphate. Those found in trained
      athletes were slow migrating heparan sulphate I, chondroitin 4-6-sulphate (or
      keratan sulphate I), and fast migrating heparan sulphate. Total plasma
      concentrations of GAGs were higher in athletes than in sedentary subjects at
      rest. In sedentary subjects, plasma GAGs did not change after cycle ergometric
      exercise at 80% of their anaerobic threshold. However, the appearance of a novel
      band of heparan sulphate migrating faster than fast migrating heparan sulphate
      was observed in athletes after exercise. CONCLUSIONS: Exercise changes the amount
      and profile of plasma GAGs; these changes may play a role in protecting subjects
      who practise aerobic sports against developing cardiovascular disease.

PMID- 15039247
TI  - Evaluation of the reliability of two field hockey specific sprint and dribble
      tests in young field hockey players.
AB  - OBJECTIVES: To determine the reliability of two field hockey specific tests: the
      shuttle sprint and dribble test (ShuttleSDT) and the slalom sprint and dribble
      test (SlalomSDT). METHODS: The shuttle sprint and dribble performances of 22
      young male and 12 young female field hockey players were assessed on two
      occasions within 4 weeks. Twenty one young female field hockey players took part
      in the slalom sprint and dribble test twice in a 4 week period. The ShuttleSDT
      required the players to perform three 30 m shuttle sprints while carrying a
      hockey stick alternated with short periods of rest and, after a 5 minute rest,
      three 30 m shuttle sprints alternated with rest while dribbling a hockey ball.
      The SlalomSDT required the players to run a slalom course and, after a 5 minute
      rest, to dribble the same slalom with a hockey ball. RESULTS: There were no
      differences in mean time scores between the two test sessions. The mean
      differences were small when compared with the means of both test sessions. With
      the exception of the slalom sprint time, zero lay within the 95% confidence
      interval of the mean differences indicating that no bias existed between the two
      measurements. With the exception of delta shuttle time (0.79), all intraclass
      correlation coefficient values for the ShuttleSDT, met the criterion for
      reliability of 0.80. Intraclass correlation coefficient values for SlalomSDT were
      0.91 for slalom sprint time, 0.78 for slalom dribble time, and 0.80 for delta
      slalom time. CONCLUSIONS: ShuttleSDT and the SlalomSDT are reliable measures of
      sprint and dribble performances of young field hockey players.

PMID- 15039248
TI  - Fitness levels of middle aged martial art practitioners.
AB  - OBJECTIVES: To quantify and compare fitness levels of middle aged practitioners
      of soo bahk do (SBD; a Korean martial art similar to karate) with those of
      sedentary subjects. METHODS: Eighteen volunteers, 14 men and four women (aged 40
      60 years), participated. Nine sedentary subjects (mean age 46.7 years) and nine
      SBD practitioners (mean age 46.8 years) were matched for sex and age. All
      subjects participated in a one day battery of fitness tests. The following
      dependent variables were tested: body composition, balance, flexibility,
      quadriceps strength, grip strength, muscle endurance, and aerobic capacity.
      RESULTS: All dependent variables were analysed using paired t tests. Body
      composition (% body fat) for the SBD group was 18.9% v 30.8% for the sedentary
      group (p = 0.004). The SBD group was able to balance for 61.8 seconds v 26.2
      seconds for the sedentary group (p = 0.02). The result for the sit and reach
      flexibility test was 22.3 cm for the SBD group v 10.4 cm for the sedentary group
      (p = 0.01). The number of push ups performed in one minute was 47.0 for the SBD
      group v 18.6 for the sedentary group (p = 0.0003), and the number of sit ups
      performed was 66.1 for the SBD group and 37.3 for the sedentary group (p =
      0.00006). Aerobic capacity was 41.0 ml/kg/min v 31.1 ml/kg/min for the sedentary
      group (p = 0.04). Quadriceps strength was 99.5% (peak torque/body weight) v 83.0%
      for the sedentary group (p = 0.02). Only grip strength was not significantly
      different. CONCLUSIONS: There were significant differences between the groups for
      most of the physical fitness tests. The SBD practitioners displayed greater
      aerobic capacity, balance, flexibility, muscle endurance, and strength, and less
      body fat than the sedentary controls matched for age and sex. SBD can be
      considered an excellent form of exercise for the promotion of fitness in adults.
      Health professionals should be aware that there are alternative methods to
      traditional exercise that can increase the physical fitness and health of the
      middle aged population.

PMID- 15039249
TI  - The effect of pre-season dance training on physical indices and back pain in
      elite cross-country skiers: a prospective controlled intervention study.
AB  - OBJECTIVE: To evaluate the effect of pre-season dance training on back pain,
      joint mobility, and muscle flexibility, and on speed and agility in elite cross
      country skiers. METHODS: 26 skiers participated (mean (SD) age, 19 (3.9) years).
      An intervention group (n = 16) had 12 weeks of dance training; a control group (n
      = 10) did not dance; otherwise both groups followed a similar pre-season physical
      training programme. Joint mobility and muscle flexibility of the spine, hip, and
      ankle were measured. Two sports related functional tests (slalom and hurdle) were
      also done. All measurements/tests were carried out before and after the dancing
      period. RESULTS: Four (of six) subjects from the intervention group who initially
      complained of ski related back pain did not report back pain after the dance
      training; the three subjects with back pain from the control group were
      unchanged. At study onset the intervention group had a slightly impaired range of
      motion in the spine compared with the control group. After dance training, there
      was a better relation between kyphosis of the thoracic spine and lordosis of the
      lumbar spine, and a 7.1 degrees increase in hip flexion with the knee extended (p
      = 0.02). In the control group hip extension decreased by 0.08 m on average (p =
      0.01). No positive effects of dance training on sports related functional tests
      were observed. CONCLUSIONS: Preseason dance training improved the range of hip
      motion and joint mobility and the flexibility of the spine. These improvements
      might explain the reduction in ski related back pain in the intervention group.

PMID- 15039250
TI  - Effect of intense wrestling exercise on leucocytes and adhesion molecules in
      adolescent boys.
AB  - BACKGROUND: In adults, exercise is a powerful and natural stimulator of immune
      cells and adhesion molecules. Far less is known about exercise responses during
      childhood and adolescence and whether or not exercise in "real life" activities
      of healthy adolescents influences immune responses. OBJECTIVE: To determine if
      strenuous exercise leads to significant changes in leucocyte number and adhesion
      molecule expression in adolescent boys. METHODS: Eleven healthy, high school
      boys, aged 14-18.5 years, performed a single, typical, 1.5 hour wrestling
      practice session. Blood was sampled before and after the session. Flow cytometry
      was used to evaluate changes in immune responses. RESULTS: The exercise led to
      significant (p<0.05) and robust increases in granulocytes, monocytes, and all
      lymphocyte subpopulations. The most significant changes were observed for natural
      killer cells (p<0.0005). The number of T cytotoxic and T helper cells expressing
      CD62L increased significantly (p<0.002 and p<0.0005 respectively), as did the
      number of T cytotoxic and T helper cells not expressing CD62L (p<0.003 and
      p<0.009 respectively). The density of CD62L on lymphocytes decreased
      significantly with exercise (p<0.0005), whereas CD11a (p<0.01) and CD54 (p<0.01)
      increased. CONCLUSIONS: The data show that an intense wrestling bout in
      adolescent boys leads to profound stimulation of the immune system. The role of
      these common changes in overall immune status and the development of the immune
      and haemopoietic systems has yet to be determined.

PMID- 15039251
TI  - Effectiveness of rugby headgear in preventing soft tissue injuries to the head: a
      case-control and video cohort study.
AB  - OBJECTIVE: To determine if headgear use by rugby players was associated with a
      reduced risk of head or facial laceration, abrasion, or fracture. METHODS: An
      emergency department based case-control study in South Wales, UK, with cases
      being rugby players treated for superficial head and facial injuries and controls
      being their matched opponents during the game. A review of videos of the 41 games
      in the 1999 Rugby World Cup was also carried out to compare with the case-control
      study. Odds ratios (OR) and 95% confidence intervals (95% CI) were used to
      measure association between exposure (headgear wearing) and outcome (head and
      facial injuries). RESULTS: In the case-control study, 164 pairs were analysed,
      with headgear worn by 12.8% of cases and 21.3% of controls. Headgear use was
      associated with substantial but non-significant reductions in superficial head
      (OR = 0.43, 95% CI 0.13 to 1.19) and facial (OR = 0.57, 95% CI 0.21 to 1.46)
      injuries. The video study followed 547 players over 41 games, during which there
      were 47 bleeding injuries to the head. Headgear use significantly reduced the
      risk of bleeding head injury in forwards (OR = 0.14, 95% CI 0.01 to 0.99, p =
      0.02), but not in backs. There was also a higher risk of facial injury among
      forwards, but this was not significant. CONCLUSIONS: The combined results suggest
      that headgear can prevent certain types of superficial head injuries in players
      at all levels of the game, but the evidence is strongest for superficial head
      injury in elite forwards. A randomised controlled trial would be the best way to
      study this further.

PMID- 15039252
TI  - Reliability of a device measuring triceps surae muscle fatigability.
AB  - OBJECTIVE: To examine the test-retest reliability of a protocol using an
      apparatus designed to standardise the standing heel rise test for the triceps
      surae muscle. SUBJECTS: 40 healthy subjects volunteered to test short and medium
      term test-retest reliability (group SM, median age 24 years), and a convenience
      sample of 38 subjects with a history of unilateral deep vein thrombosis (DVT)
      volunteered to test long term test-retest reliability (group L, median age 52
      years). DESIGN: Subjects carried out 23 heel rises per minute until either the
      pace or the height could no longer be maintained. Group SM subjects repeated the
      test 30 minutes later (short term), and again 48 hours later (medium term).
      Subjects in group L did the test on the unaffected leg, and repeated the test one
      week later (long term). RESULTS: The median number of heel rises achieved per
      trial in group SM was 34 (range 16 to 120). The intraclass coefficient (ICC) was
      0.93 (SEM 2.1) for both 30 minute and 48 hour test-retest reliability. In group
      L, the median number of heel rises was 27 (range 9 to 97), with ICC 0.88 and SEM
      3.4. CONCLUSIONS: The apparatus is a simple and inexpensive standardised tool
      that reliably measures triceps surae fatigability in subjects with no current
      injury. Future research should assess its use in injured patients.

PMID- 15039253
TI  - Injuries in youth amateur soccer and rugby players--comparison of incidence and
      characteristics.
AB  - OBJECTIVES: In reviewing the literature on sports injuries, few studies could be
      found in which exposure related incidences of injury in different types of sport
      were compared. These studies indicated that ice hockey, handball, basketball,
      soccer, and rugby are popular team sports with a relatively high risk of injury.
      The aim of the study was to compare the characteristics and incidence of injuries
      in male youth amateur soccer and rugby players. METHODS: This prospective cohort
      study comprised an initial baseline examination to ascertain the characteristics
      of the players and their level of performance, and a one season observation
      period during which a physician visited the team weekly and documented all
      occurring injuries. Twelve soccer and 10 rugby school teams with male amateur
      players aged 14-18 years were selected for the study. 145 soccer and 123 rugby
      players could be followed up over one season. RESULTS: Comparison of the
      incidence of soccer and rugby injuries indicated that rugby union football was
      associated with a significantly higher rate of injury than soccer. The
      differences were pronounced for contact injuries, injuries of the head, neck,
      shoulder, and upper extremity, as well as for concussion, fractures,
      dislocations, and strains. Rugby players incurred 1.5 times more overuse and
      training injuries in relation to exposure time, and 2.7 times more match injuries
      than soccer players. Three rugby players but no soccer players had to stop their
      participation in sport because of severe injury. CONCLUSION: The incidence of
      injury in New Zealand school teams playing soccer or rugby union is high,
      probably in part because of the low ratio of hours spent in training relative to
      hours spent playing matches. The development and implementation of preventive
      interventions to reduce the rate and severity of injury is recommended.

PMID- 15039254
TI  - Effects of leg massage on recovery from high intensity cycling exercise.
AB  - BACKGROUND: The effect of massage on recovery from high intensity exercise is
      debatable. Many studies on massage suffer from methodological flaws such as poor
      standardisation of previous exercise, lack of dietary control, and inappropriate
      massage duration. OBJECTIVE: To examine the effects of leg massage compared with
      passive recovery on lactate clearance, muscular power output, and fatigue
      characteristics after repeated high intensity cycling exercise, with the
      conditions before the intervention controlled and standardised. METHODS: Nine
      male games players participated. They attended the laboratory on two occasions
      one week apart and at the same time of day. Dietary intake and activity were
      replicated for the two preceding days on each occasion. After baseline
      measurement of heart rate and blood lactate concentration, subjects performed a
      standardised warm up on the cycle ergometer. This was followed by six
      standardised 30 second high intensity exercise bouts, interspersed with 30
      seconds of active recovery. After five minutes of active recovery and either 20
      minutes of leg massage or supine passive rest, subjects performed a second
      standardised warm up and a 30 second Wingate test. Capillary blood samples were
      drawn at intervals, and heart rate, peak power, mean power, and fatigue index
      were recorded. RESULTS: There were no significant differences in mean power
      during the initial high intensity exercise bouts (p = 0.92). No main effect of
      massage was observed on blood lactate concentration between trials (p = 0.82) or
      heart rate (p = 0.81). There was no difference in the maximum power (p = 0.75) or
      mean power (p = 0.66) in the subsequent Wingate test, but a significantly lower
      fatigue index was observed in the massage trial (p = 0.04; mean (SD) fatigue
      index 30.2 (4.1)% v 34.2 (3.3)%). CONCLUSIONS: No measurable physiological
      effects of leg massage compared with passive recovery were observed on recovery
      from high intensity exercise, but the subsequent effect on fatigue index warrants
      further investigation.

PMID- 15039255
TI  - Validity and factor structure of the bodybuilding dependence scale.
AB  - OBJECTIVES: To investigate the factor structure, validity, and reliability of the
      bodybuilding dependence scale and to investigate differences in bodybuilding
      dependence between men and women and competitive and non-competitive
      bodybuilders. METHODS: Seventy two male competitive bodybuilders, 63 female
      competitive bodybuilders, 87 male non-competitive bodybuilders, and 63 non
      competitive female bodybuilders completed the bodybuilding dependence scale
      (BDS), the exercise dependence questionnaire (EDQ), and the muscle dysmorphia
      inventory (MDI). RESULTS: Confirmatory factor analysis of the BDS supported a
      three factor model of bodybuilding dependence, consisting of social dependence,
      training dependence, and mastery dependence (Q = 3.16, CFI = 0.98, SRMR = 0.04).
      Internal reliability of all three subscales was high (Cronbach's alpha = 0.92,
      0.92, and 0.93 respectively). Significant (p<0.001) and moderate correlations
      were found between all BDS and MDI subscales, and between five of the eight EDQ
      subscales. A multivariate analysis of covariance, with univariate F tests and
      Tukey HSD tests, revealed that both male and female competitive bodybuilders
      scored significantly (p<0.05) higher on all three BDS subscales than the male and
      female non-competitive bodybuilders. However, there were no significant sex
      differences on any of the BDS subscales (p>0.05). CONCLUSION: The three factor
      BDS appears to be a reliable and valid measure of bodybuilding dependence.
      Symptoms of bodybuilding dependence are more prevalent in competitive
      bodybuilders than non-competitive ones, but there are no significant sex
      differences in bodybuilding dependence.

PMID- 15039256
TI  - Comparison of three preventive methods in order to reduce the incidence of ankle
      inversion sprains among female volleyball players.
AB  - BACKGROUND: Ankle sprains are the most common form of acute injury in volleyball.
      A prevention programme consisting of technical training, proprioceptive training,
      and external support was previously designed to reduce the rate of ankle sprains
      in volleyball players. OBJECTIVE: To investigate which of these three
      interventions is the most effective in preventing ankle sprain in female
      volleyball players. METHODS: Participants were 52 players who suffered ankle
      sprains during the season 1998-1999. They were divided randomly into three
      preventive groups: group 1 (n = 18) followed the technical training programme;
      group 2 (n = 17) followed the proprioceptive programme; group 3 (n = 17) used
      orthosis. The players followed their respective programmes for the whole of the
      1999-2000 season. Data were collected at the end of the season. RESULTS: The
      three preventive strategies were all effective in preventive further ankle
      sprain. Technical training was slightly more effective than the other two
      methods. Orthosis was not effective in athletes who had suffered ankle sprains
      more than three times during their careers. Under those circumstances, technical
      training and proprioceptive training were equally effective at preventive further
      sprains. CONCLUSIONS: Technical training and proprioceptive training are
      effective methods of preventing ankle sprain in volleyball players who have
      suffered this injury four or more times during their career. Orthosis appears
      effective only in players with fewer than four previous sprains.

PMID- 15039257
TI  - Effects of exercise on the physical condition of college rugby players during
      summer training camp.
AB  - OBJECTIVES: To determine the effects of exercise training on physical condition
      in 25 college rugby players during a summer training camp, and to compare these
      variables by the different players' positions. METHODS: Changes in body
      composition parameters and blood biochemistry were examined before and after a
      summer training camp. RESULTS: Body weight and percentage body fat did not change
      significantly during the camp. There were significant decreases in levels of
      serum total cholesterol, triglycerides, phosphate, uric acid, and immunoglobulin
      G and M. In contrast, there were significant increases in levels of serum
      potassium, markers of renal, hepatic, and muscular damage (BUN, GOT, GPT, LDH,
      CK), and complement C4. Comparison of the changes in biochemical parameters
      between rugby players playing in different positions showed a significant
      increase in serum albumin level in the forwards, and significant decreases in
      serum triglyceride and sodium levels in the backs. The magnitude of change in
      serum LDH during the camp was significantly greater (p<0.05) for the forwards
      than for the backs. CONCLUSIONS: These data suggest that, in rugby players
      attending a 20 day camp, exercise training resulted in muscular damage, loss of
      electrolytes due to sweating, and changes in immune function. Backs exhibited a
      higher rate of fat metabolism and loss of electrolytes than forwards, possibly
      because they did more running during the camp. In contrast, forwards experienced
      more physical contact, performed more physically strenuous exercise, and
      exhibited higher levels of muscular damage and tissue protein degradation.

PMID- 15039259
TI  - Reliability and validity of measures taken during the Chester step test to
      predict aerobic power and to prescribe aerobic exercise.
AB  - OBJECTIVES: To evaluate the reliability and validity of measures taken during the
      Chester step test (CST) used to predict VO(2)max and prescribe subsequent
      exercise. METHODS: The CST was performed twice on separate days by 7 males and 6
      females aged 22.4 (SD 4.6) years. Heart rate (HR), ratings of perceived exertion
      (RPE), and oxygen uptake (VO(2)) were measured at each stage of the CST. RESULTS:
      RPE, HR, and actual VO(2) were the same at each stage for both trials but each of
      these measures was significantly different between CST stages (p<0.0005).
      Intertrial bias +/-95% limits of agreement (95% LoA) of HR reached acceptable
      limits at CST stage IV (-2+/-10 beats/min) and for RPE at stages III (0.2+/-1.4)
      and IV (0.5+/-1.9). Age estimated HRmax significantly overestimated actual HRmax
      of 5 beats/min (p = 0.016) and the 95% LoA showed that this error could range
      from an underestimation of 17 beats/min to an overestimation of 7 beats/min.
      Estimated versus actual VO(2) at each CST stage during both trials showed errors
      ranging between 11% and 19%. Trial 1 underestimated actual VO(2)max by 2.8
      ml/kg/min (p = 0.006) and trial 2 by 1.6 ml/kg/min (not significant). The
      intertrial agreement in predicted VO(2)max was relatively narrow with a bias +/
      95% LoA of -0.8+/-3.7 ml/kg/min. The RPE and %HRmax (actual) correlation improved
      with a second trial. At all CST stages in trial 2 RPE:%HRmax coefficients were
      significant with the highest correlations at CST stages III (r = 0.78) and IV (r
      = 0.84). CONCLUSION: CST VO(2)max prediction validity is questioned but the CST
      is reliable on a test-retest basis. VO(2)max prediction error is due more to
      VO(2) estimation error at each CST stage compared with error in age estimated
      HRmax. The HR/RPE relation at >50% VO(2)max reliably represents the recommended
      intensity for developing cardiorespiratory fitness, but only when a practice
      trial of the CST is first performed.

PMID- 15039258
TI  - Field and laboratory testing in young elite soccer players.
AB  - AIM: To determine if there are correlations between the physical fitness of young
      soccer players assessed by field and laboratory testing. METHODS: Thirty four
      male soccer players took part in the study (mean (SD) age 17.5 (1.1) years,
      height 177.8 (6.7) cm, weight 70.5 (6.4) kg). Maximal oxygen uptake (VO(2)MAX)
      during treadmill running and vertical jump height on a force platform were
      measured in the laboratory. Field tests consisted of a soccer specific endurance
      test (Bangsbo test) and 30 m sprint with 10 m lap times. RESULTS: The Bangsbo
      test correlated with the lowest velocity associated with VO(2)MAX (vVO(2)MAX;
      R(2) = 0.55, p<0.001), but not with VO(2)MAX. Sprint times at 30 m and 20 m were
      related to peak extension velocity and peak extension force measured during
      vertical jumping, but not to vertical jump height per se. The jumping force and
      velocity could explain 46% of the 30 m sprint performance (R(2) = 0.46, p<0.001).
      CONCLUSION: The Bangsbo test and 30 m sprint test correlate with vVO(2)MAX and
      vertical jump force and velocity respectively. The Bangsbo test does not give a
      good estimate of VO(2)MAX in young soccer players.

PMID- 15039260
TI  - Anthropometry, physical performance, and ultrasound patellar tendon abnormality
      in elite junior basketball players: a cross-sectional study.
AB  - OBJECTIVE: Patellar tendinopathy has been reported to be associated with many
      intrinsic risk factors. Few have been fully investigated. This cross-sectional
      study examined the anthropometric and physical performance results of elite
      junior basketball players with normal or abnormal patellar tendons to see if any
      measures were associated with changes in tendon morphology. METHODS: Agility, leg
      strength, endurance, and flexibility were measured in 71 male and 64 female
      players. A blinded radiologist ultrasonographically examined their patellar
      tendons and athletes were grouped as having normal or abnormal tendons. One-way
      ANOVA was used to test for differences in anthropometric and physical performance
      data for athletes whose tendons were normal or abnormal (unilateral or bilateral
      tendinopathy) on ultrasound. RESULTS: Results show that females with
      abnormalities in their tendons had a significantly better vertical jump (50.9+/
      6.8 cm) than those with normal tendons (46.1+/-5.4 cm) (p = 0.02). This was not
      found in males. In males, the mean sit and reach in those with normal tendons
      (13.2+/-6.7 cm) was greater (p<0.03) than in unilateral tendinopathy (10.3+/-6.2
      cm) or in bilateral tendinopathy (7.8+/-8.3 cm). In females, those with normal
      tendons (13.3+/-4.8 cm) and bilateral tendinopathy (15.8+/-6.2 cm) were
      distinctly different from those with unilateral tendinopathy (7.9+/-6.6 cm).
      CONCLUSION: Flexibility and vertical jump ability are associated with patellar
      tendinopathy and the findings warrant consideration when managing young, jumping
      athletes.

PMID- 15039262
TI  - Defining the sports medicine specialist in the United Kingdom: a Delphi study.
AB  - OBJECTIVE: To define the role and responsibilities of the sports medicine
      specialist using a recognised research technique. METHODS: A Delphi technique was
      employed using anonymous postal questionnaires sent to a random sample of 300
      members of the British Association of Sport and Exercise Medicine. The
      questionnaire of 300 putative attributes was developed in a pilot study and the
      Delphi technique used allowed participants to modify their responses according to
      the responses of other participants. RESULTS: There was a 53% response to both
      rounds of the study with 75.6% of the respondents being male, 39% having a higher
      qualification in sports medicine, and 45.6% being general practitioners. Some
      86.3% strongly agreed that sport and exercise medicine should be a recognised
      speciality and 90% strongly agreed that it should be available on the National
      Health Service (NHS). The most important specialist attributes were orthopaedic
      and soft tissue medicine (83.6% strongly agreed) and emergency medical management
      (79.7% strongly agreed). More than 75% of respondents did not agree that either
      research or personal playing experience were relevant. CONCLUSION: Sports and
      exercise medicine is an evolving speciality in the United Kingdom. We believe
      this is the first systematic attempt to define the role and responsibilities of
      the sports medicine specialist and the findings are of relevance to the future
      development of a career pathway.

PMID- 15039261
TI  - Combining isometric knee extension exercises with hip adduction or abduction does
      not increase quadriceps EMG activity.
AB  - OBJECTIVE: To determine if the combined isometric contractions of knee
      extension/hip adduction and knee extension/hip abduction will elicit a different
      quadriceps and gluteus medius electromyographic (EMG) pattern as compared to
      isometric contraction of a uniplanar knee extension exercise. METHODS: Eight
      healthy young adult volunteers without history of knee or quadriceps injury
      participated. Surface EMG data were collected from the vastus medialis oblique
      (VMO), vastus lateralis (VL), and gluteus medius (Gmed) muscles of the dominant
      leg of each subject during three single leg, weight bearing, isometric exercises
      (uniplanar knee extension, knee extension/hip adduction, knee extension/hip
      abduction). All exercises were performed at a position of 60 degrees knee
      flexion. Three trials lasting 5 s each were performed for each of the three
      exercises. EMG data from each muscle were integrated and the maximum root mean
      square activity over a 0.5 s window for each trial was averaged. Analyses of
      variance were performed with exercise (straight extension, extension/adduction,
      extension/abduction) as the independent variable and VMO, VL, and Gmed activity
      and VMO:VL ratio as dependent variables. RESULTS: A significant main effect for
      exercise was found for the VMO (p = 0.006) and VL (p = 0.02), but not the Gmed (p
      = 0.25) or the VMO:VL ratio (p = 0.13). For the VMO and VL, the uniplanar knee
      extension task produced significantly more EMG activity than the
      extension/adduction or extension/abduction tasks. CONCLUSIONS: Uniplanar knee
      extension exercises may be more appropriate than combining isometric knee
      extension exercises with hip adduction or abduction when eliciting maximal VMO
      and VL contractions.

PMID- 15039263
TI  - Acute compartment syndrome of the anterior thigh following quadriceps strain in a
      footballer.
AB  - A rare case is presented of acute anterior compartment syndrome in the thigh of a
      footballer caused by an acute quadriceps strain, exacerbated by poor first aid
      and alcohol ingestion. Decompressive fasciotomy with subsequent split skin
      grafting of the wound defect resulted in a satisfactory outcome. The diagnosis
      requires a high index of suspicion lest it be overlooked with inevitably
      disastrous consequences.

PMID- 15039264
TI  - Pseudarthrosis of the first rib in the overhead athlete.
AB  - Fractures of the first rib are uncommon in athletes and present a different
      clinical entity from traumatic first rib fracture associated with high energy
      thoracic trauma. These fractures are stress induced and precipitated by chronic
      muscular forces acting on the first rib. Typically they heal with conservative
      treatment. This report describes a fracture of the first rib in a tennis player
      that developed into a symptomatic pseudarthrosis as a result of persistent
      overhead activities. Symptoms mimicked ipsilateral shoulder injury.
      Pseudarthrosis of the first rib should be included in the differential diagnosis
      of chronic persistent shoulder pain in the overhead athlete.

PMID- 15039265
TI  - Chronic groin pain in an amateur soccer player.
AB  - Chronic groin pain is common in soccer players because of the biomechanics of
      kicking causing recurrent stress to the abdominal muscles, groin flexors, and
      adductor muscles. Myositis ossificans in adductor muscles is a rare cause of
      chronic groin pain in soccer players. Only two cases have been reported and the
      iliopsoas muscle was involved in both. This case report emphasises the importance
      of direct radiography for diagnosis in chronic groin pain and is a reminder that
      the development of myositis ossificans in the adductor muscles may be a cause.

PMID- 15039266
TI  - Failure of operative treatment in a fast bowler with bilateral spondylolysis.
AB  - Modern day fast bowling places immense strain on the spine. Stress fractures of
      the lumbar region are common. If a period of conservative treatment fails to
      return a fast bowler to professional sport, surgery is considered. Good results
      have been reported using a direct screw repair of the spondylolytic defect. A
      case is presented of a failed surgical intervention with an alternative
      technique.

PMID- 15039267
TI  - Exercise induced compartment syndrome in a professional footballer.
AB  - Recurrent pain in the lower leg caused by exercise is a common problem in
      athletes. The main causes are exercise induced compartment syndrome, periostitis
      of the tibia, stress fracture, venous diseases, obliterative arterial diseases,
      and shin splints. Exercise induced compartment syndrome is the least common. A
      recurrent tightening or tense sensation and aching in anatomically defined
      compartments is pathognomonic. The symptoms are caused by abnormally high
      pressure in compartments of the leg during and after exercise. In this report, a
      case of exercise induced compartment syndrome in a professional footballer is
      described.

PMID- 15039268
TI  - Spontaneous atrial fibrillation in a freestyle skier.
AB  - A male freestyle skier was found to have atrial fibrillation during a routine
      physiological assessment. This was found to be associated with the consumption of
      an unusually large amount of alcohol. Athletes should be counselled about the
      potential dangers of alcohol consumption before exhaustive exercise.

PMID- 15039269
TI  - A successful conservative approach to managing lower leg pain in a university
      sports injury clinic: a two patient case study.
AB  - There is a lack of information on the conservative treatment of lower leg pain
      induced by running. In this study, non-invasive treatment based on a change of
      footwear was applied to two patients, and, on the basis of pain scale
      questionnaires, deemed successful.

PMID- 15039270
TI  - Massage provision by physiotherapists at major athletics events between 1987 and
      1998.
AB  - BACKGROUND: The equivocal findings in the literature on efficacy of massage makes
      it difficult to assess the requirement for, or justify the use of, specialist
      massage personnel at major athletics events. However, the use of massage by
      athletes during training and competition remains popular. OBJECTIVES: To quantify
      the amount of their time that physiotherapists devote to massage treatment at
      major athletics events in an attempt to determine the importance of this
      treatment modality, and to examine whether the use of massage at athletics events
      is changing over time. METHODS: Data recorded by the head team physiotherapist
      from 12 major athletics events (national and international events) between 1987
      and 1998 were examined. For each event, the data included: total number of
      treatments administered by the physiotherapist, the treatment modalities used,
      and the number of attendances for treatment. The amount of massage provided was
      expressed as a percentage of the total number of treatments for each athletic
      event, and the pattern of change in use of massage treatment over time was
      evaluated. RESULTS: The percentage of time spent providing massage treatment
      ranged from 24.0% to 52.2% of the total number of treatments made. The overall
      median percentage of total treatments in the form of massage was 45.2%. No
      significant increase or decrease in the use of massage as a treatment modality
      was observed between 1987 and 1998 in the athletics events examined (p = 0.95).
      CONCLUSIONS: A significant proportion of physiotherapists' time is devoted to the
      delivery of massage treatment at athletics events. The demand for massage
      treatment has been steady over the time period, in the events for which data are
      available, indicating a consistent use of this treatment modality. Given the
      popularity of massage among athletes, consideration should be given to the use of
      specialist sports massage staff at major athletics events. Furthermore, it would
      seem prudent to further investigate the efficacy of the treatment.

PMID- 15039271
TI  - Non-participation in sports injury research: why football players choose not to
      be involved.
AB  - OBJECTIVE: To ascertain the reasons behind players not participating in a sports
      safety research project. METHODS: During the preseason, 10 Australian football
      clubs volunteered 23 teams to participate in a protective equipment randomised
      controlled trial, the Australian Football Injury Prevention Project (AFIPP). All
      players from these teams were invited to participate. Players who did not agree
      to participate in AFIPP were surveyed about their reasons for non-involvement.
      RESULTS: 110 football players (response rate 63.6%) completed the non-responder
      survey and cited the two main reasons behind non-involvement in the project as "I
      did not know about the project" (39.4%) and "I was not at training when the
      research team visited" (36.5%). CONCLUSIONS: and implications: Preseason may not
      be the best time for maximal player recruitment in community based sports safety
      research. Enhanced communication between researchers and players at community
      level football clubs during the recruitment phase is likely to improve response
      rates.

PMID- 15039272
TI  - Science versus opinion.

PMID- 15039273
TI  - Runner's stitch and the thoracic spine.

PMID- 15039276
TI  - Corticosteroid injections for osteoarthritis of the knee: meta-analysis.
AB  - OBJECTIVES: To determine the efficacy of intra-articular corticosteroid
      injections for osteoarthritis of the knee and to identify numbers needed to
      treat. DATA SOURCES: Cochrane controlled trials register, Medline (1966 to 2003),
      Embase (1980 to 2003), hand searches, and contact with authors. INCLUSION
      CRITERIA: Randomised controlled trial in which the efficacy of intra-articular
      corticosteroid injections for osteoarthritis of the knee could be ascertained.
      RESULTS: In high quality studies, the pooled relative risk for improvement in
      symptoms of osteoarthritis of the knee at 16-24 weeks after intra-articular
      corticosteroid injections was 2.09 (95% confidence interval 1.2 to 3.7) and the
      number needed to treat was 4.4. The pooled relative risk for improvement up to
      two weeks after injections was 1.66 (1.37 to 2.0). The numbers needed to treat to
      get one improvement in the statistically significant studies was 1.3 to 3.5
      patients. CONCLUSION: Evidence supports short term (up to two weeks) improvement
      in symptoms of osteoarthritis of the knee after intra-articular corticosteroid
      injection. Significant improvement was also shown in the only methodologically
      sound studies addressing longer term response (16-24 weeks). A dose equivalent to
      50 mg of prednisone may be needed to show benefit at 16-24 weeks.

PMID- 15039277
TI  - A novel maxizyme vector targeting a bcr-abl fusion gene induced specific cell
      death in Philadelphia chromosome-positive acute lymphoblastic leukemia.
AB  - Patients with Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic
      leukemia (ALL) generally have a poor prognosis and would benefit from the
      development of new therapeutic approaches. We previously demonstrated that an
      allosterically controllable ribozyme, maxizyme (Mz), can induce apoptosis in
      chronic myelogenous leukemia (CML) cells. Ph(+) ALL cells harbor a bcrabl fusion
      gene (e1a2) encoding a 190-kDa fusion protein (p190) involved in disease
      pathogenesis. In this study, we have designed a Mz that specifically cleaves e1a2
      mRNA and transduced this e1a2Mz into Ph(+) ALL cells using a third-generation
      lentiviral vector system. In 3 of 5 Ph(+) ALL cell lines, e1a2Mz transduction
      resulted in a significant decrease in viability and increased cell apoptosis. We
      observed a decrease in e1a2 mRNA in all Ph(+) ALL cells transduced with e1a2Mz,
      and the e1a2 mRNA level was higher in e1a2Mz-resistant cells than in e1a2Mz
      sensitive cells. All samples of primary Ph(+) ALL cells tested showed e1a2Mz
      induced growth inhibition and apoptosis. Importantly, e1a2Mz did not influence
      the colony formation of normal CD34(+) cord blood cells. These results indicate
      that e1a2Mz kills Ph(+) ALL cells specifically, suggesting that it may be used as
      a novel gene therapy strategy for Ph(+) ALL.

PMID- 15039278
TI  - Monoclonal antibody IAC-1 is specific for activated alpha2beta1 and binds to
      amino acids 199 to 201 of the integrin alpha2 I-domain.
AB  - In this study we describe the first monoclonal antibody, integrin activated
      conformation-1 (IAC-1), to recognize the active form of the platelet-collagen
      receptor, the integrin alpha(2)beta(1). IAC-1 has the following properties: (1)
      IAC-1 fails to bind to resting platelets but readily interacts with platelets
      stimulated by the glycoprotein VI-specific agonist, convulxin, and by other
      agonists; (2) similar concentration response relationships for binding of IAC-1
      and soluble collagen were observed in convulxin-stimulated platelets; (3) the
      epitope for IAC-1 is T199Y200K201, which is located at the opposite site of the
      metal ion-dependent adhesion site in a region not involved in the I-domain
      "shifts" that occur upon ligand binding; (4) IAC-1 strongly binds to recombinant
      alpha(2) I-domain, therefore suggesting that the neo-epitope appears to be
      exposed by an "unmasking" of I-domain-covering regions upon activation; (5) IAC-1
      binds to platelets during adhesion to collagen under shear conditions,
      demonstrating activation of alpha(2)beta(1); (6) as IAC-1 does not interfere with
      platelet-collagen binding, it defines a new class of antibodies that is distinct
      from those belonging to the "cation- and ligand-induced binding sites" (CLIBSs)
      and the "ligand mimetic" group. These characteristics make IAC-1 a very powerful
      tool to study alpha(2)beta(1) activation under dynamic and physiologically
      relevant conditions.

PMID- 15039280
TI  - A recombinant murine meizothrombin precursor, prothrombin R157A/R268A, inhibits
      thrombosis in a model of acute carotid artery injury.
AB  - Mutations in human prothrombin that generate a stable form of meizothrombin or
      meizothrombin(desF1) cause dysprothrombinemia in both the homozygous and
      heterozygous state, suggesting that meizothrombin has dominant anticoagulant
      effects in vivo. The enzymatic characterization of recombinant mouse
      meizothrombin, meizothrombin(desF1), and thrombin indicates that all 3 enzymes
      have similar activity toward the chromogenic substrate S-2238, that meizothrombin
      and meizothrombin(desF1) have less than 10% of the fibrinogen-clotting activity
      of thrombin, and that meizothrombin is more active than thrombin or
      meizothrombin(desF1) for thrombomodulin-dependent protein C activation. Thus,
      activated mouse prothrombin R157A/R268A is similar to human meizothrombin in
      activity toward S-2238, fibrinogen, and protein C. The time to occlusion after
      FeCl(3)-induced carotid artery injury was delayed (11.8 +/- 3.6 minutes, n = 5)
      in Cf2(+/-) mice infused with prothrombin R157A/R268A compared with control mice
      infused with wild-type prothrombin (5.3 +/- 1.5 minutes, n = 3; P =.006). In this
      model, prothrombin R157A/R268A has anticoagulant activity that reflects its
      decreased fibrinogen-clotting activity and preserved protein C-activating
      activity and is consistent with dominant inhibition of fibrinogen clotting.

PMID- 15039279
TI  - The peripheral cannabinoid receptor Cb2, frequently expressed on AML blasts,
      either induces a neutrophilic differentiation block or confers abnormal migration
      properties in a ligand-dependent manner.
AB  - Cb2, the gene encoding the peripheral cannabinoid receptor, is located in a
      common virus integration site and is overex-pressed in retrovirally induced
      murine myeloid leukemias. Here we show that this G protein-coupled receptor
      (GPCR) is also aberrantly expressed in a high percentage of human acute myeloid
      leukemias. We investigated the mechanism of transformation by Cb2 and demonstrate
      that aberrant expression of this receptor on hematopoietic precursor cells
      results in distinct effects depending on the ligand used. Cb2-expressing myeloid
      precursors migrate upon stimulation by the endocannabinoid 2-arachidonoylglycerol
      and are blocked in neutrophilic differentiation upon exposure to another ligand,
      CP55940. Both effects depend on the activation of G(alphai) proteins and require
      the mitogen-induced extracellular kinase/extracellular signal-regulated kinase
      (MEK/ERK) pathway. Down-regulation of cyclic adenosine monophosphate (cAMP)
      levels upon G(alphai) activation is important for migration induction but is
      irrelevant for the maturation arrest. Moreover, the highly conserved G protein
      interacting DRY motif, present in the second intracellular loop of GPCRs, is
      critical for migration but unimportant for the differentiation block. This
      suggests that the Cb2-mediated differentiation block requires interaction of
      G(alphai) proteins with other currently unknown motifs. This indicates a unique
      mechanism by which a transforming GPCR, in a ligand-dependent manner, causes 2
      distinct oncogenic effects: altered migration and block of neutrophilic
      development.

PMID- 15039281
TI  - A report from the LALA-94 and LALA-SA groups on hypodiploidy with 30 to 39
      chromosomes and near-triploidy: 2 possible expressions of a sole entity
      conferring poor prognosis in adult acute lymphoblastic leukemia (ALL).
AB  - To reveal the relationship between hypodiploidy with 30 to 39 chromosomes and
      near-triploidy in acute lymphoblastic leukemia (ALL), we studied 24 patients
      presenting with one of these aneuploidies among 623 adults with ALL registered in
      the Leucemie Aigue Lymphoblastique de l'Adulte (LALA) protocols. The 2 ploidy
      groups presented a striking similarity of their cytogenetic profiles: chromosomes
      2, 3, 4, 7, 13, 15, 16, and 17, significantly monosomic in hypodiploidy 30 to 39,
      were also frequently disomic in near-triploidy, whereas those retained in pairs
      in hypodiploidy 30 to 39 were frequently tetrasomic in near-triploidy. DNA
      content data revealed the simultaneous presence of 2 aneuploid peaks in most
      tested cases (DNA indexes: 0.72-0.87/1.39-1.89) and a multiple correspondence
      analysis applied on cytogenetic profiles ascertained their strong relationship.
      We thus assumed that near-triploidy derives from the duplication of hypodiploidy
      with 30 to 39 chromosomes and that both aneuploid groups are 2 expressions of the
      same disease. These 24 patients presented with B-cell phenotype, low leukocytoses
      (median white blood cell count, 4.2 x 10(9)/L), and poor prognosis (complete
      remission, 57%; median disease-free-survival, 8 months; median survival, 10.4
      months) comparable to that of Ph(+) patients treated according to the same
      protocol. We suggest that hypodiploidy with 30 to 39 chromosomes or near
      triploidy should be regarded as a new high-risk factor in the risk stratification
      of adult ALL protocols.

PMID- 15039282
TI  - Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+
      cytotoxic T-cell response in natural infection.
AB  - Although cytomegalovirus (CMV) expresses proteins that interfere with antigen
      presentation by class I major histocompatibility complex (MHC) molecules, CD8+
      cytotoxic T cells (CTLs) are indispensable for controlling infection and
      maintaining latency. Here, a cytokine flow cytometry assay that employs
      fibroblasts infected with a mutant strain of CMV (RV798), which is deleted of the
      4 viral genes that are responsible for interfering with class I MHC presentation,
      was used to examine the frequency and specificity of the CD8+ CTLs to CMV in
      immunocompetent CMV-seropositive individuals. A large fraction of the CD8+ CTL
      response was found to be specific for viral antigens expressed during the
      immediate early and early phases of virus replication and presented by
      fibroblasts infected with RV798 but not wild-type CMV. These results demonstrate
      that the inhibition of class I antigen presentation observed in CMV-infected
      cells in vitro is not sufficient to prevent the induction of a broad repertoire
      of CD8+ CTLs after natural infection in vivo. Thus, reconstitution of T-cell
      immunity in immunodeficient patients by cell therapy or by vaccination may need
      to target multiple viral antigens to completely restore immunologic control of
      CMV.

PMID- 15039283
TI  - New approach for bone marrow transplantation in patients with class 3 thalassemia
      aged younger than 17 years.
AB  - When prepared for transplantation with busulfan (BU) 14 mg/kg and
      cyclophosphamide (CY) 120 to 160 mg/kg, patients with thalassemia in risk class
      3, aged younger than 17 years, who receive transplants from HLA-identical donors,
      had a 30% incidence of transplant rejection with recurrence of thalassemia. This,
      relatively poor, outcome was ascribed to insufficient immune suppression or to
      inadequate eradication of the thalassemic marrow, or both. In an attempt to
      enhance both immune suppression and eradication of the thalassemic clones,
      hydroxyurea, azathioprine, and fludarabine were added to the BU and CY. This
      regimen, called protocol 26, was applied to 33 consecutive patients with class 3
      thalassemia aged younger than 17 years and was well tolerated with 93% survival.
      The incidence of recurrent thalassemia after the transplantation decreased from
      30% to 8%.

PMID- 15039284
TI  - Bortezomib and flavopiridol interact synergistically to induce apoptosis in
      chronic myeloid leukemia cells resistant to imatinib mesylate through both
      Bcr/Abl-dependent and -independent mechanisms.
AB  - Interactions between the cyclin-dependent kinase (CDK) inhibitor flavopiridol and
      the proteasome inhibitor bortezomib were examined in Bcr/Abl(+) human leukemia
      cells. Coexposure of K562 or LAMA84 cells to subtoxic concentration of
      flavopiridol (150-200 nM) and bortezomib (5-8 nM) resulted in a synergistic
      increase in mitochondrial dysfunction and apoptosis. These events were associated
      with a marked diminution in nuclear factor kappaB (NF-kappaB)/DNA binding
      activity; enhanced phosphorylation of SEK1/MKK4 (stress-activated protein
      kinase/extracellular signal-related kinase 1/mitogen-activated protein kinase
      kinase 4), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein
      kinase (MAPK); down-regulation of Bcr/Abl; and a marked reduction in signal
      transducer and activator of transcription 3 (STAT3) and STAT5 activity. In
      imatinib mesylate-resistant K562 cells displaying increased Bcr/Abl expression,
      bortezomib/flavopiridol treatment markedly increased apoptosis in association
      with down-regulation of Bcr/Abl and BclxL, and diminished phosphorylation of Lyn,
      Hck, CrkL, and Akt. Parallel studies were performed in imatinib mesylate
      resistant LAMA84 cells exhibiting reduced expression of Bcr/Abl but a marked
      increase in expression/activation of Lyn and Hck. Flavopiridol/bortezomib
      effectively induced apoptosis in these cells in association with Lyn and Hck
      inactivation. The capacity of flavopiridol to promote bortezomib-mediated Bcr/Abl
      down-regulation and apoptosis was mimicked by the positive transcription
      elongation factor-b (P-TEFb) inhibitor DRB (5,6-dichloro 1-beta-d
      ribofuranosylbenzinida-sole). Finally, the bortezomib/flavopiridol regimen also
      potently induced apoptosis in Bcr/Abl(-) human leukemia cells. Collectively,
      these findings suggest that a strategy combining flavopiridol and bortezomib
      warrants further examination in chronic myelogenous leukemia and related
      hematologic malignancies.

PMID- 15039285
TI  - Interleukin-1beta but not IL-1alpha binds to fibrinogen and fibrin and has
      enhanced activity in the bound form.
AB  - Fibrin is formed at sites of injury or inflammation and provides the temporary
      matrix to support vascular cell responses that are also mediated by cytokines
      including interleukin-1 (IL-1). We have shown previously that fibroblast growth
      factor 2 (FGF-2) binds with high affinity to fibrin(ogen). Because IL-1 has a
      structure similar to FGF-2, we have investigated the possible binding of IL-1 to
      fibrin(ogen). Experiments using IL-1 immobilized on Sepharose beads and soluble
      iodine 125 ((125)I)-labeled fibrinogen demonstrated no specific interaction of IL
      1alpha with fibrinogen, but IL-1beta showed saturable and specific binding.
      Scatchard analysis indicated a single binding site with an apparent K(d) = 1.5 nM
      and a maximum molar binding ratio of IL-1beta to fibrinogen of 1.8:1. Binding of
      (125)I-IL-1beta to Sepharose-immobilized fibrinogen also demonstrated a single
      binding site with an apparent K(d) of 3.5 nM. IL-1beta also bound specifically to
      fibrin monomer and polymerized fibrin with apparent K(d)s of 3.4 nM and 2.3 nM,
      respectively. IL-1beta displaced FGF-2 for binding to fibrin, indicating an
      interaction with the same or a closely related site. Compared with free form,
      fibrinogen-bound IL-1beta stimulated increased activation of endothelial cell
      nuclear factor kappaB (NF-kappaB), monocyte chemoattractant protein-1 (MCP-1)
      secretion, and nitric oxide (NO) synthesis. We conclude that IL-1beta binds with
      high affinity to fibrin(ogen) and demonstrates increased activity in the bound
      form.

PMID- 15039286
TI  - A decision analysis of allogeneic bone marrow transplantation for the
      myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is
      associated with improved outcome.
AB  - Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS),
      although transplantation carries significant risks of morbidity and mortality.
      Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed
      a Markov model to examine 3 transplantation strategies for newly diagnosed MDS:
      transplantation at diagnosis, transplantation at leukemic progression, and
      transplantation at an interval from diagnosis but prior to leukemic progression.
      Analyses using individual patient risk-assessment data from transplantation and
      nontransplantation registries were performed for all 4 International Prognostic
      Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For
      low and intermediate-1 IPSS groups, delayed transplantation maximized overall
      survival. Transplantation prior to leukemic transformation was associated with a
      greater number of life years than transplantation at the time of leukemic
      progression. In a cohort of patients under the age of 40 years, an even more
      marked survival advantage for delayed transplantation was noted. For intermediate
      2 and high IPSS groups, transplantation at diagnosis maximized overall survival.
      No changes in the optimal transplantation strategies were noted when QoL
      adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT
      is associated with maximal life expectancy, whereas immediate transplantation for
      intermediate-2- and high-risk disease is associated with maximal life expectancy.

PMID- 15039287
TI  - Transcriptional suppression of cytochrome P450 genes by endogenous and exogenous
      chemicals.
AB  - This article is an invited report of a symposium sponsored by the Division for
      Drug Metabolism of the American Society for Pharmacology and Experimental
      Therapeutics held at Experimental Biology 2003 in San Diego, California, April 11
      15, 2003. Several members of the cytochrome P450 (P450) superfamily are induced
      after exposure to a variety of chemical signals, and we have gained considerable
      mechanistic insight into these processes over the past four decades. In addition,
      the expression of many P450s is suppressed in response to various endogenous and
      exogenous chemicals; however, relatively little is known about the molecular
      mechanisms involved. The goal of this symposium was to critically examine our
      current understanding of molecular mechanisms involved in transcriptional
      suppression of CYP genes by endogenous and exogenous chemicals. Specific examples
      were drawn from the following chemical categories: polycyclic and halogenated
      aromatic hydrocarbon environmental toxicants, inflammatory mediators, the
      endogenous sterol dehydroepiandrosterone and peroxisome proliferators, and bile
      acids. Multiple molecular mechanisms are involved in transcriptional suppression,
      and these processes often involve rather complex cascades of transcription
      factors and other regulatory proteins. Mechanistic studies of CYP gene
      suppression can enhance our understanding of how organisms respond to xenobiotics
      as well as to perturbations in endogenous chemicals involved in maintaining
      homeostasis.

PMID- 15039289
TI  - Identification of human cytochrome P450 2D6 as major enzyme involved in the O
      demethylation of the designer drug p-methoxymethamphetamine.
AB  - p-Methoxymethamphetamine (PMMA) is a new designer drug, listed in many countries
      as a controlled substance. Several fatalities have been attributed to the abuse
      of this designer drug. Previous in vivo studies using Wistar rats had shown that
      PMMA was metabolized mainly by O-demethylation. The aim of the study presented
      here was to identify the human hepatic cytochrome P450 (P450) enzymes involved in
      the biotransformation of PMMA to p-hydroxymethamphetamine. Baculovirus-infected
      insect cell microsomes, pooled human liver microsomes (pHLMs), and CYP2D6 poor
      metabolizer genotype human liver microsomes (PM HLMs) were used for this purpose.
      Only CYP2D6 catalyzed O-demethylation. The apparent K(m) and V(max) values in
      baculovirus-infected insect cell microsomes were 4.6 +/- 1.0 microM and 92.0 +/-
      3.7 pmol/min/pmol P450, respectively, and 42.0 +/- 4.0 microM and 412.5 +/- 10.8
      pmol/min/mg protein in pHLMs. Inhibition studies with 1 microM quinidine showed
      significant inhibition of the metabolite formation (67.2 +/- 0.6%; p < 0.0001),
      and comparison of the metabolite formation between pHLMs and PM HLMs revealed
      significantly lower metabolite formation in the incubations with PM HLMs (87.3 +/
      1.1%; p < 0.0001). According to these studies, CYP2D6 is the major P450 involved
      in O-demethylation of PMMA.

PMID- 15039288
TI  - Cloning CYP2D21 and CYP3A22 cDNAs from liver of miniature pigs.
AB  - To compare the identity of the primary structure of drug-metabolizing cytochrome
      P450 between miniature pigs and humans, two cDNA clones, coding for miniature pig
      CYP2D21 and CYP3A22, were isolated. The deduced amino acid sequences of CYP2D21
      and CYP3A22 were 78.3 and 75.0% identical to human CYP2D6 and CYP3A4,
      respectively. These values were nearly the same as those of bovine, dog, and some
      rodent isoforms, and 12.2 to 18.4% lower than those of nonhuman primates such as
      cynomolgus monkeys, Japanese monkey, and marmosets. These data indicate that
      miniature pig P450s are genetically not so close as monkey P450s to human P450s
      as previously expected. The recombinant CYP2D21 enzyme, however, showed bufuralol
      1'-hydroxylase activity, suggesting that miniature pig CYP2D21 is capable of
      metabolizing some of the same substrates associated with human CYP2D6 despite its
      low identity to human counterparts.

PMID- 15039291
TI  - New metabolic pathways for flavanones catalyzed by rat liver microsomes.
AB  - Flavonoids represent a diverse group of natural pigments widely distributed in
      the plant kingdom and are an important component of human diet due to their high
      content in fruits and vegetables. Since many flavonoids have been shown to be
      potent inhibitors, substrates, and even inducers of various cytochrome P450
      isoforms, there is considerable interest in studying interactions of this class
      of molecules with the cytochrome P450 enzyme system. In this study, the
      metabolism of several simple flavanones by rat liver microsomes was investigated
      and compared. In addition to the expected aromatic hydroxylation products,
      several novel metabolic pathways were observed including C-ring desaturation to
      form the corresponding flavones, oxidation of the B-ring to generate an unusual
      quinol oxidation product, B-ring cleavage with the formation of chromone
      derivatives, and reduction of carbonyl group to form flavan-4-ol derivatives. The
      metabolites were characterized and identified primarily by using liquid
      chromatographytandem mass spectrometry with comparison to authentic standards.
      Formation of flavones from dietary flavanones might have biological significance
      since flavones often exhibit pharmacological activities that are different from
      those of flavanones. However, little is known about the pharmacological
      activities of the other types of flavonone metabolites.

PMID- 15039290
TI  - A proteomic approach to the identification of cytochrome P450 isoforms in male
      and female rat liver by nanoscale liquid chromatography-electrospray ionization
      tandem mass spectrometry.
AB  - Nanoscale reversed-phase liquid chromatography (LC) combined with electrospray
      ionization-tandem mass spectrometry (ESI-MS/MS) has been used as a method for the
      direct identification of multiple cytochrome P450 (P450) isoforms found in male
      and female rat liver. In this targeted proteomic approach, rat liver microsomes
      were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis
      followed by in-gel tryptic digestion of the proteins present in the 48- to 62-kDa
      bands. The resultant peptides were extracted and analyzed by LC-ESI-MS/MS. P450
      identifications were made by searching the MS/MS data against a rat protein
      database containing 21,576 entries including 47 P450s using Sequest software
      (Thermo Electron, Hemel Hempstead, UK). Twenty-four P450 isoforms from the
      subfamilies 1A, 2A, 2B, 2C, 2D, 2E, 3A, 4A, 4F, CYP17, and CYP19 were positively
      identified in rat liver.

PMID- 15039292
TI  - Comparison of prediction methods for in vivo clearance of (S,S)-3-[3
      (methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, a dopamine D2 receptor
      antagonist, in humans.
AB  - The purpose of this study is to investigate reliable prediction methods for in
      vivo pharmacokinetics and the likelihood of drug interactions with several
      cytochrome P450 inhibitors in humans for (S,S)-3-[3-(methylsulfonyl)phenyl]-1
      propylpiperidine (PNU-96391). By allometric scaling of in vivo animal data,
      clearance of PNU-96391 in humans was over-predicted by 4-fold, half-life was
      under-predicted by 3-fold, and volume of distribution was accurately predicted.
      High correlation coefficients (>0.99) were observed for these parameters. Neither
      the in vitro-in vivo correlation approach nor the modified allometric scaling
      with maximum life span potential or brain weight accurately provided the
      predicted clearance value. Using an alternative method, based on normalization of
      in vitro human data with the ratio of in vivo to in vitro animal data, the in
      vivo clearance in humans was predicted to be 0.39 l/h/kg. This value correlated
      well with the in vivo value (0.43 l/h/kg). Regarding the interactions of PNU
      96391 with cytochrome P450 inhibitors, only quinidine, haloperidol, and
      ketoconazole showed significant inhibition on the metabolic clearance of PNU
      96391 in human hepatocytes. By comparing in vitro K(i) values with in vivo
      maximum unbound concentrations of the inhibitor, the increases in systemic
      exposure of PNU-96391 by coadministration of the inhibitors were estimated to be
      less than 1.5-fold. A preliminary comparison of pharmacokinetics of PNU-96391
      between CYP2D6 extensive and poor metabolizers in the clinical study showed only
      a slight increase in systemic exposure in poor metabolizers (approximately 1.4
      fold as area under the concentration-time curve). Therefore, clinically
      significant drug-drug interactions of PNU-96391 would be unlikely to occur with
      coadministration of CYP2D6 inhibitors.

PMID- 15039293
TI  - Hepatobiliary excretion of berberine.
AB  - Berberine is a bioactive herbal ingredient isolated from the roots and bark of
      Berberis aristata or Coptis chinensis. To investigate the detailed
      pharmacokinetics of berberine and its mechanisms of hepatobiliary excretion, an
      in vivo microdialysis coupled with high-performance liquid chromatography was
      performed. In the control group, rats received berberine alone; in the drug
      treated group, 10 min before berberine administration, the rats were injected
      with cyclosporin A (CsA), a P-glycoprotein (P-gp) inhibitor; quinidine, both
      organic cation transport (OCT) and P-gp inhibitors; SKF-525A (proadifen), a
      cytochrome P450 inhibitor; and probenecid to inhibit the glucuronidation. The
      results indicate that berberine displays a linear pharmacokinetic phenomenon in
      the dosage range from 10 to 20 mg kg(-1), since a proportional increase in the
      area under the concentration-time curve (AUC) of berberine was observed in this
      dosage range. Moreover, berberine was processed through hepatobiliary excretion
      against a concentration gradient based on the bile-to-blood distribution ratio
      (AUC(bile)/AUC(blood)); the active berberine efflux might be affected by P-gp and
      OCT since coadministration of berberine and CsA or quinidine at the same dosage
      of 10 mg kg(-1) significantly decreased the berberine amount in bile. In
      addition, berberine was metabolized in the liver with phase I demethylation and
      phase II glucuronidation, as identified by liquid chromatography/tandem mass
      spectrometry. Also, the phase I metabolism of berberine was partially reduced by
      SKF-525A treatment, but the phase II glucuronidation of berberine was not
      obviously affected by probenecid under the present study design.

PMID- 15039295
TI  - Expression studies and functional characterization of renal human organic anion
      transporter 1 isoforms.
AB  - The human organic anion transporter 1 (hOAT1) facilitates the basolateral entry
      of organic anions such as endogenous metabolites, xenobiotics, and drugs into the
      proximal tubule cells. In the present study we investigated the general
      occurrence of hOAT1 isoforms in the kidneys and performed functional
      characterizations. Kidney specimens of 10 patients were analyzed by reverse
      transcription-polymerase chain reaction. We detected hOAT1-2 as the main
      transcript in almost all patients, and weak transcripts of hOAT1-1, hOAT1-3, and
      hOAT1-4 in many of them. An evaluation of the renal distribution showed all four
      mRNAs mostly restricted to the cortex. Western blot analysis of membrane
      fractions from two kidney specimens yielded two bands corresponding to the
      observed mRNA expression, suggesting hOAT1-3 and hOAT1-4 to be expressed on the
      protein level in vivo. This observation is further supported by
      immunofluorescence analyses of all four cloned hOAT1 isoforms transiently
      transfected in COS 7 cells. Functional characterizations did not show any
      transport activity of hOAT1-3 and hOAT1-4 for the tested substrates.
      Cotransfection studies of each of them with hOAT1-1 did not alter fluorescein
      uptake indicating no regulatory impact of these isoforms. Further functional
      comparisons of hOAT1-1 and hOAT1-2 in fluorescein uptake studies exhibited almost
      identical affinities for fluorescein with Michaelis constants of 11.6 +/- 3.7
      microM (hOAT1-1) and 11.9 +/- 6.4 microM (hOAT1-2), and similar sensitivities to
      inhibition by p-aminohippurate [IC(50): 16 microM (hOAT1-1), 10 microM (hOAT1
      2)], urate [IC(50): 440 microM (hOAT1-1), 385 microM (hOAT1-2)], and furosemide
      (IC(50): 14 microM (hOAT1-1), 20 microM (hOAT1-2)], implying functional
      equivalence.

PMID- 15039294
TI  - Human udp-glucuronosyltransferases: isoform selectivity and kinetics of 4
      methylumbelliferone and 1-naphthol glucuronidation, effects of organic solvents,
      and inhibition by diclofenac and probenecid.
AB  - The glucuronidation kinetics of the prototypic substrates 4-methylumbelliferone
      (4MU) and 1-naphthol (1NP) by human UDP-glucuronosyltransferases (UGT) 1A1, 1A3,
      1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15, and 2B17 were investigated. Where
      activity was demonstrated, inhibitory effects of diclofenac, probenecid, and the
      solvents acetone, acetonitrile, dimethyl sulfoxide, ethanol, and methanol were
      characterized. All isoforms except UGT1A4 glucuronidated 4MU, whereas all but UGT
      1A4, 2B15, and 2B17 metabolized 1NP. However, kinetic models varied with
      substrate (for the same isoform) and from isoform to isoform (with the same
      substrate). Hyperbolic (Michaelis-Menten), substrate inhibition, and sigmoidal
      kinetics were variably observed for both 4MU and 1NP glucuronidation by the
      various UGTs. K(m) or S(50) (sigmoidal kinetics) and V(max) values varied 525- (8
      4204 microM) and 1386-fold, respectively, for 4MU glucuronidation, and 1360- (1.3
      1768 microM) and 37-fold, respectively, for 1NP glucuronidation. The use of a two
      site model proved useful for those reactions exhibiting non-Michaelis-Menten
      glucuronidation kinetics. The organic solvents generally had a relatively minor
      effect on UGT isoform activity. UGT 2B15 and 2B17 were most susceptible to the
      presence of solvent, although solvent-selective inhibition was occasionally
      observed with other isoforms. Diclofenac and probenecid inhibited all isoforms,
      precluding the use of these compounds for the reaction phenotyping of xenobiotic
      glucuronidation pathways in human tissues. Diclofenac and probenecid K(i) values,
      determined for selected isoforms, ranged from 11 to 52 microM and 96 to 2452
      microM, respectively. Overall, the results emphasize the need for the careful
      design and interpretation of kinetic and inhibition studies with human UGTs.

PMID- 15039296
TI  - Assessment of arginine 97 and lysine 72 as determinants of substrate specificity
      in cytochrome P450 2C9 (CYP2C9).
AB  - CYP2C9 is distinguished by a preference for substrates bearing a negative charge
      at physiological pH. Previous studies have suggested that CYP2C9 residues R97 and
      K72 may play roles in determining preference for anionic substrates by
      interaction at the active site or in the access channel. The aim of the present
      study was to assess the role of these two residues in determining substrate
      selectivity. R97 and K72 were substituted with negative, uncharged polar and
      hydrophobic residues using a degenerate polymerase chain reaction-directed
      strategy. Wild-type and mutant enzymes were expressed in bicistronic format with
      human cytochrome P450 reductase in Escherichia coli. Mutation of R97 led to a
      loss of holoenzyme expression for R97A, R97V, R97L, R97T, and R97E mutants. Low
      levels of hemoprotein were detected for R97Q, R97K, R97I, and R97P mutants.
      Significant apoenzyme was observed, suggesting that heme insertion or protein
      stability was compromised in R97 mutants. These observations are consistent with
      a structural role for R97 in addition to any role in substrate binding. By
      contrast, all K72 mutants examined (K72E, K72Q, K72V, and K72L) could be
      expressed as hemoprotein at levels comparable to wild-type. Type I binding
      spectra were obtained with wild-type and K72 mutants using diclofenac and
      ibuprofen. Mutation of K72 had little or no effect on the interaction with these
      substrates, arguing against a critical role in determining substrate specificity.
      Thus, neither residue appears to play a role in determining substrate
      specificity, but a structural role for R97 can be proposed consistent with
      recently published crystallographic data for CYP2C9 and CYP2C5.

PMID- 15039297
TI  - Endotoxin-mediated disturbance of hepatic cytochrome P450 function and
      development of endotoxin tolerance in the rat model of dextran sulfate sodium
      induced experimental colitis.
AB  - Hepatobiliary abnormalities have been described in patients with chronic
      inflammatory bowel diseases. Hepatic cytochrome P450 (P450)-dependent drug
      metabolizing enzyme activities and susceptibility to a hepatotoxin, d
      galactosamine, were determined in rats with dextran sulfate sodium (DSS)-induced
      colitis to assess whether liver function is affected in the model of inflammatory
      bowel disease. Colitis was induced by treatment of rats with 3% DSS in drinking
      water for 7 days. Liver microsomes for enzyme activities and serum for biological
      analysis were prepared from the rats with colitis, along with untreated and
      lipopolysaccharide (LPS)-treated rats. Other rats received intraperitoneal
      injection of d-galactosamine to assess their susceptibility to the toxin-induced
      liver injury. Treatment of rats with DSS resulted in not only colitis but also
      decreases in hepatic P450-dependent drug-metabolizing enzyme activities. Elevated
      endotoxin was found in portal blood, which was not associated with liver injury.
      The potency and the isoform selectivity in the suppression of the P450 enzymes by
      DSS treatment were similar to those of LPS-treated rats. Coadministration of
      antibiotics, polymyxin B or metronidazole, with DSS protected rats from decreases
      in some but not all P450 enzyme activities, indicating partial involvement of
      bacterial endotoxin in the P450 decreases. The rats with colitis were less
      susceptible than untreated rats to d-galactosamine-induced liver injury and TNF
      alpha production, suggesting development of endotoxin tolerance in DSS-colitis.
      In conclusion, these results suggest that the DSS-colitis leads to endotoxin
      mediated down-regulation of hepatic P450 enzymes and protection against d
      galactosamine-induced liver injury, probably due to endotoxin tolerance.

PMID- 15039298
TI  - Incorporation of an oxygen from water into troglitazone quinone by cytochrome
      P450 and myeloperoxidase.
AB  - Troglitazone (TGZ) was the first glitazone used for the treatment of type II
      diabetes mellitus. TGZ undergoes an oxidative chroman ring-opening reaction to
      form a quinone product. Recently, cytochrome P450 (P450) was shown to be able to
      catalyze the formation of TGZ quinone. TGZ quinone was the major metabolite
      formed by dexamethasone-induced rat liver microsomes or myeloperoxidase (MPO)
      incubated with TGZ. The ultimate source for the quinone carbonyl oxygen atom of
      TGZ quinone was investigated using (18)O water in both enzyme reaction systems
      followed by liquid chromatography/tandem mass spectometry analysis of the TGZ
      quinone product. The resultant TGZ quinone formed by either liver microsomes or
      MPO contained a single atom of (18)O. The (18)O atom was determined to be the
      quinone carbonyl oxygen by collision-induced dissociation fragmentation of the
      (18)O-labeled TGZ quinone. The formation of TGZ quinone was inhibited
      approximately 90% by coincubation with ascorbic acid or cysteine in the MPO
      reaction system but only 10 to 20% in liver microsomes, which might reflect the
      difference in the mechanism by which TGZ quinone is formed by P450 and
      peroxidase. These results suggest that P450 catalyze an atypical reaction to form
      TGZ quinone, involving the incorporation of an oxygen from water into the quinone
      carbonyl position.

PMID- 15039299
TI  - Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human
      liver and intestinal microsomes.
AB  - Oxycodone undergoes N-demethylation to noroxycodone and O-demethylation to
      oxymorphone. The cytochrome P450 (P450) isoforms capable of mediating the
      oxidation of oxycodone to oxymorphone and noroxycodone were identified using a
      panel of recombinant human P450s. CYP3A4 and CYP3A5 displayed the highest
      activity for oxycodone N-demethylation; intrinsic clearance for CYP3A5 was
      slightly higher than that for CYP3A4. CYP2D6 had the highest activity for O
      demethylation. Multienzyme, Michaelis-Menten kinetics were observed for both
      oxidative reactions in microsomes prepared from five human livers. Inhibition
      with ketoconazole showed that CYP3A is the high affinity enzyme for oxycodone N
      demethylation; ketoconazole inhibited >90% of noroxycodone formation at low
      substrate concentrations. CYP3A-mediated noroxycodone formation exhibited a mean
      K(m) of 600 +/- 119 microM and a V(max) that ranged from 716 to 14523
      pmol/mg/min. Contribution from the low affinity enzyme(s) did not exceed 8% of
      total intrinsic clearance for N-demethylation. Quinidine inhibition showed that
      CYP2D6 is the high affinity enzyme for O-demethylation with a mean K(m) of 130 +/
      33 microM and a V(max) that ranged from 89 to 356 pmol/mg/min. Activity of the
      low affinity enzyme(s) accounted for 10 to 26% of total intrinsic clearance for O
      demethylation. On average, the total intrinsic clearance for noroxycodone
      formation was 8 times greater than that for oxymorphone formation across the five
      liver microsomal preparations (10.5 microl/min/mg versus 1.5 microl/min/mg).
      Experiments with human intestinal mucosal microsomes indicated lower N
      demethylation activity (20-50%) compared with liver microsomes and negligible O
      demethylation activity, which predict a minimal contribution of intestinal mucosa
      in the first-pass oxidative metabolism of oxycodone.

PMID- 15039300
TI  - Amino acid residue ILE211 is essential for the enzymatic activity of human UDP
      glucuronosyltransferase 1A10 (UGT1A10).
AB  - Conjugation of exogenous and endogenous compounds by uridine
      diphosphoglucuronosyltransferases (UGTs) is a pathway catalyzing the transfer of
      a glucuronic acid molecule from UDP glucuronic acid to lipophilic aglycones,
      which become more polar and more easily excretable in the bile or urine. UGTs are
      divided into two major families, UGT1 and UGT2. The isoform UGT1A10, along with
      UGT1A7 and UGT1A8, is expressed exclusively in extrahepatic tissues, notably in
      the gastrointestinal tract. Here, we report the isolation of a mutant clone of
      the human UGT1A10, at position 211 of the protein, where a threonine residue
      replaces an isoleucine residue (allele Thr211). Because the isoleucine is
      conserved among many UGT1A isoforms, we proceeded to the analysis of the activity
      of the wild-type UGT1A10 (T211I) and compared it with that of the variant enzyme
      (I211T(*)). In vitro assays with microsomal extracts from stably expressing human
      embryonic kidney 293 (HEK293) cells showed that the mutant enzyme lost all
      detectable activity toward major substrates, which demonstrate that the residue
      isoleucine at position 211 is essential for UGT1A10 activity. Mutant UGT1A10
      (I211T(*)) also lost all detectable activity toward mycophenolic acid. Genomic
      DNA from 103 unrelated individuals was sequenced for this mutation, and two
      heterozygous genotypes were detected for this mutation (frequency: 2 per 100
      individuals). Because UGT1A10 appears to be expressed in all gastrointestinal
      tissues and is active toward a wide range of substrates, lack of activity of this
      isoform may have an impact on individual glucuronidation efficiency.

PMID- 15039302
TI  - Key structural features of ligands for activation of human pregnane X receptor.
AB  - The ligand-binding domain of human pregnane X receptor (hPXR) is highly
      hydrophobic and flexible, allowing promiscuity in accepting structurally diverse
      ligands. However, little information is available regarding the critical
      substituents of compounds involved in the activation of hPXR. The aim of this
      study was to determine the structure-activity relationships for hPXR-mediated
      transactivation by barbiturates, hydantoins, and macrolide antibiotics. Most of
      the barbiturates studied (mephobarbital, pentobarbital, phenobarbital, etc.)
      activated hPXR. However, barbital, which has a low hydrophobic moiety at the 5
      position, and primidone, which has no carbonyl moiety at the 2-position, did not
      activate hPXR. Therefore, a hydrophobic moiety at the 5-position and a hydrogen
      bond acceptor being sufficiently separated from the phenyl-ring are responsible
      for activation of hPXR by barbiturates. In the case of hydantoins, only
      mephenytoin and ethotoin, which have an alkylchain at the R1-position, strongly
      activated hPXR at 300 microM. Phenytoin and 5-(4-methylphenyl)-5-phenylhydantoin,
      which contain a phenyl or methylphenyl group at both R2- and R3-positions, also
      activated hPXR, whereas 5-(4-hydroxyphenyl)-5-phenylhydantoin did not activate
      the receptor. These results suggest that the presence of an alkyl-chain at the R1
      position and the presence of bulky and hydrophobic moieties at both R2- and R3
      positions are important factors for activation of hPXR by hydantoins. In the case
      of macrolide antibiotics, troleandomycin, but not oleandomycin, showed
      significant activation of hPXR. Therefore, triacetate esterification of
      oleandomycin might increase the hydrophobicity and enhance the activation of
      hPXR. These findings suggest that hydrophobicity of the ligand and adequate
      distance between the hydrogen-bond acceptor and the hydrophobic group are
      important for hPXR activation.

PMID- 15039303
TI  - Chlamydial persistence: beyond the biphasic paradigm.

PMID- 15039304
TI  - Mechanisms involved in apoptosis of human macrophages induced by
      lipopolysaccharide from Actinobacillus actinomycetemcomitans in the presence of
      cycloheximide.
AB  - Actinobacillus actinomycetemcomitans is a major periodontopathic bacterium with
      multiple virulence factors, including lipopolysaccharide (LPS). Previous reports
      have demonstrated that LPS induced apoptosis in a murine macrophage-like cell
      line, J744.1, as well as in peritoneal macrophages from C3H/HeN mice in the
      presence of cycloheximide (CHX). However, the detailed molecular mechanisms
      involved in the apoptosis of macrophages induced by LPS and CHX are not well
      known. To clarify the possible role of LPS in the induction of macrophage
      apoptosis, we investigated cell death induced by LPS from A.
      actinomycetemcomitans and CHX in human macrophage-like U937 cells, which were
      differentiated by 12-O-tetradecanoylphorbol 13-acetate (TPA), and also assessed
      the molecular mechanisms involved in the process. We found that TPA
      differentiated U937 cells usually showed resistance to LPS-induced apoptosis.
      However, in the presence of CHX, LPS induced release of cytochrome c without
      modifying steady-state levels of Bcl-2, Bcl-xL, Bax, and Bak. Treatment with LPS
      in the presence of CHX also led to activation of caspase-3 and apoptosis via, in
      part, the CD14/toll-like receptor 4 (TLR4). The induction of cytochrome c release
      may have been due to dephosphorylation of Akt and Bad, which were cooperatively
      induced by CHX and LPS. However, endogenous tumor necrosis factor alpha- and Fas
      induced signals, extracellular signal-regulated kinase kinase/mitogen-activated
      protein kinases and I-kappa B alpha/nuclear factor-kappa B (NF-kappa B) were not
      required for caspase-3-dependent apoptosis. These results emphasize the possible
      important role of the mitochondrial apoptotic pathway leading to caspase-3
      activation in LPS-induced apoptosis of human macrophages in the presence of CHX.

PMID- 15039305
TI  - Effect of Escherichia coli and Lactobacillus rhamnosus on macrophage inflammatory
      protein 3 alpha, tumor necrosis factor alpha, and transforming growth factor beta
      release by polarized rat uterine epithelial cells in culture.
AB  - Entry of bacteria from the vagina into the uterus raises the question of uterine
      epithelial cell (UEC) signaling in response to the presence of bacteria. Our
      model system helps to define microbially elicited UEC basolateral cytokine
      release, important in regulating underlying stromal immune cell protection. UECs
      from adult rats were grown in cell culture inserts to establish a confluent
      polarized monolayer as was determined by transepithelial resistance (TER).
      Polarized epithelial cell cultures were treated apically with live or heat-killed
      Escherichia coli or Lactobacillus rhamnosus prior to collection of basolateral
      media after 24 h of incubation. Coculture of polarized UECs with live E. coli had
      no effect on epithelial cell TER. In response to exposure to live E. coli,
      epithelial cell basolateral release of macrophage inflammatory protein 3 alpha
      (MIP3 alpha) and tumor necrosis factor alpha (TNF-alpha) increased at a time when
      basolateral release of biologically active transforming growth factor beta (TGF
      beta) decreased. Incubation of UECs with heat-killed E. coli resulted in an
      increased basolateral release of MIP3 alpha and TNF-alpha, without affecting TER
      or TGF-beta. In contrast to E. coli, live or heat-killed L. rhamnosus had no
      effect on TER or cytokine release. These studies indicate that polarized rat UECs
      respond to gram-negative E. coli by releasing the cytokines MIP3 alpha and TNF
      alpha, signals important to both the innate and adaptive immune systems. These
      findings suggest that UEC responses to bacteria are selective and important in
      initiating and regulating immune protection in the female reproductive tract.

PMID- 15039307
TI  - Analysis of genes that encode DtxR-like transcriptional regulators in pathogenic
      and saprophytic corynebacterial species.
AB  - Metal-dependent transcriptional regulators of the diphtheria toxin repressor
      (DtxR) family have been identified in a wide variety of bacterial genera, where
      they control gene expression in response to one of two metal ions, Fe(2+) or
      Mn(2+). DtxR of Corynebacterium diphtheriae is the best characterized of these
      important metal-dependent regulators. The genus Corynebacterium includes many
      phenotypically diverse species, and the prevalence of DtxR-like regulators within
      the genus is unknown. We assayed chromosomal DNA from 42 different
      corynebacterial isolates, representing 33 different species, for the presence of
      a highly conserved region of the dtxR gene that encodes the DNA-binding helix
      turn-helix motif and metal-binding site 1 within domains 1 and 2 of DtxR. The
      chromosome of all of the isolates contained this conserved region of dtxR, and
      DNA sequencing revealed a high level of nucleotide sequence conservation within
      this region in all of the corynebacterial species (ranging from 62 to 100%
      identity and averaging 70% identity with the dtxR prototype). The level of
      identity was even greater for the predicted protein sequences encoded by the dtxR
      like genes, ranging from 81 to 100% identity and averaging 91% identity with
      DtxR. Using a DtxR-specific antiserum we confirmed the presence of a DtxR-like
      protein in extracts of most of the corynebacterial isolates and determined the
      precise amount of DtxR per cell in C. diphtheriae. The high level of identity at
      both DNA and protein levels suggests that all of the isolates tested encode a
      functional DtxR-like Fe(2+)-activated regulatory protein that can bind homologs
      of the DtxR operator and regulate gene expression in response to iron.

PMID- 15039306
TI  - The LspB protein is involved in the secretion of the LspA1 and LspA2 proteins by
      Haemophilus ducreyi.
AB  - The LspA1 and LspA2 proteins of Haemophilus ducreyi 35000 are two very large
      macromolecules that can be detected in concentrated culture supernatant fluid.
      Both of these proteins exhibit homology with the N-terminal region of the
      Bordetella pertussis filamentous hemagglutinin (FHA), which is involved in
      secretion of the latter macromolecule. The lspA2 open reading frame is flanked
      upstream by a gene, lspB, that encodes a predicted protein with homology to the
      B. pertussis FhaC outer membrane protein that is involved in secretion of FHA
      across the outer membrane. The H. ducreyi lspB gene encodes a protein with a
      predicted molecular mass of 66,573 Da. Reverse transcription-PCR analysis
      suggested that the lspB gene was transcribed together with the lspA2 gene on a
      single mRNA transcript. Polyclonal H. ducreyi LspB antiserum reacted with a 64
      kDa antigen present in the Sarkosyl-insoluble cell envelope fraction of H.
      ducreyi 35000, which indicated that the LspB protein is likely an outer membrane
      protein. Concentrated culture supernatant fluids from H. ducreyi lspB and lspA1
      lspB mutants did not contain detectable LspA1 and detectable LspA2, respectively.
      However, complementation of the lspB mutant with the wild-type lspB gene on a
      plasmid restored LspB protein expression and resulted in release of detectable
      amounts of the LspA1 protein into culture supernatant fluid. When evaluated in
      the temperature-dependent rabbit model of infection, the lspB mutant was
      attenuated in the ability to cause lesions and was never recovered in a viable
      form from lesions. These results indicated that the H. ducreyi LspB protein is
      involved in secretion of the LspA1 and LspA2 proteins across the outer membrane.

PMID- 15039308
TI  - Bovine ileal intraepithelial lymphocytes represent target cells for Shiga toxin 1
      from Escherichia coli.
AB  - The discovery that bovine peripheral lymphocytes are sensitive to Stx1 identified
      a possible mechanism for the persistence of infections with Shiga toxin (Stx)
      producing Escherichia coli (STEC) in the bovine reservoir host. If
      intraepithelial lymphocytes (IEL) are also sensitive to Stx1, the idea that Stx1
      affects inflammation in the bovine intestine is highly attractive. To prove this
      hypothesis, ileal IEL (iIEL) were prepared from adult cattle, characterized by
      flow cytometry, and subjected to functional assays in the presence and absence of
      purified Stx1. We found that 14.9% of all iIEL expressed Gb(3)/CD77, the Stx1
      receptor on bovine lymphocytes, and 7.9% were able to bind the recombinant B
      subunit of Stx1. The majority of Gb(3)/CD77(+) cells were activated CD3(+) CD6(+)
      CD8 alpha(+) T cells, whereas only some CD4(+) T cells and B cells expressed
      Gb(3)/CD77. However, Stx1 blocked the mitogen-induced transformation to enlarged
      blast cells within all subpopulations to a similar extent and significantly
      reduced the percentage of Gb(3)/CD77(+) cells. Although Stx1 did not affect the
      natural killer cell activity of iIEL, the toxin accelerated the synthesis of
      interleukin-4 (IL-4) mRNA and reduced the amount of IL-8 mRNA in bovine iIEL
      cultures. Because the intestinal system comprises a rich network of interactions
      between different types of cells and any dysfunction may influence the course of
      intestinal infections, this demonstration that Stx1 can target bovine IEL may be
      highly relevant for our understanding of the interplay between STEC and its
      reservoir host.

PMID- 15039309
TI  - The Moraxella catarrhalis porin-like outer membrane protein CD is an adhesin for
      human lung cells.
AB  - The outer membrane protein CD (OMPCD) of Moraxella catarrhalis is an outer
      membrane protein with several attributes of a potential vaccine antigen. We
      isolated four transposon mutants of strain O35E on the basis of their reduced
      binding to A549 human lung cells in microcolony formation assays, and we
      determined that they contain a transposon in ompCD. We also found that these
      transposon insertions had pleiotropic effects: mutants grew slower, became serum
      sensitive, bound approximately 10-fold less to A549 cells, and appeared
      transparent when grown on solid medium. We confirmed that these various
      phenotypes could be attributed solely to disruption of ompCD by constructing the
      isogenic strain O35E.CD1. O35E-ompCD was cloned, and recombinant Escherichia coli
      bacteria expressing the gene product exhibited a 10-fold increase in adherence to
      A549 cells. This is the first report of M. catarrhalis ompCD mutants, and our
      findings demonstrate that this gene product is an adhesin for human lung cells.

PMID- 15039310
TI  - GNA33 of Neisseria meningitidis is a lipoprotein required for cell separation,
      membrane architecture, and virulence.
AB  - GNA33 is a membrane-bound lipoprotein with murein hydrolase activity that is
      present in all Neisseria species and well conserved in different meningococcal
      isolates. The protein shows 33% identity to a lytic transglycolase (MltA) from
      Escherichia coli and has been shown to be involved in the degradation of both
      insoluble murein sacculi and unsubstituted glycan strands. To study the function
      of the gene and its role in pathogenesis and virulence, a knockout mutant of a
      Neisseria meningitidis serogroup B strain was generated. The mutant exhibited
      retarded growth in vitro. Transmission electron microscopy revealed that the
      mutant grows in clusters which are connected by a continuous outer membrane,
      suggesting a failure in the separation of daughter cells. Moreover, sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis analysis of culture
      supernatant revealed that the mutant releases several proteins in the medium. The
      five most abundant proteins, identified by matrix-assisted laser desorption
      ionization-time-of-flight mass spectrometry analysis, belong to the outer
      membrane protein family. Finally, the mutant showed an attenuated phenotype,
      since it was not able to cause bacteremia in the infant rat model. We conclude
      that GNA33 is a highly conserved lipoprotein which plays an important role in
      peptidoglycan metabolism, cell separation, membrane architecture, and virulence.

PMID- 15039311
TI  - Toll-like receptor 4 contributes to efficient control of infection with the
      protozoan parasite Leishmania major.
AB  - The essential role of Toll-like receptors (TLR) in innate immune responses to
      bacterial pathogens is increasingly recognized, but very little is known about
      the role of TLRs in host defense against infections with eukaryotic pathogens.
      For the present study, we investigated whether TLRs contribute to the innate and
      acquired immune response to infection with the intracellular protozoan parasite
      Leishmania major. Our results show that TLR4 contributes to the control of
      parasite growth in both phases of the immune response. We also addressed the
      mechanism that results in killing or growth of the intracellular parasites.
      Control of parasite replication correlates with the early induction of inducible
      nitric oxide synthase in TLR4-competent mice, whereas increased parasite survival
      in host cells from TLR4-deficient mice correlates with a higher activity of
      arginase, an enzyme known to promote parasite growth. This is the first study
      showing that TLR4 contributes to the effective control of Leishmania infection in
      vivo.

PMID- 15039312
TI  - Immunoglobulin-mediated agglutination of and biofilm formation by Escherichia
      coli K-12 require the type 1 pilus fiber.
AB  - The binding of human secretory immunoglobulin A (SIgA), the primary
      immunoglobulin in the gut, to Escherichia coli is thought to be dependent on type
      1 pili. Type 1 pili are filamentous bacterial surface attachment organelles
      comprised principally of a single protein, the product of the fimA gene. A minor
      component of the pilus fiber (the product of the fimH gene, termed the adhesin)
      mediates attachment to a variety of host cell molecules in a mannose inhibitable
      interaction that has been extensively described. We found that the aggregation of
      E. coli K-12 by human secretory IgA (SIgA) was dependent on the presence of the
      pilus fiber, even in the absence of the mannose specific adhesin or in the
      presence of 25 mM alpha-CH(3)Man. The presence of pilus without adhesin also
      facilitated SIgA-mediated biofilm formation on polystyrene, although biofilm
      formation was stronger in the presence of the adhesin. IgM also mediated
      aggregation and biofilm formation in a manner dependent on pili with or without
      adhesin. These findings indicate that the pilus fiber, even in the absence of the
      adhesin, may play a role in biologically important processes. Under conditions in
      which E. coli was agglutinated by SIgA, the binding of SIgA to E. coli was not
      increased by the presence of the pili, with or without adhesin. This observation
      suggests that the pili, with or without adhesin, affect factors such as cell
      surface rigidity or electrostatic repulsion, which can affect agglutination but
      which do not necessarily determine the level of bound immunoglobulin.

PMID- 15039313
TI  - Aeromonas flagella (polar and lateral) are enterocyte adhesins that contribute to
      biofilm formation on surfaces.
AB  - Aeromonas spp. (gram-negative, aquatic bacteria which include enteropathogenic
      strains) have two distinct flagellar systems, namely a polar flagellum for
      swimming in liquid and multiple lateral flagella for swarming over surfaces. Only
      approximately 60% of mesophilic strains can produce lateral flagella. To evaluate
      flagellar contributions to Aeromonas intestinal colonization, we compared polar
      and lateral flagellar mutant strains of a diarrheal isolate of Aeromonas caviae
      for the ability to adhere to the intestinal cell lines Henle 407 and Caco-2,
      which have the characteristic features of human intestinal enterocytes. Strains
      lacking polar flagella were virtually nonadherent to these cell lines, while loss
      of the lateral flagellum decreased adherence by approximately 60% in comparison
      to the wild-type level. Motility mutants (unable to swim or swarm in agar assays)
      had adhesion levels of approximately 50% of wild-type values, irrespective of
      their flagellar expression. Flagellar mutant strains were also evaluated for the
      ability to form biofilms in a borosilicate glass tube model which was optimized
      for Aeromonas spp. (broth inoculum, with a 16- to 20-h incubation at 37 degrees
      C). All flagellar mutants showed a decreased ability to form biofilms (at least
      30% lower than the wild type). For the chemotactic motility mutant cheA, biofilm
      formation decreased >80% from the wild-type level. The complementation of
      flagellar phenotypes (polar flagellar mutants) restored biofilms to wild-type
      levels. We concluded that both flagellar types are enterocyte adhesins and need
      to be fully functional for optimal biofilm formation.

PMID- 15039315
TI  - Salivary secretory leukocyte protease inhibitor and oral candidiasis in human
      immunodeficiency virus type 1-infected persons.
AB  - Oropharyngeal candidiasis, typically caused by Candida albicans, is the most
      common oral disease associated with human immunodeficiency virus type 1 (HIV-1)
      infection. Secretory leukocyte protease inhibitor (SLPI), a 12-kDa antiprotease,
      suppresses the growth of C. albicans in vitro. To determine whether the mucosal
      protein plays a role in protecting oral tissues against fungal infection, we
      conducted a cross-sectional study investigating the oral and systemic health and
      salivary SLPI levels in 91 dentate HIV-1-infected adults receiving medical care
      in the southeastern United States. Participants with a self-reported history of
      clinical oropharyngeal candidiasis during the previous 2 years constituted the
      test group (n = 52), while the comparison group (n = 39) had no oropharyngeal
      candidiasis during that period. Data collected from medical records, oral
      examination, and SLPI enzyme-linked immunosorbent assay quantitation of whole
      saliva were analyzed by t test, analysis of variance, linear regression, and
      unconditional logistic regression. The test group had a significantly higher mean
      salivary SLPI level than the comparison group (1.9 microg/ml versus 1.1
      microg/ml, P < 0.05). Linear regression modeling identified CD4 cell count and
      history of oropharyngeal candidiasis as key predictors of salivary SLPI and
      revealed a significant interaction (P < 0.05) between immunosuppression (CD4 cell
      count below 200 cells/ microl) and positive history of oropharyngeal candidiasis
      in predicting salivary SLPI level. By logistic regression modeling, a salivary
      SLPI level exceeding 2.1 microg/ml, low CD4 count, antiretroviral monotherapy,
      and smoking were key predictors of oropharyngeal candidiasis. These data support
      a key role for SLPI in the oral mucosal defense against C. albicans. The
      antimicrobial mucosal protein may serve as an indicator of previous oropharyngeal
      candidiasis infection among immunosuppressed persons.

PMID- 15039314
TI  - N-linked glycosylation is required for c1 inhibitor-mediated protection from
      endotoxin shock in mice.
AB  - C1 inhibitor (C1INH) prevents endotoxin shock in mice via a direct interaction
      with lipopolysaccharide (LPS). This interaction requires the heavily glycosylated
      amino-terminal domain of C1INH. C1INH in which N-linked carbohydrate was removed
      by using N-glycosidase F was markedly less effective in protecting mice from LPS
      induced lethal septic shock. N-deglycosylated C1INH also failed to suppress
      fluorescein isothiocyanate (FITC)-LPS binding to and LPS-induced tumor necrosis
      factor alpha mRNA expression by the murine macrophage-like cell line, RAW 264.7,
      and cells in human whole blood. In an enzyme linked immunosorbent assay, the N
      deglycosylated C1INH bound to LPS very poorly. In addition, C1INH was shown to
      bind to diphosphoryl lipid A (dLPA) but only weakly to monophosphoryl lipid A
      (mLPA). As with intact LPS, binding of N-deglycosylated C1INH to dLPA and mLPA
      was diminished in comparison with the native protein. Removal of O-linked
      carbohydrate had no effect on any of these activities. Neither detoxified LPS,
      dLPA, nor mLPA had any effect on the rate or extent of C1INH complex formation
      with C1s or on cleavage of the reactive center loop by trypsin. These data
      demonstrate that N-linked glycosylation of C1INH is essential to mediate its
      interaction with the LPA moiety of LPS and to protect mice from endotoxin shock.

PMID- 15039316
TI  - Involvement of Salmonella pathogenicity island 2 in the up-regulation of
      interleukin-10 expression in macrophages: role of protein kinase A signal
      pathway.
AB  - Salmonellae are facultative intracellular bacteria capable of surviving within
      macrophages. Salmonella pathogenicity island 2 (SPI-2) is required for growth
      within macrophages and for virulence in mice. In this study, we show the
      involvement of SPI-2 in a signal transduction pathway that induces cytokine
      expression in Salmonella-infected macrophages. High levels of interleukin-10 (IL
      10) mRNA were induced in macrophages by infection with wild-type salmonellae
      compared to a strain carrying a mutation in the spiC gene, which is encoded
      within SPI-2. The two strains had the same effect on the expression of
      proinflammatory cytokines such as IL-1 alpha, IL-6, and tumor necrosis factor
      alpha. IL-10 expression was dose dependently blocked by treatment of infected
      macrophages with the protein kinase A (PKA) inhibitor H-89, while IL-10
      expression was increased by the PKA activator dibutyryl cyclic AMP. Cyclic AMP
      dependent PKA activity was higher in macrophages infected with wild-type
      salmonellae compared to the spiC mutant, and Ser(132) phosphorylation of cyclic
      AMP response element-binding protein (CREB), which is an important mediator of
      PKA activation, correlated with the levels of PKA activity. Taken together, these
      results indicate that salmonellae cause an SPI-2-dependent increase in PKA
      activity that leads to CREB phosphorylation, resulting in up-regulation of IL-10
      expression in Salmonella-infected macrophages. Suppression of IL-10 expression by
      an antisense oligonucleotide did not affect the growth of wild-type salmonellae
      within macrophages, whereas growth was dose dependently inhibited by H-89,
      suggesting that the PKA signaling pathway plays a significant role in
      intramacrophage Salmonella survival.

PMID- 15039317
TI  - Effects of gamma interferon, interleukin-10, and transforming growth factor beta
      on the survival of Mycobacterium avium subsp. paratuberculosis in monocyte
      derived macrophages from naturally infected cattle.
AB  - Gamma interferon (IFN-gamma) plays a significant role in the control of
      mycobacterial infections, including Mycobacterium avium subsp. paratuberculosis.
      However, the contribution of other immunoregulatory cytokines, such as
      interleukin-10 (IL-10) and transforming growth factor beta (TGF-beta), in Johne's
      disease has not been investigated as yet. In this study, we examined the effects
      of in vivo and in vitro infection with M. avium subsp. paratuberculosis on the
      production of IFN-gamma, IL-10, and TGF-beta by peripheral blood mononuclear
      cells (PBMC). We also examined the effects of exogenous IFN-gamma, IL-10, and TGF
      beta on M. avium subsp. paratuberculosis survival in the cell cultures. PBMC
      obtained from naturally infected cows, regardless of their disease status,
      specifically upregulated IL-10 and TGF-beta in culture supernatants in response
      to stimulation with live M. avium subsp. paratuberculosis. Nonstimulated PBMC
      recovered from subclinically infected animals secreted the lowest levels of TGF
      beta, but after stimulation with live M. avium subsp. paratuberculosis, TGF-beta
      levels in the culture supernatants increased to levels similar to that produced
      by PBMC from healthy animals. The numbers of viable M. avium subsp.
      paratuberculosis recovered from cultures from naturally infected animals were
      higher than those from healthy cows after in vitro infection with M. avium subsp.
      paratuberculosis. The addition of exogenous IL-10 and TGF-beta to PBMC isolated
      from healthy cows inhibited the bactericidal activity of these cells as evidenced
      by the increased number of viable M. avium subsp. paratuberculosis recovered from
      these cultures compared to cell cultures containing medium alone. These data
      suggest important immune regulatory roles for IL-10 and TGF-beta during infection
      with M. avium subsp. paratuberculosis that may be directly related to their
      effects on macrophage activation and killing of M. avium subsp. paratuberculosis.

PMID- 15039318
TI  - An abundance of Escherichia coli is harbored by the mucosa-associated bacterial
      flora of interleukin-2-deficient mice.
AB  - Mice deficient in interleukin-2 are well suited for use as an animal model for
      inflammatory bowel disease. Raised under specific-pathogen-free conditions,
      interleukin-2-deficient mice develop an inflammatory bowel disease resembling
      ulcerative colitis in humans. The finding that colitis was attenuated when the
      mice were kept under germfree conditions implies that the resident intestinal
      flora is involved in the pathogenesis of colitis. The present study addresses the
      composition of the mucosa-associated bacterial flora in colon samples from
      interleukin-2-deficient mice that developed colitis. This was investigated by
      comparative 16S ribosomal DNA (rDNA) sequence analysis and fluorescence in situ
      hybridization using rRNA-targeted fluorescent probes to quantify the bacterial
      populations of the mucosa-associated flora. The investigations revealed distinct
      differences in the bacterial composition of the mucosa-associated flora between
      interleukin-2-deficient mice and healthy controls. Fluorescence in situ
      hybridization identified up to 10% of the mucosa-associated flora in interleukin
      2-deficient mice as Escherichia coli, whereas no E. coli was detected in the
      mucosa from healthy wild-type mice. This finding was consistent with the results
      from comparative 16S rDNA analysis. About one-third of the clones analyzed from
      16S rDNA libraries of interleukin-2-deficient mice represented
      Enterobacteriaceae, whereas none of the clones analyzed from the healthy controls
      harbored 16S rDNA from Enterobacteriaceae. The abundance of E. coli in the
      colonic mucosa of interleukin-2-deficient mice strongly suggests a participation
      in the pathogenesis of colitis in the interleukin-2-deficient mouse model for
      inflammatory bowel disease.

PMID- 15039319
TI  - Dendritic cell populations in Leishmania major-infected skin and draining lymph
      nodes.
AB  - Using a metacyclic promastigote ear infection model of cutaneous leishmaniasis,
      we examined the phenotype, parasite load, and cytokine production of dendritic
      cells in the skin and draining lymph nodes of resistant C57BL/6J and susceptible
      BALB/c mice. Five dendritic cell populations were isolated from the skin and
      lymph nodes, and the main difference between the groups of mice was an increased
      number of plasmacytoid dendritic cells in the lymph nodes of the susceptible
      mice. Although similar cell types were present in the skin emigrants of both
      strains, there was a 10-fold larger number of cells in BALB/c mouse skin early in
      infection than in C57BL/6J mouse skin. None of the dendritic cells in the lymph
      nodes harbored parasites until 3 weeks after infection, with the Langerhans cells
      having the largest load and the plasmacytoid dendritic cells having the smallest
      load but the longest lasting infection. Although parasites could be detected in
      the lymph nodes a few hours after infection, none of the skin emigrants harbored
      parasites, indicating that they are not the vehicle that ferries the parasites
      from the skin to the lymph nodes. The presence of larger numbers of plasmacytoid
      cells in infected BALB/c mice, the more protracted infection of these cells, and
      their production of alpha interferon point to a complex and important role for
      the plasmacytoid cells in leishmaniasis.

PMID- 15039321
TI  - Induction of protective cellular immunity against Mycobacterium tuberculosis by
      recombinant attenuated self-destructing Listeria monocytogenes strains harboring
      eukaryotic expression plasmids for antigen 85 complex and MPB/MPT51.
AB  - We report here the induction of specific protective cellular immunity against
      Mycobacterium tuberculosis by the employment of vaccination with recombinant
      attenuated Listeria monocytogenes strains. We constructed self-destructing
      attenuated L. monocytogenes Delta 2 strains carrying eukaryotic expression
      plasmids for the antigen 85 complex (Ag85A and Ag85B) and for MPB/MPT51
      (mycobacterial protein secreted by M. bovis BCG/mycobacterial protein secreted by
      M. tuberculosis) molecules. Infection of these recombinant bacteria allowed
      expression of the genes in the J774A.1 murine macrophage cell line.
      Intraperitoneal vaccination of C57BL/6 mice with these recombinant bacteria was
      capable of inducing purified protein derivative-specific cellular immune
      responses, such as foot pad reactions, proliferative responses of splenocytes,
      and gamma interferon production from splenocytes, suggesting the efficacy of
      vaccination against mycobacterial infection by use of these recombinant L.
      monocytogenes strains. Furthermore, intravenous vaccination with recombinant
      bacteria carrying expression plasmids for Ag85A, Ag85B, or MPB/MPT51 in BALB/c
      mice elicited significant protective responses, comparable to those evoked by a
      live Mycobacterium bovis BCG vaccine. Notably, this is the first report to show
      that MPB/MPT51 is a major protective antigen in addition to Ag85A and Ag85B,
      which have been reported to be major mycobacterial protective antigens.

PMID- 15039320
TI  - Lon protease activity causes down-regulation of Salmonella pathogenicity island 1
      invasion gene expression after infection of epithelial cells.
AB  - Salmonella enterica serovar Typhimurium causes self-limiting gastroenteritis in
      humans and a typhoid-like disease in mice that serves as a model for typhoid
      infections in humans. A critical step in Salmonella pathogenesis is the invasion
      of enterocytes and M cells of the small intestine via expression of a type III
      secretion system, encoded on Salmonella pathogenicity island 1 (SPI-1), that
      secretes effector proteins into host cells, leading to engulfment of the bacteria
      within large membrane ruffles. The in vitro regulation of invasion genes has been
      the subject of much scientific investigation. Transcription of the hilA gene,
      which encodes an OmpR/ToxR-type transcriptional activator of downstream invasion
      genes, is increased during growth under high-osmolarity and low-oxygen
      conditions, which presumably mimic the environment found within the small
      intestine. Several negative regulators of invasion gene expression have been
      identified, including HilE, Hha, and Lon protease. Mutations within the
      respective genes increase the expression of hilA when the bacteria are grown
      under environmental conditions that are not favorable for hilA expression and
      invasion. In this study, the intracellular expression of invasion genes was
      examined, after bacterial invasion of HEp-2 epithelial cells, using Salmonella
      strains containing plasmid-encoded short-half-life green fluorescent protein
      reporters of hilA, hilD, hilC, or sicA expression. Interestingly, the expression
      of SPI-1 genes was down-regulated after invasion, and this was important for the
      intracellular survival of the bacteria. In addition, the effects of mutations in
      genes encoding negative regulators of invasion on intracellular hilA expression
      were examined. Our results indicate that Lon protease is important for down
      regulation of hilA expression and intracellular survival after the invasion of
      epithelial cells.

PMID- 15039322
TI  - The nature of extracellular iron influences iron acquisition by Mycobacterium
      tuberculosis residing within human macrophages.
AB  - We have reported that Mycobacterium tuberculosis residing within the phagosomes
      of human monocyte-derived macrophages (MDM) can acquire Fe from extracellular
      transferrin (TF) and sources within the MDM. In the lung, Fe is also bound to
      lactoferrin (LF) and low-molecular-weight chelates. We therefore investigated the
      ability of intraphagosomal M. tuberculosis to acquire Fe from these sources. M.
      tuberculosis acquired 30-fold and 3-fold more Fe from LF and citrate,
      respectively, compared to TF, in spite of similar MDM-associated Fe. M.
      tuberculosis infection decreased MDM-associated Fe relative to uninfected MDM as
      follows: TF (38.7%), citrate (21.1%), and LF (15.3%). M. tuberculosis Fe
      acquisition from extracellular chelates (exogenous source) and from endogenous
      MDM Fe initially acquired from the three chelates (endogenous source) was
      compared. M. tuberculosis Fe acquisition was similar from exogenous and
      endogenous sources supplied as Fe-TF. In contrast, there was much greater
      intracellular M. tuberculosis Fe uptake from LF and citrate from the exogenous
      than endogenous source. Gamma interferon (IFN-gamma) reduced MDM Fe uptake from
      each chelate by approximately 50% and augmented the M. tuberculosis-induced
      decrease in MDM Fe uptake from exogenous TF, but not from LF or citrate. IFN
      gamma minimally decreased intracellular M. tuberculosis Fe acquisition from
      exogenous Fe-TF but significantly increased Fe uptake from LF and citrate.
      Intraphagosomal M. tuberculosis Fe acquisition from both exogenous and endogenous
      MDM sources, and the effect of IFN-gamma on this process, is influenced by the
      nature of the extracellular Fe chelate. M. tuberculosis has developed efficient
      mechanisms of acquiring Fe from a variety of Fe chelates that it likely
      encounters within the human lung.

PMID- 15039323
TI  - Degenerate peptide recognition by Candida albicans adhesins Als5p and Als1p.
AB  - Candida albicans and Saccharomyces cerevisiae expressing the adhesins Als5p or
      Als1p adhere to immobilized peptides and proteins that possess appropriate
      sequences of amino acids in addition to a sterically accessible peptide backbone.
      In an attempt to further define the nature of these targets, we surveyed the
      ability of yeast cells to adhere to 90- micro m-diameter polyethylene glycol
      beads coated with a 7-mer peptide from a library of 19(7) unique peptide-beads.
      C. albicans bound to ca. 10% of beads from the library, whereas S. cerevisiae
      expressing Als5p or Als1p bound to ca. 0.1 to 1% of randomly selected peptide
      beads. S. cerevisiae expressing Als1p had a distinctly different adherence
      phenotype than did cells expressing Als5p. The former adhered in groups or clumps
      of cells, whereas the latter adhered initially as single cells, an event which
      was followed by the build up of cell-cell aggregates. Beads with adherent cells
      were removed, and the peptide attached to the bead was determined by amino acid
      sequencing. All adhesive beads carried a three-amino-acid sequence motif (tau
      phi+) that possessed a vast combinatorial potential. Adherence was sequence
      specific and was inhibited when soluble peptide identical to the immobilized
      peptide was added. The Als5p adhesin recognized some peptides that went
      unrecognized by Als1p. The sequence motif of adhesive peptides identified by this
      method is common in proteins and offers so many possible sequence combinations
      that target recognition by the Als proteins is clearly degenerate. A degenerate
      recognition system provides the fungi with the potential of adhering to a
      multitude of proteins and peptides, an advantage for any microorganism attempting
      to establish a commensal or pathogenic relationship with a host.

PMID- 15039325
TI  - Role for cystic fibrosis transmembrane conductance regulator protein in a
      glutathione response to bronchopulmonary pseudomonas infection.
AB  - The lung maintains an elevated level of glutathione (GSH) in epithelial lining
      fluid (ELF) compared to serum. The mechanism(s) by which the lung maintains high
      levels of ELF GSH and factors that modulate them are largely unexplored. We
      hypothesized that lung cystic fibrosis transmembrane conductance regulator
      protein (CFTR) modulates GSH efflux in response to extracellular stress, which
      occurs with lung infections. Mice were challenged intratracheally with
      Pseudomonas aeruginosa, and on the third day of infection bronchoalveolar lavage
      fluid was obtained and analyzed for cytokines and antioxidants. Lung tissue
      antioxidants and enzyme activities were also assessed. P. aeruginosa lung
      infection increased levels of inflammatory cytokines and neutrophils in the ELF.
      This corresponded with a marked threefold increase in GSH and a twofold increase
      in urate levels in the ELF of P. aeruginosa-infected wild-type mice. A twofold
      increase in urate levels was also observed among lung tissue antioxidants of P.
      aeruginosa-infected wild-type mice. There were no changes in markers of lung
      oxidative stress associated with the P. aeruginosa lung infection. In contrast
      with wild-type mice, the CFTR knockout mice lacked a significant increase in ELF
      GSH when challenged with P. aeruginosa, and this correlated with a decrease in
      the ratio of reduced to oxidized GSH in the ELF, a marker of oxidative stress.
      These data would suggest that the lung adapts to infectious agents with elevated
      ELF GSH and urate. Individuals with lung diseases associated with altered
      antioxidant transport, such as cystic fibrosis, might lack the ability to adapt
      to the infection and present with a more severe inflammatory response.

PMID- 15039326
TI  - Flea-borne transmission model to evaluate vaccine efficacy against naturally
      acquired bubonic plague.
AB  - A flea-to-mouse transmission model was developed for use in testing new candidate
      vaccines for the ability to protect against flea-borne plague. The model was used
      to evaluate a recombinant fusion protein vaccine consisting of the Yersinia
      pestis F1 and V antigens. After one to three challenges with Y. pestis-infected
      fleas, 14 of 15 unvaccinated control mice developed plague, with an average
      septicemia level of 9.2 x 10(8) Y. pestis CFU/ml. None of 15 vaccinated mice
      developed the disease after similar challenges, and serological testing indicated
      that transmitted bacteria were eliminated by the immune system before extensive
      replication and systemic infection could occur. The transmission and development
      of disease in control mice correlated with the number of bites by blocked fleas
      but not with the total number of fleabites. The model provides a means to
      directly assess the efficacy of new vaccines to prevent naturally acquired
      bubonic plague and to study events at the vector-host interface that lead to
      dissemination and disease.

PMID- 15039327
TI  - Analysis of relative levels of production of pertussis toxin subunits and Ptl
      proteins in Bordetella pertussis.
AB  - Pertussis toxin is transported across the outer membrane of Bordetella pertussis
      by the type IV secretion system known as the Ptl transporter, which is composed
      of nine different proteins. In order to determine the relative levels of
      production of pertussis toxin subunits and Ptl proteins in B. pertussis, we
      constructed translational fusions of the gene for alkaline phosphatase, phoA,
      with various ptx and ptl genes. Comparison of the alkaline phosphatase activity
      of strains containing ptx'- or ptl'-phoA fusions indicated that pertussis toxin
      subunits are produced at higher levels than Ptl proteins, which are encoded by
      genes located toward the 3' end of the ptx-ptl operon. We also engineered strains
      of B. pertussis by introducing multiple copies of the ptl genes or subsets of
      these genes and then examined the ability of each of these strains to secrete
      pertussis toxin. From these studies, we determined that certain Ptl proteins
      appear to be limiting in the secretion of pertussis toxin from the bacteria.
      These results represent an important first step in assessing the stoichiometric
      relationship of pertussis toxin and its transporter within the bacterial cell.

PMID- 15039324
TI  - Whole-genome DNA array analysis of the response of Borrelia burgdorferi to a
      bactericidal monoclonal antibody.
AB  - Identification and characterization of genes that contribute to infection with
      Borrelia burgdorferi and, of those, genes that are targets of host responses is
      important for understanding the pathogenesis of Lyme disease. The complement
      independent bactericidal monoclonal antibody (MAb) CB2 recognizes a carboxy
      terminal, hydrophilic epitope of the outer surface protein B (OspB). CB2 kills B.
      burgdorferi by an unknown bactericidal mechanism. Upon binding of CB2 to OspB,
      differentially expressed gene products may be responsible for, or associated
      with, the death of the organism. A time course of the response of B. burgdorferi
      to CB2 was completed to analyze the differential gene expression in the bacteria
      over a period of visual morphological changes. Bacteria were treated with a
      sublethal concentration in which spirochetes were visibly distressed by the
      antibody but not lysed. Preliminary whole-genome DNA arrays at various time
      points within 1 h of incubation of B. burgdorferi with the antibody showed that
      most significant changes occurred at 25 min. Circular plasmid 32 (cp32)-encoded
      genes were active in this period of time, including the blyA homologs, phage
      holin system genes. DNA array data show that three blyA homologs were upregulated
      significantly, >/==" BORDER="0">2 standard deviations from the mean of the log
      ratios, and a P value of </=0.01. Quantitative real-time PCR analysis verified
      blyA and blyB upregulation over an 18- to 35-min time course. The hypothesis to
      test is whether the killing mechanism of CB2 is through uncontrolled expression
      of the blyA and blyB phage holin system.

PMID- 15039328
TI  - Mycobacterium tuberculosis lipomannan induces apoptosis and interleukin-12
      production in macrophages.
AB  - The mycobacterial cell wall component lipoarabinomannan (LAM) has been described
      as a virulence factor of Mycobacterium tuberculosis, and modification of the
      terminal arabinan residues of this compound with mannose caps (producing mannosyl
      capped LAM [ManLAM]) in M. tuberculosis or with phosphoinositol caps (producing
      phosphoinositol-capped LAM [PILAM]) in Mycobacterium smegmatis has been
      implicated in various functions associated with these lipoglycans. A structure
      function analysis was performed by using LAMs and their biosynthetic precursor
      lipomannans (LMs) isolated from different mycobacterial species on the basis of
      their capacity to induce the production of interleukin-12 (IL-12) and/or
      apoptosis of macrophage cell lines. Independent of the mycobacterial species,
      ManLAMs did not induce IL-12 gene expression or apoptosis of macrophages, whereas
      PILAMs induced IL-12 secretion and apoptosis. Interestingly, uncapped LAM
      purified from Mycobacterium chelonae did not induce IL-12 secretion or apoptosis.
      Furthermore, LMs, independent of their mycobacterial origins, were potent
      inducers of IL-12 and apoptosis. The precursor of LM, phosphatidyl-myo-inositol
      dimannoside, had no activity, suggesting that the mannan core of LM was required
      for the activity of LM. The specific interaction of LM with Toll-like receptor 2
      (TLR-2) but not with TLR-4 suggested that these responses were mediated via the
      TLR-2 signaling pathway. Our experiments revealed an important immunostimulatory
      activity of the biosynthetic LAM precursor LM. The ratio of LAM to LM in the cell
      wall of mycobacteria may be an important determinant of virulence, and enzymes
      that modify LM could provide targets for development of antituberculosis drugs
      and for derivation of attenuated strains of M. tuberculosis.

PMID- 15039329
TI  - Phagocytosis of apoptotic cells increases the susceptibility of macrophages to
      infection with Coxiella burnetii phase II through down-modulation of nitric oxide
      production.
AB  - Coxiella burnetii, the agent of Q fever in humans and coxiellosis in other
      mammals, is an obligate intracellular bacterium which is sheltered and multiplies
      within typically large phagolysosome-like replicative vacuoles (LRVs). We have
      previously shown that, compared with fibroblasts, mouse resident peritoneal
      macrophages control the development of LRVs and bacterial multiplication within
      these vacuoles. Earlier experiments with the nitric oxide (NO) synthase inhibitor
      aminoguanidine (AG) revealed that the control is exerted by NO induced by the
      bacteria. We report here that phagocytosis of apoptotic-like, but not of aldehyde
      killed, lymphocytes by the macrophages reduced the production of NO induced by
      the bacteria and increased the development of LRVs and, therefore, the total
      bacterial load in the cultures. Experiments with macrophages from mice deficient
      for inducible NO synthase (iNOS(-)/(-)) confirmed the involvement of NO in the
      control of infection, since neither apoptotic lymphocytes nor AG affected the
      development of LRVs in these phagocytes. Since macrophages are important for the
      clearance of apoptotic bodies and C. burnetii is able to induce apoptosis in
      human monocytes, the phenomenon shown here may be biologically relevant to the
      development of Q fever and coxiellosis.

PMID- 15039330
TI  - Intraspleen delivery of a DNA vaccine coding for superoxide dismutase (SOD) of
      Brucella abortus induces SOD-specific CD4+ and CD8+ T cells.
AB  - In the development of vaccines capable of providing immunity against brucellosis,
      Cu-Zn superoxide dismutase (SOD) has been demonstrated to be one of the
      protective immunogens of Brucella abortus. In an earlier study, we provided
      strong evidence that intramuscular injection with a plasmid DNA carrying the SOD
      gene (pcDNA-SOD) was able to induce a protective immune response. The present
      study was designed to characterize T-cell immune responses after an intraspleen
      (i.s.) vaccination of BALB/c mice with pcDNA-SOD. Animals vaccinated with pcDNA
      SOD did not develop SOD-specific antibodies, at least until week 4 after
      immunization (the end of the experiment), and in vitro stimulation of their
      splenocytes with either recombinant Cu-Zn SOD or crude Brucella protein induced
      the secretion of gamma interferon (IFN-gamma), but not interleukin-4, and
      elicited the induction of cytotoxic-T-lymphocyte activity. Upon analyzing the SOD
      specific T-cell responses, the pcDNA-SOD vaccination was found to be stimulating
      both CD4(+)- and CD8(+)-T-cell populations. However, only the CD4(+) population
      was able to produce IFN-gamma and only the CD8(+) population was able to induce
      cytotoxic activity. Nevertheless, although i.s. route vaccination induces a
      significant level of protection in BALB/c mice against challenge with the
      virulent B. abortus strain 2308, vaccination by the intramuscular route with a
      similar amount of plasmid DNA does not protect. Based on these results, we
      conclude that i.s. immunization with pcDNA-SOD vaccine efficiently induced a Th1
      type of immune response and a protective response that could be related to IFN
      gamma production and cytotoxic activity against infected cells by SOD-specific
      CD4(+) and CD8(+) T cells, respectively.

PMID- 15039331
TI  - Vaccine potential of the Neisseria meningitidis 2086 lipoprotein.
AB  - A novel antigen that induces cross-reactive bactericidal antibodies against a
      number of Neisseria meningitidis strains is described. This antigen, a
      approximately 28-kDa lipoprotein called LP2086, was first observed within a
      complex mixture of soluble outer membrane proteins (sOMPs) following a series of
      fractionation, protein purification, and proteomics steps. Approximately 95
      different neisserial isolates tested positive by Western blotting and PCR
      screening methods for the presence of the protein and the gene encoding LP2086.
      The strains tested included isolates of N. meningitidis serogroups A, B, C, W135,
      and Y, Neisseria gonorrhoeae, and Neisseria lactamica. To better understand the
      microheterogeneity of this protein, the 2086 genes from 63 neisserial isolates
      were sequenced. Two different subfamilies of LP2086 were identified based on
      deduced amino acid sequence homology. A high degree of amino acid sequence
      similarity exists within each 2086 subfamily. The highest degree of genetic
      diversity was seen between the two subfamilies which share approximately 60 to
      75% homology at the nucleic acid level. Flow cytometry (fluorescence-activated
      cell sorting) analyses and electron microscopy indicated that the LP2086 is
      localized on the outer surface of N. meningitidis. Antiserum produced against a
      single protein variant was capable of eliciting bactericidal activity against
      strains expressing different serosubtype antigens. Combining one recombinant
      lipidated 2086 (rLP2086) variant from each subfamily with two rPorA variants
      elicited bactericidal activity against all strains tested. The rLP2086 family of
      antigens are candidates worthy of further vaccine development.

PMID- 15039333
TI  - Novel program of macrophage gene expression induced by phagocytosis of Leishmania
      chagasi.
AB  - Leishmania spp. are protozoans that survive and replicate intracellularly in
      mammalian macrophages. Antileishmanial immunity requires gamma interferon (IFN
      gamma)-mediated macrophage activation and generation of microbicidal effector
      molecules. The presence of intracellular Leishmania sp. impairs macrophage
      responses to IFN-gamma, which has led to the description of macrophages as
      deactivated. It has recently become apparent that in addition to classical
      activation, macrophages can be activated by distinct triggers to express
      noninflammatory or anti-inflammatory genes. These nonclassical activation
      programs have been called alternative or type II pathways. We hypothesized that
      during initial contact with a phagocyte, leishmaniae activate one of these
      nonclassical pathways, resulting in expression of genes whose products suppress
      microbicidal responses. Using DNA microarrays, we studied gene expression in RNAs
      from BALB/c bone marrow macrophages with and without Leishmania chagasi
      infection. Some changes were verified by an RNase protection assay, reverse
      transcription-PCR, immunoblotting, or a bioassay. The pattern of genes activated
      by leishmania phagocytosis differed from the pattern of genes activated by
      bacteria or lipopolysaccharide and IFN-gamma. Genes encoding some proinflammatory
      cytokines, receptors, and Th1-type immune response genes were down-modulated, and
      some genes associated with anti-inflammatory or Th2-like immune responses were up
      regulated. Nonetheless, some markers of alternative (arginase) or type II
      activation (interleukin-10, tumor necrosis factor alpha) were unchanged. These
      data suggest that macrophages infected with L. chagasi exhibit a hybrid
      activation profile that is more characteristic of alternative or type II
      activation than of classical activation but does not strictly fall into either of
      these categories. We speculate that the pattern of genes upregulated by
      leishmania phagocytosis optimizes the chance of parasite survival in this hostile
      environment.

PMID- 15039332
TI  - Inhibition of major histocompatibility complex II expression and antigen
      processing in murine alveolar macrophages by Mycobacterium bovis BCG and the 19
      kilodalton mycobacterial lipoprotein.
AB  - Alveolar macrophages constitute a primary defense against Mycobacterium
      tuberculosis, but they are unable to control M. tuberculosis without acquired T
      cell immunity. This study determined the antigen-presenting cell function of
      murine alveolar macrophages and the ability of the model mycobacterium,
      Mycobacterium bovis BCG, to modulate it. The majority (80 to 85%) of alveolar
      macrophages expressed both CD80 (B7.1) and CD11c, and 20 to 30% coexpressed major
      histocompatibility complex II (MHC-II). Gamma interferon (IFN-gamma) enhanced MHC
      II but not B7.1 expression. Naive or IFN-gamma-treated alveolar macrophages did
      not express CD86 (B7.2), CD11b, Mac-3, CD40, or F4/80. M. bovis BCG and the 19
      kDa mycobacterial lipoprotein inhibited IFN-gamma-regulated MHC-II expression on
      alveolar macrophages, and inhibition was dependent on Toll-like receptor 2. The
      inhibition of MHC-II expression by the 19-kDa lipoprotein was associated with
      decreased presentation of soluble antigen to T cells. Thus, susceptibility to
      tuberculosis may result from the ability of mycobacteria to interfere with MHC-II
      expression and antigen presentation by alveolar macrophages.

PMID- 15039334
TI  - Reactive oxygen and nitrogen species differentially regulate Toll-like receptor 4
      mediated activation of NF-kappa B and interleukin-8 expression.
AB  - Toll-like receptor 4 (TLR4) has been identified as a transmembrane protein
      involved in the host innate immune response to gram-negative bacterial
      lipopolysaccharide (LPS). Upon activation by LPS recognition, the TIR domain of
      TLR4 signals through MyD88 to activate the nuclear factor kappa B (NF-kappa B)
      pathway, a critical regulator of many proinflammatory genes, including
      interleukin-8 (IL-8). Emerging evidence suggests that reactive oxygen species
      (ROS) can contribute to diverse signaling pathways, including the LPS-induced
      cascade. In the present study we investigated the role of ROS in TLR-mediated
      signaling. Purified Escherichia coli LPS, a highly specific TLR4 agonist,
      elicited an oxidative burst in the monocyte-like cell line THP-1 in a time- and
      dose-dependent manner. This oxidative burst was shown to be dependent on the
      presence of TLR4 through transfection studies in HEK cells, which do not normally
      express this protein, and with bone marrow-derived macrophages from C3H/HeJ mice,
      which express a mutated TLR4 protein. LPS-stimulated IL-8 expression could be
      blocked by the antioxidants N-acetyl-L-cysteine and dimethyl sulfoxide at both
      the protein and mRNA levels. These antioxidants also blocked LPS-induced IL-8
      promoter transactivation as well as the nuclear translocation of NF-kappa B.
      These data provide evidence that ROS regulate immune signaling through TLR4 via
      their effects on NF-kappa B activation.

PMID- 15039335
TI  - Toll-like receptor 2 is required for optimal control of Listeria monocytogenes
      infection.
AB  - The control of Listeria monocytogenes infection depends on the rapid activation
      of the innate immune system, likely through Toll-like receptors (TLR), since mice
      deficient for the common adapter protein of TLR signaling, myeloid
      differentiation factor 88 (MyD88), succumb to Listeria infection. In order to
      test whether TLR2 is involved in the control of infections, we compared the host
      response in TLR2-deficient mice with that in wild-type mice. Here we show that
      TLR2-deficient mice are more susceptible to systemic infection by Listeria than
      are wild-type mice, with a reduced survival rate, increased bacterial burden in
      the liver, and abundant and larger hepatic microabscesses containing increased
      numbers of neutrophils. The production of tumor necrosis factor, interleukin-12,
      and nitric oxide and the expression of the costimulatory molecules CD40 and CD86,
      which are necessary for the control of infection, were reduced in TLR2-deficient
      macrophages and dendritic cells stimulated by Listeria and were almost abolished
      in the absence of MyD88, coincident with the high susceptibility of MyD88
      deficient mice to in vivo infection. Therefore, the present data demonstrate a
      role for TLR2 in the control of Listeria infection, but other MyD88-dependent
      signals may contribute to host resistance.

PMID- 15039337
TI  - Normally occurring human anti-GM1 immunoglobulin M antibodies and the immune
      response to bacteria.
AB  - Anti-GM(1) antibodies of the immunoglobulin M (IgM) isotype are normal components
      of the antibody repertoire of adult human serum. Using a sensitive high
      performance thin-layer chromatography (HPTLC) immunostaining assay, we found that
      these antibodies were absent in the umbilical vein and children <1 month of age
      but could be detected after 1 month of age. Although most of the children older
      than 6 months of age were positive, there were still a few negative children. The
      appearance of anti-GM(1) IgM antibodies showed a perfect concordance with two
      well-characterized antibacterial antibodies, anti-Forssman and anti-blood group
      A, which indicates a similar origin. We also studied IgM reactivity with
      lipopolysaccharides (LPSs) from gram-negative bacteria isolated from stool
      samples from healthy babies and from Escherichia coli HB101 in serum from
      individuals of different ages. We found a positive reaction with both LPSs in all
      the children more than 1 month of age analyzed, even in those that were negative
      for anti-GM(1) antibodies. Anti-GM(1) IgM antibodies were purified from adult
      serum by affinity chromatography and tested for the ability to bind LPSs from
      different bacteria. This highly specific preparation showed reactivity only with
      LPS from a strain of Campylobacter jejuni isolated from a patient with diarrhea.
      We conclude that normally occurring IgM antibodies are generated after birth,
      probably during the immune defense against specific bacterial strains.

PMID- 15039336
TI  - Effect of bronchoalveolar lavage fluid from Pneumocystis carinii-infected hosts
      on phagocytic activity of alveolar macrophages.
AB  - Alveolar macrophages from Pneumocystis carinii-infected rats are defective in
      phagocytosis. To investigate whether this defect is due to a certain factor
      present in P. carinii-infected lungs, alveolar macrophages from uninfected rats
      were incubated with bronchoalveolar lavage (BAL) fluid samples from P. carinii
      infected rats. Alveolar macrophages treated with these BAL fluid samples became
      defective in phagocytosis but remained normal when treated with BAL fluid samples
      from noninfected or Toxoplasma gondii-infected rats. The suppressive activity of
      the BAL fluid samples from P. carinii-infected rats on phagocytosis was retained
      when the BAL fluid samples were passed through a filter with a pore size of 0.45
      microm but was lost when the BAL fluid samples were digested with proteases such
      as trypsin, pepsin, papain, or endopeptidase Gly-C. Lipid fractions of these BAL
      fluid samples had no suppressive activity on phagocytosis. The suppressive
      activity of these BAL fluid samples was also lost when they were incubated with
      concanavalin A-agarose beads, suggesting that the inhibitor is a glycoprotein.
      The inhibitor was estimated to be larger than 100,000 Da by exclusion filtration.
      After binding to the concanavalin A-agarose beads, the inhibitor in BAL fluid
      samples and P. carinii lysate could be eluted with 200 mM methylmannose.
      Treatment of both the crude BAL fluid samples and P. carinii lysate and the 200
      mM methylmannose eluate with antibody against the major surface glycoprotein of
      P. carinii eliminated their suppressive activity. These results suggest that the
      factor capable of suppressing the phagocytic activity of alveolar macrophages is
      P. carinii major surface glycoprotein or one or more of its derivatives.

PMID- 15039338
TI  - Rapid expression of chemokines and proinflammatory cytokines in newly hatched
      chickens infected with Salmonella enterica serovar typhimurium.
AB  - Poultry meat and eggs contaminated with Salmonella enterica serovar Enteritidis
      or Salmonella enterica serovar Typhimurium are common sources of acute
      gastroenteritis in humans. However, the exact nature of the immune mechanisms
      protective against Salmonella infection in chickens has not been characterized at
      the molecular level. In the present study, bacterial colonization, development of
      pathological lesions, and proinflammatory cytokine and chemokine gene expression
      were investigated in the liver, spleen, jejunum, ileum, and cecal tonsils in
      newly hatched chickens 6, 12, 24, and 48 h after oral infection with Salmonella
      serovar Typhimurium. Very high bacterial counts were found in the ileum and cecal
      contents throughout the experiment, whereas Salmonella started to appear in the
      liver only from 24 h postinfection. Large numbers of heterophils, equivalent to
      neutrophils in mammals, and inflammatory edema could be seen in the lamina
      propria of the intestinal villi and in the liver. Interleukin 8 (IL-8), K60 (a
      CXC chemokine), macrophage inflammatory protein 1 beta, and IL-1 beta levels were
      significantly upregulated in the intestinal tissues and in the livers of the
      infected birds. However, the spleens of the infected birds show little or no
      change in the expression levels of these cytokines and chemokines. Increased
      expression of the proinflammatory cytokines and chemokines (up to several hundred
      fold) correlated with the presence of inflammatory signs in those tissues. This
      is the first description of in vivo expression of chemokines and proinflammatory
      cytokines in response to oral infection with Salmonella in newly hatched
      chickens.

PMID- 15039340
TI  - Cell envelope protein PPE68 contributes to Mycobacterium tuberculosis RD1
      immunogenicity independently of a 10-kilodalton culture filtrate protein and ESAT
      6.
AB  - The protective efficacy of Mycobacterium bovis BCG can be markedly augmented by
      stable integration of Mycobacterium tuberculosis genomic region RD1. BCG
      complemented with RD1 (BCG::RD1) encodes nine additional proteins. Among them, 10
      kDa culture filtrate protein (CFP-10) and ESAT-6 (6-kDa early secreted antigenic
      target) are low-molecular-weight proteins that induce potent Th1 responses. Using
      pools of synthetic peptides, we have examined the potential immunogenicity of
      four other RD1 products (PE35, PPE68, Rv3878, and Rv3879c). PPE68, the protein
      encoded by rv3873, was the only one to elicit gamma interferon (IFN-gamma)
      producing cells in C57BL/6 mice infected with M. tuberculosis. Anti-PPE68 T cells
      were predominantly raised against an epitope mapped in the N-terminal end of the
      protein. Importantly, inactivation of rv3873 in BCG::RD1 did not modify CFP-10
      and ESAT-6 secretion. Moreover, the generation of IFN-gamma responses to these
      antigens following immunization with BCG::RD1 was independent of PPE68
      expression. Taken together, these results show that PPE68 is an immunogenic
      product of the RD1 region, which does not interfere with the secretion and
      immunogenicity of CFP-10 and ESAT-6.

PMID- 15039341
TI  - Role of biofilm-associated protein bap in the pathogenesis of bovine
      Staphylococcus aureus.
AB  - Staphylococcus aureus is a common cause of intramammary infections, which
      frequently become chronic, associated with the ability of the bacteria to produce
      biofilm. Here, we report a relationship between the ability to produce chronic
      bovine mastitis and biofilm formation. We have classified bovine mastitis S.
      aureus isolates into three groups based on the presence of particular genetic
      elements required for biofilm formation: group 1 (ica(+) bap(+)), group 2
      (ica(+), bap negative), and group 3 (ica negative, bap negative). Overall,
      animals naturally infected with group 1 and 2 isolates had a lower milk somatic
      cell count than those infected with isolates of group 3. In addition, Bap
      positive isolates were significantly more able to colonize and persist in the
      bovine mammary gland in vivo and were less susceptible to antibiotic treatments
      when forming biofilms in vitro. Analysis of the structural bap gene revealed the
      existence of alternate forms of expression of the Bap protein in S. aureus
      isolates obtained under field conditions throughout the animal's life. The
      presence of anti-Bap antibodies in serum samples taken from animals with
      confirmed S. aureus infections indicated the production of Bap during infection.
      Furthermore, disruption of the ica operon in a bap-positive strain had no effect
      on in vitro biofilm formation, a finding which strongly suggested that Bap could
      compensate for the deficiency of the PIA/PNAG product (a biofilm matrix
      polysaccharide). Altogether, these results demonstrate that, in the bovine
      intramammary gland, the presence of Bap may facilitate a biofilm formation
      connected with the persistence of S. aureus.

PMID- 15039342
TI  - Detergent-resistant membrane microdomains facilitate Ib oligomer formation and
      biological activity of Clostridium perfringens iota-toxin.
AB  - Clostridium perfringens iota-toxin consists of two separate proteins identified
      as a cell binding protein, iota b (Ib), which forms high-molecular-weight
      complexes on cells generating Na(+)/K(+)-permeable pores through which iota a
      (Ia), an ADP-ribosyltransferase, presumably enters the cytosol. Identity of the
      cell receptor and membrane domains involved in Ib binding, oligomer formation,
      and internalization is currently unknown. In this study, Vero (toxin-sensitive)
      and MRC-5 (toxin-resistant) cells were incubated with Ib, after which detergent
      resistant membrane microdomains (DRMs) were extracted with cold Triton X-100.
      Western blotting revealed that Ib oligomers localized in DRMs extracted from
      Vero, but not MRC-5, cells while monomeric Ib was detected in the detergent
      soluble fractions of both cell types. The Ib protoxin, previously shown to bind
      Vero cells but not form oligomers or induce cytotoxicity, was detected only in
      the soluble fractions. Vero cells pretreated with phosphatidylinositol-specific
      phospholipase C before addition of Ib indicated that glycosylphosphatidyl
      inositol-anchored proteins were minimally involved in Ib binding or oligomer
      formation. While pretreatment of Vero cells with filipin (which sequesters
      cholesterol) had no effect, methyl-beta-cyclodextrin (which extracts cholesterol)
      reduced Ib binding and oligomer formation and delayed iota-toxin cytotoxicity.
      These studies showed that iota-toxin exploits DRMs for oligomer formation to
      intoxicate cells.

PMID- 15039339
TI  - Cell surface-associated elongation factor Tu mediates the attachment of
      Lactobacillus johnsonii NCC533 (La1) to human intestinal cells and mucins.
AB  - The aim of this work was to identify Lactobacillus johnsonii NCC533 (La1) surface
      molecules mediating attachment to intestinal epithelial cells and mucins.
      Incubation of Caco-2 intestinal epithelial cells with an L. johnsonii La1 cell
      wall extract led to the recognition of elongation factor Tu (EF-Tu) as a novel
      La1 adhesin-like factor. The presence of EF-Tu at the surface of La1 was
      confirmed by analysis of purified outer surface protein extract by immunoblotting
      experiments, by electron microscopy, and by enzyme-linked immunosorbent assays of
      live bacteria. Furthermore, tandem mass spectrometry analysis proved that EF-TU
      was expressed at the La1 surface as an intact molecule. Using recombinant La1 EF
      Tu protein, we were able to determine that its binding to intestinal cells and to
      mucins is pH dependent. Competition experiments suggested that EF-Tu has an
      important role in La1 mucin binding capacity. In addition, immunomodulation
      studies performed on HT29 cells showed that EF-Tu recombinant protein can induce
      a proinflammatory response in the presence of soluble CD14. Our in vitro results
      indicate that EF-Tu, through its binding to the intestinal mucosa, might
      participate in gut homeostasis.

PMID- 15039343
TI  - Identification and molecular characterization of a gene encoding a protective
      Leishmania amazonensis Trp-Asp (WD) protein.
AB  - Several Leishmania proteins have been identified and characterized in pursuit of
      understanding pathogenesis and protection in cutaneous leishmaniasis. In the
      present study, we utilized sera from infected BALB/c mice to screen a Leishmania
      amazonensis amastigote cDNA expression library and obtained the full-length gene
      that encodes a novel Trp-Asp (WD) protein designated LAWD (for Leishmania
      antigenic WD protein). The WD family of proteins mediates protein-protein
      interactions and coordinates the formation of protein complexes. The single-copy
      LAWD gene is transcribed as a approximately 3.1-kb mRNA in both promastigotes and
      amastigotes, with homologues being detected in several other Leishmania species.
      Immunoelectron microscopy revealed a predominant localization of the LAWD protein
      in the flagellar pocket. Analyses of sera from human patients with cutaneous and
      mucocutaneous leishmaniasis indicated that these individuals mounted significant
      humoral responses against LAWD. Given that recombinant LAWD protein elicited the
      production of high levels of gamma interferon, but no detectable levels of
      interleukin-10 (IL-10), in CD4(+) cells of L. amazonensis-infected mice, we
      further examined whether LAWD could elicit protective immunity. DNA vaccination
      with the LAWD and IL-12 genes significantly delayed lesion development, which
      correlated with a dramatic reduction in parasite burdens. Thus, we have
      successfully identified a promising vaccine candidate and antigenic vehicle to
      aid in the dissection of the complicated pathogenic immune response of L.
      amazonensis.

PMID- 15039344
TI  - Purification and molecular cloning of and immunization with Ancylostoma
      ceylanicum excretory-secretory protein 2, an immunoreactive protein produced by
      adult hookworms.
AB  - Hookworms remain major agents of global morbidity, and vaccination against these
      bloodfeeding parasites may be an attractive complement to conventional control
      methods. Here we describe the cloning of Ancylostoma ceylanicum excretory
      secretory protein 2 (AceES-2), a novel immunoreactive protein produced by adult
      worms. Native AceES-2 was purified from excretory-secretory (ES) products by
      reverse-phase high-pressure liquid chromatography, subjected to amino-terminal
      sequencing, and cloned from adult worm RNA by using reverse transcription-PCR.
      The translated AceES-2 cDNA predicts that the mature protein consists of 102
      amino acids and has a molecular mass of 11.66 kDa. Western immunoblot and enzyme
      linked immunosorbent assay analyses demonstrated that recombinant AceES-2 (rAceES
      2) reacted strongly with antibodies from A. ceylanicum-infected hamsters.
      Immunization of hamsters with native ES products adsorbed to alum induced
      antibodies that recognized rAceES-2, while rAceES-2-alum vaccination resulted in
      antibodies that reacted with a single protein band in ES products that closely
      approximated the size predicted for the native molecule. Infected hamsters that
      were passively immunized with hyperimmune rabbit anti-rAceES-2 serum exhibited
      more rapid and complete recovery from anemia than controls that received normal
      serum. Oral immunization with rAceES-2 was associated with significantly reduced
      anemia upon challenge, an outcome similar to the outcome observed in hamsters
      that were orally vaccinated with soluble hookworm extract (the latter animals
      were also resistant to weight loss). These data suggest that AceES-2 plays an
      important role in the host-parasite interaction and that vaccination against this
      protein may represent a useful strategy for controlling hookworm anemia.

PMID- 15039345
TI  - Molecular characterization of Ancylostoma ceylanicum Kunitz-type serine protease
      inhibitor: evidence for a role in hookworm-associated growth delay.
AB  - Hookworm infection is a major cause of iron deficiency anemia and malnutrition in
      developing countries. The Ancylostoma ceylanicum Kunitz-type inhibitor (AceKI) is
      a 7.9-kDa broad-spectrum inhibitor of trypsin, chymotrypsin, and pancreatic
      elastase that has previously been isolated from adult hookworms. Site-directed
      mutagenesis of the predicted P1 inhibitory reactive site amino acid confirmed the
      role of Met(26) in mediating inhibition of the three target serine proteases. By
      using reverse transcription-PCR, it was demonstrated that the level of AceKI gene
      expression increased following activation of third-stage larvae with serum and
      that the highest level of expression was reached in the adult stage of the
      parasite. Immunohistochemistry studies performed with polyclonal immunoglobulin G
      raised against recombinant AceKI showed that the inhibitor localized to the
      subcuticle of the adult hookworm, suggesting that it has a potential in vivo role
      in neutralizing intestinal proteases at the surface of the parasite. Immunization
      with recombinant AceKI was shown to confer partial protection against hookworm
      associated growth delay without a measurable effect on anemia. Taken together,
      the data suggest that AceKI plays a role in the pathogenesis of hookworm
      associated malnutrition and growth delay, perhaps through inhibition of nutrient
      absorption in infected hosts.

PMID- 15039346
TI  - Fc-dependent polyclonal antibodies and antibodies to outer membrane proteins A
      and B, but not to lipopolysaccharide, protect SCID mice against fatal Rickettsia
      conorii infection.
AB  - An emphasis on cellular immunity against Rickettsia has led to neglect of
      analysis of the role of antibody. The availability of an excellent mouse model of
      spotted fever rickettsiosis enabled investigation of a potential role of antibody
      in immunity to Rickettsia conorii. C3H severe combined immunodeficiency (SCID)
      mice were passively transfused with monoclonal antibodies against rickettsial
      outer membrane protein A (OmpA), OmpB, or lipopolysaccharide (LPS), polyclonal
      anti-R. conorii serum, Fab fragments of polyclonal antiserum, or no antibodies
      and then challenged 48 h later with 10 50% lethal doses (LD(50)) of R. conorii.
      All mice that received monoclonal antibodies against OmpA and two of four mice
      that received monoclonal antibodies against OmpB or polyclonal antisera were
      completely protected, but the recipients of anti-LPS antibodies or the Fab
      fragments were not protected. Polyclonal antibody treatment of C3H SCID mice that
      had been infected with 10 LD(50) of R. conorii 4 or 5 days earlier prolonged the
      life of the infected mice from 10.4 to 22.5 days and resulted in decreased levels
      of infectious rickettsiae in the spleen and liver 24 and 48 h later. Treatment
      with protective antibodies resulted in the development of large aggregates of R.
      conorii antigens in splenic macrophages and intraphagolysosomal rickettsial death
      and digestion. The kinetics of development of antibodies to R. conorii determined
      by immunoblotting revealed antibodies to LPS on day 6 and antibodies to OmpA and
      OmpB on day 12, when recovery from the infection had already occurred. Antibodies
      to particular epitopes of OmpA and OmpB may protect against reinfection, but they
      may not play a key role in immunity against primary infection. Antibodies might
      be useful for treating infections with antibiotic-resistant organisms, and some B
      cell epitopes should be included in a subunit vaccine.

PMID- 15039347
TI  - Role of extracellular phospholipases and mononuclear phagocytes in dissemination
      of cryptococcosis in a murine model.
AB  - Secreted phospholipase B (PLB) activity promotes the survival and replication of
      Cryptococcus neoformans in macrophages in vitro. We therefore investigated the
      role of mononuclear phagocytes and cryptococcal PLB in the dissemination of
      infection in a mouse model, using C. neoformans var. grubii wild-type strain H99,
      a PLB1 deletion mutant (Delta plb1), and a reconstituted strain (Delta
      plb1(rec)). PLB facilitated the entry of endotracheally administered cryptococci
      into lung IM. PLB was also required for lymphatic spread from the lung to
      regional lymph nodes and for entry into the blood. Langhans-type giant cells
      containing budding cryptococci were seen free in the lymphatic sinuses of hilar
      nodes of H99- and Delta plb1(rec)-infected mice, suggesting that they may have a
      role in the dissemination of cryptococcal infection. The transfer of infected
      lung macrophages to recipient mice by tail vein injections demonstrated that
      these cells can facilitate hematogenous dissemination of cryptococci to the
      brain, independent of cryptococcal PLB secretion. PLB activities of cryptococci
      isolated from lung macrophages or infected brains were not persistently
      increased. We conclude that mononuclear phagocytes are a vehicle for cryptococcal
      dissemination and that PLB activity is necessary for the initiation of
      interstitial pulmonary infections and for dissemination from the lung via the
      lymphatics and blood. PLB is not, however, essential for the establishment of
      neurological infections when cryptococci are presented within, or after passage
      through, mononuclear phagocytes.

PMID- 15039348
TI  - Probiotic bifidobacteria protect mice from lethal infection with Shiga toxin
      producing Escherichia coli O157:H7.
AB  - The anti-infectious activity of probiotic Bifidobacteria against Shiga toxin
      producing Escherichia coli (STEC) O157:H7 was examined in a fatal mouse STEC
      infection model. Stable colonization of the murine intestines was achieved by the
      oral administration of Bifidobacterium breve strain Yakult (naturally resistant
      to streptomycin sulfate) as long as the mice were treated with streptomycin in
      their drinking water (5 mg/ml). The pathogenicity of STEC infection,
      characterized by marked body weight loss and subsequent death, observed in the
      infected controls was dramatically inhibited in the B. breve-colonized group.
      Moreover, Stx production by STEC cells in the intestine was almost completely
      inhibited in the B. breve-colonized group. A comparison of anti-STEC activity
      among several Bifidobacterium strains with natural resistance to streptomycin
      revealed that strains such as Bifidobacterium bifidum ATCC 15696 and
      Bifidobacterium catenulatum ATCC 27539(T) did not confer an anti-infectious
      activity, despite achieving high population levels similar to those of effective
      strains, such as B. breve strain Yakult and Bifidobacterium pseudocatenulatum DSM
      20439. The effective strains produced a high concentration of acetic acid (56 mM)
      and lowered the pH of the intestine (to pH 6.75) compared to the infected control
      group (acetic acid concentration, 28 mM; pH, 7.15); these effects were thought to
      be related to the anti-infectious activity of these strains because the
      combination of a high concentration of acetic acid and a low pH was found to
      inhibit Stx production during STEC growth in vitro.

PMID- 15039349
TI  - Measuring the effects of an ever-changing environment on malaria control.
AB  - The effectiveness of malaria control measures depends not only on the potency of
      the control measures themselves but also upon the influence of variables
      associated with the environment. Environmental variables have the capacity either
      to enhance or to impair the desired outcome. An optimal outcome in the field,
      which is ultimately the real goal of vaccine research, will result from prior
      knowledge of both the potency of the control measures and the role of
      environmental variables. Here we describe both the potential effectiveness of
      control measures and the problems associated with testing in an area of
      endemicity. We placed canaries with different immunologic backgrounds (e.g.,
      naive to malaria infection, vaccinated naive, and immune) directly into an area
      where avian malaria, Plasmodium relictum, is endemic. In our study setting,
      canaries that are naive to malaria infection routinely suffer approximately 50%
      mortality during their first period of exposure to the disease. In comparison,
      birds vaccinated and boosted with a DNA vaccine plasmid encoding the
      circumsporozoite protein of P. relictum exhibited a moderate degree of protection
      against natural infection (P < 0.01). In the second year we followed the fate of
      all surviving birds with no further manipulation. The vaccinated birds from the
      first year were no longer statistically distinguishable for protection against
      malaria from cages of naive birds. During this period, 36% of vaccinated birds
      died of malaria. We postulate that the vaccine-induced protective immune
      responses prevented the acquisition of natural immunity similar to that
      concurrently acquired by birds in a neighboring cage. These results indicate that
      dominant environmental parameters associated with malaria deaths can be addressed
      before their application to a less malleable human system.

PMID- 15039350
TI  - Growth control of small-colony variants by genetic regulation of the hemin uptake
      system.
AB  - Small-colony variants (SCVs) are slow-growing variants of human bacterial
      pathogens. They are associated with chronic persistent infections, and their
      biochemical identification and antimicrobial treatment are impaired by altered
      metabolic properties. To contribute to the understanding of SCV-mediated
      infections, we analyzed a clinical SCV isolate derived from a chronic prosthetic
      hip infection. A sequence analysis of housekeeping genes identified an
      Enterobacter hormaechei-like organism. The SCV phenotype, with growth as
      microcolonies, was caused by a block within the heme biosynthesis pathway through
      deletion of the hemB locus, as shown by hybridization and complementation
      experiments. At a low frequency, large-colony variants (LCVs) arose that were
      dependent on exogenous hemin. To investigate this phenomenon, we cloned and
      sequenced the 5.8-kb hemin uptake system, denoted ehu. Gene expression analysis
      indicated regulation of this locus in wild-type bacteria by the global iron
      regulator Fur. Inactivation of Fur in LCVs caused the derepression of ehu
      expression and facilitated bacterial growth. Genetic alterations of the fur locus
      in LCVs were identified as insertions of IS1A elements and point mutations. In
      contrast, SCVs could utilize exogenous hemin only in the absence of iron. Thus,
      we provide the first molecular characterization of the growth properties of a
      clinical SCV isolate, which may help to improve the diagnostic and therapeutic
      management of patients with chronic persistent infections.

PMID- 15039351
TI  - Molecular cloning and characterization of cgt, the Brucella abortus cyclic beta
      1,2-glucan transporter gene, and its role in virulence.
AB  - The animal pathogen Brucella abortus contains a gene cgt, which complemented
      Sinorhizobium meliloti nodule development (ndvA) and Agrobacterium tumefaciens
      chromosomal virulence (chvA) mutants. Complemented strains recovered the presence
      of anionic cyclic beta-1,2-glucan, motility, tumor induction in A. tumefaciens,
      and nodule occupancy in S. meliloti, all traits strictly associated with the
      presence of cyclic beta-1,2-glucan in the periplasm. Nucleotide sequencing
      revealed that B. abortus cgt contains a 1,797-bp open reading frame coding for a
      predicted membrane protein of 599 amino acids (65.9 kDa) that is 58.5 and 59.9%
      identical to S. meliloti NdvA and A. tumefaciens ChvA, respectively.
      Additionally, B. abortus cgt, like S. meliloti ndvA and A. tumefaciens chvA
      possesses ATP-binding motifs and the ABC signature domain features of a typical
      ABC transporter. Characterization of Cgt was carried out by the construction of
      null mutants in B. abortus 2308 and S19 backgrounds. Both mutants do not
      transport cyclic beta-1,2-glucan to the periplasm, as shown by the absence of
      anionic cyclic glucan, and they display reduced virulence in mice and defective
      intracellular multiplication in HeLa cells. These results suggest that cyclic
      beta-1,2-glucan must be transported into the periplasmatic space to exert its
      action as a virulence factor.

PMID- 15039352
TI  - Fusobacterium nucleatum induces premature and term stillbirths in pregnant mice:
      implication of oral bacteria in preterm birth.
AB  - Fusobacterium nucleatum is a gram-negative anaerobe ubiquitous to the oral
      cavity. It is associated with periodontal disease. It is also associated with
      preterm birth and has been isolated from the amniotic fluid, placenta, and
      chorioamnionic membranes of women delivering prematurely. Periodontal disease is
      a newly recognized risk factor for preterm birth. This study examined the
      possible mechanism underlying the link between these two diseases. F. nucleatum
      strains isolated from amniotic fluids and placentas along with those isolated
      from orally related sources invaded both epithelial and endothelial cells. The
      invasive ability may enable F. nucleatum to colonize and infect the pregnant
      uterus. Transient bacteremia caused by periodontal infection may facilitate
      bacterial transmission from the oral cavity to the uterus. To test this
      hypothesis, we intravenously injected F. nucleatum into pregnant CF-1 mice. The
      injection resulted in premature delivery, stillbirths, and nonsustained live
      births. The bacterial infection was restricted inside the uterus, without
      spreading systemically. F. nucleatum was first detected in the blood vessels in
      murine placentas. Invasion of the endothelial cells lining the blood vessels was
      observed. The bacteria then crossed the endothelium, proliferated in surrounding
      tissues, and finally spread to the amniotic fluid. The pattern of infection
      paralleled that in humans. This study represents the first evidence that F.
      nucleatum may be transmitted hematogenously to the placenta and cause adverse
      pregnancy outcomes. The results strengthen the link between periodontal disease
      and preterm birth. Our study also indicates that invasion may be an important
      virulence mechanism for F. nucleatum to infect the placenta.

PMID- 15039353
TI  - Localization of BmpA on the exposed outer membrane of Borrelia burgdorferi by
      monospecific anti-recombinant BmpA rabbit antibodies.
AB  - BmpA (P39) is an immunodominant chromosomally encoded Borrelia burgdorferi
      protein. The potential strong cross-reactivity of anti-BmpA antibodies with the
      other members of this paralogous protein family and the previous use of
      antibodies whose reactivity to the other Bmp proteins was uncharacterized have
      resulted in continued controversy over its localization in B. burgdorferi. In an
      effort to provide a definitive demonstration of the localization of BmpA, rabbit
      antibodies raised to recombinant BmpA (rBmpA) were rendered monospecific by
      absorption with rBmpB. This reagent did not react with rBmpB, rBmpC, or rBmpD in
      dot immunobinding, detected only a single 39-kDa band and a single 39-kDa, pI 5.0
      spot on one- and two-dimensional immunoblots of B. burgdorferi lysates,
      respectively, and immunoprecipitated a single 39-kDa protein from these lysates.
      It detected BmpA in the Triton X-114-soluble and -insoluble fractions of B.
      burgdorferi, suggesting association with both inner and outer bacterial cell
      membranes. Treatment of intact B. burgdorferi with proteinase K partially
      digested BmpA, consistent with a limited surface exposure on the outer bacterial
      membrane, a suggestion confirmed by immunofluorescence of unfixed B. burgdorferi
      cultured in vitro and in vivo. Anti-rBmpA antibody was bacteriostatic for B.
      burgdorferi B31 in culture, again suggesting localization of BmpA on the exposed
      spirochetal outer surface. Surface localization of BmpA, growth inhibition by
      anti-rBmpA antibodies, and the previously reported conservation of bmpA in
      different B. burgdorferi sensu lato strains may indicate that BmpA plays an
      essential role in B. burgdorferi biology.

PMID- 15039354
TI  - Identification of a novel Citrobacter rodentium type III secreted protein, EspI,
      and roles of this and other secreted proteins in infection.
AB  - Citrobacter rodentium is a member of a group of pathogens that colonize the lumen
      of the host gastrointestinal tract via attaching and effacing (A/E) lesion
      formation. C. rodentium, which causes transmissible colonic hyperplasia in mice,
      is used as an in vivo model system for the clinically significant A/E pathogens
      enterohemorrhagic and enteropathogenic Escherichia coli. These bacteria all
      contain a pathogenicity island called the locus of enterocyte effacement (LEE),
      which encodes a type III secretion system that is designed to deliver effector
      proteins into eukaryotic host cells. These effectors are involved in the
      subversion of host eukaryotic cell functions to the benefit of the bacterium. In
      this study we used mutant strains to determine the effects of the C. rodentium
      LEE-encoded effectors EspF, EspG, EspH, and Map on virulence in the mouse model.
      In addition, we identified a novel secreted protein, EspI encoded outside the
      LEE, whose secretion is also dependent on a functional type III secretion system.
      Mutant strains with each of the effectors investigated were found to be
      outcompeted by wild-type bacteria in mixed-infection experiments in vivo,
      although the effects of EspF and EspH were only subtle. In single-infection
      experiments, we found that EspF, EspG, and EspH are not required for efficient
      colonization of the mouse colon or for the production of hyperplasia. In
      contrast, strains producing EspI and Map had significant colonization defects and
      resulted in dramatically reduced levels of hyperplasia, and they exhibited very
      different growth dynamics in mice than the wild-type strain exhibited.

PMID- 15039355
TI  - Impairment of intramacrophagic Brucella suis multiplication by human natural
      killer cells through a contact-dependent mechanism.
AB  - Brucella spp. are facultative intracellular bacteria that can establish
      themselves and cause chronic disease in humans and animals. NK cells play a key
      role in host defense. They are implicated in an early immune response to a
      variety of pathogens. However, it was shown that they do not control Brucella
      infection in mice. On the other hand, NK cell activity is impaired in patients
      with acute brucellosis, and recently it was demonstrated that human NK cells
      mediate the killing of intramacrophagic Mycobacterium tuberculosis in in vitro
      infection. Therefore, we have analyzed the behavior of Brucella suis infecting
      isolated human macrophages in the presence of syngeneic NK cells. We show that
      (i) NK cells impair the intramacrophagic development of B. suis, a phenomenon
      enhanced by NK cell activators, such as interleukin-2; (ii) NK cells cultured in
      the presence of infected macrophages are highly activated and secrete gamma
      interferon and tumor necrosis factor alpha; (iii) impairment of bacterial
      multiplication inside infected cells is marginally associated with the cytokines
      produced during the early phase of macrophage-NK cell cocultures; (iv) direct
      cell-to-cell contact is required for NK cells to mediate the inhibition of B.
      suis development; and (v) inhibition of B. suis development results from an
      induction of NK cell cytotoxicity against infected macrophages. Altogether, these
      findings show that NK cells could participate early in controlling the
      intramacrophagic development of B. suis in humans. It seems thus reasonable to
      hypothesize a role for NK cells in the control of human brucellosis. However, by
      impairing the activity of these cells in the acute phase of the illness, the
      pathogen should avoid this control.

PMID- 15039356
TI  - Role for moesin in lipopolysaccharide-stimulated signal transduction.
AB  - Moesin is a 78-kDa protein with diverse functions in linking the cytoskeleton to
      the membrane while controlling cell shape, adhesion, locomotion, and signaling.
      The aim of this study was to characterize the expression and localization of
      moesin in mononuclear phagocytes by using confocal microscopy, flow cytometry,
      immunoprecipitation, and Western blotting and to analyze the function of moesin
      as a lipopolysaccharide receptor, utilizing an antisense oligonucleotide approach
      to knock down the moesin gene. Results revealed that moesin is expressed on the
      surface of monocytes/macrophages and surface expression is increased after
      lipopolysaccharide stimulation. The total protein mass of moesin is increased in
      monocytes after lipopolysaccharide stimulation. Immunoprecipitation showed that
      moesin coprecipitates with TLR4, a well-known lipopolysaccharide receptor,
      suggesting an early role of moesin in the formation of the initiation complex for
      lipopolysaccharide signaling. Two antisense and two control sense
      oligonucleotides were synthesized and introduced every 4 h for 48 h in adherent
      macrophage-like cells. Cells were then stimulated with lipopolysaccharide for 4
      h, and the supernatants were assayed for tumor necrosis factor alpha (TNF-alpha)
      production. Cell lysates were assayed for moesin expression by Western blotting
      immediately after the 48-h treatment period and also after 116 h of recovery to
      assess the return of moesin expression and function. Moesin gene expression was
      completely suppressed after 48 h of incubation with antisense oligonucleotides.
      The antisense elimination of moesin gene expression led to a significant
      reduction of lipopolysaccharide-induced TNF-alpha secretion. Restoration of
      moesin gene expression led to restoration of TNF-alpha production. These data
      suggest an important role for moesin in lipopolysaccharide-induced TNF-alpha
      production, highlighting its importance in lipopolysaccharide-mediated signal
      transduction.

PMID- 15039357
TI  - Plasmodium falciparum merozoite surface protein 6 is a dimorphic antigen.
AB  - Merozoite surface protein 1 (MSP1) is a highly polymorphic Plasmodium falciparum
      merozoite surface protein implicated in the invasion of human erythrocytes during
      the asexual cycle. It forms a complex with MSP6 and MSP7 on the merozoite
      surface, and this complex is released from the parasite around the time of
      erythrocyte invasion. MSP1 and many other merozoite surface proteins contain
      dimorphic elements in their protein structures, and here we show that MSP6 is
      also dimorphic. The sequences of eight MSP6 genes indicate that the alleles of
      each dimorphic form of MSP6 are highly conserved. The smaller 3D7-type MSP6
      alleles are detected in parasites from all malarious regions of the world,
      whereas K1-type MSP6 alleles have only been detected in parasites from mainland
      Southeast Asia. Cleavage of MSP6, which produces the p36 fragment in 3D7-type
      MSP6 and associates with MSP1, also occurs in K1-type MSP6 but at a different
      site in the protein. Anti-3D7 MSP6 antibodies weakly inhibited erythrocyte
      invasion by homologous 3D7 merozoites but did not inhibit a parasite line
      expressing the K1-type MSP6 allele. Antibodies from hyperimmune individuals
      affinity purified on an MSP3 peptide cross-reacted with MSP6; therefore, MSP6 may
      also be a target of antibody-dependent cellular inhibition.

PMID- 15039358
TI  - Modulation of enteropathogenic Escherichia coli virulence by quorum sensing.
AB  - Enteropathogenic Escherichia coli (EPEC) produces a lesion on epithelial cells
      called the attaching and effacing (AE) lesion. All genes necessary for AE are
      encoded within the locus of enterocyte effacement (LEE). EPEC also adheres in a
      characteristic pattern to epithelial cells by forming microcolonies, usually
      referred to as localized adherence (LA). LA is mediated by the bundle-forming
      pilus and flagella. The LEE genes are directly activated by the LEE-encoded
      regulator (Ler). Transcription of Ler is under the control of Per, integration
      host factor, Fis, BipA, and quorum sensing (QS), specifically through the luxS
      system. QS activates expression of the LEE genes in EPEC, with QseA activating
      transcription of ler. Here we report that transcription of the LEE genes and type
      III secretion are diminished in both luxS and qseA mutants. Transcription of the
      LEE genes is affected in both mutants mostly during the mid-exponential phase of
      growth. Transcription of qseA itself is diminished throughout growth in a luxS
      mutant and is under autorepression. Furthermore, QS activation of type III
      secretion is independent of per, given that QseA still activates type III
      secretion in a per mutant strain. Both mutants are deficient in adherence to
      epithelial cells and form smaller microcolonies. Several factors may contribute
      to this abnormal behavior: transcription of LEE genes and type III secretion are
      diminished, and expression of flagella and Per is altered in both mutants. These
      results suggest that QS is involved in modulating the regulation of the EPEC
      virulence genes.

PMID- 15039360
TI  - Pathology affects different organs in two mouse strains chronically infected by a
      Trypanosoma cruzi clone: a model for genetic studies of Chagas' disease.
AB  - Chagas' disease is a chronic infection caused by Trypanosoma cruzi and represents
      an important public health burden in Latin America. Frequently the disease
      evolves undetectable for decades, while in a significant fraction of the affected
      individuals it culminates in death by heart failure. Here, we describe a novel
      murine model of the chronic infection with T. cruzi using a stable clone isolated
      from a human patient (Sylvio X10/4). The infection in the C3H/HePAS mouse strain
      progresses chronically and is mainly characterized by intense cardiac
      inflammatory lesions that recapitulate the chronic cardiac pathology observed in
      the human disease. Moderate striated muscle lesions are also present in C3H/HePAS
      mice. Viable parasites are detected and recovered from the chronic heart lesions
      of C3H/HePAS mice, supporting the current notion that development of heart
      pathology in Chagas' disease is related to parasite persistence in the inflamed
      tissue. By contrast, in infected A/J mice, chronic inflammatory lesions are
      targeted to the liver and the skeletal muscle, while pathology and parasites are
      undetectable in the heart. The phenotypic analysis of F(1) (A/J x C3H/HePAS) and
      F(2) (A/J x C3H/HePAS) mice suggests that the genetic predisposition to develop
      the inflammatory lesions caused by T. cruzi (Sylvio X10/4 clone) is heterogeneous
      because the heart and liver pathology segregate in the F(2) generation. These
      findings raise the hypothesis that the pathology heterogeneity observed in humans
      with Chagas' disease (absence and presence of cardiac or digestive chronic
      lesions) may be attributable to host genetic factors.

PMID- 15039359
TI  - Cytokine and inducible nitric oxide synthase mRNA expression during experimental
      murine cryptococcal meningoencephalitis.
AB  - The immune events that take place in the central nervous system (CNS) during
      cryptococcal infection are incompletely understood. We used competitive reverse
      transcription-PCR to delineate the time course of the local expression of mRNAs
      encoding a variety of cytokines and inducible nitric oxide synthase (iNOS) during
      progressive murine cryptococcal meningoencephalitis and assessed the CNS
      inflammatory response using immunohistochemistry. Interleukin 18 (IL-18),
      transforming growth factor beta1, and IL-12p(40) mRNAs were constitutively
      expressed in the brains of infected and uninfected mice; IL-2 mRNA was not
      detected at any time. Increased levels of transcripts corresponding to IL-1
      alpha, tumor necrosis factor alpha (TNF-alpha), and iNOS were detected as early
      as day 1 postinfection, with TNF-alpha rising by approximately 30-fold and iNOS
      increasing by approximately 5-fold by day 7. Each remained at these levels
      thereafter. IL-4, IL-6, and gamma interferon transcripts were detected on day 5,
      and IL-1 beta and IL-10 transcripts were detected beginning on day 7. Once
      detected, each remained at a relatively constant level through 28 days of
      infection. This cytokine profile does not suggest a polarized Th1 or Th2
      response. Immunohistochemistry did not reveal inflammatory infiltrates before day
      7, despite the presence of cryptococci. Intraparenchymal abscesses with
      inflammatory cells in their peripheries were found beginning on day 10. The
      infiltrates were comprised primarily of cells expressing CD4, CD8, or CD11b; low
      numbers of cells expressing CD45R/B220 were also present. The persistence of
      Cryptococcus observed in the CNS may result from an ineffective immune response,
      perhaps owing to an insufficient anticryptococcal effector function of endogenous
      glial cells resulting from competing pro- and anti-inflammatory cytokines. These
      data detail the immune response in the brain and could be important for the
      future design of specific immunomodulatory therapies for this important
      opportunistic infection.

PMID- 15039362
TI  - Absence of interleukin-4 determines less severe pulmonary paracoccidioidomycosis
      associated with impaired Th2 response.
AB  - Host resistance to paracoccidiodomycosis, the main deep mycosis in Latin America,
      is mainly due to cellular immunity and gamma interferon (IFN-gamma) production.
      To assess the role of interleukin-4 (IL-4), a Th2-inducing cytokine, pulmonary
      paracoccidioidomycosis was studied in IL-4-deficient (IL-4(-/-)) and wild-type
      (WT) C57BL/6 mice at the innate and acquired phases of immune response. Forty
      eight hours after infection, equivalent numbers of viable Paracoccidioides
      brasiliensis yeast cells were recovered from the lungs of IL-4(-/-) and WT mice
      intratracheally infected with one million fungal cells. Alveolar macrophages from
      infected IL-4(-/-) mice controlled in vitro fungal growth more efficiently than
      macrophages from WT mice and secreted higher levels of nitric oxide. Compared
      with WT mice, IL-4(-/-) animals presented increased levels of pulmonary IFN-gamma
      and augmented polymorphonuclear leukocyte influx to the lungs. Decreased
      pulmonary fungal loads were characterized in deficient mice at week 2
      postinfection, concomitant with diminished presence of IL-10. At week 8, lower
      numbers of yeasts were recovered from lungs and liver of IL-4(-/-) mice
      associated with increased production of IFN-gamma but impaired synthesis of IL-5
      and IL-10. However, a clear shift to a Th1 pattern was not characterized, since
      IL-4(-/-) mice did not alter delayed-type hypersensitivity anergy or IL-2 levels.
      In addition, IL-4 deficiency resulted in significantly reduced levels of
      pulmonary IL-12, granulocyte-macrophage colony-stimulating factor, IL-3, monocyte
      chemotactic protein 1, and specific antibody isotypes. In IL-4(-/-) mice, well
      organized granulomas restraining fungal cells replaced the more extensive lesions
      containing high numbers of fungi and inflammatory leukocytes developed by IL-4
      sufficient mice. These results clearly showed that genetically determined
      deficiency of IL-4 can exert a protective role in pulmonary
      paracoccidioidomycosis.

PMID- 15039363
TI  - The hydrophobic domain of the Mycobacterial Erp protein is not essential for the
      virulence of Mycobacterium tuberculosis.
AB  - Erp (exported repetitive protein) is a member of a mycobacterium-specific family
      of extracellular proteins. A hydrophobic region that is localized at the C
      terminal domain and that represents a quarter of the protein is highly conserved
      across species. Here we show that this hydrophobic region is not essential for
      restoring the virulence and tissue damage of an erp::aph mutant strain of M.
      tuberculosis as assessed by bacterial counts and lung histology analysis in a
      mouse model of tuberculosis.

PMID- 15039361
TI  - Genes of Helicobacter pylori regulated by attachment to AGS cells.
AB  - Reciprocal interactions between Helicobacter pylori and cells of the gastric
      epithelium to which it adheres may affect colonization. Changes in gene
      expression of H. pylori induced by adhesion to AGS gastric cancer cells by
      coculture were compared to changes in gene expression of H. pylori cultured
      without AGS cells by using cDNA filter macroarrays. Adhesion was quantitatively
      verified by confocal microscopy of green fluorescent protein-expressing bacteria.
      Four experiments showed that 22 and 21 H. pylori genes were consistently up- and
      down-regulated, respectively. The up-regulated genes included pathogenicity
      island, motility, outer membrane protein, and translational genes. The sigma(28)
      factor antagonist flgM, flgG, the stress response gene, flaA, omp11, and the
      superoxide dismutase gene (sodB) were down-regulated. The up-regulation of cag3,
      flgB, tonB, rho, and deaD was confirmed by quantitative PCR, and the up
      regulation of lpxD, omp6, secG, fabH, HP1285, HP0222, and HP0836 was confirmed by
      reverse transcription (RT)-PCR. The down-regulation of flaA, sodB, and HP0874 was
      confirmed by quantitative PCR, and the down-regulation of omp11 was confirmed by
      RT-PCR. The alteration of gene expression in H. pylori after adhesion to gastric
      cells in vitro suggests that changes in motility, outer membrane composition, and
      stress responses, among other changes, may be involved in gastric colonization.

PMID- 15039364
TI  - Helicobacter pylori-mediated gastritis induces local downregulation of secretory
      leukocyte protease inhibitor in the antrum.
AB  - Helicobacter pylori-infected subjects exhibited a strong decline in antral
      secretory leukocyte protease inhibitor (SLPI) levels compared to H. pylori
      negative subjects and subjects from whom H. pylori had been eradicated (P =
      0.002). This reduction was specific for the antrum, whereas SLPI expression in
      corpus and duodenum was not affected. Antral SLPI levels were inversely
      correlated with inflammatory scores of antrum-predominant gastritis.

PMID- 15039365
TI  - Tec1p-independent activation of a hypha-associated Candida albicans virulence
      gene during infection.
AB  - The Tec1p transcription factor is involved in the expression of hypha-specific
      genes in Candida albicans. Although the induction of the hypha-associated SAP5
      gene by serum in vitro depends on Tec1p, deletion of all Tec1p binding site
      consensus sequences from the SAP5 promoter did not affect its activation. In two
      different animal models of candidiasis, the SAP5 promoter was induced even in a
      Deltatec1 deletion mutant, demonstrating that the requirement for Tec1p in gene
      expression in C. albicans depends on the environmental conditions within the
      host.

PMID- 15039366
TI  - SKN7 of Candida albicans: mutant construction and phenotype analysis.
AB  - The SKN7 two-component response regulator gene of Candida albicans was deleted,
      and the phenotype of the mutant was established. This mutant exhibited impaired
      growth on Spider agar and 10% serum agar compared to wild-type and gene
      reconstituted strains. The skn7 mutant was sensitive to H(2)O(2) in vitro, but
      its virulence was only mildly attenuated. A comparison of the Skn7p and Ssk1p
      response regulators of C. albicans is discussed.

PMID- 15039367
TI  - Genetic control of natural resistance of mouse macrophages to Coxiella burnetii
      infection in vitro: macrophages from restrictive strains control parasitophorous
      vacuole maturation.
AB  - Macrophages from A/J and BALB/c mice were more susceptible to Coxiella burnetii
      phase II infection than were those from C57BL/6, C57BL/10, B10.A, C3H/HePas, and
      Swiss mice. Resistant macrophages effectively controlled the development of large
      replication vacuoles (LRVs), which accounted for the restriction of bacterial
      multiplication within the cultures. However, compared to fibroblasts, all
      macrophages controlled bacterial multiplication within LRVs.

PMID- 15039368
TI  - MyD88-deficient mice display a profound loss in resistance to Mycobacterium
      tuberculosis associated with partially impaired Th1 cytokine and nitric oxide
      synthase 2 expression.
AB  - Mycobacterium tuberculosis possesses agonists for several Toll-like receptors
      (TLRs), yet mice with single TLR deletions are resistant to acute tuberculosis.
      MyD88(-/-) mice were used to examine whether TLRs play any role in protection
      against aerogenic M. tuberculosis H37Rv infection. MyD88(-/-) mice failed to
      control mycobacterial replication and rapidly succumbed. Moreover, expressions of
      interleukin 12, tumor necrosis factor alpha, gamma interferon, and nitric oxide
      synthase 2 were markedly decreased in the knockout animals. These results argue
      that resistance to M. tuberculosis must depend on MyD88-dependent signals
      mediated by an as-yet-undetermined TLR or a combination of TLRs.

PMID- 15039369
TI  - Spatiotemporal analysis of acid adaptation-mediated Vibrio cholerae
      hyperinfectivity.
AB  - Acid adaptation has previously been shown to increase the infectivity of Vibrio
      cholerae in the infant mouse model. To better understand this phenomenon, we
      monitored the spatial distribution and temporal changes in the ratios of acid
      adapted cells to unadapted V. cholerae cells in the small intestine, as well as
      the timing of virulence factor expression. We found that the competitive
      advantage afforded by acid adaptation does not become manifest until greater than
      3 h postinfection; thus, acid adaptation does not increase V. cholerae passage
      through the gastric acid barrier. Additionally, acid-adapted and unadapted V.
      cholerae cells colonize the same sections of the small intestine and show similar
      kinetics of transcriptional induction of the virulence genes tcpA and ctxA. These
      studies suggest that the increased infectivity of acid-adapted V. cholerae is due
      to a more rapid onset of multiplication and/or to an increased multiplication
      rate within the infant mouse intestine.

PMID- 15039370
TI  - Porphyromonas gingivalis-specific immunoglobulin G prevents P. gingivalis
      elicited oral bone loss in a murine model.
AB  - Active immunization with Porphyromonas gingivalis whole-cell preparations has
      been shown to prevent P. gingivalis infection and oral bone loss. Employing
      passive antibody transfer and opsonization, we demonstrate with this study that
      immunization-elicited P. gingivalis-specific immunoglobulin G facilitates
      clearance of P. gingivalis in a subcutaneous chamber model and prevents P.
      gingivalis-elicited oral bone loss.

PMID- 15039372
TI  - Glyceraldehyde-3-phosphate dehydrogenase of Streptococcus pneumoniae is a surface
      displayed plasminogen-binding protein.
AB  - The recruitment of plasminogen endows the bacterial cell surface of Streptococcus
      pneumoniae with proteolytic activity. In this study we demonstrate specific
      plasmin- and plasminogen-binding activity for the glycolytic enzyme
      glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which is located in the
      cytoplasm as well as on the surface of pneumococci. GAPDH exhibits a high
      affinity for plasmin and a significantly lower affinity for plasminogen.

PMID- 15039371
TI  - HLA-A2-restricted CD8+-cytotoxic-T-cell responses to novel epitopes in
      Mycobacterium tuberculosis superoxide dismutase, alanine dehydrogenase, and
      glutamine synthetase.
AB  - Major histocompatibility complex class I-restricted CD8(+) cytotoxic T
      lymphocytes (CTL) are implicated in protective Th1 immunity to Mycobacterium
      tuberculosis infection. We report the identification of three novel HLA-A*0201
      restricted CTL epitopes within mycobacterial superoxide dismutase (SodA), L
      alanine dehydrogenase (AlaDH), and L-glutamine synthetase (GlnS) proteins.

PMID- 15039373
TI  - Effect of growth state on transcription levels of genes encoding major secreted
      antigens of Mycobacterium tuberculosis in the mouse lung.
AB  - Arrest of the multiplication of Mycobacterium tuberculosis caused by expression
      of adaptive immunity in mouse lung was accompanied by a 10- to 20-fold decrease
      in levels of mRNAs encoding the secreted Ag85 complex and 38-kDa lipoprotein.
      esat-6 mRNA levels were high throughout infection. The data imply that
      multiplying and nonreplicating tubercle bacilli have different antigen
      compositions.

PMID- 15039376
TI  - Protein serine/threonine kinase StkP positively controls virulence and competence
      in Streptococcus pneumoniae.
AB  - In the Streptococcus pneumoniae genome, stkP, encoding a membrane-associated
      serine/threonine kinase, is not redundant (L. Novakova, S. Romao, J. Echenique,
      P. Branny, and M.-C. Trombe, unpublished results). The data presented here
      demonstrate that StkP belongs to the signaling network involved in competence
      triggering in vitro and lung infection and bloodstream invasion in vivo. In
      competence, functional StkP is required for activation of comCDE upstream of the
      autoregulated ring orchestrated by the competence-stimulating peptide. This is
      the first description of positive regulation of comCDE transcription in balance
      with its repression by CiaRH.

PMID- 15039375
TI  - Different responses of macrophages to smooth and rough Brucella spp.:
      relationship to virulence.
AB  - By comparing smooth wild-type Brucella strains to their rough mutants, we show
      that the lipopolysaccharide (LPS) O side chain of pathogenic Brucella has a
      dramatic impact on macrophage activation. It favors the development of virulent
      Brucella by preventing the synthesis of immune mediators, important for host
      defense. We conclude that this O chain property is firmly linked to Brucella
      virulence.

PMID- 15039374
TI  - Neutralization of interleukin-10 significantly enhances gamma interferon
      expression in peripheral blood by stimulation with Johnin purified protein
      derivative and by infection with Mycobacterium avium subsp. paratuberculosis in
      experimentally infected cattle with paratuberculosis.
AB  - Monoclonal antibody neutralization of interleukin-10 (IL-10) increased Johnin
      purified protein derivative-induced whole-blood gamma interferon (IFN-gamma)
      secretion 23-fold and also increased IFN-gamma secretion ninefold following in
      vitro Mycobacterium avium subsp. paratuberculosis infection of peripheral blood
      mononuclear cells. These results demonstrate the suppressive effect of IL-10 on
      immune responses to M. avium subsp. paratuberculosis infection in cattle.

PMID- 15039378
TI  - Adaptation of diverse lyme disease spirochetes in a natural rodent reservoir
      host.
AB  - We compared the relative reservoir competence of European wood mice for two
      genospecies of Lyme disease spirochetes by analyzing susceptibility, intrinsic
      incubation period, and degree and duration of infectivity. Borrelia afzelii,
      specializing in particular reservoir hosts, is better adapted to those hosts than
      is the more generalist genospecies B. burgdorferi sensu stricto.

PMID- 15039377
TI  - Yersinia pseudotuberculosis anti-inflammatory components reduce trinitrobenzene
      sulfonic acid-induced colitis in the mouse.
AB  - Rectal instillation of trinitrobenzene sulfonic acid (TNBS) induces acute colitis
      in the mouse. We tested the efficacy of Yersinia pseudotuberculosis anti
      inflammatory components in preventing TNBS-triggered colitis. Animals were orally
      inoculated with virulence-attenuated Yersinia cells (a phoP mutant) prior to TNBS
      administration. Under these experimental conditions, colonic lesions and tumor
      necrosis factor alpha mRNA levels were significantly reduced.

PMID- 15039380
TI  - Salmonella flagellin is not a dominant protective antigen in oral immunization
      with attenuated live vaccine strains.
AB  - We found that oral immunization with flagellum-defective mutant strains of
      Salmonella enterica serovar Typhimurium with the ClpXP-deficient background
      protected mice against oral challenge with the virulent strain. These data
      indicate that Salmonella flagellin is not a dominant protective antigen in oral
      immunization with attenuated live vaccine strains.

PMID- 15039379
TI  - Enterococcal aggregation substance and binding substance are not major
      contributors to urinary tract colonization by Enterococcus faecalis in a mouse
      model of ascending unobstructed urinary tract infection.
AB  - Isogenic Enterococcus faecalis strains that differ in their expression of
      aggregation substance (AS) and its cognate receptor, enterococcal binding
      substance (EBS), were compared for urovirulence in mice. Strain OG1SSp/pCF500
      (inducible AS(+), constitutive EBS(+)) failed to outcompete isogenic derivative
      INY3000 (AS(-) EBS(-)) in the urine, bladders, or kidneys of mice harvested at 48
      h postinoculation. Neither mouse nor human urine induced AS expression by
      OG1SSp/pCF500. Recombinant strain OG1SSp/pINY1801 (constitutive AS(+), EBS(+))
      exhibited plasmid segregation that was as extensive in vivo as in vitro. These
      data suggest that AS and EBS do not contribute to upper or lower urinary tract
      colonization by E. faecalis and that growth in urine does not induce AS
      expression by strains carrying plasmids in the pCF10 family.

PMID- 15039381
TI  - A deep-rough mutant of Campylobacter jejuni 81-176 is noninvasive for intestinal
      epithelial cells.
AB  - A waaF mutant of Campylobacter jejuni 81-176 showed decreased invasion of INT407
      cells in vitro and increased sensitivity to some antibiotics compared to what was
      seen with the wild-type strain.

PMID- 15039382
TI  - Rectification of age-related impairment in Ig gene hypermutation during a memory
      response.
AB  - The deficiency in generating high-affinity antibodies due to impaired somatic
      hypermutation of Ig genes in the germinal center (GC) is considered the major
      mechanism responsible for the compromised humoral responses in aging. Since the
      intrinsic capability of aged B lymphocytes to respond to initial antigenic
      stimuli is largely intact and the expression of activation-induced cytidine
      deaminase, a key component required for Ig somatic hypermutation, is comparable
      between B cells from aged and young mice, it is possible to restore the age
      related deficiency in the humoral response by circumventing the requirement for
      signals from other immune components. Here, we show that GC B cells from aged
      mice during a memory response carried mutated Ig genes with mutational
      frequencies comparable to that of GC B cells from young mice. Additionally,
      characterization of mutations in VDJ segments, and analysis of antibody-forming
      cells and antibodies demonstrated that the processes of antigen-driven clonal
      selection and affinity maturation are largely intact in aged animals. Thus, we
      conclude that the diminished antibody responses in aged animals may be
      significantly improved by repeated immunizations. These findings may have
      important implications in designing vaccines and immunization protocols for the
      elderly population and patients with certain immune deficiencies such as AIDS.

PMID- 15039383
TI  - Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR
      (CD155) and nectin-2 (PRR-2/CD112).
AB  - CD226 (DNAM-1) is an adhesion molecule involved in NK and T cell-mediated
      cytotoxicity against certain tumors. Here, we have identified the human
      poliovirus receptor-related (PRR) family members CD155 [poliovirus receptor
      (PVR)] and CD112 (nectin-2/PRR-2) as the ligands for human CD226. Ectopic
      expression of human CD155 and/or CD112 rendered mouse BW5147 T cells more
      susceptible to IL-2-activated T and NK cell-mediated cytotoxicity, and killing
      was specifically inhibited by anti-CD226 mAb, demonstrating functional
      interactions of CD226 with CD155 and CD112. Although the binding affinities
      between soluble CD226 and CD155 or CD112 were comparable, the homophilic
      interaction of cell-surface CD112 may adversely affect CD226 binding to CD112. We
      also demonstrate that ligation of CD226 and LFA-1 with their respective ligands
      cooperates in triggering cytotoxicity and cytokine secretion by T and NK cells.

PMID- 15039385
TI  - Staggered AID-dependent DNA double strand breaks are the predominant DNA lesions
      targeted to S mu in Ig class switch recombination.
AB  - Class switch recombination (CSR) is the process whereby B cells alter the
      effector properties of their Ig molecules. Whilst much is known about the
      cellular regulation of this process, many of the molecular details remain
      elusive. Recent evidence suggests that CSR involves blunt DNA double strand
      breaks (dsbs), and that formation of these dsbs requires the function of the
      activation-induced cytidine deaminase (AID). We sought to characterize the
      structural properties and kinetics of induction of the DNA lesions associated
      with CSR. Using ligation-mediated PCR, we found that AID-dependent DNA dsbs were
      specifically induced in the S mu region of murine B cells stimulated to undergo
      CSR. While blunt dsbs were detected, they were only a minor species, with
      staggered breaks being more than an order of magnitude more abundant. In
      addition, these breaks could be detected at equal frequency at upstream and
      downstream portions of S mu, and were induced prior to expression of newly
      switched isotypes. Collectively, these results provide direct evidence that
      staggered, S mu-targeted AID-dependent dsbs are the predominant DNA lesion
      associated with CSR, with important implications for the mechanisms by which CSR
      DNA lesions are made and processed.

PMID- 15039384
TI  - Tyrosine-mediated inhibitory signals contribute to CTLA-4 function in vivo.
AB  - The ability of CTLA-4 to inhibit T cell activation may be either negatively or
      positively regulated by a critical tyrosine at position 201 (Y201) within the
      CTLA-4 cytoplasmic domain. By binding to the clathrin-associated adaptor complex
      AP-2 and inducing endocytosis, Y201 reduces the amount of CTLA-4 on the cell
      surface, thereby down-regulating CTLA-4 inhibitory function. Alternatively, Y201
      may function to transmit CTLA-4 inhibitory signals, perhaps through binding to
      intracellular proteins that oppose TCR- and/or CD28-induced signal transduction.
      Results from studies performed in vitro have cast doubt on whether this second
      mechanism contributes significantly to CTLA-4 function. In order to determine if
      a role existed for Y201 in mediating CTLA-4 inhibitory signaling in vivo, we
      studied lymphocyte activation and homeostasis in CTLA-4(-/-) mice that were
      reconstituted with a transgenic CTLA-4 receptor in which Y201 was mutated to
      valine (Y201V/CTLA-4(-/-)). We found that despite augmented levels of CTLA-4 on
      the cell surface of T cells, Y201V/CTLA-4(-/-) mice developed a
      lymphoproliferative syndrome characterized by lymphadenopathy and the
      accumulation of T cells that secreted IL-4. Mutant T cells exhibited increased
      cell division when treated with suboptimal doses of mitogenic stimuli in vitro.
      These results demonstrate that in addition to down-modulating CTLA-4 expression
      on the cell surface of T cells, the Y201 residue also functions to transmit CTLA
      4 inhibitory signals in vivo. Elucidating the biochemical pathways downstream of
      Y201 will be important for a full understanding of the molecular basis for CTLA-4
      function.

PMID- 15039386
TI  - Anti-MOG autoantibodies in Italian multiple sclerosis patients: specificity,
      sensitivity and clinical association.
AB  - There is considerable evidence that multiple sclerosis (MS) is an immune-mediated
      disease characterized by infiltration of inflammatory cells into the CNS and
      demyelination. Several myelin proteins may be encephalitogenic, including myelin
      basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein (MOG),
      the latter being expressed on the external layer of myelin sheaths and hence
      accessible to antibody attack. We investigated MOG autoreactivity in serum and
      cerebrospinal fluid (CSF) by ELISA, employing the recombinant extracellular
      domain of MOG as antigen. We tested serum samples from 262 MS patients (175
      relapsing-remitting, 43 primary progressive and 44 secondary progressive), 131
      patients with other neurological diseases (OND) and 307 healthy controls. No
      patients or controls were receiving immunomodulating treatments. We found anti
      MOG antibodies in the serum of 13.7% MS patients, mainly in those with secondary
      progressive MS (25%), in 13.7% of OND patients and in 6.2% of controls. We found
      a direct correlation (R(2) = 0.6, P = 0.002) between disease severity and anti
      MOG titer only in patients with primary and secondary progressive MS. Anti-MOG
      antibodies were present in the CSF of 11.4% MS patients and 18.9% OND patients.
      Intrathecal synthesis of anti-MOG antibodies was demonstrated in four (4.5%) of
      MS patients and no OND patients. Anti-MOG antibodies are not specific for MS;
      however, they may characterize a subset of MS patients and this may be revealed
      by serial assays in relation to changing disease phase.

PMID- 15039387
TI  - In vitro hematopoiesis produces a distinct class of immature dendritic cells from
      spleen progenitors with limited T cell stimulation capacity.
AB  - The study of dendritic cells (DC) has been hampered by the difficulty of
      isolating rare cells for analysis of their phenotype and function. Interpretation
      of the DC lineage has been largely influenced by studies on cell populations
      which can be readily isolated and amplified in the presence of cytokines. Long
      term cultures (LTC) from murine spleen have been shown to support continuous in
      vitro hematopoiesis of DC dependent on interaction with a stromal cell monolayer.
      LTC-DC represent a single, stable class of DC derived by constant turnover of
      spleen DC progenitors maintained within stroma. They represent a resident DC
      population in spleen. The functional characteristics of LTC-DC have been studied
      in terms of capacity to stimulate T cells and response to activation by
      environmental stimuli. LTC-DC have many morphological, phenotypic and functional
      properties reflecting an immature or partially mature, marginal zone-like CD4(
      )CD8(-) splenic DC subset. They are highly endocytic and can process and present
      protein antigen to naive hen egg lysozyme (HEL)-specific MHC-II-restricted TCR-Tg
      CD4(+) T cells. They do not, however, induce T cell proliferation in a mixed
      lymphocyte reaction. LTC-DC do not respond in a typical fashion to common DC
      activators like LPS and CD40L. They upregulate MHC-I and CD80/CD86 but not MHC-II
      and CD40. They reflect an endogenous, immature DC subset in spleen with
      properties distinct from immature DC located in peripheral tissues.

PMID- 15039388
TI  - Expression of HLA-G in inflammatory bowel disease provides a potential way to
      distinguish between ulcerative colitis and Crohn's disease.
AB  - In addition to being involved in nutrient uptake, the epithelial mucosa
      constitute the first line of defense against microbial pathogens. A direct
      consequence of this physiological function is a very complex network of
      immunological interactions that lead to a strong control of the mucosal immune
      balance. The dysfunction of immunological tolerance is likely to be a cause of
      inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease
      (CD). HLA-G is a non-classical major histocompatibility complex (HLA) class I
      molecule, which is highly expressed by human cytotrophoblast cells. These cells
      play a role in immune tolerance by protecting trophoblasts from being killed by
      uterine NK cells. Because of the deregulation of immune system activity in IBD,
      as well as the immunoregulatory role of HLA-G, we have analyzed the expression of
      HLA-G in intestinal biopsies of patients with UC and CD. Our study shows that the
      differential expression of HLA-G provides a potential way to distinguish between
      UC and CD. Although the reason for this differential expression is unclear, it
      might involve a different mechanism of immune regulation. In addition, we
      demonstrate that in the lamina propria of the colon of patients with UC, IL-10 is
      strongly expressed. In conclusion, the presence of HLA-G on the surface of
      intestinal epithelial cell in patients with UC lends support to the notion that
      this molecule may serve as a regulator of mucosal immune responses to antigens of
      undefined origin. Thus, this different pattern of HLA-G expression may help to
      differentiate between the immunopathogenesis of CD and UC.

PMID- 15039390
TI  - DNA vaccination with gp96-peptide fusion proteins induces protection against an
      intracellular bacterial pathogen.
AB  - Effective vaccination using in vitro peptide-loaded heat-shock proteins (HSP),
      tumor-derived HSP and HSP fusion proteins has been shown in viral, parasite and
      tumor model systems. We demonstrate protective DNA vaccination using gp96-peptide
      fusion proteins against the intracellular bacterial pathogen Listeria
      monocytogenes in a mouse model. In contrast to previous studies using pathogen
      derived HSP as vaccine vehicles, we used recombinant endogenous (Mus musculus)
      gp96 (GRP94) as a carrier for immunodominant listerial peptides. Analyses of the
      cellular immune response revealed profound epitope-specific IFN-gamma and
      cytotoxic T cell responses. Our findings suggest a predominantly MHC I-restricted
      T cell response to DNA vaccination with gp96 fusion proteins in the model
      employed. Most importantly, DNA vaccination induced protection against an
      otherwise lethal dose of L. monocytogenes.

PMID- 15039389
TI  - Helminth infection modulates the development of allergen-induced airway
      inflammation.
AB  - It has been proposed that infections with helminths can protect from the
      development of allergic diseases. However, epidemiological and experimental
      studies have yielded conflicting results. Therefore we investigated if an
      infection with Nippostrongylus brasiliensis influenced the development of
      allergen-induced Th2 cell responses in mice. We found a decrease in allergen
      induced airway eosinophilia and Eotaxin levels in the airways when mice were
      infected with the helminths 8 weeks, and especially 4 weeks, but not 1 or 2 weeks
      before ovalbumin (OVA)-airway challenge. While OVA-specific IgG1 and IgE serum
      levels and cutaneous hypersensitivity reactions were not reduced by the helminth
      infection, there was a reduction in OVA-specific IgG1 and IgE levels in
      bronchoalveolar lavage fluid of mice. Suppression of allergen-induced airway
      eosinophilia and reduction of Eotaxin production was not observed in IL-10
      deficient mice. In addition, we found that helminth-induced airway eosinophilia
      and Eotaxin production was strongly increased in IL-10 deficient mice infected
      with the helminths in comparison to control mice. Taken together, these results
      show that infection with N. brasiliensis suppresses the development of allergen
      induced airway eosinophilia and that this effect may be mediated by IL-10. Our
      results support the view that helminth infections can contribute to the
      suppression of allergies in humans.

PMID- 15039391
TI  - Mouse IgA inhibits cell growth by stimulating tumor necrosis factor-alpha
      production and apoptosis of macrophage cell lines.
AB  - Potent Fcalpha-mediated actions of IgA have previously been shown for myeloid
      cells from man, but much less is known in relation to murine cells. Here, we
      report that mouse monoclonal IgA, irrespective of their antigenic specificity,
      inhibit the proliferation of mouse macrophage cell lines. The anti-proliferative
      activity was manifested by both monomeric and polymeric mouse IgA, but not by
      mouse monoclonal IgG and IgM. Growth of J774 cells was significantly inhibited
      during the 4-8 days of logarithmic growth, followed by a subsequent recovery of
      cell numbers prior to the stationary phase. We demonstrated that IgA binds to
      J774 cells, stimulates tumor necrosis factor (TNF)-alpha production and induces
      apoptosis which is not dependent on NO or FAS/CD95. We also demonstrated that
      IgA, in synergy with IFN-gamma, induced TNF-alpha production and apoptosis of
      thioglycollate-elicited mouse peritoneal macrophages. Thus, the in vitro actions
      of IgA described may also play a regulatory role for mouse macrophages in vivo.

PMID- 15039393
TI  - A piece of my mind. Diner on commercial street.

PMID- 15039392
TI  - Immune modulation with high-dose heat-shock protein gp96: therapy of murine
      autoimmune diabetes and encephalomyelitis.
AB  - Immunization with heat-shock protein (HSP) gp96 elicits protective immunity to
      the cancer or virus-infected cells from which it is derived. Low doses of gp96
      generate immunity, while doses 10 times the immunizing dose do not. We show here
      that injection of high doses of gp96 generates CD4(+) T cells that down-regulate
      a variety of ongoing immune responses. Immunization with high doses of gp96
      prevents myelin basic protein- or proteolipid protein-induced autoimmune
      encephalomyelitis in SJL mice and the onset of diabetes in non-obese diabetic
      mice. The suppression of immune response can be adoptively transferred with
      CD4(+) cells and does not partition with the CD25 phenotype. The immunomodulatory
      properties of gp96 (and possibly other HSP) may be used for antigen-specific
      activation or suppression of cellular immune responses. The latter may form the
      basis for novel immunotherapies for autoimmune diseases.

PMID- 15039394
TI  - Agencies prepare worst-case flu vaccine.

PMID- 15039396
TI  - Researchers identify protein that helps tumor cells resist cancer drugs.

PMID- 15039395
TI  - Researchers report findings on HIV drug resistance, new infections.

PMID- 15039403
TI  - Intra-articular hyaluronic acid for treatment of osteoarthritis of the knee.

PMID- 15039404
TI  - Intra-articular hyaluronic acid for treatment of osteoarthritis of the knee.

PMID- 15039405
TI  - Cost-effectiveness of screening for proteinuria.

PMID- 15039406
TI  - Etiology of the metabolic syndrome.

PMID- 15039407
TI  - Etiology of the metabolic syndrome.

PMID- 15039408
TI  - Screening of newborns for metabolic disorders with mass spectrometry.

PMID- 15039409
TI  - Synthetic thyroxine vs dessicated thyroid.

PMID- 15039410
TI  - Memories of loved ones about care at the end of life.

PMID- 15039411
TI  - Effect of hysterectomy vs medical treatment on health-related quality of life and
      sexual functioning: the medicine or surgery (Ms) randomized trial.
AB  - CONTEXT: Although a quarter of US women undergo elective hysterectomy before
      menopause, controlled trials that evaluate the benefits and harms are lacking.
      OBJECTIVE: To compare the effect of hysterectomy vs expanded medical treatment on
      health-related quality of life. DESIGN, SETTING, AND PARTICIPANTS: A multicenter,
      randomized controlled trial (August 1997-December 2000) of 63 premenopausal
      women, aged 30 to 50 years, with abnormal uterine bleeding for a median of 4
      years who were dissatisfied with medical treatments, including
      medroxyprogesterone acetate. The participants, who were patients at gynecology
      clinics and affiliated practices of 4 US academic medical centers, were followed
      up for 2 years. INTERVENTIONS: Participants were randomly assigned to undergo
      hysterectomy or expanded medical treatment with estrogen and/or progesterone
      and/or a prostaglandin synthetase inhibitor. The hysterectomy route and medical
      regimen were determined by the participating gynecologist. MAIN OUTCOME MEASURES:
      The primary outcome was mental health measured by the Mental Component Summary
      (MCS) of the 36-Item Short-Form Health Survey (SF-36). Secondary outcomes
      included physical health measured by the Physical Component Summary (PCS),
      symptom resolution and satisfaction, body image, and sexual functioning, as well
      as other aspects of mental health and general health perceptions. RESULTS: At 6
      months, women in the hysterectomy group had greater improvement in MCS scores
      than women in the medicine group (8 vs 2, P =.04). They also had greater
      improvement in symptom resolution (75 vs 29, P<.001), symptom satisfaction (44 vs
      7, P<.001), interference with sex (41 vs 22, P =.003), sexual desire (21 vs 3, P
      =.01), health distress (33 vs 13, P =.009), sleep problems (13 vs 1, P =.03),
      overall health (12 vs 2, P =.006), and satisfaction with health (31 vs 14, P
      =.01). By the end of the study, 17 (53%) of the women in the medicine group had
      requested and received hysterectomy, and these women reported improvements in
      quality-of-life outcomes during the 2 years that were similar to those reported
      by women randomized to the hysterectomy group. Women who continued medical
      treatment also reported some improvements (P<.001 for within-group change in many
      outcomes), with the result that most differences between randomized groups at the
      end of the study were no longer statistically significant in the intention-to
      treat analysis. CONCLUSIONS: Among women with abnormal uterine bleeding and
      dissatisfaction with medroxyprogesterone, hysterectomy was superior to expanded
      medical treatment for improving health-related quality-of-life after 6 months.
      With longer follow-up, half the women randomized to medicine elected to undergo
      hysterectomy, with similar and lasting quality-of-life improvements; those who
      continued medical treatment also reported some improvements.

PMID- 15039412
TI  - Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system
      or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up.
AB  - CONTEXT: Because menorrhagia is often a reason for seeking medical attention, it
      is important to consider outcomes and costs associated with alternative treatment
      modalities. Both the levonorgestrel-releasing intrauterine system (LNG-IUS) and
      hysterectomy have proven effective for treatment of menorrhagia but there are no
      long-term comparative studies measuring cost and quality of life. OBJECTIVE: To
      compare outcomes, quality-of-life issues, and costs of the LNG-IUS vs
      hysterectomy in the treatment of menorrhagia. DESIGN, SETTING, AND PARTICIPANTS:
      Randomized controlled trial conducted between October 1, 1994, and October 6,
      2002, and enrolling 236 women (mean [SD] age, 43 [3.4] years) referred to 5
      university hospitals in Finland for complaints of menorrhagia. INTERVENTIONS:
      Participants were randomly assigned to treatment with the LNG-IUS (n = 119) or
      hysterectomy (n = 117) and were monitored for 5 years. MAIN OUTCOME MEASURES:
      Health-related quality of life (HRQL) as measured by the 5-Dimensional EuroQol
      and the RAND 36-Item Short-Form Health Survey, other measures of psychosocial
      well-being (anxiety, depression, and sexual function), and costs. RESULTS: After
      5 years of follow-up, 232 women (99%) were analyzed for the primary outcomes. The
      2 groups did not differ substantially in terms of HRQL or psychosocial well
      being. Although 50 (42%) of the women assigned to the LNG-IUS group eventually
      underwent hysterectomy, the discounted direct and indirect costs in the LNG-IUS
      group (2817 dollars [95% confidence interval, 2222 dollars-3530 dollars] per
      participant) remained substantially lower than in the hysterectomy group (4660
      dollars [95% confidence interval, 4014 dollars-5180 dollars]). Satisfaction with
      treatment was similar in both groups. CONCLUSIONS: By providing improvement in
      HRQL at relatively low cost, the LNG-IUS may offer a wider availability of
      choices for the patient and may decrease costs due to interventions involving
      surgery.

PMID- 15039413
TI  - Cognitive behavior therapy for hypochondriasis: a randomized controlled trial.
AB  - CONTEXT: Hypochondriasis is a chronic, distressing, and disabling condition that
      is prevalent in ambulatory medical practice. Until recently, no specific
      treatment has been clearly demonstrated to be effective. OBJECTIVE: To assess the
      efficacy of a cognitive behavior therapy (CBT) for hypochondriasis. DESIGN: A
      randomized, usual care control group design, conducted between September 1997 and
      November 2001. The individual primary care physician was the unit of
      randomization, and all patients clustered within each physician's practice were
      assigned to the experimental treatment (individual CBT and a consultation letter
      to the primary care physician) or to the control condition. Subjects were
      assessed immediately before and 6 and 12 months after the completion of
      treatment. SETTING AND PARTICIPANTS: Participants were 80 patients from primary
      care practices and 107 volunteers responding to public announcements, all of whom
      exceeded a predetermined cutoff score on a hypochondriasis self-report
      questionnaire on 2 successive occasions. INTERVENTION: A scripted, 6-session,
      individual CBT intervention was compared with medical care as usual. The CBT was
      accompanied by a consultation letter sent to the patient's primary care
      physician. MAIN OUTCOME MEASURES: Hypochondriacal beliefs, fears, attitudes, and
      somatic symptoms; role function and impairment. RESULTS: A total of 102
      individuals were assigned to CBT and 85 were assigned to medical care as usual.
      The sociodemographic and clinical characteristics of the 2 groups were similar at
      baseline. Using an intent-to-treat analytic strategy, a consistent pattern of
      statistically and clinically significant treatment effects was found at both 6-
      and 12-month follow-up, adjusting for baseline covariates that included
      educational level, generalized psychiatric distress, and participant status
      (patient vs volunteer). At 12-month follow-up, CBT patients had significantly
      lower levels of hypochondriacal symptoms, beliefs, and attitudes (P<.001) and
      health-related anxiety (P =.009). They also had significantly less impairment of
      social role functioning (P =.05) and intermediate activities of daily living
      (P<.001). Hypochondriacal somatic symptoms were not improved significantly by
      treatment. CONCLUSION: This brief, individual CBT intervention, developed
      specifically to alter hypochondriacal thinking and restructure hypochondriacal
      beliefs, appears to have significant beneficial long-term effects on the symptoms
      of hypochondriasis.

PMID- 15039414
TI  - Human rights abuses and concerns about women's health and human rights in
      southern Iraq.
AB  - CONTEXT: Although human rights abuses have been reported in Iraq, the full scope
      of these abuses has not been well documented. OBJECTIVE: To assess the prevalence
      of human rights abuses since 1991 in southern Iraq, along with attitudes about
      women's health and human rights and women's rights and roles in society, to
      inform reconstruction and humanitarian assistance efforts in Iraq. DESIGN: Cross
      sectional, randomized survey of Iraqi men and women conducted in July 2003 using
      structured questionnaires. SETTING: Three major cities in 3 of the 9 governorates
      in southern Iraq. PARTICIPANTS: A total of 1991 respondents representing 16 520
      household members. MAIN OUTCOME MEASURES: Respondent demographics, information on
      human rights abuses that occurred among household members since 1991, women's
      health and human rights, opinions regarding women's rights and roles in society,
      and conditions for community health and development. RESULTS: Respondents were a
      mean age of 38 years and were mostly of Arab ethnicity (99.7% [1976/1982]) and
      Muslim Shi'a (96.7% [1906/1971]). Overall, 47% of those interviewed reported 1 or
      more of the following abuses among themselves and household members since 1991:
      torture, killings, disappearance, forced conscription, beating, gunshot wounds,
      kidnappings, being held hostage, and ear amputation, among others. Seventy
      percent of abuses (408/586) were reputed to have occurred in homes. Baath party
      regime-affiliated groups were identified most often (95% [449/475]) as the
      perpetrators of the abuses; 53% of the abuses occurred between 1991 and 1993,
      following the Shi'a uprising, and another 30% between 2000 and the first 6 months
      of 2003. While the majority of men and women expressed support for women's equal
      opportunities for education, freedom of expression, access to health care,
      equality in deciding marriage and the number and spacing of children, and
      participation in community development decisions, there was less support among
      both men and women for women's freedom of movement, association with people of
      their choosing, and rights to refuse sex. Half of women and men (54% and 50%,
      respectively) reported agreeing that a man has the right to beat his wife if she
      disobeys. Fifty-three percent of respondents reported that there were reasons to
      restrict educational opportunities for women at the present time and 50% reported
      that there were reasons to restrict work opportunities for women at the present
      time. CONCLUSIONS: Nearly half of participating households in 3 southern cities
      in Iraq reported human rights abuses among household members between 1991 and
      2003. The households surveyed supported a government that will protect and
      promote human rights, including the rights of women. However, currently, neither
      men nor women appear to support a full range of women's human rights.

PMID- 15039415
TI  - Physician participation in human rights abuses in southern Iraq.
AB  - CONTEXT: Physicians are known to have participated in human rights abuses in Iraq
      during Saddam Hussein's Baathist regime, but the nature and extent of that
      participation are not well documented. OBJECTIVES: To characterize the nature of
      physician participation in human rights abuses, identify structural factors that
      facilitated physician participation, and assess approaches for accountability and
      for prevention of future physician participation in abuses. DESIGN, SETTING, AND
      PARTICIPANTS: A self-administered survey in June and July, 2003, of a convenience
      sample of 98 physicians and semistructured interviews of hospital directors and
      physicians in 3 major hospitals with general surgical units in 2 cities in
      southern Iraq. MAIN OUTCOME MEASURE: Respondent reports of peer and self
      participation in human rights abuses in Iraq since 1988. RESULTS: The majority of
      participants were male (88% [86/98]) and Shi'a Muslims (97% [95/98]). Respondents
      reported a mean of 6.8 years in practice. A total of 71% of respondents (65/91)
      reported that torture was a problem to an extreme extent in Iraq since 1988. The
      proportion of respondents indicating that, since 1988, their physician peers as a
      group were extremely or quite a bit involved in human rights abuses included 50%
      (42/83) for nontherapeutic amputation of ears as a form of punishment, 49%
      (39/79) for falsification of medical-legal reports of torture, and 32% (25/78)
      for falsification of death certificates. Fewer numbers of respondents (range, n =
      2 to 6) reported participation in abuses themselves. More than half (52% [48/92])
      indicated that physicians did not willingly participate in these abuses; 93%
      (52/71) reported that the Iraqi paramilitary force Fedayeen Saddam was
      responsible for initiating physician complicity. Fear of harm to oneself or
      family members was a common explanation for complicity. Respondents reported that
      physicians who refused to participate in abuses faced consequences including loss
      of job, imprisonment, torture, and disappearance. Respondents reported on
      preventive measures that should be undertaken to prevent physician involvement in
      future abuses, including increasing human rights and ethics education of
      physicians (99% [79/80]), legal provisions to ensure effective monitoring (97%
      [73/75]), punitive sanctions for physicians who commit abuses (96% [77/80]), and
      ensuring the independence of physicians from state authorities (95% [76/80]).
      CONCLUSIONS: Although not generalizable beyond the study participants, the
      findings of this study suggest that among those surveyed, physician participation
      in human rights abuses included falsification of medical-legal reports of alleged
      torture, physical mutilation as a form of punishment, and falsification of death
      certificates. As Iraq rebuilds, it is essential that the country address these
      violations and enact measures to prevent physicians from future complicity in
      human rights abuses.

PMID- 15039416
TI  - Preventing visual loss from chronic eye disease in primary care: scientific
      review.
AB  - CONTEXT: Vision loss is common in the United States and its prevalence increases
      with age. Visual disability significantly impacts quality of life and increases
      the risk of injury. Although at least 40% of blindness in the United States is
      either preventable or treatable with timely diagnosis and intervention, many
      people with vision loss are undiagnosed and untreated. OBJECTIVE: To review the
      evidence regarding screening and management of eye disorders and visual
      disability among adults in the primary care setting. DATA SOURCES AND STUDY
      SELECTION: MEDLINE, HealthSTAR, EMBASE, The Cochrane Database of Systematic
      Reviews, and the National Guidelines Clearinghouse were searched for articles and
      practice guidelines about screening and management of eye diseases and vision
      loss among adults in the primary care setting using key words and free-text
      terms, such as vision screening, glaucoma prevention and control, from 1985 to
      2003. References in these articles and those suggested by experts in eye care,
      vision loss, and vision screening were reviewed as well. DATA EXTRACTION:
      Articles were searched for the most clinically important information and
      emphasized randomized controlled trials where available. DATA SYNTHESIS: Most
      major guidelines recommend periodic referral of older adults to an eye care
      professional for comprehensive evaluation to detect eye diseases and visual
      disability. The value of routine screening for vision loss in the primary care
      setting has not been established. Timely identification and treatment of eye
      diseases can substantially reduce the incidence and prevalence of visual
      disability among older adults. Optimizing management of systemic diseases, such
      as diabetes, hypertension, and hyperlipidemia, significantly reduces the risk of
      related eye disorders. CONCLUSIONS: Primary care clinicians can play a vital role
      in preserving vision in their patients by managing systemic diseases that impact
      eye health and by ensuring that patients undergo periodic evaluations by eye care
      professionals and receive needed eye care.

PMID- 15039417
TI  - Preventing and managing visual disability in primary care: clinical applications.
AB  - Clinicians in primary care settings are well positioned to participate in the
      prevention and management of visual disability. They can have a significant
      impact on their patients' visual health by screening for vision problems,
      aggressively controlling known risk factors for visual loss, ensuring adherence
      to ophthalmologic treatment and continuity of eye care, and by timely referral of
      specific patient populations to qualified eye care professionals (eg,
      ophthalmologists and optometrists). Using their knowledge about common ophthalmic
      medications, clinicians can detect adverse effects of these agents, including
      exacerbations of heart or lung disease. They can ensure that appropriate patients
      are screened for common serious eye diseases, such as glaucoma, and that patients
      with disabilities related to vision problems are assessed for treatable
      conditions, such as cataracts or refractive error. Finally, clinicians can direct
      patients with low vision from any cause to resources designed to help enhance
      patient function and emotional support.

PMID- 15039418
TI  - Evaluating gynecological surgical procedures: trials and tribulations.

PMID- 15039419
TI  - Medical ethics suborned by tyranny and war.

PMID- 15039420
TI  - JAMA patient page. Hysterectomy.

PMID- 15039422
TI  - CD28 costimulation controls histone hyperacetylation of the interleukin 5 gene
      locus in developing th2 cells.
AB  - Interleukin 5 (IL-5) plays a unique role in allergic inflammatory responses, and
      the understanding of molecular mechanisms underlying the generation of IL-5
      producing cells is crucial for the regulation of allergic disorders.
      Differentiation of naive CD4 T cells into type-2 helper (Th2) cells is
      accompanied by chromatin remodeling including hyperacetylation of histones H3 and
      H4 in the nucleosomes associated with the IL-4, IL-13, and IL-5 genes. Histone
      hyperacetylation of the IL-5 gene displayed a delayed kinetics compared with that
      of the IL-4 and IL-13 genes, suggesting a distinct remodeling mechanism for the
      IL-5-gene locus. Here we studied the role of CD28 costimulation in the generation
      of IL-5-producing cells and the histone hyperacetylation of the IL-5 gene locus.
      CD28-costimulation selectively enhanced histone hyperacetylation of the IL-5 gene
      locus that appeared to be mediated through NF-kappaB activation and subsequent up
      regulation of GATA3. The CD28 costimulation-sensitive histone hyperacetylation
      spanned almost the entire intergenic region between the IL-5 and RAD50
      accompanied with intergenic transcript. Thus, this is the first demonstration
      that CD28 costimulation controls a chromatin-remodeling process during Th2 cell
      differentiation.

PMID- 15039421
TI  - Caspase-1 activates nuclear factor of the kappa-enhancer in B cells independently
      of its enzymatic activity.
AB  - The proteolytic activity of caspases is involved in apoptosis and inflammation.
      In this regard, caspase-1 is required for pro-interleukin (IL)-1beta and pro-IL
      18 maturation. We report here on a novel function of caspase-1 as an activator of
      nuclear factor of the kappa-enhancer in B-cells (NF-kappaB) and p38 mitogen
      activated protein kinase (MAPK). This function is not shared by the murine
      caspase-1 homologues caspase-11 and -12. In contrast to pro-IL-1beta maturation,
      caspase-1-induced NF-kappaB activation is not inhibited by the virus-derived
      caspase-1 inhibitor cytokine response modifier A and is equally induced by the
      enzymatically inactive caspase-1 C285A mutant. Although the general NF-kappaB
      inhibiting protein A20 inhibits caspase-1-derived activation of NF-kappaB,
      dominant-negative forms of TRAF2 and RIP1 have no effect. We demonstrate that
      caspase-1 interacts with RIP2 and that dominant-negative forms of RIP2 and
      IkappaB kinase complex-beta inhibit caspase-1-mediated NF-kappaB activation.
      Structure-function analysis shows that the caspase recruitment domain of caspase
      1 mediates the activation of NF-kappaB and p38 MAPK. These data demonstrate that
      caspase-1 contributes to inflammation by two distinct pathways: proteolysis of
      pro-IL-1beta, and RIP2-dependent activation of NF-kappaB and p38 MAPK mediated by
      the caspase recruitment domain.

PMID- 15039423
TI  - Protease-activated receptor 2-dependent phosphorylation of the tissue factor
      cytoplasmic domain.
AB  - Tissue factor (TF) is the physiological activator of the coagulation cascade that
      plays pathophysiological roles in metastasis, angiogenesis, and inflammation.
      Downstream in coagulation, thrombin is the central protease that signals through
      G protein-coupled, protease-activated receptors (PARs). However, the TF-VIIa-Xa
      complex upstream in coagulation also activates PAR1 and 2. Here, we address the
      question of whether signaling of the TF initiation complex is a relevant pathway
      that leads to TF cytoplasmic domain phosphorylation. In heterologous expression
      systems and primary endothelial cells, we demonstrate that the ternary TF-VIIa-Xa
      complex induces TF phosphorylation specifically by activating PAR2 but not
      through PAR1 signaling. In addition, TF cytoplasmic domain phosphorylation is
      induced only by TF-dependent signaling but not by other coagulation factors in
      endothelial cells. Phosphorylation of the Pro-directed kinase target site Ser258
      is dependent on prior phosphorylation of Ser253 by protein kinase C (PKC) alpha.
      TF phosphorylation is somewhat delayed and coincides with sustained PKCalpha
      activation downstream of PAR2 but not PAR1 signaling. Phosphatidylcholine
      dependent phospholipase C is the major pathway that leads to prolonged PKCalpha
      recruitment downstream of PAR2. Thus, PAR2 signaling specifically phosphorylates
      TF in a receptor cross-talk that distinguishes upstream from downstream
      coagulation protease signaling.

PMID- 15039424
TI  - The Src family kinase Yes triggers hyperosmotic activation of the epidermal
      growth factor receptor and CD95.
AB  - Hyperosmotic exposure of rat hepatocytes triggers epidermal growth factor
      receptor (EGFR) activation, which results in an activation of the CD95 system and
      sensitizes the cells toward apoptosis (Reinehr, R., Schliess, F., and Haussinger,
      D. (2003) FASEB J. 17, 731-733). The mechanisms underlying the hyperosmotic EGFR
      activation were studied. Hyperosmotic exposure (405 mosm) resulted in a rapid
      activation of the Src kinase family members Yes, Fyn, and Lck. Hyperosmotic Yes,
      but not Fyn activation, was antioxidant-sensitive and was followed by a rapid
      Yes/EGFR association. PP-2 abolished the hyperosmotic activation of Fyn and Lck
      but not activation of Yes and EGFR and their association. However, these latter
      processes were prevented in the presence of SU6656. SU6656 and antioxidants, but
      not PP-2 and AG1478, also inhibited the hyperosmotic JNK activation. Cyclic AMP
      had no effect on hyperosmotic Yes and JNK activation but prevented EGFR/Yes
      association and EGFR activation in an H89-sensitive way. When the hyperosmolarity
      induced Yes-EGFR protein complex started to disappear after 30 min, an
      association between EGFR and CD95 became apparent, which was followed by CD95
      tyrosine phosphorylation and activation. SU6656 but not PP-2 also inhibited
      EGFR/CD95 association, CD95 tyrosine phosphorylation, CD95 membrane trafficking,
      and death-inducing signaling complex (DISC) formation. EGFR knockdown had no
      effect on hyperosmotic Yes activation but prevented CD95 tyrosine
      phosphorylation, membrane targeting, and DISC formation. Hyperosmotic EGFR and
      CD95 activation was also largely blunted following Yes knockdown. The data
      suggest that hyperosmotic signaling triggers an oxidative stress-dependent Yes
      activation, which is followed by JNK and EGFR activation and subsequent
      activation of the CD95 system. However, the functional relevance of
      hyperosmolarity-induced Fyn and Lck activation remains to be elucidated.

PMID- 15039425
TI  - Horseradish peroxidase mutants that autocatalytically modify their prosthetic
      heme group: insights into mammalian peroxidase heme-protein covalent bonds.
AB  - The mammalian peroxidases, including myeloperoxidase and lactoperoxidase, bind
      their prosthetic heme covalently through ester bonds to two of the heme methyl
      groups. These bonds are autocatalytically formed. No other peroxidase is known to
      form such bonds. To determine whether features other than an appropriately placed
      carboxylic acid residue are important for covalent heme binding, we have
      introduced aspartate and/or glutamic acid residues into horseradish peroxidase, a
      plant enzyme that exhibits essentially no sequence identity with the mammalian
      peroxidases. Based on superposition of the horseradish peroxidase and
      myeloperoxidase structures, the mutated residues were Leu(37), Phe(41), Gly(69),
      and Ser(73). The F41E mutant was isolated with no covalently bound heme, but the
      heme was completely covalently bound upon incubation with H(2)O(2). As predicted,
      the modified heme released from the protein was 3-hydroxymethylheme. The S73E
      mutant did not covalently bind its heme but oxidized it to the 8-hydroxymethyl
      derivative. The hydroxyl group in this modified heme derived from the medium. The
      other mutations gave unstable proteins. The rate of compound I formation for the
      F41E mutant was 100 times faster after covalent bond formation, but the reduction
      of compound I to compound II was similar with and without the covalent bond. The
      results clearly establish that an appropriately situated carboxylic acid group is
      sufficient for covalent heme attachment, strengthen the proposed mechanism, and
      suggest that covalent heme attachment in the mammalian peroxidases relates to
      peroxidase biology or stability rather than to intrinsic catalytic properties.

PMID- 15039426
TI  - Requirement of PEN-2 for stabilization of the presenilin N-/C-terminal fragment
      heterodimer within the gamma-secretase complex.
AB  - Gamma-secretase is a protease complex composed of presenilin (PS), nicastrin
      (NCT), APH-1, and PEN-2, which catalyzes intramembrane cleavage of several type I
      transmembrane proteins including the Alzheimer's disease-associated beta-amyloid
      precursor protein. We generated stable RNA interference-mediated PEN-2 knockdown
      cells to probe mutant PEN-2 variants for functional activity. Knockdown of PEN-2
      was associated with impaired NCT maturation and deficient PS1 endoproteolysis,
      which was efficiently rescued by wild type or N-terminally tagged PEN-2 but not
      by C-terminally tagged PEN-2 or by the C-terminally truncated PEN-2-DeltaC
      mutant. Although the latter mutants rescued the PS1 holoprotein accumulation
      associated with the PEN-2 knockdown, they failed to restore normal levels of the
      PS1 N- and C-terminal fragments and to maturate NCT. PEN-2-DeltaC was highly
      unstable and rapidly turned over by proteasomal degradation consistent with its
      failure to become stably incorporated into the gamma-secretase complex. In
      addition, expression of PEN-2-DeltaC caused a selective instability of the PS1 N
      /C-terminal fragment heterodimer that underwent proteasomal degradation, whereas
      NCT and APH-1 were stable. Interestingly, when we knocked down PEN-2 in the
      background of the endoproteolysis-deficient PS1 Deltaexon9 mutant, immature NCT
      still accumulated, demonstrating that PEN-2 is also required for gamma-secretase
      complex maturation when PS endoproteolysis cannot occur. Taken together, our data
      suggest that PEN-2 is required for the stabilization of the PS fragment
      heterodimer within the gamma-secretase complex following PS endoproteolysis. This
      function critically depends on the PEN-2 C terminus. Moreover, our data show that
      PEN-2 is generally required for gamma-secretase complex maturation independent of
      its activity in PS1 endoproteolysis.

PMID- 15039428
TI  - Classification of nuclear receptors based on amino acid composition and dipeptide
      composition.
AB  - Nuclear receptors are key transcription factors that regulate crucial gene
      networks responsible for cell growth, differentiation, and homeostasis. Nuclear
      receptors form a superfamily of phylogenetically related proteins and control
      functions associated with major diseases (e.g. diabetes, osteoporosis, and
      cancer). In this study, a novel method has been developed for classifying the
      subfamilies of nuclear receptors. The classification was achieved on the basis of
      amino acid and dipeptide composition from a sequence of receptors using support
      vector machines. The training and testing was done on a non-redundant data set of
      282 proteins obtained from the NucleaRDB data base (1). The performance of all
      classifiers was evaluated using a 5-fold cross validation test. In the 5-fold
      cross-validation, the data set was randomly partitioned into five equal sets and
      evaluated five times on each distinct set while keeping the remaining four sets
      for training. It was found that different subfamilies of nuclear receptors were
      quite closely correlated in terms of amino acid composition as well as dipeptide
      composition. The overall accuracy of amino acid composition-based and dipeptide
      composition-based classifiers were 82.6 and 97.5%, respectively. Therefore, our
      results prove that different subfamilies of nuclear receptors are predictable
      with considerable accuracy using amino acid or dipeptide composition.
      Furthermore, based on above approach, an online web service, NRpred, was
      developed, which is available at www.imtech.res.in/raghava/nrpred.

PMID- 15039427
TI  - Estrogen-induced smooth muscle cell growth is regulated by tuberin and associated
      with altered activation of platelet-derived growth factor receptor-beta and ERK
      1/2.
AB  - The mechanisms that regulate the diverse responses to estrogen (E2) are unknown.
      Loss of function of the tuberous sclerosis 2 gene (TSC2), a tumor suppressor
      gene, has been associated with a growth-promoting effect of E2. We hypothesized
      that tuberin, the protein product of TSC2, binds to estrogen receptors (ER) and
      regulates the growth effect of E2. An in vivo association between full-length
      tuberin and ERalpha was observed in HEK 293 cells and ELT-3 smooth muscle cells.
      In contrast, poor association was observed between tuberin and ERbeta. Complex
      formation with ERalpha and the C-terminal end of tuberin was also observed in
      vivo and in vitro, indicating that binding between ERalpha and tuberin occurs at
      the C-terminal end of the tuberin molecule. We examined the effect of tuberin
      expression in ELT-3 smooth muscle cells on the growth response to E2. The growth
      promoting effect of E2 in tuberin-null ELT-3 smooth muscle cells was ERalpha
      specific, associated with up-regulation and activation of platelet-derived growth
      factor receptor-beta (PDGFRbeta) and activation of the signaling intermediate,
      extracellular signal-regulated kinase-1/-2 (ERK-1/2). In contrast, the expression
      of tuberin in ELT-3 smooth muscle cells resulted in significant abrogation of E2
      stimulated growth. In parallel with this observation, the expression of tuberin
      in ELT-3 cells also resulted in significant inhibition of PDGFRbeta and ERK-1/2
      activation in response to E2. These results demonstrate that tuberin binds
      specifically to ERalpha and inhibits E2-induced proliferation of ELT-3 cells.
      Furthermore, the opposing effects of tuberin on estrogen-induced activation of
      PDGFRbeta and ERK-1/-2 suggest a pivotal role for tuberin in directing the
      signaling events that dictate the growth response to E2.

PMID- 15039429
TI  - Protein related to DAN and cerberus is a bone morphogenetic protein antagonist
      that participates in ovarian paracrine regulation.
AB  - Bone morphogenetic proteins (BMPs) are important for body patterning and
      morphogenesis, whereas several BMP antagonists regulate the functions of BMPs
      during embryonic development and tissue differentiation. Protein related to DAN
      and cerberus (PRDC) is a secreted protein with a cystine knot structure
      identified by gene trapping in embryonic stem cells. Although PRDC shows sequence
      homology with proteins of the BMP antagonist family, its biological activity and
      physiological functions are unclear. We generated recombinant PRDC and its
      paralog, gremlin, and tested their ability to suppress actions initiated by
      diverse BMP proteins. Similar to the known BMP antagonist, gremlin, PRDC blocked
      ligand signaling induced by BMP2 and BMP4 but had minimal effects on reporter
      gene activation induced by GDF-9, activin, or transforming growth factor-beta. Co
      precipitation assays further demonstrated the direct protein-protein interactions
      between PRDC and BMP2 or BMP4. Reverse transcriptase-PCR analyses indicated that
      PRDC transcripts are widely expressed showing higher levels in ovary, brain, and
      spleen. In mouse ovary, PRDC transcripts were increased following gonadotropin
      treatment. In situ hybridization analyses further indicated that ovarian PRDC
      transcripts are localized in granulosa cells of selective follicles. In addition,
      co-treatment with PRDC antagonized the inhibitory effects of BMP4 on the follicle
      stimulating hormone stimulation of progesterone production by cultured rat
      granulosa cells. Thus, PRDC is a potent BMP antagonist with a wide tissue
      expression pattern, and ovarian PRDC expressed in granulosa cells could be
      involved in follicular development by antagonizing the actions of theca cell
      derived BMPs.

PMID- 15039430
TI  - Localization to the proteasome is sufficient for degradation.
AB  - The majority of unstable proteins in eukaryotic cells are targeted for
      degradation through the ubiquitin-proteasome pathway. Substrates for degradation
      are recognized by the E1, E2, and E3 ubiquitin conjugation machinery and tagged
      with polyubiquitin chains, which are thought to promote the proteolytic process
      through their binding with the proteasome. We describe a method to bypass the
      ubiquitination step artificially both in vivo and in a purified in vitro system.
      Seven proteasome subunits were tagged with Fpr1, and fusion reporter constructs
      were created with the Fpr1-rapamycin binding domain of Tor1. Reporter proteins
      were localized to the proteasome by the addition of rapamycin, a drug that
      heterodimerizes Fpr1 and Tor1. Degradation of reporter proteins was observed with
      proteasomes that had either Rpn10 or Pre10 subunits tagged with Fpr1. Our
      experiments resolved a simple but central problem concerning the design of the
      ubiquitin-proteasome pathway. We conclude that localization to the proteasome is
      sufficient for degradation and, therefore, any added functions polyubiquitin
      chains possess beyond tethering substrates to the proteasome are not strictly
      necessary for proteolysis.

PMID- 15039431
TI  - Coupling of folding and binding of thymosin beta4 upon interaction with monomeric
      actin monitored by nuclear magnetic resonance.
AB  - Thymosin beta4 is a major actin-sequestering protein, yet the structural basis
      for its biological function is still unknown. This study provides insight
      regarding the way this 43-amino acid peptide, mostly unstructured in solution,
      binds to monomeric actin and prevents its assembly in filaments. We show here
      that the whole backbone of thymosin beta4 is highly affected upon binding to G
      actin. The assignment of all amide protons and nitrogens of thymosin in the bound
      state, obtained using a combination of NMR experiments and selective labelings,
      shows that thymosin folds completely upon binding and displays a central extended
      region flanked by two N- and C-terminal helices. The cleavage of actin by
      subtilisin in the DNase I binding loop does not modify the structure of thymosin
      beta4 in the complex, showing that the backbone of the peptide is not in close
      proximity to segment 42-47 of actin. The combination of our NMR results and
      previously published mutation and cross-link data allows a better
      characterization of the binding mode of thymosins on G-actin.

PMID- 15039432
TI  - Ruthenium red-induced bundling of bacterial cell division protein, FtsZ.
AB  - The assembly of FtsZ plays a major role in bacterial cell division, and it is
      thought that the assembly dynamics of FtsZ is a finely regulated process. Here,
      we show that ruthenium red is able to modulate FtsZ assembly in vitro. In
      contrast to the inhibitory effects of ruthenium red on microtubule
      polymerization, we found that a substoichiometric concentration of ruthenium red
      strongly increased the light-scattering signal of FtsZ assembly. Further,
      sedimentable polymer mass was increased by 1.5- and 2-fold in the presence of 2
      and 10 microm ruthenium red, respectively. In addition, ruthenium red strongly
      reduced the GTPase activity and prevented dilution-induced disassembly of FtsZ
      polymers. Electron microscopic analysis showed that 4-10 microm of ruthenium red
      produced thick bundles of FtsZ polymers. The significant increase in the light
      scattering signal and pelletable polymer mass in the presence of ruthenium red
      seemed to be due to the bundling of FtsZ protofilaments into larger polymers
      rather than the actual increase in the level of polymeric FtsZ. Furthermore,
      ruthenium red was found to copolymerize with FtsZ, and the copolymerization of
      substoichiometric amounts of ruthenium red with FtsZ polymers promoted
      cooperative assembly of FtsZ that produced large bundles. Calcium inhibited the
      binding of ruthenium red to FtsZ. However, a concentration of calcium 1000-fold
      higher than that of ruthenium red was required to produce similar effects on FtsZ
      assembly. Ruthenium red strongly modulated FtsZ polymerization, suggesting the
      presence of an important regulatory site on FtsZ and suggesting that a natural
      ligand, which mimics the action of ruthenium red, may regulate the assembly of
      FtsZ in bacteria.

PMID- 15039433
TI  - A gelsolin-like protein from Papaver rhoeas pollen (PrABP80) stimulates calcium
      regulated severing and depolymerization of actin filaments.
AB  - The cytoskeleton is a key regulator of plant morphogenesis, sexual reproduction,
      and cellular responses to extracellular stimuli. During the self-incompatibility
      response of Papaver rhoeas L. (field poppy) pollen, the actin filament network is
      rapidly depolymerized by a flood of cytosolic free Ca2+ that results in cessation
      of tip growth and prevention of fertilization. Attempts to model this dramatic
      cytoskeletal response with known pollen actin-binding proteins (ABPs) revealed
      that the major G-actin-binding protein profilin can account for only a small
      percentage of the measured depolymerization. We have identified an 80-kDa, Ca(2+)
      regulated ABP from poppy pollen (PrABP80) and characterized its biochemical
      properties in vitro. Sequence determination by mass spectrometry revealed that
      PrABP80 is related to gelsolin and villin. The molecular weight, lack of filament
      cross-linking activity, and a potent severing activity are all consistent with
      PrABP80 being a plant gelsolin. Kinetic analysis of actin assembly/disassembly
      reactions revealed that substoichiometric amounts of PrABP80 can nucleate actin
      polymerization from monomers, block the assembly of profilin-actin complex onto
      actin filament ends, and enhance profilin-mediated actin depolymerization.
      Fluorescence microscopy of individual actin filaments provided compelling, direct
      evidence for filament severing and confirmed the actin nucleation and barbed end
      capping properties. This is the first direct evidence for a plant gelsolin and
      the first example of efficient severing by a plant ABP. We propose that PrABP80
      functions at the center of the self-incompatibility response by creating new
      filament pointed ends for disassembly and by blocking barbed ends from profilin
      actin assembly.

PMID- 15039434
TI  - Modulation of the stathmin-like microtubule destabilizing activity of RB3, a
      neuron-specific member of the SCG10 family, by its N-terminal domain.
AB  - RB3 is a neuron-specific homologue of the SCG10/stathmin family proteins,
      possessing a unique N-terminal membrane-associated domain and the stathmin-like
      domain at the C terminus, which promotes microtubule (MT) catastrophe and/or
      tubulin sequestering. We examined herein the contribution of the N-terminal
      subdomain of RB3 to the regulation of MT dynamics. To begin with, we determined
      the effects of full-length (RB3-f) and short truncated (RB3-s) forms of RB3 on
      the polymerization of MT in vitro. RB3-s had a deletion of amino acids 1-75 from
      the N terminus, leaving the so-called stathmin-like domain, consisting of
      residues 76-217. Although both RB3-f and RB3-s exhibited MT-depolymerizing
      activity, RB3-f was less effective. The binding affinity for tubulin was also
      lower in RB3-f. Direct observation of the dynamics of individual MTs using dark
      field microscopy revealed that RB3-s slowed MT elongation velocity, increased
      catastrophes, and reduced rescues. This effect is almost identical to that by
      stathmin/oncoprotein 18. On the other hand, the MT elongation rate increased at
      lower concentrations of RB3-f. In addition, RB3-f, indicated higher rescue
      frequency than control as well as the catastrophe in a dose-dependent manner. The
      functionality of RB3-f indicated that full-length RB3 has not only stathmin-like
      MT destabilizing activity but also MT-associated protein-like MT stabilizing
      activity. Possibly, the balance of these activities is altered in a concentration
      dependent manner in vitro. This interesting regulatory role of the unique N
      terminal domain of RB3 in MT dynamics would contribute to the physiological
      regulation of neuronal morphogenesis.

PMID- 15039435
TI  - The Trypanosoma brucei cyclin, CYC2, is required for cell cycle progression
      through G1 phase and for maintenance of procyclic form cell morphology.
AB  - CYC2 is an essential PHO80-like cyclin that forms a complex with the cdc2-related
      kinase CRK3 in Trypanosoma brucei. In both procyclic and bloodstream form T.
      brucei, knock-down of CYC2 by RNA interference (RNAi) led to an accumulation of
      cells in G(1) phase. Additionally, in procyclic cells, but not in bloodstream
      form cells, CYC2 RNAi induced a specific cell elongation at the posterior end.
      The G(1) block, as well as the posterior end elongation in the procyclic form,
      was irreversible once established. Staining for tyrosinated alpha-tubulin and
      morphometric analyses showed that the posterior end elongation occurred through
      active microtubule extension, with no repositioning of the kinetoplast. Hence,
      these cells can be classified as exhibiting the "nozzle" phenotype as has been
      described for cells that ectopically express TbZFP2, a zinc finger protein that
      is involved in the differentiation of the bloodstream form to procyclic form.
      Within the tsetse fly, procyclic trypanosomes differentiate to elongated
      mesocyclic cells. However, although mesocyclic trypanosomes isolated from tsetse
      flies also show active microtubule extension at the posterior end, the
      kinetoplast is coincidentally repositioned such that it always lies approximately
      midway between the nucleus and posterior end of the cell. Thus, in the procyclic
      form CYC2 has dual functionality and is required for both cell cycle progression
      through G(1) and for the maintenance of correct cell morphology, whereas in the
      bloodstream form only a role for CYC2 in G(1) progression is evident.

PMID- 15039436
TI  - Reductions in linker histone levels are tolerated in developing spermatocytes but
      cause changes in specific gene expression.
AB  - H1 linker histones are involved in packaging chromatin into 30-nm fibers and
      higher order structures. Most eukaryotic cells contain nearly one H1 molecule for
      each nucleosome core particle. Male germ cells in mammals contain large amounts
      of a germ cell-specific linker histone, HIST1HT, herein denoted H1t, which is
      particularly abundant in pachytene spermatocytes. Despite its abundance in male
      germ cells and significant divergence in primary sequence from other H1 subtypes,
      inactivation of the H1t gene in mice showed that it is not required for
      spermatogenesis. Analysis of germ cell chromatin from H1t null mice showed that
      other H1 subtypes, especially the testis-enriched HIST1H1A, herein denoted as the
      H1a subtype, were able to compensate for the absence of H1t to maintain a normal
      total H1 to nucleosome core ratio. To disrupt the compensation, we generated H1t
      and H1a double null mice by two sequential gene-targeting steps in embryonic stem
      cells. Elimination of both H1t and H1a led to a 25% decrease in the ratio of H1
      to nucleosome cores in double null germ cells. Surprisingly, the reduction in H1
      did not perturb spermatogenesis or produce detectable defects in meiotic
      processes. Microarray analysis of gene expression showed that the reduced linker
      histone levels did not affect global gene expression, but it did cause changes in
      expression of specific genes. Our results indicate that a partial reduction in
      linker histone-nucleosome core particle stoichiometry is tolerated in developing
      male germ cells.

PMID- 15039437
TI  - Disruption of Meox or Gli activity ablates skeletal myogenesis in P19 cells.
AB  - Gli2 and Meox1 are transcription factors that are expressed in the developing
      somite and play roles in the commitment of cells to the skeletal muscle lineage.
      To further define their roles in regulating myogenesis, the function of wild type
      and dominant-negative forms of Gli2 and Meox1 were examined in the context of
      differentiating P19 stem cells. We found that Gli2 overexpression up-regulated
      transcript levels of Meox1 and, conversely, Meox1 overexpression resulted in the
      upregulation of Gli2 transcripts. Furthermore, dominant-negative forms of either
      Meox1 or Gli2 disrupted the ability of P19 cells to commit to the muscle lineage
      and to properly express either Gli2 or Meox1, respectively. Finally, Pax3
      transcripts were induced by Gli2 overexpression and lost in the presence of
      either mutants Meox1 or Gli2. Taken together, these results support the existence
      of a regulatory loop between Gli2, Meox1, and Pax3 that is essential for
      specification of mesodermal cells into the muscle lineage.

PMID- 15039440
TI  - The significance of circulating factor IXa in blood.
AB  - The presence of activation peptides (AP) of the vitamin K-dependent proteins in
      the phlebotomy blood of human subjects suggests that active serine proteases may
      circulate in blood as well. The goal of the current study was to evaluate the
      influence of trace amounts of key coagulation proteases on tissue factor
      independent thrombin generation using three models of coagulation. With
      procoagulants and select coagulation inhibitors at mean physiological
      concentrations, concentrations of factor IXa, factor Xa, and thrombin were set
      either equal to those of their AP or to values that would result based upon the
      rates of AP/enzyme generation and steady state enzyme inhibition. In the latter
      case, numerical simulation predicts that sufficient thrombin to produce a solid
      clot would be generated in approximately 2 min. Empirical data from the synthetic
      plasma suggest clotting times of 3-5 min, which are similar to that observed in
      contact pathway-inhibited whole blood (4.3 min) initiated with the same
      concentrations of factors IXa and Xa and thrombin. Numerical simulations
      performed with the concentrations of two of the enzymes held constant and one
      varied suggest that the presence of any pair of enzymes is sufficient to yield
      rapid clot formation. Modeling of states (numerical simulation and whole blood)
      where only one circulating protease is present at steady state concentration
      shows significant thrombin generation only for factor IXa. The addition of factor
      Xa and thrombin has little effect (if any) on thrombin generation induced by
      factor IXa alone. These data indicate that 1) concentrations of active
      coagulation enzymes circulating in vivo are significantly lower than can be
      predicted from the concentrations of their AP, and 2) expected trace amounts of
      factor IXa can trigger thrombin generation in the absence of tissue factor.

PMID- 15039439
TI  - Molecular basis of elastic fiber formation. Critical interactions and a
      tropoelastin-fibrillin-1 cross-link.
AB  - We have investigated the molecular basis of elastic fiber formation on fibrillin
      microfibrils. Binding assays revealed high affinity calcium-independent binding
      of two overlapping fibrillin-1 fragments (encoded by central exons 18-25 and 24
      30) to tropoelastin, which, in microfibrils, map to an exposed "arms" feature
      adjacent to the beads. A further binding site within an adjacent fragment
      (encoded by exons 9-17) was within an eight-cysteine motif designated TB2
      (encoded by exons 16 and 17). Binding to TB2 was ablated by the presence of N
      terminal domains (encoded by exons 1-8) and reduced after deleting the proline
      rich region. A novel transglutaminase cross-link between tropoelastin and
      fibrillin-1 fragment (encoded by exons 9-17) was localized by mass spectrometry
      to a sequence encoded by exon 17. The high affinity binding and cross-linking of
      tropoelastin to a central fibrillin-1 sequence confirm that this association is
      fundamental to elastic fiber formation. Microfibril-associated glycoprotein-1
      showed calcium-dependent binding of moderate affinity to fibrillin-1 N-terminal
      fragment (encoded by exons 1-8), which localize to the beads. Microfibril
      associated glycoprotein-1 thus contributes to microfibril organization but may
      also form secondary interactions with adjacent microfibril-bound tropoelastin.

PMID- 15039438
TI  - Proteasomal degradation of N-acetyltransferase 1 is prevented by acetylation of
      the active site cysteine: a mechanism for the slow acetylator phenotype and
      substrate-dependent down-regulation.
AB  - Many drugs and chemicals found in the environment are either detoxified by N
      acetyltransferase 1 (NAT1, EC 2.3.1.5) and eliminated from the body or
      bioactivated to metabolites that have the potential to cause toxicity and/or
      cancer. NAT1 activity in the body is regulated by genetic polymorphisms as well
      as environmental factors such as substrate-dependent down-regulation and
      oxidative stress. Here we report the molecular mechanism for the low protein
      expression from mutant NAT1 alleles that gives rise to the slow acetylator
      phenotype and show that a similar process accounts for enzyme down-regulation by
      NAT1 substrates. NAT1 allozymes NAT1 14, NAT1 15, NAT1 17, and NAT1 22 are devoid
      of enzyme activity and have short intracellular half-lives ( approximately 4 h)
      compared with wild-type NAT1 4 and the active allozyme NAT1 24. The inactive
      allozymes are unable to be acetylated by cofactor, resulting in ubiquitination
      and rapid degradation by the 26 S proteasome. This was confirmed by site-directed
      mutagenesis of the active site cysteine 68. The NAT1 substrate p-aminobenzoic
      acid induced ubiquitination of the usually stable NAT1 4, leading to its rapid
      degradation. From this study, we conclude that NAT1 exists in the cell in either
      a stable acetylated state or an unstable non-acetylated state and that mutations
      in the NAT1 gene that prevent protein acetylation produce a slow acetylator
      phenotype.

PMID- 15039442
TI  - Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha
      complex reveals conformation differences with a complex bearing von Willebrand
      disease mutations.
AB  - The adhesion of platelets to the subendothelium of blood vessels at sites of
      vascular injury under high shear conditions is mediated by a direct interaction
      between the platelet receptor glycoprotein Ibalpha (GpIbalpha) and the A1 domain
      of the von Willebrand factor (VWF). Here we report the 2.6-A crystal structure of
      a complex comprised of the extracellular domain of GpIbalpha and the wild-type A1
      domain of VWF. A direct comparison of this structure to a GpIbalpha-A1 complex
      containing "gain-of-function" mutations, A1-R543Q and GpIbalpha-M239V, reveals
      specific structural differences between these complexes at sites near the two
      GpIbalpha-A1 binding interfaces. At the smaller interface, differences in
      interaction show that the alpha1-beta2 loop of A1 serves as a conformational
      switch, alternating between an open alpha1-beta2 isomer that allows faster
      dissociation of GpIbalpha-A1, as observed in the wild-type complex, and an
      extended isomer that favors tight association as seen in the complex containing
      A1 with a type 2B von Willebrand Disease (VWD) mutation associated with
      spontaneous binding to GpIbalpha. At the larger interface, differences in
      interaction associated with the GpIbalpha-M239V platelet-type VWD mutation are
      minor and localized but feature discrete gamma-turn conformers at the loop end of
      the beta-hairpin structure. The beta-hairpin, stabilized by a strong classic
      gamma-turn as seen in the mutant complex, relates to the increased affinity of A1
      binding, and the beta-hairpin with a weak inverse gamma-turn observed in the wild
      type complex corresponds to the lower affinity state of GpIbalpha. These findings
      provide important details that add to our understanding of how both type 2B and
      platelet-type VWD mutations affect GpIbalpha-A1 binding affinity.

PMID- 15039441
TI  - Wounding induces motility in sheets of corneal epithelial cells through loss of
      spatial constraints: role of heparin-binding epidermal growth factor-like growth
      factor signaling.
AB  - Cellular responses to wounding have often been studied at a molecular level after
      disrupting cell layers by mechanical means. This invariably results in damage to
      cells at the edges of the wounds, which has been suggested to be instrumental for
      initiating wound healing. To test this, we devised an alternative procedure to
      introduce gaps in layers of corneal epithelial cells by casting agarose strips on
      tissue culture plates. In contrast to mechanical wounding, removal of the strips
      did not lead to detectable membrane leakage or to activation of the stress
      activated kinase JNK. Nonetheless, cells at the edge underwent the typical
      morphological transition to a highly motile phenotype, and the gaps closed at
      rates similar to those of mechanically induced wounds. To allow biochemical
      analysis of cell extracts, a procedure was devised that makes cell-free surface
      area acutely available to a large proportion of cells in culture. Rapid
      activation of the epidermal growth factor receptor (EGFR) was detected by
      immunoblotting, and the addition of an EGFR-blocking antibody completely
      abolished wound healing. In addition, wound healing was inhibited by agents that
      block signaling by the heparin-binding epidermal growth factor-like growth factor
      (HB-EGF). Cells stimulated with cell-free tissue culture surface released a
      soluble factor that induced activation of the EGFR, which was distinct from HB
      EGF. These studies suggest that the triggering event for the induction of
      motility in corneal epithelial cells is related to the sudden availability of
      permissive surface area rather than to mechanical damage, and they demonstrate a
      central role of signaling through HB-EGF.

PMID- 15039443
TI  - Co-expression of MG29 and ryanodine receptor leads to apoptotic cell death:
      effect mediated by intracellular Ca2+ release.
AB  - Perturbation of intracellular Ca2+ homeostasis has been shown to regulate the
      process of cell proliferation and apoptosis. Our previous studies show that
      mitsugumin 29 (MG29), a synaptophysin-related protein localized in the triad
      junction of skeletal muscle, serves an essential role in muscle Ca2+ signaling by
      regulating the process of store-operated Ca2+ entry. Here we report a functional
      interaction between MG29 and the ryanodine receptor (RyR)/Ca2+ release channel.
      The purified MG29 protein enhances activity of the RyR/Ca2+ release channel
      incorporated into the lipid bilayer membrane. Co-expression of MG29 and RyR in
      Chinese hamster ovary cells leads to apoptotic cell death resulting from
      depletion of intracellular Ca2+ stores, despite neither protein expression alone
      exhibits any significant effect on cell viability. In transient expression
      studies, the presence of RyR in the endoplasmic reticulum leads to retention of
      MG29 from the plasma membrane into the intracellular organelles. This functional
      interaction between MG29 and RyR could have important implications in the Ca2+
      signaling processes of muscle cells. Our data also show that perturbation of
      intracellular Ca2+ homeostasis can serve as a key signal in the initiation of
      apoptosis.

PMID- 15039444
TI  - Eotaxin-3/CCL26 is a natural antagonist for CC chemokine receptors 1 and 5. A
      human chemokine with a regulatory role.
AB  - Eotaxin-3 (CCL26), like eotaxin (CCL11) and eotaxin-2 (CCL24), has long been
      considered a specific agonist for CC chemokine receptor 3 (CCR3), attracting and
      activating eosinophils, basophils, and Th2 type T lymphocytes. Although not
      characterized extensively yet, its expression profile coincides with a potential
      role in allergic inflammation. We recently reported that eotaxin-3 is an
      antagonist for CCR2 (Ogilvie, P., Paoletti, S., Clark-Lewis, I., and Uguccioni,
      M. (2003) Blood 102, 789-784). In the present report, we provide evidence that
      eotaxin-3 acts as a natural antagonist on CCR1 and -5 as well. Eotaxin-3 bound to
      cells transfected with either CCR1 or -5 as well as to monocytes expressing both
      receptors. Further, it inhibited chemotaxis, the release of free intracellular
      calcium, and actin polymerization when cells were stimulated with known agonists
      of CCR1 and -5. An analysis of its three-dimensional structure indicated the
      presence of two distinct epitopes that may be involved in specific binding to
      CCR1, -2, -3, and -5. Taken together, our data thus indicate eotaxin-3 to be the
      first human chemokine that features broadband antagonistic activities, suggesting
      that it may have a modulatory rather than an inflammatory function. Further,
      eotaxin-3 may play an unrecognized role in the polarization of cellular
      recruitment by attracting Th2 lymphocytes as well as eosinophils and basophils
      via CCR3, while concomitantly blocking the recruitment of Th1 lymphocytes and
      monocytes via CCR1, -2, and -5.

PMID- 15039445
TI  - QO site deficiency can be compensated by extragenic mutations in the hinge region
      of the iron-sulfur protein in the bc1 complex of Saccharomyces cerevisiae.
AB  - The mitochondrial bc(1) complex catalyzes the oxidation of ubiquinol and the
      reduction of cytochrome (cyt) c. The cyt b mutation A144F has been introduced in
      yeast by the biolistic method. This residue is located in the cyt b cd(1)
      amphipathic helix in the quinol-oxidizing (Q(O)) site. The resulting mutant was
      respiration-deficient and was affected in the quinol binding and electron
      transfer rates at the Q(O) site. An intragenic suppressor mutation was selected
      (A144F+F179L) that partially alleviated the defect of quinol oxidation of the
      original mutant A144F. The suppressor mutation F179L, located at less than 4 A
      from A144F, is likely to compensate directly the steric hindrance caused by
      phenylalanine at position 144. A second set of suppressor mutations was obtained,
      which also partially restored the quinol oxidation activity of the bc(1) complex.
      They were located about 20 A from A144F in the hinge region of the iron-sulfur
      protein (ISP) between residues 85 and 92. This flexible region is crucial for the
      movement of the ISP between cyt b and cyt c(1) during enzyme turnover. Our
      results suggested that the compensatory effect of the mutations in ISP was due to
      the repositioning of this subunit on cyt b during quinol oxidation. This genetic
      and biochemical study thus revealed the close interaction between the cyt b cd(1)
      helix in the quinol-oxidizing Q(O) site and the ISP via the flexible hinge region
      and that fine-tuning of the Q(O) site catalysis can be achieved by subtle changes
      in the linker domain of the ISP.

PMID- 15039446
TI  - Identification of an interleukin-15alpha receptor-binding site on human
      interleukin-15.
AB  - To identify the epitopes in human interleukin-15 (IL-15) that are responsible for
      binding to the interleukin-15 receptor alpha chain, antibody and receptor mapping
      by peptide scanning and site-directed mutagenesis was used. By using peptide
      scanning, we identified four regions in IL-15. The first region
      ((85)CKECEELEEKN(95)) is located in the C-D loop and is recognized by a set of
      non-inhibitory antibodies. The second region ((102)SFVHIVQMFIN(112)) is located
      in helix D and is recognized by two antibodies that are inhibitory of IL-15 bio
      activity but not of IL-15 binding to IL-15Ralpha. The two remaining regions react
      with a recombinant soluble form of the IL-15Ralpha; the first ((44)LLELQVISL(52),
      peptide 1) corresponds to a sequence located in the B-helix and the second
      ((64)ENLII(68), peptide 2) to a sequence located in helix C. The latter is also
      contained in the epitope recognized by an antibody (monoclonal antibody B-E29)
      that prevents IL-15 binding to IL-15Ralpha. By site-directed mutagenesis, we
      confirmed that residues present in peptide 1 (Leu-45, Glu-46, Val-49, Ser-51, and
      Leu-52) and peptide 2 (Leu-66 and Ile-67) are involved in the binding of IL-15 to
      IL-15Ralpha. Furthermore, the results presented indicate that residues in the
      second peptide (Glu-64, Asn-65, and Ile-68) participate in IL-2Rbeta recruitment.
      This finding could have implications for the dynamics of receptor assembly. These
      results also indicate that the modes of interaction of IL-15 and IL-2 with their
      respective alpha chains are not completely analogous. Finally, some of the IL-15
      mutants generated in this study displayed agonist or antagonist properties and
      may be useful as therapeutic agents.

PMID- 15039447
TI  - Hox transcription factor ultrabithorax Ib physically and genetically interacts
      with disconnected interacting protein 1, a double-stranded RNA-binding protein.
AB  - The Hox protein family consists of homeodomain-containing transcription factors
      that are primary determinants of cell fate during animal development. Specific
      Hox function appears to rely on protein-protein interactions; however, the
      partners involved in these interactions and their function are largely unknown.
      Disconnected Interacting Protein 1 (DIP1) was isolated in a yeast two-hybrid
      screen of a 0-12-h Drosophila embryo library designed to identify proteins that
      interact with Ultrabithorax (Ubx), a Drosophila Hox protein. The Ubx.DIP1
      physical interaction was confirmed using phage display, immunoprecipitation, pull
      down assays, and gel retardation analysis. Ectopic expression of DIP1 in wing and
      haltere imaginal discs malforms the adult structures and enhances a decreased Ubx
      expression phenotype, establishing a genetic interaction. Ubx can generate a
      ternary complex by simultaneously binding its target DNA and DIP1. A large region
      of Ubx, including the repression domain, is required for interaction with DIP1.
      These more variable sequences may be key to the differential Hox function
      observed in vivo. The Ubx.DIP1 interaction prevents transcriptional activation by
      Ubx in a modified yeast one-hybrid assay, suggesting that DIP1 may modulate
      transcriptional regulation by Ubx. The DIP1 sequence contains two dsRNA-binding
      domains, and DIP1 binds double-stranded RNA with a 1000-fold higher affinity than
      either single-stranded RNA or double-stranded DNA. The strong interaction of Ubx
      with an RNA-binding protein suggests a wider range of proteins may influence Ubx
      function than previously appreciated.

PMID- 15039448
TI  - Glutathione propagates oxidative stress triggered by myeloperoxidase in HL-60
      cells. Evidence for glutathionyl radical-induced peroxidation of phospholipids
      and cytotoxicity.
AB  - Glutathione acts as a universal scavenger of free radicals at the expense of the
      formation of the glutathionyl radicals (GS*). Here we demonstrated that GS*
      radicals specifically interact with a reporter molecule, paramagnetic and non
      fluorescent 4-((9-acridinecarbonyl)-amino)-2,2,6,6-tetramethylpiperidine-1-oxyl
      (Ac-Tempo), and convert it into a non-paramagnetic fluorescent product,
      identified as 4-((9-acridinecarbonyl)amino)-2,2,6,6-tetramethylpiperidine (Ac
      piperidine). Horseradish peroxidase-, myeloperoxidase-, and
      cyclooxygenasecatalyzed oxidation of phenol in the presence of H2O2 and GSH
      caused the generation of phenoxyl radicals and GS* radicals, of which only the
      latter reacted with Ac-Tempo. Oxidation of several other phenolic compounds (e.g.
      etoposide and tyrosine) was accompanied by the formation of GS* radicals along
      with a characteristic fluorescence response from Ac-Tempo. In myeloperoxidase
      rich HL-60 cells treated with H2O2 and phenol, fluorescence microscopic imaging
      of Ac-Tempo revealed the production of GS* radicals. A thiol-blocking reagent, N
      ethylmaleimide, as well as myeloperoxidase inhibitors (succinyl acetone and
      azide), blocked formation of fluorescent acridine-piperidine. H2O2/phenolinduced
      peroxidation of major classes of phospholipids in HL-60 cells was completely
      inhibited by Ac-Tempo, indicating that GS* radicals were responsible for
      phospholipid peroxidation. Thus, GSH, commonly viewed as a universal free radical
      scavenger and major intracellular antioxidant, acts as a pro-oxidant during
      myeloperoxidase-catalyzed metabolism of phenol in HL-60 cells.

PMID- 15039449
TI  - Unraveling functional and structural interactions between transmembrane domains
      IV and XI of NhaA Na+/H+ antiporter of Escherichia coli.
AB  - A functionally important, interface domain between transmembrane segments (TMSs)
      IV and XI of the NhaA Na+/H+ antiporter of Escherichia coli has been unraveled.
      Scanning by single Cys replacements identified new mutations (F136C, G125C, and
      A137C) that cluster in one face of TMS IV and increase dramatically the Km of the
      antiporter. Whereas G125C, in addition, causes a drastic alkaline shift to the pH
      dependence of the antiporter, G338C alleviates the pH control of NhaA. Scanning
      by double Cys replacements (21 pairs of one replacement per TMS) identified
      genetically eight pairs of residues that showed very strong negative
      complementation. Cross-linking of the double mutants identified six double
      mutants (T132C/G338C, D133C/G338C, F136C/S342C, T132C/S342C, A137C/S342C, and
      A137C/G338C) of which pronounced intramolecular cross-linking defined an
      interface domain between the two TMSs. Remarkably, cross-linking by a short and
      rigid reagent (N,N'-o-phenylenedimaleimide) revived the Li+/H+ antiport activity,
      whereas a shorter reagent (1,2-ethanediyl bismethanethiosulfonate) revived both
      Na+/H+ and Li+/H+ antiporter activities and even the pH response of the dead
      mutant T132C/G338C. Hence, cross-linking at this position restores an active
      conformation of NhaA.

PMID- 15039450
TI  - Stimulatory actions of caffeic acid phenethyl ester, a known inhibitor of NF
      kappaB activation, on Ca2+-activated K+ current in pituitary GH3 cells.
AB  - Caffeic acid phenethyl ester (CAPE), a phenolic antioxidant derived from the
      propolis of honeybee hives, is known to be an inhibitor of activation of nuclear
      transcript factor NF-kappaB. Its effects on ion currents have been investigated
      in pituitary GH(3) cells. This compound increased Ca(2+)-activated K(+) current
      (I(K(Ca))) in a concentration-dependent manner with an EC(50) value of 14 +/- 2
      microm. However, the magnitude of CAPE-induced stimulation of I(K(Ca)) was
      attenuated in GH(3) cells preincubated with 2,2'-azo-bis-(2-amidinopropane)
      hydrochloride (100 microm) or t-butyl hydroperoxide (1 mm). CAPE (50 microm)
      slightly suppressed voltage-dependent L-type Ca(2+) current. In inside-out
      configuration, CAPE (20 microm) applied to the intracellular face of the detached
      patch enhanced the activity of large conductance Ca(2+)-activated K(+) (BK(Ca))
      channels with no modification in single-channel conductance. After BK(Ca) channel
      activity was increased by CAPE (20 microm), subsequent application of
      nordihydroguaiaretic acid (20 microm) did not further increase the channel
      activity. CAPE-stimulated channel activity was dependent on membrane potential.
      CAPE could also increase Ca(2+) sensitivity of BK(Ca) channels in these cells.
      Its increase in the open probability could primarily involve a decrease in the
      mean closed time. In current-clamp conditions, CAPE hyperpolarized the membrane
      potential and reduced the firing of action potentials. The stimulatory effects on
      these channels may partly contribute to the underlying mechanisms through which
      this compound influences the functional activities of neurons or neuroendocrine
      cells. Caution has to be used in attributing its response in the activation of NF
      kappaB.

PMID- 15039451
TI  - A Gcn4p homolog is essential for the induction of a ribosomal protein L41 variant
      responsible for cycloheximide resistance in the yeast Candida maltosa.
AB  - Cycloheximide (CYH) resistance in the yeast Candida maltosa is based on the
      inducible expression of genes encoding a variant of ribosomal protein L41-Q, with
      glutamine at position 56 instead of the proline found in normal L41. The promoter
      of L41-Q2a, one of the L41-Q gene alleles encoding L41-Q, has an element similar
      to the Gcn4p-responsive element of Saccharomyces cerevisiae. In a previous study,
      this element was shown to be essential for the induction of L41-Q by CYH. In the
      present study, a C. maltosa GCN4 homolog, C-GCN4, was cloned. It had a long 5'
      leader region with three upstream open reading frames. Enhanced expression of the
      C-GCN4 reporter fusion gene upon the addition of 3-aminotriazole or by mutations
      in start codons of all three upstream open reading frames indicates that C-GCN4
      expression is under translation repression as was seen with GCN4. The C-GCN4
      depleted mutant was unable to grow in a nutrient medium containing CYH and did
      not express L41-Q genes. Recombinant C-Gcn4p bound to the consensus DNA element
      for Gcn4p, 5'-(G/A)TGACTCAT-3', located upstream of L41-Q2a. Thus, C-Gcn4p, which
      likely functions in the general control of amino acid biosynthesis, is essential
      for the expression of L41-Q genes.

PMID- 15039452
TI  - Metformin causes reduction of food intake and body weight gain and improvement of
      glucose intolerance in combination with dipeptidyl peptidase IV inhibitor in
      Zucker fa/fa rats.
AB  - An incretin hormone, glucagon-like peptide-1 (GLP-1), has been shown to lower
      plasma glucose via glucose-dependent insulin secretion and to reduce appetite. We
      previously found that the biguanide metformin, an antidiabetic agent, causes a
      significant increase of plasma active GLP-1 level in the presence of dipeptidyl
      peptidase IV (DPPIV) inhibitor in normal rats. This finding suggested that the
      combination treatment might produce a greater antidiabetic and anorectic effect,
      based on enhanced GLP-1 action. In this study, we assessed the effects of
      subchronic treatment with metformin and a DPPIV inhibitor, valine-pyrrolidide
      (val-pyr), on glycemic control, food intake, and weight gain using Zucker fa/fa
      rats, a model of obesity and impaired glucose tolerance. The combination
      treatment caused a significant increase of GLP-1 level in Zucker fa/fa rats. In a
      subchronic study, val-pyr, metformin, or both compounds were administered orally
      b.i.d. for 14 days. The combination treatment significantly decreased food intake
      and body weight gain, although neither metformin nor val-pyr treatment alone had
      any effect. In an oral glucose tolerance test on day 1, the coadministration
      caused a greater improvement of glucose tolerance and a prominent increase of
      plasma active GLP-1 without marked insulin secretion. The 14-day combination
      treatment produced a potent reduction of fasting blood glucose and plasma insulin
      levels. These results demonstrate that the combination therapy of metformin with
      DPPIV inhibitor leads to reduced food intake and body weight gain, most likely
      through the significant increase of plasma GLP-1 level. The combination therapy
      seems to be a good candidate for treatment of type 2 diabetes with obesity.

PMID- 15039453
TI  - A pulmonary formulation of L-dopa enhances its effectiveness in a rat model of
      Parkinson's disease.
AB  - The efficacy of oral L-dopa becomes problematic with the progression of
      Parkinson's disease, due in large part to a lost ability to accommodate L-dopa's
      inherently poor pharmacokinetics. Pulmonary delivery represents a novel approach
      to reducing this problem. L-dopa was formulated into inhalable (Alkermes AIR)
      particles, and its pharmacokinetics and pharmacodynamics compared with those of
      an oral formulation. Pulmonary administration of L-dopa (2 mg) to rats resulted
      in a rapid elevation of plasma levels (C(max) = 4.8 +/- 1.10 microg/ml at 2 min),
      whereas oral administration of L-dopa produced a much delayed and lower C(max)
      (1.8 +/- 0.40 microg/ml at 30 min). In a rat model of Parkinson's disease
      (unilateral 6-hydroxydopamine lesion), the pulmonary formulation of L-dopa (0.5
      2.0 mg) yielded more rapid and robust elevations in striatal L-dopa, dopamine,
      and dihydroxyphenylacetic acid levels, as well as 2.5 to 3.7 times as many c-fos
      expressing striatal neurons. Moreover, motor function was significantly improved
      by 10 min after administration, with peak improvements occurring within 15 to 30
      min. In contrast, considerably higher doses (6.8-10 mg) of orally administered L
      dopa took over three times longer to produce similar effects. These results
      suggest that an inhalable formulation of l-dopa has superior pharmacokinetic
      properties and may provide patients with a more effective form of rescue therapy
      as well as being a reliable adjuvant or replacement for first-line oral therapy.

PMID- 15039454
TI  - Metallothionein mediates the level and activity of nuclear factor kappa B in
      murine fibroblasts.
AB  - The zinc-binding protein metallothionein (MT) is associated with resistance to
      apoptosis. We examined whether MT regulates the zinc-dependent antiapoptotic
      transcription factor nuclear factor KappaB (NF-KappaB), which is up-regulated
      under many conditions that lead to elevated MT expression. NF-KappaB protein
      levels and NF-KappaB-dependent reporter gene activity were examined in clonal
      MT(+) (MT-WT) and MT(-) (MT-KO) fibroblastic cell lines. The amount of cellular
      NF-KappaB p65 protein in MT-KO was less than 20% of the amount in MT-WT cells, in
      accord with increased sensitivity of MT-KO cells to apoptosis. NF-KappaB p65 mRNA
      levels, and NF-KappaB p50 subunit and IKappaBalpha protein levels, were
      unchanged. NF-KappaB activity assessed by expression of a transfected NF-KappaB
      reporter construct was less than half that observed in MT-KO cells. Decreased
      nuclear localization of NF-KappaB p65 in MT-KO clones was not responsible for
      differences in activity. In fact, MT-KO cells had higher nuclear levels of NF
      KappaB p65 than did MT-WT cells, despite a lower cellular NF-KappaB level and
      function, suggesting that metallothionein mediated the specific activity of NF
      KappaB. Reconstitution of MT by stable incorporation of an MT-1 expression vector
      in MT-KO cells resulted in increased NF-KappaB p65 (but not IKappaBalpha or NF
      KappaB p50), increased NF-KappaB-dependent reporter activity, and increased
      resistance to apoptosis. These data support the hypothesis that metallothionein
      positively regulates the cellular level and activity of NF-KappaB.

PMID- 15039455
TI  - Cell type-specific recruitment of Drosophila Lin-7 to distinct MAGUK-based
      protein complexes defines novel roles for Sdt and Dlg-S97.
AB  - Stardust (Sdt) and Discs-Large (Dlg) are membrane-associated guanylate kinases
      (MAGUKs) involved in the organization of supramolecular protein complexes at
      distinct epithelial membrane compartments in Drosophila. Loss of either Sdt or
      Dlg affects epithelial development with severe effects on apico-basal polarity.
      Moreover, Dlg is required for the structural and functional integrity of synaptic
      junctions. Recent biochemical and cell culture studies have revealed that various
      mammalian MAGUKs can interact with mLin-7/Veli/MALS, a small PDZ-domain protein.
      To substantiate these findings for their in vivo significance with regard to Sdt-
      and Dlg-based protein complexes, we analyzed the subcellular distribution of
      Drosophila Lin-7 (DLin-7) and performed genetic and biochemical assays to
      characterize its interaction with either of the two MAGUKs. In epithelia, Sdt
      mediates the recruitment of DLin-7 to the subapical region, while at larval
      neuromuscular junctions, a particular isoform of Dlg, Dlg-S97, is required for
      postsynaptic localization of DLin-7. Ectopic expression of Dlg-S97 in epithelia,
      however, was not sufficient to induce a redistribution of DLin-7. These results
      imply that the recruitment of DLin-7 to MAGUK-based protein complexes is defined
      by cell-type specific mechanisms and that DLin-7 acts downstream of Sdt in
      epithelia and downstream of Dlg at synapses.

PMID- 15039456
TI  - Palmitoylation controls trafficking of GAD65 from Golgi membranes to axon
      specific endosomes and a Rab5a-dependent pathway to presynaptic clusters.
AB  - The GABA-synthesizing enzyme GAD65 is synthesized as a soluble cytosolic protein
      but undergoes post-translational modification(s) to become anchored to the
      cytosolic face of Golgi membranes before targeting to synaptic vesicle membranes
      in neuroendocrine cells. Palmitoylation of cysteines 30 and 45 in GAD65 is not
      required for targeting to Golgi membranes but is crucial for post-Golgi
      trafficking to presynaptic clusters in neurons. Here, we show that palmitoylated
      GAD65 colocalizes with the small GTP-binding protein Rab5a in Golgi membranes and
      in axons but not in dendrites. In the presence of the constitutively positive
      mutant Rab5(Q79L) palmitoylation resulted in polarized targeting of GAD65 to
      giant Rab5a-positive axonal endosomes, characterized by the absence of the Rab5a
      effector molecule EEA1 and the transferrin receptor. By contrast, Rab5a
      positive/EEA1-positive somatodendritic giant endosomes containing the transferrin
      receptor were devoid of GAD65. Palmitoylation-deficient GAD65 was excluded from
      endosomal compartments. A dominant negative mutant of Rab5a, Rab5a(S34N),
      specifically blocked axonal trafficking and presynaptic clustering of
      palmitoylated GAD65, but did not affect axonal trafficking of mutants of GAD65
      that fail to traffic to giant axonal endosomes containing Rab5a(Q79L). Two
      transmembrane synaptic vesicle proteins, VAMP2 and VGAT also localized to the
      axonal giant endosomes, and their axonal trafficking and presynaptic clustering
      was blocked by Rab5a(S34N). The results suggest that palmitoylation of GAD65
      regulates the trafficking of the protein from Golgi membranes to an endosomal
      trafficking pathway in axons that is dependent on Rab5a and is required for the
      targeting of several synaptic vesicle proteins to presynaptic clusters.

PMID- 15039457
TI  - Sister chromatid separation at human telomeric regions.
AB  - Telomeres are nucleoprotein complexes located at chromosome ends, vital for
      preserving chromosomal integrity. Telomeric DNA shortens with progressive rounds
      of cell division, culminating in replicative senescence. Previously we have
      reported, on the basis of fluorescent in situ hybridization, that several human
      telomeric regions display solitary signals (singlets) in metaphase cells of
      presenescent fibroblasts, in comparison to other genomic regions that hybridize
      as twin signals (doublets). In the current study, we show that an additional 12
      out of 12 telomeric regions examined also display metaphase singlet signals in
      pre-senescent cells, and that excess telomere-metaphase singlets also occur in
      earlier passage cells harvested from elderly individuals. In cancer cell lines
      expressing telomerase and in pre-senescent fibroblasts ectopically expressing
      hTERT, this phenomenon is abrogated. Confocal microscope image analysis showed
      that the telomere metaphase singlets represent regions that have replicated but
      not separated; this is presumably because of persistent cohesion. The
      introduction of mutations that interfere with the normal dissolution of cohesion
      at the metaphase to anaphase transition induced the cut (chromosomes untimely
      torn) phenotype in early passage fibroblasts, with predominantly telomeric rather
      than centromeric DNA, present on the chromatin bridges between the daughter
      nuclei. These results suggest that telomeric regions in animal cells may
      potentially be sites of persistent cohesion, and that this cohesion may be the
      basis for an observed excess of fluorescent in situ hybridization metaphase
      singlets at telomeres. Persistent cohesion at telomeres may be associated with
      attempted DNA repair or chromosomal abnormalities, which have been described in
      pre-senescent cells.

PMID- 15039458
TI  - Myofilament anchoring of protein kinase C-epsilon in cardiac myocytes.
AB  - Regulatory proteins on muscle filaments are substrates for protein kinase C (PKC)
      but mechanisms underlying activation and translocation of PKC to this non
      membrane compartment are poorly understood. Here we demonstrate that the epsilon
      isoform of PKC (epsilon-PKC) activated by arachidonic acid (AA) binds reversibly
      to cardiac myofibrils with an EC(50) of 86 nM. Binding occurred near the Z-lines
      giving rise to a striated staining pattern. The delta isoform of PKC (delta-PKC)
      did not bind to cardiac myofibrils regardless of the activator used, and the
      alpha isoform (alpha-PKC) bound only under strong activating conditions. Three
      established PKC anchoring proteins, filamentous actin (F-actin), the LIM domain
      protein Cypher-1, and the coatamer protein beta'-COP were each tested for their
      involvement in cytoskeletal anchoring. F-actin bound epsilon-PKC selectively over
      delta-PKC and alpha-PKC, but this interaction was readily distinguishable from
      cardiac myofilament binding in two ways. First, the F-actin/epsilon-PKC
      interaction was independent of PKC activation, and second, the synthetic
      hexapeptide LKKQET derived from the C1 region of epsilon-PKC effectively blocked
      epsilon-PKC binding to F-actin, but was without effect on its binding to cardiac
      myofilaments. Involvement of Cypher-1 was ruled out on the basis of its absence
      from detergent-skinned myofibrils that bound epsilon-PKC, despite its presence in
      intact cardiac myocytes. The epsilon-PKC translocation inhibitor peptide EAVSLKPT
      reduced activated epsilon-PKC binding to cardiac myofibrils in a concentration
      dependent manner, suggesting that a RACK2 or a similar protein plays a role in
      epsilon-PKC anchoring in cardiac myofilaments.

PMID- 15039459
TI  - The small GTPase Rab27B regulates amylase release from rat parotid acinar cells.
AB  - Small GTPase Rab is a large family of putative membrane trafficking proteins, and
      each member is thought to regulate a specific type(s) of membrane trafficking.
      However, little is known about the involvement of Rab protein(s) in secretory
      granule exocytosis in exocrine cells or the molecular mechanism underlying this
      process. We show that Rab27B, a closely related isoform of Rab27A that regulates
      lysosome-related granule exocytosis in cytotoxic T lymphocytes, is abundantly
      expressed on amylase-containing secretory granules in rat parotid gland acinar
      cells. We also identify the putative Rab27B effector protein, Slac2-c (Slp
      homologue lacking C2 domains-c)/MyRIP, which was originally described as a myosin
      Va/VIIa and actin binding protein, in rat parotid glands. The results of
      subcellular fractionation, immunoprecipitation and immunohistochemical studies
      indicate that the Rab27B-Slac2-c complex is formed on secretory granules in vivo.
      The introduction of either a specific Rab27 binding domain (i.e. a recombinant
      Slp homology domain of Slac2-b that specifically binds Rab27A/B but not other
      Rabs) or functionally blocking antibodies that specifically disrupt Rab27B-Slac2
      c complex in vitro strongly inhibited isoproterenol-stimulated amylase release
      from streptolysin O-permeabilized parotid acinar cells. Our results indicate that
      the Rab27B-Slac2-c complex is an important constituent of secretory granule
      exocytosis in parotid acinar cells.

PMID- 15039460
TI  - Length control is determined by the pattern of cytoskeleton.
AB  - In our previous experiments with linear strips of adhesive substrate, we found
      that elongated cultured fibroblasts preserve their length regardless of cell
      width and the number of cytoplasmic processes. This constancy of length was
      called 'length control'. In contrast to fibroblasts, single cultured
      epitheliocytes have nearly discoid shape on the plane substrata and have no
      length-controlling mechanism: their length on the narrow strips of adhesive
      substrate increased significantly in comparison with the diameter on the plane
      substrate. These results suggested that control of length is cell specific. An
      alternative suggestion is that length control is associated not with the cell
      type but with the cell cytoskeletal pattern (namely, with epithelioid circular
      actin bundles or straight actin bundles). Experiments described in this paper
      were made to choose between these two suggestions. Mouse embryo fibroblasts
      spreading on the planar substrate first acquire discoid epithelioid shape with a
      circular actin bundle. Only later did they acquire a polarized shape with
      straight actin bundles. Polarized, fully spread fibroblasts temporarily acquire
      discoid epithelioid shape when treated with the Taxol, disorganizing
      microtubules. However, epithelial discoid cells can be transformed into elongated
      fibroblast-like cells by scatter factor (HGF/SF; a cytokine) and by agents
      inhibiting Rho kinase. These reversible transitions from fibroblastic to
      epithelioid shape and vice versa were accompanied by a corresponding
      disappearance and appearance of length control. Fibroblasts with stress fibers
      destroyed by the Rho-kinase inhibitor Y27632 became considerable longer on the
      adhesive strips than on the plane while retaining a near-polarized shape. Thus,
      length control is typical not of the cell origin but of the cell phenotype (i.e.
      for polarized cells with microtubules and intact actin cytoskeleton).

PMID- 15039461
TI  - Glucose induces de novo lipogenesis in rat muscle satellite cells through a
      sterol-regulatory-element-binding-protein-1c-dependent pathway.
AB  - We previously reported that sterol-regulatory-element-binding-protein-1c (SREBP
      1c) mediates insulin upregulation of genes encoding glycolytic and lipogenic
      enzymes in rat skeletal muscle. Here, we assessed whether glucose could regulate
      gene expression in contracting myotubes deriving from cultured muscle satellite
      cells. Glucose uptake increased twofold after a 30 minute treatment with a high
      glucose concentration, suggesting an acute glucose-stimulated glucose uptake.
      Time-course experiments showed that, within 3 hours, glucose stimulated the
      expression of hexokinase II, fatty acid synthase and acetyl-CoA-carboxylase-2
      proteins, leading to an increased lipogenic flux and intracellular lipid
      accumulation in contracting myotubes. Furthermore, kinetic experiments indicated
      that glucose upregulated SREBP-1c precursor and nuclear proteins within 30
      minutes, SREBP-1c nuclear translocation being confirmed using
      immunocytochemistry. In addition, the knockdown of SREBP-1 mRNA using a RNA
      interference technique totally abrogated the glucose-induced upregulation of
      lipogenic enzymes, indicating that SREBP-1c mediates the action of glucose on
      these genes in rat skeletal muscle. Finally, we found that glucose rapidly
      stimulated SREBP-1c maturation through a Jak/STAT dependent pathway. We propose
      that increased intramuscular lipid accumulation associated with muscle insulin
      resistance in obesity or type-2 diabetes could arise partly from de novo fatty
      acid synthesis in skeletal muscle.

PMID- 15039462
TI  - Syntaxin 8 impairs trafficking of cystic fibrosis transmembrane conductance
      regulator (CFTR) and inhibits its channel activity.
AB  - The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic AMP
      dependent chloride channel that mediates electrolyte transport across the luminal
      surface of epithelial cells. In this paper, we describe the CFTR regulation by
      syntaxin 8, a t-SNARE protein (target soluble N-ethylmaleimide-sensitive factor
      attachment protein receptor) involved in the SNARE endosomal complex. Syntaxin
      family members are key molecules implicated in diverse vesicle docking and
      membrane fusion events. We found that syntaxin 8 physically interacts with CFTR:
      recombinant syntaxin 8 binds CFTR in vitro and both proteins co-immunoprecipitate
      in HT29 cells. Syntaxin 8 regulates CFTR-mediated currents in chinese hamster
      ovary (CHO) cells stably expressing CFTR and syntaxin 8. Iodide efflux and whole
      cell patch-clamp experiments on these cells indicate a strong inhibition of CFTR
      chloride current by syntaxin 8 overexpression. At the cellular level, we observed
      that syntaxin 8 overexpression disturbs CFTR trafficking. Confocal microscopy
      shows a dramatic decrease in green fluorescent protein-tagged CFTR plasma
      membrane staining, when syntaxin 8 is coexpressed in COS-7 cells. Using
      antibodies against Lamp-1, TfR or Rab11 we determined by immunofluorescence
      assays that both proteins are mainly accumulated in recycling endosomes. Our
      results evidence that syntaxin 8 contributes to the regulation of CFTR
      trafficking and chloride channel activity by the SNARE machinery.

PMID- 15039463
TI  - Oxygen radical-induced natural killer cell dysfunction: role of myeloperoxidase
      and regulation by serotonin.
AB  - Natural killer (NK) cells are functionally suppressed and induced to apoptosis by
      reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs). These
      inhibitory events are reversed by the biogenic amine serotonin. MPs generate
      hydrogen peroxide (H(2)O(2)), which is processed further by myeloperoxidase (MPO)
      to even more toxic compounds. Earlier studies suggest that serotonin scavenges MP
      derived oxygen radicals generated by the MPO-H(2)O(2) system. These findings led
      us to explore the capability of MPO-deficient MPs to induce NK cell dysfunction.
      We show that MPs recovered from subjects with MPO deficiency trigger inhibition
      of NK cells. In addition, MPs recovered from healthy subjects conveyed
      suppression of NK cells in the presence of the MPO inhibitor ceruloplasmin. We
      conclude that ROS-dependent inhibition of NK cell function is unrestricted by the
      availability of MPO-derived oxygen radicals and that the protecting properties of
      serotonin may operate in the absence of functional MPO. Our data suggest a
      complex mechanism of MP-induced NK cell inhibition, which comprises the
      generation of interchangeable oxygen radicals.

PMID- 15039464
TI  - TGF-beta down-regulates IL-1alpha-induced TLR2 expression in murine hepatocytes.
AB  - We have previously reported that the proinflammatory cytokine interleukin (IL)
      1alpha can up-regulate functional Toll-like receptor 2 (TLR2) expression in
      primary-cultured murine hepatocytes, and bacterial lipopeptide (BLP) is capable
      of signaling through TLR2 to induce serum amyloid A (SAA) expression in
      hepatocytes. In the present study, we investigated the effect of the anti
      inflammatory cytokine transforming growth factor-beta (TGF-beta) on TLR2
      expression in primary-cultured murine hepatocytes. At the mRNA and protein
      levels, TGF-beta up-regulated TLR2 expression but inhibited TLR2 expression
      induced by IL-1alpha at 24 h. BLP-induced SAA promoter activity could be
      augmented by pretreatment with IL-1alpha but not TGF-beta or the combination of
      TGF-beta and IL-1alpha. TLR2 promoter activity and nuclear factor (NF)-kappaB
      activation by IL-1alpha were inhibited by TGF-beta treatment. Pretreatment with
      TGF-beta strongly suppressed IL-1alpha-induced TLR2 promoter activity and NF
      kappaB activation, which was consistent with the down-regulation of type I IL-1
      receptor (IL-1RI) mRNA expression. IL-1alpha up-regulated IL-1RI mRNA, but it was
      inhibited by the treatment with TGF-beta. These results suggest that TGF-beta
      suppresses the induction of TLR2 expression by IL-1alpha through down-regulation
      of IL-1RI expression. These results also demonstrate the disparity between IL
      1alpha and TGF-beta in regulating TLR2-mediated SAA production in hepatocytes.

PMID- 15039465
TI  - Ascorbate-mediated enhancement of reactive oxygen species generation from
      polymorphonuclear leukocytes: modulatory effect of nitric oxide.
AB  - Recent studies from our laboratory have demonstrated that ascorbate potentiated
      enzymatic synthesis of nitric oxide (NO) from polymorphonuclear leukocytes
      (PMNs). NO is known to modulate various function of PMNs such as chemotaxis,
      adherence, aggregation, and generation of reactive oxygen species (ROS). The role
      of ascorbate in the PMN phagocytosis, ROS generation, and apoptosis was thus
      evaluated in the present study. Ascorbate and its oxidized and cell-permeable
      analog, dehydroascorbate (DHA), did not affect the phagocytosis but enhanced ROS
      generation and apoptosis following treatment with Escherichia coli or arachidonic
      acid. A detailed investigation on the DHA-mediated response indicated that
      inhibitors of DHA uptake, reduced nicotinamide adenine dinucleotide phosphate
      oxidase, NO synthase, or ROS scavengers attenuated ROS generation. In DHA-treated
      cells, enhanced generation of peroxynitrite was also observed; thus, ascorbate
      mediated ROS and reactive nitrogen species generation might mediate cytotoxicity
      toward the ingested microbes and subsequently, augmented PMN apoptosis. Results
      of the present study have helped in delineating the role of ascorbate in the
      modulation of NO-mediated ROS generation from PMNs.

PMID- 15039466
TI  - Infection of C57BL/10ScCr and C57BL/10ScNCr mice with Leishmania major reveals a
      role for Toll-like receptor 4 in the control of parasite replication.
AB  - The innate immune system is essential for host defense; it senses the presence of
      potentially pathogenic-invading microorganisms, and the contribution of Toll-like
      receptors (TLRs) to this response is increasingly recognized. In the present
      study, we investigated the contribution of TLR4 to the course of cutaneous
      leishmaniasis in vivo. We used C57BL/10ScNCr (TLR4(0/0)) and C57BL/10ScCr
      [TLR4/interleukin-12 (IL-12)Rbeta2(0/0)] mice and compared the course of
      Leishmania major infection, parasite load, cell recruitment, and cytokine profile
      with those of wild-type C57BL/10ScSn mice. Our results confirm the importance of
      IL-12 receptor-mediated signaling in resistance to L. major infections.
      Importantly, we show that the lack of TLR4 results in an increased permissiveness
      for parasite growth during the innate and adaptive phase of the immune response
      and in delayed healing of the cutaneous lesions. The use of the tlr4 transgenic
      mouse strain TCr5 demonstrated unequivocally that TLR4 contributes to the
      efficient control of Leishmania growth in vivo.

PMID- 15039467
TI  - Aging and innate immune cells.
AB  - The innate immune system serves an important role in preventing microbial
      invasion. However, it experiences significant changes with advancing age. Among
      the age-associated changes are: Aged macrophages and neutrophils have impaired
      respiratory burst and reactive nitrogen intermediates as a result of altered
      intracellular signaling, rendering them less able to destroy bacteria. Aged
      neutrophils are also less able to respond to rescue from apoptosis. Aged
      dendritic cells (DC) are less able to stimulate T and B cells. The altered T cell
      stimulation is a result of changes in human leukocyte antigen expression and
      cytokine production, and lower B cell stimulation is a result of changes in DC
      immune complex binding. Natural killer (NK) cells from the elderly are less
      capable of destroying tumor cells. NK T cells increase in number and have greater
      interleukin-4 production with age. Levels of various complement components are
      also altered with advancing age.

PMID- 15039468
TI  - Immunopathogenesis of atherosclerosis.
AB  - Recent clinical studies indicate that the number of microbial infections (the
      "pathogen burden") critically determines the development and progression of
      atherosclerotic disease. Viruses or bacteria with a specific tropism for cells of
      the vascular wall may contribute to the initial vascular injury via direct
      cytopathic effects or via the induction of genuine autoimmune responses.
      Immunopathological processes such as molecular mimicry, epitope spreading, or
      bystander activation of self-reactive lymphocytes most likely fuel the chronic
      inflammatory process in the vascular wall. Recognition of atherogenesis as a
      pathogen-driven, immunopathological process makes this disease amenable to new
      treatment strategies such as vaccination or immunomodulation.

PMID- 15039470
TI  - Tumor lysis syndrome following a single dose of capecitabine.

PMID- 15039469
TI  - Morphine-induced macrophage apoptosis: oxidative stress and strategies for
      modulation.
AB  - Occurrence of macrophage apoptosis has been implicated for the altered immune
      function found in an opiate milieu. In the present study, we evaluated the role
      of oxidative stress in morphine-induced macrophage apoptosis. Morphine promoted
      the apoptosis of macrophages. This effect of morphine was associated with the
      production of superoxide and nitric oxide (NO). Antioxidants provided protection
      against morphine-induced macrophage injury. In addition, diphenyleneiodonium
      chloride, an inhibitor of reduced nicotinamide adenine dinucleotide phosphate
      (NADPH) oxidase activation, attenuated the proapoptotic effect of morphine.
      Antitransforming growth factor-beta (anti-TGF-beta) antibody and propranolol (an
      inhibitor of the phospholipase D pathway) inhibited morphine-induced superoxide
      generation as well as apoptosis. N'-Tetraacetic acid tetra (acetoxymethyl) ester,
      a calcium-chelating agent, inhibited morphine-induced apoptosis, whereas
      thapsigargin (a calcium agonist) stimulated macrophage apoptosis under basal as
      well as morphine-stimulated states. These studies suggest that morphine-induced
      macrophage apoptosis is mediated through downstream signaling involving TGF-beta
      and NO production. Moreover, there is NADPH oxidation activation involving
      phospholipase D and Ca(2+), leading to the generation of superoxide. In in vivo
      studies, administration of N-acetyl cysteine and preinduction of heme oxygenase
      activity and epoetin alpha prevented morphine-induced peritoneal macrophage
      apoptosis, thus further confirming the role of oxidative stress in morphine
      induced macrophage apoptosis.

PMID- 15039471
TI  - Warfarin resistance with poor CYP2C9 activity and CYP2C9*1*2 genotype.

PMID- 15039473
TI  - Parecoxib for parenteral analgesia in postsurgical patients.
AB  - OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy and
      safety studies, adverse effects, drug interactions, and dosage and administration
      of parecoxib sodium, a selective cyclooxygenase-2 (COX-2) inhibitor. DATA
      SOURCES: Information was obtained from MEDLINE searches of the English-language
      literature (1996-May 2003). Search terms included parecoxib, parecoxib sodium, SC
      69124A, and selective cyclooxygenase-2 inhibitor. STUDY SELECTION AND DATA
      EXTRACTION: We reviewed available literature, which included abstracts, clinical
      trials, and data on file with the manufacturer. DATA SYNTHESIS: Parecoxib sodium
      is a novel selective COX-2 inhibitor under development for parenteral
      administration. It has produced efficacious analgesia following dental,
      gynecologic, and orthopedic surgery. The adverse effect profile has been compared
      with that of ketorolac; no statistically significant differences were identified.
      There are no documented drug interactions when parecoxib is coadministered with
      midazolam, propofol, or unfractionated heparin. CONCLUSIONS: Parecoxib sodium is
      in the final stages of Phase III trials and has a favorable safety and efficacy
      profile. Its place in moderate to severe postsurgical pain management will be
      further defined when more pharmacoeconomic and postmarketing safety data are
      available. Theoretical benefits are its lower potential for gastrointestinal
      adverse effects compared with ketorolac and lower opioid requirements after
      surgery.

PMID- 15039472
TI  - Fenoldopam versus nitroprusside for the treatment of hypertensive emergency.
AB  - BACKGROUND: While sodium nitroprusside remains first-line therapy for
      hypertensive emergency (HEM), fenoldopam is increasingly being used because of
      its benign safety profile and potential renal protective effects. OBJECTIVE: To
      compare the efficacy, safety, and cost of sodium nitroprusside versus fenoldopam
      for the treatment of HEM. METHODS: This study was a retrospective analysis of
      consecutive patients with HEM admitted to a university-affiliated, level 1 trauma
      center from 1999 to 2001 and treated with either nitroprusside (n = 21) or
      fenoldopam (n = 22) for >30 minutes. Time to reach mean arterial pressure (MAP)
      goal, change in MAP over time, time to initiation of oral antihypertensive
      therapy, change in renal function, incidence of cyanide toxicity, and cost of
      therapy were compared between groups. RESULTS: Demographic parameters were
      similar between groups, except renal failure, which was more prevalent in the
      fenoldopam group (10% vs 46%; p = 0.009). Neither the mean +/- SD pretreatment
      MAP (nitroprusside 168 +/- 19; fenoldopam 163 +/- 19; p = 0.45), time to reach
      MAP goal (3.6 [0.4-30] vs 4 [1-22] h; p = 0.51), nor infusion duration (18 [0.7
      113] vs 18 [3-74] h; p = 0.45) differed between the patient groups. Time to
      initiation of oral antihypertensive therapy was similar between nitroprusside-
      (4.5 h [0.5-22] and fenoldopam--(6.5 h [1-100] treated patients; p = 0.65).
      Additional intravenous antihypertensives were administered to 16 patients in each
      group (p = 0.80). Change in creatinine clearance and incidence of tachycardia did
      not differ between groups. No symptoms of cyanide toxicity were detected. Cost of
      drug therapy was greater with fenoldopam (597.60 dollars, 199.20-6675.20
      dollars); than nitroprusside (2.66 dollars, 1.68-3.48 dollars; p < 0.001).
      CONCLUSIONS: Treatment of HEM with fenoldopam appears to result in patient
      outcomes equivalent to those with nitroprusside but at a substantially higher
      cost. Further study is required to delineate the exact role of fenoldopam for
      treatment of HEM.

PMID- 15039474
TI  - Dexmedetomidine overdose in the perioperative setting.
AB  - OBJECTIVE: To report 3 cases of accidental dexmedetomidine overdose in the
      perioperative setting and review the pathophysiology of alpha2-agonist overdose.
      case summaries: Three patients accidentally received overdoses of
      dexmedetomidine, one intraoperatively (192 microg over 20 min) and 2
      postoperatively (4 and 2 rather than 0.4 and 0.2 microg/kg/h; 0.5 microg/kg/min
      rather than 0.5 microg/kg/h). Hemodynamic parameters remained stable for all 3
      patients. The most notable sign was oversedation diagnosed either clinically or
      using a bispectral index monitor; Naranjo criteria suggest possible or probable
      association of the reactions with dexmedetomidine. In all 3 cases, oversedation
      resolved within one hour of drug discontinuation. There were no other sequelae,
      and the remainder of each patient's hospital course was unremarkable. DISCUSSION:
      As of this writing, dexmedetomidine dosing in excess of the label recommendation
      has been reported, but accidental dexmedetomidine overdose in clinical practice
      has not been described. Excessive levels of sedation were the only significant
      finding in all 3 patients. Dexmedetomidine's short redistribution half-life of 6
      minutes should lead to rapid resolution of oversedation induced by overdoses if
      the overall duration of infusion is short (< or =8 h). While the patients
      reported here were hemodynamically stable, dexmedetomidine may engender
      significant hemodynamic changes either because of sympatholysis at normal doses
      or vasoconstriction at higher than recommended doses. The absence of a
      significant hypertensive response to high dexmedetomidine concentrations suggests
      that dexmedetomidine-induced hypertension may be multifactorial, not simply
      related to plasma drug concentrations. CONCLUSIONS: Practitioners presented with
      dexmedetomidine overdose should be prepared to manage oversedation. While
      hemodynamic alterations may be seen with dexmedetomidine use, hypertension from
      high dexmedetomidine plasma concentrations is not a consistent response.
      Practitioners using dexmedetomidine should carefully note that dosing for this
      agent is described by the manufacturer in microg/kg/h, not microg/kg/min.

PMID- 15039475
TI  - Rate versus rhythm control in atrial fibrillation.
AB  - OBJECTIVE: To determine whether rate control is a viable initial treatment
      approach in persistent atrial fibrillation (AF) through the evaluation of
      recently completed trials comparing rate and rhythm control. DATA SOURCES:
      Biomedical literature was obtained through MEDLINE (1966-December 2003) and the
      Iowa database. STUDY SELECTION AND DATA EXTRACTION: Articles identified from the
      biomedical literature search were reviewed and included if deemed relevant. DATA
      SYNTHESIS: Currently available data suggest that rate control is not inferior to
      rhythm control in patients with persistent AF with respect to mortality. Rate
      control also reduces hospitalizations and the occurrence of proarrhythmias. No
      significant difference was observed between treatments with respect to
      thromboembolism and strokes. CONCLUSIONS: Due to the increased incidence of
      hospitalizations and antiarrhythmic adverse effects associated with rhythm
      control, rate control is a reasonable first-line strategy in the treatment of
      recurrent AF, especially in elderly patients who are asymptomatic or mildly
      symptomatic. Further studies are needed to clearly define the role of rate
      control in younger patients.

PMID- 15039477
TI  - Fever and eosinophilia associated with voriconazole.

PMID- 15039476
TI  - Thiazolidinedione-induced congestive heart failure.
AB  - OBJECTIVE: To report 2 cases of thiazolidinedione (TZD)-associated congestive
      heart failure (CHF). As of March 13, 2004, one of the cases may represent the
      first description of TZD-associated cardiomyopathy in humans. case summaries: A
      57-year-old obese white man with type 2 diabetes was treated with pioglitazone 30
      mg/day and insulin. He had no prior history of CHF and had an excellent exercise
      tolerance. Over the first 4 weeks of pioglitazone therapy, the patient
      experienced significant weight gain and subsequently developed CHF and pulmonary
      edema. A 50-year-old obese white man with type 2 diabetes presented with
      cardiogenic shock. Rosiglitazone 4 mg once daily had been initiated 6 weeks prior
      to presentation. He had no prior history of cardiac disease, and investigations
      did not reveal a cause for the cardiogenic shock. Rosiglitazone therapy was
      discontinued on admission. He improved and was discharged 21 days later.
      DISCUSSION: TZDs are oral agents used for the treatment of type 2 diabetes. TZD
      associated CHF and pulmonary edema have been reported in patients with a prior
      history of CHF. These 2 cases highlight that this adverse event can occur even in
      the absence of any preexisting history of clinical heart failure or cardiac
      disease. The second case may represent the first description of TZD-associated
      cardiomyopathy in humans. In both cases, an objective causality assessment using
      the Naranjo probability scale revealed that the adverse drug reaction between
      cardiomyopathy and rosiglitazone in this patient was probable. CONCLUSIONS: TZD
      should be considered as a cause in the differential diagnosis of CHF and
      pulmonary edema in patients without a prior history of clinical CHF or cardiac
      disease. Healthcare professionals should be aware of the possible association
      between TZDs and cardiomyopathy.

PMID- 15039478
TI  - Intermittent visceral edema induced by long-term enalapril administration.
AB  - OBJECTIVE: To describe a case of intermittent visceral angioedema associated with
      long-term enalapril use. CASE SUMMARY: A 72-year-old white woman developed severe
      abdominal pain as a result of visceral angioedema associated with long-term
      enalapril therapy. She had been taking enalapril 20 mg/day for 9 years prior to
      the first reported episodes of abdominal pain. DISCUSSION: Visceral angioedema
      associated with angiotensin-converting enzyme (ACE) inhibitors is a documented
      adverse effect. However, onset of symptoms has never been reported after 9 years
      of use. Not until 2 years after initial presentation were the symptoms correlated
      to enalapril administration. Since discontinuation of enalapril, the patient has
      not reported any symptoms for >2 years. An objective causality assessment
      categorized this adverse drug event as a result of enalapril as possible.
      CONCLUSIONS: Development of angioedema from ACE inhibitors occurs in <1% of the
      population. Limited case reports have identified intermittent visceral angioedema
      from ACE inhibitors. However, it is important to recognize that this adverse
      effect can also occur in patients who have been treated with ACE inhibitor
      therapy for several years.

PMID- 15039479
TI  - Transitory ataxia related to topically administered lidocaine.
AB  - OBJECTIVE: To report 2 cases of transitory cerebellar ataxia related to lidocaine
      administered topically for endoscopy. case summaries: Two patients developed
      transitory cerebellar ataxia a few minutes after local anesthesia using lidocaine
      10% spray and lidocaine 2% orally for a bronchoscopy and transesophageal
      echocardiography. This effect completely disappeared in 3-5 hours. In neither
      case was an alternate etiology of cerebellar ataxia identified. The second
      patient had previously experienced a similar reaction to lidocaine. DISCUSSION:
      Several central neurologic effects of lidocaine have been reported, but until
      now, only few cases of cerebellar ataxia. In these 2 cases, the Naranjo
      probability scale indicated that a probable and a highly probable relationship
      existed between lidocaine administration and the transitory cerebellar ataxia.
      CONCLUSIONS: Cerebellar ataxia may occur after local anesthesia with lidocaine;
      therefore, care must be taken to avoid overdose, even when administered
      topically.

PMID- 15039480
TI  - Urinary retention following repeated high-dose quetiapine.

PMID- 15039481
TI  - Weight gain mitigation with topiramate in mood disorders.
AB  - OBJECTIVE: To review the evidence of weight loss with use of topiramate in
      patients with mood disorders. DATA SOURCES: Literature search included MEDLINE
      (1966-December 2003), International Pharmaceutical Abstracts (1970-December
      2003), and EMBASE (1980-December 2003). Search terms included topiramate, weight
      loss, adverse effect, mood disorders, bipolar disorder. DATA SYNTHESIS: Weight
      gain is a common adverse effect of many agents used to treat mood disorders.
      Topiramate has been evaluated in the management of some mood disorders, and
      weight loss may be a beneficial side effect in these patients. Case reports,
      letters to the editor, prospective investigations, and retrospective
      observational studies were reviewed to identify evidence of weight loss with
      topiramate use in patients with mood disorders. CONCLUSIONS: Current evidence
      suggests an association between topiramate and weight loss. Based on the limited
      data, controlled studies need to be conducted to define the role of topiramate in
      patients with mood disorders who would also benefit from weight reduction.

PMID- 15039482
TI  - Early experiences and clinical implications of restenosis and drug-eluting
      stents: Part 2.
AB  - OBJECTIVE: To review early clinical experience and future implications of drug
      eluting stents (DES) in percutaneous coronary interventions. DATA SOURCES: Using
      the search terms sirolimus, paclitaxel, and drug-eluting stents, a literature
      review was conducted to identify peer-reviewed articles and abstracts in MEDLINE
      (1966-June 2003). Recent meeting abstracts were also accessed through the
      American Heart Association and the American College of Cardiology Web sites.
      Citations from available articles were reviewed for additional references. STUDY
      SELECTION AND DATA EXTRACTION: Published reviews and studies showing the effects
      of in-stent restenosis and drug-coated and -eluting stents were evaluated and
      reviewed. DATA SYNTHESIS: Current antiplatelet and antithrombotic therapy have
      proven successful in preventing acute in-stent thrombosis, but not in-stent
      restenosis. Recently, stents eluted with certain antimitotic agents have
      demonstrated positive findings in reducing restenosis (eg, sirolimus, paclitaxel
      eluting stents) compared with bare-metal stents. However, data regarding long
      term benefits and adverse effects are only beginning to accumulate. CONCLUSIONS:
      While the current clinical efficacy and safety of DES appear promising, further
      investigations are required to examine long-term efficacy, safety, and cost
      effectiveness. Subanalysis of the current data may help to determine the specific
      patient population that may benefit maximally from DES.

PMID- 15039483
TI  - Effect of high glucose on gene expression in mesangial cells: upregulation of the
      thiol pathway is an adaptational response.
AB  - Pathological alterations in glomerular mesangial cells play a critical role in
      the development of diabetic nephropathy, the leading cause of end-stage renal
      disease. Molecular mechanisms mediating such alterations, however, remain to be
      fully understood. The present study first examined the effect of high glucose on
      the mRNA expression profile in rat mesangial cells using cDNA microarray. Based
      on variation-weighted criteria and with a false discovery rate of 4.3%, 459 of
      17,664 cDNA elements examined were found to be upregulated and 151 downregulated
      by exposure to 25 mM d-glucose for 5 days. A large number of differentially
      expressed genes belonged to several functional categories, indicating high
      glucose had a profound effect on mesangial cell proliferation, protein synthesis,
      energy metabolism, and, somewhat unexpectedly, protein sorting and the
      cytoskeleton. Interestingly, several thiol antioxidative genes (glutathione
      peroxidase 1, peroxiredoxin 6, and thioredoxin 2) were found by microarray and
      confirmed by real-time PCR to be upregulated by high glucose. These changes
      suggested that the oxidative stress known to be induced in mesangial cells by
      high glucose might be buffered by upregulation of the thiol antioxidative
      pathway. Upregulation of thiol antioxidative genes also occurred in high-glucose
      treated human mesangial cells and in glomeruli isolated from rats after 1 wk of
      streptozotocin-induced diabetes, but not in human proximal tubule cells. High
      glucose slightly increased lipid peroxidation and decreased the amount of reduced
      thiols in rat and human mesangial cells. Disruption of the thiol antioxidative
      pathway by two different thiol-oxidizing agents resulted in a three- to fivefold
      increase in high-glucose-induced lipid peroxidation. In summary, the present
      study provided a global view of the short-term effect of high glucose on
      mesangial cells at the level of mRNA expression and identified the upregulation
      of the thiol antioxidative pathway as an adaptational response of mesangial cells
      to high glucose.

PMID- 15039484
TI  - Additive regulation of hepatic gene expression by dwarfism and caloric
      restriction.
AB  - Disrupted growth hormone/insulin-like growth factor-1 signaling (DF) and caloric
      restriction (CR) extend life span and delay the onset of age-related diseases in
      rodents. In combination, these interventions additively extend life span. To
      investigate the molecular basis for these effects, we performed genome-wide,
      microarray expression analysis of liver from homozygous and heterozygous Ames
      dwarf mice fed ad libitum or CR. CR and DF additively affected a group of 95
      genes. Individually and together, DF and CR independently affected the expression
      of 212 and 77 genes, respectively. These results indicate that DF and CR affect
      overlapping sets of genes and additively affect a subset of genes. Together, the
      interventions produced changes in gene expression consistent with increased
      insulin, glucagon and catecholamine sensitivity, gluconeogenesis, protein
      turnover, lipid beta-oxidation, apoptosis, and xenobiotic and oxidant metabolism;
      and decreased cell proliferation, lipid and cholesterol synthesis, and chaperone
      expression. These data suggest that the additive effects of DF and CR on life
      span develop from their additive effects on the level of expression of some genes
      and from their independent effects on other genes. These results provide a novel
      and focused group of genes closely associated with the regulation of life span in
      mammals.

PMID- 15039485
TI  - Genome scan for QTLs underlying bone size variation at 10 refined skeletal sites:
      genetic heterogeneity and the significance of phenotype refinement.
AB  - To identify quantitative trait loci (QTLs) underlying variation in bone size, we
      conducted a whole-genome linkage scan in 53 pedigrees with 630 subjects using 380
      microsatellite markers. Lumbar area 1, 2, 3, and 4 at the spine, femoral neck,
      trochanter, intertrochanter areas at the hip, ultradistal, mid-distal, and one
      third distal areas at the wrist were measured by dual-energy X-ray absorptiometry
      (DXA), and adjusted for age, height, weight, and sex. Two-point and multipoint
      linkage analyses were performed for skeletal bone size at each site and their
      composite measurements using the SOLAR package. Two chromosomal regions (1q22 and
      10q21) were identified with significant evidence of linkage (LOD > 4.32) to one
      third distal area, and three were identified with suggestive evidence of linkage
      (LOD > 2.93) to bone size in one skeletal site. Our results indicated that the
      low power of QTLs mapping for composite phenotypic measurements may result from
      genetic heterogeneity of complex traits.

PMID- 15039486
TI  - Critical role for transcription factor AP-2alpha in human trophoblast
      differentiation.
AB  - To examine whether AP-2alpha is a critical component of the genetic program that
      directs human trophoblast differentiation, we used DNA microarray analyses to
      characterize the effects of a dominant-negative form of the AP-2 protein upon in
      vitro differentiating cytotrophoblast cells. Human cytotrophoblast cells (>95%
      pure) were cultured for 3 days in the presence of control medium or medium
      containing an adenovirus that expresses a dominant-negative mutant of AP-2
      (Ad2.AP-2D/N) or an adenovirus lacking the AP-2 mutant gene (Ad.WT). DNA
      microarray analyses using Affymetrix human U95Av2 GeneChips were performed on RNA
      extracted from the three groups of cells immediately prior to and after 3 days of
      cell culture. Cells infected with Ad2.AP-2D/N or Ad2.WT underwent morphological
      differentiation similar to that of uninfected cells, with greater than 90% of the
      cells in each group fusing to form multinucleated syncytiotrophoblast cells.
      However, Ad2.AP-2D/N markedly inhibited the induction or repression of many genes
      that were regulated in the noninfected and Ad2.WT-infected cells during
      differentiation. Eighteen of the 25 most induced genes and 17 of the 20 most
      repressed genes during differentiation were AP-2 dependent, with the majority of
      these related to extracellular organization, cellular communication, and signal
      transduction. Taken together, these findings strongly suggest that AP-2 plays a
      critical role for both the induction and repression of genes that comprise
      postsyncytialization gene expression programs of trophoblast differentiation and
      maturation. AP-2, however, is not required for the fusion of cytotrophoblast
      cells to form a syncytium or the expression of syncytin.

PMID- 15039489
TI  - Gleevec: prototype or outlier?
AB  - The protein kinase inhibitor Gleevec has proven to be spectacularly effective in
      the treatment of chronic myelogenous leukemia (CML). But can success such as this
      be achieved for genetically complex neoplasms with other drugs targeted at
      hyperactive oncoproteins? Although only time will tell, both theoretical and
      empirical arguments suggest that the success of Gleevec in CML need not be a
      special case. As the molecular basis of various cancers is further defined, it
      should be possible to develop other new drugs that, like Gleevec, specifically
      target cancer cells by inhibiting early events that are integral to progression
      to the transformed phenotype. Encouraging in this regard are cell culture
      experiments and animal models that suggest that cancer cells often remain
      dependent on, and may become addicted to, the signals resulting from such early
      genetic changes.

PMID- 15039487
TI  - Expression of an angiotensin-(1-7)-producing fusion protein produces
      cardioprotective effects in rats.
AB  - Angiotensin-(1-7) [ANG-(1-7)] is a recently described heptapeptide product of the
      renin-angiotensin system. Because biosynthesis of ANG-(1-7) increases in animals
      treated with cardioprotective drugs and inactivation of the gene for angiotensin
      converting enzyme 2 [an enzyme involved in the biosynthesis of ANG-(1-7)] leads
      to the development of cardiac dysfunction, it has been suggested that ANG-(1-7)
      has cardioprotective properties. To directly test this possibility, we have
      generated transgenic rats that chronically overproduce ANG-(1-7) by using a novel
      fusion protein methodology. TGR(A1-7)3292 rats show testicular-specific
      expression of a cytomegalovirus promoter-driven transgene, resulting in a
      doubling of circulating ANG-(1-7) compared with nontransgenic control rats.
      Radiotelemetry hemodynamic measurements showed that transgenic rats presented a
      small but significant increase in daily and nocturnal heart rate and a slight but
      significant increase in daily and nocturnal cardiac contractility estimated by
      dP/d t measurements. Strikingly, TGR(A1-7)3292 rats were significantly more
      resistant than control animals to induction of cardiac hypertrophy by
      isoproterenol. In addition, transgenic rats showed a reduced duration of
      reperfusion arrhythmias and an improved postischemic function in isolated
      Langendorff heart preparations. These results support a cardioprotective role for
      circulating ANG-(1-7) and provide a novel tool for evaluating the functional role
      of ANG-(1-7).

PMID- 15039490
TI  - Methotrexate and Ras methylation: a new trick for an old drug?
AB  - Ras plays a central role in the development and progression of human cancer. Ras
      function depends on its ability to associate with cellular membranes. Nascent Ras
      is targeted to membranes by virtue of a series of posttranslational modifications
      of a C-terminal "CAAX" motif that include farnesylation, proteolysis, and
      carboxyl methylation. This pathway is an attractive target for anti-Ras drug
      development. Farnesyltransferase inhibitors have been developed and are in
      clinical trials. Their success has prompted interest in developing
      pharmacologically useful inhibitors of the other two enzymes in the Ras
      processing pathway. Ironically, it now appears that methotrexate, one of the
      oldest chemotherapeutic drugs, may work, in part, by inhibiting carboxyl
      methylation of Ras.

PMID- 15039491
TI  - Accessing natural products by combinatorial biosynthesis.
AB  - Enhancement and selective production of the protein phosphatase IIa inhibitor
      phoslactomycin (PLM) B by rational engineering of the PLM biosynthetic pathway
      highlights the effectiveness of combinatorial biosynthesis as a promising way to
      prepare complex natural products and their analogs.

PMID- 15039492
TI  - Life stress, genes, and depression: multiple pathways lead to increased risk and
      new opportunities for intervention.
AB  - Major depression is a common, severe, chronic, and often life-threatening
      illness. There is a growing appreciation that, far from being a disease with
      purely psychological manifestations, major depression is a systemic disease with
      deleterious effects on multiple organ systems. Stressful life events have a
      substantial causal association with depression, and there is now compelling
      evidence that even early life stress constitutes a major risk factor for the
      subsequent development of depression. The emerging evidence suggests that the
      combination of genetics, early life stress, and ongoing stress may ultimately
      determine individual responsiveness to stress and the vulnerability to
      psychiatric disorders, such as depression. It is likely that genetic factors and
      life stress contribute not only to neurochemical alterations, but also to the
      impairments of cellular plasticity and resilience observed in depression. Recent
      preclinical and clinical studies have shown that signaling pathways involved in
      regulating cell plasticity and resilience are long-term targets for the actions
      of antidepressant agents. Agents capable of reversing the hypothesized
      impairments of cellular resilience, reductions in brain volume, and cell death or
      atrophy in depression have the potential of becoming new therapeutic classes of
      antidepressant drugs. Novel cellular targets include agents targeting
      neurotrophic pathways, glucocorticoid signaling, phosphodiesterase activity, and
      glutamatergic throughput. The future development of treatments that more directly
      target molecules in critical CNS (central nervous system) signaling pathways that
      regulate cellular plasticity thus hold promise as novel, improved long-term
      treatments for major depression.

PMID- 15039493
TI  - Patient-reported outcomes better discriminate active treatment from placebo in
      randomized controlled trials in rheumatoid arthritis.
AB  - BACKGROUND: Recent randomized controlled trials (RCTs) in rheumatoid arthritis
      (RA) have used patient- and physician-reported outcomes, ESR and/or CRP as
      components of ACR response criteria to assess efficacy. OBJECTIVES: Mean changes
      from baseline in patient- and physician-reported outcome measures, ESR and CRP
      were compared in two RCTs in patients with active RA. Comparisons between active
      and placebo treatment used mean percentage improvements and standard effect sizes
      (SESs). RESULTS: In both protocols, patient-reported assessments of disease
      activity, pain and physical function reflected little or no improvement with
      placebo, best discriminating between active and placebo therapy, as did ESR and
      CRP. CONCLUSION: Improvements in signs and symptoms of active RA in placebo RCTs
      appear to be best reflected by patient-reported measures of physical function, as
      long as reported changes in global assessments of disease activity and/or pain
      reflect similar benefit. Patient-reported outcome measures should be considered
      objective; treatment-associated changes are congruent with measures of
      inflammation, and appear less susceptible to the placebo response.

PMID- 15039494
TI  - Improvement in health utility among patients with rheumatoid arthritis treated
      with adalimumab (a human anti-TNF monoclonal antibody) plus methotrexate.
AB  - OBJECTIVES: To compare health-related quality of life (HRQoL), as measured by
      health utility, in patients with rheumatoid arthritis (RA) treated with
      adalimumab (a human anti-tumour necrosis factor (anti-TNF) monoclonal antibody)
      plus methotrexate or placebo plus methotrexate. METHODS: HRQoL data were obtained
      in two randomized, double-blind, placebo-controlled, multidose clinical trials
      conducted in the United States and Canada. The Health Utilities Index Mark 3
      (HUI3) was administered in both studies at baseline, at the end of the study and
      at two time points in between. Patients' HUI3 scores were compared with
      population norm scores. Change in HUI3 was defined as the end-of-study score
      minus the baseline score. Utility gained throughout the study was measured by
      area under the utility curve and expressed as quality-adjusted life years
      (QALYs). Statistical testing adjusted for confounders and used the Dunnett test
      to account for multiple comparisons. RESULTS: Patients' utility scores at
      baseline were low (range of treatment group means 0.38-0.44) compared with
      population norms (0.88). HUI3 mean changes from baseline scores for adalimumab
      treated patients were 0.22 and 0.21 in the two trials, whereas placebo patients'
      changes were 0.04 and 0.07. The rate of QALYs gained per year in the treatment
      group compared with the placebo group were 0.145 in the ARMADA trial and 0.104 in
      the DE019 trial. All gains were clinically important and statistically
      significant. CONCLUSIONS: Treatment with adalimumab plus methotrexate provides
      clinically important and statistically significant improvements in HRQoL as
      measured by health utility in patients with RA. This translates into measurable
      and important gains in QALYs.

PMID- 15039495
TI  - Measurement of fatigue and discomfort in primary Sjogren's syndrome using a new
      questionnaire tool.
AB  - OBJECTIVE: Fatigue is a prominent symptom in primary Sjogren's syndrome (PSS). We
      set out to compare existing instruments and a new tool for measuring fatigue and
      general discomfort in PSS, with systemic lupus erythematosus (SLE), rheumatoid
      arthritis (RA) and healthy controls. METHODS: Groups of female Caucasian PSS
      patients completed a new questionnaire developed from PSS patients' own
      vocabulary, as well as the SF-36, WHOQOL-BREF and HAD scales. For comparison, the
      questionnaire was also completed by groups of SLE and RA patients and healthy
      controls. RESULTS: Each disease group differed significantly from healthy
      controls on each facet of fatigue and general discomfort in the new tool. Somatic
      fatigue was worst in RA, while mental fatigue was worst in PSS and SLE. The
      facets of somatic fatigue and discomfort in the new tool correlated well with
      comparable domains in existing scales. CONCLUSIONS: Fatigue in PSS can be
      measured using this new Sjogren's-based psychometric instrument. The new
      questionnaire tool was more sensitive than the SF-36, WHOQOL-BREF and HAD at
      distinguishing the three rheumatic disorders from controls.

PMID- 15039496
TI  - Association between knee cartilage volume and bone mineral density in older
      adults without osteoarthritis.
AB  - OBJECTIVES: Studies have suggested an inverse association between osteoarthritis
      (OA) and osteoporosis, based on the presence of osteophytes rather than joint
      space narrowing (JSN), an indirect measure of joint cartilage. We conducted a
      cross-sectional study to determine the relationship between knee cartilage
      volume, a direct measure of joint cartilage, and bone mineral density (BMD) in an
      adult population. METHODS: 86 adults aged 55.1+/-10.4 years (50% females) had
      total BMD and bone mineral content (BMC) measured using dual X-ray
      absorptiometry. Site-specific BMD was performed on men in the study. Tibial and
      patella cartilage volumes were determined by processing images acquired in the
      sagittal plane using T(1)-weighted fat saturation magnetic resonance on an
      independent work station. RESULTS: Tibial knee cartilage volume was positively
      associated with total body BMD in both men and women after adjusting for age,
      BMI, tibial bone area and physical activity. In men, tibial cartilage volume was
      positively associated with proximal femur BMD, but not lumbar spine BMD. No
      relationship was seen between patellar cartilage volume and BMD at any region.
      CONCLUSIONS: We have shown a positive association between tibial cartilage volume
      and total BMD in men and women, but no such association with patellar cartilage
      volume. The mechanism for this is unclear but may represent a common
      environmental or genetic component. This study also highlights the need to
      examine the osteophyte and joint cartilage separately when investigating factors
      affecting the joint in health and disease since each feature is likely to reflect
      different aspects of the pathogenic process in OA.

PMID- 15039497
TI  - Adult onset Still's disease and collapsing glomerulopathy: successful treatment
      with intravenous immunoglobulins and mycophenolate mofetil.
AB  - In this Grand Round we present a 32-yr-old African man who became severely ill
      after a 5-month history of weight loss, pyrexia, arthralgia, sweats and rash. He
      went on to develop pericarditis, pericardial effusion with tamponade,
      hepatomegaly with abnormal liver function tests, lymphadenopathy, massive
      proteinuria and required ventilatory, circulatory and renal support. The
      differential diagnosis was adult onset Still's disease, systemic lupus
      erythematosus (SLE), infection and lymphoma. Primary infection and lymphoma were
      excluded and he was treated, with dramatic success, with intravenous
      immunoglobulins (i.v.IG). Subsequent renal biopsy excluded SLE but confirmed
      collapsing glomerulopathy. The proteinuria improved dramatically following
      treatment with mycophenolate mofetil. We discuss some of the difficult diagnostic
      and management issues raised by this patient and the different uses and
      mechanisms of action of i.v.IG.

PMID- 15039498
TI  - User perspectives of transitional care for adolescents with juvenile idiopathic
      arthritis.
AB  - OBJECTIVES: To gain insight into the transitional needs of adolescents with
      juvenile idiopathic arthritis (JIA) and to examine how these needs may be
      addressed within a structured programme of transitional care. METHODS: A
      qualitative study using focused group discussions was performed. Groups comprised
      (i) adolescents with JIA aged 12-18 yr, (ii) young adults with JIA aged 19-30 yr,
      (iii) parents of adolescents with JIA, and (iv) parents of young adults with JIA.
      RESULTS: Transitional needs included aspects of participants' physical, social,
      psychological and vocational lives. Participants (n = 55) called for
      developmentally appropriate care based upon shared decision-making, continuity of
      health professionals, and wider access to information and community services.
      Suggestions for improved care included individualized assessment of patient's
      holistic needs and increased transfer preparation. CONCLUSIONS: These results
      provide a useful guide to transitional care and suggest an approach that is
      adolescent-focused and evidence-based.

PMID- 15039499
TI  - Interactions between autonomic nervous system activity and endothelial function:
      a model for the development of cardiovascular disease.
AB  - OBJECTIVES: Endothelial dysfunction is a new pathway in cardiovascular disease
      (CVD) development. Psychosocial factors have been little studied in relation to
      endothelial function, although they may interact via associations with the
      autonomic nervous system (ANS). The purpose of this review is to propose a model
      by which psychosocial factors are related to CVD development through interactions
      between the ANS and vascular endothelium. METHODS: The literature supporting an
      interaction between the ANS and endothelium in healthy and disease states is
      reviewed. Potential mechanisms linking the two systems are explored as a pathway
      for CVD development. RESULTS: Endothelial dysfunction and impaired cardiovascular
      ANS regulation are both markers for increased CVD risk. Sympathetic nerves and
      vascular endothelial cells share a functional antagonism in healthy states to
      maintain appropriate blood vessel tone. Alterations in sympathetic activity and
      endothelial cell function are both observed early in the development of CVD and
      may result from an inability to maintain the functional antagonism. Impairments
      in either ANS regulation or endothelial function may contribute to further
      disease development by evoking maladaptive changes in the opposing system.
      CONCLUSIONS: Although interactions between cardiovascular ANS regulation and
      endothelial function are likely involved in CVD development, further research is
      needed to determine whether ANS and endothelium interactions are a plausible
      pathway linking psychosocial factors with increased CVD risk.

PMID- 15039500
TI  - Psychological theories of depression: potential application for the prevention of
      acute coronary syndrome recurrence.
AB  - OBJECTIVE: The natural course of elevated depressive symptoms or subthreshold
      depression in patients with an acute coronary syndrome (ACS) is presented, as is
      the prognostic impact. Safe and effective psychological treatment options are
      desirable for subthreshold depression in patients with ACS, should they prove
      tolerable, efficacious, and cost-effective to cardiologists and their patients.
      To achieve this long-term goal, we propose focusing on 3 intermediate goals.
      First, we need to understand which symptoms or patterns of symptoms (eg, fatigue,
      anhedonia, guilt feelings) are specifically predictive of ACS recurrence. Second,
      the prevalence of known psychosocial vulnerabilities (proximal causes) of
      depressive disorders should be assessed in patients with ACS, to understand
      better the etiology of these symptoms in these patients. Third, randomized
      controlled trials of vulnerability-related, evidence-based psychological
      depression interventions in cardiac patients are needed. The ways in which
      psychological proximal cause theories are relevant--or irrelevant--for both the
      treatment of depressive symptoms in post-ACS patients and the prevention of ACS
      recurrence are discussed.

PMID- 15039501
TI  - For whom does it work? Moderators of the effects of written emotional disclosure
      in a randomized trial among women with chronic pelvic pain.
AB  - OBJECTIVE: Although written emotional disclosure has potential as a stress
      management intervention for people with health problems, the main (group) effects
      of disclosure in medical populations are limited. This study sought to identify
      individual difference moderators of the effects of written disclosure among women
      with chronic pelvic pain. METHODS: In a prospective, randomized trial, 48 women
      with chronic pelvic pain completed 3 individual difference measures and then
      wrote for 3 days about stressful consequences of their pain (disclosure) or
      positive events (control). Health status was assessed at baseline and 2 months
      after writing. RESULTS: Main effect group comparisons indicated that disclosure
      writing resulted in significantly lower evaluative pain intensity ratings than
      control writing at follow-up, but there were no main effects on other outcome
      variables (sensory or affective pain, disability, affect). Three baseline
      individual difference measures, however, significantly moderated group effects.
      Compared with control writing, disclosure led to less disability among women with
      higher baseline ambivalence over emotional expression or higher catastrophizing,
      and to increased positive affect among women with higher baseline negative
      affect. Ambivalence, but not catastrophizing, was independent of negative affect
      in its moderation effect. CONCLUSION: Although the main effects of writing about
      the stress of pelvic pain are limited, women with higher baseline ambivalence
      about emotional expression or negative affect appear to respond more positively
      to this intervention.

PMID- 15039502
TI  - Contribution of early and adult factors to socioeconomic variation in blood
      pressure: thirty-four-year follow-up study of school children.
AB  - OBJECTIVE: To prospectively examine the role of childhood and adulthood factors
      in the association between socioeconomic status (SES) and adult systolic and
      diastolic blood pressure (SBP, DBP). METHODS: One hundred and five boys and 101
      girls who were 8 years of age at entry into the study were observed for 34 years
      in the Jyvaskyla Longitudinal Study of Personality and Social Development,
      Finland. Data were gathered on educational attainment and occupational status, as
      indicators of SES, and potential explanatory factors related to 0, (14), 27, 36,
      and 42 years of age. SBP and DBP were assessed at 15 and 42 years of age.
      RESULTS: In a structural equation model adjusted for sex and childhood SBP,
      educational attainment was inversely associated with adult SBP (structural
      coefficient -0.17, p<.05). Incorporating the effects of parental SES and adult
      body mass index into the model attenuated this association so that it was no
      longer significant. Variation in birth weight, unemployment, smoking, alcohol
      consumption, and use of antihypertensive medication had marginal or no impact on
      the education-SBP association. No socioeconomic variation was found for DBP or
      occupational status. CONCLUSIONS: Prospective evidence suggests a weak
      association between low educational attainment and development of high SBP.
      Parental SES and adult BMI were the key explanatory factors for this association.

PMID- 15039503
TI  - Gender differences in quality of life among cardiac patients.
AB  - OBJECTIVE: Prior studies of quality of life among cardiac patients have examined
      mostly men. This study evaluated gender differences in quality of life and
      examined the degree to which social support was associated with quality of life.
      METHODS: A sample of 536 patients (35% women) was recruited during a 14-month
      period from the inpatient cardiology service of a University-based hospital.
      Participants completed assessments at baseline and at 3-month intervals over the
      subsequent 12 months, for a total of 5 assessments. Measures at each assessment
      included quality of life [Mental Component Score (MCS) and Physical Component
      Score (PCS) from the Medical Outcomes Study--Short Form 36] and social support
      [Interpersonal Support Evaluation List--Short Form]. RESULTS: A total of 410
      patients completed the baseline assessment and at least one follow-up, and were
      included in the data analyses. Linear mixed effects modeling of the MCS score
      revealed a significant effect of gender (p =.028) and time (p <.001), as well as
      a significant interaction of gender by social support (p =.009). Modeling of the
      PCS revealed a significant effect of gender (p =.010) and time (p <.001).
      CONCLUSIONS: Women with cardiac disease indicated significantly lower quality of
      life than men with cardiac disease over the course of a 12-month longitudinal
      follow-up. Social support, especially a sense of belonging or companionship, was
      significantly associated with emotional quality of life (MCS) among women.
      Strategies to increase social support may be important for health and well-being
      of women with cardiac disease.

PMID- 15039504
TI  - Sex differences in pain and hypothalamic-pituitary-adrenocortical responses to
      opioid blockade.
AB  - OBJECTIVE: Sex differences in pain sensitivity and stress reactivity have been
      well documented. Little is known about the role of the endogenous opioid system
      in these differences. This study was conducted to compare adrenocortical, pain
      sensitivity, and blood pressure responses to opioid blockade using naltrexone in
      men and women. METHODS: Twenty-six participants completed 2 sessions during which
      placebo or 50 mg of naltrexone was administered, using a double-blind,
      counterbalanced design. Thermal pain threshold and heat tolerance were assessed.
      Participants also rated pain during a 90-second cold pressor test (CPT) and
      completed the McGill Pain Questionnaire (MPQ) after each pain challenge. Blood
      and saliva samples and cardiovascular and mood measures were obtained throughout
      the sessions. RESULTS: Plasma cortisol, adrenocorticotropin, beta endorphin,
      prolactin, and salivary cortisol levels increased similarly in men and women
      after naltrexone administration compared with placebo. Women reported more pain
      during both pain procedures and had lower thermal pain tolerance. In response to
      naltrexone, women exhibited reduced blood pressure responses and reduced MPQ pain
      ratings after CPT. No effects of naltrexone on these measures were found in men.
      CONCLUSIONS: Although men and women exhibited similar hormonal responses to
      opioid receptor blockade, women reported less pain and showed smaller blood
      pressure responses during CPT. Results suggest differential effects of the
      endogenous opioid system on pain perception and blood pressure in men and women.

PMID- 15039505
TI  - Perceived work overload and chronic worrying predict weekend-weekday differences
      in the cortisol awakening response.
AB  - OBJECTIVE: The cortisol increase after awakening has been shown to be associated
      with work-related stress. Several studies demonstrated a moderate stability of
      cortisol awakening responses on subsequent days, suggesting situation-dependent
      variance. This study tests whether cortisol awakening responses are different on
      weekdays compared with weekend days and whether such differences may be explained
      by chronic work overload and worrying. METHODS: Two hundred nineteen participants
      took saliva samples immediately after awakening and 30, 45, and 60 minutes later
      on 6 consecutive days starting on Saturday. Perceived chronic work overload and
      worrying were assessed by a standardized questionnaire. RESULTS: There is a clear
      weekend-weekday difference in the cortisol response to awakening. This difference
      is associated with chronic work overload and worry. Independent of sex and
      weekend-weekday differences in time of awakening and sleep duration, participants
      who report higher levels of chronic work overload and worrying show a stronger
      increase and higher mean levels of cortisol after awakening on weekdays, but not
      on weekend days. CONCLUSIONS: The weekend-weekday differences in the cortisol
      awakening response and their association with chronic stress clearly demonstrate
      that the day of cortisol assessment is crucial in psychoendocrinological stress
      studies.

PMID- 15039507
TI  - Alexithymia does not predict the persistence of medically unexplained physical
      symptoms.
AB  - BACKGROUND: Alexithymia is thought to be associated with the development of
      medically unexplained physical symptoms (UPS). So far little research has been
      published on alexithymia as a risk factor for the persistence of UPS. OBJECTIVE:
      To determine the clinical outcome in UPS patients and to study the relative
      importance of alexithymia in predicting that outcome. METHODS: A follow-up study
      was conducted among general medical outpatients with UPS. Patients underwent
      extensive examinations at baseline and were reassessed after a mean 61-week
      interval. Outcome of the UPS and general health perception at follow-up were used
      as major outcome variables. RESULTS: Outcome of the UPS and general health
      perception at follow-up were not strongly associated with each other. More than
      half (63%) of the patients reported improvement of their initial symptoms, but
      only 38% of the patients considered themselves at follow-up to be in good health.
      UPS outcome was predominantly predicted by the duration of the UPS and the number
      of additional physical symptoms at baseline. General health perception at follow
      up was predominantly predicted by the general health perception at baseline and
      the number of additional physical symptoms and pain experience at baseline. The
      explained variance of the general health perception was three times as high as
      the explained variance for the UPS outcome. Alexithymia was not associated with
      any of the two outcome variables. CONCLUSIONS: Outcome of the UPS and general
      health perception at follow-up are not strongly associated and are predicted by
      different variables. Alexithymia, however, is not an important predictor for the
      outcome in the majority of UPS patients.

PMID- 15039506
TI  - Psychological stress and antibody response to influenza vaccination: when is the
      critical period for stress, and how does it get inside the body?
AB  - OBJECTIVES: This study attempted to determine whether stress of moderate
      intensity could modulate the antibody response to an influenza vaccination in
      healthy young adults, identify critical periods during which stress could
      influence antibody response, and delineate behavioral and biological pathways
      that might explain relations between stress and antibody. METHODS: A cohort of 83
      healthy young adults underwent 13 days of ambulatory monitoring before, during,
      and after vaccination. Four times daily, subjects reported the extent to which
      they felt stressed and overwhelmed and collected a saliva sample that was later
      used to measure cortisol. A battery of health practices (cigarette smoking,
      alcohol use, physical activity, sleep hygiene) was assessed daily. Antibody
      titers to the vaccine components were measured at baseline and at 1-month and 4
      month follow-up assessments. RESULTS AND CONCLUSIONS: To the extent that they
      reported higher levels of stress across the monitoring period, subjects exhibited
      poorer antibody responses to the New Caledonia strain of the vaccine. Stress
      ratings on the 2 days before the vaccine and the day it was given were not
      associated with antibody response. However, the 10 days afterward appeared to be
      a window of opportunity during which stress could shape the long-term antibody
      response to varying degrees. With respect to potential mediating pathways, little
      evidence emerged in favor of cortisol secretion, alcohol consumption, physical
      activity, or cigarette smoking. However, analyses were consistent with a pattern
      in which feelings of stress and loss of sleep become locked into a feed-forward
      circuit that ultimately diminishes the humoral immune response. These findings
      may shed light on the mechanisms through which stress increase vulnerability to
      infectious disease.

PMID- 15039508
TI  - Treatment with hypnotherapy reduces the sensory and motor component of the
      gastrocolonic response in irritable bowel syndrome.
AB  - OBJECTIVE: Postprandial symptoms in irritable bowel syndrome are common and
      relate to an exaggerated motor and sensory component of the gastrocolonic
      response. We investigated whether this response can be affected by hypnotherapy.
      METHODS: We included 28 patients with irritable bowel syndrome refractory to
      other treatments. They were randomized to receive gut-directed hypnotherapy 1
      hour per week for 12 weeks (N = 14) or were provided with supportive therapy
      (control group; N = 14). Before randomization and after 3 months, all patients
      underwent a colonic distension trial before and after a 1-hour duodenal lipid
      infusion. Colonic sensory thresholds and tonic and phasic motor activity were
      assessed. RESULTS: Before randomization, reduced thresholds after vs. before
      lipid infusion were seen in both groups for all studied sensations. At 3 months,
      the colonic sensitivity before duodenal lipids did not differ between groups.
      Controls reduced their thresholds after duodenal lipids for gas (22 +/- 1.7 mm Hg
      vs. 16 +/- 1.6 mm Hg, p <.01), discomfort (29 +/- 2.9 mm Hg vs. 22 +/- 2.6 mm Hg,
      p <.01), and pain (33 +/- 2.7 mm Hg vs. 26 +/- 3.3 mm Hg, p <.01), whereas the
      hypnotherapy group reduced their thresholds after lipids only for pain (35 +/-
      4.0 mm Hg vs. 29 +/- 4.7 mm Hg, p <.01). The colonic balloon volumes and tone
      response at randomization were similar in both groups. At 3 months, baseline
      balloon volumes were lower in the hypnotherapy group than in controls (83 +/- 14
      ml vs. 141 +/- 15 ml, p <.01). In the control group, reduced balloon volumes
      during lipid infusion were seen (141 +/- 15 ml vs. 111 +/- 19 ml, p <.05), but
      not after hypnotherapy (83 +/- 14 ml vs. 80 +/- 16 ml, p >.20). CONCLUSION:
      Hypnotherapy reduces the sensory and motor component of the gastrocolonic
      response in patients with irritable bowel syndrome. These effects may be involved
      in the clinical efficacy of hypnotherapy in IBS.

PMID- 15039510
TI  - Monitoring for sleep-related threat: a pilot study of the Sleep Associated
      Monitoring Index (SAMI).
AB  - OBJECTIVE: The aims of this pilot study were: 1) to establish the reliability and
      validity of a new self-report instrument designed to index monitoring for sleep
      related threat; 2) to determine the presence of ten monitoring types proposed in
      a recent cognitive model of insomnia and to examine the relationship between
      monitoring for sleep-related threat and severity of sleep disturbance; and 3) to
      explore the association between monitoring and the established constructs of
      amplification and self-focus. METHODS: Participants (N = 400) completed the Sleep
      Associated Monitoring Index (SAMI) and the Pittsburgh Sleep Quality Index (PSQI)
      (1). Based on the PSQI score, the sample was split into two groups to compare
      normal sleepers (NS) and individuals with a clinically significant sleep
      disturbance (CSSD). A subset of the sample completed the SAMI and a battery of
      questionnaires to examine convergent validity between monitoring, amplification,
      and self-focus. RESULTS: Individuals in the CSSD group had higher SAMI scores
      than the NS group and the SAMI correlated positively with severity of sleep
      disturbance as indexed by the PSQI. A principal components analysis extracted 8
      components accounting for 69% of the variance. The 30-item SAMI demonstrated high
      validity, consistency, and reliability. Scores on the SAMI were moderately
      positively correlated with scores on measures of amplification and self-focus.
      CONCLUSIONS: Preliminary evidence suggests that the SAMI offers a valid and
      reliable instrument to index monitoring before and after treatment for sleep
      disturbance. The implications for the presence of monitoring for sleep-related
      threat in chronic insomnia are discussed.

PMID- 15039509
TI  - Self-reported sleep complaints with long and short sleep: a nationally
      representative sample.
AB  - OBJECTIVE: Although the problems associated with insufficient sleep have been
      thoroughly researched, there has been far less substantiation of problems
      associated with long sleep. Recent evidence shows that habitual sleep duration
      greater than 7 hours is associated with increased rates of mortality. This study
      compared the rates of sleep problems in both long and short sleepers. METHODS:
      Self-reported sleep complaints (eg, sleep onset latency, awakenings during the
      night, early morning awakenings, nonrestorative sleep, and daytime sleepiness) of
      nearly 1000 adults who participated in the National Sleep Foundation's 2001 Sleep
      in America Poll, were compared with reported hours of weekday sleep. RESULTS:
      There are U-shaped relationships of sleep complaints with reported weekday total
      sleep time. More specifically, 8-hour sleepers reported less frequent symptoms
      than long sleepers or 7-hour sleepers. CONCLUSIONS: Thus, long sleepers, as well
      as short sleepers, report sleep problems, focusing attention to the often
      overlooked problems of the long sleeper.

PMID- 15039511
TI  - Patient psychological characteristics have minimal influence on surgical
      prioritization.
AB  - OBJECTIVE: Rationing of health care is universal in systems free at the point of
      delivery. United Kingdom National Health Service (NHS) policy is for treatment on
      the basis of "clinical need." Surgeons routinely prioritize elective cases, and
      structured assessments of symptom severity have been suggested as a rational
      method of prioritization. We hypothesized that patient psychological factors
      would play an important role in prioritization as currently practiced. METHODS:
      Two hundred thirty participants were recruited from a potential pool of 259
      eligible referrals to an orthopaedic department for assessment of lower limb
      arthroplasty. Participants were assessed at time of referral and followed for 2.5
      years. Associations were estimated between participant's psychological distress,
      illness perceptions, and the outcome of surgical prioritization. RESULTS: One
      hundred forty-one participants were listed for arthroplasty; 62 (44%) of these
      were considered urgent cases. Pain was the only univariate predictor of this
      outcome. Patient's psychological distress and illness perceptions were not
      associated with being classified as urgent even after adjusting for clinical and
      demographic status. In a multivariate model, only older age showed an independent
      effect (OR 2.75, 95% CI 1.14, 6.66) of increasing the chances of being considered
      urgent. Urgent cases had a 3-month-shorter inpatient wait among the 108
      participants operated on during the study. CONCLUSIONS: The psychological status
      of arthroplasty candidates had no significant effect on the surgical
      prioritization process. Allocation to the urgent list appears to be based
      primarily on the patient's age, but is partially influenced by patient's better
      physical health and viewing treatment as being effective.

PMID- 15039512
TI  - Experience of trauma, distress, and posttraumatic stress disorder among breast
      cancer patients.
AB  - OBJECTIVES: Cancer would appear to be the paradigmatic example of an acute or
      chronic illness that can precipitate posttraumatic stress disorder (PTSD). Few
      studies, however, have examined the applicability of PTSD criteria to patients
      with cancer. We examined the relationships between the experience of trauma,
      psychological distress, and PTSD among a waiting room sample of patients with
      breast cancer. METHODS: We assessed 115 consecutive patients with breast cancer
      in the waiting room of a large comprehensive cancer center using measures of
      general distress, posttraumatic stress symptoms, and a semistructured diagnostic
      interview. RESULTS: A substantial minority (41%) reported responding to cancer
      with intense fear, helplessness, or horror (DSM-IV A2 criterion). However, cancer
      related PTSD was uncommon (4%), and meeting the A2 criterion was a poor indicator
      of PTSD. Psychological distress was common (38%) and was strongly associated with
      A2, but was a poor predictor of PSTD. CONCLUSIONS: Although an intense negative
      emotional reaction to breast cancer was common, PTSD had low prevalence. Results
      suggest that using a trauma framework to understand the experience of most
      patients with cancer may be inaccurate.

PMID- 15039513
TI  - Psychological impact on women of miscarriage versus induced abortion: a 2-year
      follow-up study.
AB  - OBJECTIVE: To compare the psychological trauma reactions of women who had either
      a miscarriage or an induced abortion, in the 2 years after the event. Further, to
      identify important predictors of Impact of Event Scale (IES) scores. METHOD: A
      consecutive sample of women who experienced miscarriage (N = 40) or induced
      abortion (N = 80) were interviewed 3 times: 10 days (T1), 6 months (T2), and 2
      years (T3) after the event. RESULTS: At T1, 47.5% of the women who had a
      miscarriage were cases (IES score 19 points on 1 or both of the IES subscales),
      compared with 30% for women who had an induced abortion (p =.60). The
      corresponding values at T3 were 2.6% and 18.1%, respectively (p =.019). At all
      measurement time points, the group who had induced abortion scored higher on IES
      avoidance. Women who had a miscarriage were more likely to experience feelings of
      loss and grief, whereas women who had induced abortion were more likely to
      experience feelings of relief, guilt, and shame. At T3, IES intrusion was
      predicted by feelings of loss and grief at T1, whereas avoidance at T3 was
      predicted by guilt and shame at T1. CONCLUSION: The short-term emotional
      reactions to miscarriage appear to be larger and more powerful than those to
      induced abortion. In the long term, however, women who had induced abortion
      reported significantly more avoidance of thoughts and feelings related to the
      event than women who had a miscarriage.

PMID- 15039514
TI  - Effect of written emotional expression on immune function in patients with human
      immunodeficiency virus infection: a randomized trial.
AB  - OBJECTIVES: To determine whether writing about emotional topics compared with
      writing about neutral topics could affect CD4+ lymphocyte count and human
      immunodeficiency virus (HIV) viral load among HIV-infected patients. METHODS:
      Thirty-seven HIV-infected patients were randomly allocated to 2 writing
      conditions focusing on emotional or control topics. Participants wrote for 4
      days, 30 minutes per day. The CD4+ lymphocyte count and HIV viral load were
      measured at baseline and at 2 weeks, 3 months, and 6 months after writing.
      RESULTS: The emotional writing participants rated their essays as more personal,
      valuable, and emotional than those in the control condition. Relative to the drop
      in HIV viral load, CD4+ lymphocyte counts increased after the intervention for
      participants in the emotional writing condition compared with control writing
      participants. CONCLUSIONS: The results are consistent with those of previous
      studies using emotional writing in other patient groups. Based on the self
      reports of the value of writing and the preliminary laboratory findings, the
      results suggest that emotional writing may provide benefit for patients with HIV
      infection.

PMID- 15039515
TI  - Exploratory open label, randomized study of acetyl- and propionylcarnitine in
      chronic fatigue syndrome.
AB  - OBJECTIVES: We compared the effects of acetylcarnitine, propionylcarnitine and
      both compounds on the symptoms of chronic fatigue syndrome (CFS). METHODS: In an
      open, randomized fashion we compared 2 g/d acetyl-L-carnitine, 2 g/d propionyl-L
      carnitine, and its combination in 3 groups of 30 CFS patients during 24 weeks.
      Effects were rated by clinical global impression of change. Secondary endpoints
      were the Multidimensional Fatigue Inventory, McGill Pain Questionnaire, and the
      Stroop attention concentration test. Scores were assessed 8 weeks before
      treatment; at randomization; after 8, 16, and 24 weeks of treatment; and 2 weeks
      later. RESULTS: Clinical global impression of change after treatment showed
      considerable improvement in 59% of the patients in the acetylcarnitine group and
      63% in the propionylcarnitine group, but less in the acetylcarnitine plus
      propionylcarnitine group (37%). Acetylcarnitine significantly improved mental
      fatigue (p =.015) and propionylcarnitine improved general fatigue (p =.004).
      Attention concentration improved in all groups, whereas pain complaints did not
      decrease in any group. Two weeks after treatment, worsening of fatigue was
      experienced by 52%, 50%, and 37% in the acetylcarnitine, propionylcarnitine, and
      combined group, respectively. In the acetylcarnitine group, but not in the other
      groups, the changes in plasma carnitine levels correlated with clinical
      improvement. CONCLUSIONS: Acetylcarnitine and propionylcarnitine showed
      beneficial effect on fatigue and attention concentration. Less improvement was
      found by the combined treatment. Acetylcarnitine had main effect on mental
      fatigue and propionylcarnitine on general fatigue.

PMID- 15039516
TI  - Behavioral and medical treatment of chronic polydipsia in a patient with
      schizophrenia and diabetes insipidus.
AB  - OBJECTIVE: This case report describes a novel outpatient behavioral treatment
      intervention for chronic polydipsia. The program was used in an effort to reduce
      excessive fluid intake in a woman with chronic paranoid-type schizophrenia who
      also had a diagnosis of diabetes insipidus. METHODS: The 12-session individual
      behavioral intervention incorporated self-monitoring, stimulus control, coping
      skills training, and reinforcement components. RESULTS: The patient engaged fully
      in the treatment program, and she successfully restricted her fluid intake. Her
      diabetes insipidus could therefore be treated with desmopressin, a medication
      that requires fluid restriction, and she experienced a concomitant reduction in
      polyuria and urinary incontinence. CONCLUSIONS: The outpatient behavioral
      intervention demonstrated promising outcomes in a chronically mentally ill
      patient whose polydipsia had underlying psychogenic and physiological components.
      This case highlights the efficacy of combining behavioral and medical
      interventions.

PMID- 15039517
TI  - Relationship between multiple sclerosis exacerbations and stress.

PMID- 15039518
TI  - Hostility, coronary risk, and alpha-adrenergic to beta-adrenergic receptor
      density ratio.

PMID- 15039519
TI  - Assembly of Marek's disease virus (MDV) capsids using recombinant baculoviruses
      expressing MDV capsid proteins.
AB  - The genes UL18, UL19, UL26, UL26.5, UL35 and UL38 of Marek's disease virus 1 (MDV
      1) strain RB1B, encoding the homologues of herpes simplex virus type 1 (HSV-1)
      capsid proteins VP23, VP5, VP21-VP24, preVP22a, VP26 and VP19C, were identified
      and sequenced. Recombinant baculoviruses were used to express the six capsid
      genes in insect cells. Coexpression of the six genes or of UL18, UL19, UL26.5 and
      UL38 in insect cells resulted in the formation of capsids with a large core. In
      addition, electron microscopy of thin sections clearly revealed the presence of
      large numbers of small spherical particles. Experimental coinfection demonstrated
      that these small particles were associated with production of the preVP22a
      protein.

PMID- 15039520
TI  - Herpes simplex virus type 1 infection of polarized epithelial cells requires
      microtubules and access to receptors present at cell-cell contact sites.
AB  - Mucosal epithelia are invaded from the apical surface during a primary infection
      by herpes simplex virus type 1 (HSV-1). HSV-1 progeny virus, synthesized from
      latently infected peripheral neurons that innervate such epithelia, reinfects the
      epithelia most likely from the basolateral surface. The epithelial cell lines
      MDCK and Caco-2 can be induced in vitro to differentiate into polarized cells
      with distinct apical and plasma membrane domains separated by tight junctions if
      they are cultured on porous membrane filters. Our data using these culture
      systems showed that highly polarized epithelial cells were not susceptible to
      apical HSV-1 infection. However, HSV-1 infected these cells if added from the
      basolateral surface or if a depletion of extracellular Ca(2+) had weakened the
      strength of the cell-cell contacts. Basolateral infection and apical infection
      after the Ca(2+) switch required an intact microtubule network for genome
      targeting to the nucleus. This system can be used to identify the microtubule
      motors that HSV-1 uses during virus entry in polarized epithelial cells.

PMID- 15039521
TI  - Identification of a glycosylation site in the woodchuck hepatitis virus preS2
      protein and its role in protein trafficking.
AB  - The middle surface antigen (M-sAg) of hepadnaviruses is one of three envelope
      proteins that share a common C-terminal S domain. M-sAg contains the preS2 domain
      in addition to the S region. The preS2 region of woodchuck hepatitis virus (WHV)
      contains a potential glycosylation site Asn-Gln-Thr at amino acid (aa) positions
      3-5. In this study, we mutated this site by site-directed mutagenesis and
      confirmed that glycosylation occurs here. In in vitro translation assays, the
      mutation Thr to Asn at aa 5 significantly impaired glycosylation of M-sAg. The
      mutated M-sAg formed abnormal clustered structures in transfected cells as
      determined by immunofluorescent staining. Confocal microscopic analysis showed
      that an enrichment of this glycosylation-deficient protein in the Golgi apparatus
      occurred, which is not typical for the wild-type protein. These results are
      consistent with earlier findings that incorrect glycosylation of viral proteins
      may interfere with virus assembly.

PMID- 15039522
TI  - Host-dependent type 1 cytokine responses driven by inactivated viruses may fail
      to default in the absence of IL-12 or IFN-alpha/beta.
AB  - Replicating viruses generally induce type 1 immune responses, with high
      interferon (IFN)-gamma levels and antibodies of the IgG2a isotype. In the present
      study we demonstrate the intrinsic ability of non-replicating virions to induce
      comparable immune responses in the notable absence of any adjuvant. Injection of
      inactivated pseudorabies virus, an alphaherpesvirus, by various routes into mice
      resulted in the generation of T helper (Th) 1 type immune response. Co-delivery
      of inactivated pseudorabies herpesvirus (iPRV) with protein redirected IgG1
      dominated tetanus toxoid-specific responses towards an IgG1/IgG2a balanced
      response. Also inactivated preparations of viruses from the paramyxo- (Newcastle
      disease virus), rhabdo- (rabies virus), corona- (infectious bronchitis virus) and
      reovirus (avian reovirus) families led to IgG2a antibody responses; however, the
      genetic background of the host did result in considerable variation. Because
      disrupted virions also induced type 1 immune responses, we conclude that
      structural elements of virions inherently contribute to IFN-gamma-dependent
      isotype switching by inactivated viruses. Strikingly, immunizations in gene
      disrupted mice showed that a functional IFN-alpha/beta, IFN-gamma or interleukin
      (IL)-12 pathway was not required for the generation of a polarized Th1 type
      immune response initiated by inactivated virus particles. These findings have a
      bearing on the understanding of immune responsiveness to virus structures and the
      design of vaccines containing virus components.

PMID- 15039523
TI  - A role for 3-O-sulfated heparan sulfate in cell fusion induced by herpes simplex
      virus type 1.
AB  - Membrane fusion induced by herpes simplex virus (HSV) is required for both entry
      and cell-to-cell spread. It is mediated by the viral glycoprotein gB, gD, gH-gL
      and gD receptors. Although 3-O-sulfated heparan sulfate (3-OS HS) is a receptor
      for HSV-1 entry, the requirement for heparan sulfate in the fusion process has
      been ruled out. Here, it is demonstrated that cells expressing 3-OS HS, generated
      by D-glucosaminyl 3-O-sulfotransferase isoforms-3 and/or -5 (3-OST-3 and 3-OST
      5), fused with cells expressing the four glycoproteins. The cell fusion observed
      exhibited similar requirements but was independent of protein receptors, HVEM or
      nectin-1. Additionally, removal of 3-OS HS from the cell surface by heparinase-I
      treatment and, in separate experiments, the presence of soluble 3-OST-3- and 3
      OST-5-modified HS, significantly inhibited fusion. Taken together, these results
      indicate that 3-OS HS can play a crucial role in virus entry and cell fusion.

PMID- 15039525
TI  - Deletion of the Autographa californica nucleopolyhedrovirus chitinase KDEL motif
      and in vitro and in vivo analysis of the modified virus.
AB  - Infection of insect larvae with Autographa californica nucleopolyhedrovirus
      (AcMNPV) results in the liquefaction of the host, a process involving the action
      of virus-encoded chitinase and cathepsin gene products. Chitinase is localized in
      the endoplasmic reticulum (ER) during infection because of the presence of a C
      terminal ER retrieval motif (KDEL). In this study, the KDEL coding region was
      removed from the chitinase gene so that expression of the modified chitinase
      remained under the control of its own gene promoter, at its native locus. The
      deletion of KDEL resulted in the redistribution of chitinase within the cell
      during virus infection. Chitinase lacking the KDEL motif was detectable at the
      plasma membrane and was also evident in the culture medium of virus-infected
      cells from as early as 12 h post-infection (p.i.). Secretion of chitinase from
      the cell continued up to 72 h p.i., until cytolysis. The biological activity of
      the recombinant virus in Trichoplusia ni larvae was enhanced, with a significant
      reduction in the lethal dose and lethal time associated with infection.
      Furthermore, a reduction in feeding damage caused by infected larvae was observed
      compared to AcMNPV-infected individuals.

PMID- 15039524
TI  - Epidemiological and sequence differences between two subtypes (Ae and Aa) of
      hepatitis B virus genotype A.
AB  - Complete nucleotide sequences of 19 hepatitis B virus (HBV) isolates of genotype
      A (HBV/A) were determined and analysed along with those of 20 previously reported
      HBV/A isolates. Of the 19 HBV/A isolates, six including three from Japan and
      three from the USA clustered with the 14 HBV/A isolates from Western countries.
      The remaining 13 isolates including four from The Philippines, two from India,
      three from Nepal and four from Bangladesh clustered with the six HBV/A isolates
      reported from The Philippines, South Africa and Malawi. Due to distinct
      epidemiological distributions, genotype A in the 20 HBV isolates was classified
      into subtype Ae (e for Europe), and that in the other 19 into subtype Aa (a for
      Asia and Africa) provisionally. The 19 HBV/Aa isolates had a sequence variation
      significantly greater than that of the 20 HBV/Ae isolates (2.5+/-0.3 % vs 1.1+/
      0.6 %, P<0.0001); they differed by 5.0+/-0.4 % (4.1-6.4 %). The double mutation
      (T1762/A1764) in the core promoter was significantly more frequent in HBV/Aa
      isolates than in HBV/Ae isolates (11/19 or 58 % vs 5/20 or 25 %, P<0.01). In the
      pregenome encapsidation (epsilon) signal, a point mutation from G to A or T at nt
      1862 was detected in 16 of the 19 (84 %) HBV/Aa isolates but not in any of the 20
      HBV/Ae isolates, which may affect virus replication and translation of hepatitis
      B e antigen. Subtypes Aa and Ae of genotype A deserve evaluation for any clinical
      differences between them, with a special reference to hepatocellular carcinoma
      prevalent in Africa.

PMID- 15039526
TI  - Autographa californica M nucleopolyhedrovirus early GP64 synthesis mitigates
      developmental resistance in orally infected noctuid hosts.
AB  - The unusual early synthesis of the Autographa californica M nucleopolyhedrovirus
      (AcMNPV) budded virus (BV) structural protein GP64 is an important virulence
      factor during oral infection of Heliothis virescens larvae. Considering the
      breadth of the AcMNPV host range, the importance of early GP64 synthesis in
      orally infected permissive hosts (Trichoplusia ni and Spodoptera exigua) from
      subfamilies other than that of H. virescens was assessed. An AcMNPV recombinant,
      having wild-type early and late GP64 synthesis, was compared with one in which
      only late GP64 synthesis occurred. Early GP64 synthesis was found to have more of
      an effect on virulence in orally inoculated T. ni than S. exigua and that
      virulence was dependent on two factors: the ability of the host to slough
      occlusion-derived virus (ODV)-infected midgut cells and the rapidity with which
      BV was transmitted to the tracheal cells. In both host species, insects
      inoculated orally with the control virus transmitted BV to tracheal cells hours
      before those inoculated with the gp64 temporal mutant. Moreover, with early GP64
      synthesis, the lag between the onset of viral gene expression in midgut and
      tracheal cells was only 3-4 h, supporting the conclusion that in these insects,
      the first systemic infections arose from ODV-derived nucleocapsids repackaged as
      BV. These results provide further empirical proof that early GP64 synthesis is a
      component of a unique and selectively advantageous baculovirus infection strategy
      for exploiting larval lepidopterans by counteracting developmental resistance.

PMID- 15039527
TI  - Identification of a virus trans-acting regulatory element on the latent DNA
      replication of Kaposi's sarcoma-associated herpesvirus.
AB  - Latency-associated nuclear antigen 1 (LANA1) of Kaposi's sarcoma-associated
      herpesvirus (KSHV) plays a pivotal role in the maintenance of the virus genome in
      latently infected cells. LANA1 links virus genomes to host chromosomes via a C
      terminal DNA-binding domain which interacts with the sequences located in
      terminal repeats (TRs) of the virus genome and via an N-terminal chromosome
      binding sequence which associates with the host chromosomes, respectively. Recent
      data suggest that LANA1 also actively participates in the replication of KSHV TR
      containing plasmid in the transient DNA replication assay. In this report, it was
      found that C33A and COS-1, but not NIH/3T3, cell lines are permissive for the
      transient replication of KSHV TR-containing plasmid. Using several LANA1-deletion
      mutants, the minimum domain of LANA1 required for replication activity was also
      determined. In addition, the N terminus of LANA1 inhibited the transient
      replication systems of KSHV and Epstein-Barr virus (EBV) in transiently
      transfected 293 and 293T cells, but the C terminus of LANA1 specifically
      inhibited the transient replication system of KSHV in other cell lines.
      Consistent with previous reports, these data further emphasize the functional
      importance of the N terminus of LANA1 on replication from the KSHV latent origin
      of DNA replication.

PMID- 15039528
TI  - Novel herpesviruses of Suidae: indicators for a second genogroup of artiodactyl
      gammaherpesviruses.
AB  - Five novel herpesviruses were identified in suid species from Africa (common
      warthog, Phacochoerus africanus) and South-East Asia (bearded pig, Sus barbatus;
      babirusa, Babyrousa babyrussa) by detection and analysis of their DNA polymerase
      genes. Three of the novel species, P. africanus cytomegalovirus 1, P. africanus
      lymphotropic herpesvirus 1 (PafrLHV-1) and S. barbatus lymphotropic herpesvirus 1
      (SbarLHV-1), were closely related to known beta- (porcine cytomegalovirus) and
      gammaherpesviruses [porcine lymphotropic herpesvirus (PLHV) 1 and 3] of domestic
      pigs. In contrast, two novel species, S. barbatus rhadinovirus 1 (SbarRHV-1) and
      Babyrousa babyrussa rhadinovirus 1 (BbabRHV-1), were more closely related to a
      ruminant gammaherpesvirus, bovine herpesvirus 4 (BoHV-4), than to the porcine
      gammaherpesviruses PLHV-1, -2, -3, PafrLHV-1 and SbarLHV-1. SbarRHV-1, BbabRHV-1
      and BoHV-4 were therefore tentatively assigned to a novel genogroup of
      artiodactyl gammaherpesviruses. This latter genogroup may also contain an as yet
      undiscovered gammaherpesvirus of domestic pigs, thereby adding a concern to their
      use in xenotransplantation.

PMID- 15039529
TI  - Establishment of cell lines from the wasp Hyposoter didymator (Hym.,
      Ichneumonidae) containing the symbiotic polydnavirus H. didymator ichnovirus.
AB  - Cell lines derived from polydnavirus-associated wasps should constitute a
      valuable tool for investigations of polydnavirus replication, but none is yet
      available. In this work, we describe the first cell lines, named Hd-AA, -AD, -BBA
      and -K, to have been established from the ichneumonid wasp Hyposoter didymator,
      associated with the polydnavirus H. didymator ichnovirus (HdIV). Southern blot
      analysis indicated that the viral DNA was present in all four cell lines and co
      localized with high molecular mass DNA, probably the wasp chromosomes. Northern
      blot analysis of mRNAs extracted from the AA cell line showed transcription of
      some HdIV-encoded genes, although at low level. The effects of ecdysone
      treatment, HdIV re-infection and 42 degrees C heat-shock were analysed in the AA
      cell line. No effect was detected at the DNA (virus replication) or RNA (gene
      expression) levels, which may be due to the limitation of the present available
      tools.

PMID- 15039530
TI  - Productive human herpesvirus 6 infection causes aberrant accumulation of p53 and
      prevents apoptosis.
AB  - p53 plays an important role in tumour suppression in cells exposed to some
      genotoxic stresses. We found that the p53 protein level was increased in a
      variety of cell lines infected with human herpesvirus 6 (HHV-6). Because the
      elevation in p53 began very soon after infection (4 h) and did not occur with UV
      inactivated virus infection, it appeared to require the expression of one or more
      viral immediate-early (IE) genes. To elucidate the mechanism of p53 induction, we
      investigated its regulation at the protein level. Pulse-chase analysis showed
      that the stability of p53 increased in HHV-6-infected cells. In addition, the
      ubiquitination of p53 decreased after infection, indicating that the stability of
      p53 was increased through deubiquitination. We showed by confocal microscopy that
      the additional p53 mainly localized to the cytoplasm and that p53 was retained in
      the cytoplasm even after UV irradiation, but that it translocated into the
      nucleus in mock-infected cells. Furthermore, DNA fragmentation analysis, a
      terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL)
      assay and annexin V staining showed that infected cells were resistant to UV
      induced apoptosis. These results lead us to propose that HHV-6 has a mechanism
      for retaining p53 within the cytoplasm and protects the infected cells from
      apoptosis.

PMID- 15039531
TI  - Proliferation and differentiation in isogenic populations of peripheral B cells
      activated by Epstein-Barr virus or T cell-derived mitogens.
AB  - Human B cells isolated from peripheral blood were activated and induced to
      proliferate by either Epstein-Barr virus (EBV) or the T cell-derived mitogens
      CD40 ligand (CD40L) plus interleukin (IL)-4. Although both populations initially
      proliferated as B-blasts, significant differences were revealed over a longer
      period. EBV infection resulted in continuously proliferating lymphoblastoid cell
      lines (LCLs), whereas most of the CD40L/IL-4-stimulated B cells had a finite
      proliferative lifespan of 3-4 weeks. Cell cycle analysis, trypan blue staining
      and Western blot analysis for cleavage of poly(ADP-ribose) polymerase (PARP) all
      demonstrated that the decrease in proliferation in CD40L/IL-4-stimulated B cells
      is not due to cell death. Instead, these cells arrest, accumulate in G(0)/G(1)
      and undergo alterations in cell surface marker expression, cellular morphology
      and immunoglobulin production, all consistent with plasmacytoid differentiation.
      In contrast, B cells infected with EBV continued to proliferate and retained a
      blast-like phenotype. Differences in both cytokine production and the expression
      of cell cycle regulators were identified between the two B-cell populations,
      which might contribute to the differentiation of the CD40L/IL-4-stimulated B
      cells and suggest potential mechanisms by which EBV may overcome this. The study
      has also identified a window of opportunity during which a comparison of isogenic
      populations of EBV- and mitogen-driven B blasts can be made.

PMID- 15039532
TI  - Mutational analysis of the R33-encoded G protein-coupled receptor of rat
      cytomegalovirus: identification of amino acid residues critical for cellular
      localization and ligand-independent signalling.
AB  - The rat cytomegalovirus (RCMV) R33 gene encodes a G protein-coupled receptor
      (GPCR), pR33, which possesses agonist-independent, constitutive signalling
      activity. To characterize this activity further, we generated a series of point
      and deletion mutants of pR33. Both expression of and signalling by the mutants
      was evaluated. Several point mutants were generated that contained modifications
      in the NRY motif. This motif, at aa 130-132 of pR33, is the counterpart of the
      common DRY motif of GPCRs, which is known to be involved in G protein coupling.
      We found that mutation of the asparagine residue within the NRY motif of pR33
      (N(130)) to aspartic acid resulted in a mutant (N(130)D) with similar signalling
      characteristics to the wild-type (WT) protein, indicating that N(130) is not the
      determinant of constitutive activity of pR33. Interestingly, a mutant carrying an
      alanine at aa 130 (N(130)A) was severely impaired in G(q/11)-mediated,
      constitutive activation of phospholipase C, whereas it displayed similar levels
      of activity to pR33 in G(i/0)-mediated signalling. Another protein that contained
      a modified NRY motif, R(131)A, did not show constitutive activity, whereas
      mutants Y(132)F and Y(132)A displayed similar activities to the WT receptor. This
      indicated that residue R(131) is critical for pR33 function in vitro, whereas
      Y(132) is not. Finally, we identified two consecutive arginines within the C
      terminal tails of both pR33 and its homologue from human CMV, pUL33, which are
      important for correct cell-surface expression of these receptors.

PMID- 15039533
TI  - A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials:
      stimulation of HIV-specific T-cell responses by DNA and recombinant modified
      vaccinia virus Ankara (MVA) vaccines in humans.
AB  - The immunogenicities of candidate DNA- and modified vaccinia virus Ankara (MVA)
      vectored human immunodeficiency virus (HIV) vaccines were evaluated on their own
      and in a prime-boost regimen in phase I clinical trials in healthy uninfected
      individuals in the United Kingdom. Given the current lack of approaches capable
      of inducing broad HIV-neutralizing antibodies, the pTHr.HIVA DNA and MVA.HIVA
      vaccines focus solely on the induction of cell-mediated immunity. The vaccines
      expressed a common immunogen, HIVA, which consists of consensus HIV-1 clade A Gag
      p24/p17 proteins fused to a string of clade A-derived epitopes recognized by
      cytotoxic T lymphocytes (CTLs). Volunteers' fresh peripheral blood mononuclear
      cells were tested for HIV-specific responses in a validated gamma interferon
      enzyme-linked immunospot (ELISPOT) assay using four overlapping peptide pools
      across the Gag domain and three pools of known CTL epitopes present in all of the
      HIVA protein. Both the DNA and the MVA vaccines alone and in a DNA prime-MVA
      boost combination were safe and induced HIV-specific responses in 14 out of 18,
      seven out of eight and eight out of nine volunteers, respectively. These results
      are very encouraging and justify further vaccine development.

PMID- 15039534
TI  - The central region of human immunodeficiency virus type 1 p6 protein (Gag
      residues S14-I31) is dispensable for the virus in vitro.
AB  - The human immunodeficiency virus type 1 p6 region encodes p6(Gag) and the
      transframe p6(Pol) protein. The Gag frame encodes an N-terminal late assembly L
      domain and a C-terminal Vpr binding domain. In the Pol frame, substitution at a C
      terminal motif decreases protease autocleavage. The role of the highly
      polymorphic central region of p6, comprising amino acids S14-I31 (p6(Gag)) and
      R20-D39 (p6(Pol)), is unclear. Analysis of this central region demonstrated that
      35 % of p6(Gag) appears to be dispensable for virus propagation in vitro and
      smaller deletion and insertion polymorphisms can be tolerated in vivo. Extensive
      Pol deletion (deltaR20-D39, 42 % of p6(Pol)) did not alter protease autocleavage.

PMID- 15039535
TI  - Sequence analysis of the guanylyltransferase (VP3) of group A rotaviruses.
AB  - The RNA segment encoding the guanylyltransferase (VP3) from 12 group A rotavirus
      isolates has been sequenced following RT-PCR and molecular cloning of the full
      length amplicons produced. Alignment of the derived amino acid sequences
      including those of the four VP3 sequences available from GenBank revealed two
      levels of sequence divergence. Virus isolates from humans showed greater than 94%
      sequence identity, whereas those isolated from different mammalian species showed
      as low as 79% sequence identity. The exceptions were avian virus isolates, which
      diverged approximately 45% from those of mammalian origin, and the human virus
      isolates DS1 and 69M, which showed much closer (over 90%) identity to viruses of
      bovine origin, suggesting that these human isolates may have undergone recent
      reassortment events with a bovine virus. Analysis of the sequences for a putative
      enzymic active site has revealed that the KXTAMDXEXP and KXXGNNH motifs around
      amino acids 385 and 545, respectively, are conserved across both group A and C
      rotaviruses.

PMID- 15039536
TI  - The ultrastructure of the developing replication site in foot-and-mouth disease
      virus-infected BHK-38 cells.
AB  - Foot-and-mouth disease virus (FMDV) is the type species of the Aphthovirus genus
      of the Picornaviridae: Infection by picornaviruses results in a major
      rearrangement of the host cell membranes to create vesicular structures where
      virus genome replication takes place. In this report, using fluorescence and
      electron microscopy, membrane rearrangements in the cytoplasm of FMDV-infected
      BHK-38 cells are documented. At 1.5-2.0 h post-infection, free ribosomes,
      fragmented rough endoplasmic reticulum, Golgi and smooth membrane-bound vesicles
      accumulated on one side of the nucleus. Newly synthesized viral RNA was localized
      to this region of the cell. The changes seen in FMDV-infected cells distinguish
      this virus from other members of the Picornaviridae, such as poliovirus. Firstly,
      the collapse of cellular organelles to one side of the cell has not previously
      been observed for other picornaviruses. Secondly, the membrane vesicles, induced
      by FMDV, appear distinct from those induced by other picornaviruses such as
      poliovirus and echovirus 11 since they are relatively few in number and do not
      aggregate into densely packed clusters. Additionally, the proportion of vesicles
      with double membranes is considerably lower in FMDV-infected cells. These
      differences did not result from the use of BHK-38 cells in this study, as
      infection of these cells by another picornavirus, bovine enterovirus (a close
      relative of poliovirus), resulted in morphological changes similar to those
      reported for poliovirus-infected cells. With conventional fixation, FMDV
      particles were not seen; however, following high-pressure freezing and freeze
      substitution, many clusters of virus-like particles were seen.

PMID- 15039537
TI  - Hepatitis D virus RNA editing is inhibited by a GFP fusion protein containing a C
      terminally deleted delta antigen.
AB  - During its life cycle, hepatitis D virus (HDV) produces two forms of delta
      antigen (HDAg), small delta antigen (SDAg) and large delta antigen (LDAg), which
      differ in their C-terminal 19 amino acids. Host enzymes termed ADARs (adenosine
      deaminases that act on double-stranded RNA) are required for LDAg production.
      These enzymes change the stop codon (UAG) of SDAg to a tryptophan codon (UGG).
      However, the temporal and spatial regulation of HDV RNA editing is largely
      unknown. In this study, we constructed three GFP fusion proteins containing
      different lengths of SDAg and characterized their cellular localization and
      effects on HDV replication. One of these fusion proteins, designated D(1-88)-GFP,
      inhibited LDAg but not SDAg production, suggesting that D(1-88)-GFP inhibits HDV
      RNA editing. Two experiments further supported this supposition: (i). RT-PCR
      analysis combined with NcoI restriction enzyme digestion revealed that HDV RNA
      editing was reduced by 42% in HeLa-D(1-88)-GFP when compared with HeLa cells; and
      (ii). the ratio of SDAg/LDAg production from the reporter RNAs was reduced in
      cells co-transfected with ADAR-expressing and reporter plasmids in the presence
      of D(1-88)-GFP. Double fluorescence microscopy found that D(1-88)-GFP was either
      associated with SC-35 or was adjacent to PML (premyelocytic leukaemia antigen) at
      nuclear speckles, but D(1-88)-GFP was not co-localized with ADAR, which was
      mainly located in the nucleolus. In situ hybridization showing co-localization of
      HDV RNA with D(1-88)-GFP at nuclear speckles suggested that HDV RNA editing might
      occur in the nuclear speckles and require other nuclear factor(s), in addition to
      ADAR.

PMID- 15039538
TI  - Hepatitis C virus NS5A protein interacts with 2',5'-oligoadenylate synthetase and
      inhibits antiviral activity of IFN in an IFN sensitivity-determining region
      independent manner.
AB  - The non-structural protein 5A (NS5A) of hepatitis C virus (HCV) has been
      implicated in inhibition of antiviral activity of IFN. While previous studies
      have suggested an interaction between NS5A and the double-stranded RNA-dependent
      protein kinase (PKR), the possibility still remains that interaction with another
      molecule(s) is involved in the NS5A-mediated inhibition of IFN. In the present
      study, we investigated a possible interaction between NS5A and 2',5'
      oligoadenylate synthetase (2-5AS), another key molecule in antiviral activity. We
      observed that NS5A physically interacted with 2-5AS in cultured cells, with an N
      terminal portion of NS5A [aa 1-148; NS5A(1-148)] and two separate portions of 2
      5AS (aa 52-104 and 184-275) being involved in the interaction. Single point
      mutations at residue 37 of NS5A affected the degree of the interaction with 2
      5AS, with a Phe-to-Leu mutation (F37L) augmenting and a Phe-to-Asn mutation
      (F37N) diminishing it. Virus rescue assay revealed that the full-length NS5A
      (NS5A-F) and NS5A(1-148), the latter of which contains neither the IFN
      sensitivity-determining region (ISDR) nor the PKR-binding domain, significantly
      counteracted the antiviral activity of IFN. Introduction of a F37N mutation into
      NS5A(1-148) impaired the otherwise more significant IFN-inhibitory activity of
      NS5A(1-148). It was also found that the F37N mutation was highly disadvantageous
      for the replication of an HCV RNA replicon. Taken together, our results suggest
      the possibility that NS5A interacts with 2-5AS and inhibits the antiviral
      activity of IFN in an ISDR-independent manner.

PMID- 15039539
TI  - The N-terminal half of the core protein of hepatitis C virus is sufficient for
      nucleocapsid formation.
AB  - The core (C) protein of hepatitis C virus (HCV) appears to be a multifunctional
      protein that is involved in many viral and cellular processes. Although its
      effects on host cells have been extensively discussed in the literature, little
      is known about its main function, the assembly and packaging of the viral genome.
      We have studied the in vitro assembly of several deleted versions of recombinant
      HCV C protein expressed in E. coli. We demonstrated that the 75 N-terminal
      residues of the C protein were sufficient to assemble and generate nucleocapsid
      like particles (NLPs) in vitro. However, homogeneous particles of regular size
      and shape were observed only when NLPs were produced from at least the first 79 N
      terminal amino acids of the C protein. This small protein unit fused to the
      endoplasmic reticulum-anchoring domain also generated NLPs in yeast cells. These
      data suggest that the N-terminal half of the C protein is important for formation
      of NLPs. Similarities between the HCV C protein and C proteins of other members
      of the Flaviviridae are discussed.

PMID- 15039540
TI  - The influenza A virus NS1 protein binds small interfering RNAs and suppresses RNA
      silencing in plants.
AB  - RNA silencing comprises a set of sequence-specific RNA degradation pathways that
      occur in a wide range of eukaryotes, including animals, fungi and plants. A
      hallmark of RNA silencing is the presence of small interfering RNA molecules
      (siRNAs). The siRNAs are generated by cleavage of larger double-stranded RNAs
      (dsRNAs) and provide the sequence specificity for degradation of cognate RNA
      molecules. In plants, RNA silencing plays a key role in developmental processes
      and in control of virus replication. It has been shown that many plant viruses
      encode proteins, denoted RNA silencing suppressors, that interfere with this
      antiviral response. Although RNA silencing has been shown to occur in
      vertebrates, no relationship with inhibition of virus replication has been
      demonstrated to date. Here we show that the NS1 protein of human influenza A
      virus has an RNA silencing suppression activity in plants, similar to established
      RNA silencing suppressor proteins of plant viruses. In addition, NS1 was shown to
      be capable of binding siRNAs. The data presented here fit with a potential role
      for NS1 in counteracting innate antiviral responses in vertebrates by
      sequestering siRNAs.

PMID- 15039541
TI  - Human influenza virus NS1 protein enhances viral pathogenicity and acts as an RNA
      silencing suppressor in plants.
AB  - RNA silencing has a well-established function as an antiviral defence mechanism
      in plants and insects. Using an Agrobacterium-mediated transient assay, we report
      here that NS1 protein from human influenza A virus suppresses RNA silencing in
      plants in a manner similar to P1/HC-Pro protein of Tobacco etch potyvirus, a well
      characterized plant virus silencing suppressor. Moreover, we have shown that NS1
      protein expression strongly enhances the symptoms of Potato virus X in three
      different plant hosts, suggesting that NS1 protein could be inhibiting defence
      mechanisms activated in the plant on infection. These data provide further
      evidence that an RNA silencing pathway could also be activated as a defence
      response in mammals.

PMID- 15039542
TI  - The index influenza A virus subtype H5N1 isolated from a human in 1997 differs in
      its receptor-binding properties from a virulent avian influenza virus.
AB  - To gain insight into the events that occur when avian influenza viruses are
      transmitted to humans, the receptor-binding properties of the index H5N1
      influenza virus isolated from a human in 1997 and the A/turkey/Ontario/7732/66
      (H5N9) virus were compared, by using a haemadsorption assay. Cells expressing the
      haemagglutinin (HA) of the human isolate were adsorbed by both chicken red blood
      cells (RBCs) and human RBCs; those expressing the avian virus HA were only
      adsorbed by chicken RBCs. These results indicate that human and avian influenza
      virus H5 HAs differ in their recognition of sialyloligosaccharides on the RBCs of
      different animal species. Mutational analyses indicated that differences in both
      the oligosaccharide chains and in the amino acid sequences around the HA receptor
      binding site were responsible for this difference in receptor binding. These data
      further support the concept that alteration in receptor recognition is important
      for replication of avian viruses in humans.

PMID- 15039543
TI  - Amino acid changes responsible for attenuation of virus neurovirulence in an
      infectious cDNA clone of the Oshima strain of tick-borne encephalitis virus.
AB  - A stable full-length infectious cDNA clone of the Oshima strain of Tick-borne
      encephalitis virus (Far-Eastern subtype) was developed by a long high-fidelity RT
      PCR and one-step cloning procedure. The infectious clone (O-IC) had four amino
      acid substitutions and produced smaller plaques when compared with the parent
      Oshima 5-10 strain. Using site-directed mutagenesis, the substitutions were
      reverted to restore the parent virus sequence (O-IC-pt). Although genetically
      identical, parent virus Oshima 5-10 and virus recovered from O-IC-pt demonstrated
      some biological differences that are possibly explained by the presence of
      quasispecies with differing virulence characteristics within the original virus
      population. These observations may have implications for vaccines based on
      modified infectious clones. It was also demonstrated that the amino acid
      substitution E-S(40)-->P at position 40 in the envelope (E) glycoprotein was
      responsible for plaque size reduction, reduced infectious virus yields in cell
      culture and reduced mouse neurovirulence. Additionally, two amino acid
      substitutions in the non-structural (NS)5 protein (virus RNA-dependent RNA
      polymerase) NS5-V(378)-->A and NS5-R(674)-->K also contributed to attenuation of
      virulence in mice, but did not demonstrate a noticeable biological effect in baby
      hamster kidney cell culture. Comparative neurovirulence tests revealed how the
      accumulation of individual mutations (E-S(40)-->P, NS5-V(378)-->A and NS5-R(674)-
      >K) can result in the attenuation of a virus.

PMID- 15039544
TI  - Polarized glycoprotein targeting affects the spread of measles virus in vitro and
      in vivo.
AB  - We have shown previously that basolateral targeting of plasmid-encoded measles
      virus (MV) F and H protein is dependent on single tyrosine residues in the
      cytoplasmic tails of the glycoproteins and is essential for fusion activity in
      polarized epithelial cells. Here, we present data on the functional importance of
      polarized glycoprotein expression for the cytopathic properties of infectious MV
      in culture and for pathogenesis in vivo. By the introduction of single point
      mutations, we generated recombinant viruses in which the basolateral targeting
      signal of either one or both glycoproteins was destroyed (tyrosine mutants). As a
      consequence, the mutated glycoproteins were predominantly expressed on the apical
      membrane of polarized Madin-Darby canine kidney cells. In contrast to parental
      MV, none of these virus mutants was able to spread by syncytia formation in
      polarized cells showing that the presence of both MV glycoproteins at the
      basolateral cell surface is required for cell-to-cell fusion in vitro. Using
      cotton rats as an animal model that allows MV replication in the respiratory
      tract, we showed that basolateral glycoprotein targeting is also of importance
      for the spread of infection in vivo. Whereas parental MV was able to spread
      laterally within the respiratory epithelium and from there to cells in the
      underlying tissue, tyrosine mutants infected only single epithelial and very few
      subepithelial cells. These data strongly suggest that basolateral targeting of MV
      glycoproteins helps to overcome the epithelial barrier and thereby facilitates
      the systemic spread of MV infection in vivo.

PMID- 15039545
TI  - Classical swine fever virus induces proinflammatory cytokines and tissue factor
      expression and inhibits apoptosis and interferon synthesis during the
      establishment of long-term infection of porcine vascular endothelial cells.
AB  - Infection with virulent strains of classical swine fever virus (CSFV) results in
      an acute haemorrhagic disease of pigs, characterized by disseminated
      intravascular coagulation, thrombocytopenia and immunosuppression, whereas for
      less virulent isolates infection can become chronic. In view of the haemorrhagic
      pathology of the disease, the effects of the virus on vascular endothelial cells
      was studied by using relative quantitative PCR and ELISA. Following infection,
      there was an initial and short-lived increase in the transcript levels of the
      proinflammatory cytokines interleukins 1, 6 and 8 at 3 h followed by a second
      more sustained increase 24 h post-infection. Transcription levels for the
      coagulation factor, tissue factor and vascular endothelial cell growth factor
      involved in endothelial cell permeability were also increased. Increases in these
      factors correlated with activation of the transcription factor NF-kappaB.
      Interestingly, the virus produced a chronic infection of endothelial cells and
      infected cells were unable to produce type I interferon. Infected cells were also
      protected from apoptosis induced by synthetic ouble-stranded RNA. These results
      demonstrate that, in common with the related pestivirus bovine viral diarrhoea
      virus, CSFV can actively block anti-viral and apoptotic responses and this may
      contribute to virus persistence. They also point to a central role for infection
      of vascular endothelial cells during the pathogenesis of the disease, where a
      proinflammatory and procoagulant endothelium induced by the virus may disrupt the
      haemostatic balance and lead to the coagulation and thrombosis seen in acute
      disease.

PMID- 15039546
TI  - Compatibility of the movement protein and the coat protein of cucumoviruses is
      required for cell-to-cell movement.
AB  - For the cell-to-cell movement of cucumoviruses both the movement protein (MP) and
      the coat protein (CP) are required. These are not reversibly exchangeable between
      Cucumber mosaic virus (CMV) and Tomato aspermy virus (TAV). The MP of CMV is able
      to function with the TAV CP (chimera RT), but TAV MP is unable to promote the
      cell-to-cell movement in the presence of CMV CP (chimera TR). To gain further
      insight into the non-infectious nature of the TR recombinant, RNA 3 chimeras were
      constructed with recombinant MPs and CPs. The chimeric MP and one of the CP
      recombinants were infectious. The other recombinant CP enabled virus movement
      only after the introduction of two point mutations (Glu-->Lys and Lys-->Arg at aa
      62 and 65, respectively). The mutations served to correct the CP surface
      electrostatic potential that was altered by the recombination. The infectivity of
      the TR virus on different test plants was restored by replacing the sequence
      encoding the C-terminal 29 aa of the MP with the corresponding sequence of the
      CMV MP gene or by exchanging the sequence encoding the C-terminal 15 aa of the CP
      with the same region of TAV. The analysis of the recombinant clones suggests a
      requirement for compatibility between the C-terminal 29 aa of the MP and the C
      terminal two-thirds of the CP for cell-to-cell movement of cucumoviruses.

PMID- 15039547
TI  - Heterologous expression of the modified coat protein of Cowpea chlorotic mottle
      bromovirus results in the assembly of protein cages with altered architectures
      and function.
AB  - We have developed methods for producing viral-based protein cages in high yield
      that are amenable to genetic modification. Expression of the structural protein
      of Cowpea chlorotic mottle bromovirus (CCMV) using the yeast-based Pichia
      pastoris heterologous expression system resulted in the assembly of particles
      that were visibly indistinguishable from virus particles produced in the natural
      host. We have shown that a collection of non-infectious CCMV coat protein mutants
      expressed in the P. pastoris system assemble into viral protein cages with
      altered architectures and function. This provides an alternative to other
      heterologous expression systems for production of viral structural proteins in
      which expression has resulted in unassembled cages. Heterologous expression in P.
      pastoris further enhances the development of viral-based protein cages as
      biotemplates for nanotechnology and for future studies examining details of
      icosahedral virus assembly.

PMID- 15039548
TI  - Interaction of VPg-Pro of turnip mosaic virus with the translation initiation
      factor 4E and the poly(A)-binding protein in planta.
AB  - The viral protein linked to the genome (VPg) of Turnip mosaic virus (TuMV)
      interacts in vitro with the translation eukaryotic initiation factor (eIF) 4E. In
      the present study, we investigated the consequence of TuMV infection on eIF4E
      expression. Two isomers are present in plants, namely eIF4E and eIF(iso)4E.
      Expression of the latter was detected in both TuMV-infected and mock-inoculated
      Brassica perviridis plants, but expression of eIF4E was found only in infected
      plants. Membranes from TuMV-infected or mock-inoculated tissues were separated by
      sucrose gradient centrifugation and fractions were collected. Immunoblot analyses
      showed that 6K(2)-VPg-Pro/VPg-Pro polyproteins were associated with endoplasmic
      reticulum membranes and were the viral forms likely to interact with eIF(iso)4E
      and eIF4E. In planta interaction between 6K(2)-VPg-Pro/VPg-Pro and
      eIF(iso)4E/eIF4E was confirmed by co-purification by metal chelation
      chromatography. The poly(A)-binding protein (PABP) was also found to co-purify
      with VPg-Pro. Direct interaction between VPg-Pro and PABP was shown by an ELISA
      based binding assay. These experiments suggest that a multi-protein complex may
      form around VPg-Pro of TuMV.

PMID- 15039549
TI  - Diffraction and imaging study of imperfections of crystallized lysozyme with
      coherent X-rays.
AB  - Phase-contrast X-ray diffraction imaging and high-angular-resolution diffraction
      combined with phase-contrast radiographic imaging were employed to characterize
      defects and perfection of a uniformly grown tetragonal lysozyme crystal in the
      symmetric Laue case. The full-width at half-maximum (FWHM) of a 4 4 0 rocking
      curve measured from the original crystal was approximately 16.7 arcsec and
      imperfections including line defects, inclusions and other microdefects were
      observed in the diffraction images of the crystal. The observed line defects
      carry distinct dislocation features running approximately along the <1 1 0>
      growth front and have been found to originate mostly in a central growth area and
      occasionally in outer growth regions. Inclusions of impurities or formations of
      foreign particles in the central growth region are resolved in the images with
      high sensitivity to defects. Slow dehydration led to the broadening of a fairly
      symmetric 4 4 0 rocking curve by a factor of approximately 2.6, which was
      primarily attributed to the dehydration-induced microscopic effects that are
      clearly shown in X-ray diffraction images. The details of the observed defects
      and the significant change in the revealed microstructures with drying provide
      insight into the nature of imperfections, nucleation and growth, and the
      properties of protein crystals.

PMID- 15039550
TI  - Phase transition of triclinic hen egg-white lysozyme crystal associated with
      sodium binding.
AB  - A triclinic crystal of hen egg-white lysozyme obtained from a D2O solution at 313
      K was transformed into a new triclinic crystal by slow release of solvent under a
      temperature-regulated nitrogen-gas stream. The progress of the transition was
      monitored by X-ray diffraction. The transition started with the appearance of
      strong diffuse streaks. The diffraction spots gradually fused and faded with the
      emergence of diffraction from the new lattice; the scattering power of the
      crystal fell to a resolution of 1.5 A from the initial 0.9 A resolution. At the
      end of the transition, the diffuse streaks disappeared and the scattering power
      recovered to 1.1 A resolution. The transformed crystal contained two independent
      molecules and the solvent content had decreased to 18% from the 32% solvent
      content of the native crystal. The structure was determined at 1.1 A resolution
      and compared with the native structure refined at the same resolution. The
      backbone structures of the two molecules in the transformed crystal were
      superimposed on the native structure with root-mean-square deviations of 0.71 and
      0.96 A. A prominent structural difference was observed in the loop region of
      residues Ser60-Leu75. In the native crystal, a water molecule located at the
      centre of this helical loop forms hydrogen bonds to main-chain peptide groups. In
      the transformed crystal, this water molecule is replaced by a sodium ion with
      octahedral coordination that involves water molecules and a nitrate ion. The
      peptide group connecting Arg73 and Asn74 is rotated by 180 degrees so that the CO
      group of Arg73 can coordinate to the sodium ion. The change in the X-ray
      diffraction pattern during the phase transition suggests that the transition
      proceeds at the microcrystal level. A mechanism is proposed for the crystal
      transformation.

PMID- 15039551
TI  - Metals in the sporulation phosphorelay: manganese binding by the response
      regulator Spo0F.
AB  - As a part of studies on the structural characterization of the components of the
      sporulation phosphorelay in Bacillus subtilis, the crystal structure of the
      manganese derivative of an intermediate signal transducer, Spo0F, has been
      elucidated at 2.25 A resolution. The calcium complex and the apo structures have
      been analyzed previously. In apo Spo0F, the active-site cation cavity is only
      partially formed and it only becomes completed upon metal coordination. The
      carbonyl of Lys56 is coordinated to the metal and interestingly the side chain of
      Lys56 exists in a variety of conformations in the three crystal structures of
      Spo0F. The affinity of the magnesium ion for Spo0F is in fact low; however, it
      binds Spo0F when it is in complex with Spo0B. It is proposed that the existence
      of a deep pocket which extends from the surface to the metal site could attract
      and direct the metal, thereby facilitating the metal binding of the complex.

PMID- 15039553
TI  - Combined pseudo-merohedral twinning, non-crystallographic symmetry and pseudo
      translation in a monoclinic crystal form of the gammadelta T-cell ligand T10.
AB  - T10 is a non-classical class Ib-like major histocompatibility complex (MHC) cell
      surface antigen which binds directly to certain gammadelta T-cell receptors in
      the absence of any exogenous and endogenous ligands, such as peculiar lipids or
      glycolipids. The crystal structure at 2.5 A resolution of murine T10 was
      determined by molecular replacement using data from an almost perfectly twinned
      monoclinic crystal. The space group is P2(1), with unit-cell parameters a = 78.2,
      b = 70.0, c = 139.2 A, beta = 106.8 degrees. Self-rotation function analysis and
      various intensity statistics revealed the presence of pseudo-merohedral twinning,
      but these tests underestimated the true twin fraction of alpha approximately
      0.46. Native Patterson analyses pointed to the presence of pseudo-translation
      among the four molecules present in the asymmetric unit. Data analysis, structure
      determination and model refinement are discussed.

PMID- 15039552
TI  - Structure determination of tetrahydroquinazoline antifolates in complex with
      human and Pneumocystis carinii dihydrofolate reductase: correlations between
      enzyme selectivity and stereochemistry.
AB  - Structural data are reported for the first examples of the tetrahydroquinazoline
      antifolate (6R,6S)-2,4-diamino-6-(1-indolinomethyl)-5,6,7,8-tetrahydroquinazoline
      (1) and its trimethoxy analogue (6R,6S)-2,4-diamino-6-(3',4',5'-trimethoxybenzyl)
      5,6,7,8-tetrahydroquinazoline (2) as inhibitor complexes with dihydrofolate
      reductase (DHFR) from human (hDHFR) and Pneumocystis carinii (pcDHFR) sources.
      The indoline analogue (1) was crystallized as ternary complexes with NADPH and
      hDHFR (1.9 A resolution) and pcDHFR (2.3 A resolution), while the trimethoxy
      quinazoline analogue (2) was crystallized as a binary complex with hDHFR in two
      polymorphic rhombohedral R3 lattices: R3(1) to 1.8 A resolution and R3(2) to 2.0
      A resolution. Structural analysis of these potent and selective DHFR-inhibitor
      complexes revealed preferential binding of the 6S-equatorial isomer in each
      structure. This configuration is similar to that of the natural tetrahydrofolate
      substrate; that is, 6S. These data also show that in both the hDHFR and pcDHFR
      ternary complexes with (1) the indoline ring is partially disordered, with two
      static conformations that differ between structures. These conformers also differ
      from that observed for the trimethoxybenzyl ring of tetrahydroquinazoline (2).
      There is also a correlation between the disorder of the flexible loop 23 and the
      disorder of the cofactor nicotinamide ribose ring in the pcDHFR-NADPH-(1) ternary
      complex. Comparison of the Toxoplasma gondii DHFR (tgDHFR) sequence with those of
      other DHFRs provides insight into the role of sequence and conformation in
      inhibitor-binding preferences which may aid in the design of novel antifolates
      with specific DHFR selectivity.

PMID- 15039554
TI  - Structures of two lectins from the roots of pokeweed (Phytolacca americana).
AB  - Pokeweed lectin (PL), a lectin specific for N-acetylglucosamine-containing
      saccharides, stimulates peripheral lymphocytes to undergo mitosis by binding to
      their cell surfaces. Four types of lectins have been isolated from the roots of
      pokeweed (Phytolacca americana) and shown to contain homologous domains but to
      have different molecular sizes and biological properties. PL-D, the smallest
      lectin in the group, has two isolectins, PL-D1 and PL-D2. PL-D1 consists of 84
      amino-acid residues, while PL-D2 is identical to PL-D1 in sequence except for the
      lack of two C-terminal residues, Leu83 and Thr84. The crystal structures of PL-D1
      and PL-D2 were solved by the molecular-replacement method and refined to 1.65 and
      1.5 A resolution with R factors of 17.2 and 17.6%, respectively. The PL-Ds are
      composed of two repetitive chitin-binding domains, each of which has four S-S
      bridges and one putative carbohydrate-binding site. The two carbohydrate-binding
      sites in PL-D are located on one side of the molecule. The relative orientation
      of the two domains in PL-D1 differs from that in PL-D2. Two C-terminal residues
      of PL-D1 are invisible in the present crystal structure, indicating the
      flexibility of the region. PL-D2 has a Ca2+ ion bound to the C-terminus on the
      molecular surface. A wide distribution of acidic residues is characteristically
      observed on one side of the C-terminal region of PL-D.

PMID- 15039555
TI  - Structure of human translin at 2.2 A resolution.
AB  - The structure of human translin at 2.2 A resolution is reported in space group
      C222(1). Translin forms a tetramer in the asymmetric unit. Although the monomer
      structure is almost the same as the crystal structure of murine translin in space
      group P2(1)2(1)2, the relative positions of the tetramers differ between the
      human and murine translins. This suggests that the multimerization of translin is
      flexible; the flexibility may be related to the binding to DNA/RNA.

PMID- 15039556
TI  - DNA variability in five crystal structures of d(CGCAATTGCG).
AB  - The deoxyoligonucleotide d(CGCAATTGCG) has previously been crystallized in four
      different space groups. The crystals diffract to moderate resolution (2.3-2.9 A).
      Here, a fifth crystal form that diffracts to higher resolution (1.6 A) is
      presented which was obtained thanks to the use of Co2+ and cryogenic
      temperatures. The availability of five different crystal structures allows a
      thorough analysis of the conformational variability of this DNA sequence. It is
      concluded that the central hexamer sequence CAATTG has a practically constant
      conformation under all conditions, whilst the terminal base pairs at both ends
      vary considerably as a result of differing interactions in the crystals. The new
      crystal structure presented here is stabilized by guanine-Co2+-guanine
      interactions and the formation of C1+ -G8.C3 triplexes between neighbouring
      duplexes. As a result of the higher resolution of the crystal structure, a more
      regular structure was obtained and a clear definition of the spine of hydration
      was observed which was not visible in the four previous structures.

PMID- 15039557
TI  - Determination of a novel structure by a combination of long-wavelength sulfur
      phasing and radiation-damage-induced phasing.
AB  - The structure of the 115 amino-acid residue protein DsvC was determined based on
      the anomalous scattering provided by the five S atoms present in the structure.
      By collecting the diffraction data at a wavelength of 1.9 A, the anomalous signal
      provided by the S atoms was enhanced. However, significant radiation damage
      occurred during the course of the experiment, which led to differences between
      different parts of the data set. Only by dividing the total data set into five
      data sets was it possible to obtain phases; these could then be successfully
      extended to allow structure determination by the automated model-building program
      ARP/wARP. A computational correction for the radiation damage was found to
      significantly improve the success rate in determining the heavy-atom substructure
      and to improve phasing and refinement statistics.

PMID- 15039558
TI  - Assessing crystallization droplets using birefringence.
AB  - In this paper, the detection of crystalline elements in protein crystallization
      droplets containing precipitate is illustrated using the rotating-polarizer
      microscope technique. The sensitivity of this automated birefringence technique
      enables the detection of microcrystals in a precipitate that appears to be
      amorphous using traditional methods of inspection. The technique is illustrated
      with lysozyme and glucose isomerase. Glucose isomerase microcrystals were used
      successfully for seeding experiments and the conditions of both of the systems
      were refined to produce crystals suitable for X-ray analysis. The results are
      relevant to the field of high-throughput crystallography as an automated crystal
      detection method as well as being a useful tool for detailed precipitate
      analysis.

PMID- 15039559
TI  - Crystallization and X-ray analysis of bovine glycolipid transfer protein.
AB  - Glycolipid-transfer protein (GLTP) is a 24 kDa basic cytosolic protein that
      facilitates the transfer of glycolipids between bilayer membranes in vitro, but
      its in vivo function is unknown. Human, bovine, porcine and murine GLTPs have
      recently been cloned and share high sequence identity to each other. The three
      dimensional structure of GLTP has not yet been solved and no structures of any
      proteins related to GLTP are known. Therefore, the structure of GLTP might reveal
      a currently unknown fold. Here, the crystallization and preliminary X-ray
      analysis of bovine GLTP are reported for the first time. Protein prepared by
      recombinant techniques using an Escherichia coli expression system has been
      crystallized using the vapour-diffusion method. The crystals belong to space
      group P2(1), with unit-cell parameters a = 55.4, b = 34.9, c = 58.5 A, alpha =
      gamma = 90, beta = 116 degrees. The crystals diffract to 1.6 A resolution and a
      97.1% complete data set with an R(merge) of 6.7% has been collected from a single
      crystal at 100 K using synchrotron radiation.

PMID- 15039560
TI  - Crystallization and preliminary X-ray analysis of the Plasmodium vivax sexual
      stage 25 kDa protein Pvs25, a transmission-blocking vaccine candidate for
      malaria.
AB  - The Plasmodium vivax sexual stage 25 kDa protein Pvs25 is expressed on the
      surface of the ookinete form of the parasite. Monoclonal antibodies directed
      against Pvs25 block the development of P. vivax oocysts in the mosquito host.
      Thus, Pvs25 is a potential vaccine candidate for eliciting transmission-blocking
      immunity in individuals living in malaria-epidemic regions. Pvs25 which was
      expressed and purified for clinical trials was crystallized using polyethylene
      glycol as the precipitating agent and diffracts X-rays to 2.3 A. The orthorhombic
      Pvs25 crystal form belongs to space group P2(1)2(1)2(1), with unit-cell
      parameters a = 42.6, b = 59.8, c = 66.8 A and one molecule in the asymmetric
      unit. Reductively methylated Pvs25 crystallized in two forms: an orthorhombic
      P2(1)2(1)2(1) form with unit-cell parameters a = 43.4, b = 62.9, c = 66.9 A and
      one molecule in the asymmetric unit and a monoclinic P2(1) form with unit-cell
      parameters a = 53.5, b = 43.3, c = 65.3 A, beta = 104.0 degrees which was
      predicted to have one or two molecules in the asymmetric unit. Several native and
      heavy-atom data sets have been collected from Pvs25 and methylated Pvs25 crystals
      for use in MAD or MIR techniques.

PMID- 15039561
TI  - Purification, crystallization and preliminary X-ray analysis of uridine
      phosphorylase from Salmonella typhimurium.
AB  - The structural udp gene encoding uridine phosphorylase (UPh) was cloned from the
      Salmonella typhimurium chromosome and overexpressed in Escherichia coli cells. S.
      typhimurium UPh (StUPh) was purified to apparent homogeneity and crystallized.
      The primary structure of StUPh has high homology to the UPh from E. coli, but the
      enzymes differ substantially in substrate specificity and sensitivity to the
      polarity of the medium. Single crystals of StUPh were grown using hanging-drop
      vapor diffusion with PEG 8000 as the precipitant. X-ray diffraction data were
      collected to 2.9 A resolution. Preliminary analysis of the diffraction data
      indicated that the crystal belonged to space group P6(1(5)), with unit-cell
      parameters a = 92.3, c = 267.5 A. The solvent content is 37.7% assuming the
      presence of one StUPh hexamer per asymmetric unit.

PMID- 15039562
TI  - Purification, crystallization and preliminary X-ray diffraction analysis of human
      oncoprotein SET/TAF-1beta.
AB  - The human oncoprotein SET/TAF-1beta has been crystallized by the sitting-drop
      vapour-diffusion method using ammonium sulfate as a precipitant. The crystal
      belongs to space group C2, with unit-cell parameters a = 119.6, b = 62.8, c =
      61.0 A, beta = 89.7 degrees, and contains two molecules in the asymmetric unit. A
      complete data set was collected to 2.8 A resolution using synchrotron radiation.

PMID- 15039563
TI  - Crystallization and preliminary X-ray diffraction analysis of the
      hyperthermostable NAD-dependent glutamate dehydrogenase from Pyrobaculum
      islandicum.
AB  - NAD-dependent glutamate dehydrogenase from the hyperthermophilic archaeon
      Pyrobaculum islandicum was crystallized in the apo- and holoenzyme forms.
      Crystals were obtained using 2-propanol and polyethylene glycol MME 550 as
      precipitants for the apoenzyme and holoenzyme, respectively. The apoenzyme
      crystals belong to the trigonal space group P3(1)21 or its enantiomorph P3(2)21.
      The asymmetric unit contains three subunits; the values of the Matthews
      coefficient (VM) and the solvent content are 2.9 A3 Da-1 and 57%, respectively. A
      native data set was collected to a highest resolution limit of 4.0 A on an in
      house X-ray source using a rotating-anode generator (overall Rsym of 12.3% and
      completeness of 97%). The holoenzyme crystals belong to the orthorhombic space
      group P2(1)2(1)2(1); the asymmetric unit contains one hexamer, giving a VM of
      2.79 A3 Da-1 and a solvent content of 55%. Native and derivative data sets were
      collected. The crystals diffract to a maximum resolution of 2.8 A on the KEK-NW12
      beamline at the Photon Factory and gave a data set with an overall Rsym of 7.9%
      and a completeness of 91%. Attempts are being made to solve the structure by the
      SIRAS method.

PMID- 15039564
TI  - Crystallization and preliminary X-ray study of the common edible mushroom
      (Agaricus bisporus) lectin.
AB  - The lectin from the common edible mushroom Agaricus bisporus (ABL) belongs to the
      group of proteins that have the property of binding the Thomsen-Friedenreich
      antigen (T-antigen) selectively and with high affinity, but does not show any
      sequence similarity to the other proteins that share this property. The ABL
      sequence is instead similar to those of members of the saline-soluble fungal
      lectins, a protein family with pesticidal properties. The presence of different
      isoforms has been reported. It has been found that in order to be able to grow
      diffraction-quality crystals of the lectin, it is essential to separate the
      isoforms, which was performed by preparative isoelectric focusing. Using standard
      procedures, it was possible to crystallize the most basic of the forms by either
      vapour diffusion or equilibrium dialysis, but attempts to grow crystals of the
      other more acidic forms were unsuccessful. The ABL crystals belong to the
      orthorhombic space group C222(1), with unit-cell parameters a = 93.06, b = 98.16,
      c = 76.38 A, and diffract to a resolution of 2.2 A on a conventional source at
      room temperature. It is expected that the solution of this structure will yield
      further valuable information on the differences in the T-antigen-binding folds
      and will perhaps help to clarify the details of the ligand binding to the
      protein.

PMID- 15039565
TI  - Gene design, expression, crystallization and preliminary diffraction analysis of
      two isolectins from the fungus Coprinus cinereus: a model for studying functional
      diversification of galectins in the same organism and their evolutionary
      pathways.
AB  - It is the aim of comparative structural biology to define the evolutionarily
      important traits of protein function and the points of diversification.
      Consequently, structural analysis, especially of distant members in a family
      which in this case are lectins involved in cell adhesion and growth regulation in
      animals (i.e. galectins), is required. For this purpose, recent work has been
      focused on the first galectins known from outside the animal kingdom. These are
      the two isolectins from the basidiomycete Coprinus cinereus (inky cap mushroom),
      termed Cgl-1 and Cgl-2. Additionally, the close similarity (83% deduced amino
      acid identity) but the pronounced difference in the expression patterns of these
      two fungal lectins during fruiting-body formation affords a suitable object for
      study of the relation of structural difference to the observed functional
      disparity in the same organism. Both galectins were crystallized after
      recombinant production. Crystals belong to either the orthorhombic space group
      C222(1) (Cgl-1) or the monoclinic space group P2(1) (Cgl-2). The latter crystals
      diffracted to 1.6 A resolution using synchrotron radiation. To solve the phasing
      problem, a selenomethionine-containing variant of Cgl-1 was designed. Crystals
      isomorphous to those of the native counterpart were obtained. Their structural
      analysis will also be crucial to solving the structure of Cgl-2.

PMID- 15039566
TI  - Crystallization and preliminary X-ray analysis of HCE-1, a hatching enzyme of
      medaka fish, Oryzias latipes.
AB  - The hatching enzyme of medaka fish, high choriolytic enzyme (HCE-1; MW = 22.7
      kDa), was crystallized by the hanging-drop vapour-diffusion method using PEG 10
      000 as the precipitant. The hatching enzyme is a metalloproteinase which is
      secreted from the embryo at the time of hatching. The crystals diffracted X-rays
      to beyond 1.34 A resolution using a synchrotron-radiation source. The crystals
      belonged to the monoclinic space group C2, with unit-cell parameters a = 99.0, b
      = 30.4, c = 79.6 A, beta = 123.6 degrees. The crystal contains one molecule in an
      asymmetric unit (VM = 2.2 A3 Da-1) and has a solvent content of 43.7%.

PMID- 15039567
TI  - Crystallization and preliminary crystallographic analysis of the circadian clock
      protein KaiB from the thermophilic cyanobacterium Thermosynechococcus elongatus
      BP-1.
AB  - KaiB is a component of the circadian clock oscillator in cyanobacteria, which are
      the simplest organisms that exhibit circadian rhythms. KaiB consists of 108 amino
      acid residues and has a molecular weight of 12 025 Da. KaiB and Cys-substituted
      KaiB mutants from the thermophilic cyanobacterium Thermosynechococcus elongatus
      BP-1 were expressed as GST-fusion proteins in Escherichia coli, purified and
      crystallized. The crystals of wild-type KaiB belong to the monoclinic space group
      P2(1), with unit-cell parameters a = 89.6, b = 71.2, c = 106.8 A, beta = 100.1
      degrees. While the native crystals diffract to 3.7 A, osmium derivatives, which
      show an approximately 4 A shrinkage in the b axis, diffract to 2.6 A. The
      crystals of the singly Cys-substituted mutant T64C with Hg, which show different
      morphology, diffract to 2.5 A and belong to the monoclinic space group P2, with
      unit-cell parameters a = 63.7, b = 33.4, c = 93.7 A, beta = 100.1 degrees.
      Anomalous difference Patterson maps of the Os- and Hg-derivative crystals had
      significant peaks in their Harker sections, suggesting that both derivatives are
      suitable for structure determination.

PMID- 15039568
TI  - Crystallization of a Golgi-associated PR-1-related protein (GAPR-1) that
      localizes to lipid-enriched microdomains.
AB  - The human Golgi-associated PR-1-related protein (GAPR-1) is closely related to
      plant pathogenesis-related (PR-1) proteins, which are upregulated in response to
      pathogen attack. Family members have been identified in a variety of organisms,
      together constituting the superfamily of PR-1 proteins. GAPR-1 is found within
      lipid-enriched microdomains on the cytosolic side of the endomembrane system.
      GAPR-1 is tightly anchored to membranes and absent from the cytosol, although it
      does not possess a membrane-spanning domain. Crystals of recombinantly expressed
      GAPR-1 have been grown that diffract to high (1.5 A) resolution. Complete data
      sets have been collected on a trigonal crystal form (P3(1)21/P3(2)21), with unit
      cell parameters a = b = 73.5, c = 63.2 A. Molecular replacement using the NMR
      coordinates of tomato pathogenesis-related protein (28% identity) was
      unsuccessful and a search for heavy-metal derivatives or alternative phasing
      methods has been initiated.

PMID- 15039569
TI  - Crystallization and preliminary X-ray analysis of a conserved hypothetical
      protein PAE2754 from Pyrobaculum aerophilum and of a double Leu-->Met mutant
      engineered for MAD phasing.
AB  - Structural genomics offers a potential route to the discovery of protein
      function. As part of a structural genomics project focused on the
      hyperthermophilic crenarchaeon Pyrobaculum aerophilum, a conserved hypothetical
      protein, PAE2754, has been expressed in Escherichia coli, purified and
      crystallized. Because of the difficulties of preparing interpretable heavy-atom
      derivatives with limited resolution and 8-12 molecules in the asymmetric unit,
      two leucine residues were selected for mutation to methionine. The double mutant
      L65M/L80M was created, expressed incorporating SeMet and crystallized. The
      crystals are monoclinic, space group P2(1), with unit-cell parameters a = 56.4, b
      = 193.3, c = 60.5 A, beta = 94.6 degrees and eight molecules (two tetramers) in
      the asymmetric unit. The crystals diffract to 2.75 A resolution and are suitable
      for MAD phasing.

PMID- 15039570
TI  - Purification and crystallization of Escherichia coli oligoribonuclease.
AB  - Oligoribonuclease (Orn) is an essential 3'-to-5' hydrolytic exoribonuclease which
      degrades short oligoribonucleotides to 5' mononucleotides. Escherichia coli Orn
      has been crystallized under several different conditions using ammonium sulfate,
      sodium citrate and sodium acetate as precipitants. Both native and
      selenomethionine-labeled oligoribonuclease (SeMet-Orn) can be crystallized at
      room temperature in 1.4-1.55 M sodium citrate. The SeMet-Orn crystals diffract to
      2.2 A resolution and belong to space group P2(1)2(1)2(1), with unit-cell
      parameters a = 70.43, b = 72.87, c = 147.76 A, and two dimers in the asymmetric
      unit. When grown in the presence of manganese, a second crystal form (Mn-SeMet
      Orn) was obtained containing a single dimer per asymmetric unit (P2(1)2(1)2(1); a
      = 63.74, b = 74.31, c = 74.19 A). Finally, a hexagonal crystal form was obtained
      using sodium acetate as a precipitant (a = 91.5, b = 91.5, c = 111.1 A). This
      crystal (Zn-ApUp-Orn) belongs to the P6(5) space group and has three
      oligoribonuclease molecules per asymmetric unit.

PMID- 15039571
TI  - Preliminary crystallographic analysis of the complex of the human GTPase RhoA
      with the DH/PH tandem of PDZ-RhoGEF.
AB  - PDZ-containing RhoGEF (PDZ-RhoGEF) is a multidomain protein composed of 1522
      amino acids that belongs to the guanine nucleotide exchange factors family (GEF)
      active on Rho GTPases. It is highly specific for RhoA and is thought to transduce
      signals from Galpha(12/13)-coupled receptors to the RhoA-dependent regulatory
      cascades. The protein shows high sequence homology to LARG, p115-RhoGEF and
      Drosophila DRhoGEF2. The exchange reaction is catalyzed by a DH domain, which is
      directly downstream of a PH domain in all known Rho-specific GEFs. The DH/PH
      tandem of PDZ-RhoGEF and C-terminally truncated RhoA were overexpressed in
      Escherichia coli as TEV protease-cleavable fusion proteins containing GST and a
      hexahistidine tag at the N-termini, respectively. The nucleotide-free DH/PH-RhoA
      complex was purified by gel filtration and crystallized. The crystals belong to
      space group P2(1), with unit-cell parameters a = 88.6, b = 119.0, c = 91.5 A,
      beta = 114.7 degrees.

PMID- 15039572
TI  - Crystallization and preliminary crystallographic analysis of the NAD(H)-binding
      domain of Escherichia coli transhydrogenase.
AB  - Transhydrogenase is a proton-pumping membrane protein that is required for the
      cellular regeneration of NADPH. The NAD(H)-binding domain (domain I) of
      transhydrogenase from Escherichia coli was crystallized using the hanging-drop
      vapour-diffusion technique at room temperature. The crystals, which were grown
      from PEG 4000 and ammonium acetate in citrate buffer, belong to the triclinic
      space group P1, with unit-cell parameters a = 38.8, b = 66.8, c = 76.4 A, alpha =
      67.5, beta = 80.8, gamma = 81.5 degrees. X-ray diffraction data were collected to
      1.9 A resolution using synchrotron radiation. The crystals contain one dimer of
      transhydrogenase domain I per asymmetric unit.

PMID- 15039574
TI  - Crystallization and preliminary X-ray crystallographic investigations of an
      unusual type III polyketide synthase PKS18 from Mycobacterium tuberculosis.
AB  - The biosynthetic machinery of polyketide synthases involves various sequential
      enzymatic reactions, such as initiation, elongation and cyclization, to produce
      polyketides. PKS18 protein from Mycobacterium tuberculosis belongs to the type
      III polyketide synthase family and displays an unusual starter-unit specificity
      to catalyze the formation of alpha-pyrones. This enzyme uses malonyl-CoA to
      iteratively extend long-chain aliphatic coenzyme A (C12 to C20) molecules,
      producing triketide and tetraketide pyrone products. In order to aid in
      understanding the structural basis of this long-chain specificity and to further
      characterize the enzymatic mechanism of PKS18, the protein has been crystallized.
      The crystal belongs to the triclinic space group P1, with unit-cell parameters a
      = 59.9, b = 80.7, c = 99.6 A, alpha = 108.2, beta = 93.0, gamma = 103.7 degrees.

PMID- 15039573
TI  - Expression, purification, crystallization and preliminary crystallographic
      studies of the Enterococcus faecalis cytolysin repressor CylR2.
AB  - The expression of an exotoxin called cytolysin contributes to the virulence of
      Enterococcus faecalis, one of the organisms responsible for antibiotic resistant
      infections acquired in hospitals. The DNA-binding protein CylR2 is a
      transcriptional repressor of cytolysin. At a specific cell density, cytolysin
      triggers signaling events, which result in the dissociation of CylR2 from its DNA
      binding site. CylR2 was overexpressed in Escherichia coli and purified and
      crystals diffracting to 1.9 A were obtained in two different crystal forms. One
      crystal form belongs to space group P4(1), with unit-cell parameters a = 63.7, b
      = 63.7, c = 41.2 A, alpha = beta = gamma = 90 degrees, and the other belongs to
      space group P1, with unit-cell parameters a = 36.9, b = 45.0, c = 47.7 A, alpha =
      67, beta = 90, gamma = 66 degrees.

PMID- 15039575
TI  - Purification, crystallization and preliminary structural characterization of
      human Rap1GAP.
AB  - Human Rap1GAP, the GTPase-activating protein (GAP) for the small GTPase Rap1, was
      recombinantly expressed in Escherichia coli, purified and crystallized using the
      hanging-drop vapour-diffusion method. Crystals were obtained using PEG 3350 as a
      precipitating agent and belong to the orthorhombic space group P2(1)2(1)2, with
      unit-cell parameters a = 170.7, b = 224.5, c = 48.7 A. A complete data set was
      collected to 2.9 A resolution at 100 K using synchrotron radiation. The structure
      may reveal features of the unique reaction mechanism of Rap1GAP.

PMID- 15039576
TI  - Single-stranded DNA bound to bacterial cold-shock proteins: preliminary
      crystallographic and Raman analysis.
AB  - The cold-shock response has been described for several bacterial species. It is
      characterized by distinct changes in intracellular protein patterns whereby a set
      of cold-shock-inducible proteins become abundant. The major cold-shock proteins
      of Bacillus subtilis (Bs-CspB) and Bacillus caldolyticus (Bc-Csp) are small
      oligonucleotide/oligosaccharide-binding (OB) fold proteins that have been
      described as binding single-stranded nucleic acids. Bs-CspB (Mr = 7365) and Bc
      Csp (Mr = 7333) were crystallized in the presence of the deoxyhexanucleotide
      (dT)6. Crystals of (dT)6 with Bs-CspB grew in the orthorhombic space group
      C222(1), with unit-cell parameters a = 49.0, b = 53.2, c = 77.0 A. Crystals with
      Bc-Csp grew in the primitive orthorhombic space group P2(1)2(1)2, with unit-cell
      parameters a = 74.3, b = 64.9, c = 31.2 A. These crystals diffract to maximal
      resolutions of 1.78 and 1.29 A, respectively. The presence of protein and DNA in
      the crystals was demonstrated by Raman spectroscopy.

PMID- 15039577
TI  - Purification, crystallization and preliminary X-ray analysis of the lytic
      transglycosylase MltA from Escherichia coli.
AB  - The lytic transglycosylase MltA from Escherichia coli with its membrane anchor
      and signal sequence deleted has been purified to homogeneity by means of cation
      exchange chromatography. The enzyme was crystallized using the hanging-drop
      vapour-diffusion method. The crystals belong to space group P3(1)21 or P3(2)21,
      with unit-cell parameters a = b = 103.70, c = 109.84 A and one molecule per
      asymmetric unit. Crystals diffract to 2.2 A resolution on a synchrotron-radiation
      source.

PMID- 15039578
TI  - Crystallization and preliminary crystallographic analysis of 2-keto-3
      deoxygluconate kinase from Thermus thermophilus.
AB  - 2-Keto-3-deoxygluconate kinase (KDGK) catalyzes the phosphorylation of 2-keto-3
      deoxygluconate (KDG) to 2-keto-3-deoxy-6-phosphogluconate. Two crystal forms of
      KDGK from Thermus thermophilus were obtained by vapour-diffusion and microbatch
      methods. Crystals in the form of triangular plates (TtKDGK-1) were obtained that
      belong to space group P3, with unit-cell parameters a = b = 145.83, c = 74.63 A,
      and diffract to 3.2 A. These crystals exhibited nearly perfect hemihedral
      twinning. Assigning six subunits of TtKDGK to the asymmetric unit of the crystal
      corresponds to a 46.2% solvent content. A single plate-like crystal (TtKDGK-2)
      belonged to space group P6(3), with unit-cell parameters a = b = 84.83, c =
      168.49 A, and diffracts to 2.25 A. This crystal exhibits only partial hemihedral
      twinning, with a twin fraction of 24.4%. Diffraction-quality crystals of TtKDGK
      with bound ATP (TtKDGK-ATP), a = b = 84.72, c = 321.61 A and with bound KDG plus
      the ATP analogue AMP-PNP (TtKDGK-ATP-KDG), with unit-cell parameters a = b =
      84.32, c = 168.7 A, were also prepared and characterized.

PMID- 15039579
TI  - Crystallization and preliminary X-ray analysis of two inhibitor complexes of the
      catalytic domain of death-associated protein kinase.
AB  - The catalytic domain of death-associated protein kinase (DAPK) has been
      overexpressed, purified and crystallized using the sitting-drop vapour-diffusion
      method with PEG 8000 and magnesium acetate as precipitants. Complexes with the
      inhibitor staurosporine and its analogue BDB402 were also crystallized in the
      presence of PEG 400 and PEG 8000, respectively. Diffraction data were collected
      to 2.4 A for the native catalytic domain, to 2.9 A for the staurosporine complex
      and to 2.7 A for the BDB402 complex. All three crystals belong to space group
      P2(1)2(1)2(1), with unit-cell parameters a = 77.992, b = 109.909, c = 50.063 A
      for the catalytic domain, a = 78.911, b = 113.162, c = 50.658 A for the
      staurosporine complex and a = 77.337, b = 108.869, c = 50.186 A for the BDB402
      complex. In both complexes the inhibitor molecule was clearly assigned in the
      difference Fourier map calculated on the basis of the phases obtained from the
      structure of the catalytic domain.

PMID- 15039580
TI  - Crystallization and preliminary X-ray diffraction data of an archaeal asparagine
      synthetase related to asparaginyl-tRNA synthetase.
AB  - The archaebacterial-type asparagine synthetase A from Pyrococcus abyssi (AS-AR),
      which is related to asparaginyl-tRNA synthetase, was crystallized in two
      different conditions using the hanging-drop vapour-diffusion method. Crystals
      belonging to space group C2 with unit-cell parameters a = 103.6, b = 43.3, c =
      121.5 A, beta = 112.6 degrees and one dimer per asymmetric unit were obtained in
      the presence of 2-propanol and PEG 4000 at pH 5.6. Another crystal form was
      obtained in the presence of dioxan and belongs to the monoclinic space group
      P2(1), with unit-cell parameters a = 96.8, b = 103.9, c = 98.4 A, beta = 107.5
      degrees and two dimers per asymmetric unit. Two different native diffraction data
      sets were collected to 2.3 and 3.0 A resolution using synchrotron radiation and
      cryocooling for crystals belonging to space groups C2 and P2(1), respectively.

PMID- 15039581
TI  - Crystallization and X-ray analysis of the Y75N mutant of Mucor pusillus pepsin
      complexed with inhibitor.
AB  - Y75N mutant Mucor pusillus pepsin has been overexpressed in yeast, purified and
      cocrystallized with the iodine-containing human renin inhibitor CP-113972
      [(2R,3S]-isopropyl 3-[(L-prolyl-p-iodo-L-phenylalanyl-S-methyl-cysteinyl)amino-4]
      cyclohexyl-2-hydroxybutanoate] for X-ray crystallography. Tetragonal complex
      crystals with space group P4(3)2(1)2 were produced by the hanging-drop vapour
      diffusion method and diffracted to 3.0 A. The crystals exhibited unit-cell
      parameters a = b = 182.5, c = 99.1 A and contained four molecules in the
      asymmetric unit. A 96% complete data set was collected at 298 K using Cu Kalpha X
      rays from a rotating-anode generator. Solution of the crystal structure of Y75N
      mutant M. pusillus pepsin is under way by molecular replacement using the
      molecular coordinates of wild-type M. pusillus pepsin as a model.

PMID- 15039582
TI  - Crystallization and preliminary X-ray analysis of the acyl carrier protein
      synthase (AcpS) from Staphylococcus aureus.
AB  - Acyl carrier protein synthase (AcpS) catalyzes the transfer of 4'
      phophopantetheine from coenzyme A to the acyl carrier protein (ACP) to activate
      it for fatty-acid biosynthesis. Two crystal forms of Staphylococcus aureus AcpS
      have been generated at 277 K using either NaCl or PEG 6000 as a precipitant. The
      diffraction patterns of the crystals extend to 1.65 and 1.8 A, respectively. Full
      sets of X-ray diffraction data were collected from native crystals and the
      crystal structures were solved by molecular replacement.

PMID- 15039583
TI  - Expression, purification, crystallization and preliminary diffraction studies of
      the tRNA pseudouridine synthase TruD from Escherichia coli.
AB  - Pseudouridine, the 5-ribosyl isomer of uridine, is the most common modification
      of structural RNA. The recently identified pseudouridine synthase TruD belongs to
      a widespread class of pseudouridine synthases without significant sequence
      homology to previously known families. TruD from Escherichia coli was
      overexpressed, purified and crystallized. The crystals diffract to a minimum
      Bragg spacing of 2.4 A and belong to space group P2(1)2(1)2(1), with unit-cell
      parameters a = 63.4, b = 108.6, c = 111.7 A.

PMID- 15039584
TI  - Expression, purification, crystallization and preliminary X-ray crystallographic
      studies of Mycobacterium tuberculosis thioredoxin reductase.
AB  - Mycobacterium tuberculosis (H37Rv), the causative agent of the dreaded disease
      tuberculosis, contains three thioredoxins and a single thioredoxin reductase.
      Thioredoxin reductase is a member of the pyridine-nucleotide disulfide
      oxidoreductase family of flavoenzymes. The thioredoxin reductase gene with a His
      tag at the C-terminus was expressed in Escherichia coli and purified. The dimeric
      (70 kDa) protein was incubated with 10 mM DTT for 30 min and then crystallized
      using the hanging-drop vapour-diffusion method in the presence of 15% PEG 3350
      and phosphate-citrate buffer pH 5 at room temperature (298 K). A diffraction data
      set complete to 3 A resolution has been collected under cryoconditions and the
      space group was determined to be P4(1)2(1)2, with unit-cell parameters a = 107.4,
      c = 118.2 A. Matthews coefficient calculations revealed the presence of two
      monomers in the asymmetric unit.

PMID- 15039585
TI  - Characterization, crystallization and preliminary X-ray analysis of bifunctional
      dihydrofolate reductase-thymidylate synthase from Plasmodium falciparum.
AB  - The full-length pfdhfr-ts genes of the wild-type TM4/8.2 and the double mutant
      K1CB1 (C59R+S108N) from the genomic DNA of the corresponding Plasmodium
      falciparum parasite have been cloned into a modified pET(17b) plasmid and
      expressed in Escherichia coli BL21 (DE3) pLysS. Conditions for the expression and
      purification of the P. falciparum dihydrofolate reductase-thymidylate synthase
      (PfDHFR-TS) have been established that yield approximately 1 mg of the soluble
      active enzyme per litre of culture. The purified enzymes have been crystallized
      using a modified microbatch method with PEG 4000 as the primary precipitating
      agent. X-ray diffraction data were collected to 2.50 and 2.64 A resolution under
      cryogenic conditions from single crystals of the two PfDHFR-TS proteins in
      complex with NADPH, dUMP and either Pyr30 or Pyr39. Preliminary X-ray analysis
      indicated that the crystals belong to the orthorhombic space group P2(1)2(1)2(1),
      with two molecules per asymmetric unit and approximately 52% solvent content (VM
      approximately 2.6 A3 Da-1). The use of a particular type of baby oil in the
      microbatch setup appeared to be beneficial to PfDHFR-TS crystallization and a
      preliminary comparison with another commonly used oil is described.

PMID- 15039586
TI  - Crystallization, microPIXE and preliminary crystallographic analysis of the
      complex between the third KH domain of hnRNP K and single-stranded DNA.
AB  - hnRNP K is one of the major proteins found in hnRNP particles which are
      ribonucleoprotein complexes containing proteins and pre-mRNA. hnRNP K contains
      hnRNP K homology (KH) domains which bind both CT-rich single-stranded DNA (ssDNA)
      and CU-rich ssRNA. Co-crystallization of the third KH domain of human hnRNP K
      with a 15-mer ssDNA gave rod-shaped crystals belonging to the trigonal space
      group P3(1)21 (unit-cell parameters a = 54.0, c = 149.7 A) and diffracting to 2.4
      A resolution. MicroPIXE (proton-induced X-ray emission) experiments showed that
      the crystals contained the complex and that the phosphorus to sulfur atomic ratio
      was consistent with the asymmetric unit containing three KH3 domains per 15-mer
      ssDNA. This was confirmed by structure solution by molecular replacement.

PMID- 15039587
TI  - Purification, crystallization and X-ray diffraction analysis of a recombinant Fab
      that recognizes a human blood-group antigen.
AB  - The NNA7 Fab fragment recognizes the human glycopeptide N blood-group antigen and
      has a high affinity for N-type glycophorin A (GPA). To provide insight into how
      antibodies recognize glycopeptide antigens, soluble Fab fragments were expressed
      in Escherichia coli, purified and crystallized using the hanging-drop vapor
      diffusion method at 293 K. The best crystals were obtained from solutions of PEG
      monomethyl ether 5000 containing 4-8 mM yttrium chloride (YCl3). This rare-earth
      ion, which could be substituted with various lanthanides, changed the habit of
      crystals from multinucleated rods with a diffraction limit of 4.25 A resolution
      to a diamond-shaped morphology that grew as single crystals and diffracted X-rays
      to 1.75 A resolution. Data were collected that indicated that the crystals
      belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 57.9, b =
      77.1, c = 118.1 A and one Fab fragment per asymmetric unit. A molecular
      replacement solution has been obtained and 86% of the molecule was fitted by use
      of an automated refinement procedure (ARP).

PMID- 15039588
TI  - Structure of bovine carbonic anhydrase II at 1.95 A resolution.
AB  - Carbonic anhydrase (CA) is a zinc-containing enzyme that catalyzes the reversible
      hydration of CO2 to HCO3-. In eukaryotes, the enzyme plays a role in various
      physiological functions, including interconversion between CO2 and HCO3- in
      intermediary metabolism, facilitated diffusion of CO2, pH homeostasis and ion
      transport. The structure of bovine carbonic anhydrase II (BCA II) has been
      determined by molecular replacement and refined to 1.95 A resolution by simulated
      annealing and individual B-factor refinement. The final R factor for the BCA II
      structure was 19.4%. BCA II has a C-terminal knot structure similar to that
      observed in human CA II. It contains one zinc ion in the active site coordinated
      to three histidines and one putative water molecule in a tetrahedral geometry.
      The structure of BCA II reveals a probable alternative proton-wire pathway that
      differs from that of HCA II.

PMID- 15039589
TI  - On the potential of normal-mode analysis for solving difficult molecular
      replacement problems.
AB  - Molecular replacement (MR) is the method of choice for X-ray crystallographic
      data phasing when structural data of suitable homologues are available. However,
      MR may fail even in cases of high sequence homology when conformational changes
      arising for example from ligand binding or different crystallogenic conditions
      come into play. In this work, the potential of normal-mode analysis as an
      extension to MR to allow recovery from such drawbacks is demonstrated. Three
      examples are presented in which screening for MR solutions with templates
      perturbed in the direction of one or two normal modes allows a valid MR solution
      to be found where MR using the original template failed to yield a model that
      could ultimately be refined. It has been shown recently that half of the known
      protein movements can be modelled by displacing the studied structure using at
      most two low-frequency normal modes. This suggests that normal-mode analysis has
      the potential to break tough MR problems in up to 50% of cases. Moreover, even in
      cases where an MR solution is available, this method can be used to further
      improve the starting model prior to refinement, eventually reducing the time
      spent on manual model construction (in particular for low-resolution data sets).

PMID- 15039593
TI  - Synergistic anti-cancer effects of grape seed extract and conventional cytotoxic
      agent doxorubicin against human breast carcinoma cells.
AB  - With an approach to enhance the efficacy of chemotherapy agents against breast
      cancer treatment, here, we investigated the anti-cancer effects of grape seed
      extract (GSE) and doxorubicin (Dox), either alone or in combination, in estrogen
      receptor-positive MCF-7 and receptor-negative MDA-MB468 human breast carcinoma
      cells. GSE (25-200 micro g/ml) treatment of cells resulted in 16-72% growth
      inhibition and 9-33% cell death, in a dose- and a time-dependent manner. In other
      studies, Dox (10-100 nM) treatment showed 23-96% growth inhibition and 10-55%
      cell death. Based on these results, several combinations of GSE (25-100 micro
      g/ml) with Dox (10-75 nM) were next assessed for their synergistic, additive
      and/or antagonistic efficacy towards cell growth inhibition and death. In both
      MCF-7 and MDA-MB468 cells, a combination of 100 micro g/ml GSE with 25-75 nM Dox
      treatment for 48 h showed a strong synergistic effect [combination index (CI) <
      0.5] in cell growth inhibition, but mostly an additive effect (CI approximately
      1) in cell death. In cell-cycle progression studies, GSE plus Dox combination
      resulted in a moderate increase in G1 arrest in MCF-7 cells compared to each
      agent alone. GSE plus Dox combination showed a very strong and significant G1
      arrest in MDA-MB468 cells when compared with Dox alone, however, it was less than
      that observed with GSE alone. In quantitative apoptosis studies, GSE and Dox
      alone and in combination showed comparable apoptotic death of MCF-7 cells,
      however, a combination of the two was inhibitory to Dox induced apoptosis in MDA
      MB468 cells. This was further confirmed in another estrogen receptor-negative MDA
      MB231 cell line, in which GSE and Dox combination strongly inhibited cell growth
      but did not show any increase in apoptotic cell death caused by Dox. Together,
      these results suggest a strong possibility of synergistic efficacy of GSE and Dox
      combination for breast cancer treatment, independent of estrogen receptor status
      of the cancer cell.

PMID- 15039594
TI  - Validation of a tissue microarray to study differential protein expression in
      inflammatory and non-inflammatory breast cancer.
AB  - AIMS: Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer
      with poor prognosis. The mechanisms responsible for the aggressive clinical
      evolution are incompletely understood. We constructed a tissue microarray (TMA)
      and validated its use in translational IBC research. Differential expression of
      proteins that might play a role in causing the IBC phenotype was studied. METHODS
      AND RESULTS: A TMA containing 34 IBC and 41 non-stage matched non-IBC tumours was
      constructed. Five core biopsies were taken for each IBC and three cores for each
      non-IBC tumour. The TMA was validated using three approaches: (1) the excellent
      concordance between immunohistochemical results of the initial pathological
      examination and the results obtained with the TMA for ER, PR and HER2/neu (kappa
      > 0.74); (2) the known differential expression between IBC and non-IBC for four
      bio-markers in IBC (ER, PR, p53 and HER2/neu) was confirmed ( p < 0.01); (3) the
      HER2/neu status using three different antibodies (CB11, TAB250 and HercepTest)
      was highly concordant (kappa > 0.75). Furthermore, the overexpression of E
      Cadherin and RhoC GTPase in IBC ( p < 0.05) was confirmed. We did not find a
      differential expression pattern for carbonic anhydrase IX (CA IX) and EGFR.
      CONCLUSIONS: Using different approaches, we have validated the use of our TMA for
      studying differential protein expression in IBC and non-IBC. We confirm the
      overexpression of E-Cadherin and RhoC GTPase in IBC. The lack of differential
      expression for CA IX and EGFR might suggest the pathways are equally utilised in
      both types of breast cancer.

PMID- 15039595
TI  - A comparison of the biological and clinical features of invasive lobular and
      ductal carcinomas of the breast.
AB  - Altogether 295 consecutive pure lobular invasive breast cancers diagnosed between
      1990 and 1999 in the area of Tampere University Hospital were compared to 295
      ductal invasive breast cancers. Biological factors, DFS, OS, recurrence types,
      survival after recurrence and other primary cancers were analyzed. ILC tumors
      were more often hormone receptor-positive, slowly proliferative and Erbb-2
      negative. During the mean follow-up time of 5.1 years 76 recurrences in both
      groups were discovered. During the whole follow-up time there was more
      metastation to gynecological organs and GI tract in the ILC group. Bilateral
      breast cancers did not differ between the groups. DFS and OS were the same
      between the groups despite the fact that ILC patients received statistically
      significantly less adjuvant treatment. In conclusion, since ILC cancers are more
      often hormone receptor-positive, there is a good option to adjuvant endocrine
      therapy with present and future preparations, this possibly leading to
      improvement in OS.

PMID- 15039596
TI  - Cross-resistance studies of isogenic drug-resistant breast tumor cell lines
      support recent clinical evidence suggesting that sensitivity to paclitaxel may be
      strongly compromised by prior doxorubicin exposure.
AB  - Less than half of breast cancer patients respond to second-line chemotherapy with
      paclitaxel after failing treatment with anthracyclines such as doxorubicin. A
      recent clinical trial by Paridaens et al. [J. Clin. Oncol. 18 : 724-733, 2000]
      examined whether patients may derive a better clinical benefit if paclitaxel was
      administered before doxorubicin. While overall survival was similar regardless of
      the order of drug administration, a >4-fold reduction in the response rate to
      paclitaxel was observed after late crossover from doxorubicin, compared to the
      response rate to doxorubicin after late crossover from paclitaxel. This may be
      related to differences in the ability of the drugs to induce cross-resistance to
      each other. To test this hypothesis, we examined whether isogenic breast tumor
      cells selected for resistance to doxorubicin exhibit greater cross-resistance to
      paclitaxel and other drugs than identical cells selected for resistance to
      paclitaxel. We found that cells selected for resistance to paclitaxel showed
      strong resistance (>/=40-fold) to paclitaxel and docetaxel, with little cross
      resistance (4-fold) to doxorubicin. In contrast, cells selected for resistance to
      doxorubicin exhibited 50-fold resistance to doxorubicin and a dramatic 4700-fold
      and 14,600-fold cross-resistance to paclitaxel and docetaxel, respectively.
      Doxorubicin-resistant cells exhibited higher P-glycoprotein and breast cancer
      resistance protein (BCRP) levels than paclitaxel-resistant cells. In addition,
      procaspase-9 was strongly downregulated in doxorubicin-resistant cells but not in
      paclitaxel-resistant cells. These differences may account for the contrasting
      cross-resistance profiles observed for the two cell lines and may help to explain
      why treatment of breast cancer patients with paclitaxel appears to be compromized
      by prior doxorubicin exposure.

PMID- 15039597
TI  - Sequential versus combined treatment of human breast cancer cells with
      antiestrogens and the vitamin D analogue EB1089 and evaluation of predictive
      markers for vitamin D treatment.
AB  - Development of resistance to antihormonal therapy is a major problem in the
      treatment of breast cancer patients. Metastatic tumors, which progress after a
      period of response to treatment, often respond to second line endocrine
      treatment, but eventually develop estrogen independent growth. Vitamin D
      analogues are promising new drugs, using alternative mechanisms to inhibit growth
      of breast cancer cells. The sensitivity to antiestrogens and vitamin D analogues
      has been proposed to be inverse, indicating that the sensitivity to vitamin D
      analogues might increase after development of antiestrogen resistance and vice
      versa. In this study, the inverse sensitivity between antiestrogens and the
      vitamin D analogue EB1089 was examined in antiestrogen and vitamin D resistant
      breast cancer cell lines. The majority of the investigated antiestrogen resistant
      cell lines had increased sensitivity to treatment with the vitamin D analogue
      EB1089. In addition, growth of a vitamin D resistant cell line was more inhibited
      by the pure antiestrogen ICI 182,780 than the growth of the parental cells,
      indicating that the compounds may be used sequentially. An association between
      the expression level of the vitamin D receptor (VDR) and EB1089 sensitivity was
      observed, suggesting that VDR is a possible predictive marker for response to
      vitamin D treatment. Valuation of Bcl-2 gene expression may be useful in
      combination with VDR to predict the outcome of treatment with EB1089.
      Furthermore, we observed a synergistic growth inhibition and an abrogated
      development of resistance upon combined treatment with ICI 182,780 and EB1089.
      Therefore, antiestrogens and vitamin D analogues may also be used as combined
      treatment for breast cancer patients in the future.

PMID- 15039598
TI  - Selective cytotoxicity of a red grape wine flavonoid fraction against MCF-7
      cells.
AB  - Red wine is a rich source of polyphenolic components such as anthocyanins and
      flavonoids. The inhibitory effects of red wine polyphenolics on human breast
      cancer cells have been demonstrated earlier, but their effects on normal cells
      have not been fully established. Red wine (Merlot) was fractionated by
      hydrophobic interaction chromatography and different flavonoid fractions with
      increasing hydrophobicity were obtained. These fractions were tested for their
      inhibitory effect on human breast cancer cells (MCF-7), normal human mammary
      epithelial cells (HMEC), and a non-tumorigenic MCF-10A cell line. By contrast to
      the authentic flavonoids such as quercetin, naringenin and catechin which
      inhibited the growth of HMEC much more than that of MCF-7 cancer cells, a red
      wine fraction, that was comprised mainly of the flavonoid aglycones, showed
      maximal inhibition of the growth of breast cancer cells, with relatively low
      cytotoxicity towards HMEC and MCF-10A cells. In the presence of this flavonoid
      fraction, the normal cells grew normally, whereas the breast cancer cells
      underwent a change in morphology into spherical forms. Cytotoxicity analyses
      suggested that these cells had become apoptotic. The efficiency of inhibition of
      cell proliferation by various flavonoid fractions appeared to be related to their
      inhibition of calcium and calmodulin-promoted phosphodiesterase activity,
      suggesting that flavonoids may interfere with calcium second messenger function.
      The results suggest that certain grape wine ingredients have anticancer
      properties and these ingredients may be helpful for developing designer
      functional foods with cancer-preventive properties.

PMID- 15039599
TI  - Are medullary breast cancers an indication for BRCA1 mutation screening? A
      mutation analysis of 42 cases of medullary breast cancer.
AB  - Recommended guidelines have limited breast cancer gene ( BRCA1 ) mutation testing
      to individuals with a personal or family history of early onset breast and/or
      ovarian cancer, and those with multiple affected close relatives. Such large
      breast cancer families are rare in the general population, limiting the clinical
      application of the BRCA1 discovery. Previous reports have suggested an
      association between medullary breast cancer and BRCA1 mutation carriers. To test
      the feasibility of using these rare histological subtypes as an alternative to
      epidemiological factors, 42 cases of medullary cancer unselected for family
      history were screened for BRCA1 point mutations and large exon rearrangements.
      The large majority (83%) of these patients did not have significant family of
      breast or ovarian cancer. Two deleterious mutations resulting in a premature stop
      codon, and one exon 13 duplication were found. All mutations were detected in
      patients with typical medullary cancer, who had family history of multiple breast
      and ovarian cancers. Our findings suggest that medullary breast cancers are not
      an indication for BRCA1 mutation screening in the absence of significant family
      risk factors.

PMID- 15039600
TI  - Association of tamoxifen (TAM) and TAM metabolite concentrations with self
      reported side effects of TAM in women with breast cancer.
AB  - The positive effects of tamoxifen (TAM) on breast cancer recurrence and survival
      as well as on overall mortality have led to its use as the predominant adjuvant
      therapy among women with breast cancer. However, the association of TAM intake
      with undesirable side effects has been reported in numerous studies. This
      analysis was carried out to assess whether the concentrations of TAM or TAM
      metabolites, N -desmethyltamoxifen ( N -DMT) and 4-hydroxytamoxifen (4-OHT), were
      associated with self-reported side effects of TAM. Participants were 99 breast
      cancer patients who had been taking TAM for at least 30 days. Each participant
      completed a questionnaire that was used to ascertain whether she experienced
      certain specific symptoms while taking TAM. In addition, each woman provided a
      blood sample that was used to measure plasma concentrations of TAM, N -DMT, and 4
      OHT by high performance liquid chromatography. Results of the analysis showed
      that women who experienced at least one TAM-related side effect had significantly
      higher levels of TAM than women not experiencing any TAM-related side effects.
      Furthermore, women who reported experiencing visual problems had significantly
      higher levels of both TAM and N -DMT compared to those women who reported
      experiencing no visual problems. The levels of 4-OHT were negatively associated
      with the occurrence of vaginal discharge. The results of this study suggest that
      the self-reported occurrence of certain symptoms during TAM treatment is related
      to TAM metabolism. Future studies should assess subgroups of women with specific
      TAM and TAM metabolite profiles to determine whether alternate, equally effective
      therapies would decrease their risk of experiencing certain undesirable side
      effects.

PMID- 15039602
TI  - Psychological distress for African-American adolescent males: exposure to
      community violence and social support as factors.
AB  - This study examined exposure to community violence and depressive and post
      traumatic stress disorder (PTSD) symptoms within a non-random sample of low
      income, African-American male adolescents. The moderating effect of social
      support on these relationships was also examined. Seventy-seven African-American
      adolescent males were recruited from an inner-city, Midwestern high school and
      surveyed on exposure to violence, depression, post-traumatic stress, and social
      support. Regression analyses revealed that exposure to violence was significantly
      associated with both depressive and PTSD symptoms. However, social support was
      not found to moderate the relationship between exposure to community violence and
      psychological distress. Implications for intervention are discussed.

PMID- 15039601
TI  - The role of hemispheral asymmetry and regional activity of quantitative EEG in
      children with stuttering.
AB  - We investigated the role of delayed cerebral maturation, hemisphere asymmetry and
      regional differences in children with stuttering and healthy controls during
      resting state and hyperventilation, using conventional EEG techniques and
      quantitative EEG (QEEG) analysis. This cross-sectional case control study
      included 26 children with stuttering and age-sex matched 21 children with no
      history of stuttering. Visual EEG revealed significantly higher parieto-occipital
      slow waves and slower fronto-central asynchronic waves in the stutterers than in
      the controls. QEEG analysis showed significantly increased delta activity,
      especially in the right frontal and parietal regions and decreased alpha
      frequency in the bi-frontal regions of the stutterers, compared to the controls.
      Results are discussed interms of if the maturation hypothesis, especially
      nondominant frontal lobe (possibly supplementar motor area) and parietal lobe
      functioning.

PMID- 15039604
TI  - Strengths and difficulties as correlates of attachment style in institutionalized
      and non-institutionalized children with below-average intellectual abilities.
AB  - The current study examined attachment style, strengths, and difficulties in
      institutionalized and non-institutionalized children with below-average
      intellectual abilities. Parents/caregivers and teachers of the children completed
      a brief measure of attachment style and the Strengths and Difficulties
      Questionnaire, which assesses the most important domains of child psychopathology
      (i.e., emotional symptoms, conduct problems, hyperactivity-inattention, and peer
      problems) as well as personal strengths (i.e., prosocial behavior). Results
      indicated that institutionalized children were more frequently insecurely
      attached and generally displayed higher levels of difficulties and lower levels
      of strengths than non-institutionalized children. Furthermore, within both groups
      of children, insecure attachment status was linked to higher levels of
      difficulties but lower levels of strengths.

PMID- 15039603
TI  - A review of the validity of laboratory cognitive tasks used to assess symptoms of
      ADHD.
AB  - Reviewed the validity of frequently used laboratory assessment measures of ADHD
      symptoms using research published since 1991. Emphasized examining the validity
      of the tasks as they are commonly used by clinicians and researchers. Tasks
      evaluated included the Continuous Performance Test (CPT) and the Gordon
      Diagnostic System (GDS), the Children's Checking Task (CCT), Delay of
      Gratification Tasks, the Choice-Delay Task, (C-DT), and the Stop Signal Task
      (SST). Results showed that the CPT, C-DT, and the SST had the most support, yet
      further efforts to evaluate the validity of these measures are needed before they
      can be used for more than experimental purposes.

PMID- 15039605
TI  - Changes in outpatient psychiatric diagnosis in privately insured children and
      adolescents from 1995 to 2000.
AB  - This study examined changes in the diagnostic patterns among children and
      adolescents treated for mental health problems between the years 1995 and 2000.
      Using a large database (MarketScan) which compiles claims information from
      private health insurance plans nationwide, our sample consisted of 100,716
      children (under the age of 18) who submitted claims for outpatient mental health
      services, out of a total of 1,723,681 covered children. Over the five years
      period, there was a dramatic increase in the proportion of children diagnosed
      with both Autism and Bipolar disorders. An increase was also observed in Anxiety,
      ADHD and Depressive disorders. A decrease was observed in diagnostic prevalence
      of Oppositional, Adjustment and Substance Abuse disorders.

PMID- 15039609
TI  - Changing our view of the family.

PMID- 15039608
TI  - Positive aspects and challenges associated with caring for a dying relative at
      home.
AB  - Research has consistently shown that family caregivers have a variety of unmet
      needs, despite comprehensive professional support for caregivers being a central
      aim of palliative care. This sub-study of a larger randomized controlled trial
      sought feedback from 47 primary family caregivers of advanced cancer patients who
      had recently commenced home palliative care. During semi-structured interviews in
      their homes, family caregivers were asked to comment on the key challenges
      associated with their role and whether they could identify challenges. These were
      associated with their own ill health, family circumstances, insufficient skills
      to manage patient symptoms, limited time for themselves and inadequate support
      from health professionals. Despite these challenges, 60% of family caregivers
      were readily able to identify positive aspects of the role. Previous research has
      tended to focus on the negative impact of caregiving. The extent to which the
      positive aspects buffer the negative aspects of the role warrants further
      exploration, as does the long-term impact of the caregiver role on those who are
      unable to recognize positive elements.

PMID- 15039606
TI  - Aggressive behavior in the adolescent psychiatric patient: a clinical
      developmental perspective.
AB  - OBJECTIVE: This study examined the relationship between ego development and
      psychological defenses to aggressive behavior in a group of psychiatrically
      hospitalized adolescents. METHOD: Subjects were 245 adolescents ages 12-16, who
      were assessed for aggressive behaviors, assaultive incidents, ego development and
      defenses. RESULTS: Aggressive behavior was found to be negatively associated with
      ego development, regardless of age, gender or IQ. Defense styles which located
      the source of conflict outside of the self were associated with higher levels of
      self-reported aggressive behaviors. Hospital incidents of assault were associated
      with a lack of cognitively based defenses. CONCLUSION: Aggressive behavior is
      tied to the development of critical psychological processes which shape the
      adolescent's ability to understand themselves and their environment. The results
      are discussed in the context of a clinical-developmental approach to adolescent
      aggressive behavior.

PMID- 15039610
TI  - Forgotten voices: lessons from bereaved caregivers of persons with a brain
      tumour.
AB  - Although investigators have identified rewards and difficulties from assuming the
      role of caregiver for persons with cancer and persons with Alzheimer's disease,
      few studies have examined factors that lead to role strain for caregivers of
      persons with both oncological and neurological symptoms. In this study
      qualitative methods were used to analyse data from self-report questionnaires
      from 43 caregivers of adults with a primary malignant brain tumour (PMBT) in the
      USA. Six themes emerged from the analysis: the work of caring, informal support,
      formal support, information, dealing with symptoms, and end of life. The data
      suggest that health-care providers (HCPs) may decrease role strain by helping to
      identify competing demands, clarifying expectations of the role, providing
      information to caregivers on how to use formal and informal support systems to
      delegate care tasks, and by teaching caregivers how and when to ask for help.
      HCPs may also assist caregivers by providing information on managing cognitive
      and neuropsychiatric problems at home, what to expect at the end of life, and by
      following up to determine the caregiver's ability to integrate information into
      providing care.

PMID- 15039611
TI  - Family carers' experiences of out-of-hours community palliative care: a
      qualitative study.
AB  - Carers' feelings of uncertainty and anxiety can be particularly acute out-of
      hours, when they may not have access to familiar sources of professional help and
      advice. The present study used qualitative semi-structured interviews to explore
      carers' experiences of out-of-hours care and support services. Fifteen bereaved
      carers in the Calderdale and Kirklees area were interviewed, and the interview
      transcripts analysed thematically. In general, carers felt well supported out-of
      hours, especially by the nursing services. They appreciated opportunities to
      develop some degree of personal relationship with those they saw out-of-hours.
      However, in some cases problems were apparent. These were associated with poor
      provision of information, inadequate communication with carers, difficulties in
      accessing night-sitter services, or the inflexibility of services. The findings
      underline the importance of primary care practitioners taking an anticipatory
      approach to community palliative care.

PMID- 15039612
TI  - Evaluation of a night respite community palliative care service.
AB  - A three-phase project was undertaken to develop and evaluate a community night
      respite palliative care service for patients and family carers. An assessment
      tool to identify those most in need of night respite was developed and tested.
      The tool was reliable and feasible for use in practice. Care aides were trained
      to provide night respite. Fifty-three patients participated over 11 months.
      Findings revealed the types of patients and families most in need of night
      respite, the amount of respite needed, and location of death. There is evidence
      that patients who would have been transferred to an inpatient setting for end-of
      life care were able to die at home with the support of the night respite service.
      Families were extremely appreciative of the service and a limited cost comparison
      suggested costs were lower than if patients had been transferred to hospital
      and/or inpatient hospice care. Recommendations for practice are offered.

PMID- 15039613
TI  - Development of a pain management programme for family carers of advanced cancer
      patients.
AB  - This article reports the first phase of a three-phase study to develop and test a
      pain education programme for family carers of patients with advanced cancer. The
      purpose of this phase was to develop the pain education programme. Interviews
      were conducted with 19 family carers to elicit their perceptions about the
      components, content, amount and timing of an educational programme that might be
      useful in educating them about pain management. Interviews were taped,
      transcribed and content analysed. Family carers reported knowledge deficits
      regarding pain, medications, comfort therapies and general comfort measures.
      Strategies for learning were described. Findings from these interviews together
      with results published in the literature were structured into a formal pain
      management programme. This programme has been pilot tested and evaluated using a
      randomized clinical trial.

PMID- 15039614
TI  - Should nurses' internal shift rotation system be stopped?

PMID- 15039615
TI  - Improving medication safety is the duty of all nurses.

PMID- 15039616
TI  - Psychiatric nurse who formed a sexual relationship with patient.

PMID- 15039617
TI  - Sexuality and sexual health promotion for the older person.
AB  - Being a sexual being and having sexual feelings is a part of what it is to be a
      human being--there are no age limits to enjoying a healthy sex life and having
      the ability to love and be loved. There are many misconceptions surrounding
      sexuality and in general these misconceptions become even more problematic as the
      older person and sexuality are discussed. This article aims to consider
      misconceptions that nurses may have about sex and sexuality concerning older
      people. The nurse is ideally placed to encourage the older person to discuss
      sexual worries and can easily correct any misconceptions. However, in order to do
      this effectively, he/she needs to have a good knowledge base about the topic.
      Nurses need to demonstrate empathy and understanding if the patient is to
      disclose intimate feelings concerning his/her sexual health. Information is
      offered that may help nurses to ensure that a truly holistic approach to care is
      provided to older patients. Finally, recommendations are suggested in order to
      act in the patient's best interests.

PMID- 15039618
TI  - Management of a dehisced abdominal wound with VAC therapy.
AB  - The management of large cavity wounds has always posed particular challenges for
      nurses and clinicians. The National Institute for Clinical Excellence (NICE,
      2001) suggests that the number of difficult-to-heal surgical wounds may increase
      in the future and that increased knowledge and expertise should be available
      across primary and secondary care. Recent research into wound healing has tended
      to focus on the biology of wound healing and manipulation of the healing
      processes with new dressings technology and other clinical and cost-effective
      treatments. Vacuum-assisted closure (VAC) is an innovation that is being given
      increasing attention. In Northampton, one patient nursed in the community setting
      has recently benefited from the technology to accelerate healing of a deep
      abdominal cavity. This article considers the historical management of cavity
      wounds and presents a case study. The feelings of the patient and the experiences
      of the district nurses in overcoming management problems are discussed. The case
      has proved to be the catalyst for a collaborative initiative across primary and
      secondary care services to ensure that all patients requiring the treatment are
      able to receive it in the community setting as well as in the hospital, when they
      are ready for discharge. It is recognized in Northampton that there are several
      applications for VAC in wound management and that the treatment has many benefits
      for patients and for those managing finite NHS resources.

PMID- 15039621
TI  - Accountability and medicinal products 2: civil law.
AB  - Lyndsey Bohanna, 23 years, had mild depression and was prescribed Prozac by
      doctors to combat insomnia and fatigue. Two months later during a routine check
      up a junior doctor changed her prescription. He gave her an antidepressant,
      dothiepin, which is for severe depression and should not be used with Prozac. It
      is also an antidepressant with one of the highest chances of overdose. Nine days
      later she was found dead. An independent review found a host of errors during her
      treatment at the hospital. The junior doctor had not asked the consultant for
      advice and had not explained to the patient the risks associated with her new
      medication. He also failed to inform her GP of how many tablets should be given.
      What is the law?

PMID- 15039619
TI  - A study into nurses' awareness of the National Service Frameworks.
AB  - This study sought to demonstrate nurses' awareness of the National Service
      Frameworks (NSFs), which began in 1999, and are an important part of the
      Government's modernization strategy for the NHS. A questionnaire was sent, in
      2002, to a systematic random sample of 228 nurses. The results were analysed for
      descriptive and comparative statistics using the computer software Statistical
      Package for the Social Sciences (SPSS), and the nurses questioned showed a low to
      moderate level of awareness. A quarter of nurses had not heard of the NSFs before
      receiving the questionnaire, and of those who had, only half had tried to find
      out more information. Despite high readership of nursing journals and good
      internet use, nurses did not think it was their responsibility to use such
      sources to find out about the NSFs, considering rather that management should
      provide study days and workplace teaching. While this outlook may be at odds with
      the concepts of lifelong learning and professional responsibilities as outlined
      by the Nursing and Midwifery Council, it is suggested that formal mechanisms of
      dissemination of reforms need to be implemented if nurses are to participate
      fully in them.

PMID- 15039620
TI  - Evidence-based practice is a time of opportunity for nursing.
AB  - The debate regarding evidence-based practice (EBP) continues to rage within
      nursing. This article reviews the existing situation regarding policy and the
      ability of nurses to engage with EBP. Recommendations are made regarding moving
      the debate away from a focus on barriers to EBP towards seizing it as an
      opportunity. The article suggests that a fundamental change in attitude is
      required by nurses in order for the nursing profession to progress. There is a
      need to recognize that the nature of health services are changing and that nurses
      need to grasp the opportunities this makes available, but in order to do this
      nurses need support.

PMID- 15039622
TI  - Can the underlying principles of art be applied to nursing?
AB  - It is a common assumption that nursing is an art, yet the art of nursing is a
      term for which there is little definitional agreement and understanding. Problems
      surrounding the art of nursing are rooted in dilemmas connected to philosophical
      issues and ideas, as well as the strong value associated with science. The
      concept of art is embedded within many theories and distinctions, for which there
      is no consensus of opinion. This article reappraises the literature on the
      artfulness in nursing, and by examining aesthetic theories, offers a different
      perspective to that of considering the existence of an art of nursing as a
      foregone conclusion.

PMID- 15039623
TI  - The importance of the nurse-patient relationship.

PMID- 15039624
TI  - [Viral cause and management of necrotizing herpetic retinopathies].
AB  - PURPOSE: To study the viral cause and present the management of necrotizing
      herpetic retinopathies. METHODS: Charts of patients presenting with acute retinal
      necrosis (ARN) or progressive outer retinal necrosis (PORN) diagnosed between
      March 1997 and June 2001 were retrospectively reviewed. Intraocular specimens
      were obtained in 33 cases to determine the viral cause using polymerase chain
      reaction-based assays and/or detection of intraocular antibody production.
      RESULTS: The mean age was 43.4 Years. Herpesvirus genome was identified in 29
      patients (80.5%). In the ARN group (32 patients, 38 eyes), herpes simplex virus
      (HSV) DNA was found in 11 patients (34.4%), varicella-zoster virus (VZV) in nine
      patients (28.1%), and cytomegalovirus (CMV) in four patients (12.5%). One patient
      (3.1%) presented an Epstein-Barr virus (EBV) infection. ARN was bilateral at
      initial examination in six patients and secondary bilateralization was observed
      in four patients. In the PORN group (four patients, eight eyes), the retinitis
      was bilateral and VZV DNA was detected in all cases. Two patients were treated
      with intravenous acyclovir, six with foscarnet alone, ten with intravenous
      foscarnet + acyclovir, 18 with intravenous foscarnet and intravitreous
      ganciclovir injections. Complications of necrotizing herpetic retinitis were
      cataract (26%), optic nerve atrophy (23.9%), and retinal detachment (17.4%).
      Final visual acuity was less or equal to 20/200 in 47.8% of cases. CONCLUSIONS:
      It is important to determine the specific viral etiology since progression and
      prognosis may be different in herpetic necrotizing retinitis caused by HSV, VZV,
      or CMV. Visual prognosis is improved by intensive antiviral therapy, but remains
      poor if complications occur.

PMID- 15039625
TI  - [Biometric study of acute-angle-closure glaucoma using Orbscan and echography].
AB  - PURPOSE: To study acute-angle-closure glaucoma (AACG) biometry using Orbscan and
      echography. MATERIAL AND METHODS: We prospectively studied 200 normal eyes of 100
      patients (including eyes with ametropia), 50 eyes of 25 patients before
      peripherial YAG laser iridotomy, 25 phakic eyes of 25 patients with a history of
      acute-angle-closure glaucoma (AACG) in the fellow eye. Both plane and polynomial
      modes of reconstruction of the iridocorneal angle measurement were analyzed.
      Biometric measurements of the three groups were compared. Biometric measurements
      (i.e., iridocorneal angle, anterior chamber depth, axial length, and lens
      thickness) and subjective spherical equivalent were correlated with the
      etiological classification. RESULTS: Age, sex, iridocorneal angle, anterior
      chamber depth, lens thickness, axial length and subjective spherical equivalent
      were significantly different in the three groups (p<0.002). The polynomial
      iridocorneal angle measurement was 43.4 degrees in the normal group, 36.5 degrees
      in the iridotomy group, and 28.4 degrees in the AACG group (p<0.001).
      Iridocorneal angle measurement correlated with the other biometric measurements
      (rs>0.51; p<0.001) and with the etiological classification (rs< or =0.68;
      p<0.001). The anterior chamber depth measurement obtained by Orbscan or
      echography was the best parameter for predicting ACCG (rs=0.77; p<0.001).
      CONCLUSION: The anterior chamber depth and polynimial iridocorneal angle obtained
      using the Orbscan device appears to be useful in predicting acute-angle-closure
      glaucoma.

PMID- 15039626
TI  - [The distribution of cup disc ratios in a general population of Southern Togo
      aged 40 years and over].
AB  - PURPOSE: Clinical reports and epidemiological surveys have raised the key issues
      of both the burden of glaucoma blindness and the high prevalence of the disease
      among the populations of Togo. This population survey aimed to collect data on
      the distribution of cup disc ratios. PATIENTS AND METHODS: The study population
      of 685 persons was selected in a remote rural area. All participants aged over 40
      years were included. Eye assessment was conducted in the local health facilities
      using a visual acuity chart, an ophthalmoscope and light magnification for
      exploration of the anterior segment. RESULTS: The mean age of participants was
      49.70 years (range, 40-99 years); men accounted for 61.8% and women 38.2%. Mean
      cup disc ratios were not different in both eyes, with 0.38 in the right eye and
      0.37 in the left. Cup disc ratios over 0.5 represented 29.3% in the right eye and
      29.8% in the left one; a cut-off point over 0.7 gave an abnormal cup ratio
      prevalence of 9.2% in the right eye and 9.3% in the left eye. In 92% of cases,
      the appearance of the cupping was round, and was elliptic in 7.6% of patients. We
      found that 75% of discs had a central round cupping. The temporal location was
      noted in 22% of cases while nasal locations were recorded in 2.4%. CONCLUSION:
      This survey has noted the various patterns of cup discs, with the mean cup disc
      ratio similar to what is usually described in similar studies. Further population
      based surveys using the cut-off ratios found here are needed to determine the
      prevalence of glaucoma in this rural area.

PMID- 15039629
TI  - [Spontaneous orbital hematoma in an adult. A case report].
AB  - Spontaneous orbital hematoma is uncommon, especially in adults. It produces
      proptosis which progress rapidly and is often associated with ocular movement
      disturbance. The Authors report a case of spontaneous orbital hematoma in a 45
      year-old woman, who had had no previous disease and had experienced sudden onset
      diplopia associated with moderate proptosis and pain in her right orbit. The
      diagnosis of orbital hematoma was made by computed tomographic scan. Further
      investigations revealed arterial hypertension. After a needle aspiration of this
      hematoma, proptosis resolved, ocular movement began to improve as well as visual
      acuity. Orbital hematoma revealing arterial hypertension is exceptional. It could
      be associated with ocular and orbital complications that lead the patient to
      consult an ophthalmologist. The diagnosis is based essentially on radiology. The
      other causes of orbital process, inflammation, tumor or vascular malformation,
      should be considered in the differential diagnosis. Therapeutic management could
      require surgical evacuation when visual function is compromised (compressive
      optic neuropathy).

PMID- 15039628
TI  - [Penicillium chrysogenum endophthalmitis: a case report].
AB  - We report a case of Penicillium chrysogenum endophthalmitis after penetrating
      ocular trauma in a 9-year-old child, describing the initial management and the
      therapeutic adaptation after biopsy culture. After a review of endophthalmitis
      treatment, we discuss mycotic endophthalmitis treatment and recommend the use of
      intravitreal antibiotics. In this case, we used amphotericin B to treat the
      fungal disorder with success.

PMID- 15039627
TI  - [Retinopathy caused by interferon alpha associated with ribavirin therapy and the
      importance of the electro-oculogram: a case report].
AB  - AIM: Ophthalmological complications with interferon alpha (INF-alpha) have been
      described since 1992: toxic retinopathy with cotton-wool spots, retinal
      hemorrhages, visual evoked potential (VEP) modifications and visual field
      abnormalities. MATERIAL AND METHOD: In 2002, a 44-year-old woman was referred
      complaining of visual problems. In 1986, she had been diagnosed with chronic
      hepatitis C and underwent INF-alpha therapy for 6 months with no ophthalmological
      symptoms. In 2001, she began a second course of INF-alpha therapy along with
      ribavirin. After 5 months, in February 2002, she developed hypothyroidism induced
      by INF, received levothyroxine and her treatment for the hepatitis C was stopped.
      One month later, in March, she complained of visual difficulties in dim light.
      Clinical ophthalmological examination and Goldmann visual field testing,
      electroretinogram (ERG) and visual evoked potentials (VEP) were normal but the
      electro-oculogram (EOG) showed that the light-peak-to-dark-trough ratios were
      very low: 148% in the right eye, 156% in the left eye. The fluorescein
      angiography was normal. The patient was followed up 4 months later, in June 2002
      (after 5 months without INF-alpha therapy), showing a slight improvement of the
      EOG and no visual symptoms. Two other follow-up examinations were done in
      September 2002 and January 2003: the slight improvement persisted but the EOGs
      remain below the normal range values. DISCUSSION AND CONCLUSION: A review of the
      literature brought out that an EOG is not usually done in the monitoring of
      patients taking INF-alpha, but we decided to do this examination because of her
      symptoms, the first case to our knowledge in a patient taking INF-alpha. This
      case report underlines the necessity of an EOG on patients with INF-alpha
      therapy. Until now, the pathogenesis of this retinal toxicity has been poorly
      understood. These results show that the retinal pigmented epithelium is probably
      implicated at an early stage in this retinal toxicity.

PMID- 15039630
TI  - [Post operative Enterococcus faecalis endophthalmitis: three case report].
AB  - We report three cases of endophthalmitis following cataract extraction.
      Enterococcus faecalis was the causative organism in all of them. Initial visual
      acuity was only light perception in all cases, final visual acuity was negative
      light perception in two cases, and light perception in one case. After initial
      improvement, inflammation was exacerbated in one patient and evisceration
      realized. The capsular bag was examined using scanning electron microscopy and it
      was shown that enterococci were adherent to the capsular bag, four months after
      the onset of the infection. Enterococcus faecalis can be the causative agent both
      of an acute and a chronic form of post operative endophthalmitis. Experimental
      studies on rabbit eyes could explain the poor prognosis of these endophtalmitis
      and focused on bacterial toxins. The contamination appears to be post operative,
      because Enterococcus faecalis is not a commensal agent of the conjunctiva. So we
      have to inform our patients about some hygienic habits, to prevent from this
      devastating complication of cataract surgery.

PMID- 15039631
TI  - [Pseudokeratoconus and ocular rosacea].
AB  - Photokeratoscopy analysis of the anterior curve of the cornea can detect
      keratoconus, particularly in the early stages of the disease. Nevertheless, all
      irregular astigmatisms are not related to keratoconus. We report here several
      cases of patients presenting high asymmetric astigmatism with features of
      keratoconus, although the clinical examination suggests corneal disease related
      to rosacea.

PMID- 15039632
TI  - [Cat-scratch disease neuroretinitis].
AB  - We report a case of cat-scratch disease neuroretinitis for which systemic and
      ocular investigations proved the responsibility of Bartonella henselae. An 11
      year-old boy was referred to the hospital in November 2002 for severe visual loss
      in the left eye over the preceding 2 weeks. At the same time, he also developed a
      flu-like illness. The best corrected acuity in the left eye was counting fingers
      at 30 cm. Posterior segment examination on the left eye showed an optic disk
      edema with papillary and peripapillary hemorrhages and serous retinal detachment,
      mild vitreous inflammation, and two little perivascular white spots. The medical
      history was unremarkable except for a cat scratch on his left forearm 2 months
      before. Four weeks of antibiotic therapy including oral rifampin and doxycycline
      was used. Bartonella henselae immunoglobulin M were first detected with
      Bartonella henselae immunoglobulin G testing negative at this time. A 3-week
      serum showed immunoglobulin M seroreversion, while Bartonella henselae
      immunoglobulin G appeared. Other causes of optic disk edema with macular star
      were excluded by biological data. Bartonella antibodies to both Bartonella
      henselae and Bartonella clarridgeiae were detected in the cat. Ophthalmic follow
      up showed progressive resorption of the neuroretinitis and the visual acuity
      increased to 5/10. The significance of this case report lies in the reminder that
      this pathology can be the cause of neuroretinitis; the prognosis can be improved
      by earlier treatment.

PMID- 15039633
TI  - [Photodynamic therapy follow-up: when to retreat, when to observe, or when to
      propose an alternative treatment?].
AB  - Clinical and angiographic progression after photodynamic therapy (PDT) is usually
      slow, sometimes fluctuating and therefore difficult to evaluate. After several
      sessions of PDT, angiographic follow-up remains the basis for therapeutic
      management involving either a new PDT session or an alternative treatment. It
      remains difficult, however, to evaluate the activity and progression potential of
      the remaining neovessels. Imaging (angiography, optical coherence tomography) and
      functional data both contribute to the therapeutic decision. Certain patients
      require several sessions for a progressive reduction of the exudation. For
      others, the persistence of metamorphopsias and accentuation of the scotoma
      despite the treatment may entail alternative treatment. Thus, a perifoveal
      photocoagulation can be proposed to limit the extension of the scotoma if after a
      reasonable number of sessions, central visual acuity is not recovered; direct
      photocoagulation of a persistent active neovascular contingent, distant from the
      fixation zone (foveal or exenterated) can be proposed if it remains on the border
      of a stabilized lesion; the treatment of a feeder vessel can be proposed if it
      becomes visible and is associated with active neovessels with a persistent
      central serous detachment of the neuroretina. Lastly, performance status and
      patient wishes are important elements in the overall therapeutic project,
      especially if the eye involved is the second eye, in view of quickly initiating
      low-vision rehabilitation.

PMID- 15039634
TI  - [CHARGE syndrome].

PMID- 15039635
TI  - [Molluscum contagiosum of the eyelid].
AB  - A 6-year-old girl had a single molluscum contagiosum of the lower eyelid.
      Clinically, the tumor had grown slowly since it had been discovered 8 months
      before the child was seen at our consultation. It appeared as a nodular lesion on
      the middle part of the eyelid. Its surface was irregular and its color was the
      same as the epidermis. It was surgically excised, using the shaving biopsy
      technique. Its histopathological study showed a papillomatous lesion with the
      typical features of a molluscum contagiosum. The patient was lost to follow-up
      soon after the surgery.

PMID- 15039636
TI  - [Surgical treatment of congenital eyelid malpositions in children].
AB  - Congenital eyelid malpositions can be isolated or associated with other
      structures such as the eyeball, ocular muscles, and lacrimal pathways. It is
      important to separate eyelid malpositions, which are topographical disorders,
      from eyelid malformations, which are constitutional morphological disorders. Only
      eyelid malpositions will be described in this paper, with a distinction made
      between static and dynamic disorders. Static disorders include epiblepharon,
      congenital ectropion and entropion, epicanthus, telecanthus, and centurion
      syndrome. Dynamic disorders group ptosis and congenital eyelid retractions.
      Epiblepharon is characterized by the absence of adhesion between the lower eyelid
      retractors and the orbicularis-skin layer, which allows the anterior lamella to
      roll over. Congenital entropion and ectropion are very rare. They most often
      require surgical treatment. Epicanthus involves a semi-lunar fold of skin
      extending from the upper eyelid across the medial canthal area to the margin of
      the lower eyelid. Four types (supra-ciliaris, palpebralis, tarsalis and inversus)
      of epicanthus are described. Treatment requires surgery. Telecanthus is defined
      as an increased distance between canthi. Primary telecanthus results from
      attenuation of the medial canthal tendons and is usually associated with other
      soft tIssue abnormalities such as epicanthus or blepharophimosis, or is seen
      after trauma. Secondary telecanthus is caused by underlying bony malpositions
      with an abnormal separation between the orbits because of an increased thickness
      of the interorbital bones such as that seen in hypertelorism or in other complex
      craniofacial syndromes. Euryblepharon is distinguished by an enlargement of the
      horizontal palpebral fissure associated with enlarged eyelids. The etiology is
      unknown and patients may benefit from surgery. Congenital ptosis is characterized
      by a deficiency of the levator muscle. They are most often unilateral and
      isolated. When associated with other abnormalities such as squint, synkinesis,
      blepharophimosis, or craniofacial syndromes, surgical treatment may require
      several-stage procedures. On the other hand, isolated congenital ptosis is
      usually treated in childhood (3-6 years) in a single stage. Congenital eyelid
      retractions may affect either the lower or the upper eyelid. They make up a rare
      condition and most cases are associated with craniofacial syndromes such as
      Crouzon or Apert syndromes. Upper eyelid retractions may spontaneously improve in
      some cases, but lower eyelid retractions do not. Treatment requires surgery,
      depending on the corneal consequences.

PMID- 15039637
TI  - Proinflammatory cytokines increase iron uptake into human monocytes and synovial
      fibroblasts from patients with rheumatoid arthritis.
AB  - BACKGROUND: It has been hypothesized that iron is stored in the synovium of
      patients with rheumatoid arthritis which perpetuates inflamation by aiding the
      production of oxygen free radicals. Proinflammatory cytokines are produced by
      macrophages and lymphocytes present within synovium and by mononuclear cells of
      in synovial fluid from patients with rheumatoid arthritis. There are two known
      systems for iron uptake. The first involves binding of iron to transferrin and
      uptake via transferrin receptors. The second involves uptake by low molecular
      weight organic anions such as ascorbate and citrate (non-transferrin bound
      uptake). MATERIALS/METHODS: Proinflammatory cytokines (IL-1, IL-6, TNFalpha and
      interferon gamma) were added to fibroblasts isolated from patients with
      rheumatoid arthritis and human monocytes in culture and their effect on 59Fe
      transferrin and citrate uptake was determined. RESULTS: Proinflammatory cytokines
      increase transferrin and non-transferrin bound iron uptake into human monocytes
      and increase transferrin-bound iron uptake by synovial fibroblasts, but have no
      effect on non-transferrin bound uptake into fibroblasts. CONCLUSIONS:
      Proinflammatory cytokines produced in human rheumatoid arthritis synovium and
      synovial fluid may contribute to the accumulation of iron that occurs in
      rheumatoid arthritis synovium which may lead to damage to synovial fibroblasts,
      macrophages and lymphocytes.

PMID- 15039638
TI  - Yogurt feeding inhibits promotion and progression of experimental colorectal
      cancer.
AB  - BACKGROUND: In BALB/c mice, a yogurt diet given before and after the carcinogen
      1, 2 dymethylhydrazine (DMH) inhibited colon cancer. This paper studied at which
      stage of tumor development (initiation, promotion or progression) yogurt exerts
      its antitumor activity. MATERIAL/METHODS: Six experimental groups were used: 1)
      non-treatment control; 2) DMH control; 3) yogurt-DMH-yogurt: yogurt administered
      before and after DMH. 4) yogurt-DMH: yogurt given only 10 days before DMH; 5) DMH
      yogurt: yogurt given cyclically after DMH; and 6) yogurt control. The groups DMH
      yogurt and yogurt-DMH were compared histologically and TNFalpha, INFgamma, IL-10
      and IL-4 cytokines, CD4+/CD25+ T cells, and apoptotic cells were determined in
      large intestine biopsies. TNFalpha and INFgamma were also determined in cells
      isolated from large intestine nodules and from Peyer's patches. RESULTS: The DMH
      yogurt group did not develop tumor. The yogurt-DMH group showed only tumor delay;
      TNFalpha, INFgamma and IL-10 increasing in this group in all the periods assayed.
      These results agree with those already reported for DMH control and yogurt-DMH
      yogurt. There was no correlation between the high levels of IL-10 and CD4+/CD25+
      T regulatory population. IL-4 and apoptotic cells increased in the yogurt-DMH
      group only in the first months. In the DMH-yogurt group, cellular apoptosis
      increased during the whole treatment. Yogurt feeding induced TNFalpha and
      INFgamma increases in cells isolated from large intestine nodules. These
      cytokines also increased in cells from Peyer's patches of the yogurt control
      group. CONCLUSIONS: These results show that yogurt inhibited tumor progression
      and promotion by modulating the immune response and stimulating cellular
      apoptosis.

PMID- 15039639
TI  - Synergistic efficacy of magnesium sulfate and FK506 on cerebral ischemia-induced
      infarct volume in gerbil.
AB  - BACKGROUND: In this study, we administered intraperitoneal magnesium sulfate (90
      mg/kg), either alone or in combination with FK506 (0.5 mg/kg) in order to
      investigate the neuroprotective synergetic effects of both, 30 min before
      permanent occlusion of the middle cerebral artery (MCA) in gerbil.
      MATERIAL/METHODS: Postmortem infarct volume was determined by quantitative image
      analysis of triphenyltetrazolium-stained brain sections, collected at 1 h, 3 h
      and 24 h after initiation of cerebral ischemia, to measure consistent infarct
      volumes of the post -ischemic gerbil brain. Twenty-four male gerbils were
      intraperitoneally injected with MgSO4 (n=7), FK506 (n=8), or MgSO4 +FK506 (n=9),
      30 min before permanent MCA occlusion. The brains of the treated groups were
      stained at 24 h after initiation of cerebral ischemia. RESULTS: Significant and
      consistent infarct volumes (78.3 +/- 3.6 mm3) were observed in the 24 H control
      group. The infarct volume in the MgSO4 + FK506 group was significantly reduced at
      each slice, compared to the untreated 24 H control group (P<0.05). Magnesium
      sulfate reduced total infarct volume by 25.4% (P<0.05), FK506 by 41% (P<0.05),
      and MgSO4 +FK506 by 50.5% (P<0.05). Also, the infarct volume (38.7 +/- 5.2 mm3)
      in the MgSO4 + FK506 group was the smallest in all the treated groups, near the
      volumes seen in the untreated 3H group. CONCLUSIONS: Acute administration of a
      combination of MgSO4 and FK506 has a synergetic efficacy against brain damage by
      permanent focal cerebral ischemia.

PMID- 15039640
TI  - Bradykinin-induced alterations of insulin-receptor interaction in rat adipose
      tissue under normo- and hypothermic conditions.
AB  - BACKGROUND: In this study we compared the effect of bradykinin (BK) on insulin
      receptor interaction in rat adipose plasma membranes under normothermic and
      hypothermic conditions. MATERIAL/METHODS: Plasma membranes were prepared and
      purified according to Havrankova and binding assay was performed using (125I) -
      insulin. The kinetic parameters of the hormone-receptor interaction were analyzed
      according to Scatchard using the LIGAND - Pc v.3.1 computer program.
      Additionally, we determined blood glucose and insulin concentrations. The results
      were interpreted statistically according to one-way analysis of variance (ANOVA).
      RESULTS: Statistically significant changes mainly involved the low-affinity
      receptor class. In normothermic rats, BK provoked a decrease in insulin-receptor
      affinity (expressed as a drop in the association constant Ka2 by 64% and
      enhancement in the dissociation constant Kd2 by 215%), which was compensated by a
      188% increase in the number of insulin receptors. Therefore, association constant
      times binding capacity remained unchanged. Administration of BK resulted in a
      decrease in serum glucose concentration by about 50%, while the insulin level did
      not change. Hypothermia lowered insulin concentration by 68% and elevated both
      the value of the association constant times binding capacity by 166% and the
      insulin-receptor affinity (Kd2 decreased by 71% and Ka2 increased markedly by
      about 771%). Administration of BK to hypothermic rats elevated blood insulinl
      level by180% and diminished (by about 64%) the value of association constant
      times binding capacity. CONCLUSIONS: The results indicate that bradykinin plays a
      significant role in carbohydrate metabolism and may influence insulin-receptor
      interaction under both normothermic and hypothermic conditions.

PMID- 15039641
TI  - Histopathological and immunohistochemical analysis of lymphoid follicles in
      labial salivary glands in primary and secondary Sjogren's syndrome.
AB  - BACKGROUND: Ectopic lymphoid follicles are considered morphological indices of
      local chronic antigen stimulation. The objective of this study was to present a
      detailed histopathological and immunohistochemical analysis of ectopic lymphoid
      follicles in salivary glands in Sjogren's syndrome (SS), compared to lymphoid
      follicles in lymph nodes. MATERIAL/METHODS: Samples of labial salivary glands
      from 37 patients with primary and 57 with secondary SS were examined by
      histopathology and immunohistochemical methods with monoclonal antibodies (DAKO)
      to identify follicular dendritic cells, T and B lymphocytes, immunoglobulins and
      class II MHC HIA DPQR. Lymph nodes from 2 patients with primary SS were also
      examined for the same markers. RESULTS: Focal inflammatory infiltrations in
      labial salivary glands in 64.9% of primary and 23.1-49.6% secondary SS were found
      to morphologically mimic lymphoid follicles in various stages of development.
      Secondary ectopic lymphoid follicles resemble the histological structure and
      immunohistochemistry of germinal centers in lymphoid follicles in reactive lymph
      nodes due to the large number of centrally located B cells (CD20+), reticular
      pattern of dendritic cells (CD21+) and T helper/inducer cells (CD4+). The centers
      of secondary ectopic lymphoid follicles contain deposits of IgG and IgM.
      CONCLUSIONS: Ectopic lymphoid follicles quite often present in labial salivary
      gland in SS show structural and immunohistochemical features typical for lymphoid
      tissue. These ectopic follicles are the place of immune complex trapping, antigen
      presentation on dendritic cells and initiation of autoimmunologic response. This
      finding seems be very important for better understanding of the pathogenesis and
      diagnosis of SS as an autoimmunlogical disorder.

PMID- 15039642
TI  - Prevalence of Helicobacter pylori in patients with portal hypertensive
      gastropathy--a study from south India.
AB  - BACKGROUND: This study was done to ascertain the prevalence of Helicobacter
      pylori in patients with PHG and determine whether it contributed to the severity
      of the disease. MATERIAL/METHODS: A total of thirty-seven consecutive patients
      who presented with portal hypertensive gastropathy were included in the study. H.
      pylori status was determined by urease test and histology. The presence of at
      least one positive test was considered as a positive H. pylori state. Correlation
      analyses of H. pylori status with age, gender, alcohol consumption, and the site
      and severity of lesion were done. RESULTS: Sixteen of the 37 patients were
      positive for H. pylori. A linear trend with age was seen in H. pylori - infected
      patients. H. pylori positivity was higher in the second and third decades of
      life, although this did not reach statistical significance. The linear trend with
      age was similar to that of the control group. There was no association between H.
      pylori status and alcohol intake or the site of lesion. Twenty-sevenlpatients had
      endoscopic evidence of mill PHG, 9 had moderate and 1 severe. The H. pylori
      status was 52%, 22%, and 0% in patients with mild, moderate, and severe
      gastropathy, respectively, indicating an inverse relatioinship of severity of PHG
      with H. pylori colonization. CONCLUSIONS: Portal hypertensive gastropathy does
      not provide a favorable environment for the colonization of H. pylori. The
      decline in H. pylori positivity with the severity of PHG suggests that this
      bacterium is unlikely to contribute in the pathogenesis of congestive gastropathy
      and that hence there might be no need for its routine eradication in patients
      with PHG.

PMID- 15039644
TI  - Subtelomeric rearrangements: results from FISH studies in 84 families with
      idiopathic mental retardation.
AB  - BACKGROUND: The etiology of mental retardation (MR) is unexplained in at least
      50% of cases. Recently it was shown that subtle telomeric rearrangements may be a
      common cause of idiopathic mental retardation (IMR). MATERIAL/METHODS: We studied
      84 families with IMR and unspecific clinical features suggesting chromosomal
      aberration, including 59 patients with moderate to severe MR and 24 with mild MR.
      One healthy father of three deceased, severely MR children was also included.
      Fluorescence in situ hybridization (FISH) using 41 subtelomeric probes (the
      Chromoprobe Multiprobe--T System) was performed in all patients. RESULTS: Ten
      (11.9%) subtle chromosome rearrangements were identified. Nine (10.7%) were
      subtelomeric abnormalities. Seven were familial, with six of paternal origin. All
      but one were products of parental balanced reciprocal translocation or inversion.
      Retrospective G-banding analysis showed that six of the nine rearrangements could
      be seen or suspected at the 450-550 band levels. Subtelomeric abnormalities were
      recognized in six patients with severe/moderate (including the father of children
      with severe MR) and in three with mild MR. CONCLUSIONS: Our results confirm
      previous findings on the importance of subtelomeric rearrangements in the
      etiology of MR. They also show the diagnostic utility of subtelomeric FISH in
      detecting subtle telomeric rearrangements in IMR cases. The high proportion of
      familial rearrangements emphasizes their importance for genetic counseling. FISH
      screening was more reliable and efficient in identifying subtle telomeric
      abnormalities than G-banding analysis. However, as many of the subtelomeric
      abnormalities could be detected in retrospect even at the 550 band level, high
      resolution G-banding analysis should always precede subtelomere assay. This is
      important for a better estimation of the real frequency of cryptic subtelomeric
      abnormalities.

PMID- 15039645
TI  - Cardiorespiratory parameters during conventional or gasless gynecological
      laparoscopy under general or regional anesthesia.
AB  - BACKGROUND: Conventional laparoscopy is aided by CO2 insufflation, which may
      impair the cardiorespiratory system and have life-threatening implications. This
      procedure is conducted under general anesthesia (GA). Gasless laparoscopy
      supposedly eliminates most of those disadvantages, but is technically more
      difficult to perform. In the present study, we compared cardiorespiratory
      parameters of conventional abdominal laparoscopy under GA to gasless laparoscopy
      under general or epidural anesthesia. MATERIAL/METHODS: This is a prospective
      study. Twenty four healthy female patients undergoing gynecological laparoscopies
      lasting <90 min were randomly assigned to one of three groups: group 1,
      conventional laparoscopy under GA; group 2, gasless laparoscopy under GA; and
      group 3, gasless laparoscopy under epidural anesthesia. Cardiorespiratory
      parameters and length of operative, postanesthesia care unit (PACU), and
      hospitalization periods as well as analgesic requirements in the PACU and
      complications in the operative and postoperative periods were recorded. RESULTS:
      No significant differences were detected between groups throughout the operative
      and postoperative periods, except for a rise in CO2 in group 1 and a lower
      analgesic requirement in the PACU in group 3. CONCLUSIONS: General and regional
      anesthesia may be employed in gasless laparoscopy for gynecological surgery.

PMID- 15039646
TI  - Interleukin 4 plasma levels in psoriasis vulgaris patients.
AB  - BACKGROUND: Psoriasis is regarded as a Th1-cell type disease. Interleukin-4, a
      Th2 type cytokine, is diminished in psoriatic skin. It has been postulated that
      switching the cytokine profile from Th1 to Th2 may be of great help in the
      treatment of psoriasis. Some recent reports demonstrate a favorable role of IL-4
      in the treatment of psoriasis. Therefore we decided to evaluate how IL-4 plasma
      levels fluctuate in the case of favorable treatment outcome observed in patients
      with clinically active and stable disease. MATERIAL/METHODS: 17 patients with
      active psoriasis vulgaris, 17 with stable disease, and 22 age- and sex-matched
      healthy controls were included in the study. IL- 4 plasma levels were evaluated
      by the ELISA method twice--before treatment implementation and 4 weeks
      thereafter. RESULTS: We observed statistically significant higher IL-4 plasma
      levels in the active psoriasis group both before treatment implementation (1st
      examination) and after 4 weeks of treatment (2nd examination) compared with both
      the control group (p<0.001) and the stable psoriasis group (1st examination:
      p<0.001, 2nd examination: p<0.01). There was no statistically significant
      difference in IL-4 plasma levels between the stable psoriasis and control groups
      in both examinations (p>0.05). CONCLUSIONS: Our data seem to support the
      hypothesis of the existence of immunologically distinct psoriasis subtypes.

PMID- 15039643
TI  - Perioperative determinants of mortality and morbidity in distal arch and proximal
      descending aortic aneurysm surgery.
AB  - BACKGROUND: The purpose of this article is to describe our experience on distal
      arch and proximal descending aortic aneurysm repair, and to evaluate
      retrospectively the determinants of mortality and morbidity. MATERIAL/METHODS:
      Between 1994 and 2002, 30 patients (mean age 53.4 years) underwent repair of
      distal arch or proximal descending aortic aneurysm approached through left
      thoracotomy with deep hypothermic circulatory arrest. Femoro-femoral bypass was
      used in all patients except for four, in whom the left subclavian artery was
      cannulated. Retrograde cerebral perfusion was performed in 16 patients. The mean
      circulatory arrest time was 30.7 min. RESULTS: Overall hospital mortality was
      13.3%. Excessive blood (p=0.008) and plasma (p=0.009) transfusions, and coronary
      artery disease (p=0.012) were correlated with mortality. The overall rate of
      postoperative complications was 30%. Renal failure and respiratory failure were
      the most frequent complications (16.7%), while the rates of stroke and transient
      neurological dysfunction were 6.7% and 3.3%, respectively. Age >70 years, bypass
      time >140 min, distal ischemia time >55 min, and excessive blood or plasma
      transfusions were determinants of postoperative complications. CONCLUSIONS: Deep
      hypothermic circulatory arrest with left thoracotomy is a valid procedure with
      acceptable mortality rates in the management of aneurysms of distal arch and
      proximal descending aorta. Prolonged bypass and distal ischemia times and
      excessive blood transfusions are associated with increased postoperative
      morbidity.

PMID- 15039647
TI  - Severe preeclampsia and eclampsia in Kerman, Iran: complications and outcomes.
AB  - BACKGROUND: Our objective was to assess the frequency, epidemiological factors,
      complications, and outcome of severe preeclampsia and eclampsia and compare them
      according to severity of the condition in Kerman, southeastern Iran.
      MATERIAL/METHODS: A prospective study was performed on 200 consecutive cases of
      severe preeclampsia and eclampsia referred to the Kerman University Maternity
      Center from June 2001 to December 2002. Demographic data and complications were
      described and severe preeclampsia and eclampsia compared using t-student's and
      chi2 tests. RESULTS: Severe preeclampsia occurred in 3% and eclampsia in 0.6% of
      deliveries during the period of study. The majority of patients were young and
      primigravida, especially in the eclampsia group. 72.7% of eclamptic patients
      suffered their first convulsion at home and not in the presence of medical help.
      HELLP syndrome, disseminated intravascular coagulation, acute renal failure,
      neurological complications, and acute respiratory distress syndrome were the main
      maternal complications, all occurring more frequently in eclamptic patients. The
      frequency of pulmonary edema, placental abruption, postpartum hemorrhage, and
      aspiration pneumonia was not significantly different between the two groups. More
      than half of patients underwent cesarean delivery. Early neonatal mortality rate
      was 13% in the entire cohort. All six maternal deaths during the period of the
      study occurred in eclamptic cases (mortality rate 18%), four relating to patients
      who had not received prenatal care. CONCLUSIONS: Severe preeclampsia carries a
      high risk of maternal and neonatal morbidities and mortality in Kerman. This risk
      increases in the presence of eclampsia, particularly in neglected cases who have
      not sought prenatal care.

PMID- 15039648
TI  - Role of light emitted by incandescent or fluorescent lamps in the development of
      myopia and astigmatism.
AB  - BACKGROUND: The purpose of our study was to determine if the development of
      refractive errors night be associated with exposure to light emitted by
      incandescent or fluorescent lamps. MATERIAL/METHODS: 3377 students from
      elementary schools, junior high schools and high schools were examined, aged 6-19
      years. Visual acuity was measured, and retinoscopy was performed after
      cycloplegia. The parents of all students examined completed a questionnaire
      concerning the child's exposure to light emitted by incandescent or fluorescent
      lamps before the age of two. The data was analyzed using the chi-squared test.
      RESULTS: Sleeping till the age of two with a room light turned on leads to an
      increase in the occurrence of myopia (P<0.01). It was also found that light
      emitted by fluorescent lamps leads to more frequent occurrence of astigmatism
      (P<0.01). CONCLUSIONS: Disturbance of the daily light/dark cycle over the time
      during which refraction develops may disrupt emmetropization and lead to
      refractive errors.

PMID- 15039650
TI  - Can the genetic code be mathematically described?
AB  - From a mathematical point of view, the genetic code is a surjective mapping
      between the set of the 64 possible three-base codons and the set of 21 elements
      composed of the 20 amino acids plus the Stop signal. Redundancy and degeneracy
      therefore follow. In analogy with the genetic code, non-power integer-number
      representations are also surjective mappings between sets of different
      cardinality and, as such, also redundant. However, none of the non-power
      arithmetics studied so far nor other alternative redundant representations are
      able to match the actual degeneracy of the genetic code. In this paper we develop
      a slightly more general framework that leads to the following surprising results:
      i) the degeneracy of the genetic code is mathematically described, ii) a new
      symmetry is uncovered within this degeneracy, iii) by assigning a binary string
      to each of the codons, their classification into definite parity classes
      according to the corresponding sequence of bases is made possible. This last
      result is particularly appealing in connection with the fact that parity coding
      is the basis of the simplest strategies devised for error correction in man-made
      digital data transmission systems.

PMID- 15039649
TI  - Myocardial infarction with normal coronary arteriogram: the role of ephedrine
      like alkaloids.
AB  - BACKGROUND: The overwhelming majority of myocardial infarctions result from
      atherosclerosis, generally with superimposed coronary thrombosis. The prevalence
      of patients who develop myocardial infarction and in whom subsequent angiography
      shows normal coronary arteries is approximately 5%. Many of these cases are
      caused by coronary artery spasm and/or thrombosis, perhaps with an underlying
      endothelial dysfunction of the epicardial coronary arteries. CASE REPORT: The
      authors present a case of acute myocardial infarction with normal coronary
      arteriogram which occurred in a 19-year-old, cigarette-smoking male following
      usage of a pseudoephedrine-containing drug for an upper respiratory tract
      infection. Coronary artery spasm, associated with taking pseudoephedrine, and a
      prothrombotic state, related to the platelet and endothelial effects of cigarette
      smoking and infection, were the possible mechanisms of myocardial infarction in
      the reported case. CONCLUSIONS: A diagnosis of acute myocardial infarction should
      be seriously considered even in relatively young tobacco-smoking patients,
      especially after acute alcohol intoxication or cocaine, amphetamine or ephedrine
      exposure. It is very important to obtain a complete history of the use of such
      'safe' drugs, which do not need to be administered by a doctor but may contain
      treacherous components. These data provide the necessary background for making an
      accurate diagnosis and appropriate decisions concerning therapy.

PMID- 15039651
TI  - Gastrectomy does not influence the levels of aminotransferases, total protein and
      albumin in humans--in reply.

PMID- 15039652
TI  - A sub-nanomolar real-time nitric oxide probe: in vivo nitric oxide release in
      heart.
AB  - BACKGROUND: Amperometric nitric oxide probes are critical in evaluating real-time
      nitric oxide levels. This valuable tool enables one to measure spontaneous
      baseline levels of nitric oxide as well as 'puffs' of the gaseous signal molecule
      that may last for only seconds to minutes. However, in the past, many probes
      suffered from a lack of sensitivity, durability and reliability, causing
      investigators to design numerous controls to support their data.
      MATERIAL/METHODS: Our laboratory evaluated the new ISO-NOPF100 NO probe
      manufactured by World Precision Instruments of Sarasota, Florida. An invertebrate
      in vivo heart preparation was used, which presents a high degree of difficuly in
      obtaining nitric oxide measurements due to space limitations, resulting in
      physical contact of the probe with tissues. Additionally, we used in vitro
      invertebrate ganglionic preparations as a comparison since this tissue releases
      spontaneous and low levels of NO. RESULTS: Calibration of the new probe
      demonstrated high linearity and sensitivity. The detection limit for this new
      probe was determined to be approximately two times lower than probes previously
      used in our laboratory. Basal nitric oxide fluctuations in Mytilus edulis heart
      and excised ganglia were able to be resolved in the sub-nanomolar range.
      CONCLUSIONS: The ISO-NOPF100 NO probe represents a significant advancement for
      measuring nitric oxide in real-time.

PMID- 15039653
TI  - The effect of long-term antiepileptic treatment on serum cholesterol (TC, HDL,
      LDL) and triglyceride levels in adult epileptic patients on monotherapy.
AB  - BACKGROUND: Antiepileptic drugs influence, among others, cholesterol and
      lipoprotein serum levels. MATERIAL/METHODS: Serum cholesterol (TC, HDL-c, and LDL
      c) and triglyceride (TG) levels were measured in 103 epileptic patients receiving
      chronic antiepileptic monotherapy and in 103 age- and sex-matched controls.
      RESULTS: Compared with controls, patients on carbamazepine showed significant
      higher TC, HDL-c, and LDL-c and non significantly higher TG values. Patients on
      phenobarbital showed no statistically significant differences in TC, HDL-c, LDL-c
      and TG values. Patients on phenytoin showed significantly higher LDL-c values and
      non-significant differences in TC, HDL-c and TG values. Patients on valproate
      showed significantly lower TC, LDL-c and TG values and non-significant
      differences in HDL-c values. Changes in serum lipid profiles did not correlate
      with drug plasma levels. CONCLUSIONS: Our results suggest a need for monitoring
      serum TC, HDL-c, LDL-c and TG levels and, perhaps, prescribing a low-cholesterol
      diet in patients receiving carbamazepine and phenytoin, but not phenobarbital.

PMID- 15039654
TI  - Prolonged intracranial pressure (ICP) monitoring in non-traumatic pediatric
      neurosurgical diseases.
AB  - BACKGROUND: A limited number of studies have addressed the methods, indications
      and particular problems that may occur when programming prolonged intracranial
      pressure (ICP) monitoring in pediatric patients. Parenchymal fiberoptic
      transducers have been shown to give reliable ICP readings; moreover, they present
      a relatively low rate of complications, are easily placed and, as they are solid
      state, they are not subject to obstruction. MATERIAL/METHODS: A recently
      developed fiberoptic ICP transducer (Codman intraparenchymal sensor) was used to
      continuously monitor intracranial pressure in seventy children with non-traumatic
      neurosurgical diseases. The admitting diagnoses were hydrocephalus or shunt
      related problems in 33 cases, single-suture (5 cases) or complex (16 cases)
      craniosynostosis in 21 patients, and sylvian scissure arachnoid cyst (SAC) in 16
      cases. A software (ICP monitoring release) designed in our department was used
      for ICP recording storage and analysis. RESULTS: Raised ICP values were found in
      six of the seventeen patients with a suspected active hydyrocephalus, 24% of
      children with non-syndromic craniosynostosis, 52.8% of syndromic craniosynostosis
      patients, 50% or the children with a Type 11 SAC and two of the three patients
      with Type II SAC. CONCLUSIONS: Overall, prolonged ICP monitoring proved to be
      extremely useful in guiding surgical indications. The fiberoptic device used in
      our unit was shown to be reliable and associated with a relatively low rate of
      complications. Finally, the software allowed easy review and analysis of the
      obtained data.

PMID- 15039656
TI  - Pharmacokinetics of erythrocyte-bound daunorubicin in patients with acute
      leukemia.
AB  - BACKGROUND: The objective of the present study was in vitro and in vivo
      investigation of erythrocytes as vehicles for anthracycline antibiotics.
      MATERIAL/METHODS: The kinetics of daunorubicin binding with erythrocytes was
      studied in blood and in washed erythrocyte suspensions from healthy donors and
      patients with acute leukemia. The effect of daunorubicin on erythrocyte
      deformability was studied using cell filtration through membranes with 3 microm
      diameter cylindrical pores. Erythrocyte-bound daunorubicin (EBD), prepared by
      equilibrating anticoagulated autologous blood with the antibiotic, was
      administered (45 or 60 mg/m2 body surface) to 14 leukemic patients as part of the
      7+ 3 or RACOP courses. The pharmacokinetics of daunorubicin and its tolerability
      were studied. RESULTS: Human erythrocytes bound daunorubicin (rubomycin) in
      citrated whole blood or in washed saline suspension. The equilibrium
      erythrocyte/medium daunorubicin concentration ratios (attained in 30-60 min at 37
      degrees C) averaged 2.9 +/- 0.5 (n=13) in blood and 5.7 +/- 0.6 (n=8) in
      suspension (p<0.001), without any significant difference between the erythrocytes
      of donors and patients with acute drug-resistant leukemia or leukemic relapses.
      Incubation of patient blood with daunorubicin (0.5 mg/ml cells) did not affect
      erythrocyte deformability (filterability). After intravenous administration, the
      peak drug concentration and its elimination rate were lower for EBD than for free
      daunorubicin. The patients tolerated EBD better than its standard free form. In
      nine patients who received three EBD infusions, side effects were less frequent
      than in those treated with free daunorubicin. CONCLUSIONS: Our results indicate
      that daunorubicin-loaded erythrocytes are promising for clinical application and
      deserve further clinical study.

PMID- 15039655
TI  - Dietary supplementation with olive oil leads to improved lipoprotein spectrum and
      lower n-6 PUFAs in elderly subjects.
AB  - BACKGROUND: Oleic acid, polyphenols, and other components abundantly present in
      olive oil are thought to be partly responsible for the antiatherogenic effects
      attributed to the Mediterranean diet. One of the expected outcomes is a positive
      impact on the lipoprotein spectrum, but also other benefits are to be expected.
      MATERIAL/METHODS: The analysis was conducted on 28 outpatients older than 50
      years of age (mean age 68.1, 95%CI 64.9-71.3). The supplement was taken for 6
      weeks and involved daily consumption of 2 tablespoons (approx. 20 g) of extra
      virgin olive oil as part of the subjects' habitual diets, without changing their
      usual total energy and fat c onsumption. This phase was followed by a 2-month
      wash-out. RESULTS: After dietary supplementation with olive oil, serum total- and
      LDL-cholesterol mean concentrations were lowered by 0.818 mmol/l (p<0.00002; 95%
      CI -1.142 to -0.493 mmol/l) and 0.782 mmol/l (p=0.00013; 95% CI -1.141 to -0.423
      mmol/l), respectively. There was also a significant decline in the total-to-HDL
      and LDL-to-HDL cholesterol ratios (p<0.03 and p<0.015). Linolic and ar achidonic
      acid content in serum phospholipids decreased significantly (p<0.01 andcl
      p<0.001, respectively). The n-3 PUFAs were not affected. CONCLUSIONS: These
      results point to an overwhelmingly beneficial influence of olive oil on the
      lipoprotein spectrum. The statistically significant reduction in arachidonic acid
      may even be regarded as clinically desirable. An excellent complementarity
      between the effects of MUFAs and long-chain n-3 PUFAs is to be expected.

PMID- 15039658
TI  - Is short height really a risk factor for coronary heart disease and stroke
      mortality? A review.
AB  - A number of studies have reported an inverse relationship between height and
      cardiovascular disease (CVD). Most of these studies have involved a relatively
      small number of deceased people and may have been confounded by socioeconomic and
      other factors. In contrast, many studies have found short populations in
      traditional and western societies have very low CVD compared to taller Western
      populations. The purpose of this study was to evaluate the impact of short height
      on coronary heart disease (CHD) and stroke incidence or mortality based on a
      variety of inter-ethnic and intraethnic groups involving much larger deceased
      populations compared to previous studies. The results of this study indicate that
      shorter people have substantially lower rates of CHD mortality and moderately
      lower levels of stroke mortality. For example, shorter southern Europeans had
      about half the CHD mortality rate of northern Europeans. In addition, shorter
      ethnic groups vs taller groups in California had substantially lower mortality
      rates. Native American, Japanese, Indian, and Pakistani studies also showed
      shorter people had lower CHD and stroke incidence or mortality compared to taller
      people within each group. The rate of increase in (CHD mortality with increasing
      height was similar for shorter females vs taller males and for shorter males vs
      taller males.

PMID- 15039659
TI  - Adjuvant drugs for end-stage liver failure and transplantation.
AB  - End-stage liver failure is currently treatable both by dialysis and by liver
      transplantation, but this does not detract from its being a complex
      pathophysiological and pharmacological entity. More patients survive after
      transplant because of the impressive developments that enabled improved liver
      preservation, anesthesia and surgical techniques, as well as immunosuppressive
      drug therapy. Because of its multifaceted metabolism, liver failure can
      nevertheless cause a complex of pathophysiological conditions and, as such, poses
      a challenge for surgeons and anesthesiologists alike, not only before surgery but
      during transplantation as well. Obviating these problems frequently requires the
      use of adjunct drugs before, during and after liver transplantation, and these
      medications must be carefully balanced with each other while being alert to the
      avoidance of negative side effects. Hepatorenal syndrome and massive bleeding are
      the two main grave phenomena that characterize these patients before and during
      liver transplant, and this article will provide an overview of the adjunct drugs
      that are used to circumvent them perioperatively. Specifically, it details the
      drugs that are used to preserve and improve the already precarious hemodynamic
      conditions (e.g, by vasopressors, vasodilators, and beta blockers), as well as
      diuretics and hepato-protective drugs (e.g, furosemide, mannitol),
      antifibrinolytics (including the new recombinant activated Factor VII) and
      immunosuppressive drugs. Their doses and the ongoing debate on their concomitant
      use are reported as well.

PMID- 15039660
TI  - Transcription factors having impact on vascular endothelial growth factor (VEGF)
      gene expression in angiogenesis.
AB  - This article discusses the role of transcription factors in vascular endothelial
      growth factor (VEGF) gene expression. Angiogenesis is a complex and multilevel
      process of new capillary formation on the basis of already existing blood
      vessels. Physiologically, it is a very strictly regulated process, which results
      in a balance between stimulatory (angiogenic) and inhibitory (angiostatic)
      factors to control the correct development of blood vessels. There are many very
      well characterized angiogenic and angiostatic factors that can modulate VEGF
      expression. Some of them (e.g. HIF-1, AP-1, and Sp-1) are transcription factors,
      proteins that bind to the VEGF promoter to initiate and activate the
      transcription of a gene directly. Others, like nitric oxide or cytokines, are
      agents that stimulate the transcription factors through different cellular
      signaling pathways. There are also oncogenes (V-SRC, bcl-2) and tumor suppressor
      genes (VHL), the mutations of which lead indirectly to increased transcription of
      the VEGF gene.

PMID- 15039661
TI  - Munchausen by proxy.

PMID- 15039663
TI  - ENA occasions many "Aha! Moments" on behalf of emergency nurses.

PMID- 15039664
TI  - "www.JENonline.org".

PMID- 15039667
TI  - A Delphi study on research priorities for emergency nurses in Western Australia.
AB  - INTRODUCTION: The Delphi Study on Research Priorities for Emergency Nurses in
      Western Australia Project was designed to allow emergency nurses to design
      research questions and then rank them in order of priority. METHODS: A
      qualitative methodology allowed the researchers to determine expert opinions from
      the membership of the Emergency Nurses Association of Western Australia to reach
      a general consensus related to research questions. RESULTS: The results placed
      nurse-initiated analgesia as the top research priority, with ED staffing issues
      in second place and ED violence issues in third place. In all, 25 research
      questions were developed and ranked according to priority. DISCUSSION:
      Development of these ranked research questions enables researchers not only to
      pick a research question "off the shelf" but also to be assured that the research
      question is clinically relevant and is a priority for practicing emergency
      nurses. These attributes will encourage potential researchers to conduct studies,
      but they also underscore the importance of the topics for the benefit of those
      who fund studies.

PMID- 15039666
TI  - A 52-year-old acyanotic man with severe hypoxia and profound metabolic acidosis
      following an industry chemical exposure.

PMID- 15039668
TI  - The first year as sexual assault nurse examiner: role transition and role-related
      stress within a new SANE team.
AB  - INTRODUCTION: There are increasing opportunities for nurses to become sexual
      assault nurse examiners (SANEs). In rural areas far from established SANE
      programs, nurses considering becoming SANEs have few opportunities to talk with
      or observe experienced SANEs to explore the role and determine if they are well
      suited to forensic and victim service work. The purpose of this exploratory,
      descriptive qualitative research project was to learn what the first year in
      practice was like for members of a new semi-rural SANE team in terms of role
      transition and role-specific stress. METHODS: Interviews were conducted with 6
      members of a SANE team at 3 time points during their first year in that role.
      RESULTS: Expertise these nurses brought from their backgrounds as emergency
      nurses, women's health nurses, and intensive care nurses transferred well and
      eased their adaptation to the SANE role in a process more akin to "role
      expansion" than "role transition." They identified comfort working with clients
      in crisis, acting on their clinical judgment, implementing complex protocols, and
      adding new skills to their regular nursing role as helpful in their transition to
      the SANE role. Themes about the first year included the contribution of prior
      experiences observing or assisting with examinations, concerns that diminished
      over time, getting used to being on call, using their usual coping, getting past
      the first examination, and finding satisfaction. DISCUSSION: Further research
      with larger samples could confirm what nurse characteristics, including prior
      experience or elements of expertise, facilitate success and ease in the SANE
      role.

PMID- 15039669
TI  - Systematic ED assessment and treatment of alcohol withdrawal syndromes: a pilot
      project at a Veterans Affairs Medical Center.

PMID- 15039670
TI  - Intranasal drug delivery: an alternative to intravenous administration in
      selected emergency cases.

PMID- 15039671
TI  - Knowledge assessment and preparation for the Certified Emergency Nurses
      examination.

PMID- 15039674
TI  - Avoid verbal orders.

PMID- 15039672
TI  - Care plans for patients with frequent ED visits for such chief complaints as back
      pain, migraine, and abdominal pain.

PMID- 15039675
TI  - Controlling bleeding in the field: hemostatic powders and dressings debut in the
      prehospital setting.

PMID- 15039677
TI  - "Portable" CEN review and triage course: one state ENA education committee's
      experience.

PMID- 15039678
TI  - Preparing for clinical NP practice in an emergency care setting.

PMID- 15039679
TI  - Acute viral myocarditis in the ED pediatric patient: three case presentations.

PMID- 15039681
TI  - Tobacco industry sponsorships: new image belies its deadly product.

PMID- 15039680
TI  - Managing pediatric ingestions of the new antidiabetic agents.

PMID- 15039682
TI  - Blunt cardiac trauma following a head-on motor vehicle crash.

PMID- 15039683
TI  - A 27-year-old man with ringing in his right ear and decreased hearing: five-level
      acuity scale discrimination of pain.

PMID- 15039684
TI  - A randomized, double-blinded, placebo-controlled trial of phenytoin for the
      prevention of early posttraumatic seizures in children with moderate to severe
      blunt head injury.
AB  - STUDY OBJECTIVE: We determine the efficacy of prophylactic phenytoin in
      preventing early posttraumatic seizures in children with moderate to severe blunt
      head injury. METHODS: Children younger than 16 years and experiencing moderate to
      severe blunt head injury were randomized to receive phenytoin or placebo within
      60 minutes of presentation at 3 pediatric trauma centers. The primary endpoint
      was posttraumatic seizures within 48 hours; secondary endpoints were survival and
      neurologic outcome 30 days after injury. A Bayesian decision-theoretic clinical
      trial design was used to determine the probability of remaining posttraumatic
      seizure free for each treatment group. RESULTS: One hundred two patients were
      enrolled, with a median age of 6.1 years. Sixty-eight percent were boys. The 2
      treatment groups were well matched. During the 48-hour observation period, 3 (7%)
      of 46 patients given phenytoin and 3 (5%) of 56 patients given placebo
      experienced a posttraumatic seizure. There were no significant differences
      between the treatment groups in survival or neurologic outcome after 30 days.
      According to these results, the probability that phenytoin has the originally
      hypothesized effect of reducing the rate of early posttraumatic seizures by 12.5%
      is 0.0053. The probability that phenytoin has any prophylactic efficacy is 0.383.
      The median effect size in this trial was -0.015 (seizure rate increased by 1.5%
      in the phenytoin group), 95% probability interval -0.127 to 0.091 (12.7% higher
      rate of posttraumatic seizures to a 9.1% lower rate of posttraumatic seizures
      with phenytoin). CONCLUSION: The rate of early posttraumatic seizures in children
      may be much lower than previously reported. Phenytoin did not substantially
      reduce that rate.

PMID- 15039685
TI  - Reaching first Bayes.

PMID- 15039686
TI  - Informed consent: time for a national dialogue?

PMID- 15039687
TI  - Emergency department management of suicidal adolescents.
AB  - Suicide is the third leading cause of death for youths aged 15 to 24 years in the
      United States. Approximately 2 million US adolescents attempt suicide each year,
      and 19% report serious consideration of suicide in the past year. Although
      suicidal adolescents are frequently treated in emergency departments (EDs), there
      are few publications about their ED management. Therefore, we reviewed the
      literature for recommendations for the management of adolescents with suicidal
      ideation or attempts. Hospitalization is recommended for adolescents who have
      attempted suicide and cannot be adequately monitored and kept safe outside of an
      inpatient setting. Discharge home can be considered for a subset of adolescents
      with suicidal thoughts if urgent follow-up mental health care can be ensured and
      responsible caregivers can adequately supervise and protect the youth. This
      subset includes adolescents who are not actively suicidal, do not have access to
      lethal methods, and have a supervising adult who can closely monitor their
      behavior. A mental health evaluation is recommended before ED discharge whenever
      feasible.

PMID- 15039688
TI  - Recalibration of the pediatric risk of admission score using a multi
      institutional sample.
AB  - STUDY OBJECTIVE: Case-mix adjustment is a critical component of quality
      assessment and benchmarking. The Pediatric Risk of Admission (PRISA) score is
      composed of descriptive, physiologic, and diagnostic variables that provide a
      probability of hospital admission as an index of severity. The score was
      developed and validated in a single tertiary pediatric hospital emergency
      department (ED) after exclusion of children with minor injuries and illnesses. We
      provide a multi-institutional recalibration and validation of the PRISA score and
      test its performance in 4 additional EDs, including patients with minor injuries
      and illnesses. METHODS: Masked, photocopied, randomly selected medical records of
      ED patients from 2000 were abstracted and were used to test the performance
      (discrimination and calibration) of the original PRISA score. This sample
      differed from the original PRISA sample by including 5 hospitals and including
      patients with minor injuries and minor illnesses. Independent variables included
      components of acute and chronic history, physiologic variables, and 3 ED
      therapies. The dependent variable was hospital admission. PRISA was then
      recalibrated as needed by using an 80% development sample and a 20% validation
      sample. Area under the curve and the Hosmer-Lemeshow goodness-of-fit test were
      used to measure, respectively, discrimination and calibration of the PRISA score
      after recalibration. We then applied the recalibrated PRISA score to secondary
      outcomes to test construct validity. We reasoned that a valid measure of ED
      severity should also be associated with the secondary outcomes of mandatory
      admissions (admissions using > or =1 inpatient resources) and ICU admissions.
      RESULTS: The recalibrated PRISA score performed well in all deciles of predicted
      probability of admission. The area under the curve was 0.81 and the calibration
      was good (Hosmer-Lemeshow 10.658; df=8; P=.222) for the development sample, and
      the area under the curve was 0.785 with excellent calibration (Hosmer-Lemeshow
      8.341; df=9; P=.500) for the validation sample. The overall development sample
      had 423.9 admissions predicted and 423 observed; the validation sample had 112.1
      predicted and 110 observed. CONCLUSION: The PRISA score has been recalibrated and
      performs well in EDs of tertiary pediatric hospitals. Comparison with this
      benchmark may allow individual EDs to improve their performance and may provide
      insight into best practices.

PMID- 15039689
TI  - Emergency medicine-trained physicians are proficient in the insertion of
      transvenous pacemakers.
AB  - STUDY OBJECTIVE: The insertion and management of a temporary transvenous
      pacemaker can be a lifesaving procedure in the emergency department setting. We
      compare the success and complication rates associated with temporary transvenous
      pacemaker insertion between physicians trained in either emergency medicine or
      cardiology. METHODS: This was a retrospective medical record review of all
      patients with a billing code for temporary transvenous pacemaker insertion at our
      institution between July 1999 and December 2002. Patients were excluded if the
      temporary transvenous pacemaker was not supervised by an attending physician or
      was placed under fluoroscopy or if the indication for pacing was asystole. Cases
      were reviewed by 2 physicians certified in emergency medicine and categorized by
      the specialty training of the attending physician providing direct supervision.
      RESULTS: During the review period, 10 emergency medicine faculty and 8
      cardiologists directly supervised 141 of the 158 temporary transvenous pacemaker
      insertions in 154 patients. Twenty-four were placed for asystole, 4 were placed
      under fluoroscopy, and 13 were placed without direct attending supervision,
      leaving a total of 117 cases (30 emergency medicine, 87 cardiology) for review.
      The procedure was successful 97% (95% confidence interval [CI] 90% to 100%) of
      the time for emergency medicine faculty and 95% (95% CI 91% to 100%) of the time
      for cardiology faculty. Complications were seen in 23% (95% CI 7% to 39%) of the
      temporary transvenous pacemakers inserted by emergency medicine attending
      physicians and 20% (95% CI 11% to 28%) of the temporary transvenous pacemakers
      inserted by cardiologists. There was no statistical difference in errors between
      the specialties, and no complication resulted in death or prolonged disability.
      CONCLUSION: Physicians trained in emergency medicine perform temporary
      transvenous pacemaker insertions in the acute care setting with a proficiency
      similar to that of their counterparts in cardiology.

PMID- 15039690
TI  - Credentialing, competency, and "see one, do one, teach one".

PMID- 15039691
TI  - Vagal response varies with Valsalva maneuver technique: a repeated-measures
      clinical trial in healthy subjects.
AB  - STUDY OBJECTIVE: Variable success rates of the Valsalva maneuver in treatment of
      paroxysmal supraventricular tachycardia may be due to variations in performance
      technique. This study aimed to compare the magnitude of the vagal reflexes
      initiated by 5 variations of the Valsalva maneuver technique (supine, supine with
      epigastric pressure, supine with leg raise, semirecumbent position, and sitting
      position). METHODS: This was a single-blinded, repeated-measures, clinical trial
      of 65 subjects in sinus rhythm. Subjects performed each Valsalva maneuver
      technique 5 times in random order. The means of the longest ECG R-R intervals
      during the relaxation phase (postmaneuver R-R interval) and the postmaneuver
      pulse rates for each technique were compared. The mean differences between the
      pre- and postmaneuver R-R intervals for each technique were also compared.
      RESULTS: The supine with epigastric pressure and supine techniques resulted in
      longer mean postmaneuver R-R intervals (1.082 seconds [95% confidence interval
      (CI) 1.045 to 1.119 seconds] and 1.075 seconds [95% CI 1.035 to 1.114 seconds],
      respectively) than the leg raise, semirecumbent, and sitting position techniques
      (1.053 seconds [95% CI 1.019 to 1.086 seconds], 1.044 seconds [95% CI 1.006 to
      1.081 seconds], and 1.024 seconds [95% CI 0.990 to 1.059 seconds], respectively),
      which equates to slower mean postmaneuver pulse rates for the supine with
      epigastric pressure and supine techniques (55.5 and 55.8 beats/min, respectively)
      than the leg raise, semirecumbent, and sitting position techniques (57.0, 57.5,
      and 58.6 beats/min, respectively). The supine with epigastric pressure and supine
      techniques also resulted in the largest premaneuver versus postmaneuver
      differences. CONCLUSION: For healthy subjects in sinus rhythm, the supine with
      epigastric pressure and supine techniques generated stronger vagal responses, as
      measured by R-R intervals and pulse rates, than the other techniques examined.
      However, the vagal responses of these 2 techniques were similar, and the addition
      of epigastric pressure may confer little advantage.

PMID- 15039692
TI  - Variability in emergency physician decision making about prescribing opioid
      analgesics.
AB  - STUDY OBJECTIVE: The purpose of this study is to determine what factors influence
      emergency physicians' decisions to prescribe an opioid analgesic for 3 common,
      painful conditions. METHODS: We developed items thought to influence the decision
      to prescribe an opioid analgesic through a review of the literature, expert
      consultation, and interviews with practicing emergency physicians. We developed a
      baseline vignette and items expected to influence the decision for each of the 3
      conditions: migraine, back pain, and ankle fracture. We surveyed 650 physicians
      randomly selected from the American College of Emergency Physicians. The
      influence of individual items was explored through a univariate analysis of the
      response distribution. Patterns were assessed by analytically creating scales.
      RESULTS: We received responses from 398 (63%) of the 634 eligible physicians.
      Physicians' likelihoods of prescribing an opioid showed marked variability, with
      at least 10% of physicians saying they were unlikely and 10% of physicians saying
      they were likely to prescribe for each condition. Physician responses to
      individual pieces of clinical information, such as the patient requesting
      "something strong" for the pain, were also highly variable, with at least 10% of
      physicians saying they would be negatively influenced by this request and at
      least 10% saying they would be positively influenced by it. CONCLUSION: Even when
      faced with identical case scenarios, physicians' decisions to prescribe opioid
      analgesics are highly variable. Moreover, the same clinical information, such as
      a patient requesting a strong analgesic, changes the likelihood of prescribing
      opioids in opposite directions for different physicians.

PMID- 15039693
TI  - Inadequate analgesia in emergency medicine.
AB  - Review of emergency department pain management practices demonstrates pain
      treatment inconsistency and inadequacy that extends across all demographic
      groups. This inconsistency and inadequacy appears to stem from a multitude of
      potentially remediable practical and attitudinal barriers that include (1) a lack
      of educational emphasis on pain management practices in nursing and medical
      school curricula and postgraduate training programs; (2) inadequate or
      nonexistent clinical quality management programs that evaluate pain management;
      (3) a paucity of rigorous studies of populations with special needs that improve
      pain management in the emergency department, particularly in geriatric and
      pediatric patients; (4) clinicians' attitudes toward opioid analgesics that
      result in inappropriate diagnosis of drug-seeking behavior and inappropriate
      concern about addiction, even in patients who have obvious acutely painful
      conditions and request pain relief; (5) inappropriate concerns about the safety
      of opioids compared with nonsteroidal anti-inflammatory drugs that result in
      their underuse (opiophobia); (6) unappreciated cultural and sex differences in
      pain reporting by patients and interpretation of pain reporting by providers; and
      (7) bias and disbelief of pain reporting according to racial and ethnic
      stereotyping. This article reviews the literature that describes the prevalence
      and roots of oligoanalgesia in emergency medicine. It also discusses the
      regulatory efforts to address the problem and their effect on attitudes within
      the legal community.

PMID- 15039694
TI  - Emergency medicine and pain: a topography of influence.

PMID- 15039695
TI  - Retrospective application of the NEXUS low-risk criteria for cervical spine
      radiography in Canadian emergency departments.
AB  - STUDY OBJECTIVE: We evaluate the accuracy, reliability, and potential impact of
      the National Emergency X-Radiography Utilization Study (NEXUS) low-risk criteria
      for cervical spine radiography, when applied in Canadian emergency departments
      (EDs). METHODS: The Canadian C-Spine Rule derivation study was a prospective
      cohort study conducted in 10 Canadian EDs that recruited alert and stable adult
      trauma patients. Physicians completed a 20-item data form for each patient and
      performed interobserver assessments when feasible. The prospective assessments
      included the 5 individual NEXUS criteria but not an explicit interpretation of
      the overall need for radiography according to the criteria. Patients underwent
      plain radiography, flexion-extension views, and computed tomography at the
      discretion of the treating physician. Patients who did not have radiography were
      followed up with a structured outcome assessment by telephone to determine
      clinically important cervical spine injury, a previously validated outcome
      measurement. Analyses included sensitivity and specificity with 95% confidence
      interval (CI), kappa coefficient, and potential radiography rates. RESULTS: Among
      8,924 patients, 151 (1.7%) patients had an important cervical spine injury. The
      combined NEXUS criteria identified important cervical spine injury with a
      sensitivity of 92.7% (95% CI 87% to 96%) and a specificity of 37.8% (95% CI 37%
      to 39%). Application of the NEXUS criteria would have potentially reduced
      cervical spine radiography rates by 6.1% from the actual rate of 68.9% to 62.8%.
      Of 11 patients with important injuries not identified, 2 were treated with
      internal fixation and 3 with a halo. CONCLUSION: This retrospective validation
      found the NEXUS low-risk criteria to be less sensitive than previously reported.
      The NEXUS low-risk criteria should be further explicitly and prospectively
      evaluated for accuracy and reliability before widespread clinical use outside of
      the United States.

PMID- 15039696
TI  - Comparison of the Canadian C-Spine rule and NEXUS decision instrument in
      evaluating blunt trauma patients for cervical spine injury.

PMID- 15039698
TI  - National Highway Traffic Safety Administration (NHTSA) notes. PIER: Public
      information, education, and relations for EMS injury prevention modules.

PMID- 15039697
TI  - Comparing NEXUS and Canadian C-Spine decision rules for determining the need for
      cervical spine radiography.

PMID- 15039700
TI  - Usefulness and validity of diagnostic nasogastric aspiration in patients without
      hematemesis.
AB  - STUDY OBJECTIVE: We estimate the test characteristics of nasogastric aspiration
      to diagnose upper gastrointestinal tract hemorrhage in patients without
      hematemesis. METHODS: In this retrospective cohort study, medical records from
      patients admitted to 2 urban hospitals between 1997 and 2002 for gastrointestinal
      tract bleeding without hematemesis were reviewed. Positive nasogastric aspiration
      results were classified by the severity of hemorrhage, and negative results were
      classified by the presence or absence of bile. The reference standard for
      nasogastric aspiration was the source of bleeding-upper versus non--upper
      gastrointestinal tract--from the hospital discharge summary. Confidence intervals
      (CIs) for proportions and likelihood ratios (LRs) were calculated. RESULTS: Of
      333 eligible patients, 235 were offered nasogastric aspiration, and 220 accepted
      the test. Results of 220 attempts were distributed as follows: negative, 158
      (72%), including 9 (4%) with bile; nasogastric aspiration aborted, 13 (6%); and
      positive, 49 (23%), including 4 (2%) that were strongly positive (> or =450 mL
      red blood). Test characteristics of nasogastric aspiration to detect upper
      gastrointestinal tract bleeding in 213 patients with a reference standard
      diagnosis were as follows: sensitivity 42% (95% CI 32% to 51%), specificity 91%
      (95% CI 83% to 95%), negative predictive value 64% (95% CI 56% to 71%), and
      positive predictive value 92% (95% CI 79% to 97%). The nasogastric aspiration
      accurately predicted the source of bleeding in 66% of patients (95% CI 59% to
      72%). The likelihood ratio of a positive nasogastric aspiration was 11 (95% CI 4
      to 30), and the likelihood ratio of a negative nasogastric aspiration was 0.6
      (95% CI 0.5 to 0.7). CONCLUSION: In patients without hematemesis, a positive
      nasogastric aspiration, seen in 23%, indicates probable upper gastrointestinal
      tract bleeding (LR+ 11), but a negative nasogastric aspiration, seen in 72%,
      provides little information (LR- 0.6).

PMID- 15039701
TI  - Images in emergency medicine. Scrotal hematoma with open book pelvis fracture and
      prostatic urethral disruption.

PMID- 15039702
TI  - Recent developments in genetic data analysis: what can they tell us about human
      demographic history?
AB  - Over the last decade, a number of new methods of population genetic analysis
      based on likelihood have been introduced. This review describes and explains the
      general statistical techniques that have recently been used, and discusses the
      underlying population genetic models. Experimental papers that use these methods
      to infer human demographic and phylogeographic history are reviewed. It appears
      that the use of likelihood has hitherto had little impact in the field of human
      population genetics, which is still primarily driven by more traditional
      approaches. However, with the current uncertainty about the effects of natural
      selection, population structure and ascertainment of single-nucleotide
      polymorphism markers, it is suggested that likelihood-based methods may have a
      greater impact in the future.

PMID- 15039703
TI  - Phenotypic plasticity of body pigmentation in Drosophila melanogaster: genetic
      repeatability of quantitative parameters in two successive generations.
AB  - In Drosophila melanogaster, body pigmentation is a quantitative trait that
      depends on developmental temperature. When investigated over the whole thermal
      range of the species, pigmentation exhibits nonlinear reaction norms that differ
      among segments. The isofemale line method was used to analyse the genetic
      variability in two natural populations that affected the shape of reaction norms.
      Each line was considered as an experimental repeat, and polynomial reaction norms
      fitted to calculate the characteristic values (eg the coordinates of a maximum).
      In total, 20 lines from two geographically distant populations (France and India)
      were investigated at seven developmental temperatures (12-31 degrees C) in two
      successive generations (G2 and G3). We analysed the genetic repeatability (ie the
      correlation between generations) of three kinds of parameters: intraclass
      correlation coefficients (isofemale heritability), family means at different
      temperatures and the characteristic values of the reaction norms. For intraclass
      correlation, a low genetic repeatability was found. For family mean values grown
      at various temperatures, an overall positive and highly significant repeatability
      was found (r=0.55+/-0.024). Finally, a positive significant G2-G3 correlation was
      also the rule for the characteristic values of the reaction norms. Significant
      differences could be found between values describing either the trait or its
      plasticity, but with no general trend. A slightly higher repeatability was
      observed in the Indian population. These results show that, with a family
      selection design, the shape of the reaction norms might be modified in various
      ways.

PMID- 15039704
TI  - Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90
      chaperone machinery.
AB  - Hsp90 is a molecular chaperone essential for the activation and assembly of many
      key eukaryotic signalling and regulatory proteins. Hsp90 is assisted and
      regulated by co-chaperones that participate in an ordered series of dynamic
      multiprotein complexes, linked to Hsp90 conformationally coupled ATPase cycle.
      The co-chaperones Aha1 and Hch1 bind to Hsp90 and stimulate its ATPase activity.
      Biochemical analysis shows that this activity is dependent on the N-terminal
      domain of Aha1, which interacts with the central segment of Hsp90. The structural
      basis for this interaction is revealed by the crystal structure of the N-terminal
      domain (1-153) of Aha1 (equivalent to the whole of Hch1) in complex with the
      middle segment of Hsp90 (273-530). Structural analysis and mutagenesis show that
      binding of N-Aha1 promotes a conformational switch in the middle-segment
      catalytic loop (370-390) of Hsp90 that releases the catalytic Arg 380 and enables
      its interaction with ATP in the N-terminal nucleotide-binding domain of the
      chaperone.

PMID- 15039706
TI  - Financial balance.

PMID- 15039708
TI  - Minimal intervention.

PMID- 15039710
TI  - Smoking cessation.

PMID- 15039711
TI  - Smoking cessation.

PMID- 15039712
TI  - Smoking cessation.

PMID- 15039714
TI  - European Parliament approves directive.

PMID- 15039723
TI  - Orthodontics. Part 8: Extractions in orthodontics.
AB  - Extractions in orthodontics remains a relatively controversial area. It is not
      possible to treat all malocclusions without taking out any teeth. The factors
      which affect the decision to extract include the patient's medical history, the
      attitude to treatment, oral hygiene, caries rates and the quality of teeth.
      Extractions of specific teeth are required in the various presentations of
      malocclusion. In some situations careful timing of extractions may result in
      spontaneous correction of the malocclusion.

PMID- 15039724
TI  - Persistent idiopathic unilateral isolated hypoglossal nerve palsy: a case report.
AB  - Isolated hypoglossal nerve palsy (IHNP) although a rare condition, has been
      previously reported. A literature review revealed that in most cases, IHNP
      indicates the presence of an intracranial or extracranial space occupying lesion,
      head and neck injury, vascular abnormality, infection, autoimmune disease or
      neuropathy. Reports of idiopathic cases are rare and the vast majority of IHNP
      are reversible. We report a case of persistent idiopathic unilateral hypoglossal
      nerve palsy, with an emphasis on the investigations necessary to be undertaken on
      presentation of such a lesion.

PMID- 15039731
TI  - An investigation of post-operative morbidity following chin graft surgery.
AB  - AIM: The aim of this prospective study was to evaluate the morbidity at the donor
      site following harvest of chin bone for intra-oral augmentation. METHOD: The
      morbidity experienced by 27 consecutive patients who had undergone chin bone
      harvesting to augment intra-oral sites prior to implant placement at the
      Department of Oral and Maxillofacial Surgery, University Dental Hospital of
      Manchester was evaluated at one week, one, three and 12 months post-operatively.
      RESULTS: Nine (33%) patients suffered post-operative morbidity. One patient
      experienced paraesthesia of the chin and lower lip and a further patient,
      paraesthesia of the gingivae immediately post-operatively. Both patients had full
      recovery when reviewed at three months. Two patients experienced pain at the
      graft site for up to three months post-operatively. Five (18.5%) patients
      experienced woodiness/numbness of the lower anterior teeth at the first post
      operative visit and at 12 months, two patients continued to have no sensitivity
      in the lower anterior incisor teeth. None of the patients reported altered
      contour or change in profile of the chin area. Twenty-three (85.2%) patients had
      successful grafts with placement of implants thereafter. CONCLUSION: It is
      important for GDPs and specialists to make patients aware of the possible
      morbidities following harvest of bone from the chin.

PMID- 15039733
TI  - Development of a structured clinical operative test (SCOT) in the assessment of
      practical ability in the oral surgery undergraduate curriculum.
AB  - Competence in undergraduate oral surgery involves assessment of the students'
      knowledge, practical skill and attitude. The assessment of practical skills can
      be achieved using a formative assessment method such as the structured clinical
      operative test (SCOT) which uses a checklist for the assessment of a clinical
      task. The aim of this study was primarily to determine whether SCOTs could be
      integrated into the oral surgery undergraduate course, and secondarily to collect
      feedback from both the students and the staff on this assessment. A validated
      checklist was used by trained examiners to assess the performance of 49 students
      in their second clinical year undertaking simple exodontia. Feedback was
      collected from the students by questionnaire and from the staff by interview. The
      SCOT was well received by both students and staff. The main problem highlighted
      by the students was the perceived inter-examiner variability and by the staff,
      the disruptive effect on the clinics. The checklist must be objective enough to
      prevent misinterpretation. Despite these limitations, the SCOT provides a more
      objective assessment and serves to highlight weaker students, allowing them to be
      targeted for closer supervision and instruction as well as providing the students
      with a tool to measure their progress in oral surgery. The use of peer assessment
      by students may alleviate the burden on the staff.

PMID- 15039732
TI  - Analysis of paediatric dental care provided under general anaesthesia and levels
      of dental disease in two hospitals.
AB  - OBJECTIVE: To compare the level of dental disease and the pattern of dental
      treatment under controlled airway general anaesthesia for ASA I and II children
      and ASA III and IV children in two hospitals. DESIGN: Prospective analysis.
      SETTING: Hospital and postgraduate dental teaching institution, UK 1996 - 2000.
      SUBJECTS AND METHODS: During a four-year period (1996-2000), data were collected
      on children aged 1 to 16 years who were admitted for treatment of dental caries
      under general anaesthesia. Outcome measures Levels of dental disease (dmft/DMFT),
      treatment provided. RESULTS: A total of 515 ASA I and II and 430 ASA III and IV
      children were treated. The dmft and DMFT values of the ASA I and II children were
      significantly higher than those of the ASA III and IV children (p = 0.03). A
      significantly greater number of restorations and fissure sealants were carried
      out for permanent teeth in ASA III and IV children (p < 0.001). The number of
      extractions for both primary and permanent teeth was significantly greater in the
      ASA I and II group (p < 0.05). CONCLUSIONS: The ASA III and IV children had
      significantly lower levels of dental caries than the ASA I and II children and
      received a higher level of preventive and restorative care.

PMID- 15039746
TI  - Bite marks--the criminal's calling cards.
AB  - Carnivorous animals, like dogs or tigers, use their teeth in two distinct ways.
      They kill their prey primarily using their canines and they tear and slice the
      flesh to produce digestible fragments. Human teeth are designed principally to
      cut and grind food which is usually previously prepared. Some people appear to
      revert to more primitive instincts and use their canines and incisors to inflict
      bites on unsuspecting victims.

PMID- 15039751
TI  - Focus Awards 2003.

PMID- 15039754
TI  - Innate immunity to malaria.

PMID- 15039755
TI  - NOX enzymes and the biology of reactive oxygen.

PMID- 15039756
TI  - Inhibitory NK-cell receptors on T cells: witness of the past, actors of the
      future.

PMID- 15039757
TI  - Identifying epitopes of HIV-1 that induce protective antibodies.

PMID- 15039758
TI  - Immune surveillance in the skin: mechanisms and clinical consequences.

PMID- 15039759
TI  - Death-defying immunity: do apoptotic cells influence antigen processing and
      presentation?

PMID- 15039760
TI  - NKT cells: what's in a name?

PMID- 15039761
TI  - Agonist-like or antagonist-like treatment for cocaine dependence with methadone
      for heroin dependence: two double-blind randomized clinical trials.
AB  - Concurrent abuse of cocaine and heroin is a common problem. Methadone is
      effective for opioid dependence. The question arises as to whether combining
      agonist-like or antagonist-like medication for cocaine with methadone for opioid
      dependence might be efficacious. Two parallel studies were conducted. One
      examined sustained release d-amphetamine and the other risperidone for cocaine
      dependence, each in combination with methadone. In total, 240 subjects
      (120/study) were recruited, who were both cocaine and heroin dependent and not
      currently receiving medication. All provided consent. Both studies were carried
      out for 26 weeks, randomized, double-blind and placebo controlled. Study I
      compared sustained release d-amphetamine (escalating 15-30 or 30-60 mg) and
      placebo. Study II examined risperidone (2 or 4 mg) and placebo. All subjects
      underwent methadone induction and were stabilized at 1.1 mg/kg. Subjects attended
      clinic twice/week, provided urine samples, obtained medication take-home doses
      for intervening days, and completed self-report measures. Each had one behavioral
      therapy session/week. In Study I, reduction in cocaine use was significant for
      the 30/60 mg dose compared to the 15/30 mg and placebo. Opioid use was reduced in
      all groups with a trend toward greater reduction in the 30/60 mg d-amphetamine
      group. In Study II, methadone reduced illicit opioid use but cocaine use did not
      change in the risperidone or placebo groups. There were no adverse medication
      interactions in either study. The results provide support for the agonist-like (d
      amphetamine) model in cocaine dependence treatment but not for antagonist-like
      (risperidone) treatment. They coincide with our previous reports of amphetamine
      or risperidone administered singly in cocaine-dependent individuals.

PMID- 15039762
TI  - Genetic and pharmacological evidence of a role for GABA(B) receptors in the
      modulation of anxiety- and antidepressant-like behavior.
AB  - Although there is much evidence for a role of the inhibitory neurotransmitter
      gamma-aminobutyric acid (GABA) in the pathophysiology of anxiety and depression,
      the role of GABA(B) receptors in behavioral processes related to these disorders
      has not yet been fully established. GABA(B) receptors are G-protein-coupled
      receptors, which act as functional heterodimers made up of GABA(B(1)) and
      GABA(B(2)) subunits. Using recently generated GABA(B(1)) -/- mice, which lack
      functional GABA(B) receptors, and pharmacological tools we assessed the role of
      GABA(B) receptors in anxiety- and antidepressant-related behaviors. In the light
      dark box, GABA(B(1)) -/- mice were more anxious than their wild-type littermates
      (less time spent in the light; reduced number of transitions). GABA(B(1)) -/-
      mice were also more anxious in the staircase test. Conversely, acute and chronic
      treatment with GS39783, a novel GABA(B) receptor positive modulator, decreased
      anxiety in the light-dark box and elevated zero maze tests for anxiety. On the
      other hand, GABA(B(1)) -/- mice had decreased immobility (antidepressant-like
      behavior) in the forced swim test (FST). These behavioral effects are unrelated
      to alterations in locomotor activity. In confirmation of the genetic data, acute
      and chronic treatment with CGP56433A, a selective GABA(B) receptor antagonist,
      also decreased immobility in the FST, whereas GS39783 did not alter this
      behavior. Taken together, these data suggest that positive modulation of the
      GABA(B) receptor may serve as a novel therapeutic strategy for the development of
      anxiolytics, whereas GABA(B) receptor antagonism may serve as a basis for the
      generation of novel antidepressants.

PMID- 15039763
TI  - Dopamine dysfunction in borderline personality disorder: a hypothesis.
AB  - Research on the biological basis of borderline personality disorder (BPD) has
      focused primarily on the serotonin model of impulsive aggression. However, there
      is evidence that dopamine (DA) dysfunction may also be associated with BPD.
      Pertinent research and review articles, identified by Medline searches of
      relevant topics, books, references from bibliographies, and conference
      proceedings from 1975 to 2003, were reviewed. Evidence of DA dysfunction in BPD
      derives from the efficacy of traditional and atypical antipsychotic agents in
      BPD, and from provocative challenges with amphetamine and methylphenidate of
      subjects with the disorder. In addition, human and animal studies indicate that
      DA activity plays an important role in emotion information processing, impulse
      control, and cognition. The results of this review suggest that DA dysfunction is
      associated with three dimensions of BPD, that is, emotional dysregulation,
      impulsivity, and cognitive-perceptual impairment. The main limitation of this
      hypothesis is that the evidence reviewed is circumstantial. There is no study
      that directly demonstrates DA dysfunction in BPD. In addition, the therapeutic
      effects of antipsychotic agents observed in BPD may be mediated by non-DA
      mechanisms of action. If the stated hypothesis is correct, DA dysfunction in BPD
      may result from genetic, developmental, or environmental factors directly
      affecting specific DA pathways. Alternatively, DA dysfunction in BPD may be a
      compensatory response to alterations in the primary neural systems that control
      emotion, impulse control, and cognition, and that are mediated by the brain's
      main neurotransmitters, glutamate, and GABA, or in one or more other
      neuromodulatory pathways such as serotonin, acetylcholine, and norepinephrine.

PMID- 15039764
TI  - Metabolite alterations in basal ganglia associated with psychiatric symptoms of
      abstinent toluene users: a proton MRS study.
AB  - Long-term toluene abuse causes a variety of psychiatric symptoms. However, little
      is known about abnormalities at the neurochemical level in the living human brain
      after long-term exposure to toluene. To detect neurochemical changes in the basal
      ganglia of subjects with a history of long-term toluene use, proton magnetic
      resonance spectroscopy (1H MRS) was performed in 12 abstinent toluene users and
      13 healthy comparisons with no history of drug abuse. N-acetylaspartate (NAA),
      creatine plus phosphocreatine (Cr + PCr), choline-containing compounds (Cho), and
      myo-inositol (MI) levels were measured in the left and right basal ganglia. The
      Cho/Cr + PCr ratio, a marker of membrane metabolism, was significantly increased
      in the basal ganglia of toluene users in comparison to that of the control
      subjects. Furthermore, the increase in the Cho/Cr + PCr ratio was significantly
      correlated with the severity of residual psychiatric symptoms. These findings
      suggest that long-term toluene use causes membrane disturbance in the basal
      ganglia, which is associated with residual psychiatric symptoms that persist even
      after long-term abstinence from toluene use.

PMID- 15039765
TI  - Enhancement of central dopaminergic activity in the kainate model of temporal
      lobe epilepsy: implication for the mechanism of epileptic psychosis.
AB  - There is an increased incidence of schizophrenia-like psychosis in temporal lobe
      epilepsy (TLE), and several risk factors have been implicated, including the
      duration of epilepsy and temporal lobe neuropathology. To investigate the
      biological mechanism of epileptic psychosis, we examined alterations of central
      dopaminergic systems in the kainate model of TLE. In adult rats, kainate was
      microinjected into the left amygdala to induce status epilepticus. An indirect
      dopamine agonist methamphetamine (MAP, 2 mg/kg, i.p.) was administered before and
      1 month after the kainate treatment. MAP-induced locomotor activity was
      significantly enhanced in the kainate group compared with the baseline (pre
      kainate) level, which was antagonized by pretreatment with haloperidol. The
      enhancement of locomotor activity in the kainate group was significantly
      correlated with the density of hippocampal CA1 neurons. Although the basal
      extracellular dopamine concentration was significantly lower in the striatum in
      the kainate group than in the control group (5.5 vs 39.2 fmol/20-min sample), the
      maximal concentration following MAP administration did not differ between the two
      groups. These results clearly demonstrate that hypersensitivity of the dopamine
      systems develops in the chronic phase of the kainate-induced TLE model, which may
      be responsible for the mechanism of epileptic psychosis.

PMID- 15039766
TI  - Alpha2A-adrenoceptors are important modulators of the effects of D-amphetamine on
      startle reactivity and brain monoamines.
AB  - Amphetamines are commonly used to treat attention-deficit hyperactivity disorder,
      but are also widely abused. They are employed in schizophrenia-related animal
      models as they disrupt the prepulse inhibition (PPI) of the acoustic startle
      response. The behavioral effects of amphetamines have mainly been attributed to
      changes in dopamine transmission, but they also involve increases in the synaptic
      concentrations of norepinephrine (NE). alpha2-Adrenoceptors (alpha2-ARs) regulate
      the excitability and transmitter release of brain monoaminergic neurons mainly as
      inhibitory presynaptic auto- and heteroreceptors. Modulation of acoustic startle
      and its PPI by the alpha2A-AR subtype was investigated with mice lacking the
      alpha2A-AR (alpha2A-KO) and their wild-type (WT) controls, without drugs and
      after administration of the alpha2-AR agonist dexmedetomidine or the antagonist
      atipamezole. The interaction of D-amphetamine (D-amph) and the alpha2-AR
      noradrenergic neuronal system in modulating startle reactivity and in regulating
      brain monoamine metabolism was assessed as the behavioral and neurochemical
      responses to D-amph alone, or to the combination of D-amph and dexmedetomidine or
      atipamezole. alpha2A-KO mice were supersensitive to both neurochemical and
      behavioral effects of D-amph. Brain NE stores of alpha2A-KO mice were depleted by
      D-amph, revealing the alpha2A-AR as essential in modulating the actions of D
      amph. Also, increased startle responses and more pronounced disruption of PPI
      were noted in D-amph-treated alpha2A-KO mice. alpha2A-AR also appeared to be
      responsible for the startle-modulating effects of alpha2-AR drugs, since the
      startle attenuation after the alpha2-AR agonist dexmedetomidine was absent in
      alpha2A-KO mice, and the alpha2-AR antagonist atipamezole had opposite effects on
      the startle reflex in alpha2A-KO and WT mice.

PMID- 15039767
TI  - Exposure to delta-9-tetrahydrocannabinol (THC) increases subsequent heroin taking
      but not heroin's reinforcing efficacy: a self-administration study in rats.
AB  - One concern about the widespread use of cannabis is that exposure to its active
      ingredient, delta-9-tetrahydrocannabinol (THC), might increase future reinforcing
      effects of other abused drugs such as heroin. In this study, we investigated the
      effects of pre-exposure to THC on subsequent intravenous self-administration of
      heroin by Sprague-Dawley rats. In one group of rats, we studied (1) acquisition
      of heroin self-administration behavior using a continuous-reinforcement (fixed
      ratio (FR) 1) schedule, (2) heroin dose-response relationships using an
      FR1/variable-dose schedule, and (3) reinforcing efficacy of heroin using a
      progressive-ratio schedule. The number of rats pre-exposed to THC that
      subsequently learned to self-administer 50 microg/kg injections of heroin within
      10 daily sessions did not differ from vehicle-pretreated controls. In contrast,
      rats pre-exposed to THC subsequently self-administered significantly more heroin
      injections per session and showed significantly shorter post-injection pauses
      over a range of heroin doses (12.5-100 microg/kg/injection) using the variable
      dose schedule. Interestingly, the maximum effort rats would exert to receive an
      injection of the different doses of heroin under the progressive-ratio schedule
      was not altered by THC pre-exposure. In a second group of rats, we varied the
      'price' of heroin (responses required/dose), by manipulating FR response
      requirements at different doses of heroin across sessions, to calculate demand
      and response output curves. Again, consumption was significantly higher in the
      THC-treated rats at the lowest prices of heroin (FR1/100 microg/kg and FR1/50
      microg/kg) but there were no differences in the reinforcing efficacy of heroin
      between THC- and vehicle-pretreated rats. Altogether, these results demonstrate
      that pre-exposure to THC alters some pharmacological effects of heroin that
      determine frequency of heroin taking, but offer no support for the hypothesis
      that pre-exposure to THC alters heroin's efficacy as a reinforcer.

PMID- 15039768
TI  - Methadone maintenance reduces heroin- and cocaine-induced relapse without
      affecting stress-induced relapse in a rodent model of poly-drug use.
AB  - Although it is well established that methadone can be an effective treatment for
      opiate addiction, it is not clear how methadone maintenance affects cocaine use
      and cravings in individuals who self-administer both opiates and cocaine. In our
      attempt to explore the effect of methadone maintenance on the effects of cocaine,
      we first assessed the locomotor stimulatory effects of cocaine in rats maintained
      on methadone (0, 10, 20, or 30 mg/kg/day, via osmotic minipumps). Chronic
      methadone elevated baseline locomotion in a dose-dependent manner and did not
      reduce the direct stimulatory effects of cocaine (5 mg/kg). We then investigated
      the effects of the highest methadone maintenance dose (30 mg/kg/day) on heroin
      and cocaine seeking in extinction, and when it was precipitated by exposure to
      heroin, cocaine, or foot-shock stress in rats trained to self-administer both
      drugs in the same experimental context (heroin 0.05 mg/kg/inf; cocaine 0.5
      mg/kg/inf, eight 3-h sessions each). In tests of reinstatement, rats responded
      selectively on the appropriate drug-associated lever after priming injections of
      heroin (0.25 mg/kg) or cocaine (20 mg/kg). Methadone maintenance blocked both
      cocaine- and heroin-induced reinstatement, but not stress-induced reinstatement,
      which was not lever selective. These results suggest that although methadone
      maintenance may not reduce the direct stimulatory effects of cocaine, it has the
      potential to reduce both spontaneous and cocaine-primed cocaine-seeking behavior.

PMID- 15039769
TI  - In vivo regulation of glycogen synthase kinase-3beta (GSK3beta) by serotonergic
      activity in mouse brain.
AB  - The goal of this study was to determine if serotonergic activity, which is
      impaired in depression, regulates the phosphorylation of glycogen synthase kinase
      3beta (GSK3beta) in mouse brain in vivo. GSK3beta is inhibited by phosphorylation
      on serine-9 and is a target of the mood stabilizer lithium. Following
      administration to mice of d-fenfluramine to stimulate serotonin (5HT) release and
      reduce its reuptake, and clorgyline to inhibit 5HT catabolism, levels of phospho
      Ser9-GSK3beta were 300-400% of control levels in the prefrontal cortex,
      hippocampus, and striatum. Treatment with monoamine reuptake inhibitors
      fluoxetine and imipramine also increased the level of phospho-Ser9-GSK3beta.
      Using receptor selective agonists and antagonists, 5HT1A receptors were found to
      mediate increases, and 5HT2 receptors decreases, in phospho-Ser9-GSK3beta levels.
      This indicates that serotonergic regulation of the phosphorylation of GSK3beta is
      achieved by a balance between the opposing actions of these 5HT receptor
      subtypes. These findings demonstrate for the first time that serotonergic
      activity regulates the phosphorylation of GSK3beta and show that this regulation
      occurs in mammalian brain in vivo. These results raise the possibility that
      impaired inhibitory control of GSK3beta may occur in conditions where
      serotonergic activity is dysregulated, such as in mood disorders.

PMID- 15039770
TI  - Anticipatory cues differentially provoke in vivo peptidergic and monoaminergic
      release at the medial prefrontal cortex.
AB  - Like primary reinforcers, the anticipation of reward ought to affect
      neurochemical release in brain regions, such as the medial prefrontal cortex
      (mPFC), which are associated with appraisal processes. To assess the
      neurochemical changes associated with anticipation, rats were exposed to the
      pairing of auditory (60-dB white noise), visual, and olfactory cues with the
      daily presentation of a palatable snack (Cue Relevant group). Rats of a second
      group were similarly trained, but for a 2-week period, the snack was no longer
      provided following cue presentation (Extinction group). In the third condition,
      the presentation of the snack and cues was uncorrelated (Cue Irrelevant group).
      Analyses of dialysates collected in vivo from the mPFC revealed that release of
      corticotropin-releasing hormone (CRH), gastrin-releasing peptide (GRP), and the 5
      HT catabolite, 5-hydroxyindole acetic acid (5-HIAA), had increased bilaterally in
      response to the anticipatory cues, whereas DA release increased only within the
      right mPFC. In the case of CRH and GRP, these increases were also apparent in the
      extinction condition, despite the fact that behavioral arousal to the
      anticipatory cues (increased exploration, rearing, grooming, and vigilance) was
      only evident in the Cue Relevant condition. In contrast, the elevated DA and 5
      HIAA were apparent exclusively in the Cue Relevant condition. Thus, CRH and GRP
      systems may serve to allocate salience and/or incentive reward value to
      biologically significant stimuli or reflect the emotional response to the
      anticipatory stimulus. The activity of DA and 5-HT neurons, in contrast, is more
      closely aligned with the cognitive appraisal of predictor stimuli.

PMID- 15039771
TI  - Behavioral and neurochemical consequences of long-term intravenous self
      administration of MDMA and its enantiomers by rhesus monkeys.
AB  - The effects of self-administered 3,4-methylenedioxymethamphetamine (MDMA) on
      behavior and neurochemistry have not been previously studied in laboratory
      primates. We investigated the capacity of MDMA and its enantiomers to maintain
      contingent responding over an extended duration, whether any decrements in the
      reinforcing effects of these compounds would be observed over time, whether such
      decrements would be MDMA-selective, and whether any neurochemical correlates
      could be identified. Animals were previously trained to self-administer cocaine,
      then exposed to periodic substitutions of various doses of racemic MDMA and its
      enantiomers; full dose-effect curves were generated for each MDMA compound
      repeatedly over the duration of the study. After approximately 18 months of MDMA
      self-administration, drug exposure was halted and after at least 2 months drug
      abstinence, animals were scanned using positron emission tomography (PET) with
      the vesicular monoamine transporter (VMAT) ligand dihydrotetrabenazine (DTBZ).
      Shortly thereafter, animals were euthanized, brains were dissected, and samples
      were assayed for brain monoamines and their metabolites using high-performance
      liquid chromatography (HPLC), and for VMAT using DTBZ binding. The reinforcing
      effects of racemic and R(-)-MDMA were reduced over a long series (months) of
      individual self-administration access periods; the reinforcing effects of S+-MDMA
      were more resistant to this effect, but were attenuated for one animal. The
      reinforcing effects of cocaine were not altered by chronic MDMA self
      administration, nor was the VMAT binding potential as assessed by PET. Further,
      there were no measurable decrements in serotonin (5-HT), 5-hydroxyindoleacetic
      acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or VMAT in
      any brain regions assayed. The reinforcing effects of MDMA are selectively
      attenuated by chronic MDMA self-administration, although this behavioral change
      appears to occur in the absence of any frank neurochemical correlates of
      toxicity.

PMID- 15039773
TI  - Simultaneous blockade of adenosine A2A and metabotropic glutamate mGlu5 receptors
      increase their efficacy in reversing Parkinsonian deficits in rats.
AB  - Recent evidence suggest that antagonism of adenosine A2A receptors represent an
      alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A2A
      and the glutamate subtype 5 metabotropic receptors (mGlu5) synergistically
      stimulates DARPP-32 phosphorylation and c-fos expression in the striatum. This
      study therefore tested the effects of a joint blockade of these receptors to
      alleviate the motor dysfunction in a rat model of PD. 6-Hydroxydopamine infusions
      in the striatum produced akinetic deficits in rats trained to release a lever
      after a stimulus in a reaction time (RT) task. At 2 weeks after the lesion, A2A
      and mGlu5 receptors selective antagonists 8-(3-chlorostyryl)caffeine (CSC) and 2
      methyl-6-(phenylethynyl)-pyridine (MPEP) were administered daily for 3 weeks
      either as a single or joint treatment. Injections of CSC (1.25 mg/kg) and MPEP
      (1.5 mg/kg) separately or in combination reduced the increase of delayed
      responses and RTs induced by 6-OHDA lesions, while the same treatment had no
      effect in controls. Furthermore, coadministration of lower doses of 0.625 mg/kg
      CSC and 0.375 mg/kg MPEP noneffective as a single treatment promoted a full and
      immediate recovery of akinesia, which was found to be more efficient than the
      separate blockade of these receptors. These results demonstrate that the combined
      inactivation of A2A and mGlu5 receptor potentiate their beneficial effects
      supporting this pharmacological strategy as a promising anti-Parkinsonian
      therapy.

PMID- 15039772
TI  - Does prenatal nicotine exposure sensitize the brain to nicotine-induced
      neurotoxicity in adolescence?
AB  - Offspring of women who smoke during pregnancy are themselves more likely to take
      up smoking in adolescence. We evaluated neurotoxicant effects of prenatal and
      adolescent nicotine exposure in developing rats to evaluate whether these
      contribute to a biological basis for this relationship. Rats were given nicotine
      or vehicle throughout pregnancy and the offspring then again received nicotine or
      vehicle during adolescence (postnatal days PN30-47.5); this regimen reproduces
      the plasma nicotine levels found in smokers. Indices of neural cell number (DNA
      concentration and content), cell size (protein/DNA ratio), and cell membrane
      surface area (membrane/total protein) were then evaluated in brain regions during
      adolescent nicotine administration (PN45) and up to 1 month post-treatment. By
      itself, prenatal nicotine administration produced cellular alterations that
      persisted into adolescence, characterized by net cell losses in the midbrain and
      to a lesser extent, in the cerebral cortex, with corresponding elevations in the
      membrane/total protein ratio. The hippocampus showed a unique response, with
      increased DNA content and regional enlargement. Adolescent nicotine treatment
      alone had similar, albeit smaller effects, but also showed sex-dependence, with
      effects on protein biomarkers preferential to females. When animals exposed to
      nicotine prenatally were then given nicotine in adolescence, the net outcome was
      worsened, largely representing summation of the two individual effects. Our
      results indicate that prenatal nicotine exposure alters parameters of cell
      development lasting into adolescence, where the effects add to those elicited
      directly by adolescent nicotine; neurotoxicant actions may thus contribute to the
      association between maternal smoking and subsequent smoking in the offspring.

PMID- 15039774
TI  - Kinetochore fibre dynamics outside the context of the spindle during anaphase.
AB  - Chromosomes move polewards as kinetochore fibres shorten during anaphase. Fibre
      dynamics and force production have been studied extensively, but little is known
      about these processes in the absence of the spindle matrix. Here we show that
      laser-microbeam-severed kinetochore fibres in the cytoplasm of grasshopper
      spermatocytes maintain a constant length while turning over in a polarized
      manner. Tubulin incorporates at or near the kinetochore and translocates towards
      severed ends without shortening the fibre. Consequently, the chromosome cannot
      move polewards unless the severed fibre reattaches to the pole through
      microtubules. A potential seclusion artefact has been ruled out, as fibres
      severed inside spindles behave identically despite being surrounded by the
      spindle matrix. Our data suggest that kinetochore microtubules constantly
      treadmill during anaphase in insect cells. Treadmilling is an intrinsic property
      of microtubules in the kinetochore fibre, independent of the context and
      attachment of the spindle. The machinery that depolymerizes minus ends of
      kinetochore microtubules is functional in a non-spindle context. Attachment to
      the pole, however, is required to cause net kinetochore fibre shortening to
      generate polewards forces during anaphase.

PMID- 15039775
TI  - Interactions of GGA3 with the ubiquitin sorting machinery.
AB  - The Golgi-localized, gamma-ear-containing, Arf-binding (GGA) proteins constitute
      a family of clathrin adaptors that are mainly associated with the trans-Golgi
      network (TGN) and mediate the sorting of mannose 6-phosphate receptors. This
      sorting is dependent on the interaction of the VHS domain of the GGAs with acidic
      cluster-dileucine signals in the cytosolic tails of the receptors. Here we
      demonstrate the existence of another population of GGAs that are associated with
      early endosomes. RNA interference (RNAi) of GGA3 expression results in
      accumulation of the cation-independent mannose 6-phosphate receptor and
      internalized epidermal growth factor (EGF) within enlarged early endosomes. This
      perturbation impairs the degradation of internalized EGF, a process that is
      normally dependent on the sorting of ubiquitinated EGF receptors (EGFRs) to late
      endosomes. Protein interaction analyses show that the GGAs bind ubiquitin. The
      VHS and GAT domains of GGA3 are responsible for this binding, as well as for
      interactions with TSG101, a component of the ubiquitin-dependent sorting
      machinery. Thus, GGAs may have additional roles in sorting of ubiquitinated
      cargo.

PMID- 15039776
TI  - GGA proteins bind ubiquitin to facilitate sorting at the trans-Golgi network.
AB  - Ubiquitination functions as a sorting signal for lysosomal degradation of cell
      surface proteins by facilitating their internalization from the plasma membrane
      and incorporation into lumenal vesicles of multivesicular bodies (MVBs).
      Ubiquitin may also mediate sorting of proteins from the trans-Golgi network (TGN)
      to the endosome, thereby preventing their appearance on the cell surface and
      hastening their degradation in the lysosome-vacuole. Substantiation of a direct
      ubiquitin-dependent TGN sorting pathway relies in part on identifying candidate
      machinery that may function as a ubiquitin-sorting 'receptor'at the TGN. Members
      of the GGA family of coat proteins localize to the TGN and promote the
      incorporation of proteins into clathrin-coated vesicles destined for transport to
      endosomes. We show that the GGA coat proteins bind directly to ubiquitin through
      their GAT domain and demonstrate that this interaction is required for the
      ubiquitin-dependent sorting of the Gap1 amino acid transporter from the TGN to
      endosomes. Thus, GGA proteins fulfill the role of ubiquitin sorting receptors at
      the TGN.

PMID- 15039777
TI  - Polypyrimidine tract-binding protein promotes insulin secretory granule
      biogenesis.
AB  - Pancreatic beta-cells store insulin in secretory granules that undergo exocytosis
      upon glucose stimulation. Sustained stimulation depletes beta-cells of their
      granule pool, which must be quickly restored. However, the factors promoting
      rapid granule biogenesis are unknown. Here we show that beta-cell stimulation
      induces the nucleocytoplasmic translocation of polypyrimidine tract-binding
      protein (PTB). Activated cytosolic PTB binds and stabilizes mRNAs encoding
      proteins of secretory granules, thus increasing their translation, whereas
      knockdown of PTB expression by RNA interference (RNAi) results in the depletion
      of secretory granules. These findings may provide insight for the understanding
      and treatment of diabetes, in which insulin secretion is typically impaired.

PMID- 15039778
TI  - Abl-dependent tyrosine phosphorylation of Sos-1 mediates growth-factor-induced
      Rac activation.
AB  - The non-receptor tyrosine kinase Abl participates in receptor tyrosine kinase
      (RTK)-induced actin cytoskeleton remodelling, a signalling pathway in which the
      function of Rac is pivotal. More importantly, the activity of Rac is
      indispensable for the leukaemogenic ability of the BCR-Abl oncoprotein. Thus, Rac
      might function downstream of Abl and be activated by it. Here, we elucidate the
      molecular mechanisms through which Abl signals to Rac in RTK-activated pathways.
      We show that Sos-1, a dual guanine nucleotide-exchange factor (GEF), is
      phosphorylated on tyrosine, after activation of RTKs, in an Abl-dependent manner.
      Sos-1 and Abl interact in vivo, and Abl-induced tyrosine phosphorylation of Sos-1
      is sufficient to elicit its Rac-GEF activity in vitro. Genetic or pharmacological
      interference with Abl (and the related kinase Arg) resulted in a marked decrease
      in Rac activation induced by physiological doses of growth factors. Thus, our
      data identify the molecular connections of a pathway RTKs-Abl-Sos-1-Rac that is
      involved in signal transduction and actin remodelling.

PMID- 15039779
TI  - Minimal nuclear pore complexes define FG repeat domains essential for transport.
AB  - Translocation through nuclear pore complexes (NPCs) requires interactions between
      receptor-cargo complexes and phenylalanine-glycine (FG) repeats in multiple FG
      domain-containing NPC proteins (FG-Nups). We have systematically deleted the FG
      domains of 11 Saccharomyces cerevisiae FG-Nups in various combinations. All five
      asymmetrically localized FG domains deleted together were non-essential. However,
      specific combinations of symmetrically localized FG domains were essential. Over
      half the total mass of FG domains could be deleted without loss of viability or
      the NPC's normal permeability barrier. Significantly, symmetric deletions caused
      mild reductions in Kap95-Kap60-mediated import rates, but virtually abolished
      Kap104 import. These results suggest the existence of multiple translocation
      pathways.

PMID- 15039780
TI  - MKK7 couples stress signalling to G2/M cell-cycle progression and cellular
      senescence.
AB  - During the development of multicellular organisms, concerted actions of molecular
      signalling networks determine whether cells undergo proliferation,
      differentiation, death or ageing. Here we show that genetic inactivation of the
      stress signalling kinase, MKK7, a direct activator of JNKs in mice, results in
      embryonic lethality and impaired proliferation of hepatocytes. Beginning at
      passage 4-5, mkk7(-/-) mouse embryonic fibroblasts (MEFs) display impaired
      proliferation, premature senescence and G2/M cell cycle arrest. Similarly, loss
      of c-Jun or expression of a c-JunAA mutant in which the JNK phosphorylation sites
      were replaced with alanine results in a G2/M cell-cycle block. The G2/M cell
      cycle kinase CDC2 was identified as a target for the MKK7-JNK-c-Jun pathway.
      These data show that the MKK7-JNK-c-Jun signalling pathway couples developmental
      and environmental cues to CDC2 expression, G2/M cell cycle progression and
      cellular senescence in fibroblasts.

PMID- 15039781
TI  - Speaking up.

PMID- 15039783
TI  - GGAing ubiquitin to the endosome.

PMID- 15039785
TI  - To cluster or not to cluster: FRETting over rafts.

PMID- 15039787
TI  - Translating prions at the synapse.

PMID- 15039786
TI  - Correcting SYNful attachments.

PMID- 15039784
TI  - Robbing from the pore.

PMID- 15039788
TI  - Resolving a Holliday romance.

PMID- 15039789
TI  - A SNAP decision in neural cell fate.

PMID- 15039791
TI  - Transduction peptides: from technology to physiology.
AB  - During the past fifteen years, a variety of peptides have been characterized for
      their ability to translocate into live cells. Most are efficient vectors that can
      internalize hydrophilic cargoes, and so provide a valuable biological (and
      potentially therapeutic) tool for targeting proteins into cells. Furthermore,
      translocation of cell-permeable peptides across the plasma membrane and their
      subsequent access to the cytosol, even when fused to large hydrophilic proteins,
      is challenging the perception of the plasma membrane as an impermeable barrier.

PMID- 15039792
TI  - Using environmental concentrations of cadmium and lead to assess human exposure
      and dose.
AB  - OBJECTIVES: Using environmental concentrations and Geographic Information Systems
      (GIS) to model human exposure is an emerging tool in environmental epidemiology.
      To evaluate the usefulness of this, we investigated to what extent cadmium and
      lead concentrations in soil and moss could be used as potential determinants for
      cadmium and lead exposure for a population living near a battery plant. METHODS:
      Cadmium in urine and blood and lead in blood, as well as food, smoking habits,
      places of residence, occupations and health, were determined for 512 individuals
      living near a closed down battery factory in Sweden. Cadmium and lead contents in
      moss were available through previous assessments by the Geological Survey of
      Sweden. Soil samples had been collected at various distances from the factory,
      and analyzed for cadmium and lead contents in 1990. Kriging technique in GIS was
      used to create areas with different metal concentrations based on these
      measurements. By linking individual address coordinates to mapped concentration
      levels, each study subject home address received a value of cadmium and lead in
      moss and soil. RESULTS: We found a statistically significant association between
      lead in soil and lead in blood, for female subjects eating homegrown vegetables
      regularly. No significant association was found between cadmium in soil and
      cadmium in urine for either gender in the study population. No clear associations
      were found for either gender regarding lead and cadmium in moss and lead in blood
      or cadmium in urine or in blood. CONCLUSION: In general, environmental
      concentrations may not be useful surrogates for assessing human exposure to lead
      and cadmium, but concentrations of metals in soil around emitting point sources
      can be a complement for estimating the exposure in certain subgroups.

PMID- 15039793
TI  - Contributions of children's activities to pesticide hand loadings following
      residential pesticide application.
AB  - The role of children's activities in leading to pesticide exposure was evaluated
      by comparing pesticide loadings on the hands of children with the activities of
      the same children observed over a 4-h period. In all, 10 children ranging in age
      from 24 to 55 months were videotaped on the second day following a routine
      professional crack and crevice chlorpyrifos application in their homes. Before
      and following the video session, the children's hands were rinsed in isopropyl
      alcohol. Thus, only the chlorpyrifos that accumulated on and remained on the
      child's hands during the videotaping were removed for analysis after the
      videotaping session. The rinsate was analyzed for chlorpyrifos. The children's
      behaviors were quantified using virtual tracking device and the frequency and
      duration of behaviors, the hourly rate of behaviors, and the locations in which
      behaviors occurred were compared to hand loadings of pesticides. Pesticide hand
      loadings obtained following the videotaping sessions were associated with
      pesticide levels on surfaces and toys, but not with air levels. Pesticide
      loadings obtained following the videotaping sessions were also associated with
      frequencies, durations, and hourly rates of contact with bottles, and object-to
      mouth behaviors, as well as contact duration with upholstered/textured surfaces.
      The hand loadings were also associated with the number of locations where the
      children exhibited object-to-mouth behavior and with children's use of house
      space during the videotaping sessions.

PMID- 15039794
TI  - Evaluation and quality control of personal nephelometers in indoor, outdoor and
      personal environments.
AB  - Personal nephelometers provide useful real-time measurements of airborne
      particulate matter (PM). Recent studies have applied this tool to assess personal
      exposures and related health effects. However, a thorough quality control (QC)
      procedure for data collected from such a device in a large-scale exposure
      assessment study is lacking. We have evaluated the performance of a personal
      nephelometer (personal DataRAM or pDR) in the field. We present here a series of
      post hoc QC procedures for improving the quality of the pDR data. The
      correlations and the ratios between the pDRs and the collocated gravimetric
      measurements were used as indices of the pDR data quality. The pDR was operated
      in four modes: passive (no pump), active (with personal sampling pumps), active
      with a heated inlet, and a humidistat. The pDRs were worn by 21 asthmatic
      children, placed at their residences indoors and outdoors, as well as at a
      central site. All fixed-site pDRs were collocated with Harvard Impactors for
      PM2.5 (HI2.5). By examining the differences between the time-weighted average
      concentrations calculated from the real-time pDRs' readings and recorded
      internally by the pDRs, we identified 9.1% of the pDRs' measurements suffered
      from negative drifts. By comparing the pDRs' daily base level with the HI2.5
      measurements, we identified 5.7% of the pDRs' measurements suffered from positive
      drifts. High relative humidity (RH) affected outdoor pDR measurements, even when
      a heater was used. Results from a series of chamber experiments suggest that the
      heated air stream cooled significantly after leaving the heater and entering the
      pDR light-scattering chamber. An RH correction equation was applied to the pDR
      measurements to remove the RH effect. The final R2 values between the fixed-site
      pDRs and the collocated HI2.5 measurements ranged between 0.53 and 0.72. We
      concluded that with a carefully developed QC procedure, personal nephelometers
      can provide high-quality data for assessing PM exposures on subjects and at fixed
      locations. We also recommend that outdoor pDRs be operated in the active mode
      without a heater and that the RH effect be corrected with an RH correction
      equation.

PMID- 15039795
TI  - Exposure to phthalate esters from indoor environment.
AB  - Phthalate esters and phosphate esters in samples of indoor air from 27 houses in
      the Tokyo Metropolitan area were quantified using gas chromatograph/mass
      spectrometer and gas chromatograph/flame photometric detector after adsorption on
      to charcoal and solvent extraction. The median concentrations of diethyl
      phthalate, dibutyl phthalate (DBP), butylbenzyl phthalate, dicyclohexyl phthalate
      and diethylhexyl phthalate were 0.10, 0.39, 0.01, 0.07 and 0.11 microg/m(3),
      respectively. The median concentrations of tributyl phosphate, tris(2
      chloroethyl) phosphate, triphenyl phosphate and tris(2-butoxyethyl) phosphate
      were less than 0.001 microg/m(3). DBP was detected at the highest concentration
      (6.18 microg/m(3)) in a new residential housing. This research indicated that
      exposure to phthalate esters through inhalation of air from the indoor
      environment is as important as dietary intake of phthalate esters, and can
      contribute to daily intake to a much greater extent than has been assumed
      hitherto.

PMID- 15039798
TI  - Out of the dog house: the emergence of the canine genome.

PMID- 15039796
TI  - Customers' exposure to PM2.5 and polycyclic aromatic hydrocarbons in
      smoking/nonsmoking sections of 24-h coffee shops in Taiwan.
AB  - In Taiwan 24-h coffee shops have become popular gathering areas for young people.
      This study assesses customers' exposures to PM(2.5) and gaseous/particulate
      polycyclic aromatic hydrocarbons (PAHs) in such an environment. Potential
      influential factors were also evaluated. Two coffee shops with different types of
      smoking/nonsmoking divisions were selected. Sampling was conducted from 1300 to
      2100 hours on Saturdays and Sundays during December 2000 and January 2001.
      Personal environmental monitors mounted with Teflon filters and polyurethane
      foams were used for particulate and gaseous sampling. PAHs were analyzed with GC
      FID. Principal component analysis was used to explore the differences in the
      patterns of gaseous and particulate PAHs. Stepwise regression analysis was used
      to evaluate the contribution of various factors. The geometric mean (GM) of
      PM(2.5), particulate and gaseous PAH exposures were 83.7, 0.46 and 1.01
      microg/m(3), respectively. Their exposure concentrations were about two to five
      times those of residential indoor environments in Taiwan. Smoking and vehicle
      exhaust were two major exposure sources. The gaseous PAH concentrations in the
      two sections of both shops were significantly correlated. The divisions between
      smoking and nonsmoking sections in neither of the coffee shops were effective to
      prevent dispersion of gaseous pollutants. In both shops, the concentrations of
      PM(2.5) and associated PAHs, respectively, were about 22-28 microg/m(3) and 0.07
      microg/m(3) higher in smoking areas compared to nonsmoking areas. It was also
      found that each additional cigarette resulted in a 0.22-0.42 microg/m(3) PM(2.5)
      incremental increase in nonsmoking customers' exposure in the smoking section.

PMID- 15039797
TI  - Participants' exposure to PM2.5 and gaseous/particulate polycyclic aromatic
      hydrocarbons during the Ma-tsu Goddess parade.
AB  - The Ma-tsu Goddess parade is a very special religious tradition in Taiwan
      attracting thousands of believers every year. This parade is an 8-day-and-7-night
      event and the entire walking distance is about 280 km. This study assesses
      participants' exposure to PM(2.5), and gaseous and particulate PAHs. The
      contribution of various exposure factors was also evaluated. Sampling was
      conducted during the entire parade period in 2001. Exposures of participants who
      were riding motorcycles or driving cars were assessed. Personal environmental
      monitors mounted with Teflon filters and polyurethane foams were used for
      particulate and gaseous sampling. PAHs were analyzed with GC-FID. Stepwise
      regression analysis was used to evaluate the contribution of various factors,
      including the number of temples visited each day, the duration of temple visits,
      the number of temple co-visitors, visitors riding motorcycles or driving cars,
      etc. During the Ma-tsu Goddess parade, the mean PM(2.5), particulate and gaseous
      PAH exposures were around 119 +/- 60.8, 0.36 +/- 0.23 and 0.86 +/- 0.48
      microg/m(3), respectively. Participants' PM(2.5) and particulate PAH exposures
      were about two to three times the exposure during daily routines. The profiles of
      16 PAH species in the particulate and gaseous phases for participants' and normal
      daily exposures were also different. Incense smoke and vehicle exhaust were two
      important sources. Worshippers would be exposed to 0.096 microg/m(3) more PM(2.5)
      for every incremental minute in temples. In addition, motorcyclists were exposed
      to 0.21 microg/m(3) higher particulate PAHs than the car drivers.

PMID- 15039801
TI  - [Trust, boners and throw of the dice].

PMID- 15039802
TI  - [Activated protein C in sepsis].

PMID- 15039803
TI  - [Different practice in hysterectomy].

PMID- 15039805
TI  - [Glycine].
AB  - BACKGROUND: Glycine is an essential component of important biological molecules,
      a key substance in many metabolic reactions, the major inhibitory
      neurotransmitter in the spinal cord and brain stem, and has anti-inflammatory,
      cytoprotective, and immunomodulatory qualities. MATERIAL AND METHODS: Based on
      available literature we discuss some important biological properties of glycine
      and give a short account of our own studies in this field. RESULTS: The main area
      of glycine research has traditionally been associated with its role as a
      neurotransmitter in the central nervous system. During the last few years there
      has been a mounting interest in effects on other organs and tissues as well.
      Glycine-gated chloride channels, originally demonstrated on neurons in the
      central nervous system, have been found on most leukocytes and a number of other
      cell types. This has provided a unifying mechanism of action that explains how
      glycine may influence such important and diverse biological processes as
      transmission of nerve signals and initiation of the immune response.
      INTERPRETATION: Glycine is a simple, easily available and inexpensive substance
      with few and innocuous side effects. Despite the recent unveiling of tantalizing
      aspects regarding its mechanism of action, biological activities and therapeutic
      potential, clinical use has remained scant.

PMID- 15039806
TI  - [Plasmapheresis in the treatment of septic shock].
AB  - BACKGROUND: Sepsis is an increasingly common cause of morbidity and mortality and
      the leading cause of death in intensive care units. In recent years many new
      therapies for sepsis have been tested in randomised clinical trials, but most of
      them have failed to reduce mortality. Plasmapheresis is a nonselective method by
      which plasma is separated from the blood and replaced with donor plasma and/or
      albumin. The theoretical rationale is that plasmapheresis removes the harmful
      mediators and replenishes the consumed plasma factors, thus restoring the
      homeostatic milieu. MATERIALS AND METHODS: This article is based upon own
      research and a review of the current literature found in PubMed. RESULTS: Over
      the last 30 years, several experimental and clinical studies have reported a
      beneficial effect of plasmapheresis in the treatment of patients with severe
      sepsis and septic shock. Most of the studies have focused on Gram-negative
      sepsis. Only a few of the clinical studies are prospective, randomised trials
      with appropriate control groups. INTERPRETATION: There is not sufficient evidence
      to justify the use of plasmapheresis as standard treatment of patients with
      severe sepsis and septic shock. However, plasmapheresis should be considered for
      fulminant Gram-negative septic shock. If applied, it should be started urgently
      and repeated in unresponsive patients and when a patient's clinical condition is
      deteriorating.

PMID- 15039804
TI  - [Treatment of T-cell prolymphocytic leukemia with monoclonal anti- CD52 antibody
      (alemtuzumab].
AB  - INTRODUCTION: T-cell prolymphocytic leukaemia (T-PLL) is a rare post-thymic T
      cell malignancy with an aggressive clinical course. It has generally been
      resistant to alkylating chemotherapy, but some effect has been observed with the
      purine analog 2-deoxycoformicin with documented partial or complete response
      rates in up to 45% of patients. Treatment with monoclonal antibodies against CD
      52 has been shown to be highly effective in T-PLL with response rates of up to
      76%. This may allow for further consolidating treatment with high-dose
      chemotherapy with autologous stem cell support or allogeneic stem cell
      transplantation. MATERIALS AND METHODS: Five patients treated at Rikshospitalet
      University Hospital are evaluated and the literature on T-PLL is reviewed.
      RESULTS AND INTERPRETATION: Four of our patients were treated with alemtuzumab.
      Three showed complete or partial response. One patient underwent allogeneic stem
      cell transplantation with an HLA-identical sibling, but died on day 21 as a
      result of transplantation complications. The treatment is generally well
      tolerated; the principal management problem is immunosuppression, as shown in one
      patient who developed a varicella-zoster meningoencephalomyelitis as a
      consequence of not receiving antiviral prophylaxis. The main infusion-related
      adverse effects are fever and chills.

PMID- 15039807
TI  - [Severe sepsis treated with activated protein C].
AB  - BACKGROUND: Severe sepsis is a common cause of mortality in critically ill
      patients. Drotrecogin alfa (activated), synonymous with recombinant human
      activated protein C (rhAPC), is a new therapeutic tool with anticoagulant, anti
      inflammatory and profibrinolytic properties with proven effect in reducing
      mortality in severe sepsis. MATERIAL AND METHODS: As part of a multi-centre
      study, the patients received an infusion of rhAPC, 24 microg/kg/h for 96 hours
      according to an open-labeled phase IIIb study protocol. RESULTS: Out of a total
      of 28 patients, 6 (21%) died before day 28. One of the deaths was classified as
      possibly related to rhAPC. In three patients rhAPC was transiently stopped
      because of surgery or postoperative bleeding. Use of the compound rarely
      interfered with commonly used diagnostic and therapeutic procedures.
      INTERPRETATION: Treatment with rhAPC is easily carried out in an intensive care
      unit. Patients with severe sepsis and two or more failing vital organs should be
      considered for treatment with rhAPC.

PMID- 15039808
TI  - [Should patients with severe sepsis be treated with activated protein C?].
AB  - BACKGROUND: Xigris (recombinant human activated protein C) has recently been
      introduced as a treatment for severe sepsis following a large multicentre trial
      (the PROWESS trial). MATERIAL AND METHODS: Critical review of the original paper,
      follow-up studies and commentaries, and subgroup analyses from the US Food and
      Drug Administration. RESULTS: Changes in trial design after the start of the
      trial as well as inconsistent results in two phases of the trial make
      interpretation difficult. The overall trial results indicate a small benefit from
      treatment with activated protein C. However, subgroup analysis reveals that
      several groups of patients appeared to have little benefit. The drug may have
      severe and potentially lethal side effects in some patients. INTERPRETATION:
      Although activated protein C may have beneficial effects in some patients with
      severe sepsis, the effect on different subgroups of patients remains to be
      clarified. We conclude that there is at present insufficient documentation for a
      recommendation of activated protein C in patients with severe sepsis.

PMID- 15039809
TI  - [Is transmission of heart murmurs via e-mail cost saving?].
AB  - BACKGROUND: The use of pre-recorded heart murmur in an electronic referral for a
      remote consultation can save children and their parents from having to travel to
      the nearest out-patient clinic. The heart sound can be recorded by the GP at the
      local health clinic and sent by e-mail to the specialist. 41 clinics in the North
      Norway healt region have invested in equipment that makes pre-recorded sound
      referrals possible. This study analyses whether this investment is a cost-saving
      technology or not. METHODS: A yearly average of 50 children with a heart murmur
      are referred to a specialist in Troms. The costs of using pre-recorded
      telemedicine were compared to the costs of patient travelling to the nearest
      secondary care centre. RESULTS: Pre-recorded heart sound referrals cost from 216
      000 NOK more per year than the alternative of bringing patients to the out
      patient clinic. The number of children with a heart murmur needed in order to
      break even must exceed 195 per year, i.e. 1.7 children per GP per year.
      INTERPRETATION: The number of children with a heart murmur in Troms is too low
      for this method to be a cost-saving approach.

PMID- 15039810
TI  - [Treatment of hypertension in patients with left ventricular hypertrophy].
AB  - BACKGROUND: The LIFE study (Losartan Intervention For Endpoint reduction in
      hypertension) is a randomized, double-blind comparison of losartan and atenolol
      based treatment. The study hypothesis was that losartan would reduce
      cardiovascular morbidity and mortality more than traditional antihypertensive
      treatment with atenolol. MATERIAL AND METHODS: The study included 9193 patients
      in seven countries. RESULTS: By the end of the study, the mean dose was losartan
      82 mg and atenonol 79 mg, whereas 94% of patients in both groups received
      additional hydrochlorothiazide. Blood pressure was reduced 30/17 mmHg by losartan
      and 29/17 mm Hg by atenolol. Despite the same reduction in blood pressure, the
      primary combined endpoint (cardiovascular mortality, non-fatal stroke and
      myocardial infarction) was reduced by 13.0% (p = 0.021) in the losartan group.
      Non-fatal and fatal strokes were reduced by 24.9% (p = 0.001). In two pre
      specified subgroup analyses, cardiovascular mortality was reduced by 46% (p =
      0.01) in patients with isolated systolic hypertension (n = 1326), and total
      mortality was reduced by 39% (p = 0.002) in patients with diabetes (n = 1159).
      INTERPRETATION: Losartan prevented more cardiovascular complications than
      atenolol for the same reduction in blood pressure and have positive additional
      effects beyond blood pressure control in patients with hypertension and left
      ventricular hypertrophy.

PMID- 15039812
TI  - [Short-term outcome after hysterectomy for benign disease].
AB  - BACKGROUND: Since 1990 in Norway, vaginal and laparoscopic hysterectomies have
      replaced laparotomy in 22% of patients with benign disease. This observational
      study describes the short-term outcome of hysterectomy at Vestfold Hospital.
      MATERIAL AND METHOD: 315 women with benign disease and no prolapse who had a
      hysterectomy done in 2000-2001 were included. 41% of the procedures were vaginal
      or laparoscopic. RESULTS: Supravaginal hysterectomy and vaginal hysterectomy
      required the shortest surgical time. 29% of all cases were complicated. There
      were seven bladder lesions, no ureteric lesions and one small bowel perforation.
      4.4% had a reoperation. Patients not having a laparotomy had the shortest
      hospital stay. INTERPRETATION: Bladder injuries and infections were more frequent
      than in other Nordic reports. The use of antibiotic prophylaxis led to fewer
      infections. When vaginal or laparoscopic hysterectomy is feasible, such
      operations may shorten hospital stay.

PMID- 15039811
TI  - [Which factors affect the choice of method for hysterectomy in benign disease?].
AB  - BACKGROUND: At Vestfold Hospital hysterectomy for benign disease is performed by
      five different methods with 14 subvariants. There are no national guidelines for
      choice of procedure. This study reports some of the preoperative patient
      characteristics and compares our hysterectomy data with national data. MATERIAL
      AND METHOD: 315 patients who had a hysterectomy at Vestfold Hospital in 2000-2001
      were included. A central registry (Norwegian Patient Register) supplied
      hysterectomy data for 51 other Norwegian hospitals. RESULTS: Hysterectomy was
      done by laparotomy in 59% of patients in our hospital compared to a national mean
      of 78%. Concomitant oophorectomy was done in 43% of our cases and 31% in all
      hospitals. Patient having similar preoperative characteristics at our hospital
      often had different procedures. There were wide variations between hospitals with
      regard to hysterectomy methods. INTERPRETATION: Patient characteristics only
      partly explain the choice of hysterectomy method in our hospital. Divergent
      hysterectomy practice in Norwegian hospitals reflects a lack of consensus between
      gynaecologists and perhaps suboptimal operative competence.

PMID- 15039813
TI  - [Treatment of gastroesophageal reflux in pregnant women].

PMID- 15039815
TI  - [Hypertension and heart disease].
AB  - Hypertension commonly leads to heart disease, in particular left ventricular
      hypertrophy, heart failure and coronary artery disease. Left ventricular
      hypertrophy and coronary artery disease are both often subclinical diseases in
      hypertensives. Symptomatic coronary artery disease in hypertension may be due to
      atherosclerosis in epicardial arteries, microvascular dysfunction, reduced
      fibrinolytic capacity, or left ventricular hypertrophy; the latter is present in
      20-50% of patients with mild to moderate and in up to 90% of patients with severe
      hypertension. Left ventricular hypertrophy in hypertension is associated with a
      twofold increase in risk of myocardial infarction, sudden death and stroke, and a
      fourfold increase in risk of heart failure. While coronary artery disease is the
      most common cause of heart failure in men, hypertension and in particular
      untreated isolated systolic hypertension is the most common cause in women. Heart
      failure symptoms may be subtle in hypertension, like tiredness or reduced
      physical capacity. Echocardiography can reveal subclinical heart disease as well
      as serve as a guide to correct diagnosis and treatment.

PMID- 15039814
TI  - [How to identify individuals with elevated cardiovascular risk?].
AB  - In spite of a substantial decline in the morbidity and the mortality from
      coronary heart disease in Norway since 1970-1975, cardiovascular disease remains
      the leading cause of death. The prevention of premature cardiovascular disease
      includes a mass strategy as well an individual strategy. While the first aims at
      changing life habits in the whole population, the latter is directed towards
      individuals with elevated cardiovascular risk. Non-pharmacological and
      pharmacological modes of treatment have been demonstrated to be effective in
      reducing cardiovascular events. However, the value of such measures depends on
      our ability to identify high-risk individuals. This paper describes different
      approaches in preventive medicine, from population screening to the screening of
      relatives of patients with premature disease. While doctors previously focused on
      whether blood pressure or cholesterol levels were above the defined limits, a
      global risk assessment is now recommended. Information regarding family history,
      smoking and exercise habits, lipid values, blood pressure, and the presence of
      diabetes must be obtained in a proper risk assessment. In some individuals with
      intermediate risk, additionally non-invasive tests may be of value in order to
      ensure that sufficient information has been obtained for a recommendation of
      preventive measures.

PMID- 15039816
TI  - [Rehabilitation of cardiac patients].
AB  - Cardiac rehabilitation has gradually been accepted as an important part of the
      management of patients after acute myocardial infarction and cardiac surgery. The
      paper describes indications, effects and mechanisms of physical importance
      concerning physical training in cardiac patients and gives an overview of some
      important studies on cardiac rehabilitation over the last 30 years, as well as
      practical advice concerning rehabilitation of heart patients.

PMID- 15039817
TI  - [Do general practitioners know what medication community nurses give their shared
      patients?].
AB  - BACKGROUND: Frail elderly outpatients often receive medicines from community
      nurses. There is little knowledge of how general practitioners (GPs) and nurses
      update and coordinate their medication lists for their shared patients. MATERIAL
      AND METHODS: Lists of regular medication for 90 randomly selected shared patients
      from GPs as well as community nurses were assessed with respect to agreement. An
      agreement score was calculated for number of medicines and for each drug: total
      daily dosage and dose regimen. Routines for updating medication lists were
      addressed in a questionnaire to GPs and community nurses. RESULTS: For three out
      of four patients, discrepancies were found between physicians' and nurses' lists
      of regular medication. 52% of the discrepancies were in relation to
      cardiovascular drugs and psychotropic drugs. Only 41% of the GPs reported
      explicit routines for updating their medication lists. INTERPRETATION: The GPs'
      lack of knowledge of what their patients actually receive may contribute to
      medication errors and adverse drug reactions.

PMID- 15039819
TI  - [The scandal in Bristol and its effect on the British health services].

PMID- 15039820
TI  - [Extremely unclear biotechnology legislation].

PMID- 15039818
TI  - [The length of the patient list, waiting lists, workload and job satisfaction
      among general practitioners in Bergen].
AB  - BACKGROUND: A list patient system was established in Norway in June 2001. Among
      general practitioners (GPs) there were much concern about workload according to
      list length, and about uneven distribution of workload among GPs. MATERIAL AND
      METHODS: In February 2003 a questionnaire about working hours, waiting time for
      appointments and job satisfaction was sent to all GPs in Bergen. RESULTS: 160 out
      of 185 (85%) GPs replied. Working hours were closely related to list length,
      waiting time was not. 79% had a waiting time of less than eight "days in
      practice". 46% rated their job satisfaction within the list system as "good/very
      good", 37% were moderately satisfied. We found lower scores among GPs with long
      waiting time and a full list. No relevant differences between male and female GPs
      were found. INTERPRETATION: GPs adjust their working hours in order to cope with
      waiting time. Job satisfaction is lower when the GP has a waiting time of more
      than three weeks and a full list, factors that could indicate a heavy workload.

PMID- 15039822
TI  - [Russian general practice].

PMID- 15039823
TI  - [Consent in connection with plastic surgery in children and adolescents].

PMID- 15039824
TI  - [Can hydrochlorothiazide and chlorthalidone be compared in the treatment of
      hypertension?].

PMID- 15039825
TI  - [Tendentious research on water quality].

PMID- 15039827
TI  - [Retinoblastoma--hereditary eye cancer in children?].

PMID- 15039834
TI  - Marine natural products.
AB  - This review covers the literature published in 2002 for marine natural products,
      with 579 citations (413 for the period January to December 2002) referring to
      compounds isolated from marine microorganisms and phytoplankton, green algae,
      brown algae, red algae, sponges, coelenterates, bryozoans, molluscs, tunicates
      and echinoderms. The emphasis is on new compounds (677 for 2002), together with
      their relevant biological activities, source organisms and country of origin.
      Syntheses that lead to the revision of structures or stereochemistries have been
      included (114), including any first total syntheses of a marine natural product.

PMID- 15039835
TI  - Investigations of the marine flora and fauna of the Islands of Palau.
AB  - The Islands of Palau have proven to be an excellent source of bioactive marine
      natural products primarily as a result of the systematic studies from the late
      1970s by the research groups of Scheuer at the University of Hawaii, Faulkner at
      the Scripps Oceanographic Institution/University of California at San Diego, and
      Paul at the University of Guam. Their efforts were materially aided by the
      excellent facilities provided by the Government of Palau and for the last 10
      years, those of the NCI's shallow water collection contractor, the Coral Reef
      Research Foundation. This review covers the structures and biological activities
      where noted, of the multitudinous marine-derived natural products isolated from
      the marine flora and fauna of this nation and demonstrates the enormous variety
      of novel structures elaborated by these organisms.

PMID- 15039836
TI  - Amphidinolides, bioactive macrolides from symbiotic marine dinoflagellates.
AB  - This review covers the structures, synthesis, biosynthesis, and bioactivity of a
      series of cytotoxic macrolides, named amphidinolides, isolated from symbiotic
      marine dinoflagellates of the genus Amphidinium which were separated from inside
      cells of marine flatworms. The structures of long-chain polyketides such as
      colopsinols isolated from Amphidinium sp. are also described.

PMID- 15039837
TI  - Biofouling and antifouling.
AB  - Most benthic organisms produce planktonic larvae in their life cycles; larval
      settlement and metamorphosis are influenced by many environmental factors,
      especially chemical cues originating from conspecific adults, prey organisms, and
      substrates. On the other hand, larval settlement of other species endangers the
      survival of benthic organisms which therefore have antifouling defense. Marine
      natural products involved in biofouling and antifouling are described.

PMID- 15039838
TI  - Merging the potential of microbial genetics with biological and chemical
      diversity: an even brighter future for marine natural product drug discovery.
AB  - Marine invertebrates and a growing number of marine bacteria are the sources of
      novel, bioactive secondary metabolites. Structurally, many of these compounds
      appear to be biosynthesized by polyketide synthases (PKS) and/or nonribosomal
      peptide synthetases (NRPS) that have also been found in terrestrial microbes.
      This review highlights scientific advances from 1999-2003 in the emerging field
      of molecular genetics of polyketide and nonribosomal peptide natural products
      isolated from marine organisms. The implications of this research towards the
      development of marine secondary metabolites as a sustainable source of new drugs
      are discussed.

PMID- 15039839
TI  - Approaches to identify, clone, and express symbiont bioactive metabolite genes.
AB  - This review discusses approaches to identify, clone, and express bioactive
      metabolite genes from symbionts of marine invertebrates. Criteria for proving
      symbiotic origin of bioactive metabolites are presented, followed by a
      comprehensive, practically-oriented overview of techniques to be applied. The
      Bugula neritina/Endobugula sertula association is used as a primary example, but
      other symbioses are discussed. Thirty-six compounds are presented and 111
      references are cited.

PMID- 15039840
TI  - Marine-derived fungi: a chemically and biologically diverse group of
      microorganisms.
AB  - A diverse array of secondary metabolites have been isolated and characterized
      from marine-derived fungi. The structures and biological activities of these
      metabolites are presented. Additionally, some basic principles of mycology are
      covered. Overall, 273 structures are presented and the review contains 162
      references

PMID- 15039841
TI  - Marine isocyanides and related natural products--structure, biosynthesis and
      ecology.
AB  - This review highlights structural and biosynthetic work on a group of nitrogen
      functionalised terpenes that are almost exclusively found in marine invertebrates
      and the animals that feed on them. The chemical functionality reviewed includes
      isocyanides, isothiocyanates, formamides, thiocyanates, isocyanates, and
      dichloroimines. The literature through mid 2003 is reviewed and there are 143
      citations.

PMID- 15039842
TI  - The role of vanadium bromoperoxidase in the biosynthesis of halogenated marine
      natural products.
AB  - Halogenated natural products are frequently reported metabolites in marine
      seaweeds. These compounds span a range from halogenated indoles, terpenes,
      acetogenins, phenols, etc., to volatile halogenated hydrocarbons that are
      produced on a very large scale. In many cases these halogenated marine
      metabolites possess biological activities of pharmacological interest. Given the
      abundance of halogenated marine natural products found in marine organisms and
      their potentially important biological activities, the biogenesis of these
      compounds has intrigued marine natural product chemists for decades. Over a
      quarter of a century ago, a possible role for haloperoxidase enzymes was first
      suggested in the biogenesis of certain halogenated marine natural products,
      although this was long before haloperoxidases were discovered in marine
      organisms. Since that time, FeHeme- and Vanadium-haloperoxidases (V-HPO) have
      been discovered in many marine organisms. The structure and catalytic activity of
      vanadium haloperoxidases is reviewed herein, including the importance of V-HPO
      catalyzed bromination and cyclization of terpene substrates.

PMID- 15039843
TI  - Chemical mediation of interactions among marine organisms.
AB  - This review covers the recent marine chemical ecology literature for macroalgae,
      sponges, octocorals and other benthic invertebrates; 332 references are cited.

PMID- 15039846
TI  - [Surgical treatment for Parkinson's disease].
AB  - In the past years there has been an increasing interest in the surgical therapies
      for Parkinson's disease. This renewed interest is related to differents factors.
      First, pharmacological treatments are still unable to alter substantially the
      progression of the disease and after a few years they generally cause motor
      complications and dyskinesias. Secondly, the great advances in the surgical
      techniques, especially with the improvement of stereotactic surgery, have
      decreased morbidity in recent years. Finally, the introduction of deep brain
      stimulation, now allows surgical treatment without damaging brain structures. In
      this review, different surgical treatments are summarized. Ablative surgery, deep
      brain stimulation and reinervation therapies are described.

PMID- 15039847
TI  - [Use of teleradiology in the evaluation and management of head-injured patients.
      Results of a pilot study of a link between a district general hospital and a
      neurosurgical referral center].
AB  - Because of the centralization of neurosurgical services, many head-injured
      patients who are initially evaluated in district general hospitals need to be
      transferred to a high technology centre for neurosurgical assessment. However,
      after assessment, many of these patients are sent back to the original hospital.
      Establishing a teleradiological system between the two hospitals would eliminate
      these unnecessary transfers. OBJECTIVES: 1) to describe our initial experience
      and the results of a pilot study of the teleradiological link between a district
      general hospital and a tertiary hospital for neurosurgical assessment of head
      injured patients, 2) to describe the infrastructure and the technological support
      required for this project, 3) to analyse the effects of the teleradiological link
      in both centers (referring and receiving), 4) to evaluate the effectiveness of
      the system in avoiding unnecessary transfers, and 5) to assess its effectiveness
      in improving the speed and the quality of transfers in head-injured patients.
      MATERIAL AND METHODS: In January 1998, the Neurotraumatology Unit of Vall
      d'Hebron University Hospital established a teleradiological link with the General
      Hospital of Vic for the neurosurgical evaluation of headinjured patients. The
      General Hospital of Vic sent the patients' clinical information by fax. CT scan
      images were digitalized, compressed and prepared for transmission with the
      StatView program, and were then transmitted by modem to the receiving center. The
      duty neurosurgeon viewed the images on a PC screen using MutiView software. After
      evaluating this clinical and radiological information the neurosurgeon sent a
      report back to the referring center recommending transfer or management
      (admission, observation, etc.). RESULTS: We analyse the results of our experience
      5 years after the implantation of the teleradiological link. CONCLUSIONS: The use
      of teleradiology in the daily management of head-injured patients provides clear
      benefits and leads to a more rational use of resources, thus significantly
      reduces costs. The effectiveness of the system in reducing the interval between
      the injury and treatment in severe cases depends more on the infrastructure of
      the health system in each geographical area than on sophisticated telemedicine
      systems. These methods should be accompanied by other measures designed to hasten
      the transfer of selected patients.

PMID- 15039848
TI  - [Descompresive craniectomy in head injury. Intractable I.C.P. ].
AB  - Decompressive craniotomy is a neurosurical technique known since the origin of
      neurosurgery, but its use as a routine started at the end of the 19th century. In
      last decades, the use of decompressive craniotomy decreased, mainly because of
      poor results obtained and the advances in medical treatment of refractory
      intracranial hypertension in the Intensive Care Units. Nevertheless, in recent
      years there has been a renewed interest with the use of this surgical techique in
      young patients with head injuries and severe intracranial hypertensio'n, but no
      surgical mass lesion, as well as in patients with ischemic stroke causing life
      threatening mass effect. The authors present a series of four young patients with
      head injuries and "malignant" intracranial hypertension on whom wide craniotomies
      were performed with an excellent outcome. The literature is reviewed.

PMID- 15039849
TI  - [Decompressive craniectomy in malignant infarction of the middle cerebral
      artery].
AB  - INTRODUCTION: Medically managed malignant infarction of the middle cerebral
      artery (MCA) is associated with an 80% mortality rate. However, several studies
      report a 40-50% increase in survival rates when decompressive craniectomy is
      performed. We present our experience with such surgical treatment and a
      literature review. PATIENTS AND METHODS: Seven decompressive craniectomies were
      performed on five patients for spaceoccupying MCA infarctions. Age ranged from 33
      to 57 years-old (three males and two females). Preoperative GCS score was 9-13.
      Cranial CT was performed within the first 12 hours. Intracranial pressure (ICP)
      was continuously measured in four patients. Two infarcts occurred in the dominant
      hemisphere and three in the non-dominant side. Wide fronto-parieto-temporal
      craniectomies were performed. The duramater was opened and a large heterologous
      dura graft was placed. RESULTS: Surgery was performed on the second day after the
      onset of symptoms (median: 47 hours). Preoperative ICP ranged from 27 to 50 mmHg
      (median: 30.5 mmHg), with immediate postoperative ICP under 15 mmHg in all
      patients. Two patients (both non-dominant side) survived with good (after
      reoperation) and excellent functional outcome. They remain stable after ten and
      five months of follow-up. Three patients died five, five and thirteen days after
      admission due to uncontrollable high ICP. In our experience, bone removal itself
      was more relevant than dural opening for ICP control. Initial wide craniectomies
      may spare reoperations. CONCLUSION: The significant mortality rate reduction, a
      wide therapeutic window (2-3 days) and a low incidence of intraoperative
      complications make decompressive craniectomy a relevant treatment in malignant
      cerebral MCA infarction.

PMID- 15039850
TI  - [Brainstem gliomas].
AB  - Brainstem gliomas have been increasingly understood in the last two decades and
      they are nowadays regarded as an heterogeneous group of tumors with tendency
      towards the pediatric age, where they account for 10-20% of brain neoplasms.
      Besides the well known diffuse tumor, several subtypes, with a different
      biological behaviour, amenable to surgical resection and better prognosis, have
      been identified, giving rise to many classifications and terms. In the other way,
      attention has been recently paid to adult brainstem gliomas in contrast to
      pediatric tumors. Based on a review of the literature, we describe the different
      subtypes of brainstem gliomas, with particular interest on therapeutic approaches
      and differences between pediatric and adult tumors, employing iconography from
      our series.

PMID- 15039851
TI  - [Postraumatic subdural collections: case report and review of the literature].
AB  - Posttraumatic and postcraniectomy subdural fluid collections have been usually
      described with the general term of hygroma. Recently, different clinical entities
      have been described, such as simple or complex hygroma, subdural effusion or
      external hydrocephalus, based on the mechanisms of formation of the fluid
      collection, its biochemical composition or the characteristics exhibited in
      modern imaging studies. However, there is no agreement in the literature
      regarding the use of these terms. We report a new case of a mixed posttraumatic
      and postcraniectomy subdural fluid collection and review the literature
      concerning these entities.

PMID- 15039852
TI  - Arachnoid cyst rupture with subdural hygroma: case report and literature review.
AB  - Arachnoid cyst rupture causing subdural hygroma is rare. Twenty-one cases have
      been previously reported in the literature. We report a case of a 9-year-old boy
      presenting signs and symptoms of increased intracranial pressure due to the
      rupture of a type III arachnoid cyst causing subdural hygroma. The clinical and
      radiological findings as well as the management of the patient are discussed in
      relation to the pertinent literature.

PMID- 15039854
TI  - Video-assisted bullectomy using needlescopic instruments for spontaneous
      pneumothorax.
AB  - Patients with spontaneous pneumothorax require immediate insertion of a chest
      drain to evacuate the intrathoracic air. During video-assisted bullectomy, we
      made use of an existing chest drain hole to insert a thoracoscope or an
      endoscopic linear stapler. Video-assisted bullectomy was performed through three
      ports-two 2-mm ports and the existing chest drain hole. Therefore, no new skin
      incisions were required for the insertion of the 2-mm ports. A chest drain was
      again inserted via the existing chest drain hole after bullectomy. This procedure
      was used on 8 of 10 patients with spontaneous pneumothorax. There were no
      postoperative complications or recurrences. Thoracoscopic bullectomy using
      needlescopic instruments is technically feasible, safe, and effective. Currently,
      the procedure is indicated only for simple cases and not for the lysis of
      adhesions.

PMID- 15039855
TI  - Development and clinical application of semi-loop-shaped retractor for gasless
      laparoscopic surgery.
AB  - BACKGROUND: Gasless laparoscopy has the advantage of avoiding the risk inherent
      in pneumoperitoneum, but has not gained widespread popularity because of limited
      exposure of the operative field. Improved retraction devices are therefore
      needed. METHODS: A loop-shaped metallic retractor was designed for planar lifting
      of the anterior abdominal wall. Four types of retractor (5/6-, 3/4-, and 1/2
      circle with rod at 90 degrees, and 1/2-circle with rod at 97 degrees ) were
      studied in 15 pigs. The device was then used for 47 patients. RESULTS: The 1/2
      circle was the most smoothly inserted retractor and was significantly safer than
      the 5/6-circle (p < 0.05, Fisher's exact probability test). The 1/2-circle with
      rod at 97 degrees was utilized for clinical cases. This retractor can be readied
      within 1 min and was used successfully for all operations. CONCLUSIONS: This new
      retractor for gasless laparoscopic surgery provides good exposure and has the
      potential to enhance the performance of advanced laparoscopic surgery.

PMID- 15039856
TI  - Feasibility hazards.

PMID- 15039858
TI  - Port-site metastasis after minimally invasive cancer surgery.

PMID- 15039862
TI  - Easy and accurate targeting of deep-seated hepatic tumors under laparoscopy with
      a forward-viewing convex-array transducer.
AB  - BACKGROUND: It is technically difficult to puncture deep-seated hepatic tumors by
      conventional laparoscopic ultrasonography with a linear-array probe. We have
      developed a laparoscopic ultrasonography system with a convex-array probe.
      METHODS: The laparoscopic system used had a fixed forward-viewing convex-array
      transducer, and a guide groove for puncture was added to the back of the unit.
      These characteristics enabled us to continuously monitor the position of the
      needle tip on the ultrasonographic image immediately after puncturing on the
      liver surface. We attempted tumor puncture in 11 patients with hepatocellular
      carcinoma under a new probe guidance. RESULTS: The mean puncturing distance up to
      the tumors was 38.7 mm. All punctures were successful on the first pass and the
      tumors were treated with radiofrequency ablation. CONCLUSION: Using this new
      equipment, puncturing hepatic tumors for treatment is relatively easy,
      irrespective of the position of the tumor.

PMID- 15039864
TI  - The laparoscopic sponge.
AB  - PURPOSE: Hemorrhage and spillage of enteric contents during laparoscopic surgery
      can be problematic and obscure the operative field. Although the suction device
      can often clear the field, we have found that use of a sponge is often more
      efficient and effective. MATERIAL AND METHODS: An unrolled 4 x 4 sponge can be
      introduced down a 10-mm port without difficulty. The addition of a suture tied to
      one corner of the sponge allows easy retrieval of the sponge and eliminates the
      possibility of leaving the sponge in the abdomen. CONCLUSIONS: The laparoscopic
      sponge is simply constructed and is easily introduced and retrieved through a
      trocar. It can be used to deal with a troublesome hemorrhage, either to put on
      direct pressure or to absorb blood. It can also be used as a blunt retractor and
      dissector. With the addition of the suture tail, it is quickly retrieved and
      cannot be forgotten within the abdomen.

PMID- 15039863
TI  - Multimedia article. Laparoscopic fundoplication in an infant.
AB  - BACKGROUND: Laparoscopic fundoplication in infants and children is rapidly
      becoming the procedure of choice for surgical correction of symptomatic
      gastroesophageal reflux because of the advantages of reduced discomfort and
      decreased hospitalization. In addition, there may be a hidden benefit of an
      earlier return to work by the parents. METHODS: This video depicts the salient
      operative features for performing a laparoscopic fundoplication in an infant who
      presented with an acute life-threatening event, which was felt secondary to
      gastroesophageal reflux. In this operation, a 5 mm cannula was placed in the
      umbilicus through which insufflation was achieved and a 5 mm, 45 degrees angled
      telescope was inserted into the peritoneal cavity. The four instruments were
      placed directly through the abdominal wall using a stab incision technique rather
      than using cannulas. Moreover, the operation was performed using AESOP, the voice
      activated telescopic holder, which provides a steady and consistent view.
      RESULTS: The operative technique was straightforward in that the short gastric
      vessels were divided, the crura were closed, and the esophagus was secured to the
      crura to keep the esophagus in an intraabdominal position and to prevent
      transmigration of the fundoplication wrap in the postoperative period. The length
      of the fundoplication should be around 2.0 cm and was measured to ensure that the
      fundoplication approximates this length. CONCLUSION: This patient made an
      eventful recovery and was discharged the following day. No complications have
      developed. [The full text of this article is a video computer file.]

PMID- 15039866
TI  - Now is not soon enough...

PMID- 15039865
TI  - Laparoscopic excision of a triple gallbladder.
AB  - Triplication of the gallbladder is a rare congenital anomaly of the biliary
      tract; there are only nine reported cases to date. We report a case in which
      laparoscopic cholecystectomy was performed in a patient with biliary colic and
      choledocholithiasis. Preoperative assessment with ultrasound and endoscopic
      retrograde cholangiopancreatography (ERCP) failed to reveal the eventual findings
      of a triple gallbladder. Successful excision of the triple gallbladder was
      carried out laparoscopically, and the final diagnosis was confirmed by the
      pathologist. The patient made an uneventful postoperative recovery and was free
      of gastrointestinal symptoms at follow-up. This case report describes the first
      laparoscopic excision of a triple gallbladder and highlights the importance of
      pre-/perioperative imaging to allow for the safe dissection of rare anomalies of
      the biliary tract via the laparoscopic approach.

PMID- 15039867
TI  - Laparoscopic extraperitoneal repair of Spigelian hernia.

PMID- 15039869
TI  - A simple technique for decompression of distended gallbladder during laparoscopic
      cholecystectomy.

PMID- 15039870
TI  - Grasping and dissecting instrument for hand-assisted laparoscopic surgery.

PMID- 15039872
TI  - Laparoscopic appendectomy for appendicular mass.

PMID- 15039874
TI  - Management of peritoneal tear during endoscopic extraperitoneal inguinal
      hernioplasty.

PMID- 15039878
TI  - Pediatric cardiology for the non-pediatric cardiologists.

PMID- 15039876
TI  - Does ischemia occur during laparoscopic cholecystectomy?

PMID- 15039879
TI  - Flail posterior leaflet of the mitral valve in acute rheumatic carditis.

PMID- 15039882
TI  - Auricular vision!

PMID- 15039885
TI  - [Interdisciplinary management of pregnant women with connective tissue diseases].
AB  - Connective tissue diseases affect frequently women during the childbearing
      period. As fertility is not considerably reduced in these patients, monitoring
      and treatment of a pregnant patient is a complex clinical setting that requires
      an intensive cooperation between gynecologists, rheumatologists and
      pediatricians. In this article, a 4-point-program for the clinical management of
      these patients is presented that addresses specifically the problems inherent
      with the identification of patients with connective tissue diseases,
      preconceptional diagnostics as well as monitoring and treatment during pregnancy
      and the postpartal period. Clinical aspects that are intensively discussed
      include immunosuppressive therapy during pregnancy, the management of
      antiphospholipid antibody-dependent problems and the prophylaxis and treatment
      options for congenital heart block.

PMID- 15039886
TI  - [Strategies for the diagnosis and treatment of prenatal toxoplasmosis - a
      survey].
AB  - Today, a decreasing number of infants with prenatal toxoplasmosis present with
      clinical signs of severe, generalised infection and cerebral involvement. The
      favourable clinical outcome - mild or subclinical infection - is considered to be
      an effect of early maternofetal treatment with spiramycin and
      pyrimethamine/sulfadiazine (PS). However, a Cochrane Review and a recently
      published European multicentre study on congenital toxoplasmosis did not only
      question this positive effect but also the efficiency of a postnatal long-term
      therapy. Both studies caused much confusion among neonatologists and
      paediatricians. The new setting requires an update of the diagnostic
      possibilities and different therapeutic strategies for prenatal toxoplasmosis.
      Only few prospective studies are available to compare the efficiency of different
      drug regimens in infected infants. However, clinical data demonstrate that the
      available therapeutics are not curative and cannot prevent late sequelae. Follow
      up studies in pregnant women and their offspring show that prenatal parasite
      detection does not predict an unfavourable clinical outcome when treatment is
      initiated early after diagnosis. In Germany, prenatal screening is not
      obligatory. In case of primary maternal infection, materno-fetal therapy is
      recommended. A combination therapy consisting of PS is considered more effective
      than a spiramycin monotherapy. Treatment is recommended for all infected newborns
      with different strategies for infants with or without clinical symptoms. The
      treatment strategies of different European countries are discussed. This paper
      provides recommendations for the diagnosis and treatment of newborn toxoplasmosis
      and materno-fetal infection as well as recommendations for the clinical
      management of infected neonates and their follow-up, including drug monitoring.

PMID- 15039887
TI  - [Perinatal mortality after previous cesarean section].
AB  - BACKGROUND: Perinatal neonatal mortality is increased where there is a maternal
      history of cesarean section (0.45 vs. 0.31 % in deliveries after previous vaginal
      delivery). In this study we have analyzed the causes of the perinatal deaths.
      PATIENTS AND METHODS: The increased risk was found by analyzing the database of
      the Swiss Working Group of Obstetric and Gynecological Institutions with its 29
      046 deliveries with a history of previous cesarean section between 1983 and 1996.
      In this time period 130 perinatal neonatal deaths in deliveries after previous
      cesarean were recorded. RESULTS: The cause of death could be established in 124
      cases. In the 42 term deliveries the causes of death were the following:
      malformations 20, uterine rupture 5, placental abruption 5, respiratory distress
      syndrome 5, and other causes 7. In the 82 preterm deliveries: prematurity caused
      by premature contractions/rupture of membranes 38, malformations 12,
      chorioamnionitis 12, placental abruption 9, severe growth retardation 4,
      complications of placenta praevia 2, uterine rupture 1, other causes 4.
      DISCUSSION: Preterm deliveries are more frequent (in births) after a previous c/s
      (7.75 vs. 5.55 % in multiparous mothers without previous cesarean) - not because
      of a higher frequency of preterm labor or premature rupture of membranes, but
      because of placental abruption, chorioamnionitis, placental insufficiency and
      severe growth retardation. Although some of the neonatal deaths are linked to the
      previous cesarean delivery, perinatal death after previous cesarean is a very
      rare event. A recommendation to routinely perform a repeat cesarean instead of a
      trial of labor seems not appropriate.

PMID- 15039888
TI  - [Congenital varicella syndrome - is it infectious?].
AB  - A 30-year-old gravida 2 suffered from chickenpox in the 13th week of gestation.
      In the 38th week of gestation she delivered by caesarean section a baby with
      typical congenital varicella syndrome (CVS). In the serum of the newborn IgG
      antibodies but no IgM or IgA antibodies were found by VZV ELISA test (Enzygnost
      Behring). On the 2nd, 5th, 8th and 11th days of life, VZV DNA was detectable in
      the cerebrospinal fluid by PCR in elevated copy numbers as well as in the fluid
      of skin lesions on the 3rd day of life in higher copy numbers, on the 11th day of
      life it was still detectable in low copy numbers. In the EDTA blood samples taken
      on the 5th day of life VZV DNA was detectable in low copy numbers. The positive
      VZV DNA detection in skin lesions led to the conclusion that newborns with CVS
      and skin lesions should be considered as infectious until the time of crusting
      and isolated in nursery care.

PMID- 15039889
TI  - [Neonatal chylothorax with trisomy 21].
AB  - Neonatal chylothorax is an uncommon cause of respiratory distress in the newborn.
      It may result from anomalous lymph drainage with or without association with
      aneuploidy syndromes (trisomy, Turner's syndrome, Noonan's syndrome), from injury
      to the thoracic duct, and from obstruction of the superior vena cava. We report a
      term newborn and a premature infant with neonatal chylothorax, both associated
      with trisomy 21. In the case of the term infant, bilateral pleural effusions were
      diagnosed immediately before birth. The baby suffered from respiratory distress.
      The physical findings were characteristic of trisomy 21. In the premature infant
      (gestational age 24 weeks, 735 g) the ductus arteriosus was ligated on day nine
      after birth. Four days after surgery a central venous line was inserted via the
      left vena mediana cubiti into the left vena subclavia. Nine days after surgery a
      left-sided chylothorax occurred. The infant had subtle signs of a trisomy 21
      (slightly enlarged tongue, brachycephalic head. questionable simian crease). In
      both children, cytogenetic studies were done and confirmed the diagnosis of
      trisomy 21. Infants with neonatal chylothorax should be carefully evaluated for
      dysmorphic signs of a trisomy or monosomy. Premature infants may present with
      only subtle clinical signs requiring cytogenetic studies to confirm an aneuploidy
      syndrome.

PMID- 15039890
TI  - [Complicating neonatal Escherichia coli meningitis].
AB  - Neonatal Escherichia coli meningitis is a serious disease with high mortality and
      poor outcome. Ventriculitis, brain abscess and subdural empyema are frequent,
      with no homogeneous recommendations available for these complications. The case
      of a newborn infant who developed sepsis and meningitis caused by E.  coli is
      presented. During intravenous treatment with ampicillin, cefotaxime and
      gentamycin in recommended doses, the patient developed severe subdural abscesses
      detected on MRI. After consequent antibiotic therapy over 2 months with
      fosfomycin, amikacin and meropenem the patient improved clinically and the
      abscesses regressed and disappeared without neurosurgical intervention. At the
      age of 6.5 months the infant is healthy and well developed. The conservative
      treatment of subdural abscesses complicating neonatal Escherichia coli meningitis
      without neurosurgical intervention is possible. The treatment of the individual
      case should be discussed between pediatrician and neurosurgeon.

PMID- 15039891
TI  - [Thrombosis of the iliac artery in a premature neonate: thrombolytic therapy
      using rt-PA].
AB  - Thromboembolic events in neonates are very rare. They are often associated with
      severe disease affecting the newborn or are secondary to central venous lines or
      arterial catheters. Most of the described cases of thromboses of the iliac or
      femoral arteries are associated with cardiac catheterisation or femoral invasive
      blood pressure monitoring. The relationship between single umbilical arteries and
      an increased incidence of structural and chromosomal anomalies is well known, but
      a higher rate of thromboembolic disease in infants with single umbilical arteries
      has not been described. Rt-PA (recombinant tissue plasminogen activator) has been
      successfully used in small studies and numerous case reports. To date controlled
      clinical trials giving guidelines for antithrombotic therapy using rt-PA are
      still lacking. We report the clinical course of a 700 g premature male, who was
      born by Caesarean section at 29 + 6 gestational weeks. On the fifth day the baby
      suffered from arterial thrombosis of the right pelvis axis. Antenatally a single
      umbilical artery was identified. Iliac arteries on the involved site appeared
      hypoplastic. Additionally, the prothrombin G20210A mutation was found. The
      patient was treated successfully using recombinant tissue plasminogen activator.
      In the case of a high risk of limb or organ loss due to arterial thrombosis,
      thrombolysis using rt-PA is justified. Appropriate rt-PA treatment has been
      studied for the adult but not the paediatric population. Hence, well-designed
      clinical trials are necessary to determine the pharmacokinetics and dynamics of
      thrombolytic agents in children.

PMID- 15039892
TI  - Cell cycle checkpoints -- molecular background.
AB  - Cell cycle checkpoints are the surveillance mechanisms monitoring both the
      fidelity and accuracy of DNA replication and the segregation of chromosomes. By
      delaying progression through the cell cycle, checkpoints provide more time for
      repair before the critical phases of DNA replication and ensure the proper
      segregation of chromosomes during mitosis. The paper provides basic information
      about the molecular mechanisms operating in various cell cycle checkpoints
      activated by DNA damage or disturbances in mitotic spindle assembly.

PMID- 15039893
TI  - The effect of angiogenesis inhibitor TNP-470 on the blood vessels of the lungs,
      kidneys and livers of treated hamsters.
AB  - The growth of solid tumours and their metastases is dependent on the development
      of new blood vessels (angiogenesis). Therefore angiogenesis inhibitors are
      potential antitumour drugs. In our previous studies it was found that the
      angiogenesis inhibitor TNP-470 given to transplantable melanoma-bearing hamsters
      can decrease the rate of the tumour growth, although the survival time of the
      animals treated was not significantly affected. It was found finally that TNP-470
      given in the vicinity of the growing tumour can cause complete remission of the
      melanoma in hamsters treated in this way. To check what side-effects could be
      evoked by such treatment, an examination of the morphology of the blood vessels
      of the lungs, kidneys and livers of the treated animals was carried out. It was
      found that the angiogenesis inhibitor applied did not cause any changes which
      could be observed by light and electron microscopes in the structure of the
      examined blood vessels of the treated animals.

PMID- 15039894
TI  - The morphology of the hypoglossal canal and its size in relation to skull
      capacity in man and other mammal species.
AB  - The hypoglossal canal is a permanent element of the human skull. As well as the
      hypoglossal nerve, the canal also contains the venous plexus and an arterial
      branch leading to the dura mater. It emerged from our earlier studies that the
      venous plexus is a dominant component in this canal. In the present work the
      morphology and dimensions of the canal were studied on macerated skulls of humans
      and animals (rhesus monkey, European bison, fox, dog, cat, hare and rat). The
      hypoglossal canal was found in all the human and animal skulls examined. In both
      humans and animals the hypoglossal canal was frequently duplicated. The double
      canal was found in 43% specimens of human skulls. However, no triple division of
      the hypoglossal canal was found in the material under investigation. It was found
      that the hypoglossal canal in man, rhesus monkey and European bison had
      significant dimensions and in fact correlated with the size of skull capacity.
      This suggests that the hypoglossal canal is an essential venous emissary in man,
      rhesus monkey and European bison, but that in the remaining species it is of
      secondary importance in this respect.

PMID- 15039895
TI  - The internal thoracic artery in human foetuses.
AB  - The aim of this study was to examine the internal thoracic artery (ITA) in human
      foetuses. The research material consisted of 32 human foetuses (18 female, 14
      male) from the 21(st) to 24(th) week of intrauterine life. After intravascular
      injection with white latex LBS 3060, the foetuses were fixed in 10% neutral
      formalin solution. The whole course of the ITA was prepared. Photographic
      documentation was performed with a Nikon Coolpix 4500 digital camera, and source
      pictures of arteries were rendered in a Digital Computer System Analysis. The ITA
      was evaluated with regard to its origin, length, distance from the edge of the
      sternum to two intercostal spaces (2(nd), 5(th)) and division into terminal
      branches. The right ITA (RITA) arose from the ascending (68.7%), arcuate (21.9%)
      and descending (3.2%) parts of the subclavian artery. In other cases (6.2%) it
      was a branch of the thyrocervical trunk. The left ITA (LITA) was a branch of the
      ascending (78.1%) and arcuate (21.9%) parts of the subclavian artery. The ITA was
      longer in male foetuses. Regardless of sex, the LITA was longer than the RITA.
      Coefficient correlation between the RITA and LITA was 0.92 (p < 0.001). The
      distance of the ITA from the edge of sternum in the 2(nd) and 5(th) intercostal
      spaces on both sides was greater in females. It appeared most frequently in the
      6(th) space (43.7% right-sided and 56.3% left-sided). Typical bifurcation of the
      ITA into the superior epigastric artery and the musculophrenic artery was
      observed in 78.1% of cases on the right side and in 81.25% of cases on the left
      side.

PMID- 15039896
TI  - The effect of fasting and refeeding on the ultrastructure of the hypothalamic
      paraventricular nucleus in young and old rats.
AB  - In order to explore the morphological basis of the altered feeding behaviour of
      old rats, an ultrastructural investigation of the magnocellular neurons of the
      hypothalamic paraventricular nucleus (PVN) was performed. Young and old male
      Wistar rats, 5 and 24 months old, respectively, and with each age group
      comprising 12 animals, were divided into 3 groups. The rats in Group I were used
      as controls (normally fed), the rats of Group II were fasted for 48 hours and in
      Group III the rats were fasted for 48 hours and then refed for 24 hours. The
      brains were fixed by perfusion and histological and ultrathin sections were
      obtained by routine methods. Common features of the magnocellular PVN neurons of
      young and old rats were abundant Golgi complexes and short fragments of RER
      localised at the cell periphery. In contrast to young rats, the PVN neurons of
      old animals showed deep indentations of the nuclear envelope and age-related
      residual bodies. In both age groups fasting for 48 hours led to the expansion of
      the Golgi complexes and dilatation of RER cisternae. In contrast to those in fed
      rats, RER cisternae in the neurons of old fasted animals were situated between
      the nuclear envelope and the Golgi zone. Prolonged RER cisternae were distributed
      in the peripheral cytoplasm of refed old rats. Our observations suggest that at
      the ultrastructural level the process of ageing does not change the
      responsiveness of magnocellular PVN neurons to fasting-refeeding.

PMID- 15039897
TI  - Two types of vascularisation of intramural uterine leiomyomata revealed by
      corrosion casting and immunohistochemical study.
AB  - The blood supply of myomatous uteri collected upon autopsy was examined. The
      uterine vascular beds were perfused via afferent vessels with fixative followed
      by Mercox resin and corroded after polymerisation of the resin. The vascular
      casts thus obtained were examined using scanning electron microscopy. The
      vascular system of the uterine fibroids was also examined using
      immunohistochemical analysis (FVIII, factor VIII-related antigen).

PMID- 15039898
TI  - A preliminary study on the relationship between the complexity of the sagittal
      suture and cranial dimensions.
AB  - The paper presents the results obtained from analysis of the correlation between
      cranial dimensions (length, width, and height) and indices against the complexity
      of the sagittal suture, which was expressed as the ratio between absolute sutural
      length to the linear length of the suture. The statistical study on 29 skulls
      shows a significant negative correlation between the height/width index of all
      skulls and suture complexity (r = -0.78 for male, r = -0.70 for female skulls)
      and a negative correlation between cranial height and suture complexity in male
      skulls only (r = -0.49). This implies that lower and broader skulls have a more
      complicated sagittal suture. Correlations of the height/length and width/length
      ratios were assessed as statistically insignificant in both sexes.

PMID- 15039899
TI  - The cystic artery in human foetuses.
AB  - The cystic artery varies in origin, course and number and it is important to
      recognise it during operative procedure. Insufficient recognition of its
      anatomical variation may contribute to a dangerous situation, especially during
      laparoscopic cholecystectomy. To prevent iatrogenic injuries of the vessels and
      bile ducts, correct preparation with clear identification of the anatomic
      structures is essential. Special attention must be given to the course of the
      cystic artery through the hepato-billiary triangle (Calot's triangle). The
      assumption of the present study was recognition of the vasculature of the
      gallbladder in human foetuses. The purpose of this investigation was to determine
      the origin of the cystic artery and its relation to Calot's triangle. In this
      study the cystic artery was most often (97.06%) a single vessel and only in one
      case (2.94%) was it a double vessel. It arose most often (82.34%) from the right
      proper hepatic artery, rarely from its trunk (8.82%) or its left branch (5.88%)
      and most rarely (2.94%) from the gastroduodenal artery. In all but one case the
      cystic artery coursed within Calot's triangle. Its exceptional course out of
      Calot's triangle concerned a cystic artery originating from the gastroduodenal
      artery (2.94%). The cystic artery most frequently (67.66%) runs behind the common
      hepatic duct, rarely (29.40%) over the common hepatic duct and most rarely
      (2.94%) on the left side of the cystic duct. In the material examined the cystic
      artery was not observed running in front of the common hepatic duct. The short
      type of cystic artery trunk (52.93%) was observed more frequently than the long
      one (44.13%).

PMID- 15039900
TI  - The growth and differentiation of aortal smooth muscle cells after calcitriol
      treatment are associated with microtubule reorganisation -- an in vitro study.
AB  - The smooth muscle cells (SMCs) of the arterial media play a predominant role in
      functional and structural alterations of the arterial wall. The transition from
      the "contractile" to the "synthetic" phenotype appears to be an early critical
      event in the development of atherosclerotic disease. A number of observations
      suggest that 1,25(OH)(2)D(3) (calcitriol) is of importance in maintaining normal
      cardiovascular function through its receptors in cardiac myocytes or aortal SMCs.
      The present study has focused on the microtubular (MT) network reorganisation
      after exposure to calcitriol. SMCs isolated by enzymatic digestion from the
      aortal media of neonatal rats were cultured on glass cover slips. 1 microM of
      1,25(OH)(2)D(3) was added to the culture medium every second day. The
      cytoskeletal features of SMCs after calcitriol were visualised by the
      immunofluorescence staining of alpha-tubulin. The alterations in alpha-tubulin
      expression and the distribution of microtubules related to the activities of the
      vascular smooth muscle cells, namely adhesion, migration, multilayer formation
      and cell division, were observed. A spindle shape, decreased cell adhesion, low
      expression of alpha-tubulin and a longitudinally arranged microtubular network
      manifested the high rate of SMC differentiation in the calcitriol-treated
      culture. A flat stellate morphology, high expression of alpha-tubulin and a
      radially distributed three-dimensional microtubular network were observed in the
      SMCs of the control culture. Destructive changes in the microtubular architecture
      which altered the cellular shape were evident in SMCs undergoing apoptosis. Cells
      with apoptotic features were more frequent in calcitriol-exposed culture. In
      contrast to the regular SMC divisions observed in the control culture, some of
      the mitotic cells exposed to calcitriol contained broader bipolar, multipolar or
      disordered spindles. These alterations in the SMCs' microtubular cytoskeleton
      after calcitriol treatment were concomitant with changes in cell growth,
      differentiation and apoptosis, and may suggest a similarity to atherosclerotic
      plaque formation.

PMID- 15039901
TI  - The effect of an infant's environmental conditions and state of health on the
      teething of the primary incisors.
AB  - The objective of this research was to determine the relationship between the time
      when an infant's first incisor teething occurred, the infant's state of health
      and selected environmental and living conditions. 483 infants participated in
      this research and their health development was monitored monthly in a local
      hospital in Wroclaw. The teething of the infants was studied from the time of
      their birth until the age of 18 months. The descriptions of the infants' living
      and environmental conditions and their developmental stages were analysed on the
      basis of 10 standardised characteristics. The results of this study showed that
      there were strong relationships between the teething of infants' incisors, their
      living conditions and individual progress in health development.

PMID- 15039902
TI  - The effect of extracellular substance components on the proliferation and
      expression of hormones in cultured cells of medullary thyroid carcinomas.
AB  - The effects were examined of selected extracellular medium (ECM) components on
      the proliferation of medullary thyroid carcinoma cells and on the production of
      calcitonin and CGRP. Human TT cells and rat rMTC cells were cultured for 24, 48
      and 72 hours on glass coated with type I collagen, fibronectin or poly-D-lysine.
      More pronounced proliferation was demonstrated by TT cells grown on poly-Dlysine
      or collagen in comparison with the control and less pronounced proliferation was
      typical of cells grown on fibronectin. On the other hand, rMTC cells were more
      markedly manifest on any ECM substrates than that on glass. Alterations in the
      proliferation were paralleled by changes in the expression of CT and CGRP.

PMID- 15039903
TI  - Age dependent changes of the diploe in the human skull.
AB  - This paper presents an approach to the investigation of age-related morphological
      changes in the diploe of the human skull. Comparative investigations were
      performed on 10 dried skulls of young and old individuals. Computer tomography
      was employed followed by filtering of the digital images to visualise more
      details of the inner structure of the calvarial bones. As a result of our
      analysis, we concluded that the diploe of the young individuals was homogenous
      cancellous bone, which tightly fills the space between the outer and inner tables
      of the calvarial bones. The diploe of the older individual is more porous,
      showing a trace of sclerosis and with lacunas. Its texture is more scattered in
      the images and presents a higher level of degradation. The structural differences
      of the diploe in the skulls of older individuals can be due to a process of
      involution related to a diminishing of trabecular density in the cancellous bone.
      These processes are usually accompanied by fluctuations in the mineral
      components.

PMID- 15039904
TI  - The arching of the palate in twin foetuses.
AB  - The aim of the study is to examine the process of change with age of hard and
      total palate arching. Differences were compared in the arching of the hard and
      total palate in pairs of twins of the same sex and in pairs of twins of opposite
      sexes aged between 4 and 7 months of foetal life. On the basis of the results
      obtained it may be stated that: 1. There is some delay in the process of
      development of twin foetuses in comparison with ones from a single pregnancy; 2.
      There are no substantial differences between male and female twins and between
      twins from heterosexual pairs; 3. Much greater differences take place in older
      twins with regard to the features under examination.

PMID- 15039905
TI  - The cellular composition of the adrenal medulla of sexually mature guinea pigs.
AB  - The adrenal glands from 15 guinea pigs aged 90 days were used in the study.
      Paraffin slices were stained with Mayer haematoxylin and eosin with Masson method
      and silvered. The histochemical reactions were carried out for catecholamines and
      the biochemical determinations of catecholamines. Ultrastructural observations
      were also performed. In the adrenal medulla of sexually mature guinea pigs
      numerous epinephrocites and no noreoinefrocites were observed when histochemical
      methods were used. The small and large ganglion cells accompanying the supporting
      and neurolemmal cells formed typical gangliar weaving (medullary ganglia). Apart
      from epinephrocytes, small and large ganglion cells and supporting and
      neurolemmal cells, small intensively fluorescent (SIF) cells were also detected.
      Biochemical investigation revealed that the mean content of adrenaline calculated
      for a pair of adrenal glands was 98.87% of the pool of catecholamines, whereas
      the mean content of noradrenaline was 1.00%, and of dopamine 0.13%.

PMID- 15039906
TI  - The influence of the vascularisation of the follicular thyroid nodules on the
      proliferative activity of the follicular cells.
AB  - The enlargement of the thyroid is, in general, benign in origin and due to
      nodular goitre. Follicular cellular proliferation of thyroid nodules has been
      increasingly observed recently. With fine needle aspiration biopsy (FNAB) this is
      classified as a follicular tumour. These lesions present various patterns of
      vascularisation in ultrasound examination. The aim of the study was to establish
      the relation between follicular nodule vascularisation and the proliferative
      activity of various types of follicular cell. According to the manner of
      proliferation, patients were divided into groups as follows: (I). patients with
      hyperplastic nodules (46 cases), (II). patients with follicular adenoma (42
      cases), and (III). patients with follicular cancer (9 cases). In each case B-mode
      sonography, Power Doppler, sonographically guided FNAB (S-FNAB), morphological
      examination and morphometry were performed. The proliferative activity was
      detected with immunohistochemical methods (PCNA, Ki 67 and MPM2) to determine the
      so-called "proliferative index". The study revealed increased proliferative
      activity in tumours of malignant origin and increased vascularisation in
      coexistence with increased proliferation of the follicular cells. As assessed by
      Power Doppler, an increased flow pattern in the centre of the nodules correlates
      with increased proliferative activity. The results suggest that Power Doppler
      examination could be helpful in selecting nodules for FNAB, especially in
      multinodular goitre.

PMID- 15039907
TI  - The morphological and histochemical neurosecretory magnocellular system in the
      rat after administration of chlorpromazine.
AB  - The effect of chlorpromazine (CPZ) on the neurosecretory action of the
      hypothalamo- hypophyseal system was investigated in 72 male rats. The
      experimental animals received CPZ in a dose of 0.4 mg, 4.0 mg and 20.0 mg/kg b.w.
      for 30 days. The rats were sacrificed by decapitation at 24 h and 7 days after
      the last dose of the drug. The neurosecretory material was stained with
      paraldehyde fuchsin in the supraoptic nucleus, paraventricular nucleus, eminentia
      mediana and neurohypophysis, the tigroid was stained with toluidine blue and the
      acid phosphatase activity was evaluated histoenzymatically. It was found that CPZ
      reduced the content of the neurosecretory material after 24 h, while an increase
      was observed 7 days after the last drug administration.

PMID- 15039908
TI  - Bone marrow morphology during haematopoietic stem cell mobilization with G-CSF in
      mice.
AB  - The aim of the work was to examine the morphology of the bone marrow of mice
      during stimulation with G-CSF. Experimental Balb C mice were daily injected
      subcutaneously with 250 microg/kg b.w. G-CSF (Neupogen). After 2, 4 and 6 days of
      the experiment femurs were obtained for morphological study. On day 2 of the
      mobilization the amount of haematopoietic cells in the bone marrow increased and
      dilatation of the sinusoids was observed. Only single leukocytes were observed in
      the lumen of the vessels. There were numerous leukocytes in the lumen of the
      sinusoids on day 4 of the mobilization. The morphology of the bone marrow on day
      6 was similar to that of the control. Mobilization of mice with G-CSF resulted in
      migration of haematopoietic cells from the bone marrow and the process is most
      pronounced on day 4.

PMID- 15039909
TI  - Dactinomycin-induced veno-occlusive disease in rats. The hepatoprotective action
      of amifostine. Evaluation in a light and electron microscope.
AB  - The purpose of the study was to draw upan experimental model of hepatic veno
      occlusive disease (VOD) induced by dactinomycin (ACT) and to investigate the
      possible hepatoprotective effects of Ethyol (amifostine). Pathological changes
      corresponding to a VOD picture of varying intensification were found in the liver
      samples obtained from all the rats receiving ACT. Amifostine appears to act
      protectively to liver changes caused by dactinomycin.

PMID- 15039911
TI  - The distribution and influence of calcitonin gene-related peptide (CGRP) on the
      perfusion pressure in the isolated ovarian artery in the pig.
AB  - A moderate number of delicate CGRP-immunoreactive (CGRP-IR) varicose nerve
      terminals were found at the adventitia-media border of the sexually mature
      porcine ovarian artery by means of a routine single immunolabelling technique.
      Additionally, a pharmacological analysis was performed of the function fulfilled
      by alpha-CGRP and its C-terminal fragment (Tyr27) alpha-CGRP(27-37) in the
      porcine isolated ovarian artery, collected on days 8-13 of the oestrous cycle. It
      was shown that alpha-CGRP (10(-8) M) caused a decrease in the perfusion pressure
      of the porcine isolated ovarian artery of 16% (p < 0.05), while (Tyr27) alpha
      CGRP(27-37), added at the same concentration, reduced perfusion pressure by 13%
      (p > 0.05). Thus, we concluded that alpha-CGRP released from perivascular
      terminals may cause relaxation of the ovarian artery and, furthermore, that the
      potency of this action is dependent on the length of the chain of this peptide
      produced during the deactivation of the molecule by tissue proteases.

PMID- 15039910
TI  - An evaluation of Ki-67 and PCNA expression in conjunctival and eyelid tumours.
AB  - The aim of our study was an evaluation of the expression of cell proliferation
      markers (PCNA and Ki-67) in conjunctival and eyelid papillomas and squamous and
      basal cell cancers. A series of 9 cases of squamous cell cancer (SCC), 15 cases
      of basal cell cancer (BCC) and 43 cases of squamous cell papilloma (SCP) were
      assessed using the immunohistochemical method with monoclonal antibodies. PCNA
      overexpression was observed in 100% of SCP, in 88.8% of SCC and in 100% of BCC
      cases. Ki-67 overexpression was seen in 32.5% of cases of SCP, in 22.2% of SCC
      and in 66.6% of BCC. The results showed that an evaluation of Ki-67 expression is
      the most valuable cell proliferation marker.

PMID- 15039912
TI  - The effects of quercetin vs cisplatin on proliferation and the apoptotic process
      in A549 and SW1271 cell lines in in vitro conditions.
AB  - Experience over several years has indicated that chemotherapy, even if widely
      used, does not always remain effective in the therapy of lung tumours and, in
      addition, is linked to serious side effects. In parallel, some plant polyphenols
      are known to exert a proapoptotic action on tumour cells while, in contrast,
      representing anti-cancerogenic anti-oxidants in living organisms. Our studies
      were aimed at comparing the effects of a polyphenol, quercetin, and cisplatin on
      cells of various types of lung cancer in in vitro conditions. In these studies we
      also attempted to define the relationship between the dose and the duration of
      the activity of the compounds. Cisplatin alone was found to induce only a small
      reaction in the cells, while in combination with quercetin its anti-proliferative
      and pro-apoptotic effects were amplified, depending upon the type of tumour, the
      dose and the duration of the drug's action.

PMID- 15039913
TI  - Evaluation of apoptosis, proliferation intensity and metallothionein (MT)
      expression in comparison with selected clinicopathological variables in primary
      adenocarcinomas of the large intestine.
AB  - Tumour growth and expansion are the result of proliferative activity and the
      capacity to eliminate cells by apoptosis and/or necrosis. The present study was
      aimed at comparing the apoptosis and proliferation intensity in cells of
      adenocarcinomas of the large intestine with the expression of metallothionein
      (MT), the grade of the tumour and the depth to which the tumour infiltrated the
      intestinal wall. The TUNEL technique and immunocytochemical reactions (expression
      of caspase-3, Ki-67, MT) were used to detect apoptosis. The results demonstrated
      augmented levels of all the variables examined, positively correlated with grade
      of malignancy, G, and with the depth of intestinal wall infiltration by the
      tumour cells. The testing of apoptosis, proliferation and MT expression may prove
      useful in the appraisal of the growth and progression of primary adenocarcinomas
      in the large intestine.

PMID- 15039914
TI  - A preliminary evaluation of thyroid and respiratory tract neuroendocrine cells in
      the rat after experimental hypercalcaemia.
AB  - The goal of this study was to investigate the influence of experimentally induced
      hypercalcaemia (after 100000 UI Vigantol and CaCl2) on neuroendocrine cells
      (NECs) in the thyroid and airways in the rat. After 24 h, 7 days and 14 days the
      thyroid and lungs were collected. Paraffin sections were immunocytochemically
      stained with specific antibodies against CGRP, calcitonin (CT) and synaptophysin
      (SY) in the airway NECs and thyroid C cells. The largest hypercalcaemia were
      observed in experimental rats after 7 days. More significant changes in the
      number and size of neuroendocrine cells were observed in the thyroid gland as
      well as in the airways. In the airways only a slight increase in the number of
      neuroepithelial bodies (NEBs) was observed, some of which gave evidence of
      hypertrophy symptoms.

PMID- 15039915
TI  - Immunolocalization of CGRP, NPY and PGP 9.5 in guinea pig skin.
AB  - By means of immunoperoxidase and immune-alkaline phosphatase methods the
      immunoreactivities to neuropeptides: neuropeptide Y (NPY), calcitonin gene
      related peptide (CGRP) and a pan-neuronal marker, the protein gene product 9.5
      (PGP 9.5), were evaluated in guinea pig deep dorsal skin specimens. CGRP
      immunoreactive (CGRP-IR) and NPY-immunoreactive (NPY-IR) nerve fibres were
      dispersed in the papillary dermis and sometimes inside the hair roots and among
      the sebaceous gland cells. Such localized nerve fibres have not so far been
      described. In the subcutaneous layer nerve trunks were found composed of CGRP-IR
      and NPY-IR nerve fibres. Some of these indicated vestigial or negative
      immunoreactivity to PGP 9.5.

PMID- 15039916
TI  - Proliferation activity and apoptosis in granulation tissue and cholesteatoma in
      middle ear reoperations.
AB  - The aim of the study was to find out the potential prognostic value of
      proliferation activity and apoptosis in cholesteatoma and granulation tissue
      removed during middle ear reoperation in recurrent middle ear inflammation.
      Granulation tissues and recurrent cholesteatoma were analysed after being
      surgically removed from the middle ear in a group of 25 patients qualified for
      middle ear reoperation procedure. Paraffin sections were stained with
      haematoxylin and eosin according to Mallory's method. Immunohistochemical
      reaction Anti-PCNA was performed. Apoptosis was evaluated using the TUNEL method.
      The percentage of PCNA-positive cells was 42-95% in the matrix of the
      cholesteatoma and 29-81% in the perimatrix. In the granulation tissue it was 35
      75%. The percentage of apoptotic cells was 12-73% in the matrix of the
      cholesteatoma, 5-72% in the perimatrix and 1-65 % in the granulation tissue. The
      prognostic value of the parameters studied in the recurrent middle ear
      inflammatory process is questionable, probably due to the small number of cases
      under examination.

PMID- 15039917
TI  - Green tea as an antioxidant which protects against alcohol induced injury in rats
      -- a histopathological examination.
AB  - Our study with animal models was designed to test the hypothesis that green tea
      protects against chronic (over 4 weeks) alcohol induced liver injury in rats. The
      research was conducted on Wistar male rats divided into 4 research groups: I -
      received the Libera-De Carli control diet (L-DC), II - received (L-DC) and green
      tea, III - received (L-DC) and ethanol and IV - received (L-DC), green tea and
      ethanol. When comparing groups I and II we saw less intensive steatosis in group
      II than in group I, which can suggest that green tea may affect the accumulation
      of fat in the hepatocytes and protect them against steatosis and disruption. In
      III, the ethanol group, the steatosis of the liver increased considerably and the
      green tea which was given with ethanol in group IV did not halt this, as in group
      IV we also observed intensive steatosis in the liver. From this data we conclude
      that green tea has an important, although not fully understood role in preventing
      liver injury.

PMID- 15039918
TI  - The activity of human telomerase in the cells of acute leukaemias.
AB  - Telomeres are the end fragments of chromosomes formed by a number of non-coding
      double-stranded TTAGGG repeats in vertebrates. During cell division the number of
      repeats decreases, leading to cell senescence or apoptosis. In immortal cells,
      including cancer cells, the telomere length is stable and maintained by, among
      other factors, telomerase. The aim of the study is to compare telomerase activity
      in normal lymphocytes and in leukaemic cells. Samples of acute leukaemia cells,
      HL 60 cell line and the lymphocytes of healthy volunteers were examined.
      Telomerase analysis was performed using TeloTAGGG Telomerase PCR ELISAplus
      (Roche). The relative telomerase activities (RTA) in leukaemic and normal cells
      were analysed. A high level of RTA was observed in leukaemic cells.

PMID- 15039921
TI  - The effect of direct and alternating electrical currents on the vessel walls of
      the tooth pulp -- TEM studies.
AB  - Devices which operate on the basis of electrical charges are increasingly being
      used in stomatology, such as in cariology for the detection of invisible caries
      lesions or for the measurement of canal lengths during patient treatment. The
      majority of these devices now emit a current of alternating frequency. The aim of
      the work was to explain how the electrical devices of labile frequency commonly
      used in stomatology influence the vessels of the tooth pulp. Teeth extracted for
      orthodontic reasons were investigated with the use of a transmission electron
      microscope. The teeth were treated with current emitted by a specially
      constructed device. The control group comprised 4 teeth. No changes were found in
      the electron microscopic studies in the slides of the teeth treated with low
      charges of current. However, in the specimen treated with current charges of 9600
      microC or more flattened endotheliocytes were found together with exudation in
      the vessel lumen. Cases are referred to in which the duration of the work was 2
      or 3 times longer than normal and in which a current of constant intensity was
      emitted uninterruptedly.

PMID- 15039920
TI  - AgNOR, Ki-67 and PCNA expression in fibroepithelial tumours of the breast in
      correlation with morphological features.
AB  - The authors retrospectively reviewed the cytological slides of 44
      histopathologically confirmed fibroepithelial lesions of the breast, of which 11
      were fibroadenoma (FA), 19 benign phyllodes tumours (PTLGM), 8 borderline (PTBM)
      and 6 malignant (PTHGM). The 2 FA misdiagnosed as PTLGM in cytological smears
      were both of cellular type. NORS were quantified in a series of the above cases
      using the silver-colloid method. Expression of Ki-67 and PCNA were evaluated by
      immunohistochemistry on sections from the corresponding paraffin blocks. The
      results were compared with morphological parameters. In phyllodes tumours (PT),
      the AgNOR scores showed a tendency to increase with degrees of malignancy. There
      was significant correlation between Ag- NOR counts and proliferation rates as
      determined by Ki-67 and PCNA immunostaining. Ki-67 and PCNA expression correlated
      with mitotic count, stromal overgrowth, cellularity and atypia in PT.
      Determination of the AgNOR number per cell revealed an overlap between FA and
      PTLGM. The proliferating activity determined by immunohistochemistry with Ki-67
      and PCNA antibodies did not reveal any significant difference between FA and
      PTLGM. In summary, Ki-67 and PCNA expression is suggested as a marker of stromal
      element proliferation. The results obtained confirm the diagnostic difficulties
      in distinguishing PTLGM from FA of the cellular type using fine needle aspiration
      cytology.

PMID- 15039919
TI  - Expression of metallothionein (MT) and gluthatione s-transferase pi (SGTP) in the
      bone marrow of patients with myeloproliferative disorders (MPD).
AB  - Overexpression of SGTP and/or MT may contribute to various carcinogenic processes
      and to resistance to anticancer treatment. The importance of these proteins,
      although clearly established in solid tumours, has not been fully understood in
      haematopoietic neoplasm. The aim of this study was to determine the expression of
      MT and SGTP in the bone marrow of patients with MPD. Twenty paraffin-embedded
      bone marrow core biopsy specimens from newly diagnosed patients with MPD were
      evaluated -- osteomyelofibrosis (OMF), n = 9 and chronic myelocytic leukaemia
      (CML), n = 11. We demonstrate increased SGTP and MT expression in the bone marrow
      of MPD patients. In our study levels of MT in OMF patients were higher than in
      CML. This suggests that MT expression may correlate with bone marrow fibrosis.
      These data, although based on a relatively small number of patients, raise the
      possibility that SGTP and MT may play a role in the pathogenesis of MPD. The
      clinical significance of this phenomenon needs further investigation.

PMID- 15039922
TI  - A retroesophageal right subclavian artery originating from the left aortic arch -
      a case report and review of the literature.
AB  - The retroesophageal right subclavian artery is an anatomical abnormality
      encountered by anatomists and pathologists and recently interventional
      cardiologists and thoracic surgeons have also come across this phenomenon. We
      report a case of a retroesophageal right subclavian artery arising from a
      normally located left aortic arch in a young male autopsied in the Department of
      Forensic Service of Warsaw Medical University. In addition to the aforementioned
      anomaly, the presence of a right non-recurrent inferior laryngeal nerve was
      noticed. The possible embryonic development of these branching patterns and their
      clinical significance is discussed.

PMID- 15039924
TI  - Maternal use of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs),
      and muscular ventricular septal defects.
AB  - BACKGROUND: Muscular ventricular septal defects (mVSDs) are the most common
      congenital heart defects. Previous studies have suggested maternal use of
      acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), and/or fever as
      risk factors. We evaluated the association between mVSDs and maternal use of
      acetaminophen or NSAIDs adjusting for fever. METHODS: Infants with nonsyndromic
      mVSDs (cases) and without birth defects (controls), with gestational age > or =37
      weeks and their mothers were enrolled in the National Birth Defects Prevention
      Study. Two exposure periods were defined: the first trimester of pregnancy, and
      one month before pregnancy through delivery. Mothers reporting fever or
      medication use at least once during either period were considered exposed.
      Adjusted odds ratios and 95% confidence intervals were estimated independently
      for each exposure period. RESULTS: The analysis included 168 cases and 692
      controls. Two case groups were evaluated: all mVSD infants (n = 168) (including
      those with associated minor cardiac defects or noncardiac defects), and infants
      with isolated mVSDs (n = 133). Mothers of cases were less likely to be African
      American than Caucasian (OR, 0.36; 95% CI, 0.18, 0.73). Approximately equal
      numbers of case mothers and control mothers (10.4 versus 9.7%, respectively)
      reported at least one febrile episode during the first trimester. Neither
      acetaminophen nor NSAID exposure was significantly associated with mVSDs. This
      was true for both case groups and both exposure periods. CONCLUSIONS: Significant
      associations were not detected between the occurrence of mVSDs and maternal use
      of NSAIDs or acetaminophen adjusting for maternal fever, nor were they detected
      between maternal fever and mVSDs.

PMID- 15039923
TI  - Evidence that the risk of spina bifida is influenced by genetic variation at the
      NOS3 locus.
AB  - BACKGROUND: There is substantial evidence that the risk of spina bifida, a
      malformation of the caudal neural tube, may be associated with maternal or
      embryonic disturbances in the folate-homocysteine metabolic axis. Hence, variants
      of genes that influence this pathway represent an intriguing group of candidate
      genes for spina bifida and other neural tube defects (NTD). A common variant of
      the gene for endothelial nitric oxide synthase (NOS3 G894T) was recently added to
      this group of NTD candidate genes, based on a report demonstrating that
      homozygosity for the T allele of this variant is associated with increased
      homocysteine levels in normal adult populations. METHODS: The association between
      the risk of spina bifida and both the maternal and embryonic genotype for the
      NOS3 G894T variant was evaluated in data from 301 families by using the
      transmission disequilibrium test (TDT) and log-linear modeling. RESULTS: Analyses
      of these data using the TDT provided no evidence that the risk of spina bifida
      was significantly related to either the maternal or embryonic NOS3 genotype.
      However, the log-linear analyses indicated that the risk of spina bifida was
      significantly associated with the embryonic, but not the maternal, genotype for
      the NOS3 G894T variant. CONCLUSIONS: The results of the present analyses suggest
      that the embryonic NOS3 G894T genotype is associated with the risk of spina
      bifida. Moreover, these analyses highlight the importance of a detailed
      examination of the study data. Had these analyses been restricted to the
      methodologically simpler TDT, the association between the NOS3 G894T genotype and
      risk of spina bifida may well have been overlooked.

PMID- 15039925
TI  - Excess birth prevalence of Hypoplastic Left Heart syndrome in eastern Wisconsin
      for birth cohorts 1997-1999.
AB  - BACKGROUND: Hypoplastic Left Heart syndrome (HLHS) is a group of cardiac
      malformations involving underdevelopment of the left heart with an inability to
      maintain systemic circulation. Because of a clinical impression of excess HLHS
      prevalence, we completed a medical record review of cases born from 1997 through
      1999 who were Wisconsin residents and seen at the Children's Hospital of
      Wisconsin (CHW). METHODS: Cases were identified either in the CHW medical records
      database or the Division of Pediatric Cardiology database and confirmed by
      echocardiogram, catheterization, surgery, or autopsy. U.S. and international
      surveillance systems were used to estimate population risk. Rates per 10,000
      births were computed for eastern Wisconsin and four regions within this portion
      of the state, and compared to the estimated population risk. The same methods
      were used to evaluate whether rates for tetralogy of Fallot and transposition of
      the great arteries were elevated. RESULTS: A total of 61 cases were ascertained
      yielding a birth prevalence of 3.7 per 10,000 births, which was greater than the
      estimated population risk of 2.79. The rate for the southeast region also
      exceeded the expected rate. The most urban and industrialized areas had the
      highest rates. Rates for the other two diagnoses evaluated were not different
      from estimated population risks. CONCLUSIONS: Eastern Wisconsin, particularly the
      urban southeast region, had elevated rates of HLHS. Because of the geographic
      clustering of high rates, environmental factors may be associated with this
      finding.

PMID- 15039926
TI  - Hypoglycemia induced changes in cell death and cell proliferation in the
      organogenesis stage embryonic mouse heart.
AB  - BACKGROUND: Hypoglycemia is a side effect of diabetes therapy and causes abnormal
      heart development. Embryonic heart cells are largely resistant to teratogen
      induced apoptosis. METHODS: Hypoglycemia was tested for effects on cell death and
      cell proliferation in embryonic heart cells by exposing mouse embryos on
      embryonic day (E) 9.5 (plug = E0.5) to hypoglycemia (30-50 mg/dl glucose) in vivo
      or in vitro for 24 hr. Long-term effects of in vivo exposure on conceptus
      viability were evaluated at E18.5. Cell death was evaluated on E10.5 by: 1) two
      TUNEL assays in sectioned embryos to demonstrate DNA fragmentation; 2) confocal
      microscopy in whole embryos stained with Lysotracker; 3) flow cytometry in
      dispersed heart cells stained for TUNEL and myosin heavy chain (MHC) to quantify
      and characterize cell type susceptibility; and 4) immunohistochemistry (IHC) and
      Western analysis in sectioned embryos to evaluate potential involvement of
      caspase-3 active subunit and p53. Effects on cell proliferation were evaluated by
      IHC and Western analysis of proliferating cell nuclear antigen (PCNA). RESULTS:
      In vivo hypoglycemic exposure on E9.5 reduced viability in conceptuses examined
      on E18.5. Hearts examined on E10.5 demonstrated increased TUNEL and Lysotracker
      staining. In hearts of embryos exposed to hypoglycemia, flow cytometry
      demonstrated increased TUNEL-positive cells and cells dual-labeled for TUNEL and
      MHC. Protein expression of caspase-3 active subunit and p53 was increased and
      PCNA was markedly reduced in hearts of embryos exposed to hypoglycemia.
      CONCLUSIONS: Hypoglycemia reduces embryonic viability, induces significant cell
      death, and reduces cell proliferation in the E9.5 mouse heart, and these
      processes may involve active caspase-3 and p53.

PMID- 15039927
TI  - Teratogenic effects of bis-diamine on the developing myocardium.
AB  - BACKGROUND: Bis-diamine induces conotruncal anomalies and disproportional
      ventricular development in rat embryos when administered to the mother. To
      evaluate the mechanisms of disproportional ventricular development in the
      anomalous heart, we analyzed the morphology of the embryonic heart and
      investigated cardiomyocytic DNA synthesis and apoptosis. METHODS: A single dose
      of 200 mg of bis-diamine was administered to pregnant rats Wistar on day 9.5 of
      pregnancy. The embryos were removed on each embryonic day from 10.5 to 18.5.
      Expression of cardiotrophin-1 and hepatocyte growth factor was investigated on
      the sections, and cardiotrophin-1, hepatocyte growth factor and myocyte enhancer
      factor 2 mRNA expression was examined by reverse transcriptase-polymerase chain
      reaction. Myocardial DNA synthesis was investigated using 5-bromo-2'-deoxyuridine
      and the labeling index was calculated for each heart. Apoptosis was also analyzed
      using TUNEL reaction and electrophoresis of DNA fragmentation. RESULTS: The
      embryos treated with bis-diamine had conotruncal anomalies associated with thin
      left ventricular wall in the later stage. The labeling index on embryonic day
      15.5 and 16.5 was significantly lower than those in the controls. Hepatocyte
      growth factor and cardiotrophin-1 mRNA expression was upregulated on embryonic
      day 12.5 and 15.5 in bis-diamine-treated hearts. Fewer apoptotic cells were
      detected in the hearts of bis-diamine-treated embryos than in control hearts from
      embryonic day 14.5 to 16.5. CONCLUSIONS: The ventricular disproportion in the bis
      diamine-treated heart may be caused by the early myocardial differentiation delay
      and poor proliferation and reduced apoptosis associated with anomalous
      circulatory condition in the later stage.

PMID- 15039928
TI  - Changes in sialylation in homozygous Sp2H mouse mutant embryos.
AB  - BACKGROUND: The splotch (Sp(2H)), Pax-3 mutant mice are characterized by
      neurulation defects, neural crest deficiencies, and altered somitogenesis. A link
      connecting all morphological abnormalities in the Pax-3 homozygous embryos is the
      composition of extracellular matrix and misexpression of cell adhesion molecules.
      The neural cell adhesion molecule (NCAM) is one of the Pax-3 target genes. Its
      adhesive properties depend on the attached polysialic acid (PSA). We have studied
      whether NCAM sialylation has been affected in the Pax-3 mutant embryos. METHODS:
      Genotyping of embryos was determined using polymerase chain reaction. The
      periodate-resorcinol method was used for quantitative determination of sialic
      acid. Immunoblotting was used to detect sialylated NCAM isoforms and sialic acids
      on the blot. This antibody was also used to detect PSA-NCAM spatial expression.
      RESULTS: Quantitative determination of sialic acid at days 10.5-13.5 showed
      decreased sialic acid content in Sp(2H) homozygotes. The results of both
      techniques used in evaluating the expression of PSA-NCAM isoforms in our study
      indicate that the 180-kDa isoform is decreased in homozygous Splotch (Sp(2H))
      embryos. Immunohistochemistry showed decreased staining in the neural tube,
      ganglion VIII, (day 13.5), frontal lobe, olfactory bulb, and neuroblastic retinal
      cells (day 18.5). CONCLUSIONS: PSA-NCAM is present in Sp(2H) embryos of all
      genotypes, starting on developmental day 9.5. Sialylation of the 180-kDa NCAM
      isoform begins to decrease on day 12.5 in Sp(2H) homozygotes. Reduced NCAM
      sialylation could contribute to the decreased migration of cells in the sensory
      organs.

PMID- 15039929
TI  - Amniotic bands and exocelomic stickiness.

PMID- 15039931
TI  - Solid-phase microextraction: a powerful sample preparation tool prior to mass
      spectrometric analysis.
AB  - Sample preparation is an essential step in analysis, greatly influencing the
      reliability and accuracy of resulted the time and cost of analysis. Solid-Phase
      Microextraction (SPME) is a very simple and efficient, solventless sample
      preparation method, invented by Pawliszyn in 1989. SPME has been widely used in
      different fields of analytical chemistry since its first applications to
      environmental and food analysis and is ideally suited for coupling with mass
      spectrometry (MS). All steps of the conventional liquid-liquid extraction (LLE)
      such as extraction, concentration, (derivatization) and transfer to the
      chromatograph are integrated into one step and one device, considerably
      simplifying the sample preparation procedure. It uses a fused-silica fibre that
      is coated on the outside with an appropriate stationary phase. The analytes in
      the sample are directly extracted to the fibre coating. The SPME technique can be
      routinely used in combination with gas chromatography, high-performance liquid
      chromatography and capillary electrophoresis and places no restriction on MS.
      SPME reduces the time necessary for sample preparation, decreases purchase and
      disposal costs of solvents and can improve detection limits. The SPME technique
      is ideally suited for MS applications, combining a simple and efficient sample
      preparation with versatile and sensitive detection. This review summarizes
      analytical characteristics and variants of the SPME technique and its
      applications in combination with MS.

PMID- 15039932
TI  - New designer drug 1-(3,4-methylenedioxybenzyl) piperazine (MDBP): studies on its
      metabolism and toxicological detection in rat urine using gas chromatography/mass
      spectrometry.
AB  - Studies are described on the metabolism and toxicological analysis of the
      piperazine-derived designer drug 1-(3,4-methylenedioxybenzyl)piperazine (MDBP) in
      rat urine using gas chromatography/mass spectrometry (GC/MS). The identified
      metabolites indicated that MDBP was metabolized by demethylenation and subsequent
      methylation to N-(4-hydroxy-3-methoxybenzyl)piperazine followed by partial
      glucuronidation or sulfation. Additionally, degradation of the piperazine moiety
      to N-(3,4-methylenedioxybenzyl)ethylenediamine and 3,4-methylenedioxybenzylamine
      and N-dealkylation to piperazine were observed. The authors' systematic
      toxicological analysis (STA) procedure using full-scan GC/MS after acid
      hydrolysis, liquid/liquid extraction and microwave-assisted acetylation allowed
      the detection of MDBP and its above-mentioned metabolites in rat urine after
      single administration of a dose calculated from the doses commonly taken by drug
      users. Assuming similar metabolism, the described STA procedure should be
      suitable for proof of an intake of MDBP by analysis of human urine.

PMID- 15039933
TI  - Simultaneous quantification of cyclophosphamide, 4-hydroxycyclophosphamide,
      N,N',N"-triethylenethiophosphoramide (thiotepa) and N,N',N"
      triethylenephosphoramide (tepa) in human plasma by high-performance liquid
      chromatography coupled with electrospray ionization tandem mass spectrometry.
AB  - The alkylating agents cyclophosphamide (CP) and N, N', N"
      triethylenethiophosphoramide (thiotepa) are often co-administered in high-dose
      chemotherapy regimens. Since these regimens can be complicated by the occurrence
      of severe and sometimes life-threatening toxicities, pharmacokinetically guided
      administration of these compounds, to reduce variability in exposure, may lead to
      improved tolerability. For rapid dose adaptations during a chemotherapy course,
      we have developed and validated an assay, using liquid chromatography coupled
      with electrospray tandem mass spectrometry (LC/MS/MS), for the routine
      quantification of CP, thiotepa and their respective active metabolites 4
      hydroxycyclophosphamide (4OHCP) and N, N', N"-triethylenephosphoramide (tepa) in
      plasma. Because of the instability of 4OHCP in plasma, the compound is
      derivatized with semicarbazide (SCZ) immediately after sample collection and
      quantified as 4OHCP-SCZ. Sample pretreatment consisted of protein precipitation
      with a mixture of methanol and acetronitrile using 100 microl of plasma.
      Chromatographic separation was performed on an Zorbax Extend C18 column (150 x
      2.1 mm i.d., particle size 5 microm), with a quick gradient using 1 mM ammonia
      solution and acetonitrile, at a flow-rate of 0.4 ml min(-1). The analytical run
      time was 10 min. The triple quadrupole mass spectrometer was operating in the
      positive ion mode and multiple reaction monitoring was used for drug
      quantification. The method was validated over the concentration ranges 200-40,000
      ng ml(-1) for CP, 50-5000 ng ml(-1) for 4OHCP-SCZ and 5-2500 ng ml(-1) for
      thiotepa and tepa, using 100 microl of human plasma. These dynamic concentration
      ranges proved to be relevant in daily practice. Hexamethylphosphoramide was used
      as an internal standard. The coefficients of variation were <12% for both intra
      day and inter-day precisions for each compound. Mean accuracies were also between
      the designated limits (+/- 15%). This robust and rapid LC/MS/MS assay is now
      successfully applied for routine therapeutic drug monitoring of CP, thiotepa and
      their metabolites in our hospital.

PMID- 15039936
TI  - Accurate mass measurement and tandem mass spectrometry of intact globin chains
      identify the low proportion variant hemoglobin Lepore-Boston-Washington from the
      blood of a heterozygote.
AB  - Within a mixture of proteins, minor polymorphic components are difficult to
      identify using a conventional proteomic approach. Their identification generally
      requires multi-dimensional separation steps, before or after proteolytic
      cleavage, followed by sequence analysis of the proteolytic products. In this
      study, we investigated the potential of tandem mass spectrometry for protein
      characterization by identifying the delta-beta hybrid human hemoglobin variant
      Lepore-Boston-Washington using electrospray ionization tandem mass spectrometry.
      Hemoglobin Lepore-Boston-Washington occurs mainly in heterozygotes, where it
      comprises approximately 10% of the total non-alpha-chains, the dominant non-alpha
      chain being the normal beta (approximately 90%). Furthermore, Hemoglobin Lepore
      Boston-Washington has an average molecular mass (15,865.23 Da) that is only 2 Da
      lower than that of the normal beta-chain (15,867.24 Da). Consequently, it cannot
      be resolved from the normal beta-chain by mass spectrometry. Here we show how
      Hemoglobin Lepore-Boston-Washington was identified directly from the diluted
      blood of a heterozygote by analyzing the product ions from the Lepore-Boston
      Washington and normal beta-chain ions without prior separation of the individual
      chains. This study shows the potential of the tandem mass spectrometry for
      identifying a minor component in an unseparated mixture of proteins.

PMID- 15039935
TI  - Quantitative analysis of the novel anticancer drug ABT-518, a matrix
      metalloproteinase inhibitor, plus the screening of six metabolites in human
      plasma using high-performance liquid chromatography coupled with electrospray
      tandem mass spectrometry.
AB  - A liquid chromatographic/tandem mass spectrometric (LC/MS/MS) assay for the
      quantitative analysis of the novel anticancer drug ABT-518 and the screening of
      six potential metabolites in human plasma has been developed and validated to
      support a phase I study with the drug. ABT-518 is an inhibitor of matrix
      metalloproteinases, which are associated with tumor growth and development of
      metastasis. Plasma samples were prepared for analysis using a simple solid-phase
      extraction method on phenyl cartridges. LC separation was performed on a Zorbax
      extend C18 column (150 x 2.1 mm i.d., 5 microm particle size) using a mobile
      phase of methanol-aqueous 10 mM ammonium hydroxide (80:20, v/v) pumped at a flow
      rate of 0.2 ml min(-1). An API2000 triple-quadrupole mass spectrometer was used
      for specific and sensitive detection. The best chromatographic speed (total run
      time 8 min) and peak shapes were obtained by employing an alkaline mobile phase
      (pH in aqueous phase approximately 10). Furthermore, an alkaline eluent was
      favored in order to obtain a better overall sensitivity for the protonated
      analytes. The dynamic range was from 10 to 1000 ng ml(-1) from 500 microl of
      plasma for ABT-518 and the metabolites were detected at levels of the same order
      of magnitude. Inter-assay accuracies for ABT-518 at five concentration levels
      were between -9.24 and 6.93% and inter-assay precisions were always <10.7%.
      Analyte stability was not critical during either storage or processing. This
      method was successfully applied in a phase I clinical study of ABT-518. The
      active drug, ABT-518, and all of the metabolites included in the assay could be
      identified in plasma from dosed patients. We believe that the method described in
      this paper using an alkaline mobile phase in combination with a basic stable
      analytical column may also be generally useful for the bioanalysis of other basic
      drugs.

PMID- 15039937
TI  - Collision-induced dissociation of valdecoxib metabolites: a novel rearrangement
      involving an isoxazole ring.
AB  - Valdecoxib is a potent COX-2 inhibitor. During metabolism studies of valdecoxib
      by liquid chromatography/tandem mass spectrometry, we observed a novel mass
      spectral rearrangement involving an isoxazole ring for some of the metabolites in
      the negative ion mode. Accurate mass measurements were performed with quadrupole
      time-of-flight mass spectrometry to determine the elemental compositions of the
      fragments. Additionally, two types of stable-isotope labeled analogues were
      prepared to assist with the assignments of these fragments and possible
      mechanistic rearrangements resulting from collision-induced dissociation (CID).
      Detailed analyses of the CID mass spectra suggest that the fragmentation process
      involves a novel two-step rearrangement. The first step consists of an
      intramolecular SN2 reaction with a five-membered ring rearrangement to form an
      intermediate. The second step involves a four-membered ring intramolecular
      rearrangement followed by a cleavage of the N-O bond on the isoxazole ring to
      form a unique fragment ion at m/z 196. The same phenomenon was observed for a
      group of structurally related metabolites that also contain a 5-hydroxymethyl or
      5-carboxylic acid moieties. A mechanism for the novel rearrangement involving an
      isoxazole ring is proposed.

PMID- 15039939
TI  - Characterization of the interglycosidic linkage in di-, tri-, tetra- and
      pentaglycosylated flavonoids and differentiation of positional isomers by liquid
      chromatography/electrospray ionization tandem mass spectrometry.
AB  - The LC/UV-DAD/ESI-MSn negative fragmentation mode of 23 O-glycosylated flavonoids
      with two, three, four and five hexoses was studied. The results show that it is
      possible to differentiate the (1-->2) and (1-->6) interglucosidic linkages and
      also to discern between the flavonoid isomers with two glucoses (sophorosides,
      gentiobiosides and X,Y-diglucosides), three glucoses (sophorotriosides and X
      sophoroside-Y-glucoside) and four glucoses (X-sophorotriosides-Y-glucoside and X
      sophoroside-Y-sophoroside). In the characterization of the (1-->2) and (1-->6)
      interglycosidic linkages, the Y1- (-162 u) and Z1- (-180 u) ions play a relevant
      role. In the first case ions with high relative abundance (13-79%) are found,
      whereas in the other cases they are in very low abundance or absent. X,Y-di-O
      glucoside flavonoids can be differentiated from the O-diglucoside flavonoids by
      the presence of Y1- (base peak) and Y0- (approximately 30%) ions and the absence
      of Z1- ions. Regarding flavonoids glycosylated with three glucoses, X-sophoroside
      Y-glucoside flavonoids show the Y7(0-) (-162 u) ion as the only peak in MS2
      events whereas in sophorotrioside flavonoids various ions due to intermediate
      fragmentations are observed. These ions are characteristic of a (1-->2)
      interglucosidic linkage. In MS2 experiments on flavonoids with four glucoses (X
      sophorotrioside-Y-glucoside and X-sophoroside-Y-sophoroside), the base peak
      indicated the total loss of the sugar moieties in position 7. In addition, the
      characterization of the type of interglycosidic linkage in flavonoids
      glycosylated with five sugars can be achieved. On the other hand, in tetra- and
      pentaglycosylated flavonoids, the ions that characterize the (1-->2)
      interglucosidic linkage formed by intermediate fragmentation of the
      oligosacharide residues (sophorosides and sophorotriosides) are found in much
      higher relative abundance in MS3 than in MS2 experiments, where they are almost
      not detected.

PMID- 15039940
TI  - A top-down method for the determination of residue-specific solvent accessibility
      in proteins.
AB  - We present a method employing top-down Fourier transform mass spectrometry (FTMS)
      for the rapid profiling of amino acid side-chain reactivity. The reactivity of
      side-chain groups can be used to infer residue-specific solvent accessibility and
      can also be used in the same way as H/D exchange reactions to probe protein
      structure and interactions. We probed the reactivity of the N-terminal and
      epsilon-lysine amino groups of ubiquitin by reaction with N-hydroxysuccinimidyl
      acetate (NHSAc), which specifically acetylates primary amines. Using a hybrid Q
      FTMS instrument, we observed several series of multiply acetylated ubiquitin ions
      that varied with the NHSAc:protein stoichiometry. We isolated and fragmented each
      member of the series of acetylated ubiquitin ions in the front end of the
      instrument and measured the fragment ion masses in the FTMS analyzer cell to
      determine which residue positions were modified. As we increased the
      NHSAc:protein stoichiometric ratio, identification of the fragments from native
      protein and protein with successively increasing modification allowed the
      assignment of the complete order of reactivity of the primary amino groups in
      ubiquitin (Met 1 approximately Lys 6 approximately Lys 48 approximately Lys
      63>Lys 33>Lys 11>Lys 27, Lys 29). These results are in excellent agreement with
      the reactivity expected from other studies and predicted from the known crystal
      structure of ubiquitin. The top-down approach eliminates the need for proteolytic
      digestion, high-performance liquid chromatographic separations and all other
      chemical steps except the labeling reaction, making it rapid and amenable to
      automation using small quantities of protein.

PMID- 15039941
TI  - Current literature in mass spectrometry.

PMID- 15039942
TI  - Primordial germ cells: what does it take to be alive?
AB  - Specification of primordial germ cells (PGCs) in the proximal epiblast enables
      about 45 founder PGCs clustered at the base of the allantoic bud to enter the
      embryo by active cell movement. Specification of the PGC lineage depends on
      paracrine signals derived from the somatic cell neighbors in the extraembryonic
      ectoderm. Secretory bone morphogenetic proteins (BMP) 4, BMP8b, and BMP2 and
      components of the Smad signaling pathway participate in the specification of
      PGCs. Cells in the extraembryonic ectoderm induce expression of the gene fragilis
      in the epiblast in the presence of BMP4, targeting competence of PGCs. The
      fragilis gene encodes a family of transmembrane proteins presumably involved in
      homotypic cell adhesion. As PGCs migrate throughout the hindgut, they express
      nanos3 protein. In the absence of nanos3 gene expression, no germ cells are
      detected in ovary and testis. During migration and upon arrival at the genital
      ridges, the population of PGCs is regulated by a balanced
      proliferation/programmed cell death or apoptosis. Paracrine and autocrine
      mechanisms, involving transforming growth factor-beta1 and fibroblast growth
      factors exert stimulatory or inhibitory effects on PGCs proliferation, modulated
      in part by the membrane-bound form of stem cell factor. Apoptosis requires the
      participation of the pro-apoptotic family member Bax, whose activity is balanced
      by the anti-apoptotic family member Bcl21/Bcl-x. In addition, a loss of cell-cell
      contacts in vitro results in the apoptotic elimination of PGCs. It needs to be
      determined whether apoptosis is triggered by a failure of PGC to establish and
      maintain appropriate cell-cell contacts with somatic cells or whether undefined
      survival factors released by adjacent somatic cells cannot reach physiological
      levels to satisfy needs of the expanding population of PGCs.

PMID- 15039943
TI  - Autocrine and paracrine mechanisms regulating primordial germ cell proliferation.
AB  - Although several mitogens and survival factors have been previously shown to act
      on primordial germ cells (PGCs) in culture, it is not clear whether they are
      responsible for controlling proliferation of PGCs in the embryo. We show here
      that during their migratory phase, PGCs do not express FGF-4, FGF-8, or FGF-17,
      but these FGFs are expressed by neighboring cells. Thus, any FGF action on
      migrating PGCs would appear to be through a paracrine mechanism. We found that
      after entering into the gonads, PGCs start to express FGF-4 and FGF-8. On this
      basis, we hypothesize that FGF signaling is involved in both a paracrine manner
      in initiating PGC proliferation during their migration and an autocrine manner in
      sustaining PGC proliferation after their arrival in the gonads. We then studied
      the role of soluble stem cell factor (SCF), which acts as a survival factor or a
      mitogen in culture, to determine whether it interacts with FGFs. We found that
      SCF has a complex effect on PGC proliferation. On one hand, soluble SCF promoted
      PGC proliferation synergistically with FGF in the absence of membrane-bound SCF.
      Conversely, soluble SCF inhibited FGF-stimulated proliferation of PGCs in the
      presence of membrane-bound SCF. We account for these findings in a model
      involving regulation of PGC proliferation, in which SCF modulates the response to
      FGFs.

PMID- 15039944
TI  - Specific gene silencing in the pre-implantation stage mouse embryo by an siRNA
      expression vector system.
AB  - Recently, small interfering RNAs (siRNAs) have become a powerful and widely used
      tool for the analysis of gene function in mammalian cells. Here we report that
      the microinjection of an siRNA expression vector into the nucleus is an efficient
      and powerful method of specific gene silencing in pre-implantation mouse embryos.
      We used this method to examine the expression of two genes EGFP and Oct4. Vectors
      encoding siRNAs targeted against EGFP or Oct4 were injected into the pronucleus
      or nucleus of zygotes, which were then cultured until the blastocyst stage. When
      the effects of RNAi were examined in blastocyst stage eggs, there was robust
      inhibition of the gene product in a concentration-dependent manner at both the
      mRNA and the protein level. The expression of other endogenous genes was not
      affected, showing the specificity of the vector-mediated RNAi. In addition, this
      method was effective for inhibiting maternally expressed mRNA. To demonstrate
      that RNAi of Oct4 induced a similar phenotype to that of Oct4-null embryos, the
      blastocysts were further cultured in ES medium. After the fourth day of culture,
      the embryos either had outgrown only a layer of trophoblast cells or showed
      developmental arrest at the blastocyst stage (>90%). Moreover, concomitant with
      Oct4 suppression at the blastocyst stage, we observed inhibition of Fgf4, a gene
      that is known to be induced downstream of Oct4 expression. Taken together, these
      results demonstrate that the use of siRNA expression vector is a powerful way to
      achieve gene silencing in the pre-implantation stage embryo.

PMID- 15039945
TI  - Bovine oocyte cytoplasm supports nuclear remodeling but not reprogramming of
      murine fibroblast cells.
AB  - Nuclear transfer (NT) is used to elucidate fundamental biological issues such as
      reversibility of cell differentiation and interactions between the cytoplasm and
      nucleus. To obtain an insight into interactions between the somatic cell nucleus
      and oocyte cytoplasm, nuclear remodeling and gene expression were compared in
      bovine oocytes that had received nuclei from bovine and mouse fibroblast cells.
      While the embryos that received nuclei from bovine fibroblast cells developed
      into blastocysts, those that received nuclei from mouse fibroblasts did not
      develop beyond the 8-cell stage. Similar nuclear remodeling procedures were
      observed in oocytes reconstructed with mouse and bovine fibroblast cells. Foreign
      centrosomes during NT were introduced into embryos reconstructed with both
      fibroblast cell types. A number of housekeeping mouse genes (hsp70, bax, and glt
      1) were abnormally expressed in embryos that had received nuclei from mouse
      fibroblast cells. However, development-related genes, such as Oct-4 and E-cad,
      were not expressed. The results collectively suggest that the bovine oocyte
      cytoplasm supports nuclear remodeling, but not reprogramming of mouse fibroblast
      cells.

PMID- 15039946
TI  - Expression of 11 members of the BCL-2 family of apoptosis regulatory molecules
      during human preimplantation embryo development and fragmentation.
AB  - Apoptosis during preimplantation development has received much interest because
      of its potential role in eliminating defective cells. Although development in
      humans is characterised by a high degree of genetic abnormality, little is known
      of the regulation of apoptosis in embryos. By PolyA PCR we analysed expression of
      11 BCL-2 genes in individual human embryos representative of normal development
      and in severely fragmented embryos. We demonstrate constitutive expression of BAX
      in virtually all embryos at all stages of development, and variable expression of
      BCL2, BCL-XL, BCL-W, MCL-1 BAK, BAD, BOKL, BID, BIK, and BCL-XS. The frequency of
      expression of pro- and anti-apoptotic BCL-2 members was similar throughout
      development, except at the two-cell stage where pro-apoptotic genes predominated.
      Protein expression was confirmed for BCL-2, MCL-1, BCL-X, BAX, BAD, and activated
      caspase 3. BCL-2 protein was associated with mitochondria but expressed
      inconsistently in the blastocyst inner cell mass. Consistent differences between
      morphologically intact and fragmented embryos included the expression of BAK in
      fragmented but not intact four-cell embryos. Our study addresses the importance
      of examining single human embryos representative of the viable population for a
      large number of genes, in order to establish meaningful expression profiles and
      provide information on overlapping function in a large gene family.

PMID- 15039948
TI  - Differential development of rabbit embryos derived from parthenogenesis and
      nuclear transfer.
AB  - Parthenogenetic development (PA) is often used as a model to investigate
      activation protocols for nuclear transfer (NT) embryos. The objective of this
      study was to compare the development, as well as the dynamics of the nuclear
      materials and microtubules of PA and NT embryos following similar activation
      treatment. Our results demonstrate that, during parthenogenesis, activation
      through either electrical pulses or chemical stimulation alone resulted in low
      cleavage rates and compromised development. A combination of two sets of
      electrical pulses and a 2-h-exposure to chemical activation medium (5 microg/ml
      cycloheximide (CHX) and 2 mM 6-dimethylaminopurine (6-DMAP) in KSOM+0.1% BSA)
      could effectively activate rabbit oocytes, and resulted in a 99% (n = 73)
      cleavage rate with greater than 60% (n = 73) developing to blastocysts at day 4.
      However, the same activation protocol following NT resulted in only 65-72% of
      oocytes cleaved (depending on donor cell type), with less than 20% developing to
      the blastocyst stage. The differences observed between NT and PA embryos
      subjected to the same activation protocol were also evident in terms of the time
      required for their development to the blastocyst stage, as well as the cell
      numbers present in blastocysts at day 6. Furthermore, laser confocal microscopy
      revealed that pronuclear formation in the NT embryos was delayed by comparison to
      that in the parthenotes. In conclusion, our study suggests that an effective
      protocol for parthenogenesis cannot promise a comparable outcome for NT embryos.

PMID- 15039947
TI  - Optimization of parthenogenetic activation protocol in porcine.
AB  - The effects of the electrical field strengths, number of pulses, and post
      activation media on chromatin conformation and parthenogenetic development were
      studied to optimize the activation protocol for porcine nuclear transfer. In
      experiment 1, electrical field strengths were examined. Oocytes were subjected to
      square direct current pulses at output voltages of 1.2, 1.7, 2.2, and 2.7 kV/cm
      for 1 x 30 microsec. The voltage resulting from experiment 1 was 2.2 kV/cm, in
      which 50.0% of activated oocytes developed to blastocysts in vitro. In experiment
      2, the influence of 1, 2, and 3 pulses on blastocyst development was tested using
      field strengths and post-activation medium described in experiment 1. Oocytes
      activated by a single 30 microsec pulse of 2.2 kV/cm DC yielded a higher
      blastocyst rate (56.3%) than oocytes activated by 2 or 3 pulses (<42.5%). In
      experiment 3 and 4, we investigated the effects of cytochalasin B (CB),
      cycloheximide (CH), and CB + CH on nuclear development stages and parthenogenetic
      development following a single 30 microsec pulse of 2.2 kV/cm DC. The percentage
      of activated oocytes was not different among CB (93.3%), CB + CH (98.3%), control
      (80.0%), and CH (80.0%) groups 12 hr after activation. Treatment with CB (57.5%)
      or CB + CH (53.8%) enhanced the blastocyst rate compared with other groups, CH
      (23.8%) treated- and control group (18.8%). The results demonstrated that a
      single 30 microsec pulse of 2.2 kV/cm DC followed by culturing in post-activation
      medium with CB for 5 hr were effective parameters for parthenogenetic activation
      and blastocyst formation of in vitro matured porcine oocytes which suggests that
      a single calcium rise is sufficient to activate pig oocytes and to achieve high
      rate of blastocyst development.

PMID- 15039949
TI  - Incidence of apoptosis in clone embryos and improved development by the treatment
      of donor somatic cells with putative apoptosis inhibitors.
AB  - This study was conducted to promote in vitro-development of clone embryos by the
      treatment of donor somatic cells with hemoglobin (Hb) and/or beta-mercaptoethanol
      (ME), based on the analysis of apoptosis after somatic cell nuclear transfer
      (SCNT). Prospective, randomized study was conducted and, in vitro-matured bovine
      oocytes and fetal fibroblasts were provided for SCNT. In the first series of
      experiment, embryo apoptosis after SCNT was monitored by a terminal
      deoxynucleotidyl transferase-mediated d-UTP nick end-labeling assay. As results,
      apoptosis occurred more (P < 0.05) frequently after SCNT than after in vitro
      fertilization (IVF) of control treatment. Subsequently, donor somatic cells
      treated with Hb (1 microg/ml) and/or ME (10 microM) were provided for SCNT.
      Either Hb or ME greatly reduced apoptosis (0.083 +/- 0.006 vs. 0.058-0.068 +/-
      0.005), while combined treatment did not. ME was more promotive than Hb;
      significant increases were found in morula compaction (86%), cell numbers of
      blastocyst (131.3 +/- 1.3 cells/blastocyst), and inner cell mass (31.9 +/- 0.8
      cells/blastocyst) cell, and the ratio of inner cell mass to trophectodermal cell
      numbers (0.24 +/- 0.01). In conclusion, the treatment of donor somatic cells with
      ME or Hb could reduce apoptosis after SCNT, resulting improved preimplantation
      development.

PMID- 15039950
TI  - Differential growth, cell proliferation, and apoptosis of mouse embryo in various
      culture media and in coculture.
AB  - Sequential culture and coculture are two methods of improving the development of
      preimplantation embryos in vitro. Direct comparison of the efficiency of these
      methods is limited. Proliferation and apoptosis determine the total number of
      blastomere in preimplantation embryo, which is a sensitive parameter for
      evaluation of the development of embryo in vitro. In this study, we compared the
      proliferation and apoptosis of mouse embryo in different culture media, including
      CZB, KSOM, MTF, G1.2/G2.2 sequential culture media, and in human oviductal cell
      coculture. Sequential culture using G1.2/G2.2 was superior to KSOM, MTF, and
      CZB/CZB + G with respect to the formation of 3-4 cell embryos, morula, and
      blastocyst. G1.2/G2.2 cultured blastocyst had significantly more proliferating
      blastomeres and higher total cell number per blastocyst than those cultured in
      KSOM or CZB/CZB + G. Compared to embryos cultured in G1.2/G2.2, embryos
      cocultured in G1.2/G2.2 hatched more frequently. Cocultured blastocysts also had
      significantly higher percentage of proliferating cell and lower percentage of
      apoptotic cell per blastocyst than those cultured in G1.2/G2.2. It was concluded
      that G1.2/G2.2 facilitated the proliferation of blastomere whilst human oviductal
      cell coculture suppressed apoptosis in addition to stimulating proliferation of
      blastomere.

PMID- 15039951
TI  - Enriched gonadal migration of donor-derived gonadal primordial germ cells by
      immunomagnetic cell sorting in birds.
AB  - This study was conducted to evaluate whether immunomagnetic treatment could
      improve the retrieval and migration capacity of avian gonadal primordial germ
      cells (gPGCs) collected from gonads in 5.5-day-old chick and 5-day-old quail
      embryos, respectively. Collected gPGCs were loaded into a magnetic-activated cell
      sorter (MACS) after being conjugated with specific gPGC antibodies and either
      MACS-treated or non-treated cells in each species were subsequently transferred
      to the recipient embryos. MACS treatment significantly (P < 0.05) increased the
      population ratio of gPGCs in gonadal cells retrieved (0.74 to 33.4% in the
      chicken and 2.68 to 45.1% in the quail). This was due to decreased number of non
      gPGCs in total cell population. MACS treatment further enhanced gonadal migration
      of gPGCs transferred in both species (10% vs. 80-85% in the chicken and 10-15%
      vs. 70-80% in the quail). Increase in the number of microinjected cells up to 600
      cells/embryo did not eliminate such promoting effect. In conclusion, MACS
      treatment greatly increased the population ratio of avian gPGCs in gonadal cells,
      resulting improved gonadal migration in recipient embryos.

PMID- 15039953
TI  - Factors affecting fertilization of porcine oocytes following intracytoplasmic
      injection of sperm.
AB  - The objective of this study was to optimize intracytoplasmic sperm injection
      (ICSI), and to assess the effects of membrane-damaged sperm on development of
      porcine oocytes following ICSI. For optimization of development following the
      ICSI process, sperm injected oocytes were activated 0.5-1.0 hr after ICSI with 1
      x 30 micros pulse of 1.2, 1.7, 2.2, and 2.7 kV/cm DC in experiment 1. After 7
      days of culture ICSI oocytes activated with [x1]2.2 kV/cm produced more
      blastocyts ([x2]34.4%, P < 0.05) than other treatment groups. In experiment 2,
      oocytes were activated with 1 x 30 micros pulse of 2.2 kV/cm at either 0, 1.5, 3,
      or 6 hr after ICSI. Oocytes activated 1.5 hr after [x3]ICSI yielded more
      blastocysts (27.6%)[M4] than in other treatments. In experiment 3, sperm were
      briefly exposed to 0.1% Triton X-100 to induce membrane damage. Live-dead
      staining of Percoll-sorted untreated spermatozoa (frozen-thawed) used in this
      study showed that over 96% were "alive" whereas none were "alive" after Triton X
      100 treatment. The rate of development to blastocyst of oocytes injected with
      Triton X-100 treated sperm combined with electrical activation (EA) at 1 x 30
      micros pulse of 2.2 kV/cm (EA, 40.0%) was the best, when compared with those
      injected with untreated sperm plus EA (P < 0.05). In experiment 4, the
      development rate of oocytes to the blastocyst stage ([x5]32.1%) following
      injection of a sperm head only was not significantly different from that of
      oocytes injected with whole sperm (31.0%). In conclusion, we found that an intact
      membrane and tail structures of pig spermatozoa are not essential for embryo
      development by ICSI, and furthermore, dead porcine spermatozoa, at an early stage
      of necrosis caused by plasma membrane damage, support better embryo development
      than do live non-damaged sperm.

PMID- 15039952
TI  - Effects of oxidative stress and inhibitors of the pentose phosphate pathway on
      sexually dimorphic production of IFN-tau by bovine blastocysts.
AB  - Bovine interferon-tau (IFN-tau), the anti-luteolytic factor secreted by
      conceptuses of pecoran ruminants, is a product of autosomal genes, yet in vitro
      produced (IVP) female expanded blastocysts (EB) secrete about twice as much IFN
      tau as males. Two possible explanations have been tested here. One is that
      embryos of one sex are differentially susceptible to oxidative stress. The second
      is that female EB produce more IFN-tau because pentose-phosphate pathway (PPP)
      activity is elevated as a result of delayed X-chromosome inactivation. IVP bovine
      zygotes were cultured to the 8-cell stage and placed under conditions designed
      either to promote oxidative stress (+/-H2O2; 20 vs. 5% O2), or to inhibit glucose
      6-phosphate dehydrogenase (G6PDH) activity (addition of dehydroepiandrosterone,
      DHEA or 6-aminonicotinamide, 6-AN to the medium). At day 8, blastocysts were
      cultured individually for a further 48 hr to assess IFN-tau production, and
      embryo sex determined retrospectively. Blastocyst numbers were reduced (P < 0.05)
      and their continued development impaired (P < 0.05) in presence of H2O2 (200
      microM) and 20% O2, but neither IFN-tau production nor sexually dimorphic
      expression of IFN-tau were affected. IFN-tau production was reduced, particularly
      in females (P < 0.05), and sexual dimorphic differences in production were lost
      in the presence of both DHEA (100 microM) and 6-AN (1 microM). In the case of 6
      AN, these effects were achieved without a significant decline in blastocyst
      developmental progression, quality, or cell number. The data suggest that the
      higher production of IFN-tau by female EB is an indirect outcome of the increased
      activity of the oxidative arm of the PPP pathway.

PMID- 15039954
TI  - Effects of scrotal heating on sperm surface protein PH-20 expression in sheep.
AB  - Sperm surface protein PH-20 expression was studied during spermatogenesis in
      pubertal and adult sheep, using molecular and histological methods. The effects
      of 24 hr of insulation raising scrotal temperatures to 39 degrees C on PH-20
      expression in ejaculated sheep sperm were also determined. A 282 nt cDNA fragment
      of ovine PH-20 was identified in total RNA extracts of sheep testes, which
      exhibited 76% identity at the nucleotide level with the equivalent region of the
      human sequence. Ovine PH-20 mRNA and immunoreactivity were identified only in
      adult ram testis and not in peri-pubertal ram testis tubules lacking round
      spermatids, nor in adult sheep brain, pituitary, heart, spleen, lung, liver,
      kidney, epididymis, or ovary. Ovine PH-20 protein was distributed predominantly
      on the postacrosomal membrane and was also present on the anterior membrane of
      the sperm head in fresh, unheated sheep semen. Scrotal heating caused a
      significant, transient decrease in the percentage of PH-20 immunoreactive sperm,
      but did not change the pattern of PH-20 staining on the sperm head. The results
      strongly suggest that ovine PH-20 is postmeiotically expressed in haploid germ
      cells in sheep testis and is arrayed on the membrane of the mature ovine
      spermatozoon. Scrotal heating appears to have few effects on PH-20 expression and
      distribution on ejaculated sperm.

PMID- 15039955
TI  - Extracellular localization of proteasomes in human sperm.
AB  - The proteasome, a multienzymatic protease complex is present in human sperm. Here
      we present evidence indicating that the proteasome has an extracellular
      localization, on the plasma membrane of the sperm head. Motile sperm (>90%) in
      PBS were incubated with the proteasome inhibitors clasto-lactacystin beta-lactone
      or epoxomicin. Then, the substrate Suc-Leu-Leu-Val-Tyr-AMC (SLLVY-AMC) was added
      and the enzyme activity evaluated in a spectrofluorometer. Other aliquots were
      resuspended in Tyrode's medium and incubated at different concentrations for
      various times with or without inhibitors in the presence of 0.4% azocasein.
      Hydrolysis of azocasein was evaluated at 440 nm. In addition, sperm membrane
      proteins were obtained incubating the sperm with Triton X-114 or with 0.5 M KCl
      plus Triton X-100 and removing insoluble material by centrifugation at 5,000g for
      40 min. Proteasomal activity was evaluated with SLLVY-AMC and its presence
      corroborated by Western blotting. Formaldehyde fixed, unpermeabilized sperm were
      incubated with anti-proteasome monoclonal antibodies and evaluated using indirect
      immunofluorescence. The effect of proteasome inhibitors upon the progesterone
      induced acrosome reaction was also evaluated. Results indicated that (a) whole,
      intact sperm were able to hydrolyze the proteasome substrates SLLVY-AMC and
      azocasein; this activity was inhibited by proteasome inhibitors; (b) proteasomal
      activity was detected in soluble sperm membrane protein preparations and Western
      blotting revealed the presence of the proteasome in these fractions; (c) indirect
      immunofluorescence revealed staining of the head region, particularly of the post
      acrosomal region; and (d) the proteasome plays an important role during the
      acrosome reaction.

PMID- 15039957
TI  - Development of solid-phase extraction method and its application for
      determination of hydrochlorothiazide in human plasma using HPLC.
AB  - A high-performance liquid chromatographic method was developed, validated and
      applied for the determination of hydrochlorothiazide in human plasma. The effects
      of mobile phase composition, buffer concentration, mobile phase pH and
      concentration of organic modifiers on retention of hydrochlorothiazide and
      internal standard were investigated. The method involves solid-phase extraction
      on RP-select B cartridges followed by isocratic reversed-phase chromatography on
      a Hibar Lichrospher 100 RP-8 column with UV detection at 230 nm. The recovery,
      selectivity, linearity, precision and accuracy of the method were evaluated from
      spiked human plasma samples. Limit of quantification was 10 ng mL(-1). The method
      has been implemented to monitor hydrochlorothiazide levels in patient samples.

PMID- 15039956
TI  - Nuclear and cytoskeletal alterations of in vitro matured porcine oocytes under
      hyperthermia.
AB  - The effects of heat shock (HS) on the nucleus and cytoskeleton of in vitro
      matured pig oocytes were examined in this study. Porcine cumulus-oocyte complexes
      (COCs) were aspirated from 3 to 6 mm diameter follicles and subjected to standard
      in vitro maturation (IVM) procedures for 42 hr. In Experiment 1, IVM-derived
      oocytes were then randomly allocated to different HS treatments at 41.5 degrees C
      for 0 (control, C0h, n = 101), 1 (HS1h, n = 113), 2 (HS2h, n = 104), and 4 hr
      (HS4h, n = 111), respectively. An additional control group of oocytes was
      cultured for 4 hr without HS (C4h, n = 93). Immunocytochemical staining was
      performed using anti-tubulins and FITC-conjugated mouse IgG for microtubule (MT)
      labeling. The chromatin and microfilaments (MFs) were stained using Hoechst 33342
      and rhodamine-phalloidin, respectively. In the severe HS (4 hr), the chromosomes
      of the MII oocytes became an aggregated chromatin structure and separated into
      groups. The spindle MTs were completely depolymerized or formed MT arrays. The
      relative fluorescence intensity (RFI) or amount of the MF structures including
      transzona processes (TZPs), vitelline ring (VR), and pericytoplasmic MF, were
      changed in various degrees. The reversibility of these alterations in the
      chromatin and the cytoskeleton depended on the duration of the HS. In general,
      abnormalities in the chromosomes, spindle MTs and the percentages of oocytes with
      pericytoplasmic MTs increased with length of HS treatment. The size of the
      spindle and the RFI of MFs in the HS oocytes were also altered. The significant
      changes in the nucleus and the cytoskeleton in porcine oocytes after HS may be
      associated with reduced development under hyperthermia and, perhaps, with the low
      pregnancy rates in domestic species during hot seasons.

PMID- 15039958
TI  - Rapid analysis of MMI270B, an inhibitor of matrix metalloproteases in human
      plasma by liquid chromatography-tandem mass spectrometry: matrix interference in
      patient samples.
AB  - A high-throughput method was developed and validated for the quantitative
      determination of MMI270B, an inhibitor of matrix metalloprotease (MMP) enzymes,
      in human plasma. The method was based on reverse-phase chromatographic separation
      of the analyte from plasma extract followed by atmospheric pressure chemical
      ionization (APCI) and tandem mass spectrometry in the selected reaction
      monitoring mode (SRM). Extraction was performed using simple protein fi ltration
      in the 96-well plate format to increase the throughput of the method. Optimised
      chromatographic separation in a short column (30 x 4.6 mm i.d.) coupled with
      positive APCI mode of ionization followed by selective SRM mode of detection
      yielded clean chromatograms with minimal signal suppression. The chromatographic
      conditions resolved isobaric interference peaks observed in samples from patients
      dosed with MMI270B. The standard curve was linear (r = 0.997) within the
      concentration range of 1.04 (lower limit of quanti fi cation) to 1040 ng/mL using
      0.1 mL of human plasma. The accuracy of the method varied from 93.6 to 103% with
      a precision of 2.17-6.71% over the concentration range. The method was simple,
      rapid, and robust with an analyte recovery of >98%.

PMID- 15039960
TI  - Determination of the uronic acid composition of seaweed dietary fibre by HPLC.
AB  - A high-performance liquid chromatographic (HPLC) method is described for
      determination of the ratio of beta-d-mannuronic acid to alpha-l-guluronic acid
      (M/G ratio) in dietary fibre of edible seaweeds. Total dietary fibre (TDF)
      content was determined gravimetrically. The TDF fraction was hydrolysed with 12 m
      and 1 m H(2)SO(4), then neutralized with AG 4 x 4 resin. The uronic acids were
      separated in a Tracer Extrasil SAX 5 micro m column (25 cm x 4 mm) at 35 degrees
      C, with 2 mm KH(2)PO(4) containing 5% methanol as mobile phase at a fl ow rate of
      1.5 mL/min. The detection wavelength was UV 210 nm. The chromatographic
      identifications of beta-d-mannuronic acid and alpha-l-guluronic acid were
      confirmed by liquid chromatography-mass spectrometry (LC-MS). The method
      precision was 1.4% for beta-d-mannuronic acid and 3.5% for alpha-l-guluronic
      acid. The method was used to determine M/G ratio in canned seaweeds (Saccorhiza
      polyschides and Himanthalia elongata) and in dried seaweeds (H. elongata,
      Laminaria ochroleuca, Undaria pinnatifida, Palmaria sp. and Porphyra sp.).

PMID- 15039959
TI  - Liquid chromatography-tandem mass spectrometry for the determination of a new
      oxazolidinone antibiotic DA-7867 in human plasma.
AB  - A liquid chromatography-tandem mass spectrometric (LC/MS/MS) method for the
      determination of a new ox-azolidinone antibiotic DA-7867, (S)-[N-3-(4-(2-(1
      methyl-5-tetrazolyl)-pyridine-5-yl)-3- fl uorophenyl)-2-oxo-5-oxazolidinyl]methyl
      acetamide, in human plasma was developed. DA-7867 and internal standard,
      linezolid, were extracted from human plasma with ethyl acetate at acidic pH. A
      reverse-phase LC separation was performed on Luna C(8) column with the mixture of
      acetonitrile-ammonium formate (10 mm, pH 4.5; 35:65, v/v) as mobile phase. The
      analytes were determined using an electrospray ionization tandem mass
      spectrometry in the multiple-reaction-monitoring mode. The lower limits of quanti
      fi cation for DA-7867 was 2.5 ng/mL. The single liquid-liquid extraction
      quantitatively recovered DA-7867 and internal standard from plasma samples at the
      ranges of 82.2-86.7%. DA-7867 was stable in blank human plasma at room
      temperature for 24 h and following three freeze-thaw cycles.

PMID- 15039961
TI  - Determination of pamidronate in human whole blood and urine by reversed-phase
      HPLC with fluorescence detection.
AB  - Pamidronate is a bisphosphonate that is effective in treating bone disease
      including osteopenia and osteoporosis in adults. A sensitive and reliable method
      for the analysis of pamidronate in whole blood and urine is key to the
      development of this drug for use in children. A previously described method for
      pamidronate analysis serum and urine did not consistently detect the drug at
      satisfactory levels in whole blood. The procedure involves co-precipitation of
      the bisphosphonates with calcium phosphate, pre-column derivitization with
      fluorescamine, HPLC utilizing a Nucleosil C(18) column, and fluorescence
      detection with excitation at 395 nm and emission at 480 nm. Changes to the
      original protocol included the use of a new internal standard (alendronate), the
      optimization of the concentration of ethylenediaminetetraacetic acid (EDTA) for
      dissolving the precipitate, and the elimination of the acidification step prior
      to deproteinization. The optimum EDTA concentration, which had a significant
      effect on the labeling capability of fluorescamine, was determined to be 20 mm.A
      good separation between pamidronate and alendronate was achieved using a heated
      (40 degrees C ) Nucleosil C(18), 10 micro m particle size column. The mobile
      phase was an aqueous solution of 1 mm Na(2)EDTA-methanol (97:3, v/v) adjusted to
      pH 6.5 using a fl ow-rate of 1 mL/min. Fluorescence detection was set at 395 nm
      for excitation and at 480 nm for emission. The limit of quantitation for
      pamidronate was 0.5 micro g/mL in whole blood and 0.1 micro g/mL in urine. The
      method was applied to both whole blood and urine samples from pediatric patients.

PMID- 15039962
TI  - Determination of organochlorine compounds in human biological samples by GC
      MS/MS.
AB  - A study was undertaken to determine the extent of organochlorine pesticide (OP)
      and polychlorinated biphenyl (PCB) contamination in infant formula milk and in
      the human milk, fat and serum of women from an agricultural area in Southern
      Spain. A procedure is proposed that simultaneously detects trace levels of
      lindane, endosulfan-ether, vinclozolin, aldrin, endosulfan-lactone, endosulfan
      alpha, 4,4'DDE, 2,4'DDT, endosulfan-beta, 4,4'DDT, kepone, endosulfate-sulfate,
      methoxychlor, mirex, 2,3,4 PCB, 2,2',4,5 PCB, 2,3,4,5 PCB and 2,2',3,3',6,6'PCB.
      After liquid-liquid or solid-liquid extraction, the extract of the sample was
      cleaned by high performance liquid chromatography (HPLC) and the fi rst eluted
      fraction was analysed by gas chromatography (GC) with mass spectrometry (MS)
      detector in tandem mode. To evaluate the validity of the method the following
      parameters were studied: linearity, detection limits, quantification limits,
      specificity, percentage recovery and precision. A study of the uncertainty
      associated with the analytical method was also carried out.

PMID- 15039963
TI  - Determination of three compounds in Aloe vera by capillary electrophoresis.
AB  - A capillary electrophoretic assay for determining aloe-emodin (AE), methyl p
      coumarate (MC), and 3,4-dihydro-6,8-dihydroxyl-[(3s)-2'-acetyl-3'-hydroxyl-5'
      methoxy-benzyl]-isocoumarin (DDI) in Aloe vera has been developed. Baseline
      separation was achieved within 15 min using a running buffer of 20 mm borax
      containing 10% (v/v) acetonitrile at pH 10.5. A linear relationship between the
      peak area and the concentration of the analytes was found in the ranges 5-500, 10
      1000 and 2-1000 micro g/mL for AE, MC and DDI, respectively, with correlation
      coefficients of 0.9992-0.9998. The relative standard deviations of migration time
      and peak area were within 0.17-0.19 and 1.52-3.37%, respectively. The recoveries
      of AE, MC and DDI were 105, 102 and 96.4%. The contents of AE, MC and DDI in Aloe
      vera were measured to be 5.13, 0.768 and 1.30 mg/g, respectively.

PMID- 15039965
TI  - Simultaneous determination of amphetamine derivatives in human urine after SPE
      extraction and HPLC-UV analysis.
AB  - Amphetamine derivatives are a class of compounds increasingly abused as
      recreational drugs in various regions of the world. Although d-amphetamine (AMPH)
      and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are among the most commonly
      used, the abuse of other designer drugs such as 4-bromo-2,5
      dimethoxyphenethylamine (2C-B) and 4-methylthioamphetamine (4-MTA) and their
      involvement in acute intoxications has been increasingly reported. There is
      evidence that abusers ingest these compounds either alone or in combination and
      the respective monitoring is important for both legal and health care purposes in
      hospital emergency. In the present study a simple and clean solid-phase
      extraction procedure from urine of AMPH and MDMA, and their major metabolites p
      hydroxyamphetamine (OH-AMPH) and methylenedioxyamphetamine (MDA) and 2C-B and 4
      MTA was developed. Analysis was performed by HPLC-UV and the precision of the
      technique was between 2.9 and 5.3% for all compounds. For the overall procedure,
      the precision values were between 3.3 and 5.9%. Recoveries obtained from spiked
      urines at three concentration levels were better than 84 +/- 4% for the six
      compounds. The limit of detection of the method for the compounds (between 5.3
      and 84.0 ng) enables their identification in urine after ingestion of fatal and
      non-fatal doses. The main advantages of the present method lie in its simple,
      clean and reliable SPE extraction method of the six amphetamine derivatives from
      urine followed by their simultaneous detection and quantification by liquid
      chromatography with UV detection.

PMID- 15039964
TI  - Determination of abamectin and doramectin in sheep faeces using HPLC with
      fluorescence detection.
AB  - An analytical procedure for the determination of abamectin and/or doramectin in
      sheep faeces has been developed. Avermectins were extracted from sheep faeces
      with acetonitrile, clean-up using solid phase extraction (SPE) and analysed by
      high performance liquid chromatography (HPLC) with fl uorescence detection after
      derivatization with N-methylimidazole.The method has a low detection limit (1.0
      ng/g of moist sheep faeces), low quanti fi cation limit (2.5 ng/g of moist sheep
      faeces), good recovery in the range 66.4-80.8% for abamectin and 67.7-85.5% for
      doramectin as well as good repeatability (>85%). The method is applicable to the
      study of the time pro fi le of excretion in sheep faeces and also for
      ecotoxicological studies of both avermectins.

PMID- 15039966
TI  - Biodegradation and bioaccumulation of fenitrothion in rat liver.
AB  - The biodegradation of fenitrothion O,O-dimethyl-O-(3-methyl-4-nitro phenyl)
      phosphorothioate was investigated in rat liver after administration of various
      doses (5 mg/100 g body weight and 20 mg/100 g body weight) in acute treatment and
      1 mg/100 g body weight in chronic treatment. High performance liquid
      chromatography of the pesticide and its metabolites formed in liver in acute
      treatment showed time-dependent sequential conversion of pesticide into three
      major metabolites within 24 h. These metabolites were separated and purified to
      homogenity by HPLC and characterized by IR spectroscopy as O,O-dimethyl-O-(3
      methyl-4-amino phenyl) phsophorothioate (metabolite 1), O,O-dimethyl
      phosphorothioate (metabolite II) and O,O-dimethyl phosphate (metabolite III) in
      the fi rst dose (5 mg/100 g body weight). Metabolite II was found to be different
      in the second dose (20 mg/100 g body weight) and identified as O,O-dimethyl O-3
      methyl-4-amino phenyl phosphate. The results with the fi rst dose indicated
      reduction of the nitro group in fenitrothion as step I followed by hydrolytic
      clevage of the P-O-aryl bond in metabolite I and oxidative desulphurylation of
      metabolite II. At higher dose (20 mg/100 g body weight) oxidative
      desulphurylation takes place as step II followed by hydrolysis of metabolite II.
      The bioaccumulation of fenitrothion within 60 days during chronic treatment
      showed no metabolite but continuous reduction in fenitrothion concentration,
      indicating excretion of pesticide and its products in urine and in faeces.

PMID- 15039967
TI  - Goethe's bone and the beginnings of morphology.
AB  - Biology as a discipline per se and its agenda, seems not to have been burdened
      from its beginnings as heavily with neo-Platonism as its subspecialty morphology,
      conceptualized at the same time by Goethe and Burdach. One of the reasons may
      have been that biologists were then regarded as "mere" naturalists, "doing"
      anatomy and embryology, breeding, and field work (as did Darwin, Wallace, Bateson
      and a legion of others during the 19th century), whereas the, perhaps more
      elitist, morphologists, ab initio devoted themselves to the origin, even to the
      Kantian analysis of causes of development and its variability within and between
      species. Since Goethe included abnormal plant development in his studies, his
      definition of morphology as the science of the form, formation and transformation
      of living organisms may be modified to include the concept of malformation,
      although the embryological and comparative analysis of vertebrate/mammalian
      malformation had its real inception somewhat later with the younger Meckel. In
      view of the meaning attached by his French contemporaries to the term
      transformisme (eventually defined as evolution) one would err considering Goethe
      as a prophet of "descent;" he was not, referring primarily to the continuous
      state of flux of living beings. Nonetheless, Goethe and Burdach independently
      coined the concept of morphology and set its agenda, increasingly freed of
      Naturphilosophie, an agenda that dominated 19th century biology but which did not
      come to fruition in its causal analysis of form and its formation until the 20th
      century, after Mendel, Darwin and the pioneers of experimental embryology (a.o.,
      Roux, Driesch, Spemann, Vogt). In his discovery of the intermaxillary bone in
      humans (Goethe's bone), he had a startling insight, against conventional wisdom,
      into the anatomical, hence developmental, similarity of primate/mammals. During
      his lifetime, this was still called analogie by his great French contemporary
      Etienne Geoffroy St-Hilaire who actually meant what Owen later called homology
      which became one of Darwin's most powerful arguments for descent. A case of a
      pearl found by a blind chicken? Definitely not; Goethe had his nose far too close
      to the ground to have missed any of the major intellectual trends in the "life
      sciences" in the late 18th/early 19th century; but, he was too much of an amateur
      to have had the kind of insights of grand plans granted to von Baer, Mendel and
      Darwin.

PMID- 15039968
TI  - Social behavior profile in young males with fragile X syndrome: characteristics
      and specificity.
AB  - The present study characterizes distinctive and specific features of social
      behavior impairment, termed social behavior profile (SBP), in young males with
      fragile X syndrome (FraX). Fourteen males with FraX and autism (FraX+Aut), ages 3
      8 years, were compared with either 41 FraX boys without autism (Aut), 7 age
      matched males with developmental language delay and autism (DLD+Aut), or with 11
      boys with non-selected (for language delay) idiopathic autism (IA), on several
      standardized instruments assessing social behavior and autistic features (i.e.,
      autism diagnostic interview-revised, ADI-R). We found that FraX+Aut subjects
      displayed more impairment in overall cognition, problem/aberrant behavior, and
      adaptive behavior than the rest of the FraX cohort, even when individuals with
      pervasive developmental disorder (PDD) were included in the latter. Compared to
      both DLD+Aut and IA, FraX+Aut males were less impaired in ADI-R reciprocal social
      interaction (RECS) domain. However, boys with FraX+Aut were in general comparable
      to DLD+Aut subjects in problem/aberrant and adaptive behaviors. Based on the
      contrast between FraX+Aut and non-autistic FraX and DLD+Aut, we were able to
      identify measures (e.g., child behavior checklist (CBCL) withdrawn subscale) that
      better define social interaction impairment in FraX. Comparisons with DLD+Aut and
      IA led to the conclusion that communication impairment (COMM) and stereotypic
      behavior contribute relatively more to the diagnosis of autism in FraX+Aut. In
      agreement with recent studies, our data suggest that FraX+Aut, and more generally
      SBP, is a distinctive subphenotype among boys with FraX, which may share some
      pathophysiological mechanisms with IA.

PMID- 15039969
TI  - Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without
      fibrosing lung disease.
AB  - Pulmonary surfactant protein C (SP-C) is a highly hydrophobic peptide produced by
      type-II alveolar cells through the processing of a high-molecular weight
      precursor (pro-SP-C), that enhances surface tension and facilitates the recycling
      of pulmonary surfactant in vitro. Recently, two seemingly dominant-negative
      mutations of the pro-SP-C-encoding gene (SFTPC, MIM 178620), were reported in
      families with vertically-inherited interstitial lung disease (Nogee et al. [2001:
      N Engl J Med 344:573-579]; Thomas et al. [2002: Am J Respir Crit Care Med
      165:1322-1328]). We have examined the SP-C protein and its precursor as well as
      the encoding gene, in a cohort of 34 sporadic or familial cases with unexplained
      respiratory distress (URD) in which surfactant protein B (SP-B) deficiency
      related to SFTPB mutation had been ruled out. One patient with complete SP-C
      deficiency had no detectable mutation of SFTPC. Of the 10 patients with abnormal
      pro-SP-C processing, as suggested from analysis of broncho-alveolar lavage (BAL)
      fluid, two distinct heterozygous SFTPC missense mutations were identified. The
      first, g.1286T > C (p.I73T), was de novo and resulted in progressive respiratory
      failure with intra-alveolar storage of a granular, protein- and lipid-rich,
      periodic acid Schiff (PAS)-positive material (pulmonary alveolar proteinosis
      (PAP)), and interstitial lung disease. The second, g.2125G > A (p.R167Q), was
      found in two PAP patients from the endogamous white settler population of Reunion
      Island in which URD has an unexpectedly high prevalence. Since this mutation was
      diagnosed in subjects from this subpopulation who did not have evidence for lung
      disease, we propose environmental exposures or modifier genes to play a role in
      the phenotype, as suggested from murine models lacking the SP-C protein, although
      we cannot rule out a rare polymorphism, hitherto restricted to that
      subpopulation. Most remarkably, these observations extend the phenotypic spectrum
      related to SFTPC mutation from interstitial lung disease to PAP. Notably, the
      reported mutations do not appear to be dominant negatives. This article contains
      supplementary material, which may be viewed at the American Journal of Medical
      Genetics website at http://www.interscience.wiley.com/jpages/0148
      7299/suppmat/index.html.

PMID- 15039970
TI  - A familial balanced inverted insertion ins(15)(q15q13q11.2) producing Prader
      Willi syndrome, Angelman syndrome and duplication of 15q11.2-q13 in a single
      family: Importance of differentiation from a paracentric inversion.
AB  - We reascertained a family in which first cousins were affected by Angelman
      syndrome and Prader-Willi syndrome. A paracentric inversion of 15q11-q15 had
      previously been reported in this family but we show, using fluorescence in situ
      hybridization (FISH), that the rearrangement segregating in this family is not a
      paracentric inversion but an inverted intrachromosomal insertion, inv
      ins(15)(q15q13q11.2). We also describe a further recombinant resulting in a
      maternal duplication of the Prader-Willi/Angelman critical region. This family
      illustrates the importance of distinguishing paracentric inversions from
      intrachromosomal insertions.

PMID- 15039971
TI  - Five haplotypes account for fifty-five percent of ATM mutations in Brazilian
      patients with ataxia telangiectasia: seven new mutations.
AB  - We have studied the molecular genetics of 27 Brazilian families with ataxia
      telangiectasia (AT). Five founder effect haplotypes accounted for 55.5% of the
      families. AT is an autosomal recessive disorder of childhood onset characterized
      by progressive cerebellar ataxia, ocular apraxia, telangiectasia,
      immunodeficiency, radiation sensitivity, chromosomal instability, and
      predisposition to cancer. The ATM gene spans more than 150 kb on chromosome
      region 11q23.1 and encodes a product of 3056 amino acids. The ATM protein is a
      member of the phosphatidylinositol 3-kinase (PI-3K) family of proteins and is
      involved in cell cycle control and DNA repair pathways. DNA was isolated from
      lymphoblastoid cell lines and haplotyped using four STR markers (D11S1818, NS22,
      D11S2179, D11S1819) within and flanking the ATM gene; all allele sizes were
      standardized in advance. In addition to the STR haplotypes, SNP haplotypes were
      determined using 10 critical polymorphisms. The entire gene was screened
      sequentially by protein truncation testing (PTT), single strand conformation
      polymorphism (SSCP), and then denaturing high performance liquid chromatography
      (dHPLC) to identify the disease-causing mutations. Of the expected 54 mutations,
      50 were identified. All mutations but one, led to a truncated or null form of the
      ATM protein (nonsense, splice site, or frameshift). Five families (18.5%) carried
      a deletion of 3450nt (from IVS28 to Ex31), making this one of the two most common
      Brazilian mutations. Mutations were located throughout the entire gene, with no
      clustering or hotspots. Standardized STR haplotype analysis greatly enhanced the
      efficiency of mutation screening.

PMID- 15039972
TI  - Recurrence risk of preeclampsia in twin and singleton pregnancies.
AB  - The etiology of preeclampsia is unknown. The relatively high risk of recurrence
      of preeclampsia in subsequent pregnancies to the same mother suggests a genetic
      basis for the disease, but the mode of inheritance is uncertain. We compare the
      risk of preeclampsia in second pregnancies for mothers whose first preeclamptic
      pregnancy was either a singleton or a twin pregnancy. The crude and adjusted
      recurrence risks of preeclampsia in twin and singleton pregnancies were estimated
      in a population-based register including the first and second pregnancies of
      550218 women registered in the Medical Birth Registry of Norway, 1967-1998. The
      recurrence risk of preeclampsia in second pregnancy for women with a singleton
      pregnancy with preeclampsia the first time was 14.1% (95% CI: 13.6-14.6). For
      women with a first time twin pregnancy the recurrence risk was lower, 6.8% (CI:
      4.3-10.1), P < 0.001. Thus, the crude excess risk for recurrent preeclampsia was
      7.3% (95% CI: 4.5-10.0) in women with a first time singleton as compared to women
      with a first time twin pregnancy. The recurrence risk of preeclampsia is lower
      when the first pregnancy was a twin as compared to a singleton pregnancy. This
      observation is consistent with a polygenic liability model.

PMID- 15039973
TI  - A study of reciprocal translocations and inversions detected by light microscopy
      with special reference to origin, segregation, and recurrent abnormalities.
AB  - We analyzed 448 independently ascertained reciprocal translocations and 220
      inversions referred to our diagnostic laboratory. Twenty-eight percent of the
      translocations and 8.5% of the inversions arose de novo, the proportion being
      influenced by the method of ascertainment. It was highest, 47%, among
      translocations ascertained through an abnormal phenotype. With the exception of
      the 3:1 unbalanced segregants, the remainders were equally likely to have been
      paternally or maternally inherited. The segregation from balanced translocation
      and inversion carriers showed an equal number of offspring with a normal
      chromosome constitution and with a balanced rearrangement. The number of
      unbalanced segregants among the translocations was 2.7% where the proband was
      balanced, and 19.2% where the proband was unbalanced. There was only a single
      unbalanced inversion. A search for recurring translocations showed only the well
      documented t(11;22) to occur with unusual frequency in our series and those of
      others, and we concluded that the few other translocations that were seen on more
      than one occasion were likely to be identical by descent (IBD). Similarly the
      majority of the recurring inversions, with the exception of "common variants,"
      seemed likely to be IBD. However, eight inversions recurred in our data and in
      most other series and may well be genuine independent rearrangements. A search of
      the known olfactory receptor (OR) loci and duplicons suggested that such
      sequences did not form an important contribution to the breakpoints of recurring
      rearrangements detected by light microscopy.

PMID- 15039974
TI  - A novel type of autosomal recessive syndactyly: clinical and molecular studies in
      a family of Pakistani origin.
AB  - Non-syndromic syndactylies have been classified into five major types (I-V), all
      showing autosomal dominant mode of inheritance. Later, the classification was
      extended and three additional variants (VI-VIII) were defined. Type VII, the
      Cenani-Lenz syndactyly, is the only non-syndromic, autosomal recessive type. It
      is characterized by fusion of all phalanges with metacarpal synostosis,
      dislocated and dysplastic carpals and infrequently, radio-ulnar fusion. Here, we
      present a Pakistani family with a novel non-syndromic autosomal recessive
      syndactyly manifesting a unique combination of clinical features. In both hands,
      reduction of certain phalanges is evident. Radiological examination shows
      synostosis of third and fourth metacarpals bearing single phalanges. The first
      three toes are webbed, with hypoplastic terminal phalanx in all the toes. Besides
      Cenani-Lenz syndactyly, the phenotype segregating in our family is the second
      well-documented autosomal recessive, non-syndromic syndactyly. A phenotype
      similar to our family was described in a Turkish kindred but was considered to be
      a homozygous expression of type I syndactyly. Since the clinical features in our
      family had minimal overlap with syndactyly types I, II, and III, we have
      performed microsatellite marker screening to look for the cosegregation of this
      phenotype with any of the known loci for these respective types. We show that the
      phenotype in our family is not linked to chromosomal regions 2q34-q36, 2q31, and
      6q22-q23 encompassing loci for syndactyly types I, II, and III.

PMID- 15039975
TI  - Psychosocial impact of predictive testing for myotonic dystrophy type 1.
AB  - In the Saguenay-Lac-Saint-Jean region (Quebec, Canada), a predictive DNA-testing
      program for myotonic dystrophy type 1 (DM1) has been available as a clinical
      service since 1988. From 1 to 12 years (median, 5 years) after receiving
      predictive testing, a total of 308 participants (44 carriers and 264 non
      carriers) answered a questionnaire to determine the psychosocial impact of this
      genetic testing. The main reasons for wanting to be tested were to learn if
      children are at risk for DM1 or for reproductive decision making (75%) and to
      relieve the uncertainty for themselves (17%). The majority of participants
      (96.1%) remembered correctly their test result. At the time of the survey, the
      perception of the general well-being, the psychological distress (Psychiatric
      Symptom Index), and the self-esteem (Rosenberg Self-Esteem Scale) were similar in
      carriers, in non-carriers, and in the reference (Quebec) population. When
      participants indicated a change in different aspects of their lives following
      predictive testing, it was perceived as a change for the better by non-carriers
      and as a change for the worse by carriers. Nevertheless, for a majority of
      carriers and of non-carriers, the test result did not bring changes in their
      lives. All respondents believed that predictive testing should be available for
      the at-risk population and the vast majority of carrier and of non-carriers would
      recommend the use of predictive testing to their family members. Predictive
      testing for individuals at-risk of DM1 can be offered safely within a well
      organized clinical and genetic counseling program that includes careful pre-test
      counseling, pre-test clinical assessment, post-test psychological support, and
      follow-up for those identified as carriers.

PMID- 15039976
TI  - Growth of heterokaryotic monozygotic twins discordant for Ullrich-Turner syndrome
      during the first years of life.
AB  - The rare observation of different karyotypes in monozygotic (MZ) twins, i.e.,
      heterokaryotic monozygosity, occurs due to chromosomal aberration in one of the
      twins after separation of the embryos. We report on the differences of
      heterokaryotic MZ Turkish twins who are discordant for Ullrich-Turner syndrome.
      Chromosomal analyses from peripheral lymphocytes revealed a 45,X/46,XX mosaicism
      in both twins. FISH analyses of buccal smears showed 99% of nuclei 45,X in twin A
      and 98% of nuclei 46,XX in twin B. These results are consistent with a non-mosaic
      45,X and 46,XX karyotype, respectively. The girls showed a different growth
      pattern in the first years. As their genotype should be identical except for the
      number of X chromosomes, the difference in phenotype may be a pure result of loss
      of one X chromosome in the affected girl. Special interest is set on the
      spontaneous and growth hormone induced growth of the twins.

PMID- 15039977
TI  - Mosaicism of a TCOF1 mutation in an individual clinically unaffected with
      Treacher Collins syndrome.
AB  - Treacher Collins syndrome (TCS) or mandibulofacial dysostosis is an autosomal
      dominant disorder of craniofacial development with 60% of its cases arising de
      novo. Other modes of inheritance such as autosomal recessive, gonadal mosaicism,
      and chromosomal rearrangement have also been proposed. This syndrome can result
      from TCOF1 gene mutations. In this study we identified a TCOF1 1408delAG
      heterozygous mutation in a patient with the clinical diagnosis of TCS. This same
      mutation was found in the clinically unaffected mother's leukocytes, hair root
      bulbs, buccal mucosa, urine, and stool. The mother has a clinically unaffected
      child and the maternal grandparents do not have the mutation. Because the mother
      has the mutation in cells derived from all three germ layers, we suspected the
      mutation was nonpenetrant. However, we could not detect the mutation in her skin
      fibroblasts, suggesting she is mosaic secondary to cell type specific selection.

PMID- 15039979
TI  - Preimplantation genetic diagnosis of human congenital heart malformation and Holt
      Oram syndrome.
AB  - Holt-Oram syndrome (HOS) is a multiple malformation syndrome associated with
      congenital heart malformation (CHM) and caused by mutations in the TBX5
      transcription factor. Effective prenatal genetic diagnosis of HOS is limited by
      factors that modify clinical manifestations and confound prediction of an
      individual's phenotype. Although preimplantation genetic diagnosis (PGD) has been
      applied to complex disorders with some cardiovascular manifestations, its utility
      in Mendelian CHM has not been previously demonstrated. We tested whether PGD and
      in vitro fertilization (IVF) technology, including oocyte donation, can identify
      fertilized eggs affected by HOS for potential embryo selection. Five donor
      oocytes were fertilized in vitro with sperm from a HOS patient heterozygous for a
      Glu69ter-TBX5 mutation and then underwent embryo biopsy and genotyping. One
      carried the Glu69ter-TBX5 mutation; all others had wildtype genotypes. Two
      wildtype blastocysts were transferred to the mother, and the resulting singleton
      pregnancy was successfully delivered. Mutational analysis of fetal amniocytes and
      postpartum umbilical cord blood confirmed PGD. Fetal ultrasonography as well as
      postpartum electrocardiography and echocardiography also validated accurate
      prediction of normal skeletal and cardiac phenotypes. We conclude that PGD is an
      effective reproductive strategy for HOS patients. As more genetic etiologies for
      CHM are identified, application of PGD as adjunctive therapy to IVF will be
      increasingly available to prevent transmission of such diseases from affected
      parents to their children. Clinical application of PGD must balance the benefits
      of avoiding disease transmission with the medical risks and financial burdens of
      IVF.

PMID- 15039980
TI  - Macrocephaly-cutis marmorata telangiectatica congenita: seven cases including two
      with unusual cerebral manifestations.
AB  - Macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) is a recently
      described multiple congenital anomaly/mental retardation (MCA/MR) syndrome of
      unknown cause. This condition is easily recognizable at birth in children with
      macrocephaly, cutis marmorata, face and/or body segmental overgrowth, toe
      syndactyly, midface capillary malformation, and hemimegalencephaly. Cutis
      marmorata may be absent in some cases. Most patients are developmentally delayed.
      We describe seven new patients, including two with unusual cerebral
      manifestations and severe outcome. One of two had a complex congenital heart
      defect (CHD) and died in the neonatal period. Brain magnetic resonance imaging
      (MRI) showed generalized cortical dysplasia. The other patient had a stroke
      episode at age 14 years. Cerebral arteriography showed an abnormal vascular
      pattern. These findings are consistent with the fact that M-CMTC is a generalized
      vasculopathy.

PMID- 15039978
TI  - Unilateral linear hyperpigmentation of the skin with ipsilateral sectorial
      hyperpigmentation of the retina.
AB  - A 32-year-old Caucasian man had a mosaic hyperpigmentation on his left arm,
      arranged in a pattern following the lines of Blaschko. In addition, a mosaic
      hyperpigmentation was noted in his left eye, in the form of grouped congenital
      hypertrophy of the retinal pigment epithelium (CHRPE). Such "bear tracks" are
      segmentally oriented, well-demarcated, flat, hyperpigmented lesions originating
      with small dots at the optic disk and expanding towards the periphery. We
      hypothesize that these mosaic pigmentary lesions involving the skin and the eye
      on the same side of the body may have originated from an early postzygotic
      mutation and thus may be etiologically related.

PMID- 15039981
TI  - XX-agonadism in a fetus with multiple congenital anomalies.
AB  - We report on an 18-week gestation fetus with 46,XX karyotype, gonadal agenesis,
      meningo-encephalocele, spina bifida, omphalocele, webbing of right upper limb,
      deformed right clavicle and right sided ribs, absent interventricular septum,
      hypoplastic aorta, hypoplastic spleen, and single umbilical artery. This case is
      similar to the one previously described by Kennerknecht et al. in 1997 and may
      represent a unique syndrome.

PMID- 15039982
TI  - Concerning 14q(22) deletion in a familial case of anophthalmia with polydactyly.

PMID- 15039983
TI  - Re: clinical report by Ahmad et al. 14q(22) deletion in a familial case of
      anophthalmia with polydactyly.

PMID- 15039985
TI  - The pathway to animal cloning and beyond--Robert Briggs (1911-1983) and Thomas J.
      King (1921-2000).

PMID- 15039986
TI  - Analysis of cerebro-spinal fluid protein composition in early developmental
      stages in chick embryos.
AB  - Foetal cerebro-spinal fluid (CSF) has a very high protein concentration when
      compared to adult CSF, and in many species five major protein fractions have been
      described. However, the protein concentration and composition in CSF during early
      developmental stages remains largely unknown. Our results show that in the
      earliest stages (18 to 30 H.H.) of chick development there is a progressive
      increase in CSF protein concentration until foetal values are attained. In
      addition, by performing electrophoretic separation and high-sensitivity silver
      staining, we were able to identify a total of 21 different protein fractions in
      the chick embryo CSF. In accordance with the developmental pattern of their
      concentration, these can be classified as follows: A: high-concentration
      fractions which corresponded with the ones described in foetal CSF by other
      authors; B: low-concentration fractions which remained stable throughout the
      period studied; C: low-concentration fractions which show changes during this
      period. The evolution and molecular weight of the latter group suggest the
      possibility of an important biological role. Our data demonstrate that all the
      CSF protein fractions are present in embryonic serum; this could mean that the
      specific transport mechanisms in neuroepithelial cells described in the foetal
      period evolve in very early stages of development. In conclusion, this paper
      offers an accurate study of the protein composition of chick embryonic CSF, which
      will help the understanding of the influences on neuroepithelial stem cells
      during development and, as a result, the appropriate conditions for the in vitro
      study of embryonic/foetal nervous tissue cells.

PMID- 15039987
TI  - Function of TGF-beta2 in the growth of chicken primordial germ cells and germinal
      ridge stroma cells during embryonic development.
AB  - The development of chicken embryonic gonads is locally regulated by the
      systematic action of growth factors. Recently, we used suppressive subtraction
      cloning to identify transforming growth factor beta2 (TGF-beta2) as a growth
      factor gene preferentially expressed in chicken embryonic ovaries and testes
      during the early periods of development (Hattori et al. 2002a. Prominent
      expression of transforming growth factor beta2 gene in the chicken embryonic
      gonad as revealed by suppressive subtraction cloning. Gen Comp Endocrinol 125:311
      316). In the present study, the function of TGF-beta2 in chicken embryonic gonads
      was investigated using a serum-free culture system in the presence of several
      growth factors, which may behave as mitogenic or survival factors of primordial
      germ cells (PGCs). Chicken germinal ridges containing PGCs and germinal ridge
      stroma cells (GRSCs) were collected from six-day embryos. Addition of TGF-beta2
      caused a dose-dependent inhibition of the number of co-cultured PGCs and GRSCs in
      the presence of these growth factors. However, there was no obvious difference
      between embryonic ovaries and testes in the effects of TGF-beta2.
      Immunocytochemical analysis using anti-SSEA-1 antibody revealed that TGF-beta2
      induced fragmentation of PGCs. Expression of the TGF-beta2 gene was estimated in
      the co-cultured PGCs and GRSCs by semi-quantitative RT-PCR. The mRNA level of TGF
      beta2 was significantly suppressed in the presence of the growth factors. These
      results suggest that TGF-beta2 is a gonadal regulator preferentially expressed at
      the early stages of chicken embryonic development and reduces the growth of PGCs
      and GRSCs by suppressing proliferation. However, expression of TGF-beta2 may be
      controlled by mitogenic or survival factors of PGCs.

PMID- 15039988
TI  - Androgen and estrogen receptors expression in the rat exorbital lacrimal gland in
      relation to "harderianization".
AB  - The rat exorbital lacrimal glands (ELG) are particularly interesting for their
      biochemical and morphological sexual differences. Our histochemical and
      ultrastuctural observations confirm a phenomenon termed "harderianization" that
      occurs in the ELG of males and females at three months of age. The
      "harderianization" consists of the appearance of lipid foci in the ELG; this
      effect increases at six months of age only in the male glands, while it is not
      detectable in those of females. Histochemical tests for mucosubstances and
      proteins evidenced that while the secretory granules of male ELG are prevalently
      composed of sulphate substances, those of the female are composed of acid
      substances, and only a few cells positive to proteins were seen in the acinar
      epithelium of the glands. Moreover, we demonstrated by RT-PCR the presence of
      androgen and estrogen receptors in the rat ELG of both sexes. Androgen receptor
      transcript is always present in male and female ELG while the expression of
      estrogen receptor is not more detectable in the ELG of males at six months of
      life. In conclusion, our results suggest that estradiol may prevent the further
      lipid degeneration of the female ELG at six months of life. In addition, the
      disappearance of both the "harderian lipid" foci in the female gland and of
      estrogen receptor in the male gland indicates a probable involvement of estrogens
      in the phenomenon of "harderianization."

PMID- 15039989
TI  - Differential effects of prenyl pyrophosphates on the phosphatase activity of
      phosphotyrosyl protein phosphatase.
AB  - Phosphotyrosyl protein phosphatase (PTPase) 1B was purified from human placenta.
      Immunoprecipitation analysis revealed that the isolated PTPase 1B appears as a
      complex with the receptor for protein kinase C (RACK1) and protein kinase C
      (PKC)delta. The abilities of PTPase 1B and PKCdelta to associate with RACK1 were
      reconfirmed by an in vitro reconstitution experiment. The E. coli expressed and
      biotinylated mice-RACK1-encoded fusion protein was capable of recruiting PTPase
      1B and PKCdelta in the antibiotin immunoprecipitate as a complex of PTPase
      1B/RACK1/PKCdelta. Thus PTPase 1B enzyme preparation was subjected to further
      purification by selective binding of PTPase 1B onto PEP(Taxol) affinity column in
      the absence of ATP. The purified PTPase 1B enzyme exihibited dose-dependent
      phosphatase activity towards [gamma-(32)P]-ATP labeled mice beta-tubulin-encoded
      fusion protein. The dephosphorylation reaction with PTPase 1B was enhanced with
      geranylgeranyl pyrophosphate, but not with farnesyl pyrophosphate. Interestingly,
      additional incubation of the purified PTPase 1B enzyme preparation with RACK1,
      geranylgeranyl pyrophosphate failed to modulate the dephosphorylation activity of
      PTPase 1B. In contrast, the enhancement effect of farnesyl pyrophosphate on the
      kinase activity of PKCdelta was sustained in the presence of RACK1. That is,
      farnesyl pyrophosphate may function as a signal to induce the kinase activity of
      PKCdelta in PTPase 1B/RACK1/PKCdelta complex but geranylgeranyl pyrophosphate may
      not for PTPase 1B. J. Exp. Zool. 301A:307-316, 2004.

PMID- 15039990
TI  - Traced studies on metabolism of astaxanthin in Atlantic salmon (Salmo salar).
AB  - The present studies were performed to investigate the metabolism of astaxanthin
      (Ax) in Atlantic salmon, especially in the liver of salmon. The investigations
      were undertaken in vivo salmon that were fed a diet containing 60 ppm 15, 15' 14C
      labelled Ax prior to sacrifice. The samples of blood, bile, liver,
      gastrointestinal tract and contents, muscle, skin, remaining carcass and feces
      were taken for scintillation counting. The highest radioactivity (71.36%) of 14C
      labelled Ax was found in the gastrointestinal contents and feces, 7.13% in the
      bile and 10.68% in the samples of liver, muscle, and skin at the end of the
      experiments. The metabolites of 14C-labelled Ax were extracted from the bile of
      the salmon and analyzed using thin-layer chromatography (TLC) and high
      performance liquid chromatography (HPLC). Predominant 14C-labelled Ax and its cis
      isomers were found and no conjugation of 14C-labelled Ax was observed. These
      results indicate that 14C-labelled Ax was not conjugated into larger colorless
      compound in Atlantic salmon liver.

PMID- 15039991
TI  - Effects of peritoneal injection of NH4HCO3 on nitrogen excretion and metabolism
      in the swamp eel Monopterus albus-- increased ammonia excretion with an induction
      of glutamine synthetase activity.
AB  - Monopterus albus has to deal with high environmental ammonia concentrations
      during dry seasons and agricultural fertilization in rice fields. In this study,
      NH4HCO3 (10 micromol per g fish) was injected into the peritoneal cavity of M.
      albus, raising the level of ammonia in the body, in order to elucidate the
      strategies involved in defense against the toxicity of exogenous ammonia. During
      the subsequent 24 h after NH4HCO3 injection, there was a significant increase in
      the ammonia excretion rate, which indicates that the main strategy adopted by M.
      albus was to remove the majority of the exogenous ammonia through enhanced
      ammonia excretion. Exogenous ammonia was not detoxified into urea for excretion
      or accumulation. Six hours post-injection of NH4HCO3, ammonia content in the
      tissues built up significantly, especially in the brain, which suggests that M.
      albus had high tolerance of ammonia toxicity at the cellular and sub-cellular
      levels. By hour 12 post-injection, there were significant increases in the
      activities of glutamine synthetase in the muscle, liver, and gut, accompanied by
      significant increases in glutamine contents in the muscle and the liver. There
      was also a significant increase in the glutamine content in the brain at hour 6
      post-injection of NH4HCO3. These results confirm the capability of M. albus to
      detoxify ammonia through glutamine synthesis. Overall, injection of NH4HCO3 had
      only minor effects on the contents of FAAs, other than glutamine, in tissues of
      M. albus because the majority (70%) of the injected ammonia was excreted within
      the 24-h period.

PMID- 15039992
TI  - Localization of vitellogenin mRNA expression and vitellogenin uptake during
      ovarian maturation in the giant freshwater prawn Macrobrachium rosenbergii.
AB  - In situ hybridization and immunohistochemical techniques were used to investigate
      the dynamics of vitellogenin (Vg) mRNA expression and Vg uptake during ovarian
      maturation in the hepatopancreas and ovary at differing stages of ovarian
      maturation in both intact and eyestalk ablated female Macrobrachium rosenbergii.
      In the hepatopancreas of intact animals, Vg mRNA expression was detected faintly
      two days after ecdysis, and signals showed a gradual increase as the molt cycle
      advanced to the premolt stages, but decreased at the late premolt stage. Vg mRNA
      was detected in the R-cells of the hepatopancreas, indicating that these cells
      are responsible for synthesizing Vg. No Vg mRNA expression was observed in the
      ovary. Immunohistochemistry results for the hepatopancreas showed a pattern of
      staining intensity similar to that of in situ hybridization. Increases in the
      accumulation of yolk protein in the oocytes occurred concomitantly with
      increasing Vg mRNA expression. In eyestalk ablated animals, Vg mRNA expression
      and Vg uptake showed similar but accelerated patterns to those of intact animals.
      This study has confirmed on the cellular level previous results that Vg synthesis
      is intrinsically correlated to ovarian maturation and the molt cycle in M.
      rosenbergii.

PMID- 15039993
TI  - Technical aspects of the piezo, laser-assisted, and conventional methods for
      nuclear transfer of mouse oocytes and their efficiency and efficacy: Piezo
      minimizes damage of the ooplasmic membrane at injection.
AB  - Assessment of the advantages and disadvantages of the piezo, laser, and
      conventional methods for nuclear transfer has remained elusive. Furthermore,
      although the piezo method had been used by some investigators for research of
      sperm injection and nuclear transfer for several years, many researchers have
      failed to operate the technique smoothly and achieve reproducible results. The
      procedures of nuclear transfer using piezo were ascertained and described in
      detail. Mouse oocytes were enucleated, and injected with cumulus cells using the
      piezo, laser, or conventional methods. We investigated the time needed and
      survival of nuclear transfer. Development was compared among the three methods
      and parthenogenetic control specimens. The average time of nuclear transfer for
      each oocyte was significantly shorter using the piezo (118 +/- 9 s) and laser
      methods (120 +/- 11 s) than using the conventional method (170 +/- 11 s). The
      damage rate was smaller for the piezo group (10%) than the laser (37%) and
      conventional (40%) groups. The percentages of blastocyst formation (14%, 12%, and
      11%) and the number of nuclei of blastocysts (54 +/- 13, 51 +/- 11, and 52 +/-
      12) were similar among the piezo, laser, and conventional groups, but
      significantly lower than for the control group (83%, 105 +/- 14). The piezo
      technique is more efficient than the conventional method for nuclear transfer.
      The laser method is easy to operate, but the equipment is expensive. In addition,
      piezo induced fewer traumas while breaking the membrane than the aspiration
      techniques used in the laser and conventional methods.

PMID- 15039994
TI  - Seasonal concentrations of reproductive steroids in the gonads of the Atlantic
      hagfish, Myxine glutinosa.
AB  - Changes in gonadal morphology, gonadal estradiol, and progesterone were examined
      in Atlantic hagfish, Myxine glutinosa, during a period of 17 months, beginning in
      April, 2001. Atlantic hagfish were captured from the ocean on a monthly basis. A
      total of 60 hagfish were divided into three different size classes of twenty
      hagfish each (small 20-35 cm, medium 35-45 cm, large 45-55+cm) and transported to
      the University of New Hampshire for sampling. Overall, in the medium and large
      size hagfish, estradiol and progesterone had significantly elevated peaks in
      January, 2001. There were significant increases in estradiol concentrations in
      January, with relatively low fluctuations in levels for the rest of the sampling
      period. Progesterone concentrations increased significantly in January, 2002, in
      medium and large hagfish, and remained elevated until June and April, 2002, for
      the two size classes respectively. The majority of hagfish sampled were females
      or hermaphrodites; few true males were identified in any of the samples. The
      number of females with large eggs increased following the estradiol peak in
      January and hermaphrodites with mature sperm were identified in the July, 2002,
      sample. These data represent the first evidence for a seasonal reproductive cycle
      in M. glutinosa and only the second seasonal reproductive cycle identified in any
      hagfish species.

PMID- 15039995
TI  - Use of the wings in manipulative and suspensory behaviors during feeding by
      frugivorous bats.
AB  - Frugivory evolved independently in Old and New World fruit bats (Families
      Pteropodidae and Phyllostomidae, respectively) and anecdotal reports state that
      these bats use their wings in different ways for manipulating food items and
      postural support during feeding. However, these often-cited behavioral
      differences have not been documented systematically. Here we report observations
      of manipulative and suspensory behavior collected from 41 individuals
      representing five phyllostomid and six pteropodid species. During feeding,
      phyllostomids used both feet to suspend themselves and invariably manipulated
      food with the wrists and thumbs of both wings. Most pteropodids in our sample
      used their thumbs for suspension during feeding and none manipulated fruit with
      their wings. The suspensory and feeding behaviors of pteropodids varied widely
      and there were significant differences between species. Discrepancies between
      phyllostomids and pteropodids in the use of the wings during feeding are
      associated with previously reported differences in wrist morphology. Based on
      examination of manipulative and suspensory behaviors in a phylogenetic context,
      we suggest that differences between pteropodids and phyllostomids reflect the
      distinct ancestral conditions from which these bats evolved.

PMID- 15039996
TI  - Comparison of the cold hardiness capacities of the oviparous and viviparous forms
      of Lacerta vivipara.
AB  - The lizard Lacerta vivipara has allopatric oviparous and viviparous populations.
      The cold hardiness strategy of L. vivipara has previously been studied in
      viviparous populations, but never in oviparous ones. The present study reveals
      that both the oviparous and viviparous individuals of this species are able to
      survive in a supercooled state at -3 degrees C for at least one week when kept on
      dry substrates. The mean crystallisation temperatures of the body, around -4
      degrees C on dry substrata and -2 degrees C on wet substrata, do not differ
      between oviparous and viviparous individuals. All the individuals are able to
      tolerate up to 48-50% of their body fluid converted into ice, but only viviparous
      individuals were able to stabilize their body ice content at 48%, and hence were
      able to survive even when frozen at -3 degrees C for times of up 24 hours. Ice
      contents higher than 51% have been constantly found lethal for oviparous
      individuals. This suggests that, in L. vivipara, the evolution towards a higher
      degree of freezing tolerance could parallel the evolution of the viviparous
      reproductive mode, a feature believed to be strongly selected under cold climatic
      conditions. This is the first report, among reptiles, of an intraspecific
      variation regarding the freeze tolerance capacities.

PMID- 15039997
TI  - Intracellular redistribution and modification of proteins of the Mre11/Rad50/Nbs1
      DNA repair complex following irradiation and heat-shock.
AB  - Mre11, Rad50, and Nbs1form a tight complex which is homogeneously distributed
      throughout the nuclei of mammalian cells. However, after irradiation, the
      Mre11/Rad50/Nbs1 (M/R/N) complex rapidly migrates to sites of double strand
      breaks (DSBs), forming foci which remain until DSB repair is complete. Mre11 and
      Rad50 play direct roles in DSB repair, while Nbs1 appears to be involved in
      damage signaling. Hyperthermia sensitizes mammalian cells to ionizing radiation.
      Radiosensitization by heat shock is believed to be mediated by an inhibition of
      DSB repair. While the mechanism of inhibition of repair by heat shock remains to
      be elucidated, recent reports suggest that the M/R/N complex may be a target for
      inhibition of DSB repair and radiosensitization by heat. We now demonstrate that
      when human U-1 melanoma cells are heated at 42.5 or 45.5 degrees C, Mre11, Rad50,
      and Nbs1 are rapidly translocated from the nucleus to the cytoplasm.
      Interestingly, when cells were exposed to ionizing radiation (12 Gy of X-rays)
      prior to heat treatment, the extent and kinetics of translocation were increased
      when nuclear and cytoplasmic fractions of protein were analyzed immediately after
      treatment. The kinetics of the translocation and subsequent relocalization back
      into the nucleus when cells were incubated at 37 degrees C from 30 min to 7 h
      following treatment were different for each protein, which suggests that the
      proteins redistribute independently. However, a significant fraction of the
      translocated proteins exist as a triple complex in the cytoplasm. Treatment with
      leptomycin B (LMB) inhibits the translocation of Mre11, Rad50, and Nbs1 to the
      cytoplasm, leading us to speculate that the relocalization of the proteins to the
      cytoplasm occurs via CRM1-mediated nuclear export. In addition, while Nbs1 is
      rapidly phosphorylated in the nuclei of irradiated cells and is critical for a
      normal DNA damage response, we have found that Nbs1 is rapidly phosphorylated in
      the cytoplasm, but not in the nucleus, of heated irradiated cells. The
      phosphorylation of cytoplasmic Nbs1, which cannot be inhibited by wortmannin,
      appears to be a unique post-translational modification in heated, irradiated
      cells, and coupled with our novel observations that Mre11, Rad50, and Nbs1
      translocate to the cytoplasm, lend further support for a role of the M/R/N
      complex in thermal radiosensitization and inhibition of DSB repair.

PMID- 15039998
TI  - Meeting report on 3rd National Congress of the Italian Society of Virology (SIV).

PMID- 15039999
TI  - From cell-ECM interactions to tissue engineering.
AB  - The extracellular matrix (ECM) consists of a complex mixture of structural and
      functional macromolecules and serves an important role in tissue and organ
      morphogenesis and in the maintenance of cell and tissue structure and function.
      The great diversity observed in the morphology and composition of the ECM
      contributes enormously to the properties and function of each organ and tissue.
      The ECM is also important during growth, development, and wound repair: its own
      dynamic composition acts as a reservoir for soluble signaling molecules and
      mediates signals from other sources to migrating, proliferating, and
      differentiating cells. Approaches to tissue engineering center on the need to
      provide signals to cell populations to promote cell proliferation and
      differentiation. These "external signals" are generated from growth factors, cell
      ECM, and cell-cell interactions, as well as from physical-chemical and mechanical
      stimuli. This review considers recent advances in knowledge about cell-ECM
      interactions. A description of the main ECM molecules and cellular receptors with
      particular care to integrins and their role in stimulation of specific types of
      signal transduction pathways is also explained. The general principles of
      biomaterial design for tissue engineering are considered, with same examples.

PMID- 15040000
TI  - Regulation of mesangial cell Na+/Ca2+ exchanger isoforms.
AB  - An isoform of the Na(+)/Ca(2+) exchanger (SDNCX1.10) was cloned from mesangial
      cells of Sprague-Dawley rat. Regulation of this isoform was compared to two other
      clones that were derived from the Dahl/Rapp salt sensitive (SNCX) and salt
      resistant rat (RNCX). All isoforms differ at the alternative splice site and at
      amino acid 218 for SNCX. PKC activates RNCX but not SNCX while SDNCX1.10 was also
      activated by PKC. Regulation of exchanger activities by intracellular calcium
      ([Ca(2+)](i)), pH, and kinases was assessed using Na-dependent (45)Ca(2+) uptake
      assays in OK-PTH cells expressing the vector, RNCX, SNCX, or SDNCX1.10.
      [Ca(2+)](i) was elevated from 50 to 125 nM (n = 4) with thapsigargin (40 nM) and
      reduced from 50 to 29 nM (n = 4) and 18 nM (n = 4) with 10 or 20 microM BAPTA,
      respectively. RNCX was active at all three [Ca(2+)](i) while SNCX and SDNCX1.10
      were only active at lower [Ca(2+)](i). Varying extracellular pH (pH(e), without
      nigericin) or pH(e) and intracellular pH (pH(i), with 10 microM nigericin) from
      pH 7.4 to 6.2, 6.8, or 8.0 showed that SNCX activity was attenuated at both low
      and high pHs. SDNCX1.10 activity was attenuated only at pH 6.2 and 6.8 (with or
      without nigericin) while RNCX activity was attenuated at pH 6.2 (with or without
      nigericin) and pH 6.8 (with nigericin). Finally, only SDNCX1.10 activity was
      stimulated by 250 microM CPT-cAMP or 250 microM DB-cGMP treatment. Thus the
      differential regulation of [Ca(2+)](i) by these exchangers is dependent upon the
      pattern of cellular Na(+)/Ca(2+) exchanger isoform expression.

PMID- 15040001
TI  - Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2
      and the serum and glucocorticoid inducible kinase SGK1.
AB  - The stimulation of cell proliferation by insulin like growth factor IGF-1 has
      previously been shown to depend on activation of voltage gated K(+) channels. The
      signaling involved in activation of voltage gated K(+) channel Kv1.3 includes the
      phosphatidylinositol-3 (PI3) protein kinase, 3-phosphoinositide dependent protein
      kinase PDK1 and the serum and glucocorticoid inducible kinase SGK1. However,
      nothing is known about mechanisms mediating the stimulation of Kv1.3 by SGK1.
      Most recently, SGK1 has been shown to phosphorylate and thus inactivate the
      ubiquitin ligase Nedd4-2. The present study has been performed to explore whether
      the regulation of Kv1.3 involves Nedd4-2. To this end Kv1.3 has been expressed in
      Xenopus oocytes with or without coexpression of Nedd4-2 and/or constitutively
      active (S422D)SGK1. In oocytes expressing Kv1.3 but not in water injected
      oocytes, depolarization from a holding potential of -80 mV to +20 mV triggers
      rapidly inactivating currents typical for Kv1.3. Coexpression of Nedd4-2
      decreases, coexpression of (S422D)SGK1 enhances the currents significantly. The
      effects of either Nedd4-2 or of SGK1 are abrogated by destruction of the
      respective catalytic subunits ((C938S)Nedd4-2 or (K127N)SGK1). Further
      experiments revealed that wild type SGK1 and SGK3 and to a lesser extent SGK2 are
      similarly effective in stimulating Kv1.3 in both, presence and absence of Nedd4
      2. It is concluded that Kv1.3 is downregulated by Nedd4-2 and stimulates by SGK1,
      SGK2, and SGK3. The data thus disclose a novel mechanism of Kv1.3 channel
      regulation.

PMID- 15040002
TI  - Genetic characterization of Pompeii and Herculaneum Equidae buried by Vesuvius in
      79 AD.
AB  - DNA extracted from the skeletons of five equids discovered in a Pompeii stable
      and of a horse found in Herculaneum was investigated. Amino acid racemization
      level was consistent with the presence of DNA. Post-mortem base modifications
      were excluded by sequencing a 146 bp fragment of the 16S rRNA mitochondrial gene.
      Sequencing of a 370 bp fragment of mitochondrial (mt)DNA control region allowed
      the construction of a phylogenetic tree that, along with sequencing of nuclear
      genes (epsilon globin, gamma interferon, and p53) fragments, gave us the
      possibility to address some questions puzzling archaeologists. What animals
      donkeys, horses, or crossbreeds-were they? And, given they had been evidently
      assigned to one specific job, were they all akin or were they animals with
      different mitochondrial haplotypes? The conclusions provided by molecular
      analysis show that the Pompeii remains are those of horses and mules. Furthermore
      one of the equids (CAV5) seems to belong to a haplotype, which is either not yet
      documented in the GenBank or has since disappeared. As its characteristics
      closely recall those of donkeys, which is the out group chosen to construct the
      tree, that appears to have evolved within the Equidae family much earlier than
      horses, this assumption seems to be nearer the truth.

PMID- 15040003
TI  - Epidermal growth factor inhibits 14C-alpha-methyl-D-glucopyranoside uptake in
      renal proximal tubule cells: involvement of PLC/PKC, p44/42 MAPK, and cPLA2.
AB  - The effect of EGF on (14)C-alpha-methyl-D-glucopyranoside (alpha-MG) uptake and
      its related signaling pathways were examined in primary cultured rabbit renal
      proximal tubule cells (PTCs). Epidermal growth factor (EGF) (50 ng/ml) was found
      to inhibit alpha-MG uptake, a distinctive proximal tubule marker. The EGF effect
      was blocked by AG1478 (an EGF receptor antagonist) or genistein and herbimycin
      (tyrosine kinase inhibitors), respectively. In addition, the EGF-induced
      inhibition of alpha-MG uptake was blocked by neomycin and U73122 (phospholipase C
      inhibitors) as well as staurosporine, H-7, and bisindolylmaleimide I (protein
      kinase C inhibitors). EGF was also observed to increase inositol phosphate
      formation. Furthermore, both the EGF-induced inhibition of alpha-MG uptake and
      increase of arachidonic acid (AA) release were blocked by AACOCF(3) (a cytosolic
      phospholipase A(2) inhibitor), indomethacin (a cyclooxygenase inhibitor), and
      econazole (a cytochrome P-450 epoxygenase inhibitor). We examined the involvement
      of mitogen-activated protein kinases (MAPKs) in mediating the effect of EGF on
      alpha-MG uptake. Indeed, EGF increased phosphorylation of p44/p42 MAPK and the
      EGF-induced inhibition of alpha-MG uptake as well as the stimulatory effect of
      EGF on AA release was blocked by PD 98059 (a p44/42 MAPK inhibitor), suggesting a
      causal relationship. However, inhibitors of PKC also prevented the EGF-induced
      increase of AA release. In conclusion, EGF partially inhibited alpha-MG uptake
      via PLC/PKC, p44/42 MAPK, and PLA(2) signaling pathways.

PMID- 15040004
TI  - Biallelic IgH rearrangements in patients with indolent lymphoproliferative
      disorders: molecular and practical implications.
AB  - We report a group of patients (pts) with indolent lymphoproliferative disorder
      who had both alleles for the immunoglobulin heavy chain genes rearranged (biIgH).
      This group of 17 pts consisted of 9 small lymphocytic lymphomas (SLL) and 8
      chronic lymphocytic leukemia (CLL). The polymerase chain reaction (PCR)
      amplification of clonal immunoglobulin heavy (IgH) rearrangement using the
      complementarity determining region III (CDRIII) constantly retrieved two distinct
      bands in all PCR informative samples of those pts. To rule out biclonality, we
      evaluated samples by fluorescein activated cell sorting (FACS) analysis and
      sequenced the PCR products. We were able to obtain both IgH sequences from 12
      patients. FACS suggested biclonality in one case, which also correlated with
      sequencing results as both IgH rearrangements were in-frame. Recently, we
      reported a patient who sustained transformation into an aggressive disease after
      biIgH was detected in the setting of monoclonal disease (Cerny et al., 2003b,
      Haematologica 88(05):ECR15 B.). We decided to compare clinical characteristics
      and prognosis of 17 pts with biIgH and 37 pts with monoIgH rearrangements.
      Although we found some minor differences in disease characteristics between both
      groups, these did not translate into a significantly different overall survival.
      Our findings suggest that true biclonal cases of CLL are rare.

PMID- 15040005
TI  - SHP-2 regulates the phosphatidylinositide 3'-kinase/Akt pathway and suppresses
      caspase 3-mediated apoptosis.
AB  - The Src homology domain 2 (SH2)-containing tyrosine phosphatase SHP-2 has been
      implicated in the regulation of the phosphatidylinositol 3'-kinase (PI3K)/Akt
      pathway. The ability of SHP-2 to regulate the PI3K/Akt pathway is suggested to
      result in the positive effect of SHP-2 on cell survival. Whether SHP-2 regulates
      insulin-like growth factor-1 (IGF-1)-dependent activation of Akt at the level of
      PI3K has yet to be established. Furthermore, the identification of the down
      stream apoptotic target engaged by SHP-2 in cell survival also has yet to be
      determined. Here, we show that overexpression of a catalytically inactive mutant
      of SHP-2 inhibited insulin-like growth factor-1 (IGF-1)-dependent PI3K and Akt
      activation. Consistent with the observation that SHP-2 participates in pro
      survival signaling fibroblasts expressing a deletion within exon 3 of SHP-2,
      which results in a truncation of the amino-terminus SH2 domain (SHP-2(Ex3-/-)),
      were hypersensitive to etoposide-induced cell death. SHP-2(Ex3-/-) fibroblasts
      exhibited enhanced levels of etoposide-induced caspase 3 activity as compared to
      wild-type fibroblasts and the enhanced level of caspase 3 activity was suppressed
      by a caspase 3-specific inhibitor. Re-introduction of wild-type SHP-2 into the
      SHP-2(Ex3-/-) fibroblasts rescued the hypersensitivity to etoposide-induced
      caspase 3 activation. The effects of abrogating SHP-2 function on cell survival
      were not specific to the loss of the amino-terminus SH2 domain of SHP-2 since
      RNAi-mediated knock-down of SHP-2 also reduced cell survival. Taken together,
      these data indicate that the catalytic activity of SHP-2 is required to regulate
      the PI3K/Akt pathway and thus likely participates in anti-apoptotic signaling by
      suppressing caspase 3-mediated apoptosis.

PMID- 15040006
TI  - p27/Kip1 mediates retinoic acid-induced suppression of ovarian carcinoma cell
      growth.
AB  - We have investigated the mechanisms by which all-trans retinoic acid (ATRA)
      causes growth inhibition of ovarian carcinoma cells. As a model, we have studied
      the CAOV3 cell line, which is sensitive to ATRA, and the SKOV3 cell line, which
      is resistant. We have found that treatment of CAOV3 cells with ATRA causes a 5-10
      fold increase in the protein level of the cyclin dependent kinase inhibitor
      p27/Kip1. p27/Kip1 protein upregulation is important in ovarian carcinoma as
      primary tumors are frequently found lacking this protein. The increase in
      p27/Kip1 is detected by day 3 of ATRA treatment of CAOV3 cells, and is maximal by
      day 5. Messenger RNA levels of p27/Kip1 do not change in CAOV3 cells following
      ATRA treatment, however, we have shown that p27/Kip1 mRNA is more stable in ATRA
      treated CAOV3 cells. Conversely, the ATRA resistant cell line SKOV3 fails to show
      p27/Kip1 accumulation. Interestingly, the SCF component protein SKP2 appears to
      be decreased in CAOV3 cells treated with ATRA. We have also shown that the ATRA
      dependent increase in p27/kip1 protein in CAOV3 cells leads to a decrease in the
      kinase activity of cyclin dependent kinase 4 (CDK4) following ATRA treatment.
      Finally, we found that CAOV3 cells stably transfected with a p27/kip1antisense
      construct, which express lower levels of p27/kip1 following ATRA treatment, and
      have a higher CDK4 kinase activity are less sensitive to ATRA induced growth
      suppression. Taken together our data suggest ATRA-induced growth inhibition in
      CAOV3 ovarian carcinoma cells involves modulation of the CDK inhibitor p27/kip1.

PMID- 15040007
TI  - CXCL12 chemokine up-regulates bone resorption and MMP-9 release by human
      osteoclasts: CXCL12 levels are increased in synovial and bone tissue of
      rheumatoid arthritis patients.
AB  - Chemokines are involved in a number of inflammatory pathologies and some of them
      show a pivotal role in the modulation of osteoclast development. Therefore, we
      evaluated the role of CXCL12 chemokine on osteoclast differentiation and function
      and we analyzed its expression on synovial and bone tissue biopsies from
      rheumatoid arthritis (RA) patients. Osteoclasts were obtained by 7 days in vitro
      differentiation with RANKL and M-CSF of CD11b positive cells in the presence or
      absence of CXCL12. The total number of osteoclast was analyzed by Tartrate
      resistant acid phosphatase (TRAP)-staining and bone-resorbing activity was
      assessed by pit assay. MMP-9 and TIMP-1 release was evaluated by ELISA assay.
      CXCL12 expression on biopsies from RA patients was analyzed by
      immunohistochemistry. Osteoclasts obtained in the presence of CXCL12 at 10 nM
      concentration displayed a highly significant increase in bone-resorbing activity
      as measured by pit resorption assay, while the total number of mature osteoclasts
      was not affected. The increased resorption is associated with overexpression of
      MMP-9. Immunostaining for CXCL12 on synovial and bone tissue biopsies from both
      rheumatoid arthritis (RA) and osteoarthritis (OA) samples revealed a strong
      increase in the expression levels under inflammatory conditions. CXCL12 chemokine
      showed a clear activating role on mature osteoclast by inducing bone-resorbing
      activity and specific MMP-9 enzymatic release. Moreover, since bone and synovial
      biopsies from RA patients showed an elevated CXCL12 expression, these findings
      may provide useful tools for achieving a full elucidation of the complex network
      that regulates osteoclast function in course of inflammatory diseases.

PMID- 15040008
TI  - Bile canalicular formation in hepatic organoid reconstructed by rat small
      hepatocytes and nonparenchymal cells.
AB  - The morphogenesis and movement of bile canaliculi (BC) are not well understood.
      This is because culture of hepatocytes that maintain polarity of cell membranes
      and possess highly differentiated functions has never been successful. We found
      that small hepatocytes (SHs), which are known to be hepatic progenitor cells,
      could proliferate and differentiate into mature hepatocytes and that BC-like
      structures developed between rising/piled-up cells. We investigated how BC-like
      structures developed with maturation of SHs and whether the structures were
      functionally active as BC. Hepatic cells, including SHs, were isolated from an
      adult rat liver and cultured. Immunocytochemistry and immunoblotting for BC
      proteins, such as ectoATPase, 5'-nucleotidase, dipeptidylpeptidase IV, and
      multidrug-resistance associated protein 2, were examined and time-lapse
      microscopy was used for the observation of BC contractions. Secretion of
      bilirubin into the reconstructed BC was also observed. The results of
      immunocytochemistry, immunoblots, and immunoelectron micrographs revealed that BC
      proteins were localized in the intercellular space that coincided with BC-like
      structures reconstructed between rising/piled-up cells. Tight junction-associated
      protein ZO-1 was also expressed along the BC-like structures. Bilirubin added to
      the medium were secreted into BC-like structure and accumulated without leakage.
      Time-lapse microscopy showed continuous contractions of reconstructed BC. In
      conclusion, BC-like structures reconstructed by SHs may be functional with
      membrane polarity, secretory ability, and motility. These results show that this
      culture system may suitable for investigating the mechanism of the formation of
      BC and their functions.

PMID- 15040009
TI  - The nucleocytoplasmic shuttling of E2F4 is involved in the regulation of human
      intestinal epithelial cell proliferation and differentiation.
AB  - The specific mechanisms controlling the transition from proliferation to terminal
      differentiation in human intestinal epithelial cells (HIEC) remain largely
      undefined. Herein, we analyzed the expression and localization of Rb and E2F
      proteins in well-established normal intestinal epithelial cell models which allow
      for the re-enactment of the crypt-villus axis in vitro as well as in intact
      epithelium and in colon cancer cells. We report that (1) expression of E2F1 is
      down-regulated while E2F4 protein is sequestered in the cytoplasm during G(0)
      arrest associated with serum deprivation, confluency, and terminal
      differentiation of intestinal cells; (2) concurrently, there is an accumulation
      of the hypophosphorylated form of the pocket proteins into the nucleus with an
      increased association of E2F4 with pRb and p130; (3) cells which expressed high
      levels of nuclear E2F4 are all positive for Ki67 staining in human fetal
      intestine; (4) activation of HIEC crypt cells by growth factors leads to an
      increase in the nuclear localization of E2F4 which may be attributable to a
      decrease in the serine/threonine phosphorylation of this transcription factor;
      (5) inhibition of p38 MAP kinase with alpha/beta inhibitor SB203580 induces E2F4
      translocation into the nucleus and its transcriptional activity. In conclusion,
      our data suggest a key role for E2F4 in proliferation of human intestinal crypt
      cells and that its cytoplasmic retention as well as its sequestration by Rb
      proteins may represent a critical step in initiating cell-cycle exit.

PMID- 15040010
TI  - S100B causes apoptosis in a myoblast cell line in a RAGE-independent manner.
AB  - S100B, a Ca(2+)-modulated protein with both intracellular and extracellular
      regulatory roles, is most abundant in astrocytes, is expressed in various amounts
      in several non-nervous cells and is also found in normal serum. Astrocytes
      secrete S100B, and extracellular S100B exerts trophic and toxic effects on
      neurons depending on its concentration, in part by interacting with the receptor
      for advanced glycation end products (RAGE). The presence of S100B in normal serum
      and elevation of its serum concentration in several non-nervous pathological
      conditions suggest that S100B-expressing cells outside the brain might release
      the protein and S100B might affect non-nervous cells. Recently we reported that
      at picomolar to nanomolar doses S100B inhibits rat L6 myoblast differentiation
      via inactivation of p38 kinase in a RAGE-independent manner. We show here that at
      >or=5 nM in the absence of and at >100 nM in the presence of serum S100B causes
      myoblast apoptosis via stimulation of reactive oxygen species (ROS) production
      and inhibition of the pro-survival kinase, extracellular signal-regulated kinase
      (ERK)1/2, again in a RAGE-independent manner. Together with our previous data,
      the present results suggest that S100B might participate in the regulation of
      muscle development and regeneration by two independent mechanism, i.e., by
      inhibiting crucial steps of the myogenic program at the physiological levels
      found in serum and by causing elevation of ROS production and myoblast apoptosis
      following accumulation in serum and/or muscle extracellular space. Our data also
      suggest that RAGE has no role in the transduction of S100B effects on myoblasts,
      implying that S100B can interact with more than one receptor to affect its target
      cells.

PMID- 15040011
TI  - Requirement of TGF-beta receptor-dependent activation of c-Jun N-terminal kinases
      (JNKs)/stress-activated protein kinases (Sapks) for TGF-beta up-regulation of the
      urokinase-type plasminogen activator receptor.
AB  - We have previously demonstrated that activation of the Ras/Mapk pathways is
      required for transforming growth factor beta (TGF-beta) induction of TGF-beta(1)
      expression. Here we examined the role of the Ras/Mapk pathways in TGF-beta
      induction of urokinase-type plasminogen activator receptor (uPAR) expression in
      untransformed intestinal epithelial cells (IECs). TGF-beta activated the stress
      activated protein kinases (Sapk)/c-Jun N-terminal kinases (JNKs) within 5-10 min,
      an effect that preceeded TGF-beta induction of uPAR expression in these cells.
      TGF-beta induction of both JNK1 activity and JunD phosphorylation was blocked by
      expression of a dominant-negative mutant of the type II TGF-beta receptor (DN
      TbetaRII), a dominant-negative mutant of MKK4 (DN MKK4), or a dominant-negative
      mutant of Ras (RasN17), or by the addition of the JNK inhibitor SP600125. TGF
      beta also induced AP-1 complex formation at the distal AP-1 site (-184 to -178)
      of the uPAR promoter within 2 h of TGF-beta addition, consistent with the time
      dependent up-regulation of uPAR expression. The primary components present in the
      TGF-beta-stimulated AP-1 complex bound to the uPAR promoter were Jun D and Fra-2.
      Moreover, addition of SP600125, or expression of DN MKK4 or DN TbetaRII, blocked
      TGF-beta up-regulation of uPAR in IECs. Accordingly, our results indicate that
      TGF-beta activates the Ras/MKK4/JNK1 signaling cascade, leading to induction of
      AP-1 activity, which, in turn, up-regulates uPAR expression. Our results also
      indicate that the type II TGF-beta receptor (RII) is required for TGF-beta
      activation of JNK1 and the resulting up-regulation of uPAR expression.

PMID- 15040012
TI  - Ultrastructural changes in the interstitial cells of Cajal and gastric
      dysrhythmias in mice lacking full-length dystrophin (mdx mice).
AB  - At least two populations of c-kit positive interstitial cells of Cajal (ICC) lie
      in the gastric wall, one located at the myenteric plexus level has a pace-making
      function and the other located intramuscularly is intermediary in the
      neurotransmission and regenerates the slow waves. Both of these ICC sub-types
      express full-length dystrophin. Mdx mice, an animal model lacking in full-length
      dystrophin and used to study Duchenne muscular dystrophy (DMD), show gastric
      dismotilities. The aim of the present study was to verify in mdx mice whether:
      (i) gastric ICC undergo morphological changes, through immunohistochemical and
      ultrastructural analyses; and (ii) there are alterations in the electrical
      activity, using intracellular recording technique. In control mice, ICC sub-types
      showed heterogeneous ultrastructural features, either intramuscularly or at the
      myenteric plexus level. In mdx mice, all of the ICC sub-types underwent important
      changes: coated vesicles were significantly more numerous and caveolae
      significantly fewer than in control; moreover, cytoskeleton and smooth
      endoplasmic reticulum were reduced and mitochondria enlarged. c-Kit-positivity
      and integrity of the ICC networks were maintained. In the circular muscle of
      normal mice slow waves, which consisted of initial and secondary components,
      occurred with a regular frequency. In mdx mice, slow waves occurred in a highly
      dysrhythmic fashion and they lacked a secondary component. We conclude that the
      lack of the full-length dystrophin is associated with ultrastructural
      modifications of gastric ICC, most of which can be interpreted as signs of new
      membrane formation and altered Ca(2+) handling, and with defective generation and
      regeneration of slow wave activity.

PMID- 15040013
TI  - NO induced apoptosis of vascular smooth muscle cells accompanied by ceramide
      increase.
AB  - We have shown previously that nitric-oxide (NO) can induce apoptosis of vascular
      smooth muscle cells (VSMCs) and that the NO-induced apoptosis is accompanied by
      an increase in arachidonic acid release via cytoplasmic Ca(2+)-dependent
      phospholipase A(2) (cPLA(2)). We have evidence that during NO-induced apoptosis
      there is an increase in ceramide synthesis. The use of inhibitors of ceramide
      synthesis, namely, fumonisin B1 and desipramine, which block ceramide synthase
      and sphingomyelinase, respectively revealed that the ceramide was produced via
      the sphingomyelinase pathway. Inhibition of acid sphingomyelinase by desipramine
      was shown to inhibit NO-induced apoptosis while fumonisin B1 failed to inhibit
      this process. C(2)-ceramide could induce apoptosis in cultured VSMCs. Apoptosis
      in smooth muscle cells was accompanied by the increased activity of DNA
      fragmentation factor-40 and the secretion of cathepsin D from the cells. In this
      study, ceramide appears to function as a mediator of apoptosis.

PMID- 15040015
TI  - Downregulation of retinoic acid receptor-beta(2) expression is linked to aberrant
      methylation in esophageal squamous cell carcinoma cell lines.
AB  - AIM: To study the role of hypermethylation in the loss of retinoic acid receptor
      beta(2) (RARbeta(2)) in esophageal squamous cell carcinoma (ESCC). METHODS: The
      role of hypermethylation in RARbeta(2) gene silencing in 6 ESCC cell lines was
      determined by methylation-specific PCR (MSP), and its methylation status was
      compared with RARbeta(2) mRNA expression by RT-PCR. The MSP results were
      confirmed by bisulfite sequencing of RARbeta(2) promoter regions. RESULTS:
      Methylation was detected in 4 of the 6 cell lines, and the expression of
      RARbeta(2) was markedly downregulated in 3 of the 4 methylated cell lines. The
      expression of RARbeta(2) was restored in one RARbeta(2) -downregulated cell line
      with the partial demethylation of promoter region of RARbeta(2) after 5-aza-2'
      deoxycytidine (5-aza-dc) treatment. CONCLUSION: The methylation of the 5' region
      may play an important role in the downregulation of RARbeta(2) in some ESCC cell
      lines, suggesting that multiple mechanisms contribute to the loss of RARbeta(2)
      expression in ESCC cell lines. This study may have clinical applications for
      treatment and prevention of ESCC.

PMID- 15040016
TI  - Expression of heparanase gene, CD44v6, MMP-7 and nm23 protein and their
      relationship with the invasion and metastasis of gastric carcinomas.
AB  - AIM: To explore the expression of heparanase gene, CD44v6, MMP-7 and nm23
      proteins in human gastric carcinoma as well as their relationship with the
      clinicopathological factors. METHODS: Reverse transcription polymerase chain
      reaction (RT-PCR) was used to measure the expressions of heparanase mRNA in 43
      human gastric carcinomas and 10 adjacent normal gastric tissues. Streptavidin
      peroxidase (S-P) two step method was used to measure the immunohistochemical
      expression of CD44v6, MMP-7 and nm23 protein in 43 human gastric carcinomas.
      RESULTS: The expression of heparanase gene was positive in 29 cases of gastric
      cancer with a positive rate of 67.4%, which was significantly higher than those
      in adjacent normal gastric tissues (P<0.05). The heparanase mRNA expression was
      significantly related to advanced stage of disease, serosal infiltration, lymph
      node metastasis and size of tumors (P<0.05), but not related to tumor location,
      gross and histological types of the cancer, peritoneal dissemination and liver
      metastasis (P>0.05). The positive rate of CD44v6, nm23 and MMP-7 proteins was
      76.7%, 37.2% and 60.5%, respectively. The CD44v6 protein expression was
      significantly related to serosal infiltration, lymph node metastasis and TNM
      stage of disease (P<0.05). The nm23 protein expression was significantly related
      to the tumor gross appearance, lymph node and peritoneal metastasis (P<0.05). The
      MMP-7 protein expression was significantly related to serosal infiltration and
      TNM stage of disease (P<0.05). In an attempt to measure the association between
      these agents, we found that the expression of heparanase mRNA had significantly
      negative correlation with the expression of CD44v6 and MMP-7 protein (P<0.05),
      the expression of MMP-7 protein had significantly positive correlation with the
      expression of CD44v6 protein (r=0.568, P<0.05), the expression of MMP-7 protein
      had no correlation with the expression of nm23 protein (P>0.05), and the
      expression of nm23 protein had no correlation with the expression of CD44v6
      protein (P>0.05). CONCLUSION: Despite their different mechanisms of action,
      heparanase, CD44v6 and nm23 may play important roles in the invasive infiltration
      and lymph node metastasis in gastric carcinomas. Instead of metastatic spreading,
      MMP-7 may be just related to the invasion of gastric carcinomas. However, co
      detection of these factors may be important to predict metastatic spreading in
      such patients.

PMID- 15040017
TI  - Expression of vascular endothelial growth factor C and chemokine receptor CCR7 in
      gastric carcinoma and their values in predicting lymph node metastasis.
AB  - AIM: To study the expression of vascular endothelial growth factor C (VEGF-C) and
      chemokine receptor CCR7 in gastric carcinoma and to investigate their
      associations with lymph node metastasis of gastric carcinoma and their values in
      predicting lymph node metastasis. METHODS: The expression of VEGF-C and CCR7 in
      gastric carcinoma tissues obtained from 118 patients who underwent curative
      gastrectomy was examined by immunohistochemistry. Among these patients, 39
      patients underwent multi-slice spiral CT (MSCT) examination. RESULTS: VEGF-C and
      CCR7 were positively expressed in 52.5 and 53.4% of patients. VEGF-C expression
      was more frequently found in tumors with lymph node metastasis than those without
      it (P<0.001). VEGF-C expression was also closely related to lymphatic invasion
      (P<0.001), vascular invasion (P<0.01), and TNM stage (P<0.001). However, there
      was no significant correlation between VEGF-C expression and age at surgery,
      gender, tumor size, tumor location, Lauren classification, and depth of invasion.
      CCR7 expression was significantly higher in patients with lymph node metastasis
      compared with those without lymph node metastasis (P<0.001) and was also
      associated with tumor size (P<0.01), depth of invasion (P<0.001), lymphatic
      invasion (P<0.001), and TNM stage (P<0.001). However, the presence of CCR7 had no
      correlation to age at surgery, gender, tumor location, Lauren classification, and
      vascular invasion. Among the 39 patients who underwent MSCT examination, only
      CCR7 expression was related to lymph node metastasis determined by MSCT (P<0.05).
      In the current retrospective study, the sensitivity, specificity, positive
      predictive value (PPV), negative predictive value (NPV), and accuracy of VEGF-C
      and CCR7 expression in the diagnosis of lymph node metastasis for patients with
      gastric carcinoma were 73.8%, 70.2%, 72.6%, 71.4% and 72.0%, and 82.0%, 77.2%,
      79.4%, 80.0% and 79.7%, respectively. After subdivision according to the
      combination of VEGF-C and CCR7 expression, receiver operating characteristic
      (ROC) analysis showed that the accuracy of the combined examination of VEGF-C and
      CCR7 expression in predicting lymph node metastasis was relatively high (area
      under ROC curve [Az]=0.83). CONCLUSION: The expression of VEGF-C and CCR7 is
      related to lymph node metastasis of gastric carcinoma and both of them may become
      new targets for the treatment of gastric carcinoma. Furthermore, the combined
      examination of VEGF-C and CCR7 expression in endoscopic biopsy specimens may be
      useful in predicting lymph node metastasis of gastric carcinoma and deciding the
      extent of surgical lymph node resection.

PMID- 15040019
TI  - Effect of mitogen-activated protein kinase signal transduction pathway on
      multidrug resistance induced by vincristine in gastric cancer cell line MGC803.
AB  - AIM: To investigate the correlation between mitogen-activated protein kinase
      (MAPK) signal transduction pathway and multidrug resistance (MDR) in MGC803
      cells. METHODS: Western blot was used to analyze the expression of MDR associated
      gene in transient vincristine (VCR) induced MGC803 cells, which were treated with
      or without the specific inhibitor of MAPK, PD098059. Morphologic analysis of the
      cells treated by VCR with or without PD098059 was determined by Wright-Giemsa
      staining. The cell cycle analysis was performed by using flow cytometric assay
      and the drug sensitivity of MGC803 cells which were exposed to VCR with or
      without PD098059 was tested by using MTT assay. RESULTS: Transient exposure to
      VCR induced P-gp but not MRP1 or GST-pi expression in MGC803 cells and the
      expression of P-gp was inhibited by PD098059. Apoptotic bodies were found in the
      cells treated with VCR or VCR+PD098059. FCM results indicated that more MGC803
      cells showed apoptotic phenotype when treated by VCR and PD098059 (rate: 31.23%)
      than treated by VCR only (rate: 18.42%) (P<0.05). The IC(50) (284+/-13.2 mug/L)
      of MGC803 cells pretreated with VCR was 2.24-fold as that of negative control
      group (127+/-17.6 mug/L) and 1.48-fold as that of the group treated with PD098059
      (191+/-27.9 mug/L). CONCLUSION: This study shows that the expression of P-gp can
      be induced by transient exposure to VCR and this induction can be prevented by
      PD098059, which can block the activity of MAPK. MAPK signal transduction pathway
      may play some roles in modulating MDR1 expression in gastric cancer.

PMID- 15040018
TI  - Coexpression of cholecystokinin-B/gastrin receptor and gastrin gene in human
      gastric tissues and gastric cancer cell line.
AB  - AIM: To compare the expression patterns of cholecystokinin-B (CCK-B)/gastrin
      receptor genes in matched human gastric carcinoma and adjacent non-neoplastic
      mucosa of patients with gastric cancer, inflammatory gastric mucosa from patients
      with gastritis, normal stomachs from 2 autopsied patients and a gastric carcinoma
      cell line (SGC-7901), and to explore their relationship with progression to
      malignancy of human gastric carcinomas. METHODS: RT-PCR and sequencing were
      employed to detect the mRNA expression levels of CCK-B receptor and gastrin gene
      in specimens from 30 patients with gastric carcinoma and healthy bordering non
      cancerous mucosa, 10 gastritis patients and normal stomachs from 2 autopsied
      patients as well as SGC-7901. The results were semi-quantified by normalizing it
      to the mRNA level of beta-actin gene using Lab Image software. The sequences were
      analyzed by BLAST program. RESULTS: CCK-B receptor transcripts were detected in
      all of human gastric tissues in this study, including normal, inflammatory and
      malignant tissues and SGC-7901. However, the expression levels of CCK-B receptor
      in normal gastric tissues were higher than those in other groups (P<0.05), and
      its expressions did not correlate with the differentiation and metastasis of
      gastric cancer (P>0.05). On the other hand, gastrin mRNA was detected in SGC-7901
      and in specimens obtained from gastric cancer patients (22/30) but not in other
      gastric tissues, and its expression was highly correlated with the metastases of
      gastric cancer (P<0.05). CONCLUSION: Human gastric carcinomas and gastric cancer
      cell line SGC-7901 cells coexpress CCK-B receptor and gastrin mRNA. Gastrin/CCK-B
      receptor autocrine or paracrine pathway may possibly play an important role in
      the progression of gastric cancer.

PMID- 15040020
TI  - Mitochondrial microsatellite instability in gastric cancer and its precancerous
      lesions.
AB  - AIM: To evaluate the role of mitochondrial microsatellite instability (mtMSI) in
      gastric carcinogenesis. METHODS: MtMSI was measured with PCR-single strand
      conformation polymorphism (PCR-SSCP) in 68 cases of advanced gastric cancer, 40
      cases of chronic gastritis, 30 cases of intestinal metaplasia and 20 cases of
      dysplasia. RESULTS: MtMSI was observed in 12.5% (5 of 40) of chronic gastritis,
      20.0% (6 of 30) of intestinal metaplasia, 25.0% (5 of 20) of dysplasia and 38.2%
      (26 of 68) of gastric cancer. These findings showed a sequential accumulation of
      mtMSI in the histological progression from chronic gastritis to gastric cancer.
      An association of mtMSI with intestinal histological type and distal location was
      found (P=0.001 and P=0.002), whereas no significant correlation was found between
      mtMSI and age at diagnosis, sex, tumor size, depth of invasion, lymph node spread
      and clinical stages (P>0.05). CONCLUSION: MtMSI may play an early and important
      role in the gastric carcinogenesis pathway, especially in the intestinal type and
      distal gastric cancer.

PMID- 15040021
TI  - Detection of micrometastasis of gastric carcinoma in peripheral blood
      circulation.
AB  - AIM: To detect the micrometastasis of gastric carcinoma in peripheral blood
      circulation using immunomagnetic beads sorting technique and RT-PCR technique,
      and to discuss its significance and the difference between the two methods.
      METHODS: Density gradient centrifugation was used to isolate mononuclear cells
      from peripheral blood, immunomagnetic beads sorting technique and RT-PCR
      technique were used to detect the disseminated carcinoma cells. HE,
      immunocytochemical and immunofluorescence staining were also used to identify the
      characteristics of the cells separated with immunomagnetic beads sorting
      technique. RESULTS: Cells expressing cytokeratin were separated and enriched from
      the peripheral blood specimens of patients suffering from gastric carcinoma or
      chronic gastritis. After HE staining, two kinds of cells with little cytoplasm
      were found. Majority of these cells had small and round nuclei, even chromatins
      and the thickness of nuclear membrane was normal. Immunohistochemical staining
      indicated that there were CD34 and CD45 expression on the cell membrane of this
      kind of cells and these cells also showed expressed human telomerase reverse
      transcriptase by immunofluorescence staining, but the expression of
      carcinoembryonic antigen was absent. So, these cells might hematopoiesis
      precursors. Another kind of cells had larger and abnormal nuclei with thicker
      nuclear membranes. Massed chromatins and poly-nucleoli were found in the nuclei.
      These cells expressed human telomerase reverse transcriptase and carcinoembryonic
      antigen, but CD34 and CD45 were not found on the cell membrane. So, these cells
      were considered as gastric carcinoma cells escaping from the original focuses and
      existing in the peripheral blood circulation. Carcinoma cells were found in 25 of
      60(41.7%) specimens of peripheral blood from patients with gastric carcinoma,
      while there were no such cells separated from the blood specimens of chronic
      gastritis patients. The difference of positive rates of disseminated carcinoma
      cells between two groups was markedly significant (P<0.005). The expressions of
      CK20 mRNA in peripheral blood specimens were examinated with RT-PCR. CK20 mRNA
      was detected from 32 of 60(53.3%) peripheral blood specimens in the group of
      gastric carcinoma patients, while none of the specimens from patients suffering
      from chronic gastritis had CK20 mRNA. Significant difference was also found
      between two groups (P<0.005). Statistic analyses also showed that there was a
      significant difference between the positive rates of two methods in detecting the
      disseminated carcinoma cells from the peripheral blood circulation of gastric
      carcinoma patients (P<0.05). CONCLUSION: The results demonstrated that there were
      disseminated carcinoma cells in the peripheral blood circulation of some patients
      with gastric carcinoma. Disseminated carcinoma cells can be detected from the
      peripheral blood samples with immunomagnetic beads sorting technique and RT-PCR
      technique. The positive rate of RT-PCR technique is higher than that of
      immunomagnetic beads sorting technique in detecting micrometastasis.

PMID- 15040022
TI  - Effects of PI3K and p42/p44 MAPK on overexpression of vascular endothelial growth
      factor in hepatocellular carcinoma.
AB  - AIM: To study the relationship between hypoxia or epidermal growth factor (EGF)
      and the overexpression of vascular endothelial growth factor (VEGF) in
      hepatocellular carcinoma (HCC) and the signal transduction pathway of the
      transcription of VEGF in hepatoma cells. METHODS: Cobalt chloride and recombinant
      human EGF were used to stimulate the hepatoma cell lines HepG(2). VEGF mRNA was
      detected by using of semi-quantitative polymerase chain reaction (RT-PCR).
      Specific inhibitors of phosphatidylinositol 3-kinase (PI3K) and p42/p44 mitogen
      activated protein kinase (MAPK) were used to observe the effects of the two
      kinases on the regulation of the transcription of VEGF in hepatoma cells.
      RESULTS: The expression of VEGF mRNA in HepG(2) cells cultured in serum-free
      medium was 0.117. However, 100 mumol/L cobalt chloride for 24 h increased the
      expression of VEGF mRNA and VEGF mRNA increased gradually with the increase of
      the concentration and duration of cobalt chloride. Also, 25 ng/mL recombinant
      human EGF stimulated the expression of VEGF in HepG(2) cells and the expression
      increased with the increase of EGF concentration. 5 mumol/L LY294002 inhibited
      the expression of VEGF stimulated by cobalt chloride or recombinant human EGF and
      the inhibition decreased step by step with increase of the concentration of
      LY294002. But even 20 mumol/L LY294002 could not completely block the expression
      of VEGF. In contrast, PD98059 had no inhibitory effects on the transcription of
      VEGF stimulated by cobalt chloride or recombinant human EGF. CONCLUSION: The
      overexpression of VEGF in HCC could be promoted by hypoxia and EGF expression in
      HCC. The signal transduction pathway of VEGF transcription in HepG(2) cells may
      be through PI3K pathway, but not through p42/p44 MAPK pathway.

PMID- 15040023
TI  - Vascular endothelial growth factor antisense oligodeoxynucleotides with lipiodol
      in arterial embolization of liver cancer in rats.
AB  - AIM: Transcatheter arterial embolization (TAE) of the hepatic artery has been
      accepted as an effective treatment for unresectable hepatocellular carcinoma
      (HCC). However, embolized vessel recanalization and collateral circulation
      formation are the main factors of HCC growth and recurrence and metastasis after
      TAE. Vascular endothelial growth factor (VEGF) plays an important role in tumor
      angiogenesis. This study was to explore the inhibitory effect of VEGF antisense
      oligodeoxynucleotides (ODNs) on VEGF expression in cultured Walker-256 cells and
      to observe the anti-tumor effect of intra-arterial infusion of antisense ODNs
      mixed with lipiodol on rat liver cancer. METHODS: VEGF antisense ODNs and sense
      ODNs were added to the media of non-serum cultured Walker-256 cells. Forty-eight
      hours later, VEGF concentrations of supernatants were detected by ELISA.
      Endothelial cell line ECV-304 cells were cultured in the supernatants. Seventy
      two hours later, growth of ECV-304 cells was analyzed by MTT method. Thirty
      Walker-256 cell implanted rat liver tumor models were divided into 3 groups. 0.2
      mL lipiodol (LP group, n=10), 3OD antisense ODNs mixed with 0.2 mL lipiodol
      (LP+ODNs group, n=10) and 0.2 mL normal saline (control group, n=10) were infused
      into the hepatic artery. Volumes of tumors were measured by MRI before and 7 d
      after the treatment. VEGF mRNA in cancerous and peri-cancerous tissues was
      detected by RT-PCR. Microvessel density (MVD) and VEGF expression were observed
      by immunohistochemistry. RESULTS: Antisense ODNs inhibited Walker-256 cells' VEGF
      expression. The tumor growth rate was significantly lower in LP+ODNs group than
      that in LP and control groups (140.1+/-33.8%, 177.9+/-64.9% and 403.9+/-69.4%
      respectively, F=60.019, P<0.01). VEGF mRNAs in cancerous and peri-cancerous
      tissues were expressed highest in LP group and lowest in LP+ODNs group. The VEGF
      positive rates showed no significant difference among LP, control and LP+ODNs
      groups (90%, 70% and 50%, H=3.731, P>0.05). The MVD in LP+ODNs group (53.1+/
      18.4) was significantly less than that in control group (73.2+/-20.4) and LP
      group (80.3+/-18.5) (F=5.44, P<0.05). CONCLUSION: VEGF antisense ODNs can inhibit
      VEGF expression of Walker-256 cells. It may be an antiangiogenesis therapy agent
      for malignant tumors. VEGF antisense ODNs mixed with lipiodol embolizing liver
      cancer is better in inhibiting liver cancer growth, VEGF expression and
      microvessel density than lipiodol alone.

PMID- 15040024
TI  - Alpha-fetoprotein stimulated the expression of some oncogenes in human
      hepatocellular carcinoma Bel 7402 cells.
AB  - AIM: To investigate the molecular mechanism of alpha-fetoprotein (AFP) on
      regulating the proliferation of human hepatocellular carcinoma cells. METHODS:
      Alpha-fetoprotein purified from human umbilical blood was added to cultured human
      hepatocellular carcinoma Bel 7402 cells in vitro for various treatment periods.
      The expression of c-fos, c-jun, and N-ras mRNA involved in proliferation and
      differentiation of cells was analyzed by Northern blot, and the expression of
      mutative p53 and p21(ras) proteins was determined by Western blot. RESULTS: The
      results showed that AFP (20 mg/L) stimulated mRNA expression of these oncogenes
      in Bel 7402 cells. The expression of c-fos mRNA increased by 51.1%, 60.9%, 96.0%,
      and 25.5% at 2, 6, 12, and 24 h, respectively. The expression of c-jun and N-ras
      mRNA reached to the maximum which increased by 81.3% and 59.9% as compared with
      the control after 6 h and 24 h incubation with AFP, respectively. Western blot
      assay also demonstrated that AFP promoted the expression of mutative p53 and
      p21(ras) proteins, and the increased rate of those proteins was 13.0%, 39.9%, and
      70.9%, as well as 35.2%, 102.6%, and 46.8% at 6, 12, and 24 h, respectively, as
      compared with the control. Both human serum albumin (the same dosage as AFP) and
      monoclonal anti-AFP antibody failed to stimulate the expression of these
      oncogenes, but anti-AFP antibody could block the functions of AFP. CONCLUSION:
      The data indicate that AFP can stimulate the expression of some oncogenes to
      enhance the proliferation of human hepatocellular carcinoma Bel 7402 cells.

PMID- 15040025
TI  - Comparison of long-term effects between intra-arterially delivered ethanol and
      Gelfoam for the treatment of severe arterioportal shunt in patients with
      hepatocellular carcinoma.
AB  - AIM: To evaluate long-term effect of ethanol embolization for the treatment of
      hepatocellular carcinoma (HCC) with severe hepatic arterioportal shunt (APS),
      compared with Gelfoam embolization. METHODS: Sixty-four patients (ethanol group)
      and 33 patients (Gelfoam group) with HCC and APS were respectively treated with
      ethanol and Gelfoam for APS before the routine interventional treatment for the
      tumor. Frequency of recanalization of shunt, complete occlusion of the shunt,
      side effects, complications, and survival rates were analyzed between the two
      groups. RESULTS: The occlusion rate of APS after initial treatment in ethanol
      group was 70.3%(45/64), and recanalization rate of 1 month after embolization was
      17.8%(8/45), and complete occlusion rate was 82.8%(53/64). Those in Gelfoam group
      were 63.6%(21/33), 85.7%(18/21), and 18.2%(6/33). There were significant
      differences in recanalization rate and complete occlusion rate between the two
      groups (P<0.05). The survival rates in ethanol group were 78% at 6 months, 49% at
      12 months, 25% at 24 months, whereas those in Gelfoam group were 58% at 6 months,
      23% at 12 months, 15% at 24 months. The ethanol group showed significantly better
      survival than Gelfoam group (P<0.05). In the ethanol group, there was a
      significant prolongation of survival in patients with monofocal HCC (P<0.05) and
      Child class A (P<0.05). There were no significant differences in survival rate in
      the Gelfoam group with regard to the number of tumor and Child class (P>0.05).
      The incidence rate of abdominal pain during procedure in ethanol group was 82.8%.
      There was no significant difference in postembolization syndromes between two
      groups. Procedure-related hepatic failure did not occur in ethanol group.
      CONCLUSION: Ethanol embolization for patients with HCC and severe APS is
      efficacious and safe, and may contribute to prolongation of the life span versus
      Gelfoam embolization.

PMID- 15040026
TI  - Expression of transforming growth factor-alpha and hepatitis B surface antigen in
      human hepatocellular carcinoma tissues and its significance.
AB  - AIM: To evaluate the expression of transforming growth factor-alpha (TGF-alpha)
      and hepatitis B surface antigen (HBsAg) in human hepatocellular carcinoma (HCC)
      tissues and its significance. METHODS: Seventy specimens of HCC tissues were
      detected by immunohistochemical method. Five specimens of normal human liver
      tissues were used as control. RESULTS: The TGF-alpha positive expression rates in
      HCC and its surrounding tissues were 74.3%(52/70) and 88.1%(52/59), respectively.
      TGF-alpha positive granules were mainly in the cytoplasm and fewer existed on the
      karyotheca. The TGF-alpha positive expressing rate in well differentiated HCC was
      significantly higher than that in moderately and poorly differentiated HCC
      (P<0.05). The TGF-alpha positive expression also was observed in intrahepatic
      bile ducts (part of those were hyperplastic ducts). The HBsAg positive expression
      rates in HCC and its surrounding tissues were 21.4%(15/70) and 79.7%(47/59),
      respectively. HBsAg positive granules were in the cytoplasm, inclusion and on the
      karyotheca. There was a prominent positive correlation between TGF-alpha and
      HBsAg expression in HCC surrounding tissues (P<0.05, gamma=0.34). TGF-alpha was
      usually existed with HBsAg in regenerated and/or dysplastic liver cells. In the
      five normal liver tissues, TGF-alpha and HBsAg were not detectable in hepatocytes
      and bile ducts. CONCLUSION: Hepatitis B virus infection is closely related with
      hepatocarcinogenesis. The overexpression of TGF-alpha in the liver seems to be
      associated with the regeneration of hepatocytes injured by HBsAg. The continued
      expression of TGF-alpha might lead to dysplasia of liver cells and development of
      HCC. Furthermore, TGF-alpha might play a role in morphogenesis and regeneration
      of intrahepatic bile ducts.

PMID- 15040027
TI  - Somatic mutations of APC gene in carcinomas from hereditary non-polyposis
      colorectal cancer patients.
AB  - AIM: To investigate the mutational features of adenomatous polyposis coli (APC)
      gene and its possible arising mechanism in hereditary non-polyposis colorectal
      cancers (HNPCC). METHODS: PCR-based In Vitro Synthesized Protein Test (IVSP)
      assay and sequencing analysis were used to confirm somatic mutations of whole APC
      gene in 19 HNPCC cases. RESULTS: Eleven cases with 13 mutations were determined
      to harbor APC mutations. The prevalence of APC mutation was 58%(11/19). The
      mutations consisted of 9 frameshift and 4 nonsense ones, indicating that there
      were more frameshift mutations (69%). The frameshift mutations all exhibited
      deletion or insertion of 1-2 bp and most of them (7/9) happened at simple
      nucleotide repeat sequences, particularly within (A)n tracts (5/9). All point
      mutations presented C-to-T transitions at CpG sites. CONCLUSION: Mutations of APC
      gene were detected in more than half of HNPCC, indicating that its mutation was a
      common molecular event and might play an important role in the tumorigenesis of
      HNPCC. Locations of frameshift mutations at simple nucleotide repeat sequences
      and point mutations at CpG sites suggested that many mutations probably derived
      from endogenous processes including mismatch repair (MMR) deficiency. Defective
      MMR might affect the nature of APC mutations in HNPCC and likely occur earlier
      than APC mutational inactivation in some patients.

PMID- 15040029
TI  - Establishment of mice model with human viral hepatitis B.
AB  - AIM: To establish a mice model of hepatitis B by using HBV-transgenic mice, and
      to transfer HBV-specific cytotoxic T lymphocytes (CTL) induced from syngeneic
      BALB/c mice immunized by a eukaryotic expression vector containing HBV complete
      genome DNA. METHODS: HBV DNA was obtained from digested pBR322-2HBV and ligated
      with the vector pcDNA3. Recombinant pcDNA3-HBV was identified by restriction
      endonuclease assay and transfected into human hepatoma cell line HepG2 with
      lipofectin. ELISA was used to detect the expression of HBsAg in culture
      supernatant, and RT-PCR to determine the existence of HBV PreS1 mRNA. BALB/c mice
      were immunized with pcDNA3-HBV or pcDNA3 by intramuscular injection. ELISA was
      used to detect the expression of HBsAb in serum. MTT assay was used to measure
      non-specific or specific proliferation ability and specific killing activity of
      spleen lymphocytes. Lymphocytes from immunized mice were transferred into HBV
      transgenic mice (2.5X10(7) per mouse). Forty-eight hours later, the level of
      serum protein and transaminase was detected with biochemical method, liver and
      kidney were sectioned and stained by HE to observe the pathological changes.
      RESULTS: By enzyme digestion with Eco RI, Xho I and Hind III, the recombinant
      pcDNA3-HBV was verified to contain a single copy of HBV genome, which was
      inserted in the positive direction. HepG2 cells transfected with the recombinant
      could stably express PreS1 mRNA and HBsAg. After immunized by pcDNA3-HBV for 4
      weeks, HBsAb was detected in the serum of BALB/c mice. The potential of spleen
      lymphocytes for both non-specific and specific proliferation and the specific
      killing activity against target cells were enhanced. The transgenic mice in model
      group had no significant changes in the level of serum protein but had an obvious
      increase of ALT and AST. The liver had obvious pathological changes, while the
      kidney had no evident damage. CONCLUSION: A eukaryotic expression vector pcDNA3
      HBV containing HBV complete genome is constructed successfully. HepG2 cells
      transfected with the recombinant can express PreS1 mRNA and HBsAg stably.
      Specific cellular immune response can be induced in mice immunized by pcDNA3-HBV.
      A mice model of acute hepatitis with HBV has been established.

PMID- 15040028
TI  - Assessment of resin perfusion in hepatic failure in vitro and in vivo.
AB  - AIM: To observe the adsorbent effect of resin on endotoxin, cytokine, bilirubin
      in plasma of patients with hepatic failure and to determine the resin perfusion
      as an artificial liver support system in the treatment of hepatic failure.
      METHODS: One thousand milliliters of discarded plasma was collected from each of
      6 severe hepatitis patients treated with plasma exchange. The plasma was passed
      through a resin perfusion equipment for 1-2 h via extracorporeal circulation, and
      then absorbent indicators of transaminase, bilirubin, blood ammonia, endotoxin
      and cytokines were examined. In the meantime, study of in vivo resin plasma
      perfusion was performed on 7 severe hepatitis patients to compare the changes of
      endotoxin and cytokines in blood before and after perfusion. RESULTS: The levels
      of total bilirubin, endotoxin, interleukin 1beta and TNF-alpha in plasma were
      significantly decreased after in vitro resin plasma perfusion. The levels of
      interleukin 1beta, TNF-alpha and endotoxin in blood were also evidently declined
      after in vivo resin plasma perfusion. Nevertheless, no obvious changes in IL-6,
      creatinine (Cr) and urea nitrogen (UN), blood ammonia and electrolytes were found
      both in vitro and in vivo. CONCLUSION: Bilirubin, endotoxin and cytokines in
      plasma of patients with hepatic failure can be effectively adsorbed by resin in
      vitro. Most cytokines and endotoxin in plasma can also be effectively removed by
      resin in vivo. It demonstrates that resin perfusion may have good treatment
      efficacy on hepatic failure and can be expected to slow down the progression of
      hepatic failure.

PMID- 15040030
TI  - Sequence evolution of putative cytotoxic T cell epitopes in NS3 region of
      hepatitis C virus.
AB  - AIM: Quasispecies of hepatitis C virus (HCV) are the foundation for rapid
      sequence evolution of HCV to evade immune surveillance of hosts. The consensus
      sequence evolution of a segment of HCV NS3 region, which encompasses putative
      cytotoxic T cell epitopes, was evaluated. METHODS: Three male patients, infected
      with HCV through multiple transfusions, were identified from clinical symptoms
      and monitored by aminotransferase for 60 months. Blood samples taken at months 0,
      32, and 60 were used for viral RNA extraction. A segment of HCV NS3 region was
      amplified from the RNA extraction by RT-PCR and subjected to subcloning and
      sequencing. HLA types of these three patients were determined using complement
      dependent microlymphocytotoxic assay. CTL epitopes were predicted using MHC
      binding motifs. RESULTS: No patient had clinical symptoms or elevation of
      aspartate/alanine aminotransferase. Two patients showed positive HCV PCR results
      at all 3 time points. The other one showed a positive HCV PCR result only at
      month 0. A reported HLA-A2-restricted CTL epitope had no alteration in the HLA-A2
      negative carrier over 60 months. In the HLA-A2-positive individuals, all the
      sequences from 0 month 0 showed an amber mutation on the initial codon of the
      epitope. Most changes of consensus sequences in the same patient occurred on
      predicted cytotoxic T cell epitopes. CONCLUSION: Amber mutation and changes of
      consensus sequence in HCV NS3 region may be related to viral immune escape.

PMID- 15040031
TI  - Establishment of Helicobacter pylori infection model in Mongolian gerbils.
AB  - AIM: To establish a stable and reliable model of Helicobacter pylori infection
      model in Mongolian gerbils and to observe pathological changes in gastric mucosa
      in infected animals. METHODS: Mongolian gerbils were randomly divided into 18
      groups; 6 groups were infected with H pylori clinical strain Y06 (n=6, groups Y),
      6 groups were infected with H pylori strain NCTC11637 (n=6, groups N), and 6
      uninfected groups as negative controls (n=4, groups C). H pylori suspensions at
      the concentrations of 2X10(8) and 2X10(9) CFU/mL of strain NCTC11637 and strain
      Y06 were prepared. The animals in three groups N and in three groups Y were
      orally challenged once with 0.5 mL of the low concentration of the bacterial
      suspension. The animals in another three groups N and in another three groups Y
      were orally challenged with 0.5 mL of the high concentration of the bacterial
      suspension for 3 times at the intervals of 24 h, respectively. For the negative
      controls, the animals in six groups C were orally given with the same volume of
      Brucella broth at the corresponding inoculating time. The animals were killed
      after 2nd, 4(th) and 6(th) week after the last challenge and the gastric mucosal
      specimens were taken for urease test, bacterial isolation, pathological and
      immunohistochemical examinations. RESULTS: Positive isolation rates of H pylori
      in the animals of groups Y at the 2nd, 4(th) and 6(th) week after one challenge
      were 0%, 16.7% and 66.7%, while in the animals of groups N were 0%, 0% and 16.7%,
      respectively. Positive isolation rates of H pylori in the animals of groups Y at
      the 2nd, 4(th) and 6(th) week after three challenges were 66.7%, 100% and 100%,
      while in the animals of groups N were 66.7%, 66.7% and 100%, respectively. In
      animals with positive isolation of H pylori, the bacterium was found to colonized
      on the surface of gastric mucosal cells and in the gastric pits, and the gastric
      mucosal lamina propria was infiltrated with inflammatory cells. CONCLUSION: By
      using H pylori suspension at high concentration of 2X10(9) CFU/mL for multiple
      times, the orally challenged Mongolian gerbils can be used as a stable and
      reliable H pylori infection model. The 2 strains of H pylori can colonize in
      gastric mucosa of the infected animals and cause mild inflammation reaction.

PMID- 15040032
TI  - Effects of non-starch polysaccharides enzymes on pancreatic and small intestinal
      digestive enzyme activities in piglet fed diets containing high amounts of
      barley.
AB  - AIM: To investigate effects of non-starch polysaccharides(NSP) enzymes on
      pancreatic and small intestinal digestive enzyme activities in piglet fed diets
      containing high amounts of barley. METHODS: Sixty crossbred piglets averaging
      13.5 kg were randomly assigned to two treatment groups with three replications
      (pens) based on sex and mass. Each group was fed on the diet based on barley with
      or without added NSP enzymes (0.15%) for a 40-d period. At the end of the
      experiment the pigs were weighed. Three piglets of each group were chosen and
      slaughtered. Pancreas, digesta from the distal end of the duodenum and jejunal
      mucosa were collected for determination. Activities of the digestive enzymes
      trypsin, chymotrypsin, amylase and lipase were determined in the small intestinal
      sections as well as in homogenates of pancreatic tissue. Maltase, sucrase,
      lactase and gamma-glutamyl transpeptidase (gamma-GT) activities were analyzed in
      jejunal mucosa. RESULTS: Supplementation with NSP enzymes improved growth
      performance of piglets. It showed that NSP enzymes had no effect on digestive
      enzyme activities in pancreas, but decreased the activities of proteolytic
      enzyme, trypsin, amylase and lipase in duodenal contents by 57.56%, 76.08%,
      69.03% and 40.22%(P<0.05) compared with control, and increased gamma-GT
      activities in jejunal mucosa by 118.75%(P<0.05). CONCLUSION: Supplementation with
      NSP enzymes in barley based diets could improve piglets' growth performance,
      decrease activities of proteolytic enzyme, trypsin, amylase and lipase in
      duodenal contents and increase gamma-GT activities in jejunal mucosa.

PMID- 15040033
TI  - Effects of daidzein on estrogen-receptor-positive and negative pancreatic cancer
      cells in vitro.
AB  - AIM: To study the effects of daidzein on human pancreatic cancer cells in vitro.
      METHODS: Human estrogen-receptor (ER)-positive pancreatic cancer cells MiaPaCa-2
      and ER-negative pancreatic cancer cells PANC-1 were treated by 0.1 micromol/L, 1
      micromol/L, 10 microL, 25 microL, 50 microL, 75 microL and 100 microL of
      daidzein, respectively. Its antiproliferative effect was studied by MTT assay.
      RESULTS: Daidzein inhibited the growth of MiaPaCa-2 and PANC-1 cells at the
      concentrations from 0.1 microL to 100 microL. A dose- and time-dependent manner
      was found. The IC(50) of daidzein on MiaPaCa-2 and PANC-1 cells was 45 microL and
      75 micro, respectively. After MiaPaCa-2 cells were treated by daidzein for 3 d
      and at the concentrations more than IC(50), the inhibitory manner was identical
      and the inhibition appeared a saturation phenomenon, but the inhibitory manner of
      daidzein on PANC-1 cells was different from that of MiaPaCa-2 cells. CONCLUSION:
      Daidzein has antiproliferative effects on human estrogen-receptor-positive and
      negative pancreatic cancer cells, but their mechanisms may be different.

PMID- 15040034
TI  - Intravenous administration of glutathione protects parenchymal and non
      parenchymal liver cells against reperfusion injury following rat liver
      transplantation.
AB  - AIM: To investigated the effects of intravenous administration of the antioxidant
      glutathione (GSH) on reperfusion injury following liver transplantation. METHODS:
      Livers of male Lewis rats were transplanted after 24 h of hypothermic
      preservation in University of Wisconsin solution in a syngeneic setting. During a
      2-h reperfusion period either saline (controls, n=8) or GSH (50 or 100
      micromol/(h/kg), n=5 each) was continuously administered via the jugular vein.
      RESULTS: Two hours after starting reperfusion plasma ALT increased to 1457+/-281
      U/L (mean+/-SE) in controls but to only 908+/-187 U/L (P<0.05) in animals treated
      with 100 microGSH/(h/kg). No protection was conveyed by 50 micromol GSH(h/kg).
      Cytoprotection was confirmed by morphological findings on electron microscopy:
      GSH treatment prevented detachment of sinusoidal endothelial cells (SEC) as well
      as loss of microvilli and mitochondrial swelling of hepatocytes. Accordingly,
      postischemic bile flow increased 2-fold. Intravital fluorescence microscopy
      revealed a nearly complete restoration of sinusoidal blood flow and a significant
      reduction of leukocyte adherence to sinusoids and postsinusoidal venules.
      Following infusion of 50 micromol and 100 micromol GSH/(h/kg), plasma GSH
      increased to 65+/-7 mol/L and 97+/-18 mol/L, but to only 20+/-3 mol/L in
      untreated recipients. Furthermore, plasma glutathione disulfide (GSSG) increased
      to 7.5+/-1.0 mol/L in animals treated with 100 micro(h/kg) GSH but did not raise
      levels of untreated controls (1.8+/-0.5 mol/L) following infusion of 50
      microGSH/(h/kg) (2.2+/-0.2 mol/L). CONCLUSION: Plasma GSH levels above a critical
      level may act as a "sink" for ROS produced in the hepatic vasculature during
      reperfusion of liver grafts. Therefore, GSH can be considered a candidate
      antioxidant for the prevention of reperfusion injury after liver transplantation,
      in particular since it has a low toxicity in humans.

PMID- 15040035
TI  - Protective effect of exogenous adenosine triphosphate on hypothermically
      preserved rat liver.
AB  - AIM: To clarify the protective effect of exogenous adenosine triphosphate (ATP)
      on hypothermically preserved rat livers. METHODS: Establishment of continuous
      hypothermic machine perfusion model, detection of nucleotides in hepatocytes with
      HPLC, measurement of activities of LDH and AST in the perfusate, observation of
      histopathological changes in different experiment groups, and autoradiography
      were carried out to reveal the underlying mechanism of the protective effect of
      ATP. RESULTS: The intracellular levels of ATP and EC decreased rapidly after
      hypothermic preservation in control group, while a higher ATP and EC level, and a
      slower decreasing rate were observed when ATP-MgCl(2) was added to the perfusate
      (P<0.01). As compared with the control group, the activities of LDH and AST in
      the ATP-MgCl(2) group were lower (P<0.05). Furthermore, more severe hepatocyte
      damage and neutrophil infiltration were observed in the control group.
      Radioactive [alpha-(32)P] ATP entered the hypothermically preserved rat
      hepatocytes. CONCLUSION: Exogenous ATP has a protective effect on rat livers
      during hypothermical preservation. However, Mg(2+) is indispensable, addition of
      ATP alone produces no protective effect. The underlying mechanism may be that
      exogenous ATP enters the hypothermically preserved rat liver cells.

PMID- 15040037
TI  - Detection of point mutation in K-ras oncogene at codon 12 in pancreatic diseases.
AB  - AIM: To investigate frequency and clinical significance of K-ras mutations in
      pancreatic diseases and to identify its diagnostic values in pancreatic
      carcinoma. METHODS: 117 ductal lesions were identified in the available sections
      from pancreatic resection specimens of pancreatic ductal adenocarcinoma,
      comprising 24 pancreatic ductal adenocarcinoma, 19 peritumoral ductal atypical
      hyperplasia, 58 peritumoral ductal hyperplasia and 19 normal duct at the tumor
      free resection margin. 24 ductal lesions were got from 24 chronic pancreatitis.
      DNA was extracted. Codon 12 K-ras mutations were examined using the two-step
      polymerase chain reaction (PCR) combined with restriction enzyme digestion,
      followed by nonradioisotopic single-strand conformation polymorphism (SSCP)
      analysis and by means of automated DNA sequencing. RESULTS: K-ras mutation rate
      of the pancreatic carcinoma was 79%(19/24) which was significantly higher than
      that in the chronic pancreatitis 33%(8/24) (P<0.01). It was also found that K-ras
      mutation rate was progressively increased from normal duct at the tumor free
      resection margin, peritumoral ductal hyperplasia, peritumoral ductal atypical
      hyperplasia to pancreatic ductal adenocarcinoma. The mutation pattern of K-ras 12
      codon of chronic pancreatitis was GGT-GAT, GGT and CGT, which is identical to
      that in pancreatic carcinoma. CONCLUSION: K-ras mutation may play a role in the
      malignant transformation of pancreatic ductal cell. K-ras mutation was not
      specific enough to diagnose pancreatic carcinoma.

PMID- 15040036
TI  - Levels of vasoactive intestinal peptide, cholecystokinin and calcitonin gene
      related peptide in plasma and jejunum of rats following traumatic brain injury
      and underlying significance in gastrointestinal dysfunction.
AB  - AIM: To study the alterations of brain-gut peptides following traumatic brain
      injury (TBI) and to explore the underlying significance of these peptides in the
      complicated gastrointestinal dysfunction. METHODS: Rat models of focal traumatic
      brain injury were established by impact insult method, and divided into 6 groups
      (6 rats each group) including control group with sham operation and TBI groups at
      postinjury 3, 12, 24, 72 h, and d 7. Blood and proximal jejunum samples were
      taken at time point of each group and gross observations of gastrointestinal
      pathology were recorded simultaneously. The levels of vasoactive intestinal
      peptide (VIP) in plasma, calcitonin gene-related peptide (CGRP) and
      cholecystokinin (CCK) in both plasma and jejunum were measured by enzyme
      immunoassay (EIA). Radioimmunoassay (RIA) was used to determine the levels of VIP
      in jejunum. RESULTS: Gastric distension, delayed gastric emptying and intestinal
      dilatation with a large amount of yellowish effusion and thin edematous wall were
      found in TBI rats through 12 h and 72 h, which peaked at postinjury 72 h. As
      compared with that of control group (247.8+/-29.5 ng/L), plasma VIP levels were
      significantly decreased at postinjury 3, 12 and 24 h (106.7+/-34.1 ng/L, 148.7+/
      22.8 ng/L, 132.8+/-21.6 ng/L, respectively), but significantly increased at 72 h
      (405.0+/-29.8 ng/L) and markedly declined on d 7 (130.7+/-19.3 ng/L). However,
      Plasma levels CCK and CGRP were significantly increased through 3 h and 7 d
      following TBI (126-691% increases), with the peak at 72 h. Compared with control
      (VIP, 13.6+/-1.4 ng /g; CGRP, 70.6+/-17.7 ng/g); VIP and CGRP levels in jejunum
      were significantly increased at 3 h after TBI (VIP, 35.4+/-5.0 ng/g; CGRP,
      103.8+/-22.1 ng/g), and declined gradually at 12 h and 24 h (VIP, 16.5+/-1.8
      ng/g, 5.5+/-1.4 ng/g; CGRP, 34.9+/-9.7 ng/g, 18.5+/-7.7 ng/g), but were
      significantly increased again at 72 h (VIP, 48.7+/-9.5 ng/g; CGRP, 142.1+/-24.3
      ng/g), then declined in various degrees on d 7 (VIP, 3.8+/-1.1 ng/g; CGRP,
      102.5+/-18.1 ng/g). The CCK levels in jejunum were found to change in a similar
      trend as that in plasma with the concentrations of CCK significantly increased
      following TBI (99-517% increases) and peaked at 72 h. CONCLUSION: Traumatic brain
      injury can lead to significant changes of brain-gut peptides in both plasma and
      small intestine, which may be involved in the pathogenesis of complicated
      gastrointestinal dysfunction.

PMID- 15040038
TI  - Effect of local CTLA4Ig gene transfection on acute rejection of small bowel
      allografts in rats.
AB  - AIM: To evaluate the local expression of CTLA4Ig gene in small bowels and its
      effect on preventing acute rejection of the small bowel allografts. METHODS:
      Groups of Wistar rats underwent heterotopic small bowel transplantation from SD
      rats. The recipients were randomly divided into experimental group (allografts
      were transfected with CTLA4Ig gene) and control group (non CTLA4Ig gene
      transfected). In the experimental group, the donor small bowels were perfused ex
      vivo with CTLA4Ig cDNA packaged with lipofectin vector via intra-superior
      mesenteric artery before transplantation, and the CTLA4Ig expression in the small
      bowel grafts post-transplantation was assessed by immunohistology. On d 3, 7 and
      10 post-transplantation, the allografts in each group were harvested for the
      examination of histology and detection of apoptosis. RESULTS: Small bowel
      allografts treated with CTLA4Ig cDNA showed abundant CTLA4Ig expression after
      transplantation. Acute rejection of grade I on d 7 and grade II on d 10 after
      transplantation was noticed in the control allografts, and a dramatically
      increased number of apoptotic enterocytes in parallel to the progressive
      rejection could be recognized. In contrast, the allografts treated with CTLA4Ig
      cDNA showed nonspecific histological changes and only a few apoptotic enterocytes
      were found after transplantation. CONCLUSION: Local CTLA4Ig gene transfection of
      small bowel allograft is feasible, and the local CTLA4Ig expression in the
      allograft can prevent acute rejection after transplantation.

PMID- 15040039
TI  - Effects of cholesterol on proliferation and functional protein expression in
      rabbit bile duct fibroblasts.
AB  - AIM: To investigate the effect of cholesterol (Ch) on the growth and functional
      protein expression of rabbit bile duct fibroblasts. METHODS: The cultured bile
      duct fibroblasts were divided randomly into two groups: the control group and the
      experiment group (fibroblasts were incubated respectively with 0.6 g/L Ch for 12,
      24, 36 and 48 h). The growth and DNA synthesis of bile duct fibroblasts were
      measured by the means of (3)H-TdR incorporation. The total protein content of
      fibroblast was measured by BSA protein assay reagent kit, then the expression of
      alpha-actin was analyzed semi-quantitatively by Western blot. RESULTS: After
      treatment with 0.6 g/L Ch for 12, 24, 36 and 48 h, the values of (3)H-TdR
      incorporation of bile duct fibroblasts were respectively 3.1+/-0.39, 3.8+/-0.37,
      4.6+/-0.48 and 5.2+/-0.56 mBq/cell, and the values of the corresponding control
      groups were 3.0+/-0.33, 3.2+/-0.39, 3.7+/-0.49 and 4.3+/-0.43 mBq/cell. After
      comparing the values of experiment groups and their corresponding control groups,
      it was found that the (3)H-TdR incorporation of bile duct fibroblasts after
      treatment with 0.6 g/L Ch for 24, 36 and 48 h were significantly increased
      (P<0.05, P<0.01, P<0.01), while the (3)H-TdR incorporation of 12-h group was not
      different statistically from its control group. Ch had no obvious effect on the
      total protein content of fibroblasts. After incubated with 0.6 g/L Ch for 12, 24,
      36 and 48 h, the total protein content of each experiment group was not altered
      markedly compared with its corresponding control group. The values of experiment
      groups were 0.246+/-0.051, 0.280+/-0.049, 0.263+/-0.044 and 0.275+/-0.056
      ng/cell, and those of corresponding control groups were 0.253+/-0.048, 0.270+/
      0.042, 0.258+/-0.050 and 0.270+/-0.045 ng/cell. Western blot analysis revealed
      that the alpha-actin expression in fibroblasts affected by Ch for 12 and 24 h was
      not markedly changed compared with their corresponding control groups (P>0.05),
      the values of total gray scale of 12- and 24-h groups were 1748+/-185 and 1756+/
      173, respectively. But after stimulation with Ch for 36 h, the total gray scale
      of fibroblasts (1923+/-204) was significantly higher than that of control group
      (1734+/-197). When the time of Ch treatment was lengthened to 48 h, the alpha
      actin expression was markedly elevated, the total gray scale was 2 189+/-231
      (P<0.01 vs control group). CONCLUSION: Moderately concentrated Ch can promote the
      proliferation of bile duct fibroblasts at early stage. With the prolongation of
      Ch treatment, the alpha-actin expression of fibroblasts was also increased, but
      the hypertrophy of fibroblasts was not observed.

PMID- 15040040
TI  - Fenofibrate for patients with asymptomatic primary biliary cirrhosis.
AB  - AIM: Primary biliary cirrhosis (PBC) is a chronic, cholestatic disease of
      autoimmune etiology, the histology of which shows a destruction of the
      intrahepatic bile duct and portal inflammation. Ursodeoxycholic acid (UDCA) is
      now used as a first-line drug for asymptomatic PBC (aPBC) because it is reported
      that UDCA decreases mortality and prolongs the time of liver transplantation.
      However, only 20-30% of patients respond fully to UDCA. Recently, lipoprotein
      lowering agents have been found to be effective for PBC. The aim of this study
      was to examine the safety and efficacy of fenofibrate, a member of the fibrate
      class of hypolipidemic and anti-inflammatory agent via peroxysome proliferatory
      activated receptor alpha, in patients with aPBC. METHODS: Fenofibrate was
      administered for twelve weeks in nine patients with aPBC who failed to respond to
      UDCA. UDCA was used along with fenofibrate during the study. The data from aPBC
      patients were analyzed to assess the biochemical effect of fenofibrate during the
      study. RESULTS: The serum levels of alkaline phosphatase (ALP) (285+/-114.8 IU/L)
      and immunoglobulin M (IgM) (255.8+/-85.9 mg/dl) significantly decreased to
      186.9+/-76.2 IU/L and 192.9+/-67.5 mg/dL respectively, after fenofibrate
      treatment in patients with aPBC (P<0.05). Moreover, the titer of
      antimitochondrial antibody (AMA) also decreased in 4 of 9 patients with aPBC. No
      adverse reactions were observed in any patients. CONCLUSION: Fenofibrate appears
      to be significantly effective in treating patients with aPBC who respond
      incompletely to UDCA alone. Although the mechanism of fenofibrate on aPBC has not
      yet been fully clarified, combination therapy using fenofibrate and UDCA might be
      related to the anti-immunological effects, such as the suppression of AMA
      production as well as its anti-inflammatory effect.

PMID- 15040041
TI  - Clinical features and risk factors of patients with fatty liver in Guangzhou
      area.
AB  - AIM: There is still no accepted conclusion regarding the clinical features and
      related risk factors of patients with fatty liver. The large-scale clinical
      studies have not carried out yet in Guangzhou area. The aim of the present study
      was to investigate the clinical features and related risk factors of patients
      with fatty liver in Guangzhou area. METHODS: A total of 413 cases with fatty
      liver were enrolled in the study from January 1998 to May 2002. Retrospective
      case-control study was used to evaluate the clinical features and related risk
      factors of fatty liver with logistic regression. RESULTS: Obesity (OR: 21.204),
      alcohol abuse (OR: 18.601), type 2 diabetes mellitus (OR: 4.461), serum
      triglyceride (TG) (OR: 3.916), serum low-density lipoprotein cholesterol (LDL-C)
      (OR: 1.840) and fasting plasma glucose (FPG) (OR: 1.535) were positively
      correlated to the formation of the fatty liver. The levels of serum alanine
      aminotransferase (ALT) and gamma-glutamyltransferase (GGT) increased mildly in
      the patients with fatty liver and were often less than 2-fold of the normal
      limit. The higher abnormalities of aspartate aminotransferase (AST) levels
      (42.9%) with AST/ALT more than 2(17.9%) were found in patients with alcoholic
      fatty liver (AFL) than those with nonalcoholic fatty liver (NAFL) (16.9% and 5.0%
      respectively). The elevation of serum TG, cholesterol (CHOL), LDL-C was more
      common in patients with NAFL than with AFL. CONCLUSION: Obesity, alcohol abuse,
      type 2 diabetes mellitus and hyperlipidemia may be independent risk factors of
      fatty liver. The mildly abnormal hepatic functions can be found in patients with
      fatty liver. More obvious damages of liver function with AST/ALT usually more
      than 2 were noted in patients with AFL.

PMID- 15040042
TI  - Disseminated tumor cells homing into rats' liver: a new possible mechanism of HCC
      recurrence.
AB  - AIM: To detect the origin of hepatocellular carcinoma (HCC) recurring and attempt
      to propose a new recurrent mechanism. METHODS: Orthotopic liver
      allotransplantation was performed on male rats with HCC- induced by
      diethylnitrosamine using female donors. Metastatic tumors in transplanted livers
      were obtained. A DNA probe that exhibits specificity for the rat Y chromosome was
      generated by using a set of primers specific to murine sry gene. In situ
      hybridization (ISH) for Y chromosome was used to detected the origin of HCC
      recurring. Male HCC tissue was designed to be positive control. ISH on female
      tissue and using non-labeled with DIG probe was thought to be negative control.
      RESULTS: Positive marks were seen through ISH for Y chromosome in recurrent tumor
      tissue and positive control. No signal was detected in both negative controls.
      CONCLUSION: Recurrent HCC after liver transplantation originated from
      disseminated tumor cells in recipients. Extrahepatic cells homing into liver may
      be a new HCC recurrence mechanism. Likewise, it implicates that this mechanism is
      responsible for HCC recurring after hepatectomy.

PMID- 15040043
TI  - Risk factors influencing recurrence following resection of pancreatic head
      cancer.
AB  - AIM: Whether operative procedure is a risk factor influencing recurrence
      following resection of carcinoma in the head of pancreas or not remains
      controversies. In this text we compared the recurrence rate of two operative
      procedure: the Whipple procedure and extended radical operation, and inquired
      into the factors influencing recurrence after radical resection. METHODS: From
      January 1995 to December 1998, 35 cases of carcinoma of pancreas underwent the
      Whipple operadure, 21 patients received the Extended radical operation. All
      patients were followed up for more than 3 years. Prognostic factors included
      operative procedure, size of tumor, lymph node, interstitial invasion. RESULTS:
      Deaths duo to recurrence within 3 years after operation were studied. The death
      rate was 51.4% in the Whipple procedure and 42.9% in the Extended radical
      operative procedure. There was a significant difference between the two groups.
      Recurrence occurred in 75% patients with tumor large than 4 cm, in 87.5% patients
      with lymph node involvement, and in 50% patients with the presence of
      interstitial invasion. CONCLUSION: Tumor exceeding 4 cm, lymph node involvement,
      and presence of interstitial invasion are high risk factors of recurrence after
      Whipple's procedure and extended radical operation.

PMID- 15040045
TI  - Clinical value of Helicobacter pylori stool antigen test, ImmunoCard STAT HpSA,
      for detecting H pylori infection.
AB  - AIM: To evaluate the reliability of the Helicobacter pylori stool antigen test,
      ImmunoCard STAT HpSA, for detecting H pylori infection. METHODS: Stool specimens
      were collected from 53 patients who received upper endoscopy examination due to
      gastrointestinal symptoms. ImmunoCard STAT HpSA was used to detect H pylori stool
      antigens. H pylori infection was detected based on three different tests: the
      urease test, Warthin-Starry staining and culture. H pylori status was defined as
      positive when both the urease test and histology or culture alone was positive.
      RESULTS: Sensitivity, specificity, positive predictive and negative predictive
      values and the total accuracy of ImmunoCard STAT HpSA for the diagnosis of H
      pylori infection were 92.6% (25/27), 88.5% (23/26), 89.3% (25/28), 92% (23/25)
      and 90.6% (48/53), respectively. CONCLUSION: The stool antigen test, ImmunoCard
      STAT HpSA, is a simple noninvasive and accurate test for the diagnosis of H
      pylori infection.

PMID- 15040044
TI  - Efficacy and safety of lamivudine treatment for chronic hepatitis B in pregnancy.
AB  - AIM: To evaluate the efficacy and safety of lamivudine treatment of chronic
      hepatitis B disease in pregnancy. METHODS: The study group was comprised of 38
      chronic HBV patients who were diagnosed pregnant during lamivudine treatment and
      voluntary to continue the same therapy. The control group was from documented
      patient data in the literatures. We compared the following parameters with those
      of a control group: anti-HBV efficacy, complications of pregnancy (abortion,
      preterm birth, neonatal asphyxia, fetal death, and congenital anomaly), incidence
      of HBV-positive babies and developmental anomalies in pregnant women treated with
      lamivudine. RESULTS: The blocking rate of lamivudine treatment was significantly
      higher than that of active vaccine immunization for babies with double-positive
      (HBsAg/HBeAg) mothers with 30-30-10 mug doses of vaccine (74.07%) and with 30-20
      10 mug (64.87%). The natural vertical HBV transmission from mother to infant of
      "double-positive" mothers was 100% (10/10). No pregnancy complication was noted
      during the observation period, but in the control group the incidences of
      pregnancy complication were 16.67% (abortion), 43.02%(preterm), 15.62% (neonatal
      asphyxia), and 4.49% (fetal death), 10.0% (congenital anomaly). No HBV-positive
      newborn was detected and no developmental anomaly was found in the study group.
      CONCLUSION: Lamivudine is helpful to prevent maternal-infant HBV transmission and
      may reduce the complications of HBV-infected pregnant patients.

PMID- 15040047
TI  - Clinical characteristics and management of patients with early acute severe
      pancreatitis: experience from a medical center in China.
AB  - AIM: To study clinical characteristics and management of patients with early
      severe acute pancreatitis (ESAP). METHODS: Data of 297 patients with severe acute
      pancreatitis (SAP) admitted to our hospital within 72 h after onset of symptoms
      from January 1991 to June 2003 were reviewed for the occurrence and development
      of early severe acute pancreatitis (ESAP). ESAP was defined as presence of organ
      dysfunction within 72 h after onset of symptoms. Sixty-nine patients had ESAP,
      228 patients without organ dysfunction within 72 h after onset of symptoms had
      SAP. The clinical characteristics, incidence of organ dysfunction during
      hospitalization and prognosis between ESAP and SAP were compared. RESULTS:
      Impairment degree of pancreas (Balthazar CT class) in ESAP was more serious than
      that in SAP (5.31+/-0.68 vs 3.68+/-0.29, P<0.01). ESAP had a higher mortality
      than SAP (43.4% vs 2.6%, P<0.01), and a higher incidence of hypoxemia (85.5% vs
      25%, P<0.01), pancreas infection (15.9% vs 7.5%, P<0.05), abdominal compartment
      syndrome (ACS) (78.3% vs 23.2%, P<0.01) and multiple organ dysfunction syndrome
      (MODS)(78.3% vs 10.1%, P<0.01). In multiple logistic regression analysis, the
      main predisposing factors to ESAP were higher APACHE II score, Balthazar CT
      class, MODS and hypoxemia. CONCLUSION: ESAP is characterised by MODS, severe
      pathological changes of pancreas, early hypoxemia and abdominal compartment
      syndrome. Given the poor prognosis of ESAP, these patients should be treated in
      specialized intensive care units with special measures such as close supervision,
      fluid resuscitation, improvement of hypoxemia, reduction of pancreatic secretion,
      elimination of inflammatory mediators, prevention and treatment of pancreatic
      infections.

PMID- 15040046
TI  - Functional hepatic flow in patients with liver cirrhosis.
AB  - AIM: To evaluate hepatic reserve function by investigating the change of
      functional hepatic flow and total hepatic flow in cirrhotic patients with portal
      hypertension. METHODS: HPLC method was employed for the determination of
      concentration of D-sorbitol in human plasma and urine. The functional hepatic
      flow (FHF) and total hepatic flow (THF) were determined by means of modified
      hepatic clearance of D-sorbitol combined with duplex doppler color sonography in
      20 patients with cirrhosis and 10 healthy volunteers. RESULTS: FHF, evaluated by
      means of the D-sorbitol clearance, was significantly reduced in patients with
      cirrhosis in comparison to controls (764.74+/-167.91 vs 1195.04+/-242.97 mL/min,
      P<0.01). While THF was significantly increased in patients with cirrhosis in
      comparison to controls (1605.23+/-279.99 vs 1256.12+/-198.34 mL/min, P<0.01).
      Portal blood flow and hepatic artery flow all were increased in cirrhosis
      compared to controls (P<0.05 and P<0.01). D-sorbitol total clearance was
      significantly reduced in cirrhosis compared to control (P<0.01), while D-sorbitol
      renal clearance was significantly increased in cirrhosis (P<0.05). In controls
      FHF was similar to THF (1195.05+/-242.97 vs 1256.12+/-198.34 mL/min, P=0.636),
      while FHF was significantly reduced compared with THF in cirrhosis (764.74+/
      167.91 vs 1605.23+/-279.99 mL/min, P<0.01). CONCLUSION: Our method that combined
      modified hepatic clearance of D-sorbitol with duplex doppler color sonography is
      effective in the measurement of FHF and THF. FHF can be used to estimate hepatic
      reserve function.

PMID- 15040050
TI  - Picture perfect. Document imaging can capture everything a patient record holds.

PMID- 15040049
TI  - Data overflow. Options are available to hold the tide of images and information.

PMID- 15040048
TI  - Relationship between plasma D-dimer levels and clinicopathologic parameters in
      resectable colorectal cancer patients.
AB  - AIM: To assess the clinical significance of the D-dimer levels and the
      relationship between plasma D-dimer levels and clinicopathologic parameters in
      operable colorectal cancer patients. METHODS: The plasma levels of D-dimer were
      measured pre- and postoperatively in 35 patients with colorectal cancer, and 30
      healthy subjects served as controls by the method of quantitative enzyme-linked
      immunosorbent assay (ELISA). RESULTS: The mean preoperative plasma levels of D
      dimer in the patients with colorectal cancer (1.06+/-0.24 mg/L) were
      significantly higher than those of controls (0.33+/-0.12 mg/L,P<0.01). The D
      dimer levels were remarkably elevated on the 1st day after operation (1.22+/-0.55
      mg/L, P<0.01). On the 3rd day the level of D-dimer began to stepwise descend and
      on the 14(th) day nearly returned to control level. The preoperative levels of D
      dimer were significantly correlated with the lymph node metastasis and Dukes
      stage but had no association with tumor location and the degree of
      differentiation. A stepwise increase in the mean D-dimer levels was found with
      increase of the tumor stage. CONCLUSION: Hypercoagulation and higher fibrinolytic
      activities occur in patients with colorectal cancer. The operative trauma could
      enhance the fibrinolysis in the patients with colorectal cancer. The measurement
      of preoperative D-dimer levels is considered to be useful for predicting lymph
      node metastasis and stage of colorectal cancer.

PMID- 15040051
TI  - Call center triage. Advanced software plus capable nurses offer late-night
      answers and comfort.

PMID- 15040052
TI  - Releasing revenue cycle potential. IT managers have a critical role in
      organizational efficiency.

PMID- 15040054
TI  - Network facelift. Future upgrades rely on a solid network foundation.

PMID- 15040053
TI  - Customized automation. Ob/Gyn practices are finding EMR systems designed
      specifically for them.

PMID- 15040055
TI  - New technologies enhance patient safety.

PMID- 15040056
TI  - Joint ventures scrutinized anew.

PMID- 15040057
TI  - Care plan vs. total plan of care.

PMID- 15040058
TI  - Palliative care: end of life care.

PMID- 15040059
TI  - Brainstem origin of duodenal vagal preganglionic parasympathetic neurons. A WGA
      HRP study in the ferret (Mustela Putorius Furo), a human model.
AB  - The projections of vagal brainstem neurons to the duodenal segment of the
      gastrointestinal tract were studied in the ferret using the WGA-HRP
      neurohistochemical technique. Fourteen adult ferrets with weights ranging from
      800 gm to 1500 gm were used for the study. The muscular wall of the duodenum of
      six ferrets was injected with 0.1 ml of 5% WGA-HRP in 0.5 M sodium chloride. The
      eight remaining ferrets were used as controls. Two of these had injections of 0.1
      ml normal saline into the muscular wall of the duodenum. The second set of two
      ferrets was injected with 0.1 ml of 5% WGA-HRP in buffer after bilateral truncal
      vagotomy. The third set of two ferrets received intraperitoneal injection of 0.1
      ml of 5% WGA-HRP while, in the last set, the tracer was injected into the hepatic
      portal vein. Following the injections, the ferrets were allowed to survive for 48
      72 hours after which each ferret was perfused transcardially first with normal
      saline followed by a fixative containing 1% paraformaldehyde and 1.25%
      glutaraldehyde in 0.1 M phosphate buffer, pH 7.4 at room temperature and finally
      with 10% buffered sucrose at 4 degrees C. Transverse serial frozen sections of
      the brainstem were then taken and processed for WGA-HRP neurohistochemistry and
      were analyzed under light and dark-field illuminations. The analyses of the
      sections taken from the six ferrets injected with WGA-HRP revealed neurons
      labelled with the tracer in the dorsal motor nucleus of the vagus nerve (DMNV).
      Sections taken from the control ferrets did not reveal any WGA-HRP labelled
      neurons in the brainstem.

PMID- 15040060
TI  - Gynaecologic cancer incidence, Kingston and St Andrew, Jamaica, 1973-1997, and
      gynaecologic cancer mortality, Jamaica, 1999.
AB  - The incidence of gynaecologic cancers in women from Kingston and St Andrew for
      the period 1973-1997 were reviewed by analyzing data previously published by the
      Jamaica Cancer Registry. Gynaecologic cancer-related mortality statistics for the
      entire island for 1999 were compiled from data obtained from the Registrar
      General's Department (RGD) and the Statistical Institute of Jamaica (STATIN).
      Data were compared to gynaecologic cancer statistics for women from the United
      States of America for 1973-1997. A total of 2862 gynaecologic cancers were
      registered for the years 1973-1997, which represents 26.8% of all female cancers
      from Kingston and St Andrew. Cervical cancer accounted for 62% of these
      gynaecologic cancers. The 268 cancer-related deaths (168 due to cervical cancer)
      registered in Jamaican women for 1999 represent approximately 15% of all female
      cancer-related deaths. The present incidence (27.9 per 100,000) and mortality
      rate (15.8 per 100,000) of cervical cancer are much higher than that documented
      for American women--both African Americans and Caucasians--and signify the
      limited success, to date, of efforts to decrease the incidence and mortality of
      cervical cancer by the implementation of cervical cancer screening programmes.
      For the time period reviewed, an increase was noted in the incidence of cancer of
      the corpus uteri while decreases were recorded for the incidence of
      choriocarcinoma, ovarian cancer and cancers arising from the vulva, vagina and
      fallopian tube.

PMID- 15040061
TI  - Percutaneous endoscopic gastrostomy in Trinidad and Tobago.
AB  - Percutaneous endoscopic gastrostomy tube placement is rapidly becoming the
      preferred method of gastrostomy tube placement. We describe our experience with
      this procedure in nine patients. The main complications were minor and due to
      local infection. This report demonstrates the simplicity and safety of this
      technique.

PMID- 15040062
TI  - Prune belly syndrome and associated malformations. A 13-year experience from a
      developing country.
AB  - A retrospective investigation was conducted to describe clinical features and
      birth outcomes among babies with prune belly syndrome detected ante-natally and
      at birth at the University Teaching Hospital in Cameroon. A total of 11 cases
      were identified over a period of 13 years, and the majority of affected fetuses
      were male (10 of 11). Most of the mothers were less than 30 years of age, had
      singleton pregnancies, and about two-thirds were complicated by placenta praevia,
      genital infections, preeclampsia, and anaemia associated with hookworm
      infestations. The most prominent findings related to prune belly syndrome among
      our patients were clubfoot (45%), pulmonary hypoplasia (27%), Potter facies
      (27%), imperforate anus (27%), and arthrogryposis (18%). About two-thirds of the
      affected pregnancies did not reach the age of viability either due to voluntary
      termination (three of seven cases) or spontaneous abortion (four of seven cases).
      Of the remaining four viable pregnancies, two cases each of stillbirth and
      neonatal death were recorded. Among pregnancies that were not voluntarily
      terminated (n = 8), multiple concomitant anomalies and bilateral renal lesions
      were apparently the cause of fetal/infant death in the majority of cases (75%).
      In conclusion, Cameroonian babies with prune belly syndrome presented with
      clinical features that were comparable to those observed in developed nations.

PMID- 15040063
TI  - Odontogenic tumours from two centres in Jamaica. A 15-year review.
AB  - This is the author's experience with odontogenic tumours in Jamaica during the 15
      year period, 1980-1995, with special emphasis on the clinicopathological
      presentation, radiology and outcome of treatment. A retrospective review of
      histopathological reports, radiographs and case notes of patients with jaw
      tumours presenting to the Kingston Public Hospital and Cornwall Regional Hospital
      (the two hospitals in Jamaica with a maxillofacial surgery department) are
      presented. The study included 70 patients with histologically confirmed
      odontogenic tumours out of a total of 293 with tumours of the mouth and jaw, of
      which 123 were of odontogenic origin. We recorded the following; ameloblastoma (n
      = 47, 67%, M:F = 1:1), recurrent ameloblastoma (n = 12, 17.1%) odontogenic myxoma
      (n = 3, 4.3%, M:F = 2:1), odontongenic fibroma (n = 2, 2.9%, both female),
      adenomatoid odontogenic tumour (n = 3, 4.3% M:F = 1:2) ameloblastic fibroma (n =
      2, 2.9%, M:F = 1:1) and ameloblastic carcinoma (n = 1, 1.4%, a male). Of all
      these tumours, only ameloblastomas recurred. Further research is required to
      explain the high incidence of ameloblastoma, and why it has a predilection for
      people of low socioeconomic status in Jamaica.

PMID- 15040064
TI  - Antibacterial effects of Carica papaya fruit on common wound organisms.
AB  - The purpose of the study was to investigate antibacterial activity of ripe and
      unripe Carica papaya on selected micro-organisms. Cultures of micro-organisms
      were routinely maintained in nutrient agar slants at 4 degrees C. Extracts of
      immature, mature and ripe Carica papaya fruit were obtained by separately
      grinding factions of the epicarp, endocarp and seeds and filtering them through
      gauze. Sensitivity tests were conducted by adding 0.06 ml of extract to agar
      wells (6 mm diameter) prepared from 20 ml agar seeded with 10(6) cells/ml
      suspension of one of the eight organisms per plate. The inoculated plates were
      allowed to equilibrate at 4 degrees C for 1 hour, incubated at 37 degrees C for
      24 hours, and zones of inhibition measured in millimetres. Anti-bacterial
      activity was expressed in terms of the radius of zone of inhibition. Seed
      extracts from the fruit showed inhibition in the following order: B cereus > E
      coli > S faecalis > S aureus > P vulgaris > S flexneri. No significant difference
      was found in bacterial sensitivity between immature, mature and ripe fruits. No
      inhibition zone was produced by epicarp and endocarp extracts. Carica papaya
      seeds contain anti-bacterial activity that inhibits growth of gram-positive and
      gram-negative organisms. Observed activity was independent of stage of fruit
      maturity. Carica papaya has antibacterial effects that could be useful in
      treating chronic skin ulcers to promote healing.

PMID- 15040065
TI  - Who is at high risk? A comparison of the seroprevalence of human immunodeficiency
      virus in pregnant women and a high risk group.
AB  - To compare the seroprevalence of HIV in Jamaican pregnant women with that in
      substance abusers, two groups of antenatal patients were studied, one (A)
      attending a public hospital clinic and the other (B) attending private clinics.
      The HIV seroprevalence in the antenatal patients was compared with that in the
      substance abusers, group C, in 1996 and five years later in 2001. HIV antibody
      was determined by enzyme immunoassay. The HIV seroprevalence in group A more than
      doubled (1.6%-3.8%) in five-years, 1996-2001. There were no seropositives in
      group B. In group C, the seroprevalence rose from 2.08% in 1996 to 5.76% in 2001.
      There was indication that group A might no longer be considered "low risk", as
      there was no significant difference from group C in HIV seroprevalence in 1996
      and 2001. The trend seen in this study is worthy of further investigation.

PMID- 15040066
TI  - Subxiphoid pericardial window in stable cardiac proximity injuries.
AB  - The use of the subxiphoid pericardial window (SPW) in evaluating stable patients
      with cardiac proximity injuries is presented in a short case series. There were
      11 patients with four positive and seven negative SPW. There was one false
      positive and no false negatives. Review of the literature on the use of the SPW
      as a diagnostic tool in evaluating cardiac proximity injuries shows the SPW to be
      a rapid and reliable method of detecting occult cardiac injuries, and is
      especially useful in areas where emergency echocardiography is not available.

PMID- 15040067
TI  - Gender and ethnicity in first admissions to a psychiatric unit in Trinidad.
AB  - It has been recognized that there are gender disparities in the admission rates
      to psychiatric units. While the community prevalence of the major non-organic
      psychotic mental disorders are thought to have no gender bias, non-psychotic
      disorders such as depression are more commonly diagnosed in women. Gender
      differences in admission may indicate differences in severity or in presentation
      to psychiatric services and would have important implications for the targeting
      of preventative strategies. The case notes of all admissions to the psychiatric
      unit at the San Fernando General Hospital were obtained for the calendar year
      1999. The International Statistical Classification of Diseases and Related Health
      Problems, Tenth Revision (ICD-10) diagnoses and gender were analysed to determine
      the distribution of diagnostic categories by gender. A total of 119 patients were
      admitted to the unit for the first time in the period under review, 72 were male
      (60.5%) and 47 were female (39.5%). There were no significant differences in age
      by gender. Substance use related admissions and psychotic illnesses
      (schizophrenia spectrum and affective psychoses) were significantly more common
      in men (p = 0.006; p = 0.03 respectively). These differences were especially
      marked for those of East Indian descent. Non-psychotic illnesses were more
      commonly diagnosed among women (p = 0.0008). These findings suggest that a larger
      proportion of males are admitted to the general hospital psychiatric unit among
      first time admissions. This is also true for re-admissions. Men are more likely
      to be diagnosed with substance use and psychotic disorders, while for women,
      major depression and non-psychotic illnesses are the main diagnoses. Community
      surveys are needed to determine whether this demographic pattern of admission
      reflects the population prevalence of these disorders. Reduction of admission
      rates will require interventions that are sensitive to gender differences in
      diagnosis among those admitted to psychiatric units.

PMID- 15040068
TI  - Motivation for and concerns about entering a medical programme.
AB  - The motivation for and concerns about studying medicine and future career plans
      of students at the Faculty of Medical Sciences, The University of the West Indies
      (UWI), were studied using a cross-sectional survey that included Year 1 medical
      students at both the Mona (Jamaica) and St Augustine (Trinidad and Tobago)
      medical schools of the UWI. The data were collected using a self-administered
      questionnaire containing structured questions on demographics and family
      background, motivation for and concerns about studying medicine and future career
      preferences. A total of 193 students took part in the study, 103 from Mona and 90
      from St Augustine (88% response rate). Seventy per cent of the students were
      between 18 to 22 years of age with 59% being females. The highest rated motives
      for studying medicine were the 'opportunity for working with people' and an
      'interest in human biology'. Female students scored significantly higher for the
      motive of an 'opportunity for working with people', while males rated the 'social
      prestige/status' significantly higher. The greatest concerns of the students were
      'fear of failure' and 'contracting diseases'. The female students had a greater
      concern for dealing with the long hours involved in medical training than their
      male counterparts. Surgical specialties (43%), family medicine (38%) and
      paediatrics (34%) were the top choices of the students for future specialty and
      more women than men chose obstetrics. Although the motives that students have
      reported are varied, there was a reasonable spread of desirable motives. This
      study provides a baseline for observing possible changes as students advance
      through medical training. A programme of study that strives to maintain these
      well-placed motives while providing opportunities for dealing with the concerns
      of the students will assist in creating caring, empathetic physicians for the
      Caribbean.

PMID- 15040069
TI  - End of life care. Perspectives from families and caregivers.
AB  - In industrialized countries, there is growing attention to improving the quality
      of healthcare provided to patients with terminal or chronic illnesses as they
      near the end of their lives. Many patients in wealthy nations reportedly die in
      severe pain, but little has been documented about pain or suffering at the end of
      life in less economically developed nations. This qualitative study explores end
      of life concerns in the Caribbean among health professionals and people who had
      lost a loved one. It found that many patients with terminal illnesses chose to
      die in their homes where they could be cared for by family and/or friends, but
      that these patients endured much pain and their caregivers also suffered. In the
      absence of national or institutional policy on pain relief or end of life care,
      most of these patients and their caregivers seek spiritual comfort. This paper
      illustrates the need for health professionals and policy makers to do more to
      relieve suffering at the end of life.

PMID- 15040070
TI  - Routine prophylactic antibiotics for arthroplasty patients receiving dental care.
      Is it necessary?
AB  - Much of the debate regarding the prophylactic use of antibiotics for patients who
      have had a total joint replacement has focussed on their use before dental
      procedures. Despite the fact that almost all orthopaedic surgeons routinely
      recommend antibiotics for patients with prosthetic joints who require dental
      treatment, there is little evidence of a definitive link between transient
      bacteraemia occurring during dental procedures and late infections around
      prosthetic joints. An extensive review of the literature reveals that most
      authors recommend prophylactic antibiotics in high-risk patients or in those who
      undergo extensive dental surgery.

PMID- 15040071
TI  - Image and diagnosis. Hirschsprung disease (congenital aganglionic megacolon).

PMID- 15040072
TI  - Multiple clinical manifestation of HTLV1 infection in a single patient.
AB  - HTLV-1 infection is endemic in the Caribbean and several publications have
      reported the clinical disease entities seen in this population of patients. This
      case report is an account of a patient admitted to Kingstown General Hospital, St
      Vincent and the Grenadines, who had severe infective dermatitis, tropical spastic
      paraparesis (TSP) and Non-Hodgkin's Lymphoma (NHL). As far as we are aware, all
      three diseases have not been described in a single patient.

PMID- 15040073
TI  - Antimicrobial screening of Nicotiana tobacum on organisms isolated from patients
      with respiratory tract infection.

PMID- 15040074
TI  - Training clinical psychologists at the University of the West Indies.

PMID- 15040075
TI  - [Effects of 7-oxo-DHEA treatment on the immunoreactivity of BALB/c mice subjected
      to chronic mild stress].
AB  - AIM: To determine whether 7-oxo-dehydroepiandrosterone (7-oxo-DHEA) can reverse
      the hypoimmunity in BALB/c mice exposed to chronic mild stress. METHODS: A
      chronic mild stress animal model was established by subjecting BALB/c mice to a
      stressful regimen arranged in an unpredicted manner for 4 consecutive weeks.
      Immunological function alternations under chronic mild stress were assessed by
      lymphocytes proliferative response to mitogens and NK cell lysis activity test.
      RESULTS: The studies showed the correlation between the state of depression and
      abnormalities in the immune response, such as a decrease of T lymphocytes
      proliferative response to Con A and suppression of cytotoxic of NK cell.
      Meanwhile, significant decrease of T3 and T4 levels was also observed. When
      stressed mice were daily given 7-oxo-DHEA 15 mg.kg-1, lymphocyte proliferative
      response and the NK cell activity were significantly enhanced and the decreased
      levels of T3 and T4 were restored in the stressed mice. CONCLUSION: 7-oxo-DHEA
      can improve the depressive symptoms and hypoimmunity of BALB/c mice induced by
      chronic mild stress as its parent DHEA.

PMID- 15040076
TI  - [Relationship between neurotoxicity of 6-hydroxydopamine and glutamate
      transport].
AB  - AIM: To study the relationship of neurotoxicity of 6-hydroxydopamine (6-OHDA) and
      the function of glutamate transporter. METHODS: Using in vivo microdialysis
      together with high performance liquid chromatography (HPLC) to detect the
      alteration of glutamate in the striatum and extracellular fluid of the PC12 cell.
      The rate of apoptosis and the activity of PC12 cells are read in a flow cytometer
      and a photometer for enzyme-labeled assays. The function of glutamate transporter
      is decided by detecting the ability of L-[3H]-glutamate uptake. RESULTS: 6-OHDA
      was shown to induce apoptosis and decrease the activity of PC12 cells. Increased
      release of glutamate was also found in PC12 cells and the injured striatum of the
      PD rats. But glutamate uptake in PC12 cells and rat striatum synaptosomes are
      inhibited obviously. CONCLUSION: The neurotoxicity of 6-hydroxydopamine is
      associated with declined function of glutamate transporters, which may be one
      important pathogenesis mechanisms of Parkinson's disease.

PMID- 15040077
TI  - [Effects of TNF-alpha receptor blocking peptide on adjuvant arthritis in rats].
AB  - AIM: To study the effects of TNF receptor blocking peptide on adjuvant arthritis
      in rats. METHODS: The model of rat adjuvant arthritis was induced by injection of
      complete Freund's adjuvant. The TNF receptor blocking peptide was injected
      locally in the ankle. The ankle swelling, the pathologic changes in the ankle
      joint and the expression of IL-1 beta mRNA and TNF-alpha mRNA by peritoneal
      macrophages (RT-PCR) were observed. RESULTS: The model of rat adjuvant arthritis
      induced by injection of complete Freund's adjuvant was similar to human
      rheumatoid arthritis. The treatment with TNF receptor blocking peptide for 10
      days resulted in complete inhibition of joint swelling, a decrease in
      infiltration of inflammatory cell into joint tissue, an obvious alleviation of
      inflammatory pathological damages and an apparent decline of TNF-alpha mRNA and
      IL-1 beta mRNA of peritoneal macrophages of rats. CONCLUSION: The TNF receptor
      blocking peptide can protect the joint from inflammatory damage induced by
      adjuvant arthritis by suppression of TNF-alpha and IL-1 production, thereby
      alleviating the pathological injury of joint and controlling effectively the
      clinic course of arthritis.

PMID- 15040078
TI  - [Stereoselectivity in absorption of trans tramadol in rat intestine].
AB  - AIM: To investigate the stereoselectivity in absorption of trans tramadol (trans
      T) in rat intestine. METHODS: The duodenum, jejunum and ileum were separately
      perfusated in situ with trans T dissolved in Krebs-Ringer buffer. Trans T
      enantiomers in the perfusate were analyzed with a high performance capillary
      electrophoresis (HPCE) method. RESULTS: The absorbed fractions of trans T
      enantiomers were similar among the different segments of the rat intestine. The
      absorbed fraction of (+)-trans T was lower than that of (-)-trans T when the
      concentration of trans T was not higher than 40 mumol.L-1. As the concentration
      of trans T increased, the absorbed fractions of trans T enantiomers were reduced
      and the difference in absorbed fractions between trans T enantiomers became not
      significant. CONCLUSION: Trans T enantiomers can be absorbed in different parts
      of the rat intestine. The intestinal absorption of trans T was stereoselective, (
      )-trans T being preferentially absorbed.

PMID- 15040079
TI  - [Protective effect of 3,4-oxo-isopropylidene-shikimic acid on vascular
      endothelial cell injured by hydrogen peroxide].
AB  - AIM: To study the effect of 3,4-oxo-isopropylidene-shikimic acid (ISA) on H2O2
      (200 mol.L-1, 4 h) injured human umbilical vein endothelial cells (HUVEC).
      METHODS: Morphological change was observed under microscop. Cell viability was
      assessed by MTT assay. The release of intracellular lactate dehydrogenase (LDH)
      and NO was assessed by colorimetry. Radioimmunoassay was used to assess 6-keto
      prostaglandin F1 alpha (6-keto-PGF1 alpha). RESULTS: Pretreatment with ISA for 6
      h alleviated the morphological damage of H2O2 induced HUVECs. At the
      concentration of 1-100 mumol.L-1, ISA prevented the inhibitory effect on cell
      viability induced by H2O2 in dose-dependent manner, but increased the ratio of
      cell viability from 60.4% to 84.3%. ISA reduced LDH release and increased the
      level of NO and 6-keto-PGF1 alpha in H2O2 induced HUVECs. CONCLUSION: ISA exerted
      protective effect on H2O2 injured HUVEC.

PMID- 15040080
TI  - [Antagonistic effect of sodium ferulate on glycerol-induced renal oxidative
      injury in mice].
AB  - AIM: To investigate the effect of sodium ferulate (SF) on glycerol-induced renal
      injury. METHODS: Glycerol solution 50% was injected intramuscularly to establish
      a model of acute tubular necrosis in mice. SF was administered intraperitoneally
      at the dose of 100-200 mg.kg-1 at the beginning of establishing the model and its
      effect was observed by monitoring renal function, antioxidative functions and
      renal pathologic histology. RESULTS: At 6 and 72 h after glycerol injection, SF
      treatment (100-200 mg.kg-1) showed significant and dose-dependent antagonistic
      actions on the increment of blood urea nitrogen (BUN), creatinine (Cr), and N
      acetyl-beta-glucosaminidase (NAG) induced by glycerol. The increase of renal
      malondialdehyde (MDA) content and the decrease of glutathione content,
      glutathione peroxidase (GSH-Px), glutathione S-transferase (GST), catalase (Cat)
      and superoxide dismutase (SOD) activities resulting from glycerol injection were
      remarkably inversed by SF at the dose of 200 mg.kg-1. Meanwhile, improvement of
      the renal histology was observed as well. CONCLUSION: SF showed beneficial effect
      on glycerol-induced acute tubular necrosis due to its antioxidative action.

PMID- 15040081
TI  - [Effects of conjugated linoleic acid on obese MSG mice with insulin resistance].
AB  - AIM: To study the effect of conjugated linoleic acid (CLA) on obese MSG mice with
      insulin resistance. METHODS: About four months old, obese MSG mice with insulin
      resistance were divided into control, CLA and rosiglitazone groups and drugs were
      administrated ig once a day. Body weights were recorded regularly, insulin and
      glucose tolerance were tested. In addition, serum insulin and TNF-alpha
      concentrations in serum and fat tissues were determined. RESULTS: CLA was shown
      to reduce the body weight and fat weight in MSG mice, but can not improve the
      abnormal insulin and glucose tolerance in these mice. Indeed, the serum insulin
      and TNF-alpha concentrations in the fat tissues of the group treated with CLA
      were higher than those in the models and the insulin sensitivity index was
      significantly lower than that in the model mice. CONCLUSION: CLA can reduce the
      body weight of MSG mice, but can not improve the insulin resistance in these
      mice.

PMID- 15040082
TI  - [Determination of daurisoline in rabbit plasma and study on its
      pharmacokinetics].
AB  - AIM: To establish an HPLC method for the determination of daurisoline (DS) in
      rabbit plasma and investigate its pharmacokinetic characteristics after
      intravenous administration. METHODS: Dauricine was used as internal standard. The
      plasma samples were deproteinated with acetonitrile and extracted with two-step
      dichloromethane. Acetonitrile-water-triethylamine (18:82:0.28, pH 3) was used as
      mobile phase at a flow rate of 1.0 mL.min-1. The UV-detector was set at 284 nm.
      RESULTS: The linear range was 0.05-20.00 micrograms.h.mL-1 with correlation
      coefficients 0.9996. The limit of quantitation (LOQ) was 0.05 mg.L-1 of plasma.
      The absolute and relative recoveries were above 80% and (101 +/- 5)%,
      respectively. The intra- and inter-assay coefficient of variation were 1.9%-5.6%
      and 3.5%-6.5%, respectively. The plasma concentration-time profiles were
      adequately described by a two-compartment open model. CONCLUSION: A sensitive,
      precise and accurate method for the determination of DS in plasma was described,
      which can be used in its pharmacokinetic studies.

PMID- 15040083
TI  - [Inhibitory action of berberine on glucose absorption].
AB  - AIM: To study the absorption characteristics of berberine and its influence on
      glucose absorption. METHODS: Rat recirculating perfusion model was used to study
      berberine absorption characteristics and Caco-2 cell model was used to explore
      the influence of berberine on disaccharidase, using HPLC to assay the appearance
      of glucose to indicate enzyme activities. RESULTS: Berberine was found to be
      hardly absorbed in the intestine (less than 5% in 2.5 h). However, sucrase and
      maltase activities were found to be inhibited by berberine, its ID50 to sucrase
      is 1.830 mg.L-1, and showed no dose dependent influence on maltase activity.
      Berberine also showed influence on glucose absorption. However, this effect is
      not significant. CONCLUSION: Berberine may act as an alpha-glucosidase inhibitor,
      which is its main mechanism in diabetes treatment.

PMID- 15040084
TI  - [Synthesis and radiopharmacology of S-(2-18F-fluoroethyl)-L-methionine for tumor
      imaging].
AB  - AIM: To develop S-(2-18F-fluoroethyl)-L-methionine (18FEMET) as an amino acid
      positron emission tomography (PET) tracer for tumors, and to evaluate the value
      of 18FEMET in the differentiation of experimental tumor and experimental
      inflammation. METHODS: 18FEMET was prepared by nucleophilic fluorination reaction
      via a two-step procedure. Biodistribution of 18FEMET in normal mice, carcinoma
      bearing mice and inflammatory mice, and 18FEMET PET imaging for carcinoma-bearing
      mice and inflammatory mice were performed compared with 2-[18F] fluoro-2-deoxy-D
      glucose (FDG) and O-(2-[18F] fluoroethyl)-L-tyrosine (FET). RESULTS: The overall
      radiochemical yield with no decay correction was 15%-25%, the whole synthesis
      time was about 70 min by manual operation, and the radiochemical purity was above
      95%. High uptake and long retention of 18FEMET in pancreas, kidney, colon, liver
      and heart were observed. But low uptakes in brain and blood were found.
      Furthermore, high uptake of 18FEMET, FDG and FET in tumor, high uptake of FDG in
      inflammatory tissue, and almost no uptake of 18FEMET and FET in inflammatory
      tissue were also observed. CONCLUSION: 18FEMET is easy to prepare and can be used
      to differentiate between tumor and inflammatory tissue. It seems to be a
      potential amino acid tracer for tumors with PET imaging.

PMID- 15040085
TI  - [Synthesis and antitumor activity of the derivatives of cephalotaxine and
      drupacine].
AB  - AIM: To make full use of cephalotaxus plant resources and search for antitumor
      agents with higher activities and lower side effects. METHODS: The C3 hydroxy
      groups of the cephlotaxine and drupacine were acylated by taxol side chain and
      its isomers to give a series of derivatives of cephlotaxine and drupacine.
      RESULTS: Six novel alkaloid esters were designed and synthesized. The
      pharmacological screening results showed that VIIIa, VIIIb, IXa and IXc exhibited
      significant activities on KB, HCT and Bel in vitro. CONCLUSION: Novel alkaloid
      esters are worthy to be intensively studied.

PMID- 15040086
TI  - [Chemical constituents of Ligularia dictyoneura].
AB  - AIM: To study the chemical constituents of Ligularia dictyoneura. METHODS:
      Various chromatographic techniques were used to separate and purify the
      compounds. Their spectral data (MS, IR, NMR) were measured for structure
      elucidation. RESULTS: Four sesquiterpenes were isolated from Ligularia
      dictyoneura and their structures were identified as ligudicin A (1), ligudicin C
      (2), ligudicin D (3) and isopetasin (4). CONCLUSION: Compound 1 is a new
      compound, compound 2 is a new natural product, and compounds 3 and 4 are obtained
      from Ligularia dictyoneura for the first time.

PMID- 15040087
TI  - [Isolation and structure identification of lignans from pine needles of pinus
      massoniana Lamb].
AB  - AIM: To study the chemical constituents from the water-extracts of pine needles
      of Pinus massoniana Lamb. METHODS: Chromatographic techniques were used to
      separate and purify compounds. Their physico-chemical properties and spectral
      data (UV, IR, MS, 1H-1H, 13C-1H NMR, DEPT, HMBC etc.) were used to elucidate the
      structures. RESULTS: Three lignans were isolated from the n-BuOH fraction of
      water-extracts. Their structures were identified as (7S,8R)-3',4,9'-tridihydroxy
      4-methoxy- 9-O-shikimoyl-7,8-dihydrobenzofuran-1'-propylneolignan (massonianoid
      A, I), (7S,8R)-4,9-dihydroxy-3,3'-dimethoxy-7,8- dihydrobenzofuran-1'
      propylneolignan (II) and 4,4',8-trihydroxy-4,4'-dimethoxy-9-lignanolide (III).
      CONCLUSION: Compound I is a new compound. While II and III were isolated from
      this plant for the first time.

PMID- 15040088
TI  - [Daviditin B from Swertia davidi Franch].
AB  - AIM: To study the active constituents of Swertia davidi Franch. METHODS: Chemical
      components were isolated by column chromatography and their structures were
      established mainly by spectroscopic means (UV, IR, NMR, 2D-NMR, MS). RESULTS:
      Three substances were identified as 2,5-dimethoxyl-1, 4-dicarboxyl benzene
      (VIII), 1,5,8-trihydroxyl-3,4-dimethoxyl xanthone (IX) and 1,8-dihydroxyl-3-(3'
      hydroxyl-butoxy) xanthone (X). CONCLUSION: Compounds VIII and IX were isolated
      from Swertia davidi Franch, for the first time, whereas compound X is a new
      xanthone, named daviditin B with antioxygenated activity in vitro.

PMID- 15040089
TI  - [Structure identification of jujuboside E].
AB  - AIM: To study the chemical constituents of the seeds of Ziziphus jujuba Mill var.
      spinosa (Bunge) Hu ex. H.F. Chou. METHODS: To separate the constituents by using
      various kinds of chromatography methods and identify their structures on the
      basis of spectral analysis. RESULTS: Seven compounds were isolated. Their
      structures were established as jujuboside E (1), jujuboside B (2), jujuboside A
      (3), betulic acid (4), stearic acid (5), sucrose (6) and inosine (7). CONCLUSION:
      Compound 1 is a new compound named jujuboside E. Compounds 5, 6, 7 were isolated
      for the first time from this plant.

PMID- 15040090
TI  - [Ginkgo flavones in in vitro metabolism and its clinical application].
AB  - AIM: To develop a method for assaying Ginkgo flavones in rat hepatical microsome.
      METHODS: Quercetin, isorhamnetin and keampferol were added to microsome incubate
      and incubated for a given time then extracted with ether-acetone. After
      evaporated, the residue was reconstituted with 100 microL of phosphate buffer
      solution (pH 2.0)-tetrahydrofuran-methanol-isopropanol (60:15:10:20). An aliquot
      of 20 microL was injected into the HPLC system. According to the result of
      estimate by means of HPLC, the results of metabolism of Ginkgo flavones in
      different conditions was compared. RESULTS: The assay was linear over the rang of
      0.2-8 mg.L-1 for Ginkgo flavones. The limit of quantification was 0.1 mg.L-1 (n =
      3). The recoveries of three components of Ginkgo flavones were 99.9%-113.8% for
      quercetin (RSD < 0.8%), 100.8%-117.3% for isorhamnetin (RSD < 1.9%) and 100.7%
      116.5% for keampferol (RSD < 1.03%, n = 5). CONCLUSION: The method is simple,
      fast and accurate. It can be used for investigation of the metabolism of Ginkgo
      flavones.

PMID- 15040091
TI  - [Study on bioequivalence of domestic bambuterol capsules and imported tablets by
      high performance capillary zone electrophoresis].
AB  - AIM: To study bioequivalences of bambuterol and its metabolites terbutaline in 20
      healthy male volunteers. METHODS: A single oral dose of domestic bambuterol
      capsule or imported bambuterol tablet was given according to a randomized 2-way
      cross-over design. The plasma bambuterol and terbutaline concentrations were
      determined by high performance capillary zone electrophoresis (HPCZE). RESULTS:
      The pharmacokinetic parameters of the capsule and tablet of bambuterol: AUC0-1
      were (72 +/- 18) and (72 +/- 13) microgram.h.L-1, Cmax were (8.1 +/- 1.8) and
      (9.2 +/- 2.3) microgram.L-1, Tmax were (3.6 +/- 1.3) and (3.7 +/- 1.0) h,
      respectively; terbutaline: AUC0-t were (129 +/- 32) and (130 +/- 34)
      microgram.h.L-1, Cmax were (7.8 +/- 2.2) and (8.5 +/- 2.9) microgram.L-1, Tmax
      were (5.4 +/- 0.8) and (5.6 +/- 1.1) h, respectively. The bioavaiability of the
      capsule was (100 +/- 16)% (bambuterol) and (101 +/- 13)% (terbutaline).
      CONCLUSION: The results demonstrated that the two preparations of bambuterol and
      terbutaline were bioequivalent by analysis of variance, with two-one sided test
      at 90% confidential level.

PMID- 15040092
TI  - [Effects of changes in conformation and configuration of N-containing compounds
      on NMR spactra].
AB  - AIM: To find the cause of abnormal NMR spectra of lomerizine dihydrochloride,
      cetirizine dihydrochloride and flenfluramine camphoramide. METHODS:
      Hypothesizing, in given conditions, there are changes of stereoisomeric
      conformation and configuration in structure of N-containing compounds, it results
      in abnormality of NMR spectra. By using the method of NMR, it is confirmed
      credibily. RESULTS AND CONCLUSION: The moving balance exists between two chair
      conformations in lomerizine dihydrochloride and cetirizine dihydrochloride. It
      causes that spin-nuclei of whole molecule are placed in two chemical
      circumstance. In solution of DMSO-d6, the speed of conformation reversal equals
      to the NMR time scale, so that chemical shift of spin-nuclei can not be
      definitely determined, peaks are broadened and even collapsed. After dropping D2O
      or increasing the temperature, the viscosity of the solution is decreased, the
      speed of reversal is quicker than NMR time scale, then normal spectra are
      obtained. Owing to the reversal of the three bonds of nitrogen in flenfluramine
      camphoramide is limited, other pair of diastereoisomer resulted from the
      asymmetric nitrogen can be detected by NMR. Multiplication of the peaks of 13CNMR
      is reasonably explained.

PMID- 15040093
TI  - [Analysis of impurity in caderofloxacin].
AB  - AIM: To analyse the main impurity of caderofloxacin. METHODS: The impurity of
      caderofloxacin was analysed and determinated by RP-HPLC/ESI/MS with a Zorbax SB
      C18 (150 mm x 4.6 mm ID, 5 microns) column. The mobile phase was acetonitrile
      0.5% acetic acid solution (17:83). A compound was synthesized: 1-cyclopropyl-8
      (difluoromethoxy)-6-fluoro-1, 4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline
      carboxylic acid (DMCA). Its HPLC chromatogram, UV and MS spectrum were compared
      with those of the impurity in caderofloxacin. RESULTS: The molecular weight of
      the impurity was 14 less than that of caderofloxacin. It means the impurity was a
      CH2-group less than caderoflixacin. The tR, UV and MS of DMCA were the same as
      those of the impurity in caderofloxacin. CONCLUSION: Based on the tR (HPLC), UV
      and MS, the impurity of caderofloxacin is confirmed as DMCA.

PMID- 15040094
TI  - [Studies on gastrointestinal absorption enhancement effect and mechanism of
      sodium N-[8-(2-hydroxybenzyl)amino] caprylate to insulin solution].
AB  - AIM: To study the enhancement effect and mechanism of sodium N-[8-(2
      hydroxybenzyl) amino] caprylate (SNAC--a kind of synthetic enhancer) to insulin
      (INS) solution in gastrointestine. METHODS: To determine the enhancement effect
      of SNAC on INS absorption by oral administration to rats and mice; To study the
      enhancement mechanism of SNAC by three kinds of methods: Delivering SNAC and INS
      solution to different parts of rats' intestines, adding energy inhibitor 2,4
      dinitrophenol (DNP) or P-glycoprotein (P-gp) inhibitor verapamil (Ver) into SNAC
      and INS solution. RESULTS: SNAC was shown to enhance the gastrointestinal
      absorption of INS, the intensity of absorption enhancement corresponded to the
      doses of SNAC. The enhancement of SNAC to INS in different parts of the rat
      intestine was different (jejunum > colon > ileum). The effect of SNAC on INS
      absorption increased accordingly. CONCLUSION: The enhancement of SNAC to INS
      absorption presented dose dependence on SNAC; the absorption process needed
      energy and related to P-gp efflux.

PMID- 15040096
TI  - [Synthesis of prodrugs of tacrine hydrochloride and evaluation of the stability
      and biodistribution in mice].
AB  - AIM: To synthesize acylated prodrug of tacrine hydrochloride (THA) to improve the
      infiltration ability across the blood brain barrier (BBB). METHODS: A series of
      prodrugs were prepared by acylation of the 7-amino group of THA. The degradation
      of prodrugs was investigated under different conditions. Biodistribution studies
      of N-butyramide-THA (BTHA) in mice were carried out to evaluate the function of
      brain targeting. RESULTS: The structures of prodrugs were confirmed by IR, 1HNMR
      and MS. All prodrugs were stable in different medium. Octanol-water partition
      coefficients indicated increased lipophlicity for various prodrugs compared to
      the THA. In vivo distribution studies showed that BTHA was mainly distributed in
      brain, blood and liver (the maximum concentrations were 17.5725, 13.1400 and
      22.8279 mg.L-1, respectively), while the THA concentration were very low in lung
      and heart (the maximum concentrations were 4.9475 and 4.4925 mg.L-1,
      respectively). The BTHA concentration (2.4159 mg.L-1) was relatively high even 12
      h after administration, showing that BTHA degraded more slowly in brain than in
      other tissues. CONCLUSION: The infiltration ability of THA across BBB was
      increased in the form of N-acylate-THA prodrug, indicating that this kind of
      prodrug is a promising brain-targeting delivery system.

PMID- 15040095
TI  - [Study on pulmonary delivery of peptide drugs in rats: effects of absorption
      enhancers on cellular membrane fluidity].
AB  - AIM: To study the relationship between cellular membrane fluidity and relative
      bioavailability (Fr) of protein and peptide drugs combined with absorption
      enhancers after pulmonary administration in rats. METHODS: A series of model drug
      salmon calcitonin (sCT) solutions with 6 absorption enhancers (Brij78, sodium
      cholate, sodium caprylate, 2-hydroxypropyl-beta-cyclodextrin, lecithin and
      chitosan) were prepared and then delivered to rats by pulmonary route. Serum drug
      concentration was determined by radioimmunoassay method. Using the techniques of
      electron spin resonance and fluorescence polarography, the effects of enhancers
      on pulmonary cellular membrane fluidity were investigated. RESULTS: Fr values of
      sCT solution with some absorption enhancers (Brij78, sodium cholate, sodium
      caprylate, lecithin and chitosan) were significantly higher than those without
      enhancers. Brij78, lecithin and sodium caprylate, not only increased membrane
      lipid fluidity but also loosed the constitution of membrane protein. The effect
      of sodium cholate on membrane protein was low. Lipid fluidity was reduced and
      protein constitution was changed markedly, after pulmonary cellular membrane was
      treated by 0.5% chitosan solution. This result showed that the absorption
      enhancing of chitosan mainly came from its effects on membrane protein.
      Corresponded with lower Fr after pulmonary administration, 2-hydroxypropyl-beta
      cyclodextrin (0.5% and 3%) had not significant effects on both lipid fluidity and
      protein constitution. CONCLUSION: The effects of enhancers on pulmonary
      absorption of peptide drugs in vivo might be investigated on the grounds of
      determination of cellular membrane fluidity in vitro.

PMID- 15040097
TI  - [Unitary-core osmotic pump tablet for controlled release of water-insoluble
      drug].
AB  - AIM: To study unitary-core osmotic pump tablet for delivering water-insoluble
      drug for 24 hours. METHODS: Unitary-core osmotic pump tablet was prepared using
      nifedipine as the model drug. The effects of various core formulation variables
      on drug release were studied. RESULTS: Polyethylene oxide and potassium chloride
      have comparable positive effects on drug release, whereas, nifedipine has
      markedly negative effect on drug release. CONCLUSION: Unitary-core osmotic pump
      tablet is very easy in preparation and it can deliver water-insoluble drug in
      substantially constant rate for 24 hours.

PMID- 15040098
TI  - [Study on the metabolite of stilbene glucoside in mice by liquid chromatography
      tandem-mass spectrometry].
AB  - AIM: To study the metabolite of stilbene glucoside in the Chinese traditional
      medicine Polygonum multiflornm in mice and elucidate its chemical structure by
      liquid chromatography tandem-mass spectrometry. METHODS: The stilbene glucoside
      was injected into the tail vein of mice. Blood samples were collected from artery
      in the eyepit. The methanol-protein-precipitated plasma sample was introduced
      into the liquid chromatography-tandem mass spectrometer directly. The analytical
      column was C18 column (250 mm x 4.6 mm ID, 5 microns). The mobile phase consisted
      of acetonitrile-methanol-water-formic acid (15:18:66:1) for ES+, acetonitrile
      methanol-water (15:18:67) for ES-. The UV detection wavelength was set at 320 nm.
      The mass ion source type was ESI. HV capillary was 3 kV. The dry gas was nitrogen
      gas and the flow rate was set at 318 L.h-1. The ion source temperature was 150
      degrees C. RESULTS: The stilbene glucoside and its metabolite were separated
      completely under the chromatography condition. The ions at m/z 600 and m/z 605
      were detected under positive ion polarity while the ions at m/z 581 and m/z 402
      were detected under negative ion polarity. CONCLUSION: It was proposed that the
      metabolite of stilbene glucoside injected in vein was its glucuronide conjugate.

PMID- 15040099
TI  - [Effects of E1A gene on the growth and chemosensitivity of transplantation tumor
      of nude mice].
AB  - OBJECTIVE: To study the effects of E1A gene on the growth and chemosensitivity of
      transplantation tumor of nude mice of lymph node metastasis cell line (686LN-1)
      of human tongue squamous cell carcinoma. METHODS: 686LN-1, 686LN-1-vect and 686LN
      1-E1A cells were transplanted into nude mice, then the time of tumor formation,
      growth rates and weight of tumor were observed. To study the effects of the E1A
      gene on bleomycin sensitivity in vivo, 686LN-1 cells were injected into nude
      mice. After tumor formed, bleomycin, E1A gene and E1A gene + bleomycin were given
      respectively as therapy. The tumor volume was calculated, and growth curve was
      plotted. Representative histological sections were taken from mice bearing
      transplantation tumor either treated or control groups, and expression of HER
      2/neu was detected. RESULTS: In nude mice, the expression of E1A gene
      significantly suppressed the growth rates and elongated the time of tumor
      formation. Bleomycin or E1A Gene and E1A gene + bleomycin can suppress the growth
      rates of transplantation tumor of nude mice, the suppressed rates of tumor growth
      was 53.13%, 76.83% and 96.65%, respectively. The expression of E1A gene can
      significantly suppressed the expression of HER-2/neu gene in 686LN-1-E1A cells.
      CONCLUSION: E1A is able to significantly inhibit the growth rate of
      transplantation tumor of nude mice of lymph node metastasis cell line (686LN-1)
      of human tongue squamous cell carcinoma, and dramatically enhance the sensitivity
      of the cells to cytotoxic agents in vivo. Above of all functions of E1A gene may
      be related to that it suppressed the expression of HER-2/neu gene.

PMID- 15040100
TI  - [Study on the expression of the metastasis suppressor gene KAI1 in laryngeal
      squamous cell carcinoma].
AB  - OBJECTIVE: To investigate the expression of the metastasis suppressor gene KAI1
      in laryngeal squamous cell carcinoma and the relationship between expression of
      KAI1 and it's role in tumorgenesis and development. METHODS: The sections of 84
      samples of primary laryngeal squamous cell carcinoma (PLSCC), 27 samples of
      laryngeal precancerous lesion (LPL), 10 samples of vocal cords polyp (VCP) and 10
      samples of normal laryngeal tissues (NLT) were examined by in situ hybridization
      for KAI1mRNA. RESULTS: It was found that 10 samples of NLT and 10 samples of VCP
      showed strong expression of KAI1, the Integrated A Total of KIA1 in these two
      types of tissues were 136,206.8 +/- 36,675.536 and 133,674.505 +/- 42,858.456,
      respectively, with no statistically significant difference between them, and high
      prevalence of decreased expression of KAI1 in LPL and PLSCC compared with that in
      VCP and in NLT (P < 0.01). There was a significant relationship between down
      regulation of KAI1 expression with pathological grade, lymph node metastases, T
      stage and clinical stage (P < 0.01) and did not correlate with gender.
      CONCLUSION: KAI1 may play an important role on tumor genesis, development,
      invasion and metastasis of PLSCC, and become one of the molecular markers for
      early diagnosis and predicting of aggressive and metastasis potential to assess
      the clinical stage of PLSCC.

PMID- 15040102
TI  - [Diagnosis and treatment of juvenile recurrent laryngeal papillomatosis].
AB  - OBJECTIVE: To evaluate some perplexing problems in the diagnosis and treatment of
      juvenil recurrent laryngeal papillomatosis (JRLP) and the relationship between
      juvenile onset recurrent respiratory papillomatosis(JORRP) and infantile
      laryngeal condyloma accuminatum (ILCA). METHODS: A group of 44 cases with JRLP
      were analyzed retrospectively from March, 1994 to March, 2002 in the light of
      literature review. RESULTS: The average age of first visit was 1.6 years. Average
      5.3 operations had been performed per patient. There was an interval of average
      2.4 months between two surgical excisions. Of 233 operations, the total incidence
      rate of all the complications was 3.9%. At present, the laryngeal lesion of 18
      cases have withered away for over 1 year. 11 cases have being followed up. 10
      cases have lost follow-up and 5 cases have died (11.4%). Combined laryngeal
      lesion excision with tracheotomy aiming at prolonging operative interval or
      Chinese traditional medicine has received more satisfactory effect than other
      therapies. There is an extensive similarity between JORRP and ILCA. CONCLUSIONS:
      To demondrate further whether JORRP and ILCA are the same identical disease has
      important significance in both theoretical study and clinic practice. The
      treatment for JRLP is still difficult. The tracheotomy for laryngeal obstruction
      resulted from the laryngeal lesion of JRLP should be avoided as far as possible.
      Combined laryngeal lesion excision with tracheotomy aiming at prolonging opertive
      interval or Chinese traditional medicine shows optimistic prospect.

PMID- 15040101
TI  - [The detection and significance of human papilloma virus 11b virus like particles
      and its serum antibody in juvenile larynx papilloma].
AB  - OBJECTIVE: To study the relationship between human papilloma virus 11b virus like
      particles (HPV11bVLPS) serum antibody and the development and prognosis of
      juvenile larynx papilloma (JLP). METHODS: Enzyme linked immunosorbent assay
      (ELISA) was used to detect the serum HPV11bVLP antibody (Ab) of 46 JLP's samples
      in different stage and 20 controls using HPV11bVLPS which was produced by
      recombinant bacilovirus in insect cells. Grouping: A: control group (n = 20); B:
      the time of onset was 1 years (n = 15); C: the time of onset was 2 years (n =
      15); the patients were followed-up 1 year without recurrence (n = 8); E: The
      patients were followed-up 2 years without recurrence (n = 8). RESULTS: A value of
      HPV11bVLP Ab among A, B, C, D, E. group were: (0.073 +/- 0.035); (0.120 +/-
      0.049); (0.137 +/- 0.057); (0.518 +/- 0.122); (0.557 +/- 0.144). There was a
      significant difference between JLP patients and the control group (P < 0.05). The
      level of HPV11bVLP Ab in (D + E) group (0.534 +/- 0.132) was higher than (B + C)
      group (0.128 +/- 0.053) (t = 14.90, P < 0.001). CONCLUSION: The results suggested
      that HPV serum antibody was produced in JLP with HPV infection. There is close
      relationship between the development and prognosis of the disease and the level
      of HPV11Ab in serum. The assay of serum HPV11bVLPAb and HPV-VLP could be used as
      immunological study of HPV11-infection associated disease.

PMID- 15040103
TI  - [Lateral neck dissection vs radical neck dissection in the management of
      supraglottic carcinoma with pathologically negative nodes].
AB  - OBJECTIVE: To compare the effectiveness of lateral neck dissection (LND) with
      radical or modified radical neck dissection (RND) for the management of
      supraglottic carcinoma with pathologically negative nodes (pNO). METHODS: Two
      treatment groups with pNO supraglottic carcinoma were retrospectively compared:
      39 patients who were treated with RND between March of 1980 and December of 1996,
      and 54 patients who were treated with LND between January 1997 and December 2001.
      RESULTS: The neck recurrent for LND population was 2.3%, which was not
      statistically different from the neck recurrent in the RND population (0.0%).
      Also, the 5-year survival rates were no statistic difference between LND and RND
      groups (97% vs 94%). Complications and period of hospitalization were both
      decreased in LND group comparison of RND group (6.7% vs 38.5%; 28 days vs 39
      days). CONCLUSION: Comparing to the radical or modified neck dissection, the LND
      offers less invasive surgery and less morbidity without oncologic compromise for
      patients with pNO supraglottic carcinoma.

PMID- 15040104
TI  - [The application of epiglottis and cervical anterior muscle to laryngeal
      reconstruction].
AB  - OBJECTIVE: To evaluate the methods of reconstruction of laryngeal function after
      the extended laryngectomy. METHODS: The laryngeal functions were reconstructed
      after the extended laryngectomy performed on 22 cases with the laryngocarcinoma
      of T2 and T3 stages of glottic type, using epiglottis and cervical anterior
      muscle to reconstruct the laryngeal cavity and larynx bracket, from September
      1998 to October 1999. RESULTS: Twenty cases recovered normal swallow function in
      20 days post-operation as well as the entire function of larynx was recovered,
      and the rate of decannulation was 90.9% (20/22). One case with pharyngeal fistula
      recovered a month later, but the other case recovered to normal diet by operation
      repaired. All the patients pronounced clearly and were able to keep the
      characteristics of their own voice. The fibred laryngoscope examination showed
      that the sphincter valves were formed at the larynx atrium in all postoperative
      cases. The rate of 3-year survival for T2 and T3 stages was 100% (9/9) and 92.3%
      (12/13), respectively. CONCLUSION: The laryngeal cavity could be enlarged and the
      laryngeal atrium was reconstructed by employing epiglottis ifraplacement and
      cervical anterior muscle to reduce the tension of epiglottis and minimize the
      injury of the membrane as well as to overcome the shortcomings of insufficient
      material if mere employing epiglottis. The application of combined methods to
      reconstruct the laryngeal cavity is a practical way to restore the larynx
      function and improve the life quality.

PMID- 15040105
TI  - [Tracheoesophageal shunt for voice reconstruction after total laryngectomy to
      prevent from deglutition disorders].
AB  - OBJECTIVE: To observe the effect of tracheoesophageal shunt on voice
      reconstruction after total laryngectomy. METHODS: Seventy-nine patients with
      laryngeal cancer of T3 and T4 stages were conducted an operation of
      tracheoesophageal shunt after total laryngectomy. The vertical voiced slit with a
      length of 0.8-0.12 cm was made between the posterior wall of trachea and the
      frontal wall of esophagus, while the cricoid cartilage flap with the length of
      2.0 cm and width of 1.2 cm was reserved to form cartilage mucosa flap as an edge
      to prevent deglutition disorders. Finally, membranous part of trachea was sutured
      together with the neck skin as an inclination edge. RESULTS: In this series, 71
      of 79 patients kept good voice function, and 65 of 71 patients avoided
      deglutition disorders, but other patients failed to do so. The 3-year survival
      rate was 66.7% (14/21, for stage T3) and 64.9% (24/37, for stage T4),
      respectively. The 5-year survival rate was 6/10 (for stage T3) and 50.0% (10/20,
      for stage T4), respectively. CONCLUSION: The operation of tracheoesophageal shunt
      is advantageous to prevent deglutition disorders as well as to restore the voice
      function of larynx.

PMID- 15040106
TI  - [Surgical management of primary cervical tracheal cancer].
AB  - OBJECTIVE: To review the experience of surgical treatment of primary cervical
      tracheal cancer. METHODS: Six patients with primary cervical tracheal cancer were
      treated surgically from January 1997 to April 1999. The trachea anastomosis,
      platysmamyocutaneous flap combiend with the facial flap of the sternohyoid
      muscle, sternocleidomastoid myoperiosteal flap and the pectoralis major
      muculocutaneous flap were applied to restore the defects of cervical trachea. By
      pathology, there were two squamous cell carcinomas, three adenoid cystic
      carcinomas, and one adenocarcinoma. RESULTS: Six cases were decannulated from 23
      days to 3 months after operation. The length of follow-up was more than 3 years.
      Five cases have stable airway by fiberscope and good voice after decannulation
      and there is no recurrence. One case died of lung metastasis 2 years after
      operation. CONCLUSION: Trachea anastomosis is suited for small partial defect.
      The platysmamyocutaneous flap combined with the facial flap of the sternohyoid
      muscle, sternocleidomastoid myoperiosteal flap and the pectoralis major
      muculocutaneous flap are ideal transplant for cervical tracheal reconstruction.

PMID- 15040107
TI  - [Study of neurological mechanism of lidocaine's suppression to tinnitus via
      microdialysis].
AB  - OBJECTIVE: To elucidate the neurological mechanism of lidocaine's suppression to
      tinnitus. METHODS: Thirty-four Wistar rats weighing 300-350 grams were randomly
      divided into IC group (n = 17) and AC group (n = 17), according to microdialysis
      region. Each group was randomly subdivided into saline treatment group (n = 4),
      salicylate treatment group (n = 6), and salicylate + lidocaine treatment group (n
      = 7). Using in vivo microdialysis technique coupled with microbore HPLC
      electrochemical detection, the present study first monitored the 5-HT release in
      IC and AC in salicylate-induced tinnitus animal models, and then, examined the
      effects of lidocaine on salicylate-induced 5-HT changes in IC and AC. The
      statistical analysis was performed using two-way ANOVA for repeated measures of
      raw data with time and treatment condition as main effects. Individual time-point
      values between no more than two groups were compared with the unpaired Student's
      t-test. The accepted level of significance was 0.05, two-tailed. RESULTS: The 5
      HT level increased to a maximum of 268% +/- 27% (mean +/- s) basal level in IC 2
      h after salicylate application and of 277% +/- 24% basal level in AC around 3 h
      after application. And then, the 5-HT level gradually decreased to 157% +/- 16%
      of baseline in IC and 180% +/- 18% of baseline in AC by the end of the sixth
      hour. Saline did not alter the IC and AC dialysate 5-HT level in control rats.
      Two-way ANOVA with repeated measures indicated a significant effect of the
      condition factor [F (1, 8) = 413.949, P < 0.000001 in IC group; F(1,8) = 192.184,
      P < 0.000001 in AC group]. The increases of 5-HT levels in salicylate treatment
      groups were significantly reduced to 85% +/- 8% basal level in IC and 92% +/- 26%
      basal level in AC after local infusion of 1% lidocaine (P < 0.05). Compared with
      corresponding control value at that time (unpaired student t-test). Two-way ANOVA
      with repeated measures showed a significant difference between the salicylate
      group and salicylate + lidocaine group [P < 0.000001 with F(1, 11) = 329.267 for
      the condition factor in IC subgroup; P < 0.000001 with F(1, 11) = 133.844 for the
      condition factor in AC subgroup]. CONCLUSION: The suppression of lidocaine to
      tinnitus may be associated with the decrease of 5-HT level in IC and AC.

PMID- 15040108
TI  - [Histo-morphological changes of eustachian tube of guinea pigs with effusion
      after being treated by pulmonary surfactant].
AB  - OBJECTIVE: To study the effect of pulmonary surfactant on otitis media with
      effusion in guinea pigs to find a new way to manage otitis media with effusion.
      METHODS: Nonviable heat-killed pneumococci (HKP) solution was inoculated into the
      middle ear cavity in guinea pigs via a transeardrum approach to set up a model of
      otitis media with effusion in guinea pigs. Seven days after being injected with
      pulmonary surfactant (PS) by transeardrum approach, ABR threshold and
      histomorphological changes of eustachian tube mucosa of guinea pigs were examined
      by light microscopy and scanning microscopy. RESULTS: Five days following
      inoculation of HKB serous effusion were present in the middle ear cavity of
      guinea pigs, but disappearance of light cone. Response (mean +/- s) threshold
      raised from (14.0 +/- 3.1) dB to (45.0 +/- 5.7) dB. The eustachian tube mucosa
      was thickened and lined eosin-stained structureless matter over mucosa, while
      cilia of eustachian tube mucosa irregularly arranged. Seven days after being
      treated by PS, serous effusion of tympanum was reduced or disappeared, and
      response threshold decreased from (45.0 +/- 5.7) dB to (23.5 +/- 6.3) dB. There
      was significantly difference between them (P < 0.001). Eustachian tube mucosa was
      thinned, Cilia of eustachian tube mucosa regularly arranged to the nasopharynx.
      CONCLUSION: Pulmonary surfactant plays a important role in otitis media with
      effusion of guinea pigs.

PMID- 15040109
TI  - [Interleukin-5 regulate the bone marrow response in the model of allergic
      rhinitis].
AB  - OBJECTIVE: To elucidate the mechanism of bone marrow response regulated by
      interleukin-5 (IL-5) in the model of allergic rhinitis. METHODS: Twenty SD rats
      were randomly divided into allergic rhinitis (AR) group and control group. The
      leucocytes in the smears of bone marrow and peripheral blood were counted, and
      the expression of IL-5 was detected by immunohistochemistry. RESULTS: The ratio
      of eosinophils to white cells in bone marrow smears of AR group was significantly
      higher than that of control group(P < 0.01). The ratio of basophils to white
      cells in bone marrow smears of AR group was significantly higher than that of
      control group(P < 0.01). The ratio of eosinophils to white cells in peripheral
      blood smears of AR group was significantly higher than that of control group(P <
      0.01). The ratio of IL-5 positive cells to white cells in bone marrow smears of
      AR group was significantly higher than that of control group (P < 0.05). The
      ratio of IL-5 positive cells to white cells was significantly positively
      correlated with the ratio of eosinophils to white cells in bone marrow smears of
      AR group (R = 0.85, P < 0.01). CONCLUSION: IL-5 regulates the proliferation and
      differentiation of eosinophils in bone marrow.

PMID- 15040110
TI  - [Effect of erythromycin on the expression of apoptotic gene on eosinophils in
      nasal polyps in vitro].
AB  - OBJECTIVE: To study the expression of apoptotic gene in nasal polyps and the
      possible effect of erythromycin on it. METHODS: Total 40 nasal polyps biopsies
      were detected the expression of Bcl-2, Bax, Bcl-xL as well as Fas protein on
      eosinophils by immunohistochemistry. The expression of Bax, Bcl-xL, Fas on
      eosinophils in 15 nasal polyps explants which cultured with or without
      erythromycin were detected also. RESULTS: In nasal polyps, the expression of Bcl
      2, Bax, Bcl-xL and Fas protein on eosinophils are 5% (2/10), 65% (26/40), 40%
      (16/40) and 90% (36/40) respectively. As compared with inferior turbinate, there
      were significant difference in expression of Bax and Fas protein between two
      tissues (P < 0.05). After cultured with erythromycin, the expression of Bax
      protein increased (P < 0.05), but the expression of Bcl-xL and Fas protein had
      not changed. CONCLUSION: Bax may be the most significant gene which control the
      apoptosis of eosinophils in nasal polyps. And a possible mechaism which
      erythromycin promote the apoptosis of eosinophils is increase the expression of
      Bax.

PMID- 15040111
TI  - [Expression of nuclear factor-kappa B mRNA, inducible nitric oxide synthase and
      interleukin-6 in nasal polyp and its role].
AB  - OBJECTIVE: To evaluate the expression and significance of nuclear factor-kappa B
      (NF-kappa B) mRNA, inducible nitric oxide synthase(iNOS) and interleukin-6 (IL-6)
      in the pathophysiology of nasal polyp(NP). METHODS: The specimens from 59 nasal
      polyps (NP) and 20 inferior turbinates (IT) were studied by in situ hybridization
      for NF-kappa B mRNA, and by immunohistochemistry for iNOS and IL-6. Tissue
      sections were observed under optical microscope. RESULTS: NF-kappa B mRNA, iNOS
      and IL-6 overexpressions were localized mainly to the nasal polyp epithelium, the
      various inflammatory cells, in submucosal endothelial cells around the vessel and
      in submucosal glands. The positive frequency of activation of NF-kappa B mRNA was
      higher in NP (54.24%) than in IT (P < 0.01), whereas the positive frequency of
      iNOS and IL-6 overexpression were higher in NP (62.71% and 64.41%) than in IT (P
      < 0.01). Eosinophils and neutrophils in NP were higher than in IT (P < 0.01).
      CONCLUSION: These results suggest that NF-kappa B, iNOS and IL-6 are strongly
      correlated with the formation of NP. NF-kappa B, iNOS and IL-6 may act as anti
      apoptotic molecules in eosinophils and neutrophils that may be responsible for
      the recruitment of inflammatory cells, particularly eosinophils, through the
      initiation of the transcriptional pathway of the related cytokines. NF-kappa B
      might play a key role in the pathogenesis of NP process and therefore is a
      potential target for medical treatment and new therapeutic intervention.

PMID- 15040113
TI  - [The use of muscle autograft denatured by microwave for repair of gaps in removal
      of facial neuromas].
AB  - OBJECTIVE: To study the clinical value of muscle autograft denatured by microwave
      for repair of gaps in removal of facial neuromas. METHODS: Two cases of patients
      with facial nerve Schwann cell neuromas were reported. The operations for removal
      of facial neuromas were completed, and the gaps of the nerves were repaired with
      muscle autograft denatured by microwave of 250 W for 120 sec. RESULTS: The
      patients were followed up for two years, and the recovery of facial function on
      the affected sides were satisfactory. CONCLUSION: Muscle autograft denatured by
      microwave technique is convenient, highly efficient for repairing facial nerve
      gap after removal of facial neuroma.

PMID- 15040112
TI  - [Phanerogenetic retrocochlear low frequency hearing loss].
AB  - OBJECTIVE: To study the pathogenisis of retrocochlear low frequency hearing loss.
      METHODS: Clinical and audiologic findings [auditory brainstem response (ABR),
      evoked otoacoustic emission (EOAE), et al] of 29 cases with retrocochlear low
      frequency hearing loss were studied. RESULTS: The head injury, acoustic neuroma,
      peripheral neurophathy, hereditary hear loss, multiple sclerosis and brainstem
      disease can cause retrocochlear low frequency hearing loss. The typical clinical
      manifestations of retrocochlear low frequency hearing loss were normal EOAE which
      cannot be suppressed by contralateral white noise, but with abnormal ABR as well
      as with no acoustic reflex and -SP/AP > 0.44. CONCLUSIONS: The results suggest
      that phanerogenetic retrocochlear low frequency hearing loss should be a syndrome
      rather than a disease called "auditory neuropathy". The main lesions of the
      disease are brainstem, cochlear nuclei and auditory nerve.

PMID- 15040114
TI  - [Surgery of ossifying fibroma of the sinuses].
AB  - OBJECTIVE: To explore the different surgical choices for treating the ossifying
      fibroma of the sinuses. To summarize the management and characteristics of each
      surgical operation. METHODS: A retrospective evaluation of thirty-five patients
      with ossifying fibroma of the sinuses from August 1994 to July 2001 was
      presented. RESULTS: Among 22 patients operated by nasal endoscopic management,
      complete ossifying fibroma removed was achieved in 8 cases, and the majority part
      of tumor removed in 14 cases. Six patients were operated through a lateral
      rhinotomy with radical operation in 4 cases. Five ossifying fibromas were removed
      with a coronal incision. Two cases underwent Caldwell-Luc' surgery. The clinical
      symptoms, location of ossifying fibroma, and surgical procedures were analyzed.
      All patients outcomes were successful, no serious complication from the surgical
      technique occurred. Thirty-three cases were followed-up for 1 to 8 years with an
      average of three and half years. Fourteen patients had no recurrence, fourteen
      cases lived with the remains of ossifying fibroma, and five cases recurred.
      CONCLUSIONS: The choice of surgical operations on ossifying fibroma of the
      sinuses was mainly decided by the location of ossifying fibroma, in the
      meanwhile, the organ function, the cosmetology, the surgical degree of
      difficulty, and the doctor's experience were taken into account.

PMID- 15040116
TI  - [Clinical characteristics of sleep apnea-hypopnea syndrome in women].
AB  - OBJECTIVE: To realize the characteristics of symptoms and polysomnography in
      women with sleep apnea-hypopnea syndrome (SAHS) compared with that of male
      patients. METHODS: The symptoms and polysomnography were compared between men and
      women with SAHS and among mild (5 to 19 events/h), moderate (20 to 39 events/h),
      severe (> or = 40 events/h) of female patients. RESULTS: Female patients were
      older than that of male(51.1 +/- 11.2 yr versus 43.9 +/- 10.1 yr). The mean body
      mass index(BMI) for women was (27.8 +/- 3.9) kg/m2 and (28.1 +/- 3.8) kg/m2 for
      men. Women with higher AHI snored more severely, and female had a lower apnea
      hypopnea index (AHI) and apnea index (AI) but higher hypopnea index (HI) than did
      male. In addition, the respiratory events during non-rapid eye movement for men
      were significantly higher than that for women. CONCLUSION: Female patients are
      older than male but not more adipose. SAHS and respiratory events during NREM
      sleep are less severe in women.

PMID- 15040115
TI  - [Expression of cell cycle regulators in squamous cell carcinoma of maxillary
      sinus and their significance].
AB  - OBJECTIVE: To investigate the clinicopathlogical significance of cyclinE,
      cyclinD1, P21WAF1/CIP1 and P27KIP1 expression in squamous cell carcinoma of
      maxillary sinus. METHODS: The expression of cyclinE, cyclinD1, P21WAF1/CIP1 and
      P27KIP1 was examined by the method of immunohistochemistry in inflammatory mucosa
      of maxillary sinus(10), inverting papilloma of maxillary sinus(20) and squamous
      cell carcinoma of maxillary sinus (50). RESULTS: (1) In inflammatory mucosa,
      inverting papilloma and squamous cell carcinoma, the positive immunostaining
      rates of cyclinD1 protein were 10.0%, 25.0%, 48.0% respectively (P < 0.05);
      cyclinE protein was 20.0%, 35.0%, 58.0% respectively (P < 0.05); P21WAF1/CIP1
      protein was 80.0%, 65.0%, 40.0% respectively (P < 0.05) and P27KIP1 protein was
      70.0%, 75.0%, 40.0% respectively (P < 0.05). (2) There was no significance
      between the clinical type, T stage and clinical stage of carcinoma of maxillary
      sinus and the expression of cyclinD1, cyclinE, P21WAF1/CIP1 and P27KIP1 (P >
      0.05). (3) P21WAF1/CIP1 positive expression in highly, moderately and poorly
      differtiated carcinomas were 73.2% (11/15), 58.9% (11/19), 25.0% (4/16)
      respectively (P < 0.05). CONCLUSION: (1) With the development of the lesion, the
      positive immunostaining rate of cyclinE and cyclinD1 protein increases, while the
      rate of P21WAF1/CIP1 and P27KIP1 protein decreases. (2) P21WAF1/CIP1 expression
      is associated with tumour cell differentiation. (3) The mutual mechenism of cell
      cycle regulators plays an important role in the squamous cell carcinoma of
      maxillary sinus. The quantity and the frequency of four kinds of gene expression
      increase with the progression of maxillary sinus carcinogenesis.

PMID- 15040117
TI  - Poverty causes illness!

PMID- 15040118
TI  - Public health impact.

PMID- 15040119
TI  - On individualism, environmentalism, and the degree of complexity needed in
      obesity prevention: a response to Mokdad (2003).

PMID- 15040120
TI  - Comment on the obesity issue.

PMID- 15040121
TI  - Deep impact--evaluation in the sciences.
AB  - The purpose of the paper is to evaluate the psychometric properties of the impact
      factor as an assessment procedure. Detailed criteria regarding theoretical
      underpinnings, test administration, scoring and interpretation are applied. The
      impact factor appears to be of limited use for deciding which journals to
      subscribe. It is not suitable for evaluating achievements of individual
      scientists and research groups. The impact factor contains serious sources of
      errors and flaws resulting in strong biases against culture- and language-bound
      medical subspecialties and non-Anglo-American countries. Possible alternatives
      are discussed.

PMID- 15040122
TI  - The bibliographic "impact factor", the total number of citations and related
      bibliometric indicators: the need to focus on journals of public health and
      preventive medicine.

PMID- 15040123
TI  - The journal impact factor in the evaluation of research quality: villain,
      scapegoat or innocent bystander?

PMID- 15040124
TI  - Validity and fairness of the impact factor--a comment on the article by Decker et
      al.

PMID- 15040125
TI  - New horizons for impact discussions needed.

PMID- 15040126
TI  - Socio-economic differences in health among Slovak adolescents.
AB  - OBJECTIVES: To explore socio-economic health differences among Slovak
      adolescents. METHODS: Socio-economic differences in health (psychological health:
      GHQ-12, vitality and mental health scale of RAND, experienced health complaints,
      chronic illness, use of medicines, self-reported health, self-perceived
      vulnerability to illness) were explored among Slovak adolescents (n = 2,616,
      1,370 boys, 1,246 girls; mean age 15 years). RESULTS: Adolescents from lower
      socio-economic groups (parents' occupation, parents' education, type of school)
      experienced more health complaints; less frequently experienced their health as
      excellent or very good, more frequently reported to fall ill easier and less
      frequently use non-prescribed drugs in comparison with adolescents from higher
      socio-economic groups. Moreover, adolescents from lower occupational group of
      parents and lower type of school score significantly lower in mental health and
      in vitality and used prescribed drugs more frequently. We did not confirm any
      socio-economic differences in psychological health or prevalence of chronic
      illness. Our findings confirmed poorer health of girls in comparison to boys.
      There are no gender differences with regard to socio-economic differences in
      health. CONCLUSION: There are significant socio-economic health differences among
      Slovak adolescents.

PMID- 15040127
TI  - Social gradient in life expectancy and health expectancy in Denmark.
AB  - OBJECTIVES: Health status of a population can be evaluated by health expectancy
      expressed as average lifetime in various states of health. The purpose of the
      study was to compare health expectancy in population groups at high, medium and
      low educational levels. METHODS: Health interview data were combined with life
      table figures using Sullivan's method. RESULTS: Life expectancy was 4.3 years
      longer for 30-year-old men with a high educational level than for those with a
      low level. At age 30, the proportion of expected lifetime in self-rated good
      health was 67.7%, 76.1% and 82.3% for men with a low, medium and high educational
      level, respectively. Among women, life expectancy differed by 2.7 years between
      low and high educational level, and the proportion of expected lifetime in self
      rated good health was 62.5% at the low and 80.5% at the high educational level.
      CONCLUSIONS: Educational level and life expectancy are clearly related. The
      social gradient in terms of health expectancy is even greater than that in terms
      of life expectancy.

PMID- 15040129
TI  - Epidemiology and costs of gastroesophageal reflux disease in Switzerland: a
      population-based study.
AB  - OBJECTIVES: Assessment of the prevalence, health care resource use and cost of
      gastroesophageal reflux disease in Switzerland. METHODS: A population-based
      telephone survey was conducted in German and French speaking Switzerland. Reflux
      cases were defined using a questionnaire proposed by the German Gastro League and
      answered additional questions on their personal characteristics and resource use.
      RESULTS: 1,274 out of 7,222 participants were positively screened. The prevalence
      of reflux disease in Swiss adults was estimated at 17.6% (95% CI: 15.6%-19.7%) or
      993,000 individuals. Regular treatment with medication was reported by 38.0% of
      the reflux positive sample. Reflux-induced general practitioner consultations
      during the last year were reported by 25.9%. On average, there were 0.84 general
      practitioner consultations, 0.19 specialist consultations, 0.08 gastroscopies and
      0.01 hospitalisations annually. Mean direct medical costs, dominated by
      medication costs, were CHF 185 per patient-year (95% CI: CHF 140-230) or 0.5% of
      Switzerland's total health care expenditures. Total costs were CHF 234 (95% CI:
      CHF 185-284) per patient-year. CONCLUSIONS: The prevalence of reflux disease in
      Switzerland is similar to that in other industrialised countries. Reflux disease
      causes considerable costs, in the medical system and at the societal level.

PMID- 15040128
TI  - [Prevalence of physical diseases, health behavior and health care utilization in
      single homeless men: a cross sectional study].
AB  - OBJECTIVE: The aim of this cross-sectional study was to establish the prevalence
      of physical diseases, the subjective evaluation of their own health and health
      care utilization in the actually homeless and a comparison group of formerly
      homeless. METHODS: A representative sample of 82 homeless and 37 formerly
      homeless was studied. Instruments were a physical examination and a standardized
      interview. The latter included parts of the assessment of the German
      cardiovascular disease prevention study and the questionnaire
      "Funktionseinschrankungen" (functional impairments) by Potthoff (1982). RESULTS:
      Disease prevalence was high. The main diagnoses fell within the categories of
      defective dental status (over 80%), ophthalmologic diseases (over 60%) and
      diseases of the liver and musculoskeletal system (over 40% each). Morbidity in
      the formerly homeless was even higher. In both groups the subjective evaluation
      of their own health was unrealistically positive. Risk factors for cardiovascular
      diseases were high. Health care utilization was mainly acute. CONCLUSIONS: The
      medical care of the homeless in standard medical services is insufficient and
      could be improved by especially tailored projects which should include education
      about risk factors. Formerly homeless continue to show high disease prevalence.

PMID- 15040130
TI  - Public perception of risk concerning celltowers and mobile phones.
AB  - OBJECTIVE: The controversy about health risks of electromagnetic fields (EMF) has
      contributed in raising fears concerning emissions from celltowers. The study was
      to examine whether or not neighbours of celltowers are particularly concerned
      about adverse health effects of mobile phones and their base stations. METHODS:
      Prior to information delivered by medical doctors of the Institute of
      Environmental Health at public hearings a questionnaire was handed out to
      participants asking for their personal rating of several environmental health
      risks including those of mobile telecommunication (n = 123, response rate approx.
      48%). Medical students (n = 366) served as a contrast group. RESULTS:
      Participants rated health risk for both, mobile phones and celltowers higher as
      students. A trend for higher ratings was also seen with older subjects and female
      sex. The risk ratings of both exposures correlated well with each other. The
      magnitude of the perceived risks, however, resembled that of other ubiquitous
      exposures like traffic noise and air pollution. CONCLUSION: Contrary to the
      claims of the telecommunication industry, opponents of celltowers generally do
      not express unusual fears concerning electromagnetic field exposure. The outcome
      of our study indicates that the risk rating is comparable with other perceived
      common hazards of the civilised world. It is hypothesised that offering
      information and participation to the concerned population will be efficient in
      reducing exaggerated fears.

PMID- 15040131
TI  - Ethical choices in survey research.

PMID- 15040132
TI  - HHS agrees to consult on prescreening Medicaid spending.

PMID- 15040133
TI  - Perspectives. States, feds continue long squabble over Medicaid match.

PMID- 15040134
TI  - Growing pains.

PMID- 15040135
TI  - Cause and effect.

PMID- 15040136
TI  - Analysis. Acute admission.

PMID- 15040137
TI  - Clinical management. Where medicine meets management. Assistants required.
AB  - The use of US-trained physician assistants is addressing a GP shortage in the
      West Midlands and is being extended to emergency care. PAs are trained in general
      and first-contact medicine and undergo rigorous, regular re-certification.
      Birmingham University is evaluating the scheme with a view to UK-based training
      and accreditation.

PMID- 15040138
TI  - Education. Class act.
AB  - Having a course accredited by a university can add to quality and credibility. A
      project manager with both university and clinical experience will prove useful.
      Choosing the right project team and academic partner is vital.

PMID- 15040139
TI  - Mental health. Leap's early look.

PMID- 15040140
TI  - HSJ people. On the shelf.

PMID- 15040141
TI  - Effect of supplemental antioxidants vitamin C, vitamin E, and coenzyme Q10 for
      the prevention and treatment of cardiovascular disease.

PMID- 15040142
TI  - Use of glycated hemoglobin and microalbuminuria in the monitoring of diabetes
      mellitus.

PMID- 15040143
TI  - Oncology nursing research priorities: closing the circle?

PMID- 15040144
TI  - [How to find and evaluate potentially useful research instruments].

PMID- 15040146
TI  - A magical dream: a pilot project in animal-assisted therapy in pediatric
      oncology.
AB  - For children with cancer, being hospitalized represents a great source of stress.
      Hospitalized children are not only deprived of their familiar and comforting
      world, but they must also face various and often painful treatments. They must
      quickly adapt to new people and to an environment that is very different from
      that of their homes. They have greater safety needs. Thus, it is important to
      offer these children concrete ways to better adapt to the stresses of
      hospitalization. Animal-assisted therapy, considered within this project as a
      novel approach to care, constitutes an interesting solution. It involves using
      the privileged relation between children and animals to foster the process of
      adaptation to illness and the hospital environment. The experience described in
      this article is a one-year pilot project completed on a pediatric oncology unit.
      A priori, an already very heavy workload, the vulnerability of the patients, and
      many constraints added to the concerns related to the presence of animals on a
      tertiary care unit. A postiori, the rigorous design and implementation process of
      the pilot project, the strong involvement and engagement of volunteers and
      professionals, the quality of the participating "therapeutic" dogs, the
      originality of the entire process, and the satisfaction of the patients and
      nursing staff contributed to its success and to establishing the basis for a
      permanent implementation of this special care program for children hospitalized
      with cancer.

PMID- 15040147
TI  - "I just wanted to be the kid": adolescent girls' experiences of having a parent
      with cancer.
AB  - This pilot study explored the experiences of three young women who were
      adolescents when a parent was diagnosed with cancer. Semi-structured, individual
      interviews with these youths were used to discuss ways that they and their
      families were affected by cancer, as well as changes that may have made their
      experience more manageable. A thematic analysis revealed that, as adolescents,
      the girls responded to the cancer diagnosis by making their family a primary
      focus, and that this focus had positive and negative consequences for their
      development. They also highlighted several ways that parents and others can
      assist adolescents as they cope with this situation.

PMID- 15040148
TI  - Why we need oncology nurses.

PMID- 15040149
TI  - ANA's workplace advocacy program evolves into the Center for American Nurses
      (CAN).

PMID- 15040150
TI  - Tennessee Nurses Association legislative.

PMID- 15040151
TI  - [Pathogenesis of insulin resistance].
AB  - Insulin resistance characterized by a decreased biological response to insulin is
      caused by genetic and exogenous factors influencing the target tissues for
      insulin, like the muscle, adipose tissue and the liver. A hyperbolic relationship
      was found between insulin secretion and insulin action. The insulin
      hypersecretion caused by short-time B-cell stimulation with free fatty acids is
      associated with hyperinsulinemia and worsening of insulin resistance. On the
      contrary, longtime exposure of B-cells by free fatty acids is followed by a
      decreased secretion and thus by hypoinsulinemia. Triglyceride infiltration of the
      muscle tissue and B-cells further worsens the insulin resistance and impairs the
      insulin secretion. Lipotoxicity worsens the whole metabolic disorder including
      the glucose tolerance and causes apoptosis of the islet cells. Free fatty acids
      are causative factor in the pathogenesis of insulin resistance as well as of Type
      2 diabetes.

PMID- 15040152
TI  - [The metabolic syndrome].
AB  - Metabolic syndrome represents a cluster of clinical, biochemical and humoral
      abnormalities associated with impaired insulin action in glucose metabolism. In
      the literature also the term syndrome of insulin resistance, dysmetabolic
      syndrome X, Reaven syndrome or Kaplans dead quartet can be found.
      Hyperinsulinaemia, central obesity, essential hypertension, dyslipidaemia,
      impaired glucose homeostasis or type 2 diabetes, hyperuricaemia, hypercoagulable
      state, endothelial dysfunction and increased markers of inflammation such as C
      reactive protein, selectines, adhesion molecules, pro-inflammatory cytokines are
      the typical components of metabolic syndrome increasing the risk of
      cardiovascular complications. List of currently recognized clinical and
      biochemical manifestations continues to expand and include also non-alcoholic
      steatohepatitis, polycystic ovaric syndrome (PCOS), hyperhomocysteinaemia and
      others. No standard definition of metabolic syndrome has been routinely used. The
      WHO initially proposed a definition of metabolic syndrome in 1998, and more
      recently NCEP-ATP III provided a new working definition in 2001, which is more
      suitable for clinical practice. Prevalence of metabolic syndrome is very high,
      about 25-30% in Caucasians, depending on diagnostic criteria used. The clinical
      significance of metabolic syndrome is augmented by its association with increased
      and accelerated atherosclerosis. Whether IR predicts cardiovascular disease (CVD)
      independently of diabetes and other CVD risk factors is still a matter of
      controversy. Recently there is a growing evidence that metabolic syndrome
      increases also the risk of all-cause mortality and risk of certain tumors.

PMID- 15040153
TI  - [Postprandial hyperglycemia].
AB  - Chronic hyperglycaemia, confirmed with HbA1c levels, is a leading cause of
      diabetic complications. Recent studies point to a significant effect of
      postprandial glycaemia which results from an impaired ability of early secretion
      of insulin in type II diabetes. Postprandial hyperglycaemia is a frequent
      phenomenon in people with diabetes with satisfactory control of diabetes based on
      checks of HbA1c levels. Many authors demonstrate statistically more significant
      correlations between postprandial hyperglycaemia and HbA1c levels, compared to
      correlation of fasting glycaemia. Monitoring of postprandial glycaemia is a
      significant means for improving co-operation with a patient and provides a
      physician with a possibility of choice between an appropriate type of peroral
      antidiabetic or insulin.

PMID- 15040154
TI  - [Diabetic peripheral arterial disease].
AB  - Macrovascular impairment of peripheral arteries in diabetes mellitus corresponds
      with such an impairment in atherosclerosis. Furthermore, peripheral angiopathy,
      microangiopathy, and polyneuropathy resulting from microangiopathy develop in
      diabetes. Impairment of microcirculation worsens peripheral blood flow. Infection
      and insufficient trophism worsen state. A wide range of factors participate in
      development of vascular disease in diabetes with adverse influence both on veins
      and reactions coming under rheology, haemocoagulation, and immune reactions. In
      type II diabetes an average interval of arterial impairment is 9-10 years, in
      type I diabetes approximately 17-22 years. A relative risk of non-traumatic
      amputation of a lower limb in diabetics is several times higher than in non
      diabetics. A prevention of lower limbs impairment in diabetics is the most
      efficient method of reducing risk of amputation. An intervention therapy,
      endovascular intervention or angiosurgery are indicated in patients with clinical
      problems. A state of distal bed is an important factor for success of
      interventions. As a pivotal drug treatment in intervention and traditional
      methods is considered an effective antiaggregation treatment. A diabetic
      peripheral arterial disease is a complex disease requiring a wide view and
      considering various and changing pathophysiological mechanisms.

PMID- 15040155
TI  - [Diabetes mellitus cerebrovascular disease].
AB  - Cerebral vascular accident (CVA) is the second leading cause of deaths in
      developed countries. The mortality rate from CVA in the Czech Republic in people
      under 65 years is twice higher compared to countries in Western and Northern
      Europe. Every year it affects about 500/100,000 citizens with mortality within
      one year approximately in 45%. Incidence of this serious disease is three times
      more frequent in diabetics than in non-diabetics. After ictus, the prognosis is
      worse and repeated cerebral strokes more frequent. From the risk factors,
      diabetics usually suffer from hypertension which is part of a complex of
      metabolic syndrome X. There are more frequent carotid stenoses and impaired tiny
      arteries in diabetics compared to non-diabetic population. Recently, it has been
      pointed at an importance of early detection of hyperglycaemia in ischemic brain
      accidents, because hyperglycaemia seriously affects ischemic brain tissue. Apart
      from other things, it leads to impairment of motor functions. A specialist
      providing care to diabetics must consider and start treatment of all the risk
      factors. Under ideal conditions, every diabetic should be excellently compensated
      and have normal blood pressure values, low concentrations of LDL cholesterol, and
      should be treated with ACE inhibitor at the same time as with acetylsalicylic
      acid and clopidogrel.

PMID- 15040156
TI  - [The heart in diabetics].
AB  - Macrovascular complications in diabetics create a high risk for cardiovascular
      disease (CVD). Generally, the main risk factors for CVD include age, men's sex,
      elevated LDL-cholesterol and reduced HDL-cholesterol, elevated fibrinogen,
      hypertension, smoking, and diabetes mellitus. Clinical manifestation of coronary
      disease is determined by number, area, and severity of coronary stenoses,
      myocardial function, and presence of induced ischemia. Routine pharmacological
      treatment of ISHD concentrates on risk factors and hasn't been yet focused on
      changes in energy metabolism during ischemic situation which are important
      factors contributing to ischemic damage. Substances able to optmize energy
      metabolism of heart muscle offer a very tempting way both for ISHD treatment and
      for treatment of following cardiovascular complications. Optimal use of energy
      source in heart muscle can favour heart activity so that comparable amount of
      contractile work requires less oxygen. The most beneficial way of getting energy
      for myocardium while low consumption of oxygen is oxidation of glucose. Because
      of a large amount of free fatty acids (FFAs) in diabetics a more demanding way of
      oxidation takes place in them, the oxidation of FFAs. Therefore myocardium of a
      diabetic needs under normal perfusion conditions more oxygen to provide energy.
      Besides increase in demand of oxygen, FFAs separate glycolysis from glucose
      oxidation and increase undesirable production of lactate and protons. An ischemic
      myocardium of a diabetic has primarily bigger demand of oxygen then myocardium of
      a non-diabetic. Development of cell ischemia, with all the known consequences in
      forms of lactate acidosis, calcium overload, and depletion of ATP, leads to
      considerable contractile disorder. Unfavourable position of metabolic activities
      in myocardium of diabetics and faster and more serious progression of
      atherosclerosis result in a big risk of CVD in diabetics. Incidence of coronary
      events in diabetics without history of ISHD is as big as in non-diabetics with
      history of coronary events.

PMID- 15040157
TI  - [Diabetes mellitus and chronic heart failure].
AB  - Diabetes mellitus is one of the significant risk factors for many cardiovascular
      diseases. Diabetes mellitus is 3-4 times more frequent in patients with heart
      failure compared to patients without heart failure. Prognosis of patients with
      heart failure and diabetes mellitus is worse than prognosis of non-diabetic
      patients with the same left ventricular dysfunction. The term diabetic
      cardiomyopathy refers to a relation between diabetes mellitus and heart disease,
      but it probably isn't a separate morphology unit. In treatment of patients with
      diabetes mellitus general rules apply to heart failure management. The effect of
      ACE inhibitors was in majority of studies stronger in diabetics than in non
      diabetics, the effect of beta blockers was comparable or smaller. Treatment is
      based on good compensation of metabolic parameters, blood pressure, titration of
      ACE inhibitors into recommended doses, and an optimal dose of a beta blocker.
      Type II diabetics with heart failure will, due to decreased resorption and
      metabolism, need insulin more often than diabetics without heart failure.

PMID- 15040158
TI  - [Hypertension and diabetes--current views on specific questions].
AB  - Hypertension in patients with diabetes is proved to be connected with early
      development of macrovascular and atherosclerotic complications, increased
      incidence of heart failures, and development and progression of microangiopathic
      complications. We start interventions in diabetics when blood pressure values
      reach 140/90 mm Hg. Non-pharmacological treatment is often unsuccessful, so we
      apply pharmacological treatment. The target value of blood pressure does not
      exceed 130/80 mm Hg. Monotherapy is usually insufficient. Individual drugs we
      choose according to attendant complications, according to a potential benefit
      from affecting individual risks for a patient's prognosis.

PMID- 15040159
TI  - [Ambulatory monitoring of blood pressure in the treatment of hypertension in
      diabetics].
AB  - Hypertension, the most significant cardiovascular risk factor, appears twice more
      often in persons with diabetes compared to nondiabetic population. A high
      percentage of complications (40-70%) in diabetic population is caused just by
      hypertension. That is why timely diagnosis and consistent treatment of
      hypertension is stressed in patients with diabetes. Blood pressure of young
      people with type I diabetes is proved to be higher compared to their healthy
      peers. Both in people with type I and type II diabetes are, compared to other
      populations, more frequent incidence of a phenomenon called "white coat",
      increased variability in blood pressure, and higher percentage of non-dippers
      with high blood pressure. They are on a higher risk for diabetic nephropathy and
      its quicker progression. Therefore it is desirable to start medication and alter
      its combination after confirming blood pressure values by ambulatory monitoring
      so that the blood pressure is well controlled not only by day but also during
      sleep and early in the morning.

PMID- 15040160
TI  - [Dyslipidemia and the metabolic syndrome].
AB  - Dyslipoproteinemia is the common part of metabolic syndrome, it appears probably
      due tu high level of free fatty acids. The typical lipid disorders are: high
      trigylcerides concentration, low HDL-cholesterol level, elevation of small dense
      LDLs particles and elevation of apolipoprotein B100 and non-HDL cholesterol. LDL
      cholesterol concentration is usually normal. This type of dyslipoproteinemia is
      very aterogenic. Weight reduction, diet and regular physical activity is the most
      effective way how to treat this type of dyslipoproteinemia. When non
      pharmacologic treatment is not successful, treatment with hypolipidemic drugs is
      necessary to prevent atherosclerotic complications. Fibrates are recommended in
      typical dyslipidemia to lower high triglycerides level and to elevated low HDL
      cholesterol concentration. But when high LDL-cholesterol is present, statins are
      needed. In some patients with combined hyperlipidemia treating with fibrate and
      statin together is needed to reach target lipid levels.

PMID- 15040161
TI  - [Angiotensin converting enzyme inhibitors in the treatment of diabetes].

PMID- 15040163
TI  - [Obesity and diabetes].
AB  - This paper discuses issues of obesity and type II diabetes mellitus. It tries to
      demonstrate a common cause of both these signs of metabolic syndrome. It notices
      the relationship of obesity and diabetes and summarises possibilities, successes,
      and goals in treatment of obesity in diabetics.

PMID- 15040162
TI  - [Low birth weight and delayed risk of type 2 diabetes and metabolic syndrome].
AB  - Low birth weight is according to many studies associated with later incidence of
      type 2 diabetes, hypertension and in lower degree with obesity and
      hypertriacylglycerolemia. Detection of history of low birth weight could have
      some importance in detection of persons with metabolic syndrome and
      cardiovascular risk. In the pathogenesis can be involved fetal selection of
      thrifty genes which are later unable to overcome low physical activity and
      overfeeding in adult age. More probable is that low birth weight is primary of
      genetic origin. The same genetic origin can be involved in BMI rebound in
      childhood, development of insulin resistance, weight gain and later incidence of
      metabolic syndrome and type 2 diabetes. Detection of all these phenomena is
      important in selecting patients in diabetes and cardiovascular risk for
      preventive intervention.

PMID- 15040164
TI  - [Infectious and inflammatory factors in the etiology and pathogenesis of
      atherosclerosis].
AB  - Although the metabolic syndrome together with insulin resistance and their
      consequences are probably basic factors in pathogenesis of atherosclerosis,
      inflammatory and infectious aspects of this process are unquestionable only in
      some of the patients. Endothelial dysfunction was identified both in the
      experiment and in patients after herpes virus simplex 1 infection,
      cytomegaloviral infection, Chlamydia pneumoniae infection, or Helicobacter pylori
      infection. However, it is not clear whether it is always caused by direct
      specific activity of a given pathogen or whether it is a result of inflammatory
      cytokines activity, heat shock protein activity, or CRP activity. In recent years
      secondary antibiotic prevention in patients after myocardial infarction has been
      discussed. Lower mortality rate from acute myocardial infarction and cerebral
      vascular accidents were found in several observations of patients vaccinated
      against influenza. In patients with non-stable angina pectoris we have found
      significantly more frequent occurrence of IgG antibodies against Chlamydia
      pneumoniae. This occurrence was more frequent in diabetics compared to non
      diabetics. Endothelia exposed to cyto-megaloviral infection exprimed adhesive
      molecules on their surfaces. After an increase of the concentration of glucose in
      medium to 11.0 mmol/l and 16.5 mmol/l the expression of adhesive molecules after
      cyto-megaloviral infection increased. Relationship of infection, inflammation,
      and atherosclerosis has been a subject of intensive investigation in recent
      years. Discussion of possible consequences of these findings, especially from
      viewpoint of atherosclerosis prevention and its organ complications, is of the
      same intensity. Hypothesis about participation of infection and inflammation in
      pathogenesis of atherosclerosis seems to be very attractive. In spite of the fact
      that findings supporting this hypothesis cumulate final conclusion can't be made
      yet.

PMID- 15040165
TI  - [The carotid drainage system--a "window" into the atherosclerosis process in
      diabetics?].
AB  - Macrovascular complications present from the viewpoint of morbidity and mortality
      the biggest risk in type 2 diabetics. An aim of this work is to show ways of
      detecting clinical and preclinical phases of atherosclerosis with special regard
      to carotid system. In our paper we have been presenting a sample of 239 patients
      with cardiovascular incidents and findings on their extracranial carotid systems
      detected by duplex sonography. 88 patients (36.8%) in the sample had type 2
      diabetes, their average age was 68.2 +/- 8.5. 35 were on a diet, 34 were treated
      with peroral antidiabetics, and 19 with insulin. Findings on extracranial carotid
      systems were normal in 27.3% of diabetics, in stenoses up to 50% was lumen in
      50%, in stenoses 51-70% was lumen in 15.9%, and in stenoses 71-95% was lumen in
      6.8% (compared to 3.9 in nondiabetics). Intimomedial thickness (IMT) in a group
      with positive microalbuminuria was 0.9 +/- 0.3 mm and in a group with negative
      microalbuminuria 0.87 +/- 0.18 mm. Intimomedial thickness (IMT) and
      microalbuminuria (MAU) are the markers of risk for atherosclerosis and enable to
      detect preclinical stages of atherosclerosis. Another enzyme indicated in the
      process of atherosclerosis is PAPP-A, an indicator of plaque instability. Early
      detection and early intervention of the atherosclerotic process can prevent
      growth of atherosclerosis, especially during epidemic increase of type 2
      diabetes.

PMID- 15040167
TI  - A new beginning....
AB  - Microbiology is at the beginning of an exciting new era with enormous potential.
      Whether this potential is maximized is a question of communication.

PMID- 15040166
TI  - [Therapeutic use of acetylsalicylic acid in diabetics].
AB  - Aterosclerosis is a leading cause of morbidity and mortality in diabetics.
      Macrovascular diseases--myocardial infarction, cerebral vascular accident,
      ischemic lower extremities--start in persons with diabetes earlier and in a
      bigger scope then in non-diabetics. Development of these changes is determined by
      diabetic vasculopathy which is connected with endothelial dysfunction,
      hypercoagulation state, and platelet abnormalities. Treatment of a patient with
      diabetes is based on compensation of diabetes and management of hypertension and
      dyslipidaemia. Drugs that inhibit platelets constitute an important part of
      prevention of cardiovascular disabilities in diabetics.

PMID- 15040174
TI  - The value of comparison.
AB  - With the number of published microbial genomes now in excess of 100, any new
      genome that is sequenced is likely to have a close relative available for
      comparison. Indeed, it is increasingly difficult to perform any genomic analysis
      that is not comparative. This should, however, not be seen as a drawback; it is
      often the case that a large amount of information can be drawn from these
      comparisons, especially between closely related organisms. Several genome
      sequences published recently indicate the value of comparisons at the genomic
      level.

PMID- 15040175
TI  - Chagas disease.

PMID- 15040176
TI  - The damage-response framework of microbial pathogenesis.
AB  - The late twentieth century witnessed the emergence of numerous infectious
      diseases that are caused by microorganisms that rarely cause disease in normal,
      healthy immunocompetent hosts. The emergence of these diseases shows that the
      existing concepts of pathogenicity and virulence do not take into account the
      fact that both the microorganism and the host contribute to microbial
      pathogenesis. To address this impediment to studies of host-microorganism
      interactions, we propose a new theoretical approach to understanding microbial
      pathogenesis, known as the 'damage-response' framework.

PMID- 15040177
TI  - Inhibiting sexual transmission of HIV-1 infection.
AB  - The worldwide infection rate for HIV-1 is estimated to be 14,000 per day, but
      only now, more than 20 years into the epidemic, are the immediate events between
      exposure to infectious virus and the establishment of infection becoming clear.
      Defining the mechanisms of HIV-1 transmission, the target cells involved and how
      the virus attaches to and fuses with these cells, could reveal ways to block the
      sexual spread of the virus. In this review, we will discuss how our increasing
      knowledge of the ways in which HIV-1 is transmitted is shaping the development of
      new, more sophisticated intervention strategies based on the application of
      vaginal or rectal microbicides.

PMID- 15040178
TI  - Cleaning up with genomics: applying molecular biology to bioremediation.
AB  - Bioremediation has the potential to restore contaminated environments
      inexpensively yet effectively, but a lack of information about the factors
      controlling the growth and metabolism of microorganisms in polluted environments
      often limits its implementation. However, rapid advances in the understanding of
      bioremediation are on the horizon. Researchers now have the ability to culture
      microorganisms that are important in bioremediation and can evaluate their
      physiology using a combination of genome-enabled experimental and modelling
      techniques. In addition, new environmental genomic techniques offer the
      possibility for similar studies on as-yet-uncultured organisms. Combining models
      that can predict the activity of microorganisms that are involved in
      bioremediation with existing geochemical and hydrological models should transform
      bioremediation from a largely empirical practice into a science.

PMID- 15040179
TI  - Coupling cell movement to multicellular development in myxobacteria.
AB  - The myxobacteria are Gram-negative organisms that are capable of multicellular,
      social behaviour. In the presence of nutrients, swarms of myxobacteria feed
      cooperatively by sharing extracellular digestive enzymes, and can prey on other
      bacteria. When the food supply runs low, they initiate a complex developmental
      programme that culminates in the production of a fruiting body. Myxobacteria move
      by gliding and have two, polarly positioned engines to control their motility.
      The two engines undergo coordinated reversals, and changes in the reversal
      frequency and speed are responsible for the different patterns of movement that
      are seen during development. The myxobacteria communicate with each other and
      coordinate their movements through a cell-contact-dependent signal. Here, the
      cell movements that culminate in the development of the multicellular fruiting
      body are reviewed.

PMID- 15040180
TI  - The yersiniae--a model genus to study the rapid evolution of bacterial pathogens.
AB  - Yersinia pestis, the causative agent of plague, seems to have evolved from a
      gastrointestinal pathogen, Yersinia pseudotuberculosis, in just 1,500-20,000
      years--an 'eye blink' in evolutionary time. The third pathogenic Yersinia,
      Yersinia enterocolitica, also causes gastroenteritis but is distantly related to
      Y. pestis and Y. pseudotuberculosis. Why do the two closely related species cause
      remarkably different diseases, whereas the distantly related enteropathogens
      cause similar symptoms? The recent availability of whole-genome sequences and
      information on the biology of the pathogenic yersiniae have shed light on this
      paradox, and revealed ways in which new, highly virulent pathogens can evolve.

PMID- 15040181
TI  - Where will new antibiotics come from?
AB  - There is a constant need for new antibacterial drugs owing to the inevitable
      development of resistance that follows the introduction of antibiotics to the
      clinic. When a new class of antibiotic is introduced, it is effective at first,
      but will eventually select for survival of the small fraction of bacterial
      populations that have an intrinsic or acquired resistance mechanism. Pathogens
      that are resistant to multiple drugs emerge around the globe, so how robust are
      antibiotic discovery processes?

PMID- 15040182
TI  - Bioterrorism and biodefence research: changing the focus of microbiology.
AB  - Fear that terrorists can use biological agents as weapons of mass destruction is
      significantly impacting the conduct of microbiological research. Abundant new
      funds are available for biodefence research, and many researchers are racing to
      enter the field. There are some concerns, however, that a large emphasis on this
      issue could skew the microbiology research agenda. Furthermore, new
      responsibilities for safely conducting research with biothreat agents and concern
      that information might be misused could drive some researchers away from the
      field.

PMID- 15040184
TI  - Leading during times of trouble: a roundtable discussion of recent terror events.

PMID- 15040185
TI  - If syndromic surveillance is the answer, what is the question?

PMID- 15040186
TI  - Government controls of information and scientific inquiry.

PMID- 15040183
TI  - Discovering viroids--a personal perspective.
AB  - During 1970 and 1971, I discovered that a devastating disease of potato plants is
      not caused by a virus, as had been assumed, but by a new type of subviral
      pathogen, the viroid. Viroids are so small--one fiftieth of the size of the
      smallest viruses--that many scientists initially doubted their existence. We now
      know that viroids cause many damaging diseases of crop plants. Fortunately, new
      methods that are based on the unique properties of viroids now promise effective
      control.

PMID- 15040187
TI  - Anthrax 2001: observations on the medical and public health response.

PMID- 15040189
TI  - Microbial forensics: building a national capacity to investigate bioterrorism.

PMID- 15040188
TI  - The anthrax epidemiologic tool kit: an instrument for public health preparedness.

PMID- 15040190
TI  - High-throughput laboratories for Homeland and National Security.

PMID- 15040191
TI  - Validating the performance of biological detection equipment: the role of the
      federal government.

PMID- 15040192
TI  - The psychological impacts of bioterrorism.

PMID- 15040193
TI  - Interview with Michael Goldblatt, Director, Defense Sciences Office, DARPA.
      Interview by John Travis.

PMID- 15040194
TI  - Biotechnology: impact on biological warfare and biodefense.
AB  - Advances in biological research likely will permit development of a new class of
      advanced biological warfare (ABW) agents engineered to elicit novel effects. In
      addition, biotechnology will have applications supporting ABW weaponization,
      dissemination, and delivery. Such new agents and delivery systems would provide a
      variety of new use options, expanding the BW paradigm. Although ABW agents will
      not replace threats posed by traditional biological agents such as Bacillus
      anthracis (anthrax) and Variola (smallpox), they will necessitate novel
      approaches to counterproliferation, detection, medical countermeasures, and
      attribution.

PMID- 15040195
TI  - Vaccine liability in the era of bioterrorism.

PMID- 15040196
TI  - Public resistance or cooperation? A tale of smallpox in two cities.

PMID- 15040197
TI  - Biodefense R&D: anticipating future threats, establishing a strategic
      environment.

PMID- 15040198
TI  - The pace and proliferation of biological technologies.

PMID- 15040199
TI  - The challenge of hospital infection control during a response to bioterrorist
      attacks.

PMID- 15040200
TI  - Aerosols from insect control measures show dangers of bioterrorism.

PMID- 15040201
TI  - Homeland insecurity: building the expertise to defend America from bioterrorism.

PMID- 15040203
TI  - The Kay report to congress on the activities of the Iraq Survey Group: former
      bioweapons inspectors comment.

PMID- 15040202
TI  - Interview with David L. Heymann, MD, representative for polio eradication and
      former Executive Director, Communicable Diseases, World Health Organization.
      Interview by Madeline Drexler.

PMID- 15040204
TI  - Syndromic surveillance: the case for skillful investment.

PMID- 15040205
TI  - Evaluating the success of terror risk communications.

PMID- 15040206
TI  - Sources of bioterrorism information among emergency physicians during the 2001
      anthrax outbreak.

PMID- 15040207
TI  - New York City's communication trials by fire, from West Nile to SARS.

PMID- 15040208
TI  - The role of schools in meeting community needs during bioterrorism.

PMID- 15040210
TI  - Interview with Julie L. Gerberding, M.D., M.P.H. Director, Centers for Disease
      Control and Prevention. Interview by Madeline Drexler.

PMID- 15040209
TI  - Toward biosecurity.

PMID- 15040211
TI  - Iraq's bio-warfare option: last resort, preemption, or a blackmail weapon?

PMID- 15040212
TI  - Biosecurity: responsible stewardship of bioscience in an age of catastrophic
      terrorism.

PMID- 15040213
TI  - Potential for aerosol dissemination of biological weapons: lessons from
      biological control of insects.

PMID- 15040214
TI  - Under siege: one state's perspective of the Anthrax events of October/November
      2001.

PMID- 15040215
TI  - Ethical considerations in the formation of smallpox vaccine policy.

PMID- 15040216
TI  - Key information regarding smallpox vaccine.

PMID- 15040217
TI  - [Main topics of SBK 2004].

PMID- 15040218
TI  - [Violence and social bonding. Not being heard engenders violence].

PMID- 15040219
TI  - [Violence in home nursing. Without guilt facing blame].

PMID- 15040220
TI  - [Violence toward the elderly. Response to failed relationship].

PMID- 15040221
TI  - [Economizing by the health care system. The costs and value of nursing].

PMID- 15040222
TI  - [Salary equality process of Geneva nurses. With full speed back to the 19th
      century].

PMID- 15040223
TI  - [The snow crunches under the soles].

PMID- 15040224
TI  - ["Being there cannot be quantified" (interview by Margrit Bachl)].

PMID- 15040225
TI  - [Independence of elderly women. "Maintaining balanced position"].

PMID- 15040226
TI  - [Preventing violence: a practical approach. "This is enough"].

PMID- 15040227
TI  - [From the struggle of classes to the struggle of places].

PMID- 15040228
TI  - [The era of "travelers of the fronteer"].

PMID- 15040229
TI  - [Nursing care will must maintain a expanded vision (interview by Josianne Bodart
      Senn)].

PMID- 15040230
TI  - [Changing the role and acquiring a new identity. Nursing expert to novice in
      training].

PMID- 15040231
TI  - Alpha 1-antitrypsin deficiency causing cirrhosis--case series.

PMID- 15040232
TI  - Utilization of the Dementia Rating Scale-2 and cognitive enhancers in the
      diagnosis and treatment of cognitive disorders and dementia.

PMID- 15040234
TI  - The impact of mental disability on modern history.

PMID- 15040233
TI  - Hospitalizations and emergency room visits for acute pesticide poisonings in
      South Carolina, 1997-2001.

PMID- 15040235
TI  - Advancing medical professionalism. I. Our public image.

PMID- 15040236
TI  - Perspectives. Medicaid revenue prescreening: fiscal prudence or sea change?

PMID- 15040237
TI  - Chronic kidney disease: making a case for early intervention.

PMID- 15040238
TI  - Unique partnership makes a solid case for on-site DM.
AB  - Don't discount such factors as high visibility and easy access when putting
      together your DM program. These advantages figured strongly into the development
      of a unique diabetes program in Massachusetts that is actually making a profit
      for the provider group that funds the program. In fact, the effort has gotten so
      much positive attention that other practices are now referring patients to the
      program.

PMID- 15040239
TI  - Unique vendor makes the case for a different kind of DM.
AB  - Most health plans lack the resources to manage rare and complex diseases with any
      degree of sophistication. However, a Greensboro, NC-based vendor that specializes
      in this arena is showing there is ample opportunity for cost savings, although
      demonstrating value with regards to clinical and functional indicators can be a
      challenge with these types of patients.

PMID- 15040240
TI  - New five-item questionnaire gives physicians added insight into asthma control.
AB  - There is ample evidence that many PCPs do not, in fact, adequately understand the
      extent to which asthma is impacting their patients' lives. Part of the problem
      has been the lack of any quick and efficient measuring tool. Now, however, a five
      item screen has been developed that is showing early promise for delivering just
      this type of information. Check out the Asthma Control Test.

PMID- 15040241
TI  - [Georges Christoffel Maria Evers--departure of a pioneer in nursing science].

PMID- 15040242
TI  - [The manner of care, self care and quality of life dialysis patients].
AB  - BACKGROUND: The aim of this cross-sectional study was to describe specific
      strategies used by ESRD patients to manage their illness on their own behalf in
      order to attain their health goals, promote personal development and well-being.
      METHODS: A representative sample of 178 patients on dialysis of the Swiss German
      speaking population was selected. The participants were treated in-centre on
      hemodialysis (HD) or had ambulatory peritoneal dialysis (CAPD). Data collection
      procedure for specific self-care activities was structured interviews. Self-care
      capabilities were measured with the ASA-scale and well-being was rated on the
      Cantril's ladder. RESULTS: Both patient groups were comparable on demographics,
      severity of illness except for dialysis duration, social support and general self
      care capabilities. Both patient groups scored their subjective well-being 7 or
      higher on a scale of 10. There was a significant positive correlation between
      amount of dialysis self-care and subjective well-being. There was no difference
      in effectiveness of dialysis self-care between in-centre HD and CAPD patients.
      CONCLUSION: The results demonstrate that patients in this study perform a
      substantial amount of self-care and perceive their subjective well-being as good.
      These findings indicate that treatment modalities both of HD and CAPD provide
      equal opportunities for quality of life if patient selection is based on history
      of renal disease, available social support and self-care capabilities.

PMID- 15040243
TI  - [Discomfort of the bed pan--translating and evaluating the Belgian Bedpan Ongemak
      Schaal (BOS)].
AB  - The systematic translation of standardized instruments is an alternative method
      to the development of an own instrument. Neither German nor English literature
      provide an answer to the patient view of the discomfort of bedpans. Therefore the
      Belgian Bedpan Ongemak Schaal((BOS) was translated into German. To maintain the
      content validity of the instrument is of utmost importance when translating it
      into a foreign language. It is important too that the new instrument is
      understandable and easy to handle. The translation of the Bedpan Ongemak
      Schaal((BOS) shows that it is possible to transfer an instrument from one
      language to another without losing validity and feasibility.

PMID- 15040244
TI  - [Development of the "Whittener Activity Catalog of Self-Care in Venous Ulcer"].
AB  - Poor rates of healing and high rates of re-ulceration are characteristic of
      venous leg ulcer. The performing of special health-deviation self-care is
      important for the successful treatment and prevention of this chronic disease.
      This study aimed to validate a newly designed instrument for the measurement of
      specific self-care. The "Wittener Aktivitatenkatalog der Selbstpflege bei venos
      bedingten offenen Beinen" (WAS-VOB) (a catalogue containing self-care activities
      for venous leg ulcer) was conceptualized on the basis of Orem's theory and on
      pathophysiological processes. The items were created by using patient interviews
      (n = 20) and a literature review. An analysis of the reliability was used to
      reduce the raw scale. The quality of the WAS-VOB was assessed for face-validity
      (n = 6), feasibility (n = 8), test-retest-reliability (n = 60) and the internal
      consistency (n = 234). The involvement of patients was based on an informed
      consent. The WAS-VOB is a self-describing instrument, includes 59 self-care
      activities and describes those in eight scales which deal with "general
      compression", "wearing compression bandages", "wearing compression hosiery",
      "mobility", "temperature", "overload of the venous system", "prevention of skin
      damage" and "wound healing". The WAS-VOB is practicable and has good psycho
      metric characteristics. The test-retest-coefficient (Kendall's tau b) is 0.58,
      Cronbach's alpha 0.72. The instrument WAS-VOB is suitable for the assessment of
      self-care deficits.

PMID- 15040245
TI  - [Quality criteria of assessment scales--Cohen's kappa as measure of interrator
      reliability (1)].
AB  - A far spread index for the quantification of the interrater-reliabilty of
      assessment instruments or procedures is the chance-corrected agreement measure
      "Cohen's Kappa". Although or even though Cohen's Kappa proves to be a common
      measure of agreement of two raters, it is increasingly being used uncritically.
      Many authors, but also readers don't seem to take the central and paradox
      characteristics of Kappa into consideration for the interpretation of their
      results. The article intends to introduce Cohen's Kappa to a wide range of
      readers. The implicit assumptions that are related to the chance correction and
      to the typical and paradox characteristics of Kappa are presented and explained
      in detail. This is in particular, when results of an investigation reveal
      particularly high values of observer agreement but low value of Cohen's Kappa or
      when differences in the overall assessment can even lead to an increase of Kappa.
      Only the knowledge about these characteristics makes a meaningful presentation
      and interpretation of the results of reliability studies possible. In a following
      second part of this paper, practicable alternatives to the problem areas
      presented and paradox characteristics of Kappa will be shown.

PMID- 15040246
TI  - [Christen Lisanne et al. Nursing with and without ether oils (Pflege 4/2003).
      Response to the letter by Prof. Klaus-Dieter Neander (Pflege 5/2003)].

PMID- 15040247
TI  - NHS--time to clean up your act.
AB  - Hospital-acquired infection in the NHS is an urgent problem that requires
      immediate action at the level of patient care.

PMID- 15040248
TI  - Better the devil you know.

PMID- 15040249
TI  - Vesicles in virulence.

PMID- 15040250
TI  - Regulating osmosensing.

PMID- 15040251
TI  - Proteasome power.

PMID- 15040252
TI  - Curl up with Caulobacter.

PMID- 15040253
TI  - Pathogenic E. coli--getting intimate.

PMID- 15040254
TI  - Pathogens mind out!

PMID- 15040255
TI  - Ascending to a UTI vaccine?

PMID- 15040256
TI  - Unlocking chitin degradation.

PMID- 15040257
TI  - Pathogenomics of non-pathogens.
AB  - Analysing the genomes of non-pathogenic microorganisms, in addition to its basic
      and applied scientific interest, can also shed considerable light on the study of
      pathogenic microorganisms. Two of the three microorganisms described here are
      rarely pathogenic, but carry genetic determinants that have previously been
      identified as being important for the pathogenicity of other microorganisms. This
      underlines the growing understanding that many so-called 'virulence genes' are
      probably involved in more general interactions between the microorganism and the
      host or the environment.

PMID- 15040258
TI  - SARS.

PMID- 15040259
TI  - Bacterial biofilms: from the natural environment to infectious diseases.
AB  - Biofilms--matrix-enclosed microbial accretions that adhere to biological or non
      biological surfaces--represent a significant and incompletely understood mode of
      growth for bacteria. Biofilm formation appears early in the fossil record
      (approximately 3.25 billion years ago) and is common throughout a diverse range
      of organisms in both the Archaea and Bacteria lineages, including the 'living
      fossils' in the most deeply dividing branches of the phylogenetic tree. It is
      evident that biofilm formation is an ancient and integral component of the
      prokaryotic life cycle, and is a key factor for survival in diverse environments.
      Recent advances show that biofilms are structurally complex, dynamic systems with
      attributes of both primordial multicellular organisms and multifaceted
      ecosystems. Biofilm formation represents a protected mode of growth that allows
      cells to survive in hostile environments and also disperse to colonize new
      niches. The implications of these survival and propagative mechanisms in the
      context of both the natural environment and infectious diseases are discussed in
      this review.

PMID- 15040260
TI  - Pathogenic Escherichia coli.
AB  - Few microorganisms are as versatile as Escherichia coli. An important member of
      the normal intestinal microflora of humans and other mammals, E. coli has also
      been widely exploited as a cloning host in recombinant DNA technology. But E.
      coli is more than just a laboratory workhorse or harmless intestinal inhabitant;
      it can also be a highly versatile, and frequently deadly, pathogen. Several
      different E. coli strains cause diverse intestinal and extraintestinal diseases
      by means of virulence factors that affect a wide range of cellular processes.

PMID- 15040261
TI  - Tapping into microbial diversity.
AB  - Even though significant advances have been made in understanding microbial
      diversity, most microorganisms are still only characterized by 'molecular
      fingerprints' and have resisted cultivation. Many different approaches have been
      developed to overcome the problems associated with cultivation of microorganisms
      because one obvious benefit would be the opportunity to investigate the
      previously inaccessible resources that these microorganisms potentially harbour.

PMID- 15040262
TI  - What does the future hold for clinical microbiology?
AB  - In the past decade, clinical microbiology laboratories have undergone important
      changes with the introduction of molecular biology techniques and laboratory
      automation. In the future, there will be a need for more rapid diagnoses,
      increased standardization of testing and greater adaptability to cope with new
      threats from infectious microorganisms, such as agents of bioterrorism and
      emerging pathogens. The combination of the new tools that are now being developed
      in research laboratories, the general reorganization of clinical laboratories and
      improved communication between physicians and clinical microbiologists should
      lead to profound changes in the way that clinical microbiologists work.

PMID- 15040263
TI  - Electronic noses and disease diagnostics.
AB  - Rapid developments in sensor technology have facilitated the production of
      devices--known as electronic noses--that can detect and discriminate the
      production profiles of volatile compounds from microbial infections in situ. Such
      qualitative and semi-quantitative approaches could have a significant role in the
      early diagnosis and detection of microbial diseases. Using artificial
      intelligence and web-based knowledge systems, electronic noses might also have a
      valuable role in monitoring disease epidemiology.

PMID- 15040264
TI  - Population and evolutionary dynamics of phage therapy.
AB  - Following a sixty-year hiatus in western medicine, bacteriophages (phages) are
      again being advocated for treating and preventing bacterial infections. Are
      attempts to use phages for clinical and environmental applications more likely to
      succeed now than in the past? Will phage therapy and prophylaxis suffer the same
      fates as antibiotics--treatment failure due to acquired resistance and ever
      increasing frequencies of resistant pathogens? Here, the population and
      evolutionary dynamics of bacterial-phage interactions that are relevant to phage
      therapy and prophylaxis are reviewed and illustrated with computer simulations.

PMID- 15040265
TI  - Nurses' work environments require change for the safety of patients.

PMID- 15040267
TI  - Go the distance. Doing a good job? Tell the boss. Self-promotion goes a long way.

PMID- 15040266
TI  - Consolidation of health and human services in Texas.

PMID- 15040268
TI  - Sneak preview. A look at the 2001 edition of AIA's Guidelines.

PMID- 15040269
TI  - Bad medicine. Managing drug waste liabilities.

PMID- 15040270
TI  - Facility profile. Cleveland Clinic unveils 'signature' design.

PMID- 15040271
TI  - Taking charge. Keeping a tight rein on health facility construction costs.

PMID- 15040272
TI  - Health care construction cost data and trends.

PMID- 15040273
TI  - Wayfinding woes. Common obstacles to a successful wayfinding system.

PMID- 15040274
TI  - Dust busters. Revised standard targets airborne IC threats from construction.

PMID- 15040275
TI  - All clear. Some helpful tips on hospital window cleaning.

PMID- 15040276
TI  - Partnering with children and families for evidence-based practice.

PMID- 15040279
TI  - Waiting together: translating the principles of therapeutic relationships one
      step further.
AB  - ISSUES AND PURPOSE: Inconsistent nursing practices created nurse-patient boundary
      issues on a cardiac step-down unit related to confidentiality, limit setting, and
      professionalism with patients and families awaiting organ transplantation.
      CONCLUSIONS: A staff work group designed and implemented a plan to translate the
      principles of therapeutic relationships into daily practice. PRACTICE
      IMPLICATIONS: A work plan developed for nursing staff outlined concrete solutions
      and resources available within the hospital. This framework can be used to
      empower staff in the ongoing effort to manage relationships with chronically ill
      patients and their families.

PMID- 15040278
TI  - Ethical considerations for a child's participation in research.
AB  - ISSUES AND PURPOSE: To analyze ethical considerations for a child's involvement
      in research. CONCLUSIONS: Pediatric research can proceed only when the welfare of
      children is protected. Although research with children as research subjects
      constitutes only a small portion of research efforts, its continual growth
      requires nurses be aware of the rights of pediatric subjects. PRACTICE
      IMPLICATIONS: As nursing research increases in sophistication, the nurse should
      include an assessment of the informed consent process in the care of the patient,
      including the child's comprehension, the age and development of the child, and
      the child's perception of the research.

PMID- 15040277
TI  - Lack of relationship between acceptance and knowledge of asthma in school-age
      children and early adolescents.
AB  - ISSUES AND PURPOSE: Early adolescents diagnosed with asthma have difficulty
      accepting their condition. This study is part of an ongoing program of research
      designed to increase understanding of the adolescent process of coming to
      acceptance. The purpose was to explore relationships among variables in the
      Acceptance of Asthma Model. DESIGN AND METHODS: A cross-sectional, theory-testing
      design with a sample of 94 students ages 9 to 14 years. RESULTS: Acceptance was
      dependent on psychosocial influences and disease characteristics rather than
      knowledge of asthma. PRACTICE IMPLICATIONS: Psychosocial interventions are needed
      to facilitate acceptance.

PMID- 15040280
TI  - SIDS risk-reduction language in state childcare regulations as of July 2002:
      lessons learned.

PMID- 15040281
TI  - [Expression of hemispheric asymmetry and the psychological type in the dynamics
      of the EEG "traveling wave"].

PMID- 15040282
TI  - [Functional brain asymmetry and individual differences in hand preference in
      early ontogenesis].

PMID- 15040283
TI  - [Size estimation in Ebbinghaus illusion in adults and children of different age].

PMID- 15040284
TI  - [The study of the classification mechanisms of the visual objects in children
      with different styles of cognitive activity].

PMID- 15040285
TI  - [Changes in bioelectric activity in the human retina after transcranial magnetic
      stimulation].

PMID- 15040286
TI  - [Features of the brain functional organization in right- and left-handed 6-7
      years old children during visuospatial performance of different complexity. Part
      II. Analysis of EEG parameters during visuospatial performance of high level
      complexity].

PMID- 15040288
TI  - [Spectral analysis of the human EEG during listening to musical compositions].

PMID- 15040287
TI  - [Effect of caffeine on light and color sensitivity of the eye in healthy subjects
      depending on psychophysiological features and time of the day].

PMID- 15040289
TI  - [The study of the mismatch negativity phenomena during during exposure to non
      moving and moving acoustic stimuli].

PMID- 15040290
TI  - [Effects of the long-term variations in cosmic rhythms upon human biochemical
      parameters].

PMID- 15040291
TI  - [Estimation of the coronary reserve by the results of the dynamic
      electrocardiography ].

PMID- 15040292
TI  - [Functional evaluation of the perivascular innervation of the skin of the
      extremities using laser Doppler flowmetry].

PMID- 15040294
TI  - [The compensatory and adaptation reactions in sailors during voyages of different
      length].

PMID- 15040293
TI  - [The activity of the sympathoadrenal system during the adaptation process of the
      human organism to the living in the closed space].

PMID- 15040296
TI  - [The interval distribution in the speech flow of healthy persons and in patients
      with paroxysmal disorders ].

PMID- 15040297
TI  - [Anti-endotoxin immunity induces and the concentration of the intestinal
      microflora lipopolysaccharide in human blood under the conditions of the physical
      exercise ].

PMID- 15040295
TI  - [Ergometric criteria of anaerobic working capacity in athletes of the different
      age and gender].

PMID- 15040298
TI  - [Structure and function of nuclear matrix associated regions (S/MARs)].
AB  - Modern concepts on the chromatin loop-domain organization and the role of the DNA
      regions specifically binding the nuclear matrix (nuclear scaffold, or S/MARs) in
      its formation, maintenance, and regulation are discussed. Some S/MAR structural
      features, properties of binding the nuclear matrix, and probable mechanisms of
      their involvement in regulation of gene activity are considered. The English
      version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no.
      1; see also http://www.maik.ru.

PMID- 15040299
TI  - [Dendrimers based lysine and their "starburst" polymeric derivatives: prospects
      of use in compacting DNA and in vitro delivery of genetic constructs].
AB  - We attempted to find some compounds for the effective delivery of gene constructs
      into cells and obtained two trispherical dendrimers on the basis of lysine,
      (Lys)8-(alpha, epsilon-Lys)4-(alpha, epsilon-Lys)2-(alpha, epsilon-Lys)-Ala-NH2
      (D1) and (Lys)8-(alpha, epsilon-Lys)4-(alpha, epsilon-Lys)2-(alpha, epsilon-Lys)
      Ala-[Lys(Plm)]2-Ala-NH2 (D2), as well as the starburst polymeric derivatives of
      D1, (pVIm)8-D1 and (pLys)n-D1, containing poly(N-vinylimidazole) and polylysine
      chains bound at a single point to the dendrimer amino groups. The conditions of
      dendrimer-plasmid DNA complex formation were studied. The intracellular
      localization of these complexes and the expression of gene constructs delivered
      with their help were analyzed in transfection experiments on the HeLa cell
      cultures of human epithelial carcinoma and on C2C12 mouse myoblasts. It was found
      that the chemical structure of dendrimer D1 and its derivatives significantly
      affected the structure and properties of complex. The English version of the
      paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see also
      http://www.maik.ru.

PMID- 15040300
TI  - [Immunodetection of RNA-dependent RNA polymerase from turnip yellow luteovirus
      using monoclonal antibodies].
AB  - Monoclonal antibodies (MAs) to the RNA-dependent RNA polymerase from turnip
      yellow luteovirus (TYV) were prepared using a recombinant protein as immunogen
      and were shown to be directed to C-terminal part of the viral replicase. These
      MAs were found to interact with a 70-kDa protein found in extracts from TYV
      infected plants. Our result is the first successful attempt at detecting the RNA
      dependent RNA polymerase of a luteovirus in infected plant extracts. We also
      found that the protein is not processed further and its accumulation and content
      in the infected plant obey a definite dynamics during the infection. The English
      version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no.
      1; see also http://www.maik.ru.

PMID- 15040302
TI  - [Design of chimeric proteins based on pentameric superhelical fragments of COMP.
      I. Properties of a hybrid containing an immunodominant segment of the surface
      protein of Plasmodium falciparum].
AB  - The oligomeric recombinant protein DB-1 containing the immunodominant sites of
      the circumsporozoite protein of Plasmodium falciparum and tetanus toxin was
      constructed to optimize the schemes of presentation of B-cell epitopes during
      vaccination with chimeric proteins without the use of adjuvants. A fragment of
      the pentameric coiled-coil human cartilage oligomeric matrix protein was used as
      an oligomerization matrix. The expression of the protein in Escherichia coli
      cells was studied, a method for its purification was developed, and it was
      biochemically characterized. The English version of the paper: Russian Journal of
      Bioorganic Chemistry, 2004, vol. 30, no. 1; see also http://www.maik.ru.

PMID- 15040301
TI  - [Expression of neurotoxin II from Naja oxiana cobra venom in Escherichia coli in
      a hybrid form with thioredoxin].
AB  - Neurotoxin II from the venom of cobra Naja oxiana is a short type alpha
      neurotoxin, which competitively inhibits nicotinic acetylcholine receptor. The
      toxin gene was expressed as a construct fused with the thioredoxin gene and the
      linker encoding the enteropeptidase recognition site and a Met residue between
      the genes. The fusion protein was mainly cleaved by cyanogen bromide, since
      enteropeptidase was less effective. The yield of neurotoxin II was 6 mg/l of the
      bacterial culture. The resulting recombinant protein was identified with native
      neurotoxin II by its N-terminal analysis, mass spectrometry, and NMR
      spectroscopy. The English version of the paper: Russian Journal of Bioorganic
      Chemistry, 2004, vol. 30, no. 1; see also http://www.maik.ru.

PMID- 15040303
TI  - [Design of chimeric proteins based on a pentameric superhelical fragment of COMP.
      II. Properties of a hybrid, containing an VNTR (MUC1) antigen of human tumors].
AB  - An oligomeric chimeric protein DB-2 was constructed, to design drugs with
      antitumor activity and to develop highly sensitive immunospecific tests for the
      diagnostics of a wide variety of malignant epithelial cells in humans. DB-2
      contains an immunodominant site of tetanus toxin and a fragment of the locus of
      the human tumor-associated antigen MUC1 with a variable number of tandem repeats.
      A pentameric superhelical fragment of the human cartilage oligomeric matrix
      protein was used as an oligomerization matrix. The expression of the protein in
      Escherichia coli cells was studied, a method for its purification was developed,
      and its main biochemical properties were determined. The English version of the
      paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see also
      http://www.maik.ru.

PMID- 15040304
TI  - [Polynucleotides and their components in the process of aromatic nucleophilic
      substitution. I. Chemistry and dynamics of nucleotide arylation with
      pentafluoropyridine. Intermediate product ofr molecular design of nucleic acid
      analogs].
AB  - Pentafluoropyridine reacts with thymidine, adenosine, and uridine hydroxy groups
      to give quantitative yields of the corresponding nucleoside di- and triaryl
      ethers. The nucleophilic substitution reactions proceed successively and in
      parallel, with the slowest step being the nucleophilic substitution of the
      nucleoside secondary hydroxyls. The resulting ethers contain tetrafluoropyridyl
      moieties, which could be smoothly modified by nucleophilic substitution of
      fluorine atoms. The ethers are useful intermediate synthons (both isolated and in
      situ) for molecular design of oligonucleotide analogues. The English version of
      the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see
      also http://www.maik.ru.

PMID- 15040305
TI  - [Synthesis and immunostimulating activity of cysteine-containing glycopeptide
      derivatives of glycyrrhizic acid].
AB  - New cysteine-containing derivatives of glycyrrhizic acid were synthesized by its
      coupling with Cys(Bzl) esters or the Cys(Bzl)-Val-OBu(t) dipeptide by the active
      ester method (DCC/HOSu) or by Woodward's reagent K. The derivatives with Cys(Bzl)
      and Cys(Bzl)-Val residues attached to the carbohydrate part of the molecule
      stimulated the primary immune response and the reaction of delayed-type
      hypersensitivity in mice at a dose of 2 mg/kg. The English version of the paper:
      Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see also
      http://www.maik.ru.

PMID- 15040306
TI  - [Synthesis of aminoethylglycosides with oligosaccharide GM1 and asialo-GM1
      ganglioside chains].
AB  - 4'-O-Glycosylation of 2-azidoethyl 2,3,6-tri-O-benzyl-4-O-(2,3-di-O- benzyl-6-O
      benzoyl-beta-D-galactopyranosyl)-beta-D-glucopyranoside with a disaccharide
      donor, 4-trichloroacetamidophenyl 4,6-di-O-acetyl-2-deoxy-3-O-(2,3,4,6-tetra-O
      acetyl-beta-D- galactopyranosyl)-1-thio-2-trichloroacetamido-beta-D
      galactopyranoside, in dichloromethane in the presence of N-iodosuccinimide and
      trifluoromethanesulfonic acid resulted in a tetrasaccharide, 2-azidoethyl
      (2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-(1-->3)- (4,6-di-O-acetyl-2
      deoxy-2-trichloroacetamido-beta-D-galactopyranosyl)- (1-->4)-(2,3-di-O-benzyl-6-O
      benzoyl-beta-D-galactopyranosyl)- (1-->4)-2,3,6-tri-O-benzyl-beta-D
      glucopyranoside, in 69% yield. The complete removal of O-protecting groups in the
      tetrasaccharide, the replacement of N-trichloroacetyl by N-acetyl group, and the
      reduction of the aglycone azide group to amine led to the target aminoethyl
      glycoside of beta-D-Gal- (1-->3)-beta-D-GalNAc-(1-->4)-beta-D-Gal-(1-->4)-beta-D
      Glc-OCH2CH2NH2 containing the oligosaccharide chain of asialo-GM1 ganglioside in
      72% overall yield. Selective 3'-O-glycosylation of 2-azidoethyl 2,3,6-tri-O-
      benzyl-4-O-(2,6-di-O-benzyl-beta-D-galactopyranosyl)-beta-D-glucopyranoside with
      thioglycoside methyl (ethyl 5-acetamido-4,7,8,9-tetra-O- acetyl-3,5-dideoxy-2
      thio-D-glycero-alpha-D-galacto-2-nonulopyranosyl)oate in acetonitrile in the
      presence of N-iodosuccinimide and trifluoroacetic acid afforded 2-azidoethyl
      [methyl (5-acetamido-4,7,8,9-tetra-O-acetyl- 3,5-dideoxy-D-glycero-alpha-D
      galacto-2-nonulopyranosyl)oate in acetonitrile in the presence of N
      iodosuccinimide and tri-fluoracetic acid afforded 2-azidoethyl[methyl (5
      acetamido-4,7,8,9-tetra-O-acetyl- 3,5-dideoxy-D-glycero-alpha-D-galacto-2
      nonulopyranosyl) (2,6-di-O-benzyl-beta-D-galactopyranosyl)-(1-->4)-2,3,6-tri-O
      benzyl-beta-D- glucopyranoside, the selectively protected derivative of the
      oligosaccharide chain of GM3 ganglioside, in 79% yield. Its 4'-O-glycosylation
      with a disaccharide glycosyl donor, (4-trichloroacetophenyl-4,6-di-O-acetyl-2
      deoxy-3-O-(2,3,4,6-tetra-O- acetyl-beta-D-galactopyranosyl) 1-thio-2
      trichloroacetamido-beta-D-galactopyranoside in dichloromethane in the presence of
      N-iodosuccinimide and trifluoroacetic acid gave 2-azidoethyl (2,3,4,6-tetra-O
      acetyl-beta-D-galactopyranosyl)- (1-->3)-(4,6-di-O-acetyl-2-deoxy-2
      trichloroacetamido-beta-D- galactopyranosyl)-(1-->4)-[[methyl (5-acetamido
      4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-alpha-D- galacto-2
      nonulopyranosyl)onate]-(2-->3)]-(2,6-di-O-benzyl-beta-D- galactopyranosyl)-(1-
      >4)-2,3,6-tri-O-benzyl-beta-D-glucopyranoside in 85% yield. The resulting
      pentasaccharide was O-deprotected, its N-trichloroacetyl group was replaced by N
      acetyl group, and the aglycone azide group was reduced to afford in 85% overall
      yield aminoethyl glycoside of beta-D-Gal-(1-->3)-beta-D-GalNAc-(1-->4)-[alpha-D
      Neu5Ac-(2-->3)]- beta-D-Gal-(1-->4)-beta-D-Glc-OCH2CH2NH2 containing the
      oligosaccharide chain of GM1 ganglioside. The English version of the paper:
      Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see also
      http://www.maik.ru.

PMID- 15040308
TI  - [Synthesis of new analogs of 15-ketosterine from ergosterine].
AB  - Ergosteryl acetate was converted through three stages into 3 beta-acetoxy-24
      methyl-5 alpha-cholesta-8(14),22-diene-15-one in 32% overall yield. The product
      was transformed to 3 beta-hydroxy-24- methyl-5 alpha-cholesta-8(14),22-diene-15
      one, 3 alpha-hydroxy-24-methyl-5 alpha-cholesta-8(14),22-diene-15-one, and 24
      methyl-5 alpha-cholesta-8(14),22-diene-3,15-dione. The compounds were
      characterized by 1H and 13C NMR spectra. The English version of the paper:
      Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see also
      http://www.maik.ru.

PMID- 15040307
TI  - [Synthesis and properties of fluorescently-labelled triglyceride, derivative of
      the antineoplastic agent sarcolysin].
AB  - A new fluorescent probe, a 3-perylenoyl derivative of the lipophilized antitumor
      drug merphalan (sarcolysine), was synthesized. The probe is suitable for studying
      intracellular traffic and metabolism of merphalan and its derivatives. The
      perylenoyl fluorescence is partially quenched by the merphalan chromophore, which
      broadens the probe potentialities. The English version of the paper: Russian
      Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see also
      http://www.maik.ru.

PMID- 15040309
TI  - [Synthesis and antiviral activity of amides and conjugates of betulonic acid with
      amino acids].
AB  - Betulonic acid amides with aliphatic and heterocyclic amines and with L-amino
      acids were synthesized by the acid chloride method. Betulonic acid amide and L
      methionine derivatives of betulonic acid and its 3-oxime effectively inhibit the
      influenza A virus. Betulonic acid octadecylamide is active against the herpes
      simplex type 1 virus. The conjugate of betulonic acid 3-oxime with L-methionine
      is also active toward HIV-1. The tested compounds mainly show no activity toward
      the ECHO6 virus, which is devoid of a coat. The English version of the paper:
      Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see also
      http://www.maik.ru.

PMID- 15040310
TI  - [Synthesis of conjugates of bovine serum albumin with water-soluble ytterbium
      porphyrins].
AB  - The ytterbium complex of 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin was
      synthesized as an IR-fluorescent label and covalently bound to bovine serum
      albumin. The resulting conjugate fluoresces at 985 nm and is of interest for use
      in IR-fluorescent tumor diagnostic, immunoassay, and energy transfer studies. The
      English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol.
      30, no. 1; see also http://www.maik.ru.

PMID- 15040311
TI  - [Mass spectrum and uniformity of decomposition of certain 2-substituted 9-(o
      chlorbenzyl)-8-azahypoxanthines].
AB  - The regularities of mass spectrometric fragmentation under electron impact of new
      9-(o-chlorobenzyl)-8-azahypoxantines with (N-aryl)amidocarbonylmethylthiomethyl
      substituents in position 2 were studied. The main fragmentation pathways are the
      elimination of Ar-NH+ and o-chlorobenzyl ions and cleavage of C-S bonds,
      characteristic of organic sulfides. During the fragmentations, some
      rearrangements occur, consisting in the transfer of labile hydrogen atoms from
      the alpha-positions to ions being eliminated. Fragmentation of 8-azapurine parts
      of the molecules does not prevail. Peaks of molecular ions are clearly visible in
      the mass spectra of all the substances studied. The English version of the paper:
      Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see also
      http://www.maik.ru.

PMID- 15040312
TI  - [Liquid phase method of synthesizing polyamides binding DNA using
      oligocarboxamide blocks].
AB  - A method was developed for the synthesis of sequence-specific polyamides on the
      basis of 4-amino-1-methylpyrrole-2-carboxylic acid, 4-amino-1-methylimidazole-2
      carboxylic acid, beta-alanine, and gamma-aminobutyric acid. Dimeric and trimeric
      oligocarboxamides were used as building blocks. Our synthetic scheme was applied
      for the synthesis of DNA minor groove binders containing up to twelve carboxamide
      units. The English version of the paper: Russian Journal of Bioorganic Chemistry,
      2004, vol. 30, no. 1; see also http://www.maik.ru.

PMID- 15040313
TI  - [Blocking the transmission of hepatitis B virus from mother to baby].

PMID- 15040314
TI  - [Is department of medicine necessary].

PMID- 15040316
TI  - Sequencing a zoo.

PMID- 15040315
TI  - FDA eyes pharmacogenomics data.

PMID- 15040317
TI  - Cluster busters.

PMID- 15040319
TI  - [Active progress of experimental hematology research in China: a brief report on
      the 9th Congress of Chinese Society of Experimental Hematology].

PMID- 15040318
TI  - Taking stock of toxicogenomics: mini-monograph offers overview.

PMID- 15040320
TI  - Celebrating public health lives: John Francis Skone TD 1924-2002.

PMID- 15040321
TI  - Variant Creutzfeldt-jakob disease: between lymphoid organs and brain.
AB  - Prion diseases are often caused by peripheral uptake of the infectious agent. To
      reach their ultimate target, the central nervous system (CNS), prions enter their
      host, replicate in lymphoid organs and spread via peripheral nerves. Once the
      agent has reached the CNS disease progression is rapid, resulting in
      neurodegeneration and death. many of these mechanisms have been uncovered using
      genetically modified mice. A recently published study demonstrated the presence
      of pathological prion protein in sympathetic ganglia of patients suffering from
      variant Creutzfeldt-Jakob disease, suggesting that these mechanisms might apply
      to humans.

PMID- 15040323
TI  - The certitude of astrology: The scientific methodology of Al-Qabisi and Abu
      Ma'shar.
AB  - Abu Ma'shar (787-886) and al-Qabisi (mid-10th century) were active astrologers
      and defenders of the scientific character of their discipline. They wrote works
      on criticisms brought forward against the discipline and challenged practitioners
      whom they considered as detrimental for the esteem and future fate of their
      science. Nevertheless, both writers can be seen as heirs to a single tradition of
      thought, which took its origins in Ptolemy's Tetrabiblios and developed largely
      independently of the religious philosophical beliefs of a specific community. The
      arguments developed for proving the scientific value of astrology are interesting
      in their own right, and merit further study not only by historians of science but
      also by historians of philosophy.

PMID- 15040322
TI  - Horizontal gene transfer and microbial adaptation to xenobiotics: new types of
      mobile genetic elements and lessons from ecological studies.
AB  - The characterization of bacteria that degrade organic xenobiotics has revealed
      that they can adapt to these compounds by expressing 'novel' catabolic pathways.
      At least some of them appear to have evolved by patchwork assembly of
      horizontally transmitted genes and subsequent mutations and gene rearrangements.
      Recent studies have revealed the existence of new types of xenobiotic catabolic
      mobile genetic elements, such as catabolic genomic islands, which integrate into
      the chromosome after transfer. The significance of horizontal gene transfer and
      patchwork assembly for bacterial adaptation to pollutants under real
      environmental conditions remains uncertain, but recent publications suggest that
      these processes do occur in a polluted environment.

PMID- 15040324
TI  - The upper temperature of life--where do we draw the line?
AB  - A new archaeal isolate has been reported that is capable of growing at up to 121
      degrees C. The hyperthermophile, dubbed strain 121, grows chemoautotrophically
      using formate as an electron donor and FeIII as an electron acceptor and is
      closely related to members of the archaeal genera Pyrodictium and Pyrobaculum.
      Although the reported maximum growth temperature of strain 121 is 8 degrees C
      higher than the previous record holder (Pyrolobus fumarii; Tmax = 113 degrees C),
      the two organisms have virtually the same optimal growth temperatures.

PMID- 15040325
TI  - The power in comparison.

PMID- 15040326
TI  - Food for Terri Schiavo: 'when humans eat, it is not like filling up a gas tank'.

PMID- 15040327
TI  - What can bioethics contribute to ethical theory?

PMID- 15040328
TI  - Does bioethics represent a challenge to ethical theory?

PMID- 15040329
TI  - Is bioethics a challenge to ethical theory?

PMID- 15040330
TI  - Parental authority, children's rights, and health care.

PMID- 15040331
TI  - Vaginal birth after caesarean section: clinical and legal perspectives.

PMID- 15040333
TI  - Access to emergency contraception.

PMID- 15040332
TI  - Ethical issues in home health care.

PMID- 15040334
TI  - Pediatric ethics and responsibility for children: clearing the ground.

PMID- 15040335
TI  - Adolescent autonomy in health care?

PMID- 15040337
TI  - Embryonic stem cell research: a moral defense.

PMID- 15040336
TI  - Commentary: parental authority and health care decisions.

PMID- 15040339
TI  - Revulsion is simply not enough: the impending culture war over advances in
      genetics.

PMID- 15040338
TI  - Do healthcare professionals have an obligation to be vaccinated against smallpox?

PMID- 15040342
TI  - Toward the relief of suffering and the restoration of person.

PMID- 15040340
TI  - [Juvenile ischemic brain infarction. Clinical aspects, etiology spectrum,
      diagnosis and therapy].
AB  - Ischemic stroke in the young (age: 18-45 years) constitutes a diagnostic and
      therapeutic challenge. A broad spectrum of potential causes of juvenile strokes
      exists. Above all, nonatherosclerotic arteriopathies with dissections as their
      main proponent, paradoxical embolism, and thrombophilias have to be considered.
      Transient brief episodes with neurological deficits are difficult to discriminate
      from migrainous aura, epileptic seizure, psychogenic disorder. Therefore, the
      diagnostic work-up of juvenile stroke patients usually exceeds the amount of
      compulsory tests recommended in official guidelines. Various therapeutic
      modalities are not based on randomized large-scale studies and have to be
      selected on an individual basis. Despite good compliance, the annual risk of
      stroke recurrence is 2-3% and 1% for myocardial infarction.

PMID- 15040343
TI  - Artificial nutrition and hydration in patients in persistent vegetative state:
      continuing reflections.

PMID- 15040341
TI  - Wrestling SARS from uncertainty.

PMID- 15040344
TI  - The impressive and rapidly expanding knowledge base on SARS.

PMID- 15040345
TI  - Autonomy, euthanasia, and the Holy Spirit.

PMID- 15040346
TI  - Global surveillance, national surveillance, and SARS.

PMID- 15040347
TI  - How then should we die?: California's 'Death with Dignity' Act.

PMID- 15040348
TI  - Hope, healing, and justice in the abortion debate.

PMID- 15040349
TI  - Rape protocols and moral certitude.

PMID- 15040350
TI  - What philosophy of mind can tell us about the morality of abortion: personhood,
      materialism, and the existence of self.
AB  - I attempt to show that, under materialist assumptions about the nature of mind,
      it is a necessary condition for fetal personhood that electrical activity has
      begun in the brain. First, I argue that it is a necessary condition for a thing
      to be a moral person that it is (or has) a self--understood as something that is
      capable of serving as the subject of a mental experience. Second, I argue that it
      is a necessary condition for a fetus to be (or have) a self that some form of
      electrical brain activity occurs. Third, I argue that since the beginning of
      brain activity typically occurs at around 10 weeks of gestational age, most
      fetuses are not persons during the first 10 weeks of pregnancy and hence that
      abortion of most fetuses during this period does not rise to the moral level of
      murder.

PMID- 15040352
TI  - [Dendritic cells and bronchial asthma].

PMID- 15040351
TI  - Drug labeling; orally ingested over-the-counter drug products containing calcium,
      magnesium, and potassium. Final rule.
AB  - The Food and Drug Administration (FDA) is amending the general labeling
      provisions for over-the-counter (OTC) drug products to require that the labeling
      of all OTC drug products intended for oral ingestion include: The calcium content
      per dosage unit when the product contains 20 milligrams (mg) or more per single
      dose; a warning statement that persons with kidney stones and persons on a
      calcium-restricted diet should ask a doctor before using when the product
      contains more than 3.2 grams (g) of calcium in the labeled maximum daily dose;
      the magnesium content per dosage unit when the product contains 8 mg or more per
      single dose; a warning statement that persons with kidney disease and persons on
      a magnesium-restricted diet should ask a doctor before using if the product
      contains more than 600 mg magnesium in the labeled maximum daily dose; the
      potassium content per dosage unit when the product contains 5 mg or more per
      single dose; and a warning statement that persons with kidney disease and persons
      on a potassium restricted diet should ask a doctor before using if the product
      contains more than 975 mg potassium in the labeled maximum daily dose. FDA is
      issuing this final rule in order to provide uniform calcium, magnesium, and
      potassium content and warning labeling for all OTC drug products intended for
      oral ingestion whether marketed under an OTC drug monograph, the ongoing OTC drug
      review, a new drug application (NDA) or abbreviated new drug application (ANDA),
      or no application.

PMID- 15040353
TI  - The role of responsibility in gynecological oncology.

PMID- 15040354
TI  - Cytotoxic effects of B lymphocytes mediated by reactive oxygen species.
AB  - Reactive oxygen species (ROS) are produced in all mammalian cells as a result of
      norman cellular metabolism and due to the activation of oxidant-producing enzymes
      in response to exogenous stimuli. The balance between ROS production and
      antioxidant defenses determines the degree of oxidative stress. Generation of ROS
      has been associated with cell signaling, stress responses, cell proliferation,
      aging and cancer development. The ability of ROS to induce cellular damage and to
      cause cell death opens the possibility to exploit this property in the treatment
      of cancer through a fee radical-mediated mechanism.

PMID- 15040355
TI  - Ethical and medical considerations in the treatment of ectopic pregnancy.

PMID- 15040356
TI  - Duress and contraceptive sterilization: a reply to Prof. Thomas Kopfensteiner.

PMID- 15040357
TI  - Early induced delivery of severely handicapped infants.

PMID- 15040358
TI  - Methotrexate treatment of ectopic pregnancy: observations on the medical
      literature.

PMID- 15040359
TI  - The law relating to dealing with dead bodies.
AB  - Since March 1999 there have been three inquiries concerned either in whole or in
      part with the removal of human tissue from bodies during post-mortem examinations
      and its retention thereafter. Two of these at least have had to consider the law
      relating to the matter, and a commissioned paper and a submission about it to
      one, the Bristol Royal Infirmary Inquiry, have been mounted on the Inquiry's Web
      site. The main part of this article consists of the slightly revised text of a
      submission to the Inquiry by way of comment on these. Among the major points made
      in this submission are that (a) insufficient consideration has been given to the
      present status of the common law right of a person arranging a funeral to have
      the body of the deceased given Christian burial in the burial ground of the
      parish in which he or she died or of which he or she was a parishoner; (b)
      insufficient account has been taken of the scope of permissible modes of dealing
      with a dead body; and that (c) the implications this has for the common law
      offence of preventing Christian (or decent) burial have not been fully explored.

PMID- 15040361
TI  - Drug-testing on seropositive pregnant women in the developing world: moral and
      legal implications.

PMID- 15040363
TI  - Regulating germ-line gene therapy to avoid sliding down the slippery slope.
AB  - Many arguments can be made for or against various regulatory approaches towards
      germ-line gene therapy and its associated research. A popular conclusion is that
      it ought to be prohibited, and this is commonly defended by use of a slippery
      slope argument. This paper will begin by outlining the regulatory approaches
      adopted towards germ-line gene therapy in EU countries, demonstrating the
      popularity of the restrictive approach. The slippery slope argument will then be
      examined. A number of variants of the slippery slope argument will be
      distinguished, highlighting the conceptually different claims made by each.
      Finally, examples of slippery slope arguments often invoked to support the
      prohibition of germ-line gene therapy will be examined with regard to the
      conditions that each must satisfy to form a theoretically sound argument. I will
      argue that these conditions are rarely given sufficient consideration. For the
      purposes of this paper, "germ-line gene therapy" is defined as the deliberate
      genetic modification of germ cells (sperm or oocytes), their precursors, or the
      cells of early embryos where the germ-line has yet to be segregated.

PMID- 15040367
TI  - Richard Haeder: a strong voice for trustees.

PMID- 15040366
TI  - Vaccination and other altruistic medical treatments: should autonomy or
      communitarianism prevail?
AB  - The publication of a report into a case where an organ donor's constraints on the
      race of potential recipients raises questions about whether respect for autonomy
      or communitiarianism should prevail in altruistic medical procedures. This
      article briefly reviews how autonomy and communitarianism are balanced in
      cadaveric and live organ donation, bone marrow donation, gamete donation, blood
      donation and vaccination. It criticizes vaccination policy for ostensibly
      respecting patient autonomy yet in practice compromising that autonomy in various
      ways. Vaccination is properly viewed as an altruistic medical procedure because
      some vaccines are of more good to society than to the vaccinee, who runs
      associated health risks. The conclusion is that there is a spectrum of attitudes
      to the value of autonomy, depending principally upon the invasiveness of the
      procedure. In most cases the autonomy-communitarianism balance is satisfactory,
      but this is not so in respect of cadaveric organ donation and vaccination. The
      article proposes that cadaveric organ donation should be governed by the
      communitarian law of well-publicised presumed consent. It proposes two
      alternatives for vaccination: that vaccination should be compulsory or,
      preferably, that procedures be modified so that parents have real autonomy in
      their decisions whether to vaccinate their children.

PMID- 15040368
TI  - The Human Rights Act 1998 and the individual's right to treatment.
AB  - The right to demand treatment--even when life-saving--is not recognised by
      English common law. The courts have consistently stated that they do not have the
      jurisdiction to order a doctor to perform a particular treatment. This article
      considers whether the impending Human Rights Act 1998 can be interpreted so as to
      allow this right. While a general right to treatment is discussed the argument
      focuses on life-saving treatment. As an illustration, the David Glass case will
      be analysed and the impact of the Human Rights Act will be examined by
      considering how the judgment might have differed had the Act been in force.

PMID- 15040369
TI  - Betrayal of confidence in the Court of Appeal.
AB  - In overturning Latham J's judgment in R v Department of Health, Ex Parte Source
      Informatics Ltd. that anonymisation does not obviate breaching a personal
      confidence, the Court of Appeal holds that where the duty of confidence arises in
      equity it does not prohibit the confidant using the confided information without
      the consent of the confider if this does not treat the confider unfairly
      (relative to the Court's view of the confider's legitimate interests). We argue
      that this principle--by bringing fairness to bear on the scope of the duty of
      confidence rather than on whether a breach of it may be lawful--has no authority
      in usable precedents; that the Court's interpretation of fairness in applying
      this principle is, in any event, incompatible with the Data Protection Act 1998
      (in part because the Court has too narrow a conception of privacy); that the
      Court errs in holding that neither anonymisation of personal data nor use of
      anonymous data falls under the Data Protection Act; and that the Court's
      insensitivity to the vulnerability that leads patients to disclose information
      about themselves to health professionals for their treatment, leads it to
      misidentify the basis of the duty of confidence in such disclosures. The Court of
      Appeal's reasoning does not clarify the duty of confidence, but virtually
      abolishes it in the face of competing commercial and research interests.

PMID- 15040371
TI  - Objectivity and subjectivity in dental admissions.

PMID- 15040370
TI  - [Psychological pain diagnosis in children].
AB  - Pain in premature infants, neonates, and young children impairs their development
      to a great extent and may lead to long-lasting pain memories and undertreatment
      of pain. Up to 15 years ago, the opinion prevailed that babies -- especially
      neonates -- could not feel pain generally, because they could not report their
      pain sensations to adults and were not able to verbalize their feelings. In the
      past decade, standardized scales have been developed to assess pain in children.
      While in neonates and children up to 2 years standardized scales were developed
      for observation of their reactions, for children 3 years and older self-report
      scales are used to assess pain sensations. The text describes a variety of
      standardized pain assessment scales which fulfil the requirements of reliability
      and validity.

PMID- 15040372
TI  - Poverty using official and experimental measures.

PMID- 15040373
TI  - Autogenous mandibular canine transplantation.

PMID- 15040374
TI  - The consilia attributed to Arnau de Vilanova.
AB  - Four of the works attributed to Arnau de Vilanova may be considered consilia,
      which is the name of the genre of texts that expound medical treatments for
      illnesses suffered by specific individuals. In this paper, I first address the
      problem of their autheticity within the framework of the so-called "Arnaldian
      question". The evidence presented here confirms that Arnau de Vilanova was the
      author of the Regimen podagre and the Epistola ad Bremundum Montisferrarii, while
      the question regarding the authorship of the Regimen quartane and the Cura febris
      ethice remains unresolved. This article furthermore documents the degree to which
      the actual cures prescribed by the physician in the consilia agreed with the
      doctrinal works of the Galenic tradition. It is explained how medieval university
      trained physician had to compete with other practitioners and how they tried to
      outrival them by applying the doctrines of learned medicine to the individual
      cases at hand.

PMID- 15040375
TI  - Participation of children in clinical trials: UK, European and international
      legal perspectives on consent.
AB  - The Declaration of Helsinki was, until recently, the leading international code
      on the conduct of clinical trials on human subjects. The Council of Europe's
      Convention on Human Rights and Biomedicine (1997) and the ICH guidelines for Good
      Clinical Practice (1996) represent a significant step towards increased
      harmonization of standards in the conduct of medical experiments on human
      subjects. But in spite of emerging areas of consensus, there remain important
      areas of unclarity and divergence. Medical practitioners involved in paediatric
      research in the UK are concerned about the lack of certainty in the law,
      particularly on the application of consent rules to emergency research. This
      paper examines UK, European and International norms on the participation of
      children in medical research and compares the circumstances under which consent
      rules may be waived under each normative regime.

PMID- 15040376
TI  - Genetics and patients' rights: where are the limits?

PMID- 15040377
TI  - Regulating surrogacy--a contravention of human rights?
AB  - On the 2nd of October 2000, The Human Rights Act 1998 came into full force,
      signalling the incorporation of The European Convention on Human Rights into U.K.
      law. Areas of law believed to be inconsistent with the Convention may now be
      challenged in both The European Court of Human Rights and domestic courts. This
      article considers whether existing laws on the regulation of access to
      infertility services, in particular surrogacy, will be deemed incompatible with
      the ECHR. Human rights as enshrined within Articles 8 and 12 will be examined in
      light of recent suggestions that there may arise legal challenges by those who
      have had access to reproductive services restricted or denied. It will be shown
      that, although existing and potential future controls may arguably infringe these
      rights, it is nevertheless unlikely that they will be held to be in contravention
      of The Human Rights Act 1998.

PMID- 15040378
TI  - Anticipatory refusals and the action of 'wrongful living'.
AB  - After years of debate, opinion among bioethicists and medical lawyers seems to
      have accepted that anticipatory refusals of medical treatment can, and
      furthermore should, be accorded the same legal status as contemporaneous
      refusals. But what would be the legal repercussions for a medic who treated an
      incompetent patient in contravention of such a directive? What remedies would be
      available to the claimant whose life had been extended contrary to his express
      wishes? This issue has never been explicitly addressed by the UK courts, but this
      paper looks at some of the conclusions and inferences we can perhaps draw from
      other, possible analogous areas of law. It also considers several North American
      cases that have addressed this issue, and asks what lessons we can learn
      therefrom.

PMID- 15040379
TI  - The BESST way to judge the success of IVF clinics.

PMID- 15040380
TI  - Fact sheet on "emergency contraception" and treatment of victims of sexual
      assault.

PMID- 15040381
TI  - Leapfrog standards haven't made much impact on hospital patient safety practices,
      report says.

PMID- 15040383
TI  - Blood test may lower antibiotic usage in lower respiratory tract infections.

PMID- 15040382
TI  - "Morbus," Locke and Boyle - A response to Peter Anstey.

PMID- 15040384
TI  - Non-prescription medication usage is common and often under-reported by rural
      women.

PMID- 15040385
TI  - New study finds chickenpox vaccine works.

PMID- 15040386
TI  - Hypertension and insulin resistance syndrome.

PMID- 15040387
TI  - Iron gathering by zoopathogenic fungi.
AB  - Iron is a metal required by most microorganisms and is prominently used in the
      transfer of electrons during metabolism. The gathering of iron is, then, an
      essential process and its fulfillment becomes a crucial pathogenetic event for
      zoopathogenic fungi. Iron is rather unavailable because it occurs on the earth's
      surface in its insoluble ferric form in oxides and hydroxides. In the infected
      host iron is bound to proteins such as transferrin and ferritin. Solubilization
      of ferric iron is the major problem confronting microorganisms. This process is
      achieved by two major mechanisms: ferric reduction and siderophore utilization.
      Ferric reductase is frequently accompanied by a copper oxidase transport system.
      There is one example of direct ferric iron transport apparently without prior
      reduction. Ferric reduction may also be accomplished by low molecular mass
      compounds. Some fungi have evolved a process of iron acquisition involving the
      synthesis of iron-gathering compounds called siderophores. Even those fungi that
      do not synthesize siderophores have developed permeases for transport of such
      compounds formed by other organisms. Fungi can also reductively release iron from
      siderophores and transport the ferrous iron often by the copper oxidase transport
      system. There is a great diversity of iron-gathering mechanisms expressed by
      pathogenic fungi and such diversity may be found even in a single species.

PMID- 15040388
TI  - Bridges from hospitals to the laboratory: genetic portraits of methicillin
      resistant Staphylococcus aureus clones.
AB  - Methicillin-resistant Staphylococcus aureus (MRSA) emerged in the early 1960's
      after the acquisition of the methicillin resistance gene mecA, which is carried
      by the staphylococcal cassette chromosome mec (SCCmec). MRSA seemed to have
      arisen by multiple introductions of SCCmec into successful methicillin
      susceptible S. aureus (MSSA) lineages. MRSA is one of the most common agents of
      nosocomial infections worldwide increasing the cost and mortality compared to
      MSSA infections. Little by little, MRSA has acquired resistance to all
      antibiotics available in clinical practice, which complicates treatment. This
      situation was further aggravated by the recent reports of vanA-mediated
      vancomycin-resistant S. aureus. As a reaction to the emergence and spread of
      multidrug-resistant MRSA worldwide, international surveillance systems such as
      the CEM/NET initiative have been created. The characterization of over 3000 MRSA
      isolates from different regions of the world evidenced the existence of only a
      few epidemic clones spread worldwide, namely the Iberian, Brazilian, Hungarian,
      New York/Japan, Pediatric and EMRSA-16 clones. It was found that in surveillance
      or evolutionary studies strains should be characterized by a combination of
      different typing methods, namely pulsed-field gel electrophoresis, multi-locus
      sequence typing and SCCmec typing. In recent years, community-acquired MRSA (CA
      MRSA) has become a growing public health concern. However, although many authors
      reported the emergence of CA-MRSA isolates, a standard definition has not been
      created and the prevalence of MRSA among persons without risk factors seems to
      remain very low. CA-MRSA has distinct properties compared to epidemic nosocomial
      clones and its origin is still unclear. Certain authors suggest there is MRSA
      transmission from the hospital setting to the community, namely transfer of
      nosocomial MRSA minor clones or sporadic isolates showing a high degree of
      similarity with CA-MRSA; others believe CA-MRSA strains represent new
      acquisitions of SCCmec DNA in susceptible backgrounds. Many questions concerning
      this extraordinarily versatile and threatening pathogen remain unanswered,
      needing future investigation

PMID- 15040389
TI  - Introduction to the history of the Pancreas Club, Inc.

PMID- 15040390
TI  - Information on Pancreas Club associations/organizations.

PMID- 15040391
TI  - Galenic Dietetics. [Review of: Grant M. Galen on food and diet. London,
      Routledge, 2000].

PMID- 15040392
TI  - Epidemiology of breast cancer among BRCA mutation carriers: an overview.
AB  - Mutations in BRCA1 and BRCA2 have been associated with an increased lifetime risk
      of breast and ovarian cancers. Many of the well-recognized risk factors and risk
      modifiers in other women appear to operate similarly in BRCA mutation carriers.
      However, current evidence suggests that BRCA-related breast cancer risk is
      positively associated with pregnancy and parity, while smoking may reduce the
      risk. The incidence of BRCA1-related breast cancer is high before the age of 35
      years and oral contraceptive use for 5 or more years is associated with increased
      risk of this disease among women carrying BRCA1 mutations.

PMID- 15040393
TI  - Erratum to "Apotransferrin administration prevents growth of Staphylococcus
      epidermidis in serum of stem cell transplant patients by binding of free iron".
      [FEMS Immunol. Med Microbiol. 37 (2003) 45-51].
AB  - We investigated the effect of free, non-transferrin-bound iron occurring in
      haematological stem cell transplant patients on growth of Staphylococcus
      epidermidis in serum in vitro, and prevention of bacterial growth by exogenous
      apotransferrin. S. epidermidis did not grow in normal serum at inoculated
      bacterial densities up to 10(3) cfu ml(-1) but slow growth could be detected at
      higher initial inocula. Addition of free iron abolished the growth-inhibitory
      effect of serum, whereas addition of apotransferrin again restored it. Appearance
      of free iron and loss of growth inhibition coincided in patient serum samples
      taken daily during myeloablative therapy. Intravenously administered
      apotransferrin effectively bound free iron and restored the growth inhibition in
      patient sera. The results suggest that exogenous apotransferrin might protect
      stem cell transplant patients against infections by S. epidermidis and possibly
      other opportunistic pathogens.

PMID- 15040394
TI  - 3-D reconstruction of hemocyanins and other invertebrate hemolymph proteins by
      cryo-TEM: an overview.

PMID- 15040395
TI  - Ureteroscopic surgery: changing times and perspectives.
AB  - Ureteroscopy developed as an extension of cystoscopic techniques into the upper
      urinary tract with smaller, rigid, and flexible endoscopes. Smaller working
      instruments have made therapeutic procedures possible. Ureteroscopy has become
      the technique of choice to diagnose and treat benign essential hematuria and has
      a major role in treating ureteropelvic junction obstruction, upper tract
      neoplasms, and calculi. Finally, there is a need for smaller and more effective
      endoscopes and working devices.

PMID- 15040396
TI  - The evolution and progress of ureteroscopy.
AB  - Technology and refinements in urology have prospered with the bonding of
      engineers and surgeons. The introduction of fiberoptics and the development of
      the ureteroscope opened the doors to the field of ureteroscopy. Advances in rigid
      and flexible ureteroscopy with irrigating and working channels have expanded the
      capability of the urologist to diagnose and treat most abnormalities of the upper
      tracts in adult and pediatric populations. Instrument development has easily
      paralleled the growth and development of the ureteroscope and has improved
      success, patient safety, and comfort with the incorporation of access sheaths,
      nitinol materials, and Ho:YAG laser technology. Owing to their minimal morbidity
      and high success rate, ureteroscopic evaluation and therapeutic interventions in
      the upper tract represent the gold standard of management. Albert Einstein said,
      "There are only two ways to live your life. One is as though nothing is a
      miracle. The other is as though everything is a miracle." Contemporary
      ureteroscopy is a historical miracle that has opened a vista of endless limits in
      upper tract endoscopy (Fig. 4, Box 1).

PMID- 15040397
TI  - Anatomic and physiologic considerations in ureteroscopy.
AB  - The successful and safe implementation of ureteroscopic techniques depends on
      considerations of anatomy and physiology. Combining knowledge of the drainage
      system of the kidney with its vascular supply, predictive patterns of incisions
      can be applied within the collecting system to safely avoid vascular injury. In
      addition, awareness of the variation in normal and pathologic anatomy and
      physiology is key to effective interventions. An appreciation of the impact of
      ureteroscopy on normal anatomy and physiology can prevent complications and
      promote improved therapeutic outcomes.

PMID- 15040398
TI  - Ureteroscopes: flexible, rigid, and semirigid.
AB  - Since its introduction, the ureteroscope has undergone significant improvements.
      Using the currently available rigid, semirigid, and flexible ureteroscopes and
      working instruments, urologists can diagnose and treat lesions throughout the
      upper urinary tract. Over the past 25 years, the ureteroscope in combination with
      shock wave lithotripsy has transformed the diagnosis and treatment of more than
      90% of upper urinary tract pathology from an open to an endourologic procedure.
      With endoscope manufacturers continually incorporating new technology into their
      ureteroscopes, future models will undoubtedly provide better optics, increased
      durability, and improved capabilities, resulting in greater success when
      urologists perform endoscopic forays into the upper urinary tract.

PMID- 15040400
TI  - Ureteroscopy: anesthetic considerations.
AB  - Ureterorenoscopy (URS) is a vital procedure in the armamentarium of the modern
      day urologist for the management of ureteral and renal pathology. With advances
      in ureteroscopic design and the introduction of short-acting anesthetics, URS can
      now be performed efficiently with high patient satisfaction and minimal
      posteroperative recovery time. Recently, URS under local anesthesia, with or
      without sedation, has become a viable option for a high percentage of correctly
      selected patients. For those patients who then require deeper sedation or general
      anesthesia, anesthesia can be induced quickly with the new agents such as
      remifentanil, propofol, and desflurane, without a prolonged postoperative
      recovery period.

PMID- 15040399
TI  - Advances in video and imaging in ureteroscopy.
AB  - Advances in image processing and display technologies, such as digital imaging,
      HDTV, and virtual reality, will ultimately allow integration of endoscopic
      imaging with diagnosis and therapy during ureteroscopic procedures. Further
      improvements in simulation technology and telemedicine should improve surgical
      training and greatly benefit patient care.

PMID- 15040401
TI  - Ancillary instrumentation for ureteroscopy.
AB  - As the quality of ureteroscopy continues to improve, ancillary instrumentation
      will advance. The endourologist now has a vast supply of specially designed
      guidewires, stents, balloons, and baskets. These technologies have expanded the
      realm of cases that may be managed endoscopically. As the urologist becomes more
      familiar with the options at his or her disposal, patient care will improve.

PMID- 15040402
TI  - Techniques of ureteroscopy.
AB  - The flexible ureteroscope has revolutionized the diagnosis and treatment of the
      entire upper urinary tract. Endoscopic tools have evolved, providing the surgeon
      with the armamentarium necessary to treat many different pathologic processes.
      Almost all renal calculi can be treated with retrograde ureteroscopy. The
      fragility of these new endoscopes is a concern, and great care must be taken when
      using them. With good technique and proper use of instruments, their working life
      can be extended.

PMID- 15040403
TI  - Ureteral access strategies: pro-access sheath.
AB  - Routine use of the ureteral access sheath during flexible ureteroscopic
      procedures provides consistent, reliable, and unencumbered access to the upper
      tracts. The ureteral access sheath can be reliably and easily deployed if used
      properly and requires no special training. As such, it can be easily adopted into
      current urologic practice. Not only does the access sheath facilitate rapid,
      repeated, and atraumatic access to the upper tracts, but it also avoids back
      loading over a superstiff guidewire, which may incur costly damage to the
      ureteroscope. The access sheath reduces overall costs and decreases operative
      times. Furthermore, application of a ureteral access sheath reduces the
      frustration associated with complex and some routine ureteroscopic procedures by
      optimizing irrigant flow to improve the surgeon's endoscopic vision while
      minimizing the intrarenal pressures that the kidney must tolerate. There is no
      evidence that the access sheath results in clinically significant ureteral
      ischemia, and extensive clinical use of the access sheath for long procedures has
      not resulted in increased stricture formation. Finally, the ureteral access
      sheath is useful for other procedures, such as PCNL, by improving visualization
      and minimizing the requirement for multiple percutaneous access sites. Winston
      Churchill said it best: "Give us the tools and we will finish the job." Industry
      has provided urologists with the tools in the form of advanced flexible
      ureteroscopes, the holmium laser, nitinol baskets, and the ureteral access
      sheath. Now it is up to urologists to finish the job.

PMID- 15040404
TI  - The argument against the routine use of ureteral access sheaths.
AB  - The current authors' experience with thousands of ureteroscopic procedures has
      led them to believe that ureteral access sheaths are seldom necessary. No study
      to date has accurately determined an advantage of using these sheaths for routine
      ureteroscopy. The current authors have outlined their alternative methods that
      eliminate the reported advantages of the sheaths. Their philosophy of stone
      treatment uses laser lithotripsy for small stone burdens and SWL or PNL for
      larger stone burdens and eliminates the need for prolonged ureteroscopic
      procedures. Several disadvantages of access sheaths are evident. When this
      information is taken into account, the routine use of a ureteral access sheath
      becomes unnecessary. It is only in unusual cases that ureteral access sheaths are
      of any utility.

PMID- 15040406
TI  - Retrograde ureteroscopic endopyelotomy.
AB  - Several different procedures can be used to treat UPJ obstruction. Retrograde
      ureteroscopic endopyelotomy provides a safe and adequate first line of treatment
      for this condition. With the advent of smaller ureteroscopes and ancillary
      devices, this technique has evolved to include children. Adherence to strict
      endourologic principles and direct visualization make retrograde ureteroscopic
      endopyelotomy a safe and effective treatment modality. This procedure represents
      an extension of the basic endoscopic skills of the urologist, creating a short
      learning curve and wide margin of safety.

PMID- 15040405
TI  - Ureteroscopic treatment of renal calculi.
AB  - Although ureteroscopic treatment of renal calculi is safe and effective. it is
      relatively inefficient compared with ESWL and PCNL. It should be considered
      primary therapy for patients with lower pole stones who have adverse ESWL
      characteristics and patients who are not suitable candidates for PCNL. There are
      also numerous clinical situations, as outlined previously, where the
      ureteroscopic approach is favored over other treatment modalities.

PMID- 15040407
TI  - Ureteroscopic management of ureteral and ureteroenteral strictures.
AB  - The ureteroscopic approach to ureteral strictures has diminished morbidity
      because of smaller-caliber equipment, improved optics, Ho:YAG laser, and a better
      understanding of the risk factors for ureteral strictures. Direct visualization
      by means of retrograde ureteroscopy provides a safe and effective approach to
      treat ureteral strictures without the need for an open incision or percutaneous
      nephrostomy access. All patients with a ureteral stricture require an extensive
      evaluation and planning before treatment. Generally, patients with ureteral
      strictures and a history of carcinoma should undergo biopsy of the area of
      stricture. With recurrent cancer, patients may present with pain, nausea,
      vomiting, pyelonephritis, or loss of the ipsilateral renal unit. Malignant
      strictures tend to not respond well to balloon dilation alone. Open or
      laparoscopic resection and reconstruction may be indicated if there is a chance
      for cure. In patients who are not good surgical candidates or in those who have
      advanced disease, the urologist is left with the option of an indwelling stent or
      nephrostomy tube.

PMID- 15040408
TI  - Ureteroscopic management of upper tract transitional cell carcinoma.
AB  - The expanding experience with endoscopic techniques for treating upper tract
      urothelial malignancy demonstrates its safety and efficacy in carefully selected
      patients. Diagnostic accuracy can be enhanced, and pathologic confirmation of
      tumor grade and stage is possible. In carefully selected patients who have low
      grade and low-stage disease, the results of endourologic management have been
      encouraging. Patients with an anatomic or functionally solitary kidney, bilateral
      disease, or significant renal insufficiency can often be considered candidates
      for endoscopic treatment as the first line of therapy. In the setting of low
      grade, low-stage disease in a patient with a normal contralateral kidney, the
      role of endourologic management remains controversial. Adjuvant topical therapy
      with mitomycin C or BCG seems to be safe and well tolerated after endoscopic
      management of upper tract TCC.

PMID- 15040409
TI  - Advanced intrarenal ureteroscopic procedures.
AB  - The role of flexible ureteroscopy in the management of intrarenal pathology has
      undergone a dramatic evolution, powered by improvements in flexible ureteroscope
      design; deflection and image quality; diversification of small, disposable
      instrumentation; and the use of holmium laser lithotripsy. This article reviews
      the application of flexible ureteroscopy for advanced intrarenal procedures.

PMID- 15040410
TI  - Ureteroscopy for benign hematuria.
AB  - Any patient presenting with hematuria of unknown origin should undergo a thorough
      history, physical examination, and laboratory and radiographic work-up. All
      attempts should be made to exclude malignancy. Renal hemangiomas are the most
      likely cause of chronic benign hematuria, particularly in young patients. In the
      past these lesions were treated with complete or partial nephrectomy. With the
      availability of small, flexible ureteroscopes capable of primary and secondary
      deflection, ureterorenoscopy has become an excellent means of diagnosing and
      treating these lesions. Various instruments--including an electrocautery probe,
      Nd:YAG laser, and Holmium:YAG laser--have been used with similar results.

PMID- 15040411
TI  - Pediatric ureteroscopy.
AB  - Endoscopic evaluation and management of the diverse conditions involving the
      upper urinary tract of children is now feasible and has been shown to be safe and
      efficacious. This modality should be considered an essential part of the
      armamentarium of any urologist involved in the care of children. Continued
      technological advances will allow the indications for pediatric ureteroscopy to
      evolve. The benefits of minimally invasive surgery that have been proved in adult
      patients can now be offered to pediatric patients. A thorough knowledge of
      available equipment and the anatomic and physiologic differences of pediatric
      patients will ensure a successful outcome with minimal morbidity.

PMID- 15040412
TI  - Complications of ureteroscopy.
AB  - Ureteroscopy has undergone a dramatic evolution over the last two decades.
      Although ureteroscopic injury is the most common cause of ureteral trauma because
      of the large number of ureteroscopic procedures performed, improvements in
      instrumentation and technique have resulted in a reduced incidence of serious
      complications. Despite significant technologic advances, however, surgical
      misadventures still occur, some of which have lasting consequences. Careful
      attention to instrument selection and surgical technique are critical to reduce
      untoward events related to ureteroscopy. As such, adverse sequelae associated
      with ureteroscopy should be related to the underlying pathology itself rather
      than to the treatment.

PMID- 15040413
TI  - Stenting after ureteroscopy: pros and cons.
AB  - The results of the numerous trials evaluating stenting after uncomplicated
      ureteroscopy suggest that the routine placement of a stent is no longer
      necessary. Patients with stents seem to have significantly more pain and
      irritative voiding symptoms. In addition, the routine placement of a stent
      significantly adds to the overall cost of the procedure. There is a subgroup of
      patients who would likely benefit from a stent as evidenced by the higher
      readmission to hospital rate than in nonstented patients. Ideally, future trials
      will help unmask a method to identify these patients.

PMID- 15040414
TI  - Current trends in ureteroscopy.
AB  - The advances of technology are having substantial ramifications in medicine and
      in urology, in particular. This article discusses these advances and explores
      current trends in ureteroscopy.

PMID- 15040415
TI  - Subgroup demographic may have skewed ALLHAT results.

PMID- 15040416
TI  - Strength in collaboration.

PMID- 15040417
TI  - Let's learn from the influenza epidemic.

PMID- 15040418
TI  - Why are our patients still in pain? Finding a balance in treating patients for
      nonmalignant pain.
AB  - Osteopathic physicians would agree that the cornerstone principle of osteopathic
      medicine is enveloped in the Latin phrase, Primum non nocere (first, do no harm).
      Are physicians doing patients harm by allowing them to remain in chronic pain?
      Conversely, are physicians doing patients harm by supporting a dependence on pain
      relieving medication that allows normal functions of daily life? There is a
      delicate balance that each physician must find in the context of his or her
      practice of medicine.

PMID- 15040419
TI  - Outpatient osteopathic single organ system musculoskeletal exam form: training
      and certification.
AB  - The Outpatient Osteopathic Single Organ System Musculoskeletal Exam Form (SOS
      form) is a standardized examination data form. A standardized form is necessary
      to ensure that essential quality data are collected during osteopathic studies
      and that each submitted form is completed adequately and uniformly. Use of the
      standardized form permits reliable statistical computations from the collected
      data. The training process for the SOS form incorporated the following elements:
      (1) training investigators to use the form; (2) having trainees transcribe three
      clinical case examples onto SOS forms; (3) comparing each transcribed clinical
      case to a prepared key; (4) evaluating the trainees' work for accuracy; and (5)
      statistically evaluating the trainees' records for intraexaminer and
      interexaminer reliability. The success or failure of trainees to receive
      certification in their training process involved evaluating their ability to
      accurately and appropriately record data collected from three case examples.
      These cases were designed to evaluate recording accuracy and intraexaminer and
      interexaminer reliability. All trainees scored 80% or better for accuracy, and
      their work had good intraexaminer and interexaminer reliability. As a result, all
      trainees were awarded a numbered certificate for successful completion of the
      training process. Having a pool of well-trained, certified investigators
      available and ready to participate in the gathering of data through the use of
      the SOS form ensures that necessary data are collected and that the resulting
      databases are unified. It will also facilitate comparisons and statistical
      analysis of osteopathic research projects. Standardized forms and certified
      investigators will improve the quality of osteopathic research throughout the
      profession.

PMID- 15040420
TI  - AOA membership and board certification of residency graduates: comparison of
      three programs accepting osteopathic physicians--implications for graduate
      medical education.
AB  - The purpose of this study was to determine membership status in the American
      Osteopathic Association (AOA) and osteopathic board certification status for
      osteopathic physicians completing osteopathic, allopathic, and dually accredited
      residency programs. Rates of AOA membership and osteopathic board certification
      of osteopathic graduates from a dually accredited residency were compared to
      rates of osteopathic graduates of an allopathic residency in the same training
      facility. These same two parameters were compared between the dually accredited
      residency and an osteopathic residency. Osteopathic graduates from the dually
      accredited residency had significantly higher rates of AOA membership and
      osteopathic board certification when compared with the osteopathic graduates of
      an allopathic residency. Moreover, no significant difference existed between the
      rates of these two measures for osteopathic resident graduates from the dually
      accredited residency when compared with graduates of an osteopathic residency.
      Implications of the results are discussed.

PMID- 15040421
TI  - J-tip spring guidewire entrapment by an inferior vena cava filter.
AB  - The number of complications between guidewires and inferior vena cava filters is
      unknown and most likely underreported. Since 1993, at least 17 cases of central
      venous catheter guidewires entangled in inferior vena cava filters have been
      reported. The placement of both devices in the intensive care setting has
      increased the number of incidents in which a guidewire from a central venous
      catheter becomes entrapped in an inferior vena cava filter. The authors report a
      case in which entrapment of a guidewire occurred without causing displacement of
      the filter. In addition, a review of simple but useful recommendations to prevent
      and manage these complications is presented.

PMID- 15040422
TI  - Preface: Thematic issue on sickle cell disease.

PMID- 15040423
TI  - Beta-globin-gene haplotypes, mitochondrial DNA, the Y-chromosome: their impact on
      the genetic epidemiology of the major structural hemoglobinopathies.
AB  - The history of the discovery of the globin beta-like globin-gene haplotypes and
      their importance in the understanding of hemoglobinopathies has been reviewed
      recently. We will add in this review more recent findings and other molecular
      genetic tools that can help in the understanding of the genetic epidemiology of
      structural hemoglobinopathies, leaving the thalassemias for a later effort.

PMID- 15040424
TI  - Polymorphisms near a chromosome 6q QTL area are associated with modulation of
      fetal hemoglobin levels in sickle cell anemia.
AB  - In patients with sickle cell anemia, fetal hemoglobin (HbF) concentrations vary
      by 2 orders of magnitude. This variance may be a result of heterogeneity in gene
      regulatory elements; accordingly, we searched for single nucleotide polymorphisms
      (SNPs) that might identify this variation. More than 180 SNPs were studied in 38
      genes in 280 sickle cell anemia patients. The strongest association with HbF was
      found with SNPs near a QTL previously localized on chromosome 6q22.3-q23.2.
      Initially, two SNPs were identified in intergenic portions of this QTL and were
      associated with about a 20% difference in percent HbF. Subsequently, we genotyped
      44 additional SNPs in the genomic region between 136.1 Mb and 137.5 Mb on
      chromosome 6q. Twelve SNPs, associated with a 20%-30% difference in HbF
      concentrations, were located in the introns of four genes, PDE7B, MAP7, MAP3K5
      and PEX7. In K562 cells, the p38-MAPK pathway has been associated with the
      activation of gamma-globin gene expression by histone deacetylase inhibitors.
      Haplotypes C-T-T-T in MAP7 and T-C-C in PEX7 were significantly associated with
      increases in concentration of HbF, both showing strong dominance. Genetic
      elements abutting the 6q22.3-q23.2 QTL, may harbor trans-acting elements that
      help modulate baseline HbF level in sickle cell anemia.

PMID- 15040425
TI  - Dominant influence of gamma-globin promoter polymorphisms on fetal haemoglobin
      expression in sickle cell disease.
AB  - Polymorphisms of multiple cis-acting elements in the beta-globin locus are
      associated with variable fetal haemoglobin (HbF) level in sickle cell disease. We
      developed a multiplex assay permitting simultaneous analysis of three polymorphic
      cis elements spanning 53 kb of the beta-globin locus. We identified concordance
      between polymorphic alleles in gamma- and beta-globin promoters however a
      significant number of betaS-chromosomes were identified with polymorphisms in
      hypersensitive site 2 (HS2) of the beta-globin locus control region juxtaposed to
      atypical cis alleles in the gamma-promoter. Analysis of an unusually large number
      of such hybrid haplotype chromosomes provided unique insight into HbF level
      associated with specific cis alleles. Associations between cis alleles and HbF
      level in patients were verified by in vitro functional analysis. Our findings
      indicate that compared to HS2, polymorphism in the gamma-promoter exerts a
      dominant influence on HbF level in sickle cell disease.

PMID- 15040426
TI  - Selective inhibition of beta-globin RNA transcripts by antisense RNA molecules.
AB  - Inhibition of beta-globin gene expression by antisense nucleic acids is a
      potentially powerful therapeutic strategy for sickle cell disease. To develop
      clinically relevant beta-globin antisense agents we created nine stable mouse
      erythroleukemia cell lines expressing unique anti-beta-globin RNA transcripts
      with different potentials for cross-hybridization with gamma-globin mRNA. We
      observed variable inhibition of beta-globin expression independent of the
      hybridization potential of the respective antisense beta-globin RNA transcript.
      Similarly, inhibition of gamma-globin expression by anti-beta transcripts varied
      widely in the nine stable cell lines. Three neighboring regions in the beta
      globin gene with low RNA folding potentials conferred significantly stronger
      antisense effect toward beta-globin while sparing the homologous targets in gamma
      globin. We have identified for the first time targets in the beta-globin gene for
      which the homologous regions in gamma-globin are relatively inaccessible to
      antisense attack. Our findings offer the prospect of using this approach to
      reduce the proportion of intracellular hemoglobin S. Gene therapy strategies
      which combine gamma-globin induction along with beta-globin inhibition using
      antisense vectors may yield more favorable anti-sickling effects longterm.

PMID- 15040427
TI  - The irreversibly sickled cell: a perspective.
AB  - The irreversibly sickled cell (ISC) is poorly deformable, dehydrated, of short
      life span, correlated to hemolysis, and a contributor to the pathophysiology of
      vaso-occlusive (VOC) episodes. The altered redox status and increased oxygen
      radical levels within high density sickle cells leads to oxidative damage and
      glutathiolation of cysteine residues. The formation of a disulfide bridge between
      Cys 284 and Cys 373 in ISC beta-actin leads to actin filaments which depolymerize
      poorly at 37 degrees C. Glutathiolation of cysteines within spectrin results in
      this key membrane skeletal protein losing it's E2/E3 ubiquitin
      ligating/conjugating activity and therefore ability to self ubiquitinate. The
      resulting loss of ubiquitination in ISC alpha-spectrin repeats 20/21 causes a
      higher affinity ISC spectrin-4.1-actin ternary complex. Therefore, reversible
      oxidative damage to beta-actin and loss of ubiquitination of alpha-spectrin leads
      to an ISC membrane skeleton that disassembles poorly at 37 degrees C. The result
      is a membrane skeleton which is "locked" because it cannot disassemble or
      reassemble. N-acetylcysteine (NAC) is an antioxidant which raises intracellular
      reduced glutathione levels, and blocks the formation of ISCs in vitro. NAC, in a
      phase II human trial, caused a downward trend in ISCs, significantly decreased
      dense cells, and substantially decreased the rate of VOC episodes.

PMID- 15040428
TI  - Ankyrin is a target of spectrin's E2/E3 ubiquitin-conjugating/ligating activity.
AB  - Ubiquitin is a small protein of 8.6 kDa molecular weight. When polyubiquitin is
      attached to target proteins, they are tagged for destruction by cytoplasmic
      organelles called proteasomes. We now know that ubiquitination of target proteins
      also regulates functions as diverse as the sorting of proteins to different
      intracellular destinations, cell signaling, cell division, gene transcription,
      and protein-protein interactions. The ubiquitination of target proteins requires
      a cascade of enzymes: E1 ubiquitin activating enzyme, E2 ubiquitin conjugating
      enzyme and E3 ubiquitin ligating enzyme. Recently we have demonstrated that the
      red blood cell (RBC) membrane skeletal protein, spectrin, has E2/E3 enzymatic
      activities in its alpha-subunit, that can transfer ubiquitin to itself. We have
      now created a cell free assay using biotinylated ubiquitin that allows detection
      of target proteins by streptavidin peroxidase. This approach coupled with
      immunoprecipitation, purification and micro liquid chromatography coupled to
      tandem mass spectrometry has identified ankyrin as a target of spectrin's E2/E3
      activity. Western blotting, with ubiquitin antibody, of purified ankyrin and its
      well characterized functional domains, has demonstrated that both the spectrin
      and band 3 binding domains are ubiquitinated in vivo.

PMID- 15040429
TI  - Ubiquitination of spectrin regulates the erythrocyte spectrin-protein-4.1-actin
      ternary complex dissociation: implications for the sickle cell membrane skeleton.
AB  - It has been demonstrated by our laboratory that the irreversibly sickled cell
      (ISC) spectrin-4.1-actin complex dissociates slowly as compared to ternary
      complexes formed out of control (AA) and reversibly sickle cell (RSCs) core
      skeletons. These studies indicated that the molecular basis for the inability of
      irreversibly sickled cells (ISCs) to change shape is a skeleton that
      disassembles, and therefore reassembles, very slowly. The present study is based
      on the following observations: a) alpha-spectrin repeats 20 and 21 contain
      ubiquitination sites, and b) The spectrin repeats beta-1 and beta-2 are in direct
      contact with spectrin repeats alpha-20 and alpha-21 during spectrin heterodimer
      formation, and contain the protein 4.1 binding domain. We demonstrate here that
      alpha-spectrin ubiquitination at repeats 20 and 21 increases the dissociation of
      the spectrin-protein-4.1-actin ternary complex thereby regulating protein 4.1's
      ability to stimulate the spectrin-actin interaction. Performing in vitro ternary
      complex dissociation assays with AA control and sickle cell SS spectrin (isolated
      from high-density sickle cells), we further demonstrate that reduced
      ubiquitination of alpha-spectrin is, in part, responsible for the locked membrane
      skeleton in sickle cell disease.

PMID- 15040430
TI  - Ubiquitination of erythrocyte spectrin regulates the dissociation of the spectrin
      adducin-f-actin ternary complex in vitro.
AB  - We demonstrate that ubiquitinated red blood cell (RBC) spectrin dissociates more
      rapidly from the spectrin-adducin-actin ternary complex, than non-ubiquitinated
      spectrin. Homozygous (SS) sickle cell spectrin has substantially diminished
      ubiquitination of alpha-spectrin resulting in slower dissociation from the
      spectrin-adducin-actin ternary complex, than normal (AA) cell spectrin. These
      results supply a partial explanation of the slow dissociation of the irreversible
      sickle cell (ISC) membrane skeleton, which leads to the inability of the ISC to
      change shape.

PMID- 15040431
TI  - Erythrocyte aging in sickle cell disease.
AB  - Physiological removal of old erythrocytes from the circulation by macrophages is
      initiated by binding of autologous IgG to senescent cell antigen (SCA). SCA is
      generated from the anion exchanger band 3. This process is accompanied by a
      number of alterations in the function and structure of band 3. We measured these
      aging-related parameters in erythrocytes from individuals with sickle cell
      anemia. Most sickle erythrocytes have characteristics that are also found in
      senescent normal erythrocytes, such as an increased density and considerable
      concentrations of cell-bound IgG. Together with the concomitant changes in
      structure and function of band 3, these data suggest that most sickle
      erythrocytes have undergone a process of accelerated aging. Preliminary results
      indicate that this process is reversed upon vitamin E supplementation. These data
      show that the erythrocyte aging paradigm may provide a useful conceptual
      framework for the study of the pathophysiology and the evalution of therapeutic
      intervention in sickle cell disease, and support the view that oxidation can
      generate neoantigens that are recognized by autoantibodies.

PMID- 15040432
TI  - The role of secretory phospholipase A2 in acute chest syndrome.
AB  - Acute chest syndrome (ACS) is the leading cause of death in sickle cell disease.
      Severe ACS often develops in the course of a vasoocclusive crisis (VOC), and
      frequently involves pulmonary fat embolism. Secretory phospholipase A2 (sPLA2), a
      potent inflammatory mediator, is elevated in ACS, and sPLA2 levels in serum or
      plasma predict impending ACS. In addition sPLA2 may play a major role in the
      actual damage to the lung resulting in a new pulmonary infiltrate on chest
      radiography, respiratory symptoms, and ultimately alveolar collapse and the
      impairment of gas exchange. The data indicate that measurement of sPLA2 can be
      useful in alerting the clinician to patients with impending ACS, and suggest that
      instituting early therapies based on sPLA2 levels, including inhibition of sPLA2
      activity, may be useful to prevent or reduce the clinical morbidity of ACS in
      sickle cell disease.

PMID- 15040433
TI  - Oxidant-mediated impairment of nitric oxide signaling in sickle cell disease-
      mechanisms and consequences.
AB  - In addition to its mediation of vascular relaxation and neurotransmission, nitric
      oxide (*NO) potently modulates oxygen radical reactions and inflammatory
      signaling. This participation of *NO in free radical and oxidative reactions will
      yield secondary oxides of nitrogen that display frequently-undefined reactivities
      and unique signaling properties. In sickle cell disease (SCD) inflammatory
      derived oxidative reactions impair *NO-dependent vascular function. A combination
      of clinical and knockout-transgenic SCD mouse studies show increased rates of
      xanthine oxidase-dependent superoxide (O2*-) production and reveal the presence
      of an oxidative and nitrative inflammatory milieu in the sickle cell vasculature,
      kidney and liver. Considering the critical role of endothelial *NO production in
      regulating endothelial adhesion molecule expression, platelet aggregation, and
      both basal and stress-mediated vasodilation, the O2*- mediated reduction in *NO
      bioavailability can significantly contribute to the vascular dysfunction and
      organ injury associated with SCD.

PMID- 15040434
TI  - Two cheers for ecology.

PMID- 15040436
TI  - behavioral interventions to promote breastfeeding: recommendations and rationale.

PMID- 15040435
TI  - The effectiveness of primary care-based interventions to promote breastfeeding:
      systematic evidence review and meta-analysis for the US Preventive Services Task
      Force.
AB  - PURPOSE: We wanted to systematically review whether primary care-based
      interventions improve initiation and duration of breastfeeding. METHODS: Studies
      were found by searching MEDLINE (1966-2001), Health-STAR, the Cochrane Database
      of Systematic Reviews, the National Health Service Centre for Reviews and
      Dissemination Databases, and bibliographies of identified trials and review
      articles. Studies were included if they originated in the primary care setting
      and were conducted in a developed country, written in English, and contained a
      concurrent control group. RESULTS: Thirty randomized and nonrandomized controlled
      trials and 5 systematic reviews of breastfeeding counseling were included.
      Educational programs had the greatest effect of any single intervention on both
      initiation (difference 0.23; 95% confidence interval [CI], 0.12-0.34) and short
      term duration (difference 0.39; 95% CI, 0.27-0.50). Support programs conducted by
      telephone, in person, or both increased short-term (difference 0.11; 95% CI, 0.03
      0.19) and long-term duration (difference 0.08; 95% CI, 0.02-0.16). In contrast,
      written materials such as pamphlets did not significantly increase breastfeeding.
      Data were insufficient to determine whether the combination of education with
      support was more effective than education alone. CONCLUSIONS: Educational
      programs were the most effective single intervention. One woman would breast-feed
      for up to 3 months for every 3 to 5 women attending breastfeeding educational
      programs. Future research and policy should focus on translating these findings
      into more widespread practice in diverse primary care settings.

PMID- 15040437
TI  - Variation in the ecology of medical care.
AB  - BACKGROUND: We wanted to quantify how the location in which medical care is
      delivered in the United States varies with the sociodemographic characteristics
      and health care arrangements of the individual person. METHODS: Data from the
      1996 Medical Expenditures Panel Survey (MEPS) were used to estimate the number of
      persons per 1,000 per month in 1996 who had at least 1 contact with physicians'
      offices, hospital outpatient departments, or emergency departments, hospitals, or
      home care. These data were stratified by age, sex, race, ethnicity, household
      income, education of head of household, residence in or out of metropolitan
      statistical areas, having health insurance, and having a usual source of care.
      RESULTS: Physicians' offices were overwhelmingly the most common site of health
      care for all subgroups studied. Lacking a usual source of care was the only
      variable independently associated with a decreased likelihood of care in all 5
      settings, and lack of insurance was associated with lower rates of care in all
      settings but emergency departments. Generally, more complicated patterns emerged
      for most sociodemographic characteristics. The combination of having a usual
      source of care and health insurance was especially related to higher rates of
      care in all settings except the emergency department. CONCLUSION: Frequency and
      location of health care delivery varies substantially with sociodemographic
      characteristics, insurance, and having a usual source of care. Understanding this
      variation can inform public consideration of policy related to access to care.

PMID- 15040438
TI  - Do HMOs affect educational disparities in health care?
AB  - BACKGROUND: We wanted to examine how membership in a health maintenance
      organization (HMO) is related to delivery of preventive clinical services to
      patients with different educational levels. METHODS: We conducted a cross
      sectional analysis of the 1996-1997 Community Tracking Study Household Survey
      among adults aged 18 to 64 years with private or Medicaid health insurance. We
      examined interactions between respondent educational level and HMO membership for
      the following measures: having a regular source of care and, in the past year,
      having had a physician visit, a mental health visit, a mammogram (women > or = 50
      years), an influenza vaccination (ages > or = 55 years), or smoking cessation
      counseling (smokers). RESULTS: After adjustment for sociodemographic factors,
      community size, insurance type, physical and mental health status, and smoking,
      respondents with less education were significantly less likely to have had a
      physician visit or mental health visit, mammogram, or influenza vaccination in
      the past year. Disparities in receipt of preventive care by educational level
      were smaller among HMO members. Differences in disparities between HMO members
      and non-HMO members reached statistical significance for influenza vaccination
      and showed a trend for mental health visits (P = .06). Moreover, HMO members with
      less than 12 years of education received services at levels comparable to non-HMO
      members with more education. CONCLUSIONS: There are appreciable disparities in
      receipt of preventive care by education among nonelderly insured persons. HMO
      membership is associated with smaller disparities for some services. Those with
      the lowest levels of education appeared to benefit the most from HMO membership.

PMID- 15040440
TI  - Patient-provider racial and ethnic concordance and parent reports of the primary
      care experiences of children.
AB  - PURPOSE: Studies among adults suggest that patient-provider racial concordance is
      associated with higher satisfaction and partnership with physicians. It remains
      unknown whether similar findings are true for children. This study examines the
      association of race/ethnicity concordance with parent reports of children's
      primary care experiences. METHODS: We completed telephone interviews with a
      random, cross-sectional sample of 413 parents of elementary school children, aged
      5 to 12 years, enrolled in a single large school district serving 3 cities in San
      Bernardino, Calif. Parents reported on their children's primary care experiences,
      and the responses were compared between children in race concordant and
      discordant patient-provider relationships. RESULTS: We assessed parent reports of
      6 structure and process features of primary care: first-contact care
      (accessibility, utilization), longitudinality (strength of affiliation,
      interpersonal relationship), and comprehensiveness (services offered, received).
      Before and after controlling for demographics, socioeconomic status, and health
      system factors, race/ethnicity concordance was not associated with children's
      primary care experiences. Minority parents generally reported poorer experiences
      than whites in several domains of primary care, but the only significant effect
      of race/ethnicity concordance was slightly better primary care utilization for
      whites in concordant relationships, which did not hold after adjustment.
      CONCLUSION: In contrast with studies among adults, patient-provider
      race/ethnicity concordance was not associated with parent reports of primary care
      experiences in our sample of children. It is possible that provider biases or
      patient expectations that contribute to disparities in care for adults are
      attenuated in relationships involving children.

PMID- 15040439
TI  - Who is caring for the underserved? A comparison of primary care physicians and
      nonphysician clinicians in California and Washington.
AB  - PURPOSE: Little is known about whether different types of physician and
      nonphysician primary care clinicians vary in their propensity to care for
      underserved populations. The objective of this study was to compare the
      geographic distribution and patient populations of physician and nonphysician
      primary care clinicians. METHODS: This study was a cross-sectional analysis of
      1998 administrative and survey data on primary care clinicians (family
      physicians, general internists, general pediatricians, nurse practitioners,
      physician assistants, and certified nurse-midwives) in California and Washington.
      For geographic analysis, main outcome measures were practice in a rural area, a
      vulnerable population area (communities with high proportions of minorities or
      low-income residents), or a health professions shortage area (HPSA). For patient
      population analysis, outcomes were the proportions of Medicaid, uninsured, and
      minority patients in the practice. RESULTS: Physician assistants ranked first or
      second in each state in the proportion of their members practicing in rural areas
      and HPSAs, and in California physician assistants also had the greatest
      proportion of their members working in vulnerable populations areas (P < .001).
      Compared with primary care physicians overall, nurse practitioners and certified
      nurse-midwives also tended to have a greater proportion of their members in rural
      areas and HPSAs (P < .001). Family physicians were much more likely than other
      primary care physicians to work in rural areas and HPSAs (P < .001). Compared
      with physicians, nonphysician clinicians in California had a substantially
      greater proportion of Medicaid, uninsured, and minority patients (P < .001).
      CONCLUSIONS: Nonphysician primary care clinicians and family physicians have a
      greater propensity to care for underserved populations than do primary care
      physicians in other specialties. Achieving a more equitable pattern of service to
      needy populations will require ongoing, active commitment by policy makers,
      educational institutions, and the professions to a mission of public service and
      to incentives that support and promote care to the underserved.

PMID- 15040441
TI  - Cultural expressions of bodily awareness among chronically ill Filipino
      Americans.
AB  - PURPOSE: To describe Filipino Americans' cultural traditions surrounding bodily
      awareness, especially how the principle of balance informs their views, and the
      link to self-management of chronic illness. METHODS: This qualitative study used
      semistructured interviews with 85 Filipino Americans between the ages of 46 and
      97 years. Volunteers were recruited from numerous health care sites in 1
      geographic location in the United States. Respondents had 1 or more chronic
      illnesses. Taped and transcribed interviews were coded and evaluated for themes.
      RESULTS: The concept of balance was central to Filipino Americans' portrayal of
      bodily awareness of signs and symptoms related to chronic illnesses, as well as
      to actions they took to manage their chronic illnesses. Efforts were made to
      control chronic illnesses through a variety of self-care practices. Diet posed a
      particular challenge because of the symbolic importance of food in Filipino
      culture and its use in the maintenance of social relationships. CONCLUSIONS: The
      ways in which Filipino Americans combine attention to the body, values of balance
      and harmony, and emphasis on social well-being result in heightened attention to
      bodily processes. Filipino Americans' emphasis on bodily awareness suggests that
      this particular cultural strength can be used to enhance chronic illness
      management. Awareness of the cultural traditions of Filipino Americans can
      facilitate patient education about how to manage chronic illnesses.

PMID- 15040442
TI  - Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics.
AB  - Studies of nonsense-mediated mRNA decay in mammalian cells have proffered
      unforeseen insights into changes in mRNA-protein interactions throughout the
      lifetime of an mRNA. Remarkably, mRNA acquires a complex of proteins at each exon
      exon junction during pre-mRNA splicing that influences the subsequent steps of
      mRNA translation and nonsense-mediated mRNA decay. Complex-loaded mRNA is thought
      to undergo a pioneer round of translation when still bound by cap-binding
      proteins CBP80 and CBP20 and poly(A)-binding protein 2. The acquisition and loss
      of mRNA-associated proteins accompanies the transition from the pioneer round to
      subsequent rounds of translation, and from translational competence to substrate
      for nonsense-mediated mRNA decay.

PMID- 15040443
TI  - Traffic jams affect plant development and signal transduction.
AB  - Analysis of the Arabidopsis thaliana endomembrane system has shown that plant
      cell viability depends on a properly functioning vacuole and intact vesicular
      trafficking. The endomembrane system is also essential for various aspects of
      plant development and signal transduction. In this review, we discuss examples of
      these newly discovered roles for the endomembrane system in plants, and new
      experimental approaches and technologies that are based on high-throughput
      screens, which combine chemical genetics and automated confocal microscopy.

PMID- 15040444
TI  - Sorting GPI-anchored proteins.
AB  - The study of glycosylphosphatidylinositol-anchored-protein sorting has led to
      some surprising new findings and concepts. Evidence is accumulating that, during
      their delivery to the surface, different types of plasma membrane protein might
      be sorted from each other early in this pathway, in the endoplasmic reticulum.
      Furthermore, membrane-lipid composition and microdomains might have a role in the
      process of protein sorting in both the secretory and endocytic pathways.

PMID- 15040445
TI  - Endocytic recycling.
AB  - After endocytosis, most membrane proteins and lipids return to the cell surface,
      but some membrane components are delivered to late endosomes or the Golgi. We now
      understand that the pathways taken by internalized molecules that eventually
      recycle to the cell surface can be surprisingly complex and can involve a series
      of sorting events that occur in several organelles. The molecular basis for many
      of these sorting processes is only partly understood.

PMID- 15040446
TI  - The dynamin superfamily: universal membrane tubulation and fission molecules?
AB  - Dynamins are large GTPases that belong to a protein superfamily that, in
      eukaryotic cells, includes classical dynamins, dynamin-like proteins, OPA1, Mx
      proteins, mitofusins and guanylate-binding proteins/atlastins. They are involved
      in many processes including budding of transport vesicles, division of
      organelles, cytokinesis and pathogen resistance. With sequenced genomes from Homo
      sapiens, Drosophila melanogaster, Caenorhabditis elegans, yeast species and
      Arabidopsis thaliana, we now have a complete picture of the members of the
      dynamin superfamily from different organisms. Here, we review the superfamily of
      dynamins and their related proteins, and propose that a common mechanism leading
      to membrane tubulation and/or fission could encompass their many varied
      functions.

PMID- 15040447
TI  - Repairing DNA-methylation damage.
AB  - Methylating agents modify DNA at many different sites, thereby producing lethal
      and mutagenic lesions. To remove all the main harmful base lesions, at least
      three types of DNA-repair activities can be used, each of which involves a
      different reaction mechanism. These activities include DNA-glycosylases, DNA
      methyltransferases and the recently characterized DNA-dioxygenases. The
      Escherichia coli AlkB dioxygenase and the two human homologues, ABH2 and ABH3,
      represent a novel mechanism of DNA repair. They use iron-oxo intermediates to
      oxidize stable methylated bases in DNA and directly revert them to the unmodified
      form.

PMID- 15040448
TI  - The SANT domain: a unique histone-tail-binding module?

PMID- 15040449
TI  - A conserved sequence upstream of the B29 (Ig beta, CD79b) gene interacts with
      YY1.
AB  - The human, murine, and rat B29 (Ig beta, CD79b) genes are highly conserved in
      sequence and organization and exhibit strict B cell-specific expression. In the
      human and rat genomes, the B29 gene is located between the skeletal muscle
      specific Na-channel alpha subunit (SCN4A) gene and the pituitary-specific growth
      hormone (GH-N) gene. The human pituitary-specific GH-N gene is controlled by a
      tissue-specific locus control region (LCR) located just upstream of the B29
      promoter that mediates tissue-specific enhancement, histone acetylation, and an
      open chromatin conformation across the B29 gene in growth hormone (GH)-expressing
      pituitary cells. Here we show that B29 mRNA is not detected in a GH-expressing
      pituitary cell line and that GH-N mRNA is not detected in B cells. This
      differential expression suggests that the B29 gene is insulated or otherwise
      protected from the regulatory influences of the closely proximal GH LCR. We
      searched available sequences upstream of the human, mouse, and rat B29 genes and
      found a highly conserved sequence that fulfills the criteria recently established
      for non-coding DNA elements potentially involved in gene control. This B29
      conserved sequence (BCS) bound ubiquitously expressed nuclear protein complexes.
      DNase I protection analysis of the BCS revealed a central 'footprinted' core
      which was confirmed to bind the multifunctional transcription factor, YY1.
      However, neither the BCS nor the YY1-binding core motif exhibited silencer or
      enhancer activity in transient transfections or position-independent insulator
      activity in enhancer-blocking assays. Thus, the BCS may function as a tissue
      specific LCR or position-dependent insulator specifically countering the
      influences of the 5' GH LCR and controlling B29 gene expression.

PMID- 15040450
TI  - Generation and characterization of a constitutively active Stat3 protein.
AB  - Stats are latent transcription factors involved in normal cellular signaling in
      response to cytokine or growth factor stimulation. Constitutive activation of
      Stats (primarily Stat3 and Stat5) has been implicated in growth dysregulation and
      oncogenesis. Furthermore, increased activation of Stats has been observed in
      several human tumors and tumor-derived cell lines. To assess the contribution of
      aberrant Stat activation in oncogenesis, we have created a chimeric molecule
      between Stat3beta and a portion of the Herpes simplex virus VP16 activation
      domain. The resulting protein, Stat3beta-VAD (VP16 activation domain), is
      tyrosine phosphorylated on Y705 and can bind DNA in the absence of upstream
      activation by c-Src or epidermal growth factor (EGF). Unlike Stat3alpha and
      Stat3beta, Stat3beta-VAD robustly activates transcription of several reporter
      genes without cytokine or growth factor stimulation. In addition, we show marked
      upregulation of the endogenous c-myc and c-fos genes upon inducible expression of
      Stat3beta-VAD in COS-7 cells. Our protein displays the constitutive
      transcriptional activation of Stat3alpha seen in human tumors and will be a
      valuable tool in screens for Stat3-regulated genes. In response to the
      established Stat3 involvement in human cancers, Stat3beta-VAD will also
      facilitate assessing the contribution of other cancer signaling cascades in the
      context of aberrant Stat3alpha activity in cancer development and progression.

PMID- 15040452
TI  - Stability of non-Watson-Crick G-A/A-G base pair in synthetic DNA and RNA
      oligonucleotides.
AB  - A non-Watson-Crick G-A/A-G base pair is found in SECIS (selenocysteine-insertion
      sequence) element in the 3'-untranslated region of Se-protein mRNAs and in the
      functional site of the hammerhead ribozyme. We studied the stability of G-A/A-G
      base pair (bold) in 17mer GT(U)GACGGAAACCGGAAC synthetic DNA and RNA
      oligonucleotides by thermal melting experiments and gel electrophoresis. The
      measured Tm value of DNA oligonucleotide having G-A/A-G pair showed an
      intermediate value (58 degrees C) between that of Watson-Crick G-C/C-G base pair
      (75 degrees C) and that of G-G/A-A of non-base-pair (40 degrees C). Similar
      thermal melting patterns were obtained with RNA oligonucleotides. This result
      indicates that the secondary structure of oligonucleotide having G-A/A-G base
      pair is looser than that of the G-C type Watson-Crick base pair. In the
      comparison between RNA and DNA having G-A/A-G base pair, the Tm value of the RNA
      oligonucleotide was 11 degrees C lower than that of DNA, indicating that DNA has
      a more rigid structure than RNA. The stained pattern of oligonucleotide on
      polyacrylamide gel clarified that the mobility of the DNA oligonucleotide G-A/A-G
      base pair changed according to the urea concentration from the rigid state (near
      the mobility of G-C/C-G oligonucleotide) in the absence of urea to the random
      state (near the mobility of G-G/A-A oligonucleotide) in 7 M urea. However, the
      RNA oligonucleotide with G-A/A-G pair moved at an intermediate mobility between
      that of oligonucleotide with G-C/C-G and of the oligonucleotide with G-G/A-A, and
      the mobility pattern did not depend on urea concentration. Thus, DNA and RNA
      oligonucleotides with the G-A/A-G base pair showed a pattern indicating an
      intermediate structure between the rigid Watson-Crick base pair and the random
      structure of non-base pair. RNA with G-A/A-G base pair has the intermediate
      structure not influenced by urea concentration. Finally, this study indicated
      that the intermediate rigidity imparted by Non-Watson-Crick base pair in SECIS
      element plays an important role in the selenocysteine expression by UGA codon.

PMID- 15040451
TI  - Stress-dependent regulation of the gene encoding gamma-glutamylcysteine
      synthetase from the fission yeast.
AB  - Glutathione (GSH), an important antioxidant involved in stress response, is
      synthesized in two sequential reactions. Gamma-glutamylcysteine synthetase (GCS)
      catalyzes the first step in GSH biosynthesis, which is usually known to be rate
      limiting. In this work, regulatory patterns of the GCS gene from the fission
      yeast Schizosaccharomyces pombe have been investigated. The 607 bp upstream
      region from the translational initiation point was amplified by the two synthetic
      primers. The amplified DNA was ligated into the BamHI/HindIII site of the shuttle
      vector YEp367R to generate the fusion plasmid pUGCS101. The GCS-lacZ fusion gene
      construct was confirmed by restriction mapping and nucleotide sequencing. The GCS
      lacZ fusion gene was used to study effects of various agents on the transcription
      of the GCS gene. The synthesis of beta-galactosidase from the fusion plasmid
      pUGCS101 was enhanced by metals, oxidative and nitrosative stresses, and
      glutathione-depleting agents. The GCS mRNA level in the wildtype S. pombe cells
      was significantly elevated by the treatment with sodium nitroprusside or
      menadione, which was detected by RT-PCR. It was also induced by low
      concentrations of glucose and sucrose. These results suggest that the expression
      of S. pombe GCS gene is regulated by various stresses and carbon sources.

PMID- 15040453
TI  - Establishment of the amplified fragment length polymorphism (AFLP) technique for
      genotyping of pollen beetle (Meligethes aeneus)--a noxious insect pest on oilseed
      rape (Brassica napus).
AB  - In order to conduct studies concerning genetic variability of pollen beetles
      (Meligethes aeneus), a genotyping protocol was established. No genome information
      is available for pollen beetles so the amplified fragment length polymorphism
      (AFLP) technique was chosen since it does not depend on any prior sequence
      information of the samples and also is a sensitive and robust technique. However,
      several modifications were needed in order to adapt the method for analysis of
      pollen beetles. Basic modifications included (i) alterations of DNA purification,
      (ii) use of two six-cutter restriction enzymes, (iii) and modified PCR
      conditions. This protocol resulted in a favourable number of fragments of an
      appropriate size range for standard gel analysis by a DNA sequencer applicable to
      a single insect and even body parts enabling different assays to be conducted on
      a single specimen. Pollen beetles from different areas of Sweden were analysed to
      verify the reproducibility and efficacy of the protocol as well as for phenetic
      analysis. The high reproducibility of the modified AFLP protocol allows it to be
      used as a reliable tool for genotype analysis of pollen beetles.

PMID- 15040454
TI  - Expression of muscle creatine kinase gene of mice and interaction of nuclear
      proteins with MEF-2, E boxes and A/T-rich elements during aging.
AB  - The changes in the expression of muscle creatine kinase (MCK) gene in the heart
      and skeletal muscle of mice during aging were studied. Its expression declines as
      a function of age in the heart, however, no age-related change is observed in the
      skeletal muscle. The cis-acting elements, MEF-2, E boxes and A/T rich elements
      present in the enhancer region of the mouse MCK gene are known to regulate the
      expression of the gene. Hence, these elements were subcloned and electrophoretic
      mobility shift assay was carried out to investigate the changes in the binding of
      the nuclear trans-acting protein factors of the heart with these elements as a
      function of age. These factors showed specificity for the respective cis-acting
      elements. Furthermore, the binding of these factors was found to decrease during
      aging which may contribute to the age-related decline in the expression of the
      MCK gene and activity of the heart.

PMID- 15040455
TI  - cDNA cloning and expression analysis of a novel human F-box domain containing
      gene.
AB  - F-box proteins are a large family of eukaryotic proteins that are characterized
      by an approximately 40 amino acid motif. Some F-box proteins are critical for the
      controlled degradation of cellular regulatory proteins. Here we report that a
      novel member of F-box proteins, FBXO35 gene, was cloned and identified during the
      large-scale sequencing analysis from a human fetal brain cDNA library. FBXO35
      gene shares amino acid similarity with several putative mouse genes not only in F
      box domain but also in the rest of the sequence, which indicates that FBXO35
      might also contain some other unknown conserved domain. RT-PCR analysis indicated
      that FBXO35 gene had a ubiquitously low expression pattern in most human adult
      tissues. According to bioinformatics analysis, the FBXO35 gene was found located
      in chromosome 3p21.

PMID- 15040457
TI  - The Italian way to nanotherapies.

PMID- 15040456
TI  - Characterization of a human Sec14-like protein cDNA SEC14L3 highly homologous to
      human SPF/TAP.
AB  - Supernatant protein factor (SPF) and alpha-tocopherol-associated protein (TAP)
      both belong to a widespread lipid-binding Sec 14-like protein family. All the
      members of the family have the lipid-binding motif called CRAL_TRIO. SPF is
      showed to stimulate the conversion of squalene to lanosterol and enhance
      cholesterol biosynthesis. TAP is identified to be involved in the intracellular
      distribution of alpha-tocopherol. Recently TAP is identified as SPF though they
      have very different functions. Here we report a human SPF/TAP homology SEC14L3
      with 2082 base pairs in length and contains an open reading frame encoding a 400
      amino acids protein. Analysis shows that SEC14L3 is mapped to 22q12 and expresses
      only in the liver among the used sixteen tissues in the test.

PMID- 15040458
TI  - Intravenous versus subcutaneous injections of apomorphine in rabbits: a
      pharmacokinetic paradox.
AB  - The objective of this investigation was an attempt to conclusively prove the
      accidental observation that the AUC of apomorphine in rabbits was repeatedly
      lower after intravenous injection compared to subcutaneous injection. Apomorphine
      was administered to rabbits by intravenous and subcutaneous routes at 2 different
      doses (0.31 mg/kg, n=10; and 0.25 mg/kg, n=6). Plasma drug concentrations were
      measured by HPLC-ECD and pharmacokinetic parameters were estimated by
      compartmental and non-compartmental approaches. The AUC of apomorphine in rabbits
      were: for subcutaneous injection, 14138 +/- 502 ng/ml/min and 12680 +/- 855
      ng/ml/min, n=10 and 6, respectively; for intravenous injection, 11850 +/- 718
      ng/ml/min and 9147 +/- 671 ng/ml/min, n=10 and 6, respectively. These AUC values
      were statistically significantly lower when given as intravenous injection
      compared to subcutaneous injection (p=0.0011 and 0.0117, n=10 and 6,
      respectively). The T1/2,elim values were: for subcutaneous injection, 17.1 +/-
      1.70 min and 18.7 +/- 1.68 min, n=10 and 6, respectively; for intravenous
      injection, 15.3 +/- 1.20 min and 15.0 +/- 2.24 min, n=10 and 6, respectively.
      There were no significant differences between the T1/2,elim from both
      administration routes (p=0.3984 and 0.2158, n=10 and 6, respectively). Given the
      reproducibility of the results, it was concluded that the AUC of apomorphine
      after intravenous injection in rabbits is anomalously lower than that of
      subcutaneous injection.

PMID- 15040459
TI  - Pulsatile and sustained peptides release from Zn(II) suspensions.
AB  - The dynamics of peptide release from suspensions in the form of solid, sparingly
      soluble Zn(II)-Peptide complexes in molar ratio 50:1 was observed in vitro
      conditions. Thyroliberine and dalareline release from suspensions is
      statistically significant in comparison with gonadrenaline release. Pulsatile
      character of peptide release in 6 significant peaks of released dalareline, 5--of
      gonadoreline release and 4--thyroliberine were observed. Thyroliberine was
      released fastest from the obtained suspensions--63 h +/- 3.1, and dalareline was
      released slowest--26.5 h +/- 2.3. The release time for gonadoreline from
      suspensions was 12.0 h +/- 1.0. Molecular weight of the peptide and properties of
      the Zn(II)-Peptide complexes have major influence upon the character and time of
      peptide release from suspensions. The greater is the molecular weight and
      durability of Zn(II)-Peptide complex, the bigger is the number of peaks of the
      peptide released from suspensions. The release time of the peptides is longer
      when the molecular weight of the released peptide is bigger.

PMID- 15040460
TI  - O/W microemulsions for oral drug delivery.
AB  - Quaternary microemulsion compositions for oral administration using isopropyl
      myristate, polysorbate 80 and ethanol 96 degrees were developed and three ratio
      of polysorbate to ethanol were selected. Isotropic single-phase compositions were
      considered as microemulsions and were registered on a Pseudo-Ternary Phase
      Diagram. The objective was to formulate a therapeutic dose for lorazepam and
      loperamide in a drop liquid form. Another aim was to obtain a liquid oral formula
      for nifedipine taking advantage of its insured fast absorption to be used in
      hypertensive crises. The physical stability of the compositions was evaluated by
      normal aging, centrifugal resistance time and by cycling as well. The selected
      formulation characterization included density, pH and conductivity measurements.
      The particle size distribution was determined by a light scattering method and,
      finally the carried drugs concentration was valued. The versatility showed by
      this type of systems allows both to carry drugs of different physico-chemical
      properties and to deal with a number of pharmacotherapeutic objectives.

PMID- 15040461
TI  - Optimal conditions for accumulation of bioavailable iron in Saccharomyces
      cerevisiae cells.
AB  - Growth and proliferation of brewer's yeast Saccharomyces cerevisiae in the
      presence of different Fe2+ levels was studied with the aim of finding optimal
      conditions for a maximum accumulation of bioavailable iron bound to constituents
      of yeast cells. The results demonstrated that iron stimulates growth and
      proliferation only under conditions of intensive aeration. Iron accumulation and
      the effect of aeration were examined in the presence 3.6 microM - 7.2 mM Fe2+,
      while its content in the cells after 20 h cultivation was determined by atomic
      absorption spectrophotometry. Control cultures were grown in no iron added
      medium. Further experiments revealed that iron concentrations ranging from 3.6
      microM to 3.6 mM were beneficial to growth and proliferation, while higher levels
      did not affect these processes. The above range of iron concentrations also led
      to a more extensive iron accumulation, while further increase expressed no
      effect. So, Fe2+ concentration of 3.6 mM, enabling its high accumulation within
      the cells, while not negatively affecting biomass yield was selected for further
      studies. Iron uptake led to the modifications in transport of several other
      elements (Ca2+, Zn2+, K+ and Na+) and thus to the change in ion composition of
      the cells in comparison with the corresponding control.

PMID- 15040462
TI  - Analgesic effects of crude extracts of Miconia albicans (Melastomataceae).
AB  - The present study describes the analgesic effects of the crude extracts (hexane,
      methylene chloride and ethanol) obtained from the aerial parts of Miconia
      albicans (Melastomataceae) using the writhing test and the hot plate models for
      pain in mice. The extracts in hexane and methylene chloride, given orally,
      produced significant antinociception in the writhing test. On the other hand,
      none of the extracts had a significant effect on the hot plate test, a fact
      suggesting that the substances present in the extracts may rather have peripheral
      analgesic activity.

PMID- 15040463
TI  - Influence of polymers weight ratio and pH of polymers solution on the
      characteristics of chitosan-carboxymethyl cellulose microspheres containing
      theophylline.
AB  - Optimization of formulation for chitosan-carboxymethyl cellulose (CH-CMC)
      microspheres that contain a drug of narrrow therapeutic index was the interest of
      this study. Theophylline (TPH) was chosen as a model drug. The effects of
      chitosan:sodium carboxymethyl cellulose (CH:SCMC) weight ratio (X1) and pH of
      polymers solution (X2) as independent variables on the physical characteristics
      of the microspheres as well as release profile of TPH from microspheres prepared
      by the emulsion coacervation-phase separation technique were studied. The
      influence of each of the two variables on responses such as angle of repose,
      compressibility index, incorporation efficiency particle size, initial drug
      release, time for 50% drug release (T50%) and % drug released in 8 hours was
      investigated. Generally, the increase in CH:SCMC weight ratio showed to increase
      the incorporation efficiency of the drug, increase the particle size and decrease
      the flowability of the microspheres. The increase of CH:SCMC ratio was also
      responsible to get low initial drug release, slow drug release (long T50%) and
      incomplete total drug released in 8 hours. On the other hand, high and low pHs of
      polymers solution were responsible to decrease drug incorporation in the
      microspheres and to produce small particles while, good flowability was obtained
      at pHs 2.5 and 4. A full factorial experimental design was employed to
      investigate the effect of the two independent variables on the responses. The
      results were analyzed by a general quadratic equation and response surfaces
      generated. From the obtained regression, it was concluded that the effect of
      CH:SCMC polymers ratio is more significant in changing the values of flowability
      particle size and drug release in 8 hours while pH values were more significant
      in changing the values of initial drug release and T50%. On the other hand the
      interaction coefficients of the two variables showed synergistic effect on
      flowability and drug release in 8 hours while, there were antagonist effects on
      particle sizes and T50%. From the optimization studies it is possible to choose
      the conditions required for the preparation of microspheres with the desired
      characteristics.

PMID- 15040464
TI  - Studies of wet granulation in small scale high shear mixer of 20 mg tablets of
      policosanol.
AB  - It was studied the influence of three factors in the manufacturing process of
      tablets containing 20 mg of policosanol in a small scale when was used a high
      shear mixer. A factorial design without repetitions was used, considering as
      independent variables: volume of binder solution, kneading time and the use or
      not of chopper. Data analysis was carried out using the Yates algorithm,
      considering the effect of these three factors over the diameter of the granules,
      the percent of fine powders in granulate and the compression forces. The diameter
      of the granules was increased with an increase in the volume of the binder
      solution added and with an increase in the kneading time and was decreased when
      the chopper was used. The percent of fine powders, present in granulate, was
      significantly diminished with an increase of the volume of binder solution and
      diminished with an increase in the kneading time, the influence of the use of
      chopper was insignificant. The compression forces diminished with the use of
      chopper, with the increase of the volume of binder solution used and are not
      affected with the changes in the kneading time.

PMID- 15040465
TI  - Diclofenac sodium loaded gelatin magnetic microspheres for intra-arterial
      administration: formulation, characterization and in vitro release studies.
AB  - Gelatin magnetic microspheres loaded with diclofenac sodium were prepared by
      emulsification and crosslinking by glutaraldehyde. The microspheres were
      formulated with 23-30% theoretical diclofenac sodium and magnetite content. The
      formulated microspheres were characterized by drug loading, entrapment
      efficiency, encapsulation efficiency, magnetite content, FT-IR spectroscopy,
      particle size analysis, optical microscopy, scanning electron microscopy, and in
      vitro release studies. The data obtained from the in vitro release studies were
      applied to various kinetic models. The FT-IR revealed no drug/polymer
      interaction. The average particle size was between 36 to 61 microm depending on
      quantity of magnetite and gelatin used. Optical microscopy and SEM showed
      spherical and compact nature of microspheres. The formulated microspheres
      released the drug for a period of 42 to 78 hours depending on drug loading. The
      release was diffusion controlled at lower drug loading and dissolution/diffusion
      controlled at higher drug loading.

PMID- 15040466
TI  - An empirical assessment of the possibility of interchangeability between
      multisource ciprofloxacin hydrochloride tablets marketed in Nigeria.
AB  - A critical quality control of seven brands of ciprofloxacin hydrochloride tablets
      marketed in Nigeria [Cifran (Ranbaxy, Nigeria), Ciproxin (Bayer, Nigeria), Cenox
      (Micro labs, India), Ciprotab (Fidson Drugs, India), Ciprofloxacin MS1 and MS2
      (Sintacrus Medical stores] were carried out with the aim of selecting brands that
      are interchangeable. The weight uniformity, disintegration time, absolute drug
      content and in vitro dissolution profile of the various brands of the tablets
      were evaluated in simulated intestinal fluid (SIF) and simulated gastric fluid
      (SGF) without enzymes. The concept of dissolution efficiency (DE) was used to
      predict the likely in vivo availability. The weight uniformity and the
      disintegration time of most of the tablets were within the acceptable official
      ranges. The DE varies widely in the two media. Based on the DE in SGF, Cifran,
      Ciproxin, Cenox and Ciproflox are bioequivalent and therefore interchangeable. In
      SIF, however only Ciproflox and Ciprofloxacin MS1 (blue label) were bioequivalent
      with the innovator brand (Ciproxin, Bayer). In vitro dissolution studies using
      the concept of dissolution efficiency could serve as a rapid means of selecting
      probable therapeutically effective brands of ciprofloxacin HCl marketed in
      Nigeria. Using this concept, four brands (Cifran, Ciproflox, Cenox and Ciproxin)
      have been shown to be bioequivalent.

PMID- 15040467
TI  - In vitro study on sustained release capsule formulation of acetazolamide.
AB  - In the present study formulation of sustained release capsule of acetazolamide
      250 mg was tried using nonpareil seeds. Nonpareil seeds were coated with drug,
      polyvinylpyrrolidone, glyceryl monostearate, microcrystalline wax, and glyceryl
      distearate either individually or in combination to achieve sustained release
      capsule 250 mg. In successful formulation 20% drug coated pellets and 80% wax
      coated pellets were taken. Wax coated pellets for successful formulation
      contained coating of microcrystalline wax and glyceryl distearate on drug coated
      pellets of the same concentration of 1.6% w/w. Successful formulated sustained
      release capsule 250 mg of acetazolamide was compared in in vitro study with
      theoretical sustained release formulation suggested by wagner and one marketed
      sustained release capsule 250 mg. Formulated capsule showed result superior to or
      on par with marketed capsule. For successful formulation pellets were filled in
      '1' size hard gelatin capsule and stability study was carried out in hot air over
      at room temperature and 45 degrees C for 5 weeks. The formulation was found
      stable in respect of drug content and release rate.

PMID- 15040469
TI  - In vivo assessment of iron and ascorbic acid in psoriatic dermis.
AB  - Reactive oxygen species play an important role in inflammatory skin diseases such
      as psoriasis. Reactive oxygen species synthesis is catalysed by iron and some
      species are scavenged by ascorbic acid. The aim of this work was to assess iron
      and ascorbic acid in uninvolved and involved psoriatic dermis and to compare the
      corresponding concentrations in the dermis of healthy subjects. Microdialysis
      associated with atomic absorption spectrometry and gas chromatography-mass
      spectrometry was used to assess iron and ascorbic acid, respectively. Seven
      psoriatic patients and five healthy volunteers were studied. Iron concentrations
      in the involved (57.1 +/- 19.3 microg/l) and uninvolved (49.7 +/- 27.1 microgl/l)
      psoriatic dermis were higher than the corresponding value determined in the
      dermis of healthy subjects (21.8 +/- 2.4 microg/l) (p<0.05). Ascorbic acid in
      involved (47.3 +/- 8.2 microg/ml) and uninvolved (42.0 +/- 14.0 microg/ml)
      psoriatic dermis was statistically lower than that found in healthy dermis (176.8
      +/- 29.0 microg/ml) (p<0.05). These results demonstrate that psoriatic patients
      exhibit high iron and low ascorbic acid concentrations in the dermis, but there
      were no significant differences between involved and uninvolved skin.

PMID- 15040468
TI  - Evaluation of efficiency of insulin suppository formulations containing sodium
      salicylate or sodium cholate in insulin dependent diabetic patients.
AB  - Two formulations of insulin suppositories were prepared to contain different
      amounts of sodium salicylate and sodium cholate as absorption promoters and also
      of insulin with the purpose of obtaining the most effective formulation in
      reducing plasma glucose levels after rectal administration to diabetic patients.
      The results show that insulin suppositories containing 100 mg sodium salicylate
      and 100 or 200 U of crystalline insulin showed no significant difference in AUC,
      Cmax and Tmax and both formulations showed significant reduction in plasma
      glucose level compared to initial values within 1.5-2 h. The results from
      experiments carried out in health volunteers showed that 100 mg sodium salicylate
      is the optimum amount to be included in insulin suppositories producing
      significantly higher Cmax and AUC compared to those produced after rectal
      administration of insulin suppositories containing 50 or 200 mg sodium
      salicylate. The results also show that using sodium cholate in 50 mg amount did
      not produce any significant reduction in plasma glucose levels of insulin
      dependent diabetic patients given suppositories containing 100 U of insulin, but
      this amount in suppositories containing 200 U of insulin was able to produce
      significant (p < 0.05) reduction in plasma glucose level within 1 h which lasted
      till end of experiment producing Cmax of 29.7 +/- 6.61% at Tmax of 1.5 +/- 0.61
      h. On increasing the amount of sodium cholate to 100 mg in the suppositories, a
      marked (p < 0.01) reduction in plasma glucose level took place and the Cmax
      increased to 47.7 +/- 12.24% at Tmax of 1.5 +/- 0.63 h. This resulted in AUC of
      86.7 +/- 22.4 mg%h which was non significantly higher from that produced after
      administration of suppositories containing 50 mg sodium cholate and 200 U insulin
      (62.5 +/- 17.6 mg%h). The results also show that insulin suppositories containing
      100 mg sodium cholate and 200 U insulin resulted in a non significant differences
      in Cmax and AUC from those produced by S.C. injection of insulin (20 U) but
      significantly (p < 0.001) shorter Tmax. This formulation also shows non
      significant differences in Tmax and AUC and significantly (p < 0.05) higher Cmax
      than from those produced after rectal administration of suppositories containing
      100 mg of sodium salicylate and same amount of insulin. Further more this
      formulation produced severe hypoglycemia in control healthy volunteers within 1 h
      of administration producing Cmax of 57.0 +/- 18.8% at Tmax of 0.75 +/- 0.35 h.
      The results of this study showed that the formulation containing 100 mg of sodium
      cholate and 200 U of insulin tested in fasted insulin dependent diabetic patients
      produced a maximum % reduction in plasma glucose levels (Cmax) of 47.7 +/- 12.24%
      at tmax of 1.5 +/- 0.63 h compared to Cmax of 50.56 +/- 6.8% at tmax of 2.93 +/-
      0.19 h resulted after subcutaneous injection of 20 U insulin. These suppositories
      produced an area under the curve (AUC) of 87 +/- 22.4 mg%h compared to an AUC of
      81 +/- 13.4 mg%h obtained after subcutaneous injection. This formulation of
      suppositories studied in 7 insulin dependent diabetic patients was found to
      abolish the 2-h post-prandial significant rise in plasma glucose levels after
      meal. These results show that these insulin suppositories containing 100 mg of
      sodium cholate and 200 U of insulin can serve as effective buffer against meal
      related hyperglycemia. The suppositories were safe, effective, accepted and well
      tolerated by the tested individuals.

PMID- 15040470
TI  - Comparative analysis of TCR-gamma gene rearrangements by Genescan and
      polyacrylamide gel-electrophoresis in cutaneous T-cell lymphoma.
AB  - Demonstrating T-cell clonality has become an important approach supporting a
      diagnosis of malignant T-cell neoplasms. A comparative study between Genescan
      analysis, polyacrylamide gel and agarose gel electrophoresis in visualizing T
      cell receptor gamma gene rearrangement was performed on 25 biopsy specimens from
      18 patients with different forms of cutaneous T-cell lymphomas. Clonality was
      detected in 17 biopsy specimens when PCR products were evaluated by Genescan
      analysis. Seventeen showed discrete bands when visualized in polyacrylamide gel
      and 14 cases were clonal when visualized with agarose gel. In five cases, a
      clonal population was seen in the gels, but not with Genescan. On sequencing the
      PCR products we demonstrated non-clonality of these five samples. Our results
      confirm that PCR-Genescan is a useful, reliable and specific screening method for
      detecting dominant clones in patients with T-cell lymphoma.

PMID- 15040471
TI  - Contact allergy to the isomers of diglycidyl ether of bisphenol F.
AB  - Diglycidyl ether of bisphenol A (DGEBA) is the monomer and main allergen in the
      most common epoxy resin, DGEBA-R. Epoxy resin(s) based on bisphenol F (DGEBF-R)
      contains the 3 isomers of the diglycidyl ether of bisphenol F. Contact allergy to
      these isomers (p,p'-DGEBF, o,p'-DGEBF and o,o'-DGEBF) has not previously been
      described in humans. To investigate contact allergies to the DGEBF isomers in
      patients with contact allergy to DGEBF-R, 9 patients were patch-tested with
      dilution series of the isomers. All 9 were found to have contact allergy to p,p'
      DGEBF and 7/9 to o,p'-DGEBF. Additionally, of 20 workers employed in epoxy-based
      manufacture and with contact allergy to DGEBA-R and DGEBF-R, 18 reacted to p,p'
      DGEBF and 15/20 to o,p'-DGEBF. According to a guinea pig maximization test, all 3
      DGEBF isomers are strong sensitizers. Still, o,o'-DGEBF elicited only 3 positive
      reactions in all participants.

PMID- 15040472
TI  - Epidermal hyperproliferation and decreased skin barrier function in mice
      overexpressing stratum corneum chymotryptic enzyme.
AB  - Stratum corneum chymotryptic enzyme (SCCE; also known as kallikrein 7) is a
      serine protease that may have an important role in the skin desquamation process.
      We have recently described transgenic mice overexpressing human SCCE in
      suprabasal epidermal keratinocytes, leading to increased epidermal thickness,
      hyperkeratosis, dermal inflammation and signs of severe pruritus in older
      animals. In order to further evaluate the scce-transgenic mice as a potential
      disease model, we compared transgenic animals and wild-type littermates for
      patterns of epidermal keratin expression, in situ hybridization of scce-mRNA,
      scratching behaviour and measurements of transepidermal water loss (TEWL). In 3
      day-old mice, despite readily detectable amounts of human scce-mRNA in the
      epidermis of transgenic animals, there were no histological differences in skin
      appearance, and no differences could be found in epidermal expression of the
      keratins 5, 6 and 10. In mice 7-8 weeks of age and older, there was strong
      suprabasal expression of keratins 5 and 6 in the epidermis of transgenic animals,
      suggesting that the thickened epidermis in these animals is the result of
      keratinocyte hyperproliferation. In transgenic animals 11 weeks of age and older
      there was an increased frequency of scratching, suggestive of pruritus, and also
      signs of a deteriorating skin barrier function, as reflected by an increased
      TEWL. There was no correlation between increased TEWL and increased frequency of
      scratching in individual animals, suggesting that the defect barrier function was
      not an effect of skin damage caused by scratching.

PMID- 15040473
TI  - Cutaneous side effects in non-small cell lung cancer patients treated with Iressa
      (ZD1839), an inhibitor of epidermal growth factor.
AB  - We report the cutaneous side effects of Iressa (ZD1839), a new anti-cancer agent
      that acts by inhibiting epidermal growth factor receptor signal transduction. The
      most common cutaneous adverse effect was the development of an acneiform eruption
      on the face, anterior trunk and back (39%). The second most common side effect
      was xerosis or desquamation of the face, body or distal parts of the fingers or
      toes (36%). Additional cutaneous side effects included multiple ingrown
      paronychial inflammation of the toes and fingers (6%), small ulcers of the oral
      mucosa or nasal mucosa, and urticaria. The cutaneous adverse effects of Iressa
      are similar to those of other epidermal growth factor receptor-targeted agents
      and result from direct interference with the functions of epidermal growth factor
      receptor signalling in the skin. Iressa-induced acne may be related to excessive
      follicular hyperkeratosis, follicular plugging, obstructions of the follicular
      ostium and alteration of hair cycle progression, which lead to an inflammatory
      response. Xerosis or desquamation reflects a disturbance of the equilibrium
      between proliferation and differentiation of epidermis. The mechanism by which
      Iressa leads to the development of paronychia and ingrown nail remains unclear.

PMID- 15040474
TI  - Self-reported dermatological problems and preferences for health: an
      epidemiological survey.
AB  - Patient preferences for health can be assessed and expressed in quantitative
      terms known as health state utilities. In this epidemiological study, we
      demonstrate the importance of dermatological problems for health state utilities.
      A cross-sectional survey including 5,404 individuals aged 20-84 years was
      conducted in the County of Uppland, Sweden. Information on dermatological
      problems and use of prescription-only topical drugs was obtained by self-report.
      Dermatological problems were reported by 20.5%. A rating scale used to assess
      utilities showed that persons reporting dermatological problems had lower health
      state utilities than those not reporting such problems (p<0.001). Persons using
      prescription-only topical drugs had lower health state utilities than others with
      dermatological problems. Dermatological problems had an independent and
      statistically significant effect on health state utilities when age, sex, somatic
      and psychiatric co-morbidity, and pain were included in the multivariate
      analysis. It is shown that skin disorders are a considerable problem in the
      population and results in a significant decrease in health state utilities.

PMID- 15040475
TI  - Relationship between skin bacterial colonization and the occurrence of allergen
      specific and non-allergen-specific antibodies in sera of children with atopic
      eczema/dermatitis syndrome.
AB  - In this study we investigated skin bacterial colonization, allergen-specific IgE
      and antiphospholipid/antinuclear antibodies in 72 children with atopic
      eczema/dermatitis syndrome (age 2-17 years). Bacteria were found on the skin in
      41 cases and serological allergen-specific IgE positivity in 37. The different
      forms of antibodies appeared in the ratio 21/72 (33 antibodies in 21 children).
      The occurrence of antiphospholipid antibodies was significantly higher in the
      patients than in the controls. There were significantly more allergens in the
      group with bacterial colonization than in the group without colonization. The
      SCORAD index showed a significant positive association with the skin
      colonization. We conclude that there are significant relationships between the
      occurrence of Staphylococcus aureus colonization and the levels of inhalant
      allergen-specific IgE in children with atopic eczema/dermatitis syndrome, and
      between the occurrence of antiphospholipid IgM positivity and atopic
      eczema/dermatitis syndrome.

PMID- 15040476
TI  - Determinants of quality of life in a psoriasis population in northern Sweden.
AB  - The aim of this study was to assess possible determinants of quality of life in
      psoriasis patients in northern Sweden, and to analyse the association between
      these determinants and quality of life. A questionnaire was mailed to 1,707
      subjects, resulting in a response rate of 74%. The study is therefore based on
      1,060 subjects, since 195 denied having psoriasis. Quality of life was measured
      using a version of the Dermatology Life Quality Index. The extent of the disease
      was estimated using the patients' sketches. The association between determinants
      and quality of life was calculated in a risk analysis using logistic regression.
      Large disease extent and joint symptoms were the strongest indicators for
      impaired quality of life. Other indicators were withdrawal from medical treatment
      due to distance to treatment facilities, which strongly influenced the quality of
      life and choice of treatment.

PMID- 15040477
TI  - Risk factors for incomplete excision of basal cell carcinomas.
AB  - Incomplete excision of basal cell carcinomas (BCCs) may be followed by recurrence
      of the tumor. In order to detect risk factors for incomplete excision of BCCs we
      performed a cross-sectional study of 1278 patients who underwent a primary
      excision of BCCs, during a four-year period, within an ambulatory and hospital
      plastic surgery department setting. Incomplete excision occurred in 159 of 1478
      primary excisions of BCCs (10.8%) and was significantly associated with location
      of the tumors in the eyelids (OR 3.64, 95% CI 1.96-6.71), ears (OR 2.51, 95% CI
      1.25-4.94), naso-labial folds (OR 2.26, 95% CI 0.99-5.04) and nose (OR 1.88, 95%
      CI 1.30-2.71). There was an inverse association with location of the tumors in
      the upper limbs (OR 0.44, 95% CI 0.21-0.90), back (OR 0.12, 95% CI 0.02-0.48) or
      chest (OR 0.09, 95% CI 0.00-0.57). Baso-squamous differentiation was associated
      with incomplete excision of BCCs (p = 0.03). No association was observed between
      incomplete excision of BCCs and gender, age, setting of the operation (ambulatory
      vs. hospital), clinical appearance of the lesion (suspected BCCs vs. other
      diagnoses) or diameter of the lesions. In conclusion, incomplete excision of BCCs
      was associated with location of the tumors in the eyelids, ears, naso-labial
      folds and nose. We recommend that in patients with BCCs located in these sites,
      surgeons should commence particular surgical measures to avoid inadequate
      excisions of the tumors.

PMID- 15040478
TI  - Serum levels of autoantibodies to desmoglein 3 in patients with therapy-resistant
      pemphigus vulgaris successfully treated with adjuvant intravenous
      immunoglobulins.
AB  - The mainstay of treatment of pemphigus vulgaris is systemic corticosteroids.
      Intravenous immunoglobulins have been reported as an adjuvant corticosteroid
      sparing regimen in recalcitrant pemphigus vulgaris. The purpose of the study was
      to monitor disease activity, serum levels of autoantibodies and doses of oral
      corticosteroids in 4 patients with recalcitrant pemphigus vulgaris adjuvantly
      treated with intravenous immunoglobulins (2 g kg(-1) monthly). After initiation
      of intravenous immunoglobulins, all patients showed clinical improvement and a
      decrease in autoantibody serum levels, as detected by both indirect
      immunofluorescence microscopy and ELISA. Corticosteroids and immunosuppressants
      could be reduced and even discontinued in one patient. In 3 patients, intravenous
      immunoglobulins were discontinued after 12 cycles. Subsequently, new blisters
      developed and autoantibody levels rose again. After re-initiation of intravenous
      immunoglobulins, in 2 patients, the condition quickly improved again, along with
      a decrease in autoantibody serum levels. It is concluded that the administration
      of intravenous immunoglobulins was associated with a decrease in circulating
      autoantibodies and clinical improvement in our patients.

PMID- 15040479
TI  - Blastic CD56+ natural killer-cell lymphoma with primary cutaneous manifestation.
AB  - T/natural killer-cell lymphomas belong to a heterogeneous group of non-Hodgkin
      lymphomas with predominant extranodal, often cutaneous, manifestations. In
      contrast to B- and T-cell lymphomas, T/NK-cell lymphomas were only recently
      regarded as a distinct entity. These rather aggressive malignancies arise from
      cytotoxic T cells, NK-cells or NK-like T cells, which share several phenotypic
      and functional properties. We report a man with a blastic NK-cell lymphoma with
      nodular skin infiltrations as the leading clinical manifestation of the disease.
      Complicated of tuberculosis, the patient died within 9 months of diagnosis,
      despite aggressive polychemotherapy.

PMID- 15040482
TI  - Drug-induced eosinophilia and multisystemic failure with positive patch-test
      reaction to spironolactone: DRESS syndrome.
AB  - We report the case of a 58-year-old man who suffered from a generalized and
      intolerable itching one month after starting treatment with colchicine,
      amiodarone, perindopril, allopurinol and spironolactone. From the start of
      treatment he had progressively developed erythroderma, fever, anorexia and
      prostration, oedema of both hands and face, hypereosinophilia (42%; 5810
      eosinophils/mm3), hepatic failure (including cholestatic jaundice, cytolysis,
      coagulation abnormalities and hypoproteinaemia), exocrine pancreatic failure
      (with severe steatorrhoea), renal failure, metabolic acidosis, aggravation of pre
      existing cardiac insufficiency and oedema of the lower extremities. All
      medications were stopped and the condition improved slowly until complete
      remission was reached 4 months later. Patch-testing was performed, including the
      various drugs. All the tests (including components of the vehicles) were
      negative, except for spironolactone, which gave a strong positive reaction. Ten
      controls in healthy volunteers were negative. The diagnosis of drug rash with
      eosinophilia and systemic symptoms (DRESS) induced by spironolactone was made.
      This is the first report of DRESS due to spironolactone.

PMID- 15040481
TI  - Unusual spindle cell squamous carcinoma in a renal transplant patient.
AB  - The histopathological diagnosis of spindle cell tumours is often difficult. We
      present a patient who developed a painful tumour on his head 6 years after renal
      transplantation. Histologically, the tumour was first interpreted as scar tissue
      with an unusual fibrohistiocytic component. Cytokeratins, desmin, CD31, CD34 and
      S100 could not be detected using conventional immunohistochemistry. After two
      recurrences and intensive immunohistochemical examinations, cytokeratin-positive
      tumour areas in direct connection with the epidermis were detected. The final
      diagnosis was therefore spindle cell squamous carcinoma. The patient finally died
      from brain metastases after experiencing further painful recurrences that were
      removed surgically. Our case underscores the importance of refined
      immunohistochemical methods in establishing the diagnosis of spindle cell
      squamous carcinomas, methods that should be taken into account especially if
      painful spindle cell tumours arise on sun-exposed skin in immunosuppressed
      patients.

PMID- 15040480
TI  - Progressive hyperpigmentation and generalized lentiginosis without associated
      systemic symptoms: a rare hereditary pigmentation disorder in south-east Germany.
AB  - Familial progressive hyperpigmentation is rarely described in the literature. We
      report on five patients from three different families presenting with a peculiar
      progressive pigmentary disorder. The patients show a progressive diffuse, partly
      blotchy, hyperpigmentation, intermixed with scattered small hypopigmented
      macules, a few large hypopigmented areas, occasional cafe-au-lait spots and, most
      remarkably, a generalized lentiginosis. Histology revealed different degrees of
      basal layer hyperpigmentation and pigment incontinence, also in the spots
      appearing hypopigmented. Ultrastructural analysis showed a normal mode of
      Caucasian-like melanogenesis with varying content of regular melanosome complexes
      within the keratinocytes. All families are clustered in a small area around the
      town of Teublitz in south-east Germany with about 20,000 inhabitants, suggesting
      a genetic founder effect. Pedigree analysis is compatible with an autosomal
      dominant mode of inheritance with variable penetrance. Only a few similar, but
      not identical, cases have been reported in the past. This cluster of cases may
      therefore represent a rare and perhaps novel variant of a familial progressive
      disorder of hyperpigmentation.

PMID- 15040483
TI  - UVA1 phototherapy of Netherton syndrome.

PMID- 15040484
TI  - Successful treatment of severe foot dermatitis by iontophoresis and local bath
      PUVA.

PMID- 15040485
TI  - Association of infantile cutaneous haemangioma on the face and neck with
      respiratory distress in infancy.

PMID- 15040486
TI  - Prognosis of subglottic haemangiomas associated with facial haemangiomas in a
      paediatric population: a preliminary study.

PMID- 15040488
TI  - Cheilitis glandularis: a case report.

PMID- 15040487
TI  - Rosacea and personality.

PMID- 15040489
TI  - Linear verrucous haemangioma on the abdomen.

PMID- 15040490
TI  - Dermatitis caused by Balaustium murorum.

PMID- 15040491
TI  - Pemphigus foliaceus developing on pre-existing psoriasis: a supposed pathogenetic
      linkage.

PMID- 15040492
TI  - Lymph node false-positive FDG-PET after recent surgery in primary melanoma.

PMID- 15040493
TI  - Simultaneous onset of chronic graft versus host disease and alopecia areata
      following allogeneic haematopoietic cell transplantation.

PMID- 15040494
TI  - Anderson-Fabry disease: enzyme replacement therapy.

PMID- 15040495
TI  - Early cyclosporine treatment of incipient toxic epidermal necrolysis induced by
      concomitant use of lamotrigine and sodium valproate.

PMID- 15040496
TI  - Systemic contact dermatitis due to captopril without cross-sensitivity to
      fosinopril, quinapril and benazepril.

PMID- 15040497
TI  - Drug rash with eosinophilia and systemic symptoms (DRESS) due to streptomycin.

PMID- 15040498
TI  - Inflammation of Montgomery glands.

PMID- 15040499
TI  - Wilderness preventive medicine.

PMID- 15040500
TI  - Reported knowledge, perceptions, and behavior of tourists and North Queensland
      residents at risk of contact with jellyfish that cause the "Irukandji syndrome".
AB  - OBJECTIVE: To determine the knowledge, beliefs, and behavior of local residents
      and visitors to North Queensland who may be at risk of contact with "Irukandji"
      jellyfish. METHODS: Structured interviews were conducted with 208 ferry
      passengers (92.9% response) traveling between Magnetic Island and Townsville (19
      degrees S). RESULTS: A total of 88.1% of the locals, 69.8% of the domestic
      tourists, and 34% of the international tourists knew what an Irukandji was (P <
      .001). Half of the international tourists, 20% of the domestic tourists, and 3.9%
      of the locals with this knowledge incorrectly assumed it was safe to swim inside
      stinger-resistant enclosures or were unsure (P < .001). Visitors to Magnetic
      Island who had swum or intended to swim in the sea (47%) knew less about
      Irukandji than other visitors (P = .05). Only 42.3% of the respondents realized
      that Irukandji posed a risk to swimmers on the outer reefs, and only 33.1% knew
      that Irukandji were also found outside North Queensland. CONCLUSIONS:
      International tourists had little knowledge about Irukandji. Thus, accurate
      educational messages may need to be targeted at this group. Offshore water sport
      and reef tour operators should be encouraged to provide clients with protective
      clothing to minimize the risk of stings. A coordinated educational response
      across northern Australia may be necessary to inform the public about both the
      box jellyfish (Chironex fleckeri) and Irukandji.

PMID- 15040501
TI  - Epidemiology of wilderness search and rescue in New Hampshire, 1999-2001.
AB  - OBJECTIVE: To describe the epidemiology of wilderness search and rescue in a
      region with easily accessible, heavily used wilderness areas. METHODS: We
      conducted a retrospective review of New Hampshire Fish and Game Department
      wilderness search-and-rescue reports between January 1999 and December 2001. The
      study group consisted of all the subjects of the New Hampshire Fish and Game
      Department search and rescue in the state of New Hampshire during the study
      period. Demographics, types of incidents, type and location of injuries,
      environmental factors, fatalities, and use of medical services for all the
      subjects were analyzed. RESULTS: Three hundred twenty-one incidents involving 457
      subjects were analyzed. The mean age of the subjects in the incidents was 35.6
      years, with 64.5% men and 35.4% women; 73% of the subjects resided in New
      Hampshire and Massachusetts. At the time of the incident, 57.3% of the subjects
      were hiking. Injuries precipitated 39.3% of the rescues, whereas lost and missing
      persons accounted for 41.4%. Fractures accounted for 33.7% of the reported
      injuries; 49.7% of the injuries were to the lower extremities. Sixty-four of the
      subjects (14%) died; 32.8% drowned, and 23.4% died from cardiac events.
      Volunteers were used in 53.3% of the rescues, a rescuer was injured in 2.5% of
      the incidents, and at least 36.4% of the subjects were transported to a hospital.
      CONCLUSIONS: The most prevalent demographic group requiring search-and-rescue
      efforts in New Hampshire was men aged 30 to 40 years who were hiking and who
      resided within a 4-hour drive of the area where they encountered difficulty. To
      decrease the number of people involved in most search and rescue, efforts should
      be focused on preventing wilderness users from getting lost and preventing lower
      extremity musculoskeletal injuries. Wilderness deaths may be prevented by
      focusing attention on cardiac health in wilderness users older than 50 years and
      on water safety.

PMID- 15040502
TI  - Ventilation after supplemental oxygen administration at high altitude.
AB  - OBJECTIVE: The present study assessed the effects of acute hyperoxia on resting
      minute ventilation (VE) during altitude acclimatization to 4300 m. METHODS:
      Resting-minute ventilation, end-tidal partial pressure carbon dioxide (PETCO2)
      and oxygen (P(ET)O2), and arterial oxygen saturation (SpO2) were measured during
      chronic poikilocapnic hypobaric hypoxia, supplemental oxygen breathing, and the
      subsequent return to hypobaric poikilocapnic hypoxia at altitude. Fifteen adult
      male lowlanders were studied at sea level and on the 3rd and 12th days at 4300 m.
      At sea level, subjects first breathed room air that was followed by 25-minute
      steady-state poikilocapnic hypoxia (FIO2 = 0.125). Ventilatory responses to acute
      poikilocapnic hypoxia (APH) were collected over the first 1-10 minutes, and
      responses to chronic poikilocapnic hypoxia (CPH) were collected over the last 3
      minutes of the hypoxia exposure. At altitude, CPH was provided by ambient-air
      breathing (PIO2 = 86 mm Hg) that was interrupted by 10 minutes of oxygen
      breathing (FIO2 = 1.0, PIO2 = 460 mm Hg) and then a subsequent return to ambient
      air to measure APH ventilatory responses. RESULTS: Between day 1 and day 12,
      during CPH, VE and SpO2 increased (P < .05) by 46% and 6%, respectively, whereas
      P(ET)CO2 decreased. On day 3 and day 12, breathing oxygen did not lower VE
      compared with CPH. However, the VE during APH immediately after oxygen breathing
      at high altitude was always greater (P < .05) than during CPH and did not change
      with duration of residence at altitude. CONCLUSIONS: These results show that
      short-duration oxygen breathing increases the subsequent ventilatory response to
      poikilocapnic hypoxia in altitude-acclimatized lowlanders, resulting in a
      transient elevation of SpO2.

PMID- 15040503
TI  - Medroxyprogesterone at high altitude. The effects on blood gases, cerebral
      regional oxygenation, and acute mountain sickness.
AB  - OBJECTIVE: To study the effect of medroxyprogesterone on blood gases and cerebral
      regional oxygenation at high altitude, alone and in conjunction with
      acetazolamide, and to assess the effect on acute mountain sickness (AMS). DESIGN:
      Two placebo-controlled trials during rapid ascent to high altitude. PARTICIPANTS:
      In the first trial, 20 participants, and in the second trial, 24 participants.
      SETTING: During rapid ascent to 4680 m and on rapid ascent to 5200 m.
      INTERVENTION: In the first trial, participants were randomized to receive
      medroxyprogesterone 30 mg or a placebo twice a day. In the second trial,
      participants were randomly assigned to one of 4 groups: a placebo twice daily,
      medroxyprogesterone 30 mg twice daily, acetazolamide 250 mg plus a placebo twice
      daily, or acetazolamide 250 mg plus medroxyprogesterone 30 mg twice daily. MAIN
      OUTCOME MEASURES: Blood gas changes and symptom scores of AMS in both trials and
      cerebral regional oxygen saturations in the first trial only. RESULTS:
      Medroxyprogesterone improved peripheral oxygen saturations in both trials and
      improved PaO2 in combination with acetazolamide. Cerebral regional oxygen
      saturation was not altered by medroxyprogesterone. The reduction in symptom
      scores and in the extent of AMS was not significant in this limited study.
      CONCLUSIONS: Medroxyprogesterone acts as a respiratory stimulant, but the
      clinical benefit regarding the development of AMS was unproven at high altitude.
      Combined medroxyprogesterone and acetazolamide gave the best PaO2.

PMID- 15040504
TI  - Inhibitors of hypoxic pulmonary vasoconstriction prevent high-altitude pulmonary
      edema in rats.
AB  - OBJECTIVE: Rapid ascent to high altitude causes hypoxic pulmonary
      vasoconstriction (HPV) and leads to high-altitude pulmonary edema (HAPE) in
      susceptible humans. Vasodilating agents lessen HAPE (as evidenced by radiographic
      and gas exchange measurements), but data establishing their effectiveness on
      alveolar protein content and hemorrhage are lacking. This study was designed to
      assess whether preventing HPV reduces the alveolar-capillary barrier leak
      characteristic of HAPE. METHODS: Rats were pretreated with saline (control group)
      or acetazolamide (20 mg/kg) or nickel chloride (60 mg/kg) (experimental groups)
      to prevent HPV and were exposed to high altitude (0.5 atm for 24 hours) in a
      hypobaric chamber. High-altitude pulmonary edema was then assessed by gravimetric
      analysis of heart and lung tissue, a visual score of lung hemorrhage, and
      measurement of protein content in bronchoalveolar lavage fluid. RESULTS: Saline
      treated rats developed a mild protein leak indicative of early HAPE that was
      prevented by inhibition of HPV: protein in bronchoalevolar lavage fluid of saline
      treated rats, 21.6 +/- 3.2 mg/dL (mean +/- SEM); HPV-inhibited rats, 12.6 +/- 0.7
      mg/dL; air-exposed rats, 13.4 +/- 1.4 mg/ dL (P < .05 saline vs other groups,
      analysis of variance [ANOVA]). The lungs of saline-treated rats were also mildly
      hemorrhagic (3.4 +/- 0.9 on a scale of 1-9, where 1 is normal), and the lungs of
      HPV-inhibited rats appeared normal (1.2 +/- 0.1) (P = .032). Finally, right
      ventricle weight (adjusted for initial body weight) increased in saline-treated
      rats: saline-treated, 0.64 +/- 0.02; HPV-inhibited, 0.56 +/- 0.02; air-exposed,
      0.59 +/- 0.02 (P < .05, saline vs HPV-inhibited group). CONCLUSION: The results
      demonstrate that treatment with NiCl2 or acetazolamide prevents HAPE in rats and
      are consistent with a role for elevated pulmonary artery pressure in the
      pathogenesis of HAPE.

PMID- 15040505
TI  - Mountaineering and mountain rescue--an introduction.

PMID- 15040506
TI  - Climbing the education mountain: designing the new Diploma in Mountain Medicine
      for the United Kingdom.
AB  - This article aims to use educational theory to help plan the course for the new
      Diploma in Mountain Medicine in the United Kingdom. The course is administered by
      Medical Expeditions, a charity devoted to mountain medicine education and
      research. One of the authors (K.P.) is a member of the faculty for the Diploma in
      Mountain Medicine.

PMID- 15040507
TI  - Clinical images. A mystery.

PMID- 15040508
TI  - Pulley injuries in rock climbers.

PMID- 15040509
TI  - Degassed liquids to prevent/treat decompression sickness.

PMID- 15040510
TI  - Evaluation of decision rules for identifying low bone density in postmenopausal
      African-American women.
AB  - OBJECTIVE: While African-American women tend to have greater bone mineral density
      (BMD) than caucasian women, they are still at risk of developing osteoporosis
      later in life. Clinical decision rules (i.e., algorithms) have been developed to
      assist clinicians identify women at greatest risk of low BMD. However, such tools
      have only been validated in caucasian and Asian populations. Accordingly, the
      objective of this study was to compare the performance of five clinical decision
      rules in identifying postmenopausal African-American women at greatest risk for
      low femoral BMD. METHODOLOGY: One hundred-seventy-four (n=174) postmenopausal
      African-American women completed a valid and reliable oral questionnaire to
      assess lifestyle characteristics, and completed height and weight measures. BMD
      at the femoral neck was measured via dual energy x-ray absorptiometry (DXA). We
      calculated sensitivity, specificity, positive predictive value, and negative
      predictive value for identifying African-American women with low BMD (T-Score <
      or = -2.0 SD) using five clinical decision rules: Age, Body Size, No Estrogen
      (ABONE), Osteoporosis Risk Assessment Instrument (ORAI), Osteoporosis Self
      Assessment Tool (OST), Simple Calculated Osteoporosis Risk Estimation (SCORE),
      and body weight less than 70 kg. RESULTS: Approximately 30% of African-American
      women had low BMD, half of whom had osteoporosis (BMD T-Score < or = -2.5 SD).
      Sensitivity for identifying women with a low BMD (T-Score < or = -2.0 SD) ranged
      from 65.57-83.61%, while specificity ranged from 53.85-78.85%. Positive
      predictive values ranged from 80.95-87.91%, while negative predictive values
      ranged from 48.44-58.33%. CONCLUSION: Our data suggest that the clinical decision
      rules analyzed in this study have some usefulness for identifying postmenopausal
      African-American women with low BMD. However, there is a need to establish cut
      points for these clinical decision rules in a larger, more diverse sample of
      African-American women.

PMID- 15040511
TI  - Bone mass in physicians: a Howard University Hospital pilot study.
AB  - PURPOSE: This observational cross-sectional study was done to determine bone mass
      in physicians and to determine if variables, such as calcium intake and exercise,
      were related to their bone mass. METHODS: One-hundred physicians of different
      ethnicities (African, African American, Asian, Caribbean, and Hispanic) were
      studied. Using dual-energy x-ray absorptiometry (DEXA), bone mass (BMD) of the
      lumbar spine and hips was measured. A validated questionnaire was used to
      determine the daily calcium intake and exercise. Student t-test, logistic
      regression, and Pearson chi-square were used to analyze the data. RESULTS: The
      study population consisted of 52% men and 48% women, with a mean age of 42 years
      old and a body mass index of 18.5 to 39.9 kg/m2. Low BMD occurred in 68% of the
      physicians (osteoporosis in 12%, osteopenia in 56%). Low calcium intake was found
      in 71%-14% of whom had osteoporosis and 49% osteopenia. Two-thirds of the
      physicians had inadequate exercise; 57% of this group had decreased BMD
      (osteoporosis in 9%, osteopenia in 38%). There was no statistical significance
      between BMD and calcium intake or exercise. CONCLUSION: A high percentage of the
      physicians in this unique study had a reduced BMD. Most of the physicians with
      low BMD were less than 45 years of age. This study indicates the need to define
      BMD in a larger cohort of young, ethnically diverse clinicians, and other health
      workers.

PMID- 15040512
TI  - Differential control of systolic and diastolic blood pressure in blacks with
      essential hypertension.
AB  - OBJECTIVE: The risk of cardiovascular and renal diseases has been shown to be
      higher for systolic blood pressure than diastolic blood pressure. The aim of this
      study was to assess the differential control of systolic and diastolic blood
      pressure in Nigerians with primary hypertension. DESIGN AND SETTING: This was a
      prospective observational study carried out at the Medical Outpatient Department
      of the State Hospital, Abeokuta, Nigeria. Ethical approval for the study was
      obtained from the ethical committee of the hospital. METHODOLOGY: The study
      population consisted of 185 consecutive patients (65 males, 120 females), aged 35
      85 years with primary hypertension who had been on drugs one- to 25 years prior
      to the onset of the study. Clinic blood pressure control was assessed during a
      year period. Six consecutive clinic blood pressure readings were recorded for
      each patient and the average calculated (systolic blood pressure and diastolic
      blood pressure separately). Patients were classified into subgroups based on the
      pattern of blood pressure control. RESULTS: Clinic systolic blood pressure and
      diastolic blood pressure was controlled in 58 patients (31.4%). Systolic blood
      pressure control was less frequent than diastolic blood pressure control (35.7%
      versus 51.4%, p<0.05). Patients with uncontrolled systolic blood pressure were
      significantly older than patients with only uncontrolled diastolic blood pressure
      (66.7+/-7.4 versus 52.9+/-8.7 years, p<0.001). CONCLUSION: Systolic blood
      pressure is less frequently controlled than diastolic blood pressure in Nigerians
      treated for primary hypertension. This may increase the patient's risk of
      developing stroke, and cardiovascular and renal complications.

PMID- 15040513
TI  - Lower rates of low birthweight and preterm births in the California Black Infant
      Health Program.
AB  - OBJECTIVES: The objective of this study was to determine the impact of prenatal
      interventions in the California Black Infant Health (BIH) Program on low
      birthweight (LBW) and preterm births (PTB) outcomes. METHODS: A prospective
      observational study design with a comparison group was used. BIH participants
      with a delivery recorded between July 1996 and September 1998 were included in
      the birthweight and PTB analyses. These outcomes for BIH participants who entered
      the BIH program prior to 32 weeks' gestation (n=1,553) were compared to those of
      all African-American women in the BIH Program targeted ZIP codes (n=11,633).
      RESULTS: No statistically significant differences in LBW and PTB were found
      between the BIH population and the comparison group. However, a comparison of the
      BIH infant VLBW (<1,500 g) rate (1.9%) with the VLBW rate for the comparison
      group (3.0%) shows that the BIH rate is 63% of the comparison group rate. For
      very PTB (<32 weeks), the BIH rate (3.5%) is 81% of the comparison group rate
      (4.3%). BIH participants had higher risk profiles (pregnancy history, current
      pregnancy, and psychosocial; p=<0.01) than women in the comparison group.
      CONCLUSIONS: The BIH Program retained high-risk women in the program to delivery
      and assisted them with maintenance of prenatal care. Even though the program
      participants were higher risk, their LBW and PTB outcomes were comparable to the
      geographic area overall. More importantly, there was a trend among women in the
      BIH Program toward better outcomes than the comparison group in both VLBW and
      VPTB.

PMID- 15040514
TI  - Factors influencing infant feeding method in an urban community.
AB  - The benefits of breastfeeding are well established. However, despite this fact,
      rates of breastfeeding continue to be low, falling far below the goals of Healthy
      People 2010. Rates are even lower among ethnic minority and low-income women. In
      this study, we attempt to identify the factors that most influence a mother's
      choice of infant feeding method in an urban predominately African-American
      population. Phone interviews of 70 women who delivered full-term infants at an
      urban tertiary care hospital were conducted in order to explore knowledge,
      attitudes, and beliefs about breastfeeding of the mothers and that of members of
      their social support network. Ten mothers (14%) exclusively breastfed. Older,
      caucasian, and married women were more likely to breastfeed. Breastfeeding
      mothers reported more partner support as well as more family knowledge about
      breastfeeding and had more positive attitudes about breastfeeding. Healthcare
      providers were not directly influential in mother's feeding choice. From this
      study, we conclude that in this population, the mother's partner and family are
      most influential in the choice of infant feeding method and, thus, should be
      included in breastfeeding promotion programs.

PMID- 15040515
TI  - Dyslipidemia and insulin resistance in relation to genetic admixture among
      Hispanics and non-Hispanic blacks of Caribbean origin.
AB  - The tendency to develop insulin resistance and dyslipidemia varies between black
      Africans, white Europeans, and Amerindian racial groups. Genetic admixture of
      these three racial groups has resulted in hybrid populations of Hispanics and non
      Hispanic blacks. The current study was undertaken to examine the relationship of
      white European admixture to insulin resistance and dyslipidemia among Hispanics
      and non-Hispanic blacks of Caribbean origin. The study population included 224
      Hispanics and 684 non-Hispanic blacks without a history of diabetes who were
      recruited between 1995 and 1999 on the island of St. Croix in the U.S. Virgin
      Islands. For each participant, anthropometric measurements were performed, and a
      fasting blood sample was analyzed for glucose, insulin, and serum lipids
      (triglycerides, HDL cholesterol). Genetic admixture was determined from
      grandparent race data. Hispanics were more likely than non-Hispanic blacks to
      have dyslipidemia and insulin resistance (measured by HOMA-IR method). White
      European admixture was significantly and inversely associated with insulin
      resistance among Hispanics. There was no significant relationship between white
      European admixture and insulin resistance or dyslipidemia among non-Hispanic
      blacks. Individuals who classified themselves as Hispanic blacks appeared to have
      a greater risk for cardiovascular disease than Hispanic whites or non-Hispanic
      blacks.

PMID- 15040516
TI  - Anthrax in America 2001-2003.
AB  - Anthrax caused by Bacillus anthracis in humans is rare. Two recent outbreaks that
      were intentionally caused occurred among postal employees, politicians, and
      journalists in the United States. This has caused tremendous fear, and our
      experience with these "anthrax incidents" has changed our views on the natural
      history of this disease in people. In this paper, we review the lifecycle and
      biology of this micro-organism. Anthrax that occurs from a weaponized form of
      this micro-organism has a specific clinical presentation that requires a
      suspicion of anthrax exposure to be diagnosed. New methods of testing for anthrax
      have been developed and may simplify diagnosis in the future. The range of
      illness caused by B. anthracis from the molecular level to the clinical symptoms
      is discussed. We also review the diagnostic criteria and differential diagnosis
      as well as treatment of this condition.

PMID- 15040517
TI  - Maternal perception of body size as a determinant of infant adiposity in an
      African-American community.
AB  - For 10 weeks, a sample of 105 postpartum African-American clients of three inner
      city clinics, were recruited for this nine-month prospective study. Data from 54
      mother-infant dyads were used to explore the associations between maternal
      perceptions of infant body size and the development of adiposity at six- to seven
      months of age. Correlations, chi-square, paired t-test, ANOVA, and logistic
      regression analyses were performed. Quantitative assessments of BMI using weight
      and length measures and qualitative assessments of body size perceptions using
      questionnaires, silhouette, and ranking scales were conducted. At six- to seven
      months of age, 40% of the infants were above the 85th percentile and 31% were
      above the 95th percentile of the NCHS standards for weight for height. Maternal
      perception of infant body size was positively correlated with early introduction
      of nonmilk foods. Significantly, more infants perceived as small were introduced
      to nonmilk foods earlier, compared to infants perceived as average, p=0.03.
      Additionally, it was observed that the earlier the introduction of nonmilk foods,
      the greater the infant's BMI at six- to seven months of age (r=0.59, p=0.02).
      Finally, one-third of mothers were obese with BMI's exceeding 30, and 31.1% were
      overweight with BMI's between 25 and 30.

PMID- 15040518
TI  - Heterotopic pregnancy in a large inner-city hospital: a report of two cases.
AB  - While ectopic pregnancy is a common occurrence, especially in the nonwhite female
      patient population, heterotopic pregnancy has traditionally been regarded as a
      rare clinical event until recently, especially with the advent of assisted
      reproductive procedures. We reported two cases, one in which an intrauterine
      pregnancy was discovered after a diagnosis of tubal abortion, another in which a
      patient underwent laparotomy for a tubal ectopic pregnancy with a concomitant
      previously diagnosed intrauterine pregnancy. The first patient subsequently
      delivered at term, while the second was lost to follow-up. In both cases, there
      was a delay in detecting the ectopic pregnancy component. These cases suggest
      that the clinician maintain a reasonable index of suspicion while evaluating a
      patient presenting with pelvic pain in the face of a documented intrauterine
      pregnancy. They also demonstrate the need for prompt and immediate action at the
      first sign indicating ectopic pregnancy to avoid missing this potentially life
      threatening condition.

PMID- 15040519
TI  - Prevalence of HIV among women with vaginal discharge in a gynecological clinic.
AB  - OBJECTIVE: Vaginal discharge is a common complaint among women with sexually
      transmitted diseases (STDs) in Nigeria. Given the association between STDs and
      HIV and the alarming rise in the prevalence of HIV in Nigeria, we performed this
      study to determine the prevalence of HIV in patients with vaginal discharge.
      STUDY DESIGN: Between April 2000 and August 2000, women who attended the Lagos
      University Teaching Hospital and complained of vaginal discharge were adequately
      counseled for HIV serotest. High vaginal/endocervical swabs and venous blood were
      taken for microbiological studies and HIV serotest, respectively. RESULTS: Out of
      the 230 women counseled for HIV serotest 140 (60.9%) consented. The mean age of
      the 140 was 31.1+/-6.9 years (range 18-50 years). In 31 (22.1%), Candida albicans
      was isolated, in 26 Gardnerella vaginalis (18.8%), in 17 Staphylococcal spp.
      (12.1%); and E. coli, Trichomonas vaginalis, and Neisseria gonococcus in 7.9%,
      4.3%, and 1.4%, respectively. Four (2.9%) of the 140 patients were HIV
      seropositive, and all had Candida albicans isolated. The prevalence of HIV among
      patients with Candida albicans was 12.9%. Association between HIV seropositivity
      and Candida albicans infection is significant (X2=14.48; p=0.002). CONCLUSION:
      Candida albicans is a common cause of vaginal discharge among HIV-seropositive
      women in Lagos.

PMID- 15040520
TI  - Training African-American residents in the 20th century.
AB  - Bellevue Hospital, the oldest public hospital in the United States and a lineal
      descendant of an infirmary for slaves, accepted its first African-American
      resident, Dr. Ubert Conrad Vincent, in 1918. This occurred at a time when many
      medical centers were not accepting African-American residents. At the end of
      WWII, one-third of the accredited medical schools still barred African Americans.
      However, Bellevue Hospital continued to train African-American residents. Between
      the 1920s and 1940s four African Americans matriculated at Bellevue Hospital.
      There were six in the 1950s, four in the 1960s, and 25 in the 1970s. By the
      1980s, 40 African Americans matriculated, and between 1990 and 1995, 61
      matriculated. Despite its historic first, Bellevue lagged slightly behind the
      national average. While the number of African-American residents occupying U.S.
      residency slots increased from 2.8% in 1978 to 6.5% in 1996, African Americans
      comprised 3.6% of residency slots at Bellevue between 1985-1995. Currently, only
      7% of practicing physicians and 5% in faculty positions are latino, African
      American, and Native American. Increasing the number of under-represented
      minority (URM) physicians is important to the United States, as URM physicians
      are more likely to serve the poor and uninsured, therefore improving the overall
      healthcare of the underprivileged. A study by the Association of American Medical
      Colleges indicated that minority medical school graduates were five times more
      likely to report that they planned to serve minority populations than other
      graduates. In their position paper, the American College of Physicians expressed
      the belief that increasing the number of URM physicians will help reduce
      healthcare disparities that can hurt minority populations and lead to poor health
      outcomes. The Supreme Court acknowledged the importance of racial diversity by
      upholding the University of Michigan affirmative action admissions policy in its
      June 2003 ruling. URM physicians are needed not only to serve minority
      populations but also to serve as mentors and role models for prospective and
      current students. The first African-American resident to graduate from the
      Bellevue Residency Program did indeed treat the underserved, as Dr. Vincent
      founded the Vincent Sanatorium, dedicated to treating African-American patients,
      and training African-American nurses and doctors. Over the course of the 20th
      century, Bellevue Hospital has trained increasing numbers of African-American
      physicians. It is hoped that, like their predecessor, Dr. Vincent, they will
      provide care to underserved communities and to the community as a whole, as well
      as serve as role models for generations to come.

PMID- 15040521
TI  - Harlem healthcare: a look back. An interview with Harlem pediatrician Thomas
      Hyatt, MD.

PMID- 15040522
TI  - Hypothyroidism masquerading as depression: the role of noncompliance.
AB  - Compliance with prescribed medication is an important but complex issue which is
      incompletely understood. Depression is also a factor that can lead to
      noncompliance. A 30-year-old lady was seen in the outpatient clinic with
      complaints of palpitations and tremor. Her medical history revealed a subtotal
      thyroidectomy for multinodular goiter five years earlier. During a period of
      depression, she stopped taking levothyroxine for 45 days. Discontinuation of
      therapy worsened her depression. At her visit, the dosage of levothyroxine was
      increased, and the symptoms of depression improved. However, increasing the
      dosage of thyroid supplement resulted in a hyperthyroid state. The role of
      depression on noncompliance is also discussed.

PMID- 15040523
TI  - Response to "Hepatitis C virus, sickle cell disease treatment options"--a
      February letter to the editor.

PMID- 15040524
TI  - Spinal stenosis.

PMID- 15040525
TI  - Dielectric properties of certain biological materials at microwave frequencies.
AB  - In the medical field, microwaves play a larger role for treatment than diagnosis.
      For the detection of diseases by microwave methods, it is essential to know the
      dielectric properties of biological materials. For the present study, a cavity
      perturbation technique was employed to determine the dielectric properties of
      these materials. Rectangular cavity resonators were used to measure the complex
      permittivity of human bile, bile stones, gastric juice and saliva. The
      measurements were carried out in the S and J bands. It is observed that normal
      and infected bile have different dielectric constant and loss tangent. Dielectric
      constant of infected bile and gastric juice varies from patient to patient.
      Detection and extraction of bile stone with possible method of treatment is also
      discussed.

PMID- 15040526
TI  - Application of the resistive sheet in finite element microwave heating systems.
AB  - The use of the resistive sheet for characterizing thin metallic films is
      presented in a microwave heating context. A finite edge element formulation is
      used to include the resistive sheet surface integral in both the frequency and
      time domains. The properties of the resistive sheet are compared with analytical
      expressions for the reflection, transmission and absorption coefficients and a
      correction factor is suggested to improve the accuracy of the numerical
      implementation. Results are presented for single and multimode systems.

PMID- 15040527
TI  - TLM simulation of microwave sintering of ceramics using SiC stimulus.
AB  - Microwave heating technology is becoming a successful technique used for
      sintering ceramic materials. However, various aspects of sintering experiments,
      such as the use of process stimulus and the preparation of sample arrangements,
      depend mainly on human expertise. The Transmission Line Matrix (TLM) method is
      first used to solve the combined electromagnetic and thermal equations modeling
      microwave heating of dielectric materials. It is then used to simulate microwave
      sintering of a low-loss ceramic material in a multimode microwave cavity. To
      enhance the microwave sintering process, Silicon Carbid (SiC) was first used as a
      susceptor and in a picket fence arrangement. As multiple samples may be processed
      in a microwave oven, the TLM was used to model such a process, and the
      introduction of SiC as a stimulus was also examined. Results show the importance
      of the stimulus thickness and configuration on the uniformity and density of the
      electromagnetic field distribution and, therefore, on the power dissipation
      within the ceramic load.

PMID- 15040528
TI  - Permittivity measurement of thermoplastic composites at elevated temperature.
AB  - The material properties of greatest importance in microwave processing of a
      dielectric are the complex relative permittivity epsilon = epsilon'-jepsilon",
      and the loss tangent, tan delta = epsilon"/epsilon'. This paper describes two
      convenient laboratory based methods to obtain epsilon', epsilon" and hence tan
      delta of fibre-reinforced thermoplastic (FRTP) composites. One method employs a
      microwave network analyzer in conjunction with a waveguide transmission
      technique, chosen because it provides the widest possible frequency range with
      high accuracy. The values of the dielectric constant and dielectric loss of glass
      fibre reinforced (33%) low density polyethylene, LDPE/GF (33%), polystyrene,
      PS/GF (33%), and Nylon 66/GF (33%), were obtained. Results are compared with
      those obtained by another method using a high-temperature dielectric probe.

PMID- 15040529
TI  - Microwave-assisted synthesis of Zn/Al layered double hydroxide-(anthraquinone-2,6
      disulfonate) nanocomposite.
AB  - Nanocomposites of Zn/Al-layered double hydroxide(anthraquinone-2,6-disulfonate)
      were synthesized by spontaneous direct assembly of inorganic and organic phases
      from aqueous solution. Powder X-ray diffraction patterns showed that a pure,
      single nanocomposite phase of good crystallinity was obtained using 1.0 M
      antraquinone-2,6-disulfonate ion (AQ26) and aging at 80 degrees C using
      conventional heating for 7 days or 0.5 h under microwave radiation, and these
      samples are denoted as ZAAN26C or ZAAN26MH, respectively. Zn/Al-nitrate-layered
      double hydroxide synthesized by a conventional method (ZANLC) showed a basal
      spacing of 8.3 A while both the nanocomposites showed 18.8 A as a result of AQ26
      intercalation. FTIR study showed that the resulting nanocomposites are free from
      nitrate, the co-anion present in the mother liquor, indicating that only AQ26 is
      preferred during intercalation for the formation of the nanocomposite. The
      Brunauer, Emmet and Teller (BET) and micropore surface areas for ZAAN26C
      decreased relative to the ZANLC from 16.2 to 4.7 and 1.6 to 1.3 m2/g,
      respectively. These results indicate that AQ26 can be rapidly interdcalated in
      layered double hydroxide using microwave-aging resulting in a nanocomposite.

PMID- 15040530
TI  - Polymorphisms, resistance and drug response: beyond subtype-B HIV-1.

PMID- 15040531
TI  - Antiretroviral drug resistance in non-subtype B HIV-1, HIV-2 and SIV.
AB  - Patients infected with HIV-1 of subtype other than B ('non-subtype B') or with
      HIV-2 are being treated with antiretroviral drugs in increasing numbers. In
      addition, healthcare providers and laboratory workers working with clinical
      specimens or animals infected with HIV, SIV or SHIV are at risk of being exposed
      to the virus and might require post-exposure prophylactic treatment. Thus, it is
      important to understand the inherent antiviral susceptibility of non-subtype B
      HIV-1, HIV-2 and SIV to currently available antiretroviral drugs, which have been
      developed with subtype B HIV-1-infected patients as the primary target
      population. In addition, knowledge about the consequences of treatment failure in
      non-subtype B HIV-1- and HIV-2-infected patients, with respect to the development
      of drug resistance, is crucial for designing optimal treatment strategies. This
      review summarizes the current state of knowledge in these areas. Non-subtype B
      group M HIV-1 appears to be susceptible to available agents, but follows several
      unique pathways to resistance to some drugs that have important clinical
      implications. Group O HIV-1 is naturally resistant to the non-nucleoside reverse
      transcriptase inhibitors (NNRTIs). HIV-2 and SIVsm are also naturally resistant
      to the NNRTIs as well as the protease inhibitor amprenavir. More research into
      the clinical responses to existing drugs and interpretation of genotypic
      information is needed, as well as development of diagnostic assays specific for
      non-subtype B HIV-1 and HIV-2.

PMID- 15040532
TI  - The impact of HIV antiviral therapy on human papillomavirus (HPV) infections and
      HPV-related diseases.
AB  - Human papillomavirus (HPV) infections play an important role in the pathogenesis
      of anogenital cancer and its precursors. HIV-infected individuals exhibit a high
      prevalence of HPV DNA. Several studies have further shown that HIV-infected
      individuals have an increased prevalence of squamous intraepithelial lesions
      (SIL) of the cervix, vulva and anus. The incidence of invasive cervical cancer is
      also elevated in HIV-positive women as well as that of anal cancer in HIV
      positive women and men. Given the relationship between HIV-induced
      immunosuppression and HPV-associated disease, treatment with highly active
      antiretroviral therapy (HAART) has the potential, through immune reconstitution
      of the host, to alter the natural history of HPV infection and SIL. However, data
      on the impact of HAART on HPV disease are sparse and mixed results have been
      reported.

PMID- 15040534
TI  - Cost effectiveness analysis of routine use of genotypic antiretroviral resistance
      testing after failure of antiretroviral treatment for HIV.
AB  - OBJECTIVES: Single use of genotypic antiretroviral resistance testing (GART)
      after first failure of highly active antiretroviral therapy (HAART) was reported
      to be cost effective; its use prior HAART initiation is unknown. Guidelines
      recommend GART after each treatment failure. We assessed the cost effectiveness
      of GART used routinely after first and subsequent treatment failures.
      Furthermore, we determined the minimum effectiveness required for GART prior to
      the first HAART to be as cost effective as after treatment failure. DESIGN AND
      METHODS: We developed a decision-analytic Markov model to estimate lifetime
      clinical and economic outcomes in a cohort of HIV patients starting HAART. Rates
      of treatment failure, estimates of GART effectiveness and data on disease
      progression were derived from published trials and observational studies. A cost
      effectiveness analysis was performed from the perspective of the healthcare
      system using cost data from a Central European healthcare setting. Deterministic
      and probabilistic sensitivity analyses using Monte Carlo technique were
      performed. RESULTS: GART after treatment failures increased life expectancy by 9
      months and undiscounted life-time costs per case by 16,406 euros. The discounted
      incremental cost effectiveness ratio was 22,510 euros per life-year gained
      (euros/LY). Best- and worst-case scenarios yielded 16,512 euros/LY and 42,900
      euros/LY, respectively. GART prior to the initiation of HAART would be equally
      cost effective if it could reduce the probability of first HAART failure by at
      least 36%. CONCLUSION: Routine use of GART after treatment failures is cost
      effective. GART prior to the first HAART would be equally cost effective if it
      could lower the probability of first HAART failure by approximately a third.

PMID- 15040533
TI  - Comparison of antiviral effect of lamivudine with interferon-alpha2a versus 
      alpha2b in children with chronic hepatitis B infection.
AB  - AIM: To compare additive efficacy of combination therapy including interferon
      (IFN)-alpha2a+lamivudine (3TC) to IFN-alpha2b+3TC in children with chronic
      hepatitis B virus (HBV) infection. MATERIAL AND METHODS: Chronic hepatitis B
      infection was determined by presence of HBsAg, HBeAg and HBV DNA in serum
      screened at 3 months intervals for at least 1 year, serum alanine transaminase
      (ALT) levels more than 1.5-times the upper normal limit and chronic hepatitis
      with histological activity index (HAI) more than 6 by liver biopsy. Sixty-three
      children with chronic hepatitis B infection were treated randomly with thrice
      weekly subcutaneous injections of 5 MU/m2 recombinant IFN-alpha2a (n=29) or
      recombinant IFN-alpha2b (n=34) with the same dose, intervals for 6 months.
      Patients also received 3TC (4 mg/kg/day, max 100 mg/day) orally daily combined
      with IFN and continued for 12 months. End of therapy response was defined as ALT
      normalization, HBV DNA clearance and HBe/anti-HBe seroconversion. Breakthrough
      infection was determined as re-emergence of HBV DNA in serum after its clearance.
      Response rate, incidence of side effects and breakthrough infection were compared
      between IFN-alpha2a+3TC- and IFN-alpha2b+3TC-treated patients. RESULTS: Response
      rate was 44.8% (n=13) with IFN-alpha2a+3TC and 47.1% (n=16) with IFN-alpha2b+3TC
      (P=1.0). No significant difference was found in respect to the DNA clearance
      (P=0.32), anti-HBe (P=1.0), anti-HBs (P=0.09) seroconversion and response rates
      (P=1.0) between the groups. Breakthrough infection was detected in 1 (3.4%) case
      on IFN-alpha2a and none of the cases on IFN-alpha2b (P=0.46). All of the patients
      experienced flu-like symptoms, malaise and fatigue; however, side effect
      interfering with therapy was not encountered. CONCLUSION: No significant
      difference was found in response rates achieved by combination therapies based on
      IFN-alpha2a and IFN-alpha2b. Clinical efficacy of 3TC and two different IFN
      subtypes was found similar.

PMID- 15040535
TI  - Antiviral efficacy of abacavir in antiretroviral therapy-experienced adults
      harbouring HIV-1 with specific patterns of resistance to nucleoside reverse
      transcriptase inhibitors.
AB  - OBJECTIVE: To evaluate HIV-1 reverse transcriptase genotypic and phenotypic
      indicators of resistance to abacavir (ABC) as predictors of ABC antiviral
      efficacy. DESIGN: The study was a retrospective, combined analysis of five
      multicentre trials in which ABC was added as a single agent to background
      antiretroviral therapy in experienced adults. METHODS: Baseline HIV-1 genotype
      and phenotypic susceptibility to ABC were determined and the association of
      genotype and phenotype with virological response after addition of ABC was
      analysed. RESULTS: Overall, 68% of these therapy-experienced subjects had a
      virological response (>0.5 log10 or <400 copies/ml; 42% <400 copies/ml) 4 weeks
      after addition of ABC. Multivariable analyses revealed no significant difference
      in the response rate between subjects with wild-type virus and those carrying
      virus with 1-2 nucleoside reverse transcriptase inhibitor (NRTI)-associated
      mutations. At the 4-week time-point subjects harbouring virus with > or = 3
      mutations associated with NRTI resistance were significantly less likely to
      respond to ABC than were subjects harbouring wild-type virus (P=0.015). However,
      at the last viral RNA measurement after addition of ABC (12-28 weeks), > or = 4
      mutations were required to diminish virological response significantly (P=0.012).
      Phenotypic resistance was also predictive of antiviral response. Significant
      breakpoints were identified for virological responses for the PhenoSense HIV
      assay and the Antivirogram assay. CD4 responses generally paralleled the
      antiviral responses with a median increase of 55 cells/microl by weeks 12-28.
      CONCLUSIONS: Virological response to ABC may be diminished significantly by
      multiple NRTI-associated mutations and/or by reductions in phenotypic
      susceptibility to ABC. However, many subjects with baseline samples showing
      evidence of resistance to NRTIs respond to ABC.

PMID- 15040536
TI  - Mitochondrial effects of antiretroviral therapies in asymptomatic patients.
AB  - BACKGROUND: A decrease in the mitochondrial (mt) DNA to nuclear DNA ratio has
      gained acceptance as a marker of mitochondrial toxicity in treated HIV-infected
      patients, but the functional meaning of this alteration is unclear. METHODS: We
      assessed mtDNA content, mitochondrial content and function in peripheral blood
      mononuclear cells (PBMCs) of consecutive asymptomatic HIV-infected patients.
      Patients selected had been receiving a first-line highly active antiretroviral
      therapy (HAART) regimen for at least 6 months, consisting of zidovudine plus
      lamivudine or stavudine plus didanosine plus either nelfinavir or nevirapine, or
      were antiretroviral-naive. The mtDNA content was assessed by quantitative real
      time PCR, mitochondrial content by citrate synthase activity, enzyme activity of
      complexes III and IV (both partially encoded by mtDNA) of the electron transport
      chain by spectrophotometry, oxygen consumption by polarography, and oxidative
      damage in cell membranes by monitoring cis-parinaric acid fluorescence. RESULTS:
      Mitochondrial content was significantly lower in all treated groups. Patients
      receiving stavudine plus didanosine had mtDNA depletion and a decrease in complex
      IV activity. However, oxygen consumption capacity and lipid peroxidation were
      unaffected in all groups. CONCLUSION: Long-term HAART may induce mitochondrial
      abnormalities in PBMC mitochondria, which do not necessarily translate into
      functional abnormalities, at least in asymptomatic patients.

PMID- 15040537
TI  - Susceptibility of HIV-2, SIV and SHIV to various anti-HIV-1 compounds:
      implications for treatment and postexposure prophylaxis.
AB  - Limited information is available on the activity of antiretroviral drugs against
      human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus
      (SIV) strains to guide their use in treatment or prophylaxis. We evaluated the
      antiviral activity of 16 approved drugs and one experimental drug, AMD3100,
      against two wild-type HIV-2 (ROD and EHO) isolates, two strains of SIV (mac251
      and B670), and two strains of simian-human immunodeficiency virus (SHIV) that
      contain the reverse transcriptase (RTSHIV) or envelope glycoprotein (SHIV89.6) of
      human immunodeficiency virus type 1 (HIV-1) in a SIV(mac239) background. Drug
      susceptibility was measured conventionally by the MT-4/MTT assay, and results
      were analysed as fold changes in 50% effective concentration (EC50) relative to
      the EC50 for HIV-1 (IIIB). The nucleoside reverse transcriptase inhibitors
      (NRTIs) zidovudine, lamivudine, stavudine, didanosine, zalcitabine and abacavir
      as well as the nucleotide reverse transcriptase inhibitor tenofovir retained full
      activity against all six viruses except for SIV and SHIV89.6 that showed low
      level resistance to didanosine. The protease inhibitors (PIs) ritonavir,
      indinavir, saquinavir and nelfinavir were found to be active against some HIV-2
      or SIV strains. However, a significant reduction in susceptibility was seen with
      indinavir against SHIV89.6 (3.3-fold), and with amprenavir against HIV-2(ROD)
      (8.8-fold). All viruses except for RTSHIV showed a >200-fold decrease in
      susceptibility for the non-nucleoside reverse transcriptase inhibitors (NNRTIs)
      nevirapine, delavirdine and efavirenz, indicating high-level resistance. AMD3100,
      a CXCR4 antagonist, was active against HIV-2 and SHIV89.6, a finding consistent
      with the use of the CXCR4 co-receptor by these isolates, but was inactive against
      SIV strains. In contrast, enfuvirtide (T-20) was active against SHIV89.6 but had
      reduced inhibitory activity against both HIV-2 and SIV strains predicting little
      therapeutic value against these viruses. These findings support the use of NRTIs,
      tenofovir, but not NNRTIs, for treating HIV-2-infected persons or for prophylaxis
      against HIV-2 and SIV. The clinical significance of the low-level resistance of
      HIV-2 and SIV to some PIs is unclear. Co-receptor antagonists such as AMD3100
      show promising anti-HIV-2 therapeutic modalities. Both AMD3100 and enfuvirtide
      could be used for prophylaxis against SHIV89.6.

PMID- 15040538
TI  - Enhanced T-cell maturation, differentiation and function in HIV-1-infected
      individuals after growth hormone and highly active antiretroviral therapy.
AB  - BACKGROUND: Strong virus-specific helper and cytotoxic T-cell responses correlate
      with non-progression during HIV-1 infection. Administration of antiretroviral
      therapy (ART) during the chronic phases of HIV-1 infection fails to restore these
      responses in most patients. DESIGN AND METHODS: We assessed the changes in immune
      function of 12 HIV-1-positive individuals treated with ART for over 4 years, who
      received 4 mg/day of recombinant human growth hormone (rhGH) for 12 weeks and
      were then randomized into groups receiving either placebo, twice weekly or
      alternate day dosing of rhGH. Peripheral blood was drawn for phenotypic analysis
      and functional assays at time points 0, 12 and 24 weeks. RESULTS: At week 12, we
      observed significant increases in naive CD4 T cells (P<0.01) and effector CD8 T
      cells based on CD45RA and CCR7 expression (P<0.02). In addition, we observed a
      rise in HIV-1 antigen-specific CD4 (P<0.005) and CD8 (P<0.05) T-cell responses.
      Twelve weeks post-randomization into placebo, alternate day or twice weekly
      dosing (24 weeks post-baseline), the phenotype and function of the virus-specific
      effector CD8 T cells seen at week 12 was maintained in most patients regardless
      of randomization arm and despite the disappearance of HIV-1-specific CD4 T-cell
      responses. CONCLUSIONS: Concomitant administration of rhGH at 4 mg/day with
      highly active ART appears to partially reverse some of the defects exerted on the
      immune system by HIV-1. This combination may represent a valuable
      immunotherapeutic intervention aiding in the treatment of chronic HIV-1
      infection.

PMID- 15040539
TI  - Intracellular and plasma pharmacokinetics of nelfinavir and M8 in HIV-infected
      patients: relationship with P-glycoprotein expression.
AB  - One of the targets of antiretroviral therapy is within cells infected with HIV.
      In order to improve therapeutic efficacy, it is therefore important that the
      intracellular pharmacokinetics of drugs, such as nelfinavir mesylate and its
      active metabolite M8, are studied in addition to plasma pharmacokinetics.
      Previously, the intracellular accumulation of protease inhibitors has been
      reported in vivo, displaying the following hierarchy: nelfinavir > saquinavir >
      ritonavir > indinavir. Multidrug resistance transporters, such as P-glycoprotein
      (P-gp), may result in a lower intracellular concentration of drug via an efflux
      mechanism, thus contributing to sanctuary site formation. The objective of this
      study was to determine concentrations of nelfinavir and M8 in plasma and
      peripheral blood mononuclear cells from HIV-infected patients, and to ascertain
      the relationship between intracellular accumulation and lymphocyte P-gp
      expression. Venous blood samples from 12 HIV-infected patients (viral load <50
      copies/ml) receiving nelfinavir (1250 mg twice daily) and dual nucleoside reverse
      transcriptase inhibitor therapy were collected over a full dosage interval (0, 2,
      4, 8 and 12 h). Plasma and intracellular (cell-associated) drug concentrations
      were measured by HPLC-MS/MS. Drug exposure in plasma and cells was expressed as
      the area under the concentration-time curve (AUC(0-12h)), derived from non
      compartmental modelling. The ratio of intracellular AUC(0-12h)/total plasma AUC(0
      12h) was calculated to determine cellular drug accumulation. P-gp expression on
      lymphocytes was determined by flow cytometry. The median (range) AUC(0-12h) of
      nelfinavir in plasma and cellular compartments was 21.8 mg x h x l(-1) (5.64
      50.8) and 104.6 mg x h x l(-1) (23.1-265.7), respectively. Corresponding values
      for M8 in plasma and cells were 6.60 mg x h x l(-1) (2.16-17.3) and 19.6 mg x h x
      l(-1) (5.14-60.8). A ratio of plasma M8/plasma nelfinavir (AUC(0-12h)) and
      intracellular M8/intracellular nelfinavir (AUC(0-12h)) gave median values of 0.32
      and 0.17, respectively. The cellular accumulations [median; (range)] of
      nelfinavir and M8 were 5.30 (2.28-16.2) and 2.32 (1.01-10.7), respectively. A
      significant correlation between plasma and intracellular nelfinavir minimum
      concentration (Cmin) (r2=0.34; P=0.049), but not between plasma and intracellular
      M8 Cmin was observed. C(0h) concentrations were higher than C(12h) for both
      nelfinavir and M8. No relationship was observed between nelfinavir or M8
      accumulation and lymphocyte cell surface expression of P-gp. This study
      illustrates that intracellular concentrations were higher than plasma
      concentrations for both nelfinavir and M8, suggesting lymphocyte accumulation.
      The mechanism of differential intracellular accumulation of nelfinavir and M8
      remains to be elucidated. It may be that affinities for influx transporters or
      fundamental drug characteristics play a major role in the greater accumulation of
      nelfinavir than M8.

PMID- 15040540
TI  - Effect of individual cognitive behaviour intervention on adherence to
      antiretroviral therapy: prospective randomized trial.
AB  - OBJECTIVE: A high level of adherence to antiretroviral therapy is required for
      complete suppression of HIV replication, immunological and clinical
      effectiveness. We investigated whether cognitive behaviour therapy can improve
      medication adherence. DESIGN: Prospective randomized 1-year trial. SETTING:
      Collaboration of HIV university outpatient clinic and psychotherapists in private
      practice. PARTICIPANTS: 60 HIV-infected persons on stable antiretroviral
      combination therapy and viral load below 50 copies/ml. INTERVENTION: Cognitive
      behaviour intervention in individual patients, in addition to standard of care.
      MAIN OUTCOME MEASURES: Feasibility and acceptance of intervention; adherence to
      therapy assessed using medication event monitoring system (MEMS) and self-report
      questionnaire; virological failure; psychosocial measures. RESULTS: The median
      number of sessions for cognitive behaviour intervention per patient during the 1
      year trial was 11 (range 2-25). At months 10-12, mean adherence to therapy as
      assessed using MEMS was 92.8% in the intervention and 88.9% in the control group
      (P=0.2); the proportion of patients with adherence > or = 95% was 70 and 50.0%
      (P=0.014), respectively. While there was no significant deterioration of
      adherence during the study in the intervention arm, adherence decreased by 8.7%
      per year (P=0.006) in the control arm. No differences between the intervention
      group and standard of care group were found regarding virological outcome.
      Compared with the control group, participants in the intervention group perceived
      a significant improvement of their mental health during the study period.
      CONCLUSIONS: Cognitive behavioural support in addition to standard of care of HIV
      infected persons is feasible in routine practice, and can improve medication
      adherence and mental health.

PMID- 15040541
TI  - Sequential switching of DNA polymerase and thymidine kinase-mediated HSV-1 drug
      resistance in an immunocompromised child.
AB  - Sequential herpes simplex virus type 1 (HSV-1) isolates were obtained from a
      paediatric haematopoietic stem cell transplant (HSCT) patient who received
      prolonged therapy with acyclovir (ACV) followed by foscarnet (PFA) and topical
      cidofovir (HPMPC) for severe persistent mucocutaneous HSV-1 infection. The
      isolates were retrospectively studied for drug resistance. The first resistant
      isolate associated with clinical failure of antiviral therapy emerged 44 days
      post-ACV treatment initiation. Susceptibility testing revealed an ACV-resistant
      HSV strain that demonstrated cross resistance to PFA in the absence of any
      previous PFA treatment. The observed cross resistance was conferred by a single
      amino acid substitution, Ser724Asn, in the HSV DNA polymerase (DNA pol) gene.
      During the subsequent course of ACV therapy, the ACV/PFA-cross-resistant isolates
      were replaced by ACV-resistant, PFA-sensitive isolates. These isolates carried no
      DNA pol mutations, but had an Arg163His substitution in the thymidine kinase
      gene. Upon subsequent switching of antiviral therapy from ACV to PFA, the
      original ACV/PFA-cross-resistant DNA pol mutant re-appeared. Our study shows the
      emergence of different drug-resistant HSV variants during ongoing, unchanged ACV
      therapy. Furthermore, a rapid re-selection of the original resistant variant was
      observed after switch. For optimal antiviral management of HSV infections in HSCT
      recipients, therapeutic decisions should be guided by drug susceptibility results
      whenever therapeutic failure is observed and/or when changes in antiviral
      treatment are considered.

PMID- 15040543
TI  - Intracellular accumulation of nelfinavir and its relationship to P-glycoprotein
      expression and function in HIV-infected patients.
AB  - OBJECTIVE: To compare plasma and intracellular nelfinavir pharmacokinetics, and
      determine their relationship to P-glycoprotein (P-gp) expression and function in
      lymphocytes of HIV-infected patients. METHODS: A pharmacokinetic study of 12
      patients receiving nelfinavir plus dual nucleoside analogue therapy. Blood
      samples were taken at intervals to 12 h. Peripheral blood mononuclear cells
      (PBMCs) were isolated by density gradient centrifugation, and nelfinavir
      extracted from cells in the presence of 60% methanol and evaporated to dryness.
      Both plasma and intracellular nelfinavir samples were assayed by high performance
      liquid chromatography linked to mass spectrometry. P-gp expression and function
      were measured by flow cytometric analysis. Data were analysed by non
      compartmental analysis using WinNonLin pharmacokinetic software. RESULTS: The
      mean intracellular nelfinavir AUC(0-12) (mean +/-SE) was about ninefold higher
      than that of plasma (264,200 +/- 63,420 vs 29,250 +/- 6629 ng/ml/h; P<0.001, and
      intracellular Cmin and C0 values for nelfinavir were five- to sixfold higher than
      that of plasma (Cmin: 5712 +/- 2156 vs 1062 +/- 357 ng/ml; C0: 15,860 +/- 3662 vs
      2553 +/- 539 ng/ml; P<0.0005). The intracellular nelfinavir Cmax was 15-fold
      higher than plasma (59,420 +/- 13,940 vs 3986 +/- 822 ng/ml; P<0.0005). There
      were no differences between plasma and intracellular values for Tmax, elimination
      half-life or mean residence time. In patients chronically treated with nelfinavir
      mean P-gp expression was 8.85 +/- 1.3 MFI, there was no correlation between P-gp
      expression and either intracellular AUC(0-12) (r=-0.35; P=0.29) or intracellular
      C0 values. There was a correlation between intracellular nelfinavir
      concentrations and P-gp function at baseline (r=0.59; P<0.05). Basal P-gp
      mediated rhodamine efflux was 61.0 +/- 4.2%. In the presence of ritonavir,
      cellular rhodamine efflux decreased to 25.6 +/- 5.5% (P=0.001), representing an
      additional reversible efflux potential of 56.1 +/- 9.78%. There was a strong
      correlation between plasma and intracellular AUC(0-12) for nelfinavir (r=0.75;
      P=0.011). CONCLUSIONS: Nelfinavir undergoes significant intracellular
      accumulation within the PBMCs of HIV-infected patients, which may be in part
      related to its moderate ability to inhibit P-gp-mediated drug efflux. The
      addition of ritonavir further reduced P-gp function. Intracellular accumulation
      of nelfinavir correlated with P-gp function but not P-gp expression, suggesting
      pump activity is substrate concentration-dependant. There was a significant
      correlation between plasma and intracellular nelfinavir concentrations,
      suggesting one is a good surrogate marker of the other.

PMID- 15040542
TI  - Changes in body fat composition after 1 year of salvage therapy with
      lopinavir/ritonavir-containing regimens and its relationship with lopinavir
      plasma concentrations.
AB  - OBJECTIVE: To determine whether an association existed between lopinavir (LPV)
      plasma concentrations and changes in body fat composition. DESIGN: A prospective,
      non-randomized study. SETTING: HIV clinic of a University Hospital. SUBJECTS,
      PARTICIPANTS: HIV-infected subjects who had virological failure on protease
      inhibitor-containing regimens. Twenty-two consecutive patients were enrolled, 19
      completed 24 weeks of treatment and 16 completed the full 48-week study period.
      INTERVENTION: Patients were treated with LPV/ritonavir (LPV/r) in combination
      with other antiretroviral agents. LPV trough plasma concentrations were measured
      at baseline and weeks 4, 8, 12, 24, 36 and 48. Body fat composition was
      quantified by computerized tomographic scanning at baseline, and weeks 24 and 48.
      RESULTS: LPV trough concentrations correlated with absolute and proportional
      changes in limb fat from baseline to week 48. Significant differences were found
      in mean LPV trough concentrations between patients losing less than 5% of limb
      fat, those experiencing a limb fat loss between 5 and 20%, and those losing more
      than 20% at week 24 [mean (SD), 4.67 (1.67); 8.57 (1.77); 9.49 (2.67) microg/ml,
      respectively; P=0.013] and week 48 [mean (SD), 4.5 (2.24); 7.04 (1.77); 9.7 (2.8)
      microg/ml, respectively; P=0.027]. Most patients losing more than 5% of limb fat
      during LPV/r therapy had mean LPV trough concentrations > or = 8 microg/ml.
      CONCLUSIONS: In patients receiving salvage therapy with LPV/r there was an
      association between LPV plasma trough concentrations and limb fat loss. The risk
      of peripheral limb fat loss may be greater among patients achieving higher LPV
      trough concentrations.

PMID- 15040544
TI  - Strategies to decrease viral load rebound, and prevent loss of CD4 and onset of
      resistance during structured treatment interruptions.
AB  - BACKGROUND: Toxicity and other drug adherence-related factors have contributed to
      decreased compliance to antiretroviral regimens amongst HIV-infected patients.
      Irregular therapy disruption causes loss of CD4 T cells, onset of drug resistance
      and rapid rebound of plasma viral load (VL). However, an appropriate choice of
      drugs and properly scheduled structured treatment interruptions (STIs) may limit
      VL rebound, maintain CD4 counts and minimize resistance. METHODS: We conducted a
      clinical study of STIs, RIGHT 901, involving 60 drug-naive patients with chronic
      HIV infection (CD4 >300, VL >10,000) randomized to receive didanosine-stavudine
      indinavir (IDV group) or didanosine-stavudine-hydroxyurea (HU group), for 12
      weeks. Subsequently, all patients were randomized again to start STI (short
      induction) or to continue the therapy for an additional 24 weeks before starting
      STI (long induction). Both groups underwent four STI cycles and then stopped
      therapy as long as viraemia remained below 10,000 copies/ml before reinitiating
      another four cycles of STI. RESULTS: During continuous therapy VLs were
      suppressed at similar rates in both the HU and IDV groups, while a blunted CD4
      count was documented in the HU group. Following the first stop median VL
      rebounded close to baseline values in both groups, however, during the following
      STI median VL rebound decreased in the HU group, while in the IDV group VL
      continued to rebound to values close to baseline, and the difference between the
      two groups was statistically significant. Moreover, patients treated with HU had
      a constant and stable CD4 increase during STI, whereas CD4 counts fluctuated in
      the IDV group, with sharp falls during treatment interruptions and partial CD4
      recovery following treatment restart. Even in the presence of IDV resistance
      predisposing mutations at baseline, no genotypic change in the protease sequence
      was observed during STI. A relevant mutation in the reverse transcriptase
      sequence (K70R) emerged in one patient interrupting treatment after 36 weeks of
      continuous therapy and in one patient after four STI cycles. Side effects (no
      major events) were similar among groups. CONCLUSIONS: An appropriate choice of
      STI schedule and regimens containing drugs less prone to resistance and/or able
      to prevent CD4 fluctuation may contribute to optimizing STI for chronically
      infected patients with respect to limiting viral rebound, improving CD4 counts
      and maintaining a resistance profile comparable to continuous highly active
      antiretroviral therapy.

PMID- 15040545
TI  - High rate of didanosine-related mitochondrial toxicity in HIV/HCV-coinfected
      patients receiving ribavirin.
AB  - BACKGROUND: Nucleoside analogues may induce mitochondrial toxicity, particularly
      didanosine. Ribavirin increases didanosine exposure, which might be clinically
      relevant when coadministered in HIV/HCV-coinfected patients. OBJECTIVE: To
      evaluate, among 89 patients receiving highly active antiretroviral therapy
      (HAART) and therapy for chronic hepatitis C, clinically relevant mitochondrial
      toxicity in those treated with concomitant ribavirin and didanosine (n=35, 39%).
      METHODS: From January 2000 to July 2002 longitudinal analysis of the incidence
      and clinical course of didanosine-related hyperamylasaemia, pancreatitis,
      hyperlactataemia/lactic acidosis or neuropathy. Risk factors were evaluated using
      univariate and multivariate Cox's proportional hazards model. RESULTS: Among 35
      patients who received concomitant didanosine (400 mg/day in 86%) and ribavirin (>
      or = 10 mg/kg/day in 91%), 20 (57%) developed one or more adverse events after a
      mean of 87 days. Most frequent laboratory abnormalities were hyperamylasaemia (18
      patients, 51%) and hyperlactataemia (eight patients, 23%). Acute pancreatitis and
      symptomatic hyperlactataemia developed in 10 (28%) and six (17%) patients,
      respectively. Two patients (6%) with pancreatitis and severe lactic acidosis
      died; the other patients recovered uneventfully despite continuation of anti-HCV
      therapy in 83% after didanosine withdrawal in 40%. In the Cox's model higher
      baseline amylase levels (HR: 1.04, 95% CI: 1.02-1.06, P=0.001) and three
      nucleoside reverse transcriptase inhibitor-based HAART (HR: 5.3, 95% CI: 1.73
      16.24, P=0.003) were significantly associated to toxicity. CONCLUSIONS: The
      coadministration of didanosine and ribavirin should be avoided in HIV/HCV
      coinfected patients, due to a high rate of clinically significant toxicity,
      particularly in triple nucleoside-based HAART. Amylase levels should be strictly
      monitored, especially if elevated at baseline.

PMID- 15040546
TI  - Suppression of hepatitis C virus replication is maintained long term following
      HAART therapy, in an individual with HCV/HIV co-infection.

PMID- 15040547
TI  - Neuroimaging studies of working memory: a meta-analysis.
AB  - We performed meta-analyses on 60 neuroimaging (PET and fMRI) studies of working
      memory (WM), considering three types of storage material (spatial, verbal, and
      object), three types of executive function (continuous updating of WM, memory for
      temporal order, and manipulation of information in WM), and interactions between
      material and executive function. Analyses of material type showed the expected
      dorsal-ventral dissociation between spatial and nonspatial storage in the
      posterior cortex, but not in the frontal cortex. Some support was found for left
      frontal dominance in verbal WM, but only for tasks with low executive demand.
      Executive demand increased right lateralization in the frontal cortex for spatial
      WM. Tasks requiring executive processing generally produce more dorsal frontal
      activations than do storage-only tasks, but not all executive processes show this
      pattern. Brodmann's areas (BAs) 6, 8, and 9, in the superior frontal cortex,
      respond most when WM must be continuously updated and when memory for temporal
      order must be maintained. Right BAs 10 and 47, in the ventral frontal cortex,
      respond more frequently with demand for manipulation (including dual-task
      requirements or mental operations). BA 7, in the posterior parietal cortex, is
      involved in all types of executive function. Finally, we consider a potential
      fourth executive function: selective attention to features of a stimulus to be
      stored in WM, which leads to increased probability of activating the medial
      prefrontal cortex (BA 32) in storage tasks.

PMID- 15040549
TI  - Descriptive and evaluative judgment processes: behavioral and
      electrophysiological indices of processing symmetry and aesthetics.
AB  - Descriptive symmetry and evaluative aesthetic judgment processes were compared
      using identical stimuli in both judgment tasks. Electrophysiological activity was
      recorded while participants judged novel formal graphic patterns in a trial-by
      trial cuing setting using binary responses (symmetric, not symmetric; beautiful,
      not beautiful). Judgment analyses of a Phase 1 test and main experiment
      performance resulted in individual models, as well as group models, of the
      participants' judgment systems. Symmetry showed a strong positive correlation
      with beautiful judgments and was the most important cue. Descriptive judgments
      were performed faster than evaluative judgments. The ERPs revealed a phasic,
      early frontal negativity for the not-beautiful judgments. A sustained posterior
      negativity was observed in the symmetric condition. All conditions showed late
      positive potentials (LPPs). Evaluative judgment LPPs revealed a more pronounced
      right lateralization. It is argued that the present aesthetic judgments engage a
      two-stage process consisting of early, anterior frontomedian impression formation
      after 300 msec and right-hemisphere evaluative categorization around 600 msec
      after onset of the graphic patterns.

PMID- 15040548
TI  - Processing emotional tone from speech in Parkinson's disease: a role for the
      basal ganglia.
AB  - In this study, individuals with Parkinson's disease were tested as a model for
      basal ganglia dysfunction to infer how these structures contribute to the
      processing of emotional speech tone (emotional prosody). Nondemented individuals
      with and without Parkinson's disease (n = 21/group) completed neuropsychological
      tests and tasks that required them to process the meaning of emotional prosody in
      various ways (discrimination, identification, emotional feature rating).
      Individuals with basal ganglia disease exhibited abnormally reduced sensitivity
      to the emotional significance of prosody in a range of contexts, a deficit that
      could not be attributed to changes in mood, emotional-symbolic processing, or
      estimated frontal lobe cognitive resource limitations in most conditions. On the
      basis of these and broader findings in the literature, it is argued that the
      basal ganglia provide a critical mechanism for reinforcing the behavioral
      significance of prosodic patterns and other temporal representations derived from
      cue sequences (Lieberman, 2000), facilitating cortical elaboration of these
      events.

PMID- 15040550
TI  - Effects of methylphenidate on working memory in pigeons.
AB  - To assess the effects of methylphenidate on working memory, pigeons were trained
      in a delayed matching-to-sample task. Delay interval duration (0.2, 1, 3, 6, or
      12 sec) was varied within sessions in order to separate delay-dependent from
      delay-independent effects of the drug on performance. A reduction in the sample
      response requirement from five responses to one response effectively reduced
      attention to the stimulus and impaired overall accuracy. Methylphenidate was
      administered in doses of 0.0 (saline control), 0.25, 2.5, and 10 mg/kg. Relative
      to performance with saline, accuracy was significantly reduced with 10 mg/kg
      methylphenidate to the same extent in both fixed ratio (FR) 1 and FR 5
      conditions. The smaller doses had no effect, and there was no evidence that
      accuracy improved with drug administration. Intercepts and slopes of exponential
      functions fitted to measures of discriminability plotted as a function of delay
      showed that methylphenidate affected delay-independent aspects of performance
      (initial discriminability), but not delay-dependent aspects (rate of forgetting).

PMID- 15040551
TI  - Dorsal stream activation during retrieval of object size and shape.
AB  - We investigated dorsal visual stream involvement in the retrieval of a variety of
      visual attributes of common objects, using functional magnetic resonance imaging.
      Seven subjects made binary decisions about the shape, color, and size of named
      objects during scanning. Bilateral parietal activity was significantly greater
      during retrieval of shape and size information than during retrieval of color
      information. Consistent with a domain-specific distributed model of semantic
      organization, the finding that dorsal stream activity is associated with size and
      shape retrieval, as compared with color retrieval, may indicate that both size
      and shape information are learned partly through dorsally mediated processes,
      such as visually guided grasping. These results demonstrate that both visual
      processing streams (i.e., the ventral "what" pathway and the dorsal "where"
      pathway) are involved in the storage and/or retrieval of knowledge of object
      appearance but that, just as in vision, these two pathways may play different
      roles in conceptual processing.

PMID- 15040552
TI  - Neural processing associated with true and false memory retrieval.
AB  - We investigated the neural bases for false memory with fMRI by examining neural
      activity during retrieval processes that yielded true or false memories. We used
      a reality monitoring paradigm in which participants saw or imagined pictures of
      concrete objects. (A subsequent misinformation task was also used to increase
      false memory rates.) At test, fMRI data were collected as the participants
      determined whether they had seen or had only imagined the object at study. True
      memories were of seen pictures accurately endorsed as seen, and for false
      memories were of imagined pictures falsely endorsed as seen. Three distinct
      patterns of activity were observed: Left frontal and parietal activity was not
      different for true and for false memories, whereas activity was greater for true
      than for false memories in occipital visual regions and posterior portions of the
      parahippocampal gyrus, and activity was greater for false than for true memories
      in right anterior cingulate gyrus. Possible interpretations are discussed.

PMID- 15040554
TI  - Household water management: refining the dominant paradigm.

PMID- 15040553
TI  - Activation of human motion processing areas during event perception.
AB  - Observers are able to segment continuous everyday activity into meaningful parts.
      This ability may be related to processing low-level visual cues, such as changes
      in motion. To address this issue, the present study combined measurement of
      evoked responses to event boundaries with functional identification of the
      extrastriate motion complex (MT+) and the frontal eye field (FEF), two regions
      related to motion perception and eye movements. The results provided strong
      evidence that MT+ is activated by event boundaries: Individuals' MT+ regions
      showed strong responses to event boundaries, and MT+ was collocated with a
      lateral posterior region that responded at event boundaries. The evidence
      regarding the FEF was less conclusive: The FEF showed reliable but relatively
      reduced responses to event boundaries, but the FEF was medial and superior to a
      frontal area that responded at event boundaries. These results suggest that
      motion cues, and possibly eye movements, may play key roles in event structure
      perception.

PMID- 15040555
TI  - Artemether-lumefantrine for uncomplicated malaria: a systematic review.
AB  - BACKGROUND: The World Health Organization (WHO) is promoting artemether
      lumefantrine for treating uncomplicated malaria. The objective of this review is
      to summarize available evidence of its effects compared with other antimalarial
      regimens. METHODS: We sought randomized and quasi-randomized studies comparing
      artemether-lumefantrine with any other antimalarial drug regimen. Databases
      searched were MEDLINE (to February 2003), EMBASE (to February 2003), and the
      Cochrane Controlled Trials Register (issue 1, 2003). Conference proceedings and
      reference article lists were searched and malaria researchers and the drug
      manufacturer were contacted. Two reviewers independently applied inclusion
      criteria and extracted data. RESULTS: Six trials (1698 participants) studied the
      four-dose regimen. Fever and parasite clearance tended to be shorter with
      artemether-lumefantrine, but parasitological failure on day 28 was more common
      with artemether-lumefantrine in comparison with mefloquine (one trial, n = 233),
      halofantrine (one trial, n = 86) and mefloquine-artesunate (one trial, n = 537);
      but less common with chloroquine (two trials, n = 378). For the six-dose regimen,
      two studies compared artemether-lumefantrine with mefloquine-artesunate, but
      there was insufficient data to demonstrate any meaningful comparative effects for
      day 28 parasitaemia, and no difference in parasite or fever clearance time was
      detected. There were 11 parasitological failures with artemether-lumefantrine and
      none with mefloquine-artesunate. CONCLUSION: There is no evidence to demonstrate
      the four-dose regimen of artemether-lumefantrine results in a higher cure rate
      than other antimalarial regimens against which it has been tested, apart from
      chloroquine in areas with high chloroquine resistance. Artemether-lumefantrine
      has potential advantages over non-artemisinin regimens because of the faster
      clearance time and gametocyte clearance. There is insufficient evidence about the
      six-dose regimen to know whether it is less or more effective than current
      antimalarial drug regimens.

PMID- 15040556
TI  - Efficacy of chloroquine, amodiaquine, sulphadoxine-pyrimethamine and combination
      therapy with artesunate in Mozambican children with non-complicated malaria.
AB  - This paper reports a two-phase study in Manhica district, Mozambique: first we
      assessed the clinical efficacy and parasitological response of Plasmodium
      falciparum to chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine
      (AQ), then we tested the safety and efficacy in the treatment of uncomplicated
      malaria, of three combinations: AQ + SP, artesunate (AR) + SP and AQ + AR. Based
      on the WHO (1996, WHO/MAL/96.1077) in vivo protocol, we conducted two open,
      randomized, clinical trials. Children aged 6-59 months with axillary body
      temperature > or = 37.5 degrees C and non-complicated malaria were randomly
      allocated to treatment groups and followed up for 21 days (first and second
      trial) and 28 days (first trial). The therapeutic efficacy of AQ (91.6%) was
      better than that of SP (82.7%) and CQ (47.1%). After 14 days, 69% of the strains
      were parasitologically resistant to CQ, 21.4% to SP and 26% to AQ. Co
      administration of AQ + SP, AR + SP and AQ + AR was safe and had 100% clinical
      efficacy at 14-day follow-up. The combination therapies affected rapid fever
      clearance time and reduced the incidence of gametocytaemia during follow-up.

PMID- 15040557
TI  - CV8, a new combination of dihydroartemisinin, piperaquine, trimethoprim and
      primaquine, compared with atovaquone-proguanil against falciparum malaria in
      Vietnam.
AB  - OBJECTIVES: To study a new combination, based on dihydroartemisinin and
      piperaquine (CV8) and atovaquone/proguanil (Malarone) for treatment of
      uncomplicated falciparum malaria in Vietnam. METHODS: Vietnamese adults with
      falciparum malaria were allocated randomly to treatment with
      dihydroartemisinin/piperaquine/trimethoprim/primaquine 256/2560/720/40 mg (CV8, n
      = 84) or Malarone 3000/1200 mg (n = 81), both over 3 days. Patients were followed
      up for 28 days. RESULTS: All patients recovered rapidly. The mean (95% CI)
      parasite elimination half-life of CV8 was 6.8 h (6.2-7.4) and of Malarone 6.5 h
      (6.1-6.9) (P = 0.4). Complete parasite clearance time was 35 (31-39) and 34 h (31
      38) (P = 0.9). The 28-day cure rate was 94% and 95%, respectively (odds ratio
      0.84, 95% CI 0.18-3.81). No significant side-effects were found. CONCLUSION: CV8
      and Malarone are effective combinations against multi-drug resistant falciparum
      malaria. CV8 has the advantage of a low price.

PMID- 15040558
TI  - Efficacy of mefloquine and mefloquine-artesunate for the treatment of
      uncomplicated Plasmodium falciparum malaria in the Amazon region of Bolivia.
AB  - We assessed the efficacy of mefloquine monotherapy and mefloquine-artesunate (MQ
      AS) combination therapy for the treatment of Plasmodium falciparum malaria at
      four sites in the Bolivian Amazon region. Patients with uncomplicated P.
      falciparum infections between 5 and 60 years of age were randomly assigned to be
      treated with either MQ (15 mg/kg in a single oral dose) or MQ (15 mg/kg) plus AS
      (4 mg/kg daily for 3 days). A total of 143 patients were enrolled and followed
      for 28 days. None of the 73 patients who received MQ alone or the 70 patients who
      received MQ-AS combination therapy had recurrences of parasitaemia during the 28
      day follow-up period. Asexual parasite densities fell significantly more rapidly
      and the proportion of patients with gametocytes was significantly lower on days 7
      28 in patients treated with MQ-AS than in those treated with MQ alone. All
      patients tolerated the medications well. After this study, the Bolivian Ministry
      of Public Health changed its treatment policy for uncomplicated P. falciparum
      malaria in the Amazon region to combination therapy with MQ-AS to slow or prevent
      the development of resistance.

PMID- 15040561
TI  - Post-injury malaria: a risk factor for wound infection and protracted recovery.
AB  - OBJECTIVE: To assess the impact of post-injury falciparum malaria on morbidity
      parameters in Cambodia. METHOD: Retrospective study of 227 trauma patients
      managed at a surgical centre in Battambang, Cambodia. RESULTS: Within 10 days of
      the injury, 42.7% of the study population developed symptomatic malaria. In
      patients with post-injury malaria, the rate of wound infection was 36.1% compared
      with 10.0% in patients without symptomatic malaria (95% confidence interval for
      difference 15.2-36.9%). The average hospital stay in the post-injury malaria
      group was 31.2 days compared with 19.4 days in the patients without the
      complication (95% confidence interval for difference 7.2-16.4 days). CONCLUSION:
      Symptomatic malaria after trauma is common in Cambodia. Post-injury malaria seems
      to increase the risk of wound infection, delays postoperative recovery, and thus
      adds to the burden of trauma.

PMID- 15040560
TI  - Malaria transmission and major malaria vectors in different geographical areas of
      Southeast Asia.
AB  - During the last decade, major progress in malaria control has been achieved in
      Vietnam, Laos and Cambodia. However, malaria is still a potentially fatal disease
      in some hilly-forested areas and continues to be endemic in a few coastal foci.
      To estimate the risk that stems from the major vectors after a decade of
      intensive malaria control, an entomological study based on human landing
      collections was conducted between April 1998 and November 2000 in six study
      villages (four in Vietnam, one in Cambodia and one in Laos) located in different
      physio-geographical areas. Five villages were selected in places where new cases
      of malaria still occurred. In the sixth village, in the northern hilly area of
      Vietnam, no case of malaria was detected during the past 3 years. In three study
      villages of the hilly forested areas of Cambodia and central Vietnam, Anopheles
      dirus A still played an important role in malaria transmission and maintain
      perennial transmission inside the villages despite its low density. Anopheles
      minimus A was found in all study villages except in the southern coastal village
      of Vietnam. Its role in malaria transmission, however, varied between localities
      and surveys. In one study village of central Vietnam it was almost absent (one
      specimen collected over 480 man nights), and in another village sporozoite
      positive specimens (2.8%) were only observed during the first two surveys whereas
      this species disappeared from the collections from November 1998 onwards (six
      surveys: 360 man nights). In the northern study site An. minimus A and C were
      found in all collections, but no local malaria transmission occurred. However,
      the constant presence of these two species associated with a high longevity
      (parous rate up around 80% and 65%, respectively), suggests that transmission can
      occur at almost any time if parasite reservoirs are reintroduced in the area. The
      proper management of malaria cases and population movement is, therefore,
      important to prevent outbreaks and the reintroduction of malaria in northern
      Vietnam. In the study site of the Mekong delta, An. sundaicus occurred at high
      densities (up to 190 bites/man/night). The recent changes in land use from rice
      cultivation to shrimp farming probably explains the increase of this brackish
      water breeding species during the study period. However, none of the 11,002
      specimens was positive for Plasmodium circumsporozoite protein (CSP). The
      relative low survival rate as estimated by the parous rate (around 47%) may
      reflect its low vectorial status that could explain the very low malaria
      incidence (1.9 case/100 persons/year) in this study site. A calculated sporozoite
      rate of maximum 1/300,000 is enough to explain this low malaria incidence.
      Despite the successes in malaria control, the vector An. dirus A continues to
      play an important role in malaria transmission, whereas An. minimus A showed
      temporal and spatial variation in its role as vector. The role of An. sundaicus
      as vector could not be confirmed because of the low incidence in the coastal
      study village. Other Anopheles species may be locally involved, but in the five
      study villages where malaria is still present they probably do not contribute
      significantly to malaria transmission. The study also points towards the fact
      that in Southeast Asia it will become increasingly difficult to incriminate
      Anopheles species in malaria transmission while the risk for malaria transmission
      still persist.

PMID- 15040559
TI  - Efficacy of sulphadoxine-pyrimethamine alone or combined with amodiaquine or
      chloroquine for the treatment of uncomplicated falciparum malaria in Ugandan
      children.
AB  - The rapid development of falciparum resistance to sulphadoxine-pyrimethamine (SP)
      in East and Central Africa has raised concerns as to the efficacy of combining it
      with another drug. In 2002, we assessed the efficacy of SP alone and combined
      with amodiaquine (AQ/SP) or chloroquine (CQ/SP) in Ugandan children with
      uncomplicated falciparum malaria. At day 14, adequate clinical response was 100%
      (84/84) for AQ/SP, 93% (92/101) for CQ/SP and 91% (73/80) for SP. At day 28,
      parasitological failure (RI-RIII) occurred in 16% (13/80) of children treated
      with AQ/SP, in 48% (48/100) of those treated with CQ/SP and in 61% (48/79) of
      those treated with SP alone. Compared with the AQ/SP arm, the odds for
      parasitological failure at day 28 were five times higher (95% CI, 2-10) in the
      CQ/SP group and sevenfold higher (95% CI, 3-17) in that of SP alone. CQ/SP does
      not offer any significant added benefit over SP alone while AQ/SP is an
      efficacious low-cost combination. These findings have important policy
      implications for Uganda and other resource-constrained African countries faced
      with the problematic choice of a new first-line antimalarial treatment in a
      context of high CQ resistance.

PMID- 15040562
TI  - Research for control: the onchocerciasis experience.
AB  - Onchocerciasis control has been very successful in Africa and research has played
      a critical role. An overview of the main epidemiological and implementation
      research activities undertaken over the last 20 years in collaboration with the
      African onchocerciasis control programmes and of the impact this research had on
      control is given. The research included the development of epidemiological
      modelling and its application in programme evaluation and operational planning,
      research on disease patterns and disease burden in different bioclimatic zones to
      justify and guide control operations, community trials of ivermectin to determine
      its safety for large-scale use and its impact on transmission, rapid assessment
      methods to identify target communities for treatment and community-directed
      treatment for sustained drug delivery. Lessons learned during this unique
      collaboration between research and control are discussed.

PMID- 15040563
TI  - Use of intermittent presumptive treatment and insecticide treated bed nets by
      pregnant women in four Kenyan districts.
AB  - The roll back malaria (RBM) movement promotes the use of insecticide-treated
      bednets (ITNs) and intermittent presumptive treatment (IPT) of malaria infection
      as preventive measures against the adverse effects of malaria among pregnant
      women in Africa. To determine the use of these preventive measures we undertook a
      community-based survey of recently pregnant women randomly selected from
      communities in four districts of Kenya in December 2001. Of the 1814 women
      surveyed, only 5% had slept under an ITN. More than half of the 13% of women
      using a bednet (treated or untreated) had bought their nets from shops or
      markets. Women from rural areas used bednets less than urban women (11% vs. 27%;
      P < 0.001), and 41% of the bednets used by rural women had been obtained free of
      charge from a research project in Bondo or a nationwide UNICEF donation through
      antenatal clinics (ANCs). Despite 96% of ANC providers being aware of IPT with
      sulphadoxine-pyrimethamine (SP), only 5% of women interviewed had received two or
      more doses of SP as a presumptive treatment. The coverage of pregnant women with
      at least one dose of IPT with SP was 14%, though a similar percentage also had
      received at least a single dose as a curative treatment. The coverage of
      nationally recommended strategies to prevent malaria during pregnancy during 2001
      was low across the diverse malaria ecology of Kenya. Rapid expansion of access to
      these services is required to meet international and national targets by the year
      2005. The scaling up of malaria prevention programmes through ANC services should
      be possible with 74% of women visiting ANCs at least twice in all four districts.
      Issues of commodity supply and service costs to clients will be the greatest
      impediments to reaching RBM targets.

PMID- 15040564
TI  - Anaemia in pregnancy and infant mortality in Tanzania.
AB  - Tanzania is an area of moderate to high risk for severe anaemia during pregnancy.
      There is extensive literature examining the consequences of severe anaemia for
      pregnant women, but the impact this problem has on their infants in malaria
      endemic regions is poorly understood. Between 1999 and 2001 we used a demographic
      surveillance system in the Kilombero Valley, Tanzania to link morbidity and socio
      economic status data for 301 pregnant women to the survival of 365 days of their
      singleton babies, looking for evidence of an association between infant mortality
      and maternal haemoglobin (Hb). The hazards ratio for infant mortality amongst
      women who had been severely anaemic in pregnancy (Hb < 8 g/dl) was 3.1 [95%
      confidence interval (CI) 1.1-9.1, P = 0.04] compared with women with Hb above
      this level after controlling for other factors. Prevention of anaemia in
      pregnancy may lead to an improvement in infant survival.

PMID- 15040565
TI  - Does reducing malaria improve household living standards?
AB  - Living in malaria-endemic regions places an economic burden on households even if
      they do not actually suffer an episode of malaria. Households living in endemic
      malarial regions are less likely to have access to economic opportunities and may
      have to modify agricultural practices and other household behaviour to adapt to
      their disease environment. Data from Vietnam demonstrate that reductions in
      malaria incidence through government-financed malaria control programmes can
      contribute to higher household income for all households in endemic areas.
      Empirically, the roughly 60% decline in malaria cases over the 1990s in Vietnam
      translated to a dollars 12.60 average improvement in annual consumption of all
      households, or a roughly dollars 180 million annual economic benefit in the form
      of improved living standards.

PMID- 15040566
TI  - Out-of-pocket health expenditure and debt in poor households: evidence from
      Cambodia.
AB  - OBJECTIVES: To document how out-of-pocket health expenditure can lead to debt in
      a poor rural area in Cambodia. METHODS: After a dengue epidemic, 72 households
      with a dengue patient were interviewed to document health-seeking behaviour, out
      of-pocket expenditure, and how they financed such expenditure. One year later, a
      follow-up visit investigated how the 26 households with an initial debt had coped
      with it. RESULTS: The amount of out-of-pocket health expenditure depended mostly
      on where households sought care. Those who had used exclusively private providers
      paid on average US dollars 103; those who combined private and public providers
      paid US dollars 32, and those who used only the public hospital US dollars 8. The
      households used a combination of savings, selling consumables, selling assets and
      borrowing money to finance this expenditure. One year later, most families with
      initial debts had been unable to settle these debts, and continued to pay high
      interest rates (range between 2.5 and 15% per month). Several households had to
      sell their land. CONCLUSIONS: In Cambodia, even relatively modest out-of-pocket
      health expenditure frequently causes indebtedness and can lead to poverty. A
      credible and accessible public health system is needed to prevent catastrophic
      health expenditure, and to allow for other strategies, such as safety nets for
      the poor, to be fully effective.

PMID- 15040567
TI  - Strengthening health services to control epidemics: empirical evidence from
      Guinea on its cost-effectiveness.
AB  - OBJECTIVE: To assess the cost-effectiveness of control measures implemented
      against epidemics in Guinea, West Africa. METHODS: We collected all routine data
      available on incidence, mortality, control measures implemented and their cost
      during epidemics of cholera, measles and meningococcal meningitis in 1993-95.
      Then we estimated for one prefecture the effectiveness and cost-effectiveness of
      epidemic control measures for three scenarios: (i) 'natural' situation, (ii)
      'routine' health services and (iii) 'intervention'. Where uncertainty was
      considerable, we used sensitivity analysis and estimated ranges. FINDINGS:
      Routine health services reduced potential deaths by 51% (67%, 37% and 60% for
      cholera, measles and meningitis, respectively), and additional interventions
      further decreased potential deaths by 28% (28%, 27% and 30% for cholera, measles
      and meningitis, respectively). The marginal cost-effectiveness of epidemic
      control measures in routine health services was US dollars 29 per death averted.
      The marginal cost-effectiveness of additional interventions was US dollars 93 per
      death averted. CONCLUSION: Even with the data weaknesses that characterize
      situations of epidemics it is possible to show that strengthening health services
      to control epidemics as was performed in Guinea was highly cost-effective.
      Moreover, sensitivity analysis over a range of assumptions confirms that (i) well
      functioning health services averted the major part of avoidable deaths, (ii)
      combining existing health services with additional interventions minimizes the
      health impact of epidemics and (iii) case management should be a cornerstone of
      control of epidemics of cholera, measles and meningococcal meningitis.

PMID- 15040569
TI  - Climate variability and Ross River virus transmission in Townsville Region,
      Australia, 1985-1996.
AB  - BACKGROUND: How climate variability affects the transmission of infectious
      diseases at a regional level remains unclear. We assess the impact of climate
      variation on the Ross River virus (RRv) transmission in the Townsville region,
      Queensland, north-east Australia. METHODS: We obtained population-based
      information on monthly variations in RRv cases, climatic factors, sea level, and
      population growth between 1985 and 1996. Cross-correlations were computed for a
      series of associations between climate variables (rainfall, maximum temperature,
      minimum temperature, relative humidity and high tide) and the monthly incidence
      of RRv disease over a range of time lags. We assessed the impact of climate
      variability on RRv transmission using the seasonal auto-regressive integrated
      moving average (SARIMA) model. RESULTS: There were significant correlations of
      the monthly incidence of RRv to rainfall, maximum temperature, minimum
      temperature and relative humidity, all at a lag of 2 months, and high tide in the
      current month. The results of SARIMA models show that monthly average rainfall
      (beta = 0.0007, P = 0.01) and high tide (beta = 0.0089, P = 0.04) were
      significantly associated with RRv transmission and maximum temperature was also
      marginally significantly associated with monthly incidence of RRv (beta = 0.0412,
      P = 0.07), although relative humidity did not seem to have played an important
      role in the Townsville region. CONCLUSIONS: Rainfall, high tide and maximum
      temperature were likely to be key determinants of RRv transmission in the
      Townsville region.

PMID- 15040568
TI  - Viewpoint: the Brazilian HIV/AIDS 'success story'--can others do it?

PMID- 15040572
TI  - Colonizing therapeutic space: the overlooked science of drug husbandry.

PMID- 15040571
TI  - Tuberculous meningitis and miliary tuberculosis in young children.
AB  - OBJECTIVES: To document the clinical and diagnostic features of tuberculous
      meningitis (TBM) in young children with and without concomitant miliary
      tuberculosis (TB). METHODS: A retrospective comparative study. RESULTS: Of 104
      children with TBM, 32 (31%), median age 17.0 months, had a miliary appearance on
      chest radiograph; 72 (69%), median age 30.5 months, had TBM only (P = 0.04).
      Mediastinal adenopathy was noted in 27 (84%) of the children with miliary TB and
      33 (46%) of those with TBM only (P = 0.0005). The mean cerebrospinal fluid (CSF)
      lymphocyte and polymorphonuclear counts of all children (no significant
      differences between groups) were 137 x 10(6)/l and 38 x 10(6)/l and the mean
      protein and glucose concentrations were 1.45 g/l and 0.72 mmol/l, respectively.
      Polymorphonuclear leukocytes were predominant in the CSF of 17% of children, in
      16% the CSF glucose was > 2.2 mmol/l and in 26% the CSF protein was < 0.8 g/l. On
      Mantoux testing 37 (65%) of 57 children with TBM only and 12 (48%) of 25 children
      with TBM and miliary TB had an induration of > or = 10 mm (P = 0.23). Ten
      children (10%) died, five (7%) who had TBM only and five (16%) who had TBM and
      miliary TB. CONCLUSION: Children with TBM and miliary TB were younger and more
      likely to have mediastinal adenopathy on chest radiography than those with TBM
      only. Diagnostic features and investigations in both groups may be misleading at
      times.

PMID- 15040570
TI  - Seroepidemiology of dengue in the adult population of Singapore.
AB  - Urbanization is one of the reasons for the resurgence of dengue in tropical and
      subtropical countries. We conducted a cross-sectional seroepidemiological study
      in Singapore to determine the extent at which the Singapore population has been
      exposed to dengue infections. Dengue antibodies were measures with PanBio Dengue.
      Of 298 enrolled subjects (age 18-45), 133 (45%) had a positive dengue serology.
      In multivariate analysis, age and nationality (Singaporean vs non-Singaporean
      Asians) were found to be significant independent predictors. The odds ratio of
      dengue seroprevalence increased by 4.13 (95% CI: 2.88-5.93) for every 10 year
      increase in age. Dengue infections remain a major problem in Singapore.

PMID- 15040573
TI  - 2003 approvals: a year of innovation and upward trends.

PMID- 15040574
TI  - The licensing gamble: raising the stakes.

PMID- 15040575
TI  - Memantine hydrochloride.

PMID- 15040576
TI  - Current status and future potential of transdermal drug delivery.
AB  - The past twenty five years have seen an explosion in the creation and discovery
      of new medicinal agents. Related innovations in drug delivery systems have not
      only enabled the successful implementation of many of these novel
      pharmaceuticals, but have also permitted the development of new medical
      treatments with existing drugs. The creation of transdermal delivery systems has
      been one of the most important of these innovations, offering a number of
      advantages over the oral route. In this article, we discuss the already
      significant impact this field has made on the administration of various
      pharmaceuticals; explore limitations of the current technology; and discuss
      methods under exploration for overcoming these limitations and the challenges
      ahead.

PMID- 15040577
TI  - cAMP detection methods in HTS: selecting the best from the rest.
AB  - The number of technologies that enable high-throughput functional screening of G
      protein-coupled receptors has expanded markedly over the past 5 years.
      Consequently, choosing the most appropriate technology can be a daunting task,
      particularly for Gi- or Gs-coupled receptors. The most common systems for cyclic
      AMP detection are reviewed, highlighting the practical and theoretical aspects
      that are important in their application to high-throughput screening. Current
      technologies can do the job, but it is likely that the future may require
      development of technologies that provide even greater biological information.

PMID- 15040579
TI  - Cytokine-receptor pairing: accelerating discovery of cytokine function.
AB  - Over the past decade, advances in both gene discovery and ligand-receptor pairing
      techniques have led to the recognition that systematic pairing of 'orphan'
      database-derived cytokines and/or cytokine receptors with their cognate partners
      can lead to a marked acceleration in the elucidation of biological function. The
      sometimes-restricted tissue distribution of the receptor, coupled with the highly
      specific bioactivity of the corresponding ligand, can direct investigators
      rapidly towards regulatory function and site-of-action studies. The power of
      cytokine-receptor pairing to accelerate the understanding of function will be
      illustrated, citing several examples of candidate drug discoveries. Several of
      these discoveries, resulting from cytokine-receptor pairings, are at present
      advancing towards human clinical evaluation.

PMID- 15040578
TI  - From monoamines to genomic targets: a paradigm shift for drug discovery in
      depression.
AB  - Depression, a complex psychiatric disorder that affects approximately 15% of the
      population, has an enormous social cost. Although the disorder is thought to be
      the outcome of gene-environmental interactions, the causative genes and
      environmental factors underlying depression remain to be identified. All the
      antidepressant drugs now in use--the forerunner of which was discovered
      serendipitously 50 years ago--modulate monoamine neurotransmission, and take six
      to eight weeks to exert their effects, but each drug is efficacious in only 60
      70% of patients. A conceptually novel antidepressant that acted rapidly and
      safely in a high proportion of patients would almost certainly become the world's
      bestselling drug. Yet such a drug is not on the horizon. Here, we cover the
      different phases of antidepressant drug discovery in the past, present and
      future, and comment on the challenges and opportunities for antidepressant
      research.

PMID- 15040580
TI  - Engaging biotechnology companies in the development of innovative solutions for
      diseases of poverty.

PMID- 15040581
TI  - Biotechnology: identifying advances from the hype.

PMID- 15040582
TI  - Human antibody-Fc receptor interactions illuminated by crystal structures.
AB  - Immunoglobulins couple the recognition of invading pathogens with the triggering
      of potent effector mechanisms for pathogen elimination. Different immunoglobulin
      classes trigger different effector mechanisms through interaction of
      immunoglobulin Fc regions with specific Fc receptors (FcRs) on immune cells.
      Here, we review the structural information that is emerging on three human
      immunoglobulin classes and their FcRs. New insights are provided, including an
      understanding of the antibody conformational adjustments that are required to
      bring effector cell and target cell membranes sufficiently close for efficient
      killing and signal transduction to occur. The results might also open up new
      possibilities for the design of therapeutic antibodies.

PMID- 15040583
TI  - p47 GTPases: regulators of immunity to intracellular pathogens.
AB  - Activation of the innate immune system by interferon-gamma (IFN-gamma is crucial
      for host resistance to infection. IFN-gamma induces the expression of a wide
      range of mediators that undermine the ability of pathogens to survive in host
      cells, including a newly discovered family of 47-kDa GTPases. Elimination of
      different p47 GTPases in mice by gene targeting severely cripples IFN-gamma
      regulated defence against Toxoplasma gondii, Listeria monocytogenes,
      Mycobacterium spp. and other pathogens. In this article, we review our
      understanding of the role of p47 GTPases in resistance to intracellular infection
      and discuss the present evidence concerning their mode of action.

PMID- 15040584
TI  - Role of the cytoskeleton during leukocyte responses.
AB  - The cytoskeleton is a cellular network of structural, adaptor and signalling
      molecules that regulates most cellular functions that are related to the immune
      response, including migration, extravasation, antien recognition, activation and
      phagocytosis by different subsets of leukocytes. Recently, a large number of
      regulatory elements and structural constituents of the leukocyte cytoskeleton
      have been identified. In this review, we discuss the composition and regulation
      of the different cytoskeletal elements and their role in immune responses.

PMID- 15040585
TI  - The many important facets of T-cell repertoire diversity.
AB  - In the thymus, a diverse and polymorphic T-cell repertoire is generated by random
      recombination of discrete T-cell receptor (TCR)-alphabeta gene segments. This
      repertoire is then shaped by intrathymic selection events to generate a
      peripheral T-cell pool of self-MHC restricted, non-autoaggressive T cells. It has
      long been postulated that some optimal level of TCR diversity allows efficient
      protection against pathogens. This article focuses on several recent advances
      that address the required diversity for the generation of an optimal immune
      response.

PMID- 15040587
TI  - Elucidation of Lyme arthritis.
AB  - Before the first description of Lyme arthritis in 1976, patients with this
      disease were often thought to have juvenile or adult rheumatoid arthritis. It is
      now known that Lyme arthritis is caused by a tick-borne spirochete that
      disseminates to joints, where it induces marked pro-inflammatory responses. In
      most patients, the arthritis resolves with antibiotic treatment. However, in the
      United States, about 10% of patients with Lyme arthritis develop persistent
      synovitis, which lasts for months or even several years after the apparent
      eradication of the spirochete from the joint with antibiotic therapy. The
      elucidation of Lyme arthritis, from acute infection to chronic synovitis, might
      help in our understanding not only of this entity, but also of other forms of
      chronic inflammatory arthritis, including rheumatoid arthritis.

PMID- 15040588
TI  - Monoclonal antibodies: the story of a discovery that revolutionized science and
      medicine.

PMID- 15040586
TI  - The dark side of C5a in sepsis.
AB  - Sepsis is a major clinical problem for which therapeutic interventions have been
      largely unsuccessful, in spite of promising strategies that were successful in
      animals, especially rodents. There is new evidence that sepsis causes excessive
      activation of the complement system and that this induces paralysis of innate
      immune functions in phagocytic cells due to effects of the powerful complement
      activation product, C5a. This review describes our present understanding of how
      and why sepsis is a life-threatening condition and how it might be more
      effectively treated.

PMID- 15040589
TI  - [Balance, voice, and power for Earth. Life comes from life only, says an old
      axiom].

PMID- 15040590
TI  - [Prevention and treatment of pathological scars].
AB  - At times, the appearance of a pathological scar is a result of the scar process
      itself which can bring with it important physical and psychological complications
      for an affected person. The appearance of such a scar is more frequent in
      injuries which have followed a scar process caused as the consequence of a second
      operation and a disgraceful healing process. Preventive measures should be taken
      right at the start of treatment of the injury and continue during a set time
      after its initial closure. When, in spite of everything, a pathological scar
      appears, there are various materials and treatment techniques which provide
      different degrees of effectiveness.

PMID- 15040591
TI  - [Working with the scientific method].
AB  - In order to improve the quality of nursing service provided to patients, the
      Nursing Directors for Area 7 Primary Health Care "IMSALUD" in Madrid drew up a
      work plan based, fundamentally, on a progressive installation of the scientific
      method in habitual nursing work. This transversal descriptive study measures the
      degree of installation of this method 18 months after the development of this
      plan and compares these results with those obtained 6 months after the
      development of this plan. After 18 months, Nursing Directors had planned to
      obtain a 50% complete compliance in the nursing process for immobilized and
      terminal patients. This objective has been achieved in terms of an evaluation by
      patterns and a register of nursing diagnosis. Improvement is needed in compliance
      of treatment plans and in recording evaluations in clinical files.

PMID- 15040592
TI  - [The management of medical waste].
AB  - Sanitary residues fall inside the general category of residues produced;
      therefore, we must begin with general aspects such as the habit of producing
      residues, the awareness a country has regarding this problem and the treatment
      policy to apply in order to deal with these residues. The author also established
      the characteristics and the classification for these residues as well as the way
      identify the diverse types of residues for each specific area they come from.

PMID- 15040593
TI  - [Medical waste management].
AB  - The author describes the treatment systems which should be applied, particularly
      when dealing with groups III and IV as explained in the previous article, in
      order to counteract their noxious effects on persons and the environment. Some
      treatment systems are compared and the author explains how to treat radioactive
      wastes, residues and sterilization, microwaves and the incineration of sanitary
      residues.

PMID- 15040594
TI  - [How does a medical waste incinerator work? Experience of the Hospital de
      Cruces].

PMID- 15040596
TI  - [The babysitting method].
AB  - The great advances made in neonatal care have posed changes in the attitudes and
      in nursing care treatment, proposing new techniques such as the babysitting
      method which without being an aggressive method favors the evolution of a child
      during his/her hospital stay and the parent-child tie.

PMID- 15040597
TI  - [Already in the 21st century ... a new leadership in health sciences].
AB  - It is a fact to state that health care has never succeeded in covering such a
      wide series of sectors of the population in our country. The health care network
      created both by public as well as private efforts, and occasionally due to the
      collaboration by both fields, offers a framework of health care services which
      ensures there is a satisfactory coverage for the general population. It is
      difficult to provide a rebuttal to this statement; all one needs to do is recall
      what the status of our health care system was a few years ago. We have not
      achieved a perfect system. The development of our health care network has been
      produced by expansion. As we have come to believe that health is an unalienable
      right, we have to expand health care services to cover everyone. This effort
      leads to a second phase which brings to bear upon us new problems. One is the
      quality of health care services and the second is cost.

PMID- 15040595
TI  - [Which factors affect adhesion to diabetes treatment?].
AB  - Diabetes Mellitus is one of the gravest public health problems due to its
      frequency and importance. Its prevalence is estimated between 2 to 6% of the
      adult population and 16% for those over 65. Due to the personal, economic and
      sanitary repercussions which it generates and to its own associated degenerative
      complications, this disease is responsible for a high percentage of deaths. This
      sickness can not be cured, but it can be controlled and its degenerative
      complications reduced over the long-term. In recent years, the medical profession
      has paid special attention to the adherence to treatment plans to control
      diabetes, bearing in mind which factors interfere in treatment and which are
      favorable to treatment. The author values the main determining factors for
      adherence to a treatment plan, such as age, knowledge about diabetes, self care
      skills, a patient's ability to accept this disease, self-sufficient beliefs,
      perception of one's symptoms, treatment variables, stress and social assistance.

PMID- 15040598
TI  - [What is the University Hospital "Sagrat Cor" of Barcelona, and what does it
      offer?].

PMID- 15040599
TI  - Transgenic Sertoli cells as a vehicle for gene therapy.
AB  - Gene therapy involves the manipulation of genetic material to replace defective
      or deficient proteins to restore function in disease states. These genes are
      introduced into cells by mechanical, chemical, and biological approaches. To
      date, cell-based gene therapy has been hampered by the lack of an abundant, safe,
      and immunologically acceptable source of tissue. As an alternative, transgenic
      animals designed to produce therapeutic proteins could overcome some of the
      issues facing gene therapy but the problem of immune rejection of the tissue
      remains. This article reports on recently published work indicating the potential
      to use transgenic Sertoli cells surviving in an allogeneic host by virtue of
      their ability to create a locally immunoprivileged environment, thereby providing
      for the continued delivery of a therapeutic protein to the systemic circulation.

PMID- 15040600
TI  - Autotransplantation of unmanipulated bone marrow into scarred myocardium is safe
      and enhances cardiac function in humans.
AB  - Stem cell transplants into damaged myocardium may have the potential to improve
      cardiac function. We investigated the safety of transplanting unmanipulated
      autologous bone marrow into infarcted myocardium of patients undergoing coronary
      bypass surgery and assessed its efficacy to improve cardiac function. Fourteen
      patients with one or more areas of transmural myocardial infarction were studied.
      Autologous bone marrow was obtained by sternal bone aspirate at the time of
      surgery, diluted in autologous serum at a ratio of 1:2, and then injected 1 cm
      apart into the mid-depth of the left ventricular scar. There were no deaths, no
      perioperative myocardial infarctions, and no significant ventricular arrhythmias.
      Dobutamine stress echocardiography demonstrated overall improvement in the global
      and regional left ventricular function 6 weeks and 10 months after surgery. Of 34
      infarcted left ventricular segments, 11 were injected with bone marrow alone, 13
      were revascularized with a bypass graft alone, and 10 received bone marrow
      transplantation and a bypass graft in combination. Only the left ventricle
      segmental wall motion score of the areas injected with bone marrow and receiving
      a bypass graft in combination improved at low dose and at peak dobutamine stress.
      These findings suggest that transplantation of unmanipulated autologous bone
      marrow into scar tissue of the human heart is safe and enhances cardiac function
      only when used in combination with myocardial revascularization. This benefit can
      be seen after 6 weeks of the bone marrow transplant and is maintained after 10
      months of follow-up.

PMID- 15040601
TI  - Development and transplantation of a mineralized matrix formed by osteoblasts in
      vitro for bone regeneration.
AB  - The use of extracellular matrix materials as scaffolds for the repair and
      regeneration of tissues is receiving increased attention. The current study was
      undertaken to test whether extracellular matrix formed by osteoblasts in vitro
      could be used as a scaffold for osteoblast transplantation and induce new bone
      formation in critical size osseous defects in vivo. Human osteoblasts derived
      from alveolar bone were cultured in six-well plates until confluent and then in
      mineralization media for a further period of 3 weeks to form an osteoblast-
      mineralized matrix complex. Histologically, at this time point a tissue structure
      with a "connective tissue"-like morphology was formed. Type I collagen was the
      major extracellular component present and appeared to determine the matrix
      macrostructure. Other bone-related proteins such as alkaline phosphatase (ALP),
      bone morphogenetic protein (BMP)-2 and -4, bone sialoprotein (BSP), osteopontin
      (OPN), and osteocalcin (OCN) also accumulated in the matrix. The osteoblasts
      embedded in this matrix expressed mRNAs for these bone-related proteins very
      strongly. Nodules of calcification were detected in the matrix and there was a
      correlation between calcification and the distribution of BSP and OPN. When this
      matrix was transplanted into a critical size bone defect in skulls of
      immunodeficient mice (SCID), new bone formation occurred. Furthermore, the cells
      inside the matrix survived and proliferated in the recipient sites, and were
      traceable by the human-specific Alu gene sequence using in situ hybridization. It
      was found that bone-forming cells differentiated from both transplanted human
      osteoblasts and activated endogenous mesenchymal cells. This study indicates that
      a mineralized matrix, formed by human osteoblasts in vitro, can be used as a
      scaffold for osteoblast transplantation, which subsequently can induce new bone
      formation.

PMID- 15040602
TI  - The origin of biliary ductular cells that appear in the spleen after
      transplantation of hepatocytes.
AB  - Transplantation of rat hepatocytes into the syngeneic rat spleen results in the
      appearance of cytokeration (CK)-19-positive biliary cells that form ductules. The
      exact origin of CK-19-positive cells is not known and the possibility that they
      are derived from biliary cells or precursors of oval cells in transplanted
      hepatocyte preparations has been raised. In the present study, we found that the
      number of CK-19-positive biliary cells increased rapidly after transplantation of
      hepatocytes, reached the maximum at 4 weeks, and then gradually decreased.
      However, a Ki-67 labeling index of CK-19-positive biliary cells was low and
      showed no significant changes throughout the experimental period. In addition, no
      or few CK-19-positive cells appeared in the spleen after transplantation of
      nonparenchymal liver cells enriched with biliary cells. These results showed that
      biliary cells were not the source of CK-19-positive cells in the spleen.
      Impairment of precursors of oval cells in the liver by administration of 4,4'
      diaminodiphenylmethane 24 h before transplantation of hepatocytes did not prevent
      the appearance of CK-19-positive biliary cells in the spleen. Moreover,
      transplantation of nonparenchymal cells carrying an increased number of oval
      cells by means of treatment with 2-acetylaminofluorene and partial hepatectomy
      resulted in no appearance of CK-19-positive biliary cells in the spleen. These
      results ruled out oval cells as the origin of CK-19-positive biliary cells in the
      spleen. Because CK-19-positive biliary cells appeared in the spleen only when
      hepatocyte fractions were transplanted, we suggest transdifferentiation of
      heptocytes may be the mechanism by which CK-19-positive biliary cells are
      generated.

PMID- 15040604
TI  - Y chromosome detection of three-dimensional tissue-engineered skeletal muscle
      constructs in a syngeneic rat animal model.
AB  - Surgical reconstruction of muscle tissue lost by trauma or tumor ablation is
      limited by the lack of availability of functional native tissue substitution.
      Moreover, so far most inherited or acquired muscle diseases are lacking
      sufficient treatment, because only few alternatives exist to provide functional
      restoration of lost muscle tissues. Engineering those tissues and transplantation
      into sites of dysfunction may be an alternative approach and may allow
      replacement of such damaged or failing skeletal muscle tissues. Techniques
      attempting reconstruction of some human tissues and organs (tissue engineering)
      have been introduced into clinical practice recently. One major problem that
      previous transplantation studies were facing is the ability of detection of
      transplanted cells after integration. Using the Y chromosome in situ
      hybridization technique in a syngeneic rat model allows transplantation of cell
      constructs orthotopically, without manipulation of the cells, with no rejection
      or immunosuppression being implied, but providing a nondilutable genetic marker
      to identify transplanted cells. The purpose of our study was to create functional
      skeletal muscle tissue in vivo using the transplantation of primary myoblasts
      precultivated within a three-dimensional (3D) fibrin matrix and to determine the
      fate of the transplanted cells using the Y chromosome detection technique. 3D
      myoblast cultures were established derived from male donor rats and after 7 days
      of cultivation we performed an orthotopic transplantation of 3D cell constructs
      into a created muscle defect within the gracilis muscle of syngeneic female rats.
      Anti-desmin immunostaining and Y chromosome in situ hybridization indicated the
      survival and integration of transplanted male myoblasts into the female recipient
      animal, thus demonstrating the feasibility of this approach in tissue engineering
      and the research of cell transplantation in general.

PMID- 15040603
TI  - Cryopreservation of alginate-encapsulated recombinant cells for antiangiogenic
      therapy.
AB  - The potential benefit of continuous local administration of antiangiogenic
      proteins to CNS tumors in vivo has recently been demonstrated using endostatin
      producing recombinant cells encapsulated in alginate beads. Due to the treatment
      potential of transplanted alginate-encapsulated cells producing therapeutic
      proteins, we describe a successful method of cryopreservation (CP) of such beads,
      in which cellular viability, alginate structure, and protein secretion were
      maintained. Alginate beads containing human embryonic kidney cells (HEK 293
      cells) stably transfected with the gene encoding for endostatin were
      cryopreserved in dimethyl sulfoxide (DMSO) using a slow freezing procedure.
      Briefly, the DMSO concentration was gradually increased prior to the freezing
      procedure. The cryotubes were further supercooled to -7.5 degrees C and
      nucleated. Thereafter, the samples were cooled at a rate of 0.25 degrees C/min
      and stored in liquid nitrogen. The viability of the encapsulated cells was
      assessed using confocal microscopy quantification (CLSM) technique and a MTS
      assay. The cell cycle distribution inside the beads was assessed by DNA flow
      cytometry and endostatin production was determined by an endostatin-specific
      ELISA assay, both prior to and after CP. CLSM measurements showed sustained
      esterase activity in the beads after thawing, with only a slight transient
      decrease 24 h after CP. The MTS assay verified these findings by displaying
      similar variations of intracellular dehydrogenase activity. Flow cytometric
      analyses revealed no cryorelated disturbances in cellular ploidy. Furthermore,
      ELISA measurements showed a well-preserved endostatin production after CP. In
      conclusion, this work describes the successful CP of alginate-encapsulated
      recombinant cells secreting a therapeutic protein. Together with previous
      published reports, these results further substantiate the feasibility and
      potential of cell encapsulation therapy in the treatment of malignant tumors.

PMID- 15040605
TI  - Use of D-STAT to prevent bleeding following percutaneous transhepatic intraportal
      islet transplantation.
AB  - An infrequent but nevertheless concerning complication associated with
      percutaneous transhepatic islet transplantation is bleeding. Historically in 61
      procedures at this institution, we experienced four bleeding complications in
      three patients (6.6%), two requiring blood transfusion (3.3%) and two
      asymptomatic intraperitoneal bleeds detected sonographically at 24 h
      postprocedure (3.3%). It is suggested that the source of the majority of these
      bleeds is the liver parenchymal tract following removal of the infusion catheter
      combined with a significant dose of heparin administered to prevent portal vein
      thrombosis. Various techniques have been used to reduce the risk of tract
      bleeding, including gelfoam, intravascular coils, and cautery. In our experience
      gelfoam alone has been used to plug the catheter tract (n = 47); however, in the
      aforementioned three patients, this technique failed, either due to dislodgement
      of, or bleeding peripheral to, the plug. This article describes the use of D
      Stat, a collagen/thrombin paste that is injected into the peripheral tract. In
      five consecutive cases performed using D-Stat, there has been no bleeding or
      thromboses detected. D-Stat combined with a single gelfoam plug offers a quick,
      easy, efficacious way of sealing the entire catheter tract without leaving any
      permanent hardware in the liver. This new method may simplify tract closure and
      reduce bleeding complications in islet transplantation.

PMID- 15040606
TI  - Effect of the embolization of completely unpurified islets on portal vein
      pressure and hepatic biochemistry in clinical practice.
AB  - Here we report on the impact of completely unpurified islet transplantation on
      the portal vein pressure (PVP) and the hepatic biochemistry in the peritransplant
      period and on follow-up. Type I diabetic patients underwent simultaneous kidney
      and islet transplantation. Islets were not purified from the acinar tissue to
      prevent loss of endocrine mass. Each patient received a mean 521,846 +/-
      201,539.4 islet equivalents (7812.1 islet equivalents/kg/recipient).
      Immunosuppression and peritransplant medication were given according to the
      Giessen protocol. The islets were injected into the left hepatic lobe through the
      umbilical vein. PVP was recorded at time 0 and every 5 min throughout cell
      infusion. Liver function was assessed daily for the first 10 days, and on follow
      up. Basal, peak, and final PVP were 12 +/- 3.8, 25.1 +/- 7.9, and 19.5 +/- 6.2
      mmHg, respectively (basal vs. final, p < 0.05). Bilirubin, alkaline phosphatase,
      prothrombin time, and APTT stayed within normal range. Peak aspartate
      aminotransferase (AST), alanine aminotransferase (ALT), and serum amylase were
      109.4 +/- 61.2 IU/L (basal vs. peak, not significant), 79.5 +/- 56.9 IU/L (basal
      vs. peak, not significant), and 887.5 +/- 153.6 IU/L (basal vs. peak, p = 0.02),
      respectively. In all cases AST, ALT, and amylase normalized within 6 days
      posttransplant and remained so on follow-up (longest control, 33 months
      posttransplant). Although the intrahepatic infusion of unpurified pancreatic
      islets affects both the portal vein pressure and the hepatic biochemical profile,
      this effect is transient and does not compromise the safety of the procedure.

PMID- 15040607
TI  - Short-term storage of the ischemically damaged human pancreas by the two-layer
      method prior to islet isolation.
AB  - A two-layer cold storage method (TLM) allows sufficient oxygen delivery to
      pancreata during preservation and resuscitates the viability of ischemically
      damaged pancreata in the canine pancreas transplant model. In this study, we
      applied a short-term preservation of the TLM to human pancreata after prolonged
      cold ischemia prior to islet isolation, and investigated the mechanisms of
      resuscitation of the ischemically damaged human pancreas by the TLM. Human
      pancreata were procured from cadaveric donors and preserved by the TLM for 3.2 +/
      0.5 h after 11.1 +/- 0.9 h of cold storage in UW (TLM group), or by cold UW
      alone for 11.0 +/- 0.3 h (UW group). Islet isolations of all pancreata were
      performed using the Edmonton protocol. Islet recovery and in vitro functional
      viability of isolated islets were significantly increased in the TLM group
      compared with the UW group. According to the criteria of the Edmonton protocol,
      10/14 cases (71%) in the TLM group were transplanted to patients with type I
      diabetes mellitus compared with only 5/21 cases (24%) in the UW group. In the
      metabolic assessment of human pancreata, levels of energetic parameters (ATP,
      total adenylates, and energy charge) were significantly increased, and
      malondialdehyde (MDA) levels were significantly decreased after the TLM
      preservation. There was no observable change in the incidence or degree of
      mitochondrial injury after the TLM preservation. Additional short-term storage by
      the TLM resuscitates the ischemically damaged human pancreas by regenerating the
      energetic status and prevents further damage by oxidative stress, ultimately
      leading to improvements of islet recovery and in vitro function. Use of the TLM
      following prolonged storage in UW provides an excellent adjunctive protocol for
      treating human pancreata for the rigors of the islet isolation process.

PMID- 15040608
TI  - CD86 blockade in genetically modified porcine cells delays xenograft rejection by
      inhibiting T-cell and NK-cell activation.
AB  - Porcine xenografts transplanted into primates are rejected in spite of
      immunosuppression. Identification of the triggering mechanisms and the strategies
      to overcome them is crucial to achieve long-term graft survival. We hypothesized
      that porcine CD86 (pCD86) contributes to xenograft rejection by direct activation
      of host T cells and NK cells. Formerly, we designed the human chimeric molecule
      hCD152-hCD59 to block pCD86 in cis. To test the efficacy in vivo, we have
      utilized a pig-to-mouse xenotransplant model. First, we showed that hCD152-hCD59
      expression prevents the binding of murine CD28Ig to pCD86 on porcine aortic
      endothelial cells (PAEC) and dramatically reduces IL-2 secretion by Con A
      stimulated mouse splenocytes in coculture. Moreover, IFN-gamma secretion by IL-12
      stimulated mouse NK cells was averted after coculture with hCD152-hCD59 PAEC. In
      vivo, control PAEC implanted under the kidney capsule were rapidly rejected (2-4
      weeks) in BALB/c and BALB/c SCID mice. Rejection of hCD152-hCD59 PAEC was
      significantly delayed in both cases. Signs of immune modulation in the hCD152
      hCD59-PAEC BALB/c recipients were identified such as early hyporesponsiveness and
      diminished antibody response. Thus, simply modifying the donor xenogeneic cell
      can diminish both T cell and NK cell immune responses. We specifically
      demonstrate that pCD86 contributes to rejection of porcine xenografts.

PMID- 15040609
TI  - The evaluation of scientific information in medicine.

PMID- 15040610
TI  - Blood and aqueous humour antioxidants in cataractous poodles.
AB  - BACKGROUND: Cataract is an important cause of blindness in dogs and frequently
      develops in young animals of certain breeds, such as the English cocker spaniel
      and the poodle. Protein oxidation is one of the mechanisms involved in lens
      opacification and may be causally related to depleted or diminished endogenous
      antioxidant defences. We evaluated the levels of enzymatic and nonenzymatic
      antioxidants in blood and aqueous humour of cataractous poodles in comparison to
      noncataractous poodles. METHODS: We studied 35 cataractous poodles aged 2 to 11
      years, 14 noncataractous poodles and 15 noncataractous mixed-breed dogs. The
      activity of erythrocyte antioxidant enzymes (superoxide dismutase, catalase,
      glutathione peroxidase and glucose-6-phosphate dehydrogenase [G6PD]) was
      evaluated in 18 cataractous poodles and 14 noncataractous poodles. We evaluated
      ascorbic acid levels in plasma of all animals and in aqueous humour of
      cataractous poodles and mixed-breed dogs. The dogs were deprived of food for 12
      hours before sampling. Blood samples were obtained from the jugular vein before
      and during anesthesia. Aqueous humour samples were obtained just before the
      anterior chamber was opened. RESULTS: The activity of superoxide dismutase, G6PD
      and catalase was significantly higher in noncataractous poodles than in
      cataractous poodles (p < or = 0.05). The activity of glutathione peroxidase was
      lower in noncataractous poodles than in cataractous poodles, but not
      significantly so. There was no difference in mean plasma ascorbic acid
      concentration between cataractous poodles (21.3 microM [standard deviation (SD)
      7.4 microM]), noncataractous poodles (21.6 microM [SD 7.4 microM]) and non
      cataractous mixed-breed dogs (25.8 microM [SD 7.5 microM]). Similarly, there was
      no difference in mean aqueous humour ascorbic acid concentration between
      cataractous poodles (191.7 microM [SD 62.0 microM] and noncataractous mixed-breed
      dogs (215.7 microM [SD 91.8 microM]). INTERPRETATION: The results indicate that,
      at least in the population studied here, no correlation exists between the onset
      of cataract and ascorbic acid concentration in blood and aqueous humour. The
      decreased activity of antioxidant enzymes may explain in part the onset of
      cataract in poodles.

PMID- 15040611
TI  - Cataract surgical coverage and outcome of cataract surgery in a rural district in
      Malawi.
AB  - BACKGROUND: Cataract is the leading cause of blindness in Malawi. We sought to
      determine the cataract surgical coverage and the outcome of cataract surgery in a
      rural district in Malawi to assess past performance of cataract surgical
      services. METHODS: From July to October 1999 we conducted a multistage random
      cluster survey to include 1630 residents aged 50 years or more in Chikwawa
      District. Visual acuity, cause of vision loss, history of cataract surgery and
      cause of poor vision (if less than 6/60) were assessed. Cataract surgical
      coverage, sight restoration rate and outcome were calculated by person and eye
      and for men and women separately. RESULTS: We examined 1384 people (84.9% of
      target). Twenty-one people (12 men and 9 women) (30 eyes) had received cataract
      surgery. The cataract surgical coverage rate was 35.6% (44.4% for men and 28.1%
      for women [odds ratio 2.0, 95% confidence interval 0.6-7.0]) at a visual acuity
      level of 6/60, and 55.3% (60.0% for men and 50.0% for women [odds ratio 1.5, 95%
      confidence interval 0.3-6.7]) at a level of 3/60. Only one eye of one subject had
      received an intraocular lens. Presenting visual acuity was 6/18 or better in 7
      eyes (23.3%), 6/24 to 6/60 in 7 eyes, and worse than 6/60 in 16 eyes (53.3%).
      Among the 16 eyes with visual acuity less than 6/60, the vision could be improved
      in 8 with provision of aphakic spectacles. INTERPRETATION: Cataract surgical
      coverage in this population is similar to that reported from other countries in
      Africa. As in other settings, cataract surgical coverage was lower in women than
      in men. Poor outcomes in this population are partly due to surgical complications
      and partly due to a lack of aphakic correction. Surgical promotion programs will
      need to focus on differentiating intraocular lens surgery from (previously
      practised) intracapsular cataract extraction surgery.

PMID- 15040612
TI  - Waiting times for eye surgery at a Toronto teaching hospital.
AB  - BACKGROUND: Waiting times for eye surgery in Ontario have increased dramatically
      in recent years. We performed a study to compare the waiting times, the amount of
      operating time and the number of cases performed for various eye surgical
      procedures in 1999, 2000 and 2001 at a major Toronto teaching hospital. METHODS:
      For 3 months (May, June and July) of 1999, 2000 and 2001, eye surgeons at the
      hospital reported how long their patients had to wait for surgery and how many
      patients they had waiting for surgery. The number of operating hours for eye
      surgery and the number of eye surgery cases in fiscal years 1999-2000, 2000-01
      and 2001-02 were collected from a hospital database. Surgical procedures that
      were captured were cataract extraction, corneal transplantation, trabeculectomy
      (including phacotrabeculectomy), vitreoretinal surgery and adult strabismus
      surgery. RESULTS: All surgeons responded to the survey. Median waiting times
      increased for all types of eye surgery between 1999 and 2001. The median wait for
      cataract extraction increased by 92%, from 3.0 to 5.8 months. For corneal
      transplantation the median wait doubled, from 5.5 to 11.0 months. The median wait
      for trabeculectomy increased by 60%, from 2.5 to 4.0 months. The median wait for
      vitreoretinal surgery almost tripled (191%), from 1.2 to 3.4 months. For adult
      strabismus surgery the median wait increased by 56%, from 8.0 to 12.5 months.
      Operating time was cut by over 1000 hours (from 5481 to 4434) from 1999-2000 to
      2000-01 and then again, by 255 hours, from 2000-01 to 2001-02. Despite this, the
      number of surgical procedures performed decreased only slightly over the study
      period, from 4292 to 4099. INTERPRETATION: The waiting times for all eye
      operations increased substantially between 1999 and 2001 at this Toronto teaching
      hospital. In addition, for each type of surgery the median waiting time was
      longer than the Ontario median, by 13% (cataract surgery) to 191% (vitreoretinal
      surgery). The fact that the number of cases performed decreased only slightly
      despite a dramatic decrease in operating time indicates that there was an
      increase in efficiency. Possible ways to reduce the long waits include
      implementing prioritization programs, increasing operating time and moving
      cataract surgery out of the hospital to a day surgical centre.

PMID- 15040613
TI  - Cataract surgical outcome at the Vancouver Eye Care Centre: can it be predicted
      using current data?
AB  - BACKGROUND: Patients selected for cataract surgery have an increasingly wider
      range of coexisting ocular and systemic diseases. The aim of this study was to
      determine whether preoperative patient characteristics can assist surgeons in
      identifying patients who are at increased risk of having little or no improvement
      in visual outcome after cataract surgery. METHODS: We prospectively studied a
      randomly selected subset (20%) of patients with cataract undergoing cataract
      extraction at a tertiary centre in Vancouver. There were no patient exclusion
      criteria. Pre-, intra- and postoperative clinical data were collected from
      medical records. RESULTS: We studied 1329 cataract surgical procedures from March
      1999 to December 2000. Of the 1329, 851 had complete pre- and postoperative
      visual acuity data. The mean age of the 851 patients was 73.2 (standard deviation
      10.6) years, 575 (67.6%) were women, and 472 procedures (55.5%) were first-eye
      procedures. Preoperatively, the best-corrected visual acuity was 20/40 or better
      in 146 eyes (17.2%), 20/50 in 173 (20.3%), 20/60 to 20/70 in 248 (29.1%), and
      20/80 or worse in 284 (33.4%). Almost half of the patients (419 [49.2%]) had at
      least one coexisting eye disease in the operated eye. At about 3 months
      postoperatively, the best-corrected visual acuity had improved in 786 eyes
      (92.4%), remained the same in 42 (4.9%) and had worsened in 23 (2.7%). Of the 23
      eyes with worse visual acuity, half had preoperative visual acuity of 20/40 or
      better; most of the remaining eyes had preoperative vision of 20/50 to 20/70. Of
      the 42 eyes with unchanged vision, 22 (52%) had preoperative visual acuity worse
      than 20/100; the remaining eyes were distributed across the visual acuity range.
      An increase of 1 year of age increased the odds of having a poor visual acuity
      outcome by 2% to 4%. Worse preoperative visual acuity predicted an increased
      likelihood of a poor outcome; this effect increased sharply for eyes with
      preoperative visual acuity of 20/80 or worse. After adjustment for age and
      preoperative visual acuity, patients with three or more coexisting eye diseases
      in the operated eye were 10 to 24 times more likely to have the worst
      postoperative visual acuity. INTERPRETATION: The presence and number of
      coexisting ocular diseases, increased age and poor preoperative visual acuity
      predicted an unchanged or worse visual acuity after cataract surgery.

PMID- 15040614
TI  - Development and assessment of a priority score for cataract surgery.
AB  - BACKGROUND: Point-count measures of clinical priority are increasingly put
      forward for managing waiting lists. However, their development does not consider
      explicitly the appropriateness of the indications. Furthermore, an estimate of
      their effect in clinical practice is needed, assessing the amount of gains and
      losses in terms of time waited for patients with different priority scores.
      METHODS: We developed appropriateness criteria for cataract surgery using the
      RAND method and applied them to a sample of 567 patients consecutively placed on
      a waiting list for cataract surgery. In addition, clinicians were asked to
      express the priority attributed to each patient using a 10-cm visual analogue
      scale, where 0 = minimal priority and 10 = maximum priority. We developed a
      priority score, using regression analysis to identify the set of clinical
      characteristics that best predicted clinicians' priority rating and to estimate
      their individual weight. We used a computer simulation model to compare mean
      waiting times with management of the waiting list using the priority score and
      using the "first-come, first-served" approach. RESULTS: Overall, 332 patients
      (60.8%) were referred for cataract surgery for indications deemed appropriate,
      and their mean priority rating was 5.9 (95% confidence interval [CI] 5.7-6.1).
      The corresponding figures for the 201 (36.8%) uncertain indications and the 13
      (2.4%) inappropriate indications were 4.5 (95% CI 4.1-4.7) and 2.6 (95% CI 1.3
      3.9) respectively. The clinical characteristics included in the priority score
      (visual acuity in the operated eye and in the contralateral eye, visual function
      and ability to live or work independently) accounted for 35% of the variance in
      clinicians' ratings of priority. In the computer simulation model, patients with
      the highest priority experienced a variable reduction in mean waiting time (9% to
      27%) depending to how time spent waiting was integrated into the clinical score.
      INTERPRETATION: We conclude that the use of priority ratings in the management of
      a waiting list for cataract surgery leads to results that maintain the desirable
      coherence between priority and appropriateness of indication. The results also
      suggest that the implementation in clinical practice of priority scores may be
      worth the effort, given the potential reduction in waiting time for patients at
      high priority.

PMID- 15040615
TI  - Macular perimetry in low vision.
AB  - BACKGROUND: Detection of residual visual function is critical for vision
      rehabilitation. Macular perimetry may provide essential information in this
      regard. In the presence of reduced vision, fixation maintenance is paramount for
      perimetric test validation. We performed a study to determine the validity of
      perimetric test results in the presence of low vision, as expressed by the
      relation between scotoma location, acceptable fixation maintenance and visual
      acuity. METHODS: The study was a prospective observational case series. Macular
      perimetry testing was performed with the Humphrey Automated Perimeter in eyes of
      consecutive patients attending our low-vision clinic between July and December
      1999. The main outcome measures referred to scotoma location, acceptable fixation
      maintenance and visual acuity. RESULTS: We tested 46 eyes of 46 patients, 24 men
      and 22 women aged 33 to 88 years (mean 69.0 [standard deviation 15.41] years). Of
      the 35 eyes with best corrected visual acuity of 20/200 or better, 18 (51.4%) had
      acceptable fixation maintenance (p = 0.052), and 31 (88.6%) had scotoma patterns
      displaced eccentrically (p < 0.001). INTERPRETATION: We conclude that in the
      presence of residual vision of 20/200 or better, acceptable fixation maintenance
      is possible, probably with a new preferred retinal locus, and, as a result,
      scotoma patterns are recorded eccentrically. Therefore, perimetric results in
      such cases should be viewed as valid, and interpretation should always account
      for eccentric fixation. Concomitant testing with scanning laser ophthalmoscopy or
      eye tracking equipment could further clarify this issue.

PMID- 15040616
TI  - Age-related changes in the human retina.
AB  - BACKGROUND: In a previous study, scanning electron microscopy (SEM) showed age
      related changes in the rat retina. We carried out a study to evaluate age-related
      changes in the human retina. METHODS: Samples of fresh retinal tissue obtained
      from younger (age 22 years or less) and older (age 66 years or more) donors were
      studied by means of traditional histologic methods and by SEM. Eight retinas were
      obtained from four donors whose corneas had been used for transplantation, and
      four retinas were obtained from four subjects whose eyes had been enucleated
      owing to injury. All morphologic results were subjected to quantitative analysis
      of images. The concentration of cytoplasmic (free) and structural (tissue
      associated) protein in retinal tissue homogenates was determined by means of
      biochemical methods. RESULTS: There was a decrease in all features studied with
      the exception of structural protein concentration. The mean retinal thickness
      (and standard error of the mean) was 426 (34.2) microm in the younger subjects
      and 261 (18.9) microm in the older subjects. The mean numbers of ganglion cells
      (and standard error of the mean) were 413.5/mm2 (32.3/mm2) and 256.2/mm2
      (26.8/mm2) respectively, of capillaries 3.6/mm2 (1.4/mm2) and 1.8/mm2 (1.2/mm2)
      respectively, of synaptic bodies 122.4 (4.9) conventional units (CU)/area
      observed and 38.5 (1.6) CU/area observed respectively, of cellular processes 82.3
      (3.1) CU/area observed and 13.1 (1.5) CU/ area observed respectively, and of
      intercellular connections 36.4 (2.5) CU/area observed and 14.3 (1.4) CU/area
      observed respectively. The mean concentration of total protein per milligram of
      fresh tissue (and standard error of the mean) was 92.1 (1.8) microg in the
      younger subjects and 78.7 (1.3) microg in the older subjects; the corresponding
      values for cytoplasmic protein were 27.6 (1.3) microg and 11.8 (0.8) microg, and
      for structural protein, 64.4 (1.6) microg and 86.9 (1.4) microg. All differences
      between the younger and older subjects were significant (p < 0.001) with the
      exception of mean concentration of cytoplasmic and of structural protein.
      INTERPRETATION: The human retina undergoes specific changes with aging. SEM
      provides new morphometric information regarding age-related changes in
      photoreceptor cells, bipolar cells and ganglion cells that increases our
      understanding of this topic. Our results may be adopted as a model or as normal
      values when studying other changes that may occur in the human retina in
      pathological conditions.

PMID- 15040617
TI  - Retinal peripheral changes after laser in situ keratomileusis in patients with
      high myopia.
AB  - BACKGROUND: Retinal detachment has been reported after laser in situ
      keratomileusis (LASIK) in myopic eyes. This complication may be related to the
      risk from myopia before surgery or may be induced by LASIK surgery itself. We
      performed a study to evaluate retinal peripheral changes after LASIK in patients
      with high myopia and to correlate symptoms on presentation and vitreoretinal
      anatomic changes. METHODS: The study was carried out at a university-affiliated
      hospital in Sao Paulo between November 1997 and February 1999. Patients scheduled
      to undergo LASIK were included if their spherical equivalent was greater than
      6.00 dioptres. The exclusion criteria were previous retinal treatment and myopic
      macular degenerations. We performed binocular indirect ophthalmoscopy with
      scleral indentation and fundus biomicroscopy with Goldmann lens before LASIK and
      1, 3 and 6 months after surgery. RESULTS: We examined 198 eyes preoperatively. Of
      the 198, 50 did not undergo LASIK surgery owing to refractive criteria, and 79
      were lost to follow-up. We thus studied 69 eyes. The mean spherical equivalent
      preoperatively was -8.00 D (standard deviation 1.95 D). Twenty-four eyes had
      normal retinal periphery preoperatively; all 24 remained without alterations
      after LASIK. Forty-five eyes had peripheral alterations: 17 (24.6%) had cystic
      degeneration, 14 (20.3%) had lattice degeneration, 11 (15.9%) had white-without
      pressure, 5 (7.2%) had cystic tufts, 3 (4.3%) had pavingstone degeneration, 2
      (2.9%) had pigmentary alteration, 1 (1.4%) had holes with free operculum, and 1
      (1.4%) had punctiform holes. The only alteration after surgery was almost
      punctiform holes around the previous cystic tuft 1 month after surgery in one
      patient. Retinal detachment did not develop in any of the eyes. INTERPRETATION:
      In this group of patients it appears that LASIK did not lead to progressive
      peripheral retinal lesions in asymptomatic patients during the period studied.

PMID- 15040618
TI  - Management of ophthalmic zoster mucous plaque keratopathy: report of three cases.

PMID- 15040619
TI  - Pediatric orbital pseudotumour presenting as a painless orbital and periocular
      mass.

PMID- 15040620
TI  - Preretinal hemorrhages as the presenting sign of subacute bacterial endocarditis.

PMID- 15040621
TI  - Ocular ischemia associated with uncontrolled hypertension in lupus erythematosus.

PMID- 15040622
TI  - In the interest of humanity and the cause of science.

PMID- 15040623
TI  - Individual reactions following vaccinations or inoculations are highly variable.

PMID- 15040624
TI  - Comparing the cost of gastric bypass surgery in military hospitals with the cost
      of the same surgery in the private sector.

PMID- 15040626
TI  - A Turkish medical rescue team against nuclear, biological, and chemical weapons.
AB  - Medical aid is one of the primary responses given in the deliberate release of
      weapons of mass destruction for both military and terrorist purposes. From this
      point of view, a nuclear, biological, and chemical (NBC) Medical Rescue Team was
      established in the structure of Gulhane Military Medical Academy. The staff in
      the team is composed of physicians, nurses, and paramedics who are assigned in
      Medical Intervention Units, Medical Nursing Units, and Decontamination Units,
      respectively. The main aim of this team is to give a medical response including
      first aid, airway, breathing, and circulation resuscitation, decontamination, and
      triage under any NBC attack. For this purpose, the communication and coordination
      between the team members were standardized. Moreover, the team was equipped with
      the required protective clothing, masks, antidotes, and other drugs and agents
      used for victims exposed to NBC weapons. Within this concept, the personnel in
      the team were trained with respect to first aid and treatment of NBC casualties
      in both theoretical and practical scenario. All of this background information
      was used in a practical operation held in Gulhane Military Medical Academy under
      a chemical attack scenario given.

PMID- 15040625
TI  - Safety concerns regarding ephedrine-type alkaloid-containing dietary supplements.
AB  - OBJECTIVES: The U.S. Air Force has adopted a policy "strongly discourag(ing) the
      use of ... ephedra." However, the literature regarding this topic is limited and
      widely opinioned. In light of growing public and medical debate over the safety
      and efficacy of ephedrine-type alkaloid-containing dietary supplements, a review
      of the literature and assessment of the data were accomplished. METHODS: Studies
      regarding Ma Huang, ephedra, ephedrine-type alkaloids, ephedrine, and dietary
      supplements were reviewed (from databases Medline, HealthSTAR, CINAHL, Cochrane
      Clinical Trials Database). Food and Drug Administration and Government Accounting
      Office documents (including reports and interagency communications) were
      reviewed. RESULTS: Significant manufacturing quality control issues exist. Few
      studies support their efficacy or safety. Weight loss and athletic performance
      appear to be only modestly improved, for short durations, in the setting of large
      numbers of (some serious) adverse event reports. Studies examining over-the
      counter use are minimal. CONCLUSIONS: The current U.S. Air Force policy strongly
      discouraging the use of ephedrine-type alkaloid-containing dietary supplements
      appears to be supported.

PMID- 15040627
TI  - "Surgical research at the Uniformed Services University: one graduate's
      perspective--from student to Chief, Division of Surgical Research".
AB  - In the 23 years since Dr. John Sharefkin presented his personal experience with
      Surgical Research at the Uniformed Services University, the opportunities offered
      have expanded. In addition, there have been many contributions to the surgical
      literature, including some leading to improved care of combat casualties. This
      article outlines how these opportunities have impacted the education of our
      students, the academic advancement of our active duty surgeons, and will offer
      benefit to our surgical patients of the future. USUHS is a unique resource for
      military medical research because its breadth of staffing and equipment and its
      neighbors make all these kinds of help and expertise available. It offers an
      opportunity for cooperation between military and civilian researchers of the kind
      that marked the great research success of WWII and radar, mass blood-banking,
      code breaking computers and antibiotic production.

PMID- 15040628
TI  - Variables associated with attrition from Uniformed Services University of the
      Health Sciences Medical School.
AB  - Attrition among medical students is a concern for the institution, the
      individual, and the profession. Disenrollment has an impact on the institution,
      in terms of academic reputation and resources expended, and the individual, in
      terms of self-esteem, personal finances, and opportunity costs. This study
      summarizes the results of an epidemiologic study of student attrition conducted
      at the only federal medical school in the United States--the Uniformed Services
      University of the Health Sciences in Bethesda, Maryland--and describes the
      association between demographic and selected quantitative variables for those
      students who graduated or remained enrolled and those who disenrolled. Both sex
      (female) and a decelerated curriculum were predictive of attrition in this
      medical student population. The records of the students who left Uniformed
      Services University of the Health Sciences without graduating were examined to
      ascertain the presence of noncognitive issues surrounding disenrollment; over one
      half of the students who disenrolled left voluntarily and for nonacademic
      reasons.

PMID- 15040629
TI  - Unusual case of labial and lingual talon cusps.
AB  - Talon cusp is an uncommon developmental anomaly affecting the anterior teeth,
      characterized by cusp-like projections, usually presenting on the lingual surface
      of the affected tooth. The occurrence ranges from 0.73% to 8% of the population.
      Talon cusp has been associated with other dental anomalies such as dens
      invaginatus, odontomas, and impacted teeth; associations with somatic anomalies
      such as Mohr's, Rubenstein-Taybi, and Sturge-Weber syndromes have also been
      reported. Only a few cases of labial talon cusp have been reported and only one
      previously published report exists documenting talons appearing both labially and
      lingually on the same tooth. This study reports the unusual case of a 10-year-old
      girl with bilateral talon cusps and one tooth possessing both lingual and labial
      talons. The lingual talon on the right maxillary lateral incisor was interfering
      with normal occlusion and was responsible for labioversion of the tooth.
      Treatment options were presented.

PMID- 15040630
TI  - Factors associated with breastfeeding intentions of African-American women at
      military health care facilities.
AB  - Studies have shown that 21% to 51% of African-American women (AAW) reported
      breastfeeding, lagging behind Caucasian (61%-71%) and Hispanic (67%-71%) women
      despite breastfeeding's health benefits. This study aimed to assess AAWs "intent"
      to breastfeed and describe the relationship among knowledge, age, education,
      parity, and selected factors of the theory of planned behavior with their intent.
      The theory of planned behavior assumes intentions are immediate antecedent of
      behavior. Voluntary surveys of 95 AAW who intended to breastfeed were collected
      at two U.S. military prenatal clinics. The results were that breastfeeding intent
      was related to AAW's age, education, and perceived subjective norms (social
      pressures) and behavioral control (success in breastfeeding); only age and
      perceived behavior-control best "predicted" breastfeeding intent. Healthy People
      2010's objectives are to increase numbers to 75% of women who breastfeed. This
      study notes the importance of health care providers in promoting AAW to
      breastfeed by initiating culturally sensitive strategies that enhances AAW's
      social support and personal confidence toward breastfeeding success.

PMID- 15040632
TI  - Evaluation of CO2 accumulation in respiratory protective devices.
AB  - A simple mathematical model was developed to grade the results of the fraction of
      inspiratory CO2 levels in respiratory protective devices (RPDs). Using this
      model, the level of FiCO2 of two chemical warfare RPDs was monitored during the
      examination of 54 young male volunteers at rest and exercise. No set of results
      distributed in a normal Gaussian mode; therefore, parametric statistics could not
      be used to analyze the group's results. Yet the model allowed simple and
      insightful evaluation of the results, stressing differences between the similar
      RPDs. We suggest continued use of the analysis model as a tool for quantitative
      evaluation of results and further understanding of the respiratory patterns of
      RPDs.

PMID- 15040631
TI  - Retropubic urethrolysis without resuspension for the management of
      posturethropexy urinary retention and voiding dysfunction.
AB  - OBJECTIVE: The goal of this study was to determine the efficacy of retropubic
      urethrolysis without resuspension for the surgical treatment of postoperative
      urinary retention. METHODS: A retrospective chart review was done of six women
      with posturethropexy urinary retention or voiding dysfunction who underwent
      retropubic urethrolysis between July 1999 and June 2000. RESULTS: An average of
      27.0 (+/- 19.6) months elapsed between obstructive incontinence procedure and
      urethrolysis. The mean maximum detrusor pressure during voiding was elevated at
      52.7 (+/- 31.7) cm H2O. The mean maximum flow rate during voiding was decreased
      at 16.3 (+/- 10.8) cm H2O. The average postvoid residual volume was 152.9 +/-
      71.6 mL, significantly decreased postoperatively to 36.9 +/- 40.0 mL (t = 3.37, p
      = 0.043). Postoperative cystourethroscopy showed a completely free and mobile
      urethra. In the short-term, all patients had resolution of their symptoms. No
      patient had return of stress incontinence in a mean clinical follow-up of 3.3 +/-
      2.3 months. CONCLUSIONS: Our results are comparable to other series of
      urethrolyses, despite omission of resuspension. Retropubic urethrolysis offers
      favorable relief of persistent postoperative urinary retention and voiding
      dysfunction, particularly after retropubic urethropexy.

PMID- 15040633
TI  - Major surgery and anesthetic technique in epidermolysis bullosa.
AB  - Epidermolysis bullosa is a hereditary rare condition characterized with local and
      generalized lesions and autosomal dominant trait with variable penetrance. It was
      decided to amputate the left leg under the knee of a female patient with
      epidermolysis bullosa with squamous cell carcinoma. The smallest trauma may cause
      formation of serious bullous in the skin in epidermolysis bullosa. Surgeons,
      dermatologists, and anesthesiologists must evaluate the cases. During
      preoperative, intraoperative, and postoperative periods, all interventions that
      may cause interruption in circulation of the tissues cause irritation, or delay
      healing of the wounds must be avoided.

PMID- 15040634
TI  - Self-rated health and subsequent health care use among military personnel
      returning from international deployments.
AB  - Individual health status assessment upon completion of U.S military deployments
      was standardized in 1999 with a brief health assessment questionnaire. This
      cohort study analyzed health status responses and their relationship to
      postdeployment health outcomes among 16,142 military personnel who completed a
      health questionnaire after a deployment ending in 1999. Respondents were Army and
      Air Force personnel returning from Europe or Southwest Asia. Fourteen percent
      documented at least one health concern and 1.8% had fair/poor self-rated health.
      In the 6 months after deployment, 1.4% were hospitalized, 25% made five or more
      outpatient visits, and 4% separated from military service. Deployers with
      fair/poor self-rated health were at a significantly increased risk for high use
      of outpatient services (risk ratio, men 1.8, women 1.7) but not for
      hospitalization or separation. Self-report of low health status or other health
      concerns may help identify deployers with higher health care needs after future
      deployments.

PMID- 15040635
TI  - Posterior sternoclavicular joint dislocation in a wrestler.
AB  - Injury to the sternoclavicular joint is uncommon but may be a life-threatening
      injury if the diagnosis is not made acutely. Posterior sternoclavicular joint
      dislocation is associated with a number of complications including tracheal tear
      or trauma to the great vessels. Diagnosis by conventional radiography is
      difficult. Even experienced examiners may miss the diagnosis unless a high level
      of suspicion exists and the appropriate imaging studies are ordered. Computed
      tomography is the imaging modality of choice, and prompt diagnosis is essential
      for early, successful reduction of the joint.

PMID- 15040636
TI  - Oral and maxillofacial aspects of diving medicine.
AB  - Sport diving has witnessed explosive growth in the past decade, as 8.5 million
      people are certified in the United States alone. Even though scuba diving is a
      relatively safe sport, there are serious risks that all divers must consider.
      Beyond the better-known sequelae such as decompression sickness, middle ear
      dysfunction, and potential central nervous system effects, scuba diving also
      carries inherent risk to the maxillofacial region. Atypical facial pain,
      temporomandibular joint dysfunction, sinus barotraumas, and barodontalgia have
      all been reported by dentists and physicians treating military, commercial, and
      sport divers. Additionally, clinicians must address anatomic concerns for would
      be divers, including cleft lip and palate, edentulism, or patients with pre
      existing temporomandibular dysfunction, midfacial trauma, or craniomaxillofacial
      surgery. Health care professionals should have a thorough understanding of the
      implications of scuba diving for consultation and recommendation regarding diving
      fitness and the treatment of adverse effects of scuba diving to the maxillofacial
      region.

PMID- 15040637
TI  - Assessing chemical exposures during military deployments.
AB  - Before the first Persian Gulf War, military chemical concerns were focused on
      life-threatening/performance-impairing effects from exposures to chemical warfare
      agents. Now, hazards of concern include both high and low levels of chemical
      warfare agents and toxic industrial chemicals in air, soil, and water. The types
      of health effects considered have expanded to include both immediate, acute
      effects (mild and severe), and delayed or chronic outcomes. Because federal
      exposure standards are not applicable to deployed personnel, the U.S. Army Center
      for Health Promotion and Preventive Medicine established military-specific
      exposure guidelines in Technical Guide 230, Chemical Exposure Guidelines for
      Deployed Military Personnel. Methods used to develop the guidelines address
      toxicological data limitations, uniqueness of military populations and exposure
      scenarios, and a risk assessment process compatible with existing military
      operational risk management doctrine. The Technical Guide 230 helps ensure
      chemical hazards are addressed in various deployment scenarios.

PMID- 15040638
TI  - Land mine injury: functional testing outcome.
AB  - We present a case of a war patient treated with external fixation for a complex
      land mine injury involving the fracture of the tibial and fibular bones, which
      occurred at the front line during the war in Croatia and Bosnia and Herzegovina.
      Excessive destruction and foreign body penetration into the distal two-thirds of
      the right leg and foot endangered not only the patient's lower extremity but his
      life as well. Nevertheless, the patient's life, as well as extremity, was saved
      due to an intensive treatment. A 100-month follow-up showed a bridge callus
      between the tibia and fibula, tibial bone defects, tibial anterior angulation of
      5 degrees, and arthrosis of the right upper ankle joint. Despite a relatively
      unsatisfactory X-ray finding, the functional testing on the dynamometry system
      Cybex 300 showed surprisingly good results. There was a satisfactory functional
      recovery of the treated extremity: the patient could walk without any help even
      on rocky grounds and was actively involved in his sheep farm duties.

PMID- 15040639
TI  - Pectoralis major tendon avulsion from rappelling.
AB  - To our knowledge, we are reporting the first case of a pectoralis major tendon
      avulsion from rappelling. The mechanism of injury in this case differs
      biomechanically from the commonly associated activity of bench pressing. The
      patient's initial presentation, course of corrective treatment, and postoperative
      rehabilitation is discussed in detail. A review of the historical and current
      literature on pectoralis major tendon injuries is included. The results of
      current biomechanical studies are discussed in relation to the complex anatomy of
      the pectoralis major muscle. This report is relevant to individuals involved in
      rappelling, high-demand athletes, and the surgeons who treat them. Nonoperative
      management of pectoralis major tendon tears is contrasted with operative repair.
      The current literature supports operative treatment in high-demand athletes,
      laborers, and military personnel to allow them to regain full strength and
      endurance.

PMID- 15040640
TI  - Leiomyosarcoma of the urinary bladder in a teenage male.
AB  - Malignant neoplasms of the bladder are typically transitional cell carcinoma with
      squamous cell carcinoma and adenocarcinoma comprising nearly all of the remaining
      cases. Leiomyosarcoma is a rarely seen neoplasm of the bladder with a generally
      poor prognosis. It is important to distinguish leiomyosarcomas from
      rhabdomyosarcoma with the aid of immunohistochemical markers. A therapeutic
      dilemma exists with regard to the need for urethrectomy. We present the third
      reported case of leiomyosarcoma of the bladder in a teenage male patient.

PMID- 15040641
TI  - A 22-year-old Army private with chest pain and weight loss.
AB  - The objective of this study was to delineate an efficient and effective
      diagnostic approach in evaluating a patient with weight loss and a posterior
      mediastinal mass. This case demonstrates the evaluation and management of a 22
      year-old Army private with weight loss, chest pain, and a posterior mediastinal
      mass on chest X-ray. The importance of obtaining a thorough travel history to
      formulate the differential diagnosis is highlighted.

PMID- 15040642
TI  - Chloroform and the Civil War.

PMID- 15040643
TI  - Pharmacodynamic effects of zidovudine 600 mg once/day versus 300 mg twice/day in
      therapy-naive patients infected with human immunodeficiency virus.
AB  - STUDY OBJECTIVE: To compare the virologic activity of zidovudine monotherapy
      administered as 600 mg once/day versus 300 mg twice/day. DESIGN: Phase II,
      randomized (1:1), open-label study. SETTING: Thirteen medical centers in the
      United States. PATIENTS: Thirty-two antiretroviral-naive patients infected with
      human immunodeficiency virus (HIV). INTERVENTION: Patients were administered
      either zidovudine 600 mg every 24 hours (16 patients) or 300 mg every 12 hours
      (16 patients) for 13 days. MEASUREMENTS AND MAIN RESULTS: Plasma HIV-1 RNA
      concentration was measured daily. Study end points were between-group differences
      in change from baseline of log10-transformed HIV-1 RNA and in rates of viral load
      decline measured by the slope of HIV-1 RNA over time. At baseline, mean HIV-1 RNA
      was similar in the once/day and twice/day groups (4.33 and 4.40 log10 copies/ml,
      respectively). At day 14, a trend toward lower mean reduction in HIV-1 RNA from
      baseline was observed in the once/day group (-0.585, 95% confidence interval [CI]
      -0.728 to -0.442 log10 copies/ml) compared with the twice/day group (-0.849, 95%
      CI -1.067 to -0.630 log10 copies/ml, p=0.056). Viral load reduction also tended
      to be slower in the once/day group, as indicated by the smaller slope of viral
      load decline in the once/day group than in the twice/day group during days 1-14 (
      0.045 vs -0.065 logic copies/ml/day, p=0.065). Both zidovudine regimens were
      similarly well tolerated. CONCLUSION: Zidovudine 600 mg once/day has antiviral
      activity, although less pronounced and more slowly achieved than that seen with
      zidovudine 300 mg twice/day. No differences were observed between the two
      treatment groups with respect to safety profile or tolerability

PMID- 15040644
TI  - Evaluation of the US Oncology Network's recommended guidelines for therapeutic
      substitution with darbepoetin alfa 200 microg every 2 weeks in both naive
      patients and patients switched from epoetin alfa.
AB  - STUDY OBJECTIVE: To evaluate the efficacy of darbepoetin alfa 200 microg
      subcutaneously every 2 weeks after therapeutic substitution for epoetin alfa.
      DESIGN: Retrospective multicenter chart review. SETTING: Three US Oncology
      affiliated outpatient sites. PATIENTS: Three hundred thirty anemic patients with
      nonmyeloid malignancies, of whom 174 had been treated previously with epoetin
      alfa (switched group) and 156 had not been treated recently with epoetin alfa
      (naive group). INTERVENTIONS: Therapeutic substitution with darbepoetin alfa was
      started according to the US Oncology Pharmacy and Therapeutics Committee's
      recommended dosing guidelines: anemic patients with cancer received a starting
      dosage of darbepoetin alfa 200 microg every 2 weeks regardless of whether or not
      they had previously received epoetin alfa. Hematologic and darbepoetin alfa usage
      data were abstracted from consecutive medical records dated from May 2002-March
      2003. MEASUREMENTS AND MAIN RESULTS: Median exposure to darbepoetin alfa was 10
      weeks (25th quartile 6 wks, 75th quartile 17 wks) and 10 weeks (25th quartile 5
      wks, 75th quartile 18 wks) for the naive and switched groups, respectively. The
      week before the switch to darbepoetin alfa, the 174 patients receiving epoetin
      alfa were administered the following weekly doses: less than 40,000 U (9%),
      40,000 U (50%), or 45,000-90,000 U (41%). Mean hemoglobin level increased from
      baseline (wk 0) in both the naive and switched groups. The proportion of patients
      receiving a red blood cell transfusion in the darbepoetin alfa treatment phase
      was low (15% in each group). No variation in transfusion rates was observed
      across weight categories in patients who received a fixed dosage of darbepoetin
      alfa. Darbepoetin alfa was well tolerated. A detailed usage algorithm was
      validated by these results and is being used in these three US Oncology
      affiliated practices. CONCLUSION: A darbepoetin alfa starting dosage of 200
      microg subcutaneously every 2 weeks administered according to US Oncology
      recommended dosing guidelines is effective in treating chemotherapy-induced
      anemia in both epoetin alfa-naive patients and those switched from epoetin alfa.

PMID- 15040645
TI  - Failure of computerized treatment suggestions to improve health outcomes of
      outpatients with uncomplicated hypertension: results of a randomized controlled
      trial.
AB  - STUDY OBJECTIVE: To assess the effects of evidence-based treatment suggestions
      for hypertension made to physicians and pharmacists using a comprehensive
      electronic medical record system. DESIGN: Randomized controlled trial with a 2 x
      2 factorial design of physician and pharmacist interventions, which resulted in
      four groups of patients: physician intervention only, pharmacist intervention
      only, intervention by physician and pharmacist, and intervention by neither
      physician nor pharmacist (control). SETTING: Academic primary care internal
      medicine practice. SUBJECTS: Seven hundred twelve patients with uncomplicated
      hypertension. MEASUREMENTS AND MAIN RESULTS: Suggestions were displayed to
      physicians on computer workstations used to write outpatient orders and to
      pharmacists when filling prescriptions. The primary end point was generic health
      related quality of life. Secondary end points were symptom profile and side
      effects from antihypertensive drugs, number of emergency department visits and
      hospitalizations, blood pressure measurements, patient satisfaction with
      physicians and pharmacists, drug therapy compliance, and health care charges. In
      the control group, implementation of care changes in accordance with treatment
      suggestions was observed in 26% of patients. In the intervention groups,
      compliance with suggestions was poor, with treatment suggestions implemented in
      25% of patients for whom suggestions were displayed only to pharmacists, 29% of
      those for whom suggestions were displayed only to physicians, and 35% of the
      group for whom both physicians and pharmacists received suggestions (p=0.13).
      Intergroup differences were neither statistically significant nor clinically
      relevant for generic health-related quality of life, symptom and side-effect
      profiles, number of emergency department visits and hospitalizations, blood
      pressure measurements, charges, or drug therapy compliance. CONCLUSION: Computer
      based intervention using a sophisticated electronic physician order-entry system
      failed to improve compliance with treatment suggestions or outcomes of patients
      with uncomplicated hypertension.

PMID- 15040646
TI  - Macrolide therapy for Chlamydia pneumoniae in the secondary prevention of
      coronary artery disease: a meta-analysis of randomized controlled trials.
AB  - STUDY OBJECTIVE: As recent studies have shown that antibiotic therapy to
      eradicate Chlamydia pneumoniae may be beneficial in the secondary prevention of
      coronary artery disease, and studies to date may have lacked statistical power,
      we conducted a meta-analysis of randomized controlled trials to determine the
      role of antibiotic therapy in this patient population. DESIGN: Systematic review
      and meta-analysis of randomized controlled trials. PATIENTS: A total of 12,032
      patients from nine studies. MEASUREMENTS AND MAIN RESULTS: We searched MEDLINE,
      EMBASE, the Cochrane Controlled Trials Register, and abstracts of conference
      proceedings to identify pertinent studies. The random effects model was used to
      estimate a pooled relative risk. Heterogeneity was assessed using the bootstrap
      version of the Q statistic with 1000 replications. In total, we reviewed nine
      randomized controlled trials enrolling 12,032 patients; six enrolled patients
      with acute coronary syndrome, two enrolled patients with stable coronary artery
      disease, and one enrolled a mixed population. Compared with placebo, macrolide
      therapy was not associated with a significant reduction in any coronary event
      (relative risk [RR] 0.98, 95% confidence interval [CI] 0.88-1.08), myocardial
      infarction or angina (RR 0.89, 95% CI 0.68-1.16), or overall mortality (RR 0.95,
      95% CI 0.81-1.12). CONCLUSION: Our results do not support routine use of
      antichlamydial therapy for secondary prevention of coronary events.

PMID- 15040647
TI  - Relationship between symptoms and health-related quality of life in patients
      treated for hypertension.
AB  - STUDY OBJECTIVE: To determine the relationship between symptoms and health
      related quality of life (HRQOL) in patients receiving drug therapy for
      hypertension. DESIGN: Cross-sectional survey. SETTING: Outpatient general
      medicine and university-based hypertension clinics. PATIENTS: All patients
      prescribed one or more antihypertensive drugs seen during a 6-month period in the
      clinics. INTERVENTION: Data were obtained from a mailed questionnaire and medical
      records. MEASUREMENTS AND MAIN RESULTS: Symptoms were measured by a symptom count
      and total symptom distress. Two scores derived from the Short Form-36 (SF-36)-
      the Physical Component Summary (PCS) and the Mental Component Summary (MCS)--were
      used to assess HRQOL. Responses were received from 125 of 220 patients (56.8%).
      Mean +/- SD values were 8.8 +/- 7.8 for symptom count, 31.6 +/- 46.2 for total
      symptom distress, 48.7 +/- 9.3 for PCS, and 51.6 +/- 10.1 for MCS. Higher symptom
      counts and symptom distress scores were strongly associated with lower HRQOL
      scores in multivariate models, with standardized coefficients from -0.62 to 
      0.41. These were greater in magnitude than any other predictor, including
      demographic information (age, sex, race, education level, income), disease
      variables (blood pressure, years of hypertension), and drug treatment (number of
      antihypertensive drugs and duration of regimen). Model-adjusted R2 values were
      0.22-0.41. CONCLUSION: Symptoms have a greater impact on HRQOL than patient
      characteristics, blood pressure, or drug-related factors. Among patients
      receiving drug therapy for hypertension, detailed review of symptoms may yield
      important information for assessing and improving HRQOL.

PMID- 15040648
TI  - Angiotensin-converting enzyme inhibitor therapy in patients with heart failure
      enrolled in a managed care organization: effect on costs and probability of
      hospitalization.
AB  - STUDY OBJECTIVE: To evaluate the effect of angiotensin-converting enzyme (ACE)
      inhibitor therapy on risk of hospitalization and resource utilization in patients
      with heart failure enrolled in a managed care organization. DESIGN: Retrospective
      medical and pharmacy claims analysis. PATIENTS: One thousand five hundred seventy
      three patients with heart failure enrolled in a managed care organization.
      MEASUREMENTS AND MAIN RESULTS: Medical and pharmacy claims from January 1, 1997
      December 31, 1999, from a managed care organization covering approximately
      350,000 individuals were analyzed. Patients aged 35 years or older with a
      diagnostic code for heart failure and 18 months of continuous eligibility were
      selected. From this group (1573 patients), two cohorts were selected based on
      exposure to an ACE inhibitor. Dependent variables of interest were all-cause
      hospitalization and total direct medical costs during the 12-month study period.
      A logistic regression model and an ordinary least-squares model adjusting for
      patient demographics, comorbidities, and concomitant drug therapy were used to
      analyze the risk of all-cause hospitalization and total direct medical costs,
      respectively. Therapy with an ACE inhibitor for 180 days was associated with a
      decreased risk of all-cause hospitalization (odds ratio 0.65, p<0.0001) and lower
      total costs (mean dollars 2397, p<0.001) compared with no ACE inhibitor therapy.
      CONCLUSION: In patients with a diagnosis of heart failure, exposure to ACE
      inhibitor therapy is associated with fewer hospitalizations and lower total costs
      than no ACE inhibitor exposure.

PMID- 15040649
TI  - Assessment of hypothyroidism in patients with chronic heart failure.
AB  - STUDY OBJECTIVE: To determine whether appropriate thyroid function measurements
      were being conducted in patients receiving care at a multidisciplinary heart
      failure clinic. DESIGN: Retrospective chart review. SETTING: University
      affiliated outpatient clinic. PATIENTS: One hundred ninety-three patients with
      heart failure. INTERVENTION: Patients enrolled in the heart failure clinic at the
      Medical University of South Carolina from January 2000-April 2003 were
      identified. Their medical records were reviewed for demographics, New York Heart
      Association (NYHA) functional classification, laboratory data, and date of most
      recent heart failure clinic appointment. MEASUREMENTS AND MAIN RESULTS: The
      records of 193 patients (43% women) were reviewed. Overall and subgroup analyses
      were performed based on patient characteristics such as presence of thyroid
      stimulating hormone (TSH) level, interval since last heart failure clinic
      appointment, presence of thyroid replacement therapy, amiodarone use, NYHA
      functional class, and attending physician. Of the 193 patients, 77 (40%) had
      appropriate TSH monitoring, whereas 10 (32%) of 31 patients receiving amiodarone
      had appropriate monitoring. Forty-four (27%) patients not receiving amiodarone
      had no record of a TSH level. In 22 patients (11%), hypothyroidism was diagnosed
      and treated, whereas 16 patients (8%) had an abnormal TSH level but received no
      therapy. CONCLUSION: Forty percent of the 193 patients at this outpatient heart
      failure clinic received appropriate TSH monitoring. An opportunity exists for
      protocol implementation and education of pharmacists, nurse practitioners, and
      physicians concerning appropriate thyroid function monitoring in the heart
      failure population.

PMID- 15040650
TI  - Delaying the onset of type 2 diabetes mellitus in patients with prediabetes.
AB  - The frequency of type 2 diabetes mellitus is increasing at an alarming rate.
      Prediabetes, also referred to as impaired glucose tolerance (IGT) and/or impaired
      fasting glucose, is a major risk factor for development of type 2 diabetes
      mellitus. In addition, IGT has been associated with an increased risk of
      cardiovascular disease and mortality. Several studies have measured the effects
      of various interventions in patients with IGT on the development of type 2
      diabetes mellitus. Intensive lifestyle modifications through alterations in diet
      and improvement in exercise have delayed the development of type 2 diabetes
      mellitus by 58% in patients with IGT. Therapy with metformin, troglitazone, or
      acarbose also has reduced the progression of IGT to diabetes mellitus by 31%, 49%
      and 25%, respectively. The mechanisms by which lifestyle interventions and drugs
      reduce the progression may be through alterations in insulin sensitivity. The
      American Diabetes Association recommends screening for prediabetes in patients
      who are 45 years or older and those with a body mass index of 25 kg/m2 or greater
      who have additional diabetes mellitus risk factors. Pharmacists can promote
      awareness, counsel patients on intervention strategies to delay the onset of
      diabetes mellitus, and screen high-risk patients.

PMID- 15040651
TI  - Pharmacist compensation for cognitive services: focus on the physician office and
      community pharmacy.
AB  - We provide a stepwise approach for the clinical pharmacy practitioner in the
      physician clinic or community pharmacy setting to secure compensation for
      cognitive services. How to establish compensation for pharmacist services is
      explored, including evaluating the payer mix, developing a relationship with the
      first- or third-party payer, becoming credentialed with a third-party payer, and
      creating a fee structure. We detail the physical process of billing, which
      involves completing appropriate billing forms, appropriately using billing codes,
      documenting cognitive services in the patient record, and obtaining the proper
      waivers and/or approvals to provide specific services such as laboratory services
      and immunizations. This comprehensive review of compensation for cognitive
      services available in the community pharmacy and physician office environment is
      designed to be a template for pharmacists to further develop specific strategies,
      implement fee structures, and obtain compensation in their pharmacy environment
      and payer mix. Exploration into these innovative markets will enable pharmacists
      to increase revenue as they enhance and expand their cognitive services for
      patients.

PMID- 15040653
TI  - Board of Pharmaceutical Specialties-certified faculty: a survey of United States
      colleges of pharmacy.
AB  - Board certification of pharmacists has been a reality in the United States since
      1976, when the Board of Pharmaceutical Specialties (BPS) was founded. Little has
      been reported about the effects of board certification of pharmacists,
      particularly pharmacy practice faculty, since 1992, when the BPS administered its
      first certification examination. We developed and pretested a survey to describe
      and measure the effect of BPS certification on the realm of academia as perceived
      by deans of colleges of pharmacy in the United States. Deans or other appropriate
      officials at all 84 colleges of pharmacy in the United States were asked to
      complete and submit this 13-question survey, which was administered through the
      Web and maintained respondents' anonymity. Officials from 35 of the 84 colleges
      completed the survey, for a response rate of 42%. No college reported that board
      certification was a condition for employment. Eight schools (23%) anticipated a
      certification requirement in the future. The most commonly reimbursed items
      associated with certification were fees for the American College of Clinical
      Pharmacy preparatory course and the BPS examination. Twelve schools (34%)
      provided no reimbursement toward certification. The most common incentive for
      faculty to obtain certification was consideration in promotion and tenure (66%).
      We believe that this information will facilitate efforts to gauge the effects of
      BPS certification on colleges of pharmacy. We also anticipate that it will assist
      colleges as they attempt to recruit and retain the most qualified faculty members
      possible, particularly in light of the national pharmacist shortage.

PMID- 15040652
TI  - Greater effect of enhanced pharmacist care on cholesterol management in patients
      with diabetes mellitus: a planned subgroup analysis of the Study of
      Cardiovascular Risk Intervention by Pharmacists (SCRIP).
AB  - STUDY OBJECTIVE: To determine the effect of enhanced pharmacist care on
      cholesterol management in patients with and without diabetes mellitus. METHODS:
      We conducted a planned subgroup analysis of the Study of Cardiovascular Risk
      Intervention by Pharmacists (SCRIP), a 54-center randomized trial of pharmacist
      intervention compared with usual care in patients at high risk for cardiovascular
      events. The patients involved had atherosclerotic disease or diabetes. We
      compared the effect of pharmacist intervention in patients with and without
      diabetes. The primary end point was a composite of performing a fasting
      cholesterol profile, or adding or increasing the dosage of a cholesterol-lowering
      drug. Secondary end points were individual components of the primary end point
      and change in 10-year risk for cardiovascular events, using the Framingham risk
      equation. RESULTS: Of the 675 patients enrolled in the SCRIP study, 294 (44%) had
      diabetes. Enhanced pharmacist care had a more beneficial effect on cholesterol
      management in those with diabetes (odds ratio [OR] 4.8) than without diabetes (OR
      2.1), p=0.01. Secondary end points showed similar trends, and reduction in
      Framingham risk was greater in patients with diabetes than without. CONCLUSION:
      Pharmacist intervention for dyslipidemia appears to have a greater impact in
      patients with diabetes. Results of this substudy suggest that pharmacists should
      target this patient group for interventions in cholesterol risk management.

PMID- 15040654
TI  - Apraxia of lid opening: dose-dependent response to carbidopa-levodopa.
AB  - A 67-year-old woman with an 8-year history of Parkinson's disease and Lewy body
      dementia experienced difficulty in opening her eyelids (apraxia of lid opening
      [ALO]); she could close them without difficulty. This problem emerged 2 weeks
      after the patient's dosage of carbidopa 50 mg-levodopa 200 mg 3 times/day was
      decreased to twice/day. Two weeks after the onset of ALO the patient visited her
      physician, who suspected carbidopa-levodopa of causing the problem; the drug was
      discontinued. When the patient's condition worsened rather than improved, she was
      referred to a neuro-ophthalmologist, who confirmed the diagnosis of ALO. However,
      the neuro-ophthalmologist noted that this may not have been a true apraxia but
      rather a form of sustained blepharospasm that prevented the eyelid from opening.
      Carbidopa-levodopa was restarted, and her condition improved dramatically when
      her dosage was increased gradually to carbidopa 50 mg-levodopa 200 mg in the
      morning and at noon, and carbidopa 25 mg-levodopa 100 mg in the evening.
      Clinicians should be aware of adverse reactions, such as AOL, in patients taking
      carbidopa-levodopa who have dementia of the Lewy body type.

PMID- 15040655
TI  - Prolonged cardiac repolarization after tacrolimus and haloperidol administration
      in the critically ill patient.
AB  - A 42-year-old woman who underwent single lung transplantation who received
      tacrolimus and a 58-year-old woman with pneumonia and multiple comorbidities who
      received haloperidol both experienced drug-induced prolongation of cardiac
      repolarization. The second woman also developed torsade de pointes. Critically
      ill patients are particularly susceptible to developing torsade de pointes due to
      various comorbidities, electrolyte disturbances, and receipt of numerous drugs.
      These two case reports illustrate the increased risk for drug-induced
      cardiotoxicity in the critically ill patient. They also indicate the need for
      current knowledge derived from basic research and retrospective case reports on
      drug-induced torsade de pointes to be integrated into the existing body of
      knowledge. Guidelines can then be developed to help prospectively reduce the
      frequency of adverse effects in intensive care patients. Research is necessary
      regarding identification of high-risk patients before drugs are administered, and
      clarification of the proper role of therapeutic QT monitoring in clinical
      practice.

PMID- 15040656
TI  - Argatroban dosing in intensive care patients with acute renal failure and liver
      dysfunction.
AB  - STUDY OBJECTIVE: To demonstrate dosing adjustment difficulties of argatroban
      encountered in critically ill patients with acute liver dysfunction who are
      receiving continuous renal replacement therapy. DESIGN: Case description.
      SETTING: Medical and surgical intensive care unit in a tertiary care, university
      affiliated hospital. PATIENTS: Four consecutive patients with proven heparin
      induced thrombocytopenia (HIT), acute renal failure requiring continuous renal
      replacement therapy, and various levels of transient hepatic impairment.
      INTERVENTION: Argatroban, a direct synthetic thrombin inhibitor, was given
      continuously and stabilized at 0.125-0.85 microg/kg/minute to attain an activated
      partial thromboplastin time (aPTT) 1.5-2.5 times the normal value for periods of
      6-36 days. MEASUREMENTS AND RESULTS: Argatroban was started at the usual dosage
      of 2 microg/kg/minute, which resulted in significant overshooting of the aPTT and
      international normalized ratio (INR). No patient experienced bleeding or
      thrombotic complications. All patients were stabilized with reduced dosages such
      as those recommended for patients with chronic hepatic impairment. CONCLUSION: We
      recommend argatroban therapy for intensive care patients with HIT, especially
      those with renal failure. However, in all patients with suspected liver
      dysfunction due to recent elevation of liver transaminase levels and combined
      renal failure, a decrease in the initial dosage and careful titration of the
      infusion are mandatory. Further studies are needed to fully elucidate argatroban
      elimination and dosage adjustments for intensive care patients.

PMID- 15040658
TI  - Donepezil for alcohol-related dementia: a case report.
AB  - A 75-year old man with a 40-year history of alcoholism was admitted to the
      hospital for intoxication and inability to care for himself. He had been admitted
      frequently in the past for detoxification and rehabilitation. The patient had no
      family history of Alzheimer's disease, no history of head injury, and single
      photon emission computed tomography showed no typical findings of Alzheimer's
      disease. His cognitive function was impaired. He was treated with donepezil for
      alcohol-related dementia, and 3 months later, his cognitive function had
      improved. More research is needed to confirm donepezil's role in treating alcohol
      related dementia.

PMID- 15040659
TI  - Clinical pharmacists save thousands of lives: big decrease in dose-related
      adverse effects.

PMID- 15040657
TI  - Tenofovir-related nephrotoxicity: case report and review of the literature.
AB  - Tenofovir is a nucleotide reverse transcriptase inhibitor for treatment of human
      immunodeficiency virus (HIV) infection. Several cases of renal failure associated
      with tenofovir therapy recently have been reported. A 54-year-old man with HIV
      experienced decreasing renal function and Fanconi's syndrome secondary to
      tenofovir therapy. His condition gradually improved after discontinuation of the
      drug. The available medical literature for reported cases of tenofovir-related
      nephrotoxicity indicates that this complication is apparently rare. However, our
      case report and literature review underscore the importance of monitoring renal
      function when treating patients with any nucleotide reverse transcriptase
      inhibitor.

PMID- 15040660
TI  - Aggregation of helminths: the role of feeding behavior of fish hosts.
AB  - Individual Arctic charr (Salvelinus alpinus) from Fjellfrosvatn, northern Norway,
      could be categorized by their stomach contents as zooplanktivores or benthivores.
      Feeding specialization among these fish was evident from negative correlations
      between helminths transmitted by pelagic copepods (Diphyllobothrium dendriticum
      and D. ditremum) and those transmitted by the benthic amphipod Gammarus lacustris
      (Cystidicola farionis and Cyathocephalus truncatus). Occurrences of parasite
      species acquired from the same types of invertebrate were positively correlated
      in the fish. Strong relationships among habitat use, diet, and helminth
      infections among the Arctic charr indicated persistent foraging patterns
      involving long-term habitat use and feeding specialization. The distribution of
      all parasite species was highly aggregated in the fish samples, measured by the
      exponent k of the fitted negative binomial distributions (range: 0.5-7.5) and the
      variance-to-mean ratios (s2/mean, range: 5-85). Charr specializing on either
      copepods or Gammarus predominantly contributed to high-intensity class intervals
      within the overall frequency distributions of the corresponding parasite species.
      Such fish had low infection intensities of helminths transmitted by other prey
      organisms. The detailed analyses of the parasite frequency distributions for fish
      with different habitat or feeding preferences evidently show how heterogeneity in
      trophic behavior contributes strongly to the commonly observed aggregation of
      helminths among hosts under natural conditions.

PMID- 15040661
TI  - The involvement of cyclic adenosine monophosphate in the control of schistosome
      miracidium cilia.
AB  - This study examined the possible involvement of cyclic adenosine monophosphate
      (cAMP) in the control of ciliary action of Schistosoma mansoni miracidia.
      Miracidia immobilized in hypertonic NaCl solution were treated with 3 compounds
      that are known to increase intracellular cAMP concentrations. Forskolin, at a
      concentration of 50 microM, induced 50.1% of the miracidia to swim in hypertonic
      solution. The corresponding values obtained for 3-isobutyl-1-methylxanthine
      (IBMX) at 1 mM and 8-bromo-cAMP at 10 mM were 42.2 and 50.4%, respectively. The
      motility-enhancing effect of these compounds was dose dependent. Nevertheless,
      the swimming speed of miracidia activated in this way was only 10% of that
      observed in artificial pond water (APW). Cholera toxin had no apparent effect on
      miracidia swimming in hypertonic NaCl solution. Likewise, swimming in APW treated
      with forskolin at 50 microM, IBMX at 1 mM, or 8-bromo-cAMP at 10 mM did not
      induce any apparent change in motility. Miracidia swimming in APW were then
      treated with 3 compounds that decrease the intracellular concentration of cAMP.
      MDL-12,330A, at a concentration of 250 microM, caused a dramatic decrease in
      swimming over a period of 1 hr. Likewise, SQ22536 and imidazole, at
      concentrations of 20 and 50 mM, respectively, caused 36.5 and 73.4% decreases in
      swimming under the same conditions. Finally, inhibitors of cAMP-dependent protein
      kinase, i.e., PKI(14-22)amide, H89, and H88, completely inhibited miracidia
      swimming in APW at concentrations of 25, 50, and 100 microM, respectively. These
      results suggest that cAMP and cAMP-dependent protein kinase are involved in
      osmosis-controlled ciliary motion of schistosome miracidia.

PMID- 15040662
TI  - Opiate alkaloids and nitric oxide production in the nematode Ascaris suum.
AB  - The tissue distribution, course of secretion, and sex differences of morphine
      were delineated in Ascaris suum. Nitric oxide (NO) release in various tissues in
      response to morphine and its metabolite morphine-6-glucuronide (M6G) were also
      examined. Ascaris suum of both sexes along with their incubation fluid were
      analyzed for morphine concentrations by high-performance liquid chromatography
      (HPLC) over a 5-day period. Various tissues were also dissected for HPLC and NO
      analysis. Morphine was found to be most prevalent in the muscle tissue, and there
      is significantly more morphine in females than males, probably because of the
      large amounts present in the female uterus. Morphine (10(-9) M) and M6G (10(-9)
      M) stimulated the release of NO from muscles. Naloxone (10(-7) M) and N-nitro-L
      arginine methyl ester (10(-6) M) blocked (P < 0.005) morphine-stimulated NO
      release from A. suum muscle tissue. D-Phe-Cys-Tyr-D-Trp-Om-Thr-Pen-Thr-NH2 (CTOP)
      (10(-7) M) did not block morphine's NO release. However, naloxone could not block
      M6G-stimulated NO release by muscles, whereas CTOP (10(-7) M) blocked its
      release. These findings were in seeming contradiction to our earlier inability to
      isolate a mu opiate receptor messenger RNA by reverse transcriptase-polymerase
      chain reaction using a human mu primer. This suggests that a novel mu opiate
      receptor was possibly present and selective toward M6G.

PMID- 15040664
TI  - Spermiogenesis and ultrastructure of the spermatozoon of the liver fluke Fasciola
      gigantica Cobbold, 1856 (Digenea: Fasciolidae), a parasite of cattle in Senegal.
AB  - The present paper describes the spermiogenesis and the ultrastructure of the
      spermatozoon of Fasciola gigantica, as revealed by transmission electron
      microscopy. Spermiogenesis in F. gigantica begins with the formation of a
      differentiation zone containing 2 centrioles with associated striated roots and
      an intercentriolar body between them. Each centriole develops a flagellum.
      Proximodistal fusion of these flagella with the median cytoplasmic extension
      gives rise to the spermatozoon. Spermiogenesis in F. gigantica is characterized
      by the formation of a dorsolateral cytoplasmic expansion, an external
      ornamentation of the cell membrane, and spinelike bodies. These 3 structures were
      also observed in the anterior part of the spermatozoon. Our study describes for
      the first time the simultaneous presence of dorsolateral cytoplasmic expansion,
      external ornamentation of the plasma membrane, and spinelike bodies in the
      spermatozoon of a trematode.

PMID- 15040663
TI  - Reinvestigation of spermiogenesis in the proteocephalidean cestode Proteocephalus
      longicollis (Zeder, 1800).
AB  - The reinvestigation of spermiogenesis in the proteocephalidean cestode
      Proteocephalus longicollis (Zeder, 1800) provides new details that were not
      described previously for this species. The 2 centrioles with roots are oriented
      at the first tangential to the long axis of the nucleus in a differentiation
      zone. They come to be arranged in the same plane only when a single
      intercentriolar body (ICB) appears between them. The ICB had been described
      previously as consisting of a number of dense elements (Swiderski, 1985) but, in
      the present study, appeared as a single, electron-dense plate. Also new for this
      species is the observation of 2 arching membranes that appear at the base of the
      differentiation zone only when the 2 flagella rotate toward the median
      cytoplasmic protrusion. Moreover, the formation of a crested body is described
      for the first time in P. longicollis. The present data support the suggestion
      that the process of spermiogenesis in proteocephalidean tapeworms corresponds in
      most features to that observed in some members of the unrelated tetraphyllidean
      clades, the Onchobothriidae and Phyllobothriidae. This may represent more
      evidence regarding the close relationship between tetraphyllidean and
      proteocephalidean cestodes, but existing information is fragmentary and
      controversial in some characters.

PMID- 15040665
TI  - Community structure and seasonal dynamics of helminth parasites in Lepomis
      cyanellus and L. macrochirus from Charlie's Pond, North Carolina: host size and
      species as determinants of community structure.
AB  - The community structure and seasonal dynamics of 16 helminth species infecting
      green (Lepomis cyanellus) and bluegill (L. macrochirus) sunfishes in Charlie's
      Pond, North Carolina, was examined. One hundred and fifty-four fishes including
      90 green sunfish and 64 bluegill sunfish were collected between March and
      November 2000 and examined for the presence of helminth parasites. Five of these
      species underwent significant changes in abundance in green sunfish
      infracommunities, 3 of which also displayed seasonal changes in prevalence. Three
      of the 16 species fluctuated seasonally in bluegill infrapopulations; 2 also
      underwent changes in prevalence. Species richness and diversity varied across the
      9-mo period for both host species, whereas total helminth abundance remained
      constant. Analysis of component communities revealed differences in community
      structure for the 2 host species. Bluegills were found to harbor larger and more
      diverse communities. Bluegills also contained larger infrapopulations of 5
      species, whereas green sunfish had greater abundance of 2 species. Interpretation
      of these data suggests that host species and size are strongly associated with
      the predictability of community structure.

PMID- 15040666
TI  - Factors influencing the distribution of digenetic trematode infections in a
      mudsnail (Hydrobia ventrosa) population inhabiting salt marsh ponds in Iceland.
AB  - This study analyzed the influence of several abiotic and biotic variables on the
      distribution of digenetic trematode infections in a mudsnail, Hydrobia ventrosa,
      population inhabiting 12 ponds on the Melabakkar salt marsh in Iceland, the
      northwestern limits of the geographical distribution. Nine trematode species were
      found to infect the snail population, which included Microphallus pirum,
      Microphallus breviatus, Microphallus claviformis, Maritrema subdolum
      (Microphallidae), Cercaria Notocotylidae sp. 11 Deblock, 1980, C. Notocotylidae
      sp. 12 Deblock, 1980, C. Notocotylidae sp. 13 Deblock, 1980 (Notocotylidae),
      Cryptocotyle concavum (Heterophyidae), and Psilostomum brevicolle
      (Psilostomatidae). Correlations between biotic variables (snail density in the
      ponds and vegetation cover), abiotic variables (distance of each pond from the
      sea, pond elevation above chart datum, size, average depth, salinity, and some
      characters of the littoral zone and sediments), and trematode infections were
      analyzed. These variables indirectly affected the trematode infections because
      some determined how attractive the ponds were for the final hosts, which were
      various species of marine and shore birds. We propose that their habitat use and
      defecating habits are the main determinants of the trematode distribution in the
      area.

PMID- 15040667
TI  - Geographical structuring of feather mite assemblages from the Australian brush
      turkey (Aves: Megapodiidae).
AB  - Populations of a host species may exhibit different assemblages of parasites and
      other symbionts. The loss of certain species of symbionts (lineage sorting, or
      "missing-the-boat") is a mechanism by which geographical variation in symbiont
      assemblages can arise. We studied feather mites and lice from Australian brush
      turkeys (Aves: Megapodiidae: Alectura lathami) and expected to observe
      geographical structuring in arthropod assemblages for several reasons. First,
      because the brush-turkey is a sedentary ground-dwelling bird, we predicted that
      geographically close host populations should share more similar arthropod
      assemblages than distant ones. Second, because brush-turkeys do not brood their
      young, vertical transfer of arthropods is unlikely, and brush-turkeys probably
      acquire their mites and lice at social maturity through contact with other birds.
      Young birds could disperse and found new populations without carrying complete
      sets of symbionts. We predicted that young birds would have fewer species of
      arthropods than older birds; in addition, we expected that males (which are
      polygynous) would have more species than females. Birds were sampled from 12
      sites (=populations) along the east coast of Queensland, Australia, that were
      separated by a distance of 12.5-2,005 km. In total, 5 species of mites from the
      Pterolichidae and 1 species from the Ascouracaridae were found. Two species of
      lice were collected but in numbers too low to be statistically useful.
      Differentiation of mite assemblages was evident; in particular, Leipobius sp.
      showed 100% prevalence in 3 host populations and 0% in the remaining 9. A
      dendrogram of brush-turkey populations based on mite assemblages showed 2
      geographically correlated clusters of sites, plus 1 cluster that contained 2
      sites near Brisbane and 1 approximately at a distance of 1,000 km. There was no
      strong effect of host age or sex on number of mite species carried. Horizontal
      transfer of feather mites by hippoboscid flies, in addition to physical contact
      between hosts, may play a role in homogenizing symbiont assemblages within
      populations.

PMID- 15040668
TI  - Molecular and biologic characteristics of Toxoplasma gondii isolates from
      wildlife in the United States.
AB  - Toxoplasma gondii isolates can be grouped into 3 genetic lineages. Type I
      isolates are considered more virulent in outbred mice and have been isolated
      predominantly from clinical cases of human toxoplasmosis, whereas types II and
      III isolates are considered less virulent for mice and are found in humans and
      food animals. Little is known of genotypes of T. gondii isolates from wild
      animals. In the present report, genotypes of isolates of T. gondii from wildlife
      in the United States are described. Sera from wildlife were tested for antibodies
      to T. gondii with the modified agglutination test, and tissues from animals with
      titers of 1:25 (seropositive) were bioassayed in mice. Toxoplasma gondii was
      isolated from the hearts of 21 of 34 seropositive white-tailed deer (Odocoileus
      virginianus) from Mississippi and from 7 of 29 raccoons (Procyon lotor); 5 of 6
      bobcats (Lynx rufus); and the gray fox (Urocyon cinereoargenteus), red fox
      (Vulpes vulpes), and coyote (Canis latrans) from Georgia. Toxoplasma gondii was
      also isolated from 7 of 10 seropositive black bears (Ursus americanus) from
      Pennsylvania by bioassay in cats. All 3 genotypes of T. gondii based on the SAG2
      locus were circulating among wildlife.

PMID- 15040670
TI  - Infrapopulation dynamics of a wild strain of Taenia crassiceps (WFU) (Cestoda:
      Taeniidae) in BALB/cJ mice.
AB  - Taenia crassiceps cysticerci form large infrapopulations that persist in the
      tissues of their rodent hosts. Early infrapopulation growth appears inhibited and
      is followed by rapid increases that appear not to be controlled by the host
      immune response. This investigation was undertaken to examine the infrapopulation
      growth dynamics of a normally developing strain (WFU) of T. crassiceps during a
      60-day primary intraperitoneal (i.p.) infection. Three, 6, 9, 14, 28, and 60 days
      after i.p. inoculation of 5 cysticerci, mice were killed, and the numbers of
      larvae, developmental stage, and buds per larva were recorded. Larval
      infrapopulation abundance increased exponentially beginning on day 6
      postinoculation (PI), indicating an initial lag in reproduction. A stage
      structured exponential growth model, assuming no mortality, fits the larval
      infrapopulation dynamics in terms of the numbers of larvae in reproductive and
      nonreproductive stages, indicating that cysticerci evade or suppress (or both)
      host immune mechanisms that are parasite restrictive after the first week of
      infection.

PMID- 15040671
TI  - Antiegressin acts late in the intracellular growth cycle of Trypanosoma cruzi to
      inhibit parasite egress.
AB  - Trypanosoma cruzi is the causative agent of Chagas disease, which is
      characterized by acute and chronic phases. During the former, parasitemia rises
      dramatically, then decreases significantly during the chronic phase. Immune
      mechanisms responsible for the parasitemia reduction have not been thoroughly
      elucidated. The goal of the present study was to further characterize the immune
      response during chronic infection. Previously, we described antiegressin, an
      antibody in sera from chronically infected mice. The in vitro presence of
      antiegressin inhibits parasite egress from infected host cells. Antiegressin
      appears by day 14 of an in vivo infection and is maintained through at least day
      280 postinfection. The in vitro functional activity of antiegressin is initiated
      late in the 4-6 days intracellular growth cycle of T. cruzi; antiegressin may be
      added at day 4, inhibiting parasite release at day 5. Immunocytochemical staining
      using antineuraminidase demonstrates the presence of mature parasites inside host
      BALB/c fibroblasts grown in the presence of antiegressin. These results
      demonstrate the ability of antiegressin to inhibit emergence of developmentally
      mature trypomastigotes from infected host cells late in their intracellular
      growth cycle. We believe this antibody plays an important and novel role in
      achieving the low-parasitemia characteristic of chronic Chagas disease.

PMID- 15040669
TI  - Cloning and sequencing of putative calreticulin complementary DNAs from four hard
      tick species.
AB  - Calreticulin (CRT) is a calcium-binding protein and has many functions in
      eukaryotic cells. CRT is possibly involved in parasite host immune system
      evasion. To better understand the molecular basis of CRT in ticks, we cloned and
      sequenced 4 full-length complementary DNAs (cDNAs) from the hard tick species,
      Dermacentor variabilis, Haemaphysalis longicornis, Ixodes scapularis, and
      Rhipicephalus sanguineus, using the technique of rapid amplification of cDNA
      ends. The deduced amino acid sequences share high identities (between 77 and 98%)
      with 3 known tick CRT sequences. The major characteristics of known CRTs are
      observed in all 4 of our deduced tick CRTs. These include 3 major domains, a
      signal peptide sequence at the beginning of the coding region, 2 triplets of
      conserved regions, cysteine sites providing disulfide bridges for N-terminal
      folding, and a nuclear localization signal. Remarkably, the replacement of the
      endoplasmic reticulum retention signal KDEL by HEEL, which is believed to be
      associated with secretion of CRT into the host during feeding and was previously
      recorded only in 2 ticks and a hookworm, is also present in all 4 of our tick
      putative CRTs. In addition, the CRT gene is potentially useful for tick
      phylogenetic reconstruction.

PMID- 15040672
TI  - Mitotic responses to extracts of miracidia and cercariae of Schistosoma mansoni
      in the amebocyte-producing organ of the snail intermediate host Biomphalaria
      glabrata.
AB  - Suspensions of miracidia and cercariae of Schistosoma mansoni were subjected to
      repeated freeze-thaw cycles and then injected into resistant Salvador strain
      Biomphalaria glabrata snails. A pronounced increase in the number of mitotic
      figures, relative to uninjected, sham-injected, or diluent (water)-injected
      controls, was observed in the amebocyte-producing organ (APO) at 3 days
      postinjection (PI). After centrifugation of miracidia freeze-thaw extract (FTE),
      the resulting supernatant (FTS) and pellet possessed equal stimulatory activity
      that was approximately half that seen with FTE. Ultracentrifugation of miracidia
      FTS resulted in a supernatant that retained full activity, indicating a soluble
      molecule. Heat treatment of miracidia FTE reduced but did not eliminate activity,
      suggesting a nonprotein active component. Concentration or dilution of FTS by a
      factor of 10 gave a nonlinear dose-response relationship. Susceptible NIH albino
      snails injected with miracidia FTE had increased mitotic activity in the APO,
      which was much less than that seen in Salvador snails, whereas injection of
      miracidia FTE into Helisoma duryi had no discernable effect. Measurement of
      mitotic activity as a function of time PI showed no increase in numbers of
      mitotic figures in the APO at 18 hr but a large increase at 24 hr PI. Mitotic
      activity returned to preinjection levels by 96 hr PI, although a subsequent
      increase occurred at 120 hr PI.

PMID- 15040673
TI  - Acanthoparyphium tyosenense (Digenea: Echinostomatidae): experimental
      confirmation of the cercaria and its complete life history in Korea.
AB  - Cercaria yamagutii Ito, 1957, was found in the marine mesogastropods Lunatia
      fortuni and Glossaulax didyma from the tidelands of Simpo located at the estuary
      of the Mankyoung River, which runs to the western coast of Korea. Metacercariae
      were found in a marine bivalve Mactra veneriformis after being infected with C.
      yamagutii experimentally. When a sea gull, Larus crassiostris, was fed with the
      metacercariae collected from the infected M. veneriformis, adult worms were
      recovered 10 days later. It was confirmed that the parasites collected from L.
      crassiostris were Acanthoparyphium tyosenense Yamaguti, 1939. From the results of
      this life cycle study, it was determined that the first intermediate hosts of A.
      tyosenense are L. fortuni and G. didyma. The second intermediate and final hosts
      are M. veneriformis and L. crassiostris, respectively. Mactra veneriformis was
      experimentally infected with C. yamagutii isolated from L. fortuni and G. didyma
      by maintaining them in a water tank for 30 min at about 20 C. The cercariae
      entered M. veneriformis through their incurrent siphons. Five hours after
      infection, the cercariae tails began to separate from the bodies, and the
      cercariae formed cysts. Mature cysts were formed 340 hr (14 days) after infection
      and identified as the metacercariae of A. tyosenense. The prevalence of A.
      tyosenense metacercariae was 99.5% in naturally infected M. veneriformis. This is
      the first report of C. yamagutii as the cercaria of A. tyosenense, and the
      complete life cycle of A. tyosenense was established in Korea.

PMID- 15040674
TI  - Postcyclic transmission and its effect on the distribution of Paulisentis
      missouriensis (Acanthocephala) in the definitive host Semotilus atromaculatus.
AB  - The relationship of fish age class to parasitism by Paulisentis missouriensis was
      determined by sampling at least 29 creek chubs, Semotilus atromaculatus, from
      Easly Creek, Richardson County, Nebraska, every month from February 1996 to March
      1997. In general, mean abundance and prevalence of the acanthocephalans increased
      with the age or length of chubs. It is unlikely that this distribution is
      explained by increased consumption of intermediate hosts by older, larger fish or
      by predatory fish acquiring parasites from paratenic hosts. The intermediate host
      for P. missouriensis is the cyclopoid copepod Acanthocyclops robustus, and creek
      chubs do not consume more microscopic crustaceans as they age or grow. Instead,
      the percentage of fish in the diet of creek chubs increases. Furthermore, P.
      missouriensis apparently does not use paratenic hosts. In laboratory infections,
      P. missouriensis survived predation of its original definitive host and
      transferred to the predator. Postcyclically transmitted P. missouriensis survived
      at least 14 days in the intestine of creek chubs, where they localized around the
      first flexure beyond the stomach. All stages of development of both sexes were
      transferred successfully. Postcyclic transmission is a plausible explanation, in
      some cases, for the greater worm burden frequently observed in older, larger
      hosts and for the occurrence in top carnivores of parasites not known to have
      paratenic hosts. This method of transmission appears to result in distribution of
      acanthocephalans to groups of animals that otherwise would be inaccessible.

PMID- 15040675
TI  - Life-history studies on two molecular strains of mesocestoides (Cestoda:
      Mesocestoididae): identification of sylvatic hosts and infectivity of immature
      life stages.
AB  - Life-cycle studies were conducted on 2 molecular strains of Mesocestoides
      tapeworms that represent different evolutionary lineages (clades A and B). Wild
      carnivores, reptiles, and rodents were examined for tapeworm infections at 2
      enzootic sites: (1) San Miguel Island (SMI), a small island off the coast of
      southern California and (2) Hopland Research and Extension Center (HREC), a field
      station in northern California. Results indicate that deer mice (Peromyscus
      maniculatus) and coyotes (Canis latrans) may play an important role in the life
      cycles of Mesocestoides (clades A and B) in California. Over half the coyotes at
      HREC and at least a third of the population of island fox (Urocyon littoralis) at
      SMI were found to harbor clade A adult Mesocestoides spp. One of every 4
      Mesocestoides-infected coyotes had tapeworms representing both clades A and B.
      Experimental inoculations revealed that proglottids (clades A and B) were not
      directly infectious to rodents, reptiles, or dogs. On the other hand, mice,
      lizards, and hamsters fed tetrathyridia of Mesocestoides spp. (clades A or B)
      developed peritoneal tetrathyridial infections. A dog that was fed tetrathyridia
      (clade B) developed an adult tapeworm infection. Acephalic metacestodes given
      orally to western fence lizards, laboratory mice, or domestic dogs did not result
      in metacestode or adult tapeworm infections. Whereas most clade A acephalic
      metacestodes from dogs were asexually proliferative, clade A tetrathyridia
      isolated from wild deer mice did not show evidence of asexual replication. Our
      study supports the hypothesis that a second, as of yet unidentified, intermediate
      host is necessary to complete the life cycles of Mesocestoides spp., and that
      acephalic metacestodes represent an aberrant form, incapable of further
      development.

PMID- 15040676
TI  - Female biased parasitism and the importance of host generation overlap in a
      sexually transmitted parasite of beetles.
AB  - Sexual transmission is a widespread means of infection, but apart from those in
      humans, the ecology of sexually transmitted organisms is not well known. In this
      study, we present an ecological study of a sexually transmitted mite, Parobia
      husbandi Seeman and Nahrung (Acari: Podapolipidae), that lives beneath the elytra
      of Chrysophtharta agricola (Chapuis) (Coleoptera: Chrysomelidae). In each of 2
      yr, prevalence of mites on beetles began each spring at about 10-20% but
      gradually increased to 80-100% by late summer. Overlap of adult beetle
      generations at this time (i.e., the parental generation mating with the F1
      generation) is essential for the persistence of these mites. Mites exhibited
      temporal change in their spatial distribution on beetles; these changes were
      probably a response to beetle activity (e.g., emergence from diapause) and the
      need for dispersal from parental to F1 generation beetles. Prevalence and mean
      intensity of mites was higher on female beetles compared with male beetles.
      Female bias of sexually transmitted infection has been predicted in animals but
      hitherto observed only in primates. We speculate that variable male mate-finding
      success is the cause of these sex-based differences of mite infections, and that
      female bias in sexually transmitted disease (STD) infection will be widespread in
      the animal kingdom.

PMID- 15040677
TI  - Variation of the internal transcribed spacer 1 sequence within individual strains
      and among different strains of Neospora caninum.
AB  - Small differences have been reported in the internal transcribed spacer 1 (ITS1)
      region among strains of Neospora caninum. We compared ITS1 sequences among 6 N.
      caninum strains analyzed in our laboratory, including 2 strains that have not
      been examined previously (NC-Illinois and NC-Bahia). Five sequences showed 100%
      similarity and also were identical to 7 of 11 sequences that were previously
      reported by others. In contrast, initial attempts to sequence the ITS1 of NC
      Bahia generated 12 nucleotide differences compared with the other 5 strains, and
      several ambiguous bases. However, the single band containing the ITS1 region, as
      observed after electrophoresis on a 2% agarose gel, became divided into 2
      distinct bands when reanalyzed using 5 or 10% polyacrylamide gel electrophoresis
      (PAGE), and the ITS1 within these separate bands were sequenced without
      ambiguity. The other 5 N. caninum strains were also reexamined using PAGE, and in
      each strain 2 distinct bands were discovered. In comparison, 2 strains of
      Toxoplasma gondii continued to show only 1 band when examined using PAGE. The
      ITS1 sequence of NC-Bahia, from Brazil, differs in several base pairs from those
      of North American and European strains of N. caninum. Intrastrain variation of
      the ITS1 region appears to be common in N. caninum, in contrast to T. gondii.

PMID- 15040678
TI  - Isolation and characterization of gangliosides from Trypanosoma brucei.
AB  - Gangliosides were isolated from Trypanosoma brucei and analyzed by thin-layer
      chromatography (TLC) and TLC immunostaining test. Four species of gangliosides,
      designated as G-1, G-2, G-3, and G-4, were separated by TLC. G-1 ganglioside had
      the same TLC migration rate as GM3. In contrast, G-2, G-3, and G-4 gangliosides
      migrated a little slower than GM1, GD1a, and GD1b, respectively. To characterize
      the molecular species of gangliosides from T. brucei, G-1, G-2, G-3, and G-4
      gangliosides were purified and analyzed by TLC immunostaining test with
      monoclonal antibodies against gangliosides. G-1 ganglioside showed the reactivity
      to the monoclonal antibody against ganglioside GM3. G-2 was recognized by the
      anti-GM1 monoclonal antibody. G-3 showed reaction with the monoclonal antibody to
      GD1a. G-4 had the reactivity to anti-GD1b monoclonal antibody. Using 4 kinds of
      monoclonal antibodies, we also studied the expression of GM3, GM1, GD1a, and GD1b
      in T. brucei parasites. GM3, GM1, GD1a, and GD1b were detected on the cell
      surface of T. brucei. These results suggest that G-1, G-2, G-3, and G-4
      gangliosides are GM3 (NeuAc alpha2-3Gal beta1-4Glc beta1-1Cer), GM1 (Gal beta1
      3GalNAc beta1-4[NeuAc alpha2-3]Gal beta1-4Glc beta1-1Cer), GD1a (NeuAc alpha2
      3Gal beta1-3GalNAc beta1-4[NeuAc alpha2-3]Gal beta1-4Glc beta1-1Cer), and GD1b
      (Gal beta1-3GalNAc beta1-4[NeuAc alpha2-8NeuAc alpha2-3]Gal beta1-4Glc beta1
      1Cer), respectively, and also that they are expressed on the cell surface of T.
      brucei.

PMID- 15040679
TI  - Two new species of Cardicola (Digenea: Sanguinicolidae) in drums (Sciaenidae)
      from Mississippi and Louisiana.
AB  - Two new species of Cardicola (Digenea: Sanguinicolidae) are described from the
      heart of drums (Perciformes: Sciaenidae) in and off Mississippi and Louisiana.
      Cardicola palmeri n. sp. infects the black drum, Pogonias cromis, and, in mature
      individuals, is distinguished from its congeners by the combination of a body 1.9
      2.9 times longer than wide, an esophagus 44-52% of the body length, posterior
      ceca 1.0-1.8 times longer than the anterior ones, a gland encircling the seminal
      vesicle that is 30-37% of maximum body width in diameter, and a sinistral and
      nearly medial male pore. Cardicola currani n. sp. infects the red drum, Sciaenops
      ocellatus, and is distinguished from its congeners by the combination of
      posterior ceca 1.8-4.2 times longer than anterior ones, a male pore located well
      posterior to the ootype, a female pore and transverse metraterm located just
      anterior to the level of the ootype, and a medial and posttesticular ovary
      located at the level of the terminal ends of the posterior ceca. No adult blood
      fluke had been described previously from the northern Gulf of Mexico west of
      Florida. Each of the 2 flukes infected only 1 host species despite the hosts
      being sympatric.

PMID- 15040680
TI  - Parapharyngodon duniae n. sp. (Nematoda: Pharyngodonidae) in Phrynohyas venulosa
      (Anura: Hylidae) from the Area de Conservacion Guanacaste, Guanacaste, Costa
      Rica.
AB  - Parapharyngodon duniae n. sp. (Nematoda: Pharyngodonidae) in the large intestine
      of the veined tree frog, Phrynohyas venulosa, from the Area de Conservacion
      Guanacaste in northwestern Costa Rica is described and illustrated.
      Parapharyngodon duniae n. sp. represents the 34th species assigned to the genus,
      the 10th species from the Neotropical Realm, and only the third species to
      parasitize anurans. It is distinguished from the other Neotropical species by
      having postbulbar ovaries and a prebulbar excretory pore.

PMID- 15040681
TI  - Cosmocerca vrcibradici n. sp. (Ascaridida: Cosmocercidae), Oswaldocruzia vitti n.
      sp. (Strongylida: Molineoidae), and other helminths from Prionodactylus
      eigenmanni and Prionodactylus oshaughnessyi (Sauria: Gymnophthalmidae) from
      Brazil and Ecuador.
AB  - Cosmocerca vrcibradici n. sp. and Oswaldocruzia vitti n. sp., intestinal
      parasites of Prionodactylus eigenmanni (type host) and P. oshaughnessyi, are
      described and illustrated. Of the 19 valid species of Cosmocerca, C. vrcibradici
      n. sp. represents the 12th Neotropical species and the first species to be
      reported from lizard hosts. Of the 76 valid species of Oswaldocruzia, O. vitti n.
      sp. represents the 14th Neotropical species and the eighth species to be reported
      from lizard hosts. In addition, 1 species of Digenea, Mesocoelium monas, and 1
      species of Acanthocephala, Acanthocephalus saurius, were found.

PMID- 15040682
TI  - The first complete monogenean ribosomal RNA gene operon: sequence and secondary
      structure of the Gyrodactylus salaris Malmberg, 1957, large subunit ribosomal RNA
      gene.
AB  - The sequence of the Gyrodactylus salaris Malmberg, 1957, large subunit, or 28S,
      ribosomal RNA (rRNA) gene has been determined. This gene is the final portion of
      the Gyrodactylus rRNA gene operon to be sequenced and results in the first
      complete sequence of all rRNA genes and spacers from a monogenean. The nucleotide
      sequence was used to predict the secondary structure of the large subunit rRNA,
      and regions of conserved and variable sequence and structure were identified. The
      site where the 5' terminus of the 5.8S rRNA binds to a region within the large
      subunit rRNA was predicted and complements the anticipated interaction of the 3'
      terminus of the 5.8S with the 5' terminus of the large subunit rRNA. The large
      subunit gene may be useful in phylogenetic analysis of the Monogenea or
      Platyhelminthes and comparisons with other eukaryotes. The variable domains C and
      H may be most suitable for this purpose.

PMID- 15040684
TI  - Use of monoclonal antibodies for flow cytometric detection of intracellular
      Toxoplasma gondii in murine splenic lymphocytes.
AB  - Various monoclonal antibodies (mAbs) against Toxoplasma gondii RH tachyzoites
      were used for flow cytometric detection of intracellular parasites in murine
      splenic lymphocytes. Tg110 and Tg563 (reacting with the major surface protein
      SAG1), Tg505 (with another surface protein SAG2), Tg695 and Tg786 (with rhoptry
      proteins), Tg507, Tg621, and Tg317 (with dense granule proteins), Tg536 (with a
      microneme protein), and Tg685 (with a cytosol antigen) were the mAbs used. After
      an in vitro infection of lymphocytes with tachyzoites and reactions with the
      different mAbs, flow cytometry was performed using an indirect immunofluorescent
      technique. The proportions of whole infected lymphocytes and of each infected
      lymphocyte phenotype, CD4+ T cells, CD8+ T cells, and B cells, were determined,
      and their fluorescent intensities were quantified. The best reaction was seen
      when Tg110 or Tg695 was used as the mAbs. The results suggest that mAbs against
      surface or rhoptry proteins are highly useful for the flow cytometric detection
      of intracellular T. gondii in host cells.

PMID- 15040683
TI  - Plasmodium yoelii: identification and partial characterization of an MDR1 gene in
      an artemisinin-resistant line.
AB  - The molecular mechanisms by which the malarial parasite has managed to develop
      resistance to many antimalarial drugs remain to be completely elucidated.
      Mutations in the pfmdr1 gene of Plasmodium falciparum, as well as an increase in
      pfmdr1 copy number, have been associated with resistance to the quinoline
      containing antimalarial drugs. We investigated the mechanisms of drug resistance
      in Plasmodium using a collection of P. yoelii lines with different drug
      resistance profiles. The mdr1 gene of P. yoelii (pymdr1) was identified and
      characterized. A 2- to 3-fold increase in the pymdr1 gene copy number was
      observed in the P. yoelii ART line (artemisinin resistant) when compared with the
      NS parental line. The pymdr1 gene was mapped to a chromosome of 2.1 Mb in all
      lines analyzed. Reverse transcriptase-polymerase chain reaction and Western blot
      experiments confirmed the expression of the gene at the RNA and protein levels.

PMID- 15040685
TI  - Molecular characterization of a Cryptosporidium isolate from a banded mongoose
      Mungos mungo.
AB  - Cryptosporidium spp. has been found in more than 150 species of mammals, but
      there has been no report in mongooses. In this study, we report the isolation of
      Cryptosporidium sp. in a banded mongoose Mungos mungo, which was brought from
      Tanzania to Japan; the isolate was analyzed genetically to validate the
      occurrence of a new, host-adapted genotype. Cryptosporidium diagnostic fragments
      of 18S ribosomal RNA and 70-kDa heat shock protein genes were amplified from this
      isolate and compared with the other Cryptosporidium species and genotypes
      reported previously. Analyses showed that the mongoose isolate represents a new
      genotype, closely related to that of bears.

PMID- 15040686
TI  - Paleoparasitological analysis of coprolites from K2, an Iron Age archaeological
      site in South Africa: the first finding of Dicrocoelium sp. eggs.
AB  - Until now, Dicrocoelium sp. eggs have only been recorded from European and 1
      North American archaeological sites. We present evidence for the first record of
      Dicrocoelium sp. from an African archaeological site. A paleoparasitological
      study was conducted on 7 coprolite samples from K2, a Late Iron Age site on the
      farm Greefswald, in the Northern Province of South Africa. Standard
      parasitological analysis revealed the presence of Dicrocoelium sp. and Trichuris
      sp. eggs. Today, the parasite does not occur in this region. Trichurid eggs are a
      relatively common find in paleoparasitological analysis. The presence of
      Dicrocoelium sp. provides new clues about the antiquity of this parasite, as well
      as aspects of ancient environment, climate, and interactions among humans,
      animals, and parasites.

PMID- 15040687
TI  - Parasitic helminths of black bear cubs (Ursus americanus) from Florida.
AB  - Twenty-two Florida black bear (Ursus americanus floridanus) cubs (< or = 12 mo
      old) from Florida were examined for endoparasites between 1998 and 2003. Eleven
      species of helminths were found (8 nematodes, 2 trematodes, and 1
      acanthocephalan). The most prevalent helminths were Ancylostoma caninum (64%),
      Macracanthorhynchus ingens (36%), Strongyloides sp. (27%), Baylisascaris
      transfuga (23%), and A. tubaeforme (14%). New host records include A. tubaeforme
      and Brachylaima virginianum. This is the first report of B. transfuga in black
      bears from Florida.

PMID- 15040688
TI  - Muscular anatomy and aspects of the structure of the antennae of Anthosoma
      crassum (Dichelesthiidae: Siphonostomatoidae: Copepoda).
AB  - The muscular anatomy and fine structure of the antennae of adult Anthosoma
      crassum are described from specimens collected from jaws of shortfin makos.
      Casual observations of live parasites showed that embedded adult A. crassum can
      move toward or away from the host by shortening or lengthening the antennae,
      respectively. These movements were controlled by antennal retractor muscles.
      Microprotuberances located on the distal antennal segments may increase friction
      between these copepods and their hosts, thus strengthening parasite attachment.

PMID- 15040689
TI  - Pathogenicity of the gill artery worm Philometra obturans (Nematoda) in northern
      pike (Esox lucius) in southwest Finland.
AB  - The pathogenicity of female Philometra obturans (Prenant, 1886) was investigated.
      Fish samples were taken in May and June 2001 from Lake Littoistenjarvi, in
      southwest Finland. The intensity of infection varied between 1 and 4 worms, these
      being found in the afferent artery of the 2 outermost gill arches. The prevalence
      was 33.9% (n = 59). Host condition and tissue reactions were investigated through
      dissection and analysis of histopathology. The parasites obstructed the gill
      arteries, and the arterial wall was stretched around intact worms. Hypertrophy of
      the arterial wall was observed, especially when only disintegrating remains of
      the parasites were present. Infected pike were in a poorer condition after catch,
      transportation, and holding in aquaria and thus less tolerant to stress than
      uninfected pike. This was correlated with the number of infected gill arteries (P
      < 0.05). The results show that infection with this nematode has a detrimental
      effect on the host when combined with environmental or physiological stress and
      may result in host mortality.

PMID- 15040691
TI  - Occurrence of Ergasilus megaceros Wilson, 1916, in the sea lamprey and other
      fishes from North America.
AB  - Ergasilus megaceros (Copepoda: Ergasilidae) was recovered from the nasal fossae
      (lamellae) of the olfactory sac in 1 (1.8%) of 56 sea lampreys, Petromyzon
      marinus Linne, 1758, collected in May 2002 from the Cheboygan River, Michigan.
      Although the sea lamprey is a new host record for E. megaceros, this fish species
      may not be a preferred host because of its low prevalence. Ergasilus megaceros is
      the second ergasilid species reported from the sea lamprey in North America. This
      is the third report of an ergasilid species infecting the nasal fossae of fishes
      in North America, with E. rhinos being the only other species reported from this
      site.

PMID- 15040690
TI  - Variation of circumsporozoite 26 and 29 genotypes of Plasmodium falciparum
      infecting patients and association with HLA-DQA allotypes in western Thailand.
AB  - We evaluated the proportion of variants of circumsporozoite protein (cp) gene 26
      and cp29 antigenic epitopes of Plasmodium falciparum infecting patients among 3
      provinces in western Thailand, in addition to published variants from Gambia. The
      proportion of patients coinfected with cp26 and cp29 strains was significantly
      higher in patients reporting to malaria clinics in Tak than in Kanchanaburi and
      Ratchaburi and higher in Kanchanaburi than in Ratchaburi. In western Thailand,
      coinfection with cp26 and cp29 appears to increase with increasing latitude.
      There were also significant differences in proportion of these variants among
      Thai provinces and Gambia. An association of patient human leukocyte antigen
      (HLA) class II genotype was associated with P. falciparum strains. There were
      significant associations among the HLA-DQA alleles in patients, the province of
      origin, and cp variants of P. falciparum.

PMID- 15040692
TI  - Molecular characterization of the first internal transcribed spacer of ribosomal
      DNA of the most common species of eyeworms (Thelazioidea: Thelazia).
AB  - Spirurid nematodes of the genus Thelazia cause ocular infection in several
      mammals and are transmitted by dipteran flies. Of the 10 described species, T.
      gulosa, T. rhodesi, T. skrjabini (affecting cattle), T. lacrymalis (affecting
      horses), and T. callipaeda (affecting carnivores and humans) are the most common.
      The aim of this study was to characterize the first internal transcribed spacer
      (ITS1) ribosomal DNA sequences of these 5 species. The length of the ITS1
      sequences ranged from 357 bp (T. lacrymalis) to 905 bp (T. callipaeda).
      Interspecific differences ranged from 35 to 77%. Polymorphic sites were detected
      in each species. Intraspecific variation varied from 0.3 to 2.5%. The
      characteristics of the ITS1 of Thelazia spp. show similarities to those of other
      Spirurida. The findings of this present study show that the ITS1 represent a
      powerful genetic marker for the molecular identification of eyeworms and a useful
      tool for developing molecular epidemiological techniques to study Thelazia spp.
      transmission patterns and prevalence in definitive and intermediate hosts.

PMID- 15040693
TI  - Expanded geographical range, new host accounts, and observations of the nematode
      Gyrinicola batrachiensis (Oxyuroidea: Pharyngodonidae) in tadpoles.
AB  - We describe the first account of the nematode Gyrinicola batrachiensis in the
      gastrointestinal tracts of tadpoles of Bufo terrestris, Gastrophryne
      carolinensis, Hyla femoralis, H. squirella, Rana heckscheri, and R. utricularia.
      Infection by G. batrachiensis was also noted in tadpoles of R. catesbeiana and R.
      clamitans, species previously described as harboring these nematodes. These
      observations represent a major expansion of the known geographical range of G.
      batrachiensis to include the southeastern United States. In our study, female G.
      batrachiensis nematodes in ranid host species were didelphic, but females in B.
      terrestris tadpoles were monodelphic. Furthermore, only female nematodes were
      found in the latter host species. Such variations in nematode uterine morphology
      and sex ratios among these tadpole host species are in accordance with the
      apomictic and haplodiploid reproductive strategies previously reported for G.
      batrachiensis. These observations also support a generalized pattern relating G.
      batrachiensis reproductive modes and the life cycles of their tadpole hosts.

PMID- 15040694
TI  - A new nested polymerase chain reaction method very efficient in detecting
      Plasmodium and Haemoproteus infections from avian blood.
AB  - Recently, several polymerase chain reaction (PCR)-based methods for detection and
      genetic identification of haemosporidian parasites in avian blood have been
      developed. Most of these have considerably higher sensitivity compared with
      traditional microscope-based examinations of blood smears. These new methods have
      already had a strong impact on several aspects of research on avian blood
      parasites. In this study, we present a new nested PCR approach, building on a
      previously published PCR method, which has significantly improved performance. We
      compare the new method with some existing assays and show, by sequence-based
      data, that the higher detection rate is mainly due to superior detection of
      Plasmodium spp. infections, which often are of low intensity and, therefore, hard
      to detect with other methods.

PMID- 15040696
TI  - The transmission of Haemoproteus belopolskyi (Haemosporida: Haemoproteidae) of
      blackcap by Culicoides impunctatus (Diptera: Ceratopogonidae).
AB  - Haemoproteus belopolskyi of blackcap, Sylvia atricapilla, underwent sporogony in
      wild-caught female biting midges, Culicoides impunctatus, which were
      experimentally infected by feeding them on naturally infected birds. The engorged
      flies were held for 8-12 days to allow development of sporozoites and then
      aspirated and triturated in 0.85% saline. Seven uninfected nestlings of blackcap
      at the age of 20-21 days were inoculated into the pectoral muscle with 0.3 ml of
      the slurry containing approximately 45 sporozoites. Parasitemia of H. belopolskyi
      developed in 6 nestlings, with a prepatent period of 11-12 days. The maximum
      parasitemia varied between 0.9 and 16% of erythrocytes in different experimental
      hosts. Culicoides impunctatus is an experimental vector of H. belopolskyi. It is
      likely to be the important natural vector of Haemoproteus spp. of passerine birds
      in Europe.

PMID- 15040695
TI  - Detrimental effects of Haemoproteus infections on the survival of biting midge
      Culicoides impunctatus (Diptera: Ceratopogonidae).
AB  - The effects of Haemoproteus belopolskyi, Haemoproteus fringillae, and
      Haemoproteus lanii on the survival of their vector the biting midge Culicoides
      impunctatus were examined. Wild-caught females were infected experimentally by
      allowing them to feed on naturally infected birds. A group of flies, which fed on
      an uninfected bird, was used as a control. There was a highly significant
      difference in the survival rate between the noninfected group and all groups of
      infected flies for postfeeding (PF) periods 1-2, 3-4, 5-6, and 7-8 days. For days
      7-8, the percentage of noninfected surviving flies was 4.4 times higher than the
      percentage of infected surviving flies, testifying to the detrimental effects of
      avian Haemoproteus infections on the longevity of C. impunctatus. The mortality
      rates of the infected flies were highest for days 1-2 and 3-4 PF, indicating
      possible negative effects of ookinetes and early oocysts on the vector.

PMID- 15040698
TI  - Erroneous reports of the neotropical Echinococcus oligarthrus as a cause of
      echinococcosis in India.
AB  - Two cases of submandibular echinococcosis have been reported in adult residents
      of India (Kini et al., 1997; Sahni et al., 2000). It was stated in both
      publications that the cestode was E. oligarthrus, "a rare variety of E.
      granulosus", based on morphogical characteristics. It was also mentioned that 3
      cases of E. granulosus with similar submandibular metacestode had been previously
      diagnosed in India. The metacestode is readily distinguishable from that of E.
      oligarthrus. The final hosts of E. oligarthrus are several neotropical species of
      wild cats and metacestode occurs in hystricognath, all of them absent in India.
      The larval stage of all 4 species of Echinococcus can be differentiated on the
      basis of the form and dimensions of rostellar hooks of protoescoleces. With the
      information provided in the two papers we concluded that the 2 cases of
      echinococcosis described in India were due to E. granulosus.

PMID- 15040697
TI  - Temporal allozyme divergence in infrapopulations of the hemiurid fluke
      Lecithochirium fusiforme.
AB  - The effect of time on genetic differentiation was studied among infrapopulations
      of mature specimens of the hemiurid fluke, Lecithochirium fusiforme, a parasite
      of marine fishes. Genetic distances and genetic structure within and among
      different temporal samples of a geographical population were investigated using
      starch gel electrophoresis, by screening 6 polymorphic loci in 2 groups of
      infrapopulations corresponding to different sampling data, i.e., winter 1997-1998
      and autumn 1998. The genetic distance among infrapopulations was low (D = 0.000
      0.058 +/- 0.041). However, genetic divergence among infrapopulations from the
      same geographic location was clearly lower within each temporal sample (G(ST) =
      0.021 and 0.034) than the corresponding value obtained for 12 infrapopulations
      sampled at different seasons of the year (G(ST) = 0.067). These results suggest
      the existence of a relatively important temporal effect that accounts for the
      differences in genetic variability among adult infrapopulations of L. fusiforme.
      Therefore, a hypothetical temporal gene flow favored by the existence of
      persistent life-cycle stages of this species in paratenic hosts is not sufficient
      to mask the temporal differentiation caused by genetic drift.

PMID- 15040699
TI  - [The treatment of leprosy in 2003].

PMID- 15040700
TI  - [Histoid leprosy with erythema nodosum leprosum].
AB  - Histoid leprosy is a particular variant of lepromatous leprosy presenting as
      cutaneous or subcutaneous nodular and/or plaque-like lesions arising form
      apparently normal skin. It is characterized histologically by spindle-shaped
      histiocytes in interlacing bundles and whorls, containing numerous intact and rod
      shaped Mycobacterium leprae. It can occur de novo or secondary in patients
      treated for a long course by dapsone alone. We describe a case of lepromatous
      leprosy treated according to the national Moroccan protocol who developed histoid
      lesions during his treatment by dapsone. The patient responded well to
      fluoroquinolone, rifampicin and clofazimine, with however, the occurrence of
      erythema nodosum leprosum.

PMID- 15040701
TI  - Antibodies to diverse lipids in the serum of patients with clinically cured
      leprosy and tuberculosis.
AB  - In this study we looked for the presence of antibodies to cardiolipin,
      cerebrosides, and whole lipids extracted from M. leprae, M. tuberculosis and M.
      habana, in the serum of patients with clinically cured lepromatous leprosy
      (sixteen) or tuberculosis (sixteen), 8 to 12 months after arresting the
      corresponding multi-drug therapy (MDT). Compared to healthy controls (sixteen),
      both leprosy and tuberculosis ex-patients had still significant levels of
      antibodies to the three mycobacterial lipids but no detectable levels of
      antibodies to cardiolipin or cerebroside lipids. Although leprosy and
      tuberculosis sera recognized the homologous mycobacterial lipids in a
      preferential fashion, all of them, on the average, reacted more strongly with the
      lipids of M. habana. This observation backs up, in a certain way, the proposition
      of using M. habana as a prospective vaccine for leprosy and tuberculosis.

PMID- 15040702
TI  - [Pentoxifylline in the treatment of erythema nodosum leprosum: results of an open
      study].
AB  - Erythema nodosum leprosum (ENL) is a well-known immunological serious
      complication affecting lepromatous multibacillary leprosy patients. For a long
      time, ENL has been regarded as an immune complex-mediated disease or Arthus
      phenomenon. Recently, it has been reported that ENL was associated with high
      serum tumor necrosis factor-alpha (TNFa) levels, suggesting that this cytokine
      could also play a central role in the manifestations of ENL. Thalidomide (TH) and
      systemic steroids (S), both TNFa production inhibitors, are the two current
      effective drugs for the management of ENL. However, TH is rarely available in
      leprosy endemic countries, and its teratogenicity and neurotoxicity strongly
      limit its use. Moreover, the morbidity of S and the frequent steroid-dependence
      of ENL also create real therapeutic problems. Recently, the efficacy of
      pentoxifylline (PTX), which also inhibits in vitro and in vivo production of
      TNFa, has been suggested for ENL treatment. We report our experience on its use
      for the treatment of 15 leprosy patients suffering from a first ENL. attack. (11
      cases), a chronic steroid-dependent ENL (3 cases) or chronic steroid- and
      thalidomide-dependent ENL (1 case). PTX has been given at 800 mg t.i.d, (2 cases)
      or 400 mg t.i.d. (13 cases) doses. The patients received PTX at the initiating
      dosage until complete clinical cure. At the end of ENL attacks, PTX was either
      abruptly stopped or tapered down over the next 4 months. In ten of 11 patients
      who developed ENL for the first time, the systemic symptoms and neuritic pains
      disappeared within one week; at three weeks, half of the patients were cured and
      the other half had striking clinical improvement; complete cure was obtained
      within 7 to 35 days (mean: 27 days). A relapse occurred within 2-3 months in the
      5 patients, in which PTX was abruptly stopped. In contrast, no relapse occurred
      in the patients who benefited from decreasing doses of PTX. Recurrent ENL
      episodes also responded well to PTX. The 3 patients who had chronic steroid
      dependent ENL failed to show any improvement after 3 to 6 weeks of PTX. In
      contrast, steroid therapy could be stopped in the steroid- and thalidomide
      dependent patient. Our results confirm the action of PTX if it is slowly tapered
      down (4 months seem sufficient) and not abruptly to avoid relapses. As it is safe
      use, PTX could constitute the first line of ENL attack treatment.

PMID- 15040703
TI  - Pattern of bacillary clearance in multibacillary leprosy patients with multidrug
      therapy.
AB  - The bacteriological index (BI) of the skin smears is traditionally one of the
      important parameters of assessment of severity and of progress of leprosy under
      multidrug therapy. The present study reports on BI clearance among 578
      multibacillary treated leprosy patients and the factors that influence this
      clearance. The patients were treated till smear negativity or for 2 years fixed
      duration and their skin smears periodically examined every 6 to 12 months till
      negativity (and even afterwards). We confirm that bacterial clearance is a slow
      process. The time taken for each log-unit decline in BI is between 13.6 to 24
      months probably depending on initial BI level. The rate of smear negativity
      appears to be dependent on immune competence of the patients as reflected by a
      rapid BI decline in borderline BT-BB patients vis-a-vis BL-LL lepromatous
      patients both in the low and high BI group. Patients who had several episodes of
      ENL, took significantly longer time (63.7 months versus 53.5 months, p<0.0001) to
      become smear negative than those without ENL.

PMID- 15040704
TI  - The changing world of long-term care: a state perspective.
AB  - Based on data from an eight year longitudinal study of Ohio's long-term care use
      patterns, this paper describes the changes now being experienced by this
      industry. Although Ohio has been a state with a heavy reliance on institutional
      services, the data suggest a change in how long-term care is provided in the
      state. Over the past eight years, despite an increasing disabled older
      population, nursing home occupancy rates have fallen from 92.5% to 83.5%. At the
      same time, in-home service and assisted living use has increased. The paper
      concludes by describing how such changes are likely to impact the system of the
      future.

PMID- 15040705
TI  - The potential of the SSI program to reduce poverty among the elderly.
AB  - Is it more effective to reduce poverty among the elderly by increasing the
      benefits paid by the Supplemental Security Income (SSI) program or by increasing
      eligibility for the program? This paper answers that question from a
      policymaker's perspective. At given program cost levels, we compare the potential
      reduction in poverty from increasing benefit levels to the potential reduction
      associated with a variety of policy proposals that would increase eligibility for
      the program. This paper employs a microsimulation model containing an eligibility
      and benefits calculator, a participation model, and an optimization algorithm.
      The data are from the Survey of Income and Program Participation supplemented by
      the administrative records of the SSI program. The results show that increasing
      eligibility by relaxing the restrictions of the means tests can be more effective
      in reducing poverty than raising benefit levels.

PMID- 15040706
TI  - Health care for older persons in Singapore: integrating state and community
      provisions with individual support.
AB  - Health care policy in Singapore is similar to that in the United States and the
      United Kingdom, where a residualist strategy is used to pass health care costs to
      individuals and their families, the rationale being that this enables the state
      to concentrate on devolution of care to the community and ensure efficient and
      affordable service to all Singaporeans. The services include public restructured
      hospitals and outpatient poly-clinics as well as community services such as
      community hospitals and hospitals for the chronically ill, nursing homes, day
      care centers, and home help services. Availability does not translate into
      optimum usage because current and potential users and their families are not able
      to match their financial and social resources with the services. Instead, the
      state acts as the case manager and places parameters on what individuals can
      access.

PMID- 15040708
TI  - National policy approaches to social care for elderly people in the United
      Kingdom and Singapore 1945-2002.
AB  - The authors compare policy approaches in the United Kingdom and Singapore on
      social care for older persons. The context of these approaches is discussed
      showing the development of policies, in each country from the aftermath of the
      Second World War to the present. Given that Singapore is a former British colony,
      it is of interest to scholars of social policy to examine its welfare approach as
      compared to the welfare state approach espoused by the United Kingdom. Both
      nations are faced with the challenges of an aging population, which necessitates
      handling similar problems with strategies that are in harmony with their
      respective economic, social, and cultural contexts. This paper considers their
      divergence of philosophies and policies, concluding with the recognition that the
      major difference lies in national and governmental expectations regarding the
      extent of the financial and regulatory responsibility for care for older people
      carried by the individual, the family, and the state.

PMID- 15040707
TI  - Health care reform and older adults: notes from the Polish experience.
AB  - Poland enacted in 1997 legislation that founded a health care system in which
      health insurance societies contract with providers to deliver health services to
      the insured population. Through a review of the new statutes, interviews with key
      informants, analysis of public opinion polls and surveys of insurance
      administrators and health care workers, we examined the impact of reform on
      Poland's older citizens. The findings indicate that older adults are likely to be
      adversely affected by the inadequacies of insurance premiums as a source of
      finance, the lack of emergent private medical enterprise, and the failure to
      eradicate private health in its earlier, black market incarnation.

PMID- 15040709
TI  - Difficulties in diagnosing the vegetative state.

PMID- 15040710
TI  - Concepts of neurosurgical management of chronic subdural haematoma: historical
      perspectives.
AB  - The history of chronic subdural haematoma (CSH), spanning from its possibly
      earliest beginnings throughout the centuries until the early 1980s, was
      investigated within the context of four different epochs. In the 'era of
      uncertainty', successful trephination, the modem method of choice for the
      treatment of CSH, was developed by neolithic men. Various historical sources
      indicate that patients with CSH might have undergone surgery at that time. CSH
      might have been one of the ailments that had spectacular courses of salvation
      after trephination. The entity of CSH was first described in the 'era of
      pioneers' in the seventeenth century by Johann Jacob Wepfer. The misconception of
      'pachymeningitis hemorrhagica interna' was introduced by Rudolf Virchow in 1857.
      By the end of the nineteenth century it became more widely accepted that trauma
      was a possible cause of CSH. Successful neurosurgical treatment of CSH was first
      reported by Hulke in 1883. Putnam and Cushing, in 1925, focused on surgery as the
      treatment of choice for CSH. In the 'era of diagnostic refinement', the
      introduction of pneumencephalography and angiography allowed the diagnosis of CSH
      much earlier. Subsequently, the typical signs and symptoms of patients suffering
      from CSH changed from apathy and coma to headaches and discrete focal
      neurological symptoms. In the 'era of surgical routine', neurosurgical approaches
      became smaller and less invasive. Removal of the haematoma was identified as the
      primary goal of surgery. The use of closed system drainage markedly improved
      reexpansion of the brain after surgery. Burr hole craniostomy and twist drill
      craniostomy became the surgical treatment of first choice because of their low
      morbidity and mortality. There is growing evidence, however, that the
      neurosurgical learning curve has reached a plateau.

PMID- 15040711
TI  - Deep brain stimulation of the subthalamic nucleus in Parkinson's disease 1993
      2003: where are we 10 years on?
AB  - Since its advent in 1993, high frequency stimulation (HFS) of the subthalamic
      nucleus (STN) has rapidly developed into the most commonly practiced surgical
      procedure for the treatment of Parkinson's Disease (PD). Although its exact
      mechanism of action, be it through an inhibitory depolarization block,
      desynchronization of neuronal circuits or other means, is not clear, the efficacy
      and safety of the technique are now well established. HFS of the STN improves the
      motor function by at least 60%, drastically reduces the levodopa requirement and
      significantly improves the quality of life in PD. This review updates the recent
      concepts on the pathophysiology of PD and analyses the basic science principles
      underlying the clinical practice of the STN HFS. The evolution of the surgical
      technique and long-term patients' outcome are further discussed.

PMID- 15040712
TI  - Phenytoin penetration into chronic subdural haematomas.
AB  - The pathophysiology of chronic subdural haematomas (CSH) is still unclear. In the
      light of recent ultrastructural examination, exudation from the macrocapillaries
      in the outer membrane of CSH may play an important role in the enlargement of
      CSH. In this study, exudation from the macrocapillaries was assessed by the
      measurement of phenytoin, a protein-bound antiepileptic agent used in cases of
      CSH. In 22 patients, 1 h after the administration of 250 mg of phenytoin
      intravenously, blood and subdural haematoma samples were taken and phenytoin
      levels were measured. The ratio of subdural haematoma level to the blood
      phenytoin level was determined and defined as the phenytoin penetration ratio
      (PPR). The correlation between the phenytoin penetration ratio and clinical
      neurological grades (Markwalder and Glasgow Coma Scale), age of the patients and
      the CT appearance of CSH were investigated. The mean phenytoin penetration ratio
      was 19.5%. As the neurological grades of patients increased, average PPR also
      increased. The average PPR values were 17.64 and 20.84% in the patients younger
      than 60 years (nine patients) and older patients (13 patients), respectively.
      Mean PPRs in the groups according to the CT appearance were as follows: low
      density 11.21% (seven patients), isodensity in 15.88% (10 patients), high density
      in 38.5% (five patients). A subdural reaccumulation was detected in nine patients
      with a mean PPR of 27.72%, while mean PPR was 14.56% in the others. Exudation
      from macrocapillaries in the outer membrane of chronic subdural haematomas
      probably plays an important role in the enlargement of chronic subdural
      haematoma, and measuring phenytoin levels in the chronic subdural haematoma is a
      simple method for the quantitative estimation of the exudation in CSH.

PMID- 15040713
TI  - Use of diffusion-weighted magnetic resonance imaging in empyema after
      cranioplasty.
AB  - External decompression can be an effective treatment for acute intracranial
      hypertension, but the cranial defect must be repaired. The most serious
      complication of cranioplasty is late infection. Confusing an empyema that occurs
      after cranioplasty with a fluid collection (haematoma or liquor) can have
      catastrophic consequences, such as the development of cerebritis. The goal of
      this study was to assess the ability of diffusion-weighted (DW) magnetic
      resonance imaging (MRI) to diagnose empyema after cranioplasty. DW MRI and
      apparent diffusion coefficient (ADC) maps were studied in six patients with
      surgically verified empyema after cranioplasty. The findings were compared with
      those in five patients who had surgically verified haematoma or liquorrhoea. In
      the patients with empyema, the lesion was hyperintense, whereas the fluid
      collections (haematoma and liquorrhoea) were visualized as hypointense lesions.
      The ADC maps showed that empyema had a significantly lower intensity than the
      fluid collections (haematoma or liquorrhoea). DW MRI can be used to identify
      empyema after cranioplasty and can help to differentiate it from other fluid
      collections. Hence, this is a useful additional imaging modality for the
      diagnosis of empyema after cranioplasty.

PMID- 15040714
TI  - After facial nerve damage, regenerating axons become aberrant throughout the
      length of the nerve and not only at the site of the lesion: an experimental
      study.
AB  - After facial nerve trauma, aberrant regeneration is associated with synkinesis.
      Animal models of mechanical nerve guides or reparative cell transplants at the
      site of a lesion have not been shown to improve disorganized regeneration. We
      examined whether this is because regenerating axons become disorganized
      throughout the length of the nerve and not only at the site of the lesion. In
      rats (n = 12), retrograde fluorescent tracer techniques were used to establish
      that most of the temporal branch fibres were carried in the superior half of the
      facial nerve trunk. In two further groups of rats (n = 24) a complete proximal
      facial nerve lesion was made, and the nerve immediately repaired by suture. After
      4 weeks, at a second operation, the superior half of the facial nerve trunk was
      cut, either proximal or distal to the original lesion, and retrograde tracers
      were applied to distal branches of the nerve. It was possible to localize the
      points at which regenerating fibres became aberrant in their course by studying
      the number of labelled motoneurons in the facial nucleus after application of the
      tracer to the temporal branch of the nerve: this was similar in the distal and
      proximal hemisection groups, suggesting that aberrant axonal development occurred
      throughout the length of the nerve. Future strategies aimed at improving the
      organization of regeneration need to provide guidance cues not only at the site
      of the lesion as previously thought, but also throughout the length of the nerve.

PMID- 15040715
TI  - Craniovertebral junction Pott's disease.
AB  - Pott's disease of the craniovertebral junction is extremely rare. The authors
      studied the immediate and long-term outcome after transoral decompression,
      occipitocervical stabilization with fusion and antitubercular therapy (ATT) in
      patients who had neurological deficits due to craniovertebral junction (CVJ)
      tuberculosis. This is a retrospective study of the management and outcome in 10
      consecutive patients in whom features of spinal cord (with or without)
      compression were observed, and CVJ tuberculosis was diagnosed in two different
      neurological departments between 1990 and 2002. They ranged in age from 15 to 72
      years. The onset of symptoms was either acute or subacute. Patients presented
      with neck and occipital pain (90%), progressive tetraparesia (40%), sensory
      symptoms (40%), neck stiffness (30%) and urinary dysfunction (20%). The disease
      caused spinal cord compression in six patients, atlantoaxial dislocation in five
      patients, basilar impression in one and upper vertebral column destruction
      without dislocation in three. Two patients presented with multiple spinal
      tuberculosis. Antitubercular therapy was used in all cases for 15 months.
      Surgical treatment performed in all patients. Four patients underwent transoral
      drainage of retropharyngeal abscess with granulation tissue and one
      odontoidectomy. Six patients then underwent occipitocervical (occiput -C3 or -C4)
      fusion with insertion of titanium plate and screw. Postoperatively, ATT was
      prescribed for 15 months. At long-term follow-up (median 50.2 months), functional
      status considerably improved. Two patients died 2 months later due to myocardial
      infarction. Patients with CVJ with features of cervical myelopathy are ideally
      treated with transoral decompressive procedures followed by occipitocervical
      fusion, because this therapy provides immediate neurological improvement,
      stability and allows early mobilization. The long-term prognosis in patients with
      this disease is excellent, provided it is treated with appropriate surgical
      intervention and with adequate duration of ATT. This approach provides excellent
      access to this region, with a low operative morbidity and no mortality.

PMID- 15040716
TI  - Link between vasogenic waves of intracranial pressure and cerebrospinal fluid
      outflow resistance in normal pressure hydrocephalus.
AB  - Recent studies on normal pressure hydrocephalus (NPH) have pointed to a possible
      link between the disturbance in CSF circulation and cerebrovascular factors. We
      investigated the quantitative relationship between the resistance to CSF outflow
      (Rcsf) and vasogenic waves of ICP in patients with normal pressure hydrocephalus.
      Forty-five patients with NPH were investigated by an infusion study. The
      magnitudes of vasogenic ICP components: pulse, respiratory and slow vasogenic
      waves were assessed, and compared with Rcsf. Both baseline respiratory and slow
      waves of ICP were positively correlated with Rcsf. The respiratory wave at
      baseline was a single independent predictor of Rcsf (r = 0.66, p < 0.0002). All
      vasogenic components increased significantly during the infusion test. The
      magnitude of the increase was positively correlated with Rcsf. The vasogenic ICP
      waves, notably the respiratory wave of ICP, correlate with the resistance to CSF
      outflow.

PMID- 15040717
TI  - Post-traumatic leptomeningeal cyst mimicking a skull tumour in an adult.
AB  - A 53-year-old female presented with a post-traumatic leptomeningeal cyst
      manifesting as bulging of the scalp, dizziness and tinnitus. She had known of the
      bulging of her forehead for about 20 years. She had suffered an injury to the
      head in childhood. Brain CT revealed a bone cyst associated with a round bone
      defect in the left frontal bone, bulging of the very thin outer layer and the
      defective inner layer. She was treated surgically with a diagnosis of skull
      tumour, but only gray cystic membranous tissue was found. The dural defect was
      repaired with fascia and the bone defect with bone cement. Bulging of the skull
      in adults can be caused by a bone cyst originating from a skull fracture.

PMID- 15040718
TI  - 'Disappearing' recurrent craniopharyngioma.

PMID- 15040719
TI  - A sphenoidal wing meningioma presenting as a subacute subdural haematoma.

PMID- 15040720
TI  - A case of spontaneous acute subdural haematoma in the posterior fossa following
      anticoagulation.

PMID- 15040721
TI  - Tonsillar herniation and syringomyelia secondary to a posterior fossa tumour.

PMID- 15040722
TI  - Acute transverse myelitis mimicking an intramedullary neoplasm.

PMID- 15040723
TI  - Cranial blade: retained for three years.

PMID- 15040724
TI  - Comment on Hussain et al.'s 'Cauda equina syndrome'.

PMID- 15040725
TI  - A novel colorimetric and fluorescent anion chemosensor based on the flavone quasi
      crown ether-metal complex.
AB  - The metal-ligand complex 1 ([Mg (L)] (2+)) (or 2 ([Ca (L)]( 2+))) was
      demonstrated to selectively bind HSO(4)(-) (or H(2)PO(4)(-)) over other anions by
      using UV-vis absorption and fluorescence spectroscopy. The studied complex
      exhibits the remarkable color change and fluorescence quenching upon introducing
      HSO(4)(-) (or H(2)PO(4)(-)) anion in acetonitrile. Both the mechanism and
      structure of the secondary complex of complex 1 with anion were proposed on the
      basis of theoretical computation.

PMID- 15040726
TI  - Controllable, selective per-functionalization of dendritic oligoamines.
AB  - A method allowing for an unprecedented controllable functionalization of
      oligoamines via N,N-bis-sulfonylation with various sulfonyl chlorides has been
      developed. Depending on the nature of the sufonyl chloride and reaction
      conditions such as base, time of reaction, and temperature, each amino group can
      be selectively mono- or bis-sufonylated. The procedure was investigated in detail
      with the model substance tris(2-aminoethyl)amine and applied for the preparation
      of dumbbell-shaped coupled dendrons and second-generation sulfonimide-decorated
      dendrimers.

PMID- 15040727
TI  - Versatile formation of [2]catenane and [2]pseudorotaxane structures; threading
      and noncovalent stoppering by a self-assembled macrocycle.
AB  - A self-assembled dimeric macrocycle between 4,4'-bis(4-pyridylmethoxy)biphenyl
      (L) and (en)Pd(NO(3))(2) was constructed, and its interactions with cyclodextrins
      of different cavity size resulted in the formation of [2]catenane and
      [2]pseudorotaxane systems, respectively. The structures were identified by 1D and
      2D NMR spectroscopy and cold spray ionization mass (CSI-MS) spectrometry.

PMID- 15040728
TI  - Synthesis of novel S-neoglycopeptides from glycosylthiomethyl derivatives.
AB  - Reaction of glycosylthiomethyl azides with amino acid and peptide derivatives
      containing aspartate and glutamate thio acids gave the corresponding
      glycosylthiomethyl amides in excellent yields. Another type of neoglycopeptides
      was obtained via reaction of glycosylthiomethyl bromide with cysteine and
      homocysteine containing peptide derivatives, thus affording the corresponding S
      (glycosylthiomethyl) peptides.

PMID- 15040729
TI  - Structure and photoluminescence of a benzil nanocolumn in a C
      methylcalix[4]resorcinarene-based framework.
AB  - A new framework based on C-methylcalix[4]resorcinarene and the flexible
      nonconjugated spacer 1,4-bis(imidazol-1yl-methyl)benzene encloses a large one
      dimensional channel, containing benzil nanocolumns. Unlike in a previously
      reported series of benzil-containing supramolecular solids with conjugated linker
      molecules, benzil luminescence is observed, but the lifetime of 580 ns at 77 K is
      considerably shorter than the 145 micros reported for neat benzil at room
      temperature.

PMID- 15040730
TI  - p-(1H-phenanthro[9,10-d]imidazol-2-yl)- substituted calix[4]arene, a deep cavity
      for guest inclusion.
AB  - The reaction of tetra-p-formyltetra-O-propylcalix[4]arene with
      phenanthrenequinone in the presence of NH(4)OAc affords compound 2, a new class
      of calixarene with an expanded aromatic cavity, that could be stabilized by
      hydrogen-bonded bridges and/or ion pairing, thus preventing collapse into fully
      stacked pinched cone conformations as depicted. Two partially protonated
      calixarenes interdigitate in the solid state to give rise to a self-assembled
      face-to-face dimer, stabilized by pi-pi stacking interactions.

PMID- 15040731
TI  - Helical chirality in donor-acceptor catenanes.
AB  - A [2]catenane in which the macrocyclic polyether, bisparaphenylene[34]crown-10,
      is interlocked with the tetracationic cyclophane, cyclobis(paraquat-p-phenylene),
      is shown by dynamic (1)H NMR spectroscopy, using (i). neutral and (ii). anionic
      chiral shift reagents (CSRs), to exist at low temperatures (197 K) in acetone
      d(6) solutions as 1:1 and 2:1 mixtures of diastereoisomeric complexes and salts,
      respectively, as a consequence of the helical chirality associated with the
      [2]catenane interacting with the CSRs.

PMID- 15040732
TI  - Synthesis of selenium-derivatized cytidine and oligonucleotides for X-ray
      crystallography using MAD.
AB  - Synthesis of the novel 2'-Se-cytidine phosphoramidite was achieved via
      transformation of the uridine analogue to the cytidine derivative in high yield.
      This 2'-Se-cytidine phosphoramidite was used to synthesize selenium-derivatized
      DNA and RNA oligonucleotides for X-ray crystallography using MAD. The nucleotide
      coupling yield using this novel phosphoramidite was over 99% when 5
      benzylmercaptotetrazole (5-BMT) was used as the coupling reagent.

PMID- 15040733
TI  - Efficient solid-phase synthesis of clavulones via sequential coupling of alpha-
      and omega-chains.
AB  - We describe an efficient solid-phase synthesis of clavulones via the sequential
      coupling of the alpha- and omega-chains, involving two separate carbon-carbon
      bond-forming steps. The tetrahydropyranyl linker survived these reaction
      conditions and was cleaved without decomposing the unstable cross-conjugated
      dienones. Our methodology has allowed us to prepare six clavulone derivatives
      that are varied within the alpha-chain.

PMID- 15040734
TI  - Copper-catalyzed coupling of imines, acid chlorides, and alkynes: a
      multicomponent route to propargylamides.
AB  - The use of imines in a metal-catalyzed coupling with alkynes and acid chlorides
      is described. This process proceeds rapidly with CuI as the catalyst and provides
      an efficient and general three-component coupling method to prepare
      propargylamides. The coupling can also be diversified to allow the formation of N
      carbamate-protected propargylamines with the use of chloroformates.

PMID- 15040735
TI  - Semisynthesis of an analogue of antitumor bicyclic hexapeptide RA-VII by fixing
      the Ala-2/Tyr-3 bond to Cis by incorporating a triazole cis-amide bond surrogate.
AB  - We prepared an analogue of an antitumor bicyclic hexapeptide RA-VII whose amide
      configuration between residues 2 and 3 was fixed to cis by incorporating a
      triazole cis-amide bond surrogate. This analogue was shown, by NMR studies, to
      take almost the same conformation as that of the minor conformer of RA-VII. It
      showed no cytotoxic activity.

PMID- 15040736
TI  - Autocatalytic domino Michael reaction leading to bicyclo[2.2.2]octane-2,5-dione
      derivatives.
AB  - In the presence of a catalytic amount of lithium amide, the reaction of
      oxophorone with electron-deficient olefins afforded bicyclo[2.2.2]octane-2,5
      dione derivatives in high yields. The reaction proceeds autocatalytically by an
      enolate of bicyclo[2.2.2]octane-2,5-dione, generated by an initial domino Michael
      reaction.

PMID- 15040737
TI  - Synthesis of phosphaisocoumarins via iodocyclization.
AB  - 4-Iodophosphaisocoumarins can be prepared in good yield and with high
      regioselectivity under mild conditions by the reaction of o-(1
      alkynyl)phenylphosphonates with I(2) or ICl. The present reaction represents the
      first example of a phosphonate iodocyclization onto a C-C triple bond. The
      resulting iodides can be further elaborated using palladium-catalyzed coupling
      reactions.

PMID- 15040738
TI  - Total synthesis of (+/-)-kalihinol C.
AB  - The total synthesis of kalihinol C, a bis-isonitrile marine diterpenoid isolated
      from Acanthella sp., is reported. The decalin framework was established via an
      intramolecular Diels-Alder cycloaddition and subsequently functionalized through
      a series of substrate-controlled diastereoselective transformations to install
      the tertiary isonitrile, beta-hydroxy isonitrile, and pendant tetrahydrofuranyl
      ring.

PMID- 15040739
TI  - Full orthogonality between Dde and Fmoc: the direct synthesis of PNA--peptide
      conjugates.
AB  - New deprotection conditions for the Dde amine protecting group that are fully
      orthogonal to Fmoc are described and successfully applied to the dual synthesis
      of PNA-peptide conjugates.

PMID- 15040740
TI  - Ligand-controlled highly stereoselective syntheses of e- and z-allylsilanes from
      dienes and aldehydes using nickel complex.
AB  - Synthetic methods of highly stereocontrolled E- and Z-allylsilanes were
      developed. When a toluene solution of diene having a silicon moiety and aldehyde
      was refluxed in the presence of silane using a catalytic amount of Ni(cod)(2)
      bearing PPh(3), E-allylsilane was obtained in high yield. On the other hand, when
      the reaction was carried out in THF upon heating in the presence of Ni(cod)(2),
      imidazolium salt, Cs(2)CO(3), and PPh(3), Z-allylsilane was formed as a sole
      product.

PMID- 15040741
TI  - Hydroselenation of alkynes by lithium butylselenolate: an approach in the
      synthesis of vinylic selenides.
AB  - Vinylic selenides were prepared in good yields by hydroselenation of alkynes with
      lithium butylselenolate generated by reaction of n-butyllithium with elemental
      selenium. The regio- and stereochemistry of the hydroselenation depend on the
      nature of the substituents bonded to the alkyne.

PMID- 15040742
TI  - Enantiodivergent synthesis of both enantiomers of marine alkaloids haliclorensin
      and isohaliclorensin, a constituent of halitulin.
AB  - Starting from (3R)-5-benzotriazolyl-3-phenylperhydropyrido[2,1-b][1,3]oxazole 9,
      the enantiodivergent syntheses of both enantiomers of the marine alkaloids
      haliclorensin 1 and isohaliclorensin 3 have been achieved. Our syntheses feature
      ring-expansion reactions for the formation of the aza-macrocycle ring system of 3
      and sequential ring-expansion reactions (aza-Claisen rearrangement and Zip
      reaction) for the formation of the aza-macrocycle ring system of 1.

PMID- 15040743
TI  - Solid-phase synthesis of 5-biphenyl-2-yl-1H-tetrazoles.
AB  - The combinatorial synthesis of novel biphenyl tetrazoles is described. Key steps
      include the simultaneous biphenyl formation and phenol deallylation under Suzuki
      cross-coupling conditions as well as the tetrazole ring formation on solid
      support. A representative library of 20 biphenyl tetrazoles was synthesized.

PMID- 15040744
TI  - Palladium-phosphinous acid-catalyzed NaOH-promoted cross-coupling reactions of
      arylsiloxanes with aryl chlorides and bromides in water.
AB  - A palladium-phosphinous acid-catalyzed and NaOH-promoted coupling method using
      arylsiloxanes and aryl halides in water has been developed. The POPd1-catalyzed
      reaction between aryl chlorides or bromides and arylsiloxanes is compatible with
      various functional groups and affords biaryls in up to 99% yield. This cross
      coupling reaction does not require additives such as surfactants or organic
      cosolvents and proceeds under air, which greatly facilitates operation and
      catalyst handling.

PMID- 15040745
TI  - Copper sulfate-pentahydrate-1,10-phenanthroline catalyzed amidations of alkynyl
      bromides. Synthesis of heteroaromatic amine substituted ynamides.
AB  - A practical cross-coupling of amides with alkynyl bromides using catalytic
      CuSO(4).5H(2)O and 1,10-phenanthroline is described here. This catalytic protocol
      is more environmentally friendly than the use of CuCN or copper halides and
      provides a general entry for syntheses of ynamides including various new sulfonyl
      and heteroaromatic amine substituted ynamides. Given the interest in ynamides,
      this N-alkynylation of amides should be significant for the future of ynamides in
      organic synthesis.

PMID- 15040746
TI  - Aminopyridine-benzoxanthene enantioselective receptor for sulfonylamino acids.
AB  - Combination of a cis-tetrahydrobenzoxanthene skeleton with a benzoxazole and an
      amidopyridine provides an enantioselective receptor for sulfonylamino acids with
      chiral recognitions of up to 18. The structure of the complex between receptor 1
      and the leucine triflate is known by X-ray analysis. The receptor racemic mixture
      can be suitably resolved through crystalization in the presence of leucine
      triflate as guest. Receptor 1 can be used for the enantioselective extraction of
      sulfonylamino acids from aqueous solutions of their salts.

PMID- 15040747
TI  - Palladium-catalyzed arylation and heteroarylation of indolizines.
AB  - A highly effective protocol for palladium-catalyzed selective arylation and
      heteroarylation of indolizines at C-3 has been developed. Mechanistic studies
      unambiguously support an electrophilic substitution pathway for this
      transformation.

PMID- 15040748
TI  - Triplet H-C-SiHCl(2): combined matrix-IR and CCSD(T) identification, and the role
      of the open-shell singlet state.
AB  - Triplet carbene H-C-SiHCl(2) (1), prepared by a photochemical [1,2]H-shift from
      1,1-dichlorosilaethylene, was identified by matching experimental and [CCSD(T)/cc
      pVTZ] infrared absorptions. Parts of the potential energy surface were explored
      utilizing CCSD(T)/cc-pVTZ and B3LYP/6-311+G computations. DFT reproduces the
      experimental features and CCSD(T) computations for the triplet surface but fails
      in the description of the open-shell singlet state of 1. We emphasize the notion
      of electropositive heterosubstitution for the generation of persistent ground
      state triplet carbenes.

PMID- 15040749
TI  - A new look at boron enolate chemistry: aminative C-C bond formation using
      diaminoboron enolate with aldehyde.
AB  - Unlike ordinary boron enolates, such as dialkylboryl (R(2)B) and dialkoxyboryl
      ((RO)(2)B) derivatives, reactions of diaminoboryl ((R(2)N)(2)B) enolates with
      aldehydes proceed with the concurrent transfer of amino and enoxy groups from the
      boron to the aldehyde carbon, yielding beta-amino ketones in a selective manner.

PMID- 15040750
TI  - Transformation of an optically active decahydro-6-isoquinolone scaffold: perfect
      Felkin-Anh diastereoselectivity.
AB  - Diastereomerically and enantiomerically pure decahydro-6-isoquinolone derivative
      7 (>99% de, 97% ee) was obtained from the Michael addition product 3.
      Interestingly, aldehyde 7 reacted with a number of different Grignard reagents to
      give the secondary alcohols 9 in good yields as single diastereomers. This result
      can be explained by taking the Felkin-Anh model into account.

PMID- 15040751
TI  - Lewis acid-mediated cycloaddition of methylenecyclopropanes with aldehydes and
      imines: a facile access to indene, THF, and pyrrolidine skeletons via homoallylic
      rearrangement protocol.
AB  - Methylenecyclopropanes (MCPs) 1 can react with aldehydes and aldimines to give
      the corresponding indene, THF, and pyrrolidine cycloaddition products in the
      presence of BF(3).OEt(2) under mild reaction conditions.

PMID- 15040752
TI  - Novel poly(p-phenylenevinylene)s with a phenylazomethine dendron as a metal
      collecting site.
AB  - Novel poly(p-phenylenevinylene)s (PPVs) with a dendritic phenylazomethine (DPA)
      as a metal-collecting site were synthesized via the Heck reaction by filling the
      coordination site of DPA moiety via complexation with rare earth metal ions.

PMID- 15040753
TI  - A Pauson-Khand-type reaction between alkynes and olefinic aldehydes catalyzed by
      rhodium/cobalt heterobimetallic nanoparticles: an olefinic aldehyde as an olefin
      and CO source.
AB  - Co/Rh (Co:Rh = 2:2) heterobimetallic nanoparticles derived from
      Co(2)Rh(2)(CO)(12) react with alkynes and alpha,beta-unsaturated aldehydes such
      as acrolein, crotonaldehyde, and cinnamic aldehyde and release products resulting
      from [2 + 2 + 1]cycloaddition of alkyne, carbon monoxide, and alkene. alpha,beta
      Unsaturated aldehydes act as a CO and alkene source. These reactions produce 2
      substituted cyclopentenones.

PMID- 15040756
TI  - Cost effectiveness of cholinesterase inhibitors in the treatment of Alzheimer's
      disease: a review with methodological considerations.
AB  - Cholinesterase inhibitors have been available for the treatment of Alzheimer's
      disease since 1993. They have significantly positive effects on cognitive
      functioning and other domains of functional capacity, such as activities of daily
      life in terms of efficacy, but the clinical value of these effects are under
      discussion. Cholinesterase inhibitors may also influence behavioural and
      psychological symptoms in Alzheimer's disease. Cholinesterase inhibitors are also
      regarded as rather expensive and, therefore, the question of cost effectiveness
      is essential. Pharmacoeconomic evaluations of cholinesterase inhibitors have so
      far been conducted in retrospect on efficacy data from prospective randomised
      clinical trials combined with economic data from other sources. There are no
      published specific cost-effectiveness studies of cholinesterase inhibitors which
      prospectively collected empirical data on costs and outcomes. There is only one
      published randomised clinical trial with such empirical data with a cost
      consequence analysis design, indicating cost neutrality. Several types of models
      to describe the long-term effects have been published, indicating cost
      effectiveness. However, due to methodological considerations, the validity of
      these models is difficult to judge. A research agenda for the cost effectiveness
      of cholinesterase inhibitors is proposed, including long-term studies with
      empirical data on resource use, costs and outcomes, studies on quality of life,
      informal care and behavioural and psychological symptoms, combination and
      comparative studies on mild cognitive impairment.

PMID- 15040757
TI  - Tinnitus in the older adult: epidemiology, pathophysiology and treatment options.
AB  - Tinnitus is the perception of sound in the absence of an apparent acoustic
      stimulus. More than 35 million Americans experience tinnitus, with 2-3 million
      severely debilitated by this distressing symptom. The prevalence increases with
      age and there is a high incidence associated with both noise-induced and age
      related hearing loss. Although there are several theories regarding the
      pathophysiology of tinnitus, the precise mechanism remains to be elucidated. The
      most compelling of these is the hypothesis that tinnitus occurs as a result of
      spontaneous and aberrant neural activity at any level along the auditory axis,
      even after cochlear nerve transection or labyrinthine ablation. There are
      numerous aetiologies associated with tinnitus. Tinnitus, in clinical practice, is
      characterised as either objective or subjective. The distinction is relevant in
      terms of both aetiology and treatment. Despite a large number of therapeutic
      interventions and studies claiming success in treating tinnitus, a cure remains
      elusive. However, there are several potential treatment options that offer
      patients varying degrees of symptomatic improvement and enhanced quality of life.
      It is imperative to formulate a rational and systematic approach in evaluating an
      older adult with tinnitus. An individualised treatment regimen and the creation
      of a strong therapeutic relationship are the hallmarks of successful management
      of the patient with tinnitus.

PMID- 15040760
TI  - Insulin pumps: what every school nurse needs to know.
AB  - The results of the Diabetes Control and Complications Trial revolutionized the
      care of people with Type 1 diabetes mellitus (DM). The era of "tight control" of
      blood sugars to decrease microvascular complications dawned. The subsequent
      technological development of insulin pumps has made it possible for individuals
      with Type 1 DM, as well as those with Type 2 who are insulin dependent, to keep
      their blood sugars in a more normal range. Children of all ages with Type 1 DM
      have been switching from multiple daily injections of insulin to insulin pumps.
      School nurses who have not had a child with a pump certainly will in the near
      future. It is important for school nurses to understand the function and possible
      complications of using an insulin pump to assist and support children in their
      transition to pump therapy. School nurses need to be aware of available technical
      support resources for insulin pumps should problems arise at school with pump
      management.

PMID- 15040761
TI  - Lumps, bumps, and things that go itch in your office!

PMID- 15040758
TI  - Obstructive sleep apnoea in the elderly: recognition and management
      considerations.
AB  - Obstructive sleep apnoea is characterised by repetitive interruptions of
      breathing during sleep due to upper airway collapse. It affects sleep quality,
      daytime alertness and quality of life. It is associated with increased
      cardiovascular morbidity and mortality and an increased risk of road traffic
      accidents. Sleep apnoea is common among older people and its effects can be more
      severe than in younger people. The added impact is because of a physiological
      decline in sleep quality with age in most people and the increasing frequency of
      other comorbidities with increasing years that affect both sleep and daytime
      function. It is important to be alert to the diagnosis, bearing in mind these
      other influences on sleep quality. The diagnosis is generally straightforward
      once appropriate tests are performed. Treatment is aimed at minimising upper
      airway obstruction during sleep and the most effective therapy is continuous
      positive airway pressure. Weight loss can also be effective. Other management
      options, including surgery, mandibular advancement devices and drug treatment,
      are less effective, but there are interesting advances in the understanding of
      the pharmacology of the upper airway. Specific serotonergic agonists hold the
      greatest potential for a useful drug treatment for this widespread and
      debilitating condition.

PMID- 15040763
TI  - HIPAA-FERPA revisited.
AB  - Since April 2003, school nurse and school health officials have been clamoring
      for guidance on how the Health Insurance Portability and Accountability Act
      (HIPAA) and the Family Education Rights Privacy Act (FERPA) interface in the
      school environment. This article provides an up-to-date explanation of how school
      health leaders are interpreting the practical implications of the federal privacy
      laws. With the attention and scrutiny given to personally identifiable health
      information in all settings, it is imperative for school nurses, school
      administrators, and school attorneys to revisit policies and procedures for
      protecting the privacy of student and family health information in schools.

PMID- 15040764
TI  - School staff's satisfaction with school health services.
AB  - The School Nurse Impact Committee of the Columbus Public Schools in Columbus,
      Ohio, initiated a survey to determine staff satisfaction with the delivery of
      health services. School nurses need the cooperation and support of the staff to
      successfully deliver school health services, therefore, the staff's satisfaction
      with school health services is crucial to the school nurses' ability to fulfill
      their role. The objectives of the survey were to (a) determine staff satisfaction
      with school nurse interventions, (b) determine staff satisfaction with the
      effectiveness of interventions, (c) identify areas of health service delivery
      which may need improvement, and (d) determine areas of school health services
      where school nurses may need to more effectively communicate their involvement.
      Critical elements of school nurse practice included staff health, safety and
      environment, classroom education, medication, school system collaboration, and
      program management. Several key issues were identified through the survey. School
      system collaboration issues need more school nurse involvement. School nurses
      also need to improve their visibility regarding school system collaboration, and
      in classroom and individual pupil education. Traditional school nurse functions
      were adequately covered. Results indicate that staff would be more satisfied if
      they had more nursing support in the classroom and more nurse time in their
      building.

PMID- 15040765
TI  - A multi-factor analysis of job satisfaction among school nurses.
AB  - Although job satisfaction has been widely studied among registered nurses working
      in traditional health care settings, little is known about the job-related values
      and perceptions of nurses working in school systems. Job satisfaction is linked
      to lower levels of job-related stress, burnout, and career abandonment among
      nurses. This study evaluated the level of job satisfaction among a convenience
      sample of school nurses practicing in California. The Index of Work Satisfaction
      (IWS) was the instrument used. Although the sampled school nurses rated autonomy
      and interaction as the most important and satisfying factors contributing to job
      satisfaction, the overall findings indicated that school nurses are relatively
      dissatisfied with their jobs.

PMID- 15040759
TI  - Drug therapy in transplant recipients: special considerations in the elderly with
      comorbid conditions.
AB  - Elderly patients with end-stage organ failure are now more frequently undergoing
      transplantation. Medication management in this population is challenging because
      of the combination of multiple comorbidities, polypharmacy, and immunological,
      pharmacokinetic and pharmacodynamic changes attributable to the aging process.
      Immunosuppressive medications can exacerbate pre-existing medical conditions and
      promote the development of disease processes. Cardiovascular disorders, such as
      hypertension, coronary artery disease, congestive heart failure and arrhythmias
      are common in elderly transplant recipients, and account for most of the deaths
      in this population. Blood pressure, blood glucose and cholesterol control is of
      particular concern because elderly transplant recipients frequently have or
      develop these complications. Elderly transplant recipients are commonly receiving
      anticoagulation therapy with warfarin and are at a higher risk of bleeding,
      especially if they have renal dysfunction. Infectious complications occur
      frequently in the transplanted population, with pneumonia being the most common
      infection seen in hospitalised patients. Attention to vaccination for the
      prevention of influenza and pneumococcal infections is important because of the
      increased risk of these diseases in this population. Depression itself has been
      associated with decreased survival in older individuals, and depression in
      elderly transplant recipients may be reversible with the administration of
      pharmacological agents. Effective long-term care of transplant recipients demands
      an understanding of how particular medications affect clinical evaluation and
      treatment. This article addresses some of the practical issues surrounding
      medication management and prevention of these particular problems in elderly
      transplant recipients.

PMID- 15040766
TI  - A study of school nurse job satisfaction.
AB  - This study explored job satisfaction and changes needed to help boost levels of
      job satisfaction. Self-reported job satisfaction data were collected from 71
      school nurses employed in elementary, middle, and high school settings via
      interactive focus groups. The subjects participated in a 30- to 45-minute focus
      group session that was audiotaped and transcribed by the principal investigator.
      Beliefs about job satisfaction were identified and classified into exclusive
      categories or themes. While the majority of school nurses expressed contentment
      with their jobs, certain factors that would increase job satisfaction, such as
      salary and control issues, were discussed. Overall, 83% of school nurses in this
      study were satisfied in their present positions; however, issues of coping and
      role strain were identified as major contributors to low morale. Only 17% of the
      school nurses voiced job dissatisfaction, primarily attributed to low salaries
      and lack of trust and support from administration. As school nurses face a
      diverse community with complex needs, adaptation is needed for job satisfaction
      to be maintained. For this to occur, school nurses must take the initiative to
      educate administrators, parents, and communities about their role in the school
      setting.

PMID- 15040767
TI  - The lived experience of violence: using storytelling as a teaching tool with
      middle school students.
AB  - This qualitative study explored 8th-grade students' responses to hearing stories
      about the lived experience of violence. A convenience sample of 13 students
      attending health education classes at a public middle school was used. After
      hearing each story, students answered a series of questions using the process of
      free writing. Free writing is a technique that allows students to explore their
      thoughts and reactions while promoting critical thinking. Student free writing
      samples were analyzed using a process of constant comparison. Three themes
      emerged from the data: (a) students gain insights into the realities of violence
      through hearing these stories, (b) students respond on an emotional level to both
      the stories and the storytellers, and (c) students respond positively to and are
      engaged by these stories. The findings lend support to the use of storytelling in
      teaching youth about violence. School nurses can develop and implement violence
      prevention education programs using the storytelling model, seek grant and
      community support for such programs, and conduct further research into the use of
      the storytelling model.

PMID- 15040768
TI  - Severe acute respiratory syndrome (SARS) prevention in Taiwan.
AB  - Severe Acute Respiratory Syndrome (SARS) is a newly identified respiratory
      disease that threatened Taiwan between April 14 and July 5, 2003. Chang Gung
      University experienced various SARS-related episodes, such as the postponement of
      classes for 7 days, the reporting of probable SARS cases, and the isolation of
      students under Level A and B quarantines. Ninety-eight percent of the students at
      the university live in dormitories; thus the prevention of SARS became an
      important issue. Preventive strategies are classified into primary, secondary,
      and tertiary prevention, with a different focus and strategy for each level of
      prevention. The university emphasized personal hygiene and a healthy lifestyle as
      the key to SARS prevention. Our experiences as school nurses during this crisis
      can help other school nurses to prevent the spread of SARS during similar
      situations.

PMID- 15040771
TI  - Promoting job satisfaction--a challenge for school nurses.

PMID- 15040772
TI  - Research into macular degeneration provides better ways to assess its prognosis.

PMID- 15040769
TI  - War, terrorism, and children.
AB  - Many caregivers are encountering the issue of communicating with children and
      adolescents about current world events, specifically war and terrorism. As health
      care providers, it is important to raise awareness of how children may
      understand, interpret, and respond to related fears and concerns. Although
      honesty and reassurance are clearly the best approach, it is important to provide
      information that is developmentally appropriate. Providing education and guidance
      can reduce stress and enhance understanding of the chaotic events confronting our
      nation. It also provides a platform for communication and exploration should
      additional terrorist attacks or acts of war occur. It is important to examine how
      to approach children and adolescents to communicate with them about these
      sensitive issues.

PMID- 15040773
TI  - Retinitis pigmentosa: understanding the clinical presentation, mechanisms and
      treatment options.
AB  - Retinitis pigmentosa (RP) is a leading cause of human blindness due to
      degeneration of retinal photoreceptor cells. Causes of retinal degeneration
      include defects in the visual pigment, defects in the proteins important for
      photoreceptor function or in enzymes involved in initiating visual transduction.
      Despite the diversity of genetic mutations identified in inherited forms of
      retinal dystrophy, there is a common end result of photoreceptor death and
      functional blindness. In this review, pertinent anatomical and physiological
      pathways involved in RP and the underlying genetic mutations are outlined,
      including a discussion on the inheritance patterns revealed by advances in
      molecular biological techniques. Characteristics of progression rates of visual
      field loss and current management options will provide useful clinical guidelines
      for the management of patients with RP.

PMID- 15040775
TI  - Error rate of axons at the owl's optic chiasm.
AB  - BACKGROUND: In owls, the visual pathways from the retina are totally crossed.
      Attempts to find ganglion cells with uncrossed axons have failed consistently,
      when retrograde labeling with HRP is used for their identification. In the
      present investigation we have used retrograde fluorescent tracers of
      complementary colour in each optic tectum to demonstrate a tiny population of
      ipsilaterally-projecting retinal ganglion cells in the owl. METHODS: We studied
      two species, one from each of the two important owl families: the Southern
      boobook owl, Ninox boobook: (Family Strigidae); and the Barn Owl, Tyto alba:
      (Family Tytonidae). RESULTS: The small numbers, random distribution and
      heterogeneity of the mis-projecting ganglion cells, taken together, argue against
      a functional role for them. Instead, they appear to be the result of
      developmental errors in the specification of laterality. At a number of different
      eccentricities and ganglion cell densities, the error rate was roughly a constant
      fraction of the neurons involved, at around 10-4 for the tytonid owl (lacking a
      fovea) and around 10-5 for the strigid owl (which has a fovea and a higher
      overall density of ganglion cells). CONCLUSIONS: These values are close to the
      error rates of replicating enzymes, such as nucleic acid polymerases. The
      evolution of a higher retinal ganglion cell density and a fovea in the Strigidae
      appears to be accompanied by an improvement in the error rate.

PMID- 15040774
TI  - Collagen fibril characteristics at the corneo-scleral boundary and rabbit corneal
      stromal swelling.
AB  - BACKGROUND: The aim of this investigation was to reassess the impact of the
      scleral rim on the swelling of the mammalian corneal stroma and to investigate
      the ultrastructural features of the scleral rim and corneal stromal tissues.
      METHODS: The epithelium and endothelium were removed from corneas excised from
      three-month-old female rabbits. The resulting preparations consisted of the
      corneal stroma plus a surrounding scleral rim, excised corneal stroma or a nine
      millimetre button of central corneal stroma. These preparations were immersed in
      a 35 mM bicarbonate-buffered mixed salt solution (equilibrated with five per cent
      CO2-air, pH 7.54 at 37 degrees Centigrade for nine hours. Some sclero-corneal
      preparations were fixed for light or transmission electron microscopy. RESULTS:
      The initial rate of swelling of corneal stromal buttons was greatest at 127 +/- 8
      per cent per hour, less for complete stromal preparations (118 +/- 9 per cent per
      hour) and least for sclero-stromal preparations (76 +/- 12 per cent per hour).
      The swelling continued over three to nine hours but sclera preparations swelled
      up to 40 per cent with no further swelling. Light microscopy demonstrated that
      the sclero-corneal rim tissue limited the swelling of the posterior corneal
      stroma. TEM sections of the episclera and sclera indicate that most fibril
      bundles show a radial orientation to the cornea. There are marked anterio
      posterior differences in the collagen fibrils of the scleral surround that are
      distinctly different from previous reports. Average fibril diameters were 62.8 +/
      7.9 nm in the episclera, 122.4 +/- 18.9 nm, 133.5 +/- 51.9 nm and 56.5 +/- 11.2
      nm in the anterior, mid- and posterior scleral stroma, compared to an average
      fibril diameter of 33.5 +/- 3.5 nm for the posterior corneal stroma. CONCLUSIONS:
      When there is a scleral rim in place, the swelling of the corneal stroma is
      substantially less than for isolated corneal stroma. The effect can be attributed
      to the absence of a cut-edge effect for the sclero-corneal stromal preparation
      but the unique and largely radial arrangement of the collagen fibrils in the
      scleral rim plays a part in limiting the swelling of the adjacent corneal stroma.
      The heterogeneous nature of this sclero-corneal interface requires further
      investigation to define the mechanism of the effect.

PMID- 15040776
TI  - Keratoconus in Asian eyes at a tertiary eye care facility.
AB  - BACKGROUND: The purpose of this study was to assess the demographic variables,
      age at diagnosis, keratometry and slitlamp signs in keratoconus. METHODS: Thirty
      one patients with 61 keratoconic eyes were selected provided they met one of two
      criteria: 1. They had an irregular corneal surface, Vogt's striae, Fleischer's
      ring or apical sub-epithelial corneal scarring characteristic of keratoconus; 2.
      Corneal topography revealed an average simulated keratometry of more than 45.2 D,
      central corneal power higher than 47.2 D or infero-superior asymmetry greater
      than 1.4 D. The main outcome measures were demographic variables, age at
      diagnosis, disease severity on keratometry and biomicroscopic signs. RESULTS: The
      patients' mean age at presentation was 20.2 +/- 6.4 years. Based on average
      keratometry values, 67.2 per cent of eyes had severe and 32.8 per cent had
      moderate keratoconus. Eyes with severe keratoconus presented at a younger average
      age (18.8 +/- 5.35 years) than moderate keratoconus (23.69 +/- 8.07 years).
      Thirty-eight eyes (92.5 per cent) with severe and 13 eyes (65 per cent) with
      moderate keratoconus demonstrated biomicroscopic signs of keratoconus. Twenty
      eyes (32.7 per cent) demonstrated apical sub-epithelial cornea scarring and 95
      per cent of these eyes had severe keratoconus. CONCLUSIONS: The majority of
      keratoconic eyes in Asian-Indian patients demonstrate the severe stage of the
      disease by the second decade.

PMID- 15040777
TI  - Delayed onset diffuse lamellar keratitis following enhancement LASIK surgery.
AB  - BACKGROUND: Diffuse lamellar keratitis (DLK) is a relatively uncommon
      complication of the refractive procedure, laser-assisted in situ keratomileusis
      (LASIK). If detected and diagnosed in a timely fashion, it can be treated and
      should resolve with minimal sequelae. If untreated, or misdiagnosed and treated
      incorrectly, there may be loss of visual acuity. Optometrists should be familiar
      with this condition, its signs, symptoms and correct treatment protocol. CASE
      HISTORY: A 58-year-old male Caucasian developed delayed onset diffuse lamellar
      keratitis, seemingly in the absence of an epithelial defect, 25 days following an
      enhancement LASIK procedure to his right eye. The DLK in this patient is delayed
      longer than typically reported in the literature. Subsequent management with
      topical steroids was complicated as the patient was a steroid responder and
      developed a markedly raised intraocular pressure that was managed with a topical
      anti-glaucoma agent. The diagnosis, pathogenesis and issues relevant to the
      treatment of this condition are discussed. CONCLUSION: Optometrists, particularly
      those actively participating in the shared care of refractive surgery patients,
      must be familiar with diffuse lamellar keratitis so that diagnosis is not
      delayed. As the number of cases of refractive surgery in Australia increases,
      optometrists will encounter this condition more frequently.

PMID- 15040778
TI  - Recurrent superior oblique myokymia in a patient with retinitis pigmentosa.
AB  - Superior oblique myokymia is an infrequently encountered condition, presenting
      with episodes of oscillopsia and/or vertical or oblique nystagmus, accompanied by
      a fine, monocular, cyclorotational nystagmus. Recent research suggests it is
      caused by vascular compression of the trunk of the trochlear nerve. The clinical
      features of a patient reporting three episodes of superior oblique myokymia, each
      following childbirth, are described. She had previously been diagnosed with
      retinitis pigmentosa. The possible aetiologies of superior oblique myokymia are
      described and appropriate assessment and possible referral for further testing
      detailed.

PMID- 15040779
TI  - Complementary and alternative medicine: the move into mainstream health care.
AB  - The use of complementary and alternative medicine (CAM) in Australia is extensive
      with over 50 per cent of the Australian population using some form of
      complementary medicine and almost 25 per cent of Australians visiting CAM
      practitioners. Expenditure on CAM by Australians is significant. The scope of CAM
      is extremely broad and ranges from complete medical systems such as Chinese
      medicine to well-known therapies, such as massage and little known therapies,
      such as pranic healing. There is a growing focus on CAM in Australia and
      worldwide by a range of stakeholders including government, the World Health
      Organization, western medical practitioners and private health insurance
      companies. CAM practices may offer the potential for substantial public health
      gains and challenge the way that we view human beings, health and illness.
      Several issues are emerging that need to be addressed. They include safety and
      quality control of complementary medicines, issues related to integration of CAM
      with western medicine and standards of practice. The evidence base of forms of
      CAM varies considerably: some forms of CAM have developed systematically over
      thousands of years while others have developed much more recently and have a less
      convincing evidence base. Many forms of CAM are now being investigated using
      scientific research methodology and there are increasing examples of good
      research. Certain forms of CAM, including Chinese medicine in which ophthalmology
      is an area of clinical specialty, view the eye in a unique way. It is important
      to keep an open mind about CAM and give proper scrutiny to new evidence as it
      emerges.

PMID- 15040781
TI  - Can true monocular keratoconus occur?

PMID- 15040783
TI  - Randomized double-blind placebo-controlled study of an angiotensin
      immunotherapeutic vaccine (PMD3117) in hypertensive subjects.
AB  - Immunization against components of the renin-angiotensin system offers a
      potential alternative to daily medication in some patients with hypertension or
      heart failure. Our primary objective was to determine whether a sustained
      antibody titre to Ang I (angiotensin I) can be achieved in hypertensive patients.
      The secondary objective was to determine whether the antibodies block the renin
      system. Patients (n=27) with essential hypertension responsive to an ACEi
      (angiotensin-converting enzyme inhibitor) or ARB (angiotensin blocker) were
      randomly assigned to receive three or four injections of the Ang I vaccine
      PMD3117 or aluminium hydroxide (Alhydrogel trade mark ) over a 6 week period.
      Antibody titre was measured prior to each injection and every 30 days until
      disappearance. Indices of renin blockade were changes in renin and aldosterone
      (blood and urine) and a within-patient comparison of the pre- and post
      vaccination rise in 24 h ambulatory blood pressure after 2 weeks of withdrawal of
      ACEi or ARB. The anti-(Ang I) antibody titre rose from the second injection in
      both regimes and peaked on day 64. Median half-life was 85 (95% CI, 44 and 153)
      days (where CI is confidence interval). Vaccination did not influence blood
      pressure, but significantly blunted the fall in plasma renin following withdrawal
      of ACEi or ARB. At 42 days after the first injection, aldosterone excretion was
      decreased by PMD3117 to 6 (95% CI, 1 and 31)% of values in patients receiving
      Alhydrogel trade mark (P=0.012). In patients with essential hypertension, PMD3117
      generated a prolonged antibody response to Ang I. Biochemical measurements show
      evidence of blockade of the renin system, but higher titres will be required to
      achieve a decrease in blood pressure.

PMID- 15040785
TI  - Combinational clustering of receptors following stimulation by bacterial products
      determines lipopolysaccharide responses.
AB  - The innate immune system has the capacity to recognize a wide range of pathogens
      based on conserved PAMPs (pathogen-associated molecular patterns). In the case of
      bacterial LPS (lipopolysaccharide) recognition, the best studied PAMP, it has
      been shown that the innate immune system employs at least three cell-surface
      receptors: CD14, TLR4 (Toll-like receptor 4) and MD-2 protein. CD14 binds LPS
      from Enterobacteriaceae and then transfers it to MD-2, leading to TLR4
      aggregation and signal transduction. LPS analogues such as lipid IVa seem to act
      as LPS antagonists in human cells, but exhibit LPS mimetic activity in mouse
      cells. Although TLR4 has been shown to be involved in this species-specific
      discrimination, the mechanism by which this is achieved has not been elucidated.
      The questions that remain are how the innate immune system can discriminate
      between LPS from different bacteria as well as different LPS analogues, and
      whether or not the structure of LPS affects its interaction with the CD14-TLR4-MD
      2 cluster. Is it possible that the 'shape' of LPS induces the formation of
      different receptor clusters, and thus a different immune response? In the present
      study, we demonstrate using biochemical as well as fluorescence-imaging
      techniques that different LPS analogues trigger the recruitment of different
      receptors within microdomains. The composition of each receptor cluster as well
      as the number of TLR4 molecules that are recruited within the cluster seem to
      determine whether an immune response will be induced or inhibited.

PMID- 15040786
TI  - Regulation of cytosolic prostaglandin E synthase by phosphorylation.
AB  - cPGES [cytosolic PG (prostaglandin) E synthase] is constitutively expressed in
      various cells and can regulate COX (cyclo-oxygenase)-1-dependent immediate PGE2
      generation. In the present study, we found that cPGES underwent serine
      phosphorylation, which was accelerated transiently after cell activation. Several
      lines of evidence suggest that a cPGES-activating protein kinase is CK-II (casein
      kinase II). Recombinant cPGES was phosphorylated directly by and associated with
      CK-II in vitro, resulting in marked reduction of the K m for the substrate PGH2.
      In activated cells, cPGES phosphorylation occurred in parallel with increased
      cPGES enzymic activity and PGE2 production from exogenous and endogenous
      arachidonic acid, and these processes were facilitated by Hsp90 (heat-shock
      protein 90), a molecular chaperone that formed a tertiary complex with cPGES and
      CK-II. Treatment of cells with inhibitors of CK-II and Hsp90 and with a dominant
      negative CK-II attenuated the formation of the cPGES-CK-II-Hsp90 complex and
      attendant cPGES phosphorylation and activation. Mutations of either of two
      predicted CK-II phosphorylation sites on cPGES (Ser113 and Ser118) abrogated its
      phosphorylation and activation both in vitro and in vivo. Moreover, the CK-II
      Hsp90-mediated activation of cPGES was ameliorated by the p38 mitogen-activated
      protein kinase inhibitor SB20358 or by the anti-inflammatory glucocorticoid
      dexamethasone. Taken together, the results of the present study have provided the
      first evidence that the cellular function of this eicosanoid-biosynthetic enzyme
      is under the control of a molecular chaperone and its client protein kinase.

PMID- 15040787
TI  - Syncollin inhibits regulated corticotropin secretion from AtT-20 cells through a
      reduction in the secretory vesicle population.
AB  - Syncollin is a 13 kDa protein that is highly expressed in the exocrine pancreas.
      Syncollin normally exists as a doughnut-shaped homo-oligomer (quite probably a
      hexamer) in close association with the luminal surface of the zymogen granule
      membrane. In the present study, we examine the effect of expression of syncollin
      in AtT-20 neuroendocrine cells, which do not normally express this protein.
      Efficient expression was achieved by infection of the cells with adenoviral
      constructs encoding either untagged or GFP (green fluorescent protein)-tagged
      syncollin. Both forms of the protein were sorted into corticotropin (ACTH)
      positive secretory vesicles present mainly at the tips of cell processes. Neither
      form affected basal corticotropin secretion or the constitutive secretion of
      exogenously expressed secreted alkaline phosphatase. In contrast, regulated
      secretion of corticotropin was inhibited (by 49%) by untagged but not by GFP
      tagged syncollin. In parallel, untagged syncollin caused a 46% reduction in the
      number of secretory vesicles present at the tips of the cell processes. Syncollin
      GFP was without effect. We could also show that native syncollin purified from
      rat pancreas was capable of permeabilizing erythrocytes. We suggest that
      syncollin may induce uncontrolled permeabilization of corticotropin-containing
      vesicles and subsequently destabilize them. Both forms of syncollin were tightly
      membrane-associated and appeared to exist as homooligomers. Hence, the lack of
      effect of syncollin-GFP on regulated exocytosis suggests that the GFP tag
      interferes in a subtler manner with the properties of the assembled protein.

PMID- 15040784
TI  - Signalling to actin assembly via the WASP (Wiskott-Aldrich syndrome protein)
      family proteins and the Arp2/3 complex.
AB  - The assembly of a branched network of actin filaments provides the mechanical
      propulsion that drives a range of dynamic cellular processes, including cell
      motility. The Arp2/3 complex is a crucial component of such filament networks.
      Arp2/3 nucleates new actin filaments while bound to existing filaments, thus
      creating a branched network. In recent years, a number of proteins that activate
      the filament nucleation activity of Arp2/3 have been identified, most notably the
      WASP (Wiskott-Aldrich syndrome protein) family. WASP-family proteins activate the
      Arp2/3 complex, and consequently stimulate actin assembly, in response to
      extracellular signals. Structural studies have provided a significant refinement
      in our understanding of the molecular detail of how the Arp2/3 complex nucleates
      actin filaments. There has also been much progress towards an understanding of
      the complicated signalling processes that regulate WASP-family proteins. In
      addition, the use of gene disruption in a number of organisms has led to new
      insights into the specific functions of individual WASP-family members. The
      present review will discuss the Arp2/3 complex and its regulators, in particular
      the WASP-family proteins. Emphasis will be placed on recent developments in the
      field that have furthered our understanding of actin dynamics and cell motility.

PMID- 15040790
TI  - Providing evidence-based information to patients in general practice and
      pharmacies: what is the acceptability, usefulness and impact on drug use?
AB  - BACKGROUND: A common and often integral method of delivering patient information
      is the use of patient guides. However, the acceptability, utility and impact of
      evidence-based therapeutic guides on physicians, pharmacists and patients have
      not been well evaluated. METHODS: This study was a prospective evaluation of 53
      general practitioners' offices and 30 community pharmacies from three locations
      in Canada. Evidence-based guides were provided to 1176 patients who presented to
      either a general practitioner or a community pharmacist and were interested in
      receiving information about sore throat, heartburn, or osteoporosis
      (http://www.ti.ubc.ca/canadadrugguide). The acceptability, utility and impact of
      the guides were assessed via structured patient telephone interviews, structured
      health professional interviews, and patient chart audits. RESULTS: Eighty to 90%
      of patients reported that the guides were 'very easy' to understand. Fifty six
      per cent/47%/38% (sore throat/heartburn/osteoporosis) of patients rated the
      guides as 'very' or 'extremely' useful. Seventy-two per cent/67%/58% of
      respondents reported that the information helped them make decisions about their
      treatment. Ninety eight per cent of physicians and 92% of pharmacists reported
      that the guides helped their patients understand the issues involved in their
      treatment. None of the analyses showed any significant differences in prescribing
      of medications between the intervention and control groups. INTERPRETATIONS:
      Patients found these evidence-based guides to be useful, easy to understand, and
      that they helped them in their understanding of treatment options and the
      decision-making process. Physicians and pharmacists reported that the guides
      helped their patients understand the issues involved in their treatment. Further
      research is required to determine the degree to which providing evidence-based
      guides to patients can impact on prescribing and patient outcomes.

PMID- 15040791
TI  - Impact of patient information booklet on treatment decision--a randomized trial
      among women with heavy menstruation.
AB  - OBJECTIVE: Does a patient information booklet influence treatment for
      menorrhagia? DESIGN: Randomized trial and a pre-trial prospective cohort study.
      SETTING: Gynaecology outpatient clinics in 14 Finnish hospitals. PARTICIPANTS: A
      total of 363 (randomized trial) plus 206 (cohort study) patients with
      menorrhagia. INTERVENTION: An information booklet about menorrhagia and treatment
      options, mailed before the first visit to the outpatient clinic. MAIN OUTCOME
      MEASURES: Distribution of treatment modalities, knowledge about treatment
      options, satisfaction with communication with personnel and anxiety. RESULTS:
      Treatment decision within 3 months was made more often in the intervention group
      than in the control group (96% and 89% respectively, P = 0.02). Oral medication
      was more frequently chosen, and newly introduced treatments (minor surgery,
      hormonal intrauterine system) were less frequently used in the intervention group
      (at 3-month follow-up 21% and 29%, respectively). The differences persisted at
      the 12-month follow-up. In the pre-trial group, new treatment methods were less
      frequently chosen and used than in the control group. Additional information did
      not increase the number of surgical procedures used, improve knowledge, or
      influence satisfaction or anxiety. CONCLUSIONS: Additional information led to an
      increase in specific treatment decisions and changed the distribution of used
      treatments without increasing the number of surgical procedures. The study
      suggests that well-informed women adopting an active role may counteract
      physicians' emphasis on newly introduced treatments.

PMID- 15040788
TI  - Differences in substrate and inhibitor sequence specificity of human, mouse and
      rat tissue kallikreins.
AB  - The kininogenase activities of mouse (mK1), rat (rK1) and human (hK1) tissue
      kallikreins were assayed with the bradykinin-containing synthetic peptides Abz
      MTEMARRPPGFSPFRSVTVQNH2 (where Abz stands for o-aminobenzoyl) and Abz
      MTSVIRRPPGFSPFRAPRV-NH2, which correspond to fragments Met374-Gln393 and Met375
      Val393 of mouse and rat LMWKs (low-molecular-mass kininogens) with the addition
      of Abz. Bradykinin was released from these peptides by the mK1- and rK1-mediated
      hydrolysis of Arg-Arg and Arg-Ser (or Arg-Ala) peptide bonds. However, owing to
      preferential hydrolysis of Phe-Arg compared with the Arg-Ala bond in the peptide
      derived from rat LMWK, hK1 released bradykinin only from the mouse LMWK fragment
      and preferentially released des-[Arg9]bradykinin from the rat LMWK fragment (Abz
      MTSVIRRPPGFSPFRAPRV-NH2). The formation of these hydrolysis products was examined
      in more detail by determining the kinetic parameters for the hydrolysis of
      synthetic, internally quenched fluorescent peptides containing six N- or C
      terminal amino acids of bradykinin added to the five downstream or upstream
      residues of mouse and rat kininogens respectively. One of these peptides, Abz
      GFSPFRAPRVQ-EDDnp (where EDDnp stands for ethylenediamine 2,4-dinitrophenyl), was
      preferentially hydrolysed at the Phe-Arg bond, confirming the potential des
      [Arg9]bradykinin-releasing activity of hK1 on rat kininogen. The proline residue
      that is two residues upstream of bradykinin in rat kininogen is, in part,
      responsible for this pattern of hydrolysis, since the peptide Abz-GFSPFRASRVQ
      EDDnp was preferentially cleaved at the Arg-Ala bond by hK1. Since this peptidase
      accepts the arginine or phenylalanine residue at its S1 subsite, this preference
      seems to be determined by the prime site of the substrates. These findings also
      suggested that the effects observed in rats overexpressing hK1 should consider
      the activation of B1 receptors by des-[Arg9]bradykinin. For further comparison,
      two short internally quenched fluorescent peptides that bind to hK1 with affinity
      in the nM range and some inhibitors described previously for hK1 were also
      assayed with mK1 and rK1.

PMID- 15040792
TI  - Consumer information materials for diagnostic breast tests: women's views on
      information and their understanding of test results.
AB  - OBJECTIVES: To explore women's views on diagnostic breast test information and
      elicit their preferences for this information. DESIGN: In-depth, face-to-face
      interview. SETTING AND PARTICIPANTS: Thirty-seven women who had previously
      participated in a population-based telephone survey. MAIN OUTCOME MEASURES:
      Qualitative thematic analysis. RESULTS: Analysis of interview transcripts
      revealed information about: (1) the wide range of information participants wanted
      about diagnostic mammography; (2) general reactions to diagnostic breast test
      information, including positive and negative reactions, views of test accuracy
      information and perceived influences on information preferences; (3) preferences
      for information content and presentation including the need for written
      information, the meaning of statistical information, different views on a simple
      presentation style, and variation in preferences; and (4) women's understanding
      of diagnostic test results. CONCLUSION: Women want a range of information about
      diagnostic mammography, which is relevant at different times in the decision
      making and testing process. Many women have difficulty interpreting test results.

PMID- 15040793
TI  - Consumer choice of social health insurance in managed competition.
AB  - OBJECTIVE: To promote managed competition in Dutch health insurance, the insured
      are now able to change health insurers. They can choose a health insurer with a
      low flat-rate premium, the best supplementary insurance and/or the best service.
      As we do not know why people prefer one health insurer to another, we
      investigated their reasons for selecting their health insurer and assessed the
      importance of the supplementary benefit package and the flat-rate premium.
      METHODS: A self-administered questionnaire was completed by 468 of a total of 884
      (52.9%). Data were compared among three groups. The first group comprised those
      who left one health insurer for another (exit). The second group had joined the
      health insurer (entry) and the third group comprised those who did not switch
      (stayers). RESULTS: Those in the entry group were statistically significantly
      less satisfied with their former insurance organization than those in the other
      groups (exit and stayers) with the insurance organization under investigation.
      They were also less satisfied than the other groups in respect of the flat-rate
      premium. Those in the exit group were younger and seemed to be in better health.
      In general, the insured were only aware of small differences between health
      insurance funds and the three groups did not differ from each other in this
      respect. About a quarter of the entry group reported the flat-rate premium as a
      reason for selecting a particular health insurance fund. However, the most
      frequently reported reason, for both exit and entry, was the benefit package of
      the supplementary insurance. CONCLUSIONS: In the absence of clear differences
      between insurance organizations, the advantages of managed competition maybe too
      difficult to achieve.

PMID- 15040794
TI  - Medical messages in the media--barriers and solutions to improving medical
      journalism.
AB  - CONTEXT: Medical issues are widely reported in the mass media. These reports
      influence the general public, policy makers and health-care professionals. This
      information should be valid, but is often criticized for being speculative,
      inaccurate and misleading. An understanding of the obstacles medical reporters
      meet in their work can guide strategies for improving the informative value of
      medical journalism. OBJECTIVE: To investigate constraints on improving the
      informative value of medical reports in the mass media and elucidate possible
      strategies for addressing these. DESIGN: We reviewed the literature and organized
      focus groups, a survey of medical journalists in 37 countries, and semi
      structured telephone interviews. RESULTS: We identified nine barriers to
      improving the informative value of medical journalism: lack of time, space and
      knowledge; competition for space and audience; difficulties with terminology;
      problems finding and using sources; problems with editors and commercialism. Lack
      of time, space and knowledge were the most common obstacles. The importance of
      different obstacles varied with the type of media and experience. Many health
      reporters feel that it is difficult to find independent experts willing to assist
      journalists, and also think that editors need more education in critical
      appraisal of medical news. Almost all of the respondents agreed that the
      informative value of their reporting is important. Nearly everyone wanted access
      to short, reliable and up-to-date background information on various topics
      available on the Internet. A majority (79%) was interested in participating in a
      trial to evaluate strategies to overcome identified constraints. CONCLUSIONS:
      Medical journalists agree that the validity of medical reporting in the mass
      media is important. A majority acknowledge many constraints. Mutual efforts of
      health-care professionals and journalists employing a variety of strategies will
      be needed to address these constraints.

PMID- 15040795
TI  - Involving users in low back pain research.
AB  - OBJECTIVE: To involve users in the design of a research project that aims at
      describing a 12-month course of low back pain in an adult population sample
      (epidemiological strand), and to determine how patient and professional
      perceptions of low back pain and its treatment relate to the use of health-care
      and to subsequent outcome (qualitative strand). DESIGN: Three focus groups were
      organized in the preparatory phase of the project with general practitioners,
      other health professionals and low back pain sufferers. Issues pertaining to the
      experience of living with, or treating low back pain were explored and users were
      asked to identify relevant research questions for consideration within the study.
      FINDINGS: The focus groups revealed tensions between involving users as co
      researchers for design issues and their role as sufferers and health
      professionals who want to share their narrative accounts of low back pain. The
      group discussions produced a wealth of material for analysis, but no explicitly
      stated research topics. Three key themes and the process of user involvement in
      the focus groups are discussed. CONCLUSIONS: The focus group format could be
      restrictive in that it allows for detailed exchange between participants, but is
      insufficiently geared towards the production of a research agenda. We draw
      conclusions as to possible approaches for user involvement in health services
      research design.

PMID- 15040796
TI  - 'Follow the Fish': involving young people in primary care in Midlothian.
AB  - OBJECTIVES: The project aims were to enable young people to contribute their
      views about health services, to encourage professionals and policy makers to
      listen to the young people and to stimulate action to address the issues raised.
      DESIGN: Peer interviews were undertaken by a team of five young people to
      identify the experience and views of young people of various ages about health
      services. Drama workshop sessions were conducted with 10-15 young people,
      encompassing initial issue-identifying activities and group discussion about
      their own experience of, and views about health services, followed by role-play
      and improvisation to construct drama scenarios about the issues gathered from the
      interviews and discussions. SETTING AND PARTICIPANTS: Twenty young people aged 12
      16 years from the Mayfield and Gorebridge areas of Midlothian were recruited from
      Newbattle Community High school. The project was conducted as a voluntary after
      school activity for 12 weeks. RESULTS: A drama was constructed from research
      conducted by young people into the experiences and views of their peer group
      about health services. A cast of young people performed the drama to an invited
      audience of 30 health and education professionals and held a post-performance
      question and answer session with the audience to explore the issues raised. The
      drama engendered a number of practical outcomes related to improving the usage
      and experience of health services of young people. CONCLUSIONS: Drama can offer a
      means to encourage participation, facilitate participants' self-expression and
      explore health/health service themes and issues. In conjunction with conventional
      techniques such as interviews and group discussions, a drama project can also be
      used to communicate the experience, views and needs of the wider client group to
      service providers and planners. Such initiatives can generate outcomes to improve
      service users' experience of health services.

PMID- 15040799
TI  - Use of Internet information by women with breast cancer.

PMID- 15040797
TI  - Provider-sponsored virtual communities for chronic patients: improving health
      outcomes through organizational patient-centred knowledge management.
AB  - Patients with long-term chronic disease experience numerous illness patterns and
      disease trends over time, resulting in different sets of knowledge needs than
      patients who intermittently seek medical care for acute or short-term problems.
      Health-care organizations can promote knowledge creation and utilization by
      chronic patients through the introduction of a virtual, private, disease-specific
      patient community. This virtual socialization alters the role of chronic disease
      patients from external consumers of health-care services to a 'community of
      practice' of internal customers so that, with the tacit support of their health
      care organization, they have a forum supporting the integration of knowledge
      gained from the experiences of living with chronic disease in their self
      management. Patient-centred health-care organizations can employ the virtual
      community to direct and support the empowerment of chronic patients in their
      care.

PMID- 15040801
TI  - Fundulus heteroclitus gonadotropins.5: Small scale chromatographic fractionation
      of pituitary extracts into components with different steroidogenic activities
      using homologous bioassays.
AB  - Fractionation and characterization of gonadotropins (GtH) from Fundulus
      heteroclitus pituitary extracts were carried out using a biocompatible liquid
      chromatographic procedure (Pharmacia FPLC system). Chromatographic fractions were
      monitored for gonadotropic activities (induction of oocyte maturation and steroid
      production) using homologous follicle bioassays in vitro. Size-exclusion
      chromatography eluted gonadotropic activity in one major protein peak (Mr
      approximately 30,000). Anion-exchange and hydrophobic-interaction chromatography
      (HIC) yielded two distinct peaks of 17beta-estradiol (E2)- and 17alpha
      hydroxy,20beta-dihydroprogesterone (DHP)-promoting activity with associated
      oocyte maturation. Two-dimensional chromatography (chromatofocusing followed by
      HIC) resolved pituitary extracts into two active fractions; both induced E2
      synthesis, but one was relatively poor in eliciting DHP and testosterone
      production. Thus, using homologous bioassays, at least two quantitatively
      different gonadotropic (steroidogenic) activities: an E2-promoting gonadotropin
      (GtH I-like) and a DHP-promoting gonadotropin (GtH II-like), which has a lower
      isoelectric point but greater hydrophobicity than the former, can be
      distinguished from F. heteroclitus pituitaries by a variety of chromatographic
      procedures. This study complements previous biochemical and molecular data in F.
      heteroclitus and substantiates the duality of GtH function in a multiple-spawning
      teleost.

PMID- 15040800
TI  - A mouse model of sitosterolemia: absence of Abcg8/sterolin-2 results in failure
      to secrete biliary cholesterol.
AB  - BACKGROUND: Mutations in either of two genes comprising the STSL locus, ATP
      binding cassette (ABC)-transporters ABCG5 (encoding sterolin-1) and ABCG8
      (encoding sterolin-2), result in sitosterolemia, a rare autosomal recessive
      disorder of sterol trafficking characterized by increased plasma plant sterol
      levels. Based upon the genetics of sitosterolemia, ABCG5/sterolin-1 and
      ABCG8/sterolin-2 are hypothesized to function as obligate heterodimers. No
      phenotypic difference has yet been described in humans with complete defects in
      either ABCG5 or ABCG8. These proteins, based upon the defects in humans, are
      responsible for regulating dietary sterol entry and biliary sterol secretion.
      METHODS: In order to mimic the human disease, we created, by a targeted
      disruption, a mouse model of sitosterolemia resulting in Abcg8/sterolin-2
      deficiency alone. Homozygous knockout mice are viable and exhibit sitosterolemia.
      RESULTS: Mice deficient in Abcg8 have significantly increased plasma and tissue
      plant sterol levels (sitosterol and campesterol) consistent with sitosterolemia.
      Interestingly, Abcg5/sterolin-1 was expressed in both liver and intestine in
      Abcg8/sterolin-2 deficient mice and continued to show an apical expression.
      Remarkably, Abcg8 deficient mice had an impaired ability to secrete cholesterol
      into bile, but still maintained the ability to secrete sitosterol. We also report
      an intermediate phenotype in the heterozygous Abcg8+/- mice that are not
      sitosterolemic, but have a decreased level of biliary sterol secretion relative
      to wild-type mice. CONCLUSION: These data indicate that Abcg8/sterolin-2 is
      necessary for biliary sterol secretion and that loss of Abcg8/sterolin-2 has a
      more profound effect upon biliary cholesterol secretion than sitosterol. Since
      biliary sitosterol secretion is preserved, although not elevated in the
      sitosterolemic mice, this observation suggests that mechanisms other than by
      Abcg8/sterolin-2 may be responsible for its secretion into bile.

PMID- 15040803
TI  - An assessment of quality of sleep and the use of drugs with sedating properties
      in hospitalized adult patients.
AB  - BACKGROUND: Hospitalization can significantly disrupt sleeping patterns. In
      consideration of the previous reports of insomnia and apparent widespread use of
      benzodiazepines and other hypnotics in hospitalized patients, we conducted a
      study to assess quality of sleep and hypnotic drug use in our acute care adult
      patient population. The primary objectives of this study were to assess sleep
      disturbance and its determinants including the use of drugs with sedating
      properties. METHODS: This single-centre prospective study involved an assessment
      of sleep quality for consenting patients admitted to the general medicine and
      family practice units of an acute care Canadian hospital. A validated Verran and
      Snyder-Halpern (VSH) Sleep Scale measuring sleep disturbance, sleep
      effectiveness, and sleep supplementation was completed daily by patients and
      scores were compared to population statistics. Patients were also asked to
      identify factors influencing sleep while in hospital, and sedating drug use prior
      to and during hospitalization was also assessed. RESULTS: During the 70-day study
      period, 100 patients completed at least one sleep questionnaire. There was a
      relatively even distribution of males versus females, most patients were in their
      8th decade of life, retired, and suffered from multiple chronic diseases. The
      median self-reported pre-admission sleep duration for participants was 8 hours
      and our review of PharmaNet profiles revealed that 35 (35%) patients had received
      a dispensed prescription for a hypnotic or antidepressant drug in the 3-month
      period prior to admission. Benzodiazepines were the most common sedating drugs
      prescribed. Over 300 sleep disturbance, effective and supplementation scores were
      completed. Sleep disturbance scores across all study days ranged 16-681, sleep
      effectiveness scores ranged 54-402, while sleep supplementation scores ranged
      between 0-358. Patients tended to have worse sleep scores as compared to healthy
      non-hospitalized US adults in all three scales. When compared to US non
      hospitalized adults with insomnia, our patients demonstrated sleep disturbance
      and supplementation scores that were similar on Day 1, but lower (i.e. improved)
      on Day 3, while sleep effectiveness were higher (i.e. better) on both days. There
      was an association between sleep disturbance scores and the number of chronic
      diseases, the presence of pain, the use of bedtime tricyclic antidepressants, and
      the number of chronic diseases without pain. There was also an association
      between sleep effectiveness scores and the length of hospitalization, the in
      hospital use of bedtime sedatives and the presence of pain. Finally, an
      association was identified between sleep supplementation scores and the in
      hospital use of bedtime sedatives (tricyclic antidepressants and loxapine), and
      age. Twenty-nine (29%) patients received a prescription for a hypnotic drug while
      in hospital, with no evidence of pre-admission hypnotic use. The majority of
      these patients were prescribed zopiclone, lorazepam or another benzodiazepine.
      CONCLUSIONS: The results of this study reveal that quality of sleep is a problem
      that affects hospitalized adult medical service patients and a relatively high
      percentage of these patients are being prescribed a hypnotic prior to and during
      hospitalization.

PMID- 15040802
TI  - Stimulation of TM3 Leydig cell proliferation via GABA(A) receptors: a new role
      for testicular GABA.
AB  - The neurotransmitter gamma-aminobutyric acid (GABA) and subtypes of GABA
      receptors were recently identified in adult testes. Since adult Leydig cells
      possess both the GABA biosynthetic enzyme glutamate decarboxylase (GAD), as well
      as GABA(A) and GABA(B) receptors, it is possible that GABA may act as auto
      /paracrine molecule to regulate Leydig cell function. The present study was aimed
      to examine effects of GABA, which may include trophic action. This assumption is
      based on reports pinpointing GABA as regulator of proliferation and
      differentiation of developing neurons via GABA(A) receptors. Assuming such a role
      for the developing testis, we studied whether GABA synthesis and GABA receptors
      are already present in the postnatal testis, where fetal Leydig cells and, to a
      much greater extend, cells of the adult Leydig cell lineage proliferate.
      Immunohistochemistry, RT-PCR, Western blotting and a radioactive enzymatic GAD
      assay evidenced that fetal Leydig cells of five-six days old rats possess active
      GAD protein, and that both fetal Leydig cells and cells of the adult Leydig cell
      lineage possess GABA(A) receptor subunits. TM3 cells, a proliferating mouse
      Leydig cell line, which we showed to possess GABA(A) receptor subunits by RT-PCR,
      served to study effects of GABA on proliferation. Using a colorimetric
      proliferation assay and Western Blotting for proliferating cell nuclear antigen
      (PCNA) we demonstrated that GABA or the GABA(A) agonist isoguvacine significantly
      increased TM3 cell number and PCNA content in TM3 cells. These effects were
      blocked by the GABA(A) antagonist bicuculline, implying a role for GABA(A)
      receptors. In conclusion, GABA increases proliferation of TM3 Leydig cells via
      GABA(A) receptor activation and proliferating Leydig cells in the postnatal
      rodent testis bear a GABAergic system. Thus testicular GABA may play an as yet
      unrecognized role in the development of Leydig cells during the differentiation
      of the testicular interstitial compartment.

PMID- 15040804
TI  - Hyperthermia using magnetite cationic liposomes for hamster osteosarcoma.
AB  - BACKGROUND: We have developed magnetite cationic liposomes (MCLs) and applied
      them to local hyperthermia as a mediator. MCLs have a positive charge and
      generate heat under an alternating magnetic field (AMF) by hysteresis loss. In
      this study, the effect of hyperthermia using MCLs was examined in an in vivo
      study of hamster osteosarcoma. METHOD: MCLs were injected into the osteosarcoma
      and then subjected to an AMF. RESULTS: The tumor was heated at over 42 degrees C,
      but other normal tissues were not heated as much. Complete regression was
      observed in 100% of the treated group hamsters, whereas no regression was
      observed in the control group hamsters. At day 12, the average tumor volume of
      the treated hamsters was about 1/1000 of that of the control hamsters. In the
      treated hamsters, no regrowth of osteosarcomas was observed over a period of 3
      months after the complete regression. CONCLUSION: These results suggest that this
      treatment is effective for osteosarcoma.

PMID- 15040805
TI  - Efficacy and safety of acupuncture for chronic pain caused by gonarthrosis: a
      study protocol of an ongoing multi-centre randomised controlled clinical trial
      [ISRCTN27450856].
AB  - BACKGROUND: Controlled clinical trials produced contradictory results with
      respect to a specific analgesic effect of acupuncture. There is a lack of large
      multi-centre acupuncture trials. The German Acupuncture Trial represents the
      largest multi-centre study of acupuncture in the treatment of chronic pain caused
      by gonarthrosis up to now. METHODS: 900 patients will be randomised to three
      treatment arms. One group receives verum acupuncture, the second sham
      acupuncture, and the third conservative standard therapy. The trial protocol is
      described with eligibility criteria, detailed information on the treatment
      definition, blinding, endpoints, safety evaluation, statistical methods, sample
      size determination, monitoring, legal aspects, and the current status of the
      trial. DISCUSSION: A critical discussion is given regarding the considerations
      about standardisation of the acupuncture treatment, the choice of the control
      group, and the blinding of patients and observers.

PMID- 15040807
TI  - 188Re radiopharmaceuticals for radiosynovectomy: evaluation and comparison of tin
      colloid, hydroxyapatite and tin-ferric hydroxide macroaggregates.
AB  - BACKGROUND: Radiosynovectomy is a therapy used to relieve pain and inflammation
      from rheumatoid arthritis and related diseases. In this study three 188Re
      particulate compounds were characterized according to their physico-chemical
      properties and their biological behavior in rabbits. The results were compared in
      order to establish which was the radiopharmaceutical that better fits the
      requirements of this kind of radiotherapy. METHODS: Three radiopharmaceutical
      formulations, tin colloid, hydroxyapatite particles (HA) and ferric hydroxide
      macroaggregates coated with tin colloid (FHMA), were physically characterized
      (number, volume and surface of the particles). For this purpose laser diffraction
      methodology was used. To evaluate cavity leakage of activity the following
      studies in New Zealand rabbits were performed: scintigraphic images for 48 hr
      after intraarticular injection of each radiopharmaceutical, biodistribution at 48
      hr and urine samples collection during the first 24 hr post-radiopharmaceutical
      administration. RESULTS: Labeling procedures for 188Re-HA and 188Re-Sn-FHMA were
      labour intensive while 188Re-Sn was easily prepared. Furthermore, 188Re-Sn
      colloid offered the greatest surface area in the 2-10 microm range and was
      obtained with a radiochemical purity over 95%, while percentage of bound activity
      for 188Re-HA and 188Re-Sn-FHMA were 55% and 92% respectively. Stability was
      verified for the three radiopharmaceuticals for 24 hr. Scintigraphic studies and
      biodistribution in rabbits after intraarticular administration of the
      radiopharmaceuticals showed relevant activity only in the knee, this being over
      90% of the residual activity in the whole body at 48 hr in every case. Renal
      elimination of 188Re-Sn colloid and 188Re-Sn-FHMA was detected by activity
      measurements in urine samples, during the first 12 hr post-radiopharmaceutical
      injection.The percentage of activity retained in the knee was 69.1% for 188Re-Sn
      colloid, 55.1% for 188Re-Sn-FHMA and 33.6% for 188Re-HA. CONCLUSION: The 188Re-Sn
      colloid was easy to prepare, minimum facilities were required, was stable for 24
      hr and showed minimal leakage from the joint after intraarticular injection into
      the rabbit's knee. Furthermore, 188Re-Sn colloid has greater retention in the
      knee when it is compared with the other radiopharmaceuticals, so it could provide
      the best therapeutic effect/absorbed dose ratio for the patient.

PMID- 15040806
TI  - Thymidylate synthetase mRNA levels are increased in liver metastases of
      colorectal cancer patients resistant to fluoropyrimidine-based chemotherapy.
AB  - BACKGROUND: Fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluoro
      2'deoxyuridine (FUDR) are among the most effective chemotherapeutic agents for
      treatment of metastatic colorectal cancer (CRC). Increased expression of
      thymidylate synthetase (TS) in CRC metastases has been proposed to be an
      important mechanism of resistance to fluoropyrimidine-based chemotherapy.
      METHODS: The present study investigated whether TS mRNA levels in liver
      metastases of 20 CRC patients before treatment with FUDR by hepatic arterial
      infusion (HAI) correlated with frequency of clinical response or survival
      duration. RESULTS: Median survival duration of patients with TS mRNA levels above
      and below the median was 15 and 18 months, respectively (p > 0.05). Clinical
      response was achieved in 40% of patients with low TS mRNA levels, but in only 20%
      of patients with high TS mRNA levels (p = 0.01). TS mRNA levels were also
      measured for liver metastases of 7 of the patients that did not achieve a
      clinical response. A statistically significant increase in expression of TS mRNA
      was observed for liver metastases resistant to chemotherapy (21 +/- 14) in
      comparison to liver metastases of the same patients before chemotherapy (8 +/- 4)
      (p = 0.03). CONCLUSION: This is the first report to demonstrate increased TS
      expression in liver metastases from CRC patients resistant to fluoropyrimidine
      based chemotherapy. These findings are consistent with previous studies
      indicating that increased TS expression is associated with resistance to
      fluoropyrimidine-based chemotherapy.

PMID- 15040808
TI  - Glutathione S-Transferase Omega 1 variation does not influence age at onset of
      Huntington's disease.
AB  - BACKGROUND: Huntington's disease (HD) is a fully penetrant, autosomal dominantly
      inherited disorder associated with abnormal expansions of a stretch of perfect
      CAG repeats in the 5' part of the IT15 gene. The number of repeat units is highly
      predictive for the age at onset (AO) of the disorder. But AO is only modestly
      correlated with repeat length when intermediate HD expansions are considered.
      Circumstantial evidence suggests that additional features of the HD course are
      based on genetic traits. Therefore, it may be possible to investigate the genetic
      background of HD, i.e. to map the loci underlying the development and progression
      of the disease. Recently an association of Glutathione S-Transferase Omega 1
      (GSTO1) and possibly of GSTO2 with AO was demonstrated for, both, Alzheimer's
      (AD) and Parkinson's disease (PD). METHODS: We have genotyped the polymorphisms
      rs4925 GSTO1 and rs2297235 GSTO2 in 232 patients with HD and 228 controls.
      RESULTS: After genotyping GSTO1 and GSTO2 polymorphisms, firstly there was no
      statistically significant difference in AO for HD patients, as well as secondly
      for HD patients vs. controls concerning, both, genotype and allele frequencies,
      respectively. CONCLUSION: The GSTO1 and GSTO2 genes flanked by the investigated
      polymorphisms are not comprised in a primary candidate region influencing AO in
      HD.

PMID- 15040809
TI  - A case of familial isolated hemihyperplasia.
AB  - BACKGROUND: Hemihyperplasia (hemihypertrophy) is defined as asymmetric body
      overgrowth of one or more body parts. Hemihyperplasia can be isolated or be part
      of well-defined syndromes such as in the case of Beckwith-Wiedemann syndrome
      (BWS). Isolated hemihyperplasia is usually sporadic, but a number of familial
      occurrences have been described. CASE PRESENTATION: We describe a Tunisian family
      in which three maternal cousins and their maternal grandfather present with
      isolated hemihyperplasia. CONCLUSIONS: The etiology of isolated hemihyperplasia
      is unknown although in BWS, genomic imprinting has been shown to play a role in
      the asymmetric overgrowth. Given the similarity between these two conditions, it
      is possible that both may share a common pathogenesis. We also discuss the
      possible genetic mechanisms leading to the production of hemihyperplasia in this
      family.

PMID- 15040810
TI  - The presence of non-organ-specific autoantibodies is associated with a negative
      response to combination therapy with interferon and ribavirin for chronic
      hepatitis C.
AB  - BACKGROUND: Non-organ-specific autoantibodies are found in a considerable number
      of anti-HCV positive patients. Previous studies investigated the clinical
      relevance of these antibodies in patients treated with interferon monotherapy,
      but not combination therapies. METHODS: Anti-nuclear, anti-smooth muscle, anti
      mitochondrial, anti-neutrophil-cytoplasmatic and anti-liver/kidney microsomal
      antibodies were determined in 78 consecutive anti-HCV positive patients by
      indirect immunofluorescence. The presence of these antibodies was related to
      demographic variables and to the outcome of antiviral combination therapy with
      interferon-alpha and ribavirin in 65 patients. RESULTS: In our study, positivity
      for autoantibodies was associated with higher alanine aminotransferase levels and
      higher mean values for HCV-RNA (p < 0.01). Furthermore, negativity for non-organ
      specific autoantibodies was associated with a favourable treatment outcome of
      combination therapy with at least one negative RT-PCR for HCV-RNA during
      treatment (OR 4.65, 95% CI 1.31 to 16.48, p = 0.02). ANA and SMA staining
      patterns and titers were not correlated to treatment response. With multiple
      logistic regression analysis, positivity for autoantibodies and HCV genotype were
      independently associated with outcome of antiviral combination therapy (p =
      0.02). CONCLUSIONS: The absence of non-organ-specific autoantibodies might
      indicate a significantly higher chance for viral clearance in response to
      combination therapy for chronic hepatitis C infection. Therefore, despite of an
      overall higher treatment response, the addition of the immunomodulatory drug
      ribavirin could accentuate immunological differences that affect treatment
      outcome and might have been less obvious in earlier studies analysing interferon
      monotherapy.

PMID- 15040811
TI  - Triptolide, an active compound identified in a traditional Chinese herb, induces
      apoptosis of rheumatoid synovial fibroblasts.
AB  - BACKGROUND: Extracts of Tripterygium wilfordii Hook F (TWHF), a traditional
      Chinese herb, have been reported to show efficacy in patients with rheumatoid
      arthritis (RA). Since RA is not only characterized by inflammation but also by
      synovial proliferation in the joints, we examined whether triptolide (a
      constituent of TWHF) could influence the proliferation of rheumatoid synovial
      fibroblasts (RSF) by induction of apoptosis. RESULTS: RSF were obtained from RA
      patients during surgery and were treated with triptolide under various
      conditions. The viability and proliferation of RSF were measured by the 4-[3-(4
      iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1)
      assay and by 5-bromo-2'-deoxyuridine incorporation, respectively. Apoptosis was
      identified by detection of DNA fragmentation using an enzyme-linked immunosorbent
      assay and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling
      (TUNEL). The role of caspases in apoptosis of RSF was analyzed by measuring
      caspase-3 activity. Activation of the peroxisome proliferator-activated receptor
      (PPAR) gamma was assessed by a luciferase reporter gene assay using RSF
      transfected with a plasmid containing the peroxisome proliferator response
      element. Triptolide decreased viability, inhibited proliferation, and induced
      apoptosis of RSF in a concentration-dependent manner at very low (nM)
      concentrations. Caspase-3 activity was increased by treatment with triptolide and
      was suppressed by caspase inhibitors. Although PPARgamma activation was induced
      by 15-deoxy-Delta12,14-prostaglandin J2, triptolide did not induce it under the
      same experimental conditions. An extract of TWHF also induced DNA fragmentation
      in RSF. CONCLUSION: The mechanism of action remains to be studied; however,
      triptolide may possibly have a disease-modifying effect in patients with RA.

PMID- 15040812
TI  - Rat pro-inflammatory cytokine and cytokine related mRNA quantification by real
      time polymerase chain reaction using SYBR green.
AB  - BACKGROUND: Cytokine mRNA quantification is widely used to investigate cytokine
      profiles, particularly in small samples. Real-time polymerase chain reaction is
      currently the most reliable method of quantifying low-level transcripts such as
      cytokine and cytokine receptor mRNAs. This accurate technique allows the
      quantification of a larger pattern of cytokines than quantification at the
      protein level, which is limited to a smaller number of proteins. RESULTS:
      Although fluorogenic probes are considered more sensitive than fluorescent dyes,
      we have developed SYBR Green real-time RT-PCR protocols to assay pro-inflammatory
      cytokines (IL1a, IL1b and IL6, TNFa), cytokine receptors (IL1-r1, IL1-r2, IL6-r,
      TNF-r2) and related molecules (IL1-RA, SOCS3) mRNA in rats. This method enables
      normalisation against several housekeeping genes (beta-actin, GAPDH, CypA, HPRT)
      dependent on the specific experimental treatments and tissues using either
      standard curve, or comparative CT quantification method. PCR efficiency and
      sensitivity allow the assessment of; i) basal mRNA levels in many tissues and
      even decreases in mRNA levels, ii) mRNA levels from very small samples.
      CONCLUSION: Real-time RT-PCR is currently the best way to investigate cytokine
      networks. The investigations should be completed by the analysis of genes
      regulated by cytokines or involved in cytokine signalling, providing indirect
      information on cytokine protein expression.

PMID- 15040813
TI  - Evolutionary history of Oryza sativa LTR retrotransposons: a preliminary survey
      of the rice genome sequences.
AB  - BACKGROUND: LTR Retrotransposons transpose through reverse transcription of an
      RNA intermediate and are ubiquitous components of all eukaryotic genomes thus far
      examined. Plant genomes, in particular, have been found to be comprised of a
      remarkably high number of LTR retrotransposons. There is a significant body of
      direct and indirect evidence that LTR retrotransposons have contributed to gene
      and genome evolution in plants. RESULTS: To explore the evolutionary history of
      long terminal repeat (LTR) retrotransposons and their impact on the genome of
      Oryza sativa, we have extended an earlier computer-based survey to include all
      identifiable full-length, fragmented and solo LTR elements in the rice genome
      database as of April 2002. A total of 1,219 retroelement sequences were
      identified, including 217 full-length elements, 822 fragmented elements, and 180
      solo LTRs. In order to gain insight into the chromosomal distribution of LTR
      retrotransposons in the rice genome, a detailed examination of LTR
      retrotransposon sequences on Chromosome 10 was carried out. An average of 22.3
      LTR-retrotransposons per Mb were detected in Chromosome 10. CONCLUSIONS: Gypsy
      like elements were found to be >4 x more abundant than copia-like elements.
      Eleven of the thirty-eight investigated LTR-retrotransposon families displayed
      significant subfamily structure. We estimate that at least 46.5% of LTR
      retrotransposons in the rice genome are older than the age of the species (<
      680,000 years). LTR-retrotransposons present in the rice genome range in age from
      those just recently inserted up to nearly 10 million years old. Approximately 20%
      of LTR retrotransposon sequences lie within putative genes. The distribution of
      elements across chromosome 10 is non-random with the highest density (48 elements
      per Mb) being present in the pericentric region.

PMID- 15040814
TI  - Genomic structure and alternative splicing of murine R2B receptor protein
      tyrosine phosphatases (PTPkappa, mu, rho and PCP-2).
AB  - BACKGROUND: Four genes designated as PTPRK (PTPkappa), PTPRL/U (PCP-2), PTPRM
      (PTPmu) and PTPRT (PTPrho) code for a subfamily (type R2B) of receptor protein
      tyrosine phosphatases (RPTPs) uniquely characterized by the presence of an N
      terminal MAM domain. These transmembrane molecules have been implicated in
      homophilic cell adhesion. In the human, the PTPRK gene is located on chromosome
      6, PTPRL/U on 1, PTPRM on 18 and PTPRT on 20. In the mouse, the four genes ptprk,
      ptprl, ptprm and ptprt are located in syntenic regions of chromosomes 10, 4, 17
      and 2, respectively. RESULTS: The genomic organization of murine R2B RPTP genes
      is described. The four genes varied greatly in size ranging from approximately 64
      kb to approximately 1 Mb, primarily due to proportional differences in intron
      lengths. Although there were also minor variations in exon length, the number of
      exons and the phases of exon/intron junctions were highly conserved. In situ
      hybridization with digoxigenin-labeled cRNA probes was used to localize each of
      the four R2B transcripts to specific cell types within the murine central nervous
      system. Phylogenetic analysis of complete sequences indicated that PTPrho and
      PTPmu were most closely related, followed by PTPkappa. The most distant family
      member was PCP-2. Alignment of RPTP polypeptide sequences predicted putative
      alternatively spliced exons. PCR experiments revealed that five of these exons
      were alternatively spliced, and that each of the four phosphatases incorporated
      them differently. The greatest variability in genomic organization and the
      majority of alternatively spliced exons were observed in the juxtamembrane
      domain, a region critical for the regulation of signal transduction. CONCLUSIONS:
      Comparison of the four R2B RPTP genes revealed virtually identical principles of
      genomic organization, despite great disparities in gene size due to variations in
      intron length. Although subtle differences in exon length were also observed, it
      is likely that functional differences among these genes arise from the specific
      combinations of exons generated by alternative splicing.

PMID- 15040815
TI  - Detection of allelic variations of human gene expression by polymerase colonies.
AB  - BACKGROUND: Quantification of variations of human gene expression is complicated
      by the small differences between different alleles. Recent work has shown that
      variations do exist in the relative allelic expression levels in certain genes of
      heterozygous individuals. Herein, we describe the application of an immobilized
      polymerase chain reaction technique as an alternative approach to measure
      relative allelic differential expression. RESULTS: Herein, we report a novel
      assay, based on immobilized polymerase colonies, that accurately quantifies the
      relative expression levels of two alleles in a given sample. Mechanistically,
      this was accomplished by PCR amplifying a gene in a cDNA library in a thin
      polyacrylamide gel. By immobilizing the PCR, it is ensured that each transcript
      gives rise to only a single immobilized PCR colony, or "polony". Once polony
      amplified, the two alleles of the gene were differentially labeled by performing
      in situ sequencing with fluorescently labeled nucleotides. For these sets of
      experiments, silent single nucleotide polymorphisms (SNPs) were used to
      discriminate the two alleles. Finally, a simple count was then performed on the
      differentially labeled polonies in order to determine the relative expression
      levels of the two alleles. To validate this technique, the relative expression
      levels of PKD2 in a family of heterozygous patients bearing the 4208G/A SNP were
      examined and compared to the literature. CONCLUSIONS: We were able to reproduce
      the results of allelic variation in gene expression using an accurate technology
      known as polymerase colonies. Therefore, we have demonstrated the utility of this
      method in human gene expression analysis.

PMID- 15040816
TI  - The iron-sulfur cluster assembly genes iscS and iscU of Entamoeba histolytica
      were acquired by horizontal gene transfer.
AB  - BACKGROUND: Iron-sulfur (FeS) proteins are present in all living organisms and
      play important roles in electron transport and metalloenzyme catalysis. The
      maturation of FeS proteins in eukaryotes is an essential function of
      mitochondria, but little is known about this process in amitochondriate
      eukaryotes. Here we report on the identification and analysis of two genes
      encoding critical FeS cluster (Isc) biosynthetic proteins from the
      amitochondriate human pathogen Entamoeba histolytica. RESULTS: E. histolytica
      IscU and IscS were found to contain all features considered essential for their
      biological activity, including amino acid residues involved in substrate and/or
      co-factor binding. The IscU protein differs significantly from other eukaryotic
      homologs and resembles the long type isoforms encountered in some bacteria.
      Phylogenetic analyses of E. histolytica IscS and IscU showed a close relationship
      with homologs from Helicobacter pylori and Campylobacter jejuni, to the exclusion
      of mitochondrial isoforms. CONCLUSIONS: The bacterial-type FeS cluster assembly
      genes of E. histolytica suggest their lateral acquisition from epsilon
      proteobacteria. This is a clear example of horizontal gene transfer (HGT) from
      eubacteria to unicellular eukaryotic organisms, a phenomenon known to contribute
      significantly to the evolution of eukaryotic genomes.

PMID- 15040818
TI  - The tissue microarray data exchange specification: implementation by the
      Cooperative Prostate Cancer Tissue Resource.
AB  - BACKGROUND: Tissue Microarrays (TMAs) have emerged as a powerful tool for
      examining the distribution of marker molecules in hundreds of different tissues
      displayed on a single slide. TMAs have been used successfully to validate
      candidate molecules discovered in gene array experiments. Like gene expression
      studies, TMA experiments are data intensive, requiring substantial information to
      interpret, replicate or validate. Recently, an open access Tissue Microarray Data
      Exchange Specification has been released that allows TMA data to be organized in
      a self-describing XML document annotated with well-defined common data elements.
      While this specification provides sufficient information for the reproduction of
      the experiment by outside research groups, its initial description did not
      contain instructions or examples of actual implementations, and no implementation
      studies have been published. The purpose of this paper is to demonstrate how the
      TMA Data Exchange Specification is implemented in a prostate cancer TMA. RESULTS:
      The Cooperative Prostate Cancer Tissue Resource (CPCTR) is funded by the National
      Cancer Institute to provide researchers with samples of prostate cancer annotated
      with demographic and clinical data. The CPCTR now offers prostate cancer TMAs and
      has implemented a TMA database conforming to the new open access Tissue
      Microarray Data Exchange Specification. The bulk of the TMA database consists of
      clinical and demographic data elements for 299 patient samples. These data
      elements were extracted from an Excel database using a transformative Perl
      script. The Perl script and the TMA database are open access documents
      distributed with this manuscript. CONCLUSIONS: TMA databases conforming to the
      Tissue Microarray Data Exchange Specification can be merged with other TMA files,
      expanded through the addition of data elements, or linked to data contained in
      external biological databases. This article describes an open access
      implementation of the TMA Data Exchange Specification and provides detailed
      guidance to researchers who wish to use the Specification.

PMID- 15040817
TI  - A scale invariant clustering of genes on human chromosome 7.
AB  - BACKGROUND: Vertebrate genes often appear to cluster within the background of
      nontranscribed genomic DNA. Here an analysis of the physical distribution of gene
      structures on human chromosome 7 was performed to confirm the presence of
      clustering, and to elucidate possible underlying statistical and biological
      mechanisms. RESULTS: Clustering of genes was confirmed by virtue of a variance of
      the number of genes per unit physical length that exceeded the respective mean.
      Further evidence for clustering came from a power function relationship between
      the variance and mean that possessed an exponent of 1.51. This power function
      implied that the spatial distribution of genes on chromosome 7 was scale
      invariant, and that the underlying statistical distribution had a Poisson-gamma
      (PG) form. A PG distribution for the spatial scattering of genes was validated by
      stringent comparisons of both the predicted variance to mean power function and
      its cumulative distribution function to data derived from chromosome 7.
      CONCLUSION: The PG distribution was consistent with at least two different
      biological models: In the microrearrangement model, the number of genes per unit
      length of chromosome represented the contribution of a random number of smaller
      chromosomal segments that had originated by random breakage and reconstruction of
      more primitive chromosomes. Each of these smaller segments would have necessarily
      contained (on average) a gamma distributed number of genes. In the gene cluster
      model, genes would be scattered randomly to begin with. Over evolutionary
      timescales, tandem duplication, mutation, insertion, deletion and rearrangement
      could act at these gene sites through a stochastic birth death and immigration
      process to yield a PG distribution. On the basis of the gene position data alone
      it was not possible to identify the biological model which best explained the
      observed clustering. However, the underlying PG statistical model implicated
      neutral evolutionary mechanisms as the basis for this clustering.

PMID- 15040819
TI  - SeeGH--a software tool for visualization of whole genome array comparative
      genomic hybridization data.
AB  - BACKGROUND: Array comparative genomic hybridization (CGH) is a technique which
      detects copy number differences in DNA segments. Complete sequencing of the human
      genome and the development of an array representing a tiling set of tens of
      thousands of DNA segments spanning the entire human genome has made high
      resolution copy number analysis throughout the genome possible. Since array CGH
      provides signal ratio for each DNA segment, visualization would require the
      reassembly of individual data points into chromosome profiles. RESULTS: We have
      developed a visualization tool for displaying whole genome array CGH data in the
      context of chromosomal location. SeeGH is an application that translates spot
      signal ratio data from array CGH experiments to displays of high resolution
      chromosome profiles. Data is imported from a simple tab delimited text file
      obtained from standard microarray image analysis software. SeeGH processes the
      signal ratio data and graphically displays it in a conventional CGH karyotype
      diagram with the added features of magnification and DNA segment annotation. In
      this process, SeeGH imports the data into a database, calculates the average
      ratio and standard deviation for each replicate spot, and links them to
      chromosome regions for graphical display. Once the data is displayed, users have
      the option of hiding or flagging DNA segments based on user defined criteria, and
      retrieve annotation information such as clone name, NCBI sequence accession
      number, ratio, base pair position on the chromosome, and standard deviation.
      CONCLUSIONS: SeeGH represents a novel software tool used to view and analyze
      array CGH data. The software gives users the ability to view the data in an
      overall genomic view as well as magnify specific chromosomal regions facilitating
      the precise localization of genetic alterations. SeeGH is easily installed and
      runs on Microsoft Windows 2000 or later environments.

PMID- 15040820
TI  - TLR4 signaling is essential for survival in acute lung injury induced by virulent
      Pseudomonas aeruginosa secreting type III secretory toxins.
AB  - BACKGROUND: The relative contributions of the cytotoxic phenotype of P.
      aeruginosa expressing type III secretory toxins and an immunocompromised
      condition lacking normal Toll-like receptor 4 (TLR4) signaling in the
      pathogenesis of acute lung injury and sepsis were evaluated in a mouse model for
      Pseudomonas aeruginosa pneumonia. By using lipopolysaccharide-resistant C3H/HeJ
      mice missing normal TLR4 signaling due to a mutation on the tlr4 gene, we
      evaluated how TLR4 signaling modulates the pneumonia caused by cytotoxic P.
      aeruginosa expressing type III secretory toxins. METHODS: We infected C3H/HeJ or
      C3H/FeJ mice with three different doses of either a cytotoxic P. aeruginosa
      strain (wild type PA103) or its non-cytotoxic isogenic mutant missing the type
      III secretory toxins (PA103DeltaUT). Survival of the infected mice was evaluated,
      and the severity of acute lung injury quantified by measuring alveolar epithelial
      permeability as an index of acute epithelial injury and the water to dry weight
      ratios of lung homogenates as an index of lung edema. Bacteriological analysis
      and cytokine assays were performed in the infected mice. RESULTS: Development of
      acute lung injury and sepsis was observed in all mouse strains when the cytotoxic
      P. aeruginosa strain but not the non-cytotoxic strain was instilled in the
      airspaces of the mice. Only C3H/HeJ mice had severe bacteremia and high mortality
      when a low dose of the cytotoxic P. aeruginosa strain was instilled in their
      lungs. CONCLUSION: The cytotoxic phenotype of P. aeruginosa is the critical
      factor causing acute lung injury and sepsis in infected hosts. When the P.
      aeruginosa is a cytotoxic strain, the TLR4 signaling system is essential to clear
      the bacteria to prevent lethal lung injury and bacteremia.

PMID- 15040821
TI  - Prevention of postmenopausal bone loss by a low-magnitude, high-frequency
      mechanical stimuli: a clinical trial assessing compliance, efficacy, and safety.
AB  - A 1-year prospective, randomized, double-blind, and placebo-controlled trial of
      70 postmenopausal women demonstrated that brief periods (<20 minutes) of a low
      level (0.2g, 30 Hz) vibration applied during quiet standing can effectively
      inhibit bone loss in the spine and femur, with efficacy increasing significantly
      with greater compliance, particularly in those subjects with lower body mass.
      INTRODUCTION: Indicative of the anabolic potential of mechanical stimuli, animal
      models have demonstrated that short periods (<30 minutes) of low-magnitude
      vibration (<0.3g), applied at a relatively high frequency (20-90 Hz), will
      increase the number and width of trabeculae, as well as enhance stiffness and
      strength of cancellous bone. Here, a 1-year prospective, randomized, double
      blind, and placebo-controlled clinical trial in 70 women, 3-8 years past the
      menopause, examined the ability of such high-frequency, low-magnitude mechanical
      signals to inhibit bone loss in the human. MATERIALS AND METHODS: Each day, one
      half of the subjects were exposed to short-duration (two 10-minute
      treatments/day), low-magnitude (2.0 m/s2 peak to peak), 30-Hz vertical
      accelerations (vibration), whereas the other half stood for the same duration on
      placebo devices. DXA was used to measure BMD at the spine, hip, and distal radius
      at baseline, and 3, 6, and 12 months. Fifty-six women completed the 1-year
      treatment. RESULTS AND CONCLUSIONS: The detection threshold of the study design
      failed to show any changes in bone density using an intention-to-treat analysis
      for either the placebo or treatment group. Regression analysis on the a priori
      study group demonstrated a significant effect of compliance on efficacy of the
      intervention, particularly at the lumbar spine (p = 0.004). Posthoc testing was
      used to assist in identifying various subgroups that may have benefited from this
      treatment modality. Evaluating those in the highest quartile of compliance (86%
      compliant), placebo subjects lost 2.13% in the femoral neck over 1 year, whereas
      treatment was associated with a gain of 0.04%, reflecting a 2.17% relative
      benefit of treatment (p = 0.06). In the spine, the 1.6% decrease observed over 1
      year in the placebo group was reduced to a 0.10% loss in the active group,
      indicating a 1.5% relative benefit of treatment (p = 0.09). Considering the
      interdependence of weight, the spine of lighter women (<65 kg), who were in the
      highest quartile of compliance, exhibited a relative benefit of active treatment
      of 3.35% greater BMD over 1 year (p = 0.009); for the mean compliance group, a
      2.73% relative benefit in BMD was found (p = 0.02). These preliminary results
      indicate the potential for a noninvasive, mechanically mediated intervention for
      osteoporosis. This non-pharmacologic approach represents a physiologically based
      means of inhibiting the decline in BMD that follows menopause, perhaps most
      effectively in the spine of lighter women who are in the greatest need of
      intervention.

PMID- 15040822
TI  - Effect of 6-month whole body vibration training on hip density, muscle strength,
      and postural control in postmenopausal women: a randomized controlled pilot
      study.
AB  - High-frequency mechanical strain seems to stimulate bone strength in animals. In
      this randomized controlled trial, hip BMD was measured in postmenopausal women
      after a 24-week whole body vibration (WBV) training program. Vibration training
      significantly increased BMD of the hip. These findings suggest that WBV training
      might be useful in the prevention of osteoporosis. INTRODUCTION: High-frequency
      mechanical strain has been shown to stimulate bone strength in different animal
      models. However, the effects of vibration exercise on the human skeleton have
      rarely been studied. Particularly in postmenopausal women-who are most at risk of
      developing osteoporosis-randomized controlled data on the safety and efficacy of
      vibration loading are lacking. The aim of this randomized controlled trial was to
      assess the musculoskeletal effects of high-frequency loading by means of whole
      body vibration (WBV) in postmenopausal women. MATERIALS AND METHODS: Seventy
      volunteers (age, 58-74 years) were randomly assigned to a whole body vibration
      training group (WBV, n = 25), a resistance training group (RES, n = 22), or a
      control group (CON, n = 23). The WBV group and the RES group trained three times
      weekly for 24 weeks. The WBV group performed static and dynamic knee-extensor
      exercises on a vibration platform (35-40 Hz, 2.28-5.09g), which mechanically
      loaded the bone and evoked reflexive muscle contractions. The RES group trained
      knee extensors by dynamic leg press and leg extension exercises, increasing from
      low (20 RM) to high (8 RM) resistance. The CON group did not participate in any
      training. Hip bone density was measured using DXA at baseline and after the 6
      month intervention. Isometric and dynamic strength were measured by means of a
      motor-driven dynamometer. Data were analyzed by means of repeated measures ANOVA.
      RESULTS: No vibration-related side effects were observed. Vibration training
      improved isometric and dynamic muscle strength (+15% and + 16%, respectively; p <
      0.01) and also significantly increased BMD of the hip (+0.93%, p < 0.05). No
      changes in hip BMD were observed in women participating in resistance training or
      age-matched controls (-0.60% and -0.62%, respectively; not significant). Serum
      markers of bone turnover did not change in any of the groups. CONCLUSION: These
      findings suggest that WBV training may be a feasible and effective way to modify
      well-recognized risk factors for falls and fractures in older women and support
      the need for further human studies.

PMID- 15040823
TI  - Low magnitude mechanical loading is osteogenic in children with disabling
      conditions.
AB  - The osteogenic potential of short durations of low-level mechanical stimuli was
      examined in children with disabling conditions. The mean change in tibia vTBMD
      was +6.3% in the intervention group compared with -11.9% in the control group.
      This pilot randomized controlled trial provides preliminary evidence that low
      level mechanical stimuli represent a noninvasive, non-pharmacological treatment
      of low BMD in children with disabling conditions. INTRODUCTION: Recent animal
      studies have demonstrated the anabolic potential of low-magnitude, high-frequency
      mechanical stimuli to the trabecular bone of weight-bearing regions of the
      skeleton. The main aim of this prospective, double-blind, randomized placebo
      controlled pilot trial (RCT) was to examine whether these signals could
      effectively increase tibial and spinal volumetric trabecular BMD (vTBMD; mg/ml)
      in children with disabling conditions. MATERIALS AND METHODS: Twenty pre-or
      postpubertal disabled, ambulant, children (14 males, 6 females; mean age, 9.1 +/-
      4.3 years; range, 4-19 years) were randomized to standing on active (n = 10;
      0.3g, 90 Hz) or placebo (n = 10) devices for 10 minutes/day, 5 days/week for 6
      months. The primary outcomes of the trial were proximal tibial and spinal (L2)
      vTBMD (mg/ml), measured using 3-D QCT. Posthoc analyses were performed to
      determine whether the treatment had an effect on diaphyseal cortical bone and
      muscle parameters. RESULTS AND CONCLUSIONS: Compliance was 44% (4.4 minutes per
      day), as determined by mean time on treatment (567.9 minutes) compared with
      expected time on treatment over the 6 months (1300 minutes). After 6 months, the
      mean change in proximal tibial vTBMD in children who stood on active devices was
      6.27 mg/ml (+6.3%); in children who stood on placebo devices, vTBMD decreased by 
      9.45 mg/ml (-11.9%). Thus, the net benefit of treatment was +15.72 mg/ml (17.7%;
      p = 0.0033). In the spine, the net benefit of treatment, compared with placebo,
      was +6.72 mg/ml, (p = 0.14). Diaphyseal bone and muscle parameters did not show a
      response to treatment. The results of this pilot RCT have shown for the first
      time that low-magnitude, high-frequency mechanical stimuli are anabolic to
      trabecular bone in children, possibly by providing a surrogate for suppressed
      muscular activity in the disabled. Over the course of a longer treatment period,
      harnessing bone's sensitivity to these stimuli may provide a non-pharmacological
      treatment for bone fragility in children.

PMID- 15040824
TI  - Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly
      community dwelling residents: a pragmatic population-based 3-year intervention
      study.
AB  - This study of 9605 community-dwelling residents supports that vitamin D and
      calcium supplementation may prevent osteoporotic fractures in elderly in a
      northern European region known to be deficient in vitamin D, especially during
      winter periods. INTRODUCTION: We evaluated the effect of two programs for the
      prevention of osteoporotic fractures leading to acute hospital admission in a
      population of elderly community-dwelling residents. MATERIALS AND METHODS: This
      was a factorial, cluster-randomized, pragmatic, intervention study. We included
      9605 community-dwelling residents aged 66+ years. We offered a prevention program
      of a daily supplement of 1000 mg of elemental calcium as calcium carbonate and
      400 IU (10 microg) of vitamin D3 to a total of 4957 participants. Another program
      with evaluation and suggestions for the improvement of the domestic environment
      was offered to a total of 5063 participants. Both programs included revision of
      the resident's current pharmaceutical treatment. We achieved information on
      osteoporotic fractures in the study population from the Danish Hospital
      Registration Database. We defined osteoporotic fractures as low energy fractures
      of the proximal humerus, distal forearm, vertebral column, pelvis, cervical
      femur, and intertrochanteric femur. RESULTS: Active participation was 50.3% in
      the Calcium and Vitamin D Program and 46.4% in the Environmental and Health
      Program. We observed a 16% reduction in fracture incidence rate (relative risk
      [RR], 0.84; CI, 0.72-0.98; p < 0.025) among male and female residents offered the
      Calcium and Vitamin D Program (intention-to-prevent analysis). CONCLUSIONS: This
      study supports that vitamin D and calcium supplementation may prevent
      osteoporotic fractures in community-dwelling elderly people in a northern
      European region known to be deficient in vitamin D, especially during winter
      periods.

PMID- 15040825
TI  - Reproducibility and side differences of mechanical tests for determining the
      structural strength of the proximal femur.
AB  - In this experimental study, we evaluated the reproducibility error of mechanical
      strength tests of the proximal femur when simulating a fall on the trochanter.
      Based on side differences in femoral failure loads in 55 pairs of femora, we
      estimated the upper limit of the precision error to be 15% for the side impact
      test, whereas the intersubject variability was >40%. INTRODUCTION: Mechanical
      tests are commonly used as the gold standard for determining one of the main
      functions of bones, that is, to provide mechanical strength. However, it is
      unknown what magnitude of error is associated with these tests. Here we
      investigate the precision error and side difference of a side impact test of the
      proximal femur. MATERIALS AND METHODS: BMC was measured using DXA in 54 pairs of
      femora from donors 79.0 +/- 10.6 years of age. Bones were tested to failure,
      simulating a fall on the greater trochanter. RESULTS: Failure loads were 3951 +/-
      1659N (CV% = 42%) on the right and 3900 +/- 1652N (CV% = 42%) on the left (no
      significant side difference). The average random difference of femoral BMC was 7
      +/- 7% and that of femoral failure loads was 17 +/- 12%. The correlation between
      BMC and failure load was 79% (r2), but the association between side differences
      in failure load with those in BMC was only 4%. When confining the analysis to
      pairs with less than 5% differences in BMC (n = 31), side differences in failure
      loads were 15 +/- 13%. When correcting failure loads for side differences of BMC,
      the difference was 16 +/- 15% CONCLUSIONS: These results suggest that the upper
      limit of the precision error for femoral strength tests is approximately 15% in a
      side impact configuration. Given the large intersubject variability of failure
      loads, this test provides an efficient tool for determining the structural
      strength of the proximal femur in a fall.

PMID- 15040826
TI  - Biochemical markers of bone metabolism and prediction of fracture in elderly
      women.
AB  - We studied the ability of various markers of bone turnover to predict fracture in
      1040 randomly recruited 75-year-old women. A total of 178 of the women sustained
      at least one fracture during follow-up (mean, 4.6 years). In elderly women,
      TRACP5b and urinary fragments of osteocalcin are promising new markers for
      prediction of fracture, in particular, vertebral fracture. INTRODUCTION:
      Biochemical markers reflecting bone turnover may improve the prediction of
      fractures. MATERIALS AND METHODS: The ability of 10 markers of bone turnover to
      predict fracture in 1040 elderly women in the Malmo OPRA study was studied. Serum
      bone-specific alkaline phosphatase and four different forms of serum osteocalcin
      (S-OC) were analyzed as markers of bone formation and serum C-terminal cross
      linking telopeptides of type I collagen (S-CTX), serum TRACP isoform 5b (S
      TRACP5b) and urinary free deoxypyridinoline (U-DPD) as markers of bone
      resorption. Two novel assays for osteocalcin fragments in urine (U-OC) were
      analyzed. Areal BMD (aBMD) was measured by DXA in the femoral neck and lumbar
      spine. RESULTS: In total, 231 fractures were sustained by 178 of the women during
      a 3- to 6.5-year (mean, 4.6 years) follow-up period. When women with prospective
      fractures were compared with women without fractures, S-TRACP5b, S-CTX, one S-OC,
      and one U-OC were higher in women with a fracture of any type (all p < 0.05), and
      all bone markers were higher in women with clinical vertebral fracture (all p <
      0.05). Markers were not significantly elevated in women with hip fracture. When
      women within the highest quartile of a bone marker were compared with all others,
      S-TRACP5b and one U-OC predicted the occurrence of a fracture of any type (odds
      ratio [OR]), 1.55 and 1.53; p < 0.05). S-TRACP5b, the two U-OCs, and S-CTX
      predicted vertebral fracture (OR, 2.28, 2.75, 2.71, and 1.94, respectively; all p
      < 0.05), and the predictive value remained significant for S-TRACP5b and the two
      U-OCs after adjusting for aBMD (OR, 2.02-2.25; p < 0.05). Bone markers were not
      able to predict hip fracture. CONCLUSION: These results show that biochemical
      markers of bone turnover can predict fracture, and in particular, fractures that
      engage trabecular bone. S-TRACP5b and U-OC are promising new markers for
      prediction of fracture.

PMID- 15040827
TI  - Relationship between changes in biochemical markers of bone turnover and BMD to
      predict vertebral fracture risk.
AB  - The change in BMD is a poor predictor of vertebral fracture risk after raloxifene
      treatment. One-year percent change in bone turnover and BMD was used to predict
      vertebral fracture risk. The percent change in osteocalcin was determined to be a
      better predictor of vertebral fracture risk than BMD. INTRODUCTION: The
      association between baseline BMD and fracture risk is well understood. However,
      the relationship between changes in BMD and fracture risk is not well defined. It
      has previously been demonstrated that BMD change was a poor predictor of
      vertebral fracture risk in raloxifene-treated women, whereas bone turnover
      markers were significantly associated with fracture risk. In the current
      analysis, we explore the prediction of vertebral fracture risk using changes in
      both BMD and bone turnover. MATERIALS AND METHODS: The Multiple Outcomes of
      Raloxifene Evaluation (MORE) trial was a randomized, placebo-controlled trial of
      7705 women with osteoporosis treated with raloxifene 60 or 120 mg/day for 3
      years. Markers of bone turnover were measured in one-third of the study
      population (n = 2503), and the present analyses include these women. Logistic
      regression models were constructed using one-year percent changes in BMD and bone
      turnover and relevant baseline demographics to predict the risk of vertebral
      fracture with pooled raloxifene therapy at 3 years. All covariates were
      standardized before modeling to facilitate direct comparisons between changes in
      BMD and bone turnover. RESULTS AND CONCLUSION: Prevalent vertebral fracture
      status (p < 0.0001), baseline lumbar spine BMD (p < 0.0001), and number of years
      postmenopausal (p = 0.0005) were independent predictors of fracture risk in
      raloxifene-treated patients. Therapy-by-change in femoral neck BMD (p = 0.02) and
      therapy-by-change in osteocalcin (OC; p = 0.01) were also significant for all
      treatment groups, indicating that changes in BMD and OC have different effects on
      fracture risk for the placebo and pooled raloxifene groups. The final model
      included significant baseline variables and change in OC (p = 0.01), whereas
      change in femoral neck BMD was not significant. After adjustment of each
      significant baseline variable, the percent change in OC was better able to
      predict the reduction in vertebral fracture risk than the percent change in
      femoral neck BMD in patients treated with raloxifene.

PMID- 15040828
TI  - BMD is reduced in HIV-infected men irrespective of treatment.
AB  - Osteoporosis has be reported to be a complication of active antiretroviral
      therapy of HIV infection. We studied 148 HIV-infected men stratified according to
      their treatment. Our data show that these patients have an average 9% decreased
      BMD, irrespective of their treatment. Low body mass index and high resorption
      markers were associated with low bone density. INTRODUCTION: Osteoporosis has
      been reported in HIV-infected (HIV+) patients, and it has been suggested that it
      may be linked to protease-inhibitor treatments (PI). MATERIALS AND METHODS: To
      assess this risk and to investigate its putative link with treatments, we
      compared the bone density of HIV+ men, who were either receiving treatment
      (including PI [PI+], n = 49; without PI [PI-], n = 51) or untreated (UT, n = 48).
      We included 81 age-matched control HIV-negative (HIV-) males (age, 40 +/- 8
      years). RESULTS: BMD adjusted for age (Z-score) was lower in the HIV+ patients at
      the lumbar spine (HIV+: -1.08 +/- 1.21, HIV-: -0.06 +/- 1.26, p < 0.001) and the
      femoral neck (HIV+: -0.39 +/- 1.05, HIV-: 0.25 +/- 0.87, p < 0.001). The
      prevalence of osteoporosis was 16% in HIV+ and 4% in HIV- subjects (p < 0.01). In
      the HIV+ subjects, the Z-score was correlated only to body mass index (r = 0.27
      at lumbar spine and 0.35 at femoral neck). Untreated HIV+ patients had a negative
      Z-score (-0.82 +/- 1.15 for the lumbar spine), which was not different from the
      one of treated HIV+ patients. In the PI+ and PI- groups, the Z-score did not
      depend on the presence of lipodystrophy or the proportion of fat in the abdomen
      and legs measured by DXA. Markers of bone remodeling were measured in the 132
      HIV+ and 35 HIV- subjects. Compared with controls, HIV+ patients had lower bone
      alkaline phosphatase and higher urinary cross-laps/Cr, which was negatively
      correlated with the Z-score at both the femoral neck (r = -0.22) and lumbar spine
      (r = -0.21). TNFalpha was increased in untreated compared with treated HIV+
      subjects and was not correlated to the Z-score. CONCLUSION: Our cross-sectional
      study does not show any deleterious effect of the treatment but does indicate a
      decrease in bone density in HIV+ patients irrespective of the treatment. This low
      bone density is in part related to the low body weight and is associated with
      increased bone resorption.

PMID- 15040829
TI  - Association of a common polymorphism in the methylenetetrahydrofolate reductase
      (MTHFR) gene with bone phenotypes depends on plasma folate status.
AB  - A study of a polymorphism in the MTHFR gene, plasma folate, and bone phenotypes
      in 1632 individuals revealed that the genotype effect on BMD and quantitative
      ultrasound was dependent on the level of folate. Our findings support the
      hypothesis that the association between an MTHFR polymorphism and bone phenotypes
      depends on folate status. INTRODUCTION: Genome-wide screens using quantitative
      ultrasound (QUS) and BMD phenotypes have shown suggestive linkage on chromosome
      1pter-1p36.3, a region containing the methylenetetrahydrofolate reductase (MTHFR)
      gene. Individuals homozygous (TT) for the MTHFR C677T polymorphism who have low
      plasma folate concentrations exhibit elevated plasma homocysteine (tHcy)
      concentrations that may compromise bone quality. We hypothesized that folate
      status might modify an association between the C677T polymorphism and bone,
      possibly by influencing homocysteine concentrations. MATERIALS AND METHODS: QUS
      (broadband ultrasound attenuation [BUA], speed of sound, and quantitative
      ultrasound index) of the heel and BMD of the hip and spine were measured in 1632
      male and female members of the Framingham Offspring Study (1996-2001).
      Participants were assessed for plasma folate concentration and genotyped for the
      MTHFR C677T polymorphism. TT participants were compared with individuals in the
      CC + CT group using analysis of covariance. RESULTS: Adjusted mean QUS and BMD
      measures did not differ between C677T groups. Although all participants with
      plasma folate concentrations > or =4 ng/ml had approximately 2% higher QUS and
      BMD than those with folate <4 ng/ml, the association disappeared after
      controlling for tHcy. Suggestive interactions between folate status and the C677T
      group (CC + CT versus TT) were found for hip BMD (p < or = 0.05) and BUA (p =
      0.11). Compared with CC + CT participants, TT individuals had lower mean BUA (p =
      0.06) and Ward's area BMD (p = 0.08) within the folate <4 ng/ml group and
      significantly higher hip BMD (p < or = 0.05) within the folate > or =4 ng/ml
      group. For both folate groups, TT participants had higher age-adjusted mean
      plasma tHcy versus CC + CT participants. Controlling for tHcy in these models did
      not affect the statistical significance of the interaction effects. CONCLUSIONS:
      Our findings support the hypothesis that the association between the C677T MTHFR
      polymorphism and bone phenotypes depends on folate status. The mechanism
      mediating the association, however, remains unclear, but may be partially caused
      by homocysteine effects on bone.

PMID- 15040830
TI  - Meta-analysis of molecular association studies: vitamin D receptor gene
      polymorphisms and BMD as a case study.
AB  - With the rise of molecular and genetic epidemiology, molecular association
      studies are increasingly common; however, meta-analysis of these studies has been
      a neglected area. This study performed a meta-analysis of the association of the
      vitamin D receptor (VDR) gene polymorphisms and BMD. We also highlight
      methodological issues that need to be resolved. INTRODUCTION: With the rise of
      molecular and genetic epidemiology, molecular association studies are
      increasingly common; however, meta-analysis of these studies has been a neglected
      area. This study performed a meta-analysis of the association of vitamin D
      receptor (VDR) gene polymorphisms and BMD/osteoporosis and highlights
      methodological issues. MATERIALS AND METHODS: Studies published from 1994 to 2001
      were identified through Medline using PubMed software. The reference lists of the
      articles retrieved were also reviewed. Where eligible papers had insufficient
      information, we contacted authors by mail (up to three mailings) for additional
      information. Any observational study, which tested the association between VDR
      BsmI genotypes and either BMD or osteoporosis at the femoral neck or spine in
      adult women, was included in the review. Data were extracted independently by two
      reviewers (AT and JA) using a standardized data extraction form. RESULTS: The B
      allele was significantly associated with BMD at the spine; it seemed to follow a
      recessive model, with the BB genotype having lower BMD than Bb/bb genotypes at
      baseline, which led to greater bone mineral loss over time. Highlighted
      methodological lessons included the need to check Hardy-Weinberg equilibrium and
      the importance of exploring heterogeneity, pooling data in a manner that is
      sensitive to genetic models, and avoiding multiple comparisons. CONCLUSION: With
      the proliferation of molecular association studies, there will be an increased
      need to quantify the magnitude of the risk associated with genetic polymorphisms.
      This will likely entail meta-analytic methods, and this meta-analysis highlights
      some of the methodological issues that will need to be resolved.

PMID- 15040831
TI  - FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.
AB  - We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction
      in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for
      the vitamin D metabolism followed by hypophosphatemia. This study indicates that
      FGF-23 is a potent regulator of the vitamin D and phosphate metabolism.
      INTRODUCTION: The pathophysiological contribution of FGF-23 in hypophosphatemic
      diseases was supported by animal studies in which the long-term administration of
      recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with
      a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no
      clear understanding of how FGF-23 causes these changes. MATERIALS AND METHODS: To
      elucidate the molecular mechanisms of the FGF-23 function, we investigated the
      short-term effects of a single administration of recombinant FGF-23 in normal and
      parathyroidectmized animals. RESULTS: An injection of recombinant FGF-23 caused a
      reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate
      was first observed 9 h after the injection and was accompanied with a reduction
      in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter
      (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level
      throughout the experiment, and hypophosphatemia was reproduced by FGF-23 in
      parathyroidectomized rats. Before this hypophosphatemic effect, the serum
      1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the
      administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1alpha
      hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at
      1 h. In addition, an injection of calcitriol into normal mice increased the serum
      FGF-23 level within 4 h. CONCLUSIONS: FGF-23 regulates NaPi-2a independently of
      PTH and the serum 1,25(OH)2D level by controlling renal expressions of key
      enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator
      of phosphate and vitamin D homeostasis.

PMID- 15040832
TI  - Skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) by
      inhibiting activation of the IGF-I signaling pathways.
AB  - We showed that unloading markedly diminished the effects of IGF-I to activate its
      signaling pathways, and the disintegrin echistatin showed a similar block in
      osteoprogenitor cells. Furthermore, unloading decreased alphaVbeta3 integrin
      expression. These results show that skeletal unloading induces resistance to IGF
      I by inhibiting activation of the IGF-I signaling pathways at least in part
      through downregulation of integrin signaling. INTRODUCTION: We have previously
      reported that skeletal unloading induces resistance to insulin-like growth factor
      I (IGF-I) with respect to bone formation. However, the underlying mechanism
      remains unclear. The aim of this study was to clarify how skeletal unloading
      induces resistance to the effects of IGF-I administration in vivo and in vitro
      with respect to bone formation. MATERIALS AND METHODS: We first determined the
      response of bone to IGF-I administration in vivo during skeletal unloading. We
      then evaluated the response of osteoprogenitor cells isolated from unloaded bones
      to IGF-I treatment in vitro with respect to activation of the IGF-I signaling
      pathways. Finally we examined the potential role of integrins in mediating the
      responsiveness of osteoprogenitor cells to IGF-I. RESULTS: IGF-I administration
      in vivo significantly increased proliferation of osteoblasts. Unloading markedly
      decreased proliferation and blocked the ability of IGF-I to increase
      proliferation. On a cellular level, IGF-I treatment in vitro stimulated the
      activation of its receptor, Ras, ERK1/2 (p44/42 MAPK), and Akt in cultured
      osteoprogenitor cells from normally loaded bones, but these effects were markedly
      diminished in cells from unloaded bones. These results were not caused by altered
      phosphatase activity or changes in receptor binding to IGF-I. Inhibition of the
      Ras/MAPK pathway was more impacted by unloading than that of Akt. The disintegrin
      echistatin (an antagonist of the alphaVbeta3 integrin) blocked the ability of IGF
      I to stimulate its receptor phosphorylation and osteoblast proliferation, similar
      to that seen in cells from unloaded bone. Furthermore, unloading significantly
      decreased the mRNA levels both of alphaV and beta3 integrin subunits in
      osteoprogenitor cells. CONCLUSION: These results indicate that skeletal unloading
      induces resistance to IGF-I by inhibiting the activation of IGF-I signaling
      pathways, at least in part, through downregulation of integrin signaling,
      resulting in decreased proliferation of osteoblasts and their precursors.

PMID- 15040833
TI  - Transcriptional regulation of a BMP-6 promoter by estrogen receptor alpha.
AB  - The effects of 17beta-estradiol (E2) and ICI 182,780 (ICI) on activity of a BMP-6
      promoter were compared in osteoblast-like and breast cancer cells transiently
      transfected with ERalpha. E2 but not ICI stimulated BMP-6 reporter activity in
      breast cancer cells, whereas the opposite was observed in osteoblast-like cells,
      associated with lack of AF-2 dependence of the response, and absent intranuclear
      localization of ERalpha, suggesting the involvement of a distinct ERalpha
      dependent response mechanism in osteoblasts. INTRODUCTION: Previous studies
      suggest that the tissue-selective effect of antiestrogens on bone reflects the
      ability of these compounds to target certain osteoblast regulatory genes. To
      explore this hypothesis, we examined whether antiestrogens preferentially
      stimulate the bone morphogenetic protein 6 (BMP-6) promoter in bone cells, and if
      so, whether this activity is associated with a distinct estrogen receptor
      (ER)alpha-dependent response mechanism to that in other cell types. MATERIALS AND
      METHODS: We compared the effects of 17beta-estradiol (E2) and ICI 182,780 (ICI)
      on activity of a 4.3-kb BMP-6 reporter construct in osteoblast-like cells (human
      MG63 and SaOS-2 cells and rat ROS 17/2.8 cells), human MCF-7 and T47-D breast
      cancer cell lines, and HepG2 hepatoma cells, after transient transfection with
      ERalpha, ERbeta, and mutant ER constructs. RESULTS: E2, but not ICI, stimulated
      BMP-6 reporter activity by approximately 100% in MCF-7, T47-D cells, and HepG2
      cells when transfected with ERalpha. In contrast, in ERalpha-transfected
      osteoblast-like cells, an increase in reporter activity of approximately 75% was
      observed after treatment with ICI but not E2. The response of MG63 cells to ICI
      and MCF-7 cells to E2 both required ERalpha as opposed to ERbeta and the ERalpha
      activation function (AF)-1 activation domain. However, whereas the AF-2 domain
      was also required for E2 to stimulate reporter activity in MCF-7 cells, the
      response to ICI in MG63 cells was AF-2 independent. In further studies where we
      compared the intracellular distribution of ERalpha associated with these
      responses, E2-dependent stimulation of the BMP-6 reporter in MCF-7 cells was
      associated with intranuclear localization of ERalpha, whereas extranuclear
      localization was seen in rat osteosarcoma cells (ROS) cells treated with ICI.
      CONCLUSIONS: Antiestrogens selectively stimulate BMP-6 reporter activity in
      osteoblast-like cells through a distinct ERalpha-dependent mechanism
      characterized by independence of the AF-2 domain and extranuclear localization of
      ERalpha.

PMID- 15040835
TI  - Cooperation between TGF-beta and Wnt pathways during chondrocyte and adipocyte
      differentiation of human marrow stromal cells.
AB  - Human marrow stromal cells have the potential to differentiate to chondrocytes or
      adipocytes. We show interactions between TGF-beta and Wnt signaling pathways
      during stimulation of chondrogenesis and inhibition of adipogenesis. Combining
      these signals may be useful in marrow stromal cell therapies. INTRODUCTION: Human
      bone marrow stromal cells (hMSCs) have the potential to differentiate to lineages
      of mesenchymal tissues, including cartilage, fat, bone, tendon, and muscle.
      Agents like transforming growth factor (TGF)-beta promote chondrocyte
      differentiation at the expense of adipocyte differentiation. In other processes,
      TGF-beta and Wnt/wingless signaling pathways play major roles in controling
      certain developmental events and activation of specific target genes. We tested
      whether these pathways interact during differentiation of chondrocytes and
      adipocytes in human marrow stromal cells. MATERIALS AND METHODS: Both a line of
      human marrow stromal cells (KM101) and freshly isolated hMSCs were studied.
      Reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, and
      macroarrays were used for analysis of the modulation of TGF-beta1 on Wnt
      signaling-associated genes, chondrocyte differentiation genes, and TGFbeta/bone
      morphogenetic protein (BMP) signaling-associated genes in KM101 cells. Early
      passage hMSCs obtained from 42- and 58-year-old women were used for the effects
      of TGF-beta and/or Wnt (mimicked by LiCl) signals on chondrocyte and adipocyte
      differentiation in two-dimensional (2-D) cultures, 3-D pellet cultures, and
      collagen sponges. RESULTS: As indicated by macroarray, RT-PCR, and Western blot,
      TGF-beta activated genes in the TGF-beta/Smad pathway, upregulated Wnt2, Wnt4,
      Wnt5a, Wnt7a, Wnt10a, and Wnt co-receptor LRP5, and increased nuclear
      accumulation and stability of beta-catenin in KM101 cells. TGF-beta upregulated
      chondrocyte gene expression in KM101 cells and also stimulated chondrocyte
      differentiation and inhibited adipocyte differentiation in hMSCs, synergistically
      with Wnt signal. Finally, hMSCs cultured in 3-D collagen sponges were stimulated
      by TGF-beta1 to express aggrecan and collagen type II mRNA, whereas expression of
      lipoprotein lipase was inhibited. CONCLUSIONS: In summary, TGF-beta stimulated
      chondrocyte differentiation and inhibited adipocyte differentiation of hMSCs in
      vitro. The activation of both TGF-beta and Wnt signal pathways by TGF-beta, and
      synergy between TGF-beta and Wnt signals, supports the view that Wnt-mediated
      signaling is one of the mechanisms of TGF-beta's effects on chondrocyte and
      adipocyte differentiation of hMSCs.

PMID- 15040834
TI  - A synthetic peptide fragment of human MEPE stimulates new bone formation in vitro
      and in vivo.
AB  - Matrix extracellular phosphoglycoprotein (MEPE) was proposed as a candidate for
      the phosphaturic hormone phosphatonin. We found that a synthetic peptide fragment
      of MEPE containing the RGD and SGDG sequence stimulated new bone formation in
      vitro and in vivo. INTRODUCTION: Matrix extracellular phosphoglycoprotein (MEPE)
      was recently identified as a candidate for the phosphaturic hormone phosphatonin,
      which has been implicated in disturbed phosphate metabolism, rickets, and
      osteomalacia associated with X-linked hypophosphatemic rickets (XLH) and
      oncogenic hypophosphatemic osteomalacia (OHO). MEPE expression was predominantly
      found in osteoblasts, and mice deficient in a homolog of MEPE showed increased
      bone density, suggesting that MEPE produced in osteoblasts negatively regulates
      bone formation. In this study, we examined the effects of a synthetic 23mer
      peptide fragment of MEPE (AC-100, region 242-264) containing the RGD (integrin
      binding) and SGDG (glycosaminoglycan-attachment) motif on bone formation in vitro
      and in vivo. MATERIALS AND METHODS: The osteogenic activity of AC-100 was
      examined in organ cultures of neonatal mouse calvariae and in vivo by injecting
      AC-100 onto the calvariae of mice. RESULTS: Histomorphometric examination showed
      that AC-100 stimulated new bone formation with increased numbers of osteoblasts
      in neonatal mouse calvariae in organ culture. In contrast, synthetic MEPE
      fragment peptides without either the RGD or SGDG motif failed to increase new
      bone formation. Repeated daily subcutaneous injections of AC-100 onto the
      calvariae in mice increased bone thickness and stimulated new bone formation as
      determined by the calcein double-labeling technique. However, peptides in which
      the RGD or SGDG sequence was scrambled did not stimulate new bone formation in
      vivo. AC-100 increased cell proliferation and alkaline phosphatase activity and
      activated focal adhesion kinase (FAK) and extracellular signal-regulated protein
      kinase (ERK) in human primary osteoblasts. CONCLUSION: Our results show that a
      synthetic peptide corresponding with the sequence of human MEPE fragment
      stimulates new bone formation with increased number of osteoblasts. The results
      also suggest that the RGD and SGDG motifs are critical to the osteogenic activity
      of AC-100, presumably through activating integrin signaling pathways in
      osteoblasts. The anabolic effects of AC-100 may be beneficial for bone diseases
      associated with decreased bone formation.

PMID- 15040836
TI  - Terminal differentiation of osteoblasts to osteocytes is accompanied by dramatic
      changes in the distribution of actin-binding proteins.
AB  - Immunofluorescence staining of actin-binding proteins in osteoblasts and
      osteocytes was performed. alpha-Actinin, myosin, and tropomyosin showed similar
      organization in both osteoblastic stress fibers and osteocyte processes. However,
      fimbrin, villin, filamin, and spectrin showed dramatic differences in
      distribution between osteoblasts and osteocytes. This study suggested that
      terminal differentiation of osteoblasts to osteocytes is accompanied by highly
      dramatic changes in the distribution of actin-binding proteins. INTRODUCTION: We
      previously reported that osteocyte shape is dependent on actin filaments. To
      analyze the terminal differentiation from osteoblasts to osteocytes, we
      investigated the actin-binding proteins, which are the control elements in the
      dynamic organization of the actin cytoskeleton. MATERIALS AND METHODS: We used
      primary chick osteocytes and osteoblasts, the phenotypes of which were confirmed
      by use of OB7.3, a chick osteocyte-specific monoclonal antibody and by detection
      of alkaline phosphatase activity, respectively. Immunofluorescence staining was
      performed for visualizing actin-binding proteins. Furthermore, we applied shear
      stress at 12 dyns/cm2 to the cells and compared the changes in fimbrin
      distribution. RESULTS: Immunofluorescence staining of fimbrin and alpha-actinin
      showed their presence in the processes of osteocytes, with especially strong
      signals of fimbrin at the sites of divarication of the processes. Anti-villin was
      reactive with the osteocyte cytoplasm but not with the processes. Interestingly,
      anti-villin immunoreactivity was much stronger in osteocytes than in osteoblasts.
      Filamin was localized along the stress fibers of osteoblasts but was seen only in
      those in the proximal base of osteocyte processes. Myosin and tropomyosin were
      found to have a similar pattern in both stress fibers of osteoblasts and
      osteocyte processes. The difference in the distribution of anti-spectrin staining
      was highly dramatic. Osteoblasts immunostained with anti-spectrin showed punctate
      signals on their cytoplasmic membranes, whereas anti-spectrin in osteocytes
      detected a filamentous organization; and the spectrin was totally colocalized
      with actin from the distal portion of the cytoplasmic processes to the cell
      center. In osteoblasts, shear stress induced recruitment of fimbrin to the end of
      stress fibers. However, fimbrin in the osteocyte processes did not change its
      localization. CONCLUSION: We found that terminal differentiation of osteoblasts
      to osteocytes was accompanied by highly dramatic changes in the distribution of
      actin-binding proteins, changes of which may affect cellular function.

PMID- 15040837
TI  - Prevention of glucocorticoid-induced apoptosis in osteocytes and osteoblasts by
      calbindin-D28k.
AB  - This study show for the first time that calbindin-D28k can prevent glucocorticoid
      induced bone cell death. The anti-apoptotic effect of calbindin-D28k involves
      inhibition of glucocorticoid induced caspase 3 activation as well as ERK
      activation. INTRODUCTION: Recent studies have indicated that deleterious effects
      of glucocorticoids on bone involve increased apoptosis of osteocytes and
      osteoblasts. Because the calcium-binding protein calbindin-D28k has been reported
      to be anti-apoptotic in different cell types and in response to a variety of
      insults, we investigated whether calbindin-D28k could protect against
      glucocorticoid-induced cell death in bone cells. MATERIALS AND METHODS: Apoptosis
      was induced by addition of dexamethasone (dex; 10-6 M) for 6 h to MLO-Y4
      osteocytic cells as well as to osteoblastic cells. Apoptosis percentage was
      determined by examining the nuclear morphology of transfected cells. Caspase 3
      activity was evaluated in bone cells and in vitro. SELDI mass spectrometry (MS)
      was used to examine calbindin-D28k-caspase 3 interaction. Phosphorylation of
      calbindin-D28k was examined by 32P incorporation as well as by MALDI-TOF MS. ERK
      activation was determined by Western blot. RESULTS: The pro-apoptotic effect of
      dex in MLO-Y4 cells was completely inhibited in cells transfected with calbindin
      D28k cDNA (5.6% apoptosis in calbindin-D28k transfected cells compared with 16.2%
      apoptosis in vector-transfected cells, p < 0.05). Similar results were observed
      in osteoblastic cells. We found that dex-induced apoptosis in bone cells was
      accompanied by an increase in caspase 3 activity. This increase in caspase 3
      activity was inhibited in the presence of calbindin-D28k. In vitro assays
      indicated a concentration-dependent inhibition of caspase 3 by calbindin-D28k (Ki
      = 0.22 microM). Calbindin-D28k was found to inhibit caspase 3 specifically
      because the activity of other caspases was unaffected by calbindin-D28k. The anti
      apoptotic effect of calbindin-D28k in response to dex was also reproducibly
      associated with an increase in the phosphorylation of ERK 1 and 2, suggesting
      that calbindin-D28k affects more than one signal in the glucocorticoid-induced
      apoptotic pathway. CONCLUSION: Calbindin-D28k, a natural non-oncogenic protein,
      could be an important target in the therapeutic intervention of glucocorticoid
      induced osteoporosis.

PMID- 15040838
TI  - Parathyroid cells cultured in collagen matrix retain calcium responsiveness:
      importance of three-dimensional tissue architecture.
AB  - Primary cultures of bovine parathyroid cells rapidly lose calcium responsiveness.
      Here, we show that bovine parathyroid cells grown in collagen coalesce into an
      organoid ("pseudogland") with stable calcium responsiveness. These findings also
      illustrate the importance of 3-D cellular architecture in parathyroid gland
      function. INTRODUCTION: The ability of extracellular calcium to suppress
      parathyroid hormone (PTH) secretion is quickly lost in primary monolayer cultures
      of bovine parathyroid cells. This has been attributed to a decrease in the
      expression of the cell surface calcium-sensing receptor (CaR), but other factors,
      including normal cell-to-cell interaction, may be critical. Here we describe a
      novel system for culturing bovine parathyroid cells that promotes re-formation of
      a three-dimensional (3-D) cellular architecture and re-establishment of calcium
      responsiveness. MATERIALS AND METHODS: Dispersed bovine parathyroid cells were
      cultured as monolayers or were mixed with type I collagen and placed in culture
      plates. CaR mRNA and the calcium regulation of PTH secretion were measured over a
      period of several weeks in parathyroid cells cultured both in collagen matrix and
      as monolayers. Calcium regulation of PTH mRNA was also investigated. RESULTS AND
      CONCLUSIONS: Within 1-2 weeks in collagen culture, parathyroid cells coalesced
      into a small mass approximately 1-2 mm in size (referred to as a pseudogland).
      Suppression of PTH secretion by high calcium was blunted at 1 day in collagen,
      but returned within 1 week, and was retained through 3 weeks; the calcium set
      point (1.05 +/- 0.04 mM) was similar to that reported for freshly dispersed
      cells. PTH mRNA was also suppressed by increasing extracellular calcium. CaR mRNA
      expression was decreased at 1 day in collagen and increased with time in culture,
      although never reaching the level found in dispersed cells. In bovine parathyroid
      cells cultured as monolayers, however, suppression of PTH by calcium was observed
      only at day 1 in culture. CaR mRNA content fell by 70% at day 1 but remained
      stable thereafter. Thus, a total loss of calcium responsiveness in monolayers was
      observed despite significant residual expression of CaR, suggesting that loss of
      the calcium response cannot be attributed solely to decreased CaR. In summary,
      the pseudogland model illustrates the importance of the 3-D cellular architecture
      in parathyroid gland function and provides a useful model in which to investigate
      calcium-mediated control of parathyroid gland functions, especially those
      requiring extended treatment.

PMID- 15040839
TI  - Actin-related protein 2/3 complex is required for actin ring formation.
AB  - Actin rings are vital for osteoclastic bone resorption, and actin-related protein
      2/3 complex is a pivotal regulator of actin polymerization. Actin-related protein
      2/3 complex was found in the podosomes of actin rings. A short interfering RNA
      knocked down expression of actin-related protein 2 in osteoclasts and disrupted
      actin rings, suggesting that the complex is crucial to actin ring formation.
      INTRODUCTION: To resorb bone, osteoclasts form an extracellular acidic
      compartment segregated by a sealing zone. This is dependent on an actin ring that
      is composed of filamentous actin organized into dynamic structures called
      podosomes. The actin-related protein 2/3 (Arp2/3) complex is a vital regulator of
      actin polymerization. We tested whether the Arp2/3 complex is a component of
      actin rings and is important for actin ring formation. MATERIALS AND METHODS:
      Western blot analysis was used to determine levels of Arp2 and Arp3, two
      components of the Arp2/3 complex in osteoclast-like cells. Confocal microscopy
      studies using antibodies for immunocytochemistry demonstrated localization of
      Arp2/3 complex in osteoclasts. Short interfering RNA oligonucleotides (siRNAs)
      were made against Arp2 and used to knock down its expression. RESULTS: A 3-fold
      increase in Arp2 and Arp3 was detected during RANKL-induced differentiation of
      RAW 264.7 cells into osteoclast-like cells. Arp2/3 complex was concentrated in
      actin rings and enriched near the sealing zone. Arp2/3 complex co-localized with
      cortactin, a component of podosomes, but not vinculin, which surrounds podosomes.
      siRNA against Arp2, transfected into RAW 264.7 cells 5 days after stimulation
      with RANKL, reduced Arp2 protein levels 70% compared with cells transfected with
      ineffective siRNAs. Cytochemical characterization of RAW 264.7 osteoclast-like
      cells and marrow osteoclasts in which Arp2 was knocked down revealed fewer
      podosomes and no actin rings, although many cells remained well spread.
      CONCLUSIONS: These data show that Arp2/3 complex is a component of actin rings
      and that the presence of Arp2/3 complex is vital to the formation of actin rings.
      In addition, the results show the use of siRNAs for the study of RAW 264.7
      osteoclast-like cells.

PMID- 15040841
TI  - Bilateral femoral head osteonecrosis after septic shock and multiorgan failure.
AB  - A case of bilateral femoral head osteonecrosis after septic shock is presented.
      We suggest that the osteonecrosis was caused by ischemic insults to the proximal
      femora. The association between septic shock and osteonecrosis has not been
      previously reported. INTRODUCTION: Osteonecrosis is an uncommon disorder
      characterized by the in situ death of bone. A diverse range of conditions has
      been associated with osteonecrosis. We present a case of bilateral femoral head
      osteonecrosis that occurred after an episode of septic shock. MATERIALS AND
      METHODS: A 66-year-old woman presented with a left-sided renal stone and a
      urinary tract infection. Her condition rapidly progressed to a life-threatening
      illness with septic shock complicated by multiorgan failure, which necessitated
      prolonged intensive care and inotropic support. She made a full recovery but 3
      months later developed bilateral osteonecrosis of the femoral heads requiring
      bilateral total hip joint replacement. RESULTS AND CONCLUSIONS: We propose that
      the osteonecrosis was caused by ischemic insults to the femoral heads as a result
      of the widespread systemic ischemia that occurred during her initial illness. To
      our knowledge, septic shock has not been previously described as a cause of
      osteonecrosis. Clinicians should be aware of this association, particularly in
      patients presenting with bone pain after episodes of sepsis.

PMID- 15040840
TI  - Activation of protease-activated receptor-2 leads to inhibition of osteoclast
      differentiation.
AB  - PAR-2 is expressed by osteoblasts and activated by proteases present during
      inflammation. PAR-2 activation inhibited osteoclast differentiation induced by
      hormones and cytokines in mouse bone marrow cultures and may protect bone from
      uncontrolled resorption. INTRODUCTION: Protease-activated receptor-2 (PAR-2),
      which is expressed by osteoblasts, is activated specifically by a small number of
      proteases, including mast cell tryptase and factor Xa. PAR-2 is also activated by
      a peptide (RAP) that corresponds to the "tethered ligand" created by cleavage of
      the receptor's extracellular domain. The effect of activating PAR-2 on osteoclast
      differentiation was investigated. MATERIALS AND METHODS: Mouse bone marrow
      cultures have been used to investigate the effect of PAR-2 activation on
      osteoclast differentiation induced by parathyroid hormone (PTH), 1,25
      dihydroxyvitamin D3 [1,25(OH)2D3], and interleukin-11 (IL-11). Expression of PAR
      2 by mouse bone marrow, mouse bone marrow stromal cell-enriched cultures, and the
      RAW264.7 osteoclastogenic cell line was demonstrated by RT-PCR. RESULTS: RAP was
      shown to inhibit osteoclast differentiation induced by PTH, 1,25(OH)2D3, or IL
      11. Semiquantitative RT-PCR was used to investigate expression of mediators of
      osteoclast differentiation induced by PTH, 1,25(OH)2D3, or IL-11 in mouse bone
      marrow cultures and primary calvarial osteoblast cultures treated simultaneously
      with RAP. In bone marrow and osteoblast cultures treated with PTH, 1,25(OH)2D3,
      or IL-11, RAP inhibited expression of RANKL and significantly suppressed the
      ratio of RANKL:osteoprotegerin expression. Activation of PAR-2 led to reduced
      expression of prostaglandin G/H synthase-2 in bone marrow cultures treated with
      PTH, 1,25(OH)2D3, or IL-11. RAP inhibited PTH- or 1,25(OH)2D3-induced expression
      of IL-6 in bone marrow cultures. RAP had no effect on osteoclast differentiation
      in RANKL-treated RAW264.7 cells. CONCLUSION: These observations indicate that PAR
      2 activation inhibits osteoclast differentiation by acting on cells of the
      osteoblast lineage to modulate multiple mediators of the effects of PTH,
      1,25(OH)2D3, and IL-11. Therefore, the role of PAR-2 in bone may be to protect it
      from uncontrolled resorption by limiting levels of osteoclast differentiation.

PMID- 15040842
TI  - Development of excitation-contraction coupling in cardiomyocytes.
AB  - The excitation-contraction (E-C) coupling system during the development of heart
      can be investigated because of marked progression in electrophysiology and
      microfluorescence studies. During the developmental period, Ca2+ influx mediating
      the E-C coupling is mainly through the L-type Ca2+ channels. In the fetal period,
      T-type Ca2+ channels and the reverse mode of the Na-Ca exchange system also
      contribute to Ca2+ influx. These contributions probably reduce gradually until
      adulthood. The contraction of fetal cardiomyocytes has been thought to depend
      mainly on the Ca2+ influx. However, recent studies reveal that immature
      sarcoplasmic reticulum (SR) already works in the early fetal period. Ca2+ spark,
      a local and unitary movement of Ca2+, can be observed in adult cardiomyocytes by
      the use of a confocal microscope. On the other hand, no Ca2+ spark is observed in
      fetal cardiomyocytes. The frequency of Ca(2+)-spark evocation increases during
      the postnatal period. Therefore a close distance between the L-type Ca2+ channel
      and the SR Ca(2+)-release channel is essential to the establishment of the Ca2+
      spark.

PMID- 15040844
TI  - Effects of angiotensin II type 1 receptor antagonist, losartan, on ventilatory
      response to exercise and neurohormonal profiles in patients with chronic heart
      failure.
AB  - Chronic heart failure (CHF) is associated with abnormal neurohormonal profiles
      and increased ventilatory response to exercise. This study determined if
      treatment with angiotensin II type 1 receptor antagonist, losartan, improves
      ventilatory efficiency and neurohormonal factors in patients with CHF. Symptom
      limited cardiopulmonary exercise testing was performed after a 2-week placebo
      period (baseline) and after 16 weeks of treatment with losartan (40 +/- 4 mg/day)
      in 10 patients with CHF (age 57.7 +/- 3.7 years). Echocardiogram, daily physical
      activity (by the specific activity scale), and neurohormones were evaluated.
      Treatment with losartan increased left ventricular ejection fraction (baseline
      vs. losartan: 31 +/- 3 vs. 39 +/- 3%, p<0.01) and specific activity scale score
      (5.3 +/- 0.5 vs. 6.4 +/- 0.4 METS, p<0.05). Losartan decreased the ventilatory
      response to carbon dioxide production during exercise (VE/VCO2 slope: 34.6 +/-
      2.4 vs. 32.0 +/- 2.2, p<0.05). Plasma brain natriuretic peptide concentrations
      were decreased after therapy (301 +/- 79 vs. 176 +/- 53 pg/ml, p<0.05). In
      summary, the results of this open-label, uncontrolled study suggest that chronic
      treatment with losartan may improve ventilatory efficiency and decrease plasma
      brain natriuretic peptide concentrations with the improvement of physical
      activity and left ventricular systolic function in patients with CHF.

PMID- 15040843
TI  - ATP-conducting maxi-anion channel: a new player in stress-sensory transduction.
AB  - The regulated release of ATP is a fundamental process in cell-to-cell signaling.
      The electrogenic translocation of ATP via an anion channel has been suggested as
      one possible mechanism of the release. In this review, we survey possible
      candidate channels for this pathway. The maxi-anion channel characterized by an
      exceedingly large unitary conductance has been a stray channel with regard to its
      function. A newly discovered property, its ATP conductivity and its activation in
      response to stress signals, indicates that this channel has a central role in
      stress-sensory transduction for cell volume regulation and tubuloglomerular
      feedback.

PMID- 15040846
TI  - Cell-volume regulation by swelling-activated chloride current in guinea-pig
      ventricular myocytes.
AB  - The cell-volume regulation by swelling-activated Cl- current (I(Cl,swell)) was
      studied in guinea pig ventricular myocytes, using a microscopic video-image
      analysis. We have previously shown that in ventricular cells depolarized in high
      K+ ([K+]o>45 mM) solution, an activation of the cyclic AMP-dependent Cl- current
      (I(Cl,cAMP)) leads to cell swelling. We first investigated the mechanism
      underlying the I(Cl,cAMP)-independent recovery (shrinkage) of the swollen cells.
      They shrank when the membrane potential (Vm) was made negative to the equilibrium
      potential of Cl- (ECl) by lowering [K+]o or [Cl-]o in the high-K+ solution. This
      shrinkage was attenuated by the inhibitors (DIDS, glibenclamide, furosemide) of
      swelling-activated Cl- current (I(Cl,swell)). These findings suggested an
      involvement of I(Cl,swell) in the observed isosmotic cell shrinkage. On the other
      hand, an application of hyposmotic (70% of control) solution to the cells at
      normal [K+]o (ECl>Vm) induced a cell swelling, and the swollen cells underwent a
      slight but definite spontaneous cell shrinkage during hyposmotic challenge,
      indicating the operation of the mechanism of regulatory volume decrease (RVD).
      This RVD was pronounced at low [Cl-]o, at which ECl was much more positive than
      Vm. On the contrary, when the hyposmotic solution was applied to the cells at
      high [K+]o, at which ECl was negative to Vm, the cells swelled vigorously and
      monotonically without showing RVD, the swelling being much greater than that seen
      at normal [K+]o. Both the RVD at normal [K+]o and the extra cell swelling at high
      [K+]o were suppressed by DIDS. These results suggest that I(Cl,swell) activated
      by cell swelling can shrink or inflate the cardiac cells under hyposmotic as well
      as isosmotic conditions, depending on Vm and ECl.

PMID- 15040845
TI  - Identification of caspase-independent PKCepsilon-JNK/p38 MAPK signaling module in
      response to metabolic inhibition in H9c2 cells.
AB  - To understand the molecular mechanism of ischemia-induced cardiac myocyte cell
      death, H9c2 cells were studied by chemical hypoxia (CH), using metabolic
      inhibition buffer. CH suppressed the activities of caspase-3, -8, and -9. c-Jun N
      terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) were
      activated, whereas extracellular regulated kinase (ERK) was inactivated. Only
      protein kinase Cepsilon (PKCepsilon) among PKC isotypes was translocated to the
      membrane fraction implying its activation. Moreover, the administration of
      PKCepsilon inhibitor suppressed the phosphorylations of JNK/p38 MAPK and reduced
      CH-induced cell death. An administration of JNK/p38 MAPK inhibitors also
      decreased CH-induced cell deaths, implying JNK/p38 MAPK's causative roles in the
      deaths. Collectively, this study identified a novel caspase-independent
      PKCepsilon-JNK/p38 MAPK signaling module induced by CH in cardiac myocytes. Our
      data show that the PKCepsilon-JNK/p38 MAPK signaling module contributes to CH
      induced H9c2 cell death. This contrasts with previous notions, i.e., PKCepsilon's
      protective effect against ischemic death. Thus our data suggest that PKCepsilon
      can mediate alternative signals, i.e., beneficiary or deleterious signals,
      depending on the cell type, intensity, and/or type of injury.

PMID- 15040847
TI  - Verapamil prevents impairment in filterability of human erythrocytes exposed to
      oxidative stress.
AB  - Effects of oxidative stress on intact human erythrocytes were investigated using
      tert-butyl hydroperoxide (tBHP). Exposure of erythrocytes to tBHP caused a marked
      decrease in filterability in a time-dependent manner. Erythrocytes exposed to
      tBHP also show an increase in mean corpuscular volume and a remarkable formation
      of methemoglobin (met-Hb) without any appearance of hemichromes that form Heinz
      bodies. High performance liquid chromatography demonstrated that the tBHP-treated
      erythrocytes exhibited an apparent decrease in the membrane phospholipid,
      phosphatidylethanolamine (PE). The decrease in PE was inhibited by pretreatment
      with ascorbate, but not with verapamil. SDS-polyacrylamide gel electrophoresis of
      the tBHP-treated erythrocyte membrane showed a degradation of spectrin, band 3,
      band 4.2, and band 4.5, accompanied by the appearance of low-molecular-weight
      products. The degradation of the membrane proteins was not prevented by
      pretreatment with verapamil or ascorbate. However, the pretreatment with
      verapamil but not with ascorbate revealed significant inhibition of the tBHP
      induced impairment in filterability in the presence of extracellular Ca2+. Thus,
      the present study shows that verapamil, a potent drug in reperfusion therapy,
      plays an important role in protection against oxidative injury, based on a close
      linkage among decreased filterability, met-Hb formation, and impaired membrane
      integrity.

PMID- 15040848
TI  - Effect of high-intensity intermittent swimming training on fatty acid oxidation
      enzyme activity in rat skeletal muscle.
AB  - We previously reported that high-intensity exercise training significantly
      increased citrate synthase (CS) activity, a marker of oxidative enzyme, in rat
      skeletal muscle to a level equaling that attained after low-intensity prolonged
      exercise training (Terada et al., J Appl Physiol 90: 2019-2024, 2001). Since
      mitochondrial oxidative enzymes and fatty acid oxidation (FAO) enzymes are often
      increased simultaneously, we assessed the effect of high-intensity intermittent
      swimming training on FAO enzyme activity in rat skeletal muscle. Male Sprague
      Dawley rats (3 to 4 weeks old) were assigned to a 10-day period of high-intensity
      intermittent exercise training (HIT), low-intensity prolonged exercise training
      (LIT), or sedentary control conditions. In the HIT group, the rats repeated
      fourteen 20 s swimming sessions with a weight equivalent to 14-16% of their body
      weight. Between the exercise sessions, a 10 s pause was allowed. Rats in the LIT
      group swam 6 h/day in two 3 h sessions separated by 45 min of rest. CS activity
      in the triceps muscle of rats in the HIT and LIT groups was significantly higher
      than that in the control rats by 36 and 39%, respectively. Furthermore, 3-beta
      hydroxyacyl-CoA dehydrogenase (HAD) activity, an important enzyme in the FAO
      pathway in skeletal muscle, was higher in the two training groups than in the
      control rats (HIT: 100%, LIT: 88%). No significant difference in HAD activity was
      observed between the two training groups. In conclusion, the present
      investigation demonstrated that high-intensity intermittent swimming training
      elevated FAO enzyme activity in rat skeletal muscle to a level similar to that
      attained after 6 h of low-intensity prolonged swimming exercise training.

PMID- 15040849
TI  - Effects of hyperthermia on ventilation and metabolism during hypoxia in conscious
      mice.
AB  - Hyperthermia and hypoxia influence ventilation and metabolism; however, their
      synergistic effects remain unanswered. We hypothesized that an enhancement of
      ventilation induced by hyperthermia is competitive with hypoxic hypometabolism.
      We then examined the relationship of body temperature, hypoxia, and respiration
      in conscious mice, measuring minute ventilation (VE), aerobic metabolism, and
      arterial blood gases. All parameters were measured at two different body
      temperatures (BTs), approximately 37 degrees C (normothermia) and 39 degrees C
      (hyperthermia), under both normoxia (room air inhalation) and hypoxia (7% O2
      inhalation). Under normoxia, VE and O2 consumption (VO2) were lower at
      hyperthermia than at normothermia, and the VE-VO2 ratio remained constant. PaCO2
      values were normal at both BTs under normoxia. Hypoxic gas inhalation increased
      VE, which reached a peak in 2 min, then decreased at both BTs. VE remained at a
      higher level during hyperthermia than during normothermia throughout the 10 min
      experiment. VO2 decreased during hypoxia at both BTs. Hypoxia increased the VE
      VO2 ratio because of relatively high VE with respect to the decreased VO2, which
      means hyperventilation. At hypoxia under hyperthermia, serious hyperventilation
      occurred with a further increase in VE. The augmented ventilation may be due to
      the thermal stimulus and a lowered thermoregulatory set point for hypoxia. Thus
      hyperthermia reduces ventilation and metabolism to maintain normocapnia; as a
      result, thermogenesis is reduced under normoxia. Hyperthermia augments
      hyperventilation induced by hypoxia, leading to severe hypoxic hypocapnia.
      Thermal stimuli may impair the adjustment of ventilation and metabolism when O2
      is limited.

PMID- 15040850
TI  - Excitatory neurotoxic properties of pontamine sky blue make it a useful tool for
      examining the functions of focal brain parts.
AB  - Pontamine sky blue (PSB) is used in brain studies to mark the position of
      microelectrode and micropipette tips. However, few studies have been made on the
      effects of PSB on neurons; therefore we examined these effects. When puffed on
      isolated sensory ganglion cells of rats, PSB increased membrane conductance,
      depolarized membrane potential, and reduced the amplitude of action potentials.
      When dripped on frog sympathetic ganglion, much like hexamethonium, PSB decreased
      the amplitude of compound action potentials of the postganglionic strand. A bath
      application of PSB to sartorius muscle fibers that had been treated with
      tetrodotoxin depolarized the membrane potential and increased the frequency and
      amplitude of miniature end-plate potentials. All these effects were reversible.
      When injected into the rat's pontine part corresponding to the location of the
      canine pontine defecation reflex center, PSB produced repetitive colorectal
      contractions and irreversibly abolished them in response to anal-canal
      stimulation. The excitatory and blocking effects of PSB and its staining ability
      make it a useful tool for examining the functions of focal brain parts.

PMID- 15040851
TI  - Leukotrienes-mediated effects of water extracts from Sargassum horneri, a marine
      brown alga, on Cl- absorption in isolated rat colon.
AB  - Sargassum horneri is an edible marine brown alga distributed along the seacoast
      of Japan. Here we examined effects on the water-soluble (ethanol-insoluble)
      extracts (EIS) from Sargassum horneri on ion transports across the isolated rat
      colonic mucosa set in Ussing chambers. The nonpolysaccharide fraction of EIS (EIS
      2) significantly decreased short-circuit current (Isc) across the mucosa, and
      increased the tissue conductance (Gt). The half-maximal effect of EIS-2 was
      obtained at 20 microg/ml. In contrast, the polysaccharide fraction of EIS (EIS-1;
      100 microg/ml) had little effect on Isc and Gt. The effect of EIS-2 depended on
      the presence of Cl- and HCO3- but not K+ in the bathing solution. These results
      suggest that EIS-2 stimulates Cl)absorption in the colonic mucosa. The EIS-2
      induced changes in Isc and Gt were inhibited by 3-(1-[p-chlorobenzyl]-5
      [isopropyl]-3-t-butylthioindol-2-yl)-2,2-dimethyl-propanoic acid sodium (MK-886;
      10 microM), a 5-lipoxygenase-activating protein inhibitor, and 5-nitro-2-(3
      phenylpropylamino)-benzoate (NPPB; 100 microM), a Cl- channel blocker. EIS-2
      attenuated the prostaglandin E2 (0.5 microM)-increased Isc, and the half-maximal
      effect of EIS-2 was obtained at 50 microg/ml. The present study suggests that the
      EIS-2 stimulates Cl- absorption mediated by basolateral leukotriene-sensitive Cl-
      channels and apical Cl-/HCO3- exchanger in the rat colonic mucosa.

PMID- 15040852
TI  - Absorber's effect projected directly above improves spatial resolution in near
      infrared backscattered imaging.
AB  - The spatial resolution of near infrared spectroscopic imaging in brain function
      mapping studies needs to be improved. Most near infrared spectroscopic imaging
      systems use optical fibers that are arranged like a lattice. The light source and
      the detector have one-on-one correspondence at intervals of about 3 cm. In this
      study, we apply several detectors against one source to improve spatial
      resolution. We assume that a local absorber within a strong scattering medium is
      a model for local cerebral activation. When we calculate absorbance, which is
      used to spectroscopically calculate hemoglobin concentration, the peak position
      shifts away from above the position where an absorber is located. As far as
      absorbance is calculated, we cannot obtain spatial information about the absorber
      even if many detectors are used against one source. When we calculate the
      difference between detected light intensities, however, we demonstrate that an
      absorber projected onto the measuring surface has an influence directly above it.
      We predict this property from a light diffusion equation and also prove it
      experimentally through measurements of a uniform resinous phantom with an
      absorber. This is one of the basic principles supporting the achievement of
      higher spatial resolutions with near infrared spectroscopic imaging.

PMID- 15040853
TI  - Alternans decay of postextrasystolic potentiation in human left ventricle.
AB  - An organ-level assessment of the total Ca2+ handled in the excitation-contraction
      coupling in a beating heart has been accomplished in canine left ventricles
      (LVs). This approach combines the intramyocardial Ca2+ recirculation fraction
      (RF) with the cardiac O2 consumption for the excitation-contraction coupling. The
      RF has conventionally been obtained from the exponential decay of the
      postextrasystolic (PES) potentiation of myocardial contractility. However, in
      canine LVs, the PES contractility in terms of Emax (end-systolic pressure-volume
      ratio) has been shown to decay generally in alternans under both physiological
      and pathological conditions. Nevertheless, the RF can be obtained from the
      exponential decay component in the PES Emax alternans decay. We expected that the
      same Ca2+ assessment could be applied to the human heart. As the first step, we
      investigated whether the PES Emax would decay in alternans or exponentially in
      patient LVs. We retrospectively analyzed 13 patient cases that had stable regular
      beats unexpectedly interrupted by a spontaneous extrasystole followed by a PES
      compensatory pause during their diagnostic examination. These patients had either
      mitral regurgitation, old myocardial infarction, or dilated cardiomyopathy. Their
      LV Emax decayed consistently in alternans within the first several PES beats.
      These Emax alternans decays resemble those reported in canine LVs. This finding
      suggests for the first time the applicability of the same organ-level RF
      assessment method developed for canine hearts to human hearts.

PMID- 15040854
TI  - Central administration of ghrelin stimulates pancreatic exocrine secretion via
      the vagus in conscious rats.
AB  - Ghrelin, a novel growth-hormone releasing peptide, was originally isolated from
      rat and human stomach. Immunohistochemical analyses revealed that ghrelin
      immunoreactive neurons were localized in the hypothalamic arcuate nucleus. The
      function of the digestive organs is controlled from the central nervous system,
      and the vagus nerve plays an important role. Intracerebroventricular and
      intravenous administration of ghrelin significantly increased gastric acid
      secretion, and its effect was abolished by vagotomy. In the present study, the
      effect of centrally injected ghrelin on pancreatic exocrine secretion was
      examined in conscious rats. Moreover, an electrophysiologic study was conducted
      in anesthetized rats to examine whether the excitation of vagal efferent nerve
      could be induced by ghrelin. To determine the pancreatic exocrine secretion, rats
      were prepared with cannulae draining bile and pancreatic juice separately. The
      experiments were conducted in conscious rats on day 4 or 5 after the operation.
      To exclude the involvement of gastric acid, a proton pump inhibitor omeprazole (5
      micromol/kg) was administered into the duodenum 1 h before ghrelin injection. An
      intracerebroventricular administration of ghrelin (12, 60, and 300 pmol/10
      microl) significantly increased pancreatic fluid and protein output in a dose
      dependent manner. Pretreatment with the ganglion blocker hexamethonium and with
      atropine completely abolished the stimulatory effect of central ghrelin. In
      contrast, an intravenous injection of ghrelin (300 pmol/10 microl) had no effect.
      Centrally administered ghrelin stimulated the vagal efferent nerve in
      anesthetized rats. In conclusion, centrally administered ghrelin stimulates
      pancreatic exocrine secretion through the vagal efferent nerve, and the
      stimulatory action is independent of gastric acid secretion.

PMID- 15040856
TI  - The anti-HER2 monoclonal antibody pertuzumab may be effective in androgen
      independent prostate cancer.

PMID- 15040855
TI  - Highlights from the XII European Cancer Conference Copenhagen, Denmark.

PMID- 15040857
TI  - Complications of androgen-deprivation therapy for prostate cancer.
AB  - With the increasing indications for the use of androgen-deprivation therapy in
      the treatment of men with prostate cancer, side effects of the therapy deserve
      greater attention. Side effects such as hot flashes, decreased libido, decreased
      sexual function, and fatigue primarily affect the patients quality of life. Other
      side effects such as osteoporosis and changes in lipid profiles may also affect
      the patients overall health. Treatments such as estrogen, megestrol acetate,
      antidepressants, and bisphosphonates are useful in the management of many of the
      deleterious side effects of androgen deprivation. In addition, alternative
      management strategies such as intermittent androgen ablation and antiandrogen
      monotherapy may be useful in minimizing side effects caused by androgen ablation.
      Patients and physicians should be well aware of the potential side effects of
      androgen-deprivation therapy as well as the preventive and treatment strategies
      for these side effects in order to improve patients quality of life and health.

PMID- 15040859
TI  - Clinical strategies in the management of biochemical recurrence after radical
      prostatectomy.
AB  - Prostate cancer is the most frequently diagnosed cancer and the second leading
      cause of cancer death in men, following lung cancer. Although radical
      prostatectomy continues to be a curative treatment for most patients diagnosed
      with prostate cancer, nearly 25% of patients undergoing radical prostatectomy
      will have biochemical recurrence as defined by an increase in serum prostate
      specific antigen (PSA) level to >0.4 ng/mL after prostatectomy or a rapid
      doubling of the PSA over a 10-year follow-up period. The clinical challenges, an
      overview of available data, and a framework for the integration of this
      information for clinical management of biochemical recurrence postprostatectomy
      for prostate carcinoma are presented in this article. Therapeutic options, in
      addition to conservative management and watchful waiting, include radiation
      therapy and androgen deprivation. These options are discussed herein along with
      expected outcomes.

PMID- 15040858
TI  - The combination of antiangiogenic and cytotoxic agents in the treatment of
      prostate cancer.
AB  - Metastatic prostate cancer is one of the leading causes of cancer death in men.
      Although initially responsive to hormone therapy, it eventually progresses in
      almost all patients. For this reason, there has been a search for novel agents to
      use in the fight against androgen-independent prostate cancer. Antiangiogenesis
      is a relatively new antitumor strategy that has been employed in the treatments
      of many malignancies. As prostate cancer is likely dependent on angiogenesis for
      its growth and progression, it would logically serve as a good target for this
      modality. Initially met with great enthusiasm, antiangiogenic drugs have seen
      only limited success when used as single agents. This has been attributed to many
      possible etiologies including lack of cytotoxicity and use in situations of large
      tumor burden. In order to overcome these problems, many investigators are
      combining antiangiogenic agents with more traditional cytotoxic chemotherapy
      regimens in hope of augmenting the effects of either drug alone. This article
      will review the background of angiogenesis inhibition and the use of such
      combinations in metastatic prostate cancer.

PMID- 15040860
TI  - Weekly docetaxel in elderly patients with prostate cancer: efficacy and toxicity
      in patients at least 70 years of age compared with patients younger than 70
      years.
AB  - We sought to determine whether age was significantly associated with efficacy and
      toxicity of weekly docetaxel in patients with metastatic androgen-independent
      prostate cancer (AIPC). Individual patient data were pooled from 2 phase II
      clinical trials of weekly docetaxel 36 mg/m(2) for 6 of every 8 weeks in men with
      metastatic AIPC. Baseline characteristics and outcome measures of men > 70 years
      of age (n = 52) were compared with patients < 70 of age (n = 34) using Pearson c2
      test for categoric variables, Mann-Whitney U test for continuous variables, and
      log-rank test of Kaplan-Meier estimates for time-dependent variable. Multivariate
      analysis was used to adjust for any imbalances in baseline characteristics. At
      baseline, older patients had a lower hemoglobin level (P = 0.05) and a higher
      serum prostate-specific antigen (PSA; P = 0.04). The PSA response rate was 47%
      (95% CI, 33%-62%) in older patients and 40% (95% CI, 23%-59%) in younger patients
      (P = 0.75). Similarly, measurable disease response rate (P = 0.43), time to
      progression (P = 0.28), and survival (P = 0.52) were not affected by age in both
      univariate and multivariate analyses. There was also no difference in overall
      hematologic and nonhematologic toxicity > grade 2. This comparison of pooled
      individual patient data from 2 phase II studies of weekly docetaxel in AIPC did
      not reveal significant differences in efficacy or toxicity in men aged > 70 years
      compared with younger patients. These findings are consistent with the hypothesis
      that docetaxel chemotherapy in patients with AIPC is equally well tolerated and
      effective across a wide range of ages.

PMID- 15040861
TI  - Comparison of total prostate-specific antigen and derivative levels in a
      screening population of black, white, and Korean-American men.
AB  - Numerous studies have assessed serum total PSA (tPSA) levels among different
      races. We extended the serum biomarker profiling using prostate-specific antigen
      (PSA) derivatives in age-matched screening populations that included white,
      black, and Korean-American patients. The median ages were 61 years for white and
      black patients and 63 years for Korean-American patients. Serum samples from 70
      men in each ethnic group were analyzed using 3 different tPSA assays (Tosoh AIA
      600II, Bayer Immuno-1, Roche Elecsys 2010). The percentage of free PSA (fPSA) was
      measured directly by Roche Elecsys 2010 immunoassay and then calculated from
      complexed PSA (cPSA) and tPSA results determined with the Bayer Immuno-1. The
      percentage of cPSA was determined using cPSA and tPSA assayed by the Immuno-1
      method. Statistical analyses included nonparametric Kruskal-Wallis and analysis
      of variance (ANOVA) evaluations. There were no differences noted in the tPSA
      values based on ANOVA among the 3 races irrespective of the assay platform
      methodology employed. Also, the PSA derivatives, percentages of fPSA and cPSA,
      evaluated using the Kruskal-Wallis test, showed no significant differences for
      either derivative assayed on 2 different assay platforms among the 3 groups. In a
      contemporary screening population comparing tPSA, percentage of fPSA, and
      percentage of cPSA levels in 3 races, there were no significant differences
      identified among the groups.

PMID- 15040862
TI  - Mutations in ribonuclease L gene do not occur at a greater frequency in patients
      with familial prostate cancer compared with patients with sporadic prostate
      cancer.
AB  - Several genetic loci are suspected to be involved in hereditary prostate cancer,
      including the hereditary prostate cancer 1 (HPC1) locus at chromosome 1q24-25.
      The ribonuclease L (RNase L) gene has been reported as the putative hereditary
      prostate cancer gene located at HPC1. If this is the case, mutations of RNase L
      should be found at a greater frequency in familial cancers than in sporadic
      prostate cancers. Examination of familial and sporadic cases of prostate cancer
      by polymerase chain reaction and DNA sequencing resulted in a mutational
      frequency rate that was not statistically different between the 2 forms of the
      disease. These results suggest that the mutations examined within this study are
      rare and may contribute to very few familial prostate cancers.

PMID- 15040863
TI  - Therapeutic approaches targeting prostate cancer progression using novel voltage
      gated ion channel blockers.
AB  - The early detection and treatment of prostate cancer have increased survival and
      improved clinical outcomes. The nature of the disease and pathologic understaging
      result in a high proportion of patients developing locally recurrent disease or
      distant metastases. The development of prostate cancer the time from tumor
      initiation and progression to invasive carcinoma often begins in men in the
      fourth or fifth decades of life and extends across decades. This prolonged window
      highlights the tremendous clinical impact that early intervention with
      therapeutic agents that selectively target the invasive and metastatic potential
      of the prostate cancer cell could have on patient survival and quality of life.
      Our research is currently focused on the development and testing of novel voltage
      gated ion channel blockers. The expression of voltage-gated sodium channels
      (VGSCs) was recently associated with the metastatic behavior of prostate cancer
      cells. In these studies, VGSC blockers altered prostate cancer cell morphology
      and arrested prostate cancer cell migration. Clinically, one of the most widely
      used sodium channel blockers is phenytoin. We have used rational drug design
      based on the phenytoin binding site in a VGSC to make novel sodium channel
      blockers with enhanced activity and minimal acute toxicity. Our initial studies
      in vitro demonstrate enhanced binding of the compounds to the sodium channel and
      increased inhibition of prostate cancer cell growth in culture and in soft
      agarose compared with phenytoin. These derivatives are currently being tested for
      their antitumor activity in human prostate cancer xenografts.

PMID- 15040864
TI  - Ion channels as molecular targets in prostate cancer.

PMID- 15040865
TI  - Clinical prostate cancer in year two: new and promising therapies for treatment
      and possible prevention of prostate cancer.

PMID- 15040866
TI  - Highlights from the 39th Annual meeting of the American Society of Clinical
      Oncology Chicago, Illinois.

PMID- 15040867
TI  - Autologous dendritic cells pulsed with prostatic acid phosphatase (APC8015) for
      patients with hormone-refractory prostate cancer with a Gleason score <or= 7.

PMID- 15040869
TI  - Population screening for prostate cancer and emerging concepts for young men.
AB  - Prostate cancer is the most common malignancy in American men, accounting for >
      29% of all diagnosed cancers and approximately 13% of all cancer deaths. Nearly 1
      of every 6 men will be diagnosed with the disease at some time in their lives. In
      2003 alone, an estimated 221000 men in the United States will be diagnosed with
      prostate cancer and > 28000 will die of the disease. An elevated level of
      prostate-specific antigen (PSA) is correlated with the presence of prostate
      cancer, and since 1989 we have been living in the "PSA era," in which the PSA
      screening test is widely used in clinical practice. This article summarizes what
      has been learned about the use of PSA screening, including the intricacies of
      free PSA, PSA doubling time, and various factors that may affect PSA and confound
      screening in young men. Although population-based screening for prostate cancer
      has yet to be definitively proven to affect disease-specific mortality, PSA
      testing is detecting cancers in younger men and at earlier stages of disease
      progression and, partly as a result, 5-year cancer-specific survival is
      increasing. Even though this lead-time effect may not translate into long-term
      improvement, these changes are very promising and are a necessary prerequisite to
      effective screening. For patients at high risk with a family history of the
      disease and for black men, a strategy consisting of an annual PSA blood test and
      digital rectal examination for men >or=40 years of age appears to be prudent. Use
      of age- and race-specific reference ranges for PSA based on sensitivity, or
      maximal cancer detection, is the most appropriate approach in this high-risk
      group. Specifically among black men 40-49 years of age, those with a PSA value >
      2.0 ng/mL should consider further evaluation. Many men at low/average risk aged
      40-49 years also request testing and it is reasonable to offer testing and risk
      assessment to these young men. The exact screening threshold for total PSA in
      these men is unknown, but 95% of these men will have a PSA < 2.5 ng/mL. Prostate
      specific antigen velocity, percentage of free PSA, and perhaps complexed PSA may
      be used to help determine risk, but further study of young men is needed. In the
      future, a risk-stratified approach using molecular biomarkers and/or proteomics
      in young men is anticipated.

PMID- 15040868
TI  - Clinical trials of atrasentan in hormone-refractory prostate cancer.

PMID- 15040870
TI  - Intensity-modulated radiation therapy for prostate cancer.
AB  - Prostate cancer is among the most common solid malignancies. A number of
      treatment alternatives exist for localized prostate cancer, including
      observation, prostatectomy, brachytherapy, and external-beam radiation therapy
      (EBRT). External-beam radiation therapy has changed dramatically during the past
      several years. Older techniques paved the way for 3-dimensional conformal
      radiation therapy (CRT), which in turn facilitated the introduction of intensity
      modulated radiation therapy (IMRT). The prostate has served as a model disease
      site for the implementation of IMRT. As indicated by a growing body of
      experience, IMRT for prostate cancer represents a major technologic and clinical
      advance for radiation therapy. In this article, a review is provided of the
      evolution of EBRT leading to IMRT, the unique features making the prostate an
      ideal disease site for employing IMRT, the details of the clinical implementation
      of prostate IMRT and supporting technologic advancements, and the currently
      reported clinical outcomes of IMRT in prostate cancer. In addition, future
      directions of prostate IMRT, both technologic and clinical, are discussed.

PMID- 15040871
TI  - Active surveillance with selective delayed intervention: a biologically nuanced
      approach to favorable-risk prostate cancer.
AB  - Prostate cancer is an indolent, slow-growing disease in many patients and may not
      pose a threat during a patient's lifetime. The challenge is to identify those
      patients who are not likely to experience significant progression while offering
      radical therapy to those who are at risk. To date, molecular markers have failed
      to provide sufficiently reliable predictive information to influence decision
      making. The approach to favorable-risk prostate cancer described in this article
      uses estimation of prostate-specific antigen doubling time (PSA DT) to stratify
      patients according to the risk of progression. Patients who select this approach
      initially undergo management with active surveillance; those who have a PSA DT
      <or=3 years (based on a minimum of 3 determinations over a period of 6 months)
      are offered radical intervention. The remainder are closely monitored. In a
      series of 231 patients in a study by our group, the median doubling time was 7.0
      years; 42% had a PSA DT > 10 years and 20% had a PSA DT > 100 years. The majority
      of patients in this study continue to undergo surveillance. The approach of
      active surveillance with selective delayed intervention based on PSA DT
      represents a practical compromise between radical therapy for all (which results
      in overtreatment of patients with indolent disease) and watchful waiting with
      palliative therapy only (which results in undertreatment of patients with
      aggressive disease).

PMID- 15040873
TI  - Characterization of prostate cancer missed by sextant biopsy.
AB  - There is a trend to increase the number of prostate biopsies taken to increase
      the detection rate of prostate cancer. We examined radical prostatectomy
      specimens and correlated the findings to those of preoperative sextant biopsy in
      an effort to identify the characteristics of tumors that went undetected by our
      biopsy regimen. Seventy-one patients diagnosed with prostate cancer based on
      sextant biopsy who underwent radical prostatectomy at our institution from June
      1995 to November 2001 had prostatectomy specimens and biopsy slides reviewed.
      These specimens were step-sectioned and whole-mounted. The location, size, and
      grade of individual cancer foci in the prostatectomy specimens were correlated
      with results of the original sextant biopsies. Clinically significant tumors were
      defined as those with volume > 0.5 mL or Gleason score > or= 7 and extracapsular
      extension. In 33 patients (46%), there was concordance of biopsy and
      prostatectomy findings. In 38 patients (54%), additional lesions were
      demonstrated in the prostatectomy specimens that were not detected by our sextant
      biopsies. These included 13 cases (34%) with tumors > 0.5 mL and 25 cases in
      which the lesions were < 0.5 mL in size. However, 7 of these cases contained
      tumors with Gleason score > or =7. Tumors were located in the transition zone in
      8 of these 38 cases (21%), and the remaining tumors were located in the
      peripheral zone (79%). No tumors with extracapsular extension were missed. Thus,
      20 of the 71 cases (28%) had clinically significant cancers that went undetected
      by the traditional sextant biopsy method. Greater than 50% of patients who
      underwent sextant biopsy of the prostate had additional tumors that were missed
      when compared to the pathologic specimen. As many as 28% of these patients had
      clinically significant cancer based on size and grade criteria. A strategy of
      increased numbers of biopsies would improve the detection rate of these
      clinically important tumors. However, the ideal strategy for optimizing cancer
      detection requires further investigation because increased numbers of biopsies
      would also increase detection of clinically insignificant tumors.

PMID- 15040872
TI  - Salvage cryosurgery for recurrent prostate cancer after radiation therapy: a
      seven-year follow-up.
AB  - Cryosurgery of the prostate presents as an efficient therapy following failed
      radiation therapy. We report on a 7-year retrospective analysis evaluating the
      morbidity adn biochemical disease-free survival(bDFS) of this therapy. Between
      1993 and 2001, 59 patients who had been previously treated with radiation therapy
      and had rising serum prostate-specific antigen(PSA) values underwent salvage
      cryoablation of the prostate for localized, histologically proven, recurrent
      prostate cancer. Serial serum PSA testing was performed, and biopsies were taken
      at 6, 12, and 24 months, and again at 5 years, and any time the PSA rose above
      0.5 ng/mL. Patients were stratified along clinical parameters. The combined
      postsalvage bDFS rate using a PSA cutoff of 0.5 ng/mL was 59% and 69% with a 1.0
      ng/mL PSA cut off. Using a PSA threshold of 0.5 ng/mL as evidence of biochemical
      recurrence, 61%, 62%, and 50% of patients with <4 ng/mL, 4-10 ng/mL, and > 10
      ng/mL PSA, respectively, remain biochemically relapse free at 7 years. A
      threshold of 1.0 ng/mL yielded a disease-free status of 78%, 74%, and 46%
      respectively. Patients biopsies showed no evidence of residual or recurrent
      disease. Improved survival rates and no known latent complications indicate
      cryosurgery is a promising form of treatment for radiation-resistant prostate
      cancer. This 7-year analysis shows a promising validation of cryosurgery as an
      efficacious treatment modality for locally confined T1-T3 prostate cancer
      following primary radiation therapy failure.

PMID- 15040874
TI  - The role of cyclooxygenase-2 inhibition for the prevention and treatment of
      prostate carcinoma.
AB  - Experimental and epidemiologic studies have demonstrated that nonsteroidal
      antiinflammatory drugs (NSAIDs) are effective in the prevention of human cancers.
      Nonsteroidal antiinflammatory drugs inhibit the cyclooxygenase (COX) enzyme that
      functions to convert arachidonic acid to prostaglandins (PGs). Cyclooxygenase-2,
      a key COX isoenzyme, is rapidly induced in response to inflammatory stimuli,
      growth factors, cytokines, and promoters of neoplastic growth. Cyclooxygenase-2
      catalyzed reactions may be involved in carcinogenesis via 2 distinct mechanisms:
      (1). DNA damage and (2). PG-mediated effects. Reactions mediated by COX-2 form
      reactive oxygen species that can directly induce the oxidation of DNA or
      instigate the bioactivation of carcinogens. Prostaglandin E2, a byproduct of COX
      2-mediated arachidonic acid metabolism, exhibits several biologic actions that
      have been shown to promote tumorigenesis and tumor progression. These actions
      include increased cell proliferation, promotion of angiogenesis, and the elevated
      expression of the antiapoptotic protein Bcl-2. In addition, PGE2 decreases
      natural killer cell activity and alters immune surveillance. In vitro
      experimental studies find that COX-2 inhibitors decrease cellular proliferation,
      increase apoptosis, and modulate genes involved in cell cycle regulation.
      Evidence from animal studies supports a role for NSAIDs in prostate cancer (CaP)
      prevention. Population-based studies have observed a reduced incidence of CaP
      among men using NSAIDs. Because CaP evolves slowly and rarely strikes men before
      the sixth or seventh decade of life, any strategy to delay or lengthen the time
      to development of clinically evident CaP, such as chemoprevention strategies,
      would greatly impact the natural history of this disease. Recent progress and
      critical analyses in the roles of COX-2 inhibition on prostate carcinogenesis and
      CaP prevention will be presented.

PMID- 15040875
TI  - The clinical rationale for immediate androgen deprivation without estrogen
      deprivation.

PMID- 15040876
TI  - Third annual meeting of the Society of Urologic Oncology: Bethesda, Maryland,
      December 13-14, 2002.

PMID- 15040877
TI  - Prostate-specific antigen doubling time predicts disease progression and
      survival.

PMID- 15040878
TI  - Current studies with docetaxel in hormone-refractory prostate cancer: selected
      presentations from the 27th European Society for Medical Oncology Congress, 2002.

PMID- 15040880
TI  - Algorithms for prostate-specific antigen recurrence after treatment of localized
      prostate cancer.
AB  - Nomograms are devices that predict outcome probabilities for the individual
      patient. Herein we discuss their strengths and limitations, focusing on responses
      to several frequently asked questions about nomograms. We believe these tools are
      useful and necessary for patient counseling, follow-up scheduling, and clinical
      trial design and analysis.

PMID- 15040879
TI  - Prostate cancer prevention: what do we know now and when will we know more?
AB  - Prostate cancer prevention is now one of the most aggressively investigated areas
      of urologic oncology, with > 30,000 men currently participating in clinical
      trials in the United States alone. The Prostate Cancer Prevention Trial will
      complete end-of-study prostate biopsies in May 2004, and the Selenium and Vitamin
      E Cancer Prevention Trial is rapidly reaching its accrual goal 1-2 years ahead of
      schedule. These 2 studies will give definitive answers regarding 3 of the most
      important potential preventive interventions: finasteride, vitamin E, and
      selenium. Many phase II and biomarker-modulation studies are also ongoing,
      testing a host of other interventions. It is hoped that, within a short period of
      time, the clinician will be provided with strategies to reduce the risk of the
      disease.

PMID- 15040881
TI  - Prostate cancer on the internet: impact on patients and how technology helps
      physicians and researchers.
AB  - The Internet is a repository of information unparalleled in history. The
      abundance of published material about prostate cancer has never been greater.
      Couple this with burgeoning pharmaceutical public-relations budgets and the
      result is a bewildering maze of hundreds of thousands of prostate cancer-oriented
      Internet pages. Our purposes are to help practitioners understand the profound
      handicap that patients are faced with when they attempt to search the Internet
      for information about their newly diagnosed disease and to succinctly evaluate
      the presence or absence of key aspects of prostate cancer on some of the most
      easily accessible sites. Part two of this paper will then discuss 4 of the most
      valuable Web sites for the prostate cancer specialist. Surfing the World Wide Web
      can be frustrating and time-consuming, but it can also be rewarding and
      informative.

PMID- 15040882
TI  - Radiation therapy for increasing prostate-specific antigen levels after radical
      prostatectomy.
AB  - Herein we present data on outcomes in patients with increasing prostate-specific
      antigen (PSA) levels treated with irradiation to the pelvis and/or prostatic bed
      after radical prostatectomy. Between 1988 and 1998, 92 patients who presented
      with increasing PSA levels after radical prostatectomy were treated with
      irradiation, 29 to the pelvis and prostatic bed and 63 to the prostatic bed only.
      The mean follow-up was 4 years for the 3D-CRT group and 6.5 years for the
      standard radiation therapy group. Criterion for biochemical failure was an
      increase in post irradiation PSA level on > or = 1 consecutive measurement.
      Patients were classified into 3 risk groups based on prognostic factors:
      pathologic tumor extent and stage, Gleason score, and PSA levels before
      irradiation. Acute and late morbidity was quantitatively evaluated in all
      patients. There was a close correlation between the preirradiation PSA level and
      the probability of 4-year biochemical failure-free survival (75% with PSA levels
      < or = 1 ng/mL, 30% with PSA levels of 1.1-2 ng/mL, and 20% with PSA levels > 2
      ng/mL; P = 0.05). The 4-year chemical failure rate was 20% in the
      low/intermediate-risk group and 65% in the high-risk group (P = 0.36). In 20
      patients in the low-PSA group (< or =1 ng/mL) receiving doses > 62 Gy, no
      biochemical failures have been detected in comparison to a 70% failure rate at 4
      years in patients treated with lower doses (P = 0.15). In the higher-PSA groups,
      no impact of irradiation dose on outcome was noted (40%-60% incidence of failure
      at 3 years). Pelvic irradiation was associated with a trend toward decreased
      biochemical failure rate in the low-PSA group (70% vs. 0% at 4 years; P = 0.35),
      but not in the high-PSA group. Only 1 patient (1.5%) experienced clinical local
      recurrence in the prostatic bed and 2 patients (1.8%) had distant metastases.
      Treatment has been very well tolerated, with only 3 patients in the arc-rotation
      group experiencing grade 2 treatment toxicity. Prostate bed irradiation is an
      effective treatment in a significant proportion of patients who present with a
      biochemical failure after radical prostatectomy.

PMID- 15040883
TI  - Ten-year survival after radical prostatectomy: specimen Gleason score is the
      predictor in organ-confined prostate cancer.
AB  - Pathologic stage is a major prognostic factor in patients with clinically
      localized prostate cancer. However, disease recurrence occurs even in patients
      with organ-confined disease. With the advent of prostate-specific antigen (PSA)
      testing, the percentage of patients with pathologically organ-confined tumors has
      increased significantly. We studied clinical/pathologic factors that will predict
      disease recurrence in patients with pathologically organ-confined tumors.
      Patients with clinically localized newly diagnosed prostate cancer who had not
      received prior therapeutic intervention but who underwent radical prostatectomy
      as definitive treatment between 1990 and 1999, were included in this study.
      Clinical/pathologic parameters including age, race, clinical stage, preoperative
      PSA, and biopsy and specimen Gleason scores (grouped as 2-6, 7, and 8-10) were
      correlated with disease-free survival in patients with organ-confined disease.
      Metastasis-free and cancer-specific survival for the cohort was also assessed. A
      total of 1045 patients fulfilled our inclusion criteria. Overall, the 10-year
      estimates of PSA progression-free, metastasis-free, and cancer-specific survival
      were 75%, 91%, and 92%, respectively. Cancer was confined to the prostate in 532
      of 1045 patients (51%), of whom 96% (511 of 532) remain PSA progression-free,
      compared to 65% (335 of 513) with extraprostatic disease (P = 0.0001).
      Interestingly, in patients with organ-confined disease, the specimen Gleason
      score was the only prognostic factor for disease recurrence after multivariable
      analysis. Radical prostatectomy provided excellent cancer control. For patients
      with pathologically organ-confined tumors, the specimen Gleason score is the only
      factor predictive of disease-free survival. Of note, Gleason scores of 8-10 are
      uncommon in these patients.

PMID- 15040884
TI  - The revolution of the biology of the genome.
AB  - Sequence data of entire eukaryotic genomes and their detailed comparison have
      provided new evidence on genome evolution. The major mechanisms involved in the
      increase of genome sizes are polyploidization and gene duplication. Subsequent
      gene silencing or mutations, preferentially in regulatory sequences of genes,
      modify the genome and permit the development of genes with new properties.
      Mechanisms such as lateral gene transfer, exon shuffling or the creation of new
      genes by transposition contribute to the evolution of a genome, but remain of
      relatively restricted relevance. Mechanisms to decrease genome sizes and, in
      particular, to remove specific DNA sequences, such as blocks of satellite DNAs,
      appear to involve the action of RNA interference (RNAi). RNAi mechanisms have
      been proven to be involved in chromatin packaging related with gene inactivation
      as well as in DNA excision during the macronucleus development in ciliates.

PMID- 15040885
TI  - Arabidopsis RAV1 is down-regulated by brassinosteroid and may act as a negative
      regulator during plant development.
AB  - RAV1 is a novel DNA-binding protein with two distinct DNA-binding domains unique
      in higher plants, but its role in plant growth and development remains unknown.
      Using cDNA array, we found that transcription of RAV1 is down-regulated by
      epibrassinolide (epiBL) in Arabidopsis suspension cells. RNA gel blot analysis
      revealed that epiBL-regulated RAV1 transcription involves neither protein
      phosphorylation/dephosphorylation nor newly synthesized protein, and does not
      require the functional BRI1, suggesting that this regulation might be through a
      new BR signaling pathway. Overexpressing RAV1 in Arabidopsis results in a
      retardation of lateral root and rosette leaf development, and the underexpression
      causes an earlier flowering phenotype, implying that RAV1 may function as a
      negative regulatory component of growth and development.

PMID- 15040886
TI  - Mechanical stretch induces mitochondria-dependent apoptosis in neonatal rat
      cardiomyocytes and G2/M accumulation in cardiac fibroblasts.
AB  - Heart remodeling is associated with the loss of cardiomyocytes and increase of
      fibrous tissue owing to abnormal mechanical load in a number of heart disease
      conditions. In present study, a well-described in vitro sustained stretch model
      was employed to study mechanical stretch-induced responses in both neonatal
      cardiomyocytes and cardiac fibroblasts. Cardiomyocytes, but not cardiac
      fibroblasts, underwent mitochondria-dependent apoptosis as evidenced by
      cytochrome c (cyto c) and Smac/DIABLO release from mitochondria into cytosol
      accompanied by mitochondrial membrane potential (Deltapsi(m)) reduction,
      indicative of mitochondrial permeability transition pore (PTP) opening.
      Cyclosporin A, an inhibitor of PTP, inhibited stretch-induced cyto c release,
      Deltapsi(m) reduction and apoptosis, suggesting an important role of
      mitochondrial PTP in stretch-induced apoptosis. The stretch also resulted in
      increased expression of the pro-apoptotic Bcl-2 family proteins, including Bax
      and Bad, in cardiomyocytes, but not in fibroblasts. Bax was accumulated in
      mitochondria following stretch. Cell permeable Bid-BH3 peptide could induce and
      facilitate stretch-induced apoptosis and Deltapsi(m) reduction in cardiomyocytes.
      These results suggest that Bcl-2 family proteins play an important role in
      coupling stretch signaling to mitochondrial death machinery, probably by
      targeting to PTP. Interestingly, the levels of p53 were increased at 12 h after
      stretch although we observed that Bax upregulation and apoptosis occurred as
      early as 1 h. Adenovirus delivered dominant negative p53 blocked Bax upregulation
      in cardiomyocytes but showed partial effect on preventing stretch-induced
      apoptosis, suggesting that p53 was only partially involved in mediating stretch
      induced apoptosis. Furthermore, we showed that p21 was upregulated and cyclin B1
      was downregulated only in cardiac fibroblasts, which may be associated with G2/M
      accumulation in response to mechanical stretch.

PMID- 15040887
TI  - Alpha-picolinic acid, a fungal toxin and mammal apoptosis-inducing agent, elicits
      hypersensitive-like response and enhances disease resistance in rice.
AB  - Alpha-picolinic acid (PA), a metabolite of tryptophan and an inducer of apoptosis
      in the animal cell, has been reported to be a toxin produced by some of plant
      fungal pathogens and used in screening for disease resistant mutants. Here, we
      report that PA is an efficient apoptosis agent triggering cell death of
      hypersensitive-like response in planta. Confirmed by Fluorescence Activated Cell
      Sorter (FACS), rice suspension cells and leaves exhibited programmed cell death
      induced by PA. The PA-induced cell death was associated with the accumulation of
      reactive oxygen species that could be blocked by diphenylene iodonium chloride,
      indicating that the generation of reactive oxygen species was NADPH-oxidase
      dependent. We also demonstrated the induction of rice defense-related genes and
      subsequent resistant enhancement by PA against the rice blast fungus Magnaporthe
      grisea. Hence, it was concluded that the PA-stimulated defense response likely
      involves the onset of the hypersensitive response in rice, which also provides a
      simple eliciting tool for studying apoptosis in the plant cell.

PMID- 15040888
TI  - DNA chip-based expression profile analysis indicates involvement of the
      phosphatidylinositol signaling pathway in multiple plant responses to hormone and
      abiotic treatments.
AB  - The phosphatidylinositol (PI) metabolic pathway is considered critical in plant
      responses to many environmental factors, and previous studies have indicated the
      involvement of multiple PI-related gene families during cellular responses.
      Through a detailed analysis of the Arabidopsis thaliana genome, 82 polypeptides
      were identified as being involved in PI signaling. These could be grouped into
      different families including PI synthases (PIS), PI-phosphate kinases (PIPK),
      phospholipases (PL), inositol polyphosphate phosphatases (IPPase), inositol
      polyphosphate kinases (IPK), PI transfer proteins and putative inositol
      polyphosphate receptors. The presence of more than 10 isoforms of PIPK, PLC, PLD
      and IPPase suggested that these genes might be differentially expressed during
      plant cellular responses or growth and development. Accordingly, DNA chip
      technology was employed to study the expression patterns of various isoforms. In
      total, 79 mRNA clones were amplified and used for DNA chip generation. Expression
      profile analysis was performed using samples that represented multiple tissues or
      cellular responses. Tested samples included normal leaf, stem and flower tissues,
      and leaves from plants treated with various hormones (auxin, cytokinin,
      gibberellin, abscisic acid and brassinosteroid) or environmental factors
      (temperature, calcium, sodium, drought, salicylic acid and jasmonic acid).
      Results showed that many PI pathway-related genes were differentially expressed
      under these experimental conditions. In particular, the different isoforms of
      each family were specifically expressed in many cases, suggesting their
      involvement in tissue specificity and cellular responses to environmental
      conditions. This work provides a starting point for functional studies of the
      relevant PI-related proteins and may help shed light onto the role of PI pathways
      in development and cellular responses.

PMID- 15040889
TI  - Expression of MRP14 gene is frequently down-regulated in Chinese human esophageal
      cancer.
AB  - Migration inhibitory factor-related protein 14 (MRP14) is one of calcium-binding
      proteins, referred as S100A9. The heterodimeric molecule formed by MRP14 with its
      partner MRP8 (S100A8) is the major fatty acid carrier in neutrophils. The MRP8/14
      complex has been also implicated in the intracellular transport of arachidonic
      acid and its precursors in keratinocytes. We show here the involvement of MRP14
      in human esophageal cancer. In an initial study, mRNA differential display
      reverse transcription polymerase chain reaction (DD-PCR) was performed with two
      esophageal carcinomas, one esophageal adenocarcinoma and matched normal adjacent
      mucosa. DD-PCR with the arbitrary primer OPA3 showed that one cDNA band was
      highly expressed in normal tissues, but disappeared or substantially decreased in
      tumor counterparts. It was later identified to be the 3'-end of migration
      inhibitory factor-related protein 14 (MRP14). Northern blotting, RT-PCR and
      Western blotting corroborated the down-regulation of MRP14 in 58/64 squamous cell
      carcinomas and 2/2 adenocarcinomas as compared with adjacent normal epithelia of
      the esophagus. MRP14 was undetectable in 3/3 esophageal-carcinoma cell lines.
      Immunochemistry demonstrated that expression of MRP14 was restricted to normal
      esophageal epithelia. No mutation was found in the genomic DNA of the MRP14 gene
      by PCR and directed DNA sequencing. Our finding suggested that the reduction of
      MRP14 expression is a frequent event in Chinese human esophageal cancer.

PMID- 15040891
TI  - Cisplatin-induced premature senescence with concomitant reduction of gap
      junctions in human fibroblasts.
AB  - To examine the role of gap junctions in cell senescence, the changes of gap
      junctions in cisplatin-induced premature senescence of primary cultured
      fibroblasts were studied and compared with the replicative senescent human
      fibroblasts. Dye transfer assay for gap junction function and immunofluorescent
      staining for connexin 43 protein distribution were done respectively.
      Furthermore, cytofluorimetry and DAPI fluorescence staining were performed for
      cell cycle and apoptosis analysis. p53 gene expression level was detected with
      indirect immunofluorescence. We found that cisplatin (10 mM) treatment could
      block cell growth cycle at G1 and induced premature senescence. The premature
      senescence changes included high frequency of apoptosis, elevation of p53
      expression, loss of membranous gap junctions and reduction of dye-transfer
      capacity. These changes were comparable to the changes of replicative senescence
      of human fibroblasts. It was also concluded that cisplatin could induce premature
      senescence concomitant with inhibition of gap junctions in the fibroblasts. Loss
      of functional gap junctions from the cell membrane may account for the reduced
      intercellular communication in the premature senescent fibroblasts. The cell
      system we used may provide a model useful for the study of the gap junction thus
      promoting agents against premature senescence.

PMID- 15040890
TI  - Impaired reproduction in transgenic mice overexpressing Gamma-aminobutyric acid
      transporter I (GAT1).
AB  - It is well documented that g-aminobutyric acid (GABA) system existed in
      reproductive organs. Recent researches showed that GABAA and GABAB receptors were
      present in testis and sperm, and might mediate the acrosome reaction induced by
      GABA and progesterone. GABA transporter I (GAT1) also existed in testis and
      sperm, but its physiological function was unknown. In the present study, we used
      GAT1 overexpressing mice to explore GAT1 function in male reproductive system. We
      found that the expression level of GAT1 continuously increased in wild-type mouse
      testis from 1 month to 2 months after birth. GAT1 overexpression in mouse
      affected testis development, which embodied reduced testis mass and slowed
      spermatogenesis in transgenic mice. Moreover, transgenic mice showed increase of
      the percentage of broken sperm. The further study revealed that the reproductive
      capacity was impaired in GAT1 overexpressing mice. In addition, testosterone
      level was significantly low in transgenic mice compared with that in wild-type
      mice. Our findings provided the first evidence that abnormal expression of GAT1
      could result in dysgenesis, and indicated that GAT1 might be therapeutically
      targeted for contraception or dysgenesis treatment.

PMID- 15040892
TI  - Expression of prolactin receptor and response to prolactin stimulation of human
      NK cell lines.
AB  - We have previously shown a critical role of prolactin (PRL) during maturation and
      anti-tumor effects of murine natural killer (NK) cells in vitro and in vivo. We
      extended that study by exploring the ability of human NK cell lines (NK-92 and YT
      cell) to express PRL receptor (PRL-R) and to respond to PRL stimulation in vitro.
      Both human NK cell lines constitutively expressed PRL-R on membrane and mRNA
      transcripts, NK-92 cells contained higher level of PRL-R than YT cells, which
      correlated to the enhanced capacity of the cells to proliferate and to lyse
      target cells in response to PRL stimulation in the presence of trace amount of IL
      2 or IL-15 in vitro. Two differences between IL-2 and IL-15 in functioning on
      human NK cells were for the first time observed. PRL synergized with IL-15 to
      improve proliferation of NK cells in a dose-dependent manner without double peak
      manifesting like IL-2. Although PRL enhanced the cytotoxicity of IL-2 or IL-15
      activated NK cells, it exerted the function through up-regulating gene expression
      of perforin without influence of FasL in IL-2-stimulated NK cells, while in IL-15
      stimulated NK cells, PRL did the function through up-regulating gene expression
      of both perforin and FasL but not IFN-gamma. PRL increased expressions of IL
      2Ralpha on membrane and of IL-2 mRNA in cells, indicating that PRL up-regulated
      NK cell function by improving positive feedback between IL-2 and IL-2R. The
      similar results were also observed in network between IL-15 and IL-15R. These
      data indicate a potential role of PRL in human NK cell modulation.

PMID- 15040893
TI  - Aberrant expression and function of TCF4 in the proliferation of hepatocellular
      carcinoma cell line BEL-7402.
AB  - Wnt signaling pathway is essential for development and tumorigenesis, however,
      this signaling pathway in the progress of hepatocellular carcinoma (HCC) remains
      unclear. In this paper, we studied the function of human T-cell transcription
      factor-4 (TCF4), a key factor of Wnt signaling pathway, on the proliferation of
      HCC cell line. We showed that the expression of TCF4 mRNA in HCC cell line BEL
      7402 was higher than that in immortalized normal liver cell line L02. Blockage of
      Wnt pathway by Delta-NTCF4, a dominant negative TCF4, could suppress BEL-7402
      cells growth and decrease the expression of cyclin D1 and c-myc, two of target
      genes of Wnt pathway. On the other hand, stimulating Wnt pathway by introducing a
      degradation-resistant -catenin S37A could increase BEL-7402 cells proliferation.
      But all the treatments had no effect on L02 cells. Our data indicated that TCF4
      might be another key factor in Wnt pathway involved in HCC cells proliferation
      and TCF4 could be an effective therapeutic target for suppressing the growth of
      hepatocellular cancers.

PMID- 15040894
TI  - The cell cycle related apoptotic susceptibility to arsenic trioxide is associated
      with the level of reactive oxygen species.
AB  - Double staining flow cytometry was performed using 7-amino actinomycin D and 6
      carboxy-2', 7'-dichlorodihydrofluorescein diacetate, to detect the level
      fluctuation of reactive oxygen species (ROS) during the cell cycle of normal NB4
      cells. Our results showed that NB4 cells possessed higher level of ROS in G2/M
      phase than in G1 and S phases. Double staining flow cytometry, with TdT mediated
      dUTP nick end labeling (Tunel) and propidium iodide (PI), indicated that As2O3 (2
      microM) could induce apoptosis in NB4 cells prevailingly from G2/M phase, and
      this efficacy was enhanced upon co-administration of 2, 3-dimethoxy-1, 4
      naphthoquinone (DMNQ) (2.5 microM) which could produce the endogenous ROS. These
      results suggested that different ROS level in different cell cycle phases of NB4
      cells might determine the selective induction of G2/M apoptosis and the cells'
      susceptibility to apoptosis by As2O3.

PMID- 15040896
TI  - The efficiency of designs for fine-mapping of quantitative trait loci using
      combined linkage disequilibrium and linkage.
AB  - In a simulation study, different designs were compared for efficiency of fine
      mapping of QTL. The variance component method for fine-mapping of QTL was used to
      estimate QTL position and variance components. The design of many families with
      small size gave a higher mapping resolution than a design with few families of
      large size. However, the difference is small in half sib designs. The proportion
      of replicates with the QTL positioned within 3 cM of the true position is 0.71 in
      the best design, and 0.68 in the worst design applied to 128 animals with a
      phenotypic record and a QTL explaining 25% of the phenotypic variance. The design
      of two half sib families each of size 64 was further investigated for a
      hypothetical population with effective size of 1000 simulated for 6000
      generations with a marker density of 0.25 cM and with marker mutation rate 4 x10(
      4) per generation. In mapping using bi-allelic markers, 42 approximately 55 of
      replicated simulations could position QTL within 0.75 cM of the true position
      whereas this was higher for multi allelic markers (48 approximately 76 ). The
      accuracy was lowest (48%) when mutation age was 100 generations and increased to
      68% and 76% for mutation ages of 200 and 500 generations, respectively, after
      which it was about 70% for mutation ages of 1000 generations and older. When
      effective size was linearly decreasing in the last 50 generations, the accuracy
      was decreased (56 to 70%). We show that half sib designs that have often been
      used for linkage mapping can have sufficient information for fine-mapping of QTL.
      It is suggested that the same design with the same animals for linkage mapping
      should be used for fine-mapping so gene mapping can be cost effective in
      livestock populations.

PMID- 15040895
TI  - Intermediate fertile Triticum aestivum (+) Agropyron elongatum somatic hybrids
      are generated by low doses of UV irradiation.
AB  - We report the production and characterization of somatic hybrids between Triticum
      aestivum L. and Agropyron elongatum (Host) Nevishi (the synonym is Thinopyrum
      ponticum). Asymmetric protoplast fusion was performed between Agropyron elongatum
      protoplasts irradiated with a low UV dose and protoplasts of wheat taken from
      nonregenerable suspension cultures. More than 40 green plantlets were obtained
      from 15 regenerated clones and one of them produced seeds. The phenotypes of the
      hybrid plants and seeds were intermediate between wheat and Agropyron elongatum.
      All of the regenerated calli and plants were verified as intergeneric hybrids on
      the basis of morphological observation and analysis of isozyme, cytological,
      5SrDNA spacer sequences and random amplified polymorphic DNA (RAPD). RFLP
      analysis of the mitochondrial genome revealed evidence of random segregation and
      recombination of mtDNA.

PMID- 15040898
TI  - Bootstrapping of gene-expression data improves and controls the false discovery
      rate of differentially expressed genes.
AB  - The ordinary-, penalized-, and bootstrap t-test, least squares and best linear
      unbiased prediction were compared for their false discovery rates (FDR), i.e. the
      fraction of falsely discovered genes, which was empirically estimated in a
      duplicate of the data set. The bootstrap-t-test yielded up to 80% lower FDRs than
      the alternative statistics, and its FDR was always as good as or better than any
      of the alternatives. Generally, the predicted FDR from the bootstrapped P-values
      agreed well with their empirical estimates, except when the number of mRNA
      samples is smaller than 16. In a cancer data set, the bootstrap-t-test discovered
      200 differentially regulated genes at a FDR of 2.6%, and in a knock-out gene
      expression experiment 10 genes were discovered at a FDR of 3.2%. It is argued
      that, in the case of microarray data, control of the FDR takes sufficient account
      of the multiple testing, whilst being less stringent than Bonferoni-type multiple
      testing corrections. Extensions of the bootstrap simulations to more complicated
      test-statistics are discussed.

PMID- 15040897
TI  - Quantitative trait loci mapping in dairy cattle: review and meta-analysis.
AB  - From an extensive review of public domain information on dairy cattle
      quantitative trait loci (QTL), we have prepared a draft online QTL map for dairy
      production traits. Most publications (45 out of 55 reviewed) reported QTL for the
      major milk production traits (milk, fat and protein yield, and fat and protein
      concentration (%)) and somatic cell score. Relatively few QTL studies have been
      reported for more complex traits such as mastitis, fertility and health. The
      collated QTL map shows some chromosomal regions with a high density of QTL, as
      well as a substantial number of QTL at single chromosomal locations. To extract
      the most information from these published records, a meta-analysis was conducted
      to obtain consensus on QTL location and allelic substitution effect of these QTL.
      This required modification and development of statistical methodologies. The meta
      analysis indicated a number of consensus regions, the most striking being two
      distinct regions affecting milk yield on chromosome 6 at 49 cM and 87 cM
      explaining 4.2 and 3.6 percent of the genetic variance of milk yield,
      respectively. The first of these regions (near marker BM143) affects five
      separate milk production traits (protein yield, protein percent, fat yield, fat
      percent, as well as milk yield).

PMID- 15040899
TI  - Genetic variability of the pattern of night melatonin blood levels in relation to
      coat changes development in rabbits.
AB  - To assess the genetic variability in both the nocturnal increase pattern of
      melatonin concentration and photoresponsiveness in coat changes, an experiment on
      422 Rex rabbits (from 23 males) raised under a constant light programme from
      birth was performed. The animals were sampled at 12 weeks of age, according to 4
      periods over a year. Blood samples were taken 7 times during the dark phase and
      up to 1 h after the lighting began. Maturity of the fur was assessed at pelting.
      Heritability estimates of blood melatonin concentration (0.42, 0.17 and 0.11 at
      mid-night, 13 and 15 h after lights-out respectively) and strong genetic
      correlations between fur maturity and melatonin levels at the end of the dark
      phase (-0.64) indicates that (i) the variability of the nocturnal pattern of
      melatonin levels is under genetic control and (ii) the duration of the nocturnal
      melatonin increase is a genetic component of photoresponsiveness in coat changes.

PMID- 15040901
TI  - Geographic distribution of haplotype diversity at the bovine casein locus.
AB  - The genetic diversity of the casein locus in cattle was studied on the basis of
      haplotype analysis. Consideration of recently described genetic variants of the
      casein genes which to date have not been the subject of diversity studies,
      allowed the identification of new haplotypes. Genotyping of 30 cattle breeds from
      four continents revealed a geographically associated distribution of haplotypes,
      mainly defined by frequencies of alleles at CSN1S1 and CSN3. The genetic
      diversity within taurine breeds in Europe was found to decrease significantly
      from the south to the north and from the east to the west. Such geographic
      patterns of cattle genetic variation at the casein locus may be a result of the
      domestication process of modern cattle as well as geographically differentiated
      natural or artificial selection. The comparison of African Bos taurus and Bos
      indicus breeds allowed the identification of several Bos indicus specific
      haplotypes (CSN1S1*C-CSN2*A2-CSN3*AI / CSN3*H) that are not found in pure taurine
      breeds. The occurrence of such haplotypes in southern European breeds also
      suggests that an introgression of indicine genes into taurine breeds could have
      contributed to the distribution of the genetic variation observed.

PMID- 15040900
TI  - A short-term divergent selection for resistance to Teladorsagia circumcincta in
      Romanov sheep using natural or artificial challenge.
AB  - This experiment was conducted to assess the efficiency of selection on the basis
      of response to artificial challenges in order to breed sheep resistant to natural
      infection. A short-term divergent selection process was designed to estimate the
      genetic parameters of these two traits. Two flocks, including 100 Romanov ram
      lambs each, were challenged in 1990 when they were 6 months old. One flock
      received three artificial infections with 20 000 third-stage Teladorsagia
      circumcincta larvae, at intervals of 7 weeks. Faecal egg counts (FEC) were
      performed on Days 22, 25 and 28 post infection (p.i.) and the animals were
      drenched on Day 28 p.i. The other flock was grazed for 5 months on a pasture
      contaminated with the same species. Faecal samples were taken from the lambs at
      similar ages. About 5 rams with the lowest FEC and 5 with the highest FEC were
      selected in each flock and mated with unselected ewes. Their offspring (200
      animals) were challenged in 1992, half in the same way as their sires, and the
      other half by the other method. Because of a drought in the summer of 1990, it
      was necessary to repeat part of the experiment, and in 1992 the 5 and 8 rams with
      the lowest and highest FEC, respectively, were selected from the offspring
      challenged on the pasture in 1992 and were mated with unselected ewes. Their
      progeny (about 80 animals) were challenged in 1994, half by natural infection,
      half by artificial infection. The mean FEC of the flock increased from the first
      to the third artificial infection. The natural infection was highly variable in
      different years, reflecting the difficulty of assessing resistance using this
      mode of challenge. Genetic parameters were estimated using animal models and REML
      solutions. The repeatabilities of the FEC following artificial and natural
      infection were 0.49 and 0.70 respectively within a period of one week, and 0.22
      and 0.41 respectively for periods separated by intervals of 7 weeks; the
      heritabilities of the single egg count were 0.22 and 0.38 respectively. The
      genetic correlation was 0.87: the FEC recorded under natural or artificial
      infection appear to depend on the same genetic potential.

PMID- 15040902
TI  - Pathologic features of suicidal complete decapitations.
AB  - Despite high suicide rates all over the world, complete decapitation as a
      consequence of violent suicide methods is exceptionally rare and there is always
      a potential for confusion with homicide as well as with body dismemberment or
      mutilation. We analyzed the phenomenology and morphology of 10 cases (six male,
      four female; individual age 18-60 years) of suicidal complete decapitation that
      were subjected to medico-legal autopsies at the Institute of Legal Medicine,
      University of Hamburg, Germany, between 1995 and 2002. All decapitations occurred
      while the person was alive as proven by signs of vitality. Blood alcohol levels
      were positive in five cases and ranged between 28 and 202 mg/dl. The applied
      methods of suicide were running over by a train in eight cases and hanging in two
      cases. In suicidal hanging resulting in complete decapitation the wound margins
      were clear-cut with an adjacent sharply demarcated circumferential band-like
      abrasion zone showing a homogenous width, the latter determined by the thickness
      of the rope. In decapitations due to railway interference a broad spectrum of
      pathologic alterations such as the co-existence of irregular, ragged and sharp
      edged wound margins, vascular and nervous pathways forming bridges in the depth
      of the wound and bruising could be observed. In such cases skin abrasion zones
      were generally not circumferential and showed a heterogenous width. Concerning
      hanging-related complete decapitations, our findings are well in line with those
      of other authors, namely that heavy body weight of the suicidal, fall from a
      great height and in some cases inelastic and/or thin rope material used for the
      noose are the determining factors decisive for complete decapitation.

PMID- 15040903
TI  - Adult sudden death caused by aspiration of chewing gum.
AB  - A case of a fatal foreign material aspiration is presented in the following text.
      A 24-year-old white male died suddenly. A piece of chewing gum lodged in a pool
      of frothy fluid was revealed at autopsy. Microscopic examinations revealed
      atelectasia emphysema, eosinophilic exudate and empty spaces. Blood and urine
      samples were analyzed, for alcohol and drug use by fluorescence polarization
      immunoassay (FPIA) on an Abbott AXSYM system. No alcohol or other drugs were
      detected in blood or urine.

PMID- 15040904
TI  - High-throughput Y-STR typing of U.S. populations with 27 regions of the Y
      chromosome using two multiplex PCR assays.
AB  - Two Y-chromosome short tandem repeat (STR) multiplex polymerase chain reaction
      (PCR) assays were used to generate haplotypes for 19 single copy and 3 multi-copy
      Y-STRs. A total of 27 PCR products were examined in each sample using the
      following loci: DYS19, DYS385 a/b, DYS388, DYS389I/II, DYS390, DYS391, DYS392,
      DYS393, DYS426, DYS437, DYS438, DYS439, DYS447, DYS448, DYS450, DYS456, DYS458,
      DYS460, DYS464 a/b/c/d, H4, and YCAII a/b. The first multiplex is the Y-STR
      20plex previously described by Butler et al. [Forensic Sci. Int. 129 (2002) 10].
      The second multiplex is a novel Y-STR 11plex and includes DYS385 a/b, DYS447,
      DYS448 and the new markers DYS450, DYS456, DYS458, and DYS464 a/b/c/d. These two
      multiplexes were tested on 647 males from three United States population sample
      sets: 260 African Americans, 244 Caucasians, and 143 Hispanics. Haplotype
      comparisons between common loci included in the 20plex and 11plex assays as well
      as commercially available kits found excellent agreement across a sampling of the
      population samples. The multi-copy loci DYS464, DYS385, and YCAII were the most
      polymorphic followed by the following single copy Y-STRs: DYS458, DYS390, DYS447,
      DYS389II, DYS448, and DYS456. Samples containing the most common type in the
      European database could be well resolved with additional markers beyond the
      minimal haplotype loci.

PMID- 15040906
TI  - Preparation of degraded human DNA under controlled conditions.
AB  - DNA typing through analysis of short tandem repeats (STRs) and mitochondrial DNA
      (mtDNA) by means of the polymerase chain reaction (PCR) and sequencing are the
      common methods for the forensic identification of persons and reconstruction of
      kinship, especially when skeletal human remains have to be analyzed. Furthermore,
      samples typically found at crime scenes may be both quantitatively and
      qualitatively inadequate since they may contain very scarce and often degraded
      DNA due to exposure to heat, light, humidity, and microorganisms. In order to
      improve the performance of STR typing technology in those cases where DNA
      availability is limited, it would be desirable to have a source of degraded DNA
      with known properties. For this purpose, we have developed a method to prepare
      artificially degraded DNA under controlled conditions. By treatment of genomic
      DNA with sonication and DNAse I we have produced DNA fragments within a defined
      range of lengths. STR typing of this degraded DNA with a commercially available
      multiplex kit could only produce partial profiles as indicated by the absence of
      STR alleles with sizes >200 bp. This artificially degraded DNA can be used for
      the improvement and standardization of STR typing protocols when only highly
      degraded DNA is available for analysis.

PMID- 15040907
TI  - Real-time PCR designs to estimate nuclear and mitochondrial DNA copy number in
      forensic and ancient DNA studies.
AB  - We explore different designs to estimate both nuclear and mitochondrial human DNA
      (mtDNA) content based on the detection of the 5' nuclease activity of the Taq DNA
      polymerase using fluorogenic probes and a real-time quantitative PCR detection
      system. Human mtDNA quantification was accomplished by monitoring the real-time
      progress of the PCR-amplification of two different fragment sizes (113 and 287
      bp) within the hypervariable region I (HV1) of the mtDNA control region, using
      two fluorogenic probes to specifically determine the mtDNA copy of each fragment
      size category. This mtDNA real-time PCR design has been used to assess the mtDNA
      preservation (copy number and degradation state) of DNA samples retrieved from
      500 to 1500 years old human remains that showed low copy number and highly
      degraded mtDNA. The quantification of nuclear DNA was achieved by real-time PCR
      of a segment of the X-Y homologous amelogenin (AMG) gene that allowed the
      simultaneous estimation of a Y-specific fragment (AMGY: 112 bp) and a X-specific
      fragment (AMGX: 106 bp) making possible not only haploid or diploid DNA
      quantitation but also sex determination. The AMG real-time PCR design has been
      used to quantify a set of 57 DNA samples from 4-5 years old forensic bone remains
      with improved sensitivity compared with the slot-blot hybridization method. The
      potential utility of this technology to improve the quality of some PCR-based
      forensic and ancient DNA studies (microsatellite typing and mtDNA sequencing) is
      discussed.

PMID- 15040905
TI  - STR analysis of artificially degraded DNA-results of a collaborative European
      exercise.
AB  - Degradation of human DNA extracted from forensic stains is, in most cases, the
      result of a natural process due to the exposure of the stain samples to the
      environment. Experiences with degraded DNA from casework samples show that every
      sample may exhibit different properties in this respect, and that it is difficult
      to systematically assess the performance of routinely used typing systems for the
      analysis of degraded DNA samples. Using a batch of artificially degraded DNA with
      an average fragment size of approx. 200 bp a collaborative exercise was carried
      out among 38 forensic laboratories from 17 European countries. The results were
      assessed according to correct allele detection, peak height and balance as well
      as the occurrence of artefacts. A number of common problems were identified based
      on these results such as strong peak imbalance in heterozygous genotypes for the
      larger short tandem repeat (STR) fragments after increased PCR cycle numbers,
      artefact signals and allelic drop-out. Based on the observations, strategies are
      discussed to overcome these problems. The strategies include careful balancing of
      the amount of template DNA and the PCR cycle numbers, the reaction volume and the
      amount of Taq polymerase. Furthermore, a careful evaluation of the results of the
      fragment analysis and of automated allele calling is necessary to identify the
      correct alleles and avoid artefacts.

PMID- 15040908
TI  - Persisting fetal microchimerism does not interfere with forensic Y-chromosome
      typing.
AB  - Forensic Y-chromosome typing applies Y-chromosomal polymorphisms to the analysis
      of male/female mixed stains such as vaginal swabs in rape cases. The sensitivity
      of this approach exceeds that of cytological techniques combined with autosomal
      DNA typing. Y-chromosome typing is based on the assumption that Y-chromosomal DNA
      found in tissue or secretions of women must originate from a male individual,
      usually the perpetrator. Nevertheless, it was shown recently that fetal cells can
      migrate into the female body during pregnancy and can persist for decades
      ("persisting fetal microchimerism"). The body of a woman after a pregnancy with a
      male embryo can thus display a small fraction of fetal cells with Y-chromosomes.
      Using high sensitivity PCR protocols (reamplification with nested primers and up
      to 60 PCR cycles) fetal cells were previously identified in a number of maternal
      tissues including skin, blood, muscle and solid organs. It is, however, not clear
      at present, whether these cells can occur in vaginal secretions, and whether they
      are capable of producing false positive results in forensic Y-chromosome typing.
      To evaluate these questions, 66 blood samples of women with at least one son and
      nine vaginal swabs of women without sexual intercourse in the last 2 weeks were
      amplified for a stretch of the SRY gene. Eight thyroid gland tissues with already
      established male fetal microchimerism were used as positive control samples.
      Blood samples of 10 young girls without history of pregnancy were used as
      negative controls. Using a PCR with 10 ng of extracted DNA and 30 PCR cycles
      ("routine sensitivity assay") none of the samples yielded positive results.
      However, in a PCR with 200 ng of extracted DNA and 45 PCR cycles ("high
      sensibility assay"), 14% of the blood samples of mothers and 33% of the vaginal
      swabs amplified for SRY. Our results thus show that increasing the sensitivity of
      the PCR method and the amount of template DNA produce positive results while
      protocols used for routine Y-chromosomal typing with small amounts of DNA
      (approximately 10 ng of DNA) and with a limited number of PCR cycles
      (approximately 30) can clearly eliminate this peril.

PMID- 15040909
TI  - Y-chromosome STR haplotype in Szekely population.
AB  - Eight Y-chromosome STR markers (DYS19, DYS389/I, DYS389/II, DYS390, DYS391,
      DYS392, DYS393, DYS385) were examined in an isolated Szekely (known as old
      Hungarian) population living in Corund, Romania. Ninety different haplotypes were
      obtained from 99 unrelated Szekely males.

PMID- 15040910
TI  - Evaluation of gastrointestinal cancer tissues as a source of genetic information
      for forensic investigations by using STRs.
AB  - Malignant tissue samples may sometimes be the only source of biological material
      for forensic investigations, including identification of individuals or paternity
      testing. However, in use of such samples, uncertainties due to microsatellite
      instability (MSI) and loss of heterozygosity (LOH) often associated with
      neoplasias may be encountered. In this study, we have analysed the applicability
      of autosomal tetranucleotide short tandem repeat (STR) markers, which are
      routinely used in forensic analysis, to gain genetic information. MSI and LOH
      were analysed in 41 surgically removed gastrointestinal cancer specimens and the
      adjascent non-cancerous tissue marginals. The cancer specimens showed great
      variability in their genetic phenotypes due to MSI or LOH, with only 32% being
      microsatellite-stable. Of the 15 autosomal STR loci analysed, only TH01 had no
      MSI-type alteration in these samples. The loci most frequently affected by MSI
      were D8S1179, D21S11, D18S51 and D19S433 (MSI in 15-17% of cases). LOH-type
      alterations were observed at all of the loci, including the amelogenin locus used
      for sex determination. The highest LOH frequency was found at locus D18S51 (27%).
      The genetic alterations at the marker loci may indicate false homozygosity or
      heterozygosity, and false gender may result from erroneous deduction of DNA
      profiles. Therefore, typing of autosomal STRs from malignant tissues in forensic
      settings warrants careful interpretation of MSI and LOH results together with
      microscopic analysis of a tissue specimen. Results by two commercially available
      and widely used forensic DNA profiling kits used here were comparable.

PMID- 15040911
TI  - Trial for the geographical identification using JC viral genotyping in Japan.
AB  - Despite progress in methods of scientific investigation, the increasing number of
      unidentified cadavers is a growing problem world-wide. We performed detailed
      statistical analysis based on reported data for Japanese JC virus (JCV) genotype
      distribution, and obtained two curves showing a marked north-south difference in
      the JC viral genotype, in spite of the frequent movement of people in Japan. This
      suggested the possibility of determining the origin of unidentified cadavers
      numerically, thus making the police investigation of unidentified cadavers much
      more economical and efficient. If the distribution of JC viral genotypes could be
      investigated in detail, it would be possible to obtain geographic information
      about unidentified cadavers even in a certain area.

PMID- 15040912
TI  - Statistical analyses of 14 short tandem repeat loci in Brazilian populations from
      Rio de Janeiro and Mato Grosso do Sul states for forensic and identity testing
      purposes.
AB  - This work describes the statistical features of a database for two Brazilian
      populations (one from the Rio de Janeiro State (southeast region), and one from
      the Mato Grosso do Sul State (central western region) using fourteen short tandem
      repeat loci (STR).

PMID- 15040913
TI  - Preparation and usage of a new solid phase micro-extraction membrane.
AB  - Liquid-liquid or solid phase extraction methods are widely used for isolating
      analytes from urine, blood and other samples. But the preparation procedures of
      the samples are laborious, intensive, and costly. In addition, the organic
      solvents used are toxic to both the human body and the environment. An accurate,
      simple and rapid method for analysis of some compounds is required for forensic,
      judicial, and clinical purposes. Solid phase micro-extraction membrane (SPMEM) is
      a new, simple and solventless preparation technique. It integrates sampling,
      extraction and concentration into a single step and has the advantages of both
      the solid phase micro-extraction (SPME) and membrane separation. In this paper, a
      new kind of membrane used for the solid phase micro-extraction was prepared with
      amide compounds. The extraction conditions such as adsorption time, desorption
      solvents, methods and time are studied and optimized. The dichlorvos in the
      blood, morphine and phenobarbital in the urine were perfectly separated by using
      this solid phase micro-extraction membrane, and were tested by gas chromatograph
      mass spectrometer (GC-MS). All the data were acquired in scan mode except that of
      morphine which was obtained in a selected ion monitoring (SIM) mode. Ions used
      for identification were those with m/z 57, 115, 162, 215, 285.

PMID- 15040914
TI  - The possible influence of micro-organisms and putrefaction in the production of
      GHB in post-mortem biological fluid.
AB  - In recent years, the post-mortem production of the drug of abuse gamma
      hydroxybutyric acid (GHB) in biological fluids (e.g. blood and urine) has caused
      various interpretative problems for toxicologists. Previously, other researchers
      have shown certain microbial species (Pseudomonas spp. and Clostridium
      aminobutyricum) possess the necessary enzymes to convert GABA to GHB. A
      preliminary investigation involving putrefied post-mortem blood indicated there
      was no observed relationship between "endogenous" GHB concentrations and
      concentrations of common putrefactive markers (tryptamine and phenyl-2
      ethylamine). Microbiological analysis identified the presence of various micro
      organisms: Clostridia spp., Escherichia coli, Proteus vulgaris, Enterococcus
      faecalis and Aeromonoas spp. Equine plasma, human blood and urine samples were
      inoculated with these and an additional micro-organism (Pseudomonas aeruginosa)
      and incubated at 22 degrees C for 1 month. Following comparison with control
      samples and pre-inoculation concentrations, the data indicated an apparent
      production of GHB in unpreserved P. aeruginosa inoculated blood (2.3 mg/l). All
      other fluoride-preserved and unpreserved samples (including controls) had GHB
      concentrations <1mg/l. Although this concentration is lower than is typically
      associated with "endogenous" post-mortem GHB concentrations, this paper proposes
      a potential microbial production of GHB with time.

PMID- 15040915
TI  - Determination of phenol and o-cresol by GC/MS in a fatal poisoning case.
AB  - A fatality due to the ingestion of solution containing phenol and o-cresol is
      described. The pathological findings were typical of acute substantial poisoning.
      Blood, urine and stomach content were obtained during post mortem examinations.
      Phenol and o-cresol were identified using GC/MS. The extractions from autopsy
      materials were obtained as follows: by gel permeation with
      cyclohexane/dichloromethane from stomach content, by solid phase extraction (SPE)
      from urine and by deproteinization with acetonitrile from blood. The phenol and o
      cresol concentrations in the samples were found, respectively, as follows: 115.0
      and 5.0 microg/g in the stomach contents, 58.3 and 1.9 microg/ml in the blood,
      3.3 and 20.5 microg/ml in the urine. Distributions of phenol in fatal poisonings
      have been reported, but, usually, colorimetry was used as the analytical method
      and it cannot exclude the interference of other phenolic compounds.

PMID- 15040916
TI  - Discrimination among species of Papaver based on the plastid rpl16 gene and the
      rpl16-rpl14 spacer sequence.
AB  - An attempt was made to discriminate among six species of Papaver (P. bracteatum,
      P. orientale, P. pseudo-orientale, P. rhoeas, P. setigerum and P. somniferum) by
      comparing the nucleotide sequences of the plastid rpl16 gene and the rpl16-rpl14
      spacer region. Comparison of sequences allowed us to distinguish five species,
      namely P. bracteatum, P. orientale, P. pseudo-orientale, P. rhoeas and P.
      setigerum plus P. somniferum from one another, but sequences from P. setigerum
      and P. somniferum were identical. It is difficult to distinguish between P.
      bracteatum, P. orientale and P. pseudo-orientale at the vegetative stage of
      growth. However, our method allowed us to distinguish between these three species
      and the others using nucleotide sequences and should allow identification of P.
      bracteatum that has been cultivated illegally in the garden in Japan.
      Furthermore, P. rhoeas was clearly discriminated from P. setigerum and P.
      somniferum by reference to the sequence of the rpl16 exon using young seedlings.

PMID- 15040917
TI  - Contribution for an African autosomic STR database (AmpF/STR Identifiler and
      Powerplex 16 System) and a report on genotypic variations.
AB  - Allele frequencies, together with some parameters of forensic interest, for 17
      STRs included in the AmpF/STR Identifiler (CSF1PO, D2S1338, D3S1358, D5S818,
      D7S820, D8S1179, D13S317, D16S539, D18S51, D19S433, D21S11, FGA, TH01, TPO and
      VWA) and Powerplex 16 System (CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317,
      D16S539, D18S51, D21S11, FGA, Penta D, Penta E, TH01, TPO and VWA) were estimated
      from a sample of 135-144 unrelated individuals from Mozambique. No deviations
      from Hardy-Weinberg equilibrium were observed with the exception of the FGA locus
      (using the Bonferroni correction for the number of loci analysed, the departure
      observed at this locus was not significant). Comparative analyses between our
      population data and other African databases, namely Promega's African-Americans,
      AB Applied Biosystems African-Americans and two other population samples from
      Mozambique and Guine Bissau, are presented and discussed. Genotype
      inconsistencies between both commercial kits (for D16S539 and D8S1179) and other
      genotypic variations (three-banded allele patterns for TPO) are also reported.

PMID- 15040918
TI  - Updated Brazilian genetic data, together with mutation rates, on 19 STR loci,
      including D10S1237.
AB  - Allelic frequencies for 19 STR loci (F13B, TPOX, D3S1358, FGA, CSF1PO, D5S818,
      F13A01, D7S820, D8S1179, D10S1237, TH01, VWA, D13S317, FESFPS, Penta E, D16S539,
      D18S51, D19S253, and D21S11) were obtained from an average of 13,000 unrelated
      Brazilian adults undergoing parentage testing. D10S1237 is a tetranucleotide
      repeat locus shown to be useful for forensic and paternity studies. Null allele
      frequencies and mutation rates were ascertained from this population sample.

PMID- 15040919
TI  - Belgian population data for 15 STR loci (AmpFlSTR SGM Plus and AmpFlSTR profiler
      PCR amplification kit).
AB  - The allele and genotype distributions for 15 STR loci included in the AmpFlSTR
      SGM Plus and AmpFlSTR Profiler kits (Applied Biosystems, Foster City, USA) were
      determined in a sample of 222 unrelated individuals of Belgian origin.

PMID- 15040921
TI  - Y-STR polymorphism in Central Anatolian Region of Turkey.
AB  - Eight Y-chromosome specific STR (Y-STR) loci including DYS19, DYS388, DYS389I,
      DYS389II, DYS390, DYS391, DYS392 and DYS393 were investigated in a group of males
      from Central Anatolian Region of Turkey. Healthy 59 males living in this region
      for at least three generations were included in the study. PCR analysis was
      carried out with Y-STR specific primers on genomic DNA obtained from peripheral
      blood samples and size determination of PCR products was performed by silver
      staining following 6% polyacrylamide gel electrophoresis (PAGE). DYS388 was found
      to be the locus with lowest diversity (D) whereas DYS389II was the locus with
      highest diversity. The current study presented a framework of variation for the
      eight Y-STR loci in Central Anatolian population.

PMID- 15040920
TI  - The EDNAP mitochondrial DNA population database (EMPOP) collaborative exercises:
      organisation, results and perspectives.
AB  - This paper presents an overview of the organisation and the results of the
      collaborative exercises (CE) of the European DNA Profiling (EDNAP) Group's
      mitochondrial DNA population database project (EMPOP). The aim of the
      collaborative exercises was to determine whether uniformity of mtDNA sequencing
      results could be achieved among different laboratories. These were asked to
      sequence either the complete mtDNA control region or the two hypervariable
      regions HVI (16024-16365) and HVII (73-340) from DNA extracts, buccal swabs or
      bloodstains, proceeding in accordance with the protocol and strategies used in
      each individual laboratory. The results of the collaborative exercises were
      employed to identify possible sources of errors that could arise during the
      analysis and interpretation of mtDNA profiles. These findings were taken as a
      basis to tentatively make suitable arrangements for the construction of a high
      quality mtDNA database. One hundred fifty mtDNA profiles were submitted to the
      evaluating laboratory, and disaccording profiles were classified into four groups
      corresponding to the source of error: clerical errors, sample mix-ups,
      contaminations and discrepancies with respect to the mtDNA nomenclature. Overall,
      14 disaccording haplotypes (16 individual errors) were observed. The errors
      included 10 clerical errors, 3 interpretation problems, 2 cases of sample mix-up
      and 1 case of point heteroplasmic mixture, where the 2 sequencing reactions
      brought inconsistent base calls. This corresponds to an error rate of 10.7% in a
      virtual mtDNA database consisting of the collaborative exercise results. However,
      this estimate is still conservative compared to conclusions drawn by authors of
      meanwhile numerous publications critically reviewing published mtDNA population
      databases. Our results and earlier published concerns strongly emphasize the need
      for appropriate safety regulations when mtDNA profiles are compiled for database
      purposes in order to accomplish the high standard required for mtDNA databases
      that are used in the forensic context.

PMID- 15040922
TI  - A Spanish population study of 17 Y-chromosome STR loci.
AB  - Haplotype, allele frequencies and population data of 17 Y-chromosome STR loci
      DYS19, DYS385, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438,
      DYS439, DYS460 (GATA A7.1), DYS461 (GATA A7.2), GATA A10, GATA C4 and GATA H4
      were determined from a sample of 148 unrelated male individuals from Spain. A
      total of 144 haplotypes were identified by the 17 Y-STR markers, of which 141
      were unique, two were found in two individuals and one was found in three
      individuals. The haplotype diversity (99.95%) and discrimination capacity
      (97.30%) were calculated. Comparisons were made with previously published
      haplotype data on other Iberian population samples and no significant differences
      were found.

PMID- 15040923
TI  - Cardiac tamponade caused by migration of a swallowed sewing needle.
AB  - The case of a 20-year-old female prisoner who died due to cardiac tamponade
      caused by a swallowed sewing needle migration is reported. According to the
      autopsy report and complete analysis of medical records, the migration of the
      swallowed needle was reconstructed: from esophagus and stomach, through diaphragm
      and pericardium up to the left heart ventricle, where the needle was found at the
      autopsy. The case is very interesting and unique: there has been no similar case
      described in medical literature so far.

PMID- 15040924
TI  - Fatal intoxication as a consequence of intranasal administration (snorting) or
      pulmonary inhalation (smoking) of heroin.
AB  - In recent years we have noticed an increasing proportion of mortalities resulting
      from an overdose of heroin that involve routes of administration other than
      injection. Of 239 cases of fatal heroin intoxication examined at our department
      during the period 1997-2000, 18 deaths were associated with non-parental
      administration. Seven of these fatalities were experienced heroin users who had
      begun to use more sporadically, seven were recreational "party-users", while the
      remaining four persons had relapsed into heroin use following long periods of
      abstinence. The median blood morphine concentration of these non-injectors was
      0.095 microg/g (range: 0.02-0.67 microg/g), significantly lower than that of the
      injectors. Concurrent use of alcohol, other illicit drugs and/or pharmaceutical
      preparations was observed in 17 of the 18 cases. However, there were no
      statistically significant differences between the victims of heroin intoxication
      by injection or by other routes with respect to the proportion who had
      simultaneously consumed alcohol or benzodiazepines. Pathological alterations like
      lung fibrosis, liver cirrhosis, endocarditis, etc. were not found to play a
      significant role in any of the 18 mortalities. We conclude that snorting or
      smoking heroin probably involves a reduced risk of obtaining high blood
      concentrations of morphine but still constitutes a considerable risk of lethal
      outcome due to high variability in blood concentrations. Furthermore, decreased
      tolerance resulting from periods of reduced or sporadic use appears to be an
      important risk factor in connection with heroin overdosing by snorting or
      smoking, which indicate that some heroin addicts may inaccurately assume that
      these routes of administration are safe when resuming their use of heroin after a
      period of abstinence.

PMID- 15040925
TI  - Post mortem cohabitation-shell growth as a measure of elapsed time: a case
      report.
AB  - A partial calvaria, dredged from the sea-bed some years previously, was referred
      to us for examination. The presence of a well-established mollusc colony on the
      vault allowed us to establish a minimum elapsed time since death. Such a cross
      disciplinary co-operative study is of great advantage in expediting a
      satisfactory conclusion.

PMID- 15040926
TI  - Primer binding site mutations affecting the typing of STR loci contained within
      the AMPFlSTR SGM Plus kit.
AB  - The Forensic Science Service carries out human identification and familial
      investigations using the AMPFlSTR SGM Plus kit (PE Biosystems, Warrington,
      England). We have studied approximately 42,000 parent/child allelic transfers
      (meioses) for deviations from expected Mendelian Inheritance patterns. Of 55
      apparent mutations detected, 20 had patterns suggestive of the presence of a
      primer binding site mutation producing a silent/null allele. The presence of a
      silent allele was unequivocally demonstrated in 13 of the 20 suspected cases by
      using alternative primer sets. Of the 13 confirmed cases, 9 involved the D18S51
      locus. As the individuals in these cases all originated from the same geographic
      region of the Middle East, this cluster suggests the presence of a relatively
      common variant D18S51 allele in that particular group. These data taken together
      with our previously published work, confirm that the primer binding sites
      utilised for amplification of the loci contained in the AMPFlSTR SGM Plus kit
      have highly conserved nucleotide sequences.

PMID- 15040927
TI  - STR data for the power plex-16 loci in a population from Central Poland.
AB  - The allele frequencies for the 13 CODIS core loci and two recently developed but
      not extensively validated in Central European populations pentanucleotide STRs
      (Penta E and D) were determined using the Power Plex-16 (Promega) kit in a sample
      of 430 unrelated individuals born in Central Poland. The calculated parameters of
      polymorphism showed Penta E to be the most valuable marker from the studied set.
      The obtained distribution of Penta E and D alleles was statistically
      significantly different from that previously reported for a population of
      Southern Poland. Analysis of Hardy-Weinberg equilibrium revealed a deviation for
      the D5S818 locus which may reflect presence of a null allele.

PMID- 15040928
TI  - Allele distribution of 15 STR loci in a population sample of Byelorussian
      minority residing in the northeastern Poland.
AB  - Allele frequencies for the 15 STRs included in the AmpFlSTR Identifiler kit were
      determined in a population sample of 212 unrelated individuals of the
      Byelorussian minority residing in the northeastern Poland. All loci, except TPOX,
      met Hardy-Weinberg expectations. Exact tests disequilibrium analysis revealed 5
      departures from independence out of 105 pairwise comparisons.

PMID- 15040929
TI  - The potential and limitations of utilising head impact injury models to assess
      the likelihood of significant head injury in infants after a fall.

PMID- 15040930
TI  - Meeting summary: possibilities for active and passive vaccination against
      opportunistic infections.

PMID- 15040931
TI  - Interactions of commensal gut microbes with subsets of B- and T-cells in the
      murine host.
AB  - Although mechanisms operative in the induction and maintenance of specific,
      adaptive immunity, including 'cognate' B/T interactions, have been extensively
      studied and defined, we still know little about the mechanisms operative in
      developing and maintaining B- and T-cell dependent 'natural' immunity.
      Particularly, we are still rather ignorant concerning gut microbial/gut or
      systemic APC, T cell and B cell interactions that lead to lymphoid cell mediated
      'natural' immunity: specific or broadly reactive, activation via TCR and BCR
      and/or via other receptors such as the TLR series, and whether T/B interactions
      are operative at this level? Here we will address: (1) the general role of gut
      microbes in the development and maintenance of the intestinal, humoral immune
      system; (2) the general role of gut microbes in the development of B1 cell
      mediated, 'natural' gut IgA and the dependence of these B1 cells on bystander T
      cell help; (3) the relative contributions of B1 versus B2 cells to gut 'natural'
      and specific IgA responses; (4) the role for particular 'normal' gut microbes in
      the initiation of inflammatory bowel diseases (IBD) in mice with a dysregulated
      immune system; and (5) the possible roles of gut microbes in facilitating oral
      tolerance, a mechanism likely operative in forestalling or ameliorating IBD. A
      central theme of this paper is to attempt to define the specificities of
      activated, functional CD4+ T cells in the gut for Ags of particular, usually
      benign gut microbes. We will also consider the still-unresolved issue of whether
      the contributions of B1-derived IgA in the gut to the 'natural' Ab pool are Ag
      selected and driven to proliferation/differentiation or whether the main stimuli
      are not via BCRs but rather other receptors (TLRs, etc.). The main experimental
      approach has been to use antigen-free, germ-free, or gnotobiotic (mono- or oligo
      associated with precisely known bacterial species) mice.

PMID- 15040932
TI  - Development of an anti-core lipopolysaccharide vaccine for the prevention and
      treatment of sepsis.
AB  - Sepsis continues to be a leading cause of death among hospitalized patients.
      Despite advances in supportive care and the availability of potent
      antimicrobials, the mortality exceeds 20%. The passive infusion of antibodies
      directed against a conserved region of the lipopolysaccharide (LPS) of Gram
      negative bacteria was highly protective in an early study (NEJM 307 [1982] 1225).
      When this and similar preparations were unable to show consistent efficacy,
      efforts were directed towards other strategies, including cytokine modulation.
      Our group found that a whole bacterial vaccine made from the Escherichia coli
      O111:B4, J5 (Rc chemotype) mutant induced protective antibodies when given
      passively as treatment for sepsis in a neutropenic rat model. A subunit vaccine,
      composed of detoxified J5 LPS complexed to group B meningococcal outer membrane
      protein (OMP), provided similar protection when antibodies were given passively,
      or induced actively in both the neutropenic and cecal ligation/puncture models of
      sepsis. A phase I study in 24 subjects (at 5, 10 and 25 microg doses [based on
      LPS] for each group of 8) revealed the vaccine to be well-tolerated with no
      systemic endotoxin-like effects. Although a two to three-fold increase in
      antibody levels over baseline (by ELISA assay) was observed at the 10 and 25
      microg doses, the plasma from both high and low responders reduced LPS-induced
      cytokine generation in whole blood. Reimmunization of six subjects at 12 months
      did not convert low responders to high responders or boost the still elevated
      anti-J5 LPS levels of high responders. If functional assays of anti-LPS
      antibodies are better predictors of vaccine efficacy than ELISA antibody levels,
      then it will be necessary to determine which of many potential assays best
      correlates with protection in animal models. We are currently comparing a panel
      of functional assays with protective efficacy in animal models of sepsis, as well
      as the ability of adjuvants to enhance vaccine efficacy. The availability of an
      effective anti-endotoxin vaccine will provide additional therapeutic options for
      the prevention and/or treatment of sepsis.

PMID- 15040933
TI  - O antigen seroepidemiology of Klebsiella clinical isolates and implications for
      immunoprophylaxis of Klebsiella infections.
AB  - Prevention of Klebsiella infections by passive immunotherapy has received more
      attention during the last decade. Both K antigen-and O antigen-specific antisera
      and monoclonal antibodies (mAbs) have been studied with respect to phagocytosis
      enhancing and in vivo protective capacities. Our own work has focussed on the
      generation of O serogroup-specific rabbit antisera and O antigen specific murine
      antibodies. O-specific rabbit sera were absorbed extensively with heterologous O
      antigen strains in order to obtain highly specific typing reagents. Using these
      for typing a collection of 378 clinical strains, we found that 82% of them
      belonged to one of the four serogroups O1, O2ab, O3 and O5. Phagocytosis
      experiments using antisera and mAbs showed that O antigen specific antibodies
      were able to opsonize non-encapsulated strains, while fully encapsulated bacteria
      were rather resistant against the opsonizing effect. Nevertheless, in vivo
      experiments demonstrated a prophylactic effect on both Klebsiella septicemia and
      pneumonia in a mouse model of lethal infection. Given the limited number of O
      serogroups, O antigen-specific antibodies may be suited to supplement K antigen
      specific hyperimmune globulins for passive immunoprophylaxis of Klebsiella
      infections.

PMID- 15040934
TI  - Enterococcal infections: host response, therapeutic, and prophylactic
      possibilities.
AB  - The emergence of resistance against multiple antibiotics and the increasing
      frequency with which Enterococcus faecalis and Enterococcus faecium are isolated
      from hospitalized patients underscore the necessity for a better understanding of
      the virulence mechanisms of this pathogen and the development of alternatives to
      current antibiotic treatments. The genetic plasticity of enterococci and their
      ability to rapidly acquire and/or develop resistance against many clinically
      important antibiotics and to transfer these resistance determinants to other more
      pathogenic microorganisms makes the search for alternative treatment and
      preventive options even more important. A capsular polysaccharide antigen has
      recently been characterized that is the target of opsonic antibodies. A limited
      number of clinically relevant serotypes exist, and the development of an
      enterococcal vaccine based on capsular polysaccharides may improve our ability to
      prevent and treat these infections. Additional enterococcal surface antigens,
      including ABC transporter proteins and other virulence factors, such as
      aggregation substance (AS), may also be useful targets for therapeutic
      antibodies.

PMID- 15040935
TI  - Pseudomonas immunotherapy: a historical overview.
AB  - The historic development of vaccines to be used as immunotherapy for Pseudomonas
      aeruginosa infections, in various patient populations, is reviewed. Commentary is
      offered concerning the relevance of each approach in light of our current
      understanding of the pathological process of these infections.

PMID- 15040938
TI  - Dendritic cell-based vaccination against opportunistic fungi.
AB  - Efficient responses to the different forms of fungi require different mechanisms
      of immunity. Dendritic cells (DCs) are uniquely able to decode the fungus
      associated information and translate it in qualitatively different T helper (Th)
      immune responses, in vitro and in vivo. DCs sense fungi in a morphotype-specific
      manner, through the engagement of distinct recognition receptors ultimately
      affecting cytokine production and costimulation. Adoptive transfer of different
      types of DCs activates protective and non-protective Th cells as well as
      regulatory T cells and affects the outcome of the infections. DCs transfected
      with fungal RNA also restore antifungal resistance in hematopoietic
      transplantation. Thus, the remarkable functional plasticity of DCs in response to
      fungi can be exploited for the deliberate targeting of cells and pathways of cell
      mediated immunity in response to fungal vaccines.

PMID- 15040937
TI  - Active and passive immunization against Clostridium difficile diarrhea and
      colitis.
AB  - Clostridium difficile, a gram-positive bacterium, is the major cause of hospital
      acquired infectious diarrhea and colitis in industrialized nations. C. difficile
      colonization results from antibiotic administration and subsequent loss of
      protection provided by intestinal flora. C. difficile induced-colitis is caused
      by the release of two exotoxins, toxin A and B. Host factors including advanced
      age, pre-existing severe illness and weakened immune defenses predispose
      individuals to symptomatic infection. The generation of antibody responses to
      toxin A through natural exposure is associated with protection from disease. In
      addition, an inability to acquire immunity to toxin A puts individuals at risk
      for recurrent and/or severe disease. Immunological approaches for the management
      of this disease are being developed which could reduce the reliance on
      antibiotics for treatment and allow for re-establishment of the natural barrier
      provided by an intact commensal flora. An active vaccine and various
      immunotherapeutic strategies under evaluation may prove to be effective against
      severe or relapsing C. difficile infection.

PMID- 15040936
TI  - Recombinant OprF-OprI as a vaccine against Pseudomonas aeruginosa infections.
AB  - A vaccine against Pseudomonas aeruginosa based on recombinant outer membranes has
      been developed. After intramuscularly injecting into patients with severe burns,
      antibodies against P. aeruginosa were induced. Vaccination was well tolerated.
      Intranasal application of the vaccine into volunteers, induced specific s-IgA
      antibodies. We conclude that the newly developed vaccine may be suitable for
      protection of the main risk groups of P. aeruginosa infections. In particular,
      for the protection of burn patients and patients with cystic fibrosis.

PMID- 15040939
TI  - Recombinant antibodies: a natural partner in combinatorial antifungal therapy.
AB  - Monotherapy, in the form of amphotericin B or one of its liposomal derivatives,
      is the usual treatment for invasive fungal infections, due to lack of a safe,
      effective combination of antifungal drugs. Combination therapy is not necessarily
      beneficial-there may be mutual antagonism or indifference, increased toxicity or
      interference with concomitant medication. But the benefits of a well-tolerated,
      synergistic combination would be great-the enhanced efficacy would improve
      clinical outcome, reduce the need for prolonged courses of treatment and prevent
      the emergence of antifungal drug resistance. Antifungal antibodies would be a
      natural partner in a combinatorial approach to antifungal therapy. Analysis of
      the antibody response which occurs in patients with invasive candidiasis, being
      treated with amphotericin B, showed a close correlation between recovery and
      antibody to the immunodominant heat shock protein 90 (hsp90). The molecular
      chaperone hsp90 is essential for yeast viability. Mycograb is a human recombinant
      antibody to hsp90 which shows intrinsic antifungal activity and synergy with
      amphotericin B both in vitro and in vivo. It is now the subject of a
      multinational, double-blind, placebo-controlled trial, in patients with culture
      confirmed invasive candidiasis on liposomal amphotericin B.

PMID- 15040940
TI  - Biologic properties and vaccine potential of the staphylococcal poly-N-acetyl
      glucosamine surface polysaccharide.
AB  - Staphylococci have become the most common causes of nosocomial bacterial
      infections, and this fact, along with increasing problems associated with
      antimicrobial resistance, spurs the need for finding immunotherapeutic
      alternatives to prevent and possibly treat these infections. Most virulent,
      clinical isolates of both coagulase-negative staphylococci (CoNS) and
      Staphylococcus aureus carry the ica locus which encodes proteins that synthesize
      a polymer of beta-1-6 linked N-acetyl glucosamine residues (PNAG). Animal studies
      have shown purified PNAG can elicit protective immunity against both CoNS and S.
      aureus, suggesting its potential as a broadly protective vaccine for many
      clinically important strains of staphylococci.

PMID- 15040941
TI  - Development of StaphVAX, a polysaccharide conjugate vaccine against S. aureus
      infection: from the lab bench to phase III clinical trials.
AB  - Staphylococcus aureus is the most common nosocomial pathogen and is responsible
      for approximately one-third of hospital-acquired bacteremias. The emergence of
      strains with multidrug resistance, including resistance to vancomycin, the
      antibiotic of last resort, presents the medical community with a major public
      health problem. Alternative therapies, including immunotherapy, have been in
      development for several decades. The discovery of S. aureus capsular
      polysaccharides from clinical isolates, and their importance to pathogenicity via
      antiphagocytic activity, opened a new window of opportunity for development of
      vaccines and immunotherapy against this pathogen. A conjugate vaccine, StaphVAX
      that includes the two most prevalent capsular polysaccharides, types 5 and 8,
      coupled to a carrier protein efficient in promoting a Th2 response, was
      developed. In a recent phase III clinical study in hemodialysis patients,
      StaphVAX was shown to prevent S. aureus bacteremia for up to 10 months following
      a single immunization. The history, epidemiology, serology, and development of
      StaphVAX, including preclinical and clinical studies demonstrating efficacy are
      described in this review.

PMID- 15040942
TI  - Clearance of Helicobacter pylori infection through immunization: the site of T
      cell activation contributes to vaccine efficacy.
AB  - Helicobacter pylori vaccine development has progressed rapidly in animal models.
      Both H. pylori-associated pathogenesis and protective immunity are CD4+ T cell
      dependent, with no discernable phenotypic difference to distinguish pathogenic T
      cells from protective T cells. Functionally however, protective T cells promote
      enhanced inflammation upon H. pylori challenge. Additionally, only mouse models
      such as phagocyte oxidase- or IL-10-deficient mice that respond to H. pylori
      infection with intense gastritis are capable of demonstrating spontaneous
      eradication of the bacteria. These data, combined with recent descriptions of
      down-regulatory T cells in infected humans and mice, support an emerging model of
      H. pylori pathogenesis in which H. pylori induces inflammation that is limited by
      regulatory T cells in the stomach. Immunization therefore may succeed by
      activating T cells in peripheral lymph nodes that are capable of promoting
      qualitatively or quantitatively different inflammation when recruited to the
      stomach. Evidence in support of this model will be discussed.

PMID- 15040943
TI  - Neisseria meningitidis, Neisseria lactamica and Moraxella catarrhalis share cross
      reactive carbohydrate antigens.
AB  - Carriage of commensal bacteria species is associated with the development of
      natural immunity to meningococcal disease, with lipo-oligosaccharides (LOS) of
      meningococci being one of the main virulence factors associated with severity of
      meningococcal disease. Meningococcal reference strains and isolates from the
      commensal species Neisseria lactamica and Moraxella catarrhalis were assessed for
      the presence of cross-reactive glycoconjugate antigens. Binding of human blood
      group antibodies of the P and Ii system to meningococcal immunotype reference
      strains were in accordance with the presence of known LOS carbohydrate
      structures. Binding studies with meningococcal immunotyping antibodies and blood
      group phenotyping antibodies to N. lactamica strains from different European
      countries showed, that a greater number of isolates obtained from native Greek
      and Scottish adults and children bound anti-meningococcal L(3, 7, 9) immunotyping
      (P < 0.001), pK (P = 0.035) and paragloboside (P < 0.001) blood group typing
      antibodies compared to isolates obtained from children of Russian immigrants in
      Greece. A greater number of M. catarrhalis strains isolated from children in
      Scotland bound anti-L(3, 7, 9) antibodies (38.2%) compared to strains isolated
      from adults (22.2%) (P = 0.017). These findings provide evidence that blood group
      like glycoconjugate antigens found on the commensal species N. lactamica and M.
      catarrhalis might be involved in the development of natural immunity to
      meningococcal endotoxins during childhood, and might be exploited as anti
      meningococcal vaccine candidates.

PMID- 15040944
TI  - A yeast intron as a translational terminator in a plasmid shuttle vector.
AB  - Plasmid shuttle vectors that contain both prokaryotic (Escherichia coli) and
      eukaryotic origins of replication are routinely used in molecular biology since
      E. coli is generally the organism of choice for manipulation of recombinant DNA.
      Initial transformation of the shuttle vector into E. coli allows production of
      microgram quantities of DNA suitable for transformation of low-transformation
      efficiency hosts. A shuttle/expression vector for the yeast Kluyveromyces lactis,
      pCWK1, allows recombinant protein fused to the killer toxin signal sequence to be
      secreted to the medium. The heterologous genes are transcribed under the control
      of the K. lactis LAC4 promoter, which is tightly regulated in K. lactis. However,
      in E. coli the LAC4 promoter functions constitutively, and as a result,
      uncontrolled transcription and translation of genes that are toxic in E. coli can
      result in cell death, and subsequent failure to recover intact E. coli
      transformants. We have constructed and tested a modified shuttle vector that
      contains a K. lactis ribosomal intron that acts as a translational terminator in
      E. coli, preventing or reducing the expression of recombinant proteins and
      avoiding toxicity. When transcribed in K. lactis, the intron is spliced from the
      mRNA allowing the translation of intact full-length, active recombinant gene
      product.

PMID- 15040945
TI  - Four new yeast species of the genus Sporobolomyces from plant leaves.
AB  - Among the ballistoconidium-forming yeast strains isolated from various plant
      leaves collected in North and Northeast China, 12 strains forming orange to
      orange-red colored colonies were revealed to represent four novel species of the
      genus Sporobolomyces by conventional, chemotaxonomic and molecular phylogenetic
      studies, based on the 26S-rDNA D1/D2 domain and internal transcribed spacer (ITS)
      region sequences. Sporobolomyces beijingensis sp. nov., represented by eight
      strains (type strain CB 80T = AS 2.2365T = CBS 9730T), and Sporobolomyces
      jilinensis sp. nov., represented by two strains (type strain CB 118T = AS 2.2301T
      = CBS 9728T), clustered in the Johnsonii clade of the Sporidiobolus lineage.
      Sporobolomyces clavatus sp. nov., represented by strain CB 281T (= AS 2.2318T =
      CBS 9729T), belonged to the Agaricostilbum lineage and showed a close
      relationship to Sporobolomyces ruber and Sporobolomyces dracophylli.
      Sporobolomyces symmetricus sp. nov., represented by strain CB 64T(= AS 2.2299T =
      CBS 9727T), formed nearly symmetrical ballistoconidia and was closely related
      with Sporobolomyces vermiculatus and Sporobolomyces gracilis in the Gracilis
      clade of the Erythrobasidium lineage.

PMID- 15040946
TI  - Speciation in the large-spored Metschnikowia clade and establishment of a new
      species, Metschnikowia borealis comb. nov.
AB  - The reproductive boundaries among species in the large-spored Metschnikowia clade
      were studied by prototrophic recombinant selection, electrophoretic karyotyping,
      mitochondrial DNA restriction analysis, and DNA sequence analysis. Inviable
      ascospores arose from crosses between the two varieties of Metschnikowia
      continentalis, indicating that they should be recognized as separate species.
      Prototrophic recombinants were recovered from crosses between auxotrophic mutants
      of Metschnikowia borealis, M. continentalis, Metschnikowia lochheadii,
      Metschnikowia sp. UWO(PS)00-154.1, and Candida ipomoeae, showing that some
      genetic exchange is possible in spite of the sterility of the asci formed in
      interspecific crosses. Metschnikowia hawaiiensis, although capable of ascus
      formation when its h(-) mating type is crossed with the h(+) mating type of the
      other species, did not give rise to recombinants. In the other species, some
      recombinants acquired the ability to form asci directly from single cells. These
      often contained the chromosomes of both parents, suggesting formation of
      allodiploid hybrids. Other recombinants behaved as haploids and were similar to
      one parent except for having inherited the selectable wild-type allele from the
      other parent. In most, but not all cases, inheritance of the mitochondrial genome
      was uniparental and correlated with the inheritance of the nuclear chromosome
      complement. In some cases, what appeared to be a recombinant mitochondrial genome
      was observed. Phylogenies derived from the sequences of various DNA regions were
      not congruent, indicating that hybridization may have taken place in nature as
      the large-spored species diverged from their common ancestor. Further evidence
      that C. ipomoeae arose from a natural recombination event was obtained, but a
      pair of Metschnikowia species that might represent derived forms of the parents
      could not be identified conclusively. C. ipomoeae and most of its closely related
      Metschnikowia species contained a group-II intron in the mitochondrial small
      subunit ribosomal gene. The intron was absent in M. borealis, M. hawaiiensis, and
      other species in the genus Metschnikowia.

PMID- 15040947
TI  - Diversity of Cryptococcus and Dioszegia yeasts (Basidiomycota) inhabiting
      arbuscular mycorrhizal roots or spores.
AB  - The genera Cryptococcus and Dioszegia contain basidiomycetous yeasts found in a
      wide range of habitats. Primers to amplify the internal transcribed spacer (ITS)
      region of the nuclear ribosomal DNA (nrDNA) of arbuscular mycorrhizal fungi (AMF)
      also allow detecting members of this yeast group. Here we report the results of a
      sequence analysis using maximum parsimony on a set of 50 ITS sequences of yeasts
      associated with AMF structures (roots of 26 plant species, AM spores) from six
      field sites in Central Germany. Among 10 separated taxa, respectively five in the
      Tremellales and two in the Filobasidiales had unknown sequences. Therefore it was
      not possible to assign these sequences to any known species. The study indicates
      that exploring the diversity of Cryptococcus and Dioszegia in soil habitats with
      molecular methods might enlarge the actually estimated biodiversity of the group.

PMID- 15040948
TI  - Metschnikowia kunwiensis comb. nov., the teleomorph of Candida kunwiensis.
AB  - The teleomorph of Candida kunwiensis Hong, Bae, Herzberg, Titze, Lachance,
      Metschnikowia kunwiensis, is described. Repeated attempts to obtain ascospore
      formation succeeded using modified V8 sporulation media and extended incubation
      times. The asci are ovoid, with only a small protrusion caused by the spore(s).
      The species is diplontic, possibly homothallic, with one or two ascospores per
      ascus. Aside from having atypical ovoid asci, the acicular shape of the spores is
      characteristic of the genus Metschnikowia. The type strain is CBS 9676(T).

PMID- 15040950
TI  - On the role of Trk1 and Trk2 in Schizosaccharomyces pombe under different ion
      stress conditions.
AB  - Trk1 and Trk2 are the major K(+) transport systems in Schizosaccharomyces pombe.
      Both transporters individually seem to be able to cope with K(+) requirements of
      the cells under normal conditions, since only the double mutant shows defective
      K(+) transport and defective growth at limiting K(+) concentrations. We have
      studied in detail the role of SpTrk1 and SpTrk2 under different ion stress
      conditions. Results show that the strain with only Trk1 (trk1(+)) is less
      sensitive to Li(+) and to hygromycin B, it grows better at low K(+) and it
      survives longer in a medium without K(+) than the strain expressing only Trk2
      (trk2(+)). We conclude that Trk1 contributes more efficiently than Trk2 to the
      performance of the fission yeast under ion stress conditions. In the wild type
      both trk1(+) and trk2(+) genes are expressed and probably collaborate for the
      performance of the cells.

PMID- 15040949
TI  - Comparison of cultural methods for the identification and molecular investigation
      of yeasts from sourdoughs for Italian sweet baked products.
AB  - Twenty-five yeast strains isolated from sourdough samples for Panettone, Pandoro
      and Cornetto brioche manufactured by eight different bakeries in northern Italy
      were characterised. Classification was performed by the simplified identification
      method (SIM), Kurtzman and Fell's identification protocol, the API system from
      bioMerieux (France) and the MicroLog system from Biolog (USA). Genetic diversity
      was investigated by randomly amplified polymorphic DNA fingerprinting and
      mitochondrial-DNA restriction enzyme analysis. Sequences of the internal
      transcribed spacers between 18S and 26S rDNA genes were analysed. Candida humilis
      was the predominant species (56% of isolates), whereas the remaining strains
      (44%) were related to the Saccharomyces cerevisiae sensu stricto group.
      Identification systems based on phenotypic analysis proved to be unreliable to
      identify yeasts from sourdough. Either RAPD-PCR or mtDNA restriction analysis
      showed to be suitable for the identification of species, but could not be used to
      differentiate among the isolates at the strain level. Sequencing of the ITS
      region permitted a consistent classification of the sourdough yeasts.

PMID- 15040951
TI  - Nitrogen catabolite repression in Saccharomyces cerevisiae during wine
      fermentations.
AB  - We carried out fermentations with several nitrogen sources in different
      concentrations and studied nitrogen regulation by following the transcriptional
      profile of the general amino-acid permease (GAP1) and the ammonium permeases
      (MEP1, MEP2, MEP3). In wine fermentations the cells evolve from a nitrogen
      repressed situation at the beginning of the process to a nitrogen-derepressed
      situation as the nitrogen is consumed. These nitrogen-repressed/derepressed
      conditions determined the different patterns of ammonium and amino-acid
      consumption. Arginine and alanine were hardly used under the repressed
      conditions, while the uptake of branched-chain and aromatic amino acids
      increased.

PMID- 15040952
TI  - Yeast cells display a regulatory mechanism in response to methylglyoxal.
AB  - Methylglyoxal (MG), a glycolytic by-product, is an extremely toxic compound. This
      fact suggests that its synthesis and degradation should be tightly controlled.
      However, little is known about the mechanisms that protect yeast cells against MG
      toxicity. Here, we show that in Saccharomyces cerevisiae, MG exposure increased
      the internal MG content and activated the expression of GLO1 and GRE3, two genes
      involved in MG detoxification; GPD1, the gene for glycerol synthesis; and TPS1
      and TPS2, the trehalose pathway genes. This response was specific as demonstrated
      by the analysis of marker genes and effectors of the general stress response.
      Physiological experiments with MG-treated cells showed that this compound
      triggers the overproduction of glycerol. Furthermore, a gpd1 gpd2 double mutant
      showed enhanced MG contents compared with the wild-type. Overall, these results
      appeared to indicate that up-variations in the intracellular content of the toxic
      compound are perceived by the cell as a primary signal to trigger the
      transcriptional response. In agreement with this, MG-instigated GPD1 activation
      was enhanced in strains lacking GLO1, and this effect correlated with the
      internal MG content. Finally, induction of GPD1, TPS1 and GRE3, and enhanced MG
      contents were also observed in low-glucose-growing cells subjected to a sudden
      increase in glucose availability. The implications of this regulatory mechanism
      on protection against MG are discussed.

PMID- 15040953
TI  - Inorganic polyphosphate in mitochondria of Saccharomyces cerevisiae at phosphate
      limitation and phosphate excess.
AB  - Isolated mitochondria of Saccharomyces cerevisiae cells grown on glucose possess
      acid-soluble inorganic polyphosphate (polyP). Its level strongly depends on
      phosphate (P(i)) concentration in the culture medium. The polyP level in
      mitochondria showed 11-fold decrease under 0.8 mM P(i) as compared with 19.3 mM
      P(i). When spheroplasts isolated from P(i)-starved cells were incubated in the
      P(i)-complete medium, they accumulated polyP and exhibited a phosphate overplus
      effect. Under phosphate overplus the polyP level in mitochondria was two times
      higher than in the complete medium without preliminary P(i) starvation. The
      average chain length of polyP in mitochondria was of <15 phosphate residues at
      19.3 mM P(i) in the culture medium and increased at phosphate overplus.
      Deoxyglucose inhibited polyP accumulation in spheroplasts, but had no effect on
      polyP accumulation in mitochondria. Uncouplers (FCCP, dinitrophenol) and
      ionophores (monensin, nigericin) inhibited polyP accumulation in mitochondria
      more efficiently than in spheroplasts. Fast hydrolysis of polyP was observed
      after sonication of isolated mitochondria. Probably, the accumulation of polyP in
      mitochondria depended on the proton-motive force of their membranes.

PMID- 15040954
TI  - A distinct type of alcohol dehydrogenase, adh4+, complements ethanol fermentation
      in an adh1-deficient strain of Schizosaccharomyces pombe.
AB  - In the fission yeast Schizosaccharomyces pombe, only one alcohol dehydrogenase
      gene, adh1(+), has been identified. To elucidate the influence of adh1(+) on
      ethanol fermentation, we constructed the adh1 null strain (delta adh1). The delta
      adh1 cells still produced ethanol and grew fermentatively as the wild-type cells.
      Both DNA microarray and RT-PCR analysis demonstrated that this ethanol production
      is caused by the enhanced expression of a Saccharomyces cerevisiae ADH4-like gene
      product (SPAC5H10.06C named adh4(+)). Since the strain lacking both adh1 and adh4
      genes (delta adh1 delta adh4) showed non-fermentative retarded growth, only these
      two ADHs produce ethanol for fermentative growth. This is the first observation
      that a S. cerevisiae ADH4-like alcohol dehydrogenase functions in yeast ethanol
      fermentation.

PMID- 15040955
TI  - Minimal metabolic engineering of Saccharomyces cerevisiae for efficient anaerobic
      xylose fermentation: a proof of principle.
AB  - When xylose metabolism in yeasts proceeds exclusively via NADPH-specific xylose
      reductase and NAD-specific xylitol dehydrogenase, anaerobic conversion of the
      pentose to ethanol is intrinsically impossible. When xylose reductase has a dual
      specificity for both NADPH and NADH, anaerobic alcoholic fermentation is feasible
      but requires the formation of large amounts of polyols (e.g., xylitol) to
      maintain a closed redox balance. As a result, the ethanol yield on xylose will be
      sub-optimal. This paper demonstrates that anaerobic conversion of xylose to
      ethanol, without substantial by-product formation, is possible in Saccharomyces
      cerevisiae when a heterologous xylose isomerase (EC 5.3.1.5) is functionally
      expressed. Transformants expressing the XylA gene from the anaerobic fungus
      Piromyces sp. E2 (ATCC 76762) grew in synthetic medium in shake-flask cultures on
      xylose with a specific growth rate of 0.005 h(-1). After prolonged cultivation on
      xylose, a mutant strain was obtained that grew aerobically and anaerobically on
      xylose, at specific growth rates of 0.18 and 0.03 h(-1), respectively. The
      anaerobic ethanol yield was 0.42 g ethanol x g xylose(-1) and also by-product
      formation was comparable to that of glucose-grown anaerobic cultures. These
      results illustrate that only minimal genetic engineering is required to recruit a
      functional xylose metabolic pathway in Saccharomyces cerevisiae. Activities
      and/or regulatory properties of native S. cerevisiae gene products can
      subsequently be optimised via evolutionary engineering. These results provide a
      gateway towards commercially viable ethanol production from xylose with S.
      cerevisiae.

PMID- 15040956
TI  - Autoimmunity and the female liver.
AB  - In common with several other autoimmune diseases, there is a marked female
      preponderance in both autoimmune hepatitis (AIH) and primary biliary cirrhosis
      (PBC). Whether this is due to gender differences relating specifically to the
      liver or more generally to the female constitution is unknown. The clinical
      expression of these disorders provides few clues to explain their predilection
      for females. Sexual dimorphism in the metabolic functions of the liver is well
      recognised, and several studies have suggested that donor-recipient gender
      matching/mismatching has a major impact on the outcome of orthotopic liver
      transplantation (OLT) but, overall, the available evidence does not support the
      concept that the female liver is inherently more susceptible to immune mediated
      damage. Since the majority of patients present peri-menopausally and
      endocrinopathy is frequently associated with these conditions, it seems more
      likely that hormonal factors may be involved. Review of the available information
      about hormonal effects on the immune system and how they might impact on what is
      known about the pathogenetic mechanisms, and interact with genetic factors, in
      the two conditions unfortunately provides no definitive explanation for the
      predilection of these disorders for females. However, this is clearly a
      potentially fruitful area for further research.

PMID- 15040958
TI  - Relationship between indocyanine green test and technetium-99m galactosyl serum
      albumin scintigraphy in patients scheduled for hepatectomy: Clinical evaluation
      and patient outcome.
AB  - The clinical significance of and discrepancy between the indocyanine green
      retention rate at 15min (ICGR15) and liver activity at 15min (LHL15) by
      technetium-99m galactosyl human serum albumin ( [Formula: see text] -GSA)
      scintigraphy and clinical outcome were examined in 140 patients who underwent
      hepatectomy. Both ICGR15 and LHL15 were significantly associated with portal
      pressure and liver function tests, fibrotic degree and regeneration of the
      remnant liver ( [Formula: see text] ). The significance of the correlation
      between LHL15 and liver functions and HAI score appeared to be better than that
      with ICGR15. A significant correlation was observed between ICGR15 and LHL15 (
      [Formula: see text] 0.591, [Formula: see text] ) for all but 12 patients (8.6%).
      Of three patients with LHL15 better than ICGR15, two had obstructive jaundice and
      one had an intrahepatic shunt. Patient outcome was relatively good. In nine
      patients with LHL15 worse than ICGR15, the HAI score was higher (=7) and six of
      the nine had hepatic failure or uncontrolled ascites. Complications were
      frequently observed in patients with LHL15 below 0.875 (80% versus 30%, [Formula:
      see text] ). Our results indicate that [Formula: see text] -GSA scintigraphy is a
      reliable auxiliary test of hepatic functional reserve combined with ICGR15 for
      selecting the extent of hepatectomy and predicting patient outcome.

PMID- 15040957
TI  - Hepatocellular carcinoma in heavy drinkers with negative markers for viral
      hepatitis.
AB  - Alcohol has been known to be associated with an increased risk of cancer. We
      investigated the characteristics of hepatocellular carcinoma (HCC) in heavy
      drinkers with negative serum markers for viral hepatitis (non-B, non-C) to
      determine whether ethanol enhances the development of HCC in Japanese patients
      with or without serum markers for viral hepatitis. Among the 432 HCC cases seen
      at our hospital between 1995 and 2000, 26 patients had negative serum markers
      (non-B, non-C) and were heavy drinkers. The mean patient age at the time of HCC
      diagnosis was [Formula: see text] years. The mean total ethanol intake was
      [Formula: see text] kg. Most of the patients also had liver cirrhosis (LC),
      although the frequency was significantly higher in non-B, non-C, heavy drinkers
      HCC cases than in non-B, non-C, non-alcoholic HCC cases. Among the hepatitis C
      virus (HCV)-positive cases, the mean age at the time of HCC diagnosis was lower
      in heavy drinkers; this trend was not seen in HBV-positive cases. In HCC cases
      with heavy drinking, a high frequency of gastrointestinal (oropharynx, esophagus,
      stomach, colon and anal) cancers was seen. As for the aldehyde dehydrogenase-2
      (ALDH2) genotype, the frequency of normal homozygotes was 87.5% in heavy drinkers
      with HCC and the frequency of heterozygotes was 12.5%; the frequency of
      heterozygotes was 58.3% in alcoholics with esophageal cancer. More than half of
      the non-B, non-C, heavy drinkers HCC cases had a normal range of serum alpha
      fetoprotein (AFP) levels. These results indicate that heavy drinking enhances HCV
      related hepatocarcinogenesis. Whether or not ethanol is directly involved in
      hepatocarcinogenesis remains controversial, but LC may progress HCC in heavy
      drinkers even if their serum markers for HBV (including tissue) or HCV are
      negative. Therefore, close observation, including radiographic examinations, is
      recommended for non-B, non-C, heavy drinkers with LC. In HCV-positive cases,
      abstinence or a reduction in daily ethanol intake is recommended.

PMID- 15040959
TI  - Role of combined CT hepatic angiography and CT during arterial portography in the
      management of patients with hepatocellular carcinomas and liver metastases.
AB  - The purpose of this study was to evaluate the role of combined CT hepatic
      angiography (CTHA) and CT during arterial portography (CTAP) in the diagnosis and
      management of patients with hepatocellular carcinomas (HCC) and liver metastases.
      Fifty patients with HCC and 19 patients with liver metastases were referred for
      CTHA and CTAP prior to surgery or interventional therapy. Diagnosis was
      established by either surgery or clinical observation. Alterations of diagnosis
      and management resulting from CTHA and CTAP information were recorded. In
      patients with HCC, diagnosis was altered either by number, location or extent of
      lesions in 46% of patients and was 78% correct. Alterations of management were
      performed in 32% of the patients in total, and were correct in all but one. In
      patients with liver metastases, diagnosis was altered regarding either number,
      location or extent of lesions in 21% of patients and were 50% correct. Management
      was not altered after CTHA and CTAP in the patients with liver metastases. We
      conclude that CTHA and CTAP provide valuable clinical information for patients
      with HCC and significantly corrected their previous diagnosis and plans of
      management. CTHA and CTAP should be performed in patients with HCC when either
      surgical or interventional therapy is the treatment option.

PMID- 15040960
TI  - Rotation culture with a newly developed holder enables long-term liver slice
      culture for study of liver fibrosis.
AB  - Background/aims: Conventional slice rotation culture has employed fibrin that is
      produced from fibrinogen by thrombin, to fix tissue slices on a slide glass.
      However, thrombin transmits various stimuli to cells through the thrombin
      receptor and affects experimental results. To exclude this disadvantage of
      thrombin, we developed a new holder and studied long-term liver rotation culture
      without using thrombin. Methods: Liver slices about [Formula: see text] were
      produced from the liver of 8-day-old Wister rats. The slice was fixed to a newly
      development holder on a slide glass and cultured in tube on rotary culture
      system. To evaluate whether slice survives and maintains functions, morphological
      structure, LDH leakage into the medium, ATP synthesis, glutathione-S-transferase
      activity and glycogen synthesis were examined. We also studied collagen synthesis
      after treatment with TGF-beta or thrombin. Results: Slice tissue survived and
      maintained its functions for over 10 days. After treatment with TGF-beta or
      thrombin, the tissue became shrunken and showed increased collagen synthesis. On
      the other hand, no stimulation of collagen synthesis was found in cultured tissue
      without treatment. Conclusions: Our data indicate that rotation culture with the
      new holder is suitable for long-term culture for study of liver fibrosis.

PMID- 15040961
TI  - The effect of taurine treatment on oxidative stress in experimental liver
      fibrosis.
AB  - Oxidative stress is important in pathogenesis of liver fibrosis, which is the
      result of deposition of excessive ECM proteins produced by activated hepatic
      stellate cells (HSCs). Reducing reactive oxygen species (ROS) production
      decreases collagen accumulation in liver. We investigated the benefits of
      antioxidant therapy in liver fibrosis and its association with HSC apoptosis.
      Forty-five male Spraque-Dawley rats were subdivided into three groups. Group I
      was treated with CCl(4) plus taurine, Group II with CCl(4) plus saline, and Group
      III with saline for 12 weeks. Erythrocyte and liver malondialdehyde (MDA) levels,
      superoxide dismutase (SOD) activities, Glutathione peroxidase (GSHpx) activities,
      and serum and liver TIMP-1 and MMP-13 levels were measured. Histopathological
      examinations were performed. Activated and total HSCs were quantified
      immunohistochemically. Apoptotic HSCs were detected by terminal deoxynucleotidyl
      transferase-mediated dUTP nick end-labeling (TUNEL) staining. Taurine decreased
      histopathological injury scores and oxidative stress parameters significantly.
      The number of activated HSCs was significantly higher in taurine untreated group
      ( [Formula: see text] ). Serum and tissue MMP-13 levels were significantly higher
      and TIMP-1 levels were significantly lower in taurine-treated group ( [Formula:
      see text] and [Formula: see text], respectively). The number of apoptotic
      activated hepatic stellate cells was significantly higher with taurine treatment
      ( [Formula: see text] ). Preventing the production of reactive oxygen species is
      effective in inhibiting fibrogenesis in experimental rat model. Inhibitory
      activity of this agent on HSCs' activation, apoptosis, and further fibrogenic
      events should be clearly identified.

PMID- 15040962
TI  - Mesenchymal hamartoma of the liver; Clinicopathological, immunohistochemical and
      flow cytometric study of two cases.
AB  - Mesenchymal hamartoma (MH) is a rare liver lesion of infancy. Due to its rapid
      increase in size, it is often misdiagnosed clinically as a malignant tumour or as
      a hepatic cyst because of its cystic appearance. We present the
      clinicopathological, immunohistochemical and flow cytometric features of two
      cases, involving an 11-month-old boy and a 13-month-old girl. In both cases, the
      histological appearance and the immunohistochemical findings were identical. Bile
      ducts and blood vessels showed the expected immunohistochemical profile, whereas
      the mesenchymal component showed immunoreactivity not only for vimentin but also
      for muscular markers. Flow cytometry disclosed an aneuploid population in one
      case, thus favouring the interpretation of MH as a neoplastic lesion. Unlike the
      characteristically continuous and rapid growth of MH before or shortly after
      birth, these two cases showed low proliferative and apoptotic indexes and a high
      immunohistochemical expression of bcl-2 protein. This prompted us to hypothesize
      that MH might undergo a brief initial proliferative phase, but the cells would
      later become 'immortalized' by bcl-2 overexpression.

PMID- 15040963
TI  - Clinical anatomy serving manual therapy.

PMID- 15040964
TI  - A proposed new classification system for whiplash associated disorders-
      implications for assessment and management.
AB  - The development of chronic symptoms following whiplash injury is common and
      contributes substantially to costs associated with this condition. The currently
      used Quebec Task Force classification system of whiplash associated disorders is
      primarily based on the severity of signs and symptoms following injury and its
      usefulness has been questioned. Recent evidence is emerging that demonstrates
      differences in physical and psychological impairments between individuals who
      recover from the injury and those who develop persistent pain and disability.
      Motor dysfunction, local cervical mechanical hyperalgesia and psychological
      distress are present soon after injury in all whiplash injured persons
      irrespective of recovery. In contrast those individuals who develop persistent
      moderate/severe pain and disability show a more complex picture, characterized by
      additional impairments of widespread sensory hypersensitivity indicative of
      underlying disturbances in central pain processing as well as acute posttraumatic
      stress reaction, with these changes present from soon after injury. Based on this
      heterogeneity a new classification system is proposed that takes into account
      measurable disturbances in motor, sensory and psychological dysfunction. The
      implications for the management of this condition are discussed.

PMID- 15040965
TI  - The sensory and sympathetic nerve supply within the cervical spine: review of
      recent observations.
AB  - The purpose of this review is to identify recently observed features of the
      sympathetic and sensory systems and their pathways which characterize cervical
      spine innervation and their potential relevance to the clinical pain syndromes.
      The results of studies examining the innervation patterns of the zygoapophysial
      joints serve to demonstrate that structures in the cervical spine, as in other
      spinal regions, are partly innervated by sensory nerves traveling along
      sympathetic pathways. These studies also demonstrate that the neuropeptide levels
      in the cell bodies located within the dorsal root ganglion of these sensory
      nerves fluctuate according to the physiological state of the zygoapophysial
      joint. Additional to the sympathetic nerves accompanying the vertebral artery,
      the innervation patterns of dura and posterior longitudinal ligament in the upper
      cervical spine are distinctive features of cervical spine innervation. The
      possible clinical implications of cervical innervation patterns are considered
      with reference to referred pain, the pain patterns associated with a dissecting
      vertebral artery and cervicogenic headaches.

PMID- 15040966
TI  - The initial effects of a Mulligan's mobilization with movement technique on
      dorsiflexion and pain in subacute ankle sprains.
AB  - Physiotherapists frequently use manipulative therapy techniques to treat
      dysfunction and pain resulting from ankle sprain. This study investigated whether
      a Mulligan's mobilization with movement (MWM) technique improves talocrural
      dorsiflexion, a major impairment following ankle sprain, and relieves pain in
      subacute populations. Fourteen subjects with subacute grade II lateral ankle
      sprains served as their own control in a repeated measures, double-blind
      randomized controlled trial that measured the initial effects of the MWM
      treatment on weight bearing dorsiflexion and pressure and thermal pain threshold.
      The subacute ankle sprain group studied displayed deficits in dorsiflexion and
      local pressure pain threshold in the symptomatic ankle. Significant improvements
      in dorsiflexion occurred initially post-MWM ( F(2,26) = 7.82, P = 0.002 ), but no
      significant changes in pressure or thermal pain threshold were observed after the
      treatment condition. Results indicate that the MWM treatment for ankle
      dorsiflexion has a mechanical rather than hypoalgesic effect in subacute ankle
      sprains. The mechanism by which this occurs requires investigation if we are to
      better understand the role of manipulative therapy in ankle sprain management.

PMID- 15040967
TI  - Reliability of ultrasonography for the cervical multifidus muscle in asymptomatic
      and symptomatic subjects.
AB  - A test-retest and inter-tester study was designed to assess the reliability of
      ultrasonography to depict the size of the cervical multifidus muscle in
      asymptomatic and symptomatic subjects. Ten asymptomatic women (range 19-48 years)
      and 10 women with chronic whiplash associated disorder (WAD), grade II, (range 19
      49 years), matched for height and weight participated. The women were imaged by
      ultrasonography on two separate occasions by two different testers. On each
      occasion the cross-sectional area (CSA), and the transverse versus the anterior
      posterior dimensions (shape ratio) at the C4 level were measured. The repeated
      measurements of the CSA were plotted against their means to reveal the limit of
      agreement. Good agreement was found for the asymptomatic group measurements and
      the intra-tester agreement for the symptomatic group. The inter-tester agreement
      for the symptomatic group was questionable. The size of the multifidus muscle was
      significantly reduced in the symptomatic group ( P<0.05 ). The results indicate
      that loss of clarity of the fascial layer between the semispinalis cervicis
      muscle and the cervical multifidus muscle may be a diagnostic sign of muscle
      atrophy. Ultrasonography can be used to precisely measure the size of the
      cervical multifidus muscle at the C4-level in asymptomatic young female subjects;
      it is also reliable for symptomatic subjects if the same tester performs the
      measurements. Additional criteria are recommended to improve the inter-tester
      agreement for symptomatic subjects.

PMID- 15040968
TI  - Impairment in the cervical flexors: a comparison of whiplash and insidious onset
      neck pain patients.
AB  - There has been little investigation into whether or not differences exist in the
      nature of physical impairment associated with neck pain of whiplash and insidious
      origin. This study examined the neck flexor synergy during performance of the
      cranio-cervical flexion test, a test targeting the action of the deep neck
      flexors. Seventy-five volunteer subjects participated in this study and were
      equally divided between Group 1, asymptomatic control subjects, Group 2, subjects
      with insidious onset neck pain and Group 3, subjects with neck pain following a
      whiplash injury. The cranio-cervical flexion test was performed in five
      progressive stages of increasing cranio-cervical flexion range. Subjects'
      performance was guided by feedback from a pressure sensor inserted behind the
      neck which monitored the slight flattening of the cervical lordosis which occurs
      with the contraction of longus colli. Myoelectric signals (EMG) were detected
      from the muscles during performance of the test. The results indicated that both
      the insidious onset neck pain and whiplash groups had higher measures of EMG
      signal amplitude (normalized root mean square) in the sternocleidomastoid during
      each stage of the test compared to the control subjects (all P<0.05) and had
      significantly greater shortfalls from the pressure targets in the test stages
      (P<0.05). No significant differences were evident between the neck pain groups in
      either parameter indicating that this physical impairment in the neck flexor
      synergy is common to neck pain of both whiplash and insidious origin.

PMID- 15040969
TI  - Pre-manipulative testing of the cervical spine review, revision and new clinical
      guidelines.
AB  - Members of the Manipulative Physiotherapists Association of Australia (now
      Musculoskeletal Physiotherapy Australia) were surveyed to determine their use of
      cervical manipulation, compliance with and attitudes to the Australian
      Physiotherapy Association's (APA) Protocol for Pre-manipulative Testing of the
      Cervical Spine, and the incidence of adverse effects from cervical manipulation.
      The questionnaire was mailed to 740 members and returned by 480 members (65%).
      Cervical manipulation (84.5%) and passive mobilization (99.8%) were used by a
      high percentage of respondents. Most were familiar with the protocol with 63%
      supporting its continued endorsement. Adverse effects were reported at a rate of
      one per 1000 years of practice (or 0.003/week). The most common effects were
      symptoms potentially related to VBI (94.4% responses), with no reported major
      complications. Only 37.1% of respondents always informed the patient about
      potential dangers of cervical manipulation and consent was sought on every
      occasion by 33% of respondents. The results suggest that the use and
      interpretation of the protocol are variable among members of MPA. The risk of
      adverse effects from manipulative (musculoskeletal) physiotherapy practice,
      including cervical manipulation, appears to be very low. Recommendations for
      revision of the protocol were made on the basis of results of the survey and
      treatment diary, in addition to a review of the literature related to testing for
      vertebro-basilar insufficiency, adverse incidents related to cervical mobilizing
      and manipulative technique, differentiating features of VBI related dizziness and
      vertigo related to benign paroxysmal positional vertigo (BPPV) and current issues
      surrounding informed consent. Finally, a summary of the content of the new
      Clinical Guidelines for Pre-Manipulative Testing of the Cervical Spine (APA,
      2000) is provided.

PMID- 15040970
TI  - The presence and utilization of psoas musculature despite congenital absence of
      the right hip.

PMID- 15040971
TI  - Quantitative analysis of traction in the glenohumeral joint: in vivo radiographic
      measurements. By Gokeler A, van Paridon-Edauw GH, DeClercq S, Matthijs O,
      Dijkstra U. Manual Therapy 8 (2) (2003) 97-102.

PMID- 15040973
TI  - Determination of the electron relaxation rates in paramagnetic metal complexes:
      applicability of available NMR methods.
AB  - Four different approaches for determining the electron relaxation rates in
      paramagnetic metallo-proteins are investigated, using a paramagnetic Ni2+ complex
      of a protein as an example. All four approaches rely on the determination of the
      longitudinal paramagnetic relaxation enhancements, R1p, of the 1H nuclei and the
      backbone 15N nuclei. Three of the methods utilize the field dependence of the R1p
      rates. It is found that the applicability of each of these methods depends on
      whether the fast-motion condition, omegaS2tau2<<1, applies to the electron
      relaxation, omegaS being the Larmor frequency of the electron spin S and tau the
      correlation time of the electron relaxation. If the fast-motion condition is
      fulfilled, the electron relaxation rate can be obtained from the ratio of the R1p
      rates of one or more protons at two magnetic field strengths (method A). On the
      other hand, if the fast-motion condition does not apply, more elaborate methods
      must be used that, in general, require a determination of the R1p rates over a
      larger range of magnetic field strengths (method C). However, in the case of
      paramagnetic metal ions with relatively slow electron relaxation rates only two
      magnetic field strengths suffice, if the R1p rates of a hetero nucleus are
      included in the analysis (method B). In the fourth method (method D), the
      electron relaxation is estimated as a parameter in a structure calculation, using
      distance constraints derived from proton R1p rates at only one magnetic field
      strength. In general, only methods B and C give unambiguous electron relaxation
      rates.

PMID- 15040974
TI  - DEPT spectral editing in HCCONH-type experiments. Application to fast protein
      backbone and side chain assignment.
AB  - 2D DEPT-H(alpha,beta)C(alpha,beta)(CO)NH and 2D CT-DEPT-HC(CO)NH-TOCSY
      experiments are presented which allow fast resonance assignment of aliphatic
      protein side chains. In these 2D reduced-dimensionality experiments, two or three
      nuclei are frequency labeled in the indirect dimension. DEPT spectral editing
      reduces the number of correlation peaks detected in each 2D spectrum, and helps
      in amino-acid-type determination during sequential backbone resonance assignment.
      Applications are shown for a small 68-residue, and a highly deuterated 167
      residue protein. The new experiments complement the set of 2D HNX correlation
      experiments, previously proposed for fast protein resonance assignment [J.
      Biomol. NMR, 27 (2003) 57].

PMID- 15040975
TI  - Minimum energy pulse synthesis via the inverse scattering transform.
AB  - This paper considers a variety of problems in the design of selective RF-pulses.
      We apply a formula of Zakharov and Manakov to directly relate the energy of an RF
      envelope to the magnetization profile and certain auxiliary parameters used in
      the inverse scattering transform (IST) approach to RF-pulse synthesis. This
      allows a determination of the minimum possible energy for a given magnetization
      profile. We give an algorithm to construct both the minimum energy RF-envelope as
      well as any other envelope that produces a given magnetization profile. This
      includes an algorithm for solving the Gel'fand-Levitan-Marchenko equations with
      bound states. The SLR method is analyzed in terms of traditional scattering data,
      and shown to be a special (singular) case of the IST approach. RF-envelopes are
      computed for a variety of examples.

PMID- 15040976
TI  - Magnetic resonance imaging of isolated single liposome by magnetic resonance
      force microscopy.
AB  - Magnetic resonance imaging (MRI) is very useful spectroscopy to visualize a three
      dimensional (3D) real structure inside the sample without physical destruction.
      The spatial resolution of the readily available MRI spectrometer is, however,
      limited by a few ten to hundreds of microns due to a technological boundary of
      generating larger magnetic field gradient and to the insensitivity inherent to
      the inductive signal detection. Magnetic resonance force microscopy (MRFM) is new
      alternative MRI spectroscopy which is anticipated to significantly surpass the
      conventional MRI in both resolution and sensitivity. We report two imaging
      experiments on our MRFM spectrometer operated at room temperature and in vacuum
      approximately 10(-3)Pa. One is for approximately 20 microm liposome membrane
      labeled entirely by a nitroxide imaging agent and the other for approximately 15
      microm DPPH particles, both are nearly the same size as that of human cell. The
      reconstructed images at spatial resolution approximately 1 microm were in
      satisfactory agreement with the scanning electron microscope images. The
      potential capability of visualizing intrinsic radicals in the cell is suggested
      to investigate redox process from a microscopic point of view.

PMID- 15040977
TI  - A longitudinally detected high-field ESR spectrometer for the measurement of spin
      lattice relaxation times.
AB  - We describe a high-field longitudinally detected electron spin resonance (LOD
      ESR) spectrometer operating at 35 and 75 GHz. The lack of resonant microwave
      circuits facilitates operation at different microwave frequencies without
      changing the probehead. A very low noise radio frequency detection compensates
      partially the resulting low sensitivity. The major elements of the LOD-ESR
      spectrometer are commercially available and may be adapted to usual high
      frequency spectrometers. The instrument allows field and frequency dependent spin
      lattice relaxation time (T1) studies. T1 in the range of 2-80 ns can be
      determined from the phase sensitively detected LOD-ESR spectra. We demonstrate
      the performance of the apparatus by the measurement of T1 in the normal state of
      RbC60, an electrically conducting alkaline fulleride polymer.

PMID- 15040978
TI  - REDCAT: a residual dipolar coupling analysis tool.
AB  - Recent advancements in the utilization of residual dipolar couplings (RDCs) as a
      means of structure validation and elucidation have demonstrated the need for, not
      only a more user friendly, but also a more powerful RDC analysis tool. In this
      paper, we introduce a software package named REsidual Dipolar Coupling Analysis
      Tool (REDCAT) designed to address the above issues. REDCAT is a user-friendly
      program with its graphical-user-interface developed in Tcl/Tk, which is highly
      portable. Furthermore, the computational engine behind this GUI is written in
      C/C++ and its computational performance is therefore excellent. The modular
      implementation of REDCAT's algorithms, with separation of the computational
      engine from the graphical engine allows for flexible and easy command line
      interaction. This feature can be utilized for the design of automated data
      analysis sessions. Furthermore, this software package is portable to Linux
      clusters for high throughput applications. In addition to basic utilities to
      solve for order tensors and back calculate couplings from a given order tensor
      and proposed structure, a number of improved algorithms have been incorporated.
      These include the proper sampling of the Null-space (when the system of linear
      equations is under-determined), more sophisticated filters for invalid order
      tensor identification, error analysis for the identification of the problematic
      measurements and simulation of the effects of dynamic averaging processes.

PMID- 15040979
TI  - Local structure in perovskite relaxor ferroelectrics: high-resolution 93Nb 3QMAS
      NMR.
AB  - Solid solutions of (1'-x)Pb(Mg(1/3)Nb(2/3))O3xPb(Sc(1/2)Nb(1/2))O3 (PMN/PSN) have
      been investigated using high-resolution 93Nb 3-quantum magic-angle spinning
      nuclear magnetic resonance experiments (3QMAS NMR). In previous MAS NMR
      investigations, the local B-cation ordering in these relaxor ferroelectric solid
      solutions was quantitatively determined. However, in conventional one-dimensional
      MAS spectra the effects of chemical shifts and quadrupole interaction are
      convoluted; this, in addition to the insufficient resolution, precludes reliable
      extraction of the values of isotropic chemical shift and quadrupole coupling
      product. In the current 3QMAS investigation, 93Nb spectra are presented for
      concentrations x=0, 0.1, 0.2, 0.6, 0.7, and 0.9 at high magnetic field (19.6 T)
      and fast sample spinning speed (35.7 kHz). Seven narrow peaks and two broad
      components are observed. The unique high-resolution of the two-dimensional 3QMAS
      spectra enables unambiguous and consistent assignments of spectral intensities to
      the specific 28 nearest B-site neighbor (nBn) configurations, (NMg, NSc, NNb)
      where each number ranges from 0 to 6 and their sum is 6. It is now possible to
      isolate the isotropic chemical shift and quadrupole coupling product and
      separately determine their values for most of the 28 nBn configurations. The
      isotropic chemical shift depends linearly on the number of Mg2+ cations in the
      configuration; delta iso CS=(13.7 +/- 0.1)NMg-970 +/- 0.4 ppm, regardless of the
      ratio NSc/NNb. For the seven Nb5+-deficient configurations (NMg, 6-NMg, 0) and
      the pure niobium configuration (0, 0, 6), the quadrupole coupling products (and
      hence the electric field gradients) are small (PQ approximately 6-12 MHz) and for
      the remaining configurations containing small, ferroelectric active Nb5+ ions,
      the quadrupole coupling products are significantly larger (PQ approximately 40
      MHz), indicating larger electric field gradients.

PMID- 15040980
TI  - Sensitivity-enhanced IPAP experiments for measuring one-bond 13C'-13Calpha and
      13Calpha-1Halpha residual dipolar couplings in proteins.
AB  - Sensitivity-enhanced 2D IPAP experiments using the accordion principle for
      measuring one-bond 13C'-13Calpha and 1Halpha-13Calpha dipolar couplings in
      proteins are presented. The resolution of the resulting spectra is identical to
      that of the decoupled HSQC spectra and the sensitivity of the corresponding 1D
      acquisitions are only slightly lower than those obtained with 3D HNCO and 3D
      HN(COCA)HA pulse sequences due to an additional delay 2Delta. For cases of
      limited resolution in the 2D 15N-1HN HSQC spectrum the current pulse sequences
      can easily be modified into 3D versions by introducing a poorly digitized third
      dimension, if so desired. The experiments described here are a valuable addition
      to the suites available for determination of residual dipolar couplings in
      biological systems.

PMID- 15040981
TI  - Some conjectures for cogwheel phase cycling.
AB  - Cogwheel phase cycles are often significantly shorter than traditional nested
      phase cycles. However, optimal solutions for cogwheel cycles are often difficult
      to find. This paper presents techniques and conjectures which the authors have
      found useful for generating cogwheel phase cycles either without the need for
      computer searches or with significantly smaller searches than would otherwise be
      necessary. The conjectures presently lack proofs but have been tested
      successfully for a large number of cases.

PMID- 15040982
TI  - Spin-state-selective excitation in gradient-selected heteronuclear cross
      polarization NMR experiments.
AB  - Several heteronuclear coherence transfer mechanisms involved in proton-detected
      heteronuclear J-cross-polarization (HCP) NMR experiments have been theoretically
      derived and experimentally verified in isotropic solution. It is shown that in
      phase and/or anti-phase heteronuclear coherence transfer can take place
      separately or simultaneously during the HCP process as a function of the relative
      phase between the HCP mixing sequence and the corresponding input magnetization.
      As the more important consequence, clean coherence-order and spin-state selective
      (S3) excitation with maximum sensitivity can be achieved from gradient-enhanced
      HCP experiments by proper co-addition/subtraction of in-phase and anti-phase
      magnetizations, offering an attractive alternative to widely used HSQC-type
      experiments.

PMID- 15040983
TI  - Internal dynamics of hydroxymethyl rotation from CH2 cross-correlated dipolar
      relaxation in methyl-beta-D-glucopyranoside.
AB  - Conventional relaxation parameters (T1(-1), T2(-1), and NOE), obtained at
      different temperatures and magnetic fields, are reported for the hydroxymethyl
      (C6) carbon in methyl-beta-D-glucopyranoside in a D2O/DMSO cryosolvent. These
      data are interpreted with the Lipari-Szabo model. In addition, two-field
      measurements of longitudinal and spin-locked relaxation rates related to the
      cross-correlated carbon-proton dipole-dipole interactions for the same carbon are
      reported. The complete data set consisting the conventional and cross-correlated
      relaxation parameters is interpreted using a new "hybrid" approach, in which the
      Lipari-Szabo model for the auto-correlated spectral densities is combined with
      the two-site jump model for the cross-correlated spectral densities, with the
      global correlation time as a common parameter. The two-site jump rates thus
      obtained are in reasonable agreement with the ultrasonic relaxation measurements,
      and have reasonable temperature dependence.

PMID- 15040984
TI  - Remotely detected high-field MRI of porous samples.
AB  - Remote detection of NMR is a novel technique in which an NMR-active sensor
      surveys an environment of interest and retains memory of that environment to be
      recovered at a later time in a different location. The NMR or MRI information
      about the sensor nucleus is encoded and stored as spin polarization at the first
      location and subsequently moved to a different physical location for optimized
      detection. A dedicated probe incorporating two separate radio frequency (RF)
      circuits was built for this purpose. The encoding solenoid coil was large enough
      to fit around the bulky sample matrix, while the smaller detection solenoid coil
      had not only a higher quality factor, but also an enhanced filling factor since
      the coil volume comprised purely the sensor nuclei. We obtained two-dimensional
      (2D) void space images of two model porous samples with resolution less than 1.4
      mm2. The remotely reconstructed images demonstrate the ability to determine fine
      structure with image quality superior to their directly detected counterparts and
      show the great potential of NMR remote detection for imaging applications that
      suffer from low sensitivity due to low concentrations and filling factor.

PMID- 15040985
TI  - Cascaded z-filters for efficient single-scan suppression of zero-quantum
      coherence.
AB  - A simple and robust method to suppress zero-quantum coherence (ZQC) in NMR
      experiments, in a single scan and with very high suppression ratio, is described.
      It is an appreciable improvement on a previous technique by Thrippleton and
      Keeler [Angew. Chem. Int. Ed. 42 (2003) 3938]. The method, called a z-filter
      cascade, preserves longitudinal, or z-magnetization, with high efficiency. Losses
      depend mostly on T1 relaxation but not T2 relaxation mechanisms. At the same
      time, suppression of ZQC can be essentially complete in a single scan. The time
      duration of the z-filter cascade scales inversely to representative chemical
      shift differences between the coupled spins, and is typically a few tens of
      milliseconds. The high efficiency of the zero-quantum suppression and excellent
      retention of the desired z-magnetization, in a single scan without resort to
      phase cycling or difference spectroscopy, makes the z-filter cascade a useful new
      pulse sequence building block for a whole range of NMR experiments. In cases
      where unwanted residual ZQC may have previously contributed to baseline " t1
      noise" in two-dimensional NMR spectra, the z-filter cascade can deliver a
      noteworthy improvement in spectral quality.

PMID- 15040987
TI  - T1rho-weighted MRI using a surface coil to transmit spin-lock pulses.
AB  - T1rho-weighted MRI is a novel basis for generating tissue contrast. However, it
      suffers from sensitivity to B1 inhomogeneity. First, excitation with a spatially
      varying B1 causes flip-angle artifacts and second, spin locking with an
      inhomogeneous B1 results in non-uniform T1rho contrast. In this study, we
      overcome the former complication with a specially designed spin-locking pulse
      sequence and we successfully obtain T1rho-weighted images with a surface coil. In
      this pulse sequence, the spin-lock pulse was divided into segments of equal
      duration and alternating phase. This "self-compensating" T1rho-preparatory pulse
      sequence was analyzed and the effect of an inhomogeneous B1 field was simulated
      using the Bloch equations. T1rho-weighted MR images of a phantom and a human knee
      joint in vivo were obtained on a clinical scanner with a surface coil to
      demonstrate the utility of the pulse sequence. The self-compensating T1rho
      prepared pulses sequence resulted in substantially reduced image artifacts
      compared to the conventional, single-phase spin-lock pulse.

PMID- 15040986
TI  - Time resolved spectroscopic NMR imaging using hyperpolarized 129Xe.
AB  - We have visualized the melting and dissolution processes of xenon (Xe) ice into
      different solvents using the methods of nuclear magnetic resonance (NMR)
      spectroscopy, imaging, and time resolved spectroscopic imaging by means of
      hyperpolarized 129Xe. Starting from the initial condition of a hyperpolarized
      solid Xe layer frozen on top of an ethanol (ethanol/water) ice block we measured
      the Xe phase transitions as a function of time and temperature. In the pure
      ethanol sample, pieces of Xe ice first fall through the viscous ethanol to the
      bottom of the sample tube and then form a thin layer of liquid Xe/ethanol. The
      xenon atoms are trapped in this liquid layer up to room temperature and keep
      their magnetization over a time period of 11 min. In the ethanol/water mixture
      (80 vol%/20%), most of the polarized Xe liquid first stays on top of the
      ethanol/water ice block and then starts to penetrate into the pores and cracks of
      the ethanol/water ice block. In the final stage, nearly all the Xe polarization
      is in the gas phase above the liquid and trapped inside the pores. NMR spectra of
      homogeneous samples of pure ethanol containing thermally polarized Xe and the
      spectroscopic images of the melting process show that very high concentrations of
      hyperpolarized Xe (about half of the density of liquid Xe) can be stored or
      delivered in pure ethanol.

PMID- 15040988
TI  - Pure nuclear quadrupole resonance determination of the electric field gradient
      asymmetry for broad lines.
AB  - We present an angle dependent nuclear quadrupole resonance (ADNQR) method to
      determine the electric field gradient asymmetry parameter eta in systems where
      the resonance line is so broad that the radio frequency field can excite only a
      portion of the nuclear spins. In this situation, the recently developed
      spectroscopic methods are not applicable. ADNQR is useful for single crystals and
      oriented powders, and, for small eta determines eta4. Therefore, it can be used
      to evaluate fluctuations in eta due to inhomogeneities. We demonstrate the
      application of ADNQR experimentally to oriented superconducting YBa2Cu3O7 powder.

PMID- 15040989
TI  - Magnetic resonance microscopy of biofilm structure and impact on transport in a
      capillary bioreactor.
AB  - Microorganisms that colonize surfaces, biofilms, are of significant importance
      due to their role in medical infections, subsurface contaminant remediation, and
      industrial processing. Spatially resolved data on the distribution of biomass
      within a capillary bioreactor, the heterogeneity of the biofilm itself and the
      impact on transport dynamics for a Staphylococcus epidermidis biofilm in the
      natural growth state are presented. The data demonstrate the ability of magnetic
      resonance microscopy to study spatially resolved processes in bacterial biofilms,
      thus providing a basis for future studies of spatially resolved metabolism and in
      vivo clinical detection.

PMID- 15040990
TI  - A new type of sample tube for reducing convection effects in PGSE-NMR
      measurements of self-diffusion coefficients of liquid samples.
AB  - Pulsed gradient spin-echo (PGSE) NMR measurements of the self-diffusion
      coefficients of low viscosity liquids are greatly hampered by the effects of
      convection especially away from ambient temperature. Here we report on a new NMR
      tube designed to minimize the deleterious effects of convection. In this tube,
      which derives from a Shigemi symmetrical NMR tube, the sample is contained in an
      annulus formed from a concentric cylinder of susceptibility matched glass. The
      performance of this tube was demonstrated by conducting measurements on the
      electrochemically important LiN(SO3CF3)2 (LiTFSI)-diglyme (DG) system.
      Calibrations were first made using DG at column heights of 2, 3, and 4-mm in the
      temperature range between -40 and 100 degrees C. Measurements of the diffusion
      coefficients of the lithium, anion, and DG were then performed to probe the
      solvent-ion and ion-ion interactions in the DG doped with LiTFSI. Changes in the
      1H, 7Li, and 19F PGSE-NMR attenuation curves at -40 degrees C provided clear
      evidence of interactions between the DG and lithium ion.

PMID- 15040991
TI  - Correction of spin diffusion during iterative automated NOE assignment.
AB  - Indirect magnetization transfer increases the observed nuclear Overhauser
      enhancement (NOE) between two protons in many cases, leading to an
      underestimation of target distances. Wider distance bounds are necessary to
      account for this error. However, this leads to a loss of information and may
      reduce the quality of the structures generated from the inter-proton distances.
      Although several methods for spin diffusion correction have been published, they
      are often not employed to derive distance restraints. This prompted us to write a
      user-friendly and CPU-efficient method to correct for spin diffusion that is
      fully integrated in our program ambiguous restraints for iterative assignment
      (ARIA). ARIA thus allows automated iterative NOE assignment and structure
      calculation with spin diffusion corrected distances. The method relies on
      numerical integration of the coupled differential equations which govern
      relaxation by matrix squaring and sparse matrix techniques. We derive a
      correction factor for the distance restraints from calculated NOE volumes and
      inter-proton distances. To evaluate the impact of our spin diffusion correction,
      we tested the new calibration process extensively with data from the Pleckstrin
      homology (PH) domain of Mus musculus beta-spectrin. By comparing structures
      refined with and without spin diffusion correction, we show that spin diffusion
      corrected distance restraints give rise to structures of higher quality (notably
      fewer NOE violations and a more regular Ramachandran map). Furthermore, spin
      diffusion correction permits the use of tighter error bounds which improves the
      distinction between signal and noise in an automated NOE assignment scheme.

PMID- 15040994
TI  - Taking advantage of opportunities: community involvement, well-being, and urban
      youth.
AB  - Positive interpersonal and community factors were examined as predictors of
      psychological outcomes. Over 200 African-American adolescents participated in
      four assessments across 2 years. Self-report surveys were administered to 5th
      through 8th grade students from three schools, and data were analyzed through
      hierarchical linear regressions. Results suggest that having a role model, school
      belonging, community involvement, and church attendance predicted better
      psychological outcomes.

PMID- 15040993
TI  - More than heights and weights: what parents of urban adolescents want from health
      care providers.
AB  - To examine health care providers' expected role in health promotion counseling to
      urban adolescents from the perspective of parents. Although participating parents
      wanted health care providers to counsel their adolescents on sensitive health
      issues, their desires and expectations were rarely met.

PMID- 15040995
TI  - Young adults' attitudes, beliefs, and feelings about testing for curable STDs
      outside of clinic settings.
AB  - The purpose of this paper was to elicit attitudes, beliefs, and feelings about
      testing for curable STDs outside of clinic settings. Telephone interviews were
      conducted with 120 black, Latino, and white young adults aged 18 to 25 years.
      Data were analyzed with descriptive frequencies and content analyses. Most (73%)
      reported people their age would use self-test urine STD kits if available.
      Perceived advantages were privacy and convenience. Disadvantages included not
      having an immediate "face-to-face" discussion with a medical professional about
      positive tests. Young adults report a range of attitudes, beliefs, and feelings
      that may influence the success of efforts to screen for curable STDs in nonclinic
      settings.

PMID- 15040996
TI  - Perceived quality of life: a neglected component of adolescent health assessment
      and intervention.
AB  - The contribution of the construct of perceived quality of life (PQOL) to
      adolescent health assessment and promotion is discussed. Theory, measurement, and
      correlates of PQOL in adolescence are reviewed, with a focus on the incremental
      validity of PQOL data in relationship to more traditional pathology-based health
      indices. Similar to Diener's proposal, which pertained exclusively to adults, we
      call for the inclusion of PQOL data in national databases that monitor adolescent
      health outcomes.

PMID- 15040997
TI  - A controlled evaluation of a school-based intervention to promote physical
      activity among sedentary adolescent females: project FAB.
AB  - PURPOSE: To evaluate the effect of a school-based intervention designed to
      increase physical activity among sedentary adolescent females. METHODS: Sedentary
      adolescent females were assigned to a control (n = 22) or intervention (n = 25)
      group based on school attended. Students at the intervention school enrolled in a
      special physical education class. All participants completed clinical and
      behavioral assessments at baseline and after 4 months. Physiological tests
      included cardiovascular fitness (VO(2) peak via bicycle ergometer), body
      composition (via dual x-ray absorptiometer; DEXA), and body mass index (BMI).
      Psychosocial assessments included a physical activity recall, report of lifestyle
      activity, and self-efficacy, perceived barriers, social support, and enjoyment
      related to physical activity. Data were analyzed using repeated measures analyses
      of variance (ANOVAs) for continuous variables, and logistic regression for hard
      activity (scored as a dichotomous variable). RESULTS: The intervention had a
      significant effect on cardiovascular fitness (p =.017), lifestyle activity (p
      =.005), and light (p =.023), moderate (p =.007), and hard (p =.006) activity. All
      changes were in a direction that favored the intervention. There was no effect of
      the intervention on psychosocial factors related to exercise. CONCLUSIONS: A
      school-based intervention targeting sedentary adolescent females can increase
      physical activity and prevent a decline in cardiovascular fitness. Moreover, the
      effect of the intervention generalized to lifestyle activity.

PMID- 15040998
TI  - Cardiovascular risk factors in Mexican-American children at risk for type 2
      diabetes mellitus (T2DM).
AB  - PURPOSE: To assess risk factors for type 2 diabetes mellitus (T2DM) and
      cardiovascular disease (CVD) with the hypothesis that risk for T2DM in children
      would be associated with an increase in risk factors for CVD. METHODS: Subjects
      from a group of Mexican-American school children (aged 10-12 years) identified to
      be at risk for T2DM, and their siblings, were selected for this study. There were
      68 children with acanthosis nigricans (AN+), and 71 without AN (AN-). Both AN+
      and AN- children were assessed for T2DM and CVD risk factors. Probands and
      siblings were evaluated by physical examination, family history, and fasting
      serum parameters: glucose, insulin, body mass index (BMI), serum lipoproteins,
      and oxidized lipids. Data were analyzed by descriptive, univariate, and
      multivariate procedures. RESULTS: BMI, waist/hip ratio, systolic and diastolic
      blood pressure were all significantly higher (p <.002) in AN+, whereas Tanner
      stages were similar in both groups. Fasting serum glucose was in the normal
      range, whereas insulin was elevated in AN+ compared with AN- (30.0 +/- 1.9
      microU/mL vs. 14.8 +/- 1.0 p <.0001). Insulin resistance as assessed by the
      homeostasis assessment model (HOMA-IR) was elevated in both groups, although
      higher among AN+ (p <.0001). High-density lipoprotein-cholesterol (HDL-C) was
      lower (6.2 mg/dL) in the AN+ group (p <.003). The lower HDL-C in AN+ was
      associated with elevated triglycerides and a higher serum total cholesterol
      TC/HDL-C ratio when contrasted with the AN- values (145.9 +/- 7.6 mg/dL vs. 97.1
      +/- 0.07, p <.0001; 4.1 +/- 0.2 vs. 3.4 +/- 0.1, p <.0001, respectively). In
      addition to the high prevalence of overweight/obesity (BMI > 85th percentile) in
      this population (76.3%, 106/139), elevated insulin (59.7% >15 microU/mL), low HDL
      C (27.3% <40 mg/dL), and elevated low-density lipoprotein cholesterol (LDL-C)
      (41.0% >100 mg/dL) were also detected. CONCLUSIONS: The altered metabolic pattern
      observed in this group of Mexican-American children is characteristic of
      metabolic syndrome, a condition associated with obesity and increased risk for
      both T2DM and CVD in adults. This study points to the value of BMI and acanthosis
      nigricans as easily accessible markers for children and nuclear families at
      increased risk for developing T2DM and CVD.

PMID- 15041000
TI  - Evaluation of a screening instrument for developmental coordination disorder.
AB  - PURPOSE: To validate the Children's Self-Perceptions of Adequacy in, and
      Predilection for Physical Activity (CSAPPA) scale as a proxy for the BOTMP test
      in diagnosing DCD. METHODS: A sample of 209 children (M = 121; F = 87) consented
      to the BOTMP test, CSAPPA scale, Participation Questionnaire, Leger 20-meter
      Shuttle Run, and body fat using bioelectric impedance. Receiver Operating
      Characteristic (ROC) curve analysis and Kappa statistic were used to validate the
      CSAPPA scale as a predictor for significant clumsiness on the BOTMP test.
      RESULTS: Prevalence of DCD was.09 +/-.03 of both males and females, all
      previously undiagnosed. A positive cutoff of < 47 and < 53 for DCD on the CSAPPA
      scale was identified in male and females, respectively. Both gender cut-offs
      demonstrated significant agreement (p <.01) with a positive BOTMP test. Males'
      results indicated a sensitivity and specificity values of.90 (CI =.18) and.89 (CI
      =.22). Likewise, the female subject cutoff demonstrated high sensitivity [.88 (CI
      =.05)] and specificity [75 (CI =.09)]. Gender specific analysis of variance
      (ANOVA) indicated that students identified as clumsy were not significantly
      different in age or height from their peers, but demonstrated significantly (p
      <.01) lower self-efficacy, aerobic fitness, and had significantly (p <.01) higher
      relative body fat. These results held true for both genders. CONCLUSIONS: These
      findings are consistent with the characteristics of children with DCD. These
      results suggest that the CSAPPA scale is a promising instrument for use in
      screening children for developmental coordination disorder.

PMID- 15040999
TI  - Ethnic differences in BMI and body/self-dissatisfaction among Whites, Asian
      subgroups, Pacific Islanders, and African-Americans.
AB  - PURPOSE: To distinguish body mass index (BMI) and body/self-dissatisfaction among
      Asian subgroups. METHOD: 211 white, 155 Japanese, 112 African-American, 79
      Filipino, 70 Chinese, 70 Hawaiian, and 124 multiethnic college students in Hawaii
      completed: Figure Drawings (index of body-dissatisfaction), self-loathing
      subscale (SLSS, exercise-based measure of self-dissatisfaction), Eating Disorder
      Inventory-2 (EDI), and symptom self-report. Pearson correlation analyses were
      performed to determine whether BMI scores were related to self- and body
      dissatisfaction and the relationship between self- and body-dissatisfaction.
      RESULTS: BMI was highly correlated with body and self-dissatisfaction for males
      and females. Males appeared more satisfied than females with the body and more
      diverse in choice of larger or smaller ideal body type. Highly significant
      BMI/ethnic group differences emerged. White males were large (high BMI) but very
      satisfied with body and self. Filipino males were the largest of all male groups
      but followed a female pattern of strong body/self-dislike and preference for
      smaller body. Chinese females were small and highly satisfied with body/self
      whereas Japanese females were small but highly dissatisfied with body/self.
      CONCLUSION: Combining various ethnic groups under a single "Asian" category
      obscures important group differences. Study clearly demonstrates Asian ethnic
      subgroup differences in BMI and body/self dissatisfaction.

PMID- 15041001
TI  - Depressive symptoms: how do adolescents compare with adults?
AB  - PURPOSE: To compare depressive symptoms between U.S. adolescents and adults.
      METHODS: Data are from the National Longitudinal Study of Adolescent Health (N =
      18,488), the Americans' Changing Lives Project (N = 3,164), and the National
      Health and Nutrition Examination Survey I (N = 3,023). Depressive symptoms were
      assessed with items from the Center for Epidemiologic Studies-Depression (CES-D)
      Scale, operationalized as present or persistent. Multivariate regression analyses
      were used to assess correlates of depressive symptoms within each sample.
      RESULTS: Older adolescents reported the highest symptom presence, but symptom
      persistence was similar between adolescents and young to middle aged adults. The
      oldest adults reported the lowest symptom presence but the highest symptom
      persistence. For adolescents and for adults, low household income and ethnic
      minority status were the most consistent multivariate correlates of depressive
      symptoms. CONCLUSIONS: Older adolescents experience more depressive symptoms than
      adults and comparable symptom persistence, suggesting that these adolescents may
      be at the highest risk for depression. This risk may be especially pronounced
      among economically disadvantaged ethnic minority adolescents.

PMID- 15041002
TI  - Second neoplasms in survivors of childhood and adolescent cancer are often
      treatable.
AB  - PURPOSE: To estimate the incidence and types of second neoplasms in survivors of
      childhood and adolescent cancer, as well as the characteristics of those who
      developed second neoplasms. METHODS: Survivors who were under age 21 years at
      initial diagnosis, off therapy, and in remission for 2 years are referred to the
      Long Term Survivors' Clinic (LTSC) at Children's National Medical Center (CNMC).
      This review includes patients entered in the clinic database from January 1, 1997
      to August 30, 2002. RESULTS: Twenty-three (2.3%) of 987 childhood cancer
      survivors followed in the LTSC had 26 (2.6%) second and third neoplasms. The mean
      age was 6.7 years at initial diagnosis, 20.3 years at diagnosis of the second
      neoplasm, and 20.5 years at diagnosis of the third neoplasm. Of 10 female and 13
      male patients, 15 were white, six black, one Hispanic, and one Asian. All but two
      of the patients received radiation. Nineteen neoplasms, including seven thyroid
      carcinomas, six central nervous system tumors (three meningiomas), three basal
      cell carcinomas, two breast cancers, and one soft tissue sarcoma, occurred at
      sites within or contiguous to radiation sites. Five patients died, but the
      majority of neoplasms were treatable and most patients had good outcomes.
      CONCLUSION: Indefinite follow-up in a long-term survivors' clinic is indicated
      for adolescent and adult survivors of childhood cancer, with routine examination
      and screening for recurrence of the initial cancer as well as late effects,
      including second neoplasms.

PMID- 15041003
TI  - The influence of parental occupation and the pupils' educational level on
      lifestyle behaviors among adolescents in Belgium.
AB  - PURPOSE: To analyze the associations of lifestyle behaviors with educational
      level and social background based on parental occupation in adolescence. METHODS:
      Data from secondary school pupils participating in the Belgian (Flemish) Health
      Behavior in School-aged Children (HBSC) survey of the year 2002 (N = 12,490) were
      analyzed. Multiple logistic regressions adjusting for age and gender were used to
      assess the effects of parental occupation and pupil educational level on the
      selected lifestyle behaviors. RESULTS: Pupils of lower educational level reported
      less healthy food habits, less teeth brushing, less seatbelt use, more TV
      watching, more smoking, more drunkenness, more use of hashish, and more lifetime
      use of Ecstasy. Pupils of parents with lower socioeconomic status (SES) (based on
      the occupation of the head of the household) reported less healthy food habits,
      less teeth brushing, more TV watching, and less seatbelt use. Daily smoking and
      the lifetime use of Ecstasy varied among pupils of different parental occupation,
      although the effect disappeared when the pupils' educational level was introduced
      into the models. Regular drunkenness and regular use of hashish did not vary
      among pupils of different SES backgrounds. However, after controlling for
      educational level, an effect of parental occupation on regular hashish use became
      visible, with a higher percentage of regular users among the pupils of higher
      parental occupation. CONCLUSION: A lower educational level is associated with
      higher prevalence of indicators of an unhealthy lifestyle. The results are less
      straightforward for the relationship between SES and lifestyle behaviors.

PMID- 15041004
TI  - Evaluation of aortic stiffness in tobacco-smoking adolescents.
AB  - PURPOSE: To measure the aortic stiffness in tobacco-smoking adolescents and to
      investigate its relationship to tobacco smoke. METHODS: Aortic strain (S),
      pressure strain elastic modulus (E(p)), and normalized E(p) (E(p)*) in tobacco
      smoking adolescents and the healthy control group were measured by a
      sphygmomanometer with cuff and transthoracic echocardiography. The study group
      consisted of 30 healthy cases (M/F: 27/3) as a control group and 30 tobacco
      smoking volunteer adolescents (M/F: 28/2). Unpaired Student's t-test was used for
      comparison of these groups. RESULTS: The mean ages were 16.1 +/- 1.8 years and
      16.2 +/- 1.4 years, respectively. The number of cigarettes smoked per day was 31
      +/- 7.1 and the duration of smoking was 3.4 +/- 1.1 years. S, E(p) and E(p)*
      measurements of tobacco smokers were different than the control groups' and this
      difference was statistically significant. S values were significantly higher in
      nonsmokers than in smokers; whereas E(p) and E(p)* values were significantly
      higher in smoker group. CONCLUSIONS: This study demonstrated that measurement of
      aortic stiffness with S, E(p), and E(p)* can be used as an early indicator of
      atherosclerosis in tobacco-smoking adolescents.

PMID- 15041006
TI  - Difficulties around family presence during resuscitation.

PMID- 15041005
TI  - Knowledge of sleep in Italian high school students: pilot-test of a school-based
      sleep educational program.
AB  - PURPOSE: To evaluate knowledge about sleep and the effect of a sleep educational
      program on a group of Italian adolescents. METHODS: The program consisted of a 2
      hour interactive sleep educational course. To assess students' sleep patterns and
      habits, the School Sleep Habits Survey was completed by 540 students, aged 17 to
      19 years, who were attending three secondary public schools. Students were
      randomly assigned to the control and intervention group. Only the latter
      participated in the educational program. A pre-test evaluated baseline knowledge
      about sleep, a post-test measured the gain in knowledge after the course, and a 3
      month follow-up test evaluated long-term retention of information. Improvement in
      knowledge was measured by increase in correct answers and comparisons of means
      between baseline and follow-up mean scores. Control group completed only baseline
      and 3-month follow-up tests. Data were analyzed using repeated measures analysis
      of variance, Cochran Q, and McNemar tests. RESULTS: Paired data were available
      for 425 students. Results showed unhealthy sleeping habits in 34% of students
      associated with high level of subjective sleepiness, increased vulnerability to
      injuries, and poor daytime functioning. Pre-test score showed a value of 4.2,
      post-test of 8.6 and 3-month follow-up of 6.7. Low baseline knowledge about
      sleep, an increase in knowledge, with an average of 50% gain in the percentage of
      correct answers immediately after the course, with a good long-term retention of
      information were found for the students who received the intervention as compared
      with control group. CONCLUSION: Sleep educational programs for secondary students
      are recommended to improve information about sleep.

PMID- 15041007
TI  - Violence towards emergency department nurses by patients.
AB  - Emergency department (ED) violence is a significant problem in many hospitals.
      This study identified the incidence of violence by patients towards nurses in two
      EDs. Patient factors related to violence were identified and the circumstances
      surrounding the violent incident were described. Of the 71 ED nurses who
      participated, 50 (70%) reported 110 episodes of violence in a five-months period.
      That is approximately five violent incidents per week. Violence was reported most
      often on evening shifts (n=41, 37%). The nurses' perceived that the perpetrators
      of violence were under the influence of alcohol (n=30, 27%) and drugs (n=27, 25%)
      and displayed behaviours associated with mental illness (n=42, 38%). Nurses in
      this study were sworn at (n=67, 61%), pushed (n=11, 10%), hit (n=3, 3%), and
      kicked (n=3, 3%). Identification of trends and patterns of violence is necessary
      so that better health care planning and service provision as well as effective
      preventative and safe strategies for nurses in the workplace can be implemented.

PMID- 15041008
TI  - The use of topical anaesthesia at children's minor lacerations: an experimental
      study.
AB  - BACKGROUND: In a great many situations within health care and treatment, children
      are subjected to unnecessary pain and suffering. When local anaesthetics is to be
      administered the child can experience this as incomprehensible especially when
      the nursing staff assures the child that no pain would be felt, only to discover
      soon after, that it actually did hurt at the moment of anaesthetic infiltration.
      The soothing of pain during the suturing of wounds in emergency wards can be
      reduced, ensuring that unnecessary pain in the cafe-and-treatment process is mot
      meted out to children. In order to prevent this (subjection to unnecessary pain),
      and by improving accepted practice, it was interesting to investigate whether
      children felt pain at the time of infiltration anaesthesia following the initial
      topical anaesthesia. AIM: The aim of the present study was to investigate the
      effects of introductory topical anaesthesia using Xylocain solution dropped in
      the wound prior to a definitive infiltration-anaesthesia. An experimental,
      prospective design was used where children were included in either an
      experimental group or a control group. The experimental group (n=10) were given a
      Xylocain solution while the control group (n=10) received physiological Sodium
      solution. Data collection for the study was made by making VAS estimates and by
      interviews. RESULT: The study shows that a certain alleviation of pain does occur
      when using Xylocain but no statistically significant difference exists between
      the two groups. Irrespective of whether the children received an introductory
      topical anaesthesia with Xylocain or Sodium solution at the time of infiltration
      anaesthesia, they expressed pain in connection with infiltration. The study also
      shows that many children express fear and anxiety. CONCLUSION: Current research
      highlights the difficulties involved in offering children a really satisfactory
      form of pain relief in connection with infiltration anaesthesia and suturing of
      wounds. It is urgent to throw more light on children's pain, both from a nursing
      and from a medical point of view. No statistically significant difference was
      found in children's reported pain, after treatment with Xylocain but the solution
      can have a positive effect at the time of the infiltration jab, but a larger
      study needs to be done in order to establish this firmly.

PMID- 15041009
TI  - The complex causes of delays in A&E.
AB  - An extremely busy 48-h period in our Accident and Emergency (A&E) department
      prompted a close examination of clinical decision making. Decisions that were
      made both at the time of attendance at A&E and during the patients' subsequent
      hospital stay were gathered from patient records and the patient information
      system. A number of vignettes are presented to illustrate our findings. The brief
      case reviews provide a range of alternative explanations for the delays and
      prolongation of patient stays, aside from the often-cited 'shortage of capacity'.
      Amongst the key difficulties that were identified were poor communication between
      clinicians and hospital teams, a lack of co-ordination in respect to assessment
      and care of patients and admissions to hospital for patients who could quite
      safely be treated in primary care settings. Data are also presented on the high
      number of different locations that patients were moved to within the hospital
      along with contextual information. All findings are discussed in the context of
      clinical decision making and the allocation of a fixed 'hospital resource'. A
      number of specific suggestions are made for the improvement of both the local A&E
      system and more broad suggestions are made for clinicians in other A&E
      departments to consider.

PMID- 15041010
TI  - Nursing role on preventing secondary brain injury.
AB  - Secondary brain injury is a complicated, multifactorial process that results from
      hypoxemia, hypercapnia or hypocapnia, and increased ICP. Implementation of a
      traumatic brain injury protocol for patients with head injury including
      hemodynamic management, pulmonary care, maintenance of body temperature, control
      of the environment, positioning of patients, and seizure prophylaxis provides
      critical care nurses a proactive means to prevent or minimize the development of
      secondary brain injury in the emergency department.

PMID- 15041011
TI  - Accuracy of abdominal examination in the diagnosis of non-ruptured abdominal
      aortic aneurysm.
AB  - BACKGROUND: Early detection of abdominal aortic aneurysms (AAA) is paramount to
      reducing the very high mortality rates associated with rupture. This literature
      review was undertaken to assess the accuracy of abdominal examination in the
      detection of non-ruptured AAA. METHOD: A comprehensive literature search was
      performed to retrieve prospective studies comparing the accuracy of physical
      examination (PE) in the diagnosis of non-ruptured AAA confirmed by the gold
      standard, ultrasonography. RESULTS: The sensitivity of PE in the diagnosis of AAA
      ranges from 33% to 100%, the specificity from 75% to 100%, and the positive
      predictive value from 14% to 100%. Detection rates increase with increasing
      aortic diameter, increasing age, male sex, presence of recognisable risk factors,
      examination by an experienced clinician, PE directed specifically towards the
      detection of AAA, prevalence of AAA in study population, and thin patients.
      CONCLUSION: Clinical examination cannot be relied upon to exclude AAA. Larger
      aneurysms are usually palpable and more likely to be detected on examination
      especially in thin patients. Due to the poor sensitivity of PE together with the
      high sensitivity and specificity of ultrasound, obese patients in whom there is
      difficulty palpating an aneurysm, despite a history suggestive of possible non
      ruptured AAA, should be referred for ultrasound examination to assist with the
      diagnosis.

PMID- 15041013
TI  - Caring for families in A&E departments: Scottish and Icelandic nurses' opinions
      and experiences.
AB  - Results from two studies are represented here. The aims of the studies were to
      survey Accident and Emergency (A&E) nurses' opinions and experiences of caring
      for families when the patient's condition is critical and suddenly bereaved
      families. The participants were 111 A&E nurses in Scotland and Iceland. A
      descriptive study design was used for the purpose of the studies. Data were
      collected by a questionnaire. The participants perceived themselves to have
      responsibility for patients' families. The main implications from these studies
      were that caring for families was not a specially defined factor in these A&E
      departments and education in caring for families was missing.

PMID- 15041012
TI  - Self-harm patients who take early discharge from the accident and emergency
      department: how do they differ from those who stay?
AB  - There is evidence that patients presenting at a hospital Accident and Emergency
      (A&E) department with self-harm are considerably more likely than many others to
      discharge themselves before their assessment or treatment are complete. This
      paper reports a study that is part of a broader analysis of all self-harm
      presentations to a hospital A&E department over a five-year period. Self-harm
      patients who chose to remain for assessment and treatment were compared with
      those who chose to discharge themselves prematurely. We found a mean proportion
      of 18% of self-harm patients per annum took early discharge between 1996 and 2000
      and noted that these patients were more likely than other self-harm patients to
      have consumed alcohol in the hours immediately prior to their self-harm and
      attendance at the hospital. Self-harm patients who took early discharge were less
      likely than other self-harm patients to be admitted to an in-patient bed and less
      likely to receive a psychosocial assessment from a mental health specialist. We
      also found that aftercare arrangements were significantly less likely to be made
      for those patients who took early discharge. Some suggestions are made about
      approaches that clinical staff could adopt in order to reduce early discharge in
      self-harm patients.

PMID- 15041015
TI  - Characterisation of cysteine proteinases responsible for digestive proteolysis in
      guts of larval western corn rootworm (Diabrotica virgifera) by expression in the
      yeast Pichia pastoris.
AB  - Cysteine proteinases are the major class of enzymes responsible for digestive
      proteolysis in western corn rootworm (Diabrotica virgifera), a serious pest of
      maize. A larval gut extract hydrolysed typical cathepsin substrates, such as Z
      phe-arg-AMC and Z-arg-arg-AMC, and hydrolysis was inhibited by Z-phe-tyr-DMK,
      specific for cathepsin L. A cDNA library representing larval gut tissue mRNA
      contained cysteine proteinase-encoding clones at high frequency. Sequence
      analysis of 11 cysteine proteinase cDNAs showed that 9 encoded cathepsin L-like
      enzymes, and 2 encoded cathepsin B-like enzymes. Three enzymes (two cathepsin L
      like, DvRS5 and DvRS30, and one cathepsin B-like, DvRS40) were expressed as
      recombinant proteins in culture supernatants of the yeast Pichia pastoris. The
      cathepsin L-like enzymes were active proteinases, whereas the cathepsin B-like
      enzyme was inactive until treated with bovine trypsin. The amino acid residue in
      the S2 binding pocket, the major determinant of substrate specificity in
      cathepsin cysteine proteinases, predicted that the two cathepsin L-like enzymes,
      DvRS5 and DvRS30, should differ in substrate specificity, with the latter
      resembling cathepsin B in hydrolysing substrates with a positively charged
      residue at P2. This prediction was confirmed; DvRS5 only hydrolysed Z-phe-arg-AMC
      and not Z-arg-arg-AMC, whereas DvRS30 hydrolysed both substrates. The enzymes
      showed similar proteolytic activity towards peptide substrates.

PMID- 15041016
TI  - Characterization and molecular cloning of a glutathione S-transferase from the
      whitefly Bemisia tabaci (Hemiptera: Aleyrodidae).
AB  - Glutathione S-transferases (GST) catalyzing the conjugation of reduced
      glutathione to a vast range of xenobiotics including insecticides were
      characterized in the whitefly Bemisia tabaci. GST activities were determined in
      susceptible and resistant strains of B. tabaci towards artificial substrates,
      i.e. 1-chloro-2,4-dinitrobenzene (CDNB) in a photometric microplate assay and
      monochlorobimane (MCB) in a fluoroemtric microplate assay and characterized by
      their Michaelis-Menten kinetics. The inhibitory potential of ethacrynic acid was
      very effective with IC50-values between 0.9 and 5.8 microM depending on substrate
      and strain. The inhibitory effect of dicumarol was 10 times lower. Glutathione
      affinity chromatography purified GST enzymes of two different B. tabaci strains
      appeared as a single band on SDS-PAGE and had a molecular mass of 23.5 kDa
      determined by MALDI mass spectrometry. The N-terminus of the purified enzyme was
      sequenced by Edman degradation. The nearly full-length cDNA of the enzyme was
      isolated by RT-PCR using a degenerate primer derived from the N-terminal amino
      acid sequence and contained an open reading frame encoding a 194-amino-acid
      protein. Comparison of the deduced amino acid sequence with GSTs from other
      species revealed that the enzyme is closely related to insect class sigma GSTs.

PMID- 15041017
TI  - A genomic BAC library and a new BAC-GFP vector to study the holocentric pest
      Spodoptera frugiperda.
AB  - Two genomic tools for the study of Lepidoptera and the holocentric structure of
      their chromosomes are presented in this paper. A bacterial artificial chromosome
      (BAC) library was constructed using nuclear DNA partially digested with HindIII
      from eggs of Spodoptera frugiperda. The library contains a total of 36,864 clones
      with an average insert size of 125 kb, which corresponds to approximately 11.5
      genome equivalents. Hybridization screening of the library was performed with
      eight single-copy genes, giving an average hit of 10 clones per marker gene.
      Colinearity between the genome and BACs was demonstrated at the triose phosphate
      isomerase (tpi) locus. Probing of the library with a PCR fragment internal to the
      18S ribosomal gene allowed an estimation of the rDNA locus size close to 115
      repeats per haploid genome. A new vector (pBAC3.6eGFP) for transient transfection
      into S. frugiperda cell lines has been constructed. It is based on the BAC
      vector, pBAC3.6e, in which a gene encoding GFP was inserted under the control of
      the densovirus P9 promoter. This vector has the advantage to accommodate large
      genomic inserts and to be transfected in a large lepidopteran host range. It was
      used to construct a second BAC library from Sf9 cell nuclear DNA in order to
      allow a comparison between somatic and cell line genome organization.

PMID- 15041018
TI  - Sequence variability in the fibroin-H intron of domesticated and wild silk moths.
AB  - The single intron of the heavy-chain fibroin gene in domesticated (Bombyx mori)
      and wild (B. mandarina) silk moths has a length of approximately 1000
      nucleotides. It is located only 57 bp from the gene's core promoter and harbors
      multiple AT-rich regulatory elements that have been found to enhance the basal
      level of transcription in vitro. In this work, the intronic nucleotide
      variability among members of both Bombyx species is analyzed. The intron
      sequences of B. mori strains k120 and Nistari, as well as B. mandarina specimens
      from Japan and Korea, were obtained. This information was compared with the
      previously reported sequences of B. mori strains p50 and C-108, as well as an
      additional B. mandarina specimen collected in Japan. We found a total of 26
      variant positions, including variants shared by members of both species and
      species-specific changes. The potential functional role of these variants was
      investigated by using the program MatInspector to search for putative binding
      sites of transcription factors within the intron. We detected a multitude of
      putative binding elements distributed along the entire intronic sequence. Among
      them, 22 correspond to protein binding domains that are known to regulate fibroin
      transcription. The mapping of multiple variant positions within these putative
      binding sequences as well as in known regulatory elements of the intron argue for
      functional significance on the regulation of transcription.

PMID- 15041019
TI  - Hydrolysis of organophosphorus insecticides by in vitro modified carboxylesterase
      E3 from Lucilia cuprina.
AB  - Resistance of the blowfly, Lucilia cuprina, to organophosphorus (OP) insecticides
      is due to mutations in LcalphaE7, the gene encoding carboxylesterase E3, that
      enhance the enzyme's ability to hydrolyse insecticides. Two mutations occur
      naturally, G137D in the oxyanion hole of the esterase, and W251L in the acyl
      binding pocket. Previous in vitro mutagenesis and expression of these
      modifications to the cloned gene have confirmed their functional significance.
      G137D enhances hydrolysis of diethyl and dimethyl phosphates by 55- and 33-fold,
      respectively. W251L increases dimethyl phosphate hydrolysis similarly, but only
      10-fold for the diethyl homolog; unlike G137D however, it also retains ability to
      hydrolyse carboxylesters in the leaving group of malathion (malathion
      carboxylesterase, MCE), conferring strong resistance to this compound. In the
      present work, we substituted these and nearby amino acids by others expected to
      affect the efficiency of the enzyme. Changing G137 to glutamate or histidine was
      less effective than aspartate in improving OP hydrolase activity and like G137D,
      it diminished MCE activity, primarily through increases in Km. Various
      substitutions of W251 to other smaller residues had a broadly similar effect to
      W251L on OP hydrolase and MCE activities, but at least two were quantitatively
      better in kinetic parameters relating to malathion resistance. One, W251G, which
      occurs naturally in a malathion resistant hymenopterous parasitoid, improved MCE
      activity more than 20-fold. Mutations at other sites near the bottom of the
      catalytic cleft generally diminished OP hydrolase and MCE activities but one,
      F309L, also yielded some improvements in OP hydrolase activities. The results are
      discussed in relation to likely steric effects on enzyme-substrate interactions
      and future evolution of this gene.

PMID- 15041020
TI  - Molecular basis of Colorado potato beetle adaptation to potato plant defence at
      the level of digestive cysteine proteinases.
AB  - Potato synthesises high levels of proteinase inhibitors in response to insect
      attack. This can adversely affect protein digestion in the insects, leading to
      reduced growth, delayed development and lowered fecundity. Colorado potato beetle
      overcomes this defence mechanism by changing the composition of its digestive
      proteinases. The induced cysteine proteinases in the adapted gut sustain a normal
      rate of protein hydrolysis either by inactivating the inhibitors by cleavage or
      by insensitivity to the inhibitors as a result of high Kis. In this study cDNA
      clones of cysteine proteinases in adapted guts were isolated by nested PCR on the
      basis of N-terminal sequences previously determined for purified enzymes (Gruden
      et al., 2003). The cysteine proteinase cDNAs can be classified into three groups:
      intestains A, B and C. The amino acid identity is more than 91% within and 35-62%
      between the groups. They share 43-50% identity to mammalian cathepsins S, L, K,
      H, J and cathepsin-like enzymes from different arthropods. Homology modelling
      predicts that intestains A, B and C follow the general fold of papain-like
      proteinases. Intestains from each group, however, differ in some specific
      structural characteristics in the S1 and S2 binding sites that could influence
      enzyme-inhibitor interaction and thus, provide different mechanisms of resistance
      to inhibitors for the different enzymes. Gene expression analysis revealed that
      the intestains A and C, but not B, are induced twofold by potato plants with high
      levels of proteinase inhibitors.

PMID- 15041021
TI  - Identification of two mariner-like elements in the genome of the mosquito
      Ochlerotatus atropalpus.
AB  - Two distinct mariner-like elements, Atmar-1 and Atmar-2, were isolated from the
      genome of the mosquito Ochlerotatus atropalpus. Full-sized Atmar-1 elements,
      obtained by screening a genomic library, have a 1293-bp consensus sequence with
      27-bp inverted terminal repeats and a 1047-bp open reading frame (ORF) encoding
      the transposase. The Atmar-2 elements were amplified by polymerase chain reaction
      from genomic DNA and contain the central part of the transposase ORF. Individual
      clones of both mariner elements contain deletions, frameshifts, and stop codons.
      The Atmar-1 elements are present in 370-1200 copies, while the Atmar-2 elements
      are present in approximately 100-300 copies per haploid genome. One of the Atmar
      1 elements, Atmar-1.33, could be mobilized, suggesting the presence of functional
      Atmar-1 elements elsewhere in the genome. Phylogenetic analysis demonstrated that
      Atmar-1 elements belong to the irritans subfamily and Atmar-2 elements to the
      cecropia subfamily of mariner elements.

PMID- 15041022
TI  - Purification and characterization of Manduca sexta serpin-6: a serine proteinase
      inhibitor that selectively inhibits prophenoloxidase-activating proteinase-3.
AB  - The proteolytic activation of prophenoloxidase (proPO) is a critical defense
      mechanism in insects and crustaceans. We have isolated three prophenoloxidase
      activating proteinases (PAPs) from cuticular extracts or hemolymph of Manduca
      sexta pharate pupae, which are negatively regulated by serpin-1J and serpin-3. To
      test if other serpins may also inhibit the PAPs, we fractionated the induced
      hemolymph by ammonium sulfate precipitation, gel filtration, and lectin affinity
      chromatography. A 47 kDa protein, designated M. sexta serpin-6, was identified in
      concanavalin A-bound fractions, which formed an SDS-stable complex with PAP-3.
      This inhibitor, not recognized by the serpin-1 or serpin-3 antibodies, was
      further purified on HPLC anion exchange and hydroxylapatite columns. The
      molecular mass and isoelectric point of serpin-6 were found to be 46,710 +/- 10
      Da and 5.4. While its amino terminus was blocked, we obtained five internal
      peptide sequences, one of which is highly similar to M. sexta serpins-1, -2, and 
      3. Serpin-6 strongly inhibited PAP-3 but not PAP-1 or PAP-2, suggesting that the
      proPO activation by PAPs is differentially regulated by multiple serpins. When
      included in the reaction mixture containing proPO, PAP-3, and its cofactor,
      serpin-6 efficiently blocked the cleavage activation of proPO.

PMID- 15041023
TI  - Mutations in acetylcholinesterase associated with insecticide resistance in the
      cotton aphid, Aphis gossypii Glover.
AB  - Two acetylcholinesterase genes, Ace1 and Ace2, have been fully cloned and
      sequenced from both organophosphate-resistant and susceptible clones of cotton
      aphid. Comparison of both nucleic acid and deduced amino acid sequences revealed
      considerable nucleotide polymorphisms. Further study found that two mutations
      occurred consistently in all resistant aphids. The mutation F139L in Ace2
      corresponding to F115S in Drosophila acetylcholinesterase might reduce the enzyme
      sensitivity and result in insecticide resistance. The other mutation A302S in
      Ace1 abutting the conserved catalytic triad might affect the activity and
      insecticide sensitivity of the enzyme. Phylogenetic analysis showed that insect
      acetylcholinesterases fall into two subgroups, of which Ace1 is the paralogous
      gene whereas Ace2 is the orthologous gene of Drosophila AChE. Both subgroups
      contain resistance-associated AChE genes. To avoid confusion in the future work,
      a nomenclature of insect AChE is also suggested in the paper.

PMID- 15041024
TI  - Amblyomma americanum salivary glands: double-stranded RNA-mediated gene silencing
      of synaptobrevin homologue and inhibition of PGE2 stimulated protein secretion.
AB  - Protein secretion into the saliva from the tick salivary glands is due to
      exocytosis of vesicular membrane bound granular material regulated by SNARE
      complex proteins after salivary gland stimulation by PGE2 [Insect Biochem. Mol.
      Biol. 32 (2002) 1711]. Proteins associated with vesicles (v-SNAREs) are essential
      components of the exocytotic process. Synaptobrevin is a key v-SNARE in all
      secreting cells studied to date. A vesicle-associated synaptobrevin cDNA fragment
      homologue from the salivary glands of partially fed lone star tick females was
      cloned and sequenced. Double-stranded (ds) RNA interference (RNAi) is an
      effective method to silence specific gene expression. The functional role of
      synaptobrevin in protein secretion in partially fed tick salivary glands was
      studied with an in vitro RNAi method. Incubation of isolated salivary glands with
      double-stranded RNA (dsRNA) transcribed from a tick salivary gland synaptobrevin
      cDNA fragment resulted in decreased expression of the transcript, a reduction in
      the level of synaptobrevin protein and inhibition of PGE2 stimulated
      anticoagulant protein secretion by isolated salivary glands. We demonstrate the
      applicability of RNAi for studying individual steps in the mechanism of PGE2
      stimulated exocytosis in the salivary glands of ixodid ticks.

PMID- 15041025
TI  - Can fat explain the human brain's big bang evolution?-Horrobin's leads for
      comparative and functional genomics.
AB  - When David Horrobin suggested that phospholipid and fatty acid metabolism played
      a major role in human evolution, his 'fat utilization hypothesis' unified
      intriguing work from paleoanthropology, evolutionary biology, genetic and nervous
      system research in a novel and coherent lipid-related context. Interestingly,
      unlike most other evolutionary concepts, the hypothesis allows specific
      predictions which can be empirically tested in the near future. This paper
      summarizes some of Horrobin's intriguing propositions and suggests as to how
      approaches of comparative genomics published in Cell, Nature, Science and
      elsewhere since 1997 may be used to examine his evolutionary hypothesis. Indeed,
      systematic investigations of the genomic clock in the species' mitochondrial DNA,
      the Y and autosomal chromosomes as evidence of evolutionary relationships and
      distinctions can help to scrutinize associated predictions for their validity,
      namely that key mutations which differentiate us from Neanderthals and from great
      apes are in the genes coding for proteins which regulate fat metabolism, and
      particularly the phospholipid metabolism of the synapses of the brain. It is
      concluded that beyond clues to humans' relationships with living primates and to
      the Neanderthals' cognitive performance and their disappearance, the suggested
      molecular clock analyses may provide crucial insights into the biochemical
      evolution-and means of possible manipulation-of our brain.

PMID- 15041026
TI  - Fatty acids and homocysteine levels in patients with recurrent depression: an
      explorative pilot study.
AB  - Major depressive disorders (MDD) and cardiovascular disease are mutually
      associated. They share signs and symptoms of the "metabolic syndrome". Two
      observations that may be causally related with the metabolic syndrome and
      therefore with both MDD and cardiovascular disease are a decrease in omega-3
      polyunsaturated fatty acids (PUFAs) and a rise in plasma homocysteine (tHcy)
      levels. Both the rise in tHcy and the decrease in omega-3 PUFAs may be associated
      with enhanced lipid peroxidation. We exploratively studied 44 randomly chosen
      patients out of a cohort of 134 patients with the recurrent form of MDD (MDD-R).
      We measured tHcy levels together with saturated FAs, monounsaturated fatty acids
      (MUFAs) and PUFAs of the omega-3, omega-6 and omega-9 series in plasma and
      erythrocytes. Levels were compared with laboratory reference values. The main
      findings were a decrease in the erythrocytes of C22:5omega-3, C22:6omega-3,
      C24:1omega-9 and C20:3omega-9 and in the plasma a decrease in C24:1omega-9 and
      C20:3omega-9. The only significant association we found was between the total of
      omega-6 fatty acids and plasma tHcy. The FA alterations were found in patients
      although most of them were clinically recovered, suggesting that the alterations
      may represent a biological" trait" marker for recurrent depression.

PMID- 15041027
TI  - In vivo MR spectroscopy in diagnosis and research of neuropsychiatric disorders.
AB  - Magnetic resonance spectroscopy is one of the most important tools for
      quantitative analysis of chemical composition and structure, and this non
      invasive technique is now being applied in vivo to study biochemical processes in
      those neuropsychiatric disorders that are part of the phospholipid spectrum.
      Interpretation of a clinical magnetic resonance spectrum can provide information
      about membrane phospholipid turnover, cellular energetics, neuronal function,
      selected neurotransmitter activity and intracellular pH. Cerebral proton and
      phosphorus magnetic resonance spectroscopy findings are summarized in relation to
      schizophrenia, dyslexia and chronic fatigue syndrome.

PMID- 15041028
TI  - Docosahexaenoic acid in the diet: its importance in maintenance and restoration
      of neural membrane function.
AB  - The central nervous system has the second highest concentration of lipids after
      adipose tissue. Long chain fatty acids, particularly arachidonic acid and
      docosahexaenoic acid, are integral components of neural membrane phospholipids.
      Alterations in neural membrane phospholipid components cannot only influence
      crucial intracellular and intercellular signaling but also alter many membrane
      physical properties such as fluidity, phase transition temperature, bilayer
      thickness, and lateral domains. A deficiency of docosahexaenoic acid markedly
      affects neurotransmission, membrane-bound enzyme and ion channel activities, gene
      expression, intensity of inflammation, and immunity and synaptic plasticity.
      Docosahexaenoic acid deficiency is associated with normal aging, Alzheimer
      disease, hyperactivity, schizophrenia, and peroxisomal disorders. Although the
      molecular mechanism of docosahexaenoic acid involvement in the disorders remains
      unknown, the supplementation of docosahexaenoic acid in the diet restores gene
      expression and modulates neurotransmission. Also, improvements are seen in signal
      transduction processes associated with behavioral deficits, learning activity,
      peroxisomal disorders, and psychotic changes in schizophrenia, depression,
      hyperactivity, stroke, and Alzheimer disease.

PMID- 15041029
TI  - Regulation of the specific release of arachidonic acid by cytosolic phospholipase
      A2.
AB  - Cytosolic phospholipase A(2) alpha (cPLA(2)alpha) is the only PLA(2) that
      exhibits specificity for sn-2 arachidonic acid consistent with its primary role
      in mediating the agonist-induced release of arachidonic acid for eicosanoid
      production. It is subject to complex mechanisms of regulation that ensure that
      levels of free arachidonic acid are tightly controlled. The calcium-induced
      translocation of cPLA(2)alpha from the cytosol to membrane regulates its
      interaction with phospholipid substrate. cPLA(2)alpha is additionally regulated
      by phosphorylation on sites in the catalytic domain. Because of its central
      position as the upstream regulatory enzyme for initiating production of several
      classes of bioactive lipid mediators (leukotrienes, prostaglandins and platelet
      activating factor), it is a potentially important pharmacological target for the
      control of inflammatory diseases.

PMID- 15041030
TI  - The investigation of cytosolic phospholipase A2 using ELISA.
AB  - Two studies of the behaviour of cytosolic phospholipase A(2) (cPLA(2)) in the red
      blood cell (RBC), as measured by ELISA, are described. In the first study we show
      a significant increase in cPLA(2) in patients with schizophrenia compared to
      controls and suggest that this measure, if corroborated, could be used as a
      diagnostic marker. In a second study we found that washing the RBC introduced an
      unknown confounding variable which led us to reject this study. A subsequent
      investigation of washing red cells showed that the washing effect may be due to a
      plasma factor likely to be more than 5kDa MW which can be removed from red cells
      by washing with buffers. When the cells are washed, the concentration of cPLA(2)
      in the red cell, as measured by ELISA, significantly increases. We advise against
      washing the red cell in any study that involves measuring cPLA(2) by ELISA.

PMID- 15041031
TI  - Clinical trials of fatty acid treatment in ADHD, dyslexia, dyspraxia and the
      autistic spectrum.
AB  - Considerable clinical and experimental evidence now supports the idea that
      deficiencies or imbalances in certain highly unsaturated fatty acids may
      contribute to a range of common developmental disorders including ADHD, dyslexia,
      dyspraxia and autistic spectrum disorders (ASD). Definitive evidence of a causal
      contribution, however, can only come from intervention studies in the form of
      randomised, double-blind, placebo-controlled trials. Published studies of this
      kind are still fairly few in number, and mainly involve the diagnostic categories
      of ADHD and dyslexia, although other trials involving individuals with dyspraxia
      or ASD are in progress. The main findings to date from such studies are reviewed
      and evaluated here with the primary aim of guiding future research, although
      given that fatty acid supplementation for these conditions is already being
      adopted in many quarters, it is hoped that some of the information provided may
      also help to inform clinical practice.

PMID- 15041032
TI  - Eicosapentaenoic acid and gamma-linolenic acid increase hippocampal
      concentrations of IL-4 and IL-10 and abrogate lipopolysaccharide-induced
      inhibition of long-term potentiation.
AB  - Inflammatory changes in brain exert a negative impact on cognitive function and
      in animal studies, these changes are associated with impairment in hippocampal
      dependent learning paradigms and in long-term potentiation (LTP), which is a
      putative biological substrate for learning and/or memory. Lipopolysaccharide
      (LPS), a component of the cell wall of gram negative bacteria, induces
      inflammatory changes in the brain and leads to impairment of LTP. Since
      eicosapentaenoic acid (EPA) inhibits LPS-induced changes in vitro, we assessed
      the possibility that treatment of rats with EPA, alone or in combination with
      gamma-linolenic acid (GLA) might inhibit LPS-induced changes in vivo. The data
      presented indicate that the LPS-induced inhibition of LTP and decrease in
      hippocampal concentration of anti-inflammatory cytokines IL-10 and IL-4 are
      blocked in rats treated with EPA, GLA or both. The evidence suggests that these
      effects may be coupled with fatty acid-induced up-regulation of peroxisome
      proliferator-activated receptor-gamma which possesses known anti-inflammatory
      effects.

PMID- 15041033
TI  - The use of eicosapentaenoic acid in the treatment of chronic fatigue syndrome.
AB  - There is evidence that there is an association between chronic fatigue syndrome,
      a condition of unknown aetiology, and essential fatty acids. This evidence is
      based on the actions of essential fatty acids, the results of proton
      neurospectroscopy studies, and essential fatty acid trial data. A series of
      patients with chronic fatigue syndrome were treated solely with a high
      eicosapentaenoic acid-containing essential fatty acid supplement. All showed
      improvement in their symptomatology within eight to 12 weeks. These results,
      which are consistent with a recent detailed report of cerebral and clinical
      changes associated with a high intake of eicosapentaenoic acid, suggest that this
      n-3 highly unsaturated fatty acid may offer the hope of effective treatment for
      at least some patients with chronic fatigue syndrome.

PMID- 15041035
TI  - Cerebral metabolism in male patients with schizophrenia who have seriously and
      dangerously violently offended: a 31P magnetic resonance spectroscopy study.
AB  - There is biochemical evidence to suggest that membrane phospholipid metabolism
      may be impaired in some patients with schizophrenia. The aim of this study was to
      test the hypothesis that patients with schizophrenia who have violently offended
      while psychotic suffer from changes in cerebral phospholipid metabolism. Cerebral
      31-phosphorus magnetic resonance spectroscopy was carried out in 15 male patients
      with schizophrenia who had violently offended (homicide, attempted murder, or
      wounding with intent to cause grievous bodily harm) while psychotic and in a
      control group of 13 age-matched healthy male control subjects. Spectra were
      obtained from 70x70x70mm(3) voxels in the brain using an image-selected in vivo
      spectroscopy pulse sequence. betaNTP was lower (P < 0.04) and gammaNTP was higher
      (P < 0.04) in the patient group compared with the normal control group. Our
      results are suggestive of increased cerebral energy metabolism taking place in
      the forensic patients.

PMID- 15041034
TI  - Acetylcholine mediated vasodilatation in the microcirculation of patients with
      chronic fatigue syndrome.
AB  - The aetiology of chronic fatigue syndrome (CFS) remains controversial and a
      number of hypotheses have been put forward to explain it. Research into the
      condition is hindered by the considerable heterogeneity seen across patients but
      several reports have highlighted disturbances to cholinergic mechanisms in terms
      of central nervous system activity, neuromuscular function and autoantibodies to
      muscarinic cholinergic receptors. This paper examines an altogether separate
      function for acetylcholine and that is its role as an important and generalized
      vasodilator. Most diseases are accompanied by a blunted response to acetylcholine
      but the opposite is true for CFS. Such sensitivity is normally associated with
      physical training so the finding in CFS is anomalous and may well be relevant to
      vascular symptoms that characterise many patients. There are several mechanisms
      that might lead to ACh endothelial sensitivity in CFS patients and various
      experiments have been designed to unravel the enigma. These are reported here.

PMID- 15041036
TI  - A study of a genetic association between the PTGS2/PLA2G4A locus and
      schizophrenia.
AB  - Six single nucleotide polymorphisms (SNPs) present in the PTGS2/PLA2G4A locus
      were detected among 118 British family trios of schizophrenia patients. The
      transmission disequilibrium test showed that SNP4 located in the 5'-flanking
      region of the PLA2G4A gene was associated with schizophrenia and that the
      haplotype analysis also showed a genetic association between the PTGS2 gene and
      schizophrenia. Because these two genes are arranged in a head-to-head
      configuration and separated by just about 149kb of DNA, they may have a combined
      effect on susceptibility to schizophrenia in some cases.

PMID- 15041037
TI  - Nutrition and schizophrenia: beyond omega-3 fatty acids.
AB  - There are now five placebo-controlled trials of EPA in the treatment in
      schizophrenia, and four of these have given positive or partly positive findings.
      A cross-national ecological analysis of international variations in outcome of
      schizophrenia in relation to national dietary practices, showed that high
      consumption of sugar and of saturated fat is associated with a worse long-term
      outcome of schizophrenia. It is known that a high sugar, high fat diet leads to
      reduced brain expression of brain-derived neurotrophic factor (BDNF) which is
      responsible for maintaining the outgrowth of dendrites. Low brain BDNF levels
      also lead to insulin resistance which occurs in schizophrenia and is associated
      with diseases of the metabolic syndrome. It appears that the same dietary factors
      which are associated with the metabolic syndrome, including high saturated fat,
      high glycaemic load, and low omega-3 PUFA, may also be detrimental to the
      symptoms of schizophrenia, possibly through a common mechanism involving BDNF.

PMID- 15041038
TI  - A transgenic mouse model for T-cell ignorance of a glial autoantigen.
AB  - The fate of autoreactive CD4+T cells was investigated in HNT-TCR x GFAP-HA double
      transgenic mice, in which the majority of CD4+T cells is specific for a neo
      selfantigen expressed under a glial cell-specific promoter. These mice do not
      develop any clinical or histological signs of central or enteric nervous system
      autoimmunity. Although HA is transcribed in the thymus of GFAP-HA mice, similar
      numbers of CD4+ CD8- thymocytes, expressing comparable levels of the transgenic
      TCR, developed in HNT-TCR x GFAP-HA double transgenic and HNT-TCR single
      transgenic mice, indicating that HA-specific thymocytes are not negatively
      selected. In the periphery, the HA-specific T cells remained similarly unaffected
      as they displayed a naive phenotype and were neither deleted nor anergized.
      Finally, immunization of HNT-TCR x GFAP-HA mice with the HNT peptide in CFA
      and/or in vivo depletion of CD25+ cells did not reverse this state of immune
      ignorance as judged by the lack of clinical manifestations of intestinal and
      neurological disease in these mice. Taken together these data demonstrate a
      profound state of immune ignorance towards a self-antigen expressed in the
      enteric and central nervous system.

PMID- 15041040
TI  - Intracellular localization of histidyl-tRNA synthetase/Jo-1 antigen in T24 cells
      and some other cells.
AB  - Anti-Jo-1 antibody is characteristic of patients suffering from autoimmune
      disease myositis. Since the antigen has been identified to be a histidyl-tRNA
      synthetase (HisRS), it is reasonable to suppose that it localizes mainly in the
      cytoplasm. However, contradictory results (localization in the nucleus,
      cytoplasm, or both) have been reported on this point. This study examined whether
      or not HisRS tagged with a green fluorescent protein (GFP) localizes, even if
      partially, in particular regions of the nucleus. The cDNA of human HisRS was
      ligated into either pEGFP-N1 or pEGFP-C1, and transfected into T24 cells.
      Transfectants expressed either HisRS-GFP or GFP-HisRS, both with the expected LDS
      PAGE mobility. Observations with a confocal fluorescence microscope revealed
      that, in most cells, both GFP-tagged HisRSs were present solely in the cytoplasm.
      Occasional fluorescent spots seen in the nuclear region coincided with the
      immunofluorescent stain of the nuclear pore complex, indicating that they
      represent GFP-tagged HisRS in the cytoplasm that had invaginated deeply into the
      nucleus. Transient transfection into HeLa and L6 cells also resulted in the
      cytoplasmic localization of GFP-tagged HisRSs. These results indicate that HisRS
      would localize predominantly in the cytoplasm. The possible nuclear antigens
      other than HisRS that might be detected by anti-Jo-1 antisera are discussed.

PMID- 15041041
TI  - Frequency and significance of anti-glutathione S-transferase autoantibody (anti
      GST A1-1) in autoimmune hepatitis.
AB  - Several phase I and phase II multi-drug metabolizing enzymes, such as CYP2D6,
      3A4, and UGTA1, were reported to act as immunotargets in a subset of autoimmune
      hepatitis and hepatic autoimmunity. However, it is uncertain whether glutathione
      S-transferase (GST) A1-1, one of the phase II multi-drug metabolizing enzymes, is
      also an immunotarget in autoimmune hepatitis. So, in the present study, we
      investigated the frequency and significance of anti-GST A1-1 in sera from
      patients with autoimmune hepatitis. A total of 74 serum samples from patients
      with autoimmune hepatitis were examined in the present study. As controls, 20
      serum samples from patients with primary biliary cirrhosis, 10 serum samples from
      patients with primary sclerosing cholangitis, 40 serum samples from patients with
      liver cirrhosis type B and C, 32 serum samples from patients with systemic lupus
      erythematosus, and 20 serum samples from normal controls were used. Anti-GST A1-1
      antibody was determined by immunoblotting using the recombinant full-length GST
      A1-1 protein as the antigen. The immunofluorescent staining pattern of anti-GST
      A1-1 was investigated using rat liver and kidney sections. We compared
      clinicopathologic findings between anti-GST A1-1-positive and -negative
      autoimmune hepatitis patients. Anti-GST A1-1 was detected in 12 (16%) of 74
      patients with autoimmune hepatitis, however, it was not detected in any control
      serum samples except for two patients with primary biliary cirrhosis. The
      immunofluorescence staining pattern of anti-GST A1-1 was found to be unique and
      different from those of anti-mitochondrial antibody or anti-liver-kidney
      microsome type 1 antibody. Anti-GST A1-1 coexisted with other autoantibodies such
      as anti-nuclear or anti-smooth muscle antibodies, but did not coexist with anti
      soluble liver antigen/liver pancreas. Anti-GST A1-1-positive autoimmune hepatitis
      patients had severe clinical features and a poor prognosis compared with anti-GST
      A1-1-negative patients. These findings suggested that despite the low frequency,
      anti-GST A1-1 might be the marker of an early progression in autoimmune
      hepatitis.

PMID- 15041039
TI  - Autoimmune diabetes is blocked in Stat4-deficient mice.
AB  - Signal transducers and activators of transcription (STAT) proteins are activated
      in response to many cytokines, growth factors and hormones. STAT4 mediates IL-12
      signaling and regulates T helper 1 (Th1) cell differentiation. Both IL-12 and Th1
      cell activation participate in the development of autoimmune diabetes. In this
      study, we investigated the role of STAT4 in autoimmune diabetes. We crossbred
      Stat4 deficient (Stat4-/-) mice with nonobese diabetic (NOD) mice to generate the
      Stat4-/- NOD model. In Stat4-/- NOD mice, serum levels of both IFN-gamma and IL-2
      were significantly reduced as compared to the controls. Insulin secretion in
      pancreatic islets was preserved in Stat4-/- NOD mice. Significantly, disruption
      of Stat4 activation completely prevented the development of spontaneous diabetes
      in NOD mice. This study reveals the important role of STAT4 in autoimmune
      diabetes pathogenesis.

PMID- 15041042
TI  - A peptide that shares similarity with bacterial antigens reverses thrombogenic
      properties of antiphospholipid antibodies in vivo.
AB  - OBJECTIVE: The factors causing production of antiphospholipid (aPL) antibodies
      remain unidentified. Recently, studies have shown that aPL and anti
      beta2Glycoprotein I (anti-beta2GPI) antibodies with pathogenic properties can be
      generated with peptides from bacterial and viral origin, that mimic regions of
      beta2GPI. These data suggest a molecular mimicry between bacterial/viral antigens
      and self-proteins. In this study we examined the ability of a synthetic peptide
      (named peptide A, NTLKTPRVGGC) that shares similarity with common bacterial
      antigens, to reverse aPL-mediated thrombosis in mice in vivo. Peptide A is also
      found in region I/II of beta2GPI. A scrambled form of peptide A (named scA,
      GTKGCPNVRLT) was used as a control. METHODS AND RESULTS: Sera from 29 patients
      with APS bound to peptide A but not to peptide scA by ELISA in a dose-dependent
      fashion. Cardiolipin (CL) liposomes inhibited the binding of IgG-APS by ELISA to
      peptide A by 35% and to CL by 56%. The inhibition of binding to cardiolipin and
      to peptide A was enhanced by addition of beta2GPI to the liposomes. CL/peptide A
      liposomes but not peptide A alone inhibited the binding of IgG-APS to peptide A.
      beta2GPI alone did not inhibit binding of IgG-APS to peptide A, to beta2GPI or to
      CL. For the in vivo experiments, CD1 mice in groups of 20 were injected with
      affinity purified aPL antibodies or with control IgG-NHS twice intraperitoneally.
      Seventy hours after the first injection, and 30 min before the surgical procedure
      (induction of experimental thrombus) mice were infused i.v. in each group with
      either peptide A or with peptide scA. The femoral vein of the anesthetized mice
      were dissected to examine the dynamics of an induced thrombus in treated and
      control mice. The mean aCL titer of mice injected with aPL was 60 GPL units. Mice
      treated with aPL and infused with peptide scA produced significantly larger
      thrombi when compared to mice treated with IgG-NHS and peptide scA (2466+/-462
      microm2 vs 772.5+/-626.4 microm2). Treatment with peptide A significantly
      decreased thrombus size in mice injected with aPL antibodies (1063+/-890 microm2
      compared to 2466+/-462 microm2). CONCLUSION: The data indicates that a synthetic
      peptide that shares similarity with common bacterial antigens and with regions of
      beta2GPI is capable to inhibit thrombogenic properties of aPL in mice. This may
      have important implications in designing new modalities of prevention and/or
      treatment of thrombosis in APS.

PMID- 15041044
TI  - Antinucleosome antibodies in SLE: a two-year follow-up study of 101 patients.
AB  - We prospectively analyzed the diagnostic sensitivity and specificity as well as
      the clinical relevance of antinucleosome antibodies in SLE. One hundred and one
      consecutive SLE patients were followed for 3 years. Three serial serum samples
      from each patient were tested for antinucleosome antibodies by ELISA (optimum cut
      off value 10 U/ml), and for anti-dsDNA antibody (by ELISA and IIF on Crithidia
      luciliae), and anti-dsDNA avidity (by Scatchard plot analysis). Sera from 100
      healthy individuals (HI), 35 patients with systemic sclerosis (SSc), 30 with
      primary Sjogren's syndrome (SS), 20 with rheumatoid arthritis (RA) and 48 with
      infectious diseases (ID), were assayed as controls. SLE activity and damage were
      evaluated using the ECLAM score and the SLICC/ACR index. At baseline,
      antinucleosome antibodies were found in 87 patients with SLE (86.1%), in 8
      patients with SSc (22.8%), in 2 HI (2%), and in 1 ID (2.1%). The sensitivity and
      specificity of antinucleosome testing for SLE were 86.1% and 95.3%, respectively.
      The prevalence of antinucleosome antibodies in SLE was significantly higher than
      that of anti-dsDNA antibodies, with a correlation between them. No relevant
      relationship was found between antinucleosome antibodies and disease features,
      including renal involvement, disease activity, and disease damage. During follow
      up, no significant variation was observed in antinucleosome level, nor in anti
      dsDNA antibody level or avidity. We conclude that antinucleosome antibodies are
      commonly found in SLE. Low antibody levels can be detected in SSc, whereas
      medium/high levels are highly specific for SLE. Their clinical relevance during
      the disease course and utility for monitoring the individual patient seem to be
      poor.

PMID- 15041043
TI  - IL10 resistant PGS2 expression in at-risk/Type 1 diabetic human monocytes.
AB  - Aberrant prostaglandin synthase 2 (PGS2/COX2) expression constitutes an antigen
      presenting cell (APC) dysfunction seen in monocytes of humans at risk for or with
      Type 1 diabetes. During endotoxin activation of PGS2 expression in healthy
      monocytes, granulocyte-monocyte colony stimulating factor (GM-CSF) is activated
      and, in turn, promotes PGS2 gene activation. GM-CSF is considered a major target
      the action for IL10 in its suppression of PGS2. We found that the PGS2 expression
      in monocytes from 47% of at-risk and diabetic humans tested were highly resistant
      to suppression by IL10 (maintaining > or =50% of their untreated expression), and
      had significantly increased GM-CSF production in vitro (1043+/-SD2798
      pg/10(6)cells, subject n=35, vs 29.7+/-SD91 pg/10(6)cells, control n=20;
      P=0.0165). The PGS2 insensitivity to IL10 of these cells was not due to a lack of
      IL10 functionality or its suppression of GM-CSF. In contrast to its effects on
      PGS2, IL10 regulation of GM-CSF and other monocyte factors (i.e., DR, IL1beta,
      TNFalpha, IL12, CD54, and CD64) remained intact. These findings suggest that the
      inability of IL10 to properly downregulate PGS2 gene expression may contribute to
      its dysregulation in Type 1 diabetes.

PMID- 15041045
TI  - Methods of choice for diagnostic antinuclear antibody (ANA) screening: benefit of
      adding antigen-specific assays to immunofluorescence microscopy.
AB  - OBJECTIVES: To evaluate and compare the performances of three enzyme-immunoassays
      (EIAs) and a double radial immunodiffusion (DRID) test in addition to
      immunofluorescence (IF) microscopy for routine laboratory screening of patient
      sera sent for antinuclear antibody (ANA) analysis. METHODS: 3079 consecutive
      patient sera sent for routine testing of ANA were analysed by IF microscopy on
      HEp-2 cells (IF-ANA), three different ANA-EIAs, and a DRID test for antibodies
      against extractable nuclear antigens. The IF-ANA and DRID tests were regarded as
      reference methods. RESULTS: By IF-ANA and/or DRID, 375 sera (12%) turned out ANA
      positive. A further 171 sera (6%) were positive by EIA, but could not be
      confirmed either by IF microscopy or DRID. 32 of the 375 ANA-positive (9%) sera
      were negative by IF microscopy, but had precipitating antibodies against Ro/SS-A
      (52 and/or 60 kD). CONCLUSIONS: Different assays for ANA analysis give
      overlapping results to a certain extent, but are by no means interchangeable.
      Thus, different ANA tests reflect different aspects of these autoantibodies. The
      diagnostic utility of ANA testing still mainly refers to IF-microscopy and
      precipitin tests. IF-ANA should not be abandoned as the golden standard in
      clinical routine, until diagnostic and classification criteria for systemic lupus
      erythematosus and other systemic inflammatory autoimmune diseases have been
      revised. However, in addition we strongly advocate that a specific test for anti
      Ro/SS-A antibodies is always included.

PMID- 15041046
TI  - cDNA microarray analysis of gene expression in coeliac disease jejunal biopsy
      samples.
AB  - In coeliac disease in the jejunum of a genetically susceptible person wheat
      gliadin and related prolamins from rye and barley trigger an immunological
      reaction, which induces small-bowel mucosal transformations, villous atrophy and
      crypt hyperplasia. Though CD4+ specific T cells, intraepithelial lymphocytes,
      infiltrating plasma cells and autoantibodies are known to have an effect on the
      coeliac disease, the pathogenic mechanisms leading to the tissue injury remain to
      be elucidated. Our aim was to find novel gene transcripts, which might have a
      role in coeliac disease pathogenesis. The gene expression in duodenal biopsy
      samples from untreated coeliac patients (n=4), patients on gluten-free diet (n=4)
      and healthy controls (n=4) was studied by cDNA microarray analysis. The method
      allows monitoring of the expression of thousands of genes simultaneously.
      Compared to healthy controls, the expression of 156 and 60 genes was changed in
      untreated and treated coeliac disease, respectively. Between treated and
      untreated coeliac disease, 98 genes had altered expression. Of the 5184 genes or
      expressed sequence tags, altogether 263 were affected. Many of these genes are
      directly or indirectly connected to T-cell activation, B-cell maturation or
      epithelial cell differentiation. By the microarray method, numerous genes were
      found to evince altered mRNA expression in coeliac disease. The method holds
      promise in exploring the pathogenetic mechanisms in the small bowel and may
      reveal new target genes for the therapy of coeliac disease.

PMID- 15041047
TI  - Localization of osteopontin at calcification sites of cholesteatoma: possible
      role as a regulator of deposition of calcium phosphate in the middle ear.
AB  - OBJECTIVE: Recently, we showed that osteopontin (OPN), a major acidic
      phosphorylated glycoprotein of bone, participates in the pathological
      calcification that occurs as a result of chronic otitis media. To investigate the
      possibility of OPN as a common regulator of the pathological calcification in the
      middle ear, we here examined whether or not OPN is localized at the calcification
      sites of cholesteatoma, which is clearly different from chronic otitis media in
      the pathogenesis. METHODS: Middle ear tissues including cholesteatoma were
      obtained from 32 cases who underwent tympanoplasty. The tissues of 29 cases were
      used for the immunohistochemistry of OPN and CD68, the marker of macrophages, and
      in situ hybridization of OPN mRNA. And those of the other three for reverse
      transcriptase polymerase chain reaction (RT-PCR). RESULTS: Middle ear tissues
      including cholesteatoma were histologically classified as to the degree of
      calcification. In hyalinized tissues with macroscopic calcification, OPN was
      immunohistochemically found at the calcification sites. In inflammatory tissues
      with microscopic calcification, OPN was also found in the calcifying foci, and
      many OPN mRNA-expressing cells, as determined by in situ hybridization, were
      located near the foci. Moreover, immunohistochemical double staining for OPN and
      CD68 showed that the OPN-expressing cells were CD68-positive, indicating the
      cells were macrophages. In inflammatory tissues without calcification,
      immunohistochemistry of CD68 and in situ hybridization of OPN mRNA revealed that
      most OPN mRNA-expressing cells were CD68-positive. The expression of OPN mRNA in
      cholesteatoma tissues was also demonstrated by means of RT-PCR. CONCLUSION: OPN
      secreted by exudate macrophages was localized in the pathological calcification
      that occurs in association with cholesteatoma. These results are consistent with
      the observations in chronic otitis media. Therefore, it is suggested the
      possibility that OPN might contribute as a common regulator of the deposition of
      calcium phosphate in the middle ear.

PMID- 15041048
TI  - Monocular versus binocular vision in postural control.
AB  - OBJECTIVE: In previous studies about the control of posture there have been
      controversial findings. Our aim was to examine the role of monocular and
      binocular vision in controlling posture in quiet stance. METHODS: Twenty-eight
      normal subjects were tested. We used a force platform in measuring postural
      stability. In main experiment, postural stability was measured in four
      conditions: both eyes open (BEO), dominant eye open (DEO) non-dominant eye open
      (NDEO), and both eyes closed (BEC). In a further experiment, 11 subjects were
      tested in conditions where a vertical prism was placed in front of dominant eye.
      Prism was strong enough to cause diplopia. Our interest was to see, if diplopia
      affected the balance. RESULTS: In main experiment, at level of group the body
      sway in any of the three ocular (viewing) conditions did not differ from each
      other. At level of individuals, binocular vision was more effective on
      controlling posture in only half of subjects. In prism experiment, relative to
      normal binocular viewing the postural stability was modified in both prism
      conditions, but there was no difference between monocular and binocular viewing
      with prism. CONCLUSION: In quiet stance and in subjects with perfect binocular
      vision and stereopsis, the benefit out of binocular viewing in postural stability
      is subject-dependent. At the level of group, monocular vision provides equally
      good postural stability as binocular vision.

PMID- 15041049
TI  - Comparative analysis of serum homocysteine, folic acid and Vitamin B12 levels in
      patients with noise-induced hearing loss.
AB  - OBJECTIVE: The aim of the present study was to determine the levels of
      homocysteine, folic acid, and Vitamin B12 in subjects with noise-induced hearing
      loss. Furthermore, possible links between these parameters and noise-induced
      hearing loss were aimed to be evaluated. METHODS: In the present study, blood
      samples were obtained from all subjects after overnight fasting for biochemical
      analysis. We examined the levels of homocysteine, Vitamin B12 and folic acid
      levels in subjects with noise-induced hearing loss. Twenty-eight male patients
      with noise-induced hearing loss (mean age 37 +/- 5 year) were included in the
      study group whereas the control group was composed of 32 healthy male volunteers
      (mean age 36 +/- 4 year). RESULTS: It was found that homocysteine levels of
      subjects with noise-induced hearing loss as significantly high compared to
      healthy controls (P < 0.05). On the other hand, Vitamin B12 and folic acid levels
      of patients with noise-induced hearing loss were determined to be significantly
      low compared to the controls (P < 0.05 and < 0.01, respectively). CONCLUSION: Our
      findings indicate that there might be a link between increased homocysteine
      levels and noise-induced hearing loss. Since increased homocysteine levels cause
      elevated levels of free radicals in addition to its atherogenic and thrombogenic
      effects. Further experimental studies are needed to decipher how this
      relationship is linked.

PMID- 15041050
TI  - A comparison of patient satisfaction with conventional and nurse led outpatient
      follow-up after grommet insertion.
AB  - OBJECTIVE: The need to reduce costs while providing a first class service has led
      to the expansion in the role of nurses in otolaryngology practice in the National
      Health Service (NHS) in recent years. The aim of this study was to compare
      patient satisfaction with conventional and nurse led follow-up after grommet
      insertion. The hypothesis was that patient satisfaction is much greater with
      doctor led conventional follow-up as compared with nurse led out-patient follow
      up. METHODS: The study was performed using a questionnaire survey using a
      validated patient satisfaction questionnaire. RESULTS: Our results indicate that
      there is no statistically significant difference in the mean factorial scores for
      interpersonal skills and technical competence, physical surroundings, and
      convenience between the conventional and nurse led follow-up clinic. The overall
      patient satisfaction was higher with nurse led grommet follow-up clinic than with
      conventional doctor led out-patient follow-up. This was statistically significant
      (Mann-Whitney U = 1357.50, Z = 02.39, P = 0.01). The waiting time in out-patients
      was also significantly less in the nurse led grommet clinic. CONCLUSIONS: We
      conclude that nurses provide a high quality service resulting in high patient
      satisfaction. Nurse led grommet follow-up clinic has the potential for
      substantial reduction in outpatient access times in the NHS.

PMID- 15041051
TI  - Behcet's disease and hearing loss.
AB  - OBJECTIVES: The aim of this study was to determine the incidence and severity of
      hearing loss in different frequencies in Behcet's patients in a Turkish
      population. MATERIAL AND METHOD: Sixty-three consecutive cases with Behcet's
      syndrome and 63 sex- and age-matched healty subjects as control group were
      included in this study. A detailed history was taken, all patients underwent
      neuro-otolological, ophthalmologic and dermatologic examination. Audiometric pure
      tone thresholds at 125-8000Hz were obtained in all subjects in both groups. The
      results of the two groups were statistically evaluated by Chi-square, Student's-t
      and McNemar tests. RESULTS: In 35 patients (55%), a hearing loss equal or more
      than 30dB hearing level was detected. 24 of 35 patients (68%) showed hearing loss
      in the higher frequencies (6 and 8kHz). 12 of 35 patients (34%) showed hearing
      loss in speech frequencies (500-2000Hz). No relationship could be found between
      hearing loss and other system involvements in Behcet's group. Also there was no
      correlation between hearing loss and duration of the disease, but the mean age of
      Behcet's patients with hearing loss was found to be significantly higher than the
      mean age of the patients without hearing loss. CONCLUSION: We suggest that
      presence of hearing loss in Behcet's disease is prevalent and represents a fourth
      clinical symptom after oral, genital ulcers and skin lesions and especially there
      is a statistically significant hearing loss at high frequencies when compared
      with the speech frequencies.

PMID- 15041052
TI  - Expression of E-cadherin, and CD44s and CD44v6 and its association with prognosis
      in head and neck cancer.
AB  - OBJECTIVES: In the current study, the expression of E-cadherin, CD44s, and CD44v6
      has been noted as markers for tumor metastasis and prognosis in several tumors,
      so we examined whether or not E-cadherin, CD44s, and CD44v6 are useful markers
      for evaluating the prognosis of mesopharyngeal cancer patients. METHODS: The
      expression of E-cadherin, CD44s, and CD44v6, was evaluated immunohistochemically
      using monoclonal antibodies against epitopes of standard and variant proteins, in
      paraffin-embedded mesopharyngeal cancer tissues from 57 patients who had received
      curative therapy. RESULTS: Tumor tissues from 47 (82.5%) patients showed positive
      immunoreactivity with monoclonal antibody against E-cadherin, 43 (75.4%) patients
      showed positive expression with CD44, and 45 (78.9%) patients showed positive
      expression with CD44v6. The expression of CD44v6 was slightly correlated with
      tumor volume, and lymph node metastasis, and stage classification (P > 0.05).
      However, there was no significant correlation between the expression of E
      cadherin, CD44s and CD44v6 and clinicopathological characteristics. Concerning
      the prognosis, the survival period of patients with CD44s positive tumors was
      shorter than that of patients with CD44s negative tumors (18.2% versus 52.1%, 5
      year survival, P > 0.05). The survival period of patients with CD44v6 positive
      tumors was also shorter than that of patients with CD44v6 negative tumors (12.8%
      versus 55.6%, 5-year survival, P > 0.05). CONCLUSION: These results suggest that
      CD44v6 may be related to tumor invasion and metastasis, and both CD44s and CD44v6
      may be useful markers for poor prognosis in head and neck cancer.

PMID- 15041053
TI  - Concurrent chemo-radiotherapy for nasopharyngeal carcinoma.
AB  - OBJECTIVE: Because of the low incidence of nasopharyngeal carcinoma (NPC) in
      Japan, few studies have reported on the use of concurrent chemo-radiotherapy
      (CCRT) for treatment of this disease. The present study investigated the efficacy
      and toxicity of CCRT with Carboplatin (CBDCA) and UFT for NPC. PATIENTS AND
      METHODS: CCRT with injection of CBDCA and oral administration of UFT was given to
      21 patients in our institution during 1996-2000. We compared the patients treated
      with CCRT with those treated with RT alone from 1976 to 1995 or those treated
      with RT after chemotherapy (Pre-RT chemotherapy) from 1985 to 1995. Overall
      survival rate (OS), progression free survival rate (PFS) and cause specific
      survival (CSS) rate were analyzed. RESULTS: The actual 2-year OS, PFS, and CSS of
      CCRT were 85.7, 66.7 and 90%, respectively. The rates were improved compared to
      RT alone (37.9, 31.0, and 56.6%) and Pre-RT chemotherapy (58.8, 41.2, and 64.7%).
      The most frequent and severe acute toxicities were leukopenia (42.9%) and
      mucositis with grade 3-4 (28.6%), both of which eventually resolved. CONCLUSION:
      CCRT with CBDCA and UFT is considered to be an effective, convenient, and
      tolerable treatment, which improves survival rates for NPC patients. Therefore,
      we recommend this CCRT method for the treatment of NPC.

PMID- 15041055
TI  - Long term results of reconstruction plates in lateral mandibular defects.
      Revision of nine cases.
AB  - OBJECTIVE: Although microsurgical bone transplant is still the gold standard,
      mandibular reconstruction plates (MRP) were for several years considered a fast
      and safe way to restore mandibular continuity without using a bone graft. New
      plate designs with locking screws have been recently introduced, and these may
      overcome some of the complications related to previous designs. We review the
      results of mandibular reconstruction plates in our institution from 1991 to 1995.
      METHODS: The records of nine cancer patients who underwent lateral mandibular
      resections (with preservation of both condyle and symphysis) followed by
      reconstruction with a mandibular reconstruction plate, were retrospectively
      reviewed. Patients were treated between 1991 and 1995 with regular Synthes and
      Leibinger plates (without locking screws). Immediately after tumour resection,
      the bone defect was reconstructed with an MRP without bone grafting. Three cases
      required soft tissue coverage: two flaps and one buccal fat pad flap. RESULTS:
      There was immediate orocervical fistula in six cases, one of which required
      surgical closure; and late complications were common. One patient died due to
      distant metastasis 13 months after surgery without symptoms related to the plate.
      The remaining eight patients had their plates removed at between 9 and 52 months
      after reconstruction, due to screw loosening (four cases), plate exposure (one
      case), or both (three cases). CONCLUSION: Lateral mandibular reconstruction with
      non-locking screws and regular profile plates is no longer recommended. New
      plates with improved designs are currently available. Their low profile and
      locking screws are the usual characteristics of these new plates. More clinical
      experience is necessary before plate reconstruction can be recommended over
      microvascular bone transfer.

PMID- 15041054
TI  - Immunohistochemical distribution of CD9 in parotid gland tumors.
AB  - OBJECTIVE: CD9 is a member of the tetra-membrane-spanning glycoprotein family
      called tetraspanin. CD9 suppresses breeding and motion in some types of cancer
      cells. At present, the expression of CD9 in the salivary gland has not yet been
      elucidated. METHODS: We examined the expression of CD9 not only in the normal
      salivary glands of human embryo and adults but also in the parotid gland tumors
      using immunohistochemical staining. RESULTS: CD9 was not detected in embryos at
      18 weeks of gestation, but was observed at 24 weeks in the salivary gland. CD9
      was constantly detected in the adult normal parotid gland. In benign parotid
      gland tumors, CD9 was present in the 11 of 16 pleomorphic adenomas, every Warthin
      tumors (18/18) and basal cell adenoma (1/1). In contrast, positive staining for
      CD9 in malignant parotid tumors was observed in only the case of mucoepidermoid
      carcinomas. Neither acinic cell carcinomas or adenoid cystic carcinomas did show
      positive reaction in examined cases. The localization of CD9 was also observed in
      intercalated duct cells. CONCLUSION: There was a statistically significant
      reduced expression of CD9 in malignant parotid gland tumors as compared to benign
      parotid gland tumors (P = 0.003).

PMID- 15041056
TI  - A solitary fibrous tumor in the external auditory meatus.
AB  - We herein describe a rare case of a spindle-cell neoplasm arising in the external
      auditory canal. A 38-year-old man presented with a progressive swelling of the
      entrance of left external auditory meatus. The patient underwent a surgical
      removal of the tumor. A light microscopic study showed a spindle-cell
      proliferation with a collagenous stroma and a staghorn-like vascular pattern. The
      tumor cells were immunohistochemically positive for vimentin and CD34. The tumor
      was thereafter diagnosed to be a solitary fibrous tumor (SFT). SFTs most commonly
      occur in the pleura and are supposed to originate from submesothelial connective
      tissue. Although, several cases of extrapleural SFT have been reported, no SFT
      arising in the entrance of left external auditory canal have ever been reported
      in the literature. As a basically benign tumor, it occasionally relapses or
      metastasizes after excision, and therefore a careful follow up is necessary.

PMID- 15041057
TI  - Ipsilateral beating nystagmus after acoustic schwannoma resection.
AB  - OBJECTIVE: To highlight the alert value of an ipsilateral beating nystagmus to
      detect any potential vascular complication in the early postoperative course of
      acoustic schwannoma (AS) surgery. METHODS: In a series of 432 cases of AS
      operated by the same surgeons between January 1991 and December 2000, two cases
      of vascular complications were detected by an ipsilateral beating nystagmus
      toward the operated side. RESULTS: One case of arterial infarction giving rise to
      a partial AICA syndrome and one case of hematoma of the cerebello-pontine angle
      (CPA) were revealed by an ipsilateral beating nystagmus. It was the first or the
      only objective neurologic sign encountered in the early postoperative course of
      AS surgery. CONCLUSIONS: An ipsilateral beating nystagmus after AS resection,
      even appearing as the only abnormal objective neurologic finding, should always
      raise suspicion of a brain stem event. Early extubation is recommended for
      systematic neurologic assessment in order to detect as quickly as possible any
      potential vascular complication in the early postoperative course of AS.

PMID- 15041059
TI  - Successful treatment of disseminated nasal T-cell lymphoma using high-dose
      chemotherapy and autologus peripheral blood stem cell transplantation: a case
      report.
AB  - It is reported that the prognosis of relapse nasal lymphoma is invariably fatal,
      and high-dose chemotherapy using autologous peripheral blood stem cell
      transplantation (auto-PBSCT) has been established as an effective treatment for
      patients with relapsing aggressive non-Hodgkin's lymphoma. We experienced a case
      with T-cell lymphoma in the nasal cavity that relapsed after the initial
      treatment consisting of chemotherapy and radiation therapy. We treated with high
      dose chemotherapy and auto-PBSCT to the patient. The patient has been disease
      free without therapy for 30 months following auto-PBSCT. Our experience suggests
      that high-dose chemotherapy using auto-PBSCT may be one of effective treatment
      option for relapsed nasal T-cell lymphoma when conventional chemotherapy fails.

PMID- 15041060
TI  - Polymorphous low-grade adenocarcinoma of the tongue.
AB  - Polymorphous low-grade adenocarcinoma has been recently recognized as a distinct
      entity with a predilection for minor salivary glands. We present an unusual case
      of polymorphous low-grade adenocarcinoma of the tongue. Only a few cases located
      at the tongue have been reported in the English literature. Current literature
      concerning the histopathological and clinical features of this tumor was
      discussed.

PMID- 15041058
TI  - Synchronous oncocytoma and Warthin's tumor in the ipsilateral parotid gland.
AB  - We encountered an 81-year-old Japanese man with oncocytoma of the parotid gland
      occurring simultaneously with a Warthin's tumor in the ipsilateral parotid gland.
      The patient complained of swelling in the right infra-auricular region. Computed
      tomographic images, magnetic resonance images, and ultrasonography showed two
      masses in the right parotid gland. Technetium 99m pertechnetate scintigraphy
      revealed a high accumulation in both tumors. We performed a superficial lobectomy
      of the parotid gland. Preoperative diagnosis was multiple Warthin's tumor, but
      upon histopathological examination Warthin's tumor proved to coexist with
      oncocytoma. In general, the presence of synchronous, major, salivary gland tumors
      with different histopathology in the ipsilateral parotid gland appears to be
      unique. This is especially true for the combination of oncocytomas and Warthin's
      tumors, which is extremely rare. Only eight cases of this kind coincidence were
      found in our review of the literature. The similarity of oncocytomas and
      Warthin's tumors based on epidemiology, image diagnostics, and histopathology is
      discussed.

PMID- 15041062
TI  - Metastasis of renal cell carcinoma to the thyroid gland 19 years after
      nephrectomy: a case report.
AB  - Although metastases to the thyroid are never uncommon at autopsy in patients who
      died of malignancy, metastatic thyroid carcinomas are rarely detected in clinical
      practice in most cases and cases of secondary thyroid cancer which require
      thyroid surgery clinically are few. A clinical case of thyroid metastasis from
      renal cell carcinoma with thyroidectomy is described herein. An 87-year-old
      Japanese woman was referred to us for a slow-growing palpable neck tumor with
      dysphagia. She had undergone a nephrectomy for renal clear cell carcinoma 19
      years earlier at another hospital. Preoperative imaging examinations suspected an
      adenomatous goiter and a fine needle aspiration (FNA) cytology was suggestive of
      an atypical follicular tumor. Hemithyroidectomy was performed as a follicular
      tumor of thyroid for restriction of subjective symptom. A pathological
      examination of the thyroid tumor revealed clear cell carcinoma, postoperatively.
      The negative result of immunohistochemical staining for thyroglobulin also
      suggested metastatic renal cell carcinoma to the thyroid. Clinically significant
      metastases to the thyroid gland are relatively infrequent. However, if patient
      who bears a thyroid tumor has a history of malignancy, the possibility of
      metastatic disease should be taken under consideration.

PMID- 15041061
TI  - Composite lymphoma arising in the parotid gland: a case report.
AB  - A case of composite lymphoma (CL) arisen in the parotid gland in a 58-year-old
      male is reported. Histologically, most of the tumor region was follicular
      lymphoma (FL), grade 2. However complicating classical Hodgkin lymphoma (CHL) was
      noted inside the lesion. There have been a few reports of composite lymphoma,
      complicated by multiple histologic types in the same organ. Extra-nodal cases are
      particularly rare. This is a very significant case with regard to differences
      between B cell-derived non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) and
      its histological origin.

PMID- 15041063
TI  - Horizontal eye response to an abrupt lateral head drop in normal subjects and
      patients with Meniere's disease.

PMID- 15041066
TI  - Cadmium in oysters and scallops: the BC experience.
AB  - Health effects of non-occupational lifetime exposure to cadmium (Cd) are of
      growing concern worldwide. This overview provides some context for the current
      situation in coastal British Columbia, Canada, which arose in 1999 from the
      discovery of problematic residues of Cd in farmed Pacific oysters (Crassostrea
      gigas). Efforts are underway to define Cd sources and the geographical and
      seasonal variation of these Cd residues. The recent application by the European
      Community of a 1 microg Cd/g (wet weight) import limit to bivalve molluscs and
      the current deliberation by CODEX to adopt the same value, pose significant
      threats to the shellfish export trade in the Pacific Northwest (British Columbia,
      Washington and Alaska), where natural oceanographic conditions and coastal
      geology contribute to levels of Cd that usually exceed the 1 ppm limit. Human
      health aspects of chronic Cd exposure comprise an active field of study (this
      Symposium) and the validity of existing Provisional Tolerable Weekly Intake is
      being questioned. Bioavailability of Cd from the oyster and scallop matrix is
      unknown and requires study. Ramifications of this uncertainty may include damage
      to public perception of the safety of the cultured shellfish product, loss of
      export market and general undermining of an industry being encouraged by both the
      Province of British Columbia and Federal aquaculture initiatives. There is
      therefore a pressing need to redefine what the "safe" limit of lifetime Cd intake
      is from all sources, and determine bioavailability, specifically from bivalve
      molluscs. Such information would facilitate the definition of scientifically
      defensible Cd limits by CODEX.

PMID- 15041067
TI  - Cadmium and nutritional intake in pregnant Japanese women.
AB  - A study to clarify the food composition and nutritional factors that contribute
      to the levels of blood and urinary cadmium (Cd) was conducted on 50 pregnant
      Japanese women with mean age of 29 years. The mean iron (Fe) intake of subjects
      was 9.2 mg, which is much lower than the recommended level of 20 mg for pregnant
      women. Cd in urine samples collected at 30-32 weeks of gestation were correlated
      (r = 0.354), but urinary Cd was related to age more than blood Cd. Urinary Cd and
      blood Cd levels were inversely related to total energy (rpartial = -0.325, and 
      0.334, respectively) and fat intake (rpartial = -0.419, and -0.379,
      respectively), even after adjustment for age. Blood Cd was also correlated to
      protein and iron intake (rpartial = -0.299, and -0.353, respectively). These
      results indicate that Cd exposure levels of pregnant women with low energy
      intake, especially less fat intake, were higher than those of women with more
      energy and fat intake. In particular, blood Cd may be affected by protein and
      iron intake in pregnant women with increased these nutrients demand.

PMID- 15041065
TI  - A commentary on the impacts of metals and metalloids in the environment upon the
      metabolism of drugs and chemicals.
AB  - The salient feature of metals is that unlike organic compounds they do not
      degrade in the environment and barely move from one environmental matrix to
      another. Human interventions take these compounds from their stable and non
      bioavailable geological matrix into situations of biological accessibility.
      Studies in the 1970s and the 1980s of metal bioavailability and impacts of metals
      and metalloids were driven by the process of abatement of lead in the
      environment. Humans have clear and identifiable sources of exposure from fuels,
      food and leaded water pipes to lead. Interventions started at that time have
      dramatically lowered human lead exposure. Attention has now shifted to other
      metals, in particular, cadmium, which has seen increasing use. It is generally
      accepted that food crops grown on cadmium containing soils or soils naturally
      rich in this metal are the major source of exposure to humans other than exposure
      from smoking of cigarettes. This mini-review gives a summary and commentary on
      early studies on effects of lead on haem metabolism that provide us the clue to
      why investigations of the impacts of other toxic heavy metals and metalloids such
      as cadmium and arsenic on different human cytochrome P450 forms have become of
      great interest at the current time.

PMID- 15041068
TI  - Influence of body iron store status and cigarette smoking on cadmium body burden
      of healthy Thai women and men.
AB  - The influence of cigarette smoking, body iron store status and gender on cadmium
      (Cd) body burden was examined in a group of 197 healthy Thais with overall mean
      age of 30.5 year (19-47 year). The lowest, geometric mean, and the highest
      urinary Cd excretion rate was 0.04, 0.46 and 3.84 microg/g creatinine,
      respectively. The prevalence of low iron stores (serum ferritin <20 microg/l) was
      16% and 2% in women and men, respectively. All women (n = 99) were non-smokers,
      but they had the same Cd body burden as did men (n = 47) who on average smoked
      8.7 cigarettes per day for 9 years. These women and men had 1.9-fold greater body
      Cd burden than did non-smoking men (t = 4, P < 0.001). In addition, the women Cd
      body burden was found to be inversely correlated with serum ferritin (r = -0.39,
      P < 0.001) and those with low iron stores showed a 3.4-fold greater Cd body
      burden than did women whose serum ferritin being between 101 and 200 microg/l (F
      = 6.2, P = 0.003, one-way ANOVA). In contrast, men's Cd body burden did not show
      a significant correlation with serum ferritin, but it did show a positive
      correlation with cumulative cigarette smoking index (r = 0.29, P = 0.02). Thus,
      iron status and cigarette smoking were found to be determinants of Cd body burden
      in young adult Thai women and men.

PMID- 15041069
TI  - Effects of chronic exposure to low-level cadmium on renal tubular function and
      CYP2A6-mediated coumarin metabolism in healthy human subjects.
AB  - Relationships between cadmium (Cd) body burden, kidney function and coumarin
      metabolism were investigated using two groups of 197 and 200 healthy Thais with
      men and women in nearly equal numbers. A mean age of one group was 30.5 years and
      it was 39.3 years for the other group. Of 397, 20 subjects (5%) excreted urine Cd
      between 1.4 microg/g and 3.8 microg/g creatinine and these subjects faced 10-15%
      increase in the probability of having abnormal urinary excretion of N-acetyl-beta
      D-glucosaminidase (NAG-uria). The prevalence of NAG-uria varied with Cd body
      burden in a dose-dependent manner (chi2 = 22, P < 0.008). Also NAG-nuria was one
      of the three kidney effect markers tested that showed the greatest strength of
      correlation with urine Cd in both men and women (r = 0.48, P < 0.001). In
      addition, urine Cd excretion of men and women showed a positive correlation (r =
      0.46 to 0.54, P < 0.001) with urine 7-hydroxycoumarin (7-OHC) excretion which was
      used as a marker of liver cytochrome P450 2A6 (CYP2A6) enzyme activity. Urinary
      Cd excretion accounted for 25% of the total variation in urine 7-OHC excretion (P
      < 0.001). These data suggest that Cd may increase the expression of CYP2A6 in
      liver, resulting in enhanced coumarin metabolism in subjects with high Cd body
      burden.

PMID- 15041070
TI  - Acute cadmium chloride administration induces hepatic and renal CYP2A5 mRNA,
      protein and activity in the mouse: involvement of transcription factor NRF2.
AB  - Modulation of the cytochrome P450 (CYP) monooxygenase system by cadmium was
      investigated in male, adult DBA/2J mice treated with a single dose (16
      micromol/kg body weight, i.p.) of cadmium chloride (CdCl2). Total CYP content of
      liver and kidney microsomes decreased maximally (56% and 85%, respectively) 24
      and 18 h, respectively, after CdCl2 treatment. Progressive increases of hepatic
      coumarin 7-hydroxylase (COH) activity; indicative of CYP2A5 activity, relative to
      the total CYP content were seen at 8 h (2-fold), 12 h (3-fold), 18 h (12-fold),
      and 24 h (15-fold). Similar changes were seen in the kidney. Liver and kidney
      CYP2A5 mRNA levels increased maximally 12 and 4 h after treatment and decreased
      to almost half 6 h later. In contrast, kidney and liver CYP2A5 protein levels
      increased maximally at 18 and 24 h. The CYP2A5 mRNA levels in the kidney and
      liver increased after Cd treatment in Nrf2 +/+ but not in Nrf2 -/- mouse. This
      study demonstrates that hepatic and kidney CYP2A5 is upregulated by cadmium with
      a somewhat faster response in the kidney than the liver. The strong upregulation
      of the CYP2A5 both at mRNA and enzyme activity levels, with a simultaneous
      decrease in the total CYP concentration suggest an unusual mode of regulation of
      CYP2A5 in response to cadmium exposure, amongst the CYP enzymes. The observed
      decrease in the mRNA but not in protein levels after maximal induction may
      suggest involvement of post-transcriptional mechanisms in the regulation.
      Upregulation of CYP2A5 by cadmium in the Nrf2 +/+ mice but not in the Nrf2-/-
      mice indicates a role for this transcription factor in the regulation.

PMID- 15041071
TI  - Associations between perceived cancer risk and established risk factors in a
      national community sample.
AB  - INTRODUCTION: Perceptions of personal cancer risk may not accurately reflect
      individual's exposure to established risk factors. The purpose of this study was
      to assess associations between perceived cancer risk and selected established
      risk factors, using a large nationally representative sample. METHODS: We used
      data from the 2000 National Health Interview Survey (NHIS) to perform a cross
      sectional analysis of 30,223 adults without a cancer diagnosis. Multinominal
      logistic regression analyses were used to assess factors associated with medium
      and high perceived cancer risk. RESULTS: The effects of age, family history, and
      smoking status on perceived risk were linear and more pronounced on those with
      high perceived risk. High perceived risk was associated with every day smoking
      (relative risk ratio [RRR] = 4.27, 95% confidence intervals [CI] = 3.65-5.01),
      alcohol consumption (e.g. RRR = 1.26, 95% CI = 1.01-1.56 for current drinker),
      number of relatives with cancer (e.g. RRR = 20.64, 95% CI = 16.37-26 for those
      with both parents positive), low income (RRR = 1.25, 95% CI = 1.08-1.45), and
      female (RRR = 1.39, 95% CI = 1.23-1.57). Obesity (RRR = 1.32, 95% CI 1.1-1.6),
      but not overweight, was identified as an independent determinant. High perceived
      risk was inversely related to age (e.g. RRR = 0.19, 95% CI = 0.16-0.24 for adults
      60 and older). Ethnic minorities were less likely to perceive cancer risk.
      Physical inactivity was not associated with high perceived risk. CONCLUSIONS:
      Among established risk factors, family history appears to be most reflected in
      the single measure of perceived cancer risk. The relationship between perceived
      cancer risk and exposure to established risk factors differs in important ways
      from what public campaigns have communicated with the public. Prevention messages
      should highlight that cancer risk increases with age and certain modifiable risk
      factors, including overweight and physical inactivity. The relationship between
      cancer risk perceptions and ethnicity merits further exploration.

PMID- 15041073
TI  - Phagocytosis of Candida albicans by metastatic and non metastatic human breast
      cancer cell lines in vitro.
AB  - Experiments were carried out to investigate the kinetic characteristics of
      phagocytosis of candida by metastatic (MCF-7 and ZR-75-1) and nonmetastatic
      (HCC70) breast cancer cell (BCC) lines. Cancer cells were mixed with candida at a
      ratio of 1:10 and attachment/phagocytosis were examined using cytospin
      preparations stained with either Giemsa or tannic acid and May-Grunwald Giemsa
      and by using flow cytometry. A high attachment of candida to cancer cells (29
      39%) was detected as early as 10 min. Following attachment, cancer cells
      phagocytized yeast. The phagocytic activity of MCF-7 and ZR-75 cells was
      significantly higher (58-61%) than that of HCC70 cells (26%). A similar trend was
      observed with respect to the phagocytic index. Phagocytosis of candida by tumor
      cells was inhibited significantly by both cytochalasin B (50%) and by lowering
      temperature to 4 degrees C (66%). Phagocytosis was not associated with oxidative
      burst in any cell lines used. In conclusion, metastatic breast cancer cells
      possess phagocytic activity which may explain their invasive property.

PMID- 15041072
TI  - Selenium and selenomethionine levels in prostate cancer patients.
AB  - OBJECTIVE: Selenium (Se) and selenomethionine (Se-Met) have been identified as
      potential chemopreventive agents of prostate cancer. Using an assay for the
      speciation (separation and identification) and quantification of selenoamino
      acids, Se-Met was profiled in serum and prostate tissue from prostate cancer
      patients. Total Se was measured also. METHODS: Serum and prostate tissue samples
      were analyzed using high performance liquid chromatography ion channel plasma
      mass spectrometry (HPLC ICP-MS). Samples were provided by 25 subjects undergoing
      radical prostatectomy for the treatment of prostate cancer. RESULTS: The mean
      serum Se-Met concentration was 59.4 +/- 19.5 ng/ml. Mean total serum Se levels
      were 133.8 +/- 29.2 ng/ml. Total Se levels in paired samples from the
      transitional and peripheral zones of the prostate were also compared. Total mean
      Se levels in peripheral zone tissue was higher than in transitional zone tissue
      (0.432 +/- 0.212 microg/g versus 0.293 +/- 0.172 microg/g, P = 0.01). Se-Met was
      detected in the majority of prostate tissues. CONCLUSION: This group of prostate
      cancer patients had total Se levels in serum and in prostate tissue in a range
      expected for normal Se intake. There was a significantly higher total Se level
      found in peripheral versus transitional zone tissues. This is the first time that
      Se-Met has been detected in prostate tissue.

PMID- 15041074
TI  - Prostate-specific antigen expression in nipple aspirate fluid is associated with
      advanced breast cancer.
AB  - We previously demonstrated that prostate-specific antigen (PSA) is present in
      breast nipple aspirate fluid (NAF) and its expression is inversely associated
      with the presence of breast cancer. The purpose of this study was to determine if
      PSA levels in NAF decrease with disease progression from DCIS to metastatic
      breast cancer. One hundred and forty-nine women underwent nipple aspiration
      before or in conjunction with surgery to treat their breast cancer. PSA levels
      decreased with more advanced disease stage (P = 0.016), larger tumor size (P =
      0.031), and nodal involvement (P = 0.041). PSA levels were lower in women with
      than without distant disease spread (P = 0.049). We also evaluated the
      association of PSA with these clinical parameters based on menopausal status. In
      general, PSA predicted disease involvement better in pre- than in post-menopausal
      women. There was no association between PSA and race. Spearman's rank analysis
      demonstrated that PSA was inversely related to tumor size (P = 0.009), nodal
      status (P = 0.005), disease stage (P = 0.004), and distant metastases (P = 0.04).
      NAF PSA provides useful prognostic information which may assist with breast
      cancer treatment.

PMID- 15041075
TI  - Discrimination between normal and malignant human gastric tissues by Fourier
      transform infrared spectroscopy.
AB  - The aim of this study was to determine whether malignant and normal human gastric
      tissues can be distinguished by Fourier transform infrared (FTIR) spectroscopy.
      Compared with normal tissue, malignant tissues showed significant increases in
      infrared (IR) absorption in 10 bands lying in a region of 925-1660 cm(-1). Using
      the 10 IR absorption bands as markers, discriminant analysis was carried out for
      tissue discrimination. As a result, 22 out of the 23 gastric cancer samples and 9
      out of the 12 gastric normal samples were correctly segregated, yielding 88.6%
      accuracy. The present results suggest that FTIR spectroscopy is a useful tool for
      screening gastric cancer.

PMID- 15041076
TI  - The value of a complete blood count in predicting cancer of the colon.
AB  - Mortality from colon cancer could be reduced with routine screening, yet
      screening rates are low. Current screening tools are limited by expense and
      suboptimal acceptance. A retrospective case-control study of all cases of colon
      cancer diagnosed at our institution over a 5-year period was performed to
      determine the frequency of blood count abnormalities in these patients upon
      presentation. One hundred twenty-seven patients had right-sided colon cancer: 107
      (84%) had an elevated red cell distribution width (RDW); 87 (69%) had anemia; and
      70 (55%) had a low mean corpuscular volume (MCV). Ninety-eight patients had left
      sided colon cancer: 49 (50%) had an elevated red cell distribution width; 43
      (44%) had anemia; and 22 (22%) had a low mean corpuscular volume. The red cell
      distribution width was 84% sensitive and 88% specific for right-sided colon
      cancer. An elevated red cell distribution width may help better identify those
      patients who should be referred for full colonoscopy.

PMID- 15041077
TI  - Acceptance of flexible sigmoidoscopy screening for colorectal cancer.
AB  - This study was conducted in the Kaiser Permanente Medical Care Program of
      Northern California to identify patient characteristics that explain interest in
      flexible sigmoidoscopy (FS) screening. A mailed screening invitation to 6837 age
      eligible patients elicited responses from 49%. Efforts to reach and interview
      both eligible respondents and non-respondents resulted in 2728 computer-assisted
      telephone interviews (CATI), with 60% indicating interest in FS screening. Five
      components of the Integrated Behavioral Model were measured with respect to FS
      screening: attitude, affect, social influence, facilitators/barriers, and
      perceived risk of colorectal cancer. All five model components were significantly
      and independently associated with interest in FS, with patient attitude being the
      strongest predictor. Of the 32 items comprising the model components, nine items
      having the highest correlations with FS interest were identified as potentially
      important issues to address by efforts to increase interest in screening. Six of
      these were attitudinal beliefs. The findings from this theory-driven study
      provide specific targets for the design of interventions to increase FS interest
      and screening rates.

PMID- 15041078
TI  - A mistletoe lectin (ML-1)-containing diet reduces the viability of a murine non
      Hodgkin lymphoma tumor.
AB  - In this study we show that the characteristics of non-Hodgkin lymphoma (NHL)
      tumors in female Naval Medical Research Institute (NMRI, USA) mice fed mistletoe
      lectin (ML)-containing diets were different from those in mice fed control diet.
      The non-Hodgkin lymphoma tumor was originally established from a spontaneous
      tumor which developed in the inguinal region of a male mouse. Mice (five animals
      per group) were fed a lactalbumin (LA)-based control diet or a diet which
      provided up to 10 mg lectin per day. At the highest daily intake (10 mg lectin)
      the degree of mitotic activity in tumors was reduced by 75% and the nuclear area
      had diminished by 21%. The overall level of lymphocyte infiltration (CD3 positive
      cells) in tumors from mistletoe lectin fed mice was increased by a factor of two.
      Other morphological studies showed a high incidence of apoptotic bodies in non
      Hodgkin lymphoma tumors obtained from mice fed mistletoe lectin diets. The
      feeding of such diets thus produced several identifiable changes in the
      morphology of non-Hodgkin lymphoma tumors. These were consistent with the
      observed reduction in tumor mass. In 4/15 mice fed a mistletoe lectin diet for 11
      days there was no longer evidence of viable tumor. The results show that this
      lectin exerts powerful anti-tumor effects when provided by the oral route.

PMID- 15041079
TI  - Transforming growth factor-beta (TGF-beta)-resistant B cells from chronic
      lymphocytic leukemia patients contain recurrent mutations in the signal sequence
      of the type I TGF-beta receptor.
AB  - B cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in
      western societies, and is currently incurable. B cells of some B-CLL patients are
      resistant to the anti-proliferative effects of transforming growth factor-beta
      (TGF-beta). Herein, we identified two mutations within the putative signal
      sequence of TGF-beta type I receptor (TbetaR-I) gene of TGF-beta-resistant B-CLL
      patients (i.e., a Leu12Gln substitution together with an in-frame single Ala
      deletion). Although TbetaR-I mutants were expressed to the cell surface and
      interacted normally with TGF-beta-bound TbetaR-II, their expression significantly
      reduced gene transcription stimulated by TGF-beta, suggesting a causal
      relationship in the development of TGF-beta-resistant B-CLL. Screening of
      additional B-CLL patients solely for the presence of TbetaR-I signal sequence
      mutations showed that these mutations correlated with and predicted for B-CLL
      patient insensitivity to TGF-beta. Our results demonstrate that TGF-beta
      resistant B-CLL is linked to signal sequence mutations within the TbetaR-I gene,
      and may eventually be employed as a prognostic indicator in B-CLL.

PMID- 15041080
TI  - Results and failures with or without cisplatin containing induction chemotherapy
      in the treatment of squamous cell carcinoma of the head and neck.
AB  - This prospective randomised study was undertaken to assess the effects and
      effectiveness of cisplatin in a pre-operative setting. Thirty-eight patients were
      treated with stage II-IVa (AJCC) squamous cell cancer of the oral cavity and
      oropharynx. Nineteen patients received a combination of bleomycin, vincristine,
      methotrexate (BVM; group I.), 19 received BVM and cisplatin (group II). Patients
      underwent surgery within 3 weeks after chemotherapy. Biopsy and surgical
      specimens were compared. A clinical complete response was seen in five patients
      in group I (26.3%) and in four patients in group II (21.1%). Partial response was
      noted in 11 patients in group I (57.8%) and in 13 patients in group II (68.4%).
      There was no statistical difference in clinical response between the two groups.
      Microscopic response was better in the cisplatin treated group. Median follow up
      of patients is 52 (36-70) months. Disease free survival showed a significant
      difference, favouring the no cisplatin group (P = 0.03). There was no significant
      difference in overall survival (P > 0.6). Cisplatin in combination with BVM
      showed significantly higher levels of microscopic response, but the lower disease
      free survival is mostly due to a higher rate of regional neck failure.

PMID- 15041081
TI  - Differences in the hepatic P450-dependent metabolism of estrogen and tamoxifen in
      response to treatment of rats with 3,3'-diindolylmethane and its parent compound
      indole-3-carbinol.
AB  - Indole-3-carbinol (I3C), present in cruciferous vegetables, and its major in vivo
      product 3,3'-diindolylmethane (DIM), have been reported to suppress estrogen
      responsive cancers. This effect may be mediated through the modification of
      cytochrome P450 (CYP) complement and activities leading to estrogen
      detoxification. We examined the effects of a 4-day treatment of female Sprague
      Dawley rats with DIM at 8.4 and 42 mg/kg body weight (bwt), on the hepatic CYP
      protein level, CYP1A1, 1A2, 2B1/2 and 3A1/2 probe activities and CYP-dependent
      metabolism of 17beta-estradiol (E2) and estrone (E1). At 42 mg/kg bwt, DIM
      effected a small increase (2.8-fold) in CYP1A1 activity, and at both dose levels
      it reduced CYP3A1/2 activity by approximately 40%. At the higher dose level, DIM
      decreased the rates of oxidation of E2 to 4-OH-E2, 4-OH-E1, 6alpha-OH-E2 and
      6(alpha+beta)-OH-E1 by 39, 44, 71 and 60%, respectively, and E1 to 6(alpha+beta)
      OH-E1 by 39%. These effects were considerably different from those of I3C
      reported by us previously. We also examined the effects of DIM and I3C on the
      hepatic microsomal metabolism of tamoxifen (TAM). Whereas metabolism of TAM was
      unaffected by DIM, formation of N-desmethyl-TAM (and its presumed derivative) was
      increased approximately 3-fold by I3C at 250 mg/kg bwt. Since N-desmethyl-TAM is
      transformed to a genotoxic metabolite, dietary exposure to I3C may enhance
      hepatic carcinogenicity of TAM in the rat. The differences between I3C and DIM in
      CYP-mediated activities and metabolism indicate that DIM is not a proximate
      intermediate in the mechanism of action of I3C.

PMID- 15041082
TI  - The cognitive activation theory of stress.
AB  - This paper presents a cognitive activation theory of stress (CATS), with a formal
      system of systematic definitions. The term "stress" is used for four aspects of
      "stress", stress stimuli, stress experience, the non-specific, general stress
      response, and experience of the stress response. These four meanings may be
      measured separately. The stress response is a general alarm in a homeostatic
      system, producing general and unspecific neurophysiological activation from one
      level of arousal to more arousal. The stress response occurs whenever there is
      something missing, for instance a homeostatic imbalance, or a threat to
      homeostasis and life of the organism. Formally, the alarm occurs when there is a
      discrepancy between what should be and what is-between the value a variable
      should have (set value (SV)), and the real value (actual value (AV)) of the same
      variable. The stress response, therefore, is an essential and necessary
      physiological response. The unpleasantness of the alarm is no health threat.
      However, if sustained, the response may lead to illness and disease through
      established pathophysiological processes ("allostatic load"). The alarm elicits
      specific behaviors to cope with the situation. The level of alarm depends on
      expectancy of the outcome of stimuli and the specific responses available for
      coping. Psychological defense is defined as a distortion of stimulus
      expectancies. Response outcome expectancies are defined as positive, negative, or
      none, to the available responses. This offers formal definitions of coping,
      hopelessness, and helplessness that are easy to operationalize in man and in
      animals. It is an essential element of CATS that only when coping is defined as
      positive outcome expectancy does the concept predict relations to health and
      disease.

PMID- 15041083
TI  - Loneliness and neuroendocrine, cardiovascular, and inflammatory stress responses
      in middle-aged men and women.
AB  - Loneliness is a psychological experience related to social isolation and
      perceived lack of companionship, and may be relevant to health risk. The revised
      UCLA loneliness scale was completed by 240 working men and women aged 47-59
      years, and related to affective state and neuroendocrine, cardiovascular, and
      inflammatory responses. Loneliness scores were not associated with gender, age or
      socioeconomic position, but were lower in married than single or divorced
      participants, and were positively related to social isolation, low emotional
      support, ratings of depression, hopelessness and low self-esteem, and to reported
      sleep problems. Diastolic blood pressure reactions to acute mental stress were
      positively correlated with loneliness in women but not men, independently of age,
      socioeconomic status, smoking, body mass and marital status (p = 0.014). Lonely
      individuals also displayed significantly greater fibrinogen (p = 0.038) and
      natural killer cell responses (p = 0.042) to stress, independently of covariates.
      The cortisol response over the first 30 min following waking was positively
      associated with loneliness after adjusting for waking cortisol value, sex,
      socioeconomic status, smoking, time of waking, and body mass (p = 0.046). We
      conclude that loneliness is a psychological experience with potentially adverse
      effects on biological stress processes that may be relevant to health.

PMID- 15041084
TI  - A single administration of testosterone improves visuospatial ability in young
      women.
AB  - Previous research has documented correlations between endogenous testosterone
      levels and visuospatial cognitive function. Some causal relations have also been
      established in treatment designs in which testosterone was administered to
      elderly subjects for a number of weeks. Particularly, one study reported a
      selective effect of a single administration of testosterone on some aspects of
      spatial memory in 15 women. The present study tested the hypothesis whether a
      single administration of 0.5 mg of sublingual testosterone would improve
      visuospatial ability in healthy young women on a test that has consistently been
      associated with male superiority. Twenty-six women participated in a double-blind
      placebo-controlled cross-over trial of single administration of testosterone and
      placebo. Subjects were tested in the same phase of the menstrual-cycle. Four to
      five hours after both administrations, subjects completed a standardized measure
      of visuospatial ability (3-D Mental Rotations Test). Visuospatial ability
      improved significantly after testosterone administration compared to placebo,
      after controlling for learning effects due to repeated testing. Testosterone is
      suggested to be causally related to visuospatial ability in young women.

PMID- 15041085
TI  - Genomic and non-genomic effects of glucocorticoids on aggressive behavior in male
      rats.
AB  - An increasing body of evidence suggests that glucocorticoids--besides their well
      known genomic effects--can affect neuronal function via mechanisms that do not
      involve the genome. Data obtained mainly in amphibians and birds suggest that
      such mechanisms play a role in the control of behavior. Acute glucocorticoid
      treatments increase aggressive behavior in rats, but the mechanism of action has
      not been investigated to date. To clarify the issue, we have assessed the
      aggressiveness of male rats after treating them with the corticosterone synthesis
      inhibitor metyrapone, corticosterone, and the protein synthesis inhibitor
      cycloheximide. Metyrapone applied intraperitoneally (i.p.) decreased the
      aggressiveness of residents faced with smaller opponents. Corticosterone
      administered i.p. 20 or 2 min before a 5-min encounter abolished these changes
      irrespective of the delay of behavioral testing. Thus, the effects of
      glucocorticoids on aggressive behavior occurred in less than 7 min (the delay and
      duration of testing taken together), and lasted more than 25 min. Corticosterone
      applied centrally (infused into the right lateral ventricle) also stimulated
      aggressive behavior rapidly, which shows that the effect was centrally mediated.
      The protein synthesis inhibitor cycloheximide did not affect the aggression
      promoting effects of corticosterone when the hormone was injected 2 min before
      the aggressive encounter. Surprisingly, however, the effects were completely
      abolished when the hormone was injected 20 min before the encounter. These data
      suggest that glucocorticoids rapidly increase aggressive behavior via non-genomic
      mechanisms. In later phases of the aggressive encounter, aggressive behavior
      appears to be stimulated by genomic mechanisms.

PMID- 15041086
TI  - Salivary cortisol sampling compliance: comparison of patients and healthy
      volunteers.
AB  - OBJECTIVE: Problems of compliance with in vivo data collection and treatment
      protocols have been identified. This study investigated compliance with salivary
      cortisol sampling in a 7-day protocol. Impact of non-compliance on cortisol data
      was evaluated. METHODS: Female fibromyalgia patients were matched with healthy
      female volunteers and randomized to Aware or Unaware conditions regarding
      objective monitoring of their sampling compliance. The protocol entailed
      collecting five saliva samples at prescribed times on each of 7 consecutive days.
      Participants self-reported time of each sample, and electronic monitor caps
      provided an objective date and time stamp of each sample. RESULTS: Objective
      compliance among participants unaware of monitoring was 71%, though their self
      reported compliance was 93%. Aware participants' objective compliance was 90%
      which was consistent with self-reported compliance of 93%. Within-subject
      comparison of early morning rise and day slope of cortisol for compliant and non
      compliant samples found significant differences with non-compliant samples
      resulting in flatter slopes. Patients were somewhat more compliant than healthy
      volunteers. Slight decrements in compliance were found for the afternoon sample
      (1600 h) and for the last 3 days of sampling. Compliance did not differ on
      weekdays versus weekends. CONCLUSIONS: Self-report of compliance in a salivary
      cortisol sampling protocol substantially overestimates actual compliance in the
      absence of objective monitoring. Non-compliance with the sampling protocol
      results in cortisol data that significantly differs from compliant data.
      Awareness of electronic monitoring of sampling results in satisfactory
      compliance.

PMID- 15041087
TI  - Socio-economic status covaries with central nervous system serotonergic
      responsivity as a function of allelic variation in the serotonin transporter gene
      linked polymorphic region.
AB  - It was reported recently that exposure to an adverse rearing environment lowers
      central nervous system (CNS) serotonergic activity in a nonhuman primate (rhesus
      monkeys), but only among animals having the shorter variant of a functional,
      biallelic repeat polymorphism in the regulatory region of the serotonin
      transporter (5-HTT) gene. Because repeat variants of the same core sequence
      affect transcriptional efficiency of the 5-HTT gene in humans, we examined
      whether biallelic variation in the 5-HTT gene-linked polymorphic region (5
      HTTLPR) acts analogously to modulate a previously described association between
      socio-economic status (SES) and CNS serotonergic function. The 5-HTTLPR was
      genotyped in 139 adult men and women (n = 75 and 64) who were administered a
      standard neuroendocrine challenge to assess central serotonergic responsivity
      (plasma prolactin (PRL) response to the serotonin releasing agent, fenfluramine).
      Socio-economic status was estimated from reported income and years of education.
      Hierarchical linear regression showed serotonergic responsivity to be predicted
      by the interaction of 5-HTTLPR genotype and SES (p = 0.018). Individuals of lower
      income and less education had lower peak PRL concentrations following
      administration of fenfluramine than did subjects ranking higher on these
      dimensions, but only among persons possessing at least one 5-HTTLPR short allele.
      Within genotype, SES covaried moderately with the PRL response to fenfluramine
      among subjects who were homozygous for the short allele (r18 = 0.50, p < 0.03). A
      similar association was present at lesser magnitude in heterozygotes (r70 = 0.24,
      p < 0.05) and absent among subjects homozygous for the long allele (r45 = -0.04,
      n.s.). Findings were comparable for men and women and persisted on re-analysis
      restricted to persons without current Axis I psychopathology. We conclude that
      allelic variation at 5-HTTLPR moderates the influence of social position on CNS
      serotonergic responsivity.

PMID- 15041088
TI  - Circulating neurotransmitters during the different wake-sleep stages in normal
      subjects.
AB  - We investigated the changes of circulating neurotransmitters during the wake
      sleep cycle in order to find possible correlations with the activity of central
      neurocircuitry functioning. Noradrenaline (NA), adrenaline (Ad), dopamine (DA),
      platelet serotonin (p-5HT), plasma serotonin (f-5HT) and plasma tryptophan (TRP)
      were assessed during the morning (supine resting + 1-min orthostasis + 5-min
      exercise) and at night (supine resting + slow wave sleep (SWS) + REM sleep). Only
      NA increased in the plasma during short-lasting (1-min) orthostasis morning
      waking period. Both NA and Ad rose during moderate exercise. The nocturnal
      results demonstrated that whereas Ad dropped during the supine resting, NA did
      not fall until SWS period. Although DA did not show significant changes during
      the nocturnal test, the NA/DA ratio showed significant reduction. The analysis of
      correlations supports the postulation that this finding reflects the DA
      modulatory role on neural sympathetic activity. Both f-5HT and p-5HT values were
      lower during sleep cycle than wake periods. However, they showed progressive
      rises during sleep stages. Conversely, the f-5HT/p-5HT ratio showed significantly
      greater values during the SWS period than during supine resting and REM periods.
      These findings are consistent with the postulation that f-5HT/p-5HT ratio is
      positively associated with parasympathetic activity during the sleep-cycle. We
      concluded that the profile of sleep-cycle circulating neurotransmitters differs
      from that obtained during waking periods. According to the above, we attempted to
      correlate the profile of circulating neurotransmitters with the very well-known
      central neurocircuitry functioning during wake-sleep cycle, in experimental
      mammals.

PMID- 15041089
TI  - Correlation between serum levels of interleukin-4 and alexithymia scores in
      healthy female subjects: preliminary findings.
AB  - OBJECTIVE: Some studies suggest that inaccuracy in recognizing and describing
      emotional states, combined with a highly descriptive mode of expression, as in
      alexithymia, may influence the immune response. We therefore investigated in
      healthy women the relationship between alexithymia and circulating levels of IL
      1, IL-2 and IL-4. METHOD: Seventeen mentally and physically healthy women aged
      between 20 and 25 years completed psychological questionnaires to assess
      alexithymia (Toronto Alexithymia Scale: TAS) and depressed mood (Hospital Anxiety
      and Depression Scale: HAD). Serum concentrations of IL-1, IL-2 and IL-4 were
      measured by ELISA. RESULTS: We found a significant positive correlation between
      serum levels of IL-4 and TAS score (r = 0.55; p = 0.021) and between factor 1 of
      the TAS (difficulty in identifying feelings) and IL-4 (r = 0.57; p = 0.017) while
      serum IL-1 and IL-2 were not detected in ten and six patients, respectively.
      Although there was a significant correlation between age and IL-4 levels, a
      linear regression with BMI, age, depressed mood and TAS as independent variables
      showed that only alexithymia could predict significantly increased levels of IL
      4. CONCLUSION: Alexithymia and difficulty in identifying feelings could be
      associated with increased levels of IL-4 which may result in chronic impairment
      of pro/anti-inflammatory cytokine balance with psychological and somatic
      consequences. Nevertheless, these intriguing findings would deserve replication
      and extension in a larger sample of subjects.

PMID- 15041090
TI  - Letter to the Editor: Similar fasting ghrelin levels in binge eating/purging
      anorexia nervosa and restrictive anorexia nervosa.

PMID- 15041091
TI  - Prevalence of Toxoplasma gondii antibodies in wild red deer, roe deer, moose, and
      reindeer from Norway.
AB  - Serum samples from 4339 wild cervids collected in Norway were tested for
      antibodies against Toxoplasma gondii using the direct agglutination test. The
      association between seroprevalence and species, sex, age, and geographic region
      was investigated. Positive titers (> or =1:40) were found in 33.9% of 760 roe
      deer (Capreolus capreolus); 12.6% of 2142 moose (Alces alces); 7.7% of 571 red
      deer (Cervus elaphus); and 1.0% of 866 reindeer (Rangifer tarandus). The
      seroprevalences were significantly different between the species. There was a
      significant increase in prevalence with age in roe deer, moose, and red deer,
      except from yearling to adult in red deer. A significant age-sex interaction was
      found in moose, and the effect of age was most distinct for females. No
      association between seropositive animals and sex was found for roe deer and red
      deer. There were significant differences in prevalence between geographic regions
      in roe deer and male moose. A widespread exposure to T. gondii in Norwegian
      cervids is documented, and meat from Norwegian cervids, particularly roe deer,
      should be regarded a potential source of infection for humans.

PMID- 15041092
TI  - First record of Cryptosporidium infection in a raccoon dog (Nyctereutes
      procyonoides viverrinus).
AB  - Cryptosporidium species have been found in more than 150 species of mammals, but
      there has been no report in raccoon dogs. Here we found the Cryptosporidium
      organism in a raccoon dog, Nyctereutes procyonoides viverrinus, and identified
      this isolate using PCR-based diagnostic methods. Cryptosporidium diagnostic
      fragments of the 18S ribosomal RNA, Cryptosporidium oocyst wall protein and 70
      kDa heat shock protein genes were amplified from the isolate and sequenced to
      reveal the phylogenetic relationships between it and other Cryptosporidium
      species or genotypes reported previously. The results showed that the raccoon dog
      isolate represented the C. parvum cattle genotype which could be a causative
      agent in human cryptosporidiosis.

PMID- 15041093
TI  - Field studies on the biological control of nematode parasites of sheep in the
      tropics, using the microfungus Duddingtonia flagrans.
AB  - Long-term field studies were conducted on two government managed small ruminant
      research farms, located in different geo-climatic regions and approximately 300
      km separate from each other, on Peninsula Malaysia. The Infoternak trial (48
      weeks) and the Chalok trial (43 weeks) each compared nematode parasite control in
      separately managed groups of young sheep, either short-term rotationally grazed
      around a suite of 10 paddocks in addition to receiving a daily supplement of
      Duddingtonia flagrans spores (Fungus Group); or similar groups of sheep being
      rotationally grazed alone (Control Group). The prevailing weather conditions at
      Infoternak farm were of below average rainfall conditions for the most of the
      trial. As a consequence, only very low worm infections (almost exclusively
      Haemonchus contortus) were acquired by the 17 sets of tracer lambs that grazed
      sequentially with the experimental lambs. However on all except 2 occasions in
      the early part of the trial, the mean tracer worm burdens were significantly
      lower (P < 0.05) and the experimental lambs grew significantly better (P = 0.054)
      in the Fungus Group. Rainfall at Chalok farm during the course of the trial was
      also below average. As a consequence infectivity of pastures was assumed to be
      relatively low based on faecal egg counts (epg) of the experimental sheep, which
      following an anthelmintic treatment prior to allocation, remained very low in
      both treatment groups. Faecal egg counts of undosed replacement lambs in the
      latter half of the Chalok study, showed a progressive increase in the Control
      Group to levels exceeding 3000 epg, whereas the Fungus Group remained static at
      approximately 500 epg. These results show that the deployment of the
      nematophagous fungus, D. flagrans, can improve the level of parasite control of
      sheep in the tropics above that which can be achieved by the short-term
      rotational grazing strategy alone.

PMID- 15041095
TI  - Inhibition of bovine T lymphocyte responses by extracts of the stomach worm
      Ostertagia ostertagi.
AB  - Lowered immune responses during bovine ostertagiosis have been reported in both
      in vivo and in vitro assay systems. In the present study we have employed three
      different life cycle stages of the nematode Ostertagia ostertagi to determine if
      products of this economically important parasite inhibit in vitro proliferation
      of Con A-stimulated cells from uninfected animals. We have demonstrated an
      inhibitory effect upon the growth of Con A-stimulated lymphocytes after addition
      of fourth stage larval (L4) soluble extract (L4SE) to the cultures. In contrast,
      extracts from the third stage larvae (L3) had little or no inhibitory activity.
      The suppressive products were also shown to be secreted by the late L4. The
      suppressive activity is reversible if the L4 products are removed from culture.
      There is no immediate effect on proliferating cells and the L4SE must be in
      culture for 24-48 h before suppression is observable. The L4SE caused slight but
      not statistically significant decreases in the percentage of T cells and
      increases in B cell percentages in cultures when compared with cultures
      stimulated with Con A alone. No changes were seen in percentage of cells positive
      for markers for CD4, CD8, gammadelta T cells, or monocytes/macrophages as a
      consequence of the addition of L4SE. In contrast, there was a strong and
      significant reduction in the expression of the IL-2 receptors in cells cultured
      in the presence of the worm extract. There was no evidence of either necrosis or
      apoptosis resulting from the presence of L4 products in culture. The expression
      of messenger RNA for interleukin-2, -4, -13, tumor necrosis factor-alpha (TNF
      alpha), and gamma-interferon (gamma-IFN) was decreased when L4SE was included in
      cultures of Con A-stimulated cells compared to cultures stimulated with Con A
      only. In contrast, messenger RNA expression of transforming growth factor-beta
      (TGF-beta) and interleukin-10 (IL-10) was increased in cells growing in the
      presence of L4 products. The potential role of these cytokines during
      ostertagiosis is discussed.

PMID- 15041094
TI  - Chemoattraction and chemorepulsion of Strongyloides stercoralis infective larvae
      on a sodium chloride gradient is mediated by amphidial neuron pairs ASE and ASH,
      respectively.
AB  - Depending on its concentration, sodium chloride acts as either an attractant or a
      repellant to the infective larvae (L3i) of Strongyloides stercoralis. On a
      concentration gradient, L3i are attracted to 0.05 M NaCl, but repelled by 2.8M.
      To test the hypothesis that amphidial neurons ASE and ASH might mediate
      attraction and repulsion, respectively, these neurons, and control neurons as
      well, were ablated in hatchling larvae with a laser microbeam. After the larvae
      attained infectivity (L3i), they were tested on a NaCl gradient. When placed at
      low salinity, 73.5% of normal controls migrated "up" the gradient, while 26.4%
      crawled randomly. In contrast, only 20.6% of ASE-ablated L3i migrated "up" the
      gradient, while 79.4% migrated randomly. Ablation-control ASK-ablated L3i (58.8%)
      migrated "up" the gradient while 41.1% crawled randomly. When placed at a region
      of high salinity, 100% of normal control L3i migrated "down" the gradient,
      whereas 62.5% of ASH-ablated L3i migrated randomly, the remaining 37.5% migrating
      "down" the gradient. In sharp contrast with ASH-ablated L3i, 94.1% of ablation
      control larvae, i.e. ASK-ablated L3i, migrated "down" the gradient. Migration
      behavior of ASE- and ASH-ablated L3i was significantly different (P < 0.001) from
      that of ASK-ablated L3i and normal controls. It is noteworthy that 87.5% of ASE
      ablated L3i that failed to exhibit chemoattractive behavior were actively
      chemorepelled from high salinity. Also, 70.0% of ASH-ablated L3i that failed to
      be chemorepelled from high salinity were capable of chemoattractive behavior,
      indicating that the worms had retained their behavioral responses except for
      those associated with the targeted neurons.

PMID- 15041096
TI  - Persistent activity of moxidectin long-acting injectable formulations against
      natural and experimentally enhanced populations of lice infesting cattle.
AB  - A study was conducted under a common protocol in Wisconsin and Wyoming, USA, to
      evaluate therapeutic and persistent efficacy of two long-acting injectable
      formulations of moxidectin against lice populations infesting cattle. At each
      site, 30 beef calves were blocked into groups of three based on naturally
      acquired Linognathus vituli populations, then randomly assigned to treatments
      within blocks. Treatments, injected subcutaneously into the proximal third of the
      ear on Day 0, included saline, a long-acting oil-based formulation containing 10%
      moxidectin given at the rate of 1 mg moxidectin/kg body weight (M10/1.0), or a
      long-acting oil-based formulation containing 15% moxidectin given at the rate of
      0.75 mg moxidectin/kg b.w. (M15/0.75). Species of sucking and chewing lice were
      quantified on nine predilection sites before treatment, then 28, 63, 98, 133 and
      168 days after treatment. During intervals between lice counts after Day 28,
      study animals from the three treatment groups were commingled for 32 days with
      two lice-free sentinels plus four to six seeder calves with infestations of both
      sucking and chewing lice. Following each 32-day commingling interval, seeder and
      sentinel animals were removed, and principal animals were sorted into pens by
      treatment. Lice were quantified on sentinel animals on the day of removal, and
      lice were quantified on principal study animals 3 days after removal of sentinel
      and seeders. Moxidectin was generally not efficacious against Bovicola bovis in
      the injectable formulations tested, whereas Haematopinus eurysternus infestations
      were inadequate to judge product effectiveness. Based on geometric means, both
      M15/0.75 and M10/1.0 provided statistically significant therapeutic efficacy
      against existing infestations of L. vituli and Solenopotes capillatus (100%
      efficacy on Day 28), and provided persistent protection against reinfestation
      with L. vituli and S. capillatus (efficacy >97%) for at least 133 days following
      treatment.

PMID- 15041097
TI  - The first record in the Americas of an autochthonous case of Leishmania
      (Leishmania) infantum chagasi in a domestic cat (Felix catus) from Cotia County,
      Sao Paulo State, Brazil.
AB  - A case of feline cutaneous leishmaniasis is reported in a domestic cat (Felis
      catus) as an apparently natural infection in a non-endemic area. Amastigotes were
      seem in smears of a nodular lesion on the cat's nose. No parasite could be seen
      in cytological preparations of liver or spleen but DNA obtained from a sample of
      the spleen produced the expected fragment in a Leishmania specific rDNA based PCR
      assay. The PCR product, a 520 bp fragment, was sequenced and the nucleotide
      sequence was identical to that of Leishmania (Leishmania) infantum chagasi. These
      results are surprising since no autochthonous human or canine cases of visceral
      leishmaniasis have ever been reported from this region. This case suggests that
      natural transmission of this disease is occurring in this area, and that cats
      could act as a reservoir of L. (L.) infantum chagasi.

PMID- 15041098
TI  - Molecular and phylogenetic analysis of Blastocystis isolates from various hosts.
AB  - Blastocystis hominis is a protozoan parasite found in humans. B. hominis-like
      organisms have been found in a variety of animals, but have been called
      Blastocystis sp. because the isolates from animals were indistinguishable from B.
      hominis morphologically. Recent molecular studies show that some isolates from
      animals have genetic similarity with B. hominis. However, it has been unclear
      whether the isolates from animals have zoonotic potential or not. In the present
      study, the SSUrDNA of 19 Blastocystis isolates from these animals was sequenced
      in its entirety, and the phylogenetic relationship among isolates from humans and
      animals was clarified using available nucleotide sequences of the same locus.
      Phylogenetic analysis showed that the 19 isolates analyzed in the present study
      could be classified into seven groups (I-VII): Group I consisted of the isolates
      from humans, primates, cattle, pigs and birds; Group II of the isolates from
      humans and primates; Group III of the isolates from humans, cattle and pigs;
      Group IV of the isolates from primates, birds and rodents; Group V of the
      isolates from cattle and pigs; Groups VI and VII of the isolates from humans and
      birds. These results indicate that many of the isolates harboring in animals have
      zoonotic potential, or have cross-transmissibility among heterogeneous hosts.

PMID- 15041099
TI  - Prevalence of dogs with intestinal parasites in Tochigi, Japan in 1979, 1991 and
      2002.
AB  - A total of 772 canine fecal specimens were collected in Tochigi in 1979, 1991 and
      2001. The frequency of dogs that were kept indoor in 2002 (72.8%) was
      significantly higher than that for 1979 (21.2%, P < 0.001) and 1991 (40.6%, P <
      0.01). The frequency of parasitized dogs in 2002 (18.8%) was significantly lower
      than that for 1979 (41.9%, P < 0.01). The findings of this study confirm the
      declining trend in Japan in the prevalence of helminth parasites in dogs,
      particularly Ancylostoma caninum and Trichuris vulpis. The reduction in the
      frequency of dogs with helminths may be mainly a result of the improvement in the
      environment and the routine use of filaricides.

PMID- 15041100
TI  - T1G3 bladder cancer: conservative management or cystectomy?

PMID- 15041101
TI  - T1G3 bladder tumours: the case for conservative treatment.

PMID- 15041102
TI  - T1G3 bladder tumours: the case for radical cystectomy.
AB  - INTRODUCTION: Many factors degrade the initially favourable results of
      conservative treatment of T1G3 bladder tumours, leading to a permanent risk of
      progression and death. On the other hand, immediate radical cystectomy, while
      ensuring optimal local control of the disease, would be excessive in some
      patients in part because of its purported impact on quality of life. METHODS: To
      contribute to the ongoing debate on T1G3 optimal treatment the literature was
      reviewed to organize evidences in favour of radical cystectomy by focusing on two
      main issues: the impact of time on the initial results of conservative treatment
      and quality of life after cystectomy. RESULTS: A critical appraisal of
      conservative treatment efficacy was structured by comparing survival curves after
      either conservative treatment or radical cystectomy. It highlighted that after
      conservative treatment the patients remained under the burden of lifelong risk of
      progression and death. The positive impact of maintenance BCG and the frequent
      resort to cystectomy after conservative treatment further illustrated the limits
      of bladder conservative treatments. On the other hand, evidences were shown that
      quality of life was not critically affected by radical cystectomy and that
      surgical techniques could be further adapted to its preservation. The influence
      of age at cystectomy on functional results was highlighted. However, identifying
      a prognostic factor for the success of conservative treatment would put an end to
      the controversy by allowing a tailored attitude to every patient's unique
      situation. The importance of uropathologist's expert evaluation, including the
      depth of invasion, was emphasized. CONCLUSION: While ensuring optimal control of
      the disease, the indiscriminate use of radical surgery would be excessive in a
      significant minority of patients who do well under conservative treatment. It is
      suggested to consider as typical cases for immediate surgery, young patients with
      "deep" T1 tumours (>T1a or >1.5mm in depth) with at least one additional factors
      of bad prognosis: multifocality, association of carcinoma-in-situ, prostatic
      involvement, site difficult to resect.

PMID- 15041103
TI  - Optimising the medical management of benign prostatic hyperplasia.

PMID- 15041104
TI  - Darifenacin, an M3 selective receptor antagonist, is an effective and well
      tolerated once-daily treatment for overactive bladder.
AB  - OBJECTIVES: To evaluate the efficacy, tolerability and safety of darifenacin, a
      once-daily M3) selective receptor antagonist (M3 SRA), in patients with
      overactive bladder (OAB). METHODS: This multicentre, double-blind, placebo
      controlled, parallel-group study enrolled 561 patients (19-88 years; 85% female)
      with OAB symptoms for >6 months, and included some patients with prior exposure
      to antimuscarinic agents. After washout and a 2-week placebo run-in, patients
      were randomised (1:4:2:3) to once-daily oral darifenacin controlled-release
      tablets (3.75 mg [n=53], 7.5 mg [229] or 15 mg [n=115]) or matching placebo
      (n=164) for 12 weeks. Patients recorded daily incontinence episodes, micturition
      frequency, bladder capacity (mean volume voided), frequency of urgency, severity
      of urgency, incontinence episodes resulting in change of clothing or pads and
      nocturnal awakenings due to OAB using an electronic diary during weeks 2, 6 and
      12 (directly preceding clinic visits). Tolerability data were evaluated from
      adverse event reports. RESULTS: Darifenacin 7.5 mg and 15 mg had a rapid onset of
      effect, with significant improvement compared with placebo being seen for most
      parameters at the first clinic visit (week 2). This effect was sustained through
      week 12. At this time the number of incontinence episodes per week was reduced
      from baseline by 67.7% with darifenacin 7.5 mg and 72.8% with darifenacin 15 mg
      compared with 55.9% with placebo (p=0.010 and p=0.017, respectively, versus
      placebo). The 3.75 mg group (null dose arm) was included for proof of concept of
      dose flexibility, therefore formal sample sizing and statistical analysis were
      not performed for this group. Darifenacin 7.5 mg and 15 mg, respectively, were
      significantly superior to placebo for improvements in micturition frequency
      (p<0.001, p<0.001), bladder capacity (p<0.040, p<0.001), frequency of urgency
      (p<0.001, p=0.005), severity of urgency (p<0.001, p=0.002) and number of
      incontinence episodes leading to a change in clothing or pads (p<0.001, p=0.002).
      There was no significant reduction in nocturnal awakenings due to OAB. The most
      common adverse events were mild-to-moderate dry mouth and constipation. However,
      no patients withdrew from the study as a result of dry mouth and discontinuation
      related to constipation was rare (0.6% placebo versus 0.9% darifenacin). In
      addition, there was a low need for laxative use, with no difference between the
      darifenacin groups and those taking placebo. There were no reports of blurred
      vision and the CNS and cardiac safety profile was comparable to placebo.
      CONCLUSIONS: Darifenacin significantly improves the major symptoms of OAB. No
      significant CNS (primarily M1-receptor mediated) adverse events or cardiac
      (primarily M2-receptor mediated) adverse events were identified in this study, as
      may be predicted from the M3 selective receptor profile of darifenacin.

PMID- 15041105
TI  - Chronic testicular pain: an overview.
AB  - Chronic testicular pain (orchialgia, orchidynia or chronic scrotal pain) is
      common and well recognized but its pathophysiology is poorly understood.
      Currently treatment is largely empirical. This article aims to present an
      overview of its prevalence, possible aetiology and the available treatment
      options. The contribution of psychological factors is unclear, although some of
      these patients undoubtedly are depressed. Post vasectomy chronic testicular pain
      may be due to functional obstruction of the vas, or to spermatic granuloma. The
      surgical technique used may be relevant and the application of intraoperative
      local anaesthetic may have a role in reducing the risk. The importance of the
      sympathetic nervous system and the role of a possible alteration of the
      adrenergic receptors of the vas deferens in patients with chronic testicular pain
      are discussed. For patients failing to respond to conservative treatment,
      microsurgical denervation of the spermatic cord, epididymectomy and vasovasostomy
      have all shown a degree of relief. Unfortunately a small number of patients fail
      to respond to both conservative and more invasive treatment methods and for them
      the only available therapeutic option is inguinal orchiectomy.

PMID- 15041106
TI  - Handling and pathology reporting of renal tumor specimens.
AB  - The gold standard in the treatment of renal tumors is radical or partial
      nephrectomy. The surgical specimen handling is important since the pathologic
      features result in clinico-pathologic knowledge that determines prognosis,
      additional treatment and scientific studies. The correct handling of the specimen
      by urologists and pathologists becomes very basic in order to enable retrieval of
      a maximum of information. This protocol aims at standardization of the minimal
      criteria for handling, cellular subtyping, grading, staging and margin evaluation
      that must allow the comparison among the different scientific groups.

PMID- 15041107
TI  - An extended 10-core transrectal ultrasonography guided prostate biopsy protocol
      improves the detection of prostate cancer.
AB  - OBJECTIVE: To evaluate the efficacy of TRUS guided 10-core biopsy strategy for
      Turkish patients who had biopsy of the prostate for the first time. METHODS:
      Between February 2001 and May 2003, 303 consecutive men with suspected prostate
      cancer were included in the study. Indications for TRUS guided prostate biopsy
      were: abnormal digital rectal examination and/or a serum PSA over 2.5 ng/ml. All
      of the patients underwent a 10-core biopsy protocol with additional core from the
      each suspicious area detected by TRUS. Besides the sextant technique, 4 more
      biopsies were obtained from the lateral peripheral zone. We aimed to analyze
      whether cancer detection improved with the extended versus the standard sextant
      biopsy in our series overall and in each subgroup. RESULTS: Of 303 patients 94
      (31%) were positive for prostate cancer. Median age and PSA of prostate cancer
      patients were significantly higher than of the non-cancer patients. Besides
      prostate volumes of the cancer patients were significantly lower than of the non
      cancer ones. The cancer detection rates were 31% (94/303) and 23.1% (70/303) for
      the 10-core biopsy strategy and sextant biopsy strategies, respectively. Thus the
      10-core biopsy technique increased cancer detection rate by 25.5% (24/94) for the
      whole group of patients. A statistically significant number of additional cancers
      were detected with 10-core biopsy strategy for all the subgroups of the patients.
      Furthermore 10-core biopsy protocol detected more cancers (at least 6.4%) than
      all the probable different combinations of 8-core biopsy protocols. Among the 94
      cancer patients, biopsy from a suspicious area revealed cancer in 31.9% of them;
      however, in all of these patients cancer was already present in the 10-core
      biopsy. On the other hand, lesion biopsies revealed 5.7% additional cancers if
      sextant technique was used. There were only 3 (0.9%) serious complications
      requiring hospitalization and all 3 were infections controlled by appropriate
      antibiotics. CONCLUSION: Adding 4 lateral peripheral biopsies to the conventional
      sextant biopsy (10-core biopsy strategy) technique has increased the cancer
      detection rate by 25.5% without significant morbidity and without increasing the
      number of insignificant cancers. 10-core biopsy protocol was superior to all
      probable 8-core biopsy protocols in our study group. Additional biopsies from
      suspicious areas detected by transrectal ultrasonography revealed no further
      benefit if 10-core technique was used. We therefore suggest that 10-core biopsy
      protocol should be the preferred strategy in early detection of prostate cancer.

PMID- 15041108
TI  - Morbidity of prostatic biopsy for different biopsy strategies: is there a
      relation to core number and sampling region?
AB  - OBJECTIVES: The standard sextant prostatic biopsy is a safe procedure associated
      with low morbidity. Newer biopsy protocols suggest an increase in core numbers or
      sampling in distinct areas. In this respect we investigated the morbidity of
      different biopsy regimens. METHODS: Morbidity was assessed using self
      administered questionnaires 1 week and 1 month after biopsy in a prospective
      randomized trial of 405 men with three different biopsy protocols. We compared a
      sextant biopsy regimen to a 10-core biopsy strategy, as well as patients with a
      re-biopsy including t-zone sampling. We investigated pain during and after
      biopsy, gross hematuria, rectal bleeding, hematospermia, fever and chills.
      RESULTS: There is a trend towards a more painful biopsy and higher rate of side
      effects if the number of core samples is increased, this difference did not reach
      statistical significance. There was no increase in severity of side effects.
      Regarding the rate and severity of side effects of biopsy strategies to different
      areas of the prostate we could not find a difference. About 95% of patients would
      accept a repeat biopsy based on their experience on first biopsy. CONCLUSIONS:
      Morbidity of transrectal prostatic biopsy is low and increasing the number of
      cores correlates with a minor and statistically not significant increase in the
      rate of side effects. Transrectal sextant prostatic biopsy and extensive biopsy
      protocols are generally well tolerated and widely accepted from patients.

PMID- 15041110
TI  - Conservative management of mucosal prostatic urethral involvement in patients
      with superficial transitional cell carcinoma of the bladder.
AB  - OBJECTIVE: Treatment of patients with mucosal prostatic urethral transitional
      cell carcinoma (TCC) is controversial. In this study, we evaluated the outcome of
      patients with mucosal prostatic urethral TCC who were managed conservatively.
      METHODS: The data of 290 consecutive male patients with superficial TCC of the
      bladder who were treated at our institution were reviewed. Median age was 63
      years and median follow-up was 63 months. Initially, all patients with mucosal PU
      involvement without evidence of ductal and/or stromal involvement underwent
      intravesical BCG or Epirubicin therapy. RESULTS: Nineteen patients (6.6%) had
      mucosal involvement of the prostatic urethra (PU) and concomitant multifocal TCC
      of the bladder. Of those, 12 patients (12/19, 4.2%) had macroscopic mucosal
      involvement of the PU, while the other 7 patients (7/19, 2.4%) had microscopic PU
      tumor. Seven of 12 patients who were treated with BCG and 2 of 7 patients who
      were treated with Epirubicin achieved complete response. Progression occurred in
      3 patients who received BCG and no patients progressed in the Epirubicin group.
      CONCLUSIONS: Prostatic urethral sampling should be considered necessary in
      intermediate and high risk patients with superficial TCC of the bladder.
      Intravesical therapy, especially with BCG seems to be an effective treatment
      alternative in the management of mucosal PU involvement.

PMID- 15041111
TI  - Biopsy of the red patch at cystoscopy: is it worthwhile?
AB  - OBJECTIVE: At cystoscopy red patches of urothelium are commonly seen within the
      bladder and frequently biopsied in order to exclude carcinoma in situ (CIS),
      which classically presents as a red, velvety patch. This appearance however is
      not specific and it is possible that many lesions are biopsied without
      significant benefit to the patient. The objective of this study was to determine
      whether routine biopsy of red patches seen in the bladder at cystoscopy is
      warranted. PATIENTS AND METHODS: 193 biopsies were taken from red patches seen at
      flexible and rigid cystoscopy during a 4-year period from December 1997 to
      January 2002 and examined by histopathology. Patients included in the study were
      those on cystoscopic follow-up for transitional cell carcinoma (TCC) of the
      bladder and those undergoing investigation for haematuria or lower urinary tract
      symptoms. RESULTS: In 193 (17.7% of total biopsies) red patch biopsies,
      malignancy was found in 23 (11.9%) and 18 of 23 (78.3%) were CIS. No malignancies
      were detected in red patches from patients under the age of 60 years. CONCLUSION:
      Red patch biopsy yields a positive finding of malignancy in 12% and was concluded
      to be a valuable exercise, particularly in those over the age of 60 years and on
      follow-up for TCC.

PMID- 15041109
TI  - Metastatic prostate cancer treated by flutamide versus cyproterone acetate. Final
      analysis of the "European Organization for Research and Treatment of Cancer"
      (EORTC) Protocol 30892.
AB  - OBJECTIVES: This trial was designed to compare the efficacy of Flutamide (FLU)
      versus Cyproterone acetate (CPA) in men with metastatic prostate cancer and
      favourable prognostic factors. The primary endpoint of the trial was overall
      survival, disease specific survival, time to progression and side effects were
      secondary endpoints. The results pertaining to sexual function were already
      reported [Br J Cancer 82(2) (2000) 283]. MATERIAL AND METHODS: The trial was
      designed to detect a 50% improvement in median overall survival with 80% power.
      At the time of the present report, the trial provides 88% power to detect the
      planned difference of 50% with a 2-sided Logrank test and 80% power to detect a
      difference of 43% in median survival. RESULTS: 310 patients were randomized to
      treatment by FLU (250 mg t.i.d. p.o.) or CPA (100 mg t.i.d. p.o.). Of the 310
      patients, 12 (3.9%) were ineligible. The baseline characteristics of the two
      groups were similar except for age which was significantly younger in the CPA
      group and for the presence of soft tissue metastases which were absent in the FLU
      group and present in 6 patients in the CPA group. The median follow-up was 8.6
      years, 245 patients died, 158 (64.5%) of prostate cancer. There was no
      significant difference between the treatment arms with respect to overall
      survival, specific survival nor time to progression. Side effect profiles were
      studied and found to be more favourable for CPA overall and in particular with
      respect to gynecomastia, diarrhea and nausea. CONCLUSIONS: The trial shows no
      significant differences in efficacy between Flutamide and CPA monotherapy. The
      number of patients who died of prostate cancer up to this time is insufficient
      for a definitive analysis of specific survival. Erectile function and sexual
      activity are not preserved with FLU but decay slowly with both antiandrogens,
      toxicity is more pronounced with FLU.

PMID- 15041112
TI  - Pretreatment p53 nuclear overexpression as a prognostic marker in superficial
      bladder cancer treated with Bacillus Calmette-Guerin (BCG).
AB  - INTRODUCTION: Altered p53 gene product correlates with the stage and grade of
      bladder tumor, but its value as a predictor of BCG response has been
      disappointing. In order to revisit the prognostic value of pretreatment p53
      nuclear overexpression for the BCG response, we studied a large cohort of
      consecutive patients with superficial bladder cancer treated with BCG. METHODS:
      From 1988 to 2001, 102 patients with a history of multifocal, recurrent, and/or
      high-risk papillary transitional cell carcinoma or carcinoma in situ, were
      treated for the first time with BCG. p53 immunostaining was performed on paraffin
      embedded tissues using monoclonal antibody DO7 and an automated immunostainer.
      Special attention was paid to the conditions of tumor fixation. p53
      overexpression was defined as more than 20% tumor cells with p53-stained nuclei.
      RESULTS: Immunostaining was significantly higher for Ta/T1 G3 +/- Cis (p <
      0.001), tumoral substage T1b (p = 0.001), grade 3 (p = 0.0001), and Cis (p =
      0.002). Times to recurrence, progression and cancer death were shorter among
      patients with p53 overexpression (p = 0.03; p < 0.0001; p = 0.0003). In
      multivariate analysis, p53 overexpression was an independent predictor of
      recurrence (p = 0.0003) [RR = 0.15; 95%CI, 0.06 to 0.42]. CONCLUSION:
      Pretreatment p53 nuclear overexpression in superficial bladder tumors is
      associated with a high risk of disease recurrence, progression and cancer death
      after BCG therapy. Applying antibody DO7 with an automated immunostainer and
      stringent fixative conditions, p53 nuclear immunostaining yields clinically
      relevant information and may be a useful tool for selecting patients with
      superficial bladder cancer who might be resistant to BCG.

PMID- 15041113
TI  - Laparoscopic radical nephrectomy: techniques, results and oncological outcome in
      125 consecutive cases.
AB  - OBJECTIVES: Renal cell carcinoma is likely to become one of the most important
      indication for laparoscopic surgery. The laparoscopic technique combines the
      benefits of minimal invasive approach with established surgical principles. In
      our institution the laparoscopic transperitoneal approach with intact specimen
      removal has become the standard technique for radical nephrectomies. We report
      the indications, techniques and oncological outcome in a single center
      experience. PATIENTS AND METHODS: Between July 1999 and March 2003 we performed
      laparoscopic radical nephrectomies for renal cell cancer in 125 patients. Their
      initial staging, complications, and postoperative course were evaluated. During
      this period a total of about 1800 laparoscopic cases were performed. To date 82
      patients were available for follow up data and have been analyzed for oncological
      outcome. Patients with primary metastatic disease were excluded from this
      analysis. RESULTS: 123 procedures out of 125 were successful. In two cases (1.6%)
      conversion to open surgery was necessary due to bleeding (1 case) or bowel injury
      (1 case). In additional 3 cases (2.4%) intraoperative complications could be
      managed laparoscopically. In two cases (1.6%) postoperative bleeding lead to open
      revision for hemostasis. The mean tumor size was 5.1cm (range 2-14 cm); median
      blood loss was 210 ml (range 50-900 ml). The mean surgical time was 200 min
      (range 90-435), including the learning curves of five surgeons. Histological
      findings were pT1 in 78 (62.4%), pT2 in 12 (9.6%) and pT3 in 28 (22.4%) patients.
      In 7 cases (5.6%) histology did not confirm malignant disease. Positive lymph
      nodes were detected in 3 cases (2.4%); surgical margins were negative for tumor
      in all patients. Follow-up was between 3 and 50 months with an average of 23.5
      months. Disease progression was observed in 3 cases after 6, 11 and 12 months. No
      cases of local recurrence or port metastasis occurred during observation.
      CONCLUSIONS: Laparoscopic radical nephrectomy is a routine, effective treatment
      for patients with pT1-2N0M0 renal cell carcinoma. With more experience a tumor up
      to 10-12 m in size can be managed safely offering all the benefits of minimal
      surgery to the patients. Although no long-term follow-up is available our follow
      up data up to 50 months confirm the effectiveness of laparoscopic radical
      nephrectomy in terms of surgical principles and oncological outcome.

PMID- 15041114
TI  - The changing evolution of renal tumours: a single center experience over a two
      decade period.
AB  - OBJECTIVES: To study the evolution of renal tumours treated in a single
      institution over a 2-decade period. MATERIAL AND METHODS: 729 patients surgically
      treated due to a renal tumour were included in this study. Age at diagnosis,
      gender, tumour size, TNM stage, percentage (%) of benign tumours, type of
      treatment, histologic subtype and mode of presentation were compared over 3
      periods (1984-1992, 1993-1997, and 1998-2003). RESULTS: During the period of the
      study, the median tumour size decreased from 7.5 to 6 cm while the rate of
      nephron-sparing surgery (NSS) increased from 1.6 to 19.6% and from 3.1 to 46.9%
      in all tumours and in tumours measuring less than 4 cm respectively. In this
      former group, the percentage of benign tumours increased from 6.3 to 15.2% while
      the percentage of radical nephrectomies decreased from 100% to 54.2%. CONCLUSION:
      We are treating today a great amount of small good prognosis renal tumors as well
      as an increasing percentage of benign tumours. In both cases, expanding the role
      of NSS will significantly reduce the rate of useless radical nephrectomies.

PMID- 15041115
TI  - Spermatocytic seminoma: a review.
AB  - OBJECTIVE: Spermatocytic seminoma is a rare testicular tumour that has an
      extremely low rate of metastasis. We present a review of the management of this
      malignancy at our institution. METHOD AND MATERIALS: Between 1981 and 1999, 771
      patients were treated at our institution for testicular seminoma. Of these, 13
      had spermatocytic seminoma; one was excluded as he had treatment elsewhere. All
      patients were initially diagnosed at other hospitals and subsequently referred
      for management and had their pathology reviewed locally prior to any treatment.
      RESULTS: All patients had stage I disease, 5 patients received radiotherapy to
      the para-aortic and pelvic nodes, the other 7 were followed on a surveillance
      program. The median age was 62 years. With a median follow-up of 8.5 years no
      relapses were observed. Some patients exhibited adverse histological features
      associated with increased risk of relapse in seminoma including rete testis
      invasion and large primary tumour size. CONCLUSIONS: Spermatocytic seminoma may
      occur in younger patients and may not be restricted to the older population as
      commonly reported. Surveillance following orchidectomy is the preferred
      management option.

PMID- 15041116
TI  - A multicenter, randomized, double-blind, crossover study to evaluate patient
      preference between tadalafil and sildenafil.
AB  - PURPOSE: To assess patient preference for erectile dysfunction treatment between
      either sildenafil or tadalafil, each administered with their respective dosing
      instructions, and to evaluate preference for either sildenafil or tadalafil
      dosing instructions during tadalafil therapy. METHODS: We conducted a randomized,
      double-blind, crossover study consisting of four treatment arms. Because the
      dosing instructions for sildenafil and tadalafil are different, a unique
      methodology using sham placebo arms was employed to maintain the blind. To assess
      drug preference, 219 patients were randomized to either sildenafil 50 mg or
      tadalafil 20 mg, with dosing instructions reflecting their respective product
      profiles. To assess dosing instruction preference during tadalafil therapy, 46
      patients were randomized to tadalafil 20 mg with either tadalafil or sildenafil
      dosing instructions. After 12 weeks, patients were crossed-over. After 4 weeks of
      each treatment, all patients following sildenafil dosing instructions were
      offered the opportunity for an upward dose titration. In a double-blind fashion,
      all patients who requested an upward titration received additional capsules. To
      mimic the pattern of dose usage observed in clinical practice, the number of
      patients who received additional double-blind active medication was limited to
      35% of patients taking sildenafil in each treatment period in each country.
      Following the crossover treatment period, patients chose their preferred double
      blind treatment with dosing instructions to receive in the 12-week extension
      period. RESULTS: In the drug preference assessment, 132 of 181 (73%) evaluable
      patients chose to receive tadalafil (p < 0.001) during the extension period. In
      the dosing instruction preference assessment, 24 of 36 (67%) evaluable patients
      preferred tadalafil with tadalafil dosing instructions (p = 0.046). Sildenafil
      and tadalafil were well tolerated. CONCLUSIONS: In the doses utilized in this
      study, 73% of patients preferred tadalafil with tadalafil dosing instructions for
      the treatment of their erectile dysfunction over sildenafil with sildenafil
      dosing instructions. During tadalafil therapy, 67% of patients preferred
      tadalafil dosing instructions over sildenafil dosing instructions.

PMID- 15041117
TI  - European experience of 200 cases treated with botulinum-A toxin injections into
      the detrusor muscle for urinary incontinence due to neurogenic detrusor
      overactivity.
AB  - OBJECTIVES: To present a comprehensive experience with botulinum-A toxin (BTA)
      injected into the detrusor muscle in patients with spinal cord injuries/diseases
      causing neurogenic incontinence. METHODS: Ten European medical centers provided
      the results of 231 patients with neurogenic detrusor overactivity who were
      treated with BTA. 300 units of Botox (Allergan Inc.) were injected
      cystoscopically into the detrusor muscle at 30 different locations, while sparing
      the trigonum. Urinary continence status, concomitant anticholinergic medication
      use and patient satisfaction were recorded. Key urodynamic parameters (reflex
      volume, maximum detrusor pressure during voiding, detrusor compliance and maximum
      cystometric bladder capacity) at baseline and at the first and second urodynamic
      follow-up examinations were analyzed. RESULTS: By the time of the initial (mean
      12 weeks after injection) as well as at the second urodynamic follow-up
      examinations (mean 36 weeks after injection), the mean cystometric bladder
      capacity (p < 0.0001) and the mean reflex volume (p < 0.01) increased
      significantly, while the mean voiding pressure (p < 0.0001) decreased
      significantly. The mean bladder compliance had increased significantly (p <
      0.0001) by the first follow-up examination and non-significantly by the time of
      the second follow-up. No injection related complications or toxin related side
      effects were reported. The patients considerably reduced or even stopped taking
      anticholinergic drugs without recurrence of reflex incontinence and were
      satisfied with the treatment. CONCLUSIONS: This retrospective European
      multicenter study presents the most extensive experience to date with BTA
      injections into the detrusor muscle to treat neurogenic incontinence due to
      detrusor overactivity and confirms that this new treatment is safe and valuable.
      Significant improvement of bladder function corresponds with continence and the
      subjective satisfaction indicated by the treated patients.

PMID- 15041118
TI  - Oral nitric oxide donors: a new pharmacological approach to detrusor-sphincter
      dyssynergia in spinal cord injured patients?
AB  - PURPOSE: Detrusor-sphincter dyssynergia is a common cause of bladder outlet
      obstruction in spinal cord injured patients and leads to poor bladder emptying
      and high bladder pressures, which if left untreated might cause renal failure. In
      this study, we tested the recently published hypothesis that oral administration
      of a nitric oxide donor could be a new pharmacological approach to treat detrusor
      sphincter dyssynergia in humans with spinal cord injury. METHODS: 12 male spinal
      cord injured patients presenting with neurogenic detrusor overactivity and
      detrusor-sphincter dyssynergia were studied. 6 performed clean intermittent
      catheterisation and 6 used suprapubic tapping for bladder emptying. During
      cystometry the bladder was filled until the first overactive bladder contraction
      accompanied by detrusor-sphincter dyssynergia occurred while bladder and external
      urethral sphincter pressures were continuously recorded. Then the bladder was
      emptied and the patients received 10 mg of isosorbide dinitrate sublingually.
      Resting pressures were recorded and cystometry was repeated starting 15 min after
      drug administration. Maximal and mean values for bladder and external urethral
      sphincter pressures were calculated in both fillings and statistically compared
      by analysis of variance for repeated measurements (level of significance p <
      0.05). RESULTS: Nitric oxide significantly reduced external urethral sphincter
      pressures at rest (p < 0.05) and during dyssynergic contraction (p < 0.05) while
      bladder pressures at rest and during contraction as well as the reflex volume
      remained unchanged. In the patients who used suprapubic tapping for bladder
      emptying the mean post triggering residual volume was significantly reduced (p <
      0.05). CONCLUSIONS: Oral administration of nitric oxide donors significantly
      reduced bladder outlet obstruction due to detrusor-sphincter dyssynergia
      suggesting a role for nitric oxide in inhibitory neurotransmission to the
      urethral sphincter. This new approach could offer a potential pharmacological
      option to treat detrusor-sphincter dyssynergia in spinal cord injured patients.

PMID- 15041119
TI  - Cytostatic and apoptotic effects of bisphosphonates on prostate cancer cells.
AB  - BACKGROUND: Bisphosphonates are potent inhibitors of bone resorption frequently
      used for breast cancer and myeloma-induced bone disease. Zoledronic acid has been
      recently shown to also reduce skeletal morbidity from prostate cancer. METHODS:
      We have investigated the biological effects of bisphosphonates on PC-3 cell
      survival (MTT assay and DNA content). We compared four bisphosphonates at doses
      ranging from 10(-6) to 10(-4) M: clodronate, pamidronate, ibandronate and
      zoledronic acid. We analyzed cell cycle phases and assessed apoptotic effects of
      bisphosphonates by three different methods. RESULTS: Clodronate exhibited only a
      slight inhibitory effect on cell growth. In contrast, aminobisphosphonates
      markedly decreased cell growth in a time- and dose-dependent manner exerting
      cytostatic and apoptotic effects. The largest effects were observed after six
      days of exposure to 10(-4) M bisphosphonates. Cytostatic effects were observed
      with all three aminobisphosphonates whereas apoptotic effects were especially
      evident after zoledronic acid incubation. CONCLUSIONS: Aminobisphosphonates,
      especially zoledronic acid, markedly inhibited PC-3 cancer cell growth, through a
      variable combination of cytostatic and apoptotic effects. This activity could
      potentially contribute to the beneficial effects of bisphosphonates in prostate
      cancer patients with bone metastases.

PMID- 15041120
TI  - Fertility preservation in cancer patients. Proceedings of a symposium. April 21
      22, 2002, Taormina, Italy.

PMID- 15041121
TI  - Testicular function following chemo-radiotherapy.
AB  - Improvements in cancer survival raise infertility issues in young patients
      suffering from malignancies. The aim of the study is to review current knowledge
      on the effect of chemotherapy (CT) and radiotherapy (RT) for testis and
      hematological neoplasms on testicular function. Cisplatin-based regimens for
      testis neoplasm induce temporary azoospermia; permanent damage can occur with
      high doses (400-600 mg/m(2)). Alkylating agents are very effective for
      hematological neoplasm therapy but extremely dangerous to germinal epithelium.
      Damage can be irreversible. Spermatozoa cannot tolerate irradiation doses higher
      than 6 Gy. Leydig cells are damaged by doses higher than 15 Gy. A-Spermatogonia
      have been shown to survive after CT and RT and their recovery for post-treatment
      graft has been recently developed in animal models. Infertility counselling
      before treatment in young oncological patients is mandatory. Cryopreservation is
      the best option for fertility protection.

PMID- 15041123
TI  - Semen cryopreservation from oncological patients: the Italian experience.
AB  - The aim of the study is to summarize official data on semen cryopreservation for
      oncological patients in Italy. The first private semen bank for oncological
      patients in Italy was founded by Colpi in 1983 in Milan. In 1987, the first
      public semen bank was established in "Macedonio Melloni" Hospital (Milan) by
      Ragni. Normal semen samples are usually present in only 40% of oncological
      patients. The rate of semen sample use for assisted reproduction techniques is
      similar to international data (5%). At present, semen cryopreservation is
      possible only in about 20 Italian centers.

PMID- 15041122
TI  - Sperm cryopreservation for male patients with cancer: an epidemiological analysis
      at the University of Pennsylvania.
AB  - Many cancers strike young males who have not yet started or completed families.
      Since cancer treatments such as chemotherapy and radiation can irreversibly
      affect spermatogenesis, sperm cryopreservation is an important option for storing
      male reproductive potential. In this report, we review our database of 10 years
      of experience with cryostorage for male cancer patients. We assess types of
      cancer, timing of collection, sperm quality, and utilization for reproductive
      purposes. We also report specimen disposal and rates of patient death. There were
      a total of 164 oncology patients electing to freeze sperm at our institution
      during the study period. Types of cancer were varied, with testicular cancer,
      Hodgkin's lymphoma, leukemia, and gastrointestinal cancers comprising the largest
      groups. Evaluation of semen parameters for these groups revealed that
      oligospermia, even prior to initiation of cancer therapy, was common. Sperm
      counts, motility, and morphology did not differ by type of cancer. Interestingly,
      less than 5% of patients utilized their specimens for reproductive purposes.
      Seven insemination cycles yielded no pregnancies, while one of two IVF attempts
      and the single ICSI case were successful. In conclusion, the epidemiological
      review of our database suggests that sperm cryostorage for fertility preservation
      in male cancer patients is under-utilized. Additionally, there is minimal use of
      cryopreserved specimens for reproductive purposes. We speculate that this under
      utilization may be due to the paucity of reports regarding reproductive outcome
      after freezing. It is our objective to provide a compilation of data that will
      prove useful to both physicians and patients who are considering sperm
      cryopreservation.

PMID- 15041124
TI  - Oocyte cryopreservation in oncological patients.
AB  - The use of chemotherapy and radiotherapy in oncological patients may reduce their
      reproductive potential. Sperm cryopreservation has been already used in men
      affected by neoplastic disease. Oocyte cryopreservation might be an important
      solution for these patients at risk of losing ovarian function. A program of
      oocyte cryopreservation for oncological patients is also present in our center.
      From June 1996 to January 2000, 18 patients awaiting chemotherapy and
      radiotherapy for neoplastic disease were included in our oocyte cryopreservation
      program. Our experience documents that oocyte storage may be a concrete and
      pragmatic alternative for oncological patients. The duration of oocyte storage
      does not seem to interfere with oocyte survival as pregnancies occurred even
      after several years of gamete cryopreservation in liquid nitrogen.

PMID- 15041126
TI  - Human oocyte cryopreservation: a valid alternative to embryo cryopreservation?
AB  - Embryo cryopreservation has become an ethical necessity due to the way human in
      vitro fertilization (IVF) infertility therapy has developed. Limited embryonic
      implantation has by necessity driven IVF therapy to adopt ways to maximize the
      harvest of oocytes following ovarian hyperstimulation with its attendant risks.
      Collection of more oocytes has allowed more embryos to be generated to compensate
      for poor embryonic viability, often leading to transfer of multiple embryos to
      increase per transfer pregnancy rates. In an era of improving embryonic viability
      and prevailing trend toward single embryo transfers, production of excessive
      numbers of surplus embryos appears increasingly inappropriate. At which stage
      embryo cryopreservation can be undertaken most effectively remains controversial.
      Embryo cryopreservation nevertheless represents the current solution to the
      problem of excessive embryo production, but inherently raises ethical concerns
      for certain couples uncomfortable with what they might perceive to be
      "experimental" cryostorage, who in extreme circumstances may even choose to limit
      the number of oocytes inseminated to obviate the production of spare embryos. On
      a more practical level, cryostored embryos are co-owned by two people who may
      separate, and as such the embryos then face an uncertain fate, commonly decided
      in courts of law. Oocyte cryopreservation, if consistent and successful, offers a
      way to avoid the above complications of routine IVF therapy. Oocytes may need to
      be cryostored in the event of unforeseen non-production of sperm during IVF
      therapy, allowing a more measured consideration of donor sperm use or other means
      of sperm retrieval. Beyond IVF for infertility therapy using a couple's own
      gametes, oocyte cryopreservation provides a wonderful opportunity to optimize
      donor oocyte cryo-banking, reducing costs and improving convenience. Meanwhile,
      frozen embryo donation is an approach that many couples are uncomfortable with,
      and allows only for retrospective donor screening, and less gametic choice.
      Advances in ovarian tissue cryopreservation will probably provide the best
      approach for long term storage of female gametes for women wishing to elect to
      prolong their reproductive potential, or prior to cancer therapy. However,
      improved consistency with vitrification technology through standardization of
      protocols and cell-carrying systems is bringing routine single oocyte
      cryostorage, at all stages of egg maturity, closer to reality. This, coupled with
      in vitro maturation, will aid development of oocyte collection protocols using
      minimal amounts of gonadotropins. All of which will help drive IVF programs to
      consider cryostorage of excess oocytes and not embryos, inseminating post
      thaw/warming only a limited number of oocytes at any one time, in anticipation of
      the need for only one or two embryos at transfer. The question then is how close
      are we to being able to provide routine clinical application of human oocyte
      cryostorage, and when will it be appropriate?

PMID- 15041125
TI  - Effects of cryopreservation on the meiotic spindle of human oocytes.
AB  - The microtubular meiotic spindle of most mammals, including humans, is very
      sensitive to cooling [Hum. Reprod. 16 (2001) 2374; Fertil. Steril. 54 (1990) 102;
      Fertil. Steril. 75 (2001) 769; Zygote 3 (1995) 357] and is rapidly depolymerised
      even after a slight reduction in temperature to 33 degrees C. Spindle disassembly
      is dependent on the extent of temperature decrease and its duration. After
      rewarming, the recovery is far from complete. Cryoprotectants themselves may
      alter the spindle structure, depending on the duration and temperature of
      exposure, the duration of recovery at 37 degrees C and the species [Hum. Reprod.
      Update 2 (1996) 193]. Damage to the meiotic spindle is considered to be the cause
      of aneuploid embryos, by inducing chromatid non-disjunction and chromosome
      scattering and by disturbing the sequence of events leading to the completion of
      meiosis and fertilisation. Nevertheless, a consensus arose from all the studies:
      appropriate exposure to cryoprotectants and appropriate rates of cooling and
      thawing allow the cryopreservation of mature oocytes without any significant
      changes in their second meiotic spindle organisation and without any increase in
      the rate of aneuploid embryos [Mol. Hum. Reprod. 2 (1996) 445; Hum. Reprod. 8
      (1993) 1101; Hum. Reprod. 9 (1994) 684; Microsc. Res. Technol. 27 (1994) 165;
      Fertil. Steril. 75 (2001) 354]. These fundamental studies in humans, showing good
      preservation of cell structures after freeze-thaw procedures opened the way to
      new successful clinical trials with embryos derived from cryopreserved mature
      oocytes [Fertil. Steril. 68 (1997) 724]. Considering immature oocyte freezing at
      prophase I (germinal vesicle (GV) stage), a stage which was thought to be less
      sensitive to cryoinjury, pooled data from the literature showed no advantage in
      terms of survival rates, fertilisation rates of in vitro matured oocytes and
      developmental ability of the resulting embryos, especially in unstimulated
      cycles. Moreover, conflicting results are reported on the effects of freezing on
      the spindle-chromosome configuration of immature oocytes or in vitro matured
      oocytes, highlighting the need for large scale studies [Hum. Reprod. 10 (1995)
      1816; Hum. Reprod. 13 (Suppl. 3) (1998) 161; Hum. Reprod. 17 (2002) 1885;
      Microsc. Res. Technol. 27 (1994) 165; Fertil. Steril. 68 (1997) 920]. One child
      has been born after the use of cryopreserved immature oocytes at GV stage,
      matured in vitro and fertilised by ICSI [Hum. Reprod. 13 (1998) 3156],
      demonstrating at least the feasibility of this technique. Improvements are
      required so as to make mature and immature oocyte cryopreservation an established
      and safe technique for ART.

PMID- 15041127
TI  - Cryopreservation of IVF embryos: which stage?
AB  - Embryo freezing is a mandatory tool in IVF technology as controlled ovarian
      hyperstimulation usually leads to extra embryos which are not transferred. One
      dilemma is the embryonic stage at which the embryos are to be frozen. Early stage
      freezing (PNs or cleavage stage) leads to a two step selection: at the time of
      thawing and a few hours or a day after. Then the recovering embryos are submitted
      to the classical in vitro developmental arrests in relation with maternal,
      paternal and cytogenetic factors. The "take home baby rate" per frozen embryo is
      low, rarely over 5%. Blastocyst have overcome the blocks in vitro: a first
      selection has already been made. The quality of freezing at this stage depends
      greatly on the culture conditions. It allows freezing of fewer embryos, but with
      higher yields: a >10% take home baby rate can be expected. It is clear to us that
      vitrification, beside the technical problems, has to be handled with care,
      especially if ethylene glycol (EG) is used. Metabolic products of EG might have
      negative effects on organogenesis.

PMID- 15041128
TI  - Ovarian function following radiation and chemotherapy for cancer.
AB  - High-dose chemotherapy and radiotherapy have increased the long-term survival of
      young patients with cancer; nevertheless, the toxic effects on ovarian function
      causing amenorrhoea, premature menopause and infertility, are still severe.

PMID- 15041129
TI  - Cryopreservation of human ovarian tissue.
AB  - Approaches to the cryopreservation of human ovarian tissue are typically
      characterised by the use of slow freezing/rapid thawing methods using dimethyl
      sulfoxide or 1,2-propanediol (PROH) as cryoprotectants. This paper reviews
      current experience with these procedures.

PMID- 15041130
TI  - Ovarian transplantation in humans: indications, techniques and the risk of
      reseeding cancer.
AB  - Laboratory research on ovarian cryopreservation and transplantation began in the
      1950s leading to clinical studies in the 2000s. The research that was performed
      during this half century indicated that cryopreserved ovarian tissue has the
      potential to restore fertility in women who face premature ovarian failure due to
      chemotherapy, radiotherapy or surgery. To date, ovarian function has been
      restored in at least four women. Even though no pregnancies have been reported so
      far from these clinical studies, animal studies indicate that this is a valid
      prospect for humans. Future clinical trials will determine on a larger number of
      patients the longevity of ovarian grafts, normality of hormone production and
      ovarian follicle development, possibility and safety of pregnancy, and the safety
      of auto-transplantation in cancer patients. However, the major improvement in the
      efficiency of ovarian transplantation is anticipated to come from research
      exploring the revascularization process.

PMID- 15041131
TI  - Autotransplantation of ovarian tissue and the risk of disease transmission.
AB  - Temporary ovarian function has been reported following reimplantation of
      frozen/thawed cortical tissue and it is hoped that in time this technique will
      allow women sterilised by treatment for cancer to regain their fertility. There
      is however a concern, supported by animal data, that ovarian tissue may be
      contaminated by disease capable of causing a relapse after transplantation. One
      experiment, in which ovarian tissue from women with lymphoma was xenografted into
      immunodeficient mice, showed no evidence of transmission but these results
      require confirmation and no data exists for other malignancies. For the time
      being, therefore, it is recommended that harvesting and reimplantation of ovarian
      tissue should only take place within the confines of carefully designed clinical
      trials.

PMID- 15041132
TI  - Cryopreservation and culture of human ovarian cortical tissue containing early
      follicles.
AB  - Maturation of oocytes from primordial follicles after cryopreservation of ovarian
      tissue with subsequent in vitro fertilisation would be an important method of
      infertility treatment for young women who are to undergo premature ovarian
      failure due to chemotherapy or genetic causes. Cryopreservation of human ovarian
      tissue is already feasible. Human primordial follicles can be cultured regularly
      to secondary and occasionally to early antral stages, yet cultures have to be
      further optimised before meiotically competent oocytes can be achieved for final
      maturation in vitro. Maturation in vitro (IVM) of oocytes obtained by aspiration
      from small antral follicles is already a feasible technique resulting in
      pregnancies, with many healthy infants born.

PMID- 15041133
TI  - Long-term ovarian function in sheep after ovariectomy and autotransplantation of
      cryopreserved cortical strips.
AB  - Transplantation of cryopreserved ovarian tissue offers a means of preserving
      reproductive function in girls/women whose ovarian function is compromised by
      radio- and/or chemotherapy for cancer. Studies in small laboratory rodents have
      demonstrated that fertility can be restored by transplanting whole cryopreserved
      ovaries. In large animals, it is not possible to freeze or transplant ovaries
      without vascular anastomosis. However, primordial oocytes in cortical strips
      survive freezing, thawing and culture in vitro. We have used sheep as an
      experimental model for the human because the size of the ovary and length of
      folliculogenesis (4-6 months) are similar. Following orthotopic transplantation
      the grafts, become vascularised within a few days and ovulatory cycles become
      established by 4 months. Several lambs have been born in ewes after
      autotransplantation of the grafts which continue to function for up to 2 years.
      The levels of FSH remain consistently raised after transplantation due to a
      reduced secretion of inhibin A, reflecting the reduction in the size of the
      ovarian pool of follicles.

PMID- 15041134
TI  - Follicle development following cryopreservation of human ovarian tissue.
AB  - Despite the recent increase in human ovarian tissue banking, there has been
      little progress in establishing whether follicles within this tissue are viable
      and capable of function following cryopreservation. Two methods to assess growth
      and developmental potential of cryopreserved tissue are evaluated; (1). isolated
      follicle culture and (2). xenografting of tissue into a host animal. Development
      of numerous antral follicles following xenografting of cryopreserved tissue
      indicates that the cryopreservation procedure can preserve the developmental
      competence of primordial follicles.

PMID- 15041135
TI  - Time course and nature of stimulus evaluation in category induction as revealed
      by visual event-related potentials.
AB  - Category induction involves abstraction of features common to two or more
      stimuli. We predicted that category induction affects processing of each
      stimulus, before completion of perceptual analysis. Event-related potentials
      (ERPs) were recorded from ten 11-13-year olds while they were performing visual
      category-induction tasks. Subjects viewed a series of two geometric shapes
      belonging to the same perceptual category (size, color, or shape), defined by one
      or two shared features, and decided if a probe stimulus shared membership in that
      category. Large frontal N120, frontal-central N300 and smallest P450 were
      elicited by the first stimulus; number of shared features affected P150, N170,
      and P450 amplitudes to the second stimulus. Principal Component Analysis (PCA)
      indicated networks of frontal, parietal and occipital activity, different to each
      stimulus. Results suggest that in young adolescents category induction affects
      early stages of stimulus processing. Processing is based on selective analysis of
      stimuli for shared features, not exhaustive examination of all features of all
      stimuli.

PMID- 15041136
TI  - Rhythmic context influences the auditory evoked potentials of musicians and non
      musicians.
AB  - In this study, we investigated how rhythms are processed in the brain by
      measuring both behaviourally obtained ratings and auditory evoked potentials
      (AEPs) from the EEG. We presented probe beats on seven positions within a test
      bar. Two bars of either a duple- or triple meter rhythm preceded probe beats. We
      hypothesised that sequential processing would lead to meter effects at the 1/3
      and 1/2bar positions, whereas hierarchical processing would lead to context
      effects on the 1/3, 1/2 and 2/3bar positions. We found that metric contexts
      affected behavioural ratings. This effect was more pronounced for rhythmic
      experts. In addition, both the AEP P3a and P3b component could be identified.
      Though metric context affected the P3a amplitudes, group effects were less clear.
      We found that the AEP P3a component is sensitive to violation of temporal
      expectancies. In addition, behavioural data and P3a correlation coefficients
      (CCs) suggest that temporal patterns are processed sequentially in nonmusicians
      but are processed in a hierarchical way in rhythmic experts.

PMID- 15041137
TI  - Changes in P300 amplitude during an active standard auditory oddball task.
AB  - This study evaluated whether P300 amplitude declines in response to repeated
      presentation of the target in a standard auditory oddball task; to what extent
      the decrease is affected by the number of targets presented, interrupted by an
      interblock interval (IBI, 3 min) and consistent. We also aimed to identify
      factors inducing P300 amplitude decrease and its psychological significance. Two
      blocks of 500 tones (each divided into five subblocks of 100 tones) were
      presented. First block: P300 amplitude was smaller in the first subblock than in
      the second, which we attribute to processing resources during the first subblock
      being divided between the task of identifying the target and the process of
      estimating subjective probability. Amplitude decreased from the second subblock
      onwards. The interblock interval was sufficient for amplitude to return to pre
      decrease levels. The intrablock decline was replicated in the second block. The
      decline in P300 amplitude might to reflect a progressive automation of the
      context-updating operations.

PMID- 15041138
TI  - Apprehension of the subsequent working day is associated with a low amount of
      slow wave sleep.
AB  - Stress is probably the most frequent cause of short-term insomnia, although it
      has seldom been documented polysomnographically. A few studies have shown that
      apprehension is associated with a reduction of slow wave sleep (SWS). The aim of
      the present study was to examine whether apprehension of the next working day
      would be related to sleep polysomnography and subjective sleep quality. In this
      analysis we made use of two different studies (n = 37, mean age: 37 years) that
      provided inter-individual variation in apprehension of the subsequent working
      day. The results confirm previous findings that apprehension of a difficult next
      day is associated with decreased amount of SWS, increased percentage of stage 2
      sleep, bedtime state anxiety and subjectively poor sleep. It is concluded that
      moderate "everyday" stress may disturb physiological restoration as indicated by
      the reduction of SWS.

PMID- 15041139
TI  - A metabolic measure of mental effort.
AB  - Previous studies have operationalised mental effort via various indices of
      psychophysiology, particularly cardiovascular measures. Metabolic measures
      represent a complementary approach wherein mental effort investment is explicitly
      linked to the process of energy mobilisation. The purpose of this study was to
      contrast cardiovascular variables (heart rate, 0.1 Hz component of heart rate
      variability) with a metabolic measure (blood glucose) of mental effort. Twenty
      nine participants were exposed to Stroop stimuli over a 45 min period under two
      conditions: (a) congruent (i.e. 100% congruent Stroop stimuli); and (b)
      incongruent (i.e. 100% incongruent Stroop stimuli). Performance, blood glucose,
      cardiovascular activity and subjective mood were measured. The results indicated
      that blood glucose levels were sensitive to both Stroop and time-on-task
      variables, whilst cardiovascular measures were only sensitive to the latter.
      There was also evidence of an association between blood glucose levels and
      response accuracy. The implications of these findings for the operationalisation
      of mental effort are discussed.

PMID- 15041140
TI  - Multiple sources of dietary calcium-some aspects of its essentiality.
AB  - The increasing recognition of the important role of calcium in the myriad
      regulation of cellular processes in the health and well being throughout one's
      lifetime has focused on the need to ensure a sufficiency of its intake for
      nutritional, physiological, and medical reasons. Additionally, the recognition of
      the dynamic dietary changes and preferences of various populations in terms of
      their consumption of calcium-containing products coupled with large variations of
      food patterns and availability of calcium, highlights the need to consider and
      evaluate multiple sources of calcium (dairy, non-dairy, fortified foods, and
      supplemental). Aspects of the essentiality of calcium are thus considered via an
      initial consideration of: the salient aspects of absorption and bioavailability,
      changes in individual and societal dietary habits and preferences and the
      evaluation of various RDAs, AIs, and DRIs for calcium.

PMID- 15041141
TI  - SIDS reprotoxicity screening test update: testing strategies and use.
AB  - The OECD screening information data set (SIDS) project is a cooperative effort of
      OECD member countries and industry to assess the hazard/risk posed to human
      health and the environment by high production volume (HPV) chemicals, and to
      assign priorities for further work. To date, work has been initiated on about
      1000 HPV chemicals. Abbreviated reproduction and developmental toxicity screening
      tests (OECD test guidelines 421 and 422) were developed specifically for the SIDS
      project. These tests, though not providing a complete characterization of
      reproductive or developmental hazard, are accepted in USA and Japan as fulfilling
      the requirement of an initial reproduction and developmental toxicity evaluation
      for HPV chemicals. Based on the OECD-approved SIDS initial assessments for 54
      substances tested according to guideline 421 or 422, these tests are providing
      useful data for initial hazard assessment.

PMID- 15041142
TI  - A multi-laboratory evaluation of a common in vitro pepsin digestion assay
      protocol used in assessing the safety of novel proteins.
AB  - Rationale. Evaluation of the potential allergenicity of proteins derived from
      genetically modified foods has involved a weight of evidence approach that
      incorporates an evaluation of protein digestibility in pepsin. Currently, there
      is no standardized protocol to assess the digestibility of proteins using
      simulated gastric fluid. Potential variations in assay parameters include: pH,
      pepsin purity, pepsin to target protein ratio, target protein purity, and method
      of detection. The objective was to assess the digestibility of a common set of
      proteins in nine independent laboratories to determine the reproducibility of the
      assay when performed using a common protocol. Methods. A single lot of each test
      protein and pepsin was obtained and distributed to each laboratory. The test
      proteins consisted of Ara h 2 (a peanut conglutin-like protein), beta
      lactoglobulin, bovine serum albumin, concanavalin A, horseradish peroxidase,
      ovalbumin, ovomucoid, phosphinothricin acetyltransferase, ribulose diphosphate
      carboxylase, and soybean trypsin inhibitor. A ratio of 10U of pepsin
      activity/microg test protein was selected for all tests (3:1 pepsin to protein,
      w:w). Digestions were performed at pH 1.2 and 2.0, with sampling at 0.5, 2, 5,
      10, 20, 30, and 60min. Protein digestibility was assessed from stained gels
      following SDS-PAGE of digestion samples and controls. Results. Results were
      relatively consistent across laboratories for the full-length proteins. The
      identification of proteolytic fragments was less consistent, being affected by
      different fixation and staining methods. Overall, assay pH did not influence the
      time to disappearance of the full-length protein or protein fragments, however,
      results across laboratories were more consistent at pH 1.2 (91% agreement) than
      pH 2.0 (77%). Conclusions. These data demonstrate that this common protocol for
      evaluating the in vitro digestibility of proteins is reproducible and yields
      consistent results when performed using the same proteins at different
      laboratories.

PMID- 15041143
TI  - Health effect levels for risk assessment of childhood exposure to arsenic.
AB  - Health risks to children from chemicals in soil and consumer products have become
      a regulatory focus in the U.S. This study reviews short-term health effect levels
      for arsenic exposure in young children (i.e., 0-6 years old). Acute health
      effects are described mostly in adults in case reports of arsenic poisoning from
      water or food and in studies of medicinal arsenic treatment. Several
      epidemiological studies report health effects from subchronic arsenic exposure in
      children primarily from drinking water in developing countries. Acute health
      effects typically include gastrointestinal, neurological, and skin effects, and
      in a few cases facial edema and cardiac arrhythmia. Dermatoses are most
      consistently reported in both adults and children with subchronic exposure. With
      low exposure, the prevalence and severity of disease generally increases with age
      (i.e., length of exposure) and arsenic dose. The available data collectively
      indicate a lowest-observed-adverse-effect level around 0.05mg/kg-day for both
      acute and subchronic exposure. At low doses, children do not appear to be more
      sensitive than adults on a dose-per-body-weight basis, although data for acute
      exposures are limited and uncertainties exist for quantifying potential
      neurological or vascular effects at low-level subchronic exposures. Based on
      these data, possible reference levels for acute and subchronic exposure in young
      children are 0.015 and 0.005mg/kg-day, respectively.

PMID- 15041144
TI  - Mainstream smoke constituent yields and predicting relationships from a worldwide
      market sample of cigarette brands: ISO smoking conditions.
AB  - The study objective is evaluation of a benchmark approach for predicting
      mainstream smoke constituent machine-yields for conventional cigarette brands
      from worldwide markets. Results for ISO smoke yields support the validity of
      benchmarking when brands, for which yields are to be predicted, have design
      characteristics within boundaries established by the exploratory brands. Yields
      of ISO-method mainstream smoke constituents were generally well described by
      weighted least squares regression relationships with ISO tar (R2>0.80 and
      coefficient p values <0.05). The impact of the varied chemical composition of
      cigarette tobaccos from different regions on smoke constituent yields was
      recognized. Mainstream smoke nitrogen oxides and tobacco-specific nitrosamine
      (TSNA) yield prediction relationships improved by including tobacco nitrate or
      TSNA concentration factors in respective independent parameters. For carbon
      filter brands, inclusion of a carbon factor improved the predicting relationships
      for several vapor-phase constituents. Relationships were validated with a subset
      of additional validation brands. Greater than 90% of the validation brands' smoke
      chemistry yields were within the 95% prediction intervals. Average differences
      between measured and predicted yields were generally within the range of one to
      two measurement standard deviations. The estimation methods proposed relate to
      machine-smoking conditions and are not intended to reflect the actual exposure of
      any given consumer to smoke constituents.

PMID- 15041145
TI  - A responsive, sensitive, and reproducible dermal tumor promotion assay for the
      comparative evaluation of cigarette smoke condensates.
AB  - The mouse dermal initiation/promotion bioassay has been used for several decades
      to study cigarette smoke condensates (CSCs). However, these studies have used
      highly variable methodologies that differ in the manner of CSC collection,
      duration of treatment, mouse strain, number of mice and endpoints measured. In
      this report, a protocol that uses female SENCAR mice and standardizes many of the
      procedures is presented. A reference cigarette (University of Kentucky 1R4F),
      readily available to researchers, was used. This report presents the combined
      data from four independent studies. Female, SENCAR mice (40/group) were treated
      with a single dose (75microg) of dimethylbenz[a]anthracene (DMBA) as an
      initiator, followed 1 week later by treatment (three times/week) with 10, 20 or
      40mg "tar"/application of 1R4F CSC for 29 weeks. There were no treatment-related
      effects on body weights. Histological diagnosis of all masses at study
      termination indicated a dose-dependent increase in the number of tumor-bearing
      mice and total tumor number. These studies support the conclusion that the 1R4F
      cigarette is suitable for use as a reference standard and the protocol presented
      is an appropriate and standardized model suitable for the comparative evaluation
      of CSC.

PMID- 15041146
TI  - Epidemiologic evidence for assessing the carcinogenicity of acrylamide.
AB  - Acrylamide (ACM) has recently been found in fried and baked foods, suggesting
      widespread public exposure. ACM is an industrial chemical that causes
      neurotoxicity in humans and an increase in benign tumors of the endocrine system
      of laboratory rats. The U.S. EPA and the International Agency for Research on
      Cancer (IARC) have designated ACM as a probable human carcinogen based on the
      bioassay data and evidence for a DNA reactive mechanism. We report here an
      assessment of the published epidemiological data with regard to exposure to ACM.
      The results of an epidemiology mortality study of heavily exposed workers
      published in 1999 failed to reveal any increase in total cancer in this
      workforce. The average total exposure in the exposed group was equivalent to over
      100% of the estimated average lifetime dietary intake, assuming a U.S. diet.
      However, this epidemiologic information had limited power to detect modest
      increases in specific tumors of the type reported in the rodent studies. Although
      the mortality study could not have picked up the small increases in cancer or in
      specific cancer types predicted by EPA's linear extrapolation model, research on
      biochemical and physiological mechanisms suggests that EPA's assessment
      overstates the potency, and therefore, the risk from foods and other sources of
      exposure may be lower than previously anticipated.

PMID- 15041147
TI  - Ranking and prioritization of environmental risks of pharmaceuticals in surface
      waters.
AB  - Pharmaceuticals have been reported in surface waters, prompting legitimate public
      concern, as pharmaceuticals are biologically active compounds used daily by the
      public. Currently there are ecotoxicological data available for <1%, thus, the
      European Union Commission's Scientific committee on Toxicity, Ecotoxicity, and
      Environment (CSTEE) recommended use of (Q)SAR models and precaution to prioritize
      further risk assessment of approximately 4500 compounds and their adjuvants. We
      ranked 2986 different pharmaceutical compounds in 51 classes relative to hazard
      toward algae, daphnids, and fish using the EPIWIN program. This ranking cannot be
      used to acquit a compound based on predicted relative ranking. Modifying
      additives were the most toxic classes. Cardiovascular, gastrointestinal,
      antiviral, anxiolytic sedatives hypnotics and antipsychotics, corticosteroid, and
      thyroid pharmaceuticals were the predicted most hazardous therapeutic classes.
      The overall relative order of susceptibility was estimated to be daphnids > fish
      > algae. Expert judgment is needed to assess specific hazards for classes like
      microbial resistance and antibiotics, sex hormones, and endocrine disruptors. As
      human health and the function of ecological systems are interconnected and
      subject to the precautionary principle, harmonization of evidence for correlation
      and causality of adverse effects seems sensible in an ethical and cost-effective
      context to facilitate substitution of hazardous compounds. Data available:
      http://www.uoguelph.ca/~hsander/.

PMID- 15041148
TI  - Development of acute exposure guideline levels for airborne exposures to
      hazardous substances.
AB  - Hazardous substances can be released into the atmosphere due to industrial and
      transportation accidents, fires, tornadoes, earthquakes, and terrorists, thereby
      exposing workers and the nearby public to potential adverse health effects.
      Various enforceable guidelines have been set by regulatory agencies for worker
      and ambient air quality. However, these exposure levels generally are not
      applicable to rare lifetime acute exposures, which possibly could occur at high
      concentrations. Acute exposure guideline levels (AEGLs) provide estimates of
      concentrations for airborne exposures for an array of short durations that
      possibly could cause mild (AEGL-1), severe, irreversible, potentially disabling
      adverse health effects (AEGL-2), or life threatening effects (AEGL-3). These
      levels can be useful for emergency responders and planners in reducing or
      eliminating potential risks to the public. Procedures and methodologies for
      deriving AEGLs are reviewed in this paper that have been developed in the United
      States, with direct input from international representatives of OECD member
      countries, by the National Advisory Committee for Acute Exposure Guidelines for
      Hazardous Substances and reviewed by the National Research Council. Techniques
      are discussed for the extrapolation of effects across different exposure
      durations. AEGLs provide a viable approach for assisting in the prevention,
      planning, and response to acute airborne exposures to toxic agents.

PMID- 15041149
TI  - The safety of ethyl oleate is supported by a 91-day feeding study in rats.
AB  - The purpose of this study was to determine the safety of ethyl oleate (EO) in a
      91-day feeding study in Sprague-Dawley rats. EO was mixed into AIN-93G purified
      diet at levels of 0, 3.3, 6.7, and 10% by weight (the high-dose males and females
      consumed 5.5 and 6.1g/kg/day EO, respectively). All diets were calorie- and fat
      matched using high oleic safflower oil (HOSO) as the control fat. The study
      design followed the 1993 FDA draft "Redbook II" guidelines (Toxicological
      Principles for the Safety Assessment of Direct Food Additives and Color Additives
      Used in Food). There were 20 male and 20 female rats per group. EO in the diet
      was well tolerated and there were no toxicologically significant findings in any
      of the measured parameters (clinical observations, body weight gains, appearance
      of the feces, ophthalmic examinations, hematology, clinical chemistry,
      urinalysis, organ weights, histopathology, or male and female reproductive
      assessments). Mortality was limited to three males during the course of the study
      whose cause of death was unrelated to test material administration. The terminal
      body weight of the mid- and high-dose females was approximately 10% lower than
      that of the control group. This finding does not represent a toxicologically
      significant effect because rats on the EO diets gained more weight during the
      course of the study than historical control data on this strain of rats. The
      lower body weight relative to control rats is directly related to lower food
      consumption relative to the controls. The lower food consumption relative to
      controls is fully consistent with a decrease in the palatability of the EO
      containing food versus the triglyceride-containing food. This conclusion is based
      on (1) a decrease in food consumption was noted within the first week (consistent
      with palatability preferences), (2) there was not a dose-response with regard to
      food consumption (mid-dose consumed less than high-dose), (3) the lack of
      cumulative decreases in food consumption which often are observed with toxicity,
      and (4) anecdotal experiences in our lab show that rats prefer diets containing
      high triglyceride fat over high EO-fat. Hepatocellular vacuolation typical of fat
      accumulation was noted for both control and high-dose animals. The incidence and
      severity of the vacuolation were higher for animals given 10% HOSO (controls)
      than for the animals given 10% EO. Serum calcium and phosphorous levels in high
      dose males were slightly, but statistically significantly, lower than in the
      controls. There was a dose-related increase in fecal fat concentration in both
      sexes from approximately 9% (control) to 18% in males, and from 4 (control) to
      13% in females There were no visually obvious differences with regard to feces
      quality or quantity at any level of EO in the diet (i.e., color, diarrhea,
      weight, etc.). The increase in fat most likely represents small amounts of
      unabsorbed EO at the mid- and high-dose (estimates of EO absorption in this study
      are >80%). The No Observable Adverse Effect Level was determined to be 10% EO
      when administered daily in the diet for 91-days (approximately 6g EO/kg bw/day).

PMID- 15041150
TI  - Production of toxic metabolites in Aspergillus niger, Aspergillus oryzae, and
      Trichoderma reesei: justification of mycotoxin testing in food grade enzyme
      preparations derived from the three fungi.
AB  - Aspergillus niger, Aspergillus oryzae, and Trichoderma reesei are three important
      production organisms used in industrial fermentations. Several of the fungal
      secondary metabolites produced by selected strains of these three fungi are
      capable of eliciting toxicity in animals. Among those toxic substances are the
      well-known mycotoxins 3-nitropropionic acid and ochratoxin A. However, many
      others, such as kojic acid, may not be true mycotoxins. The production,
      extraction, chemical structure, and the toxicity (expressed as LD(50)) of these
      substances are reviewed. Production of toxic secondary metabolites in A. niger,
      A. oryzae, and T. reesei is strain-specific and environment-dependent.
      Considering all of the safety measures taken in the industrial production
      process, these three fungal species are safe to use. The recently revised JECFA
      specification for mycotoxins in food enzyme preparations is also discussed. The
      extent of mycotoxin tests in food enzyme preparations should be judged on a case
      by-case basis, through a careful evaluation based on knowledge of taxonomy,
      biochemistry, and genetics. In many cases, the testing scope at the level of
      genus should be sufficient. In other cases, the scope can even be further
      narrowed based on scientific knowledge and assessment.

PMID- 15041152
TI  - Pesticide exposure assessment.

PMID- 15041151
TI  - Testosterone-stimulated weanlings as an alternative to castrated male rats in the
      Hershberger anti-androgen assay.
AB  - We showed previously that stimulation of weanling male rats with the synthetic
      androgen 17-methyltestosterone (17MT) caused premature growth of the sex
      accessory tissues such that the activity of the two anti-androgens flutamide and
      DDE could be demonstrated (Regul. Toxicol. Pharmacol. 35 (2002) 280). We
      suggested that that protocol should be evaluated as an alternative to the
      castrated male rat Hershberger assay. In the present paper we justify changing
      the assay protocol to use testosterone propionate (TP), in place of 17MT, as the
      stimulating androgen. This change enables biochemical formation of
      dihydrotestosterone from testosterone, a conversion not possible when using 17MT.
      This change in the protocol enables detection of the testosterone-5-reductase
      inhibitor finasteride. The modified TP-stimulated weanling male rat assay is
      shown to have similar sensitivity to that of the castrated male rat Hershberger
      assay in detection of the anti-androgens flutamide, procymidone, vinclozolin, and
      DDE, and of the biochemical inhibitor finasteride. The anti-androgen linuron and
      the anabolic steroid trenbolone were also detected as positive by the TP
      stimulated weanling male assay. It is suggested that this modified assay for anti
      androgens should be validated as an alternative to the Hershberger assay, thereby
      reducing animal stress by obviating the need for surgical castration.

PMID- 15041153
TI  - Di-alkyl phosphate biomonitoring data: assessing cummulative exposure to
      organophosphate pesticides Duggan et al. (2003).

PMID- 15041155
TI  - Environmental data are neither normally nor lognormally distributed: re Duggan et
      al. (2003).

PMID- 15041157
TI  - Pathway of apoptosis induced in Jurkat T lymphoblasts by anti-HLA class I
      antibodies.
AB  - We demonstrated recently that human leukocyte antigen (HLA) class I human
      monoclonal antibodies (mAbs) are able to induce apoptosis of resting human
      lymphocytes as well as Jurkat lymphoblastic T cells. We now analyzed the
      signaling pathway involved in apoptosis mediated by human HLA class I allele
      specific mAb OK2F3 and mouse monomorphic mAb W6/32. An inhibitor of a broad
      spectrum of caspases had only a moderate inhibiting effect, and an inhibitor of
      caspase 3 failed to inhibit HLA class I-mediated apoptosis. Although caspase 3
      activation was not observed, internucleosomal DNA fragmentation was found in half
      of the apoptotic cells. Importantly, the mitochondrio-nuclear redistribution of
      apoptosis inducing factor (AIF), a caspase-independent mitochondrial death
      effector, was detected after 1 hour of treatment with human anti-HLA mAb and was
      associated with large-scale DNA fragmentation, whereas the release of cytochrome
      c, which is responsible for caspase-dependent internucleosomal fragmentation,
      followed AIF translocation and occurred after 2 hours. Our results indicate that
      apoptosis mediated through HLA class I molecules represents a unique mechanism of
      cell death in Jurkat T lymphoblasts that involves two parallel pathways, one
      caspase-independent and the other caspase-dependent. This study clarifies the
      precise mechanism of anti-HLA antibody-induced apoptosis which might have
      clinical implications.

PMID- 15041158
TI  - Truncated HLA-G isoforms are retained in the endoplasmic reticulum and
      insufficiently provide HLA-E ligands.
AB  - The preferential expression of the non-polymorphic human leukocyte antigen G (HLA
      G) on invading extravillous cytotrophoblast cells that are, with the exception of
      HLA-C and -E, HLA class I negative led to the hypothesis that HLA-G plays a major
      role in controlling the effector functions of the large granular leukocytes
      (LGL), a specialized natural killer (NK) cell population present in large numbers
      in the decidua. Transcription of the HLA-G gene is characterized by extensive
      alternative splicing producing at least seven potentially membrane bound or
      secreted isoforms. Except for HLA-G1 and its soluble variant (HLA-G1s), there is
      still dispute as to whether any of the other isoforms displays a major
      immunological function. Here we describe that the membrane-bound isoforms HLA-G2,
      -G3, and G4 as well as the soluble variant of HLA-G2 (HLA-G2s) do not egress the
      endoplasmic reticulum as determined by Endo H sensitivity assays. Moreover these
      isoforms seem not to have a major immunological function with respect to NK cell
      inhibition by providing a ligand for HLA-E, which would allow the interaction of
      this molecule with the inhibitory CD94/NKG2A NK cell receptor.

PMID- 15041159
TI  - Influence of HLA-DRB1 alleles on lymphoproliferative responses to a naturally
      processed and presented measles virus phosphoprotein in measles immunized
      individuals.
AB  - Identification of stimulatory T-cell epitopes recognized by CD4+ T lymphocytes is
      important for vaccine development. Our previous studies using mass spectrometry
      identified a naturally processed HLA class II restricted DRB1*0301 T cell epitope
      in the measles virus phosphoprotein, MV-P1 (residues 179-197). Here we provide
      lymphocyte proliferation data from peripheral blood mononuclear cells (PBMC)
      obtained from 131 HLA-DRB1*0301-positive and HLA-DRB1*0301-negative (HLA
      discordant) individuals previously immunized against measles and report that a
      single amino acid substitution in the MV-P1 T cell epitope can reduce T cell
      proliferation and CD4+ T-cell recognition. Measles virus and measles peptide
      specific lymphoproliferative responses and HLA-DRB1 allele associations reveal
      that the DRB1*0701 allele provided suggestive evidence of association with both
      measles virus (p = 0.03) and MV-P1 peptide (p = 0.06) lymphoproliferation. A
      marginally significant increase in the frequency of the *0301 allele (p = 0.10)
      was found among subjects who demonstrated low cellular responses to the measles
      virus. We found no associations between proliferation levels to the MV-P1 and MV
      P2 peptides with *0301 alleles. We speculate that the glutamic acid at position
      192 of the measles phosphoprotein is a critical immunogenicity factor and may
      influence the antigenicity of the naturally processed HLA class II MV-P1 epitope.

PMID- 15041160
TI  - Stimulation of peripheral blood and intestinal mucosa cells by synthetic CpG
      oligodeoxynucleotides.
AB  - The breakdown of tolerance to autologous bacterial flora has been implicated as a
      major factor contributing to the initiation and perpetuation of chronic
      inflammation in inflammatory bowel diseases (IBD). To test whether bacterial DNA
      is at the origin of inflammation in IBD, we have examined the response of lamina
      propria (LPMC) or peripheral mononuclear cells (PBMC) and purified T cells from
      IBD patients and control patients to stimulations with a set of
      oligodeoxynucleotides (ODNs) characterized by the presence or absence of cytosine
      guanosine dinucleotides (CpG) and/or 3' poly-guanosine (poly-G) extension.
      Furthermore we have evaluated the costimulatory activities of these ODNs on T
      cells activated via CD2 or CD3 pathway. We demonstrated that CpG ODNs induce
      higher proliferation of LPMC from inflammatory intestinal mucosa compared to
      healthy mucosa. We confirmed that CpG ODNs do not directly costimulate peripheral
      blood T cells activated by CD3 pathway. Finally, we revealed that CpG or non-CpG
      ODNs with 3' poly-G extension inhibit completely CD2 activation of purified PB or
      LP T-cells whereas only CpG ODNs without poly-G extension enhance proliferation
      and IFN-gamma production of PB T cells stimulated by CD2 pathway only in presence
      of NK and NK T cells. Our data suggest that NK T cells may be the primary target
      of ODNs and play a crucial role in indirect T-cell activation by ODN.

PMID- 15041161
TI  - HLA class I noninherited maternal antigens in cord blood and breast milk.
AB  - Maternally induced allotolerance both in clinical and experimental organ
      transplantation appears to require both in utero and oral exposure to
      noninherited maternal antigens (NIMA). Soluble major histocompatibility complex
      (MHC) class I antigens were studied in 18 mother-baby pairs in order to determine
      the extent of neonatal exposure to NIMA. Enzyme-linked immunoabsorbent assay
      (ELISA) analysis of cord blood from three genetically HLA-A2 negative babies born
      to HLA-A2+ mothers and from two HLA-A3 negative babies born to HLA-A3+ mothers
      revealed significant NIMA HLA-A levels in cord plasma. The level of NIMA-A2 or 
      A3 in cord blood were approximately 10% of the predicted value for a baby
      genetically positive for that allele. HLA-A2 or -A3 was undetectable (< 1.0
      ng/ml) in cord blood from HLA-A2 or -A3 negative babies whose mothers were also
      HLA-A2 or -A3 negative. Breast milk from HLA-A2+ mothers contained soluble HLA-A2
      (sHLA-A2) at levels averaging 36.2 ng/ml, resulting in milligram quantities of
      ingested antigen over 3 months of nursing. Western blot analysis of cord plasma
      confirmed that bands corresponding to NIMA HLA-A protein were present. This study
      demonstrates that oral and intravenous exposure to NIMA sHLA in the fetus and
      newborn is much higher than previously thought, and emphasizes the importance of
      nursing in the overall antigen dose achieved.

PMID- 15041162
TI  - Unappreciated risk factors for transplant patients: HLA antibodies in blood
      components.
AB  - One of the more aggressive approaches in renal transplantation is the use of
      plasmapheresis (PP) and intravenous immunoglobulin to eliminate donor-directed
      human leukocyte antigen (HLA) alloantibodies. A potential complication of a PP
      protocol is iatrogenic hypocoagulability resulting from the removal of
      coagulation factors. To prevent bleeding, hypocoagulable patients may require
      transfusions with fresh frozen plasma (FFP) and/or cryoprecipitate (Cryo).
      Although HLA alloantibodies in these components have been linked to
      complications, such as transfusion-related acute lung injury (TRALI), whether
      they cause complications following transfusion into allograft recipients is
      unknown. The incidence of complications would be dependent, in part, upon the
      frequency of HLA alloantibodies in the various blood components. In this study,
      segments from 77 units of FFP, 66 units of Cryo, 106 units of packed red blood
      cells (RBCs), and 59 units of apheresis platelets (Plts) were tested for
      antibodies to HLA class I and class II antigens using FlowPRA, an HLA antigen
      specific flow cytometric assay. On average, 22% of blood components tested
      contained HLA alloantibodies, tenfold greater than previously reported. This
      unappreciated frequency of HLA alloantibodies in blood components may pose a risk
      to transplant patients requiring transfusions by promoting allograft dysfunction
      or loss.

PMID- 15041163
TI  - Clinical significance of recipient antibodies to stem cell donor mismatched class
      I HLA antigens.
AB  - A stem cell transplant candidate whose best-matched related donor had a mismatch
      for A68 by virtue of the patient's maternal human leukocyte antigen A/B (HLA-A/B)
      recombinant haplotype, was referred to Wilford Hall Medical Center for
      transplantation. She was determined prior to transplant to have a high-titered
      antibody to that HLA type and to several crossreactive antigens (A2 and A24).
      When she initially failed to engraft, plasmapheresis was tried three times with
      no effect on the antibody titer. Subsequently, plasmapheresis followed by
      intravenous immunoglobulin treatment and retransplant completely eliminated the
      donor-specific antibody. Engraftment occurred, and several weeks after the second
      transplant antibodies to A68 could no longer be detected although the antibodies
      to other HLA types were still present. This case report should serve to remind
      stem cell transplant programs of the importance of checking for the presence of
      recipient antibodies to donor-mismatched antigens and suggests that patients with
      such antibodies be treated prior to transplant.

PMID- 15041164
TI  - The effect of recipient cytokine gene polymorphism on cardiac transplantation
      outcome.
AB  - We determined the association between clinical outcomes after heart
      transplantation and gene polymorphism in five cytokines (tumor necrosis factor
      alpha, transforming growth factor (TGF)-beta, interleukin-10, interleukin-6, and
      interferon-gamma) reported to influence expression in vitro. Ninety-five patients
      were studied. Cytokine genotyping was performed by sequence specific priming
      polymerase chain reaction. Clinical outcomes studied in the first posttransplant
      year included: (1) documented viral, bacterial, or fungal infection; (2)
      cytomegalovirus infection; (3) acute cellular rejection (International Society
      for Heart and Lung Transplantation > or = grade IIIA); (4) time to first
      rejection episode; and (5) the development of allograft vasculopathy. Patients
      with the TGF-beta genotype 10 T/T 25 G/G or 10 T/C 25 G/G had a longer time to
      first rejection (median time to first rejection episode 321 days) than those with
      the TGF-beta genotype 10C/C 25 G/C or 10 C/C 25 C/C (median time to first
      rejection 88 days). There was a trend toward a higher frequency of the tumor
      necrosis factor-alpha genotype -308 G/A or A/A in patients without infection
      (19/59, 32%) as compared with patients with infection (5/31, 16%). In both cases,
      these differences failed to reach significance when adjusted for multiple
      comparisons. No other significant association was found with clinical outcomes
      and polymorphisms in the five cytokine genes studied in this population.

PMID- 15041165
TI  - Role of HLA class II alleles in susceptibility to and protection from localized
      cutaneous leishmaniasis.
AB  - Localized cutaneous leishmaniasis (LCL) is the prevalent form of leishmaniasis in
      Mexico. It is limited to the skin; reversible upon treatment and the host
      cellular immune response is intact. Several genes that influence the expression
      of LCL have been described in the mouse. In humans, we, as well as others, have
      demonstrated that HLA-DQ3 antigens seem to play some role in host susceptibility.
      We therefore analyzed at the DNA level, the class II loci of the same patients
      that were previously studied by serology. The purpose of this study was to assess
      the contribution of HLA DR, DQ, and DP genes in the protection and/or the
      susceptibility to LCL. Sixty-five patients with LCL from Comalcalco, state of
      Tabasco, were recruited and 100 healthy controls were included for comparison.
      All were Mexican Mestizos. DRB1, DQA1, DQB1, DPA1, and DPB1 alleles were typed
      using two different methods: PCR-SSO and PCR-SSP. Results indicate that class II
      genes are relevant for the expression of LCL and several loci contribute
      independently and sinergically. DRB1*0407 participates in susceptibility with an
      etiological fraction (EF) of 20% and an odds ratio (OR) of 2.92. Two additional
      susceptibility genes were found. These are located to the DP locus: DPA1*0401 (OR
      = 10.07; EF=7%) and DPB1*0101 (OR = 5.99 EF = 13%). Resistance was found
      associated to DPB1*0401, thus *0401 "motif" could be an ideal candidate for the
      development of a vaccine. DR2 (DRB1*1500+DRB1*1600) has also a significant p for
      protection, suggesting that the sequence common to this group of antigens may
      anchor parasite peptides which trigger a protective response.

PMID- 15041166
TI  - HLA-DRB1 alleles encoding the "shared epitope" are associated with susceptibility
      to developing rheumatoid arthritis whereas HLA-DRB1 alleles encoding an aspartic
      acid at position 70 of the beta-chain are protective in Mexican Mestizos.
AB  - The risk to develop rheumatoid arthritis (RA) has been associated with the
      presence of HLA-DRB1 alleles encoding the "shared epitope" (SE). Additionally,
      HLA-DRB1 alleles encoding an aspartic acid at position 70 (D70+ ) have been
      associated with protection against the development of RA. In this study we tested
      the association between either SE or D70+ and rheumatoid arthritis in Mexican
      Mestizos. We included 84 unrelated Mexican Mestizos patients with RA and 99
      unrelated healthy controls. The HLA-typing was performed by PCR-SSO and PCR-SSP.
      We used the chi-squared test to detect differences in proportions of individuals
      carrying at least one SE or D70+ between patients and controls. We found that the
      proportion of individuals carrying at least one HLA-DRB1 allele encoding the SE
      was significantly increased in RA cases as compared to controls (p(c) = 0.0004,
      OR = 4.1, 95% CI = 2.2-7.7). The most frequently occurring allele was HLA
      DRB1*0404 (0.161 vs 0.045). Moreover, we observed a significantly increased
      proportion of HLA-DRB1 SE+ cases with RF titers above the median (p = 0.005).
      Conversely, the proportion of individuals carrying at least one HLA-DRB1 allele
      encoding the D70+ was significantly decreased (p(c) = 0.004, OR = 0.4, 95% CI 0.2
      0.7) among RA patients compared with controls. In conclusion, the SE is
      associated with RA in Mexican Mestizos as well as with the highest titers of RF.

PMID- 15041168
TI  - Nomenclature for factors of the HLA system, update October 2003.

PMID- 15041167
TI  - HLA-DRB1 and -DRB3 allele frequencies and haplotypic associations in Koreans.
AB  - We have investigated the frequencies of human leukocyte antigen-DRB1 (HLA-DRB1)
      and -DRB3 alleles and DRB1-DRB3 haplotypic associations in 800 Koreans. DRB1
      genotyping was done using polymerase chain reaction-sequence-specific
      oligonucleotide (PCR-SSO) and PCR-single strand conformation polymorphism (SSCP)
      methods. DRB3 genotyping was done on 447 samples carrying DRB3-associated DRB1
      alleles (DRB1*03, *11, *12, *13, and *14) using PCR-SSCP method. The allele
      frequencies of DRB3*0101, DRB3*0202, and DRB3*0301 were 0.073, 0.136, and 0.120,
      respectively, and we found one case of a probable new allele (DRB3*01new, 0.001).
      DRB1-DRB3 haplotypes with frequency (HF) > 0.005 exhibited strong associations
      between DRB3*0101 and DRB1*1201, *1301, and *1403; between DRB3*0301 and
      DRB1*1202 and *1302; between DRB3*0202 and DRB1*0301, *1101, *1401, *1405, and
      *1406 alleles. Most of the DRB1 alleles with frequency > 0.005 were exclusively
      associated with particular DRB3 alleles with relative linkage disequilibrium
      values of 1.0, except for DRB1*1201, *1202 and *1301; the rare presence (HF <
      0.005) of DRB3*0202 associations were observed for these DRB1 alleles. We also
      investigated and presented rare DRB1-DRB3 associations in additional 6000
      Koreans. Comparison with other ethnic groups revealed that DRB1*0301 and *1301
      related DRB1-DRB3 haplotypes vary among different populations, in that Koreans
      and other Asian populations show less diversity compared with Caucasoids or
      African Americans.

PMID- 15041169
TI  - Nomenclature for factors of the HLA system, update November 2003.

PMID- 15041170
TI  - Nomenclature for factors of the HLA system, update December 2003.

PMID- 15041171
TI  - Rethinking WNT signaling.
AB  - Recent research on the WNT signaling pathway warrants a reassessment of the basic
      mechanism that transmits signal from the membrane-bound receptor to the nucleus.
      This article incorporates these findings into a revised model for pathway
      activation. We propose that the control of Axin stability, rather than the
      control of ZW3 phosphorylation of the Armadillo protein, is the key step in
      signaling. Axin degradation is controlled by a stabilizing effect of ZW3
      dependent phosphorylation, and a destabilizing effect of active Arrow. Removing
      Axin enables Armadillo to accumulate and re-localize to the nucleus. We argue
      that nuclear localization of Armadillo is required for transcriptional pathway
      activity. Finally, we speculate on the effects this revision will have on the
      major questions facing the WNT field of research.

PMID- 15041172
TI  - Cladogenesis, coalescence and the evolution of the three domains of life.
AB  - In this article, we explore the large-scale structure of the tree of life by
      using a simple model with a constant number of species and rates of speciation
      that equal the rates of extinction. In addition, we discuss the consequences of
      horizontal gene transfer for the concept of a most recent common ancestor of all
      living organisms (cenancestor). A simple null hypothesis based on coalescence
      theory explains some features of the observed topologies of the tree of life.
      Simulations of genes and organismal lineages suggest that there was no single
      common ancestor that contained all the genes ancestral to those shared among the
      three domains of life. Each contemporary molecule has its own history that traces
      back to an individual molecular cenancestor. However, these molecular ancestors
      were likely to be present in different organisms and at different times.

PMID- 15041173
TI  - Plants, pairing and phenotypes--two's company?
AB  - An RNA-based communication network appears to play a crucial role in regulating
      gene expression and in repressing viral and transposon sequences in plant
      genomes. In this article, we consider the evidence that gene expression might
      also be controlled epigenetically at a level other than non-coding RNA species
      chromosome pairing. This epigenetic communication between sequences might be
      based--as it is in other organisms--on the physical pairing between homologues
      and the transfer of information between corresponding epigenetic landscapes. We
      suggest that paramutation might represent just one--albeit extreme and obvious-
      facet of a pairing-based gene expression regulation system in plants. Further
      exciting evidence for pairing occurring between homologues in plants is now
      mounting. An appreciation that pairing interactions might be important throughout
      plant development could assist in understanding phenomena such as endosperm
      imprinting, hybrid phenotypes and inbreeding depression.

PMID- 15041174
TI  - Justified chauvinism: advances in defining meiotic recombination through sperm
      typing.
AB  - Sperm typing offers an efficient means of studying the quantitative and
      qualitative aspects of meiotic recombination that are virtually unapproachable by
      pedigree analysis. Since the initial development of the technique >10 years ago,
      several salient findings based on empirically derived recombination data have
      been described. The precise rates and distributions of recombination have been
      reported for specific regions of the genome, serving as the prototype for high
      resolution genome-wide recombination patterns. Identification and
      characterization of molecular genetic events, such as unequal crossing over, gene
      conversion and crossover asymmetry, are under close inspection for the first time
      as a result of this technology. The influence of these phenomena on the evolution
      of the genome is of primary interest from a scientific and medical perspective.
      In this article, we review the novel discoveries in mammalian meiotic
      recombination that have been revealed through sperm typing.

PMID- 15041175
TI  - Cardiac histone acetylation--therapeutic opportunities abound.
AB  - Diverse etiologic factors trigger a cardiac remodeling process in which the heart
      becomes abnormally enlarged with a consequent decline in cardiac function and
      eventual heart failure. Heart failure is traditionally treated with drugs that
      antagonize early signaling events at or near the cell membrane. Although such
      approaches have short-term efficacy, the five-year mortality rate for patients
      with late-stage heart failure continues to exceed 50%. Because of the redundant
      nature of the signaling networks that drive cardiac pathogenesis, targeting the
      common downstream elements of the cascades would be a more effective therapeutic
      strategy. Recent studies point to the importance of enzymes that control histone
      acetylation as stress-responsive regulators of gene expression in the heart.
      Given their role as nuclear integrators that couple divergent upstream signals to
      the gene program for cardiac remodeling, we propose that these chromatin
      modifying factors represent auspicious targets for the pharmacological
      manipulation of cardiac disease.

PMID- 15041176
TI  - Phosphorylation of histone H3: a balancing act between chromosome condensation
      and transcriptional activation.
AB  - In recent years, the covalent modification of histone tails has emerged as a
      crucial step in controlling the transcription of eukaryotic genes.
      Phosphorylation of the serine 10 residue of the N-terminal tail of histone H3 is
      crucial for chromosome condensation and cell-cycle progression during mitosis and
      meiosis. In addition, this modification is important during interphase because it
      enables the transcription of an increasing number of genes that are activated as
      a consequence of a variety of cell-signaling events. The location of the serine
      10 residue in close proximity to other modifiable amino acids in the histone H3
      tail enables the possibility of an interaction between phosphorylation of serine
      10 and methylation and/or acetylation of lysine 9 and lysine 14. Finally, the
      finding that the histone H3.3 variant, which has a conserved N-terminal tail, can
      replace histone H3 at sites of active transcription, adds a new layer of
      complexity and possibilities to the regulation of transcription through changes
      in chromatin structure.

PMID- 15041177
TI  - Identification of essential and non-essential genes of the guinea pig
      cytomegalovirus (GPCMV) genome via transposome mutagenesis of an infectious BAC
      clone.
AB  - We report application of a transposition methodology that allows the easy
      characterization and mutation of genes encoded on an infectious bacterial
      artificial chromosome (BAC) clone. We characterized mutants generated by
      transposome (Tn) mutagenesis of a BAC clone of guinea pig cytomegalovirus
      (GPCMV). A pool of Tn mutant GPCMV BACs were screened initially by restriction
      profile analysis to verify they were full-length, and subsequently GPCMV BAC DNA
      from individual mutants was transfected onto guinea pig lung fibroblast cells in
      order to generate virus. Tn GPCMV BAC mutants were classed as either essential or
      non-essential gene insertions, depending upon their ability to regenerate viable,
      replication-competent virus. Representative mutants were more fully
      characterized. Analysis by sequencing the Tn insertion site on the mutated BACs,
      and by regeneration of virus using transfection of guinea pig fibroblasts (GPL),
      demonstrated that a recombinant with a Tn insertion in the UL35 homolog gene
      (GP35) was a non-essential gene for viral replication in tissue culture. A mutant
      with an insertion in the UL46 homolog (GP46) was nonviable, a phenotype which
      could be rescued by homologous recombination of BAC DNA with wild-type UL46
      sequences, suggesting an essential role of this putative capsid gene in virus
      replication.

PMID- 15041178
TI  - Systemic and in vitro infection process of Bombyx mori nucleopolyhedrovirus.
AB  - To analyse the systemic progression of infection by Bombyx mori
      nucleopolyhedrovirus (BmNPV) through oral ingestion by the silkworm larvae, a
      recombinant virus (vBmp10GFP) expressing the green fluorescent protein (GFP)
      under the control of the very late, viral p10 promoter (which still forms the
      polyhedral occlusion bodies) was constructed. Infection of B. mori derived BmN
      cells with the recombinant virus resulted in the expression of GFP from 12 h post
      infection (hpi), with maximal accumulation of the expressed protein by 60 hpi. B.
      mori larvae that ingested the polyhedra containing vBmp10GFP showed localized
      expression of GFP in the midgut epithelial cells within 24 hpi, indicating virus
      replication. The primary spread of the virus infection occurred through the
      tracheae. Viral multiplication was subsequently detected in nearly all the larval
      tissues including the neurons and regions of silk-glands that were in contact
      with the tracheae. Infection in fat bodies was widespread by 48 hpi, by which
      time the haemocytes also showed infection. In vitro infection of isolated
      organs/tissues from B. mori with the budded virions (BV) of vBmp10GFP also showed
      viral multiplication in the cells that were associated with the tracheae,
      confirming the role of tracheae in spreading the infection.

PMID- 15041179
TI  - Induction of apoptosis in a carp leucocyte cell line infected with turbot
      (Scophthalmus maximus L.) rhabdovirus.
AB  - A rhabdovirus was observed from the diseased turbot (Scophthalmus maximus L.)
      with lethal syndrome. In this study, a carp leucocyte (CLC) cell line was used to
      investigate the infection process and cell death mechanism occurring during the
      virus infection. Strong cytopathogenic effect (CPE) and the morphological
      changes, such as extreme chromatin condensation, nucleus fragmentation, and
      apoptotic body formation, were observed under fluorescence microscopy after DAPI
      staining in the infected CLC cells. Transmission electron microscopy analysis
      showed cell shrinkage, plasma membrane blebbing, cytoplasm vacuolization,
      chromatin condensation, nuclear breakdown and formation of discrete apoptotic
      bodies. The bullet-shaped nucleocapsids were measured and ranged in size from 110
      to 150 nm in length and 40 to 60 nm in diameter. And therefore the virus is
      called Scophthalmus maximus rhabdovirus (SMRV). Agarose gel electrophoresis
      analysis of the DNA extracted from infected cells showed typical DNA ladder in
      the course of SMRV infection. Flow cytometry analysis of SMRV infected CLC cells
      detected apoptotic peak in the virus infected CLC cells. Virus titre analysis and
      electron microscopic observation revealed that the virus replication fastigium
      was earlier than that of the apoptosis occurrence. No apoptosis was observed in
      the CLC infected with UV-inactivated SMRV. All these supported that SMRV infected
      CLC cells undergo apoptosis and the virus replication is necessary for apoptosis
      induction of CLC cells.

PMID- 15041180
TI  - Genetic and antigenic characterization of the Amur virus associated with
      hemorrhagic fever with renal syndrome.
AB  - The genetic and antigenic characteristics of the Amur (AMR) and Far East (FE)
      virus lineages, which are both within the genus Hantavirus, were studied.
      Representative viruses, H5 and B78 for AMR and Bao 14 for FE, were used. The
      entire small (S) and medium (M) segments, except for the 3'- and 5'-ends, were
      sequenced. The deduced amino acid sequences of AMR had 96.7 and 92.0-92.2%
      identities with the Hantaan (HTN) virus in the S and M segments, respectively.
      The amino acid sequences of FE had 99.1 and 97.9% identities in the S and M
      segments, respectively. The three viral strains and HTN virus had similar binding
      patterns to a panel of monoclonal antibodies (MAbs), except that one MAb did not
      bind AMR. However, sera from Apodemus peninsulae, naturally infected with AMR
      virus, neutralized homologous viruses at 1:160 to 1:320 dilutions and HTN at 1:20
      to 1:40 dilutions. The anti-AMR serum neutralized homologous viruses at a 1:80
      dilution and HTN at a 1:40 dilution. The anti-HTN serum did not neutralize AMR
      (<1:40 dilution), although it had a high neutralizing titer (1:320) against the
      homologous virus. Therefore, we suggest that AMR virus may constitute a distinct
      serotype within the genus Hantavirus.

PMID- 15041181
TI  - Complete genome sequencing of dengue virus type 1 isolated in Buenos Aires,
      Argentina.
AB  - Dengue (DEN) constitutes a major viral arthropod-borne human illness. South
      America was last considered free of dengue two decades ago when a dramatic
      increase in the number of dengue fever and hemorrhagic dengue cases had been
      reported. Five viruses were isolated in Buenos Aires City from the 1999-2000
      Paraguay outbreak. RT-PCRs obtained directly from plasma were cloned into pGemT
      vectors and sequences of the structural genes and NS1 were analyzed. Three
      viruses were full-length sequenced from RT-PCR obtained from cell-culture
      isolates. Excess of synonymous over non-synonymous mutations suggested that the
      structural proteins were under strong functional constraints while a weak
      purifying selection was operating in the whole polyprotein. Sequence diversity
      and selective pressures varied among patients but results were significantly
      above the procedure threshold. One sample showed small-plaque phenotype and
      impaired growth coupled to 3'untranslated region mutations. Phylogenetic analysis
      of full-length sequences split Buenos Aires isolates into two clusters within
      American DEN-1 genotype V: Clade I was phylogenetically linked to Brazilian
      samples and Clade II with samples from Paraguay and Northeastern Argentina. In
      Buenos Aires City, only dengue virus serotype 1 imported from Paraguay has been
      detected, though without evidence of local transmission.

PMID- 15041182
TI  - Recovery of a persistent Canine distemper virus expressing the enhanced green
      fluorescent protein from cloned cDNA.
AB  - Wild-type A75/17-Canine distemper virus (CDV) is a highly virulent strain, which
      induces a persistent infection in the central nervous system (CNS) with
      demyelinating disease. Wild-type A75/17-CDV, which is unable to replicate in cell
      lines to detectable levels, was adapted to grow in Vero cells and was designated
      A75/17-V. Sequence comparison between the two genomes revealed seven nucleotide
      differences located in the phosphoprotein (P), the matrix (M) and the large (L)
      genes. The P gene is polycistronic and encodes two auxiliary proteins, V and C,
      besides the P protein. The mutations resulted in amino acid changes in the P and
      V, but not in the C protein, as well as in the M and L proteins. Here, a rescue
      system was developed for the A75/17-V strain, which was shown to be attenuated in
      vivo, but retains a persistent infection phenotype in Vero cells. In order to
      track the recombinant virus, an additional transcription unit coding for the
      enhanced green fluorescent protein (eGFP) was inserted at the 3' proximal
      position in the A75/17-V cDNA clone. Reverse genetics technology will allow us to
      characterize the genetic determinants of A75/17-V CDV persistent infection in
      cell culture.

PMID- 15041183
TI  - Analysis of synonymous codon usage in SARS Coronavirus and other viruses in the
      Nidovirales.
AB  - In this study, we calculated the codon usage bias in severe acute respiratory
      syndrome Coronavirus (SARSCoV) and performed a comparative analysis of synonymous
      codon usage patterns in SARSCoV and 10 other evolutionary related viruses in the
      Nidovirales. Although there is a significant variation in codon usage bias among
      different SARSCoV genes, codon usage bias in SARSCoV is a little slight, which is
      mainly determined by the base compositions on the third codon position. By
      comparing synonymous codon usage patterns in different viruses, we observed that
      synonymous codon usage pattern in these virus genes was virus specific and
      phylogenetically conserved, but it was not host specific. Phylogenetic analysis
      based on codon usage pattern suggested that SARSCoV was diverged far from all
      three known groups of Coronavirus. Compositional constraints could explain most
      of the variation of synonymous codon usage among these virus genes, while gene
      function is also correlated to synonymous codon usages to a certain extent.
      However, translational selection and gene length have no effect on the variations
      of synonymous codon usage in these virus genes.

PMID- 15041184
TI  - In Hodgkin's disease Reed-Sternberg cells and normal B-lymphocytes are infected
      by related Epstein-Barr virus strains.
AB  - In Hodgkin's disease (HD), both neoplastic Reed-Sternberg (RS) cells and
      bystander B-lymphocytes may be infected by Epstein-Barr virus (EBV). We
      postulated that if tumorigenic EBV strains did exist, they would be
      preferentially found in consistently EBV-associated tumors, such as RS cells, and
      differ significantly from the strains present in other, non-pathological sites of
      the same patients. In the present study we have compared LMP1-BNLF1 polymorphism
      of EBV strains infecting RS cells and B-lymphocytes in lymph nodes effected by HD
      on the one hand, and bystander B-lymphocytes in reactive lymph nodes on the
      other. It appeared that viral strains detected in HD tissues including RS cells
      and bystander B-lymphocytes were infected by different, but related EBV strains
      and were four times more polymorphic than EBV strains infecting bystander B
      lymphocytes of reactive lymph nodes. The question arises as to the biological
      significance of these observations and the origin and chronology of multiple
      infections in the same patient. Since RS cells are derived from B-lymphocytes it
      is conceivable that the latter events could have occurred during the
      proliferation of bystander B-lymphocytes and their EBV episome following an
      antigenic stimulation.

PMID- 15041185
TI  - Basic fibroblast growth factor (bFGF) and its receptor expression (bek and flg)
      In bone marrow stroma of murine AIDS.
AB  - Murine acquired immunodeficiency disease (MAIDS) induced by LPBM5 MuLV is
      characterized by a late-stage lymphoma and hematopoietic cytopenias similar to
      those observed in human AIDS. The pathogenesis of MAIDS-related
      lymphoma/cytopenia is unknown but it has been postulated to involve a defective
      marrow microenvironment or stroma. The basic Fibroblast Growth Factor (bFGF) of
      stromal origin is an important stimulator for hematopoietic progenitors of
      several lineages. Long-term bone marrow cultures (LTBMCs) were established and
      pure stromal cell cultures were used for in vitro infection hematopoietic
      reconstitution studies. Reverse transcription-polymerase chain reaction (RT-PCR)
      was used to analyze bFGF gene expression in stromal cells derived from either
      viral-infected marrow or uninfected marrow. RT-PCR analysis showed a 40%
      reduction in the expression of bFGF transcript expression from viral-infected
      stromal cells, however, the levels of bek and flg bFGF receptors remained
      unchanged indicating virus-infection only inhibited bFGF gene expression in
      stromal cells. Viral infection was associated with a progressive decrease in bFGF
      transcript expression 35% of control at day 7, 50% of control at day 14 and 60%
      of control at day 21 compared to the mock-infected cultures. In addition, for bek
      and flg the transcript expression in, in vitro-infected primary cultures were
      comparable to the mock-infected cultures and remained essentially unchanged
      throughout culture period. Western blot analysis revealed viral-infected stromal
      cells produced a 45% decrease in bFGF protein production. Reduction of bFGF
      protein was confirmed by indirect immunofluorescent staining. We report MuLV
      infection reduces bFGF transcript expression but not its surface-receptors (bek
      and flg) in infected stromal cells. Impaired hematopoiesis consistently exhibited
      from MuLV-infected stromal cultures was restored by exogenous bFGF; therefore,
      bFGF was responsible in restoration of normal marrow stromal support function.
      These results suggest a role for bFGF deficiency in the pathogenesis of MAIDS
      related marrow failure.

PMID- 15041186
TI  - An entomopoxvirus and a granulovirus use different mechanisms to prevent pupation
      of Adoxophyes honmai.
AB  - Adoxophyes honmai larvae inoculated with 10x the 95% lethal concentration of an
      entomopoxvirus (AdhoEPV) did not pupate, underwent a prolonged larval stage, and
      died during their final instar, unlike non-infected larvae which pupated after
      five larval instars. In previous work we showed that a granulovirus (AdhoGV) also
      retarded host development and prevented pupation of A. honmai larvae. In this
      study, endocrinological alterations in AdhoEPV-infected larvae were compared to
      those in AdhoGV-infected larvae. AdhoEPV-infected larvae had no peak of juvenile
      hormone (JH) esterase activity during the final instar, suggesting that JH titers
      in virus-infected larvae remained high during this period. In AdhoEPV-infected
      larvae the ecdysteroid titer remained low during the final instar, whereas in
      AdhoGV-infected larvae it peaked during the final instar and remained high
      towards the later stages of this instar. Ecdysteroid UDP-glucosyltransferase
      (EGT) activity was detected in the hemolymph of AdhoGV-infected A. honmai larvae,
      suggesting that the ecdysteroid would be inactivated in these insects. No EGT
      activity was detected in the hemolymph of either AdhoEPV-infected or non-infected
      A. honmai larvae. Thus, while AdhoEPV and AdhoGV both prevent pupation of A.
      honmai larvae, the mechanisms by which they do so appear to be different.

PMID- 15041187
TI  - Genetic diversity of bluetongue viruses in south east Asia.
AB  - Bluetongue viruses (BTV) were isolated from sentinel cattle in Malaysia and at
      two sites in Indonesia. We identified eight serotypes some of which appeared to
      have a wide distribution throughout this region, while others were only isolated
      in Malaysia or Australia. Nearly half of the 24 known BTV serotypes have now been
      identified in Asia. Further, we investigated the genetic diversity of their RNA
      segments 3 and 10. Using partial nucleotide sequences of the RNA segment 3 (540
      bp) which codes for the conserved core protein (VP3), the BTV isolates were found
      to be unique to the previously defined Australasian topotype and could be further
      subdivided into four distinct clades or genotypes. Certain of these genotypes
      appeared to be geographically restricted while others were distributed widely
      throughout the region. Similarly, the complete nucleotide sequences of the RNA
      segment 10 (822 bp), coding for the non-structural protein (NS3/3A), were also
      conserved and grouped into the five genotypes; the BTV isolates could be grouped
      into three Asian genotypes and two Nth American/Sth African genotypes.

PMID- 15041188
TI  - Monitoring and switching of cortico-basal ganglia loop functions by the thalamo
      striatal system.
AB  - Recent physiological and tract tracing studies revealed tight coupling of the
      centre median and parafascicular nuclei (the CM-Pf complex), which are posterior
      intralaminar nuclei (ILN) of the thalamus, with basal ganglia circuits. These
      nuclei have previously been classified as part of the ascending reticulo-thalamo
      cortical activating system, with studies of single neuron activity and of
      interruption of neuronal activity suggested that they participate in the
      processes of sensory event-driven attention and arousal, particularly in the
      context of unpredicted events or events contrary to predictions. In this article,
      we propose a hypothetical model that envisions that the CM-Pf complex functions
      in two different modes depending on the predictability of external events, i.e.,
      one for monitoring 'top-down' biased control through the cortico-basal ganglia
      loop system for selecting signals for action and cognition and the other for
      switching from biased control to 'bottom-up' control based on the signals of
      salient external events. This model provides a new insight into the function of
      the CM-Pf complex and should lead to a better understanding of this important
      brain system.

PMID- 15041189
TI  - Sensory processing and functional reorganization of sensory transmission under
      pathological conditions in the spinal dorsal horn.
AB  - The superficial dorsal horn, particularly substantia gelatinosa (SG) in the
      spinal cord, receives inputs from small-diameter primary afferents that
      predominantly convey noxious sensation. This sensory information via the high
      threshold Adelta and C afferents is modified and integrated in SG, and
      consequently regulates the outputs of projection neurons located in lamina I and
      laminae IV-V. Recent studies using slice and in vivo patch-clamp recordings
      indicate that the sensory inputs to SG are functionally reorganized during post
      natal development. Even in the mature state, the synaptic connectivity and
      receptor expression in SG can be altered easily following peripheral tissue
      damage. In addition, the descending pain inhibitory system to SG is also modified
      under certain pathological conditions. Considering that the pain system is
      phylogenetically primitive, it is, therefore, not surprising that the system
      easily exhibits a plastic change in response to inflammation or nerve damage.
      Because such plastic changes in the neuronal circuit or receptor expression in SG
      are now generally accepted to be one of the explanations for the induction of
      pathological pain, SG is thought to be a primary therapeutic target for chronic
      pain. We review here recent results demonstrating plastic changes in SG under
      pathological conditions.

PMID- 15041190
TI  - A time course analysis of the changes in neuropeptide Y immunoreactivity in the
      rat cuneate nucleus following median nerve transection.
AB  - Using median nerve injury and immunocytochemical methods, we examined the
      temporal changes in neuropeptide Y (NPY) expression in the cuneate nucleus (CN)
      in rats following median nerve transection. Under normal circumstances,
      neuropeptide Y-immunoreactive (NPY-IR) fibers was not detectable in the CN. A few
      NPY-IR fibers were observed in the ipsilateral CN 5 days after the median nerve
      transection, and peaked at 4 weeks. Thereafter, they were gradually returned to
      nearly control level after 16 weeks. Quantitative evaluation showed that the mean
      percentage of area occupied by NPY-IR fibers in entire and three subregions of
      the CN at 4 weeks were significantly higher than that at other post-operated time
      points, respectively. The present ultrastructural observations in the middle
      region of CN showed that the significantly increased NPY immunoreactivity was
      confined only in the myelinated axons and terminals but not detected in the
      dendrites, somata, and glial cells. The NPY-IR terminals made axodendritic
      synaptic contacts with unlabeled elements. The present results indicate that the
      time course of the increase of NPY immunoreactivity is similar to c-Fos
      expression as described in a previous study. It is speculated that the increased
      NPY in the CN after axotomy may affect the excitability of postsynaptic cuneate
      neurons, however, the functional interaction between NPY and c-Fos-IR neurons
      needs to be further studied.

PMID- 15041191
TI  - Localization of enolase in synaptic plasma membrane as an alphagamma heterodimer
      in rat brain.
AB  - Enolase, a glycolytic enzyme, is a multifunctional protein with location
      diversity. We revealed the intracellular distribution of enolase isozymes, such
      as alphaalpha-, alphagamma- and gammagamma-enolases, in rat brain synaptic
      terminals by biochemical and immunoelectron microscopic analyses. Specific
      activity of enolase of synaptic plasma membrane fraction (SPM2) obtained from
      synaptosomes was 23.2 +/- 4.4 x 10(-2) micromol/mg protein/min in the presence of
      0.25% Triton X-100 and that of synaptosomal cytoplasm (LS) was 67.4 +/- 12.1 x
      10(-2) micromol/mg protein/min. About half of enolase activity in synaptosomes
      was distributed to soluble fraction while the remaining stayed in particulate
      membrane fractions by ultracentrifugation. Immunoblot analysis of the fractions
      demonstrated both alpha and gamma subunits were distributed in SPM. In addition,
      immunoelectron microscopic analysis also revealed that both subunits were
      immunoreactive on the SPM. Using coimmunoprecipitation assay, we confirmed that
      the enolase was present not only as a homodimer form but also as an alphagamma
      hybrid form associated with membrane, where both subunits were
      coimmunoprecipitated from lysate of SPM2 in the presence of Mg(2+). These
      findings indicate that all forms (alphaalpha, alphagamma, and gammagamma) of
      enolase translocate to the plasma membrane and associate with some components in
      the SPM.

PMID- 15041192
TI  - Quantitative age-related changes in dorsal lateral geniculate nucleus relay
      neurons of the rat.
AB  - An ultrastructural and quantitative study of the age-related changes occurring in
      the relay neurons of the dorsal lateral geniculate nucleus (dLGN) was carried out
      using male Wistar rats aged 3, 18, 24, and 28 months. Morphometric techniques
      were used to obtain data regarding cellular activity including soma, nuclear, and
      nucleolar size. Volume fractions for rough endoplasmic reticulum (RER),
      mitochondria, and lipofuscin, as well as numbers and sizes of mitochondria and
      dense bodies (DB) was also calculated. Among the few alterations found in the
      perikaryon, we can highlight the redistribution and fragmentation of RER and an
      increase and progressive aggregation of lipofuscin. Quantitative data show a
      significant decrease in the volume of the soma (-42.77%) and the nucleus (
      33.66%), and in the volume fraction of the RER (-18.81%) and mitochondria (
      10.16%). A significant increase in lipofuscin (+213.29%), and variations in size
      and number of mitochondria and dense bodies were also found. Some
      histophysiological considerations about the findings are discussed. The findings
      lead to the conclusion that a relative degree of morphological stability is
      exhibited by relay neurons, although the quantitative data show evident
      intracellular changes, especially from 24 to 28 months. These changes suggest
      that accompanying physiological alterations may occur, with putative effects on
      visual function during ageing.

PMID- 15041194
TI  - Cerebellar interpositus nuclear and gastric vagal afferent inputs reach and
      converge onto glycemia-sensitive neurons of the ventromedial hypothalamic nucleus
      in rats.
AB  - The glycemia-sensitive neurons of the ventromedial hypothalamic nucleus (VMN)
      have traditionally been implicated in feeding regulation. Some studies reported
      that the neuronal activity of the VMN could be modulated by inputs from the
      gastric vagal afferent, and the cerebellum might participate in regulating non
      somatic visceral activities via the cerebellohypothalamic projections. The
      present study was therefore undertaken to investigate whether the inputs from the
      gastric vagal nerves and the cerebellar interpositus nucleus (IN) could reach and
      converge onto single VMN neurons, especially those glycemia-sensitive ones. Among
      recorded 283 VMN neurons, 187 (66.1%) and 139 (49.1%) responded to the gastric
      vagal and the cerebellar IN stimulations, respectively. Within the VMN neurons
      that were responsive to either of the gastric vagal or cerebellar IN stimulation,
      91 responded to both of the stimuli, suggesting a convergence of gastric vagal
      and cerebellar inputs on the cells. When the gastric vagal nerves and cerebellar
      IN were stimulated simultaneously, a summation of the responses could be observed
      (n = 22). Moreover, of the 91 cells that responded to both of the gastric vagal
      and cerebellar IN stimuli, 61 (67.0%) were identified to be glycemia-sensitive
      neurons. These results demonstrate that the visceral signals conveyed by the
      gastric vagal afferents and the somatic information forwarded by the cerebellar
      IN could converge onto single VMN neurons, especially the glycemia-sensitive
      neurons. And the findings suggest that an integration of the somatic-visceral
      response related to the food intake could take place in the VMN and the
      cerebellum might actively participate in the short-term feeding regulation
      through the cerebellohypothalamic projections.

PMID- 15041193
TI  - A short cerebral ischemic preconditioning up-regulates adenosine receptors in the
      hippocampal CA1 region of rats.
AB  - Pharmacologically blocking or stimulating studies have showed the crucial role of
      adenosine receptors in the protective effect of cerebral ischemic preconditioning
      (CIP). However, little is know about whether the adenosine receptors are up
      regulated in the process. In the present study, changes in expression of
      adenosine receptors in the CA1 hippocampus after a short CIP in a period of 3 min
      were investigated in rat four-vessel occluding (4VO) brain ischemic model using
      immunohistochemistry. The experiments were performed on groups of sham, 4 h, 1,
      3, and 7 days (n = 6 in each group) after the CIP. The number and immunostaining
      density of immunoreactive cells for A1 and A2b adenosine receptors in the CA1
      hippocampus were significantly increased after the CIP. For A1 adenosine
      receptor, the increase occurred in CA1 pyramidal neurons. While for A2b adenosine
      receptor, the increase occurred in the stratum radiatum of the CA1. The
      immunoreactive cells for A2b receptor showed distinct morphological
      characteristics of astrocytes. The increases were consistent in time course (1-7
      days) with the development of the ischemic tolerance induced by the CIP. It was
      concluded that up-regulation of adenosine receptors may also play an important
      role in the protective effect of CIP.

PMID- 15041195
TI  - Effect of simultaneous presentation of multiple attractants on chemotactic
      response of the nematode Caenorhabditis elegans.
AB  - Chemotactic behaviors of the nematode, Caenorhabditis elegans in response to
      chemical attractants, such as water-soluble sodium acetate and an odorant
      diacetyl, which were sensed by different sensory neurons, were investigated using
      various concentrations of these chemical attractants. In the presence of only
      sodium acetate attractant, the fraction of animals that were roaming around the
      outside of the attractant and original locations correlated negatively with the
      chemotaxis index for sodium acetate (P < 0.01). In contrast, the fraction of
      animals that remained in the original location correlated negatively with the
      chemotaxis index in the presence of only diacetyl attractant (P < 0.05). These
      results indicate that the manner of chemotaxis responses differs between sodium
      acetate and diacetyl. In order to investigate the effect of multiple attractants
      on chemotactic behaviors, the chemotactic responses to simultaneous presentation
      of sodium acetate and diacetyl were examined. The fraction of animals that
      gathered at the 0.7 M sodium acetate location was greater than that at the 0.1%
      diacetyl location in the presence of both attractants (P < 0.05), although the
      chemotaxis indexes for 0.7 M sodium acetate and 0.1% diacetyl were similar in the
      presence of a single attractant. On the other hand, the fraction of animals that
      gathered at the 0.02% diacetyl location was greater than that at the 0.1M sodium
      acetate location in the presence of both attractants (P < 0.05), although the
      chemotaxis indexes for 0.02% diacetyl and 0.1M sodium acetate were similar in the
      presence of a single attractant. These results suggest the existence of
      excitatory and/or inhibitory connections in the neuronal circuit for attractant
      selection, and that the efficacy of these connections may change according to the
      concentrations of both attractants.

PMID- 15041196
TI  - Actions of MDMA at glutamatergic neuromuscular junctions.
AB  - 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") compels mammalian
      serotonergic neurons to release serotonin (5-HT). In this study, MDMA altered
      synaptic transmission presynaptically by enhancing quantal release in two model
      glutamatergic synapses-the neuromuscular junction (NMJ) of the crayfish opener
      muscle, which is enhanced by exogenous 5-HT application, and the NMJ of a larval
      body wall muscle in Drosophila melanogaster, which is insensitive to exogenous 5
      HT application. At the crayfish NMJ, MDMA mimicked the actions of 5-HT but only
      at a substantially higher concentration. At the Drosophila NMJ, MDMA altered
      synaptic transmission but not through a 5-HT receptor. Using simple invertebrate
      preparations, we have demonstrated an additional non-serotonergic mechanism of
      MDMA activity that has not yet been addressed in vertebrate systems and that may
      play an important role in understanding the mechanism of action for a commonly
      abused drug.

PMID- 15041198
TI  - Influences of motor instructions on the reaction times of saccadic eye movements.
AB  - When a gap period is inserted between the fixation point extinction and the
      target presentation, the distribution of saccadic reaction times has two distinct
      peaks: one at 150-250 ms (ordinary saccades) and another at approximately 100 ms
      (express saccades). The distribution of saccadic reaction times can be explained
      by the linear approach to threshold with ergodic rate (LATER) model, in which the
      value of a decision signal increases linearly from a start level to initiate a
      saccade when the signal value reaches a threshold. We hypothesized that a gap
      period and/or an instruction signal can modulate the parameters of the model to
      determine when a saccade is initiated. Two reciprobit plots of reaction times,
      one for ordinary and the other for express saccades, for a task with both a gap
      period and visuospatial instruction, were constrained by a common infinite-time
      intercept, although no such constraint was observed during task performance
      without a visuospatial instruction. We interpreted the results that either the
      threshold, the start level, or the rate of increase of the decision signal of the
      model was switched in a bistable manner by both the visuospatial instruction and
      a gap period, but not by the gap period alone.

PMID- 15041197
TI  - Neuronal protein NP25 interacts with F-actin.
AB  - Neuronal protein NP25 is a neuron-specific protein present in highly
      differentiated neural cells, but its functional properties have not been well
      characterized. NP25 shows high amino acid sequence homology with the smooth
      muscle cell cytoskeleton-associated proteins, SM22, mp20, and calponin. To gain
      an insight into the biological functions of NP25, we first examined its
      subcellular localization in the human neuroblastoma cell line, SK-N-SH. NP25
      diffusely distributed in the cytoplasm and fiber-like staining was also observed.
      It showed that NP25 co-localized with F-actin on stress fibers. A co
      sedimentation assay demonstrated that NP25 bound to filamentous actin. Further
      investigations using fluorescence resonance energy transfer (FRET) technique
      revealed intracellular binding of NP25 and actin. The significance of the
      interaction between NP25 and F-actin is discussed.

PMID- 15041199
TI  - Modulation of motor patterns by sensory feedback during earthworm locomotion.
AB  - Role of sensory feedback to motor pattern activity concerning locomotion in the
      earthworm, Eisenia fetida, was investigated. We have previously reported that
      bath application of octopamine induces fictive locomotion in the earthworm. In
      this study, we have examined the role of sensory feedback during fictive
      locomotion by analyzing electrical activities from the cut end and intact first
      lateral nerves of the ventral nerve cord (VNC). From the cut end recordings,
      motor activity associated with fictive locomotion was measured. A mixture of
      sensory and motor activities was measured from the intact first lateral nerve
      using en passant recordings, and sensory activity was separated by subtraction of
      the cut end recording (mainly motor activities) from the intact first lateral
      nerve recording. We estimated the effect of sensory feedback from the earthworm
      body wall by comparing recordings that made when the preparation was in-contact
      with a substrate or suspended above it. Motor pattern activities and the
      coefficient of variation for inter-spike-interval of motor outputs were increased
      under suspended conditions during circular muscle contraction. These results
      indicate that sensory feedback modulates the pattern of motor activity in the
      earthworm during locomotion.

PMID- 15041200
TI  - Enhanced production of monocyte chemoattractant protein-1 in the dorsal root
      ganglia in a rat model of neuropathic pain: possible involvement in the
      development of neuropathic pain.
AB  - Chemokines are a family of peptides originally identified as the factors
      regulating the migration of leukocytes in inflammatory and immune responses.
      Recently, they have been shown to be produced in the central and peripheral
      nervous systems under various pathological conditions and act on neuronal and
      glial cells. In this study, we examined the production of monocyte
      chemoattractant protein-1 (MCP-1), a well-characterized chemokine, in dorsal root
      ganglia (DRG) in a rat model of neuropathic pain. Partial ligation of the sciatic
      nerve induced mechanical allodynia in the ipsilateral hindpaw with weaker
      allodynia in the contralateral one. Immunohistochemical analyses revealed that
      the number of MCP-1 immunoreactivity (ir)-positive cells was increased in the
      ipsilateral DRG. The increase started by 4h after the ligation, peaked at 24h and
      continued to at least 48 h. The weaker but significant increase was observed in
      the contralateral DRG. Double immunofluorescent staining demonstrated that almost
      all of the MCP-1ir-positive cells were neuronal cells. In situ hybridization
      histochemistry showed that MCP-1 mRNA expression was markedly upregulated in the
      ipsilateral DRG with weaker increase in the contralateral one at 24 h after the
      ligation, indicating that the elevation in MCP-1ir detected by
      immunohistochemistry was due to an upregulation of MCP-1 production by the DRG
      neurons themselves. Furthermore, intrathecal administration of MCP-1 induced
      mechanical allodynia. These results suggest that MCP-1 produced in the DRG
      neurons is involved in the development of mechanical allodynia induced by nerve
      injury.

PMID- 15041201
TI  - Neural cell adhesion molecule L1 is required for fasciculation and routing of
      thalamocortical fibres and corticothalamic fibres.
AB  - To examine the role of neural cell adhesion molecule L1 in thalamocortical
      projections, we analysed L1 deficient (L1-/y) mice. Immunohistochemistry of
      pleiotrophin/HB-GAM, a marker for thalamocortical axons and axonal tracing
      experiments showed that thalamocortical axons were abnormally and highly
      fasciculated when they pass through the developing internal capsule. Within the
      cortex, however, their course was more diffuse. The corticofugal fibres
      immunoreactive for TAG-1 were also more strongly fasciculated and their number
      was decreased in L1-/y mice. Furthermore, no TAG-1-positive corticofugal axons
      reached the dorsal thalamus. These data suggest that L1 plays an important role
      in the fasciculation and routing of axons connecting between the thalamus and the
      cortex.

PMID- 15041202
TI  - Veterinary medicine protecting and promoting the public's health and well-being.
AB  - Dr. Calvin Schwabe's vision of "One Medicine" has long inspired many in the
      public health community to strive toward bringing human and veterinary medicine
      together to improve the public's health and well-being around the world. In an
      increasingly human-dominated world, as Dr. Schwabe suggested many years ago,
      human health provides the most-logical unifying or apical cause in veterinary
      medicine's hierarchy of values. Veterinarians in all aspects of the profession
      have opportunity and responsibility to protect the health and well-being of
      people in all that they do, including protecting food security and safety;
      addressing threats to antibiotic sensitivity; preventing and controlling zoonotic
      emerging infectious diseases; protecting environments and ecosystems;
      participating in bio- and agro-terrorism preparedness and response; using their
      skills to confront non-zoonotic diseases (such as malaria, HIV/AIDS, vaccine
      preventable diseases, chronic diseases and injuries); strengthening the public
      health infrastructure; and advancing medical science through research. This
      article provides an overview of contributions made by veterinarians in each of
      these areas, and discusses the challenges to be overcome and the need for
      strategic thinking and action to achieve the vision of "one medicine".

PMID- 15041203
TI  - Measuring health and disease: progress in analytical approaches.
AB  - In this paper, Dr. Martin reviews the progress in analytical approaches used in
      veterinary medicine between the 1970s and today. The newer applications are used
      in such activities as monitoring/surveillance, analysis of observational study
      data, evaluation of tests in the absence of gold standards, the analysis of
      clustered data (including geographically clustered data) and modeling disease in
      populations. Future work will be more complex but will demand an increased
      emphasis on ways to enhance our biological understanding of the results of data
      analysis and modeling.

PMID- 15041204
TI  - Controlling emerging diseases in the 21st century.
AB  - The presentation addressed the following points: the role of veterinary
      epidemiology in emerging and global disease outbreaks; the contribution of
      veterinary epidemiology discipline to understanding and prevention of infections
      and other emerging animal disease, and the challenges for the discipline of
      veterinary epidemiology in the near future. The emerging and re-emerging
      infections animal diseases have contributed to expand the outlook of veterinary
      epidemiology. Methods and approaches in this discipline have been modified to
      satisfy the needs of society and of the scientific community. Mistakes and "bad
      turns" were made and should be avoided in the future. Veterinary epidemiology is
      alive and growing.

PMID- 15041205
TI  - Impacting policy through science and education.
AB  - Scientists, researchers, and their findings are critical factors in helping to
      resolve contemporary societal problems. Because of the tremendous
      interconnectivity of our lives and the expanded scope and scale of the medical
      and health problems we face, the research community needs to be both more
      involved and more competent in the development of public policy and to become
      more effective participants in the political and media activities in which their
      work is firmly embedded. This article suggests that researchers and scientists
      will be more relevant, have more impact, and be more productive if they can blend
      outstanding science with new non-cognitive skills that can reinforce the
      important social context of their work.

PMID- 15041206
TI  - Rapid detection and simultaneous subtype differentiation of influenza A viruses
      by real time PCR.
AB  - A real time RT-PCR, using the LightCycler, was developed and compared with rapid
      antigen enzyme immunoassay (AgEIA) and enhanced virus culture for rapid detection
      of influenza A viruses in stored and prospectively collected respiratory
      specimens. Specific hybridization probes were used for simultaneous detection and
      differentiation between H1N1 and H3N2 subtypes. The sensitivity of the RT-PCR for
      influenza A H1N1 was 120 copies and H3N2 350 copies of in vitro transcribed RNA.
      A specimen was considered positive for influenza A when it was culture positive
      or at least two methods yielded a positive test result. Using these criteria,
      with stored samples, the RT-PCR sensitivity, specificity, positive and negative
      predictive values were 82.9, 95.5, 98.9 and 52.5%, respectively. In specimens
      collected prospectively the RT-PCR sensitivity, specificity, positive and
      negative predictive values were 100, 87.9, 82.8 and 100%, respectively. There was
      complete concordance with subtype differentiation by hybridization probe melting
      temperature analysis and haemagglutination inhibition assay.

PMID- 15041207
TI  - Rhinovirus detection: comparison of real-time and conventional PCR.
AB  - Rhinoviruses are important human respiratory viruses and the major causative
      agents of the common cold. Historically, detection of rhinovirus has been by
      virus culture and this was significantly improved by the use of PCR assays.
      Recently real-time PCR was developed but to date there have been no reported
      comparisons of conventional and real-time PCR assays for detection of rhinovirus.
      In this study, we first compared real-time PCR (SYBR Green I) to conventional PCR
      for the detection of rhinovirus in serially diluted standard DNA and rhinovirus
      stock to determine the limits of detection. Next, assays were compared for
      sensitivity to detect rhinovirus in cell culture with a known number of infected
      cells. Finally, the assays were compared using clinical samples known to contain
      rhinovirus. Real-time PCR was 10-fold more sensitive than conventional PCR to
      detect rhinovirus in standard DNA and in virus stock and >10-fold more sensitive
      to detect rhinovirus in cultured cells. Real-time PCR was significantly superior
      for detection of rhinovirus in patients' nasal aspirates (sensitivity 72% versus
      39%, P < 0.05). In summary, we found that real-time PCR was more sensitive than
      conventional PCR and reduced post-PCR processing. Hence, real-time PCR is
      suitable for both research and clinical purposes.

PMID- 15041208
TI  - In situ hybridization of a marine fish virus, Singapore grouper iridovirus with a
      nucleic acid probe of major capsid protein.
AB  - A DNA probe of 531 base pairs for Singapore grouper iridovirus (SGIV) was
      generated by polymerase chain reaction and labeled with nonradioactive
      digoxigenin. An in situ hybridization based method was developed to detect SGIV
      in formalin-fixed tissues from maricultured Malabar grouper, Epinephelus
      malabaricus Bloch and Schneider. The in situ hybridization detected SGIV in the
      kidney, spleen, liver, intestine, stomach and gills from naturally infected fish.
      Strong hybridization signals were obtained from the kidney and spleen tissues,
      while intermediate intensity signals were observed in the intestine and liver
      tissues. The weakest signals were obtained from the stomach and gills. The
      signals were located specifically within epithelial, endothelial and sub
      endothelial hypertrophic cells in all tested tissues. The in situ hybridization
      procedure will provide an important diagnostic tool to complement
      histopathological methods, and contribute to epidemiological studies on the
      origin and distribution of iridovirus in mariculture.

PMID- 15041210
TI  - Generic detection and differentiation of tobamoviruses by a spot nested RT-PCR
      RFLP using dI-containing primers along with homologous dG-containing primers.
AB  - A spot nested RT-PCR-RFLP method to detect and identify all members of the
      Tobamovirus genus is described. It involves a one-step RT-PCR, in which the
      combination of degenerate deoxyinosine (dI)-substituted primers amplified part of
      the polymerase region of tobamoviruses, followed by a nested PCR amplification
      that increased specificity and sensitivity of detection. Virus species
      differentiation was achieved by subsequent restriction enzyme analysis. The
      sensitivity of the method was increased further when along with one primer
      containing many dIs, another homologous primer in which dIs were substituted by
      dGs was used. The homologous primer was shorter than the dI-containing primer and
      with lower degeneracy, resulting in higher overall amplification efficiency due
      to the increased stability of the primer-target duplex. With this strategy,
      highly degenerate primers containing many dIs can be used effectively to improve
      detection sensitivity, alleviating problems of primer-target duplex
      destabilisation that can occur due to many dI substitutions. This method can be
      useful on the diagnosis, epidemiological investigation, and characterisation of
      known and unidentified Tobamovirus species.

PMID- 15041209
TI  - Development of a novel recombinant adenovirus containing gfp-zeocin fusion
      expression cassette for conditional replication in p53-deficient human tumor
      cells.
AB  - Two obstacles limiting the efficacy of nearly all cancer gene therapy trails are
      low gene transduction efficiency and the lack of tumor specificity. Fortunately,
      a replication-competent, E1B-deficient adenovirus (dl1520) was developed that
      could overcome these limitations, because it was capable of efficiently and
      selectively destroying tumor cells lacking functional p53. In an attempt to
      appraise the efficiency and safety of this approach, a novel recombinant
      adenovirus, r3/Ad, containing a gfp-zeocin expression cassette was constructed in
      this work. The study in vitro demonstrated that r3/Ad has the ability to
      replicate in and lyse only the p53-deficient human tumor cells such as the human
      glioblastoma cells (U251) and human bladder cells (EJ) but not in the human
      fibroblast cells (MRC-5) with functional p53. Importantly, this gfp-zeocin fusion
      gene driven by the bipromoter (CMV and EM-7) could be used as an effective
      selective marker and reporter in prokaryotic and eukaryotic cells; and also
      zeocin as a selective marker could minimize contamination of the recombinant
      virus by the wt-Ad5. Additionally, it was found that the r3/Ad could be useful
      for studying the selective replication of E1B-deficient adenovirus in vivo, it
      could be used as a "guide" to study the ability of the recombinant adenovirus to
      spread and to infect distant tumor cells in any tumor bearing animal model by GFP
      as a reporter. This may help determine the safety of using any E1B-deficient
      adenovirus in cancer gene therapy.

PMID- 15041211
TI  - Piezoelectric biosensors for real-time monitoring of hybridization and detection
      of hepatitis C virus.
AB  - The piezoelectric quartz crystal resonators modified with oligonucleotide probes
      were used for detection of hepatitis C virus (HCV) in serum. The gold electrodes
      on either rough or smooth surface crystals were modified with a self-assembled
      monolayer of cystamine. After activation with glutaraldehyde, either avidin or
      streptavidin were immobilized and used for attachment of biotinylated DNA probes
      (four different sequences). Piezoelectric biosensors were used in a flow-through
      setup for direct monitoring of DNA resulting from the reverse transcriptase
      linked polymerase chain reaction (RT-PCR) amplification of the original viral
      RNA. The samples of patients with hepatitis C were analyzed and the results were
      compared with the standard RT-PCR procedure (Amplicor test kit of Roche,
      microwell format with spectrophotometric evaluation). The piezoelectric
      hybridization assay was completed in 10 min and the same sensing surface was
      suitable for repeated use.

PMID- 15041213
TI  - Detection of Australasian Flavivirus encephalitic viruses using rapid fluorogenic
      TaqMan RT-PCR assays.
AB  - The development of single, sensitive, fluorogenic reverse transcriptase
      polymerase chain reaction (TaqMan) assays were required for the rapid and
      specific detection of three encephalitic viruses found in the Australasian
      region, namely; Japanese encephalitis virus (JEV), Murray Valley encephalitis
      virus (MVEV), and Kunjin virus (KUNV). Primers and a fluorogenic probe were
      individually designed to be complementary to a nucleotide region encompassing the
      3' terminus of the nonstructural (NS) 5 gene and a portion of the 3' untranslated
      region (NS5-3'UTR) of each of the viral genomes respectively. Synthetically
      produced primer and probe controls were developed to minimize the likelihood of
      contamination and generation of false positives. Viral RNA from singly infected
      mosquitoes could be detected in pools of 1000 mosquitoes and positive mosquito
      pools collected from the field have been identified using each assay, indicating
      a high level of sensitivity and suitability for use in mosquito surveillance
      programs. In addition, the JEV TaqMan assay has been used to detect successfully
      viral RNA in sentinel pig serum samples. These assays potentially offer superior
      and timely detection of encephalitic viruses from surveillance samples, which is
      essential for the rapid implementation of vector control measures and continued
      monitoring of virus activity in the Australasian region.

PMID- 15041212
TI  - The reliable detection of Barley yellow and mild mosaic viruses using real-time
      PCR (TaqMan).
AB  - Barley yellow mosaic virus (BaYMV) and Barley mild mosaic virus (BaMMV) are
      economically-important, soil-borne pathogens of winter barley. Until recently,
      laboratory diagnosis of these pathogens has relied upon ELISA using polyclonal
      antiserum. However, due to the unstable nature of these viruses, combined with
      the inability to sap transmit BaYMV, high quality antiserum has been difficult to
      obtain and as a result the performance of ELISA is often unsatisfactory. As an
      alternative approach two TaqMan assays (one BaYMV-specific and the other BaMMV
      specific) have been developed. These assays have been validated for three
      seasons, by testing samples in parallel with ELISA. This testing indicates that
      TaqMan is a more reliable detection method than ELISA, especially with late
      season and mixed infection samples. Data is also provided on a comparison of
      using simplex assays versus a multiplex assay for detecting BaYMV and BaMMV. The
      results indicate that while multiplexing does lead to a small reduction in
      sensitivity, it can be used reliably to streamline routine diagnosis. Further
      improvements in the development of a routine diagnostic procedure are also
      described including details of a rapid automated extraction procedure
      (Kingfisher) and the use of a novel cereal-specific control assay.

PMID- 15041214
TI  - Development of a biotin mimic tagged ScFv antibody against western equine
      encephalitis virus: bacterial expression and refolding.
AB  - Single chain antibodies (ScFvs) are heavy and light chain variable domains
      connected by an artificial linker. Because of their smaller size, ScFvs show
      improved tissue penetration in vivo and reduced immunogenicity, making them ideal
      for therapeutic applications. We have cloned a ScFv against western equine
      encephalitis (WEE) using rDNA technology. The ScFv was generated from a hybridoma
      cell line (11D2) specific to the WEE virus E1 glycoprotein and is arranged in the
      V(L)-V(H) orientation with a (gly(4)ser)(3) linker. This ScFv was engineered
      successfully with a biotin mimic tag (11 amino acid peptide) and cloned in the
      pET22b+ expression vector. The ScFv was expressed as a approximately 32kDa
      protein in Escherichia coli as inclusion bodies, with an estimated yield of 20-40
      mg/l. Different refolding protocols were used to solubilise the inclusion bodies.
      Most of the functional ScFv was generated when the inclusion bodies were
      solubilized in a detergent, air oxidised in the presence of CuSO(4) and then
      denatured in urea buffer in comparison to other protocols. The product was
      renatured finally in Tris arginine buffer (pH 8.0). Refolded protein was dialysed
      against phosphate buffer saline (PBS) (pH 7.3) to remove the Tris and arginine.
      Our refolding protocol generated up to a 50% yield of soluble protein, which
      retained antigen-binding activity with whole inactivated WEE virus as
      demonstrated by ELISA and Western blot analysis. This 11D2-biotin mimic ScFv
      complexed with streptavidin horseradish peroxidase (St-HRPO) will be useful as a
      detector reagent in the ultrasensitive ELISA detection of WEE virus antigen.

PMID- 15041215
TI  - Estimation of the number of infectious measles viruses in live virus vaccines
      using quantitative real-time PCR.
AB  - The potency of live attenuated virus vaccines is determined by counting or
      titrating viable viruses in cell cultures. These classical potency tests have the
      drawback that they are time consuming and laborious and show a high laboratory-to
      laboratory variation. In the present study we describe the development and
      validation of a fast method to measure the potency of measles in trivalent
      measles, mumps and rubella (MMR) vaccines using quantitative real-time PCR
      (qPCR). Vero cells were infected with serial dilutions of a trivalent vaccine or
      a trivalent reference with known potency. Virus was allowed to replicate and
      subsequently replicated virus was quantitated by qPCR using the LightCycler
      technology. The virus titer in vaccine samples was estimated against reference
      preparations using parallel line analysis. In comparison to the plaque assay, the
      qPCR infectivity assay was faster and less laborious, while accuracy and
      intermediate precision were similar.

PMID- 15041216
TI  - Statistical analyses of karyotypic complexity in head and neck squamous cell
      carcinoma.
AB  - More than 250 head and neck squamous cell carcinomas (HNSCCs) with clonal
      chromosomal abnormalities have been reported. Even though the pattern of
      aberrations is nonrandom, no specific primary or secondary karyotypic
      abnormalities have been identified. One explanation for the still-rudimentary
      understanding of the cytogenetic evolution in HNSCC could be the pronounced
      karyotypic complexity seen in these tumors. In an attempt to overcome this
      difficulty, we have applied several statistical methods such as hierarchical
      cluster analysis, multidimensional scaling, and k-means clustering, which allow
      the identification and interpretation of karyotypic pathways, as well as
      establishing a temporal order of chromosomal imbalances on 241 published and 70
      previously unpublished HNSCC karyotypes. From the analysis of the distribution of
      the number of imbalances per tumor we suggest that the carcinomas evolve through
      three phases representing different stages of chromosomal instability. Two major
      cytogenetic pathways, one dominated by gains and another by losses, were
      identified by means of principal component analysis. These were initiated by +7
      and by any of the aberrations 1p-, 3p-, or 7q-, respectively.

PMID- 15041217
TI  - Wilms tumors develop through two distinct karyotypic pathways.
AB  - Wilms tumor is an embryonic neoplasm characterized by a large variation in
      histologic patterns. Cytogenetic investigations have identified nonrandom
      chromosomal changes characteristic for this tumor type, of which numerical
      changes, mostly trisomies for chromosomes 7, 8, and 12, are particularly
      frequent. Despite the abundance of cytogenetic information, with more than 350
      published karyotypes, very little is known about the mode of karyotypic
      evolution. In this investigation, we have used 355 karyotypes of Wilms tumor to
      identify frequent imbalances. The most frequent were +1q, +6, +7q, +8, +12, +13, 
      11, and -16. Tumor cases were then classified with respect to the presence or
      absence of these imbalances and statistically analyzed to assess the order of
      appearance of chromosomal imbalances, as well as possible karyotypic pathways. We
      show that Wilms tumors develop through one major mode of karyotypic evolution,
      common to both low- and high-complex tumors, and that polyploid cases are
      relatively rare. We also establish a temporal order by which the different
      imbalances occur and show that at least two cytogenetic pathways exist, one
      dominated by gains and another by losses. We also show that these pathways are
      well separated and do not share a common set of late imbalances.

PMID- 15041218
TI  - Detection of micronuclei formation and nuclear anomalies in regenerative nodules
      of human cirrhotic livers and relationship to hepatocellular carcinoma.
AB  - Human cirrhosis is considered an important factor in hepatocarcinogenesis. The
      lack of substantial genetics and cytogenetics data in human cirrhosis led us to
      investigate spontaneous micronuclei formation, as an indicator of chromosomal
      damage. The analysis was performed in hepatocytes of regenerative,
      macroregenerative, and tumoral nodules from 30 cases of cirrhosis (paraffin
      embedded archival material), retrospectively selected: cryptogenic, hepatitis C
      virus, and hepatitis C virus associated with hepatocellular carcinoma (HCC).
      Thirteen control liver samples of healthy organ donors were included.
      Micronucleated hepatocytes were analyzed with Feulgen-fast-green dyeing
      techniques. The spontaneous frequency of micronucleated hepatocytes in both
      regenerative and macroregenerative nodules of all cirrhotic patients was
      significantly higher than for the normal control group. There was no significant
      difference in frequency of micronucleated hepatocytes in regenerative nodules
      compared with macroregenerative nodules for all cases analyzed, whereas a
      significantly higher frequency of micronucleated hepatocytes was detected in
      tumoral nodules, compared with cirrhotic regenerative nodules and normal
      parenchyma. A higher frequency of the nuclear anomalies termed broken-eggs was
      observed in hepatitis C virus-related samples. Chromatinic losses and
      genotoxicity already existed in the cirrhotic regenerative nodules, which might
      predispose to development of HCC.

PMID- 15041219
TI  - Detection of t(14;18) in follicular lymphoma by dual-color fluorescence in situ
      hybridization on paraffin-embedded tissue sections.
AB  - We studied the incidence of t(14;18)(q32;q21) in 54 patients with follicular
      lymphoma (FL) by dual-color fluorescence in situ hybridization on paraffin
      embedded tissue sections (tissue-FISH) using probes for BCL2 and immunoglobulin
      heavy chain (IGH) genes. The t(14;18) was detected in 28 (56%) of 50 patients,
      who were successfully analyzed. On the other hand, BCL2 protein expression was
      detected in 45 (83%) of 54 patients evaluated by immunohistochemical staining.
      There was a discrepancy between t(14;18) and BCL2 expression. The absence of
      t(14;18) was associated with disease-free survival (P=0.02). There was no
      statistical difference, however, in overall survival and failure-free survival
      between the t(14;18)-positive and -negative groups. Tissue-FISH should be of
      great value to detect t(14;18) in FL because this method enabled us to
      demonstrate specifically t(14;18)-positive individual cells in neoplastic
      follicles on paraffin-embedded tissue sections. Furthermore, tissue-FISH can be
      applied to small specimens obtained from endoscopic biopsy or specimens obtained
      more than 10 years ago. We validated the usefulness of tissue-FISH as a
      diagnostic procedure and retrospective meta-analysis for malignant lymphoma.

PMID- 15041220
TI  - Characterization of large chromosome markers in a malignant fibrous histiocytoma
      by spectral karyotyping, comparative genomic hybridization (CGH), and array CGH.
AB  - In this study, we characterized the chromosomal composition of an intra-abdominal
      soft tissue sarcoma diagnosed as a malignant fibrous histiocytoma (MFH). By
      applying a combination of spectral karyotyping, G-banding, and comparative
      genomic hybridization (CGH), this case was shown to carry large chromosome
      markers with material mainly from chromosomes 6 and 8. Further characterization
      of this unique tumor revealed high-level amplifications at the 6q21 approximately
      q23, 8p21 approximately pter, 8q24 approximately qter, and 12q13 approximately
      q21 regions. Using array CGH, these amplified regions were found to include MASL1
      in 8p, as well s MDM2 and CDK4 in 12q, which have been shown to be amplified in
      MFH. Similarly, gains of 6q and 8q have also been seen in MFH. In conclusion, our
      study demonstrates the occurrence of large chromosome markers in MFH and suggests
      that the regions 6q21 approximately q23, 8p21 approximately pter, 8q24
      approximately qter, and 12q13 approximately q21 might harbor oncogenes that could
      play a role in MFH's tumorigenesis. In addition, gain of 12q13 approximately q21,
      which is typical of well-differentiated liposarcoma, may also occur in MFH,
      supporting the previously suggested overlap in genetic etiologies between these
      two tumor types.

PMID- 15041221
TI  - Constitutional genomic instability, chromosome aberrations in tumor cells and
      retinoblastoma.
AB  - Although retinoblastoma (Rb) is initiated as a result of biallelic inactivation
      of the RB1 gene, additional genetic events (M3) in tumor cells are indicative of
      their role in the full transformation of retinal cells. We investigated the
      constitutional genetic instability by fragile site (FS) expression studies and
      checked its relationship with loci of tumor cytogenetics in a series of 36
      retinoblastoma patients (34 nonfamilial and 2 familial cases). Tumor cytogenetics
      revealed -13/+13, del/t(13)(q14) (50%), +1/del/t(1p/q) (65%), +6/i(6p) (60%), and
      del(16)(q13)/(q22 approximately q23) (60%). Conventional cytogenetics in
      leukocytes revealed constitutional del(13q14) in five unilateral Rb (URB) and one
      trilateral Rb (TRB). Constitutional del(16)(q22) and t(6;12) were also identified
      in two cases. Constitutional FS analysis showed a significant increase in the
      cellular fragility, with high prevalence at 13q14, 3p14, 6p23, 16q22
      approximately q23, and 13q22 loci in retinoblastoma patients (P<0.05). Patients
      with constitutional del(13)(q14) demonstrated higher fragility than those with
      normal constitution. A strong correlation between loci of constitutional FSs and
      loci of recurrent chromosomal abnormalities in tumors strengthen and support the
      proposal that FS loci present as inherent genomic instability in retinoblastoma.
      The chromosomal changes and resultant genetic mutations, along with RB1 mutation
      events, probably contribute synergistically to the development and progression of
      Rb malignancy. Implementation of fluorescence in situ hybridization to
      nonfamilial Rb on a large scale (113 cases) could detect constitutional RB1
      deletion in 12.3% of cases, with equally higher incidence in URB (14.7%) and
      bilateral Rb (13.6%), demonstrating that the true prevalence of patients with
      predisposition to RB1 mutation in sporadic URB is definitely higher in our
      populations. Also, higher incidence of constitutional RB1 deletion mosaicism in
      unilateral than in bilateral Rb indicates that the constitutional genetic
      mosaicism in URB should be given serious consideration during genetic counseling.

PMID- 15041222
TI  - Analysis of human papillomavirus prevalence and TP53 polymorphism in head and
      neck squamous cell carcinomas.
AB  - Head and neck squamous cell carcinoma is a disease associated with tobacco and
      alcohol abuse. There is evidence that the oncogenic human papillomavirus (HPV)
      may also be a risk for upper aerodigestive tract cancers. High-risk HPVs encode
      two early proteins, E6 and E7, that can bind to p53 and pRb, respectively, and
      induce its degradation or inactivation. The TP53 gene has a single polymorphism
      at codon 72 of exon 4 that encodes either arginine (Arg) or proline (Pro). The
      purpose of this study was to evaluate the role of HPV infection and TP53
      polymorphism in head and neck cancer. We analyzed 50 tumors, as well swabs of
      oral mucosa from 142 control individuals, with a polymerase chain reaction
      technique. The prevalence of HPV in controls was 10.6% and in cancer specimens
      16%. The frequency distribution of genotypes in controls was 50% Arg/Arg, 43%
      Arg/Pro and 7% Pro/Pro; in tumors, it was 52% Arg/Arg, 32% Arg/Pro, and 16%
      Pro/Pro. Contrary to the results of some studies on cervical cancer, no
      association between any TP53 genotype or allele and the development of head and
      neck cancer was observed, regardless of HPV status, except for the Pro/Pro
      genotype, which is associated with the absence of HPV. The arginine allele
      appears to protect against head and neck cancers. Also, the data showed that HPV
      infection results in no increased risk of developing head and neck tumors.

PMID- 15041223
TI  - High frequency of genomic instability in Ewing family of tumors.
AB  - We tested Ewing sarcoma tumors for microsatellite instability (MSI) and loss of
      heterozygosity (LOH) to investigate the role of genomic instability (GI) in this
      sarcoma. We detected a high frequency of GI (57%), mostly on 1p and 11p, 35% and
      30%, respectively. Patients with GI compared to those with stable genome had a
      median progression-free survival (PFS) and overall survival (OS) of 24 months and
      70 months, compared with 39 and 84 months, respectively. MSI was observed in 48%
      (11/23) of the tumor samples. Low-MSI (L-MSI) patients (with MSI presented at
      only one locus) tended to have a better prognosis, 70% PFS, compared with 25% in
      the high-MSI (H-MSI) group (P=0.13). LOH without MSI did not correlate with
      progression. H-GI (MSI and/or LOH in > or =30% of tested markers) tended to
      associate with an adverse prognosis (P=0.28), and correlated significantly with
      the pelvic site of the primary tumor (P=0.02). The instability of 1p was not
      associated with progression, while alterations at the 11p locus tended to
      correlate with a more aggressive disease (P=0.18). Our data suggest that GI may
      play a role in Ewing sarcoma clinical behavior and outcome.

PMID- 15041224
TI  - The occurrence of chromosome segregational defects is an intrinsic and heritable
      property of oral squamous cell carcinoma cell lines.
AB  - Chromosomal segregational defects are commonly observed in cancer cells and are
      an important source of genetic instability. It is currently unknown whether these
      mitotic defects are the result of a subpopulation of defective cells or reflect
      characteristics of the population of cells as a whole. In this study, we compared
      chromosomal segregational defects in two oral squamous cell carcinoma cell lines
      and five single-cell clones from each of those cell lines. We used
      immunofluorescence microscopy to quantitate the occurrence of multipolar
      metaphase spindles, lagging chromosomes at metaphase and anaphase, and anaphase
      bridges. We conclude that chromosome segregational defects in these cancer cell
      lines represent an intrinsic and inherited tendency toward segregational defects
      in the general cell population, rather than the existence of a subpopulation of
      cells with segregational defects.

PMID- 15041225
TI  - T-cell acute lymphoblastic leukemia with add(1)(p36) and del(12)(p11) following
      acute myelocytic leukemia with partial deletion of 9p.
AB  - We describe the case of a 40-year-old man whose disease was initially diagnosed
      as acute myelocytic leukemia. The patient achieved remission with chemotherapy,
      but relapsed shortly afterwards with an acute T-cell lymphoblastic leukemia. He
      died of intracranial bleeding. Karyotyping analysis showed a del(9p?) as a common
      abnormality in the leukemic cells at onset and relapse. Fluorescence in situ
      hybridization analysis demonstrated allelic loss of the CDKN2A gene in cells from
      both stages of the disease. At relapse the leukemia cells had additional
      abnormalities such as add(1)(p36) and del(12)(p11). We postulate that the loss of
      CDKN2A is involved in leukemogenesis but does not determine the lineage of the
      leukemic cells. Instead, abnormalities of genes at 1p36, 12p11, or both may be
      involved in driving a lymphoid phenotype.

PMID- 15041226
TI  - Trisomy 4 as the sole karyotypic abnormality in a case of acute biphenotypic
      leukemia with T-lineage markers in minimally differentiated acute myelocytic
      leukemia.
AB  - We report an unusual case of acute biphenotypic leukemia with trisomy 4. A 22
      year-old woman presented with acute leukemia characterized by the presence of two
      cell populations (prothymocytic and myeloblastic). The leukemic cells were
      resistant to standard induction chemotherapy and were cleared from the bone
      marrow only after a salvage chemotherapy regimen. To our knowledge, this is the
      fourth reported case of acute biphenotypic leukemia with trisomy 4 and perhaps
      the first case with T-lineage markers and acute myelocytic leukemia.

PMID- 15041227
TI  - Gonadoblastoma in Turner syndrome patients with nonmosaic 45,X karyotype and Y
      chromosome sequences.
AB  - Turner syndrome (TS) is a disorder caused by partial or complete X-chromosome
      monosomy. Studies in TS patients with different karyotypes have demonstrated the
      presence of Y-chromosome-derived sequences (4-61%). Early detection of Y
      chromosome sequences in TS is of great importance because of the high risk of
      gonadal tumor development. We investigated the presence of Y-chromosome sequences
      in TS patients with a 45,X karyotype. One hundred seven unrelated 45,X Mexican TS
      patients recruited between 1992 and 2003 were included. Y-chromosome-derived
      sequences were found by polymerase chain reaction in 10 (9.3%) patients. Six
      subjects underwent gonadectomy and in one of them a gonadoblastoma was found;
      another developed a gonadoblastoma with dysgerminoma. Because of the high
      proportion (33%) of gonadal tumors in patients with Y-chromosome sequences found
      among our patients of mestizo origin, adequate counseling regarding a gonadectomy
      should be given.

PMID- 15041228
TI  - Clonal chromosome abnormalities in a plexiform cellular schwannoma.
AB  - Cellular schwannomas are uncommon tumors of Schwann cells that can rarely have a
      plexiform architecture. Cellular schwannomas can be confused with low-grade
      malignant peripheral nerve sheath tumors (MPNST) but have been noted to have a
      benign clinical course. There are few published cytogenetic analyses of cellular
      schwannomas and, to our knowledge, there are no reports of the plexiform variant
      of cellular schwannoma to date. Cellular schwannomas are reported to have
      cytogenetic changes similar to those seen in benign schwannomas with near-diploid
      karyotypes having simple numerical changes often involving chromosomes 22, 7, and
      the sex chromosomes. MPNST are markedly different, with extensive genetic
      heterogeneity and complex karyotypes. We report clonal numerical changes in a
      cellular schwannoma with plexiform architecture: 47,XY,+17 and 48,XY,+17,+18.
      These findings add to the karyotypic spectrum of peripheral nerve sheath tumors.

PMID- 15041229
TI  - Translocation (11;13)(q23;q14) as the sole abnormality in a childhood de novo
      acute myelocytic leukemia.
AB  - We report a case of childhood de novo acute myelocytic leukemia (AML) with
      hyperleukocytosis with monoblastic features and deranged hemostasic function. G
      band karyotyping demonstrated a previously unreported t(11;13)(q23;q14) in
      metaphase preparations from a fluorodeoxyuridine synchronized 1-day culture of
      leukophoresed cells. Multicolor fluorescence in situ hybridization revealed no
      cryptic rearrangements except for the translocation. Reverse transcriptase
      polymerase chain reaction showed no concomitant positivity of AML1/ETO, BCR/ABL,
      PML/RARA, and CBFbeta/MYH11 resulting from t(8;21)(q22;q22), t(9;22)(q34;q11),
      t(15;17)(q22;q11), and inv(16) (p13q22), respectively. This report of childhood
      de novo AML harboring t(11;13)(q23;q14) as the sole cytogenetic abnormality
      provides more data on the leukemogenesis of de novo AML with a 11q23
      rearrangement.

PMID- 15041231
TI  - Detection of inv(16)(p13q22) by means of chromosome painting with a 16q-specific
      probe.

PMID- 15041230
TI  - A fluorescence in situ hybridization study of complex t(9;22) in two chronic
      myelocytic leukemia cases with a masked Philadelphia chromosome.
AB  - The t(9;22)(q34;q11) is evident in more than 90% of patients with chronic
      myelocytic leukemia (CML) and gives rise to the Philadelphia chromosome (Ph).
      Approximately 5%-10% of CML patients show variant translocations involving other
      chromosomes in addition to chromosomes 9 and 22. In some variant translocations,
      additional material is transferred on der(22), resulting in a masked Ph
      chromosome. In this paper, we report two apparently Ph-negative (Ph-) CML cases
      showing a t(7;9;22)(q22;q34;q11) and a t(8;9;22)(q12;q34;q11), respectively. A
      detailed molecular cytogenetic characterization was performed by fluorescence in
      situ hybridization (FISH), which disclosed the presence of the 5'BCR/3'ABL fusion
      gene on the der(7) and der(8) chromosomes, respectively. Derivative (22) appeared
      as a masked Ph chromosome in both cases. FISH analysis with appropriate BAC/PAC
      clones allowed us to precisely characterize the complex chromosomal
      rearrangements that were not detected by conventional cytogenetic analysis.

PMID- 15041233
TI  - A t(20;21)(q12;q22.3) in a patient with chronic myelocytic leukemia in blastic
      phase.

PMID- 15041232
TI  - A case of adult acute myelocytic leukemia (M5a) with a near-tetraploid karyotype
      characterized by monosomies 5 and 16.

PMID- 15041234
TI  - Coordination properties of 2-aminocyclopentene-1-dithiocarboxylic acid to
      transition metal ions as studied by ab initio calculations.
AB  - The question of the(N, S) vs. (S, S) coordination mode on M x (ACDA)(2) complexes
      (ACDA=2-aminocyclopentene-1-dithiocarboxylic acid, M=Ni(2+), Pd(2+), Pt(2+)) was
      assessed through an extensive ab initio study, using the hybrid B3LYP density
      functional approach. The (S,S)coordination was found to be the most stable one,
      with an energy difference of ca. 50 kJ mol(-1) relative to the(N, S) coordination
      mode. Detailed analysis of the ab initio results indicates that this preference
      is a result of the combined effect of geometry constraints and electron
      distribution within the complex.

PMID- 15041235
TI  - Study of Ni(II) ion-DNA interactions with methylene blue as fluorescent probe.
AB  - Spectroscopic studies of the interactions of Ni(II) ion with herring sperm DNA
      have been performed in this contribution using methylene blue (MB) as the
      fluorescent probe molecule. MB binds to double helical DNA via the intercalative
      mode, and its fluorescence is efficiently quenched by the DNA nucleobases. The
      fluorescence intensity of the probe molecule increases distinctly when Ni(II) ion
      is added to the MB-DNA solution system. These results indicate that the Ni(II)
      ions may be complexed with the DNA helix and probably bind at N-7 of adenine or
      guanine; consequently, some intercalated MB molecules are released due to the
      binding of Ni(II) ions to N-7 nitrogen of the purines. The Ni(II) ion-DNA
      interactions are further investigated by performing the photobleaching
      experiments of the MB-DNA complex in the presence and absence of Ni(II) ion. The
      bi-exponential decay functions of the fluorescence intensity have been observed
      in both cases and the shortening of the slow decay component when added Ni(II)
      ion also agrees with the release of MB from the DNA duplex.

PMID- 15041236
TI  - Pyrococcus abyssi alkaline phosphatase: the dimer is the active form.
AB  - Alkaline phosphatases (APs), E.C. 3.1.3.1, are non-specific phosphomonoesterases
      optimally active under alkaline conditions. They are classically known to be
      homodimeric metalloenzymes. This quaternary structure has been considered
      necessary for activity, although the relationship between quaternary structure
      and activity is not well understood. Recombinant Pyrococcus abyssi AP was
      previously isolated and characterized, appearing to have two active quaternary
      structures on native polyacrylamide gel electrophoresis: a monomer and a
      homodimer. The purpose of the present work was to determine the actual quaternary
      structure of P. abyssi AP in solution, by isolating each of the two quaternary
      forms and establishing the parameters governing the assembly and dissociation of
      the dimer. pH appeared to be an important parameter: in acidic media, the
      monomer/dimer ratio shifted towards monomer. Buffer composition also affected the
      quaternary structure: at the same pH, in potassium phosphate buffer, the two
      quaternary structures were observed, whereas in tris(hydroxymethyl)aminomethane
      hydrochloride buffer, only the dimer was observed. Metals bound to the enzyme
      were found to be involved in the stability of the quaternary structure. Indeed,
      the P. abyssi AP obtained upon removal of the metals was monomeric. Reactivation
      of the latter was achieved with variable efficiency. From these experiments, no
      active monomer could be isolated, leading the conclusion that the active form of
      P. abyssi AP is the homodimer.

PMID- 15041237
TI  - Electrochemical studies of kanamycin immobilization on self-assembled monolayer
      and interaction with DNA.
AB  - The electrochemical characteristics of kanamycin onto self-assembled monolayer
      (SAM) modified gold electrode (SAM/Au) is investigated by cyclic voltammetry. In
      the potential range 0-0.6 V, Cu(II) yields a pair of stable redox waves at the
      bare gold electrode. E(pa) is located at 0.189 V and E(pc) at 0.254 V. In
      contrast, Cu(II) is reduced at a more positive potential and a decreasing current
      at the kanamycin SAM/Au electrode. Cu(II) and kanamycin can form a stoichiometry
      complex with chemical ratio of 2:1. The interaction of Cu(II)-kanamycin complex
      with calf thymus DNA is also studied in the solution. And the interactive mode
      between Cu(II)-kanamycin complex and DNA is verified by the fluorescence method.
      Binding constants (K) of the Cu(II)-kanamycin complex to DNA and binding site
      size (s) are calculated from voltammetric data and equal to 1.5 x 10(7) l/mol and
      4 bp, respectively.

PMID- 15041238
TI  - The interaction of native DNA with iron(III)- N ,N'-ethylene
      bis(salicylideneiminato)-chloride.
AB  - The interaction between native calf thymus deoxyribonucleic acid (DNA) and
      Fe(III)- N ,N'-ethylene-bis (salicylideneiminato)-chloride, Fe(Salen)Cl, was
      investigated in aqueous solutions by UV-visible (UV-vis) absorption, circular
      dichroism (CD), thermal denaturation and viscosity measurements. The results
      obtained from CD, UV-vis and viscosity measurements exclude DNA intercalation and
      can be interpreted in terms of an electrostatic binding between the Fe(Salen)(+)
      cation and the phosphate groups of DNA. The trend of the UV-vis absorption band
      of the Fe(Salen)Cl complex at different ratios [DNA(phosphate)]/[Fe(Salen)Cl] and
      the large increase of the melting temperature of DNA in the presence of
      Fe(Salen)Cl, support the hypothesis of an external electrostatic interaction
      between the negatively charged DNA double helix and the axially stacked
      positively charged Fe(Salen)(+) moieties, analogously to what reported for a
      number of porphyrazines and metal-porphyrazine complexes interacting with DNA.

PMID- 15041239
TI  - [Au(2)(micro-G)(micro-dmpe)].(KBr)(0.75) 2H(2)O, a cyclic dinuclear gold(I)
      complex with an N3,N9-bridging coordination mode of guanine and aurophilic
      interactions: synthesis, X-ray crystal structure and luminescence properties
      (dmpe=1,2-bis(dimethylphosphino)ethane and G=guaninato dianion).
AB  - The digold complex [Au(2)(micro-G)(micro-dmpe)](KBr)(0.75) x 2H(2)O (dmpe=1,2
      bis(dimethylphosphino)ethane (1)) has been prepared by nucleophilic attack of the
      guaninate dianion on the gold(I) atoms of [(AuBr)(2)(micro-dmpe)] and has been
      characterised by X-ray crystallography and spectroscopic studies. The structure
      of 1 consists of dinuclear nine-membered ring molecules, K(+) cations, Br(-)
      anions and water molecules, all of them involved in either weak K....O or
      hydrogen bonding interactions. Within the cyclic dinuclear molecules, gold(I)
      atoms are bridged on one side by the diphosphine ligand and on the other side by
      a doubly deprotonated guaninate anion coordinated through neighbouring N3 and N9
      nitrogen atoms, with gold(I)....gold(I) interactions of 3.030(2) A. This is the
      first X-ray example showing an N3,N9-bridging mode for guanine. There are two
      types of K(+) cations in the structure, K1 and K2. The former interacts with
      water molecules to form a unique [K(H(2)O)(3)(micro-H(2)O)(2)K(H(2)O)(3)](2+)
      dipotassium unit whereas K2 interact with the O6 atom of the guaninate ligands
      and oxygen atoms of the dipotassium unit leading to a chain running along the c
      axis. Each chain is interdigitated with four neighbouring ones to give rise to an
      intricate network in which Br1, Br2 and [K(H(2)O)(3)(micro
      H(2)O)(2)K(H(2)O)(3)](2+) fit snugly into cavities defined by digold molecules.
      Complex 1 luminescence at room temperature and 77 K in the solid state with
      excitation maxima at 385 nm and emission maxima at 451.8 and 448.7 nm,
      respectively. The emission spectrum of a saturated solution of 1 in DMSO
      (dimethyl sulfoxide) shows the maximum at about 440 nm.

PMID- 15041240
TI  - Syntheses, crystal structures and antimicrobial activities of monomeric 8
      coordinate, and dimeric and monomeric 7-coordinate bismuth(III) complexes with
      tridentate and pentadentate thiosemicarbazones and pentadentate semicarbazone
      ligands.
AB  - Novel bismuth(III) complexes 1-4 with the tridentate thiosemicarbazone ligand of
      2N1S donor atoms [Hmtsc (L1); 2-acetylpyridine (4N-morpholyl thiosemicarbazone)],
      the pentadentate double-armed thiosemicarbazone ligand of 3N2S donor atoms
      [H2dmtsc (L3); 2,6-diacetylpyridine bis(4N-morpholyl thiosemicarbazone)] and the
      pentadentate double-armed semicarbazone ligand of 3N2O donor atoms [H2dasc (L4b);
      2,6-diacetylpyridine bis(semicarbazone)], were prepared by reactions of
      bismuth(III) nitrate or bismuth(III) chloride and characterized by elemental
      analysis, thermogravimetric and differential thermal analysis (TG/DTA), FTIR and
      NMR (1H and 13C) spectroscopy. The crystal and molecular structures of complexes
      1, 2a, 2b and 4b, and the "free" ligand L1 were determined by single-crystal X
      ray structure analysis. The dimeric 7-coordinate bismuth(III) complex
      [Bi(dmtsc)(NO3)]2, 1, and the monomeric 7-coordinate complexes
      [Bi(Hdasc)(H2O)](NO3)2.H2O (major product), 2a, and [Bi(dasc)(H2O)]NO3.H2O (minor
      product), 2b, all with pentagonal bipyramidal bismuth(III) centers, are depicted
      with one electron pair (6s2) of the bismuth(III) atom, deprotonated forms of
      multidentate thiosemicarbazone or semicarbazone ligands, and monodentate NO3 or
      H2O ligands, respectively. These complexes are related to the positional isomers
      of one electron pair of the bismuth(III) atom; 1 has an electron pair positioned
      in the pentagonal plane (basal position), while 2a and 2b have an electron pair
      in the apical position. The monomeric 8-coordinate complex [Bi(mtsc)2(NO3)], 4b,
      which was obtained by slow evaporation in MeOH of the 1.5 hydrates 4a, was
      depicted with one electron pair of the bismuth(III) atom, two deprotonated mtsc-
      ligand and one nitrate ion. On the other hand, crystals of the complex
      "[Bi(mtsc)Cl2]", 3, prepared by a reaction of BiCl3 with L1 showed several
      polymorphs (3a, 3b, 3c and 3d) due to coordination and/or solvation of dimethyl
      sulfoxide (DMSO) used in the crystallization. Bismuth(III) complexes 1 and 4a
      showed selective and effective antibacterial activities against Gram-positive
      bacteria. The structure-activity relationship was discussed.

PMID- 15041241
TI  - Synthesis and characterization of the biological activity of the cisplatin
      analogs, cis-PtCl(2)(dexrazoxane) and cis-PtCl(2)(levrazoxane), of the
      topoisomerase II inhibitors dexrazoxane (ICRF-187) and levrazoxane (ICRF-186).
AB  - The individual stereoisomers cis-PtCl(2)(dexrazoxane) and cis
      PtCl(2)(levrazoxane) were synthesized and their structures were determined by X
      ray crystallography. Dexrazoxane and levrazoxane inhibit cell growth because they
      are strong catalytic inhibitors of DNA topoisomerase II, whereas cisplatin acts
      through the formation of DNA cross-links. It was hypothesized that platinum(II)
      complexes of dexrazoxane and levrazoxane would retain both activities and yield
      drugs with a dual mode of action. Both cis-PtCl(2)(dexrazoxane) and cis
      PtCl(2)(levrazoxane) inhibited Chinese hamster ovary cell growth, but more weakly
      than dexrazoxane and levrazoxane did. Based on their weak topoisomerase II
      inhibitory activity, it was concluded that these compounds did not inhibit cell
      growth by targeting topoisomerase II. A comparison of the conformation of cis
      PtCl(2)(dexrazoxane) to that of dexrazoxane bound to the dimer interface of
      topoisomerase II showed that the highly constrained cis-PtCl(2)(dexrazoxane) was
      in a highly unfavorable conformation for binding. Neither of the platinum
      complexes were able to cross-link DNA. Thus the cell growth inhibitory activity
      of these complexes was also not likely due to any cisplatin-type cross-linking
      activity.

PMID- 15041243
TI  - Uracilato and 5-halouracilato complexes of Cu(II), Zn(II) and Ni(II). X-ray
      structures of [Cu(uracilato-N(1))(2)(NH(3))(2)].2(H(2)O), [Cu(5-chlorouracilato
      N(1))(2)(NH(3))(2)](H(2)O)(2), [Ni(5-chlorouracilato-N(1))(2)(en)(2)].2H(2)O and
      [Zn(5-chlorouracilato-N(1))(NH(3))(3)].(5-chlorouracilato-N(1)).(H(2)O).
AB  - Four new complexes of uracilato and 5-halouracilato with the divalent metal ions
      Cu(II), Zn(II) and Ni(II) were obtained and structurally characterized.
      [Cu(uracilato- N(1))(2)(NH(3))(2)].2(H(2)O) (1) and [Cu(5-chlorouracilato
      N(1))(2)(NH(3))(2)](H(2)O)(2) (2) complexes present distorted square planar co
      ordination geometry around the metal ion. Although an additional axial water
      molecule is present [Cu(II)-OH(2)=2.89 A (for 1) and 2.52 A (for 2)] in both
      cases, only in the complex 2 would be considered in the limit of a bond distance.
      The Zn(II) in [Zn(5-chlorouracilato-N(1))(NH(3))(3)].(5-chlorouracilato
      N(1)).(H(2)O) presents a tetrahedral co-ordination with three ammonia molecules
      and the N(1) of the corresponding uracilato moiety. A non-coordinated uracilato
      molecule is present as a counterion and a recognition between co-ordinated and
      free ligands, by means a tandem of H-bonds, should be mentioned. Finally, the
      complex [Ni(5-chlorouracilato-N(1))(2)(en)(2)] (H(2)O)(2) (where en is
      ethylenediamine) presents a typical octahedral trans co-ordination with
      additional hydrogen bonds between 5-chlorouracilato and the NH(2) groups of
      ethylenediamine units.

PMID- 15041242
TI  - Inhibition of vanadium chloroperoxidase from the fungus Curvularia inaequalis by
      hydroxylamine, hydrazine and azide and inactivation by phosphate.
AB  - The first detailed inhibition study of recombinant vanadium chloroperoxidase
      (rVCPO) using hydroxylamine, hydrazine and azide has been carried out.
      Hydroxylamine inhibits rVCPO both competitively and uncompetitively. The
      competitive inhibition constant K(ic) and the uncompetitive inhibition constant
      K(iu) see are 40 and 80 microM, respectively. The kinetic data suggest that rVCPO
      may form a hydroxylamido complex, hydroxylamine also seems to react with the
      peroxovanadate complex during turnover. The kinetic data show that the type of
      inhibition for hydrazine and azide is uncompetitive with the uncompetitive
      inhibition constant K(iu) of 350 microM and 50 nM, respectively, showing that in
      particular azide is a very potent inhibitor of this enzyme. Substitution of
      vanadate in the active site by phosphate also leads to inactivation of vanadium
      chloroperoxidase. However, the presence of H(2)O(2) clearly prevents the
      inactivation of the enzyme by phosphate. This shows that pervanadate is bound
      much more strongly to the enzyme than vanadate.

PMID- 15041245
TI  - Preparation of dehydro-l-(+)-ascorbic acid dimer by oxidation of ascorbic acid
      with arsenic acid/iodine and formation of complexes between arsenious acid and
      ascorbic acid.
AB  - Ascorbic acid in the presence of a catalytic amount of iodine reduces arsenic
      acid in methanol giving the arsenious acid bound to the 2-methyl hemi-ketal of
      dehydroascorbic acid, 5, in 1:1 and in a more stable 2:1 5/As(III) molar ratio.
      Removal of the As(III) and treating the 2-methyl hemi-ketal of dehydroascorbic
      acid with refluxing acetonitrile affords the pure, crystalline dehydroascorbic
      acid dimer in good yields. Ascorbic acid also binds to As(III) of H(3)AsO(3) in a
      1:1 and 2:1 ascorbic acid/As(III) molar ratio. The 1:1 complex is not stable and
      by expulsion of H(3)AsO(3) is transformed to the more stable 2:1 complex. The
      data do not permit distinguishing the 2:1 complexes between [AsL(2)(H(2)O)](
      )H(+) or AsL(LH)(H(2)O) where L is the bis deprotonated and LH is the mono
      deprotonated 2-methyl hemi-ketal of dehydroascorbic acid or ascorbic acid. The
      2:1 ascorbic acid/As(III) complex is oxidized by dioxygen, in a solvent-dependent
      manner, to dehydroascorbic acid implying dioxygen activation by the bound
      As(III). With thiophenol the same complex gives quantitatively triphenyl
      trithioarsenite, As(SPh)(3).

PMID- 15041246
TI  - Reaction of iron(III) with theaflavin: complexation and oxidative products.
AB  - Theaflavins are a family of compounds, whose chemistry has been sparsely
      investigated. They can comprise up to 40% the dry weight of black tea. They are
      known to chelate metals, however very little knowledge exists on the mechanisms
      involved. There is some correlation between both of these areas in that following
      degradation of the iron theaflavin complex, subsequent redox reactions may lead
      to the formation of similar products on both occasions. The interaction of
      iron(III) with theaflavin at pH < 3.0 is investigated by means of liquid
      chromatography mass spectroscopy (LC-MS), stopped flow spectroscopy and
      multivariate data analysis. Iron theaflavin complexes are formed which
      subsequently decay to form a number of oxidative species. The difficulties
      involved in the elucidation of the structure of polymeric phenolic compounds from
      black tea has been highlighted by numerous authors. The intermediates and major
      low molecular weight oxidised theaflavin products from the reaction of excess
      iron with theaflavin have been detected and identified using multivariate data
      analysis of diode array spectroscopic data. It is not possible to characterise
      the extremely polar high molecular weight oxidation products obtained from
      polyphenol oxidation. High performance liquid chromatography (HPLC) and
      electrospray mass spectroscopy (ES-MS) detected the low molecular weight oxidised
      theaflavin species present in the system. Enzymatic oxidation of theaflavin using
      peroxidase (POD) resulted in the formation of one major low molecular weight
      species oxidative product, which was fully characterised using nuclear magnetic
      resonance spectroscopy (NMR), high performance liquid chromatography (HPLC),
      electrospray mass spectroscopy (ES-MS), UV-visible (UV-Vis) and Fourier transform
      infra-red spectroscopy (FT-IR). The major objective of this work is to
      investigate the reaction of iron(III) with theaflavin and to add some insight
      into the mechanistic interaction of iron(III) with this family of compounds.

PMID- 15041244
TI  - Interprotein metal exchange between transcription factor IIIa and apo
      metallothionein.
AB  - Zn(2+) and Cd(2+) ion exchange between transcription factor IIIA (TFIIIA) and apo
      metallothionein (MT) were studied using a combination of methods including
      chromatography, ultrafiltration and UV spectroscopy. Under near stoichiometric
      conditions, apoMT was able to remove most if not all of the zinc ions from
      TFIIIA, whether or not the TFIIIA was bound to the 5S DNA internal control region
      (ICR), and concomitantly inhibit its DNA-binding activity as indicated by an
      electrophoretic mobility shift assay. The kinetics of the two processes were
      similar. The rate of the metal exchange reaction increased with the
      concentrations of both reactants. A second-order rate constant of 30+/-10 M(-1)s(
      1) was calculated. Similar observations were made for the reaction between apoMT
      and Cd-substituted TFIIIA, which proceeded without observable intermediates
      according to a spectrophotometric analysis. A very slow metal ion exchange
      occurred between Cd-TFIIIA and Zn-MT, but not between Cd-MT and Zn-TFIIIA.
      Comparative studies on the reaction of TFIIIA with a small competing ligand,
      ethylenedinitrilo-tetraacetic acid (EDTA), were also conducted. Although EDTA
      reacts with free Zn-TFIIIA, under similar conditions it failed to compete for
      Zn(2+) bound as Zn-TFIIIA-ICR.

PMID- 15041248
TI  - Cassava cyanogens and fish mercury are high but safely consumed in the diet of
      native Amazonians.
AB  - The two most important staple foods (cassava and fish) in the diet of native
      Amazonians contain neurotoxins (linamarin and monomethyl mercury, MMHg). These
      same neurotoxins are public health issues in other parts of the world. Factors
      such as chemistry, environment, and human ecology determine the endemism of
      neuropathies caused by consumption of cassava (Manihot esculenta Crantz) and
      fish. Linamarin is a natural component of cassava tubers that can be destroyed
      before consumption by proper processing. Furthermore, small amounts of the toxin
      absorbed by people consuming cassava can be effectively metabolized if the diet
      contains adequate protein-containing sulfur amino acids. Naturally occurring Hg
      in the waters of the Amazonian rain forest is methylated to MMHg by
      microorganisms and bioconcentrated in the aquatic food chain. There is no
      effective method for MMHg removal from fish. Despite high concentrations of
      naturally occurring neurotoxins in cassava (linamarin) and fish (MMHg), daily
      consumption of these foods in large amounts over the course of a lifetime poses
      no health hazards for Amazonians.

PMID- 15041247
TI  - Metallothionein can function as a chaperone for zinc uptake transport into
      prostate and liver mitochondria.
AB  - In mammalian cells the cytosolic concentration of free Zn(2+) ions is extremely
      low (nM-fM range) and unlikely to provide an adequate pool for the uptake and
      accumulation of zinc in mitochondria. We previously identified a mitochondrial
      uptake transport process that effectively transports zinc directly from low
      molecular weight zinc ligands independent of and in the absence of available free
      Zn(2+) ions. Since metallothionein (MT) is an important ligand form of cellular
      zinc, we determined if Zn(7)-MT was an effective chaperone and donor for delivery
      and uptake of zinc by prostate and liver mitochondria. The results reveal that
      both intact mitochondria and mitoplasts effectively accumulated zinc from Zn(7)
      MT. The study confirms and extends our previous report that the putative zinc
      transporter is associated with the inner mitochondrial membrane and involves a
      direct exchange of zinc from the ligand to the transporter. The ventral prostate
      cells contain no detectable MT; so that ligands (such as citrate, aspartate)
      other than MT are zinc donors for mitochondrial zinc accumulation. However, in
      liver and perhaps other cells, Zn(7)-MT is probably important in the cytosolic
      trafficking of zinc to the mitochondria for the uptake of zinc into the
      mitochondrial matrix by the putative zinc uptake transporter.

PMID- 15041250
TI  - Comparative investigation of behavioral, neurotoxicological, and
      immunotoxicological indices in detection of subacute combined exposure with
      methyl parathion and propoxur in rats.
AB  - The effects of 6 weeks of oral exposure to propoxur (PR; at doses of 0.851 and
      8.51 mg/kg body wt.), methylparathion (MP; at doses of 0.218 and 0.872 mg/kg body
      wt.), and their combinations were investigated in male Wistar rats. Measurement
      endpoints of the investigation were certain general toxicological parameters
      (body weight gain, organ weights), plaque-forming cell (PFC) count from the
      spleen, open field (OF) behavior, auditory startle response (ASR), prepulse
      inhibition (PPI), rotarod performance, somatosensory and auditory cortical evoked
      potentials, and peripheral nerve conduction velocity. The treated rats did not
      show any sign of acute intoxication during the 6 weeks of exposure. The higher
      dose of PR, but not of MP, significantly decreased the relative liver weight.
      Both agents produced a significant dose-dependent increase of OF activity, with
      larger expression after 2 weeks than after 6 weeks. The number of ASR responses
      and the ASR amplitude increased. The amplitude after PPI was increased by MP but
      only minimally altered by PR and the combinations. There was a small, but with
      high-dose PR significant, increase in the latency of the somatosensory evoked
      potentials. Neither of the two substances alone had any effect on the PFC
      response. The effect of the combination of high-dose PR and low-dose MP was
      significantly different from that of high-dose PR alone on the liver weight, on
      the ASR amplitude, and on the PFC/10(6) cell and PFC/spleen counts. With high
      dose MP and low-dose PR, no such interaction was observed. According to the
      results, the noneffective dose of MP can influence the toxicity of the effective
      dose of PR in a combined exposure situation.

PMID- 15041249
TI  - Review of 15 years of research on ecotoxicology and remediation of land
      contaminated by agricultural drainage sediment rich in selenium.
AB  - The consequences of elevated Se accumulation at the Kesterson Reservoir National
      Wildlife Refuge in the Central Valley of California created adverse effects on
      wildlife and led to extensive research on the behavior of Se in both the wetland
      and upland ecosystems. Selenium concentrations in water entering the Kesterson
      Reservoir averaged 300 microg L(-1). In pond waters 20-30% of the Se was
      selenate, while only 2% was selenite in the drainage water entering the
      reservoir. Submerged rooted aquatic plants fed on by water birds were found to
      contain 18-390 mg Se kg(-1) dry weight. Mosquitofish collected from the San Luis
      Drain contained 332 mg Se kg(-1), and those collected from the ponds ranged from
      339 to 380 mg kg(-1). Livers of water birds had Se concentrations ranging from
      19.9 to 127 mg kg(-1). The high concentrations of Se accumulation in the food
      chain of the wetland strongly suggest that Se bioaccumulation was the cause of
      death and deformity of embryos of the waterfowl nesting at the wetland habitat.
      In June 1986, the Kesterson Reservoir was closed to drain-water inputs, and the
      wetland was transformed to an upland grassland. New remedial plans were proposed.
      These new plans involved soil, water, and vegetation management to dissipate Se
      by bioaccumulation and volatilization through soil microorganisms and plants. The
      investigations of the potential transfer of Se from farm land into the crop and
      vegetables in the Central Valley indicated that plant tissue Se concentrations
      generally fall in a nonseleniferous category, except that the highest Se
      concentration of cotton was at a threshold where toxicity in animals could occur
      at a relatively low frequency. At the Kesterson upland grassland habitat, average
      total Se concentrations ranged from 500 to 8000 microg kg(-1) and water
      extractable Se ranged from 10 to 700 microg kg(-1) in the top 15 cm of soil and
      varied greatly, by a factor greater than 100, among soil samples. Uptake of Se by
      the plants was profoundly affected by the soil available Se concentration, soil
      moisture, pH, soil salinity, soil sulfate concentration, soil reoxidation
      condition, kind of plant species, and soil-management practices. The rate of soil
      Se dissipation at the Kesterson grassland system was from 1% (low methylation
      rate) to 5% (high methylation rate) Se inventory per year and it will take from
      46 to 230 years to bring the soil Se down to a normal level, 4 mg Se kg(-1) soil.
      However, the Kesterson upland grassland habitat had Se bioaccumulation values
      less than 10% of those of the previous wetland. The potential food-chain
      contamination at the existing Kesterson grassland is much less problematic. No
      negative impact on wildlife has been reported for the upland habitat. Plants may
      contribute to the Se reoxidation process and be able to reduce the movement of Se
      in the soil. At the Kesterson grassland, the distribution of soil Se is extremely
      uneven; high levels of soil Se concentrated only in isolated spots. Therefore,
      leaching of soil Se is not at an area level. It is unlikely that problems of
      transport of Se from the Kesterson soil to the adjacent uncontaminated
      environment by leaching can occur.

PMID- 15041252
TI  - Enzymatic and nonenzymatic antioxidants as an adaptation to phagocyte-induced
      damage in Anguilla anguilla L. following in situ harbor water exposure.
AB  - Anguilla anguilla L. were caged for 8 and 48 h in harbor water of Aveiro Lagoon,
      Portugal. Respiratory burst activity (RBA) of peritoneal, head kidney, and gill
      phagocytes was measured. Lipid peroxidation (LPO) was estimated in gill, kidney,
      and liver. Liver ethoxyresorufin-O-deethylase (EROD) activity, cytochrome P450
      (Cyt P450) content, and bile metabolites were assayed. Various antioxidant
      enzymes, viz., glutathione peroxidase, catalase, and glutathione S-transferase
      and nonenzymatic antioxidant, viz., total reduced glutathione were also studied.
      Harbor water xenobiotics induced a significant RBA increase in gill after 8 h;
      whereas in peritoneum and head kidney it increased after 48 h exposure. These
      responses were adversely associated with tissue-specific peroxidative damage
      since significant LPO increase was observed in gill (8 and 48 h), kidney (48 h),
      and liver (48 h). The tissue most affected was gill. Moreover, liver EROD
      activity, Cyt P450 content and bile metabolites remain unaltered after 8 h; in
      contrast, 48 h exposure showed significant EROD activity decrease and pyrene-type
      bile metabolites increase. Decreased EROD activity may be associated with
      concomitant liver damage, as increased LPO was observed after 48 h. Furthermore,
      the tissue-specific damage corresponded to the differences in the antioxidant
      potentials of the tissues, since the initial exposure period caused a significant
      increase in liver antioxidant activities, whereas gill and kidney showed a
      significant decrease, demonstrating that liver is highly adaptive to oxidative
      damage. However, at 48 h exposure gill, kidney, and liver showed a suppressive
      antioxidant effect, probably due to PAHs, since a significant induction at PAH
      type bile metabolites has been seen. Our results demonstrate that phagocyte
      activation and associated peroxidative damage are concomitantly corroborated with
      enzymatic and nonenzymatic antioxidant activity differences. In addition, hepatic
      antioxidant induction after short-term exposure may serve as a potent biomarker
      for water pollutants in fish.

PMID- 15041251
TI  - Toxic effects of mining effluents on fish gills in a subarctic lake system in NW
      Russia.
AB  - The mining company Karelian Pellet in northwestern Russia extracts iron ore and
      processes it locally into pellets. The production operations affect the
      environment in the form of air pollution and wastewater emissions to lakes
      downstream from the factory. The toxic effects of the mining effluents on gills
      of perch (Perca fluviatilis) and roach (Rutilus rutilus) were studied. In lakes
      close to the factory, heavy metal concentrations in gills were not high, even
      though the metal content in sediment was elevated. In fish gills the relative
      proportion of phosphatidylcholine was elevated and cholesterol reduced, while the
      histological structure of the gills was changed. The number of mucus cells, as
      well as the sizes and the lengths of open areas in the chloride cells, had
      increased in spring and summer. The hypertrophy of chloride cells is possibly
      caused by the increased ambient concentrations of K+ and Li+. Changes in gill
      cholesterol and phospholipid proportions increase the fluidity of membranes and
      possibly strengthen their protective qualities, counterbalancing the adverse
      changes in chloride cell structure. The bioavailability and toxic effects of
      metals on fish are reduced by the hardness and high pH of water discharged by the
      mining plant.

PMID- 15041253
TI  - Temporal and spatial variability in the estrogenicity of a municipal wastewater
      effluent.
AB  - The estrogenicity of a municipal wastewater effluent was monitored using the
      vitellogenin biomarker in adult male fathead minnows (Pimephales promelas). The
      variability in the expression of vitellogenin was evident among the monitoring
      periods. Significant (alpha< or =0.05) increases in plasma vitellogenin
      concentrations were detected in March and December, but not in August or June.
      Additionally, the magnitude of expression was variable. Variability in the
      spatial scale was also evident during the March and June exposure months.
      Concurrent exposures in both the creek receiving the effluent from a wastewater
      treatment plant and an experimental wetland showed estrogenicity to be different
      with distance from the respective effluent inflow sites. March exposures showed
      estrogenicity to be somewhat persistent in the receiving creek (>600 m), but to
      decrease rapidly within the experimental wetland (<40 m). Results are discussed
      relative to the monitoring season, to the spatial distribution of the response in
      both receiving systems, and to possible causative factors contributing to the
      effluent estrogenicity.

PMID- 15041254
TI  - Effects of long-term exposure to Cu2+ and Cd2+ on the pentose phosphate pathway
      dehydrogenase activities in the ovary of adult Bufo arenarum: possible role as
      biomarker for Cu2+ toxicity.
AB  - The effects of copper and cadmium on metabolism through the pentose phosphate
      pathway were evaluated in Bufo arenarum toad ovary. The effects of the two metals
      on dehydrogenases from this pathway were evaluated by three experiments: (1) in
      samples obtained from control females with addition of the metals to the reaction
      mixture (in vitro), (2) in samples obtained from control females and after long
      term exposure of females to 4 and 100 microg/L of Cu or Cd in the incubation
      media (in vitro after exposure to the metals in vivo), and (3) 14CO2 production
      through the pentose phosphate pathway was evaluated after [U-14C]glucose
      microinjection on ovulated oocytes (in vivo after microinjection of the metals).
      Results from (1) evidenced inhibition of both enzyme activities but only above
      1.5 mM Cu and Cd added to the reaction mixture. In (2) both glucose 6-phosphate
      dehydrogenase and 6-phosphogluconate dehydrogenase activities decreased in
      samples from the ovaries of females exposed in vivo to Cu, in a concentration
      dependent manner (up to 90% in females exposed to 100 microg/L Cu: 2.12 +/- 1.57
      NADPH micromol/min microg protein x 10(-5) vs 19.97 +/- 8.54 in control females).
      Cd treatment of the toads only rendered an inhibitory effect on 6
      phosphogluconate dehydrogenase activity after exposure to 4 microg/L of the
      bivalent cation. (3) In vivo 14CO2 evolution significantly decreased in oocytes
      coinjected with 6.3 x 10(-3) mM Cu (calculated intracellular final concentration
      of the metal injected) and radioactive glucose. Cu and Cd concentration in
      samples from exposed females were always under detection limit by particle
      induced X-ray emission. The results presented here are in agreement with a role
      for both glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase
      activities determination as biomarkers of effect and exposure for Cu but not for
      Cd toxicity.

PMID- 15041255
TI  - Characterization of grit in arable birds to improve pesticide risk assessment.
AB  - To describe the grit in bird gizzards, we examined the gizzard content of some
      200 birds of varying size and diet (e.g., granivores and nongranivores). Grit use
      (frequency, size, amount, and shape) was characterized for 27 bird species that
      forage, at least part of the year, on arable land in the Netherlands. Three
      different groups could be recognized: the nongranivores with predominantly small
      "grit" particles (the result of inadvertent ingesting soil while foraging), the
      granivores with larger grit particles (the result of intentionally selecting soil
      particles), and the group in between (omnivores), which shows features of both
      other groups. Sample calculations made in this article show a probability of 3
      277 in 1000 times for unintentionally consuming one granule. Therefore, attention
      should also be paid to nongranivorous birds when assessing the hazard or risk of
      the use of granular pesticide formulations. A risk assessment model is presented
      in the Appendix.

PMID- 15041256
TI  - Effects of 17alpha-ethinylestradiol in a fathead minnow (Pimephales promelas)
      gonadal recrudescence assay.
AB  - To contribute to the development and evaluation of a practical and cost-effective
      in vivo testing system for endocrine disruption (specifically environmental
      estrogens), the effects of 17alpha-ethinylestradiol (EE2) were assessed in a
      gonadal recrudescence assay with the fathead minnow (Pimephales promelas). Mature
      male and female fathead minnows were kept first at 15 degrees C on a 8 h light/16
      h dark regime and then transferred to 25 degrees C and a 16 h light/8 h dark
      regime to induce gonadal recrudescence. They were then exposed to various nominal
      concentrations of the synthetic estrogen EE2 (0, 0.1, 1, 3, 10, 100 ng/L). After
      3 weeks of chemical exposure, effects on plasma vitellogenin (VTG), secondary sex
      characteristics, gonad growth (gonadosomatic index; GSI), and condition factor
      were assessed. Additionally, the effects on liver and gonad tissue morphology
      were investigated by means of light (LM) and electron microscopy (EM).
      Reproductive output (egg production) and fertilization rate were measured during
      a subsequent 3-week period in breeding adults maintained in clean water. Exposure
      to EE2 resulted in a significant decrease in GSI, condition factor, and number of
      batches of eggs and their fertilization rate at EE2 exposure concentrations
      between 10 and 100 ng/L. A reduction in the extent of parenchymatic areas in
      ovaries and ultrastructural changes in the livers of females could be detected at
      EE2 concentrations > or =3 ng/L. The lowest observed effective concentration
      (LOEC) of EE2 for plasma VTG induction in both sexes and for ultrastructural
      changes in the testes and livers was 1 ng/L. A significant increase in the mean
      number of eggs spawned per pair occurred at EE2 exposure doses of 0.1 and 1 ng/L.
      However, at higher EE2 concentrations, a dose-dependent decrease in the mean
      number of eggs per pair was apparent. Therefore, the LOEC for a biological effect
      of EE2 in the fathead minnow using the selected endpoints in the recrudescence
      assay was 1 ng/L for biomarkers such as plasma VTG and number of tubercles, and
      0.1 ng/L for an increased number of eggs spawned per pair.

PMID- 15041257
TI  - Separation, bioactivity, and dissipation of enantiomers of the organophosphorus
      insecticide fenamiphos.
AB  - Most chiral pesticides are used as racemates despite the fact that the pesticidal
      activity of the given pesticide is usually the result of the preferential
      reactivity of only one enantiomer while the other enantiomers may have toxic
      effects against other nontarget organisms. Accordingly, the enantiomer of
      fenamiphos, an organophosphorus pesticide, was separated by high-performance
      liquid chromatography with reverse phase and normal phase on a Pirkle model
      chiral stationary phase column. It was found that n-hexane/isopropanol (95/5) was
      the best solvent system for enantiomer resolution of fenamiphos. Chromatographic
      data including capacity factor (k'), separation factor (alpha), and resolution
      (Rs) are presented. Inhibitory activity to enzyme butyrylcholinesterase and
      toxicity to Daphnia of enantiomers and racemic insecticide fenamiphos were also
      studied. In the toxicity tests of Daphnia, the lethal concentration (LC50) of (+)
      fenamiphos, (-)-fenamiphos, and racemate were 0.0016, 0.0061, and 0.0019
      microg/mL, respectively. No significant difference of LC50 values between (+)
      fenamiphos and racemate were found, but (-)-fenamiphos showed significantly lower
      toxicity to Daphnia. The inhibitory concentration (IC50) to the cholinesterase
      were 0.008, 0.15, and 0.46 microg/mL for (+)-fenamiphos, (-)-fenamiphos, and
      racemate, respectively. Both enantiomers and the racemate showed significant
      difference in inhibiting the cholinesterase. However, (+)-fenamiphos proved to be
      about 20 times more toxic to Daphnia and only about four times more inhibitory
      activity to butyrylcholinesterase than (-)-fenamiphos. The dissipation of (+)
      fenamiphos, (-)-fenamiphos, and racemate in selected soils and natural water
      samples were also studied. The half-life (t(1/2)) of (+)-, (-)-, and racemate in
      soils showed no related to the soil texture, pH, or organic carbon content. By
      comparing the residues of (+)-, (-)-, and racemate in the water, it was found
      that (+)-fenamiphos was degraded faster than the others after 21 days. Briefly,
      (+)-fenamiphos is more toxic than (-)-fenamiphos to a nontarget organism
      (Daphnia), but the environmental persistence of the two compounds showed no
      significant difference.

PMID- 15041258
TI  - Integrated laboratory and field assessments of heavy metals accumulation in
      edible periwinkle, Tympanotonus fuscatus var radula (L.).
AB  - Laboratory and field bioaccumulation experiments were employed in assessing the
      impact of metal-laden effluents on the tissue concentrations of heavy metals in
      edible periwinkle, Tympanotonus fuscatus, in Lagos Lagoon. The field experiments
      showed that Zn and Pb accumulated in T. fuscatus collected from impacted stations
      were found to be about 10 times higher than the concentrations detected in
      control animals. A similar observation was also recorded in the laboratory
      experiment whereby the concentrations of the metals accumulated in whole body
      tissues of exposed animals were about 3-4 times higher than the concentrations
      detected in control animals. With respect to accumulation of Cu in T. fuscatus,
      the pattern was neither regular nor consistent throughout the duration of the
      experiment, under both the field and the laboratory conditions. The termination
      of metal-laden effluent discharges into the experimental creek, after 150 days of
      contamination, resulted in a rapid and significant decline in the concentrations
      of the metals detected in the sediment. However, the concentrations of metals
      accumulated in tissues of the periwinkles remained high. The significance of the
      observations for heavy metal pollution management in aquatic ecosystems and for
      consumer safety are discussed.

PMID- 15041259
TI  - Phytotoxicity and bioaccumulation of copper and chromium using barley (Hordeum
      vulgare L.) in spiked artificial and natural forest soils.
AB  - The toxicities of two heavy metals, copper (Cu2+) and chromium (Cr6+), to barley
      (Hordeum vulgare L.) were evaluated using two types of substrates: artificial and
      natural forest soils. Phytotoxicity was assessed using a standardized toxicity
      test. Endpoints included plant emergence and shoot and root growth. Shoot and
      root concentrations of Cu and Cr were also measured. Data indicated that the root
      biomass was the most sensitive endpoint. The results showed that toxicity of Cr
      to root growth (IC50=6.6 microg/g in artificial soil; IC50=61.8 microg/g in
      forest soil) was higher than that of Cu (IC50=13.7 microg/g in artificial soil;
      IC50>322 microg/g in forest soil). Data also indicated that the toxicity of Cu
      and Cr was significantly decreased in the spiked forest soil, suggesting lower
      metal bioavailability to barley in the natural soil. Analysis of tissue
      concentrations in barley showed that Cu and Cr were mainly accumulated in the
      roots. Toxicity was correlated with Cr residues in shoots (< or =11.2 microg Cr/g
      and < or =5.3 microg Cr/g for artificial and natural soils, respectively) and
      roots (< or =161 microg Cr/g and < or =51.7 microg Cr/g for artificial and
      natural soils, respectively) and Cu residues in roots (< or =61.8 microg Cu/g and
      < or =91.3 microg Cu/g for artificial and natural soils, respectively). Cu
      concentration in shoot tissues was < or =61.8 microg Cu/g. Since it may
      overestimate toxicity, effect and risk assessment using spiked soils,
      particularly in artificial soil, must be used with diligence.

PMID- 15041260
TI  - Evaluating the toxicity of Triton X-100 to protozoan, fish, and mammalian cells
      using fluorescent dyes as indicators of cell viability.
AB  - Three viability assays using fluorescent dyes effectively detected a loss of
      viability in cultures of three mammalian cell lines (H4IIE, Caco2, and HepG-2),
      two fish cell lines (RTgill-W1 and RTL-W1), and a ciliated protozoan, Tetrahymena
      thermophila, after exposure to Triton X-100, used as a model toxicant. The dyes
      were Alamar Blue (AB), neutral red (NR), and propidium iodide, which respectively
      monitored energy metabolism, lysosomal activity, and membrane integrity. A fourth
      fluorescent dye, 5-carboxyfluorescein diacetate acetoxymethyl ester, was
      problematic. For 2-h Triton X-100 exposures, mammalian cell lines were as
      susceptible as piscine cell lines, whereas T. thermophila was approximately
      twofold less sensitive as detected with AB and NR. Despite being less sensitive,
      cytotoxicity tests on T. thermophila could be done in spring water, which means
      that unlike animal cells they could be directly exposed to most industrial
      effluents without osmolality adjustments. Therefore, T. thermophila could be a
      useful complement to animal cells as alternatives to fish in toxicity testing.

PMID- 15041261
TI  - The effects of a pesticide mixture on aquatic ecosystems differing in trophic
      status: responses of the macrophyte Myriophyllum spicatum and the periphytic
      algal community.
AB  - The effects of a pesticide mixture (asulam, fluazinam, lambda-cyhalothrin, and
      metamitron) on aquatic ecosystems were investigated in 20 outdoor aquatic
      microcosms. Ten of the microcosms simulated mesotrophic aquatic ecosystems
      dominated by submerged macrophytes (Elodea). The others simulated eutrophic
      ecosystems with a high Lemna surface coverage (Lemna). This paper describes the
      fate of the chemicals as well as their effects on the growth of Myriophyllum
      spicatum and the periphytic algal community. In the Elodea-dominated microcosms
      significant increase in the biomass and alterations of species composition of the
      periphytic algae were observed, but no effect on M. spicatum growth could be
      recorded in response to the treatment. The opposite was found in the Lemna
      dominated microcosms, in which decreased growth of M. spicatum was observed but
      no alterations could be found in the periphytic community. In the Elodea
      dominated microcosms the species composition of the periphytic algae diverged
      from that of the control following treatment with 0.5% spray drift emission of
      the label-recommended rate (5% for lambda-cyhalothrin), while reduced growth of
      M. spicatum in the Lemna-dominated microcosms was recorded at 2% drift (20% for
      lambda-cyhalothrin). This study shows that the structure of the ecosystem
      influences the final effect of pesticide exposure.

PMID- 15041262
TI  - Does zinc produce reactive oxygen species in Ruditapes decussatus?
AB  - Zinc is an essential trace element with many enzymatic functions that include
      antioxidant properties. To investigate whether an excess of Zn in the cells
      produces cytotoxicity or tissue damage or an imbalance in the antioxidant
      systems, marine clams (Ruditapes decussatus) were exposed to two sublethal Zn
      concentrations (100 and 1000 microg L(-1)) for 28 days. The effects of Zn on the
      activities of protective antioxidant enzymes (superoxide dismutase, catalase, and
      glutathione peroxidase, both total and selenium-dependent), lipid peroxidation,
      and metallothionein induction were followed in the gills and digestive gland of
      these clams. The results indicate that the effect of Zn exposure in this clam
      species depends not only on the tissue but also on the Zn concentration present.
      In the gills, catalase activity was enhanced by Zn exposure, whereas total
      glutathione peroxidase activity was inhibited. Lipid peroxidation occurred only
      in the clams exposed to the highest Zn concentration. In the digestive gland, the
      impact of Zn exposure on metabolic activity was less evident than in the gills.
      The most evident effect in both tissues was the enhancement of catalase activity
      by Zn exposure. Catalase and total glutathione peroxidase activities as well as
      lipid peroxidation are promising biomarkers to assess the effects of Zn in the
      gills of R. decussatus.

PMID- 15041264
TI  - Time course of brain cholinesterase inhibition and recovery following acute and
      subacute azinphosmethyl, parathion and carbaryl exposure in the goldfish
      (Carassius auratus).
AB  - Laboratory toxicity data contrasting mortality and brain cholinesterase
      inhibition in the goldfish (Carassius auratus) are presented. Brain
      cholinesterase (ChE) was greatly reduced after 96 h of exposure in vivo at
      sublethal concentrations of azinphosmethyl and parathion. The inhibition of the
      enzyme was dose dependent, and concentrations higher than 0.1mg/L caused more
      than 90% inhibition. The effect of carbaryl was less pronounced, achieving an 86%
      inhibition at concentrations corresponding to the 96-h LC50. After in vivo
      exposure to sublethal concentrations of parathion and azinphosmethyl (0.1 mg/L)
      and carbaryl (3.0 mg/L), the activity of the goldfish brain ChE was greatly
      reduced. In the following 96 h of recovery, the enzyme inhibited with carbaryl
      was restored to 75% activity, while the enzyme inhibited with organophosphates
      (OPs) required more than 35 days for recovery. Goldfish were able to withstand
      high percentages of brain ChE inhibition without mortality, suggesting that
      another target may be responsible for the lethal effects. However, the enzyme is
      a good biomarker of acute and subacute exposure to OPs and carbamates.

PMID- 15041263
TI  - Effects of imidacloprid and deltamethrin on associative learning in honeybees
      under semi-field and laboratory conditions.
AB  - We have compared the sublethal effects of two insecticides in the honeybee
      (imidacloprid and deltamethrin) in both semi-field and laboratory conditions. A
      sugar solution containing 24 microg kg(-1) of imidacloprid or 500 microg kg(-1)
      of deltamethrin was offered to a colony set in an outdoor flight cage. In
      contrast to imidacloprid, deltamethrin had lethal effect on workers bees. The
      contamination of syrup with imidacloprid or deltamethrin induced a decrease in
      both the foraging activity on the food source and activity at the hive entrance.
      Negative effects of imidacloprid were also observed in an olfactory learnt
      discrimination task. Free-flying foragers were taken from the contaminated feeder
      and subjected to a conditioned proboscis extension response (PER) assay under
      laboratory conditions. As with free-flying bees, no impact of deltamethrin was
      found on the learning performances of restrained individuals in the PER
      procedure, whilst significant effects were found with imidacloprid in both semi
      field and laboratory conditions.

PMID- 15041266
TI  - Reproductive and biochemical biomarkers in largemouth bass sampled downstream of
      a pulp and paper mill in Florida.
AB  - The objective of this study was to evaluate the effects of bleached/unbleached
      kraft mill effluents (B/UKME) on the reproductive parameters of free-ranging
      Florida largemouth bass (Micropterus salmoides floridanus). The reproductive
      parameters measured included gonadosomatic index (GSI), histological evaluation
      of gonads, and plasma concentrations of vitellogenin (VTG), 17beta-estradiol, and
      11-ketotestosterone (11-KT). Hepatic ethoxyresorufin-O-deethylase (EROD) activity
      was measured as a marker of exposure to cytochrome P450-inducing agents in these
      effluents. Endpoints were compared among adult bass sampled from tributary and
      mainstream effluent-contaminated and reference sites. Females sampled from the
      site closest to the mill outfall had a significant five-fold increase in EROD
      activity compared to bass sampled from reference streams. Although sex hormones
      were significantly reduced in bass from exposed sites, there were no differences
      in VTG and GSI across sites. The absence of organism-level responses was probably
      not related to a lack of sensitivity, as previous studies in our laboratory have
      shown that bass exposed to these effluents exhibit changes in GSI and in other
      measures associated with reproductive success. In females, inverse relationships
      were observed between VTG and GSI and EROD activity. These relationship, however,
      were not consistent within all of the sites studied. Collectively, our findings
      indicate that hepatic EROD induction is an effective marker of B/UKME exposure in
      largemouth bass and that it might be associated with antiestrogenic effects in
      this species.

PMID- 15041265
TI  - Application of toxicity identification evaluation procedures on wastewaters and
      sludge from a municipal sewage treatment works with industrial inputs.
AB  - A comparison of influent and effluent wastewater toxicities to Daphnia magna was
      undertaken to determine the most representative aqueous fraction for future
      toxicity identification evaluation (TIE) studies. Wastewater samples originated
      from a wastewater treatment plant which receives mainly domestic wastewater and
      industrial effluents. The TIE results reveal that the key toxicant contained in
      the influent was 2-propylbezaldehyde oxime. Results suggest that greater
      attention needs to be given to the receiving influent containing 2
      propylbezaldehyde oxime to avoid damaging the bacterial populations in the
      primary activated sludge process. In addition, in order to evaluate the
      applicability of the reuse of activated sludge as a fertilizer in agriculture,
      TIE studies were also performed on water extracts from surplus sludge.

PMID- 15041267
TI  - Prophylactic vena cava filters for trauma patients: a systematic review of the
      literature.

PMID- 15041268
TI  - Review of clinical, biochemical and genetic aspects of combined factor V and
      factor VIII deficiency, and report of a new affected family.

PMID- 15041269
TI  - The epidemiological night where all patients are black: will pharmacogenetics
      shed some light?

PMID- 15041270
TI  - Mutations within the cyclooxygenase-1 gene in aspirin non-responders with
      recurrence of stroke.
AB  - INTRODUCTION: Aspirin is a common antiplatelet drug used in the prevention of
      ischemic stroke due to its inhibitory effect on platelet cyclooxygenase-1 (Cox
      1). Patients can be categorized as either aspirin 'responders' or 'non
      responders' depending on whether they are protected against a secondary stroke
      event or not. In this study, we have searched for variants of the Cox-1 gene that
      could possibly result in an unblocked and thus, aspirin-resistant Cox-1 enzyme
      and phenotype. MATERIALS AND METHODS: The Cox-1 gene was sequenced in 68 patients
      with recurrent ischemic stroke despite taking aspirin. The genotype distribution
      of identified variants was determined and compared with healthy control subjects.
      Mutations that involved amino acid substitutions of the mature Cox-1 molecule
      were analysed by molecular modelling and functional analysis using whole blood
      aggregometry. RESULTS: Fourteen variants of the Cox-1 gene were identified. Seven
      of the variants involved amino acid substitutions of the Cox-1 molecule. None of
      the mutations were located near the catalytic site as judged from a three
      dimensional model of the human Cox-1. Carriers and non-carriers of one of the
      mutations behaved similarly when aggregation and granule content release function
      were studied using collagen, ADP and arachidonic acid as agonists. CONCLUSION:
      The results do not support the hypothesis that common variants of the Cox-1 gene
      results in unblocked Cox-1 molecules in aspirin non-responders.

PMID- 15041271
TI  - Randomized comparison of platelet-leukocyte aggregates and platelet activation in
      blood: heparin-coated coiled wire stent implantation versus balloon angioplasty
      in acute myocardial infarction.
AB  - INTRODUCTION: Stent implantation has been shown to be superior to balloon
      angioplasty in patients with acute myocardial infarction (AMI). Newer trials
      indicate that platelet-leukocyte aggregates are a more sensitive marker for
      platelet activation than platelet surface marker. Our study examined platelet
      activation and platelet-leukocyte interaction in blood in patients with AMI
      randomized to heparin-coated stent implantation versus balloon angioplasty.
      MATERIALS AND METHODS: Forty-seven patients with AMI were included into our
      study. Patients were randomized to heparin-coated stent implantation (n=31) or
      balloon angioplasty (n=16). Platelet activation, total platelet-leukocyte
      aggregates and aggregate composition in blood were assessed by flow cytometry
      before, immediately after and 24 h after intervention. RESULTS: No differences in
      platelet activation, total platelet-leukocyte aggregates and aggregate
      composition were found between both groups before intervention. Immediately after
      intervention, platelet activation was comparably increased in both groups.
      Patients treated with heparin-coated stent showed a decrease in total platelet
      leukocyte aggregates 24 h after intervention (3.9% [2.8; 4.7] versus 3.2% [2.4;
      4.1]; p<0.01). Platelet-monocyte conjugates decreased 24 h after heparin-coated
      stent implantation compared to balloon angioplasty alone (0.28% [0.17; 0.42]
      versus 0.49% [0.45; 0.79]; p<0.05). No difference in total platelet-leukocyte
      aggregates was found in patients treated with balloon angioplasty alone.
      CONCLUSIONS: An inhibitory effect of heparin-coated stent implantation on total
      platelet-leukocyte aggregates and platelet-monocyte conjugates in blood was
      demonstrated in patients with AMI. This reflects heparin-coated stent
      implantation to be less thrombogenic than balloon angioplasty alone.

PMID- 15041272
TI  - A first Taiwanese Chinese family of type 2B von Willebrand disease with R1306W
      mutation.
AB  - Clinical, laboratory and genetic defect of a Taiwanese family with type 2B von
      Willebrand disease (VWD) were studied. The proband was a 55-year-old woman who
      gave birth to two daughters and one son aged 30, 29 and 27, respectively. All had
      abnormal mucocutaneous bleedings since their childhood. In proband, PT, PTT and
      platelet count were normal; template bleeding time was 14 min; VIII:C was 51%,
      von Willebrand factor antigen (VWF:Ag), 42% and von Willerand factor ristocetin
      cofactor (VWF:RCo, 15%); ristocetin-induced platelet aggregation (RIPA) at 0.3
      and 0.6 mg/ml of ristocetin was 16% and 68%, respectively. The enhanced response
      to ristocetin was identified to be in plasma, not in platelet itself, by mixing
      studies. Analysis of von Willebrand factor (VWF) multimer of plasma but not of
      platelets showed absence of high-molecular weight (HMW) multimer. All three
      children had similar laboratory findings. Exon 28 of VWF gene was amplified using
      polymerase chain reaction (PCR) and sequenced. The proband and three children
      were all found to be heterozygous for C to T transition at nucleotide 3916
      resulting in Arg 1306 Trp (R1306W) substitution. This mutation in the
      glycoprotein Ib (GPIb)-binding site has been found to increase the affinity of
      plasma VWF for platelets, and thus cause loss of HMW multimers and often
      thrombocytopenia. In conclusion, a first report of type 2B VWD in a Taiwanese
      Chinese family who show R1306W mutation in VWF gene was described.

PMID- 15041273
TI  - Disturbances of anticoagulation and fibrinolytic systems in monoclonal
      gammopathies-another mechanism of M-protein interference with hemostasis.
AB  - Monoclonal gammopathies (MG) may be associated with unique monoclonal
      immunoglobulin (MIg)-induced disturbances of either primary hemostasis or plasma
      coagulation. We have investigated the possible interference of MIg with
      antithrombotic systems in 49 patients with MG. Although an increase of tissue
      type plasminogen activator (t-PA) activity was the most frequent abnormality in
      our group, defect of anticoagulation factors was found in 26.5% of patients. The
      relationship between MIg type and concentration and frequency of antithrombotic
      factor abnormalities was not found. The risk of venous thrombosis was higher in
      patients with the defect in comparison with the unaffected group (46% vs. 22%),
      but the difference was not statistically significant. Bleeding complications were
      markedly less frequent in the group of patients with defect of anticoagulation
      mechanisms (0% vs. 17%). In conclusion, we have found abnormalities in
      anticoagulation and/or fibrinolytic system, analogous to well-known disturbances
      of hemostatic mechanisms, in more than a quarter of patients with MG. The
      interference of M-protein with antithrombotic pathways is supposed to be another
      mechanism of secondary deficiencies of antithrombin III (AT III), protein C (PC),
      protein S (PS), plasminogen and APC resistance. Together with other factors, it
      could contribute to higher risk of thromboembolism in myeloma patients.

PMID- 15041274
TI  - Evaluation of a novel point-of-care enoxaparin monitor with central laboratory
      anti-Xa levels.
AB  - BACKGROUND: Measurement of enoxaparin's anticoagulant activity has been limited
      to specialized coagulation laboratories and has been impractical for areas
      needing rapid results, such as during coronary angioplasty. A new point-of-care
      device, Rapidpoint ENOX, was recently developed to measure clotting times with
      enoxaparin use. OBJECTIVES: To correlate ENOX times with anti-Xa levels among
      patients receiving enoxaparin. METHODS: A total of 166 patients receiving
      enoxaparin for the prevention of deep venous thrombosis or as treatment during
      acute coronary syndromes or angioplasty were prospectively studied. Citrated and
      non-citrated whole-blood (CWB and NCWB) samples were obtained at baseline and
      peak enoxaparin activity. ENOX times were measured with whole-blood, and the
      Stachrom anti-Xa assay was performed on the plasma from the remainder of the
      samples. The Pearson correlation coefficient was used to assess the relationship
      between these two assays. RESULTS: There was a strong linear correlation between
      the ENOX times and the anti-Xa activities for both CWB (r=0.89, p<0.001) and NCWB
      (r=0.82, p<0.001) when considering all 332 samples (baseline and peak). When
      baseline samples were excluded, the correlation remained strong for CWB ENOX
      times and anti-Xa levels (r=0.84, p<0.001), but was only moderate for NCWB
      (r=0.73, p<0.001). A CWB ENOX time of </=160 s corresponded to anti-Xa level of
      </=0.5 IU/ml in 95% (188/197) of patients. A CWB ENOX time >/=200 s corresponded
      to anti-Xa levels >/=0.8 IU/ml in 96% (93/96) of patients. CONCLUSIONS:
      Rapidpoint ENOX times correlate strongly to anti-Xa activities measured by the
      Stachrom Heparin Assays for citrated whole-blood samples. This novel test can be
      used for rapid bedside measurements of enoxaparin anticoagulant activity.

PMID- 15041275
TI  - Relationship between serum 5'-nucleotide phosphodiesterase activity and
      thrombophilia: enzyme activity in fetus and in patients with acute coronary
      syndrome.

PMID- 15041277
TI  - Apolipoprotein (a) mediates the lipoprotein (a)-induced biphasic shift in human
      platelet cyclic AMP.
AB  - Lipoproteins are known to influence platelet cyclic adenosine monophosphate (c
      AMP) levels. Lipoprotein (a) (Lp(a))'s impact on platelet c-AMP levels has never
      been assessed. Increasing levels of purified human Lp(a) (1-100) mg/dl were
      incubated with washed human platelets. Lp(a) concentrations of 1-25 mg/dl
      resulted an initial statistically significant increase of platelet c-AMP above
      basal levels and decreased collagen-stimulated platelet aggregation levels.
      Higher concentrations progressively returned the platelet c-AMP concentrations to
      basal levels accompanied by further decreases in platelet aggregation. Increasing
      concentrations of purified apolipoprotein (a) (apo(a)) also resulted in a similar
      biphasic c-AMP response while Lp(a) without apo(a) was without impact. One
      antibody directed against apo(a) in intact Lp(a) removed the biphasic c-AMP
      pattern and eliminated Lp(a) platelet aggregation. Antibodies directed against
      apo B in intact Lp(a) gave results similar to intact Lp(a) in terms of the
      biphasic response of c-AMP upon platelet exposure to increasing levels of Lp(a).
      It is concluded that apo(a) mediates the Lp(a)-induced biphasic response in
      platelet c-AMP as the result of platelet exposure to increasing levels of Lp(a).
      The biphasic response in c-AMP assists in platelet aggregation decreases up to a
      concentration of 25 mg/dl Lp(a), such assistance being lost at higher Lp(a)
      concentrations.

PMID- 15041276
TI  - Induction of tissue factor expression in human monocytic cells by protease
      inhibitors through activating activator protein-1 (AP-1) with phosphorylation of
      Jun-N-terminal kinase and p38.
AB  - Tissue factor (TF) is expressed rapidly by human monocytes exposed to a variety
      of agonists such as lipopolysaccharide (LPS) or tumor necrosis factor-alpha.
      Activation of both activator protein-1 (AP-1; c-Jun/c-Fos) and nuclear factor
      kappaB (NF-kappaB) pathways is necessary for maximal induction of the TF gene. It
      has been demonstrated that activation of both AP-1 and NF-kappaB is correlated
      with the degradation of both phosphorylated c-Jun and inhibitor kappaB (IkappaB)
      by proteasome. The present study was designed to investigate whether various
      protease inhibitors, including proteasome inhibitors, affect TF expression in
      monocytic cells. Protease inhibitors, 3,4-dichloroisocoumarin (DCI), N-tosyl-l
      phenylalanine chloromethyl ketone (TPCK), and N-acetyl-Leu-Leu-norleucinal (ALLN)
      induced TF activity in monocytic cells in a dose- and time-dependent manner at
      the level of the transcription of the TF gene, which was mediated through
      inducing phosphorylation of both Jun-N-terminal kinase and p38. The early growth
      response-1 (Egr-1) pathway was not affected. The NF-kappaB pathway was not
      activated; rather it was inhibited. These results were distinct from the findings
      previously reported for LPS-stimulated cells. The present study demonstrated that
      some protease inhibitors might act as stress and induced TF expression with
      direct phosphorylation of JNK and p38, followed by phosphorylation and activation
      of AP-1 in monocytic cells. This evidence may help elucidate further regulatory
      mechanisms of TF induction, and might have physiological significance for the
      clinically challenged use of proteasome inhibitors. In addition to
      phosphorylation of JNK and p38, an unknown signal pathway needs to be clarified
      for TF induction.

PMID- 15041278
TI  - Estrogen administration enhances thrombin generation in rats.
AB  - Venous thrombosis is a serious disorder that may be fatal if complicated by
      pulmonary embolism. Venous thrombosis is usually related to one of three factors:
      reduced blood flow, changes in vessel wall integrity, or changes in the blood
      composition. Factors leading to thrombosis are classified as either genetic or
      acquired. Puerperium and oral contraceptives are examples of the acquired
      factors. The risk of thrombosis during pregnancy is high compared to that in the
      overall population,. however, this increases by three to five times in
      puerperium. Deep vein thrombosis (DVT) complicated by pulmonary thromboembolism
      (PE) is considered the leading cause of maternal death in the United States and
      Europe [Am. J. Obstet. Gynecol. 164 (1991) 603; Obstet. Gynecol. 84 (1994) 240]
      and the third cause in Japan [M Ishikawa, Maternal mortality and pulmonary
      thromboembolism. Study on maternal mortality in Japan. Report from the Ministry
      of Health of Japan in Maternal and Child Health Research, 1996. p. 123-128].
      Patients without history of familial thrombophilia have 14-fold higher risk of
      DVT during puerperium [Thromb. Haemost. 25 (1999) 610]. Little is known about the
      underlying mechanism of thrombotic disorders in puerperium. It is recognized that
      oral contraceptive estrogen enhances the risk of DVT [Am. J. Epidemiol. 133
      (1991) 32]. However, there is little research regarding the relation between
      estrogen and blood coagulation, although it is known that plasma estrogen reaches
      extremely high levels near term. We assume that high-level plasma estrogen plays
      an important role in the blood coagulation activity that results in the
      occurrence of DVT. To assess this likely association, we studied the effects of
      high estrogen levels on coagulation in rat plasma.

PMID- 15041279
TI  - A new euglobulin clot lysis assay for global fibrinolysis.
AB  - Plasma fibrinolytic activity has been measured by the euglobulin clot lysis time
      (ELT) since the late 1950s. The euglobulin clot lysis assay (ECLA) method has
      been modified using a computerized kinetic spectrophotometric microtiter plate
      reader and measures optical density changes of recalcified euglobulin fraction of
      plasma samples over time. This method has been applied to normal healthy adults,
      children, pregnant women and newborn infants, which represent physiologic
      extremes of the ELT. The ECLA method adds measurements of maximum absorbance (Max
      Abs), area under the curve (AUC) and mean velocity to the standard clot lysis
      time. The resulting curves are unique to this method and have been analyzed and
      compared in order to establish normal ranges. Fibrinogen levels, plasminogen
      activator inhibitor-1 (PAI-1) antigen, PAI-1 activity and thrombin activatable
      fibrinolytic inhibitor (TAFI) antigen levels were measured in each individual of
      the four groups. Each protein measured within each study group except TAFI
      correlated with the lysis time, maximum absorbance and area under the curve.
      Considering all four groups together, PAI correlates most highly with lysis time,
      fibrinogen correlates the highest with Max Abs; fibrinogen and PAI-1 antigen have
      equally high correlations to AUC. Area under the curve is highly correlated with
      all coagulation parameters measured; the most significant contributor is
      fibrinogen. These observations are interesting, but at this time, it cannot be
      said that any of the test parameters are better than lysis time in distinguishing
      between these normal physiologic states.

PMID- 15041280
TI  - Purification and characterization of a serine protease with fibrinolytic activity
      from the dung beetles, Catharsius molossus.
AB  - Catharsius protease-1 (CPM-1) was isolated from the whole body of the dung
      beetles, Catharsius molossus, using three purification steps (ammonium sulfate
      fractionation, gel filtration on Bio-Gel P-60, and affinity chromatography on
      DEAE Affi-Gel Blue gel). The purified CPM-1 that has a molecular weight of 27 kDa
      was assessed homogeneous by SDS-polyacrylamide gel electrophoresis and an
      isoelectric point of 4.4 was determined by isoelectric focusing. N-terminal amino
      acid sequence of the protease was composed of Ile-Val-Gly-Gly-Gln-Ala-Val-Glu-Ile
      Gly-Asp-Tyr-Pro-Ala-Gln. The enzyme was inactivated by Cu(2+) and Zn(2+) and
      strongly inhibited by typical serine proteinase inhibitors such as TLCK, soybean
      trypsin inhibitor, aprotinin, benzamidine and alpha-antitrypsin. However, EDTA,
      EGTA, cysteine, beta-mercaptoethanol, E64, chymostatin, elastatinal and TPCK did
      not/less affect activity. Also, antiplasmin and antithrombin III were not
      sensitive to CPM-1. On the basis of amidolytic activity test, CPM-1 preferably
      hydrolysed chromogenic protease substrates containing Arg or Lys residues of the
      P1 position at pH 7.0 and 37 degrees C. CPM-1 preferentially cleaved the oxidized
      B-chain of insulin between Arg(22) and Gly(23). CPM-1 readily digested Aalpha-
      and gamma-chains and more slowly Bbeta-chain of fibrinogen. The nonspecific
      action of the enzyme resulted in extensive hydrolysis, releasing a variety of
      fibrinopeptides of fibrinogen and fibrin. D-dimer concentration increased on
      incubation of cross-linked fibrin with CPM-1, indicating that the enzyme has a
      significant fibrinolytic activity.

PMID- 15041281
TI  - Pseudo-protein S deficiency due to activated protein C resistance.

PMID- 15041282
TI  - Homozygous C677T mutation in the MTHFR gene as an independent risk factor for
      multiple small artery occlusions.

PMID- 15041283
TI  - Estimation of PAHs dry deposition and BaP toxic equivalency factors (TEFs) study
      at Urban, Industry Park and rural sampling sites in central Taiwan, Taichung.
AB  - The concentrations of polycyclic aromatic hydrocarbons (PAHs) in gas phase and
      particle bound were measured simultaneously at industrial (INDUSTRY), urban
      (URBAN), and rural areas (RURAL) in Taichung, Taiwan. And the PAH concentrations,
      size distributions, estimated PAHs dry deposition fluxes and health risk study of
      PAHs in the ambient air of central Taiwan were discussed in this study. Total PAH
      concentrations at INDUSTRY, URBAN, and RURAL sampling sites were found to be 1650
      +/- 1240, 1220 +/- 520, and 831 +/- 427 ng/m3, respectively. The results
      indicated that PAH concentrations were higher at INDUSTRY and URBAN sampling
      sites than the RURAL sampling sites because of the more industrial processes,
      traffic exhausts and human activities. The estimation dry deposition and size
      distribution of PAHs were also studied. The results indicated that the estimated
      dry deposition fluxes of total PAHs were 58.5, 48.8, and 38.6 microg/m2/day at
      INDUSTRY, URBAN, and RURAL, respectively. The BaP equivalency results indicated
      that the health risk of gas phase PAHs were higher than the particle phase at
      three sampling sites of central Taiwan. However, compared with the BaP
      equivalency results to other studies conducted in factory, this study indicated
      the health risk of PAHs was acceptable in the ambient air of central Taiwan.

PMID- 15041284
TI  - Pesticides and PCBs in sediments and fish from the Salton Sea, California, USA.
AB  - The Salton Sea, the largest manmade lake in California, is officially designated
      by the State of California as an agricultural drainage reservoir. The purpose of
      this study was to determine organochlorine and organophosphorous pesticides, as
      well as polychlorinated biphenyl (PCB) concentrations in sediments and fish
      tissues in the Salton Sea and evaluate the relative ecological risk of these
      compounds. Sediment samples were taken during 2000-2001 and fish tissues (Tilapia
      mossambique, Cynoscion xanthulu) were collected in May 2001. All samples were
      analyzed for 12 chlorinated pesticides, 6 organophosphorus pesticides, and 55
      polychlorinated biphenyl (PCB) congeners. SigmaDichlorodiphenyltrichloroethane
      (SigmaDDT) and total PCB concentrations observed in sediments ranged from 10 to
      40 and 116 to 304 ng/g dry wt, respectively. DDT/DDD ratios in sediments and fish
      tissues of the northern Sea in 2001 indicated recent DDT exposure. Lindane,
      dieldrin, dichlorodiphenylethane (DDE) and total PCB concentrations detected in
      sediments exceeded probable effect levels established for freshwater ecosystems,
      and pp-DDE and total PCB concentrations were higher than effect range-median
      values developed for marine and estuarine sediments. In fish liver,
      concentrations of endrin and SigmaDDT exceeded threshold effect level established
      for invertebrates. SigmaDDT concentrations detected in fish tissues were higher
      than threshold concentrations for the protection of wildlife consumers of aquatic
      biota. DDE concentrations in fish muscles tissues were above the 50 ng/g
      concentration threshold for the protection of predatory birds. Dimethoate,
      diazinon, malathion, chlorpyrifos, disulfoton varied from < or = 0.15 to 9.5 ng/g
      dry wt in sediments and from < or = 0.1 to 80.3 ng/g wet wt in fish tissues.
      Disulfoton was found in relatively high concentrations (up to 80.3 ng/g) in all
      organs from Tilapia and Corvina. These results demonstrate continued
      contamination of specific organochlorine compounds in sediments and resident fish
      species of the Salton Sea.

PMID- 15041285
TI  - A model for evaluation of the phytoavailability of trace elements to vegetables
      under the field conditions.
AB  - Currently, several single extraction methods are used for the evaluation of the
      phytoavailability of metals using pot experiments. A systematic comparison,
      however, is lacking. It is especially true for the field studies. This study was
      to investigate the phytoavailability of trace elements to vegetables grown on
      metal-contaminated soils under the field conditions. All soils collected were
      typical calcareous soils in northern China. Four frequently used methods using
      CaCl2, diethylenetriaminepentaacetic acid (DTPA), CH3COOH, and water as
      extractants were compared for phyto-availability. The concentrations of metals
      extracted by these four extraction methods ranged from 3.42 to 815, 1.51- 6965,
      0.732-24473, 0.688-7863, 0.246-685, 1.99-5337 0.203-4649 ng/g for Cr, Ni, Zn, Cu,
      Cd, Pb and REEs, respectively. Simple correlation analysis indicated that a
      significant correlation (Cr: r = 0.5411**; Zn: r = 0.6352**; Cd: r = 0.6979**;
      Pb: r = 0.5537** and REEs: r = 0.5185** -0.6684**) was observed between the CaCl2
      extractable metals in soil solution and that in Chinese cabbage. In addition,
      soil pH, organic matter (OM), and cation exchange capacity (CEC) also affect the
      phytoavailability. An empirical model was developed to express the combined
      effect of soil properties on the phytoavailability. The stepwise multiple
      regression analysis demonstrated that the phytoavailability of trace elements
      strongly correlated with the extractable fraction by CaCl2, total metal
      concentration in soils, and soil pH, OM, CEC. This model can describe
      approximately 75-95% of the variability of metal uptake and the r2 values ranged
      from 0.741** to 0.954**, which were much better than the single correlation
      analysis. For celery and cole, a strong correlation was obtained for Cr, Ni, Zn,
      Cu, Cd, La, Ce, Pr and Nd. For spinach and Chinese cabbage, however, a positive
      correlation was only observed for 1 and 3 metals, respectively. Generally, the
      developed empirical model can integrate the combined effects of soil properties,
      extractable metal fractions in soil solutions and plant species on the
      phytoavailability of metals to vegetables in the field conditions.

PMID- 15041286
TI  - Biomassbed: a biological system to reduce pesticide point contamination at farm
      level.
AB  - A potential method for cleaning water from point-source pollution by organic
      compounds is using biological reactors. In this study, four reactors were tested
      for their ability to retain and degrade pesticides. The pesticides tested were
      the insecticide chlorpyrifos, the fungicide metalaxyl and the herbicide imazamox.
      The reactors were filled with differing mixtures of vine-branch, citrus peel,
      urban waste and public green compost. The reactor volume was 188 l. Forced
      circulation of the contaminated solution was programmed to decontaminate the
      solution. Both retention and degradation of the compounds by the reactors was
      studied. Chlorpyrifos was the best retained, due to its physico-chemical
      characteristics, while only one substrate effectively retained metalaxyl and
      imazamox (citrus peel+urban waste compost). Degradation of the pesticides in the
      reactors was faster than published values for degradation in soil. The half-life
      of all pesticides in the reactors was less than 14 days, compared to literature
      values of 60-70 days in soil. The combined retention and fast degradation make
      the biofilter a feasible technique to reduce spill-related and point
      environmental contamination by pesticides. The technique is most effective
      against persistent pesticides, while for mobile pesticides, the efficiency can be
      improved with several passages of the contaminated solution through biofilters.

PMID- 15041287
TI  - Adsorption kinetics of herbicide paraquat from aqueous solution onto activated
      bleaching earth.
AB  - In the present study, the activated bleaching earth was used as adsorbent for the
      herbicide paraquat adsorption in a batch adsorber. The rate of adsorption has
      been investigated under the controlled process parameters like agitation speed,
      initial paraquat concentration, adsorbent dosage and temperature. A batch kinetic
      model, based on the assumption of a pseudo-second order mechanism, has been
      tested to predict the rate constant of adsorption, equilibrium adsorption
      capacity, time of half-adsorption, and equilibrium concentration by the fittings
      of the experimental data. The results of the kinetic studies show that the
      adsorption process can be well described with the pseudo-second order equation.
      Based on the isotherm data obtained from the fittings of the adsorption kinetics,
      Freundlich model appears to fit the adsorption better than Langmuir model. In
      addition, the effective diffusion coefficient has also been estimated based on
      the restrictive diffusion model.

PMID- 15041288
TI  - Identification and behavior of reaction products formed by chlorination of
      ethynylestradiol.
AB  - Six products were formed by reaction of ethynylestradiol (EE2) with sodium
      hypochlorite in buffered solutions. 4-Chloroethynylestradiol (4-ClEE2) and 2,4
      dichloroethynylestradiol (2,4-diClEE2) were identified as the two major reaction
      products, using preparative HPLC, MS, and NMR. When EE2 reacted with chlorine at
      different pHs (pH 5, 7, and 9) or chlorine concentrations (0.2, 1, 2, and 5
      mmol/l, corresponding to molar ratios to EE2, 1, 5, 10, and 25, respectively),
      the formation of 4-ClEE2 and 2,4-diClEE2 was observed under the above conditions,
      and the highest yields were 20 and 52 mol%, respectively. EE2 was consumed almost
      completely within 5 min of chlorination by addition of chlorine of more than 1
      mmol/l (molar ratio to EE2, 5). On the other hand, the two products existed in
      highly chlorinated solutions after 60 min (4ClEE2, 1-6 mol%; 2,4-diClEE2, 3-25
      mol%). The estrogenic activities of 4-ClEE2 by estrogen receptor alpha or beta
      binding assay were similar to those of the parent EE2, and the activities of 2,4
      diClEE2 were lower about 10 times.

PMID- 15041289
TI  - Geochemistry of inorganic arsenic and selenium in a tropical soil: effect of
      reaction time, pH, and competitive anions on arsenic and selenium adsorption.
AB  - Factors that can affect As and Se adsorption by soils influence the
      bioavailability and mobility of these elements in the subsurface. This research
      attempted to compare the adsorption capacities of As(III), As(V), Se(IV), and
      Se(VI) on a tropical soil commonly found in Singapore in a single-species system.
      The effect of reaction time, pH, and competitive anions at different
      concentrations on the adsorption of both As and Se species were investigated. The
      As and Se adsorption isotherm were also obtained under different background
      electrolytes. The batch adsorption experiments showed that the sequence of the As
      and Se adsorption capacities in the soil was As(V) > Se(IV) > As(III) > Se(VI).
      The adsorption kinetics could be best described by the Elovich equation. The
      adsorption of As(V), Se(IV), and Se(VI) appeared to be influenced by the variable
      pH-dependent charges developed on the soil particle surfaces. Phosphate had more
      profound effect than SO4(2-) on As and Se adsorption in the soil. The competition
      between PO4(3-) and As or Se oxyanions on adsorption sites was presumably due to
      the formation of surface complexes and the surface accumulation or precipitation
      involving PO4(3-). The thermodynamic adsorption data for As(V) and Se(IV)
      adsorption followed the Langmuir equation, while the As(III) and Se(VI)
      adsorption data appeared to be best-represented by the Freundlich equation.

PMID- 15041290
TI  - Leaching of bisphenol A (BPA) from polycarbonate plastic to water containing
      amino acids and its degradation by radical oxygen species.
AB  - In this study, (1) the change in the concentration of bisphenol A (BPA) leached
      from polycarbonate plastic (PCP) tube to water samples containing phosphate,
      sodium barbital, glycine, methionine or albumin at 37 degrees C as a function of
      time, and (2) the degradation rate of BPA leached from PCP tube to amino acid
      solutions in the presence of radical oxygen species (ROS) were investigated. The
      BPA leaching velocity (BPA-LV) from PCP tube to 50 mM glycine at pH 6 or 7 was
      twice that to control water, and the leaching was enhanced above pH 8. At pH 11,
      BPA-LV was significantly higher in 50 mM glycine and methionine solutions than in
      50 mM NaOH. These results indicate that basic pH and amino acids contained in
      water could accelerate BPA leaching. The BPA-LV in phosphate buffer was different
      from the BPA-LVs in other buffers (barbital and glycine) at the same pH. BPA
      leached to the glycine or methionine solutions at pH 11 was degraded time
      dependently in a similar manner as the control water in the presence of ROS. The
      degradation of leached BPA was inhibited in the glycine solution, but was
      accelerated in the methionine solution. However, degradation of BPA added to
      freshly prepared methionine was inhibited in a similar manner to BPA in glycine.
      BPA degradation could be influenced by some kinds of amino acids, but glycine and
      methionine might be involved in BPA degradation in different ways.

PMID- 15041291
TI  - Modelling the absorption and desorption of cadmium on paper pulp using kinetic
      approaches.
AB  - The presence of toxic metals on paper pulp and the migration of these metals to
      food from the food package is receiving significant attention. The final exposure
      levels for consumers depend on two main processes. First the potential of metals
      to bind paper pulp during manufacture. Second, the metal potential to migrate
      from paper to food during storage and use. Binding and unbinding processes are
      modelled for cadmium kinetics through kinetic approaches. The cadmium
      concentration in paper pulp is estimated from the cadmium concentration in the
      water-pulp liquor during manufacture, the temperature, and contact time. Two food
      simulants have been employed for desorption studies, water and acetic solution
      (3%, w/w). As expected, under acidic conditions desorption is total and rapid
      (close to 100% desorption reached in a few minutes). However, the desorption of
      cadmium into the neutral food simulant depends on the initial cadmium
      concentration in the paper pulp, temperature and contact time. Surface response
      curves for each combination are presented. Temperature did not affect cadmium
      binding, but played a significant role for the desorption processes into the
      neutral food simulant. The proposed equations offer a good fitting of the
      experimental values, with p < 0.001 and residuals within a factor of 3 for over
      99% of the measured data. These models allow estimations of the expected exposure
      levels in consumers, on the basis of manufacture and use conditions. Linking the
      expected exposure with toxicity thresholds, such as the admissible daily intake
      (ADI), would allow a scientific assessment of the maximum acceptable cadmium
      levels in water-pulp liquors during manufacture and in the final paper pulp on
      the basic of the use patterns of each food packaging material.

PMID- 15041293
TI  - Fluorescence behaviour of Zn and Ni complexes of humic acids from different
      sources.
AB  - Conventional fluorescence spectroscopy in the excitation, emission and
      synchronous scan modes and three-dimensional fluorescence spectroscopy in the
      form of an excitation-emission matrix (EEM) of fluorescence intensity as a
      function of excitation and emission wavelengths have been applied to the study of
      three humic acids (HAs) extracted from soil (SHA), peat (PHA) and compost (CHA)
      and their interaction products with Zn(II) and Ni(II) ions. Fluorescence spectra
      of HAs appear to be related to the nature and origin of the sample. A strong
      reduction of intensity of all peaks is observed in the spectra of HAs-metal
      complexes as compared to those of untreated HAs. Ni(II) exhibits greater
      quenching ability than Zn(II). Fluorescence quenching measured for complexes of
      HAs at increasing Ni(II) concentrations was linearly correlated with metal ion
      concentration. The different capacity to interact with metal ions showed by
      various HAs is attributed to their different molecular complexity.

PMID- 15041292
TI  - Effect of photosensitizer diethylamine on the photodegradation of polychlorinated
      biphenyls.
AB  - The objective of this study was to investigate the effect of diethylamine and
      xenon simulated sunlight on the photodegradation of two forms of PCBs including
      PCBs in transformer oil and PCB congener 138. The result of GC chromatograms
      illustrated the shifting pattern of higher chlorinated biphenyls in transformer
      oil degraded to lower chlorinated biphenyls with the extension of exposure time.
      The effect of diethylamine and xenon simulated sunlight was significant on the
      photodegradation of both PCBs in transformer oil and congener 138. The initial
      degradation rates of congener 138 (1.14 x 10(-9) to 4.47 x 10(-9) mol l(-1) h(
      1)) were in direct proportion to the initial concentrations of congener 138 which
      confirmed the pseudo-first-order reaction of PCB photodegradation. The apparent
      quantum yields (phi) of congener 138 using diethylamine in xenon photoreactor
      were ranged between 2.08 x 10(-2) and 9.8 x 10(-4). PCB congeners 123, 97, 70,
      67, 33, 29, 17, 12, and 9 were detected as the descendants of the
      photodegradation of congener 138 through dechlorination. The major pathway of
      congener 138 photodegradation in this study was via para-dechlorination.

PMID- 15041294
TI  - Photocatalytic degradation of formaldehyde containing wastewater from
      veterinarian laboratories.
AB  - The photocatalytic destruction of methanol, formaline (mixture of formaldehyde,
      methanol and water) and formaline wastes from the preservation of vertinarian
      physiologic samples has been attempted by two different processes, at high
      concentrations of reagents and by dossification of reagents, varying pH in both.
      Experiment evolution has been monitored by measuring the organic matter such as
      TOC and formaldehyde concentrations [H2CO]. Also, methanol and methanol
      formaldehyde interactions with the TiO2 surface have been analysed by FTIR
      spectroscopy. Results indicate that at high concentrations the catalyst surfacial
      alterations given by methoxy, formates or carbonates, according to the pH of the
      sample can profoundly affect catalyst behaviour. It has been established that
      reagent dossification is advantageous for enhancing photonic efficiency as it
      minimizes the adsorbate presence that hampers the photocatalytic process.

PMID- 15041295
TI  - Pesticide uses and transfers in urbanised catchments.
AB  - An investigation on herbicide uses in two semi-urban catchments was performed
      simultaneously with sampling campaigns at six stations inside both watersheds
      from April to July 1998. Urban uses of herbicides exceeded agricultural uses, and
      transfer coefficients were also higher in urban areas. Therefore, the most used
      product in urban areas (diuron) was by far the most contaminating product.
      Householders accounted for 30% of all uses. The highest measured diuron
      concentration in water surface was 8.7 microg l(-1) due to its use on impervious
      surfaces. Compared to EEC standards for drinking water production (0.1 microg l(
      1)), it is clear that suburban uses of herbicides may severely endanger drinking
      water production from river water.

PMID- 15041296
TI  - Biodegradation of haloacetic acids by bacterial enrichment cultures.
AB  - Haloacetic acids (HAAs) are toxic organic chemicals that are frequently detected
      in surface waters and in drinking water distribution systems. The aerobic
      biodegradation of HAAs was investigated in serum bottles containing a single HAA
      and inoculated with washed microorganisms obtained from enrichment cultures
      maintained on either monochloroacetic acid (MCAA) or trichloroacetic acid (TCAA)
      as the sole carbon and energy source. Biodegradation was observed for each of the
      HAAs tested at concentrations similar to those found in surface waters and in
      drinking water distribution systems. The MCAA culture was able to degrade both
      MCAA and monobromoacetic acid (MBAA) with pseudo-first order rate constants of
      1.06 x 10(-2) and 1.13 x 10(-2) l(mg protein)(-1) d(-1), respectively, for
      concentrations ranging from 10(-5) to 2 mM. The pseudo-first order rate constant
      for TCAA degradation by the TCAA culture was 6.52 x 10(-3) l(mg protein)(-1) d(
      1) for concentrations ranging from 5.33 x 10(-5) to 0.72 mM. The TCAA culture was
      also able to degrade MCAA with the rate accelerating as incubation time
      increased. Experiments with radiolabeled HAAs indicated that the 14C was
      primarily converted to 14CO2 with minor incorporation into cell biomass. The
      community structure of the enrichment cultures was analyzed by both cultivation
      dependent and cultivation-independent approaches. Denaturing gradient gel
      electrophoresis (DGGE) of the PCR-amplified 16S rRNA gene fragments showed that
      each of the two enrichment cultures had multiple bacterial populations, none of
      which corresponded to HAA-degrading bacteria cultivated on HAA-supplemented agar
      plates. This research indicates that biodegradation is a potential loss mechanism
      for HAAs in surface waters and in drinking water distribution systems.

PMID- 15041298
TI  - The era of cyclosporine: twenty years forward, twenty years back.

PMID- 15041297
TI  - Impurities in industrial grade 4,4'-isopropylidene diphenol (bisphenol A):
      possible implications for estrogenic activity.
AB  - Fifteen trace impurities, including a novel cyclohexene derivative, have been
      identified and quantified in samples of an industrial grade of the oestrogen
      active compound 4,4'-isopropylidene diphenol (bisphenol A). All of these
      compounds, like bisphenol A itself, possess phenolic hydroxyl groups para to
      other substituents and all thus might also have oestrogenic properties. Published
      studies on the endocrine disrupting properties of bisphenol A have not considered
      potentially active impurities but full assessment of the oestrogenicity of
      bisphenol A, as it is used commercially, will become possible when adequate
      supplies of these compounds are available through synthesis.

PMID- 15041299
TI  - Novartis celebrates 20 years in transplantation.

PMID- 15041300
TI  - Cyclosporine as a milestone in immunosuppression.
AB  - In this short review I show how cyclosporine fits into the broader picture of
      immunosuppression for organ allografting. Before cyclosporine there were some
      good results, particularly in kidney grafting, but also a failure rate of 50% of
      grafts by 1 year. Cyclosporine changed the graft survival of 1 year to 80%,
      although at 10 years the graft survival was little different from patients
      treated with azathioprine and steroids. Nevertheless, many patients achieved good
      function in their kidneys when treated with cyclosporine; these patients would
      have lost the kidneys under the old regimen. The cause of the late failure in
      patients treated with cyclosporine was predominantly nephrotoxicity due to the
      calcineurine inhibition, damaging the kidneys. Now that this is better understood
      and new drugs are available, many regimens have been tried but cyclosporine
      remains an important tool for the clinician in the treatment of patients with
      organ allografts.

PMID- 15041302
TI  - Early experience with cyclosporine: a historic perspective.
AB  - Cyclosporine, a new antilymphocyte peptide, was tested in heterotopic heart
      transplantation between two different strains of rats. Prolongation of rat heart
      allograft survival was observed in treated hosts as compared with untreated
      controls (P<.001). These pioneering studies in pedicle animal grafts proved that
      cyclosporine is an extremely potent immunosuppressive drug. Its ability to
      suppress allograft rejection episodes could be applied to other species of
      animals and to humans.

PMID- 15041301
TI  - Role of HLA molecules in the induction of alloimmune responses: clinical
      significance in the cyclosporine era.
AB  - HLA molecules are peptide-presenting molecules for T cells. T-cell receptors
      (TCR) recognize antigen-derived peptides bound to HLA molecules in cell
      membranes, namely, peptide-HLA (pHLA) complexes. An allograft will be recognized
      as foreign by recipient T cells via two slightly different mechanisms--direct and
      indirect allorecognition. In direct allorecognition, recipient T cells directly
      recognize foreign pHLA complexes on donor cells, in particular on donor dendritic
      cells (DC). In indirect allorecognition, recipient T cells recognize foreign
      peptides from the graft presented by self-HLA molecules on recipient DC.
      Cyclosporine (CsA) inhibits some activation signals in T cells as the result of
      allorecognition. Notwithstanding the strong immunosuppressive effects of CsA,
      reducing the degree of allorecognition through HLA matching is still of clinical
      significance. Data from our own transplant center and results from others
      demonstrate that the introduction of CsA as a main immunosuppressive drug does
      not nullify the significant beneficial effects of HLA matching on the frequency
      and strength of rejection episodes as well as on graft survival after
      allotransplantation. In cadaveric donor transplantation we observe significant
      effects of matching just for a limited number of (broad) HLA-DR molecules. We
      conclude that one should take advantage both of the strong immunosuppressive
      effects of CsA and other modern immunosuppressants as well as the beneficial
      effects of optimal HLA matching in clinical transplantation.

PMID- 15041304
TI  - Composite outcomes in renal transplantation using cyclosporine.

PMID- 15041303
TI  - Pharmacology of calcineurin antagonists.
AB  - Cyclosporine and tacrolimus share the same pharmacodynamic property of activated
      T-cell suppression via inhibition of calcineurin. The introduction of these drugs
      to the immunosuppressive repertoire of transplant management has greatly improved
      the outcomes in organ transplantation and constitutes arguably one of the major
      breakthroughs in modern medicine. To this date, calcineurin inhibitors are the
      mainstay of prevention of allograft rejection. The experience gained from the
      laboratory and clinical use of cyclosporine and tacrolimus has greatly advanced
      our knowledge about the nature of many aspects of immune response. However, the
      clinical practice still struggles with the shortcomings of these drugs: the
      significant inter- and intraindividual variability of their pharmacokinetics, the
      unpredictability of their pharmacodynamic effects, as well as complexity of
      interactions with other agents in transplant recipients. This article briefly
      reviews the pharmacological aspects of calcineurin antagonists as they relate to
      the mode of action and pharmacokinetics as well as drug interactions and
      monitoring.

PMID- 15041305
TI  - Cyclosporine: advantages versus disadvantages vis-a-vis tacrolimus.
AB  - Despite a different molecular structure and biochemical properties, cyclosporine
      and tacrolimus--by inhibiting calcineurin activity--have been shown in the
      previous two decades of solid organ transplantation to be well tolerated and
      effective immunosuppressants. Initial randomized clinical trials showed a lower
      incidence of acute rejection in tacrolimus than in cyclosporine-treated patients,
      in combination with steroids and azathioprine. But in conjunction with
      mycophenolate mofetil, the difference in the incidence of acute rejection
      episodes is less clear. In general, short- and medium-term outcome variables (1
      year serum creatinine, graft and patient survival) with cyclosporine and
      tacrolimus are excellent, and (almost) identical, with both substances having the
      same intrinsic nephrotoxic potential. On the other hand, cyclosporine and
      tacrolimus have a different impact on cardiovascular risk factors with tacrolimus
      having a better profile on arterial tension and lipid metabolism and cyclosporine
      on glucose metabolism. However, at present no data are available to discern that
      these differences in risk profile alter patient or graft survival or long-term
      cardiovascular morbidity/mortality. Therefore, prospective long-term trials are
      needed to study the quantitative impact of different immunosuppressive agents and
      concomitant cardiovascular risk factors on long-term patient and graft survival,
      before evidence-based (patient, graft, or cardiovascular) risk reduction can be
      firmly claimed by tailoring calcineurin inhibitors.

PMID- 15041306
TI  - Optimizing the use of cyclosporine (Neoral) for recipients of living donor
      kidneys.

PMID- 15041307
TI  - Experience with cyclosporine.
AB  - Cyclosporine ended the azathioprine-prednisone era of transplantation. For years
      prior to cyclosporine, regimens in transplant centers were relatively fixed and
      all patients received the same two drugs in nearly the same doses with
      adjustments made primarily for toxicities. Transplant physicians became expert in
      the side effects of steroids and azathioprine. Cyclosporine changed everything.
      Change is never easy, however, and initial resistance to changing protocols
      (especially for a new nephrotoxic drug) was only overcome by randomized,
      controlled trials. Cyclosporine increased allograft and patient survival rates
      without increasing opportunistic infections. However, as important were the
      changes in thinking that came about. It can be argued that cyclosporine
      contributed to expanding multicenter controlled trials in the transplant
      community. It also helped bring about concepts such as tailoring drugs to
      individual patients, drug minimization or elimination, use of polypharmacy, and
      focus on the first few weeks after transplant. Understanding of T-cell function
      and causes of renal dysfunction were brought into clearer focus by this exciting
      new agent.

PMID- 15041308
TI  - Experience with cyclosporine.

PMID- 15041309
TI  - Evolution of immunosuppression at the University of Minnesota.
AB  - Immunosuppressive protocols at the University of Minnesota have evolved from
      identical immunosuppression for all recipients (prednisone, azathioprine, and
      antilymphocyte globulin) to differing protocols for living (triple therapy) and
      cadaver (sequential therapy) donor recipients, and then to our current protocol
      in which all recipients receive induction therapy with rapid discontinuation of
      prednisone. At the same time, progress has been made in the prevention and
      treatment of cytomegalovirus infection along with numerous parallel improvements
      in patient care, including in anesthesia, dialysis, and intensive care unit care.
      The net result has been an incremental improvement in recipient and graft
      survival.

PMID- 15041310
TI  - Insights into subclinical rejection.
AB  - Several groups have performed graft biopsies at set times posttransplant
      ("protocol biopsies") and found unequivocal histologic criteria for acute
      rejection in a high proportion of patients with stable graft function. The
      significance of "subclinical" rejection remains controversial. Our group and
      others have shown that clinically silent infiltrates have inflammatory and
      cytotoxic potential. Furthermore, in a randomized trial, we demonstrated that
      treatment of subclinical rejection results in better graft histology and renal
      function. Although a decrease in the prevalence of subclinical rejection may
      reduce the rate of late graft losses, the risks and cost of protocol biopsies
      require that noninvasive methods for the diagnosis of subclinical rejection be
      developed.

PMID- 15041312
TI  - Impact of cyclosporine in the development of immunosuppressive therapy.
AB  - Cyclosporine has been of great interest to the transplant community during the
      last 20 years. It has permitted an evolution of knowledge through the changes in
      its original galenic formulation of Sandimmune to Neoral, and now through the
      recent application of the knowledge of pharmacodynamics and pharmacokinetics to
      tailor drug doses to each individual. The achievements of cyclosporine are still
      valid and possibly will be for the next years.

PMID- 15041311
TI  - Long-term kidney transplant outcomes in patients receiving oil-based or
      microemulsion formulations of cyclosporine.
AB  - In the last 20 years long-term experience with cyclosporine use in kidney
      transplantation has increased, allowing a more precise identification of its
      benefits. METHODS: We performed a retrospective analysis of 1619 kidney
      transplants that received cyclosporine-based immunosuppressive therapy. Patients
      were divided into three groups (1) oil-based cyclosporine (SIM) with trough
      monitoring (GI, n=617); (2) microemulsion formulation (NEO) with trough
      monitoring (GII, n=962); and (3) NEO with C2 monitoring (GIII, n=40). Information
      was obtained on transplant demography; adjunctive immunosuppressive agent; living
      (LD) versus cadaveric (CAD) recipients; delayed graft function; any treated acute
      rejection; graft function at 3, 6, and 12 months, patient and graft survival, as
      well as causes of graft loss and death. RESULTS: At 15 years follow-up, patient
      and graft survival were 67.5% and 41.6%, being superior, among LD versus CAD
      recipients (patient: 78.7% vs 57.7%, P<.001; graft: 56.4% vs 30.5%, P<.001). In
      LD (54% vs 32%, P<.001) and CAD (69% vs 55%, P<.001) NEO reduced the incidence of
      AR and improved 8-year patient (LD: 81.8% vs 94.7%; CAD: 66.4 vs 79.9%, P<.01)
      and graft survival (LD: 58.3 vs. 80%; CAD: 40.2% vs. 59.5%, P<.01), compared to
      SIM. Overall 8-year graft survival was inferior among patients with increased 1
      year creatinine values (< or =1.5, 1.6-2.5 and >2.5 mg/dL) level (74% vs 63.9% vs
      22.4%, P<.001) or change in Cr (< or =0.1, 0.2-0.4, >0.5 mg/dL) level (73.1% vs
      61.9% vs 37.2%, P<.001). In patients at the same level of graft function, those
      receiving NEO showed superior 8-year patient and graft survival compared with
      SIM. CONCLUSION: Compared to SIM, NEO reduced the incidence of acute rejection
      and produced superior long-term patient and graft survival.

PMID- 15041313
TI  - Single-center experience with cyclosporine therapy for kidney transplantation:
      analysis of a twenty-year period in 1200 patients.
AB  - Since the introduction of cyclosporine (CyA) in our center in February 1983, 1267
      kidney transplant patients have received an immunosuppressive regimen based on
      CyA, usually in association with azathioprine and steroids and following an
      induction therapy in three quarters of patients. The aim of this study was to
      retrospectively analyze our 20-year experience with CyA and examine the evolution
      of therapy during this period. Induction treatment has been less commonly used
      during the past 5 years. Even in the early years of our experience, CyA doses
      were low (under 6 mg/kg per day at 3 months after transplantation). Acute tubular
      necrosis was observed in 39.4% of patients. The incidence of acute rejection
      episodes has dramatically decreased since 1984, but the frequency of steroid
      resistant rejection has remained constant (around 20%). The first year of
      transplantation, 32.7% of patients had arterial hypertension. De novo diabetes
      mellitus occurred in 2.5% of patients. An incidence of 11.8% of malignancies was
      observed. Skin cancer and lymphomas accounted for 50% and 12% of neoplasms. Five
      year graft and patient survivals were 70% and 87%, respectively. Renal function
      remained remarkably constant during the first 10 years of follow-up with a mean
      creatinine of 150 micromol/L. Chronic allograft nephropathy resulted in 43% graft
      losses. In conclusion, CyA has been well tolerated in our patients. However, the
      occurrence of chronic allograft nephropathy was a major concern in our cohort.

PMID- 15041314
TI  - Experience with cyclosporine in 1519 kidney transplantations from living donors
      in a national transplant programme, 1983-2002.
AB  - Following the introduction of cyclosporine as basic immunosuppression in our
      national transplant programme in 1983, the pool of grafts from living donors
      (LDs) was expanded 2 years later by also accepting LDs mismatched for 2 HLA
      haplotypes and living unrelated donors (LURDs), mostly spouses. A policy of
      approaching family members to promote donation was consistently pursued. During
      1983 through 2002, nephrectomy was performed on 1519 LDs without mortality. From
      1983 through 1988, our learning phase in managing cyclosporine-immunosuppression,
      382 patients received first grafts from LDs. One-year graft survival (GS) rates
      were 94.4%, 90%, 89%, and 82% in 71 HLA identical, 260 haploidentical, 18 2
      haplotypes disparate, and 33 LURD graft recipients, respectively. Corresponding
      half-lives were 15.8, 10.3, 11, and 9.1 years, respectively. Results improved in
      1028 patients receiving first LD grafts from 1989 through 2002. Corresponding 1
      year GS rates were 96.6% (n=117), 93.5% (n=650), 90.4% (n=73), and 88.8% (n=188),
      and half-lives were 30, 13.3, 13.5, and 12.3 years, respectively. Similar GS
      rates were observed in 109 recipients of repeat grafts from LDs. LDs contributed
      44% and 21.6% of all first and repeat grafts transplanted, providing grafts to 11
      patients (in 1983) increasing to 23 patients (in 2002) per million population per
      year (pmp/y). When added to grafts from cadaveric donors, 40 to 48 pmp/y were
      provided with a first or repeat graft since 1990, thus covering at least 65% of
      the national need for kidney transplantations.

PMID- 15041315
TI  - Two decades of experience with cyclosporine in renal transplantation in Helsinki.
AB  - We present our experience on cyclosporine (CsA) triple immunosuppression in 2445
      cadaveric kidney transplantations performed from 1984 to 2002 in Helsinki.
      Overall, delayed onset of graft function occurred in 30.2% and acute rejection in
      25.6% of the transplantations. The 1-, 5-, and 10-year patient survival was
      95.1%, 84.5%, and 69.1%; the graft survival rates were 90.0%, 74.9%, and 56.7%;
      and the death-censored graft survival, 93.3%, 83.5%, and 72.4%. During the study
      period, the 5-year patient survival improved from 70.8% to 90.6% and the graft
      survival from 58.2% to 88.0% with the graft half-life estimate of 1-year
      survivors improving from 7.6 to 21.8 years. Acute rejection episodes decreased
      from 33.0% to 19.9% and the calculated creatinine clearance at 1 year improved
      from 50.3 mL/min to 74.3 mL/min. Mean CsA dose diminished significantly, both at
      3 weeks (from 8.2 mg/kg to 4.9 mg/kg) and at 1 year posttransplant (from 3.7
      mg/kg to 2.8 mg/kg). In 16.7% of transplantations where azathioprine had to be
      discontinued early, significantly more rejections occurred (38.0% vs 23.2%) with
      inferior 1-year graft survival (80.2% vs 94.8%) compared to the transplantations
      continuing on triple therapy. Among 1-year survivors, the 6-month serum
      creatinine level was strongly associated with death-censored long-term graft
      survival. In this material, the CsA dosage at 1 year did not predict long-term
      graft survival.

PMID- 15041316
TI  - The use of cyclosporine in renal transplantation.
AB  - The introduction of cyclosporine (CsA) into clinical practice resulted in a
      dramatic reduction in the incidence and severity of acute rejection. As a result,
      short-term and medium-term kidney allograft survival increased greatly. However,
      the long-term patient and graft survival have not improved to a similar degree.
      This can partly be attributed to the side effects of CsA and partly to the fact
      that the use of CsA has not led to a reduced incidence of chronic allograft
      nephropathy. Thus, there has been a continuing search for strategies that
      minimize CsA toxicity but maintain adequate immunosuppression. This has resulted
      in the development of the CsA microemulsion formulation and improved methods for
      therapeutic drug monitoring. With the introduction of newer immunosuppressive
      drugs, early CsA withdrawal and CsA-free immunosuppressive therapy have become
      feasible. However, CsA weaning or complete avoidance is associated with a
      slightly higher risk of acute rejection, and the long-term efficacy and safety of
      such strategies remain to be established. Therefore, it is to be expected that in
      the near future CsA will remain part of the standard immunosuppressive regimen in
      many transplant centers.

PMID- 15041317
TI  - Use of cyclosporine in renal transplantation.
AB  - The first cyclosporine trials in renal transplantation began in Cambridge in
      1978. Between 1982 and 1985 several large multicenter trials and the reports from
      large series of patients evidenced that cyclosporine was a major advance in the
      prevention of acute rejection episodes and in improving short-term and long-term
      graft survival. Cyclosporine also showed the capacity to mitigate immunologic
      risk factors, HLA mismatching, and lack of pretransplant transfusions. However,
      cyclosporine has the serious defect of being nephrotoxic. Induction therapy with
      OKT3, polyclonal antibodies, and more recently with anti IL-2R monoclonal
      antibodies allowed the delay of introduction cyclosporine in patients showing
      posttransplant graft dysfunction. Other relatively unsuccessful attempts for
      overcoming cyclosporine nephrotoxicity were made before the association of new
      xenobiotics such as mycophenolate mofetil or sirolimus permitted cyclosporine
      doses to be reduced. These combinations reduce acute rejection incidence to below
      20%, with its consequent positive impact on long-term graft outcome and also
      allow a safer steroid sparing and withdrawal early posttransplantation. Also, the
      association of cyclosporine with other new compounds such as the lymphocyte
      homing FTY20 or the peripheral lymphocyte-depleting Campath-1-IgG is currently
      under clinical investigation. Cyclosporine's future place is yet to be
      established in the new era of immunosuppression.

PMID- 15041318
TI  - Lessons from cyclosporine monotherapy in renal transplantation: the impact of
      acute rejection on long-term allograft outcome.
AB  - The introduction of cyclosporine in kidney transplantation rapidly improved short
      and medium term graft and patient survival rates. Initially many trials used
      cyclosporine monotherapy to avoid steroid toxicity, but high acute rejection
      rates lead to a change in the immunosuppressant scheme. The use of prophylactic
      steroids significantly decreased acute rejection rates, but the long-term benefit
      of such a reduction has not been assessed. METHODS: Retrospective analysis of the
      impact of early acute rejection on long-term outcome (10 years) in 264
      consecutive renal transplants performed in a single institution between 1986 and
      1993 using cyclosporine monotherapy (CM) (n=139) versus cyclosporine and
      prednisone (CS) (n=125). Different protocols were used for elderly or
      immunological high-risk patients and for transplants with delayed graft function
      and therefore these patients are not included. The incidence and severity of
      acute rejection episodes and long-term patient and graft survivals were analyzed.
      RESULTS: At 1 year, acute rejection episodes showed significantly higher
      frequency in the CM group than in the CS group (72.66% vs 46.40%). Nevertheless,
      graft and patient survival rates were similar at 1, 5, and 10 years (Graft:
      96.38%, 78.77%, and 59.84% vs 92.59%, 75.62%, and 53.44%; PATIENT: 99.27%,
      95.06%, and 84.76% and 95.9%, 93.09%, and 88.28%). CONCLUSION: The addition of
      prophylactic steroids decreases the incidence of acute rejection but does not
      improve the long-term graft survival. These findings suggest that in an era of
      new immunosuppressants, fewer acute rejection episodes will be evident requiring
      more effort to detect and treat subclinical rejections.

PMID- 15041319
TI  - Spanish experience with cyclosporine.
AB  - Our experience with cyclosporine (CsA) in de novo renal transplantation (RT) may
      be systematized in four consecutive periods. From February 1986 to December 1989,
      patient survival was higher among 128 consecutive CsA-prednisone-treated cadaver
      allograft recipients than in previous patients on azathioprine. One-year graft
      survival was significantly higher in CsA patients, a difference that was
      thereafter progressively reduced: at 10 years graft survivals were 50% versus
      45%, and at 15 years 37% versus 35%, respectively. The most frequent cause of
      graft loss was death with a functioning graft. Acute rejection caused more graft
      losses among Aza-treated patients than CsA-treated ones. However, chronic
      allograft nephropathy produced more graft losses in CsA patients. After this
      initial experience with CsA-based immunosuppression we developed a second phase
      in which better results were obtained in 209 first cadaveric RT recipients. The
      use of lower initial CsA doses, more rapid steroid tapering, and a better
      approach to CsA nephrotoxicity or chronic nephropathy by substantial reductions
      in CsA exposure and delayed azathioprine addition, lead to these improvements.
      From March 1995 through 2000, we used the new microemulsion CsA formulation
      (Neoral) with steroids or azathioprine in 110 first de novo RT recipients. Mean
      donor and recipient ages were significantly higher in this phase than in previous
      ones; consequently, survival and function results were slightly worse. Blood CsA
      concentrations measured 2 hours after administration represent a more precise
      predictor of exposure than trough concentrations. The last step in optimizing
      Neoral use in RT on our service was application of reduced-dosage with C2
      monitoring instead of classical C0 testing. Acute rejection and treatment failure
      rates were low and renal allograft function improved with respect to previous
      full-dose C0 experiences. CsA use has evolved in these two decades in four
      consecutive phases. Short-term results have improved or been maintained from
      phase to phase, even with expanded-criteria donors until excellent features
      during last years with C2 monitoring and combination with potent drugs such as
      MMF or everolimus. During the coming years, new drugs and protocols will allow
      even more optimized use.

PMID- 15041320
TI  - Experience with cyclosporine in the Canary Islands.
AB  - Cyclosporine (CsA) is currently the basis of most immunosuppressive protocols
      after solid organ transplantation. The introduction of Neoral, a new
      microemulsion formulation of CsA, and more recently a range of adjunctive
      immunosuppressants have further enhanced short-term efficacy and tolerability of
      CsA-based immunosuppression. In addition, Neoral C2 monitoring has been shown to
      have advantages not only in the early posttransplant period, but also for
      maintenance transplant patients. The major long-term disadvantage associated with
      CsA is the development of nephrotoxicity and chronic allograft nephropathy (CAN),
      which is the second major cause of graft failure. Thus, strategies to reduce the
      risk of CAN include CsA-sparing protocols, use of C2 level monitoring,
      introduction of non-nephrotoxic adjunctive immunosuppressants, and optimal
      management of additional risk factors. Other important side effects related to
      CsA-based immunosuppression include hypertension, diabetes, and hyperlipidemia.
      Optimal management of these conditions may lead to significant reduction of
      cardiovascular-related morbidity and mortality following solid organ
      transplantation.

PMID- 15041321
TI  - Cyclosporine: 20 years of experience at the University of Munich.
AB  - The history of solid organ transplantation is, from an immunotherapeutic
      standpoint, divided in the era before and after the introduction of cyclosporine
      to the clinic. The introduction of cyclosporine to the clinic in 1978 is looked
      upon as a turning point in transplantation. The immediate success of the new drug
      was based on the reduction of early graft rejection and the substantial
      improvement of 1-year graft survival. With growing experience in the use of this
      new compound, together with the ability to measure drug levels in serum,
      allograft rejection and organ survival could be improved even further. Because of
      the clinical results, cyclosporine became the gold standard in immunosuppressive
      therapy after organ transplantation. Even after 20 years, as more and more new
      immunosuppressants emerge, the clinical evaluation of a new drug is frequently
      compared versus a cyclosporine-based regimen. Today, cyclosporine is probably one
      of the best investigated drugs in the field of organ transplantation. Beside the
      undoubted benefits of cyclosporine, experimental and clinical studies have also
      revealed some unwanted effects, such as nephrotoxicity and an increased risk in
      development of malignant tumors. Here, we review the experience at our
      institution with transplant recipients receiving cyclosporine as the main
      immunosuppressant over the past 20 years.

PMID- 15041322
TI  - Impact of cyclosporine on the development of immunosuppressive therapy.
AB  - With the advent of cyclosporine (CsA) 20 years ago, graft survival increased
      considerably to more than 80% at 2 years posttransplant. The early formulation of
      CsA, Sandimmun, is effective in preventing organ rejection, although its
      absorption profile means it is subject to a high degree of variability. The
      development of a microemulsion formulation, Neoral, provided a therapy with
      superior efficacy in kidney, liver, and heart transplantation with an improved
      pharmacokinetic profile. Calcineurin inhibitors (CNIs), including CsA, have a
      narrow therapeutic range, so frequent blood measurements to control drug levels
      are required. Recent research has demonstrated that the measurement of blood CsA
      concentration at 2 hours postdosing--C2 monitoring--has the potential to optimize
      efficacy and reduce the side effects associated with CNI use. In heart and de
      novo kidney transplantation, C2 monitoring may help to further reduce the
      incidence of acute rejection, while in maintenance renal transplant recipients,
      C2 monitoring can help to detect overexposure and thus allows safe dose
      reduction, which may improve blood pressure and renal function. C2 monitoring
      thus facilitates a better balance between effective Neoral immunosuppression and
      unwanted side effects. Today, CsA remains the cornerstone of immunosuppression,
      and ongoing studies aim to further optimize patient management strategies with
      Neoral. With other trials evaluating the impact of Neoral in combination with
      newer therapies such as Certican, myfortic, and FTY720, the use of CsA in
      transplant recipients looks set to continue.

PMID- 15041323
TI  - Experience with cyclosporine.
AB  - The introduction of cyclosporine (CyA) was a landmark in transplantation, and in
      the two decades that have followed, enormous experience has been acquired in its
      use. This has led to both an understanding of its mechanism, pharmacokinetics and
      toxicity, and the continued evolution of its clinical application. Many of the
      initial complexities related to the hydrophobic nature of the molecule, and its
      variable absorption were addressed by the introduction of the microemulsion
      formulation Neoral. Despite this, the therapeutic window for CyA remains narrow,
      and therapeutic drug monitoring, recognized early after its introduction, is
      essential. However, this too has been redefined with single-point, 2-hour,
      postdose monitoring being demonstrated to correlate better with dose and outcome
      than the traditional 12-hour trough level. Implementation of such techniques may
      impact on efficacy and the long-term effects of nephrotoxicity. The need to gain
      experience with new facets of CyA is likely to continue. In particular, the use
      of reduced doses to minimize nephrotoxicity during long-term management has
      produced favorable early results. Furthermore, in the near future the
      availability of generic CyA formulations will increase. It cannot be assumed that
      these will be bioequivalent to the current preparations, and modifications of
      therapy, outside of current experience, may be required. However, if 20 years of
      CyA usage has taught us anything, it is that different formulations may have very
      different biological behavior, and at least this situation can be approached with
      a caution gained from long experience.

PMID- 15041324
TI  - Cyclosporine in renal transplantation: a Scottish experience.
AB  - The renal transplant unit in Glasgow has performed over 1500 renal transplants
      since the introduction of cyclosporine (CyA) in 1984. We extracted data on all
      renal transplants from cadaveric donors, where the recipient received primary
      immunosuppression with CyA, between 1984 and 2002. A total of 1262 transplants
      were analyzed in four eras (1984-1988, 1989-1992, 1993-1996, 1997-2002). Over
      this time period we observed progressive improvement in graft and patient
      survival, with the clearest improvements coinciding with the introduction of the
      Neoral formulation of CyA.

PMID- 15041325
TI  - The impact of cyclosporine on the development of immunosuppressive therapy.
AB  - The first immunosuppressive regimens based on glucocorticoids and azathioprine
      were introduced in the early 1960s. However, many patients developed acute
      rejection, which required treatment with high doses of prednisolone. Leading to a
      high mortality due to opportunistic infection. Prior to 1985, our center used a
      regimen of prednisolone and azathioprine for 352 renal transplantations with 1
      year graft and patient survival rates of 63.9% and 82.4%, respectively.
      Cyclosporine was introduced into clinical practice in 1978, enabling more
      effective control of acute rejection. In 1985, our center adopted a protocol
      consisting of prednisolone, azathioprine, and cyclosporine producing
      significantly increased 1-, 3-, and 5-year patient and graft survival rates for
      living-related and cadaveric renal transplants. Newer drug combinations, which
      are less toxic and more potent than cyclosporine based protocols, have further
      decreased acute rejection rates from 60% to approximately 10%. Still, graft loss
      continues to be a problem. We believe that the most recent strategy of combining
      monoclonal antibodies with less toxic agents, such as sirolimus and mycophenolate
      mofetil, may eventually replace calcineurin inhibitors. Such protocols would
      eliminate the side effects of calcineurin inhibitors, and possibly permit steroid
      free maintenance therapy. The immunosuppressive therapy that is currently
      available is not ideal; the ability to convert patients to a state of permanent
      immunologic tolerance would minimize the need for these drugs. The new generation
      of agents that includes FTY 20, anti-sense oligonucleotides, and agents capable
      of blocking the costimulatory pathway of allorecognition may improve host
      tolerance.

PMID- 15041326
TI  - Application of cyclosporine in renal transplantation: experience at the
      University of Padua.
AB  - Cyclosporine (CsA) therapy has evolved considerably since its introduction as the
      primary immunosuppressant drug in the early 1980s and its use in renal
      transplantation continues to expand globally. In the last 20 years, there have
      been significant advances in formulation design, therapeutic drug monitoring
      guidelines, and the emerging role of CsA-based combination therapies that have
      resulted in a substantial improvement in clinical outcomes in renal transplant
      recipients. The aim of this work is to review developments in the application of
      CsA in kidney transplantation at our Center in Padua and to evaluate the clinical
      outcome of our patients in the last 15 years in relation to the new trends in CsA
      management strategies.

PMID- 15041327
TI  - Experience with cyclosporine.
AB  - Six hundred thirty-eight cadaveric kidney transplant patients between 1983 and
      2001 were treated with cyclosporine (CsA) for 87 +/- 58 months. Among 571
      patients with follow-up greater than 12 months, the 15-year renal function was
      investigated to assess the probability of a >30% increase in serum creatinine
      (sCr) above the month-6 value (baseline) and the impact on graft survival. At 15
      years, patient and graft survival rates were 82.7% and 56.1%, respectively, with
      a 19.5-year half-life (censored for deaths). The main causes of graft loss were
      chronic rejection (33.0%) and patient death (24%). Cardiovascular disease and
      neoplasms were the main causes of death. Renal function remained stable in 266
      patients (46.6%) with excellent sCr values observed even after a 15-year
      treatment period. An increased sCr was observed in 305 patients (53.4%) with a 15
      year probability of 74%. In 178 patients (59.3%) it was self-limited; their
      grafts are still functioning well. One hundred three patients (32.8%) lost their
      graft which was more likely when the sCr had increased >45%. Twenty-four patients
      (7.9%) died with a functioning graft. Multivariate analysis showed the
      progression of graft deterioration to be related to proteinuria (P<.0001), a late
      acute rejection episode (P<.002), or the extent of sCr increase (P<.008). In
      conclusion, the long-term use of CsA has allowed us to achieve excellent long
      term patient and transplant survival rates. Our data indicate a high 15-year
      probability of an increased sCr, but the rate of progression is slow.

PMID- 15041328
TI  - Cyclosporine--lessons from the first 20 years.
AB  - The introduction of cyclosporine in clinical practice led to a dramatic increase
      in long-term graft survival. At the Transplantation Center of the University of
      Rome La Sapienza, the survival rate at 5, 10, and 20 years was 35%, 22%, and 20%
      in the precyclosporine era and 75%, 60%, and 45%, respectively, after the use of
      cyclosporine-based immunosuppressive therapy. However, because of the
      nephrotoxicity of this, drug efforts are being made to reduce or avoid the use of
      calcineurin inhibitors. We advocate tailoring of immunosuppression to a minimal
      level on the basis of immunologic tests that permit a quantitative and
      qualitative evaluation of regulatory and effector cells.

PMID- 15041329
TI  - Experience with conversion from Sandimmun to Neoral cyclosporine and the
      correlation of C2 levels with renal function.
AB  - Pharmacologic monitoring of the cyclosporine microemulsion Neoral is an important
      tool to improve the efficacy and to avoid toxicity of the drug. Recent trials
      have shown that the absorption profiling tools represented by the area under the
      time-concentration curve from 0 to 4 hours postdose and concentration 2 hours
      postdose (C2) levels are the best predictors of acute rejection in the early
      posttransplant period. Since similar data regarding maintenance immunosuppression
      are scarce, we report our experience on Neoral C2 monitoring in renal transplant
      recipients during the late posttransplant period. However, available data on
      optimal Neoral C2 levels in the late posttransplantation period are scant and
      have not been correlated with well-defined endpoints such as chronic allograft
      nephropathy.

PMID- 15041331
TI  - Immunosuppression in kidney transplantation in Poland.
AB  - This paper presents experience with cyclosporine A in kidney allograft recipients
      at the Transplantation Institute, the Medical University of Warsaw. Comparative
      studies on pharmacokinetics and bioavailability of CsA and Neoral as well as
      monitoring of the drug immunosuppressive activity are presented. The
      implementation of CsA to immunosuppressive therapy in renal allograft recipients
      have greatly improved the grafts and patients survival. CsA has been used in a
      great percentage of patients after renal allograft in Poland (72%) and seems to
      be in some patients the gold standard of immunosuppression.

PMID- 15041330
TI  - Use of cyclosporine in renal transplantation.
AB  - Since 1983, cyclosporine has been the backbone of immunosuppression in clinical
      organ transplantation. Cyclosporine is usually used in combination with steroids
      and with another second-line immunosuppressant like azathioprine or mycofenolate
      mofetil. With these regimens, graft survival at 1 year exceeds 90% and long-term
      results are excellent. The main complication is renal toxicity, which is usually
      secondary to excessive exposure. The new microemulsion formulation of
      cyclosporine, introduced in recent years, has improved intestinal absorption and
      bioavailability and resulted in much less intrapatient variation than the older
      formulation. The introduction of 2-hour peak blood level monitoring, which
      corresponds closely to the area under the curve of the drug, allows more
      appropriate dosing, thus minimizing rejection owing to underexposure or toxicity
      owing to overexposure. As new effective immunosuppressants are currently becoming
      available for use in combination with cyclosporine, the transplant community can
      look forward to more effective and safer immunosuppression.

PMID- 15041333
TI  - Optimization of the use of cyclosporine in renal transplantation.
AB  - The immunological barrier remains the major obstacle to the widespread use of
      transplantation as a replacement therapy for terminal organ failure. Since the
      first successful renal transplant performed by Hume et al in 1952, there has been
      an elusive search for agents rendering the immune mechanism unresponsive to the
      specific alloantigen stimulus of the engrafted organ while sparing nonspecific
      host resistance. Immunosuppressive therapies in organ transplantation can be
      divided into the following four main classes; chemical (pharmaceutical),
      biological (immunological), physical (radiological), and surgical. Of these,
      chemical agents (drugs) have continued to play a principal role. The discovery of
      new immunosuppressive drugs such as corticosteroids, azathioprine, cyclosporine
      (CsA), tacrolimus, mycophenolate mofetils and so on made an epoch at each stage
      in history of clinical organ transplantation. The recent immunosuppressants were
      designed to focus their action selectively on T and /or B cells by inhibiting
      cytokine synthesis (CsA, FK506), cytokine action (Rapamycin), or cell
      differentiation (15-deoxyspergualin) pathways rather than to act on immune
      systems in a nonselective fashion. CsA has improved the success of kidney
      transplantation, reducing the incidence and severity of acute rejection and
      improving the patient and graft survival. Sandimmun Neoral offers promise due to
      its better bioavailability and limited dependence on bile flow for absorption.
      Long-term studies are under way to determine its effectiveness and safety.
      Therapeutic drug monitoring and combination therapy with CsA are investigated
      also.

PMID- 15041332
TI  - Ten years of cyclosporine use in renal transplantation: a single-center
      experience with 479 renal transplants.
AB  - INTRODUCTION: From 1983 to 1996 therapy with cyclosporine in association with low
      dose azathioprine and prednisone has been used for transplantation
      immunosuppression. The aim of our study was to present 10 years experience with
      cyclosporine. MATERIAL AND METHOD: Among 479 renal transplants performed since
      1992, 61 were performed with cadaver donor grafts and 58 in pediatric recipients.
      From 1992 to 1998, the immunosuppressive protocol included CsA, azathioprine, and
      prednisone. Since 1998, mycophenolate mofetil (MMF) replaced azathioprine. In
      2002, tacrolimus and rapamycin were introduced into our protocols. The patients
      were assessed in terms of serum creatinine, incidence of acute rejection,
      cyclosporine side effects, and graft and patient survivals. RESULTS: Five-year
      patient and graft survivals were higher among recipients receiving CsA-MMF
      prednisone when compared with CsA-azathioprine-prednisone. The incidence of acute
      rejection episodes during the first year after transplantation was less frequent
      among recipients receiving MMF compared to those treated with azathioprine. The
      overall 5-year survivals for patients was 86.29% and for grafts 74.04%.
      CONCLUSION: Cyclosporine remains a useful immunosuppressive drug, which
      represents a major step toward efficient renal transplantation. The availability
      of multiple effective immunosuppressive agents allows individualized protocols to
      reduce toxic effects. The advent of new induction regimens offers more
      opportunities to prolong graft life.

PMID- 15041334
TI  - Experience with cyclosporine in adult living donor kidney transplantation: from
      1984 to 2002 at Yonsei University.

PMID- 15041335
TI  - Accommodation in ABO-incompatible kidney transplantation: why do kidney grafts
      survive?
AB  - Owing to the extreme shortage of cadaveric kidneys in Japan, ABO-incompatible
      kidney transplantation has been performed since 1989. We followed 441 recipients
      of ABO-incompatible kidney transplants. The long-term outcome did not differ
      significantly from that in recipients of living donor kidney transplants as a
      historic control group. Our data provide further evidence that humoral rejection
      due to ABO-antigen-antibody reaction does not occur once accommodation has been
      established. This report describes the characteristics of hyperacute and delayed
      hyperacute rejection as well as the mechanisms whereby accommodation is
      established in association with changes in donor (graft)-derived ABO histo-blood
      group glycosyltransferase, appearing in recipient blood after transplantation.

PMID- 15041337
TI  - Cyclosporine in pediatric kidney transplantation.
AB  - Before the era of cyclosporine (CsA), immunosuppression with azathioprine and
      steroids resulted in high rejection rates and severe growth retardation in
      pediatric renal transplant recipients. In the early 1980s, immunosuppression with
      CsA was introduced for children. Because of differences in metabolism rates and
      relation of weight and body surface area, special pediatric dosing regimens and
      monitoring strategies had to be developed. Use of CsA led to a decreased number
      of acute rejections and, consequently, to a marked increase in graft survival
      rates. The growth rates of transplanted children were significantly higher under
      CsA-based immunosuppression than with classical regimens. This was due to a
      decreased need of steroid co-administration. Main side effects of CsA in children
      were nephrotoxicity and hirsutism. The introduction of CsA microemulsion in the
      1990s led to more reliable absorption profiles and to a lower interindividual
      variability of CsA area-under-the-curve concentrations and thus to another
      improvement in rejection rates. New monitoring strategies, based on CsA levels
      taken 2 hours' postdose, seem promising. In pediatric transplantation, CsA is
      often successfully combined with an antibody-induction therapy in order to reduce
      the number of early acute rejections. Combination with mycophenolate mofetil
      reduces the appearance of chronic rejection. Additional therapy with ToR
      inhibitors might enforce a reduction of CsA doses and therefore lead to a
      reduction of CsA toxic effects.

PMID- 15041336
TI  - The impact of cyclosporine on the development of immunosuppressive therapy-
      pediatric transplantation using cyclosporine.
AB  - Cyclosporine A (CsA) was introduced to pediatric renal transplantation more than
      20 years ago, and it has greatly improved graft survival and made transplantation
      the treatment of choice for children with end-stage renal failure. Exposure to
      CsA was shown to be highly variable among transplant recipients. Therefore, major
      efforts have been employed to monitor CsA blood levels. The widely used trough
      levels had never been formally validated, and every center had defined its own
      target values. With the advanced microemulsion formula of CsA, drug exposure
      became more predictable, but scientifically evaluated monitoring concepts are
      still lacking. Monitoring the absorption phase using single time points (eg, 2
      hours after ingestion) is promising, as shown in adult trials. In pediatric
      transplant recipients, randomized clinical trials have to be implemented urgently
      to fully exploit the potential of CsA in the prevention of graft rejection while
      minimizing toxicity. Although newer immunosuppressive drugs have been developed,
      further studies should be undertaken to define the role of CsA in combination
      protocols.

PMID- 15041339
TI  - Experience with cyclosporine in pediatric renal transplantation.
AB  - Three decades ago renal transplantation had become the accepted therapy for end
      stage renal disease in children. Cyclosporine (CsA) was introduced into the
      majority of clinical immunosuppressive protocols in the 1980s and attained a
      vital place in the armamentarium of antirejection drugs for children. However,
      CsA therapy is not without adverse effects, notably posttransplant hypertension,
      hyperlipidemia, and nephrotoxicity. The cosmetic side effects of CsA, principally
      hirsutism and gum hyperplasia, are significant and very important to children
      particularly when drug compliance issues are vital to achieve success. The
      central role CsA has played to date in the development of successful treatment
      protocols for children undergoing renal transplantation is explored, including
      the importance of therapeutic drug level monitoring to optimize clinical
      outcomes.

PMID- 15041338
TI  - Renal outcome of children exposed to cyclosporine in utero.
AB  - The number of pregnancies in immunosuppressed women has increased during the
      recent years and this has become a major part of the rehabilitation and quality
      of life of treated patients. Most of them are organ transplant recipients and
      large series from the literature have shown that children born to such women may
      present with intrauterine growth retardation, a condition which may be associated
      with significant reduction in nephron number and oligomeganephronia. On the other
      hand, experimental data in animals have demonstrated that in utero exposure to
      CsA may alter nephrogenesis and further alter renal function. Therefore offspring
      of organ transplant women treated with CsA exhibit a theoretical risk of renal
      impairment, due to both IUGR and fetal nephrotoxicity. However, despite the
      limited experience of long term studies in children, there is no evidence of any
      significant deleterious adverse effect of in utero exposure to CsA. However
      further studies based on large series are required in order to demonstrate that
      renal fetal effects have limited clinical consequences.

PMID- 15041340
TI  - A prospective trial of steroid withdrawal after renal transplantation in
      children: results obtained 1990 and 2002.
AB  - Ten-year graft survival rate was 89% after immunosuppressive therapy with
      cyclosporine, methylprednisolone, and mizoribine in pediatric renal transplant
      recipients enrolled in our multicenter study. Adrenocorticosteroids, which cause
      growth retardation, were reduced by administration on alternate days in 67% and
      withdrawn in 23% of recipients. Acute rejection episodes occurred in 30% of
      patients after withdrawal of steroids. Graft function returned to prerejection
      levels after treatment with high-dose methylprednisolone. Catch-up growth
      occurred after alternate day administration and steroid withdrawal. Twenty-eight
      of 94 patients reached the final height of 156 cm in boys and 145 cm in girls,
      because of the gradually reduced growth rate. Management of growth retardation
      before transplantation, especially in patients with congenital renal diseases,
      and early reduction of the steroid dose after transplantation will increase the
      final height of children with chronic renal failure.

PMID- 15041341
TI  - Cyclosporine nephrotoxicity.
AB  - The introduction of cyclosporine (CSA) into organ transplantation was a landmark
      achievement leading to a substantial improvement of the early transplant results.
      It was particularly the reduction in early severe acute rejections that accounted
      for this improvement. However, on a long-term basis development of chronic
      transplant nephropathy did not seem to become counteracted by CSA. Conversely,
      CSA may cause both acute and chronic nephrotoxicity, with reduced renal
      transplant function along with arteriolopathy and interstitial fibrosis. This is
      the shortcoming of CSA as well as other calcineurin inhibitors (CNIs) such as
      tacrolimus (TAC). Other immunosuppressive agents were developed subsequently,
      including Target of Rapamycin (ToR) blockers and mycophenolate mofetil (MMF),
      which were not nephrotoxic. Current strategies to overcome CNI toxicity include
      reduction or even stopping administration of CSA or TAC along with switching to a
      sirolimus, everolimus or MMF based regimen. This strategy has been documented
      (and there are currently additional ongoing studies) to cause an improvement in
      renal transplant function or to reduce the deterioration rate. These measures to
      deal with CSA toxicity need further documentation, since a preserved good renal
      function seems to not only have an important impact on graft survival but also on
      patient survival.

PMID- 15041342
TI  - Cyclosporine-induced renal dysfunction.
AB  - The most practical way to assess and to quantitate the renal function in renal
      transplant patients is the Cockcroft-Gault equation or an equation used to
      estimate the glomerular filtration rate (GFR), derived from the Modification of
      Diet in Renal Disease study. Chronic cyclosporine (CsA) nephrotoxicity causes
      structural lesions in the kidney and an impairment in the GFR. Determining the
      composition of the interstitial collagens may be helpful to establish the
      diagnosis. CsA trough levels are a poor indicator of drug exposure; drug exposure
      should be quantitated using more accurate methods. Although routine biopsies
      often show histopathological evidence of structural damage, the excellent kidney
      graft half-life and the documentation that the creatinine clearance usually
      remains stable over years in CsA-treated renal transplant patients suggest that
      its use in kidney transplant patients does not inexorably lead to graft failure.
      Protocol biopsies show a high incidence of chronic structural CsA toxicity but
      transplant nephrectomies show that CsA nephrotoxicity as the sole cause of graft
      loss is extremely rare.

PMID- 15041343
TI  - Cyclosporine nephrotoxicity.
AB  - Cyclosporine (CsA) is the current primary immunosuppressant for the prevention of
      allograft rejection in solid organ transplantation. However, owing to its
      molecular mechanism of action the drug is associated with various adverse side
      effects (eg, nephrotoxicity). Histological changes appear as obliterative
      vasculopathy of the afferent arteriole and tubulointerstitial fibrosis in
      advanced cases. The underlying pathomechanisms of this condition reflect an
      altered release of vasoactive substances, such as angiotensin II, endothelin,
      prostaglandins, and nitric oxide as well as the stimulation of proliferative
      genes such as transforming growth factor-beta, osteopontin, and collagen I and
      IV. Potential strategies for the prevention of nephrotoxicity are discussed.

PMID- 15041344
TI  - Nephrotoxic aspects of cyclosporine.
AB  - Over the last 20 years cyclosporine (CsA) has improved the survival of kidney,
      heart, and liver transplants. However, with increasing use, evidence has
      accumulated that CsA therapy carries a variety of side effects, the most
      important being renal toxicity. CsA can lead to a wide spectrum of renal function
      impairments, including a marked and rapidly reversible decrease in renal
      hemodynamics (acute CsA nephrotoxicity), and a chronic form of renal damage that
      potentially progress irreversibly to end-stage renal disease (chronic CsA
      nephrotoxicity). All these manifestations are the consequence of the drug toxic
      effects on renal vessels and the tubulointerstitium. A proper diagnosis of CsA
      toxicity at early stages, the combination of low CsA doses with non-nephrotoxic
      immunosuppressants, and the development of more feasible strategies to monitor
      daily CsA exposure may contribute to a better CsA management, improve quality of
      life of transplant recipients, and prolong graft survival.

PMID- 15041345
TI  - Cyclosporine nephrotoxicity.
AB  - The polypeptide immunosuppressant cyclosporine is a prodrug that binds an
      intracellular immunophilin. The complex cyclosporine-cyclophilin binds and
      inhibits the phosphatase activity of calcineurin interfering with the
      dephosphorilation of members of the nuclear factor of activated T cells, which is
      involved in the regulation of genes encoding many cytokines. However, calcineurin
      is not exclusive from T cells; it is also present in many organs, such as the
      kidney, and their inhibition accounts for both the immunosuppressive and the
      nephrotoxic effects of cyclosporine. In renal transplantation, it was shown that
      graft survival improved progressively between 1998 to 1996, mainly due to
      reduction of acute rejection episodes. There is no doubt that cyclosporine
      contributed to that success. After 20 years, cyclosporine targets for maintenance
      immunosuppression have not been defined and the magnitude of chronic cyclosporine
      nephrotoxicity in renal allografts is not known, in part by the limitations of
      histologic classification of chronic allograft nephropathy. In the future, the
      new technology based on DNA microarrays can be a valuable tool to separate
      chronic drug toxicity from other causes of graft deterioration. On the other
      hand, in the cyclosporine era, chronic renal failure has emerged as a frequent
      adverse event after transplantation of nonrenal organs and it is associated with
      increased risk of death. Although there is not yet enough evidence to support a
      generalization of calcineurin-free immunosuppression, we should open our minds to
      the upcoming new concepts on immunosuppression.

PMID- 15041346
TI  - Cyclosporine renal dysfunction.
AB  - Cyclosporine (CsA), introduced as an immunosuppressive agent in the 1980s,
      quickly become the first-line treatment in organ transplantation. However, these
      improvements were associated with an increased incidence of renal dysfunction.
      CsA causes histopathological changes in renal transplants that are often
      difficult to distinguish from other processes, especially chronic allograft
      nephropathy. Enhanced angiotensin II, transforming growth factor-beta, and
      vascular endothelial growth factor expression together with down-regulation of
      nitric oxide synthesis may play roles in chronic CsA nephropathy. Efforts have
      recently focused upon protocols that minimize the risk of CsA nephrotoxicity
      while preserving low rates of acute rejection. Four types of CsA-sparing studies
      have emerged from recent clinical experience: (1) conversion studies in which a
      nonnephrotoxic drug is substituted to allow CsA reduction, (2) minimal CsA
      exposure studies in which reduced CsA doses are combined with nonnephrotoxic
      drugs, (3) withdrawal studies in which CsA is completely discontinued at some
      time after transplantation, and (4) CsA-free studies in which the drug is
      completely avoided from the time of transplantation. Monitoring of CsA
      immunosuppression according to C2 blood levels, which better correlate with the
      area under the time-concentration curve than trough concentrations, should reduce
      the risk for toxicity; however, the most appropriate target range has not yet
      been clearly established. Because of interindividual differences in CsA
      absorption and susceptibility to renal dysfunction, the current therapeutic drug
      monitoring should be supplemented with pharmacogenetic information on genetic
      variability of relevant genes for pharmacokinetic parameters and therapeutic
      targets. This approach may guide choices for immunosuppressants for particular
      patients, with low toxicity. Thus, despite of 20 years of its history, CsA renal
      dysfunction remains an important clinical challenge.

PMID- 15041347
TI  - Cyclosporine-A-based immunosuppression and renal functional reserve in organ
      transplant patients.
AB  - The glomerular filtration rate (GFR) may increase after oral protein overload or
      after an amino acid infusion. Renal functional reserve (RFR) is defined as the
      difference between the poststimulation and the baseline glomerular filtration
      rate. RFR has been studied in transplant patients. The results have been
      conflicting because RFR may be affected by donor age, the time from
      transplantation, the type of immunosuppression, the basal GFR, the body surface
      area, and the presence of calcium channel blocker therapy. We observed that
      during the first year posttransplantation renal recipients maintained on
      cyclosporine (CsA) therapy retain a level of RFR that represents approximately
      30% of the baseline GFR. Moreover, hypertensive cyclosporine treated renal
      transplant patients on calcium channel blocker therapy do not exhibit permanent
      glomerular hyperfiltration until 8 months posttransplantation. Finally, both
      renal and heart transplant patients on cyclosporine therapy possess renal
      reserve, but the single renal graft in renal transplant patients shows a
      proportionally higher baseline GFR and a better ability to exhibit a RFR than the
      two native kidneys in heart transplant patients. Many studies, although not all,
      have documented a positive RFR in both children and adult cyclosporine-treated
      kidney graft recipients, demonstrating that hyperfiltration is not the rule
      following single kidney transplantation.

PMID- 15041348
TI  - Cyclosporine nephrotoxicity: how does it affect renal allograft function and
      transplant morphology?
AB  - Chronic CSA nephrotoxicity is the second most important diagnosis responsible for
      the late graft failure. CSA associated arteriolopathy (CAA) is a well-known
      lesion of chronic CSA nephrotoxicity. The clinicopathological characteristics and
      the significance of CSA nephrotoxicity have changed following reduction in CSA
      doses and implementation of monitoring of blood levels. Seventy-four CAA patients
      on CSA therapy were classified as functioning (n=30) or loss groups (n=44). There
      was no significant difference in severity of CAA. The concomitant lesion of
      chronic rejection, but not the severity of CAA, was the most important risk
      factor for graft loss. Among 54 recipients with focal segmental
      glomerulosclerosis lesions (FGS), 32 (59%) were diagnosed as CAA associated
      glomerulopathy (CAG). Eighteen of the 32 CAG patients lost their grafts upon
      follow-up. Decreasing the CSA dosage to maintain lower blood levels than the
      usually optimal concentrations, but not discontinuation of CSA, has been useful
      to retard the progression of graft dysfunction in half of 15 isolated pure CAG
      patients. Patients with increasing daily proteinuria exceeding 2 grams lost their
      graft function despite CSA reductions. CAA is not a specific lesion of chronic
      CSA nephrotoxicity; the FGS lesion is also a nonspecific lesion often seen in
      renal allografts. Isolated chronic CSA arteriolopathy of severe degree has a
      fairly good prognosis under controlled CSA therapy. The FGS lesion accompanying
      CAA is considered to be CSA-associated glomerulopathy. These data contribute to
      therapeutic plans for renal transplant patients during long-term CSA treatment.

PMID- 15041349
TI  - Preservation of renal function during maintenance therapy with cyclosporine.
AB  - During the last 20 years the management of cyclosporine (CsA) has improved due to
      the introduction of microemulsion technology, C2 monitoring, and combination with
      other new immunosuppressants. All these modifications have reduced the incidence
      of biopsy-proven acute rejection episodes to approximately 10%. However despite
      the wide experience, there are unanswered questions regarding CsA monitoring
      after the first year. Available clinical and histological data suggest that the
      therapeutic range to avoid nephrotoxicity or underimmunosuppression during the
      maintenance period is rather narrow. Furthermore, the combination of CsA with new
      immunosuppressants may modify the target CsA levels. Although the utility of C2
      levels during the first year has been well characterized, there are few data on
      its utility for maintenance therapy, particularly the therapeutic range for C2
      levels in patients receiving different immunosuppressive combinations. Since
      serum creatinine does not precisely reflect the progression of chronic allograft
      nephropathy, the efficacy of C2 monitoring during the maintenance period must be
      assessed not only by means of evaluation of renal function, but also histologic
      assessment using protocol biopsies.

PMID- 15041350
TI  - Learning and new discovery with cyclosporine in the Cambridge-King's Programme: a
      personal view.
AB  - Immunosuppressive regimens in the early precyclosporine days of liver
      transplantation for the Cambridge-King's Programme from 1968 until the early
      1980s were inadequate in the control of rejection. The consequent use of high
      dose steroids led to many infections, which seriously affected outcome.
      Nevertheless, occasional patients did well but a consistent increase in survival
      was not seen until after the introduction of cyclosporine and experience was
      gained with its proper usage in terms of toxicity. The development of Neoral with
      its greater oral bioavailability marked a major step forward in the development
      of the drug. Whether 2-hour postdose monitoring with reduction in rejection
      frequency and toxicity as described recently better match results with tacrolimus
      in comparison-controlled trials remains to be determined.

PMID- 15041352
TI  - Living related liver transplantation.
AB  - The introduction of cyclosporine was a major advance in liver transplantation,
      leading to increased numbers of liver transplant cases and, at the same time, a
      relative shortage of available donor organs. As one of the modalities to decrease
      the mortality rate on the waiting list, living related liver transplantation
      (LRLT) was initiated. In the LRLT program of Kyoto University, which started in
      June 1990, the number of cases has increased yearly as its application expanded
      from pediatric to adult patients. A landmark in LRLT was the introduction of
      right lobe grafts, which have become a standard procedure in adult-to-adult
      living donor liver transplantation. The basic immunosuppressive regimen consisted
      of tacrolimus and low-dose steroids from the beginning of our LRLT program.
      However, since documentation of significant improvements in clinical efficacy
      with Neoral compared to Sandimmun-based immunosuppression, the role of
      cyclosporine in LRLT is now being reevaluated.

PMID- 15041354
TI  - Experience with cyclosporine.
AB  - The concentration at 2 hours after drug intake (C2) is proposed to optimise
      clinical outcomes in organ transplantation and for adjustment of the regimen of
      cyclosporine. A population based pharmacokinetic study was undertaken during the
      first 30 days post-liver transplantation. Preliminary results observed during
      this study on C0 and C2 values are described here. Thirty-seven patients with
      first hepatic transplantation were included in a single center, prospective study
      conducted under conditions of normal practice. Dose adjustments were made
      according to C0. Cyclosporine C0 and C2 were assayed by an immunoassay (EMIT) and
      by a HPLC technique. Clinical outcome was assessed by occurrence and severity of
      acute rejection. Our data shows that average blood C0 and C2 concentrations are
      significantly different with the two techniques. From the third day to the end of
      the study, mean C2 (EMIT) were within or near the recommended values. This was
      associated with a low rejection rate (8.8%). Nevertheless, individual values are
      largely dispersed and low cyclosporine absorption profiles are identified. Mean
      cyclosporine dose was low compared to a previous study (7.65 +/- 4.28 mg/kg/day).
      Our data suggest that the target ranges need to be adjusted when different
      techniques are applied and that optimal cyclosporine regimen to achieve the C2
      goal and low rejection rate remains to be defined. Pharmacokinetic models based
      on population study are needed to describe normal and abnormal cyclosporine
      absorption profiles with higher accuracy.

PMID- 15041353
TI  - Evolution of immunosuppression in liver transplantation: contribution of
      cyclosporine.
AB  - Liver transplantation has become the standard therapy for patients with end-stage
      liver disease or acute liver failure, with excellent outcomes in terms of quality
      of life and length of survival. The use of immunosuppressive agents, without any
      doubt, has played a crucial role in the establishment of this technique and
      improved short- and long-term survival rates. Eventually, mortality from acute or
      chronic rejection may be entirely eliminated. Minimizing the adverse effects of
      immunosuppressive agents is essential to improve long-term survival and quality
      of life. In this chapter, we review the history of immunosuppressive agents for
      liver transplantation with consideration of the pre- and the postcyclosporine
      eras. We also review the development and contributions of cyclosporine, the
      excellent outcomes from C2 monitoring, comparisons between the cyclosporine
      microemulsion and the oil-based formula, as well as between cyclosporine
      microemulsion versus tacrolimus. In addition, details are provided on the newer
      immunosuppressive agents: mycophenolate mofetil, sirolimus, and the IL-2 receptor
      antagonists, as well as agents in development: CAMPATH 1-H, thymoglobulin,
      everolimus, FT720, and FK778.

PMID- 15041351
TI  - Optimization of cyclosporine for liver transplantation.
AB  - Our understanding of cyclosporine (CsA) administration for liver transplantation
      has significantly improved over the past decade. Cyclosporine is a highly
      lipophilic molecule, and the original galenic formulation, Sandimmune, was highly
      dependent on bile flow and gut motility for its absorption. Sandimmune's poor
      absorption profile produced erratic CsA levels after liver transplantation. A new
      microemulsification formulation of CsA, Neoral (CsA-ME), was developed to
      overcome these limitations. The NOF-1 study confirmed the superiority of CsA-ME's
      absorption compared with Sandimmune; CsA-ME had a more consistent and reliable
      absorption, with lower intrapatient variability and improved dose linearity with
      drug exposure as measured by area under the concentration-time curve (AUC). These
      advantages translated into more reliable CsA predose concentrations and less
      toxicity. An analysis of the pharmacokinetic data showed that 2-hour postdose CsA
      levels (C2) provided a better measure of immune suppression than did trough
      levels (C0). The LIS2T study recently confirmed and extended these data by
      showing equivalent efficacy between CsA-ME using C2 monitoring or tacrolimus in
      liver transplant patients, with a similar incidence of adverse events except for
      a higher rate of diabetes mellitus and diarrhea with tacrolimus. These data
      confirmed that the improved CsA-ME formulation, when used in conjunction with
      optimized drug-monitoring protocols, is well tolerated after transplantation and
      provides low rates of graft rejection.

PMID- 15041355
TI  - Impact of cyclosporine on the development of immunosuppressive therapy in liver
      transplantation.
AB  - Over the last 20 years, immunosuppression protocols in liver transplant patients
      have been based on calcineurin inhibitors, such as cyclosporine (CsA). Currently,
      there are three outstanding clinical issues related to the use of CsA in the
      liver transplant setting that merit further attention: (1) dose adjustment
      according to 2-hour postdose (instead of trough) concentrations to improve
      efficacy and safety, (2) possible synergistic effect between CsA and antiviral
      treatments for recurrent posttransplant hepatitis C infection, and (3)
      preliminary results showing favorable outcomes after liver transplantation in HIV
      positive patients receiving antiviral therapy.

PMID- 15041356
TI  - The impact of cyclosporine on the development of immunosuppressive therapy for
      pediatric liver transplantation.
AB  - Since the introduction of cyclosporine into pediatric liver transplantation
      remarkable progress in patient and graft survival has been observed: survival
      rates 60%; acute (60%), steroid-resistant (22%) and chronic rejection (4%);
      infections (60%); and side effects (20%). Individualization of cyclosporine
      therapy complements the development of new immunosuppressive agents such as
      tacrolimus, mycophenolate mofetil, and sirolimus for specific indications. The
      ultimate goal of transplantation to achieve immunotolerance a waits future
      progress.

PMID- 15041357
TI  - Conversion from tacrolimus to cyclosporine microemulsion therapy in liver
      transplant recipients.
AB  - The calcineurin inhibitors cyclosporine and tacrolimus have distinct advantages
      and drawbacks. Therefore it is important to tailor their use to the patient's
      tolerance. In some patients, the need to ameliorate the adverse effects of
      tacrolimus may necessitate a switch to cyclosporine-based therapy. Rescue therapy
      with a cyclosporine microemulsion (Neoral)-based regimen for transplant patients
      intolerant of tacrolimus has been evaluated to assess the best method of
      switching and determine the initial and maintenance doses of Neoral in children
      and adults. Our aims were to evaluate not only these facets, but also the
      pharmacokinetics of Neoral in stable patients, including target 2-hour postdose
      blood concentrations (C2) of cyclosporine in liver transplant recipients.
      Eighteen liver transplant patients switched from tacrolimus to Neoral underwent a
      program of cyclosporine blood level monitoring. The conversions were conducted
      safely; the incidence of acute rejection episodes was low (11.1%). Statistical
      analysis showed that the C2 correlated with the area under the time-blood
      concentration curve of cyclosporine for 0 to 4 hours after dosing (R=0.970). We
      determined the maintenance doses of Neoral for pediatric and adult patients as
      well as the feasibility of C2 quantitated monitoring in liver transplantation.

PMID- 15041358
TI  - Cyclosporine in thoracic organ transplantation.
AB  - The discovery of cyclosporine proved to be a breakthrough that helped transform
      the status of both heart and lung transplantation from experimental to
      established therapeutic procedures. Cyclosporine inhibits the early phase of T
      cell activation and thus of the alloimmune response. It proved to be highly
      effective in prophylaxis against acute rejection but its use has been limited by
      dose-related renal toxicity. Consequently, it has generally been used in regimens
      that combine it with other immunosuppressive agents with the aim of preventing
      acute rejection while minimising toxicity. For many years 'triple therapy' using
      cyclosporine, azathioprine and corticosteroids was the most commonly used regimen
      for both heart and lung transplantation. Other agents have now become available
      that provide more effective prophylaxis against acute rejection than
      azathioprine; these include, mycophenolate and the TOR inhibitors sirolimus and
      everolimus. Everolimus has also been shown to inhibit the early phase of cardiac
      allograft vasculopathy. Unfortunately, the TOR inhibitors also potentiate the
      nephrotoxicity of cyclosporine. Both mycophenolate and the TOR inhibitors are
      subject to pharmacokinetic interactions with cyclosporine. We are now entering a
      new phase of clinical immunosuppression where we need to learn how to best
      combine the agents that are currently available to provide the safest and most
      effective immunosuppression for patients undergoing heart or lung
      transplantation.

PMID- 15041360
TI  - Experience with cyclosporine: from revolution to evolution of immunosuppressive
      protocols in thoracic organ transplantation.
AB  - The introduction of cyclosporine into clinical practice of thoracic organ
      transplantation had a dramatic and positive effect on both short- and long-term
      survival. Today, the majority of patients are still treated with this drug, and
      different immunosuppressive combination therapies have further resulted in
      improved long-term survival. Such combinations to calcineurin inhibitors include
      prednisolone, mycophenolate mofetil, azathioprine, and Rapamycin. Based on data
      from our own institution 1- and 5-year survival rates of 86% and 78% can be
      obtained after heart transplantation and 76% and 59% after lung transplantation.
      Causes of death are described. Future immunosuppressive strategies will have to
      concentrate further on the omission of organ-damaging side effects. Also, not a
      single compound or combination for immunosuppression after thoracic organ
      transplantation has proved to be effective in cases with chronic rejection (eg,
      transplant vasculopathy in heart transplantation and bronchiolitis obliterans in
      lung transplantation). Moreover, with current survival data in mind, quality of
      life has to be considered a major focus for future designs of immunosuppressive
      protocols.

PMID- 15041361
TI  - Use of cyclosporine in lung transplantation.
AB  - Prior to the cyclosporine (CsA) era, there were no long-term survivors from lung
      transplantation as the immunosuppressive drugs made patients very susceptible to
      opportunistic infections and anastomotic complications. CsA is a calcineurin
      inhibitor that binds to cyclophilins and inhibits transcription of interleukin 2
      in T cells, thereby preventing proliferation of activated T cells. The initial
      immunosuppressive regimen at our institution includes CsA, azathioprine, and
      steroids. Blood levels of CsA (whole blood, TDx assay) are maintained between 250
      and 350 ng/mL for 0 to 6 months, 200 to 300 ng/mL for 6 to 12 months, and around
      200 ng/mL beyond 12 months following lung transplantation. Nephrotoxicity,
      hypertension, susceptibility to infections, and malignancy are some of the
      serious side effects of CsA that limit its therapeutic usefulness. Acute
      rejection is relatively common with this regimen, and about 60% of all lung
      transplant recipients are treated for an episode of acute rejection within the
      first 12 months after lung transplantation. Acute rejection is a probable risk
      factor for chronic rejection, and obliterative bronchiolitis develops in about
      50% of the patients who survive 5 years. Treatment of chronic rejection continues
      to be a challenge in lung transplantation. CsA and tacrolimus seem to have
      equivalent results in lung transplantation, although a few patients may benefit
      from the use of tacrolimus.

PMID- 15041362
TI  - Cardiac transplant experience with cyclosporine.
AB  - The advent of cyclosporine 20 years ago was a major advance in the field of solid
      organ transplantation. Its use enabled directed immunosuppression with a
      consequent decrease in the incidence of graft failure, acute rejection, and
      systemic infection. The early oil-based preparation, however, was difficult to
      administer and had limited bioavailability and unpredictable pharmacokinetics.
      The drug also has a fairly narrow therapeutic window with major long-term side
      effects, which include nephrotoxicity, malignancy, hyperlipidemia, and
      hypertension. The introduction of a microemulsion preparation (Neoral) with
      improved bioavailability has been associated with lower rates of rejection and
      comparable tolerability, therefore allowing the use of lower doses. Traditionally
      cyclosporine toxicity has been minimized by monitoring trough levels. Monitoring
      of levels 2 hours after dosing may provide a more accurate determination of
      cyclosporine exposure. The next phase in cardiac transplantation
      immunosuppression will most likely see a significantly diminished role for
      cyclosporine with the introduction of newer, more potent immunosuppressive agents
      with more favorable side-effect profiles. These agents, which include
      mycophenolate mofetil, sirolimus, and everolimus, also hold the promise of having
      a major impact on the development of transplant vasculopathy, which up to now has
      been an important determinant of limiting long-term allograft survival.

PMID- 15041359
TI  - Immunosuppression for cardiac transplantation--the past, present and future.
AB  - The field of cardiac transplant immunosuppression is rapidly developing and has
      evolved over the past 35 years. Anecdote, experience and registry based practice
      is giving way to an increasing bounty of well designed, randomized controlled
      trials which will guide future therapy. Current therapy is based on triple
      therapy with corticosteroids, a calcineurin inhibitor and an antimetabolite, but
      these regimens may be replaced by substitution or addition of newer
      antiproliferative agents. The true nemesis is coronary graft vasculopathy, which
      affects 50% of patients at 5 years and until recently had very few preventive
      therapeutic options. Renal toxicity remains among the most challenging adverse
      effects of immunosuppression to be overcome.

PMID- 15041363
TI  - Use of cyclosporine in thoracic transplantation.
AB  - The use of cyclosporine (CyA) in clinical thoracic transplantation has markedly
      improved the survival and quality of life of patients in the past 2 decades. In
      the mid-1990s a significant advance in formulation design took place with the
      introduction of Neoral. This new microemulsion formulation of CyA demonstrates
      reduced intersubject and intrasubject variability in absorption and improved oral
      bioavailability compared with the oil-based CyA formulation. Moreover, C2
      measurements of CyA could result in an even better method to avoid
      overimmunosuppression. On the other hand, generic alternatives of CyA could
      potentially reduce costs to transplant recipients as well as to the general
      community. Since the initiation of tacrolimus, mycophenolate mofetil, and
      rapamycin, slow but expanding variations of immunosuppressive protocols have
      taken place. Transplantation medicine is thus becoming an increasingly exciting
      and innovative field, in which CyA continues to play a central role as the core
      immunosuppressant of choice for the majority of patients.

PMID- 15041364
TI  - Impact of cyclosporine on cardiac transplantation in Berlin.

PMID- 15041365
TI  - Experience with cyclosporine in heart transplantation.
AB  - The introduction of cyclosporine as an immunosuppressant in early 1980s
      dramatically improved the outcome of organ transplantation. The adverse effects
      of nephrotoxicity and increased incidence of lymphomas were recognized with high
      doses of cyclosporine during the early part of that decade. This led to lower
      doses of cyclosporine and combination with prednisolone and azathioprine as the
      basis of immunosuppression in transplantation. During the second half of the
      1990s, the microemulsion formulation of cyclosporine was introduced that gave
      superior and predictable drug absorption profiles. Therapeutic drug monitoring is
      considered as a tool to optimize transplantation results and minimize side
      effects. The nephrotoxicity associated with long-term cyclosporine therapy is
      recognized; we are learning to take measures to minimize it. As we enter the
      third decade of cyclosporine use, cyclosporine-based immunosuppressive protocols
      remain the most popular method in heart transplantation. Newer agents in
      combination with cyclosporine as the core immunosuppressant are being explored.

PMID- 15041366
TI  - Experience with cyclosporine in living-donor lobar lung transplantation.
AB  - Living-donor lobar lung transplantation is an alternative to conventional
      cadaveric lung transplantation for both pediatric and adult patients. In 16
      patients, postoperative immunosuppression included cyclosporine, azathioprine,
      and corticosteroids. Cyclosporine delivery began during the first few
      postoperative hours via a nasal feeding tube inserted to the proximal jejunum.
      The dosage was adjusted to maintain trough levels in the target range of 250 to
      350 ng/dL during the first 3 months; however, it was often reduced when renal
      dysfunction was suspected. We judged acute rejection on the basis of radiographic
      and clinical findings without lung biopsy. During the first month, 15 of 16
      patients experienced at least one episode of acute rejection with an average of
      1.7 episodes/patient. Cyclosporine was switched to tacrolimus in four patients
      (25%) due to repeated episodes of acute rejection. No patients experienced
      infectious complications during the first months. All 16 patients are currently
      alive with a follow-up period of 3 to 59 months. Three patients (19%) have
      developed unilateral bronchiolitis obliterans. Cyclosporine-based
      immunosuppression can be safely given to the recipients of LDLLT without
      significant adverse effects but the incidence of acute rejection is relatively
      high. The optimal long-term immunosuppressive regimen remains to be established.

PMID- 15041367
TI  - The use of cyclosporine in renal and pancreas transplantation.
AB  - Pancreas transplantation started in December 1966 at the University of Minnesota
      but the number of transplants eventually increased in the early 1980s for two
      main reasons: the refinement in surgical techniques and the advent of
      cyclosporine. In that period, we moved from segmental grafts (duct injection,
      open-duct, pancreaticojejunostomy on a Roux-en-Y loop) to whole
      pancreaticoduodenal transplants with bladder and enteric drainage of the exocrine
      secretion. Despite its toxic effect at high dosage, cyclosporine was the basic
      immunosuppressive therapy and helped to develop the principle of the combination
      therapy as well as the pancreas transplantation field. Today, simultaneous
      pancreas and kidney transplantation is the gold standard procedure for end-stage
      type 1 diabetic nephropathy recipients.

PMID- 15041369
TI  - Immunosuppression for pancreatic islet transplantation.
AB  - Protocols for islet transplantation have to take into account the
      diabetogenicity/islet toxicity of the immunosuppressive agents, namely
      corticosteroids and calcineurin inhibitors, most notably tacrolimus. The
      development by the Edmonton group of a sirolimus-based, steroid-free, low
      tacrolimus regimen was a significant breakthrough that allowed the rate of
      insulin independence after islet transplantation to increase from 13% to 80% at 1
      year. Drawbacks include the side effects of sirolimus and the reduction in
      insulin independence to 50% at 3 years, the latter being attributed to prolonged
      tacrolimus exposure. Currently explored alternatives to tacrolimus include
      cyclosporine, mycophenolate mofetil, and the novel agent FTY 720. Perspectives
      for the near future involve the achievement of "prope tolerance" by strategies
      using lymphocyte-depleting antibodies (anti-thymocyte globulin, campath-1H,
      hOKT3gamma1 [ala,ala]), or costimulatory blockade (anti-CD154 mAbs, CTLA4-Ig).

PMID- 15041368
TI  - Pancreas-kidney transplantation in Japan: impact of cyclosporine on the
      development of immunosuppressive therapy.
AB  - The number of pancreas transplants reached 16,043 worldwide in October 2001, with
      1800 performed in 2000. Since the introduction of cyclosporine (CyA) in 1979, a
      regimen consisting of CyA, azathioprine, and steroids has been shown to improve
      long-term survival of clinical transplants. In Japan, the first simultaneous
      pancreas-kidney transplantation was performed in 1984, using organs from a brain
      dead donor. This procedure was followed by 14 pancreas transplantations from
      cardiac arrest donors. All cases utilized a CyA-based regimen with antilymphocyte
      globulin or OKT3 induction. Six of the 15 recipients required less insulin
      postoperatively. Under a new transplant law enforced in 1997, 10
      pancreas/pancreas-kidney transplantations were performed in patients diagnosed
      with end-stage renal failure due to diabetes mellitus type 1. In 1 patient, the
      graft failed due to venous thrombosis, but the other 9 recipients achieved an
      increased quality of life without the need for insulin or for dialysis. Pancreas
      transplantation represents an effective treatment worldwide and in Japan, due to
      the availability of CyA or tacrolimus in combination with other agents such as
      antilymphocyte globulin, OKT3, or mycophenolate mofetil. This investigation
      presents the results of pancreas-kidney transplantation in Japan, in comparison
      with those worldwide, and describes a recent case in Japan.

PMID- 15041370
TI  - Use of cyclosporine in hematopoietic cell transplantation.
AB  - Early attempts to perform successful allogeneic hematopoietic stem cell
      transplants were plagued by graft rejection and graft-versus-host disease,
      leading many investigators to lose hope that bone marrow transplantation could
      ever become a useful therapeutic approach in clinical medicine. Although many
      subsequent discoveries contributed to the successful transformation of this area
      of research into lifesaving therapy, there can be no doubt that the discovery of
      cyclosporine (CsA) constituted one of the major advances. Even today, more than
      25 years after the first description of its use in humans, CsA remains one of the
      cornerstones of therapy for the majority of patients undergoing allogeneic
      hematopoietic cell transplantation (HCT). In this review we will recount the
      events that have established CsA as a foundation of HCT.

PMID- 15041371
TI  - Experience with cyclosporine in endogenous uveitis posterior.
AB  - Treatment with cyclosporine (CsA) has considerably improved the visual prognosis
      of patients suffering from endogenous posterior uveitis (EPU). However, the
      therapeutic benefits of CsA are partially outweighed by its many side effects,
      most notably nephrotoxicity and hypertension. Low-dose CsA regimens have reduced
      toxicity but have not been able to completely eliminate this problem. New
      therapeutic approaches, such as anti-tumor necrosis factor alpha treatment or
      immunosuppression with drugs including tacrolimus, sirolimus, and interleukin-2
      receptor antibodies, are currently under evaluation. Hopefully such strategies
      will further reduce the morbidity of EPU and minimize the adverse effects
      associated with conventional therapies.

PMID- 15041372
TI  - Therapeutic drug monitoring of cyclosporine: 20 years of progress.
AB  - Since its introduction 20 years ago, cyclosporine (CyA), a powerful
      immunosuppressant with a narrow therapeutic window, remains the cornerstone of
      many drug regimens in renal transplantation. However, attempts to balance its
      therapeutic value with its pleiotropic side effects continue to challenge
      clinicians. To address the wide intraindividual and interindividual differences
      in absorption, distribution, metabolism, and elimination of the oil-based
      formulation of CyA (Sandimmune), a microemulsion (Neoral) was introduced; it
      displayed better absorption and lower intraindividual variability. Neoral also
      improves the utility of therapeutic monitoring of CyA to estimate exposure to the
      drug and predict patient outcomes. Drug monitoring techniques are undergoing
      continual refinement: today, a limited sampling strategy--C2 monitoring--shows
      great promise as a comparatively simple, safe, and effective method to optimize
      patient outcomes during both short-term and maintenance CyA therapy. However, it
      is not clear whether this method is useful for treatment optimization with
      generic formulations of CyA. Although generic substitutes meet federal
      bioequivalence criteria, they may not display the same pharmacokinetic
      properties. Further, preliminary data have shown a 10% lower 1-year graft
      survival rate among patients treated with generic versus Neoral CyA. Current
      challenges in optimizing CyA therapy include determining pretransplant patient
      characteristics relevant to selection of the appropriate exposure or the
      development of a Bayesian forecasting technique that predicts dose adjustments
      necessary to achieve the optimal drug regimen during the critical period
      immediately posttransplant.

PMID- 15041373
TI  - Neoral C2 monitoring in solid organ transplantation.

PMID- 15041374
TI  - Therapeutic drug monitoring of cyclosporine.
AB  - The introduction of cyclosporine into clinical practice improved transplant
      outcome. However, the use of cyclosporine is not without problems. A narrow
      therapeutic index (the drug causes irreversible kidney damage when given in too
      high a dose) coupled with variable absorption and unpredictable pharmacokinetics
      has resulted in the need to measure cyclosporine blood concentrations to enable
      the dose of the drug to be individualised to the patient. When this is done
      correctly therapeutic efficacy can be maximised while toxicity is kept to a
      minimum. The evolution of cyclosporine dose optimisation started with the
      adjustment of empirical fixed doses by clinical "judgement;" progressed to
      therapeutic drug monitoring of trough, predose, C0 concentration with non
      specific assays that measured parent drug and metabolite; then on to "specific"
      cyclosporine C0 measurements; through area under curve monitoring using full
      profile measurements and limited sampling scheme procedures; and finally ending
      up with absorption profiling that targets AUC in the first 4 hours or the 2 hour
      blood cyclosporine concentration, C2. At the same time the formulation of
      cyclosporine has changed from Sandimmune to Neoral and now generic forms of the
      latter are available. The evidence base supporting C2 monitoring continues to
      grow and the technique will need to be customised as new combination therapies
      emerge. Therapeutic drug monitoring of cyclosporine may also need to be tailored
      to avoid the potential negative impact of switching patients to generic forms of
      the drug.

PMID- 15041375
TI  - Pharmacologic monitoring and outcomes of cyclosporine.
AB  - Cyclosporine was introduced into clinical transplantation as an immunosuppressive
      agent 20 years ago. Cyclosporine is a critical dose drug with a narrow
      therapeutic index and requires monitoring through blood levels to avoid rejection
      through underexposure or toxicity through overexposure. Traditional monitoring
      was by measuring the trough level taken 12 hours after an oral dose, but the
      results correlated poorly with drug dose, toxicity, and outcome. Monitoring
      cyclosporine by calculating total drug exposure correlated better with outcome
      but was time consuming and labour intensive. An abbreviated measure of exposure
      over the first 4 hours after administration was found to predict outcome and
      allow dose adjustment. This was based on the observation that the majority of
      variability in the absorption of the drug was during the first 4 hours after
      administration--the absorption phase--and this was not reflected in the trough
      level. Cyclosporine exerts its immunosuppressive action by inhibition of
      calcineurin. The peak of this inhibition occurs during the peak concentration of
      the drug, which occurs during the absorption phase. On the basis of the fact that
      as a single time point the 2-hour level was the best surrogate marker of the
      maximum level, a strategy for monitoring by 2-hour levels (C2) evolved. It was
      shown in all organ types to be the best single point predictor of exposure and
      has led to an improvement in outcome both in de novo and in maintenance
      transplant patients.

PMID- 15041376
TI  - The impact of cyclosporine on the development of immunosuppressive therapy:
      perspective from a transplant nephrologist involved with the development of C2.
AB  - The availability of Neoral in place of Sandimmun offered better pharmacokinetics
      and improved results but emphasized the poor accuracy of trough levels as a tool
      for monitoring drug exposure and dosage adjustment. Subsequent studies confirmed
      that Neoral exposure correlated with clinical events and it was found that C2 was
      the single point that correlated best with exposure as determined by AUC(0-4h).
      Single and multicenter studies have now shown that C2 monitoring is practically
      feasible and that its use resulted in very low rates of acute rejection with
      excellent renal function. One retrospective comparison suggested that rates of
      acute rejection were lower with C2 than with C0 monitoring. This tool has now
      been shown to be effective in managing African-American renal transplants and
      those with delayed graft function. A very recent international randomized trial
      has shown equivalent rates of acute rejection in liver transplant recipients
      treated with both Neoral and Prograf. Studies now in progress will permit further
      refinement of target levels with the potential to improve long-term results.

PMID- 15041378
TI  - Evolution of the therapeutic drug monitoring of cyclosporine.
AB  - The argument for the therapeutic monitoring of cyclosporin A (TDM-CyA), to
      optimize efficacy and safety, has been discussed in the last 25 years and it is
      still debated. Although CyA has been for more than 20 years the mainstay of
      immunosuppression in organ transplantation, no consensus has yet been achieved on
      TDM-CyA. The first proposed use of CyA was at fixed doses, but this was soon
      abandoned, and the predose, trough C0 blood level concept was introduced as a
      tool for TDM-CyA; however, no correlation could ever be shown between the various
      proposed trough therapeutic windows and major clinical events. On the contrary,
      the TDM-CyA of full area-under-the-curve (AUC) 0-12 exposure, significantly
      correlated with acute rejection and renal toxicity. The use of Neoral
      demonstrated that the region of most variability in CyA pharmacokinetics and the
      greatest calcineurin inhibition were confined within the AUC0-4, introducing the
      concept of absorption profiling. A further simplification come from the
      demonstration that C2, the single blood concentration measurement 2 hours after
      Neoral administration, was a significant accurate predictor of AUC0-4. The TDM
      CyA with C2 has now been clinically validated in kidney, liver, and heart
      transplant recipients. In the last 25 years of TDM-CyA, some concepts have become
      clear: inadequate CyA exposure is a key risk factor for acute rejection and may
      contribute to the development of chronic rejection; C0 predose monitoring does
      not accurately measure CyA exposure. Thus, C2 single sampling offers today an
      innovative, simple, and accurate alternative for the pharmacokinetic clinical
      monitoring of CyA.

PMID- 15041377
TI  - Therapeutic monitoring of cyclosporine in kidney transplantation: the Halifax
      experience.
AB  - Appropriate dosing of an immunosuppressive agent is critical to its efficacy and
      tolerability. Finding a simple and effective method of monitoring cyclosporine
      (CsA/CyA) has been formidable despite a long history of widespread usage. Earlier
      reports linked CsA dosing to trough levels (C0), whereas later more elaborate
      systems have evaluated efficacy linked to 12-hour area-under-the-curve (AUC(0
      12)) as a measure of total drug exposure. Recent work done at our center and
      elsewhere has shown that the 2-hour postdose concentration (C2) to be simple and
      more effective than the C0 or the AUC. With C2 monitoring as a guide to CsA
      dosing, acute rejection (AR) and nephrotoxicity (NT) can be effectively reduced.
      Furthermore, absorption profile as per C2 levels further emphasizes the
      importance of achieving the targeted peak concentration in the first week of
      transplantation. The C2 concentration strategy is discussed in light of newer
      induction agents and other immunosuppression.

PMID- 15041379
TI  - Experience with therapeutic drug monitoring of cyclosporine.
AB  - During the past 20 years, cyclosporine (CsA) has become the main part of
      immunosuppressive protocols. Its impact to improve the quality and quantity of
      transplantation surgery has been enormous. Immunosuppression in allograft
      recipients 10 years after renal transplantation CsA continued to demonstrate
      benefits on graft survival without evidence of long-term morbidity. The
      pharmacokinetic properties of CsA show wide interpatient variation. After being
      subject of intense investigation for more than 20 years, it only recently has the
      full potential of the drug been realized, primarily due to two advances: first,
      the development of a microemulsified formulation, (Neoral), that improves drug
      delivery; second, substantial improvements in CsA monitoring. Sparse-sampling
      algorithms were developed specifically to predict AUCs. We prospectively
      investigated the practicality, intrapatient variability, and impact on the
      outcomes of toxicity and rejection episodes using an algorithm. Rejection
      episodes were diminished by 43.5% in the first 3 months compared to the results
      in the previous 3 years. Furthermore, the relation of the trough versus C2
      concentrations performed at day 3 to 5 and 10 to 12 predicted the probability of
      an acute rejection episode. Using a truncated AUC to identify patients at risk
      for rejection episodes early provides optimal and individualized
      immunosuppression. This pharmacokinetic rationale has now eventuated in an
      international consensus statement that represents a further step toward optimal
      immunosuppression.

PMID- 15041380
TI  - Therapeutic drug monitoring of cyclosporine.
AB  - Therapeutic drug monitoring of cyclosporine has been established as part of the
      routine clinical treatment for patients after organ transplantation. The
      inability to define optimal dose (maximize efficacy/minimize toxicity) has been a
      problem related to drug monitoring of cyclosporine. The original cyclosporine
      formula showed high intra-patient and inter-patient variability and low
      bioavailability. The microemulsion formulation of cyclosporine (Neoral) was
      introduced to address the absorption problems related to the original
      cyclosporine formulation. With the introduction of Neoral, renewed interest in
      methods of therapeutic drug monitoring brought us from trough monitoring (C0) to
      levels measured 2 hours after dosing (C2). The pharmacokinetic rationale for
      using C2 to monitor patients receiving Neoral has demonstrated a reduced
      incidence of rejection in de novo patients and improvements in safety profile in
      both renal and hepatic transplant recipients. Monitoring C2 levels is a more
      precise method for optimizing cyclosporine dosing and a better way to
      individualize therapy. Further data are required from prospective trials to
      evaluate the clinical benefits of adopting C2 monitoring in cardiac and lung
      transplant recipients as well as in long-term maintenance patients.

PMID- 15041381
TI  - Experience with cyclosporine: approaching the therapeutic window for C2 levels in
      maintenance kidney transplant recipients.
AB  - This study was aimed to evaluate the clinical benefit of C2 monitoring in 191
      stable renal transplant patients previously monitored by C0. All patients had
      been transplanted for at least 1 year and received cyclosporine (CsA)-based
      immunosuppression since the start. At the inceptions C0 levels were significantly
      correlated with C2 values (P<.0001). Patients with starting C2 levels >1000 ng/mL
      showed significantly higher levels of serum creatinine (sCr) both at inception
      (1.66 +/- 0.50 vs 1.44 +/- 0.41 mg/dL; P=.0021) and at the end of a 2-year follow
      up (1.84 +/- 0.80 vs 1.46 +/- 0.51 mg/dL; P=.005). C2 monitoring revealed that a
      high percentage of patients were overexposed to CsA, mainly in the subgroup with
      most recent renal engraftments (12 to 24 months). The switch to C2 monitoring was
      associated with a slower deterioration of graft function (P=.02). Further, the
      mean values of C2 over a 2-year follow-up were inversely correlated with sCr at
      the end of follow-up (P=.0005). Finally, patients with mean threshold C2 levels
      above 720 ng/mL, roughly corresponding to the median value of C2, showed
      significantly lower levels of sCr at the end of follow-up (P=.0004). In
      conclusion, C2 monitoring of maintenance renal transplant patients allows one to
      identify a significant percentage of overexposed subjects, possibly limiting the
      rate of progression of chronic graft dysfunction. Target range values between 700
      and 900 ng/mL appear to be associated with better long-term kidney graft
      function.

PMID- 15041382
TI  - New concepts in cyclosporine pharmacokinetic and dynamic monitoring: the impact
      of concomitant immunosuppression on target C2 concentrations.
AB  - BACKGROUND: There is a correlation between cyclosporine (CsA) pharmacokinetics
      (PK) and pharmacodynamics (PD), especially 2 hours after drug administration.
      AIM: To evaluate the relationship between CsA PK and PD profiles in two groups of
      stable renal transplant patients treated with CsA alone or CsA plus mycophenolate
      mofetil (CsA+MMF), so as to define the best target for C2 and clarify the impact
      of concomitant immunosuppression. METHODS: Thirty-eight stable renal transplant
      recipients were treated with CsA (n=20) or CsA+MMF (n=18). Twelve nontreated
      normal healthy controls (NHC) were also included. Calcineurin activity (CNa), IL
      2 production, and CsA levels were measured at 0 and 2 hours postdose. RESULTS:
      There were no significant differences in median CsA C2 values and CNa between the
      CsA alone and the CsA+MMF groups (388 microg/L and 497.5 microg/L and CNa 2h;
      3.92% alkaline phosphatase [AP]; 3.94% AP, respectively). In vitro production of
      IL-2 was significantly lower in the CsA+MMF group than in the CsA group (median
      IL-2 2h: 280.52 ng/L, 169.48 ng/L, P<.001). The correlations (r) between C2 and
      CNa 2h were: CsA r=0.74; CsA+MMF r=0.84 (P<.001 in both cases). CONCLUSIONS: In
      stable renal transplant patients, median CsA C2 values below 500 microg/L were
      associated with inhibition of CNa and IL-2 synthesis. CNa and IL-2 production may
      be good biological markers of CsA immunosuppression. The measurement of CNa
      depends mainly on CsA concentration, whereas in vitro IL-2 production reflects
      the effect of both CsA and MMF. Further studies are necessary to define the
      optimal C2 target concentration and the possible impact of concomitant
      immunosuppression.

PMID- 15041383
TI  - History of C2 monitoring in heart and liver transplant patients treated with
      cyclosporine microemulsion.
AB  - Therapeutic drug monitoring of CsA has evolved since the introduction of CsA
      microemulsion. The purpose of the present review is to summarize the history of
      CsA concentration 2 hours postdose (C2) monitoring in heart and liver
      transplantation. C2 has been shown to be the best single time point that
      correlates with the area-under-the-curve, with a correlation coefficient (r2)
      ranging between .83 and.93. C2 monitoring (300 to 600 ng/mL) has resulted in a
      significant clinical benefit in long-term heart and liver transplant patients
      compared to trough level (C0) monitoring. Moreover, a C2 range of 300 to 600
      ng/mL resulted in a similar calcineurin inhibition compared to a C2 range of 700
      to 1000 ng/mL or a C0 range of 100 to 200 ng/mL while being less injurious to
      renal function. In de novo liver transplant patients not receiving induction
      therapy, the achievement of a target C2 of 850 to 1400 ng/mL by postoperative day
      3 has resulted in a low acute rejection rate. Furthermore, C2 monitoring has been
      associated with a lower rejection rate in hepatitis C virus (HCV)-negative
      patients and with an overall lesser severity of acute rejection compared to C0
      monitoring. In de novo heart transplant patients who receive antithymocyte
      globulin induction, a lower C2 range may be sufficient to prevent rejection and
      renal dysfunction. Future studies should help to fine-tune the optimal C2 range
      in heart or liver transplant patients receiving induction therapy and different
      maintenance immunosuppressive combinations.

PMID- 15041385
TI  - Impact of C2 measurement on cyclosporine Neoral dosing in a Latin-American
      transplant program: the Guatemalan experience.
AB  - Optimal dosing of cyclosporine is difficult in transplant recipients. The
      introduction of the microemulsion Neoral in 1997 into our program and the
      measurement of C2 levels since 2000 in our center has allowed for more accurate
      individual dose finding. In our series, 141 transplant recipients (92 de novo, 49
      maintenance) were followed for a 3-year period with C2 monitoring and serum
      creatinine levels as well as creatinine clearance studies. Biopsy proven acute
      rejection episodes appeared in three patients. The target levels of C2 during the
      first week were of vital importance to prevent acute rejection. Targets for the
      later periods of our study were somewhat lower than those recommended in North
      American or European studies. Even so, the incidence of acute rejection was low
      (3.2% for the de novo group). We feel that special populations like ours (mostly
      Mayan) deserve more attention regarding the finding of the optimal dose for
      immunosuppressive therapy after kidney transplantation.

PMID- 15041384
TI  - Total cholesterol correlates with cyclosporine C2 levels in kidney transplant
      recipients under maintenance immunosuppression.
AB  - The aim of this study was to assess the relationship between cyclosporine (CyA)
      trough level (C0) and 2-hour postdose (C2) and total cholesterol (TC) in kidney
      transplant (KT) recipients on Neoral maintenance immunosuppression. In KT
      recipients who had more than 5 years of follow-up, stable graft function, and
      stable Neoral dose, we measured C2 and C0 blood levels, serum creatinine, mean
      total cholesterol (TC) over the last 5 years, prednisone dose, use of beta
      blockers and thiazides. Correlations between C0 and C2 levels and TC were
      performed with the Pearson coefficient. Receiver operating characteristics (ROCs)
      were used to define the threshold with greater accuracy for significant variables
      at the correlation test. Statistical tests were performed with SPSS 9.5 The C2
      correlated with TC (0.31; P=.008) whereas C0 did not. The C2 level was an
      independent predictor for TC after adjusting for recipient age, gender, dose of
      prednisone, creatinine clearance, and use of beta-blockers and thiazides (B
      coefficient=1.124(E-3); P=.009). A threshold C2 value of 700 microg/L yielded to
      a TC level of 5.2 mmol/L. This is the first study to report a correlation between
      C2 levels and TC. Although C2 explained a small fraction of TC variability, it is
      an independent predictor of TC in KT recipients on Neoral maintenance
      immunosuppression. A long-term C2 value under 700 microg correlates with better
      control of hypercholesterolemia.

PMID- 15041386
TI  - Follow-up study of renal transplant recipients treated at the Guatemalan Social
      Security Hospital.
AB  - Guatemala is Central America's westernmost country, with a ratio of 500,000
      inhabitants per nephrologist. Yearly reports show an average of 150 new end-stage
      renal disease patients and 40 renal transplants, which are performed at two
      public health care facilities. The aim of this study was to describe the results
      of the transplant program at one of these centers (Social Security Hospital of
      Guatemala). Our program began in 1986, performing an average of 17 transplants
      per year. Cyclosporine has been used since 1992, and since 2001, C2 has been
      routinely monitored. Data on 255 patients (of 293) were available for analysis.
      Male-to-female ratio was 7:1, with 94% having received hemodialysis as their
      replacement therapy. The mean age at transplant was 35 years and living related
      donors used in 95%. The average duration of follow-up was 7 years. The mean
      creatinine and C2 level at most recent visit were 1.36 mg/dL and 864 ng/mL,
      respectively. A significant reduction in the incidence of acute rejection
      episodes was seen after the initiation of C2 monitoring (3% vs 1.2%). In general,
      these results are similar to data in other countries. The number of transplants
      performed must be increased to meet the current demand, and the cadaveric source
      of donation is the obvious way to do so. C2 monitoring is an example of technical
      improvements directed to optimize available resources.

PMID- 15041387
TI  - Investigation of the pharmacokinetics of cyclosporine in patients following long
      term administration after a kidney transplant: comparison of Neoral and
      Sandimmune.
AB  - A crossover administration of Neoral and Sandimmune was performed in 43 renal
      allograft recipients who had been on cyclosporine maintenance therapy for 2 to 19
      years posttransplant to investigate the pharmacokinetics of cyclosporine.
      Although there was no difference in C0 values (trough values) when Neoral and
      Sandimmune were administered at the same doses, AUC(0-4) and AUC(0-12) values of
      Neoral were 1.57- and 1.36-fold greater than those of Sandimmune, respectively.
      For both Neoral and Sandimmune, there was a high correlation between the C2 value
      and AUC(0-4). The Pearson's product-moment coefficient for the correlation
      between the C2 value and AUC(0-4) was R=0.91642. On the other hand, the
      correlation with the C0 value (trough value) was low (R=0.53181). During the
      period of the study, there was no acute rejection episode, onset of adverse drug
      reaction symptoms, or marked change in laboratory test values.

PMID- 15041388
TI  - Clinical success of Neoral absorption profile.
AB  - We investigated the clinical benefits of cyclosporine microemulsion
      preconcentrate (CyA-MEPC; Neoral) in 16 de novo renal transplant recipients. The
      dose of CyA-MEPC was managed from AUC(0-4h), with serial target values of AUC(0
      4h) at 5000-->4000-->3000-->2000 ng. hr/mL. The frequency of acute rejection
      episodes was 25%. The decreased renal function reached a low value of 12.5%, and
      creatinine was stable. Therefore, setting the target AUC(0-4h) value in the early
      phase at 5000 ng.hr/mL is an effective strategy to prevent acute rejection
      episodes. The single dose of Neoral given immediately after the renal transplant
      was 6 mg/kg (making a daily dose of 12 mg/kg). Thereafter, the dose-normalized
      AUC(0-4h) was set at a constant value to 4 weeks posttransplant. At week 4, the
      single dose was decreased to 4 mg/kg twice daily (a daily dose of 8 mg/kg). From
      these studies a daily dose of 12 mg/kg is suggested to be the appropriate amount
      for the first dose immediately after transplant. The renal biopsy performed at 6
      months posttransplant showed neither cyclosporine-induced renal impairments, nor
      findings of chronic rejection, suggesting that 2000 ng.hr/mL is an appropriate
      target AUC(0-4h) value in the maintenance phase. These results suggest that it is
      possible to set the target value of C2 monitoring in the maintenance phase to a
      value slightly lower than that proposed from other studies.

PMID- 15041389
TI  - Correlation between Neoral 2 hours post-dose levels and histologic findings on
      surveillance biopsies.
AB  - Use of 2-hour postdose (C2) monitoring has been a major step in optimizing
      immunosuppression following kidney transplantation, and extensive data has
      confirmed the superiority of C2 monitoring over the conventional trough
      monitoring (C0) in reducing the occurrence of acute rejection early after
      transplantation. In this retrospective study, we explored the relationship
      between Neoral pharmacokinetic parameters and the presence of subclinical
      rejections (ScRj). In the absence of acute rejection, lower C2 level was
      associated with more frequent episodes of ScRj. C0 monitoring was not predictive
      of AR, ScRj or any combinations thereof. Fast elimination in a subgroup of
      patients is not detected by the C0 and may lead to unnecessary increase of the
      drug dosage and increased risk of rejection.

PMID- 15041390
TI  - Experience with Simulect.

PMID- 15041391
TI  - Simulect induction facilitates Neoral-based steroid-free immunosuppression in
      primary kidney transplant recipients.
AB  - This study compares outcomes of kidney transplantation with two distinct
      induction protocols Basiliximab (Simulect) versus Muromonab (OTK 3) in the
      setting of cyclosporine (Neoral)-based immunosuppression. Postinduction protocols
      included either total prednisone avoidance or prednisone sparing versus standard
      prednisone dosing. Two hundred forty five adult patients receiving kidney
      transplantation between 1995 and 2000 were included in the study. Treatment in
      group 1 was OKT 3 + Neoral + adjunct + standard prednisone; group 2, Simulect +
      Neoral + adjunct + steroid sparing; group 3, Simulect + Neoral + adjunct + no
      prednisone. The demographics between all groups were similar. The mean (+/- SD)
      trough cyclosporine levels at 1 month were 276 +/- 128 versus 291 +/- 180 versus
      398 +/- 365 (P=.020); at 3 months were 261 +/- 120 versus 280 +/- 152 versus 399
      +/- 408 (P=.32); at 12 month were 235 +/- 144 versus 245 +/- 154 versus 234 +/-
      132 (P=.96). Creatinine clearance at 1 month was 59 +/- 24 versus 58 +/- 18
      versus 47 +/- 23 mL/min (P=.004); at 3 months was 66 +/- 28 versus 62 +/- 22
      versus 53 +/- 25 mL/min (P=.007); at 12 months was 68 +/- 38 versus 65 +/- 22
      versus 64 +/- 29 mL/min (P=.556). Serum creatinine at 1 month was 1.8 +/- 0.9
      versus 1.6 +/- 1.2 versus 2.8 +/- 2.21 mg/dL (P=.005); at 3 months was 1.7 +/-
      0.6 versus 1.9 +/- 1.0 versus 2.3 +/- 1.3 mg/dL (P=.007); at 12 months was 1.9 +/
      1.3 versus 2.1 +/- 1.0 versus 2.3 +/- 1.7 mg/dL (P=.179). The incidence of acute
      rejection within 1 year in the respective groups were 28% versus 15% versus 16%.
      Therefore, we conclude that using Simulect in transplant recipients results in
      long-term patient and graft survival similar to those achieved with OKT 3. The
      use of Simulect resulted in significant reduction in clinical rejection incidence
      within the first year regardless of steroid use. Thus, the use of Simulect allows
      complete steroid avoidance in Neoral-based immunosuppression regimen.

PMID- 15041392
TI  - Early steroid withdrawal protocol using basiliximab in kidney transplantation.

PMID- 15041393
TI  - Simulect and HHV-6 in pediatric renal transplantation.
AB  - Herpes virus reactivation is of increasing interest as we aim to decrease
      morbidity and mortality in the pediatric renal transplant population. We
      previously reported increased reactivation of HHV-6 and Epstein Barr virus (EBV)
      with anti-thymocyte globulin/ALG induction therapy. HHV-6 reactivation and de
      novo infection has been monitored in 31 consecutive pediatric renal transplant
      patients receiving antibody induction with Simulect. Human Herpes virus-6 (HHV-6)
      was correlated with EBV reactivation and de novo infection rates, allograft
      function at 1 year, donor source and number, and patient age and gender. One HHV
      6 de novo infection was associated with an early grade II rejection that was
      steroid resistant but ATG/ALG responsive. Sixteen of 31 (54.8%) patients had HHV
      6 reactivation during the first year and eight patients had a prior reactivation
      profile before transplant. Thirteen patients (41.9%) were naive to EBV infection
      prior to transplant with evidence of primary infection in 11 of 13 patients
      between 6 weeks and 1 year posttransplant. EBV reactivation was noted in four
      patients with past immunity to EBV. IgM Ab to EBV or HHV-6 during the first year
      posttransplant did not correlate with risk of rejection during the first year or
      graft function one year posttransplant. The only patient with positive HHV-6 IgM
      Ab in the first posttransplant month was a de novo infection in a 2-year-old boy
      who was naive for HHV-6 at the time of transplant. Simulect appears safe in
      pediatric renal transplant with low risk of HHV-6 or EBV infection in the first 1
      to 2 months posttransplant.

PMID- 15041396
TI  - Experience with everolimus.
AB  - Everolimus is a novel macrolide immunosuppressant that acts as a T-lymphocyte
      proliferation signal inhibitor. Its actions are complementary to and synergistic
      with those of the calcineurin inhibitors. Compared with sirolimus, everolimus has
      unique pharmacokinetic characteristics including greater bioavailability and a
      shorter half-life, allowing more rapid achievement of a steady state. Clinical
      experience to date, largely limited to use in kidney transplant patients
      receiving cyclosporine-based immunosuppression, indicates that administration of
      everolimus is associated with low rates of acute rejection and a tolerable safety
      profile. Recent observations in heart transplant patients suggest that the
      antiproliferative effects of everolimus may prevent allograft vasculopathy.

PMID- 15041394
TI  - Monitoring of T-cell subsets in patients treated with anti-CD 25 antibody.
AB  - Daclizumab and basiliximab, the antibodies to the interleukin-2 receptor (anti-IL
      2R), decrease the incidence of acute rejection in renal transplantation. However,
      prolonged blockade of IL-2 receptor (IL-2R:CD25) may hamper apoptosis of reactive
      T-cell clones and thus may obstruct tolerance induction. We determined the effect
      of varying doses of anti-IL-2R on the number of CD3+CD25+ cells as an index of CD
      25 blockade. The number of CD3+CD25+ cells was determined in four groups of
      induction therapies: no antibody induction; two doses of 50 or 25 mg daclizumab
      on day 0 and day 14; and two doses of 20 mg basiliximab at day 0 and day 4 (n=10,
      24, 10, and 10, respectively). The number of CD3+CD25+ cells were monitored in
      whole blood before antibody infusion as well as 24 hours thereafter and weekly
      after transplantation. With two doses of 50 mg daclizumab, two doses of 25 mg
      daclizumab, and two doses of 20 mg basiliximab, the expression of CD3+CD25+ cells
      was completely suppressed for 12, 10, and 12 weeks posttransplantation,
      respectively. The reappearance of CD3+CD25+ cells above the baseline for each
      induction regimen was: 17 weeks for two doses of 50 mg daclizumab, 11 weeks for
      two doses of 25 mg daclizumab, and 13 weeks for two doses of 20 mg basiliximab.
      Monitoring of CD3+CD25+ cells may be utilized to tailor anti-IL-2R administration
      at a minimal dosage, yet retaining adequate IL-2R blockade for at least 3 months
      posttransplantation.

PMID- 15041395
TI  - The evolving experience using everolimus in clinical transplantation.
AB  - Everolimus is a derivative of sirolimus, a macrocyclic lactone, originally
      isolated from Streptomyces hygroscopicus. Both everolimus and sirolimus have a
      similar mechanism of action, exerting potent inhibition of growth factor-induced
      proliferation of lymphocytes, as well as other hematopoietic and nonhematopoietic
      cells of mesenchymal origin. Each agent complexes with the FK506 binding protein
      12 to inhibit cyclin dependent kinase(s), collectively termed the target of
      rapamycin (TOR), causing G1-S phase cell cycle arrest. Safety and efficacy have
      been documented in large-scale, blinded, randomized, international clinical renal
      and cardiac transplant trials. Everolimus is more hydrophilic, exhibits a shorter
      elimination half-life (approximately 30 hours), and demonstrates greater relative
      bioavailability compared to sirolimus. However, similar to the calcineurin
      inhibitors and sirolimus, everolimus is biotransformed by the cytochrome P450,
      3A4 isozyme. Also similar to sirolimus, clinical experiences identified
      biologically relevant side effects including hyperlipidemia and exacerbation of
      cyclosporine (CsA)-associated nephrotoxicity. However, also similar to sirolimus,
      accumulating evidence suggests that the hyperlipidemia can be controlled and the
      CsA-associated renal effects appear reduced with a low incidence of acute
      rejection when everolimus is administered in combination with reduced CsA doses.
      The experience using everolimus in cardiac transplantation has also provided
      potentially important insights into the consequences of antiproliferative effects
      on vascular smooth muscle cells and fibroblasts where reduction in intimal
      expansion was identified by intravascular coronary ultrasound examination among
      those patients receiving everolimus. Therefore, available results suggest that
      the introduction of everolimus as the newest TOR inhibitor should enhance
      therapeutic options for immunosuppression after organ transplantation.

PMID- 15041397
TI  - The promise of C2, Simulect, and Certican in heart transplantation.
AB  - Immunosuppressive therapy in clinical transplantation has evolved from general
      nonspecific suppression of the immune system to selective blockade of
      intracellular immune events, maximizing graft tolerance while minimizing
      toxicity. Cyclosporine 2-hour postdose level monitoring has been recommended as
      the single most sensitive sampling point for assessment of the area under the
      curve, and predictor of clinical outcomes in heart transplantation. Strategies
      for monitoring immunosuppressive drugs to improve efficacy without increased
      toxicity are critical as we move into the 21st century. Everolimus, a derivative
      of rapamycin, is a macrocyclic immunosuppressive agent with antiproliferative
      activity that is efficacious in preventing graft vasculopathy. Agents that
      increase the armamentarium against rejection allowing individualized therapy
      tailored to minimize complications, and prevent graft vasculopathy will improve
      our flexibility and may translate into improved long-term outcomes.

PMID- 15041398
TI  - Promise of Neoral C2, basiliximab, and everolimus in lung transplantation.
AB  - Immunosuppressive therapy to prevent rejection of allografts is continually
      evolving in terms of development of new medications and the application of
      established ones. This review summarizes current knowledge regarding monitoring
      blood cyclosporine microemulsion (Neoral) levels 2 hours postdose (C2), as well
      as the relatively new immunosuppressants basiliximab and everolimus, with a
      particular view to lung transplantation. C2 monitoring appears to have merit over
      the traditional method of trough-level monitoring. Based on short-term studies in
      various solid organ transplant systems, C2 seems better able to predict the area
      under the time-concentration curve for Neoral, a benefit that extends to improved
      clinical outcomes. Further studies are needed to verify the robustness of
      clinical improvement, particularly in lung transplant recipients. Basiliximab and
      everolimus target stages of the immune response distinct from that targeted by
      Neoral. Studies conducted to date in various solid organ transplant systems
      suggest that use of Neoral concomitantly with one or both of these drugs provides
      enhanced protection from allograft rejection while improving the tolerability of
      immunosuppressive therapy. If these results are confirmed in lung transplant
      patients, improvements in lung transplantation outcomes are to be expected.

PMID- 15041399
TI  - Enteric-coated mycophenolate sodium: therapeutic equivalence to mycophenolate
      mofetil in de novo renal transplant patients.
AB  - The introduction of mycophenolate mofetil (MMF)--the morpholino ester prodrug of
      mycophenolic acid (MPA)--has improved graft and patient survival, but its use has
      been linked with the occurrence of adverse events, particularly gastrointestinal
      (GI) side effects. These can be sufficiently severe to require dose reductions or
      discontinuation, which may lead to acute rejection episodes or graft failure. An
      enteric-coated formulation delivering mycophenolic acid-enteric-coated
      mycophenolate sodium (EC-MPS)-has been developed with the aim of improving upper
      GI tolerability. Therapeutic equivalence of EC-MPS 720 mg b.i.d. vs MMF 1000 mg
      b.i.d. has been established in a pivotal phase III, 12-month, international,
      randomized, double-blind, parallel group study, involving patients undergoing de
      novo renal transplantation. The incidence of efficacy failure (composite variable
      of biopsy-proven acute rejection [BPAR], graft loss, death or loss to follow-up)
      was similar between the two groups at 6 months (EC-MPS 25.8% vs MMF 26.2%; 95% CI
      [-8.7, +8.0]), demonstrating therapeutic equivalence. Efficacy failure remained
      similar between the two treatment groups at 12 months. The overall incidence of
      adverse events and GI side effects were also comparable between treatment groups
      throughout the 12-month study period, although fewer patients in the EC-MPS group
      experienced study drug discontinuations, interruptions, or dose reductions (12
      months: EC-MPS 15.0% vs MMF 19.5%). Subgroup analysis revealed similar safety
      profiles for EC-MPS and MMF in elderly patients and patients with diabetes at
      baseline. The EC-MPS 720 mg b.i.d. and MMF 1000 mg b.i.d. show therapeutic
      equivalence in de novo renal transplant patients. Therefore, EC-MPS offers
      transplant physicians and their patients an alternative MPA therapy that is as
      effective and safe as MMF.

PMID- 15041400
TI  - Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in
      maintenance renal transplant patients: preliminary results from the myfortic
      prospective multicenter study.
AB  - Mycophenolate mofetil (MMF), in combination with cyclosporine and
      corticosteroids, improves long-term graft survival in renal transplant
      recipients. However, optimal MMF therapy may be limited by gastrointestinal (GI)
      intolerance, which may result in the need for MMF dose reduction, interruption,
      or discontinuation, leading to increased risk of acute rejection. Enteric-coated
      mycophenolate sodium (EC-MPS) is a new formulation delivering mycophenolic acid
      developed with the aim of improving upper GI tolerability. A large prospective,
      open-label, multicenter program (myPROMS: myfortic PROspective Multicenter Study)
      is underway to determine the efficacy and safety of EC-MPS, in combination with
      cyclosporine microemulsion (CsA; Neoral) in a large population of de novo and
      maintenance renal transplant recipients. myPROMS consists of one global protocol
      with 14 subprotocols. Each subprotocol is designed to address further specific
      objectives, such as specific patient populations, steroid regimens, and various
      CsA C2 targets. The preliminary data summarized here are from two subprotocols,
      which investigated the benefits of converting maintenance renal transplant
      patients receiving MMF to EC-MPS. The 3-month interim analyses suggest that the
      conversion from MMF to EC-MPS is well tolerated in maintenance renal transplant
      recipients.

PMID- 15041401
TI  - Enteric-coated mycophenolate sodium: safe conversion from mycophenolate mofetil
      in maintenance renal transplant recipients.
AB  - Mycophenolate mofetil (MMF), in combination with cyclosporine and
      corticosteroids, improves long-term graft function and survival in renal
      transplant recipients. However, optimal MMF therapy may be limited by
      gastrointestinal (GI) intolerance, which may result in the need for MMF dose
      reduction, interruption, or discontinuation, leading to increased risk of acute
      rejection. Enteric-coated mycophenolate sodium (EC-MPS) is an advanced
      formulation delivering mycophenolic acid (MPA), developed with the objective of
      improving MPA-related upper GI adverse events. A pivotal, 12-month, phase III,
      randomized, multicenter, double-blind, double-dummy, parallel group study
      investigated whether stable renal transplant patients can be converted from MMF
      to EC-MPS therapy without compromising tolerability or efficacy. Stable renal
      transplant recipients received either MMF, 1000 mg b.i.d. (n=159), or EC-MPS, 720
      mg b.i.d. (n=163), for 12 months. The incidence of GI adverse events was
      comparable between both treatment groups at 3 and 6 months, but there was a trend
      toward reduced severity of GI side effects in the EC-MPS group. There were fewer
      serious adverse events with EC-MPS and significantly fewer serious infections
      (P<.05). This comparable safety profile for EC-MPS and MMF also extended to
      elderly patients and patients with diabetes at baseline. For the composite
      efficacy variable of biopsy-proven acute rejection, graft loss, death, or loss to
      follow-up, EC-MPS had a lower 12-month efficacy failure rate (EC-MPS: 7.5% vs
      MMF: 12.3%; P=ns). These data demonstrate that stable renal transplant recipients
      receiving MMF can be converted to EC-MPS with no efficacy or tolerability
      compromise.

PMID- 15041402
TI  - FTY720: from bench to bedside.
AB  - FTY720, a synthetic myriocin analogue derived from culture filtrates of Isaria
      sinclairii, is a novel immunosuppressant that in experimental animals and
      nonhuman primates produces lymphocytopenia and prolongs allograft survival in
      dose-dependent fashion. FTY720 exerts synergistic interactions not only with
      calcineurin antagonists, but also with proliferation signal inhibitors. These
      interactions offer the possibility of reducing exposure to and mitigating
      toxicity of existing drugs. The mechanism of drug action is not entirely clear.
      FTY720 appears to undergo phosphorylation by sphingosine phosphokinase 2,
      rendering it capable of interacting with the specific G protein-linked receptors
      for its structural homologue-sphingosine-1-phosphate. However, it is not clear
      how this interaction leads to emigration of lymphocytes from the peripheral blood
      and sequestration in secondary lymphoid structures. Present theories suggest that
      the drug prevents emigration rather than directing the onset of sequestration.
      Thus, the drug is the archetype of a new class of agents that alter lymphocyte
      homing patterns: the adhesion-migration paradigm. These modalities reduce
      interstitial infiltration of grafts and attenuate their release from lymph nodes.
      Since FTY720 seems to spare nonspecific elements of host resistance, it may not
      only represent a useful addition to the immunosuppressive armamentarium but also
      address the not infrequent complications of infections associated with existing
      therapies.

PMID- 15041403
TI  - FTY720: early clinical experience.
AB  - FTY720 is the first in a new class of immunomodulators--sphingosine 1-phosphate
      receptor (S1P-R) agonists. It is highly effective in prolonging allograft
      survival in preclinical models of transplantation. Furthermore, FTY720 acts
      synergistically with calcineurin inhibitors and proliferation inhibitors in these
      models, suggesting that use of FTY720 in combination with classical
      immunosuppressants may be a promising new option for transplant patients. Phase I
      studies conducted in stable renal transplant patients maintained on a
      cyclosporine (CsA)-based regimen have revealed a tolerable profile of FTY720 for
      transplant pharmacotherapy. The pharmacokinetics of FTY720 is characterized by
      linear dose-proportional exposure over a wide range of doses, only moderate
      interpatient variability, and a prolonged elimination half-life (t(1/2) 89 to 157
      hours). These factors suggest that FTY720 can be administered according to a
      simple once-daily schedule, without the need for blood-level monitoring or dose
      titration. The pharmacodynamics of FTY720 in humans are characterized by a
      significant reduction in peripheral blood count by up to 85%. In contrast to the
      nonspecific myelosuppressive effects of other immunosuppressants, this effect of
      FTY720 is specific for lymphocytes, with no effect observed on monocytes or
      granulocytes. In combination with CsA, FTY720 was well tolerated following single
      or multiple dosing, without any evidence of additional toxicities, indicating
      that FTY720 may be useful in the future design of more effective and less toxic
      regimens for prevention of graft rejection.

PMID- 15041404
TI  - FTY720 immunomodulation: optimism for improved transplant regimens.
AB  - FTY720, a sphingosine 1-phosphate receptor (S1P-R) agonist, is the first in a new
      class of immunomodulators. FTY720 has been shown to be highly effective for
      preventing graft rejection in preclinical models of cardiac, renal, and hepatic
      transplantation. To date, phase I single and multiple dosing studies conducted in
      stable renal transplant patients have revealed a favorable efficacy and
      tolerability profile. Following these preliminary clinical evaluations, phase II
      studies have determined optimal dosing for prevention of acute rejection and the
      efficacy and tolerability of FTY720 in combination with reduced and full-dose
      cyclosporine (CsA). Data available for these studies demonstrate that FTY720 5 mg
      combined with reduced-dose CsA provides equivalent freedom from acute rejection
      to a standard mycophenolate mofetil (MMF)/CsA regimen. Moreover, rejection
      prophylaxis with a 5-mg dose of FTY720 appears to allow for a 50% reduction in
      the dose of calcineurin inhibitors while effectively preventing graft rejection.
      These studies have also shown that FTY720 has no overlapping toxicity with
      classical immunosuppressive agents; FTY720 can be used safely in combination with
      CsA and everolimus. Overall, these synergistic effects suggest that FTY720 has
      the potential to provide a real improvement in the efficacy and tolerability of
      future immunosuppressive regimens.

PMID- 15041405
TI  - From cyclosporine to the future.
AB  - Most of the experience acquired in our unit with cyclosporine (CsA) comes from
      randomized trials. A first trial demonstrated that CsA-treated patients had a
      better 10-year graft survival than azathioprine-treated patients. A second trial
      showed equivalence between double therapy with CsA plus steroids and triple
      therapy with CsA, steroids, and azatioprine. A third trial showed similar 2-year
      graft survival with CsA monotherapy and triple therapy. A larger multicenter
      study that compared three different CsA-based regimens showed similar long-term
      graft survival with monotherapy, double therapy, and triple therapy. However,
      patients given monotherapy had less frequent steroid-related side-effects.
      Finally a more recent multicenter international trial showed that the rate of
      acute rejection can be reduced without increasing side effects by adding the
      monoclonal antibody basiliximab to the triple therapy. By reviewing our
      cumulative experience with CsA we found a mean graft half-life of 18.7 years for
      cadaver renal transplant recipients and 31.9 for the living transplant
      recipients. No significant attrition of graft function was found for patients
      with grafts functioning at 15 years. Two important issues with the present
      immunosuppression concern the long-term nephrotoxicity of calcineurin inhibitors
      and the cardiovascular disease, which is at least in part related to the use of
      steroids. To face these problems, we are currently involved in two multicenter
      trials, one comparing sirolimus plus mycophenolate mofetil to sirolimus plus low
      dose CsA, while the other trial compares certican plus CsA to certican plus CsA
      plus corticosteroids.

PMID- 15041406
TI  - Tolerance mechanisms and recent progress.
AB  - There has been tremendous progress in our understanding of the mechanisms
      mediating allograft tolerance, which have been revealed to be far more complex
      and regulated than hitherto suspected. New results have enriched our
      understanding of the relative contributions of the direct and indirect pathways
      to immunity and tolerance over time. The role of central tolerance has been
      expanded with the surprising discovery of "ectopic" or "promiscuous" antigens
      expressed by medullary thymic epithelial cells, and the function of the thymus in
      generating naturally occurring CD4+ CD25+ regulatory T cells. In the periphery,
      it is increasingly appreciated that tolerance is a highly active process, with
      tolerogenic dendritic cells and regulatory T cells being the major players.
      However, the challenge of understanding the complex interactions regulating the
      dynamic balance between immunity and tolerance are formidable, and new tools from
      the more formal disciplines of nonlinear dynamics and systems engineering may
      help provide insight. Although many hurdles remain, the progress in elucidating
      the basic mechanisms of tolerance is rapidly being translated into clinical
      trials and provides grounds for optimism that clinical tolerance will eventually
      become a reality.

PMID- 15041407
TI  - The antagonism of calcineurin inhibitors and costimulatory blockers: fact or
      fiction?
AB  - Blockade of T-cell costimulatory pathways has proven to be a useful approach in
      inhibiting allograft rejection and/or inducing tolerance in some experimental
      models of transplantation, and clinical development of B7 blockade by CTLA4-Ig in
      kidney transplant recipients is under way. Although calcineurin inhibitors are
      clinically effective immunosuppressive agents in their own right, conflicting
      findings have been reported as to whether concomitant use of these drugs with
      costimulatory blockade has a beneficial or adverse effect on preventing rejection
      and promoting long-term allograft survival or transplant tolerance. Here, we
      summarize the current understanding of the interaction between calcineurin
      inhibitors and T-cell costimulatory blockade strategies in transplantation.

PMID- 15041408
TI  - Future directions in immunosuppression.
AB  - As liver transplantation is now being performed with an excellent 5-year survival
      rate of approximately 70% at selected centers, attention has been shifted to
      reduce long-term complications of calcineurin inhibitors including diabetes,
      hypertension, and hyperlipidemia, which have a major effect on morbidity and
      mortality within the transplant setting. Cyclosporine (CsA) monitoring has been
      performed traditionally by measurement of predose "trough" blood concentrations
      (C0). Recent development of 2 hour postdose CsA (C2) monitoring strategy has
      emerged as a much more sensitive approach for assessing the pharmacokinetics and
      providing greater precision in the optimization of Neoral dosing than C0
      measurements. Furthermore, a reduction of risk factors for atherosclerotic
      vascular disease and in the incidence and severity of acute cellular rejection
      have been associated with the adoption of C2 monitoring. However, further data
      from multicenter trials are required to evaluate the long-term benefits of this
      new therapeutic monitoring strategy.

PMID- 15041409
TI  - The future of immunosuppression: a personal view.

PMID- 15041410
TI  - Biological ultrastructure research; the first 50 years.
AB  - The second half of the 20th century has witnessed the birth and growth of
      biological ultrastructure research--a branch of cell biology in which electron
      microscopy plays an important role. After a humble start in around 1950, when
      only a limited arsenal of instrumentation was available, a wealth of auxiliary
      methodologies were developed and gradually put in use. Here we review these
      techniques: ultramicrotomy of "optimally" fixed and prepared samples,
      histochemical methods such as immuno-electron microscopy and electron microscope
      autoradiography, negative staining techniques, freeze-fracturing and other
      techniques. Closer to the millennium shift, various cryotechniques have gradually
      developed. Together with computer-based reconstruction methods they are likely to
      play increasingly more important roles in the future.

PMID- 15041411
TI  - Increase of melanogenesis by retinoic acid: an ultrastructural and morphometric
      study.
AB  - Melanin is a dark pigment protecting the skin against UV radiation in some
      organisms. Studies on invasion and metastasis using retinoic acid as inhibitor
      agent are well known, but its role in melanin production (melanogenesis),
      especially at ultrastructural level and using morphometry were not well studied.
      In the present study, we analyzed the effects of retinoic acid on the melanosomes
      in B16F10 melanoma cells. These organelles were identified and quantified using
      routine electron microscopy and the specific HMB45 antibody. Other approaches
      such as immunofluorescence, and flow cytometry were also used. Our results
      indicated that retinoic acid increased the melanogenesis process in B16F10
      melanoma cells. Furthermore, this work also provided evidence that this substance
      interferes at the subcellular level altering the numerical density of
      melanosomes, as well as the relative volume of the nucleus and nucleolus. In
      addition, the cells displayed altered morphology and an increase in the
      percentage of the relative volume of melanosomes, mainly the stages II-III and
      IV, leading to melanin formation. Furthermore, a decrease in the cells number
      after retinoic acid treatment was also observed.

PMID- 15041412
TI  - In vitro deregulation of markers characteristic of human prostate epithelial
      cells.
AB  - We have screened primary cultures of human prostate for the expression of markers
      reported to be characteristic of specific cell lineages in vivo, in order to
      ascertain whether human prostate cells in vitro maintain and reflect their in
      vivo differentiated phenotypes and to evaluate the homogeneity of the populations
      of cells that can be derived from this tissue. Using single and dual stain
      immunofluorescent microscopy to analyse very early organoid and subsequently
      derived monolayer stage cultures, we have observed that expression of markers
      characteristic of human prostate epithelial cells in vivo is deregulated within
      48h, indicating that dissociation of human prostate tissue and cultivation of
      prostate epithelial cells in culture can result in promiscuous expression of cell
      type specific markers of prostate epithelial cells. These observations have
      important implications for studies of cell lineage and differentiation of
      prostate cells in vitro.

PMID- 15041413
TI  - Prenatal development of the palatine gland of rats.
AB  - The present study aimed to elucidate the prenatal development of the rat palatine
      gland. Parasagittal 5 microm thick serial sections made from Wistar rats at
      embryonic days (E) 17 to 22 were stained with haematoxylin-eosin (HE), Alcian
      blue-Kernechtrot or immunohistochemistry for 5-bromo-2'-deoxyuridine (BrdU) as a
      marker of proliferating cells. Additionally, three-dimensional images of
      developing glandular parenchyma were reconstructed from serial HE sections with a
      personal computer. At E 17, several thickenings of the palatal epithelium had
      appeared which thereafter became the epithelial cords. Branching and lumenization
      commenced at E 20, and immature acini were observed at E 21. Three-dimensional
      reconstruction showed that the proximal part of the epithelial cord
      differentiated into the duct, and the distal part of the epithelial cord
      differentiated into the acinus. In immunohistochemical staining, there were many
      BrdU-positive cells in the epithelial cords including thickenings of the palatal
      epithelium, ducts, and acini. The BrdU labeling index of the cells of the
      epithelial cord was the highest (statistically significant) of the three in the
      primitive palatine gland. In conclusion, during the development of the rat
      palatine gland, epithelial cords with very high proliferative activity arise from
      the palatal epithelium, and then the proximal part of the epithelial cord
      differentiates into the duct, and the distal part of the epithelial cord
      differentiates into the acinus. Proliferation of these glandular parenchyma
      contributes to the growth of the developing palatine gland.

PMID- 15041414
TI  - Expression of cys-cys chemokine ligand 21 on human gingival lymphatic vessels.
AB  - The cys-cys (C-C) chemokine ligand 21 is a member of the C-C chemokines that
      constitute a group of heparin-binding cytokines with a pattern of four or six
      conserved cysteines. The CCL21 is known to be expressed in secondary lymphoid
      tissues, however it has rarely been reported for the expression on peripheral
      lymphatic vessels in somatic tissue. Here we investigated the expression of CCL21
      on lymphatic vessels identified by anti-desmoplakin in uninflamed and inflamed
      human gingiva. In uninflamed tissue the expression of CCL21 was detected on
      lymphatic vessels in gingiva. In uninflamed gingiva the expression of CCL21 was
      detected on all lymphatic capillaries of the mucosal connective tissue papillae.
      There were two types of collecting lymphatic vessels in the lamina propria
      mucosae expressing CCL21 strongly or very weakly. In inflamed gingiva no
      expression of CCL21 was detected on lymphatic vessels. In all tissue sections no
      blood vessels expressing CCL21 were observed. These results may suggest that the
      expression of CCL21 is predominantly induced in the peripheral lymphatic
      endothelium of the uninflamed mucosal microcirculation, and that under inflamed
      conditions a reduction of CCL21 occurs in lymphatic endothelium.

PMID- 15041416
TI  - Ultrastructure of Pagrus major and Rhabdosargus sarba spermatozoa (Perciformes:
      Sparidae: Sparinae).
AB  - Transmission and scanning electron microscopy were used to investigate the
      ultrastructure of spermatozoa in two Sparinae species Pagrus major and
      Rhabdosargus sarba. Ultrastructurally, the spermatozoa of P. major and R. sarba
      both consist of a spherical, homogeneously electron-dense nucleus with a deep
      axial nuclear fossa, and an unusual notch, in the nuclear region. The midpiece
      contains two spherical mitochondria in R. sarba and one in P. major. The
      comparison of spermatozoal ultrastructure of these two species of Sparidae shows
      that they closely resemble one another and suggests that they are closely
      related. Variation in the geometry and dimensions of the mitochondrion and
      nucleus is substantial in these two Sparidae species. It is concluded that the
      spermatozoa of both species are of primitive type, and they are distinguished by
      several unique features which may provide useful systematic characteristics.

PMID- 15041415
TI  - Morphogenesis of the laminated, tripartite cytoarchitectural design of the blood
      gas barrier of the avian lung: a systematic electron microscopic study on the
      domestic fowl, Gallus gallus variant domesticus.
AB  - Formation of a thin blood-gas barrier in the respiratory (gas exchange) tissue of
      the lung of the domestic fowl, Gallus gallus variant domesticus commences on day
      18 of embryogenesis. Developing from infundibulae, air capillaries radiate
      outwards into the surrounding mesenchymal (periparabronchial) tissue,
      progressively separating and interdigitating with the blood capillaries. Thinning
      of the blood-gas barrier occurs by growth and extension of the air capillaries
      and by extensive disintegration of mesenchymal cells that constitute transient
      septa that divide the lengthening and anastomosing air capillaries. After they
      contact, the epithelial and endothelial cells deposit intercellular matrix that
      cements them back-to-back. At hatching (day 21), with a thin blood-gas barrier
      and a large respiratory surface area, the lung is well prepared for gas exchange.
      In sites where air capillaries lie adjacent to each other, epithelial cells
      contact directly: intercellular matrix is lacking.

PMID- 15041418
TI  - POPs--need for target research on high risk stage.

PMID- 15041417
TI  - Phorbol myristate acetate induces changes on F-actin and vinculin content in
      immature rat Sertoli cells.
AB  - Actin and vinculin are two of the most abundant cytoskeletal proteins, widely
      expressed in nearly all types of eukaryotic cells. It has been well established
      that long-term exposure to the tumor promoter phorbol myristate acetate (PMA)
      affects Sertoli cell morphology, as well as F-actin and vinculin organization in
      vitro. To analyze in a quantitative manner the F-actin and vinculin content of
      rat immature Sertoli cells in vitro in response to PMA exposure, cytoskeletal
      fractions were prepared following extraction with Triton X-100. Analysis of the
      isolated cytoskeletal fractions by immunoblotting showed that exposure of
      immature rat Sertoli cells to PMA for 8h has an appreciable effect on the
      cellular level of both the actin and vinculin. Interestingly, as revealed by
      using calphostin C, a specific protein kinase C inhibitor, the observed F-actin
      and vinculin changes are most probably mediated by a mechanism that depends on
      protein kinase activity. A discussion is made concerning PKC modulation by PMA
      and the subsequent actin and vinculin quantitative changes and reorganization,
      phenomena that have been closely related to cell transformation.

PMID- 15041419
TI  - Challenges in global ballast water management.
AB  - Ballast water management is a complex issue raising the challenge of merging
      international regulations, ship's specific configurations along with ecological
      conservation. This complexity is illustrated in this paper by considering ballast
      water volume, discharge frequency, ship safety and operational issues aligned
      with regional characteristics to address ecological risk for selected routes. A
      re-estimation of ballast water volumes gives a global annual level of 3500 Mton.
      Global ballast water volume discharged into open sea originating from ballast
      water exchange operations is estimated to approximately 2800 Mton. Risk based
      decision support systems coupled to databases for different ports and invasive
      species characteristics and distributions can allow for differentiated treatment
      levels while maintaining low risk levels. On certain routes, the risk is
      estimated to be unacceptable and some kind of ballast water treatment or
      management should be applied.

PMID- 15041420
TI  - Impacts of pollution on coastal and marine ecosystems including coastal and
      marine fisheries and approach for management: a review and synthesis.
AB  - The history of aquatic environmental pollution goes back to the very beginning of
      the history of human civilization. However, aquatic pollution did not receive
      much attention until a threshold level was reached with adverse consequences on
      the ecosystems and organisms. Aquatic pollution has become a global concern, but
      even so, most developing nations are still producing huge pollution loads and the
      trends are expected to increase. Knowledge of the pollution sources and impacts
      on ecosystems is important not only for a better understanding on the ecosystem
      responses to pollutants but also to formulate prevention measures. Many of the
      sources of aquatic pollutions are generally well known and huge effort has been
      devoted to the issue. However, new concepts and ideas on environmental pollution
      are emerging (e.g., biological pollution) with a corresponding need for an update
      of the knowledge. The present paper attempts to provide an easy-to-follow
      depiction on the various forms of aquatic pollutions and their impacts on the
      ecosystem and organisms.

PMID- 15041421
TI  - The effect of urbanisation on Laajalahti Bay, Helsinki City, as reflected by
      sediment geochemistry.
AB  - Sediment geochemical techniques were used to assess how the sediment record
      reflects the loading and land use history of Laajalahti Bay, a semi-enclosed bay
      adjacent to the city of Helsinki, Finland. A dated sediment core was analysed for
      concentrations of Al, Ca, K, Mg, Na, Fe, Mn, Cu and Zn and total concentrations
      of C, N and P together with P fractions and biogenic silica (BSi) at intervals of
      1 cm to a depth of 88 cm. Furthermore, five phases of development were identified
      in the sediment record by using principal components analysis and cluster
      analysis. The lithology of the core indicates sharp changes in the sedimentation
      environment in the earlier history of the embayment that are most likely due to
      isostatic uplift and changes in salinity. The most prominent recent trends were
      the increasing sedimentation rates and nutrient concentrations towards present.
      In addition, significant increases were observed in the concentrations of
      anthropogenic indicators Cu and Zn. In spite of decreased nutrient loading to
      Laajalahti Bay no significant signs of improvement were observed in the sediment
      record yet.

PMID- 15041422
TI  - Dissolved metal contamination in the East River-Long Island sound system:
      potential biological effects.
AB  - A suite of dissolved trace metals (Ag, Cd, Cu and Pb), inorganic nutrients
      (NO(3), PO(4)), and chlorophyll a was measured along a 55 mile transect from the
      East River into western and central Long Island Sound. The main objectives of
      this study were to determine the relative levels of contamination from sewage,
      and to assess its possible biological impact on local waters. The East River-Long
      Island Sound system receives large volumes of treated sewage and industrial
      effluent as a result of the heavy urbanization of the area. Despite these strong
      environmental pressures, this study is among the first to report dissolved metal
      levels from that region. Consistent with the locations of anthropogenic sources,
      a strong east-west concentration gradient was observed for Ag, Pb, NO(3) and
      PO(4) with the highest levels found in the East River. In contrast, dissolved Cd
      and Cu were relatively constant throughout the area of study, suggesting that
      sewage sources have a more limited influence on the levels of those metals.
      Remobilization from contaminated sediments may represent the primary source of Cd
      and Cu to the Long Island Sound under low-runoff conditions in summer.
      Chlorophyll a concentrations, used as an indicator of total biomass, were also
      low in the East River. These low chlorophyll concentrations could not be
      explained by nutrient or light limitation, water column stratification, or to
      advection of phytoplankton out of the river during tidal flushing. These
      preliminary results suggest a potential toxic effect of sewage on the biological
      communities of the East River.

PMID- 15041424
TI  - Anthropogenic regulation of the phosphorus balance in the Thau catchment-coastal
      lagoon system (Mediterraean Sea, France) over 24 years.
AB  - In the Thau lagoon, despite there being no phosphate limitation policy, the
      annual mean phosphate concentrations decreased by 90% between 1971 and 1994. The
      present study indicates a relationship between the decrease of phosphate
      concentrations and changes in urban, industrial and agricultural activities
      within the catchment generating phosphorus (P) inputs; and shellfish farming
      leading to phosphorus storage and export. The relationship (tonnes of P) is: P
      PO(4)(3-) in the lagoon waters=1.0124 anthropogenic phosphorus balance--47.62
      (r(2) = 0.824, p < 0.000). As population growth is expected in coastal zones,
      sustainable development requires the need for addressing the role played by human
      activities and the multi-scale regulation of them. As an element of integrated
      coastal zone management, the present study provides a regional scale analysis of
      these aspects.

PMID- 15041423
TI  - Numerical simulation of organic chemicals in a marine environment using a coupled
      3D hydrodynamic and ecotoxicological model.
AB  - For ecotoxicological risk assessment in a marine ecosystem, we constructed a
      coupled three-dimensional hydrodynamic and ecotoxicological model (EMT-3D), and
      applied it to Tokyo Bay. The model was calibrated with field data obtained in
      2002. The results of sensitivity analysis for dissolved Bisphenol A showed that
      biodegradation rate was the most important factor for concentration change.
      Bioconcentration coefficient was the most important factor for Bisphenol A in
      phytoplankton. Therefore, the parameters must be carefully considered in the
      modeling. The mass balance results showed that standing stocks of Bisphenol A in
      water, in particulate organic carbon and in phytoplankton are 7.85 x 10(4), 1.78
      x 10(2) and 3.44 x 10(-1) g, respectively. With respect to flux, biodegradation
      in the water column had the highest value of 1.06 x 10(3) g/day, and next were
      effluent to the open sea, partition to particulate organic carbon, and
      bioconcentration in phytoplankton.

PMID- 15041425
TI  - Tracing the anthropogenic lead sources in coastal sediments of SE-pacific (36
      degrees Lat. S) using stable lead isotopes.
AB  - This study evaluates the main sources of antropogenic Pb in one of the most
      industrialized centers of the southern Chilean coast (36 degrees S). Stable lead
      isotopes ((206)Pb/(207)Pb, (208)Pb/(207)Pb) were used to trace main Pb sources to
      coastal sediments, considering the suspended particulate matter (SPM) from marine
      (traps), continental (rivers) and industrial effluents, sediments and leaded
      gasoline samples. The atmospheric input was evaluated through natural collectors;
      i.e. Raqui-Tubul salt marsh. Results show that marine samples lie on a trend
      between industrial effluents ( approximately 1.16, 2.44) and natural sources
      (1.20, 2.50), not related to gasoline consumption. Salt marsh sediments show
      comparable isotopic composition to marine samples, suggesting the importance of
      the atmospheric input in the coastal sediments, not related to the leaded
      gasoline composition either. The continental input (1.18, 2.48) is highly
      influenced by precipitation, being difficult to separate both sources (atmosphere
      and continental runoff), showing also similar isotopic ratio to marine sediments.
      The signal of industrial emissions is masked with the introduction of Pb with
      higher isotopic ratios, compared to the values observed in the material collected
      from traps (SPM approximately 1.19, 2.48). The contribution of more radiogenic Pb
      by the upwelling is suggested.

PMID- 15041426
TI  - Presence, infectivity, and stability of enteric viruses in seawater: relationship
      to marine water quality in the Florida Keys.
AB  - Concerns about the presence of enteric viruses in the surface waters of the
      Florida Keys prompted analyses of virus stability and persistence in these
      waters. In an in vitro study we evaluated the survival of poliovirus and
      stability of viral RNA in filtered natural seawater (FSW), unfiltered natural
      seawater (USW), artificial seawater (ASW) and DI water. This study compared cell
      culture infectivity with direct reverse transcription-polymerase chain reaction
      analysis. Attenuated poliovirus was seeded in the above water types and incubated
      in the dark at 22 and 30 degrees C for 60 days. At 22 degrees C, enhanced
      poliovirus survival and enhanced detection of viral RNA was observed in the
      seeded DI water control, artificial seawater and FSW samples. Detection of
      viruses in unfiltered seawater decreased rapidly at both temperatures by both
      methods of detection, suggesting that in the natural environment detection of
      enteroviral RNA may indicate a recent contamination event. In addition, in situ
      sampling in the Florida Keys during the late winter of 2000 revealed the presence
      of infectious enteroviruses at two sites and no sites exceeded recommended levels
      of microbial water quality indicators (enterococci or fecal coliform bacteria).

PMID- 15041427
TI  - Quantifying fish metallothionein transcript by real time PCR for its utilization
      as an environmental biomarker.
AB  - The study is aimed at introducing the hepatic level of metallothionein transcript
      in the fish Lithognathus mormyrus as environmental biomarker, including: (a).
      establishing real time PCR procedure for the evaluation of metallothionein and
      18S ribosomal RNA transcript levels, (b). examining the suitability of two
      alternate normalization factors, 18S- and total RNA, (c). partially
      characterizing hepatic metallothionein transcript expression--(1). in two samples
      of feral fish, aimed at determining within-sample variability, (2). during a 318
      days depuration experiment aimed at determining basal transcript level, (3).
      after cadmium injection aimed at determining maximal induced level. Hepatic
      transcript levels of cytochrome p4501A measured in the same individuals and
      published elsewhere [Environ. Toxicol. Chem. 22 (2003)], were re-analysed
      concurrent with the metallothionein ones. 18S rRNA was chosen as normalizing
      agent of choice, compensating for demonstrated partial RNA degradation in part of
      the preparations. Minimal and maximal metallothionein transcript levels were
      determined, 61+/-47 and 2159+/-905 atomol/pmol 18S rRNA, respectively. Within
      sample variability of the two feral fish samples, or of similarly treated
      experimental fish groups, expressed as percentage of the standard deviation from
      the average transcript level, ranged between 41% and 80%, and as low as 3.8-fold
      difference between pairs of feral or experimental groups was statistically
      significant.

PMID- 15041428
TI  - Verification of mid-ocean ballast water exchange using naturally occurring
      coastal tracers.
AB  - We examined methods for verifying whether or not ships have performed mid-ocean
      ballast water exchange (BWE) on four commercial vessels operating in the Pacific
      and Atlantic Oceans. During BWE, a ship replaces the coastal water in its ballast
      tanks with water drawn from the open ocean, which is considered to harbor fewer
      organisms capable of establishing in coastal environments. We measured
      concentrations of several naturally occurring chemical tracers (salinity, six
      trace elements, colored dissolved organic matter fluorescence and radium
      isotopes) along ocean transects and in ballast tanks subjected to varying degrees
      of BWE (0-99%). Many coastal tracers showed significant concentration changes due
      to BWE, and our ability to detect differences between exchanged and unexchanged
      ballast tanks was greatest under multivariate analysis. An expanded dataset,
      which includes additional geographic regions, is now needed to test the
      generality of our results.

PMID- 15041430
TI  - Polychlorinated biphenyl and organochlorine pesticide residues in Lophius
      budegassa from the Mediterranean Sea (Italy).
AB  - Persistent organochlorines, such as polychlorinated biphenyls, including coplanar
      congeners and DDT compounds, were measured in the liver of a teleost species:
      namely, Lophius budegassa. The mean concentrations of PCBs (1249 ng/g wet wt)
      were comparable with DDTs mean levels (1459 ng/g wet wt). Among DDTs the compound
      found at the highest concentration was p,p'-DDE representing 76% of the total DDT
      burden. The PCB profiles were dominated by congeners 153, 180, and 138 accounting
      for 49.8%, 16.0% and 13.7% of the total PCBs. The total 2,3,7,8-TCDD toxic
      equivalent (TEQs) of six coplanar PCBs, including mono- and non-ortho congeners,
      was 0.98 pg/g wet wt. The congeners with highest TEQs values were non-ortho
      congeners followed by mono-ortho ones.

PMID- 15041429
TI  - Partitioning of semi-soluble organic compounds between the water phase and oil
      droplets in produced water.
AB  - When selecting produced water treatment technologies, one should focus on
      reducing the major contributors to the total environmental impact. These are
      dispersed oil and semi-soluble hydrocarbons, alkylated phenols, and added
      chemicals. Experiments with produced water have been performed offshore on the
      Statoil operated platforms Gullfaks C and Statfjord B. These experiments were
      designed to find how much of the environmentally relevant compounds were
      dissolved in the water phase and not associated to the dispersed oil in the
      produced water. Results show that the distribution between the dispersed oil and
      the water phase varies highly for the different components groups. For example
      the concentration of PAHs and the C6-C9 alkylated phenols is strongly correlated
      to the content of dispersed oil. Therefore, the technologies enhancing the
      removal of dispersed oil have a higher potential for reducing the environmental
      impact of the produced water than previously considered.

PMID- 15041431
TI  - Recent contamination by persistent organochlorines in Baikal seal (Phoca
      sibirica) from Lake Baikal, Russia.
AB  - Blubber samples of Baikal seals pups (Phoca sibirica) collected in 2001 and 2002
      were analyzed for persistent organochlorines (OCs) such as PCBs (polychlorinated
      biphenyls), DDTs (dichlorodiphenyltrichloroethane and its metabolites), HCHs
      (hexachlorocyclohexane isomers), CHLs (chlordane related compounds), TCPMe
      [tris(4-chlorophenyl)methane] and TCPMOH [tris(4-chlorophenyl)methanol]. The
      distribution pattern of OCs was in the following order:
      DDTs>PCBs>CHLs>HCHs>TCPMOH>TCPMe. Organochlorine concentrations and composition
      patterns in eight pup blubber samples (2002) analyzed in the present study were
      compared with the corresponding levels in juvenile Baikal seals from 1992 survey,
      and it was found that residue levels of OC compounds have declined during the 10
      year period. In particular, concentrations of PCBs, HCHs and CHLs in seals
      collected in 2002 were approximately two times lower, while DDTs levels were
      three times lower than the corresponding levels in 1992. Furthermore, higher
      ratios of beta-HCH/HCHs and p,p(')-DDE/DDTs were found in 2002 samples. While
      comparing the OC levels with those in other seal pups it appeared that all the OC
      concentrations were lower than the levels in seals from coastal California known
      as one of the most polluted areas. PCB and DDT concentrations in the present
      specimens were higher than that in Arctic seal pups. The proportions of tri-,
      tetra-, penta- and hexachlorobiphenyls in pups captured in 2002 were higher than
      those in 1992. TEQ concentrations of non- and mono-ortho coplanar PCBs in Baikal
      seals collected in 2002 were higher than those in seals collected from some
      locations in the world, where human and industrial activities are extensive,
      suggesting potential for toxic implications of coplanar PCBs in Baikal seals.

PMID- 15041432
TI  - Molecular and organism biomarkers of copper pollution in the ascidian
      Pseudodistoma crucigaster.
AB  - We studied the effects of pollution in the colonial ascidian Pseudodistoma
      crucigaster at organismal and suborganismal levels. Our goal was to find early
      biomarkers to detect some effect of pollution before changes in community
      structure or species composition occur. We examined the effect of Cu on the
      production of heat-shock proteins, defence metabolites, growth rates and presence
      of resistance forms. We performed a transplant experiment to a Cu polluted
      harbour and observed negative growth and presence of resistance forms but not
      depressed production of toxic metabolites or an increase in stress proteins (hsp)
      in the ascidian. In a laboratory experiment, stress proteins were induced only
      under half the Cu concentration found in the harbour. We conclude that hsp can be
      used in this ascidian as an early warning system for sublethal pollution but that
      the response is inhibited above a threshold of the stressing agent, which may
      vary among species.

PMID- 15041433
TI  - Resurvey of a reef flat in American Samoa after 85 years reveals devastation to a
      soft coral (Alcyonacea) community.
AB  - One of the earliest quantitative surveys of soft corals, on a reef flat in Pago
      Pago Harbour, American Samoa, was repeated 85 years later. The alcyoniid
      communities there, which were the dominant benthic organisms during the initial
      survey, have suffered a drastic decline of 99% cover in the interim. The most
      likely causes of the decline are anthropogenic disturbance associated with
      reclamation along the harbour from the 1940s to early 1960s, compounded by
      chronic pollution from industrial wastewater discharge from the mid-1950s to late
      1980s. The decline in one dominant species, Sinularia polydactyla, is likely to
      have serious consequences for the reef as unusually for a soft coral, this had
      been the major reef building species. Life-history traits of certain Sinularia
      and Sarcophyton, such as slow growth and low rates of sexual reproduction, mean
      they will be slower to recover from severe disturbance than many scleractinian
      corals.

PMID- 15041434
TI  - Fish waste as an alternative resource for gulls along the Patagonian coast:
      availability, use, and potential consequences.
AB  - We evaluated the volumes of waste from fish processing plants in Chubut Province,
      Argentina, and discuss its potential consequences for Kelp Gull (Larus
      dominicanus) population dynamics and coastal management. Mean volume of waste
      produced between 1989 and 2001 in three coastal cities was 49.8+/-10.9 thousand
      tonsy(-1). The amount of waste varied between years and cities, being larger at
      Puerto Madryn and Comodoro Rivadavia than at Rawson (24.1, 19.3 and 6.4 thousand
      tonsy(-1), respectively). Waste was disposed at the three cities during all
      months of the sampled years. Large numbers of Kelp Gulls have been recorded
      taking advantage of fish waste disposed at these waste sites throughout the year.
      Considering its energetic content, waste generated at processing plants may
      support a population of between 101000 and 209000 Kelp Gulls. Fish waste could be
      contributing to their population expansion through increased survival and
      breeding success. Conflicts due to the use of waste and derived effects on other
      coastal species and human populations could be minimized by adequate fish waste
      management.

PMID- 15041435
TI  - The occurrence of NADPH-ferrihemoprotein reductase in Corbula caribea, from a
      natural oil seep at La Brea, Trinidad.
AB  - Corbula caribea is the most common non-polychaete macrofaunal organism identified
      at a large natural oil seep at La Brea in south Trinidad. It is hypothesized that
      these animals may possess (NADPH-ferrihemoprotein reductase) a component of the
      Mixed Function Oxygenase system (MFO), which may allow them to ameliorate the
      potentially deleterious effects resulting from exposure to the high levels of
      petroleum hydrocarbons within this environment. This study was designed to
      determine whether organisms from the seep site showed greater enzyme activity
      when compared to organisms from a non-seep reference site. NADPH-ferrihemoprotein
      reductase activity was determined by incubating 10 microm cryostat sections with
      nitro-blue tetrazolium. The reaction product was determined by visual assessment
      and quantified by measuring the relative mean stain intensity. The intense
      staining, indicative of enzyme activity was evident in the digestive epithelia of
      seep animals. Observations indicated that organisms from the seep showed more
      intense staining, indicating greater enzyme activity, when compared to animals
      from a non-seep reference site. The relative stain intensity of NADPH
      ferrihemoprotein reductase determined for organisms from the seep was 61.30. This
      was significantly higher than the stain intensity determined for organisms from
      the non-seep reference site (7.11). This supported visual assessments, which
      suggested that the seep organisms showed higher enzyme activity than organisms
      from the non-seep site. The results suggest that NADPH-ferrihemoprotein reductase
      may be present in Corbula caribea from the seep site and not in those from the
      non-seep site. It is possible that this enzyme may contribute to these animals
      ability to tolerate chronic exposure to petroleum hydrocarbons and offer then a
      selective advantage for survival the seep environment.

PMID- 15041436
TI  - Quantitative analysis of small-plastic debris on beaches in the Hawaiian
      Archipelago.
AB  - Small-plastic beach debris from nine coastal locations throughout the Hawaiian
      Archipelago was analyzed. At each beach, replicate 20 l samples of sediment were
      collected, sieved for debris between 1 and 15 mm in size, sorted by type, counted
      and weighed. Small-plastic debris occurred on all of the beaches, but the
      greatest quantity was found at three of the most remote beaches on Midway Atoll
      and Moloka'i. Of the debris analyzed, 72% by weight was plastic. A total of 19100
      pieces of plastic were collected from the nine beaches, 11% of which was pre
      production plastic pellets. This study documents for the first time the presence
      of small-plastic debris on Hawaiian beaches and corroborates estimates of the
      abundance of plastics in the marine environment in the North Pacific.

PMID- 15041437
TI  - HCH and DDT residues in molluscs from Chinese Bohai coastal sites.

PMID- 15041438
TI  - Accelerator analyses of tributyltin chloride associated with a tributyltin
      resistant marine microorganism.

PMID- 15041439
TI  - Response to Beckmen et al. ("Organochlorine contaminant exposure and associations
      with haematological and humoral immune functional assays with dam age as a factor
      in free-ranging northern fur seal pups"; Marine Pollution Bulletin 46: 594-606).

PMID- 15041441
TI  - Paclitaxel-induced neuropathic hypersensitivity in mice: responses in 10 inbred
      mouse strains.
AB  - Mechanical allodynia, or hypersensitivity to tactile stimuli, is a frequent
      clinical symptom of neuropathy. Large interindividual differences have been
      observed in neuropathic pain, both in susceptibility to its development and in
      its severity. Identification of genetic factors relevant to this variability
      would be of obvious utility. Although many animal models of neuropathic pain
      following peripheral nerve injury have been developed, most involve intricate
      surgeries and are thus poorly suited for large-scale linkage mapping
      investigations in the mouse. Recently, a schedule of intraperitoneal injections
      of the chemotherapeutic agent, paclitaxel (Taxol(R)), has been shown to produce a
      long-lasting, bilateral neuropathy in the rat, featuring hypersensitivity to
      mechanical, thermal and cold stimuli. We present here a survey of the responses
      of 10 inbred mouse strains to paclitaxel injections. Virtually all strains
      developed statistically significant mechanical allodynia, with one strain,
      DBA/2J, exhibiting especially robust changes. Strain sensitivities to paclitaxel
      induced mechanical allodynia were similar to those obtained previously using a
      surgical model of neuropathic pain, supporting our contention that genetic
      sensitivity to mechanical allodynia is independent of the precise mode of
      induction. Using sensitive DBA/2 mice and a resistant strain, C57BL/6J, for
      comparison, we further characterized the paclitaxel model in mice by examining
      cold allodynia and thermal hyperalgesia. Both strains displayed equivalent cold
      allodynia but neither strain developed thermal hyperalgesia. The present data
      confirm a genetic component in mechanical allodynia using this model, while
      dissociating mechanical hypersensitivity from other pain modalities.

PMID- 15041442
TI  - Dissecting out mechanisms responsible for peripheral neuropathic pain:
      implications for diagnosis and therapy.
AB  - Peripheral neuropathic pain, that clinical pain syndrome associated with lesions
      to the peripheral nervous system, is characterized by positive and negative
      symptoms. Positive symptoms include spontaneous pain, paresthesia and dysthesia,
      as well as a pain evoked by normally innocuous stimuli (allodynia) and an
      exaggerated or prolonged pain to noxious stimuli (hyperalgesia/hyperpathia). The
      negative symptoms essentially reflect loss of sensation due to axon/neuron loss,
      the positive symptoms reflect abnormal excitability of the nervous system.
      Diverse disease conditions can result in neuropathic pain but the disease
      diagnosis by itself is not helpful in selecting the optimal pain therapy.
      Identification of the neurobiological mechanisms responsible for neuropathic pain
      is leading to a mechanism-based approach to this condition, which offers the
      possibility of greater diagnostic sensitivity and a more rational basis for
      therapy. We are beginning to move from an empirical symptom control approach to
      the treatment of pain to one targeting the specific mechanisms responsible. This
      review highlights some of the mechanisms underlying neuropathic pain and the
      novel targets they reveal for future putative analgesics.

PMID- 15041443
TI  - Analysis of receptive fields revealed by in vivo patch-clamp recordings from
      dorsal horn neurons and in situ intracellular recordings from dorsal root
      ganglion neurons.
AB  - It has been thought that spinal dorsal horn neurons receive convergent inputs
      from not only somatosensory but also visceral pathways. For instance, the
      referred pain is presumed to be due to the convergence of sensory inputs from
      cardiac and shoulder receptive fields. However, precise investigation has not
      been made from dorsal horn neurons yet, because of difficulty in studying the
      pathways from those regions by means of conventional electrophysiology. The
      purpose of this study is to clarify the convergent inputs to single dorsal horn
      neurons from wide receptive fields using an in vivo patch-clamp recording
      technique from the superficial spinal dorsal horn and an intracellular recording
      from dorsal root ganglion neurons that keep physiological connections with the
      peripheral sites. Identified dorsal root ganglion neurons received an input from
      a quite small area, about 1 x 1 mm in width of the skin. In contrast, substantia
      gelatinosa neurons in the spinal cord received inputs from an unexpectedly wide
      area of the skin. Previous extracellular recordings have, however, revealed that
      substantia gelatinosa neurons have small receptive field. This discrepancy is
      probably due mainly to an availability of the in vivo patch-clamp method to
      analyze sub-threshold synaptic responses. In contrast, the extracellular
      recording technique allows us to analyze predominantly the firing frequency of
      neurons. Thus, the in vivo patch-clamp recordings from dorsal horn neurons and
      the intracellular recordings from DRG neurons will be useful for well
      understanding the sensory processing in the spinal cord.

PMID- 15041444
TI  - Effects of the suppression of acute herpetic pain by gabapentin and amitriptyline
      on the incidence of delayed postherpetic pain in mice.
AB  - The inoculation of mice with herpes simplex virus type-1 (HSV-1) causes herpes
      zoster-like skin lesions and pain-related responses (tactile allodynia and
      mechanical hyperalgesia) from day 5 after inoculation. Skin lesions completely
      heal by day 15 after inoculation, but about half of mice with acute herpetic pain
      show pain-related responses long after the lesions heal. Using this mouse model,
      we examined the effects of repeated administration of gabapentin and
      amitriptyline on the acute herpetic pain and the incidence of postherpetic pain.
      Gabapentin and amitriptyline were administered three times daily from day 5 to 11
      after inoculation. Postherpetic pain-related responses were assessed on day 30
      after inoculation. Gabapentin (10-100 mg/kg) produced the dose-dependent
      inhibition of acute herpetic pain-related responses. This medication produced
      marked reduction in the incidence of delayed postherpetic pain and the dose of
      100 mg/kg produced the complete inhibition. Amitriptyline (10 mg/kg) did not
      affect the acute pain-related responses in the initial 3- and 2-day periods and
      then gradually inhibited them. This dosage produced a substantial but non
      significant decrease in the incidence of postherpetic pain-related responses.
      Amitriptyline (1 and 3 mg/kg) was without effects on acute herpetic and
      postherpetic pain-related responses. The results strongly support the idea that
      the severity of the acute herpetic pain is a risk factor of postherpetic
      neuralgia. It may be worth testing the effects of gabapentin on acute herpetic
      pain and the incidence of postherpetic neuralgia in human subjects.

PMID- 15041445
TI  - Distribution and immunocytochemical characterization of dorsal root ganglion
      neurons innervating the lumbar intervertebral disc in rats: a review.
AB  - Previously, it was believed that the lumbar intervertebral disc was innervated
      segmentally by dorsal root ganglion (DRG) neurons via the sinuvertebral nerves.
      Recently, it was demonstrated using retrograde tracing methods that the lower
      disc (L5-L6) is innervated predominantly by upper (L1 and L2) DRG neurons via the
      sympathetic trunks. Furthermore, we investigated the expression of various pain
      related molecules such as calcitonin gene-related peptide (CGRP), isolectin B4
      (IB4), P2X(3) receptor and vanniloid receptor 1 (VR1) in DRG neurons innervating
      the disc using a combination of immunostaining with the retrograde tracing
      method. This review outlines the distribution and immunocytochemical
      characterization of DRG neurons innervating the disc. Small nociceptive DRG
      neurons are classified into nerve growth factor (NGF)-dependent neurons and glial
      cell line-derived neurotrophic factor (GDNF)-dependent neurons and they can be
      distinguished by their reactivity for CGRP and IB4, respectively. We found that
      about half of the neurons innervating the disc were CGRP-immunoreactive (-ir),
      whilst, only 0.6% of the DRG neurons were IB4-positive, thereby indicating that
      NGF-dependent neurons are the main subpopulation which transmits and modulates
      nociceptive information from the disc. In addition, we also demonstrated P2X(3)-
      and VR1-immunoreactivity in DRG neurons innervating the disc and noted that they
      were mainly localized in NGF-dependent neurons. It is well known that NGF has
      sensitizing effects on DRG neurons, with a recent study demonstratng the presence
      of NGF in the painful intervertebral disc. Therefore, it is suggested that NGF is
      involved in the generation of discogenic low back pain.

PMID- 15041446
TI  - MAPK activation in nociceptive neurons and pain hypersensitivity.
AB  - Extracellular signal-regulated protein kinase (ERK) is a mitogen-activated
      protein kinase (MAPK) that mediates intracellular signal transduction in response
      to a variety of stimuli. ERK is involved in cell proliferation and
      differentiation and in neuronal plasticity, including long-term potentiation,
      learning, and memory. Here, we present recently accumulating data about the roles
      of MAPK pathways in mediating the neuronal plasticity that contributes to pain
      hypersensitivity. The phosphorylation of ERK in the dorsal root ganglion (DRG)
      and dorsal horn neurons occurs in response to noxious stimulation of the
      peripheral tissue or electrical stimulation to the peripheral nerve, i.e.,
      activity-dependent activation of ERK in nociceptive neurons. In addition, the
      activation of ERK occurs in these nociceptive neurons after peripheral
      inflammation and axotomy and contributes to persistent inflammatory and
      neuropathic pain, via transcriptional regulation of key gene products. On the
      other hand, peripheral inflammation and axotomy also induces p38 MAPK activation
      in DRG neurons. Taken together, these findings indicate that activation of MAPK
      in nociceptive neurons may participate in generating pain hypersensitivity
      through transcription-dependent and -independent means. Thus, inhibition of MAPK
      signaling in the primary afferents, as well as in the spinal cord, may provide a
      fruitful strategy for the development of novel analgesics.

PMID- 15041447
TI  - Molecular mechanism of changes in the morphine-induced pharmacological actions
      under chronic pain-like state: suppression of dopaminergic transmission in the
      brain.
AB  - In the present study, we demonstrated whether a neuropathic pain-like state
      induced by sciatic nerve ligation in rodents could cause a long-lasting change in
      intracellular signaling in both supraspinal and spinal cord related to the
      suppression of morphine's effect. Mice with sciatic nerve ligation exhibited a
      significant suppression of the morphine-induced antinociception. Under this
      condition, phosphorylated-conventional protein kinase C-like immunoreactivity (p
      cPKC-IR) and phosphorylated-micro-opioid receptor (p-MOR)-IR were clearly
      increased on the ipsilateral side in the dorsal horn of the spinal cord of nerve
      ligated mice. It is of interest to note that astroglial hypertrophy as well as
      its proliferation was also noted in this area of sciatic nerve-ligated mice. Like
      nerve injury, the increase in cPKC activities and astroglial
      hypertrophy/proliferation in this region was observed by repeated morphine
      treatment. These findings suggest that the phosphorylation of both cPKC and MOR
      in the dorsal horn of the spinal cord by sciatic nerve ligation may play a
      substantial role in the suppression of morphine-induced antinociception under a
      neuropathic pain-like state. Sciatic nerve injury also caused a significant
      inhibition of MOR-mediated G-protein activation onto GABAergic neurons and a
      dramatic reduction in ERK activities onto dopaminergic neurons in the ventral
      tegmental area (VTA) regulating the rewarding effect of opioids. Furthermore, we
      found that the inhibition of ERK cascade in the VTA by treatment with specific
      inhibitors suppressed the morphine-induced rewarding effect in normal mice. These
      findings provide evidence that the direct reduction in MOR function and the
      persistent decrease in ERK activity of dopaminergic neurons in the VTA may
      contribute to the suppression of the morphine-induced rewarding effect under a
      neuropathic pain-like state. Conclusively, our recent findings provide novel
      evidences for the mechanism underlying the less sensitivity to opioids under a
      neuropathic pain-like state.

PMID- 15041449
TI  - The assessment of ocular injury by ultrasound.
AB  - Ocular trauma is readily investigated by ultrasound, which is of particular value
      when the light conducting media are opacified by haemorrhage or other injury. In
      this situation, direct visualization of the ocular contents by ophthalmoscopy is
      difficult or impossible. Severe complications are treated by microsurgical
      techniques, and ultrasound evaluation represents the only practicable method of
      examination for surgical planning. This review illustrates the grey-scale (B scan
      or two-dimensional) features of the traumatized eye and describes the examination
      technique.

PMID- 15041450
TI  - Melanoma.
AB  - The incidence of malignant melanoma in the UK is still rising despite public
      health warnings about the risks of excessive sun exposure. This aggressive tumour
      can metastasize to virtually any organ, even years after resection of the primary
      lesion and cause a variety of radiological appearances. This review provides
      examples of both typical and non-specific imaging features of melanoma
      metastases, as well as examples of primary choroidal melanoma.

PMID- 15041451
TI  - Essentials of shoulder MR arthrography: a practical guide for the general
      radiologist.
AB  - Lesions of the glenoid labrum and ligamentous structures commonly occur secondary
      to shoulder trauma and are a frequent cause of shoulder joint instability.
      Numerous eponyms, acronyms and subclassifications are used to describe the often
      confusing array of bony and labro-ligamentous abnormalities of the shoulder. This
      aim of this review is to illustrate the relevant features of these lesions and to
      provide a systematic and practical approach to imaging of the shoulder using MR
      arthrography.

PMID- 15041452
TI  - Magnetic resonance angiography in potential live renal donors: a joint
      radiological and surgical evaluation.
AB  - AIM: To assess the impact of a joint surgical and radiological audit on the
      accuracy of contrast-enhanced magnetic resonance angiography (MRA) reports in the
      evaluation of potential renal donors. MATERIALS AND METHODS: We analysed the
      records of live renal donors who underwent gadolinium-enhanced MRA as part of the
      pre-operative evaluation to assess renal vasculature between August 1999 and July
      2002 when feedback from surgical findings to radiology had been available. In
      cases of discrepancy between MRA reports and surgical findings, studies were
      retrieved from the magnetic resonance imaging (MRI) workstation and subjected to
      detailed joint clinical and radiological review. Scan quality was assessed and
      sources of discrepancy were identified. RESULTS: There were 45 donors, 23 men and
      22 women with a mean age of 41 years. Reported MRA findings were fully confirmed
      at surgery in 38 of 45 cases. These images were not analysed further. In seven
      donors the findings at surgery were discrepant with the radiological reports:
      there were four cases of "missed" early branches and three cases of "missed"
      accessory arteries. In the first year of the audit there were four discrepant
      cases out of 18 (22%), all of which were radiological reporting errors. The
      number of discrepant cases in the second year was two out of 19 cases (11%).
      Neither of these was a radiological reporting error. There was one "missed" early
      renal artery branch in the third year of audit, which was identified on MRA
      review. CONCLUSION: The study highlights the importance of detecting and clearly
      reporting not only accessory renal arteries, but also early renal arterial
      branches in the pre-operative evaluation of renal donors. The accuracy of pre
      operative MRA in potential renal donors is high, but radiological reporting of
      MRA examinations is improved through careful clinical feedback, audit and
      interdisciplinary co-operation.

PMID- 15041453
TI  - CT diagnosis of splenic infarction in blunt trauma: imaging features, clinical
      significance and complications.
AB  - AIM: The object of this study is to describe the appearance, complications, and
      outcome of segmental splenic infarctions occurring after blunt trauma using
      computed tomography (CT). MATERIALS AND METHODS: Thirteen blunt trauma patients
      were identified with splenic infarction on contrast-enhanced CT. CT images were
      retrospectively reviewed and the percentage of infarcted splenic tissue and
      presence of splenic injury separate from the site of infarction were identified.
      Splenic angiograms were reviewed and follow-up CT images were assessed for
      interval change in the appearance of the infarcts. RESULTS: The mean age of
      patients was 32 years and the most common mechanism of injury was road traffic
      accident. The majority (54%) had 25-50% infarction of the spleen. Splenic
      angiograms were performed in nine patients and seven demonstrated wedge-shaped
      regions of decreased perfusion corresponding to the infarction seen on CT with no
      need for intervention. Eleven patients underwent a follow-up CT that demonstrated
      the following: no significant change in six, near-complete resolution in two,
      delayed appearance of infarction in one, abscess formation in one, and delayed
      splenic rupture in one. CONCLUSION: Segmental splenic infarction is a rare
      manifestation of blunt splenic trauma. The diagnosis is readily made using
      contrast-enhanced CT. The majority will decrease in size on follow-up CT and
      resolve without clinical sequelae. Resolution of infarction is also seen and
      these cases are best described as temporary perfusion defects. Splenic abscess or
      delayed rupture are uncommon complications that may necessitate angiographic or
      surgical intervention.

PMID- 15041454
TI  - To clot or not to clot? That is the question in central venous catheters.
AB  - AIM: To establish the relationship between the tip position of tunnelled central
      venous catheters (CVC) and the incidence of venous thrombosis. MATERIALS AND
      METHODS: A randomly sampled, retrospective review of 428 CVC inserted into 334
      patients was performed. The chest radiograph obtained post-catheter insertion, as
      well as follow-up radiographs, linograms, venograms and Doppler ultrasounds (US),
      were reviewed. RESULTS: The median follow-up was 72 days (range 1-720 days), with
      a total follow-up of 23,040 line days. Venous thrombosis occurred in five out of
      191 (2.6%) CVC in a distal position (distal third of the superior vena cava (SVC)
      or right atrium (RA)), five of 95 (5.3%) in an intermediate position (middle
      third of the SVC) and 20 of 48 (41.7%) in a proximal position (proximal third SVC
      or thoracic inlet veins). There was a significant difference in thrombosis rate
      between lines sited with the tip in a distal compared with a proximal position
      (p<0.0005). CVC with tips in a proximal position were 16 times more likely to
      thrombose than those in a distal position. None of the 58 CVC with the tip
      located in the RA thrombosed or caused complications. CONCLUSION: Distal
      placement of tunnelled CVC, either in the distal third of the SVC or proximal RA
      is optimal.

PMID- 15041455
TI  - Conventional digital subtraction x-ray angiography versus magnetic resonance
      angiography in the evaluation of carotid disease: patient satisfaction and
      preferences.

PMID- 15041456
TI  - Conventional digital subtraction x-ray angiography versus magnetic resonance
      angiography in the evaluation of carotid disease: patient satisfaction and
      preferences.
AB  - AIM: To compare conventional digital subtraction x-ray angiography (DSA) and
      contrast-enhanced magnetic resonance angiography (MRA) of the carotid arteries in
      terms of patient satisfaction and preferences. METHODS: One hundred and sixty
      seven patients with symptomatic carotid artery disease, who underwent both DSA
      and MRA, were prospectively recruited in this study. Patients' perceptions of
      each method were assessed by the use of a questionnaire after each procedure.
      Main outcome measures were anxiety, pain, satisfaction rate and patient
      preferences. RESULTS: DSA generated more anxiety and pain during the procedure,
      but the severity of these ill-effects was mild. Satisfaction rates for each
      method were similar. More patients were, however, willing to have a repeat MRA
      compared with DSA (67 versus 41%). The majority of patients (62%) preferred MRA
      over DSA (31%). The shorter MRA imaging time was found to be a significant factor
      in patients' acceptance of the technique. The main reasons cited by patients for
      their dislike of a particular procedure was noise and claustrophobia for MRA and
      invasiveness, pain and post-procedural bed rest for DSA. CONCLUSIONS: MRA is the
      method that is preferred by the majority of patients, although the actual
      disutility of DSA may be small. Assuming equal diagnostic accuracy, our data
      supports replacement of DSA by MRA for routine carotid imaging.

PMID- 15041457
TI  - Complications from radiographer-performed double contrast barium enemas.
AB  - AIM: To determine the types and rates of complications encountered by
      radiographers when performing double contrast barium enemas (DCBE). MATERIALS AND
      METHODS: Seven hundred and forty-one questionnaires were posted to radiographers
      who had in the last 5 years attended one of the biannual barium enema training
      courses. RESULTS: Of 741 questionnaires posted 407 (54.9%) were returned
      completed. Approximately 348,000 barium enema examinations had been performed.
      Fifty-nine radiographers reported 89 complications, including 13 intra-peritoneal
      and 11 extra-peritoneal perforations. There were five deaths (mortality 1 in
      70,000). Deaths resulted from two of 24 (10%) perforations, two of 45 (5%)
      cardiac events and one cerebrovascular accident that occurred during an
      examination. CONCLUSIONS: Radiographers have been regularly performing DCBEs for
      almost a decade. The mortality for radiographer-performed DCBE is similar to that
      previously reported for radiologists, although a slightly higher rate of
      perforation is noted and so this is an area where radiographer training should be
      targeted.

PMID- 15041458
TI  - Does Doppler analysis of musculoskeletal soft-tissue tumours help predict tumour
      malignancy?
AB  - AIM: To investigate whether analysing vascularity of soft-tissue tumours on
      ultrasound assists differentiating benign from malignant tumours. MATERIALS AND
      METHODS: One hundred and forty-eight vascular soft-tissue tumours in 148 patients
      (88 males, mean age 45.6 years) were studied. Final diagnosis was established
      histologically in 95 (64%) of cases. For each tumour, three-colour Doppler
      imaging features (vascularity, vascular density, vascular organization) and 13
      pulsed Doppler (spectral analysis) parameters were assessed. Data analysis was
      performed to isolate optimal discriminatory criteria for differentiating benign
      from malignant tumours. RESULTS: Significantly more benign soft-tissue tumours
      had an organized vascular pattern on colour Doppler imaging. If the vascular
      pattern is organized, this is a good indicator of tumour benignity. However, this
      pattern was apparent in less then one-third of the soft-tissue tumours. Benign
      tumours also had significantly higher minimum end diastolic velocity (EDVmin) and
      lower mean ratio of resistive index (RImean) than malignant soft-tissue tumours,
      though considerable overlap existed between the two groups. CONCLUSION: Colour
      Doppler imaging analysis of soft-tissue tumours is of limited value when
      differentiating benign from malignant tumours. If an organized vascular pattern
      is present, the tumour is more likely to be benign. Flow characteristics were not
      specific enough to be applicable in clinical practice.

PMID- 15041459
TI  - Parosteal (nodular) fasciitis of the hand.

PMID- 15041461
TI  - Fluorescence microscopy studies with a fluorescent glibenclamide derivative, a
      high-affinity blocker of pancreatic beta-cell ATP-sensitive K+ currents.
AB  - Hypoglycemic sulfonylureas (e.g. tolbutamide, glibenclamide) exert their
      stimulatory effects on pancreatic beta-cells by closure of ATP-sensitive K(+)
      (K(ATP)) channels. Pancreatic K(ATP) channels are composed of two subunits, a
      pore-forming inwardly rectifying K(+) channel (Kir6.2) subunit and a regulatory
      subunit (the sulfonylurea receptor of subtype 1 (SUR1)) in a (SUR1/Kir6.2)(4)
      stoichiometry. The aim of the present study was to characterize the interaction
      of green-fluorescent 3-[3-(4,4 difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-S-indacen
      3-yl)propanamido] glibenclamide (Bodipy-glibenclamide) with pancreatic beta-cell
      K(ATP) channels using patch-clamp and fluorescence microscopy techniques. Bodipy
      glibenclamide inhibited K(ATP) currents from the clonal insulinoma cell line
      RINm5F half-maximally at a concentration of 0.6nM. Using laser-scanning confocal
      microscopy Bodipy-glibenclamide was shown to induce a diffuse fluorescence across
      the RINm5F cell, but only about 17% of total Bodipy-glibenclamide-induced
      fluorescence intensity in RINm5F cells was due to specific binding to SUR1. Using
      fluorescence correlation spectroscopy, it could be demonstrated that the
      fluorescence label contributes to the protein binding and, therefore, possibly
      also to the non-specific binding of Bodipy-glibenclamide observed in RINm5F
      cells. Specific binding of Bodipy-glibenclamide to SUR1 in RINm5F cells might be
      localized to different intracellular structures (nuclear envelope, endoplasmic
      reticulum, Golgi compartment, insulin secretory granules) as well as to the
      plasma membrane. In conclusion, Bodipy-glibenclamide is a high-affinity blocker
      of pancreatic beta-cell K(ATP) currents and can be used for visualizing SUR1 in
      intact pancreatic beta-cells, although non-specific binding must be taken into
      account in confocal microscopy experiments on intact beta-cells.

PMID- 15041460
TI  - Down-regulation of cytochrome P450 proteins and its activities by Shiga-like
      toxin II from Escherichia coli O157:H7.
AB  - Escherichia coli O157:H7 infection frequently induces clinical complications such
      as hemolytic uremic syndromes and intestinal dysfunctions. These changes could
      alter the disposition of drugs, consequently changing their efficacy. However,
      the possible changes of drug-metabolizing activities by E. coli O157:H7 infection
      have not been addressed. Thus, we have investigated the effect of Shiga-like
      toxin type II (SLT-II), derived from E. coli O157:H7, on the hepatic cytochrome
      P450 (CYP) content and its activity in rats. SLT-II (2microg per animal, i.v.)
      time-dependently decreased total CYP content and the contents of CYP2C11 and
      CYP3A2 in hepatic microsomal preparations up to 24hr following injection.
      Consistently, SLT-II time-dependently decreased CYP activity in vivo, as
      represented by systemic clearance of antipyrine. An inhibitor of inducible nitric
      oxide synthase, S-methylisothiourea, restored the decreased systemic clearance of
      antipyrine by SLT-II, suggesting the involvement of the overproduction of nitric
      oxide by SLT-II. Moreover, dexamethasone restored the decreased systemic
      clearance of antipyrine by SLT-II. In the hepatic microsomal preparation,
      dexamethasone restored the SLT-II-induced decrease of CYP3A2 whereas S
      methylisothiourea did not affect both CYP subtypes. Taken together, these results
      suggest that SLT-II might alter hepatic drug-metabolizing function during E. coli
      O157 infection and that more than one cytokines induced by SLT-II, including
      nitric oxide, might make a critical contribution to the decrease of CYP content
      and its activity.

PMID- 15041462
TI  - Arachidonic and eicosapentaenoic acid metabolism by human CYP1A1: highly
      stereoselective formation of 17(R),18(S)-epoxyeicosatetraenoic acid.
AB  - Human cytochrome P450 1A1 (CYP1A1) and human NADPH-cytochrome P450 reductase were
      expressed and purified from Spodoptera frugiperda insect cells. A reconstituted
      enzymatically active system metabolized polyunsaturated fatty acids such as
      arachidonic (AA) and eicosapentaenoic acid (EPA). CYP1A1 was an AA hydroxylase
      which oxidizes this substrate at a rate of 650+/-10 pmol/min/nmol CYP1A1, with
      over 90% of metabolites accounted for by hydroxylation products and with 19-OH-AA
      as major product. Epoxyeicosatrienoic acid (EET), mainly 14,15-EET, accounted for
      about 7% of total metabolites. Unlike rat CYP1A1, the human enzyme exhibited no
      20-OH-AA as product. In contrast, with EPA as substrate CYP1A1 was mainly an
      epoxygenase, oxidizing with over 68% of total metabolites EPA to 17(R),18(S)
      epoxyeicosatetraenoic acid (17(R),18(S)-EETeTr). 19-OH-EPA accounted for about
      31% of total metabolites. Significantly, the 17,18-olefinic bond of EPA was
      epoxidized to 17(R),18(S)-EETeTr with nearly absolute regio- and
      stereoselectivity. Molecular modeling analyses provided rationale for high
      efficiency of AA hydroxylation at C(19) and its gradual decrease down to C(14),
      as well as for the limited EPA 17(S),18(R) epoxidation due to unfavorable enzyme
      substrate interactions. The absence of omega-hydroxylation for both substrates is
      not due to steric factors, but probably a consequence of different reactivities
      of omega and (omega-1) carbons for hydrogen abstraction. It is suggested that the
      capacity of human CYP1A1 to metabolize AA and EPA and its inducibility by
      polycyclic aromatic hydrocarbons may affect the production of physiologically
      active metabolites, in particular, in the cardiovascular system and other
      extrahepatic tissues including lung.

PMID- 15041463
TI  - Cisplatin-induced apoptosis in Hep3B cells: mitochondria-dependent and 
      independent pathways.
AB  - Human hepatoma cell lines undergo apoptosis after treatment with cisplatin (CP),
      by mechanisms that are not fully understood, although our previous study
      demonstrated that Fas-dependent or -independent pathways are involved. To
      elucidate the mechanisms of CP-induced apoptosis in Hep3B cells, which are Fas-
      and p53-negative, we investigated mitochondria associated pathways, the
      involvement of NF-kappaB, and p73 activation. Results of Western blot and flow
      cytometry assay revealed that the translocation of Bax, resulted in the loss of
      mitochondrial membrane potential (Deltaphi(m)) and the efflux of cytochrome c and
      of second mitochondria-derived activator of caspase/DIABLO from mitochondria into
      the cytosol. Caspase-3, -8 and -9 were activated by CP treatment, however, CP
      induced apoptosis was not completely blocked by pretreating with the pan-caspase
      inhibitor, benzyloxycarbonyl-valinyl-alaninyl-aspartyl-(O-methyl)
      fluoromethylketone, indicating that caspase-independent apoptotic pathways might
      also be involved. RNase protection assay confirmed that NF-kappaB downregulation
      leading to the suppression of its target genes, such as XIAP and TRAF2, and p73
      accumulation were also observed in Hep3B cells treated with CP. CP-induced
      apoptosis was inhibited to some extent by transiently overexpressed p73 dominant
      negative and XIAP, but not by p73DN or XIAP alone. In conclusion, this study
      demonstrates that CP-induced apoptosis in Hep3B cells is associated with
      mitochondrial dysregulation, NF-kappaB downregulation and p73 accumulation.

PMID- 15041465
TI  - Iron mobilization, cytoprotection, and inhibition of cell proliferation in normal
      and transformed rat hepatocyte cultures by the hydroxypyridinone CP411, compared
      to CP20: a biological and physicochemical study.
AB  - The present study analyzes the iron mobilization, the cytoprotective, and the
      antiproliferative effects of the lipophilic hydroxypyridinone CP411, in
      comparison with the hydrophilic chelator CP20 or deferiprone used in the
      treatment of iron overload. Primary rat hepatocyte cultures and the rat hepatoma
      cell line Fao were used. Chelator cell uptake was evaluated by mass spectrometry
      in the two models. This method was also used to investigate the stability of the
      chelators in an acellular system as well as their scavenging and chelating
      effects against the hydroxyl radical generated by the Fenton reaction. The iron
      mobilization and the cytoprotective effects of the chelators were evaluated in
      primary cultures by measuring respectively 55Fe and lactate dehydrogenase release
      in the culture medium. The antiproliferative effect of the chelators was studied
      using the Fao cell line and measuring DNA synthesis by thymidine incorporation
      and DNA content by flow cytometry. We observed that CP411 entered the hepatocytes
      and the Fao cells respectively 4 and 13 times more than CP20. CP411 was 2.5 times
      more effective than CP20 to mobilize iron from preloaded hepatocytes.
      Pretreatment of the hepatocytes with CP20 or CP411 decreased the toxic effect of
      iron and CP411 was 1.6 times more effective than CP20. A dose-dependent decrease
      of DNA synthesis, correlated to an accumulation of cells in S phase, was observed
      in the Fao cell line in the presence of CP411, while CP20 was without effect.
      CP411 effect was inhibited by addition of iron simultaneously with the chelator,
      the addition of Zn or Cu was without effect. The inhibitory effect of CP411 was
      reversible since, 24hr after removal of the chelator, DNA replication reached the
      control level. The results show that CP411 is more efficient to protect the
      hepatocyte from the toxic effect of iron load and to inhibit tumor cell
      proliferation. Its higher efficiency may result from its better cell uptake since
      equimolar solutions of the two chelators in an acellular system exhibit the same
      ability to inhibit the Fenton reaction.

PMID- 15041464
TI  - Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of
      celecoxib in human colon carcinoma cells.
AB  - Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is the only non
      steroidal anti-inflammatory drug so far which has been approved by the FDA for
      adjuvant treatment of patients with familial adenomatous polyposis. The molecular
      mechanism responsible for the anticarcinogenic effects of celecoxib is still not
      fully understood. To investigate the extent to which the anticarcinogenic effect
      of celecoxib depends on COX-2 expression, we transfected human colon carcinoma
      cells (Caco-2) with the human COX-2 cDNA, in both sense and in antisense
      orientation, to generate cells which either overexpress COX-2 (human COX-2-sense,
      hCOX-2-s), express no COX-2 (human COX-2-antisense, hCOX-2-as) or express only
      very small amounts of COX-2 (control cells). Treatment of these cells with
      celecoxib dose-dependently (0-100microM) reduced cell survival which was
      accompanied by an induction of a G(0)/G(1) phase block and apoptosis. The effect
      of celecoxib treatment on both, cell survival and induction of apoptosis in hCOX
      2-as cells was less marked than in the COX-2-expressing cells. Apoptosis was
      accompanied by an activation of caspase-3 and caspase-9 and cytochrome c release.
      In contrast, we observed no difference in sensitivity with regard to the
      induction of a cell cycle block between the different cell clones. The G(0)/G(1)
      phase block caused by celecoxib correlated with a decrease in expression levels
      of cyclin A and cyclin B1 and an increase in the expression of the cell cycle
      inhibitory proteins p21(Waf1) and p27(Kip1) irrespective of the type of cell
      used. These data indicate that apoptosis-inducing effects of celecoxib partly
      depend on COX-2 expression of the cells, whereas induction of a cell cycle block
      occurred COX-2 independently. Thus, the anticarinogenic effects of celecoxib can
      be explained by both COX-2-dependent and -independent mechanisms.

PMID- 15041466
TI  - Reactive blue 2 inhibition of cyclic AMP-dependent differentiation of rat C6
      glioma cells by purinergic receptor-independent inactivation of
      phosphatidylinositol 3-kinase.
AB  - Cyclic AMP-dependent differentiation of rat C6 glioma cells into an astrocyte
      type II is characterized by inhibition of cell growth and induction of glial
      fibrillary acidic protein (GFAP) synthesis. Activation of the P2Y(12) receptor
      with 2-methylthioadenosine-5'-diphosphate inhibited beta-adrenergic receptor
      induced differentiation. The selective P2Y(12) receptor antagonist N(6)-(2
      methylthioethyl)-2-(3,3,3-trifluoropropylthio)-beta,gamma-dichloromethylene ATP
      abolished the receptor-mediated effect on differentiation. In contrast non
      selective antagonists of P2Y receptors did not revert the inhibiting effect of
      the P2Y(12) receptor on differentiation. Reactive blue 2 (RB2), a potent P2Y(12)
      receptor antagonist, completely inhibited the synthesis of GFAP, while the P2Y
      receptor antagonists suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic
      acid were less efficient. However, although P2Y receptor antagonists inhibited
      GFAP synthesis to a different extent they were unable to relieve the growth
      inhibition that accompanied induction of differentiation, whereas stimulation of
      the P2Y(12) receptor with 2-methylthioadenosine-5'-diphosphate inhibited GFAP
      expression and restored cell proliferation. Assay of the activity of
      phosphatidylinositol 3-kinase (PI 3-K), an enzyme required for GFAP expression
      [J. Neurochem. 76 (2001) 610], showed that RB2 inhibited this enzyme after
      cellular uptake, while suramin and pyridoxalphosphate-6-azophenyl-2',4'
      disulfonic acid inhibited PI 3-K to a lesser extent. The intracellular
      concentration of RB2 increased in time and attained the ic(50) for PI 3-K
      inhibition (4microM) after 40-min incubation with 50microM RB2. In conclusion,
      cAMP-induced differentiation in C6 cells is inhibited by activation of the
      P2Y(12) receptor. In addition, synthesis of GFAP is also inhibited by cellular
      uptake of non-selective nucleotide receptor antagonists that inhibit PI 3-K, a
      kinase required for the cAMP-dependent induction of differentiation.

PMID- 15041467
TI  - Nuclear factor Y regulation and promoter transactivation of human ribonucleotide
      reductase subunit M2 gene in a Gemcitabine resistant KB clone.
AB  - Overexpression of human ribonucleotide reductase subunit M2 (hRRM2) has been
      shown as a potential factor causing Gemcitabine (Gem) resistance. We hypothesized
      the nuclear factor Y (NF-Y) would transcriptionally regulate hRRM2 and contribute
      to overexpression of hRRM2 in a Gem resistant clone. A luciferase and gel shift
      assay, and a Southwestern blot were employed to analyze the promoter activity of
      hRRM2. The data exhibited the hRRM2 promoter was upregulated almost 5-fold in the
      Gem resistant KB clone (KBGem) via three sequential CCAAT boxes located in the
      proximal promoter region. Nuclear extracts from KB and KBGem could interact with
      the CCAAT motif of the hRRM2 proximal promoter region, and could form DNA-protein
      complexes with different binding patterns. The complexes could be further
      recognized with antibodies against NF-Y subunits A and B. Histone deacetylases
      (HDAC) involvement in NF-Y transcription repression in the KBGem clone was
      examined. A HDAC activity assay revealed a 3-fold decrease of HDAC activity in
      the KBGem clone compared to KB cells. Parental cells were treated with
      trichostatin A (TSA), a HDAC inhibitor. NF-Y transactivation was induced,
      resulting in an increase of hRRM2 expression. This led to an expanded dCTP pool
      and an abrogated [3H]Gemcitabine incorporation. In addition, microarray analysis
      results showed most of the proliferation-related genes were upregulated in KBGem.
      This finding was consistent with enhanced NF-Y transactivation in KBGem. In
      summary, upregulation of NF-Y transactivation increased hRRM2 transcription,
      which played a pivotal role in the Gem resistant KB clone.

PMID- 15041468
TI  - Calpain as a multi-site regulator of cell cycle.
AB  - Calpain has long been implicated in the regulation of cell cycle, mostly based on
      studies with inhibitors that lack strict specificity toward the enzyme. Further,
      previous work has primarily focused on one particular point, the G(1) checkpoint,
      and made no attempt at dissecting the full cycle in terms of calpain action. To
      extend and complement these findings, we tested the effect of a specific
      inhibitor, PD 150606, on granulocyte-macrophage-colony stimulating factor (GM
      CSF)-stimulated human TF-1 cells by flow cytometry following single- and double
      labelling by propidium iodide and bromodeoxyuridine. Using a new algorithm of
      analysis, we determined the time-dependence of the absolute number of cells
      leaving G(1), S and G(2)M phases following the application of the inhibitor. Our
      results point to the simultaneous involvement of calpain activity in promoting
      the cycle at the G(1) checkpoint and somewhere in the G(2)M compartment.
      Furthermore, the inhibitor significantly impedes the progress of cells through
      the S phase, indicating calpain activity in S phase checkpoint signalling.
      Overall, our analysis suggests that calpain regulates the cell cycle at more
      points than previously thought.

PMID- 15041469
TI  - Reduction of androgen receptor expression by benzo[alpha]pyrene and 7,8-dihydro
      9,10-epoxy-7,8,9,10-tetrahydrobenzo[alpha]pyrene in human lung cells.
AB  - 5Alpha-dihydrotestosterone significantly increased cell growth of lung
      adenocarcinoma cell line H1355. Benzo[alpha]pyrene (BaP) was a pulmonary
      carcinogen found in cigarette smoke. Treatment with 1microM BaP tremendously
      reduced constitutive androgen receptor (AR) expression, as determined with
      Western immunoblotting and the real-time RT-PCR assay, as well as testosterone
      induced AR protein levels in H1355 cells. Similarly, 1microM BaP significantly
      reduced AR mRNA levels in human bronchial epithelial cells BEAS-2B. Although BaP,
      2,3,7,8-tetrachlorodibenzo-p-dixin and polychlorinated biphenyl 126 activated
      aryl hydrocarbon receptor (AhR), which subsequently induced cytochrome P4501A1
      (CYP1A1) and P4501B1 (CYP1B1) expression in H1355 cells, unexpectedly, neither
      TCDD nor PCB126 reduced AR expression. Antagonizing AhR activation and cytochrome
      P4501 activity with alpha-naphthoflavone, or inhibiting CYP1B1 activity with
      2,4,3',5'-tetramethoxystilbene, however, prevented BaP-induced AR reduction.
      Furthermore, 7,8-dihydro-9,10-epoxy-7,8,9,10-tetrahydrobenzo[alpha]pyrene, a BaP
      carcinogenic metabolite catalyzed by CYP1A1 and CYP1B1, significantly reduced AR
      expression in H1355 cells and human lung fibroblasts WI-38. This was the first
      study that reports that BaP and BPDE reduced endogenous AR expression. These data
      suggest that metabolically activated BaP may disrupt androgen function by
      reducing AR levels in androgen-responsive organs.

PMID- 15041470
TI  - Suppression of receptor-mediated Ca2+ mobilization and functional leukocyte
      responses by hyperforin.
AB  - We have recently identified hyperforin, a lipophilic constituent of the herb
      Hypericum perforatum (St. John's wort), as a dual inhibitor of the
      proinflammatory enzymes cyclooxygenase-1 and 5-lipoxygenase. The aim of the
      present study was to further elucidate antiinflammatory properties and respective
      targets of hyperforin. We found that hyperforin inhibited the generation of
      reactive oxygen species (ROS) as well as the release of leukocyte elastase
      (degranulation) in human isolated polymorphonuclear leukocytes (PMNL), challenged
      by the G protein-coupled receptor (GPCR) ligand N-formyl-methionyl-leucyl
      phenylalanine (fMLP) with an IC 50 approximately equal 0.3 microM. When PMNL were
      stimulated with phorbol-12-myristate-13-acetate (PMA) or ionomycin, hyperforin
      (up to 10 microM) failed to inhibit ROS production and elastase release,
      respectively. Moreover, hyperforin blocked receptor-mediated Ca(2+) mobilization
      ( IC 50 approximately equal 0.4 and 4 microM, respectively) in PMNL and monocytic
      cells, and caused a rapid decline of the intracellular Ca(2+) concentration in
      resting cells. In contrast, the Ca(2+) influx induced by ionomycin or
      thapsigargin was not suppressed. Comparative studies with the specific
      phospholipase C inhibitor U-73122 and hyperforin revealed similarities between
      both compounds. Thus, U-73122 and hyperforin blocked fMLP- and PAF-induced Ca(2+)
      mobilization, ROS formation, and elastase release, but failed to suppress these
      responses when cells were stimulated by PMA or ionomycin. Also, both compounds
      rapidly decreased basal Ca(2+) levels in resting cells and led to a rapid decline
      of the Ca(2+) elevations evoked by fMLP or PAF. Our data suggest that hyperforin
      targets component(s) within G protein signaling cascades that regulate Ca(2+)
      homeostasis, coupled to proinflammatory leukocyte functions.

PMID- 15041471
TI  - Folate concentration dependent transport activity of the Multidrug Resistance
      Protein 1 (ABCC1).
AB  - The Multidrug Resistance Protein MRP1 (ABCC1) can confer resistance to a variety
      of therapeutic drugs. In addition, MRP1/ABCC1 mediates cellular export of natural
      folates, such as folic acid and l-leucovorin. In this study we determined whether
      cellular folate status affected the functional activity of MRP1/ABCC1 mediated
      efflux of an established substrate, the anthracycline daunorubicin (DNR). As a
      model system we used the human ovarian carcinoma cell line 2008wt, and its
      MRP1/ABCC1 transfected subline 2008/MRP1. Both types of these moderate- and high
      MRP1/ABCC1 expressing cells displayed efflux of DNR when maintained in standard
      culture media (2.3microM folic acid). The initial total cellular DNR efflux rate
      in 2008/MRP1 cells was approximately 2-fold higher compared to 2008wt cells. This
      efflux consisted of MRP1/ABCC1 mediated transport, possibly non-MRP1 mediated
      transport, as well as passive diffusion. Benzbromarone, a specific MRP1
      inhibitor, decreased the initial efflux rate in 2008/MRP1 cells (4-fold) and in
      2008wt cells (2-fold). When 2008/MRP1 cells were challenged for 2 days in folate
      free medium, total cellular DNR efflux was decreased to 43% of the initial efflux
      rate under folate-rich conditions. In 2008wt cells DNR efflux was decreased to
      84% of the folate-rich conditions. Benzbromarone did not inhibit DNR efflux after
      the folate-free period in both cell lines. Repletion of folate by a 2-24hr
      exposure to 2.5microM l-leucovorin or folic acid resulted in a complete
      restoration of DNR efflux. In contrast, expression of MRP1/ABCC1 protein was not
      changed significantly during the folate-free period or the repletion-period, nor
      were cellular ATP or ADP pools. In conclusion, this study demonstrates that the
      cellular folate status can influence the transport activity of MRP1/ABCC1. These
      results have potentially important implications in the understanding of the
      (patho-)physiological roles of MRP1/ABCC1, and possibly other ABC transporter
      proteins in cellular folate homeostasis and drug resistance.

PMID- 15041472
TI  - Inhibition of lipopolysaccharide-induced expression of inducible nitric oxide
      synthase and tumor necrosis factor-alpha by 2'-hydroxychalcone derivatives in RAW
      264.7 cells.
AB  - In cultures of the murine macrophage cell line RAW 264.7, effects of four 2'
      hydroxychalcone derivatives, 2'-hydroxy-4'-methoxychalcone (compound 1), 2',4
      dihydroxy-4'-methoxychalcone (compound 2), 2',4-dihydroxy-6'-methoxychalcone
      (compound 3) and 2'-hydroxy-4,4'-dimethoxychalcone (compound 4), on
      lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and tumor
      necrosis factor (TNF)-alpha were examined. Compounds 1, 2 and 3 at 3-30microM
      inhibited the production with almost the same potency. Compound 4 showed no
      inhibitory activity. Compounds 1, 2 and 3 at 3-30microM inhibited the LPS-induced
      expression of inducible nitric oxide synthase (iNOS) and TNF-alpha mRNA. To
      clarify the mechanism involved, effects of compounds 1, 2 and 3 on the activation
      of nuclear factor (NF)-kappaB and activator protein-1 (AP-1) were examined. Both
      the LPS-induced activation of NF-kappaB and AP-1 were blocked by compounds 1, 2
      and 3 at 3-30microM. Moreover, the three compounds at such concentrations
      inhibited the LPS-induced IkappaB degradation and the phosphorylation of c-jun N
      terminal kinase (JNK) and c-jun. These findings suggest that the inhibition of
      the LPS-induced production of NO and TNF-alpha by the 2'-hydroxychalcone
      derivatives is due to the inhibition of NF-kappaB and AP-1 activations.

PMID- 15041473
TI  - Control of platelet activation by cyclic AMP turnover and cyclic nucleotide
      phosphodiesterase type-3.
AB  - Prostaglandin-induced cAMP elevation restrains key signaling pathways in platelet
      activation including Ca(2+) mobilization and integrin alphaIIbbeta3 affinity
      regulation. We investigated how cAMP turnover by cyclic nucleotide
      phosphodiesterases (PDEs) regulates platelet activation. In washed human
      platelets, inhibition of all PDEs and also specific inhibition of PDE3 but not of
      PDE5 suppressed thrombin-induced Ca(2+) responses. The effect of general PDE or
      PDE3 inhibition was accompanied by an increase in cAMP, and potentiated by Gs
      stimulation with prostaglandin E(1). In platelet-rich plasma, general or PDE3
      inhibition blocked platelet aggregation, integrin activation, secretion and
      thrombin generation. In contrast, inhibition of PDE5 increased the cGMP level,
      but without significant influence on aggregation, alphaIIbbeta3 activation,
      secretion or procoagulant activity. Nitroprusside (nitric oxide) potentiated the
      effect of PDE5 inhibition in elevating cGMP. Nitroprusside inhibited platelet
      responses, but this was accompanied by elevation of cAMP. Together, these results
      indicate that cAMP is persistently formed in platelets, independently of agonist
      induced Gs stimulation. PDE3 thus functions to keep cAMP at a low equilibrium
      level and reduce the cAMP-regulated threshold for platelet activation. This
      crucial role of PDE3, but not of PDE5, extends to all major processes in thrombus
      formation: assembly of platelets into aggregates, secretion of autocrine
      products, and procoagulant activity.

PMID- 15041475
TI  - Native human nitric oxide sensitive guanylyl cyclase: purification and
      characterization.
AB  - The only published report of the purification of native human soluble guanylyl
      cyclase (sGC) used placenta as starting material. This enzyme preparation showed
      low fold-activation by NO and a maximal absorption of the prosthetic heme-group
      at 417nm indicative of a prosthetic heme-group in a hexa-coordinate state. These
      data are in contrast to what has subsequently been found for the recombinant
      human enzymes. Apart from this placental enzyme preparation, a native functional
      human NO-sensitive sGC has not been successfully purified. The aim of the current
      study was to purify and characterize native human sGC from another source, to see
      whether the discrepancies between native and recombinant sGC seen for placenta
      are a general phenomenon. We chose human platelets as starting material since the
      properties of this enzyme are directly relevant for the development of innovative
      antiplatelet and antianginal drugs. Our results indicate that the native platelet
      enzyme exists as a highly NO-sensitive, heterodimeric enzyme with an alpha(1) and
      beta(1) subunit. In contrast to the native human placental enzyme and in
      accordance with the human recombinant enzymes, the native human platelet enzyme
      contains a ferrous, penta-coordinate heme group. To our knowledge this is the
      first report of the successful purification and characterization of the native
      human nitric oxide sensitive alpha(1)/beta(1) isoform of sGC which is widely
      expressed in the cardiovascular system and is an important target of innovative
      drugs.

PMID- 15041474
TI  - CysLT1 signal transduction in differentiated U937 cells involves the activation
      of the small GTP-binding protein Ras.
AB  - We investigated the signal transduction pathway(s) of leukotriene D(4) (LTD(4))
      in the human promonocytic U937 cells, a cell line known to constitutively express
      CysLT(1) receptors. Herein, we demonstrate that LTD(4) specifically acts on a
      CysLT(1) receptor to dose-dependently increase (three to five-fold over basal)
      RasGTP through a G(i/o) protein. In fact, while cytosolic Ca(2+) ([Ca(2+)](i))
      increase was only partially sensitive to pertussis toxin (PTx), Ras activation
      was almost completely inhibited by the same toxin. Furthermore, the phospholipase
      C (PLC) inhibitor U73122 completely inhibited both [Ca(2+)](i) and RasGTP
      increase, suggesting that in these cells PLC is the point of convergence for both
      PTx insensitive and sensitive pathways leading to [Ca(2+)](i) release and Ras
      activation. Indeed, chelating intracellular Ca(2+) strongly (>70%) prevented
      LTD(4)-induced Ras activation, indicating that this ion plays an essential role
      for CysLT(1)-induced downstream signaling in differentiated U937 (dU937) cells.
      In addition, while Src did not appear to be substantially involved in CysLT(1)
      induced signaling, genistein was able to partially inhibit LTD(4)-induced
      [Ca(2+)](i) transient ( approximately 34%) and almost completely prevented Ras
      activation (>90%), suggesting a potential role for other Ca(2+)-dependent
      tyrosine kinases in LTD(4)-induced signaling. Finally, agonist-induced CysLT(1)
      stimulation was followed by a specific extracellular regulated kinase (ERK) 1/2
      phosphorylation, an event with a pharmacological profile similar to that of Ras
      activation, partially ( approximately 40%) sensitive to Clostridium sordellii
      lethal toxin and totally blocked by PTx. In conclusion, LTD(4)-induced CysLT(1)
      receptor activation in dU937 cells leads to Ras activation and ERK
      phosphorylation mostly through a PTx-sensitive G(i/o) protein, PLC, and Ca(2+)
      dependent tyrosine kinase(s).

PMID- 15041476
TI  - Analysis of cell-cycle kinetics and sulfur amino acid metabolism in methionine
      dependent tumor cell lines; the effect of homocysteine supplementation.
AB  - Methionine dependence is a feature unique to cancer cells, exhibited as inability
      to grow in a methionine-depleted environment supplemented with homocysteine, the
      immediate metabolic precursor of methionine. This study explores the effect of
      methionine depletion and homocysteine supplementation on the viability, sulfur
      amino acid metabolism and cell-cycle kinetics of normal and cancer cells, as well
      as their ability to recover from the treatments. An array of cells including
      hepatomas (HTC, Phi-1), prostate adenocarcinomas (PC-3) and transformed (3T3) and
      normal (HS-27) fibroblasts, has been used aiming to evaluate the importance of
      tissue specificity. All cell lines proliferated well in methionine-complete media
      (M+H-), whilst only the normal fibroblasts HS-27 grew in methionine-depleted
      homocysteine-supplemented media (M-H+). None of the tested cell lines were able
      to grow in media without methionine or homocysteine (M-H-). HTC was the only cell
      line that did not recover from the M-H+ treatment whilst PC-3 did not recover
      from the M-H- treatment. Methionine and homocysteine depletion (M-H+ and M-H-)
      were found to induce arrest at different phases of the cell cycle, depending on
      the cell line: the methionine-dependent HTC, PC-3 and 3T3 arrested at the S and
      G2/M phase, whilst Phi-1 and the methionine-independent HS-27 accumulated in the
      G1 phase. The cell-cycle kinetics showed that the observed blockades were
      reversible. The information resulting from these studies is important for not
      only the behavior of cancer cells, but also for appreciating the potential of
      developing cancer therapies based on methionine-depletion strategies.

PMID- 15041477
TI  - Effect of saponin and filipin on antagonist binding to AT 1 receptors in intact
      cells.
AB  - In the present study, [ 3H ]-candesartan binding experiments were performed on
      intact Chinese Hamster Ovary cells transfected with the human AT1 receptor (CHO
      AT1 cells). Cells were pre-treated with 0.01mg/ml saponin or filipin. Both pre
      treatments resulted in an increased dissociation rate and decreased affinity of
      the insurmountable non-peptide antagonist [3H ]-candesartan. A similar decrease
      in affinity was observed for the peptide antagonist Sar1-Ile8 angiotensin II and
      for other non-peptide antagonists, irrespectively of their degree of
      insurmountability. A similar discrepancy in [ 3H ]-candesartan binding was
      earlier observed when comparing intact CHO-AT1 cells and membrane preparations
      thereof. This similarity is further highlighted by the observations that saponin
      or filipin no longer affect [ 3H ]-candesartan binding to CHO-AT1 cell membranes
      and that both agents permeabilise the CHO-AT1 cells. This suggests that the
      intracellular composition and/or organisation of living cells play an active role
      with regard to antagonist-AT1 receptor interactions.

PMID- 15041478
TI  - Structural requirements for the flavonoid-mediated modulation of glutathione S
      transferase P1-1 and GS-X pump activity in MCF7 breast cancer cells.
AB  - The objective of this study was to investigate the structural requirements
      necessary for inhibition of glutathione S-transferase P1-1 (GSTP1-1) and GS-X
      pump (MRP1 and MRP2) activity by structurally related flavonoids, in GSTP1-1
      transfected MCF7 cells (pMTG5). The results reveal that GSTP1-1 activity in MCF7
      pMTG5 cells can be inhibited by some flavonoids. Especially galangin was able to
      inhibit almost all cellular GSTP1-1 activity upon exposure of the cells to a
      concentration of 25microM. Other flavonoids like kaempferol, eriodictyol and
      quercetin showed a moderate GSTP1-1 inhibitory potential. For GSTP1-1 inhibition,
      no specific structural requirements necessary for potent inhibition could be
      defined. Most flavonoids appeared to be potent GS-X transport inhibitors with
      IC(50) values ranging between 0.8 and 8microM. Luteolin and quercetin were the
      strongest inhibitors with IC(50) values of 0.8 and 1.3microM, respectively.
      Flavonoids without a C2-C3 double bond like eriodictyol, taxifolin and catechin
      did not inhibit GS-X pump activity. The results of this study demonstrate that
      the structural features necessary for high potency GS-X pump inhibition by
      flavonoids are (1) the presence of hydroxyl groups, especially two of them
      generating the 3',4'-catechol moiety; and (2) a planar molecule due to the
      presence of a C2-C3 double bond. Other factors, like lipophilicity and the total
      number of hydroxyl groups do not seem to be dominating the flavonoid-mediated GS
      X pump inhibition. To identify the GS-X pump responsible for the DNP-SG efflux in
      MCF7 cells, the effects of three characteristic flavonoids quercetin, flavone and
      taxifolin on MRP1 and MRP2 activity were studied using transfected MDCKII cells.
      All three flavonoids as well as the typical MRP inhibitor (MK571) affected MRP1
      mediated transport activity in a similar way as observed in the MCF7 cells. In
      addition, the most potent GS-X pump inhibitor in the MCF7 cells, quercetin, did
      not affect MRP2-mediated transport activity. These observations clearly indicate
      that the GS-X pump activity in the MCF7 cells is likely to be the result of
      flavonoid-mediated inhibition of MRP1 and not MRP2. Altogether, the present study
      reveals that a major site for flavonoid interaction with GSH-dependent
      toxicokinetics is the GS-X pump MRP1 rather than the conjugating GSTP1-1 activity
      itself. Of the flavonoids shown to be most active especially quercetin is
      frequently marketed in functional food supplements. Given the physiological
      levels expected to be reached upon supplement intake, the IC(50) values of the
      present study point at possible flavonoid-drug and/or flavonoid-xenobiotic
      interactions especially regarding transport processes involved in toxicokinetics.

PMID- 15041479
TI  - Effects of phosphodiesterase inhibition on cortical spreading depression and
      associated changes in extracellular cyclic GMP.
AB  - Cortical spreading depression (CSD) is a temporary disruption of local ionic
      homeostasis that propagates slowly across the cerebral cortex, and may contribute
      to the pathophysiology of stroke and migraine. Previous studies demonstrated that
      nitric oxide (NO) formation promotes the repolarisation phase of CSD, and this
      effect may be cyclic GMP (cGMP)-mediated. Here, we have examined how
      phosphodiesterase (PDE) inhibition, either alone or superimposed on NO synthase
      (NOS) inhibition, alters CSD and the associated changes in extracellular cGMP.
      Microdialysis probes incorporating an electrode were implanted into the
      frontoparietal cortex of anaesthetised rats for quantitative recording of CSD,
      pharmacological manipulations, and dialysate sampling for cGMP measurements. CSD
      was induced by cathodal electrical stimulation in the region under study by
      microdialysis. Extracellular cGMP increased, but only slightly, during CSD.
      Perfusion of either zaprinast or sildenafil through the microdialysis probe, at
      concentrations that inhibited both PDE5 and PDE9 (and possibly other PDE),
      increased significantly extracellular cGMP. Unexpectedly, these levels remained
      high when NOS was subsequently inhibited with N(omega)-nitro-l-arginine methyl
      ester hydrochloride (l-NAME, 1mM). The most interesting pharmacological effect on
      CSD was obtained with sildenafil. This drug altered neither CSD nor the
      subsequent characteristic effect of NOS inhibition, i.e. a marked widening of
      CSD. The fact that NOS inhibition still widened CSD in the presence of the high
      extracellular levels of cGMP associated with PDE inhibition, suggests that NO may
      promote CSD recovery, independently of cGMP formation.

PMID- 15041480
TI  - Salivary micelles: identification of complexes containing MG2, sIgA, lactoferrin,
      amylase, glycosylated proline-rich protein and lysozyme.
AB  - Micelles represent macromolecular structures in saliva and the aim of this study
      was to identify salivary proteins that occur in these globular particles.
      Micelles were isolated from whole saliva (WS) collected from three individuals
      and analysed in different experiments. Samples were subjected to polyacrylamide
      gel electrophoreses, hydrolysed to determine their amino acid composition and
      total protein concentration, examined by scanning electron microscopy and
      examined on Western blots probed with a panel of antibodies directed against
      salivary proteins. On Coomassie Brilliant Blue stained gels, the banding pattern
      of whole saliva and micelles was similar but the intensity of bands was quite
      different. Amino acid analysis confirmed that the amino acid composition of
      micelles was distinct from that of whole saliva. Scanning electron microscopy
      showed that micelles exhibit a complex pattern consisting of individual particles
      or clusters of particles with different sizes and shapes. Micelles contain
      proteins with high (MG2 and secretory IgA), intermediate (lactoferrin, amylase
      and glycosylated proline-rich protein (PRP)) and low (lysozyme) molecular weight
      that were immuno-detected on blots probed with specific antibodies. Micelles
      represent particulate multicomponent structures in whole saliva that contain a
      subset of salivary proteins known to be important components of the innate immune
      system and are likely to play an important role in the maintenance of homeostasis
      in the oral environment.

PMID- 15041481
TI  - Expressions of CCAAT-enhancer-binding proteins and c-Myc in the parotid gland of
      the rat: in vivo effects of isoprenaline, bethanechol, vasoactive intestinal
      peptide and food intake.
AB  - Parotid glands of adult female rats were exposed to agonists mimicking
      sympathetic (isoprenaline, 1mg/kg, I.P.) or parasympathetic activity
      (bethanechol, 10 microg/kg/min i.v. for 30 min, and vasoactive intestinal
      peptide, VIP, 0.2 microg/kg/min, i.v. for 30 min) or they were reflexly activated
      by a meal demanding chewing. The stimulated glands were removed at varying times
      (15(30)-360 min) following the onset of the agonist administration or 75-300 min
      after the start of a 1h long feeding period, and a number of transcription
      factors was studied using Western blot. The protein bands were semi
      quantitatively measured by densitometry. In response to isoprenaline, C/EBPalpha
      of 42, 38 and 30 kDa increased by 45-50% above control value, C/EBPbeta LAP
      (38/35 kDa) by 80% and C/EBPdelta (35 kDa) by 230%, while C/EBPbeta LIP (20 kDa)
      decreased by 45%. In response to VIP, C/EBPalpha of 42 kDa increased by 75% and
      C/EBPalpha of 30 kDa by 10%, C/EBPbeta LAP by 65% and C/EBPdelta by 410%, while
      C/EBPalpha of 38 kDa as well as C/EBPbeta LIP were not changed. In response to
      bethanechol, C/EBPalpha of 42 kDa increased by 105%, C/EBPbeta LAP by 40% and
      C/EBPdelta by 170%, while C/EBPalpha of 30 kDa decreased by 30% and C/EBPalpha of
      38 kDa and C/EBPbeta LIP remained unchanged. c-Myc increased in response to
      isoprenaline and VIP by 40-55%, but not to bethanechol. In rats offered a
      pelleted diet, the parotid glands displayed increases in C/EBPalpha of 42 kDa by
      105%, of 30 kDa by 40% and of 38 kDa, by 10%, in C/EBPbeta LAP by 65% and in
      C/EBPdelta by 215%, whereas C/EBPbeta LIP decreased by 25%. Thus, in parotid
      glands transcription factors of importance for growth and metabolism were shown
      to be influenced by autonomimetics as well as by nervous activity.

PMID- 15041482
TI  - Salivary calcium reflects skeletal bone density of heavy smokers.
AB  - OBJECTIVE: Our recent studies suggest, that elevated calcium concentration of
      saliva is characteristic of periodontitis. In this study we analyzed the effect
      of smoking on salivary calcium and bone density by comparing the level of
      salivary calcium and the ultrasound scale of bone density of heavy smokers to
      those of non-smokers. DESIGN: Salivary samples were collected from 603 women (50
      62 years) participating in a pre-screen referral program for osteoporosis. Out of
      this group a total of 577 were accepted for the present study. General health,
      medications and tobacco smoking were recorded. The group included 487 non
      smokers, 37 moderate smokers (1-10 cigarettes per day) and 53 heavy smokers (>10
      cigarettes per day). Bone density was measured at the right heel by the
      quantitative ultrasound technique. Calcium and phosphate concentrations of saliva
      were measured and expressed as microg/ml of saliva. RESULTS: The ultrasonographic
      variables of the heel, broadband ultrasound attenuation (BUA), speed of sound
      (SOS) and T-score (a standard deviation unit from mean values of healthy young
      adults) of heavy smokers were significantly lower than those of women who did not
      smoke (P = 0.007, 0.014 and 0.011, respectively). Salivary calcium concentration
      of heavy smokers 70.5 (14.6) microg/ml was higher than that of non-smokers 64.0
      (14.1) microg/ml (P = 0.001). There were no significant differences in salivary
      phosphate level or in the salivary flow rate between heavy smokers and non
      smokers. CONCLUSIONS: Heavy smokers seem to have lower bone mineral density and
      higher salivary calcium than their non-smoking counterparts. We suggest that the
      high salivary calcium concentration of smokers is in connection with skeletal
      calcium disturbances.

PMID- 15041483
TI  - Hydroxyapatite solubility in simple inorganic solutions.
AB  - OBJECTIVE: To use solid titration and laser-scattering end-point detection to
      determine the hydroxyapatite (HAP) solubility isotherm at 37 degrees C in a plain
      KCl solution, with CO(2) present, and with additional phosphate. DESIGN:
      Pulverised HAP solid was used to perform a titration to saturation. A very
      sensitive detector capable of detecting the light scattered at small forward
      angles from a laser beam was adopted to monitor the onset of precipitation (or
      failure to dissolve) near the equilibrium point. Each addition of HAP solid
      caused a step increase in scattered light and this signal decreased quasi
      exponentially with time. When a steady but elevated scattering was obtained,
      small portions of 1M HCl were added to lower the pH by about 0.5-2 units,
      according to need, to dissolve excess solid and allow a further titration. The
      scatter signal and pH data, plotted against the amount of HAP added, were used to
      estimate the actual end-point by interpolation and thus construct each point on
      the solubility isotherm. RESULTS: The solubility isotherm for HAP in plain KCl
      solution in the absence of CO(2) obtained now differs substantially from the
      results of previous solubility studies (i.e. much lower). The increase in
      solubility due to CO(2) reported earlier was confirmed, while the effect of
      excess phosphate was found to be to increase the apparent solubility of HAP,
      contrary to elementary mass-action expectations. CONCLUSIONS: The solid titration
      method is a more reliable approach than that of conventional excess solid method
      with respect to the determination of the HAP-carrying capacity. The solubility of
      HAP appears to be substantially lower than previously reported, and a
      reconsideration of all aspects of the system is warranted.

PMID- 15041484
TI  - Correlating the mechanical properties to the mineral content of carious dentine-
      a comparative study using an ultra-micro indentation system (UMIS) and SEM-BSE
      signals.
AB  - The deterioration of the mechanical properties of carious dentine was assumed to
      be associated with the decrease in mineral content due to the carious process.
      This study aimed to compare the mechanical properties of carious dentine studied
      by an ultra-micro-indentation-system (UMIS) and the mineral content determined
      using backscattered scanning electron (BSE) imaging. Eight axial sectioned and
      fine polished primary molar teeth with untreated carious dentine were measured
      for hardness and elastic modulus using the UMIS. On each specimen two centrally
      located linear arrays of indentations were made from the pulp to lesion cavity
      floor, followed by the capture of a BSE image using a solid-state detector. The
      BSE intensity at the same spot as the indentation array on each specimen was
      analysed and compared to the UMIS results. The results show that the mechanical
      properties of dentine are dependent on its mineral content. The decrease in
      mechanical properties of carious dentine, namely hardness and elastic modulus are
      directly linked to the reduction in its mineral content (r2 = 0.93 and 0.92,
      respectively). The relationship between dentine hardness and elastic modulus
      values (y) can be expressed as an exponential function of the mineral content in
      wt.% (x) that is y = ae(bx).

PMID- 15041485
TI  - Statherin is an in vivo pellicle constituent: identification and immuno
      quantification.
AB  - Recently, we demonstrated that anti-statherin monoclonal antibodies could be
      generated upon immunisation of mice with in vivo formed human acquired enamel
      pellicle, indicating that statherin is a constituent of pellicle. To gain insight
      in the in vivo adsorption behaviour of statherin we tested the abundance of
      statherin in pellicle and investigated the relationship between statherin and
      protein levels in salivary secretions and pellicle using a capture ELISA.
      Statherin levels were approximately 20-fold higher in parotid and submandibular
      sublingual secretions than in cleared whole saliva supernatant or pellicle,
      suggesting the rapid degradation of statherin in the oral cavity. A strong
      positive correlation was observed between statherin and protein levels in
      pellicle but not in saliva indicating that statherin and protein adsorption to
      pellicle are related processes. This indicates that statherin represents the
      integral part of proteins that constitute the pellicle structure and may play a
      key role in its formation.

PMID- 15041486
TI  - Comparative permeability of various chemical markers through human vaginal and
      buccal mucosa as well as porcine buccal and mouth floor mucosa.
AB  - A number of drugs undergo extensive first-pass metabolism after oral
      administration, necessitating large doses for effective therapeutic responses in
      the body. Buccal administration of drugs is becoming more popular because the
      drugs diffuse into the systemic circulation directly, circumventing the first
      pass metabolism. Lower concentrations thus need to be administered and side
      effects may be minimized. In this study, one of the classic models for human
      buccal permeability, i.e. the porcine buccal mucosal model, is compared with the
      more recent human vaginal model and both these are in turn further compared to
      porcine mouth floor mucosa. To determine the permeability of the different
      markers (arecoline, 17beta-estradiol, water and vasopressin), a continuous flow
      through perfusion system was used (20 degrees C, 24h). Mean steady state flux
      values were compared statistically using a t-test at a significance level of 5%.
      Porcine buccal mucosa showed a consistently lower permeability towards all the
      markers than the other mucosae tested. Porcine mouth floor mucosa was found to be
      more permeable than porcine buccal mucosa. From these studies we concluded that
      human vaginal and porcine mouth floor mucosae were superior models for human
      buccal mucosa than porcine buccal mucosa, using in vitro permeability studies
      with various chemical markers.

PMID- 15041487
TI  - Incisor disocclusion in rats affects mandibular condylar cartilage at the
      cellular level.
AB  - The effect of altered occlusion on the mandibular condylar cartilage remains
      unclear. OBJECTIVE: This study investigated the effect of unilateral incisor
      disocclusion on cartilage thickness, on mitotic activity and on chondrocytes
      maturation and differentiation in the mandibular condylar cartilage of rats.
      DESIGN: The upper and lower left incisors were trimmed 2mm every second day in
      five rats. In other five rats, the incisor occlusion was not altered. Condylar
      tissues from both sides of each mandible were processed and stained for
      Herovici's stain and immunohistochemistry for bromodeoxyuridine (BrdU),
      transforming growth factor-beta1 (TGF-beta1), alkaline phosphatase (ALP) and
      osteocalcin (OCN). Measurements of cartilage thickness and the numbers of
      immunopositive cells for each antibody were analysed by one-way analysis of
      variance (ANOVA). RESULTS: No significant differences were observed in cartilage
      thickness after 7 days of unilateral incisor disocclusion. However, the numbers
      of immunopositive cells for BrdU as a marker of DNA synthesising cells, TGF-beta1
      as a marker of chondrocytes differentiation, and ALP and OCN as markers of
      chondrocytes maturation, were significant higher in the cartilage cells on both
      sides when incisor occlusion was unilaterally altered. Interestingly, alkaline
      phosphatase was highly expressed on the condylar side of incisor disocclusion,
      whereas osteocalcin was highly expressed on the side opposite to the incisor
      disocclusion. CONCLUSIONS: It is demonstrated that after 7 days, unilateral
      incisor disocclusion affects the mandibular condylar cartilage at the cellular
      level by increasing the mitotic activity and by accelerating chondrocytes
      maturation. Chondrocytes maturation appears more accelerated on the side opposite
      to incisor disocclusion.

PMID- 15041488
TI  - Quantitative assessment of post-extraction healing and alveolar ridge remodelling
      of the mandible in female rats.
AB  - OBJECTIVE: To quantitatively evaluate the healing and bone changes in the
      mandible of adult female rats following unilateral extraction of the mandibular
      molars and the incisor. METHODS: Six-month old female rats had their mandibular
      molars and the incisor on one side of the mandible extracted. Nine rats were
      sacrificed at 0, 14, 28, 56 and 112 days post-extraction. Bone mineral density
      (BMD) as observed by dual energy X-ray absorptiometry (DEXA) and
      histomorphometric measurements of total bone volume (TBV/TV%) as well as changes
      in size; height and width on backscattered electron microscopy images of cross
      sections of the mandible were evaluated. RESULTS: There was a total increase of
      28% in BMD of the body of the mandible and 35.1% increase in TBV/TV% at 112 days
      post-extraction. A maximal increase of 25% in BMD was observed at 14 days post
      extraction. TBV/TV% increased by 9.5% at 14 days post-extraction and further
      increased by 15.9% (P < 0.001) from 14 to 28 days and by 9.2% (P < 0.001) from 28
      to 56 days. A further slight but non-significant increase of 6% (P = 0.108)
      occurred from 56 to 112 days post-extraction. Regression equations demonstrated
      that the maximal increase in TBV/TV% and BMD occurred between 0 and 28 days,
      which subsequently slowed down between 28 and 56 days and further declined
      between 56 and 112 days post-extraction. Healing was associated with a reduction
      in cross-sectional area (32.89%), height (21%) and width of the mandible
      (12.84%). CONCLUSIONS: BMD of the edentulous mandible following extraction of
      mandibular molars and the incisor on one side of the mandible increases up to 56
      days, but that total bone volume increases up to 112 days post-extraction. This
      indicates that bone volume measurement is more sensitive than BMD measurements in
      detecting small increase in bone formation at later stages of healing, possibly
      because of changes in geometry of the edentulous mandible following teeth
      extraction. The edentulous mandible undergoes a significant reduction in size as
      a result of reduction in both height and width up to 112 days post-extraction.

PMID- 15041489
TI  - Therapeutic ultrasound to stimulate osteoconduction; A placebo controlled single
      blind study using e-PTFE membranes in rats.
AB  - To decrease healing time of bone defects covered with osteoconductive membranes,
      an attempt was made to stimulate the osteoconductive process with therapeutic
      ultrasound. In 72 rats, a circular mandibular defect was created and covered on
      both sides with an e-PTFE membrane. A control group, an ultrasound treatment
      group and a placebo treatment group were studied. At 2 and 4 weeks, the
      osteoconduction was expressed as the percentage of defect closure using digitized
      microradiographs. At 2 weeks, there was no significant difference in the
      percentage of defect closure between the groups. At 4 weeks, there was
      significantly more bone defect closure in the placebo group (77.9%) as compared
      to the control group (59.3%). Membrane ultrasound attenuation measurements
      indicated that the membrane blocks most of the applied ultrasound. In conclusion,
      low intensity pulsed ultrasound does not appear to significantly stimulate
      osteoconduction into a bone defect in the rat mandible that is covered by an e
      PTFE membrane.

PMID- 15041490
TI  - Crevicular fluid levels of TGFbeta1 in drug-induced gingival overgrowth.
AB  - OBJECTIVE: To determine if local, gingival crevicular fluid (GCF) levels of
      TGFbeta1 were altered in drug-induced gingival overgrowth. PATIENTS AND METHODS:
      GCF samples were collected on Periopaper strips from 45 renal transplant
      recipients who had been medicated with cyclosporin or cyclosporin in combination
      with other putative overgrowth-inducing drugs for a minimum of 6 months. Twenty
      two subjects had gingival overgrowth while the other 23 patients showed no signs
      of gingival changes and constituted the medicated control group. Non-medicated
      controls consisted 20 periodontally healthy individuals who had never taken
      overgrowth-inducing drugs. GCF levels of TGFbeta1 and alkaline phosphatase, a
      marker of inflammation, were determined by enhanced chemiluminescence ELISA and
      enzyme activity assays, respectively. RESULTS: TGFbeta1 levels in GCF from
      overgrowth and non-overgrowth sites in overgrowth sufferers did not differ.
      However, there were significant differences in median concentration (P = 0.001)
      and GCF levels of TGFbeta1 per sample (P = 0.05) between study groups with
      overgrowth patients having higher amounts per sample and lower concentrations
      than medicated and healthy controls. Median levels of alkaline phosphatase per
      GCF sample differed between site (P = 0.01) with higher levels present at
      overgrowth sites. Despite this, the concentration of enzyme in GCF did not differ
      between site or patient group. CONCLUSIONS: GCF TGFbeta1 detected in overgrowth
      patients could reflect a higher level of gingival inflammation because of
      difficulties in plaque control consequent on the development of overgrowth.
      However, the higher local levels of total TGFbeta1 in overgrowth patients could
      indicate that it is a risk factor for developing gingival overgrowth.

PMID- 15041491
TI  - Factors contributing to failure of laparoscopic Nissen fundoplication and the
      predictive value of preoperative assessment.
AB  - BACKGROUND: Laparoscopic Nissen fundoplication (LNF) has established itself as
      the procedure of choice in the surgical management of the majority of patients
      suffering from gastroesophageal reflux disease (GERD). There are, however, few
      available data on the assessment of long-term failures after LNF. METHODS: We
      sought to clarify the mechanisms of failure among a group of patients who
      reported suboptimal results after LNF. In addition, we attempted to identify
      specific elements in the preoperative evaluation of GERD patients that might
      herald a predisposition to anatomical or physiological failure. RESULTS: One
      hundred and thirty-one consecutive patients who underwent LNF by a single surgeon
      were analyzed to identify reasons for surgical failure. Fourteen patients (10.6%)
      comprised the failure group. Detailed independent statistical analysis identified
      a hiatus hernia greater than 3 cm at operation (P = 0.003), abnormal preoperative
      pH analysis in the upright position (P = 0.039), failure to respond to proton
      pump inhibition preoperatively (P = 0.015), and a preoperative psychiatric
      history (P = 0.0012) as predictors of subsequent failure. CONCLUSIONS: In
      patients who do not respond to proton pump inhibition preoperatively, the
      evaluating surgeon should be circumspect in advocating antireflux surgery. A
      detailed assessment of underlying psychiatric or psychological symptoms must also
      be made. If a large (>3 cm approximately) hiatus hernia is identified or there is
      abnormal pH analysis in the upright position preoperatively, the surgeon should
      be guarded about the long-term outcome, and patients should be advised
      accordingly.

PMID- 15041492
TI  - Laparoscopic adhesiolysis for small bowel obstruction.
AB  - BACKGROUND: Historically, laparotomy and open adhesiolysis have been the
      treatment for patients requiring surgery for small bowel obstruction.
      Laparoscopic adhesiolysis has not gained wide acceptance. The indications and
      outcomes of laparoscopic adhesiolysis for small bowel obstruction are not well
      established. The purpose of this paper is to review the literature on
      laparoscopic adhesiolysis for small bowel obstruction and to discuss patient
      selection, surgical technique, and outcomes. DATA SOURCES: Medline search from
      1980 to 2002. CONCLUSIONS: Laparoscopic adhesiolysis has been shown to be safe
      and feasible in experienced hands. For selected patients, laparoscopic
      adhesiolysis offers the advantages of decreased length of stay, faster return to
      full activity, and decreased morbidity. Patient selection and surgical judgment
      appear to be the most important factors for a successful outcome.

PMID- 15041493
TI  - Video-assisted thoracoscopic surgery for thoracic empyema: primarily, or after
      fibrinolytic therapy failure?
AB  - BACKGROUND: Traditional and modern treatments are proposed for thoracic empyema.
      The efficacy of video-assisted thocoscopic surgery (VATS) has been studied when
      the method is applied either as primary treatment for thoracic empyema or after
      the failure of fibrinolytic therapy. METHODS: Thirty-eight patients treated with
      VATS for thoracic empyema have been reviewed. Of those, 20 patients (group 1)
      with empyema thoracis were referred to VATS after failure of the fibrinolytic
      treatment. Another 18 patients (group 2) with primary empyema thoracis were
      treated thoracoscopically immediately when empyema was diagnosed. Both groups
      were staged 5, 6, or 7 according to Light's criteria. RESULTS: The group 2
      patients showed a higher empyema resolving rate (95% versus 85%), shorter
      hospital stay (4.5 versus 7.5 days), and significantly shorter duration of the
      procedure (70 +/- 14 versus 62 +/- 10 minutes) in comparison with the patients of
      group 1. CONCLUSIONS: The VATS technique for thoracic empyema is a well
      tolerated, minimally invasive technique, with excellent therapeutic results, mild
      postoperative complications, and reduced hospitalization. VATS should be
      considered as the treatment of choice for thoracic empyema, in the
      fibrinopurulent stage, as it is more effective when applied primarily than when
      applied after fibrinolytic therapy.

PMID- 15041494
TI  - Is laparoscopic intraoperative cholangiogram a matter of routine?
AB  - BACKGROUND: Intraoperative cholangiography during laparoscopic cholecystectomy
      reveals the anatomy of the biliary tree and any stones contained within it. The
      use of intraoperative cholangiography may be routine for all laparoscopic
      cholecystectomy. An alternative approach is a selective policy, performing
      intraoperative cholangiography only for those cases in which choledocholithiasis
      is suspected on clinical grounds, or those for which the anatomy appears unclear
      at operation. The literature pertaining to both approaches is reviewed, to
      delineate their respective merits. METHODS: Relevant articles in English were
      identified from the Medline database, and reviewed. RESULTS: The literature
      reviewed consisted of retrospective analyses. Overall the incidence of
      unsuspected retained stones was 4%, but only 15% of these would go on to cause
      clinical problems. The incidence of complete transection of the common bile duct
      was rare for both routine and selective intraoperative cholangiography policies,
      and did not differ between them. Rates of minor bile duct injury did not differ
      between groups, but was more likely to be recognized in the routine group than
      the selective (P = 0.01). CONCLUSIONS: Routine intraoperative cholangiography
      yields very little useful clinical information over and above that which is
      obtained with selective policies. Large numbers of unnecessary intraoperative
      cholangiography are performed under routine intraoperative cholangiography
      policy, and therefore a selective policy is advocated.

PMID- 15041495
TI  - Determinants of in-hospital mortality and length of stay for acute intestinal
      gangrene.
AB  - BACKGROUND: Intestinal gangrene carries high operative mortality and morbidity
      rates. This study was undertaken to identify predictors of in-hospital death and
      length of stay. METHODS: Retrospective review of hospital data over a 6-year
      period identified 107 patients diagnosed with acute bowel gangrene. RESULTS:
      Among the baseline factors that had a significant univariable association with
      mortality (51%) were age (P = 0.04), symptom duration (P = 0.01), preoperative
      and postoperative pH and lactic acid (P < or = 0.02), history of hypertension (P
      = 0.001), and renal failure (P = 0.008). Symptom duration and history of
      hypertension were independent risk factors for mortality. Longer length of stay
      was univariably associated with symptom duration (P = 0.006), systemic acidosis
      (P < or =0.005), vascular etiology (P = 0.04), amount of resected bowel (P =
      0.001), and need for second-look procedures (P <0.001). CONCLUSIONS: The presence
      of multiple risk factors predictive of a high mortality rate may aid more
      realistic decision making for physicians, patients, and family members.

PMID- 15041496
TI  - One surgeon's philosophy of surgical education.
AB  - The concept of a philosophy of surgical education provides a vehicle for ensuring
      that there is a united and comprehensive approach to surgical training. This is
      important because none of the current approaches to higher education provides a
      suitable model for surgical training and it is dangerous to uncritically adopt
      every prevailing fashion in education.

PMID- 15041497
TI  - Radio-guided occult lesion localization in patients undergoing breast-conserving
      surgery and sentinel node biopsy.
AB  - BACKGROUND: The objective of the study was to evaluate the feasibility of radio
      guided occult lesion localization (ROLL) in breast-conserving surgery for
      nonpalpable breast cancer. METHODS: Altogether 215 breast cancer patients were
      included in a prospective study. Ultrasonographically guided intratumoral
      injection of radioactive tracer was used for tumor localization in 64 patients
      with nonpalpable tumors, visible in breast ultrasonography (the ROLL group).
      Nonpalpable tumors, visible only in mammography, were localized with a help of a
      guidewire in 14 patients (the WGR group). The remaining 137 patients had palpable
      tumors. RESULTS: The proportion of specimens with close or involved margins (0 to
      3 mm) was the same in the ROLL group (6%) and among cases with palpable tumors
      (5%). In addition the median length of the closest margin did not differ
      significantly between the groups. CONCLUSIONS: The results of ROLL for
      nonpalpable breast cancer are comparable with those for resection of palpable
      tumors.

PMID- 15041498
TI  - Long-term prognosis of patients with obstructing carcinoma of the right colon.
AB  - BACKGROUND: The long-term prognosis of patients with colon cancer is dependent on
      many factors. The aim of this retrospective study was to assess the long-term
      prognosis of patients with obstructing carcinoma of the right colon. METHODS:
      From 1981 to 1988, 256 patients at the Veterans General Hospital-Taipei who were
      status postcurative resection of right colon adenocarcinoma were classified as
      obstruction group (n = 35) or nonobstruction group (n = 221) as appropriate.
      RESULTS: Analysis revealed no differences in age, sex, tumor location, or stage
      (P >0.05) between the two groups. However, the overall and distant recurrence
      rates were significant higher in obstructed patients than in nonobstructed
      patients. Further, long-term crude and cancer-specific survival rates were
      significantly lower in obstructed patients when examining either overall patient
      outcome or stage-matched outcomes. Multivariate analysis demonstrated that
      obstruction and tumor stage were both independent prognostic factors.
      CONCLUSIONS: Obstruction status was an independent prognostic factor for patients
      with right colon carcinoma. The long-term prognosis of patients with obstructing
      carcinoma of the right colon was poor.

PMID- 15041499
TI  - Surgery in heart and lung transplant patients.
AB  - BACKGROUND: Heart and lung transplantation is an increasingly successful
      procedure. After transplant, these patients may need surgery for common diseases
      and for problems caused by immunosuppression. The purpose of this study was to
      determine surgical outcomes heart and lung transplant patients after
      transplantation. METHODS: All patients in the cardiopulmonary transplant registry
      were reviewed. Data collected included sex, age at transplantation, age at
      subsequent procedure, number and type of surgical procedures performed, number
      and type of postoperative complications, grade of complications (using the
      Clavien classification), and outcome (discharge to home, disabled, dead).
      RESULTS: During a 15-year period, 222 (64%) of 345 heart or lung transplant
      patients underwent a surgical procedure. Seven hundred fifty-four procedures were
      performed (median 3 procedures/patient). Sixty-seven patients suffered 72
      complications (10% complication rate). Twenty-one (29%) complications were grade
      I; 20 (28%) were grade IIA; 21 (29%) were grade IIB; 8 (11%) were grade III; and
      2 (3%) were grade IV. Twelve percent of the complications in the heart transplant
      patients were cardiac in nature, whereas 0% of the complications in the lung
      transplant patients were pulmonary in nature. There were 475 (63%) discharges to
      home, 2 (0.2%) inpatient deaths, and 18 (2%) deaths within 30 days; 49 (7%)
      procedures resulted in disability; and 210 (28%) patients were lost to follow-up.
      CONCLUSIONS: Heart or lung transplant patients will frequently need subsequent
      surgical procedures. Overall, the patients tolerated the procedures well, and the
      morbidity and mortality rates were acceptable. Most complications were not
      related to the transplanted organ.

PMID- 15041500
TI  - Recurrent neurogenic thoracic outlet syndrome.
AB  - BACKGROUND: Although 90% of patients with neurogenic thoracic outlet syndrome
      (NTOS) experience "excellent" or "good" results after thoracic outlet
      decompression, recurrent symptoms may develop in certain patients. METHODS: This
      is a retrospective review of patients with NTOS who developed recurrent symptoms
      of upper extremity/shoulder/neck pain, weakness and limitation of motion at least
      3 months after initial relief of symptoms by surgical decompression. Diagnostic
      procedures and outcomes of reoperative surgery were assessed. RESULTS: Among
      almost 500 patients undergoing initial successful thoracic outlet decompression
      for symptoms of NTOS during the last decade, 17 redeveloped classic NTOS symptoms
      (3 of them bilaterally) at intervals from 3 to 80 months (mean 18 months) after
      the initial operative procedure. Ultimate diagnoses included incomplete first-rib
      resection (n = 1), compression of the brachial plexus by an ectopic band (n = 1),
      persistent brachial plexus compression by an intact first (n = 2) or second (n =
      1) rib, brachial plexus compression by the pectoralis minor tendon (n = 13) and
      adherent residual scalene muscle (n = 14). Anterior scalene muscle block was
      positive in 9 patients later found to have recurrent symptoms from adherent
      residual scalene muscle. Among these 20 cases of osseous or musculotendinous
      causes of recurrent NTOS, all had "excellent" or "good" results from repeat
      surgery to eliminate the underlying structural problem (removal of intact or
      residual rib, pectoralis minor tenotomy, brachial plexus neurolysis, or a
      combination of these). CONCLUSIONS: Complete excision of cervical or first ribs
      and subtotal excision (instead of simple division) of the scalene muscles will
      decrease the incidence of recurrent NTOS. Pectoralis minor tenotomy should be
      considered part of complete thoracic outlet decompression. Anterior scalene
      muscle block accurately predicts outcome of reoperation for certain types of
      recurrent NTOS.

PMID- 15041501
TI  - Early experiences with computed axial tomography colonography.
AB  - BACKGROUND: Computed axial tomography (CT) colonography is the latest radiologic
      technique to be used to image the large bowel. We studied its role as a
      diagnostic tool in colorectal practice. METHODS: One hundred and three patients
      suspected of having colorectal pathology underwent CT colonography. RESULTS: CT
      colonography suggested a diagnosis of colonic carcinoma in 18 patients, and 17 of
      these underwent surgery. A colorectal neoplasm was not found in only 1 patient
      who had extrinsic colonic compression by an ovarian cyst. Twenty-one patients had
      suspected colonic polyps on scanning. Subsequent endoscopy in 19 of these
      patients confirmed the presence of polyps in only 10. CT colonography also
      revealed valuable extracolonic pathology: 8 occult noncolonic neoplasms and 163
      other incidental findings. CONCLUSIONS: CT colonography has good patient
      compliance and is a useful diagnostic modality in detecting colorectal neoplasms.
      Its main advantage over other such investigative tools is its ability to detect
      extracolonic pathology.

PMID- 15041502
TI  - Video-assisted thyroidectomy under local anesthesia.
AB  - One theoretical limit of video-assisted thyroidectomy (VAT) was the supposed
      necessity of general anesthesia. Herein we describe a technique for VAT performed
      under locoregional anesthesia. Eligibility criteria were small thyroid nodules
      (<2 cm) in small or normal thyroid glands (thyroid volume < or =20 mL), no
      previous neck surgery or irradiation, and patient motivation for local
      anesthesia. VAT using locoregional anesthesia was performed under a superficial
      cervical block. During the procedure, the patients were completely awake and able
      to speak with members of the surgical team. Intraoperative and postoperative
      pain, as evaluated by a visual analogue scale, was usually negligible. No
      complications occurred. Mean postoperative stay was 26 hours. All of the patients
      were completely satisfied with the cosmetic result, the procedure, and the
      surgical outcome. VAT is also feasible and safe under local anesthesia. We are
      optimistic about the future of this approach, which opens a new frontier for
      minimally invasive procedures in thyroid surgery.

PMID- 15041503
TI  - Cystic artery pseudoaneurism from an evolved acute calculous cholecystitis.

PMID- 15041504
TI  - Combination tramadol plus acetaminophen for postsurgical pain.
AB  - BACKGROUND: This multicenter, randomized, double-blind, active- and placebo
      controlled trial evaluated tramadol plus acetaminophen (APAP) for orthopedic (n =
      153) and abdominal (n = 152) postsurgical pain. METHODS: Patients with moderate
      pain or greater were randomized to an initial two tablets of 37.5 mg tramadol
      plus 325 mg APAP (n = 98), codeine 30 mg plus APAP 300 mg (n = 109), or placebo
      (n = 98); thereafter, they received 1 to 2 tablets every 4 to 6 hours as needed
      for pain for 6 days. Outcome measures were pain relief and pain intensity, total
      pain relief, sum of pain intensity differences, and sum of pain relief and pain
      intensity differences during 4 hours and the daily averages. RESULTS: Tramadol
      plus APAP was superior to placebo for total pain relief, sum of pain intensity
      differences, and sum of pain relief and pain intensity differences (P < or
      =0.015); tramadol plus APAP and codeine plus APAP did not separate (P >
      or=0.281). For average daily pain relief, average daily pain intensity, and
      overall medication assessment, tramadol plus APAP was superior to placebo (P < or
      =0.038); codeine plus APAP did not separate from placebo (P > or =0.125).
      Discontinuation because of adverse events occurred in 8.2% of tramadol plus APAP,
      10.1% of codeine plus APAP, and 3.0% of placebo patients. Except for constipation
      (4.1% tramadol plus APAP vs 10.1% codeine plus APAP) and vomiting (9.2% vs 14.7%,
      respectively), adverse events were similar for active treatments. CONCLUSIONS:
      Tramadol plus APAP (mean dose 4.4 tablets) was effective and well tolerated for
      postsurgical pain and showed better tolerability than did codeine plus APAP.

PMID- 15041505
TI  - Pure mucinous carcinoma of the breast.
AB  - BACKGROUND: The lack of a standard definition of "pure" mucinous carcinoma of the
      breast has made it difficult to compare data from different studies. This study
      used the most stringent criteria to define parameters for truly pure lesions.
      METHODS: Sixty-five patients were identified. The database was used to evaluate
      patients' demographics, tumor characteristics, and outcomes. Survival curves and
      predictors of survival were analyzed. RESULTS: The mean age of presentation was
      67 years. The majority (96%) of patients presented with early-stage disease. The
      5- and 10-year overall survival rates were 93.6% and 72.8%, respectively. The
      number of involved axillary lymph nodes was the only significant predictor of
      death (P = 0.02). CONCLUSIONS: Pure mucinous carcinoma of the breast has a
      favorable prognosis. Tumor size does not appear to impact survival, perhaps
      because the volume of mucin overestimates tumor burden. The number of involved
      axillary lymph nodes was the only significant predictor of death from disease.

PMID- 15041506
TI  - Is fear of anaphylactic shock discouraging surgeons from more widely adopting
      percutaneous and laparoscopic techniques in the treatment of liver hydatid cyst?
AB  - BACKGROUND: Sources of reports about laparoscopic and percutaneous treatment of
      liver hydatid cysts are limited to just a few countries. To address the reason
      behind this, we carried out a survey of 30 surgeons in northern Jordan. METHODS:
      A questionnaire was distributed to collect data regarding the surgical technique
      preferred by each surgeon. Further information was collected from those not
      adopting minimal-access techniques to determine their reasons for not doing so.
      RESULTS: Only 3 surgeons (10%) considered laparoscopy as the first line of
      treatment. Of the 27 surgeons who did not consider percutaneous or laparoscopic
      treatment, fear of anaphylaxis and/or dissemination was the main reason given by
      21 surgeons (78%) for not using minimal access techniques. CONCLUSIONS: The
      seemingly exaggerated traditional fear of anaphylaxis seems to discourage
      surgeons from more widely adopting minimal access techniques for the treatment of
      hydatid cyst.

PMID- 15041507
TI  - Prognostic factors in node-negative intrahepatic cholangiocarcinoma with special
      reference to angiogenesis.
AB  - BACKGROUND: The aim of this study was to clarify prognostic factors and
      recurrence patterns in patients with node-negative intrahepatic
      cholangiocarcinoma (IHCC). METHODS: A retrospective study was performed to review
      prognostic factors and recurrence patterns (1) in 22 patients with node-negative
      IHCC after curative hepatic resection and (2) in 49 patients who underwent
      resection and lymph node dissection for IHCC. In addition to determining the
      clinicopathologic factors, the investigators also performed immunohistochemical
      examination of microvessel counts using antihuman CD-31 and antibody. RESULTS:
      The significant poor prognostic factors in node-negative IHCC were the presence
      of intrahepatic metastasis, portal vein invasion of cancer cells, and high
      microvessel counts. After multivariate analysis was conducted, the independent
      poor prognostic factors were the presence of intrahepatic metastases and high
      microvessel counts. Of 9 patients who had postoperative recurrence of their
      disease, intrahepatic recurrence was observed in 7 (78 %). CONCLUSIONS: The
      factors linked to poor prognosis in IHCC were tumor angiogenesis and the presence
      of intrahepatic metastasis. Because intrahepatic recurrence was common, regional
      and adjuvant chemotherapy to the liver may improve the outcome of patients with
      these risk factors and node-negative IHCC.

PMID- 15041508
TI  - Surgery for stage IV gastric cancer.
AB  - BACKGROUND: Surgical treatment for stage IV gastric cancer is controversial.
      METHODS: We analyzed the surgical experience with advanced gastric carcinoma in a
      tertiary referral center in Mexico City from 1995 through 2000. We analyzed
      surgical morbidity, mortality, and factors associated with prognosis. Survival
      was analyzed with the Kaplan-Meier method, and the curves were compared with the
      log-rank test. Significance was assigned at P <0.05. RESULTS: Seventy-six cases
      were identified. Mean patient age was 56 +/- 14.5 years. Thirty-nine patients
      (51.3%) were women. Patients were grouped according to surgical procedure: group
      1 underwent resection (40 patients), group 2 underwent bypass procedures (10
      patients), and group 3 underwent either celiotomy and biopsy alone or jejunostomy
      placement (26 patients). Twenty patients (26%) developed operative complications,
      but most were minor. There was no difference in morbidity between surgical groups
      and no difference according to patient's age. Operative mortality was 2.6%. Good
      palliation of symptoms was significantly more common in group 1 patients (82%)
      than in group 2 patients (60%) (P = 0.0001). Median survival was 8 months (95%
      confidence interval 4 to 12) for the entire cohort and 13, 5, and 3 months for
      groups 1, 2, and 3, respectively (P = 0.00001 for group 1 vs groups 2 and 3).
      CONCLUSIONS: Surgical resection for stage IV gastric cancer can be done with low
      operative mortality and acceptable morbidity rates, and it provides patients with
      good symptomatic relief. Advanced patient age is not a contraindication for
      surgical treatment.

PMID- 15041509
TI  - Bouveret's syndrome.

PMID- 15041510
TI  - Forty-three cases of obturator hernia.
AB  - BACKGROUND: Obturator hernia is a relatively rare pelvic hernia and usually
      occurs in elderly, thin, multiparous women. Because symptoms are nonspecific, the
      diagnosis is often delayed until laparotomy is performed form to treat bowel
      obstruction. METHODS: Forty-three patients with obturator hernia undergoing
      surgery at Tokyo Metropolitan Geriatric Hospital were divided retrospectively
      into two groups (group A = 23 patients from 1968 to 1986 before computed axial
      tomography [CAT] was developed; group B = 20 patients from 1987 to 1999 after
      CAT). Preoperative diagnosis, operative procedures, and postoperative course were
      reviewed and compared between the 2 groups. RESULTS: Preoperative diagnostic
      accuracy was significantly higher in group B at 80.0% (16 of 20 patients) than in
      group A at 43.5% (10 of 23 patients) (P = 0.0146). Rate of gut resection and
      mortality were significantly lower in group B at 25.0% (4 of 20) and 5.0% (1 of
      20) than in group A at 52.2% (12 and 23) and 30.4% (7 of 23) (P = 0.0295 and P =
      0.0385, respectively). CONCLUSIONS: The use of pelvic CAT in cases of suspected
      obturator hernia significantly enhances preoperative diagnostic accuracy and
      helps to decrease both intestinal resection rate and surgical mortality.

PMID- 15041511
TI  - Vascular tumors of the abdominal wall.
AB  - BACKGROUND: Vascular tumors of the abdominal wall are rare, benign congenital
      malformations that may cause pain or cosmetic disfigurement and are of
      significance for their ability to mimic more clinically aggressive tumors. There
      have been no previous reports of vascular tumors of the abdominal wall. This
      investigation reports the clinical presentation, diagnosis, and treatment of
      three patients with vascular tumors of the abdominal wall. METHODS: Magnetic
      resonance angiography (MRA) was used to identify feeding and draining vessels and
      to aid in operative planning for two patients; in a third patient, standard
      magnetic resonance imaging revealed the feeding vessels. RESULTS: MRA accurately
      identified the feeding and draining vessels and aided in operative planning, thus
      facilitating complete tumor resection. To date, patients have not experienced
      tumor recurrence. CONCLUSIONS: These cases suggest that MRA can be employed as a
      noninvasive imaging technique and should be the standard preoperative modality to
      plan the operative approach to vascular tumors of the abdominal wall.

PMID- 15041512
TI  - Meckel's diverticulum-induced ileocolonic intussusception.

PMID- 15041513
TI  - Influence of age on surgical treatment of peripheral cholangiocarcinoma.
AB  - BACKGROUND: Peripheral cholangiocarcinoma (PCC) constitutes the second most
      common primary liver cancer. Information is lacking on patients with PCC <40
      years old undergoing surgical treatment. The aim of this study was to evaluate
      the influence of age on surgical treatment of patients with PCC based on
      reviewing the clinicopathologic features and survival rate of 23 patients with
      PCC <40 years old who received surgical treatment. METHODS: The clinical features
      of 23 younger patients with PCC (<40 years old) who underwent surgical treatment
      between 1977 and 2000 were reviewed. Clinical features of 284 patients with PCC
      >40 years old were used for comparison. RESULTS: Three hundred seven patients
      with PCC with an age range between 28 and 93 years (mean 57.2, median 56.0) were
      investigated. The fiftieth decade was the peak PCC age in the series. Clinical
      presentations and physical findings were similar between younger and older PCC
      groups. Similar positive serum carcinoembryonic antigen and carbohydrate antigen
      19-9 rates (42.9% and 66.7% vs 41.2% and 74.4%, respectively) and a similar rate
      of hepatolithiasis associated with PCC were also observed between the 2 groups
      (43.5% vs 48.9%). Younger patients with PCC tended to show less mucobilia, less
      papillary-type PCC, and a more advanced stage of tumor compared with older
      patients with PCC. However, postoperative adjuvant chemotherapy and radiotherapy
      were used more frequently in the older patients with PCC. Operative morbidity and
      mortality were similar between the 2 groups (surgical mortality rate 7.8%).
      Follow-up ranged from 1.0 to 167.6 months (mean 13.0, median 5.7). The 1- and 2
      year actuarial survival rates were 6.3% and 0% in the younger PCC group and 31.3%
      and 15.0% in the older PCC group, respectively. Prognosis was dismal for the
      younger patients with PCC (P = 0.0008), but they may benefit from hepatic
      resection. CONCLUSIONS: Younger patients with PCC had a significantly worse
      survival rate than older patients with PCC. Hepatectomy is rational and may
      benefit younger patients with PCC.

PMID- 15041514
TI  - Prophylactic pylorus-preserving gastric transposition in unresectable carcinoma
      of the pancreatic head.
AB  - Patients with unresectable carcinoma of the pancreas head often present with
      intestinal obstruction during their disease, but the efficacy of a prophylactic
      gastrointestinal anastomosis is still under debate. Some investigators consider
      the population of patients who eventually develop this complication too small to
      justify the prophylactic use of this procedure. When done prophylactically, the
      gastrointestinal anastomosis tends not to function and close. Other surgeons have
      proposed supplementing the gastric bypass using technique alternatives. To
      demonstrate the low morbidity, the feasibility, and the advantages and
      disadvantages of this procedure, we report our personal experience with
      transection of the duodenum and re-establishment of the continuity of the
      alimentary tract with a duodenojejunal anastomosis performed in 34 patients.

PMID- 15041515
TI  - Partial portal decompression using inferior mesenteric vein in portal
      hypertension.

PMID- 15041517
TI  - Core biopsy is accurate in determining the hormone receptor status of early
      breast cancer.

PMID- 15041519
TI  - Ideas from my undergraduate years: an autobiographical fragment.
AB  - This brief autobiographical essay reports a fragment of a life covering four
      undergraduate years, 1934 to 1938, at the University of California at Los Angeles
      and focuses on the intellectual impact of 5 professors. The more pervasive
      influence of Henry A. Murray at Harvard is reported--with pleasure.

PMID- 15041520
TI  - Indirect personality assessment of the violent true believer.
AB  - The violent true believer is an individual committed to an ideology or belief
      system which advances homicide and suicide as a legitimate means to further a
      particular goal. The author explores useful sources of evidence for an indirect
      personality assessment of such individuals. He illustrates both idiographic and
      nomothetic approaches to indirect personality assessment through comparative
      analyses of Timothy McVeigh, an American who bombed the federal building in
      Oklahoma City in 1995, and Mohamed Atta, an Egyptian who led the airplane attacks
      against the World Trade Center and the Pentagon in 2001. The risks of indirect
      personality assessment and ethical concerns are identified.

PMID- 15041521
TI  - The measurement of curiosity as a feeling of deprivation.
AB  - Curiosity as a feeling of deprivation (CFD) reflects feelings of uncertainty and
      tension that motivate information-seeking and problem-solving behavior. Twenty
      seven CFD items were administered to 321 participants (248 women, 73 men) along
      with other measures of curiosity and other personality traits such as anxiety,
      anger, and depression. Factor analyses of the CFD items identified 3 factors from
      which 5-item subscales were developed: (a) a need to feel competent, (b)
      intolerance experienced when information is inaccessible or inadequate, and (c) a
      sense of urgency to solve problems. Moderately high correlations of the CFD
      scales with other measures of curiosity provided evidence of convergent validity,
      whereas divergent validity was demonstrated by minimal correlations of the CFD
      scales with the other personality traits.

PMID- 15041522
TI  - Food intake with an antiobesity drug (sibutramine) versus placebo and rorschach
      data: a crossover within-subjects study.
AB  - We related the effect of the satiety enhancing drug sibutramine (Meridia,
      Reductil) on food intake to Rorschach Comprehensive System (Exner, 1991, 1993)
      personality factors. A placebo-controlled crossover, within-subjects design (n =
      36) was used. Food intake after 2 weeks in the sibutramine and placebo conditions
      was assessed with a test meal using the VIKTOR (Cabmek, Stockholm, Sweden) setup,
      a computerized eating monitor. Building on baseline VIKTOR measurements, we had
      earlier studied the microstructure of eating (Elfhag, Barkeling, Carlsson, &
      Rossner, 2003). In this study, a model including Afr, MOR, and Populars could
      explain the variance in the effect of sibutramine. Sibutramine may reduce food
      intake in single test meals for participants whose appetite is prompted by
      external stimuli including food cues, suggested by the Affective ratio. Distress
      related to the body in obesity seen in damaged self-imagery (MOR) and adjustment
      to social expectations (Populars) could also have a moderating effect on the
      participants' consumption of test meals in an experimental design. Bodily concern
      (An + Xy) was also related to sibutramine response in univariate analyses.

PMID- 15041523
TI  - Informant personality descriptions of postintimate stalkers using the five factor
      profile.
AB  - Psychological descriptions of stalkers are few, especially nonforensic cases. As
      direct assessment is often hindered by lack of cooperation, assessment by
      informants may be a next-best approach. Indirect assessment may be most
      fruitfully applied among postintimate stalkers using instruments that are
      specifically validated for this purpose. Accordingly, in this study, we
      documented the psychological profile of 112 male postintimate stalkers as judged
      by ex-partners and/or subsequent victims using the Five Factor Personality
      Inventory (Hendriks, Hofstee, & de Raad, 1999b) and indexes of attachment and
      psychopathology. As compared to the Dutch norms, postintimate stalkers were
      described as extremely low on Agreeableness and moderately low on
      Conscientiousness and Emotional Stability. Most often insecurely attached with
      underlying negative self-representations, they were characterized as relatively
      functional people with strong sensitivities to rejection, abandonment, and loss.

PMID- 15041524
TI  - MMPI-2 profile code types and measurement error.
AB  - We studied simulated MMPI-2 (Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer,
      1989) code type stability and change expected with measurement error for 12 MMPI
      2 well-defined mean code type profiles. Profile scores for the 2 scales defining
      the code type were systematically varied to represent target code type profiles
      at 9 different levels of T-score profile definition. We randomly generated
      samples of 50 simulated, estimated true score profiles at each level of profile
      definition for each code type around the estimated true scores for each scale at
      each level of profile definition. Two sets of simulated profiles were developed.
      The first simulation was based on the reported means, test-retest reliabilities,
      and the standard errors of measurement for the MMPI-2 normative group. The second
      simulation was based on the means, standard deviations, and estimated retest
      stability for a clinical group of psychiatric patients. We calculated frequencies
      and percentages of simulated profiles with the highest estimated true scores on
      the same 2 scales as the original code type profile. Percentages of simulated
      profiles with the same 2 highest scales as the original code type profiles
      increased from 27% to 37% for the 3-point level of definition, 37% to 49% for the
      5-point definition, 46% to 61% for 7-point definition, 63% to 78% for 10-point
      definition, 78% to 89% for 13-point definition, 83% to 93% for 15-point
      definition, and greater than 90% for profile definition greater than 15 points.

PMID- 15041526
TI  - A personological examination of self- and other-forgiveness in the five factor
      model.
AB  - In a sample composed of 147 undergraduates (age range 18 to 55 years; M = 22), we
      conducted an examination of the convergent and discriminant validity of self- and
      other-forgiveness in the Five-factor model of personality (FFM). Using multiple
      measures of each construct, principal components analysis (PCA) supported a 2
      component model of forgiveness. Findings for the PCA and external correlates with
      the FFM provided evidence for a largely orthogonal relationship between self- and
      other-forgiveness. Specifically, self-forgiveness was negatively related to
      Neuroticism and unrelated to Agreeableness, whereas other-forgiveness was
      unrelated to Neuroticism and positively related to Agreeableness. Overlap between
      the constructs was found in which both self- and other-forgiveness were
      negatively related to the hostility facet of Neuroticism and the order facet from
      Conscientiousness and positively related to the warmth and positive emotions
      facet scales from the Extraversion domain of the Revised NEO Personality
      Inventory (Costa & McCrae, 1992). Overall, these findings suggest that self- and
      other-forgiveness, although seemingly similar, carry very different motivational
      underpinnings.

PMID- 15041525
TI  - Methodological issues in cross-cultural and multicultural rorschach research.
AB  - Hermann Rorschach researched the utility of his inkblot experiment to understand
      psychopathology and cultural differences. Contemporary research with the
      Rorschach has evaluated its utility as a test, although it may more properly
      represent a clinical method with somewhat different evaluation criteria. Recent
      controversy regarding the adequacy of the Rorschach as a test and the adequacy of
      its normative data has at times distorted and oversimplified important
      methodological issues inherent in the study of cultural difference. Cultural
      processes remain a central and inadequately examined variable in Rorschach
      research; an important emergent area of inquiry is the Rorschach's clinical
      utility as a cross-cultural assessment instrument. We review multicultural and
      cross-cultural methodological issues intrinsic to contemporary Rorschach research
      here. Consideration of cultural issues enlarges and enriches the Rorschach
      clinical utility debate and suggests underexplored research strategies that can
      contribute to its resolution.

PMID- 15041530
TI  - Gender identity: affected by social change?
AB  - To determine whether social changes in attitudes toward the role of men and women
      have influenced gender identity measures, 60 male and female college students
      were assessed using both a Thematic Apperception Test measure (May's, 1966,
      Deprivation/Enhancement measure) and a self-report measure (Bem's, 1974, Sex Role
      Identity [BSRI]), both of which were developed more than 20 years ago. Although
      some recent research has found the BSRI to no longer differentiate between men
      and women (Twenge, 1997; Wilcox & Francis, 1997), this study found significant
      gender differences for both gender identity measures.1

PMID- 15041527
TI  - Factorial structure and invariance across gender of the Swedish self
      consciousness scale.
AB  - In this study, I tested different factor models and the factorial invariance
      across gender for the Self-Consciousness Scale (Fenigstein, Scheier, & Buss
      (1975) using confirmatory factor analyses. University students (251 women and 259
      men) completed the Swedish version of the scale. A respecified (Item 15 loading
      on the factor Internal State Awareness [ISA] instead of on the factor Self
      Reflection [SR]) 17-item, 4-factor model of Burnkrant and Page (1984) including
      the factors SR, ISA, Public Self-Consciousness, and Social Anxiety demonstrated
      the best fit for both men and women. Factor intercorrelations were overall
      stronger for women. The respecified model demonstrated factorial invariance
      across gender. I discuss the strengthening of scale reliability through the
      expansion of subscale items and invariance testing across groups.

PMID- 15041531
TI  - Hypercompetitiveness in academia: achieving criterion-related validity from item
      context specificity.
AB  - A measurement of a conditional disposition, academic hypercompetitiveness, was
      created via the contextualization of hypercompetitiveness scale items into
      situations and circumstances relevant to academic life. An investigation of the
      construct and criterion-related validity of this new instrument, the
      Hypercompetitiveness in Academia (HIA) scale, was conducted. The HIA scale was
      found to be more strongly associated with academic outcomes and achievements than
      a scale measuring individual differences in a generalized, context-independent,
      hypercompetitive disposition. Conversely, the generalized hypercompetitiveness
      scale was found to be more strongly associated with measures of antisocial
      dispositions. The implications of this research on Horney's (1937) theory of
      neurosis, the possible negative repercussions of academic hypercompetitiveness,
      and the study of individual differences through investigations of conditional
      dispositions were discussed.

PMID- 15041532
TI  - Effect of inhibition of EBV-encoded latent membrane protein-1 by small
      interfering RNA on EBV-positive nasopharyngeal carcinoma cell growth.
AB  - OBJECTIVE: To evaluate the feasibility of using small interfering RNA (siRNA) for
      selective inhibiting latent membrane protein-1 (LMP1) expression in Epstein-Barr
      virus (EBV)-positive nasopharyngeal carcinoma (NPC) cell line C611, and observe
      the effects of LMP1 gene silencing on the NPC cell growth. METHODS: Four
      synthesized double-strand siRNA were respectively transfected into NPC cells,
      using Oligofectamine reagent. The subsequent changes in LMP1 mRNA level were
      determined by semi-quantitative reverse transcriptase (RT)-PCR. Flow cytometry
      and MTT assay were employed to examine the alterations in cell cycle and cell
      proliferation. RESULTS: The most effective sequence was identified among the 4
      candidate siRNAs, and its single dose caused nearly 90% loss of LMP1 mRNA in C611
      cells, with sustained specific inhibition for 96 h following a re-transfection.
      LMP1 siRNA treatment resulted in cell cycle arrest at G(0)-G(1) phase,
      accompanied by a reduction of cell proliferation by 33%, whereas EBV-negative NPC
      cells appeared unaffected. CONCLUSIONS: EBV-encoded LMP-1 is vulnerable to RNA
      interference and selective inhibition of LMP1 suppresses the proliferation of EBV
      positive NPC cells, a finding that sheds light on the possible use of RNA
      interference in further investigations of LMP1 and for therapeutic purposes of
      EBV-related NPC.

PMID- 15041533
TI  - Green tea polyphenols inhibit advanced glycation end product-induced rat vascular
      smooth muscle cell proliferation.
AB  - OBJECTIVE: To determine the effects of green tea polyphenols(GTP) on advanced
      glycation end products (AGEs)-induced proliferation and expression of p44/42
      mitogen-activated protein kinase (MAPK) of rat vascular smooth muscle cells
      (VSMCs) METHODS: Rat aortic VSMCs isolated and cultured in vitro were stimulated
      with AGEs in the presence or absence of GTP at different concentrations, followed
      by quantitative analysis of the cell proliferation with colorimetric assay. The
      p44/42 MAPK activity was evaluated by immunoblotting technique using anti-p44/42
      phospho-MAPK antibody. RESULTS: Compared with the control cells(without GTP
      treatment), GTP dose-dependently inhibited AGE-stimulated VSMC proliferation
      (P<0.05), and the p44/42 MAPK activity was significantly enhanced. The effects of
      AGEs were antagonized by GTP (372+/-41 vs 761+/-56, P<0.05). CONCLUSION: GTP can
      inhibit the AGE-induced proliferation and p44/42 MAPK expression of rat VSMCs.

PMID- 15041534
TI  - [Screening and identification of human telomerase reverse transcriptase epitopes
      from random phage display peptide library].
AB  - OBJECTIVE: To identify and characterize the epitopes of human telomerase reverse
      transcriptase (hTERT). METHODS: A random phage displayed dodecapeptide library
      was screened with anti-hTERT antibody. The selected phage clones were identified
      by sandwich enzyme-linked immunosorbent assay, anti-hTERT antibody blocking assay
      and competitive inhibition assay. RESULTS: After 3 rounds of screening, 13 of 24
      randomly selected phage clones were identified as positive clones that could
      specifically bind to anti-hTERT antibody but not to normal mouse IgG. Amino acid
      sequences deduced from DNA sequences showed 11 different sequences with high
      percentage of histone and hydrophilic amino acids. CONCLUSION: Eleven epitopes
      have been obtained that can effectively mimic hTERT, which will be useful for the
      research of small-molecule inhibitor targeting at hTERT.

PMID- 15041535
TI  - [Differences in gene expression profile between high and low metastatic human
      colorectal cancer cell lines].
AB  - OBJECTIVE: To analyze the gene expression profiles in colorectal cancer cell
      lines including high metastatic LoVo and SW620 cell lines and low metastatic
      SW480 and LS174T cells lines using cDNA microarray for tumor metastasis
      associated gene and to screen specific colorectal cancer metastasis-associated
      genes. METHODS: The cDNAs reversely transcribed from the mRNA derived
      respectively from the 4 cell lines and normal colorectal tissues were labeled
      with cy3 and cy5 prior to hybridization with the microarray containing 399 genes.
      The acquired image was analyzed by software. RESULTS: There were significant
      differences in gene expression profiles between high- and low- metastatic cell
      lines, and 44 up-regulated genes and 60 down-regulated genes were found to have
      statistical significance. CONCLUSIONS: The complex alterations in gene expression
      underlie the development of metastasis of colorectal cancer. The genes that are
      expressed differentially in high- and low- metastatic cell lines are probably
      related to the high metastatic potentials.

PMID- 15041537
TI  - [Effect of Bifidobacterial adhesin on lipopolysaccharide- and H2O2-induced
      proliferation and apoptosis of intestinal epithelial cells in vitro].
AB  - OBJECTIVE: To study the effect of Bifidobacterial adhesin on proliferation and
      apoptosis of intestinal epithelial cell induced by lypopolysaccharide (LPS) and
      H(2)O(2) in vitro. METHODS: With (3)H-TdR incorporation method, flow cytometry
      and fluorochrome staining, the proliferation and apoptosis of intestinal
      epithelial cells induced by LPS and H(2)O(2) in vitro were studied. RESULTS: LPS
      at the dose of 100 microg/L effectively stimulated the proliferation and
      apoptosis of cells, whereas H(2)O(2) at the dose of 200 micromol/L obviously
      restrained the proliferative ability while enhanced the apoptosis of the cells.
      Fluorochrome staining showed cell shrinkage, nuclear condensation and
      fragmentation under microscope. After treatment with Bifidobacterial adhesin, the
      cell proliferation and apoptosis decreased significantly in LPS group, and in
      H(2)O(2) group, cell apoptosis was significantly decreased. CONCLUSIONS:
      Bifidobacterial adhesin can protect intestinal epithelial cells from the damage
      by LPS and H(2)O(2), and maintain the balance between the proliferation and
      apoptosis of the cells.

PMID- 15041538
TI  - [Effects of a novel recombinant polypeptide from the sea anemone Anthopleura sp.
      on left ventricular function in New Zealand rabbits with chronic congestive heart
      failure].
AB  - OBJECTIVE: To observe the effects of recombinant hk2a, a novel neurotoxin from
      the sea anemone Anthopleura sp. on the left ventricular function in New Zealand
      rabbits with chronic congestive heart failure(CCHF). METHODS: CHF model was
      established using New Zealand rabbits by abdominal aortic coarctation. The left
      ventricular ejection fraction (LVEF) was measured by Acuson ultrasound systems
      (Sequoia 512) at 0, 5, 15, 30, 45 and 60 min respectively after intravenous
      injection with a single dose of recombinant hk2a (20 microg/kg x b x w.). The
      response of the rabbits to hk2a treatment was observed in comparison with that of
      the control group. RESULTS: Recombinant hk2a immediately and significantly
      increased the left ventricular ejection fraction of the rabbit models of CCHF
      after intravenous injection (P<0.05), and its effects were maintained for more
      than 1 h without affecting the heart rate. CONCLUSION: recombinant hk2a
      significantly increases the left ventricular ejection fraction in New Zealand
      rabbits with CCHF.

PMID- 15041536
TI  - [Cloning and sequence analysis of the preprotein cDNA of human bone morphogenetic
      protein 12].
AB  - OBJECTIVE: To clone the cDNA of the preprotein cDNA of human bone morphogenetic
      protein 12 (hBMP12). METHODS: Two primers were designed according to hBMP12
      sequence reported in GenBank. The hBMP12 preprotein cDNA was obtained by reverse
      transcriptional (RT)-PCR from the mRNA extracted from human placenta, followed by
      cloning into pTARGETTM plasmid and sequence analysis of the plasmid pT(ARGE)T(TM)
      BMP12. RESULTS: DNA agarose gel electrophoresis showed that the product of RT-PCR
      was about 920 bp, as was consistent with the result of PCR detection of the
      recombinant plasmid. The result of sequence analysis was in agreement with the
      reported hBMP12 sequence in GenBank. CONCLUSION: The preprotein of hBMP12 cDNA
      has been successfully cloned with correct sequence.

PMID- 15041539
TI  - [Construction and identification of yeast expression vectors containing human
      platelet-derived growth factor B-chain gene].
AB  - OBJECTIVE: To investigate the expression efficiency of human platelet-derived
      growth factor B-chain (PDGF-B) gene in yeast and assess the activity of the
      expressed product. METHODS: A full-length complementary DNA of human PDGF-B gene
      was amplified from the total RNA extracted from human vascular endothelial cells
      using reverse transcription (RT)-PCR and then cloned into pGEM-T vector. The PCR
      products with specific primers were recombined into yeast expression plasmids
      pMETB or pMETalphaA, followed by identification with restriction endonuclease.
      RESULTS: The 578 bp fragment encoding mature PDGF-BB peptide with signal peptide
      and the 340 bp fragment without signal peptide were identified and verified by
      restriction endonuclease mapping and sequencing, and two yeast expression vectors
      pMETB-PDGFB(1) and pMETalphaA-PDGFB(2) were reconstructed. CONCLUSION: The yeast
      expression vectors containing human PDGF-B gene have been successfully
      constructed for further studies of gene expression in yeast.

PMID- 15041540
TI  - [Changes of nitric oxide content and nitric oxide synthase activity during rabbit
      cartilage endplate degeneration].
AB  - OBJECTIVE: To study the role of nitric oxide (NO) and nitric oxide synthase (NOS)
      in the degeneration of rabbit cartilage endplate (CEP). METHODS: Twenty-four New
      Zealand rabbits were divided into experiment (n=12) and control (n=12) groups,
      and in the former group rabbit models of lumbar CEP degeneration was established
      by resection of all the lumbar supraspinous and interspinous ligaments and
      excision of part of the zygapophyseal joints followed by detachment of the
      posterior paravertebral muscles from the lumbar vertebrae. Lumbar X-ray was
      performed in both groups 12, 24 and 36 weeks after operation, respectively. The
      content of NO and NOS activity in the CEP were also measured. RESULTS: X-ray of
      the CEP reveal gradual calcification of the cartilage endplate with the elapse of
      time, which was more obvious in the experiment group. The content of NO and NOS
      activity was significantly increased in the experiment group after the operation
      (P<0.05), but their difference between the measurements at 24 and 36 weeks
      postoperatively was not obvious (P>0.05). CONCLUSION: NO may play an important
      role in the development and progression of rabbit cartilage endplate
      degeneration.

PMID- 15041541
TI  - [Effects of mitogen-activated protein kinase on phorbol 12-myristate 13-acetate
      induced matrix metalloproteinase-9 gene expression in cytotrophoblastic cells].
AB  - OBJECTIVE: To explore the regulatory mechanism of matrix metalloproteinase-9 (MMP
      9) gene expression induced by phorbol 12-myristate 13-acetate (PMA) in
      cytotrophoblastic cells. METHODS: Enzyme-linked immunosorbent assay (ELISA) was
      used to determine the kinase activity, and MMP-9 gene expression was detected by
      semi-quantitative reverse transcription (RT)-PCR in the cytotrophoblastic cells.
      RESULTS: Cytotrophoblastic cells treated with PMA showed markedly increased MMP-9
      mRNA level. PMA treatment caused an increase in extracellular signal-regulated
      kinase (ERK), c-jun N-terminal kinase (JNK), and p38 mitogen-activated protein
      kinase (p38 MAPK) activities. Both SB203580 (specific inhibitor of the p38 MAPK)
      and PD98059 (specific inhibitor of the ERK), when preincubated for 30 min with
      the cytotrophoblastic cells, substantially reduced MMP-9 mRNA accumulation in PMA
      primed cells. However, neither SB203580 nor PD98059 used alone, or their
      combination, was able to completely inhibit MMP-9 mRNA expression. CONCLUSION:
      Both p38 MAPK and ERK pathways are involved in the regulation of MMP-9 gene
      expression in the cytotrophoblastic cells induced by PMA, and both signaling
      pathways are indispensable for full activation of MMP-9 gene expression.

PMID- 15041542
TI  - [Detection of IgH gene rearrangement in Reed-Sternberg cells microdissected from
      classical Hodgkin's lymphoma].
AB  - OBJECTIVE: To study the origins and clonality of Hodgkin and Reed-Sternberg
      (H/RS) cells and their relations with the background lymphocytes in classical
      Hodgkin's lymphoma. METHOD: IgH gene rearrangement was detected in paffin
      embedded tissues from 33 patients with Hodgkin's lymphoma and a further analysis
      of the gene rearrangement was conducted in 6 of the positive cases identified
      after immunostaining of the sections with B-cell-specific activator protein
      (BSAP) followed by microdissection of the positivity labeled H/RS cells and
      background lymphocytes. RESULTS: IgH gene rearrangement was identified in 16 of
      the 33 cases. Microdissection of the lymphoma tissues was successfully performed
      in the 6 positive cases, and of the 19 tubes of H/RS cells obtained, 14 presented
      clonal bands of the rearrangement, and difference in cell numbers did not
      significantly influence the positive rate (P=0.290); in the 12 tubes of
      microdissected background lymphocytes obtained, 2 were positive for the
      rearrangement, and the positive rates for the rearrangement significantly
      differed between H/RS cells and the background lymphocytes (P=0.002). CONCLUSION:
      The results appear to support the hypothesis that H/RS cells originates from B
      cells, and a part of the background lymphocytes may possess neoplastic
      proliferation potentials to function as the precursors of H/RS cells.

PMID- 15041543
TI  - [Differentiation of rabbit bone marrow mesenchymal stem cells into myogenic cells
      in vitro and expression of vascular endothelial growth factor gene after
      transfection].
AB  - OBJECTIVE: To induce the differentiation of rabbit bone marrow mesenchymal stem
      cells (MSCs) into myogenic cells in vitro, and to investigate the expression of
      vascular endothelial growth factor (VEGF) gene in AdTrackCMV-hVEGF165-
      transfected MSCs. METHODS: Twenty rabbits were divided equally into control group
      and experimental group, and MSCs were isolated and purified from their bone
      marrow by Percoll (1.073 g/ml) followed by cell culture in low-glucose DMEM
      supplemented with 10% fetal bovine serum. 5-azacytidine (5-Aza) was added into
      the cell culture of the experimental group on the third day. The expression of
      troponin I in MSCs was assayed by immunohistochemistry on the 28th day.
      AdTrackCMV- hVEGF165 eukaryotic expression vector was constructed and transfected
      into the MSCs, and subsequent VEGF expression was detected by Northern blotting
      and Western blotting while enzyme-linked immunosorbent assay (ILISA) was employed
      to examine the VEGF concentration in the supernatant of the culture medium.
      RESULTS: Following successful isolation and culture of the MSCs from rabbit bone
      marrow, 5-Aza-induced differentiation of the cells into myogenic cells was
      demonstrated by their positive staining for cardiac troponin I (cTnI). Northern
      blotting showed that the expression of VEGF 165 mRNA was much higher in the
      VEGF165 gene-transfected cells than in the control cells. Western blotting showed
      VEGF expression in the transfected cells. The concentration of VEGF in the
      supernatant mounted to the peak level 3-5 d after VEGF165 gene transfection
      (1,011-1,027 pg/ml) and decreased gradually thereafter, but still maintaining
      higher levels than those in the control group and pAdTrackCMV group (349 pg/ml vs
      116 pg/ml and 125pg/ml, respectively, P<0.01). CONCLUSION: MSCs can be induced to
      differentiate into myogenic cells in vitro and express VEGF after VEGF gene
      transfection, and this success may provided a basis for combining MSC
      transplantation with gene therapy for regeneration of the damaged myocardial
      cells.

PMID- 15041544
TI  - [Preliminary study of human calicivirus infection in Guangzhou].
AB  - OBJECTIVE: To investigate of human calicivirus (HuCV) infection in the children
      of Guangzhou, the capital of Guangdong Province at China, and conduct preliminary
      study of the prevalence of the virus. METHODS: Serum specimens from 266 children
      of different ages were tested by an indirect enzyme-linked immunosorbent assay
      (ELISA) for specific IgG against recombinant Norwalk virus particles (rNV),
      recombinant Mexico virus partides(rMX) and recombinat 387 Virus particles(r387),
      respectively, and fecal specimens were collected for detection of HuCV RNA using
      reverse transcriptional (RT)-PCR assisted by sequence analysis on the basis of
      comparison of the amplified product with the sequence entries in GenBank.
      RESULTS: The seroprevalence was 68.0% for rNV, 51.5% for rMX and 71.1% for r387
      in the cohort of children enrolled in this study. Norwalk-like viruses (NLVs)
      were detected in 4 out of the 100 fecal specimens collected from cases of
      nonbacterial gastroenteritis during the peak season of diarrhea, and also in 3 of
      the 10 fecal specimens collected during the outbreak of diarrhea in an elementary
      school. CONCLUSIONS: Sporadic and fulminant NLV infections are present in
      Guangzhou. The children have the infection in their infancy, and the infection
      rate increases sharply with age.

PMID- 15041545
TI  - [Preventive effects of heat-shock response against circulatory collapse induced
      by hyperthermia].
AB  - OBJECTIVE: To investigate the preventive effects of heat-shock response (HSR)
      against circulatory collapse induced by hyperthermia and understand its
      mechanism. METHODS: Twenty-four SD rats were randomized equally into heat-shock
      group (HS group), high temperature control group (HC group) and normal
      temperature control group (NC group). The rats in HS group, but not HC group,
      were subjected to heat shock pretreatment. After a recovery period for 20 h at
      room temperature, the rats in HS and HC groups were exposed to high temperature
      environment, and their blood pressures and electrocardiograms were measured
      continuously. Heat exposure was terminated at 73 min and the contents of
      myocardial malondialdehyde (MDA) and NO were measured. Using Chart software, the
      data of the mean arterial pressure (MAP), systolic pressure (SP), diastolic
      pressure (DP), heart rate (HR) were acquired. The rats in NC group did not
      receive any treatment to obtain the measurements in normal condition. RESULTS:
      Compared with NC group, the MAP, SP and DP were significantly lowered (P P<0.01)
      in HS and HC group and HR accelerated (P P<0.01) after a 73-min heat exposure,
      and HS group had significantly higher measurements of the above indices than HC
      group did. In comparison with NC group, the contents of MDA and NO in the
      myocardium in HC group were significantly elevated after the exposure (P P<0.01).
      The MDA content in HS group, which was comparable with that of NC group, was
      significantly lower than that of HC group (P P<0.05), and compared with HC group,
      HS also had lower NO content (P<0.01). CONCLUSION: HSR may relieve circulatory
      collapse induced by hyperthermia, which involves the inhibitory effect of HSR on
      the production of MDA and NO in the myocardium.

PMID- 15041546
TI  - [Detection of oprI gene of Pseudomonas aeruginosa by reverse dot-blot
      hybridization].
AB  - OBJECTIVE: To establish a rapid method for detecting Pseudomonas aeruginosa at
      the early stage of infection. METHODS: Specific primers were designed according
      to oprI gene sequence of Pseudomonas aeruginosa, and the specific probe was
      synthesized by PCR. After photosensitive biotin labeling of the bacterial DNA,
      reverse dot-blot hybridization was used to detect Pseudomonas aeruginosa.
      RESULTS: The probe synthesized was highly specific to Pseudomonas aeruginosa
      without cross reaction with other bacteria, viruses or fungi. The method was
      capable of detecting 100 ng bacteria DNA. CONCLUSION: Reverse dot-blot
      hybridization possesses the merits of speediness and specificity in the detection
      of Pseudomonas aeruginosa in the early stage of infection.

PMID- 15041547
TI  - [Three-dimensional dynamic contrast-enhanced magnetic resonance angiography in
      liver transplantation].
AB  - OBJECTIVE: To investigate the clinical value of three-dimensional dynamic
      contrast-enhanced magnetic resonance (MR) angiography in the liver
      transplantation. METHODS: MR scanning was performed both before and after the
      operation in 9 patients elected for liver transplantation, and after three
      dimensional reconstruction at a computer workstation, the three- dimensional
      images of the inferior vena cava, hepatic veins, portal vein and bile duct were
      obtained. RESULTS: The three- dimensional images could be rotated in space to
      show the size, shape, lining of the veins and anatomic relationships between each
      other. CONCLUSION: Three-dimensional dynamic contrast-enhanced MR angiography can
      be of value in liver transplantation.

PMID- 15041549
TI  - [Effect of cooling therapy on the heart rate and mean arterial pressure of rats
      with the second-degree scald burn in hot and humid environment].
AB  - OBJECTIVE: To observe the changes of heart rate (HR) and mean arterial pressure
      MAP after immediate cooling therapy (ICT) in rats with superficial second-degree
      scald burn in hot and humid environment, and assess the effect of the cooling
      dressing materials. METHODS: Twenty-four Wistar rats were randomized equally into
      4 groups including normal temperature control (NTC) group, normal temperature
      cooling therapy (NCT) group, hot and humid control (HHC) group and hot and humid
      cooling therapy (HCT) group. Different interventions were applied as indicated in
      the rats with superficial second-degree scald burn, with the dry bulb temperature
      Tdb at 26.33+/-1.29 degrees celsius; and relative humidity (rh) of 71.05%+/-4.57%
      for two normal temperature groups, and Tdb at 35.33+/-0.35 degrees Celsius; and
      rh of 70.81%+/-1.38% for the two hot and humid groups. The exposure time was 120
      min in NCT and HCT groups, and the HR and MAP were measured every 20 min.
      RESULTS: MAP is not influenced by environmental temperature and the cooling
      therapy (P>0.05), whereas HR was higher in HHC than in NTC group and also in HCT
      than in NCT group (P=0.003), lower in HCT and NCT groups than in HHC and NTC
      groups (P=0.002), respectively. HR did not undergo any significant changes during
      the observation in the 4 groups (P>0.05). HR was higher in HHC and HCT than in
      NTC and NCT groups at 65, 85, 105 and 125 min after the burns, but compared with
      the two control groups, cooling therapy decreased HR at 5, 25, 45 and 85 min.
      CONCLUSION: Cooling therapy does not affect MAP but efficiently decreases HR,
      which may prevent further heat injury.

PMID- 15041548
TI  - [Analysis of the difference in NIH3T3 cell protein expression profiles before and
      after TPA treatment using two-dimensional polyacrylamide gel electrophoresis and
      image analysis software].
AB  - OBJECTIVE: To establish and optimize two-dimensional (2-D) polyacrylamide gel
      electrophoresis (PAGE) for comparative analysis of the protein expression
      profiles in mouse fibroblast NIH3T3 cells before and after 12-O-tetradecanoy-
      lphorbol-13-acetate (TPA) treatment using image analysis software, so as to
      prepare for more intensive study in the identification of the proteins that
      mediate the biological effect of TPA. METHODS: The total cellular protein
      extracted from NIH3T3 cells with or without TPA treatment underwent 2-D PAGE and
      silver nitrate staining prior to the analysis of the differential protein
      expressions using image analysis software. RESULTS: Image analysis revealed
      obvious differential protein expressions of the cells in response to TPA
      treatment. CONCLUSION: High-quality instruments for 2-D PAGE, skilled
      electrophoretic operation and efficient image processing are all essential in the
      reliable identification of stable functional proteins.

PMID- 15041550
TI  - [Clinical application of GnRHa before uterine myomectomy: report of 20 cases].
AB  - OBJECTIVE: To study the clinical application of GnRHa prior to uterine myomectomy
      and its effect on the clinical outcome of pregnancy. METHODS: A retrospective
      review of the medical records in 20 cases of uterine myomectomy over a period of
      6 years was performed. The changes of uterus and myoma volumes in response to
      preoperative GnRHa was observed, and the rate of relapse in the follow-up, time
      of impregnation, spontaneous abortion after the impregnation, time of delivery
      after the operation and the aura threatening uterine rupture, and uterine rupture
      during the delivery were assessed. RESULTS: Application of GnRHa produced
      significant improvement in the clinical symptoms and resulted in obviously
      reduced volumes of the uterus and myoma. The myoma volume reduction was close to
      50% in these cases, and relapse occurred in only 1 case. No spontaneous abortion
      was found after GnRHa application. The average time of pregnancy was 34+/-3.5
      weeks, and aura for uterine rupture was found in 1 case at 33 weeks of pregnancy
      after GnRHa application. CONCLUSION: Application of GnRHa can correct anemia,
      decrease the relapse rate of myoma, reduce uterus and myoma volumes, to make
      possible smaller incision for uterine myomectomy that leaves smaller scar in the
      uterus and decrease intraoperative bleeding, also relieving endometrial injuries
      to promote the conditions for impregnation and minimize the risks of uterine
      rupture and total hysterectomy for the benefit of normal delivery.

PMID- 15041551
TI  - [Dentine hypersensitivity treated with Nd: YAG laser: experience with 262 cases].
AB  - OBJECTIVE: To observe the curative effect of neodymium-doped yttrium aluminum
      garnet (Nd:YAG) laser pulse in treating dentine hypersensitivity. METHOD: A total
      of 262 teeth with dentine hypersensitivity were divided equally into 2 groups,
      namely the test group which received treatment with pulse Nd: YAG laser and the
      control group treated with sodium fluoride. RESULTS: The instant, 1-month and 6
      month effectiveness in the test group was better than that in the control group,
      showing significant difference between the two groups (P<0.01). CONCLUSION: Nd:
      YAG laser is safe and highly effective in treating dentine hypersensitivity.

PMID- 15041552
TI  - [Purification and activity assay of recombinant growth hormone-releasing
      hormone].
AB  - OBJECTIVE: To express recombinant growth hormone-releasing hormone (GHRH) peptide
      in E.coli by genetic engineering and examine its biological activity. METHOD:
      GHRH peptide was purified to homogeneity by means of cell lysis, washing, ethanol
      precipitation, acid hydrolysis, SP-Sephadex C25 and Sephadex G-25 column
      chromatographies. RESULT: SDS-PAGE showed that the recombinant plasmid pET-28a /L
      ansB-GHRH in E.coli BL21(DE3) expressed the fusion protein under the induction
      with IPTG. The fusion protein was expressed in the form of inclusion body,
      accounting for 30% of the total bacterial protein. After the purification
      procedures, the peptide was purified about 147-fold with a peptide yield of
      0.68%. The molecular mass of the peptide was 5 235 Da as determined by
      electrospray ionization (ESI) mass spectrum, in agreement with the predicted
      value, and SDS-PAGE presented a single peak in assessment of the purity.
      Experiment showed that there were significant differences in the growth hormone
      released by the peptide between the dose groups and the blank control group, and
      the differences tended to be more obvious with the increase of the doses.
      CONCLUSION: The recombinant GHRH peptide possesses good biological activities.

PMID- 15041553
TI  - [Suppression of neutrophil immune function in rabbit models of hemorrhagic shock
      complicated by intra-abdominal hypertension].
AB  - OBJECTIVE: To investigate the effects of hemorrhagic shock and intra-abdominal
      hypertension (IAH) on inflammatory responses of peripheral circulating
      neutrophils such as intracellular cytokine production, phagocytic capacity and
      expression of nuclear factor (NF)- kappaB. METHODS: Twenty-four rabbits were
      divided equally into 4 groups including a hemorrhagic shock (HS) group
      complicated by abdominal compartment syndrome (ACS) (Group A), a HS group (Group
      B), a ACS group (Group C) and a normal control group (Group D). Intracellular
      interleukin (IL)-8 production in the peripheral neutrophils were measured in the
      rabbits by flow cytometry, phagocytic function of the neutrophils evaluated by a
      chemiluminescence method and the NF-kappaB expression detected by
      immunocytochemistry before, immediately and 4 h after the traumatization.
      RESULTS: Four hours after the trauma, decreased intracellular IL-8 production and
      impaired phagocytic function of the peripheral neutrophils were observed in Group
      A along with suppressed NF-kappaB expression. But in Group B and Group C, the
      intracellular IL-8 production, phagocytic function and expression of NF-kappaB
      returned to the normal levels 4 hours after the trauma following the early-stage
      changes. In Group D, no significant changes occurred during the observation.
      CONCLUSIONS: Responsiveness and function of the neutrophils to the stimuli by
      endotoxin are suppressed by the sequential second-hit of IAH after hemorrhagic
      shock, which may contribute to the occurrence of sepsis in ACS.

PMID- 15041554
TI  - [Hierarchical image segmentation based on watershed filtering and fuzzy cluster].
AB  - Watershed algorithms is an automatic segmentation scheme to generate closed
      outlines, which might give rise to over-segmentation, i.e., numerous small
      segmented closed regions that blur the target contours or shapes. In this paper,
      the author proposed a scheme to merge the small regions and generate a
      hierarchical segmentation representation. We first define the dissimilarity
      measure between the neighboring regions, and based on this dissimilarity
      measurement, a fuzzy matrix calculation followed by hierarchical segmentation is
      performed. Experiments with various types of images are given.

PMID- 15041555
TI  - [Association of reflux esophagitis with Helicobacter pylori].
AB  - OBJECTIVE: To investigate the association of the pathogenesis of reflux
      esophagitism (RE) with Helicobacter pylori (H. pylori) infection. METHODS: The
      prevalences of H. pylori among the patients with RE, normal control subjects,
      patients with chronic gastritis and patients with duodenal ulcer, as well as the
      prevalence of H. pylori infection in RE patients of each grade, were compared.
      Forty patients with endoscopically verified RE grades B or C, along with 20
      patients with and another 20 without H. pylori infection were enrolled to receive
      a 4-week course of rabeprazole treatment, and the subsequent healing rates and
      symptom relief were compared. RESULTS: The prevalences of H. pylori in groups RE,
      control, chronic gastritis and duodenal ulcer were 30.4%, 28.8%, 59.0% and 91.5%
      respectively. The rate of H. pylori infection in patients with RE was
      significantly lower than that in those with chronic gastritis and duodenal ulcer,
      but was comparable with that in the control subjects. H. pylori infection varied
      little among RE patients of different grades. In RE patients positive or negative
      for H. pylori, the healing rates and relief of the symptoms were not different
      after the treatment. CONCLUSION: H. pylori infection might not be responsible for
      the susceptibility to RE.

PMID- 15041556
TI  - [Equivalence test and its performance with computer software].
AB  - Following brief introduction of the equivalence test, a sample is given to
      exemplify its performance with EquivTestTM 2.0 software and with the major
      results were interpreted.

PMID- 15041557
TI  - [99mTc-N-NOET myocardial perfusion imaging during exercise for diagnosis of
      coronary artery disease].
AB  - OBJECTIVE: To investigate the value of (99m)Tc-N-NOET(NOET) myocardial perfusion
      imaging during exercise in the diagnosis of coronary artery disease (CAD), and
      the relationship between exercise NOET lung/heart ratio and left ventricular
      diastolic function. METHODS: Exercise-delayed NOET myocardial perfusion imaging
      was performed in 49 patients undergoing coronary angiography, among whom 29 had
      coronary stenosis>or=50% and 20 normal coronary artery. RESULTS: The sensitivity
      and specificity of exercise NOET myocardial perfusion imaging were 86.2% and
      95.0%, respectively, in the detection of CAD. The NOET lung/heart ratio of CAD
      patients with multiple branch involvement (0.76+/-0.13) was significantly higher
      than those of patients with single branch lesion (0.62+/-0.06) and with normal
      coronary artery (0.58+/-0.13, F=18.04, P=0.002- 0.001). When the lung/heart ratio
      was over 0.70, the sensitivity and specificity of the imaging for detecting the
      presence of multiple branch involvement were 93.5% and 83.3%, respectively. NOET
      lung/heart ratio showed a significant correlation with E/A ratio (r=-0.771,
      P<0.000 1). CONCLUSION: Exercise NOET lung/heart ratios has diagnostic values for
      multiple branch lesions and left ventricular diastolic function abnormalities in
      patients with CAD.

PMID- 15041558
TI  - [Posterior lumbar intervertebral fusion device and a new transpedical screw
      system for treatment of lumbar spondylolisthesis].
AB  - OBJECTIVE: To observe the effect of posterior lumbar intervertebral fusion (PLIF)
      device and a novel transpedical screw system for the treatment of lumbar
      spondylolisthesis. METHODS: Thirty-three patients with lumbar spondylolisthesis
      were treated with PLIF device for intervertebral fusion after total laminectomy
      and internal fixation with the novel transpedical screw system. RESULTS: The
      patients were followed up for 6 to 36 months with an average of 18.6 months.
      Nerve injuries and infection of the incisions occurred in none of the cases
      postoperatively, and no cases exhibited PLIF device displacement or transpedical
      screw loosening or breaking, nor were other complications seen in this group. The
      clinical results were excellent in 21 cases, good in 10 cases, and acceptable in
      2 cases according to the standard of Brantigan. CONCLUSION: PLIF device and new
      transpedical screw system constitute good treatment modalities for lumbar
      spondylolisthesis, with such merits as full decompression of the spinal canal,
      good restoration of the vertebral body, immediate pain relief and reliable
      fixation of the vertebral body to allow early force loading postoperatively, and
      are therefore suitable for treating lumbar spondylolisthesis.

PMID- 15041559
TI  - [Partial splenic embolization for idiopathic thrombocytopenic purpura:
      therapeutic effect and influence of the embolization on splenic function].
AB  - OBJECTIVE: To explore the therapeutic effect of partial splenic embolization of
      different embolized volumes for idiopathic thrombocytopenic purpura (ITP) and
      consequent changes of the splenic function. METHODS: Forty-five ITP patients were
      randomized into 2 groups to receive splenic embolization with gelatin sponge
      particles, and the embolized volume ranged between 60% and 80% in the former
      group (group A), and between 40% and 60% in the latter group (group B). RESULTS:
      The platelet counts of the patients in both groups markedly increased one week
      after the operation, and the average count was significant higher in group A than
      in group B one year after the operation (P<0.01). The splenic function of the
      patients in neither of groups underwent any significant changes after the
      operation (P>0.05). CONCLUSION: Splenic embolization of different volumes
      produces similar therapeutic effect on ITP, but more extensive embolization may
      insure long-lasting effect with better safety and less influence on splenic
      function.

PMID- 15041560
TI  - [Influence of blood supply of the esophageal and gastric stumps on anastomotic
      healing after esophagogastrostomy in rabbits].
AB  - OBJECTIVE: To study how blood supply of the esophageal and gastric stumps
      influences the anastomotic healing after esophagogastrostomy in rabbits. METHODS:
      Twenty-seven New Zealand rabbits were randomly divided into 3 groups to receive
      esophagogastrostomy, followed by different procedures. Except for those in group
      I, all the rabbits were subjected to procedures of reducing the blood supply
      either of the esophageal or the gastric stump (group II and group III,
      respectively), followed by single-layer esophagogastric anastomoses using
      interrupted 5-0 polypropylene sutures. Ten days after operation, all the rats
      were killed and the anastomotic sites excised for measurement of the inner
      diameter, tensile strength, and hydroxyproline concentration. RESULTS: Healing of
      the esophagograstric anastomosis was obtained in all the rabbits but one with
      anastomotic leakage in group I and one with perforation of the gastric fundus in
      group III. The anastomotic inner diameters were similar in all the three groups,
      whereas the tensile strength and hydroxyproline concentration at the anastomoses
      decreased in group III in comparison with the other two groups (P<0.05) that had
      similar measurements (P>0.05). CONCLUSIONS: Extended length of the free
      esophageal stump does not significantly affect anastomotic healing as decrease of
      blood supply in the gastric stump.

PMID- 15041561
TI  - [Investigation of the bacteria in the seawater of Xisha in the South China Sea
      and their antibiotic sensitivity profile].
AB  - OBJECTIVE: To investigate the distribution and antibiotic sensitivity of the
      bacteria in the seawater of Xisha in the South China Sea. METHODS: The samples of
      the seawater in Xisha were collected for bacterial counting, identification and
      antibiotic sensitivity tests. RESULT: Of the 84 bacterial strains isolated from
      the 80 seawater samples, 38 (45.24%) belonged to Vibrio alginolyticus, 11
      (13.10%) to Sphingomonas, 9 (10.72%) to Comamonas terrigena, 7 (8.33%) to
      Werepseudomonas, 6 (7.14%) to Moraxella, 5 (5.95%) to Cedeceadavisae, and 8 to
      other bacteria including 2 Aeromona, 2 Acinetobacter, 1 Pantoea agglomerans, 1
      Kingella kingae, 1 Shewanella putrefaciens and 1 Suttonella indologenes. Tests of
      the antibiotic sensitivity showed that all the bacteria were high sensitive to 16
      kinds of the antibiotics with the exception of Vibrio alginolyticus, Sphingomonas
      and comamonas terrigena that were less sensitive to aztreonam or piperacillin and
      Sphingomonas to cefotaxime or cefepime. CONCLUSION: The investigation will be of
      great significance for early-stage prevention and cure of bacterial infection
      acquired from the seawater.

PMID- 15041562
TI  - [Co-expression of two spliceosomes of cyclin-dependent kinase-2 in SH-SY5Y
      cells].
AB  - OBJECTIVE: To investigate the expression of cyclin-dependent kinase-2 (CDK-2)
      gene in SH-SY5Y cells. METHODS: The expression of CDK-2 gene was examined with
      reverse transcriptional (RT)-PCR, and the PCR products underwent electrophoresis
      on non-denaturing poly-acrylamide gel (PAG) followed by silver staining. The
      separated and purified DNAs were ligated into pMD18-T vector, and the positive
      clones identified by sequence analysis. RESULTS: Two DNA bands were displayed on
      PAG, and the one with smaller molecular weight was less intensively stained. The
      sequences of the two clones indicated that both were products of CDK-2 gene.
      CONCLUSION: Two kinds of CDK-2 gene products are co-expressed in the SH-SY5Y
      cells, one of which lacks the fifth exon and is expressed at a low level.

PMID- 15041563
TI  - [Preparation of drug-loaded polylactic acid nanospheres and drug-releasing
      performance evaluation].
AB  - The polylactic acid (PLA) nanospheres containing griseofulvin were prepared by a
      water-in-oil solvent evaporation method adopting an uniformly designed
      experiment, and the drug-releasing rates were compared between the microsphere
      and nanosphere. The results showed that the nanospheres was good in spherical
      shape with narrow distribution of the particle sizes. The particle diameter was
      about 114 nm, and the comprehensive score of the nanosphere was 95.59, with the
      error of 3.66% and the drug content of 13.55% by the linearity regression
      averaged from the results of the three repeat experiments. The drug-releasing
      rate of the microsphere was relatively slow, while that of the nanosphere can
      have an abrupt increase, indicating its function of solubilizing the drug.

PMID- 15041564
TI  - [Epidemiological investigation of nosocomial infection of SARS in medical staff
      of a hospital].
AB  - OBJECTIVE: To investigate the epidemiological features of nosocomial infection of
      severe acute respiratory syndrome (SARS) in the medical staff of a hospital.
      METHODS: The medical staff associated with nosocomial infection of SARS in a
      hospital were investigated with standard procedures of epidemiological survey.
      RESULTS: The source of SARS infection was identified as the husband of a tumor
      patient who received chemotherapy in the Department of Oncology, during which
      they maintained intimate contact for at least two weeks when the husband had
      typical symptoms of SARS. The tumor patient had no any signs of SARS before her
      death. The mean latent period of SARS was 12.6 days in the 8 nurses transferred
      temporarily from other departments to assist in the management of the tumor
      patient. All 57 persons with close contact with the 12 medical staff suffering
      SARS in the latent period or with one having early-stage SARS did not show any
      signs of SARS during one month for observation in isolation. CONCLUSION: SARS
      patients may have no or very limited infectivity during the latent period.
      Infection of SARS might be concerned with the intensity and persistence of
      contact with the infectious sources. The pathogenesis of SARS might involve the
      immune status of the potential patients, and immunodeficient individuals are at
      the risk of becoming asymptomatic carriers of SARS virus and the infectious
      sources.

PMID- 15041565
TI  - [Clinical analysis of 31 cases of traumatic interhemispheric subdural hematomas].
AB  - OBJECTIVE: To analyze the clinical characteristics, pathogenesis and management
      of traumatic interhemispheric subdural hematomas (ISH). METHODS: Thirty-one
      traumatic ISH cases were reviewed and analyzed retrospectively. RESULTS: Of the
      31 patients, 29 were cured and 2 died of multi-system organ failure (MSOF) and
      cerebral hernia respectively. Typically, ISH manifested hemiplegia or paralysis
      of the counterlateral lower limb known as falx syndrome. CONCLUSIONS: CT scans
      showing hematocele in the interhemispheric subdural space in excess of 20 ml, or
      with a thickness of hematocele over 1cm, may serve as a diagnostic criteria for
      ISH. For the treatment of ISH, surgery and conservative management are suggested
      on the basis of functional disturbance or the stability of the disease.

PMID- 15041566
TI  - Anaphylactic reactions to neuromuscular blocking drugs: are we making the correct
      diagnosis?

PMID- 15041567
TI  - Neither the accuracy nor the precision of thermal dilution cardiac output
      measurements is altered by acute tricuspid regurgitation in pigs.
AB  - Whether measurement of cardiac output using the thermal dilution technique (TDCO)
      is valid in the presence of tricuspid regurgitation (TR) is controversial. We
      assessed the accuracy and precision of the technique in pigs by comparison with
      data from an electromagnetic flowmeter on the aorta (EMCO). TR was created with
      sutures that immobilized the free-wall leaflets of the tricuspid valve, and
      cardiac output was adjusted with dobutamine to give values comparable to control
      measurements. TR reduced forward stroke volume from 17.2 to 12.6 mL/beat and
      caused the right atrium to dilate and pulse in synchrony with the right
      ventricle. Acute TR did not affect the linear regression relation between TDCO
      and EMCO and did not alter the correlation coefficient (r = 0.94 during both
      control and TR). These data demonstrate that acute TR does not affect the
      accuracy or precision of TDCO in pigs. IMPLICATIONS: Cardiac output is a valuable
      measurement that guides the medical care of patients with heart and lung disease.
      This study demonstrates that the thermal dilution technique of determining
      cardiac output is valid when acute tricuspid valve regurgitation is present in
      pigs.

PMID- 15041570
TI  - Intrathecal morphine reduces infarct size in a rat model of ischemia-reperfusion
      injury.
AB  - Systemically-administered morphine reduces infarct size in rat models of
      myocardial ischemia-reperfusion. We sought to determine whether much smaller
      doses of spinally-administered morphine offer a similar cardioprotective benefit.
      Barbiturate-anesthetized, open-chested, Wistar rats with chronic indwelling
      thoracic intrathecal catheters were instrumented for hemodynamic measurements and
      subjected to 30 min of coronary occlusion and 90 min of reperfusion. Myocardial
      infarct size was determined using triphenyl-tetrazolium staining. Rats were
      randomly assigned to receive intrathecal (IT) 0.9% saline (vehicle), IV morphine
      (0.3 mg/kg) plus IT saline, small-dose IT morphine (0.3 microg/kg), or large-dose
      IT morphine (3 microg/kg) 20 min before occlusion. IV and both doses of IT
      morphine reduced infarct size, defined as area of necrosis expressed as a
      percentage of area at risk (%AN/AAR), as compared with vehicle. The %AN/AAR group
      means were as follows: IV (n = 7), 30% +/- 6%; IT(small-dose) (n = 9), 30% +/-
      5%; IT(large-dose) (n = 9), 18% +/- 4%; and vehicle (n = 10), 47% +/- 5%. There
      were no significant differences in infarct size among the morphine-pretreated
      rats. During ischemia-reperfusion, heart rate was unchanged from baseline in the
      IT(large-dose) group, whereas in the IT(small-dose), IV and vehicle groups,
      significant declines in heart rate occurred. Changes in arterial blood pressure
      were similar among groups. These results indicate that IT morphine reduces
      infarct size in rats, and this benefit is as great as that provided by IV
      morphine administration. IMPLICATIONS: Our findings suggest that spinally
      administered morphine provides a previously unrecognized cardioprotective
      benefit. In anesthetized rats subjected to ischemia-reperfusion injury, we show
      that very small doses of intrathecal morphine reduce infarct size in rats, and
      this benefit is as great as that provided by much larger doses of IV morphine.

PMID- 15041568
TI  - Inotropes improve right heart function in patients undergoing aortic valve
      replacement for aortic stenosis.
AB  - The administration of inotropes after aortic valve replacement (AVR) for aortic
      stenosis (AS) is controversial. Issues include the risk of left ventricular (LV)
      systolic outflow obstruction (LVOTO) and the proper treatment of diastolic
      dysfunction for patients in whom LV systolic function is often preserved and
      subsequently improved. In this study, we assessed the hemodynamic benefits of
      inotropes for patients undergoing AVR for AS. Thirty-four patients were
      prospectively randomized to one of three groups: epinephrine, milrinone, or
      placebo. Hemodynamic and echocardiographic data were obtained before and
      immediately after cardiopulmonary bypass (CPB). Data were also obtained before
      and after increases in ventricular preload to assess the effects of inotropes on
      diastolic function. The use of inotropes was associated with significantly larger
      increases in right ventricular (RV) (placebo, 0.5%; epinephrine, +9%; milrinone,
      +8%; P < 0.01) and LV (placebo, +7%; epinephrine, +18%; milrinone, +20%; P =
      0.07) ejection fractions (EF) and cardiac output after CPB. Changes in cardiac
      output and index were more strongly correlated with changes in RVEF (r = 0.56, P
      < 0.01; r = 0.47, P < 0.01, respectively) than with LVEF (r = 0.22, r = 0.08). Of
      all patients receiving epinephrine or milrinone, only one (1 of 22) had a
      decrease in RVEF, whereas 6 of 12 patients receiving placebo had a reduction in
      RVEF from pre-CPB to post-CPB. Correspondingly, for LVEF, 1 of 22 patients
      receiving inotropes had a decrease in LVEF, whereas 3 of 12 placebo patients had
      a reduction in LVEF from pre-CPB to post-CPB. No patient had evidence of LVOTO.
      Inotropes improved hemodynamics after AVR for AS. This was attributable more to
      improved RV function than to changes in LV function. Although there were no
      changes in diastolic function, it is possible that this study did not allow
      significant timing to observe benefits of inotropes on diastolic function in this
      setting. IMPLICATIONS: Compared with placebo, both epinephrine and milrinone
      similarly improved biventricular performance after aortic valve replacement, with
      a greater impact on right ventricular function. Choice of either inotropic drug
      should be driven by blood pressure and hemodynamic goals in this setting.

PMID- 15041571
TI  - Accurate central venous port-A catheter placement: intravenous
      electrocardiography and surface landmark techniques compared by using
      transesophageal echocardiography.
AB  - Using transesophageal echocardiography (TEE) to locate the tip of central venous
      catheters inserted via the right subclavian vein, we compared IV
      electrocardiography (IV-ECG)-guided catheter tip placement with the conventional
      surface landmark technique. Sixty patients were randomly assigned into two
      groups. In Group E, the IV-ECG signal was conducted along an NaHCO(3)-filled
      catheter to facilitate catheter placement. In Group S, surface landmarks on the
      chest wall were used to determine the appropriate catheter length. The goal was
      to visualize the catheter tip with TEE at the superior edge of the crista
      terminalis, which is the junction of the superior vena cava (SVC) and right
      atrium (RA). The catheter tip position was considered to be satisfactory, as the
      tip was within 1.0 cm of the upper crista terminalis edge. All 30 Group E
      patients had satisfactory catheter tip placement when the ECG P wave was at its
      maximum. In contrast, 16 of the 30 patients in Group S had satisfactory tip
      positions (P < 0.001). All catheters were repositioned under TEE guidance to
      adjust the tip to the SVC-RA junction. After the catheter tips were confirmed to
      be located at the SVC-RA junction, the catheter tips were still visualized in the
      mid portion of RA in 12 of 60 patients on supine chest radiographs. We concluded
      that IV-ECG guidance to position a catheter resulted in satisfactory catheter tip
      placement that is in accordance with TEE views. Catheter placement at the SVC-RA
      junction with the surface landmark technique was unreliable. IMPLICATIONS:
      Intravenous electrocardiography guidance to position catheters obtains a
      satisfactory catheter tip placement that is in accordance with transesophageal
      echocardiography views. The surface landmark technique does not result in
      reliable placement at the superior vena cava-right atrium junction.

PMID- 15041572
TI  - The variable effects of dopamine among human isolated arteries commonly used for
      coronary bypass grafts.
AB  - The direct actions of dopamine on human arterial coronary bypass grafts are not
      well known. We investigated its effects on isolated rings cut from radial
      arteries (RA), gastroepiploic arteries (GEA), and internal mammary arteries (IMA)
      harvested from patients undergoing coronary artery bypass surgery. Dopamine
      produced dose-dependent contractile responses in RA, an effect independent of the
      presence of a functional endothelium. The contractions were enhanced by the
      dopamine A(1) (DA(1))-receptor antagonist SCH23390, whereas they were blocked by
      an alpha(1)-adrenergic antagonist, prazosin. Results qualitatively similar to
      these were obtained in both GEA and IMA, although the contractile responses were
      far smaller. In RA, DA enhanced the norepinephrine (NE)-induced contraction, and
      this action of dopamine was enhanced by SCH23390. In GEA, small concentrations
      (<10(-7) mol/L) of DA attenuated the NE-induced contraction but larger
      concentrations did not. In IMA, DA induced a vasorelaxation on the NE-contraction
      only at higher concentrations (10(-6)-10(-5) mol/L). In both GEA and IMA, the
      dopamine-induced vasorelaxations on the NE contraction were completely inhibited
      by SCH23390. These results suggest that the affinities of DA for DA(1)- and
      alpha(1)-adrenergic receptors may explain its variable contractile and
      vasorelaxant effects among these arteries. IMPLICATIONS: Differing affinities of
      dopamine for dopamine A(1)- and alpha(1)-adrenergic receptors may lead to it
      having variable contractile and vasorelaxant effects among the arteries supplying
      grafts for coronary bypass surgery.

PMID- 15041574
TI  - Cardiac anesthesiology, professionalism and ethics: a microcosm of anesthesiology
      and medicine.
AB  - The granting of professional status to medicine by society at large entails
      obligations by physicians. Those physicians in the young subspecialty of cardiac
      anesthesiology have fulfilled these obligations by developing a body of
      scientific and clinical knowledge and the technical bases to increase survival
      and decrease morbidity of patients with heart disease undergoing either cardiac
      or noncardiac surgery. Furthermore, they have contributed effectively to the
      broad practice of medicine. However, a strong argument can be made that these
      contributions, though benefiting many individual patients, do not by themselves
      completely fulfill our obligations. The concept of Civic Professionalism states
      that our moral responsibilities as physicians must be expanded beyond our
      immediate patients. Physicians have the obligation to use their knowledge and
      influence to promote the common good. The Universal Declaration of Human Rights
      includes access to health care as a basic tenet. The present health care system
      of the United States excludes many people. Thus, cardiac anesthesiologists have a
      moral obligation to actively advocate for universal access to health care until
      it is achieved. Doing so will make the specialty of cardiac anesthesiology an
      example to the entire profession of medicine. IMPLICATIONS: Cardiac
      anesthesiologists have contributed to enhanced survival and decreased morbidity
      of patients with heart disease undergoing surgery. These achievements do not by
      themselves fulfill the moral obligations incurred by the concept of Civic
      Professionalism, however. Cardiac anesthesiologists, in common with all
      physicians, must share the obligation to advocate for the human right of
      universal access to health care.

PMID- 15041575
TI  - Massive gastrointestinal bleeding complicating portal vein cross-clamping during
      liver transplantation.
AB  - This case report describes the occurrence of massive upper gastrointestinal
      hemorrhage immediately after cross-clamping of the inferior vena cava and hepatic
      portal vein. This case suggests that acute intraoperative hemorrhage from a varix
      should always be a consideration before liver transplantation in patients who
      have a history of upper gastrointestinal bleeding. IMPLICATIONS: A case of severe
      bleeding during liver transplantation is described in a patient who had a history
      of bleeding from the stomach before surgery. The importance of understanding
      surgical options and the ability to provide rapid massive transfusion in the
      management of this complication are discussed.

PMID- 15041573
TI  - The effect of erythropoietin on allogeneic blood requirement in patients
      undergoing elective liver resection: a model simulation.
AB  - We investigated whether recombinant human erythropoietin (rHuEPO) administration
      would reduce red blood cell (RBC) transfusion requirements in patients undergoing
      elective liver resection. We retrospectively investigated 200 patients undergoing
      elective liver resection. Factors likely to predict perioperative RBC transfusion
      were studied using a logistic regression analysis. A mathematical model was used
      to simulate RBC transfusion requirements if (a). transfusion thresholds had been
      predefined at a hemoglobin concentration of 7-8 g/dL, (b). preoperative
      hemoglobin concentrations had been increased to 15 g/dL by rHuEPO administration
      in patients with preoperative hemoglobin concentration in the range 10-13 g/dL,
      and (c). both interventions had been used. A cost/benefit evaluation of rHuEPO
      administration formed part of this simulation. RBC transfusion was correlated
      with major and median liver resection, total liver vascular exclusion, and a
      combined nonhepatic abdominal surgery but was not correlated with a preoperative
      hemoglobin concentration in the range 10-13 g/dL. Adherence to a small
      transfusion threshold or rHuEPO administration alone would have resulted in a
      slight reduction in transfusion requirements and transfusion rates for the whole
      population. However, the two interventions in combination would have
      significantly reduced both variables. One-hundred-eighteen patients undergoing
      median and major liver resection received 92% of RBC transfused. Sixty-six of
      these 118 patients had preoperative hemoglobin concentrations in the range 10-13
      g/dL and could have received rHuEPO before surgery. rHuEPO alone would have
      avoided the transfusion of 63 RBC packs of 203 in this subgroup and 12 transfused
      patients of 31 (P = 0.02). rHuEPO administration to these 66 patients would have
      cost 186000 Euro. The 63 RBC saved would have cost 10,710 Euro. IMPLICATIONS: A
      mathematical model simulation suggests that the routine preoperative
      administration of erythropoietin to patients scheduled for major and median liver
      resection presenting with a preoperative hemoglobin concentration in the range 10
      13 g/dL could reduce blood transfusion requirements. However, the cost/benefit
      ratio warrants consideration.

PMID- 15041576
TI  - Profound hypoxemia resulting from shunting across an inadvertent atrial septal
      tear after left ventricular assist device placement.
AB  - Defects within the interatrial septum (IAS) can be a source of significant right
      to-left shunting and hypoxemia, particularly after placement of a left
      ventricular assist device (LVAD). We report a case of LVAD placement in which an
      unrecognized IAS tear occurred intraoperatively, leading to profound arterial
      desaturation. Transesophageal echocardiography (TEE) was instrumental in making
      the diagnosis. Certain intraoperative events increased the pressure gradient
      between the right and left atria, aggravating hypoxemia. We recommend that
      patients undergoing LVAD placement be screened intraoperatively with TEE for
      unrecognized IAS defects. Re-examination of the IAS should occur on weaning from
      cardiopulmonary bypass. IMPLICATIONS: A traumatic atrial septal defect after
      atrial cannulation caused a right-to-left intracardiac shunt on initiation of
      left ventricular assist device support that was further aggravated by chest
      closure and pleural suction, culminating in severe hypoxemia.

PMID- 15041577
TI  - The influence of anthracycline therapy on cardiac function during anesthesia.
AB  - Cardiotoxicity is a well recognized complication of anthracycline (AC) therapy.
      Subtle abnormalities in myocardial function that become apparent only after
      exercise may exist in survivors of childhood cancer who have previously received
      AC, yet have normal resting cardiac function. To evaluate if anesthesia-induced
      changes in cardiac function differ in pediatric patients with previous AC therapy
      from healthy children and adolescents, we evaluated in a prospective study 43
      patients, of whom 42 were analyzed. Twenty-one patients (AC-group), mean age 9.6
      yr (range, 3-16 yr), who had received 193 (30-490) mg/m(2) of AC as a mean
      cumulative dose with normal resting cardiac function (shortening fraction [SF]
      0.34, normal value > 0.30) underwent removal of a Hickman catheter under general
      anesthesia. Twenty-one patients, mean age 10.9 yr (range, 4-17 yr), who underwent
      placement of a Hickman catheter before chemotherapy served as the control. All
      children were premedicated with midazolam 0.5 mg/kg orally. Anesthesia was
      induced by sodium thiopental (5 mg/kg), fentanyl (3 micro g/kg), and rocuronium
      (0.6 mg/kg) and maintained with isoflurane (1 MAC) in N(2)O/O(2) (70/30). Before
      induction (baseline), 5 and 20 min after intubation (T1 and T2), and 20 min after
      extubation (control), cardiac function was assessed by transthoracic (baseline,
      control) and transesophageal (T1, T2) echocardiography. Compared with baseline
      (SF: 34.9 +/- 3.7 [AC], 34.1 +/- 3.7 [C] [not significant]; stroke volume index
      [SVI] 36 +/- 6 mL/m(2)[AC], 35 +/- 4 mL/m(2)[C] [not significant]; cardiac index
      [CI] 3.6 +/- 0.6 L/min/m(2)[AC], 3.2 +/- 0.5 L/min/m(2)[C] [not significant]), we
      found a significant decrease in SF and SVI in both groups at T1 (SF: 26.2 +/- 3.6
      [AC] versus 28.6 +/- 3.6 [C] [P < 0.05]; SVI: 26 +/- 4 mL/m(2) [AC] versus 30 +/-
      46 mL/m(2) [C] [P < 0.05]) and T2 (SF: 24.1 +/- 3.2 [AC] versus 28.2 +/- 2.5 [C]
      [P < 0.01], SVI: 26 +/- 6 mL/m(2) [AC] versus 31 +/- 5 mL/m(2) [C] [P < 0.01]),
      which was significantly greater in the AC group. There were no significant
      changes of variables of diastolic function (E/A ratio, isovolumetric relaxation
      time) between both groups. Previous treatment with AC may enhance the myocardial
      depressive effect of anesthetics even in patients with normal resting cardiac
      function. IMPLICATIONS: Previous treatment with anthracylines, a group of
      chemotherapeutic drugs in use for childhood cancer, may enhance the myocardial
      depressive effect of anesthetics even in children and adolescents with normal
      resting cardiac function.

PMID- 15041578
TI  - The effects of spread of block and adrenaline on cardiac output after epidural
      anesthesia in young children: a randomized, double-blind, prospective study.
AB  - Epidural anesthesia is considered to be without significant hemodynamic
      consequence in young children. However, conversely to adults, few studies have
      investigated cardiac output. Using transesophageal Doppler monitoring of cardiac
      output, we prospectively investigated hemodynamic alterations in 48 children
      (median age, 22.5 mo) receiving sevoflurane general anesthesia combined with
      caudal or thoracolumbar epidural anesthesia. They were randomly assigned to
      receive 0.8 mL/kg of plain local anesthetic mixture (lidocaine 1% + bupivacaine
      0.25% (50/50) + 1 microg/mL of fentanyl) or 1 mL/kg of the same mixture with 5
      microg/mL of adrenaline. No significant hemodynamic alteration was elicited in
      caudal and thoracolumbar groups receiving the plain mixture except a moderate
      decrease in heart rate. Conversely, a mixture with adrenaline added provoked a
      significant decrease in mean arterial blood pressure by 14% and 17%, in systemic
      vascular resistance by 24% and 40%, and an increase in cardiac output by 20% and
      34% in caudal and thoracolumbar groups, respectively. The adrenaline effect was
      greater by the thoracolumbar than the caudal approach. In young children,
      epidural anesthesia induces an increase in cardiac output only when adrenaline is
      added to local anesthetics, probably through its systemic absorption from the
      epidural space. IMPLICATIONS: Epidural anesthesia may induce significant
      hemodynamic changes, well documented in adults. Using noninvasive hemodynamic
      monitoring in children, we reported an increase in cardiac output and a decrease
      in arterial blood pressure only when epinephrine was added to epidurally-injected
      local anesthetics.

PMID- 15041580
TI  - A review of intrathecal and epidural analgesia after spinal surgery in children.
AB  - In view of the overall experience regarding regional anesthetic techniques to
      control postoperative pain in infants and children, it is feasible that a similar
      efficacy and safety profile can be obtained when using such techniques after
      major orthopedic procedures such as anterior or posterior spinal fusion. I
      reviewed previous reports regarding the use of neuraxial techniques to provide
      analgesia after spine surgery in the pediatric population. Variations in both the
      surgical procedure and the analgesic technique may make the comparison among
      studies somewhat impractical. Variations of the analgesic technique include 1).
      the dose of the medications used; 2). the route of delivery (intrathecal or
      epidural); 3). the mode of delivery (single dose, intermittent bolus dosing, and
      continuous infusion); 4). the number of epidural catheters used (one versus two);
      5). the medications infused (opioids, local anesthetics, or both); 6). the opioid
      used (morphine, fentanyl, hydromorphone); and 7). the analgesic regimen of the
      control group (intermittent "as needed" morphine or patient-controlled
      analgesia). Although limited data are available to document the analgesic
      superiority of these techniques over parenteral opioids, clinical data offer
      evidence of other benefits, including decreased intraoperative blood loss and
      quicker return of gastrointestinal function.

PMID- 15041581
TI  - An epidural hematoma in an adolescent patient after cardiac surgery.
AB  - An 18-yr-old patient had a thoracic epidural placed under general anesthesia
      preceding an uneventful aortic valve replacement with a bioprosthetic valve. On
      the second postoperative day, he was anticoagulated and also received an
      antithrombotic medication. While ambulating, he experienced pain in his back, and
      there was blood in his epidural catheter. The catheter was removed, and he
      developed motor and sensory loss. Rapid surgical decompression resulted in
      recovery of his lost neurological function. Management and strategies for
      preventing this problem are discussed. IMPLICATIONS: Epidural hematoma is a rare
      complication of epidural anesthesia and has not been reported in pediatric
      patients undergoing cardiac surgery. The successful treatment of this
      complication requires swift recognition, diagnosis, and surgical intervention.

PMID- 15041582
TI  - Perioperative rofecoxib improves early recovery after outpatient herniorrhaphy.
AB  - Non-opioid analgesics have become increasingly popular as part of a multimodal
      regimen for pain management in the ambulatory setting. We designed this
      randomized, double-blind, placebo-controlled study to evaluate the effect of
      perioperative administration of the cyclooxygenase-2 inhibitor rofecoxib on
      patient outcome after inguinal herniorrhaphy procedures. Sixty consenting
      outpatients undergoing elective hernia repair surgery were randomly assigned to
      one of two treatment groups: control (vitamin C, 500 mg) or rofecoxib (rofecoxib,
      50 mg). The first oral dose of the study medication was administered 30-40 min
      before entering the operating room, and a second dose of the same medication was
      given on the morning of the first postoperative day. Recovery times,
      postoperative pain scores, the need for "rescue" analgesics, and side effects
      were recorded at 1- to 10-min intervals before discharge from the recovery room.
      Follow-up evaluations were performed at 36 h, 7 days, and 14 days after surgery
      to assess postdischarge pain, analgesic requirements, resumption of normal
      activities, as well as patient satisfaction with their postoperative pain
      management. Rofecoxib significantly decreased the early recovery times, leading
      to an earlier discharge home after surgery (88 +/- 30 vs 126 +/- 44 min, P <
      0.05). When compared with the control group, the patients' median [range] quality
      of recovery score was also significantly higher in the rofecoxib group (18 [14
      18] vs 16 [13-18], P < 0.05). In the predischarge period, a significantly larger
      percentage of patients required rescue pain medications in the control group (67%
      vs 37% in the rofecoxib group, P < 0.05). At the 36-h follow-up assessment,
      rofecoxib-treated patients reported significantly reduced oral analgesic
      requirements (0 [0-20] vs 9 [1-33] pills, P < 0.05) and lower maximal pain
      scores, resulting in improved patient satisfaction with their postoperative pain
      management (3 [1-4] vs 2 [0-3], P < 0.05). However, there were no differences in
      the times required to resume their activities of daily living. In conclusion,
      perioperative rofecoxib, 50 mg per os, significantly decreased postoperative pain
      and the need for analgesic rescue medication, leading to a faster and improved
      quality of recovery after outpatient hernia surgery. However, perioperative use
      of rofecoxib failed to improve recovery end points in the postdischarge period.
      IMPLICATIONS: Rofecoxib (50 mg per os), given before and after surgery, was
      effective in improving postoperative pain management, as well as the speed and
      quality of recovery after outpatient inguinal herniorrhaphy. However, it failed
      to accelerate the postdischarge resumption of normal activities of daily living.

PMID- 15041583
TI  - Modafinil improves recovery after general anesthesia.
AB  - Recovery from general anesthesia often involves residual sedation, drowsiness,
      fatigue, and lack of energy that may last hours to days. Modafinil is a
      wakefulness-promoting drug approved for patients with excessive daytime
      sleepiness associated with narcolepsy. We evaluated the effect of single doses of
      modafinil (200 mg) and placebo in patients recovering from general anesthesia.
      Thirty-four subjects participated in this prospective, randomized, double-blind
      study approved by our IRB. Preoperatively, patients were asked to rate various
      symptoms they had experienced over the previous 24-h using a verbal analog scale
      (VAS) of 0 to 10 as well as discrete scale when indicated. Postoperatively, once
      the patient was able to tolerate oral intake and met our institutional discharge
      criteria, the study drug (modafinil 200 mg or placebo) was administered with a
      sip of water. Patients were contacted 24 (1) hours after dosing to evaluate
      postdischarge symptoms. Patients in the placebo group reported significantly more
      postoperative fatigue (4.8 [3.3] versus 1.4 [1.8]), exhaustion (4.3 [3.3] versus
      2.4 [3.1]), or degree of feeling worn out (4.7 [3.6] versus 2.9 [2.4]).
      Significantly more patients reported moderate to severe fatigue in the placebo
      group (65% versus 12%). Two major themes of "alertness" and "energy" were
      expressed by 71% of the patients receiving modafinil versus 18% of those
      receiving placebo. Patients recovering from general anesthesia can significantly
      benefit from modafinil. IMPLICATIONS: Modafinil significantly reduces fatigue and
      improves feelings of alertness and energy in postoperative patients. Patients
      recovering from general anesthesia can significantly benefit from modafinil
      administration.

PMID- 15041585
TI  - Skin sensitivity to rocuronium and vecuronium: a randomized controlled prick
      testing study in healthy volunteers.
AB  - Prick tests are frequently used for the authentication of neuromuscular blocking
      drugs (NMBDs) as causative drugs for anaphylactic reactions during anesthesia.
      Unfortunately, the actual threshold concentration for skin testing remains
      debatable for most NMBDs. We studied the flare and wheal responses to prick tests
      with rocuronium and vecuronium. Thirty healthy, nonatopic, anesthesia-naive male
      and female volunteers (14 men and 16 women) from 18 to 40 yr of age were assigned
      randomly to receive a total of 10 prick tests-4 ascending dilutions (1:1000,
      1:100, 1:10, and 1) of rocuronium and vecuronium and 2 controls-on both forearms.
      An assessor blinded to the assignment monitored systemic and skin responses to
      NMBDs and measured wheal and flare surfaces immediately after and 15 min after
      prick tests. None of the volunteers experienced any immediate systemic or
      cutaneous responses to rocuronium or vecuronium. Although a dilution of 1:1000 of
      both NMBDs failed to promote any skin response at 15 min, 50% and 40% of the
      subjects had a positive skin reaction to undiluted rocuronium and vecuronium,
      respectively. We demonstrated a sex effect related to smaller threshold
      concentration-induced cutaneous reactions in female volunteers to both muscle
      relaxants. Our observation questions the reliability of prick testing with
      undiluted solutions of rocuronium and vecuronium for the diagnosis of allergy.
      IMPLICATIONS: Building concentration-skin response curves to prick tests with
      rocuronium and vecuronium in healthy, nonatopic, anesthesia-naive male and female
      volunteers demonstrated that the nonreactive concentration for both muscle
      relaxants is the 1:1000 dilution of the stock solutions. Our observation calls
      into question the past practice of prick-testing skin for sensitivity to
      neuromuscular blocking drugs by using undiluted solutions.

PMID- 15041584
TI  - Warm steaming enhances the topical anesthetic effect of lidocaine.
AB  - Warm steaming has been used for hydrating the skin, thereby increasing its
      permeability. We studied whether skin pretreatment with a steamed towel (at 45
      degrees C) for 5 min could enhance the anesthetic effect of a topical lidocaine
      tape in 14 female volunteers. After each volunteer received the skin pretreatment
      on one of the forearms, lidocaine tape was applied for 30 min on both the treated
      and the untreated forearms. Superficial anesthesia was scored by recording the
      number of painful experience during 5 pinpricks delivered with a 27-gauge needle.
      To assess anesthesia of the deeper layer, single insertion of a 27-gauge needle
      to a depth of 3 mm was made and pain was scored by a visual analog scale (VAS).
      There were significant reductions in the scores of superficial anesthesia (median
      [range]: treated arm, 2 [0-5], versus untreated arm, 4 [1-5]; P < 0.01) and the
      VAS scores of deeper insertion (median [range]: treated arm, 4.5 [0-8], versus
      untreated arm, 8 [2-10]; P < 0.01). In conclusion, the application of a warm
      steamed towel enhanced the anesthetic effect of a topical lidocaine tape.
      IMPLICATIONS: We showed that the skin pretreatment with a steamed towel (at 45
      degrees C) enhanced the anesthetic effect of a topical lidocaine tape in female
      volunteers.

PMID- 15041586
TI  - A comparison of liver function after hepatectomy in cirrhotic patients between
      sevoflurane and isoflurane in anesthesia with nitrous oxide and epidural block.
AB  - In this study, we compared postoperative liver function in patients with liver
      cirrhosis between isoflurane and sevoflurane anesthesia with nitrous oxide
      (N(2)O) and epidural block. Forty cirrhotic patients with Child-Pugh Grade A,
      aged 40 to 70 yr, scheduled for liver segmentectomy, had anesthesia induced with
      midazolam 0.1 mg/kg and fentanyl 4 micro g/kg. For maintenance, intermittent
      epidural administration of 1.5% lidocaine 4 to 6 mL and sevoflurane (sevoflurane
      group) or isoflurane (isoflurane group) with N(2)O 3 L/min in oxygen 3 L/min was
      used. Aspartate aminotransferase, alanine aminotransferase, total bilirubin,
      alkaline phosphatase, choline esterase, albumin, prothrombin time, and platelet
      count were measured before and 1, 3, and 7 days after surgery. Aspartate
      aminotransferase, alanine aminotransferase, and alkaline phosphatase increased
      significantly, with the peaks at 3 days after surgery in both groups. The
      increases in these variables were significantly larger in the isoflurane group
      than those in the sevoflurane group. No patient developed hepatic failure. All
      increases in liver enzymes were small and of questionable clinical relevance.
      Whether sevoflurane might be a better anesthetic when combined with N(2)O and
      epidural block for cirrhotic patients than isoflurane with respect to liver
      damage remains to be determined. IMPLICATIONS: In cirrhotic patients with Child
      Pugh Grade A, isoflurane induced more of an increase in serum concentrations of
      liver enzymes after surgery than sevoflurane when combined with nitrous oxide and
      epidural block. However, the increases were small, and there was no clinical
      liver damage.

PMID- 15041587
TI  - Preoperative oral dextromethorphan attenuated tourniquet-induced arterial blood
      pressure and heart rate increases in knee cruciate ligament reconstruction
      patients under general anesthesia.
AB  - The precise mechanism of tourniquet-induced arterial blood pressure increase is
      unknown. We determined the effect of preoperative oral dextromethorphan (DM) on
      arterial blood pressure and heart rate changes during tourniquet inflation in
      knee cruciate ligament reconstruction patients under general anesthesia. Patients
      in the DM group (n = 38) received oral DM 30 mg, and patients in the control
      group (n = 38) received oral placebo 2 h before the induction of anesthesia.
      Anesthesia was maintained with sevoflurane 2.0% and N(2)O in 33% oxygen, and the
      trachea was intubated until the end of surgery. Arterial blood pressure and heart
      rate were measured at 0, 30, and 60 min after the start of tourniquet inflation.
      Systolic arterial blood pressure and heart rate at 60 min in the control group
      were significantly more than those in the DM group (131.1 +/- 15.8 mm Hg versus
      123.6 +/- 15.9 mm Hg [P < 0.05] and 74.1 +/- 11.3 bpm versus 67.8 +/- 8.5 bpm [P
      < 0.01], respectively). The percentage increase in systolic arterial blood
      pressure and heart rate in the DM group was also attenuated when compared with
      that in the control group (P < 0.05). In conclusion, preoperative oral DM 30 mg
      significantly attenuated arterial blood pressure and heart rate increases during
      tourniquet inflation under general anesthesia. IMPLICATIONS: We demonstrated that
      preoperative oral dextromethorphan 30 mg significantly attenuated arterial blood
      pressure and heart rate increases at 60 min during tourniquet inflation in
      patients undergoing knee cruciate ligament reconstruction under general
      anesthesia.

PMID- 15041588
TI  - Isoflurane pretreatment supports hemodynamics and leukocyte rolling velocities in
      rat mesentery during lipopolysaccharide-induced inflammation.
AB  - We hypothesized that the protective effects of isoflurane (ISO) pretreatment on
      the vasculature may be attributed, in part, to altered leukocyte-endothelial
      interactions. Rats were anesthetized with pentobarbital and then randomized into
      four groups: control, ISO-control (pretreatment with 30 min of 1.4% ISO),
      lipopolysaccharide (LPS; 10 mg/kg IV), and ISO-LPS (ISO pretreatment and then
      LPS). The mesentery was prepared for intravital videomicroscopy. Mean arterial
      blood pressure (MAP), along with microcirculatory variables that included
      postcapillary venular and arteriolar blood flow velocity and leukocyte dynamics
      (number of rolling and adherent leukocytes and individual rolling leukocyte
      velocities), were measured hourly (baseline and at 0-4 h). In LPS rats, ISO
      pretreatment significantly (P < 0.05) attenuated the decrease in MAP at 2 and 4 h
      after LPS and increased leukocyte rolling velocities after 2-4 h. Four hours
      after LPS, leukocyte rolling velocities were >200% more rapid (63.7 +/- 27.6
      microm/s versus 19.8 +/- 6.4 micro m/s) in ISO-LPS versus LPS rats. In control
      rats, ISO pretreatment had no effect on MAP or leukocyte rolling velocities but
      increased the number of rolling leukocytes. ISO pretreatment had no effect on
      arteriolar and postcapillary venular blood flow velocity in LPS rats or leukocyte
      adherence in LPS or control rats. In conclusion, ISO pretreatment supported
      hemodynamics and increased leukocyte rolling velocities but did not alter the
      number of rolling or adherent leukocytes in the mesenteric microcirculation
      during LPS-induced inflammation. IMPLICATIONS: Isoflurane pretreatment supported
      hemodynamics and increased leukocyte rolling velocities in the mesenteric
      microcirculation during lipopolysaccharide-induced inflammation. Faster rolling
      velocities may reduce the incidence of inflammation by decreasing leukocyte
      endothelial interactions and cellular injury.

PMID- 15041589
TI  - Xenon and isoflurane differentially modulate lipopolysaccharide-induced
      activation of the nuclear transcription factor KB and production of tumor
      necrosis factor-alpha and interleukin-6 in monocytes.
AB  - Anesthetics are known to interfere with the production of inflammatory cytokines.
      In this study, we investigated the effect of xenon and isoflurane on the
      lipopolysaccharide (LPS)-induced activation of the nuclear transcription factor
      (NF)-kappaB and production of tumor necrosis factor (TNF)-alpha and interleukin
      (IL)-6 in vitro. Whole blood was incubated with LPS in the absence or presence of
      the either xenon (30 and 60 Vol%) and isoflurane (1 and 2 minimum alveolar
      anesthetic concentration [MAC]). After 4 h, TNF-alpha and IL-6 were assayed in
      the supernatant. Involvement of NF-kappaB was investigated using isolated
      monocytes from the blood samples. Whole-cell lysates were prepared, and binding
      of the NF-kappaB p50 and p65 subunit to its target DNA were measured with an
      enzyme-linked immunosorbent assay-based NF-kappaB kit. LPS-induced production of
      TNF-alpha and IL-6 as well as activation of NF-kappaB were significantly
      increased in the presence of xenon compared with controls. In contrast,
      isoflurane inhibited the activation of NF-kappaB, which was associated with a
      decreased production of TNF-alpha and IL-6. Our results demonstrate that xenon
      and isoflurane have opposite effects on the LPS-induced production of TNF-alpha
      and IL-6. Furthermore, xenon increases, whereas isoflurane inhibits the
      activation of NF-kappaB, providing a possible molecular mechanism for the
      different effects on monocyte TNF-alpha and IL-6 production. IMPLICATIONS: This
      study has shown that monocytes respond to lipopolysaccharide (LPS) in the
      presence of xenon with an increased activation of nuclear transcription factor
      (NF)-kappaB, whereas isoflurane inhibits LPS-induced activation of NF-kappaB.
      These findings suggest a possible molecular mechanism for the different effects
      of both anesthetics on monocyte tumor necrosis factor-alpha and interleukin-6
      production.

PMID- 15041590
TI  - The effects of alfentanil on cytosolic Ca(2+) and contraction in rat ventricular
      myocytes.
AB  - Previous investigations of the effects of potent opioid analgesics on the heart
      have concentrated on effects on contraction magnitude and time course, but little
      is known about their effects on cytosolic Ca(2+) regulation in cardiac tissue. In
      this study, we sought to assess the effects of alfentanil on contractility and
      the cytosolic Ca(2+) transient in ventricular myocytes isolated from the rat
      ventricle by enzymatic dispersion. Cells were loaded with fura-2 and electrically
      stimulated at 1 Hz, and Ca(2+) transients and contractions were recorded
      optically at 30 degrees C. Alfentanil 10(-8) and 10(-7) M had no effect on the
      magnitude or time course of contraction or the cytosolic Ca(2+) transient. In
      contrast, 10(-6) M alfentanil induced a significant (P < 0.001) positive
      inotropic effect, increasing the mean (+/-SEM) unloaded shortening from 7.3 +/-
      1.3 microm to 8.7 +/- 1.4 microm (an increase of 20%), with no change in the
      cytosolic Ca(2+) transient. Myofilament Ca(2+) sensitivity was significantly (P =
      0.027) increased by 10(-6) M alfentanil but unaffected at 10(-7) M alfentanil.
      These data show that 10(-6) M alfentanil, a concentration close to the maximum
      clinical free plasma concentration, induced a positive inotropic effect due to
      sensitization of the myofilaments to Ca(2+) rather than to modified cytosolic
      Ca(2+) regulation. IMPLICATIONS: Alfentanil, at concentrations achieved in
      clinical practice, increased contraction in ventricular cells by a mechanism
      involving an increase in the sensitivity of the contractile apparatus to Ca(2+).

PMID- 15041591
TI  - The effects of propofol on hypothalamic paraventricular nucleus neurons in the
      rat.
AB  - The mechanism of hypotension induced by anesthetics is not completely understood.
      Because no electrophysiologic examination of the effects of propofol on the
      central nervous system has shown its involvement in the control of sympathetic
      and cardiovascular functions, we investigated the actions of propofol on rat
      hypothalamic paraventricular nucleus (PVN) neurons using the whole-cell mode of
      the patch-clamp technique in rat hypothalamic PVN slice preparations. Propofol
      induced Cl(-) currents at concentrations of 10(-5) and 10(-4) M, which were
      sensitive to picrotoxin and, to a lesser extent, to strychnine. Propofol (10(-6)
      M) enhanced gamma-aminobutyric acid(A) (GABA(A); 10(-6) M)-induced current
      synergistically. Moreover, propofol (10(-5) and 10(-4) M) significantly increased
      the decay time of evoked-inhibitory postsynaptic currents, which suggests a
      postsynaptic modulation of GABA(A) receptors. In addition, propofol (10(-5), 10(
      4), and 2 x 10(-4) M) reversibly inhibited voltage-gated Ca(2+) currents. Taken
      together, these results suggest that propofol enhancement of GABA(A)-receptor
      mediated currents and inhibition of voltage-gated Ca(2+) currents at the central
      level, which is involved in the control of cardiovascular and sympathetic
      functions may be, at least in part, involved in general anesthetic-induced
      cardiovascular and sympathetic depression. IMPLICATIONS: We investigated the
      actions of propofol on the rat hypothalamic paraventricular nucleus neurons,
      which are involved in the control of cardiovascular and sympathetic functions.
      The results suggest that propofol enhancement of gamma-aminobutyric acid(A)
      receptor mediated currents and inhibition of voltage-gated Ca(2+) currents at the
      central level may be, at least in part, involved in general anesthetic-induced
      cardiovascular and sympathetic depression.

PMID- 15041592
TI  - The effect of local anesthetics on monocyte mCD14 and human leukocyte antigen-DR
      expression.
AB  - It has been demonstrated that local anesthetics have several effects on the
      immune system. Monocytes and macrophages are essential components of the host
      response to microbial infection; however, the effect of local anesthetics on
      monocyte surface receptor expression remains unclear. We designed this study to
      investigate the effects of local anesthetics on monocyte mCD14 and human
      leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced or
      staphylococcal enterotoxin B (SEB)-induced tumor necrosis factor (TNF)-alpha
      production. Blood samples were obtained from 10 healthy volunteers. The effects
      of local anesthetics on LPS- or SEB-induced TNF-alpha production were determined
      by using an enzyme-linked immunosorbent assay. After different doses of local
      anesthetics were added, the blood was stimulated with LPS (10 ng/mL) or SEB (10
      micro g/mL) for 4 h. The effects of local anesthetics on monocyte mCD14 and HLA
      DR expression were measured by dual monoclonal antibody staining and flow
      cytometry. Local anesthetics showed no effect on LPS- or SEB-induced TNF-alpha
      production in human whole blood. Local anesthetics suppressed monocyte HLA-DR
      expression in a dose-dependent manner (P < 0.05) but had no effect on monocyte
      mCD14 expression. This study demonstrated that local anesthetics suppress HLA-DR
      expression on the surface of human monocytes. IMPLICATIONS: Monocyte surface
      receptors have a crucial role in the host response to microbial infection. We
      investigated the effects of local anesthetics on monocyte mCD14 and human
      leukocyte antigen (HLA)-DR expression. Our results show that local anesthetics
      suppress HLA-DR expression on the surface of human monocytes.

PMID- 15041593
TI  - Bispectral index as an indicator of seizure inducibility in electroconvulsive
      therapy under thiopental anesthesia.
AB  - The prediction of seizure thresholds in electroconvulsive therapy (ECT) remains
      problematic. We examined the relationship between bispectral index (BIS) score
      and seizure duration in ECT performed under thiopental anesthesia in patients
      receiving their usual regimen of antidepressant medication for its potential as a
      predictor of seizure inducibility. One-hundred ECT treatments were evaluated in
      16 adult patients diagnosed with depression. BIS scores were recorded at the
      preanesthetic and preictal periods and at recovery from ECT. Seizure duration was
      defined as the duration of the electroencephalogram seizure pattern. The
      relationships between preanesthetic and preictal BIS scores and seizure duration
      were evaluated. Effective seizure threshold was determined by receiver operator
      characteristic analysis, and the area under the curve (AUC) was calculated for
      seizure durations of more than 10 s, more than 20 s, and more than 30 s. The
      relationship between seizure duration and thiopental estimated effect-site and
      plasma concentrations was analyzed as well. Preictal BIS scores for seizures
      lasting longer than 30 s were significantly higher than those for seizures
      lasting <30 s. A preictal BIS score of 55 or more represents a strongly
      determinant condition for achieving seizures that last longer than 30 s (AUC,
      0.937; receiver operator characteristic), as well as for briefer seizures that
      last more than 20 or 10 s (AUC: 0.938 and 0.959, respectively). There was no
      significant correlation between seizure duration and the estimated thiopental
      effect-site or plasma concentration. We conclude that during thiopental
      anesthesia, the minimum threshold for inducing seizures of any duration
      correlates with a preictal BIS score of 55. This threshold was independent of
      antidepressant regimen and thiopental dosage. We suggest that the preictal BIS
      score is useful in predicting the ictogenic threshold in ECT. IMPLICATIONS: We
      found that the bispectral index (BIS) score serves as an indicator of seizure
      inducibility in electroconvulsive therapy (ECT) under thiopental anesthesia and
      that the relationship between BIS score and seizure duration was not linear,
      suggesting that the pharmacological mechanisms by which thiopental and propofol
      suppress ECT seizure activity are different.

PMID- 15041594
TI  - Unusually low bispectral index values during emergence from anesthesia.
AB  - We observed unusually low BIS values during emergence from anesthesia apparently
      caused by misanalysis (as "suppression") of low voltage electroencephalogram.
      IMPLICATIONS: When BIS values do not adequately correspond with clinical status,
      it is necessary to check raw electroencephalogram waveforms to more clearly
      characterize patient status.

PMID- 15041595
TI  - Preoperative oral rofecoxib reduces postoperative pain and tramadol consumption
      in patients after abdominal hysterectomy.
AB  - We designed this study to determine whether the administration of a preoperative
      dose of rofecoxib to patients undergoing abdominal hysterectomy would decrease
      patient-controlled analgesia (PCA) tramadol use or enhance analgesia. Sixty
      patients were randomized to receive either oral placebo or rofecoxib 50 mg 1 h
      before surgery. All patients received a standard anesthetic protocol.
      Intraoperative blood loss was determined. At the end of surgery, all patients
      received tramadol IV via a PCA-device. Pain scores, sedation scores, mean
      arterial blood pressure, heart rate, and peripheral oxygen saturation were
      assessed at 1, 2, 4, 6, 8, 12, and 24 h after surgery. Total and incremental
      tramadol consumption at the same times was recorded from the PCA-device.
      Antiemetic requirements and adverse effects were noted during the first
      postoperative 24 h. Duration of hospital stay was also recorded. The pain scores
      were significantly lower in the rofecoxib group compared with the placebo group
      at 6 times during the first 12 postoperative h (P < 0.05). The total consumption
      of tramadol (627 +/- 69 mg versus 535 +/- 45 mg; P < 0.05) and the incremental
      doses at 1, 2, 4, 6, 8, and 12 h after surgery were significantly more in the
      placebo group than in the rofecoxib group. There were no differences between
      groups in intraoperative blood loss, sedation scores, hemodynamic variables,
      peripheral oxygen saturation, antiemetic requirements, or adverse effects after
      surgery. The length of hospital stay was also similar in the groups. We conclude
      that the preoperative administration of oral rofecoxib provided a significant
      analgesic benefit and decreased the opioid requirements in patients undergoing
      abdominal hysterectomy. IMPLICATIONS: This study was designed to determine
      whether the administration of a preoperative dose of rofecoxib to patients
      undergoing abdominal hysterectomy would decrease patient-controlled analgesia
      tramadol use or enhance analgesia. We conclude that the preoperative
      administration of oral rofecoxib provided a significant analgesic benefit and
      decreased the opioid requirements in patients undergoing abdominal hysterectomy.

PMID- 15041596
TI  - Preoperative ketamine improves postoperative analgesia after gynecologic
      laparoscopic surgery.
AB  - In this study, we evaluated the preemptive effect of a small dose of ketamine on
      postoperative wound pain. In a randomized, double-blinded, controlled trial, we
      compared the analgesic requirement in patients receiving preincision ketamine
      with ketamine after skin closure or placebo after gynecologic laparoscopic
      surgery. One-hundred-thirty-five patients were randomly assigned to receive
      preincision or postoperative ketamine 0.15 mg/kg or saline IV. Anesthetic
      technique was standardized. Patients were interviewed regularly up to 4 wk after
      surgery. Pain score, morphine consumption, side effects, and quality of recovery
      score were recorded. Patients receiving preincision ketamine had a lower pain
      score in the first 6 h after operation compared with the postoperative (P =
      0.001) or placebo groups (P < 0.001). The mean (95% confidence intervals) time to
      first request for analgesia in the preincision group, 1.8 h (1.4-2.1), was longer
      than the postoperative group, 1.2 h (0.9-1.5; P < 0.001), or the placebo group,
      0.7 h (0.4-0.9; P < 0.001). The mean +/- SD morphine consumption in the
      preincision group, 1.5 +/- 2.0 mg, was less than that in the postoperative group,
      2.9 +/- 3.1 mg (P = 0.04) and the placebo group, 3.4 +/- 2.7 mg (P = 0.003).
      There was no significant difference among groups with respect to hemodynamic
      variables or side effects. No patient complained of hallucinations or nightmares.
      We conclude that a small dose of ketamine is not only safe, but it also provides
      preemptive analgesia in patients undergoing gynecologic laparoscopic surgery.
      IMPLICATIONS: In women undergoing laparoscopic gynecologic surgery, a small
      preoperative dose of ketamine (0.15 mg/kg) produced preemptive analgesia. There
      were no significant hemodynamic and psychological side effects with this dose.

PMID- 15041598
TI  - Intrathecal clonidine and bupivacaine have synergistic analgesia for acute
      thermally or inflammatory-induced pain in rats.
AB  - We investigated the interaction between spinally administered bupivacaine and
      clonidine using an animal model of acute and inflammatory pain. Rats implanted
      with lumbar intrathecal catheters were injected intrathecally with saline
      (control), bupivacaine (1 to 100 microg), or clonidine (0.1 to 3 microg) and
      tested for their responses to thermal stimulation to the tail (tail flick test)
      and subcutaneous formalin injection into the hindpaw (formalin test). The effects
      of the combination of bupivacaine and clonidine on both stimuli were tested by
      isobolographic analysis. General behavior and motor function were examined as
      side effects. The 50% effective doses of bupivacaine and clonidine were
      significantly smaller when combined compared with each single drug in both the
      tail flick test (2.82 and 0.11 microg versus 7.1 and 0.29 microg, respectively)
      and phase 1 (0.24 and 0.009 microg versus 5.7 and 0.15 microg) and phase 2 (0.31
      and 0.012 microg versus 3.2 and 0.16 microg) of the formalin test. Side effects
      were decreased by the combination. These results suggest a favorable combination
      of intrathecal bupivacaine and clonidine in the management of acute and
      inflammatory pain. IMPLICATIONS: The analgesic interaction between intrathecally
      administered bupivacaine and clonidine was examined during acute thermal and
      inflammatory-induced pain in rats. The analgesia produced by the combination of
      these two drugs was synergistic in both acute thermal and inflammatory induced
      pain, with a decrease in behavioral side effects.

PMID- 15041597
TI  - Perioperative intravenous lidocaine has preventive effects on postoperative pain
      and morphine consumption after major abdominal surgery.
AB  - Sodium channel blockers are approved for IV administration in the treatment of
      neuropathic pain states. Preclinical studies have suggested antihyperalgesic
      effects on the peripheral and central nervous system. Our objective in this study
      was to determine the time course of the analgesic and antihyperalgesic mechanisms
      of perioperative lidocaine administration. Forty patients undergoing major
      abdominal surgery participated in this randomized and double-blinded study.
      Twenty patients received lidocaine 2% (bolus injection of 1.5 mg/kg in 10 min
      followed by an IV infusion of 1.5 mg. kg(-1). h(-1)), and 20 patients received
      saline placebo. The infusion started 30 min before skin incision and was stopped
      1 h after the end of surgery. Lidocaine blood concentrations were measured.
      Postoperative pain ratings (numeric rating scale of 0-10) and morphine
      consumption (patient-controlled analgesia) were assessed up to 72 h after
      surgery. Mean lidocaine levels during surgery were 1.9 +/- 0.7 microg/mL. Patient
      controlled analgesia with morphine produced good postoperative analgesia (numeric
      rating scale at rest, <or=3; 90%-95%; no group differences). Patients who
      received lidocaine reported less pain during movement and needed less morphine
      during the first 72 h after surgery (103.1 +/- 72.0 mg versus 159.0 +/- 73.3 mg;
      Student's t-test; P < 0.05). Because this opioid-sparing effect was most
      pronounced on the third postoperative day, IV lidocaine may have a true
      preventive analgesic activity, most likely by preventing the induction of central
      hyperalgesia in a clinically relevant manner. IMPLICATIONS: The perioperative
      administration of systemic small-dose lidocaine reduces pain during surgery
      associated with the development of pronounced central hyperalgesia, presumably by
      affecting mechanoinsensitive nociceptors, because these have been linked to the
      induction of central sensitization and were shown to be particularly sensitive to
      small-dose lidocaine.

PMID- 15041599
TI  - Analgesic effects of intraarticular sufentanil and sufentanil plus
      methylprednisolone after arthroscopic knee surgery.
AB  - We studied the effect of intraarticular saline, sufentanil, or sufentanil plus
      methylprednisolone after knee arthroscopic meniscectomy. In a double-blind
      randomized study, 60 patients undergoing knee arthroscopic meniscectomy were
      allocated to groups receiving intraarticular saline, intraarticular sufentanil 10
      microg, or sufentanil 10 microg plus methylprednisolone 40 mg at the end of
      arthroscopy during general anesthesia. Postoperatively, pain levels at rest and
      during movement (i.e., active flexion of the knee) were measured by a visual
      analog scale and were significantly decreased in the sufentanil and sufentanil
      plus methylprednisolone groups compared with the control group. Moreover, we
      found that there was a significant reduction in intraarticular sufentanil and
      sufentanil plus methylprednisolone in the postoperative consumption of
      analgesics. We also found that the use of intraarticular sufentanil or sufentanil
      plus methylprednisolone after knee arthroscopic meniscectomy decreases the amount
      of supplementary analgesic needed for pain relief during the early postoperative
      period. In addition, we detected that sufentanil provided prolonged pain relief
      up to 24 h when compared with control, whereas when we combined sufentanil plus
      methylprednisolone, we found that it further reduced pain and use of analgesics
      when compared with sufentanil. IMPLICATIONS: The combined use of intraarticular
      sufentanil (10 microg) and methylprednisolone (40 mg) in arthroscopic
      meniscectomy surgery reduced both postoperative pain scores and the use of
      additional analgesics.

PMID- 15041600
TI  - A dose ranging study of dexamethasone for preventing patient-controlled analgesia
      related nausea and vomiting: a comparison of droperidol with saline.
AB  - We designed this study to determine the minimum dose of dexamethasone for
      preventing nausea and vomiting associated with the use of morphine by patient
      controlled analgesia (PCA). Two hundred forty female patients were randomly
      assigned to receive dexamethasone 2, 4, 8, or 12 mg IV immediately before
      induction of anesthesia. Droperidol (0.1 mg/mL with morphine 1 mg/mL in PCA pump)
      and saline were used as controls. The complete response (no postoperative nausea
      and vomiting and no need for rescue antiemetic for a 24-h postoperative period)
      rates for dexamethasone 8 mg (72.2%) and 12 mg (78.9%) were significantly more
      than for saline (42.9%) (P < 0.05). Patients who received dexamethasone 12 or 8
      mg also reported higher patient satisfaction than those who received saline (P <
      0.05). These results were as effective as adding droperidol 0.1 mg/mL to the
      morphine PCA without causing drowsiness, restlessness, or arrhythmias. Smaller
      doses of dexamethasone (4 or 2 mg) were not effective for this propose. The
      results suggest that dexamethasone 8 mg IV is the minimum effective dose for the
      reduction of PCA morphine-related nausea and vomiting. IMPLICATIONS: Morphine
      administration by patient-controlled analgesia (PCA) is often associated nausea
      and vomiting. In this double-blind study, the minimum effective dose of
      dexamethasone for reducing this complication was 8 mg. This was as effective as
      adding droperidol 0.1 mg/mL to the morphine PCA without causing drowsiness,
      restlessness or arrhythmias.

PMID- 15041601
TI  - Single-dose haloperidol for the prophylaxis of postoperative nausea and vomiting
      after intrathecal morphine.
AB  - Postoperative nausea and vomiting (PONV) occurs frequently with the use of
      intrathecal morphine. We studied the ability of a single, small dose of the
      inexpensive, long-acting, dopamine receptor-blocking drug, haloperidol, to
      prevent PONV after spinal anesthesia using local anesthetic with morphine 0.3 mg.
      One-hundred-eight adult patients undergoing elective lower limb orthopedic or
      endoscopic urologic procedures under spinal anesthesia were randomized to receive
      IM haloperidol 1 mg (H1), haloperidol 2 mg (H2), or placebo (P) after an
      intrathecal injection. Patients were assessed for 24 h after surgery, with
      treatment failure being defined as nausea >1 on a 10-cm visual analog scale or
      any vomiting or request for rescue antiemetic. Most treatment failures occurred
      during the first 12 h (60% overall), and haloperidol led to a dose-dependent
      decrease in PONV (first 12 h: 76% P, 56% H1, and 50% H2; P = 0.012). A history of
      PONV was strongly associated with PONV in the current study, regardless of
      treatment group. There were no dystonic reactions noted to either dose of
      haloperidol. We conclude that haloperidol reduces the incidence of PONV after
      intrathecal morphine, although this incidence remains a significant problem even
      with treatment. IMPLICATIONS: In this randomized, double-blinded, placebo
      controlled trial, a single, small IM dose of haloperidol 1 mg or 2 mg reduced the
      incidence of postoperative nausea and vomiting after spinal anesthesia with local
      anesthetic and intrathecal morphine.

PMID- 15041602
TI  - The efficacy of continuous fascia iliaca compartment block for pain management in
      burn patients undergoing skin grafting procedures.
AB  - Postoperative pain from split skin donor sites is often more intense than the
      pain at the grafted site. In this prospective, randomized, double-blind study we
      assessed the efficacy of a continuous fascia iliaca compartment block (FICB) in
      reducing the pain at the thigh donor site. Twenty patients, with a total burn
      surface area of 16% +/- 13% (mean +/- SD) were randomized 1:1 to receive either
      ropivacaine 0.2% or saline 0.9%. All patients received a general anesthesic
      followed by preincision continuous FICB with 40 mL of the randomized solution,
      then an infusion of 10 mL/h of either ropivacaine or saline until the first
      dressing change (72 h later). Postoperative analgesia consisted of propacetamol
      2g/6h, IV patient-controlled analgesia of morphine chlorhydrate (2 mg/mL), and
      morphine hydrochlorate 0.5 mg/kg PO once 60 min before first dressing change. The
      visual analog scale (VAS) scores were compared using the Mann-Whitney U-test
      preoperatively, 24 and 48 h postoperatively, and during the first dressing
      change. The cumulative morphine consumption was compared with repeated-measures
      analysis of variance followed by Scheffe's method if indicated. Patients with
      continuous FICB had significantly reduced postoperative morphine consumption at
      all time points (23 +/- 20 versus 88 +/- 29 mg after 72 h, study versus control
      groups, respectively; P < 0.05). In both groups, VAS scores remained low but were
      only significantly lower for patients with continuous FICB during the first
      dressing change (3 [1] versus 7 [3]; median [interquartile range]; P < 0.05). We
      conclude that continuous FICB is an efficient method for diminishing pain at the
      thigh donor site. (250 words) IMPLICATIONS: Postoperative pain at the split skin
      donor sites is often more intense than the pain at the grafted site. This
      prospective, randomized, double-blind study assessed the efficacy of a continuous
      fascia iliaca compartment block in reducing the pain at the thigh donor site.

PMID- 15041603
TI  - Acetylsalicylic acid, diclofenac, and lornoxicam, but not rofecoxib, affect
      platelet CD 62 expression.
AB  - Nonsteroidal antiinflammatory drugs are routinely administered in the
      perioperative period. Because of the absence of cyclooxygenase-2 in platelets,
      cyclooxygenase-2-selective drugs are thought not to cause platelet inhibition.
      Because platelets play an important role in the coagulation process, the absence
      of platelet function inhibition may lead to fewer bleeding complications after
      surgery. We studied the influence of aspirin, diclofenac, lornoxicam, and
      rofecoxib on arachidonic acid and collagen-induced CD 62 P (P selectin)
      expression by using flow cytometry. Blood from 68 volunteers was obtained before
      and 1, 3, and 12 h after the oral ingestion of 1 of the randomly assigned study
      medications. Aspirin, diclofenac, and lornoxicam had a significant effect on
      arachidonic acid and collagen-induced CD 62 P expression in platelets, whereas
      rofecoxib did not show this effect. We conclude that rofecoxib is safe to use
      perioperatively with respect to inhibition of platelet function. IMPLICATIONS: We
      compared the effect of rofecoxib and three nonselective nonsteroidal
      antiinflammatory drugs on platelet function, measured by CD 62 P expression.
      Platelet function was not altered by rofecoxib, but it was inhibited by aspirin,
      diclofenac, and lornoxicam. Rofecoxib may be safer than classic NSAIDs with
      respect to platelet function during the perioperative period.

PMID- 15041605
TI  - The effects of pretreatment with lidocaine or bupivacaine on the spatial and
      temporal expression of c-Fos protein in the spinal cord caused by plantar
      incision in the rat.
AB  - We investigated the spatial and temporal patterns of c-Fos protein (Fos)
      expression in the dorsal horn of the spinal cord caused by plantar incision in
      the rat and the effects of pretreatment with local anesthetics. Bupivacaine
      (0.5%), lidocaine (2%), or saline for control was injected for nerve block and
      local infiltration before the plantar incision was made under anesthesia. Pain
      behavior and Fos expression in the L4-L5 segments of the spinal cord were
      assessed at 1, 3, 6, 24, 48, 72, and 120 h after the incision. The withdrawal
      threshold to mechanical stimulation decreased significantly at 1 h until 120 h (1
      72 h, P < 0.01;120 h, P < 0.05), and pretreatment with local anesthetics
      increased the threshold significantly at 1 h (both groups: P < 0.01), 3 h (both
      groups: P < 0.01), and 6 h (bupivacaine, P < 0.01; lidocaine, P < 0.05) in
      comparison with that in the saline group. In the saline group, Fos expression was
      detected predominantly in laminae I-II and V-VI, and the total Fos expression was
      maximal at 1 h and then decreased gradually. Pretreatment with local anesthetics
      suppressed Fos expression significantly in all layers, and this suppression
      continued for several days. This study provides evidence of spatial and temporal
      changes in Fos expression induced by plantar incision. Our results indicate that
      although pretreatment with local anesthetics suppresses Fos expression for
      several days in the postoperative period, the analgesic effect is observed only
      for the expected duration of the local anesthetic used. IMPLICATIONS: Prevention
      of early pain by pretreatment with local anesthetics provides little benefit for
      postoperative pain relief in the plantar incision model, although c-Fos
      expression is suppressed. The number of c-Fos-expressing neurons is not
      necessarily correlated with pain behavior.

PMID- 15041604
TI  - Postoperative epidural anesthesia preserves lymphocyte, but not monocyte, immune
      function after major spine surgery.
AB  - Extensive spine surgery is associated with postsurgical pain. Epidural pain
      therapy may reduce postoperative stress responses and thereby influence immune
      functions. In a randomized, controlled, double-blinded prospective trial, 54
      patients received either conventional patient-controlled IV analgesia (PCIA;
      morphine 3 mg/15 min) or patient-controlled epidural analgesia (PCEA; 0.125%
      ropivacaine plus sufentanil 1 microg/mL at a base rate of 12 mL/h and bolus
      application of 5 mL/15 min). Circulating cytokines, C-reactive protein (CRP),
      cortisol, and cell-surface receptor expression of immune cells (cluster of
      differentiation [CD]14, human leukocyte antigen-DR, CD86, CD71, CD3, CD4, CD8,
      CD16, and CD19) were measured perioperatively to characterize immunological
      functions. PCEA, compared with PCIA, had no influence on altered levels of
      circulating cytokines (interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor
      alpha, monocyte chemoattractant protein-1, and macrophage inhibitory factor) or
      indicators of the stress response (CRP and cortisol). Also, no significant
      difference was found in monocyte numbers or their human leukocyte antigen-DR,
      CD86, or CD71 expression. In contrast, the postoperative decrease in B
      lymphocytes and T-helper cells was significant in the PCEA group. Natural killer
      cells decreased significantly in patients receiving PCEA compared with PCIA.
      Therefore, postoperative epidural pain therapy has no influence on monocyte
      functions but reduces natural killer cells and preserves B-cell and T-helper cell
      populations. Epidural analgesia thus influences the specific rather than the
      innate immune system and potentially blunts the postsurgical lymphocyte
      depression, which is relevant for infectious resistance. IMPLICATIONS: Epidural
      analgesia affects the immune system. Postoperative epidural analgesia, compared
      with conventional IV opioid therapy, preserves lymphocyte rather than monocyte
      functions. An improvement of postoperative immune function by epidural analgesia
      therefore may improve postoperative resistance to infectious complications or to
      chronic pain states.

PMID- 15041606
TI  - Patient satisfaction with preoperative assessment in a preoperative assessment
      testing clinic.
AB  - Preoperative Assessment Testing Clinics (PATCs) coordinate preoperative surgical,
      anesthesia, nursing, and laboratory care. Although such clinics have been noted
      to lead to efficiencies in perioperative care, patient experience and
      satisfaction with PATCs has not been evaluated. We distributed a one-page
      questionnaire consisting of satisfaction with clinical and nonclinical providers
      to patients presenting to our PATC over three different time periods. Eighteen
      different questions had five Likert scale options that ranged from excellent (5)
      to poor (1). We achieved a 71.4% collection rate. The average for the subscale
      that indicated overall satisfaction was 4.48 +/- 0.67 and the average for the
      total instrument was 4.46 +/- 0.55. Although the highest scores were given for
      subscales describing the anesthesia, nurse, and lab, only the anesthesia subscale
      improved with time (P = 0.007). The subscale that involved information and
      communication had the highest correlation with the overall satisfaction subscale
      (r = 0.76; P < 0.0001). The satisfaction with the total duration of the clinic
      visit (3.71 +/- 1.26) was significantly less (P < 0.0001) than the satisfaction
      to the other items. The authors conclude that the practitioner and functional
      aspects of the preoperative visit have a significant impact on patient
      satisfaction, with information and communication versus the total amount of time
      spent being the most positive and negative components, respectively.
      IMPLICATIONS: Patient satisfaction can serve as an important indicator of the
      quality of preoperative care delivered in Preoperative Assessment Testing Clinics
      (PATC). Information and communication, both from clinical and nonclinical service
      providers, remain the most important positive components, and the total duration
      of the clinic visit represents the most negative component, of patient
      satisfaction in a PATC.

PMID- 15041607
TI  - Are patients comfortable consenting to clinical anesthesia research trials on the
      day of surgery?
AB  - Consent for clinical anesthesia research trials is often sought on the day of
      surgery when patients are most anxious and have little privacy or time for
      reflection. We conducted a retrospective survey of patients' perceptions and
      concerns regarding consent for clinical anesthesia trials on the day of surgery.
      Questionnaires were mailed to 175 patients who had participated in 1 of 6
      negligible- or minimal-risk clinical anesthesia trials within the preceding year.
      Seventy-six patients responded (43%). Most patients (80%) reported that they
      understood the purpose of their trial, did not feel obligated (61%) or pressured
      (67%) to participate, and were satisfied (mean visual analog scale: 71 mm) with
      the recruitment and consent process on the day of surgery. Few patients (7%)
      believed that their well-being was put at risk because of their participation in
      the trial. IMPLICATIONS: This retrospective survey suggests that patient
      recruitment and consent for negligible- or minimal-risk clinical anesthesia
      research trials is appropriate when performed on the day of surgery.

PMID- 15041608
TI  - Do anesthesiologists die at a younger age than other physicians? Age-adjusted
      death rates.
AB  - I designed this study to determine whether anesthesiologists are susceptible to
      premature death. Three specialty groups were studied: anesthesiologists,
      internists, and all other physicians. Records were examined of all American
      physicians who died in the years 1989, 1990, 1995, 2000, and 2001, and those who
      were alive at the end of 1989, 1995, 2000, and 2001. Anesthesiologists had a
      statistically significant younger mean age at death (crude mortality) (68.98 +/-
      15.55 yr) (n = 723) than did internists (74.41 +/- 14.24 yr) (n = 2285) and all
      other physicians (75.21 +/- 13.3 yr) (n = 18,328) (P < 0.001). However, by
      factoring in the ages of the living members of the study populations, there was
      no statistical difference in age-specific mortality. IMPLICATIONS: It has been
      suggested that one of the potential occupational hazards of the practice of
      anesthesiology is premature death. This study disproves the notion that
      anesthesiologists die at a younger age than other physicians.

PMID- 15041609
TI  - The antiinflammatory effects of ketamine in endotoxemic rats during moderate and
      mild hypothermia.
AB  - Endotoxemia is a common problem among critically-ill patients. We previously
      found that ketamine inhibited hypotension, metabolic acidosis, and increase of
      plasma cytokines during endotoxemia in rats. Although endotoxic patients often
      develop hypothermia, it has not been determined whether ketamine retains its
      antiinflammatory effects during hypothermia. We investigated the effects of
      ketamine on endotoxemic rats subjected to moderate and mild hypothermia. Male
      Wistar rats (n = 100) were anesthetized intraperitoneally with pentobarbital
      sodium and assigned to one of two protocols: one representing moderate
      hypothermia (30 degrees C-32 degrees C) and the other, mild hypothermia (33
      degrees C-35 degrees C). Each protocol included 5 equal groups: 1). Escherichia
      coli endotoxin (15 mg/kg IV) in normothermia, 2). ketamine (10 mg x kg(-1) x h(
      1) IV) during and after endotoxin injection in normothermia, 3). saline in
      hypothermia, 4). endotoxin (15 mg/kg IV) in hypothermia, and 5) ketamine (10 mg x
      kg(-1) x h(-1) IV) in hypothermia after endotoxin injection. Rats were then
      warmed or cooled to maintain rectal temperatures as above for 6 h. We assessed
      hemodynamics, acid-base status, and plasma concentrations of tumor necrosis
      factor-alpha, and interleukin-6. Endotoxemic rats developed hypotension and
      metabolic acidosis as well as increased plasma cytokine concentrations. At 6 h
      after endotoxin injection, the mean systolic arterial blood pressure decreased by
      71% in the saline/normothermia/endotoxin group, whereas it decreased by only 6%,
      41%, and 29% in the ketamine/normothermia/endotoxin, saline/moderate
      hypothermia/endotoxin, and ketamine/moderate hypothermia/endotoxin groups,
      respectively. Ketamine administration to endotoxemic rats with hypothermia,
      whether moderate or mild, also attenuated hypotension, metabolic acidosis, and
      cytokine increase, but these effects were not superior to those of hypothermia
      alone. Our findings suggest that, during hypothermia, ketamine administration may
      not have additive beneficial antiinflammatory effects. IMPLICATIONS: Although
      ketamine administration decreased the severity of hypotension and acidosis in
      endotoxemic rats, ketamine administration may not have additive beneficial
      antiinflammatory effects during hypothermia.

PMID- 15041610
TI  - Paradoxical embolus after multiple trauma resulting in a cerebrovascular
      accident.
AB  - We present the case of a 57-yr-old patient who suffered an unexplained
      cerebrovascular event 3 days after being struck by a motor vehicle. Workup
      demonstrated a previously unknown patient foramen ovale. The etiologies of
      paradoxical embolism in trauma are discussed. IMPLICATIONS: Paradoxical embolism
      after multiple traumas is described. Delay in diagnosis may occur given the need
      for near continuous sedation in the patient with injuries undergoing multiple
      surgeries and diagnostic tests.

PMID- 15041611
TI  - Prolonged cardiovascular collapse due to unrecognized latex anaphylaxis.
AB  - We present a case of a prolonged anaphylactic reaction that occurred in temporal
      relationship to the administration of cefazolin. Subsequent allergy testing was
      positive for latex and negative for cefazolin-both unexpected results. Our case
      illustrates that medications administered before the onset of anaphylaxis should
      not be assumed to be the causative allergen and that a latex allergy should be
      considered in the differential diagnosis. Because the etiology of an anaphylactic
      reaction cannot be immediately determined, patients experiencing intraoperative
      cardiovascular collapse should be treated in a latex-free environment.
      IMPLICATIONS: We describe a patient who experienced latex-induced intraoperative
      anaphylaxis. The event coincided with antibiotic administration, which prompted
      us to erroneously assume that the causative allergen was medication related.
      Allergy to latex must always be considered as a potential culprit of
      perioperative cardiovascular collapse.

PMID- 15041612
TI  - The comparative effects of desflurane and isoflurane on lumbar cerebrospinal
      fluid pressure in patients undergoing craniotomy for supratentorial tumors.
AB  - We compared the effects of desflurane and isoflurane on cerebral perfusion
      pressure (CPP), lumbar cerebrospinal fluid pressure (LCSFP), and mean arterial
      blood pressure (MAP) in patients anesthetized with desflurane or isoflurane
      undergoing craniotomy for supratentorial mass lesions. Additionally, emergence
      from anesthesia was examined to determine if neurologic function could be
      assessed earlier after isoflurane or desflurane anesthesia. Thirty-six patients
      were randomized to receive either desflurane or isoflurane for maintenance of
      anesthesia at 1.2 minimum alveolar concentration (MAC). Patients were
      hyperventilated (PaCO(2), 30 +/- 2 mm Hg) after baseline LCSFP was obtained via
      the subarachnoid catheter. At a MAC of 1.2, mean LCSFP was not statistically
      different between the two study groups either before or after hyperventilation.
      Additionally, CPP was not significantly different between the two groups.
      Finally, patient's time to respond to commands was 50% shorter in the desflurane
      group (30 +/- 36 min) (mean +/- SD) when compared with the isoflurane group (72
      +/- 126 min); however, this was not significant (P = 0.17). In patients
      undergoing craniotomy for supratentorial mass lesions, desflurane and isoflurane
      have similar effects on CPP and MAP. Additionally, desflurane in the setting of
      hyperventilation does not cause significant changes in LCSFP. IMPLICATIONS: This
      is the largest study to date comparing the effects of desflurane and isoflurane
      on patients undergoing craniotomy for supratentorial mass lesion with evidence of
      midline shift or edema. Neither desflurane nor isoflurane significantly altered
      lumbar cerebrospinal fluid pressure when moderate hypocapnia was maintained.

PMID- 15041613
TI  - Continuous assessment of cerebral autoregulation in subarachnoid hemorrhage.
AB  - Cerebral vasospasm remains a leading cause of morbidity and mortality after
      subarachnoid hemorrhage (SAH). Cerebral ischemia may ensue when autoregulation
      fails to compensate for spasm. We examined how autoregulation is affected by
      vasospasm by using transcranial Doppler. The moving correlation coefficient
      between slow changes of arterial blood pressure and mean or systolic flow
      velocity (FV), termed "Mx" and "Sx," respectively, was used to characterize
      cerebral autoregulation. Vasospasm was declared when the mean FV increased to
      more than 120 cm/s and the Lindegaard ratio was more than 3. This occurred in 15
      of 32 SAH patients. On the basis of the bilateral transcranial Doppler recordings
      of the middle cerebral artery in vasospastic patients, Mx and Sx were calculated
      for baseline and vasospasm. Mx increased during vasospasm (0.46 +/- 0.32; mean +/
      SD) and was significantly higher (P = 0.021) than at baseline (0.21 +/- 0.24).
      Sx was also increased (0.22 +/- 0.26 vs 0.05 +/- 0.21 at baseline; P = 0.03). Mx
      correlated with mean FV (r = 0.577; P = 0.025) and the Lindegaard ratio (r =
      0.672; P < 0.006). Mx (P = 0.006) and Sx (P = 0.044) were higher on the
      vasospastic side (Mx, 0.44 +/- 0.27; Sx, 0.24 +/- 0.23) when compared with the
      contralateral side (Mx, 0.34 +/- 0.29; Sx, 0.16 +/- 0.25). The increased Mx and
      Sx during cerebral vasospasm demonstrate impaired cerebral autoregulation. Mx and
      Sx provide additional information on changes in autoregulation in SAH patients.
      IMPLICATIONS: The moving correlation coefficients between slow changes of
      arterial blood pressure and mean or systolic flow velocity, termed "Mx" and "Sx,"
      respectively, characterize cerebral autoregulation but have not been applied to
      subarachnoid hemorrhage. A study in 15 patients revealed that Mx and Sx were
      significantly increased, indicating impaired autoregulation during vasospasm as
      compared with baseline, as well as on the side of vasospasm in comparison with
      the contralateral side.

PMID- 15041614
TI  - Bispectral index values at sevoflurane concentrations of 1% and 1.5% in lower
      segment cesarean delivery.
AB  - Inadequate hypnosis in the absence of opioid analgesia may account for the
      increased incidence of awareness in cesarean delivery. An end-tidal concentration
      of 0.5 MAC isoflurane in 50% nitrous oxide (N(2)O) during cesarean delivery
      resulted in bispectral index (BIS) values >60, the threshold below which
      consciousness is unlikely. Our aim was to determine the BIS values achieved with
      the equivalent end-tidal concentration of sevoflurane and to determine if a
      larger concentration would consistently maintain BIS values <60. Twenty ASA
      physical status I-II parturients were randomized to receive an end-tidal
      concentration of either 1% sevoflurane or 1.5% sevoflurane delivered in 50% N(2)O
      throughout surgery. Thiopental 4 mg/kg was used for anesthetic induction.
      Morphine 0.1-0.15 mg/kg was administered only after delivery. Mean BIS values in
      the period between skin incision and neonatal delivery were 61 (95% confidence
      interval, 57-64) in the 1% sevoflurane group, versus 42 (95% confidence interval,
      37-47) in the 1.5% sevoflurane group. BIS values were significantly different
      between groups at skin incision, uterine incision, delivery, and 10 min after
      delivery, but not thereafter. Indices of maternal and neonatal outcome were
      similar between groups. IMPLICATIONS: Bispectral index (BIS) values <60 are
      consistent with a high probability of unconsciousness. An end-tidal concentration
      of 1.5% sevoflurane maintained BIS values <60 during cesarean delivery, whereas
      1% did not. Adverse effects were not seen with the use of larger concentrations
      of sevoflurane.

PMID- 15041615
TI  - Epidural infusions of ropivacaine and bupivacaine for labor analgesia: a
      randomized, double-blind study of obstetric outcome.
AB  - Studies have shown better obstetric outcome when ropivacaine 0.25% was used for
      labor epidural analgesia compared with bupivacaine 0.25%, but it is controversial
      whether there is any difference at smaller concentrations. In a prospective,
      double-blind trial, we randomized 350 ASA physical status I and II parturients
      with term cephalic singleton pregnancies to receive epidural labor analgesia
      using ropivacaine or bupivacaine. Analgesia was initiated with a 0.25% solution
      and maintained with a continuous infusion of a 0.1% solution with fentanyl
      0.0002%. Supplementary boluses of 0.25% solution were given when requested. Labor
      was managed according to institutional standard labor ward protocols. Among
      patients who delivered vaginally, the duration of the first stage of labor was
      shorter in the ropivacaine group (median, 520 min; interquartile range, 377-745
      min) compared with the bupivacaine group (645 min; interquartile range, 460-820
      min; P = 0.009), but there was no difference in any other obstetric or neonatal
      outcomes. The mode of delivery was similar between groups, with operative
      (instrumental vaginal and cesarean) delivery rates of 61.8% (95% confidence
      interval, 54.4%-68.8%) in the ropivacaine group and 58.4% (95% confidence
      interval, 50.9%-65.5%) in the bupivacaine group (P = 0.72). IMPLICATIONS: In a
      randomized-controlled study, we found no major outcome advantage of continuous
      epidural infusion of ropivacaine 0.1% with fentanyl 0.0002% over bupivacaine 0.1%
      with fentanyl 0.0002% for labor analgesia. Although ropivacaine was associated
      with a shorter first stage of labor, the relative difference is probably of
      limited clinical importance, and there was no difference in the mode of delivery.

PMID- 15041617
TI  - Perioperative management with epidural anesthesia for a parturient with superior
      vena caval obstruction.
AB  - Perioperative management of patients with superior vena cava obstruction presents
      an anesthetic challenge because of severe cardiopulmonary compromise. This is
      particularly important in the parturient because of increased upper airway edema
      and inferior vena caval compression. We describe the management of a parturient
      who presented at 34 wk of gestation with signs and symptoms of superior vena cava
      obstruction from metastatic breast cancer. The patient was scheduled for a
      cesarean delivery followed by chemotherapy, as other therapies were deemed
      excessively risky because of the anatomic characteristics of the large
      mediastinal mass. This report describes the successful use of regional anesthesia
      in this setting and discusses the relevant anesthetic and perioperative
      management considerations for this complex scenario. IMPLICATIONS: Perioperative
      management of patients with superior vena caval obstruction presents an
      anesthetic challenge because of the severe cardiopulmonary compromise. This case
      report describes a parturient who presented for cesarean delivery with superior
      vena caval obstruction resulting from metastasis from breast cancer.

PMID- 15041616
TI  - Intrathecal sufentanil and fetal heart rate abnormalities: a double-blind, double
      placebo-controlled trial comparing two forms of combined spinal epidural
      analgesia with epidural analgesia in labor.
AB  - Combined spinal epidural analgesia (CSE) for labor pain relief has become
      increasingly popular. However, the effect of intrathecal sufentanil on the
      incidence of uterine hyperactivity and fetal heart rate (FHR) abnormalities
      remains controversial. We hypothesized that the use of intrathecal sufentanil in
      a dose of 7.5 microg is more likely to induce a nonreassuring FHR tracing than a
      small dose of spinal sufentanil combined with bupivacaine or epidural analgesia.
      Three-hundred parturients were randomized into three groups. In the first group,
      epidural analgesia was initiated with 12.5 mg of bupivacaine, 12.5 microg of
      epinephrine, and 7.5 microg of sufentanil in a volume of 10 mL (EPD group). In
      Group 2, initial intrathecal analgesia consisted of 2.5 mg of bupivacaine, 2.5
      microg of epinephrine, and 1.5 microg of sufentanil (BSE group); in Group 3,
      spinal analgesia consisted of 7.5 microg of sufentanil (SUF group). Analgesia was
      maintained in all groups with patient-controlled epidural analgesia using
      bupivacaine 0.125%, 1.25 microg/mL of epinephrine, and 0.75 microg/mL of
      sufentanil (bolus, 4 mL; lockout, 15 min). Cardiotocography was monitored
      continuously 15 min before analgesia and for 60 min after the start of analgesia.
      The quality of analgesia, labor, and neonatal outcome and side effects were
      recorded. Twenty-four percent of patients in the SUF group developed FHR
      abnormalities (bradycardia or late decelerations) during the first hour after
      initiation of analgesia compared with 12% in the BSE group and 11% in the EPD
      group. Uterine hyperactivity occurred in 12% of parturients in the SUF group but
      in only 2% in the other groups. Onset of analgesia was more rapid in both CSE
      groups as compared with the EPD group. However, 29% of patients in the BSE group
      developed severe hypotension, requiring IV ephedrine (29% in the BSE group versus
      7% and 12% in the EPD and SUF groups, respectively). All these differences
      reached statistical significance. The present data corroborate previous
      recommendations of caution when performing CSE using a large dose (7.5 microg or
      more) of spinal sufentanil because of the risk of uterine hyperactivity and FHR
      abnormalities. IMPLICATIONS: Combined spinal epidural analgesia (CSE) produces
      pain relief during labor. Fetal heart rate changes after CSE using intrathecal
      sufentanil have been reported. We performed a randomized, blinded trial
      confirming that fetal heart rate changes are more frequent after CSE using 7.5
      micro g of intrathecal sufentanil as compared with other forms of neuraxial labor
      analgesia.

PMID- 15041618
TI  - Boerhaave's syndrome after postoperative vomiting.
AB  - Postoperative nausea and vomiting are common after general anesthesia but rarely
      produce life-threatening conditions. We report a case of postoperative vomiting
      complicated by esophageal rupture (Boerhaave's syndrome). As this complication is
      quite rare and can have varied and atypical presentations, anesthesiologists may
      fail to consider this diagnosis. IMPLICATIONS: We report a case of postoperative
      vomiting complicated by esophageal rupture (Boerhaave's syndrome). As this
      complication is quite rare, anesthesiologists may fail to consider this
      diagnosis.

PMID- 15041619
TI  - The supraclavicular block with a nerve stimulator: to decrease or not to
      decrease, that is the question.
AB  - Portable nerve stimulators for nerve blocks have been available for more than 40
      yr. It is generally accepted that seeking a motor response at low outputs
      increases the chances of success. It is customary to start the procedure at a
      higher current with the goal of finding the nerve. After an adequate response is
      elicited, the current is decreased before the local anesthetic is injected.
      However, how low is low enough and, for that matter, how high is too high have
      not been adequately determined. Our experience seems to indicate that, in the
      supraclavicular block, the type of response obtained is as important as the
      output at which it is elicited, provided that this current is not higher than 1
      mA. In this context, it is theoretically possible that our initial seeking
      current of 0.9 mA could be an adequate injection current if it is combined with
      an appropriate response. We designed this study to test the hypothesis that a
      response of the fingers in flexion or extension, elicited at 0.9 mA, could be
      followed immediately by the local anesthetic injection. We did not intend to
      compare 0.5 and 0.9 mA as minimum stimulating currents but rather as currents
      able to elicit an unmistakable motor twitch. Sixty patients were randomly
      assigned to one of two groups. Group 1 (n = 30) was injected with a motor twitch
      in the fingers that was still visible at 0.5 mA. Group 2 (n = 30) was injected
      after a similar response to that in Group 1 was elicited, but at the initial
      output of 0.9 mA, without any further decrease. The blocks were injected with 40
      mL of local anesthetic solution. One patient was excluded from the study for
      failing to meet protocol criteria. The success rate in the remaining 59 patients
      was 100%; success was defined as complete sensory blockade at the median, ulnar,
      and radial nerve territories of the hand that was accomplished in <or=30 min from
      the time of injection and that did not require supplementation or general
      anesthesia. In fact, all blocks became complete within 22 min of the injection.
      The onset of anesthesia occurred in 10.9 +/- 5.4 min in the 0.5-mA group and 11.4
      +/- 4.8 min in the 0.9-mA group; this difference was not statistically different.
      The onset of analgesia and the duration of anesthesia were also similar in both
      groups. There were no complications, and the respondents in both groups graded
      their experience at a similar level of satisfaction. We conclude that during the
      performance of a supraclavicular block eliciting a clearly visible response of
      the fingers at 0.9 mA can be immediately followed by the injection of local
      anesthetic, because decreasing the output to 0.5 mA does not seem to improve the
      overall quality of the block as measured by the onset and duration of anesthesia
      or patient satisfaction. IMPLICATIONS: When nerve blocks are performed with a
      nerve stimulator, it is customary to reduce the nerve stimulator output to <= 0.5
      mA before injecting. Apparently this is not necessary with a supraclavicular
      block.

PMID- 15041621
TI  - The incidence of lumbar ligamentum flavum midline gaps.
AB  - Lumbar epidural anesthesia and analgesia has gained increasing importance in
      perioperative pain therapy for abdominal and lower limb surgery. The loss-of
      resistance technique, used to identify the epidural space, is thought to rely on
      the penetration of the ligamentum flavum. However, the exact morphology of the
      ligamentum flavum at different vertebral levels remains controversial. Therefore,
      in this study, we directly investigated the incidence of lumbar ligamentum flavum
      midline gaps in embalmed cadavers. Vertebral column specimens were obtained from
      45 human cadavers. On each dissected level, ligamentum flavum midline gaps were
      recorded. The incidence of midline gaps per number of viable specimens at the
      following levels was: L1-2 = 10 of 45 (22.2%), L2-3 = 5 of 44 (11.4%), L3-4 = 5
      of 45 (11.1%), L4-5 = 4 of 43 (9.3%), L5/S1 = 0 of 33 (0%). In conclusion, the
      present study determined the frequency of lumbar ligamentum flavum midline gaps.
      Gaps in the lumbar ligamentum flavum are most frequent between L1 and L2 but are
      more rare below this level. When using the midline approach, the ligamentum
      flavum may not impede entering the epidural space in all patients. IMPLICATIONS:
      The ligamentum flavum is a crucial anatomical landmark for the safe performance
      of epidural anesthesia. However, the present study demonstrates some failure of
      the lumbar ligamentum flavum as a landmark. This may mean that, using a midline
      approach, one cannot always rely on the ligamentum flavum as a perceptible
      barrier to epidural needle advancement.

PMID- 15041620
TI  - Tramadol added to 1.5% mepivacaine for axillary brachial plexus block improves
      postoperative analgesia dose-dependently.
AB  - Adjuncts to local anesthetics for peripheral plexus blockade may enhance the
      quality and duration of anesthesia and postoperative analgesia. The analgesic,
      tramadol, has a unique mechanism of action that suggests efficacy as such an
      adjunct. It displays a central analgesic and peripheral local anesthetic effect.
      We designed a prospective, randomized, controlled and double-blind clinical trial
      to assess the effect of tramadol added to brachial plexus anesthesia. One-hundred
      patients scheduled for carpal tunnel release surgery under brachial plexus
      anesthesia were randomized into four groups. All patients received 1.5%
      mepivacaine 40 mL plus a study solution containing either isotonic sodium
      chloride (Group P, n = 17), tramadol 40 mg (Group T(40), n = 22), tramadol 100 mg
      (Group T(100), n = 20) or tramadol 200 mg (Group T(200), n = 20). We evaluated
      the time of onset of anesthesia, duration of sensory and motor blockade, duration
      and quality of postoperative analgesia, and occurrence of adverse effects. Onset
      and duration of sensory and motor blocks were not different among groups. The
      number of patients requesting analgesia in the postoperative period was
      significantly less in the 3 tramadol groups compared with the placebo group (P =
      0.02); this was also noted with the placebo and T(40) groups compared with the
      T(200) group. No statistical significance was demonstrated between the placebo
      and the T(40) group or the T(100) group and the T(200) group. Furthermore, there
      was a significant trend effect among groups applying the Cochran-Armitage
      tendency test (P = 0.003), suggesting a dose-dependent decrease for additional
      postoperative analgesia requirements when tramadol was added. Side effects did
      not differ among groups, although they were more frequently recorded in the T
      groups. Our study suggests that tramadol added to 1.5% mepivacaine for brachial
      plexus block enhances in a dose-dependent manner the duration of analgesia with
      acceptable side effects. However, the safety of tramadol has to be investigated
      before allowing its use in clinical practice. IMPLICATIONS: Tramadol's unique
      mechanism of action suggests efficacy as a local anesthetic adjunct for
      peripheral plexus blockade. Our study demonstrates that tramadol, added to
      mepivacaine for brachial plexus anesthesia, extends the duration and improves the
      quality of postoperative analgesia in a dose dependent fashion with acceptable
      side effects.

PMID- 15041622
TI  - Epidural hematoma after spinal anesthesia in a patient with undiagnosed epidural
      lymphoma.
AB  - The incidence of hemorrhagic complications after neuroaxial anesthesia is very
      infrequent. We report a case of a woman developing epidural bleeding 3 wk after
      performing an uneventful spinal anesthesia at the lumbar level L3-4 for removal
      of a wire loop in her left knee. No hemostasis altering medication had been taken
      before and after spinal puncture. The hematoma presenting at the lumbar level L2
      3 had to be removed via laminectomy. Pathological examination of the hematoma
      revealed a highly vascularized centroblastic non-Hodgkin's lymphoma that was not
      diagnosed before surgery. The patient did not develop any neurological deficits.
      IMPLICATIONS: We report a case of a women developing epidural bleeding 3 wk after
      performing an uneventful spinal anesthesia for removal of a wire loop in her left
      knee. Pathological examination of the neurosurgically removed hematoma revealed a
      highly vascularized epidural centroblastic non-Hodgkin lymphoma.

PMID- 15041623
TI  - Severe hypercapnia due to pulmonary embolism of polymethylmethacrylate during
      vertebroplasty.
AB  - Pulmonary polymethylmethacrylate embolism is a rare but potentially fatal
      complication of percutaneous vertebroplasty. Clinical signs are typical for
      pulmonary embolism: they include respiratory distress, hypotension, and decreases
      in end-tidal CO(2). We report a case of fatal pulmonary polymethylmethacrylate
      embolism during percutaneous vertebroplasty that initially presented with
      hypertension (arterial blood pressure 190/90 mm Hg), normocardia, and hypercapnia
      (PaCO(2) 96 mm Hg), along with loss of consciousness. Several pieces of
      polymethylmethacrylate were found in the pulmonary vasculature at autopsy.
      IMPLICATIONS: Osteoporotic spine fractures are increasingly treated by injection
      of bone cement into the vertebral body. Polymethylmethacrylate embolism is a rare
      but potentially fatal complication. We report on a case of polymethylmethacrylate
      embolism that was at first unrecognized because of uncharacteristic signs and
      symptoms.

PMID- 15041624
TI  - Massive pulmonary embolism after application of an Esmarch bandage.
AB  - A 71-yr-old patient who underwent spinal anesthesia for left femoral fracture
      operation became hypotensive and unconscious after the application of an Esmarch
      bandage. The transesophageal echocardiography performed during resuscitation
      revealed pulmonary embolism and acute right ventricular failure. Pulmonary
      embolectomy with cardiopulmonary bypass was undertaken immediately after the
      echocardiographic diagnosis. Extracorporeal membrane oxygenation was used after
      the operation to support the failing right ventricle. The patient was
      successfully weaned from extracorporeal membrane oxygenation 10 days after the
      operation. We conclude that transesophageal echocardiography can be very useful
      in the immediate differential diagnosis of sudden cardiovascular collapse and
      that extracorporeal membrane oxygenation can be very helpful when acute right
      ventricular failure follows massive pulmonary embolism. IMPLICATIONS:
      Transesophageal echocardiography was highly valuable in finding the cause of
      sudden intraoperative cardiovascular collapse. The use of extracorporeal membrane
      oxygenation to support the failing right ventricle after emergent pulmonary
      embolectomy could help to rescue patients with massive pulmonary embolism.

PMID- 15041625
TI  - Tumescent anesthesia: a concern of anesthesiologists.

PMID- 15041626
TI  - A method to quickly estimate remaining time for an oxygen E-cylinder.

PMID- 15041628
TI  - Abbreviations.

PMID- 15041627
TI  - Con: the FMS 2000 blood/fluid warmer is not better than the level 1 H1025.

PMID- 15041630
TI  - Phonocardiographic recording from the trachea: use of a special endotracheal
      tube.

PMID- 15041631
TI  - Haeckel's recapitulation theory should not be used as a defense of the ASA
      difficult airway algorithm.

PMID- 15041629
TI  - Clomethiazole alters immune function within an isolated cardiopulmonary bypass
      circuit.

PMID- 15041632
TI  - Damage to the three-way valves by a clear propofol formulation.

PMID- 15041633
TI  - The safety of hemoglobin blood substitutes.

PMID- 15041634
TI  - Remember the simple digital alternative.

PMID- 15041635
TI  - Dynamic water networks in cytochrome C oxidase from Paracoccus denitrificans
      investigated by molecular dynamics simulations.
AB  - We present a molecular dynamics study of cytochrome c oxidase from Paracoccus
      denitrificans in the fully oxidized state, embedded in a fully hydrated
      dimyristoylphosphatidylcholine lipid bilayer membrane. Parallel simulations with
      different levels of protein hydration, 1.125 ns each in length, were carried out
      under conditions of constant temperature and pressure using three-dimensional
      periodic boundary conditions and full electrostatics to investigate the
      distribution and dynamics of water molecules and their corresponding hydrogen
      bonded networks inside cytochrome c oxidase. The majority of the water molecules
      had residence times shorter than 100 ps, but a few water molecules are fixed
      inside the protein for up to 1.125 ns. The hydrogen-bonded network in cytochrome
      c oxidase is not uniformly distributed, and the degree of water arrangement is
      variable. The average number of solvent sites in the proton-conducting K- and D
      pathways was determined. In contrast to single water files in narrow geometries
      we observe significant diffusion of individual water molecules along these
      pathways. The highly fluctuating hydrogen-bonded networks, combined with the
      significant diffusion of individual water molecules, provide a basis for the
      transfer of protons in cytochrome c oxidase, therefore leading to a better
      understanding of the mechanism of proton pumping.

PMID- 15041636
TI  - Ionic wave propagation along actin filaments.
AB  - We investigate the conditions enabling actin filaments to act as electrical
      transmission lines for ion flows along their lengths. We propose a model in which
      each actin monomer is an electric element with a capacitive, inductive, and
      resistive property due to the molecular structure of the actin filament and
      viscosity of the solution. Based on Kirchhoff's laws taken in the continuum
      limit, a nonlinear partial differential equation is derived for the propagation
      of ionic waves. We solve this equation in two different regimes. In the first,
      the maximum propagation velocity wave is found in terms of Jacobi elliptic
      functions. In the general case, we analyze the equation in terms of Fisher
      Kolmogoroff modes with both localized and extended wave characteristics. We
      propose a new signaling mechanism in the cell, especially in neurons.

PMID- 15041638
TI  - A nonlinear discrete dynamical model for transcriptional regulation: construction
      and properties.
AB  - Transcriptional regulation is a fundamental mechanism of living cells, which
      allows them to determine their actions and properties, by selectively choosing
      which proteins to express and by dynamically controlling the amounts of those
      proteins. In this article, we revisit the problem of mathematically modeling
      transcriptional regulation. First, we adopt a biologically motivated continuous
      model for gene transcription and mRNA translation, based on first-order rate
      equations, coupled with a set of nonlinear equations that model cis-regulation.
      Then, we view the processes of transcription and translation as being discrete,
      which, together with the need to use computational techniques for large-scale
      analysis and simulation, motivates us to model transcriptional regulation by
      means of a nonlinear discrete dynamical system. Classical arguments from chemical
      kinetics allow us to specify the nonlinearities underlying cis-regulation and to
      include both activators and repressors as well as the notion of regulatory
      modules in our formulation. We show that the steady-state behavior of the
      proposed discrete dynamical system is identical to that of the continuous model.
      We discuss several aspects of our model, related to homeostatic and epigenetic
      regulation as well as to Boolean networks, and elaborate on their significance.
      Simulations of transcriptional regulation of a hypothetical metabolic pathway
      illustrate several properties of our model, and demonstrate that a nonlinear
      discrete dynamical system may be effectively used to model transcriptional
      regulation in a biologically relevant way.

PMID- 15041637
TI  - First principles predictions of the structure and function of g-protein-coupled
      receptors: validation for bovine rhodopsin.
AB  - G-protein-coupled receptors (GPCRs) are involved in cell communication processes
      and with mediating such senses as vision, smell, taste, and pain. They constitute
      a prominent superfamily of drug targets, but an atomic-level structure is
      available for only one GPCR, bovine rhodopsin, making it difficult to use
      structure-based methods to design receptor-specific drugs. We have developed the
      MembStruk first principles computational method for predicting the three
      dimensional structure of GPCRs. In this article we validate the MembStruk
      procedure by comparing its predictions with the high-resolution crystal structure
      of bovine rhodopsin. The crystal structure of bovine rhodopsin has the second
      extracellular (EC-II) loop closed over the transmembrane regions by making a
      disulfide linkage between Cys-110 and Cys-187, but we speculate that opening this
      loop may play a role in the activation process of the receptor through the
      cysteine linkage with helix 3. Consequently we predicted two structures for
      bovine rhodopsin from the primary sequence (with no input from the crystal
      structure)-one with the EC-II loop closed as in the crystal structure, and the
      other with the EC-II loop open. The MembStruk-predicted structure of bovine
      rhodopsin with the closed EC-II loop deviates from the crystal by 2.84 A
      coordinate root mean-square (CRMS) in the transmembrane region main-chain atoms.
      The predicted three-dimensional structures for other GPCRs can be validated only
      by predicting binding sites and energies for various ligands. For such
      predictions we developed the HierDock first principles computational method. We
      validate HierDock by predicting the binding site of 11-cis-retinal in the crystal
      structure of bovine rhodopsin. Scanning the whole protein without using any prior
      knowledge of the binding site, we find that the best scoring conformation in
      rhodopsin is 1.1 A CRMS from the crystal structure for the ligand atoms. This
      predicted conformation has the carbonyl O only 2.82 A from the N of Lys-296.
      Making this Schiff base bond and minimizing leads to a final conformation only
      0.62 A CRMS from the crystal structure. We also used HierDock to predict the
      binding site of 11-cis-retinal in the MembStruk-predicted structure of bovine
      rhodopsin (closed loop). Scanning the whole protein structure leads to a
      structure in which the carbonyl O is only 2.85 A from the N of Lys-296. Making
      this Schiff base bond and minimizing leads to a final conformation only 2.92 A
      CRMS from the crystal structure. The good agreement of the ab initio-predicted
      protein structures and ligand binding site with experiment validates the use of
      the MembStruk and HierDock first principles' methods. Since these methods are
      generic and applicable to any GPCR, they should be useful in predicting the
      structures of other GPCRs and the binding site of ligands to these proteins.

PMID- 15041639
TI  - Beta-hairpin folding mechanism of a nine-residue peptide revealed from molecular
      dynamics simulations in explicit water.
AB  - The beta-hairpin fold mechanism of a nine-residue peptide, which is modified from
      the beta-hairpin of alpha-amylase inhibitor tendamistat (residues 15-23), is
      studied through direct folding simulations in explicit water at native folding
      conditions. Three 300-nanosecond self-guided molecular dynamics (SGMD)
      simulations have revealed a series of beta-hairpin folding events. During these
      simulations, the peptide folds repeatedly into a major cluster of beta-hairpin
      structures, which agree well with nuclear magnetic resonance experimental
      observations. This major cluster is found to have the minimum conformational free
      energy among all sampled conformations. This peptide also folds into many other
      beta-hairpin structures, which represent some local free energy minimum states.
      In the unfolded state, the N-terminal residues of the peptide, Tyr-1, Gln-2, and
      Asn-3, have a confined conformational distribution. This confinement makes beta
      hairpin the only energetically favored structure to fold. The unfolded state of
      this peptide is populated with conformations with non-native intrapeptide
      interactions. This peptide goes through fully hydrated conformations to eliminate
      non-native interactions before folding into a beta-hairpin. The folding of a beta
      hairpin starts with side-chain interactions, which bring two strands together to
      form interstrand hydrogen bonds. The unfolding of the beta-hairpin is not simply
      the reverse of the folding process. Comparing unfolding simulations using MD and
      SGMD methods demonstrate that SGMD simulations can qualitatively reproduce the
      kinetics of the peptide system.

PMID- 15041640
TI  - Evaluation of the flow-dialysis technique for analysis of protein-ligand
      interactions: an experimental and a monte carlo study.
AB  - Flow dialysis has found widespread use in determining the dissociation constant
      (KD) of a protein-ligand interaction or the amount of available binding sites
      (E0). This method has the potency to measure both these parameters in a single
      experiment and in this article a method to measure simultaneously the KD and E0
      is presented, together with an extensive error analysis of the method. The flow
      dialysis technique is experimentally simple to perform. However, a number of
      practical aspects of this method can have a large impact on the outcome of KD and
      E0. We have investigated all sources of significant systematic and random errors,
      using the interaction between mannitol and its transporter from Escherichia coli
      as a model. Monte Carlo simulations were found to be an excellent tool to assess
      the impact of these errors on the binding parameters and to define the
      experimental conditions that allow their most accurate estimation.

PMID- 15041642
TI  - Theoretical investigations on Azotobacter vinelandii ferredoxin I: effects of
      electron transfer on protein dynamics.
AB  - Structural, energetic, and dynamical studies of Azotobacter vinelandii ferredoxin
      I are presented for native and mutant forms. The protein contains two iron-sulfur
      clusters, one of which ([3Fe-4S]) is believed to play a central role in the
      electron-coupled proton transfer. Different charge sets for the [3Fe-4S] cluster
      in its reduced and oxidized state are calculated with broken symmetry ab initio
      density functional theory methods and used in molecular dynamics (MD)
      simulations. The validity of the ab initio calculations is assessed by comparing
      partially optimized structures of the [3Fe-4S] clusters with x-ray structures.
      Possible proton transfer pathways between the protein and the iron-sulfur cluster
      are examined by both MD simulations and ab initio calculations. The MD
      simulations identify three main-chain hydrogen atoms--HN(13), HN(14), and HN(16)-
      that are within H-bonding distance of the [3Fe-4S] cluster throughout the MD
      simulations. They could thus play a role in the proton transfer from the protein
      to the iron-sulfur cluster. By contrast, the HD2(15) atom of the Asp-15 is seldom
      close enough to the [3Fe-4S] cluster to transfer a proton. Poisson-Boltzmann
      calculations indicate that there is a low, but nonzero probability, that Asp-15
      is protonated at pH 7; this is a requirement for it to serve as a proton donor.
      Ab initio calculations with a fragment model for the protein find similar
      behavior for the transfer of a proton from the OH of the protonated side chain
      and the main-chain NH of Asp-15. The existence of a stable salt bridge between
      Asp-15 and Lys-84 in the D15E mutant, versus its absence in the wild-type, has
      been suggested as the cause of the difference in the rate of proton transfer.
      Extensive MD simulations were done to test this idea; the results do not support
      the proposal. The present findings, together with the available data, serve as
      the basis for an alternative proposal for the mechanism of the coupled electron
      proton transfer reaction in ferredoxin I.

PMID- 15041641
TI  - A computational model for the electrostatic sequestration of PI(4,5)P2 by
      membrane-adsorbed basic peptides.
AB  - The multivalent acidic phospholipid phosphatidylinositol 4,5-bisphosphate
      (PI(4,5)P2) plays a key role in many biological processes. Recent studies show
      that unstructured clusters of basic residues from a number of peripheral proteins
      can laterally sequester PI(4,5)P2 in membranes. Specifically, experiments suggest
      that the basic effector domain of the myristoylated alanine-rich C kinase
      substrate (MARCKS), or a peptide corresponding to this domain, MARCKS(151-175),
      sequesters several PI(4,5)P2 and that this sequestration is due to nonspecific
      electrostatic interactions. Here, we use the finite difference Poisson-Boltzmann
      method to test this hypothesis by calculating the electrostatic free energy of
      lateral sequestration of PI(4,5)P2 by membrane-adsorbed basic peptides: Lys-7,
      Lys-13, and FA-MARCKS(151-175), a peptide based on MARCKS(151-175). In agreement
      with experiments, we find that the electrostatic free energy becomes more
      favorable when: 1), Lys-13 and FA-MARCKS(151-175) sequester several PI(4,5)P2;
      2), the linear charge density of the basic peptide increases; 3), the mol percent
      monovalent acidic lipid in the membrane decreases; and 4), the ionic strength of
      the solution decreases. In addition, the electrostatic sequestration free energy
      is in excess of the entropic penalty associated with localizing PI(4,5)P2. Our
      calculations, thus, provide a structural and quantitative description of the
      observed interaction of PI(4,5)P2 with membrane-adsorbed basic sequences.

PMID- 15041643
TI  - Metastable network model of protein transport through nuclear pores.
AB  - To reconcile the observed selectivity and the high rate of translocation of cargo
      importin complexes through nuclear pores, we propose that the core of the nuclear
      pore complex is blocked by a metastable network of phenylalanine and glycine
      nucleoporins. Although the network arrests the unfacilitated passage of objects
      larger than its mesh size, cargo-importin complexes act as catalysts that reduce
      the free energy barrier between the cross-linked and the dissociated states of
      the Nups, and open the network. Using Brownian dynamics simulations we calculate
      the distribution of passage times through the network for inert particles and
      cargo-importin complexes of different sizes and discuss the implications of our
      results for experiments on translocation of proteins through the nuclear pore
      complex.

PMID- 15041644
TI  - Finite element solution of the steady-state Smoluchowski equation for rate
      constant calculations.
AB  - This article describes the development and implementation of algorithms to study
      diffusion in biomolecular systems using continuum mechanics equations.
      Specifically, finite element methods have been developed to solve the steady
      state Smoluchowski equation to calculate ligand binding rate constants for large
      biomolecules. The resulting software has been validated and applied to mouse
      acetylcholinesterase. Rates for inhibitor binding to mAChE were calculated at
      various ionic strengths with several different reaction criteria. The calculated
      rates were compared with experimental data and show very good agreement when the
      correct reaction criterion is used. Additionally, these finite element methods
      require significantly less computational resources than existing particle-based
      Brownian dynamics methods.

PMID- 15041645
TI  - Protein control of electron transfer rates via polarization: molecular dynamics
      studies of rubredoxin.
AB  - The protein matrix of an electron transfer protein creates an electrostatic
      environment for its redox site, which influences its electron transfer
      properties. Our studies of Fe-S proteins indicate that the protein is highly
      polarized around the redox site. Here, measures of deviations of the
      environmental electrostatic potential from a simple linear dielectric
      polarization response to the magnitude of the charge are proposed. In addition, a
      decomposition of the potential is proposed here to describe the apparent
      deviations from linearity, in which it is divided into a "permanent" component
      that is independent of the redox site charge and a dielectric component that
      linearly responds or polarizes to the charge. The nonlinearity measures and the
      decomposition were calculated for Clostridium pasteurianum rubredoxin from
      molecular dynamics simulations. The potential in rubredoxin is greater than
      expected from linear response theory, which implies it is a better electron
      acceptor than a redox site analog in a solvent with a dielectric constant
      equivalent to that of the protein. In addition, the potential in rubredoxin is
      described well by a permanent potential plus a linear response component. This
      permanent potential allows the protein matrix to create a favorable driving force
      with a low activation barrier for accepting electrons. The results here also
      suggest that the reduction potential of rubredoxin is determined mainly by the
      backbone and not the side chains, and that the redox site charge of rubredoxin
      may help to direct its folding.

PMID- 15041646
TI  - A statistical-thermodynamic model of viral budding.
AB  - We present a simple statistical thermodynamic model for budding of viral
      nucleocapsids at the cell membrane. The membrane is modeled as a flexible lipid
      bilayer embedding linker (spike) proteins, which serve to anchor and thus wrap
      the membrane around the viral capsids. The free energy of a single bud is
      expressed as a sum of the bending energy of its membrane coat, the spike-mediated
      capsid-membrane adhesion energy, and the line energy associated with the bud's
      rim, all depending on the extent of wrapping (i.e., bud size), and density of
      spikes in the curved membrane. This self-energy is incorporated into a simple
      free energy functional for the many-bud system, allowing for different spike
      densities, and hence entropy, in the curved (budding) and planar membrane
      regions, as well as for the configurational entropy of the polydisperse bud
      population. The equilibrium spike densities in the coexisting, curved and planar,
      membrane regions are calculated as a function of the membrane bending energy and
      the spike-mediated adhesion energy, for different spike and nucleocapsid
      concentrations in the membrane plane, as well as for several values of the bud's
      rim energy. We show that complete budding (full wrapping of nucleocapsids) can
      only take place if the adhesion energy exceeds a certain, critical, bending free
      energy. Whenever budding takes place, the spike density in the mature virions is
      saturated, i.e., all spike adhesion sites are occupied. The rim energy plays an
      important role in determining the size distribution of buds. The fraction of
      fully wrapped buds increases as this energy increases, resulting eventually in an
      all-or-nothing mechanism, whereby nucleocapsids at the plasma membrane are either
      fully enveloped or completely naked (just touching the membrane). We also find
      that at low concentrations all capsids arriving at the membrane get tightly and
      fully enveloped. Beyond a certain concentration, corresponding approximately to a
      stoichiometric spike/capsid ratio, newly arriving capsids cannot be fully
      wrapped; i.e., the budding yield decreases.

PMID- 15041647
TI  - Theoretical model for the formation of caveolae and similar membrane
      invaginations.
AB  - We study a physical model for the formation of bud-like invaginations on fluid
      lipid membranes under tension, and apply this model to caveolae formation. We
      demonstrate that budding can be driven by membrane-bound proteins, provided that
      they exert asymmetric forces on the membrane that give rise to bending moments.
      In particular, caveolae formation does not necessarily require forces to be
      applied by the cytoskeleton. Our theoretical model is able to explain several
      features observed experimentally in caveolae, where proteins in the caveolin
      family are known to play a crucial role in the formation of caveolae buds. These
      include 1), the formation of caveolae buds with sizes in the 100-nm range and 2),
      that certain N- and C-termini deletion mutants result in vesicles that are an
      order-of-magnitude larger. Finally, we discuss the possible origin of the
      morphological striations that are observed on the surfaces of the caveolae.

PMID- 15041648
TI  - A transient diffusion model yields unitary gap junctional permeabilities from
      images of cell-to-cell fluorescent dye transfer between Xenopus oocytes.
AB  - As ubiquitous conduits for intercellular transport and communication, gap
      junctional pores have been the subject of numerous investigations aimed at
      elucidating the molecular mechanisms underlying permeability and selectivity. Dye
      transfer studies provide a broadly useful means of detecting coupling and
      assessing these properties. However, given evidence for selective permeability of
      gap junctions and some anomalous correlations between junctional electrical
      conductance and dye permeability by passive diffusion, the need exists to give
      such studies a more quantitative basis. This article develops a detailed
      diffusion model describing experiments (reported separately) involving transport
      of fluorescent dye from a "donor" region to an "acceptor" region within a pair of
      Xenopus oocytes coupled by gap junctions. Analysis of transport within a single
      oocyte is used to determine the diffusion and binding characteristics of the
      cellular cytoplasm. Subsequent double-cell calculations then yield the
      intercellular junction permeability, which is translated into a single-channel
      permeability using concomitant measurements of intercellular conductance, and
      known single-channel conductances of gap junctions made up of specific connexins,
      to count channels. The preceding strategy, combined with use of a graded size
      series of Alexa dyes, permits a determination of absolute values of gap
      junctional permeability as a function of dye size and connexin type.
      Interpretation of the results in terms of pore theory suggests significant levels
      of dye-pore affinity consistent with the expected order of magnitude of typical
      (e.g., van der Waals) intermolecular attractions.

PMID- 15041649
TI  - Membrane model for the G-protein-coupled receptor rhodopsin: hydrophobic
      interface and dynamical structure.
AB  - Rhodopsin is the only member of the pharmacologically important superfamily of G
      protein-coupled receptors with a known structure at atomic resolution. A
      molecular dynamics model of rhodopsin in a POPC phospholipid bilayer was
      simulated for 15 ns, revealing a conformation significantly different from the
      recent crystal structures. The structure of the bilayer compared with a protein
      free POPC control indicated hydrophobic matching with the nonpolar interface of
      the receptor, in agreement with deuterium NMR experiments. A new generalized
      molecular surface method, based on a three-dimensional Voronoi cell construction
      for atoms with different radii, was developed to quantify cross-sectional area
      profiles for the protein, lipid acyl chains and headgroups, and water. Thus, it
      was possible to investigate the bilayer deformation due to curvature of the
      individual lipid monolayers. Moreover, the generalized molecular surface derived
      hydrophobic interface allowed benchmarking of the hydropathy sequence analysis,
      an important structural genomics tool. Five water molecules diffused into
      internal hydration sites during the simulation, yielding a total of 12 internal
      waters. The cytoplasmic loops and the C-terminal tail, containing the G-protein
      recognition and protein sorting sequences, exhibited a high mobility, in marked
      contrast to the extracellular and transmembrane domains. The proposed functional
      coupling of the highly conserved ERY motif to the lipid-water interface via the
      cytoplasmic loops provides insight into lipid effects on G-protein-coupled
      receptor activation in terms of a flexible surface model, involving the
      spontaneous monolayer curvature.

PMID- 15041650
TI  - Concerted gating mechanism underlying KATP channel inhibition by ATP.
AB  - KATP channels assemble from four regulatory SUR1 and four pore-forming Kir6.2
      subunits. At the single-channel current level, ATP-dependent gating transitions
      between the active burst and the inactive interburst conformations underlie
      inhibition of the KATP channel by intracellular ATP. Previously, we identified a
      slow gating mutation, T171A in the Kir6.2 subunit, which dramatically reduces
      rates of burst to interburst transitions in Kir6.2DeltaC26 channels without SUR1
      in the absence of ATP. Here, we constructed all possible mutations at position
      171 in Kir6.2DeltaC26 channels without SUR1. Only four substitutions, 171A, 171F,
      171H, and 171S, gave rise to functional channels, each increasing Ki,ATP for ATP
      inhibition by >55-fold and slowing gating to the interburst by >35-fold.
      Moreover, we investigated the role of individual Kir6.2 subunits in the gating by
      comparing burst to interburst transition rates of channels constructed from
      different combinations of slow 171A and fast T171 "wild-type" subunits. The
      relationship between gating transition rate and number of slow subunits is
      exponential, which excludes independent gating models where any one subunit is
      sufficient for inhibition gating. Rather, our results support mechanisms where
      four ATP sites independently can control a single gate formed by the concerted
      action of all four Kir6.2 subunit inner helices of the KATP channel.

PMID- 15041651
TI  - Loss-of-function mutations at the rim of the funnel of mechanosensitive channel
      MscL.
AB  - MscL is a bacterial mechanosensitive channel that is activated directly by
      membrane stretch. Although the gene has been cloned and the crystal structure of
      the closed channel has been defined, how membrane tension causes conformational
      changes in MscL remains largely unknown. To identify the site where MscL senses
      membrane tension, we examined the function of the mutants generated by random and
      scanning mutagenesis. In vitro (patch-clamp) and in vivo (hypoosmotic-shock)
      experiments showed that when a hydrophilic amino acid replaces one of the
      hydrophobic residues that are thought to make contact with the membrane lipid
      near the periplasmic end of the M1 or M2 transmembrane domain, MscL loses the
      ability to open in response to membrane tension. Hydrophilic (asparagine)
      substitution of the other residues in the lipid-protein interface did not impair
      the channel's mechanosensitivity. These observations suggest that the disturbance
      of the hydrophobic interaction between the membrane lipid and the periplasmic rim
      of the channel's funnel impairs the function of MscL.

PMID- 15041652
TI  - The role of calsequestrin, triadin, and junctin in conferring cardiac ryanodine
      receptor responsiveness to luminal calcium.
AB  - The level of Ca inside the sarcoplasmic reticulum (SR) is an important
      determinant of functional activity of the Ca release channel/ryanodine receptor
      (RyR) in cardiac muscle. However, the molecular basis of RyR regulation by
      luminal Ca remains largely unknown. In the present study, we investigated the
      potential role of the cardiac SR luminal auxiliary proteins calsequestrin (CSQ),
      triadin 1, and junctin in forming the luminal calcium sensor for the cardiac RyR.
      Recordings of single RyR channels incorporated into lipid bilayers, from either
      SR vesicle or purified RyR preparations, were performed in the presence of MgATP
      using Cs+ as the charge carrier. Raising luminal [Ca] from 20 microM to 5 mM
      increased the open channel probability (Po) of native RyRs in SR vesicles, but
      not of purified RyRs. Adding CSQ to the luminal side of the purified channels
      produced no significant changes in Po, nor did it restore the ability of RyRs to
      respond to luminal Ca. When triadin 1 and junctin were added to the luminal side
      of purified channels, RyR Po increased significantly; however, the channels still
      remained unresponsive to changes in luminal [Ca]. In RyRs reassociated with
      triadin 1 and junctin, adding luminal CSQ produced a significant decrease in
      activity. After reassociation with all three proteins, RyRs responded to rises of
      luminal [Ca] by increasing their Po. These results suggest that a complex of CSQ,
      triadin 1, and junctin confer RyR luminal Ca sensitivity. CSQ apparently serves
      as a luminal Ca sensor that inhibits the channel at low luminal [Ca], whereas
      triadin 1 and/or junctin may be required to mediate interactions of CSQ with RyR.

PMID- 15041653
TI  - Purification and functional reconstitution of N- and C-halves of the MscL
      channel.
AB  - MscL is a mechanosensitive channel gated by membrane tension in the lipid bilayer
      alone. Its structure, known from x-ray crystallography, indicates that it is a
      homopentamer. Each subunit comprises two transmembrane segments TM1 and TM2
      connected by a periplasmic loop. The closed pore is lined by five TM1 helices. We
      expressed in Escherichia coli and purified two halves of the protein, each
      containing one of the transmembrane segments. Their electrophysiological activity
      was studied by the patch-clamp recording upon reconstitution in artificial
      liposomes. The TM2 moiety had no electrophysiological activity, whereas the TM1
      half formed channels, which were not affected by membrane tension and varied in
      conductance between 50 and 350 pS in 100 mM KCl. Coreconstitution of the two
      halves of MscL however, yielded mechanosensitive channels having the same
      conductance as the native MscL (1500 pS), but exhibiting increased sensitivity to
      pressure. Our results confirm the current view on the functional role of TM1 and
      TM2 helices in the MscL gating and emphasize the importance of helix-helix
      interactions for the assembly and functional properties of the channel protein.
      In addition, the results indicate a crucial role of the periplasmic loop for the
      channel mechanosensitivity.

PMID- 15041654
TI  - Functional influence of the pore helix glutamate in the KcsA K+ channel.
AB  - The E71 residue is buried near the selectivity filter in the KcsA K+ channel and
      forms a carboxyl-carboxylate bridge with D80. We have investigated the importance
      of E71 by examining neutralization mutants at this position using biochemical and
      electrophysiological methods. E71 mutations differentially destabilize the
      detergent-solubilized tetramer; among them, the E71V neutralization mutant has a
      relatively subtle effect. The E71V channel displays electrical activity when
      reconstituted into planar lipid bilayers. In single channel recordings, the
      mutant retains K+/Na+ selectivity, and its conductance in the outward direction
      is unaltered. Some conduction properties are changed: inward conductance is
      increased. Our results show that that the E71 side chain is not a primary
      determinant of ion selectivity or conduction in the wild-type channel, either
      directly or through the E71:D80 carboxyl-carboxylate bridge.

PMID- 15041656
TI  - Molecular dynamics simulations of hydrophilic pores in lipid bilayers.
AB  - Hydrophilic pores are formed in peptide free lipid bilayers under mechanical
      stress. It has been proposed that the transport of ionic species across such
      membranes is largely determined by the existence of such meta-stable hydrophilic
      pores. To study the properties of these structures and understand the mechanism
      by which pore expansion leads to membrane rupture, a series of molecular dynamics
      simulations of a dipalmitoylphosphatidylcholine (DPPC) bilayer have been
      conducted. The system was simulated in two different states; first, as a bilayer
      containing a meta-stable pore and second, as an equilibrated bilayer without a
      pore. Surface tension in both cases was applied to study the formation and
      stability of hydrophilic pores inside the bilayers. It is observed that below a
      critical threshold tension of approximately 38 mN/m the pores are stabilized. The
      minimum radius at which a pore can be stabilized is 0.7 nm. Based on the critical
      threshold tension the line tension of the bilayer was estimated to be
      approximately 3 x 10(-11) N, in good agreement with experimental measurements.
      The flux of water molecules through these stabilized pores was analyzed, and the
      structure and size of the pores characterized. When the lateral pressure exceeds
      the threshold tension, the pores become unstable and start to expand causing the
      rupture of the membrane. In the simulations the mechanical threshold tension
      necessary to cause rupture of the membrane on a nanosecond timescale is much
      higher in the case of the equilibrated bilayers, as compared with membranes
      containing preexisting pores.

PMID- 15041655
TI  - Potassium-dependent slow inactivation of Kir1.1 (ROMK) channels.
AB  - The ROMK (Kir1.1) family of epithelial K channels can be inactivated by a
      combination of low internal pH and low external K, such that alkalization does
      not reopen the channels unless external K is elevated. Previous work suggested
      that this inactivation results from an allosteric interaction between an inner pH
      gate and an outer K sensor, and could be described by a simple three-state
      kinetic model. In the present study, we report that a sustained depolarization
      slowly inactivated (half-time = 10-15 min) ROMK channels that had been engineered
      for increased affinity to internal polyamines. Furthermore, this inactivation
      occurred at external [K] < or =1 mM in ROMK mutants whose inner pH gate was
      constitutively open (ROMK2-K61M mutation). Both pH and voltage inactivation
      depended on external K in a manner reminiscent of C-type inactivation, but having
      a much slower time course. Replacement of ROMK extracellular loop residues by
      Kir2.1 homologous residues attenuated or abolished this inactivation. These
      results are consistent with the hypothesis that there are (at least) two separate
      closure processes in these channels: an inner pH-regulated gate, and an outer
      (inactivation) gate, where the latter is modulated by both voltage and external
      [K].

PMID- 15041657
TI  - Increased concentration of polyvalent phospholipids in the adsorption domain of a
      charged protein.
AB  - We studied the adsorption of a charged protein onto an oppositely charged
      membrane, composed of mobile phospholipids of differing valence, using a
      statistical-thermodynamical approach. A two-block model was employed, one block
      corresponding to the protein-affected region on the membrane, referred to as the
      adsorption domain, and the other to the unaffected remainder of the membrane. We
      calculated the protein-induced lipid rearrangement in the adsorption domain as
      arising from the interplay between the electrostatic interactions in the system
      and the mixing entropy of the lipids. Equating the electrochemical potentials of
      the lipids in the two blocks yields an expression for the relations among the
      various lipid fractions in the adsorption domain, indicating a sensitive
      dependence of lipid fraction on valence. This expression is a result of the two
      block picture but does not depend on further details of the protein-membrane
      interaction. We subsequently calculated the lipid fractions themselves using the
      Poisson-Boltzmann theory. We examined the dependence of lipid enrichment, i.e.,
      the ratio between the lipid fractions inside and outside the adsorption domain,
      on various parameters such as ionic strength and lipid valence. Maximum
      enrichment was found for lipid valence in the range between -3 and -4 in
      physiological conditions. Our results are in qualitative agreement with recent
      experimental studies on the interactions between peptides having a domain of
      basic residues and membranes containing a small fraction of the polyvalent
      phosphatidylinositol 4,5-bisphosphate (PIP2). This study provides theoretical
      support for the suggestion that proteins adsorbed onto membranes through a
      cluster of basic residues may sequester PIP2 and other polyvalent lipids.

PMID- 15041658
TI  - Giant lipid vesicles filled with a gel: shape instability induced by osmotic
      shrinkage.
AB  - We report the properties of giant lipid vesicles enclosing an agarose gel. In
      this system, the lipid bilayer retains some basic properties of biological
      membranes and the internal fluid exhibits viscoelastic properties, thus
      permitting us to address the question of the deformation of a cell membrane in
      relation to the mechanical properties of its cytoskeleton. The agarose gel
      (concentration c0gel = 0.07%, 0.18%, 0.36%, and 1% w/w), likely not anchored to
      the membrane, confers to the internal volume elastic moduli in the range of 10
      10(4) Pa. Shapes and kinetics of de-swelling of gel-filled and aqueous solution
      filled vesicles are compared upon either a progressive or a fast osmotic
      shrinkage. Both systems exhibit similar kinetics. Shapes of solution-filled
      vesicles are well described using the area difference elasticity model, whereas
      gel-filled vesicles present original patterns: facets, bumps, spikes (c0gel <
      0.36%), or wrinkles (c0gel > or = 0.36%). These shapes partially vanish upon re
      swelling, and some of them are reminiscent of echinocytic shapes of erythrocytes.
      Their characteristic size (microns) decreases upon increasing c0gel. A possible
      origin of these patterns, relying on the formation of a dense impermeable gel
      layer at the vesicle surface and associated with a transition toward a collapsed
      gel phase, is advanced.

PMID- 15041660
TI  - Characterization of a quasicrystalline phase in codispersions of
      phosphatidylethanolamine and glucocerebroside.
AB  - Synchrotron x-ray diffraction, differential scanning calorimetry, and electron
      spin resonance spectroscopy have been employed to characterize a quasicrystalline
      phase formed in aqueous dispersions of binary mixtures of glucocerebroside and
      palmitoyloleoylphosphatidylethanolamine. Small- and wide-angle x-ray scattering
      intensity patterns were recorded during temperature scans between 20 degrees and
      90 degrees C from mixtures of composition 2, 5, 10, 20, 30, and 40 mol
      glucocerebroside per 100 mol phospholipid. The quasicrystalline phase was
      characterized by a broad lamellar d-spacing of 6.06 nm at 40 degrees C and a
      broad wide-angle x-ray scattering band centered at approximately 0.438 nm, close
      to the gel phase centered at approximately 0.425 nm and distinct from a broad
      peak centered at 0.457 nm observed for a liquid-crystal phase at 80 degrees C.
      The quasicrystalline phase coexisted with gel and fluid phase of the pure
      phospholipid. An analysis of the small-angle x-ray scattering intensity profiles
      indicated a stoichiometry of one glucosphingolipid per two phospholipid molecules
      in the complex. Structural transitions monitored in cooling scans by synchrotron
      x-ray diffraction indicated that a cubic phase transforms initially into a
      lamellar gel. Thermal studies showed that the gel phase subsequently relaxes into
      the quasicrystalline phase in an exothermic transition. Electron spin resonance
      spectroscopy using spin labels located at positions 7, 12, and 16 carbons of
      phospholipid hydrocarbon chains indicated that order and motional constraints at
      the 7 and 12 positions were indistinguishable between gel and quasicrystalline
      phases but there was a significant decrease in order and increase in rate of
      motion at the 16 position on transformation to the quasicrystalline phase. The
      results are interpreted as an arrangement of polar groups of the complex in a
      crystalline array and a quasicrystalline packing of the hydrocarbon chains
      predicated by packing problems in the bilayer core requiring disordering of the
      highly asymmetric chains. The possible involvement of quasicrystalline phases in
      formation of membrane rafts is considered.

PMID- 15041661
TI  - Temperature dependence of the surface topography in
      dimyristoylphosphatidylcholine/distearoylphosphatidylcholine multibilayers.
AB  - Simple lipid binary systems are intensively used to understand the formation of
      domains in biological membranes. The size of individual domains present in the
      gel/fluid coexistence region of single supported bilayers, determined by atomic
      force microscopy (AFM), generally exceeds by two to three orders of magnitude
      that estimated from multibilayers membranes by indirect spectroscopic methods. In
      this article, the topography of equimolar
      dimyristoylphosphatidylcholine/distearoylphosphatidylcholine (DMPC/DSPC)
      multibilayers, made of two superimposed bilayers supported on mica surface, was
      studied by AFM in a temperature range from room temperature to 45 degrees C. In
      the gel/fluid phase coexistence region the size of domains, between approximately
      100 nm and a few micrometers, was of the same order for the first bilayer facing
      the mica and the top bilayer facing the buffer. The gel to fluid phase separation
      temperature of the first bilayer, however, could be increased by up to 8 degrees
      C, most likely as a function of the buffer layer thickness that separated it from
      the mica. Topography of the top bilayer revealed the presence of lipids in ripple
      phase up to 38-40 degrees C. Above this temperature, a pattern characteristic of
      the coexistence of fluid and gel domains was observed. These data show that
      difference in the size of lipid domains given by AFM and spectroscopy can hardly
      be attributed to the use of multibilayers models in spectroscopy experiments.
      They also provide a direct evidence for metastable ripple phase transformation
      into a gel/fluid phase separated structure upon heating.

PMID- 15041659
TI  - Electrostatic sequestration of PIP2 on phospholipid membranes by basic/aromatic
      regions of proteins.
AB  - The basic effector domain of myristoylated alanine-rich C kinase substrate
      (MARCKS), a major protein kinase C substrate, binds electrostatically to acidic
      lipids on the inner leaflet of the plasma membrane; interaction with
      Ca2+/calmodulin or protein kinase C phosphorylation reverses this binding. Our
      working hypothesis is that the effector domain of MARCKS reversibly sequesters a
      significant fraction of the L-alpha-phosphatidyl-D-myo-inositol 4,5-bisphosphate
      (PIP2) on the plasma membrane. To test this, we utilize three techniques that
      measure the ability of a peptide corresponding to its effector domain, MARCKS(151
      175), to sequester PIP2 in model membranes containing physiologically relevant
      fractions (15-30%) of the monovalent acidic lipid phosphatidylserine. First, we
      measure fluorescence resonance energy transfer from Bodipy-TMR-PIP2 to Texas Red
      MARCKS(151-175) adsorbed to large unilamellar vesicles. Second, we detect
      quenching of Bodipy-TMR-PIP2 in large unilamellar vesicles when unlabeled
      MARCKS(151-175) binds to vesicles. Third, we identify line broadening in the
      electron paramagnetic resonance spectra of spin-labeled PIP2 as unlabeled
      MARCKS(151-175) adsorbs to vesicles. Theoretical calculations (applying the
      Poisson-Boltzmann relation to atomic models of the peptide and bilayer) and
      experimental results (fluorescence resonance energy transfer and quenching at
      different salt concentrations) suggest that nonspecific electrostatic
      interactions produce this sequestration. Finally, we show that the PLC-delta1
      catalyzed hydrolysis of PIP2, but not binding of its PH domain to PIP2, decreases
      markedly as MARCKS(151-175) sequesters most of the PIP2.

PMID- 15041662
TI  - Effect of sterols on beta-amyloid peptide (AbetaP 1-40) channel formation and
      their properties in planar lipid membranes.
AB  - We investigate the role played by membrane composition on the interaction and
      self-assembly of beta-amyloid peptide (AbetaP1-40) during pore formation in
      planar lipid membranes (PLMs). Incorporation studies showed that AbetaP does not
      interact with zwitterionic membranes made up of phosphatidylcholine, whereas the
      addition of cholesterol or ergosterol to the membranes leads to channel
      formation. Among the PLMs used, a higher propensity of AbetaP to form channels at
      low applied potential (+/-20 mV) was observed in 7-dehydrocholesterol and in
      oxidized cholesterol PLMs. These channels present long lifetimes, high-occurrence
      frequencies, and are voltage dependent. In particular, the AbetaP channel in
      oxidized cholesterol showed anion selectivity. Thus cholesterol (and sterols in
      general) could be considered as targets for AbetaP, which prevents the
      fibrillation process by increasing incorporation into membranes. Furthermore, by
      switching the channel selectivity versus anions, cholesterol helps to reduce the
      imbalance of the cellular ions, calcium included, induced by membrane
      depolarization, which could be one of the factors responsible for cytotoxicity in
      Alzheimer's disease.

PMID- 15041663
TI  - The external K+ concentration and mutations in the outer pore mouth affect the
      inhibition of kv1.5 current by Ni2+.
AB  - By examining the consequences both of changes of [K+]o and of point mutations in
      the outer pore mouth, our goal was to determine if the mechanism of the block of
      Kv1.5 ionic currents by external Ni2+ is similar to that for proton block. Ni2+
      block is inhibited by increasing [K+]o, by mutating a histidine residue in the
      pore turret (H463Q) or by mutating a residue near the pore mouth (R487V) that is
      the homolog of Shaker T449. Aside from a slight rightward shift of the Q-V curve,
      Ni2+ had no effect on gating currents. We propose that, as with Ho+, Ni2+ binding
      to H463 facilitates an outer pore inactivation process that is antagonized by Ko+
      and that requires R487. However, whereas Ho+ substantially accelerates
      inactivation of residual currents, Ni2+ is much less potent, indicating
      incomplete overlap of the profiles of these two metal ions. Analyses with Co2+
      and Mn2+, together with previous results, indicate that for the first-row
      transition metals the rank order for the inhibition of Kv1.5 in 0 mM Ko+ is Zn2+
      (KD approximately 0.07 mM) > or = Ni2+) (KD approximately 0.15 mM) > Co2+ (KD
      approximately 1.4 mM) > Mn2+ (KD > 10 mM).

PMID- 15041664
TI  - Divalent cations increase lipid order in erythrocytes and susceptibility to
      secretory phospholipase A2.
AB  - Elevated concentrations of intracellular calcium in erythrocytes increase
      membrane order and susceptibility to secretory phospholipase A2. We hypothesize
      that calcium aids the formation of domains of ordered lipids within erythrocyte
      membranes by interacting directly with the inner leaflet of the cell membrane.
      The interface of these domains with regions of more fluid lipids may create an
      environment with weakened neighbor-neighbor interactions that would facilitate
      phospholipid migration into the active site of bound secretory phospholipase A2.
      This hypothesis was investigated by determining the effects of seven other
      divalent ions on erythrocyte membrane properties. Changes in membrane order were
      assessed with steady-state fluorescence spectroscopy and two-photon microscopy
      with an environment-sensitive probe, laurdan. Each ion increased apparent
      membrane order in model membranes and in erythrocytes when introduced with an
      ionophore, suggesting that direct binding to the inner face of the membrane
      accounts for the effects of calcium on membrane fluidity. Furthermore, the degree
      to which ions affected membrane properties correlated with the ionic radius and
      electronegativity of the ions. Lastly, erythrocytes became more susceptible to
      enzyme hydrolysis in the presence of elevated intracellular levels of nickel and
      manganese, but not magnesium. These differences appeared related to the ability
      of the ions to induce a transition in erythrocyte shape.

PMID- 15041665
TI  - Cholesterol modulates the organization of the gammaM4 transmembrane domain of the
      muscle nicotinic acetylcholine receptor.
AB  - A 28-mer gammaM4 peptide, obtained by solid-state synthesis and corresponding to
      the fourth transmembrane segment of the nicotinic acetylcholine receptor gamma
      subunit, possesses a single tryptophan residue (Trp453), making it an excellent
      model for studying peptide-lipid interactions in membranes by fluorescence
      spectroscopy. The gammaM4 peptide was reconstituted with synthetic lipids
      (vesicles of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, i.e., POPC) rich
      and poor in cholesterol and analyzed using steady-state and time-resolved
      fluorescence techniques. The decrease in gammaM4 intrinsic fluorescence lifetime
      observed upon incorporation into a cholesterol-rich lo phase could be
      rationalized on the basis of a dynamic self-quenching owing to the formation of
      peptide-rich patches in the membrane. This agrees with the low Forster type
      resonance energy transfer efficiency from the Trp453 residue to the fluorescent
      cholesterol analog, dehydroergosterol, in the lo phase. In the absence of
      cholesterol the gammaM4 nicotinic acetylcholine receptor peptide is randomly
      distributed in the POPC bilayer with its hydrophobic moiety matching the membrane
      thickness, whereas in the presence of cholesterol the increase in the membrane
      thickness and variation of the material properties favor the formation of peptide
      enriched patches, i.e., interhelix interaction energy is essential for obtaining
      a stabilized structure. Thus, the presence of a cholesterol-rich, ordered POPC
      phase drives the organization of peptide-enriched patches, in which the gammaM4
      peptide occupies approximately 30% of the patch area.

PMID- 15041667
TI  - X-ray diffraction from a left ventricular wall of rat heart.
AB  - We studied x-ray diffraction from the left ventricular wall of an excised,
      perfused whole heart of a rat using x rays from the third-generation synchrotron
      radiation facility, SPring-8. With the beam at right angles to the long axis of
      the left ventricle, well-oriented, strong equatorial reflections were observed
      from the epicardium surface. The reflections became vertically split arcs when
      the beam passed through myocardium deeper in the wall, and rings were observed
      when the beam passed into the inner myocardium of the wall. These diffraction
      patterns were explained by employing a layered-spiral model of the arrangement of
      muscle fibers in the heart. In a quiescent heart with an expanded left ventricle,
      the muscle fibers at the epicardium surface were found to have a (1,0) lattice
      spacing smaller than in the rest of the wall. The intensity ratio of the (1,0)
      and (1,1) equatorial reflections decreased on contraction with a similar time
      course in all parts of the wall. The results show that it is possible to assign
      the origin of reflections in a diffraction diagram from a whole heart. This study
      offers a basis for interpretation of x-ray diffraction from a beating heart under
      physiologically and pathologically different conditions.

PMID- 15041666
TI  - Interaction of the disaccharide trehalose with a phospholipid bilayer: a
      molecular dynamics study.
AB  - The disaccharide trehalose is well known for its bioprotective properties.
      Produced in large amounts during stress periods in the life of organisms able to
      survive potentially damaging conditions, trehalose plays its protective role by
      stabilizing biostructures such as proteins and lipid membranes. In this study,
      molecular dynamics simulations are used to investigate the interaction of
      trehalose with a phospholipid bilayer at atomistic resolution. Simulations of the
      bilayer in the absence and in the presence of trehalose at two different
      concentrations (1 or 2 molal) are carried out at 325 K and 475 K. The results
      show that trehalose is able to minimize the disruptive effect of the elevated
      temperature and stabilize the bilayer structure. At both temperature, trehalose
      is found to interact directly with the bilayer through hydrogen bonds. However,
      the water molecules at the bilayer surface are not completely replaced. At high
      temperature, the protective effect of trehalose is correlated with a significant
      increase in the number of trehalose-bilayer hydrogen bonds, predominantly through
      an increase in the number of trehalose molecules bridging three or more lipid
      molecules.

PMID- 15041668
TI  - Myosin-induced movement of alphaalpha, alphabeta, and betabeta smooth muscle
      tropomyosin on actin observed by multisite FRET.
AB  - The interaction of the alphaalpha, betabeta, and alphabeta smooth muscle
      tropomyosin (Tm) isoforms with F-actin was systematically studied in the absence
      and in the presence of myosin subfragment 1 (S1) using multifrequency
      phase/modulation Forster resonance energy transfer (FRET). A Gaussian double
      distance distribution model was adopted to fit FRET data between a 5-(2
      iodoacetyl-amino-ethyl-amino)naphthalene-1-sulfonic acid donor at either Cys-36
      of the beta-chain or Cys-190 of the alpha-chain and a 4
      dimethylaminophenylazophenyl 4'-maleimide acceptor at Cys-374 of F-actin.
      Experimental data were obtained for singly and doubly labeled alphabeta Tm (donor
      only at alpha, only at beta, or both) and for doubly labeled alphaalpha or
      betabeta Tm. Data for singly labeled alphabetaTm were combined in a global
      analysis with doubly labeled alphabetaTm. In all doubly labeled isoforms, upon S1
      binding, one donor-acceptor "apparent" distance increased slightly by 0.5-2 A,
      whereas the other decreased by 6-9 A. These changes are consistent with a uniform
      "rolling" motion of Tm over the F-actin surface. The analysis indicates that Tm
      occupies relatively well-defined positions, with some flexibility, in both the
      predominantly closed (-S1) and open (+S1) thin-filament states. The results for
      the alphabetaTm heterodimer indicate that the local twofold symmetry of
      alphaalpha or betabeta Tm is effectively broken in alphabetaTm bound to F-actin,
      which implies a difference between the alpha- and beta-chains in terms of their
      interaction with F-actin.

PMID- 15041669
TI  - Changes in orientation of actin during contraction of muscle.
AB  - It is well documented that muscle contraction results from cyclic rotations of
      actin-bound myosin cross-bridges. The role of actin is hypothesized to be limited
      to accelerating phosphate release from myosin and to serving as a rigid substrate
      for cross-bridge rotations. To test this hypothesis, we have measured actin
      rotations during contraction of a skeletal muscle. Actin filaments of rabbit
      psoas fiber were labeled with rhodamine-phalloidin. Muscle contraction was
      induced by a pulse of ATP photogenerated from caged precursor. ATP induced a
      single turnover of cross-bridges. The rotations were measured by anisotropy of
      fluorescence originating from a small volume defined by a narrow aperture of a
      confocal microscope. The anisotropy of phalloidin-actin changed rapidly at first
      and was followed by a slow relaxation to a steady-state value. The kinetics of
      orientation changes of actin and myosin were the same. Extracting myosin
      abolished anisotropy changes. To test whether the rotation of actin was imposed
      by cross-bridges or whether it reflected hydrolytic activity of actin itself, we
      labeled actin with fluorescent ADP. The time-course of anisotropy change of
      fluorescent nucleotide was similar to that of phalloidin-actin. These results
      suggest that orientation changes of actin are caused by dissociation and
      rebinding of myosin cross-bridges, and that during contraction, nucleotide does
      not dissociate from actin.

PMID- 15041670
TI  - Myosin regulatory light chain phosphorylation and strain modulate adenosine
      diphosphate release from smooth muscle Myosin.
AB  - The effects of myosin regulatory light chain (RLC) phosphorylation and strain on
      adenosine diphosphate (ADP) release from cross-bridges in phasic (rabbit bladder
      (Rbl)) and tonic (femoral artery (Rfa)) smooth muscle were determined by
      monitoring fluorescence transients of the novel ADP analog, 3'-deac-eda-ADP (deac
      edaADP). Fluorescence transients reporting release of 3'-deac-eda-ADP were
      significantly faster in phasic (0.57 +/- 0.06 s(-1)) than tonic (0.29 +/- 0.03 s(
      1)) smooth muscles. Thiophosphorylation of regulatory light chains increased and
      strain decreased the release rate approximately twofold. The calculated (k
      ADP/k+ADP) dissociation constant, Kd of unstrained, unphosphorylated cross
      bridges for ADP was 0.6 microM for rabbit bladder and 0.3 microM for femoral
      artery. The rates of ADP release from rigor bridges and reported values of Pi
      release (corresponding to the steady-state adenosine triphosphatase (ATPase) rate
      of actomyosin (AM)) from cross-bridges during a maintained isometric contraction
      are similar, indicating that the ADP-release step or an isomerization preceding
      it may be limiting the adenosine triphosphatase rate. We conclude that the strain
      and dephosphorylation-dependent high affinity for and slow ADP release from
      smooth muscle myosin prolongs the fraction of the duty cycle occupied by strongly
      bound actomyosin.ADP state(s) and contributes to the high economy of force.

PMID- 15041671
TI  - Bifunctional rhodamine probes of Myosin regulatory light chain orientation in
      relaxed skeletal muscle fibers.
AB  - The orientation of the regulatory light chain (RLC) region of the myosin heads in
      relaxed skinned fibers from rabbit psoas muscle was investigated by polarized
      fluorescence from bifunctional rhodamine (BR) probes cross-linking pairs of
      cysteine residues introduced into the RLC. Pure 1:1 BR-RLC complexes were
      exchanged into single muscle fibers in EDTA rigor solution for 30 min at 30
      degrees C; approximately 60% of the native RLC was removed and stoichiometrically
      replaced by BR-RLC, and >85% of the BR-RLC was located in the sarcomeric A-bands.
      The second- and fourth-rank order parameters of the orientation distributions of
      BR dipoles linking RLC cysteine pairs 100-108, 100-113, 108-113, and 104-115 were
      calculated from polarized fluorescence intensities, and used to determine the
      smoothest RLC orientation distribution-the maximum entropy distribution
      consistent with the polarized fluorescence data. Maximum entropy distributions in
      relaxed muscle were relatively broad. At the peak of the distribution, the
      "lever" axis, linking Cys707 and Lys843 of the myosin heavy chain, was at 70-80
      degrees to the fiber axis, and the "hook" helix (Pro830-Lys843) was almost
      coplanar with the fiber and lever axes. The temperature and ionic strength of the
      relaxing solution had small but reproducible effects on the orientation of the
      RLC region.

PMID- 15041672
TI  - Chlamydomonas sensory rhodopsins A and B: cellular content and role in
      photophobic responses.
AB  - Two retinylidene proteins, CSRA and CSRB, have recently been shown by
      photoelectrophysiological analysis of RNAi-transformants to mediate phototaxis
      signaling in Chlamydomonas reinhardtii. Here we report immunoblot detection of
      CSRA and CSRB apoproteins in C. reinhardtii cells enabling assessment of the
      cellular content of the receptors. We obtain 9 x 10(4) CSRA and 1.5 x 10(4) CSRB
      apoprotein molecules per cell in vegetative cells of the wild-type strain 495, a
      higher value than that for functional receptor cellular content estimated
      previously from photosensitivity measurements and retinal extraction yields.
      Exploiting our ability to control the CSRA/CSRB ratio by transformation with
      receptor gene-directed RNAi, we report analysis of the CSRA and CSRB roles in the
      photophobic response of the organism by action spectroscopy with automated cell
      tracking/motion analysis. The results show that CSRA and CSRB each mediate the
      photophobic swimming response, a second known retinal-dependent photomotility
      behavior in C. reinhardtii. Due to the different light saturation and spectral
      properties of the two receptors, CSRA is dominantly responsible for photophobic
      responses, which appear at high light intensity.

PMID- 15041673
TI  - Ultrafast conformational dynamics in cyclic azobenzene peptides of increased
      flexibility.
AB  - Structural changes of peptides containing the azobenzene dye 4-aminomethyl
      phenylazobenzoic acid (AMPB) are studied with ultrafast spectroscopy. AMPB
      peptides are a new class of molecules where the photoisomerizable dye azobenzene
      is linked to the peptide moiety via a flexible methylene spacer. The ultrafast
      reactions in the femtosecond to nanosecond time domain are investigated for the
      optical switch AMPB, a linear and cyclic octapeptide, and a bicyclic octapeptide
      containing an additional disulfide bridge. These molecules with increasing
      conformational constraints are studied for the cis to trans and the trans to cis
      photoreactions. For the cis to trans reaction the isomerization of the
      chromophore occurs fast in the 1-ps range, whereas it is slower (10-ps range) in
      the trans to cis reaction. In all peptides the structural changes of the
      chromophore lead to modifications in the peptide structure in the 10-ps-1-ns time
      range. The results indicate that the chromophore AMPB acts simultaneously as a
      fast molecular switch and as a sensor for initial conformational dynamics in the
      peptide. Experiments in the mid-infrared range where the structural changes of
      the peptide backbone are directly observed demonstrate that the essential part of
      the structural dynamics in the bicyclic AMPB peptide occurs faster than 10 ns.

PMID- 15041674
TI  - In vitro self-assembly of the light harvesting pigment-protein LH2 revealed by
      ultrafast spectroscopy and electron microscopy.
AB  - Controlled ensemble formation of protein-surfactant systems provides a
      fundamental concept for the realization of nanoscale devices with self-organizing
      capability. In this context, spectroscopic monitoring of pigment-containing
      proteins yields detailed structural information. Here we have studied the
      association behavior of the bacterial light-harvesting protein LH2 from
      Rhodobacter spheroides in an n,n-dimethyldodecylamine-n-oxide/water environment.
      Time-resolved studies of the excitation annihilation yielded information about
      aggregate sizes and packing of the protein complexes therein. The results are
      compared to transmission electron microscopy images of instantaneously frozen
      samples. Our data indicate the manifestation of different phases, which are
      discussed with respect to the thermodynamic equilibrium in ternary protein
      surfactant-water systems. Accordingly, by varying the concentration the formation
      of different types of aggregates can be controlled. Conditions for the appearance
      of isolated LH2 complexes are defined.

PMID- 15041675
TI  - Time-resolved resonance raman structural studies of the pB' intermediate in the
      photocycle of photoactive yellow protein.
AB  - Time-resolved resonance Raman spectroscopy is used to obtain chromophore
      vibrational spectra of the pR, pB', and pB intermediates during the photocycle of
      photoactive yellow protein. In the pR spectrum, the C8-C9 stretching mode at 998
      cm(-1) is approximately 60 cm(-1) lower than in the dark state, and the
      combination of C-O stretching and C7H=C8H bending at 1283 cm(-1) is insensitive
      to D2O substitution. These results indicate that pR has a deprotonated, cis
      chromophore structure and that the hydrogen bonding to the chromophore phenolate
      oxygen is preserved and strengthened in the early photoproduct. However, the
      intense C7H=C8H hydrogen out-of-plane (HOOP) mode at 979 cm(-1) suggests that the
      chromophore in pR is distorted at the vinyl and adjacent C8-C9 bonds. The
      formation of pB' involves chromophore protonation based on the protonation state
      marker at 1174 cm(-1) and on the sensitivity of the COH bending at 1148 cm(-1) as
      well as the combined C-OH stretching and C7H=C8H bending mode at 1252 cm(-1) to
      D2O substitution. The hydrogen out-of-plane Raman intensity at 985 cm(-1)
      significantly decreases in pB', suggesting that the pR-to-pB' transition is the
      stage where the stored photon energy is transferred from the distorted
      chromophore to the protein, producing a more relaxed pB' chromophore structure.
      The C=O stretching mode downshifts from 1660 to 1651 cm(-1) in the pB'-to-pB
      transition, indicating the reformation of a hydrogen bond to the carbonyl oxygen.
      Based on reported x-ray data, this suggests that the chromophore ring flips
      during the transition from pB' to pB. These results confirm the existence and
      importance of the pB' intermediate in photoactive yellow protein receptor
      activation.

PMID- 15041676
TI  - Dynamic properties of the N-terminal swapped dimer of ribonuclease A.
AB  - Bovine pancreatic ribonuclease (RNase A) forms two 3-dimensional domain-swapped
      dimers with different quaternary structures. One dimer is characterized by the
      swapping of the C-terminal region (C-Dimer) and presents a rather loose
      structure. The other dimer (N-Dimer) exhibits a very compact structure with
      exchange of the N-terminal helix. Here we report the results of a molecular
      dynamics/essential dynamics (MD/ED) study carried out on the N-Dimer. This
      investigation, which represents the first MD/ED analysis on a three-dimensional
      domain-swapped enzyme, provides information on the dynamic properties of the
      active site residues as well as on the global motions of the dimer subunits. In
      particular, the analysis of the flexibility of the active site residues agrees
      well with recent crystallographic and site-directed mutagenesis studies on
      monomeric RNase A, thus indicating that domain swapping does not affect the
      dynamics of the active sites. A slight but significant rearrangement of N-Dimer
      quaternary structure, favored by the formation of additional hydrogen bonds at
      subunit interface, has been observed during the MD simulation. The analysis of
      collective movements reveals that each subunit of the dimer retains the
      functional breathing motion observed for RNase A. Interestingly, the breathing
      motion of the two subunits is dynamically coupled, as they open and close in
      phase. These correlated motions indicate the presence of active site
      intercommunications in this dimer. On these bases, we propose a speculative
      mechanism that may explain negative cooperativity in systems preserving
      structural symmetry during the allosteric transitions.

PMID- 15041677
TI  - Conformational transitions in beta-lactoglobulin induced by cationic amphiphiles:
      equilibrium studies.
AB  - The conformational transition from the native state in water ("beta-state") to a
      state containing a considerable amount of alpha-helices ("alpha-state") was
      studied for the protein beta-lactoglobulin (BLG), from bovine milk, in several
      colloidal solutions containing mixed micelles or spontaneous vesicles. These
      aggregates were formed in the bicationic system containing the surfactant
      dodecyltrimethylammonium chloride (DTAC) and the lipid didodecyldimethylammonium
      bromide (DDAB). The beta-->alpha transition in BLG, investigated by far
      ultraviolet circular dichroism spectroscopy, is induced to the same protein alpha
      state by pure and mixed DDAB/DTAC micelles or vesicles. This implies a similar
      interaction mechanism of BLG with DDAB or DTAC, once the colloidal aggregates are
      formed. In premicelle DTAC solutions, the fraction of alpha-helix is lower and
      increases with the DTAC concentration. DDAB and DTAC also promote conformational
      changes in the protein tertiary structure that expose the tryptophans to a less
      constrained environment. These unfolding transitions were investigated by near
      ultraviolet circular dichroism and steady-state fluorescence spectroscopies. In
      equilibrium conditions, it was found that higher DTAC (and, probably, DDAB)
      concentrations are needed to induce the beta-->alpha transition than to unfold
      the protein. beta-Lactoglobulin may therefore be considered as a model for
      protein-surfactant and protein-lipid interactions.

PMID- 15041678
TI  - Detection and characterization of partially unfolded oligomers of the SH3 domain
      of alpha-spectrin.
AB  - For the purpose of equilibrium and kinetic folding-unfolding studies, the SH3
      domain of alpha-spectrin (spc-SH3) has long been considered a classic two-state
      folding protein. In this work we have indeed observed that the thermal unfolding
      curves of spc-SH3 measured at pH 3.0 by differential scanning calorimetry,
      circular dichroism, and NMR follow apparently the two-state model when each
      unfolding profile is considered individually. Nevertheless, we have found that
      protein concentration has a marked effect upon the thermal unfolding profiles.
      This effect cannot be properly explained in terms of the two-state unfolding
      model and can only be interpreted in terms of the accumulation of intermediate
      associated states in equilibrium with the monomeric native and unfolded states.
      By chemical cross-linking and pulsed-field gradient NMR diffusion experiments we
      have been able to confirm the existence of associated states formed during spc
      SH3 unfolding. A three-state model, in which a dimeric intermediate state is
      assumed to be significantly populated, provides the simplest interpretation of
      the whole set of thermal unfolding data and affords a satisfactory explanation
      for the concentration effects observed. Whereas at low concentrations the
      population of the associated intermediate state is negligible and the unfolding
      process consequently takes place in a two-state fashion, at concentrations above
      approximately 0.5 mM the population of the intermediate state becomes significant
      at temperatures between 45 degrees C and 80 degrees C and reaches up to 50% at
      the largest concentration investigated. The thermodynamic properties of the
      intermediate state implied by this analysis fall in between those of the unfolded
      state and the native ones, indicating a considerably disordered conformation,
      which appears to be stabilized by oligomerization.

PMID- 15041679
TI  - The efficiency of different salts to screen charge interactions in proteins: a
      Hofmeister effect?
AB  - Understanding the screening by salts of charge-charge interactions in proteins is
      important for at least two reasons: a), screening by intracellular salt
      concentration may modulate the stability and interactions of proteins in vivo;
      and b), the in vitro experimental estimation of the contributions from charge
      charge interactions to molecular processes involving proteins is generally
      carried out on the basis of the salt effect on process energetics, under the
      assumption that these interactions are screened out by moderate salt
      concentrations. Here, we explore experimentally the extent to which the screening
      efficiency depends on the nature of the salt. To this end, we have carried out an
      energetic characterization of the effect of NaCl (a nondenaturing salt),
      guanidinium chloride (a denaturing salt), and guanidinium thiocyanate (a stronger
      denaturant) on the stability of the wild-type form and a T14K variant of
      Escherichia coli thioredoxin. Our results suggest that the efficiency of
      different salts to screen charge-charge interactions correlates with their
      denaturing strength and with the position of the constituent ions in the
      Hofmeister rankings. This result appears consistent with the plausible relation
      of the Hofmeister rankings with the extent of solute accumulation/exclusion from
      protein surfaces.

PMID- 15041681
TI  - Probing the Q-proton pathway of ba3-cytochrome c oxidase by time-resolved Fourier
      transform infrared spectroscopy.
AB  - In cytochrome c oxidase, the terminal respiratory enzyme, electron transfers are
      strongly coupled to proton movements within the enzyme. Two proton pathways (K
      and D) containing water molecules and hydrophobic amino acids have been
      identified and suggested to be involved in the proton translocation from the
      mitochondrial matrix or the bacterial cytoplasm into the active site. In addition
      to the K and D proton pathways, a third proton pathway (Q) has been identified
      only in ba3-cytochrome c oxidase from Thermus thermophilus, and consists of
      residues that are highly conserved in all structurally known heme-copper
      oxidases. The Q pathway starts from the cytoplasmic side of the membrane and
      leads through the axial heme a3 ligand His-384 to the propionate of the heme a3
      pyrrol ring A, and then via Asn-366 and Asp-372 to the water pool. We have
      applied FTIR and time-resolved step-scan Fourier transform infrared (TRS2-FTIR)
      spectroscopies to investigate the protonation/deprotonation events in the Q
      proton pathway at ambient temperature. The photolysis of CO from heme a3 and its
      transient binding to CuB is dynamically linked to structural changes that can be
      tentatively attributed to ring A propionate of heme a3 (1695/1708 cm(-1)) and to
      deprotonation of Asp-372 (1726 cm(-1)). The implications of these results with
      respect to the role of the ring A propionate of heme a3-Asp372-H2O site as a
      proton carrier to the exit/output proton channel (H2O pool) that is conserved
      among all structurally known heme-copper oxidases, and is part of the Q-proton
      pathway in ba3-cytochrome c oxidase, are discussed.

PMID- 15041680
TI  - Force spectroscopy of the double-tethered concanavalin-A mannose bond.
AB  - We present the measurement of the force required to rupture a single protein
      sugar bond using a methodology that provides selective discrimination between
      specific and nonspecific binding events and helps verify the presence of a single
      functional molecule on the atomic force microscopy tip. In particular, the
      interaction force between a polymer-tethered concanavalin-A protein (ConA) and a
      similarly tethered mannose carbohydrate was measured as 47 +/- 9 pN at a bond
      loading rate of approximately 10 nN/s. Computer simulations of the polymer
      molecular configurations were used to determine the angles that the polymers
      could sweep out during binding and, in conjunction with mass spectrometry, used
      to separate the angular effects from the effects due to a distribution of tether
      lengths. We find that when using commercially available polymer tethers that vary
      in length from 19 to 29 nm, the angular effects are relatively small and the
      rupture distributions are dominated by the 10-nm width of the tether length
      distribution. In all, we show that tethering both a protein and its ligand allows
      for the determination of the single-molecule bond rupture force with high
      sensitivity and includes some validation for the presence of a single-tethered
      functional molecule on the atomic force microscopy tip.

PMID- 15041682
TI  - Experimental and computational studies of the desensitization process in the
      bovine rhodopsin-arrestin complex.
AB  - The deactivation of the bovine G-protein-coupled receptor, rhodopsin, is a two
      step process consisting of the phosphorylation of specific serine and threonine
      residues in the cytoplasmic tail of rhodopsin by rhodopsin kinase. Subsequent
      binding of the regulatory protein arrestin follows this phosphorylation. Previous
      results find that at least three phosphorylatable sites on the rhodopsin tail
      (T340) and at least two of the S338, S334, or S343 sites are needed for complete
      arrestin-mediated deactivation. Thus, to elucidate the details of the interaction
      between rhodopsin with arrestin, we have employed both a computational and an in
      vitro experimental approach. In this work, we first simulated the interaction of
      the carboxy tail of rhodopsin with arrestin using a Monte Carlo simulated
      annealing method. Since at this time phosphorylation of specific serines and
      threonines is not possible in our simulations, we substitute either aspartic or
      glutamic acid residues for the negatively charged phosphorylated residues
      required for binding. A total of 17 simulations were performed and analysis of
      this shows specific charge-charge interactions of the carboxy tail of rhodopsin
      with arrestin. We then confirmed these computational results with assays of
      comparable constructed rhodopsin mutations using our in vitro assay. This dual
      computational/experimental approach indicates that sites S334, S338, and T340 in
      rhodopsin and K14 and K15 on arrestin are indeed important in the interaction of
      rhodopsin with arrestin, with a possible weaker S343 (rhodopsin)/K15 (arrestin)
      interaction.

PMID- 15041684
TI  - Conformation of prion protein repeat peptides probed by FRET measurements and
      molecular dynamics simulations.
AB  - We report the combined use of steady-state fluorescence resonance energy transfer
      (FRET) experiments and molecular dynamics (MD) simulations to investigate
      conformational distributions of the prion protein (PrP) repeat system. FRET was
      used for the first time to probe the distance, as a function of temperature and
      pH, between a donor Trp residue and an acceptor dansyl group attached to the N
      terminus in seven model peptides containing one to three repeats of the second
      decarepeat of PrP from marsupial possum (PHPGGSNWGQ)nG, and one and two human PrP
      consensus octarepeats (PHGGGWGQ)nG. In multirepeat peptides, single-Trp mutants
      were made by replacing other Trp(s) with Phe. As previous work has shown PrP
      repeats do not adopt a single preferred stable conformation, the FRET values are
      averages reflecting heterogeneity in the donor-acceptor distances. The T
      dependence of the conformational distributions, and derived average dansyl-Trp
      distances, were obtained directly from MD simulation of the marsupial dansyl
      PHPGGSNWGQG peptide. The results show excellent agreement between the FRET and MD
      T-dependent distances, and demonstrate the remarkable sensitivity and
      reproducibility of the FRET method in this first-time use for a set of disordered
      peptides. Based on the results, we propose a model involving cation-pi or pi-pi
      His-Trp interactions to explain the T- (5-85 degrees C) and pH- (6.0, 7.2)
      dependencies on distance, with HW i, i + 4 or WH i, i + 4 separations in sequence
      being more stable than HW i, i + 6 or WH i, i + 6 separations. The model has
      peptides adopting loosely folded conformations, with dansyl-Trp distances very
      much less than estimates for fully extended conformations, for example,
      approximately 16 vs. 33, approximately 21 vs. 69, and approximately 22 vs. 106 A
      for 1-3 decarepeats, and approximately 14 vs. 25 and approximately 19 vs. 54 A
      for 1-2 octarepeats, respectively. The study demonstrates the usefulness of
      combining FRET with MD, a combination reported only once previously. Initial
      "mapping" of the conformational distribution of flexible peptides by simulation
      can assist in designing and interpreting experiments using steady-state intensity
      methods, and indicating how time-resolved or anisotropy methods might be used.

PMID- 15041685
TI  - Self-association process of a peptide in solution: from beta-sheet filaments to
      large embedded nanotubes.
AB  - Lanreotide is a synthetic octapeptide used in the therapy against acromegaly.
      When mixed with pure water at 10% (w/w), Lanreotide (acetate salt) forms liquid
      crystalline and monodisperse nanotubes with a radius of 120 A. The molecular and
      supramolecular organization of these structures has been determined in a previous
      work as relying on the lateral association of 26 beta-sheet filaments made of
      peptide noncovalent dimers, the basic building blocks. The work presented here
      has been devoted to the corresponding self-association mechanisms, through the
      characterization of the Lanreotide structures formed in water, as a function of
      peptide (acetate salt) concentration (from 2% to 70% (w/w)) and temperature (from
      15 degrees C to 70 degrees C). The corresponding states of water were also
      identified and quantified from the thermal behavior of water in the Lanreotide
      mixtures. At room temperature and below 3% (w/w) Lanreotide acetate in water,
      soluble aggregates were detected. From 3% to 20% (w/w) long individual and
      monodisperse nanotubes crystallized in a hexagonal lattice were evidenced. Their
      molecular and supramolecular organizations are identical to the ones
      characterized for the 10% (w/w) sample. Heating induces the dissolution of the
      nanotubes into soluble aggregates of the same structural characteristics as the
      room temperature ones. The solubilization temperature increases from 20 degrees C
      to 70 degrees C with the peptide concentration and reaches a plateau between 15%
      and 25% (w/w) in peptide. These aggregates are proposed to be the beta-sheet
      filaments that self-associate to build the walls of the nanotubes. Above 20%
      (w/w) of Lanreotide acetate in water, polydisperse embedded nanotubes are formed
      and the hexagonal lattice is lost. These embedded nanotubes exhibit the same
      molecular and supramolecular organizations as the individual monodisperse
      nanotubes formed at lower peptide concentration. The embedded nanotubes do not
      melt in the range of temperature studied indicating a higher thermodynamic
      stability than individual nanotubes. In parallel, the thermal behaviors of water
      in mixtures containing 2-80% (w/w) in peptide have been studied by differential
      scanning calorimetry, and three different types of water were characterized: 1),
      bulk water melting at 0 degrees C, 2), nonfreezing water, and 3), interfacial
      water melting below 0 degrees C. The domains of existence and coexistence of
      these different water states are related to the different Lanreotide
      supramolecular structures. All these results were compiled into a binary
      Lanreotide-water phase diagram and allowed to propose a self-association
      mechanism of Lanreotide filaments into monodisperse individual nanotubes and
      embedded nanotubes.

PMID- 15041683
TI  - High metal concentrations are required for self-association of synaptotagmin II.
AB  - Several members of the synaptotagmin (syt) family of vesicle proteins have been
      proposed to act as Ca2+ sensors on synaptic vesicles. The mechanism by which
      calcium activates this class of proteins has been the subject of controversy, yet
      relatively few detailed biophysical studies have been reported on how isoforms
      other than syt I respond to divalent metal ions. Here, we report a series of
      studies on the response of syt II to a wide range of metal ions. Analytical
      ultracentrifugation studies demonstrate that Ca2+ induces protein dimerization
      upon exposure to 5 mM Ca2+. Whereas Ba2+, Mg2+, or Sr2+ do not potentiate self
      association as strongly as Ca2+, Pb2+ triggers self-association of syt II at
      concentrations as low as 10 microM. Partial proteolysis studies suggest that the
      various divalent metals cause different changes in the conformation of the
      protein. The high calcium concentrations required for self-association of syt II
      suggest that the oligomerized state of this protein is not a critical
      intermediate in vesicle fusion; however, low-affinity calcium sites on syt II may
      play a critical role in buffering calcium at the presynaptic active zone. In
      addition, the high propensity of lead to oligomerize syt II offers a possible
      molecular explanation for how lead interferes with calcium-evoked
      neurotransmitter release.

PMID- 15041686
TI  - Modeling sample disorder in site-specific dichroism studies of uniaxial systems.
AB  - Site-specific infrared dichroism is an emerging method capable of proposing a
      model for the backbone structure of a transmembrane alpha-helix within a helical
      bundle. Dichroism measurements of single, isotopically enhanced vibrational modes
      (e.g., Amide I 13C=18O or Gly CD2 stretching modes) can yield precise
      orientational restraints for the monomer helix protomer that can be used as
      refinement constraints in model building of the entire helical bundle. Essential,
      however, for the interpretation of the dichroism measurements, is an accurate
      modeling of the sample disorder. In this study we derive an enhanced and more
      realistic modeling of the sample disorder based on a Gaussian distribution of the
      chromophore around a particular angle. The enhanced utility of the Gaussian model
      is exemplified by the comparative data analysis based on the aforementioned model
      to previously employed models.

PMID- 15041687
TI  - Graphical analysis of mass and anisotropy changes observed by plasmon-waveguide
      resonance spectroscopy can provide useful insights into membrane protein
      function.
AB  - Plasmon-waveguide resonance spectroscopy is a recently developed optical method
      that allows characterization of mass and structural changes in two-dimensionally
      ordered thin films (e.g., proteolipid membranes) deposited onto a sensor surface.
      Full analysis of these systems involves fitting theoretical curves (obtained
      using Maxwell's equations) to experimental spectra measured using s- and p
      polarized excitation. This allows values to be obtained for refractive indices
      and optical extinction coefficients in these two directions, as well as a value
      for film thickness, thereby providing information about mass density and
      anisotropy changes. This is a time-consuming process that works well for simple
      systems in which only a single conformational event occurs, but cannot
      distinguish between events involving multiple conformations that proceed either
      sequentially or in a parallel series of events. This article describes a
      graphical method that can distinguish between mass density and anisotropy changes
      in a simpler, more rapid procedure, even for processes that proceed via multiple
      conformational events. This involves measurement of plasmon-waveguide resonance
      spectral shifts obtained upon molecular interactions occurring in deposited films
      with both s- and p-polarized excitation, and transforming these from an (s-p)
      coordinate system into a (mass-structure) coordinate system. This procedure is
      illustrated by data obtained upon the binding of a small peptide, penetratin, to
      solid-supported lipid bilayer membranes.

PMID- 15041688
TI  - Correcting confocal acquisition to optimize imaging of fluorescence resonance
      energy transfer by sensitized emission.
AB  - Imaging of fluorescence resonance energy transfer (FRET) between suitable
      fluorophores is increasingly being used to study cellular processes with high
      spatiotemporal resolution. The genetically encoded Cyan (CFP) and Yellow (YFP)
      variants of Green Fluorescent Protein have become the most popular donor and
      acceptor pair in cell biology. FRET between these fluorophores can be imaged by
      detecting sensitized emission. This technique, for which CFP is excited and
      transfer is detected as emission of YFP, is sensitive, fast, and straightforward,
      provided that proper corrections are made. In this study, the detection of
      sensitized emission between CFP and YFP by confocal microscopy is optimized. It
      is shown that this FRET pair is best excited at 430 nm. We identify major sources
      of error and variability in confocal FRET acquisition including chromatic
      aberrations and instability of the excitation sources. We demonstrate that a
      novel correction algorithm that employs online corrective measurements yields
      reliable estimates of FRET efficiency, and it is also shown how the effect of
      other error sources can be minimized.

PMID- 15041689
TI  - Probing single-stranded DNA conformational flexibility using fluorescence
      spectroscopy.
AB  - Single-stranded DNA (ssDNA) is an essential intermediate in various DNA metabolic
      processes and interacts with a large number of proteins. Due to its flexibility,
      the conformations of ssDNA in solution can only be described using statistical
      approaches, such as flexibly jointed or worm-like chain models. However, there is
      limited data available to assess such models quantitatively, especially for
      describing the flexibility of short ssDNA and RNA. To address this issue, we
      performed FRET studies of a series of oligodeoxythymidylates, (dT)N, over a wide
      range of salt concentrations and chain lengths (10 < or = N < or = 70
      nucleotides), which provide systematic constraints for testing theoretical
      models. Unlike in mechanical studies where available ssDNA conformations are
      averaged out during the time it takes to perform measurements, fluorescence
      lifetimes may act here as an internal clock that influences fluorescence signals
      depending on how fast the ssDNA conformations fluctuate. A reasonably good
      agreement could be obtained between our data and the worm-like chain model
      provided that limited relaxations of the ssDNA conformations occur within the
      fluorescence lifetime of the donor. The persistence length thus estimated ranges
      from 1.5 nm in 2 M NaCl to 3 nm in 25 mM NaCl.

PMID- 15041690
TI  - Photoisomerization and photoionization of the photoactive yellow protein
      chromophore in solution.
AB  - Dispersed pump-dump-probe spectroscopy has the ability to characterize and
      identify the underlying ultrafast dynamical processes in complicated chemical and
      biological systems. This technique builds on traditional pump-probe techniques by
      exploring both ground- and excited-state dynamics and characterizing the
      connectivity between constituent transient states. We have used the dispersed
      pump-dump-probe technique to investigate the ground-state dynamics and competing
      excited-state processes in the excitation-induced ultrafast dynamics of
      thiomethyl p-coumaric acid, a model chromophore for the photoreceptor photoactive
      yellow protein. Our results demonstrate the parallel formation of two relaxation
      pathways (with multiple transient states) that jointly lead to two different
      types of photochemistry: cis-trans isomerization and detachment of a hydrated
      electron. The relative transition rates and quantum yields of both pathways have
      been determined. We find that the relaxation of the photoexcited chromophores
      involves multiple, transient ground-state intermediates and the chromophore in
      solution does not generate persistent photoisomerized products, but instead
      undergoes photoionization resulting in the generation of detached electrons and
      radicals. These results are of great value in interpreting the more complex
      dynamical changes in the optical properties of the photoactive yellow protein.

PMID- 15041691
TI  - Interresidual distance determination by four-pulse double electron-electron
      resonance in an integral membrane protein: the Na+/proline transporter PutP of
      Escherichia coli.
AB  - Proximity relationships within three doubly spin-labeled variants of the
      Na+/proline transporter PutP of Escherichia coli were studied by means of four
      pulse double electron-electron resonance spectroscopy. The large value of 4.8 nm
      for the interspin distance determined between positions 107 in loop 4 and 223 in
      loop 7 strongly supports the idea of these positions being located on opposite
      sides of the membrane. Significant smaller values of between 1.8 and 2.5 nm were
      found for the average interspin distances between spin labels attached to the
      cytoplasmic loops 2 and 4 (position 37 and 107) and loops 2 and 6 (position 37
      and 187). The large distance distribution widths visible in the pair correlation
      functions reveal a high flexibility of the studied loop regions. An increase of
      the distance between positions 37 and 187 upon Na+ binding suggests ligand
      induced structural alterations of PutP. The results demonstrate that four-pulse
      double electron-electron resonance spectroscopy is a powerful means to
      investigate the structure and conformational changes of integral membrane
      proteins reconstituted in proteoliposomes.

PMID- 15041692
TI  - Rho mediates the shear-enhancement of endothelial cell migration and traction
      force generation.
AB  - The migration of vascular endothelial cells in vivo occurs in a fluid dynamic
      environment due to blood flow, but the role of hemodynamic forces in cell
      migration is not yet completely understood. Here we investigated the effect of
      shear stress, the frictional drag of blood flowing over the cell surface, on the
      migration speed of individual endothelial cells on fibronectin-coated surfaces,
      as well as the biochemical and biophysical bases underlying this shear effect.
      Under static conditions, cell migration speed had a bell-shaped relationship with
      fibronectin concentration. Shear stress significantly increased the migration
      speed at all fibronectin concentrations tested and shifted the bell-shaped curve
      upwards. Shear stress also induced the activation of Rho GTPase and increased the
      traction force exerted by endothelial cells on the underlying substrate, both at
      the leading edge and the rear, suggesting that shear stress enhances both the
      frontal forward-pulling force and tail retraction. The inhibition of a Rho
      associated kinase, p160ROCK, decreased the traction force and migration speed
      under both static and shear conditions and eliminated the shear-enhancement of
      migration speed. Our results indicate that shear stress enhances the migration
      speed of endothelial cells by modulating the biophysical force of tractions
      through the biochemical pathway of Rho-p160ROCK.

PMID- 15041693
TI  - Longitudinal diffusion in retinal rod and cone outer segment cytoplasm: the
      consequence of cell structure.
AB  - Excitation signals spread along photoreceptor outer segments away from the site
      of photon capture because of longitudinal diffusion of cGMP, a cytoplasmic second
      messenger. The quantitative features of longitudinal diffusion reflect the
      anatomical structure of the outer segment, known to be profoundly different in
      rod and cone photoreceptors. To explore how structural differences affect
      cytoplasmic diffusion and to assess whether longitudinal diffusion may contribute
      to the difference in signal transduction between photoreceptor types, we
      investigated, both theoretically and experimentally, the longitudinal diffusion
      of small, hydrophilic molecules in outer segments. We developed a new theoretical
      analysis to explicitly compute the longitudinal diffusion constant, Dl, in terms
      of outer segment structure. Using time-resolved fluorescence imaging we measured
      Dl of Alexa488 and lucifer yellow in intact, single cones and validated the
      theoretical analysis. We used numerical simulations of the theoretical model to
      investigate cGMP diffusion in outer segments of various species. At a given time
      interval, cGMP spreads further in rod than in cone outer segments of the same
      dimensions. Across all species, the spatial spread of cGMP at the peak of the dim
      light photocurrent is 3-5 microm in rod outer segments, regardless of their
      absolute size. Similarly the cGMP spatial spread is 0.7-1 microm in cone outer
      segments, independently of their dimensions.

PMID- 15041695
TI  - Diastolic calcium release controls the beating rate of rabbit sinoatrial node
      cells: numerical modeling of the coupling process.
AB  - Recent studies employing Ca2+ indicators and confocal microscopy demonstrate
      substantial local Ca2+ release beneath the cell plasma membrane (subspace) of
      sinoatrial node cells (SANCs) occurring during diastolic depolarization.
      Pharmacological and biophysical experiments have suggested that the released Ca2+
      interacts with the plasma membrane via the ion current (INaCa) produced by the
      Na+/Ca2+ exchanger and constitutes an important determinant of the pacemaker
      rate. This study provides a numerical validation of the functional importance of
      diastolic Ca2+ release for rate control. The subspace Ca2+ signals in rabbit
      SANCs were measured by laser confocal microscopy, averaged, and calibrated. The
      time course of the subspace [Ca2+] displayed both diastolic and systolic
      components. The diastolic component was mainly due to the local Ca2+ releases; it
      was numerically approximated and incorporated into a SANC cellular
      electrophysiology model. The model predicts that the diastolic Ca2+ release
      strongly interacts with plasma membrane via INaCa and thus controls the phase of
      the action potential upstroke and ultimately the final action potential rate.

PMID- 15041694
TI  - Role of sarcoplasmic reticulum and mitochondria in Ca2+ removal in airway
      myocytes.
AB  - The aim of this study was to use both a theoretical and experimental approach to
      determine the influence of the sarco-endoplasmic Ca2+-ATPase (SERCA) activity and
      mitochondria Ca2+ uptake on Ca2+ homeostasis in airway myocytes. Experimental
      studies were performed on myocytes freshly isolated from rat trachea. [Ca2+]i was
      measured by microspectrofluorimetry using indo-1. Stimulation by caffeine for 30
      s induced a concentration-graded response characterized by a transient peak
      followed by a progressive decay to a plateau phase. The decay phase was
      accelerated for 1-s stimulation, indicating ryanodine receptor closure. In Na2+
      Ca2+-free medium containing 0.5 mM La3+, the [Ca2+]i response pattern was not
      modified, indicating no involvement of transplasmalemmal Ca2+ fluxes. The
      mathematical model describing the mechanism of Ca2+ handling upon RyR stimulation
      predicts that after Ca2+ release from the sarcoplasmic reticulum, the Ca2+ is
      first sequestrated by cytosolic proteins and mitochondria, and pumped back into
      the sarcoplasmic reticulum after a time delay. Experimentally, we showed that the
      [Ca2+]i decay after Ca2+ increase was not altered by the SERCA inhibitor
      cyclopiazonic acid, but was slightly but significantly modified by the
      mitochondria uncoupler carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone. The
      experimental and theoretical results indicate that, although Ca2+ pumping back by
      SERCA is active, it is not primarily involved in [Ca2+]i decrease that is due, in
      part, to mitochondrial Ca2+ uptake.

PMID- 15041696
TI  - Theoretical investigation of the neuronal Na+ channel SCN1A: abnormal gating and
      epilepsy.
AB  - Epilepsy is a paroxysmal neurological disorder resulting from abnormal cellular
      excitability and is a common cause of disability. Recently, some forms of
      idiopathic epilepsy have been causally related to genetic mutations in neuronal
      ion channels. To understand disease mechanisms, it is crucial to understand how a
      gene defect can disrupt channel gating, which in turn can affect complex cellular
      dynamic processes. We develop a theoretical Markovian model of the neuronal Na+
      channel NaV1.1 to explore and explain gating mechanisms underlying cellular
      excitability and physiological and pathophysiological mechanisms of abnormal
      neuronal excitability in the context of epilepsy. Genetic epilepsy has been shown
      to result from both mutations that give rise to a gain of channel function and
      from those that reduce the Na+ current. These data may suggest that abnormal
      excitation can result from both hyperexcitability and hypoexcitability, the
      mechanisms of which are presumably distinct, and as yet elusive. Revelation of
      the molecular origins will allow for translation into targeted pharmacological
      interventions that must be developed to treat syndromes resulting from divergent
      mechanisms. This work represents a first step in developing a comprehensive
      theoretical model to investigate the molecular mechanisms underlying runaway
      excitation that cause epilepsy.

PMID- 15041697
TI  - Spontaneously formed monodisperse biomimetic unilamellar vesicles: the effect of
      charge, dilution, and time.
AB  - Using small-angle neutron scattering and dynamic light scattering, we have
      constructed partial structural phase diagrams of lipid mixtures composed of the
      phosphatidylcholines dimyristoyl and dihexanoyl doped with calcium ions (Ca2+)
      and/or the negatively charged lipid, dimyristoyl phosphatidylglycerol (DMPG). For
      dilute solutions (lipid concentration < or =1 wt %), spontaneously forming
      unilamellar vesicles (ULVs) were found, and their polydispersity was determined
      to be approximately 20%. The stability of the Ca2+- or DMPG-doped ULVs was
      monitored over a period of 4 days and their structural parameters (e.g., average
      outer radius, <Ro>) were found to be insensitive to the lipid concentration
      (Clp). However, doping the dimyristoyl/dihexanoyl system with both Ca2+ and DMPG
      resulted in ULVs whose <Ro> was found to be Clp dependent. The <Ro> of DMPG-doped
      ULVs remained unchanged over an extended period of time (at least 4 days), a good
      indication of their stability.

PMID- 15041698
TI  - Scaling and mean-field theories applied to polymer brushes.

PMID- 15041700
TI  - Clinical trial substantiates the predictive value of O-6-methylguanine-DNA
      methyltransferase promoter methylation in glioblastoma patients treated with
      temozolomide.
AB  - PURPOSE: In the setting of a prospective clinical trial, we determined the
      predictive value of the methylation status of the O-6-methylguanine-DNA
      methyltransferase (MGMT) promoter for outcome in glioblastoma patients treated
      with the alkylating agent temozolomide. Expression of this excision repair enzyme
      has been associated with resistance to alkylating chemotherapy. EXPERIMENTAL
      DESIGN: The methylation status of MGMT in the tumor biopsies was evaluated in 38
      patients undergoing resection for newly diagnosed glioblastoma and enrolled in a
      Phase II trial testing concomitant and adjuvant temozolomide and radiation. The
      epigenetic silencing of the MGMT gene was determined using methylation-specific
      PCR. RESULTS: Inactivation of the MGMT gene by promoter methylation was
      associated with longer survival (P = 0.0051; Log-rank test). At 18 months,
      survival was 62% (16 of 26) for patients testing positive for a methylated MGMT
      promoter but reached only 8% (1 of 12) in absence of methylation (P = 0.002;
      Fisher's exact test). In the presence of other clinically relevant factors,
      methylation of the MGMT promoter remains the only significant predictor (P =
      0.017; Cox regression). CONCLUSIONS: This prospective clinical trial identifies
      MGMT-methylation status as an independent predictor for glioblastoma patients
      treated with a methylating agent. The association of the epigenetic inactivation
      of the DNA repair gene MGMT with better outcome in this homogenous cohort may
      have important implications for the design of future trials and supports efforts
      to deplete MGMT by O-6-benzylguanine, a noncytotoxic substrate of this enzyme.

PMID- 15041702
TI  - Melanoma computer-aided diagnosis: reliability and feasibility study.
AB  - BACKGROUND: Differential diagnosis of melanoma from melanocytic nevi is often not
      straightforward. Thus, a growing interest has developed in the last decade in the
      automated analysis of digitized images obtained by epiluminescence microscopy
      techniques to assist clinicians in differentiating early melanoma from benign
      skin lesions. PURPOSE: The aim of this study was to evaluate diagnostic accuracy
      provided by different statistical classifiers on a large set of pigmented skin
      lesions grabbed by four digital analyzers located in two different dermatological
      units. EXPERIMENTAL DESIGN: Images of 391 melanomas and 449 melanocytic nevi were
      included in the study. A linear classifier was built by using the method of
      receiver operating characteristic curves to identify a threshold value for a
      fixed sensitivity of 95%. A K-nearest-neighbor classifier, a nonparametric method
      of pattern recognition, was constructed using all available image features and
      trained for a sensitivity of 98% on a large exemplar set of lesions. RESULTS: On
      independent test sets of lesions, the linear classifier and the K-nearest
      neighbor classifier produced a mean sensitivity of 95% and 98% and a mean
      specificity of 78% and of 79%, respectively. CONCLUSIONS: In conclusion, our
      study suggests that computer-aided differentiation of melanoma from benign
      pigmented lesions obtained with DB-Mips is feasible and, above all, reliable. In
      fact, the same instrumentations used in different units provided similar
      diagnostic accuracy. Whether this would improve early diagnosis of melanoma
      and/or reducing unnecessary surgery needs to be demonstrated by a randomized
      clinical trial.

PMID- 15041701
TI  - Safety and efficacy of dose-intensive oral vitamin A in subjects with sun-damaged
      skin.
AB  - PURPOSE: Previously, we reported the results of a Phase III, placebo-controlled
      trial in 2297 randomized participants with moderately severe actinic keratoses
      wherein 25000 IU/day vitamin A caused a 32% risk reduction in squamous cell skin
      cancers. We hypothesized that dose escalation of vitamin A to 50000 or 75000
      IU/day would be both safe and more efficacious in skin cancer chemoprevention.
      EXPERIMENTAL DESIGN: One hundred and twenty-nine participants with severely sun
      damaged skin on their lateral forearms were randomized to receive placebo or
      25000, 50000, or 75000 IU/day vitamin A for 12 months. The primary study end
      points were the clinical and laboratory safety of vitamin A, and the secondary
      end points included quantitative, karyometric image analysis and assessment of
      retinoid and rexinoid receptors in sun-damaged skin. RESULTS: There were no
      significant differences in expected clinical and laboratory toxicities between
      the groups of participants randomized to placebo, 25000 IU/day, 50000 IU/day, and
      75000 IU/day. Karyometric features were computed from the basal cell layer of
      skin biopsies, and a total of 22600 nuclei from 113 participants were examined,
      showing statistically significant, dose-response effects for vitamin A at the
      25000 and 50000 IU/day doses. These karyometric changes correlated with increases
      in retinoic acid receptor alpha, retinoic acid receptor beta, and retinoid X
      receptor alpha at the 50000 IU/day vitamin A dose. CONCLUSIONS: The vitamin A
      doses of 50000 and 75000 IU/day for 1 year proved safe and equally more
      efficacious than the 25000 IU/day dose and can be recommended for future skin
      cancer chemoprevention studies.

PMID- 15041703
TI  - Detection of bladder cancer in urine by a tumor suppressor gene hypermethylation
      panel.
AB  - PURPOSE: Bladder cancer is potentially curable in the majority of cases; however,
      the prognosis for patients with advanced disease at presentation remains poor.
      Current noninvasive tests such as cytology lack sufficient sensitivity to detect
      low-grade, low-stage tumors. Silencing of tumor suppressor genes, such as
      p16(INK4a), VHL, and the mismatch repair gene hMLH1, has established promoter
      hypermethylation as a common mechanism for tumor suppressor inactivation in human
      cancers. It is also a promising new target for molecular detection in bodily
      fluids including urine, a readily accessible fluid known to contain bladder
      cancer cells. Methylation-specific PCR (MSP) can determine the presence or
      absence of methylation of a gene locus at a sensitivity level of up to 1
      methylated allele in 1000 unmethylated alleles, appropriate for identifying
      cancer cell DNA in a bodily fluid. EXPERIMENTAL DESIGN: We first determined the
      frequency of hypermethylation of the Rb tumor suppressor gene by bisulfite
      sequencing and of the p16(INK4a), p14(ARF), APC, and RASSF1A tumor suppressor
      genes by MSP in 45 bladder cancers. We then designed a panel optimal for
      diagnostic coverage composed of the APC, RASSF1A, and p14(ARF) tumor suppressor
      genes. This panel was tested for detection of hypermethylation in matched
      sediment DNA from urine specimens obtained before surgery from the same 45
      bladder cancer patients (2 Tis, 16 Ta, 10 T1, and 17 T2-4) as well as normal and
      benign control DNAs. RESULTS: Hypermethylation of at least one of three
      suppressor genes (APC, RASSF1A, and p14(ARF)) was found in all 45 tumor DNAs
      (100% diagnostic coverage). We detected gene hypermethylation in the matched
      urine DNA from 39 of 45 patients (87% sensitivity), including 16 cases that had
      negative cytology. No hypermethylation of APC, RASSF1A, or p14(ARF) was observed
      in normal transitional cell DNAs or in urine DNAs from normal healthy individuals
      and patients with inflammatory urinary disease (cystitis). Furthermore, an
      unmethylated gene in the tumor DNA was always found to be unmethylated in the
      matched urine DNA (100% specificity). CONCLUSIONS: Promoter hypermethylation of
      tumor suppressor genes is common in bladder cancer and was found in all grades
      and stages of tumors examined. Hypermethylation was detected in the urine DNA
      from 39 of 45 (87%) patients, including cases of early-stage disease amenable to
      cure. MSP may enhance early detection of bladder cancer using a noninvasive urine
      test.

PMID- 15041704
TI  - Reconstitution of caspase-3 confers low glucose-enhanced tumor necrosis factor
      related apoptosis-inducing ligand cytotoxicity and Akt cleavage.
AB  - PURPOSE AND EXPERIMENTAL DESIGN: We have previously observed that glucose
      deprivation enhances tumor necrosis factor-related apoptosis-inducing ligand
      (TRAIL)-induced apoptotic death as well as caspase activation (caspase-3, -9, and
      -8) in human prostate adenocarcinoma DU-145 cells. In this study, we used caspase
      3-deficient MCF-7 breast cancer cells to examine the possible role of caspase-3
      in glucose deprivation-enhanced TRAIL cytotoxicity. RESULTS: Combined glucose
      deprivation and 200 ng/ml TRAIL treatment markedly induced cytotoxicity in
      caspase-3 cDNA transfected cells (MCF-7/casp-3) but not in control vector
      transfected cells (MCF-7/vector). We also observed that the level of Akt, an
      antiapoptotic protein, was reduced by treatment with TRAIL in MCF-7/casp-3 cells
      but not in MCF-7/vector cells. The reduction of Akt by TRAIL was promoted in the
      absence of glucose in MCF-7/casp-3 cells. However, pretreatment with 20 micro M Z
      LEHD-FMK, a caspase-9 inhibitor, protected MCF-7/casp-3 cells from the
      combinatorial treatment of TRAIL and glucose deprivation-induced cytotoxicity.
      This compound also prevented the reduction of Akt level during the combinatorial
      treatment. Moreover, this Akt reduction was not inhibited by treatment with MG
      132, a proteosome inhibitor. Data from site-directed mutagenesis show that Akt
      was cleaved at amino acid 108, but not 119, during treatment with TRAIL and
      glucose deprivation. CONCLUSIONS: Our results suggest that caspase-3 is involved
      in the reduction of Akt level, and its involvement is mediated through caspase-9
      activation. The reduction of Akt level is also due to cleavage of Akt rather than
      degradation of Akt.

PMID- 15041705
TI  - Transendothelial migration of myeloma cells is increased by tumor necrosis factor
      (TNF)-alpha via TNF receptor 2 and autocrine up-regulation of MCP-1.
AB  - The proinflammatory cytokine tumor necrosis factor (TNF)-alpha has been shown to
      facilitate leukocyte transendothelial migration. In multiple myeloma, TNF-alpha
      is an important factor in the promotion of growth and survival of the malignant
      cells. Studies have shown that enhanced TNF-alpha levels in myeloma patients
      correlated with aggressive disease. Therefore, we investigated the effect of
      recombinant human TNF-alpha on the migrational behavior of myeloma cells across
      the physiological barrier of the major disease compartment, i.e., human bone
      marrow endothelial cells. In the presence of TNF-alpha, we observed significantly
      increased migration both in established myeloma cell lines and in plasma cells
      from myeloma patients. Expression of TNF-receptor 2 (TNF-R2) but not TNF-receptor
      1 (TNF-R1) was detected in myeloma cell lines. Myeloma cells of patients also
      showed expression of TNF-R2 but not TNF-R1. The effect of TNF-alpha could not be
      explained by altered expression of adhesion molecules or metalloproteases.
      Instead, we found an up-regulation of monocyte chemoattractant protein (MCP)-1
      and confirmed that myeloma cells express the relevant receptor C-C chemokine
      receptor 2. Preincubation of myeloma cells with recombinant human MCP-1 also
      enhanced cell migration, and this effect, as well as the effect of TNF-alpha, was
      abolished by treatment with anti-MCP-1 antibody. In contrast, migration of
      myeloma cells in the direction of an MCP-1 gradient, i.e., chemotaxis, could not
      be observed in the cell lines investigated. Additionally, the mRNA level of TNF
      alpha was up-regulated by the cytokine treatment, which points to an autocrine
      loop augmenting and/or stabilizing the TNF-alpha-MCP-1 pathway. In summary, our
      data clearly support additional investigations using anti-MCP-1 antibodies in
      myeloma progression.

PMID- 15041706
TI  - Up-regulation of p21 gene expression by peroxisome proliferator-activated
      receptor gamma in human lung carcinoma cells.
AB  - PURPOSE: The peroxisome proliferator-activated receptor gamma (PPARgamma), a
      ligand-dependent transcription factor belonging to the family of nuclear
      receptors, has been implicated in the regulation of cell growth and
      differentiation although the exact mechanism(s) of this activity has not been
      elucidated. In this study, we explored the role of PPARgamma signaling on the
      control of gene expression of the cycle-dependent kinase inhibitor p21 in human
      lung carcinoma cells. EXPERIMENTAL DESIGN: Using several human lung carcinoma
      cell lines (small and non-small carcinoma cells), we assayed for cell growth
      inhibition and apoptosis induction. We also assayed for p21 mRNA and protein
      expression by reverse transcription-PCR, real-time reverse transcription-PCR, and
      Western blot analysis. Nuclear protein binding activities to three response
      elements located in the p21 promoter [nuclear factor (NF)-kappaB, Sp1, and NF
      interleukin 6 (IL6) CAAT/enhancer binding protein (C/EBP)] were measured by gel
      mobility shift assays. We used transient transfection assays with p21 promoter
      reporter gene constructs to determine the transcriptional regulation by PPARgamma
      ligands. Finally, by using p21 antisense oligonucleotides, we tested the link
      between PPARgamma activation and p21 signaling in cell growth inhibition assays
      and by Western blot analysis. RESULTS: We showed that the PPARgamma ligands PGJ2
      and ciglitazone inhibit the growth and induce the apoptosis of several human lung
      carcinoma cell lines, whereas the PPARalpha agonist WY14643 has little effect.
      Treatment of lung carcinoma cells with the PPARgamma ligands PGJ2, ciglitazone,
      troglizaone, and GW1929 elevated p21 mRNA and protein levels and reduced cyclin
      D1 mRNA levels. These results were supported by transient transfection assays,
      which indicated that PPARgamma ligands increased p21 gene promoter activity in
      human lung carcinoma cells. In addition, p21 antisense oligonucleotides inhibited
      PPARgamma ligand-induced p21 protein expression and significantly blocked lung
      carcinoma cell growth inhibition induced by PPARgamma ligands. Finally,
      electrophoresis mobility shift experiments demonstrated that PPARgamma ligands
      increased the nuclear binding activities of Sp1 and NF-IL6 (C/EBP), two
      transcription factors with regulatory elements in the promoter region of the p21
      gene. CONCLUSION: PPARgamma ligands inhibit human lung carcinoma cell growth and
      induce apoptosis by stimulating the cyclin-dependent kinase inhibitor p21 and by
      reducing cyclin D1 gene expression. The induction of p21 gene expression by
      PPARgamma ligands may be mediated through increased Sp1- and NF-IL6 (C/EBP)
      dependent transcriptional activation. These observations unveil a mechanism for
      p21 gene regulation in lung carcinoma that represents a potential target for
      therapy.

PMID- 15041707
TI  - A novel human cancer vaccine elicits cellular responses to the tumor-associated
      antigen, human chorionic gonadotropin beta.
AB  - PURPOSE: The oncofetal antigen, human chorionic gonadotropin beta subunit
      (hCGbeta), is expressed by a number of carcinomas and is a prognostic indicator
      in renal, colorectal, bladder, and pancreatic cancers. We describe the
      development of a novel antibody-based dendritic cell (DC)-targeted cancer vaccine
      capable of eliciting cellular immune responses directed against hCGbeta.
      EXPERIMENTAL DESIGN: The tumor-associated antigen hCGbeta was coupled genetically
      to a human anti-DC antibody (B11). The resulting fusion protein (B11-hCGbeta) was
      evaluated for its ability to promote tumor antigen-specific cellular immune
      responses in a human in vitro model. Monocyte-derived human DCs from normal
      donors were exposed to purified B11-hCGbeta, activated with CD40 ligand, mixed
      with autologous lymphocytes, and tested for their ability to promote hCGbeta
      specific proliferative and cytotoxic T-lymphocyte responses. RESULTS: B11-hCGbeta
      was found to be a soluble, well-defined, and readily purified product that
      specifically recognized the human mannose receptor via the B11 antibody portion
      of the fusion protein. B11-hCGbeta functionally promoted the uptake and
      processing of tumor antigen by DCs, which led to the generation of tumor-specific
      HLA class I and class II-restricted T-cell responses, including CTLs capable of
      killing human cancer cell lines expressing hCGbeta. CONCLUSIONS: Although other
      hCG vaccines have been shown to be capable of eliciting antibody responses to
      hCGbeta, this is the first time that cellular immune responses to hCGbeta have
      been induced by a vaccine in a human system. This DC-targeted hCGbeta vaccine
      holds promise for the management of a number of cancers and merits additional
      clinical development.

PMID- 15041708
TI  - A phase I and pharmacokinetic study of weekly paclitaxel and carboplatin in
      patients with metastatic esophageal cancer.
AB  - PURPOSE: To determine the maximum-tolerated dose, toxicity profile, and
      pharmacokinetics of a fixed dose of paclitaxel followed by increasing doses of
      carboplatin, given weekly to patients with advanced esophageal or gastric
      junction cancer. EXPERIMENTAL DESIGN: Paclitaxel was administered on day 1 as a 1
      h infusion at a fixed dose of 100 mg/m(2) followed by a 1-h infusion of
      carboplatin targeting an area under the curve (AUC) of 2-5 mg x min/ml, with
      cycles repeated on days 8, 15, 29, 36, and 43. RESULTS: Forty patients [36 males;
      median (range) age, 57 (40-74) years] were enrolled. Dose-limiting toxicity was
      observed at a carboplatin AUC of 5 mg x min/ml and consisted of treatment delay
      attributable to myelosuppression. No grade 3/4 treatment-related nonhematological
      toxicity was observed. The highest dose intensity (>95% of the planned dose over
      time) was achieved with a carboplatin AUC of 4 mg x min/ml. The mean (+/-SD) AUCs
      of unbound (Cu) and total paclitaxel were 0.662 +/- 0.186 and 7.37 +/- 1.33 micro
      M x h, respectively. Clearance of Cu was 188 +/- 44.6 liter/h/m(2), which is not
      significantly different from historical data (P = 0.52). Cremophor EL clearance
      was 123 +/- 23 ml/h/m(2), similar to previous findings. Of 37 patients evaluable
      for response, 1 had complete response, 19 had partial response, and 10 had stable
      disease, accounting for an overall response rate of 54%. CONCLUSIONS: This
      regimen is very tolerable and effective, and the recommended doses for additional
      studies are paclitaxel (100 mg/m(2)), with carboplatin targeting an AUC of 4 mg x
      min/ml.

PMID- 15041709
TI  - Immunological consequences of interleukin 12 administration after autologous stem
      cell transplantation.
AB  - PURPOSE: The purpose is to determine the immunological effects of recombinant
      human interleukin (rhIL)-12 therapy after autologous stem cell transplantation.
      EXPERIMENTAL DESIGN: Twelve patients (8 non-Hodgkin's lymphoma, 2 Hodgkin's
      disease, and 2 plasma cell myeloma) were treated with rhIL-12 by bolus i.v.
      injection in doses of 30, 100, or 250 ng/kg starting at a median of 66 days
      posttransplant. Immunological assays were performed using serum and peripheral
      blood mononuclear cell (PBMC) samples obtained on study. RESULTS: Dose-dependent
      increases in the total lymphocyte count occurred during rhIL-12 therapy. The
      absolute number of peripheral blood CD4 T cells increased up to 16.3-fold, CD8 T
      cells up to 20.5-fold, B cells up to 11-fold, and natural killer (NK) cells up to
      12.3-fold during rhIL-12 administration and returned to pretreatment baseline
      levels after discontinuation of rhIL-12. CD56(bright) NK cells expanded
      dramatically in the blood of a patient with baseline lymphopenia before rhIL-12
      therapy. In vitro proliferation of patient PBMCs in response to IL-12 was
      indistinguishable from that of PBMCs obtained from healthy control sub-jects.
      Moreover, spontaneous in vitro proliferation of patient PBMCs increased
      significantly during rhIL-12 therapy. Increased levels of IFN-gamma and IL-18
      were detected in the serum of patients treated in the 100 and 250 ng/kg dose
      cohorts during the first multiple dose cycle. CONCLUSIONS: Expansion of T, B, and
      NK cells occurs in vivo during rhIL-12 therapy after autologous stem cell
      transplantation for hematological malignancies. In contrast to their striking
      defect in IL-12-induced IFN-gamma production, posttransplant patient PBMCs
      exhibit normal proliferative responses to IL-12 in vitro. Additional
      investigation of rhIL-12 for posttransplantation immunotherapy is warranted.

PMID- 15041710
TI  - Pilot study evaluating the pharmacokinetics, pharmacodynamics, and safety of the
      combination of exemestane and tamoxifen.
AB  - PURPOSE: We conducted a pilot study assessing the effects of the selective
      estrogen receptor modulator, tamoxifen, on the pharmacokinetics,
      pharmacodynamics, and safety of the steroidal, irreversible aromatase inhibitor
      (AI), exemestane, when the two were coadministered in postmenopausal women with
      metastatic breast cancer. EXPERIMENTAL DESIGN: Patients with documented or
      unknown hormone receptor sensitivity were eligible. Patients received oral
      exemestane at 25-mg once daily. Starting day 15, oral tamoxifen at 20-mg once
      daily, was added. We measured plasma concentrations of exemestane, estrone,
      estrone sulfate, and estradiol after 14 days of exemestane monotherapy and after
      approximately 4 weeks of combination therapy. The incidence and severity of
      adverse events were assessed by physical examination and patient reporting.
      RESULTS: We treated 18 patients. All had received prior chemotherapy and/or
      hormonal therapy, eight and six, respectively, with single-agent selective
      estrogen receptor modulators or irreversible aromatase inhibitors; no hormonal
      therapy was given within 30 days of study entry. Plasma exemestane concentrations
      and estrone, estrone sulfate, and estradiol suppression were unchanged after
      approximately 4 weeks of tamoxifen coadministration. All drug-related adverse
      events were grades 1 or 2; none was unexpected. Although not a formal study end
      point, antitumor activity was noted, with two partial responses and four cases of
      stable disease among 17 evaluable patients after a 9-month median follow-up
      (range, 2.5-19 months). CONCLUSIONS: This pilot study provides evidence that
      coadministration of tamoxifen does not affect exemestane pharmacokinetics or
      pharmacodynamics and that the combination is well-tolerated and active. Further
      clinical investigation is warranted.

PMID- 15041711
TI  - Phase I and pharmacokinetic study of the polyamine synthesis inhibitor SAM486A in
      combination with 5-fluorouracil/leucovorin in metastatic colorectal cancer.
AB  - PURPOSE: The purpose of our study was to determine the maximum-tolerated dose,
      dose-limiting toxicity, safety profile, and pharmacokinetics of the polyamine
      synthesis inhibitor SAM486A given in combination with 5-fluorouracil/leucovorin
      (5-FU/LV) in cancer patients. EXPERIMENTAL DESIGN: Patients with advanced
      colorectal cancer were treated with 5-FU [bolus (400 mg/m(2)) followed by a 22-h
      infusion (600 mg/m(2))] and LV (200 mg/m(2)) and escalating doses of SAM486A, 1-3
      h infusion daily for 3 days. Plasma sampling was performed to characterize the
      pharmacokinetics and pharmacodynamics of the combination RESULTS: Twenty-seven
      patients with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were
      treated. Twenty-six patients received SAM486A in the combination at doses ranging
      from 25 to 150 mg/m(2)/day. Dose-limiting toxicity consisting of fatigue grade 3
      was seen at 150 mg/m(2)/day. Other adverse events included neutropenia, hand and
      foot syndrome, nausea, vomiting, diarrhea, and constipation. Fifteen of 26
      patients evaluable for best response according to the Southwest Oncology Group
      criteria achieved a partial response [8 (30%) of 26] or stable disease [9 (35%)
      of 26]. SAM486A did not influence the pharmacokinetics of 5-FU, and SAM486A
      clearance was similar to that when used as a single agent. CONCLUSIONS: The novel
      molecular agent SAM486A is tolerable and safe in combination with a standard 5-FU
      regimen in patients with advanced colorectal cancer. The dose of SAM486A
      recommended for additional studies with this combination is 125 mg/m(2)/day. A
      disease-directed evaluation of SAM486A using this regimen is warranted.

PMID- 15041712
TI  - Competing causes of death and second primary tumors in patients with
      locoregionally advanced head and neck cancer treated with chemoradiotherapy.
AB  - PURPOSE: The purpose of this retrospective analysis was to evaluate the emergence
      of second primary malignancies and the contribution of different causes of death
      to the outcome of patients with locoregionally advanced head and cancer receiving
      primary chemoradiotherapy. EXPERIMENTAL DESIGN: We studied 324 patients with
      stage IV squamous cell head and neck cancer who were enrolled on five consecutive
      multicenter Phase II studies of concurrent chemoradiotherapy. All of the regimens
      included concurrent 5-fluorouracil and hydroxyurea on an alternate week schedule
      with radiotherapy, either alone (FHX) or with cisplatin (C-FHX) or paclitaxel (T
      FHX). The cumulative incidence of second primary tumors or death from any cause
      was estimated using methods of competing risk analysis. RESULTS: Median follow-up
      of surviving patients was 5.2 years (2-10.6 years). The 5-year overall survival
      and progression-free survival of the cohort were 46% and 65%, respectively.
      Causes of death and median time of occurrence were as follows: disease (n = 88;
      1.5 years), treatment-associated acute or late complications (n = 30; 4 months),
      second primary tumors (n = 18; 3.5 years), comorbidities (n = 41; 1.9 years), and
      unknown (n = 20; 5.1 years). Predominant causes of death from comorbidities were
      cardiac and respiratory illnesses. Twenty-six patients (8%) developed a second
      primary tumor at a median time of 2.8 years (4 months to 10 years). The
      cumulative incidence of second primary tumors was 5%, 7%, and 13% at 3, 5, and 10
      years, respectively. The most frequent site of second primaries was the lung (n =
      13), followed by the esophagus (n = 3) and head and neck (n = 2) CONCLUSIONS:
      Patients with locoregionally advanced head and neck cancer treated with
      concurrent chemoradiotherapy are potentially curable but face significant risks
      of mortality from causes other than disease progression. Ameliorating toxicity,
      and implementing secondary screening and chemoprevention strategies are major
      goals in the management of head and neck cancer.

PMID- 15041713
TI  - A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing
      matrix metalloproteinase inhibitor, in patients with advanced or metastatic
      cancer.
AB  - PURPOSE: BMS-275291 is a novel broad-spectrum inhibitor of matrix
      metalloproteinase (MMPs) rationally designed to spare a class of closely related
      metalloproteinases known as sheddases. Inadvertent sheddase inhibition is
      hypothesized to play a role in the dose-limiting joint toxicities occurring with
      hydroxamate-based MMP inhibitors. This trial was conducted to establish the
      recommended phase II dose; determine safety, toxicity, and pharmacokinetics of
      BMS-275291; and to assess potential markers of sheddase activity [tumor necrosis
      factor-alpha (TNFalpha) release and TNFalpha-RII shedding]. EXPERIMENTAL DESIGN:
      This was an open label, single arm, phase I study conducted at two centers.
      Patients with advanced or metastatic cancer were treated with once-daily oral BMS
      275291 at doses escalating from 600 to 2400 mg/day. Six to eight patients/dose
      level were to be studied with the recommended phase II dose level expanded to a
      total of 15 patients. Pharmacokinetic sampling was performed on days 1, 15, and
      29 at 0, 0.5, 1, 2, 4, 6, 8, and 24 h after dosing. Radiological tumor assessment
      was performed every 8 weeks. RESULTS: Forty-four evaluable patients were enrolled
      in this study with the most frequent tumor types being colorectal cancer and non
      small cell lung cancer. Dose limiting toxicities were observed at 600 mg/day (one
      of eight patients with grade 3 transaminitis) and at 1200 mg/day (1 of 15
      patients with grade 3 rash and grade 4 shortness of breath), both in the context
      of predisposing conditions. No dose-limiting toxicities occurred at 900, 1800, or
      2400 mg/day. The most frequent adverse events considered possibly, probably, or
      definitely drug-related were joint toxicity (myalgia/arthralgia), rash, fatigue,
      headache, nausea, and taste change, all of which were mild, grade 1, grade 2, and
      not dose-limiting. No objective tumor responses were observed. Twelve of forty
      four patients received treatment for 4+ months, six for 8+ months, three for >1
      year. Desired trough levels of parent BMS-275291 were maintained with once daily
      dosing. The mean plasma concentration of parent BMS-275291 at trough exceeded the
      calculated in vitro IC(80) value for MMP-2 and IC(90) value for MMP-9 at the
      recommended phase II dose of 1200 mg/day. No major changes in serum
      concentrations of sheddase enzymatic products, TNFalpha or TNFalpha-RII, were
      observed. CONCLUSIONS: BMS-275291 is a nonhydroxamate MMP inhibitor with a novel
      mercaptoacyl zinc-binding group. In this study, plasma concentrations of BMS
      275291 continuously exceeded in vitro MMP IC(50) values without dose-limiting
      joint toxicity. In this refractory patient population, a suggestion of disease
      stabilization was observed in 12 patients. On the basis of preclinical, clinical,
      and pharmacokinetic data, the recommended phase II dose for future study is 1200
      mg/day.

PMID- 15041714
TI  - A randomized phase II feasibility trial of BMS-275291 in patients with early
      stage breast cancer.
AB  - PURPOSE: This pilot trial was performed to evaluate the safety, pharmacokinetics
      and feasibility of incorporating BMS-275291, a matrix metalloproteinase inhibitor
      (MMPI), into adjuvant breast cancer therapy. EXPERIMENTAL DESIGN: Patients with
      stage I (T1c)-IIIA breast cancer were eligible if planned adjuvant therapy
      consisted of either tamoxifen alone, doxorubicin + cyclophosphamide every 21 days
      for four cycles (AC), or AC followed by paclitaxel every 21 days for 4 cycles
      (AC>T). Patients were stratified by planned adjuvant therapy and randomized (2:1
      ratio) to BMS-275291 (1200 mg/day) or matched placebo for 1 year. RESULTS:
      Seventy-two patients were recruited from March 2001 to July 2002. Grade >or=2
      musculoskeletal toxicity, generally reversible arthralgia, was reported by 36.2%
      of patients receiving BMS-275291 compared with 16.7% of patients receiving
      placebo; difference = 19.5% (95% confidence interval: -0.06, 0.44; P = NS). Two
      patients receiving BMS-275291 developed palpable nodules along tendons. Grade
      >or=3 rash was reported by 8.5% of patients receiving BMS-275291 compared with
      4.2% of patients receiving placebo; difference = 4.3% (95% confidence interval: 
      0.18, 0.3; P = NS). Overall, 33% of BMS-275291 patients and 21% of placebo
      patients discontinued treatment due to adverse events. BMS-275291 trough levels
      tended to decrease over time; 9 of 47 (19%) had >or=50% of trough concentrations
      > 124 ng/ml (IC(90) for matrix metalloproteinase-9). CONCLUSIONS: The pattern of
      arthralgia in BMS-275291-treated patients was consistent with matrix
      metalloproteinase inhibitor toxicity. Although the differential incidence of
      arthralgia did not reach statistical significance, the trial was terminated. An
      adjuvant trial in this patient population is not feasible.

PMID- 15041715
TI  - Comparative pharmacokinetics of weekly and every-three-weeks docetaxel.
AB  - PURPOSE: Weekly administration of docetaxel has demonstrated comparable efficacy
      together with a distinct toxicity profile with reduced myelosuppression, although
      pharmacokinetic data with weekly regimens are lacking. The comparative
      pharmacokinetics of docetaxel during weekly and once every 3 weeks (3-weekly)
      administration schedules were evaluated. EXPERIMENTAL DESIGN: Forty-six patients
      received weekly docetaxel (35 mg/m(2)) as a 30-min infusion alone (n = 8) or in
      combination with irinotecan (n = 12), or in 3-weekly regimens, as a 1-h infusion
      at 60 mg/m(2) with doxorubicin (n = 10), 75 mg/m(2) alone (n = 9), or 100 mg/m(2)
      alone (n = 7). Serial blood samples were obtained immediately before and up to 21
      days after the infusion. Plasma concentrations were measured by liquid
      chromatography-mass spectrometry and analyzed by compartmental modeling. RESULTS:
      Mean +/- SD docetaxel clearance values were similar with weekly and 3-weekly
      schedules (25.2 +/- 7.7 versus 23.7 +/- 7.9 liter/h/m(2)); half-lives were also
      similar with both schedules of administration (16.5 +/- 11.2 versus 17.6 +/- 7.4
      h). With extended plasma sampling beyond 24 h post-infusion, docetaxel clearance
      was 18% lower and the terminal half-life was 5-fold longer. At 35 mg/m(2), the
      mean +/- SD docetaxel concentration on day 8 was 0.00088 +/- 0.00041 microg/ml
      (1.08 +/- 0.51 nM) at 75 mg/m(2), concentrations on day 8, 15, and 22 were 0.0014
      +/- 0.00043 microg/ml (1.79 +/- 0.53 nM), 0.00067 +/- 0.00025 microg/ml (0.83 +/-
      0.31 nM), and 0.00047 +/- 0.00008 microg/ml (0.58 +/- 0.099 nM), respectively.
      CONCLUSION: Docetaxel pharmacokinetics are similar for the weekly and 3-weekly
      regimens. Prolonged circulation of low nanomolar concentrations of docetaxel may
      contribute to the mechanism of action of docetaxel through suppression of
      microtubule dynamics and tumor angiogenesis and enhanced cell radiosensitivity in
      combined modality therapy.

PMID- 15041716
TI  - Skp2 gene copy number aberrations are common in non-small cell lung carcinoma,
      and its overexpression in tumors with ras mutation is a poor prognostic marker.
AB  - PURPOSE: Skp2 plays a critical role in cell cycle progression, especially at the
      G(1)-S transition, putatively through its control of several cell cycle regulator
      proteins. The Skp2 gene is located on a region of chromosome 5p that is commonly
      overrepresented in lung cancer. The present study aimed to evaluate Skp2
      abnormalities and their prognostic value in non-small cell lung cancer (NSCLC).
      EXPERIMENTAL DESIGN: In total 16 NSCLC cell lines and 163 primary tumors were
      included in studies to measure Skp2 relative gene copy number, mRNA abundance,
      and protein level. The tumors were also evaluated for p27 protein expression
      level and ras mutation. These values were correlated with the clinical and
      pathological features of the patients. RESULTS: Skp2 relative gene copy number
      aberrations were found in 88 and 65% of NSCLC cell lines and primary tumors,
      respectively. Overrepresentation was especially common among squamous cell
      carcinoma (74%). Both gene copy overrepresentation (13%) and loss (35%) were
      found in adenocarcinoma. Skp2 relative gene copy number was significantly
      correlated with mRNA and protein levels, but none of these were correlated with
      p27 protein levels. Neither high Skp2 protein expression nor ras mutation was
      prognostically significant. In NSCLCs with ras mutation, however, high Skp2
      protein expression was a significant independent poor prognostic marker.
      CONCLUSION: There appears to be a synergistic interaction between high Skp2
      protein expression and ras mutation with negative impact on the survival of NSCLC
      patients.

PMID- 15041717
TI  - Association of pre- and postoperative plasma levels of transforming growth factor
      beta(1) and interleukin 6 and its soluble receptor with prostate cancer
      progression.
AB  - PURPOSE: We have shown that preoperative plasma levels of transforming growth
      factor-beta(1) (TGF-beta(1)), interleukin 6 (IL)-6, and its receptor (IL-6sR) are
      associated with prostate cancer progression and metastasis. The objectives of
      this study were to confirm these findings and to examine the association of
      changes in plasma levels of these markers after surgery with disease progression
      in a large consecutive cohort of patients. EXPERIMENTAL DESIGN: Plasma levels of
      TGF-beta(1), IL-6, and IL-6sR were measured pre- and postoperatively (6-8 weeks
      after surgery) in 302 consecutive patients who underwent radical prostatectomy
      for clinically localized disease. RESULTS: Pre- and postoperative levels of TGF
      beta(1) were significantly elevated in patients with extraprostatic extension,
      seminal vesicle involvement, and metastases to lymph nodes. In contrast,
      preoperative levels of IL-6 and IL-6sR, but not postoperative levels, were
      significantly associated with tumor volume, prostatectomy Gleason sum, and
      metastases to lymph nodes. In a postoperative model that included pre- and
      postoperative TGF-beta(1), IL-6, and IL-6sR and standard postoperative
      parameters, postoperative TGF-beta(1) and prostatectomy Gleason sum were
      significant predictors of overall and aggressive disease progression. Although,
      for all patients, plasma levels of all three markers declined significantly after
      prostate removal, for patients that experienced disease progression, only IL-6
      and IL-6sR levels decreased significantly. CONCLUSIONS: For patients undergoing
      radical prostatectomy, preoperative plasma levels of TGF-beta(1) and IL-6sR are
      associated with metastases to regional lymph nodes, presumed occult metastases at
      the time of primary treatment, and disease progression. After prostate removal,
      postoperative TGF-beta(1) level increases in value over preoperative levels for
      the prediction of disease progression.

PMID- 15041718
TI  - Epigenetic inactivation of TMS1/ASC in ovarian cancer.
AB  - PURPOSE: The purpose of this work was to explore the role of epigenetic
      inactivation of apoptotic pathways in ovarian cancer by examining the DNA
      methylation and expression status of four proapoptotic genes in primary ovarian
      cancers and cancer cell lines and to correlate those findings with the
      clinicopathological features of ovarian cancer patients. EXPERIMENTAL DESIGN:
      Genomic DNA was isolated from 15 ovarian cancer cell lines, 80 primary ovarian
      cancer specimens, and 4 normal ovary specimens using phenol-chloroform
      extraction. The methylation status of the DNA was evaluated using combined
      bisulfite restriction analysis, gene expression was evaluated using reverse
      transcription-PCR, and histone acetylation was evaluated using chromatin
      immunoprecipitation. RESULTS: Of the four proapoptotic genes studied, expression
      of TMS1/ASC was absent in six ovarian cancer cell lines. Dense methylation of the
      5' region of TMS1/ASC was detected in cells not expressing TMS1/ASC. Treating
      methylated cells with 5-aza-deoxycytidine restored gene expression, confirming
      the role of methylation in silencing the gene. Chromatin immunoprecipitation
      revealed histone to be deacetylated in cells not expressing TMS1/ASC, indicating
      that histone deacetylation is also involved in silencing TMS1/ASC. Aberrant
      methylation of TMS1/ASC was detected in 15 of 80 ovarian cancer tissues (19%) but
      in none of the normal ovary specimens. Aberrant methylation of TMS1/ASC was
      observed significantly more often in clear cell-type ovarian cancers than in
      other tumor types (P < 0.0001). CONCLUSIONS: Methylation-mediated silencing of
      TMS1/ASC confers a survival advantage to tumor cells by enabling them to escape
      apoptosis. The role for aberrant methylation in human ovarian tumorigenesis may
      be particularly important for ovarian cancers with the clear cell phenotype.

PMID- 15041719
TI  - Identification of altered protein expression and post-translational modifications
      in primary colorectal cancer by using agarose two-dimensional gel
      electrophoresis.
AB  - PURPOSE: Although numerous proteome studies have been performed recently to
      identify cancer-related changes in protein expression, only a limited display of
      relatively abundant proteins has been identified. The aim of this study is to
      identify novel proteins as potential tumor markers in primary colorectal cancer
      tissues using a high-resolution two-dimensional gel electrophoresis (2-DE).
      EXPERIMENTAL DESIGN: 2-DE using an agarose gel for isoelectric focusing was used
      to compare protein profiling of 10 colorectal cancer tissues and adjacent normal
      mucosa. Altered expression and post-translational modification of several
      proteins were examined using Western blot analysis and immunohistochemistry.
      RESULTS: Ninety-seven proteins of 107 spots (90.7%) that were differentially
      expressed between matched normal and tumor tissues were identified by mass
      spectrometry. Among them, 42 unique proteins (49 spots) significantly increased
      or decreased in the tumors. They include eukaryotic translation initiation factor
      4H, inorganic pyrophosphatase, anterior gradient 2 homologue, aldolase A, and
      chloride intracellular channel 1, whose elevated expression in tumor tissues was
      confirmed by Western blot analysis and immunohistochemistry. Interestingly, only
      isoform 1 of two transcript variants of eukaryotic translation initiation factor
      4H was greatly up-regulated in most of the tumor tissues. Moreover, post
      translational modifications of the prolyl-4-hydroxylase beta subunit and annexin
      A2 also were identified. CONCLUSIONS: We identified several novel proteins with
      altered expression in primary colorectal cancer using agarose 2-DE. This method
      is a powerful technique with which to search for not only quantitative but also
      qualitative changes in a biological process of interest and may contribute to the
      deeper understanding of underlying mechanisms of human cancer.

PMID- 15041720
TI  - Polymorphisms of the CYP1B1 gene as risk factors for human renal cell cancer.
AB  - PURPOSE: CYP1B1 activates various environmental carcinogens in human tissues,
      including renal tissues. We hypothesize that certain polymorphisms of the CYP1B1
      gene are risk factors for renal cell cancer. The rationale for this hypothesis is
      that chemical procarcinogenic compounds require metabolic activation by oxidative
      enzymes such as CYP1B1 to be transformed into potentially carcinogenic forms. To
      test this hypothesis, we investigated the genotypic distributions of six
      different loci on the CYP1B1 gene and their association with renal cell cancer.
      EXPERIMENTAL DESIGN: DNA from 211 cases of human renal cell cancer and 200
      healthy controls was analyzed by sequence-specific PCR and direct DNA sequencing
      to determine the genotypic frequencies of six different polymorphic loci on the
      CYP1B1 gene. RESULTS: The results of this study demonstrate that the frequencies
      of genotype 119T/T and genotype 432G/G were significantly higher in renal cell
      cancer patients compared with healthy normal controls. The relative risks were
      calculated as 3.01 and 2.17 for genotypes 119T/T and 432G/G, respectively, in
      renal cell carcinoma patients. These genotypic distributions were also
      significantly different between male and female patients. The relative risks of
      genotype 119T/T were calculated as 3.95 in males and 1.92 in females, and the
      relative risks of genotype 432G/G were calculated as 2.81 in males and 1.35 in
      females. CONCLUSIONS: The present study demonstrates for the first time that the
      polymorphisms at codons 119 and 432 may be risk factors for renal cancer,
      especially in the male population.

PMID- 15041721
TI  - Increased expression and secretion of interleukin-6 in patients with Barrett's
      esophagus.
AB  - PURPOSE: Barrett's esophagus (BE) is a common premalignant lesion of the distal
      part of the esophagus that arises as a consequence of chronic
      duodenogastroesophageal reflux. Interleukin (IL)-6 is a pleiotropic cytokine that
      regulates immune defense mechanisms and hematopoiesis. In addition, IL-6 may also
      be involved in malignant transformation and tumor progression. IL-6 has been
      shown to inhibit apoptosis. The major aim of this study was to evaluate
      expression of IL-6 in BE at the protein and mRNA levels. In addition, we tested
      whether proteins that are associated with IL-6 signaling, phosphorylated signal
      transducer and activator of transcription 3 and two antiapoptotic proteins, Bcl
      x(L) and Mcl-1, are also expressed in the same tissues. EXPERIMENTAL DESIGN:
      Biopsies of duodenum, BE, and squamous epithelium were evaluated by using a human
      cytokine protein array, ELISA, real-time PCR, and immunohistochemistry. RESULTS:
      Increased IL-6 levels were found to be secreted from BE tissue compared with
      duodenum or squamous epithelium from sites adjacent or 5 cm away from the BE
      lesion. IL-6 mRNA was also elevated in BE compared with duodenum or squamous
      epithelium in five of seven patients. Immunohistochemical studies confirmed IL-6
      expression in intestinal glandular epithelium in BE tissue. Activated signal
      transducer and activator of transcription 3, Mcl-1, and Bcl-x(L) are present at
      higher levels in BE glands, with lower levels being found in duodenum or squamous
      epithelium CONCLUSIONS: These data, taken together, suggest that elevated IL-6
      levels in BE may contribute to the development of apoptosis resistance, thereby
      placing this epithelium at higher risk of developing malignancy.

PMID- 15041722
TI  - Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence
      of age, grade, and histological type.
AB  - PURPOSE: BRCA1-related breast cancers are more frequently estrogen receptor (ER)
      negative than are either BRCA2-related or nonhereditary breast cancers. The
      relationship between ER status and other clinical features of hereditary breast
      cancers has not been well studied. EXPERIMENTAL DESIGN: ER status, grade, and
      histological tumor type were evaluated in 1131 women with invasive breast cancer,
      ascertained at 10 centers in North America. There were 208 BRCA1 mutation
      carriers, 88 BRCA2 carriers, and 804 women without a known mutation. We
      stratified the patients by mutation status, grade, age, and histological type and
      calculated the percentage of ER-positive tumors within each stratum. RESULTS:
      BRCA1 mutation carriers were more likely to have ER-negative breast cancers than
      were women in other groups, after adjustment for age, grade, and histological
      subtype (P < 0.001). Only 3.9% of BRCA1-related breast cancers were ER-positive
      cancers occurring in women in their postmenopausal years. The direction and
      magnitude of the change in ER status with increasing age at diagnosis in BRCA1
      carriers was significantly different from in BRCA2 carriers (P(intercept) =
      0.0002, P(slope) = 0.04). Notably, changes in ER status with age at diagnosis for
      BRCA1 carriers and noncarriers were almost identical (P(slope) = 0.98).
      CONCLUSIONS: The strong relationship between the presence of a BRCA1 mutation and
      the ER-negative status of the breast cancers is neither a consequence of the
      young age at onset nor the high grade but is an intrinsic property of BRCA1
      related cancers. The ER-negative status of these cancers may reflect the cell of
      origin of BRCA1-related cancers.

PMID- 15041723
TI  - Gene expression profiling identifies platelet-derived growth factor as a
      diagnostic molecular marker for papillary thyroid carcinoma.
AB  - PURPOSE: Cancer diagnostics and therapeutics are often based on clinically
      relevant markers that are expressed specifically in a malignant tissue at levels
      higher than in normal tissue. We examined potential markers for papillary thyroid
      carcinoma (PTC) by monitoring PTC-specific gene expression using cDNA microarray.
      EXPERIMENTAL DESIGN: Gene expression profiles for PTC tissue, normal thyroid
      tissue, and healthy peripheral blood cells were compared by use of a human 4000
      gene cDNA microarray. Protein expressions of the up-regulated genes in PTC were
      examined in thyroid tissues by immunohistochemistry. RESULTS: Sixty-four genes
      were overexpressed in PTC tissue relative to normal thyroid tissue and healthy
      peripheral blood cells. The genes that were up-regulated in PTC were involved in
      cell cycle regulation, DNA damage response, angiogenesis, and oncogenesis. Among
      these genes, basic fibroblast growth factor and platelet-derived growth factor
      were identified by immunochemical methods as proteins that are specifically
      expressed at high levels in thyroid neoplasms. Basic fibroblast growth factor,
      which has been identified as a biomarker for PTC, was overexpressed in 54% of PTC
      cases, 67% of follicular thyroid carcinomas, and 36% of benign thyroid neoplasms.
      Platelet-derived growth factor was overexpressed in 81% of PTC cases and 100% of
      follicular carcinomas, but was immunonegative in normal thyroid tissues and
      benign thyroid neoplasms. CONCLUSIONS: Platelet-derived growth factor may be a
      potential biomarker for PTC and follicular carcinoma. Expression profile analysis
      using a microarray followed by immunohistochemical study can be used to
      facilitate the development of molecular biomarkers for cancer.

PMID- 15041724
TI  - Id-1 and Id-2 proteins as molecular markers for human prostate cancer
      progression.
AB  - PURPOSE: Id proteins are dominant-negative regulators of basic helix-loop-helix
      transcription factors that control malignant cell behavior in many different
      tissues. This study aimed to identify the potential role of Id-1 and Id-2
      proteins as molecular makers for prostate cancer progression. EXPERIMENTAL
      DESIGN: Using the technique of immunohistochemistry, we determined Id-1 and Id-2
      expression in a panel of 67 human prostate biopsies. We also manipulated Id-1 and
      Id-2 expression in LNCaP and PC3 prostate cancer cell lines and determined the
      effects on invasion in vitro, matrix metalloproteinase secretion, and
      proliferation. RESULTS: Both Id-1 and Id-2 proteins were up-regulated during
      human prostate cancer progression in vivo and were overexpressed in highly
      aggressive prostate cancer cells. In vitro, constitutive expression of Id-1, and
      to a lesser extent Id-2, converted nonaggressive LNCaP prostate cancer cells into
      more proliferative and invasive cells and increased their secretion of matrix
      metalloproteinases. Conversely, the down-regulation of Id-2 expression in highly
      metastatic PC3 cells reduced their growth potential and invasiveness.
      CONCLUSIONS: We propose that both Id-1 and Id-2 proteins control prostate cancer
      cell phenotypes and could serve as molecular markers of aggressive human prostate
      cancer.

PMID- 15041725
TI  - Estrogen receptor/progesterone receptor-negative breast cancers of young African
      American women have a higher frequency of methylation of multiple genes than
      those of Caucasian women.
AB  - PURPOSE: To provide a molecular rationale for negative prognostic factors more
      prevalent in African-American (AA) than Caucasian (Cau) women, we investigated
      the frequency of promoter hypermethylation in invasive ductal breast cancers in
      the two races. EXPERIMENTAL DESIGN: HIN-1, Twist, Cyclin D2, RAR-beta, and
      RASSF1A were analyzed in DNA from 67 AA and 44 Cau invasive ductal breast
      cancers, stratified by age and estrogen receptor/progesterone receptor (ER/PR)
      status, by methylation-specific PCR. Hierarchical multiple logistic regression
      analysis was applied to determine estimated probabilities of methylation.
      Expression of HIN-1 mRNA was analyzed by in situ hybridization and quantitative
      reverse transcribed PCR. RESULTS: Significant differences between races were
      observed in the ER-/PR-, age < 50 subgroup; AA tumors had higher frequency of
      methylation (P < 0.001) in four of five genes as compared with Cau and also a
      higher prevalence (80 versus 0%; P < 0.005) of three or more methylated genes per
      tumor. No differences in gene methylation patterns were observed across the two
      races for ER+/PR+ tumors in all ages and ER-/PR- tumors in age > 50. ER+/PR+
      status was associated with higher frequency of methylation in Cau tumors of all
      ages but only with the age > 50 subgroup in AA. Frequent Cyclin D2 methylation
      was significantly associated (P = 0.01) with shorter survival time. CONCLUSION:
      ER-/PR-, age < 50 tumors in AA women, have a significantly higher frequency of
      hypermethylation than in those of Cau women. Comparative studies, such as these,
      could provide a molecular basis for differences in tumor progression and
      pathology seen in the two races.

PMID- 15041726
TI  - Immunohistochemical assessment of the peripheral benzodiazepine receptor in
      breast cancer and its relationship with survival.
AB  - PURPOSE: The peripheral benzodiazepine receptor (PBR) expression has been shown
      dramatically increased in neoplastic tissues and tumor cell lines originated from
      ovary, liver, colon, breast, or brain relative to untransformed tissues. Its
      expression has been also associated with tumor progression and aggressiveness. To
      explore whether PBR expression level could be of prognostic value in invasive
      breast cancer, we studied a series of 117 patients who underwent surgery for
      primary breast carcinomas and were followed-up for 8 years. EXPERIMENTAL DESIGN:
      Using an immunohistochemical approach, we first compared PBR expression in normal
      and tumoral tissues, then we studied PBR expression together with
      clinicopathological variables (histological type, histological grade, lymph node,
      estrogen and progesterone receptor status), and biological markers such as BclII,
      Ki-67, and HER2/Neu. RESULTS: Our results revealed a significant increase of PBR
      expression in tumoral versus normal breast cells. We found a negative correlation
      between PBR expression and estrogen receptor status (P = 0.03) as well as a
      positive correlation between PBR and Ki-67 (P = 0.044). Although the disease-free
      survival was not affected by PBR in the whole population, high PBR expression
      level was significantly correlated with a shorter disease-free survival in the
      lymph node-negative patients, P = 0.038. CONCLUSIONS: As the axillary lymph node
      negative status is generally considered as a good prognosis factor, the high
      expression of PBR in this patient subgroup may be used to identify a new high
      risk population, for which a more specific therapy would be beneficial.

PMID- 15041727
TI  - Overexpression and amplification of Aurora-A in hepatocellular carcinoma.
AB  - PURPOSE: Aurora-A/STK15/BTAK, a centrosome-associated serine/threonine kinase,
      has been shown to induce chromosomal instability, leading to aneuploidy and cell
      transformation. The purpose of this study was to investigate the expression and
      amplification of Aurora-A in hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN:
      Aurora-A mRNA levels were measured in 224 HCCs and 199 paired nontumorous liver
      tissues by reverse transcription-PCR. Aurora-A mRNA and protein levels of 8 were
      also measured by reverse transcription-PCR and Western blot hybridization in 8
      liver cancer cell lines. Amplification of Aurora-A was determined by Southern
      blot hybridization in 99 cases. RESULTS: Aurora-A was overexpressed in 137 of 224
      (61%) HCCs and all 8 of the cell lines. Overexpression of Aurora-A was associated
      with high-grade (grade II-IV), and high-stage (stage IIIB-IV) tumors, p53
      mutation, infrequent beta-catenin mutation, and poor outcome. Aurora-A
      overexpression and p53 mutation acted synergistically toward poor prognosis.
      Amplification of Aurora-A was detected only in 3 HCCs. CONCLUSION: The results
      show that Aurora-A is overexpressed frequently in HCC, and correlated with high
      grade and high stage, indicating that overexpression of Aurora-A plays a role in
      the development and progression of HCC.

PMID- 15041728
TI  - Levels of expression of CYR61 and CTGF are prognostic for tumor progression and
      survival of individuals with gliomas.
AB  - The biological properties of CCN proteins include stimulation of cell
      proliferation, migration, and adhesion, as well as angiogenesis and
      tumorigenesis. We quantified CYR61, CTGF, WISP-1, and NOV mRNA expression levels
      in samples from sixty-six primary gliomas and five normal brain samples using
      quantitative real-time PCR assay. Statistical analysis was performed to explore
      the links between expression of the CCN genes and clinical and pathological
      parameters. Overexpression of CYR61, CTGF, WISP-1, and NOV occurred in 48% (32 of
      66), 58% (38 of 66), 36% (24 of 66), and 15% (10 of 66) of primary gliomas,
      respectively. Interestingly, significant associations were found between CYR61
      expression versus tumor grade, pathology, gender, and age at diagnosis. Also, a
      significant correlation existed between CTGF mRNA levels versus tumor grade,
      gender, and pathology. In contrast to CYR61 and CTGF, no significant association
      was found between expression of either WISP-1 or NOV versus any of the
      pathological features. Furthermore, Cox regression analysis showed that CYR61 and
      CTGF expression had a significant correlation with patient survival. These
      results suggest that CYR61 and CTGF may play a role in the progression of
      gliomas; their levels at diagnosis may have prognostic significance; and these
      proteins might serve as valuable targets for therapeutic intervention.

PMID- 15041729
TI  - Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in
      breast cancer.
AB  - PURPOSE: Human DOC-2/DAB2 interactive protein (hDAB2IP) gene is a novel member of
      the Ras GTPase-activating family and has been demonstrated to be a tumor
      suppressor gene inactivated by methylation in prostate cancer. We analyzed
      methylation and expression status of hDAB2IP in breast cancer. EXPERIMENTAL
      DESIGN: The promoter region of hDAB2IP was divided into two regions (m2a and m2b)
      following our previous report on prostate cancer, and methylation status was
      determined in breast cancer cell lines with bisulfited DNA sequencing. Expression
      was semiquantified with real-time reverse transcription-PCR to find that aberrant
      methylation showed the inverse relationship with expression. On the basis of
      sequence data, we developed methylation-specific PCR for m2a and m2b regions and
      applied to samples. RESULTS: Aberrant methylation was detected in 11 of 25 breast
      cancer cell lines (44%) and 15 of 39 primary tumors (38%) at the m2a region and
      in 12 of 25 cell lines (48%) and 13 of 39 tumors (33%) at the m2b region. In
      addition, gene expression was restored in methylated cell lines with 5-aza-2'
      deoxycytidine, confirming that methylation caused gene down-regulation. We also
      examined the relationship between hDAB2IP methylation and clinicopathologic
      features in primary tumors and found that methylation in the m2b region was
      associated with progressive nodal status of tumors. CONCLUSIONS: We developed
      methylation-specific PCR for hDAB2IP and examined its methylation status in
      breast cancer. Our results demonstrate that hDAB2IP methylation frequently is
      present in breast cancer and plays a key role in hDAB2IP inactivation, suggesting
      the relationship between hDAB2IP methylation and lymph node metastasis of breast
      cancer.

PMID- 15041730
TI  - Expression of UDP-N-acetyl-alpha-D-galactosamine-polypeptide N
      acetylgalactosaminyltransferase isozyme 3 in the subserosal layer correlates with
      postsurgical survival of pathological tumor stage 2 carcinoma of the gallbladder.
AB  - PURPOSE AND EXPERIMENTAL DESIGN: Little is known about the molecular events
      leading to the development and progression of pathological tumor stage 2 (pT(2))
      gallbladder carcinoma. An alteration in the site of O-glycosylation may be
      associated with malignant behavior of carcinoma cells by modulation of the
      biological properties of the target mucin. The UDP-N-acetyl-alpha-D-galactosamine
      polypeptide N-acetylgalactosaminyltransferase isozyme 3 (GalNAc-T3) has the
      epithelial gland-specific expression and catalyzes mucin-type O-glycosylation. In
      this study, immunohistochemistry was performed to determine the expression level
      of GalNAc-T3 in 34 cases of pT(2) gallbladder carcinoma to determine the
      correlation of the GalNAc-T3 expression level with mode of recurrence and
      postsurgical survival. RESULTS: The expression levels of GalNAc-T3 protein and
      mRNA were increased in gallbladder carcinomas compared with the levels in
      adjacent noncancerous tissues and in intact gallbladders. Immunostaining of
      GalNAc-T3 was recognized in the cancerous epithelia, and the subcellular
      localization was classified into granular and diffuse types. In the 34 cases of
      pT(2) carcinoma, the localization of GalNAc-T3 was granular type in 50% and
      diffuse type in 50% of the cases at the deepest invading sites in the subserosal
      layer. Postsurgical recurrence was significantly more frequent in cases showing
      diffuse-type localization of GalNAc-T3 at the deepest invading sites (65%) than
      in those showing granular-type localization (23%; P < 0.05). Postsurgical
      survival was significantly poorer in cases showing diffuse-type localization than
      in those showing granular-type localization (P = 0.033) CONCLUSIONS: In pT(2)
      gallbladder carcinoma, the presence of diffuse-type localization of GalNAc-T3 in
      the subserosal layer is correlated with aggressiveness of the disease. This
      phenotype may serve as a unique biological feature associated with the malignant
      behavior.

PMID- 15041731
TI  - Antisense oligonucleotide targeting of Raf-1: importance of raf-1 mRNA expression
      levels and raf-1-dependent signaling in determining growth response in ovarian
      cancer.
AB  - PURPOSE: We sought to identify determinants of growth response to the Raf-1
      targeted antisense oligonucleotide (ASO; ISIS 5132) using a large panel of
      ovarian cancer cell lines. EXPERIMENTAL DESIGN: First-(ISIS 5132) and second
      generation (ISIS 13650) anti-Raf 1 ASOs were compared with control
      oligonucleotides. Growth was assessed by cell counts; apoptosis was assessed by
      poly(ADP-ribose) polymerase cleavage; and cell cycle analysis was assessed by
      flow cytometry. Protein expression was detected by Western blot analysis, and
      mRNA expression was detected by quantitative reverse transcription-PCR. Raf-1
      kinase activity was detected by anti-Raf-1 immunoprecipitation, followed by
      myelin basic protein phosphorylation. RESULTS: A panel of 15 ovarian cancer cell
      lines was used to model a range of growth responses to ASOs targeting Raf-1 mRNA.
      Growth inhibition varied from 10% to >90% inhibition. Growth inhibition was
      associated with increased apoptosis and accumulation of cells in the G(2)-M and S
      phases of the cell cycle. Growth response was not related to level of Raf-1
      protein expression, Raf-1 kinase activity, intracellular ASO uptake, or degree of
      Raf-1 protein inhibition. However, ASO growth response was associated with a high
      proportion of Raf-1 mRNA [relative to total (i.e., Raf-1 + A-Raf + B-Raf) Raf
      mRNA] and significantly higher Raf-1 kinase activity induction following growth
      factor (transforming growth factor alpha) stimulation in the cell lines
      consistent with dependency of these cell lines on Raf-1. CONCLUSIONS: These data
      indicate that ovarian cancers demonstrate differential sensitivity to ASOs
      targeted against Raf-1, and target expression levels and degree of utilization of
      Raf-1 signaling are implicated. Clinically sensitive tumors could feasibly be
      identified.

PMID- 15041732
TI  - Rapamycin-induced endothelial cell death and tumor vessel thrombosis potentiate
      cytotoxic therapy against pancreatic cancer.
AB  - PURPOSE: Despite current chemotherapies, pancreatic cancer remains an
      uncontrollable, rapidly progressive disease. Here, we tested an approach
      combining a recently described antiangiogenic drug, rapamycin, with standard
      gemcitabine cytotoxic therapy on human pancreatic tumor growth. EXPERIMENTAL
      DESIGN: Tumor growth was assessed in rapamycin and gemcitabine-treated nude mice
      orthotopically injected with metastatic L3.6pl human pancreatic cancer cells. H&E
      staining was performed on tumors, along with Ki67 staining for cell proliferation
      and immunohistochemical terminal deoxynucleotidyl transferase-mediated nick end
      labeling and CD31 analysis. Rapamycin-treated tumor vessels were also directly
      examined in dorsal skin-fold chambers for blood flow after thrombosis induction.
      Cell death in human umbilical vein endothelial cells was assessed by flow
      cytometry after annexin-V staining. RESULTS: Rapamycin therapy alone inhibited
      tumor growth and metastasis more than gemcitabine, with remarkable long-term
      tumor control when the drugs were combined. Mechanistically, H&E analysis
      revealed tumor vessel endothelium damage and thrombosis with rapamycin treatment.
      Indeed, dorsal skin-fold chamber analysis of rapamycin-treated tumors showed an
      increased susceptibility of tumor-specific vessels to thrombosis. Furthermore,
      terminal deoxynucleotidyl transferase-mediated nick end labeling/CD31 double
      staining of orthotopic tumors demonstrated apoptotic endothelial cells with
      rapamycin treatment, which also occurred with human umbilical vein endothelial
      cells in vitro. In contrast, gemcitabine was not antiangiogenic and, despite its
      known cytotoxicity, did not reduce proliferation in orthotopic tumors;
      nevertheless, rapamycin did reduce tumor proliferation. CONCLUSIONS: Our data
      suggest a novel mechanism whereby rapamycin targets pancreatic tumor endothelium
      for destruction and thrombosis. We propose that rapamycin-based vascular
      targeting not only reduces tumor vascularization, it decreases the number of
      proliferating tumor cells to be destroyed by gemcitabine, thus introducing a new,
      clinically feasible strategy against pancreatic cancer.

PMID- 15041733
TI  - Induction of apoptosis in human myeloid leukemic cells by 1'-acetoxychavicol
      acetate through a mitochondrial- and Fas-mediated dual mechanism.
AB  - PURPOSE: The purpose of this investigation was to determine the antileukemic
      effects of 1'-acetoxychavicol acetate (ACA) obtained from rhizomes of the
      commonly used ethno-medicinal plant Languas galanga (Zingiberaceae). EXPERIMENTAL
      DESIGN: We evaluated the effects of ACA on various myeloid leukemic cells in
      vitro and in vivo. We further examined the molecular mechanisms of ACA-induced
      apoptosis in myeloid leukemic cells. RESULTS: Low-dose ACA dramatically inhibited
      cellular growth of leukemic cells by inducing apoptosis. Because NB4
      promyelocytic leukemic cells were most sensitive to ACA, we used NB4 cells for
      further analyses. Production of reactive oxygen species triggered ACA-induced
      apoptosis. ACA-induced apoptosis in NB4 cells was in association with the loss of
      mitochondrial transmembrane potential (DeltaPsim) and activation of caspase-9,
      suggesting that ACA-induced death signaling is mediated through a mitochondrial
      oxygen stress pathway. In addition, ACA activated Fas-mediated apoptosis by
      inducing of casapse-8 activity. Pretreatment with the thiol antioxidant N-acetyl
      L-cysteine (NAC) did not inhibit caspase-8 activation, and the antagonistic anti
      Fas antibody ZB4 did not block generation of reactive oxygen species, indicating
      that both pathways were involved independently in ACA-induced apoptosis.
      Furthermore, ACA had a survival advantage in vivo in a nonobese diabetic/severe
      combined immunodeficient mice leukemia model without any toxic effects.
      CONCLUSIONS: We conclude that ACA induces apoptosis in myeloid leukemic cells via
      independent dual pathways. In addition, ACA has potential as a novel therapeutic
      agent for the treatment of myeloid leukemia.

PMID- 15041735
TI  - A human cytotoxic T-lymphocyte epitope and its agonist epitope from the
      nonvariable number of tandem repeat sequence of MUC-1.
AB  - PURPOSE: MUC-1/DF-3 remains an attractive target for vaccine therapy. It is
      overexpressed in the majority of human carcinomas and multiple myeloma. Clinical
      trials using MUC-1-based vaccines have demonstrated safety, clinical responses,
      and the induction of T-cell responses directed against MUC-1. Previous studies in
      experimental models and in clinical trials have demonstrated that altering the
      amino acid sequence of a "self" epitope can lead to the generation of an enhancer
      agonist epitope capable of eliciting stronger T-cell responses than the native
      epitope can. EXPERIMENTAL DESIGN AND RESULTS: We describe here the identification
      of six novel class I HLA-A2 epitopes of MUC-1 that reside outside of the variable
      number of tandem repeat region. Each is shown to have the ability to activate
      human T cells as measured by IFN-gamma production. One epitope (ATWGQDVTSV, at
      amino acid position 92-101 and designated P-92), which demonstrated the highest
      level of binding to HLA-A2 and which induced the highest level of IFN-gamma in
      human T cells, was further studied for the generation of potential enhancer
      agonist epitopes. Of four potential agonists identified, one epitope (ALWGQDVTSV,
      designated P-93L) was identified as an enhancer agonist. Compared with the native
      P-92 peptide, the P-93L agonist (a). bound HLA-A2 at lower peptide
      concentrations, (b). demonstrated a higher avidity for HLA-A2 in dissociation
      assays, (c). when used with antigen-presenting cells, induced the production of
      more IFN-gamma by T cells than with the use of the native peptide, and (d). was
      capable of more efficiently generating MUC-1-specific human T-cell lines from
      normal volunteers and pancreatic cancer patients. Most importantly, the T-cell
      lines generated using the agonist epitope were more efficient than those
      generated with the native epitope in the lysis of targets pulsed with the native
      epitope and in the lysis of HLA-A2 human tumor cells expressing MUC-1.
      CONCLUSIONS: In addition to the identification of novel MUC-1 epitopes outside
      the variable number of tandem repeat region, the studies reported here describe
      the first agonist epitope of MUC-1. The employment of this agonist epitope in
      peptide-, protein-, and vector-based vaccines may well aid in the development of
      effective vaccines for a range of human cancers.

PMID- 15041734
TI  - Pharmacokinetics, methionine depletion, and antigenicity of recombinant
      methioninase in primates.
AB  - Pharmacokinetics, methionine depletion, antigenicity, and toxicity of recombinant
      methioninase (rMETase), which has shown efficacy in achieving cell kill in a
      broad range of human tumor models, were examined in macaque monkeys. Dose-ranging
      studies at 1000, 2000, and 4000 units/kg i.v. identified the 4000 units/kg dose
      as able to reduce plasma methionine to an undetectable level (less than 0.5
      microM) by 30 min, and the level so remained for 8 h. Pharmacokinetic analysis
      showed that rMETase was eliminated with a T(1/2) of 2.49 h. A 2-week i.v.
      administration of 4000 units/kg every 8 h/day for 2 weeks resulted in a steady
      state depletion of plasma methionine to less than 2 microM. The only manifest
      toxicity was decreased food intake and slight weight loss. Serum albumin and red
      cell values declined transiently during treatment, which may be related to
      extensive blood sampling. Re-challenge on day 28 resulted in anaphylactic shock
      and death in one animal. Subsequent pretreatment with hydrocortisone prevented
      the anaphylactic reaction, although vomiting was frequently observed. Re
      challenge was carried out at days 66, 86, and 116. Anti-rMETase antibodies (at
      10(-3)) were found after the first challenge, and these increased to 10(-6) after
      the fourth challenge and decreased to 10(-2) by 2 months post therapy. The main
      rMETase antibody was IgG, and although it has some in vitro features of being a
      neutralizing antibody, each challenge dose was effective in depleting plasma
      methionine levels. Thus, rMETase was able to effectively deplete plasma
      methionine levels with minimal toxicity in a primate model. These data provide
      the bases for alteration by polyethyleneglycol conjugation (PEGylation) of the
      enzyme to increase its duration of effect and reduce its immunogenicity.

PMID- 15041736
TI  - Orthotopic implantation of human hepatocellular carcinoma in mice: analysis of
      tumor progression and establishment of the BCLC-9 cell line.
AB  - PURPOSE: To allow the longitudinal investigation of molecular events associated
      with the progression of human hepatocellular carcinoma (HCC), we sought to
      develop a murine model by orthotopic implantation of tumor fragments obtained
      from patients diagnosed at early stage. EXPERIMENTAL DESIGN: Tumor pieces (2 x 2
      mm) were implanted on the liver surface of nu/nu mice. After xenograft growing,
      subsequent passages were performed to achieve long-term implant viability.
      Isolation of tumoral hepatocytes was done to establish new cell lines. HCC
      characteristics, proliferation rate, apoptotic index (terminal deoxynucleotidyl
      transferase-mediated nick end labeling), and expression of cell-cycle regulators
      (cyclins E and A, p21(Cip1), p27(Kip1), p16(INK4a), pRb, and p53) were assessed
      by Western Blot and immunohistochemistry, to correlate them with tumor
      progression. RESULTS: Five (50%) of the 10 primary HCCs resulted in small slow
      growing liver implants. Three of them are viable after 48 months, whereas the
      remaining two survived for 15 and 13 months. Xenografts throughout passages
      exhibited a more aggressive phenotype with a poorer degree of differentiation,
      intense proliferation, moderate apoptosis, cell-cycle deregulation, p53
      alterations, microvascular invasion, and dissemination. In one single passage, we
      observed critical growth delay, which was associated with significant p27(kip1)
      overexpression. We established the anchor-free growing BCLC-9 cell line from one
      xenograft. This has gains of chromosomes 7, 5p, 6q, and 9q, is hepatitis B virus
      DNA positive, does not secrete alpha-fetoprotein, and has TP53 missense mutations
      in codons 192 and 242. CONCLUSIONS: The orthotopic implantation of early HCC
      fragments in nude mice provides a useful model to investigate the mechanisms of
      human HCC evolution and to establish new cell lines.

PMID- 15041737
TI  - Characterization of p53 wild-type and null isogenic colorectal cancer cell lines
      resistant to 5-fluorouracil, oxaliplatin, and irinotecan.
AB  - To elucidate mechanisms of resistance to chemotherapies currently used in the
      first-line treatment of advanced colorectal cancer, we have developed a panel of
      HCT116 p53 wild-type (p53(+/+)) and null (p53(-/-)) isogenic colorectal cancer
      cell lines resistant to the antimetabolite 5-fluorouracil (5-FU), topoisomerase I
      inhibitor irinotecan (CPT-11), and DNA-damaging agent oxaliplatin. These cell
      lines were generated by repeated exposure to stepwise increasing concentrations
      of each drug over a period of several months. We have demonstrated a significant
      decrease in sensitivity to 5-FU, CPT-11, and oxaliplatin in each respective
      resistant cell line relative to the parental line as determined by 3-(4,5
      dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, with increases in
      IC(50 (72 h)) concentrations ranging from 3- to 65-fold. Using flow cytometry, we
      have also demonstrated compromised apoptosis and cell cycle arrest in 5-FU-,
      oxaliplatin-, and CPT-11-resistant cell lines compared with the parental lines
      after exposure to each drug. In addition, we found that resistance to 5-FU and
      oxaliplatin was higher in parental p53(-/-) cells compared with parental p53(+/+)
      cells, with an approximately 5-fold increase in IC(50 (72 h)) for each drug. In
      contrast, the IC(50 (72 h)) doses for CPT-11 were identical in the p53 wild-type
      and null cell lines. Furthermore, apoptosis after treatment with 5-FU and
      oxaliplatin, but not CPT-11, was significantly reduced in parental p53(-/-) cells
      compared with parental p53(+/+) cells. These data suggest that p53 may be an
      important determinant of sensitivity to 5-FU and oxaliplatin but not CPT-11.
      Using semiquantitative reverse transcription-PCR, we have demonstrated down
      regulation of thymidine phosphorylase mRNA in both p53(+/+) and p53(-/-) 5-FU
      resistant cells, suggesting that decreased production of 5-FU active metabolites
      may be an important resistance mechanism in these lines. In oxaliplatin-resistant
      cells, we noted increased mRNA levels of the nucleotide excision repair gene
      ERCC1 and ATP-binding cassette transporter breast cancer resistance protein. In
      CPT-11-resistant cells, we found reduced mRNA levels of carboxylesterase, the
      enzyme responsible for converting CPT-11 to its active metabolite SN-38, and
      topoisomerase I, the SN-38 target enzyme. In addition, we noted overexpression of
      breast cancer resistance protein in the CPT-11-resistant lines. These cell lines
      are ideal tools with which to identify novel determinants of drug resistance in
      both the presence and absence of wild-type p53.

PMID- 15041738
TI  - Novel temperature-sensitive liposomes with prolonged circulation time.
AB  - Hyperthermia increases the efficiency of various chemotherapeutic drugs and is
      administered as an adjunct to chemotherapy for the treatment of cancer patients.
      The temperature-dependent effect can be strongly increased by the use of
      temperature-sensitive liposomes in combination with regional hyperthermia, which
      specifically releases the entrapped drug in the heated tumor tissue. The novel
      lipid 1.2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG), which is
      closely related to the naturally occurring 1.2-dipalmitoyl-sn-glycero-3
      phosphoglycerol, in combination with 1.2-dipalmitoyl-sn-glycero-3-phosphocholine
      and 1.2-distearoyl-sn-glycero-3-phosphocholine provides long-circulating
      temperature-sensitive liposomes with favorable properties under mildly
      hyperthermic conditions (41-42 degrees C). DPPGOG facilitates temperature
      triggered drug release from these liposomes (diameter, 175 nm) and leads to a
      substantially prolonged plasma half-life for the encapsulated drug with t(1/2) =
      9.6 h in hamsters and t(1/2) = 5.0 h in rats. Quantitative fluorescence
      microscopy of amelanotic melanoma grown in the transparent dorsal skin fold
      chamber of hamsters demonstrated a favorable drug accumulation in heated tissue
      after i.v. application of these liposomes (42 degrees C for 1 h). The mean area
      under the curve for tissue drug concentration was increased by more than sixfold
      by application of the new liposomes compared with nonliposomal drug delivery. In
      summary, we present a new DPPGOG-based liposomal formulation enabling long
      circulation time combined with fast and efficient drug release under mild
      hyperthermia. This adds positively to the results with lipid-grafted
      polyethylenglycol used thus far in temperature sensitive liposomes and widens the
      possibilities for clinical applications.

PMID- 15041739
TI  - Murine endothelial cell lines as models of tumor endothelial cells.
AB  - Identification of appropriate models for in vivo and in vitro preclinical testing
      of inhibitors of tumor angiogenesis and progression is vital to the successful
      development of anticancer therapeutics. Although the focus is on human molecular
      targets, most preclinical in vivo efficacy testing occurs in mice. The goal of
      the current studies was to identify a murine endothelial cell line to model tumor
      endothelium for studying the antiangiogenic activity of therapeutic compounds in
      vitro. In situ hybridization was performed on three s.c. grown syngeneic murine
      tumors (B16 melanoma, Lewis lung carcinoma, and CT26 colon carcinoma) to assess
      expression of murine homologs of human tumor endothelial cell markers in the
      vasculature of these tumor models. Seven murine endothelial cell lines were
      characterized for expression of the murine homologs of recognized endothelial
      cell surface markers as well as for tumor endothelial cell surface markers. The
      seven murine endothelial cell lines had similar generation times and five of the
      seven lines were able to form tubes on Matrigel. Real-time-PCR and flow cytometry
      analysis were used to evaluate relative mRNA and protein expression of murine
      homologs of several recognized endothelial cell surface markers in the seven cell
      lines. The expression of the mRNA for the murine homologs of five tumor
      endothelial cell surface markers was also evaluated. The 2H11 cell line expressed
      all five of the tumor endothelial cell surface markers as well as several well
      recognized endothelial cells markers. The 2H11 cell line responds to known and
      novel antiangiogenic agents by inhibition of proliferation and tube formation.
      These cells can be used in in vitro angiogenesis assays for evaluating the
      potential antiangiogenic properties and interspecies cross-reactivity of novel
      compounds.

PMID- 15041740
TI  - Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats.
AB  - PURPOSE: We wanted to investigate the antitumor effects and effect on
      angiogenesis of resveratrol in rat RT-2 gliomas. EXPERIMENTAL DESIGN: RT-2 glioma
      cells were treated with resveratrol, and then cytotoxicity was assayed, apoptosis
      was measured by flow-activated cell sorter flow cytometry, and expression of
      vascular endothelial growth factor was measured by reverse transcription-PCR.
      Tumor size, animal survival time, and survival rate were followed in resveratrol
      treated rats with s.c. or intracerebral gliomas. Furthermore, in vitro
      proliferation was assayed to explore the effect of resveratrol on the
      proliferation of ECV304 human umbilical vein endothelial cells. Expression of
      CD31 in resveratrol-treated gliomas was followed immunohistochemically to study
      the effect of resveratrol on the glioma-induced angiogenesis. RESULTS:
      Resveratrol was demonstrated to exert cytotoxic effects and induce glioma cell
      apoptosis in a concentration- and time-dependent manner (P < 0.05). Resveratrol
      (40 mg/kg/day) exerted significant antitumor effects on s.c. tumors, including
      slower tumor growth rate, longer animal survival time, and higher animal survival
      rate (P < 0.05). In contrast, resveratrol affected intracerebral tumors at only
      an increased dose (100 mg/kg/day), prolonging animal survival (P < 0.05) without
      affecting survival rate. The expression of vascular endothelial growth factor in
      the glioma cells and the proliferation of ECV304 cells were inhibited by
      resveratrol in a concentration-dependent manner. Immunohistochemical analyses
      showed that the s.c. gliomas from resveratrol-treated rats had fewer microvessel
      densities than did control rats (P < 0.01). CONCLUSIONS: Resveratrol caused
      significant glioma cell cytotoxicity and apoptosis, exerted antitumor effects on
      the s.c. and intracerebral gliomas, and inhibited angiogenesis in s.c. gliomas.
      Thus, resveratrol might be considered a possible treatment strategy for gliomas.

PMID- 15041741
TI  - Galanin acts as a neuroprotective factor to the hippocampus.
AB  - The expression of the neuropeptide galanin is markedly up-regulated in many areas
      of the central and peripheral nervous system after injury. We have recently
      demonstrated that peripheral sensory neurons depend on galanin for neurite
      extension after injury, mediated by activation of the second galanin receptor
      subtype (GALR2). We therefore hypothesized that galanin might also act in a
      similar manner in the CNS, reducing cell death in hippocampal models of
      excitotoxicity. Here we report that galanin acts an endogenous neuroprotective
      factor to the hippocampus in a number of in vivo and in vitro models of injury.
      Kainate-induced hippocampal cell death was greater in both the CA1 and CA3
      regions of galanin knockout animals than in WT controls. Similarly, exposure to
      glutamate or staurosporine induced significantly more neuronal cell death in
      galanin knockout organotypic and dispersed primary hippocampal cultures than in
      WT controls. Conversely, less cell death was observed in the hippocampus of
      galanin overexpressing transgenic animals after kainate injection and in
      organotypic cultures after exposure to staurosporine. Further, exogenous galanin
      or the previously described high-affinity GALR2 agonist, both reduced cell death
      when coadministered with glutamate or staurosporine in WT cultures. These results
      demonstrate that galanin acts an endogenous neuroprotective factor to the
      hippocampus and imply that a galanin agonist might have therapeutic uses in some
      forms of brain injury.

PMID- 15041743
TI  - Stable association between strains of Mycobacterium tuberculosis and their human
      host populations.
AB  - Mycobacterium tuberculosis is an important human pathogen in virtually every part
      of the world. Here we investigate whether distinct strains of M. tuberculosis
      infect different human populations and whether associations between host and
      pathogen populations are stable despite global traffic and the convergence of
      diverse strains of the pathogen in cosmopolitan urban centers. The recent global
      movement and transmission history of 100 M. tuberculosis isolates was inferred
      from a molecular epidemiologic study of tuberculosis that spans 12 years. Genetic
      relationships among these isolates were deduced from the distribution of large
      genomic deletions, which were identified by DNA microarray and confirmed by PCR
      and sequence analysis. Phylogenetic analysis of these deletions indicates that
      they are unique event polymorphisms and that horizontal gene transfer is
      extremely rare in M. tuberculosis. In conjunction with the epidemiological data,
      phylogenies reveal three large phylogeographic regions. A host's region of origin
      is predictive of the strain of tuberculosis he or she carries, and this
      association remains strong even when transmission takes place in a cosmopolitan
      urban center outside of the region of origin. Approximate dating of the time
      since divergence of East Asian and Philippine clades of M. tuberculosis suggests
      that these lineages diverged centuries ago. Thus, associations between host and
      pathogen populations appear to be highly stable.

PMID- 15041742
TI  - Simvastatin induces apoptosis of Epstein-Barr virus (EBV)-transformed
      lymphoblastoid cell lines and delays development of EBV lymphomas.
AB  - Simvastatin and pravastatin are inhibitors of 3-hydroxy-3-methylglutaryl CoA
      reductase, and are used as antihypercholesterolemia drugs. Simvastatin, but not
      pravastatin, binds to the inserted domain of leukocyte function antigen (LFA)-1
      and inhibits the function of LFA-1, including adhesion and costimulation of
      lymphocytes. Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines
      (LCLs) express high levels of LFA-1 on their surface and grow in tight clumps.
      Here we show that simvastatin (2 microM) inhibits clump formation and induces
      apoptosis of EBV-transformed LCLs. The apoptosis-inducing effect of simvastatin
      depends on binding to the inserted domain of LFA-1. Simvastatin, but not
      pravastatin, dissociates EBV latent membrane protein 1 from lipid rafts of LCLs,
      resulting in down-regulation of nuclear factor kappaB activity and induction of
      apoptosis. Analysis of multiple EBV-positive and -negative cell lines indicated
      that both LFA-1 and EBV latent membrane protein 1 expression were required for
      simvastatin's effects. Administration of simvastatin to severe combined
      immunodeficiency mice followed by inoculation with LCLs resulted in delayed
      development of EBV lymphomas and prolonged survival of animals. To our knowledge,
      this is the first report in which a drug that targets LFA-1 has been used to
      treat B cell lymphoma. These data suggest that simvastatin may have promise for
      treatment or prevention of EBV-associated lymphomas that occur in
      immunocompromised persons.

PMID- 15041744
TI  - Total chemical synthesis and electrophysiological characterization of
      mechanosensitive channels from Escherichia coli and Mycobacterium tuberculosis.
AB  - Total chemical protein synthesis was used to generate multimilligram quantities
      of the mechanosensitive channel of large conductance from Escherichia coli (Ec
      MscL) and Mycobacterium tuberculosis (Tb-MscL). Cysteine residues introduced to
      allow chemical ligation were masked with cysteine-reactive molecules, resulting
      in side chain functional groups similar to those of the wild-type protein.
      Synthetic channel proteins were transferred to 2,2,2-trifluoroethanol and
      reconstituted into vesicle membranes. Fluorescent imaging of vesicles showed that
      channel proteins were membrane-localized. Single-channel recordings showed that
      reconstituted synthetic Ec-MscL has conductance, pressure dependence, and
      substate distribution similar to those of the recombinant channel. Reconstituted
      synthetic Tb-MscL also displayed conductance and pressure dependence similar to
      that of the recombinant protein. Possibilities for the incorporation of unnatural
      amino acids and biophysical probes, and applications of such synthetic ion
      channel analogs, are discussed.

PMID- 15041745
TI  - Protein kinetics: structures of intermediates and reaction mechanism from time
      resolved x-ray data.
AB  - We determine the number of authentic reaction intermediates in the later stages
      of the photocycle of photoactive yellow protein at room temperature, their atomic
      structures, and a consistent set of chemical kinetic mechanisms, by analysis of a
      set of time-dependent difference electron density maps spanning the time range
      from 5 micros to 100 ms. The successful fit of exponentials to right singular
      vectors derived from a singular value decomposition of the difference maps
      demonstrates that a chemical kinetic mechanism holds and that structurally
      distinct intermediates exist. We identify two time-independent difference maps,
      from which we refine the structures of the corresponding intermediates. We thus
      demonstrate how structures associated with intermediate states can be extracted
      from the experimental, time-dependent crystallographic data. Stoichiometric and
      structural constraints allow the exclusion of one kinetic mechanism proposed for
      the photocycle but retain other plausible candidate kinetic mechanisms.

PMID- 15041746
TI  - Tigers and their prey: Predicting carnivore densities from prey abundance.
AB  - The goal of ecology is to understand interactions that determine the distribution
      and abundance of organisms. In principle, ecologists should be able to identify a
      small number of limiting resources for a species of interest, estimate densities
      of these resources at different locations across the landscape, and then use
      these estimates to predict the density of the focal species at these locations.
      In practice, however, development of functional relationships between abundances
      of species and their resources has proven extremely difficult, and examples of
      such predictive ability are very rare. Ecological studies of prey requirements of
      tigers Panthera tigris led us to develop a simple mechanistic model for
      predicting tiger density as a function of prey density. We tested our model using
      data from a landscape-scale long-term (1995-2003) field study that estimated
      tiger and prey densities in 11 ecologically diverse sites across India. We used
      field techniques and analytical methods that specifically addressed sampling and
      detectability, two issues that frequently present problems in macroecological
      studies of animal populations. Estimated densities of ungulate prey ranged
      between 5.3 and 63.8 animals per km2. Estimated tiger densities (3.2-16.8 tigers
      per 100 km2) were reasonably consistent with model predictions. The results
      provide evidence of a functional relationship between abundances of large
      carnivores and their prey under a wide range of ecological conditions. In
      addition to generating important insights into carnivore ecology and
      conservation, the study provides a potentially useful model for the rigorous
      conduct of macroecological science.

PMID- 15041747
TI  - Defective transcription factor activation for proinflammatory gene expression in
      poly(ADP-ribose) polymerase 1-deficient glia.
AB  - Poly(ADP-ribose) polymerase 1 (PARP-1) activity is detected in both neuronal and
      nonneuronal cells in the CNS, and excessive PARP-1 activity is known to be
      detrimental to tissue because of the cellular energy loss. Accordingly, PARP-1
      deficient (PARP-1(-/-)) mice have been shown to be resistant to cerebral ischemia
      and several forms of inflammation. Recently, PARP-1 in glial cells has been shown
      to mediate the expression of proinflammatory genes in response to inflammatory
      stimuli by, in part, enhancing cognate DNA-binding capacities of transcription
      factors such as NF-kappaB and activator protein 1. Here, we demonstrate an
      additional mechanism whereby a significant reduction of proinflammatory gene
      expression such as IL-1beta, tumor necrosis factor alpha, and inducible
      nitricoxide synthase in PARP-1(-/-) glial cells is linked to defective
      inflammatory stimuli-induced p38MAPK-mediated phosphorylation of ATF-2 and cAMP
      response element-binding protein and phosphorylation of NF-kappaB p65.
      Importantly, an inflammatory stimuli-induced p38MAPK activation is impaired in
      PARP-1(-/-) glial cells in a signaling pathway- and cell/tissue type-specific
      manner. These findings indicate that PARP-1 is an essential host factor among
      factors that actively mediate excessive production of proinflammatory molecules
      in glial cells, which may in turn contribute to the initiation of neuronal
      injuries.

PMID- 15041748
TI  - Reciprocal relationships between Fgf8 and neural crest cells in facial and
      forebrain development.
AB  - Fgf8 exerts a strong effect on the mesenchymal cells of neural crest (NC) origin
      that are fated to form the facial skeleton. Surgical extirpation of facial
      skeletogenic NC domain (including mid-diencephalon down through rhombomere 2),
      which does not express Hox genes, results in the failure of facial skeleton
      development and inhibition of the closure of the forebrain neural tube, while
      Fgf8 expression in the telencephalon and in the branchial arch (BA) ectoderm is
      abolished. We demonstrate here that (i) exogenous FGF8 is able to rescue facial
      skeleton development by promoting the proliferation of NC cells from a single
      rhombomere, r3, which in normal development contributes only marginally to
      mesenchyme of BA1, and (ii) expression of Fgf8 in forebrain and in BA ectoderm is
      subjected to signal(s) arising from NC cells, thus showing that the development
      of cephalic NC-derived structures depends on FGF8 signaling, which is itself
      triggered by the NC cells.

PMID- 15041749
TI  - Protection against zinc toxicity by metallothionein and zinc transporter 1.
AB  - Cells protect themselves from zinc toxicity by inducing proteins such as
      metallothionein (MT) that bind it tightly, by sequestering it in organelles, or
      by exporting it. In this study, the interplay between zinc binding by MT and its
      efflux by zinc transporter 1 (ZnT1) was examined genetically. Inactivation of the
      Znt1 gene in baby hamster kidney (BHK) cells that do not express their Mt genes
      results in a zinc-sensitive phenotype and a high level of "free" zinc.
      Restoration of Mt gene expression increases resistance to zinc toxicity
      approximately 4-fold, but only slightly reduces free zinc levels. Expression of
      ZnT1 provides greater protection (approximately 7-fold) and lowers free zinc
      substantially. Selection for zinc resistance in BHK cells that cannot synthesize
      either MT or ZnT1 is ineffective. However, parental BHK cells that grow in high
      concentrations (>500 microM) of zinc can be selected; these cells have amplified
      their endogenous Znt1 genes. The Znt1 gene is also amplified in zinc-resistant
      mouse cells that cannot induce their Mt genes. However, if Mt genes can be
      expressed, then they are preferentially amplified. Thus, both ZnT1 and MT genes
      contribute to zinc resistance in BHK cells, whereas ZnT1 plays a larger role in
      regulating free zinc levels.

PMID- 15041750
TI  - The basal layer in human squamous tumors harbors more UVA than UVB fingerprint
      mutations: a role for UVA in human skin carcinogenesis.
AB  - We hypothesized that a substantial portion of the mutagenic alterations produced
      in the basal layer of human skin by sunlight are induced by wavelengths in the
      UVA range. Using laser capture microdissection we examined separately basal and
      suprabasal keratinocytes from human skin squamous cell carcinomas and
      premalignant solar keratosis for both UVA- and UVB-induced adduct formation and
      signature mutations. We found that UVA fingerprint mutations were detectable in
      human skin squamous cell carcinomas and solar keratosis, mostly in the basal
      germinative layer, which contrasted with a predominantly suprabasal localization
      of UVB fingerprint mutations in these lesions. The epidermal layer bias was
      confirmed by immunohistochemical analyses with a superficial localization of
      cyclobutane thymine dimers contrasting with the localization of 8-hydroxy-2'
      deoxyguanine adducts to the basal epithelial layers. If unrepaired, these adducts
      may lead to fixed genomic mutations. The basal location of UVA-rather than UVB
      induced DNA damage suggests that longer-wavelength UVR is an important carcinogen
      in the stem cell compartment of the skin. Given the traditional emphasis on UVB,
      these results may have profound implications for future public health initiatives
      for skin cancer prevention.

PMID- 15041751
TI  - Differential expression patterns of the hox gene are associated with differential
      growth of insect hind legs.
AB  - Diversification of leg appendages is one of the hallmarks of morphological
      evolution in insects. In particular, insect hind (T3) legs exhibit a whole
      spectrum of morphological diversification, ranging from uniform to extremely
      modified. To elucidate the developmental basis of T3 leg evolution, we have
      examined the expression patterns of two homeotic genes, Ultrabithorax and
      abdominal-A (collectively referred to as UbdA), in a broad range of species.
      First, our results show that UbdA expression in hemimetabolous insects is
      localized only in specific T3 leg segments undergoing differential growth
      (compared to their foreleg counterparts). In contrast, in basal hexapod and
      insect lineages, the absence of the UbdA signal coincides with uniform leg
      morphology. The same situation exists in first instar larvae of holometabolous
      insects, in which absence of UbdA expression in the embryonic T3 legs is
      associated with the lack of larval T3 leg diversification. Second, there is a
      clear difference in the timing of expression between species with greatly
      enlarged T3 leg, such as crickets and grasshoppers, and species that exhibit more
      moderate enlargement of hind legs, such as mantids and cockroaches. In the
      former, the UbdA expression starts much earlier, coinciding with the elongation
      of T3 limb buds. In the latter, however, the UbdA expression starts at much later
      stages of development, coinciding with the establishment of distinct leg
      segments. These results suggest that diversification of insect hind legs was
      influenced by changes in both the spatial and temporal regulation of the UbdA
      expression.

PMID- 15041752
TI  - Chronic obstructive pulmonary disease. National clinical guideline on management
      of chronic obstructive pulmonary disease in adults in primary and secondary care.

PMID- 15041753
TI  - Activity of the germline-specific Oct4-GFP transgene in normal and clone mouse
      embryos.

PMID- 15041754
TI  - Analysis of germline chromatin silencing by double-stranded RNA-mediated
      interference (RNAi) in Caenorhabditis elegans.

PMID- 15041755
TI  - cDNA subtraction and cloning in the field of trophoblast/placental development.

PMID- 15041757
TI  - Differentiating embryonic stem cells into embryoid bodies.

PMID- 15041756
TI  - PCR-based cloning and differential screening of RNAs from Xenopus primordial germ
      cells: cloning uniquely expressed RNAs from rare cells.

PMID- 15041759
TI  - Using multiphoton excitation to explore the murky depths of developing embryos.

PMID- 15041758
TI  - The derivation of murine embryonic stem and embryonic germ cells by selective
      ablation.

PMID- 15041760
TI  - Dual-channel confocal ratioing of calcium dynamics in living eggs and oocytes.

PMID- 15041761
TI  - A method for producing cloned pigs by using somatic cells as donors.

PMID- 15041762
TI  - Pronuclear microinjection of mouse zygotes.

PMID- 15041763
TI  - Parthenogenesis and nuclear transfer in rabbit oocytes.

PMID- 15041764
TI  - Nuclear transfer in cattle.

PMID- 15041765
TI  - In vitro fertilization and embryo transfer in felids.

PMID- 15041766
TI  - Production of chimeric chickens.

PMID- 15041767
TI  - Production of haploid and diploid androgenetic zebrafish.

PMID- 15041768
TI  - Construction and detection of fluorescent, germline transgenic zebrafish.

PMID- 15041769
TI  - Production of zebrafish germline chimeras from cultured cells.

PMID- 15041770
TI  - Studying nuclear reprogramming with cell hybrids.

PMID- 15041772
TI  - Conventional technologies for cryopreservation of human oocytes and embryos.

PMID- 15041771
TI  - Cytoplasmic transfer in Mammalian eggs and embryos.

PMID- 15041773
TI  - Vitrifying and warming of human oocytes, embryos, and blastocysts: vitrification
      procedures as an alternative to conventional cryopreservation.

PMID- 15041774
TI  - Microfluidic removal of cumulus cells from Mammalian zygotes.

PMID- 15041775
TI  - Mammalian embryo culture in a microfluidic device.

PMID- 15041776
TI  - Application of alginate gels to the study of Mammalian development.

PMID- 15041777
TI  - Using TUNEL in combination with an active caspase-3 immunoassay to identify cells
      undergoing apoptosis in preimplantation Mammalian embryos.

PMID- 15041779
TI  - Effects of supplemental L-methionine on E-64 [trans-epoxysuccinyl-1-leucyl-amido
      (4-guanido) butane]-induced dysmorphology in rat embryos cultured in vitro.
AB  - E-64 [trans-epoxysuccinyl-1-leucyl-amido (4-guanido) butane] is teratogenic,
      inducing a spec-trum of malformations in vivo and producing similar effects in
      vitro. Numerous studies support the concept that E-64-induced malformations
      result from embryonic nutritionaldeficiency, without affecting the maternal
      nutritional status. This has provided a useful model with which to investigate
      the nutritional requirements of the early embryo, as well as the role of various
      nutrients in the etiology of congenital defects. In the current investigation, we
      examined effects of L-methionine on E-64-induced embryotoxicity in vitro. For
      these experiments, we cultured rat embryos 9.5 days postconception (p.c.) for 48
      hours with E-64 and/or L-methionine. We found that the addition of L-methionine
      to E-64-exposed cultures reduced optic abnormality and increased embryo protein.
      These results suggest that embryopathy largely results from a deficiency of L
      methionine although E-64 limits the supply of all amino acids to the embryo.
      Furthermore, although endocytosis and degradation of proteins by the visceral
      yolk sac (VYS) supply most amino acids to the embryo, free amino acids may be
      compensatory when this source is reduced. These results support those of previous
      investigations that suggest L-methionine is a limiting nutrient for embryonic
      development.

PMID- 15041778
TI  - Effects of oyster extract on the reproductive function of zinc-deficient mice:
      bioavailability of zinc contained in oyster extract.
AB  - Zinc is a vital nutrient in the normal reproductive function and embryonic
      development of mammals, and it is well known that oyster extract contains
      significant amounts of zinc. The effects of oyster extract on reproductive
      function, such as embryonic development, serum levels of zinc and sperm
      maturation were examined in zinc-deficient mice. Zinc deficiency in dams during
      pregnancy induced a decrease in the successful pregnancy rate, maternal weight
      gain, the number of live fetuses and fetal body weight. Zinc deficiency for 12
      weeks in male mice induced a decrease in body weight, testis weight and sperm
      count in the epididymis. However, reproductive failure, embryonic defects and
      decreased sperm motility in zinc-deficient mice were improved by supplementation
      with oyster extract. Some nutrients contained in oyster extract, such as taurine
      and glycogen, may be related to the recovery of reproductive function. There were
      significantly lower serum concentrations of zinc in dams fed a zinc-deficient
      diet. However, the serum zinc concentration was normal in the oyster extract
      supplemented group. No difference in the concentration of serum zinc was observed
      between the oyster extract- and zinc carbonate-supplemented groups. From these
      findings, it is suggested that oyster extract is a useful supplement that can
      prevent reproductive defects from zinc deficiency, and the bioavailability of
      zinc may be identical to zinc carbonate.

PMID- 15041780
TI  - Trend of congenital anomalies over 20 years ascertained by population-based
      monitoring in Ishikawa Prefecture, Japan.
AB  - Monitoring in Ishikawa Prefecture (mean population; 1,150,000), during the 20
      year period from 1981 to 2000, involved monitoring the prevalence of congenital
      anomalies starting at gestational week 22. The main objectives of the present
      study were (1) to investigate the trend over the past 20 years in the prevalence
      of congenital anomalies, and (2) to investigate whether there is area
      accumulation in congenital anomalies or not. In addition, the prevalence of well
      known risk factors such as smoking, drinking and family history among cases with
      congenital anomalies was analyzed to obtain clues to the background of such
      anomalies. During the 20 years, more than 200,000 births have been observed.
      Thirty-three selected congenital anomalies, consisting mainly of external
      anomalies, were analyzed in this study. The percentage of children born with
      congenital anomalies did not change markedly between the first and second halves
      of the monitoring period, remaining at approximately 4.5/1,000 births. There was
      also no significant change in annual trends in either Ishikawa Prefecture as a
      whole or in the three regions within Ishikawa. The prevalence of congenital
      anomalies by type showed a significant decrease in anencephaly and spina bifida.
      In contrast, Down syndrome and microcephaly increased significantly. The mean
      maternal age for Down syndrome increased significantly from the first-half period
      to the second-half period. The percentage of children with polydactyly whose
      mother smoked were relatively higher than that for the other congenital
      anomalies.

PMID- 15041781
TI  - Defective balancing ability and hyperactivity in the CLX (circling behavior
      linked to the X-chromosome) mutant rat.
AB  - We have reported that the recently described circling behavior rat (CLX) is a
      hereditary mutant controlled by a single sex-linked recessive gene (gene symbol:
      clx). This mutant shows intermittent circle walking and/or running and head
      tossing with the neck twisted. The abnormal behavior begins to appear around
      weaning and continues throughout life. In the present study, behavioral tests
      were performed during the suckling and post-weaning periods and when the rats
      reached maturity, and the following peculiar abnormalities were revealed: (1) in
      the righting reflex test, the CLX young show a tendency to take a longer time to
      revert to normal posture; (2) in the negative geotaxis test, they had difficulty
      moving upward at 12 days of age; (3) in the air righting reflex test, they
      frequently fell on their backs or shoulders even after weaning; (4) almost none
      of the CLX rats showed nystagmus, which is invariably observed in normal rats
      after rotating stimulation, at 20 weeks of age; and (5) they showed hyperactivity
      in the open field test at the age of 5 or 6 weeks and a higher degree of
      locomotor activity in the home cage at the age of 7 and 15 weeks. These results
      suggest that CLX mutant rats may have some defect in vestibular function (balance
      sense) or abnormalities in an area of the central nervous system responsible for
      posture control, e.g., in the dopaminergic or GABAergic neurons.

PMID- 15041782
TI  - FGFR2 mutation in a patient with Apert syndrome associated with humeroradial
      synostosis.
AB  - Most cases of Apert syndrome are due to S252W or P253R mutations in the
      fibroblast growth factor receptor 2 (FGFR2) gene. Differences in the effects of
      S252W and P253R mutations on the clinical features of Apert syndrome have been
      studied, but little is known about the type of FGFR2 mutation in Apert syndrome
      with humeroradial synostosis. To study a correlation between the FGFR2 mutations
      and the clinical complications, we examined the FGFR2 gene in a patient with
      Apert syndrome associated with humeroradial synostosis, and found that the
      mutation was S252W. This report suggested that S252W mutation in FGFR2 may cause
      humeroradial synostosis in Apert syndrome.

PMID- 15041784
TI  - The role of glucose allostasis in type 2 diabetes.

PMID- 15041783
TI  - Alterations of glucose metabolism in type 2 diabetes mellitus. An overview.

PMID- 15041785
TI  - The role of the liver in type 2 diabetes.

PMID- 15041786
TI  - Insulin signaling defects in type 2 diabetes.

PMID- 15041788
TI  - The role of lipid accumulation in liver and muscle for insulin resistance and
      type 2 diabetes mellitus in humans.

PMID- 15041787
TI  - AMP-activated protein kinase: a master switch in glucose and lipid metabolism.

PMID- 15041789
TI  - Molecular defects in insulin secretion in type-2 diabetes.

PMID- 15041790
TI  - New insights into the integrated physiology of insulin action.

PMID- 15041792
TI  - Peroxisome proliferator activated receptor-gamma (PPAR-gamma) ligands and
      angiogenesis.
AB  - The peroxisome proliferator activated receptor (PPAR)- gamma ligands have been
      initially described as important regulators of adipogenic differentiation and
      glucose homeostasis. Detailed studies in different tissues pointed to the roles
      of these ligands in cell proliferation and cancer, establishing their anticancer
      properties against a wide variety of neoplastic cells. The growth of any solid
      tumor depends on angiogenesis, as tumor vascularization is a vital process for
      tumor volume increase and its metastatic potential. Recently, the role of PPAR-
      gamma ligands as potent angiogenesis modulators in vitro and in vivo, has been
      referred. This review takes into consideration the latest data concerning the
      participation of PPAR- gamma ligands in the biological mechanisms underlying
      angiogenesis inhibition (important in anticancer therapy) and the controversy
      concerning angiogenesis induction (important in non-neoplastic diseases). As
      inhibition of angiogenesis represents one of the more promising, new approaches
      to anticancer therapy, PPAR- gamma ligands in addition to their established role
      as tumor cell cycle modulators could be implicated in future strategies for
      cancer treatment.

PMID- 15041793
TI  - New insights into the function and regulation of endothelial cell apoptosis.
AB  - The sculpting of blood vessels to meet the changing requirements of the tissues
      they supply is essential for life. Many researchers believe that endothelial cell
      apoptosis plays an important role in this process. This belief is bolstered by
      the detection of endothelial apoptosis within remodeling vessels in vivo, the
      dramatic vascular phenotypes of mice in which regulators of endothelial apoptosis
      have been inactivated and the apparent dependence of angiogenesis on endothelial
      apoptosis in vitro. However, when examined carefully, the evidence for or against
      endothelial cell apoptosis playing an important role in vascular biology is
      largely indirect and is far from clear-cut. In this review, we will discuss the
      idiosyncratic process of endothelial cell apoptosis. We will then examine its
      complex regulation and weigh the in vitro and in vivo evidence that it plays a
      significant role in mammalian vascular biology.

PMID- 15041795
TI  - The mouse aorta model: influence of genetic background and aging on bFGF- and
      VEGF-induced angiogenic sprouting.
AB  - Angiogenesis can be studied ex vivo by culturing rat or mouse aortic rings in
      collagen gels. Unlike rat aorta explants, unstimulated mouse aortic rings were
      unable to spontaneously produce an angiogenic response under serum-free
      conditions. They, however, responded to bFGF and VEGF, generating networks of
      branching neovessels. Aortic rings from GFP-Tie2-transgenic mice generated GFP
      labeled neovessels that could be easily identified by their distinctly green
      fluorescence. Aortic rings from 1- to 2-month-old mice produced microvessels
      faster, more uniformly and in greater number than aortic rings from 6- to 10
      month-old mice, particularly in VEGF-treated cultures. Aortic rings from 129/SVJ
      mice were capable of a much stronger and sustained angiogenic response to bFGF
      than those of C57BL/6 or BALB/c mice, which were in turn more angiogenic than
      aortic rings from FVB mice. The same strains of mice responded differently to
      VEGF, as C57BL/6 mouse aortic rings produced more microvessels than those of
      BALB/c, FVB, and 129/SVJ mice, which were capable of only a limited response. The
      significant impact that aging and genetic background have on mouse aortic
      angiogenesis should be taken into account when the aortic-ring assay is used to
      evaluate function of genes that have been deleted or overexpressed in genetically
      modified mice.

PMID- 15041794
TI  - combination of vascular endothelial growth factor (VEGF) and thymidine
      phosphorylase (TP) to improve angiogenic gene therapy.
AB  - To improve current angiogenic gene therapy with a vascular endothelial growth
      factor (VEGF)-encoding plasmid (Baumgartner et al. Circulation 1998; 97: 1114-23
      [1]; Kusumanto et al. Fifth Annual Meeting of the American Society of Gene
      Therapy, Boston, 2002, Abstr. 621 [2]), we have generated a combination plasmid,
      encoding the VEGF gene and the thymidine phosphorylase (TP, also known as
      platelet-derived endothelial growth factor (PD-ECGF) or gliostatin (GLS)) gene:
      phVEGF165-TP.MB. Upon transfection in COS-7 cells both gene products were
      expressed and functional as shown by Western blots, ELISAs and bioassays. Culture
      supernatants of COS-7 cells transfected with this plasmid were able to induce
      endothelial proliferation. In an in vitro angiogenesis assay with recombinant
      proteins, TP was able to increase VEGF-induced tube formation. The phVEGF165
      TP.MB plasmid is therefore a promising candidate for in vivo angiogenesis
      studies.

PMID- 15041796
TI  - An engineered heparin-binding form of VEGF-E (hbVEGF-E). Biological effects in
      vitro and mobilizatiion of precursor cells.
AB  - Vascular endothelial growth factor (VEGF-A) is the founding member of a family of
      angiogenic proteins with various binding abilities to three cognate VEGF
      receptors. Previously, a gene encoding from the genome of parapox orf virus (OV)
      with about 25% amino acid identity to mammalian VEGF-A was named VEGF-E and shown
      to bind and specifically activate the vascular endothelial growth factor receptor
      VEGFR-2 (KDR/flk-1). Here, we have generated a novel heparin-binding form of VEGF
      E by introducing the heparin-domain of the human VEGF-A(165) splice variant into
      the viral VEGF-E protein. Recombinant heparin-binding VEGF-E (hbVEGF-E) is shown
      to stimulate proliferation and sprout formation of macro- and microvascular
      endothelial cells to a similar extent as the parental OV-VEGF-E but fails to
      activate peripheral mononuclear cells. However, hbVEGF-E is more potent in
      binding competition assays with primary human endothelial cells when compared to
      the OV-VEGF-E. This can be explained by our finding that binding of hbVEGF-E but
      not of parental OV-VEGF-E to the VEGFR-2 is strongly increased by the addition of
      neuropilin-1 (NP-1), a cognate co-receptor for VEGF-A. The engineered hbVEGF-E
      was compared with the VEGFR-1 selective and also heparin-binding form of placenta
      growth factor (PlGF-2) in vivo. Both heparin-binding homologues induced
      mobilization of endothelial progenitor cells from the bone marrow and gave rise
      to similar colony numbers of myeloic cells in a colony-forming assay. These
      findings suggest that both VEGFR-1 and VEGFR-2 are involved in stem cell
      mobilization.

PMID- 15041797
TI  - Anti-angiogenic activity of contortrostatin, a disintegrin from Agkistrodon
      contortrix contortrix snake venom.
AB  - Previous work in our laboratory has shown that contortrostatin (CN), a
      disintegrin from southern copperhead snake venom, possess anti-angiogenic
      activity. In the present study we further examined the anti-angiogenic activity
      of CN, focusing on the mechanisms of CN inhibition of angiogenesis. CN inhibited
      migration and invasion, and significantly altered Matrigel-induced tube formation
      of human umbilical vein endothelial cells (HUVEC), but did not affect cell
      viability, or MMP-2 and MMP-9 activity. Immunocytochemistry of HUVEC revealed
      that CN disrupted actin cytoskeleton and altered VE-cadherin distribution at cell
      cell contacts. CN downregulated focal adhesion kinase (FAK) and paxillin tyrosine
      phosphorylation in adherent HUVEC. There was also significant inhibition of
      angiogenesis in vivo by CN as assessed by implanting Matrigel plugs in C57 mice
      and measuring ingrowth of blood vessels using either factor VIII staining or
      hemoglobin determination. In conclusion, the present findings confirm our earlier
      studies and demonstrate conclusively that CN possess strong anti-angiogenic
      activity in vitro and in vivo.

PMID- 15041791
TI  - Candidate genes for type 2 diabetes.

PMID- 15041798
TI  - Angiogenesis and the ET-1/ETA receptor system: immunohistochemical expression
      analysis in bone metastases from patients with different primary tumors.
AB  - Angiogenesis is necessary for the growth of primary tumors and the formation of
      metastases. It is well known that vascular endothelial growth factor (VEGF) and
      its receptors play a major role in this process. To date, the formation of bone
      metastases has been poorly understood. Tumor cells must interact with the
      microenvironment of the bone and new blood vessels must spread. The ET/ET(A)
      (endothelin) receptor system seems to play an important role in this process.
      Specimens from metastatic bone lesions and non-malignant bone tissue were
      analyzed by histological and immunohistochemical staining. Sections were stained
      with antibodies against CD31, Flt-1, KDR, endothelin-1 (ET-1) and endothelin
      receptor A (ET(A)). Our studies show that there is an increased microvessel
      density (MVD) in metastatic bone lesions from different primary tumors in
      contrast to normal bone tissue. In nearly all tumor formations of the bone, ET-1
      and its receptor ET(A) was found by immunohistochemistry. We also performed
      immunohistochemical staining for the VEGF-receptors Flt-1 and KDR. In conclusion,
      there is an increased vessel density in metastatic bone lesions in contrast to
      normal bone tissue. The ET/ET(A) system can be detected in nearly all bone
      specimens and is upregulated in metastatic bone lesions in contrast to healthy
      bone tissue.

PMID- 15041799
TI  - Effect of human Angiostatin protein on human angiogenesis in vitro.
AB  - Angiostatin, a 38-kD fragment of plasminogen, inhibits angiogenesis in both
      animal tumor models and in vitro endothelial cell models. However, human
      Angiostatin has not been tested in vitro against an intact human tissue target to
      determine its ability to inhibit the initiation or subsequent promotion of the
      human angiogenic response. We hypothesized that high doses of human Angiostatin
      would inhibit the development of an angiogenic response in an intact human vessel
      target, and would suppress the subsequent growth of blood vessels following the
      initiation of an angiogenic response. To test these hypotheses, full-thickness
      human placental vein disks were cultured for 15 days in an in vitro fibrin
      thrombin clot assay. This assay system had been used to evaluate the efficacy of
      a wide variety of compounds. Vessels were obtained from three placentas.
      Treatments included a control medium plus fetal bovine serum (FBS), heparin
      steroid (300 micro g/ml heparin and 350 micro g/ml hydrocortisone; a treatment
      known to inhibit angiogenesis) and Angiostatin at doses from 1 x 10(-4) to 1 x
      10(-9) M. In the control groups, 81% of vessels initiated an angiogenic response
      compared to 53% of the vessels treated with heparin-steroid. Angiostatin (10(-4)
      10(-9) M) decreased the initiation of an angiogenic response, but this was not
      statistically significant. Of the disks that initiated an angiogenic response,
      the mean ( +/- standard error of the mean (SEM)) semi-quantitative visual
      angiogenic index (AI) of the control vessels was 9 +/- 1.7 on day 15. In
      comparison, the mean AI of heparin-steroid treated vessels was 3.7 +/- 0.4.
      Angiostatin at doses of 10(-4)-10(-9) M also failed to inhibit blood vessel
      growth after initiation of the angiogenic response. Based on these observations,
      we cannot demonstrate significant activity of human Angiostatin (10(-4)-10(-9) M)
      against the initiation or promotion of a human angiogenic response in this in
      vitro model of angiogenesis using an intact human vessel target.

PMID- 15041802
TI  - [Time for renewal and publishing original articles in English].

PMID- 15041801
TI  - A modified chorioallantoic membrane assay allows for specific detection of
      endothelial apoptosis induced by antiangiogenic substances.
AB  - Current in vivo angiogenesis assays allow for the assessment of vascular growth
      inhibition induced by a test substance, but they usually do not provide
      information about the mechanisms underlying such an inhibition. A potential
      antiangiogenic mechanism is the triggering of endothelial apoptosis in the
      growing vessels. Apoptogenic substances can be of interest for antiangiogenic
      therapy specially if they specifically perform their action on the angiogenic
      endothelium. We have developed a modification of the chorioallantoic membrane
      (CAM) assay using embryos of quail ( Coturnix coturnix japonica ). This novel
      assay allows to elucidate whether an antiangiogenic substance is specifically
      triggering an apoptotic response in endothelial cells. We have used a quail
      specific monoclonal endothelial marker (QH1), a standard TUNEL technique of
      apoptotic cell labelling together with a general nuclear counterstaining with
      propidium iodide. Through laser confocal microscopy, paraffin sections of
      chorioallantoic membranes treated with test substances are stained in three
      colours: red for normal cell nuclei, yellow-green for apoptotic nuclei and blue
      for endothelial cells and endothelial progenitors. In a test experience, our
      assay showed significant differences in the apoptogenic properties of two
      antiangiogenic substances, camptothecin and aeroplysinin-1.

PMID- 15041803
TI  - [Quality of life in medicine: from clinical research to practice].

PMID- 15041800
TI  - Early contribution of pericytes to angiogenic sprouting and tube formation.
AB  - Immunostaining with endothelial and pericyte markers was used to evaluate the
      cellular composition of angiogenic sprouts in several types of tumors and in the
      developing retina. Confocal microscopy revealed that, in addition to conventional
      endothelial tubes heavily invested by pericytes, all tissues contained small
      populations of endothelium-free pericyte tubes in which nerve/glial antigen 2
      (NG2) positive, platelet-derived growth factor beta (PDGF beta ) receptor
      positive perivascular cells formed the lumen of the microvessel. Perfusion of
      tumor-bearing mice with FITC-dextran, followed by immunohistochemical staining of
      tumor vasculature, demonstrated direct apposition of pericytes to FITC-dextran in
      the lumen, confirming functional connection of the pericyte tube to the
      circulation. Transplantation of prostate and mammary tumor fragments into NG2
      null mice led to the formation of tumor microvasculature that was invariably NG2
      negative, demonstrating that pericytes associated with tumor microvessels are
      derived from the host rather than from the conversion of tumor cells to a
      pericyte phenotype. The existence of pericyte tubes reflects the early
      participation of pericytes in the process of angiogenic sprouting. The ability to
      study these precocious contributions of pericytes to neovascularization depends
      heavily on the use of NG2 and PDGF beta -receptor as reliable early markers for
      activated pericytes.

PMID- 15041804
TI  - Relationship between severity of symptoms and quality of life in 858 patients
      with irritable bowel syndrome.
AB  - AIMS: Heath-related quality of life (QoL) is decreased in patients with irritable
      bowel syndrome (IBS) but the relationship between symptom intensity of IBS and
      QoL remains largely unknown. The aim of this prospective survey was to
      investigate the relationship between intensity of IBS and changes in QoL.
      METHODS: Eight hundred and fifty-eight patients with IBS, according to Rome II
      criteria, completed a symptom questionnaire to measure intensity of IBS, and the
      gastrointestinal quality of life (GIQLI) questionnaire, which is a general QoL
      measure in patients with gastrointestinal disorders. RESULTS: 37.2% of the
      patients had constipation-predominant type IBS, 37.3% had diarrhea-predominant
      IBS and 25.4% had alternating diarrhea and constipation type symptoms. IBS was
      considered to be in remission or mild in 8.3% of patients; 41.3% had moderate IBS
      and 50.4% had severe IBS. The mean GIQLI score was 88 +/- 20. There was a
      significant correlation between symptom intensity and changes in QoL. Other
      significantly related factors were the type of bowel abnormality and gender.
      CONCLUSION: In IBS patients, symptom intensity and type of IBS have a negative
      impact on health-related QoL.

PMID- 15041805
TI  - Impact of anal incontinence and chronic constipation on quality of life.
AB  - AIM: To determine the impact of symptoms related to chronic constipation and
      fecal incontinence on quality of life. PATIENTS AND METHODS: This prospective
      study included 173 consecutive patients who referred addressed to our laboratory
      for anorectal manometry. Quality of life was evaluated using the GIQLI
      questionnaire, and severity of symptoms using the Cleveland Clinic scores for
      constipation and fecal incontinence. A correlation study was performed between
      the quality of life and symptoms scores. RESULTS: The GIQLI questionnaire was
      correctly completed by 157 patients (90.7%). The mean GIQLI score was 89 +/- 24,
      without any significant difference between constipated and incontinent patients.
      The mean constipation score was 15.7/30 (range: 6-25). The mean fecal
      incontinence score was 10.5/20 (range: 3-16). Correlation between quality of life
      and symptom scores was poor. Thus, a significant threshold value for symptom
      scores corresponding to major alteration of quality of life could not be
      determined. CONCLUSIONS: Quality of life is profoundly altered both in patients
      with chronic constipated and incontinence. Symptom scores do not allow
      satisfactory evaluation of the impact of chronic constipation or fecal
      incontinence on patients' quality of life. These results confirm the need for
      systematic exploration of quality of life in these patients, to correctly address
      the severity of functional diseases, and the influence of therapy.

PMID- 15041806
TI  - [Colorectal cancer: prognostic molecular markers].

PMID- 15041807
TI  - [Towards molecular management of systemic mastocytosis].

PMID- 15041808
TI  - Effects of prolonged oral nutritional support in malnourished cirrhotic patients:
      results of a pilot study.
AB  - OBJECTIVES: The aim of this prospective study was to evaluate the acceptance and
      the effects of nutritional supplementation in malnourished ambulatory patients
      with liver cirrhosis. METHODS: From June 1999 through June 2000, alcoholic
      cirrhotic patients with moderate to severe malnutrition as assessed with the
      Detsky index were included in the study. Patients were instructed to consume, in
      addition to their regular diet, a commercial solution that provided 500 kcal/day.
      Physical examination, dietary recalls and laboratory tests were performed at 1, 2
      and 3 Month. RESULTS: Twenty-nine patients with a mean age of 52 Years were
      included. The Child-Pugh grade was A in 6 patients, B in 14 and C in 8. Eighteen
      patients (62%) completed the 3 Month study protocol. Mean non-alcohol calorie
      intake increased significantly by 31% at 1 Month and by 48% at 3 Months. At the
      same time alcohol calorie intake decreased significantly by 68% and 77%,
      respectively. Subjective improvement in nutritional status was associated with
      significant improvement of mean Child-Pugh score (P=0.0007) and triceps skinfold
      thickness (P=0.005). The increase of mid-arm circumference was not significant.
      CONCLUSION: This study showed that oral supplementation in ambulatory patients
      with liver cirrhosis is feasible and associated with a significant improvement of
      nutritional status and biological parameters including the Child-Pugh score. This
      benefit was associated with a concomitant reduction of alcohol intake.

PMID- 15041809
TI  - [Non surgical treatment of Budd-Chiari syndrome: a review].

PMID- 15041810
TI  - [Vaccination against hepatitis B virus: ANAES and INSERM experts take a view].

PMID- 15041812
TI  - [Medical management of cholangiocarcinoma].

PMID- 15041813
TI  - [Case report illustrating multidisciplinary management of hilar
      cholangiocarcinoma].

PMID- 15041815
TI  - [Acute cytomegalovirus (CMV) recto-colitis mimicking rectal carcinoma without
      apparent cause of immunodeficiency].
AB  - Cytomegalovirus (CMV) infection of the gastrointestinal tract occurs mainly in
      immunosuppressed patients. We report here the case of a 76-Year-old woman,
      without obvious cause of immunosuppression, who developed severe proctitis. The
      clinical course was favourable with ganciclovir therapy. In the absence of
      controlled data in the field of CMV intestinal infections in immunocompetents, we
      discuss the potential benefit of an antiviral therapy in those patients who do
      not recover rapidly and spontaneously.

PMID- 15041816
TI  - [Alpha-fetoprotein-producing poorly differentiated gastric adenocarcinoma:
      hepatoid carcinoma?].
AB  - We report the case of a 42-Year-old man with a poorly differentiated gastric
      cancer revealed by a very high level of serum alpha-fetoprotein-protein,
      associated with liver metastasis, and treated by chemotherapy. We discuss the
      possible diagnosis of hepatoid carcinoma.

PMID- 15041817
TI  - [Liver involvement revealing systemic mastocytosis: report of two cases].
AB  - Systemic mastocytosis is a disease defined by an abnormal infiltration of mast
      cells involving several extra-cutaneous organs. Hepatic involvement is frequent,
      however it rarely reveals the disease. We report two cases of systemic
      mastocytosis revealed by hepatic symptoms: liver failure in one case and jaundice
      in the second case. The diagnosis is often difficult. Mast cell tissular
      infiltration can be identified on paraffin sections by tryptase or CD117 (c-kit)
      immuno-staining.

PMID- 15041818
TI  - [Hepatoid adenocarcinoma of the lower esophagus].

PMID- 15041819
TI  - [Contribution of MR cholangiography after Teslascan infusion for the diagnosis of
      post-traumatic biliary injury].

PMID- 15041820
TI  - [Is sarcoidosic anal fistula a real entity?].

PMID- 15041821
TI  - [Gastric metastasis of ductal breast cancer revealed by a perforated ulcer].

PMID- 15041822
TI  - [Ascites associated with prostate cancer metastases: an unusual localisation].

PMID- 15041823
TI  - [Nome gesrol (lutenyl) induced severe acute hepatitis].

PMID- 15041824
TI  - Spontaneous intrahepatic hematoma revealing nodular periarteritis.

PMID- 15041825
TI  - [Control of secretory diarrhea and colorectal cancer growth by cannabinoids in
      the gut].

PMID- 15041826
TI  - [Gene therapy, hepatocyte growth factor (HGF) and anti-fibrotic effect].

PMID- 15041827
TI  - [Chronic viral hepatitis and needle liver biopsy: controversy or nonsense?].

PMID- 15041828
TI  - [Yves Lallemant (1917-2003)].

PMID- 15041829
TI  - [Surgical and/or endoscopic treatment of acquired tracheal stenosis in adult
      patients].
AB  - OBJECTIVES: Retrospective survey (over 13 Years) of the surgical treatment of 46
      acquired tracheal stenosis, in adult patients. Our goals were to study their
      epidemiology, changes in the surgical technique with the cervical or endoscopic
      approach, and the recent contribution of endoprotheses. MATERIALS AND METHODS:
      Sixty-six therapeutic procedures were performed for 46 tracheal stenoses. Most of
      stenoses were post-intubation and/or post-tracheotomy and were fixed in 50% of
      the cases. We used 21 sleeve resections with end-to-end anastomoses, 9 tracheal
      stents, 27 dilations, 6 calibrations, and 3 electro-coagulations. RESULTS: The
      sleeve resection gave 91% success (1 failure and 1 death). The endoscopic
      treatments were less efficient: 79% for tracheal stents (2 mobilizations), 50%
      success for iterative dilations. The respiratory tests were meaningfully improved
      with a mean follow-up of 18 Months. CONCLUSION: Sleeve resection remains the gold
      standard treatment. For all temporary or definitive contraindications to open
      surgery, tracheal stents would be an excellent alternative to avoid often
      inefficient iterative dilations.

PMID- 15041830
TI  - [Severe laryngomalacia: surgical indications and results in 33 patients].
AB  - INTRODUCTION: Laryngomalacia is the most common course of stridor in children:
      with a 50% to 75% incidence. About 50% to 60% of congenital laryngeal anomalies
      that present with stridor are due to laryngomalacia. In most cases, the disease
      followed a benign course but the prognosis is less favorable in 10% to 15% of
      cases. These patients may require surgical intervention. MATERIALS AND METHODS:
      This prospective study included 33 patients referred to our institution from May
      1998 to May 2003 for severe laryngomalacia. The diagnosis of severe
      laryngomalacia was based on clinical and if necessary paraclinical data. An
      endoscopic laser resection of arytenoid mucosal excess associated if necessary
      with suprahyoid epiglottectomy was performed in all patients. RESULTS: Mean age
      of the children was 7.5 Months (range, 2 weeks-4 Years). Ninety-six percent of
      the patients had complete resolution of symptoms before the fourth postoperative
      week. Ninety one percents of the patients had effective oral feeding within the
      first Month (48% immediately after surgery). The average hospital stay was 6 days
      (range, 3 to 14). Weight gains were found to be satisfactory in all cases since
      children were discharged the hospital. CONCLUSION: Endoscopic laryngeal surgery
      is an appropriate therapy for treatment of severe forms of laryngomalacia. It is
      a safe and effective surgical procedure.

PMID- 15041831
TI  - [Vibratory test and head shaking test and caloric test: a series of 87 patients].
AB  - OBJECTIVES: The purpose of this work was to study the complementary contribution
      of the vibratory test (VT), the head shaking test (HST) and the caloric test (CT)
      in patients with total or partial vestibular lesions. We investigated the
      usefulness of these three tests, particularly the high frequency VT, for multiple
      frequency vestibular study. MATERIALS AND METHODS: The study cohort included 40
      patients with total vestibular lesions (TVL) and 47 patients with partial
      vestibular lesions (PVL), the latter group including 21 patients with recent
      Meniere disease, 15 with sudden-onset loss of vestibular function (SLVF), 5 with
      tumors of the cerebropontine angle, and six with diverse conditions. The HST
      protocol was 2 Hz stimulation (head speed greater than 180 degrees /s). The VT
      used an ABC 100 Hz vibrator operating at 0.8 mm and an S stimulator delivering
      frequencies between 30 and 115 Hz during 10 s stimulations. An LIVN-2 videoscope
      (biodigital France) and a 2D and 3D videonystagmograph (synapsis France) were
      used for the recordings. Mastoid stimulation was used for the VT. RESULTS: For
      the 40 patients with TVL, the three tests (VT, CT, HST) were in agreement for all
      frequencies. The nystagmus produced by the VT demonstrated a horizontal component
      in 96% of the patients, a vertical component in 47%, and a rotational component
      in 30%. For the 47 patients with PVL, 9 of the 21 with Meniere disease had a
      normal CT. Conversely, nystagmus was triggered by the HST in 10 and by the VT in
      6. Nystagmus triggered by the VT and the HST was non-coherent with opposing
      direction in two-thirds of the patients. In certain cases, the VT demonstrated a
      variation in the direction of the nystagmus depending on the stimulation
      frequency, 30 or 100 Hz. Among the 15 patients with SLVF, the HST triggered
      nystagmus in only 5 and the VT in 14 (5 patients had nystagmus non-coherent with
      the side of the lesion). For the 5 patients with tumors of the cerebropontine
      angle (small neuroma or meningioma), the CT was negative in all 5, the HST was
      negative in 3, and the VT demonstrated lesional nystagmus in 4. Looking at the
      overall results, in the 47 patients with PVL (including 21 cases of Meniere
      disease outside an acute phase) the CT demonstrated significant hypovalence in
      70%, while the nystagmus demonstrated asymmetrical response in 44% when triggered
      by the HST and in 85% when triggered by the VT. CONCLUSION: The VT is less
      invasive than the HST, particularly for elderly patients with osteoarthritis. It
      would be interesting in patients with bilateral tympanic perforation since the CT
      cannot be performed. It can reveal vestibular asymmetry. For unilateral partial
      vestibular lesions, the VT triggers nystagmus more often than the HST. It is
      particularly sensitive between acute episodes in patients with Meniere disease. A
      discordance between the direction of the nystagmus triggered by the HST and the
      VT is particularly frequent in patients with labyrinthine hydropsis who exibit a
      normal CT. In certain cases of apparent bilateral areflexia to the CT for low
      frequencies, the VT can disclose vestibular asymmetry for high frequencies. The
      nystagmus triggered by the VT begins and ends with stimulation with little or no
      tiring. The nystagmus triggered by the HST occurs after the stimulation and
      depends on the frequency of the head shaking. Thus, the HST (2 Hz and its
      harmonics), the VT (100 Hz) and the CT (<0.01 Hz) all make significant
      contributions to multiple-frequency analysis of vestibular function, particularly
      useful in patients with partial vestibular lesions. These tests probably solicit
      cells with different topographies or different frequency sensitivities.

PMID- 15041832
TI  - [ENT Resident Activity in the Strasbourg Hospital ENT Emergency Clinic].
AB  - OBJECTIVES: We present an original study about ENT resident activity in an
      emergency ENT clinic. MATERIALS AND METHODS: The emergency unit's activity was
      analyzed over a seven-Month period from December 1, 1999 to June 30, 2000. ENT
      residents reported patient age, gender, duration of consultation, symptoms, and
      care delivered as well as the level of emergency and referral (general
      practitioner, emergency unit, other clinic, direct). RESULTS: A total of 147
      emergency days were analyzed. During the study period, 1237 patients were
      examined, representing 8.4 patients per day and 26.5% of the ENT clinic
      outpatient activity. Mean patient age was 31.8 Years; 58% of the patient were
      male. Most of the cases did not correspond to true emergencies (53%). Half of the
      patients were not referred by a general practitioner. Emergency care was more
      justified when the patients were referred by a general practitioner or another
      emergency unit. The predominant pathological situations managed were acute
      external and middle ear otitis, epistaxis, angina, vertigo, and facial injuries.
      CONCLUSION: Over half of the patients came to the emergency clinic spontaneously,
      presenting minor problems. These data can be explained by the fact that residents
      are permanently present at the ENT emergency clinic. It would be interesting to
      conduct a similar study in ENT emergency care units where the resident is not
      permanently present.

PMID- 15041833
TI  - [Beneficial effect of cochlear implants in the elderly].
AB  - OBJECTIVE: To evaluate the benefit of cochlear implantation in older adults aged
      60 Years and over. METHODS: Fifty-six profoundly or totally hearing-impaired
      patients, aged 60 Years and over, were studied retrospectively. At the end of the
      preoperative evaluation, 28 patients received a cochlear implant. The mean age
      was 66 Years and the median follow-up was 22.5 Months. Speech perception scores
      before and after implantation were analyzed in order to evaluate the benefit of
      cochlear implantation. The speech perception score before implantation was
      compared to that of the non-implanted patients. RESULTS: There was a significant
      improvement of the dissyllabic words and sentences scores after implantation. The
      patients who are over 70 Years performed as well as those who are younger
      (between 60 and 70 Years). One patient developed a postoperative vertigo due a
      perilymphatic fistula. There was no flap-related problems. In the non-implanted
      group (mean age: 68 Years), 18 patients declined the cochlear device because they
      thought the subjective benefit of their hearing aid was sufficient and 5 patients
      declined because of surgical risk. The mean age, the cause and the duration of
      the deafness, and the speech perception scores were similar between implanted and
      non-implanted patients. CONCLUSION: This study demonstrates the beneficial effect
      of cochlear implantation in the elderly. These results suggest that a similar
      benefit could have been obtained in the patients who declined surgery. An early
      implantation could reduce the duration of the deafness and preserve binaural
      sound perception allowing increased performance in older people.

PMID- 15041834
TI  - [Surgical treatment of paraosmia secondary to an upper respiratory infection].
AB  - Many people experience some degree of olfactory dysfunction during the acute
      stages of an upper respiratory infection (URI). The olfactory function usually
      returns to the preinfection level in few days. In some cases, the dysosmia
      remains even after the reopening of the air passageways. The olfactory loss after
      URI associates an hyposmia and odor distortions. We report a rare case of odor
      distortions after URI treated by surgery.

PMID- 15041835
TI  - [Medication-assisted and non-medication-assisted strategies for smoking
      cessation. Practical therapeutic check list: routine practices for smoking
      cessation. Guidelines for good clinical practices].

PMID- 15041836
TI  - [Our best wishes for 2004].

PMID- 15041837
TI  - [Molecular genetics and the skin: genes or pleasure?].

PMID- 15041838
TI  - [Clinical assessment of the risk of Human Immunodeficiency virus (HIV) infection
      in the population consulting an anonymous and free screening center].
AB  - INTRODUCTION: The anonymous and free AIDS screening centers were developed in
      France in 1987 to incite the general population to undergo screening for HIV
      infection. The aim of this paper was to conduct a prospective study describing
      the principle characteristics and level of risk of those consulting a center in
      the Year 1999. POPULATION AND METHODS: A face to face physician-consultant
      questionnaire was proposed to all the consultants that Year. It included 20
      questions regrouped in general characteristics of the subject, number of previous
      screenings, reason for screening, type of risk taken, date of last risk taken,
      and number of sexual partners during the past 12 Months and throughout their life
      without the use of a condom. RESULTS: Two thousand six hundred seventy-eight
      persons consulted (sex ratio=1) aged a mean of 25.8 Years. The men were older
      than the women (respectively 27 versus 24.6; p<0.05). The reason for screening
      was a decision made by the couple in 44.6 p. 100, an unprotected sexual
      relationship in 47.6 p. 100 another reason in 7.6 p. 100 and drug abuse in 0.2 p.
      100 of cases. The sex mode declared was heterosexual in 94.5 p. 100 and homo or
      bisexual in 5.4 p. 100. The majority of those consulting (66.2 p. 100) had had
      between 0 and 2 partners during the past 12 Months; 66 p. 100 had had more than
      10 during their life without using a condom. The assessment of the global risk by
      the physician was: very high in 1 p. 100, high in 2.5 p. 100, moderate in 13.3 p.
      100, low in 70.7 p. 100 and nil in 12.5 p. cent. Five HIV infections were
      diagnosed, all in persons at high or very high risk. DISCUSSION: These results
      should stimulate the radical differentiation of the management of persons
      consulting according to the level of risk identified by the medical
      questionnaire.

PMID- 15041840
TI  - [Cutaneous tumors during xeroderma pigmentosum in Morocco: study of 120
      patients].
AB  - INTRODUCTION: Xeroderma pigmentosum is a rare recessive and autosomically
      transmitted genodermatosis. Its cutaneous manifestations are dominated by skin
      cancers. This investigation aims at studying the epidemiologic, clinic,
      histologic, therapeutic and evolutive aspects of the skin tumors during xeroderma
      pigmentosum. PATIENTS AND METHODS: A retrospective monocentric study was carried
      out in the Dermatology and Veneorology Department of Ibn Rochd University
      Hospital of Casablanca, Morocco. It included all the xeroderma pigmentosum
      admitted to hospital or followed-up from 1990 to 2000. All the dossiers were
      included. The anatomopathologic study was carried out in all the skin tumor
      cases. RESULTS: One hundred and twenty xeroderma pigmentosum were admitted in 10
      Years. Fifty-four percent of the cases were females and 46 p. 100 were males. The
      mean apparition of the first tumor was 7.7 Years. One hundred and fifty-three
      skin tumors were diagnosed in 96 patients (80 p. 100). These tumors were of
      basocellular carcinoma type in 32.6 p. 100, of squamous cell carcinoma type in
      33.9 p. 100 and of melanoma type in 11 p. 100. Ocular tumors were found in 31
      cases (25.8 p. 100) and buccal in 8 cases. Therapeutically, the surgical exeresis
      of one or many tumors was performed in all cases. Electrocoagulation was
      associated in 42 p. 100 of the cases and skin graft in 52 p. 100. Cutaneous
      relapses after surgery were noticed in 55 cases (57.2 p. 100). Twenty-five
      patients died and 31 were lost to follow-up. DISCUSSION: Our series is
      characterized by a large frequency of mainly cutaneous tumors (80 p. 100) in
      comparison with the largest review of literature (45 p. 100). These tumors were
      mainly represented by basocellular and squamous cell carcinoma with onset at an
      early age (7.7 Years). Our series is also characterized by a large frequency of
      cutaneous relapses after surgery (51.6 p. 100). Neglecting advice on
      photoprotection and the lack of regular control visits lead to the proliferation
      of large size tumors, making therapeutic strategies difficult or even impossible.

PMID- 15041839
TI  - [An epidemiological model of genital herpes for assessment of potential impact of
      therapy and prophylaxis: application to France].
AB  - OBJECTIVES: This study was performed to quantify the development of the number of
      cases of genital herpes and to assess the impact of different treatment
      strategies in France. METHOD: A model for the natural history of herpes simplex
      virus genital infection is presented and applied to the French population. The
      model encompasses infection by herpes simplex virus type 1 (HSV-1) or type 2 (HSV
      2), first episodes, recurrences, viral shedding and the effect of treatment on
      infected individuals. RESULTS: In the Year 2000, 270,000 individuals would have
      suffered from genital herpes in France. A total annual cumulated number of 1.5
      million episodes of recurrence and 23 million days of viral shedding were
      estimated. Seventy percent of viral shedding occurred in sub-clinical
      seropositive individuals. The expected number of attributable neonatal deaths
      remained very low. Systematic treatment of clinical episodes might reduce the
      number of days with lesions (- 27 p. 100), and is also effective on viral
      shedding (symptomatic: - 50 p. 100). Continuous treatment of the most severe
      patients (>or=6 recurrences per Year) might reduce viral shedding slightly more (
      85 p. 100). Antiviral treatment might have a major impact on the quality of life
      of these patients but would only slightly curb the number of new infections.
      DISCUSSION: This model tries to integrate the various data currently available at
      international level on the epidemiology of genital herpes. However, many aspects
      are still not well documented and remain uncertain. It is therefore necessary to
      define various assumptions in order to simulate the natural history of the
      disease in a population. The lack of French data especially on the HSV-1 and HSV
      2 seroprevalence profiles reinforces these uncertainties. Our results should
      hence be considered as exploratory. However, this modeling approach is the only
      possible way to integrate the multiple parameters describing the pathology and
      predicting of the public health impact of different interventions. This model is
      an open tool which may be modified when new data become available.

PMID- 15041841
TI  - [Contact urticaria to natural rubber latex in childhood and associated atopic
      symptoms: a study of 27 patients aged under 15 years].
AB  - BACKGROUND: Although natural rubber latex hypersensitivity is considered as a
      major problem in adult, it may be still misdiagnosed in childhood. PATIENTS AND
      METHOD: We collected 27 observations of natural rubber latex contact urticaria in
      children under 15 Years of age, 21 of them aged under 8. RESULTS: All of them
      where atopic and 19 out of 27 presented with other association paroxystic signs
      of immediate hypersensitivity, that were lately related to latex allergy (i. e.
      asthma, rhinitis, conjunctivitis, fainting). Cross-allergy to food allergens was
      present in 33 p. 100. Average level of specific IgE to natural rubber latex was
      21.7 kU/l. One to 4 Years follow up confirmed the benefit of latex eviction on
      urticaria as well as on associated symptoms. It led to the early detection of
      ficus allergy in 4 of them. DISCUSSION: This series confirms that atopy is at
      high risk for natural rubber latex allergy in children. These data suggest that
      atopic children are exposed too early to latex devices such as pacifiers, toodles
      of latex toys. Contact urticaria in children must be considered as a possible
      marker of other respiratory or general symptoms that may have been misconsidered
      under other etiologies.

PMID- 15041842
TI  - [Topical corticosteroids].
AB  - Therapeutics in dermatology underwent complete change after the introduction of
      topical hydrocortisone in the Fifties. At the time, stronger derivatives than
      hydrocortisone were synthetised and the indications for topical corticosteroids
      were expanded. Around twenty different molecules, classified according to their
      strength, are currently available for prescription in France. Many inflammatory
      or tumoral skin diseases respond to these products. The choice of a topical
      corticosteroid (strength, vehicle.) and of its mode of application (technique,
      rhythm of application) is oriented by the context (dermatitis treated,
      localization) and must respect "Good clinical practice" guidelines so as to
      select the best benefit/risk ratio.

PMID- 15041843
TI  - [Sarcoidosis granuloma on a tattoo induced by interferon alpha].
AB  - BACKGROUND: The side effects attributed to interferon alpha are numerous,
      including autoimmune events such as lupus, arthritis or thyroiditis. Emergence of
      sarcoidosis in patients with interferon alpha therapy is much more rare. We
      describe a case occurring in a patient treated for melanoma. CASE REPORT: A 54
      Year-old woman who had been treated for fifty Months with low dose interferon
      alpha (Roferon(R), 3 millions units, three times a week) for a melanoma of the
      scalp (adjuvant therapy), developed labial nodules on a permanent tattoo. The
      diagnosis of sarcoid granuloma was confirmed by histopathologic analysis.
      Physical examination revealed dyspnea on exertion with a moderate pulmonary
      interstitial infiltrate on the CT Scan. The diagnosis of cutaneous and pulmonary
      sarcoidosis in association with interferon alpha therapy was made. Within 4
      weeks, skin nodules began to regress although interferon was pursued at the same
      dose. Four Months later, at the end of interferon therapy, the nodules had
      totally disappeared. DISCUSSION: About forty cases of cutaneous or systemic
      sarcoidosis in patients treated with interferon alpha have been reported, but
      none of these cases concerned patients treated for melanoma. Interferon alpha
      might promote the development of sarcoid granuloma by inducing a switch of
      cytokine secretion from a Th2 to a Th1 cytokine pattern. It is very important to
      recognize cutaneous sarcoidosis during interferon alpha treatment because
      pulmonary sarcoidosis can be confused with common general side effects observed
      with such treatment.

PMID- 15041844
TI  - [Pseudolymphomatous folliculitis].
AB  - INTRODUCTION: A case of a rare variety of cutaneous pseudo-lymphoma is reported.
      CASE REPORT: A 13 Year-old boy presented with a nodule on the nose groove which
      corresponded histologically to a dense, peri follicular lymphocyte infiltration
      penetrating the hair. Following partial biopsy, the lesion disappeared within a
      fortnight. COMMENTS: Our case report corresponds to the entity described in 1999
      in the Japanese. Our case occurred in a Caucasian French adolescent. The
      papulonodule, usually unique, is composed histologically of a dense, peripilary
      infiltrate that penetrates and disrupt the hair. The majority of cases have been
      removed surgically. Those that have not usually disappear following partial
      biopsy. The individualization of this entity is debatable: the involvement of the
      hair follicles by the infiltration of pseudolymphomas on the face is frequent and
      non-specific.

PMID- 15041846
TI  - [Discoid lupus erythematosus involving the eyelids: 4 cases].
AB  - BACKGROUND: Discoid lupus erythematosus is a chronic skin disease frequently
      involving the face, scalp and ears. Palpebral lesions are rare. We report 4 cases
      of this uncommon localization. In one case, palpebral lesions were the sole
      manifestation of the discoid lupus erythematosus. CASE REPORTS: Four patients
      aged between 26 and 45 Years had lesions of the lower eyelid as erythematous,
      infiltrated and scaly plaques. One patient, without diagnosis despite 2 skin
      biopsies of lesion, presented with a 2-Year history of blepharitis in the absence
      of any other cutaneous abnormality. In one case, chronic blepharitis has been
      present for 4 Years and associated with inflammatory arthralgia. Alopecia
      occurred 4 Years after the onset of blepharitis and led to the diagnosis of
      discoid lupus erythematosus. In 2 cases, blepharitis was associated with typical
      cutaneous lesions of discoid lupus erythematosus. Antimalaria drugs were very
      effective in 3 cases. In one patient the antimalaria drug failed, but thalidomide
      was effective. DISCUSSION: The location of lesions on the eyelids in the absence
      of any other cutaneous abnormality is rare and can easily lead to the
      misdiagnosis of discoid lupus erythematosus. Most Authors mention a predilection
      of the lesions to the inferior portion of the eyelid, more specifically to the
      external third. The involvement of the eyelids with permanent scarring and severe
      eye impairment is explained by the long duration of the disease without
      diagnostic and appropriate treatment. Clinical examination is highly consistent
      with discoid lupus erythematosus: the lesions typically present as well
      circumscribed, erythematous plaques with telangiectasia and scales and atrophy in
      long-standing disease. Antimalaria drugs are remarkably effective.

PMID- 15041845
TI  - [Miescher's cheilitis and lymphocytic clonal expansion: 2 cases].
AB  - INTRODUCTION: Melkersson Rosenthal's syndrome is a rare disease that classically
      combines: orofacial edema, peripheral facial paralysis and a plicated tongue.
      Miescher's cheilitis represents the monosymptomatic form of the disease. Its
      etiopathogenesis is unknown. We report 2 cases of Miescher's cheilitis during
      which the discovery of a monoclonal lymphocyte expansion raised the question of
      an eventual link between these two diseases. CASE REPORTS: CASE No 1. A 30 Year
      old man, without medical past history, had been followed up for 3 Years for
      Miescher's cheilitis. The supplementary examinations permitted elimination of an
      infectious cause, Crohn's disease, sarcoidosis or a contact allergy. A serum
      monoclonal IgG kappa was discovered fortuitously. An X-ray of the skeleton and
      the myelogram were normal. There was no detectable monoclonal rearrangement of
      the genes of the blood or bone marrow T or B-cell lymphocyte receptor. In the
      absence of progression towards a malignant blood disease three Years later, we
      concluded in a benign monoclonal gammapathy. CASE No 2. A 36 Year-old Algerian
      man, without past medical history, had been followed-up for 8 Years for a
      granulomatous macrocheilitis. The search for Crohn's disease, sarcoidosis or a
      contact allergy was negative and the diagnosis of an incomplete Melkersson
      Rosenthal syndrome was retained. The blood count revealed persisting
      hyperlymphocytosis in the blood. The etiological search for a hyperlymphocytosis
      showed a monoclonal rearrangement of the T-cell lymphocyte receptor genes in the
      blood lymphocytes. The myelogram was normal. COMMENTS: Melkersson Rosenthal's
      syndrome is a rare granulomatous disease of the mucosa of the mouth. The
      etiopathogenesis of this affection is unknown and controversial, several case
      reports suggest that it could be a disease of immunological origin. A clonal T
      cell lymphocyte population was revealed in the labial lesions of a 12 Year-old
      patient presenting with Melkersson Rosenthal's syndrome during a control visit,
      without the role of this lymphocyte population having been determined. We report
      two other cases associating blood lymphocyte proliferation and Melkersson
      Rosenthal' syndrome. This association is not necessarily fortuitous because of
      the rarity of the syndrome on the one hand and the uncommon nature of the
      detection of lymphocyte clones in young patients on the other. The presence of a
      clonal population can be interpreted in two manners: it can demonstrate chronic
      antigen stimulation, which with a super-antigenic effect leads to the expansion
      of a lymphocyte population making it detectable. The other hypothesis would be an
      increased secretion of cytokines by the lymphocyte clone provoking a
      granulomatous organization, as during granulomatous lymphomas.

PMID- 15041847
TI  - [Acquired lymphangiectasias or mammary dermolytic blisters with spontaneous
      resolution].
AB  - INTRODUCTION: Spontaneous occurrence of hemorrhagic blisters on the lower side of
      the breasts is an unusual clinical presentation of acquired lymphangiectasia.
      CASE REPORT: A 64 Year-old and a 85 Year-old woman had developed recurrent
      bleeding blisters in the sub-mammary region for several Months. Histological,
      immunohistochemical and electron microscopic examination revealed a subpapillary
      dermal bullous dehiscence, parallel to the epidermis, which was connected to
      lymphangiectasias of the superficial dermis. Their extreme dilatation and rupture
      were probably responsible for the clinical inflammatory and bleeding aspect of
      the lesions, which have not recurred after 1 and 3 Years, respectively.
      DISCUSSION: The presence of subpapillary inflammatory lymphangiectasias might be
      responsible for recurrent dermal blister formation. The reason for the presence
      of these hemorrhagic lymphangiectasias, restricted to the sub-mammary location
      and their spontaneous regression after several flare-ups, remain unclear. The
      unusual clinical presentation of the lesions observed in these two women
      constitutes a differential diagnosis of acquired dermolytic blisters.

PMID- 15041848
TI  - [Treatment of solar urticaria by intravenous immunoglobulins and PUVA therapy].
AB  - BACKGROUND: Solar urticaria is a rare form of urticaria occurring a few minutes
      after solar exposure. It is particularly incapaciting because it limits outdoor
      activities. Antihistamine and phototherapy are sometimes disappointing. CASE
      REPORT: A 32 Year-old woman had been suffering from severe solar urticaria since
      November 2000, which was confirmed by photobiological data. High-dose
      antihistamine treatment (fexofenadine 180 mg twice a day) was inefficient.
      Despite a first UVA desensitization, PUVAtherapy produced only a partial
      improvement and short lasting for protection, with an important handicap in daily
      life. In March 2002, among the others treatments, we chose intravenous
      immunoglobulins: 0.5 g/kg the first day then 1 g/kg the second and the third
      days. The minimal urticaria dose was raised from 1 J/cm2 in UVA before perfusion
      up to 15.6 J/cm2 48 hours later and in UVB from 100 mJ/cm2 up to 2,200 mJ/cm2.
      Clinically the improvement was significant but partial in daily activities. It
      was possible to reintroduce PUVAtherapy without UVA-desensitization and, for the
      first time, to obtain complete remission for more than 2 Months with an
      association of intravenous immunoglobulins, PUVAtherapy and antihistamine
      treatment. In July 2002, treatment was successfully repeated. DISCUSSION: First
      intention treatments (antihistamine and PUVAtherapy) are sometimes inefficient.
      Others treatments (plasmapheresis, ciclosporin, doxepin, cimetidine) are
      restrictive, not always efficient and can induce severe side-effects. We report
      the second case of solar urticaria improved by intravenous immunoglobulins. In
      spite of the cost, intravenous immunoglobulins seem to be an interesting
      treatment, at least by avoiding UVA-desensitization in severe cases of solar
      urticaria.

PMID- 15041849
TI  - [Pain sedation with MEOPA].

PMID- 15041850
TI  - [The good use of serodiagnosis during Lyme's borreliosis].

PMID- 15041851
TI  - [Cannabis in relation to juvenile ulcer. Two cases].

PMID- 15041852
TI  - [Cutaneous manifestations of anhidrotic ectodermal dysplasia].

PMID- 15041853
TI  - [Erythematous and cold plaque of the breast].

PMID- 15041854
TI  - [Papules along the borders of the hands and feet].

PMID- 15041856
TI  - [Contact dermatitis].

PMID- 15041855
TI  - [The Carney complex].

PMID- 15041857
TI  - [Sarcoidosis].

PMID- 15041858
TI  - [The role of dendritic cells in immunity. Potential clinical use].

PMID- 15041860
TI  - [Basal cell-like hyperplasia on a histiocytofibroma].

PMID- 15041859
TI  - [Hopf's verruciform acrokeratosis and Darier's disease are related to mutations
      in the same gene, ATP2A2].

PMID- 15041861
TI  - [Toxic epidermal necrolysis and celecoxib (Celebrex)].

PMID- 15041862
TI  - [Bone distraction and conventional procedures in maxillofacial surgery].

PMID- 15041863
TI  - [Bone distraction and conventional procedures in maxillofacial surgery].

PMID- 15041864
TI  - [Predictability of maxillary distraction with the trans-sinusoidal distractor].
AB  - INTRODUCTION: This work was conducted to evaluate a new maxillary distractor with
      an activating system introduced into the maxilary sinus. PATIENTS AND METHOD:
      Fourteen patients age 8 to 55 Years with severe maxillary and midfacial
      hypoplasia were treated in our center. A trans-sinusoidal maxillary distractor
      (TS-MD, developed by Dr. N. Nadjmi in cooperation with Martin, Tuttlingen,
      Germany) was placed intra-orally at each side of the maxilla. The distraction
      vector was predicted with devoted software (Medicim N.V Belgium), and was
      transferred to the patients using stereolithographic models and individual
      templates. A high Lefort I type osteotomy was performed. RESULTS: Forward
      maxillary movement at distractor level varied from 7 to 22 mm. Soft and hard
      tIssue formation resulted in complete healing across the distraction gaps. The
      maxillary movements and new bone formation in the sagittal, horizontal, and
      vertical planes could be predicted and achieved. Distractors were designed to
      allow clockwise rotation of the maxilla during the distraction phase allowing the
      correction of the anterior open-bite in all patients with this skeletal
      deformity. The distractors were almost completely submerged, and could be left in
      place as long as necessary to avoid relapse. DISCUSSION: The TS-MD distractor has
      the advantage of good tolerance since the most voluminous part is placed within
      the maxilary sinus. Implantation via an exclusively oral approach is a further
      advantage. The devise does not interfere with the patient's social life and does
      not require alveolodental fixation. The TS-MD distractor can also aleviate the
      need for bone grafting in cases with major advancement. Correct position of the
      vector is crucial but one-sided catch-up distraction is possible.

PMID- 15041865
TI  - [Quadruple internal distraction with early frontal-facial avancement for
      faciocraniodysostosis].
AB  - INTRODUCTION: Frontofacial monobloc advancement (FFMA), known as a high risk
      procedure, was evaluated in combination with distraction. PATIENTS AND METHOD:
      Twenty patients with faciocraniosynostosis, were treated with FFMA and quadruple
      internal distraction. Mean age at surgery was 3.2 Years and mean follow-up was 14
      Months (3-32 Months). Four distractors were used per patient in combination with
      complete osteotomy FFMA. Rate of distraction was classical (0.5 mm to 1mm per
      day) starting on day 7. The rate of short-term complications was evaluated.
      Correction of exorbitism and the dental occlusion relationship were assessed to
      evaluate achievement of advancement. Rate of relapse was evaluated by measuring
      the orbital bony gap on horizontal CT slices, before and 6 Months after removal
      of the distractor. Respiratory impairment when present was also evaluated.
      RESULTS: Distraction was completed in 18/20 patients. Fifteen patients completed
      their distraction uneventfully during the initial period. In three patients with
      CSF leaks, distraction was delayed at day 14 and 16, but was resumed and
      completed normally. Second operations were required for two patients during the
      early phase: the distractor failed in one requiring immediate reoperation to
      change the device; distraction was completed successfully. Device infection
      developed in two patients requiring removal of the device and abortion of
      distraction. One patient died the day after surgery from acute tonsillar
      herniation before distraction could be initiated. Exorbitism was clinically
      corrected in all cases in whom distraction was completed (n=18). Class I
      occlusion was obtained in 16/18 patients. When present, respiratory impairment
      was corrected in all cases. Septic frontal necrosis occurred in one patient two
      Months after distraction was completed and necessitated removal of the forehead
      flap. Distractors were easily removed through a coronal approach at 6 Months, but
      reossification was limited. Relapse was observed in three patients whose
      retaining phase was less than five Months. Rate of relapse was much lower when
      distraction was maintained more than six Months. DISCUSSION: Internal distraction
      can provide early correction of respiratory impairment due to
      faciocraniosynostosis in infancy and can reduce the major risks of frontofacial
      monobloc advancement. Morbidity is higher in patients with prior surgery before
      FFMA. Further evaluation is necessary to determine whether the two stage
      treatment strategy for faciocraniosynostosis (fronto-orbital advancement before
      one Year of age, and later facial Lefort III type advancement) could be replaced
      by a routine FFMA procedure.

PMID- 15041866
TI  - [Correlation between ultrasound and radiographic data for assessment of
      symphyseal bony callus maturation after distraction].
AB  - OBJECTIVE: To search for means of reducing ionizing radiation during treatment
      planning for transmandibular osteodistraction. MATERIAL AND METHODS: Eleven
      patients (6 female, 5 male) underwent combined bimaxillary osteodistraction at a
      mean age of 18 Years. The following investigations were performed to determine
      symphyseal callus maturation: occlusal radiographs (O-RX) preoperatively, after
      the active phase of distraction (mean 27 days); ultrasound investigations (US)
      after the active and consolidation phase. RESULTS: US showed calcification foci
      at the end of the active phase, when O-RX failed to do so. Both US and O-RX
      detected callus immaturity after 2 Months of consolidation in 1 patient. Both
      detected bridging ossification one Month later. DISCUSSION: US can replace
      radiography in the diagnosis of callus maturation related to distractor removal.

PMID- 15041867
TI  - [The molecular biology of distraction osteogenesis].
AB  - Distraction osteogenesis has become a mainstay in bone engineering and the recent
      application of this technique to the membranous craniofacial skeleton has
      significantly improved our armamentarium for reconstructive craniomaxillofacial
      procedures. However, if the biomechanical, histological and ultrastructural
      changes associated with distraction osteogenesis have been widely described, the
      molecular mechanisms governing the formation of new bone in the interfragmental
      gap of gradually distracted bone segments remain largely unclear. Recently, our
      laboratory has described a rat mandibular distraction model that provides an
      excellent environment for deciphering the molecular mechanisms that mediate
      distraction osteogenesis. In this Article, we present the hypotheses and current
      research that have furthered our knowledge of the molecular mechanisms that
      govern distraction osteogenesis. Recent studies have implicated a growing number
      of cytokines that are intimately involved in the regulation of bone synthesis and
      turnover. The gene regulation of numerous cytokines (Transforming Growth Factor
      B, Bone Morphogenetic Proteins, Insulin-like Growth Factor-1, Fibroblast Growth
      Factor-2) during distraction osteogenesis have been best characterized and will
      be discussed in this text. We believe that novel systems like the rat model will
      facilitate our understanding of the biomolecular mechanisms that mediate
      membranous distraction osteogenesis and will ultimately guide the development of
      targeted-strategies designed to accelerate bone healing.

PMID- 15041868
TI  - [Rapid palatal expansion for the treatment of maxillary constriction].
AB  - Rapid Palatal Expansion (RPE) has become a classical technique yielding a
      morphological expansion similar to that obtained with bone distraction. This non
      surgical approach based on the application of dental bands take advantage of
      incomplete closure of facial sutures in children, especially the palatal suture,
      which opens under the pressure of the appliance. Semi-rapid expansion, 0.5 mm
      expansion per day for 15 days, is a compromise between pain and efficiency. The
      morphological expansion assures correction of maxillary width, even when only two
      bands are used. The etiology is often difficult to determine but interestingly,
      mouth breathing is associated in a large number of patients. The consequences of
      this ventilatory dysfunction are complex and involve increased posterior
      rotation, maxillary and mandibular developmental disorders, sleeping disorders
      and nocturnal enuresis behavior and at the dental level a characteristic open
      bite. RPE is not a perfect solution, but it does allow recovery of transversal
      growth by mechanical enlargement. Palatal expansion also widens the nasal cavity
      which becomes more permeable to airflow. Nasal breathing becomes easier but still
      requires retraining. Spectacular effects on dento-facial development can be
      observed, including closure of open bite and reorientation of mandibular growth.
      Stability is particularly dependent on the success of functional correction. A
      global approach, considering both the morphological and functional aspects of the
      problem is required to achieve harmonious and stable correction. Early treatment
      (7-8 Years old) provides excellent results. RPE can be performed at an older age
      (13 to 14) but with less spectacular effects on growth.

PMID- 15041869
TI  - [Vertical alveolar distraction in the posterior mandible].

PMID- 15041870
TI  - [Cartilage reshaping by laser in stomatology and maxillofacial surgery].
AB  - The restoration of congenital and traumatic malformations of the head and neck,
      together with the defects resulting from the trauma of ablative surgery, continue
      to pose significant problems to surgeons. The post-operative results are not
      always satisfactory because of the difficulty of shaping the cartilage and
      because of the tendency of cartilage to return to its original shape. Better
      understanding of laser-cartilage interaction and the development of a specific
      instrumentation Lasers (CO2, Nd: YAG, Ho: YAG) has enabled ex situ and in situ
      cartilage reshaping. A recent clinical study has demonstrated that nondestructive
      laser irradiation can reshape septal deviations

PMID- 15041871
TI  - [Eagle syndrome: case report].
AB  - Eagle's syndrome, also known as elongated styloid process, is an entity that may
      be the source of craniofacial and cervical pain. It is frequently reported but is
      probably more common than generally considered. The symptoms related to Eagle's
      syndrome can be confused with those attributed to a wide variety of Oropharyngeal
      and Maxillofacial diseases. The paucity of information in the radiologic
      literature prompted this report.

PMID- 15041872
TI  - [The management of stroke in France, a new stake in the organisation of hospital
      care].

PMID- 15041874
TI  - [Stem cells and therapeutic cloning, medical perspectives under discussion].
AB  - Innovative biotechnical progress over the past few years regards stem cells and
      therapeutic cloning, which open promising medical horizons for many presently
      incurable diseases. THE CURRENT DEBATE: The research work in France has been
      stalled because of the prohibitions listed in the so-called "bioethical" laws of
      1994. The ongoing revision of these laws is based on a certain number of ethical
      questions and launches a disputable parlementary debate. Other than reproductive
      cloning and research on the embryo, the possibilities provided by stem cells and
      therapeutic cloning should be emphasized and the different positions advanced
      specified, showing an evolution in the laws in France. ABUSIVE LEGISLATIVE
      PROHIBITIONS: The proposed law, which maintains the prohibition for research on
      the embryo, with a 5-Year dispensation, and which explicitly prohibits
      therapeutic cloning, is not in keeping with the widening of in this field
      expected by research teams. Many scientists and physicians, supported by
      patients' associations, are aware of the importance of therapeutic progress
      attached to such research. They should not be stalled in their studies by the
      prohibitions maintained in the new law.

PMID- 15041877
TI  - [Primary pulmonary hypertension associated with HTLV-I retrovirus infection at
      the adult T-cell leukemia lymphoma stage].
AB  - INTRODUCTION: Primary pulmonary hypertension is a rare condition characterized by
      sustained elevation of pulmonary artery pressure without demonstrable cause. Risk
      factors such as HIV infection are associated with this disease. HTLV-1 is a
      retrovirus endemic in Japan and in the Caribbean and an adult T-cell leukaemia
      lymphoma is the most severe complication induced. OBSERVATION: A 59 Year-old West
      Indian woman who had an HTLV-1 retrovirus infection complicated by adult T-cell
      leukaemia lymphoma developed primary pulmonary hypertension. COMMENT: The link
      between HIV infection and primary pulmonary hypertension is already known. The
      hypothesis of a link with an other retrovirus has to be confirmed by furthers
      studies.

PMID- 15041875
TI  - [Treatment of functional signs of acute maxillary rhinosinusitis in adults.
      Efficacy and tolerance of administration of oral prednisone for 3 days].
AB  - OBJECTIVE: Acute maxillary rhinosinusitis (AMRS) is a pathology in which the pain
      is often severe and requires appropriate treatment. Although the use of
      antibiotics is widely documented, the interest of short cycles of corticosteroids
      in the treatment of the functional manifestations of AMRS is based on
      professional experience. The aim of this study was to assess the efficacy and
      tolerance to prednisone administered for 3 days in addition to antibiotherapy in
      patients presenting with an AMRS. METHOD: This was a double blind, randomised
      study in parallel groups and controlled versus a placebo, involving patients aged
      over 18, presenting with an AMRS confirmed by X-ray and endoscopy, having
      developed less than 5 days and complaining of spontaneous pain assessed as >or=50
      millimetres on a visual analog scale (VAS). Together with cefpodoxime, the
      patients received either prednisone (0.8 to 1.2 mg/kg) for 3 days or a placebo.
      The primary efficacy endpoint was the mean of the differences versus the baseline
      value of pain (MPID - mean pain intensity difference) assessed on the VAS from
      Day 1 to Day 3. The secondary endpoints assessed were the mean of the differences
      in intensity of nasal obstruction, assessed in the same way as the MPID, the time
      lapse before the orally expressed relief of the pain (PRID - pain reflief
      intensity difference) and the administration of paracetamol during the first 3
      days. RESULTS: 289 patients (placebo 147, prednisone 142) were assessable for
      analysis in intent-to-treat (ITT). The global spontaneous pain on inclusion,
      measured by a VAS was of 73.0 +/- 14.1 mm. The assessments made during the first
      3 days of treatment showed a statistically significant difference in favour of
      the prednisone group regarding MPID: - 4.82 mm (CI 95% -9.25; -0.40) (p=0.03),
      nasal obstruction - 5.0 mm (CI 95% -9.1; -0.8) (p=0.02) and consumption of
      paracetamol (p=0.03). There was no difference between the two groups after the
      end of the antibiotherapy. The tolerance measured throughout the study was
      comparable between the two groups. CONCLUSION: This study clearly showed the
      efficacy of a short course of oral prednisone (3 days), versus a placebo, in the
      treatment of the functional signs of acute maxillary rhinosinusitis with severe
      pain in adults in addition to an appropriate antibiotic treatment.

PMID- 15041876
TI  - [Predictive factors of virological response to primary antiretroviral treatment].
AB  - OBJECTIVES: During 1999, first-line antiretroviral combinations for the treatment
      of HIV infections have diversified. The aim of our study was two-fold: define the
      factors associated with initial success and define the factors associated with
      virological rebound in patients in whom a primary antiretroviral therapy (ARV)
      had been initiated between 1999 and 2000. METHOD: We conducted a retrospective
      multicenter study regrouping 6 HIV clinics in the North-East of France. Data were
      Issued from the patients medical files. Primary success was defined as plasma HIV
      RNA viral load (VL<200 copies/ml within 6 Months of therapy and two consecutive
      VL<200 copies/ml. Virological rebound was defined as two consecutive VL>1000
      copies/ml after primary success. Predictors of success were determined using
      multivariate logistic regression and SAS 8.2 software. RESULTS: Analysis
      concerned 123 patients, with 19% stage C when ARV was initiated. Their median CD4
      and PVL values at baseline were 233/mm3 and 73,000 copies/ml respectively. The
      median duration of follow-up was of 20.7 Months [(mean (STD): 20.6 (6.7)].
      Initial treatments were distributed as follows: 2 NRTI + 1NNRTI, n=66 (54%); 2
      NRTI+1PI, n=44 (36%); 3 NRTI, n=13 (10%). Primary success was obtained in 100
      (81,3%) patients. Among these, 6 (6%) developed secondary virologic failure. The
      absence of change in initial ARV treatment within first 4 Months, and good
      compliance to treatment were statistically associated with primary success in
      univariate (p values respectively: 0.004 and 0.04) and in multivariate analysis
      (p respectively: 0.009 and 0.03). The proportion of failure was higher in the
      patients with lower baseline CD4 levels lesser than 200/mm3 (p=0.09). CONCLUSION:
      In this cohort of patients, tolerance and compliance to the first regimen were
      associated to primary success. These results emphasize the role of compliance in
      primary success and reinforces need to work on compliance in such patients.

PMID- 15041878
TI  - [Multiple actinomycosis brain abscesses].
AB  - BACKGROUND: Actinomycosis is a subacute or chronic bacterial infection, which can
      affect immunocompetent or immunodeficient subjects. It most often occurs in
      cervico-facial or thoracic-abdominal locations. Central nervous system infection
      is rare but of severe prognosis. CASE REPORT: A 56 year-old woman with no history
      of immunodepression was admitted with unexplained fever, inappropriate behaviour,
      and spatial and temporal disorientation. The progressive worsening of the
      neurological signs let to coma and mechanical ventilation was required. Brain
      imaging showed multilocation cerebral abscesses. Stereotaxial biopsy permitted
      diagnosis of actinomycosis. Patient's outcome was favourable following
      appropriate dual antibiotherapy without surgical exeresis. DISCUSSION: When
      lacking bacteriologic identification, diagnosis of cerebral actinomycosis is
      performed by pathologic findings. Dual antibiotherapy allows full recover, even
      in the case of multilocation cerebral abscesses.

PMID- 15041879
TI  - [The uterine sarcoma, a new risk identified for tamoxifen].

PMID- 15041880
TI  - [Pregnancy in a rudimentary uterine horn].

PMID- 15041881
TI  - [Forty years survival after myocardial infarction complicated by an unoperated
      inter-ventricular communication].

PMID- 15041883
TI  - [Results of a survey on practices in onco-hematology in France in 2001].
AB  - Further to the organisation of out-patient management, it appeared necessary to
      understand the type of organisation of the hospital teams working in oncology and
      haematology. Questions were asked on the medical workforce in the hospital, the
      rules for the organisation of the management fo these patients, the type of
      organisation in the patients homes and the choice of treatment. THE PERCENTAGE OF
      RESPONSE: Thiry-one centres (46%) replied to the survey: 20 hospital centres with
      5 departments of paediatrics and 11 oncology departments. Around two thirds of
      the centres in France confronted with short lasting neutropenia with fever opted
      for their treatment at home. WHAT IS IMPORTANT: Although the responsibility of
      those surrounding the patient and that of the treating physician are clearly
      implied, the general practitioner frequently has no access to training or to the
      information necessary to be able to manage the initial assessment and the
      potentially unfavourable evolution. And this is the pivotal point of the external
      hospital treatment system.

PMID- 15041884
TI  - [Treatment with oral antibiotics of febrile neutropenia in onco-haematology. The
      experience of the EORTC antimicrobial group].
AB  - THE CONTEXT: Up until the nineties, the intravenous administration of a broad
      spectrum antibiotic was the classical treatment of any patient presenting with
      febrile neutropenia. Since then, in patients considered at low risk and with
      expected of neutropenia less than 7-10 days, oral antibiotherapy has become an
      attractive option. TWO LARGE STUDIES: A study by the antimicrobial group of the
      EORTC (European organisation for research and treatment of cancer) and a North
      American study have compared the efficacy of an oral combination of
      ciprofloxacine and amoxicillin/clavulanic acid with that of an intravenous
      antibiotherapy in low-risk patients presenting febrile neutropenia. In both
      studies, the success rate was the same in the group of patients treated with oral
      antibiotics and those treated with intravenous antibiotics. RESERVATIONS: These
      two studies were conducted in hospitalised patients. No conclusions can be drawn
      with regard to out-patient treatment. Out-patient management would only be
      possible after appropriate selection of patients at low risk.

PMID- 15041885
TI  - [Outpatient antibiotherapy in children with neutropenia and fever. A review of
      the literature].
AB  - NEW STRATEGIES: Fever in a neutropenic patient requires the rapid initiation of a
      broad spectrum antibiotic and continued until correction of the neutropenia.
      Several studies have been conducted recently in order to define the populations
      of children in whom the antibiotherapy could be suspended early without risk of
      relapse of fever and/or severe infection. Moreover, the high costs of
      hospitalisation and the limited number of beds in the departments of Paediatric
      Oncology Haematology have led to studies on the feasibility of an antibiotherapy
      at home. THE EARLY SUSPENSION OF THE ANTIBIOTHERAPY: The criteria retained in
      several studies for the early suspension of the antibiotherapy have been:
      apyrexia for at least 24 hours, a satisfactory clinical status, the absence of
      positive haemocultures and haematological signs showing the end of aplasia in
      patients in remission of their disease. Studies have confirmed the possibility of
      early suspension of intravenous antibiotics in low-risk patients, without fever
      and without microbiological signs. THE PLACE OF ORAL ANTIBIOTICS: In several
      comparative studies, the success rate with intravenous antibiotics and oral
      antibiotics was comparable. The rate of failures was greater in patients with
      severe initial neutropenia. OUTPATIENT ANTIBIOTICS: In children, 2 types of
      studies have been conducted. The first studied the feasibility of an
      antibiotherapy at home following antibiotherapy in the hospital in order to
      reduce the costs and duration of hospitalisation. The others proposed an
      antibiotherapy at home from the start, either with the intravenous or the oral
      route. Following all these studies, it appeared that, in certain low-risk
      neutropenic children with fever, not only the antibiotics could be suspended
      before the complete correction of the neutropenia, but also a large spectrum oral
      antibiotherapy could replace the intravenous antibiotherapy and outpatient
      treatment would therefore be feasible.

PMID- 15041886
TI  - [An organizational and economic approach in France to the ambulatory treatment of
      febrile neutropenia].
AB  - A NEW OBJECTIVE: Keeping neutropenic patients with fever in their homes helps to
      preserve their quality of life and reduces the costs. However, it is important to
      specify the conditions and the means necessary for the organisation so that home
      treatment can be applied safely because of the high risk of morbidity due to
      infection. THE FUNDAMENTAL CONDITIONS FOR ITS MANAGEMENT: The patients who could
      potentially benefit from an outpatient treatment strategy when presenting with
      neutropenia and fever must not have a tumour progressing and must not exhibit
      signs of co-morbidity and be affected by neutropenia and fever at home. Moreover,
      full information and the patient's and relatives' consent, a hospital nearby, the
      permanent presence of someone with the patient, the possibility of a telephone
      contact, the patient's full compliance, prior consent and excellent communication
      and excellent patient-physician relationship are all essential conditions. THE
      PARTICIPANTS AT HOME: The patient is essentially followed-up by the treating
      physician. Private nurses can intervene at the patient's home. Hospitalisation at
      home is presently the only alternative medical structure to classical
      hospitalisation. The development of nursing networks ensure the continuity
      between the hospital and the town and the good coordination of the health workers
      caring for the patient. The steps to be taken during an episode of fever are
      debated: complete discharge from hospital for some, initial outpatient controls
      in the hospital for several hours for others and the initial hospitalisation for
      24 to 72 hours for some others. Whatever the case, haemocultures must be
      performed before the initiation of any antibiotherapy. SURVEILLANCE: The optimal
      clinical surveillance is ensured daily by a private nurse and the treating
      physician. An assessment every 2 to 3 days in a hospital unit is recommended.
      CARE NETWORKS: Their development should increase and hence create the continuity
      between the hospital and the town. The outpatient management of neutropenia with
      fever is a major source of economy; it allows the patients to be kept at home
      whilst ensuring the quality and security of their treatment.

PMID- 15041887
TI  - [Severe acute respiratory syndrome: a singular epidemic of viral pneumonia].
AB  - INFECTIOUS AGENT: The severe acute respiratory syndrome (SARS) is a febrile
      pneumonia initially observed in China at the end of 2002. The infectious agent
      has rapidly been identified as a new coronavirus, baptised SARS-associated
      coronavirus (CoV-SARS). Transmission is inter-human, via respiratory particles
      mainly. CLINICAL PRESENTATION AND TREATMENT: The clinical presentation is highly
      variable, from a mild fever to an acute respiratory distress syndrome. There is
      no specific treatment. Ribavirin associated with steroids have been used with
      success in numerous cases. EPIDEMIOLOGY: During the first half of 2003, the
      spreading of the virus has been very fast, with a pandemic mode of evolution.
      More than 8,000 people were infected and 774 died. The reservoir of the virus,
      which may be animal, is still unknown. The epidemic seems to be controlled, but
      sporadic or epidemic re-emergences may occur and have been observed in China
      during January 2004.

PMID- 15041888
TI  - [Daily chronic headaches related to excessive ingestion of medicinal products].

PMID- 15041889
TI  - Folic acid supplementation to prevent neural tube defects.

PMID- 15041890
TI  - Sildenafil for pulmonary hypertension.

PMID- 15041891
TI  - An injectable hyaluronic acid (Restylane) for wrinkles.

PMID- 15041893
TI  - Current concepts in alcohol metabolism.
AB  - Alcohol metabolism is a complex process with large individual variations related
      to absorption, distribution and elimination. Among the multiple factors which
      influence these variations, genetic factors especially those related to the
      different alleles of ADH2 and ALDH2, are the most well known and are related to
      the development of alcohol dependence, particularly in some populations such as
      those of Asian origin. The importance of new polymorphisms such as those in the
      ALDH promotor region requires further study. Furthermore, the importance of other
      factors such as nutrition and gastric metabolism should be taken into account to
      explain the variations in ethanol metabolism. The metabolic alterations produced
      by alcohol in the liver are responsible for liver damage. The individual
      variations in the metabolism of alcohol are responsible for the different
      toxicity of alcohol in both the liver and other organs.

PMID- 15041894
TI  - Alcohol-induced liver disease: when fat and oxidative stress meet.
AB  - Reactive oxygen species (ROS) act as signaling intermediates regulating multiple
      cellular processes. The fate and disposal of the signaling species are determined
      by the actions of antioxidants, particularly glutathione (GSH). The mitochondrial
      pool of GSH (mGSH) arises from the transport of cytosol GSH by a specific
      mitochondrial carrier and is responsible for the maintenance of a healthy
      competent organelle. The depletion of mGSH upon impairment of the mitochondrial
      transport activity leaves mitochondria unprotected from damaging effects of ROS
      overgeneration within the mitochondrial electron transport chain. Tumor necrosis
      factor-alpha (TNF-alpha) has emerged as a key player in the progression of the
      alcohol-induced liver disease (ALD), and is known to target mitochondria. Key
      components of TNF signaling include sphingolipids, particularly ceramide
      generated from acidic sphingomyelinase activation serving as a source for
      gangliosides. In experimental models alcohol consumption enhances cholesterol
      levels and subsequent deposition into mitochondria resulting in selective
      decrease in the mGSH stores which is sufficient by itself to sensitize
      hepatocytes to TNF-alpha-mediated cell death. Thus, the combination of TNF-alpha
      overproduction, enhanced glycosphingolipid generation and selective mGSH
      depletion by alcohol intake cooperate making the liver sensitive to alcohol.

PMID- 15041895
TI  - A rational use of laboratory tests in the diagnosis and management of hepatitis C
      virus infection.
AB  - The prevalence of HCV infection is very diversified according to geographical
      areas and ranges from 1% in the Northern regions of the world to more than 20% as
      we move South. Due to the presence of HCV-associated liver diseases and the
      development of effective treatments, the diagnosis of HCV infection is a growing
      medical need. Several tests are available, from simple screening to identify the
      presence of anti-HCV antibodies to the more sophisticated quantification of viral
      load and genotyping. However, these tests are to be used in a logical,
      consequential and cost-effective manner. This review article will report on the
      protocol in use in the North-Eastern part of Italy for the screening and
      diagnosis of HCV infection. The protocol is based on a consensus among several
      experts and may be the basis for a more rational approach in this rapidly growing
      field.

PMID- 15041896
TI  - The benefit of adding sodium nitroprusside (NPNa) or S-nitrosoglutathion (GSNO)
      to the University of Wisconsin solution (UW) to prevent morphological alterations
      during cold preservation/reperfusion of rat livers.
AB  - Cold liver preservation in the University of Wisconsin solution (UW) followed by
      reperfusion alters hepatic parenchyma and extra cellular matrix. In this study we
      analyzed the benefit of adding either 500 microM Sodium Nitroprusside (NPNa) or
      100 microM S-nitrosoglutathione (GSNO) as Nitric Oxide (NO) donors to the UW
      solution to prevent hepatic injury. Wistar adult rat livers were stored in UW
      solution (0 degrees C) for 48Hs and reperfused (60 minutes) in the isolated
      perfused rat liver model (IPRL). Untreated livers were used as normal controls.
      Livers perfused but not preserved were used as controls of reperfusion.
      Parenchyma damages were evaluated by Hematoxylin-Eosin stain. Picrosirius Red and
      Gordon-Sweets stains were used for collagen and reticulin networks, respectively.
      An inmunohistochemistry assay for albumin was used as functional test. Cold
      preservation step was followed by swollen hepatocytes with "light empty halos"
      surrounding the nucleus, conserved hepatocyte cords and many rounded endothelial
      cells. The addition of NPNa or GSNO into UW solution, avoid these alterations.
      Livers preserved for 48 Hs and then reperfused showed extended areas of
      vacuolation around central veins, and many endothelial cells were rounded and
      located inside sinusoidal lumens. The collagen network was disorganized while the
      reticulin one was less altered. Albumin was distributed preferentially in
      pericentral areas. On the contrary, livers preserved in presence of NPNa or GSNO
      did not show vacuolation and both collagen and reticulin networks were unchanged.
      Albumin was more homogeneously distributed in both groups. In conclusion, the
      addition of 500 microM NPNa or 100 microM GSNO as a NO donor, improves UW
      solution properties to preserve rat livers by maintaining the hepatic morphology
      and avoiding hepatic injury post-cold preservation/reperfusion.

PMID- 15041897
TI  - Serum interleukin 6 and interleukin 12 levels in children with chronic hepatitis
      HBV treated with interferon alpha.
AB  - INTRODUCTION: The course of HBV infection and the outcome of interferon alpha
      (IFNalpha) therapy of patients with chronic hepatitis B, is determined by the
      antiviral immune response of the host. The aim of the study was to investigate 1)
      the correlation between IL-6 and IL-12 serum levels and biochemical and
      histopathological changes in children with chronic hepatitis B, 2) predictive
      value of pre-treatment serum levels of these cytokines in patients treated with
      interferon alpha and 3) changes in serum levels of these cytokines after
      interferon alpha treatment. METHODS: Serum levels of IL-6, IL-12 (heterodimer
      p70) and IL-12 (heterodimer p70 & p40 subunit) were determined by specific ELISA
      in 39 children with chronic hepatitis B on the first and the last day of IFNalpha
      therapy. RESULTS: Serum levels of IL-6, IL-12 (p70) and IL-12 (p70&p40) were
      respectively within the following ranges of values: 0-1.7 pg/mL, 3.0-85.1pg/mL,
      93.7-442.7 pg/mL and they showed no correlation with biochemical and
      histopathological changes. The pre-treatment cytokines levels in patients who
      responded and those who did not respond to IFNa therapy did not differ
      statistically. There was no statistical difference between the end and pre
      treatment cytokines levels in both groups. CONCLUSIONS: Serum levels of IL-6 and
      IL-12 do not reflect the inflammatory activity of hepatitis and have no
      predictive value of positive response to the IFNalpha therapy in children with
      chronic hepatitis B. Serum IL-6 and IL-12 levels at the end of INFalpha treatment
      do not inform of their role in immunological changes which take place while
      inhibition of HBV replication or virus clearance.

PMID- 15041898
TI  - Images in hepatology. Microhamartomas (Von Meyenburg Complexes).

PMID- 15041899
TI  - Hepatic Echinococcus granulosus. A case report.
AB  - A 32-year-old woman was admitted to hospital complaining of right upper quadrant
      and epigastrium abdominal pain, and nausea. On routine physical examination an
      abdominal mass was discovered on the right upper quadrant. Liver tests were
      normal. Magnetic resonance imaging of the abdomen revealed a low-density cystic
      mass. A cystectomy was performed. Hydatid sand containing a protoscolex of
      Echinococcus granulosus was seen on microscopical examination. Specific
      antiparasitic treatment was given and after two months the patient is
      asymptomatic

PMID- 15041900
TI  - [The supertechnologist system (discussion)].

PMID- 15041901
TI  - [The handling of survey meter].

PMID- 15041902
TI  - [An explanation of the new standard dosimetry 01].

PMID- 15041903
TI  - [From pixel to aliasing].

PMID- 15041904
TI  - [EGS4 calculation in diagnostic energy region].

PMID- 15041905
TI  - [Fundamentals of ultrasound].

PMID- 15041906
TI  - [The view of a scanning condition setup in the multi-slice CT (4DAS)].

PMID- 15041908
TI  - [Reusable imaging plate (IP) for swift and automatic measurement of X-ray CT dose
      profiles].
AB  - PURPOSE: In multi-slice CT, over beaming by penumbra effect has been reported,
      and measurements of X-ray CT beam profiles are very important for accurate
      performance assessment. This study was conducted in order to facilitate and
      economize on the measurement of CT dose profiles. METHODS: The imaging plate (IP:
      HR-V type, Fuji) was placed in its case, X-rayed, and then read with a digital IP
      reader, which then erased the data in preparation for reuse. The values were then
      compared with the values obtained with the standard one-use imaging film. The CT
      scanner used was a Toshiba Aquilion Multi (4 rows). RESULTS: The shape of the
      beam profile obtained using the IP method was for all practical purposes
      identical to that obtained using the film method. The FWHM values for 2.0, 4.0,
      8.0, 12.0, 16.0, 20.0 and 32-mm beam were 4.88, 6.61, 10.2, 14.9, 18.2, 22.4 and
      35.0 mm for the IP method and 4.81, 6.66, 10.2, 14.7, 18.1, 22.3 and 34.8 mm for
      the film method. In addition, in the IP method, the results obtained for the
      shape of the beam profile and the FWHM were found to be extremely similar
      irrespective of the X-ray tube used or individual differences between IPs.
      CONCLUSION: We have developed a new X-ray CT beam profile measurement system
      using an IP. This IP method permits data processing to be performed entirely in
      the digital domain, allowing high-precision measurements to be obtained with
      ease.

PMID- 15041907
TI  - [Measurements of Gamma-Knife helmet output factors using a radiophotoluminescent
      glass rod dosimeter and a diode detector].
AB  - A radiophotoluminescent (RPL) glass rod dosimeter (GRD) and a small active volume
      p-type silicon diode detector (stereotactic field detector, SFD) were used for
      the measurement of Gamma-Knife output factors. All measurements were done using a
      16 cm diameter spherical polystyrene phantom with the detector at the focal spot
      of Gamma-Knife. The GRD system consists of small rod-shaped glass chip detectors
      and an automatic readout device. The output factors measured with GRD of the 14,
      8 and 4 mm helmets relative to the 18 mm helmet are 0.981, 0.942 and 0.877,
      respectively. Similarly, the corresponding output factors measured with SFD are
      0.980, 0.949 and 0.867, respectively. These output factors are comparable with
      the values given in a recent publication and the values recommended by Elekta,
      the manufacture. The angular dependence of these detectors is also measured using
      a linear accelerator-based stereotactic radiosurgery system. For the Gamma-Knife
      angle ranging from 6 to 36 degrees from the vertical axis, the measured angular
      dependence of the GRD is approximately 1.0% at a 4 MV x-ray beam. The response of
      SFD indicates approximately 3-4% directional dependence for the same angle range
      for a 6 MV x-ray beam. The Gamma-Knife helmet output factors measured with SFD
      are corrected for angular dependence. In summary, GRD can be a good candidate in
      measuring small field output factor. Due to an angular dependence the small p
      type diode detector needs care when calculating the Gamma-Knife dose.

PMID- 15041909
TI  - [New hope for winning the war against cancer: IMRT=Intensity-Modulated-Radiation
      Therapy -Part 9-].

PMID- 15041910
TI  - [Influence of rotation speed of X-ray computed tomography on image quality].
AB  - The rotation speed of X-ray CT is known to influence the quality of images. We
      examined changes in imaging characteristics according to various physical
      characteristics. The physical characteristic of rotation speed (1.0, 0.8, 0.7,
      0.6, 0.5 sec/rot) was evaluated at the FOV center (isocenter) and 90 mm outside
      the center (off-center). The items of evaluation included low contrast
      resolution, high contrast resolution, noise, definition, and artifacts. High
      contrast resolution and definition declined at a rotation speed of 0.6 sec/rot or
      less at off-center. An increase in shower artifact and change in the shape of the
      wire section were found at a rotation speed of 0.6 sec/rot or less at off-center.
      It was determined that image quality was especially influenced in terms of
      definition characteristics when the speed of rotation was high. A decrease in the
      number of views can be considered the main cause; that is, the use of high-speed
      rotation degrades image quality. Therefore, it is important to consider proper
      usage as it corresponds with purpose.

PMID- 15041911
TI  - [Method of estimating 10 MV X-ray irregular field dose using the collimator
      scatter factor (Sc) and phantom scatter factor (Sp)].
AB  - It has been found that in general 10 MV X-ray dose calculation can be made
      accurately for multi-leaf collimator irregular fields by using the total scatter
      factor (S(cp)), collimator scatter factor (S(c)), and phantom scatter factor
      (S(p)) proposed by Khan et al. With respect to the collimator scatter factor
      (S(c)), we used the field-mapping method of Kim et al. to obtain equivalent
      square fields of irregular fields (the collimator reverse effect can be
      accurately dissolved using the field-mapping method). Even for extremely small
      multi-leaf fields compared with the main collimator opening, X-ray output
      calculations could be made accurately by introducing the small segment correction
      (SSC) factor. With respect to the phantom scatter factor (S(p)), highly accurate
      calculations could be made for irregular field irradiation by applying an F(MLC)
      (MLC radiation leakage) factor to the equivalent square field (in cases in which
      the ratio of the multi-leaf equivalent square field side to the main collimator
      equivalent square field side is less than 0.6). However, it has been found that
      highly accurate dose calculations can, in general, be performed when the main
      collimator is limited just at the opening determined by the multi-leaf collimator
      field.

PMID- 15041912
TI  - [Development of automatic verification system for portal image in radiotherapy].
AB  - The current method of verification for external beam radiation therapy visually
      compares a simulation image with a portal image. However, because this method
      depends largely upon the observer's experience, it sometimes results in inter
      observer differences. In this study, we developed software to measure
      atomatically the quantitative difference between the simulation image and portal
      image using an image-analysis method. The feasibility of this software was
      evaluated on a rectangular field in the pelvic region. We took 12 simulation
      images of a pelvic phantom, setting 4 different field shapes on each of 3
      isocenters. We then obtained 84 portal images setting 7 known distances from each
      of the 12 simulation images. Using this software, the direction of shift was
      detected correctly, and the distance of shift was detected correctly to within
      less than 3 mm. We consider that this software could be a useful method of
      verification.

PMID- 15041913
TI  - [Fitting of ROC curves for continuous data by using correction of the mean and
      standard deviation].
AB  - We examined ROC curve fitting with continuous rating data by using a corrected
      mean value and corrected standard deviation as binormal ROC parameters. Curve
      fitting was performed by using corrected categorical data in the same way as the
      continuous data. A large residual of curve fitting was found in cases of
      difference between means of positive and negative signal data greater than three
      times the standard deviation, or with a ratio of the standard deviation of
      positive and negative signal data above six. We conclude that our proposed method
      performed well for ROC curve fitting except in some special cases.

PMID- 15041914
TI  - [Method of calculating side scatter factor for diagnostic X-rays].
AB  - When computing the amount of leakage from a diagnostic X-ray room, the amount of
      scattered radiation released from the irradiated body in the lateral direction
      must be evaluated correctly. The side-scatter factor varies owing to change in
      the area and/or shape of the field, but the amount of variation is not always
      linearly proportional to the area of the field. Because the X-ray spectrum
      depends on the total filtration of the X-ray tube even if the irradiation
      geometry, X-ray equipment, and tube potential are the same, the side-scatter
      factor, too, is subject to change. In this paper, we propose a new method of
      calculation that uses the differential side-scatter factor computed by means of a
      Monte Carlo simulation, for obtaining the side-scatter factor of diagnostic X
      rays. This method, which can calculate the side-scatter factor under any
      conditions of irradiation, is useful in evaluating the side-scatter factor of
      diagnostic X-rays.

PMID- 15041915
TI  - [Evaluation and estimation of entrance skin dose in patients during diagnostic
      and interventional radiology procedures].
AB  - A study was performed to evaluate the total entrance skin dose (ESD) of patients
      during diagnostic and interventional radiology procedures (IVR) and to estimate
      ESD with body mass index (BMI) and fluoroscopy time. The study included 26 cases
      of transcatheter arterial embolization therapy (TAE) for hepatocellular carcinoma
      (HCC) and 19 cases of diagnostic digital subtraction angiography (DSA) for HCC.
      The ESD of patients was evaluated with a zinc-cadmium sensor linked to a digital
      counter (SDM: skin dose monitor). Exposure doses were measured with SDM attached
      to the front of the X-ray beam-limiting device like a dose area product monitor.
      ESD was calculated from the measured exposure dose. In 26 TAE for HCC, ESD was
      1793.7+/-739.1 mGy, with the mean fluoroscopic time of 23.5 minutes and 4.4 DSA
      acquisitions. The fluoroscopic dose rate was 52.4+/-11.5 mGy/min. In 19
      diagnostic DSA for HCC, ESD was 962.9+/-375.2 mGy, with the mean fluoroscopic
      time of 11.1 minutes and 4.0 DSA acquisitions. The fluoroscopic dose rate was
      32.7+/-12.7 mGy/min. Although 33.2% of ESD was from fluoroscopy in diagnostic
      procedures, the figure was 68.8% in TAE procedures. It was demonstrated that the
      increase in ESD during IVR was caused by the rise of fluoroscopy dose rate caused
      by high-magnification fluoroscopy and the extension of fluoroscopy time. In order
      to reduce ESD, it is necessary to use a low fluoroscopy dose rate with low-rate
      pulse fluoroscopy, in addition to shortening fluoroscopy time. Fluoroscopy time
      was a poor predictor of risk because it did not correlate well with ESD during
      IVR (diagnostic procedures r(2)= 0.897, IVR r(2)= 0.594). However, ESD correlated
      well with the product of BMI and fluoroscopy time (diagnostic procedures r(2)=
      0.910, IVR r(2)= 0.783). The linear relationship between ESD and the product of
      BMI and fluoroscopy time provides a simple monitoring mechanism of the ESD
      delivered to the patient during interventional radiology procedures. This linear
      relationship needs to be established for other types of interventional
      procedures.

PMID- 15041916
TI  - [Sjogren's syndrome: clinical and therapeutic features. A review of the
      literature].
AB  - Sjogren' Syndrome (SS), also named Sicca Syndrome, is a complex disease,
      characterized by a series of clinical symptoms and signs chiefly represented by
      xerostomia, xerophthalmia and connectival diseases. The pathogenetic mechanisms
      consist of an autoimmune process leading to salivary and lacrimal glands
      progressive destruction. There is a primary form with salivary and lacrimal
      glands compromission only and a second form in which xerostomia and/or
      xerophthalmia are associated with connectival diseases like rheumatoid arthritis,
      systemic lupus erythematosus and scleroderma. The diagnosis of SS is rather
      difficult and it is based on various world-wide established and accepted
      criteria: the labial minor salivary glands biopsy and the research of specific
      seric autoantibodies are the basic elements. From the therapeutic point of view,
      various types of immunomodulant treatments based on cyclosporine,
      corticosteroids, methotrexate or alpha-interferon have been proposed with
      different RESULTS: Cholinergic drugs, like pilocarpine and cevimeline, are also
      used in order to stimulate the gland functionality.

PMID- 15041917
TI  - [The role of neuromodulators (substance P and calcitonin gene-related peptide) in
      the development of neurogenic inflammation in the oral mucosa].
AB  - Vatous observations carried out in the course of the years have shown that
      certain neuropeptides have a possible role to play as inflammation mediators. The
      substances on which attention has been principally focused are: substance P,
      calcitonin gene-related peptide, capsaicin an histamine. Knowledge acquired in
      this field, however, does not yet permit us to sufficiently clarify the role, not
      to speak of the possible action mechanism, on the basis of which these
      neuropeptides act, although it is confirmed that these substances have been found
      first in laboratory animals and later also in human tissues in the course of
      experimentally induced neurogenic inflammation. The need to know more and more
      about inflammatory mechanisms and the increasingly complex possibilities offered
      by the application of technology in the field of medical research have led to
      many small advance in our knowledge of what is involved in inflammation. In fact
      it has been understood that behind the typical signs of inflammation (the famous
      four cardinal signs of Celsus: pain, redness, swelling, heat) no abstract
      entities or strange alchemies are concealed, but a series of well-known,
      classified substance, the so-called "inflammation mediators", namely a variety of
      substances of cellular or plasmatic origin united by the fact that exist, in
      stationary state conditions, in the form of inactive precursors, or sequestered
      in intracellular sites where they are unable to carry out their action. Following
      an inflammatory stimulus, they are activated, or their synthesis can be induced,
      or their release from intracellular sequestration sites in favoured; in any case
      they are stored in the disturbance district in concentrations that are such as to
      act on their respective targets, triggering event s that characterise the various
      stages of the inflammatory process.

PMID- 15041918
TI  - [Cephalometric evaluation of hyoid bone position in patients with obstructive
      sleep apnea].
AB  - AIM: The aim of this study was to evaluate cephalometrically the relationship
      between hyoid bone position and obstructive sleep apnea (OSA). METHODS: Two
      groups were examined: the experimental Group (SG), composed of 15 OSA patients,
      and the Control Group (CG), composed of 15 healthy subjects. Both SG and CG
      patients were subjected to lateral teleradiography. On each radiography were
      effected cephalometric measurements to evaluate hyoid bone position and the
      results obtained were compared. RESULTS: From data comparison it turned out that,
      as already described in the literature, in OSA patients hyoid bone is, on
      average, in a lower and in a more posterior position than in control group
      patients. CONCLUSION: This altered hyoid bone position may influence tongue
      position and upper airway patency. All this makes it clear that cephalometric
      study is important for diagnosis and treatment of OSA patients.

PMID- 15041919
TI  - [The influence of occlusion on sporting performance].
AB  - AIM: The purpose of the present study is to investigate the relationship between
      dental occlusion and physical performance using the Ergo-jump platform, and to
      highlight connections, if any. METHODS: For the purpose of this research, 30
      patients suffering from cervico-facial pathology and 10 without temporomandibular
      joint dysfunction were selected from within the Dental Clinic of the University
      of Sassari. For the first group a resin plate was prepared to correct the
      malocclusion, while for the control group a bite was prepared that created it.
      Subjects carried out exercises with the Ergo-jump platform, a device that
      assesses physical capabilities and athletic performance. Patients were asked to
      do 2 exercises, a counter movement jump and a mechanical power test, with plate
      and without plate. RESULTS: The tests of the first group were as follows: flying
      times with the bite were 0.01 s longer; the average elevation in the counter
      movement jump test did not give statistically significant results; execution of
      the mechanical power test suggests an increase in average mechanical power with
      the plate. Execution of the same exercises in the other group showed greater
      flight times without the place; average elevation was not statistically
      significant; the execution of the mechanical power test showed a decrease in
      average mechanical power with the occlusion plate. CONCLUSION: Statistical
      analysis of individual results showed that patients do not always obtain a
      benefit during physical exercise using the bite. Research shows that the same
      pathology can cause different physical performance in different individuals; in
      fact, not all craniomandibular disturbances have repercussions on posture.

PMID- 15041920
TI  - [Herpes zoster of the trigeminal nerve: a case report and review of the
      literature].
AB  - Herpes zoster (shingles) is caused when the varicella zoster virus that has
      remained latent since an earlier varicella infection (chicken-pox) is
      reactivated. Herpes Zoster is a less common and endemic disease than varicella:
      factors causing reactivation are still not well known, but it occurs in older
      and/or immunocompromised individuals. Following reactivation, centrifugal
      migration of herpes zoster virus (HZV) occurs along sensory nerves to produce a
      characteristic painful cutaneous or mucocutaneous vesicular eruption that is
      generally limited to the single affected dermatome. Herpes zoster may affect any
      sensory ganglia and its cutaneous nerve: the most common sites affected are
      thoracic dermatomes (56%), followed by cranial nerves (13%) and lumbar (13%),
      cervical (11%) and sacral nerves (4%). Among cranial nerves, the trigeminal and
      facial nerves are the most affected due to reactivation of HZV latent in
      gasserian and geniculated ganglia. The 1st division of the trigeminal nerve is
      commonly affected, whereas the 2nd and the 3rd are rarely involved. During the
      prodromal stage, the only presenting symptom may be odontalgia, which may prove
      to be a diagnostic challenge for the dentist, since many diseases can cause
      orofacial pain, and the diagnosis must be established before final treatment. A
      literature review of herpes zoster of the trigeminal nerve is presented and the
      clinical presentation, differential diagnosis and treatment modalities are
      underlined. A case report is presented.

PMID- 15041921
TI  - [Cefaclor induced pemphigus vulgaris].
AB  - Pemphigus is a chronic disease with an outcome that is not without risk. It is
      characterised by loss of the intraepithelial cell-cell relationship
      (acantholysis). Underlying the disease is an autoimmune disorder in which the
      desmosomes are damaged by antibodies directed against particular molecules called
      desmogleins (particularly 3 and 1). Various types of pemphigus have been
      described with different antibody profiles and clinical signs. In the present
      paper, a case of pemphigus vulgaris associated with the medication cefaclor
      monohydrate is reported. Histological and immunological evaluation of the biopsy
      sample led to a diagnosis of pemphigus vulgaris. The patient, who was not
      hospitalised, was treated with corticosteroids and systemic immunosuppressors. At
      present she is being controlled by low doses of systemic corticosteroids. Early
      diagnosis and the timely introduction of the therapeutic protocol permitted
      complete remission of the lesions observed at the level of the oral and
      conjunctival mucosa, preventing the involvement of other locations.

PMID- 15041922
TI  - [Autoimmune hepatitis: present knowledge].
AB  - Autoimmune hepatitis (AIH) is a rare and chronic disease which may lead to liver
      cirrhosis if not correctly treated. Its etiology is unknown, but some progresses
      have been obtained in the knowledge of damage pathogenesis, its immune mechanisms
      and genetic predisposition (female gender, presence of HLA DR3 and HLA DR4). It
      seems that such predisposition favours some agents (e.g. drugs or viruses) to
      trigger the pathological process. Patients present with variable, often few and
      unspecific symptoms. Diagnosis is made on the basis of anamnestic (absence of
      other causes, such as virus infections or alcohol abuse), serological
      (autoantibodies, high levels of aminotransferases, hypergammaglobulinemia), and
      histological data (piecemeal necrosis further to bridging necrosis, panlobular
      and multilobular necrosis); these data are processed by a scoring system which is
      helpful for the diagnostic definition. Therapy is founded in immunosuppressor
      drugs, mainly steroids and azathioprine, but a lot of other drugs have been
      studies for cases of recurrence and of intolerance to the standard treatment.

PMID- 15041923
TI  - Ribozymes as antiviral agents.
AB  - Ribozymes are RNA molecules with cleavage activity that can be engineered to
      specifically target a given RNA molecule. The hammerhead, hairpin and hepatitis
      delta virus ribozymes have been widely studied for their use as therapeutical
      agents. This review discusses the structure and properties of these ribozymes,
      along with the advances made in the development of these molecules for their
      application in the treatment of hepatitis B, hepatitis C and human
      immunodeficiency virus infections.

PMID- 15041924
TI  - [Prostate cancer and prostate specific antigen screening].
AB  - Prostate cancer diagnosis by prostate specific antigen (PSA) test is so popular
      and widespread that becomes a routine mass screening. The screening efficacy has
      not yet been proved and today remains a controversial topic. The author discusses
      about present arguments in support and in opposite to the use of PSA screening.
      Waiting for definitive results of the efficacy of PSA screening from randomised
      trials, the author shows what may be useful to do in clinical routinary practice
      with PSA test. Since PSA is tissue specific and not cancer specific, very often
      further unnecessary investigations such as prostate biopsy are required. To
      reduce false positive and false negative results of the PSA test and to indicate
      which men with negative prostate biopsy need rebiopsy, new methods improving
      specificity and sensibility of PSA test have been proposed. To clarify these
      improving PSA test methods, the author analyses each method showing limits and
      performances. New molecular forms of PSA (PSA isoforms) circulating in peripheral
      blood are also evaluated.

PMID- 15041925
TI  - Fibromyalgia: state of the art.
AB  - Fibromyalgia (FM) is a common and complex condition, defined as long lasting,
      widespread musculoskeletal pain, in the presence of tender points (TPs) at
      specific anatomical sites. Dysautonomic and functional symptoms, such as
      orthostatic hypotension, tachycardia, effort intolerance, marked fatigue, sleep
      disorders, cognitive disturbances, psychological distress, paresthesias,
      headache, genitourinary manifestations, irritable bowel syndrome and bladder
      dyskinesia, frequently occur. The etiopathogenesis of FM is presently unknown,
      but nociceptor, autonomic and neuro-endocrine system dysfunctions have been found
      in patients. Since specific serological or instrumental markers of the syndrome
      are not yet identifiable, TP search is the only useful diagnostic hallmark. The
      development of an effective therapy of FM has hitherto been hampered by the
      incomplete knowledge of its pathogenic mechanisms. In this paper, the most recent
      information on FM is reviewed.

PMID- 15041926
TI  - Post-transplant lymphoproliferative disorders. Molecular analysis of histogenesis
      and pathogenesis.
AB  - AIM: Post-transplant lymphoproliferative disorders (PTLD) represent a serious
      complication of solid organ transplantation. Despite several advances in the
      biological categorization of PTLD, current classifications are not fully
      predictive of the clinical behavior of the disease. This study assessed a
      comprehensive molecular analysis of the clinico-pathologic spectrum of PTLD in
      order to better clarify the physiopathology of these disorders. METHODS: Fifty
      two monoclonal PTLD were investigated for: 1). somatic hypermutation of IgV genes
      by direct sequencing of IgV rearrangements; 2). expression of BCL6, MUM1 and
      CD138 proteins by immunohistochemistry; 3). aberrant hypermethylation of DAP
      kinase gene by methylation-specific polymerase chain reaction (PCR); 4).
      genotypic characterization of Epstein Barr virus (EBV) in EBV infected PTLD by
      PCR analysis of the prevalence of deletions in the carboxyterminal portion of the
      LMP1 gene and for the definition of type-1/type-2 EBV infection. RESULTS: We
      report that virtually all monoclonal PTLD originate from B cells that have
      experienced the germinal center (GC) reaction reflecting different stages of
      mature B cell differentiation and that tumor development seems frequently
      associated with EBV and/or other molecular lesions preventing apoptosis of cells
      that have failed the physiological process of germinal center reaction.
      CONCLUSION: To date, classification of PTLD is mainly based on morphology and
      conventional immunophenotyping. Because current classification schemes are not
      fully predictive of prognosis, knowledge of PTLD histogenesis and pathogenesis
      may potentially contribute to refine the distinction of PTLD into more
      homogeneous categories with prognostic relevance.

PMID- 15041927
TI  - Long-term efficacy of oral microemulsion cyclosporin for refractory ulcerative
      colitis.
AB  - AIM: The 60% bioavailable oral microemulsion formulation of cyclosporin (NEORAL
      ), has replaced the intravenous route to treat both organ transplant and immune
      based disease. Its use for steroid-refractory ulcerative colitis (a recognized
      indication for intravenous cyclosporin) has been scanty. METHODS: Twenty-three
      consecutive patients (14 male/9 female, universal colitis 14/23) entered a 3
      month course of NEORAL (initially dosed at 5 mg/kg/day) because of steroid
      refractoriness (14 cases) and steroid-dependence (9 cases). Responders (at least
      showing a 50% reduction of a clinical activity score) were continued on
      azathioprine. The initial steroid dose was tapered on commencing NEORAL; patients
      requiring steroid resumption or increase in the follow-up were defined as
      relapsers. RESULTS: The target trough concentration of 200 ng/ml of whole blood
      was achieved without major titration in all but 1 patient. There were 7 non
      responders (30%). Of the 16 responders (70%), 2 have not relapsed; the remaining
      14 relapsed at the median time of 9.5 months (1.5-60) with 10 (71%) showing only
      1 relapse. Five patients were colectomized 12 months after NEORAL (1.5-24),
      leaving 11 of the initial 23 (47%) with their colon. Of the 16, all but 1 had
      azathioprine; the median daily steroid needs fell from 32 to 5 mg. CONCLUSION:
      The rates of acute and chronic response of 70% and 47% achieved by NEORAL in this
      indication duplicate the figures achieved by the traditional schedules of
      cyclosporin administration.

PMID- 15041928
TI  - The evaluation of the results of clinical trials: surrogate end points and
      composite end points.
AB  - The evaluation of the clinical outcome of patients enrolled in randomised
      controlled studies should always be accurate and objective. The methods used to
      assess and report patients' results must consequently be indicated a priori in
      the design of the clinical experimentation. Major (hard) individual end points
      currently constitute the gold standard in the definition of outcome measures, yet
      surrogate and composite end points are spreading diffusely as
      alternative/complementary outcome measures. Surrogate end points are minor
      outcome measures that are easier to record and are being adopted instead of major
      end points. They may be considered acceptable substitutes of hard end points when
      capable of predicting major events reliably, and when it may be demonstrated that
      the intervention on such surrogate end points consistently modifies the incidence
      of the event. In other cases they cannot represent predictive elements of major
      clinical outcomes. Composite (combined) primary end points may contribute to
      improve the statistical precision of a clinical trial; moreover, since clinical
      trials are particularly expensive, their identification permits more limited
      samples of patients to be enrolled. Their limits include the possibility that the
      direction in which the different outcome measures composing the combined end
      point are modified is not the same. Biomedical researchers are called upon to
      design studies adopting major (hard) end points, rather than solitary surrogate
      end points, in order to provide really useful information for the care of
      patients. The selection of composite end points requires notable methodological
      attention so as to retrieve the most reliable estimates on the efficacy and the
      effectiveness of treatments.

PMID- 15041929
TI  - Comparison of hyperkalemic cardioplegia with altered [CaCl2] and [MgCl2] on
      [Ca2+]i transients and function after warm global ischemia in isolated hearts.
AB  - AIM: [MgCl(2)] and [CaCl(2)] may modify the cardioprotective effects of
      hyperkalemic cardioplegia (CP). We changed [MgCl(2)] and [CaCl(2)] in a CP
      solution to examine their effects on [Ca(2+)]i transients and cardiac function
      before and after global normothermic ischemia. METHODS: After stabilization and
      loading of indo 1-AM in Kreb's solution (KR), each heart was perfused with either
      KR or 1 of 4 CP solutions before 37 degrees C, 30 min ischemia followed by
      reperfusion with KR. The KR solution contained, in mM, 4.5 KCl, 2.4 MgCl(2) and
      2.5 CaCl(2); the CP solutions had in addition to 18 KCl: CP 1 (control CP): 2.4
      MgCl(2), 2.5 CaCl(2); CP 2: 7.2 MgCl(2), 2.5 CaCl(2); CP 3, 7.2 MgCl(2), 1.25
      CaCl(2); CP 4: 2.4 MgCl(2), 1.25 CaCl(2). RESULTS: In the KR group [Ca(2+)]i
      markedly increased on early reperfusion while functional return (LVP,
      dLVP/dt((max and min))) was much reduced; each CP group led to reduced [Ca(2+)]i
      loading and improved function. The rates of cytosolic Ca(2+) fluxes
      (d[Ca(2+)]/dt(max) and d[Ca(2+)]/dt(min)) increased significantly compared to
      baseline in the KR group, but were mostly suppressed in the CP groups, and
      d[Ca(2+)]/dt(min) was lower after CP 4 compared to CP 1 on reperfusion. At 60 min
      reperfusion, LVP area to [Ca(2+)] area and cardiac efficiency to phasic [Ca(2+)]
      relationships were shifted after KR, but not after CP 1-4. With similar
      functional recovery, [Ca(2+)] transient and [Ca(2+)] area were significantly
      lower after CP 4 than after CP 1. CONCLUSION: Increasing [MgCl(2)] (CP 2 and 3)
      did not improve cardiac function or reduce Ca(2+) transients on reperfusion
      better than the other CP groups, but reducing [CaCl(2)] (CP 3 and 4) was more
      effective in reducing [Ca(2+)] transients on reperfusion after global ischemia.

PMID- 15041930
TI  - Is the axillary artery a suitable cannulation site in aortic surgery?
AB  - AIM: The axillary artery is currently gaining interest as an alternative to
      femoral artery cannulation in aortic surgery. It was the aim of our study to
      evaluate the feasibility, safety, and efficacy of axillary artery cannulation in
      a series of patients undergoing surgery of the ascending aorta and/or the aortic
      arch. METHODS: From 1998 to 2002 cardiopulmonary bypass (CPB) perfusion via the
      axillary artery was intended in 35 patients (28 male), median age 61 (22-77)
      years. The underlying disease was acute aortic dissection type A in 22/35 (63%),
      chronic aortic dissection type A in 2/35 (6%), ascending aortic aneurysm in 8/35
      (22%), aortic regurgitation after previous ascending aortic replacement in 1/35
      (3%), pseudoaneurysm after Bentall operation in 1/35 (3%) and coronary artery
      disease with severe arteriosclerosis of the aorta in 1/35 (3%). RESULTS:
      Conversion to femoral artery or ascending aortic cannulation was necessary in 3
      patients. In the other cases, adequate CPB flows of 2.4 l/m2/min were achieved.
      In 1 case local dissection of the axillary artery occurred after emergency
      cannulation. No postoperative complications related to axillary artery
      cannulation, such as upper extremity ischemia, brachial plexus injury, or local
      wound infection occurred. No new postoperative stroke was noted, hospital
      mortality was 4/35 (11%) patients. CONCLUSION: Axillary artery cannulation is
      feasible in the majority of cases and seems to be a safe and effective method in
      surgery of the ascending aorta and aortic arch. Several disadvantages of femoral
      artery cannulation and perfusion can be avoided.

PMID- 15041931
TI  - Atrial septal defect repair with minithoracotomy using two stage single venous
      cannula.
AB  - AIM: Repair of atrial septal defect (ASD) via minimal access has been the
      preferred method to improve cosmesis and fast rehabilitation. A 2-stage single
      venous cannula introduced via the femoral route allows better vision of the
      surgical field and improves surgical acts through a limited incision. METHODS:
      From February 1999 to December 2001 a minithoracotomy approach was used for
      closure of secundum type ASD by using single bicaval venous cannula in 17 adult
      patients. A 6 to 7 cm anterior minithoracotomy (submammary) approach with femoral
      arterial and 2-stage single venous cannula were utilized. Defects were closed
      primarily by running suture in 14 and with a patch in 3 patients. RESULTS:
      Calculated flow levels were maintained with a single venous cannula without
      assisted venous drainage in all patients. The postoperative course was uneventful
      in all patients except 1 who required revision for bleeding which was done
      through the same incision. Extension of the thoracotomy or shifting to the
      classic sternotomy was never required. CONCLUSION: Single venous bicaval cannula
      allows efficient drainage of both vena cavae and improves the surgical vision and
      manipulation through the right minithoracotomy. With this technique, repair of
      ASD can be done safely with good cosmesis.

PMID- 15041932
TI  - Platelet activity of residual blood remained in the cardiopulmonary bypass
      circuit after cardiac surgery.
AB  - AIM: We measured the platelet count and platelet function in residual blood in
      the cardiopulmonary bypass (CPB) circuit after cpb and compared them with data
      before CPB operation. METHODS: The subjects included 34 cases of patients
      subjected to CPB surgery. The residual blood was concentrated by ultrafiltration
      after CPB, collected in the bag and the platelet count and platelet activity was
      measured. ADP 2, 5, 10 microM was used as agonists and measurement was made by
      turbidimetry. RESULTS: The mean value of the platelet count was 18.3+/
      5.65x10(4)/mm(3) before surgery and 17.2+/-8.39x10(4)/mm(3) in the residual
      blood, there is no difference. Concerning the platelet aggregation activity, the
      maximum aggregation rate decreased significantly with ADP 2 microM from 47.4+/
      19.6% before surgery to 27.1+/-17.2% in the residual blood (p<0.01). Likewise, it
      decreased significantly with ADP 5 and 10 microM. The reduction rate of the
      platelet aggregation activity was higher in the group of not less than 100
      minutes compared with the group of less than 100 minutes, but no significant
      difference was found. CONCLUSION: Autotransfusing whole blood per se without the
      "cell saver" treatment is more advantageous to keep hemostasis function after
      surgery since many platelets having the aggregation activity exist in residual
      blood in the CPB circuit.

PMID- 15041933
TI  - Emergent off-pump complete myocardial revascularization in dextrocardia.
AB  - Dextrocardia is a rare condition not spared by coronary artery disease. We report
      the case of a 72-year-old patient with dextrocardia associated with situs
      inversus totalis who presented to our Institution with acute myocardial
      infarction complicated by congestive heart failure. Due to the severe general
      conditions of the patient, an emergent off-pump complete myocardial
      revascularization was undertaken. The patient tolerated the procedure well and
      was asymptomatic at discharge. The technical aspects encountered in the setting
      of mirror-image anatomy and the advantages of off-pump myocardial
      revascularization in the critically ill patient are discussed.

PMID- 15041935
TI  - Avoiding potential complications in left atrial reduction: partial heart
      autotransplantation.
AB  - Left atrial reduction is a surgical procedure designed in order to eliminate the
      chronic atrial fibrillation caused by mitral valve disease. However, this
      surgical technique is not high-risk free. Since a mount of tissue is excised from
      the left atrium, misalignment of the left atrium can be present. Bleeding of the
      posterior suture line in this chamber, as well as injury of the circumflex
      coronary artery may be fatal complications of this technique. Partial heart
      autotransplantation offers a good solution allowing an excellent visual operative
      field. The circumflex coronary artery is under direct vision while performing the
      anastomosis of the left atrium, and the suture line becomes safer and easier.

PMID- 15041934
TI  - Left ventricular outflow obstruction after Fontan procedure involving a patient
      with complete atrioventricular septal defects complicated by a small left
      ventricle.
AB  - We report a 1-year-old girl who developed ventricular outflow tract obstruction
      early after a Fontan operation, necessitating surgical relief using the Damus
      Kaye-Stansel procedure. The patient had a complete atrioventricular septal defect
      complicated by a muscular ventricular septal defect (VSD) and a small left
      ventricle, a morphology that has not previously been reported in cases of
      systemic outflow tract obstruction after the Fontan procedure. Postoperative
      systemic outflow obstruction must be considered as a possible sequela following
      Fontan surgery in patients with an atrioventricular septal defect and a small
      left ventricle.

PMID- 15041936
TI  - Surgical approach to kinking and coiling of the internal carotid artery.
AB  - AIM: Whether kinking or coiling of the internal carotid artery (ICA) simply
      represents a morphological variation without clinical relevance still remains an
      object of debate. While most patients are incidentally diagnosed in an
      asymptomatic state due to the broad use of non-invasive investigations (like
      colour coded Doppler sonography), associated neurological deficits are often
      unspecific and might be related to coexisting proximal stenotic lesions. Its
      etiology is unclear. Beside artherosclerotic genesis, a persistent embryological
      condition or underlying fibromuscular dysplasia is discussed. Moreover, in
      contrast to precise recommendations concerning the indication for endarteriectomy
      in carotid artery stenosis, general guidelines for surgical intervention in case
      of kinking or coiling are not yet established. METHODS: The characteristics of 16
      patients who underwent a total of 21 reconstructive operations for isolated
      kinking or coiling of the ICA during 5 years of observation were retrospectively
      analyzed. RESULTS: In 10 out of 14 kinkings and 5 out of 7 coilings central
      nervous symptoms were noted including unspecific vertigo, syncope, tinnitus
      synchronous to pulse, transient ischemic attacks and manifest cerebral
      infarction. All these individual complaints disappeared postoperatively. In 1
      patient presenting with an ICA coiling histological examination revealed signs of
      fibromuscular dysplasia. The other specimens showed typical changes of
      artherosclerotic disease. CONCLUSION: By precluding significant proximal stenosis
      and effective elimination of symptoms after surgical correction, a causal
      connection between cerebral dysfunction and severe ICA kinking or coiling can be
      supposed. An actual abnormality of the arterial wall structure only exists in
      exceptional cases. Rather, a sequential development from kinking to coiling was
      noticed.

PMID- 15041937
TI  - Division of incompetent perforator veins and subfascial interposition of a
      polypropylene foil in post-thrombotic syndrome. Preliminary results.
AB  - AIM: The safety, feasibility and early efficacy of subfascial endoscopic
      perforator surgery was gradually accepted for patients who had severe chronic
      venous insufficiency but, in the literature, the recurrence rate of ulceration is
      about 10-40%, especially in patients with previous deep vein thrombosis (DVT).
      METHODS: From October 1998 to February 2002, 205 patients with 280 inferior leg
      ulcers were followed; 115 had venous ulcers but only 20 patients had chronic
      ulcers with previous DVT; 4 patients were excluded and only 16 patients (9
      female, 7 male, mean age 61 years) with 18 chronic ulcers were included. These
      patients underwent sub-aponeurotic interruption of perforating veins with blind
      technique in association with subfascial interposition of a hand-made
      polypropylene foil. Eight of these patients had persistent non-healing ulcers at
      the time of surgery and 10 had chronic recurrent ulceration healed at the time of
      the surgical procedure. All patients were assessed clinically and with duplex
      scanning. RESULTS: The follow-up was done clinically and with eco-Doppler from 6
      to 38 months with a mean follow up period of 23.2 months. The healing rate was
      100%. The 2-year life table incidence of ulcer recurrence was 0%. Hospital stay
      ranged from 1-2 days, early operative complications included extensive ecchymosis
      in 1 patient, oedema in 3 patients. CONCLUSION: The division of perforating
      veins, with the subfascial support of a polypropylene foil give promising results
      in the treatment of venous ulcers in post-thrombotic syndrome with low morbidity
      and short hospital stay.

PMID- 15041938
TI  - The reverse upper arm curved graft with ringed PTFE graft as an alternative
      vascular access procedure for hemodialysis.
AB  - AIM: Prosthetic arteriovenous accesses are the last resort after efforts to place
      autogenous accesses are exhausted. During reimplantation of the graft, it is
      sometimes not convenient to dissect out the vessels to be grafted, especially
      around the venous anastomotic site and under local anesthesia. METHODS: We
      describe a technique using the ringed PTFE graft for the construction of a
      reverse upper arm curved graft in 14 patients who had received upper arm grafts
      previously. RESULTS: The mean operative time was 61+/-13 minutes, and the follow
      up interval extended to 20 months. No infections, pseudoaneurysm formations, or
      steal syndrome occurred during the follow-up period. The primary patency rate was
      calculated by Kaplan-Meier analysis, and the primary patency from graft insertion
      to clotting in the reverse graft was 91% at 3 months, 83% at 6 months, 66% at 9
      months, and 57% at 12 months. CONCLUSION: These results suggest that using the
      reverse upper arm curved graft during the reimplantation procedure was an
      alternative prosthetic arteriovenous access with the advantage of less tissue
      dissection, shorter operation time, and favorable patency rate.

PMID- 15041939
TI  - Common hepatic artery aneurysm branching from the superior mesenteric artery.
      Report of a case.
AB  - A 58-year-old man was notified as having a mass in the head of the pancreas at
      medical checkup on September 26, 2000. He was admitted to our department after
      being diagnosed as having an aneurysm in the common hepatic artery, branching
      from the superior mesenteric artery (SMA), based on selective SMA angiography.
      From an abdominal midline incision, we were able to reach his common hepatic
      artery aneurysm (CHAA) by mobilizing the pancreas through the route lateral to
      the greater curvature of the stomach. This aneurysm arose in the common hepatic
      artery immediately after branching from the SMA. After proximal and distal
      control of the SMA and common hepatic artery, the aneurysm was incised and the
      distal hepatic artery was anastomosed end to side to the SMA. The patient had an
      uneventful postoperative course.

PMID- 15041940
TI  - The histological effect of harmonic scalpel and electrocautery in lung
      resections. An experimental study in a rat model.
AB  - AIM: In the last decade, ultrasonically activated scalpels (the Harmonic Scalpel,
      HS) have been developed and used for both open and endoscopic surgical
      procedures. The present study compares the deepness of lung tissue damage caused
      by HS and unipolar electrocautery (EC) in rats. METHODS: Ten rats were used for
      the study. Morphological damage on lung parenchyma of the rats was measured with
      the ocular micrometer in light microscopy. RESULTS: The mean depth of the tissue
      damage was 0.23+/-0.08 mm in the HS group, and 0.33+/-0.10 mm in the EC group.
      The difference was statistically significant between the 2 groups (p=0.028).
      CONCLUSION: HS induces significantly less tissue damage than EC in rat lungs.

PMID- 15041941
TI  - Comparison between segmentectomy and larger resection of stage IA non-small cell
      lung carcinoma.
AB  - AIM: Stage IA non small cell lung carcinoma (NSCLC) represents early cancer and
      is best treated by surgery. The frequency of recurrence and new primary cancer
      varies from one report to another while the role of sublobar resection is still
      debated. METHODS: We retrospectively reviewed 121 consecutive patients with
      pathological stage IA after radical surgery. RESULTS: In stage IA NSCLC 1-, 3-, 5
      year survival rates were 89%, 76% and 66%. Nearly half of the deaths were
      unrelated to the original cancer. From statistical analysis we did not find any
      factor indicative of a better prognosis. We did not find any difference in
      survival between histologic types. Segmentectomy did not show a worse survival
      rate compared with larger resection. CONCLUSION: Survival is neither influenced
      by the type of resection nor by the histologic types in stage IA. However, we
      noticed a high incidence of local recurrence, segmentectomy could be a viable
      choice in patients with cardiopulmonary impairment.

PMID- 15041942
TI  - Pleural tenting in complicated primary spontaneous pneumothorax.
AB  - AIM: To assess the efficacy of pleural tenting in patients with complicated
      primary spontaneous pneumothorax (PSP). METHODS: From 1988 through 2001, 43
      patients underwent operations. Mean age was 30.4 years; the male/female ratio was
      9.7. Twenty-one (48.8%) underwent pleural tenting in addition to bulla excision
      (experimental group, EG). Twenty-two (51.2%) underwent bulla excision plus
      pleural abrasion (11 patients), apical partial pleurectomy (9 patients) and
      complete apical pleurectomy (2 patients) (control group, CG). The most frequent
      symptom was chest pain (37.2%). Surgical indications were recurrence in 21
      (48.8%), prolonged air leak in 12 (27.9%), failure of expansion without air leak
      in 6 (13.9%), high risk occupancy in 2 (4.6%) and empyema due to air leak in 2
      (4.6%). RESULTS: Air leak time was decreased by tenting (1.9 days vs 3.7 days) as
      well as time of drainage (4.8 vs 6.9) and hospital stay (5.8 vs 7.9). Morbidity
      was 9.5% in EG and 9.1% in CG. Causes of morbidity were postoperative hematoma,
      prolonged air leak, expansion failure and blunt posterior sinus one of each. Re
      operation needed for postoperative hematoma in CG. Mean follow-up was 5.1 years
      and 1 (4.5%) recurrence observed in CG. CONCLUSION: Tenting of the dependent lung
      from the apical pleura after bullectomy via axillary thoracotomy lessens air leak
      time without recurrence and low morbidity.

PMID- 15041943
TI  - Solitary pericardial hydatid cyst.
AB  - Hydatid cyst of the heart is an uncommon presentation of human echinococcosis
      which may lead to life-threatening conditions. Diagnosis should be suspected in
      every case of cyst-like mass in persons coming from areas where echinococcus
      granulosus is endemic. Echocardiography, computed tomography and magnetic
      resonance imaging can help in the differential diagnosis of the lesion. Even if
      some reports of successful therapy with benzimidazoles have been described, the
      treatment of choice is the surgical excision of the cyst. Pericardiectomy with
      cyst removal is feasible with low morbidity and mortality rates even in elder
      patients. The authors describe the successful surgical management of a single
      giant pericardial hydatid cyst in a 78-year-old woman from North Africa.

PMID- 15041944
TI  - About unilateral absence of intrapericardial pulmonary artery.

PMID- 15041946
TI  - Pseudoaneurysm of the posterior tibial artery as a complication of thrombectomy.

PMID- 15041945
TI  - Hydatid disease of a rib in a rare location.

PMID- 15041947
TI  - Follow-up of patients with previous vascular interventions: role of multidetector
      row computed tomographic angiography of the abdominal aorta and lower
      extremities.

PMID- 15041948
TI  - Asymptomatic aortic coarctation associated with loss of luminal continuity and
      intercostal artery aneurysm.

PMID- 15041949
TI  - Preliminary report of transesophageal monitoring of spinal cord ischemia using
      near-infrared spectrophotometry.

PMID- 15041950
TI  - Unintentional and undetermined poisoning deaths--11 states, 1990-2001.
AB  - During 1990-2001, the death rate from poisoning in the United States increased
      56%, from 5.0 per 100,000 population in 1990 to 7.8 in 2001. In 2001, of 22,242
      poisoning deaths, 14,078 (63%) were unintentional. To describe trends in
      poisoning deaths, state health professionals in 11 states analyzed vital
      statistics data for 1990-2001. This report summarizes the results of that
      analysis, which indicated that increases in state death rates from unintentional
      and undetermined poisonings varied, but increased by an average of 145%; a total
      of 89% of poisonings involved drugs and other biologic substances. State public
      health professionals can use local, state, and national surveillance data to
      monitor trends in drug misuse and to develop effective interventions that can
      reduce deaths from drug overdoses.

PMID- 15041951
TI  - Progress toward poliomyelitis eradication--India, 2003.
AB  - Since the World Health Assembly resolved in May 1988 to eradicate poliomyelitis,
      the estimated global incidence of polio has decreased >99%, and three World
      Health Organization (WHO) regions (Americas, Western Pacific, and European) have
      been certified as polio-free. Since 1994, when the countries of the WHO South
      East Asia Region (SEAR) began accelerating polio-eradication activities,
      substantial progress toward that goal has been made. By 2001, poliovirus
      circulation in India had been limited primarily to the two northern states of
      Uttar Pradesh and Bihar, with 268 cases reported nationwide. However, a major
      resurgence of polio occurred during 2002, with 1,600 cases detected nationwide,
      of which 1,363 (85%) were in Uttar Pradesh and Bihar. This report summarizes the
      status of polio eradication activities in India during 2003 and describes the
      actions being taken to reduce poliovirus transmission.

PMID- 15041952
TI  - Osteomyelitis/septic arthritis caused by Kingella kingae among day care attendees
      -Minnesota, 2003.
AB  - Kingella kingae is a fastidious gram-negative coccobacillus that colonizes the
      respiratory and oropharyngeal tract in children. K. kingae occasionally causes
      invasive disease, primarily osteomyelitis/septic arthritis in young children,
      bacteremia in infants, and endocarditis in school-aged children and adults.
      Although diagnosis of this organism frequently is missed, invasive disease is
      uncommon. Only sporadic, non-epidemiologically linked cases have been reported
      previously. In October 2003, the Minnesota Department of Health (MDH)
      investigated a cluster of two confirmed cases and one probable case of
      osteomyelitis/septic arthritis caused by K. kingae among children aged 17-21
      months attending the same toddler classroom in a day care center. All reported
      within the same week with onset of fever, preceding or concurrent upper
      respiratory illness (URI), and refusal to bear weight on the affected limb. This
      report summarizes these cases and describes the epidemiologic investigation of
      the day care center. The findings underscore the need for clinicians and
      laboratorians to consider K. kingae infection in young children with Gram stain-
      negative or culture-negative skeletal infections.

PMID- 15041953
TI  - Kingella kingae infections in children--United States, June 2001-November 2002.
AB  - Kingella kingae is recognized increasingly as a cause of skeletal infections in
      children. Recent studies indicate that direct inoculation of clinical specimens
      into aerobic blood culture bottles (ABCBs), instead of direct plating of
      specimens on solid media, might improve recovery of the fastidious bacteria.
      Prompted by a report of a possible cluster of osteoarticular infections caused by
      K. kingae among children, the Infectious Diseases Society of America Emerging
      Infections Network (IDSA-EIN) surveyed pediatric infectious disease consultants
      (PIDCs) about their experiences in diagnosing K. kingae and other skeletal
      infections in children. This report summarizes the findings of that survey, which
      identified 23 K. kingae pediatric cases and indicated that 35% of responding
      PIDCs did not use ABCBs in diagnosing skeletal infections. Efforts to increase
      use of ABCBs among clinicians and laboratorians might lead to increased detection
      of K. kingae cases.

PMID- 15041954
TI  - Imported measles case associated with nonmedical vaccine exemption--Iowa, March
      2004.
AB  - On March 13, 2004, the Iowa Department of Public Health (IDPH) reported to CDC
      that a male student aged 19 years with measles in the infectious stage had flown
      from New Delhi, India, to Cedar Rapids, Iowa, on March 12. Because of a
      nonmedical exemption, the student had not received measles-containing vaccine
      (MCV). This report describes the measles case, the public health response to
      prevent secondary cases, and the impact on the public health system. Health-care
      providers and state and local public health departments should be alert to
      possible cases of measles in persons who traveled with this student or their
      contacts. Parents considering nonmedical exemptions for their children should be
      aware of the potential risk for disease both for their children and the public.

PMID- 15041955
TI  - Myristoyl-CoA:protein N-myristoyltransferases: isoform identification and gene
      expression in retina.
AB  - PURPOSE: The mammalian myristoyl-CoA:protein N-myristoyltransferase (NMT) family
      consists of Type I and Type II enzymes that typically catalyze the addition of
      myristic acid (14:0) to the N-terminus of specific proteins using myristoyl
      Coenzyme A as a donor. However, the N-terminus of certain proteins in frog and
      bovine retina are modified with fatty acids other than myristic acid, and this
      utilization of alternative acyl-CoAs has not been found in any other tissues.
      This alternative use of acyl groups is known as retina heterogeneous acylation
      and occurs by an unknown mechanism. Therefore, the focus of this work has been to
      identify NMT isoforms that may be unique or differentially expressed in bovine
      retina that may utilize acyl-CoAs in addition to myristoyl-CoA. METHODS: We used
      cDNA library screening, RT-PCR, and PCR to identify NMTs in bovine retina and
      liver, then compared these proteins to previously described NMTs by amino acid
      alignments. We used northern blotting to determine the level of Type I and Type
      II NMTs in a human multi-tissue blot, in bovine retina, and in bovine liver.
      Southern blotting was done to determine if one or more genomic copies of Type II
      NMT are present in the bovine genome. A phylogenetic analysis of NMT isoforms is
      provided to describe the lineage of NMTs from a variety of species. RESULTS: We
      identified a Type I NMT in retina that is nearly identical to previously
      described Type I enzymes, as well as a novel Type II enzyme. We further
      characterized the retina specificity of the novel enzyme by evaluating which Type
      II enzymes are present in bovine liver. We find that cow liver contains a Type II
      NMT identical to the previously described NMT found in human liver, as well as a
      partial clone that is identical to the novel Type II NMT from retina. NMT Type I
      and II message expression appears to vary in a panel of tissues, and we suggest
      that retina expresses at least three NMT isoforms, with the Type I short form and
      Type II being more abundant than the Type I long form NMT. We also present
      evidence that there are two copies of Type II NMT in the bovine genome.
      CONCLUSIONS: Our efforts to find a retina-specific NMT resulted in the
      identification of a previously unknown Type II NMT, but this enzyme also appears
      to be expressed in liver. Therefore, we are unable to conclude that heterogeneous
      acylation occurs by means of an exclusive enzyme capable of efficiently utilizing
      multiple acyl-CoA substrates solely in retina. Nonetheless, our results lead to
      an improved understanding of protein acylating enzymes and encourage us to
      further identify factors that influence tissue-specific expression of each
      isoform and regulate their enzymatic activity in terms of acyl-CoA selectivity
      and heterogeneous protein acylation.

PMID- 15041956
TI  - Microarray analysis of gene expression in human donor sclera.
AB  - PURPOSE: To develop gene expression profiles of human sclera to allow for the
      identification of novel, uncharacterized genes in this tissue-type, and to
      identify candidate genes for scleral disorders. METHODS: Total RNA was isolated
      from 6 donor sources of human sclerae, and reverse transcribed into cDNA using a
      T7-(dT) 24 primer. The resulting cDNA was in vitro transcribed to produce biotin
      labeled cRNA, fragmented, and mixed with hybridization controls before a 16 h
      hybridization step with oligonucleotide probes on 6 Affymetrix U95A chips. The
      chips were scanned twice at 570 nM and the data collected using GeneChip
      software. Array analyses were carried out with Microarray Suite, version 5.0
      (Affymetrix), using the expression analysis algorithm to run an absolute analysis
      after cell intensities were computed. All arrays were scaled to the same target
      intensity using all probe sets. Reverse-transcription polymerase chain reaction
      (RT-PCR) was performed to validate the microarray results. RESULTS: There were
      3,751 genes with "present" calls assigned independently to all six human scleral
      samples. These genes could be clustered into 4 major categories; transcription
      (10%), metabolism (8.8%), cell growth and proliferation (5.4%), and extracellular
      matrix (2%). Many extracellular matrix proteins, such as collagens 6A3 and 10A1,
      thrombospondins 2 and 4, and dystroglycan have not previously been shown to be
      expressed in sclera. RT-PCR results confirmed scleral expression in 7
      extracellular matrix genes examined. CONCLUSIONS: This study demonstrated the
      utility of gene microarray technology in identifying global patterns of scleral
      gene expression, and provides an extended list of genes expressed in human
      sclera. Identification of genes expressed in sclera contributes to our
      understanding of scleral biology, and potentially provides positional candidate
      genes for scleral disorders such as high myopia.

PMID- 15041957
TI  - A missense mutation in the gammaD crystallin gene (CRYGD) associated with
      autosomal dominant "coral-like" cataract linked to chromosome 2q.
AB  - PURPOSE: Hereditary cataract is a clinically and genetically heterogeneous lens
      disorder that usually presents as a sight-threatening trait in childhood. The
      purpose of this study was to map and identify the mutation underlying an
      autosomal dominant form of coral-shaped cataract segregating in a three
      generation Caucasian pedigree. METHODS: Genomic DNA was prepared from blood
      leucocytes, genotyping was performed using microsatellite markers, and LOD scores
      were calculated using the LINKAGE programs. Mutation detection was performed
      using direct sequencing and primer extension analysis. Following site-directed
      mutagenesis, mutant and wild type expression constructs were transfected into a
      human lens epithelial cell line (HLE B-3) and recombinant protein was detected by
      immunoblotting, imunofluorescence, and immunogold microscopy. Cell death was
      monitored by fluorescence activated cell sorting. RESULTS: Significant evidence
      of linkage was detected at markers D2S371 (LOD score [Z]=3.81, recombination
      fraction [theta]=0) and D2S369 (Z=3.64, theta=0). Haplotyping indicated that the
      disease gene lay in the approximate 10 Mb physical interval between D2S1384 and
      D2S128, containing the gamma-crystallin gene (CRYGA-CRYGD) cluster on chromosome
      2q33.3-q34. Sequencing of the CRYGA-CRYGD cluster identified a C->A transversion
      in exon 2 of CRYGD that was predicted to result in the non-conservative
      substitution of threonine for proline at amino-acid residue 23 (P23T) in the
      processed CRYGD protein. Transfection studies suggested that the P23T mutant was
      less soluble than its wild type counterpart when expressed in HLE B-3 cells.
      CONCLUSIONS: This study has identified an eighth type of cataract morphology
      associated with CRYGD and suggests that a CRYGD mutation may underlie the
      historically important "coralliform" cataract first reported in 1895.

PMID- 15041958
TI  - Induction of tolerance.

PMID- 15041959
TI  - Are postoperative complications genetically determined by TNF-beta NcoI gene
      polymorphism?
AB  - BACKGROUND: Postoperative infectious complications are the leading causes for
      postoperative sepsis. In severe sepsis, tumor necrosis factor-beta (TNF-beta)
      NcoI polymorphism was associated with increased mortality. Therefore, the aim of
      this study was to determine whether the biallelic NcoI polymorphism within the
      TNF locus is associated with the development of postoperative complications.
      METHODS: One hundred sixty patients were included in this prospective observation
      study. Patients undergoing major gastrointestinal surgery, such as esophagectomy,
      gastrectomy, Whipple operation, major liver resection, or colon resection were
      included. Patients were monitored during the clinical course, and postoperative
      complications, divided into severe and minor complications, were documented. The
      NcoI restriction fragment length polymorphism of the TNF-beta gene was determined
      by polymerase chain reaction; gene expression as well as complications were
      correlated. RESULTS: The patients' genotype distribution and demographic
      characteristics were comparable within the different groups of operations.
      Patients with the heterozygous genotype TNF-beta1/beta2 had a 1.6-fold higher
      relative risk for developing complications. If patients with the homozygous
      genotype TNF-beta2 developed a complication, they had a 1.5-fold higher relative
      risk for severe complications. Furthermore, the mortality of patients with
      postoperative sepsis who were homozygous for the genotype TNF-beta2 was
      significantly elevated. CONCLUSIONS: The TNF-beta NcoI polymorphism influences
      the development of postoperative complications. While the genotype TNF
      beta1/beta2 has a higher risk for developing complications in general, the TNF
      beta2/beta2 genotype is associated with more severe complications and mortality
      from sepsis.

PMID- 15041961
TI  - Expression of Toll-like receptors 2 and 4 is downregulated after operation.
AB  - BACKGROUND: Toll-like receptors (TLR) that recognize microbial pathogens play a
      critical role in innate immunity; however, their expression and function after
      surgery remain unknown. The aim of this study was to examine TLR2 and TLR4
      expression on monocytes and their responses to each agonist after surgical
      insults. METHODS: Blood samples were obtained from 83 patients who underwent
      gastrointestinal surgery. TLR2, TLR4, and inducible nitric oxide synthase
      expressions on peripheral blood mononuclear cells (PBMCs) were analyzed by flow
      cytometry. Macrophage-activating lipopeptide-2 or lipopolysaccharide-induced
      tumor necrosis factor-alpha and interleukin-6 production was measured by enzyme
      linked immunosorbent assay. RESULTS: TLR2 and TLR4 decreased and showed the
      lowest values on the postoperative days 3 and 1, respectively. Macrophage
      activating lipopeptide-2-stimulated tumor necrosis factor-alpha and interleukin-6
      production was decreased immediately after the operation (P<.05), increased to a
      maximum value on postoperative day 1, and then decreased gradually.
      Lipopolysaccharide-stimulated tumor necrosis factor-alpha production was also
      suppressed immediately (P<.05) after operation then showed a gradual increase to
      maximum values on postoperative day 3. Inducible nitric oxide synthase in
      cultured PBMC that was obtained immediately after operation was upregulated
      (P<.05). CONCLUSION: Expressions of TLR2 and TLR4 were downregulated by
      operation, and agonist-induced cytokine production was suppressed transiently and
      soon increased through the activation of PBMC. The present study may offer new
      insights for postoperative modulation of innate immunity under surgical stress.

PMID- 15041962
TI  - Immediate and long-term outcomes of hepatectomy for hepatolithiasis.
AB  - OBJECTIVE: The aim of this study was to evaluate the perioperative and long-term
      results of hepatectomy for hepatolithiasis. PATIENTS AND METHODS: Immediate and
      long-term outcomes of 103 consecutive patients with hepatolithiasis who underwent
      hepatectomy from 1989 to 2001 were analyzed. Immediate outcomes included stone
      clearance rate, operative morbidity, and mortality. Long-term results included
      stone recurrence rate and survival. RESULTS: The immediate stone clearance rate
      was 90%, and the final stone clearance rate was 98% after subsequent
      choledochoscopic lithotripsy by cutaneous stoma or T-tube route. The operative
      morbidity and hospital mortality rates were 28% and 2%, respectively.
      Multivariate analysis showed that right hepatectomy (P=.006) and preoperative
      hyperbilirubinemia (P=.038) were predictive of postoperative complications. Ten
      patients (10%) had associated cholangiocarcinoma (four known preoperatively) at
      the time of hepatectomy. With a median follow-up of 56 months (range 6-158),
      recurrent stones developed in eight patients and cholangiocarcinoma developed in
      three patients (range: 7-30 months postoperatively). Sixteen patients had died
      during the follow-up period, none of recurrent cholangitis. Cholangiocarcinoma
      was the only significant prognostic factor of long-term survival by Cox
      regression analysis. CONCLUSIONS: Hepatectomy is a safe and effective treatment
      for hepatolithiasis, with a high immediate stone clearance rate and a low long
      term stone recurrence rate. The presence of associated cholangiocarcinoma is the
      main factor compromising long-term survival in patients with hepatolithiasis.

PMID- 15041963
TI  - The Budd-Chiari syndrome: outcome after treatment with the transjugular
      intrahepatic portosystemic shunt.
AB  - BACKGROUND: The role of portosystemic shunting in the treatment of the Budd
      Chiari syndrome is still under debate. Medical therapy and liver transplantation
      are alternative treatments. The aim of this study was to determine the outcome of
      a transjugular intrahepatic portosystemic shunt implantation. METHODS: Thirty
      five patients with severe Budd-Chiari syndrome and a Child-Pugh score of 9.2+/
      1.9, who were not responsive to medical therapy, were elected for the
      transjugular shunt treatment, which was successfully accomplished in 33. Eleven
      patients had a fulminant/acute (history <2 months); 13, a subacute (<6 months);
      and 11, a chronic course of the disease. The shunt was established by using
      conventional self-expandable stents in 25 patients and polytetrafluoroethylene
      covered stents in 8 patients. The mean follow-up was 37+/-29 months. RESULTS: The
      shunt reduced the portosystemic pressure gradient from 29+/-7 to 10+/-4 mm Hg and
      improved the portal flow velocity from 9.2+/-11 to 51+/-17 cm/s. Clinical
      symptoms as well as the biochemical test results improved significantly during 4
      weeks after shunt treatment. Three patients died and 2 received liver
      transplants. The cumulative 1- and 5-year survival rate without transplantation
      in all patients was 93% and 74%, respectively, and in patients with
      fulminant/acute disease 91% and 91% respectively (no deaths in this time period).
      On the average, 1.4+/-2.2 revisions per patient were needed during the mean
      follow-up of 3 years with a 1-year probability of 47%. CONCLUSIONS: The
      transjugular shunt provides an excellent outcome in patients with severe
      fulminant/acute, subacute, and chronic Budd-Chiari syndrome. It may be regarded
      as a treatment for the acute and long-term management of these patients.

PMID- 15041964
TI  - Total and segmental liver volume variations: implications for liver surgery.
AB  - BACKGROUND: Liver remnant volumes after major hepatic resection and graft volumes
      for liver transplantation correlate with surgical outcome. The relative
      contributions of the hepatic segments to total liver volume (TLV) are not well
      established. METHODS: TLV and hepatic segment volumes were measured with computed
      tomography (CT) in 102 patients without liver disease who underwent CT for
      conditions unrelated to the liver or biliary tree. RESULTS: TLV ranged from 911
      to 2729 cm(3). On average, the right liver (segments V, VI, VII, and VIII)
      contributed approximately two thirds of TLV (997+/-279 cm(3)), and the left liver
      (segments II, III and IV) contributed approximately one third of TLV (493+/-127
      cm(3)). Bisegment II+III (left lateral section) contributed about half the volume
      of the left liver (242+/-79 cm(3)), or 16% of TLV. Liver volumes varied
      significantly between patients--the right liver varied from 49% to 82% of TLV,
      the left liver, 17% to 49% of TLV, and bisegment II+III (left lateral section) 5%
      to 27% of TLV. Bisegment II+III contributed less than 20% of TLV in more than 75%
      of patients and the left liver contributed 25% or less of TLV in more than 10% of
      patients. DISCUSSION: There is clinically significant interpatient variation in
      hepatic volumes. Therefore, in the absence of appreciable hypertrophy, we
      recommend routine measurement of the future liver remnant before extended right
      hepatectomy (right trisectionectomy) and in selected patients before right
      hepatectomy if a small left liver is anticipated.

PMID- 15041966
TI  - Persistent evidence of circulating tumor cells detected by means of RT-PCR for
      CEA mRNA predicts early relapse: a prospective study in node-negative breast
      cancer.
AB  - BACKGROUND: In 100 consecutive patients with node-negative breast cancer who
      underwent curative surgery, we prospectively tested whether detection of
      circulating tumor cells in peripheral blood by means of reverse transcription
      polymerase chain reaction for carcinoembryonic antigen (CEA) messenger RNA (mRNA)
      could predict patient outcomes. METHODS: We performed reverse transcription
      polymerase chain reaction in blood samples taken before surgery and in repeat
      samples taken 2 to 3 weeks after surgery. Univariate and multivariate analyses of
      relapse-free survival were performed. RESULTS: Patients with CEA mRNA in
      preoperative samples had poorer survival rates than those who had no detectable
      CEA mRNA. The worst survival rate was seen in those with CEA mRNA in both pre-
      and postoperative samples. Stepwise multivariate analysis selected CEA mRNA
      expression pattern (P=.001; relative risk=0.69) and histologic tumor grade
      (P=.002; relative risk=1.35) as independent prognostic factors for disease-free
      survival. CONCLUSIONS: Molecular detection of CEA mRNA in both pre- and
      postoperative blood samples is an independent, negative prognostic factor in
      patients with node-negative breast cancer undergoing curative surgery.

PMID- 15041967
TI  - Interferon-beta gene therapy improves survival in an immunocompetent mouse model
      of carcinomatosis.
AB  - BACKGROUND: Interferon-beta (IFNbeta) has multiple antitumor effects; however,
      its use has been limited by its short half-life in vivo. This limitation may be
      overcome by IFNbeta gene therapy. We evaluated adenovirus-IFNbeta therapy in an
      immunocompetent mouse model of carcinomatosis. METHODS: Mice that were treated
      intraperitoneally 5 days after tumor (mouse ovarian teratoma) inoculation with an
      adenoviral vector that contains the mouse IFNbeta gene (Ad-IFNbeta), control
      adenoviral vector or saline solution. Mice were monitored for multiple outcome
      measures and toxicity. To determine the mechanism of antitumor effect, flow
      cytometry of ascites fluid was performed to differentiate immune cell
      populations. Nitric oxide in ascites fluid was measured with an electrochemical
      microsensor. RESULTS: Tumor burden was decreased and survival was prolonged
      (P<.001) in the Ad-IFNbeta group after a single treatment of 3.3 x 10(8) plaque
      forming units, with acceptable toxicity. By flow cytometry, an increase in the
      proportion of natural killer cells (from less than 2% of the gated population to
      more than 8%; P=.024) and an increase in macrophages were seen in the treated
      animals. Although there was a trend toward increased levels of nitric oxide in Ad
      IFNbeta treatment groups, it was not statistically significant. CONCLUSION:
      IFNbeta gene therapy results in decreased tumor burden and improved survival in
      an aggressive, immunocompetent mouse model of carcinomatosis. This therapy
      warrants further evaluation as a treatment for disseminated peritoneal cancer.

PMID- 15041965
TI  - Pancreatic head resection for chronic pancreatitis in patients with extrahepatic
      generalized portal hypertension.
AB  - BACKGROUND: Five percent to 10% of chronic pancreatitis (CP) cases are
      complicated by portal venous occlusion leading to extrahepatic generalized portal
      hypertension (GPH). Pancreatic head resections (PHR) are regarded risky or
      contraindicated in patients with extrahepatic GPH. The aim of our study was to
      analyze the outcome of patients with extrahepatic GPH undergoing PHR for CP and
      to propose recommendations for surgical strategy. METHODS: Sixteen of 185
      patients with PHR suffered from extrahepatic GPH. Perioperative and follow-up
      data were documented prospectively and analyzed to assess the outcome. RESULTS:
      Preoperative interventional thrombolysis of the portal vein was successfully
      performed in 5 patients and alleviated further PHR. Median operative time and
      blood transfusions were higher in patients with extrahepatic GPH compared with
      patients without extrahepatic GPH (P<.01). Overall complication rate was not
      statistically different (44% vs 34%). One death occurred in each group. At the
      end of follow-up (median, 18 months) 13 of 15 patients with extrahepatic GPH were
      free of pain. No variceal bleeding or cholestasis was documented. All patients
      judged their status as subjectively improved. CONCLUSION: Although technically
      demanding in the presence of extrahepatic GPH, PHR can be performed with an
      acceptable morbidity and mortality in an experienced center. Preoperative
      interventional recanalization of portal vein thrombosis may render PHR possible
      by restoring normal splanchnic blood flow in selected cases indicated for
      surgery.

PMID- 15041968
TI  - Nitrosoglutathione improves blood perfusion and flap survival by suppressing iNOS
      but protecting eNOS expression in the flap vessels after ischemia/reperfusion
      injury.
AB  - BACKGROUND: The effects of nitric oxide (NO) on the microcirculation and free
      tissue survival remain controversial. With the use of a rat inferior epigastric
      artery flap as an ischemia/reperfusion injury (I/R) model, we investigated
      whether exogenous NO donation regulates endogenous NO synthase (NOS) expression
      in the flap vessels and promotes flap survival. METHODS: Thirty minutes before
      flap reperfusion, normal saline (1 ml), nitrosoglutathione (GSNO 0.2, 0.6, 3
      mg/kg), or N(G)-nitro-L-arginine-methyl ester (L-NAME, 450 mg/kg), was injected
      intravenously into 20 rats. Total plasma NOx (NO(2)-/NO(3)-) was measured to
      reflect NO production. Immunohistochemical staining was investigated for the
      endothelin-1 (ET-1) and NOS isoforms expression on the flap vessels. NOS isoforms
      expression was evaluated by Western blot. Laser-Doppler flowmetry monitored flap
      perfusion. Survival areas were assessed by gross examination at 7 days
      postoperatively. RESULTS: Flap ischemia at 12 hours followed by reperfusion
      resulted in endothelial cell damage, as demonstrated by induction of iNOS and ET
      1 expression in the flap vessels. An optimal dose of nitrosoglutathione (0.6 mg
      GSNO/kg) significantly increased plasma NOx levels (P=.027) and improved flap
      perfusion by laser Doppler measurement (P=.014), and increased the flap viability
      area (P<.001). Additionally, it selectively suppressed iNOS induction, but
      enhanced eNOS expression and decreased ET-1 deposition in the flap vessels. In
      contrast, an NOS inhibitor, N(G)-nitro-L-arginine methyl ester, inhibited both
      iNOS and eNOS expression in the flap vessels, decreased endogenous NOx
      production, and compromised flap viability. CONCLUSION: This study indicates that
      intravenous administration of exogenous GSNO can appropriately donate NO to
      suppress iNOS induction and enhance eNOS expression in pedicle vessels, resulting
      in better blood perfusion and a higher flap survival after I/R injury.

PMID- 15041969
TI  - Editorial review of "Malignant progression from C-cell hyperplasia to medullary
      thyroid carcinoma in 167 RET germline mutations".

PMID- 15041970
TI  - An impaired surgeon, a conflict of interest, and supervisory responsibilities.

PMID- 15041973
TI  - Leiomyosarcoma of the portal venous system: a case report and review of
      literature.

PMID- 15041971
TI  - Radical retropubic prostatectomy frustrated by prior laparoscopic mesh
      herniorrhaphy.

PMID- 15041974
TI  - Biliopancreatic reflux via anomalous pancreaticobiliary junction.

PMID- 15041976
TI  - Re: "Small intestinal submucosa as a bioscaffold for biliary tract regeneration".

PMID- 15041977
TI  - Fatal hemobilia after radiofrequency thermal ablation for hepatocellular
      carcinoma.

PMID- 15041978
TI  - A case of surgical treatment of acute pulmonary embolism without the use of
      extracorporeal circulation.

PMID- 15041979
TI  - Is thyroid suppression an effective procedure in improving preoperative sestamibi
      parathyroid scintigraphy?

PMID- 15041984
TI  - Repeat courses of antenatal corticosteroids: the controversy continues.

PMID- 15041985
TI  - Repeated antenatal corticosteroids: effects on cerebral palsy and childhood
      behavior.
AB  - OBJECTIVE: This study was undertaken to determine the effects of repeated courses
      of antenatal corticosteroids on childhood behavior and disabilities, including
      cognitive delay and cerebral palsy. STUDY DESIGN: Nonrandomized regional cohort
      of 541 very preterm infants born in Western Australia from singleton pregnancies
      and alive at 3 years were included in the study. MAIN OUTCOME MEASURES: Physical,
      cognitive, and psychological assessments up to 6 years. RESULTS: Increasing
      numbers of antenatal corticosteroid courses were associated with a reduction in
      the rate of cerebral palsy. Three or more courses were also associated with
      increased rates of aggressive/destructive, distractible, and hyperkinetic
      behavior and these effects were present at both ages 3 and 6 years. Measures of
      internalizing behavior and intelligence quotient were unaffected by antenatal
      corticosteroid use. CONCLUSION: Repeated antenatal courses of corticosteroids may
      protect against cerebral palsy but are associated with hyperactivity later in
      childhood.

PMID- 15041986
TI  - Microvascular endothelial cell activation is present in the umbilical placental
      microcirculation in fetal placental vascular disease.
AB  - OBJECTIVE: Fetal growth restriction is associated with an abnormal umbilical
      artery Doppler study. A vascular disease is present in the fetal umbilical
      placental microcirculation. We hypothesized that the local production of factors
      that are injurious to microvessel endothelium is responsible for this vascular
      disease and that endothelial cell activation is a feature of this. Because the
      expression of the cell adhesion molecules is associated with endothelial cell
      activation, we isolated endothelial cells from the microvessels of the umbilical
      placenta and examined them for evidence of gene expression of cell adhesion
      molecules. STUDY DESIGN: Endothelial cells from the microcirculation of human
      placenta were isolated and purified with collagenase digestion and extraction
      with superparamagnetic beads that were coated with monoclonal antibody against
      CD31. Microvessel endothelial cells were isolated from the placentae of 13 women
      with a normal pregnancy and delivery at term and 10 placentas with umbilical
      placental vascular disease that was defined by abnormal umbilical artery Doppler
      study. Total RNA was extracted from isolated endothelial cells. The messenger RNA
      expressions of cell adhesion molecules (intercellular adhesion molecule-1,
      vascular cell adhesion molecule-1, and platelet endothelial cell adhesion
      molecule-1) were assessed by semiquantitative reverse transcription-polymerase
      chain reaction. RESULTS: Microvessel endothelial cells from the fetal placentae
      of pregnancies that were complicated by umbilical placental vascular disease
      showed an enhanced expression of intercellular adhesion molecule-1 messenger RNA
      (2.12+/-0.45 vs 0.92+/-0.25) and platelet endothelial cell adhesion molecule-1
      messenger RNA (4.29+/-0.87 vs 2.41+/-0.42) in comparison to normal pregnancies.
      There was no significant difference in expression of vascular cell adhesion
      molecule-1 messenger RNA (1.55+/-0.37 vs 1.68+/-0.38). CONCLUSION: We have shown
      that vascular disease in the fetal umbilical placental circulation is associated
      with an increase in the expression of intercellular adhesion molecule-1 and
      platelet endothelial cell adhesion molecule-1 by microvessel endothelial cells.
      We postulate that locally released factors cause injury and activation to
      microvessel endothelial cells. In this regard, the process in the fetus is
      similar to that of atherothrombotic vascular disease of later life.

PMID- 15041987
TI  - A prospective randomized trial comparing tension-free vaginal tape and
      transobturator suburethral tape for surgical treatment of stress urinary
      incontinence.
AB  - OBJECTIVE: The purpose of this study was to prospectively and randomly compare
      tension-free vaginal tape (TVT) with transobturator suburethral tape (T.O.T.) for
      the surgical treatment of stress urinary incontinence (SUI) in women. STUDY
      DESIGN: Sixty-one women with SUI were randomly assigned to either TVT (n=31) or
      T.O.T. (n=30). The preoperative evaluation included a quality-of-life
      questionnaire and a comprehensive urodynamic examination. The 1-year outcome
      included a detrusor pressure-uroflow study to compare bladder outlet obstruction.
      RESULTS: Patient characteristics, preoperative quality of life, and urodynamic
      evaluation were similar in the 2 groups. Mean operative time was significantly
      shorter in the T.O.T. group (15 min+/-4 vs 27 min+/-8, P<.001). No bladder injury
      occurred in the T.O.T. group versus 9.7% (n=3) in the TVT group (P>.05). The rate
      of postoperative urinary retention was 25.8% (n=8) in the TVT group versus 13.3%
      (n=4) in the T.O.T. group (P>.05). The rates of cure (83.9% vs 90%), improvement
      (9.7% vs 3.3%), and failure (6.5% vs 6.7%) were similar for the TVT and T.O.T.
      groups, respectively. The 1-year outcome data were collected in 29 women of the
      TVT group and 27 women of the T.O.T. group. No vaginal erosion occurred in either
      of the groups. In terms of bladder outlet obstruction, no differences were found
      after TVT and T.O.T. CONCLUSION: T.O.T. appears to be equally efficient as TVT
      for surgical treatment of stress urinary incontinence in women, with no reduction
      of bladder outlet obstruction at 1-year follow-up.

PMID- 15041988
TI  - A randomized comparison of tension-free vaginal tape and endopelvic fascia
      plication in women with genital prolapse and occult stress urinary incontinence.
AB  - OBJECTIVE: The purpose of this study was to compare 2 anti-incontinence
      procedures in women who had severe genital prolapse and potential stress
      incontinence. STUDY DESIGN: In addition to vaginal reconstructive surgery, 50
      patients with stage II or higher anterior defect and a positive stress test
      result with prolapse reduction received either tension-free vaginal tape or
      plication of the endopelvic fascia. Preoperative evaluation included history,
      physical examination, stress test, and urodynamic assessment. Data were analyzed
      with the Student t test, the Fisher's exact test, and the Wilcoxon signed-rank
      test. RESULTS: The median follow-up time was similar for both groups, 26 and 24
      months. Subjective (96% vs 64%; P=.01) and objective (92% vs 56%; P<.01)
      continence rates were higher after the tension-free vaginal tape procedure. Time
      for the resumption of spontaneous voiding, rates of urinary retention, or de novo
      urge incontinence were similar in the 2 groups. CONCLUSION: Tension-free vaginal
      tape can be recommended for patients with prolapse and occult stress
      incontinence.

PMID- 15041989
TI  - Effects of Burch colposuspension on the relative positions of the bladder neck to
      the levator ani muscle: An observational study that used magnetic resonance
      imaging.
AB  - OBJECTIVE: The purpose of this study was to use magnetic resonance imaging to
      observe the changes of the position of the levator ani muscle relative to the
      bladder neck after Burch colposuspension. STUDY DESIGN: Women with urodynamic
      stress incontinence underwent Burch colposuspension. Magnetic resonance imaging
      was performed 1 week before surgery and 1 year after the operation. The levator
      ani muscle and the bladder neck were imaged in the parasagittal and sagittal
      planes, respectively; and their position was measured in relation to the
      pubococcygeal line. The reproducibility of these measures was investigated.
      Changes that occurred to levator ani muscle anatomy after the operation were
      correlated to surgical success. Surgical outcome was assessed objectively at 1
      year with urodynamic testing. RESULTS: Of the 73 women who were studied, only 28
      women were included in the study because the medial edge of the levator ani was
      visible clearly on a parasagittal magnetic resonance image. At the 1-year follow
      up, the objective cure rate was 86%. Measures of bladder neck and levator ani
      position in relation to the pubococcygeal line were found to be reproducible.
      Burch colposuspension produces a significant elevation of the levator ani, with a
      reduced distance between the bladder neck and the levator ani muscle. Surgical
      success was associated significantly with a shorter distance between bladder neck
      and levator ani muscle. CONCLUSION: The anatomy of the levator ani muscle is
      changed by colposuspension. The apposition of the levator ani muscle to the
      bladder neck may play a role in the restoration of continence.

PMID- 15041990
TI  - Impact of menopause on collagen subtypes in the arcus tendineous fasciae pelvis.
AB  - OBJECTIVE: The arcus tendineous fasciae pelvis (ATFP) provides support to the
      anterior vagina. The objective of this study was to determine the impact of
      menopause on the structural components of the ATFP. STUDY DESIGN: Biopsy
      specimens of the ATFP were obtained from 10 premenopausal, 5 postmenopausal, and
      12 postmenopausal women on hormone therapy. Scanning confocal microscopy of
      fluorescent micrographs was used to define the amount of collagen subtypes,
      smooth muscle, and elastin. Collagen fiber orientation was determined by scanning
      electron microscopy. RESULTS: The ATFP is comprised primarily of parallel bundles
      of type III collagen fibers (84%), an intermediate amount of elastin (13%), and
      very little smooth muscle. The ratio of collagen I/(III+V) was decreased in
      postmenopausal not on hormones relative to premenopausal women (P=.04) due to a
      75% decrease in collagen I (P=.046). The decrease in collagen I and change in
      collagen ratios was not present in women on hormone therapy. Comparison of the
      amounts of elastin and smooth muscle showed no difference in the ATFP of
      premenopausal and postmenopausal women. CONCLUSION: Menopause in the absence of
      hormone therapy is associated with a decrease in quantity of collagen I in the
      ATFP resulting in a decrease in the ratio of collagen I/(III+V). This may
      compromise the tensile strength and an increase susceptibility to anterior
      vaginal wall prolapse.

PMID- 15041991
TI  - Prevention of vesicovaginal fistulas after laparoscopic hysterectomy with
      electrosurgical cystotomy in female mongrel dogs.
AB  - OBJECTIVE: Using a previously described animal model, we sought to compare 3
      methods of double-layer cystotomy repair to each other and to single-layer repair
      in the prevention of vesicovaginal fistula formation. STUDY DESIGN: Twenty-four
      female mongrels, which were divided into 3 groups, underwent laparoscopic
      hysterectomy followed by monopolar electrosurgical cystotomy. Group 1 had simple
      2-layer cystotomy repair with interrupted 2-0 polyglactin sutures; group 2 had
      resection of tissue 5 mm beyond the visible electrosurgical burn margin followed
      by 2-layer closure, and group 3 had interposition of an omental flap after 2
      layer closure. Animals were killed at least 27 days after the operation, and a
      careful evaluation for vesicovaginal fistulas was undertaken by retrograde
      bladder filling. Group results were compared with one another and to a historic
      control group of 8 dogs that had undergone cystotomy repair with single-layer
      closure. RESULTS: All groups were similar in preoperative and necropsy weight.
      Bladder perforation occurred in 1 dog in group 1 on postoperative day 3; necropsy
      revealed perforation in the area of electrosurgical thermal spread with intact
      sutures. No vesicovaginal fistulas were noted in any of the study dogs (0/23
      dogs; 95% CI, 0-12.7%) compared with 2 of 8 dogs (25%) that underwent single
      layer closure (95% CI, 0-55%; P=.06). CONCLUSION: Double-layer repair appears to
      be superior to single-layer repair for the prevention of vesicovaginal fistulas
      after monopolar cystotomy. The benefit of electrosurgical burn margin excision or
      omental flap interposition remains unclear, but both are accomplished easily with
      little risk and may play a role in fistula prevention.

PMID- 15041992
TI  - Complications of laparoscopy: an inquiry about closed- versus open-entry
      technique.
AB  - OBJECTIVE: The purpose of this study was to determine the amount of complications
      and the incidence of open- versus closed-entry (either by Veress needle or first
      trocar) technique in gynecologic laparoscopy in The Netherlands. STUDY DESIGN:
      Questionnaire analysis of members of the Dutch Society for Gynaecological
      Endoscopy and Minimal Invasive Surgery was combined with a Medline literature
      search. Data related to complications on entry from January 1,1997, through
      December 31, 2001, were collected by questionnaire and were separated into group
      I (Veress needle or first trocar) and group II (open-entry technique). The number
      of laparoscopy procedures, years of experience, and indications to perform the
      chosen entry technique were collected. RESULTS: Response rate was 98%. The
      procedures were performed by 187 gynecologists in 74 hospitals (72%) in The
      Netherlands. Groups I and II were comparable to each other, with respect to type
      of clinic (teaching vs nonteaching hospital), the number of procedures, and the
      experience of gynecologists. One hundred six gynecologists (57%) used only the
      closed-entry technique. This group reported 31 complications (0.1%) in 31,532
      procedures. Even in the case of patients who were at risk for entry-related
      complications (previous laparotomy, obesity), pneumoperitoneum was established by
      the closed-entry technique. However, most gynecologists used an alternative
      insufflation point (eg, Palmer's point). The remaining 81 gynecologists used both
      entry techniques. However, the open-entry technique was used on special
      indications and in only 2.0% of cases (range: 1-20%). These special indications
      were suspected adhesions or previous laparotomy (90%) and obese (7%) or very thin
      patients (3%). These 81 gynecologists reported 20,027 closed-entry procedures and
      579 open-entry procedures and complication rates of 0.12% and 1.38%, respectively
      (P<.001). Significantly more visceral lesions were found (P<.001) at open-entry
      technique in group II. Our literature search showed a calculated average entry
      complication rate for the closed-entry technique for visceral and vascular
      lesions of 0.44 of 1000 procedures and 0.31 of 1000 procedures, respectively.
      CONCLUSION: Although 43% of the gynecologists in this study performed the open
      entry technique in laparoscopy, Dutch gynecologists seldom use this technique.
      When it is performed in selected patients, the number of complications is not
      reduced necessarily. In contrast to published data of general surgeons' findings,
      the number of entry-related complications in the open technique was significantly
      higher than the closed-entry technique. There is no evidence to abandon the
      closed-entry technique in laparoscopy. However, the selection of patients for an
      open- or alternative-entry procedure is still recommended.

PMID- 15041993
TI  - Directed laparoscopic cryomyolysis: a possible alternative to myomectomy and/or
      hysterectomy for symptomatic leiomyomas.
AB  - OBJECTIVE: The purpose of this study was to develop a minimally invasive, safe,
      and effective technique for managing symptomatic uterine myomas. STUDY DESIGN:
      Twenty patients with symptomatic uterine fibroids were treated. All had
      complaints of abnormal bleeding and/or pelvic pain/pressure and/or urinary
      frequency. Myoma diameters were 4 to 8 cm. Power color Doppler imaging was
      performed preoperatively and postoperatively to determine the effectiveness of
      cryomyolysis in reducing or eliminating the primary blood supply, as well as
      regression of the myomas. Laparoscopic cryomyolysis was performed with use of the
      Her Option Cryoablation System (American Medical Systems Gynecology, San Diego,
      Calif). Patients were evaluated at 1, 3, and 6 months postoperatively. RESULTS:
      All patients were discharged within 24 hours of treatment. No intraoperative or
      postoperative complications occurred. Of the 20 patients treated, 19 had complete
      resolution of their complaints. Myomas regressed up to 80%, and major blood
      supply to the myomas was eliminated. CONCLUSION: Directed laparoscopic
      cryomyolysis is an effective and safe technique for symptom relief from
      leiomyomas.

PMID- 15041994
TI  - Risk factors for recurrent vulvovaginal candidiasis in women receiving
      maintenance antifungal therapy: results of a prospective cohort study.
AB  - OBJECTIVE: The purpose of this study was to examine risk factors for symptomatic
      vulvovaginal candidiasis episodes among women with recurrent vulvovaginal
      candidiasis (defined as >/=4 vulvovaginal candidiasis episodes in 1 year) who
      were receiving maintenance antifungal therapy. STUDY DESIGN: A prospective study
      of 65 women aged >/=18 years with recurrent vulvovaginal candidiasis who attended
      vaginitis clinics in Detroit, Mich, and Philadelphia, Pa. RESULTS: The 9-month
      risk of vulvovaginal candidiasis recurrence was 41.8%. Almost two fifths of the
      women reported activity limitations because of vulvovaginal candidiasis episodes,
      most or all of the time. Younger women and those women with a history of
      bacterial vaginosis were at increased risk of vulvovaginal candidiasis episodes.
      Behavioral factors that were associated significantly with increasing
      vulvovaginal candidiasis recurrence >/=2- fold included wearing pantyliners or
      pantyhose and consuming cranberry juice or acidophilus-containing products.
      CONCLUSION: The use of pantyliners or pantyhose, consumption of cranberry juice
      or acidophil-containing products, a history of bacterial vaginosis, and age <40
      years were positively associated with a symptomatic vulvovaginal candidiasis
      episode.

PMID- 15041995
TI  - Limitations of screening tests for the detection of Chlamydia trachomatis in
      asymptomatic adolescent and young adult women.
AB  - OBJECTIVE: The purpose of this study was to examine the performance of different
      test types, specimen sources, and collection methods for screening of genital
      Chlamydia trachomatis infection in young women. STUDY DESIGN: Asymptomatic women
      aged 16 to 25 years collected their own vaginal swabs and a first-voided urine
      specimen; a clinician collected urethral, vaginal, and endocervical swabs for
      culture and nucleic acid amplification tests, polymerase chain reaction and
      ligase chain reaction. A positive culture, 2 positive nucleic acid amplification
      tests, or 1 positive nucleic acid amplification test confirmed by a separate
      nested polymerase chain reaction comprised the criterion standard to define a C.
      trachomatis-infected woman. RESULTS: The prevalence of C. trachomatis was 22%
      (30/139 women). All 9 test results were available for 126 participants (91%).
      Sensitivities were comparable for polymerase chain reaction and ligase chain
      reaction (52%-63%), except for urine polymerase chain reaction (44%), and were
      lower for culture (22%-37%); specificities were 99% to 100%, except for urine
      ligase chain reaction (91%). Positive predictive values were >93%, except for
      urine ligase chain reaction (65%); negative predictive values were 83% to 91%.
      Combining nucleic acid amplification test results from 2 different specimens
      improved sensitivities without compromising specificity. CONCLUSION: When C.
      trachomatis infection was defined by multiple tests from different specimen
      sources, the sensitivity of any 1 test from a single specimen source was lower
      than generally reported. The limitations of the use of a single test to identify
      C. trachomatis infection should be considered when test type, specimen source,
      and collection method for screening young women is being determined.

PMID- 15041996
TI  - Immunoglobulin E antibodies to seminal fluid in women with vulvar vestibulitis
      syndrome: relation to onset and timing of symptoms.
AB  - OBJECTIVE: Patients with vulvar vestibulitis syndrome and control subjects were
      tested for evidence of allergy to seminal fluid to differentiate women with a
      clinical diagnosis of vulvar vestibulitis syndrome into discrete categories.
      STUDY DESIGN: Plasma samples from 52 women with vulvar vestibulitis syndrome and
      43 control subjects were tested for immunoglobulin E antibodies to seminal fluid,
      total immunoglobulin E, interleukin-4, and interleukin-12 by enzyme-linked
      immunosorbent assay. Demographic and medical histories were obtained by
      questionnaire and interview. RESULTS: Sixteen of the patients (30.8%) with vulvar
      vestibulitis syndrome and 2 control subjects (4.7%) tested positive for
      immunoglobulin E antiseminal fluid. Symptoms began after sexual intercourse in
      43.8% of the women who tested immunoglobulin E positive and 11.1% of the women
      who tested immunoglobulin E negative (P=.02). Symptom initiation after a yeast
      infection was reported by 31.3% of the women who tested immunoglobulin E positive
      and by 2.8% of the women who tested immunoglobulin E negative (P=.008). Other
      symptom-initiating events were reported by 47.2% of the women who tested
      immunoglobulin E negative and by none of the women who tested immunoglobulin E
      positive (P=.0008). Fifty percent of the women who tested immunoglobulin E
      positive, as opposed to 22.2% of the women who tested immunoglobulin E negative,
      reported pain only after intercourse (P=.05). Pain at other times occurred in 50%
      of the women who tested immunoglobulin E positive and in 72.2% of the women who
      tested immunoglobulin E negative (P=.001). There was no relation between
      immunoglobulin E antiseminal fluid and total immunoglobulin E, interleukin-4,or
      interleukin-12. CONCLUSION: A subset of women with vulvar vestibulitis syndrome
      are sensitized to seminal fluid, and an allergic reaction to seminal fluid may be
      associated with the initiation and persistence of their symptoms.

PMID- 15041997
TI  - P16 as a molecular biomarker of cervical adenocarcinoma.
AB  - OBJECTIVE: Cervical adenocarcinomas are increasing in incidence each year. The
      aim of this study was to identify a molecular biomarker to improve early
      detection. STUDY DESIGN: Fifty-five in situ and invasive cervical adenocarcinomas
      were compared with 5 normal endocervical controls by immunohistochemical analysis
      of p16, p21, p27, cyclin D1, cyclin E, p53, and Ki-67. Expression was scored from
      0 to 8 by using an automated imaging system. Western blotting and polymerase
      chain reaction-based human papillomavirus (HPV) testing were performed on 16 of
      the invasive cases having fresh-frozen tissue. RESULTS: P16 exhibited a higher
      mean expression score for in situ (7.4; P<.0001) and invasive cervical
      adenocarcinoma (6.6; P<.0001) versus controls (2.0). A cutoff p16 expression
      score of 5 had a sensitivity of 94.5% and a specificity of 100%. Western blotting
      confirmed p16 protein expression. Fourteen (88%) of 16 invasive cervical
      adenocarcinomas were HPV-positive. CONCLUSION: P16 is a putative molecular
      biomarker of cervical adenocarcinoma. Overexpression appears to primarily reflect
      HPV-induced cell cycle dysregulation.

PMID- 15041998
TI  - Aberrant p16 methylation is a biomarker for tobacco exposure in cervical squamous
      cell carcinogenesis.
AB  - OBJECTIVE: The purpose of this study was to determine the association between
      active tobacco exposure and aberrant p16 promoter methylation in primary cervical
      squamous cell cancer and high-grade squamous cervical dysplasia. STUDY DESIGN:
      p16 methylation-specific polymerase chain reaction was performed on DNA that was
      extracted from 60 cervical cancers, 30 high-grade dysplasia specimens, and 78
      normal cervical cytologic specimens. Patient data were obtained by medical record
      review or were collected prospectively. RESULTS: Aberrant p16 methylation was
      significantly higher in squamous cell cervical cancers (61%) than in squamous
      high-grade dysplasia (20%) or normal cytologic specimens (7.5%). Approximately
      one half the women with squamous cancer and one half of the women with high-grade
      dysplasia were active smokers. Aberrant p16 methylation was associated with
      active tobacco use in patients with squamous carcinoma (odds ratio, 20.6; 95% CI,
      3.6-118; P<.001) and high-grade dysplasia (odds ratio, 4.57; 95% CI, 1.63-12.78;
      P=.002). CONCLUSION: Aberrant p16 methylation is associated strongly with active
      tobacco use in squamous cell cervical cancers and high-grade dysplasia.

PMID- 15041999
TI  - Evidence for tight coupling of Gi protein-mediated lysophosphatidic acid receptor
      to stimulated cytokine production in ovarian cancer cell.
AB  - OBJECTIVE: Lysophosphatidic acid stimulates the proliferation of ovarian cancer
      cell through specific members of the guanosine triphosphate-binding protein
      coupled receptor family. We attempted to identify the guanosine triphosphate
      binding protein subtypes that are linked to lysophosphatidic acid receptor
      stimulated production of cytokine, which are involved potentially in ovarian
      cancer development. STUDY DESIGN: Cytokine assay kits were used to determine
      interleukin-6, interleukin-8, and tumor necrotic factor-alpha that were produced
      from Caov-3 and SK-OV3 ovarian cancer cell lines. Thealpha-subunit of Gi was
      detected by pertussis toxin-catalyzed adenosine diphosphate ribosylation from
      nicotinamide adenine dinucleotide in isolated plasma membrane. RESULTS: Pertussis
      toxin, but not cholera toxin, brought about adenosine diphosphate ribosylation of
      Galphai of 41 kd in the plasma membrane. Incubation with lysophosphatidic acid
      and nonhydrolyzable guanosine triphosphate analog decreased the adenosine
      diphosphate-ribosylation activity in a dose-dependent manner; a one half-maximal
      effect occurred with 10 micromol/L lysophosphatidic acid. The apparent inhibition
      by lysophosphatidic acid of the adenosine diphosphate ribosylation demonstrated
      that lysophosphatidic acid resolved the alpha-subunit of the Gi to guanosine
      triphosphate-bound form in the membranes. Pretreatment of the ovarian cancer
      cells with the pertussis toxin completely inhibited lysophosphatidic acid
      stimulated production of interleukin-6, interleukin-8 and tumor necrosis factor
      alpha. The lysophosphatidic acid-stimulated cytokine production was dose
      dependent with a one half-maximal effect at 10 micromol/L. Phosphatidic acid and
      ceramide 1-phosphate had no effect on the lysophosphatidic acid action on
      cytokine expression. CONCLUSION: These data demonstrate the coupling of
      lysophosphatidic acid receptor to Gi protein subfamily in ovarian cancer cell.
      The Gi that couples lysophosphatidic acid receptor to the effector may define the
      differences in the signaling pathways of lysophosphatidic acid-activated cytokine
      expression and proliferation.

PMID- 15042000
TI  - The chemopreventive agents 4-HPR and DFMO inhibit growth and induce apoptosis in
      uterine leiomyomas.
AB  - OBJECTIVE: This study examined the effects of the chemopreventive agents 4-(N
      hydroxyphenyl)retinamide (4-HPR) and alpha-difluoromethylornithine (DFMO) on
      leiomyoma growth. STUDY DESIGN: Primary cultures of human uterine leiomyomas and
      matched normal myometrium were established from hysterectomy specimens. After
      treatment with 4-HPR, DFMO, or the combination 4-HPR plus DFMO, cell growth was
      analyzed. Apoptosis was quantified with the use of a flow cytometric terminal
      deoxynucleotidyl transferase-mediated fluorescein-deoxyuridine-triphosphate nick
      end labeling assay. Protein extracts were analyzed with Western blot for p53,
      p21, and p16. RESULTS: 4-HPR and DFMO inhibited the growth and induced apoptosis
      of leiomyoma cells, but not matched normal myometrial cells. Both 4-HPR and DFMO
      caused cells to accumulate at G0/G1, with a corresponding decrease in the S-phase
      fraction. Both agents also caused the induction of p53, p21, and p16. CONCLUSION:
      The chemopreventive agents 4-HPR and DFMO inhibit leiomyoma cell growth in vitro
      and induce apoptosis, which implies that retinoids and polyamines are important
      regulators of leiomyoma growth.

PMID- 15042001
TI  - Medroxyprogesterone acetate, but not progesterone, protects against inflammation
      induced parturition and intrauterine fetal demise.
AB  - OBJECTIVE: This study was undertaken to determine whether progestational agents
      can prevent inflammation-induced preterm parturition and fetal demise. STUDY
      DESIGN: The activation of contractile and inflammatory pathways in response to
      localized intrauterine inflammation was investigated by using quantitative
      polymerase chain reaction (PCR). Serum progesterone (P4) levels and alterations
      in progesterone receptor-B (PR-B) were determined with radioimmunoassay and
      quantitative PCR, respectively. With our in vivo model of intrauterine
      inflammation, animals were randomly assigned to pretreatment with P4 or
      medroxyprogesterone acetate (MPA) before intrauterine lipopolysaccharide (LPS).
      Animals were observed for preterm delivery. The number of live pups 48 hours
      after intrauterine LPS was recorded for each treatment group. The ability of MPA
      to alter signal transduction pathways leading to preterm parturition were
      investigated by quantitative PCR and histochemical studies. RESULTS: Intrauterine
      inflammation is associated with decreased serum progesterone levels and decreased
      transcription of PR-B. Preterm delivery rates were 100% for LPS alone, 63% for
      LPS+P4, and 0% for LPS+MPA. No live pups remained at 48 hours in the LPS or
      LPS+P4 groups. Pretreatment with MPA significantly preserved fetal viability. MPA
      suppressed activation of contraction-associated genes and inflammatory mediators
      and prevented cervical ripening in response to intrauterine inflammation.
      CONCLUSION: MPA, with its progestational and anti-inflammatory properties,
      prevented inflammation-induced preterm parturition and significantly preserved
      fetal viability.

PMID- 15042002
TI  - Interleukin-4 and -10 gene polymorphisms and spontaneous preterm birth in
      multifetal gestations.
AB  - OBJECTIVE: The purpose of this study was to determine the relationship between
      maternal and fetal carriage of different alleles of interleukin-4 and -10 genes
      and pregnancy outcome in multifetal gestations. STUDY DESIGN: Buccal swabs from
      mother-infant pairs of 73 multifetal gestations were assayed for polymorphisms at
      position -590 of the interleukin-4 gene and position -1082 of the interleukin-10
      gene. Pregnancy outcome data were obtained subsequently. RESULTS: Spontaneous
      preterm birth occurred in 29 of the pregnancies (39.7%). A higher frequency of
      the interleukin-4 T allele was found among mothers with spontaneous preterm birth
      compared with mothers without spontaneous preterm birth (36.2% vs 18.2%; P=.02;
      odds ratio, 2.6; 95% CI, 1.1-5.9). Moreover, 20.7% of mothers who had spontaneous
      preterm birth were homozygous for the interleukin-4 T allele, as opposed to only
      2.3% of mothers who did not have a spontaneous preterm birth (P=.01; odds ratio,
      11.2; 95% CI, 1.2-69.5). Similarly, in 55.2% of the pregnancies that were
      complicated by spontaneous preterm birth, 2 fetuses carried the interleukin-4 T
      allele, compared with only 29.5% of the pregnancies that were not complicated by
      spontaneous preterm birth (p<.05; odds ratio, 2.9; 95% CI, 1.0-8.8). There was no
      relationship between mother and infant IL-10 genotype and spontaneous preterm
      birth. CONCLUSION: Maternal and fetal carriage of the interleukin-4 T allele is
      associated with an increased risk of spontaneous preterm birth in multifetal
      gestations.

PMID- 15042004
TI  - Cerebral infarction in eclampsia.
AB  - OBJECTIVE: This study was undertaken to characterize the neuroimaging findings of
      cerebral edema associated with eclamptic seizures by use of diffusion-weighted
      magnetic resonance imaging (MRI). STUDY DESIGN: During the 3-year period ending
      March 2002, 27 nulliparous women with eclampsia were evaluated with diffusion
      weighted MRI and apparent diffusion coefficient mapping. Those with findings of
      restricted diffusion suggestive of cytotoxic edema underwent neuroimaging again 6
      weeks post partum. RESULTS: All but 2 of these 27 women (93%) had reversible
      vasogenic edema. Six were also found to have areas of cytotoxic edema consistent
      with cerebral infarction. Five of these 6 women had persistent imaging findings
      of infarction when studied post partum, however, without clinical neurologic
      deficits. CONCLUSION: The spectrum of cerebral lesions in eclampsia as seen with
      MRI varies from initially reversible areas of vasogenic edema that may progress
      to cytotoxic edema and infarction in up to a fourth of women.

PMID- 15042003
TI  - Two-stage elevation of cell-free fetal DNA in maternal sera before onset of
      preeclampsia.
AB  - OBJECTIVE: The purpose was to determine whether preeclampsia (PE) is caused by
      microfragments of syncytial trophoblast shed into the maternal circulation that
      stimulate an exaggerated inflammatory response. STUDY DESIGN: A nested case
      control study was performed within the Calcium for Preeclampsia Prevention trial
      cohort of healthy nulliparous women. Each preeclampsia case was matched to 1
      normotensive control. One hundred twenty pairs were randomly chosen for analysis
      of serum cell-free fetal DNA (cffDNA), a marker of placental debris, and C
      reactive protein (CRP), a marker of inflammation, in all 658 specimens obtained
      before labor. RESULTS: At 29 to 41 weeks of gestation, cffDNA concentrations were
      significantly higher after preeclampsia than before (219 vs 112 genome
      equivalents [GE]/mL, P<.001). Before preeclampsia, cffDNA in cases exceeded
      controls at 17 to 28 weeks (36 vs 16 GE/mL, P<.001), but at 29 to 41 weeks, only
      within 3 weeks before preeclampsia (176 vs 75 GE/mL, P<.001). CRP serum
      concentrations were neither associated with cffDNA nor elevated before
      preeclampsia. CONCLUSION: Preeclampsia is accompanied by a 2-stage elevation of
      fetal DNA, but not by elevation of CRP. Elevated cffDNA at 17 to 28 weeks may be
      due to placental necrosis and apoptosis. Subsequent elevations may reflect
      impaired DNA elimination. The 2-stage elevation suggests the possibility of
      measurement of fetal DNA both to screen for preeclampsia and to indicate
      impending clinical disease.

PMID- 15042005
TI  - An outcomes analysis of five prenatal screening strategies for trisomy 21 in
      women younger than 35 years.
AB  - OBJECTIVE: This study was undertaken to examine the cost-effectiveness and
      procedural-related losses associated with 5 prenatal screening strategies for
      fetal aneuploidy in women under 35 years old. STUDY DESIGN: Five prenatal
      screening strategies were compared in a decision analysis model: triple screen:
      maternal age and midtrimester serum alpha-fetoprotein, human chorionic
      gonadotropin (hCG), and unconjugated estriol; quad screen: triple screen plus
      serum dimeric inhibin A; first-trimester screen: maternal age, serum pregnancy
      associated plasma protein A and free beta-hCG and fetal nuchal translucency at 10
      to 14 weeks' gestation; integrated screen: first-trimester screen plus quad
      screen, but first-trimester results are withheld until the quad screen is
      completed when a composite result is provided; sequential screen: first-trimester
      screen plus quad screen, but the first-trimester screen results are provided
      immediately and prenatal diagnosis offered if positive; later prenatal diagnosis
      is available if the quad screen is positive. Model estimates were literature
      derived, and cost estimates also included local sources. The 5 strategies were
      compared for cost, the numbers of Down syndrome fetuses detected and live births
      averted, and the number of procedure-related euploid losses. Sensitivity analyses
      were performed for parameters with imprecise point estimates. RESULTS: In the
      baseline analysis, sequential screening was the least expensive strategy ($455
      million). It detected the most Down syndrome fetuses (n=1213), averted the most
      Down syndrome live births (n=678), but led to the highest number of procedure
      related euploid losses (n=859). The integrated screen had the fewest euploid
      losses (n=62) and averted the second most Down syndrome live births (n=520). If
      fewer than 70% of women diagnosed with fetal Down syndrome elect to abort, the
      quad screen became the least expensive strategy. CONCLUSION: Although sequential
      screening was the most cost-effective prenatal screening strategy for fetal
      trisomy 21, it had the highest procedure-related euploid loss rate. The patient's
      perspective on detection versus fetal safety may help define the optimal
      screening strategy.

PMID- 15042006
TI  - Maternal insulin-like growth factor-I levels (IGF-I) reflect placental mass and
      neonatal fat mass.
AB  - OBJECTIVE: This study was undertaken to test the null hypothesis that serial
      changes in maternal insulin-like growth factor-I (IGF-I) and insulin-like growth
      factor binding-protein-1 (IGFBP-1) levels during pregnancy do not reflect
      differences in either corrected birth weight or placental mass at term. Study
      design Serial blood samples were obtained before pregnancy and at 8, 16, 24, 32,
      and 38 weeks from 56 healthy women enrolled in various exercise training
      regimens. Maternal, placental, and fetal morphometric parameters were monitored
      throughout. Enzyme-linking immunosorbent assays were used to determine IGF-I and
      IGFBP-1 levels. RESULTS: IGF-I and IGFBP-1 levels varied widely among the
      subjects at all time points, but there was a consistent fall in IGF-I levels in
      early pregnancy, followed by a rapid increase between 16 and 36 weeks' gestation,
      whereas IGFBP-1 levels rose in the first 16 weeks and were unchanged thereafter.
      The strongest linear correlations with morphometric outcome were between the
      increase in maternal IGF-I levels from 16 to 32 weeks and corrected birth weight
      (r(2)=0.27), neonatal fat mass (r(2)=0.65), and placental mass at term
      (r(2)=0.50). These were improved when maternal glucose level was included in a
      stepwise regression analysis (r(2)=0.50-0.70). CONCLUSION: There is a robust
      relationship among the rate of increase in individual maternal IGF-I levels after
      16 weeks, placental mass, and neonatal fat mass. This does not imply causality
      but does indicate that midpregnancy changes in IGF-I levels may be a valuable
      marker for anomalous fetal growth.

PMID- 15042008
TI  - Threatened abortion: A risk factor for poor pregnancy outcome, a population-based
      screening study.
AB  - OBJECTIVE: The purpose of this study was to determine whether patients with first
      trimester threatened abortion are at increased risk for poor pregnancy outcome.
      STUDY DESIGN: A large prospective multicenter database was studied. Subjects were
      divided into three groups: (1) no bleeding, (2) light bleeding, and (3) heavy
      bleeding. Univariate and multivariable logistic regression analyses were used.
      RESULTS: The study comprised 16,506 patients: 14,160 patients without bleeding,
      2094 patients with light bleeding, and 252 patients with heavy bleeding. Patients
      with vaginal bleeding, light or heavy, were more likely to experience a
      spontaneous loss before 24 weeks of gestation (odds ratio, 2.5 and 4.2,
      respectively) and cesarean delivery (odds ratio, 1.1 and 1.4, respectively).
      Light bleeding subjects were more likely to have preeclampsia (odds ratio, 1.5),
      preterm delivery (odds ratio, 1.3), and placental abruption (odds ratio, 1.6).
      Heavy vaginal bleeding subjects were more likely to have intrauterine growth
      restriction (odds ratio, 2.6), preterm delivery (odds ratio, 3.0), preterm
      premature rupture of membranes (odds ratio, 3.2), and placental abruption (odds
      ratio, 3.6). CONCLUSION: First-trimester vaginal bleeding is an independent risk
      factor for adverse obstetric outcome that is directly proportional to the amount
      of bleeding.

PMID- 15042009
TI  - Preinduction cervical ripening with the Foley catheter and the risk of subsequent
      preterm birth.
AB  - OBJECTIVE: The Foley catheter is a safe and effective form of preinduction
      cervical ripening and is quickly growing in popularity. Its major effect appears
      to be through mechanical dilation, which has raised the concern that the use of
      the Foley catheter for cervical ripening may damage the cervix and result in a
      higher rate of subsequent preterm birth. STUDY DESIGN: We conducted a review of
      all induction of labor at our institution from July 1998 to July 2001 that
      required preinduction cervical ripening and had a subsequent birth. The primary
      outcome variable was preterm birth at <35 weeks of gestation. Demographic and
      potential confounding variables were analyzed. A probability value of <.05 was
      considered significant. RESULTS: The cases of 126 women (63 women in the Foley
      group and 63 women in the prostaglandin group) were studied. Women in the
      prostaglandin group had a prostaglandin agent used. There was no difference in
      maternal age, gravidity, parity, Bishop score, total time of induction,
      gestational age, oxytocin use, maximum oxytocin level, tobacco or drug use, or
      type of delivery in the index pregnancy between the groups. In the subsequent
      pregnancies, there were no differences in maternal age, gravidity, parity,
      spontaneous abortions, terminations, cone or Loop Electrosurgical Excision
      Procedure (LEEP) procedures, history of cervical manipulation, tobacco or drug
      use, stillbirth, need for induction, mode of delivery, episiotomy, gestational
      age at delivery, Apgar scores, labor duration, use of oxytocin, or birth weight.
      There were no differences in preterm birth at 37, 35, or 32 weeks of gestation
      between the groups. CONCLUSION: The use of the Foley catheter for preinduction
      cervical ripening does not appear to increase the risk of preterm birth in a
      subsequent pregnancy.

PMID- 15042007
TI  - Randomized trial of inhaled beclomethasone dipropionate versus theophylline for
      moderate asthma during pregnancy.
AB  - OBJECTIVE: This study was undertaken to compare the efficacy of inhaled
      beclomethasone dipropionate to oral theophylline for the prevention of asthma
      exacerbation(s) requiring medical intervention. STUDY DESIGN: A prospective,
      double-blind, double placebo-controlled randomized clinical trial of pregnant
      women with moderate asthma was performed. RESULTS: There was no significant
      difference (P=.554) in the proportion of asthma exacerbations among the 194 women
      in the beclomethasone cohort (18.0%) versus the 191 in the theophylline cohort
      (20.4%; risk ratio [RR]=0.9, 95% CI=0.6-1.3). The beclomethasone cohort had
      significantly lower incidences of discontinuing study medications caused by side
      effects (RR=0.3, 95% CI=0.1-0.9; P=.016), and proportion of study visits with
      forced expiratory volume expired in 1 second (FEV1) less than 80% predicted
      (0.284+/-0.331 vs 0.284+/-0.221, P=.039). There were no significant differences
      in treatment failure, compliance, or proportion of peak expiratory flow rate less
      than 80% predicted. There were no significant differences in maternal or
      perinatal outcomes. CONCLUSION: The treatment of moderate asthma with inhaled
      beclomethasone versus oral theophylline resulted in similar rates of asthma
      exacerbations and similar obstetric and perinatal outcomes. These results favor
      the use of inhaled corticosteroids for moderate asthma during pregnancy because
      of the improved FEV1 and because theophylline had more side effects and requires
      serum monitoring.

PMID- 15042011
TI  - Cesarean delivery after successful external cephalic version of breech
      presentation at term: a comparative study.
AB  - OBJECTIVE: The purpose of this study was to evaluate the rate and indications of
      cesarean delivery after a successful external cephalic version. STUDY DESIGN: A
      case-control study was performed from patients who were delivered in a tertiary
      care center between 1987 and 2000. Each patient who underwent a successful
      external cephalic version (study group) was compared with the next woman with the
      same parity, who was delivered at term (control group). Nulliparous and
      multiparous women were analyzed separately. Chi-squared, Mann-Whitney, and
      Student t tests were used for statistical analysis. Multivariate logistic
      regression analysis was performed where appropriate. RESULTS: A total of 602
      patients were included in this study. The rates of cesarean delivery in
      nulliparous women (29.8% vs 15.9%; P<.001) and in multiparous women (15.9% vs
      4.7%; P<.001) were significantly higher when compared with the control group.
      Patients with successful external cephalic version were more likely to have a
      cesarean delivery for dystocia (nulliparous, 22.5% vs 11.9%; P=.01; multiparous,
      10.9% vs 1.3%; P<.01). After an adjustment for confounding variables, a
      successful external cephalic version was associated with an increased rate of
      cesarean delivery at term (nulliparous: odds ratio, 2.04; 95% CI, 1.13-3.68;
      multiparous: odds ratio, 4.30; 95% CI, 1.76-10.54). CONCLUSION: The rate of
      cesarean delivery for dystocia is increased after a successful trial of external
      cephalic version in both nulliparous and multiparous women.

PMID- 15042012
TI  - Is nuchal translucency screening associated with different rates of invasive
      testing in an older obstetric population?
AB  - OBJECTIVE: Our objective was to assess the impact of nuchal translucency
      screening for aneuploidy on chorionic villus sampling and amniocentesis rates in
      an older obstetric population. METHODS: Our study population included women >/=35
      years old who were delivered at our hospital from January 1, 2000 through
      December 31, 2002. Records were reviewed to determine whether women underwent
      nuchal translucency, chorionic villus sampling, and amniocentesis. The chi
      squared test for trend was used to evaluate changes in nuchal translucency,
      chorionic villus sampling, and amniocentesis rates over six 6-month intervals.
      Maternal characteristics were compared with the use of Mann-Whitney U test and
      Fisher's exact test. RESULTS: The 4029 women who met the inclusion criteria had a
      median age at delivery of 37 years (interquartile range, 36-39 years). The rates
      of nuchal translucency screening increased from 0% to 41.6% over the study
      interval. Women who underwent nuchal translucency screening when it was available
      were older than the women who did not (median age, 37 years [interquartile range,
      36-40 years] vs median age, 37 years [interquartile range, 36-39 years]; P=.003).
      A higher proportion of women who were >/=40 years old underwent nuchal
      translucency screening when it was available than did women who were 35 to 39
      years old (24.9% vs 20.4%; P=.01). Women who underwent nuchal translucency
      screening were less likely to have chorionic villus sampling compared with women
      who did not undergo screening (1.9% vs 7.1%; P<.001). Rates of chorionic villus
      sampling declined over time, although amniocentesis rates remained unchanged. The
      overall rate of invasive testing declined. Different trends were noted in women
      who were 35 to 39 years old compared with women who were >/=40 years old.
      CONCLUSION: Higher rates of nuchal translucency screening were associated with
      lower rates of chorionic villus sampling and invasive testing. The addition of
      first-trimester screening may lead to reduced rates of invasive testing and fewer
      losses of normal pregnancies.

PMID- 15042010
TI  - Randomized controlled trial of misoprostol for second-trimester pregnancy
      termination associated with fetal malformation.
AB  - OBJECTIVE: Our purpose was to compare the effectiveness, women's views of the
      termination procedure, and success of umbilical cord culture for vaginal and oral
      misoprostol versus intra-amniotic prostaglandin PGF(2alpha) for second-trimester
      pregnancy termination (STPT). STUDY DESIGN: We randomized 217 women, 15 to 24
      weeks' gestation, into 3 groups. Oral (OM) and vaginal (VM) misoprostol groups
      received 400 microg of misoprostol every 4 hours for 24 hours. The intra-amniotic
      PGF(2alpha) (IAPG) group received 40 mg of PGF(2alpha) followed by oxytocin
      infusion. Women completed self-administered questionnaires 3 weeks after the
      termination procedure. Umbilical cord samples were collected at delivery for
      karyotype analysis. The primary outcome was the time from start of the procedure
      to placental delivery. Secondary outcomes were maternal complications, women's
      acceptance of the termination procedure, and success rates of umbilical cord
      culture. RESULTS: The time was longer for the OM group (30.5+/-14.4 hours)
      compared with the VM group (18.3+/-8.2 hours) and the IAPG group (21.1+/-10.2
      hours), P<.001 for both comparisons. Women in the VM group reported being more
      willing to repeat the termination method in the future and reported fewer side
      effects than those in the other groups, P<.001. Failure rates for umbilical cord
      cultures were 9.6%, 17.0%, and 45.6% for the VM, OM, and IAPG groups,
      respectively. CONCLUSION: Oral misoprostol is less effective than intra-amniotic
      PGF(2alpha) or vaginal misoprostol for STPT. Women report vaginal misoprostol
      more acceptable than other methods. Umbilical cord culture failure rate is
      highest in the IAPG group.

PMID- 15042013
TI  - Is early-pregnancy proteinuria associated with an increased rate of preeclampsia
      in women with pregestational diabetes mellitus?
AB  - OBJECTIVE: The purpose of this study was to determine whether the rate of
      preeclampsia in pregnant diabetic women is increased in those women with early
      pregnancy proteinuria of 190 to 499 mg/24 hours compared with women with
      proteinuria of <190 mg/24 hours. STUDY DESIGN: Secondary analysis was performed
      with relevant data from 194 pregnant women with type 1 and type 2 diabetes
      mellitus whose condition required insulin and who were enrolled previously in a
      multicenter trial of low-dose aspirin for the prevention of preeclampsia. The
      women were assigned to 1 of 3 groups, based on the level of proteinuria at
      enrollment (13-26 weeks of gestation). Group 1 comprised women with <190 mg
      protein/24 hours (n=94); group 2 comprised women with 190 to 499 mg protein/24
      hours (n=35); and group 3 comprised women with >/=500 mg protein/24 hours (n=65).
      The rate of preeclampsia, according to strict predefined criteria, was then
      determined. RESULTS: The rate of preeclampsia was not increased statistically
      significantly in patients with early-pregnancy proteinuria of 190 to 499 mg/24
      hours (7/35 women; 20%) when compared with women with proteinuria of <190 mg/24
      hours (16/94 women; 17%). CONCLUSION: We did not find an increased rate of
      preeclampsia in women with pregestational diabetes mellitus with early-pregnancy
      proteinuria of 190 to 499 mg/24 hours when compared with women with
      pregestational diabetes mellitus with proteinuria of <190 mg/24 hours.

PMID- 15042014
TI  - The Trp64Arg polymorphism of the beta3-adrenergic receptor is not increased in
      women with preeclampsia.
AB  - OBJECTIVE: Insulin resistance is greater and obesity is more common in women with
      preeclampsia. The Trp64Arg polymorphism in the beta(3)-adrenergic receptor is
      associated with these metabolic changes. This study investigated whether the
      Trp64Arg polymorphism is more common in women with preeclampsia. STUDY DESIGN:
      beta(3)-Adrenergic receptor genotypes were determined in 177 women with a history
      of preeclampsia and in 179 normal pregnancies. We also compared prepregnancy body
      mass index (BMI), length of gestation, baby weight percentile, and glucose values
      during an oral tolerance test in women with and without the polymorphism.
      RESULTS: The genotypes and allele frequency did not differ significantly between
      women with preeclamptic and normal pregnancies (P=.17). Women with and without
      the polymorphism had similar prepregnancy BMI, glucose at 1-hour screening,
      gestational age at delivery, and adjusted baby weight. CONCLUSION: The Trp64Arg
      polymorphism of the beta(3)-receptor does not predispose to preeclampsia, and it
      is it not associated with obesity and carbohydrate intolerance in a population of
      young pregnant women.

PMID- 15042015
TI  - The association of parity with mortality outcomes among triplets.
AB  - OBJECTIVE: The purpose of this study was to evaluate the association of parity
      with stillbirth and neonatal and infant death among triplets. STUDY DESIGN: This
      was a retrospective cohort study of 15,930 triplets who were delivered in the
      United States between 1995 and 1997. Infants of nulliparous mothers were compared
      with infants of multiparous mothers. Adjusted relative risks for death by parity
      were computed with the use of the generalized estimating equations framework.
      RESULTS: The likelihood for stillbirth (odds ratio, 3.40; 95% CI, 2.20-5.26) was
      significantly greater among nulliparous mothers. Neonatal (odds ratio, 1.17; 95%
      CI, 0.95-1.43) and infant mortality rates (odds ratio, 1.10; 95% CI, 0.92-1.32)
      were comparable, however. With an increase in parity, there was a consistent
      declining trend in the risk for stillbirth (P<.0001). CONCLUSION: Nulliparity
      more than triples the risk for intrauterine fetal death among triplets. This
      parity-related disparity underscores the need for care providers to be
      particularly concerned about triplet gestations among nulliparous mothers.

PMID- 15042016
TI  - Diet-controlled gestational diabetes mellitus does not influence the success
      rates for vaginal birth after cesarean delivery.
AB  - OBJECTIVE: We sought to determine whether women with diet-controlled gestational
      diabetes mellitus who attempt vaginal birth after cesarean delivery are at
      increased risk of failure, when compared with their non-diabetic counterparts.
      STUDY DESIGN: We identified 13,396 women who attempted vaginal birth after
      cesarean delivery among 25,079 pregnant women with a previous cesarean delivery
      who were delivered between 1995 and 1999 at 16 community and university
      hospitals. Analysis was limited to 9437 women without diabetes mellitus and 423
      women with diet-controlled diabetes mellitus who attempted vaginal birth after
      cesarean delivery with a singleton gestation and 1 previous low-flap cesarean
      delivery. Data that were collected by trained abstractors, included demographics,
      medical history, and both pregnancy and neonatal outcomes. Multivariable logistic
      regression analysis was performed to determine an adjusted odds ratio for vaginal
      birth after cesarean delivery success among women with diet-controlled
      gestational diabetes compared with women with no diabetes mellitus. We controlled
      for birth weight, maternal age, race, tobacco, chronic hypertension, hospital
      settings, labor management, and obstetric history. RESULTS: Forty-nine percent of
      the women with gestational diabetes mellitus and 67% of the women with no
      diabetes mellitus attempted vaginal birth after cesarean delivery. The success
      rate for attempted vaginal birth after cesarean delivery among gestational
      diabetic women was 70%, compared with 74% for non-diabetic women. We found that
      gestational diabetes mellitus is not an independent risk factor for vaginal birth
      after cesarean delivery failure. The relative risk for vaginal birth after
      cesarean delivery success in women with gestational diabetes mellitus compared
      with women without gestational diabetes mellitus was 0.94 (95% CI, 0.87-1.00).
      After an adjustment was made for confounding, the odds ratio for success with
      gestational diabetes mellitus was 0.87 (95% CI, 0.68-1.10). CONCLUSION: Women
      with diet-controlled gestational diabetes mellitus who were carrying singleton
      fetuses who had no more than 1 previous low flap cesarean delivery should be
      counseled that their disease does not decrease their chances for a successful
      vaginal birth after cesarean delivery. Among diet-controlled diabetic women, the
      overall success rate for vaginal birth after cesarean delivery remains
      acceptable, and attempted vaginal birth after cesarean delivery should not be
      discouraged solely on the basis of gestational diabetes mellitus.

PMID- 15042017
TI  - Usefulness of quantitative polymerase chain reaction in amniotic fluid as early
      prognostic marker of fetal infection with Toxoplasma gondii.
AB  - OBJECTIVE: Our purpose was to evaluate Toxoplasma gondii concentration in
      amniotic fluid (AF) samples as a prognostic marker of congenital toxoplasmosis.
      STUDY DESIGN: A retrospective study was carried out in 88 consecutive AF samples
      from 86 pregnant women, which were found positive by prospective polymerase chain
      reaction (PCR) testing. Parasite AF concentrations were estimated by real-time
      quantitative PCR and analyzed in relation to the clinical outcome of infected
      fetuses during pregnancy and at birth, taking into account the gestational age at
      maternal infection. RESULTS: A significant negative linear regression was
      observed between gestational age at maternal infection and T gondii DNA loads in
      AF. After adjusting for time at maternal seroconversion by multivariate analysis,
      higher parasite concentrations were significantly associated with a severe
      outcome of congenital infection (odds ratio [OR]=15.38/log (parasites/mL AF) [95%
      CI=2.45-97.7]). CONCLUSION: PCR quantification of T gondii in AF can be highly
      contributive for early prognosis of congenital toxoplasmosis. Maternal infections
      acquired before 20 weeks with a parasite load greater than 100/mL of AF have the
      highest risk of severe fetal outcome.

PMID- 15042018
TI  - Elective cesarean delivery plus short-course lamivudine and zidovudine for the
      prevention of mother-to-child transmission of human immunodeficiency virus type
      1.
AB  - OBJECTIVE: The purpose of this study was to evaluate the effect of elective
      cesarean delivery plus a lamivudine-zidovudine prophylaxis regimen on non
      breastfeeding mothers with human immunodeficiency virus type 1 and their infants.
      STUDY DESIGN: Forty-six antiretroviral-naive, pregnant women with human
      immunodeficiency virus type 1 were included. The prophylactic regimen was a
      lamivudine-zidovudine tablet (150 mg/300 mg) twice daily from week 34 of
      pregnancy until cesarean delivery at week 38 of gestation, preoperative
      intravenous zidovudine, and neonatal zidovudine syrup for 4 weeks. RESULTS: At
      weeks 34 and 38 of gestation, the median maternal viral loads were, respectively,
      3.65 log(10) copies/mL (range, 2.34-4.70 log(10) copies/mL) and 2.51 log(10)
      copies/mL (range, 2.04-3.66 log(10) copies/mL; P<.001), respectively; the viral
      reduction was 1.12 log(10) copies/mL (range, -0.16-2.60 log(10) copies/mL), and
      the CD4(+) cell counts increased from 335 cells/mm(3) (range, 57-974 cells/mm(3))
      to 420 cells/mm(3) (range, 84-1,083 cells/mm(3); P=.002). No mother or infant had
      a serious adverse event. Two infants were infected (4.3%; 95% CI, 0.5%-15.7%); 1
      infant had intrapartum infection. CONCLUSION: Elective cesarean delivery plus
      short-course lamivudine-zidovudine is safe but does not eliminate mother-to-child
      transmission of human immunodeficiency virus type 1.

PMID- 15042019
TI  - Reciprocal expression of peroxisome proliferator-activated receptor-gamma and
      cyclooxygenase-2 in human term parturition.
AB  - OBJECTIVE: The objective of this study was to test the hypothesis that peroxisome
      proliferator activated receptor-gamma (PPAR-gamma) is expressed in intrauterine
      tissues before active term human parturition, and that its repression is
      associated with up-regulation of cyclooxygenase-2 (COX-2). STUDY DESIGN:
      Specimens were collected from women with term singleton pregnancies after
      spontaneous labor or cesarean section before labor, prepared for immunoblot and
      immunohistochemical analysis, and probed for PPAR-gamma or COX-2. RESULTS: PPAR
      gamma expression was prominent in fetal membranes and placenta before active
      labor. After labor, PPAR-gamma expression was significantly reduced in fetal
      membranes, but not in placenta. The ratio of COX-2:PPAR-gamma was significantly
      elevated in fetal membranes with labor. PPAR-gamma immunostaining was prominent
      in syncytiotrophoblast, extravillous cytotrophoblasts, and cells of the amnion
      and chorion. COX-2 immunostaining was abundant in the amnion and rare in the
      placenta. CONCLUSION: PPAR-gamma is highly expressed in term intrauterine
      tissues. In fetal membranes, PPAR-gamma levels are reduced once active labor
      commences, coincidental with a relative increase in COX-2 expression.

PMID- 15042020
TI  - Evidence of endothelial dysfunction in preeclampsia: decreased endothelial nitric
      oxide synthase expression is associated with increased cell permeability in
      endothelial cells from preeclampsia.
AB  - OBJECTIVE: The purposes of this study were to examine endothelial nitric oxide
      synthase expression in endothelial cells and to determine whether the inhibition
      of endothelial nitric oxide synthase could impair endothelial barrier function in
      preeclampsia. STUDY DESIGN: Messenger RNA and protein expression for endothelial
      nitric oxide synthase were examined in endothelial cells that were isolated from
      normal and preeclamptic pregnancies. Endothelial monolayer permeable response to
      interleukin-8 stimulation was determined. Normal endothelial cells that were
      treated with nitric oxide inhibitor were used to test the association of
      endothelial nitric oxide synthase and endothelial barrier function. Messenger RNA
      expression for endothelial nitric oxide synthase was determined by reverse
      transcription-polymerase chain reaction, and protein expression was determined by
      Western blot analysis. Endothelial permeability was measured by horseradish
      peroxidase leakage through endothelial cell filters. Interleukin-8 production was
      measured by enzyme-linked immunosorbent assay. Data were presented as mean+/-SE
      and analyzed by analysis of variance or nonparametric Mann-Whitney test. RESULTS:
      Relative messenger RNA expression and protein expression for endothelial nitric
      oxide synthase were decreased significantly in endothelial cells from
      preeclampsia compared with cells from normal pregnancies (messenger RNA
      expression, 0.191+/-0.057 vs 0.508+/-0.061 [P <.01]; protein expression, 0.225+/
      0.08 vs 0.786+/-0.098 [P<.01], respectively). Horseradish peroxidase leakage in
      normal endothelial cells was 0.30+/-0.26 micromol/L (interleukin-8, 1 pg/mL),
      3.14+/-2.45 micromol/L (interleukin-8, 5 pg/ml), and 9.08+/-2.69 micromol/L
      (interleukin-8, 25 pg/mL; P<.01; compared with 0.77+/-0.47 micromol/L [control
      endothelial cells]). Horseradish peroxidase leakage in preeclamptic endothelial
      cells was 6.20+/-2.19 micromol/L, 8.44+/-85 micromol/L, and 15.79+/-2.06
      micromol/L (P<.05) compared with 5.23+/-1.28 micromol/L, respectively. The ratio
      of horseradish peroxidase leakage was >7-fold increase in normal endothelial
      cells, but only a 4-fold increase in preeclamptic endothelial cells in response
      to interleukin-8 stimulation at 25 pg/mL. The inhibition of endothelial nitric
      oxide synthase with N(G)-Monomethyl-L-arginine resulted in an increase in
      interleukin-8-induced endothelial cell permeability. No difference for
      interleukin-8 production was observed between normal and preeclamptic endothelial
      cells (1.15+/-0.21 ng/mg protein vs 1.29+/-0.23 ng/mg protein, P>.5). CONCLUSION:
      Increased endothelial permeability may be associated with decreased endothelial
      nitric oxide synthase expression and activity in endothelial cells from
      preeclampsia.

PMID- 15042021
TI  - Effects of dexamethasone on the uterine and umbilical vascular beds during basal
      and hypoxemic conditions in sheep.
AB  - OBJECTIVE: The purpose of the study was to test the hypotheses that maternal
      treatment with dexamethasone leads to a reduction in basal umbilical blood flow
      and diminishes the fetal umbilical hemodynamic response to acute hypoxemic stress
      in sheep. STUDY DESIGN: While under general anesthesia, 23 ewes and their fetuses
      were instrumented with vascular catheters and transonic blood flow probes around
      a uterine and umbilical artery at 117 days of gestation (term, approximately 145
      days). At 124 days, the ewes were injected intramuscularly with 2 doses of either
      dexamethasone (12 mg) or saline solution at 24-hour intervals. All animals
      experienced 2 episodes of hypoxemia during treatment (125+/-1 days) and after
      treatment (128+/-1 days). RESULTS: Maternal dexamethasone treatment caused a
      sustained increase in fetal arterial blood pressure (from 41+/-3 mm Hg to 45+/-3
      mm Hg) and a transient fall in umbilical vascular conductance (from 6.2+/-0.9 mL.
      min(-1). [mm Hg](-1) to 5.4+/-0.7 mL. min(-1). [mm Hg](-1)). During both episodes
      of hypoxemia, there was a significant increase in umbilical blood flow in the
      controls, but not in the dexamethasone-treated animals. CONCLUSION: Maternal
      dexamethasone treatment with doses used in human clinical practice significantly
      decreased basal umbilical vascular conductance and prevented the normal increase
      in umbilical blood flow that is induced by acute hypoxemia in fetal sheep.

PMID- 15042022
TI  - Cardiovascular and endocrine responses to cutaneous electrical stimulation after
      fentanyl in the ovine fetus.
AB  - OBJECTIVE: The purpose of this study was to determine whether physical
      stimulation is stressful to the ovine fetus, as judged from physiologic changes
      that are similar to those reported for other stressors (such as hypoxia); whether
      any stress response could be blocked by clinically used doses of fentanyl; and
      whether fentanyl alone had any potentially deleterious physiologic effects in the
      fetus. STUDY DESIGN: We investigated the effect of fentanyl analgesia on the
      cardiovascular and endocrine response to cutaneous electrical stimulation in the
      late gestation (>125 days) ovine fetus (n=7 fetuses). Chronically implanted
      catheters and blood flow probes were used to measure fetal arterial blood
      pressure, heart rate, carotid and femoral blood flow, pH, Po(2), Pco(2), lactate,
      cortisol, and beta-endorphin levels before, during, and for 1 hour after 5
      minutes of cutaneous electrical stimulation to the lip, forelimb, and abdomen, in
      a crossover design. Clinically used 30 or 150 microg doses of fentanyl (which
      approximated 10 or 50 microg/kg estimated fetal weight) or saline solution were
      given intravenously to the fetus 2 minutes before stimulation. RESULTS: When
      compared with the control, stimulation caused a significant rise in fetal heart
      rate (P=.003; mean maximal rise, 48.6+/-14.0 beats/min, 0-10 minutes after the
      start of stimulation) but caused no change in any other parameters studied.
      Neither dose of fentanyl attenuated the changes in heart rate that were observed
      in response to stimulation alone. Fentanyl alone significantly increased fetal
      heart rate, carotid blood flow, and lactate and cortisol levels and significantly
      decreased pH and Po(2). CONCLUSION: Cutaneous electrical stimulation in the fetal
      sheep causes an increase in heart rate, which fentanyl does not block. Fentanyl
      itself has significant effects on the cardiovascular and endocrine system, which
      might adversely affect the fetus.

PMID- 15042023
TI  - Matrix metalloproteinase-8 is expressed in human chorion during labor.
AB  - OBJECTIVE: The purpose of this study was to investigate the expression of matrix
      metalloproteinase-8 by human fetal membranes during labor. STUDY DESIGN: Fetal
      membranes were obtained from women who underwent normal labor or elective
      cesarean delivery at term. Matrix metalloproteinase-8 levels in fetal membranes
      were determined by enzyme-linked immunosorbent assay and Western blot; the
      expression of the matrix metalloproteinase-8 gene was detected by reverse
      transcription-polymerase chain reaction. Immunohistochemistry and in situ
      hybridization was performed to localize matrix metalloproteinase-8 protein and
      messenger RNA in intact membranes. RESULTS: Matrix metalloproteinase-8 protein
      levels were increased 5-fold in fetal membranes from labor compared with
      membranes that were obtained from cesarean delivery. Western blots confirmed the
      presence of matrix metalloproteinase-8 in protein extracts. Reverse transcription
      polymerase chain reaction, in situ hybridization, and immunohistochemistry
      demonstrated that matrix metalloproteinase-8 messenger RNA and protein were
      expressed almost exclusively in the chorion after labor. CONCLUSION: We conclude
      that matrix metalloproteinase-8 is produced primarily by chorionic cells in human
      fetal membranes and that the level of matrix metalloproteinase-8 protein and
      messenger RNA expression in fetal membranes increases during labor.

PMID- 15042024
TI  - Heavier workload, less personal control: Impact of delivery on
      obstetrician/gynecologists' career satisfaction.
AB  - OBJECTIVE: Obstetrician/gynecologists' career satisfaction with certain work
      related activities was examined among clinicians who perform deliveries and
      clinicians who do not. STUDY DESIGN: A questionnaire was sent to 1500 member
      fellows of the American College of Obstetricians and Gynecologists; 842 members
      (56%) responded. The questionnaire was designed to distinguish between
      obstetrician/gynecologists who perform deliveries and clinicians who do not in
      the areas of satisfaction with specific aspects of career and work-related
      activities. Data were examined initially by multivariate analysis of variance and
      subsequently by univariate analysis of variance if the multivariate test was
      found to be significant. RESULTS: Workload and personal control were the primary
      factors for which there was a significant difference in satisfaction between
      clinicians who perform deliveries and clinicians who do not (P<.001).
      Obstetrician/gynecologists who do not perform deliveries reported working
      significantly fewer hours per week (P<.001) and had more satisfaction with their
      work activities than the delivery group overall. Despite lowered satisfaction
      with certain career aspects among the delivery Group, the highest positive
      disposition ratings that was given by respondents were for surgery, vaginal
      delivery, and planned cesarean delivery, with gender differences observed in the
      level of disposition for these particular activities. The most negative rating
      was reported for on-call/in-hospital time. CONCLUSION: Although positive
      disposition is associated with the activity of vaginal and cesarean delivery
      overall, 2 primary contributing factors of dissatisfaction that were identified
      among obstetrician/gynecologists who perform deliveries were increased workload
      and decreased personal control.

PMID- 15042025
TI  - Diet-induced obesity in the rat: a model for gestational diabetes mellitus.
AB  - OBJECTIVES: Obesity is one of the most important risk factors for the development
      of gestational diabetes mellitus (GDM). However, in obese women, it is difficult
      to disentangle the genetic and environmental contributions. The aim of this study
      was to investigate whether diet-induced obesity results in GDM in rats with the
      same genetic background. STUDY DESIGN: Female Wistar rats were fed a cafeteria
      style diet (CAF) or the standard control (C) diet from 70 days of age onward.
      After 4 weeks on the diets, subgroups of CAF and C rats were mated. In virgin and
      late-pregnant CAF and C rats, we determined body weight, body composition by dual
      energy x-ray absorptiometry (DEXA), glucose tolerance by intravenous glucose
      tolerance test (IVGTT), and insulin sensitivity by hyperinsulinemic euglycemic
      clamp in nonanesthesized rats. Plasma leptin concentrations were also measured.
      RESULTS: Body weight increased after 4 weeks in virgin CAF rats (P<.0001) and
      exceeded that of C rats throughout pregnancy. This resulted exclusively from
      increased fat mass, as determined by DEXA, and was associated with a rise in
      plasma leptin concentrations in nonpregnant and pregnant (both P<.0001) CAF rats.
      During the IVGTT, nonpregnant CAF rats showed normal glucose levels but increased
      insulin levels compared with C rats (P<.05 for the area under the curve for
      insulin: AUC(insulin)). In pregnant CAF animals, glucose tolerance was clearly
      impaired (AUC(glucose): P<.001) with insulin also raised (AUC(insulin): P<.05).
      On day 22, fetal weight was comparable between C and CAF rats, but litter weight
      was higher in CAF rats (P<.05) owing to an increase in litter size.
      Hyperinsulinemic clamp studies revealed unequivocal insulin resistance in
      nonpregnant CAF rats, which was aggravated by pregnancy, the proportional effect
      of obesity being higher than that of pregnancy. CONCLUSION: Diet-induced obesity
      in rats is associated with glucose intolerance during pregnancy but not in the
      nonpregnant state. This is likely to result from the additive effects of obesity
      and pregnancy on insulin sensitivity. This obese rat model is an attractive model
      to study further the physiologic and molecular abnormalities in GDM.

PMID- 15042026
TI  - Cesarean scar pregnancy: quantitative assessment of uterine neovascularization
      with 3-dimensional color power Doppler imaging and successful treatment with
      uterine artery embolization.
AB  - OBJECTIVE: The purpose of this study was to investigate the use of a 3
      dimensional virtual organ computer-aided analysis imaging system for the
      monitoring of the quantification of changes of uterine neovascularization before
      and after successful treatment with uterine artery embolization in cesarean scar
      pregnancy. STUDY DESIGN: A case of cesarean scar pregnancy that was associated
      with extensive uterine neovascularization was diagnosed at 8 weeks of gestation
      with the 3-dimensional virtual organ computer-aided analysis imaging system.
      After appropriate counseling, a bilateral uterine arteries embolization procedure
      was performed with nonresorbable microspheres by interventional radiologists.
      RESULTS: The gestational cystic mass at the site of previous cesarean scar
      completely disappeared at the follow-up examination 3 months later. CONCLUSION: A
      3-dimensional virtual organ computer-aided analysis imaging system can be used
      for the monitoring of the quantification of changes of uterine neovascularization
      before and after successful treatment with uterine artery embolization in
      cesarean scar pregnancy.

PMID- 15042027
TI  - Pipelle biopsy.

PMID- 15042028
TI  - The usefulness of the TDx/TDxFLx fetal lung maturity II assay.

PMID- 15042029
TI  - Pharmaco-dynamic properties of 25 microg 17-beta estradiol.

PMID- 15042032
TI  - Macronutrients.

PMID- 15042046
TI  - White heat--at last.

PMID- 15042047
TI  - NASA seeks robotic rescuers to give Hubble extra lease of life.

PMID- 15042045
TI  - Patent foramen ovale, systemic embolization and closure.
AB  - The recognition, evaluation and treatment of patent foramen ovale has attracted
      increasing interest as the importance and frequency of paradoxical embolism has
      become better understood. The interest in this field has been driven largely by
      the widespread application of echocardiography with identification of a patent
      foramen ovale and/or an atrial septal aneurysm. The evaluation of the role of a
      patent foramen ovale in patients with a neurologic event is complex because the
      patent foramen ovale or atrial septal aneurysm may either be an innocent
      bystander or could be the etiologic mechanisms involved in the paradoxical
      embolus. In patients younger than 55 years, a causal relationship between a
      patent foramen ovale/atrial septal aneurysm and a neurologic ischemic event is
      considerably stronger than in those patients older than 55 years. In patients
      with a presumed diagnosis of paradoxical embolus in the setting of a patent
      foramen ovale, percutaneous closure is now possible and 2 devices are relatively
      widely used. Both of these devices reliably close the defect with a very
      acceptable risk profile and have been found in the longer term to be associated
      with excellent outcome. The exact role, however, that these devices play vis a
      vis continued medical therapy for prevention of recurrent events is being tested
      in 2 randomized clinical trials. The field continues to change with new
      technology being developed and with new applications. A recently exciting finding
      has been the identification that closure of a patent foramen ovale may be
      associated with dramatic improvement in symptoms of patients with disabling
      migraine headaches. Other potential applications of these devices include those
      patients who are deep-sea divers, in whom the potential for "bends" exists, or
      high altitude airplane pilots.

PMID- 15042048
TI  - Link from hygiene to allergies gains support.

PMID- 15042050
TI  - Partners fail to find common ground for fusion project.

PMID- 15042051
TI  - Ice machine sheds light on climate history written in dust.

PMID- 15042049
TI  - Biology hogs the science budget, senator complains.

PMID- 15042052
TI  - US Army backs Swedish cell study.

PMID- 15042053
TI  - Societies take united stand on journal access.

PMID- 15042054
TI  - Japan shakes up council to offer scientists political clout.

PMID- 15042055
TI  - Sellafield seeks solid foundation for cleaner wastewater.

PMID- 15042057
TI  - Rice cultivation: feast or famine?

PMID- 15042058
TI  - Neuroscience: the sweet smell of success.

PMID- 15042060
TI  - Fusion: Bush agrees it's time to end the impasse.

PMID- 15042059
TI  - Fusion: choose Japan for international balance.

PMID- 15042061
TI  - Spain: politicians need to challenge the status quo.

PMID- 15042062
TI  - New law does little to ease research pain in Spain.

PMID- 15042068
TI  - Cell bodies in a cage.

PMID- 15042070
TI  - Crystallization: how come you look so good?

PMID- 15042069
TI  - Human genetics: muscling in on hominid evolution.

PMID- 15042071
TI  - RNA interference: human genes hit the big screen.

PMID- 15042073
TI  - Learning theory: past performance and future results.

PMID- 15042074
TI  - Medicine: profile of a tumour.

PMID- 15042075
TI  - Earth science: putting the squeeze on oxidation.

PMID- 15042076
TI  - Planetary science: Stardust's comet memories.

PMID- 15042077
TI  - Signal processing: neural coding by correlation?

PMID- 15042079
TI  - Equine welfare: risk of horses falling in the Grand National.
AB  - As in other competitive sports, the famous Grand National steeplechase, which is
      held at Aintree in the United Kingdom and is watched by 600 million people
      worldwide, sometimes results in injury. By analysing data from the past 15 Grand
      National races (consisting of 560 starts by horses), we are able to identify
      several factors that are significantly associated with failure to complete the
      race: no previous experience of the course and its unique obstacles, unfavourable
      ground conditions (too soft or too hard), a large number of runners, and the
      length of the odds ('starting price'). We also find that there is an increased
      risk of falling at the first fence and at the jump known as Becher's Brook, which
      has a ditch on the landing side. Our findings indicate ways in which the Grand
      National could be made safer for horses and illustrate how epidemiological
      analysis might contribute to preventing injury in competitive sport.

PMID- 15042080
TI  - Microperiodic structures: direct writing of three-dimensional webs.
AB  - Applications are emerging that require the creation of fine-scale structures in
      three dimensions--examples include scaffolds for tissue engineering, micro
      fluidic devices and photonic materials that control light propagation over a
      range of frequencies. But writing methods such as dip-pen nanolithography and ink
      jet printing are either confined to two dimensions or beset by wetting and
      spreading problems. Here we use concentrated polyelectrolyte inks to write three
      dimensional microperiodic structures directly without using masks. Our technique
      enables us to write arbitrary three-dimensional patterns whose features are
      nearly two orders of magnitude smaller than those attained with other multilayer
      printing techniques.

PMID- 15042082
TI  - Retrograde spins of near-Earth asteroids from the Yarkovsky effect.
AB  - Dynamical resonances in the asteroid belt are the gateway for the production of
      near-Earth asteroids (NEAs). To generate the observed number of NEAs, however,
      requires the injection of many asteroids into those resonant regions. Collisional
      processes have long been claimed as a possible source, but difficulties with that
      idea have led to the suggestion that orbital drift arising from the Yarkovsky
      effect dominates the injection process. (The Yarkovsky effect is a force arising
      from differential heating-the 'afternoon' side of an asteroid is warmer than the
      'morning' side.) The two models predict different rotational properties of NEAs:
      the usual collisional theories are consistent with a nearly isotropic
      distribution of rotation vectors, whereas the 'Yarkovsky model' predicts an
      excess of retrograde rotations. Here we report that the spin vectors of NEAs show
      a strong and statistically significant excess of retrograde rotations,
      quantitatively consistent with the theoretical expectations of the Yarkovsky
      model.

PMID- 15042081
TI  - Odorant receptor gene choice is reset by nuclear transfer from mouse olfactory
      sensory neurons.
AB  - Of the approximately 1,000 odorant receptor (OR) genes in the mouse genome, an
      olfactory sensory neuron (OSN) is thought to express one gene, from one allele.
      This is reminiscent of immunoglobulin and T-cell receptor genes, which undergo
      DNA rearrangements in lymphocytes. Here, we test the hypothesis that OR gene
      choice is controlled by DNA rearrangements in OSNs. Using permanent genetic
      marking, we show that the choice by an OSN to express an allele of the OR gene
      M71 is irreversible. Using M71-expressing OSNs as donors for nuclear transfer, we
      generate blastocysts, embryonic stem (ntES) cell lines and clonal mice. DNA
      analysis of these cell lines, whose genome is clonally derived from an M71
      expressing OSN, does not reveal DNA rearrangements or sequence alterations at the
      M71 locus. OSNs that differentiate from ntES cells after injection into
      blastocysts are not restricted to expression of M71 but can express other OR
      genes. Thus, M71 gene choice is irreversible but is reset upon nuclear transfer,
      and is not accompanied by genomic alterations.

PMID- 15042083
TI  - Strain-induced metal-insulator phase coexistence in perovskite manganites.
AB  - The coexistence of distinct metallic and insulating electronic phases within the
      same sample of a perovskite manganite, such as La(1-x-y)Pr(y)Ca(x)MnO3, presents
      researchers with a tool for tuning the electronic properties in materials. In
      particular, colossal magnetoresistance in these materials--the dramatic reduction
      of resistivity in a magnetic field--is closely related to the observed texture
      owing to nanometre- and micrometre-scale inhomogeneities. Despite accumulated
      data from various high-resolution probes, a theoretical understanding for the
      existence of such inhomogeneities has been lacking. Mechanisms invoked so far,
      usually based on electronic mechanisms and chemical disorder, have been
      inadequate to describe the multiscale, multiphase coexistence within a unified
      picture. Moreover, lattice distortions and long-range strains are known to be
      important in the manganites. Here we show that the texturing can be due to the
      intrinsic complexity of a system with strong coupling between the electronic and
      elastic degrees of freedom. This leads to local energetically favourable
      configurations and provides a natural mechanism for the self-organized
      inhomogeneities over both nanometre and micrometre scales. The framework provides
      a physical understanding of various experimental results and a basis for
      engineering nanoscale patterns of metallic and insulating phases.

PMID- 15042084
TI  - Onset of heterogeneous crystal nucleation in colloidal suspensions.
AB  - The addition of small 'seed' particles to a supersaturated solution can greatly
      increase the rate at which crystals nucleate. This process is understood, at
      least qualitatively, when the seed has the same structure as the crystal that it
      spawns. However, the microscopic mechanism of seeding by a 'foreign' substance is
      not well understood. Here we report numerical simulations of colloidal
      crystallization seeded by foreign objects. We perform Monte Carlo simulations to
      study how smooth spherical seeds of various sizes affect crystallization in a
      suspension of hard colloidal particles. We compute the free-energy barrier
      associated with crystal nucleation. A low barrier implies that nucleation is
      easy. We find that to be effective crystallization promoters, the seed particles
      need to exceed a well-defined minimum size. Just above this size, seed particles
      act as crystallization 'catalysts' as newly formed crystallites detach from the
      seed. In contrast, larger seed particles remain covered by the crystallites that
      they spawn. This phenomenon should be experimentally observable and can have
      important consequences for the control of the resulting crystal size
      distribution.

PMID- 15042085
TI  - Mass and volume contributions to twentieth-century global sea level rise.
AB  - The rate of twentieth-century global sea level rise and its causes are the
      subjects of intense controversy. Most direct estimates from tide gauges give 1.5
      2.0 mm yr(-1), whereas indirect estimates based on the two processes responsible
      for global sea level rise, namely mass and volume change, fall far below this
      range. Estimates of the volume increase due to ocean warming give a rate of about
      0.5 mm yr(-1) (ref. 8) and the rate due to mass increase, primarily from the
      melting of continental ice, is thought to be even smaller. Therefore, either the
      tide gauge estimates are too high, as has been suggested recently, or one (or
      both) of the mass and volume estimates is too low. Here we present an analysis of
      sea level measurements at tide gauges combined with observations of temperature
      and salinity in the Pacific and Atlantic oceans close to the gauges. We find that
      gauge-determined rates of sea level rise, which encompass both mass and volume
      changes, are two to three times higher than the rates due to volume change
      derived from temperature and salinity data. Our analysis supports earlier studies
      that put the twentieth-century rate in the 1.5-2.0 mm yr(-1) range, but more
      importantly it suggests that mass increase plays a larger role than ocean warming
      in twentieth-century global sea level rise.

PMID- 15042086
TI  - Experimental evidence for the existence of iron-rich metal in the Earth's lower
      mantle.
AB  - The oxidation state recorded by rocks from the Earth's upper mantle can be
      calculated from measurements of the distribution of Fe3+ and Fe2+ between the
      constituent minerals. The capacity for minerals to incorporate Fe3+ may also be a
      significant factor controlling the oxidation state of the mantle, and high
      pressure experimental measurements of this property might provide important
      insights into the redox state of the more inaccessible deeper mantle. Here we
      show experimentally that the Fe3+ content of aluminous silicate perovskite, the
      dominant lower-mantle mineral, is independent of oxygen fugacity. High levels of
      Fe3+ are present in perovskite even when it is in chemical equilibrium with
      metallic iron. Silicate perovskite in the lower mantle will, therefore, have an
      Fe3+/total Fe ratio of at least 0.6, resulting in a whole-rock ratio of over ten
      times that of the upper mantle. Consequently, the lower mantle must either be
      enriched in Fe3+ or Fe3+ must form by the disproportionation of Fe2+ to produce
      Fe3+ plus iron metal. We argue that the lower mantle contains approximately 1 wt%
      of a metallic iron-rich alloy. The mantle's oxidation state and siderophile
      element budget have probably been influenced by the presence of this alloy.

PMID- 15042087
TI  - Antibiotic-mediated antagonism leads to a bacterial game of rock-paper-scissors
      in vivo.
AB  - Colicins are narrow-spectrum antibiotics produced by and active against
      Escherichia coli and its close relatives. Colicin-producing strains cannot
      coexist with sensitive or resistant strains in a well-mixed culture, yet all
      three phenotypes are recovered in natural populations. Recent in vitro results
      conclude that strain diversity can be promoted by colicin production in a
      spatially structured, non-transitive interaction, as in the classic non
      transitive model rock-paper-scissors (RPS). In the colicin version of the RPS
      model, strains that produce colicins (C) kill sensitive (S) strains, which
      outcompete resistant (R) strains, which outcompete C strains. Pairwise in vitro
      competitions between these three strains are resolved in a predictable order (C
      beats S, S beats R, and R beats C), but the complete system of three strains
      presents the opportunity for dynamic equilibrium. Here we provide conclusive
      evidence of an in vivo antagonistic role for colicins and show that colicins (and
      potentially other bacteriocins) may promote, rather than eliminate, microbial
      diversity in the environment.

PMID- 15042088
TI  - Myosin gene mutation correlates with anatomical changes in the human lineage.
AB  - Powerful masticatory muscles are found in most primates, including chimpanzees
      and gorillas, and were part of a prominent adaptation of Australopithecus and
      Paranthropus, extinct genera of the family Hominidae. In contrast, masticatory
      muscles are considerably smaller in both modern and fossil members of Homo. The
      evolving hominid masticatory apparatus--traceable to a Late Miocene, chimpanzee
      like morphology--shifted towards a pattern of gracilization nearly simultaneously
      with accelerated encephalization in early Homo. Here, we show that the gene
      encoding the predominant myosin heavy chain (MYH) expressed in these muscles was
      inactivated by a frameshifting mutation after the lineages leading to humans and
      chimpanzees diverged. Loss of this protein isoform is associated with marked size
      reductions in individual muscle fibres and entire masticatory muscles. Using the
      coding sequence for the myosin rod domains as a molecular clock, we estimate that
      this mutation appeared approximately 2.4 million years ago, predating the
      appearance of modern human body size and emigration of Homo from Africa. This
      represents the first proteomic distinction between humans and chimpanzees that
      can be correlated with a traceable anatomic imprint in the fossil record.

PMID- 15042089
TI  - General conditions for predictivity in learning theory.
AB  - Developing theoretical foundations for learning is a key step towards
      understanding intelligence. 'Learning from examples' is a paradigm in which
      systems (natural or artificial) learn a functional relationship from a training
      set of examples. Within this paradigm, a learning algorithm is a map from the
      space of training sets to the hypothesis space of possible functional solutions.
      A central question for the theory is to determine conditions under which a
      learning algorithm will generalize from its finite training set to novel
      examples. A milestone in learning theory was a characterization of conditions on
      the hypothesis space that ensure generalization for the natural class of
      empirical risk minimization (ERM) learning algorithms that are based on
      minimizing the error on the training set. Here we provide conditions for
      generalization in terms of a precise stability property of the learning process:
      when the training set is perturbed by deleting one example, the learned
      hypothesis does not change much. This stability property stipulates conditions on
      the learning map rather than on the hypothesis space, subsumes the classical
      theory for ERM algorithms, and is applicable to more general algorithms. The
      surprising connection between stability and predictivity has implications for the
      foundations of learning theory and for the design of novel algorithms, and
      provides insights into problems as diverse as language learning and inverse
      problems in physics and engineering.

PMID- 15042090
TI  - Imaging cortical correlates of illusion in early visual cortex.
AB  - Exploring visual illusions reveals fundamental principles of cortical processing.
      Illusory motion perception of non-moving stimuli was described almost a century
      ago by Gestalt psychologists. However, the underlying neuronal mechanisms remain
      unknown. To explore cortical mechanisms underlying the 'line-motion' illusion, we
      used real-time optical imaging, which is highly sensitive to subthreshold
      activity. We examined, in the visual cortex of the anaesthetized cat, responses
      to five stimuli: a stationary small square and a long bar; a moving square; a
      drawn-out bar; and the well-known line-motion illusion, a stationary square
      briefly preceding a long stationary bar presentation. Whereas flashing the bar
      alone evoked the expected localized, short latency and high amplitude activity
      patterns, presenting a square 60-100 ms before a bar induced the dynamic activity
      patterns resembling that of fast movement. The preceding square, even though
      physically non-moving, created gradually propagating subthreshold cortical
      activity that must contribute to illusory motion, because it was
      indistinguishable from cortical representations of real motion in this area.
      These findings demonstrate the effect of spatio-temporal patterns of subthreshold
      synaptic potentials on cortical processing and the shaping of perception.

PMID- 15042091
TI  - A resource for large-scale RNA-interference-based screens in mammals.
AB  - Gene silencing by RNA interference (RNAi) in mammalian cells using small
      interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) has become a valuable
      genetic tool. Here, we report the construction and application of a shRNA
      expression library targeting 9,610 human and 5,563 mouse genes. This library is
      presently composed of about 28,000 sequence-verified shRNA expression cassettes
      contained within multi-functional vectors, which permit shRNA cassettes to be
      packaged in retroviruses, tracked in mixed cell populations by means of DNA 'bar
      codes', and shuttled to customized vectors by bacterial mating. In order to
      validate the library, we used a genetic screen designed to report defects in
      human proteasome function. Our results suggest that our large-scale RNAi library
      can be used in specific, genetic applications in mammals, and will become a
      valuable resource for gene analysis and discovery.

PMID- 15042092
TI  - A large-scale RNAi screen in human cells identifies new components of the p53
      pathway.
AB  - RNA interference (RNAi) is a powerful new tool with which to perform loss-of
      function genetic screens in lower organisms and can greatly facilitate the
      identification of components of cellular signalling pathways. In mammalian cells,
      such screens have been hampered by a lack of suitable tools that can be used on a
      large scale. We and others have recently developed expression vectors to direct
      the synthesis of short hairpin RNAs (shRNAs) that act as short interfering RNA
      (siRNA)-like molecules to stably suppress gene expression. Here we report the
      construction of a set of retroviral vectors encoding 23,742 distinct shRNAs,
      which target 7,914 different human genes for suppression. We use this RNAi
      library in human cells to identify one known and five new modulators of p53
      dependent proliferation arrest. Suppression of these genes confers resistance to
      both p53-dependent and p19ARF-dependent proliferation arrest, and abolishes a DNA
      damage-induced G1 cell-cycle arrest. Furthermore, we describe siRNA bar-code
      screens to rapidly identify individual siRNA vectors associated with a specific
      phenotype. These new tools will greatly facilitate large-scale loss-of-function
      genetic screens in mammalian cells.

PMID- 15042093
TI  - Functional interactions between receptors in bacterial chemotaxis.
AB  - Bacterial chemotaxis is a model system for signal transduction, noted for its
      relative simplicity, high sensitivity, wide dynamic range and robustness. Changes
      in ligand concentrations are sensed by a protein assembly consisting of
      transmembrane receptors, a coupling protein (CheW) and a histidine kinase (CheA).
      In Escherichia coli, these components are organized at the cell poles in tight
      clusters that contain several thousand copies of each protein. Here we studied
      the effects of variation in the composition of clusters on the activity of the
      kinase and its sensitivity to attractant stimuli, monitoring responses in vivo
      using fluorescence resonance energy transfer. Our results indicate that
      assemblies of bacterial chemoreceptors work in a highly cooperative manner,
      mimicking the behaviour of allosteric proteins. Conditions that favour steep
      responses to attractants in mutants with homogeneous receptor populations also
      enhance the sensitivity of the response in wild-type cells. This is consistent
      with a number of models that assume long-range cooperative interactions between
      receptors as a general mechanism for signal integration and amplification.

PMID- 15042094
TI  - Enzymic activation and transfer of fatty acids as acyl-adenylates in
      mycobacteria.
AB  - The metabolic repertoire in nature is augmented by generating hybrid metabolites
      from a limited set of gene products. In mycobacteria, several unique complex
      lipids are produced by the combined action of fatty acid synthases and polyketide
      synthases (PKSs), although it is not clear how the covalently sequestered
      biosynthetic intermediates are transferred from one enzymatic complex to another.
      Here we show that some of the 36 annotated fadD genes, located adjacent to the
      PKS genes in the Mycobacterium tuberculosis genome, constitute a new class of
      long-chain fatty acyl-AMP ligases (FAALs). These proteins activate long-chain
      fatty acids as acyl-adenylates, which are then transferred to the multifunctional
      PKSs for further chain extension. This mode of activation and transfer of fatty
      acids is contrary to the previously described universal mechanism involving the
      formation of acyl-coenzyme A thioesters. Similar mechanisms may operate in the
      biosynthesis of other lipid-containing metabolites and could have implications in
      engineering novel hybrid products.

PMID- 15042097
TI  - The fame game.

PMID- 15042098
TI  - Renaissance in Spain.

PMID- 15042100
TI  - Recruiters and industry.

PMID- 15042104
TI  - Persistent reduction in brain serotonin1A receptor binding in recovered depressed
      men measured by positron emission tomography with [11C]WAY-100635.
AB  - Positron emission tomography (PET) studies with the selective 5-HT(1A) receptor
      ligand, [(11)C]WAY-100635, have indicated that the binding potential (BP) of
      brain 5-HT(1A) receptors is lowered in unmedicated subjects with acute major
      depression. However, it is unclear if these changes persist after recovery from
      depression. To resolve this issue, we used [(11)C]WAY-100635 in conjunction with
      PET imaging to compare 5-HT(1A) BP in 18 healthy controls and 14 male subjects
      with recurrent major depression who were clinically recovered and free of
      antidepressant medication. BP values, derived from a reference tissue model, were
      analysed by region of interest and statistical parametric mapping. Both analyses
      showed a widespread and substantial (17%) decrease in 5-HT(1A) receptor BP in
      cortical areas in the recovered depressed subjects. In contrast, 5-HT(1A) BP in
      the raphe nuclei did not distinguish depressed subjects from controls. Our
      results suggest a persistent dysfunction in cortical 5-HT(1A) BP as measured by
      [(11)C]WAY-100635 in recovered depressed men. Lowered 5-HT(1A) receptor binding
      availability could represent a trait abnormality that confers vulnerability to
      recurrent major depression.

PMID- 15042106
TI  - The dose of infused lymphocytes in the autograft directly correlates with
      clinical outcome after autologous peripheral blood hematopoietic stem cell
      transplantation in multiple myeloma.
AB  - Absolute lymphocyte count at day 15 (ALC-15) after autologous peripheral blood
      hematopoietic stem cell transplantation (APHSCT) is an independent prognostic
      factor for survival in multiple myeloma (MM); however, factors affecting ALC-15
      in MM remain unknown. We hypothesized that the dose of infused peripheral blood
      autograft lymphocytes (autograft absolute lymphocyte count: A-ALC) impacts ALC-15
      recovery. Between 1989 and 2001, 267 consecutive MM patients underwent APHSCT. We
      set out to determine the correlation between A-ALC and ALC-15 and the utility of
      A-ALC as a marker for ALC-15 recovery. A-ALC was found to be both a strong
      predictor for area under curve (AUC=0.93; P=0.0001) and strongly correlated with
      (r(s)=0.83; P=0.0001) ALC-15 recovery. Higher infused A-ALC was significantly
      correlated with an ALC-15>/=500/microl. In addition, median post-transplant
      overall survival (OS) and time to progression (TTP) were longer in patients who
      received an A-ALC>/=0.5 x 10(9) lymphocytes/kg versus A-ALC <0.5 x 10(9)
      lymphocytes/kg (58 vs 30 months, P=0.00022; 22 vs 15 months, P<0.00012,
      respectively). Multivariate analysis demonstrated A-ALC as an independent
      prognostic indicator for OS and TTP. These results indicate that an infused dose
      of autograft lymphocytes significantly impacts clinical outcome post-APHSCT in
      MM.

PMID- 15042107
TI  - Graft-versus-leukemia effect in acute lymphoblastic leukemia: the importance of
      tumor burden and early detection.

PMID- 15042105
TI  - Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic
      leukemia.
AB  - Chromosome aberrations are frequently observed in precursor-B-acute lymphoblastic
      leukemias (ALL) and T-cell acute lymphoblastic leukemias (T-ALL). These
      translocations can form leukemia-specific chimeric fusion proteins or they can
      deregulate expression of an (onco)gene, resulting in aberrant expression or
      overexpression. Detection of chromosome aberrations is an important tool for risk
      classification. We developed rapid and sensitive split-signal fluorescent in situ
      hybridization (FISH) assays for six of the most frequent chromosome aberrations
      in precursor-B-ALL and T-ALL. The split-signal FISH approach uses two
      differentially labeled probes, located in one gene at opposite sites of the
      breakpoint region. Probe sets were developed for the genes TCF3 (E2A) at 19p13,
      MLL at 11q23, ETV6 at 12p13, BCR at 22q11, SIL-TAL1 at 1q32 and TLX3 (HOX11L2) at
      5q35. In normal karyotypes, two colocalized green/red signals are visible, but a
      translocation results in a split of one of the colocalized signals. Split-signal
      FISH has three main advantages over the classical fusion-signal FISH approach,
      which uses two labeled probes located in two genes. First, the detection of a
      chromosome aberration is independent of the involved partner gene. Second, split
      signal FISH allows the identification of the partner gene or chromosome region if
      metaphase spreads are present, and finally it reduces false-positivity.

PMID- 15042108
TI  - Survival of the very-low-birth-weight infants after cardiopulmonary resuscitation
      in neonatal intensive care unit.
AB  - OBJECTIVE: To assess whether advances in neonatal care in the last decade have
      altered the outcome of very-low-birth-weight (VLBW) infants after cardiopulmonary
      resuscitation (CPR) in the neonatal intensive care unit (NICU). STUDY DESIGN:
      Medical records of all VLBW infants (n=283, body weight (BW)=1066+/-281 g,
      gestational age (GA)=28.3+/-2.9 weeks) admitted to the NICU between 1999 and 2002
      were reviewed. RESULTS: In all, 29 (10.25%) infants received CPR in the NICU.
      Only one of these infants survived. After adjusting for GA, the clinical
      variables significantly associated with the need for CPR in the NICU were
      (adjusted odds ratio; 95% CI): pulmonary hemorrhage (7.89; 3.06 to 20.28),
      pulmonary air leak syndrome (23.90; 7.58 to 75.4), and delivery by Cesarian
      section (0.26; 0.1 to 0.66). The results were similar when the data were
      reanalyzed matching the 28 infants in the CPR group with 28 infants of identical
      GA in the non-CPR group. CONCLUSIONS: Survival rate for the infants who require
      CPR in the NICU remains extremely poor. This poor outcome needs to be discussed
      with parents and the option of the "do not resuscitate" (DNR) order may be
      appropriate for these infants, especially for those infants with multiple organ
      failure unresponsive to therapy.

PMID- 15042109
TI  - The Egypt National Perinatal/Neonatal Mortality Study 2000.
AB  - OBJECTIVES: To estimate stillbirth, perinatal (PMR) and neonatal mortality rates
      (NMR) in Egypt and to assign main causes of death. STUDY DESIGN: Data were
      collected from a representative sample of women who gave birth from 17,521
      households which were included in the Egypt Demographic and Health Survey (EDHS)
      2000. Comparisons were made between three systems for classifying causes of
      death. RESULTS: The NMR was 25 per 1000 live births (17 early and eight late).
      Half the deaths occurred in the first two days of life. Neonatal causes of death
      were pre-maturity (39%), asphyxia (18%), infections (7%), congenital malformation
      (6%) and unclassified (29%). The PMR was 34 per 1000 births, mainly attributed
      to: asphyxia (44%) and prematurity (21%). The revised Wigglesworth classification
      agreed well with the physicians except the panel attributed more deaths to
      infections (20%). The WHO verbal autopsy algorithm left 48% of deaths
      unclassified. CONCLUSIONS: Infant mortality in Egypt is showing an
      epidemiological transition with a significant decrease in mortality, resulting in
      a disproportionate percentage of deaths in the first week of life. Infant
      mortality in Egypt declined 64% from 124 per 1000 between 1974 and 1978 to 44 per
      1000 between 1995 and 1999, the decline being greatest among older infants; 55%
      of all infant deaths occurred during the neonatal period. The neonatal mortality
      rate in this study was estimated to be 25 per 1000 live births.

PMID- 15042110
TI  - Initial dosing of inhaled nitric oxide in infants with hypoxic respiratory
      failure.
AB  - BACKGROUND: Inhaled nitric oxide (iNO) is a potent and selective pulmonary
      vasodilator that decreases pulmonary resistance, and improves ventilation
      perfusion matching, thereby improving oxygenation and reducing the need for more
      invasive therapies. Despite the efficacy of iNO at reducing the use of
      extracorporeal membrane oxygenation, significant concern remains over the
      potential toxicity from oxidative derivatives and methemoglobinemia. At present,
      there is no universal agreement on the lowest effective starting dose. Reported
      initial doses in the neonatal literature have ranged from 1 to 80 ppm. PURPOSE:
      To determine if the initial dose of iNO altered the incidence of adverse outcome.
      METHODS: A cohort of neonates who received iNO for treatment of hypoxic
      respiratory failure and were entered into the Duke Neonatal Nitric Oxide Registry
      were evaluated. Neonates with congenital anomalies were excluded. This registry
      collects data from 36 centers that voluntarily report their experiences with iNO.
      From this database, the starting dose was recorded and the clinical course was
      followed. Adverse outcomes were prospectively defined and monitored in the
      database and included: methemoglobinemia, chronic lung disease, treatment with
      extracorporeal membrane oxygenation, or death. RESULTS: Data on 476 patients were
      analyzed. Based on starting doses, records were sorted into three groups: a low
      dose group (LDG; <18 ppm, n=57), a mid-dose group (MDG; 18 to 22 ppm, n=320), and
      a high-dose group (HDG; >22 ppm, n=99). ANOVA showed no statistically significant
      differences among the groups except for PaO(2)/FiO(2) (p<0.05). Neonates in the
      high starting dose group were more often classified as treatment failures (21% in
      the LDG, 27% in the MDG, and 38% in the HDG, p=0.04) and treated with
      extracorporeal membrane oxygenation (19% in the LDG, 23% in the MDG, and 34% in
      the HDG, p=0.05) compared to the lower dose groups. In addition, survival without
      the need for oxygen at 30 days or at discharge was higher in the lower dose
      groups (93% in the LDG, 84% in the MDG, and 76% in the HDG, p=0.03). Logistic
      regression, however, showed that the starting dose of iNO did not significantly
      influence these outcomes when corrected for the degree of hypoxemia
      (PaO(2)/FiO(2)) at the start of therapy (p>0.1). High initial doses of iNO (>22
      ppm) were associated with higher levels of methemoglobin (p< 0.05). There were no
      differences in mortality or length of hospital stay between the groups.
      CONCLUSIONS: There is significant variation in the starting dose of iNO between
      centers. Our retrospective study shows no evidence that higher doses improve
      outcome. A low concentration of iNO (<18 ppm) should be considered to minimize
      the potential toxicity of methemoglobin. Furthermore, a well-designed,
      prospective trial should be undertaken to further define the optimal starting
      dose.

PMID- 15042111
TI  - Low blood pressure among very-low-birth-weight infants with fetal vessel
      inflammation.
AB  - OBJECTIVE: To test the hypothesis that fetal vessel inflammation (FVI: funisitis
      and/or fetal vasculitis) is associated with lower blood pressure (BP) over the
      first week of life and an increased risk of periventricular leukomalacia (PVL)
      among premature infants. STUDY DESIGN: A total of 255 infants born at <1350 g to
      normotensive mothers were stratified by gestational age (GA) and grouped by
      presence/absence of FVI on placental pathology. Daily highest (Hi) and lowest
      (Lo) systolic BP (BP(sys)), mean BP (BP(mn)) and diastolic BP (BP(dia)) over
      first 7 days of life were analyzed by repeated measures ANOVA and regression
      analysis. Cranial ultrasounds were obtained at 2 weeks of life. RESULTS: Infants
      > or =30 weeks gestation with FVI had lower HiBP(sys), HiBP(mn), HiBP(dia),
      LoBP(sys), LoBP(mn) and LoBP(dia) (p<0.001) than did infants without FVI. Infants
      with PVL (all < or =27 weeks gestation) had lower LoBP(mn) and LoBP(dia) (p<0.01)
      than controls. FVI did not increase the risk of PVL in these infants. CONCLUSION:
      FVI and PVL are associated with reduced BP over the first week of life.

PMID- 15042112
TI  - End-tidal breath carbon monoxide measurements are lower in pregnant women with
      uterine contractions.
AB  - OBJECTIVE: To compare the levels of end-tidal carbon monoxide (ETCOc) among women
      with and without uterine contractions in term and preterm pregnancies. STUDY
      DESIGN: In all, 55 nonsmoking healthy pregnant women were enrolled. ETCOc levels
      were compared among women with contractions (10 preterm and 13 term) and 32 women
      without contractions (34-41 weeks gestation). RESULTS: Maternal age, gravidity
      and parity were similar among study and control groups. ETCOc levels were
      significantly lower among women that had uterine contractions (0.99+/-0.38 parts
      per million (ppm) and 1.15+/-0.34 p.p.m. respectively), compared to women with no
      contractions (1.70+/-0.52 p.p.m., P<0.002). However, there was no significant
      difference in the ETCOc levels between women with preterm or term contractions
      (P=0.48). CONCLUSIONS: Low levels of ETCOc are associated with preterm and term
      uterine contractions.

PMID- 15042113
TI  - GNB3 gene C825T and ACE gene I/D polymorphisms in essential hypertension in a
      Kazakh genetic isolate.
AB  - The Kazakh inhabitants living in Barkol pasture of northeast China belong to a
      genetic isolate characterized by ethnically homogeneous and a communal pastoral
      lifestyle. To investigate whether the polymorphisms in the G-protein beta-3
      subunit (GNB3) gene and angiotensin-converting enzyme (ACE) gene are associated
      with essential hypertension (EH), we carried out a case-control study of 290
      hypertensive subjects and 244 normotensive (NT) controls randomly selected from
      Kazakh populations of Barkol. A previous medical history of diabetes and
      hypertension, and body mass index (BMI) was recorded. Plasma glucose,
      triglyceride, and cholesterol were measured. The insertion/deletion (I/D)
      polymorphism of the ACE gene and the C825T polymorphism of the GNB3 gene were
      determined by the polymerase chain reaction (PCR) technique. The distributions of
      genotypes and alleles for the two polymorphisms did not differ significantly
      between the case and control populations, and odds ratio of EH related to the ACE
      gene D allele and GNB3 gene T allele was not significantly different from 1.0.
      Logistic regression analysis shows the variation at the GNB3 and ACE did not have
      any statistically significant synergistic effect on blood pressure (BP).
      Stratification of NT and untreated hypertensives according to I/D polymorphism of
      ACE gene and C825T polymorphism of GNB3 gene disclosed no significant difference
      across genotypes with respect to BMI, glucose, triglyceride, cholesterol,
      systolic and diastolic BP. In conclusion, the polymorphisms in the GNB3 gene and
      ACE gene, solely or combined, did not confer a significantly increased risk for
      the development of EH in the Kazakh isolate of northeast China.

PMID- 15042115
TI  - Ascending aortic blood pressure waveform may be related to the risk of coronary
      artery disease in women, but not in men.
AB  - Recent studies have demonstrated that fractional pulse pressure and fractional
      diastolic pressure are related to the risk of coronary artery disease. However,
      the effect of the ascending aortic pressure waveform on the risk of coronary
      artery disease in men and women analyzed separately has not been reported. The
      objective of the study was to assess the relation between ascending aortic blood
      pressure waveform and the presence of coronary artery disease in men and in
      women. The study group consisted of 447 patients (302 men and 145 women; mean
      age: 57.6+/-9.8 years) with preserved left ventricular function who were
      undergoing first diagnostic coronary angiography. After multivariate stepwise
      adjustments, the odds ratio (OR) and confidence interval (CI) of having coronary
      artery disease in women was (OR are reported for standard deviation increase in
      each variable): pulse pressure OR 1.61 (95% CI 1.06-2.46); fractional systolic
      pressure OR 1.72 (95% CI 1.08-2.71); fractional diastolic pressure OR 0.58 (95%
      CI 0.37-0.92); fractional pulse pressure OR 1.72 (95% CI 1.08-2.71); and
      pulsatility index OR 1.74 (95% CI 1.09-2.78). None of the studied variables was
      independently related to the presence of coronary artery disease in men. In
      conclusion, fractional systolic and diastolic pressure, pulse pressure,
      fractional pulse pressure and the ratio of pulse pressure to diastolic pressure
      may be independently related to the risk of coronary artery disease in women, but
      not in men.

PMID- 15042114
TI  - Once-daily eprosartan mesylate in the treatment of elderly patients with isolated
      systolic hypertension: data from a 13-week double-blind, placebo-controlled,
      parallel, multicenter study.
AB  - This was a double-blind, randomized, placebo-controlled multicenter, titration-to
      effect study of eprosartan in patients > or =60 years of age with isolated
      systolic hypertension. The study consisted of a 3 to 5-week placebo run-in
      period, a 13-week double-blind treatment period (6-week titration with eprosartan
      600-1200 mg/day, 3-week maintenance, 4-week combination therapy with
      hydrochlorothiazide/HCTZ 12.5 mg), and a follow-up period within 5-7 days of last
      treatment dose. Overall, 283 patients (placebo/P: 135; eprosartan /E: 148) were
      randomized [female patients-P: 55.6%, E:54.7%; white-P:66.7%, E:67.6%). Mean
      sitting systolic blood pressure (SitSBP) at baseline was comparable (P: 170+/-0.8
      mmHg; E: 171+/-0.8 mm Hg). At monotherapy end point, eprosartan produced a
      significant reduction in SitSBP (E: 16.1 mmHg vs P: 8.4 mmHg; P<0.0001). In all,
      57.4% of patients responded to eprosartan monotherapy. Among nonresponders, the
      addition of HCTZ resulted in a decrease in SitSBP from baseline (E: 21.7 mmHg; P:
      14.4 mmHg; P<0.002). Reductions were also noted in Standing SBP (monotherapy:
      P<0.001; combination therapy: P=0.03). No reductions in SitDBP >4 mmHg were found
      during the study. Age, gender, and race did not have any impact on the results.
      Post hoc analysis showed a reduction in pulse pressure from 87.3 to 78.2 mmHg
      with placebo and from 87.6 to 70.7 mmHg with eprosartan monotherapy. Treatment
      with eprosartan in once-daily doses up to 1200 mg alone or in combination with
      HCTZ was well tolerated, with dizziness and asthenia being the most common side
      effects.

PMID- 15042116
TI  - Sex-related difference in regression of left ventricular hypertrophy with
      antihypertensive treatment: the LIFE study.
AB  - While left ventricular (LV) structure and function differ between hypertensive
      women and men, it remains unclear whether sex affects regression of LV
      hypertrophy with antihypertensive treatment. We analysed paired echocardiograms
      in 500 men and 347 women enrolled in the Losartan Intervention For Endpoint
      reduction in hypertension (LIFE) study at baseline and after 12 months of
      antihypertensive treatment with either losartan or atenolol. At enrollment, 177
      women and 242 men were randomized to losartan-based treatment and 161 women and
      247 men were randomized to atenolol-based treatment (sex difference=NS). After 12
      months of antihypertensive treatment, blood pressure was lowered similarly in
      women (152/83 from 174/97 mmHg) and men (149/85 from 173/99 mmHg; both P<0.001,
      sex difference=NS), without significant change in body weight in either sex.
      Cardiac output and pulse pressure/stroke volume were equivalently reduced in both
      sexes (-0.2 vs -0.1 l/min and both -0.20 mmHg/ml/m(2), respectively; both P=NS).
      Absolute LV mass change after 12 months of antihypertensive treatment was greater
      in men than in women (-30 vs -24 g, P=0.01). However, after adjusting for
      baseline LV mass and randomized study treatment, LV mass reduction was greater in
      women than in men (-33 vs -23 g, P=0.001). LV mass regression was greater in
      women, by 8.0+/-2.8 g, after adjusting for baseline LV mass and randomized study
      treatment. After consideration of baseline LV mass and randomized study
      treatment, antihypertensive treatment regressed LV hypertrophy more in women.
      Further studies are needed to identify the mechanisms and prognostic implications
      of this sex-related difference.

PMID- 15042117
TI  - Impact of valvular regurgitation on left ventricular geometry and function in
      hypertensive patients with left ventricular hypertrophy: the LIFE study.
AB  - Mild-to-moderate aortic and mitral regurgitation are frequently detected by
      echocardiogram in asymptomatic hypertensive patients. Our goal was to assess the
      prevalence and impact of mild-to-moderate mitral and/or aortic regurgitation on
      left ventricular (LV) structure and function in patients with hypertension and LV
      hypertrophy (LVH). Hypertensive patients with ECG LVH enrolled in the Losartan
      Intervention For Endpoint reduction in hypertension (LIFE) echocardiography
      substudy were evaluated. Among 939 patients with needed LV measurements and
      Doppler data, 242 had mild (1+) valvular regurgitation, and 51 patients had
      moderate (2+ or 3+) regurgitation of one or both valves. In analyses adjusting
      for gender, patients with mild mitral and/or aortic regurgitation had larger LV
      internal dimensions (5.25 vs 5.33 cm, P<0.05), higher LV mass indexed for body
      surface area (122 vs 125 g/m(2), P<0.05) or height(2.7) (55.4 vs 57.3, P<0.05),
      and larger left atrial diameter. Patients with moderate regurgitation of one or
      both valves had larger LV chambers (5.25 vs 5.9 cm, P<0.001), greater mean LV
      mass (232 vs 248 g, P<0.001) and LV mass indexed for body surface area or
      height(2.7), and higher Doppler stroke volume. Patients with moderate valvular
      regurgitation also had a higher prevalence of LVH due to an increased prevalence
      of eccentric LVH. There were no differences among groups defined by the presence
      and severity of valvular regurgitation in cardiac output, total peripheral
      resistance, or pulse pressure/stroke volume, indicating that the observed inter
      group differences in LV geometry were not due to differences in the haemodynamic
      severity of hypertension. Hypertensive patients with mild-to-moderate mitral or
      aortic valvular insufficiency have additional LV structural and functional
      changes that may affect prognosis.

PMID- 15042118
TI  - Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood
      retinal barrier.
AB  - Several retinal and choroidal diseases are potentially treatable by intraocular
      delivery of genes whose products may counter or neutralize abnormal gene
      expression that occurs as part of the diseases. However, prior to considering a
      transgene, it is necessary to thoroughly investigate the effects of its
      expression in normal and diseased eyes. An efficient way to do this is to combine
      tissue-specific promoters with inducible promoter systems in transgenic mice. In
      this study, we used this approach to evaluate the effects of ectopic expression
      of angiopoietin-1 (Ang1) in normal eyes and those with ocular neovascularization.
      Adult mice with induced expression of Ang1 ubiquitously, or specifically in the
      retina, appeared normal and had no identifiable changes in retinal or choroidal
      blood vessels or in retinal function as assessed by electroretinography.
      Increased expression of Ang1 in eyes with severe retinal ischemia or in eyes with
      rupture of Bruch's membrane significantly suppressed the development of retinal
      or choroidal neovascularization, respectively. This inhibition of ocular
      neovascularization is particularly interesting and noteworthy, because
      overexpression of Ang1 in skin stimulates neovascularization. Ang1 also
      significantly reduced VEGF-induced retinal vascular permeability. These data
      suggest that intraocular delivery of ang1 has potential for treatment of ocular
      neovascularization and macular edema.

PMID- 15042119
TI  - Gene therapy progress and prospects: recombinant adeno-associated virus (rAAV)
      vectors.

PMID- 15042120
TI  - Green fluorescent protein: green cells do not always indicate gene expression.

PMID- 15042122
TI  - Association of subclinical vitamin D deficiency with severe acute lower
      respiratory infection in Indian children under 5 y.
AB  - OBJECTIVES: To determine whether subclinical vitamin D deficiency in Indian
      children under 5 y of age is a risk factor for severe acute lower respiratory
      infection (ALRI). DESIGN: A hospital-based case-control study. SETTING:
      Sanjeevani Paediatrics Hospital, a private hospital in Indapur, India.
      PARTICIPANTS: A total of 150 children including 80 cases and 70 controls, aged 2
      60 months, were enrolled. Case definition of severe ALRI as given by the World
      Health Organization was used for cases. Controls were healthy children attending
      outpatients' service for immunization. MAIN OUTCOME MEASURE: Association of serum
      25-hydroxyvitamin D3 (25OHD3) with severe ALRI, controlling for demographic and
      other potential risk factors. RESULTS: Serum 25OHD3 increased with age. Factors
      significantly associated with decreased risk of severe ALRI in univariate
      analysis were: exclusive breastfeeding in the first 4 months (cases 35/78 (45%),
      controls 41/64 (64%); P=0.02); introduction of other dietary liquids than milk
      only after 6 months (cases 46/70 (66%), controls 31/66 (47%); P=0.03); use of
      liquid petroleum cooking fuel (cases 32/80 (40%), controls 40/70 (57%); P=0.04);
      infant not covered in swaddling cloths when exposed to sunlight before crawling
      (cases 11/52 (21%), controls 25/54 (46%); P=0.006); and serum 25OHD3>22.5 nmol/l
      (cases 16/80 (20%), controls 48/70 (69%); P<0.001). In multivariate analysis,
      factors associated with significantly lower odds ratio for having severe ALRI
      were: serum 25OHD3>22.5 nmol/l (OR: 0.09; 95% CI 0.03-0.24; P<0.001) and
      exclusive breastfeeding in the first 4 months of life (OR 0.42; 95% CI 0.18-0.99;
      P=0.046) with age and height/age as significant covariates. CONCLUSION:
      Subclinical vitamin D deficiency and nonexclusive breastfeeding in the first 4
      months of life were significant risk factors for severe ALRI in Indian children.

PMID- 15042121
TI  - Simultaneous stimulation of Fas-mediated apoptosis and blockade of costimulation
      prevent autoimmune diabetes in mice induced by multiple low-dose streptozotocin.
AB  - Type I diabetes is the result of a selective destruction of insulin-producing
      beta cells in pancreatic islets by autoreactive T cells. Depletion of
      autoreactive T cells through apoptosis may be a potential strategy for the
      prevention of autoimmune diabetes. Simultaneous stimulation of the Fas-mediated
      pathway and blockade of costimulation by a CTLA4-Fas ligand (FasL) fusion protein
      has been reported to lead to enhanced in vitro apoptosis of peripheral
      lymphocytes. To test the feasibility of CTLA4-FasL-based gene therapy to prevent
      autoimmune diabetes, we developed a recombinant adenovirus containing the human
      CTLA4-FasL gene (AdCTLA4-FasL). A single injection of 2 x 10(8) plaque-forming
      units of AdCTLA4-FasL via the tail vein of mice greatly reduced the incidence of
      autoimmune diabetes (13%, n=15) induced by multiple low-dose streptozotocin.
      AdCTLA4-FasL administration abrogated pancreatic insulitis, significantly
      increased apoptosis of pancreatic T-lymphocytes, and altered splenocyte response
      to mitogenic and antigenic stimulation. These results indicate the therapeutic
      potential of simultaneous stimulation of the Fas-mediated pathway and blockade of
      costimulation by adenovirus-mediated CTLA4-FasL gene transfer in the prevention
      of autoimmune diabetes.

PMID- 15042123
TI  - The use of 13C-labelled glycosyl ureides for evaluation of orocaecal transit
      time.
AB  - OBJECTIVE: In the present study, cellobiose-[13C]ureide and glucose-[13C]ureide
      were synthesized and tested as alternative substrates for noninvasive evaluation
      of the orocaecal transit time (OCTT). DESIGN: Experimental study. INTERVENTION:
      In total, 1 g cellobiose-[13C]ureide was administered together with a continental
      breakfast either without or after predosing of 5 x 1 g unlabelled cellobiose
      ureide on the day prior to study commencement. After 2 weeks, the same subjects
      ingested glucose-[13C]ureide (dosage: 0.57 g) either without or after predosing
      of the respective unlabelled ureide under identical conditions. Expired air
      samples were taken over 10 h. 13CO2-enrichment was measured by isotope ratio mass
      spectrometry (PDZ Europa, Sandbach, UK). The OCTT was calculated from the
      interval between 13C-ureide administration and the detection of a significant and
      sustained 13C-rise of 2 delta over baseline in breath. SETTING: University of
      Rostock, Children's Hospital, Research Laboratory. SUBJECTS: Eight healthy adults
      aged 22-55 y. RESULTS: After application of cellobiose-[13C]ureide and glucose
      [13C]ureide OCTTs of 401 and 415 min, respectively, were measured. The predosing
      resulted in higher and steeper 13C-enrichments and caused a significant
      shortening of OCTTs of 265 and 287 min, respectively (P=0.012 and 0.017).
      CONCLUSIONS: The onset of 13CO2-enrichment reflected the degradation of glycosyl
      [13C]ureides by glucose ureide hydrolase. The predosing with unlabelled ureides
      prior to pulse labelling with cellobiose-[13C]ureide and glucose-[13C]ureide (the
      latter is the key substance of the enzymatic sugar-ureide degradation) led to an
      induction of enzyme activity and resulted in a more precise and similar
      estimation of the OCTT when using both 13C-labelled ureides.

PMID- 15042124
TI  - Comparison of the Micro-Nutrica Nutritional Analysis program and the Russian Food
      Composition Database using data from the Baltic Nutrition Surveys.
AB  - OBJECTIVE: The objective of this study was to compare the nutrient content of
      foods and diets based on data from two food composition databases used in the
      Baltic Nutrition Surveys (conducted in Estonia, Latvia and Lithuania in 1997): an
      adapted version of the Finnish Micro-Nutrica Nutritional Analysis program (used
      in Estonia) and the Russian Institute of Nutrition Food Composition Database
      (used in Latvia and Lithuania). DESIGN: The adapted Micro-Nutrica and Russian
      databases were used to estimate the energy and nutrient (protein, fat,
      carbohydrate, vitamin C, calcium and iron) content of 15 common foodstuffs in the
      region and the nutrient intakes of 32 Latvian respondents (based on 24-h
      recalls). Differences between databases were estimated. RESULTS: There were
      discrepancies in the energy and nutrient content of the 15 selected foods using
      the two databases. The adapted Micro-Nutrica database generally gave a lower
      energy content than the Russian database (median: -6%), and a lower fat content
      for typically fat-rich foods. Intakes of energy, fat, carbohydrate and calcium by
      the 32 selected respondents were significantly lower when the Micro-Nutrica
      database was used. Differences were particularly high for fat (difference=-23.5%,
      95% confidence interval=-31.1 to -15.8%, P<0.0001). CONCLUSIONS: The results
      suggest that reported comparisons of nutrient intakes in the Baltic countries
      should be treated with caution and that more research is needed for the
      development of comparable national databases in the region. Potential differences
      between databases should be investigated early when international surveys of
      dietary intake are being planned.

PMID- 15042125
TI  - Nutrition-related habits of Greek adolescents.
AB  - OBJECTIVE: To investigate nutrition-related habits of Greek school-aged
      adolescents. DESIGN: Epidemiological survey. SETTING AND SUBJECTS: The study was
      part of the Health Behavior in School Aged Children (HBSC) survey. A
      representative sample of school-aged adolescents aged 11.5, 13.5, and 15.5 y was
      obtained. The final sample consisted of 4211 students (51.6% girls and 48.4%
      boys). They were asked to complete a translated form of the international HBSC
      questionnaire, including several thematic entities. The Unhealthy Food Choices
      Score (UFCS) was devised in order to evaluate the overall quality of reported
      eating habits of respondents; the higher the score, the lower the diet quality.
      RESULTS: Among all students surveyed, 14.7% were reported to be on a diet to lose
      weight (girls: 19.5%; boys: 9.7%; P<0.001), and 22.9% were dissatisfied with
      their body weight but not on a diet. Girls were found to have lower UFCS values
      compared to boys (24.7 +/- 4.6 vs 24.1 +/- 4.5, P<0.001). Girls dissatisfied with
      their weight, but not on a diet, showed the highest UFCS values compared to both
      those on a diet and those not on a diet. TV viewing was positively associated
      with the consumption of sodas, crisps, cakes and pastries, and sweets and
      chocolates. CONCLUSIONS: Dieting is becoming a major problem, especially among
      older girls. The findings of this study suggest that eating habits of Greek
      school-aged adolescents are in the process of changing from more traditional to
      more Westernized ones.

PMID- 15042126
TI  - High plasma arginine concentrations in critically ill patients suffering from
      hepatic failure.
AB  - OBJECTIVE: In physiological conditions, the liver plays an important role in the
      regulation of plasma arginine concentrations by taking up large amounts of
      arginine from the hepatic circulation. When hepatic failure is present, arginine
      metabolism may be disturbed. Therefore, we hypothesized high arginine plasma
      concentrations in critically ill patients suffering from hepatic failure. DESIGN:
      We prospectively collected blood samples from a cross-section of intensive care
      unit patients. SETTING: Surgical intensive care unit of a Dutch university
      medical center. SUBJECTS: A total of 52 critically ill patients with clinical
      evidence of dysfunction of more than two organs were recruited. MEASUREMENTS:
      Plasma arginine concentrations were determined by HPLC. We identified
      correlations of arginine concentrations with organ failure scores and laboratory
      variables by univariate and multiple regression analyses. RESULTS: High plasma
      arginine concentrations were found in critically ill patients developing organ
      failure. Patients who were in the highest quartile of plasma arginine
      concentrations had significantly lower fibrinogen concentrations, higher lactic
      acid concentrations, and longer prothrombin time. Stepwise multiple regression
      analysis showed that concentrations of arginine were independently associated
      with the presence of hepatic failure (P=0.03) and renal failure (P=0.048). In
      addition, lactic acid proved to be an independent determinant of plasma arginine
      concentration (P=0.014). CONCLUSIONS: Critically ill patients who suffer from
      hepatic failure have elevated plasma arginine concentrations. Additional arginine
      in the treatment of these patients can be harmful, and therefore should not be
      used as a standard nutritional regimen until further evaluation.

PMID- 15042128
TI  - Alcohol consumption and its relation to cardiovascular risk factors in Germany.
AB  - OBJECTIVE: To analyse the association of alcohol consumption and blood lipids,
      haemostatic factors, and homocysteine in German adults by gender and age groups.
      DESIGN: Cross-sectional population-based survey. SETTING: Data from the German
      National Health Interview and Examination Survey 1998, representative for age,
      gender, community size, and federal state. SUBJECTS: From a sample of 7124
      Germans between 18 and 79 y old, 2420 women and 2365 men were selected. Only
      individuals who were not currently receiving medical treatment or did not have
      disorders related to cardiovascular disease were selected for this study.
      RESULTS: Using analyses of variance, mean blood levels of total cholesterol, HDL
      cholesterol, HDL/total cholesterol ratio, total glycerides, fibrinogen,
      antithrombin III, and homocysteine adjusted for age, socioeconomic status,
      East/West Germany residence, body mass index, tobacco use, sports activity, and
      coffee consumption, if appropriate are presented by alcohol consumption groups
      (0, >0-10, >10-20, >20-30 and >30 g/day). The HDL/total cholesterol ratio
      increased with higher alcohol groups up to 10-20 g/day (+15%) for women and >30
      g/day (+18%) for men, showing the strongest rise among men aged 55-79 y.
      Fibrinogen decreased with higher alcohol groups up to 10-20 g/day for women and
      20-30 g/day for men. Among women, homocysteine levels showed a U-shaped curve
      with a minimum of 8.49 mmol/l at 10-20 g alcohol/day (-8%, reference:
      nondrinking), whereas an inverse association was observed for men. CONCLUSIONS:
      Moderate alcohol consumption is associated with favourable levels of several
      cardiovascular risk factors. The most favourable cardiovascular risk factor
      profile among women was observed among those drinking 10-20 g alcohol/day.
      Beneficial effects seem to be more pronounced among older men.

PMID- 15042127
TI  - Nutrient adequacy and dietary diversity in rural Mali: association and
      determinants.
AB  - OBJECTIVE: To examine the association between nutrient adequacy and dietary
      diversity, and to assess and compare the determinants for the two constructs in
      an adult population in rural Mali. DESIGN: Cross-sectional study assessing food
      intake by a validated 7-day quantitative food frequency questionnaire. Two
      different dietary diversity indexes were created: food variety score (FVS), a
      simple count of food items, and diet diversity score (DDS) a count of food
      groups. Mean adequacy ratio, the mean ratio of intake to recommended intake (each
      truncated at one) of energy and nine nutrients, was calculated as an indicator of
      nutrient adequacy. Information on household and individual characteristics,
      including demography, socioeconomic conditions and food production strategies was
      obtained using precoded questionnaires. SETTING: Bafoulabe district, Kayes
      region, Western Mali. SUBJECTS: In total, 502 subjects (55% women) aged 15-45 y
      from 319 different households. RESULTS: Both FVS and DDS had a positive
      correlation with mean adequacy ratio (MAR). Multivariate analysis (linear
      regression) showed that the most important factors explaining MAR was the number
      of milk products, vegetables and green leaves consumed, as well as sex and the
      number of crops produced in the household. Dietary diversity was associated with
      socioeconomic status, residence and age. CONCLUSION: Dietary diversity is useful
      as an indicator of nutrient adequacy. It is important to examine how various food
      groups contribute to the nutrient adequacy of the diet in an area.

PMID- 15042129
TI  - Soyfood consumption and risk of glycosuria: a cross-sectional study within the
      Shanghai Women's Health Study.
AB  - OBJECTIVE: To assess the association between soyfood intake and risk of
      glycosuria. DESIGN AND METHODS: A cross-sectional study was conducted among
      participants of the Shanghai Women's Health Study, a population-based cohort
      study of women aged 40-70 y. Information on usual intake of soyfoods was obtained
      at baseline survey through an in-person interview using a validated food
      frequency questionnaire. Included in this study were 39,385 cohort members
      screened for diabetes at the baseline survey and free of previously diagnosed
      diabetes, cardiovascular diseases, kidney diseases, and cancer. There were 323
      women who tested positive for urine glucose. Odds ratios (ORs) and 95% confidence
      intervals (CIs) were employed to measure the association between soyfood intake
      and glycosuria using unconditional logistic regression. SETTING: Urban
      communities of Shanghai, China. RESULTS: Overall, soyfood intake was not related
      to the risk of glycosuria. Among postmenopausal women, however, intake of tofu
      and other soy products was inversely associated with risk of glycosuria after
      adjustment for potential confounders. The ORs across quintiles of intake were
      1.0, 0.75 (95% CI=0.47-1.20), 0.79 (95% CI=0.51-1.25), 0.53 (95% CI=0.32-0.88),
      and 0.51 (95% CI=0.26-0.98; P for trend=0.05). Further analyses showed that the
      inverse association was primarily confined to postmenopausal women with a body
      mass index (BMI) of <25 kg/m2. The adjusted OR comparing the extreme quintiles
      was 0.36 (95% CI=0.13-0.97; P for trend=0.004). CONCLUSIONS: Soyfoods may play a
      role in the development of glycosuria, an important indicator of diabetes, among
      postmenopausal women with a low BMI.

PMID- 15042130
TI  - Arabinoxylan fibre improves metabolic control in people with Type II diabetes.
AB  - OBJECTIVE: To determine whether diet supplementation with arabinoxylan-rich (AX)
      fibre from wheat improves glycaemic control in Type II diabetes. DESIGN:
      Randomized, crossover intervention trial. SETTING: Monash Medical Centre.
      SUBJECTS: A total of 15 subjects with Type II diabetes. INTERVENTIONS: Over two 5
      week periods, subjects supplemented their usual diet with control bread and
      muffins (50% whole wheat, 50% white flour) (control diet) or with AX-bread and
      muffins (50% whole wheat, 36% white flour, 14% AX fibre) (AX diet). Subjects
      completed a 7-day food diary. At 0 and 5 weeks, venous blood was collected for
      determination of fasting and 2 h glucose, insulin, fructosamine and blood lipids.
      Blood pressure, body weight and body fat were also determined. A 24 h faecal
      sample, from 12 subjects, was weighed and analysed for faecal polysaccharide as a
      marker for dietary compliance. RESULTS: Control and AX diets were similar except
      the AX diet supplied an additional 15.1 (12.0-18.5) (mean (95% confidence
      intervals)) g/day dietary fibre (P=0.000). Consumption of the AX diet increased
      faecal output by 61.5 (0.2-122.8) g/day (P=0.05) on a wet weight basis and
      significantly lowered fasting and 2 h plasma glucose, 2 h insulin and serum
      fructosamine (P=0.002, 0.000, 0.015, and 0.02, respectively). Blood lipids, body
      weight, fat mass and blood pressure remained unchanged. CONCLUSION: A supplement
      of 15 g/day of AX-rich fibre can significantly improve glycaemic control in
      people with Type II diabetes.

PMID- 15042131
TI  - Detection and recognition thresholds to the 4 basic tastes in Mexican patients
      with primary Sjogren's syndrome.
AB  - BACKGROUND: Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease
      characterized by inflammatory lymphocytic infiltration of the salivary glands,
      leading to dryness of the mouth (xerostomia). It has been postulated that
      xerostomia is the preceding stage for the development of alterations in taste
      acuity (dysgeusia) in this type of patients. OBJECTIVES: To determine detection
      and recognition thresholds to the 4 basic tastes (sweet, salty, sour and bitter)
      in pSS patients and compare them to a control group. To determine if the long
      term consumption of chile peppers and spicy Mexican diets had an effect on the
      taste perception and acuity of the pSS patients. SETTING: This study was done in
      the Department of Food Science and Technology of the Instituto Nacional de
      Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ), a third-level hospital
      in Mexico City. SUBJECTS: The patient group consisted of 21 Mexican females (mean
      +/- s.d., age: 53.1 +/- 9.8 y) diagnosed with pSS (time of duration of the
      disease, 8.6 +/- 6.6 y, median 7 y, range 1-25 y) who were recruited at the
      outpatient service of the Department of Immunology and Rheumatology of the
      INCMNSZ. The control group consisted of 20 healthy nonsmokers age-matched Mexican
      women (50.3 +/- 11.9 y) most of them personnel of the INCMNSZ, and some friends
      and nonblood relatives to the patients (sisters-in-law) who volunteered to
      participate in the study. INTERVENTIONS: Detection and recognition thresholds
      were determined by the method of least noticeable differences on three occasions
      during three nonconsecutive days. Saliva production was determined by Saxon's
      test on two separate occasions. RESULTS: Although saliva production was severely
      reduced in pSS patients (1.35 +/- 0.55 ml/2 min, P<0.001) compared to controls
      (6.26 +/- 2.41 ml/2 min), all subjects recognized the 4 basic tastes when these
      were tested at suprathreshold concentrations. The detection thresholds for the
      sweet, sour and bitter tastes were higher in pSS patients, as well as the
      recognition thresholds for the salty, sour and bitter tastes. A relationship
      between time of evolution of the disease and saliva production with individual
      thresholds could not be established. CONCLUSIONS: pSS patients exhibited
      different degrees of dysgeusia depending on the taste being studied, that is,
      they were mildly dysgeusic for the sweet and salty tastes and clearly dysgeusic
      for the sour and bitter tastes. Although both pSS patients and controls had
      consumed 'typical Mexican diets' their entire lives, our results showed that the
      consumption of chile peppers and spicy foods did not have any effect on the taste
      perception and acuity of the pSS patients.

PMID- 15042132
TI  - Rapid carbohydrate digestion rate produced lesser short-term satiety in obese
      preschool children.
AB  - OBJECTIVE: To examine whether high carbohydrate meals with different carbohydrate
      digestion rates have an effect on the short-term satiety in normal and obese
      preschool children. SUBJECTS AND SETTING: In total, 48 children of both gender,
      24 normal and 24 obese, according to body mass index, aged between 3 and 6 y,
      were selected from children who were attending to a day-care center where they
      consumed three meals in the day. INTERVENTIONS: Rapid (potato-based meal) and
      lente (spaghetti-based meal) carbohydrate digestion rate meal were given at
      lunch, matching energy intake, carbohydrate, protein and fat levels, and then the
      preschool children's energy intake at the subsequent mealtime was observed. In
      this last mealtime, the children received varied types of high-acceptability
      foods in higher quantities than the normal serving. RESULTS: At lunch, a
      significant higher energy intake, lesser satiation, was observed in both groups,
      normal-weight and obese children, when they consumed the potato-based meal. In
      the subsequent mealtime, a significant effect of carbohydrate digestion rate was
      demonstrated, but only in obese preschool children, being higher in the meal with
      rapid digestion rate carbohydrates. CONCLUSIONS: Rapid carbohydrate digestion
      rate meal produced a significative lesser satiation in normal-weight and obese
      children. However, only in obese children a significant lesser satiety was
      observed after consumption of the rapid carbohydrate digestion rate meal,
      indicating a decreased capacity of energy regulation in obese children. The
      finding of the present work could provide dietary strategies required for
      decreasing prevalence in overweight and obesity in preschool children.

PMID- 15042133
TI  - From milk to solids: a reference standard for the transitional eating process in
      infants and preschool children in Japan.
AB  - OBJECTIVE: This paper aims to establish a potential reference standard for the
      process of transition from milk to solid food in infants and preschool children
      in Japan, using the transitional food process (TFP) scale described by Sakashita
      et al. The background for variation and delay in the process are also discussed.
      DESIGN: A randomized sample survey covering entire Japan. SETTING: Mailing self
      completion of questionnaires. SUBJECTS: Randomized sample of 14 000 children aged
      0-6 y and their family from 13 prefectures in Japan, namely Hokkaido, Aomori,
      Iwate, Niigata, Tokyo, Saitama, Fukui, Nagano, Nagoya, Hyogo, Yamaguchi,
      Kagoshima, and Okinawa. METHODOLOGY: Questionnaires requesting the TFP scale and
      background factors were sent to 14,000 children and families. The percentile ages
      were calculated. An eating ability index (EAI: number of accepted foods/total
      number of foods) x 100) was calculated. Regression analysis by analysis of
      covariance (ANCOVA; SPSS, 1997) was used to determine the influence of background
      factors on EAI. RESULTS: From the 6747 (48.2%) effective answers received,
      percentile curves of the acceptability of each food on the scale were drawn, and
      used as initial reference standards. The 50 percentile age range of these 20
      standard foods covers from 5 to 42 months after birth. The sensitive period for
      increasing the acceptance of foods in children was between 6 months and 2(1/2) y
      of age. ANCOVA regression model (R2=0.605) showed that EAI was mostly influenced
      by age (P=0.000), followed by feeding style (P=0.000), infant food preparation
      (P=0.000), information source (P=0.000), and birth order (P=0.003). The dominant
      cause of digestive system problems was shown to be infection, not too-hard food.
      It seems that breast feeding, bottle feeding with chewing-type nipples, and the
      manner of preparing infant foods from the family table promote the progress in
      acceptance. Children whose mothers followed the information given in books or
      magazines showed a slower progress. CONCLUSIONS: It seems appropriate to use this
      reference standard in the study of the transitional process from milk to solid
      food in infants and preschool children in Japan.

PMID- 15042134
TI  - Two variants in the resistin gene and the response to long-term overfeeding.
AB  - OBJECTIVE AND SUBJECTS: To investigate the role of resistin gene variants on the
      adiposity and metabolic changes observed in response to a 100-day overfeeding
      protocol conducted with 12 pairs of monozygotic twins. MEASUREMENTS: Body-fat
      measurements included hydrodensitometry and abdominal fat from computed
      tomography. Plasma glucose and insulin during fasting and in response to an oral
      glucose tolerance test (OGTT) were assayed. A 4.2 MJ test meal was consumed,
      after which calorimetric measurements were performed for 240 min. RESULTS:
      Respiratory quotient (RQ) decreased (P=0.001) more in AA/AG than in GG subjects
      of the IVS2+181G>A polymorphism after the caloric surplus and the significance
      persisted when correction for multiple testing was performed. Total abdominal
      (P=0.027) and visceral (P=0.004) fat increased more in TC than in TT subjects of
      the IVS2+39C>T polymorphism. In response to overfeeding, glucose area under the
      curve during the OGTT showed a slight decrease (P=0.031) in the TC while it
      increased in TT subjects. OGTT insulin area tended to increase less (P=0.055) in
      TC than in TT subjects. After overfeeding, fasting insulin was lower in TC than
      in TT subjects (P=0.010). In addition, TC subjects experienced more decrease in
      RQ than TT subjects (P=0.034). CONCLUSION: The IVS2+181G>A variant was associated
      with the changes in RQ in response to overfeeding. The IVS2+39C>T polymorphism
      was associated with overfeeding-induced changes in abdominal visceral fat, OGTT
      glucose area and RQ. The results suggest that sequence variation in the resistin
      gene is involved in the adaptation to chronic positive energy balance.

PMID- 15042135
TI  - Changes in the nutritional status of Bolivian women 1994-1998: demographic and
      social predictors.
AB  - INTRODUCTION: Bolivia, as one of the poorest Latin American countries, has dealt
      with the problems of undernutrition for the last 50 y. Little importance has been
      given to the increase in overweight and obesity among the population, despite the
      scientific evidence linking overweight and obesity with mortality and morbidity.
      OBJECTIVE: To describe the social and demographic determinants of the nutritional
      status among women in Bolivia between 1989 and 1998 to gain a better
      understanding of the nutrition transition phenomena and to identify urgent
      research needs. METHODOLOGY: Secondary analysis of the raw data of the Bolivian
      National Demographic and Health Surveys of 1994 and 1998. Changes in the
      prevalence of underweight, obesity and overweight are described by
      sociodemographic characteristics of Bolivian women. Social and demographic
      determinants of nutritional status have been fitted into a logistic model.
      RESULTS: The prevalence of overweight (defined as 25< or =BMI<30 kg/m2) among
      women of reproductive age (20-44 y) increased by 9 percentage points between 1994
      and 1998 (P<0.001), while the prevalence of normal BMI decreased by 10 percentage
      points (P<0.001). The decrease in the prevalence of underweight (defined as BMI
      <18.5 kg/m2) from 2.4% in 1994 to less than 1% in 1998 was statistically
      significant (P<0.001). Obesity (defined as BMI> or =30 kg/m2) was positively
      associated with geographical region (P=0.001), educational level (P<0.001), age
      (P=0.003) and total number of children (P=0.001) and negatively associated to
      rural locality (P=0.001) and native languages (P<0.001). Overweight was inversely
      associated with rural locality (P=0.013) and with Quechua language (P=0.04),
      while the total number of children (P<0.001) and year of survey (P<0.001) were
      positively associated. Underweight decreased dramatically (P<0.001), being
      positively associated with the region of residence (P=0.04) and inversely
      associated with the total number of children (P=0.006). CONCLUSION: The present
      study suggests that the population of Bolivia is in a transitional stage, with
      overweight becoming as much of a problem as undernutrition.

PMID- 15042136
TI  - The effect of grape-seed extract on 24 h energy intake in humans.
AB  - OBJECTIVE: Since grape-seed extract has been shown to stimulate lipolysis in
      vitro and reduce food intake in rats, we assessed the efficacy of grape-seed
      extract with respect to energy intake (EI) and satiety. DESIGN: In a randomized,
      placebo-controlled, double-blind, cross-over study, 51 subjects (age 18-65 y,
      body mass index 22-30 kg/m2) ate an ad libitum lunch and dinner twice in the
      University Restaurant for 3 days. Standard breakfasts and snacks were provided.
      Supplements were taken 30-60 min prior to each meal. RESULTS: In the total study
      population, no difference in 24 h EI was found between the grape-seed extract and
      placebo. However, in the subgroup of subjects (n=23) with an energy requirement >
      or =the median of 7.5 MJ/day, EI was reduced by 4% (DeltaEI 352.1 kJ/24 h,
      P=0.05) after grape-seed extract compared to placebo treatment. Meanwhile, there
      were no significant differences in macronutrient composition, attitude towards
      eating, satiety, mood or tolerance. CONCLUSIONS: Grape seed reduced 24 h EI, with
      on average 4% in subjects who had an energy requirement > or =7.5 MJ/day, without
      further effects on satiety, mood or tolerance. These findings suggest that grape
      seed could be effective in reducing 24 h EI in normal to overweight dietary
      unrestrained subjects, and could, therefore, play a significant role in body
      weight management.

PMID- 15042138
TI  - Prevalence and severity of anemia and iron deficiency: cross-sectional studies in
      adolescent schoolgirls in western Kenya.
AB  - OBJECTIVE: Anemia is a major public health concern in preschool children and
      pregnant women in the developing world. While many studies have examined these
      two at-risk groups, there is a paucity of data on anemia in adolescents living in
      developing countries in the complex ecologic context of poverty, parasitism, and
      malnutrition. We evaluated the prevalence, severity, and risk factors of anemia
      in adolescent schoolgirls in an area with intense malaria transmission in western
      Kenya. DESIGN: Two cross-sectional surveys were conducted, using a multistage
      random sample design. SETTING: Public primary schools in an area with intense
      malaria transmission in western Kenya. SUBJECTS: A total of 648 randomly selected
      adolescent schoolgirls aged 12-18 y. RESULTS: The prevalence of anemia (Hb <120
      g/l) was 21.1%; only one girl had an Hb less than 70 g/l. Ferritin levels were
      available from a subsample of 206 girls. The prevalence of iron deficiency
      (ferritin <12 microg/l) was 19.8, and 30.4% of anemic girls were iron deficient.
      Malaria and schistosomiasis were the main risk factors for anemia in younger
      girls (12-13 y), while menstruation was the principal risk factor in older girls
      (14-18 y). CONCLUSIONS: Iron deficiency and anemia in school-attending girls in
      western Kenya were more prevalent than in developed countries, but considerably
      less prevalent than in preschool children and pregnant women from the same study
      area. Our findings are consistent with other recent school-based surveys from
      western Kenya, but not with recent community- and school-based cross-sectional
      surveys from other parts of sub-Saharan Africa. It deserves further study to
      determine if adolescent girls not attending school are at higher risk of anemia.

PMID- 15042139
TI  - Post-prandial plasma ghrelin levels in people with different breakfast hours.
AB  - OBJECTIVES: To investigate the changes in post-meal plasma ghrelin levels in
      people with different breakfast hours. DESIGN AND INTERVENTIONS: The subjects
      adhered to strict breakfast times starting 2 weeks before the study. Blood was
      drawn hourly from 0530 or 0630 until 1130. Plasma ghrelin, leptin, and insulin
      levels were measured by radioimmunoassay. SETTING: Medical Research Institute,
      Pusan National University Hospital, Korea. SUBJECTS: A total of 16 healthy
      volunteers. RESULTS: The mean plasma ghrelin level in subjects consuming
      breakfast was 548.7 +/- 239.6 fmol/ml before breakfast and 384.8 +/- 168.7
      fmol/ml 1 h after breakfast, with leptin levels of 6.8 +/- 2.6 and 6.5 +/- 2.5
      ng/ml, respectively. Plasma ghrelin levels were lowest 1 h after the meal,
      although the breakfast times differed. The plasma ghrelin level was lowest at
      0730 in subjects not eating breakfast. CONCLUSIONS: These findings suggest that
      the plasma ghrelin levels are lowest 1 h after breakfast despite the variance in
      breakfast times. This timing might best reflect an individual's plasma ghrelin
      level and enable reasonable comparisons.

PMID- 15042137
TI  - Reproducibility and validity of coffee and tea consumption in Italy.
AB  - OBJECTIVE: The reproducibility and validity of coffee, decaffeinated coffee and
      tea intake has not been adequately studied, particularly in Italy, where coffee
      drinking is peculiar in terms of type and amount of coffee consumed. DESIGN: We
      compared coffee and tea consumption, measured by two interviewer-administered
      food frequency questionnaires (FFQ), with average intake derived from two 7-day
      dietary (DD) records (the reference method) on 395 volunteers. The Pearson
      correlation coefficients (r) were used to assess both reproducibility and
      validity of information on coffee intake. RESULTS: A satisfactory level of
      reproducibility and validity of the pattern consumption was observed for coffee,
      decaffeinated coffee and tea. The reproducibility for both sex combined showed r
      of 0.74-0.78 for coffee, 0.57-0.65 for decaffeinated coffee and 0.61-0.67 for
      tea. The validity was about 0.70 for coffee, around 0.58 for decaffeinated coffee
      and 0.56-0.60 for tea intake. CONCLUSIONS: The FFQ is a satisfactorily reliable
      and valid instrument for collecting information on coffee, decaffeinated coffee
      and tea intake.

PMID- 15042141
TI  - Testing the glycaemic index of foods: in vivo, not in vitro.

PMID- 15042140
TI  - Gender differences in TNF-alpha levels among obese vs nonobese Latino children.
AB  - OBJECTIVE: To examine the relationships between TNF-alpha, obesity, and insulin
      resistance among prepubescent children. DESIGN: Cross-sectional study. SETTING
      AND SUBJECTS: Data were collected from 112 nondiabetic Latino schoolchildren from
      public schools in three South Florida communities. Of the enrolled participants,
      43.8% were obese (BMI 95th percentile) and 51.8% presented with a family history
      of type 2 diabetes mellitus (T2DM). With one exception, all demonstrated normal
      glucose tolerance. INTERVENTIONS: Plasma TNF-alpha levels were determined with
      enzyme-linked immunosorbance assay (ELISA). Homeostasis model assessment (HOMA
      IR) was calculated as an index of insulin resistance. Mean levels of TNF-alpha
      among obese vs nonobese children were compared with a one-way analysis of
      variance with two groups, and the association between TNF-alpha and HOMA-IR was
      assessed with a Pearson's correlation. RESULTS: Higher circulating TNF-alpha
      levels were revealed among nonobese vs obese children. Nonobese girls
      demonstrated higher TNF-alpha levels than obese girls, whereas there were no
      significant differences for boys. There were no significant differences after
      stratifying for family history of T2DM. There was a modest relationship between
      increased TNF-alpha levels and decreased insulin resistance. CONCLUSIONS: The
      observed elevated circulating TNF-alpha concentrations among leaner participants
      may reflect an inflammatory process that has been associated with higher levels
      of physical fitness in both adults and prepubescent children. This effect may
      remain stronger for prepubescent girls, and the mechanism may be attenuated by
      the hormonal changes that occur with the onset of puberty.

PMID- 15042143
TI  - Representational oligonucleotide microarray analysis (ROMA) in pharmacogenomics.

PMID- 15042144
TI  - Clinical implications of pharmacogenomics for tardive dyskinesia.

PMID- 15042145
TI  - Comprehensive expression analysis of a rat depression model.
AB  - Herein we report on a large-scale analysis of gene expression in the 'learned
      helplessness' (LH) rat model of human depression, using DNA microarrays. We
      compared gene expression in the frontal cortex (FC) and hippocampus (HPC) of
      untreated controls, and LH rats treated with saline (LH-S), imipramine or
      fluoxetine. A total of 34 and 48 transcripts were differentially expressed in the
      FC and HPC, respectively, between control and LH-S groups. Unexpectedly, only
      genes for NADH dehydrogenase and zinc transporter were altered in both the FC and
      HPC, suggesting limited overlap in the molecular processes from specific areas of
      the brain. Principal component analysis revealed that sets of upregulated
      metabolic enzyme genes in the FC and downregulated genes for signal transduction
      in the HPC can distinguish clearly between depressed and control animals, as well
      as explain the responsiveness to antidepressants. This comprehensive data could
      help to unravel the complex genetic predispositions involved in human depression.

PMID- 15042146
TI  - Chemistry and biology of calystegines.

PMID- 15042147
TI  - Biogenetic speculation and biosynthetic advances.

PMID- 15042148
TI  - Fatty acid desaturases: selecting the dehydrogenation channel.

PMID- 15042149
TI  - Anti-staphylococcal plant natural products.

PMID- 15042150
TI  - Simple indole alkaloids and those with a nonrearranged monoterpenoid unit.

PMID- 15042151
TI  - Diterpenoids.

PMID- 15042158
TI  - What mass spectrometry can reveal about protein function.

PMID- 15042159
TI  - Differential mobility spectrometry of chlorocarbons with a micro-fabricated drift
      tube.
AB  - Chlorocarbons were ionized through gas phase chemistry at ambient pressure in air
      and resultant ions were characterized using a micro-fabricated drift tube with
      differential mobility spectrometry (DMS). Positive and negative product ions were
      characterized simultaneously in a single drift tube equipped with a 3 mCi (63)Ni
      ion source at 50 degrees C and drift gas of air with 1 ppm moisture. Scans of
      compensation voltage for most chlorocarbons produced differential mobility
      spectra with Cl(-) as the sole product ion and a few chlorocarbons produced
      adduct ions, M (.-) Cl(-). Detection limits were approximately 20-80 pg for gas
      chromatography-DMS measurements. Chlorocarbons also yielded positive ions through
      chemical ionization in air and differential mobility spectra showed peaks with
      characteristic compensation voltages for each substance. Field dependence of
      mobility was determined for positive and negative ions of each substance and
      confirmed characteristic behavior for each ion. A DMS analyzer with a membrane
      inlet was used to continuously monitor effluent from columns of bentonite or
      synthetic silica beads to determine breakthrough volumes of individual
      chlorocarbons. These findings suggest a potential of DMS for monitoring
      subsurface environments either on site or perhaps in situ.

PMID- 15042161
TI  - Functional lipid microstructures immobilized on a gold electrode for voltammetric
      biosensing of cholera toxin.
AB  - Redox functionalized microstructures of diacetylene lipids containing cell
      surface ligand GM1 have been prepared for the construction of an electrochemical
      biosensor for cholera toxin from Vibrio cholerae. Incorporation of lipid
      molecules with disulfide functionality into the microstructures allows for firm
      attachment of the microstructures on a gold surface to form a sensing interface.
      The observed morphology of the microstructures is platelet, with size around 240
      nm as determined by dynamic light scattering and transmission electron
      microscopy. The electrochemical response stems from electron transfer between the
      electrode and the redox sites on the microstructures, and the Faradaic current is
      influenced by the binding events of protein toxins to the ligands displayed on
      the crystalline surface. Electrochemical characterization indicates that electron
      transfer of surface ferrocene on the gold electrode is facile. Differential pulse
      voltammetry was used to measure the current magnitude as a function of toxin
      concentration, and a working range expanding from 1.0 x 10(-8) to 5.0 x 10(-7) M
      was obtained. Bovine serum albumin (BSA) was used as a control agent with which
      no interference to Faradaic response was found in the same concentration range.
      Atomic force microscopy (AFM) was used to characterize the morphology and
      distribution of microstructures on the gold surface. The effectiveness of the
      design for bypassing surface fouling of proteins in electrochemical detection has
      been demonstrated, and a binding regulated electron hopping mechanism for the
      observed electrochemical behavior has been proposed.

PMID- 15042162
TI  - Optimization of a method for determining dioxin in whole blood samples based on
      solvent extraction and simplified cleanup.
AB  - Dioxins, including polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDDs/Fs) and
      coplanar polychlorinated biphenyls (Co-PCBs), such as mono-ortho-PCBs and non
      ortho-PCBs, are environmental pollutants that have deleterious effects on human
      health. Although screening of blood samples for dioxins is necessary, the current
      methods are time-, reagent- and labor-intensive. To optimize the extraction and
      cleanup of dioxins, we have designed a column chromatography method, coupled with
      a water washing step. We used a tandem simplified multilayer silica gel-activated
      carbon dispersed silica gel column (TS-ML-AC) rather than the conventional two
      columns. We compared three liquid-liquid extraction (LLE) methods and two
      pressurized liquid extraction (PLE) methods, when used with this column. For each
      of these extraction methods, we compared the quantity of lipid obtained when the
      water washing step was omitted and when it was performed by shaking 30 times by
      hand or 30 min by a machine. We found that TS-ML-AC was superior to the
      conventional pair of columns in that only about one third of the solvent and only
      one quarter of the time was necessary. Of the five extraction methods, the
      acetone/hexane PLE (AcP) method was superior, since it reduced the amount of
      organic solvent to half or less of the amount required for the LLE methods. The
      cleanup step using water was best accomplished by the hand-shaking method. Our
      results indicate that, for the analysis of dioxin in whole blood samples, the use
      of AcP together with TS-ML-AC and water washing by hand shaking should be used.

PMID- 15042164
TI  - High-throughput analysis of human serum for selected polychlorinated biphenyls
      (PCBs) by gas chromatography-isotope dilution time-of-flight mass spectrometry
      (GC-IDTOFMS).
AB  - A method for the high-throughput analysis of human serum for the 38 most
      prevalent polychlorinated biphenyls (PCBs) based on the use of fast gas
      chromatography-isotopic dilution time-of-flight mass spectrometry (GC-IDTOFMS) is
      presented. The chromatographic separation time was 8 min. The separation of the
      congeners was carried out either chromatographically or analytically using the
      mass spectral deconvolution capability of the TOFMS. The instrument and the
      method limits of detection (LODs) were 0.5 pg microL(-1) and 20 pg microL(-1),
      respectively, which is not as good as the one achieved using high resolution mass
      spectrometry (HRMS) but allows the detection and quantification of the prevalent
      PCBs present in real human serum samples. The dynamic range covered 3 orders of
      magnitude. The comparison with the high resolution mass spectrometry (HRMS)
      reference method (28 min) was good and some separation improvements have been
      observed. This method allows the analysis of 100 samples per day per instrument.

PMID- 15042168
TI  - Determination of glycerol by gas chromatography using meso-erythritol as internal
      standard.
AB  - A simple chemical method for the determination of the glycerol moiety of
      triacylglycerols in lipids is described. The internal standard meso-erythritol is
      added and the mixture saponified in 0.5 M sodium hydroxide in methanol under
      reflux for 10 min. After cooling, the mixture is acidified with 2 M hydrochloric
      acid and the fatty acids extracted with hexane. The aqueous phase is then passed
      over a mixed cation-anion exchange resin, the eluate concentrated on the rotary
      evaporator below 40 [degree]C, dried overnight in a desiccator and glycerol plus
      meso-erythritol converted into their respective trimethylsilyl ethers by
      treatment with chlorotrimethylsilane and hexamethyldisilazane in pyridine. The
      silyl ethers are separated by capillary gas chromatography yielding the glycerol
      content of the lipid. As phospholipids yield mainly (>95%) glycerophosphate under
      our conditions of hydrolysis, which is subsequently removed by the mixed ion
      exchange resin, the glycerol content is a measure of the triacylglycerol content
      of the original sample. A suitable correction for the presence of phospholipids
      can be applied by determining the phosphorus content of the lipids. In the
      majority of cases encountered this correction was negligible. The method is
      suitable for all compounds releasing glycerol on saponification, but it is
      especially useful for determining small amounts of triacylglycerols in an excess
      of wax esters. Examples of triacylglycerol determinations in the lipids of a
      number of South Atlantic fish species are presented.

PMID- 15042169
TI  - Simultaneous quantification of analytes in quaternary mixtures using dual pulse
      staircase voltammetry and genetically optimised neural networks.
AB  - This paper describes the simultaneous quantification of four aliphatic compounds
      (ethanol, methanol, fructose and glucose) mixed in varying concentrations. The
      method used employs dual pulse staircase voltammetry (DPSV) to acquire an
      electrochemical voltammogram from the mixture. An artificial neural network,
      optimised using an elitist genetic algorithm, is then used to determine the
      concentration of each individual analyte from the voltammogram. The best average
      RMS errors achieved when testing with unseen data were 5.03%, 7.72%, 3.29% and
      4.00% for maximum analyte concentrations of ethanol, methanol, fructose and
      glucose respectively. This work represents an important step forward because DPSV
      data is notoriously difficult to calibrate due to complex electrode-analyte
      interactions, and had not previous been shown to be amenable to quaternary
      mixtures.

PMID- 15042170
TI  - A pilot study of routine quality control of sampling by the SAD method, applied
      to packaged and bulk foods.
AB  - A recently proposed method of looking at sampling uncertainty has been tested by
      its application to the sampling and analysis of several types of food and an
      animal feedstuff. In this 'SAD' method, increments comprising the conventional
      sample (that is, collected in the fashion prescribed by the standard sampling
      protocol) are allocated to either of two equal sized 'splits', which are prepared
      and analysed separately. The absolute difference between the analytical results
      for the two splits (the split absolute difference, or SAD) is plotted on a one
      sided control chart. A non-compliance indicates that the combined uncertainty of
      sampling or analysis is larger than expected and the result of the measurement
      (the mean of the two split results) is possibly not fit for purpose. In addition,
      the SAD results give rise to a rugged estimate the uncertainty associated with
      the sampling protocol, often a major part of the total measurement uncertainty.

PMID- 15042171
TI  - MMNTP-a new tailor-made modular derivatization agent for the selective
      determination of isocyanates and diisocyanates.
AB  - The synthesis of a new tailor-made derivatization agent for the selective
      determination of (di)isocyanates is presented. Starting from cyanuric chloride,
      the reagent 4-methoxy-6-(4-methoxy-1-naphthyl)-1,3,5-triazine-2-(1
      piperazine)(MMNTP) is synthesized by subsequent substitution of the three
      chlorine atoms. This new derivatization agent and the five urea derivatives of
      phenylisocyanate (PI), hexamethylene-diisocyanate (HDI), toluene-2,4-diisocyanate
      (2,4-TDI), toluene-2,6-diisocyanate (2,6-TDI) and methylenebisphenyl-4,4
      diisocyanate (MDI) show good spectroscopic properties with small compound-to
      compound variabilities (RSD([epsilon])= 5.3 %, RSD(relative fluorescence)= 9.4
      %). Therefore, using UV detection, a single calibration is needed for the
      quantification of all diisocyanates and isocyanates respectively. For separation
      and analysis a HPLC method with a RP column and a binary gradient is presented.
      All derivatives are separated and show low limits of detection. In addition to
      the good spectroscopic properties and low limits of detection, good reactivity
      for the derivatizations at room temperature is observed. The aromatic
      diisocyanates can be measured immediately whereas aliphatic diisocyanates need 2
      h incubation. These advantages make MMNTP a powerful and versatile derivatization
      agent for (di)isocyanates which is demonstrated by a real sample with solid phase
      sampling, where the reagent is coated on a sorbent.

PMID- 15042172
TI  - [Serologic survey for yellow fever and other arboviruses among inhabitants of Rio
      Branco, Brazil, before and three months after receiving the yellow fever 17D
      vaccine].
AB  - During a yellow fever vaccination campaign among residents of Rio Branco (Acre
      State), the frequency of HI antibodies to the most prevalent arboviruses in the
      Amazon region and to yellow fever virus was determined before and three months
      after immunization with YF 17D vaccine. From 390 inhabitants included in the
      first phase of serologic survey (August 1999), only 190 provided a second serum
      sample, after the use of 17D vaccine (January 2000). Among first phase samples,
      the frequency of HI antibodies was: 17D (27.2%); Ilheus (5.9%); Mayaro (5.4%);
      Caraparu (4.9%); Dengue-2 (4.1%); Oropouche (2.3%); and Dengue-1 (0.3%). In the
      second study phase, the serologic conversion to YF reached 89.7% among previously
      negative persons. Serologic conversions were also observed to Ilheus (6.2%);
      Dengue-3 (3.2%); Mayaro (1.1%); and Oropouche (1.1%) viruses. In conclusion,
      considering the high YF antibody rate after vaccination, the risk of urban yellow
      fever seems insignificant, although the lower prevalence of HI antibodies to
      dengue viruses, is of concern and inhabitants are under high risk of dengue
      outbreaks, especially to DEN-3 recently introduced in Brazil, as was observed in
      2000 and 2001 with DEN-1 and DEN-2.

PMID- 15042174
TI  - Using epidemiological survey data to infer geographic distributions of
      leishmaniasis vector species.
AB  - An important aspect of tropical medicine is analysis of geographic aspects of
      risk of disease transmission, which for lack of detailed public health data must
      often be reduced to an understanding of the distributions of critical species
      such as vectors and reservoirs. We examine the applicability of a new technique,
      ecological niche modeling, to the challenge of understanding distributions of
      such species based on municipalities in the state of Sao Paulo in which a group
      of 5 Lutzomyia sandfly species have been recorded. The technique, when tested
      based on independent occurrence data, yielded highly significant predictions of
      species' distributions; minimum sample sizes for effective predictions were
      around 40 municipalities.

PMID- 15042173
TI  - Adverse reactions associated with a Fuenzalida-Palacios rabies vaccine: a quasi
      experimental study.
AB  - The Fuenzalida-Palacios rabies vaccine has been used in South America for rabies
      post-exposure prophylaxis. To determine the frequency of adverse reactions
      associated with this vaccine compared to a control group a quasi-experimental
      study was carried out in Uberlandia, Brazil, from May 1997 to April 1998. Victims
      of bites or other injuries by dogs or other mammals and who received or not post
      exposure prophylaxis with Fuenzalida-Palacios rabies vaccine were compared as to
      the occurrence of a list of signs and symptoms. Out of 2,440 victims of bites and
      other injuries from dogs and other mammals 2,114 participated in the study; 1,004
      of them provided follow-up information within 10 to 15 days. Headache and pain at
      the injection sites were the most commonly found symptoms (125/1,000). No
      neuroparalytic event was detected. Patients who were given Fuenzalida-Palacios
      rabies vaccine and those who were not had similar incidences of symptoms (risk
      ratios close to 1). Regarding the occurrence of adverse reactions, Fuenzalida
      Palacios rabies vaccine is a valid alternative for rabies post-exposure
      prophylaxis.

PMID- 15042176
TI  - [Identification of the cutoff value for serum alanine aminotransferase in
      hepatitis C screening of patients with chronic renal failure on hemodialysis].
AB  - The patients with chronic renal failure in hemodialysis present low levels of
      serum alanine aminotransferases. In order to establish a better cutoff value for
      ALT in hepatitis C screening of hemodialysis patients, the ALT levels were
      measured monthly in 235 patients, being excluded those that presented average
      above the upper limit of normality. The cutoff value was identified by
      construction of a ROC curve (receiver operating characteristic). Among 202
      patients, 15 (7.4%) presented antibodies to hepatitis C virus (anti-HCV) and 187
      (92.6%) were anti-HCV negative, with an ALT average of 0.7 and of 0.5 from ULN (p
      <0.0001), respectively. The better cutoff value for ALT was at 0.6 from ULN, with
      sensitivity of 67% and specificity of 75% in anti-HCV screening. These results
      suggest that ULN of ALT could be reduced for 60% from conventional limit, when we
      are evaluating patients with CRF in hemodialysis.

PMID- 15042175
TI  - [Association of humans leucocitary antigens with humoral nonresponsive to
      hepatitis B vaccine in chronic hemodialysis patients].
AB  - Vaccination using surface antigen from hepatitis B virus has not been
      successfully responded by hemodialysis patients. The present study was aimed at
      assessing a possible relationship between human leukocyte antigens and the low
      production of protective antibodies (anti-HbS) against the surface antigen from
      hepatitis B by patients with chronic renal failure submitted to hemodialysis
      programs. The antigens HLA-DR and HLA-DQ were identified in 76 hemodialysis
      patients through classic microlymphotoxicity. Our results showed that 34.2% of
      the patients were non-responsive to the vaccine VHB. The most frequent HLA
      specificity were: HLA-DR3, DR-7 and DQ2 with a significant association for HLA
      DR3 (p=0.0025; OR 5.1; IC 95% 1.36-19.10). Such data suggest an association
      between genes from HLA class II antigens and the humoral non-response to the
      vaccine VHB.

PMID- 15042178
TI  - The usefulness of Umelosa hepatitis C virus qualitative kit as supplemental test
      for confirmation of hepatitis C virus infection.
AB  - Forty voluntary blood donors from two different blood banks in Havana, Cuba, who
      were repeatedly reactive on the routine screening of antibodies to hepatitis C
      virus, by Umelisa HCV test, were analyzed for the presence of HCV RNA using a
      nested PCR assay of the HCV 5' untranslated region, Umelosa HCV qualitative. Sera
      from 45 patients of a specialized gastroenterology consultation, positive to
      Umelisa HCV, were also assayed with the Umelosa HCV qualitative, to establish
      their condition related to the presence of HCV RNA previously to the indication
      of a treatment or after three, six or twelve months of antiviral therapy. Serum
      HCV-RNA was detected in 21/40 (52.5%) donors who had repeatedly positive ELISA
      results, confirming the HCV infection for them. In specialized consultation HCV
      RNA was detected by PCR analysis in 30/45 (66%) analyzed sera.

PMID- 15042177
TI  - [Effects of cyclosporin A or betamethasone on experimental murine toxocariasis].
AB  - The effects of administration of either cyclosporin A or betamethasone 15 days
      before or 45 days after experimental infection with Toxocara canis on mice had
      been studied. The dynamics of IgG antibody production, employing an enzyme-linked
      immunosorbent assay, was studied 60 and 90 days after mice infection by Toxocara
      canis. In the 90th day after infection all surviving mice were sacrificed and the
      tissue trapped larvae recovered by acid digestion in the muscles, lungs, liver
      and brain. A significative delay in the production of IgG antibodies anti
      Toxocara was observed in all the mice treated with cyclosporin A or betamethasone
      15 days before infection. On the other side, mice treated with cyclosporine 15
      days before infection, but not with betamethasone, showed a significative higher
      number of trapped Toxocara canis larvae in the examined tissues.

PMID- 15042179
TI  - [Soroprevalence of HTLV-I/II, HIV, siphylis and toxoplasmosis among pregnant
      women seen at Botucatu - Sao Paulo - Brazil: risk factors for HTLV-I/II
      infection].
AB  - In order to asses the soroprevalence of HTLV- I/II, HIV, siphylis, and
      toxoplasmosis infection among pregnant women seen at Basic Health Units in the
      municipality of Botucatu - Sao Paulo - Brazil, and risk factors for HTLV- I/II
      infection, sorologic surveys were carried out and results of sorologic surveys
      carried in pregnance routine evaluation were assessed. Seroprevalence was 0.1% (1
      in 913) for both HTLV-I and HTLV-II. Seroprevalence was 0.1% (1 in 913) for both
      HTLV-I and HTLV-II. Siphylis, toxoplasmosis and HIV were identified. None of the
      factors or characteristics risks was found to be useful to identify those prenant
      women HTLV-II infected. Infection among pregnant women and southeast brazilian
      blood donnors were not diferent in statistical evaluation.

PMID- 15042180
TI  - [Infeccious diseases as causes of death in autopsied elderly].
AB  - The population aging in Brazil was associated with the alterations in the
      morbimortality of the population. The aim of this study was to verify the causes
      of death and other pathological processes in autopsied elderly. The elderly with
      60 years or more in the period from 1976 to 1998 represented 394 cases (24.4%).
      The age median was 69 years ranged from 60 to 120 years, being higher in the
      women (70.5 versus 68 yrs;p<0.05). The male gender (67.5%), white color (69.8%),
      and the cardiovascular (43.7%) and infectious (31%) causes of death were
      dominate. In the malnourished (76.2%) it had association of pneumonia and
      cystitis, (p<0.05). Arteriosclerosis (61.9%), and the chagasic (42.1%) and
      hypertensive cardiopathies (39.1%) were the most frequent processes. Therefore,
      it was observed an overlapping of chronic-degenerative and infectious causes of
      death. This study shows the necessity to value of follow up of body mass index
      and of risk factors for the development of illness in aging patients like
      pneumonia.

PMID- 15042181
TI  - [Alterations in cholesterol, triglyceride and total phospholipid levels in plasma
      of Callithrix jacchus (sagui) reinfected by Schistosoma mansoni].
AB  - Little information is available on the lipid changes caused by Schistosoma
      mansoni reinfection. In this work it was evaluated alteration in the plasma
      lipids due to one reinfection by Schistosoma mansoni in the non human primate
      Callithrix jacchus (sagui). Blood samples from C. jacchus, prior and after 60
      days infection and reinfection, were collected by intravenous puncture,
      anticoagulated with EDTA (1mg/mL) and centrifuged at 2,500 xg, in order to obtain
      the plasma. Total cholesterol, cholesteryl ester, total phospholipid and
      triglyceride levels were determined by spectrophotometer methods. The results
      showed that there are significant reduction in cholesterol total, cholesteryl
      ester, total phospholipid and triglyceride concentrations in plasma of animals
      reinfected by Schistosoma mansoni, in comparison to the same animals prior and
      after one infection. This study showed that a second infection of Callithrix
      jacchus by Schistosoma mansoni causes plasma lipid alterations, which are more
      significant than after a single infection.

PMID- 15042182
TI  - [History, epidemiology and control of malaria in Campinas region, Sao Paulo
      State, Brazil, 1980 to 2000].
AB  - It is a retrospective descriptive study about 3314 notified cases of malaria in
      Superintendencia de Controle de Endemias, Campinas, an area that covers 88 cities
      and 5.366.081 inhabitants, during 80's and 90's. The region data were compared to
      national statistics looking at disease history and control program impact in
      endemic areas. It was observed a decrease in notified cases in Campinas region,
      while over the same period incidence in Amazonia was increasing. The highest
      prevalence was in men (83%) between 20 and 49 years old, mainly from Rondonia,
      Para and Mato Grosso State; 59% were diagnosed in three first days of symptoms.
      It was suggested the impact of educational campaigns addressed to risk population
      and health professionals in the Campinas region. In no endemic areas, early
      diagnostic and treatment are a great challenge because it may extend patient
      access and proper heath care decreasing lethality and impeding local
      transmission. It can also facilitate integration among vector control,
      epidemiologic surveillance and attendance to patients.

PMID- 15042183
TI  - Characteristics of pulmonary tuberculosis in HIV seropositive and seronegative
      patients in a Northeastern region of Brazil.
AB  - The aim of this study was to analyse the clinical, epidemiological and
      bacteriological features present in 60 pulmonary tuberculosis patients who were
      also infected with human immunodeficiency virus (HIV) and to compare these with
      120 TB patients who were not infected with HIV. The patients with pulmonary
      tuberculosis and HIV coinfection were mostly male (p = 0.001), showed a higher
      frequency of weight loss >10 kilos (p <0.001), had a higher rate of non-reaction
      result to the tuberculin skin test (p <0.001), a higher frequency of negative
      sputum smear examination for acid-fast bacilli (p = 0.001) and negative sputum
      culture for Mycobacterium tuberculosis (p = 0.001). Treatment failure was more
      common in those who were HIV positive (p <0.000). No higher frequency of
      resistance to antituberculosis drugs was found to be associated with TB/HIV
      coinfection (p = 0.407). Association between extrapulmonary and pulmonary
      tuberculosis was more frequent in those seropositive to HIV than those without
      HIV virus, 30% and 1.6% respectively. These findings showed a predominance of
      atypical clinical laboratory features in co-infected patients, and suggest that
      health care personnel should consider the possibility this diagnosis.

PMID- 15042184
TI  - [Male circumcision and HIV infection: an international debate with no Brazilian
      participation].
AB  - The authors discuss male circumcision as a protective factor against HIV
      transmission. The absence is noted of Brazilian data published in the
      international literature regarding this issue. Finally, it is emphasized that
      self-declared circumcision status is subject to substantial misclassification
      with the generation of biased risk estimates.

PMID- 15042185
TI  - [Cerebral Malaria in Ceara: a case report].
AB  - Starting from a case of cerebral malaria in Ceara, the authors get the attention
      for that possibility of this occurrence in no-endemic zone, due to the retard of
      the diagnosis. Besides the serious implications of the disease, uncommon for this
      determined species, Plasmodium vivax, it is observed the probable existence of
      mixed infection and the potential dissemination with the presence of the sand fly
      transmitter.

PMID- 15042186
TI  - [Human pulmonary dirofilariasis at Rio de Janeiro, Brazil: a case report].
AB  - We report a case of human pulmonary dirofilariasis in a female patient 45-years
      old, derived from Rio de Janeiro, Brazil. The chest radiologic finding consisted
      of single pulmonary nodule located on the left lower lobe that simulated lung
      tumor. Human pulmonary dirofilariasis might be investigated in nodules that are
      not malignants and require conclusive diagnosis.

PMID- 15042188
TI  - Pseudoneoplastic lesion of the breast caused by Schistosoma mansoni.
AB  - A case of a pseudoneoplastic lesion of the breast clinically and sonographically
      suggestive of a fibroadenoma is reported. Excisional biopsy revealed the nodule
      was an inflammatory process consequent to infection by Schistosoma mansoni.

PMID- 15042187
TI  - Histoplasmosis presenting as addisonian crisis in an immunocompetent host.
AB  - A 71-year-old man with presumptively treated pulmonary tuberculosis ten years
      earlier and previous alcoholism presented with adrenal insufficiency. HIV
      serology was negative. A computerized tomography scan of the abdomen showed
      enlarged right adrenal. He recovered after emergency treatment with
      hydrocortisone IV. Right adrenalectomy was performed. Histoplasmosis was
      diagnosed and the patient was treated with itraconazole, corticosteroid
      replacement, and discharged with good health.

PMID- 15042189
TI  - [Cryptococcal mastitis after corticosteroid therapy].
AB  - We described a case of cryptococcal mastitis in a 46 years old female patient
      receiving corticosteroids for sarcoidosis. There was radiological pulmonary
      deterioration and a cystic lesion was found in the left breast. The mycosis was
      diagnosed by histopathology and cryptococcal antigens. We emphasized the sarcoid
      granuloma diagnostic's dilemma an the rare manifestation of cryptococcal
      infection as mastitis.

PMID- 15042190
TI  - Fulminant hepatic failure in children and adolescents in Northern Brazil.
AB  - The histological findings of fulminant hepatic failure were correlated to the
      demographic, clinical, biochemical and virological features in children and
      adolescents, native to the Amazonas State in Northern Brazil. 96.2% had evidence
      of infection by primary hepatotrophic viruses. Histological analysis revealed
      three distinct patterns of fulminant hepatic failure.

PMID- 15042192
TI  - Campylobacter upsaliensis isolated from young dogs with and without diarrhea.

PMID- 15042191
TI  - [Frequency of Serratia sp in urine infections of intern patients in the Santa
      Casa de Misericordia in Fortaleza].
AB  - In the present time the Serratia is considered an important human pathogen, which
      has been found as causal agent of nosocomial infections mainly urine infections.
      We verify the frequency of the Serratia sp in urine samples, in intern patients.
      Were studied 1197 urine samples, this study show 15 positive for the Serratia sp.
      The species found were: 7 Serratia liquefaciens (46,7%), 5 Serratia odorifera
      (33,3%) and 3 Serratia rubidaea (20%).

PMID- 15042193
TI  - Acute pancreatitis caused by meglumine antimoniate given for the treatment of
      visceral leishmaniasis.

PMID- 15042194
TI  - Care for the elderly: national policy and nursing training.

PMID- 15042195
TI  - [Elderly with hematological neoplastic disorders: actions and difficulties
      related to self-care at the beginning of the disease].
AB  - This study aims at identifying the actions and difficulties related to self-care
      at the initial period of the oncological-hematological disease, as reported by
      elderly persons attended at an outpatient setting. Interviews were carried out
      with 30 elderly at a hematology center in Campinas (SP). Data analysis allowed us
      to identify that, at the beginning of the disease, the most relevant self-care
      action was seeking medical care. However, the delay or difficulty in reaching a
      diagnosis, as well as coping with the disease and accessing health care services
      were the difficulties mentioned most frequently.

PMID- 15042196
TI  - [Impact of a health promotion program carried out by nursing among type 2
      diabetes patients, within the community].
AB  - The goal of this quasi-experimental study was to measure the impact of a health
      promotion program on the knowledge of the type 2 diabetic population in
      Queretaro, Mexico about diabetes mellitus type 2. A nursing intervention was
      carried out with 40 patients, who accepted to participate in the study through
      informed consent. In order to determine the knowledge the patients attained on
      the disease, each patient answered a questionnaire before and after the nursing
      intervention. In data analysis, percentage and absolute figures were used for
      measuring the qualitative variables, and chi(2) with alpha=0.05 was used for the
      significance test. After the intervention, the percentage of patients with
      knowledge about the illness increased from 10% to 72.5%. The nursing program
      contributed to the improvement of knowledge on diabetes mellitus.

PMID- 15042197
TI  - [The difference in acute myocardial infarction pain between diabetic and non
      diabetic patients].
AB  - The goal of this study was to compare the acute myocardial infarction (AMI) pain
      between diabetic and non diabetic patients. A sample of 80 AMI patients was
      divided in two groups, with and without diabetes mellitus (DM), being 29%
      diabetic and 71% non diabetic patients. The patients with DM said they had no
      pain (p<0.05) and gave lower scores for pain when compared with patients without
      DM. There was a significant difference between average scores for pain among
      diabetic and non diabetic patients (p<0.001). In conclusion, the diabetic
      patients presented no pain or diminished pain when compared with patients without
      diabetes.

PMID- 15042198
TI  - [Morphologic trachea alterations in intubated patients in function of intubation
      time].
AB  - This is a descriptive analytic study which aimed to describe the morphologic
      alterations of the trachea in intubated patients with cannulas of high-residual
      volume and low-pressure cuff, maintained on mechanical ventilation with lower
      pressure inside the "cuff" than the tracheal capillary pressure (20-30 mmHg) in
      function of intubation time. The study population consisted of 23 adult patients
      admitted at an Intensive Care Unit, who were intubated for periods ranging from
      27 to 317 hours and died, needing necropsy to identify the cause of deaths. The
      observed alterations were limited to the tracheal mucous membrane, affecting only
      the epithelium tissue and the lamina propria. Intubation time was a determinant
      factor to aggravate tracheal wall injuries.

PMID- 15042199
TI  - [Fluid management: a nursing intervention for the patient with fluid volume
      excess].
AB  - The objective of this research is to identify which nursing activities contained
      in the fluid management intervention proposed by the Nursing Intervention
      Classification (NIC) are realized and considered important by nurses, to attend
      patients who received fluid volume excess as a nursing diagnosis, as proposed by
      the North American Nursing Diagnoses Association (NANDA). Data were collected in
      three hospitals. The sample included 77 nurses, who chose the best alternative on
      a Likert scale, to indicate the realization of which of those actives they
      considered important and which activities are realized in their daily care
      practice. It was concluded that most of the nursing activities were always
      considered important and were always performed by the nurses. These activities
      were classified as independent and dependent.

PMID- 15042200
TI  - [Caring for children with neurogenic bladder dysfunction: social representation
      of these children's and their mothers' needs].
AB  - The purpose of this study was to know and analyze the representations and needs
      of school-age children with neurogenic bladder dysfunction and of their mothers.
      This is a qualitative study; whose methodology was based on social
      representations. According to the interposition of empirical end analytical
      categories, the living and caring are respectively represented by mothers as "a
      problem" and "all me"; the children, in turn, interpret the differentiated and
      prejudiced interaction they suffer in the setting they live in as "it is not
      fair".

PMID- 15042201
TI  - [Having an infarction: the meanings of the disease from the patient's
      perspective].
AB  - This study aimed to identify the meaning of acute myocardial infarction for
      patients, on the basis of their experiences reports. Given the nature of the
      problem, this descriptive study used Symbolic Interactionism as a methodological
      reference framework. Data where obtained through semi-structured interviews with
      thirteen patients, diagnosed as acute myocardial infarction, admitted at a
      coronary center of a specialized public hospital in Fortaleza-CE, Brazil. Data
      analysis enabled us to identify that "Having an acute myocardial infarction
      according to the patient's perspective" was predominantly unexplained, generating
      negative and sudden feelings.

PMID- 15042202
TI  - [Injury diagnosis quality of life among motorcyclists, victims of traffic
      accidents].
AB  - This study characterizes motorcyclists living at Maringa-Parana-Brazil, who were
      victims of traffic accidents and were attended in hospitals for trauma
      treatments. The injured have been characterized according to trauma severity,
      body regions affected and the body region with the most serious injury, besides
      identifying possible differences in the quality of life of the victims who
      developed traumatic brain injury. While the Injury Severity Score was used to
      evaluate trauma severity, the Medical Outcomes Study 36-Item Short Form Health
      Survey was applied to assess the victims' quality of life. With respect to trauma
      severity, victims with mild injuries (73.14%) were predominant. Most victims
      (59.70%) were injured in the lower members of the body, followed by injuries in
      the upper ones (58.21%) and in the head (31.34%). Limbs were most affected when
      compared to other body regions. There was no difference in the quality of life of
      post-trauma victims with or without cranium-encephalic trauma.

PMID- 15042204
TI  - [Understanding the theoretical bases of participative planning in the integrated
      curriculum of a nursing course].
AB  - This paper deals with an exploratory study aimed at identifying the theoretical
      bases that sustain participative planning as described in the framework of
      Situational Strategic Planning, which are used in the integrated curriculum of
      undergraduate nursing education for the development of participative planning
      performance. Data were obtained through documentary analysis of twenty-two
      notebooks of the Educational Units that are part of the Marilia Medical School
      Nursing Course curriculum, with a view to recognizing those parts of knowledge
      that contributed to the formation of the social actor, situation and social
      production concepts. Result analysis recognized the lack of theoretical bases, as
      well as the predominance of knowledge aims and the description of performance as
      objectives. However, attempts were revealed to integrate knowledge and
      approximate them to participative planning, with a view to achieving coherence
      with the principles of the integrated curriculum.

PMID- 15042203
TI  - [The meaning of health and disease from the child's point of view].
AB  - This study aimed to understand the meaning of health and disease for the child in
      the age range from 7 to 12 years old. The population was divided in two groups.
      The first group consisted of children in a school environment, while the second
      consisted of hospitalized children. This study was based on Symbolic
      Interactionism as a theoretical framework and on Grounded Theory as a
      methodological framework. Data were collected by means of semi-structured
      interviews, since this allowed us to explore the definitions exposed by the
      child. We perceived that, in both groups, the definition of health is similar,
      that is, in other words, something that provides them freedom and is conditioned
      by body care and feeding. About the conception of disease, the school child tries
      to understand the disease, its causes and consequences. Hospitalized children
      tell their experiences by focusing on their own disease and situation.

PMID- 15042205
TI  - [Life project of a group of adolescents based on the theory of Paulo Freire].
AB  - This study aims to get to know the life project of a group of adolescents at a
      Basic Health Unit in Marilia-SP. A qualitative research was carried out through
      semi-structured interviews and group meetings, using the educational group
      technique with participant observation from the focus of Paulo Freire's theory.
      Throughout group discussions, three questions arose: what is being an adolescent;
      what is being healthy and what is the adolescent's life project. These themes
      were analyzed from the focus of Minayo. The analysis indicated that the
      adolescents have a life project, in spite of the characteristic difficulties of
      the socioeconomic conditions they belong to, a fact they perceive. The practice
      of Freire's ideals enhanced dialogue between the researcher and the group,
      pointing out that this is one way for a true critical reflection of the
      identified problems, providing adolescents with a means for making others aware
      and fighting for their life project.

PMID- 15042206
TI  - [Users of a Psychosocial Care Center: a study of their social outcomes about
      psychiatric treatment].
AB  - The purpose of this study is to identify and analyze representations users of a
      psychosocial care center construct about psychiatric treatment. Interviews were
      held with 11 individuals at a Psychosocial Care Center. Data were analyzed
      through content analysis, according to Bardin, using the Moscovician social
      representation theory as a methodological-theoretical reference framework. Data
      analysis allowed us to define three categories. The first category--treatment is
      to be medicated--contains issues like medication as psychiatric treatment, the
      effects of treatment, various professionals involved and their participation in
      treatment. The second category--treatment is to be cared for (or not)--was
      outlined as: care in psychiatric treatment, violence and closed institutions. The
      third category--treatment is to be active--was based on: treatment and
      occupational therapy, psychiatric treatment and work. We concluded that the
      representations about psychiatric treatment are closely linked to the use of
      medication and to the physician as the precursor of the treatment.

PMID- 15042207
TI  - [Metacognition and nursing teaching: a possible combination?].
AB  - Teaching students to learn how to learn is a challenge for schools that intend to
      form autonomous people who are capable of taking decisions. These are essential
      aspects for health professionals who are permanently confronted with complex
      situations and a multiplicity of problems to be solved by professional actions.
      The desire for changes, which is explicit in educators' discourse, does not
      guarantee substantial changes in the form teaching is being developed. The
      question about how to promote these alterations still remains unanswered. Studies
      developed in the last two decades about cognition and metacognition seem to
      indicate a possible strategy to transform knowledge into relevant professional
      behavior, since it favors thinking about the thinking process as well as the
      development and control of mental abilities that are capable of maximizing the
      use of the individual potentialities necessary for a nurse to solve health
      problems.

PMID- 15042208
TI  - [Connections between health/mental illness process comprehension and care
      technologies].
AB  - The history of humanity has registered conventions about illness and treatment,
      in a dialectics that is mediated by material and objective conditions, where
      health practices can be identified. In the field of mental health, conceptions of
      psychic sickening and therapeutics can be identified in different periods of
      political and economic development and in the organization of human society,
      since the origin of times to the contemporary period. This article proposes a
      connection between health/mental illness process comprehension and treatments,
      referring to the historical contexts in which they were/are registered and
      searches for the meaning of practices and their current social meaning.

PMID- 15042209
TI  - [About the theoretic, philosophical, epistemological bases of scientific
      research: the case of nursing].
AB  - As indicated by the title, this paper discusses the theoretic, philosophical,
      epistemological basis of scientific research--the case of nursing. The author
      points out the fundamental questions in nursing--science and art. Nursing is
      considered both as a social practice and as a profession that encompasses
      scientific practice and the construction of knowledge. Thus, Nursing is
      understood as a "science under construction" or as specific knowledge, even if it
      is imprecise and, therefore, on its way to become scientific due to its
      evidences. In other words, knowledge that is justified not by total precision, on
      the contrary, by the need to find answers to the question about raising the
      epistemological reach of nursing research results--its knowing and knowing what
      to do. The discussion emphasizes the crucial nature of nursing care.

PMID- 15042210
TI  - [Construction and implementation of nursing actions in the gastroenterology
      outclinic].
AB  - The reorganization of the Schistosomiasis Sector of Gastroenterology at UNIFESP
      started in 1998, when the Nursing Service was implanted. OBJECTIVE: to develop
      administrative nursing actions, systematization of care and orientation program
      for the schistosomic patient. METHOD: a descriptive study carried out at the
      Gastroenterology Outclinic, which attends schistosomic patients of different
      clinical types. RESULTS AND DISCUSSION: the reorganization of activities in this
      Sector resulted in the creation of an organizational structure and the
      implantation of the nursing visit; creation and distribution of explanatory
      leaflets and development of the Schistosomiasis Education Program; beginning of
      the database pilot project with all outpatients and an electronic register of the
      collection of biologic material. CONCLUSION: this initiative opens up a new
      opportunity for nursing actions and contributes to quality improvement in
      ambulatory care.

PMID- 15042211
TI  - [Daily life and work: conceptions of chronic renal insufficiency (CRI) patients
      and their relatives].
AB  - This descriptive and exploratory research aimed to know the conceptions,
      attitudes and behaviors about work as reported by 16 chronic renal insufficiency
      patients and their relatives. Data were collected from April to August 2000
      through semi-structured interviews. The results revealed that work is valued by
      all families as a source of health and financial resources, besides being
      important for individuals' character formation; that most CRI patients do not
      carry out any remunerated activities and, when they do, they count on the help
      and understanding of the boss and relatives. We conclude that CRI and its
      treatment do not directly or absolutely impede the realization of this kind of
      activity, but entail important limitations. We consider it is necessary for
      health professionals to join in the search for support by relatives and society,
      so that these people can be inserted in the labor market when they want to and
      are in the right conditions.

PMID- 15042212
TI  - [Nursing staff dimensioning at a university hospital].
AB  - This study presents the dimensioning of nursing staff at a university hospital.
      The main study goals were: to determine the number of nurses, nursing technicians
      and aids for the several sectors; to define the Technical Security Index that
      reflects reality at the Hospital; to verify the adequacy of a Patient
      Classification System and of the method used at the hospitalization sectors.
      Methodologically speaking, we used a structure that considers progressive care,
      we calculated the Technical Security Index, adapted and testes a Patient
      Classification System and applied a questionnaire to evaluate the methods in use.
      We concluded that: the study allowed us to attain the necessary number of staff
      for each hospital sector; the Technical Security Index reached the goal of
      covering for absences; the patient classification system proved to be adequate,
      except for two sectors, and that the structure used for the hospitalization
      sectors is adequate.

PMID- 15042213
TI  - [Not Available].

PMID- 15042214
TI  - [A hierarchical model for analysis of socio-economic variables and water contact
      patterns associated with the hepatosplenic form of schistosomiasis].
AB  - A study of factors associated with the hepatosplenic clinical form of
      schistosomiasis was carried out in an endemic area (Comercinho, Minas Gerais)
      where prevalence of Schistosoma mansoni infection was 70.4%. Of the 1,408
      inhabitants aged two years and over, 1,162 (82.5%) participated in the study.
      Socio-demographic characteristics and reasons for water contacts of individuals
      with the hepatosplenic form (n = 73) were compared to those who did not present
      splenomegaly and eliminated (positive controls; n + 804) or did not eliminate S.
      mansoni eggs in stools (negative controls; n = 285). Multivariate analysis was
      performed, considering the existence of colinearity among socio-economic status
      of the family, running water in the household, and bathing in streams. The
      hepatosplenic form in children was strongly associated with occupation of the
      head of the family (manual workers) (OR = 11.4; 95% CI = 1.4 - 91.8), absence of
      running water in the household (OR = 7.7; 95% CI = 2.6 - 23.1), and bathing in
      streams (OR and 95% CI 7.6; 2.5-22.9 and 5.7; 1.3-25.5 for frequencies > weekly
      and <= weekly, respectively); bathing in streams, which implies intense contacts,
      was a consequence of the first two factors. Our results suggest that running
      water in the household can decrease morbidity from schistosomiasis because it
      reduces the need for intense contacts with streams.

PMID- 15042215
TI  - [Epidemiology of schistosomiasis mansoni in a low endemic area].
AB  - We discuss the epidemiological patterns of schistosomiasis mansoni in areas with
      low transmission in Brazil. We define as areas of low endemicity those where the
      prevalence is less than 10%, the number Schistosoma mansoni eggs per gram of
      feces (epg) is less than 96, and carriers are asymptomatic. Data are from the
      county of Pedro de Toledo in the Ribeira Valley (Sao Paulo State) and were
      collected randomly according to the aggregate pattern of S. mansoni within the
      hosts. We suggest the replacement of parasitological methods by more sensitive
      and specific serological techniques. The main risk factor for infection is type
      of leisure activity. Infection is more frequent in the 10-14, 15-19, and 20-24
      year age brackets. Geometric mean epg is 58.5. Intensity of infections correlates
      well (rs = 0.745) with prevalence. The highest index of potential contamination
      is in the 5-20-year age bracket (57.6%). Autochthonous cases show close
      association with Biomphalaria tenagophila, which has a low infection rate (2%).
      Prevalence, incidence, and intensity of infection patterns are similar to those
      of moderate and high endemic areas. Social and cultural aspects must be studied
      in order to obtain a global epidemiological view of schistosomiasis.

PMID- 15042216
TI  - [Evaluation of the efficacy of the Chagas' Disease Control Program:
      methodological aspects].
AB  - The efficacy of the Chagas' Disease Control Program was estimated in Minas Gerais
      State. Areas with different intervention times (10 and 5 years) and without
      intervention (control) were compared in order to verify a possible reduction in
      Trypanosoma cruzi infection incidence rates among those born after the Control
      Program. The Program efficacy was estimated comparing this study's infection
      rates with rates published by the Chagas' Disease Serological Survey, conducted
      between 1975-1980. The cross-sectional comparison for the 2-6-year age group
      showed a reduction of 94.7%, 63.2%, and 65.2% respectively, in areas where
      interventions had been carried for 10 years, 5 years, and in control areas.
      Cohort comparison, however indicated that reduction (52.6) occurred only in the
      area with 10 years of intervention. The data routinely collected by the Control
      Program were also analyzed and correlated with the incidence of T. cruzi
      infection. The results showed association between the Control Program and
      reduction in T. cruzi infection, measured by serological tests.

PMID- 15042217
TI  - [Impact of Chagas' infection on some demographic characteristics: results of an
      ecological study].
AB  - This study aimed to analyze the impact of T. cruzi infection on some demographic
      characteristics in the State of Bahia. It is a place where Chagas' disease is
      endemic in general. In the endemic areas, similar infection rates were observed
      in males and females. However, males, mainly those aged 30 or more, had higher
      mortality rates than females. Analyses were conducted on a set of secondary data
      from several different sources. They included prevalence of T. cruzi infection,
      specific mortality related to Chagas' disease, and demographic characteristics.
      The data were aggregated at two different levels: municipality and homogeneous
      micro-regions. Significant positive correlations were observed between prevalence
      of T. cruzi infection and mortality rates. These indicators, in turn, were
      correlated with the proportion of widows and widowers in the population. Findings
      were higher for widows. In areas where prevalence of T. cruzi infection was 15%
      or greater, there were 22% more widows as compared to infection free areas.
      Places with high prevalence presented some skew in the age structure, and there
      was a consistent decrease in the proportion of males in the 35-44 age group. A
      possible confounding effect of migration on these finding was not demonstrated.

PMID- 15042218
TI  - [Factors associated with household and family in leprosy transmission in Rio de
      Janeiro, Brazil].
AB  - A cross-sectional study was carried out to characterize the contribution of
      several household characteristics to the transmission of leprosy. Households with
      diagnosed cases of illness were compared to two healthy groups. All randomly
      selected households were located in the municipality of Sao Goncalo, in the State
      of Rio de Janeiro. Using an aerial map with the description of the census tract,
      2,412 cases were marked. Three groups were established, while the household was
      the analytical unit: group I - households with cases; group II - neighboring
      households; and group III - households located in tracts with no reported case of
      illness, that is, outside disease foci. Group I was compared with that of
      neighboring households using a multiple logistic regression model by conditional
      methods. Unconditional methods were used to compare groups I and III. Group I as
      compared to Group II showed an association with age and educational level for
      households and heads of families. Comparison of characteristics of the heads of
      families and households with cases of leprosy with those located outside the
      focus showed that the differential factors were age, type of dwelling, and
      availability of running water. This is probably due to more recent settlement in
      a peripheral region where water resources are not available yet. Households are
      the basic ecological unit, and age and educational level are determinant factors
      for leprosy morbidity in this area.

PMID- 15042219
TI  - [Present status of bancroftian filariasis in Maceio, State of Alagoas, Brazil].
AB  - Epidemiological and entomological surveys were carried out in the human and
      mosquito populations in Maceio, Alagoas, in order to assess the present status of
      bancroftian lymphatic filariasis. Examination of thick blood smears of 10,450
      students from different areas of the city revealed 0.66% Wuchereria bancrofti
      microfilaria carriers. The distribution of filariasis is focal in the city, 80%
      of the individuals with patent infection living in two neighboring areas with
      1.24% and 5.25% prevalence. Parallel studies performed with samples of all age
      groups in the human population showed similar microfilaria prevalence rates
      observed previously in the student survey. However, thick blood smears taken from
      members of families with at least one subject with patent infection gave a
      prevalence six times greater suggesting, increased transmission in households.
      The percentage of carriers was higher in the youngest age group (< 20 years).
      Culex quinquefasciatus mosquitos caught at the locations where the autochthonous
      cases were found presented natural infection rates ranging from 0.28% to 4.62%.
      The combination of all these findings indicates occurrence of active transmission
      of W. bancrofti in the urban area of Maceio, Alagoas State. Based on these data,
      measures for the potential control of filariasis were planned.

PMID- 15042221
TI  - Malaria vaccines: lessons from field trials.
AB  - Malaria vaccine candidates have already been tested and new trials are being
      carried out. We present a brief description of specific issues of validity that
      are relevant when assessing vaccine efficacy in the field and illustrate how the
      application of these principles might improve our interpretation of the data
      being gathered in actual malaria vaccine field trials. Our discussion assumes
      that vaccine evaluation shares the same general principles of validity with
      epidemiologic causal inference, i.e., the process of drawing inferences from
      epidemiologic data aiming at the identification of causes of diseases. Judicious
      exercise of these principles indicates that, for meaningful interpretation,
      measures of vaccine efficacy require definitions based upon arguments conditional
      on the amount of exposure to infection, and specification of the initial and
      final states in which one believes the effect of interest takes place.

PMID- 15042220
TI  - [Comparative studies on endemic areas of bancroftian filariasis in Greater
      Recife, Brazil].
AB  - Two districts in Recife (Santo Amaro and Campo Grande) and two districts in
      Olinda (Sapucaia and Salgadinho), were selected for a comparative study of
      bancroftian filariasis in Greater Recife. Selection parameters included similar
      socio-economic, demographic, and endemic levels of lymphatic filariasis. In the
      districts studied, streets were chosen randomly. These clusters consisted of 110
      people each. A population sample was stratified by sex and age: 0-4, 5-9, 10-14,
      15-19, 20-29, 30-39, 40-49, 50-59 and 60 years old and over. The parasitological
      data were obtained by measuring thick blood smears (60 micro l), collected from
      8:00 to 12:00 PM and processed and stained with hematoxylin. The data were
      described in tables, and logarithimic expression graphics were used to analyze
      parasitic densities. In general, Recife showed a prevalence of 13.5%, and Olinda
      12.3%. Mean parasitic densities were 41 and 70 microfilariae/60 micro l (mf/60
      micro l), respectively. Higher microfilaremic rates were observed in Recife for
      the 20-29-year age bracket and in Olinda in the 30-39-year bracket. The authors
      concluded that the disease has returned to former endemic levels, and the data
      described call for a reevaluation of control campaigns carried out by the
      Brazilian National Health Foundation, since the endemic has already reached
      serious proportions.

PMID- 15042222
TI  - [Epidemiological, social, and sanitary aspects in an area of the Rio Negro, State
      of Amazonas, with special reference to intestinal parasites and Chagas' disease].
AB  - A cross-sectional study was carried out on the residents of one in every four
      dwellings in the town of Barcelos (in the northern part of the State of Amazonas,
      on the right bank of the Rio Negro, 490 kilometers from Manaus by river), in
      order to evaluate social and sanitary conditions and specific indicators for
      intestinal parasites and Chagas' infection. During the survey, two questionnaires
      were applied, a household one to evaluate social and sanitary aspects, and an
      individual one, for social and epidemiological evaluation of the population
      conditions. A conglomerate family sample of 171 dwellings was studied. From each
      of the 658 habitants, a sample was requested for stool examination by Lutz
      sedimentation and Baermann-Moraes-Coutinho techniques modified by Willcox & Coura
      (1989), and blood was collected in filter paper for immunofluorescence test by
      Camargo (1966) and Souza & Camargo (1966) methods modified by Petana & Willcox
      (1975). The stool examination showed 69.4% of samples with one or more parasites.
      Ascaris lumbricoides was predominant with 51% of positivity and Entamoeba
      histolytica, although surveyed by a non-specific method, was present in 19.7%.
      Surprisingly, 20.1% of the 658 sera samples were reactive for T. cruzi antibodies
      at a dilution of 1:20 and 13.7% at 1:40. There was a strong correlation between
      this result and the level of human contact with wild triatomines, known locally
      as "piasava lice", and we succeeded in isolating by xenodiagnosis one strain of
      T. cruzi from one patient, a sixty-one-year old man (n. 209 -1), a native of the
      area, with positive serology for Chagas' disease and who worked in agriculture
      and transporting piasava and was very familiar with "piasava lice".

PMID- 15042223
TI  - Environmental intervention as a tool for control of schistosomiasis: suggestions
      from a field study in Northeast Brazil.
AB  - The present survey from the State of Alagoas (Brazil) emphasized, once again, the
      importance of peridomestic or neighbourhood foci in the transmission of
      schistosomiasis mansoni. Although the study area consisted of a compact and
      densely populated urban community (Bairro Frio, Uniao dos Palmares county),
      prevalence as well as the distribution of high egg counts was quite patchy,
      exhibiting a spatial pattern correlated with the distribution of ditches and
      other small-sized collections of surface water. Despite the availability of
      satisfactory water supply in most households, as well as the absence of any major
      body of water capable of furthering transmission, egg counts in Bairro Frio
      exceeded any other in our previous experience. Morbidity, however, appeared to be
      insignificant, a trend which has been observed over the last decade in several
      other highly endemic areas. It appears clear to the authors that the control of
      transmission requires investment in environmental intervention and that this
      proposal, far from being utopic, can be furthered by quite modest means and
      through the participation of community or neighbourhood groups.

PMID- 15042224
TI  - An epidemiological approach to study congenital Chagas' disease.
AB  - Transplacental transmission of Trypanosoma cruzi has been the focus of much
      attention in highly endemic areas in South America. Frequency of congenital
      transmission and factors associated with risk of it are still not well
      understood. Parasite strains may account for part of the geographical variation
      observed. Methodological differences between the studies do not permit a combined
      interpretation of results. This paper examines the epidemiological data available
      from Brazil, Bolivia, and Argentina and discusses possible epidemiological study
      design to investigate risk factors for transmission.

PMID- 15042225
TI  - Ecological aspects of the vectorial control of Chagas' disease in Brazil.
AB  - The feasibility and most important ecological aspects of vectorial Chagas'
      disease control are discussed. The spread and maintenance of this disease involve
      multiple ecological and sociopolitical factors that must be taken into account
      when control programs are planned, executed and evaluated. In spite of its
      complexity, Chagas disease can be controlled using methods that target specific
      mechanisms of transmission, the most important being vectorial and transfusional.
      Major ecological problems in Chagas' disease control do not exist, even in the
      case of the chemical control of triatomine vectors. The main challenges for the
      Brazilian Control Program at this moment are: its maintenance as a political
      priority; the threat of peridomestic vectors; and the consolidation of permanent
      horizontal and participative epidemiological surveillance systems against the
      vector.

PMID- 15042226
TI  - Tegumentary and visceral leishmaniases in Brazil: emerging anthropozoonosis and
      possibilities for their control.
AB  - The existence of a number of different species of Leishmania, the persistent
      increase in the infection rate of diseases caused by this parasite (tegumentary
      and visceral forms), the different epidemiological situations found in regions of
      both recent and older colonization, and the trend towards urbanization have led
      to the adoption of different strategies to control leishmaniases in Brazil. The
      control measures involve studies related to the parasite, vectors, sources of
      infection (animal and human), clinical aspects, geographical distribution,
      historical and socioeconomic factors, integration of health services, and
      adequate technologies for diagnosis, treatment, and immunoprophylaxis. Finally,
      successful control requires work with human communities, involving education,
      provision of information, health promotion, and participation of these
      communities in the planning, development, and maintenance of control programs.

PMID- 15042227
TI  - Mortality certification and cause-of-death reporting in developing countries.

PMID- 15042228
TI  - Insecticide-treated nets for malaria control: real gains.

PMID- 15042229
TI  - Child mortality in a West African population protected with insecticide-treated
      curtains for a period of up to 6 years.
AB  - OBJECTIVES: To determine the impact of insecticide-treated curtains (ITC) on all
      cause child mortality (6-59 months) over a period of six years. To determine
      whether initial reductions in child mortality following the implementation of ITC
      are sustained over the longer term or whether "delayed" mortality occurs.
      METHODS: A rural population of ca 100 000 living in an area with high, seasonal
      Plasmodium falciparum transmission was studied in Burkina Faso. Annual censuses
      were conducted from 1993 to 2000 to measure child mortality. ITC to cover doors,
      windows, and eaves were provided to half the population in 1994 with the
      remainder receiving ITC in 1996. Curtains were re-treated or, if necessary,
      replaced annually. FINDINGS: Over six years of implementation of ITC, no evidence
      of the shift in child mortality from younger to older children was observed.
      Estimates of the reduction in child mortality associated with ITC ranged from 19%
      to 24%. CONCLUSIONS: In our population there was no evidence to suggest that
      initial reduction in child mortality associated with the introduction of
      insecticide-treated materials was subsequently compromised by a shift in child
      mortality to older-aged children. Estimates of the impact of ITC on child
      mortality in this population range from 19% to 24%.

PMID- 15042231
TI  - Hepatitis B vaccine freezing in the Indonesian cold chain: evidence and
      solutions.
AB  - OBJECTIVES: To document and characterize freezing temperatures in the Indonesian
      vaccine cold chain and to evaluate the feasibility of changes designed to reduce
      the occurrence of freezing. METHODS: Data loggers were used to measure
      temperatures of shipments of hepatitis B vaccine from manufacturer to point of
      use. Baseline conditions and three intervention phases were monitored. During
      each of the intervention phases, vaccines were removed progressively from the
      standard 2-8 degrees C cold chain. FINDINGS: Freezing temperatures were recorded
      in 75% of baseline shipments. The highest rates of freezing occurred during
      transport from province to district, storage in district-level ice-lined
      refrigerators, and storage in refrigerators in health centres. Interventions
      reduced freezing, without excessive heat exposure. CONCLUSIONS: Inadvertent
      freezing of freeze-sensitive vaccines is widespread in Indonesia. Simple
      strategies exist to reduce freezing - for example, selective transport and
      storage of vaccines at ambient temperatures. The use of vaccine vial monitors
      reduces the risk associated with heat-damaged vaccines in these scenarios. Policy
      changes that allow limited storage of freeze-sensitive vaccines at temperatures
      >2-8 degrees C would enable flexible vaccine distribution strategies that could
      reduce vaccine freezing, reduce costs, and increase capacity.

PMID- 15042232
TI  - Comparison of patient evaluations of health care quality in relation to WHO
      measures of achievement in 12 European countries.
AB  - OBJECTIVES: To gain insight into similarities and differences in patient
      evaluations of quality of primary care across 12 European countries and to
      correlate patient evaluations with WHO health system performance measures (for
      example, responsiveness) of these countries. METHODS: Patient evaluations were
      derived from a series of Quote (QUality of care Through patients' Eyes)
      instruments designed to measure the quality of primary care. Various research
      groups provided a total sample of 5133 patients from 12 countries: Belarus,
      Denmark, Finland, Greece, Ireland, Israel, Italy, the Netherlands, Norway,
      Portugal, United Kingdom, and Ukraine. Intraclass correlations of 10 Quote items
      were calculated to measure differences between countries. The world health report
      2000 - Health systems: improving performance performance measures in the same
      countries were correlated with mean Quote scores. FINDINGS: Intra-class
      correlation coefficients ranged from low to very high, which indicated little
      variation between countries in some respects (for example, primary care providers
      have a good understanding of patients' problems in all countries) and large
      variation in other respects (for example, with respect to prescription of
      medication and communication between primary care providers). Most correlations
      between mean Quote scores per country and WHO performance measures were positive.
      The highest correlation (0.86) was between the primary care provider's
      understanding of patients' problems and responsiveness according to WHO.
      CONCLUSIONS: Patient evaluations of the quality of primary care showed large
      differences across countries and related positively to WHO's performance measures
      of health care systems.

PMID- 15042230
TI  - Control of tuberculosis in an urban setting in Nepal: public-private partnership.
AB  - OBJECTIVES: To implement and evaluate a public-private partnership to deliver the
      internationally recommended strategy DOTS for the control of tuberculosis (TB) in
      Lalitpur municipality, Nepal, where it is estimated that 50% of patients with TB
      are managed in the private sector. METHODS: A local working group developed a
      public-private partnership for control of TB, which included diagnosis by private
      practitioners, direct observation of treatment and tracing of patients who missed
      appointments by nongovernmental organizations, and provision of training and
      drugs by the Nepal National TB Programme (NTP). The public-private partnership
      was evaluated through baseline and follow-up surveys of private practitioners,
      private pharmacies, and private laboratories, together with records kept by the
      Nepal NTP. FINDINGS: In the first 36 months, 1328 patients with TB were
      registered in the public-private partnership. Treatment success rates were >90%,
      and <1% of patients defaulted. Case notification of sputum-positive patients in
      the study area increased from 54 per 100 000 to 102 per 100 000. The numbers of
      patients with TB started on treatment by private practitioners decreased by more
      than two-thirds, the number of private pharmacies that stocked anti-TB drugs by
      one-third, the number of pharmacies selling anti-TB drugs by almost two-thirds,
      and sales of anti-TB drugs in pharmacies by almost two-thirds. Private
      practitioners were happy to refer patients to the public-private partnership. Not
      all private practitioners had to be involved: many patients bypassed private
      practitioners and went directly to free DOTS centres. CONCLUSIONS: A combination
      of the strengths of private practitioners, nongovernmental organizations, and the
      public sector in a public-private partnership can be used to provide a service
      that is liked by patients and gives high rates of treatment success and increased
      rates of patient notification. Similar public-private partnerships are likely to
      be replicable elsewhere, as inputs are not large and no special requirements
      exist.

PMID- 15042233
TI  - Patient advocacy and arthritis: moving forward.
AB  - Patient advocacy is based on the premise that people have the right to make their
      own choices about their health care. Personal advocacy is centred on the
      experiential expertise of the individual affected by the condition, whereas group
      advocacy is grounded on patient-centred strategies and actions. The first patient
      advocacy groups for arthritis were set up over 20 years ago in the USA and have
      subsequently spread to many other countries. This paper discusses the growth and
      impact of personal advocacy as well as recent developments in group advocacy in
      the Asia-Pacific region, Europe, and North America, in terms of arthritis
      awareness, research, corporate partnerships, and the Bone and Joint Decade global
      initiative.

PMID- 15042234
TI  - Second-generation HIV surveillance: better data for decision-making.
AB  - This paper seeks to outline the key elements of the expanded surveillance efforts
      recommended by the second-generation HIV surveillance approach. Second-generation
      systems focus on improving and expanding existing surveillance methods and
      combine them in ways that have the greatest explanatory power. The main elements
      of this approach include: considering biological surveillance - HIV, AIDS,
      sexually transmitted infections (STIs) - and behavioural surveillance as integral
      components, targeting surveillance efforts at segments of the population where
      most new infections are concentrated - which might differ depending on the stage
      and type of the epidemic - and providing the rationale for the optimal use of
      data generated for monitoring the HIV epidemic and evaluating national AIDS
      control programmes. The paper emphasizes improvements in existing surveillance
      methodologies and discusses in detail crucial issues such as the validity of HIV
      prevalence data measured in pregnant women and linking HIV surveillance and
      behavioural data collection. In addition, a strategic partnership between second
      generation surveillance and AIDS programme evaluation is proposed that stresses
      the complementary roles of these data collection activities in determining the
      effectiveness of prevention and care programmes and explaining the
      epidemiological trend data collected by sentinel serosurveillance systems. In
      conclusion, second-generation HIV surveillance systems provide a comprehensive,
      cost-effective and appropriate response to the information needs of AIDS control
      programmes. The implementation of such systems, including a better use of the
      data generated by the system, will ensure that national programmes are in the
      best possible position to respond to the challenges of the epidemic.

PMID- 15042235
TI  - Regulatory pathways for vaccines for developing countries.
AB  - Vaccines that are designed for use only in developing countries face regulatory
      hurdles that may restrict their use. There are two primary reasons for this: most
      regulatory authorities are set up to address regulation of products for use only
      within their jurisdictions and regulatory authorities in developing countries
      traditionally have been considered weak. Some options for regulatory pathways for
      such products have been identified: licensing in the country of manufacture, file
      review by the European Medicines Evaluation Agency on behalf of WHO, export to a
      country with a competent national regulatory authority (NRA) that could handle
      all regulatory functions for the developing country market, shared manufacturing
      and licensing in a developing country with competent manufacturing and regulatory
      capacity, and use of a contracted independent entity for global regulatory
      approval. These options have been evaluated on the basis of five criteria:
      assurance of all regulatory functions for the life of the product,
      appropriateness of epidemiological assessment, applicability to products no
      longer used in the domestic market of the manufacturing country, reduction of
      regulatory risk for the manufacturer, and existing rules and regulations for
      implementation. No one option satisfies all criteria. For all options, national
      infrastructures (including the underlying regulatory legislative framework,
      particularly to formulate and implement local evidence-based vaccine policy) must
      be developed. WHO has led work to develop this capacity with some success. The
      paper outlines additional areas of action required by the international community
      to assure development and use of vaccines needed for the developing world.

PMID- 15042236
TI  - Can measles be eradicated globally?
AB  - Measles is one of the most infectious diseases. Before measles vaccine was
      introduced, nearly everyone contracted the disease at some point in childhood. By
      the late 1980s, most countries had incorporated measles vaccine into their
      routine immunization programmes. Globally, about 800 000 children nevertheless
      still die from measles annually, half of them in Africa. Eradicating measles
      would therefore play an important role in improving children's survival. The 24th
      Pan American Sanitary Conference in 1994 established a goal of eradicating
      measles from the Americas. Progress to date has been remarkable and the disease
      is no longer endemic in the Americas, with most countries having documented
      interruption of transmission. As of November 2003, 12 months had elapsed since
      the last indigenous case was detected in Venezuela. This experience shows that
      measles transmission can be interrupted, and that this can be sustained over a
      long period of time. Global eradication is feasible if an appropriate strategy is
      implemented. Even under a new paradigm in which immunization is not discontinued
      after measles is eradicated, eradication will be a good investment to avoid
      expensive epidemics and save the lives of almost one million children annually. A
      world free of measles by 2015 is not a dream.

PMID- 15042237
TI  - Kenneth Arrow and the birth of health economics.

PMID- 15042238
TI  - Uncertainty and the welfare economics of medical care. 1963.

PMID- 15042239
TI  - SARS virus returns to China as scientists race to find effective vaccine.

PMID- 15042240
TI  - Mali takes grass roots approach to ending female genital mutilation.

PMID- 15042241
TI  - Science meets tradition and identifies herbal treatment for jaundice.

PMID- 15042242
TI  - Delays in legislation slow the progress of CME in India.

PMID- 15042243
TI  - WHO joins international effort to help Bam earthquake survivors.

PMID- 15042244
TI  - Health-related Millennium Development Goals out of reach for many countries.

PMID- 15042245
TI  - Polio will be finished by year's end, say Ministers of Health.

PMID- 15042246
TI  - [Past, present and future].

PMID- 15042247
TI  - Race and hypertensive target-organ damage in patients from an university
      affiliated outpatient care referral clinic in the city of Salvador.
AB  - OBJECTIVE: To assess whether a patient's race is associated with the presence of
      left ventricular hypertrophy, stroke, and renal failure in hypertensive patients
      from an outpatient care referral clinic in the city of Salvador in the state of
      Bahia. METHODS: We assessed the data of 622 patients collected during their first
      visit to the hypertension outpatient care clinic between 1982 and 1986,
      identifying those with a previous history or sequela of stroke, left ventricular
      hypertrophy, or renal failure (serum creatinine > 1.4 mg/dL). Logistic regression
      models were used to estimate the odds ratio (OR) of the association between race
      (mulattos or black vs white individuals) and hypertensive target-organ damage
      adjusted for sex and age. RESULTS: The mean age of the patients was 53.8+/-14.3
      years, and 74.1% were women. In regard to race, 15.1% were white, 65.9% mulatto,
      and 19.0% black. Stroke was significantly more frequent in blacks or mulattos
      than in white individuals [adjusted odds ratio (aOR) = 3.44; 95% confidence
      interval (CI) = (1.23-9.67). In regard to the associations involving race and the
      events of left ventricular hypertrophy and renal failure, the aORs were not
      statistically significant but were consistent with a greater prevalence of left
      ventricular hypertrophy and renal failure in blacks and mulattos. CONCLUSION:
      Hypertensive mulattos and blacks have a greater risk of target-organ damage than
      white individuals do, with a greater racial difference for nonfatal stroke.
      Whether racial differences in mortality related to hypertensive complications
      influence the associations observed between race and target-organ damage should
      be assessed.

PMID- 15042248
TI  - Epidemiology of decompensated heart failure in the city of Niteroi: EPICA -
      Niteroi Project.
AB  - OBJECTIVE: To compare the epidemiological and socioeconomic profiles, clinical
      features, etiology, length of hospitalization, and mortality of patients with
      decompensated heart failure admitted to public and private hospitals in the city
      of Niteroi. METHODS: We carried out a prospective, multicenter study (from July
      to September 2001) comprising all patients older than 18 years with the primary
      diagnosis of heart failure and admitted to hospitals in the city of Niteroi,
      whose scores according to the Boston criteria were 8 or above. Proportions were
      compared using the chi-square and Fisher exact tests. RESULTS: The sample
      comprised 203 patients as follows: 1) 98 patients from public hospitals: 50% were
      men, their mean age was 61.1+/-11.3 years, 65% were black, 57% had an income of 1
      minimum wage or less, 56% were illiterate, 66% had ischemic heart disease, their
      mean length of hospitalization was 12.6 days, and the mortality rate adjusted for
      age was 5.23; 2) 105 patients from private hospitals: 49% were men, their mean
      age was 72+/-12.7 years, 20% were black, 58% had an income greater than 6 minimum
      wages, 11% were illiterate, 62% had ischemic heart disease, their mean length of
      hospitalization was 8 days, and the mortality rate adjusted for age was 2.94. The
      distribution of comorbidities and risk factors was similar among the patients of
      the 2 hospital systems, except for the smoking habit, which was more frequent
      among patients from public hospitals. CONCLUSION: In addition to the
      socioeconomic asymmetries, the hospitalization length and the mortality rate
      adjusted for age were greater in patients in the public health system.

PMID- 15042249
TI  - Thyroid hormone levels in patients with aortic dissection: comparison with
      controls and correlation with the percentage of the aortic media composed of
      myxoid deposits.
AB  - OBJECTIVE: Deposits of myxoid material, similar to myxedema related to thyroid
      disease, are described in the medial layer of aortas with dissection. We analyzed
      the clinical or subclinical thyroid dysfunction of patients with this disease and
      analyzed whether a correlation exists between serum levels of thyroid-related
      hormones and the myxoid content of the aortic media. METHODS: We measured, with
      standard methods, serum levels of triiodothyronine (T3), thyroxine (T4), and
      thyroid stimulating hormone (TSH) in 28 patients who underwent aortic dissection
      and free T4 in 20 of them. The same hormones were quantified in 20 control
      patients matched by sex and age. Results were compared by using the Mann-Whitney
      test. We also measured the percentage of the aortic media occupied by myxoid
      material in the surgical specimens of 25 of the patients with aortic dissection
      and analyzed its correlation with hormone levels by using the Pearson test.
      RESULTS: In the 20 pairs in which the amount of hormones was compared, the mean
      values for T3, T4, free T4, and TSH were 1.22ng/mL, 9.89mcg/dL, 1.18ng/dL, and
      5.45 microIU/mL in study patients and 1.15ng/mL, 8.57mcg/dL, 1.32ng/dL, and 2.15
      microIU/mL in controls. Neither these differences nor the correlation between the
      percentage of myxoid content (mean=30%) and the values for T3, T4, free T4, and
      TSH (mean 1.22ng/mL, 9.44mcg/dL, 1.20ng/dL, and 5.08 microIU/mL, respectively; n=
      25) were significant. CONCLUSION: Our data suggest that serum levels of thyroid
      hormones have no relation with the myxoid content in the aortic media in cases of
      aortic dissection.

PMID- 15042251
TI  - Exercise stress testing is useful, safe, and efficient even in patients aged 75
      years or older.
AB  - OBJECTIVE: To describe the clinical and hemodynamic variables obtained with
      exercise testing in elderly patients SW >75 years. METHODS: This study assessed
      100 patients aged 75-94 years (80+/-4 years) undergoing symptom-limited exercise
      testing, 65% of whom were asymptomatic, 25% had nonanginal chest pain, and 10%
      had typical precordialgia. Of the 100 patients, 32% were males, 50% were
      hypertensive, 36% were dyslipidemic, 14% were diabetic, and 9% had had previous
      coronary artery disease. A ramp-adaptation of the Bruce protocol (ramped Bruce
      protocol) was used, preceded by a 1-minute warm-up with no treadmill incline and
      a velocity of 1.0 mph. RESULTS: No complications were observed, and 92% of the
      tests were efficient. On average, the patients reached 95% of the maximum heart
      rate predicted. The mean duration of the test and the mean metabolic equivalent
      reached were, respectively, 6.8 +/-2 minutes and 6.6 +/-2.3 METs. Eleven patients
      had a hyperreactive inotropic response, and 37% of the sample had noncomplex
      ventricular and supraventricular arrhythmias. Eighteen percent of the tests were
      positive for myocardial ischemia. The patients with typical precordialgia had
      more ischemic responses than did those with nonanginal chest pain or those who
      were asymptomatic: 70% vs 16% (P<0.001) and 70% vs 10% (P<0.01), respectively.
      CONCLUSION: The symptom-limited exercise test is useful, safe, and efficient for
      analyzing ischemic and hemodynamic responses, even in very elderly individuals.

PMID- 15042250
TI  - Comparison of the lipid profile, blood pressure, and dietary habits of
      adolescents and children descended from hypertensive and normotensive
      individuals.
AB  - OBJECTIVE: To compare blood pressure, lipid profile, food intake, and
      anthropometric data of adolescents with or without a familial history of
      hypertension. METHODS: Forty-three adolescents from both sexes were assessed,
      with ages ranging from 11 to 18 years old. Twenty had hypertensive parents, and
      23 had normotensive parents. The following variables were examined: blood
      pressure, food intake, anthropometric data, lipid profile, and the results of
      following dietary guidelines (American Heart Association). RESULTS: The offspring
      of hypertensive parents had greater baseline systolic blood pressure (109 +/- 3
      vs. 99 +/- 2 mm Hg, P=0.01), diastolic blood pressure (68 +/- 2 vs. 62 +/- 2 mm
      Hg, p=0.04), greater TC/HDL-C ratio (4.1 +/- 0.3 vs. 3.2 +/- 0.2, P<0.01), and
      greater LDL/HDL-C (2.7 +/- 0.2 vs. 1.9 +/- 0.1, P<0.01), and smaller values of
      HDL-C (43 +/- 2 vs.53 +/- 2 mg/dL, P<0.005). Dietary intake and anthropometric
      measures assessed did not differ between the groups. Even though dietary
      intervention resulted in reductions in body mass index (21.0+/- 1.2 vs. 20.1 +/-
      1.1 kg/m(2), P<0.01), it did not change dyslipidemia present in the offspring of
      hypertensive individuals. CONCLUSION: Increased blood pressure levels and less
      favorable lipid profiles are found among offspring of hypertensive parents, where
      low levels of HDL-C were the most relevant finding regardless of anthropometric
      or nutritional variables.

PMID- 15042252
TI  - Pulmonary veins isolation to treat patients with refractory paroxysmal atrial
      fibrillation: clinical results after a single procedure.
AB  - OBJECTIVE: The purpose of this study was to access the clinical outcome of
      patients submitted to a single procedure of radiofrequency pulmonary veins (PV)
      isolation to treat refractory paroxysmal atrial fibrillation (AF). METHODS: This
      study included 49 consecutive patients (36 male; mean age 54+/-10 years old) who
      had frequent symptomatic paroxysmal AF refractory to at least three
      antiarrhythmic drugs. We used a circular decapolar catheter for mapping PVs -
      left atrial connections and a 4-mm distal tip catheter for ablation (30 W and 50
      C), aiming to achieve electrical isolation of 3 -4 PVs. RESULTS: Twenty-five
      patients (51%) did not present any AF recurrence in a mean follow-up of 12+/-5
      months. Twenty-four (49%) had at least one recurrence during outcome; twenty
      (83%) of them within the first month after the procedure and four after two to
      nine months. After introducing antiarrhythmic drugs 15 (63%) patients were under
      control, 10 were asymptomatic and five complained of sporadic short duration AF
      episodes. Nine (37%) patients remained very symptomatic despite the use of
      antiarrhythmic drugs and were referred to a new procedure of PV isolation. No
      patient presented major complications. At the end of the follow-up, 35 (71%)
      patients remained in stable sinus rhythm with no AF recurrences after a single
      procedure, 50% of them without antiarrhythmic drugs. CONCLUSION: Most patients
      who present symptomatic paroxysmal AF refractory to antiarrhythmic drugs obtain a
      good clinical control after a single PV isolation procedure.

PMID- 15042253
TI  - Persistent respiratory insufficiency secondary to diastolic heart failure.
AB  - This study assessed two 85-year-old patients diagnosed with diastolic heart
      failure and persistent respiratory insufficiency characterized by severe
      obstructive ventilatory disorder and gas exchange alterations. The possibility
      that the respiratory impairment was consequent to primary pulmonary disease was
      excluded. Radiological signs of mild pulmonary edema had been observed in 1 of
      the patients during the 4 years preceding the first hospitalization. The
      respiratory findings were attributed to pulmonary lesions conditioned to the
      presence of chronic pulmonary edema. The incidence of the disease in very elderly
      patients may create an illness that can be called congestive pulmonary disease.

PMID- 15042254
TI  - Pheochromocytoma-induced segmental myocardial dysfunction mimicking an acute
      myocardial infarction in a patient with normal coronary arteries.
AB  - We report a case of pheochromocytoma-induced segmental myocardial dysfunction and
      electrocardiographic abnormalities mimicking an acute anterior myocardial
      infarction, probably due to coronary spasm. Coronary angiography showed normal
      coronaries, and the electrocardiographic and echocardiographic changes resolved
      completely after therapy with an alpha-adrenergic blocker and tumor removal. Our
      case illustrates the importance of maintaining a high index of suspicion in
      patients presenting with an unexpected myocardial event and a hypertensive
      crisis.

PMID- 15042255
TI  - Bone marrow cell transplantation to the myocardium of a patient with heart
      failure due to Chagas' disease.
AB  - We report the first case of bone marrow cell transplantation to the myocardium of
      a patient with heart failure due to chagas' disease. The patient is a 52-year-old
      man with chronic heart failure, NYHA functional class III, despite the optimized
      clinical therapy. The procedure consisted of aspiration of 50 mL of bone marrow
      through puncture of the iliac crest, followed by filtration, separation of the
      mononuclear cells, resuspension, and intracoronary injection. The left
      ventricular ejection fraction at rest, measured using radionuclide
      ventriculography with labeled red blood cells prior to transplantation, was 24%,
      and, after 30 days, it increased to 32% with no change in the medicamentous
      schedule. The following measurements were assessed before and 30 days after
      transplantation: left ventricular end diastolic diameter (82 mm and 76 mm,
      respectively); Minnesota living with heart failure questionaire score (55 and 06,
      respectively); and distance walked in the 6-minute walking test (513 m and 683 m,
      respectively). Our findings show that intracoronary injection of bone marrow
      cells may be performed, suggesting that this is a potentially safe and effective
      procedure in patients with due to Chagas' disease heart failure.

PMID- 15042256
TI  - Left ventricular lipoma.
AB  - We report the case of a 21-year-old female referred to our institution
      complaining of dizziness when standing up, which improved in the dorsal decubitus
      position and at rest, after a few minutes. The symptom, which had lasted for
      years, was not accompanied by vertigo, syncope, or neurological changes, but was
      gradually getting worse. Transthoracic echocardiogram showed a hyperechoic mass
      in the middle-apical region of the left ventricular posterior wall and normal
      pericardium. The cardiac nuclear magnetic resonance allowed the diagnosis of the
      left ventricular tumor suggestive of lipoma. Surgery was performed and the tumor
      was resected. The patient recovered well and is currently asymptomatic.

PMID- 15042257
TI  - [Case 1/2004 - Abnormal Q wave at ECG after mitral valve change in a 20-year-old
      woman].

PMID- 15042258
TI  - [Case 2/2004 - Instituto do Coracao do Hospital das Clinicas da FMUSP].

PMID- 15042259
TI  - [Hemodynamic monitoring in pediatric heart surgery].

PMID- 15042260
TI  - Contextual modulation in V1: the Rossi-Zipser controversy.
AB  - A recent study (Rossi et al. 2001) implied the absence of figure-ground based
      contextual modulation in macaque V1, in contrast to the study on which it was
      modelled (Zipser et al. 1996). We suggest that Rossi et al. may have
      underestimated the extent of modulation by considering only positive and not also
      negative modulation and that their data may have shown figure-ground based
      contextual modulation. We then suggest a paradigm to assess whether it reflects
      figure-ground segregation, boundaries, or both.

PMID- 15042262
TI  - The perceptual control of goal-directed locomotion: a common control architecture
      for interception and navigation?
AB  - Intercepting a moving object while locomoting is a highly complex and demanding
      ability. Notwithstanding the identification of several informational candidates,
      the role of perceptual variables in the control process underlying such skills
      remains an open question. In this study we used a virtual reality set-up for
      studying locomotor interception of a moving ball. The subject had to walk along a
      straight path and could freely modify forward velocity, if necessary, in order to
      intercept-with the head-a ball moving along a straight path that led it to cross
      the agent's displacement axis. In a series of experiments we manipulated a local
      (ball size) and a global (focus of expansion) component of the visual flow but
      also the egocentric orientation of the ball. The experimental observations are
      well captured by a dynamic model linking the locomotor acceleration to properties
      of both global flow and egocentric direction. More precisely the changes in
      locomotor velocity depend on a linear combination of the change in bearing angle
      and the change in egocentric orientation, allowing the emergence of adaptive
      behavior under a variety of circumstances. We conclude that the mechanisms
      underlying the control of different goal-directed locomotion tasks (i.e. steering
      and interceptive tasks) could share a common architecture.

PMID- 15042261
TI  - Long-lasting body leanings following neck muscle isometric contractions.
AB  - Our objective was to investigate the neural mechanisms and the functional
      relevance of motor effects that develop involuntarily following the release of a
      sustained isometric muscle contraction. The few data available in the literature
      deal only with post-contractions occurring in a body segment. Although these data
      emphasise the role of proprioceptive input, the question as to whether this
      phenomenon is of central or peripheral origin remains unclear. Given the leading
      role of neck muscle proprioceptive input in body orientation and posture
      regulation, we designed two experiments to test for postural posteffects after
      voluntary and involuntary neck muscle contraction. The spatiotemporal
      characteristics of the posteffects were analysed by means of stabilometric
      recordings following 30-s isometric contraction of splenius, trapezius and
      levator muscle groups, and 30-s electrically-induced contraction of the levator
      muscle group. Results show that a postural response occurred after voluntary
      contraction of each muscle group tested, which was oriented in the plane of
      action of the muscle, and lasted 14 min at least. In contrast, no clearly
      oriented body leanings were found after electrical stimulation of the levator
      muscle, except for a slight increase in natural postural instability. Data are
      interpreted as a change in the postural reference resulting from an increase in
      proprioceptive inflow accompanying mainly the voluntary muscle contraction.

PMID- 15042263
TI  - Interactions between eye movement systems in cats and humans.
AB  - Eye movements can be broadly classified into target-selecting and gaze
      stabilizing eye movements. How do the different systems interact under natural
      conditions? Here we investigate interactions between the optokinetic and the
      target-selecting system in cats and humans. We use combinations of natural and
      grating stimuli. The natural stimuli are movies and pictures taken from the cat's
      own point of view with a head-mounted camera while it moved about freely in an
      outdoor environment. We superimpose linear global motion on the stimuli and use
      measurements of optokinetic nystagmus as a probe to study the interaction between
      the different systems responsible for controlling eye movements. Cats display
      higher precision stabilizing eye movements in response to natural pictures as
      compared to drifting gratings. In contrast, humans perform similarly under these
      two conditions. This suggests an interaction of the optokinetic and the pursuit
      system. In cats, the natural movies elicit very weak optokinetic responses. In
      humans, by contrast, the natural movie stimuli elicit effectively stabilizing eye
      movements. In both species, we find a unimodal distribution of saccades for all
      stimulus velocities. This suggests an early interaction of target-selecting and
      gaze-stabilizing saccades. Thus, we argue for a more integrated view in humans of
      the different eye movement systems.

PMID- 15042264
TI  - Learning multi-finger synergies: an uncontrolled manifold analysis.
AB  - We used the uncontrolled manifold (UCM) approach to study the synergy formation
      during learning an unusual multi-finger task. The subjects produced accurate
      force ramps with challenging sets of four fingers (two per hand). We tested
      hypotheses on stabilization of the contributions of subsets of effectors to the
      task force ( F(TASK)) and to the moment in the frontal plane (force-stabilization
      and moment-stabilization, respectively). Force signals were used to compute
      magnitudes of hypothetical independent signals, modes. The variance of the mode
      magnitudes across repetitions of the task was partitioned into two components,
      within the UCM ( V(UCM)), which did not affect the average value of a selected
      performance variable (force or moment), and orthogonal to the UCM ( V(ORT)),
      which affected the variable. Prior to practice, subjects showed high error
      indices and failed to show stabilization of each hand's contribution to F(TASK) (
      V(ORT)> or = V(UCM)), while the pronation-supination moment was stabilized by the
      fingers of each hand ( V(ORT)< V(UCM)). The total forces produced by each of the
      two hands showed negative covariation across trials, which supported the force
      stabilization hypothesis but not moment-stabilization hypothesis. Both force
      stabilization and moment-stabilization hypotheses were supported by analysis of
      mode magnitudes to all eight fingers. Over 2 days of practice, the performance of
      the subjects improved considerably. This was accompanied by the emergence of
      within-a-hand force-stabilization for each of the two hands without deterioration
      of moment-stabilization. Quantitatively better within-a-hand force-stabilization
      was seen in male subjects as compared to females throughout the course of the
      experiment. Force-stabilization by all eight fingers improved quantitatively with
      practice. Practice also resulted in higher finger forces in maximal force
      production (MVC) trials and higher forces produced by unintended fingers in
      single-finger MVC trials (higher enslaving). We conclude that the UCM approach
      allows quantifying changes in the coordination of effectors during practice, and
      offers insights into the microstructure of this coordination with respect to
      different performance variables and different subsets of effectors. The approach
      can be used to test whether new synergies emerge in the process of practice.

PMID- 15042266
TI  - Chemometric procedure for the study of fractionated wastewater ingredients using
      RP-HPLC/diode array spectrophotometer.
AB  - A fast screening method of domestic wastewater is reported based on fractionation
      with RP-HPLC and diode array absorption detection implemented by chemometric
      treatment of the spectra using cluster analysis, deconvolution, simulation, and
      multiple regression statistical techniques. The proposed method is limited to
      constituents that absorb in the UV-Vis region which include most of the toxic
      organic pollutants.

PMID- 15042267
TI  - Capacitive chemical sensor for fenvalerate assay based on electropolymerized
      molecularly imprinted polymer as the sensitive layer.
AB  - A capacitive chemical sensor for fenvalerate is reported. By using ac impedance
      measurements the sensor has been based on the decrease in capacitance caused by
      the analyte used as the template in the formulation of an electropolymerized
      molecularly imprinted polymer as receptor layer. Improvement of the insulating
      properties of the sensor was investigated in detail. The capacitive sensor was
      prepared by a deposition of a self-assembled monolayer of 2-mercaptobenzimidazole
      (2-MBI) before electropolymerization of 2-MBI and subsequent treatment with n
      dodecanethiol to eliminate pinholes and defects in the polymerized 2-MBI film.
      From the calibration curve concentrations of fenvalerate up to 9 microg mL(-1)
      could be detected with a linear determination range up to 5 microg mL(-1) and a
      detection limit of 0.36 microg mL(-1). No significant interference was observed
      from common pyrethroid insecticides.

PMID- 15042265
TI  - Participation of primary motor cortical neurons in a distributed network during
      maze solution: representation of spatial parameters and time-course comparison
      with parietal area 7a.
AB  - Traditionally, primary motor cortex (M1) has been thought to be involved solely
      in planning and generating movements. Recent evidence suggests that the arm area
      of M1 plays a role in other functions, such as the representation of serial order
      (Pellizzer et al. 1995, Science 269:702-705; Carpenter et al. 1999, Science
      283:1752-1757) and spatial processing (Georgopoulos et al. 1989, Science 243:234
      236). Previous studies of such cognitive processes have used tasks in which a
      directed arm movement was required, raising a question as to whether this brain
      area is involved in cognitive processing per se, or whether such cognitive
      signals may be gated into the arm area of M1 only when arm movements are
      required. To study this question, we developed a task that required a spatial
      analysis of a complex visual stimulus, but required no arm movement as a
      response. In this task, monkeys were shown an octagonal maze. After an imposed
      delay of 2 to 2.5 s, they indicated whether a path that emanated from the center
      of the maze exited at the perimeter (exit maze) or terminated within the maze (no
      exit maze) by pressing a pedal with their left or right foot, respectively. We
      recorded from 785 cells from the arm area of M1 from two monkeys during the delay
      period of the maze task. We found that cell activity was influenced by both the
      exit status and the direction of the path, beginning soon after the maze was
      displayed. This activity was not related to the activation of arm muscles,
      suggesting that the directional signals observed represented abstract spatial
      aspects of maze processing. Finally, we compared maze-related activity of M1
      neurons with those recorded from posterior parietal area 7a, reported previously
      (Crowe et al. 2004). Interestingly, cells from each area exhibited similar
      properties. Both the exit status and path direction were encoded by cells in M1
      and 7a, although to different extents. An analysis of the time-course of the
      neural representation of these factors revealed that area 7a and M1 begin to
      encode these factors at the same time, suggesting these brain areas are part of a
      distributed system performing the spatial computations involved in maze solution.

PMID- 15042268
TI  - Dilatometric and mass spectrometric investigations on lithium ion battery anode
      materials.
AB  - Lithium ion batteries operate beyond the thermodynamic stability of the aprotic
      organic electrolyte used. In 1 M LiClO(4) propylene carbonate electrolyte, with
      and without the addition of ethylene sulfite as a film forming electrolyte
      additive, we have used in situ electrochemical dilatometry and on-line
      electrochemical mass spectrometry to study the volume expansion/contraction of
      graphitic anodes and the formation of propylene gas, which both can occur during
      the graphite anode reduction (charge) process. The combination of both methods
      allows us to get insights into the respective electrolyte reduction mechanisms.
      The results indicate that the major failure mechanisms of graphitic anodes in
      pure PC electrolyte can be attributed to the intercalation of solvated lithium
      ions and the formation of propylene gas, which causes the graphite particles to
      exfoliate and crack.

PMID- 15042269
TI  - Pulsed amperometric detection of DNA with an ssDNA/polypyrrole-modified
      electrode.
AB  - Pulsed amperometric detection (PAD) of target DNA with platinum electrodes
      modified by single-stranded DNA (ssDNA) entrapped within polypyrrole (ssDNA/Ppy)
      is reported for the first time. Single-stranded DNA 20-mers complementary to the
      target DNA were used to construct the DNA biosensors. Polymerase chain reaction
      (PCR) amplified bovine leukaemia virus (BLV) provirus DNA was used as target DNA.
      Electrochemical impedance spectroscopic (EIS) investigation of ssDNA/Ppy before
      and after incubation in target DNA-containing sample revealed significant changes
      in terms of an imaginary (Z") vs. a real (Z') component. The PAD results were in
      good agreement with EIS investigations. The PAD method was selected, because it
      does not require such sophisticated equipment as it is used to perform EIS and
      the results obtained can be more easily estimated. Optimum conditions for
      performing PAD and evaluating an analytical signal were elaborated. No label
      binding step was necessary for detection of target DNA in PCR-amplified amplicons
      and detection time was reduced by as much as 30-35 min. The changes of PAD
      signals were at least 6-7 times higher if ssDNA/Ppy-modified electrodes instead
      of blank Ppy-modified electrodes were incubated in the target DNA solutions. If
      ssDNA/Ppy modified electrodes were incubated in non-complementary (control) DNA
      solution changes in PAD signals were smaller than those detected after incubation
      in complementary (target) DNA-containing solution by a factor of at least 6-8.

PMID- 15042270
TI  - Estimation of binding constants between ristocetin and teicoplanin and peptides
      using on-column ligand derivatization coupled to affinity capillary
      electrophoresis.
AB  - This work utilizes on-column ligand synthesis and affinity capillary
      electrophoresis (ACE) to determine binding constants ( K(b)) of 9
      flourenylmethyloxy carbonyl (Fmoc)-amino acid derivatives to the glycopeptide
      antibiotics ristocetin (Rist) and teicoplanin (Teic). In this technique, two
      separate plugs of sample are injected on to the capillary column and
      electrophoresed. The initial sample plug contains a D-Ala- D-Ala terminus peptide
      and either one or two non-interacting standard(s). The second plug contains a
      Fmoc-amino acid- N-hydroxysuccinimide (NHS) ester. The electrophoresis is then
      carried out with an increasing concentration of Rist or Teic in the running
      buffer. Upon electrophoresis the initial D-Ala- D-Ala peptide reacts with the
      Fmoc-amino acid yielding a new Fmoc-amino acid- D-Ala- D-Ala peptide derivative.
      Continued electrophoresis results in the binding of Rist or Teic to the Fmoc
      amino acid- D-Ala- D-Ala peptide derivatives. Analysis of the change in the
      relative migration time ratio ( RMTR) or electrophoretic mobility (mu) of the
      Fmoc-amino acid- D-Ala- D-Ala peptide derivatives relative to the non-interacting
      standards, as a function of the concentration of Rist and Teic, yields a value
      for K(b). These findings demonstrate the advantage of coupling on-column ligand
      synthesis to ACE for estimating binding parameters between antibiotics and
      ligands.

PMID- 15042271
TI  - Assessment of drinking water radioactivity content by liquid scintillation
      counting: set up of high sensitivity and emergency procedures.
AB  - In our institute, different procedures have been developed to measure the
      radioactivity content of drinking water both in normal and in emergency
      situations, such as those arising from accidental and terrorist events. A single
      radiometric technique, namely low level liquid scintillation counting (LSC), has
      been used. In emergency situations a gross activity screening is carried out
      without any sample treatment by a single and quick liquid scintillation counting.
      Alpha and beta activities can be measured in more than one hundred samples per
      day with sensitivities of a few Bq/L. Higher sensitivity gross alpha and beta,
      uranium and radium measurements can be performed on water samples after specific
      sample treatments. The sequential method proposed is designed in such a way that
      the same water sample can be used in all the stages, with slight modifications.
      This sequential procedure was applied in a survey of the Lombardia district. At
      first tap waters of the 13 largest towns were examined, then a more detailed
      monitoring was carried out in the surroundings of Milano and Lodi towns. The high
      sensitivity method for the determination of uranium isotopes was used to check
      the presence of depleted uranium in Lake Garda. Reduced equipment requirements
      and relative readiness of radiochemical procedures make LSC an attractive
      technique which can also be applied by laboratories lacking specific
      radiochemistry facilities and experience.

PMID- 15042272
TI  - Modification of the Limulus amebocyte lysate assay for the analysis of glucan in
      indoor environments.
AB  - beta-1,3- D-Glucan is a biologically active component mainly from fungi that has
      been shown in several studies to be related to respiratory health outcomes from
      damp building exposures. Here, we report the development and application of a
      method for the analysis of the glucan extracted in 0.5 N NaOH solution making use
      of an available preparation of Limulus amebocyte lysate (LAL). The method yields
      reproducible beta-1,3- D-glucan measurements from samples of outdoor air, yeast
      cells, fungal spore preparations and ragweed pollen, and is more sensitive than
      competing measurements. The LAL-based measurement compared favourably to that
      based on size-exclusion chromatography using UV and refractive index detection.
      Growth conditions of the fungi did not materially change the concentrations of
      glucan in spores indicating that this is a stable property. Glucan content was
      proportional to spore surface area; however, some species contain higher relative
      spore glucan contents.

PMID- 15042273
TI  - Application of heated electrodes operating in a non-isothermal mode for
      interference elimination with amperometric biosensors.
AB  - Heated electrodes were applied for the non-isothermal operation of amperometric
      glucose biosensors based on glucose oxidase immobilised on the electrode surface
      by entrapment within a polymer layer. The localised deposition of the polymer
      film under simultaneous entrapment of the enzyme was achieved by an
      electrochemically induced pH-modulation in the diffusion zone in front of the
      electrode, thus altering the solubility of the polymer chains. This non-manual
      sensor preparation protocol could be successfully used for the modification of a
      novel indirectly heated electrode. The non-isothermal operating mode allows
      working at the optimum temperature of the enzyme sensors without any thermal
      distortion of the bulk solution. Increased surface temperature of the sensor thus
      accelerates transport as well as kinetic processes, resulting in an enhanced
      amperometric signal. In the presence of interfering compounds such as ascorbic
      acid, the proposed technique allows use of the diverging thermal impact on the
      sensing process, for different electrochemically active compounds, for a
      deconvolution of the amperometric signal at different electrode temperatures. A
      calculation method for determination of glucose in the presence of one
      interfering compound is presented as a basis for a calculative interference
      elimination.

PMID- 15042274
TI  - The effects of chronic hypoperfusion on rat cranial bone mineral and organic
      matrix. A Fourier transform infrared spectroscopy study.
AB  - Arteriovenous malformations (AVM) of the brain, errors in the development of the
      vasculature, produce high flow arteriovenous shunts. They steal blood from
      surrounding brain tissue, which is chronically hypoperfused. Hypoperfusion is a
      condition of inadequate tissue perfusion and oxygenation resulting in abnormal
      tissue metabolism. In the present study Fourier transform infrared (FTIR)
      spectroscopy was used to investigate the effects of hypoperfusion on rat cranial
      bone mineral and organic matrix at the molecular level. FTIR spectroscopic
      analysis revealed that in cranial bones of an experimental group the relative
      amount of carbonate and phosphate groups increased whereas that of protein (amide
      I) decreased. Curve-fitting analysis of the v(2) carbonate band showed that
      amounts of type A and type B carbonates increased slightly ( p=0.423 for both)
      whereas, type L carbonate decreased slightly ( p=0.522) in hypoperfused cranial
      bones. Analysis of the C-H region revealed a significant increase ( p=0.037) in
      the lipid to protein ratio. Because the lipid content is high, hypoperfused
      cranial bone tissue is more prone to lipid peroxidation. Dialdehydes derived from
      lipid peroxidation can make cross-links with collagen and might lead to
      disturbances in the collagen cross-link profile. The 1660 cm(-1)/1690 cm(-1)
      partial area ratio derived from curve-fitting analysis of the Amide I band is
      sensitive to the relative amount of collagen non-reducible cross-link
      hydroxylysyl/lysylpyridinolines (Pyr) and reducible cross-link
      dihydroxylysinonorleucine (DHLNL) and this ratio reflects collagen maturity. In
      chronic hypoperfusion a significant decrease ( p=0.004) was observed in this
      ratio. This means there were less mature collagen cross-links. Disturbances in
      the collagen maturation can affect mineralization process and lead to formation
      of pathologic structures in cranial bones. These findings clearly demonstrate
      that FTIR spectroscopy can be used to extract valuable information at molecular
      level, leading to better understanding of the effect of hypoperfusion on rat
      cranial bones.

PMID- 15042275
TI  - Effects of extended access to high versus low cocaine doses on self
      administration, cocaine-induced reinstatement and brain mRNA levels in rats.
AB  - RATIONALE: The investigation of rodent cocaine self-administration (SA) under
      conditions that promote escalating patterns of intake may provide insight into
      the loss of control over drug use that is central to human addiction. OBJECTIVE:
      This study examines the effects of daily long-access (LgA) SA of high or low
      cocaine doses on drug intake, extinction, reinstatement, and brain mRNA levels.
      METHODS: Three groups of male Sprague-Dawley rats were trained to self-administer
      cocaine during multiple-dose sessions. Short-access (ShA) rats were tested daily
      for multi-dose SA then remained in the chambers for 7 h with no cocaine
      available. LgA rats had access to low (0.5 mg/kg per infusion; LgA-LD) or high
      (2.0 mg/kg per infusion; LgA-HD) cocaine doses for 7 h after multi-dose SA. After
      14 days, responding was extinguished, cocaine-induced reinstatement was
      determined, and preproenkephalin (ppENK), preprodynorphin (ppDYN), corticotropin
      releasing factor (CRF) and dopamine D(2) receptor (D(2)R) mRNA levels were
      measured in various brain regions using a quantitative solution hybridization
      RNase protection assay. RESULTS: Whereas SA was not altered in ShA rats and only
      increased during the "loading phase" in LgA-LD rats, a general escalation of
      intake was found in LgA-HD rats. LgA, particularly LgA-HD, rats were more
      susceptible to reinstatement than ShA rats. Caudate-putamen ppENK and nucleus
      accumbens D(2)R mRNA levels were elevated in LgA-HD rats. Overall, D(2)R mRNA
      levels were positively correlated with reinstatement. CONCLUSIONS: The escalation
      of cocaine SA under LgA conditions is dose-dependent and is associated with
      heightened susceptibility to drug-induced relapse. The characterization of
      neurobiological alterations that accompany escalated SA should facilitate the
      identification of mechanisms underlying the onset of human addiction.

PMID- 15042277
TI  - Effects of different doses of glucose and insulin on morphine state-dependent
      memory of passive avoidance in mice.
AB  - RATIONALE: Behavioral effects of morphine, including its effect on memory, have
      been demonstrated to be influenced by glucose pretreatment. The measurement of
      step-down latency in passive avoidance has been used to study memory in
      laboratory animals. The pre-training injection of 5 mg/kg morphine impaired
      memory, which was restored when 24 h later the same dose of the drug was
      administered. OBJECTIVES: To investigate the effects of glucose and insulin alone
      or in combination with morphine, on pre-test day, on memory recall in mice.
      METHODS: The effects of different doses of glucose (50, 100, and 200 mg/kg, IP)
      and insulin (5, 10, and 20 IU/kg, IP) alone or in combination with morphine, have
      been studied in mice. The blood glucose level and locomotor activity of the
      animals were also measured. RESULTS: Although the administration of glucose alone
      showed no effect on morphine-induced memory impairment, its co-administration
      with morphine resulted in a significant and dose-dependent memory enhancement
      compared with the effects of morphine administration alone. Like glucose, the
      administration of different doses of insulin alone produced no change in the
      memory, but when the drug was co-administered with morphine, it significantly
      reduced morphine-induced memory retrieval. The effect of insulin was the opposite
      of glucose. None of the animals subjected to insulin treatment showed
      convulsions. CONCLUSIONS: Glucose is suggested to increase, on the test day, the
      morphine-induced memory enhancement by three different mechanisms: cholinergic or
      opioidergic modulations, or regulation of the ATP-dependent potassium channels.

PMID- 15042276
TI  - Olanzapine attenuates cue-elicited craving for tobacco.
AB  - RATIONALE: Recent biological conceptualizations of craving and addiction have
      implicated mesolimbic dopamine activity as a central feature of the process of
      addiction. Imaging, and pharmacological studies have supported a role for
      dopaminergic structures in cue-elicited craving for tobacco. OBJECTIVE: If
      mesolimbic dopamine activity is associated with cue-elicited craving for tobacco,
      a dopamine antagonist should attenuate cue-elicited craving for tobacco. Thus,
      the aim of the present study was to determine whether an atypical antipsychotic
      (olanzapine, 5 mg) decreased cue-elicited craving for tobacco. METHOD:
      Participants were randomly assigned to 5 days of pretreatment with olanzapine (5
      mg; n=31) or were randomly assigned to 5 days of a matching placebo (n=28).
      Approximately 8 h after the last dose, participants were exposed to a control cue
      (pencil) followed by exposure to smoking cues. Participants subsequently smoked
      either nicotine cigarettes or de-nicotinized cigarettes. RESULTS: Olanzapine
      attenuated cue-elicited craving for tobacco but did not moderate the subjective
      effects of smoking. DISCUSSION: This study represents one of the first
      investigations of the effect of atypical antipsychotics on cue-elicited craving
      for tobacco. The results suggest that medications with similar profiles may
      reduce cue-elicited craving, which in turn, may partially explain recent
      observations that atypical antipsychotics may reduce substance use.

PMID- 15042279
TI  - Nitric oxide (NO) is not involved in accentuated antagonism for chronotropy in
      the isolated mouse atrium.
AB  - Nitric oxide (NO) is reportedly involved in accentuated antagonism in the canine
      blood-perfused sinoatrial (SA) node, and is thought to modulate cholinergic
      control of heart rate in rabbits. In the present study, we evaluated the
      involvement of NO in accentuated antagonism in an isolated preparation of both
      atria from C57BL/6J mice. Isoprenaline (10(-10) M-10(-7) M) had positive
      chronotropic effects but decreased rather than increased contraction strength.
      Carbachol (10(-8) M-3x10(-6) M) had a concentration-dependent, negative
      chronotropic action. In the presence of a submaximal concentration of
      isoprenaline (30 nM), the same concentration range of carbachol elicited a larger
      decrease in heart rate than in the absence of isoprenaline. The larger decrease
      in heart rate (accentuated antagonism) was not modified by the presence of the NO
      synthase inhibitor N(omega)-nitro-L-arginine methylester (L-NAME). Similar
      results were obtained using ICR strain mice. Isoprenaline increased cAMP content
      but not cGMP; carbachol in the presence of isoprenaline increased cGMP but had no
      further effects on cAMP. In the presence of L-NAME, the increase in cGMP elicited
      by carbachol was attenuated. In the isolated mouse atria, it appears that NO is
      not involved in accentuated antagonism due to lack of coupling between cGMP
      signalling and chronotropic function.

PMID- 15042280
TI  - Identification of thermostable glyoxalase I in the fission yeast
      Schizosaccharomyces pombe.
AB  - Glyoxalase I is a ubiquitous enzyme that detoxifies methylglyoxal, which is
      derived from glycolysis but inhibits the growth of cells from microorganisms to
      mammals. Here, the structural gene for glyoxalase I ( glo1(+)) from the fission
      yeast Schizosaccharomyces pombe was identified. Disruption of glo1(+) enhanced
      susceptibility to methylglyoxal, while expression of glo1(+) in a Delta glo1
      mutant of Saccharomyces cerevisiae restored tolerance to this aldehyde. The
      glo1(+) gene product was purified. The glyoxalase I of S. pombe was a monomeric
      enzyme with a molecular weight of 34000 and the k(cat)/ K(m) value for
      methylglyoxal was 4.3 x 10(7) M(-1) x min(-1). Treatment of purified enzyme with
      EDTA in imidazole buffer completely abolished enzyme activity, whereas the EDTA
      treated enzyme was reactivated by several divalent metal ions, such as Zn(2+),
      Co(2+), Ni(2+) and Mn(2+). The glyoxalase I of S. pombe exhibited fairly high
      thermal stability, and almost 100% activity was retained after incubating the
      enzyme at 60 degrees C for 4 h.

PMID- 15042278
TI  - Effects of serotonergic and noradrenergic antidepressants on auditory startle
      response in patients with major depression.
AB  - RATIONALE: Amplitude, habituation and prepulse inhibition (PPI) of the acoustic
      startle response (ASR) in rodents and humans are sensitive to psychotropic drugs.
      Studies with rodents suggest that an increase or decrease in serotonin level in
      the brain alters several modalities of the ASR. So far, little is known about
      serotonergic and noradrenergic startle modulation in humans. OBJECTIVE: This
      study was designed to investigate the effects of the selective serotonin uptake
      inhibitor sertraline versus the selective noradrenalin uptake inhibitor
      reboxetine on magnitude, habituation and PPI of ASR in patients with major
      depression. METHODS: We studied ASR in 23 patients with the diagnosis of major
      depression according to DSM-IV who were randomly treated either with sertraline
      or with reboxetine. Initially, ASR assessment was carried out when patients were
      drug-free for at least 2 weeks and again after 14 days of treatment. RESULTS: The
      habituation of ASR was strongly attenuated by sertraline and not significantly
      altered by reboxetine. None of the substances altered the startle reactivity. In
      addition, PPI was not altered by sertraline, but reboxetine tended to decrease
      PPI. The startle reactivity at baseline was correlated with improvement of
      depressive symptoms at the end of the study. CONCLUSION: These results provide
      the first evidence for different effects of noradrenergic and serotonergic
      antidepressants on the startle response in depressed patients.

PMID- 15042281
TI  - Hospital-treated minimal-trauma rib fractures in elderly Finns: long-term trends
      and projections for the future.
AB  - We determined the current trends in the number and incidence of hospital-treated
      minimal-trauma rib fractures (low- to moderate-energy traumas typically caused by
      a fall from standing height or less) in Finnish elderly people by collecting from
      the National Hospital Discharge Register all patients 60 years of age or more who
      were admitted to hospitals in 1970-2001 for primary treatment of such fractures.
      The number and incidence (per 100,000 persons) of these fractures clearly
      increased from 268 (number) and 41 (incidence) in 1970 to 737 and 70 in 2001,
      while in younger patients (aged 20-49 years) the trend was decreasing, the
      corresponding numbers being 194 and 10 in 1970, and 153 and 7 in 2001. In the
      elderly Finns, also the age-adjusted incidence of these hospital-admitted rib
      fractures showed an increase, from 37 (1970) to 51 (2001) in women, and from 63
      to 77 in men. In women aged 80 years and over, the age-specific incidence of
      fracture increased from 88 to 186, while in the other age groups only slight
      secular changes were found. If the above-described trends continue, the number of
      elderly Finns admitted to a hospital due to a rib fracture will more than double
      in next three decades.

PMID- 15042283
TI  - Bone structure of the calcaneus: analysis with magnetic resonance imaging and
      correlation with histomorphometric study.
AB  - The purpose of this study was to compare structural measurements obtained from MR
      images of the calcaneus with those obtained from conventional histomorphometry.
      Sagittal magnetic resonance (MR) images of the calcaneus of 24 fresh human
      cadaveric feet were obtained at a spatial resolution achievable in vivo. A three
      dimensional gradient echo-sequence was used with a slice thickness of 700 microm
      and in plane resolution of 172 x 172 microm. Structural analysis (four
      histomorphometric parameters; seven connectivity parameters) was performed in the
      superior region of the calcaneus. Bone biopsy specimens were obtained in the same
      area and were sectioned for histomorphometric study. Most of the MR
      histomorphometric parameters were overestimated (by a factor ranging from 0.8 to
      3), as compared with histomorphometry. However, significant ( P<0.05)
      correlations were found between MR imaging and histomorphometric measurements for
      bone volume/tissue volume, trabecular separation, trabecular number, star volume
      of the marrow space, node count and terminus count. MR histomorphometric
      parameters correlated much better with histomorphometry than connectivity
      parameters. This study suggests that structural parameters characterizing
      cancellous bone in the calcaneus can be derived from MR images in the limited
      spatial resolution regime applicable in vivo.

PMID- 15042282
TI  - Prevalence and risk factors of distal radius and calcaneus bone mineral density
      in Korean population.
AB  - To estimate the prevalence and the related risk factors of low bone mineral
      density of the calcaneus and the distal radius, a community-based study was
      conducted in three rural areas of Korea. A total of 1420 women and 732 men aged
      40 years and older participated in this study. Information on sociodemographic
      characteristics and the potential risk factors for osteoporosis were collected by
      an interviewer-administered standardized questionnaire. Bone mineral density
      (BMD) of the calcaneus and the distal radius were measured by dual-energy X-ray
      absorptiometry (DXA). Three hundred and seventeen women and 183 men aged 20-29
      years who participated in a regular health check-up were used as a reference
      population. Osteoporosis was defined using WHO criteria. Odds ratios of the risk
      factors of osteoporosis were calculated by the unconditional logistic regression
      model. The standardized prevalence of osteoporosis of the calcaneus was 8.4% for
      males and 27.3% for females using the Korean population of year 2000 as a
      standard population. The standardized prevalence of osteoporosis of the distal
      radius was 4.2% for males and 18.8% for females. Older age and lower body mass
      index (BMI) were related with low BMD in both the calcaneus and distal radius in
      males and females. The duration after menopause and the number of live births
      were an independent risk factor for osteoporosis of the calcaneus (OR = 1.1, 95%
      CI = 1.00-1.11; the duration after menopause; OR = 2.0, 95% CI = 1.20-3.35, the
      number of live birth) and a familial history of non-traumatic fractures or
      osteoporosis among the first-degree relatives was significantly related to a
      increased risk of osteoporosis of the distal radius in females (OR = 2.9, 95% CI
      = 1.36-6.31).

PMID- 15042284
TI  - The relative effect of endogenous estradiol and androgens on menopausal bone
      loss: a longitudinal study.
AB  - OBJECTIVE: The aim of this study was to assess the relative strength of the
      association of endogenous estradiol and androgens with bone loss at the lumbar
      spine and femoral neck during the menopausal transition. DESIGN: A longitudinal
      study of a population-based cohort of 159 Australian-born women who at baseline
      had a mean age of 50.0 years (SD=2.4) and had menstruated in the prior 3 months.
      BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine and
      femoral neck on up to three occasions. RESULTS: Of the 159 participants, 50 had
      two BMD measurements and 109 had a third measure. The mean time between the first
      and final measures for the whole group was 39 months and at the time of the final
      measures 49% of the participants had become postmenopausal. The mean percentage
      change/year in lumbar spine BMD was -0.9% (95% CI, -1.1 to -0.6) and at the
      femoral neck, -0.5% (95% CI, -0.7 to -0.2). A highly significant association with
      estradiol at the final time point was found, whereas the contribution of
      estradiol at baseline was negligible. The variance explained by estradiol levels
      was 19% and 11% for change in BMD at the LS and FN, respectively. Excluding
      baseline estradiol values and using the average of change in BMD at the LS and
      FN, the final regression equation estimated that an estradiol level of 330 pmol/l
      (95% CI, 274 to 386) and 245 pmol/l (95% CI, 194 to 296) is required for
      preservation of LS and FN BMD, respectively. A stepwise linear regression model
      was used to assess the effect of age, BMI, estradiol, testosterone, DHEAS, SHBG,
      and free testosterone index on changes in BMD and found that only the final
      estradiol level had a significant association with change in BMD. CONCLUSION:
      Endogenous estradiol was the only hormone among those investigated to have a
      significant effect on bone mineral density during the menopausal transition.

PMID- 15042285
TI  - Fixation strength of a novel bioabsorbable expansion bolt for patellar tendon
      bone graft fixation: an experimental study in calf tibial bone.
AB  - This biomechanical study compares the initial fixation strength of a novel
      bioabsorbable two-shell expansion bolt (EB) with that of a well-established
      interference-screw technique in bone-patellar tendon-bone (BPTB) reconstruction
      in a calf model. Thirty tibia plateaus (age 5-6 months) were assigned to three
      groups: In groups I and II, trapezoidal bone plugs of BPTB grafts were fixed with
      bioabsorbable poly-L-lactide interference screws (8 x 23 mm) or titanium
      interference screws (8 x 25 mm) respectively. In group III, semicircular grafts
      were fixed using bioabsorbable poly-D, L-lactide expansion bolts (5.8/8.7 x 10 x
      35 mm). The tensile axis was parallel to the bone tunnel, and the construction
      was loaded until failure applying a displacement rate of 1 mm per second. In
      group II the mean ultimate loads to failure (713 N+/-218 N) were found to be
      significantly higher than those of groups I (487 N+/-205 N) and III (510 N+/-133
      N). Measurement of stiffness showed 45 N/mm+/-13.3 in group I, 58 N/mm+/-17.4 in
      group II and 46 N/mm+/-6.9 in group III, and did not demonstrate significant
      differences. We found a correlation between insertion torque and wedge insertion
      force and ultimate loads to failure in all groups (r=0.53 in group I, r =0.54 in
      group II, and r =0.57 in group III). Cross-section planes of bone tunnel
      increased by 51%, 30% and 31% respectively, following insertion of screws or
      expansion of bolts (p<0.05). We conclude that ACL graft fixation by means of the
      presented expansion bolt demonstrates a fixation strength similar to the
      established bioabsorbable screw fixation, and is a reasonable alternative
      fixation method, especially since some of the specific pitfalls of screw fixation
      can be avoided.

PMID- 15042286
TI  - Graft healing in a bone tunnel: bone-attached graft with screw fixation versus
      bone-free graft with extra-articular suture fixation.
AB  - The purpose of this study was to clarify differences in tendon graft-to-bone
      tunnel healing between bone-attached tendon grafts with interference-screw
      fixation and bone-free tendon grafts with extra-articular suture fixation. In 42
      Japanese White rabbits, anterior half replacement of the medial collateral
      ligament was performed using half of the ipsilateral patellar tendon. At the
      femoral attachment, the bone-plug-attached graft was fixed with an interference
      screw (group A). The bone-plug-free graft was fixed by the extra-articular suture
      fixation technique with sutures tied over a button (group B). Biomechanical and
      histological evaluations were performed at 2, 4 and 8 weeks postoperatively. In
      biomechanical evaluation, at 2 or 4 weeks 27 of 28 specimens (96%) were pulled
      out from the femoral tunnel, while one 4-week specimen and all four 8-week
      specimens failed at the graft's mid-substance. At 2 weeks, the maximum failure
      load was 25+/-10 N and 24+/-6 N for group A and group B respectively (mean+/-SD).
      At 4 weeks, the maximum failure load was 42+/-17 N and 35+/-15 N respectively.
      There were no significant differences in maximum pullout failure load between the
      groups at 2 or 4 weeks postoperatively. (P=0.887 at 2 weeks and P=0.339 at 4
      weeks using ANOVA measurement). Histologically, the bone-attached grafts showed
      partial bone-to-bone union at the graft-bone tunnel interface at 4 weeks, and
      complete bony union at 8 weeks. The bone-free grafts exhibited newly formed
      Sharpey-like collagen fibers at 4 weeks, and strong connection by mature
      granulation tissue at 8 weeks. Graft-to-bone tunnel healing of bone-attached
      graft with screw fixation and bone-free graft with extra-articular suture
      fixation are comparable in terms of biomechanical evaluation during the early
      postoperative periods.

PMID- 15042287
TI  - Helicobacter pylori in intensive care.

PMID- 15042288
TI  - Ventilator-associated pneumonia: caveats for benchmarking.

PMID- 15042289
TI  - Advantages and disadvantages of different nasal CPAP systems in newborns.
AB  - OBJECTIVE: To compare three different systems of continuous positive airway
      pressure (CPAP): the naso-pharyngeal tube and two-prong systems in newborns,
      focusing on duration of CPAP, side effects and cost. DESIGN: Randomized clinical
      study. PATIENTS: Between July 2000 and September 2001 newborns were randomized to
      three different CPAP systems. Forty infants in two weight groups (>2500 g and
      1250-2500 g; 20 patients in each group) were included. RESULTS: In the group
      >2500 g the median duration of CPAP was 1.1 days (range 0.25-14.3 days). The
      median time on a naso-pharyngeal CPAP was 1 day (range 0.25-14.3 days), on Hudson
      prongs 1.6 days (range 0.5-3.3 days) and on the Infant Flow system 0.7 days
      (range 0.3-13.6 days; p>0.05 for comparison between groups, Fisher's exact test).
      With naso-pharyngeal CPAP, 2 patients developed moderate nasal injuries. On
      Hudson, 2 patients developed moderate and three mild nasal injuries. One patient
      on the Infant Flow showed mild and one moderate nasal injuries. In the weight
      group 1250-2500 g the median duration of CPAP was 1.1 days (range 0.1-7.0 days).
      The median time on the naso-pharyngeal tube was 0.9 days (range 0.1-7 days), on
      Hudson prongs 1.1 days (range 0.7-6.6 days) and on the Infant Flow system 1.3
      days (range 0.25-5.9 days; p>0.05 for comparison between groups, Fisher's exact
      test). With a naso-pharyngeal tube, one infant developed mild and one moderate
      nasal injuries. On Hudson prongs, two had moderate nasal injuries. On Infant
      Flow, one newborn showed a severe nasal injury and two mild injuries. None of the
      patients developed a pneumothorax. CONCLUSION: The naso-pharyngeal tube is an
      easy, safe and economical CPAP system usable with every common ventilator. For
      very low birth weight newborns, a prong system may have advantages.

PMID- 15042290
TI  - [Chemoprevention of prostate cancer].
AB  - Despite advances in the detection and management of prostate cancer, this disease
      remains a major cause of morbidity and mortality in men. Increasing attention has
      focused on the role of chemoprevention for prostate cancer, i.e., the
      administration of agents that inhibit one or more steps in the natural course of
      prostate carcinogenesis. We review prostate cancer chemoprevention studies in
      Europe. Published studies were identified in a search of MEDLINE. Information
      about ongoing studies was provided by author access to protocols. A variety of
      chemoprevention studies have focused on the role of dietary factors, vitamins,
      and trace elements in prostate cancer. Some of these studies have been
      prospective, randomized, and double-blinded, while others have used retrospective
      or epidemiological approaches. Large-scale randomized studies are also evaluating
      the role of 5alpha-reductase inhibitors, which inhibit the conversion of
      testosterone to the more potent androgen dihydrotestosterone. Robust evidence is
      lacking for the value of chemopreventive agents in prostate cancer. Current
      evidence does suggest that vitamin E and selenium may have a role in prostate
      cancer chemoprevention. Data from two studies, one examining the type 1 5alpha
      reductase selective inhibitor finasteride and the other using the dual 5a
      reductase inhibitor dutasteride, will determine the benefits of androgen
      inhibition strategies for prostate cancer chemoprevention.

PMID- 15042291
TI  - [Prognosis of Wilm's tumor in the course of the SIOP trials and studies].
AB  - Wilms' tumor is the most common malignant renal tumor in children. Dramatic
      improvements in survival have occurred as the result of advances in anesthetic
      and surgical management, irradiation, and chemotherapy. Today treatments are
      based on several multicenter trials and studies conducted by the SIOP in Europe
      and NWTS in the USA. The main objectives of these trials and studies are to treat
      patients according to well-defined risk groups in order to achieve the highest
      cure rates, to decrease the frequency and intensity of acute and late toxicity,
      and to minimize the cost of therapy. The SIOP trials and studies largely focus on
      the issue of preoperative therapy whereas patients treated according to NWTS are
      primarily operated.

PMID- 15042292
TI  - [Radiofrequency ablation of liver metastases].
AB  - The liver is the second only to lymph nodes as the most common site of metastatic
      disease irrespective of the primary tumor. Up to 50% of all patients with
      malignant diseases will develop liver metastases with a significant morbidity and
      mortality. Although the surgical resection leads to an improvement of the
      survival time, only approximately 20% of the patients are eligible for surgical
      intervention. Radiofrequency (RF) ablation represents one of the most important
      alternatives as well as complementary methods for the therapy of liver
      metastases. RF ablation can lead in a selected patient group to a palliation or
      to an increased life expectancy. RF ablation appears either safer (vs.
      cryotherapy) or easier (vs. laser) or more effective (percutaneous ethanol
      instillation [PEI], transarterial chemoembolisation [TACE]) in comparison with
      other minimal invasive procedures. RF ablation can be performed percutaneously,
      laparoscopically or intraoperatively and may be combined with chemotherapy as
      well as with surgical resection. Permanent technical improvements of RF systems,
      a better understanding of the underlying electrophysiological principles and an
      interdisciplinary approach will lead to a prognosis improvement in patients with
      liver metastases.

PMID- 15042294
TI  - ["Seronegative" myasthenia with antibodies against muscle-specific tyrosine
      kinase].
AB  - About 10-20% of patients with generalized myasthenia gravis do not have
      acetylcholin receptor (AChR) antibodies and are referred to as having
      "seronegative" myasthenia. Recently, antibodies to muscle-specific kinase (MuSK),
      which mediates aggregation of AChR, were detected in half of these patients. We
      investigated six patients with seronegative myasthenia and identified two
      characteristic cases with MuSK antibodies. A 56-year-old woman developed ptosis
      and double vision followed by bulbar symptoms and respiratory insufficiency. She
      showed moderate response to treatment with pyridostigmine and no response to
      prednisolone, azathioprine, or intravenous immunoglobulin but good response to
      several plasma exchanges. A 46-year-old man with exercise-induced weakness of the
      upper limbs and mild bulbar and respiratory symptoms had a milder course for 9
      years. These cases highlight the clinical spectrum of MuSK-positive myasthenia
      and the differences to AChR-positive myasthenia with predominant bulbar symptoms
      and often severe symptoms with respiratory insufficiency. Finally, they
      illustrate the therapeutic difficulties with less response to pyridostigmine and
      immunosuppressive drugs.

PMID- 15042293
TI  - [Principles, technology and indication of hyperthermia and part body
      hyperthermia].
AB  - Clinical hyperthermia with controlled alteration of temperature (40 to 44 degrees
      C) in the target area is used in interdisciplinary treatment concepts for tumor
      treatment in combination with radiation and/or radiotherapy. Besides the direct
      cytotoxic power of hyperthermia there is an immunomodulatory effect and a
      radiation and chemotherapy sensitizing effect in the heated tissue. Clinical
      hyperthermia is an invasive or non-invasive supply of energy to the body of the
      patient, which leads to an artificial heating of the tumor and the surrounded
      tissue. The clinical hyperthermic procedures should take into account the
      oncologic disease and its pattern of organ involvement. There are three different
      types of hyperthermia: local hyperthermia (LHT), regional hyperthermia (RHT) and
      part body hyperthermia (PBH). PBH is used to heat regions of the body in case of
      metastatic disease, e. g. to the abdomen. I and phase II trials could show that
      the effects of radiation and chemotherapy can be altered by the simultaneous
      addition of hyperthermia. Data of trials involving skin metastasis in malignant
      melanoma, local relapse in breast cancer, tumors of the head and neck with
      regional lymph node metastasis, as well as trials in colorectal tumors, bladder
      cancer, pancreatic cancer, cervical cancer and sarcoma are presented. The results
      shows, that response to treatment can be improved by hyperthermia.

PMID- 15042296
TI  - [Levetiracetam in combined therapy for focal epilepsy: experience with 80
      patients].
AB  - BACKGROUND: Levetiracetam was released in 2000 as an antiepileptic drug for add
      on treatment of focal epilepsies. Its efficacy and tolerability were investigated
      in this retrospective study. METHODS: The effects of add-on treatment with
      levetiracetam on seizure frequency and side effects were analyzed retrospectively
      in 80 consecutive patients with focal epilepsy. RESULTS: With a mean follow-up of
      12.3 months, 18.8% of patients treated with levetiracetam became seizure-free,
      and additional 15.0% and 3.8% had reductions in seizure frequency of 75% and 50%,
      respectively. Increasing the dosage to more than 3,500 mg/day did not improve
      efficacy but could induce a paradoxical increase in seizure frequency and psychic
      side effects. Levetiracetam was efficacious against all seizure types
      independently of focus localization. There was no evidence for the development of
      tolerance with longer periods of treatment. The most common adverse effects were
      somnolence and aggressiveness; tolerability did not decrease with rapid
      titration. CONCLUSIONS: Levetiracetam is a potent and generally well tolerable
      new antiepileptic drug which is also efficacious in patients with difficult-to
      treat focal epilepsies.

PMID- 15042295
TI  - [Analysis of grip force during object manipulation. Method for the objective
      measurement of physiological normal and impaired hand function].
AB  - The control of prehensile finger forces is an essential feature of all skilled
      manual performance. The basic aspects of healthy grip force control have been
      well documented within the past two decades. In healthy subjects, grip force is
      accurately adjusted to the mechanical object properties such as weight, surface
      friction, and shape: when we move a hand-held object, grip force is modulated in
      parallel with movement-induced load fluctuations without an apparent temporal
      delay. At all phases of the movement, grip force is always slightly higher than
      the minimum necessary to prevent the object from slipping. The absence of a
      temporal delay between grip and load force profiles implies that the central
      nervous system is able to predict load variations precisely before the intended
      manipulation, and consequently regulates grip force in anticipation. Feedback
      from the grasping fingertips is used to adjust the force level efficiently to the
      actual load requirements. Pathologic grip force control affects the efficiency of
      the forces produced and the predictive temporal coupling between grip and load
      force profiles. Here we demonstrate pathologic grip force control in various
      neurologic disorders. The analysis of grip force control is simple and highly
      sensitive for detecting healthy and pathologic motor behaviour. The examination
      of grip force control is well suited for an objective evaluation of therapy
      during sensorimotor rehabilitation of deficient hand function.

PMID- 15042297
TI  - [Considerations in the combination of clozapine and benzodiazepines].
AB  - Serious adverse events and even sudden death have been reported during
      administration of the combination of clozapine and benzodiazepines. However, this
      combination does not necessarily result in increased frequency of serious adverse
      events. Thus it is not regarded as an absolute contraindication and might be
      useful in distinct clinical situations, e.g., during the occurrence of a
      malignant neuroleptic syndrome, "catatonic dilemma," or severe agitation during
      clozapine treatment. In the following report, certain suggestions on how to deal
      with this combination therapy are provided which may provide a basis for
      discussion that ultimately may lead to the formulation of guidelines for this
      combination therapy. Such guidelines may help psychiatrists in dealing with this
      combination in clinical situations. Moreover, the formulation of such guidelines
      would help with forensic issues in case of serious adverse events occurring
      during this combination therapy.

PMID- 15042298
TI  - [Operative stabilization of traumatic instabilities of the lower cervical spine.
      Experience with an angle instable anterior plate-screw system in 95 patients].
AB  - Traumatic instabilities of the cervical spine between C2 and T1 can successfully
      be treated by anterior spondylodesis with a plate and a tricortical iliac bone
      graft in most cases. Various plate-screw systems are available.Ninety-five
      patients with traumatic instability of the lower cervical spine were operated on
      using the Codman anterior cervical plate system (ACPS). The mean age was 42.1
      years, and the mean follow-up was 14.9 months.Twenty-three patients with initial
      neurological deficits demonstrated an improvement of their symptoms at follow-up.
      No pseudarthrosis was detected among the 86 patients who were reexamined. Implant
      related complications included one pulling out of a plate and one asymptomatic
      screw loosening. The Codman anterior cervical plate system (ACPS) is easy to use,
      safe, and a reliable method to stabilize instable injuries of the cervical spine
      by an anterior approach. The risk of dural or neurological injury is avoided.
      Implant-related complications are rare.

PMID- 15042299
TI  - [Periprosthetic supracondylar femoral fractures: LISS or retrograde
      intramedullary nailing? Problems with the use of minimally invasive technique].
AB  - Retrograde intramedullary locking nailing as well as the LIS system are
      propagated as minimally invasive treatment options for distal femoral fractures
      following total knee arthroplasty. In a retrospective study, we reviewed the
      clinical results after operative treatment of 18 periprosthetic supracondylar
      femoral fractures. The fracture was stabilized with the less invasive
      stabilization system (LISS) in nine patients (average age: 80.3 years) and with a
      retrograde intramedullary locking nail in the remaining nine patients (average
      age: 76.8 years). The mean follow-up was 18.2 months (6-35 months). We did not
      find significant differences concerning the operation time (nailing 99.8 min vs
      102.3 min with the LISS) or the length of stay in the hospital (nailing 10.6 days
      vs 12.7 days with the LISS). In one patient of the nailing group we found a
      valgus malalignment of 18 degrees. Seven patients in each group were satisfied
      with the clinical results. In one patient of the LISS group a revision due to an
      infection was necessary. In one patient of the nailing group a reosteosynthesis
      had to be performed. To sum up, both systems are useful tools in the treatment of
      dislocated periprosthetic fractures and both systems are not without any
      problems. However, under special consideration of the complications we found in
      our study, the LISS seems to be a better alternative in osteoporotic bone with a
      small distal fragment. The choice of the optimal implant should therefore depend
      on the type of fracture and knee arthroplasty, the type of bone, and the
      experience of the surgeon.

PMID- 15042300
TI  - [Open pelvic fracture. Treatment strategy and results for 12 patients].
AB  - This article presents treatment priorities for open pelvic fracture and the
      results of 12 patients. In a retrospective study we analyzed 12 patients treated
      at a level 1 trauma center between 1994 and 1998 of whom eight were male and four
      female with an average age of 29.6 years. Six type C (6 x III degrees open) and
      six type B (4 x II degrees and 2 x III degrees open) were identified. On average,
      15 EKs were necessary within the first 12 h of treatment (type C=17, type B=13).
      All type C fractures underwent emergency stabilization with the pelvic C-clamp.
      Early laparotomy was performed in 60%. Perineal laceration was identified in 58%,
      followed by nerve and plexus lesions in 42%, injuries of the genitourinary tract
      in 33%, and lesions of the fecal stream in 25%. Altogether, there were more
      peripelvic injuries associated with type C fracture than with type B (12 vs 8).
      On average, there were 27 second-look operations necessary with 3-.2 operations
      per patient. The average stay in the ICU was 82 days (80-360); 25% died. Control
      of hemorrhage is fundamental; therefore, emergency stabilization of the pelvis is
      essential followed by surgical procedures. Early surgical definitive
      stabilization of the fracture decreases septic complications. Such complex
      injuries should be treated at specialized trauma centers.

PMID- 15042301
TI  - [Identification of high-risk patients after minor craniocerebral trauma.
      Measurement of nerve tissue protein S 100].
AB  - The indication for an initial cranial computed tomography (CCT) in minor head
      trauma (MHT) patients remains the subject of discussion. The aim of this study
      was to investigate whether a newly developed, rapid test system (ELECSYS S100,
      Roche Diagnostics) might allow a diagnostically valid, reproducible measurement
      of S 100 in MHT patients. Blood samples were drawn from 75 MHT patients, a CCT
      scan was performed, and those with a post-traumatic intracranial lesion counted
      as CCT+. Results were compared to a healthy control group (n=17). Of the 75
      patients included in the study, 14 were stratified as CCT+. The systemic
      concentration of S 100 in these CCT+ patients was significantly increased (0.31
      microg/l) compared to the healthy control group (0.04 microg/l) as well as to the
      CCT-negative patients (0.08 microg/l). The ELECSYS S100 system allows a rapid,
      valid, and reproducible assessment of S 100B in patient serum and this
      concentration is significantly elevated in patients suffering from intracranial
      lesions as shown by initial CCT scan. Hence, this study is the basis for a
      multicenter trial currently underway to confirm the results of our pilot study.

PMID- 15042302
TI  - AAV gene transfer to the retina does not protect retrovirally transduced
      hepatocytes from the immune response.
AB  - Gene therapy of inherited hepatic disease relies on sustained expression of the
      therapeutic transgene. In many instances, such expression will require immune
      tolerization to the non-self therapeutic transgene product. We previously
      demonstrated that a cytotoxic immune response eliminated hepatocytes after in
      vivo transduction using recombinant retroviral vectors. In the present study we
      investigated whether prior gene transfer to the retina, which is suspected to
      induce immune tolerance, could alleviate the immune response occurring after
      retrovirus mediated gene transfer to the liver. Retinal cells were transduced
      using adeno-associated viral vectors harbouring a beta-galactosidase transgene.
      Sixty days later, regenerating hepatocytes were transduced after partial
      hepatectomy using a recombinant retrovirus carrying the transgene. Three weeks
      later, anti beta-galactosidase antibodies were present in all animals.
      Elimination of the transduced hepatocytes eventually occurred in all animals by 2
      months after liver gene transfer, although sustained beta-galactosidase
      expression was still present in the retina in 66% of the animals. We conclude
      that although the retina behaves as an immunoprivileged site, gene expression in
      the subretinal space is not sufficient to induce immune tolerance to a transgene
      product expressed in the liver.

PMID- 15042303
TI  - Refinement of the DFNA4 locus to a 1.44 Mb region in 19q13.33.
AB  - Many forms of autosomal dominant non-syndromic hearing impairment are known.
      While the underlying gene defects and causative mutations have been discovered
      for some forms, the gene responsible for DFNA4 has remained elusive to date.
      Examination of a German four-generation kindred led to the identification of a
      1.44 Mb map segment in contig NT_011109 as being the most likely DFNA4 candidate
      region in 19q13.33. The recombination breakpoints in this family and the
      intervals of two previously reported DFNA4 families allowed us to delineate a
      minimum consensus region between the markers D19S879 and D19S246. In our family,
      a maximum two-point LOD score of 4.5 was obtained at theta = 0 for the marker
      D19S867. Within the refined DFNA4 interval the public databases list more than 50
      genes, from which several appear to be promising DFNA4 candidates due to
      similarities with animal models and with other causative genes involved in
      hearing disability.

PMID- 15042304
TI  - [Voice handicap in patients with organic and functional dysphonia].
AB  - BACKGROUND: The goal of this study was to assess and compare voice handicap in
      patients with benign organic and functional dysphonia. PATIENTS AND METHODS:
      Voice handicap was assessed using a German version of the Voice Handicap Index. A
      total of 108 German speaking patients, 64 women and 44 men aged 45.3+/-15.1 years
      with benign organic ( n=69) or functional ( n=39) voice disorders completed the
      questionnaire immediately after clinical examination and without knowing their
      individual diagnosis. Fifty individuals without voice complaints and normal voice
      status, 28 women and 22 men aged 47.1+/-15.5 years, served as controls. RESULTS:
      Significant differences ( P<0.001) were found between all dysphonic patients and
      the control group. When comparing dysphonic patients according to their gender
      and diagnosis group (organic or functional) no significant differences were
      detected. CONCLUSION: It can no longer be assumed that patients with functional
      voice disorders over emphasize their disease. The data obtained in this study
      prove that there are no gender specific differences in the way a voice disorder
      is experienced. There are also no differences in the way patients with a
      different language background experience their voice handicap.

PMID- 15042306
TI  - [Interdisciplinary surgery and telemedicine].
AB  - Surgical therapy is becoming increasingly complex. Besides new surgical
      techniques, sophisticated diagnostic methods and innovative interventional
      procedures must be integrated into the therapeutic concept to increase the
      efficacy of surgery. Accurate application of these techniques requires close
      cooperation between surgeons, other medical specialists, and technicians.
      Consequently, there is a significant need for structures promoting efficient
      communication, organization, and interaction in surgical departments. New
      techniques developed from telecommunication and information technology enable the
      transferal of complex medical data at any time to any place and are therefore the
      basis for telemedical applications. Telemedicine and other new techniques such as
      virtual operation planning, simulation, and intraoperative navigation promise to
      increase the efficacy of surgical therapy in the future. This paper provides an
      overview of the applications of telesurgery and currently available techniques.

PMID- 15042307
TI  - [Interdisciplinary operative procedure-pelvis and abdomen].
AB  - Surgery for tumors in the abdomen, retroperitoneum, and pelvis requires technical
      skills and expertise sometimes beyond the capability of a single surgeon. This
      holds especially true if curative tumor resection involves replacement of
      arteries and veins, which needs careful planning to avoid long periods of
      ischemia, and the selection and provision of vascular substitutes according to
      anatomical position, postsurgical therapy, and adjuncts to avoid thrombosis and
      infection of vascular grafts. Since the works of Fortner, the value of close
      collaboration between general and vascular surgeons has been demonstrated, but
      many of the former even today continue to attempt the operation alone, although
      the result is not always a masterpiece. The authors refer to their experience in
      major tumor surgery in either the single management of vascular complications or
      collaboration. The potential value of close collaboration is presented by
      negative examples, and a plea is made for a less "eminence"-based management of
      these sometimes difficult cases, which is based on vast positive experience with
      vascular diseases of the aorta and the visceral and iliac arteries and veins,
      including safety measures and adjuncts.

PMID- 15042305
TI  - [Alcohol related diseases of the head and neck].
AB  - Chronic consumption of alcohol is an accepted social custom worldwide. In the
      upper aerodigestive tract, local morphologic, metabolic and functional
      alterations can be present due such consumption. Gastroesophageal reflux or
      alterations in sleep structure are typical examples of functional disorders.
      While alcohol was initially described as a risk enhancer only in smokers, a
      number of epidemiological studies have now shown that chronic alcohol consumption
      increases the risk of head and neck cancer independently of exposure to tobacco
      smoke. In addition, alcohol leads to an accumulation of pathologic microbes
      within the mucosa, leading to chronic infection. Susceptibility to carcinogens
      and cell proliferation in the mucosa are increased, resulting in genetic changes
      with the development of dysplasia, leucoplakia and carcinoma. Chronic alcohol
      consumption is correlated with an increased risk of cancer and increased
      mortality in a dose-dependent relationship. A number of biologically plausible
      mechanisms exist by which alcohol may cause cancer.

PMID- 15042308
TI  - [Cuff pressure monitoring and regulation in adults].
AB  - OBJECTIVES: In adults the use of cuffed endotracheal tubes is the standard
      technique. Nitrous oxide increases the cuff pressure secondary to diffusion
      through the cuff membrane. The aim of the study was to verify a newly designed
      cuff pressure regulating device and comparison of postoperative complications.
      METHODS: In a prospective, randomized, open trial the cuff pressure and the
      incidence of postoperative complications (e.g., hoarseness, coughing and pain
      while swallowing) were measured using the newly designed automatic pressure
      monitoring and regulating device Cuff Pressure Control (Tracoe) and a
      conventional handheld manometer. A total of 40 patients were assigned to the
      automatic group with a goal of 25.5 cmH(2)O and 40 patients to the conventional
      group where the pressures were kept between 20 cmH(2)0 and 40 cmH(2)0 with
      intermittent measurements and manual pressure release. RESULTS: The automatic
      device reliably maintained the pressure at the chosen constant level within +/-2
      cmH(2)O. In the control group increases in cuff pressure to 40 cmH(2)O were
      common. The incidence of postoperative complications in both groups was not
      significantly different. CONCLUSIONS: In conclusion our data demonstrate that the
      automatic cuff pressure and regulation device was useful and reliable in an adult
      population of intubated patients in the studied pressure range.

PMID- 15042309
TI  - [Legal validity of patients' "living wills". Comment on the German Federal
      Supreme Court verdict of 17 March 2003].

PMID- 15042311
TI  - [Procedure optimization in hospital management].
AB  - Starting January 1st 2004 the German diagnosis-related group (DRG) system was
      established for in-patient cases. Consequently, the detection and realization of
      cost-saving potentials are becoming more and more important. For a successful
      future, efficient allocation of resources is essential. Economically, anaesthesia
      related time delays during perioperative work-flow should be minimized. Since
      numerous entities contribute to perioperative care, it is extremely complex to
      analyze and optimize this process flow. In this publication single steps leading
      to an optimized perioperative process flow will be presented: documentation of
      predefined time points, calculation of relevant time intervals and analysis of
      key numbers for complex settings. Single steps of the given process analysis will
      be demonstrated using data from surgical patients at the University Hospital
      Schleswig-Holstein, Campus Kiel. The attached data collection sheets can be used
      by interested hospital departments and are meant to serve as a template for
      further process analyses. Based on the shown analysis, an example will be given
      to develop an optimized work-flow as a standard operating procedure (SOP). The
      implementation of the SOP module in an interdisciplinary clinical pathway (CP),
      which defines efficient medical care from admission to discharge, is mainly
      responsible for decreased process costs but increased quality of care.

PMID- 15042312
TI  - Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in
      nonhuman primates.
AB  - PURPOSE: Acetylation of histones by histone acetyl transferases (HATs) leads to
      transcriptional activation, while histone deacetylase (HDAC) activity leads to
      transcriptional repression. Abnormalities of histone acetylation are associated
      with the malignant phenotype. Depsipeptide (FR901228) inhibits HDAC and has shown
      anticancer activity in preclinical models. We studied the plasma and
      cerebrospinal fluid (CSF) pharmacokinetics of depsipeptide in a nonhuman primate
      model that is highly predictive of human CSF penetration. DESIGN: Depsipeptide
      was administered intravenously at a dose of 10 mg/m(2) over 4 h to three
      different animals. Serial blood samples were obtained from all animals and serial
      CSF samples were obtained from two animals. Plasma and CSF concentrations of
      depsipeptide were measured using liquid chromatography/tandem mass spectrometry.
      Concentration-versus-time data were modeled using model-independent and model
      dependent methods. RESULTS: The peak plasma concentration (median+/-SD) was 245+/
      50 n M and occurred within the first 2 h of the infusion. The terminal half-life
      was 205+/-315 min, the AUC extrapolated to infinity was 50+/-15 micro M.min, and
      the total body clearance was 350+/-65 ml/min/m(2). In the two animals that had
      CSF sampling performed, the CSF peak concentration was 3.6 n M in one animal and
      2.3 n M in the other, and the CSF half-lives were 250 and 325 min. The CSF
      penetration of depsipeptide (AUC(CSF):AUC(plasma)) was 2% in each animal.
      Observed changes included anorexia, fatigue, elevation of creatine phosphokinase
      (CPK) enzyme levels (muscle fraction), and transient early leukopenia. All
      animals recovered without sequelae. CONCLUSIONS: Although the CSF exposure to
      depsipeptide after intravenous administration was only 2%, CSF concentrations
      approached the IC(50) of depsipeptide in vitro for some tumors. Systemic
      administration of this agent may be useful for the treatment of leptomeningeal
      tumors.

PMID- 15042313
TI  - Rasagenthi lehyam (RL) a novel complementary and alternative medicine for
      prostate cancer.
AB  - PURPOSE: The use of complementary and alternative medicine (CAM) in cancer has
      been increasing. The therapeutic modalities which originated from India, viz.,
      Ayurveda and Siddha, have phytotherapy as their fundamental basis and, therefore,
      produce few side effects. They are among the most ancient medicinal systems and
      are still being practiced in India and elsewhere, to cure cancer and other
      diseases. Many Siddha practitioners in the southern parts of India prescribe
      rasagenthi lehyam (RL) as a drug for cancer. RL contains 38 different botanicals,
      many of which have been shown to possess therapeutic efficacy, and 8 inorganic
      compounds, all prepared into a paste in a palm sugar and hen's egg base. The
      efficacy of RL in killing prostate cancer cells in vitro was investigated in this
      study to determine whether RL could be recommended as a CAM for prostate cancer.
      METHODS: In order to scientifically validate the anticancer activity of RL on
      prostate cancer, a methanolic extract of RL was serially extracted with four
      organic solvents, and the extracts were tested for clonogenic inhibition and
      induction of apoptosis in PC-3 prostate cancer cells, with and without
      irradiation. n-Hexane, ethyl acetate and chloroform extracts of RL effectively
      killed PC-3 cells. RESULTS: The IC(50) values of n-hexane, ethyl acetate and
      chloroform extracts of RL were 3.84 microg/ml, 3.68 microg/ml and 75 ng/ml,
      respectively. All three extracts induced apoptosis in PC-3 cells. Further, all
      the three extracts when combined with radiation, caused enhanced effect on
      killing of PC-3 cells. Among the three extracts, the chloroform extract showed
      the most significant radiation-sensitizing effect. CONCLUSION: RL, either in its
      original formulation prepared under strict quality control or its chloroform
      extract, could potentially be an alternative medicine for prostate cancer, and
      also a sensitizing agent in the context of radiation therapy for prostate cancer,
      as a complementary medicine. A more directed study could lead to the
      identification of the active principle(s) in the chloroform extract of RL for use
      in prostate cancer therapy.

PMID- 15042316
TI  - Treatment results of tonsillar lymphoma: a 10-year experience.
AB  - Primary extranodal non-Hodgkin's lymphomas of the head and neck account for 10
      20% of all non-Hodgkin's lymphomas. Primary tonsillar lymphoma accounts for less
      than 1% of head and neck malignancies, although the tonsil is the most common
      primary extranodal site of head and neck non-Hodgkin's lymphomas. In this study
      we analyzed our cases of tonsillar lymphoma treated in our institution during the
      last 10 years to compare the finding of this study with those of previous
      studies. We reviewed the cases of tonsillar lymphoma treated in the Radiation
      Oncology Department of Shiraz University from 1992 to 2002. Clinical data were
      obtained from patients' files. The patients were treated by combined chemotherapy
      [a median of six cycles of a CHOP regimen (cyclophosphamide, doxorubicin,
      vincristine, and prednisolone)] and radiation therapy (40-50 Gy to the primary
      site and neck). Chemotherapy mainly preceded radiotherapy, although the sequence
      of radiotherapy and chemotherapy was determined by individual physicians and
      patients' choice. Surgery was used mainly to establish the diagnosis, and
      tonsillectomy was performed for localized small lesions. Between 1992 and 2002,
      19 patients with stage IE (10), IIE (7), and IIIE (2) disease were treated.
      Median and mean age was 48 and 44 years (range: 22-76 years), respectively, at
      the time of diagnosis, with a male to female ratio of 1.2:1. The vast majority of
      patients presented in early stages with aggressive histology. High-grade tumors
      seemed to affect mainly young people (p=0.226). Diffuse large B-cell lymphomas
      were the most prevalent. Male patients were significantly younger than females
      (p=0.021). The patients were treated by combined chemotherapy and radiation
      therapy. All patients achieved and maintained complete remission with a median of
      60 months relapse-free survival and a 5-year cause-specific survival rate of
      100%. All patients developed some degree of oropharyngeal mucositis. Three
      patients (16%) experienced grade 3 or 4 neutropenia. Mild (grade I) xerostomia
      remained persistently in four patients (21%). A late fatal side effect was
      observed in one patient who developed radiation-induced sarcoma 7 years after
      initial diagnosis and died 8 months later without evidence of recurrent lymphoma.
      Complete follow-up was obtained in all patients. The follow-up period ranged from
      18 to 141 months with a median of 60 and a mean of 60.4 months. At the time of
      last follow-up, all patients but one were alive. Age, sex, stage, bulk of
      disease, performance status, number of chemotherapy cycles, number of involved
      sites, histologic subtypes, and radiation dose were analyzed as prognostically
      significant for disease-specific survival in our cases. Significant prognostic
      factors were not identified by multivariate analysis. Combined chemotherapy and
      radiation therapy is safe, highly effective, and probably curative for most
      patients with primary tonsillar lymphoma.

PMID- 15042315
TI  - Extramedullary plasmacytoma: report of two cases with uncommon presentation.
AB  - Lymph node infiltration by monoclonal plasma cells can occur either in aggressive
      forms of myeloma or may represent regional extension of extramedullary
      plasmacytomas, whereas lymph node plasmacytoma presenting as a solitary
      extramedullary plasmacytoma is very unusual. We report two cases of lymph node
      plasmacytomas without systemic disease diagnosed after surgical excision.
      Clinical remission was achieved after local radiotherapy although one patient
      relapsed with multifocal extramedullary plasmacytomas 20 months after
      radiotherapy.

PMID- 15042317
TI  - Frequency of the hemochromatosis HFE mutations C282Y, H63D, and S65C in blood
      donors in the Faroe Islands.
AB  - The aim of the study was to assess the frequencies of the hereditary
      hemochromatosis HFE mutations C282Y, H63D, and S65C in the population in the
      Faroe Islands. The series comprised 200 randomly selected blood donors of Faroese
      heritage. The frequency of the C282Y, H63D, and S65C mutations on the HFE gene
      was assessed by genotyping using the polymerase chain reaction (PCR) technique
      and calculated from direct allele counting. We found no C282Y homozygous
      subjects; 28 (14.0%) subjects were C282Y heterozygous and four subjects were
      C282Y/H63D compound heterozygous (2.0%). The C282Y allele frequency was 8.0% (95%
      CI 5.3-10.7%). The series contained three (1.5%) H63D homozygous subjects and 60
      (30.0%) H63D heterozygous subjects. The H63D allele frequency was 17.5% (95% CI
      13.8-21.2%). There were four (2.0%) S65C heterozygous subjects. The S65C allele
      frequency was 1.0% (95% CI 0.3-2.5%). The frequency of the C282Y mutation is high
      in Faroese blood donors, being close to and not significantly different from the
      frequencies reported in other Scandinavian countries: Denmark 5.7%, Norway 6.6%,
      Iceland 5.1%, and Sweden 6.1%. The frequency of the H63D mutation in Faroese
      subjects is significantly higher than the frequency in Denmark 12.8% (p=0.007),
      Iceland 10.9% (p=0.003), and Sweden 12.4% (p=0.015), but not from the frequency
      in Norway 11.2% (p=0.063). The frequency of the S65C mutation in Faroese subjects
      is not significantly different from the frequencies in Denmark 1.5% and Sweden
      1.6%. Screening of larger groups of the Faroese population for HFE mutations
      especially C282Y should be considered in order to establish the penetrance.

PMID- 15042318
TI  - Atrial fibrillation following chemotherapy for stage IIIE diffuse large B-cell
      gastric lymphoma in a patient with myotonic dystrophy (Steinert's disease).
AB  - The authors describe the unusual association between diffuse B-cell gastric
      lymphoma and myotonic dystrophy, the most common form of adult muscular
      dystrophy, and sudden atrial fibrillation following one cycle of doxorubicin
      based chemotherapy in the same patient. Atrial fibrillation or other cardiac
      arrhythmias are unusual complications in patients treated with chemotherapy. The
      cardiac toxicity intrinsically associated with the aggressive chemotherapy
      employed could function as a triggering factor for the arrhythmia in the
      predisposed myocardium of this patient.

PMID- 15042319
TI  - Erythroblastic synartesis in a patient initially diagnosed with myelodysplastic
      syndrome.

PMID- 15042320
TI  - Normal delivery is still a challenge during pregnancy in sickle cell disease
      patients.

PMID- 15042321
TI  - A three-dimensional model of the shoulder girdle. Forces developed in deltoid and
      supraspinatus muscles during abduction.
AB  - The aim of this study was to design a three-dimensional model of the human
      shoulder girdle. Fourteen muscles were modelled geometrically using robotics
      software (Solid Dynamics System). A static study in reverse dynamics allowed the
      forces developed in seven muscles to be studied, particularly in the deltoid and
      supraspinatus during abduction of the arm with the forearm bent at 90 degrees,
      the scapula being fixed. After optimization by Excel, this model allowed
      simultaneous curves of forces developed in every modelled muscular bundle to be
      obtained during various degrees of abduction of the arm from 0 degrees to 100
      degrees, in the scapular plane. The analysis of supraspinatus and deltoid curves
      revealed an interesting chronology of action. The first muscle developed efforts
      estimated at 140 N, quickly relieved by the deltoid. It is also interesting to
      note that a constant action of supraspinatus was found throughout abduction of
      the arm. Clinical applications seem to be in simulation of muscular pathology of
      the shoulder girdle. This study is continuing by releasing the fixed scapula and
      by simulating muscle transfers proposed for massive ruptures of the rotator cuff.

PMID- 15042322
TI  - Antibiotic-loaded bone cement spacers in two-stage management of infected total
      knee arthroplasty.
AB  - We reviewed the current use of spacers in the management of the infected knee
      prosthesis. There are two types of temporary spacers: block or non-articulating
      spacers and articulating or mobile spacers. Generally, spacers improve
      mobilisation and hasten recovery with shorter hospital stay between stages.
      Furthermore, spacers facilitate the second-stage procedure by maintaining joint
      space, and articulating spacers may also maintain range of motion. Last but not
      the least, the cost of spacers represents only a small fraction of the total
      expenses for management of infected knee arthroplasties.

PMID- 15042326
TI  - Radionuclide therapy in oncology: the dawning of its concomitant use with other
      modalities?

PMID- 15042325
TI  - The dopamine D2 receptor ligand 18F-desmethoxyfallypride: an appropriate
      fluorinated PET tracer for the differential diagnosis of parkinsonism.
AB  - For therapeutic and prognostic reasons it is important to differentiate between
      idiopathic parkinsonian syndrome (IPS, Parkinson's disease) and atypical
      parkinsonian syndromes (APS) like multiple system atrophy or progressive
      supranuclear palsy. Whereas IPS patients usually show a normal or upregulated
      postsynaptic dopamine D2 receptor profile, APS patients present decreased
      postsynaptic tracer binding. The aim of this prospective study was to evaluate
      the D2 receptor antagonist fluorine-18 desmethoxyfallypride (18F-DMFP), a
      recently developed positron emission tomography (PET) tracer with better clinical
      availability than carbon-11 raclopride, for the differential diagnosis of IPS
      versus APS. The study included 16 healthy control subjects and 35 patients with
      clinically diagnosed parkinsonism (16 IPS patients, 19 APS patients). All
      patients underwent PET imaging after injection of 180-200 MBq 18F-DMFP. Receiver
      operating characteristic (ROC) analyses were performed in order to assess the
      diagnostic performance of 18F-DMFP PET. We found the striatal 18F-DMFP uptake
      ratio to be significantly (P<0.01) reduced in the APS patients (2.44+/-0.42)
      compared with the healthy control subjects (3.61+/-0.43) and the IPS patients
      (3.21+/-0.78), whereas the uptake ratios of the IPS patients and the control
      subjects did not differ significantly. For the differential diagnosis of APS
      versus IPS, the ROC analysis of caudate 18F-DMFP binding showed a specificity,
      sensitivity and accuracy of 100%, 74% and 86%, respectively, as well as positive
      and negative predictive values of 100% and 76%, respectively. Based on these
      first clinical results, we consider 18F-DMFP to be an appropriate PET tracer for
      the differential diagnosis of parkinsonian syndromes, with the advantage of
      better clinical availability than 11C-labelled D2 radioligands.

PMID- 15042327
TI  - Small, basic antifungal proteins secreted from filamentous ascomycetes: a
      comparative study regarding expression, structure, function and potential
      application.
AB  - Peptides and proteins with antimicrobial activity are produced throughout all
      kingdoms in nature, from prokaryotes to lower and higher eukaryotes, including
      fungi, plants, invertebrates and vertebrates. These proteins contribute to an
      important constitutive or induced defense mechanism of the producer against
      microorganisms. According to their variety in structure and function, these
      proteins are classified arbitrarily into groups that are based on their mechanism
      of action, their structure and their similarity to other known proteins. The
      present review focuses on a new group of antimicrobial proteins, namely small,
      basic and cysteine-rich antifungal proteins, which are secreted from filamentous
      fungi of the group Ascomycetes. These proteins are encoded by orthologous genes
      and exhibit both similarities and differences concerning their species
      specificity, primary structure, protein activity and target sites. The properties
      of these proteins, their possible mode of action and their potential application
      for human benefits are discussed in comparison with other already well known
      antimicrobial proteins.

PMID- 15042328
TI  - Features of bacterial cellulose synthesis in a mutant generated by disruption of
      the diguanylate cyclase 1 gene of Acetobacter xylinum BPR 2001.
AB  - The diguanylate cyclase 1 (DGC1) (dgc1) gene in Acetobacter xylinum BPR 2001--a
      bacterial cellulose (BC) producer--was cloned and sequenced, and a DGC1 gene
      disrupted mutant, strain DD, was constructed. The production and structural
      characteristics of the BC formed by DD were compared with those of the parental
      strain BPR 2001. BC production by DD was almost the same as that by BPR 2001 in
      static cultivation and in shake flask cultivation. However, in a jar fermentor DD
      produced about 36% more BC than the parental strain. DD produced suspended
      particle materials that cannot aggregate owing to their random structural
      characteristics in static cultivation; more uniformly dispersed BC pellicles and
      smaller BC pellets are produced on average in a jar fermentor, as reflected by
      the higher BC production by DD than by the parental strain in a jar fermentor.
      Micrographs of BC produced by DD revealed that the width of cellulose ribbons
      assemblies decreased as a result of differences in the ultrastructure and
      mechanism of formation of BC between the two strains. These results reveal that
      disruption of the dgc1 gene, which catalyzes synthesis of c-di-GMP (an effector
      of BC synthase), is not fatal for BC synthesis, although it affects BC structure.

PMID- 15042329
TI  - Characterization and expression of the immunoglobulin light chain in the fugu:
      evidence of a solitaire type.
AB  - In this study, we characterized the immunoglobulin light (IgL) chain gene and
      examined its expression in the fugu (Takifugu rubripes). The cDNA fragment that
      partially encodes the IgL chain was isolated by RACE and used as a probe for
      screening for IgL in a fugu splenic cDNA library. The IgL cDNA sequence that we
      found consisted of a variable (V(L)) and a constant (C(L)) segment. Its
      structural features were similar to the IgL isotype commonly found in teleosts.
      Genomic sequence analysis revealed that the IgL gene was organized as two V(L)
      gene segments (designed V(L1) and V(L2)) followed by single joining (J(L)) and
      C(L) segment. In addition, an unusual duplicate V(L1) gene segment was found
      downstream of the C(L) segment. The transcriptional orientation of the V(L) exons
      was found to be opposite to that of the J(L) and C(L) segments. Genomic blot
      hybridizations with V(L) and C(L) probes gave multibands, supporting the
      contention that the teleost IgL forms a multicluster. Both genomic and cDNA
      sequences analyses showed that all of the constant segments found in the fugu are
      identical, suggesting that no other isotypes could be found in this species.
      Comparison of the deduced amino acid sequence of the fugu C(L) domain with those
      of other species showed a high degree of identity (from 40 to 77%). IgL mRNAs
      were found to be expressed primarily in the lymphoid tissues. In situ
      hybridization revealed the presence of IgL-positive cells widely distributed
      throughout the spleen, head kidney, kidney, and thymus. These results support the
      contention that the lymphoid tissues are the major sites of antibody production
      in fish. Since IgL mRNA was also expressed in the skin and gill that are exposed
      to external antigens, it is likely that mucosal Ig plays an important role in
      immune protection.

PMID- 15042330
TI  - Genomic analysis of Fas and FasL genes and absence of correlation with disease
      progression in AIDS.
AB  - Apoptosis has been suggested as a major mechanism for the CD4(+) T-lymphocyte
      depletion observed in patients infected with human immunodeficiency virus 1 (HIV
      1). To evaluate the impact of genetic variations to apoptosis during progression
      of acquired immunodeficiency syndrome (AIDS), we have performed an extensive
      genetic analysis of Fas and Fas ligand ( FasL) genes. The coding regions and
      promoters of these genes were resequenced in a cohort of 212 HIV-1-seropositive
      patients presenting extreme disease phenotypes and 155 healthy controls of
      Caucasian origin. Overall, 33 single nucleotide polymorphisms (SNPs) with an
      allele frequency >1% were identified and evaluated for their association with
      disease progression. Among them, 14 polymorphisms were newly characterized. We
      did not find any statistically significant association of Fas and FasL
      polymorphisms and haplotypes with AIDS progression.

PMID- 15042331
TI  - Newborns with diaphragmatic hernia: initial chest radiography does not have a
      role in predicting clinical outcome.
AB  - BACKGROUND: The management of life-threatening congenital diaphragmatic hernia
      (CDH) has undergone significant change over the last two decades. When CDH was
      felt to be a surgical emergency treated promptly after birth, survival rates of
      50% were typical. Recent changes in medical management of these patients prior to
      surgery have had a dramatic influence on clinical outcome with survival rates
      over 80%. OBJECTIVE: This study was performed to assess under the current 80%
      survival rates whether there is predictive value in the appearance of the initial
      chest radiograph and clinical outcome in patients with CDH. MATERIALS AND
      METHODS: Initial chest radiographs on 56 newborns with CDH were retrospectively
      reviewed for percent aeration of ipsilateral lung, percent aeration of
      contralateral lung, percent mediastinal shift, and content of hernia and
      correlated with clinical outcome. RESULTS: There was no significant relationship
      between radiographic analysis of the percent of ipsilateral lung aeration
      (P=0.43), contralateral aeration (P=0.52) mediastinal shift (P=0.18), or content
      of hernia and clinical outcome. All CDH lesions tend to "look the same" on
      radiographs, regardless of favorable or fatal outcome. CONCLUSION: Chest
      radiography serves to confirm the diagnosis of CDH, but does not predict outcome.

PMID- 15042332
TI  - MR imaging and spectroscopy in juvenile Huntington disease.
AB  - Juvenile Huntington disease manifests differently from adult Huntington disease
      and has more variability in presentation. We describe a child with cognitive
      decline and adventitial movements in whom Huntington disease was confirmed with
      genetic testing. MR imaging showed abnormal T2 prolongation in the putamina and
      progressive caudate atrophy, and MR spectroscopy revealed elevated myoinositol
      and diminished N-acetyl aspartate, creatine, and phosphocreatine. Imaging
      findings of caudate atrophy and abnormal T2 prolongation in the putamina with MR
      spectroscopy findings consistent with dense gliosis can be helpful indicators of
      juvenile Huntington disease.

PMID- 15042334
TI  - Adaptive evolution of scorpion sodium channel toxins.
AB  - Gene duplication followed by positive Darwinian selection is an important
      evolutionary event at the molecular level, by which a gene can gain new
      functions. Such an event might have occurred in the evolution of scorpion sodium
      channel toxin genes (alpha- and beta-groups). To test this hypothesis, a robust
      statistical method from Yang and co-workers based on the estimation of the
      nonsynonymous-to-synonymous rate ratio (omega = d(N)/ d(S)) was performed. The
      results provide clear statistical evidence for adaptive molecular evolution of
      scorpion alpha- and beta-toxin genes. A good match between the positively
      selected sites (evolutionary epitopes) and the putative bioactive surface
      (functional epitopes) indicates that these sites are most likely involved in
      functional recognition of sodium channels. Our results also shed light on the
      importance of the B-loop in the functional diversification of scorpion alpha- and
      beta-toxins.

PMID- 15042335
TI  - Diversification of ftsZ during early land plant evolution.
AB  - The plastid division proteins FtsZ are encoded by a small nuclear gene family in
      land plants. Although it has been shown for some of the gene products that they
      are imported into plastids and function in plastid division, the evolution and
      function of this gene family and their products remain to be unraveled. Here we
      present two new ftsZ genes from the moss Physcomitrella patens and compare the
      genomic structure of members of the two plant ftsZ gene families. Comparison of
      sequence features and phylogenetic analyses confirm the presence of two clusters
      of paralogues in land plants and demonstrate that these genes were duplicated
      before the divergence of mosses, ferns and seed plants.

PMID- 15042333
TI  - Molecular evolutionary characterization of the mussel Mytilus histone multigene
      family: first record of a tandemly repeated unit of five histone genes containing
      an H1 subtype with "orphon" features.
AB  - The present work represents the first characterization of a clustered histone
      repetitive unit containing an H1 gene in a bivalve mollusk. To complete the
      knowledge on the evolutionary history of the histone multigene family in
      invertebrates, we undertake its characterization in five mussel Mytilus species,
      as an extension of our previous work on the H1 gene family. We report the quintet
      H4-H2B-H2A-H3-H1 as the major organization unit in the genome of Mytilus
      galloprovincialis with two 5S rRNA genes with interspersed nontranscribed spacer
      segments linked to the unit, which is not justified by their cotranscription with
      histone genes. Surprisingly, 3' UTR regions of histone genes show two different
      mRNA termination signals, a stem-loop and a polyadenylation signal, both related
      to the evolution of histone gene expression patterns throughout the cell cycle.
      The clustered H1 histones characterized share essential features with "orphon" H1
      genes, suggesting a common evolutionary origin for both histone subtypes which is
      supported by the reconstructed phylogeny for H1 genes. The characterization of
      histone genes in four additional Mytilus species revealed the presence of strong
      purifying selection acting among the members of the family. The chromosomal
      location of most of the core histone genes studied was identified by FISH close
      to telomeric regions in M. galloprovincialis. Further analysis on nucleotide
      variation would be necessary to assess if H1 proteins evolve according to the
      birth-and-death model of evolution and if the effect of the strong purifying
      selection maintaining protein homogeneity could account for the homologies
      detected between clustered and "orphon" variants.

PMID- 15042336
TI  - Do avian mitochondria recombine?
AB  - The dogma of strict maternal inheritance of mitochondria is now being tested with
      population genetics methods on sequence data from many species. In this study we
      investigated whether recombination occurs in the mitochondria of the blue tit (
      Parus caeruleus) by studying polymorphisms in the mitochondrial control region
      and in a recently identified (A)(n) microsatellite on the W chromosome. The
      female heterogamety of avian sex chromosomes allows a test of whether
      mitochondrial recombination affects genealogical inference by comparison of
      mitochondrial and W-linked sequence variation. There is no discrepancy between
      mitochondrial and W-linked genealogies in blue tits, consistent with no
      recombination. We also analyzed mitochondrial sequence variation in both blue
      tits and peregrine falcons ( Falco peregrinus) using a coalescent-based approach
      which accounts for recurrent mutation; in neither bird species did we find
      evidence of recombination. We conclude that it is unlikely that mitochondrial
      recombination has large effects on mitochondrial genetic variability in birds.

PMID- 15042338
TI  - Causes of size homoplasy among chloroplast microsatellites in closely related
      Clusia species.
AB  - Chloroplast DNA sequences and microsatellites are useful tools for phylogenetic
      as well as population genetic analyses of plants. Chloroplast microsatellites
      tend to be less variable than nuclear microsatellites and therefore they may not
      be as powerful as nuclear microsatellites for within-species population analysis.
      However, chloroplast microsatellites may be useful for phylogenetic analysis
      between closely related taxa when more conventional loci, such as ITS or
      chloroplast sequence data, are not variable enough to resolve phylogenetic
      relationships in all clades. To determine the limits of chloroplast
      microsatellites as tools in phylogenetic analyses, we need to understand their
      evolution. Thus, we examined and compared phylogenetic relationships of species
      within the genus Clusia, using both chloroplast sequence data and variation at
      seven chloroplast microsatellite loci. Neither ITS nor chloroplast sequences were
      variable enough to resolve relationships within some sections of the genus, yet
      chloroplast microsatellite loci were too variable to provide any useful
      phylogenetic information. Size homoplasy was apparent, caused by base
      substitutions within the microsatellite, base substitutions in the flanking
      regions, indels in the flanking regions, multiple microsatellites within a
      fragment, and forward/reverse mutations of repeat length resulting in
      microsatellites of identical base composition that were not identical by descent.

PMID- 15042337
TI  - Phylogenetic analysis of Ciona intestinalis gene superfamilies supports the
      hypothesis of successive gene expansions.
AB  - Understanding the formation of metazoan multigene families is a good approach to
      reconstitute the evolution of the chordate genome. In this attempt, the analysis
      of the genome of selected species provides valuable information. Ciona
      intestinalis belongs to the urochordates, whose lineage separated from the
      chordate lineage that later gave birth to vertebrates. We have searched available
      sequences from the small marine ascidian C. intestinalis for orthologs of members
      of five vertebrate superfamilies, including tyrosine kinase receptors, ETS, FOX
      and SOX transcription factors, and WNT secreted regulatory factors, and conducted
      phylogenetic analyses. We have found that most vertebrate subfamilies have a
      single C. intestinalis ortholog. Our results support the hypothesis of a gene
      expansion prior the base of chordate ancestry followed by another gene expansion
      during vertebrate evolution. They also indicate that Ciona intestinalis genome
      will be a very valuable tool for evolutionary analyses.

PMID- 15042340
TI  - Evolution of an arbitrary sequence in solubility.
AB  - We have investigated the evolvability of an insoluble random polypeptide, RP3-34,
      to a soluble form through iterative mutation and selection with the aid of the
      green fluorescent protein (GFP) folding reporter. To assess the solubility of the
      polypeptides in the selected clones of each generation, the polypeptide genes
      were detached from the GFP fusions and expressed with a His(6) tag. The
      solubility of the variant random polypeptides increased in each generation within
      the scope of the evolutionary process, and the polypeptides assumed a soluble
      form from the fourth generation. Analysis of the synonymous and nonsynonymous
      mutations found in the deduced amino acid sequence of the selected polypeptides
      revealed that selection had accelerated the evolutionary rate. The solubility and
      hydrophobicity of the polypeptides and the 25 arbitrarily chosen random
      polypeptides found in a previously prepared library were determined, analyzed,
      and interpreted from the landscape on the protein sequence space. This study
      showed the evolvability of an insoluble arbitrary sequence toward a soluble one,
      hence, it provides a new perspective on the field of artificial evolution.

PMID- 15042339
TI  - Exponential spread of hepatitis C virus genotype 4a in Egypt.
AB  - Hepatitis C virus (HCV) infects >10% of the general population in Egypt, in which
      intravenous injection with an antimony compound for endemic schistosomiasis in
      the past has been implicated. To simulate the epidemic history of HCV in Egypt,
      sera were obtained from 3608 blood donors at 13 governorates in or surrounding
      the Nile valley during 1999. The prevalence of antibody to HCV (anti-HCV) and
      genotypes was determined in them, and the molecular evolutionary analysis based
      on the neutral theory was applied to HCV isolates of genotype 4a, which is
      outstandingly prevalent in Egypt and indigenous there. Of 3608 sera, 317 (8.8%)
      were positive for anti-HCV. The molecular evolutionary analysis on 47 HCV
      genotype 4a isolates of carriers from various districts in Egypt indicated that
      the spread of HCV-4a would have increased exponentially during the 1940s through
      1980 when oral medications became available. In conclusion, the estimated spread
      time is consistent with the duration of intravenous antimony campaigns in Egypt.

PMID- 15042341
TI  - Molecular evolution in large genetic networks: does connectivity equal
      constraint?
AB  - Genetic networks show a broad-tailed distribution of the number of interaction
      partners per protein, which is consistent with a power-law. It has been proposed
      that such broad-tailed distributions are observed because they confer robustness
      against mutations to the network. We evaluate this hypothesis for two genetic
      networks, that of the E. coli core intermediary metabolism and that of the yeast
      protein-interaction network. Specifically, we test the hypothesis through one of
      its key predictions: highly connected proteins should be more important to the
      cell and, thus, subject to more severe selective and evolutionary constraints. We
      find, however, that no correlation between highly connected proteins and
      evolutionary rate exists in the E. coli metabolic network and that there is only
      a weak correlation in the yeast protein-interaction network. Furthermore, we show
      that the observed correlation is function-specific within the protein-interaction
      network: only genes involved in the cell cycle and transcription show significant
      correlations. Our work sheds light on conflicting results by previous researchers
      by comparing data from multiple types of protein-interaction datasets and by
      using a closely related species as a reference taxon. The finding that highly
      connected proteins can tolerate just as many amino acid substitutions as other
      proteins leads us to conclude that power-laws in cellular networks do not reflect
      selection for mutational robustness.

PMID- 15042342
TI  - The shark HoxN cluster is homologous to the human HoxD cluster.
AB  - The statistical analysis of phylogenetic footprints in the two known horn shark
      Hox clusters and the four mammalian clusters shows that the shark HoxN cluster is
      HoxD-like. This finding implies that the most recent common ancestor of jawed
      vertebrates had at least four Hox clusters, including those which are orthologous
      to the four mammalian Hox clusters.

PMID- 15042343
TI  - Pathway length and evolutionary constraint in amino acid biosynthesis.
AB  - The evolutionary properties of a metabolic network may be determined by the
      topology of the network. One attribute of pathways that make up the network is
      the number of enzymatic steps between initial substrates and final products. To
      determine the effect of pathway length on evolutionary lability of pathway
      structure, we examined amino acid biosynthetic pathways across 48 sequenced
      organisms. We demonstrate that longer pathways exhibit lower rates of change in
      pathway structure than shorter pathways. This finding suggests that increasing
      complexity may increase constraint on evolutionary change.

PMID- 15042344
TI  - Molecular evolution of hisB genes.
AB  - The sixth and eighth steps of histidine biosynthesis are catalyzed by an
      imidazole glycerol-phosphate (IGP) dehydratase (EC 4.2.1.19) and by a histidinol
      phosphate (HOL-P) phosphatase (EC 3.1.3.15), respectively. In the enterobacteria,
      in Campylobacter jejuni and in Xylella/Xanthomonas the two activities are
      associated with a single bifunctional polypeptide encoded by hisB. On the other
      hand, in Archaea, Eucarya, and most Bacteria the two activities are encoded by
      two separate genes. In this work we report a comparative analysis of the amino
      acid sequence of all the available HisB proteins, which allowed us to depict a
      likely evolutionary pathway leading to the present-day bifunctional hisB gene.
      According to the model that we propose, the bifunctional hisB gene is the result
      of a fusion event between two independent cistrons joined by domain-shuffling.
      The fusion event occurred recently in evolution, very likely in the
      proteobacterial lineage after the separation of the gamma- and the beta
      subdivisions. Data obtained in this work established that a paralogous
      duplication event of an ancestral DDDD phosphatase encoding gene originated both
      the HOL-P phosphatase moiety of the E. coli hisB gene and the gmhB gene coding
      for a DDDD phosphatase, which is involved in the biosynthesis of a precursor of
      the inner core of the outer membrane lipopolysaccharides (LPS).

PMID- 15042345
TI  - An amino-acid substitution in the influenza-B NB protein affects ion-channel
      gating.
AB  - The effects of site-directed mutations in NB, a protein encoded by the influenza
      B virus that has been shown to form cation-selective ion channels at pH 6.0, were
      studied on ion channel characteristics in artificial lipid bilayers. It was
      thought that the residues in the hydrophobic region of NB we selected for
      mutation might be involved in the transport of cations across the channel and
      that changes in these residues might affect channel properties such as gating and
      ion-selectivity. Serine residues at positions 20 and 28, threonine at position 24
      and cysteine at position 26 were replaced by alanine. We found that the mutation
      S20A gave channels that did not gate and that remained open most of the time.
      Proton permeability of NB channels, as detected by fluorescence quenching, was
      also altered by the mutation S20A: channels were no longer proton-permeable. The
      other mutations, S28A, T24A and C26A, did not have any detectable effect on the
      activity or proton permeability of channels formed by NB. The results indicate
      that serine 20 may have an important role in normal function of NB channels.

PMID- 15042346
TI  - K+ channels in cardiomyocytes of the pulmonate snail helix.
AB  - We used the patch-clamp technique to identify and characterize the
      electrophysiological, biophysical, and pharmacological properties of K(+)
      channels in enzymatically dissociated ventricular cells of the land pulmonate
      snail Helix. The family of outward K(+) currents started to activate at -30 mV
      and the activation was faster at more depolarized potentials (time constants: at
      0 mV 17.4 +/- 1.2 ms vs. 2.5 +/- 0.1 ms at + 60 mV). The current waveforms were
      similar to those of the A-type family of voltage-dependent K(+) currents encoded
      by Kv4.2 in mammals. Inactivation of the current was relatively fast, i.e., 50.2
      +/- 1.8% of current was inactivated within 250 ms at + 40 mV. The recovery of
      K(+) channels from inactivation was relatively slow with a mean time constant of
      1.7 +/- 0.2 s. Closer examination of steady-state inactivation kinetics revealed
      that the voltage dependency of inactivation was U-shaped, exhibiting less
      inactivation at more depolarized membrane potentials. On the basis of this
      phenomenon, we suggest that a channel encoded by Kv2.1 similar to that in mammals
      does exist in land pulmonates of the Helix genus. Outward currents were sensitive
      to 4-aminopyridine and tetraethylammonium chloride. The last compound was most
      effective, with an IC(50) of 336 +/- 142 micro mol l(-1). Thus, using distinct
      pharmacological and biophysical tools we identified different types of voltage
      gated K(+) channels.

PMID- 15042347
TI  - Channel activation voltage alone is directly altered in an isoform-specific
      manner by Na(v1.4) and Na(v1.5) cytoplasmic linkers.
AB  - The isoform-specific direct role of cytoplasmic loops in the gating of two
      voltage-gated sodium channel isoforms, the human cardiac channel (Na(v1.5); hH1)
      and the human adult skeletal muscle channel (Na(v1.4); hSkM1), was investigated.
      Comparison of biophysical characteristics was made among hSkM1, hH1, and several
      hSkM1/hH1 chimeras in which the putative cytoplasmic loops that join domain I to
      II (loop A) and domain II to III (loop B) from one isoform replaced one or both
      of the analogous loops from the other isoform. For all parameters measured, hSkM1
      and hH1 behavior were significantly different. Comparison of hSkM1 and hH1
      biophysical characteristics with the function of their respective chimeras
      indicate that only the half-activation voltage ( V(a)) is directly and
      differently altered by the species of cytoplasmic loop such that a channel
      consisting of one or both hSkM1 loops activates at smaller depolarizations, while
      a larger depolarization is required for activation of a channel containing one or
      both of the analogous hH1 loops. When either cardiac channel loop A or B is
      attached to hSkM1, a 6-7 mV depolarizing shift in V(a) is measured, increasing to
      a nearly 20 mV depolarization when both cardiac-channel loops are attached. The
      addition of either skeletal muscle-channel loop to hH1 causes a 7 mV
      hyperpolarization in V(a), which increases to about 10 mV for the double loop
      chimera. There is no significant difference in either steady-state inactivation
      or in the recovery from inactivation data between hSkM1 and its chimeras and
      between hH1 and its chimeras. Data indicate that the cytoplasmic loops contribute
      directly to the magnitude of the window current, suggesting that channels
      containing skeletal muscle loops have three times the peak persistent channel
      activity compared to channels containing the cardiac loops. An electrostatic
      mechanism, in which surface charge differences among these loops might alter
      differently the voltage sensed by the gating mechanism of the channel, can not
      account for the observed isoform-specific effects of these loops only on channel
      activation voltage. In summary, although the DI-DII and DII-DIII loop structures
      among isoforms are not well conserved, these data indicate that only one gating
      parameter, V(a) is affected directly and in an isoform-specific manner by these
      divergent loop structures, creating loop-specific window currents and percentages
      of persistently active channels at physiological voltages that will likely impact
      the excitability of the cell.

PMID- 15042348
TI  - Insertion of a glycosylphosphatidylinositol-anchored enzyme into liposomes.
AB  - Incorporation of alkaline phosphatase (AP), a glycosylphosphatidylinositol (GPI)
      anchored protein, into liposomes containing detergent, followed by detergent
      removal with hydrophobic resin was performed. Incorporation media were collected
      during different steps of detergent removal and were analyzed by flotation in
      sucrose gradient. The presence of protein was checked by measuring enzymatic
      activity, while the presence of (3)H-radio-labelled liposomes was followed by
      determination of the radioactivity. The incorporation yield of the protein into
      liposomes increased with incubation time in presence of hydrophobic resin.
      Protein was also incorporated at different protein/lipid ratios. At the highest
      protein lipid ratio, our data showed that 260 molecules of GPI-linked AP (AP-GPI)
      could be associated with one liposome, corresponding to 65% vesicle coverage.
      Finally, observations by electron cryomicroscopy indicated (i) that the protein
      seemed exclusively associated with the lipid bilayer via the GPI-anchor, as shown
      by the distance-about 2.5 nm-between the protein core and the liposome membrane;
      (ii) that the AP-GPI distribution was heterogeneous on the liposome surface,
      forming clusters of protein.

PMID- 15042349
TI  - Expression and coexpression of CO2-sensitive Kir channels in brainstem neurons of
      rats.
AB  - Several inward rectifier K(+) (Kir) channels are inhibited by hypercapnic
      acidosis and may be involved in CO(2) central chemoreception. Among them are
      Kir1.1, Kir2.3, and Kir4.1. The Kir4.1 is expressed predominantly in the
      brainstem. Although its CO(2) sensitivity is low, coexpression of Kir4.1 with
      Kir5.1 in Xenopus oocytes greatly enhances the CO(2)/pH sensitivities of the
      heteromeric channels. If these Kir channels play a part in the central CO(2)
      chemosensitivity, they should be expressed in neurons of brainstem cardio
      respiratory nuclei. To test this hypothesis, we performed in-situ hybridization
      experiments in which the expression of Kir1.1, Kir2.3, Kir4.1 and Kir5.1, and
      coexpression of Kir4.1 and Kir5.1 were studied in brainstem neurons using non
      radioactive riboprobes. We found that mRNAs of these Kir channels were present in
      several brainstem nuclei, especially those involved in cardio-respiratory
      controls. Strong labeling was observed in the locus coeruleus, ventralateral
      medulla, parabrachial-Kolliker-Fuse nuclei, solitary tract nucleus, and area
      postrema. Strong expression was also seen in several cranial motor nuclei,
      including the nucleus of ambiguus, hypoglossal nucleus, facial nucleus and dorsal
      vagus motor nucleus. In general, the expression of Kir5.1 and Kir4.1 was much
      more prominent than that of Kir1.1 and Kir2.3 in all the nuclei. Evidence for the
      coexpression of Kir4.1 and Kir5.1 was found in a good number of neurons in these
      nuclei. The expression and coexpression of these CO(2)/pH-sensitive Kir channels
      suggest that they are likely to contribute to CO(2) chemosensitivity of the
      brainstem neurons.

PMID- 15042350
TI  - Volume-dependent glutamate permeation depends on transmembrane ionic strength and
      extracellular Cl-.
AB  - Many mammalian cells regulate their volume by the osmotic movement of water
      directed by anion and cation flux. Ubiquitous volume-dependent anion currents
      permit cells to recover volume after swelling in response to a hypotonic
      environment. This study addressed competition between glutamate (Glu) and Cl(-)
      permeation in volume-activated anion currents in order to provide insight into
      the ionic requirements for volume regulation, volume-dependent anion channel
      activity and to the architecture of the channel pore. The effect of changing the
      intracellular molar fraction (MF) of Glu and Cl(-) on conductance and relative
      anion permeability was evaluated as a function of the extracellular permeant
      anion and/or the ionic strength. Relative permeability of Glu to Cl(-) was
      determined by measuring reversal potentials under defined ionic conditions. Under
      conditions with high (150 m M) or low (50 m M) ionic strength solutions on both
      sides of the membrane, Cl(-) was always more permeable than Glu. When a
      transmembrane ionic strength gradient (150 m M extracellular: 50 m M
      intracellular) was set to drive water into the cell, and in the presence of
      extracellular Cl(-), Glu became up to 16-fold more permeable than Cl(-).
      Replacement of extracellular Cl(-) with Glu abolished this effect. These results
      indicate that it is possible for Glu to move into the extracellular environment
      during volume-regulatory events and they support the emerging role of glutamate
      as a modulator of anion channel activity.

PMID- 15042351
TI  - Patterns of antihypertensive drug utilization in primary care.
AB  - BACKGROUND: In the treatment of hypertension, physicians' attitudes and practice
      patterns are receiving increased attention as contributors to poor blood pressure
      (BP) control. Thus, current use of antihypertensive drugs in primary care was
      analyzed and the association with selected physician and patient characteristics
      was assessed. METHODS: The Hypertension and Diabetes Risk Screening and Awareness
      (HYDRA) study is a cross-sectional point prevalence study of 45,125 primary care
      attendees recruited from a representative nationwide sample of 1912 primary care
      practices in Germany. Prescription frequencies of the various antihypertensive
      drugs in the individual patients were recorded by the physicians using
      standardized questionnaires. We assessed the association of patient variables
      [age, gender; co-morbidities such as diabetes, nephropathy or coronary heart
      disease (CHD)] and physician variables (general practitioner vs internist,
      guideline adherence, etc.) with drug treatment intensity and prescription
      patterns. RESULTS: Of all 43,549 patients for whom a physician diagnosis on
      hypertension or diabetes was available, 17,485 (40.1%) had hypertension. Of these
      hypertensive patients, 1647 (9.4%) received no treatment at all, 1191 (6.8%)
      received non-pharmacological measures only, and 14,647 (83.8%) were given one or
      more antihypertensive drugs. Drug treatment rates were lower in young patients
      (16-40 years: 57.4%). BP control was poor: 70.6% of all patients were not
      normalized, i.e., had BP >/=140/90 mmHg. Antihypertensive treatment was generally
      intensified with increasing age, or if complications or comorbidities were
      present. The use of the different drug classes was rather uniform across the
      various patient subgroups (e.g., by age and gender). Individualized treatment
      with regard to co-morbidities as recommended in guidelines was not the rule.
      Adherence to guidelines as self-reported by physicians as well as other physician
      characteristics (region, training etc.) did not result in more differentiated
      prescription pattern. CONCLUSIONS: Despite the broad armamentarium of drug
      treatment options, physicians in primary care did not treat hypertension
      aggressively enough. Treatment was only intensified at a late stage, after
      complications had occurred. Treatment should be more differentiated in terms of
      coexisting morbidities such as diabetes, nephropathy, or CHD.

PMID- 15042352
TI  - Comparison of rational pharmacotherapy decision-making competence of general
      practitioners with intern doctors.
AB  - OBJECTIVE: The aim of this study was to compare rational pharmacotherapy decision
      making competency of interns (final-year medical students) who had received
      rational pharmacotherapy education (RPE), with their classmates at another
      medical school and general practitioners (GPs) who had not been exposed to RPE.
      DESIGN: A written, objective, structured clinical examination (OSCE), consisting
      of open and structured questions, was given to all participants. The participants
      were expected to make a treatment plan and prescribe for simple, uncomplicated
      beta-hemolytic streptococcal tonsillitis and mild-to-moderate essential
      hypertension patients, explain their proposed treatment plans and reasons
      affecting their drug choice. After the OSCE, a questionnaire to assess knowledge
      of the rational use of drugs was given to the participants. RESULTS: Fifty RPE(+)
      interns, 54 RPE(-) interns and 53 GPs participated in the study. Mean scores of
      RPE(+) interns were higher than those of GPs, which were in turn found to be
      higher than those of RPE(-) interns for all cases. The RPE(+) interns scored the
      highest regarding all components of rational pharmacotherapy process for all
      cases of both indications. However, participants in all groups had higher scores
      for the structured questions compared with the corresponding open ones for both
      diseases. Prescription analysis also revealed better results for RPE(+) interns
      regarding the number of drugs/prescription and treatment costs. CONCLUSION: The
      present study demonstrated that the final-year medical students (interns)
      markedly benefited from undergraduate RPE at the medical school in developing
      rational prescribing skills compared with their classmates from a medical school
      with traditional pharmacology education. Interestingly, they got higher scores
      than not only RPE(-) interns, but also than the GPs participating in this study,
      indicating the urgent need for continuous medical education programs in this
      field throughout the country for practicing GPs.

PMID- 15042356
TI  - On the functional significance of the polypeptide PsbY for photosynthetic water
      oxidation in the cyanobacterium Synechocystis sp. strain PCC 6803.
AB  - Recent investigations have revealed that the cyanobacterial photosystem II
      complex contains more than 26 polypeptides. The functions of most of the low
      molecular-mass polypeptides, including PsbY, have remained elusive. Here we
      present a comparative characterization of the wild-type Synechocystis sp. strain
      PCC 6803 and a PsbY-free mutant derived from it. The results show that growth of
      the PsbY-free mutant was comparable to that of the wild-type when cells were
      cultivated in complete BG11 medium or under initial manganese or chloride
      limitation, and when illuminated at 20 or 200 microE m(-2) s(-1). However, while
      growth rates of both the wild-type and the PsbY-free mutant were reduced when
      cells were cultivated in BG11 medium in the absence of calcium, the reduction was
      significantly greater in the case of the PsbY-free mutant. This differential
      effect on growth of the mutant relative to the wild-type in CaCl(2) deficient
      medium was detected when the cells were illuminated with high-intensity light
      (200 microE m(-2) s(-1)) but not when light levels were lower (20 microE m(-2) s(
      1)). The differential effect on growth was associated with lower O(2) evolving
      activity in the mutant compared to wild-type cells. The mutant was also found to
      be more sensitive to photoinhibition, and showed an altered pattern of
      fluorescence emission at 77 K. In addition, mass spectrometric analysis revealed
      that PsbY-free cells cultivated in CaCl(2) sufficient medium (in which no growth
      reduction was observed) had a significantly higher O(2) evolution from hydrogen
      peroxide and a lower O(2) evolution from water under flash light illumination
      than wild-type cells. These results imply that photosystem II is slightly
      impaired in the PsbY-free mutant, and that the mutant is less capable of coping
      with low levels of Ca(2+) than the wild-type.

PMID- 15042355
TI  - Identification of temperature-sensitive dnaD mutants of Staphylococcus aureus
      that are defective in chromosomal DNA replication.
AB  - The DnaD protein in Gram-positive bacteria is thought to be essential for the
      initiation step in DNA replication. In the present study, we characterized two
      Staphylococcus aureus mutants whose temperature-sensitive growth phenotype could
      be complemented by a plasmid carrying the dnaD gene. These mutants each had a
      single amino acid substitution in the DnaD protein and showed decreased DNA
      synthesis at restrictive temperature. Analyses of the origin to terminus ratio by
      Southern blotting, and of origin numbers per cell by flow cytometry, revealed
      that, at the restrictive temperature, one mutant continued ongoing DNA
      replication but failed to initiate DNA replication. The other mutant, in
      contrast, could not complete ongoing DNA replication and proceeded to degrade the
      chromosome. However, if protein synthesis was inhibited, the second mutant could
      complete DNA replication. These results suggest that DnaD protein is necessary
      not only for the initiation step, but also to avoid replication fork blockage.
      Moreover, both mutants were sensitive to mitomycin C, a drug that induces DNA
      damage, suggesting that the DnaD protein is also involved in DNA repair.

PMID- 15042357
TI  - A novel small-molecule inhibitor of the chromosome segregation process in yeast.
AB  - The centromeres of budding yeasts contain specific and essential DNA sequences,
      in contrast to the regional heterochromatic centromeres found in higher
      organisms. Small molecules that perturb centromere function in budding yeast
      could be valuable candidates for identifying yeast-specific growth inhibitors. A
      combination of two in vivo assays, one based on transcription blockade of a
      reporter gene by the centromeric DNA-protein complex, the other on a test for
      mitotic minichromosome stability, was used to identify small molecules that
      affect the process of chromosome segregation. One compound, here named incentrom
      A, leads to a minichromosome loss phenotype, and is cytotoxic to the budding
      yeast Saccharomyces cerevisiae. Furthermore, whereas cells carrying a conditional
      mutation in a gene for an essential kinetochore protein, skp1-4, are
      hypersensitive to incentrom A, cells that overexpress the SKP1 gene are resistant
      to the compound. Incentrom A also results in mitotic loss of a centromere-bearing
      plasmid, and inhibits the growth of the pathogenic yeast Candida glabrata.
      Incentrom A will therefore be a useful tool for studying the molecular basis of
      yeast chromosome segregation and could form the basis for the development of
      novel antifungal drugs.

PMID- 15042358
TI  - High level of beta-hCG simulating pregnancy in recurrent osteosarcoma: case
      report and review of literature.
AB  - PURPOSE: A high serum level of beta human chorionic gonadotropin (hCG) normally
      indicates pregnancy in healthy women. We were confused by this finding in one of
      our patients. This 18-year-old girl presented with amenorrhoea of 1-month
      duration, a positive pregnancy test and a high beta-hCG serum level although
      taking contraceptives. Pregnancy was excluded by ultrasound. Three years
      previously, she had had an osteosarcoma of the humerus. The tumour initially had
      been wide resected and had shown a good response to neoadjuvant chemotherapy with
      COSS-96-protocol. METHODS: We reviewed the original histological result and the
      literature about possible similar findings. We analysed therapeutic options and
      the value of beta-hCG levels as a therapy monitor. RESULTS: During examination we
      detected a recurrent osteosarcoma of the left humerus. The local relapse
      evidently expressed beta-hCG which, retrospectively, could only sparsely be shown
      in the primary resectate. After intralesional surgery, chemotherapy and
      radiotherapy levels of beta-hCG normalised. CONCLUSION: Osteosarcoma very rarely
      is able to produce a paraneoplastic syndrome by high levels of beta-hCG. This may
      well be of diagnostic value and offer an additional monitoring tool. It can
      indicate tumour recurrence and dedifferentiation.

PMID- 15042359
TI  - Randomized controlled trial of screening for hepatocellular carcinoma.
AB  - PURPOSE: Screening for hepatocellular carcinoma (HCC) has been conducted for over
      20 years, but there is no conclusive evidence that screening may reduce HCC
      mortality. The aim of this study was to assess the effect of screening on HCC
      mortality in people at increased risk. METHODS: This study included 18,816
      people, aged 35-59 years with hepatitis B virus infection or a history of chronic
      hepatitis in urban Shanghai, China. Participants were randomly allocated to a
      screening (9,373) or control (9,443) group. Controls received no screening and
      continued to use health-care facilities. Screening group participants were
      invited to have an AFP test and ultrasonography examination every 6 months.
      Screening was stopped in December 1997; by that time screening group participants
      had been offered five to ten times. All participants were followed up until
      December 1998. The primary outcome measure was HCC mortality. RESULTS: The
      screened group completed 58.2 percent of the screening offered. When the
      screening group was compared to the control group, the number of HCC was 86
      versus 67; subclinical HCC being 52 (60.5%) versus 0; small HCC 39 (45.3%) versus
      0; resection achieved 40 (46.5%) versus 5 (7.5%); 1-, 3,-, and 5-year survival
      rate 65.9%, 52.6%, 46.4% versus 31.2%, 7.2%, 0, respectively. Thirty-two people
      died from HCC in the screened group versus 54 in the control group, and the HCC
      mortality rate was significantly lower in the screened group than in controls,
      being 83.2/100,000 and 131.5/100,000, respectively, with a mortality rate ratio
      of 0.63 (95%CI 0.41-0.98). CONCLUSIONS: Our finding indicated that biannual
      screening reduced HCC mortality by 37%.

PMID- 15042369
TI  - Absence of simian virus 40 DNA sequences in primary central nervous system
      lymphoma in HIV-negative patients.
AB  - Simian virus 40 (SV40) is known to induce primary brain tumors and lymphomas in
      animal models. Recently, it was also associated with the pathogenesis of human
      non-Hodgkin's lymphomas. In the present study, we investigated primary central
      nervous system lymphomas (PCNSL), a defined subgroup of diffuse large B-cell
      lymphoma confined to the central nervous system, for the presence of SV40 DNA.
      Frozen tissue samples of 23 PCNSL derived from human immunodeficiency virus
      negative patients were analyzed by two different, fully nested polymerase chain
      reaction protocols. SV40 DNA sequences could not be detected in any of these
      samples. Thus, SV40 can be added to the list of viruses that have already been
      excluded as pathogenetically relevant cofactors in PCNSL.

PMID- 15042370
TI  - Plant-derived secondary metabolites as defensive chemicals in herbivorous
      insects: a case study in chemical ecology.

PMID- 15042371
TI  - Channel-induced apoptosis of infected host cells-the case of malaria.
AB  - Infection of erythrocytes by the malaria pathogen Plasmodium falciparum leads to
      activation of several distinct anion channels and a non-selective, Ca2+-permeable
      cation channel. All channel types are presumably activated by the oxidative
      stress generated by the pathogen. Similar or identical channels are activated by
      oxidation of non-infected erythrocytes. Activation of the non-selective cation
      channel allows entry of Ca2+ and Na+, both of which are required for
      intracellular growth of the pathogen. The entry of Ca2+ stimulates an
      intraerythrocytic scramblase that facilitates bi-directional phospholipid
      migration across the bilayer, resulting in breakdown of the phosphatidylserine
      asymmetry of the cell membrane. The exposure of phosphatidylserine at the outer
      surface of the cell membrane is presumably followed by binding to
      phosphatidylserine receptors on macrophages and subsequent phagocytosis of the
      affected erythrocyte. The lysosomal degradation may eventually eliminate the
      pathogen. The channel may thus play a dual role in pathogen survival. Absence of
      the channels is not compatible with pathogen growth, enhanced channel activity
      accelerates erythrocyte "apoptosis" that may represent a host defence mechanism
      serving to eliminate infected erythrocytes.

PMID- 15042373
TI  - Functional changes in autonomic nervous system and baroreceptor reflex induced by
      14 days of 6 degrees head-down bed rest.
AB  - We studied the effects of 14 days of 6 degrees head-down bed rest (HDBR) in 16
      healthy male subjects to examine the functional changes in the autonomic nervous
      system and cardiac baroreceptor reflex response with an emphasis on dynamic
      changes during HDBR. Beat-by-beat RR intervals (RRIs) and systolic arterial
      pressures (SAPs) were measured non-invasively from simultaneous, continuous
      recordings of ECG and arterial pressure waves in supine resting postures. A power
      spectrum analysis by the fast Fourier transform was applied to a data set
      composed of interpolated 512 RRIs and 512 SAPs (256 s in duration). Three indices
      of cardiac baroreceptor reflex sensitivity (BRS) were obtained by applying a
      sequence technique and a cross-spectrum analysis technique to the spontaneous
      RRIs and SAPs. The high-frequency band power of RRI variability (HF(RRI))
      decreased significantly in the latter part of HDBR and persisted until the
      initial stage of the post-HDBR period (POST). The low-frequency band power of SAP
      variability decreased significantly only during the mid-part of HDBR. The
      BRS(sequence) obtained by the sequence technique showed a significant increase
      temporarily on the initial day of HDBR. The BRS(sequence) and the estimate of BRS
      obtained by the cross-spectrum analysis handling the high-frequency band were
      both significantly decreased on the initial day of POST. Each of the BRS
      estimates correlated negatively with heart rate and positively with HF(RRI)
      during HDBR and POST. These results suggest the following: (1) cardiac
      spontaneous baroreceptor reflex sensitivity might be transiently increased at the
      initial stage of HDBR, (2) the reduction in vagal modulation on the sinus node
      occurs from the latter part of HDBR to the initial stage of POST, (3) sympathetic
      vasomotor control is probably slightly inhibited during the mid-part of HDBR, and
      (4) the enhancement in cardiac sympathetic modulation and the impairment in
      cardiac spontaneous baroreceptor reflex sensitivity may occur in the initial
      stage of POST.

PMID- 15042372
TI  - Update on nandrolone and norsteroids: how endogenous or xenobiotic are these
      substances?
AB  - Norsteroids are xenobiotics with androgenic and anabolic properties known since
      as far back as the 1930s. In doping controls, the use of the banned xenobiotic
      norsteroids is detected in the competitor's urines by the measurement of
      norandrosterone (19-NA) and noretiocholanolone (19-NE), which are the main
      metabolites for nandrolone (NT) and most norsteroids with anabolic properties. In
      1996, the IOC subcommission "Doping and Biochemistry of Sport" informed the Heads
      of the "IOC Accredited Laboratories" that the recommended cut-off limit for
      reporting an offence was to be 1-2 ng ml(-1) urine for either 19-NA or 19-NE. We
      will discuss how technical progress in gas chromatography coupled to high
      resolution mass spectrometry permitted a dramatic increase in sensitivity with a
      detection limit of 1 pg ml(-1) urine, or less, and an assay limit of 20-50 pg ml(
      1) urine, for either 19-NA or 19-NE. As a paradox, norsteroids have been known
      for decades as not only xenobiotics but also obligatory endogenous intermediates
      in the biosynthesis of estrogens from androgens in all species, man included. It
      is this biochemical observation which fed the active scientific and medical
      controversy initiated in 1998 over the possibly endogenous production of
      nandrolone and metabolites well over the new IOC's recommended cut-off limit of 2
      ng ml(-1) urine. Notwithstanding the particular technical difficulties attached,
      we will provide data and discuss the minute endogenous levels detected and
      measured in man either at rest, after performance or training and compare them to
      the relatively high levels reported in male athlete's doping controls today. We
      will also discuss data on the pharmacological effects of some contraceptive
      therapies containing norsteroids in women. In view of the well-documented noxious
      effects repeatedly observed after anabolic steroid misuse, the confirmation and
      implementation of technically proven procedures for reporting norsteroid abuse in
      sports seems an important enough goal to protect athlete's health against such
      abuses and justifies up dating the review of the patent scientific and medical
      experience and knowledge gained over the last 50 years on nandrolone and its
      minor production in man and woman.

PMID- 15042375
TI  - Visual outcome of patients with macular edema after pars plana vitrectomy and
      indocyanine green-assisted peeling of the internal limiting membrane.
AB  - PURPOSE: To evaluate the efficacy of inner limiting membrane (ILM) peeling in
      persistent macular edema. METHODS: This retrospective review analyzed a series of
      23 eyes from 23 patients with persistent macular edema treated by pars plana
      vitrectomy (PPV) with indocyanine green (ICG)-assisted peeling of the ILM.
      Thirteen female and 10 male patients with a mean age of 57.2+/-15.6 (24-77) years
      underwent operation between May 2000 and October 2001. The main diagnoses were
      uveitis (anterior, intermediate, posterior and panuveitis) ( n=9), central
      retinal vein occlusion (CRVO) (n=4), diabetic retinopathy (DR) ( n=5),
      vitreoretinal traction syndrome ( n=2), and Irvine-Gass syndrome ( n=3). Nine
      eyes had undergone phacoemulsification (PE) previously and two eyes had been
      subjected to combined PE and ILM peeling. The eyes were tamponaded with gas (3),
      silicone oil (5) or air (11). In four cases no endotamponade was used.
      Improvement in visual acuity of 2 lines or more was regarded as significant.
      RESULTS: Visual acuity improved after 3 months in 9 of the 23 patients. After 6
      months and at the follow-up, a significant improvement was found in 6/21 and 7/21
      patients. This improvement was predominantly seen in patients with uveitis (5/9),
      or diabetic maculopathy (3/5); One patient with Irvine-Gass syndrome showed a
      significant reduction, one with vitreoretinal traction an improvement in visual
      acuity. The group of patients with CRVO showed no significant change during the
      follow-up. The choice of endotamponade did not alter the visual acuity outcome.
      CONCLUSIONS: Different patient groups respond differently to ILM peeling.
      Although overall significant visual acuity improvement was observed in only one
      third of all cases 12 months after ILM peeling for persistent macular edema,
      patients with uveitis and nonproliferative diabetic maculopathy demonstrated a
      benefit. The lack of long-term improvement in the majority of cases is in
      accordance with the hypothesis that ILM peeling may reduce the intraretinal
      edema, but does not affect the underlying mechanism causing macular edema. So
      far, only diabetics have shown improvement (still unproven) from ILM peeling, and
      this study provides no justification for extending the treatment to macular edema
      of other causes. Large-scale investigations are needed to evaluate the efficacy
      in certain diagnosis groups.

PMID- 15042376
TI  - Bilateral rhegmatogenous retinal detachment after external-beam radiotherapy:
      just a coincidence?
AB  - PURPOSE: To report an unusual case of almost simultaneous bilateral
      rhegmatogenous retinal detachment in the context of external-beam radiotherapy
      for a tumor at a non-ocular target site and in the absence of pre-existing ocular
      pathology. METHODS: Observational case report with review of corresponding
      literature. RESULTS: A 63-year-old man was referred for bilateral retinal
      detachment which was associated with many horseshoe tears and proliferative
      vitreoretinopathy. He had undergone surgery for a carcinoma of the left maxillary
      sinus 4 months prior to the presentation and had then received external-beam
      radiotherapy for 3 months. There was no familial history of retinal detachment
      and/or eye trauma in this hyperopic patient with clear native lenses. No
      chorioretinal pathology was apparent that could have predisposed the retinas to
      tearing. CONCLUSIONS: Simultaneous bilateral retinal detachment is exceptional,
      especially in a patient with no risk factors. The effect of radiotherapy on the
      vitreoretinal interface is discussed in the light of existing data and may have
      been responsible for our patient's retinal detachment.

PMID- 15042374
TI  - Pericellular proteolysis by leukocytes and tumor cells on substrates: focal
      activation and the role of urokinase-type plasminogen activator.
AB  - Previous studies have shown that the urokinase-type plasminogen activator
      receptor (uPAR) is localized to the adherence sites of leukocytes and tumor cells
      suggesting that pericellular proteolysis may accompany focal activation of
      adherence. To assess for focused pericellular proteolytic activity, we prepared
      two-dimensional substrates coated with FITC-casein or Bodipy FL-BSA. These
      molecules are poorly fluorescent, but become highly fluorescent after proteolytic
      degradation. Fluorescent peptide products were observed at adherence sites of
      stationary human neutrophils and at lamellipodia of polarized neutrophils. During
      cell migration, multiple regions of proteolysis appeared sequentially beneath the
      cell. Similarly, proteolytic action was restricted to adherence sites of resting
      HT1080 tumor cells but localized to the invadopodia of active cells. Using an
      extracellular fluorescence quenching method, we demonstrate that these
      fluorescent peptide products are extracellular. The uPA/uPAR system played an
      important role in the observed proteolytic activation. Plasminogen activator
      inhibitor-1 significantly reduced focal proteolysis. Sites of focal proteolysis
      matched the membrane distribution of uPAR. When uPA was dissociated from uPAR by
      acid washing, substantially reduced pericellular proteolysis was found. uPAR
      negative T47D tumor cells did not express significant levels of substrate
      proteolysis. However, transfectant clones expressing uPAR (for example, T47D-26)
      displayed high levels of fluorescence indicating proteolysis at adherence sites.
      To provide further evidence for the role of the uPA/uPAR system in pericellular
      proteolysis, peritoneal macrophages from uPA knock-out (uPA-/-) and control
      (uPA+/+) mice were studied. Pericellular proteolysis was dramatically reduced in
      uPA-negative peritoneal macrophages. Thus, we have: (1). developed a novel
      methodology to detect pericellular proteolytic function, (2). demonstrated
      focused activation of proteolytic enzymatic activity in several cell types, (3).
      demonstrated its usefulness in real-time studies of cell migration, and (4).
      showed that the uPA/uPAR system is an important contributor to focal pericellular
      proteolysis.

PMID- 15042377
TI  - Binocular summation in visual evoked cortical potential in patients who have
      significantly different P100 peak latencies in their two eyes.
AB  - PURPOSE: To determine whether binocular summation in visual evoked cortical
      potential (VEP) is present in patients who have significantly different P100 peak
      latencies in their two eyes. METHODS: Twelve patients with unilateral optic
      neuritis (ON) and 11 normal controls were studied. All of them had visual acuity
      of > or = 20/20 in both two eyes and good stereoacuity. Transient and steady
      state VEPs were recorded with monocular and binocular pattern-reversal
      stimulation. RESULTS: In normal controls, the binocular summation ratio was 1.05
      with transient stimulation and 1.21 with steady-state stimulation, and in ON
      patients it was 1.19 and 1.30, respectively. In ON patients, the peak latency of
      P100 components was delayed significantly when the affected eye was stimulated,
      but with binocular stimulation the waveform was very similar to that when the
      fellow eye was stimulated. CONCLUSION: Binocular summation of VECP is not present
      in ON cases with large differences in the peak latency between the two eyes even
      if they have good stereoacuity. Binocular summation may not be correlated with
      stereopsis in adults whose binocular function has already matured.

PMID- 15042378
TI  - Ocular findings in mitochondrial neurogastrointestinal encephalomyopathy: a case
      report.
AB  - PURPOSE: To describe the ocular features of a patient with mitochondrial
      neurogastrointestinal encephalomyopathy (MNGIE) due to a homozygous G1443A
      mutation in the thymidine-phosphorylase gene. METHODS: A case report with
      extensive ophthalmological investigation over a 9-year period, until death at age
      38 years. Measures used included standard ophthalmological examination, visual
      field examination and optical coherence tomography (OCT). RESULTS: Ptosis and
      external ophthalmoplegia progressively worsened during the follow-up, as did the
      neurological and general status. Corneal and optic disc alterations were also
      observed at the last visit. Glaucomatous changes of the optic disc were confirmed
      by the visual field examination and OCT. CONCLUSION: In addition to previously
      described alterations such as ptosis and external ophthalmoplegia, MNGIE may be
      associated with glaucomatous-like optic neuropathy.

PMID- 15042379
TI  - German study on sudden infant death (GeSID): design, epidemiological and
      pathological profile.
AB  - The German study on sudden infant death (GeSID) is a multi-centre case-control
      study aiming at the assessment of etiological factors and risk factors of SIDS.
      This report describes the study design and the methods applied and presents some
      general findings. Between 1998 and 2001, 455 cases of sudden and unexpected death
      of infants aged between 8 and 365 days were recruited into the study. The study
      comprised at least 11 out of the 16 German states with 18 centres involved. In
      1999 and 2000, 75% of all SIDS cases registered with the Federal Office of
      Statistics (ICD 10/R95, n=384) in the study area were recruited into the study
      (n=286). A standardised autopsy including extended histology, microbiology,
      virology, toxicology and neuropathology investigations was carried out. Of the
      parents 82% (n=373) agreed to fill in an extensive questionnaire containing 120
      questions reflecting all important aspects of the infant's development. For each
      SIDS case, the parents of three living control infants were interviewed. These
      controls were matched for age, gender and region (n=1,118). The response rate of
      the controls was 58.7%. Data were linked with medical records obtained from
      obstetrics departments, the children's hospitals, and general practitioners.
      Death scene investigation was performed in 4 study areas (cases: n=64, controls:
      n=191). All cases were classified into one of 4 categories using defined
      criteria: 7.3% of the children were assigned to category 1 (no pathological
      findings: SIDS), 61.1% to category 2 (minor findings: SIDS+), 20.4% to category 3
      (severe findings: SIDS+) and 11.2% to category 4 (findings which explained the
      death: non-SIDS). In case conferences the previous history and circumstantial
      factors were included and an extended category (E-cat.) was defined. The
      consideration of these factors for the final classification is of great
      importance in the causal explanation of some cases. An analysis of 18 main
      variables in cases of categories 1-3 (SIDS) compared to the cases of category 4
      (non-SIDS) showed significant differences for the sleeping position, coughing the
      day before death and breast-feeding indicating that the cases of both groups
      should be separated for further analyses.

PMID- 15042381
TI  - A study of pregnancy loss in 352 women with recurrent miscarriages.
AB  - AIM: The aim of the study was to investigate the type of pregnancy loss (PL) in
      women with recurrent miscarriages. MATERIALS AND METHODS: The study population
      included 411 women with a history of recurrent pregnancy loss (RPL) attending the
      Recurrent Miscarriage Clinic of the 2nd Department of Obstetrics and Gynecology,
      University of Athens (tertiary referral center). Subjects were divided in groups
      according to their underlying pathology and in some of them appropriate treatment
      was applied. RESULTS: The study of the 323 pregnancies achieved after referral,
      revealed that the PL after ultrasonographic detection of fetal heart (FH) is
      overall increased, is more common in women with anatomical uterine anomalies and
      unexplained RPL, and treatment reduces its rate in women with anatomical uterine
      anomalies and an inadequate luteal phase. The PL before the detection of FH is
      reduced after treatment in women with thrombotic tendency and an inadequate
      luteal phase.

PMID- 15042380
TI  - Simulation of (125)I decay in a synthetic oligodeoxynucleotide with normal and
      distorted geometry and the role of radiation and non-radiation actions.
AB  - Within the track structure code PARTRAC, DNA strand break induction by direct and
      indirect radiation action was calculated for the E. coli catabolite gene
      activator protein (CAP) DNA complex with (125)I located at the position of the
      H(5) atom of the cytosine near the center. The shape of the resulting DNA
      fragment size distributions was found to be in reasonable agreement with
      corresponding experimental results. However, the calculated yield was
      considerably lower than the measured one. To study possible reasons for this,
      recently published experimental data on DNA strand breaks in a 41-mer synthetic
      oligodeoxynucleotide (oligoDNA) with incorporated (125)I were analyzed aiming at
      an evaluation of the non-radiation-related component due to the neutralization of
      the initially highly charged (125m)Te daughter ion. This was done by assuming
      that the differences between simulated radiation-induced distribution and the
      measured total fragment size distributions were due to the neutralization
      process. The neutralization effect defined in this way was found to dominate the
      strand breakage frequency within a range of 5-7 base pairs around the (125)I
      decay site on both strands. After implementing this neutralization effect derived
      from the oligoDNA analysis into the PARTRAC simulation for the CAP-DNA complex,
      the agreement of the calculated DNA fragment distributions with the corresponding
      experimental data was considerably improved. The results indicate that DNA
      conformation may be explored by incorporation of (125)I into the DNA, measurement
      of fragment size distributions, and comparison with simulation calculation for
      various hypothetical DNA models.

PMID- 15042382
TI  - Fetal intra-abdominal umbilical vein dilatation associated with notching in
      umbilical artery.
AB  - INTRODUCTION: Dilatation of the fetal intra-abdominal umbilical vein is a rare
      entity. It is unclear whether prenatally diagnosed umbilical vein dilatation is
      associated with an increased risk of fetal anomalies or poor perinatal outcome.
      Umbilical artery waveform notching may be a predictor of cord abnormalities. It
      seems reasonable following the baby closely after the diagnosis of both
      conditions. CASE REPORT AND DISCUSSION: We present here a new case diagnosed by
      ultrasonography at 30 weeks of gestation with normal fetal outcome and discuss
      the clinical features and the management of these rare abnormalities.

PMID- 15042383
TI  - Two 14-epi analogues of 1,25-dihydroxyvitamin D3 protect human keratinocytes
      against the effects of UVB.
AB  - In search of photoprotective agents, we recently demonstrated a protective effect
      of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] against different events mediated
      by ultraviolet B (UVB) in human keratinocytes. Pharmacological doses of
      1,25(OH)(2)D(3) were required to obtain significant UVB protection; however,
      these doses cannot be used in vivo due to the calcemic properties of
      1,25(OH)(2)D(3). Therefore, we evaluated the photoprotective capacities of two
      low-calcemic 14-epi analogues of 1,25(OH)(2)D(3), 19-nor-14-epi-23-yne
      1,25(OH)(2)D(3) (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3) (TX 527).
      Using cultured human keratinocytes, we investigated the influence of TX 522 and
      TX 527 on two hallmark events in UVB-irradiated keratinocytes: the induction of
      apoptosis and the production of interleukin-6 (IL-6). Treatment of the
      keratinocytes with TX 522 or TX 527, 24 h before irradiation, resulted in a
      significant and dose-dependent reduction of both UVB-induced apoptosis and IL-6
      production. Both analogues were equally efficient in their anti-UVB effects and
      at least 100 times more potent than 1,25(OH)(2)D(3). We further demonstrated that
      metallothionein (MT) mRNA expression was clearly induced by 1,25(OH)(2)D(3) and
      both analogues. MT acts as a radical scavenger in oxygen-mediated UVB injury and
      its induction may therefore be relevant for the anti-UVB effects of
      1,25(OH)(2)D(3) and both analogues. Taken together, these findings create new
      perspectives for the use of active vitamin D analogues as photoprotective agents.

PMID- 15042384
TI  - Activation of murine cytomegalovirus immediate-early promoter in mouse brain
      after transplantation of the neural stem cells.
AB  - Cytomegalovirus (CMV) is the most significant infectious cause of congenital
      infection and fatal diseases in immunocompromised patients. We have previously
      described a transgenic mouse model of the murine CMV (MCMV) immediate-early (IE)
      gene promoter fused with the lacZ reporter gene (MCMV-IE-pro1) for the analysis
      of spatiotemporal changes of the promoter activity during brain development.
      Since expression of the IE genes play a pivotal role in latency and reactivation,
      we transplanted the transgene-expressing neural stem cells (NSCs) into neonatal
      mouse brains after labeling with bromodeoxyuridine (BrdU). The activation of MCMV
      IE pro1 was detected in the subventricular zone (SVZ) soon after transplantation,
      and the number of MCMV IE pro1-activated cells was decreased as the development
      proceeded. Cells that were MCMV IE pro1-activated and glial fibrillary acidic
      protein positive, but not stained with BrdU, were found in the cortex 4 weeks
      after transplantation, while BrdU-positive but not MCMV IE pro1-activated cells
      still existed in the SVZ. MCMV IE promoter activity tended to be easily detected
      in the cortex after allogenic transplantation in BALB/c mouse. These results
      suggest that the SVZ is the most susceptible site for activation of the MCMV IE
      promoter in neonatal mice in the early period after transplantation and that the
      cerebral cortex is also susceptible to the activation in the late period after
      transplantation. It may be important to avoid the use of NSCs latently infected
      with CMV as donor cells.

PMID- 15042385
TI  - Blood-brain barrier is impaired in the hippocampus of young adult spontaneously
      hypertensive rats.
AB  - A causative role of blood-brain barrier (BBB) impairment is suggested in the
      pathogenesis of vascular dementia with leakage of serum components from small
      vessels leading to neuronal and glial damage. We examined the BBB function of
      young adult spontaneously hypertensive rats (SHR) in order to determine earlier
      changes in the BBB in chronic hypertension. SHR and stroke-prone SHR (SHRSP) were
      injected with horseradish peroxidase (HRP) as an indicator of BBB function and
      compared with Wistar Kyoto rats (WKY). The brain tissues were further examined
      with cationized ferritin, a marker for evaluating glycocalyx. The staining for
      HRP was distributed around the vessels in the hippocampal fissure of SHR and
      SHRSP, but not in WKY. With electron microscopy, the extravasated reaction
      product of HRP appeared in abluminal pits of the endothelial cells of arterioles
      and within the basal lamina in the hippocampus, but not the cerebral cortex, of
      SHR and SHRSP. On the contrary, the reaction product of HRP was never seen in the
      abluminal pits of the endothelial cells or the basal lamina of vessels in WKY.
      The number of cationized ferritin particles binding to the endothelial cells of
      capillaries was decreased in the hippocampus of SHR and SHRSP, while the number
      decreased in the cerebral cortex of SHRSP compared with those in WKY. However,
      the cationized ferritin binding was preserved in the endothelial cells of the
      arterioles with an increased vascular permeability. These findings suggest that
      the chronic hypertensive state induces BBB dysfunction in the hippocampus at an
      early stage.

PMID- 15042386
TI  - Purkinje cell neuroaxonal dystrophy similar to nervous mutant mice phenotype in
      two sibling kittens.
AB  - Three 4-month-old kittens from the same litter were presented, two of which were
      exhibiting cerebellar signs. Euthanasia was requested. No cerebellum atrophy was
      disclosed on necropsy. General cerebellar anatomy was normal, including the
      thickness of the cortical layers, myelination, and neurons of the deep cerebellar
      nuclei. In the ataxic cat vermis, Purkinje cells were lacking along broad
      parasagittal bands symmetrically disposed relative to the midline. Many Purkinje
      cells were also lacking in the hemispheres. The nodulus and the flocculus were
      normal. Surviving Purkinje cells had frequent main dendrite swellings visible
      with anti-calbindin and anti-microtubule associated protein. In affected regions,
      calbindin and phosphorylated neurofilaments immunesera stained numerous axonal
      torpedoes located in the granular layer and the folial white matter. They were
      also present in processes of the deep cerebellar nuclei and lateral vestibular
      nucleus. Loss of synaptic endings onto the neurons of these nuclei was evident.
      Hypertrophied Purkinje cell recurrent axons and enhanced retrograde synaptic
      endings were present in the granular layer. Bergmann glia was strongly labeled by
      anti-GFAP, but no abnormal supplementary fibers were seen. None of these
      alterations were present in the normal sister. However, abnormal vacuolation of
      the Purkinje cell main dendrites was evident in all three cats, but not in six
      unrelated control cats that were 3-6 months old. The inferior olive and pontine
      nuclei were also normal. The two ataxic cats had a primary Purkinje cell
      degeneration that shared many common features with the abnormal Purkinje cells of
      the nervous mutant mouse.

PMID- 15042387
TI  - The leukoencephalopathy of infantile GM1 gangliosidosis: oligodendrocytic loss
      and axonal dysfunction.
AB  - A myelin deficit in the cerebral white matter in infantile GM1 gangliosidosis is
      well established. Some have proposed this deficit to be secondary to axonal loss,
      while others argue for delayed or arrested myelination. We compared the frontal
      white and gray matter of two infants with GM1 gangliosidosis with four age
      matched controls, using light microscopy with a quantitative analysis,
      immunohistochemistry, terminal deoxynucleotidyl transferase-mediated nick-end
      labeling (TUNEL), and electron microscopy (EM). In the GM1 cases, we found a
      marked decrease in the number of oligodendrocytes (85% in case 1 and 50% in case
      2) and myelin sheaths (80% and 40%), with a mild decrease in axons (20% and 10%).
      Ultrastructurally, some naked axons and dilated cisterns of rough endoplasmic
      reticulum (RER) in oligodendrocytes were observed. There was no appreciable
      storage in remaining oligodendrocytes, nor obvious neocortical neuronal loss. An
      immunohistochemical decrease in proteolipid protein (PLP) and a more profound
      deficiency of myelin basic protein (MBP) indicate that this lesion is not simply
      the result of a delay or arrest in myelination and suggests a "dying-back"
      oligopathy. TUNEL-positive oligodendrocytes correlated with activated caspase-3
      immunoreactivity. Amyloid precursor protein (APP)-immunoreactive aggregates were
      observed in proximal axons and meganeurites as well as in white matter axons.
      These data suggest that the myelin deficit results from a loss of
      oligodendrocytes and abnormal axoplasmic transport, perhaps consequent to massive
      neuronal storage of GM1.

PMID- 15042388
TI  - Improvement of oxygen metabolism in ischemic myocardium as a result of enhanced
      external counterpulsation with heparin pretreatment for patients with stable
      angina.
AB  - Enhanced external counterpulsation (EECP) is noninvasive, safe, and effective for
      stable angina. We have reported that the development of functional collateral
      vessels is one of the mechanisms of EECP therapy using ammonia positron emission
      tomography (PET). The efficacy of heparin treatment on collateral growth is shown
      in several clinical studies. We evaluated whether EECP combined with intravenous
      heparin injection is effective for exercise capacity and oxygen metabolism of
      ischemic myocardium in stable angina. Eleven patients with stable angina were
      treated with conventional EECP therapy (C group). Seven patients with stable
      angina were treated with EECP therapy with 5000 IU heparin pretreatment (H
      group). At baseline and after the completion of treatment H, 7 patients underwent
      [(11)C] acetate PET to examine the change in regional myocardial oxygen
      metabolism. Although the total treadmill exercise time was prolonged after
      treatment in both groups, the extent of the improvements was significantly
      greater in the H group compared with the C group. Although k mono, the index of
      regional myocardial oxygen metabolism, in the nonischemic region remained
      unchanged, k mono in the ischemic region increased significantly ( P << 0.05)
      from 0.038 +/- 0.004 to 0.053 +/- 0.007. In conclusion, EECP with heparin
      pretreatment appears to be a new treatment remedy for patients with stable
      angina.

PMID- 15042389
TI  - Correlation between infarct-related coronary artery patency and predischarge
      electrocardiographic patterns in patients with first anterior myocardial
      infarction who received thrombolytic therapy.
AB  - The aim of this study was to investigate the correlation between the ST-segment
      and T-wave patterns in predischarge electrocardiogram and patency of left
      anterior descending coronary artery in patients with a first anterior myocardial
      infarction (AMI). One hundred and fifty-six of 175 consecutive patients who were
      admitted to our clinic between January 2000 and September 2002 due to a first
      episode of transmural AMI and who received thrombolytic therapy were enrolled.
      Coronary angiography was performed by the Judkins method on the 6th-10th day
      after the acute infarction. The corrected TIMI frame count (CTFC) was estimated
      according to the previously described method. According to the combination of the
      ST-segment and T-wave morphology on the day (6-10) of cardiac catheterization,
      patients were classified into four groups: group A, ST elevation <<0.1 mV and
      negative T waves; group B, ST elevation >or=0.1 mV and negative T waves; group C,
      ST elevation <<0.1 mV and positive T waves; and group D, ST elevation >or=0.1 mV
      and positive T waves. Of the 99 patients with negative T waves, 47 (48%) had CTFC
      <or=27, 32 (32%) CTFC between 27 and 40, 15 (15%) CTFC >or=40-100, and 5 (5%)
      CTFC >>100. Of the 57 patients with positive T waves, CTFC was <or=27 in 14
      (25%), between 27 and 40 in 17 (30%), >or=40-100 in 11 (19%), and >>100 in 15
      (26%) ( P << 0.001). From the 76 patients with an isoelectric ST segment, 38
      (50%) had CTFC <or=27, 29 (38%) CTFC between 27 and 40, 8 (11%) CTFC >or=40-100,
      and 1 (1%) CTFC >>100. Of the 80 patients with an elevated ST segment, 23 (29%)
      had CTFC <or=27, 20 (25%) CTFC between 27 and 40, 18 (23%) CTFC >or=40-100, and
      19 (23%) CTFC >>100 ( P << 0.001). Use of the combination of two
      electrocardiographic parameters (ST segment and T waves) also indicated that
      there were significant differences between groups A and D, and groups B and D ( P
      << 0.001 and P << 0.05, respectively). Development of an isoelectric ST segment
      with negative T waves may indicate a better degree of reperfusion after AMI. In
      contrast, patients in whom ST-segment elevation and positive T waves remain at
      discharge from the coronary care unit have a higher probability of a nonpatent
      left anterior descending artery.

PMID- 15042390
TI  - Prognostic value of the Tei index combining systolic and diastolic myocardial
      performance in patients with acute myocardial infarction treated by successful
      primary angioplasty.
AB  - Cardiac systolic (left ventricular ejection fraction) and diastolic (mitral
      inflow velocity pattern and/or mitral deceleration time) function were reported
      as predictors of clinical outcome or left ventricular remodeling in patients with
      acute myocardial infarction (AMI). Recently, a new index (Doppler-derived index
      combining systolic and diastolic myocardial performance; Tei index) for combined
      systolic and diastolic ventricular function has been reported to be a useful and
      convenient method for evaluation of global ventricular function. We therefore
      investigated the usefulness of the Tei index by echocardiography for evaluation
      of infarct size and clinical outcome in patients with AMI treated by successful
      primary angioplasty. We analyzed 10 age-matched control subjects and 43
      consecutive patients with first AMI treated by successful primary angioplasty.
      The Tei index of the AMI patients was significantly greater than that of the
      control subjects (0.630 +/- 0.106 vs 0.375 +/- 0.036, P << 0.0001). Also, the Tei
      index showed a significant positive correlation with peak creatine kinase values
      and (99m)Tc-tetrofosmin scores. Moreover, multiple logistic regression analysis
      showed that the Tei index >>0.70 ( P = 0.0313, odds ratio = 14.14) was the only
      significant explanatory factor for cardiac death or developed congestive heart
      failure. The Tei index combining systolic and diastolic myocardial performance
      reflects infarct size and might be a predictor of clinical outcome in patients
      with AMI treated by successful primary angioplasty.

PMID- 15042391
TI  - The possible role of hydrogen sulfide as a smooth muscle cell proliferation
      inhibitor in rat cultured cells.
AB  - Hydrogen sulfide (H(2)S) was recently suggested to be a possible endogenous
      gasotransmitter in physiological concentration. For the purpose of understanding
      its possible role in the regulation of the cardiovascular system, we explored the
      potential effect of H(2)S on the proliferation of cultured aortic vascular smooth
      muscle cells (VSMCs) of rats and mitrogen-activated protein kinase (MAPK) as a
      signaling transduction pathway. Vascular smooth muscle cells were cultured in
      vitro and the cells were divided into six groups: (1). control group, (2). serum
      group, (3). endothelin group, (4). NaHS group, (5). serum + NaHS group, and (6).
      endothelin + NaHS group. VSMC proliferation was measured by [(3)H]thymidine
      ([(3)H]TdR) incorporation and MAPK activity in the VSMCs was determined by
      radioactivity assay. The results showed that endothelin-1 increased VSMC
      [(3)H]TdR incorporation 2.39-fold ( P << 0.01) and MAPK activity 1.62-fold ( P <<
      0.01), as compared with controls. Hydrogen sulfide at 5 x 10(-5) mol/l, 1 x 10(
      4) mol/l, and 5 x 10(-4) mol/l decreased VSMC [(3)H]TdR incorporation by 16.8%,
      26.60%, and 37.40%, respectively, and reduced MAPK activity by 7.37% ( P >>
      0.05), 23.39%, and 33.57%, respectively ( P << 0.01). The results demonstrated
      that H(2)S could dose-dependently suppress the proliferation of VSMCs through the
      MAPK pathway.

PMID- 15042392
TI  - The upregulation of endothelial nitric oxide synthase and urotensin-II is
      associated with pulmonary hypertension and vascular diseases in rats produced by
      aortocaval shunting.
AB  - The mechanism of pulmonary vascular structural remodeling and pulmonary
      hypertension induced by high pulmonary blood flow is still unclear. Nitric oxide
      (NO) and carbon monoxide (CO) are two gaseous molecules recently discovered; both
      can induce the relaxation of blood vessels and inhibit the proliferation of
      vascular smooth muscle cells. More recently, urotensin-II (U-II) has been
      considered as the most potent mammalian vasoconstrictor identified so far, which
      can promote the proliferation of vascular smooth muscle cells. The aim of this
      study was to investigate the alteration of micro- and ultrapathologic structure,
      gaseous molecules, and U-II in rats with pulmonary hypertension induced by
      increased pulmonary blood flow. Aortocaval shunting was produced in rats. After
      11-weeks of shunting, pulmonary artery mean pressure (PAMP) was measured.
      Pulmonary vascular micro- and ultrastructure was examined. Meanwhile, the
      concentration of plasma NO and CO was measured by spectrophotometry. The
      expression of endothelial nitric oxide synthase (eNOS), heme oxygenase-1 (HO-1),
      and U-II by pulmonary arteries was detected by immunohistochemistry. The results
      showed that PAMP was significantly elevated after 11 weeks of aortocaval shunting
      (2.99 +/- 0.35 kPa vs 2.09 +/- 0.38 kPa, P << 0.01). Muscularization of small
      pulmonary vessels and relative medial thickness of pulmonary arteries were
      obviously increased in shunt rats compared with controls. Ultrastructural changes
      were found in intrapulmonary arteries of shunt rats. Meanwhile, plasma NO
      concentration was increased and eNOS expression by pulmonary artery endothelial
      cells was significantly augmented in rats of the shunting group, but there was no
      significant difference in plasma CO level and HO-1 expression by pulmonary artery
      smooth muscle cells between shunting and sham groups. Urotensin-II expression by
      pulmonary artery endothelial cells and smooth muscle cells was significantly
      strengthened in shunt rats compared with sham rats. The results suggest that
      pulmonary vascular structural remodeling is an important pathologic basis of
      pulmonary hypertension induced by a left-to-right shunt. Upregulation of U-II
      might play an important role in the development of high pulmonary blood flow
      induced pulmonary hypertension. Nitric oxide, as a modifying factor, might be
      involved in the regulation of pulmonary vascular structural remodeling.

PMID- 15042393
TI  - The effect of ethylenediaminetetraacetic acid on calcific degeneration in bovine
      pericardium.
AB  - Calcification is the most frequent cause of the clinical failure of bovine
      pericardium bioprosthetic valves, preventing their widespread application for
      surgical treatment. The aim of this study was to minimize calcific degeneration
      in bovine pericardium by using a chelating agent, ethylenediaminetetraacetic acid
      (EDTA). Freshly excised bovine pericardium was dissected free from adhering fat
      tissue and cut into 1-cm(2) pieces that were rinsed in phosphate-buffered saline
      solution (PBS) and transferred into 4 degrees C PBS containing 1% glutaraldehyde
      (GA) for initial fixation, then allocated into two groups. Group I received the
      same treatment in a fresh solution for 5 more days. Group II underwent an
      additional fixation step in PBS solution (pH 7.4, 37 degrees C) containing 11%
      EDTA for a period of 48 h (30 ml/g tissue) and was then transferred into freshly
      prepared PBS + 1% GA solution at 37 degrees C for another 3 days. To investigate
      the calcification rate, pericardial patches were inserted into the dorsal pouches
      of 25 male Wistar rats for 21 days. Calcium levels were measured with an atomic
      absorption spectrophotometer and examined histo-pathologically. The calcium
      content of EDTA-treated pericardium (Group II), 21 +/- 3.8 microg/mg, was
      significantly lower than that of Group I, 43.3 +/- 9.2 microg/mg. Assessment of
      the degree of calcification in the histological sections generally agreed well
      with the results of the chemical analyses. Calcium deposition in Group I samples
      were found to be solid mineral depositions, whereas in the Group II pericardial
      samples, only smaller traces of calcium were found. Calcific degeneration in
      bovine pericardium can be reduced by using chelates such as EDTA.

PMID- 15042394
TI  - Takayasu's arteritis: case report of a patient with recurrent subclavian steal
      syndrome.
AB  - Takayasu's arteritis is a chronic inflammatory disease of unknown origin in which
      cell-mediated inflammation involves large arteries progressing from the
      adventitia to the intima, until the lumen of the vessel is narrowed. Here we
      report a case of a 48-year-old female patient who was diagnosed with Takayasu's
      arteritis 6 years ago. At that time, because of severe involvement of both the
      right and left carotid arteries, she underwent application of a Hemashield
      vascular prosthesis, including the ascending aorta, left common carotid artery,
      and right common carotid artery. Due to the fact that there were also bilateral
      subclavian artery stenoses, the application of the prosthesis induced bilateral
      subclavian steal syndrome. This year she developed stenosis of the prosthesis and
      the bilateral subclavian steal syndrome disappeared until she underwent
      percutaneous transluminal angioplasty, which restored cerebral flow through the
      carotid arteries after which the subclavian steal syndrome reappeared.

PMID- 15042395
TI  - Iatrogenic pseudoaneurysm in a hemodialysis patient: the hidden hazard of a high
      radial artery origin.
AB  - High origin of the radial artery is the most common variation in the arterial
      network of the upper extremities in humans. A 36-year-old Japanese woman
      undergoing chronic hemodialysis presented with a pseudoaneurysm originating from
      the brachial portion of the radial artery and associated with a high radial
      artery origin. Recognition of variants of the arterial network in the upper
      extremities is crucial for clinicians because their superficial position at the
      elbow joint may make these vessels vulnerable to injury.

PMID- 15042396
TI  - Three-dimensional reconstruction of a rotational abdominal aortogram showing a
      renal artery aneurysm.
AB  - This is a case of a 65-year-old woman with a history of coronary artery disease,
      who presented with hypertension that was poorly controlled by medical treatment.
      A rotational abdominal aortogram was done, followed by selective right and left
      renal artery angiograms. Imaging of renal artery aneurysms can be tricky, and
      some aneurysms might be misdiagnosed for a tortuous renal artery. In such cases,
      the physician needs to maintain a high index of suspicion towards this condition.
      Three-dimensional reconstruction allows for a better visualization of the
      aneurysm and its surrounding structures. It also guides the operator to the
      projection that best reveals the anatomical criteria of the aneurysm.

PMID- 15042397
TI  - Bilateral intermittent claudication and the aorta.
AB  - With the increasing utilization of imaging strategies such as transesophageal
      echocardiography and magnetic resonance imaging, thrombi of the aorta are
      becoming increasingly recognized as sources of peripheral emboli. This report
      describes a 70-year-old man with bilateral intermittent claudication.
      Arteriography revealed occlusion of the distal part of the right tibialis
      posterior artery and the left tibialis anterior artery, but no occlusive
      atherosclerotic disease of the iliac, femoral, or popliteal artery. Additionally,
      no calcification of the vessels could be demonstrated. In contrast, a giant
      thrombus of the descending aorta was identified as the source of systemic
      thromboembolism. The patient was treated successfully with long-term
      anticoagulation.

PMID- 15042398
TI  - Seasonal changes in serum metabolites in free-ranging alpine marmots (Marmota
      marmota).
AB  - Circannual changes in serum parameters and body mass were studied in free-ranging
      Marmota marmota that had been shot in Switzerland (Grisons) for management
      reasons in May, July, and September of 1995, 1996, and 1997; and in April 1996.
      Markers of lipid (triglycerides, cholesterol), protein (total protein, urea
      nitrogen) and mineral (calcium, inorganic phosphate) metabolism were evaluated in
      111 haemolysis-free serum samples; the effects of sex, age, reproductive status,
      season and year were tested. Mean body mass was higher in adult males than in
      adult females in July and September, and serum cholesterol concentrations were
      lower in adult males in May. Pregnant females had lower concentrations of total
      protein than non-pregnant females, and triglyceride concentrations were
      negatively correlated with the number of uterine ampullae. Inorganic phosphate
      decreased and total protein increased with age. In adults, triglycerides,
      cholesterol and urea-nitrogen increased mainly from May to July and decreased
      between September and May. Total protein, calcium and phosphate did not change
      throughout the year. This suggests that, during the active season, ingested
      lipids and amino acids were utilised for metabolic needs or lipid storage, while
      in winter, lipids were catabolised and protein was spared. Quantitative
      differences between years, observed for triglycerides and total protein during
      the active season, were probably due to different climatic conditions in each
      year.

PMID- 15042399
TI  - RFamide neuropeptide actions on molluscan proboscis smooth muscle: interactions
      with primary neurotransmitters.
AB  - The potency (muscle force-generated) of a number of long-chain RFamide
      neuropeptides was examined in mechanical experiments with the radular-retractor
      and radular-sac muscles of gastropods Buccinum undatum and Neptunea antiqua. Many
      of the heptapeptides, octapeptides and the decapeptide LMS were found to induce
      greater contraction than FMRFamide in both smooth muscles and in both species.
      RFamide neuropeptides interacted with the neurotransmitter acetylcholine in an
      additive way and RFamide-induced contractions were inhibited by the
      neuromodulator serotonin. Pre-treatment with a calcium-free saline completely
      abolished acetylcholine-induced responses but only partially inhibited RFamide
      responses in the muscles, suggesting that acetylcholine acts to cause influx of
      extracellular calcium for contraction. In contrast, RFamide neuropeptides may
      mobilise intracellular calcium to maintain sustained tonic force in calcium-free
      conditions. This suggests that an additional involvement of a fast calcium
      channel may be present in the RFamide responses, since loss of the usual
      superimposed twitch activity is observed. Force regulation in these muscles
      appears to result from a complex interaction of RFamide neuropeptides with the
      primary transmitter acetylcholine and the neuromodulator serotonin.

PMID- 15042400
TI  - Multilevel inhibition of feeding by a peptidergic pleural interneuron in the
      mollusc Lymnaea stagnalis.
AB  - The pleural interneuron PlB is a white neuron in the pleural ganglion of the
      snail Lymnaea. We test the hypothesis that it inhibits neurons at all levels of
      the feeding system, using a combination of anatomy, physiology and pharmacology.
      There is just one PlB in each pleural ganglion. Its axon traverses the pedal and
      cerebral ganglia, running into the buccal ganglia. It has neuropilar branches in
      the regions of the cerebral and buccal ganglia where neurons that are active
      during feeding also branch. Activation of the PlB blocks fictive feeding, whether
      the feeding rhythm occurs spontaneously or is driven by a modulatory interneuron.
      The PlB inhibits all the neurons in the feeding network, including protraction
      and retraction motoneurons, central pattern generator interneurons, buccal
      modulatory interneurons (SO, OC), and cerebral modulatory interneurons (CV1,
      CGC). Only the CV1 interneuron shows discrete 1:1 IPSPs; all other effects are
      slow, smooth hyperpolarizations. All connections persist in Ca(2+)/Mg(2+)-rich
      saline, which reduces polysynaptic effects. The inhibitory effects are mimicked
      by 0.5 to 100 micromol l(-1) FMRFamide, which the PlB soma contains. We conclude
      that the PlB inhibits neurons in the feeding system at all levels, probably
      acting though the peptide transmitter FMRFamide.

PMID- 15042401
TI  - Ultraviolet properties of Australian mammal urine.
AB  - The exploitation of predator signals by potential prey is well researched, but
      relatively little is known about how predators exploit chemical cues (either
      deliberate signals or waste by-products) produced by their prey. In Finland, the
      urine of some small rodents ( Microtus spp. and Clethrionomys spp.) is reflective
      in the ultraviolet range of wavelengths, and diurnal raptors with ultraviolet
      vision use these urine marks to track their rodent prey. This study examines the
      potential for such a phenomenon in Australian systems by studying the ultraviolet
      properties of urine from 13 native and introduced mammal species that are
      variously preyed upon by raptors. Urine from all 13 species displayed various
      levels of ultraviolet absorbance in their urine and fluorescence in the
      ultraviolet range. However, no signs of ultraviolet hyper-reflectance were
      detected, suggesting that the urine of European voles have unique ultraviolet
      properties. Ultraviolet-sensitive predators in Australia may be able to
      distinguish between species based on variation in the ultraviolet absorbance of
      their urine, but ultraviolet properties did not differ between prey and non-prey
      species, nor marsupial and placental groups. Moreover, because many natural
      surfaces are ultraviolet absorbing, it is unlikely that raptors could rely upon
      the ultraviolet properties of urine to target key prey species.

PMID- 15042402
TI  - [Photodynamic treatment with verteporfin for patients with idiopathic choroidal
      neovascularization. Two-year results].
AB  - BACKGROUND: The aim of this study was the evaluation of safety and effectiveness
      of photodynamic therapy (PDT) as a treatment option for idiopathic choroidal
      neovascularization (CNV). METHODS: We performed a retrospective analysis of 11
      eyes of 9 patients who were treated with standard PDT. The follow-up period was
      at least 1 year and included regular standardized ETDRS visual acuity measurement
      and fluorescein angiography. RESULTS: Eight sub- and three juxtafoveal CNV were
      treated. The mean follow-up was 23.2 months (12-41 months), the mean change in
      visual acuity was +2.1 lines (+3 for juxtafoveal and +1.9 for subfoveal
      localization), and a mean of 1.9 (1-3) treatments were performed. Visual acuity
      improved > or =2 lines in 6 of 11 eyes (54.5%) and 5 eyes (45.5%) remained stable
      (+/-1 lines). Alterations of the retinal pigmented epithelium (RPE) with window
      defects in fluorescein angiography occurred in 7 of 11 eyes (63.6%) but did not
      alter visual acuity. In 4 of 11 cases (36.4%), we saw recurrences after initially
      successful therapy, which were retreated successfully with PDT. CONCLUSION:
      Stabilization or even an improvement of visual acuity in idiopathic CNV is
      possible with PDT treatment. Side effects such as RPE changes and recurrences are
      possible, but do not seem to influence visual acuity.

PMID- 15042403
TI  - [Secondary glaucoma in hyphema, hypopyon, iris prominence and iris hyperemia].

PMID- 15042405
TI  - Three-dimensional MR digital subtraction angiography using parallel imaging and
      keyhole data sampling in cerebrovascular diseases: initial experience.
AB  - We assessed the feasibility of MR digital subtraction angiography (DSA) using
      parallel imaging and keyhole data sampling in the diagnosis of cerebrovascular
      diseases (CVDs) in 11 patients. Their diseases included arterial trunk
      stenosis/occlusion ( n=4), aneurysm ( n=3), arteriovenous malformation ( n=2),
      venous angioma ( n=1), and sinus thrombosis ( n=1). The technique depicted not
      only anatomical features, comparably to MR angiography ( n=10/11), but also
      hemodynamics such as collateral flow at a temporal resolution of 1.68 s/frame.
      When compared with conventional angiograms ( n=7), details were missed in four
      patients (incomplete demonstration of aneurysmal neck in two and poor separation
      of AVM components in two). Although inferior to conventional angiography, this
      technique can provide both anatomical and hemodynamic information of CVDs.

PMID- 15042407
TI  - High frequency Agrobacterium-mediated transformation and plant regeneration via
      direct shoot formation from leaf explants in Beta vulgaris and Beta maritima.
AB  - We have developed a new procedure for Agrobacterium-mediated transformation of
      plants in the genus Beta using shoot-base as the material for Agrobacterium
      infection. The frequency of regeneration from shoot bases was analyzed in seven
      accessions of sugarbeet ( Beta vulgaris) and two accessions of B. maritima to
      select materials suitable for obtaining transformed plants. The frequency of
      transformation of the chosen accessions using Agrobacterium strain LBA4404 and
      selection on 150-mg/l kanamycin was found to be higher than that in previously
      published methods. Genomic DNA analysis and beta-glucuronidase reporter assays
      showed that the transgene was inherited and expressed in subsequent generations.
      In our method, shoot bases are prepared by a simple procedure, and transformation
      does not involve the callus phase, thus minimizing the occurrence of somaclonal
      variations.

PMID- 15042404
TI  - New insights into the pathology and molecular biology of human germ cell tumors.
AB  - The group of human germ cell tumors (GCTs) is heterogeneous, and comprises
      neoplasms found at different anatomical locations. They are of interest not only
      for aspects of their tumor biology, but also from the point of view of
      developmental biology. GCTs show significant similarities to early germ cell
      development, most likely related to their cell of origin. Comparative analysis of
      the tumors and representative normal counterparts can therefore help to define
      events which are related to the pathogenesis of this cancer. Within the testis,
      three separate GCT entities have been identified, characterized by differing
      patho-biological, molecular/cytogenetic, and clinical observations, which will be
      described in more detail in this review. This article will highlight the most
      important contributions to the field in the last years. This includes the
      diagnostic value of OCT3/4, a transcription factor and marker for pluripotency.
      Furthermore, the invasive GCTs of young adults consistently show a gain of 12p
      sequences, of which the exact role, including the gene(s) involved, remains to be
      elucidated, although interesting candidates have been identified. Finally,
      treatment sensitivity/resistance of GCTs most likely reflect the intrinsic
      characteristics of the cells of origin and their derivatives. The pluripotency of
      GCTs, in particular the possible loss of the embryonic characteristics and
      acquisition of somatic differentiation, could be a crucial phenomenon in this
      process.

PMID- 15042406
TI  - Percutaneous coil placement prior to radiofrequency ablation of poorly visible
      hepatic tumors.
AB  - The aim of this study was to establish whether using a percutaneously inserted
      metallic coil as a target facilitates the radiofrequency (RF) ablation of tumors
      poorly seen on unenhanced computed tomography (CT) or ultrasound (US) studies. We
      inserted a metallic coil percutaneously via a 21-gauge needle under CT guidance
      into five tumors during the phase of contrast enhancement in five patients. The
      coil was subsequently used as a target to guide placement of the RF electrode
      under fluoroscopic guidance. The precision of position was then checked with CT
      or US. We also carried out a small experimental study to establish the effect of
      metallic coils on the pattern of coagulation induced by RF. Placement of a
      metallic coil into the tumor enabled rapid and accurate placement of the RF
      electrode. The tumors were ablated with no adverse effects. The experimental
      study showed that the area of coagulation extends predictably along the coil. The
      application of the above technique is useful when using RF to ablate tumors
      poorly visualized on US and unenhanced CT.

PMID- 15042409
TI  - Asynchronous meiotic rhythm as the cause of selective chromosome elimination in
      an interspecific Brachiaria hybrid.
AB  - This paper reports the occurrence of chromosome elimination during
      microsporogenesis in an interspecific hybrid between a sexual diploid accession
      (SEX) of Brachiaria ruziziensis (2n=2x=18) and an apomictic tetraploid accession
      (APO) of B. brizantha (2 n=4 x=36). Meiosis was very abnormal in the triploid
      hybrid (2n=3x=27); we observed a distinct asynchrony from metaphase I to the end
      of meiosis. The APO and the SEX genomes did not show the same meiotic rhythm.
      When the former, with nine bivalents, was in metaphase I, the nine SEX univalents
      were not yet aligned; when the latter reached the plate, the APO genome was
      already in anaphase. In subsequent stages, the APO genome had reached the poles
      while the SEX was undergoing sister-chromatid segregation. As the SEX genome
      always remained temporally behind, it gave rise to one extra-nucleus in each
      pole. In the second division, the behavior was the same but anaphase II did not
      occur for the SEX genome, and only one extra-nucleus was observed in each cell in
      telophase II. Chromosome elimination for the SEX genome ranged from partial to
      total. The importance of these findings with respect to Brachiaria breeding
      programmes is discussed.

PMID- 15042408
TI  - Antioxidants enhance in vitro plant regeneration by inhibiting the accumulation
      of peroxidase in Virginia pine (Pinus virginiana Mill.).
AB  - Plant tissue necrosis and subsequent cell death are usually observed during in
      vitro regeneration in conifers, especially in plant regeneration via somatic
      organogenesis in pine species. Cell death is correlated with the elevated levels
      of peroxides. In this investigation, the effects of antioxidants on in vitro
      regeneration of Virginia pine (Pinus virginiana Mill.) were evaluated.
      Antioxidants, polyvinylpolypyrrolidone (PVPP) and 1,4-dithio-DL-threitol (DTT),
      were found to improve callus formation, shoot differentiation and growth, and
      shoot rooting by inhibiting tissue necrosis during the initiation of cultures and
      subculture of shoots. These treatments enabled the recovery and regeneration
      plants at high frequency through somatic organogenesis. Compared to the control,
      the frequencies of callus formation, shoot growth, and shoot rooting increased
      15, 26, and 19%, respectively, by addition of 5 g/l PVPP and 2 g/l DTT. Higher
      peroxidase activity of tissue cultures during subculture from callus
      proliferation medium to shoot differentiation medium and to rooting medium was
      observed. The addition of antioxidants reduces and inhibits browning by reducing
      the accumulation of peroxidase.

PMID- 15042410
TI  - Altered susceptibility to infection by Sinorhizobium meliloti and Nectria
      haematococca in alfalfa roots with altered cell cycle.
AB  - Most infections of plant roots are initiated in the region of elongation; the
      mechanism for this tissue-specific localization pattern is unknown. In alfalfa
      expressing PsUGT1 antisense mRNA under the control of the cauliflower mosaic
      virus (CaMV) 35S promoter, the cell cycle in roots is completed in 48 h instead
      of 24 h, and border cell number is decreased by more than 99%. These plants were
      found to exhibit increased root-tip infection by a fungal pathogen and reduced
      nodule formation by a bacterial symbiont. Thus, the frequency of infection in the
      region of elongation by Nectria haematocca was unaffected, but infection of the
      root tip was increased by more than 90%; early stages of Sinorhizobium meliloti
      infection and nodule morphology were normal, but the frequency of nodulation was
      fourfold lower than in wild-type roots.

PMID- 15042411
TI  - A new tool for plant cell biology: in vivo antibody uptake in plant protoplasts.
AB  - We report on the in vivo uptake of antibodies into plant protoplasts. When
      protoplasts of sunflower, Arabidopsis or tobacco were incubated in vivo with an
      antibody, this antibody was detected by immunofluorescence in the cytoplasm
      and/or the nucleus, depending on the location of the target protein. Furthermore,
      when protoplasts were cultured in the presence of antibodies, specific effects
      were observed. Incubation with antibodies raised against p34cdc2 led to a strong
      inhibition of the division rate, and a decrease in the average DNA content of
      protoplasts. With antibodies against HaWLIM1, a LIM domain protein of the CRP
      type, a negative effect on actin organisation was observed. We conclude that
      antibodies can penetrate plant protoplasts in vivo, and thus may be used as
      powerful tools for the study of protein function.

PMID- 15042412
TI  - 1H NMR relaxation times of skeletal muscle metabolites at 3 T.
AB  - This study reports proton relaxation times of water and metabolites in soleus and
      tibialis anterior muscles of young healthy volunteers at 3 T. The results are in
      agreement with data reported for 1.5 and 4 T, showing a steady increase of spin
      lattice relaxation times of water, creatine and lipids with B(0) and no effect of
      B(0) on spin-spin relaxation. Comparison between muscles revealed a longer spin
      spin relaxation time of water in soleus than in tibialis anterior muscle (31+/-1
      ms vs. 28+/-1 ms, p<0.05). These data can be applied to relaxation correction for
      the absolute quantification of skeletal muscle metabolite concentrations and
      further sequence optimization.

PMID- 15042414
TI  - Conflict and postconflict behaviour in captive black-and-white snub-nosed monkeys
      (Rhinopithecus bieti).
AB  - Black-and-white snub-nosed monkeys (Rhinopithecus bieti) have almost never been
      the subject of any behavioural observations in captivity. This study was aimed at
      providing preliminary information about agonistic and reconciliation behaviour in
      a group kept at the Kunming Institute of Zoology in China. Established procedures
      were used for this investigation (i.e., the postconflict/matched-control method
      and the time-rule method). Intra-group aggression rates were quite low.
      Postconflict affiliation as well as selective attraction of former opponents to
      each other following conflicts was demonstrated. Former opponents contacted each
      other earlier in postconflict periods than in matched-control periods. The
      average conciliatory tendency of all focal individuals combined was 54.5%. After
      an agonistic interaction, the first affiliative contact between former aggressors
      usually took place within the first minute. The behaviours most often shown as
      first affiliations after a conflict were body contact, mount, touch, and "hold
      lumbar", of which the latter is an explicit reconciliatory gesture. Furthermore,
      the adult male intervened non-aggressively in 84% of all conflicts (n=25) among
      the adult females. Overall, the patterns of aggression and reconciliation
      observed in R. bieti bear many of the traits that characterise tolerant primate
      species.

PMID- 15042413
TI  - Diet of a muriqui group (Brachyteles arachnoides) in continuous primary forest.
AB  - The feeding behaviour of a group of free-ranging muriquis (Brachyteles
      arachnoides) was monitored in the 380 km(2) Carlos Botelho State Park (PECB),
      between February 1992 and November 1993. Scan sample data indicated that 59.1% of
      feeding time was devoted to fruit, 33.2% to leaves, 4.1% to flowers, and 3.6% to
      other items (twigs, stem and bark). Little seasonal variation was recorded. These
      results contrast with those of all previous studies of Brachyteles, in which the
      consumption of leaves was generally double that of fruit. One key difference in
      comparison with previous studies is that the PECB is part of the largest
      remaining continuous area of primary Atlantic forest, in the Serra do Mar coastal
      range. Such intraspecific differences in ecology may have important implications
      for the conservation of the species.

PMID- 15042415
TI  - Fossil woods from Janggi Group (Early Miocene) in Pohang Basin, Korea.
AB  - Sixty-four silicified fossil woods were collected from the Early Miocene Upper
      Coal-bearing Formation of Janggi Group in Pohang City, the Korean Peninsula. Out
      of them 23 specimens were identified as gymnosperms and 27 specimens as
      dicotyledons. The taxa identified include Picea palaeomaximowiczii Watari,
      Taxodioxylon cunninghamioides (Watari) Watari, T. sequoianum (Merckl.) Gothan,
      Fagus hondoensis (Watari) Watari, Cercidiphyllum sp., Camellia japonoxyla Suzuki
      et Terada, Distylium chiharu-hirayae Suzuki et Terada, Aesculus sp., Wataria
      miocenica (Watari) Terada et Suzuki and W. parvipora Terada et Suzuki. All of
      these species are reported for the first time from the Tertiary basins of Korea.
      Compared with those of the Miocene Formations in Japan, most taxa we found are
      common between the paleo-floras in Korea and Japan during the Early to Middle
      Miocene.

PMID- 15042416
TI  - Partial purification of an enzyme hydrolyzing indole-3-acetamide from rice cells.
AB  - The activity of indole-3-acetamide (IAM) hydrolase from rice cells was enriched
      ca. 628-fold by gel filtration and anion exchange column chromatography. The
      molecular masses of the IAM hydrolase estimated by gel filtration and sodium
      dodecyl sulfate polyacrylamide gel electrophoresis were approximately 50.5 kD and
      50.0 kD, respectively. The enzyme exhibited maximum activity at pH 6.0-6.5. The
      enzyme was stable against heat treatments between 4 and 50 degrees C and works
      optimally at 52 degrees C. The activity remained constant at 4 degrees C for at
      least 143 days. The purified enzyme fraction hydrolyzed indoleacetic acid ethyl
      ester (Et-IAA) in addition to IAM and its homologue, 1-naphthalene-acetamide, but
      not indole-3-acetonitrile. Km values of the enzyme were 0.96 mM and 0.55 mM for
      IAM and Et-IAA, respectively. Although the molecular mass of the enzyme was very
      similar to that of IAM hydrolase of Agrobacterium tumefaciens involved in tumor
      formation, the biochemical properties of the enzyme including its high Km value
      were considerably different from those of the A. tumefaciens enzyme. Based on
      these enzyme properties, we will discuss whether the amidohydrolase is involved
      in auxin biosynthesis in rice cells.

PMID- 15042419
TI  - Laser Bee--laser safety software user guide developed by Lucid Optical Services
      Ltd for Laser Physics, UK.

PMID- 15042417
TI  - Pollen-tube growth and fertilization mode in Gymnostoma (Casuarinaceae): their
      characteristics and evolution.
AB  - A unique mode of fertilization called "chalazogamy", whereby the pollen tube
      passes through the chalaza instead of the micropyle, is known in several species
      of derived genera in Casuarinaceae. In this paper we report the occurrence of
      chalazogamy in Gymnostoma ( G. poissonianum), the most primitive genus in the
      family. We also show that the pollen tube grows discontinuously from the stigma
      to ovules in about 3 months. At the time of pollination, the ovules have not yet
      formed in the ovary, and require a long time to develop. The pollen tube(s) lie
      in a zigzag line and are branched in the upper region of the style, and their
      growth is arrested there until the ovary develops further. Studies of the
      relevant literature further revealed discontinuous pollen-tube growth in relation
      to a prolonged period between pollination and fertilization, as well as
      chalazogamy, in Betulaceae, Juglandaceae and/or Fagaceae that are closely related
      to Casuarinaceae. This feature may have derived early in the evolution of
      Fagales.

PMID- 15042421
TI  - Two-layer simulation model of laser-induced interstitial thermo-therapy.
AB  - A two-layer model using different properties for the pathological tissue and the
      normal tissue was developed to describe the spatial photon, temperature and
      thermal damage distributions during laser-induced interstitial thermo-therapy
      (LITT). The photon distribution was simulated using the Monte Carlo method. The
      optical tissue parameters and the blood perfusion were derived based on the
      Arrhenius rate process formulation of thermal damage and kinetics of
      vasodilatation. The corresponding temperature distribution was numerically
      calculated using the Pennes bio-heat equation. The calculated results showed that
      the two-layer model predicted different results on the temperature variation and
      distribution, the thermal damage distribution and the thermal damage volume etc.
      from the one-layer model. As a more reasonable physical model, the two-layer
      model can be used to optimize the therapeutic parameters for improved LITT
      treatments.

PMID- 15042420
TI  - Differences between cytotoxicity in photodynamic therapy using a pulsed laser and
      a continuous wave laser: study of oxygen consumption and photobleaching.
AB  - Oxygen consumption at the targeted site has a significant effect on dosimetry in
      photodynamic therapy (PDT). However, oxygen consumption in PDT using a pulsed
      laser as a light source has not been clarified. We therefore investigated the
      dependence of cytotoxicity on the oxygen consumption and the photosensitizer
      photobleaching of PDT using a pulsed laser by comparing with that using a
      continuous wave (CW) laser. Mouse renal carcinoma cells (Renca) were incubated
      with a second-generation photosensitizer, PAD-S31. The cells were then irradiated
      with either a 670-nm nanosecond pulsed light from the 3rd harmonics of a Nd:YAG
      laser-pumped optical parametric oscillator with a peak fluence rate of
      approximately 1 MW/cm(2) at 30 Hz or a 670-nm CW diode laser with a total light
      dose of 40 J/cm(2). Regardless of laser source, cytotoxic effects exhibited
      cumulative dose responses to the photosensitizer ranging from 12 to 96 microg/ml.
      However, cytotoxic effect of PDT using the pulsed light was significantly less
      than that using the CW light with the photosensitizer concentrations of 24 and 48
      microg/ml under identical fluence rates. During PDT, the cells exposed to the
      pulsed light consumed oxygen more slowly, resulting in a lower amount of oxygen
      consumption when compared with PDT using CW light. In accordance with oxygen
      consumption, the pulsed light induced significantly less photobleaching of the
      photosensitizer than the CW light did. These results indicate that the efficiency
      of PDT using pulsed light is less when compared with CW light, probably being
      related to suppressed oxygen consumption during the pulsed light irradiation.

PMID- 15042422
TI  - Effects of laser-modified versus osteopromotively coated titanium membranes on
      bone healing: a pilot study in rat mandibular defects.
AB  - Regeneration of alveolar bone with membrane techniques has become an integral
      part of implant dentistry. The aim of the present study was to determine if laser
      modified titanium membranes are of value in the regeneration of so-called
      critical size defects in the rat model compared with titanium membranes that were
      coated with growth factors. A total of 24 rats were included in the study.
      Critical size defects were created bilaterally and covered by titanium membranes
      coated with (1). polylactide, (2). polylactide and clindamycin, (3). polylactide
      and growth factors, (4). polylactide, clindamycin and growth factors and (5).
      uncoated but laser-modified titanium membranes. All 18 control defects were
      covered by titanium membranes without any substrate. Four weeks after treatment
      the animals were killed. Laser-modified titanium membranes (group 5) showed new
      bone formation in many areas. Nevertheless, complete bridging was found only in
      one specimen. In contrast, in groups 3 and 4, most defects showed almost complete
      bridging of the defects. In particular, clindamycin had no inhibitory effect on
      bone healing. Furthermore, after 28 days, there was no significant difference
      between the individual groups (including controls) with respect to the total
      amount of lamellar bone. Growth-factor-coated membranes can significantly
      accelerate the healing process of bony defects in the rat mandibular model.
      Nevertheless, it is not possible to accelerate bone healing with laser-irradiated
      membranes or to enhance the quality of bone within the time period examined.

PMID- 15042423
TI  - Interaction studies of multimode pulsed HF laser with enamel tissue using
      photothermal deflection and spectroscopy.
AB  - The interaction of a multi-line (2.6-3 micro m) HF laser with enamel tissue is
      reported. The etch rate experiment showed an ablation threshold fluence of 47
      Jcm(-2), but using the dispersion theory for optical coefficients of n and k for
      enamel at dominant laser lines, this value reduced to congruent with 25 Jcm(-2),
      making it more comparable with other investigations. The main mechanism of enamel
      ablation at 2.78 microm where its absorption is very high is thought to be due to
      microexplosive evaporation of water within the enamel matrix, i.e.,
      thermomechanical decomposition. Modelling showed that with 46% reflectivity from
      the enamel surface, the maximum temperature rise will be about 500 degrees C,
      which is much less than the melting point of hydroxyapatite. Also, using a
      photothermal deflection technique showed that, at fluences below threshold a
      considerable amount of heat was emitted from the surface, which was detected as a
      single compressive wave. The spectroscopic studies indicated that calcium was the
      main chemical element observed in the plasma with emission spanning from 420 to
      620 nm.

PMID- 15042424
TI  - Mitochondrial membrane potential after low-power laser irradiation.
AB  - We used the lipophilic cationic fluorescent dye 5,5',6,6'-tetrachloro-1,1',3,3'
      tetraethyl-benzimidazol-carbocyanine iodide (JC-1) to determine mitochondrial
      membrane potential (mdeltapsi) in Hep-2 cells after irradiation with low-power
      laser (lambda=635 nm). Through this methodology it was possible to analyze the
      variation on mitochondrial number and mdeltapsi, in cells irradiated for 100, 150
      and 200 s with energy density of 100 mJ/cm(2). Our results show that JC-1 dye
      allows the identification of populations with different mitochondria morphology
      as well as the functionality of this organelle in the cells incubated for 1, 6
      and 24 h, after irradiation with low-power laser.

PMID- 15042425
TI  - Analysis of mitochondria, endoplasmic reticulum and actin filaments after PDT
      with AlPcS(4).
AB  - Photodynamic therapy (PDT) is a therapeutic modality for the treatment of tumors.
      This technique uses a visible light to activate a photosensitizer compounds,
      leading to a photo-oxidation process of biological tissue that can induce
      apoptosis or necrosis both in vivo and in vitro. However many of the cytotoxic
      effects remain an open question to be investigated. The cytotoxicity to specific
      cellular targets of classical photosensitizers used in the PDT in vitro has been
      analyzed in this work. The photosensitizing effects of Chloroaluminum
      Phthalocyanine Tetrasulfonate (AlPcS(4)) were studied on the mitochondria,
      cytoskeleton and endoplasmic reticulum of HeLa cells. The cells were irradiated
      with a diode laser (working at 670 nm; energy density of 4.5 J/cm(2 )and power
      density of 45 mW/cm(2)). The spectrofluorimetric analysis of the mitochondria
      showed changes in membrane potential. Cytoskeleton and endoplasmic reticulum
      showed basic alterations in distribution after PDT treatment, as an indicator of
      cellular death process.

PMID- 15042426
TI  - Nd:YAG laser induces long-term remission in transfusion-dependent patients with
      watermelon stomach.
AB  - Watermelon stomach (gastric antral vascular ectasia) is a rare cause of gastric
      bleeding which can render patients transfusion-dependent. Laser therapy can be
      used to stop bleeding but the long-term success of this approach is not well
      described. We present a retrospective analysis of 24 consecutive transfusion
      dependent patients who were treated in a national referral centre with Nd:YAG
      laser over an 18 year period. Laser therapy stopped all bleeding in 20 patients
      (83%) after a median of two sessions. Median follow up was 55 months (range 9
      127). Patients remained transfusion free for a median of 16 months and a second
      course of treatment succeeded in all those who re-bled. One gastric perforation
      occurred early in the series and two patients developed pyloric stenosis which
      was successfully treated with balloon pyloric dilatation. Oestrogens were not
      used in these patients. Our experience shows that long-term remission from blood
      transfusion is seen in most patients treated with Nd:YAG laser. If bleeding
      recurs, further laser treatment is usually successful.

PMID- 15042427
TI  - Optimizing treatment parameters for hair removal using long-pulsed Nd:YAG-lasers.
AB  - Our aim was to determine the most effective treatment parameters for laser
      assisted hair removal using long-pulsed Nd:YAG-lasers. 42 volunteers were treated
      with 1064 nm long-pulsed Nd:YAG-lasers. We used two different laser systems (Lyra
      XP, Wavelight and Smartepil II Deka-LMS) with various pulse lengths, fluences,
      and spot sizes. For each parameter, five test areas were treated one to five
      times at 4-week intervals. Follow-ups were performed 1, 3, 6, and 12 months after
      the last treatment. Percentual hair loss, side effects, and pain during treatment
      were evaluated. The average hair reduction 12 months after the last treatment
      using the Lyra XP was 48%, using the Smartepil II it ranged between 30% and 35%.
      There were no permanent side effects. Long-pulsed 1064 nm Nd:YAG-lasers are safe
      and effective for hair reduction. Although the different treatment parameters did
      not lead to a lot of differing hair reduction 12 months after the last treatment,
      the laser with the largest spot size and the longest pulse time showed the best
      results.

PMID- 15042429
TI  - A1166C variant of angiotensin II type 1 receptor gene is associated with severe
      hypertension in pregnancy independently of T235 variant of angiotensinogen gene.
AB  - Hypertension in pregnancy (HP) is a multifactorial disease manifested due to a
      complex combination of environmental factors and several predisposing genes
      including factors in the renin angiotensin system. The aim of this study was to
      assess the association between the A1166C variant of the angiotensin II type 1
      receptor (AT1) gene and severe HP. We carried out association studies and
      multivariate analyses including other candidate causal factors of HP such as the
      M235T variant of the angiotensinogen (AGT) gene, prepregnancy body mass index
      (BMI), and family history of hypertension in Japanese subjects. One hundred and
      fourteen patients with severe HP and 291 normal pregnancy controls were
      genotyped. Among primiparous subjects, the frequency of "AC+CC genotype of AT1"
      was significantly higher in severe HP than in the controls. A multivariate
      analysis with "AC+CC genotype of AT1" and "TT genotype of AGT" revealed that
      these were independently associated with primiparous severe HP. However, when
      "family history of hypertension" and "prepregnancy BMI > or =25" were added as
      factors examined in the multivariate analysis, only "TT genotype of AGT" and
      "family history of hypertension" were found to be independent potent factors. The
      present results suggest that the C1166 allele of the AT1 gene may be concerned
      with the predisposition to essential hypertension independently of the T235
      allele of the AGT gene.

PMID- 15042428
TI  - Towards a transcriptome definition of microglial cells.
AB  - This study provides an expression signature of interferon-gamma (IFN-gamma)
      activated microglia. Microglia are macrophage precursor cells residing in the
      brain and spinal cord. The microglial phenotype is highly plastic and changes in
      response to numerous pathological stimuli. IFN-gamma has been established as a
      strong immunological activator of microglial cells both in vitro and in vivo.
      Affymetrix RG_U34A microarrays were used to determine the effect of IFN-gamma
      stimulation on migroglia cells isolated from newborn Lewis rat brains. More than
      8,000 gene sequences were examined, i.e., 7,000 known genes and 1,000 expressed
      sequence tag (EST) clusters. Under baseline conditions, microglia expressed 326
      of 8,000 genes examined (approximately 4% of all genes, 182 known and 144 ESTs).
      Transcription of only 34 of 7,000 known genes and 8 of 1,000 ESTs was induced by
      IFN-gamma stimulation. The majority of the newly expressed genes encode pro
      inflammatory cytokines and components of the MHC-mediated antigen presentation
      pathway. The expression of 60 of 182 identified genes and of 9 of 144 ESTs was
      increased by IFN-gamma, whereas 29 of 182 known genes and 7 of 144 ESTs were down
      regulated or undetectable in IFN-gamma-stimulated cultures. Overall, the
      activating effect of IFN-gamma on the microglial transcriptome showed restriction
      to pathways involved in antigen presentation, protein degradation, actin binding,
      cell adhesion, apoptosis, and cell signaling. In comparison, down-regulatory
      effects of IFN-gamma stimulation appeared to be confined to pathways of growth
      regulation, remodeling of the extracellular matrix, lipid metabolism, and
      lysosomal processing. In addition, transcriptomic profiling revealed previously
      unknown microglial genes that were de novo expressed, such as calponin 3, or
      indicated differential regulatory responses, such as down-regulation of
      cathepsins that are up-regulated in response to other microglia stimulators.

PMID- 15042430
TI  - Novel mutations of EVER1/TMC6 gene in a Japanese patient with epidermodysplasia
      verruciformis.
AB  - Germline mutations of the EVER1/TMC6 gene are associated with epidermodysplasia
      verruciformis (EV), which is characterized by an abnormal susceptibility to human
      papillomaviruses that were considered to be innocuous for the general population.
      In this study, we have employed polymerase chain reaction and DNA sequencing
      analysis to characterize the EVER1 gene in a 65-year-old Japanese EV patient.
      Direct sequence analyses resulted in the identification of two novel mutations.
      One nonsense mutation consisting of a (C>A) transversion at nucleotide 744 in
      exon 8 in one EVER1 allele resulted in the introduction of a premature
      termination codon (Y248X). Another mutation was identified in the splice acceptor
      site of intron 8 (892-2, IVS8-2, A>T) in another allele. This is the second
      report of EVER1/TMC6 mutations in EV.

PMID- 15042431
TI  - Catalog of 300 SNPs in 23 genes encoding G-protein coupled receptors.
AB  - We previously published a series of detailed maps of single nucleotide
      polymorphisms (SNPs) in the genomic regions of 209 gene loci encoding drug
      metabolizing enzymes, transporters, receptors, and other potential drug targets.
      In addition to the maps reported earlier, we provide here high-resolution SNP
      maps of 23 genes encoding G-protein coupled receptors in the Japanese population.
      A total of 300 SNPs were identified through screening of these loci; 83 in four
      adenosine receptor family genes, 45 in three adrenergic receptor family genes, 22
      in three EDG receptor family genes, 29 in three melanocortin receptor family
      genes, 22 in two somatostatin receptor family genes, 21 in five anonymous G
      protein-coupled receptor family genes, and 78 in the others (AVPR1B, OXTR, and
      TNFRSF1A). We also discovered a total of 33 genetic variations of other types. Of
      the 300 SNPs, 132 (44%) appeared to be novel on the basis of comparisons with the
      dbSNP database of the National Center for Biotechnology Information (US) or with
      previous publications. The maps constructed in this study will serve as an
      additional resource for studies of complex genetic diseases and drug-response
      phenotypes to be mapped by linkage-disequilibrium association analyses.

PMID- 15042432
TI  - Systemic inflammatory response after endoscopic (TEP) vs Shouldice groin hernia
      repair.
AB  - Endoscopic techniques are commonly used for many different types of surgery. It
      is claimed that videoendoscopic procedures have the advantage of being less
      traumatic and of offering higher postoperative patient comfort than conventional
      open techniques. The extent of tissue trauma can be evaluated on the basis of the
      inflammatory response observed in the wake of surgery. Available studies that
      have compared endoscopic and conventional techniques suggest that endoscopic
      cholecystectomy, laparoscopic colorectal resection, and thoracoscopic pulmonary
      resection have immunologic advantages over conventional approaches. The objective
      of this prospective study was to determine whether endoscopic hernia repair
      techniques are also preferable to conventional procedures and to what extent the
      anesthetic technique (local or general anesthesia) influences the postoperative
      inflammatory response. For this purpose, biochemical monitoring of cytokine
      activity [C-reactive protein (CRP), prostaglandin F1alpha (PGF1alpha), neopterin,
      interleukin-6 (IL-6)] was done prospectively in 101 patients [totally
      extraperitoneal approach (TEP) n=32, unilateral n=12, bilateral n=20; Shouldice
      n=69, local anesthesia (LA) n=23, general anesthesia (GA) n=46] before and until
      3 days after surgery. The parameters IL-6 and PGF1alpha suggested that the immune
      trauma immediately after surgery was significantly higher in the group of
      patients with endoscopic hernia repair than in the group of patients who received
      a Shouldice repair. No significant differences were observed after the first
      postoperative day. A comparison between the TEP group and the patients who
      received conventional surgery under local anesthesia showed that the TEP approach
      was also associated with a higher postoperative neopterin level. Within the first
      3 days after surgical intervention, bilateral endoscopic hernia repair induced no
      significantly higher inflammatory response than the surgical treatment of
      unilateral conditions. The anesthetic procedure that was used in the Shouldice
      operation had no significant effect on inflammatory response. Unlike other types
      of endoscopic surgery, the repair of groin hernias using an endoscopic technique
      cannot be regarded as a minimally invasive procedure that is less traumatic than
      conventional approaches. Instead, the conventional Shouldice procedure appears to
      cause the lowest inflammatory response and to be the least traumatic approach to
      hernia repair, especially when it is performed under local anesthesia.

PMID- 15042433
TI  - Local sequential minimization of double stranded B-DNA using Monte Carlo
      annealing.
AB  - A software algorithm has been developed to investigate the folding process in B
      DNA structures in vacuum under a simple and accurate force field. This algorithm
      models linear double stranded B-DNA sequences based on a local, sequential
      minimization procedure. The original B-DNA structures were modeled using initial
      nucleotide structures taken from the Brookhaven database. The models contain
      information at the atomic level allowing one to investigate as accurately as
      possible the structure and characteristics of the resulting DNA structures. A
      variety of DNA sequences and sizes were investigated containing coding and non
      coding, random and real, homogeneous or heterogeneous sequences in the range of 2
      to 40 base pairs. The force field contains terms such as angle bend, Lennard
      Jones, electrostatic interactions and hydrogen bonding which are set up using the
      Dreiding II force field and defined to account for the helical parameters such as
      twist, tilt and rise. A close comparison was made between this local minimization
      algorithm and a global one (previously published) in order to find out advantages
      and disadvantages of the different methods. From the comparison, this algorithm
      gives better and faster results than the previous method, allowing one to
      minimize larger DNA segments. DNA segments with a length of 40 bases need
      approximately 4 h, while 2.5 weeks are needed with the previous method. After
      each minimization the angles between phosphate-oxygen-carbon A1, the oxygen
      phosphate-oxygen A2 and the average helical twists were calculated. From the
      generated fragments it was found that the bond angles are A1=150 degrees +/-2
      degrees and A2=130 degrees +/-10 degrees, while the helical twist is 36.6 degrees
      +/-2 degrees in the A strand and A1=150 degrees +/-6 degrees and A2=130+/-6
      degrees with helical twist 39.6 degrees +/-2 degrees in the B strand for the DNA
      segment with the same sequence as the Dickerson dodecamer.

PMID- 15042434
TI  - Identification of archaea and some extremophilic bacteria using matrix-assisted
      laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry.
AB  - Archaea and a number of groups of environmentally important bacteria, e.g.,
      sulfate-reducing bacteria, anoxygenic phototrophs, and some thermophiles, are
      difficult to characterize using current methods developed for phenotypically
      differentiating heterotrophic bacteria. We have evaluated matrix-assisted laser
      desorption/ionization time-of-flight (MALDI-TOF-MS) as a rapid method for
      identifying different groups of extremophilic prokaryotes using a linear mass
      spectrometer (Micromass, UK). The instrument is designed to acquire mass-spectral
      patterns from prokaryotic cell-wall components between masses of 500 and 10,000
      Da in a statistically robust manner and create a database that can be used for
      identification. We have tested 28 archaea (10 genera, 20 spp.) and 42 bacteria
      (25 genera, 37 spp.) and found that all species yield reproducible, unique mass
      spectral profiles. As a whole, the profiles for the archaea had fewer peaks and
      showed less differentiation compared to the bacteria, perhaps reflecting
      fundamental differences in cell-wall structure. The halophilic archaea all had
      consistent patterns that showed little differentiation; however, the software was
      able to consistently distinguish Halobacterium salinarium, Halococcus dombrowski,
      and Haloarcula marismortui from one another, although it could not always
      correctly distinguish four strains of Hb. salinarium from one another. The method
      was able to reliably identify 10(5) cells of either Albidovulum inexpectatum or
      Thermococcus litoralis and could detect as low as 10(3) cells. We found that the
      matrix, alpha-cyano-4-hydroxy-cinnamic acid yielded better spectra for archaea
      than 5-chloro-2-mercapto-benzothiazole. Overall, the method was rapid, required a
      minimum of sample processing, and was capable of distinguishing and identifying a
      very diverse group of prokaryotes.

PMID- 15042435
TI  - Preparation and reactivity studies of synthetic microperoxidases containing b
      type heme.
AB  - In order to create a heme environment that permits biomimicry of heme-containing
      peroxidases, a number of new hemin-peptide complexes--hemin-2(18)-glycyl-L
      histidine methyl ester (HGH), hemin-2(18)-glycyl-glycyl-L-histidine methyl ester
      (HGGH), and hemin-2,18-bis(glycyl-glycyl-L-histidine methyl ester) (H2GGH)--have
      been prepared by condensation of glycyl-L-histidine methyl ester or glycyl-glycyl
      L-histidine methyl ester with the propionic side chains of hemin.
      Characterization by means of UV/vis- and 1H NMR spectroscopy as well as cyclic-
      and differential pulse voltammetry indicates the formation of five-coordinate
      complexes in the case of HGH and HGGH, with histidine as an axial ligand. In the
      case of H2GGH, a six-coordinate complex with both imidazoles coordinated to the
      iron center appears to be formed. However, 1H NMR of H2GGH reveals the existence
      of an equilibrium between low-spin six-coordinate and high-spin five-coordinate
      species in solution. The catalytic activity of the hemin-peptide complexes
      towards several organic substrates, such as p-cresol, L-tyrosine methyl ester,
      and ABTS, has been investigated. It was found that not only the five-coordinate
      HGH and HGGH complexes, but also the six-coordinate H2GGH, catalyze the oxidation
      of substrates by H2O2. The longer and less strained peptide arm provides the HGGH
      complex with a slightly higher catalytic efficiency, as compared with HGH, due to
      formation of more stable intermediate complexes.

PMID- 15042437
TI  - Transport proteins: targets for glutamate pharmacology?

PMID- 15042436
TI  - A theoretical study of the cis-dihydroxylation mechanism in naphthalene 1,2
      dioxygenase.
AB  - The catalytic mechanism of naphthalene 1,2-dioxygenase has been investigated by
      means of hybrid density functional theory. This Rieske-type enzyme, which
      contains an active site hosting a mononuclear non-heme iron(II) complex, uses
      dioxygen and two electrons provided by NADH to carry out the cis-dihydroxylation
      of naphthalene. Since a (hydro)peroxo-iron(III) moiety has been proposed to be
      involved in the catalytic cycle, it was probed whether and how this species is
      capable of cis-dihydroxylation of the aromatic substrate. Different oxidation and
      protonation states of the Fe-O2 complex were studied on the basis of the crystal
      structure of the enzyme with oxygen bound side-on to iron. It was found that
      feasible reaction pathways require a protonated peroxo ligand, FeIII-OOH; the
      deprotonated species, the peroxo-iron(III) complex, was found to be inert toward
      naphthalene. Among the different chemical patterns which have been explored, the
      most accessible one involves an epoxide intermediate, which may subsequently
      evolve toward an arene cation, and finally to the cis-diol. The possibility that
      an iron(V)-oxo species is formed prior to substrate hydroxylation was also
      examined, but found to implicate a rather high energy barrier. In contrast, a
      reasonably low barrier might lead to a high-valent iron-oxo species [i.e.
      iron(IV)-oxo] if a second external electron is supplied to the mononuclear iron
      center before dioxygenation.

PMID- 15042438
TI  - Taurine concentration in the brain and in the plasma following intraperitoneal
      injections.
AB  - Summary. The effect of different taurine doses (0.050, 0.125, 0.250, 0.500 and
      1.000 g/kg) administered intraperitoneally to Wistar rats was studied in both the
      plasma and the hippocampal microdialysate content. The samples were analyzed by
      reverse phased HPLC for the microdialysate samples and by HPLC with ion-exchange
      post-column derivatization (ninhydrin) for the plasma samples. In both plasma and
      microdialysate, we observed a dose dependent increase of taurine concentration.
      The AUC curves obtained from both microdialysate and plasma samples showed that
      the increase of taurine concentrations were linear. The mean ratio between AUC's
      microdialysate and plasma was 1.63+/-0.21 showing thus an unbalance between
      plasma and brain taurine content; a mechanism which enhance taurine transfer from
      the plasma to the brain was assumed.

PMID- 15042439
TI  - Ethanol but not acetaldehyde induced changes in brain taurine: a microdialysis
      study.
AB  - Research has suggested that catalase plays a role in mediating ethanol's
      psychopharmacological effects. Catalase is an enzyme that oxidizes ethanol to
      acetaldehyde. It has been reported that when catalase activity is reduced by 3
      amino-1,2,4-triazole (AT), rats reduce their intake and preference for ethanol.
      The present study assessed the effects of AT on the brain amino acids levels
      following ethanol administration in Wistar rats. The study consisted of three
      parts. In the first part, we found no effects of acute and chronic
      intraperitoneally administered acetaldehyde on amino acids dialysate levels in
      nucleus accumbens. In the second part, AT was administered five hours prior to
      ethanol or its vehicle. Ethanol significantly affected the levels of taurine in
      rat pre-treated with AT. In the final part, ethanol was administered following
      the pre-treatment with AT but the dependent variable was the concentration of
      ethanol in the brain.

PMID- 15042440
TI  - Free amino acids and biogenic amines in red and white muscle of tuna stored in
      controlled atmospheres.
AB  - This paper analyses the presence of and changes in free amino acids and biogenic
      amines in red and white muscle of bigeye tuna during storage in controlled
      atmospheres with 2 gas mixes containing different concentrations of CO(2) and
      O(2). Levels of amines were generally higher in white than in red muscle, with
      the exception of putrescine and spermidine. Levels of biogenic amines increased
      (p<0.05) throughout storage, commencing later in red than in white muscle. A
      correlation between the amino acid histidine and the biogenic amine histamine was
      observed, but only in white muscle. Only in the case of tryptophan did white and
      red muscle differ (p<0.05) in terms of essential free amino acid content. They
      also differed in anserine content. Concentrations of the non-essential FAAs
      glutamic acid, glycine and alanine were higher in red than in white muscle. The
      effectiveness of the atmospheres was reflected in the evolution of both biogenic
      amines and FAAs. Gas mix 1, containing a higher concentration of CO(2), was the
      more effective.

PMID- 15042442
TI  - Synthesis of novel 3-pyridinecarbonitriles with amino acid function and their
      fluorescence properties.
AB  - A variety of N-[(4,6-diaryl-3-pyridinecarbonitrile)-2-yl] amino acid esters 2-4
      were synthesized through the reaction of 2-bromo-3-pyridinecarbonitriles 1 with
      the appropriate alpha-amino acid ester hydrochloride in refluxing dioxane in the
      presence of triethylamine as dehydrohalogenating agent. Similarly, N'
      glycylglycine analogues 5 were obtained through the reaction of 1 with the
      dipeptide ester. On the other hand, attempts were made towards the construction
      of amino acid derivatives 7 through the reaction of 1 with aqueous solution alpha
      amino acids 6 in refluxing pyridine, but were unsuccessful, and instead the
      unexpected 2-amino-3-pyridinecarbonitriles 8 were isolated. The fluorescence
      properties of the newly synthesized pyridines 2-5 were evaluated. Some of the
      prepared compounds show considerable antibacterial activity.

PMID- 15042441
TI  - Mediated exodus of L-dopa from human epidermal Langerhans cells.
AB  - L-3,4-dihydroxyphenylalanine (L-dopa) is not metabolized within human epidermal
      Langerhans cells (LC); yet they can take up substantial amounts of this amino
      acid which subsequently can be released into the extracellular space. We recently
      reported that human epidermal energy metabolism is predominantly anaerobic and
      that the influx mechanism is a unidirectional L-dopa/proton counter-transport
      system and now we describe conditions for the mediated transport of L-dopa out of
      the LC. It is demonstrated that certain amino acids and one dipeptide can
      effectively trigger the efflux of L-dopa taken up by the LC.Thus, alpha-methyl
      dopa (alpha-m-dopa), D-dopa and the dipeptide, met-ala at the outside of the
      plasma membrane stimulated the efflux of L-dopa from L-dopa loaded LC. Similar
      effects were achieved by a variety of other amino acids in the extracellular
      fluid while some other amino acids were inactive. The time required for 50% D
      methionine-induced exodus of L-dopa from L-dopa loaded LC was in the range of 5-7
      min and a complete exodus of L-dopa was attained at about 20 min of incubation.
      This dislocation of L-dopa to the extracellular fluid is interpreted as an
      expression of trans-stimulation. In the case of alpha-m-dopa, D-dopa and met-ala,
      which admittedly were not able to penetrate the plasma membrane of LC, the
      concept of trans-stimulation was given a new purport, since none of them were
      able to participate in an exchange reaction. Finally, it could be concluded that
      L-dopa escaped by a route different from the one responsible for L-dopa uptake in
      LC.Thus, while the influx of L-dopa supports extrusion of protons deriving from
      anaerobic glycolysis in the LC, L-dopa efflux can provide the cells with useful
      amino acids in an energy-saving way, altogether a remarkable biological process.
      From this follows that L-dopa has a biological function of its own, besides being
      a precursor in the catecholamine and pigment syntheses.

PMID- 15042443
TI  - Comparison of post-translational modifications of alpha A-crystallin from normal
      and hereditary cataract rats.
AB  - In order to investigate the relationship between lens opacities and the various
      modifications of lens proteins, we analyzed and compared the properties of lens
      proteins of 85-day old normal Wistar rats and the hereditary cataract model,
      ICR/f rats. The present study identified many differences between normal and
      mutant lens proteins. In the ICR/f mutant rats, the relative amounts of gamma
      crystallin decreased and high molecular weight (HMW) protein increased.
      Racemization and isomerization of Asp-151 of alpha A-crystallin was observed in
      the mutant ICR/f rats, and Met-1 of alpha A-crystallin was oxidized to methionine
      sulfoxide. These modifications were not found in the age-matched normal rats.
      These tendencies are consistent with aged and cataractous human lenses.

PMID- 15042444
TI  - Properties of synthetic ferrihydrite as an amino acid adsorbent and a promoter of
      peptide bond formation.
AB  - Ferrihydrite, an iron oxide hydroxide, is found in all kinds of environments,
      from hydrothermal hot springs to extraterrestrial materials. It has been shown
      that this material is nanoporous, and because of its high surface area, it has
      outstanding adsorption properties and in some cases catalysis properties. In this
      work we studied the adsorption properties of ferrihydrite with respect to amino
      acids. Samples of pure ferrihydrite were synthesised and exposed to solutions of
      amino acids including both proteinaceous and non-proteinaceous species. These
      experiments revealed important characteristics of this mineral as both an
      adsorbent of amino acids and a promoter of peptide bond formation.

PMID- 15042445
TI  - Protective effect of taurine on the detachment of cultured cardiac fibroblasts
      from the substratum induced by calcium depletion.
AB  - Removal of Ca2+ from the incubation medium of cultured rat cardiac fibroblasts
      causes cellular morphological changes, such as the formation of blebs, the
      ballooning of the cell membrane and the detachment from the culture dish. A 24 hr
      preincubation with 20 mM taurine blocked the Ca2+ depletion-induced detachment of
      the cardiac fibroblasts. However, taurine treatment did not prevent other
      morphological changes induced by Ca2+ depletion. The data suggest that taurine
      plays an important role in cell adhesion in the heart.

PMID- 15042446
TI  - Cysteine-induced hypoglycemic brain damage: an alternative mechanism to
      excitotoxicity.
AB  - Central neural damage caused by L-cysteine (L-Cys) was first reported more than
      30 years ago. Nevertheless, the exact mechanisms of L-Cys-mediated neurotoxicity
      are still unclear. Preliminary study in mice demonstrated that, following L-Cys
      injection, animals developed tachypnea, tremor, convulsions, and death in
      conjunction with documented hypoglycemia. The aim of the present study was to
      further investigate the mechanism of L-Cys-mediated hypoglycemic effect and
      neural damage. Neonatal ICR mice (n=6) were injected with L-Cys (0.5-1.5 mg/g
      body weight [BW]), and their blood glucose and insulin levels were determined up
      to 90 min following the injection. Experiments were repeated in chemically
      (streptozotocin [STZ]) pancreatectomized animals. Brain histology was assessed.
      Mice injected with L-Cys exhibited dose-dependent neurotoxicity and higher
      mortality as compared with controls. L-Cys (1.2-1.5 mg/g BW) caused severe
      hypoglycemia (glucose<42 mg/dl) ( P<0.001). In STZ-treated (diabetic) animals, L
      Cys (1.5 mg/g BW) increased plasma insulin levels 2.3-fold and decreased serum
      glucose levels by 50% ( P<0.01). Brain histology revealed destruction of as much
      as 51% of hippocampal neurons in the L-Cys-treated mice but not in the glucose
      resuscitated animals. These findings suggest that L-Cys injection can cause
      pronounced hypoglycemia and central neural damage which is glucose reversible.
      Since L-Cys is chemically different from the other excitatory amino acids
      (glutamate and aspartate), L-Cys-mediated neurotoxicity may be connected to its
      hypoglycemic effect.

PMID- 15042447
TI  - Threonine is the best substrate for D-lactate formation in octopus tentacle.
AB  - Carbon sources for D-lactate and enzyme activities related to D-lactate formation
      were investigated using cell-free homogenates of Octopus vulgaris tentacle
      tissue. The results are as follows: a) The best precursor for D-lactate formation
      was threonine and second best precursors were glycine and fructose-1,6
      bisphosphate. Threonine and glycine served as precursors only in presence of
      glutathione. b) Both amino acids were precursors for methylglyoxal from which D
      lactate was synthesized. Alanine, cysteine and serine were not precursors. We
      present a metabolic map for D-lactate formation in octopus in order to explain
      these experimental results.

PMID- 15042448
TI  - Novel phenomena in the 13C NMR spectra of amino acids.
AB  - 13C NMR integral areas and spin-lattice relaxation times (T1's) of a series of
      amino acids were determined at different concentrations. It was found that the
      spin-lattice relaxation times were markedly reduced in 3 M magnesium chloride
      resulting in the integral area being proportional to the number of carbon atoms
      producing each particular signal, with a reliability in excess of 95%. Magnesium
      chloride is proposed as a 13C NMR relaxation agent for amino acids.

PMID- 15042449
TI  - Effects of culture conditions on taurine uptake by various variants of human
      endometrial carcinoma cells in culture.
AB  - The general properties of the taurine uptake in human endometrial tumoral
      Ishikawa cells were similar to those usually found in other tissues. Uptake was
      notably affected by the oxygen pressure, being higher at the physiological pO(2)
      of the endometrium (40 mm Hg, equivalent to 5% O(2)) compared to that used under
      standard experimental culture conditions (160 mm Hg or 20% O(2)). Uptake of
      taurine was also density-dependent in Ishikawa cells and was significantly
      decreased at confluence. Uptake regulation by PKC driven phosphorylation occurs
      only in growing cells and not in resting cells. The taurine uptake of three
      Ishikawa cell lines was very different. The taurine uptake of one of the cell
      lines was affected by estradiol, probably through a non-genomic pathway, whereas
      tamoxifen had no effect in all cell lines.

PMID- 15042450
TI  - Excitotoxin-induced changes in transglutaminase during differentiation of
      cerebellar granule cells.
AB  - Excitotoxicity induced by NMDA receptor stimulation is able to increase the
      activity of many enzymes involved in neuronal cell death. Primary cultures of rat
      cerebellar granule cells were used to elucidate the role of transglutaminase
      reaction in the excitotoxic cell response, and to evaluate the role of glutamate
      receptors in cell survival and degeneration. Granule neurons, maintained in vitro
      for two weeks, were exposed to NMDA at different stages of differentiation.
      Following NMDA receptor activation, increases in transglutaminase activity were
      observed in cell cultures. The levels of enzyme activity were higher in cells at
      5 days in vitro than in those at 8-9 or 13-14 days in vitro. Moreover, NMDA
      exposure up-regulated tTG expression in neurons as young as 5 days in vitro.
      These cultures also exhibited morphological changes with clear apoptotic
      features. Results obtained demonstrate that susceptibility of granule cells to
      excitotoxicity depends on the developmental stage of neurons.

PMID- 15042451
TI  - Role of taurine supplementation to prevent exercise-induced oxidative stress in
      healthy young men.
AB  - To evaluate the protective effects of taurine supplementation on exercise-induced
      oxidative stress and exercise performance, eleven men aged 18-20 years were
      selected to participate in two identical bicycle ergometer exercises until
      exhaustion. Single cell gel assay (SCG assay) was used to study DNA damage in
      white blood cells (WBC). Pre-supplementation of taurine, a significant negative
      correlation was found between plasma taurine concentration before exercise and
      plasma thiobaribituric-acid reactive substance (TBARS) 6 hr after exercise (r = 
      0.642, p<0.05). WBC showed a significant increase in DNA strand breakage 6 hr and
      24 hr after exercise. Seven-day taurine supplementation reduced serum TBARS
      before exercise ( p<0.05) and resulted in a significantly reduced DNA migration
      24 hr after exercise ( p<0.01). Significant increases were also found in
      VO(2)max, exercise time to exhaustion and maximal workload in test with taurine
      supplementation ( p<0.05). After supplementation, the change in taurine
      concentration showed positive correlations with the changes in exercise time to
      exhaustion and maximal workload. The results suggest that taurine may attenuate
      exercise-induced DNA damage and enhance the capacity of exercise due to its
      cellular protective properties.

PMID- 15042452
TI  - N-Acyl derivatives of Asn, new bacterial N-acyl D-amino acids with surfactant
      activity.
AB  - New N-acyl D-amino acids were isolated from Bacillus pumilus IM 1801. Their
      structures were determined by chemical analysis and mass spectrometry. The lipid
      part was identified as a mixture of fatty acids with 11, 12, 13, 15, and 16
      carbon atoms in the iso, anteiso or n configuration linked by an amide bond with
      a D-asparagine. They exhibited surfactant properties.

PMID- 15042453
TI  - Autologous versus allogenic bone grafts in instrumented anterior cervical
      discectomy and fusion: a prospective study with respect to bone union pattern.
AB  - BACKGROUND: The purpose of this prospective semi-randomised comparative study was
      to compare fusion rates, course of fusion, and occurrence of collapse and
      subsidence of autologous and allogenic bone grafts in instrumented anterior
      cervical fusion. The number of fused levels and the smoking status were
      investigated as potential factors influencing the bone-healing process. No
      similar prospective study on instrumented anterior cervical discectomy and fusion
      was found in the literature. METHODS: Seventy-nine consecutive patients were
      operated on using the Smith-Robinson technique with a single instrumentation
      system at one or two levels. Seventy-six cadaverous fibular bone grafts and 37
      autologous iliac-crest bone grafts were inserted. All patients were followed up
      for at least 2 years. RESULTS: The radiographs obtained during the follow-up were
      analysed, and showed no statistical difference in fusion and collapse rate
      between autografts and allografts. Allografts showed significantly longer time to
      union. No case of graft migration was observed. No difference was found between
      fusion and collapse rate with respect to the number of fused levels in general,
      but greater time to union was seen in two-level fusions. When one- and two-level
      subgroups were compared, there was no evidence of any significant difference in
      fusion or collapse rates between autografts and allografts, and the healing
      process took longer in allogenic grafts. Smoking status did not alter any of the
      fusion or collapse rates, or the course of bone fusion. CONCLUSIONS: This study
      demonstrates that allografts are suitable substitutes for autografts in
      instrumented ACDF. Prolonged time to union observed in allogenic bone grafts does
      not seem to be an important factor in instrumented procedures. Two-level grafting
      does not imply a significantly lower fusion rate, but longer time to union can be
      expected than with single-level instrumented procedures in both allograft and
      autograft subgroups. Our relatively small number of patients may not have been
      sufficient to decipher significant differences between smokers and non-smokers in
      the rate or course of fusion as previously reported.

PMID- 15042455
TI  - Enhancement of oxygen mass transfer in stirred bioreactors using oxygen-vectors.
      1. Simulated fermentation broths.
AB  - Oxygen mass transfer represents the most important parameter involved in the
      design and operation of mixing-sparging equipment for bioreactors. It can be
      described and analyzed by means of the mass transfer coefficient, k(L) a. The
      k(L) a values are affected by many factors such as geometrical and operational
      characteristics of the vessels, media composition, type, concentration and
      microorganism morphology, and biocatalysts properties. The efficiency of oxygen
      transfer could be enhanced by adding oxygen-vectors in broths, such as
      hydrocarbons or fluorocarbons, without increasing the energy consumption for
      mixing or aeration. The experimental results obtained for simulated broths
      indicated a considerable increase of k(L) a in the presence of n-dodecane, and
      the existence of a certain value of n-dodecane concentration that corresponds to
      a maximum mass transfer rate of oxygen. The magnitude of the positive effect of n
      dodecane depends both on the broths' characteristics and operational conditions
      of the bioreactor.

PMID- 15042454
TI  - Frequent vaccination and immune complex deposition in unilateral nephrectomized
      mice.
AB  - The aim of this study was to investigate the effect of increased number and
      frequency of vaccination on immune complex deposition in the choroid plexus and
      glomeruli of non-nephrectomized and unilateral nephrectomized mice. Fifty-five
      non-nephrectomized, 40 nephrectomized, and 7 control Swiss albino mice were used.
      Half of each group was vaccinated only with diphtheria-tetanus and the other half
      with multiple vaccines, which are used in pediatric practice. Each group was
      divided into subgroups, which were vaccinated with increasing frequency. No
      immune deposits were detected in the choroid plexus of any vaccinated mice. There
      were immune deposits in glomeruli in 2 of 55 (3.6%) of the non-nephrectomized and
      in 3 of 40 (7.5%) of the nephrectomized mice (P=0.199). The difference between
      the diphtheria-tetanus and multiple vaccine groups in non-nephrectomized
      (P=0.236) and nephrectomized (P=1.000) mice was not significant. A significant
      positive correlation between increased frequency of vaccination and glomerular
      immune complex deposition 8 weeks after the last immunization was detected in the
      multiple vaccine group of nephrectomized mice (P=0.048, r=0.447). Our results
      suggest that the large number and frequent doses of vaccines would not lead to
      immune complex deposition in choroid plexus and do not significantly increase the
      deposition of immune complexes in glomeruli in unilateral nephrectomized mice
      compared with non-nephrectomized mice.

PMID- 15042456
TI  - Do low standing biomass and leaf area index of sub-tropical coastal dunes ensure
      that plants have an adequate supply of water?
AB  - Water status in relation to standing biomass and leaf area indices (LAI) of the
      subtropical foredune species Arctotheca populifolia, Ipomoea pes-caprae and
      Scaevola plumieri were studied in the Eastern Cape, South Africa. The plants
      showed little evidence of water stress, never developing leaf water potentials
      more negative than -1.55 MPa, a value which is typical of mesophytes rather than
      xerophytes. The plants showed no seasonal changes in osmotic potential, an
      indication that they did not need to osmoregulate, nor were there significant
      alterations in tissue elasticity. Turgor potential for the most part remained
      positive throughout the day or recovered positive values at night, a condition
      suitable for the maintenance of growth that may be essential to cope with sand
      accretion. All three species show relatively high transpiration rates and only I.
      pes-caprae showed any evidence of strong limitations of transpiration rate
      through reductions in midday stomatal conductance. All three species had
      relatively high instantaneous water use efficiencies as a result of high
      assimilation rates rather than low transpiration rates. Simple water budgets,
      accounting for losses by transpiration and inputs from rainfall, suggest that the
      water stored in the dune sands is sufficient to meet the requirements of the
      plants, although water budgets calculated for I. pes-caprae suggest that this
      species may on occasion be water limited. The results suggest that it is the low
      biomass and LAI that lead to these favourable water relations.

PMID- 15042457
TI  - Modifying the 'pulse-reserve' paradigm for deserts of North America:
      precipitation pulses, soil water, and plant responses.
AB  - The 'pulse-reserve' conceptual model--arguably one of the most-cited paradigms in
      aridland ecology--depicts a simple, direct relationship between rainfall, which
      triggers pulses of plant growth, and reserves of carbon and energy. While the
      heuristics of 'pulses', 'triggers' and 'reserves' are intuitive and thus
      appealing, the value of the paradigm is limited, both as a conceptual model of
      how pulsed water inputs are translated into primary production and as a framework
      for developing quantitative models. To overcome these limitations, we propose a
      revision of the pulse-reserve model that emphasizes the following: (1) what
      explicitly constitutes a biologically significant 'rainfall pulse', (2) how do
      rainfall pulses translate into usable 'soil moisture pulses', and (3) how are
      soil moisture pulses differentially utilized by various plant functional types
      (FTs) in terms of growth? We explore these questions using the patch arid lands
      simulation (PALS) model for sites in the Mojave, Sonoran, and Chihuahuan deserts
      of North America. Our analyses indicate that rainfall variability is best
      understood in terms of sequences of rainfall events that produce biologically
      significant 'pulses' of soil moisture recharge, as opposed to individual rain
      events. In the desert regions investigated, biologically significant pulses of
      soil moisture occur in either winter (October-March) or summer (July-September),
      as determined by the period of activity of the plant FTs. Nevertheless, it is
      difficult to make generalizations regarding specific growth responses to moisture
      pulses, because of the strong effects of and interactions between precipitation,
      antecedent soil moisture, and plant FT responses, all of which vary among deserts
      and seasons. Our results further suggest that, in most soil types and in most
      seasons, there is little separation of soil water with depth. Thus, coexistence
      of plant FTs in a single patch as examined in this PALS study is likely to be
      fostered by factors that promote: (1) separation of water use over time (seasonal
      differences in growth), (2) relative differences in the utilization of water in
      the upper soil layers, or (3) separation in the responses of plant FTs as a
      function of preceding conditions, i.e., the physiological and morphological
      readiness of the plant for water-uptake and growth. Finally, the high seasonal
      and annual variability in soil water recharge and plant growth, which result from
      the complex interactions that occur as a result of rainfall variability,
      antecedent soil moisture conditions, nutrient availability, and plant FT
      composition and cover, call into question the use of simplified vegetation models
      in forecasting potential impacts of climate change in the arid zones in North
      America.

PMID- 15042458
TI  - Conditional responses of organisms to habitat structure: an example from
      intertidal mudflats.
AB  - Habitat structure is often assumed to be a predictor of habitat function.
      However, habitat structure may be insufficient to predict the functional
      significance of a habitat if the level of resources in the habitat is a
      consequence of the interaction between the habitat structure and physical or
      biological factors. In this study, we investigated whether depressions in tidal
      flat sediments generated by stout razor clams, Tagelus plebeius, affect the
      spatial patterns of pit digging by deposit-feeding burrowing crabs, Chasmagnathus
      granulata. The pits dug by crabs while feeding overlapped with clam siphon holes
      at a frequency higher than expected at random, and measurements of pit-digging by
      crabs integrated over several days indicated a higher frequency of feeding in the
      sediment of depressions. The daily frequency of pit-digging by crabs in
      depressions was positively related to the organic matter content of their
      sediments, but was significantly higher than the frequency of pit-digging away
      from clam siphon holes only after events of high bedload sediment transport, when
      the organic matter in the sediments of these depressions peaked. This example
      demonstrates the conditional nature of the relationship between habitat structure
      and function by illustrating how a physical process--bedload sediment transport-
      may introduce variation in the function that depressions play as feeding sites
      for burrowing crabs. Published information suggests that such conditional
      responses of organisms to habitat structure: (1) occur in a variety of habitats;
      (2) involve a variety of structures either of biotic or abiotic origin; and (3)
      are the consequence of either physical or biological controls that vary in
      importance according to the general mechanism through which habitat structure
      affect resources. This broad experimental evidence suggests that the accuracy of
      predictive models linking habitat structure and function can be improved by
      incorporating a mechanistic perspective that allows recognition of the potential
      for conditional responses of organisms to habitat structure.

PMID- 15042459
TI  - Movement and spatial organization of small mammals following vertebrate predator
      exclusion.
AB  - Predation directly changes the demographics of prey, generally through a
      numerical decrease. An indirect effect of predators is alteration of movements
      and spatial patterns of prey. The relationship between these direct and indirect
      effects can be tested by excluding predators. Home range size of white-footed
      mice (Peromyscus leucopus) decreased and home range overlaps increased in the
      absence of predators. Home range size and overlaps of meadow voles (Microtus
      pennsylvanicus) did not change despite an increase in vole density. P. leucopus
      had significantly lower interspecific home range overlaps with M. pennsylvanicus
      than intraspecific overlaps. The changes in P. leucopus spatial behavior may be
      an indirect effect of predator exclusion resulting from the increase in M.
      pennsylvanicus densities.

PMID- 15042460
TI  - Feedback interactions between needle litter decomposition and rhizosphere
      activity.
AB  - The aim of our study was to identify interactions between the decomposition of
      aboveground litter and rhizosphere activity. The experimental approach combined
      the placement of labelled litter (delta13C=-37.9 per thousand ) with forest
      girdling in a 35-year-old Norway spruce stand, resulting in four different
      treatment combinations: GL (girdled, litter), GNL (girdled, no litter), NGL (not
      girdled, litter), and NGNL (not girdled, no litter). Monthly sampling of soil CO2
      efflux and delta13C of soil respired CO2 between May and October 2002 allowed the
      partitioning of the flux into that derived from the labelled litter, and that
      derived from native soil organic matter and roots. The effect of forest girdling
      on soil CO2 efflux was detectable from June (girdling took place in April), and
      resulted in GNL fluxes to be about 50% of NGNL fluxes by late August. The
      presence of litter resulted in significantly increased fluxes for the first 2
      months of the experiment, with significantly greater litter derived fluxes from
      non-girdled plots and a significant interaction between girdling and litter
      treatments over the same period. For NGL collars, the additional efflux was found
      to originate only in part from litter decomposition, but also from the decay of
      native soil organic matter. In GL collars, this priming effect was not
      significant, indicating an active role of the rhizosphere in soil priming. The
      results therefore indicate mutual positive feedbacks between litter decomposition
      and rhizosphere activity. Soil biological analysis (microbial and fungal biomass)
      of the organic layers indicated greatest activity below NGL collars, and we
      suppose that this increase indicates the mechanism of mutual positive feedback
      between rhizosphere activity and litter decomposition. However, elimination of
      fresh C input from both above- and belowground (GNL) also resulted in greater
      fungal abundance than for the NGNL treatment, indicating likely changes in fungal
      community structure (i.e. a shift from symbiotic to saprotrophic species
      abundance).

PMID- 15042461
TI  - MR-myelography as an adjunct to the MR examination of the degenerative spine.
AB  - Our objective was to analyse the usefulness of single-slice MR-myelography images
      as a complementary test to conventional MR of the spine in patients with
      clinically suspected degenerative spine disease. A prospective analysis of 1022
      consecutive patients studied with conventional MR and MR-myelography (four
      acquisitions: one coronal plane, one sagittal plane, and two oblique lateral,
      right and left planes) examinations was performed. Conventional MR and MR
      myelography studies were classified as positive when morphological or structural
      alterations were noted. Positive MR-myelography information was also categorized
      as relevant if findings were considered important and radiologically
      significative to the final diagnosis (either by increasing the radiologists
      confidence in the diagnosis or because the findings were not observed in the
      conventional study). Other positive findings were considered non- relevant. There
      were 62% cases considered positive in the MR-myelography examination. Of them, 3%
      revealed no alterations on the conventional MR examination. Of the negative MR
      myelography studies, 75% had a positive conventional MR examination. Considered
      as diagnostic techniques, their Kappa concordance was poor. However, MR
      myelography complemented the information obtained with the conventional MR
      examination of the spine, this information being relevant to the final MR
      diagnosis in 22% of the total number of cases. The contribution of MR-myelography
      was not different in the three spinal levels. In conclusion, MR-myelography
      complements the information obtained with conventional MR in a large number of
      cases.

PMID- 15042463
TI  - Long-term sequestration of fluorinated compounds in tissues after fluvoxamine or
      fluoxetine treatment: a fluorine magnetic resonance spectroscopy study in vivo.
AB  - Fluorine magnetic resonance spectroscopy (19F MRS), spectroscopic imaging (MRSI)
      and proton anatomical magnetic resonance imaging (1H MRI) were performed on
      brains and lower extremities of six subjects in vivo concurrently with HPLC of
      serum to investigate tissue and plasma drug localization and withdrawal kinetics
      in humans treated with fluvoxamine or fluoxetine. 19F MRS signal was unexpectedly
      detected in the lower extremities months after complete disappearance of signal
      from plasma and brain. MRSI suggested that the lower extremity fluvoxamine signal
      originated mainly from bone marrow. Results suggest long-term sequestration of
      these drugs or their metabolites mainly in bone marrow and possibly in
      surrounding tissue and demonstrate the usefulness of MRS to reveal drug-trapping
      compartments in the body.

PMID- 15042464
TI  - Imaging lung function using rapid dynamic acquisition of T1-maps during oxygen
      enhancement.
AB  - This paper describes imaging of lung function with oxygen-enhanced MRI using
      dynamically acquired T1 parameter maps, which allows an accurate, quantitative
      assessment of time constants of T1-enhancement and therefore lung function. Eight
      healthy volunteers were examined on a 1.5-T whole-body scanner. Lung T1-maps
      based on an IR Snapshot FLASH technique (TE = 1.4 ms, TR = 3.5 ms, FA = 7
      (composite function )) were dynamically acquired from each subject. Without
      waiting for full relaxation between subsequent acquisition of T1-maps, one T1-map
      was acquired every 6.7 s. For comparison, all subjects underwent a standard
      pulmonary function test (PFT). Oxygen wash-in and wash-out time course curves of
      T1 relaxation rate (R1)-enhancement were obtained and time constants of oxygen
      wash-in (w(in)) and wash-out (w(out)) were calculated. Averaged over the whole
      right lung, the mean w(out) was 43.90 +/- 10.47 s and the mean (w(in)) was 51.20
      +/- 15.53 s, thus about 17% higher in magnitude. Wash-in time constants
      correlated strongly with forced expired volume in one second in percentage of the
      vital capacity (FEV1 % VC) and with maximum expiratory flow at 25% vital capacity
      (MEF25), whereas wash-out time constants showed only weak correlation. Using
      oxygen-enhanced rapid dynamic acquisition of T1-maps, time course curves of R1
      enhancement can be obtained. With w(in) and w(out) two new parameters for
      assessing lung function are available. Therefore, the proposed method has the
      potential to provide regional information of pulmonary function in various lung
      diseases.

PMID- 15042465
TI  - [Assessment of Machiavellian intelligence in antisocial disorder with the MACH-IV
      Scale].
AB  - INTRODUCTION: The objective is to evaluate the presence of Machiavellian
      intelligence with the MACH-IV Scale in antisocial patients versus community
      controls. MATERIAL AND METHODS: Categorical diagnosis and dimensional evaluation
      program according to IPDE were obtained from 26 controls from the community and
      40 patients from a methadone program. Both groups were evaluated on cooperation
      with TCI and on Machiavellian intelligence with MACH-IV. RESULTS: Higher figures
      in MACH-IV Global Score, Tactics subscale (to manipulate others), Visions
      subscale (interpretations on Machiavellian behavior of others) were found in the
      20 antisocial patients compared with the 26 community controls achieving
      statistical significance. No statistical differences were found for Morality
      subscale scores (abstract morality) between groups. Dimensional evaluation of
      antisocial disorder according to IPDE shows statistically significant positive
      correlations for Tactics subscale, Visions subscale and Global Score of MACH-IV
      scale, but no statistically significant correlation was found for Morality
      subscale. There is a statistically significant negative correlation between MACH
      IV Tactics subscale and TIC altruism subscale. CONCLUSIONS: Antisocial patients
      have the same level of abstract moral attitudes as controls but are prone to use
      Machiavellian intelligence to interpret the actions of others, rationalize their
      own conduct and manipulate the behavior of others to get a benefit. These data
      support the hypothesis that many of the features of the antisocial syndrome may
      be explained by an abnormal development of an innate predisposition to be
      dominant in social relationships.

PMID- 15042466
TI  - [Sensitivity and specificity of the Overt Aggression Scale in schizophrenic
      patients].
AB  - INTRODUCTION: Research focused on the assessment of violent behavior in
      schizophrenic patients has been hindered by the lack of clinical instruments
      adapted to the Mexican psychiatric population. This study aimed to obtain
      sensitivity and specificity data as well as the most adequate cutoff point of the
      Overt Aggression Scale (OAS). METHOD: 137 schizophrenic patients were included. A
      clinical evaluation was performed with the PANSS subscale of excitability and the
      OAS. Diagnosis of violent behavior was obtained with the PANSS and clinical
      consensus of two psychiatrists. RESULTS: 66.4% of the sample was considered as
      nonviolent patients. A cutoff point of 7 points in the OAS showed sensitivity of
      0.80 and specificity of 0.97, with adequate positive and negative predictive
      power. DISCUSSION: The objective assessment of violent behavior in schizophrenic
      patients can contribute to the development of new lines of research. Adaptation
      of the OAS for the assessment of violent behavior will encourage the development
      of better strategies for the detection and intervention of violent behavior in
      schizophrenia.

PMID- 15042467
TI  - [Psychiatric disease in patients with psychogenic non-epileptic seizures referred
      from an epilepsy unit in a general hospital].
AB  - INTRODUCTION: We evaluate psychiatric disease associated with psychogenic non
      epileptic seizures (PNES) and study the role played by previous traumatic
      experiences, dissociative episodes and personality disorders. METHOD: After
      diagnosing PNES in our epilepsy unit, we obtained a sample of 46 patients and
      carried out a structured psychiatric interview (SCID) following DSM-III-R
      criteria. We looked for previous dissociative episodes and prepared a
      questionnaire for traumatic experiences and basic clinical data. RESULTS: The
      most frequent psychiatric disorders were depression, anxiety and somatoform
      disorders. Personality disorders were found in 16 patients (34.78%), dissociative
      episodes in 17 (36.95%), and previous traumatic experiences in 14 (30.43%). No
      statistically significant differences were found in regards to PNES, with respect
      to presence or absence of previous traumatic experiences, dissociative episodes,
      and personality disorders. CONCLUSIONS: As in previous studies, our research
      project confirms the co-existence of PNES with other mental disorders, and
      although we do find a higher frequency of seizures, the role played by traumatic
      experiences and dissociative disorders in CNEP remains unclear.

PMID- 15042468
TI  - [Assessment of chronic pain coping strategies].
AB  - INTRODUCTION: We made an adaptation of the Coping Strategies Questionnaire (CSQ)
      to the Spanish population. This measure, the most used in its scope, was
      developed by Rosenstiel and Keefe in 1983. METHOD: 205 participants coming from
      Primary Health Care and pain clinics made up the sample. More than half suffered
      migraine and chronic tension-type headache; the rest, fibromyalgia, low back
      pain, arthrosis or arthritis. RESULTS: Factor analyses explained 59 % of the
      total variance, on an 8-factor structure that converged into a 2-factor
      structure. In the 8-factor solution the novelty was the diversification of mental
      non-mental distraction strategies, and religious-non-religious hope strategies.
      In the 2-factor solution the novelty was the grouping according to the efficacy
      of the coping. All the CSQ factors showed inner consistency and construct
      validity. Thus, unadaptive coping strategies were related to negative, anxious
      and depressed self-talk, related to lack of control and perceived self-efficacy,
      and related to many pain behaviors. On the contrary it happened with adaptive
      coping strategies. In addition, the diagnosis of pain was related to the
      utilization and effectiveness of coping strategies. CONCLUSIONS: CSQ is shown to
      be a reliable and valid measure of coping strategies in chronic pain in the
      Spanish population, showing the difference between theoretical and empirical
      factor structures again.

PMID- 15042469
TI  - [Venlafaxine extended release for the treatment of chronic pain. A series of 50
      cases].
AB  - INTRODUCTION: The objective of this study is to investigate analgesic
      effectiveness and safety of venlafaxine extended release in chronic pain of any
      etiology. METHODS: Six month, observational, open study, carried out in two pain
      units. Initially, a daily dose of 75 mg of venlafaxine extended release was
      administered, increasing it to 150 mg, following clinical criteria. Treatment
      response was measured using the Visual Analogue Scale (VAS), rest and
      mobilization, Hospital Anxiety and Depression Scale (HAD) and Eastern Cooperative
      Oncology Group (ECOG) and an adverse event sheet to record adverse events
      occurring during the study. RESULTS: The study was carried out in a 50 patient
      sample with a mean age of 57.1 +/- 1.8 years, with chronic pain. A total of 85-90
      % of the patients was maintained with a daily dose of 75 mg of venlafaxine
      extended release. This produced a gradual reduction of the VAS scores at rest
      (significant reduction of 5.2 +/- 1.1 to 2.7 +/- 1.5 points; (p<0.0005) and
      mobilization (significant reduction of 5.5 +/- 0.8 to 3.1 +- 1.6 points;
      p<0.0005). Pain relief increased progressively. Regarding physical activity
      measured by the ECOG scale, there was a reduction of the percentage of patients
      and increase of outpatients. Tolerability to venlafaxine was "excellent", "very
      good" or "good" for 72% of the patients. CONCLUSIONS: Extended release
      venlafaxine can be an effective and well-tolerated treatment in patients with
      chronic pain of any etiology, although it must be investigated in depth.

PMID- 15042470
TI  - [Uncertainty on the measurement of intelligence].
AB  - In recent years, there has been considerable evidence on the phenomenon of
      intelligence quotient (IQ) gains over time with a gain rate of approximately
      three IQ points per decade. This phenomenon has been called the Flynn effect.
      This review article presents the evidence that supports this effect and discusses
      its implications for the measurement of intelligence. The above mentioned IQ
      gains over time obviously present serious methodological and theoretical problems
      in the use of intelligence tests. We review the methodological consequences which
      the Flynn effect presents in the reliability of the measurement of IQ as well as
      the methodological consequences which this effect has for epidemiological
      studies, especially those which focus on the study of the prevalence of mental
      retardation. Mention is made of the hypothesis that tries to explain these IQ
      gains, analyzing those which tend to explain these IQ gains as real gains in
      intelligence, as well as those that propose that these gains are due to other
      causes rather to real population IQ gains.

PMID- 15042471
TI  - [Depersonalization: from disorder to the symptom].
AB  - In contrast with the growing interest in dissociative disorders over the last few
      years, depersonalization continues to be very scarcely approached. There is no
      agreement among clinicians regarding the concept of depersonalization, and little
      is known about its etiology, epidemiology and treatment. This paper has two main
      aims: first, review the literature on this pathology focusing on nosological,
      historical, psychophysiological and treatment aspects, and second, explore the
      incidence of the depersonalization symptom in other psychiatric conditions, in
      particular in panic disorder. The Medline database over the last 5 years has been
      used for these purposes, and lack of studies on this subject has been found,
      especially regarding therapeutic issues. Some of the most relevant findings
      suggest that depersonalization, when associated to panic disorder, could
      correspond to the most severe forms of this disorder.

PMID- 15042472
TI  - [Sleep disorders with antipsychotic drugs: based on one case with clozapine].
AB  - Clozapine is a widely used atypical neuroleptic in the treatment of
      schizophrenia; its effects on sleep have been poorly studied, sedation being one
      of its side effects. We present the case of hypersomnia and marked reduction of
      REM sleep secondary to treatment with clozapine and review existing scientific
      literature on the action of neuroleptics on sleep.

PMID- 15042473
TI  - [Based on one case of dissociative disorder: a conceptual review].
AB  - Based on the description of a clinical case treated by the authors, and diagnosed
      of dissociative disorder, a review of the diagnosis of dissociative disorder and
      its polemics is carried out. The authors discuss concepts such as dissociation
      and hysteria, their historic evolution and their relationships. Some modern
      cognitive theories on dissociative disorders and their relationship or opposition
      to psychodynamic theories are presented. The differences between dissociation and
      repression with these two different approaches are also mentioned. The authors
      conclude that at the present time important questions must be solved in the area
      of dissociative disorders in order to progress in the psychiatric knowledge of
      dissociative processes.

PMID- 15042474
TI  - [Economics and practice].

PMID- 15042475
TI  - [Measuring preferences of psychiatric patients].
AB  - OBJECTIVE: Economic evaluation of health care interventions may require
      preference-based valuations of health outcomes or health effects. This paper
      provides an overview of the use of standard gamble (SG), time trade-off (TTO) and
      contingent valuation (CV) to elicit preferences of patients with depression or
      schizophrenia. METHODS: A systematic search of the literature was conducted
      covering the use of SG, TTO and CV in patients with depression or schizophrenia.
      Practicability, measurement results, construct and concurrent validity as well as
      test-retest-reliability formed the criteria for reviewing the performance of
      these measures of preference. RESULTS: SG, TTO and CV were rarely used in the two
      diagnostic groups considered. The reviewed studies mostly showed good
      practicability as well as some evidence for validity and reliability. Measured SG
      und TTO values point to substantial losses in utility caused by these diseases.
      CONCLUSIONS: Elicitation of patient preferences for the economic evaluation of
      mental health care seems possible.

PMID- 15042476
TI  - [Quality of life instruments and health state preferences to assess effects of
      medical interventions for mentally and medically ill patients].
AB  - AIM: The assessment of quality of life with a single index, which is necessary
      for cost-utility analyses, causes a loss of information. Therefore the
      suitability of such indices for mental health and non-mental health conditions
      was analysed and their ability to detect effects of medical interventions was
      examined. METHOD: Quality of life of 18 schizophrenic patients and 26 patients
      with diabetes mellitus was rated three times using disease specific instruments
      (BELP-KF, DMLQ), visual analog scale (VAS), EQ-5D and time trade-off (TTO).
      RESULTS: Effects of medical interventions were only detected with the disease
      specific instruments and EQ-5D. Using TTO and EQ-5D, there were significant, but
      reverse differences in the quality of life of patients with diabetes and patients
      with schizophrenia. EQ-5D correlated highly with DMLQ, but lowly with BELP-KF.
      CONCLUSIONS: TTO and VAS were insensitive to effects of medical interventions. EQ
      5D detected treatment-induced changes, but was inappropriate as a measure of
      quality of life in schizophrenic patients.

PMID- 15042477
TI  - [The impact of antipsychotic medication on the incidence and the costs of
      inpatient treatment in people with schizophrenia: results from a prospective
      observational study].
AB  - SUBJECT: Subject of the study is the analysis of the impact of antipsychotic
      medication on the incidence and the costs of inpatient treatment in patients with
      schizophrenia. METHODS: In a prospective longitudinal study with 5 points of
      measurement incidence and the costs of inpatient treatment, the type of
      antipsychotic medication, as well as the clinical and social characteristics of
      307 outpatients with the diagnosis of schizophrenia (ICD 10 F 20.0) were assessed
      over a period of 2.5 years. The impact of antipsychotic medication on the
      incidence of inpatient treatment was analysed by means of a random-effect logit
      model. The impact of antipsychotic medication on the costs of inpatient treatment
      was analysed by means of a random-effect tobit model. Selection effects were
      controlled by means of propensity scores. RESULTS: Patients who received
      antipsychotic treatment with conventional, new atypical or depot neuroleptics had
      a lower incidence of inpatient treatment and caused lower costs in comparison to
      patients without antipsychotic treatment. The same effect was found for patients
      who received a combined treatment with conventional and depot neuroleptics. No
      effects were found for clozapine or for a combination treatment with conventional
      and atypical neuroleptics. No significant differences between the effects of
      conventional, new atypical or depot-neuroleptics were found. CONCLUSION: The
      application of neuroleptic medication in schizophrenia treatment generally
      reduces the incidence and the costs of inpatient treatment. An extension of the
      use of clozapine or new atypical neuroleptics to all patients with schizophrenia
      will not generally improve the treatment effectiveness regarding to the incidence
      and the costs of inpatient treatment.

PMID- 15042478
TI  - [Cost of care for depressive disorders in primary and specialized care in
      Germany].
AB  - Service utilization and total direct cost of care was assessed in 270 patients
      suffering from depressive disorder. Patients were recruited from primary care
      physicians or family doctors (n = 43) or psychiatrists (n = 23) in office
      practice, from three different regions in Germany (county of Duren and city of
      Aachen, Lorrach-county, city of Munich). A detailed catalogue of unit costs
      (including inpatient, outpatient and rehabilitative services) was used for
      calculating total cost of care on an individual basis. Service utilization and
      costs referred to 2001. Mean cost of total medical care of the study patients was
      euro 3849 (excluding cost of drugs for physical illness). The cost for treating
      depressive disorders and additional psychiatric co-morbidity (which is included
      into the total cost of care) was euro 2073 per patient and year. When cross
      checking with ICD-10 criteria for depressive disorders, the original diagnosis by
      family doctors or psychiatrists could be confirmed in 186 patients of the total
      sample (n = 270), suggesting that there is a high amount of falsely diagnosed
      patients in primary and specialized care of depressive patients in Germany.
      Direct cost of the 186 confirmed patients was higher (total care cost: euro 4715,
      cost for treatment of depression and psychiatric co-morbidity: euro 2541) than in
      the total group and should be considered as reference cost, when discussing cost
      of care in depressive patients in Germany. Results suggest to analyse cost of
      care in depressive patients further and to discuss a more efficient allocation of
      health budgets in the field.

PMID- 15042479
TI  - [At what time is a reduction of medical under- or overtreatment sensible?
      Treatment of acute depression as an example].
AB  - OBJECTIVE: 1) To portray the mathematical relationship between the size of an
      underuse or overuse problem caused by non-compliance of health professionals and
      the cost-effectiveness of a quality improvement program; 2) to demonstrate the
      applicability of the models to a real-world problem (underuse and overuse in the
      treatment of major depression) and to stress the importance of the costs of a
      quality improvement program using this example. METHODS: Mathematical formulation
      of the relationship between the costs of a quality improvement program and the
      degree of underuse and overuse. RESULTS: The example of reducing underuse in the
      treatment of major depression shows that an intervention with a favorable cost
      effectiveness ratio may be economically unattractive if a quality improvement
      program incurs high costs secondary to a small quality deficit. The application
      example also shows that reducing treatment overuse is inefficient if overuse is
      small and hence the costs of a quality improvement program are higher than the
      costs of overuse. CONCLUSIONS: The explicit consideration of the size of an
      underuse or overuse problem in the cost-effectiveness ratio of a quality
      improvement program may contribute to a more efficient use of health care
      resources.

PMID- 15042480
TI  - [Post-processing of radiological data for preoperative planning in skull base
      surgery].
AB  - Preoperative planning in skull base surgery is usually based on numbers of
      different radiological data. To use this complex data digital post-processing is
      necessary. There is a significant difference between radiological and surgical
      post-processing. Planning the approach, resection of the tumour and
      reconstruction of the defect are supported by the software demonstrated in this
      study. Integration of the results in a closed workflow of Information-Guided
      Therapy will increase the potentials of surgical post-processing in the future
      (i. e. intraoperative navigation and visualization). Evidence based medicine will
      use digital data of surgical planning.

PMID- 15042481
TI  - [Use of the round window micro cath for inner ear therapy - results of a placebo
      controlled, prospective study on chronic tinnitus].
AB  - BACKGROUND: The local therapy of inner ear diseases provides a means of directly
      applying pharmacological substances and delivering electrical stimulation to
      inner ear structures. Problems relating to dosage, systemic effects and the blood
      cochlear barrier are thus avoided, which is not the case with systemic therapy.
      The preferred access point is the membrane of the round window. PATIENTS AND
      METHODS: An appropriately shaped catheter (DURECT Corporation, Cupertino, CA,
      USA), whose double-lumen passage system permits the variation of concentration
      and flow, is inserted into the round window niche. In a prospective, placebo
      controlled clinical study, this application system was tested in 20 patients with
      chronic tinnitus. Following implantation the substances lidocaine, glutamate,
      glutamic acid and caroverine were applied via an attached external micropump.
      RESULTS: The values for tinnitus loudness, level of irritation caused by the
      tinnitus and subjective effectiveness of the therapy - measured by means of the
      visual analog scale (VAS) - showed no significant change, although the most
      marked improvement was indicated for caroverine. CONCLUSIONS: These results
      indicate that a positive effect was observable only in a proportion of the
      patients. Continuous therapy of tinnitus and inner ear diseases will only be
      possible once a totally implantable microdosage system has been developed.

PMID- 15042482
TI  - [Tracheostoma valve with integrated cough lid for improvement of hands-free
      speech in laryngectomees - long term results].
AB  - BACKGROUND: Tracheostoma valves for laryngectomized patients were introduced to
      enable the laryngectomee after successful surgical voice restoration either by a
      voice prosthesis, a surgical shunt or microvascular laryngoplasty, to speak
      without using his fingers to close the tracheostoma. The basic principle of these
      aids is a mobile valve, which closes automatically at a certain air flow,
      directing the expired air of the lungs into the pharynx. In spite of the clear
      advantage of enabling a hands-free speech, the long term acceptance rate is still
      rather low, which is mainly caused by problems of an airtight fixation within or
      at the tracheostoma. Another important disadvantage of these tracheostoma valves
      is the necessity of removing the valve during coughing. The new tracheostoma
      valve "Window" (ADEVA Company, Lubeck, Germany) offers a clear improvement
      regarding this point. It is constructed with an additional coughing lid, which
      opens at a certain airflow and closes automatically after the coughing attack.
      After successful development and clinical testing of the new aid in 1999 and
      2000, it was now the question, if the previously low acceptance rate of
      tracheostoma valves could be improved in the long term use by this new type of
      valve. PATIENTS: Within the last 4 years 70 patients were provided with the
      "Window" tracheostoma valve. Patients were followed up at regular intervals in
      order to evaluate the function, the acceptance and the durability of the new
      device. Additional to the clinical examination patients had to fill in a
      questionnaire in order to investigate the subjective estimation by each patient
      himself. 15 patients did not send back their questionnaire or did not fill it in
      correctly, 5 patients refused clinical supervision after adjustment of the
      device, so finally the long term use in 50 patients could be analysed. RESULTS:
      82 % of the patients reported, that the coughing lid worked safely and opened
      immediately during the coughing attack. Most of the patients were satisfied with
      their device, but had nevertheless some proposals for a further improvement:
      although they cover the tracheostoma either with their clothes or a protection
      scarf, most of the patients would prefer a device which is smaller than the
      current model. Some patients reported on an insufficient stability of the plastic
      material, which led to a defect at the sliding mechanism of the coughing lid. The
      greatest problem regarding the regular use of the valve was - comparable to
      conventional tracheostoma valves - the occurrence of an air leakage around the
      tracheostoma. Although there are three different models of the "Window"
      tracheostoma valve available, only patients being fitted with the "standard-T
      type" version could wear the device 10 hours a day or longer without any problems
      of air leakage. CONCLUSIONS: The "Window" tracheostoma valve with an integrated
      coughing lid provides further improvement in speech rehabilitation of
      laryngectomees. The actual rate of acceptance of 62 % for all "Window" patients
      (1 month daily use for at least 2 hours) is superior to other reports on the use
      of tracheostoma valves and probably caused by the additional comfort provided by
      the coughing lid. Another important factor for the long term use of tracheostoma
      valves is however the safe fixation of the device in or around the tracheostoma.
      In this point further improvement is necessary, as only the model with the
      fixation within the trachea (T-type) led to a satisfactory long term airtight
      fixation.

PMID- 15042483
TI  - [Wegener's granulomatosis (WG) presented with hearing loss and without positive
      serologic ANCA].
AB  - BACKGROUND: Wegener's granulomatosis (WG) is a granulomatous inflammation
      involving the upper and lower respiratory tract and necrotizing vasculitis
      affecting small to medium-sized vessels. In contrast to a generalised WG with
      glomerulonephritis initial or isolated forms of the upper respiratory tract may
      be a diagnostic challenge. PATIENT: We report the case of a 33 year old man with
      clinical signs of a limited WG exhibiting an imminent irreversible hearing loss,
      negative PR3-ANCA (anti neutrophil cytoplasmic antibodies with proteinase 3 as
      target) in serum and an ambiguous histology. CONCLUSION: In case of a chronic
      otitis media and rhinitis as well as signs of a labyrinthine deafness a limited
      form of a WG has to be taken into account, even with an ambiguous histology and
      negative PR3-ANCA. This diagnosis is supported by high inflammation parameters,
      e. g. ESR and CRP, exclusion of infectious cause and response to corticosteroids.
      A quick therapeutic intervention with corticosteroids and cyclophosphamide is
      required in order to interrupt the vasculitis of the inner ear with consequential
      deafness.

PMID- 15042484
TI  - [Diffuse hyperplastic oncocytosis of the parotid gland].
AB  - BACKGROUND: Oncocytes are epithelial cells characterized by an granular,
      eosinophilic cytoplasma, and a centrally situated, pycnotic nucleus. These cells
      were first observed by Hamperl 1931 in the salivary glands. Ultrastructural
      studies have shown that the cytoplasma of these cells is filled with numerous
      large and bizarre mitochondria. The exact biological significance of oncocytes is
      unknown - Becker, Donath and Seifert suggest an intracellular metabolic
      disturbance associated with mitochondriopathy, caused by an age dependent
      metabolic defect. Oncocytes are not specific for the salivary glands; they are
      also found in the thyroid gland, parathyroid gland, liver, pancreas, esophagus
      and the kidney. Solitary oncocytes appear most often as incidental findings in
      aging salivary tissue, they are present in persons older than 70 years up to 80
      %. The diffuse hyperplastic oncocytosis of the parotid gland represents an
      extremely rare, non-tumorous alteration of the parotid gland. Caused by an
      extensive metaplasia of acinic and ductal cells nearly the entire gland consists
      of oncocytes. Clinically it is characterized by swelling of the parotid gland.
      Oncocytic adenomatous hyperplasia is a different disease. It represents a
      multifocal oncocytic proliferation of the duct system. In contrast to diffuse
      oncocytosis remnants of the original salivary tissue with acini and fatty tissue
      are usually present between the oncocytic nodules. Typical oncocytomas may
      possibly develop from such oncocytic proliferation by a tendency to confluent
      growth. METHODS: Cases of diffuse hyperplastic oncocytosis of the parotid gland
      were identified by literature review. RESULTS: Worldwide diffuse hyperplastic
      oncocytosis of the parotid gland has been observed in 8 cases (Fig. ) as of
      today. PATIENT: We report and discuss the case of a 78-year-old male, who was
      refered to our hospital because of a painless mass of the left parotid gland. MRI
      showed a tumorous lesion with a diameter of about 5 cm. Lateral parotidectomy was
      performed. Histology revealed an extremely rare case of diffuse hyperplastic
      oncocytosis. There has been no recurrence of tumor after 2 years. CONCLUSIONS:
      Diffuse hyperplastic oncocytosis of the parotid gland is an extremely rare benign
      disorder, complete excision of the tumor-like lesion is curative. In literature
      there has been no report of recurrence, malignant transformation or metastasizing
      illness.

PMID- 15042486
TI  - [The interesting case - case no. 58. Work type II duplication of the auditory
      canal].

PMID- 15042485
TI  - [Gastroesophageal reflux disease and chronic sinusitis].
AB  - BACKGROUND: It is increasingly suggested that there may be a connection between
      gastrooesophageal reflux disease (GERD) or laryngopharyngeal reflux (LPR) and
      chronic sinusitis. We therefore wished to establish whether the literature
      contains sufficient evidence to support this assumption. MATERIAL AND METHODS: We
      performed a search in Medline (PubMed) and EMBASE with the key words "GERD, GER,
      reflux, sinusitis, chronic sinusitis". The literature obtained was assessed with
      regard to the reported results and their evidence levels. The level of evidence
      was classified according to the usual levels I - IV, only levels Ia or Ib being
      considered sufficient evidence for a knowledge gain confirmed by therapeutic
      trials. RESULTS: A total of 77 references were found in Medline and 142 in
      EMBASE. A large number of these were narrative review articles addressing the
      connection between GERD or sinusitis and asthma or GERD or sinusitis and chronic
      cough. Only 12 papers and one case report dealt more or less directly with the
      question of a connection between chronic sinusitis and reflux. None of the
      studies could be classed as evidence level I (randomised controlled trials), ten
      were classed as level III studies, one as level IIb and one as level IV.
      DISCUSSION AND CONCLUSIONS: The existing studies do not allow us to pinpoint LPR
      (and even less so GERD) as a clear-cut factor in the aetiopathogenesis of chronic
      sinusitis. However, despite all their deficiencies and limitations the studies
      nevertheless do show that reflux into the pharynx and nasopharynx is possible.
      This reflux (= LPR) can lead to chronic inflammation which can be successfully
      treated with antireflux therapy with proton pump inhibitors. Quantification of
      the association is not currently possible. An above-average proportion of the
      patients with chronic rhinosinusitis appear to have GERD/LPR. However the
      prevalence of GERD in the population is generally high. It has not yet been
      established with sufficient certainty whether the LPR must be regarded as a
      causative factor, whether it exacerbates or chronifies the disease or whether it
      is merely an epi-phenomenon which does not require specific treatment. To answer
      this important question we need prospective randomised controlled studies which
      will provide evidence of sufficient quality. These should be conducted with the
      help of standardised documentation.

PMID- 15042487
TI  - [Hospitalization of non-stroke patients in a Stroke Unit].
AB  - BACKGROUND AND OBJECTIVE: Stroke care in Germany has substantially improved
      during the last decade. One column of modern stroke care is the institution of
      stroke unit which allows rapid diagnosis and treatment. The aspect of admission
      of nonstroke patients to a stroke unit is poorly evaluated. The aim of this study
      is to evaluate the number of patients who are admitted to a national stroke unit
      but do not suffer from stroke. Furthermore, we related the proportion of
      nonstroke referrals to the different referral modes. PATIENT AND METHODS:
      Observational study recording all suspected stroke referrals with regard to final
      diagnosis and type of referral during a 12-month period (1.8.2002-31.7.2003).
      RESULTS: 462 patients were admitted by 4 routes: 74 by paramedics or by self
      presentation, 138 by emergency physicians, 144 by primary care doctors, and 106
      were transferred from other hospitals. 88 patients (19 %) finally revealed no
      acute stroke. The most common nonstroke diagnoses were seizure (20 %),
      dissociative disorders (14 %), cranial nerve disorders (11 %), hypoglycaemia (8
      %) and transient global amnesia (7 %). There was no significant difference among
      the proportion of nonstroke patients referred by ambulance paramedics and self
      presentation (15 %), emergency physicians (21 %), primary care doctors (15 %) and
      interhospital transfer (24 %) [p = 0.222, X (2)-test according to Pearson].
      CONCLUSION: Due to the fact that a number of clinical neurological conditions
      mimic acute stroke, misdiagnosis of stroke is common. We advocate that all stroke
      patients are seen early in the course of the disease by a neurologist. An
      alternative could be that in stroke units of internal medicine hospitals patients
      are seen by a consulting neurologist. Alternatively, telemedicine might be used
      and the neurologist on duty of a neurological stroke unit could be consulted.

PMID- 15042488
TI  - [Dolichomegaesophagus in achalasia. Therapy by esophogectomy in an aged patient].
AB  - HISTORY AND CLINICAL FINDINGS: A 78-year-old woman suffered from achalasia since
      63 years with a progressive decompensation over the last year. 53 years ago,
      treatment with the Stark Dilator and 24 years ago, pneumatic dilation had been
      carried out. Currently, the patient presented with dysphagia for liquid and solid
      food, with permanent retrosternal pain and regurgitation for every meal, leading
      to a weight loss of 10 kg. INVESTIGATIONS: The barium esophagogram showed a
      marked dilation of the esophagus with retinated secretions and food. The cardia
      had a maximum width of 15 mm. On endoscopy, reflux esophagitis and an
      insufficient lower esophageal sphincter were evident. TREATMENT AND COURSE:
      Transhiatal esophageal resection with gastric pull-up and cervical
      esophagogastrostomy was performed. The postoperative course was without
      complications and normal alimentation could be restored with a marked improvement
      of preoperative symptoms. CONCLUSION: Esophageal resection and gastric pull up is
      the more favourable treatment option in elderly patients with decompensated
      achalasia and dolichomegaesophagus compared to a gastric tube for alimentation-
      adjusted to the individual surgical risk.

PMID- 15042490
TI  - [The diabetic foot syndrome--case report].

PMID- 15042489
TI  - [Effective treatment of anaemia with darbepoetin alfa in a patient with
      hereditary hemochromatosis].

PMID- 15042491
TI  - [The diabetic foot syndrome--diagnosis].

PMID- 15042492
TI  - [The diabetic foot syndrome--therapy].

PMID- 15042496
TI  - [Clinical trials in Germany. The gastroenterologist in private practice as a
      partner in clinical trials].

PMID- 15042495
TI  - [Who benefits from late recanalization after acute myocardial infarction?].

PMID- 15042497
TI  - [Is it useful to treat a severe renal insufficiency with thiazides?].

PMID- 15042499
TI  - [Principles of giving full information in oncology].

PMID- 15042500
TI  - [Alternatives to endotracheal intubation: a matter of statistics?].

PMID- 15042498
TI  - [Clinical features and up-to-date therapy of hypertensive emergencies].

PMID- 15042501
TI  - [Legionella prevention in intensive care units].
AB  - From time to time hospitals are in the focus of the local and national media
      because of cases of nosocomial Legionnaires' disease. In particular intensive
      care patients are a risk group because of their high amount of immunocompromised
      patients with an increased risk of developing a Legionellosis. Therefore it is an
      important aim to maintain an effective prevention system. Nevertheless in some
      hospitals legionella can be identified. Particularly in these hospitals a high
      level of attention is required to recognize cases of legionellosis and to take
      adequately steps to avoid outbreaks of legionellosis. The following article
      explains the recently published recommendations of the American hospital hygiene
      experts.

PMID- 15042502
TI  - [ProSeal-laryngeal mask versus endotracheal intubation in patients undergoing
      gynaecologic laparoscopy].
AB  - BACKGROUND: The aim of this study was to assess the practicality of the ProSeal
      laryngeal mask (PS-LMA) airway during laparoscopic surgery with capnoperitoneum
      compared to endotracheal intubation (ET). METHODS: Prospective, randomized study.
      104 patients undergoing gynaecologic, laparoscopic surgery were allocated
      randomly to two groups: 1. ET-group (n = 50). 2. PS-LMA-group (n = 54). Total
      intravenous anaesthesia was performed by the same anaesthesiologist.
      MEASUREMENTS: Mean arterial pressure, heart rate, at 4 and circuit pressure at 2
      measurement points, and the incidences of coughing and sore throat. Insertion of
      the ET and the PS-LMA was scored by using a four-point scale. Ease of placing the
      gastric tube was judged by measuring the number of attempts at insertion and the
      insertion times. A p-value of < 0.05 was considered as significant. RESULTS:
      There were no differences between PS-LMA and ET concerning circuit pressure at
      any measurement point. At the end of anaesthesia, mean arterial pressure (92 +/-
      13 vs. 100 +/- 14 mmHg; p < 0.01) and heart rate (66 +/- 13 vs. 76 +/- 14
      beats/min; p < 0.01) were lower in the PS-LMA-group compared to the ET-group. At
      the end of anaesthesia 25 patients of the ET-group coughed but nobody in the PS
      LMA-group (p < 0.00001). There was no difference with regard to postoperative
      sore throat. The insertion of the PS-LMA was easier compared to ET (p < 0.05),
      but we found no significant difference concerning insertion times. Fewer attempts
      at insertion of the gastric tube were necessary in the PS-LMA-group than in the
      ET-group (p < 0.01), whereas insertion times did not differ. CONCLUSION: The PS
      LMA is a convenient and practicable approach for anaesthesia in patients
      undergoing laparoscopic surgery.

PMID- 15042505
TI  - [Delayed onset of malignant hyperthermia crisis during a living donor liver
      transplantation caused by sevoflurane].
AB  - We report on a 25-year old ASA physical status I patient, who developed within 20
      minutes a full-blown malignant hyperthermia (MH) in the context of a living donor
      liver transplantation after 180 minutes of uneventful anaesthesia. The only
      trigger substance applied was Sevoflurane. The patient had already received a
      short, uneventful anaesthesia with Isoflurane a couple of years ago. In the
      context of the special constellation an initial dose of Dantrolene of 10 mg/kg
      body weight was administered. The patient was stabilised within 30 minutes, and
      the enzyme levels remained low compared with other case reports. The post
      operative in vitro caffeine halothane contracture testing confirmed that son and
      mother were susceptible to MH, contracture testing in the father was negative.
      All known triggers may cause life-threatening MH crisis - even after hours and
      after inconspicuous multiple exposures to known trigger substances. Therefore all
      trigger substances must be avoided in all patients susceptible to MH.

PMID- 15042504
TI  - [Theophylline induces contractures in porcine skeletal muscle preparations with
      the disposition to malignant hyperthermia].
AB  - OBJECTIVE: Theophylline, a methylxanthine, leads to an increase of the
      cytoplasmic Ca(2+)-concentration in the muscle cell. Since the in-vitro
      contracture test (IVCT) with halothane and caffeine does not distinguish a 100%
      between malignant hyperthermia susceptible (MHS) and non-susceptible (MHN), we
      examined the in-vitro effects of theophylline in porcine skeletal muscle
      preparations. METHODS: After approval by the local animal care committee ten MHS-
      and nine MHN-swine were anaesthetized and muscle biopsies taken. For IVCT, muscle
      specimens were exposed to bolus administrations of theophylline in concentrations
      of 3.0 respectively 5.0 mmol/l. Muscle contracture development and twitch
      amplitudes were recorded over a period of 30 minutes. Data are expressed as
      medians and ranges. RESULTS: After both theophylline bolus administrations MHS
      muscles developed significantly higher contractures compared to the MHN
      specimens. The MHS-muscles reached a maximum contracture of 17.0 mN (7.2-59.6 mN)
      after administration of 3.0 mmol/l theophylline. In comparison, two MHN-specimens
      showed weak contractures with a maximum of 1.4 mN. The 5.0 mmol/l theophylline
      IVCT resulted in maximum contractures of 19.1 mN (2.1-39.2 mN) for the MHS
      preparations. Just in three MHN-muscles weak contractures of 0.0 mN (0.0-0.8 mN)
      were recorded. Thus, a significant difference without overlap was revealed for
      the maximum contracture. CONCLUSION: Theophylline in concentrations of 3.0 and
      5.0 mmol/l revealed a clear difference between MHS- and MHN-porcine muscle
      preparations. Further examinations on human skeletal muscles are needed to
      demonstrate the value of theophylline in the IVCT MH-diagnosis.

PMID- 15042503
TI  - [Warming efficacy and blood damaging of blood and infusion warmers].
AB  - QUESTION: Inadequately warmed blood or infusions contribute to the development of
      perioperative hypothermia. Therefore we analysed the efficiency of several
      infusion warmers. METHOD: Tested infusion warmers: Model Autoline (Barkey)
      500OR/241(Arizant), BW 385L(Biotest), H250/D50 und D60 (Level-1), H500/D300
      (Level-1), Warmflo FW537-I/HEC40 (Tyco). Different solutions (saline, colloid
      solution and packed red blood cells PRBC) were tested varying the infusion flow,
      temperature of the solution and infusion pressure. Effective warming was defined
      as an infusion temperature > or = 33 degrees C. Haemolysis was measured by the
      increase of free plasma haemoglobin. RESULTS: The infusion warmers were effective
      within the following flow ranges: Low flow rate (< 250 ml/h): Autoline, 500OR/241
      and H250/D60. Medium flow rate (250-2500 ml/h): Autoline, 500OR/241, BW385L (>
      480 ml/h), H250/D 60 und D50 (> or = 1300 ml/h), FW537-I/HEC40 (> 950 ml/h. High
      flow rate (2500-10,000 ml/h): BW385L (up to 5000 ml/h), H250/D50, H250/D60,
      H500/D300 and FW537-I/HEC 40(R). Highest flow rates (> 10,000 ml/h): H250/D60,
      H500/D300 and FW537-I HEC40. Colloidal solutions were warmed nearly as good as
      saline, cooled PRBC had a smaller range of effective warming. There was no
      relevant haemolysis in any of the tested systems (plasma free haemoglobin raise <
      24 mg/dl in all systems). CONCLUSION: The warming capacity of the system and the
      length of the uninsulated infusion system determine the efficiency of an infusion
      warmer. The range of effective warming of an infusion warmer should be known for
      proper application.

PMID- 15042507
TI  - [Accidents with dangerous goods--how can the risks be recognized and assessed?].

PMID- 15042506
TI  - [New insights in postoperative pain therapy].
AB  - In this review, novel clinical studies on postoperative pain therapy are
      summarized. Based on these studies, several conclusions can be drawn: i)
      following tonsillectomy, postoperative therapy with NSAIDs leads to a significant
      increase in the number of reoperations; thus NSAIDs should be used with caution;
      ii) COX-2 inhibitors in combination with intravenous opioids improve recovery and
      functional outcome after knee replacement surgery; iii) the combination therapy
      of different non-opioid analgesics has no proven clinical efficacy and should not
      be used routinely; iv) patients' age is not a determinant in postoperative opioid
      titration after surgery; in contrast, it does predict opioid consumption during
      the first postoperative day; v) morphine and piritramide have identical analgesic
      efficacy and induce nausea and vomiting with the incidence; opioid selection can,
      thus, be based on economic considerations and vi) if tramadol is ineffective in
      postoperative pain therapy, this might be caused by an allelic variant of one of
      the cytochrome P450 enzymes (CYP2D6); these patients should be treated with a
      different opioid.

PMID- 15042509
TI  - Phylogeographic analysis of haplogroup E3b (E-M215) y chromosomes reveals
      multiple migratory events within and out of Africa.
AB  - We explored the phylogeography of human Y-chromosomal haplogroup E3b by analyzing
      3401 individuals from five continents. Our data refine the phylogeny of the
      entire haplogroup, which appears as a collection of lineages with very different
      evolutionary histories, and reveal signatures of several distinct processes of
      migrations and/or recurrent gene flow that occurred in Africa and western Eurasia
      over the past 25000 years. In Europe, the overall frequency pattern of haplogroup
      E-M78 does not support the hypothesis of a uniform spread of people from a single
      parental Near Eastern population. The distribution of E-M81 chromosomes in Africa
      closely matches the present area of distribution of Berber-speaking populations
      on the continent, suggesting a close haplogroup-ethnic group parallelism. E-M34
      chromosomes were more likely introduced in Ethiopia from the Near East. In
      conclusion, the present study shows that earlier work based on fewer Y-chromosome
      markers led to rather simple historical interpretations and highlights the fact
      that many population-genetic analyses are not robust to a poorly resolved
      phylogeny.

PMID- 15042510
TI  - MSH2 c.1452-1455delAATG is a founder mutation and an important cause of
      hereditary nonpolyposis colorectal cancer in the southern Chinese population.
AB  - Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for approximately 2%
      of all colorectal cancer (CRC) cases and is the most common hereditary CRC
      syndrome. We have previously reported a high incidence of microsatellite
      instability (MSI) and germline mismatch repair (MMR) gene mutations in young Hong
      Kong Chinese with CRC. Ongoing studies at the Hereditary Gastrointestinal Cancer
      Registry in Hong Kong have revealed a unique germline MSH2 c.1452-1455delAATG
      mutation that has not been reported in other ethnic groups. Detailed analysis
      showed that this specific MSH2 mutation constituted 21% of all germline MMR gene
      mutations and 36% of all MSH2 germline mutations identified. We designed a
      specific PCR-based diagnostic test on paraffin-embedded tissues and identified
      this germline mutation in 2 (1.5%) of 138 consecutive patients with early-onset
      CRC (<46 years of age at diagnosis). Haplotype analysis was performed using 11
      microsatellite markers located between D2S391 and D2S123. All 10 families had the
      same disease haplotype, suggesting a founder effect. These 10 families all
      originated from the Chinese province of Guangdong, which historically included
      Hong Kong. It is the most populous of the Chinese provinces, with a population of
      >93 million. Further analysis suggested that this founder mutation may date back
      to between 22 and 103 generations ago. The identification of this MSH2 founder
      mutation has important implications for the design of mutation-detection
      strategies for the southern Chinese population. Since there were major
      emigrations from Hong Kong and Guangdong province during the 19th and 20th
      centuries, this finding is also significant for Chinese communities worldwide.

PMID- 15042511
TI  - Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal
      cancer.
AB  - Wnt signaling regulates embryonic pattern formation and morphogenesis of most
      organs. Aberrations of regulation of Wnt signaling may lead to cancer. Here, we
      have used positional cloning to identify the causative mutation in a Finnish
      family in which severe permanent tooth agenesis (oligodontia) and colorectal
      neoplasia segregate with dominant inheritance. Eleven members of the family
      lacked at least eight permanent teeth, two of whom developed only three permanent
      teeth. Colorectal cancer or precancerous lesions of variable types were found in
      eight of the patients with oligodontia. We show that oligodontia and
      predisposition to cancer are caused by a nonsense mutation, Arg656Stop, in the
      Wnt-signaling regulator AXIN2. In addition, we identified a de novo frameshift
      mutation 1994-1995insG in AXIN2 in an unrelated young patient with severe tooth
      agenesis. Both mutations are expected to activate Wnt signaling. The results
      provide the first evidence of the importance of Wnt signaling for the development
      of dentition in humans and suggest that an intricate control of Wnt-signal
      activity is necessary for normal tooth development, since both inhibition and
      stimulation of Wnt signaling may lead to tooth agenesis. Our findings introduce a
      new gene for hereditary colorectal cancer and suggest that tooth agenesis may be
      an indicator of cancer susceptibility.

PMID- 15042512
TI  - Analyses of genetic structure of Tibeto-Burman populations reveals sex-biased
      admixture in southern Tibeto-Burmans.
AB  - An unequal contribution of male and female lineages from parental populations to
      admixed ones is not uncommon in the American continents, as a consequence of
      directional gene flow from European men into African and Hispanic Americans in
      the past several centuries. However, little is known about sex-biased admixture
      in East Asia, where substantial migrations are recorded. Tibeto-Burman (TB)
      populations were historically derived from ancient tribes of northwestern China
      and subsequently moved to the south, where they admixed with the southern natives
      during the past 2600 years. They are currently extensively distributed in China
      and Southeast Asia. In this study, we analyze the variations of 965 Y chromosomes
      and 754 mtDNAs in >20 TB populations from China. By examining the haplotype group
      distributions of Y-chromosome and mtDNA markers and their principal components,
      we show that the genetic structure of the extant southern Tibeto-Burman (STB)
      populations were primarily formed by two parental groups: northern immigrants and
      native southerners. Furthermore, the admixture has a bias between male and female
      lineages, with a stronger influence of northern immigrants on the male lineages
      (approximately 62%) and with the southern natives contributing more extensively
      to the female lineages (approximately 56%) in the extant STBs. This is the first
      genetic evidence revealing sex-biased admixture in STB populations, which has
      genetic, historical, and anthropological implications.

PMID- 15042513
TI  - Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel
      gene CYP4V2.
AB  - Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive
      retinal dystrophy characterized by multiple glistening intraretinal crystals
      scattered over the fundus, a characteristic degeneration of the retina, and
      sclerosis of the choroidal vessels, ultimately resulting in progressive night
      blindness and constriction of the visual field. The BCD region of chromosome
      4q35.1 was refined to an interval flanked centromerically by D4S2924 by linkage
      and haplotype analysis; mutations were found in the novel CYP450 family member
      CYP4V2 in 23 of 25 unrelated patients with BCD tested. The CYP4V2 gene,
      transcribed from 11 exons spanning 19 kb, is expressed widely. Homology to other
      CYP450 proteins suggests that CYP4V2 may have a role in fatty acid and steroid
      metabolism, consistent with biochemical studies of patients with BCD.

PMID- 15042514
TI  - Neurokinin-1 receptor gene expression in the mouse dorsal horn increases with
      neuropathic pain.
AB  - Peripheral nerve injury is associated with hyperesthesia and increased neurokinin
      1 receptor (NK-1) expression in the dorsal horn of the spinal cord. To test the
      hypothesis that NK-1 gene expression underlies these responses, we used solution
      hybridization-nuclease protection assays to quantify NK-1 mRNA levels in dorsal
      quadrants of the mouse lumbar dorsal horn. Partial sciatic nerve ligation was
      associated with mechanical allodynia, thermal hyperalgesia, and an increase in NK
      1 mRNA on the ipsilateral, but not contralateral, side. Regression analysis
      showed that NK-1 mRNA was significantly correlated with thermal paw withdrawal
      latency but not mechanical threshold. Our results support the idea that substance
      P is an important mediator of thermal hypersensitivity in the setting of nerve
      injury and suggest that increased NK-1 receptor transcription precedes increased
      NK-1 receptor density, ultimately leading to behavioral hypersensitivity to
      peripheral thermal stimulation. PERSPECTIVE: The therapeutic efficacy of NK-1
      receptor antagonists is unclear. The current data suggest that peripheral nerve
      injury increases the expression of substance P (NK-1) receptors in the spinal
      cord dorsal horn; this is correlated with heat hypersensitivity. The analgesic
      effects of NK-1 antagonists might become apparent if tested against heat-evoked
      pain in nerve injury patients.

PMID- 15042515
TI  - Influences of gender role and anxiety on sex differences in temporal summation of
      pain.
AB  - Previous research has consistently shown moderate to large differences between
      pain reports of men and women undergoing experimental pain testing. These
      differences have been shown for a variety of types of stimulation. However, only
      recently have sex differences been demonstrated for temporal summation of second
      pain. This study examined sex differences in response to temporal summation of
      second pain elicited by thermal stimulation of the skin. The relative influences
      of state anxiety and gender role expectations on temporal summation were
      investigated. Asymptomatic undergraduates (37 women and 30 men) underwent thermal
      testing of the thenar surface of the hand in a temporal summation protocol. Our
      results replicated those of Fillingim et al indicating that women showed
      increased temporal summation compared to men. We extended those findings to
      demonstrate that temporal summation is influenced by anxiety and gender role
      stereotypes about pain responding. When anxiety and gender role stereotypes are
      taken into account, sex is no longer a significant predictor of temporal
      summation. These findings highlight the contribution of social learning factors
      in the differences between sexes' pain perception. PERSPECTIVE: Results of this
      study demonstrate that psychosocial variables influence pain mechanisms. Temporal
      summation was related to gender role expectations of pain and anxiety. These
      variables explain a significant portion of the differences between men and
      women's pain processing, and may be related to differences in clinical
      presentation.

PMID- 15042516
TI  - Memory for stress-associated acute pain.
AB  - Negative emotions (eg, tension, anxiety, fear, anger) influence acute pain
      recall. Given reliance on patient-provided pain reports across the care
      continuum, an understanding of factors that modulate pain memory processing
      become important to patients, clinicians, and health care organizations. The
      purpose of this study was to investigate the influence of negative emotions on
      the prediction of 6-month pain recall by using an experimental stress
      manipulation (speech task) + pain (forehead cold pressor) versus nonstress
      control + pain crossover design (n = 68). Results showed that (1) negative
      emotions were greater in the stress session than the nonstress session, and
      experienced pain levels did not differ by condition or sex; (2) the level
      negative emotions at the time of the pain stimuli mediated the ability of
      experienced pain to predict pain recall; and (3) women recalled more stress
      session pain than men, and nonstress pain was accurately recalled. Integrating
      these findings with those of others, we present a model of acute pain memory
      recall in which negative emotions influence pain memory processing wherein the
      level of experienced pain predicts short-term recall and affective state at the
      time of the experience becomes a powerful predictor for the long-term recall of
      experienced pain level. PERSPECTIVE: After 6 months the level of recalled
      experimental pain delivered within a stressful context becomes exaggerated.
      Negative emotions at the time of the painful stimuli and at recall influenced the
      prediction of the level of recalled pain. Emotional arousal may influence how
      memory for pain is encoded, processed, and retrieved.

PMID- 15042517
TI  - Sex differences in thermal nociception and prostaglandin-induced thermal
      hypersensitivity in rhesus monkeys.
AB  - The present study examined thermal nociception in 4 male and 4 female rhesus
      monkeys. In the first experiment, monkeys were tested 5 days/week for 4
      consecutive weeks in a warm-water, tail-withdrawal assay of thermal nociception.
      Thermal nociception did not vary by sex or menstrual cycle phase. However, male
      monkeys tended to be slightly more sensitive to thermal stimuli than female
      monkeys in the follicular phase of the menstrual cycle. Thermal nociception did
      not correlate with estradiol or progesterone levels in female monkeys. In the
      second experiment, thermal hypersensitivity was induced by administering
      prostaglandin E(2) (0.0032 to 0.1 mg subcutaneously) into the tail. Prostaglandin
      E(2) produced slightly greater thermal hypersensitivity in male than in
      follicular phase female monkeys, but male and luteal phase female monkeys did not
      differ, and there was not a significant difference between follicular and luteal
      phase female monkeys. Exposure to the behavioral procedures produced similar
      increases in blood levels of the stress-related hormones adrenocorticotropic
      hormone and cortisol in male and female monkeys, which suggests that measures of
      thermal nociception or thermal hypersensitivity were not confounded by sex
      differences in stress responses. These results suggest that sex and gonadal
      hormone levels have only a minor influence on thermal nociception or thermal
      hypersensitivity in rhesus monkeys. PERSPECTIVE: These modest effects of sex and
      gonadal hormone levels on measures of pain in non-human primates could be
      interpreted to support the hypothesis that sex differences in pain perception in
      humans are due more to sociocultural factors than to a biological imperative.

PMID- 15042518
TI  - Analgesic effects of a soy-containing diet in three murine bone cancer pain
      models.
AB  - Bone is a common metastatic site for prostate and breast cancer, and bone cancer
      is usually associated with severe pain. Traditional treatments for cancer pain
      can sometimes be ineffective or associated with side effects. Thus an increasing
      number of patients seek alternative therapies. In this study we investigated the
      analgesic effects of a soy diet on 3 experimental models of bone cancer pain.
      Mice were fed a diet in which the protein source was either soy or casein. After
      1 week on the diet, sarcoma cells (NCTC 2472) were injected into the medullary
      cavity of the humeri, femur, or calcaneus. Experimenters blinded to diet of the
      animal assessed the pain behavior in these animals, forelimb grip force in the
      humerus model and paw withdrawal frequency to mechanical stimuli in the calcaneus
      and femur models. The effect of morphine on cancer-induced pain behavior was
      investigated in calcaneus and femur models. In addition, in the femur model, the
      effects of soy on tumor size and bone destruction were studied. The soy diet
      reduced secondary mechanical hyperalgesia in the femur model but had no effect on
      primary mechanical hyperalgesia in the calcaneus model or on movement-related
      hyperalgesia in the humerus model. No dietary impact was discerned in
      measurements of tumor size, bone destruction, and body weight in the femur model,
      suggesting that the soy diet had no effect on cancer growth. Morphine dose
      dependently reduced hyperalgesia with no diet-based difference. These results
      suggest that a soy diet might provide analgesia in certain forms of hyperalgesia
      associated with bone cancer. PERSPECTIVE: The study raises the possibility of
      dietary supplements influencing aspects of cancer pain. Further research will
      help determine if use of nutritional supplements, such as soy proteins, can
      reduce opioid analgesic use in chronic pain states and help minimize the side
      effects associated with long term use of opioids.

PMID- 15042519
TI  - Muscle pain during exercise in normotensive AfricanAmerican women: effect of
      parental hypertension history.
AB  - The purpose of the present investigation was to determine the influence of
      parental hypertension history on leg muscle pain ratings during cycling exercise
      in African American women. Eighteen women (age, 19 +/- 2 years) with a positive
      family history (+PH) of hypertension and 16 (age, 19 +/- 1 years) with a negative
      family history (-PH) underwent maximal exercise and cold pressor testing. Maximal
      exercise was conducted on a cycle ergometer. Quadriceps muscle pain intensity
      ratings were obtained each minute during the maximal exercise test by using a
      category-ratio scale. The hand cold pressor test was used to determine
      cardiovascular reactivity. Repeated measures analysis of variance showed
      significantly lower pain ratings during exercise for the +PH group compared to
      the -PH group. Psychophysical power functions indicated that the +PH participants
      had significantly lower exponents for pain throughout exercise. Systolic blood
      pressure reactivity did not significantly predict pain ratings during exercise.
      Normotensive African American women with +PH of hypertension experienced less
      muscle pain during exercise compared to normotensive African American women with
      a -PH of hypertension. The results are consistent with data demonstrating reduced
      sensitivity to experimental pain stimuli in individuals at risk for developing
      hypertension and extend them to naturally occurring muscle pain produced by
      exercise. PERSPECTIVE: African American women, a sedentary group with an elevated
      risk for developing hypertension and chronic pain, show the same negative
      relationship between +PH and pain perception as men, suggesting that central
      nervous system mechanisms of pain modulation are more related to family history
      than gender. Acute exercise provides an experimental model for manipulating
      naturally occurring pain in studies concerned with the association between pain
      and hypertension.

PMID- 15042521
TI  - Validation of the Brief Pain Inventory for chronic nonmalignant pain.
AB  - The Brief Pain Inventory (BPI; Cleeland and associates) has been used primarily
      to assess patients with cancer-related pain. Although it has been validated in
      many languages and is widely used, there has not yet been research published to
      validate its use for patients with chronic nonmalignant pain as the primary
      presenting problem. This study was designed to fill this gap by examining the
      psychometric properties of the BPI in 440 patients with chronic intractable pain
      referred to a chronic pain clinic at a metropolitan tertiary-care teaching
      hospital. Results indicated acceptable internal consistency (Cronbach alpha
      coefficients were.85 for the intensity items and.88 for the interference items).
      A factor analysis resulted in 2 distinct and independent factors, supporting the
      validity of the 2-factor structure of the BPI. Zero-order correlations indicated
      that the association with a measure of disability (the Roland-Morris Disability
      Questionnaire [RMDQ]) was significantly higher for BPI interference (r = 0.57)
      than for BPI intensity (r = 0.40, t = 5.71, P <.01) and that the correlation with
      BPI interference was not more than 0.80, supporting the conclusion that these
      scales assess related, but also distinct, dimensions. Finally, the finding that
      both BPI scales showed statistically significant improvement with treatment
      confirms the responsivity of BPI in detecting and reflecting improvement in pain
      over time. PERSPECTIVE: This paper validated the psychometric properties of a
      pain Assessment instrument (The Brief Pain Inventory) originally developed to
      assess cancer pain and extended its use for the chronic nonmalignant pain
      population. This provides an important and widely used diagnostic tool for the
      clinician treating chronic pain.

PMID- 15042520
TI  - Pain management of cancer patients with transdermal fentanyl: a study of 1828
      step I, II, & III transfers.
AB  - The aim of this observational study was to examine pain management outcomes and
      quality of life (QoL) measures in cancer patients with intolerable or chronic
      severe pain transferring from World Health Organization's step I, II, and III
      analgesics to the transdermal therapeutic fentanyl system (TTS-F). This study
      examines the safety and efficacy of TTS-F in long-term pain management,
      addressing the role of TTS-F in cancer pain. Pain measures were assessed in 1828
      patients (step I [naive], 268; step II [codeine], 1239; and step III [morphine],
      321) on the basis of selected questions from the Greek-Brief Pain Inventory.
      Overall treatment satisfaction (scale, 1 to 4), QoL, and European Collaborative
      Oncology Group (ECOG) status were also recorded. These were assessed in relation
      to TTS-F dose, stratified by transfer step, primary cancer, metastases, type of
      pain, and concomitant use of anti-inflammatory drugs. Of 1828 patients, 100
      (5.5%) withdrew, and an addition 14 (0.8%) discontinued because of side effects.
      A total of 1714 continued on study; 744 patients died, and 970 departed during
      the study period. In total, 93.8% were satisfied with their pain relief, and
      complete patient satisfaction was obtained within 2 months. Pain, QoL, and
      treatment satisfaction measures demonstrated statistically significant
      improvements over time, independent of the step transfer. Although doses of TTS-F
      were higher for step III > II > I and for metastatic than nonmetastatic, the
      median dose for all groups remained 50 microg/h throughout the study period. Pain
      and QoL improvements were independent of patient characteristic(s). Direct
      transfer to TTS-F for patients with intolerable or chronic moderate to severe
      cancer pain offers an efficient and safe long-term analgesic option for
      palliative care patients. Careful selection and follow-up by experienced
      palliative care specialists are mandatory. TTS-F as a first-line analgesic
      approach for severe cancer pain should be considered a viable option because of
      its durable efficacy and low incidences of side effects. PERSPECTIVE: At a fairly
      constant dose of 50 microg/h, the transdermal therapeutic fentanyl system offers
      a safe, well-tolerated pain relief treatment for carefully monitored patients
      with cancer pain. The authors stress that this includes patients who experience
      difficulties in their pain management while progressing through the WHO's ladder
      for pain management.

PMID- 15042523
TI  - Re: Hord ED et al. The effect of vagus nerve stimulation on migraines. J Pain.
      2003 Nov;4(9):530-4.

PMID- 15042522
TI  - Re: Rauck et al. Long-term intrathecal opioid therapy with a patient-activated,
      implanted delivery system for the treatment of refractory cancer pain. J Pain.
      2003 Oct;4(8):441-7.

PMID- 15042526
TI  - Introduction.

PMID- 15042527
TI  - Integrating monoclonal antibodies into the management of mantle cell lymphoma.
AB  - Patients with mantle cell lymphoma (MCL) have a particularly poor prognosis when
      treated with standard chemotherapy, with a median overall survival of only 3
      years. These patients have therefore been considered for first-line treatment
      with more aggressive or experimental strategies, such as high-dose therapy (HDT)
      with autologous stem cell transplantation (ASCT). While high rates of clinical
      remission have been achieved with HDT/ASCT, this procedure alone is not believed
      to be curative and different treatment strategies are being developed to improve
      outcomes in this group of patients. Single-agent rituximab is active in both
      newly diagnosed and relapsed MCL and therefore the addition of rituximab to
      chemotherapy regimens and/or HDT/ASCT may enhance their efficacy. Outside the
      transplantation setting, rituximab plus chemotherapy has been shown to be highly
      active in MCL, and preliminary data from randomized trials suggest that the
      combination may yield superior results compared with chemotherapy alone. The
      addition of rituximab to transplantation protocols appears to be a very promising
      strategy for patients with MCL, given as an in vivo purge before HDT/ASCT and/or
      as posttransplant maintenance therapy. Two phase II clinical trials with
      rituximab given as an in vivo purge during stem cell mobilization and as
      posttransplant immunotherapy in patients with previously untreated MCL have
      generated very promising data. Rituximab is an important addition to cytotoxic
      therapy and with HDT/ASCT represents a highly active therapy that may be superior
      to conventional treatment or HDT/ASCT alone in MCL. Randomized prospective
      studies and longer follow-up are needed to determine whether these regimens can
      achieve longer survival or possibly cure in this disease.

PMID- 15042528
TI  - Effective immunochemotherapy for aggressive non-Hodgkin's lymphoma.
AB  - In the past, CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine,
      prednisone) was considered the gold standard treatment for aggressive non
      Hodgkin's lymphoma (NHL). CHOP is only curative in approximately 40% of patients,
      and numerous clinical trials have been carried out to find a treatment that can
      increase the cure rate. For some patients with aggressive NHL, it is possible to
      improve survival by intensification of chemotherapy compared with standard CHOP.
      This approach is not appropriate for all patients, and careful patient selection
      is necessary to achieve benefit. Early high-dose treatment/autologous stem cell
      transplantation may be beneficial for some patients, but not in patients with low
      risk disease or those over 60 years of age who are not eligible for autologous
      stem cell transplantation. The most striking and consistent improvement over CHOP
      chemotherapy in the treatment of aggressive NHL is the addition of rituximab. A
      phase III randomized study Groupe d'Etudes des Lymphomes de l'Adulte (GELA LNH
      98.5) compared rituximab plus CHOP with CHOP alone in treatment of 399 patients
      aged 60 to 80 years of age with aggressive NHL. The addition of rituximab
      resulted in higher overall and complete response rates, and at a median follow-up
      of 3 years, event-free and overall survival were significantly higher in patients
      treated with rituximab plus CHOP compared with CHOP alone. The benefits of adding
      rituximab to CHOP were not restricted to a subgroup of patients, but were evident
      in patients with high- and low-risk disease. The addition of rituximab to CHOP
      also overcame bcl-2-associated resistance to chemotherapy. There is no standard
      chemotherapy regimen for relapsed patients, but results from several single-arm
      studies suggest the addition of rituximab will increase the complete response
      rate to many different salvage regimens. The development of newer treatment
      strategies incorporating rituximab may improve the cure rate further.

PMID- 15042529
TI  - Improving second-line therapy in aggressive non-Hodgkin's lymphoma.
AB  - The prognosis is poor for patients relapsing following treatment with standard
      chemotherapy for aggressive non-Hodgkin's lymphoma. High-dose therapy and
      autologous stem cell transplantation is a potential curative approach for these
      patients. The primary aim of second-line therapy is the attainment of a complete
      response, because response rate is predictive of outcome following autologous
      stem cell transplantation. A number of strategies have been explored to improve
      the complete response rate to standard second-line regimens. Ifosfamide,
      carboplatin, and etoposide (ICE) can offer an improved response rate compared
      with the standard regimens of dexamethasone, cisplatin, and cytarabine (DHAP) and
      etoposide, methylprednisolone, high-dose cytarabine, and cisplatin (ESHAP). The
      addition of rituximab to ICE improves the complete response rate compared with
      ICE alone. Because the addition of rituximab to chemotherapy regimens leads to
      improved complete response rates compared with chemotherapy alone, it should be
      considered as an important component of second-line regimens for aggressive NHL.

PMID- 15042530
TI  - Prolonging remission with rituximab maintenance therapy.
AB  - Maintenance therapy using rituximab is currently under consideration as a means
      of prolonging remission in patients with indolent non-Hodgkin's lymphoma. A phase
      II trial using rituximab as first-line therapy followed by maintenance treatment
      was carried out in patients with previously untreated indolent non-Hodgkin's
      lymphoma. The overall response rate improved from 47% (7% complete response)
      after initial treatment to 73% (37% complete response) after maintenance
      treatment; median progression-free survival was 37 months. A similar study in
      patients with previously untreated chronic lymphocytic leukemia or small
      lymphocytic lymphoma (SLL) also showed some improvement in response rates after
      maintenance therapy and a median progression-free survival of 19 months. The
      improved remission duration suggested in these phase II trials has been confirmed
      in a randomized, phase III trial performed by the Swiss Group for Clinical Cancer
      Research. Patients with follicular non-Hodgkin's lymphoma who had objective
      response or stable disease after a standard 4-week course of rituximab were
      randomized to either observation or further maintenance rituximab treatment.
      Median event-free survival was longer in patients who received maintenance
      therapy (23 v 12 months; P =.02). The toxicity of maintenance rituximab has been
      minimal in all trials to date. Although prolongation of progression-free survival
      has been shown in all completed trials, multiple other questions regarding
      maintenance rituximab are being addressed in ongoing trials. These include
      optimum schedule/duration, use after initial chemotherapy/rituximab combinations,
      efficacy versus retreatment at progression, and efficacy in other B-cell
      neoplasms.

PMID- 15042531
TI  - Advancing therapy for chronic lymphocytic leukemia--the role of rituximab.
AB  - Chronic lymphocytic leukemia (CLL) remains incurable despite decades of clinical
      trials. Some patients survive for long periods without requiring definitive
      therapy, while others die rapidly despite intensive treatment. Because most
      patients with CLL express CD20 on their malignant cells, the chimeric anti-CD20
      monoclonal antibody rituximab has been incorporated into treatment regimens in
      efforts to improve outcome. Rituximab monotherapy has limited activity in
      previously untreated and refractory/relapsed CLL patients with response rates
      that are generally lower than those seen in non-Hodgkin's lymphoma. Although
      increased dosing intensity and frequency leads to higher response rates than seen
      in patients treated with standard dose rituximab, responses are almost always
      partial remissions and the doses used are not feasible in routine clinical
      practice. On the other hand, combining rituximab with chemotherapy has proved to
      be feasible and appears to be synergistic with fludarabine-based chemotherapy in
      the treatment of CLL on the basis of recent phase II trials. In these studies,
      response rates (including complete remissions) to rituximab in combination with
      fludarabine-containing regimens are higher than those reported in similar phase
      II studies with any other treatment regime. The highest response rates reported
      are for the combination of rituximab, fludarabine, and cyclophosphamide. A
      randomized phase III trial has been initiated to evaluate the addition of
      rituximab to fludarabine and cyclophosphamide in patients with relapsed CLL. The
      combination of rituximab with other agents is also being investigated, and these
      ongoing trials will help define the role of rituximab in CLL.

PMID- 15042532
TI  - New treatment approaches to indolent non-Hodgkin's lymphoma.
AB  - Disseminated indolent non-Hodgkin's lymphoma (NHL) is considered incurable with
      conventional chemotherapy regimens, and more than 50% of patients die within 5
      years of their first relapse. Therefore, newer treatment approaches have been
      used to try to improve survival and ultimately provide a cure for patients with
      disseminated indolent NHL. The anti-CD20 monoclonal antibody rituximab has been
      extensively evaluated and is now an integral component of many treatment
      strategies. The activity of rituximab was first shown in the pivotal trial in
      patients with relapsed and refractory low-grade and follicular lymphoma. More
      recent studies have shown somewhat higher activity of rituximab when used first
      line, with further improvements with maintenance therapy. Rituximab in
      combination with chemotherapy has been shown to achieve high response rates, and
      two prospective randomized studies from the German Low-grade Lymphoma Study Group
      have shown significantly higher response rates and longer survival for patients
      receiving rituximab concurrently with chemotherapy compared with those receiving
      chemotherapy alone. Further data from ongoing phase III studies are still needed
      to determine whether rituximab can help alter the natural history of indolent
      NHL, and longer follow-up of these patients will help determine the optimal role
      for rituximab in treatment of indolent NHL.

PMID- 15042533
TI  - Clearing minimal residual disease with rituximab consolidation therapy.
AB  - Advanced follicular and mantle cell lymphoma are currently incurable using
      conventional chemotherapy. As such, new and potentially more effective
      therapeutic approaches such as high-dose chemotherapy with autologous stem cell
      transplantation (ASCT) and consolidation using various types of therapy are being
      increasingly considered. Rituximab has been assessed as an in vivo purge and as
      consolidation therapy both first-line and in relapsed patients with follicular
      and mantle cell lymphoma. Data from a number of studies are reviewed, focusing on
      our recently reported phase II study of patients with follicular or mantle cell
      lymphoma who received one standard course of rituximab consolidation therapy
      after ASCT to show that using rituximab in the context of high-dose chemotherapy
      and ASCT may improve patient outcomes without compromising tolerability.
      Specifically, purging and consolidation using rituximab can improve clinical and
      molecular response rates, may eliminate minimal residual disease, and may improve
      survival. These studies suggest that rituximab may have an important role in
      improving the outcome of ASCT in patients with follicular or mantle cell
      lymphoma.

PMID- 15042535
TI  - Effect of statins versus untreated dyslipidemia on serum uric acid levels in
      patients with coronary heart disease: a subgroup analysis of the GREek
      Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study.
AB  - BACKGROUND: Little is known about the effect of dyslipidemia on serum uric acid
      (SUA) levels, and less is known about the effect of statin treatment on them. The
      GREek Atorvastatin and Coronary-heart-disease Evaluation study suggested that a
      mean atorvastatin dose of 24 mg/d achieves the National Cholesterol Educational
      Program treatment goals and significantly reduces morbidity and mortality in
      patients with coronary heart disease (CHD) in comparison to the usual care. Here,
      we report the time course of SUA levels in usual-care patients undertreated for
      their dyslipidemia (12% were administered statins) in comparison to structured
      care patients treated with atorvastatin in the vast majority (98%). METHODS: Mean
      on-study SUA levels (up to 48 months) were compared with those at baseline by
      using analyses of variance to assess differences over time within and between
      treatment groups. Cox multivariate analysis was used to investigate whether
      changes in SUA levels during the study were clinically relevant. RESULTS: All
      patients had normal renal function at baseline; serum creatinine (SCr) levels
      less than 1.3 mg/dL (<115 micromol/L) and moderately elevated SUA levels (mean,
      7.1 +/- 0.9 [SD] mg/dL [425 +/- 52 micromol/L]; upper normal limit, 7.0 mg/dL
      [415 micromol/L]). Usual-care patients (n = 800) showed an increase in SUA levels
      by 3.3% ( P < 0.0001). Structured-care patients (n = 800) had an 8.2% reduction
      in SUA levels ( P < 0.0001). In all patients not administered diuretics (n =
      1,407), SUA level changes showed a positive correlation with changes in SCr
      levels ( r = 0.82; P < 0.0001) and an inverse correlation with estimated
      glomerular filtration rate ( r = -0.77; P < 0.0001). After adjustment for 19
      predictors of all CHD-related events, Cox multivariate analysis involving
      backward stepwise logistic regression showed a hazard ratio (HR) of 0.89 (95%
      confidence interval [CI], 0.78 to 0.96; P = 0.03) with every 0.5-mg (30
      micromol/L) reduction in SUA level, an HR of 0.76 (95% CI, 0.62 to 0.89; P =
      0.001) with every 1-mg (60-micromol/L) reduction, an HR of 1.14 (95% CI, 1.03 to
      1.27; P = 0.02) with every 0.5-mg increase, and an HR of 1.29 (95% CI, 1.17 to
      1.43; P = 0.001) with every 1-mg increase in SUA levels. CONCLUSION: Data suggest
      that SUA level is an independent predictor of CHD recurrent events. Atorvastatin
      treatment significantly reduces SUA levels in patients with CHD, thus offsetting
      an additional factor associated with CHD risk.

PMID- 15042536
TI  - Autosomal recessive renal proximal tubulopathy and hypercalciuria: a new
      syndrome.
AB  - BACKGROUND: The best described primary inherited proximal tubulopathies include X
      linked hypercalciuric nephrolithiasis (XLHN), caused by a mutation in the
      chloride channel gene CLCN5, and classic Fanconi's syndrome, the genetic basis of
      which is unknown. The aim of this study is to examine the clinical, biochemical,
      and genetic characteristics of a highly consanguineous Druze family with
      autosomal recessive proximal tubulopathy and hypercalciuria (ARPTH), a syndrome
      not reported previously. METHODS: Three children (2 girls, 1 boy) of the family
      referred for evaluation of renal glycosuria and hypercalciuria and 10 of their
      close relatives were evaluated clinically and biochemically. All study
      participants underwent genetic analysis to exclude involvement of the CLCN5 gene.
      RESULTS: Evaluation of the 3 affected children showed glycosuria, generalized
      aminoaciduria, hypouricemia, uricosuria, low molecular weight (LMW) proteinuria,
      and hypercalciuria in all 3 children and phosphaturia in 2 children. They had no
      metabolic acidosis or renal insufficiency. One affected girl had
      nephrocalcinosis. Two children had a history of growth retardation and
      radiological findings of metabolic bone disease. Parathyroid hormone and 1,25
      dihydroxyvitamin D [1,25(OH)2Vit D] blood levels in affected children were
      normal. Unaffected family members examined had no renal tubular defects or LMW
      proteinuria. Genetic linkage analysis excluded cosegregation of the ARPTH
      phenotype with the CLCN5 locus. CONCLUSION: ARPTH is a new syndrome characterized
      by nonacidotic proximal tubulopathy, hypercalciuria, metabolic bone disease, and
      growth retardation. It can be distinguished from XLHN by its autosomal recessive
      mode of inheritance and normal serum levels of calciotropic hormones, as well as
      the absence of LMW proteinuria in obligate carriers. The gene mutated in ARPTH
      remains to be identified.

PMID- 15042537
TI  - Resistance training to reduce the malnutrition-inflammation complex syndrome of
      chronic kidney disease.
AB  - BACKGROUND: Systemic inflammation and protein-energy malnutrition may be
      associated with poor outcomes in kidney disease. METHODS: We studied 26 adults
      (age, 65 +/- 10 [SD] years) with chronic kidney disease, not on dialysis therapy.
      Subjects were randomly assigned to resistance training (n = 14) or a control
      group (n = 12) for 12 weeks, while counseled to consume a low-protein diet
      (protein, approximately 0.6 g/kg/d). We determined whether resistance training
      reduces levels of inflammatory mediators (serum C-reactive protein [CRP] and
      interleukin-6 [IL-6]), in addition to previously reported improvements in
      nutritional and functional status in this same subject population. RESULTS: Serum
      CRP levels were reduced in subjects undergoing resistance training (-1.7 mg/L)
      compared with controls (1.5 mg/L; P = 0.05). Similarly, IL-6 levels were reduced
      in the resistance-exercise group versus controls (-4.2 versus 2.3 pg/mL; P =
      0.01). Resistance training lead to skeletal muscle hypertrophy, shown by
      increases in type I (24% +/- 31%) and type II (22% +/- 41%) muscle fiber cross
      sectional areas, compared with control subjects (-14% +/- 34% and -13% +/- 18%,
      respectively; P < 0.05). Muscle strength also improved with resistance training
      (28% +/- 14%) compared with controls (-13% +/- 22%; P = 0.001). CONCLUSION:
      Resistance training reduced inflammation and improved nutritional status in
      individuals with moderate chronic kidney disease consuming a low-protein diet.
      These results need to be investigated further in larger cohorts of patients with
      varying stages of kidney disease to determine whether resistance training can
      improve disease outcomes long term.

PMID- 15042538
TI  - Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic
      MPGN.
AB  - BACKGROUND: The influence of hepatitis C virus (HCV) treatment on the course of
      HCV cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) is
      controversial. METHODS: Twenty-five patients with nephrotic-range proteinuria,
      mixed cryoglobulinemia, MPGN proved by renal biopsy, and HCV infection were
      studied for their response to antiviral treatment. RESULTS: After first-line
      treatment with prednisone, furosemide, or plasmapheresis, antiviral therapy with
      standard or pegylated interferon alfa and ribavirin was introduced in 18
      patients. These patients were compared with 7 patients who did not receive
      antiviral treatment. Mean duration of antiviral treatment was 18 +/- 10 months,
      with a follow-up of at least 6 months after treatment withdrawal. HCV RNA
      clearance (sustained virological response) was achieved in 12 of 18 patients.
      Compared with values before antiviral therapy, a decrease in proteinuria was
      observed in sustained virological responders at the end of combination therapy,
      as well as at the end of follow-up (mean, 2.85 +/- 2.2 [SD] versus 1 +/- 1.4 and
      0.4 +/- 0.8 g/d, respectively; P < 0.05). In sustained virological responders,
      cryoglobulin levels at the end of treatment (0.29 +/- 0.4 g/L) and end of follow
      up (0.25 +/- 0.4 g/L) were decreased (P < 0.05) compared with pretreatment values
      (1.38 +/- 2.2 g/L). Conversely, no changes in serum cryoglobulinemia levels were
      observed in nonresponders or controls. Serum creatinine levels remained stable in
      the 18 patients with antiviral therapy, regardless of response to treatment.
      CONCLUSION: Anti-HCV treatment improved HCV-associated cryoglobulinemic
      glomerulonephritis.

PMID- 15042539
TI  - Patients with autosomal dominant polycystic kidney disease hyperfiltrate early in
      their disease.
AB  - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) ranks among the
      most common genetic disorders. The development of end-stage renal failure usually
      is after the fourth decade of life. Angiotensin-converting enzyme (ACE)
      inhibitors often are used as agents to slow the progression of renal failure,
      although their effectiveness and starting point in ADPKD remain unclear. METHODS:
      We measured technetium 99m diethylenetriamine pentaacetic acid glomerular
      filtration rate (GFR) and serum cystatin C (Cys-C) levels in 18 children with
      ADPKD and 41 control patients. Data are given as mean +/- SD. Mean age was 9.8 +/
      5.9 years, mean height was 137.5 +/- 34.3 cm, and mean weight was 39.2 +/- 22.8
      kg in the ADPKD group, not significantly different from controls, with an average
      age of 10.4 +/- 4.9 years, height of 138.0 +/- 26.1 cm, and weight of 38.0 +/-
      16.8 kg. RESULTS: Mean serum creatinine levels did not differ between the ADPKD
      (0.6 +/- 0.2 mg/dL [51.1 +/- 20.4 micromol/L]) and control groups (0.7 +/- 0.2
      mg/dL [59.8 +/- 15.3 micromol/L]; P = 0.19). Mean GFR was 142 +/- 33.2
      mL/min/1.73 m2 in the ADPKD group, significantly greater than that in controls
      (110 +/- 12 mL/min/1.73 m2; P < 0.0001). Mean Cys-C level for the ADPKD group was
      0.71 +/- 0.11 mg/L, significantly lower than that of controls (0.81 +/- 0.12
      mg/L; P = 0.0011). No patient with ADPKD had hypertension, and only 1 patient had
      minimal microalbuminuria. Although renal length on ultrasound was significantly
      increased, there was no correlation between renal length and GFR or number of
      cysts. CONCLUSION: Therefore, the high GFR measurements represent early
      hyperfiltration in children and adolescents with ADPKD, which may give a
      rationale to start ACE inhibitor therapy.

PMID- 15042540
TI  - The risk for mild kidney function decline associated with illicit drug use among
      hypertensive men.
AB  - BACKGROUND: Few studies have examined the deleterious effect of illicit drug use
      on kidney function. METHODS: Six hundred forty-seven patients enrolled in the
      Hypertension Clinic of the Veterans Administration Medical Center of New Orleans,
      LA, were interviewed regarding illicit drug use and followed up for a median of 7
      years to determine the incidence of mild kidney function decline (increase in
      serum creatinine level > or = 0.6 mg/dL [> or =53.0 micromol/L]) between 1977 and
      1999. RESULTS: Twenty-three percent of study participants reported the use of
      illicit drugs: 22.7%, marijuana; 6.7%, cocaine or crack; 9.3%, amphetamines;
      3.1%, psychedelics; and 4.3%, heroin. After adjustment for age, race, education,
      income, smoking, alcohol consumption, systolic blood pressure, use of
      antihypertensive medications, body mass index, and history of diabetes and
      dyslipidemia, relative risk for mild kidney function decline associated with any
      drug use was 2.3 (95% confidence interval, 1.0 to 5.1). After similar
      adjustments, risks for mild kidney function decline were 3.0 (95% confidence
      interval, 1.1 to 8.0) and 3.9 (95% confidence interval, 1.1 to 14.4) times
      greater among persons who had used cocaine and psychedelics, respectively. Use of
      marijuana, amphetamines, heroin, and other drugs was associated with elevated,
      but not statistically significant, risks for mild kidney function decline.
      CONCLUSION: Our study documented a significant, positive, and independent
      association between illicit drug use and risk for mild kidney function decline.
      This finding indicates that interventions aimed at helping patients discontinue
      illicit drug use and maintain a drug-free lifestyle may have an important role in
      delaying and/or preventing the onset of kidney disease in hypertensive men.

PMID- 15042541
TI  - Gene expression profiling in glomeruli from human kidneys with diabetic
      nephropathy.
AB  - BACKGROUND: Diabetic nephropathy (DN) is a frequent complication in patients with
      diabetes mellitus. To find improved intervention strategies in this disease, it
      is necessary to investigate the molecular mechanisms involved. To obtain more
      insight into processes that lead to DN, messenger RNA expression profiles of
      diabetic glomeruli and glomeruli from healthy individuals were compared. METHODS:
      Two morphologically normal kidneys and 2 kidneys from patients with DN were used
      for the study. Glomerular RNA was hybridized in duplicate on Human Genome U95Av2
      Arrays (Affymetrix, Santa Clara, CA). Several transcripts were tested further in
      independent patient groups and at the protein level by immunohistochemistry.
      RESULTS: Ninety-six genes were upregulated in diabetic glomeruli, whereas 519
      genes were downregulated. The list of overexpressed genes in DN includes
      aquaporin 1, calpain 3, hyaluronoglucosidase, and platelet/endothelial cell
      adhesion molecule. The list of downregulated genes includes bone morphogenetic
      protein 2, vascular endothelial growth factor (VEGF), fibroblast growth factor 1,
      insulin-like growth factor binding protein 2, and nephrin. A decrease in VEGF and
      nephrin could be validated at the protein level and also at the RNA level in
      renal biopsy specimens from 5 additional patients with diabetes. CONCLUSION:
      Results of oligonucleotide microarray analyses on control and diabetic glomeruli
      are presented and discussed in their relation to vascular damage, mesangial
      matrix expansion, proliferation, and proteinuria. Our findings suggest that
      progression of DN might result from diminished tissue repair capability.

PMID- 15042542
TI  - Transjugular kidney biopsy.
AB  - BACKGROUND: Most previous studies demonstrating the feasibility of transjugular
      kidney biopsy have used a modified Colapinto aspiration biopsy needle. We present
      25 high-risk patients, with contraindications to percutaneous renal biopsy, who
      underwent transjugular kidney biopsy using a transvenous side-cut needle. This
      technique is easier to learn and can be performed by an interventional
      radiologist with transjugular liver biopsy experience and equipment. The needle
      is designed for optimal cortical sampling but has a high incidence of capsular
      perforation. Elective coil embolization was used in selected patients to reduce
      the risk of bleeding. METHODS: We retrospectively reviewed the indications for
      obtaining renal histology, based on clinical presentation, and the specific
      indications for transjugular biopsy. Transjugular kidney biopsy was assessed for
      sampling effectiveness and adequacy, the impact of histology on patient
      management, and technique complication rates. RESULTS: Renal tissue was obtained
      in 23 cases, with diagnostic biopsies in 21 of 23 (91.3%). A mean of 3.5 cores
      were obtained with 9.9 glomeruli per procedure for light microscopy (range, 0 to
      32), 2.2 (range, 1 to 7) for electron microscopy, and adequate tissue for
      immunoflorescence available in 11 of 23 biopsies. Histology influenced patient
      management in all 23 cases. Capsular perforation was recorded in 73.9% (17 of 23)
      of cases with 6 undergoing elective coil embolization. Two major complications
      occurred, both in patients with multiple risk factors for bleeding. One required
      coil embolization of an arterio-calyseal system fistula. A further patient
      developed renal vein thrombosis 6 days after a failed transjugular kidney biopsy.
      CONCLUSION: Transjugular kidney biopsy provides a histological diagnosis in high
      risk patients, making an important contribution to patient management.

PMID- 15042543
TI  - A double-blind, placebo-controlled trial of intravenous iron dextran therapy in
      patients with ESRD and restless legs syndrome.
AB  - BACKGROUND: Restless legs syndrome (RLS) is a common disorder in patients with
      end-stage renal disease (ESRD) that causes motor agitation and insomnia. Because
      RLS has been associated with iron deficiency, we sought to investigate the
      effects of intravenous (IV) iron dextran on symptoms of RLS in a double-blind
      placebo-controlled trial. METHODS: Patients determined to have RLS by
      International RLS Study Group criteria were administered either iron dextran,
      1,000 mg, or normal saline IV in a blinded fashion. Patient demographic data were
      collected, and blood chemistry tests, liver function studies, serum iron levels,
      ferritin levels, and total iron-binding capacity were obtained at baseline and 1,
      2, and 4 weeks postinfusion. Side effects or adverse events to interventions were
      monitored, and RLS symptoms were assessed by a rating scale at the same
      intervals. RESULTS: Eleven patients were randomly assigned to the administration
      of iron dextran, and 14 patients to the administration of saline. RLS severity
      scores were slightly higher in the placebo group at baseline, but hemoglobin
      levels, iron stores, and other biochemical parameters did not differ. Although no
      change in symptoms were seen in the placebo-treated group, significant
      improvement in RLS symptom scores in response to iron dextran was seen 1 week
      after infusion (-2; interquartile range [IQR], -6 to -1; P = 0.03, Wilcoxon's
      rank sums), but was greatest at 2 weeks (-3; IQR, -5 to -2 compared with -1 to 0;
      P = 0.01). Salutary effects of iron persisted at 4 weeks, but were no longer
      statistically significant. The significant increase in serum ferritin levels and
      iron saturation observed in the iron dextran-treated group was not seen in the
      placebo-treated group. No differences in adverse events were noted between
      groups. CONCLUSION: High-dose iron dextran infusion is associated with a
      significant, but transient, reduction in symptoms of RLS in patients with ESRD.

PMID- 15042544
TI  - A low serum iron level is a predictor of poor outcome in hemodialysis patients.
AB  - BACKGROUND: Iron administration has been implicated as a cause of poor clinical
      outcome in maintenance hemodialysis (MHD) patients. However, the role of low iron
      levels in the clinical outcome of MHD patients is not clear. METHODS: We examined
      the predicting value of baseline serum iron level on prospective mortality and
      hospitalization in a cohort of all 1,283 MHD patients from 10 DaVita dialysis
      facilities in Los Angeles County, CA. RESULTS: Patients aged 57.8 +/- 15.2 years
      included 49% men, 45% Hispanics, 25% African Americans, and 53% patients with
      diabetes. During the first 3 months of the cohort, 97% of patients were
      administered erythropoietin (EPO) and 60% were administered intravenous iron
      (gluconate and/or dextran) at least once. During a 12-month follow-up, mortality
      was significantly greater (23%) in the lowest serum iron quartile (<45.3
      microg/dL [<8.1 micromol/L]) compared with other quartiles (10% to 12%).
      Multivariate Poisson and Cox models adjusted for demographic features, dialysis
      dose and vintage, serum albumin and ferritin and blood hemoglobin concentrations,
      and administered EPO and iron doses showed that both serum iron level and iron
      saturation ratio had significant, but inverse, associations with prospective
      mortality and hospitalization. There was a statistically significant trend toward
      greater rates of mortality and hospitalization with lower serum iron levels. This
      reverse association remained significant in a subcohort of 322 MHD patients after
      additional adjustments for comorbid conditions and serum C-reactive protein level
      to reflect inflammation. CONCLUSION: Low baseline serum iron indicators are
      associated with increased mortality and hospitalization in MHD patients
      independent of hemoglobin level, EPO and iron doses, indicators of nutrition and
      inflammation, and comorbid conditions. Clinical trials to examine the role of
      iron administration in improving morbidity and mortality by increasing serum iron
      levels in MHD patients are required.

PMID- 15042545
TI  - Marked reduction in the prevalence of hepatitis C virus infection in hemodialysis
      patients: causes and consequences.
AB  - BACKGROUND: The prevalence of hepatitis C virus (HCV) infection in hemodialysis
      (HD) patients has decreased significantly in the course of the past decade in
      most HD units. The objective of this study is to analyze the causes of this
      reduction and obtain additional information for the near future that could be of
      use for health services planning. METHODS: All patients who underwent HD in the
      Province of Cordoba, Spain, between January 1992 and December 2002 were studied.
      We analyzed annual exclusions from the HD program of HCV-positive patients
      (deaths and kidney transplantations) and inclusions (predialysis patients,
      patients with chronic graft rejection, and HD patients with acute HCV infection).
      The trend in the time series of measurements was calculated by means of
      exponential smoothing with 2 parameters. RESULTS: In December 1992, the
      prevalence of antibody to HCV (anti-HCV) was 24% (N = 54), whereas by December
      2002, it had decreased to 9.2% (N = 35). Of 657 predialysis patients included in
      the maintenance HD program, 2.8% (n = 19) were positive for anti-HCV. Annual mean
      incidence of acute HCV infection was 0.5%, and the median was 0.32%. Mean crude
      annual mortality rates were 12.2% for anti-HCV-positive patients versus 9.9% for
      anti-HCV-negative patients. The trend in this time series suggests that by 2006,
      the prevalence of anti-HCV in HD patients will be approximately 2.5%. CONCLUSION:
      Causes implicated in the reduction in prevalence of HCV infection in HD patients
      are a greater mortality rate, stabilization of the incidence of acute HCV
      infection, and a low percentage of HCV infection in predialysis patients. By the
      end of 2006, the rate of HCV infection in HD patients will be very close to that
      of the predialysis population.

PMID- 15042546
TI  - Glycoxidation and inflammation in renal failure patients.
AB  - BACKGROUND: Inflammation is common in patients with chronic renal failure and has
      been associated with the increased risk for cardiovascular disease (CVD) in this
      condition. Advanced glycoxidation end products (AGEs) are among the factors
      implicated in the inflammatory state of chronic renal failure. METHODS: In a
      cross-sectional study of 189 dialysis patients, we measured circulating levels of
      C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), vascular
      adhesion molecule-1 (VCAM-1), vascular endothelial growth factor (VEGF), and
      plasminogen activator inhibitor-1 (PAI-1) to test for possible relationships
      between them and serum AGE levels. In addition, these parameters were measured in
      a subgroup of 18 patients with chronic renal failure randomly assigned to a 4
      week diet, either low (L-AGE) or high (H-AGE) in AGE content. AGEs were measured
      by means of a monoclonal antibody against epsilonN-carboxymethyllysine. RESULTS:
      At baseline, serum AGE levels, as well as those for CRP, TNF-alpha, VCAM-1, and
      VEGF, were markedly elevated, although no correlation was found between AGE
      levels and the other markers. Dietary AGE modulation resulted in a significant
      decrease in levels of serum AGEs, CRP, and PAI-1 in the L-AGE group
      (approximately 35%, 44%, and 17%, respectively; P < 0.03), whereas only serum AGE
      levels increased significantly in the H-AGE group. VCAM-1 and TNF-alpha levels,
      although similar at baseline, became significantly lower in patients on an L-AGE
      compared with H-AGE diet (P < 0.05) at the end of the study. CONCLUSION: Data
      from the interventional phase of the study suggest that AGEs have a role in the
      initiation of the inflammatory state of chronic renal failure, which eventually
      leads to increased CVD. This finding opens the possibility for using anti-AGE
      strategies in the prevention and treatment of CVD in patients with chronic renal
      failure.

PMID- 15042547
TI  - Vascular access practice patterns in the New Zealand hemodialysis population.
AB  - BACKGROUND: Native arteriovenous fistula (AVF) prevalence varies significantly
      among different populations and countries. Physician practice patterns may have a
      strong influence on access type. We assessed differences in vascular access
      practice patterns across all treating centers in New Zealand. METHODS: Adult (age
      > or = 18 years) patients on hemodialysis therapy in the year ending September
      30, 2001, were studied from the Australian and New Zealand Dialysis and
      Transplant Association Registry. Multinomial logistic regression was used to
      assess factors associated with arteriovenous graft (AVG) and catheter use.
      RESULTS: Of 772 patients available for analysis, 461 patients (60%) underwent
      dialysis using an AVF; 122 patients (16%), an AVG; and 189 patients (24%), a
      catheter. On multivariable analysis, female sex (odds ratio, 5.92; P < 0.001),
      coronary artery disease (odds ratio, 1.89; P < 0.05), body mass index greater
      than 30 (odds ratio, 2.55; P < 0.05), and age (odds ratio, 1.03 per year
      increase; P < 0.001) were associated with an increased likelihood of AVG use.
      Maori and Pacific Island patients were less likely to use an AVG compared with
      Caucasians (odds ratio, 0.47; P < 0.05). Predictors of greater likelihood of
      catheter use were female sex (odds ratio, 3.9; P < 0.001), late referral (odds
      ratio, 1.60; P < 0.05), and age (odds ratio, 1.02 per year increase; P < 0.001).
      Proportions of access types varied significantly across the 7 treating centers
      (AVFs, 32% to 86%; AVGs, 2% to 32%; catheters, 9% to 33%; P < 0.001). After
      adjusting for confounding factors, significant differences persisted among access
      types in some centers and the national average. CONCLUSION: Certain patient
      characteristics, such as age and female sex, are associated strongly with
      increased AVG and catheter use. However, the significant variation in risk across
      centers suggests more attention needs to be given to physician practice patterns
      to increase AVF use rates.

PMID- 15042548
TI  - Temporal effects of dialysis on cognitive functioning in patients with ESRD.
AB  - BACKGROUND: Although dialysis has been shown to improve cognitive deficits
      resulting from uremia, little is known about potential temporal variations in
      cognitive measures between hemodialysis treatments. METHODS: We studied dialysis
      patients for possible fluctuations in attention and memory by using repeatable
      neuropsychological measures. Twenty patients undergoing hemodialysis on a thrice
      weekly dialysis schedule were assessed at intervals of 1, 24, and 67 hours after
      the last weekly hemodialysis session. For purposes of comparison, we also studied
      10 patients on continuous ambulatory peritoneal dialysis (CAPD) therapy at
      similar intervals. RESULTS: CAPD patients showed overall stable performance on
      measures of attention and memory. However, hemodialysis patients showed
      significant changes (P < 0.05) in auditory memory for both immediate and delayed
      recall, with the greatest impairment occurring 67 hours postdialysis.
      Hemodialysis patients also showed a significant change (P < 0.05) in attention
      between the second and third test periods, ie, 24 to 67 hours postdialysis, with
      the greatest impairment seen at the 67-hour assessment time. No relationship was
      found between performance on measures of cognition and levels of postdialysis
      fatigue in hemodialysis patients. CONCLUSION: CAPD patients showed cognitive
      stability, whereas hemodialysis patients showed temporal fluctuations in
      cognitive performance.

PMID- 15042549
TI  - Hyperphosphatemia in Chinese peritoneal dialysis patients with and without
      residual kidney function: what are the implications?
AB  - BACKGROUND: Hyperphosphatemia is an important predictor for mortality in
      hemodialysis patients. This study evaluated significant factors associated with
      hyperphosphatemia in peritoneal dialysis (PD) patients. METHODS: We estimated
      residual renal function (RRF), dialysis adequacy, and normalized protein
      equivalent nitrogen appearance (nPNA), together with simultaneous measurement of
      serum phosphorus levels in 252 prevalent Chinese continuous ambulatory peritoneal
      dialysis (CAPD) patients. RESULTS: Average serum phosphorus level was 5.2 +/- 1.5
      mg/dL (1.68 +/- 0.48 mmol/L). Serum phosphorus levels were 5.6 mg/dL or greater
      (> or =1.81 mmol/L) in 44.0% of anuric patients (n = 116) versus 28.7% of
      patients with RRF (n = 136; P = 0.012). Patients with RRF maintained serum
      phosphorus levels at or less than the median value (< or =5.1 mg/dL [< or=1.65
      mmol/L]), with a total creatinine clearance (CCr) of 72 +/- 25 L/wk/1.73 m2 and
      nPNA of 0.94 +/- 0.19 g/kg/d in contrast to a total CCr of 63 +/- 22 L/wk/1.73 m2
      (P = 0.031) and nPNA of 1.03 +/- 0.22 g/kg/d (P = 0.011) in patients with serum
      phosphorus levels greater than the median value. Among anuric patients, total
      CCrs were 46 +/- 9 and 42 +/- 7 L/wk/1.73 m2 (P = 0.005) and nPNA values were
      0.89 +/- 0.17 and 0.98 +/- 0.18 g/kg/d (P = 0.010) for patients with serum
      phosphorus levels at the median value or less and greater than the median value,
      respectively. Multiple regression analysis showed that residual glomerular
      filtration, despite an average of less than 2 mL/min/1.73 m2, was independently
      associated with phosphorus control in PD patients. nPNA, PD CCr or urea
      clearance, body mass index, and parathyroid hormone level were other important
      correlates of serum phosphorus levels in patients with and without RRF.
      CONCLUSION: Hyperphosphatemia is a frequent complication in Chinese CAPD
      patients. Our study not only shows the importance of RRF in maintaining serum
      phosphorus levels in PD patients, but also the limitations of PD alone to achieve
      adequate phosphorus control in anuric patients.

PMID- 15042550
TI  - Abnormal cardiac function in children after renal transplantation.
AB  - BACKGROUND: Cardiac hypertrophy frequently is found in children with a renal
      transplant. In adults with a transplant, left ventricular (LV) mass (LVM) is
      associated with cardiac dysfunction. However, in children with a transplant, the
      relationship between LVM and LV function has not been evaluated. METHODS: Twenty
      nine children who underwent transplantation and 33 controls had echocardiographic
      evaluations during rest and peak exercise. LV contractility was determined based
      on the relation between heart rate-corrected velocity of circumferential fiber
      shortening and end-systolic wall stress. Contractile reserve was assessed by the
      difference between contractility at rest and peak exercise. Early diastole was
      assessed using indices of LV relaxation derived from transmitral and tissue
      Doppler and reported as maximal early (E wave) and late (A wave) wave ratio (E-A
      ratio) and septal mitral annular velocities (Em). Late diastole was determined
      using an index of LV compliance (E-Em ratio). RESULTS: Compared with controls,
      children with a transplant had a significantly greater LVM index (P < 0.001) and
      high prevalence of LV hypertrophy (LVH; 55%). Transplant recipients had increased
      LV contractility (P < 0.001). Contractile reserve was similar to that of
      controls. Patients with a transplant had a lower E-A ratio and Em (P < 0.01 for
      both variables) and higher E-Em ratio (P < 0.001) than controls. In children with
      a transplant, LVM index was a significant independent predictor for both abnormal
      LV relaxation (Em; P = 0.03) and abnormal LV compliance (E-Em ratio; P = 0.02).
      CONCLUSION: Results show impaired cardiac structure and diastolic function in
      pediatric renal allograft recipients. This suggests that LVH may be a risk factor
      for diastolic dysfunction in these children.

PMID- 15042551
TI  - Infantile steroid-resistant nephrotic syndrome associated with double homozygous
      mutations of podocin.
AB  - Mutations of NPHS2, ie, the gene coding for podocin, are associated with
      nephrotic syndrome (NS) in children, with a clinical phenotype characterized by
      variable age at onset (from 1 to 10 years) and steroid/cyclosporine resistance.
      The authors describe an infantile variant in 2 families (3 patients) from Turkey,
      characterized by homozygosity of a complex haplotype, in which 2 podocin
      mutations (P20L-R168H) are present in cis. It results from the insertion of a new
      mutation (R168H), only found in Turkey, on a more ancient haplotype containing
      the P20L mutation observed in the European population. All patients described had
      presented with NS within the first 6 months of life with strict resistance to
      drugs and a histologic background of focal segmental glomerulosclerosis. This is
      the first description of double homozygous mutations in an autosomal recessive
      renal disease reported in the literature. The association with infantile NS
      widens the panel of clinical presentation related to NPHS2 mutations.

PMID- 15042552
TI  - Intravascular embolization therapy in a patient with an enlarged polycystic
      liver.
AB  - Because the kidneys in patients with autosomal dominant polycystic kidney disease
      (ADPKD) are usually supplied by well-developed arteries, the authors attempted
      renal contraction therapy in such patients with renal transcatheter arterial
      embolization (TAE) using intravascular coils. In most patients with marked
      nephromegaly, renal TAE was effective. However, in patients with marked
      hepatomegaly without significant nephromegaly, renal TAE was not effective, and
      hepatic treatment was always required. In June 2001, the authors obtained
      approval for a new treatment,"TAE for enlarged polycystic liver," from an ethics
      committee discussing new treatment at their hospital. A 56-year-old man
      undergoing hemodialysis for 2 months was referred to the authors' institute with
      the complaint of severe abdominal distension and loss of appetite in March 2001.
      Most of the liver (about 90%) had been replaced by multiple cysts, and near
      intact hepatic parenchyma was quite scarce. The kidneys were quite small compared
      with the liver. Angiography results showed that almost all hepatic arterial
      branches were well developed, although most of the portal vein was obstructed,
      and only the left medial portal vein was spared; the former corresponded to the
      hepatic region replaced by multiple cysts and the latter to the preserved intact
      hepatic parenchyma. The target of TAE was the hepatic arterial branches of the
      former. Microcoils were used as embolization material. Two years after TAE,
      abdominal distension has markedly decreased because of decrease in liver size (to
      54% of the previous value), and muscle and fat volume in the thoracic region have
      increased owing to improvement of appetite. Ascites became obscure. Nutrition and
      activities of daily living have improved. Hepatic TAE may be an option for
      treatment of patients in poor condition with symptomatic polycystic liver.

PMID- 15042553
TI  - Hypertension in the hemodialysis patient and the "lag phenomenon": insights into
      pathophysiology and clinical management.

PMID- 15042555
TI  - An unusual cause of gross hematuria and transient ARF in an SLE patient with
      warfarin coagulopathy.

PMID- 15042557
TI  - Late referral and access to renal transplantation.

PMID- 15042558
TI  - The access situation in the United Kingdom.

PMID- 15042560
TI  - Quiz page. HIV-associated nephropathy is the overwhelmingly most likely
      diagnosis.

PMID- 15042564
TI  - Treatment of intoxication with Cortinarius speciosissimus using an antioxidant
      therapy.
AB  - The authors present the case reports of a 30-year-old man and his 29-year-old
      wife who ingested a mushroom meal containing Cortinarius speciosissimus. Features
      of this intoxication include gastrointestinal symptoms such as nausea, vomiting,
      and diarrhea as well as back pain. The toxin orellanine is nephrotoxic and can
      lead to acute renal failure. A long symptom-free interval of 2 to 21 days is
      characteristic of this poisoning. The diagnosis can be made by mycologic testing
      or by toxicologic analysis of a renal biopsy specimen. Reported therapeutic
      options include hemodialysis, plasmapheresis, or drug therapy with
      corticosteroids, all of which have yielded variable results. Here the authors
      report the use of antioxidant therapy in 2 patients with acute renal failure
      caused by Cortinarius speciosissimus intoxication.

PMID- 15042565
TI  - Azurocidin-specific-ANCA-related idiopathic necrotizing crescentic
      glomerulonephritis.
AB  - An 80-year-old woman who had rapidly progressive glomerulonephritis unaccompanied
      by systemic vasculitis is described. On renal biopsy, she showed necrotizing
      crescentic glomerulonephritis by light microscopy and pauci-immune glomerular
      lesions by immunofluorescent study. No dense deposits were present on
      electronmicroscopic study. On serum examination, indirect immunofluorescent study
      showed perinuclear pattern antineutrophil cytoplasmic antibody (ANCA), but
      myeloperoxidase-ANCA and proteinase 3-ANCA were both negative. Her serum reacted
      only to azurocidin excluding other ANCA antigens: bactericidal permeability
      increasing protein, cathepsin G, elastase, lactoferrin, or lysozyme. Serum
      creatinine level decreased, and C-reactive protein turned negative after steroid
      therapy. Azurocidin-ANCA also turned negative. It is suggested that azurocidin
      ANCA might have been related to the inflammatory process of pauci-immune
      necrotizing crescentic glomerulonephritis in this patient.

PMID- 15042566
TI  - DNA adducts and p53 mutations in a patient with aristolochic acid-associated
      nephropathy.
AB  - BACKGROUND: Aristolochic acid-associated nephropathy (AAN) is a specific type of
      renal disease that predisposes patients to a high risk of urothelial carcinoma.
      The authors have analyzed DNA from a patient who had urothelial malignancy 6
      years after presenting with AAN and later had a breast carcinoma that
      metastasized to the liver. METHODS AND RESULTS: DNA was isolated from the primary
      breast tumor, the liver tumor, and the original urothelial malignancy and assayed
      for aristolochic acid (AA)-DNA adducts and mutations in the p53 gene. The adduct
      detected was the adenosine adduct of aristolochic acid I 7-(deoxyadenosin-N6
      yl)aristolactam I (dA-AAI). In DNA from the breast and liver tumors the authors
      showed the same missense mutation in codon 245 (GGC-->GAC; Gly-->Asp) of exon 7
      of p53. In contrast, DNA extracted from the urothelial tumor showed an AAG to TAG
      mutation in codon 139 (Lys-->Stop) of exon 5. CONCLUSION: A to T transversions,
      as observed here, are the typical mutations observed in the H-ras gene of tumors
      induced when rodents are treated with AA and correspond with DNA adduct formation
      at adenosine residues. These data indicate the probable molecular mechanism
      whereby AA causes urothelial malignancy.

PMID- 15042567
TI  - Restoration of motor function of the deep fibular (peroneal) nerve by direct
      nerve transfer of branches from the tibial nerve: an anatomical study.
AB  - Traction injuries of the common fibular (peroneal) nerve frequently result in
      significant morbidity due to tibialis anterior muscle paralysis and the
      associated loss of ankle dorsiflexion. Because current treatment options are
      often unsuccessful or unsatisfactory, other treatment approaches need to be
      explored. In this investigation, the anatomical feasibility of an alternative
      option, consisting of nerve transfer of motor branches from the tibial nerve to
      the deep fibular nerve, was studied. In ten cadaveric limbs, the branching
      pattern, length, and diameter of motor branches of the tibial nerve in the
      proximal leg were characterized; nerve transfer of each of these motor branches
      was then simulated to the proximal deep fibular nerve. A consistent, reproducible
      pattern of tibial nerve innervation was seen with minor variability. Branches to
      the flexor hallucis longus and flexor digitorum longus muscles were determined to
      be adequate, based on their branch point, branch pattern, and length, for direct
      nerve transfer in all specimens. Other branches, including those to the tibialis
      posterior, popliteus, gastrocnemius, and soleus muscles were not consistently
      adequate for direct nerve transfer for injuries extending to the bifurcation of
      the common fibular nerve or distal to it. For neuromas of the common fibular
      nerve that do not extend as far distally, branches to the soleus and lateral head
      of the gastrocnemius may be adequate for direct transfer if the intramuscular
      portions of these nerves are dissected. This study confirms the anatomical
      feasibility of direct nerve transfer using nerves to toe-flexor muscles as a
      treatment option to restore ankle dorsiflexion in cases of common fibular nerve
      injury.

PMID- 15042568
TI  - Topography and interactions of the arytenoid and cricoid articular facets:
      implications for vocal process positional shifts.
AB  - Using new computer applications and digital technologies, we provide a rigorous
      description and realistic illustrations of the arytenoid-on-the cricoid
      rotations. We also provide the articular facet topography and interactions that
      underlay those rotations and the concomitant vocal process positional shifts. The
      thyroid cartilage and all soft tissues were removed from three excised,
      preserved, normal, adult human larynges without disturbing the crico-arytenoid
      (CA) articular capsule. Three CA assemblies were thus prepared and used to
      digitize arytenoid rotations and vocal process positional shifts, and, after
      disarticulation, also the surface contour of the arytenoid and cricoid facets,
      and the cricoid lumen margin. The digitized data served to computer generate 2D
      and 3D graphic visualizations of the vocal process positional shifts, of the
      topography of the facets, and of the facet motion sequences that show that the
      anteroposteriorly concave arytenoid facet slides and conjunctly rotates on the
      anteroposteriorly convex cricoid facet. Visual details of all graphic
      representations and facet motion sequences were essentially identical across the
      three assemblies. Then, based on the computer generated data obtained from the
      largest of the CA assemblies, 3D, realistic, and hand-drawn images were made that
      illustrate the directions in which the arytenoids can rotate and the vocal
      processes concomitantly shift positions. Results indicate that when the
      arytenoids rotate by sliding from anterior to posterior on the cricoid facets
      about a primary axis of motion aligned from medial, posterior, and superior, to
      lateral, anterior, and inferior, their vocal processes shift positions along a
      plane obliquely oriented from anterior and medial, to posterior and lateral, and
      from inferior and medial, to superior and lateral.

PMID- 15042569
TI  - Vascular pedicles of infrahyoid muscles: an anatomical study.
AB  - This study was designed to determine the entering sites of vascular pedicles of
      the infrahyoid muscles. The neck regions of 12 cadavers were investigated
      bilaterally. The vascular pedicles of the infrahyoid muscles (except the
      thyrohyoid and inferior belly of the omohyoid muscle) were dissected and
      measurements taken with a caliper in reference to the attachments of the muscles.
      For the sternothyroid muscle, two vascular pedicles were found bilaterally in all
      cadavers. Two vascular pedicles were found bilaterally for the sternohyoid muscle
      in 11 cadavers; in one cadaver the inferior vascular pedicle was absent
      bilaterally. One vascular pedicle was found bilaterally for the superior belly of
      the omohyoid muscle in all cadavers. These data regarding the vascular pedicles
      of the infrahyoid muscles might be useful for preserving the vascular supply of
      the infrahyoid muscles during flap preparation.

PMID- 15042570
TI  - Lateral costal artery: accessory thoracic vessel of clinical interest.
AB  - The lateral costal artery (LCA), a supernumerary branch of the internal thoracic
      artery (ITA), occurs in several ethnic groups on one side of the thorax or on
      both, in 15-30% of cases. It has been considered responsible for the "steal
      syndrome" of the coronary blood after coronary artery bypass grafting and it used
      occasionally for myocardial revascularization. To clarify its functional
      significance, an interpretation based on our findings and human and comparative
      anatomy and embryology has been attempted. We report on a case where a right LCA
      of about 2 mm in caliber, rising from the ITA 2.5 cm below the subclavian,
      coursed as far as the 4th intercostal space for a distance of 13 cm after the
      anterior axillary line. Anastomosing with the intercostal arteries, it can act as
      a blood derivative circuit of the thoracic wall. Embryologically, this artery,
      like the normal parietal arteries of the trunk, might form a longitudinal channel
      connecting the intersegmental arteries. In mammals having a thoracic cage
      transversely restricted (quadrupeds), the ITA is more lateral than in primates
      having a circular thorax, and gives off a ventral branch toward the sternum. It
      might be hypothesized that the sternal branch occurring in quadrupeds, undergoing
      adaptation to the thoracic shape of primates, may become the main trunk of the
      ITA, whereas the LCA may be the remnant of the ITA of quadrupeds. Because the LCA
      ran partly along the "milk line" of humans, it might be regarded as a
      supernumerary mammary artery.

PMID- 15042571
TI  - Histological changes in radial forearm skin flaps in the oral cavity.
AB  - We reported previously that skin flaps transplanted to the oral cavity in
      reconstructive surgery for oral cancer frequently acquired the gross appearance
      of buccal mucosa. The changes were shown to be reactive in nature. The "changed"
      flaps generally had a heavier infiltration of leukocytes in the dermis and
      appeared to have thicker epithelium. The present study quantifies these
      parameters, as well as the numbers of intraepithelial leukocytes. The flaps that
      had acquired the gross appearance of oral mucosa had significantly thicker
      epithelium, larger numbers of dermal leukocytes, and more intraepidermal
      inflammatory cells per unit length than flaps that retained the gross appearance
      of thin skin. No correlation was found between these changes and radiotherapy.

PMID- 15042572
TI  - Multiple arterial variations in the upper limb of a South Indian female cadaver.
AB  - In a routine dissection of a female cadaver, a variation in the course of the
      radial artery in the cubital fossa and a communication between the brachial
      artery and radial artery were observed. A rare origin and course of the median
      artery was also found. These anomalies are discussed in detail and their clinical
      relevance is highlighted.

PMID- 15042573
TI  - Study on the anatomical dimensions of the human sigmoid colon.
AB  - Although the sigmoid colon is commonly afflicted with disease, studies on its
      anatomical dimensions are scarce. It is suspected that dimensions of the sigmoid
      colon change with age. This study documents data on the anatomical measurements
      of the sigmoid colon in 70 Indian subjects (51 live and 19 cadavers). Seven
      parameters of sigmoid colon anatomy measured included length and width of the
      sigmoid colon and mesocolon at specific points. Three mesocolic indices (width to
      length ratios) were calculated. Comparisons of measurements in the live and
      cadaver subjects and in the two sexes were made. The relationship of change in
      parameters with age was assessed. Appropriate statistical methods were used and
      the differences were considered significant at P < or = 0.05. The study showed
      wide ranging variations in the values of various measured parameters of the
      sigmoid colon. Seven patterns of the shape of the sigmoid loop were identified.
      In the commonest pattern the sigmoid mesocolon was vertically longer than wide
      (dolichomesocolic), the sigmoid loop having its maximum convexity located just a
      little proximal to the apex. Patterns where the width of the mesocolon was
      greater than the vertical length (brachymesocolic) were also observed. The gender
      analysis showed that the sigmoid mesocolon of the female was brachymesocolic
      (wider than long), whereas that of the male was dolichomesocolic (longer than
      wide). This might explain the higher incidence of sigmoid volvulus in the male.
      This study also showed that the measurements of the sigmoid colon and its
      mesocolon do not change significantly within the age range of 16-60 years in the
      two sexes. Also noteworthy is the observation that in the cadaver the sigmoid
      colon shows considerable shrinkage, particularly of its mesocolon; consequently
      the data from cadaver subjects, though valuable for anthropometric use, have
      limitations when used for clinical applications.

PMID- 15042575
TI  - Detailed anatomy of the abdomen and pelvis of the visible human female.
AB  - We report on a virtual anatomical preparation of the abdomen and pelvis of the
      Visible Human Female (VHF) for laparoscopic surgery training. The detailed cross
      sectional image data set from the U.S. National Library of Medicine was used as
      the basis to build an exemplary model of the female abdomen and pelvis.
      Segmentation software was developed to delineate organ outlines and more than 300
      structures of interest, including organs, blood vessels, bones, muscles, and
      ligaments, have been segmented and three-dimensionally reconstructed. Analyzing
      the normal anatomy we found several variations and pathologies of the VHF, such
      as missing muscles (gemellus superior, psoas minor), additional veins as well as
      spondylophytes (vertebral column, pubic bone), and colon diverticula. The
      complete data set may be viewed on the home page of the project
      (http://www.vision.ee.ethz.ch/projects/Lasso/start.html).

PMID- 15042574
TI  - The broad ligament: a review of its anatomy and development in different species
      and hormonal environments.
AB  - The broad ligament is a double fold of peritoneum forming a mesentery for the
      human female genital tract. We investigated the anatomy of the broad ligament in
      different species and its hormonal regulation to determine if it had a role in
      gonadal positioning. The medical and veterinary literature was reviewed for
      descriptions of broad ligament anatomy and development. In addition, four adult
      female rats were dissected to compare the macroscopic anatomy of the broad
      ligament with any homologous structures in the male (n = 2). Detailed review was
      made of human males with persistent Mullerian duct syndrome (PMDS) and of bovine
      freemartin calves to determine the effect of abnormal hormonal environments on
      broad ligament development. Human and veterinary texts show variable broad
      ligament development between species, most being consistent with the size and
      shape of the uterus and uterine tubes. The broad ligament in adult female rats is
      a simple peritoneal fold and is homologous with the mesentery of the testis and
      vas deferens in males. Patients with PMDS and bovine freemartins have a broad
      ligament with intermediate anatomy. In PMDS the broad ligament is elongated and
      narrow, and not attached to the pelvic wall. The broad ligament is the mesentery
      of the genital ducts, and its anatomy varies with the degree of Mullerian duct
      fusion. The absence of a human male homologue is unusual, as the genital
      mesentery persists in male rodents. Apparent lack of a male homologue in the
      human may relate to obliteration of the processus vaginalis. The variable
      development of the broad ligament in pathological conditions is consistent with a
      role for steroid hormones in its development.

PMID- 15042576
TI  - New views of male pelvic anatomy: role of computer-generated 3D images.
AB  - There is considerable controversy concerning the role of cadaveric dissection in
      teaching gross anatomy and the potential of using 3D computer-generated images to
      substitute for actual laboratory dissections. There are currently few high
      quality 3D virtual models of anatomy available to evaluate the utility of
      computer-generated images. Existing 3D models are frequently of structures that
      are easily examined in three dimensions by removal from the cadaver, i.e., the
      heart, skull, and brain. We have focused on developing a 3D model of the pelvis,
      a region that is conceptually difficult and relatively inaccessible for student
      dissection. We feel students will benefit tremendously from 3D views of the
      pelvic anatomy. We generated 3D models of the male pelvic anatomy from hand
      segmented color Visible Human Male cryosection data, reconstructed and visualized
      by Columbia University's in-house 3D Vesalius trade mark Visualizer.(1) These 3D
      models depict the anatomy of the region in a realistic true-to-life color and
      texture. They can be used to create 3D anatomical scenes, with arbitrary
      complexity, where the component anatomical structures are displayed in correct 3D
      anatomical relationships. Moreover, a sequence of 3D scenes can be defined to
      simulate actual dissection. Structures can be added in a layered sequence from
      the bony framework to build from the "inside-out" or disassembled much like a
      true laboratory dissection from the "outside-in." These 3D reconstructed
      anatomical models can provide views of the structures from new perspectives and
      have the potential to improve understanding of the anatomical relationships of
      the pelvic region
      (http://www.cellbiology.lsuhsc.edu/People/Faculty/Venuti_Figures/movie_index.html
      .

PMID- 15042577
TI  - Unilateral occurrence of a chondroepitrochlearis muscle.
AB  - An abnormal muscle slip was encountered during routine dissection studies of a
      male cadaver. According to its origin, attachment and innervation, the abnormal
      slip was identified a chondroepitrochlearis muscle. Arterial and nervous supply
      were from the lateral thoracic artery and the medial pectoral nerve,
      respectively. Furthermore, no axillary arch muscle was observed. In addition, an
      abnormality in the attachment of the pectoralis major muscle was observed.

PMID- 15042578
TI  - Femoral head of the rectus femoris muscle.
AB  - Variability of the muscles of the anterior thigh is minimal. After review of the
      extant medical literature, we believe this to be the first reported case of a
      femoral head of the left and right rectus femoris muscles. In addition to this
      anomaly, our anatomic specimen demonstrated an accessory head of the right
      brachialis muscle and the quadratus plantae muscles inserted into the tendons of
      both the flexor hallucis longus and flexor digitorum longus. In clinical
      practice, knowledge of the possibility of an anomalous accessory femoral head of
      the rectus femoris muscle in clinical practice would be useful for those who
      might palpate this unusual muscle or encounter it surgically.

PMID- 15042579
TI  - Fibrillar prion peptide (106-126) and scrapie prion protein hamper phagocytosis
      in microglia.
AB  - The inflammatory response in prion diseases is dominated by microglial
      activation. As macrophages of the central nervous system, the phagocytic capacity
      of microglia is well recognized, and it is possible that microglia are involved
      in the removal and processing of amyloid fibrils, thus preventing their harmful
      effect. We have analyzed the effects of a synthetic peptide of the human prion
      protein, PrP(106-126), which can form fibrils, and the pathogenic form of prion
      protein, PrPsc, on phagocytosis in microglia isolated from neonatal rat brain
      cultures. To some extent, fibrillar PrP(106-126) is internalized and processed.
      However, both synthetic prion peptide PrP(106-126) in a fibrillar form and
      pathogenic prion protein PrPsc severely hamper the phagocytic activity as
      measured by the uptake of beads by microglia. At a concentration that does not
      induce microglial death, PrP(106-126) reduced the number of beads internalized
      and altered their cytoplasmic distribution. This effect was not due to decreased
      binding of beads to the cell surface, nor restricted to specific classes of
      receptors. Although the PrP(106-126) did not prevent F-actin and Rac1
      accumulation at sites of particle engulfment, it appeared to interfere with a
      later step of the internalization process.

PMID- 15042580
TI  - Prostaglandin E(2) and 6-keto-prostaglandin F(1alpha) production is elevated
      following traumatic injury to sciatic nerve.
AB  - Sciatic nerve explants cultured either alone or in the presence of peritoneal
      macrophages were used to study prostaglandin E(2) (PGE(2)) and 6-keto-PGF(1alpha)
      production following traumatic peripheral nerve injury. Although barely
      detectable at early time points (1-3 h in vitro), the production of PGE(2) and 6
      keto-PGF(1alpha) by sciatic nerve explants increased significantly after 18 h and
      remained elevated for up to 96 h. The cyclooxygenase-2 (COX-2) selective
      inhibitor, NS-398, inhibited PGE(2) and 6-keto-PGF(1alpha) production by injured
      sciatic nerve in a dose-dependent manner. Consistent with the observed effect of
      NS-398, peripheral nerve explants, as well as Schwann cells and perineural
      fibroblasts cultured from neonatal sciatic nerve, each contained COX-2
      immunoreactivity after 24 h in vitro. Both Schwann cells and perineural
      fibroblasts produced significant amounts of PGE(2) and 6-keto-PGF(1alpha); but
      only in the presence of arachidonic acid. As observed for injured sciatic nerve,
      the production of PGE(2) and 6-keto-PGF(1alpha) by primary Schwann cells and
      perineural fibroblasts was completely inhibited by NS-398. Compared to
      macrophages cultured alone, macrophages cultured in the presence of sciatic nerve
      explants produced large amounts of PGE(2), whereas the level of 6-keto
      PGF(1alpha) was unchanged. In contrast, macrophages treated with adult sciatic
      nerve homogenate did not produce significant amounts of either PGE(2) or 6-keto
      PGF(1alpha) during the entire course of treatment. We conclude that injured
      sciatic nerves produce PGE(2) and 6-keto-PGF(1alpha) by a mechanism involving COX
      2 activity and that macrophages produce large amounts of PGE(2) in response to
      soluble factors produced by injured nerve but not during the phagocytosis of
      peripheral nerve debris.

PMID- 15042581
TI  - Astrocyte cultures from conditional connexin43-deficient mice.
AB  - Connexin43 (Cx43) mainly provides the molecular basis for astrocytic gap
      junctions. Interastrocytic coupling is thought to mediate extracellular ion
      homeostasis, long-range signaling, and neuroprotection in the brain. Cx43 has
      been implicated in astrocytic growth control and is also expressed in other cell
      types in the brain, such as leptomeningeal and vascular cells. Cx43 function has
      been studied in astrocyte cultures of Cx43-deficient mice, which lack Cx43 in all
      cell types. We have generated conditionally deficient mice with an astrocyte
      directed inactivation of Cx43, which leaves expression in other cell types
      unaffected. Other connexins have been detected in astrocytes. For the study of
      astrocytes lacking Cx45 and Cx26 in vitro, which deficiencies are embryonic
      lethal, conditionally deficient astrocyte cultures are essential. In the present
      study, we describe the developmental kinetics of Cx43 inactivation and loss of
      intercellular communication in astrocyte cultures derived from conditional Cx43
      deficient mice. Conditional ablation of Cx43 is efficient, reaches a plateau at 4
      weeks in culture, but retains Cx43 expression in contaminating nonastrocytic
      cells. Our findings indicate that conditional knockout astrocytes are a promising
      tool for the study of embryonic lethal genes in astrocyte cultures.

PMID- 15042582
TI  - Microglia expressing interleukin-13 undergo cell death and contribute to neuronal
      survival in vivo.
AB  - How to minimize brain inflammation is pathophysiologically important, since
      inflammation induced by microglial activation can exacerbate brain damage. In the
      present report, we show that injection of lipopolysaccharide (LPS) into the rat
      cortex led to increased levels of interleukin-13 (IL-13) and to IL-13
      immunoreactivity, followed by the substantial loss of microglia at 3 days post
      LPS. IL-13 levels in LPS-injected cortex reached a peak at 12 h post-injection,
      remained elevated at 24 h, and returned to basal levels at day 4. In parallel, IL
      13 immunoreactivity was detected as early as 12 h post-LPS and maintained up to
      24 h; it disappeared at 4 days. Surprisingly, IL-13 immunoreactivity was detected
      exclusively in microglia, but not in neurons or astrocytes. Following treatment
      with LPS in vitro, IL-13 expression was also induced in microglia in the presence
      of neurons, but not in the presence of astrocytes or in cultured pure microglia
      alone. In experiments designed to determine the involvement of IL-13 in microglia
      cell death, IL-13-neutralizing antibodies significantly increased survival of
      activated microglia at 3 days post-LPS. Consistent with these results, the
      expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor
      alpha (TNF-alpha) was sustained in activated microglia and neuronal cell death
      was consequently increased. Taken together, the present study is the first to
      demonstrate the endogenous expression of IL-13 in LPS-activated microglia in
      vivo, and to demonstrate that neurons may be required for IL-13 expression in
      microglia. Our data strongly suggest that IL-13 may control brain inflammation by
      inducing the death of activated microglia in vivo, resulting in an enhancement of
      neuronal survival.

PMID- 15042583
TI  - Activation of epidermal growth factor receptor causes astrocytes to form
      cribriform structures.
AB  - Epidermal growth factor receptor (EGFR) is expressed in reactive astrocytes
      following injury in the CNS. However, the effects of activation of the EGFR
      pathway in astrocytes are not well established. In the present study, we
      demonstrate that activation of EGFR causes optic nerve astrocytes, as well as
      brain astrocytes, to form cribriform structures with cavernous spaces. Formation
      of the cribriform structures is dependent on new protein synthesis and cell
      proliferation. Platelet-derived growth factor and basic fibroblast growth factor
      were not effective. Smooth muscle cells and epithelial cells do not form
      cribriform structures in response to EGFR activation. The formation of the
      cribriform structures appears to be related to a guided migration of astrocytes
      and the expression of integrin beta1 and extracellular fibronectin in response to
      activation of EGFR. The EGFR pathway may be a specific, signal transduction
      pathway that regulates reactive astrocytes to form cavernous spaces in the glial
      scars following CNS injury and in the compressed optic nerve in glaucomatous
      optic nerve neuropathy.

PMID- 15042584
TI  - Translocation of protein kinase C-betaII in astrocytes requires organized actin
      cytoskeleton and is not accompanied by synchronous RACK1 relocation.
AB  - Protein kinase C (PKC)-betaII is the most abundant PKC isoform in astrocytes.
      Upon activation, this isoform of PKC translocates from the cytosol to the plasma
      membrane (PM). In this study, we investigated in astrocytes the modality of PKC
      betaII translocation as far as the participation of the receptor for activated C
      kinase-1 (RACK1) and the requirement for intact cytoskeleton in the process. In
      astrocytes, Western blots and immunocytochemistry coupled to confocal microscopic
      quantitative analysis showed that after 5 min of phorbol-12-myristate-13-acetate
      (PMA) exposure, native PKC-betaII, but not PKC-betaI, is relocated efficiently
      from the cytosol to the PM. Translocation of PKC-betaII was not associated with
      synchronous RACK1 relocation. Furthermore, the quantity of PM-associated PKC
      betaII that co-immunoprecipitated with PM-bound RACK1 increased following PMA
      exposure, indicating a post activation binding of the two proteins in the PM.
      Because RACK1 and PKC-betaII relocation seemed not to be synchronous, we
      hypothesized that an intermediate interaction with the cytoskeleton was taking
      place. In fact, we were able to show that pharmacological disruption of actin
      based cytoskeleton greatly deranged PKC-betaII translocation to the PM. The
      requirement for intact actin cytoskeleton was specific, because depolymerization
      of tubulin had no effect on the ability of the kinase to translocate to the PM.
      These results indicate that in astrocytes, RACK1 and PKC-betaII synchronous
      relocation is not essential for relocation of PKC-betaII to the PM. In addition,
      we show for the first time that the integrity of the actin cytoskeleton plays a
      specific role in PKC-betaII movements in these cells. We hypothesize that in
      glial cells, rapidly occurring changes of actin cytoskeleton arrangement may be
      involved in the fast reprogramming of PKC targeting to specific PM location to
      phosphorylate substrates in different cellular locations.

PMID- 15042586
TI  - Diverse microglial motility behaviors during clearance of dead cells in
      hippocampal slices.
AB  - We used two-channel three-dimensional time-lapse fluorescence confocal imaging in
      live rat hippocampal slice cultures (1-7 days in vitro) to determine the motility
      behaviors of activated microglia as they engage dead and dying cells following
      traumatic brain tissue injury. Live microglia were labeled with a fluorescently
      conjugated lectin (IB(4)), and dead neurons were labeled with a membrane
      impermeant fluorescent DNA-binding dye (Sytox Orange or To-Pro-3). Tissue injury
      during the slicing procedure induced neuronal death and microglial activation,
      but the density of dead cells diminished approximately 10-fold by 7 days in vitro
      as resident microglia cleared dead cells. In time-lapse movies (4-20 h long),
      activated microglia exhibited varying levels of motile and locomotory activity.
      The motility of microglia could change abruptly following contact by other
      microglia or death of nearby cells. When neighboring cells died, some microglia
      rapidly moved toward or extended a process to engulf the dead cell, consistent
      with a chemotactic signaling response. Dead cell nuclei usually were engulfed and
      carried along by highly motile and locomoting microglia. The mean time to
      engulfment was approximately 5 times faster for newly deceased cells (33 min)
      than for extant dead cells (160 min), suggesting that the efficacy of microglial
      phagocytosis in situ might vary with time after cell death or mode of cell death.
      These observations demonstrate that activated microglia are heterogeneous with
      respect to motile activity following traumatic tissue injury and further indicate
      that cell motility in situ is temporally regulated at the single cell level,
      possibly by direct cell-cell contact and by diffusible substances emanating from
      nearby dead cells.

PMID- 15042585
TI  - IGF-I prevents glutamate-mediated bax translocation and cytochrome C release in
      O4+ oligodendrocyte progenitors.
AB  - Oligodendroglial death due to overactivation of the AMPA/kainate glutamate
      receptors is implicated in white matter damage in multiple CNS disorders. We
      previously demonstrated that glutamate induces caspase-3 activation and death of
      the late oligodendrocyte progenitor known as the pro-oligodendroblast (pro-OL)
      via activation of the AMPA/kainate glutamate receptors. We also demonstrated that
      IGF-I had the unique ability to sustain activation of Akt in the pro-OL and
      provide long-term protection of these cells from glutamate-mediated apoptosis.
      The goal of these studies was to investigate the mechanisms of glutamate toxicity
      and IGF-I-mediated survival in the pro-OL. IGF-I prevented glutamate-induced loss
      of mitochondrial membrane potential, cytochrome c release, and caspase-9
      activation. In contrast to IGF-I mediated survival mechanisms in neurons, IGF-I
      had no effect on the influx or recovery of intracellular calcium levels or on
      levels of major pro- and anti-apoptotic molecules including Bax or Bcl-xL.
      Rather, IGF-I prevented the glutamate-induced translocation of Bax to the
      mitochondria. Moreover, IGF-I prevented caspase-3 activation in pro-OLs as long
      as 8 h after exposure of the cells to glutamate, suggesting that delayed
      activation of IGF-I-mediated survival pathways can block glutamate-mediated
      apoptosis in pro-OLs. The results of these experiments define the mechanisms by
      which glutamate kills oligodendrocyte progenitor cells and by which IGF-I blocks
      glutamate-induced apoptosis in these cells. The data also demonstrate that IGF-I
      disrupts the glutamate-mediated apoptotic pathway in the pro-OL through
      mechanisms that are distinct from its survival-promoting actions in neurons.

PMID- 15042587
TI  - Apotransferrin promotes the differentiation of two oligodendroglial cell lines.
AB  - We have previously shown that addition of apotransferrin (aTf) accelerates
      maturation of oligodendroglial cells (OLGcs) in primary cultures. In this work,
      we examined the effect of aTf on two conditionally immortalized cell lines: N19
      and N20.1. These cells proliferate at 34 degrees C and differentiate into mature
      OLGcs at 39 degrees C. In vitro addition of aTf to both cell lines at the
      differentiation temperature for 7 days showed increased expression of
      galactocerebroside, O4, and myelin basic protein (MBP) and a drop in the
      percentage of BrdU+ cells. The effect on MBP expression was particularly
      interesting in the less mature N19 cells. These cells do not express either MBP
      mRNAs or proteins, so aTf induced, rather than modulated, MBP expression in this
      cell line. In addition, even though MBP mRNAs for all four isoforms were induced,
      only the 17 and 21.5 kDa appeared to be translated. OLGc differentiation has been
      shown to be stimulated by the cAMP-CREB pathway. In N19 cells, following a pulse
      of aTf, there was a 10-fold increase in cAMP levels accompanied by elevated
      levels of pCREB. In the more mature N20.1 cells, there were no changes in cAMP
      levels. We conclude that addition of aTf to immature OLGc lines can enhance their
      expression of differentiated markers, such as MBP. The action of aTf on MBP gene
      expression in the least mature line is likely to be mediated by the cAMP pathway.
      In the N20.1 cells, it appears that different signals and/or mechanisms are
      involved in modulating myelin lipid and MBP expression. The results suggest that
      aTf can influence OLGc gene expression and differentiation through multiple
      mechanisms depending on the maturation of the cell.

PMID- 15042588
TI  - Microglia enhance dorsal root ganglion outgrowth in Schwann cell cultures.
AB  - Transplantation of cellular populations to facilitate regrowth of damaged axons
      is a common experimental therapy for spinal cord injury. Schwann cells (SC) or
      microglia grafted into injury sites can promote axonal regrowth of central
      projections of dorsal root ganglion (DRG) sensory neurons. We sought to determine
      whether the addition of microglia or microglia-derived secretory products alters
      DRG axon regrowth upon cultures of SC. Rat DRG explants were grown on monolayers
      consisting of either SC, microglia, SC exposed to microglia-conditioned medium
      (MCM), or co-cultures with different relative concentrations of microglia. Image
      analysis revealed that, compared to SC alone, the extent of neurite outgrowth was
      significantly greater on SC-microglia co-cultures. Immunocytochemistry for
      extracellular matrix molecules showed that microglial cells stained positively
      for growth-promoting thrombospondin, whereas laminin and the inhibitory
      chondroitin sulfate proteoglycans (CSPGs) were localized primarily to SC.
      Notably, immunoreactivity for CSPGs appeared reduced in areas associated with DRG
      outgrowth in co-cultures and SC exposed to MCM. These results show that microglia
      or their secreted products can augment SC-mediated DRG regrowth in vitro,
      indicating that co-grafting SC with microglia provides a novel approach to
      augment sensory fiber regeneration after spinal cord injury.

PMID- 15042589
TI  - Identification of potential cell-surface proteins in Candida albicans and
      investigation of the role of a putative cell-surface glycosidase in adhesion and
      virulence.
AB  - Cell-surface proteins are attractive targets for the development of novel
      antifungals as they are more accessible to drugs than are intracellular targets.
      By using a computational biology approach, we identified 180 potential cell
      surface proteins in Candida albicans, including the known cell-surface adhesin
      Als1 and other cell-surface antigens, such as Pra1 and Csa1. Six proteins (named
      Csf1-6 for cell-surface factors) were selected for further biological
      characterization. First, we verified that the selected CSF genes are expressed in
      the yeast and/or hyphal form and then we investigated the effect of the loss of
      each CSF gene on cell-wall integrity, filamentation, adhesion to mammalian cells
      and virulence. As a result, we identified Csf4, a putative glycosidase with an
      apparent orthologue in Saccharomyces cerevisiae (Utr2), as an important factor
      for cell-wall integrity and maintenance. Interestingly, deletion of CSF4 also
      resulted in a defect in filamentation, a reduction in adherence to mammalian
      cells in an in vitro adhesion assay, and a prolongation of survival in an
      immunocompetent mouse model of disseminated candidiasis. A delay in colonization
      of key organs (e.g. kidney) was also observed, which is consistent with a
      reduction in virulence of the csf4-deletion strain. These data indicate a key
      role for extracellular glycosidases in fungal pathogenesis and represent a new
      site for therapeutic intervention to cure and prevent fungal disease.

PMID- 15042590
TI  - Expression of a plant serine O-acetyltransferase in Saccharomyces cerevisiae
      confers osmotic tolerance and creates an alternative pathway for cysteine
      biosynthesis.
AB  - Screening of a sugar beet (Beta vulgaris cv. Dita) cDNA library for clones able
      to confer osmotic tolerance to the osmosensitive gpd1 mutant of Saccharomyces
      cerevisiae identified a novel serine O-acetyltransferase (BvSAT; EC 2.3.1.30).
      This enzyme is involved in cysteine biosynthesis in plants and bacteria,
      producing O-acetylserine, which is converted into cysteine in a reaction
      catalysed by O-acetylserine sulphydrylase (EC 4.2.99.8). This pathway is not
      conserved in yeast, where cysteine is synthesized in a four-step pathway starting
      with homoserine and having O-acetylhomoserine, homocysteine and cystathionine as
      intermediates. Expression of BvSAT in yeast takes advantage of the activity of
      yeast O-acetylhomoserine sulphydrylase (MET15/MET17/MET25; EC 4.2.99.10) with O
      acetylserine as substrate and induces an alternative cysteine biosynthesis
      pathway. Our results imply that the resulting increase in cysteine production
      confers enhanced resistance against osmotic stress in the osmosensitive yeast
      strain. These data demonstrate that cysteine biosynthesis is a limiting factor in
      osmotic stress tolerance in yeast.

PMID- 15042591
TI  - Reactive oxygen species may influence the heat shock response and stress
      tolerance in the yeast Saccharomyces cerevisiae.
AB  - Moderate levels of reactive oxygen species (ROS) have been implicated as second
      messengers in a number of biochemical pathways, and in animal cells have been
      associated with the activation of the heat shock response (HSR). Here, using an
      intracellular probe, we demonstrate that differential accumulation of ROS in the
      yeast Saccharomyces cerevisiae is strongly associated with differential induction
      of an HS reporter gene over a range of heat shock temperatures. There was a good
      correlation between cellular ROS levels and the levels of HS-induced reporter
      gene expression between 37 degrees C and 44 degrees C, both reaching maximal
      values at 41 degrees C. Furthermore, the addition of 150 microM H2O2 to the yeast
      cells during heat treatment resulted in a 3 degrees C decrease in the temperature
      required for maximal induction of the HS expression vector--an increased HS
      sensitivity that corresponded to a concomitant increase in ROS levels at these
      lower HS temperatures. Conversely, cells treated with 10 mM of the antioxidant
      ascorbic acid required a temperature that was 2 degrees C above that required in
      untreated controls for maximal induction of the HS expression vector. This
      decreased HS sensitivity corresponded to a decrease in ROS levels at these higher
      HS temperatures. Finally, cell viability assays reveal that intrinsic
      thermotolerance remains high in control cells despite concomitant decreases in HS
      reporter gene expression and ROS accumulation between 41 degrees C and 44 degrees
      C. We conclude that the sensitivity of the yeast HSR is strongly associated with
      ROS accumulation, and suggest that ROS-mediated signalling ensures cooperation
      between the HS and the antioxidant responses.